Resources LongCovid -ApresJ20 | 06-09-2023 update

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1	Ref	PPLC	Authors	Title	DOI	Peer reviewed	Date	type	Link	Keys	Clés

2	D01	No	Vittori	COVID-19 Pandemic Acute Respiratory Distress Syndrome Survivors: Pain After the Storm?	https://doi.org/10.1213/ANE.0000000000004914	published	1-Jul-20		https://journals.lww.com/anesthesia-analgesia/fulltext/2020/07000/covid_19_pandemic_acute_respiratory_distress.19.aspx		_
3	D02	No	Mahase	Covid-19: What do we know about “long covid”?	https://doi.org/10.1136/bmj.m2815	published	14-Jul-20		https://www.bmj.com/content/370/bmj.m2815.short	“Long covid” is a term being used to describe illness in people who have either recovered from covid-19 but are still report lasting effects of the infection or have had the usual symptoms for far longer than would be expected	_
4	D03	No		Avis de l’Académie : Les séquelles de la Covid-19			15 juillet 2020		http://www.academie-medecine.fr/avis-de-lacademie-les-sequelles-de-la-covid-19/	"Shortness of breath, cough, a few weeks or months after infection, pulmonologists call on former patients to have a pulmonary check-up, even if they have the feeling of being totally recovered."	"Essoufflement, toux, quelques semaines ou mois après l'infection, les pneumologues appellent les anciens malades à faire un bilan pulmonaire, même s'ils ont le sentiment d'être totalement rétablis."
5	D04	No	APP - The COVID Symptom Study was created by doctors and scientists working in partnership with ZOE – a health science company.	How long does COVID-19 last?			June 6, 2020		https://covid.joinzoe.com/post/covid-long-term?fbclid=IwAR1RxIcmmdL-EFjh_aI-		_
6	D05	No	Torjesen	NICE cautions against using graded exercise therapy for patients recovering from covid-19	https://doi.org/10.1136/bmj.m2912	published	21-Jul-20		https://www.bmj.com/content/370/bmj.m2912	The large number of patients experiencing post-viral fatigue after covid-19 has now shone a spotlight on the controversial technique again.	_
7	D06	No	REVUE MÉDICALE SUISSE	COVID-19: Que sait-on aujourd’hui sur ses différentes séquelles ?	https://doi.org/10.53738/REVMED.2020.16.701.1466		Rev Med Suisse 2020; volume 16.	opinion	https://www.revmed.ch/RMS/2020/RMS-N-701/COVID-19-Que-sait-on-aujourd-hui-sur-ses-differentes-sequelles		_
8	D07	No	Nisreen A Alwan	What exactly is mild covid-19?		published	28-Jul-20		https://blogs.bmj.com/bmj/2020/07/28/nisreen-a-alwan-what-exactly-is-mild-covid-19/	We still know very little about covid-19, but we do know that we cannot fight what we do not measure I am advocating for precise case definitions for covid-19 morbidity that reflect the degree of severity of infection and allow us to measure moderate and long term health and wellbeing outcomes	_
9	D08	No	Alwan	A negative COVID-19 test does not mean recovery	https://doi.org/10.1038/d41586-020-02335-z	published	11-Aug-20		https://www.nature.com/articles/d41586-020-02335-z	Defining and measuring recovery from COVID-19 should be more sophisticated than checking for hospital discharge, or testing negative for active infection or positive for antibodies. Once recovery is defined, we can differentiate COVID that quickly goes away from the prolonged form. The ‘recovery’ definition must include duration, severity and fluctuation of symptoms, as well as functionality and quality of life	A good starting point are the studies characterizing typical symptoms on a population level. Measuring recovery is not an easy ask with health and surveillance systems already struggling to cope. It makes sense to set up disease registers, akin to cancer registries, to track people over time and record their condition. This could be done through quick monthly, and subsequently annual, check-ups with health-care providers. If national registers are not quickly forthcoming, local ones could be started.
10	D09	No	Burgers	“Long covid”: the Dutch response	https://doi.org/10.1136/bmj.m3202	published	14-Aug-20	general practitioner	https://www.bmj.com/content/370/bmj.m3202.full		_
11	D10	No		WHO Director-General's opening remarks at the media briefing on COVID-19 - 21 August 2020			21-Aug-20	WHO	https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---21-august-2020	Last month my colleague Dr Maria van Kerkhove contacted a group called Long COVID SOS, representing patients with long-term effects from COVID-19 infection. This afternoon I had the privilege of speaking with them. They told us about their experience, and the ongoing challenges they face. These patients want three things: recognition, rehabilitation and research. Recognition of their disease, appropriate rehabilitation services, and more research to be done into the long-term effects of this new illness. Although we have learned so much about this disease, we only have less than 8 months of experience to draw on. We still know relatively little about the long-term effects. My message to these patients was: we hear you loud and clear, and we are committed to working with countries to ensure you receive the services you need, and to advancing research to serve you better.	_
12	D11	No		Allocution liminaire du Directeur général de l’OMS au point de presse sur la COVID-19 – 21 août 2020			21-Aug-20	WHO	https://www.who.int/fr/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---21-august-2020	Le mois dernier, ma collègue, la Dre Maria van Kerkhove, a contacté les membres d’un groupe dont le nom est « Long COVID SOS », qui représente des patients chez qui la COVID-19 a des effets à long terme. Cet après-midi, j’ai eu le plaisir de m’entretenir avec eux. Ils m’ont parlé de leur expérience et des difficultés auxquelles ils sont confrontés. Ces patients réclament 3 choses : reconnaissance, réadaptation et recherche. Reconnaissance de leur maladie, services de réadaptation adaptés et travaux de recherche supplémentaires sur les effets à long terme de cette nouvelle maladie. Bien que nous ayons beaucoup appris sur cette maladie, nous avons moins de 8 mois de recul à peine. Nous en savons encore relativement peu sur ses effets à long terme. Voilà ce que j’ai répondu à ces patients : nous avons bien compris votre message et nous nous engageons à collaborer avec les pays pour que vous puissiez bénéficier des services dont vous avez besoin et pour faire progresser la recherche en votre faveur.	_
13	D12	?	Prerna Garg MD Umang Arora MD Arvind Kumar MD Naveet Wig MD	The “post‐COVID” syndrome: How deep is the damage?	https://doi.org/10.1002/jmv.26465	opinion published	27 August 2020	LETTER TO THE EDITOR	https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.26465	Journal of Medical Virology. Letter : «The “Post‐COVID” Syndrome: How Deep is the Damage?» symptoms due to persistent chronic inflammation (convalescent phase), sequelae of organ damage (acute lung and kidney injury resulting in pulmonary fibrosis and chronic kidney disease, respectively), and nonspecific effects from the hospitalization and social isolation (nutritional anemia, muscle wasting)	_
14	D13		Nabavi Nisreen Alwan, Paul Garner, Fiona Godlee,Trisha Greenhalgh, Nick Peters, Valentina Puntmann, Tim Spector	Long covid: How to define it and how to manage it	https://doi.org/10.1136/bmj.m3489	opinion	07 September 2020	BMJ Webinar	https://www.bmj.com/content/370/bmj.m3489 https://docs.google.com/document/d/1qlz_zdp6ZoKJpM7DEtt028hi0mzTwD11Vln8gjCboEY/edit?usp=sharing	“not recovering [for] several weeks or months following the start of symptoms that were suggestive of covid, whether you were tested or not.” A very common feature is the relapsing, remitting nature of the illness, where you feel as though you’ve recovered, then it hits you back,”	"#LongCovid Diagnostic, Prise en charge, Pronostic", un webinar d'1h13 organisé par le BMJ : [avec Liverpool Sch. of Tropical Medicine Universities of Southampton, Oxford, Hospital Frankfurt Imperial & Kings Colleges London]
15	D14		Karthikeyan P Iyengar1, Raju Vaishya2	Long-term health consequences of COVID-19 disease	https://doi.org/10.4103/am.am_109_20	Published	09-Sep-2020	REVIEW ARTICLE	https://www.apollomedicine.org/article.asp?issn=0976-0016;year=2020;volume=17;issue=5;spage=32;epage=35;aulast=Iyengar		_
16	D15	?	Benjamin Davido Sophie Seang Roland Tubiana Pierre de Truchis	Post–COVID-19 chronic symptoms: a postinfectious entity?	https://doi.org/10.1016/j.cmi.2020.07.028	Published	July 22, 2020	COMMENTARY	https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(20)30436-5/fulltext	APHP study, dysautonomia. Overall, we believe patients with persistent symptoms (beyond 8 weeks after the onset of COVID-19) should consult their general practitioner for a first evaluation, including biological tests with COVID-19 serology, antinuclear antibodies and transthoracic echocardiography to rule out other diagnosis, especially myopericarditis, with a chest computed tomographic scan to assess precisely whether there is any sequelae of COVID-19 and offer reassurance. In case of persistent symptoms beyond 3 months, it could be relevant to investigate deeply the possible relationship between those chronic inflammatory symptoms and COVID-19, and to work hand in hand with other specialists, including a psychologist, a pneumologist, a neurologist and a specialist in physical medicine and rehabilitation. SARS-CoV-2 could probably play the same role of an immune trigger, as already known in Guillain-Barré syndrome and other autoimmune diseases. Therefore, patients should be tested for antinuclear antibodies and the tests repeated over time after 6 weeks, especially if they are young women with rheumatologic pain, in order to rule out a possible dormant underlying autoimmune disease.	étude de l'APHP, évocation de la dysautonomie	N0
17	D16			From doctors as patients: a manifesto for tackling persisting symptoms of covid-19	https://doi.org/10.1136/bmj.m3565	published	15-Sep-20		https://www.bmj.com/content/370/bmj.m3565	Widespread testing was not available in the early days of the pandemic. The timing of tests for active covid-19 infection (such as RT-PCR tests) affects test performance, and even if performed at an optimal time, the test is associated with a considerable risk of false negatives.9 We know antibody tests have mainly been validated in patients in hospital and are poorly sensitive early in the illness.10 There are few data regarding testing later in the disease course, and false negatives seem to be common. Some people do not seroconvert11 despite having previously tested positive. Where current guidance has been issued, such as the statement from the National Institute for Health and Care Excellence5 cautioning against graded exercise therapy in the context of covid-19, it should be communicated quickly to clinicians on the front line. clinicians should “be open about uncertainty and transparent in the ways in which we acknowledge the limitations of the imperfect data we have no choice but to use.”2 We argue that this means accepting an emerging picture that prolonged symptoms are having a substantial impact on a significant minority of people and acknowledging that death is not the only outcome to measure.	_
18	D17		Wise	Long covid: doctors call for research and surveillance to capture disease	https://doi.org/10.1136/bmj.m3586	published	15-Sep-20	A group of doctors who have been affected by persistent symptoms of covid-19 have written a manifesto based on their personal experiences	https://www.bmj.com/content/370/bmj.m3586	the doctors warned against reliance on “one size fits all” online rehabilitation services as they risk “serious harm to patients if pathology goes undetected.”	_
19	D18	Yes	Rita Rubin, MA	As Their Numbers Grow, COVID-19 “Long Haulers” Stump Experts	https://doi.org/10.1001/jama.2020.17709	Published	September 23, 2020	Medical News & Perspectives	https://jamanetwork.com/journals/jama/fullarticle/2771111	An article in JAMA notes that #LongCovid is increasingly being likened to myalgic encephalomyelitis (ME / CFS). It affects women four times more than men, with an average age of 40 years, and concerns 10% of symptomatic patients.	Un article dans JAMA note que le #LongCovid est de plus en plus assimilé à une encéphalomyélite myalgique (ME/SFC). Il toucherait 4x plus les femmes que les hommes, de moyenne d'âge 40 ans, et concernerait 10% des malades symptomatiques.
20	D19			The BMJ interview: Anthony Fauci on covid-19	https://doi.org/10.1136/bmj.m3703	published	23-Sep-20		https://www.bmj.com/content/370/bmj.m3703.short		_
21	D20		Perego	Why the Patient-Made Term 'Long Covid' is needed	https://doi.org/10.12688/wellcomeopenres.16307.1	under-review	24-Sep-20		https://wellcomeopenresearch.org/articles/5-224	Long Covid’ is a patient-made term that, in the absence of formally agreed definitions, we use here to describe diverse symptoms persisting beyond four weeks after symptom onset suggestive of COVID-19.	_
22	D21		Hopkins	Managing long covid: don’t overlook olfactory dysfunction	https://doi.org/10.1136/bmj.m3736	published	25-Sep-20		https://www.bmj.com/content/370/bmj.m3736.full		_
23	D020		Godlee	Covid-19: We need to understand the risks to tackle them	https://doi.org/10.1136/bmj.m3790	published	1-Oct-20		https://www.bmj.com/content/371/bmj.m3790	And people do need to get back to work, to stave off the damaging effects on health and wellbeing of unemployment and economic decline	_
24	D021	Yes	Alwan	Why we need to keep using the patient made term “Long Covid”		published	1-Oct-20		https://blogs.bmj.com/bmj/2020/10/01/why-we-need-to-keep-using-the-patient-made-term-long-covid/		_
25	D022		Yelin	Long-term consequences of COVID-19: research needs	https://doi.org/10.1016/S1473-3099(20)30701-5	published	1-Oct-20		https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30701-5/fulltext#.X6Ihwv6-MLM.twitter	The participation of an international and interdisciplinary group of researchers is essential. Multisite and multinational projects are needed because a description from one group or one site cannot discern between universal features and features of the local health system or the local population.	_
26	D023	withdrawn	Martin	Long Covid: quantitative and qualitative analyses of online Long Haulers’ experiences, emotions and practices in the UK	https://doi.org/10.1101/2020.10.01.20201699	under-review	4-Oct-20	social media and discourse analysis of UK	https://www.medrxiv.org/content/10.1101/2020.10.01.20201699v1	a) the time-frames assigned to Covid-19; b) the range of symptoms, which affects testing/diagnoses; c) the emotional/intellectual impact on Long Haulers; d) lack of resources and information.	_
27	D024		Del Rio	Long-term Health Consequences of COVID-19	https://doi.org/10.1001/jama.2020.19719	published	5-Oct-20		https://jamanetwork.com/journals/jama/fullarticle/2771581	postacute COVID-19 is defined as the presence of symptoms extending beyond 3 weeks from the initial onset of symptoms and chronic COVID-19 as extending beyond 12 weeks.	_
28	D025		FelicityCallardaElisaPeregob	How and why patients made Long Covid	https://doi.org/10.1016/j.socscimed.2020.113426	Published	7 October 2020	Short communication	https://www.sciencedirect.com/science/article/pii/S0277953620306456	An article in @socscimed describes how the #LongCovid community was formed and made it known through hashtags and arrests from the authorities. "the first illness to be collectively made by patients finding one another through various social media."	Un article dans @socscimed décrit comment la communauté #LongCovid s'est constituée et fait connaître par hashtags et interpellations des autorités. "the first illness to be collectively made by patients finding one another through various social media."
29	D026		Nature	Long COVID: let patients help define long-lasting COVID symptoms	https://doi.org/10.1038/d41586-020-02796-2	Published	07 October 2020	EDITORIAL	https://www.nature.com/articles/d41586-020-02796-2	@nature editorial highlighting the call to properly define recovery (to #CountLongCovid) to descibe prolonged #COVID19 symptoms. They are also calling for the definition of recovery from COVID-19 to be based on criteria that extend beyond just testing negative for COVID. People’s symptoms should be considered, too, such as chest heaviness, breathlessness, muscle pains, palpitations and fatigue, Such terms also carry assumptions about the condition’s underlying physiology that have not yet been properly investigated. Words such as ‘post’, ‘syndrome’ and ‘chronic’ risk delegitimizing suffering, the authors argue, and that will make it harder for people to access care.	@nature editorial highlighting the call to properly define recovery (to #CountLongCovid) to descibe prolonged #COVID19 symptoms.
30	D027		John E. Morley	COVID-19 — The Long Road to Recovery		Published	05 October 2020	Editorial	https://link.springer.com/article/10.1007/s12603-020-1473-6	These symptoms of “long Covid” include: fatigue, cough, dyspnea, loss of taste and smell, muscle weakness, muscle and joint pain, headache, confusion, conjunctivitis, chest pain, decreased mobility and falls	Court éditorial sur le #LongCovid et la réadaptation à fournir aux malades, notamment âgés, dans The Journal of Nutrition, Health & Aging, évoquant le programme d'exercices "ViviFrail".
31	D028		Halpin	Long COVID and chronic COVID syndromes	https://doi.org/10.1002/jmv.26587	LETTER TO THE EDITOR Free Access	9-Oct-20		https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.26587	Long COVID or postacute COVID (symptoms beyond 3 weeks) and chronic post‐COVID syndrome (beyond 12 weeks) are multisystem syndromes and need a multifaceted approach to tackle the physical, cognitive, psychological, social, and vocational domains of this health condition.	_
32	D029		Kingstone	Finding the 'right' GP: a qualitative study of the experiences of people with long-COVID	https://doi.org/10.3399/bjgpopen20x101143	published	13-Oct-20	24 interviews.	https://pubmed.ncbi.nlm.nih.gov/33051223/	Patients require their GP to believe their symptoms and to demonstrate empathy and understanding	_
33	D030		Mahase	Long covid could be four different syndromes, review suggests	https://doi.org/10.1136/bmj.m3981	published	14-Oct-20	according to a review by the National Institute for Health Research (NIHR).	https://www.bmj.com/content/371/bmj.m3981	people experiencing long term effects of covid-19 may have different syndromes such as post-intensive care syndrome, post-viral fatigue syndrome, and long term covid syndrome	_
34	D031		NIHR	Living with Covid19	https://doi.org/10.3310/themedreview_41169	Published	15 October 2020	Themed Review	https://evidence.nihr.ac.uk/themedreview/living-with-covid19/	A dynamic review by the NIHR institute (▶ https://evidence.nihr.ac.uk/themedreview/living-with-covid19/) lists at least 4 causes of #LongCovid: - 1/ permanent lung or heart sequelae 2/ - myalgic encephalomyelitis / CFS - 3/ post-resuscitation syndrome 4/ - persistence of symptoms People experience a wide range of fluctuating and multisystem symptoms that need to be acknowledged. A common theme is that symptoms arise in one physiological system then abate only for symptoms to arise in a different system. Ongoing Covid19 needs to be considered holistically (both in service provision and in research). The varying degrees of dependency mean support in the community should be considered alongside hospital one stop clinics. “COVID-19 is clearly a complex multisystem disease and not just restricted to the cardiopulmonary systems. This is so, both in the acute phase and the post-acute recovery phase. Our service personnel who are undergoing multidisciplinary inpatient rehabilitation, at DMRC Stanford Hall, for their post COVID-19 sequalae commonly complain of fatigue (which can be severe), myalgias, anxiety, low mood, cognitive problems and atypical chest pain.” Group Captain Alex Bennett, Defence Professor of Rheumatology and Rehabilitation, Stanford Hall	Une étude dynamique de l'institut 🇬🇧 NIHR répertorie au moins 4 causes de #LongCovid : - séquelles permanentes poumons ou cœur - encéphalomyélite myalgique / SFC - syndrome post-réanimation - persistance des symptômes
35	D032			COVID-19 guideline scope: management of the long-term effects of COVID-19			19-Oct-20	NICE	https://www.nice.org.uk/guidance/gid-ng10179/documents/final-scope	Signs and symptoms that develop during or following an infection consistent with COVID-19, continue for more than 12 weeks and are not explained by an alternative diagnosis. It usually presents with clusters of symptoms, often overlapping, which can fluctuate and change over time and can affect any system in the body. Post-COVID-19 syndrome may be considered before 12 weeks while the possibility of an alternative underlying disease is also being assessed.	_
36	D033		Mannan Baig	Chronic COVID Syndrome: Need for an appropriate medical terminology for Long‐COVID and COVID Long‐Haulers	https://doi.org/10.1002/jmv.26624	published	October 23, 2020		https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.26624	the term chronic covid syndrome (CCS) would be a more traditional way of symbolizing the so‐called long‐covid and long‐haulers in COVID‐19.	_
37	D034		Ryan Syrek	Trending Clinical Topic: COVID Syndromes		opinion	October 30, 2020	DISCLOSURES	https://reference.medscape.com/viewarticle/937400	The syndromes linked to covid make the headlines in Drugs and Diseases, with the arrival of the “long covid” classification, as well as “coronaphobia” which designates the psychological and psychiatric effects of the pandemic on the population.	Les différents syndromes liés à la covid font la une dans Drugs and Diseases, avec l'arrivée de la classification "long covid", ainsi que du terme "coronaphohie" qui désigne les effets psychologiques et psychiatriques de la pandémie sur la population.
38	D035			WHO Director-General's opening remarks at the media briefing on COVID-19 - 30 October 2020		published	30-Oct-20	WHO	https://www.who.int/fr/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---30-october-2020	Over the past few months, I have heard first hand from people who face mid to long-term effects of COVID-19 infection. What’s really concerning is the vast spectrum of symptoms that fluctuate over time, often overlap and can affect any system in the body. From fatigue, a cough and shortness of breath, to inflammation and injury of major organs - including the lungs and heart. And even neurological and psychologic effects. Although we’re still learning about the virus, what’s clear is that this is not just a virus that kills people. To a significant number of people, this virus poses a range of serious long-term effects. While people do recover, it can be slow – sometimes weeks or months – and it is not always a linear route to recovery. Though exact numbers of people experiencing the long-term affects are not yet clearly defined, post COVID-19 symptoms and complications have been reported in both non-hospitalised and hospitalised patients. There have been cases in women and men, both young and old. And even in children. WHO will continue to do more research to establish best standards of care to accelerate recovery and prevent such complications. It is imperative that governments recognise the long-term effects of COVID-19 and also ensure access to health services to all of these patients. This includes primary health care and when needed specialty care and rehabilitation. I’d now like to hand over the floor to three patients who are still combatting the long-term effects of COVID-19 so that we can hear their stories. First, Professor Paul Garner from Liverpool School of Tropical Medicine who has himself been recovering from COVID-19 since March.	_
39	D036			Allocution liminaire du Directeur général de l’OMS lors du point presse sur la COVID-19 – 30 octobre 2020		published	30-Oct-20	WHO	https://www.who.int/fr/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---30-october-2020	Ce qui est vraiment inquiétant, c’est la grande diversité des symptômes qui évoluent dans le temps, se chevauchent souvent et peuvent affecter n’importe quel système corporel. Ces symptômes vont de la fatigue, la toux et l’essoufflement à une inflammation et des lésions des principaux organes, y compris les poumons et le cœur. Sans oublier les effets neurologiques et psychologiques.	_
40	D037		Alwan	Scientific consensus on the COVID-19 pandemic: we need to act now	https://doi.org/10.1016%2FS0140-6736(20)32153-X	published	31-Oct-20		https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557300/		_
41	D038		MCorkell	Patient-Led Research for COVID-19: Embedding Patients in the Long COVID Narrative	https://doi.org/10.31219/osf.io/n9e75	under-review		Patient led research	https://osf.io/n9e75	These patients have what is now referred to as Long COVID [22], which we define as being symptomatic from COVID-19 for over three weeks, with many experiencing debilitating symptoms for month	_
42	D039		Megan Tatum	I could barely function' – the devastating effects of long COVID	https://doi.org/10.1211/PJ.2020.20208498	opinion	5 Nov 2020	Analysis	https://www.pharmaceutical-journal.com/news-and-analysis/features/i-could-barely-function-the-devastating-effects-of-long-covid/20208498.article?firstPass=false	The Pharmaceutical Journal (Drapeau du Royaume-Uni) publishes an article on #longcovid, with the advice of several specialists.	Le Pharmaceutical Journal (🇬🇧) publie un article sur le #covidlong, avec l'avis de plusieurs spécialistes.
43	D040	Yes	CDC	Late Sequelae of COVID-19		Published	Nov. 13, 2020	Article	https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/late-sequelae.html	The CDC takes stock of the knowledge acquired on the sequelae of covid. Long covid appears to be protean, both in its etiology and in its symptoms. The SARS-CoV-2 virus has a very strong affinity with the ACE2 receptors present on the surface of many types of cells. We can therefore find damage to various organs, such as the heart, kidneys, or, in this study, the lungs. A persistent inflammatory state is also suspected to be the cause of symptoms over the long term, insofar as it had already been noted that a sepsis could cause immune sequelae. A third category of cause of persistent symptoms could be linked to a viral reservoir located in one or more organs, such as infected retinal cells in the case of the Ebola virus. Finally, poor regulation of neutralizing antibodies could explain other symptoms. To this basic etiology, factors may be added: 1/- physical deconditioning 2/ - pre-existing comorbidities 3/ - post-traumatic psychological sequelae or related to changes in the rhythm of life due to the pandemic. In the United States, large studies are underway on the sequelae of covid, including: In Maryland: "A longitudinal study of COVID-19 sequelae and immunity" and in San Francisco: "Long-term impact of infection with novel coronavirus (COVID-19) (LIINC)". These studies will extend over several years. The most commonly reported symptoms include fatigue, dyspnea, cough, arthralgia, and chest pain. Other reported symptoms include cognitive impairment, depression, myalgia, headache, fever, and palpitations. More serious complications appear to be less common but have been reported. These complications include: Cardiovascular: myocardial inflammation, ventricular dysfunction Respiratory: pulmonary function abnormalities Renal: acute kidney injury Dermatologic : rash, alopecia Neurological: olfactory and gustatory dysfunction, sleep dysregulation, altered cognition, memory impairment Psychiatric: depression, anxiety, changes in mood Characterization of the etiology and pathophysiology of late sequelae is underway, and may reflect organ damage from the acute infection phase, manifestations of a persistent hyperinflammatory state, ongoing viral activity associated with a host viral reservoir, or an inadequate antibody response.	Les CDC (qui représentent l'agence fédérale de santé publique des É-U) dressent un bilan des connaissances acquises sur les séquelles de la covid. Le virus SARS-CoV-2 a une affinité très forte avec les récepteurs ACE2 présents à la surface de nombreux types de cellules. On peut donc retrouver des atteintes à divers organes, comme le cœur, les reins, ou, dans cette étude, les poumons. Le covid long apparaît comme protéiforme, aussi bien dans son étiologie que dans ses symptômes. Un état inflammatoire persistant est également soupçonné d'être la cause de symptômes sur le long cours, dans la mesure où il avait déjà été noté qu'un état septique pouvait engendrer des séquelles immunitaires. Une 3e catégorie de cause de symptômes persistants pourrait être liée à un réservoir viral situé dans un ou plusieurs organes, comme les cellules rétiniennes infectées dans le cas du virus Ebola. Enfin, une mauvaise régulation des anticorps neutralisants pourrait expliquer d'autres symptômes. À cette étiologie de base, des facteurs peuvent s'ajouter : - le déconditionnement physique - des comorbidités pré-existantes - des séquelles psychologiques post-traumatiques ou liées aux changements dans le rythme de vie du fait de la pandémie. Aux États-Unis, de larges études sont en cours sur les séquelles de la covid, notamment : Dans le Maryland : "A longitudinal study of COVID-19 sequelae and immunity" et à San Francisco : "Long-term impact of infection with novel coronavirus (COVID-19) (LIINC)". Ces études vont s'étendre sur plusieurs années.
44	D041		Matthew Zirui Tay, Chek Meng Poh, Laurent Rénia, Paul A. MacAry & Lisa F. P. Ng	The trinity of COVID-19: immunity, inflammation and intervention	https://doi.org/10.1038/s41577-020-0311-8	Published	28 April 2020	Review Article	https://www.nature.com/articles/s41577-020-0311-8		Un état inflammatoire persistant est également soupçonné d'être la cause de symptômes sur le long cours
45	D042	Now published in Therapeutic Advances in Chronic Disease doi: 10.1177/2040622320976979	Wildwing	The Neurological Symptoms of Long COVID-19: A Comparison with other Neurological Conditions and Implications for Healthcare Services	https://doi.org/10.1101/2020.07.21.20158816	under-review			https://www.medrxiv.org/content/10.1101/2020.07.21.20158816v3	When compared, these Long Covid symptoms are very similar to other neurological conditions such as Chronic Fatigue Syndrome (CFS) and Functional Neurological Disorder (FND).	_
46	D043		Lancet	Facing up to long COVID	https://doi.org/10.1016/S0140-6736(20)32662-3	Published	December 12, 2020	Editorial	https://www.thelancet.com/journals/ebiom/article/PIIS0140-6736(20)32662-3/fulltext	long COVID affects even young adults, so effective public health messaging for such individuals about the risks of infection is warranted	Le COVID long affecte même les jeunes adultes, de sorte qu'un message de santé publique efficace pour ces personnes sur les risques d'infection est justifié
47	D044		National Institute for Health and Care Excellence (NICE)	COVID-19 rapid guideline: managing the long-term effects of COVID-19 NICE guideline [NG188]		Published	18 December 2020	Guideline	https://www.nice.org.uk/guidance/ng188		Le National Institute for Health and Care Excellence (NICE), le Scottish Intercollegiate Guidelines Network (SIGN) et le Royal College of General Practitioners (RCGP) éditent des lignes directrices pour le #covidlong.Le "booklet" : https://www.sign.ac.uk/patient-and-public-involvement/patient-publications/long-covid Ce site de NICE sera mis à jour en fonction des découvertes et progrès dans les soins. Un article d'opinion dans The Lancet témoigne de la déception de plusieurs spécialistes à propos de ce guide https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32705-7/fulltext Il lui est reproché une vision superficielle du sujet, une faible prise en compte des données de l'OMS et un choix contestable de dénominations.
48	D045		S. Deblina Datta, MD1; Amish Talwar, MD, MPH1; James T. Lee, MD, MSc1,2	A Proposed Framework and Timeline of the Spectrum of Disease Due to SARS-CoV-2 Infection Illness Beyond Acute Infection and Public Health Implications	https://doi.org/10.1001/jama.2020.22717	Published	November 18, 2020	Viewpoint	https://jamanetwork.com/journals/jama/fullarticle/2773338		Une présentation dans JAMA Psychiatry des phases de la covid et notamment des symptômes à distance de l'infection. La présentation date de mi-novembre.
49	D046		Nisreen A Alwan1 2 3, Luke Johnson1	Long COVID: where do we start with the case definitions?		pre-print	Dec 2020	Viewpoint	https://www.google.com/url?sa=t&source=web&rct=j&url=https://osf.io/hndtm/download/%3Fformat%3Dpdf&ved=2ahUKEwj_x8KkxOztAhVMzBoKHU6VCrwQFjAAegQIAhAB&usg=AOvVaw2RiDiXl4D_iOSKeD2JF5Nj		_
50	D047		Manoj Sivan, Sharon Taylor	NICE guideline on long covid	https://doi.org/10.1136/bmj.m4938	Published	23 December 2020	Editorial	https://www.bmj.com/content/371/bmj.m4938.full		Un éditorial dans la publication médicale BMJ émet quelques critiques sur le guide du National Institute for Health and Care Excellence concernant les effets à long terme de la covid, et appelle à des directives plus pragmatiques.
51	D048		The Lancet	6 months consequences of covid19	https://doi.org/10.1016/S0140-6736(20)32656-8	Published	07 01 2021		https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32656-8/fulltext		_
52	D049		BMJ	Managing the long term effects of covid-19: summary of NICE, SIGN, and RCGP rapid guideline	https://doi.org/10.1136/bmj.n136	Published	01/22/2021	Guidelines	https://www.bmj.com/content/372/bmj.n136.full		La revue médicale BMJ publie un résumé des recommandations pour les effets à long terme de la covid qu'avaient élaboré l'institut NICE, les réseaux académiques britanniques SIGN et RCGP (guide critiqué par certains spécialistes dans The Lancet).
53	D050		WHO - OMS	COVID-19 Clinical management: living guidance		Published	25 January 2021	Living guidance	https://www.who.int/publications/i/item/WHO-2019-nCoV-clinical-2021-1		L'OMS ajoute un chapitre sur le suivi médical des covids longs dans son guide de recommandations cliniques. -> https://who.int/publications/i/item/WHO-2019-nCoV-clinical-2021-1 PDF (pp 60-61)-> https://apps.who.int/iris/rest/bitstreams/1328457/retrieve Annexes et études utilisées (pp 10-21) -> https://apps.who.int/iris/bitstream/handle/10665/338871/WHO-2019-nCoV-clinical-web_annex-2021.1-eng.pdf
54	D051		Felicity Callard, Elisa Perego	How and why patients made Long Covid	https://doi.org/10.1016/j.socscimed.2020.113426	Published	January 2021	Short communication	https://www.sciencedirect.com/science/article/pii/S0277953620306456		Un article dans Social Science & Medicine (écrit par @felicitycallard et @elisaperego78) rappelle les étapes de la reconnaissance du covid long.
55	D052		Antonis S Manolis, Theodora A Manolis	Long COVID: An Emerging Puzzle		Published	2021-01-23	Editorial	http://rhythmos.gr/index.php/Rhythmos/article/view/497		Un éditorial dans une publication médicale grecque fait le point sur les connaissances acquises sur le covid long. Il évoque le "post Covid-19 neurological syndrome" (PCNS) ainsi que les pistes de mécanismes potentiels expliquant le covid long.
56	D053		Jean-Louis Vincent	COVID-19: it is all about sepsis	https://doi.org/10.2217/fmb-2020-0312	Published	25 Jan 2021	EDITORIAL	https://www.futuremedicine.com/doi/full/10.2217/fmb-2020-0312		Selon un éditorial dans Future Medecine, la covid, par son caractère systémique et sa gravité essentiellement en rapport avec une réponse inadéquate de l'organisme à l'infection, devrait être qualifiée de septicémie.
57	D054		Daniel M Altmann	Decoding the unknowns in long covid	https://doi.org/10.1136/bmj.n132	Published	04 February 2021	Opinion	https://www.bmj.com/content/372/bmj.n132		_
58	D055		Nina Schor	Working together to understand long-term effects of COVID-19		Published	05/02/2021	Opinion	https://schorline.ninds.nih.gov/2021/02/05/long-term-covid-19/amp/		_
59	D056		Vinod Nikhra	Living with 'Long COVID-19': The Long-term Complications and Sequelae	http://dx.doi.org/10.13140/RG.2.2.30322.84167	Pre-print	February 2021	REVIEW ARTICLE	https://www.researchgate.net/publication/349009777	As apparent, the ‘long Covid’ afflictions are more common than realised earlier. The symptoms can escalate in patients with co-morbid conditions. The persistent symptoms among COVID-19 survivors pose new challenges to the healthcare providers and may be suitably managed with a combination of pharmacological and non-pharmacological treatments, and holistic healthcare. In addition, by reducing the inflammation and continuing damage in various organs, the prognosis can be improved.	Une revue d'études en pre-print (en relecture, non publiée) fait un tour d'horizon des éléments connus sur le covid long, les symptômes et les organes affectés, et aborde la gestion sur le long terme et les traitements et soins pour la guérison.	N004
60	D057		Diego Castanares Zapatero (KCE), Germaine Hanquet (KCE), Koen Van den Heede (KCE)	EPIDEMIOLOGY OF LONG COVID: A PRAGMATIC REVIEW OF THE LITERATURE		Working paper	27 January 2021	Review	https://kce.fgov.be/sites/default/files/atoms/files/2020-04HSR_LongCOVID_COVID%20Contributions_01022021.pdf	It is estimated that in the first 12 weeks after the onset of the COVID-19 infection between 5% and 36% of patients still have symptoms. In specific patient groups (e.g. patients that have been hospitalised in the acute phase) higher rates were observed. Twelve weeks or more after onset of the disease, still about 2-15% of COVID-19 patients have symptoms. • The most commonly reported long-term symptoms of long COVID are fatigue (up to 98%), dyspnoea (up to 93%) and headache (up to 91%). Yet it should be noted that a wide range of symptoms affect different body systems (e.g. neurological, cardiovascular, gastrointestinal) and fluctuate over time. For a large group of patients it seems that symptoms improve over time. Nevertheless, in a substantial number of cases symptoms persist. In addition to the symptoms, an impact on activities of daily life and (social) functioning is reported. • Patients with long COVID are more likely to be older, suffer from pre-existing comorbidities, obesity or psychiatric disorders and have blood type A compared to COVID-19 patients that do not have long-term consequences. In addition, there are indications that a higher number of symptoms in the acute phase of the disease and the presence of specific symptoms such as fatigue, headache, dyspnoea, pain with deep breath, sensitive skin, hoarse voice and myalgia are also risk factors for developing long COVID.	Un document de travail rédigé par le KCE (Centre fédéral d'expertise des soins de santé, en Belgique) étudie l'épidémiologie du covid long : sa fréquence, la prévalence des symptômes, les facteurs de risque.	N003
61	D058		HAS	Covid-19 : diagnostiquer et prendre en charge les adultes présentant des symptômes prolongés		Published	12 févr. 2021	COMMUNIQUÉ DE PRESSE	https://www.has-sante.fr/jcms/p_3237458/fr/covid-19-diagnostiquer-et-prendre-en-charge-les-adultes-presentant-des-symptomes-prolonges	Also : https://www.has-sante.fr/jcms/p_3237041/fr/symptomes-prolonges-suite-a-une-covid-19-de-l-adulte-diagnostic-et-prise-en-charge	La Haute autorité de santé (autorité administrative indépendante en France) publie des recommandations et des fiches pratiques à destination des professionnels de santé pour suivre les patients covids longs.	N002
62	D059		Sarah Bradbury	Long COVID-19' and the implications for the dental profession	https://doi.org/10.1038/s41404-021-0655-1	Published	08 February 2021	Opinion	https://www.nature.com/articles/s41404-021-0655-1		Un article d'opinion qui traite de l'émergence mondial des cas de covid longs, et de l'implication des professionnels de chirurgie dentaire comme soignants devant être protégés.
63	D060		Robert M. DiSogra	ONLINE FEATURE \| Labeling COVID-19’s Long-Term Effects—What’s the Diagnosis?		Published	February 2021	Article	https://www.audiology.org/audiology-today-januaryfebruary-2021/online-feature-labeling-covid-19%E2%80%99s-long-term-effects%E2%80%94what%E2%80%99s	"This article addresses and defines the language associated with COVID-19 and reports on the attempts being made to establish appropriate medical terminology as it pertains to COVID-19 patients who are still experiencing medical issues for weeks and even months after the diagnosis."	Court article sur la terminologie covid et covid long.
64	D061		Terry Murray	Unpacking “long COVID”		Published	February 11, 2021	Article	https://cmajnews.com/2021/02/11/covid-longhaul-1095923/	Experts at a recent World Health Organization meeting warned that the long-term complications of COVID-19, known as “long COVID” or post COVID-19 condition, may become a crisis within a crisis for health systems already stretched thin by the pandemic.	Article sur l'alerte d'autorités sanitaires qui craignent que le covid long devienne une pandémie dans la pandémie.
65	D062		SONI, SARTHAK NILANG; NIMBALKAR, SOMASHEKHAR MARUTIRAO	Long COVID Syndrome Following Infection with SARS-CoV-2- A Devastating Influence on Health Status in Some Affected Individuals.		Published	Feb 2021	Article	https://web.a.ebscohost.com/abstract?direct=true&profile=ehost&scope=site&authtype=crawler&jrnl=0973709X&AN=148789277&h=N7m50kypExfC95QuaquuXnT9XA0gM2NtNKxQuRH1x02DKw83vt9qnODj%2bYrW%2bVcWUuoBLeLCDtvCryPl7%2bYtVw%3d%3d&crl=c&resultNs=AdminWebAuth&resultLocal=ErrCrlNotAuth&crlhashurl=login.aspx%3fdirect%3dtrue%26profile%3dehost%26scope%3dsite%26authtype%3dcrawler%26jrnl%3d0973709X%26AN%3d148789277	As more people become fatally ill with COVID19, it is now clear that many patients who developed a mild illness, recovered from a serious illness, or had an asymptomatic infection are also beginning to suffer from a newly described entity called long Covid. Studies show that show COVID-19 influences the cardiovascular framework, yet the general effects stay Obscured. Impaired diffusion capacity, lower respiratory muscle strength, and lung imaging abnormalities are seen in COVID-19 patients in the early recovery stage. As compared to non-severe cases, severe patients had a higher incidence of Diffusion capacity of lung for carbon monoxide (DLCO) impairment and are more prone to total lung capacity decrease and 6-Minute Walk Test (6MWT) decline. The degree and seriousness of long‑term well-being outcomes remain unclear, yet increasing information points in the direction of poorer physiological outcomes. Long‑term sequelae of COVID-19 will have enduring implications on those afflicted's physical, mental, and social health while having a substantial monetary impact on society.	Article non accessible pour le moment.
66	D063		John N Aucott	Long-haul COVID: heed the lessons from other infection-triggered illnesses	https://doi.org/10.1016/S0140-6736(21)00446-3	Published	March 05, 2021	CORRESPONDENCE	https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00446-3/fulltext	In listening to patients, the resolution of objective abnormalities is often not the whole story of their illness, and symptoms such as fatigue could instead be the most devastating to patients' quality of life.	"L'expérience auprès des patients permet de comprendre que le traitement des symptômes les plus objectivables n'est souvent pas l'essentiel. Ce sont les symptômes comme l'asthénie qui sont les plus dévastateurs sur leur qualité de vie"	N004
67	D064		Erin Dean	Long-COVID: what it means and how to manage the longer-term effects		Published	14 January 2021	Article	https://rcni.com/nursing-standard/newsroom/clinical-update/long-covid-what-it-means-and-how-to-manage-longer-term-effects-170741	Many people who have had COVID-19 have reported ongoing symptoms weeks and months after they first fell ill. There is growing evidence that people can experience long-term health effects and about 10% of people with initially mild illness report symptoms lasting more than four weeks.	Article non accessible pour le moment.
68	D065		Hossein Akbarialiabad * , Mohammad Hossein Taghrir , Ashkan Abdollahi , Nasrollah Ghahramani , Manasi Kumar , Shahram paydar , Babak Razani , John Mwangi , Ali A. Asadi-Pooya , Leila Malekmakan , Bahar Bastani	Long COVID, A Comprehensive Systematic Scoping Review	https://doi.org/10.1007/s15010-021-01666-x	pre-print	18 March 2021		https://www.preprints.org/manuscript/202103.0490/v1		Une étude systématique non publiée pour l'instant fait un état des lieux de la production de travaux sur le covid long. Les question de dénomintion, de diagnostic,
69	D066		Ani Nalbandian, Kartik Sehgal, Aakriti Gupta, Mahesh V. Madhavan, Claire McGroder, Jacob S. Stevens, Joshua R. Cook, Mitchell S. V. Elkind, Jean M. Connors, John P. Bilezikian, Donald W. Landry & Elaine Y. Wan	Post-acute COVID-19 syndrome	https://doi.org/10.1038/s41591-021-01283-z	Published	22 March 2021	Review Article	https://www.nature.com/articles/s41591-021-01283-z	Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics.	Un article dans Nature fait une revue d'études du covid long et décrit un cadre interdisciplinaire de soins pour les malades.	N010
70	D067		Sarah Jane Palmer	Government funding for research into long COVID	https://doi.org/10.12968/bjca.2021.0027	Published	18 Mar 2021		https://www.magonlinelibrary.com/doi/abs/10.12968/bjca.2021.0027		_
71	D068		NIHR	Living with Covid19 – Second review	https://doi.org/10.3310/themedreview_45225	Published	16 March 2021	Review	https://evidence.nihr.ac.uk/themedreview/living-with-covid19-second-review/	A dynamic review of the evidence around ongoing Covid19 (often called Long Covid). .Executive summary .NIHR Centre for Engagement and Dissemination .What are we aiming to achieve with our Living with Covid19 reviews? .Framing the evidence .What is ‘Long Covid’? .How many people who have had Covid 19 will experience ongoing symptoms? .The causes of Long Covid .Impact of Long Covid on daily living .Diagnosing and predicting the course of Long Covid .Management of Long Covid .Conclusion	L'institut britannique NIHR publie sa deuxième (très complète) revue d'études sur le covid long. "Il y a des indices qui suggèrent que le covid long est une maladie toujours active, avec des indices immunologiques de réponses inflammatoires prolongées, d'activité virale persistante et/ou de troubles de coagulation. Pour certains malades du covid long, il pourrait y avoir le potentiel d'une détérioration additionnelle."	N004A
72	D069		WIKIY	covid long haulers		Opinion	Mars 2021	Article	https://www.wikiy.org/en/Covid_long_haulers-6286462884		Résumé de quelques éléments connus sur le covid long. Sans relecture.
73	D070		Claire Davies	Key learning points: NICE COVID-19—long-term effects		Opinion	18 March 2021	Article	https://www.guidelinesinpractice.co.uk/infection/key-learning-points-nice-covid-19-long-term-effects/455901.article	Dr Claire Davies distils the NICE guideline on managing the long-term effects of COVID-19 into six key learning points for primary care	Un résumé des recommandations du National Institutre for health and Care Excellence (NICE) pour l'approche et le traitement du covid long.
74	D071		Andrea M. Lerner, MD, Daphne A. Robinson, PhD, Linda Yang, Johanna S. Schneider, PhD, Adaora A. Adimora, MD, MPH*, Emily J. Erbelding	Toward Understanding COVID-19 Recovery: National Institutes of Health Workshop on Postacute COVID-19	https://doi.org/10.7326/M21-1043	Published	30 March 2021		https://www.acpjournals.org/doi/full/10.7326/M21-1043	As the number of reports of postacute COVID-19 continues to increase, fundamental questions must be answered. We urgently need a collaborative research approach that includes harmonized case definitions; delineation of epidemiology, natural history, and pathophysiology; and strategies to address longtime health disparities. This will enable the optimum implementation of evidence-based diagnostic, therapeutic, and preventive strategies essential to help mitigate the pain and suffering of individuals with postacute COVID-19.	Bilan d'un workshop américain sur le covid long, organisé par le National Institute of Allergy and Infectious Diseases (NIAID).	N006
75	D072		Gail Carson	Research priorities for Long Covid: refined through an international multi-stakeholder forum	https://doi.org/10.1186/s12916-021-01947-0	Published	31 March 2021	Commentary	https://link.springer.com/article/10.1186/s12916-021-01947-0	Research on Long Covid will require a multi-disciplinary and globally coordinated approach that supports harmonised and large-scale case-control and interventional studies that have the power to provide quality evidence to inform policy and patient care across the full range of populations and countries affected. Governments of the world need to ensure the strengthening of health systems to be able to provide treatment, support and rehabilitation to improve long-term COVID-19 outcomes. To prevent Long Covid becoming the pandemic of 2021, controlling the high rates of infection has to remain a global priority.	Compte-rendu d'un forum sur le covid long organisé par l'International Severe Acute Respiratory and emerging Infection Consortium (ISARIC), un institut britannique.
76	D073		A.V.RaveendranabRajeevJayadevancS.Sashidharan	Long COVID: An overview	https://doi.org/10.1016/j.dsx.2021.04.007	Published	20 April 2021	Review	https://www.sciencedirect.com/science/article/pii/S1871402121001193	Highlights •Long COVID denote persistence of symptoms in those recovered from COVID-19. •Reason for the persistence of symptoms has to be identified. •Long COVID can be divided into different categories based on symptoms. •Treatment of long COVID requires a multi-disciplinary approach.	_
77	D074		Vivien Marx	Scientists set out to connect the dots on long COVID	https://doi.org/10.1038/s41592-021-01145-z	Published	28 April 2021	Article	https://www.nature.com/articles/s41592-021-01145-z		_
78	D075		Altiery De Jesus, Vivian V., Alwan, Nisreen, Callard, Felicity and Berger, Zackary	Listening to Long COVID: Epistemic Injustice and COVID-19 morbidity	http://dx.doi.org/10.31219/osf.io/tfbnd	Pre-print	22 March 2021	Article	https://eprints.soton.ac.uk/448347/	In Long Covid, symptoms do not resolve within several weeks after acute infection with SARS-CoV-2. Patients with COVID-19 and long COVID face stigma and discrimination. One important type of discrimination is epistemic injustice which includes testimonial and hermeneutical injustices. Testimonial injustices occur when healthcare professional disregard or discount patients’ symptoms. This worsens healthcare outcomes and exacerbates challenges to adequate healthcare access at the individual level. Furthermore, testimonial injustices may lead to hermeneutical injustices – systemic underrepresentation of the experiences of the marginalized and minoritized. Healthcare professionals play an essential role in mitigating injustices and have a duty to reduce harms done to patients with long COVID. It is crucial that the clinician avoid multiplying associated harms by not engaging in epistemic injustices. We suggest the disability model as an approach to improve clinicians’ response to long covid. Epistemic injustice leads to systemic inequities that affect those with chronic disease in general, particularly in populations suffering from structural inequities. The COVID-19 pandemic provides an opportunity for solidarity with those suffering from other chronic diseases that have been marginalized and stigmatized.	_
79	D076		Dr Tanu Singhal	The Chronic Effects of COVID-19 or “Long COVID”		Published	April 2021	Review	http://articles.theindianpractitioner.com/index.php/tip/article/view/1151	The term “long COVID” is used to refer to patients who have persisting symptoms for 4 weeks or more after onset of COVID-19. The prevalence of these ymptoms is reported to range from 10-80%. The commonest symptoms include fatigue, dyspnoea, chest pain, hair loss, loss of sense of taste and smell, cognitive difficulties, anxiety and depression. Serious complications in this period include thrombo embolic events (stroke, myocardial infarction, limb ischemia and venous thromboembolism), infections, pulmonary fibrosis and multi system inflammatory syndrome. Patients with post COVID-19 symptoms should be first evaluated in primary care and those with serious issues referred to appropriate specialties. The others should be provided with supportive and symptomatic care including respiratory care, nutrition, immunization, mental health support, management of comorbidities and if indicated anticoagulation and treatment of infections. The routine use of steroids, antifibrotics, anticoagulants, anti depressents and antibiotics in these patients should be avoided.	_
80	D077		Dibanur Rashid Siddiqua*1, Md. Shahadat Hossain2	Potential long term adverse health outcomes of COVID-19	https://doi.org/10.3329/bccj.v9i1.53055	Published	February 20, 2021	Review	https://www.banglajol.info/index.php/BCCJ/article/download/53055/37525	The coronavirus disease 2019(COVID-19) pandemic poses an extraordinary challenges to patients, communities and overall health care systems. It has resulted in millions of people infected worldwide and has indirectly devastated even more individuals with prolonged post-infectious symptoms. The burden of survivors having post-COVID symptoms is likely to be huge. Multidisciplinary post-COVID-19 clinics are now playing a pivotal role addressing both persistent symptoms and potential long term sequelae. In this review, we tried to summarize the adverse health outcomes based on current evidences, assess the potential risk of long-term complications and make certain recommendations.	_
81	D078		Simon Décary, PT, PhD1, Isabelle Gaboury, PhD2, Sabrina Poirier3, Christiane Garcia4, Scott Simpson, BA, CWC5, Michelle Bull, PhD6, Darren Brown, MSc, MRes7, Frédérique Daigle	Humility and Acceptance: Working Within Our Limits With Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome	https://www.jospt.org/doi/10.2519/jospt.2021.0106	Published	April 30, 2021	Editorial	https://www.jospt.org/doi/full/10.2519/jospt.2021.0106	The term long COVID was coined by patients to describe the long-term consequences of COVID-19. One year into the pandemic, it was clear that all patients—those hospitalized with COVID-19 and those who lived with the disease in the community—were at risk of developing debilitating sequelae that would impact their quality of life. Patients with long COVID asked for rehabilitation. Many of them, including previously healthy and fit clinicians, tried to fight postviral fatigue with exercise-based rehabilitation. We observed a growing number of patients with long COVID who experienced adverse effects from exercise therapy and symptoms strikingly similar to those of myalgic encephalomyelitis (ME). Community-based physical therapists, including those in private practice, unaware of safety issues, are preparing to help an influx of patients with long COVID. In this editorial, we expose growing concerns about long COVID and ME. We issue safety recommendations for rehabilitation and share resources to improve care for those with postviral illnesses.	_
82	D079		Kristine Anne Scordo, PhD, APRN, ACNP-BC, FAANP ; Misty M. Richmond, PhD, APRN, PMHNP-BC ; Nancy Munro	Post-COVID-19 Syndrome: Theoretical Basis, Identification, and Management	https://doi.org/10.4037/aacnacc2021492	Published	May 04 2021	Article	https://aacnjournals.org/aacnacconline/article/doi/10.4037/aacnacc2021492/31445	This article addresses the possible etiology of postviral syndromes and describes reported symptoms and suggested management of post-COVID syndrome.	Une très riche revue d'études fait un bilan de la physiopathologie possible du covid long, et des soins envisageables. Le parallèle avec l'encéphalomyélite myalgique (EM), voire l'équivalence dans certains cas, est souligné. L'article rappelle que les changements métaboliques de l'EM pourraient être dus aux auto-anticorps des récepteurs ß2-adrénergiques et des récepteurs de l'acétylcholine M3. Il cite égalementent les traitements étudiés de l'EM, notamment l'élimination par immunoadsorption des autoanticorps ß2, conduisant selon des études (https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193672) à une amélioration de la fatigue des patients. Des similitudes avec l'EM, pour laquelle on suspecte des troubles du drainage lymphatique de la microglie dans le cerveau, sont évoquées. Pour l'EM, le «brouillard cérébral» pourrait être dû à une diminution du flux cérébral sanguin secondaire à une vasoconstriction sympathique excessive en présence de récepteurs ß2 dysfonctionnels. La publication évoque enfin des traitements et recommandations d'examen selon les symptômes.	N009
83	D080		Waqaar Shah Melissa Heightman Stella O'Brien	UK guidelines for managing long-term effects of COVID-19	https://doi.org/10.1016/S0140-6736(21)00847-3	Published	May 08, 2021	Commentary	https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00847-3/fulltext	We stressed the need for timely referral and investigation and for the development of individualised treatment plans. We reject Gorna and colleagues'1 suggestion that we overly focus on self-management.	_
84	D081		Piero L Olliaro	An integrated understanding of long-term sequelae after acute COVID-19	https://dx.doi.org/10.1016%2FS2213-2600(21)00206-X	Published	2021 May 5	Article	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099314/	The recognition of so-called long COVID has been a great emotional relief for the many who are struggling with the aftereffects of COVID-19. Now we need to dissect this highly heterogenous syndrome; better delineate clusters of symptoms; differentiate it from other conditions and consequences of infections and hospitalisation; understand the pathophysiology, predisposing conditions, and risk factors; and indeed, learn how to better look after people with long-term complications after acute COVID-19. Dealing with such complexity requires a multidisciplinary approach and patients' involvement.	_
85	D082		Sherry Leviner	Recognizing the Clinical Sequelae of COVID-19 in Adults: COVID-19 Long-Haulers	https://doi.org/10.1016/j.nurpra.2021.05.003	Published	May 07, 2021	Article	https://www.npjournal.org/article/S1555-4155(21)00222-1/fulltext	Highlights •Long-hauler is a term that refers to the long-term effects of COVID-19 •Long-haul COVID-19 is a diagnosis of exclusion •Do not ignore the emotional dimension of long-haul COVID The persistent symptoms associated with COVID-19 are frustrating for patients who just want to be normal, to return to their previous level of function prior to COVID-19. Unfortunately there are no clear answers for them at this time and NPs should share this with them. Alternative explanations for symptoms need to be ruled out prior associating the symptoms with long-haul COVID-19. If a COVID-19 care center is available, patients should be referred. If a COVID-19 care center is not available, specialists need to be consulted. Given the impact on mental health, evaluating the mental health of long-haulers is a priority.	_
86	D083		Piotr Walczak and Miroslaw Janowski	The COVID-19 Menace	https://doi.org/10.1002/gch2.202100004	Published	May 2021	Review	https://onlinelibrary.wiley.com/doi/pdf/10.1002/gch2.202100004	Clinically, there is enormous variability in the severity of the disease. Severe consequences are seen in a relatively small number of patients, most show moderate symptoms, but asymptomatic cases, especially among young people, drive disease spread. Unfortunately, the number of local infections can quickly build up, causing disease outbreaks suddenly exhausting health services’ capacity. Therefore, COVID-19 is dangerous and unpredictable and has become the most serious threat for generations. Here, the latest research on COVID-19 is summarized, including its spread, testing methods, organ-specific complications, the role of comorbidities, long-term consequences, mortality, as well as a new hope for immunity, drugs, and vaccines.	_
87	D084		Avindra Nath	Long-Haul COVID	https://doi.org/10.1212/WNL.0000000000010640	Published	September 29, 2020	Article	https://n.neurology.org/content/95/13/559	Although there are no peer reviewed papers at the moment on these patients, many news articles have been written about this phenomenon1,–,4 and there are Facebook groups with several thousand patients describing these symptoms. They call the illness, “Long-Haul COVID” or “Long-tail COVID.” Many of these patients are health care workers who had massive exposure to the virus early in the pandemic and describe having symptoms for “100+ days.”	_
88	D085		DIEGO CASTANARES-ZAPATERO, PATRICE CHALON, KOEN VAN DEN HEEDE	COVID 19 – KCE CONTRIBUTIONS PATHOPHYSIOLOGY OF LONG COVID: A PRELIMINARY REPORT		Published	18 May 2021	Review	https://kce.fgov.be/sites/default/files/atoms/files/2020-04HSR_Long%20COVID_Scientific_Report.pdf	Key points • The pathophysiology contributing to long COVID symptoms is so far unkown. Since the spectrum of symptoms is very wide, responsible mechanisms are probably numerous and intertwined. • While many articles elaborate on the putative mechanims involved in the symptomatology, there is little empirical data on the pathophysiology based on measurements among long COVID patients. In addition, the quality of data is limited due to heterogenous timings of inclusion, different initial disease severity and a lack of a comparator group. As such, the reported results need to be interpreted with caution. The current literature is highly hypothetical, cannot be generalized and is subject to change. • A distinction has to be made between two categories of mechanisms by which persisting symptoms come about: o Organ injury at the early phase of infection; o Persisting and/or residual symptoms without evidence of readily measurable markers of organ injury. • Current literature suggests the following general pathophysiological mechanisms: (1) virus-driven tissue damage and (2) dysregulated immune and inflammatory reactions in response to the infection, giving rise to multiple disorders (microcirculation disorders associated with coagulation and fibrosis pathway activation, auto-immune manifestations and metabolic disturbances). • Long COVID has to be differentiated from Post-Intensive-Care-Syndrome (PICS), comprising long-term physical, psychological and cognitive disabilities that can occur in patients who have previously been hospitalised in Intensive care unit (ICU).	Le centre fédéral (belge) d'expertise des soins de santé (KCE) édite un rapport sur la physiopathologie du covid long. Il invite à la prudence sur les hypothèses formulées jusqu'à présent, compte tenu du peu de données empiriques sur la physiopathologie basées sur des mesures systématiques. Le rapport note que la littérature actuelle évoque les mécanismes physiopathologiques généraux suivants : 1 - lésions tissulaires causées par le virus 2 - réactions immunitaires et inflammatoires dérégulées en réponse à l'infection, donnant lieu à de multiples troubles (troubles de la microcirculation associée à l'activation des voies de coagulation et de fibrose, manifestations auto-immunes et troubles métaboliques).	N011
89	D086		Andrew Briggs & Anna Vassall	Count the cost of disability caused by COVID-19	https://doi.org/10.1038/d41586-021-01392-2	Published	26 May 2021	Article	https://www.nature.com/articles/d41586-021-01392-2	We approximate that the health burden due to COVID-induced disability across all age groups could be around 30% overall. We arrived at this crude figure using modest assumptions about the duration and severity of COVID-19-related disease (see Supplementary information). This number also assumes a loss of 0.5 DALYs for an average case of long COVID, regardless of age, and includes DALYs lost as a result of COVID-19 deaths, using standard methods5. This exercise hints at how much of the long-term health impact we could be missing by counting only deaths.	Selon une analyse dans Nature, le fardeau de santé dû au handicap induit par la covid dans tous les groupes d'âge serait d'environ 30 % sur l'ensemble des pertes de vie en bonne santé du covid. La part est d'autant plus forte dans les populations plus jeunes des pays riches.	N011
90	D087		Kevin Roe	The Symptoms and Clinical Manifestations Observed in COVID-19 Patients/Long COVID-19 Symptoms that Parallel Toxoplasma gondii Infections	https://doi.org/10.1007/s11481-021-09997-0	Published	29 May 2021	Letter to the Editor	https://link.springer.com/article/10.1007/s11481-021-09997-0	It is significant that virtually all of the diverse and distinctive symptoms of Long COVID-19 can be explained as symptoms of toxoplasmosis in patients having activated or reactivated T. gondii (Vidal 2019). Toxoplasmosis patients suffer a wide variety of symptoms, including dyspnoea, fevers, seizures, headaches, changes in vision, altered mental status, focal neurological deficits, mental confusion, cognitive dysfunction, ataxia, behavioral or psychomotor changes, involuntary movements, pneumonia, and a spectrum of cranial nerve palsies (Vidal 2019). Several distinctive Long COVID-19 symptoms can be matched if toxoplasmosis induced cranial nerve palsies affect the functions of the 12 cranial nerves, creating symptoms including anosmia from a palsy of the olfactory nerve (I), vertigo (dizziness), tinnitus and otalgia (earache) from a palsy of the vestibulocochlear nerve (VIII), and dysgeusia from palsies of the facial nerve (VII), glossopharyngeal nerve (IX), and vagus nerve (X) (Khaku et al. 2017).	Dans le Journal of Neuroimmune Pharmacology, un chercheur émet l'hypothèse que la covid pourrait réactiver partiellement ou entièrement une infection latente à la toxoplasmose (dont la prévalence atteint 60% dans certaines régions du monde). Cette synergie bidirectionnelle, par des dysfonctionnements cellulaires immunitaires, dont l'épuisement des lymphocytes T, serait une possibilité pour expliquer la mortalité de la covid et le tableau clinique, notamment les atteintes neurologiques, du covid long.	N011
91	D088		Manuela Funke-Chambour, Laurence Feldmeyer, Robert Hoepner, Uyen Huynh-Do, Britta Maurer, Emrush Rexhaj, and Thomas Geiser	Das Long-COVID-Syndrom – ein neues Krankheitsbild nach COVID-19-Infekt	https://doi.org/10.1024/1661-8157/a003678	Published	May 21, 2021	Review	https://econtent.hogrefe.com/doi/full/10.1024/1661-8157/a003678	Long-term consequences are increasingly reported in the current literature after COVID-19 infections. Some patients suffer from persistent pulmonary and extrapulmonary symptoms even months after the acute infection. Pulmonary impairment, but also dysregulation and effects on immune system, cardiovascular system, neurological system, skin and kidney are described or anticipated. This mini review gives a short update to the practitioner about the current knowledge about Long COVID.	_
92	D089		Alison Twycross	Living with long Covid: some reflections 14 months down the line	http://dx.doi.org/10.1136/ebnurs-2021-103449	Published	May 26, 2021	Editorial	https://ebn.bmj.com/content/early/2021/05/25/ebnurs-2021-103449	As I write this editorial, it is almost 14 months since I first developed COVID-19 symptoms and my journey with long COVID-19 continues. In their guideline on long COVID-19 NICE/SIGN define post-COVID-19 syndrome as signs and symptoms that develop during or after a COVID-19 infection, continuing for more than 12 weeks, and not explained by an alternative diagnosis.	_
93	D090		Emma Sheppard	Your Fear of Long Covid		Published	May 2021	Article	https://blogs.bmj.com/medical-humanities/2021/05/20/your-fear-of-long-covid/	There is a lot in media about Long Covid—and in particular about the big concerns about how living with Long Covid must be awful. This fear of Long Covid is shaped by ableism, but that same ableism—and how we talk about Long Covid—impacts people already living with chronic illnesses that have a lot in common with Long Covid.	_
94	D091		Zheng Yao Low, Ashley Jia Wen Yip, Anshika Sharma & Sunil K. Lal	SARS coronavirus outbreaks past and present—a comparative analysis of SARS-CoV-2 and its predecessors	https://doi.org/10.1007/s11262-021-01846-9	Published	01 June 2021		https://link.springer.com/article/10.1007/s11262-021-01846-9	The Coronavirus Disease 2019 (COVID-19), a pneumonic disease caused by the SARS Coronavirus 2 (SARS-CoV-2), is the 7th Coronavirus to have successfully infected and caused an outbreak in humans. Genome comparisons have shown that previous isolates, the SARS-related coronavirus (SARSr-CoV), including the SARS-CoV are closely related, yet different in disease manifestation. Several explanations were suggested for the undetermined origin of SARS-CoV-2, in particular, bats, avian and Malayan pangolins as reservoir hosts, owing to the high genetic similarity. The general morphology and structure of all these viral isolates overlap with analogous disease symptoms such as fever, dry cough, fatigue, dyspnoea and headache, very similar to the current SARS-CoV-2. Chest CT scans for SARS-CoV-2, SARS-CoV and MERS-CoV reveal pulmonary lesions, bilateral ground-glass opacities, and segmental consolidation in the lungs, a common pathological trait. With greatly overlapping similarities among the previous coronavirus, the SARS-CoV, it becomes interesting to observe marked differences in disease severity of the SARS-CoV-2 thereby imparting it the ability to rapidly transmit, exhibit greater stability, bypass innate host defences, and increasingly adapt to their new host thereby resulting in the current pandemic. The most recent B.1.1.7, B.1.351 and P.1 variants of SARS-CoV-2, highlight the fact that changes in amino acids in the Spike protein can contribute to enhanced infection and transmission efficiency. This review covers a comparative analysis of previous coronavirus outbreaks and highlights the differences and similarities among different coronaviruses, including the most recent isolates that have evolved to become easily transmissible with higher replication efficiency in humans.	_
95	D092		Daniela Giacomazza , Domenico Nuzzo Submitted by: Daniela Giacomazza	Post-Acute COVID-19 Neurological Syndrome		Published			https://encyclopedia.pub/10733	The emergency caused by SARS-CoV-2 had, and still has, devastating socio-economic aspects. Assessing the impact of COVID-19 on vulnerable groups of people is crucial for the adaptation of governments’ responses. Growing scientific evidence suggests that it is essential to keep the attention on people after acute SARS-CoV-2 infection; indeed, some clinical manifestations are frequently present even after recovery. There is consensus on the need to define which symptoms persist after the infection and which disabilities may arise after COVID-19. Recent reviews, case reports, and original contributions suggest that various organs may be affected, and neurological symptoms are present in about one third of patients with COVID-19. Neurological complications after severe COVID-19 infection might include delirium, brain inflammation, stroke, and nerve damage. In the recent pandemic, neurologists and neurobiologists have a chance to study key features of infection neurology.	_
96	D093		CésarFernández-de-las-PeñasaLidiane L.FlorencioaVíctorGómez-MayordomobMaría L.CuadradobcDomingoPalacios-CeñaaArkiath VeettilRaveendrand	Proposed integrative model for post-COVID symptoms	https://doi.org/10.1016/j.dsx.2021.05.032	Published	1 June 2021	Article	https://www.sciencedirect.com/science/article/pii/S1871402121001764	Highlights •The first differentiation is to determine the presence of new-onset or exacerbated post-COVID symptoms. •The second differentiation is to determine if the post-COVID symptom is persistent or delayed in relation to the acute phase. •Individual, biological, hospitalization/treatment and COVID-19 outbreak surrounding factors must be considered. The first consideration is to define which symptoms are of “new-onset” (symptoms never experienced by a patient before COVID-19 and experienced the first time after) and which symptoms are “exacerbated” (symptoms experienced by a patient prior to COVID-19 but aggravated later) after infection. The second consideration includes defining “persistent” (symptoms experienced at the acute phase and continuing after without remission period) and “delayed-onset” (symptoms not experienced at the acute phase of the infection but appearing after a “latency period”). This model integrates predisposing individual factors, biological factors associated to the severity of disease, hospitalization/treatment factors, and outbreak surrounding factors which may promote post-COVID. Conclusion: Since current literature on post-COVID is heterogeneous, this integrative model could help to a better characterization of long-COVID.	_
97	D094		Sheetal Gandotra 1, and Derek Russell 1,2	The Long and the Short of It: Is “Long COVID” More Than Slow Resolution of the Acute Disease?	https://doi.org/10.1513/AnnalsATS.202103-255ED	Published	June 2021	Article	https://www.atsjournals.org/doi/full/10.1513/AnnalsATS.202103-255ED	Though the COVID-19 pandemic may show signs of waning, an “epi-pandemic” of persistent symptoms from this novel disease is upon us. It is now clear that this is a concern not only to those who had life-threatening complications early in the course of infection but also to patients who were never hospitalized. Long COVID may be with us for a long time. Despite the danger and saliency of the acute phase of COVID-19, the longer-term aspects of this disease cannot be overlooked.	_
98	D095		Caroline Kamau-Mitchell	Risk that debilitating fatigue after covid-19 might last years: Evidence report for the House of Lords Select Committee on Risk Assessment and Risk Planning		Published	May 2021	Article	https://www.researchgate.net/publication/351870234_Risk_that_debilitating_fatigue_after_covid-19_might_last_years_Evidence_report_for_the_House_of_Lords_Select_Committee_on_Risk_Assessment_and_Risk_Planning	Key points • There is the risk of higher unemployment rates among people who had covid-19. • There is the risk of higher underemployment rates among people who had covid-19 e.g., more switching to part-time working or lower skilled jobs because of health problems. • There is the risk of future staff shortages in occupations with a high prevalence of covid19. • Based on the evidence, this report encourages the government to measure the percentage of people who developed CFS/ME after being infected with covid-19. The government should measure prevalence of post-covid-19 CFS/ME, conduct modelling to assess high risk occupational groups, intervene to prevent unemployment, underemployment and workforce shortages, guide healthcare staff, advise employers/workers, and inspire research into prevention of post-covid-19 CFS/ME.	Un rapport commandé par la Chambre des lords (UK) demande à ce que soit évaluée la proportion des malades du covid long qui développent une encéphalomyélite myalgique. Le texte, citant une étude sur le SRAS (https://pubmed.ncbi.nlm.nih.gov/20008700/) qui relevait qu'un quart des malades avaient toujours une fatigue chronique 4 ans après l'infection, insiste sur le fait que la pathologie de covid long pourrait s'étaler sur des années, générant un lourd impact sur l'emploi des personnes malades.	N011
99	D096		The Lancet Respiratory Medicine	COVID-19 pathophysiology: looking beyond acute disease	https://doi.org/10.1016/S2213-2600(21)00242-3	Published	June, 2021	Editorial	https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00242-3/fulltext	Little more than a year on, a picture of a new disease entity is coming into focus—with a distinct range of clinical and pathophysiological features—as described by Marcin Osuchowski and colleagues in the first of a Series of four papers in The Lancet Respiratory Medicine.	_
100	D097		Mary Fran Tracy	Understanding the Impact of COVID-19: Now and for the Future	https://doi.org/10.4037/aacnacc2021636	Published	June 15 2021	Article	https://aacnjournals.org/aacnacconline/article/32/2/157/31466/Understanding-the-Impact-of-COVID-19-Now-and-for	We will be addressing the consequences of the pandemic for years to come, whether for the patients who contracted the disease or the health care workers who cared for them.	_
101	D098		Jon D. Kaiser	Long Haulers Syndrome—An Integrative Approach to Etiology and Treatment		Published	June 2021	Article	http://www.imjournal.com/abstracts/23042.html	Many research centers, including Mount Sinai Health System’s Center for Post-COVID Care in New York City, have recently been set up to investigate and treat the growing number of patients who remain persistently symptomatic after acute COVID-19 infection. Additional research is clearly necessary to properly characterize, diagnose, and treat this highly challenging condition, as well as to develop an evidence-based, systems-oriented approach for caring for postCOVID-19 syndrome patients.	_
102	D099		Michael Marshall	The four most urgent questions about long COVID Scientists are starting to get insights into the lingering disorder that affects some people infected with SARS-CoV-2 — but many mysteries remain unsolved.	https://doi.org/10.1038/d41586-021-01511-z	Published	09 June 2021	Article	https://www.nature.com/articles/d41586-021-01511-z	How many people get long COVID and who is most at risk? What is the underlying biology of long COVID? What is the relationship between long COVID and other post-infection syndromes? What can be done to help people with long COVID?	Un article dans Nature résume les 4 questions cruciales que pose le covid long : - Combien de personnes ont un covid long et qui est le plus à risque ? - Quelle est la biologie sous-jacente du covid long ? - Quelle est la relation entre le covid long et les autres syndromes post-infection ? - Que peut-on faire pour aider les personnes atteintes du covid long ? L'article évoque les pistes médicamenteuses, notamment un agent anti-fibrosant et anti-inflammatoire (deupirfénidone) développé à Boston, ou encore au Royaume-Uni, l'apixaban, un anticoagulant, et l'atorvastatine, un anti-inflammatoire.	N011
103	D100		Dinah V. Parums	Editorial: Long COVID, or Post-COVID Syndrome, and the Global Impact on Health Care	https://doi.org/10.12659/MSM.933446		2021.06.07	Editorial	https://www.medscimonit.com/download/index/idArt/933446	The clinical manifestations of long COVID and its prevalence in all age groups who initially appear to have recovered from acute SARS-CoV-2 infection are now recognized. However, the effects on society, the economy, and healthcare provision have yet to be realized. There is also concern that in older adults, the symptoms of long COVID are under-reported and may be assumed to be due to age-related comorbidities. Now that SARS-CoV-2 infection and its variants are endemic, and vaccination programs may not be completely effective the diagnosis and management of long COVID is expected to become a global public health priority.During 2020, increasing numbers of case reports, case series, and small observational studies reported long-term complications of coronavirus disease 2019 (COVID-19) in patients who had recovered from acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Long COVID has a prevalence of between 10-30% in patients with a recent history of SARS-CoV-2 infection. Pulmonary, hematologic, cardiovascular, neuropsychiatric, renal, endocrine, gastrointestinal and hepatobiliary, and dermatologic involvement, and chronic multisystem inflammatory syndrome in children (MIS-C) highlights the requirement for a multidisciplinary approach to the management of patients with long COVID. This Editorial aims to present the current status of long COVID, or post-COVID syndrome, and its global impact on health and the provision of health care.	_
104	D101		Anthony L.Komaroff1W. IanLipkin2	Insights from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome May Help Unravel the Pathogenesis of Post-Acute COVID-19 Syndrome	https://doi.org/10.1016/j.molmed.2021.06.002	Published	7 June 2021	Review	https://www.sciencedirect.com/science/article/pii/S1471491421001349	Highlights •In some people, the aftermath of acute COVID-19 is a lingering illness with fatigue and cognitive defects, known as post-COVID-19 syndrome or “long COVID”. •Post-COVID-19 syndrome is similar to post-infectious fatigue syndromes triggered by other infectious agents, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a condition that patients often report is preceded by an infectious-like illness. •ME/CFS is associated with underlying abnormalities of the central and autonomic nervous system, immune dysregulation, disordered energy metabolism and redox imbalance. It is currently unclear if the same abnormalities will be identified in post-COVID-19 syndrome. •The US and other developed nations have committed considerable support for research on post-COVID illnesses. Abstract SARS-CoV-2 can cause chronic and acute disease. Post-Acute Sequelae of SARS-CoV-2 infection (PASC) include injury to the lungs, heart, kidneys and brain, that may produce a variety of symptoms. PASC also includes a post-COVID-19 syndrome (“long COVID”) with features that can follow other acute infectious diseases as well as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Here we summarize what is known about the pathogenesis of ME/CFS and of acute COVID-19, and speculate that the pathogenesis of post-COVID-19 syndrome in some people may be similar to that of ME/CFS. We propose molecular mechanisms that might explain the fatigue and related symptoms in both illnesses, and suggest a research agenda for both ME/CFS and post-COVID-19 syndrome.	Une revue d'études invite à s'inspirer des connaissances sur l'encéphalomyélite myalgique pour comprendre divers aspects des pathologies du covid long.	N011
105	D102		Dinah V. Parums	Editorial: Long COVID, or Post-COVID Syndrome, and the Global Impact on Health Care	https://doi.org/10.12659/MSM.933446	Published	2021-06-07	Editorial	https://www.medscimonit.com/abstract/index/idArt/933446?	During 2020, increasing numbers of case reports, case series, and small observational studies reported long-term complications of coronavirus disease 2019 (COVID-19) in patients who had recovered from acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Long COVID has a prevalence of between 10-30% in patients with a recent history of SARS-CoV-2 infection. Pulmonary, hematologic, cardiovascular, neuropsychiatric, renal, endocrine, gastrointestinal and hepatobiliary, and dermatologic involvement, and chronic multisystem inflammatory syndrome in children (MIS-C) highlights the requirement for a multidisciplinary approach to the management of patients with long COVID. This Editorial aims to present the current status of long COVID, or post-COVID syndrome, and its global impact on health and the provision of health care	_
106	D103		P.CathébrasJ.GoutteB.GramontM.Killian	« COVID long » : une opportunité pour approcher la complexité des syndromes fonctionnels post-infectieux“Long-haul COVID”: An opportunity to address the complexity of post-infectious functional syndromes	https://doi.org/10.1016/j.revmed.2021.05.020	Published	9 June 2021	Article	https://www.sciencedirect.com/science/article/pii/S024886632100518X	This clinically unspecific syndrome must be put in perspective with the post-infectious syndromes known for a long time but ultimately poorly understood and little studied, qualified, for lack of convincing arguments for a unambiguous pathophysiology and better terms, as functional somatic syndromes. The clinical implications for clinical care (“holistic” work-up and care of patients), for research (need for truly “bio-psycho-social” investigations), and the social implications of “long COVID” (social construction of the syndrome through the experiences of patients exposed on social networks, inequalities in the face of the disease and its socioeconomic consequences) are considered. “Long COVID” must be view, because of its expected prevalence, as an opportunity to address the complexity of post-infectious (functional) syndromes, their risk factors, and the biological, psychological and social mechanisms underlying them.	En évoquant d'autres syndromes post-infectieux que le covid long, comme ceux qui peuvent prolonger le SARS, le MERS, Ebola, le chikungunya ou la dengue, les auteurs de cet article essaient d'établir les particularités de ces symptômes. Ils notent également le rôle des associations de malades dans la reconnaissance de la maladie, rappellent les hypothèses physiopathologiques, et enfin dressent des pistes de prise en charge.	N011
107	D104		Harald Brüssow, Kenneth Timmis	COVID-19: long covid and its societal consequences	https://doi.org/10.1111/1462-2920.15634	Published	10 June 2021	Minireview	https://sfamjournals.onlinelibrary.wiley.com/doi/abs/10.1111/1462-2920.15634	we summarize recent findings about COVID-19 sequelae, with a particular focus on long covid. We also discuss some of the long scars that COVID-19 and long covid will collectively leave on society that we term Societal Long Covid.	_
108	D105		Loren Bonner	‘;Long COVID’ needs to be addressed by multiple specialties	https://doi.org/10.1016/j.ptdy.2021.05.011	Published	June 01, 2021	Article	https://www.pharmacytoday.org/article/S1042-0991(21)00383-2/fulltext	‘;Long COVID’ needs to be addressed by multiple specialties	_
109	D106		Garg M, Maralakunte M, Garg S, Dhooria S, Sehgal I, Bhalla AS, Vijayvergiya R, Grover S, Bhatia V, Jagia P, Bhalla A, Suri V, Goyal M, Agarwal R, Puri GD, Sandhu MS	The Conundrum of ‘Long-COVID-19ʹ: A Narrative Review	https://doi.org/10.2147/IJGM.S316708	Published	14 June 2021	Review	https://www.dovepress.com/the-conundrum-of-long-covid-19-a-narrative-review-peer-reviewed-fulltext-article-IJGM	With the data on Long-COVID-19 still emerging, the present review aims to highlight its epidemiology, protean clinical manifestations, risk predictors, and management strategies. With the re-emergence of new waves of SARS-CoV-2 infection, Long-COVID-19 is expected to produce another public health crisis on the heels of current pandemic. Thus, it becomes imperative to emphasize this condition and disseminate its awareness to medical professionals, patients, the public, and policymakers alike to prepare and augment health care facilities for continued surveillance of these patients.	_
110	D107		P Cathébras 1, J Goutte 2, B Gramont 2, M Killian 2	["Long-haul COVID": An opportunity to address the complexity of post-infectious functional syndromes]	https://doi.org/10.1016/j.revmed.2021.05.020	Published	2021 Jun 9	Article	https://pubmed.ncbi.nlm.nih.gov/34127310/	Cf D104	_
111	D108		Karen A. Hacker, MD, MPH1; Peter A. Briss, MD, MPH1; Lisa Richardson, MD, MPH1; Janet Wright, MD1; Ruth Petersen	COVID-19 and Chronic Disease: The Impact Now and in the Future	http://dx.doi.org/10.5888/pcd18.210086	Published	June 17, 2021	Article	https://www.cdc.gov/PCD/issues/2021/21_0086.htm	The impact of SARS-CoV-2, the virus that causes COVID-19, on people with or at risk for chronic disease cannot be overstated. COVID-19 has impeded chronic disease prevention and disrupted disease management. The problems and solutions outlined here are critically important to help those committed to chronic disease prevention and intervention to identify ways forward. NCCDPHP is adjusting, preparing, and implementing multiple strategies to address the future. Although the work will be challenging, opportunities abound. NCCDPHP is committed to working with the health care community and a variety of partners at federal, state, and local levels to help address the realities of the post-COVID era.	_
112	D109		Zahin Amin-Chowdhury & Shamez N. Ladhani	Causation or confounding: why controls are critical for characterizing long COVID	https://doi.org/10.1038/s41591-021-01402-w	Published	17 June 2021	Correspondence	https://www.nature.com/articles/s41591-021-01402-w	It is increasingly apparent that the long-term impact of this pandemic will be considerable and will substantially affect quality of life. Current best-guess estimates for long COVID (defined as self-reported persistence of any symptoms for 12 weeks or more after COVID-19) in population-based UK studies range from 2.2% (ref. 8) to 13.7% (ref. 4), and systematic assessment of available data identify female sex, middle age, white ethnicity and specific underlying co-morbidities as potential risk factors7. More robust, well-conducted longitudinal studies are urgently needed for proper characterization of this syndrome to inform clinicians, to develop evidence-based guidelines and to direct healthcare resources to where they are most needed.	En évoquant leur propre étude qui constate à 7 mois 3% de personnes infectées par la covid qui gardent des symptômes continus, et 11% qui gardent des symptômes épisodiques, des auteurs demandent davantage d'études sur la prévalence du covid long.	N011
113	D110		Melanie Newman, freelance journalist	Chronic fatigue syndrome and long covid: moving beyond the controversy	https://doi.org/10.1136/bmj.n1559	Published	24 June 2021	Opinion	https://www.bmj.com/content/373/bmj.n1559.full	A decade after publication it seems unlikely that a consensus will ever be reached. The National Institute for Health and Care Excellence has since reviewed its guidance on ME/CFS, and the draft guidance2 expresses concerns about inappropriate use of exercise and CBT, stating that the evidence is mixed or unclear. Tensions have now resurfaced with the advent of the pandemic and “long” covid or post-covid symptoms. As many as 376 000 people in the UK report symptoms more than 12 months after the first onset of covid-19,3 often experiencing extreme fatigue along with a wide range of other symptoms. Clinicians report a complex picture. Patients with long covid are a diverse group, and it’s hard to know what treatment path to put them on. Finding the right balance between gentle activity to avoid deconditioning and not triggering post-exercise malaise is important in each patient. But the advice given, the research conducted, and how it is communicated have become highly sensitive issues.
114	D111		Amali U Lokugamage, Frances K Simpson, founding member of Long Covid Kids and LongCovidSOS, Carolyn A Chew-Graham	Patient commentary: How power imbalances in the narratives, research, and publications around long covid can harm patients	https://doi.org/10.1136/bmj.n1579	Published	25 June 2021	Commentary	https://www.bmj.com/content/373/bmj.n1579.full	We don’t deny that all symptoms will have a psychological impact on the individual, and we would not wish psychological impacts to be stigmatised or ignored, but organic illness must be investigated and should be excluded only after appropriate investigation.1 People with long covid describe feeling “gaslighted” because the opinions of a few have tended to dominate the evolution of treatment, investigation, and a growing knowledge base.1
115	D112		Heald, Adrian; Riste, Lisa; Walther, Andreas; Stedman, Mike; Mukherjee, Annice	Reducing fatigue-related symptoms in Long COVID-19: finding an intervention that works	https://doi.org/10.1192/bjo.2021.681	Published	Jun 2021	Case series	https://www.proquest.com/openview/f6426c9cd91e2c3d56b6386beec5c116/1?pq-origsite=gscholar&cbl=3962591	It was pointed out that an early intervention applying management techniques used in patients with CFS/ME appeared to help reduce the fatigue related symptoms of Long COVID. Here we present an analysis of a consecutive case series of the first twenty patients’ data collected. Our aim was to evaluate the potential of this mode of treatment for Long COVID. Our findings indicate that this intervention based on massage and mobility exercises significantly reduced fatigue related to Long COVID. It may be that early intervention and supportive treatments at the end of the acute phase of COVID-19 can help overcome acute phase symptoms and prevent them becoming chronic/enduring
116	D113		Michael Le Page Helen Thomson Adam Vaughan Clare Wilson	Getting to grips with long covid	https://doi.org/10.1016/S0262-4079(21)01081-2	Published	26 June 2021	Article	https://www.sciencedirect.com/science/article/pii/S0262407921010812	What is clear is that even after the pandemic is brought under control, millions of people will be left with lingering symptoms that prevent them from working and enjoying life. Here is what we know so far.
117	D114		Prof John D. Potter*	Update on Long-COVID		Published	15/06/2021	Opinion	https://sciblogs.co.nz/public-health-expert/2021/06/15/update-on-long-covid/	This blog post updates an earlier post on Long-COVID and reports that estimates of prevalence are still wide at about 15 to 65% of those initially infected with the pandemic virus, SARS-CoV-2. As things stand now across the world, we do not yet have systems in place to diagnose and manage the massive burden of the disease that is Long-COVID. An elimination strategy that includes, but is not limited to, widespread vaccination is not only crucial to reduce the acute case load and high mortality associated with infection with SARS-CoV-2 but is also key to minimising the damage that Long-COVID is otherwise certain to create for individuals, whanau, communities, and nations.
118	D115		Priya Sharma, Senior Resident,a,∗ Sumit Bharti, Senior Resident,b and Isha Garg, Assistant Professorc	Post COVID fatigue: Can we really ignore it?	https://dx.doi.org/10.1016%2Fj.ijtb.2021.06.012	Published	2021 Jun 23	Review	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220285/	It's difficult for physicians to predict when symptoms will improve as it varies differently in different people. Patient's recovery depends on various factors including age, associated comorbidities, severity of COVID-19 infection. Some symptoms, like fatigue, might continue even while others improve or go away. This review addresses the pathogenesis, presentation of post covid fatigue, its severity and its management.
119	D116		Fiona Godlee, editor in chief	How can we manage covid fatigue?	https://doi.org/10.1136/bmj.n1610	Published	24 June 2021	Opinion	https://www.bmj.com/content/373/bmj.n1610.full	What’s the long term outlook after covid? And what’s the prognosis for health systems and staff struggling with covid pressures, waiting lists, and stretched resources?
120	D117		U. Tirelli, R. Taibi, S. Chirumbolo	Post COVID syndrome: a new challenge for medicine	https://doi.org/10.26355/eurrev_202106_26154	Published	June 2021	Commentary	https://www.europeanreview.org/article/26154	The scientific community is actually wondering about the etiopathogenesis and clinical development of this “post-COVID” complex symptomatology, very close to symptoms typically observed in chronic fatigue syndrome, so recently named as “post-acute sequelae of COVID-19 (PASC)”. This commentary tries to focus on the most recent news about this issue.	_
121	D118		Dr Vinod Nikhra	Exploring Etiopathophysiological Links for ‘Long Covid’	https:// .org/0000-0003-0859-5232	pre-print	June 2021	Review	https://www.researchgate.net/profile/Vinod-Nikhra/publication/352720529_Exploring_Etiopathophysiological_Links_for_'Long_Covid'/links/60d5320a299bf1ea9ebac094/Exploring-Etiopathophysiological-Links-for-Long-Covid.pdf	Long Covid is a multisystem disorder entailing multiple symptoms related to various organs. There are several theories about the etiology of Long Covid such as continuing presence of the virus and its biologically active fragments, reinfection with the same or a different variant, dysfunctional immune reactions leading to a chronic inflammatory state, an ill-defined condition exhibiting symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suggestive of a complex, multisystem disorder, post-traumatic stress following severe COVID-19 illness and critical care issues, and aftermath resulting due to disturbed microbiota in gut, lungs, and other organs. LONG COVID PATHOGENESIS -NEW INSIGHTS: The SARS-CoV-2 infection activates the humoral immunity leading to formation of antigen-antibody complexes and the antigen-antibody reactions, which may propagate to organ damage. Simultaneously, viral superantigens may overstimulate immune responses, inducing negative feedback loops to hamper immune function and allow the virus to persist and replicate. The persistent virus may contribute to long Covid There may develop various autoantibodies causing tissue injury and fibrosis in lungs and other organs. The Altered Microbiome leading to the microbial dysbiosis has also been implicated in persisting inflammatory processes culminating as Long Covid.
122	D119		Dorothy Wall	The Importance of Listening in Treating Invisible Illness and Long-Haul COVID-19	https://doi.org/10.1001/amajethics.2021.590	Published	July 2021	Opinion	https://journalofethics.ama-assn.org/article/importance-listening-treating-invisible-illness-and-long-haul-covid-19/2021-07	Yet those with invisible, controversial illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often have symptoms not explained by standard laboratory values. For instance, one of the cardinal features of ME/CFS is postexertional malaise, the exacerbation of symptoms—fatigue, pain, cognitive dysfunction—following exertion, which contradicts studies showing the health benefits of exercise. In these cases, overly physicalist approaches to caring for patients are not likely to be helpful, and a clinician’s willingness to listen to a patient’s experience of illness becomes essential.	_
123	D120		Steven Phillips, M.D., M.P.H., and Michelle A. Williams, Sc.D.	Confronting Our Next National Health Disaster — Long-Haul Covid	https://doi.org/10.1056/NEJMp2109285	Published	June 30, 2021	Opinion	https://www.nejm.org/doi/full/10.1056/NEJMp2109285	Though most Americans may be able to do so, restoration of normality does not apply to the 10% to 30% of those who are still experiencing debilitating symptoms months after being infected with Covid-19.1 Unfortunately, current numbers and trends indicate that “long-haul Covid” (or “long Covid”) is our next public health disaster in the making. What form will this disaster take, and what can we do about it? To understand the landscape, we can start by charting the scale and scope of the problem and then apply the lessons of past failures in approaching postinfection chronic disease syndromes.	_
124	D121		Jacqui Wise	Covid-19: Long covid cases are underreported in GP records, research suggests	https://doi.org/10.1136/bmj.n1685	Published	02 July 2021	Opinion	https://www.bmj.com/content/374/bmj.n1685	GPs may be underreporting long covid say researchers who analysed 58 million patients’ primary care records and found a much lower prevalence than previous survey estimates.	_
125	D122		Edward P Hoffer	Long Covid: does it exist? What is it? We can we do for sufferers?	https://doi.org/10.1016/j.amjmed.2021.05.023	Published	July 05, 2021	COMMENTARY	https://www.amjmed.com/article/S0002-9343(21)00399-5/fulltext	It is easy for physicians to attribute symptoms to anxiety, but this is neither helpful to our patients nor necessarily true. “Hard” neurologic illnesses, including ischemic strokes and intracranial hemorrhage have been found to be more common in patients recovered from even mild Covid-1911. Certainly the two leading hypotheses as to the cause of “long-Covid” are psychosomatic and immune-mediated, but persisting small vessel thrombi have also been postulated. Pending the results of larger controlled studies, what can we offer our patients? While anecdotal at this point, many patients with persisting symptoms after a mild/asymptomatic infection have reported improvement in symptoms after vaccination. Since these patients are still at risk for reinfection, advising vaccination is appropriate whether or not it helps their symptoms. Critically, we should not dismiss their complaints as being “all in their head.” This may be wrong, and even if correct is not helpful. It is appropriate to acknowledge their distress, get those with fatigue and/or dyspnea in a structured exercise program, and work with all on symptomatic relief.	_
126	D123		Vivienne Harte	Reflections on a Support Group for Doctors Recovering from Long Covid		Published	July 2021	Opinion	https://groupanalyticsociety.co.uk/contexts/issue-91/articles/reflections-on-a-support-group-for-doctors-recovering-from-long-covid/	In October 2020 I was invited by Dr Clare Gerada, in her capacity as Chair of the charity Doctors in Distress (DiD), to facilitate an on-line support group for medical doctors experiencing symptoms of Long Covid. The group was free, through the charity, to doctors at any stage of their career working in the UK.	_
127	D124		George F. Gao	Editorial: COVID-19: A Year Long and Beyond?	http://weekly.chinacdc.cn/en/article/doi/10.46234/ccdcw2021.052	Published	February 19 2021	Article	http://weekly.chinacdc.cn/en/article/doi/10.46234/ccdcw2021.052	Looking into the future, there will still be many uncertainties in 2021. One of them is that the COVID-19 pandemic might become a lasting epidemic or endemic.	_
128	D125		Guy A. Richards0 Adrian Wentzel1 Robert Miller2 Richard Van Zyl Smit3	Post-acute COVID-19 sequelae - 'COVID long hauler'	https://doi.org/10.18772/26180197.2021.v3n2a4	Published	5 Jul 2021	Review	https://journals.co.za/doi/abs/10.18772/26180197.2021.v3n2a4	Severe acute respiratory syndrome coronavirus-2 infection manifests with an acute illness of varying severity and unpredictable mortality. Those who survive may develop a more prolonged disease process called post-acute COVID-19 sequelae which causes considerable disability regardless of the severity of the acute disease. Two phenotypes have been described. First, those with persistent organ dysfunction related to the degree of the inflammatory response and second those with less well defined, but no less troublesome symptoms, that considerably impact the quality of life. This review discusses both phenotypes and the proposed mechanisms and also explores possible therapies for this condition.
129	D126		Charee M.ThompsonaKayla B.RhidenourbKate G.BlackburncAshley K.BarrettbSaraBabu	Using crowdsourced medicine to manage uncertainty on Reddit: The case of COVID-19 long-haulers	https://doi.org/10.1016/j.pec.2021.07.011	Published	13 July 2021	Study	https://www.sciencedirect.com/science/article/pii/S0738399121004705	Highlights •Online communities are a site for crowdsourced medicine and collective uncertainty management. •The social media platform Reddit helps COVID-19 long-haulers manage their uncertainty. •Long-haulers’ talk reflects information-seeking functions through symptom language. •Long-haulers’ talk reflects support-seeking functions through support and identity language. •Health care providers should employ sensitivity when addressing long-haulers’ anxiety and symptoms.	_
130	D127		Simon Denegri and Bella Starling	COVID-19 and patient engagement in health research: What have we learned?	https://doi.org/10.1503/cmaj.210998	Published	July 12, 2021	Commentary	https://www.cmaj.ca/content/193/27/E1048	KEY POINTS Patient engagement has occupied an increasingly prominent place on the agenda of health care and research systems in recent years. The COVID-19 global pandemic has highlighted both the fragility of patient engagement in research and innovative developments in this sphere. Better digital engagement of patient groups has removed some of the long-standing barriers to patient and public engagement such as geography, inaccessible environments and cost, enabling new kinds of collaboration. The research community including patients must build on the lessons learned during COVID-19 to strengthen the foundation for patient engagement in research and policy.	_
131	D128		Charles Schmidt	COVID-19 long haulers	https://dx.doi.org/10.1038%2Fs41587-021-00984-7	Published	2021 Jul 13	Article	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277229/	Without a clear unifying mechanism, long-COVID treatments face an uphill battle. “It’s challenging to treat something if you don’t know what’s causing it,” says Timothy Henrich, a physician and professor at the University of California, San Francisco. Tony Butler, managing director of Roth Capital Partners in New York, says the lack of an obvious target or mechanism in long-COVID leaves investors wary, despite the growing market. Right now, he says “it’s not seen as a growth area.” Cosme Ordonez, managing director and a senior equity research analyst who covers biotech at National Securities Corporation in Boca Raton, Florida, agrees. “To develop a novel candidate, we need something more specific to the condition,” he says. “In the case of acute COVID, we know that we need to block the virus and hyperinflammatory state. But the science behind long-COVID has lots of caveats, and we don’t really know what’s driving the disease. The targets are not well defined and correlated with the syndrome, and that might explain why industry is not jumping all over this because the market is potentially huge.” As mechanistic insights into long-COVID emerge, Ordonez expects industry funding will follow, with more biotech companies jumping in “within the next two to five years,” he says.	Un article fait un état des lieux de la recherche sur le covid long et les difficultés des chercheurs à proposer des traitements quand la cause est encore mal définie. L'auteur évoque des médicaments déjà prodigués (ivabradine), et d'autres à l'essai : - Ampligen (rintatolimod) - LYT-100 (pirfenidone) - leronlimab - LMWF5A (aspartyl-alanyl-diketopiperazine) - SNG001 (interféron bêta inhalé) qui sont ainsi testés pour différents symptômes du covid long.	N012
132	D129		M. Lagadinou, E. Kostopoulou, A. Karatza, M. Marangos, D. Gkentzi	The prolonged effects of COVID-19. A new “threat”?	https://doi.org/10.26355/eurrev_202107_26253	Published	July 2021	Article	https://www.europeanreview.org/article/26253	Coronavirus ‘long-haulers” currently represent a significant public health concern. Recent reports suggest that persistent effects of COVID-19, such as fatigue, dyspnea, chest pain, anxiety, depression, arthralgia, may last for months and lead to a decline in quality of life. Risk factors for long COVID are still not very well understood. Survivors suffer from ongoing symptoms. This new entity highlights the need for a multidisciplinary approach that would enable elose monitoring of affected patients and implementation of measures that could reduce the impact of the pandemic on the overall patient wellbeing after the resolution of acute symptoms.	_
133	D130		Xiaoying Gu Bin Cao	In-hospital complications associated with COVID-19	https://doi.org/10.1016/S0140-6736(21)00983-1	Published	July 17, 2021	COMMENT	https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00983-1/fulltext	In The Lancet, Thomas Drake and colleagues5 report their prospective study of in-hospital complications of COVID-19 and the impact on clinical prognosis at discharge, initiated at the early stages of the pandemic. 73 197 adult patients were studied, of whom 44% were female and 73% were White, from 302 UK health-care facilities, with COVID-19 and admitted to hospital between Jan 4 and Aug 4, 2020. The study showed that among those admitted to hospital with COVID-19, a high proportion (49·7%) had at least one complication. The occurrence of complications was not only associated with a higher risk of mortality during hospitalisation, but also reduced the ability of patients to self-care once discharged. Whether this difference in complications on mortality was statistically significant was not examined by the authors. This finding is independent of the presence and number of comorbidities and indicates that attention should also be paid to younger patients who are less likely to die during the acute phase but more likely to live longer with complications in the days after acute or subacute COVID-19.
134	D131		Harry Crook, research assistant1, Sanara Raza, research assistant1, Joseph Nowell, research assistant1, Megan Young, clinical research officer1, Paul Edison	Long covid—mechanisms, risk factors, and management	https://doi.org/10.1136/bmj.n1648	Published	26 July 2021	Review	https://www.bmj.com/content/374/bmj.n1648	This review summarizes studies of the long term effects of covid-19 in hospitalized and non-hospitalized patients and describes the persistent symptoms they endure. Risk factors for acute covid-19 and long covid and possible therapeutic options are also discussed.
135	D132		Ioana Visan	Long COVID	https://doi.org/10.1038/s41591-021-01433-3	Published	27 July 2021	Article	https://www.nature.com/articles/s41590-021-00992-4	The most frequent lasting symptoms in non-hospitalized patients aged 31–45 and 45–60 were disturbed taste and smell (34 and 28%, respectively), fatigue (31 and 33%), dyspnea (17 and 18%), concentration problems (19 and 21%) and memory problems (16 and 22%). Of non-hospitalized patients over 30, 7% experienced severe fatigue as compared to 24% of hospitalized patients. In non-hospitalized patients, antibody titers at 2 months were associated with the severity of the initial illness, while persistent fatigue was associated with the severity of the initial illness, fever during the initial illness and female gender.	_
136	D133		Nisreen A. Alwan	The road to addressing Long Covid	https://doir.org/10.1126/science.abg7113	Published	30 Jul 2021	Article	https://science.sciencemag.org/content/373/6554/491.full	Long Covid is likely the first illness in history that has been defined by patients through social media platforms such as Twitter and Facebook. People with Long Covid formed a movement that demanded recognition of what was happening to them. During the first wave of the pandemic in 2020, online testimonials of prolonged symptoms following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were the only source of reassurance to others with a similar experience, including this author (2). In the absence of any guidance or recognition about the possibility of a persistent illness, peer support is all that people with Long Covid had. Many previously healthy and active people described persistent symptoms of the acute illness that fluctuated, with new symptoms appearing weeks later. In many countries, most nonhospitalized people did not have lab confirmation of SARS-CoV-2 infection owing to lack of access to community testing, so their symptoms remained without a diagnosis. By summer 2020, thousands were joining social media support groups. A common theme started to emerge: lack of recognition by the medical profession. Patients, including doctors, with Long Covid were consulting their health care providers, and their symptoms were commonly minimized, dismissed, or labeled as anxiety (3). A narrative emerged of people struggling to make sense of their symptoms and forming their own groups to understand and research what was happening to them in an international citizen science movement (4). The testimonials of people living with Long Covid demonstrated themes of stigma and discrimination.	_
137	D134		Sean L Davidson, psychiatry registrar1, David B Menkes	Long covid: reshaping conversations about medically unexplained symptoms	https://doi.org/10.1136/bmj.n1859	Published	28 July 2021	Article	https://www.bmj.com/content/374/bmj.n1859.full	Patients presenting with symptoms in the presence of normal diagnostic tests account for 26-35% of consultations in primary care.4 The banner of medically unexplained symptoms encompasses heterogeneous issues—simple transient problems, recognised symptom complexes such as chronic fatigue syndrome, and emerging phenomena like long covid. All present challenges to the doctor-patient relationship, confer risks of overdiagnosis and overtreatment, and can provoke frustration and anxiety in junior and experienced clinicians alike.25 These common clinical scenarios emphasise the pressing need for a framework to aid communication with patients who are frustrated by the mismatch of disabling symptoms and normal investigations.	_
138	D135		Joan Stephenson	New Federal Guidance Says COVID-19’s Long-term Effects Can Qualify as a Disability	http://jamanetwork.com/article.aspx?doi=10.1001/jamahealthforum.2021.2820	Published	August 3, 2021	Article	https://jamanetwork.com/journals/jama-health-forum/fullarticle/2782892	People in the US who experience persistent, recurring, or new symptoms after infection with COVID-19—a condition known as long COVID—can qualify as having a disability under federal civil rights laws and receive appropriate accommodations and services, the Biden-Harris administration announced last week. The US Department of Health and Human Services (HHS) and the Department of Justice jointly released new guidance that classifies long COVID—also known in the research community as postacute sequelae of SARS-CoV-2 infection—as a physical or mental impairment, which means that those affected can qualify for discrimination protections under the Americans with Disabilities Act (ADA).
139	D136		Dietrich August, Veronika Götz, Katarina Stete	Persistierende Beschwerden nach akuter COVID-19-Erkrankung: „Long-COVID“? Persisting symptoms after COVID-19: „Long COVID“?		Published	03 August 2021	Article	https://www.thieme-connect.com/products/ejournals/abstract/10.1055/a-1447-9253	Some patients complain of persisting symptoms after acute COVID-19. There is no universal definition yet for these post-acute sequelae, also termed Long COVID. Although their prevalence remains to be established, a delayed recovery seems to be more common than after other acute infectious diseases. Common complaints include fatigue with exercise intolerance, dyspnea on exertion, chest pain, and neuropsychiatric symptoms. Female sex, comorbidities, and severity of the acute disease have been identified as risk factors for persisting symptoms. It is, however, important to highlight that they are not limited to patients after severe COVID-19. Whilst their pathogenesis and prognosis is largely unknown, diagnostic evaluation should focus on exclusion of objective organ dysfunctions. Due to the variable presentation, management is interdisciplinary and may include physiotherapy, rehabilitation programmes, and psychological support. This article aims to summarize the current – limited – evidence on persisting symptoms after COVID-19.	_
140	D137		Steven Phillips, M.D., M.P.H., and Michelle A. Williams	Confronting Our Next National Health Disaster — Long-Haul Covid	10.1056/NEJMp2109285	Published	August 12, 2021	Opinion	https://www.nejm.org/doi/full/10.1056/NEJMp2109285		_
141	D138		Akiko Iwasaki	How COVID-19 has transformed my science	https://doi.org/10.1016/j.neuron.2021.07.022	Published	6 August 2021	Opinion	https://www.sciencedirect.com/science/article/pii/S0896627321005432	In this NeuroView, I recount pivotal moments that have transformed the way I do science.	_
142	D139					From this point on, the survey of studies is no longer as exhaustive as possible. Only those studies which seem to us to bring significant new elements will be listed.
143	D140		Paul G. Auwaerter	The Race to Understand Post–COVID-19 Conditions	https://doi.org/10.7326/M21-3072	Published	31 August 2021	Opinion	https://www.acpjournals.org/doi/full/10.7326/M21-3072		_
144	D141		Jun Wang,a,b,1 Fanghua Mei,c,1 Lu Bai,a,b Suhua Zhou,c Di Liu,a,b Lulu Yao,a,b Amrita Ahluwalia,d Reza A. Ghiladi,e Lei Su,f Tong Shu,f Miaozi Gong,g Xiaofang Wang,h Lijun Zhu,i Kun Cai,c,∗ and Xueji Zhang	Serum nitrite and nitrate: A potential biomarker for post-covid-19 complications?	https://dx.doi.org/10.1016%2Fj.freeradbiomed.2021.08.237	Published	2021 Aug 30	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404395/	Dysregulation of NOx had been reported in SARS-CoV-2 infected populations, but whether patients recovered from COVID-19 disease present with restored NOx is unknown. In this study, serum NO2− and NO3− were quantified and analyzed among 109 recovered adults in comparison to a control group of 166 uninfected adults. Nitrite or nitrate levels were not significantly different among mild-, common-, severe- and critical-type patients. However, these recovered patients had dramatically lower NO2− and NO2−/NO3− than the uninfected group (p < 0.0001), with significantly higher NO3− levels (p = 0.0023) than the uninfected group. Nitrate and nitrite/nitrate were positively and negatively correlated with patient age, respectively, with age 65 being a turning point among recovered patients. These results indicate that low NO2−, low NO2−/NO3− and high NO3− may be a potential biomarker of long-term poor or irreversible outcomes after SARS-CoV-2 infection. It suggests that NO metabolites might serve as a predictor to track the health status of recovered COVID-19 patients, highlighting the need to elucidate the role of NO after SARS-CoV-2 infection.
145	D142		Adam W Gaffney, MD MPH	The Long-COVID Conundrum	https://doi.org/10.1016/j.amjmed.2021.07.037	Published	August 20, 2021	Editorial	https://www.amjmed.com/article/S0002-9343(21)00525-8/fulltext	One study1 found that 1 in 3 non-hospitalized adults report 1+ symptom 6 months post-COVID-19. While one study found eventual resolution of symptoms in children,2 another found persistence among 57% of non-hospitalized children and 36% of initially asymptomatic children.3 Such estimates fuel concerns that Long COVID is the “next public health disaster in the making” that could afflict more than one in twenty Americans.4 There are important caveats, however. First, such estimates should be interpreted in the context of what we know about symptom persistence after other common respiratory infections, and in other prevalent conditions.
146	D143		Richard Beasley Nethmi Kearns Tom Hills	Charting a course for the management of long COVID	https://doi.org/10.1016/S2213-2600(21)00314-3	Published	August 17, 2021	Comment	https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00314-3/fulltext	It is difficult to think beyond the immediate crisis, when wave after wave of the COVID-19 pandemic has repeatedly overwhelmed health systems and resulted in high rates of mortality and severe disruption to normal life. However, the recognition of a syndrome of prolonged, multisystem disability in survivors of COVID-191, 2, 3—commonly referred to as long COVID or the post-COVID-19 condition—has made obtaining knowledge of its pathogenesis, prognosis, and management an important competing priority. A comprehensive, coordinated global research strategy for the post-acute sequelae of COVID-19, rather than a piecemeal approach, is clearly required, although difficult to achieve in the midst of a pandemic. For this reason, the Position Paper from the UK-based International COVID-19 Airways Diseases Group in The Lancet Respiratory Medicine,4 presenting research priorities for the long-term effects of COVID-19 in the context of airways disease, is to be welcomed. The consensus recommendations, which are both broad and insightful, will inform future research efforts.
147	D144		Davies Adeloye, PhD * Omer Elneima, MRCP * Luke Daines, MBChB * Krisnah Poinasamy, LLM * Prof Jennifer K Quint, FRCP Samantha Walker, PhD Prof Chris E Brightling, FMedSci Prof Salman Siddiqui, FRCP Prof John R Hurst, FRCP Prof James D Chalmers, PhD Paul E Pfeffer, PhD Petr Novotny, MUDr Thomas M Drake, MBChB Prof Liam G Heaney, MRCP † Prof Igor Rudan, PhD † Prof Aziz Sheikh, MD † Prof Anthony De Soyza, PhD † on behalf of theInternational COVID-19 Airways Diseases Group	The long-term sequelae of COVID-19: an international consensus on research priorities for patients with pre-existing and new-onset airways disease	https://doi.org/10.1016/S2213-2600(21)00286-1	Published	August 17, 2021	POSITION PAPER	https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00286-1/fulltext	Persistent ill health after acute COVID-19—referred to as long COVID, the post-acute COVID-19 syndrome, or the post-COVID-19 condition—has emerged as a major concern. We undertook an international consensus exercise to identify research priorities with the aim of understanding the long-term effects of acute COVID-19, with a focus on people with pre-existing airways disease and the occurrence of new-onset airways disease and associated symptoms. 202 international experts were invited to submit a minimum of three research ideas. After a two-phase internal review process, a final list of 98 research topics was scored by 48 experts. Patients with pre-existing or post-COVID-19 airways disease contributed to the exercise by weighting selected criteria. The highest-ranked research idea focused on investigation of the relationship between prognostic scores at hospital admission and morbidity at 3 months and 12 months after hospital discharge in patients with and without pre-existing airways disease. High priority was also assigned to comparisons of the prevalence and severity of post-COVID-19 fatigue, sarcopenia, anxiety, depression, and risk of future cardiovascular complications in patients with and without pre-existing airways disease. Our approach has enabled development of a set of priorities that could inform future research studies and funding decisions. This prioritisation process could also be adapted to other, non-respiratory aspects of long COVID.	Un large groupe de chercheurs, accompagné par des malades, mène un exercice de consensus international et identifie, dans The Lancet Respiratory Medicine, des priorités de recherche dans le but de comprendre les effets à long terme de la covid.	N014E
148	D145		Catherine Tourette-Turgis a, ⁎ : Fondatrice et directrice de l'Université des patients-Sorbonne Université, Dominique Salmon b : Médecin, professeur des universités-praticien hospitalier en maladies infectieuses, Pauline Oustric c : Cofondatrice de l'association Covid-long France #ApresJ20, Faustine Hélie c : Cofondatrice de #ApresJ20, Mylène Rahel Damamme c : Cofondatrice de #ApresJ20	Expérience patient, autorité épistémique et enjeux sanitaires : l'exemple du Covid long - Patient experience, epistemic authority and health challenges: the example of long COVID	https://doi.org/10.1016/S0038-0814(21)00217-6	Published	06/08/21	Article	https://www.em-consulte.com/article/1461696/alertePM	Depuis février 2020, des centaines de milliers de malades sont confrontés à des symptômes persistants après leur infection Avec leurs cliniciens, ces patients sont exposés à un haut degré d'incertitude et à l'urgence de la production de cadres conceptuels visant la reconnaissance, la prise en charge et la légitimation de leur expérience de malades confrontés à des symptômes nouveaux et prolongés, comme à des controverses quant à la qualification de ces symptômes En ce sens, le Covid long illustre la nécessité de combiner les savoirs expérientiels collectifs des malades et les savoirs scientifiques au bénéfice des patients, des cliniciens et de la recherche.	_
149	D146		Lacedonia D. · Scioscia G. · De Pace C.C. · Laricchiuta A. · Tondo P. · Sabato R. · Foschino Barbaro M.P.	How Are We Handling the Post-COVID Patients? The Dance of Uncertainties	https://doi.org/10.1159/000518330	Published	September 03, 2021	Letter to the Editor	https://www.karger.com/Article/FullText/518330	In conclusion, despite the rich literature on this topic, the possibility of having clear recommendations about the management of patients affected by PACS still seems far away, in terms of timing of visits, clinical and functional assessments, and treatment. According to our survey, there is a tacit common line of action diffused among the pulmonologists with only some little differences in the management according to the number of patients following up. Main open issues should be solved with standardized European guidelines in order to obtain a better clinical practice for optimizing the safety of patients and the administration of health-care resources.	_
150	D147		ONS	ONS: Short report on Long COVID, 22 July 2021		Published	30 July 2021	Article	https://www.gov.uk/government/publications/ons-short-report-on-long-covid-22-july-2021	This report is provided at the request of SAGE and includes information from ongoing studies investigating long COVID including the COVID-19 Longitudinal Health and Wellbeing National Core Study-CONVALESCENCE Study, REACT-2, PHOSP-COVID, ONS’s COVID-19 Infection Survey (CIS) and the COVID Symptom Study App.
151	D148		Elizabeth Murphy, Kiera McDowall, Peter McDowall	Should long-term symptoms following COVID-19 infection be considered an occupational disease?	https://doi.org/10.1093/occmed/kqab103	Published	13 September 2021	Article	https://academic.oup.com/occmed/advance-article/doi/10.1093/occmed/kqab103/6369377?login=true	The question whether ‘long COVID’ is an occupational disease or a problem for the nation at large is clearly important and there are a wide array of questions. From an occupational health perspective, it brings an opportunity to focus on an individual’s daily function, workability and engagement in work in order to promote good health and productivity. When return to work is not feasible, NHS workers already have access to the NHS Injury Allowance and possible application for NHS pensions benefits. Given the scale of the problem and financial complexities, this may ultimately be more a question for the economists than anyone else	_
152	D149		McClymont, G.	The Role of Patients and Patient Activism in the Development of Long COVID Policy	https://doi.org/10.17863/CAM.75505	Published	2021-09-15	Article	https://www.repository.cam.ac.uk/handle/1810/328051	Long Covid awareness originated from Long Covid patients, known as long haulers, finding each other on social media and support groups. Long hauler patient activism has been the driving force behind Long Covid recognition, research and health policy development. Two support groups have played key roles: The Body Politic COVID-19 Support Group and The Long Covid Patient Support Group. These bodies have raised awareness of Long Covid in the media, and in academic and medical communities. They have also provided support for long haulers. The Body Politic COVID-19 Support Group produced a patient-led research report which catalysed research policy for Long Covid. Peer-reviewed research has revealed a diverse array of severe, multi-organ symptoms of Long Covid and has recommended a multi-disciplinary healthcare approach to Long Covid. This recommendation has been adopted by various governments and medical institutions, which have opened Long Covid clinics. Population morbidity from Long Covid is a rising challenge, requiring research, a multi-disciplinary healthcare approach and socio-economic support.	_
153	D150		Darren A Brown1, Kelly K O’Brien	Conceptualising Long COVID as an episodic health condition	http://dx.doi.org/10.1136/bmjgh-2021-007004	Published	September 22, 2021	Commentary	https://gh.bmj.com/content/6/9/e007004	Long COVID presents with multidimensional clusters of symptoms that can fluctuate, sometimes unpredictably, whereby symptoms adversely affect general well-being and ability to perform day-to-day activities, exercise or work. We propose that Long COVID should be conceptualised as an episodic illness, characterised by health-related challenges (or disability) that may be multidimensional, episodic and unpredictable in nature. Dimensions of disability experienced by people living with Long COVID may include physical, cognitive, mental and emotional health, daily activities, social inclusion and uncertainty, with uncertainty and worrying about the future a key dimension of disability. The role for rehabilitation is important for people living with Long COVID, offering a goal-oriented, person-centred approach to prevent, mitigate and address episodic disability. Future directions include establishing valid and reliable measures of episodic disability, assessing effectiveness of rehabilitation approaches and interventions and building on existing international collaborations and community-engaged partnerships to advance practice, research and policy.	_
154	D151		J. Lechner-Scott M. Levy C. Hawkes A. Yeh G. Giovannoni	Long COVID or post COVID-19 syndrome	https://doi.org/10.1016/j.msard.2021.103268	Published	September 17, 2021	EDITORIAL	https://www.msard-journal.com/article/S2211-0348(21)00535-6/fulltext	SARS-COV- 2 is now recognized to be responsible not only for a lung condition but a multi-organ syndrome1. After the initial acute infection, like many other viral disorders, a multitude of long-lasting symptoms have been described. Neuropsychiatric symptoms that occur during or after infection with SARS-2 are not simply related to emotional stress. This concept is given provisional support by the presence of inflammatory CSF in five cases of childhood Multisystem Inflammatory Syndrome (MIS-C), three of whom presented with neuropsychiatric symptoms one month after acute infection9, suggesting CNS inflammatory consequences may occur in all age groups. SARS-2 is neurotropic and appears to enter the brain through the olfactory neurons10, spreading to the frontal lobes as shown by impaired executive function and frontal abnormalities on MRI, EEG and PET11. The most supported theory is an autoimmune process with an exaggerated innate immune response and cytokine activation. Most patients with severe COVID-19 exhibit substantially elevated serum levels of pro-inflammatory cytokines including interleukin 6, 1- beta, 2, 8, 17, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, chemokine ligand 2 and 10, and tumour necrosis factor alpha, resulting in the now well- recognised cytokine storm15. The presence of oligoclonal IgG bands and activated microglia resemble the process causing fatigue and cognitive impairment in MS16.
155	D152		L.Bertoletti	COVID-19 : embolie pulmonaire ou endothélite pulmonaire ?	https://doi.org/10.1016/j.jdmv.2021.08.129	Published	25 September 2021	Article	https://www.sciencedirect.com/science/article/pii/S2542451321002339	L’analyse post-mortem des poumons de patients a permis de mettre en évidence une atteinte de la perfusion capillaire pulmonaire, puis par la démonstration d’une infection directe de l’endothélium vasculaire pulmonaire par le virus. Cette atteinte endothéliale a permis d’expliquer ensuite le développement des lésions de thrombose in situ, en combinaison avec l’orage inflammatoire secondaire décrit dans la COVID-19. Le concept de thrombo-inflammation était conforté dans notre compréhension de la maladie.	_
156	D153		Viet-Thi Tran, Carolina Riveros, Bérangère Clepier, Moïse Desvarieux, Camille Collet, Youri Yordanov, Philippe Ravaud	Development and Validation of the Long Coronavirus Disease (COVID) Symptom and Impact Tools: A Set of Patient-Reported Instruments Constructed From Patients’ Lived Experience	https://doi.org/10.1093/cid/ciab352	Published	29 April 2021	Study	https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab352/6252414	To develop and validate patient-reported instruments, based on patients’ lived experiences, for monitoring the symptoms and impact of long coronavirus disease (covid). Methods The long covid Symptom and Impact Tools (ST and IT) were constructed from the answers to a survey with open-ended questions to 492 patients with long COVID. Conclusions The long covid ST and IT tools, constructed from patients’ lived experiences, provide the first validated and reliable instruments for monitoring the symptoms and impact of long covid.	_
157	D154		Dr Ashish Chaudhry General Practitioner and Medical Educator. Member of the UK Doctors Long COVID Group. with contributions from Clare Rayner Occupational Health Physician Asad Khan Respiratory Physician Dr Harsha Master	Long Covid Dr Ashish Chaudhry General Practitioner and Medical Educator. Member of the UK Doctors Long COVID Group. with contributions from Clare Rayner Occupational Health Physician Asad Khan Respiratory Physician Dr Harsha Master GP Lead, Hertfordshire Community NHS Trust COVID-19 Rehabilitation Service Learning over the last year from those with lingering symptoms		Published	September 2021	Article	https://www.mountsinai.org/files/MSHealth/Assets/HS/Locations/Abilities-Research-Center/BJ-Sept2021-LongCovid.pdf	Consider that the sequelae after acute covid infection can be multisystem, fluctuate and last for prolonged periods. The medical profession is only just beginning to describe cases, so evidence for any interventions are still limited and usually based on expert consensus or anecdote. It is therefore vital that we focus on the possibility of illness rather than probability in initial stages, and symptoms are screened for and diagnostic nets cast wide in patients who remain symptomatic. Long covid will leave an impact on the NHS for years to come, and there is an opportunity to support your patients through the unknown with compassion and courage so they may have access to appropriate health care	_
158	D155		Pierce, Janet D.; Shen, Qiuhua; Cintron, Samantha A.; Hiebert, John B.	Post-COVID-19 Syndrome		Published	October 12, 2021	Review	https://journals.lww.com/nursingresearchonline/Abstract/9000/Post_COVID_19_Syndrome.99627.aspx	Although studies examining the pathophysiology of post-COVID-19 syndrome are still relatively few, there is growing evidence that this is a complex and multifactorial syndrome involving virus-specific pathophysiologic variations that affect many mechanisms but specifically oxidative stress, immune function, and inflammation. Further research is needed to elucidate the pathophysiology, pathogenesis, and longer-term consequences involved in post-COVID-19 syndrome.	_
159	D156		Emily R. Pfaff, Andrew T Girvin, Tellen D. Bennett, Abhishek Bhatia, Ian M. Brooks, Rachel R Deer, Jonathan P Dekermanjian, Sarah Elizabeth Jolley, Michael G. Kahn, Kristin Kostka, Julie A McMurry, Richard Moffitt, Anita Walden, Christopher G Chute, Melissa A Haendel	Who has long-COVID? A big data approach	https://doi.org/10.1101/2021.10.18.21265168	pre-print	October 22, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.10.18.21265168v1.full-text	The combined demographics of the long-COVID clinic patients supplied by the three sites (first two columns of Table 1) show significant differences from the COVID-19 patients at those sites who did not attend the long-COVID clinic (third and fourth columns of Table 1). Notably, non-hospitalized long-COVID clinic patients are disproportionately female. Long-COVID clinic patients who were hospitalized with acute COVID-19 are disproportionately Black when compared with all patients hospitalized with acute COVID-19, and are much more likely to have a pre-COVID-19 comorbidity (diabetes, kidney disease, congestive heart failure, or pulmonary disease).	_
160	D157		Noelle M. Cocoros, DSc, MPH1; Elisabeth Svensson, PhD2,3; Szimonetta Komjáthine Szépligeti, MSc2; Søren Viborg Vestergaard, MD2; Péter Szentkúti, MSc2; Reimar W. Thomsen, MD, PhD2; Per Borghammer, MD, PhD, DMSc4; Henrik Toft Sørensen, MD, PhD, DMSc, DSc2,5; Victor W. Henderson, MD, MS2,6,7	Long-term Risk of Parkinson Disease Following Influenza and Other Infections	https://doi.org/10.1001/jamaneurol.2021.3895	Published	October 25, 2021	Study	https://jamanetwork.com/journals/jamaneurology/article-abstract/2785029	Results Of 61 626 included individuals, 23 826 (38.7%) were female, and 53 202 (86.3%) were older than 60 years. A total of 10 271 individuals with Parkinson disease and 51 355 controls were identified. Influenza diagnosed at any time during a calendar year was associated with Parkinson disease more than 10 years later (OR, 1.73; 95% CI, 1.11-2.71). When influenza exposure was restricted to months of highest influenza activity, an elevated OR with a wider confidence interval was found (OR, 1.52; 95% CI, 0.80-2.89). There was no evidence of an association with any type of infection more than 10 years prior to Parkinson disease (OR, 1.04; 95% CI, 0.98-1.10). Several specific infections yielded increased odds of Parkinson disease within 5 years of infection, but results were null when exposure occurred more than 10 years prior. Conclusions and Relevance In this case-control study, influenza was associated with diagnoses of Parkinson disease more than 10 years after infection. These observational data suggest a link between influenza and Parkinson disease but do not demonstrate causality. While other infections were associated with Parkinson disease diagnoses soon after infection, null associations after more than 10 years suggest these shorter-term associations are not causal.
161	D158	Questionable methodology	Joane Matta, PhD1; Emmanuel Wiernik, PhD1; Olivier Robineau, MD, PhD2,3; Fabrice Carrat, MD, PhD3; Mathilde Touvier, PhD4; Gianluca Severi, PhD5,6; Xavier de Lamballerie, MD, PhD7; Hélène Blanché, PhD8; Jean-François Deleuze, PhD8; Clément Gouraud, MD, MSc9; Nicolas Hoertel, MD, PhD10; Brigitte Ranque, MD, PhD11; Marcel Goldberg, MD, PhD1; Marie Zins, MD, PhD1; Cédric Lemogne, MD, PhD	Association of Self-reported COVID-19 Infection and SARS-CoV-2 Serology Test Results With Persistent Physical Symptoms Among French Adults During the COVID-19 Pandemic	http://jamanetwork.com/article.aspx?doi=10.1001/jamainternmed.2021.6454	Published	November 8, 2021	Original Research	https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2785832	Findings In this cross-sectional analysis of 26 823 adults from the population-based French CONSTANCES cohort during the COVID-19 pandemic, self-reported COVID-19 infection was associated with most persistent physical symptoms, whereas laboratory-confirmed COVID-19 infection was associated only with anosmia. Those associations were independent from self-rated health or depressive symptoms. Meaning Findings suggest that persistent physical symptoms after COVID-19 infection should not be automatically ascribed to SARS-CoV-2; a complete medical evaluation may be needed to prevent erroneously attributing symptoms to the virus. The results of this cross-sectional analysis of a large, population-based French cohort suggest that physical symptoms persisting 10 to 12 months after the COVID-19 pandemic first wave may be associated more with the belief in having experienced COVID-19 infection than with actually being infected with the SARS-CoV-2 virus. Although our study cannot determine the direction of the association between belief and symptoms, our results suggest that further research regarding persistent physical symptoms after COVID-19 infection should also consider mechanisms that may not be specific to the SARS-CoV-2 virus. From a clinical perspective, patients in this situation should be offered a medical evaluation to prevent their symptoms being erroneously attributed to COVID-19 infection and to identify cognitive and behavioral mechanisms that may be targeted to relieve the symptoms.	Un article dans JAMA Internal Medicine avance que la persistance de symptômes après une infection de SARS-CoV-2 ne devrait pas être automatiquement associée au SARS-CoV-2. L'étude note que seule l'anosmie est un symptôme prolongé qui semble directement corrélé à une sérologie positive, au contraire de plusieurs autres symptômes habituellement rapportés par les personnes qui pensent avoir été infectées (fatigue, douleurs thoraciques, problèmes digestifs, difficultés à respirer...). Etaient considérés prolongés les symptômes déclarés de plus de 8 semaines. Les symptômes sont auto-déclarés dans l'étude et les tests sérologiques sont considérés positifs pour un ratio de densité optique supérieure ou égale à 1,1. La sérologie a été faite pour la protéine S (S-igG), indistinctement à l'intérieur d'un intervalle de 7 mois. Dès sa parution, cette étude est sévèrement critiquée par plusieurs experts renommés. Les interprétations qui en découlent sont jugées potentiellement non concluantes et trompeuses/fallacieuses ("misleading"). https://www.sciencemediacentre.org/expert-reaction-to-study-looking-at-the-association-of-self-reported-covid-19-infection-and-sars-cov-2-serology-test-results-with-persistent-physical-symptoms/ Francis Wilson, l'un des experts internationaux les plus réputés en conception et interprétation d'études médicales, estime l'étude française de JAMA faussée/impropre ("flawed") en raisons de lourds biais méthodologiques. https://methodsmanmd.medium.com/is-long-covid-even-real-704bb74ab619	N016
162	D159		Xiong R, Gunter C, Fleming E, Vernon SD, Bateman L, Unutmaz D, Oh J	Multi-‘omics of host-microbiome interactions in short- and long-term Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)	https://doi.org/10.1101/2021.10.27.466150	pre-print	28 Oct 2021	Study	https://europepmc.org/article/ppr/ppr413593	Overall, ME/CFS was characterized by reduced gut microbiome diversity and richness with high heterogeneity, and depletion of sphingomyelins and short-chain fatty acids in the plasma. We found significant differences when stratifying by cohort; short-term ME/CFS was associated with more microbial dysbiosis, but long-term ME/CFS was associated with markedly more severe phenotypic and metabolic abnormalities. We identified a reduction in the gene-coding capacity (and relative abundance of butyrate producers) of microbial butyrate biosynthesis together with a reduction in the plasma concentration of butyrate, especially in the short-term group. Global co-association and detailed gene pathway correlation analyses linking the microbiome and metabolome identified additional potential biological mechanisms underlying host-microbiome interactions in ME/CFS, including bile acids and benzoate pathways. Finally, we built multiple state-of-the-art classifiers to identify microbes, microbial gene pathways, metabolites, and clinical features that individually or together, were most able to differentiate short or long-term MECFS, or MECFS vs. healthy controls. Taken together, our study presents the highest resolution, multi-cohort and multi-‘omics analysis to date, providing an important resource to facilitate mechanistic hypotheses of host-microbiome interactions in ME/CFS.	Dans une étude en pre-print (non relue ni publiée) sur l'encéphalomyélite myalgique (EM), des chercheurs, en notant des similitudes avec le covid long, entreprennent de construire plusieurs classificateurs de pointe pour identifier les microbes, les voies génétiques microbiennes, les métabolites et les caractéristiques cliniques qui, individuellement ou ensemble, sont les plus à même de différencier les EM courte ou de long terme, ou les patients EM des témoins sains.	N016
163	D160		Annа Malkova 1,* ,Igor Kudryavtsev 2,Anna Starshinova 3,Dmitry Kudlay 4,5 ,Yulia Zinchenko 6 ,Anzhela Glushkova 7,Piotr Yablonskiy 1,6 andYehuda Shoenfeld	Post COVID-19 Syndrome in Patients with Asymptomatic/Mild Form	https://doi.org/10.3390/pathogens10111408	Published	30 October 2021	Review	https://www.mdpi.com/2076-0817/10/11/1408/htm	According to the analysis, PCS develops on average in 30–60% of patients, mainly among women. Fatigue, shortness of breath, cough, and anosmia were reported as the most common symptoms. The possible association between the described PCS symptoms and brain damage was revealed. We assume the possibility of an alternative course of COVID-19, which develops in genetically predisposed individuals with a stronger immune response, in which it predominantly affects the cells of the nervous system, possibly with the presence of an autoimmune component, which might have similarity with chronic fatigue syndrome or autoimmune disautonomia. Thus, the gender (female) and the presence of anosmia during an asymptomatic or mild course of the disease can be predictive factors for the development of PCS, which can be caused by autoimmune damage to neurons, glia, and cerebral vessels.	_
164	D161		Tripathi, Awatansh Kumar Rajkumar; Pinto, Lancelot Mark,	Long COVID: “And the fire rages on”	https://doi.org/10.4103/lungindia.lungindia_980_20	Published	Novembre 2021	Review	https://journals.lww.com/lungindia/Fulltext/2021/11000/Long_COVID___And_the_fire_rages_on_.12.aspx	With the increasing cohort of COVID-19 survivors worldwide, we now realize the proportionate rise in post-COVID-19 syndrome. In this review article, we try to define, summarize, and classify this syndrome systematically. This would help clinicians to identify and manage this condition more efficiently. We propose a tool kit that might be useful in recording follow-up data of COVID-19 survivors.	_
165	D162		Vinod Nikhra	COVID-19 and Long Covid: Organs Damage and Dysfunctions, and Implications for Clinical Course	https://dx.doi.org/10.29328/ebook1005	Published	18 October 2021	Review	https://www.researchgate.net/profile/Vinod-Nikhra/publication/355582623_COVID-19_and_Long_Covid_Organs_Damage_and_Dysfunctions_and_Implications_for_Clinical_Course/links/61776e4b3c987366c3e9b3a5/COVID-19-and-Long-Covid-Organs-Damage-and-Dysfunctions-and-Implications-for-Clinical-Course.pdf	Like any other infectious disease, the prognosis of COVID-19 is inϐluenced by infecting agent, the SARS-CoV-2 virus load and the extent of organs afϐliction and damage. COVID-19 having a propensity for multiorgan involvement carries an adverse prognosis during the clinical course as well as later during the post-recovery period persisting as Long Covid. The direct cytopathic effects of SARS-CoV-2 virus and the erratic and hyper-inϐlammatory response lead to tissue injury in various organs coupled with physiological dysfunctions and complications. In fact, the multi-system manifestations of COVID-19 are caused by a combination of speciϐic host defence responses with associated inϐlammatory activity and vascular involvement with coagulopathy and a distinct propensity to develop thromboembolic complications. Simultaneously, comorbidities such as diabetes, hypertension and cardiovascular diseases inϐluence the disease severity and mortality.	_
166	D163		Law, Julianne	Long COVID: the next Public Health crisis in the United Kingdom (UK) after the COVID-19 pandemic		Published	30/09/2021	Article	https://research.bangor.ac.uk/portal/en/researchoutputs/long-covid-the-next-public-health-crisis-in-the-united-kingdom-uk-after-the-covid19-pandemic(f6449a47-153c-48dc-8ad9-52e62a7ed14e).html	Recent research by the government in the UK has found that two million people are affected by long COVID. This article discusses what long COVID is, what the symptoms are, and how it is diagnosed and treated. This article also discusses how the National Health Service (NHS) plans to treat people using ‘long COVID out-patient clinics.’ Long COVID is becoming a significant public health crisis in the UK, and in the rest of the world. Long COVID has affected people in every part of society; it has affected the rich and the poor, although it has affected the poor in greater numbers than the rich. The budgetary implications of attempting to treat two million people for this disease are discussed, as are the implications of not treating people with long COVID.
167	D164		Arad Dotan Yehuda Shoenfeld	Post-COVID syndrome: the aftershock of SARS-CoV-2	https://doi.org/10.1016/j.ijid.2021.11.020	Published	November 13, 2021	Editorial	https://www.ijidonline.com/article/S1201-9712(21)00867-5/fulltext	Accumulation evidence along the pandemic raised an association between the SARS-CoV-2 and autoimmunity (1). SARS-CoV-2 infected patients have a high presence of various autoantibodies (1). Moreover, numerous cases of new-onset of autoimmune-related disorders had been documented following the infection, including both organ-specific and systemic autoimmune diseases (1). Due to the accumulating evidence of persistent post-infectious symptoms reported by numerous recovered patients, the focus of the medical and research communities might need to start shifting focus from the acute phase of COVID-19 to the chronic manifestations of the SARS-CoV-2 infection, referred to as by “post-COVID syndrome”. Post-COVID syndrome presents as non-specific symptoms, most commonly fatigue, headache, dyspnea, anosmia, and memory complaint, which is suspiciously similar to the infection-induced myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (15,18). As current studies suggest an involvement of immune-related dysfunction in the development of post-COVID syndrome, immunosuppressive therapeutic options could be beneficial in parallel to heist SARS-CoV-2 vaccination of the population (15,20,21).	_
168	D165		Alex J Walker, Brian MacKenna, Peter Inglesby, Laurie Tomlinson, Christopher T Rentsch, Helen J Curtis, Caroline E Morton, Jessica Morley, Amir Mehrkar, Seb Bacon, George Hickman, Aaron Fowles, Nasreen Parkes, Ian J Douglas and Stephen JW Evans	Clinical coding of long COVID in English primary care: a federated analysis of 58 million patient records in situ using OpenSAFELY	https://doi.org/10.3399/BJGP.2021.0301	Published	June 18, 2021	Study	https://bjgp.org/content/71/712/e806	Method Working on behalf of NHS England, OpenSAFELY data were used encompassing 96% of the English population between 1 February 2020 and 25 May 2021. The proportion of people with a recorded code for long COVID was measured overall and by demographic factors, electronic health record software system (EMIS or TPP), and week. Results Long COVID was recorded for 23 273 people. Coding was unevenly distributed among practices, with 26.7% of practices having never used the codes. Regional variation ranged between 20.3 per 100 000 people for East of England (95% confidence interval [CI] = 19.3 to 21.4) and 55.6 per 100 000 people in London (95% CI = 54.1 to 57.1). Coding was higher among females (52.1, 95% CI = 51.3 to 52.9) than males (28.1, 95% CI = 27.5 to 28.7), and higher among practices using EMIS (53.7, 95% CI = 52.9 to 54.4) than those using TPP (20.9, 95% CI = 20.3 to 21.4).	_
169	D166		Ash Routen, Lauren O’Mahoney, Daniel Ayoubkhani, Amitava Banerjee, Chris Brightling, Melanie Calvert, Nishi Chaturvedi, Ian Diamond, Rosalind Eggo, Paul Elliott, Rachael A. Evans, Shamil Haroon, Emily Herret, Margaret E. O’Hara, Roz Shafran, Julie Stanborough, Terence Stephenson, Jonathan Sterne, Helen Ward & Kamlesh Khunti	Understanding and tracking the impact of long COVID in the United Kingdom	https://doi.org/10.1038/s41591-021-01591-4	Published	22 November 2021	Correspondence	https://www.nature.com/articles/s41591-021-01591-4	The research community have joined patient researchers in their efforts to improve understanding of long COVID, including its symptoms, health impacts, pathophysiology and treatments. Patient and public involvement is a feature of all the studies described above, with research teams working with patient partners from diverse backgrounds, as well as engaging with national long-COVID support groups. Multidisciplinary research collaboration with patients at the core, as well as co-producing the research as equal partners, is crucial for developing a comprehensive approach to unraveling the complexity and heterogeneity of long COVID. This co-production will be fundamental in the development of targeted therapeutic approaches and to inform health service provision to meet the large unmet need from long COVID.	_
170	D167		KCE. - Castanares-Zapatero Diego, Kohn Laurence, Dauvrin Marie, Detollenaere Jens, Maertens de Noordhout Charline, Primus-de Jong Célia, Cleemput Irina, Van den Heede Koen	Long COVID: Pathophysiology – epidemiology and patient needs		Published	November 2021	Article	https://kce.fgov.be/en/long-covid-pathophysiology-%E2%80%93-epidemiology-and-patient-needs	In this short scientific report we describe the main rationale, research objectives and methods, results and conclusions of the KCE study on long COVID.*
171	D168		Helen Fogarty,Ellie Karampini,Andrew S. O'Donnell,Soracha E. Ward,Jamie M. O'Sullivan,James S. O'Donnell	Persistent endotheliopathy in the pathogenesis of long COVID syndrome - Reply to comment from von Meijenfeldt et al.	https://doi.org/10.1111/jth.15578	Published	4 November 2021	Letter to the editor	https://onlinelibrary.wiley.com/doi/10.1111/jth.15578	The key question posed by our collective data is whether persistent hemostatic dysfunction following COVID-19 is contributing to post-acute sequelae of SARS-CoV-2 infection (PASC or long COVID syndrome).9 In our study, we observed weak associations between 6-min walk test distance and both VWF:Ag and VWF propeptide levels at a median of 68 days after acute COVID-19.4 In contrast, using the subjective Sheehan disability scale to assess functional impairment, von Meijenfeldt et al. found no relationship with any hemostatic biomarkers at either 8 or 12 months after discharge.1 The differences in these results may be attributable to a variety of potential confounders. In particular, both studies included a relatively small number of patients (n = 50 and n = 44, respectively), and long COVID symptomatology was assessed using a combination of objective and subjective protocols performed at varying time points following discharge. Moreover, there were also differences between the study cohorts with respect to initial COVID-19 severity; patient comorbidities including obesity; and differences in patient management during acute COVID-19 (including anticoagulant therapy intensity). Finally, accumulating recent data have highlighted significant phenotypic heterogeneity amongst patients with long COVID syndrome.9, 10 In this context, it is clear that much larger stratified prospective studies that include state-of-the-art imaging will be essential to defining any relationship and/or any potential causality between PASC and persistent hemostatic dysfunction. Given the huge morbidity associated with long COVID, coupled with the limited understanding of the underlying disease pathogenesis, such studies are required as a matter of urgency.	_
172	D169		Gema M. Lledó # Jacobo Sellares # Carlos Brotons # Mireia Sans # Juana M. Díez Antón Julià Blanco Quique Bassat Adelaida Sarukhan José M. Miró ## Silvia de Sanjosé	Post-acute COVID-19 syndrome (PACS): a new tsunami requiring a universal case definition	https://doi.org/10.1016/j.cmi.2021.11.015	Published	November 23, 2021	Article	https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(21)00661-3/fulltext	The SARS-CoV-2 pandemic has led to severe socio-economic and health impacts with few comparable precedents in the contemporary era. In addition to the acute and dramatic outcomes, the longer-term consequences have become a challenge. According to current data, 80% of COVID-19 patients develop a mild or moderate disease (1), 15% a severe disease and 5% a critical disease with different complications such as acute respiratory distress syndrome (ARDS), sepsis and septic shock, thromboembolism and multi-organ failure. When compared to influenza, there are many differences in terms of clinical features, morbidity and mortality (2), and more so when considering the CFR (case fatality rate) of COVID-19 [0.1-25%] (3) with that of the more recent pandemic of influenza A H1N1 of 2009 [0.001-0.011%] (4). Patients with cancer and transplant recipients have an increased risk of worse outcomes, but no evidence on worse prognosis has been demonstrated in patients with primary immunodeficiencies and human immunodeficiency virus (HIV) infection (5, 6). However, patients with systemic autoimmune diseases and high doses of corticosteroids or rituximab seem to be associated with more unfavourable outcomes (7). The underlying cause of the persistence of symptoms has yet to be established, but many theories have been hypothesised. They mainly address virus-specific pathophysiological changes, aberrant immune responses and inflammatory damage in response to the acute infection (18) and mechanisms of viral persistence (19,20). More recently, the roles of exosomes (21) and the intervention of mast cells ((22) have also come under consideration. These potential underlying etiological causes must be explored if we are to improve our understanding of the mechanisms contributing to the pathophysiology of PACS. The ambiguity regarding PACS risk factors, due to variations in reporting, study design and clinical and demographic characteristics of participants, is currently the main problem. However, female sex, high numbers of symptoms and antibodies to SARS-CoV-2 may play a role in pathogenesis, although some studies have found no significant differences. New lines of research investigate specific biomarkers to establish clusters for both severe COVID-19 and PACS using machine learning techniques to resolve the discrepancies addressed above (23). We must ensure the follow up of these patients, with a view to finding out how long these symptoms persist and whether they develop into chronic disorders. These conditions can lead to hospital readmission, estimated at around 3.6-4.5% in the first 30 days (24,25) and up to 27% after six months (26), resulting in a dramatic impact on communities and healthcare systems. To date, there is no definitive treatment for managing the prolonged symptoms of PACS, although there are options for specific symptoms. Surprisingly, there are case reports, case series and some recent studies suggest that COVID-19 vaccines may improve or resolve long-term symptoms (27). However, effective antiviral treatment from the early stage of infection may be the best way to minimise the likelihood of developing PACS. Unfortunately, symptoms such as fatigue, are difficult to tackle, but suitable rehabilitation programmes may bring enormous benefit to “long-haulers” for pulmonary, cardiological or neurological sequelae. Furthermore, appropriate psychological support should be considered as an additional treatment.
173	D170		Alan Roth, DO, Pan San Chan, MD, Wayne Jonas, MD	Addressing the Long COVID Crisis: Integrative Health and Long COVID	https://doi.org/10.1177%2F21649561211056597	Published	November 16, 2021	Review	https://journals.sagepub.com/doi/10.1177/21649561211056597	Patients experience a wide range of symptoms, including serious organ system effects such as pulmonary fibrosis, myocarditis, new diabetes diagnoses, stroke, and other cerebrovascular events. They also experience ongoing pain, fatigue, and cognitive dysfunction. We suggest here that these patients require an integrative health approach, one that combines traditional medical management, non-pharmacological approaches, and behavior and lifestyle changes. Such an approach has been shown to be beneficial in other chronic illnesses such as fibromyalgia, chronic fatigue syndrome, and post-Lyme disease.	_
174	D171		LiqinWangabDinahFoerabcErinMacPhaulaYing-ChihLoabDavid W.BatesabLiZhouab	PASCLex: A comprehensive post-acute sequelae of COVID-19 (PASC) symptom lexicon derived from electronic health record clinical notes	https://doi.org/10.1016/j.jbi.2021.103951	Published	13 November 2021	Study	https://www.sciencedirect.com/science/article/pii/S153204642100280X	PASCLex included 355 symptoms consolidated from 1520 UMLS concepts of 16,466 synonyms. NLP achieved an averaged precision of 0.94 and an estimated recall of 0.84. Symptoms with the highest frequency included pain (43.1%), anxiety (25.8%), depression (24.0%), fatigue (23.4%), joint pain (21.0%), shortness of breath (20.8%), headache (20.0%), nausea and/or vomiting (19.9%), myalgia (19.0%), and gastroesophageal reflux (18.6%). Highlights •Research focused on post-acute sequelae of COVID-19 (PASC) symptoms. •A large COVID-19 cohort in electronic health records (EHR) was followed for post-infection sequalae. •Ontology, EHR data and natural language processing were used for lexicon development. •Symptom lexicon can support NLP to extract PASC symptoms from clinical notes.	todo
175	D172		Phillip H.RothaMariacarlaGadebusch-Bondio	The contested meaning of “long COVID” – Patients, doctors, and the politics of subjective evidence	https://doi.org/10.1016/j.socscimed.2021.114619	Published	30 November 2021	Article	https://www.sciencedirect.com/science/article/pii/S0277953621009515	Highlights •Experiential knowledge can fill crucial gaps in the pandemic discourse. •Long COVID online self-advocacy provides a rich source of subjective evidence. •Patient subjective evidence is challenging the normative role of clinical evidence. •Activism made long COVID diagnosis as a requirement for recognition obsolete. In our article, we reconstruct how the patient-made term “long COVID” was able to become a widely accepted concept in public discourses. While the condition was initially invisible to the public eye, we show how the mobilization of subjective evidence online, i.e., the dissemination of reports on the different experiences of lasting symptoms, was able to transform the condition into a crucial feature of the coronavirus pandemic. We explore how stakeholders used the term “long COVID” in online media and in other channels to create their illness and group identity, but also to demarcate the personal experience and experiential knowledge of long COVID from that of other sources. Our exploratory study addresses two questions. Firstly, how the mobilization of subjective evidence leads to the recognition of long COVID and the development of treatment interventions in medicine; and secondly, what distinguishes these developments from other examples of subjective evidence mobilization. We argue that the long COVID movement was able to fill crucial knowledge gaps in the pandemic discourses, making long COVID a legitimate concern of official measures to counter the pandemic. By first showing how illness experiences were gathered that defied official classifications of COVID-19, we show how patients made the “long COVID” term. Then we compare the clinical and social identity of long COVID to that of chronic fatigue syndrome (ME/CFS), before we examine the social and epistemic processes at work in the digital and medial discourses that have transformed how the pandemic is perceived through the lens of long COVID. Building on this, we finally demonstrate how the alignment of medical professionals as patients with the movement has challenged the normative role of clinical evidence, leading to new forms of medical action to tackle the pandemic.	_
176	D173		Olga A.Sukochevaab1RebekahMaksoudbc1Narasimha M.BeerakadSabbaRao V.MadhunapantuladeMikhailSinelnikovfVladimir N.NikolenkofMargarita E.NeganovagSergey G.KlochkovgMohammadAmjad KamalhiSonyaMarshall-GradisnikbcDonald RStaines	Analysis of post COVID-19 condition and its overlap with myalgic encephalomyelitis/chronic fatigue syndrome	https://doi.org/10.1016/j.jare.2021.11.013	Published	26 November 2021	Review	https://www.sciencedirect.com/science/article/pii/S2090123221002320	Considering the pandemic is still ongoing, more time is required to confirm post COVID-19 condition diagnosis in the COVID-19 infected cohorts, although many reported post COVID-19 symptoms overlap with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).	_
177	D174		Emily R. Pfaff, Andrew T. Girvin, Tellen D. Bennett,, Abhishek Bhatia, Ian M. Brooks, Rachel R. Deer, Jonathan P. Dekermanjian, Sarah Elizabeth Jolley, Michael G. Kahn, Kristin Kostka, Julie A. McMurry, Richard Moffitt, Anita Walden, Christopher G. Chute, Melissa A. Haendel	Who has long-COVID? A big data approach [preprint]	https://doi.org/10.1101/2021.10.18.21265168	pre-print	2021-10-22	Study	https://escholarship.umassmed.edu/umccts_pubs/253/	Findings Our models identified potential long-COVID patients with high accuracy, achieving areas under the receiver operator characteristic curve of 0.91 (all patients), 0.90 (hospitalized); and 0.85 (non-hospitalized). Important features include rate of healthcare utilization, patient age, dyspnea, and other diagnosis and medication information available within the EHR. Applying the “all patients” model to the larger N3C cohort identified 100,263 potential long-COVID patients. Interpretation Patients flagged by our models can be interpreted as “patients likely to be referred to or seek care at a long-COVID specialty clinic,” an essential proxy for long-COVID diagnosis in the current absence of a definition. We also achieve the urgent goal of identifying potential long-COVID patients for clinical trials. As more data sources are identified, the models can be retrained and tuned based on study needs.	_
178	D175		Corey H. Basch, Eunsun Park, Betty Kollia & Nasia Quinones	Online News Coverage of COVID-19 Long Haul Symptoms	https://doi.org/10.1007/s10900-021-01053-5	Published	03 December 2021	Study	https://link.springer.com/article/10.1007/s10900-021-01053-5	The purpose of this study was to describe the content of news coverage of COVID-19 long haul symptoms currently posted on the internet. This study utilized Google News, a news aggregator service, and included the first 100 English language pieces of news. Video content and news article content were coded in depth for information on COVID-19 long haul symptoms. A total of 41% of news reports mentioned the length of time that the COVID-19 related symptoms persist. The length of time was reported to range from 1 month to more than 1 year. The symptom most commonly mentioned was tiredness or fatigue (74%), followed by difficulty breathing or shortness of breath (62 cases; 62%), and difficulty thinking or concentrating (50 cases; 50%). Other symptoms were mentioned less frequently. There were no statistically significant differences in any of the content including having video, written news reports, or both video and written news reports by source of the news reports based on consumer, professional, or television or internet-based news (p = .14). More complete coverage by online news media of the long-term effects of COVID-19 enhances public awareness of the post-acute syndromes, augments health providers’ awareness of the range of chronic COVID-19 effects and the possibility of a second infection, increases the probability of patients’ seeking and obtaining the proper care for their symptoms, and contributes to preventive actions for enhancing public health.
179	D176		Janet V Diaz,corresponding author a Margaret Herridge, b Silvia Bertagnolio, c Hannah E Davis, d Tarun Dua, e Charu Kaushic, f John C Marshall, g Maria del Rosario Pérez, a Nathalie Strub-Wourgaft, h and Joan B Soriano a	Towards a universal understanding of post COVID-19 condition	https://dx.doi.org/10.2471%2FBLT.21.286249	Published	2021 Oct 5	Article	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640686/	Finally, this work must be multicentre and multidisciplinary, and involve international cooperation. Collecting standardized and harmonized data on post COVID-19 condition will be paramount, as available published studies are small, heterogeneous in nature, too short in their follow-up, and with narrow focus on a few organ systems assessed. To support systematic collection of comparable data across the world, WHO has developed a Global Clinical Platform and standardized case report forms for acute COVID-19 and post COVID-19 condition that are available for all Member States and interested parties.27 Data should be synthesized to extend the available collective experience with this condition and its insights, and should be meta-analysed to enlarge the available experience from a few hundred person-years’ experience to many more orders of magnitude. Data sharing should be undertaken in the broadest sense, to include experience in all affected patients and in subgroups by demographic and clinical variables. Technologies analysing large data sets and tools of artificial intelligence applied directly to text of electronic health records are already available to be used.28 Follow-up from existing trials that randomized patients less than one year ago could be of enormous value, with little investment required to support data collection. The recent National Institutes for Health announcement of specific funds and setting up a biospecimen bank will steer research and researchers on this topic.29 Multinational data sharing should be promoted to ensure broad demographics, variable case mix with diverse genetics and the effects of distinct health-care systems and access to treatments. Making sense of heterogeneous data sources and their appropriate interpretation are both a challenge and part of the final solution to better understand post-COVID-19 condition.	_
180	D177		Philip Hunter	Navigating the social identity of long covid	https://doi.org/10.1136/bmj.n2933	Published	26 November 2021	Opinion	https://www.bmj.com/content/375/bmj.n2933	Medical research into the pathophysiology of long covid, and how it can be treated is urgently needed, but it is also essential to consider social factors that may be implicated in the recovery of the millions of people with long covid across the world. It is not possible to holistically understand any individual’s experiences, without understanding their connection and place within the broader community around them. Research shows that social connections and belonging are essential determinants of health and wellbeing.	_
181	D178		Susanne Rabady, Johann Altenberger, Markus Brose, Doris-Maria Denk-Linnert, Elisabeth Fertl, Florian Götzinger, Maria de la Cruz Gomez Pellin, Benedikt Hofbaur, Kathryn Hoffmann MPH, MD, Renate Hoffmann-Dorninger MD, Rembert Koczulla, Oliver Lammel, Bernd Lamprecht, Judith Löffler-Ragg, Christian A. Müller, Stefanie Poggenburg, Hans Rittmannsberger, Paul Sator, Volker Strenger, Karin Vonbank, Johannes Wancata, Thomas Weber, Jörg Weber, Günter Weiss, Maria Wendler & Ralf-Harun Zwick	Leitlinie S1: Long COVID: Differenzialdiagnostik und Behandlungsstrategien	https://doi.org/10.1007/s00508-021-01974-0	Published	01 December 2021	Guideline	https://link.springer.com/article/10.1007%2Fs00508-021-01974-0	This guideline comprises the state of science at the time of the editorial deadline. In view of the high turnover of knowledge the guideline is designed as a living guideline. The main objective was to provide a tool for the use in primary care, being considered well suited as a first point of entry and for the provision of care. The guideline gives recommendations on the differential diagnosis of symptoms following SARS-CoV‑2 infection, on their therapeutic options, as well as for guidance and care of the patients concerned. It also offers advice concerning return to daily life and rehabilitation. Long COVID being a very variable condition, we chose an interdisciplinary approach.	_
182	D179		Elisa Perego	Patient made Long Covid empowers the patient voice	https://doi.org/10.31235/osf.io/796am	pre-print	December 22, 2021	Article	https://osf.io/preprints/socarxiv/796am/	Successful, patient-driven advocacy and research in Long Covid is contributing to change our understanding of SARS-CoV-2 infection, viral-onset diseases, and knowledge building in medicine and beyond. Events and epistemic shifts surrounding the rise of Long Covid represent a massive opportunity for empowering the patient voice. Strategies that have proven key to grassroots Long Covid advocacy in our digital era could be further explored and expanded across different patient communities. It is my hope that patient-centred expertise will be further incorporated into the biomedical community. This would contribute to critical changes in medical awareness of chronic diseases and patient care.	_
183	D180		Aditya Gupta, Vibha Jain & Amritpal Singh	Stacking Ensemble-Based Intelligent Machine Learning Model for Predicting Post-COVID-19 Complications	https://doi.org/10.1007/s00354-021-00144-0	Published	14 December 2021	Study	https://link.springer.com/article/10.1007/s00354-021-00144-0	In this article, a stacking ensemble learning technique based on deep neural networks is proposed for the early prediction of heart disease in COVID-19 survivors. The proposed model is trained using heart-related data collected from COVID-19 survivors under a tenfold cross-validation framework. The proposed model is tested and the performance is compared with different baseline machine learning algorithms. Various performance evaluation metrics, namely accuracy, specificity, precision, and recall, are used for performance measurement. In addition, two statistical measures are evaluated, namely, the root mean square error (RMSE) and the mean absolute error (MAE). The proposed stacking ensemble strategy achieves an accuracy of 93.23% while predicting heart disease. Moreover, the results of specificity (95.74%), precision (95.24%), and recall (92.05%) show the improved performance of the proposed approach in comparison to baseline learning algorithms.	_
184	D181		Anthony S David	Long covid: research must guide future management	https://doi.org/10.1136/bmj.n3109	Published	17 December 2021	Opinion	https://www.bmj.com/content/375/bmj.n3109	Emerging evidence suggests that long-covid is as likely to follow mild and even unconfirmed infection as severe illness requiring hospitalisation and respiratory support, although population-based studies on non-hospitalised cases are required to complete the picture.4 New preliminary data suggest that people admitted to hospital with covid-19 who reported long covid symptoms had made only limited improvement after a full year.5 The demographic risk factors for covid-19 illness: age, male sex, ethnic minority status, underlying medication conditions, etc., do not seem to apply to post-covid syndrome.6 This all points to the need to improve our understanding of post-covid syndrome. UKRI-funded research using established clinical databases and longitudinal cohorts should seek to clarify these questions. Will the new long-covid multidisciplinary teams be the setting of a never-ending journey round in circles or will they have the courage to accept uncertainty? Increasing evidence shows organ damage and pathological changes post covid, and we must be aware of many patients who have severe and debilitating fatigue and have not been believed or offered much help at all. But we must also remain open minded that some multi-symptom presentations may not be due to hitherto unidentified multi-system pathologies (with negative investigations), but a singular mechanism of heightened awareness of bodily sensations and objective malfunctions.	_
185	D182		Rita Smith	Long COVID: The Pandemic Aftermath		Published	Décembre 2021	Article	https://www.phnurse.org/assets/docs/Smith%20Rita%20Long%20Covid%20Article%20FLNursQ%202021%20APHN%20Post%20121521.pdf	History of Long COVID	_
186	D183		Pasquale Ambrosino 1 ,Anna Lanzillo 2 andMauro Maniscalco 3,*	COVID-19 and Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications	https://doi.org/10.3390/biomedicines10010047	Published	27 December 2021	Editorial	https://www.mdpi.com/2227-9059/10/1/47/htm	Growing evidence suggests a central role of endothelial dysfunction and systemic inflammation in the pathogenesis of most COVID-19 manifestations [4]. Accordingly, persistent endothelial dysfunction and a prolonged inflammatory response have been documented even after the acute phase [5]. However, the pathophysiological mechanisms determining the acute and post-acute manifestations of COVID-19 are still a matter requiring study, given that a better understanding of these mechanisms would allow for the implementation of more effective personalized approaches. In this Special Issue, we aimed to collect a number of original research articles and reviews on the pathophysiology and diagnostics of COVID-19 and post-acute COVID-19 syndrome, with a focus on new prognostic and therapeutic applications.
187	D184		Anita Slomski	Belief in Having Had COVID-19 Linked With Long COVID Symptoms	https://doi.org/10.1001/jama.2021.23318	Published	January 4, 2022	Article	https://jamanetwork.com/journals/jama/article-abstract/2787741	Researchers analyzed survey data and serology results from 26 823 adults in France. They found no relationship between the participants’ belief about whether they’d had COVID-19 and their antibody test results from blood samples collected between May and November 2020.	_
188	D185		Akshara Ramasamy	How Does Gender Impact Long COVID?		Published	January 2022	Article	http://sites.utexas.edu/melamed-lab/2021/12/20/how-does-gender-impact-long-covid/	Current evidence suggests that COVID-19 may trigger an autoimmune reaction in some people, which might explain why the syndrome tends to be more frequent in women (i.e. as women are more likely to develop autoimmune diseases).5 According to a study by women’s health experts Dr. Sabra Klein and Dr. Katie Flanagan, women tend to have stronger immune systems than men and greater vaccine efficacy as a result.6 While a robust immune response may be helpful in the early stages of a COVID-19 infection, it may also make women more susceptible to long-term autoimmune problems (as autoimmunity is thought to arise due to a mistaken overzealous immune response against the body’s self proteins, leading to damage of different body systems). Researchers are now looking into the role of estrogen in long COVID development as one possible factor that may explain differences in immunological responses between men and women. A study from King’s College in London reported that post-menopausal women between the ages of 50 and 60 with low levels of estrogen were found to be at the most risk for long-term COVID symptoms.7 This hormone interacts with the immune system in a variety of ways, including regulating the creation of immune cells and their response to infection. Consequently, sex hormones may be one potential link that could explain the significant differences and immune mechanisms involved in long COVID in women and men.	_
189	D186		Eric Lyerly Esq.	Long COVID: Accommodating a slippery fish	https://doi.org/10.1002/cala.40712	Published	10 January 2022	Article	https://onlinelibrary.wiley.com/doi/10.1002/cala.40712	Post-COVID conditions, long COVID, long-haul COVID, post-acute COVID, chronic COVID — these names each refer to the long-term effects of a COVID-19 infection. The Centers for Disease Control describes long COVID as a “wide range of new, returning, or ongoing health problems” related to COVID-19.	_
190	D187		Kieran L. Quinn ,Chaim M. Bell	Pandemic health consequences: Grasping the long COVID tail	https://doi.org/10.1371/journal.pmed.1003891	Published	January 25, 2022	Article	https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1003891	Early pandemic public messaging strategies focused on flattening the peak of the acute COVID-19 infection curve to preserve healthcare system capacity and its ability to deliver high-quality care. These efforts were generally successful. To preserve ongoing system capacity and provide high-quality patient care, the long COVID tail does not require further flattening, but rather demands new clinical and health policy strategies to address its potential for long-term suffering. Here, we must recognize that the head of the pandemic often demands our immediate attention, but we must not ignore its long and deadly tail.
191	D188		Chris Baraniuk	Covid-19: How Europe is approaching long covid	https://doi.org/10.1136/bmj.o158	Published	20 January 2022	Article	https://www.bmj.com/content/376/bmj.o158.full	In the UK, there are more than 80 NHS run long covid clinics. Long covid services were highlighted as part of £6.6bn in new funding announced in March 2021 for the ongoing NHS response to the pandemic.3 Separately, the Scottish government has announced £10m in funding for local health boards to help patients who have long term symptoms. In the European Union, specialist long covid clinics are reported to be operating in Belgium, France, Germany, and Spain, among others, but these rarely cater for more than a small part of the population. In Italy, no government funded clinics for long covid have yet been established, according to Danilo Buonsenso at Gemelli University Hospital in Rome, although some hospitals have day clinics for following up patients who had been admitted to hospital during the acute stage of covid-19. A few of the day clinics include patients who have no history of hospital admission for covid-19, however, “the waiting list is incredibly high,” Buonsenso adds. In May 2021, the Italian government allocated around €28m for 2021 and €24m for 2022, to the “respiratory care” of covid-19 patients who had been admitted to hospital.4 In July, Italy’s National Institute of Health (ISS) published a report on interim indications on long covid management,5 which refers to the need for specialist “post-covid clinics” as well as facilities linked to general practice and hospitals. The French National Authority for Health (HAS) published official guidelines for the follow-up of long covid patients in February 2021, stating that most can be followed up through primary care.
192	D189		DominiqueSALMON CÉRONabBenjaminDAVIDOcRolandTUBIANAdeFrançoiseLINARDaCatherine TOURETTETURGISfPaulineOUSTRICghAlainSOBELaiAntoineCHERETjk	Les formes prolongées de la COVID-19 ou COVID long : formes cliniques et prise en chargeLong COVID : clinical forms and management	https://doi.org/10.1016/j.mmifmc.2021.12.001	Published	21 January 2022	Article	https://www.sciencedirect.com/science/article/abs/pii/S2772743221000118	L'origine de ces symptômes n'est pas encore élucidée et certaines hypothèses sont en cours d'exploration, comme par exemple une persistance virale qui a été démontrée dans certains cas, une réponse inflammatoire notamment mastocytaire excessive, ou bien un défaut de l'immunité innée ou adaptative. Des facteurs génétiques et hormonaux sont possiblement associés. La prise en charge des patients doit être initiée dès le premier recours aux soins. Suite à une analyse approfondie des symptômes, des diagnostics seront portés et feront l'objet d'une prise en charge multidisciplinaire où les traitements symptomatiques et la rééducation tiennent une place importante. Si le recours à l'hospitalisation est rare, ces formes prolongées, maintenant appelées « COVID long », vont avoir un impact sociétal majeur nécessitant la mise en place de politiques publiques adaptées.
193	D190		Theoharis C. Theoharides	Could SARS-CoV-2 Spike Protein Be Responsible for Long-COVID Syndrome?	https://doi.org/10.1007/s12035-021-02696-0	Published	13 January 2022	Article	https://link.springer.com/article/10.1007/s12035-021-02696-0	However, increasing evidence indicates that many patients develop a chronic condition characterized by fatigue and neuropsychiatric symptoms, termed long-COVID. Most of the vaccines produced so far for COVID-19 direct mammalian cells via either mRNA or an adenovirus vector to express the spike protein, or administer recombinant spike protein, which is recognized by the immune system leading to the production of neutralizing antibodies. Recent publications provide new findings that may help decipher the pathogenesis of long-COVID. One paper reported perivascular inflammation in brains of deceased patients with COVID-19, while others showed that the spike protein could damage the endothelium in an animal model, that it could disrupt an in vitro model of the blood-brain barrier (BBB), and that it can cross the BBB resulting in perivascular inflammation. Moreover, the spike protein appears to share antigenic epitopes with human molecular chaperons resulting in autoimmunity and can activate toll-like receptors (TLRs), leading to release of inflammatory cytokines. Moreover, some antibodies produced against the spike protein may not be neutralizing, but may change its conformation rendering it more likely to bind to its receptor. As a result, one wonders whether the spike protein entering the brain or being expressed by brain cells could activate microglia, alone or together with inflammatory cytokines, since protective antibodies could not cross the BBB, leading to neuro-inflammation and contributing to long-COVID. Hence, there is urgent need to better understand the neurotoxic effects of the spike protein and to consider possible interventions to mitigate spike protein-related detrimental effects to the brain, possibly via use of small natural molecules, especially the flavonoids luteolin and quercetin.
194	D191		Olcay Y. Jones 1,* andSencer Yeralan 2,*	Is Long COVID a State of Systemic Pericyte Disarray?	https://doi.org/10.3390/jcm11030572	Published	24 January 2022	Article	https://www.mdpi.com/2077-0383/11/3/572/htm	The most challenging aspect of Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) or Long COVID remains for the discordance between the viral damage from acute infection in the recent past and susceptibility of Long COVID without clear evidence of post infectious inflammation or autoimmune reactions. In this communication we propose that disarray of pericytes plays a central role in emerge of Long COVID. We assume pericytes are agents with “Triple-A” qualities, i.e., analyze-adapt and advance, necessary for sustainability of host homeostasis. Based on this view, we further suggest Long COVID may provide a model system to integrate system theory and complex adaptive systems to explore a new class of maladies those are currently not well defined and with no remedies.
195	D192		Riccardo Cau Gavino Faa Valentina Nardi Antonella Balestrieri Josep Puig Jasjit S Suri Roberto SanFilippo Luca Saba	Long-COVID diagnosis: from diagnostic to advanced AI-driven models	https://doi.org/10.1016/j.ejrad.2022.110164	Published	January 17, 2022	Review	https://www.ejradiology.com/article/S0720-048X(22)00014-6/fulltext	Highlights •Among COVID-19 survivors, a fraction of patients reports persistent symptoms related to multiorgan involvement. •Time and resources will be needed to help clinicians understand and manage long-term COVID-19 sequelae. •Artificial intelligence in COVID-19 evaluation is promising for different tasks, including. image analysis, decision-making and prognosis prediction. Abstract SARS-COV 2 is recognized to be responsible for a multi-organ syndrome. In most patients, symptoms are mild. However, in certain subjects, COVID-19 tends to progress more severely. Most of the patients infected with SARS-COV2 fully recovered within some weeks. In a considerable number of patients, like many other viral infections, various long-lasting symptoms have been described, now defined as “long COVID-19 syndrome”. Given the high number of contagious over the world, it is necessary to understand and comprehend this emerging pathology to enable early diagnosis and improve patents outcomes. In this scenario, AI-based models can be applied in long-COVID-19 patients to assist clinicians and at the same time, to reduce the considerable impact on the care and rehabilitation unit. The purpose of this manuscript is to review different aspects of long-COVID-19 syndrome from clinical presentation to diagnosis, highlighting the considerable impact that AI can have.
196	D193		Yapeng Su 28 Dan Yuan 28 Daniel G. Chen 28 Rachel H. Ng Kai Wang Jongchan Choi Sarah Li Sunga Hong Rongyu Zhang Jingyi Xie Sergey A. Kornilov Kelsey Scherler Ana Jimena Pavlovitch-Bedzyk Shen Dong Christopher Lausted Inyoul Lee Shannon Fallen hengzhen L. Dai Priyanka Baloni Brett Smith Venkata R. Duvvuri Kristin G. Anderson Jing Li 9 Biobanking Unit, Terri Wrin Christos J. Petropoulos Hunter R. Cole Trevan D. Fischer Wei Wei Dave S.B. Hoon Nathan D. Price Naeha Subramanian Joshua A. Hill Jennifer Hadlock Andrew T. Magis Antoni Ribas Lewis L. Lanier Scott D. Boyd Jeffrey A. Bluestone Helen Chu Leroy Hood Raphael Gottardo Philip D. Greenberg Mark M. Davis Jason D. Goldman James R. Heath	Multiple Early Factors Anticipate Post-Acute COVID-19 Sequelae	https://doi.org/10.1016/j.cell.2022.01.014	Published	January 24, 2022	Study	https://www.cell.com/cell/fulltext/S0092-8674(22)00072-1	Highlights Longitudinal multiomics associate PASC with autoantibodies, viremia and comorbidities Reactivation of latent viruses during initial infection may contribute to PASC Subclinical autoantibodies negatively correlate with anti-SARS-CoV-2 antibodies Gastrointestinal PASC uniquely present with post-acute expansion of cytotoxic T cells SUMMARY Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk-factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data, and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific autoantibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.
197	D194	VP	Dominique Grandjean, Dorsaf Slama, Capucine Gallet, Clothilde Julien, Emilie Seyrat, Marc Blondot, Judith Elbaz, Maissa Benazaiez, View ProfileDominique Salmon	Screening for SARS-CoV-2 persistence in Long COVID patients using sniffer dogs and scents from axillary sweats samples	https://doi.org/10.1101/2022.01.11.21268036	pre-print	January 12, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.01.11.21268036v1	Objectives Dogs can be trained to identify several substances not detected by humans, corresponding to specific volatile organic compounds (VOCs). The presence of VOCs, triggered by SARS-CoV-2 infection, was tested in sweat from Long COVID patients. Patients and methods An axillary sweat sample of Long COVID patients and of COVID-19 negative, asymptomatic individuals was taken at home to avoid any hospital contact. Swabs were randomly placed in olfaction detection cones, and the material sniffed by at least 2 trained dogs. Results Forty-five Long COVID patients, mean age 45 (6-71), 73.3% female, with prolonged symptoms evolving for a mean of 15.2 months (5-22) were tested. Dogs discriminated in a positive way 23/45 (51.1%). Long COVID patients versus 0/188 (0%) control individuals (p<.0001). Conclusion This study suggests the persistence of a viral infection in some Long COVID patients and the possibility of providing a simple, highly sensitive, non-invasive test to detect viral presence, during acute and extended phases of COVID-19.
198	D195		Jaskiran Kaur Bhogal, Freya Mills, Amelia Dennis, Cristina Spoiala, Joanna Milward, Sidra Saeed, Leah Ffion Jones, Dale Weston, Holly Carter	The Effects of Messaging on Expectations and Understanding of Long COVID: An Online Randomised Trial	https://doi.org/10.1101/2022.01.18.22269467	pre-print	January 23, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.01.18.22269467v1	Interventions Participants were presented with a scenario describing a positive COVID-19 test result and then presented with one of eight scenarios describing a Long COVID diagnosis. Primary and Secondary Outcome Measures Various outcome measures relating to illness expectations were captured including: symptom severity, symptom duration, quality of life, personal control, treatment control and illness coherence. Results We ran a series of 2 × 2 × 2 ANOVAs on the outcome variables. We found a main effect of illness description: individuals reported longer symptom duration and less illness coherence when the illness was described as Long COVID (compared to ongoing COVID-19 recovery). There was a main effect of illness uncertainty: when uncertainty was emphasised, participants reported longer expected symptom duration, less treatment control, and less illness coherence than when uncertainty was not emphasised. There was also a main effect of efficacy of support: participants reported higher personal control and higher treatment control when support was enhanced (compared to basic support). We also found an interaction between illness description and efficacy of support: when support was enhanced, participants reported less illness coherence for Long COVID (compared to ongoing COVID-19 recovery). Conclusions Communications around Long COVID should not emphasise symptom uncertainty and should provide people with information on how they can facilitate their recovery and where they can access additional support. The findings also suggest that use of the term ongoing COVID-19 recovery, where possible, may reduce negative expectations associated with the illness.
199	D196		NIPH	COVID-19: Post COVID-19 condition. A rapid review		Published	18.01.2022	Review	https://www.fhi.no/en/publ/2022/COVID-19-Post-COVID-19-condition/	In this rapid review, we summarise research on the proportion of patients who get long-term symptoms, which long-term symptoms occur after COVID-19, how long the symptoms persist and which patient groups that have the greatest risk of experiencing long-term symptoms.
200	D197		Bevyn Jarrott,Richard Head,Kirsty G. Pringle,Eugenie R. Lumbers,Jennifer H. Martin	“LONG COVID”—A hypothesis for understanding the biological basis and pharmacological treatment strategy	https://doi.org/10.1002/prp2.911	Published	13 January 2022	Review	https://bpspubs.onlinelibrary.wiley.com/doi/10.1002/prp2.911	Infection of humans with SARS-CoV-2 virus causes a disease known colloquially as “COVID-19” with symptoms ranging from asymptomatic to severe pneumonia. Initial pathology is due to the virus binding to the ACE-2 protein on endothelial cells lining blood vessels and entering these cells in order to replicate. Viral replication causes oxidative stress due to elevated levels of reactive oxygen species. Many (~60%) of the infected people appear to have eliminated the virus from their body after 28 days and resume normal activity. However, a significant proportion (~40%) experience a variety of symptoms (loss of smell and/or taste, fatigue, cough, aching pain, “brain fog,” insomnia, shortness of breath, and tachycardia) after 12 weeks and are diagnosed with a syndrome named “LONG COVID.” Longitudinal clinical studies in a group of subjects who were infected with SARS-CoV-2 have been compared to a non-infected matched group of subjects. A cohort of infected subjects can be identified by a battery of cytokine markers to have persistent, low level grade of inflammation and often self-report two or more troubling symptoms. There is no drug that will relieve their symptoms effectively. It is hypothesized that drugs that activate the intracellular transcription factor, nuclear factor erythroid-derived 2-like 2 (NRF2) may increase the expression of enzymes to synthesize the intracellular antioxidant, glutathione that will quench free radicals causing oxidative stress. The hormone melatonin has been identified as an activator of NRF2 and a relatively safe chemical for most people to ingest chronically. Thus, it is an option for consideration of re-purposing studies in “LONG COVID” subjects experiencing insomnia, depression, fatigue, and “brain fog” but not tachycardia. Appropriately designed clinical trials are required to evaluate melatonin.
201	D198	ME	Todd E. Davenport Staci R. Stevens Jared Stevens Christopher R. Snell J. Mark Van Ness	We Already Know Enough to Avoid Making the Same Mistakes Again With Long COVID	https://doi.org//10.2519/jospt.blog.20210310	Published	March 10, 2021	Article	https://www.jospt.org/do/10.2519/jospt.blog.20210310/full/	Based on experience with past coronaviruses, the emerging challenge of prolonged symptoms after infection with the novel coronavirus 2019 (SARS-CoV-2) is unsurprising. Data from a large international web-based patient survey indicate substantial symptom overlap between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) at 6 months following the onset of first symptoms, including three quarters of participants suffering from fatigue and postexertional malaise, and over half with cognitive dysfunction.4 Apparent similarities between the presentations of long COVID and ME/CFS suggest that we may apply what we have learned from ME/CFS to long COVID.
202	D199	ME - PESE	Todd E. Davenport Staci R. Stevens Jared Stevens Christopher R. Snell J. Mark Van Ness	Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID: Postexertional Symptom Exacerbation is an Abnormal Response to Exercise/Activity	https://doi.org//10.2519/jospt.blog.20220202	Published	February 2, 2022	Article	https://www.jospt.org/do/10.2519/jospt.blog.20220202	Prolonged symptoms after infection with the novel coronavirus 2019 (SARS-COV-2) are an emerging challenge to individual patients, society, and clinicians. In a previous post on the JOSPT Blog, we identified several lessons from research and clinical practice in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) that are important lessons for long COVID. The purpose of this post is to discuss the phenomenon of postexertional symptom exacerbation (PESE) and its clinical identification to recognize the potential onset of long COVID. Data from a large international web-based patient survey indicate substantial symptom overlap between postacute SARS-COV-2 infection (long COVID) and ME/CFS at 6 months following the onset of first symptoms. Three quarters of respondents noted disabling fatigue and over half noted cognitive dysfunction.4 A unique finding of this survey was that 75% of respondents noted PESE, which is a worsening of symptoms after activity/exercise.4 PESE is foundational to the diagnosis of ME/CFS and it is common with long COVID.4,5 This observation suggests we can further extend lessons from ME/CFS to develop our understanding of long COVID.
203	D200	ME - PESE	Todd E. Davenport Staci R. Stevens Jared Stevens Christopher R. Snell J. Mark Van Ness	Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 2: Physiological Characteristics During Acute Exercise Are Abnormal in People With Postexertional Symptom Exacerbation	https://doi.org//10.2519/jospt.blog.20220209	Published	February 9, 2022	Article	https://www.jospt.org/do/10.2519/jospt.blog.20220209	In a previous post on the JOSPT Blog, we outlined the connection between postacute sequalae to novel coronavirus (long COVID) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) through their common clinical presentation: postexertional symptom exacerbation (PESE). PESE suggests the presence of abnormal physiological responses to exercise/activity. These physiological responses may be measured using cardiopulmonary exercise testing (CPET), which allows for careful characterization of cardiac, pulmonary, and metabolic functioning during exercise. We will review the characteristic findings on CPET in people with PESE.
204	D201	ME - PESE	Todd E. Davenport Staci R. Stevens Jared Stevens Christopher R. Snell J. Mark Van Ness	Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 3: “Energy System First Aid” for People With Postexertional Symptom Exacerbation	https://doi.org//10.2519/jospt.blog.20220216	Published	February 16, 2022	Article	https://www.jospt.org/do/10.2519/jospt.blog.20220216	In a previous post, we demonstrated that the symptoms and physiology of postexertional symptom exacerbation (PESE) are inconsistent with deconditioning. PESE worsens in response to exercise and demonstrates a variable clinical presentation. We will build a clinical rationale for energy system first aid as a place to start helping people with PESE. Graded Exercise May Be Harmful to People With PESE It is not surprising that patients with PESE frequently report worsening symptoms and function with exercise prescribed based on time and activity quotas,1 based on the physiological evidence. The United Kingdom’s Pacing, graded Activity, and Cognitive behaviour therapy, a randomized Evaluation (UK PACE) compared the clinical outcomes of specialist medical care, adaptive pacing, and graded exercise therapy (GET) in 641 people with idiopathic, disabling fatigue.9 In this study, GET was a quota-based progressive exercise program, where subjects incrementally increased exercise regardless of symptoms. PESE was not a specific recruitment criterion for this trial.8,9 The trial did not adhere to the published protocol, without appropriate justification. The raw data was independently reanalyzed according to the original protocol,10 Upon reanalysis, most symptomatic and functional outcome findings from the UK PACE trial did not reach thresholds for clinical relevance. Many ME/CFS experts contend the results of GET are marginal, probably not clinically relevant or beneficial.10 Despite the important concerns of the UK PACE trial, the trial continues to exert outsized influence on clinical guidelines.3 Some countries' systems developed formal treatment pathways based on flawed results. Treatment pathways involving GET may have exposed an untold number of patients with ME/CFS worldwide to a GET program that, at best, is marginally effective, and at worst, may be harmful. Recent clinical guidelines for people with PESE, such as long COVID, no longer involve GET.6,7 These omissions reflect the ongoing re-evaluation of how clinical care should proceed for people with PESE, including people with long COVID. Implicit to this re-evaluation is a further reflection on the generally accepted idea that "movement is medicine" in a way that universally benefits clinical populations.
205	D202		Duerlund LS , Shakar S, Nielsen H , Bodilsen J	Positive Predictive Value of the ICD-10 Diagnosis Code for Long-COVID	https://doi.org/10.2147/CLEP.S344515	Published	9 February 2022	Study	https://www.dovepress.com/positive-predictive-value-of-the-icd-10-diagnosis-code-for-long-covid-peer-reviewed-fulltext-article-CLEP	Purpose: To examine the positive predictive value (PPV) of International Classification version 10 (ICD-10) diagnosis codes for long coronavirus disease 2019 (long-COVID) in a Danish Health registry. Patients and Methods: This was a medical record review of all patients with a diagnosis code of long-COVID (DB948A) at all hospitals in the North Denmark Region from February 27, 2020 through June 30, 2021. Confirmed long-COVID was categorized as fulfillment of all three criteria: (1) a positive polymerase chain reaction (PCR) test for SARS-CoV-2 on a respiratory sample or a positive serum antibody test, (2) symptoms suggestive of long-COVID with no other diagnosis considered more likely, and (3) symptom duration > 6 weeks. Results: A total of 306 patients were assigned a hospital diagnosis code for long-COVID corresponding to 1.4% of all SARS-CoV-2 positive individuals during the study period (n=21,727). Next, 40 patients were excluded due to incomplete diagnostic evaluation at time of record review leaving 266 patients for analysis. The patients had a median age of 51 years (interquartile range 43– 60) and 175/266 (66%) were females. Long-COVID was confirmed in 249/266 yielding an overall PPV of 94% (95%CI: 90– 96) and did not differ substantially according to most age groups, sex, previous hospitalization for COVID-19, or by using 12 weeks of symptom duration as cut-off. The PPV was low for children and adolescents (n=5), the very elderly (n=9), and those included by secondary long-COVID diagnoses (n=10). Conclusion: The overall PPV of diagnosis codes for long-COVID in the North Denmark Region was high and was likely suitable for future registry-based studies of long-COVID. Caution is advised at the extremes of age and secondary diagnosis codes.
206	D203		Eugenie R. Lumbers1,2 \| Richard Head3 \| Gary R. Smith4 \| Sarah J. Delforce1,2 \| Bevyn Jarrott5 \| Jennifer H. Martin2,6 \| Kirsty G. Pringle	The interacting physiology of COVID-19 and the reninangiotensin-aldosterone system: Key agents for treatment	https://doi.org/10.1002/prp2.917	Published	29 November 2021	Review	https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1002/prp2.917	SARS-CoV-2 interacting with its receptor, angiotensin-converting enzyme 2 (ACE2), turns the host response to viral infection into a dysregulated uncontrolled inflammatory response. This is because ACE2 limits the production of the peptide angiotensin II (Ang II) and SARS-CoV-2, through the destruction of ACE2, allows the uncontrolled production of Ang II. Recovery from trauma requires activation of both a tissue response to injury and activation of a whole-body response to maintain tissue perfusion. Tissue and circulating renin-angiotensin systems (RASs) play an essential role in the host response to infection and injury because of the actions of Ang II, mediated via its AT1 receptor. Both tissue and circulating arms of the renin angiotensin aldosterone system's (RAAS) response to injury need to be regulated. The effects of Ang II and the steroid hormone, aldosterone, on fluid and electrolyte homeostasis and on the circulation are controlled by elaborate feedback networks that respond to alterations in the composition and volume of fluids within the circulatory system. The role of Ang II in the tissue response to injury is however, controlled mainly by its metabolism and conversion to Ang-(1-7) by the enzyme ACE2. Ang-(1-7) has effects that are contrary to Ang II-AT1R mediated effects. Thus, destruction of ACE2 by SARS-CoV-2 results in loss of control of the pro-inflammatory actions of Ang II and tissue destruction. Therefore, it is the response of the host to SARS-CoV-2 that is responsible for the pathogenesis of COVID-19.
207	D204		Nikki Kean	Long-Haul COVID-19: Gut Microbiome May Hold the Key		Published	February 2, 2022	Article	https://www.clinicaladvisor.com/home/topics/gastroenterology-information-center/long-haul-covid-19-linked-altered-microbiome/	A patient’s gut microbiome may be linked to the risk of developing long-haul COVID-19 after initial infection with SARS-CoV-2, according to a study published online in the journal Gut.1 Although most people with COVID-19 recover within weeks of infection, some experience symptoms 4 or more weeks after COVID-19, according to the Centers for Disease Control and Prevention. These long-haul COVID conditions are also known as post-COVID, long COVID, post-acute COVID-19, long-term effects of COVID, or chronic COVID.2 Huang et al have reported that up to 75% of patients hospitalized with COVID-19 described at least 1 symptom 6 months after discharge.3 These included respiratory, neuropsychiatric (headache, dizziness, loss of taste and smell, anxiety, poor concentration, disrupted sleep, low mood, poor memory, blurred vision), gastrointestinal, hair loss, and musculoskeletal symptoms as well as fatigue.
208	D205		Pustake, Manas1,; Tambolkar, Isha2; Giri, Purushottam3; Gandhi, Charmi1	SARS, MERS and CoVID-19 An overview and comparison of clinical, laboratory and radiological features	https://doi.org/10.4103/jfmpc.jfmpc_839_21	Published	January 2022	Review	https://journals.lww.com/jfmpc/Fulltext/2022/01000/SARS,_MERS_and_CoVID_19__An_overview_and.3.aspx	In the 21st century, we have seen a total of three outbreaks by members of the coronavirus family. Although the first two outbreaks did not result in a pandemic, the third and the latest outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) culminated in a pandemic. This pandemic has been extremely significant on a social and international level. As these viruses belong to the same family, they are closely related. Despite their numerous similarities, they have slight distinctions that render them distinct from one another. The Severe Acute Respiratory Distress Syndrome and Middle East Respiratory Syndrome (MERS) cases were reported to have a very high case fatality rate of 9.5 and 34.4% respectively. In contrast, the CoVID-19 has a case fatality rate of 2.13%. Also, there are no clear medical countermeasures for these coronaviruses yet. We can cross information gaps, including cultural weapons for fighting and controlling the spread of MERS-CoV and SARS-CoV-2, and plan efficient and comprehensive defensive lines against coronaviruses that might arise or reemerge in the future by gaining a deeper understanding of these coronaviruses and the illnesses caused by them. The review thoroughly summarises the state-of-the-art information and compares the biochemical properties of these deadly coronaviruses with the clinical characteristics, laboratory features and radiological manifestations of illnesses induced by them, with an emphasis on comparing and contrasting their similarities and differences.
209	D206		Daniel Munblit, Timothy R. Nicholson, Dale M. Needham, Nina Seylanova, Callum Parr, Jessica Chen, Alisa Kokorina, Louise Sigfrid, Danilo Buonsenso, Shinjini Bhatnagar, Ramachandran Thiruvengadam, Ann M. Parker, Jacobus Preller, Sergey Avdeev, Frederikus A. Klok, Allison Tong, Janet V. Diaz, Wouter De Groote, Nicoline Schiess, Athena Akrami, Frances Simpson, Piero Olliaro, Christian Apfelbacher, Regis Goulart Rosa, Jennifer R. Chevinsky, Sharon Saydah, Jochen Schmitt, Alla Guekht, Sarah L. Gorst, Jon Genuneit, Luis Felipe Reyes, Alan Asmanov, Margaret E. O’Hara, Janet T. Scott, Melina Michelen, Charitini Stavropoulou, John O. Warner, Margaret Herridge & Paula R. Williamson	Studying the post-COVID-19 condition: research challenges, strategies, and importance of Core Outcome Set development	https://doi.org/10.1186/s12916-021-02222-y	Published	04 February 2022	Opinion	https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-021-02222-y	Background A substantial portion of people with COVID-19 subsequently experience lasting symptoms including fatigue, shortness of breath, and neurological complaints such as cognitive dysfunction many months after acute infection. Emerging evidence suggests that this condition, commonly referred to as long COVID but also known as post-acute sequelae of SARS-CoV-2 infection (PASC) or post-COVID-19 condition, could become a significant global health burden. Main text While the number of studies investigating the post-COVID-19 condition is increasing, there is no agreement on how this new disease should be defined and diagnosed in clinical practice and what relevant outcomes to measure. There is an urgent need to optimise and standardise outcome measures for this important patient group both for clinical services and for research and to allow comparing and pooling of data. Conclusions A Core Outcome Set for post-COVID-19 condition should be developed in the shortest time frame possible, for improvement in data quality, harmonisation, and comparability between different geographical locations. We call for a global initiative, involving all relevant partners, including, but not limited to, healthcare professionals, researchers, methodologists, patients, and caregivers. We urge coordinated actions aiming to develop a Core Outcome Set (COS) for post-COVID-19 condition in both the adult and paediatric populations.
210	D207		Terence Stephenson1 , Benjamin Allin2 , Manjula D Nugawela1 , Natalia Rojas1 , Emma Dalrymple1 , Snehal M Pinto Pereira3 , Manas Soni4 , Marian Knight2 , Emily Y Cheung1 , Isobel Heyman1 , CLoCk Consortium5 , Roz Shafran	Long COVID (Post-COVID-19 condition) in Children: a modified Delphi Process		Published	February 2022	Study	http://press.psprings.co.uk/adc/february/AAMadc323624.pdf	Objective The aim of this study was to derive a research definition for ‘Long COVID (PostCOVID-19 condition)’ in children and young people (CYP) to allow comparisons between research studies. Design A three-phase online Delphi process was used, followed by a consensus meeting. Participants were presented with 49 statements in each phase and scored them from 1-9 based on how important they were for inclusion in the research definition of Long COVID in CYP. The consensus meeting was held to achieve representation across the stakeholder groups. Statements agreed at the consensus meeting were reviewed by participants in the Patient Public Involvement (PPI) Research Advisory Group. Setting The study was conducted remotely using online surveys and a virtual consensus meeting. Participants 120 people with relevant expertise were divided into three panels according to their area of expertise: Service Delivery, Research (or combination of research and service delivery) and Lived Experience. The PPI Research Advisory group consisted of CYP aged 11-17 years. Main outcome measures Consensus was defined using existing guidelines. If consensus was achieved in two or more panels or was on the border between one and two panels, those statements were discussed and voted on at the consensus meeting. Results Ten statements were taken forward for discussion in the consensus meeting and five statements met threshold to be included in the research definition of Long COVID among CYP. The research definition aligned to the clinical case definition of the World Health Organisation is proposed as follows: Post-COVID-19 condition occurs in young people with a history of confirmed SARS CoV-2 infection, with at least one persisting physical symptom for a minimum duration of 12 weeks after initial testing that cannot be explained by an AUTHOR ACCEPTED MANUSCRIPT 3 alternative diagnosis. The symptoms have an impact on everyday functioning, may continue or develop after COVID-19 infection, and may fluctuate or relapse over time. The positive COVID test referred to in this definition can be a lateral flow antigen test, a PCR test or an antibody test. Conclusions This is the first research definition of Long COVID (Post-COVID-19 condition) in CYP and complements the clinical case definition in adults proposed by WHO. What this study adds 1. The first research definition of Long COVID in CYP that complements the definition proposed by WHO for adults. How this study might affect research, practice or policy 1. Ability to reliably compare and evaluate studies on prevalence, course and outcome of Long COVID in CYP using this definition.
211	D208		Rafael A. Rivas-Vazquez, Gustavo Rey, Alan Quintana & Ana A. Rivas-Vazquez	Assessment and Management of Long COVID	https://doi.org/10.1007/s42843-022-00055-8	Published	09 February 2022	Review	https://link.springer.com/article/10.1007/s42843-022-00055-8	Broad variability during acute COVID-19 infection is seen, ranging from asymptomatic presentation to death. The vast majority of individuals who develop COVID-19 return to their pre-COVID-19 baseline within several weeks. However, a portion of patients will develop a post-COVID-19 syndrome of persistent cognitive, somatic, and behavioral symptoms. This syndrome, designated as post-acute sequelae of SARS-CoV-2 infection, is more commonly known as long COVID. The objectives of this paper are to inform psychologists regarding our current understanding of the underlying pathophysiology of COVID-19, review criteria for range of severity during acute illness, present clinical manifestations of long haul phenomena, and discuss the emerging literature base of evidence-based treatment and management approaches.
212	D209		BjørnBlomberg12Rebecca JaneCox13NinaLangeland12	Long-COVID: A growing problem in need of intervention	https://doi.org/10.1016/j.xcrm.2022.100552	Published	14 February 2022	Commentary	https://www.sciencedirect.com/science/article/pii/S2666379122000581	The number of people who have survived COVID-19 is overwhelming – official figures approach half a billion (https://covid19.who.int). Thus, any long-term consequences in COVID-19 survivors could have a huge impact on public health and on healthcare services in the coming months and years, with potentially 100 million individuals affected.
213	D210		Nisreen A. Alwan	Lessons from Long COVID: working with patients to design better research	https://doi.org/10.1038/s41577-022-00692-6	Published	15 February 2022	Comment	https://www.nature.com/articles/s41577-022-00692-6	The perspectives of people with lived experience of any condition being researched must actively inform the research questions asked and the way in which we go about answering them. The experience of Long Covid gives a contemporary example of how working together with patients is integral to medical research.
214	D211		Alexandra Flemming	First glimpses into the mechanisms of Long COVID	https://doi.org/10.1038/s41577-022-00691-7	Published	15 February 2022	Article	https://www.nature.com/articles/s41577-022-00691-7	Post-acute sequelae of COVID-19 (PASC), sometimes referred to as ‘Long COVID’, are observed in 30–70% of individuals post-SARS-CoV-2 infection. These can include loss of sense of smell, memory loss, fatigue, shortness of breath, gastrointestinal (GI) distress and other symptoms. Autoimmune processes and unresolved viral fragments have been proposed as causative, but experimental validation for these hypotheses is lacking. Now, a longitudinal multi-omic study of >300 patients by Su et al. reveals that some factors present at disease onset, such as pre-existing type 2 diabetes, latent EBV reactivation, circulating SARS-CoV-2 RNA fragments as well as specific autoantibodies, associate with specific PASC. The authors identified four different immune endotypes at 2–3 months post disease onset that differentially associate with PASC. Interestingly, they find that bystander activation of CMV-specific T cells during acute disease is associated with GI PASC. A second study by Vijayakumar et al. shows persistent immunological and proteomic abnormalities in the lungs of patients with ongoing respiratory symptoms after COVID-19, with continuing activation of CD8+ T cells and elevated levels of proteins associated with apoptosis, tissue repair and epithelial injury.
215	D212		Aluko A. Hope, MD, MSCE Teresa H. Evering, MD, MS	Post-Acute Sequelae of SARS CoV-2 infection	https://doi.org/10.1016/j.idc.2022.02.004	Published	February 14, 2022	Review	https://www.id.theclinics.com/article/S0891-5520(22)00025-3/fulltext	Key Points •Post-Acute-Sequelae of SARS-CoV-2 infection (PASC) or Long COVID is a heterogeneous, multi-system, relapsing and remitting illness that can affect patients infected with SARS-CoV-2 regardless of the severity of the acute infection. •Estimates of the incidence and prevalence of Long COVID symptoms vary widely across published studies. •The diagnosis of Long COVID is currently primarily based on history and physical examination and may require a multidisciplinary approach to care. •The overall approach to the treatment of Long COVID is to focus on symptom management, functional goals and improvements in the quality of life. The clinical spectrum of SARS-CoV-2 infection ranges from asymptomatic to critical illness, which may include severe sepsis and acute respiratory failure1. When symptomatic, acute COVID-19 illness will typically last days to weeks and most of the symptoms are thought to be mediated by the replication of the virus and the initial immune response to the infection2. As the COVID-19 pandemic continues, it has become increasingly clear that clinical sequelae and symptoms may persist for weeks to months beyond the acute stage of SARS-CoV-2 infection for a significant proportion of patients. This chronic illness has been termed Post-Acute Sequelae of SARS-CoV-2 Infection (PASC), post-COVID syndrome, or Long COVID. A less common post-acute hyperinflammatory illness (multisystem inflammatory syndrome in children (MIS-C) and multisystem inflammatory syndrome in adults (MIS-A) has also been characterized. MIS-C and MIS-A will typically occur two to five weeks after the initial SARS-CoV-2 infection and are thought to be mediated by a dysregulated immune response1. Patients with these syndromes may suffer from cardiovascular, gastrointestinal, neurologic, dermatologic and mucocutaneous manifestations like Kawasaki disease3,4, and is discussed further in Chapter 12. This review will highlight what is known about the epidemiology, clinical features, pathophysiology, and risk factors of Long COVID and summarize current rational approaches for diagnosis, prevention and treatment of this new syndrome based on emerging literature and expert opinion.
216	D213		Moniek van Zitteren, Marit C. van Boreen & Jerry Spanjer	Adequate beoordeling van long covid	https://doi.org/10.1007/s12498-022-1475-x	Published	22 February 2022	Article	https://link.springer.com/article/10.1007/s12498-022-1475-x	It is now known that Covid-19 can lead to long-term complaints with significant limitations. These are not always easy to objectify or factual information is missing. The development of a guideline for complaints that are difficult to objectify for occupational and insurance medical practice is desirable in order to arrive at an adequate assessment of the load capacity of lung covid patients. For the time being, one will have to fall back on known information about similar medical conditions and the currently applicable protocols. Collaboration between occupational medicine and insurance medicine seems essential in this regard, as does reaching consensus in the assessment of such complaints.
217	D214		César Fernández-de-las-Peñas, Juan Torres-Macho, María Velasco-Arribas, Susana Plaza-Canteli, José A. Arias-Navalón, Valentín Hernández-Barrera & Carlos Guijarro	Preexisting hypertension is associated with a greater number of long-term post-COVID symptoms and poor sleep quality: a case–control study	https://doi.org/10.1038/s41371-022-00660-6	Published	16 February 2022	Study	https://www.nature.com/articles/s41371-022-00660-6	There has been an increasing interest in the presence of symptoms after the acute phase (post-COVID symptoms) of infection, e.g., long COVID. Long COVID is defined as those symptoms appearing during or after SARS-CoV-2 infection during far longer than it would be expected [5]. Current evidence suggests that the presence of post-COVID symptoms ranges from 35 to 60% depending on the symptom and the follow-up period [6]; however, most studies did not consider the role of previous medical co-morbidities. This study analyzed the association of hypertension and long-term post-COVID symptoms in previously hospitalized COVID-19 patients.
218	D215		Ian Albert Clark	Chronic cerebral aspects of long COVID, post-stroke syndromes and similar states share their pathogenesis and perispinal etanercept treatment logic	https://doi.org/10.1002/prp2.926	Published	2022 Apr;10	Review	https://pubmed.ncbi.nlm.nih.gov/35174650/	The chronic neurological aspects of traumatic brain injury, post-stroke syndromes, long COVID-19, persistent Lyme disease, and influenza encephalopathy having close pathophysiological parallels that warrant being investigated in an integrated manner. A mechanism, common to all, for this persistence of the range of symptoms common to these conditions is described. While TNF maintains cerebral homeostasis, its excessive production through either pathogen-associated molecular patterns or damage-associated molecular patterns activity associates with the persistence of the symptoms common across both infectious and non-infectious conditions. The case is made that this shared chronicity arises from a positive feedback loop causing the persistence of the activation of microglia by the TNF that these cells generate. Lowering this excess TNF is the logical way to reducing this persistent, TNF-maintained, microglial activation. While too large to negotiate the blood-brain barrier effectively, the specific anti-TNF biological, etanercept, shows promise when administered by the perispinal route, which allows it to bypass this obstruction.
219	D216		A.López-SampaloaM.R.Bernal-LópezabR.Gómez-Huelgasab	Persistent COVID-19 syndrome. A narrative review Síndrome de COVID-19 persistente. Una revisión narrativa	https://doi.org/10.1016/j.rceng.2021.10.001	Published	28 February 2022	Review	https://www.sciencedirect.com/science/article/pii/S225488742200008X	As the coronavirus-2019 disease (COVID-19) pandemic, caused by the infection with severe acute respiratory syndrome (SARS-CoV-2) coronavirus type 2, has progressed, persistent COVID-19 syndrome is an increasingly recognized problem on which a significant volume of medical literature is developing. Symptoms may be persistent or appear, after an asymptomatic period, weeks or months after the initial infection. The clinical picture is as markedly heterogeneous and multisystemic as in the acute phase, so multidisciplinary management is required. In addition, their appearance is not related to the severity of the initial infection, so they can affect both mild patients, even asymptomatic, and seriously ill patients who have required hospitalization. Although it can affect people of any age, it is more common in middle-aged women. The sequelae can generate a high impact on the quality of life, and in the work and social environment. The objective of this paper is to review persistent COVID-19 syndrome, to know its clinical manifestations and the strategies for the management and follow-up of these patients.
220	D217	PESE	CristinaRoldán-JiménezabAntonio ICuesta-Vargas	Proposal for assessment of the predominant symptom and physical function in patients suffering from Long COVID	https://doi.org/10.1016/j.mehy.2022.110811	Published	1 March 2022	Article	https://www.sciencedirect.com/science/article/pii/S0306987722000512	Long COVID patients present a cluster of symptoms that overlaps with other post-infectious conditions, such as patients diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Besides fatigue, one of the most limiting clinical manifestations in ME/CFS is post-exertional malaise (PEM), which Long COVID patients also report. Therefore, there are concerns about treatment approaches in rehabilitation for long COVID patients. Up to date, Long COVID patients present fatigue and respiratory symptoms predominantly. The hypothesis presented in this paper is that the treatment approach for Long COVID patients may depend on the aetiology of their symptoms, which objective tests can assess. And the primary affected system in a given patient may determine the individual response to physical exhaustion. Then, we propose an assessment to confirm the system impaired under the predominant symptom to guide the rehabilitation intervention. Fatigue-related symptoms, PEM, physical deconditioning and response to exertion should be assessed in Long COVID patients with predominant fatigue. In contrast, the respiratory function by spirometry and the diffusion capacity should be objectively assessed in those patients with predominantly respiratory symptoms. Future research should develop and validate patient-reported outcomes or cardiopulmonary exercise testing to objectively assess the symptoms and functional status in Long COVID patients to reinforce the proposed assessment.
221	D218		LewisKazisMarySlavinHannahBaileyEmilyHickeyAileenLedinghamAnanyaVasudevanRonaldTompkins	Appraisal of Long COVID: Lessons to be Learned from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)	https://doi.org/10.1016/j.apmr.2022.01.008	Published	2 March 2022	Review	https://www.sciencedirect.com/science/article/pii/S0003999322000284	Little is known regarding after-effects of Long-COVID-19 (LC), while ME/CFS has been extensively researched. We performed a rigorous scoping review to inform a better definition of symptomatology of LC and cross-cutting similarities with ME/CFS. Our objective was to review the National Institutes of Health (NIH) ME/CFS Common Data Elements (CDEs), identify Patient Reported Outcome Measures (PROMs) and link items to the World Health Organization (WHO) International Classification of Functioning, Disability and Health (ICF) codes to inform efforts to define LC. Data Synthesis Six articles specifically compared LC and ME/CFS for symptom overlap. Similarities between ME/CFS and Long COVID symptoms include: fatigue, post exertional malaise (PEM), cognitive symptoms, sleep dysfunction, pain, noise and light hypersensitivity, orthostatic intolerance, cardiac, gastrointestinal and immune pathologies. The 944 items from 38 PROM CDEs were coded based on common ME/CFS and LC symptoms. The percent of items linked to one or more ICF categories (1288 codes) was as follows: Body Function (b codes) 73%: Fatigability, N=252 (20%); Cognitive functions, N=234 (18%); Sleep functions, N=139, 11%; and Pain, N=119, (9%). Activity and Participation (d codes), N=332, (26%). Environment (e codes), N=11, 0.9%. Conclusions The ICF provides a common language to assess ME/CFS and LC cross-cutting symptoms and their impact on body function, activity and participation. This review of ME/CFS CDE's can help identify common symptoms, such as PEM, and encourage appropriate symptom management to prevent cycles of overexertion and relapse for those with LC.
222	D219		Juan Carlos Villar Nolbert Gumisiriza Lucas Guimarães Abreu Richard J Maude Robert Colebunders	Defining post-COVID condition	https://doi.org/10.1016/S1473-3099(22)00060-3	Published	March 01, 2022	Article	https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(22)00060-3/fulltext	Joan B Soriano and colleagues1 proposed a clinical case definition for post-COVID-19 condition. We thank this WHO-led working group for their efforts to provide an operational definition for this emerging, challenging condition. Similar to previous statements by the Centers for Disease Control and Prevention2 and the National Institute for Health and Care Excellence,3 the criterion “SARS-CoV-2 laboratory confirmation” was not included in the definition proposed by this working group. There are some compelling reasons supporting this perspective. A post-COVID-19 condition can affect people who have only minor, non-specific or even no symptoms during the acute phase of the infection. Such cases are not regularly tested for SARS-CoV-2. Additionally, there has been inadequate access to testing in low-income and middle-income countries (LMICs). People also avoid testing for fear of the consequences of a positive result. Furthermore, if done late, tests can become negative, making a retrospective diagnosis unfeasible. Although a clinical definition without laboratory confirmation increases sensitivity (allowing more affected people to receive care), it comes with a trade-off with specificity. Hence, a stricter definition might be required for research purposes and comparison between different settings.
223	D220	ME - PESE	Todd E. Davenport Staci R. Stevens Jared Stevens Christopher R. Snell J. Mark Van Ness	Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 4: Heart Rate Monitoring to Manage Postexertional Symptom Exacerbation	https://doi.org//10.2519/jospt.blog.20220223	Published	February 23, 2022	Article	https://www.jospt.org/do/10.2519/jospt.blog.20220223	Summary A combination of HRM and symptom journaling will best assist patients and clinicians to track outcomes and adjust the HRM program as needed. The patient and clinician should collaborate to determine the “Key 3” symptoms of PESE that are most functionally limiting to the patient. Symptoms may be assessed using a formalized questionnaire,1,3,9 or they may be qualitatively determined based on discussion with the patient. The presence and severity of Key 3 symptoms can be reassessed over time to determine the effectiveness of the HRM program. - The physiology underlying postexertional symptom exacerbation (PESE) is abnormal in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and likely long COVID. Activity pacing approaches appear warranted to accommodate the unusual physiological deficits of PESE. The Rationale for Heart Rate Monitoring Similar to people living with ME/CFS,7 people living with long COVID have reported finding activity pacing to be helpful. This idea is reflected in current safe rehabilitation guidelines for this condition.8 PESE is challenging to self-manage because of the variability in onset, duration, and nature from person to person.2,6 Social stigma associated with PESE may lead people to overexert to meet the demands of their daily tasks. This stigma may be exacerbated by people telling patients that “it’s all in their head” or they “just need to exercise.” Variability and stigma, in turn, make it difficult to identify important activity triggers in the early stages of learning to manage PESE. PESE is characterized by aerobic system dysfunction. Pacing based on heart rate can help the patient avoid the dysfunctional aerobic system by keeping their activity intensity at a level anaerobic metabolism will dominate. Heart rate monitoring (HRM) provides an element of predictive potential for the patient to understand when their activities exceed physiological limits and eventually may result in PESE. In this post, we will discuss activity pacing to manage PESE that is based on HRM.
224	D221		Joanne Elizabeth Hunt	Making space for disability studies within a structurally competent medical curriculum: Reflections on Long Covid	https://doi.org/10.31235/osf.io/p9qyk	pre-print	February 28, 2022	Article	https://osf.io/preprints/socarxiv/p9qyk/	Whilst critically informed approaches to medical education are increasingly advocated in literature, discussion of the potential role of disability studies in informing pedagogy and practice is largely lacking. The emergence of Long Covid, alongside the possibility of a wave of covid-related disability, underlines an urgent need for medicine to develop more contextualised, nuanced and structurally competent understandings of chronic illness and disability. This article argues that the integration of thinking from disability studies into medical curricula offers a pathway to such understanding, informing a more equitable, holistic and patient-centred approach to practice. Further, a structurally competent, anti-ableist approach positions clinicians and patients as allies, working together within a structural context that constrains both parties. Such positioning may mitigate tensions within the clinical encounter, tensions that are well-documented in the realm of marginalised chronic illness and disability. Whilst the possibilities arising from a partnership between disability studies and medicine are numerous, the foci here are the social relational model of disability and the concept of psycho-emotional disablism, within a broader paradigm of critical disability studies. It is argued that inadequate healthcare provision and policy in the realm of Long Covid can be understood as a form of structural and psycho-emotional disablism, arising from and reinforcing an ableist psychosocial imaginary permeated with neoliberal assumptions, and carrying a risk of furthering both disability and impairment. After considering Long Covid through these particular lenses, the article concludes with a discussion of how a partnership between disability studies and a structurally competent approach to medical education might translate into practice.
225	D222	ES	Michael J. Peluso Steven G. Deeks	Early clues regarding the pathogenesis of long-COVID	https://doi.org/10.1016/j.it.2022.02.008	Published	March 08, 2022	Article	https://www.cell.com/trends/immunology/fulltext/S1471-4906(22)00047-3	Intense investigation into the predictors and determinants of post-acute sequelae of SARS-CoV-2 infection (PASC), including ‘long COVID’, is underway. Recent studies provide clues to the mechanisms that might drive this condition, with the goal of identifying host or virus factors that can be intervened upon to prevent or reverse PASC. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to systemic symptoms, which in most people resolve within a few weeks. A poorly characterized subset of individuals, however, have persistent symptoms that last for many weeks or longer. The syndrome has many names, including ‘post-acute sequelae of SARS-CoV-2 infection’ (PASC) and ‘post-acute coronavirus disease (COVID) syndrome’ (PACS), but is more widely known as ‘long COVID’. Due in part to the formation of a very powerful and effective advocacy community, the US Congress recently allocated over $1 billion dollars for the study of PASC. The National Institutes of Health (NIH) is now implementing a massive program [Researching COVID to Enhance Recovery (RECOVER); www.recovercovid.org]; the UK and other countries already have several ongoing initiatives. The study of PASC has become a major research priority that will presumably lead to discoveries relevant to other post-infectious syndromes, many of which are similar to PASC. There are dozens of epidemiologic studies, most leveraging electronic medical records, describing the natural history of PASC. In general, these studies have found that sex, severity of initial COVID-19, the presence of certain comorbidities (including obesity, diabetes, and chronic lung disease), and socioeconomic status can affect the risk of an individual with COVID-19 developing PASC. Newer clinical and translational studies are beginning to explore its pathogenesis, providing clues about some of the mechanistic pathways that might contribute to this condition. We can now expect the emergence of major scientific efforts addressing the pathogenesis of PASC. In one of the first systematic studies, a large collaborative group organized by the Institute for Systems Biology (Seattle, WA, USA) performed a longitudinal multi-omic systems biology analysis of over 200 individuals who were followed for 2–3 months after acute infection [1.]. Several factors were associated with the development of PASC, including pre-existing diabetes mellitus, high-level SARS-CoV-2 viremia, and Epstein-Barr virus (EBV) reactivation during acute infection. The investigators also identified the presence of certain autoantibodies, including those targeting type I interferons (IFNs), that could predict PASC. Their observations suggest plausible mechanisms by which SARS-CoV-2 infection can cause persistent symptoms. For example, a higher degree of SARS-CoV-2 viremia likely reflects higher tissue viral burden and increased likelihood of end-organ damage. Higher viremia might also be associated with immunologic perturbations that could lead to organ dysfunction; some of these might persist beyond early convalescence. The relationships for other factors are less clear, for example, EBV viremia may more plausibly reflect the severity of initial illness rather than represent a causal mechanism of PASC, although the recent observation that EBV reactivation might lead to multiple sclerosis suggests this virus can contribute to autoimmune syndromes [2.]. Furthermore, the identification of a relationship with anti-IFN antibodies, previously shown to be important in acute COVID-19 [3.], suggests another mechanism that may tie together an impaired antiviral response, an enhanced inflammatory response, and generation of downstream autoimmune processes. In a different analysis of several hundred individuals during acute infection and up to a year later [4.], Cervia and colleagues identified a distinct SARS-CoV-2 specific immunoglobulin signature during acute infection among those who went on to develop PASC. Specifically, they found that reduced IgM and IgG3 titers during acute infection were a risk factor for PASC, which the authors suggest might be related to reduced production of type I IFNs resulting in a failure of isotype switching. Using these laboratory measurements in combination with certain clinical factors (e.g., age, asthma history, number of acute COVID-19 symptoms), the team generated a prediction model to identify those who developed PASC [4.]. In yet another recent study, Liu and colleagues found differences in the gut microbiome associated with neuropsychiatric and pulmonary PASC symptoms [5.]. These studies add to a growing body of literature suggesting that a combination of virus and host factors, including potential viral antigen persistence (preliminary) [6.], residual inflammation [7.,8.], microvascular dysregulation [9.], and autoimmune phenomena [10.] might contribute to PASC (Figure 1).
226	D223		Lauren E. Wisk, PhD, Graham Nichol, MD, MPH, Joann G. Elmore	Toward Unbiased Evaluation of Postacute Sequelae of SARS-CoV-2 Infection: Challenges and Solutions for the Long Haul Ahead	https://doi.org/10.7326/M21-4664	Published	8 March 2022	Opinion	https://www.acpjournals.org/doi/10.7326/M21-4664	Early reporting of postacute SARS-CoV-2 syndrome (PASC), or “long COVID” (1), foretells a difficult challenge developing in parallel to the ongoing pandemic. Some patients with prior acute COVID-19 report multiple new or persistent symptoms affecting nearly every organ system (2). In the United States, PASC has already been approved for inclusion and protections within the Americans with Disabilities Act (3) despite limited study data or medical consensus. Yet, we do not know what constitutes long COVID or how to formally diagnose it (4). An improved understanding of this condition is needed to provide appropriate care for our patients. However, developing high-quality scientific evidence on PASC presents a unique challenge due to the evolving circumstances of SARS-CoV-2 and the pandemic itself. Such work will indeed be a long haul.
227	D224		Alain Trautmann	La fatigue chronique, un symptôme trop souvent négligé I. Une immunité dérégulée à son origine ? Mechanisms underlying chronic fatigue, a symptom too often overlooked	https://doi.org/10.1051/medsci/2021143	Published	14 octobre 2021	Article	https://www.medecinesciences.org/fr/articles/medsci/full_html/2021/08/msc200438/msc200438.html	Acute fatigue after exertion, like acute inflammation after injury, is useful for our body. On the contrary, both chronic fatigue and chronic inflammation are deleterious, and they are associated in many diseases. In this first part, we will analyze different immune phenomena (bystander activation, memory of the innate immune system, link with the intestinal microbiota) involved in triggering chronic inflammation. This review aims at looking for links between different signs and symptoms associated with chronic fatigue, as well as between different diseases in which severe chronic fatigue can manifest. Possible underlying mechanisms for these phenomena are discussed. This is a proposal made by a researcher, with no clinical experience, to doctors confronted with an entity that is still largely mysterious. The link between chronic inflammation, neuroinflammation and fatigue will be examined in a second part.	La fatigue aiguë après un effort, comme l’inflammation aiguë après une blessure, sont utiles à notre organisme. En revanche, la fatigue chronique, comme l’inflammation chronique, sont délétères, et elles sont associées dans de nombreuses maladies. Nous analyserons dans cette première partie différents phénomènes immunitaires impliqués dans le déclenchement de l’inflammation chronique. Cette revue vise à proposer des liens entre différents signes et symptômes associés à la fatigue chronique, ainsi qu’entre différentes maladies dans lesquelles peut se manifester une fatigue chronique grave. Des mécanismes possibles, sous-jacents à ces processus, et leurs liens, sont également discutés. Il s’agit ici d’une proposition faite par un chercheur, sans expérience clinique, à des médecins confrontés à une entité qui reste encore largement mystérieuse. L’articulation entre inflammation chronique, neuro-inflammation et fatigue, sera examinée dans une deuxième partie.
228	D225		Alain Trautmann	Mécanismes sous-jacents à la fatigue chronique, un symptôme trop souvent négligé II. De l’immunité dérégulée à la neuroinflammation et ses conséquences Mechanisms underlying chronic fatigue, a symptom too often overlooked II- From deregulated immunity to neuroinflammation and its consequences	https://doi.org/10.1051/medsci/2021170	Published	1 décembre 2021	Article	https://www.medecinesciences.org/fr/articles/medsci/full_html/2021/09/msc200704/msc200704.html	Hypothalamus stimulation by inflammatory and / or stress signals can trigger activation of the HPA (hypothalamic-pituitary-adrenal) axis, which includes the hypothalamus, pituitary and adrenal gland. Acute activation of the HPA axis is fundamental for the fight or flight response. It allows a maximal energy mobilization available for an effort, whilst erasing fatigue. On the contrary, the chronic activation of this axis decreases muscle efficiency and leads to chronic fatigue. In this second part of our review will be discussed several strategic points that need to be considered for attempting to understand and treat together inflammation and chronic fatigue.	L’activation de l’hypothalamus par des signaux inflammatoires et/ou de stress peut déclencher celle de l’axe HPA (hypothalamic-pituitary-adrenal axis), qui intègre l’hypothalamus, l’hypophyse et la glande surrénale. L’activation aiguë de l’axe HPA est fondamentale pour la réponse fight or flight (« combats ou fuis »). Elle permet de mobiliser un maximum d’énergie pour un effort, tout en effaçant la fatigue. En revanche, son activation chronique diminue l’efficacité musculaire et entraîne une fatigue chronique. On discutera dans cette partie de plusieurs points stratégiques à considérer pour tenter de comprendre et de traiter ensemble inflammation et fatigue chroniques.
229	D226		López-Sampalo A1, Bernal-López MR2, Gómez-Huelgas R2	Persistent COVID-19 syndrome. A narrative review Síndrome de COVID-19 persistente. Una revisión narrativa	https://doi.org/10.1016/j.rceng.2021.10.001	Published	28 Feb 2022	Review	https://europepmc.org/article/pmc/pmc8882405	As the coronavirus-2019 disease (COVID-19) pandemic, caused by the infection with severe acute respiratory syndrome (SARS-CoV-2) coronavirus type 2, has progressed, persistent COVID-19 syndrome is an increasingly recognized problem on which a significant volume of medical literature is developing. Symptoms may be persistent or appear, after an asymptomatic period, weeks or months after the initial infection. The clinical picture is as markedly heterogeneous and multisystemic as in the acute phase, so multidisciplinary management is required. In addition, their appearance is not related to the severity of the initial infection, so they can affect both mild patients, even asymptomatic, and seriously ill patients who have required hospitalization. Although it can affect people of any age, it is more common in middle-aged women. The sequelae can generate a high impact on the quality of life, and in the work and social environment. The objective of this paper is to review persistent COVID-19 syndrome, to know its clinical manifestations and the strategies for the management and follow-up of these patients.
230	D227		Khalid SaadAlharbiaYogendraSinghbWaleedHassan almalkicSushamaRawatdObaidAfzaleAbdulmalik SalehAlfawaz AltamimieImranKazmifFahad A.Al-AbbasifSami I.AlzareaaSachin KumarSinghgShvetankBhatthDinesh KumarChellappaniKamalDuajkGauravGuptalm	Gut Microbiota Disruption in COVID-19 or Post-COVID Illness Association with severity biomarkers: A Possible Role of Pre / Pro-biotics in manipulating microflora	https://doi.org/10.1016/j.cbi.2022.109898	Published	21 March 2022	Review	https://www.sciencedirect.com/science/article/pii/S000927972200103X	Highlights •COVID-19 has emerged as the world's most dangerous epidemic. •COVID-19 has had a minimal therapeutic response. •This review explained a role of gastrointestinal tract microbiome in the acute COVID-19. Coronavirus disease (COVID-19), a coronavirus-induced illness attributed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, is thought to have first emerged on November 17, 2019. According to World Health Organization (WHO). COVID-19 has been linked to 379,223,560 documented occurrences and 5,693,245 fatalities globally as of 1st Feb 2022. Influenza A virus that has also been discovered diarrhea and gastrointestinal discomfort was found in the infected person, highlighting the need of monitoring them for gastro intestinal tract (GIT) symptoms regardless of whether the sickness is respiration related. The majority of the microbiome in the intestines is Firmicutes and Bacteroidetes, while Bacteroidetes, Proteobacteria, and Firmicutes are found in the lungs. Although most people overcome SARS-CoV-2 infections, many people continue to have symptoms months after the original sickness, called Long-COVID or Post COVID. The term “post-COVID-19 symptoms” refers to those that occur with or after COVID-19 and last for more than 12 weeks (long-COVID-19). The possible understanding of biological components such as inflammatory, immunological, metabolic activity biomarkers in peripheral blood is needed to evaluate the study. Therefore, this article aims to review the informative data that supports the idea underlying the disruption mechanisms of the microbiome of the gastrointestinal tract in the acute COVID-19 or post-COVID-mediated elevation of severity biomarkers.
231	D228		Nidheesh V. R., Aswini Kumar Mohapatra, Unnikrishnan V. K., Jijo Lukose, Vasudevan Baskaran Kartha & Santhosh Chidangil	Post-COVID syndrome screening through breath analysis using electronic nose technology	https://doi.org/10.1007/s00216-022-03990-z	Published	18 March 2022	Study	https://link.springer.com/article/10.1007/s00216-022-03990-z	There is an urgent need to have reliable technologies to diagnose post-coronavirus disease syndrome (PCS), as the number of people affected by COVID-19 and related complications is increasing worldwide. Considering the amount of risks associated with the two chronic lung diseases, asthma and chronic obstructive pulmonary disease (COPD), there is an immediate requirement for a screening method for PCS, which also produce symptoms similar to these conditions, especially since very often, many COVID-19 cases remain undetected because a good share of such patients is asymptomatic. Breath analysis techniques are getting attention since they are highly non-invasive methods for disease diagnosis, can be implemented easily for point-of-care applications even in primary health care centres. Electronic (E-) nose technology is coming up with better reliability, ease of operation, and affordability to all, and it can generate signatures of volatile organic compounds (VOCs) in exhaled breath as markers of diseases. The present report is an outcome of a pilot study using an E-nose device on breath samples of cohorts of PCS, asthma, and normal (control) subjects. Match/no-match and k-NN analysis tests have been carried out to confirm the diagnosis of PCS. The prediction model has given 100% sensitivity and specificity. Receiver operating characteristics (ROC) has been plotted for the prediction model, and the area under the curve (AUC) is obtained as 1. The E-nose technique is found to be working well for PCS diagnosis. Our study suggests that the breath analysis using E-nose can be used as a point-of-care diagnosis of PCS.
232	D229		Santosh K. Chaturvedi	How Long is Your Covid? The Catch of ’22	https://doi.org/10.1007/s40737-022-00277-5	Published	17 March 2022	Editorial	https://link.springer.com/article/10.1007/s40737-022-00277-5	What is not clear is what should be the duration for considering it as a long covid. For other disorders, it was known that a disorder can be acute which is short-lasting, or chronic which is longer lasting than the acute one. Some disorders are also considered sub-acute. For example, the definition of chronic pain is when pain lasts longer than expected so it can be of a variable duration—a few days, weeks, three months, or six months. So, is long covid considered as long covid, when the duration is more than a week, two weeks, one month, 3 months, or a year or is it when it is longer than expected? In time, these issues need to be addressed for researchers to focus on long covid, based on a consensus on the duration. Thus, the impact of different variants like delta and omicron was the focus of healthcare and public attention in 2020 and 2021, long covid will be the focus in 2022, and maybe later as well. One can say that covid 19 was the catch of 2020, and delta and omicron variants were the catch of 2021. The catch of 2022 is long covid! And how long this long-covid will last, only time will tell!
233	D230		Kelly K O'Brien,corresponding author#1,2,3,4 Darren A Brown,#5,6 Colm Bergin,7,8 Kristine M Erlandson,9 Jaime H Vera,10,11 Lisa Avery,12,13 Soo Chan Carusone,14 Angela M Cheung,2,12,15 Susie Goulding,16 Richard Harding,17 Lisa McCorkell,18 Margaret O'Hara,19 Larry Robinson,20 Catherine Thomson,6 Hannah Wei,21 Natalie St Clair-Sullivan,11 Brittany Torres,1 Ciaran Bannan,7,8 Niamh Roche,22 Ruth Stokes,22 Patriic Gayle,23 and Patricia Solomon24	Long COVID and episodic disability: advancing the conceptualisation, measurement and knowledge of episodic disability among people living with Long COVID – protocol for a mixed-methods study	https://dx.doi.org/10.1136%2Fbmjopen-2022-060826	Published	2022 Mar 6	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905414/	In phase 1, we will conduct semistructured interviews with adults living with Long COVID to explore experiences of disability (dimensions, uncertainty, trajectories, influencing contextual factors) and establish an episodic disability (ED) framework in the context of Long COVID (n~10 each country). Using the conceptual framework, we will establish the Long COVID Episodic Disability Questionnaire (EDQ). In phase 2, we will examine the validity (construct, structural) and reliability (internal consistency, test–retest) of the EDQ for use in Long COVID. We will electronically administer the EDQ and four health status criterion measures with adults living with Long COVID, and readminister the EDQ 1 week later (n~170 each country). We will use Rasch analysis to refine the EDQ, and confirm structural and cross-cultural validity. We will calculate Cronbach’s alphas (internal consistency reliability), and intraclass correlation coefficients (test–retest reliability), and examine correlations for hypotheses theorising relationships between EDQ and criterion measure scores (construct validity). Using phase 2 data, we will characterise the profile of disability using structural equation modelling techniques to examine relationships between dimensions of disability and the influence of intrinsic and extrinsic contextual factors. This research involves an academic–clinical–community partnership building on foundational work in ED measurement, Long COVID and rehabilitation.
234	D231	ES	Rachel Coomey	Long Covid: The Long Road Ahead		Published	March 2022	Article	http://rcpi-live-cdn.s3.amazonaws.com/wp-content/uploads/2022/03/6.-Rachel-Coomey-TCD-Long-Covid-The-Long-Road-Ahead.pdf	The Covid-19 pandemic has dominated news headlines and public discussion for the past two years. We have been inundated with information about positivity rates and death rates, numbers in intensive care and economic impact. One aspect that has remained relatively underreported, however, is “Long Covid”, the persistence of symptoms in the weeks or months after SARS-CoV-2 infection (1). Long Covid rose to prominence due to social media, and its exact pathophysiology and long-term implications are yet to be fully understood (2). 2% of the UK population reported themselves to currently be suffering from Long Covid in January 2022, with 63% of those stating that the condition was adversely impacting their day-to-day activities (3). One in four UK employers report that Long Covid is a major cause of employee absence in their companies (4). While, thankfully, death rates due to Covid are decreasing and fewer people are being admitted to intensive care in recent months, we are yet to fully come to terms with many after-effects of the pandemic, including Long Covid. Given that many effects of Long Covid may negatively affect ability to drive safely, I believe this issue is hugely important, and pertinent to medical fitness to drive.
235	D232		MartinKaatzSteffenSpringerRogerSchubertMichaelZieger	Representation of long COVID syndrome in the awareness of the population is revealed by Google Trends analysis	https://doi.org/10.1016/j.bbih.2022.100455	Published	26 March 2022	Study	https://www.sciencedirect.com/science/article/pii/S266635462200045X	Highlights •Long COVID plays a non-negligible role in the information needs, as evidenced by the growing search interest during the pandemic. •Symptoms ageusia and anosmia became relatively well-known and relevant during the pandemic. •Google Trends is a useful tool, well suited for demonstrating the population's awareness of certain infodemiological topics. In some COVID-19 patients, symptoms persist for several weeks and sometimes, after the acute disease phase, these patients develop new symptoms, which then represents a transition into the so-called long COVID. The exact demarcation of the terms and generally applicable definitions are still discussed, but the phenomenon is most commonly referred to as long COVID. In this study, Google Trends data have been used to track levels of public awareness for long COVID and some important symptoms during the course of the COVID-19 pandemic. The results of this analysis clearly demonstrate the public interest in the new topic of long COVID, as documented by a corresponding search volume. This is related to the disease COVID-19, which is being spread by the corona pandemic. Relevant symptoms for COVID-19 or long COVID, for example ageusia and anosmia, only started to receive more public attention during the pandemic. Therefore, Google Trends is a useful tool to demonstrate the population's awareness of certain infodemiological topics like long COVID.
236	D233		Joanne Hunt, Charlotte Blease, Keith J Geraghty	Long Covid at the crossroads: Comparisons and lessons from the treatment of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)	https://doi.org/10.1177%2F13591053221084494	Published	March 27, 2022	Article	https://journals.sagepub.com/doi/10.1177/13591053221084494	Whilst parallels have been drawn between Long Covid and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), there is a well-documented history of negative stereotyping and marginalisation of patients with ME/CFS. A socio-politically oriented comparison of scientific, clinical and societal responses to Long Covid and ME/CFS is thus important to prevent similar harms arising among Long Covid patients. We identify four reasons for injustices in the treatment of ME/CFS patients, and discuss the risk of Long Covid following a similar trajectory. We conclude with policy and practice recommendations to help prevent such injustices arising again, including consideration of critical reflexivity in medical education.
237	D234		Petter Brodin, Giorgio Casari, Liam Townsend, Cliona O’Farrelly, Ivan Tancevski, Judith Löffler-Ragg, Trine H. Mogensen, Jean Laurent Casanova & The COVID Human Genetic Effort	Studying severe long COVID to understand post-infectious disorders beyond COVID-19	https://doi.org/10.1038/s41591-022-01766-7	Published	05 April 2022	Correspondence	https://www.nature.com/articles/s41591-022-01766-7	In our cohort of patients with severe long COVID, we will investigate B cell and T cell responses to SARS-CoV-2 and will assess somatic hypermutation and clonal evolution relative to the patterns seen in people who recovered from COVID-19 without persistent signs and symptoms. This will serve as an indirect test of ongoing antigen exposure in patients with severe long COVID. Also, by assessing functional states of SARS-CoV-2-specific T cells, we will determine if patients with long COVID exhibit evidence of functional impairment that could explain viral persistence. One study used structural modeling to identify a possible superantigen motif within the SARS-CoV-2 spike protein near the S1–S2 cleavage site6. As indirect support for the possibility of superantigen-mediated stimulation, expansion of TRVB21-3+ cells has been observed in patients with MIS-C2 (Fig. 1b). Many pathogens contain superantigens able to activate T cells in a nonspecific manner, such as staphylococci that cause staphylococcal toxic shock syndrome. Interestingly, this syndrome has been reported to induce persistent symptoms that bear similarity to those seen in severe long COVID10. This overlap of symptoms suggests either a direct effect of the superantigen on tissues or immune dysregulation that gives rise to persistent symptoms after infection. As for the neurological symptoms common in long COVID and other post-infectious disorders, it is worth considering possible neurotoxin motifs. Such motifs have been described for the SARS-CoV-2 coronavirus6, and these neurotoxins could in theory exert direct effects on both the central nervous system and peripheral nervous system. We plan to perform TCR sequencing in patients with severe long COVID in search of expansion of TRVB21-3+ cells, as in MIS-C, and we will also perform in vitro stimulation assays using soluble S1 protein to assess T cell reactivity and possible functional dysregulation as an element of disease. Superantigen-mediated T cell activation can trigger broad B cell activation, and production of autoantibodies against a range of tissues has been shown in MIS-C2,5 and in patients with acute COVID-19. Also, chronic activation of the immune system by viral persistence can induce autoimmune responses, and molecular mimicry between components of a pathogen and host tissue can lead to specific post-infectious autoimmunity. Structural similarity between human neuronal antigens and SARS-CoV-2 proteins has been suggested. A particular form of autoimmunity described in long COVID is postural orthostatic tachycardia syndrome, a form of autonomic dysregulation that is possibly induced by functional autoantibodies that target G protein–coupled receptors on neurons (Fig. 1b). Another type of autoimmunity relevant to SARS-CoV-2 infection is the production of neutralizing autoantibodies to type I interferons, which explains a sizeable fraction of cases of hypoxemic COVID-19 pneumonia1. If such neutralizing autoantibodies are present before SARS-CoV-2 infection, due to prior infections or vaccinations, then a patient is clearly at risk of developing severe acute COVID-19. However, such neutralizing autoantibodies might also appear after SARS-CoV-2 infection, in which case they might instead enable viral persistence, the formation of a viral reservoir and long COVID. To test this hypothesis, we will look for the presence of neutralizing autoantibodies to type I interferons in patients with long COVID. Collectively, we believe that our genetic and immunological studies of patients with severe long COVID hold potential for better understanding of this complex condition, and by focusing on severe cases that develop after mild COVID-19, we maximize our chances of success. Our results would probably be applicable beyond COVID-19 and will hopefully provide important insights of relevance into other post-infectious disorders such as myalgic encephalomyelitis.
238	D235		PeterValentMDaCemAkinMD, PhDbPatriziaBonadonnaMDcKnutBrockowMDdMarekNiedoszytkoMD, PhDeBoguslawNedoszytkoPhDfJoseph H.ButterfieldMDgIvanAlvarez-TwoseMD, PhDhKarlSotlarMDiJulianaSchwaabMDjMohamadJawharMDjAndreasReiterMDjMarianaCastellsMD, PhDkWolfgang R.SperrMDaHanneke C.Kluin-NelemansMD, PhDlOlivierHermineMD, PhDmJasonGotlibMD, MSnRobertaZanottiMDo…KarinHartmannMD	Risk and management of patients with mastocytosis and MCAS in the SARS-CoV-2 (COVID-19) pandemic: Expert opinions	https://doi.org/10.1016/j.jaci.2020.06.009	Published	5 August 2020	Article	https://www.sciencedirect.com/science/article/pii/S0091674920308393	Risk factors concerning COVID-19–induced morbidity and mortality include advanced age, an impaired immune system, cardiovascular or pulmonary diseases, obesity, diabetes mellitus, and cancer treated with chemotherapy. Here, we discuss the risk and impact of COVID-19 in patients with mastocytosis and mast cell activation syndromes. Because no published data are yet available, expert opinions are, by necessity, based on case experience and reports from patients. Although the overall risk to acquire the severe acute respiratory syndrome coronavirus 2 may not be elevated in mast cell disease, certain conditions may increase the risk of infected patients to develop severe COVID-19. These factors include certain comorbidities, mast cell activation–related events affecting the cardiovascular or bronchopulmonary system, and chemotherapy or immunosuppressive drugs. Therefore, such treatments should be carefully evaluated on a case-by-case basis during a COVID-19 infection. In contrast, other therapies, such as anti–mediator-type drugs, venom immunotherapy, or vitamin D, should be continued. Overall, patients with mast cell disorders should follow the general and local guidelines in the COVID-19 pandemic and advice from their medical provider.
239	D236		Frank Powitz	Anhaltende Beschwerden bei bis zu 15% der COVID-19-Patienten Long-/Post-Covid-Syndrom: Genesen heißt nicht gesund Long-/Post-Covid-Syndrome: Recovered doesn´t mean healthy	https://doi.org/10.1007/s15006-022-0721-6	Published	01 April 2022	Article	https://link.springer.com/article/10.1007/s15006-022-0721-6	Noch unklare Ursache Die genauen Ursachen des Long-/Post-Covid-Syndroms sind bislang nicht bekannt, und es fehlen laut Leitlinie für viele klinische Probleme noch pathophysiologische Evidenzen und klinische Studien. Diskutiert wird als Ursache die mögliche Persistenz von Viren oder Virusbestandteilen über Wochen und Monate. Aber auch postinfektiöse strukturelle Gewebeschäden - inklusive Endothelschäden und einer gestörten Mikrovaskularisierung - sowie eine Hyperkoagulabilität und Thrombosen können möglicherweise eine Rolle spielen. Das gilt ebenso für eine chronische Immundysregulation, für Autoimmunphänomene sowie für eine Dysregulation des Renin-Angiotensin-Aldosteron-Systems oder auch für Nebenwirkungen der COVID-19-Therapie.
240	D237		Sven H. Loosen, Björn-Erik Ole Jensen, Christian Tanislav, Tom Luedde, Christoph Roderburg & Karel Kostev	Obesity and lipid metabolism disorders determine the risk for development of long COVID syndrome: a cross-sectional study from 50,402 COVID-19 patients	https://doi.org/10.1007/s15010-022-01784-0	Published	30 March 2022	Article	https://link.springer.com/article/10.1007/s15010-022-01784-0	Purpose Metabolic disorders have been identified as major risk factors for severe acute courses of COVID-19. With decreasing numbers of infections in many countries, the long COVID syndrome (LCS) represents the next major challenge in pandemic management, warranting the precise definition of risk factors for LCS development. Methods We identified 50,402 COVID-19 patients in the Disease Analyzer database (IQVIA) featuring data from 1056 general practices in Germany. Multivariate logistic regression analysis was used to identify risk factors for the development of LCS. Results Of the 50,402 COVID-19 patients included into this analysis, 1,708 (3.4%) were diagnosed with LCS. In a multivariate regression analysis, we identified lipid metabolism disorders (OR 1.46, 95% CI 1.28–1.65, p < 0.001) and obesity (OR 1.25, 95% CI 1.08–1.44, p = 0.003) as strong risk factors for the development of LCS. Besides these metabolic factors, patients’ age between 46 and 60 years (compared to age ≤ 30, (OR 1.81 95% CI 1.54–2.13, p < 0.001), female sex (OR 1.33, 95% CI 1.20–1.47, p < 0.001) as well as pre-existing asthma (OR 1.67, 95% CI 1.39–2.00, p < 0.001) and depression (OR 1.27, 95% CI 1.09–1.47, p = < 0.002) in women, and cancer (OR 1.4, 95% CI 1.09–1.95, p = < 0.012) in men were associated with an increased likelihood of developing LCS. Conclusion Lipid metabolism disorders and obesity represent age-independent risk factors for the development of LCS, suggesting that metabolic alterations determine the risk for unfavorable disease courses along all phases of COVID-19.
241	D238	ES	Paula Boaventura 1,2,3,*,Sofia Macedo 1,2 ,Filipa Ribeiro 1,2,Sónia Jaconiano 4 andPaula Soares 1,2,3	Post-COVID-19 Condition: Where Are We Now?	https://doi.org/10.3390/life12040517	Published	31 March 2022	Review	https://www.mdpi.com/2075-1729/12/4/517/htm	COVID-19 is currently considered a systemic infection involving multiple systems and causing chronic complications. Compared to other post-viral fatigue syndromes, these complications are wider and more intense. The most frequent symptoms are profound fatigue, dyspnea, sleep difficulties, anxiety or depression, reduced lung capacity, memory/cognitive impairment, and hyposmia/anosmia. Risk factors for this condition are severity of illness, more than five symptoms in the first week of the disease, female sex, older age, the presence of comorbidities, and a weak anti-SARS-CoV-2 antibody response. Different lines of research have attempted to explain these protracted symptoms; chronic persistent inflammation, autonomic nervous system disruption, hypometabolism, and autoimmunity may play a role. Due to thyroid high ACE expression, the key molecular complex SARS-CoV-2 uses to infect the host cells, thyroid may be a target for the coronavirus infection. Thyroid dysfunction after SARS-CoV-2 infection may be a combination of numerous mechanisms, and its role in long-COVID manifestations is not yet established. The proposed mechanisms are a direct effect of SARS-CoV-2 on target cells, an indirect effect of systemic inflammatory immune response, and a dysfunction of the hypothalamic-pituitary-thyroid (HPT) axis leading to decreased serum TSH. Only a few studies have reported the thyroid gland status in the post-COVID-19 condition. The presence of post-COVID symptoms deserves recognition of COVID-19 as a cause of post-viral fatigue syndrome. It is important to recognize the affected individuals at an early stage so we can offer them the most adequate treatments, helping them thrive through the uncertainty of their condition.	todo
242	D239		Ahmed Samir Abdelhafiz ,Asmaa Ali,Ayman Mohamed Maaly,Mohamed Anwar Mahgoub,Hany Hassan Ziady,Eman Anwar Sultan	Predictors of post-COVID symptoms in Egyptian patients: Drugs used in COVID-19 treatment are incriminated	https://doi.org/10.1371/journal.pone.0266175	Published	March 31, 2022	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0266175	Objectives COVID-19 is a multisystem disease, and some patients suffer from physical or psychological symptoms for weeks or even months after infection, which is described as post-COVID syndrome. The goal of this study is evaluating the prevalence of post-COVID-19 symptoms among Egyptian patients and detecting the factors associated with the presence of these symptoms. Methods An on-line cross-sectional survey using Google Forms was used to conduct the present study, which took place between June and August 2021. Results Three hundred and ninety-six participants filled in the survey. The mean age of participants was 41.4 years. Most participants had mild to moderate COVID-19 (81.31%). The prevalence of post-COVID-19 symptoms was 87.63%, where the most frequent symptom was fatigue (60.86%). Female sex, the presence of comorbidities, lower degree of education, longer disease duration, as well as severe and critical forms of the disease were significantly associated with the presence of post-COVID symptoms. Using regression analysis, the predictors of post-COVID symptoms were severe and critical forms of the disease and intake of antibiotics and corticosteroids for treatment of COVID-19. Conclusions COVID-19 is followed by high prevalence of post-COVID symptoms. To the best of our knowledge, this is the first study to report the relationship between the use of antibiotics and the development of post-COVID symptoms. We recommend further studies to understand this relationship. We also recommend restricting the use of these drugs to indicated cases according to the international guidelines. More studies are needed to gain better understanding of post-COVID symptoms especially in females.
243	D240		Linzy Houchen-Wolloff1,2, Krisnah Poinasamy3, Kate Holmes4, Maryrose Tarpey5, Claire Hastie6, Kelly Raihani6, Natalie Rogers6, Nikki Smith6, Dawn Adams7, Paul Burgess7, Omer Elneima1,2, John Geddes14, Simon Heller15, Ling-Pei Ho16,17, Joseph Jacob18,19, Hamish McAuley1,2, Aarti Parmar1,2, Jennifer K Quint20, Betty Raman21, Matthew Rowland22, Amisha Singapuri2, Sally J Singh1,2, David Thomas23, Mark R Toshner24,25, Louise V Wain2,26, Alex Robert Horsley27, Michael Marks28, Christopher E Brightling1,2, Rachael A Evans	Joint patient and clinician priority setting to identify 10 key research questions regarding the long-term sequelae of COVID-19	http://dx.doi.org/10.1136/thoraxjnl-2021-218582	Published	March 30, 2022	Article	https://thorax.bmj.com/content/early/2022/03/29/thoraxjnl-2021-218582.abstract	Given the large numbers of people infected and high rates of ongoing morbidity, research is clearly required to address the needs of adult survivors of COVID-19 living with ongoing symptoms (long COVID). To help direct resource and research efforts, we completed a research prioritisation process incorporating views from adults with ongoing symptoms of COVID-19, carers, clinicians and clinical researchers. The final top 10 research questions were agreed at an independently mediated workshop and included: identifying underlying mechanisms of long COVID, establishing diagnostic tools, understanding trajectory of recovery and evaluating the role of interventions both during the acute and persistent phases of the illness.
244	D241		Michelle Medeiros1, Hillary Anne Edwards1, Claudia Rose Baquet1,2	Research in the USA on COVID-19’s long-term effects: measures needed to ensure black, indigenous and Latinx communities are not left behind	http://dx.doi.org/10.1136/medethics-2021-107436	Published	April 1, 2022	Article	https://jme.bmj.com/content/early/2022/03/31/medethics-2021-107436	The SARS-CoV-2 (COVID-19) pandemic continues to expose underlying inequities in healthcare for black, indigenous and Latinx communities in the USA. The gaps in equitable care for communities of colour transcend the diagnosis, treatment and vaccinations related to COVID-19. We are experiencing a continued gap across racial and socioeconomic lines for those who suffer prolonged effects of COVID-19, also known as ‘Long COVID-19’. What we know about the treatment for Long COVID-19 so far is that it is complex, requires a multidisciplinary approach and there is still much research needed to fully understand the effects. In this paper, we discuss pragmatic considerations for including affected communities, relevant stakeholders, and leaders from communities of colour in the planning and implementation of Long COVID-19 research.
245	D242	ES	Petter Brodin, Giorgio Casari, Liam Townsend, Cliona O’Farrelly, Ivan Tancevski, Judith Löffler-Ragg, Trine H. Mogensen, Jean Laurent Casanova & The COVID Human Genetic Effort	Studying severe long COVID to understand post-infectious disorders beyond COVID-19	https://doi.org/10.1038/s41591-022-01766-7	Published	05 April 2022	Study	https://www.nature.com/articles/s41591-022-01766-7	In our cohort of patients with severe long COVID, we will investigate B cell and T cell responses to SARS-CoV-2 and will assess somatic hypermutation and clonal evolution relative to the patterns seen in people who recovered from COVID-19 without persistent signs and symptoms. This will serve as an indirect test of ongoing antigen exposure in patients with severe long COVID. Also, by assessing functional states of SARS-CoV-2-specific T cells, we will determine if patients with long COVID exhibit evidence of functional impairment that could explain viral persistence. One study used structural modeling to identify a possible superantigen motif within the SARS-CoV-2 spike protein near the S1–S2 cleavage site6. As indirect support for the possibility of superantigen-mediated stimulation, expansion of TRVB21-3+ cells has been observed in patients with MIS-C2 (Fig. 1b). Many pathogens contain superantigens able to activate T cells in a nonspecific manner, such as staphylococci that cause staphylococcal toxic shock syndrome. Interestingly, this syndrome has been reported to induce persistent symptoms that bear similarity to those seen in severe long COVID10. This overlap of symptoms suggests either a direct effect of the superantigen on tissues or immune dysregulation that gives rise to persistent symptoms after infection. As for the neurological symptoms common in long COVID and other post-infectious disorders, it is worth considering possible neurotoxin motifs. Such motifs have been described for the SARS-CoV-2 coronavirus6, and these neurotoxins could in theory exert direct effects on both the central nervous system and peripheral nervous system. We plan to perform TCR sequencing in patients with severe long COVID in search of expansion of TRVB21-3+ cells, as in MIS-C, and we will also perform in vitro stimulation assays using soluble S1 protein to assess T cell reactivity and possible functional dysregulation as an element of disease.Superantigen-mediated T cell activation can trigger broad B cell activation, and production of autoantibodies against a range of tissues has been shown in MIS-C2,5 and in patients with acute COVID-19. Also, chronic activation of the immune system by viral persistence can induce autoimmune responses, and molecular mimicry between components of a pathogen and host tissue can lead to specific post-infectious autoimmunity. Structural similarity between human neuronal antigens and SARS-CoV-2 proteins has been suggested. A particular form of autoimmunity described in long COVID is postural orthostatic tachycardia syndrome, a form of autonomic dysregulation that is possibly induced by functional autoantibodies that target G protein–coupled receptors on neurons (Fig. 1b). Another type of autoimmunity relevant to SARS-CoV-2 infection is the production of neutralizing autoantibodies to type I interferons, which explains a sizeable fraction of cases of hypoxemic COVID-19 pneumonia1. If such neutralizing autoantibodies are present before SARS-CoV-2 infection, due to prior infections or vaccinations, then a patient is clearly at risk of developing severe acute COVID-19. However, such neutralizing autoantibodies might also appear after SARS-CoV-2 infection, in which case they might instead enable viral persistence, the formation of a viral reservoir and long COVID. To test this hypothesis, we will look for the presence of neutralizing autoantibodies to type I interferons in patients with long COVID. Collectively, we believe that our genetic and immunological studies of patients with severe long COVID hold potential for better understanding of this complex condition, and by focusing on severe cases that develop after mild COVID-19, we maximize our chances of success. Our results would probably be applicable beyond COVID-19 and will hopefully provide important insights of relevance into other post-infectious disorders such as myalgic encephalomyelitis.
246	D243		Bala Munipalli, Lynsey Seim, Nancy L. Dawson, Dacre Knight & Abd Moain Abu Dabrh	Post-acute sequelae of COVID-19 (PASC): a meta-narrative review of pathophysiology, prevalence, and management	https://doi.org/10.1007/s42399-022-01167-4	Published	04 April 2022	Review	https://link.springer.com/article/10.1007/s42399-022-01167-4	Coronavirus Disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Over 220 countries and territories have been affected by this virus, and the infection rate has continued to rise. As patients recover from the virus, many are experiencing lingering symptoms. Understanding the impact of demographics and comorbidities on symptom prevalence, manifestations, and severity is not only relevant during acute infection, it is critical to the clinical management of patients with post-acute sequelae of COVID-19, also known as PASC. Herein, we provide a comprehensive review on the most recent research related to PASC. Specifically, we focus on the description of the disorder itself, compared to acute COVID-19, and which types of patients are most affected by long-term sequelae. Further, we share recommendations for management of the most common complications of PASC. We propose the following simplified symptom course-based categorization: Subacute or ongoing COVID-19 (PACS, post-acute COVID-19 syndrome) defined as symptoms continuing beyond the 4 weeks of acute infection, up to 12 weeks. Post-COVID-19 syndrome / conditions (PCS, PCC, long-COVID, long-haulers’ syndrome) chronic ongoing COVID-19 symptoms beyond 12 weeks from acute infection. Post-acute sequelae of COVID-19 (PASC) symptoms persisting beyond the 4-week period of acute infection. Both PACS (i.e., 4–12 weeks) and PCS (i.e., > 12 weeks) are identified as two different chronological stages of Post-COVID Conditions. PASC is becoming a recognizable and crucial clinical entity as data continue to inform of its pathogenesis, presentation, and clinical course. Anecdotal reporting has also raised questions about the implications of receiving a COVID-19 vaccine and the improvement in PASC. One out of five patients report improvement, mainly brain fog and anosmia, after SARS-CoV-2 vaccination [116]. Two-thirds of patients with PASC saw no worsening of symptoms after vaccination; fever, chills, and gastro-intestinal symptoms were frequently reported, similar to the general population [116]. This will require further research. The current understanding suggests PASC is caused by ACE2 receptor-binding, immune-dysregulation, and stimulation of hyper-inflammatory and hyper-coagulation pathways [9]. Preexisting conditions and the relationship to PASC remain largely unclear. Demographic data show higher prevalence and severity in females, with significant impact on under-resourced and disparate communities. The long-term management of PASC remains largely unknown. The most reported follow-up assessments include quality of life, functional neurocognitive and psychological evaluations, pulmonary function screening, and occupational rehabilitation. The multiorgan and heterogenous manifestation of PASC requires the need for multidisciplinary, coordinated care management that includes peer and community support for patients presenting with PACS. The strength of this review study is the succinct, up-to-date information it provides, including a table summarizing current management recommendations from literature, focused to general physicians, and primary care providers who are most likely to see PASC patients front-line. The meta-narrative review approach is deemed feasible, robust, and appropriate at this stage to outline existing evidence and gaps in knowledge for future direction.
247	D244		Mark A Faghy,Thomas Maden-Wilkinson,Ross Arena,Robert J Copeland,Rebecca Owen,Henry Hodgkins &Ash Willmott	COVID-19 patients require multi-disciplinary rehabilitation approaches to address persisting symptom profiles and restore pre-COVID quality of life	https://doi.org/10.1080/17476348.2022.2063843	Published	18 Apr 2022	Study	https://www.tandfonline.com/doi/full/10.1080/17476348.2022.2063843	Background Long-COVID diagnosis is prominent, and our attention must support those experiencing debilitating and long-standing symptoms. To establish patient pathways, we must consider the societal and economic impacts of sustained COVID-19. Accordingly, we sought to determine the pertinent areas impacting quality of life (QoL) following a COVID-19 infection. Research methods Three hundred and eighty-one participants completed a web-based survey (83% female, 17% male) consisting of 70 questions across 7 sections (demographics, COVID-19 symptoms; QoL; sleep quality; breathlessness; physical activity and mental health). Mean age, height, body mass and body mass index (BMI) were 42 ± 12 years, 167.6 ± 10.4 cm, 81.2 ± 22.2 kg, and 29.1 ± 8.4 kg.m2, respectively. Results Participant health was reduced because of COVID-19 symptoms (‘Good health’ to ‘Poor health’ [P < 0.001]). Survey respondents who work reported ongoing issues with performing moderate (83%) and vigorous (79%) work-related activities. Conclusions COVID-19 patients report reduced capacity to participate in activities associated with daily life, including employment activities. Bespoke COVID-19 support pathways must consider multi-disciplinary approaches that address the holistic needs of patients to restore pre-pandemic quality of life and address experienced health and wellbeing challenges. Plain Language Summary: The long-term impact of long-COVID has a dramatic impact upon daily activities and lifestyle. The development of bespoke support pathways to support patients must address the physical and psychological considerations to adequately restore pre-COVID quality of life and address broader societal and economic implications, especially for those that are of working age.
248	D245		Arthur A. Mirin,Mary E. Dimmock &Leonard A. JasonORCID Icon	Updated ME/CFS prevalence estimates reflecting post-COVID increases and associated economic costs and funding implications	https://doi.org/10.1080/21641846.2022.2062169	Published	11 Apr 2022	Article	https://www.tandfonline.com/doi/abs/10.1080/21641846.2022.2062169	In this article, we update our earlier analyses of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) economic impact and its National Institutes of Health (NIH) funding versus disease burden, taking into account the anticipated new cases of ME/CFS resulting from COVID-19. Prior to the COVID pandemic, we estimated a United States ME/CFS prevalence of 1.5 million and an annual economic impact of $36–51 billion. Now, due to COVID and its resulting post-acute sequalae, we estimate total ME/CFS prevalence could rise to between five and nine million. This would incur an annual U.S. economic impact of $149 to $362 billion in medical expenses and lost income, exclusive of other costs, such as disability benefits, social services, and lost wages of caretakers. NIH funding for ME/CFS research would need to expand from the current amount of $15 million per year to approximately $472–$600 million annually, up to a 40-fold increase, to be commensurate with that of similarly burdensome diseases.
249	D246		Joan Stephenson, PhD1	Biden Administration Outlines Strategy to Tackle Long COVID	https://doi.org/10.1001/jamahealthforum.2022.1280	Published	April 12, 2022	Article	https://jamanetwork.com/journals/jama-health-forum/fullarticle/2791210	In a presidential memorandum issued last week, the Biden administration ordered the secretary of Health and Human Services (HHS) to create a national action plan to coordinate research on long-term effects of COVID-19, or long COVID, and support for patients experiencing the condition. The HHS “will be leading a government-wide response to Long COVID focused on three main goals: improving care services and other support for individuals with Long COVID; enhancing education and outreach among the public-private sector and the medical community; and advancing research to support both goals,” HHS Secretary Xavier Becerra said during a White House COVID-19 Response Team briefing. It is not yet clear how many people are affected by long COVID. According to a March 2022 federal government report, findings from US studies suggest that 10% to 30% of people with COVID-19 will develop symptoms that last longer than 4 weeks, with some resulting in significant disability. Based on these estimates, 7.7 million to 23 million people in the US may have developed long COVID as of February 2022. In August 2021, HHS and the Department of Justice released new guidance that classifies long COVID as a physical or mental impairment, which means that individuals who are affected can qualify as having a disability under federal civil rights laws and receive appropriate accommodations and services. The presidential memorandum directs HHS to issue a report in 120 days that will provide information about available services and support across federal agencies to help people experiencing long COVID. In addition, the report “will specifically address the long-term effects of COVID-19 on high-risk communities and efforts to address disparities in access to services and supports,” according to a White House fact sheet about the administration’s plan to address long COVID.
250	D247		Lakshmi Krishnan	An Extraordinary Sequel: The ‘Russian’ Influenza and Enduring Sequelae in Victorian Culture	https://doi.org/10.1093/jvcult/vcac012	Published	05 April 2022	Article	https://academic.oup.com/jvc/advance-article/doi/10.1093/jvcult/vcac012/6563702?login=true	In 1895, the crime-writing duo of L. T. Meade and Clifford Halifax, MD, published ‘A Doctor’s Dilemma’ in The Strand Magazine. In it, the young physician Arthur Feveral describes a recent influenza outbreak which has left an ‘extraordinary sequel . . . My health is gone—my nerve has deserted me’. Influenza plays a central role in this fiction, but Feveral’s story is simply one of many – documentary and fictionalized – that populate the pages of late nineteenth-century British periodicals. The ‘Russian’ influenza pandemic of 1889–1894 was the last great European outbreak of the nineteenth century, leaving in its wake such widely discussed neurological effects (neurasthenia, psychosis, and melancholy) that they earned their own nosography: ‘influenza nervosa’. This paper examines the pandemic’s enduring cultural and biosocial impact through the framework of sequelae – chronic conditions arising in the aftermath of acute illness. Drawing on medical case histories, criminal reports, illness narratives, and works of fiction, it explores how the Victorians taxonomized and theorized such long-term effects of infectious disease. First, sequelae became a category separate from ‘complications’, vital to broader preoccupations with prolonged illness, uncertainty, and moral and bodily weakness and degeneracy, and the Victorians scaffolded around it notions of vigour and debility, difference, predisposition, and heredity. Second, they domesticated and repurposed colonial and tropical theories of hygiene as explanatory frameworks. Through close readings of ‘long influenza’ in the clinic and in fiction, this paper also frames the kinds of narratives which gained especial purchase, and the sufferers deemed both susceptible and sympathetic. Finally, it argues that the acute phase of infectious anxiety gave way to a longue durée of sequelae, and that Victorian responses provide critical insights and warnings for our own era.
251	D248		Anushri Umesh, Kumar Pranay, Ramesh Chandra Pandey & Mukesh Kumar Gupta	Evidence mapping and review of long-COVID and its underlying pathophysiological mechanism	https://doi.org/10.1007/s15010-022-01835-6	Published	30 April 2022	Review	https://link.springer.com/article/10.1007/s15010-022-01835-6	Purpose Apart from the global disease burden of acute COVID-19 disease, the health complications arising after recovery have been recognized as a long-COVID or post-COVID-19 syndrome. Evidences of long-COVID symptoms involving various organ systems are rapidly growing in literature. The objective was to perform a rapid review and evidence mapping of systemic complications and symptoms of long-COVID and underlying pathophysiological mechanisms. Methods Publications reporting clinical trials, observational cohort studies, case–control studies, case-series, meta-analysis, and systematic reviews, focusing on the squeal of the disease, consequences of COVID-19 treatment/hospitalization, long-COVID, chronic COVID syndrome, and post acute COVID-19 were reviewed in detail for the narrative synthesis of frequency, duration, risk factors, and pathophysiology. Results The review highlights that pulmonary, neuro-psychological, and cardiovascular complications are major findings in most epidemiological studies. However, dysfunctional gastrointestinal, endocrine, and metabolic health are recent findings for which underlying pathophysiological mechanisms are poorly understood. Analysis of the clinical trial landscape suggests that more than 50% of the industry-sponsored trials are focused on pulmonary symptoms. In contrast to the epidemiological trends and academic trials, cardiovascular complications are not a focus of industry-sponsored trials, suggestive of the gaps in the research efforts. Conclusion The gap in epidemiological trends and academic trials, particularly concerning cardiovascular complications not being a focus of industry-sponsored trials is suggestive of the gaps in research efforts and longer follow-up durations would help identify other long-COVID-related health issues such as reproductive health and fertility.
252	D249		Poloni, Tino Emanuele,*; Medici, Valentina; Zito, Antonio; Carlos, Arenn Faye	The long-COVID-19 in older adults facts and conjectures	https://doi.org/10.4103/1673-5374.339483	Published	01/05/2022	Article	https://journals.lww.com/nrronline/Fulltext/2022/12000/The_long_COVID_19_in_older_adults__facts_and.27.aspx	The coronavirus disease-19 (COVID-19) has greatly affected the overall health of the elderly population through direct biological (infection-related) and indirect psychosocial (quarantine- and isolation-related) effects. Because the severe form of COVID-19 most frequently targets this population, the prevalence of long-term sequelae is expected to rise consequentially in people ≥ 65 years old. The prominent neuropsychiatric consequences of COVID-19 and the cognitive frailty seen in older adults can both have a negative impact on their mental health. To explore the behavioral, neurological, and psychosocial consequences of COVID-19, we conducted separate studies on different populations of older adult people residing in Lombardy – the Italian epicenter of the first pandemic wave in spring 2020. In one study, we found that behavioral changes (i.e., delirium) were a frequent symptom of COVID-19, manifesting at disease onset and preceding the typical symptoms in about 1/3 (36.8%) of cases, particularly in patients with neurocognitive disorders (NCD), such as dementia (major-NCD) or mild cognitive impairment (mild-NCD). Delirium was also associated with short-term mortality and potential long-term cognitive sequelae (Poloni et al., 2020). To uncover the neuropathology underlying behavioral changes and their possible effects over time, we compared 9 brains of elderly patients who had died of COVID-19 (with and without dementia) with 6 brains from age-matched non-COVID controls. The main finding was an excessive innate immune response, represented by microglial hyperactivation. Although we observed severe inflammatory changes especially in the brainstem, we did not find neuropathological evidence suggestive of SARS-CoV-2 replication in the brain (Gagliardi et al., 2021; Poloni et al., 2021). In a study evaluating the psychosocial consequences of the lockdown due to the pandemic (Carlos et al., 2021), we observed that those with mild-moderate dementia were unable to cope and adapt to the life changes caused by the restrictions and consequently suffered from depression and cognitive decline. Before COVID, patients with dementia normally engaged in habitual daily activities. The disruption of said routines, the inability to engage in new activities, and the incapability to use modern technologies all triggered psychological distress and some degree of cognitive and motor regression (Figure 1A). Although lockdown (the sternest form of quarantine in history) protected them from COVID-19, the social seclusion and the inability to access primary care treatment – aggravated by an unprepared and unequipped primary care health sector – caused further complications (Carlos et al., 2021). Moreover, the general effects of the pandemic in terms of loss of “individual freedom”, economic crisis, and mass media conditioning should not be overlooked due to their possible impact on mental health.
253	D250		Daniel Munblit Margaret E O'Hara Athena Akrami Elisa Perego Piero Olliaro Dale M Needham	Long COVID: aiming for a consensus	https://doi.org/10.1016/S2213-2600(22)00135-7	Published	May 04, 2022	Article	https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00135-7/fulltext	The spectrum of signs and symptoms that can newly occur and persist for months to years after SARS-CoV-2 infection was initially named long COVID. This term was collectively created by the patient community in the spring of 2020,1 and was later followed by other terms, such as post-COVID-19 condition, post-acute sequelae of SARS-CoV-2 infection, and post-COVID syndrome.2 This condition can affect different organs and body systems, with a wide range of signs and symptoms reported. Given the magnitude of the sequelae of SARS-CoV-2 infection, it is essential to agree upon the nomenclature and definition to assess its incidence, subtypes, and severity. This process cannot be left to agencies, health-care providers, or researchers alone, but requires extensive consultation, notably including the people affected. In early 2021, WHO established technical working groups to provide a clinical case definition for this condition and amplified the calls of patient groups for recognition, research, and rehabilitation. A rapidly increasing number of studies started to investigate the incidence and prevalence, features, and risk factors of the prolonged sequelae of SARS-CoV-2 infection, the underlying mechanisms, and case management approaches. The spectrum of signs and symptoms that can newly occur and persist for months to years after SARS-CoV-2 infection was initially named long COVID. This term was collectively created by the patient community in the spring of 2020,1 and was later followed by other terms, such as post-COVID-19 condition, post-acute sequelae of SARS-CoV-2 infection, and post-COVID syndrome.2 This condition can affect different organs and body systems, with a wide range of signs and symptoms reported. Given the magnitude of the sequelae of SARS-CoV-2 infection, it is essential to agree upon the nomenclature and definition to assess its incidence, subtypes, and severity. This process cannot be left to agencies, health-care providers, or researchers alone, but requires extensive consultation, notably including the people affected. In early 2021, WHO established technical working groups to provide a clinical case definition for this condition and amplified the calls of patient groups for recognition, research, and rehabilitation. A rapidly increasing number of studies started to investigate the incidence and prevalence, features, and risk factors of the prolonged sequelae of SARS-CoV-2 infection, the underlying mechanisms, and case management approaches.
254	D251		Emily R Pfaff, PhD * Andrew T Girvin, PhD * Tellen D Bennett, MD Abhishek Bhatia, MS Ian M Brooks, PhD Rachel R Deer, PhD Jonathan P Dekermanjian, MS Sarah Elizabeth Jolley, MD Michael G Kahn, MD Kristin Kostka, MPH Julie A McMurry, MPH Richard Moffitt, PhD Anita Walden, MS Prof Christopher G Chute, MD Prof Melissa A Haendel, PhD	Identifying who has long COVID in the USA: a machine learning approach using N3C data	https://doi.org/10.1016/S2589-7500(22)00048-6	Published	May 16, 2022	Study	https://www.thelancet.com/journals/landig/article/PIIS2589-7500(22)00048-6/fulltext	Background Post-acute sequelae of SARS-CoV-2 infection, known as long COVID, have severely affected recovery from the COVID-19 pandemic for patients and society alike. Long COVID is characterised by evolving, heterogeneous symptoms, making it challenging to derive an unambiguous definition. Studies of electronic health records are a crucial element of the US National Institutes of Health's RECOVER Initiative, which is addressing the urgent need to understand long COVID, identify treatments, and accurately identify who has it—the latter is the aim of this study. Methods Using the National COVID Cohort Collaborative's (N3C) electronic health record repository, we developed XGBoost machine learning models to identify potential patients with long COVID. We defined our base population (n=1 793 604) as any non-deceased adult patient (age ≥18 years) with either an International Classification of Diseases-10-Clinical Modification COVID-19 diagnosis code (U07.1) from an inpatient or emergency visit, or a positive SARS-CoV-2 PCR or antigen test, and for whom at least 90 days have passed since COVID-19 index date. We examined demographics, health-care utilisation, diagnoses, and medications for 97 995 adults with COVID-19. We used data on these features and 597 patients from a long COVID clinic to train three machine learning models to identify potential long COVID among all patients with COVID-19, patients hospitalised with COVID-19, and patients who had COVID-19 but were not hospitalised. Feature importance was determined via Shapley values. We further validated the models on data from a fourth site. Findings Our models identified, with high accuracy, patients who potentially have long COVID, achieving areas under the receiver operator characteristic curve of 0·92 (all patients), 0·90 (hospitalised), and 0·85 (non-hospitalised). Important features, as defined by Shapley values, include rate of health-care utilisation, patient age, dyspnoea, and other diagnosis and medication information available within the electronic health record. Interpretation Patients identified by our models as potentially having long COVID can be interpreted as patients warranting care at a specialty clinic for long COVID, which is an essential proxy for long COVID diagnosis as its definition continues to evolve. We also achieve the urgent goal of identifying potential long COVID in patients for clinical trials. As more data sources are identified, our models can be retrained and tuned based on the needs of individual studies. Notable differences include the high importance of dexamethasone in the hospitalised model, which decreased the likelihood of an individual patient being labelled as a potential long COVID patient. Dexamethasone is not present in the top 50 features of the non-hospitalised model. Similarly, cough and dyssomnia, which increased the likelihood of an individual beinglabelled as a potential long COVID patient, are important features in the non-hospitalised model, but do not appear in the hospitalised model. COVID-19 vaccination after acute disease, which is consistently an important feature in all three models, decreased the likelihood of patients being labelled as potentially having long COVID. This result is noteworthy and indicates that not only does vaccination against SARS-CoV-2 protect against hospitalisation and death, but that it might also protect against long COVID.
255	D252		Yusuke Miyazato Shinya Tsuzuki Shinichiro Morioka Mari Terada Satoshi Kutsuna Sho Saito Yumiko Shimanishi Kozue Takahashi Mio Sanada Masako Akashi Chika Kuge Yasuyo Osanai Keiko Tanaka Michiyo Suzuki Kayoko Hayakawa Norio Ohmagari	Factors associated with development and persistence of post-COVID conditions: A cross-sectional study	https://doi.org/10.1016/j.jiac.2022.04.025	Published	May 18, 2022	Survey	https://www.jiac-j.com/article/S1341-321X(22)00139-8/fulltext	Introduction The post-COVID condition has become a social concern. Although the patient characteristics associated with the development of this condition are partially known, those associated with its persistence have not been identified. Methods We conducted a cross-sectional questionnaire-based survey among patients who had recovered from COVID-19 and visited the National Center for Global Health and Medicine between February 2021 and March 2021. Demographic and clinical data, and data regarding the presence and duration of post-COVID conditions were obtained. We identified factors associated with the development and persistence of post-COVID conditions using multivariate logistic and linear regression analyses, respectively. Results We analyzed 457 of 526 responses (response rate, 86.9%). The median patient age was 47 years. Of these, 378 patients (84.4%) had mild disease in the acute phase. The number of patients with symptoms at 6 and 12 months after onset or diagnosis was 120 (26.3%) and 40 (8.8%), respectively. Women were at risk of developing fatigue (odds ratio [OR]: 2.03, 95% confidence interval [CI]: 1.31–3.14), dysosmia (OR: 1.91, 95%CI: 1.24–2.93), dysgeusia (OR: 1.56, 95%CI: 1.02–2.39), hair loss (OR: 3.00, 95%CI: 1.77–5.09), and persistence of any symptoms (coefficient: 38.0, 95%CI: 13.3–62.8). Younger age and low body mass index were factors for developing dysosmia (OR: 0.96, 95%CI: 0.94–0.98 and OR: 0.94, 95%CI: 0.89–0.99, respectively) and dysgeusia (OR: 0.98, 95%CI: 0.96–1.00 and OR: 0.93, 95%CI: 0.88–0.98, respectively). Conclusion We identified factors involved in the development and persistence of post-COVID conditions. Many patients, even those with mild conditions, experience long-term residual symptoms.
256	D253		Solomiia Savedchuk, Rasha Raslan, Sarah Nystrom and Matthew A. Sparks	Emerging Viral Infections and the Potential Impact on Hypertension, Cardiovascular Disease, and Kidney Disease	https://doi.org/10.1161/CIRCRESAHA.122.320873	Published	12 May 2022	Article	https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.122.320873	Viruses are ubiquitous in the environment and continue to have a profound impact on human health and disease. The COVID-19 pandemic has highlighted this with impressive morbidity and mortality affecting the world’s population. Importantly, the link between viruses and hypertension, cardiovascular disease, and kidney disease has resulted in a renewed focus and attention on this potential relationship. The virus responsible for COVID-19, SARS-CoV-2, has a direct link to one of the major enzymatic regulatory systems connected to blood pressure control and hypertension pathogenesis, the renin-angiotensin system. This is because the entry point for SARS-CoV-2 is the ACE2 (angiotensin-converting enzyme 2) protein. ACE2 is one of the main enzymes responsible for dampening the primary effector peptide Ang II (angiotensin II), metabolizing it to Ang-(1-7). A myriad of clinical questions has since emerged and are covered in this review. Several other viruses have been linked to hypertension, cardiovascular disease, and kidney health. Importantly, patients with high-risk apolipoprotein L1 (APOL1) alleles are at risk for developing the kidney lesion of collapsing glomerulopathy after viral infection. This review will highlight several emerging viruses and their potential unique tropisms for the kidney and cardiovascular system. We focus on SARS-CoV-2 as this body of literature in regards to cardiovascular disease has advanced significantly since the COVID-19 pandemic.
257	D254		David M. Cutler, PhD1	The Costs of Long COVID	https://doi.org/10.1001/jamahealthforum.2022.1809	Published	May 12, 2022	Article	https://jamanetwork.com/journals/jama-health-forum/fullarticle/2792505	In an October 2020 analysis, we estimated9 the then-nascent COVID-19 pandemic might result in $2.6 trillion of cost as a result of long COVID. Unfortunately, our estimate seems very much on target. The massive cost of long COVID has several policy implications. Investing in treatments for long COVID is obviously a high priority. According to a recent report from the Rockefeller Foundation, progress to date has been “achingly slow” and that needs to change.10 Experimenting with ways to make employment easier for people with long-term complications is also a high priority. People with chronic fatigue may be better able to work at home or with frequent breaks than they can with a time-delimited office day and a long commute. By speeding up the transition to telework, enhanced employment opportunities for those with long COVID may be possible. In addition, the economic cost of long COVID reinforces the value of comprehensive actions to prevent and treat new infections. Mask mandates are unpopular in many areas and a substantial share of the public resists being vaccinated—though each action should still be encouraged. But additional progress might also be made through expanding rapid COVID-19 test capability, global surveillance to detect new SARS-CoV-2 variants, and immediate action should any such variants be detected. Such measures have associated costs, but no matter how large these costs are, they pale compared with the potential benefits.
258	D255		Michael C. Sneller, MD, C. Jason Liang, PhD, Adriana R. Marques, MD, Joyce Y. Chung, MD, Sujata M. Shanbhag, MD, Joseph R. Fontana, MD, Haniya Raza, DO, Onyi Okeke, MD, Robin L. Dewar, PhD, Bryan P. Higgins, RN, Katie Tolstenko, FNP, Richard W. Kwan, MPAS, Kathleen R. Gittens, RN, Catherine A. Seamon, RN, Genevieve McCormack, Jacob S. Shaw, Grace M. Okpali, Melissa Law, RN, Krittin Trihemasava, Brooke D. Kennedy, Victoria Shi, MS, J. Shawn Justement, Clarisa M. Buckner, PhD, Jana Blazkova, PhD, Susan Moir, PhD, Tae-Wook Chun, PhD, and H. Clifford Lane, MD	A Longitudinal Study of COVID-19 Sequelae and Immunity: Baseline Findings	https://www.acpjournals.org/doi/full/10.7326/M21-4905	Published	24 May 2022	Study	https://www.acpjournals.org/doi/full/10.7326/M21-4905	Background: A substantial proportion of persons who develop COVID-19 report persistent symptoms after acute illness. Various pathophysiologic mechanisms have been implicated in the pathogenesis of postacute sequelae of SARS-CoV-2 infection (PASC). Objective: To characterize medical sequelae and persistent symptoms after recovery from COVID-19 in a cohort of disease survivors and controls. Design: Cohort study. (ClinicalTrials.gov: NCT04411147) Setting: National Institutes of Health Clinical Center, Bethesda, Maryland. Participants: Self-referred adults with laboratory-documented SARS-CoV-2 infection who were at least 6 weeks from symptom onset were enrolled regardless of presence of PASC. A control group comprised persons with no history of COVID-19 or serologic evidence of SARS-CoV-2 infection, recruited regardless of their current health status. Both groups were enrolled over the same period and from the same geographic area. Measurements: All participants had the same evaluations regardless of presence of symptoms, including physical examination, laboratory tests and questionnaires, cognitive function testing, and cardiopulmonary evaluation. A subset also underwent exploratory immunologic and virologic evaluations. Results: 189 persons with laboratory-documented COVID-19 (12% of whom were hospitalized during acute illness) and 120 antibody-negative control participants were enrolled. At enrollment, symptoms consistent with PASC were reported by 55% of the COVID-19 cohort and 13% of control participants. Increased risk for PASC was noted in women and those with a history of anxiety disorder. Participants with findings meeting the definition of PASC reported lower quality of life on standardized testing. Abnormal findings on physical examination and diagnostic testing were uncommon. Neutralizing antibody levels to spike protein were negative in 27% of the unvaccinated COVID-19 cohort and none of the vaccinated COVID-19 cohort. Exploratory studies found no evidence of persistent viral infection, autoimmunity, or abnormal immune activation in participants with PASC. Limitations: Most participants with COVID-19 had mild to moderate acute illness that did not require hospitalization. The prevalence of reported PASC was likely overestimated in this cohort because persons with PASC may have been more motivated to enroll. The study did not capture PASC that resolved before enrollment. Conclusion: A high burden of persistent symptoms was observed in persons after COVID-19. Extensive diagnostic evaluation revealed no specific cause of reported symptoms in most cases. Antibody levels were highly variable after COVID-19.
259	D256	About D255	Aluko A. HopeAluko A. Hope	Understanding and Improving Recovery From COVID-19	https://doi.org/10.7326/M22-1492	Published	https://doi.org/10.7326/M22-1492	Editorial	https://www.acpjournals.org/doi/full/10.7326/M22-1492	The study results will be unsurprising to clinicians who have been seeing a high volume of patients with PASC. First, participants with PASC reported more symptoms and worse physical and mental health status than COVID-19 survivors without PASC or control participants. Patients with PASC reported a median of 2 (IQR, 1 to 4) symptoms, with the most common being fatigue, dyspnea, changes in smell, cognitive changes, and sleep changes. Second, the investigators found few differences between COVID-19 survivors and control participants in objective tests, such as physical examination, neurocognitive assessment, and plasma inflammatory biomarkers. Importantly, they found no differences in the levels of immunologic markers that might indicate a potential immunologic mechanism for PASC. This is a small study of a group of highly motivated participants, and these findings should not lead to changes in clinical care. However, the study's strengths include that the extensive evaluations performed as part of the study protocol mirror the often exhaustive and expensive evaluations that many patients with PASC get when they seek care. After these patients endure these evaluations, they are often told that everything is normal and nothing is wrong, implying that their subjective reports are less credible than the objective findings. Unfortunately, this study did not attempt to measure an important symptom complex that many believe is the hallmark of PASC: postexertional symptom exacerbation, or postexertional malaise (PEM) (4, 9). This refers to worsening of the patient's fatigue, cognitive changes, and other symptoms after physical, cognitive, social, or emotional exertion. Patients report that the worsening is often delayed from the onset of the trigger and out of proportion to the degree of exertion. Practically, acknowledging the importance of PEM means that detailed subjective and objective assessments need to account for the fact that patients' symptoms and performance may change dramatically depending on whether they are in a restful or stressful state. In addition, assessment of PEM needs to consider stressful states in the context of a patient's pre–COVID-19 level of function and fitness across multiple health domains. Future studies need to better capture these issues. Although the investigators aimed to enroll post–COVID-19 participants with a wide spectrum of initial disease severity and without regard for the presence or absence of PASC, the nature of their recruitment process may have led to overrepresentation of patients with higher levels of physical function who were nevertheless worried about persistent symptoms. Importantly, the control participants were not matched on age or gender, and the investigators conducting the physical examinations were not blinded to study group. Although their definition of PASC has face validity, the investigators did not consider how other more restrictive definitions would have affected their findings. Their approach to identifying comorbid conditions, such as anxiety, in the study sample likely overrepresented this diagnosis in patients with PASC given that central or peripheral autonomic impairment is a common feature of many postviral fatigue syndromes and is often misdiagnosed as an anxiety syndrome. Because most of the study enrollment occurred before the advent of COVID-19 vaccines, these findings may not be generalizable to a population of fully vaccinated adults. As we emerge from the hell of the COVID-19 pandemic, it is time to insist on painstaking study and care of survivors of COVID-19. Without a fuller understanding of pathophysiology and disease course, we must not allow normal objective tests to negate our patients' subjective experiences. We need to explore whether real-world measurements during both restful and stressful conditions offer insight into the mechanisms of PASC. While we gather evidence, our patients deserve personalized care pathways that acknowledge the many biopsychosocial factors involved in illness recovery.
260	D257		D. Castanares-ZapateroORCID Icon,P. Chalon,L. Kohn,M. Dauvrin,J. Detollenaere,C. Maertens de Noordhout,C. Primus-de Jong,I. Cleemput &K. Van den Heede show less	Pathophysiology and mechanism of long COVID: a comprehensive review	https://doi.org/10.1080/07853890.2022.2076901	Published	20 May 2022	Review	https://www.tandfonline.com/doi/full/10.1080/07853890.2022.2076901	Background: After almost 2 years of fighting against SARS-CoV-2 pandemic, the number of patients enduring persistent symptoms long after acute infection is a matter of concern. This set of symptoms was referred to as “long COVID”, and it was defined more recently as “Post COVID-19 condition” by the World health Organization (WHO). Although studies have revealed that long COVID can manifest whatever the severity of inaugural illness, the underlying pathophysiology is still enigmatic. Aim: To conduct a comprehensive review to address the putative pathophysiology underlying the persisting symptoms of long COVID. Method: We searched 11 bibliographic databases (Cochrane Library, JBI EBP Database, Medline, Embase, PsycInfo, CINHAL, Ovid Nursing Database, Journals@Ovid, SciLit, EuropePMC, and CoronaCentral). We selected studies that put forward hypotheses on the pathophysiology, as well as those that encompassed long COVID patients in their research investigation. Results: A total of 98 articles were included in the systematic review, 54 of which exclusively addressed hypotheses on pathophysiology, while 44 involved COVID patients. Studies that included patients displayed heterogeneity with respect to the severity of initial illness, timing of analysis, or presence of a control group. Although long COVID likely results from long-term organ damage due to acute-phase infection, specific mechanisms following the initial illness could contribute to the later symptoms possibly affecting many organs. As such, autonomic nervous system damage could account for many symptoms without clear evidence of organ damage. Immune dysregulation, auto-immunity, endothelial dysfunction, occult viral persistence, as well as coagulation activation are the main underlying pathophysiological mechanisms so far. Conclusion: Evidence on why persistent symptoms occur is still limited, and available studies are heterogeneous. Apart from long-term organ damage, many hints suggest that specific mechanisms following acute illness could be involved in long COVID symptoms. KEY MESSAGES Long-COVID is a multisystem disease that develops regardless of the initial disease severity. Its clinical spectrum comprises a wide range of symptoms. The mechanisms underlying its pathophysiology are still unclear. Although organ damage from the acute infection phase likely accounts for symptoms, specific long-lasting inflammatory mechanisms have been proposed, as well. Existing studies involving Long-COVID patients are highly heterogeneous, as they include patients with various COVID-19 severity levels and different time frame analysis, as well.
261	D258		A.Menard1M.Chine2L.Meddeb1P.Rossi2	Du suivi Post-Covid au Covid-Long : Score pronostic à partir d'une prise en charge holistique	https://doi.org/10.1016/j.mmifmc.2022.03.125	Published	31 May 2022	Study	https://www.sciencedirect.com/science/article/pii/S277274322200143X	Introduction Le COVID long est un problème de santé publique émergent manquant à ce jour d'une définition claire (OMS). Les médecins généralistes, en première ligne, aurait besoin d'un outil holistique, reproductible et facile pour les aider à évaluer le pronostic d'évolution vers un Covid-long chez leur patient ayant contracté une infection par le Sars-Cov-19 Matériels et méthodes Depuis mai 2020 dans notre centre un suivi standardisé (tous les 3 mois) et pluri disciplinaire est proposé aux patients ayant fait une forme sévère (post hospitalisation) ou ambulatoire mais avec symptômes persistants. Ils sont inclus dans une cohorte de suivi longitudinale avec un recueil à chaque visite des auto questionnaires (qualité de vie : SF36, fatigue : Pichot,dyspnée : MRC,Borg, cognitifs : MoCa, Stress : SSPT) un examen clinique exhaustif, des avis spécialisés avec bilan sanguin et imagerie selon l'évolution. L'objectif de notre étude est de décrire l'ensemble de nos données sur les caractéristiques socio-clinico-biologiques des patients inclus (J0) avec au moins une consultation de suivi Post Covid > à 4 semaines (S4) ayant évolué ou pas vers un Covid-Long ( > 12S) pour construire un score composite du Covid-Long. Résultats 201 patients ont été inclus, 190 analysés dont 55 % de femmes, d'âge médian de 55 ans, actif dans 60 % des cas (24 % domaine santé), 58 % avec une comorbidité à risque de forme sévère. L'épisode aigue en ambulatoire pour 85 (42.2 %) patients, en hospitalisation conventionnelle pour 76 (37.8 %) ou en soins intensif/réanimation pour 40 (20 %). Une corticothérapie et une oxygénothérapie ont été prescrite pour respectivement 78 (38.8 %) et 114 (56.7 %). 49 (24.4 %) patients ont décompensé ou découvert (7 %) une maladie chronique. En moyenne les patients ont eu 2,6 visites et 48 % d'entre eux ont un suivi de plus de 12 mois. A S12 du suivi, 122 patients ont le statut de COVID Long (CL+) avec un nb moyen de symp = 3,6+/-2,2 (1-10) et 68 sont guéris (CL-). En analyse uni variée les FDR de CL+/CL- sont 1) le sexe féminin (p=0.004), un âge< à 65 ans (p=0.002) et être personnel de santé (p=0.022). 2) à J0 : anosmie/agueusie (p=0.011), myalgies (p=0.041) et épisode initiale ambulatoire (p=0.002). 3) à S4 : une dyspnée [échelle de Borg ≥ 3 (p=0.003)+ mMRC ≥ 1 (p=0.036)] et une Fatigue sévère [Pichot ≥ 20 (p<0.001)]. Dans le modèle de régression logistique multivariée, les FDR de CL+ sont à J0 d'avoir un âge < à 65 ans et fait un COVID aigue peu sévère avec prise en charge en ambulatoire avec respectivement OR 2.4 (IC95 : [1.0 ; 5.4]) et OR 2.3 (IC95 : [2.3 ; 4.6]). 2) à S4 post COVID d'avoir des difficultés cognitives OR 6.046 (IC95 : [1.82 ; 20.1]) et les signes fonctionnels psychiatriques OR 5.9 (IC95 : [1.7 ; 20.4]) ainsi qu'une Fatigue sévère OR 5.4 (IC95 : [1.2 ; 24.1]). En modélisant nos résultats nous avons construit un score composite comme outil pronostique de Covid-Long. Dans la formule chaque item en gras devra etre remplacé par 0 ou1 selon abscence ou presence, femme (1) et age en chiffre. =1/(1+(EXP((-1)((-2,745)+(-0,329)Femme+0,005AgeQuantitatif +0,589ambulatoire +(-0,418)FDR-HCSP+0,9Symptômes<5+(0,181)Borg > 3+0,263mMRC > 1+1,694Pichot > 20+1,72anosmie/agueusie+1,799DifficultésCognitives+1,766SymptomesPsychiatriques+2,008*DiagnosticDifferentiel))) Conclusion Ce score, apres une validation externe, nous permettra d'évaluer le pourcentage de risque d'évoluer vers un COVID long qu'aura chaque patient d'après ses données du J0 et de sa première consultation post covid. Cette étude objective à nouveau la nécessité de chercher à la fois la présence des symptômes mais aussi de les quantifier par des échelles simples et reproductibles.
262	D259		Haider, Saman1; Janowski, Adam J.1; Lesnak, Joseph B.1; Hayashi, Kazuhiro1; Dailey, Dana L.2; Chimenti, Ruth1; Frey-Law, Laura A.1; Sluka, Kathleen A.1,*	A comparison of pain, fatigue, and function between post-COVID-19 condition, fibromyalgia, and chronic fatigue syndrome: a survey study	https://doi.org/10.1097/j.pain.0000000000002711	Published	June 08, 2022	Study	https://journals.lww.com/pain/Abstract/9900/A_comparison_of_pain,_fatigue,_and_function.115.aspx	A growing number of individuals report prolonged symptoms following acute COVID-19 infection, known as post-COVID-19 condition (post-COVID-19). While studies have emerged investigating the symptom sequelae of post-COVID-19, there has been limited investigation into the characterization of pain, fatigue, and function in these individuals, despite initial reports of a clinical phenotype similar to fibromyalgia (FMS) and chronic fatigue syndrome/myalgic encephalomyelitis (CFS). This study aimed to characterize multiple symptom domains in individuals reporting post-COVID-19 and compare its clinical phenotype to those with FMS and CFS. A total of 707 individuals with a single or comorbid diagnosis of post-COVID-19, FMS, and/or CFS completed multiple surveys assessing self-reported pain, fatigue, physical and cognitive function, catastrophizing, kinesiophobia, anxiety, depression, dyspnea, and sleep quality. In all three diagnoses, elevated pain, fatigue, anxiety, depression, catastrophizing, and kinesiophobia were reported. Physical and cognitive function were similarly impacted among individuals with post-COVID-19, FMS, and CFS; however, individuals with post-COVID-19 reported lower pain and fatigue than FMS and CFS. The comorbid diagnosis of post-COVID-19 with FMS and/or CFS further exacerbated pain, fatigue, and psychological domains when compared to post-COVID-19 alone. In summary, individuals with post-COVID-19 report a symptom phenotype similar to FMS and CFS, negatively impacting cognitive and physical function, but with less severe pain and fatigue overall. These findings may help direct future investigations of the benefit of a biopsychosocial approach to the clinical management of post-COVID-19.
263	D260		Chen Chen, Spencer R. Haupert, Lauren Zimmermann, Xu Shi, Lars G. Fritsche, Bhramar Mukherjee	Global Prevalence of Post-Coronavirus Disease 2019 (COVID-19) Condition or Long COVID: A Meta-Analysis and Systematic Review	https://doi.org/10.1093/infdis/jiac136	Published	16 April 2022	Review	https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiac136/6569364	Background This study aims to examine the worldwide prevalence of post-coronavirus disease 2019 (COVID-19) condition, through a systematic review and meta-analysis. Methods PubMed, Embase, and iSearch were searched on July 5, 2021 with verification extending to March 13, 2022. Using a random-effects framework with DerSimonian-Laird estimator, we meta-analyzed post-COVID-19 condition prevalence at 28+ days from infection. Results Fifty studies were included, and 41 were meta-analyzed. Global estimated pooled prevalence of post-COVID-19 condition was 0.43 (95% confidence interval [CI], .39–.46). Hospitalized and nonhospitalized patients had estimates of 0.54 (95% CI, .44–.63) and 0.34 (95% CI, .25–.46), respectively. Regional prevalence estimates were Asia (0.51; 95% CI, .37–.65), Europe (0.44; 95% CI, .32–.56), and United States of America (0.31; 95% CI, .21–.43). Global prevalence for 30, 60, 90, and 120 days after infection were estimated to be 0.37 (95% CI, .26–.49), 0.25 (95% CI, .15–.38), 0.32 (95% CI, .14–.57), and 0.49 (95% CI, .40–.59), respectively. Fatigue was the most common symptom reported with a prevalence of 0.23 (95% CI, .17–.30), followed by memory problems (0.14; 95% CI, .10–.19). Conclusions This study finds post-COVID-19 condition prevalence is substantial; the health effects of COVID-19 seem to be prolonged and can exert stress on the healthcare system.
264	D261		Diane E. Griffin	Why does viral RNA sometimes persist after recovery from acute infections?	https://doi.org/10.1371/journal.pbio.3001687	Published	June 1, 2022	Article	https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001687	DNA viruses often persist in the body of their host, becoming latent and recurring many months or years later. By contrast, most RNA viruses cause acute infections that are cleared from the host as they lack the mechanisms to persist. However, it is becoming clear that viral RNA can persist after clinical recovery and elimination of detectable infectious virus. This persistence can either be asymptomatic or associated with late progressive disease or nonspecific lingering symptoms, such as may be the case following infection with Ebola or Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Why does viral RNA sometimes persist after recovery from an acute infection? Where does the RNA come from? And what are the consequences?
265	D262		JUSTIN J. FRERE RANDAL A. SERAFINI KERRI D. PRYCE MARIANNA ZAZHYTSKAKOHEI OISHI ILONA GOLYNKER MARYLINE PANISJEFFREY ZIMERING SHU HORIUCHI DAISY A. HOAGLAND RASMUS MØLLER ANNE RUIZ ALBANA KODRA JONATHAN B. OVERDEVEST PETER D. CANOLLALAIN C. BORCZUKVASURETHA CHANDARYARON BRAM ROBERT SCHWARTZ STAVROS LOMVARDAS VENETIA ZACHARIOU AND BENJAMIN R. TENOEVER	SARS-CoV-2 infection in hamsters and humans results in lasting and unique systemic perturbations post recovery	https://doi.org/10.1126/scitranslmed.abq3059	Published	7 Jun 2022	Study	https://www.science.org/doi/10.1126/scitranslmed.abq3059	The host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in prolonged pathologies collectively referred to as post-acute sequalae of COVID-19 (PASC) or long COVID. To better understand the mechanism underlying long COVID biology, we compared the short- and long-term systemic responses in the golden hamster following either SARS-CoV-2 or influenza A virus (IAV) infection. Results demonstrated that SARS-CoV-2 exceeded IAV in its capacity to cause permanent injury to the lung and kidney and uniquely impacted the olfactory bulb (OB) and epithelium (OE). Despite a lack of detectable infectious virus, the OB and OE demonstrated myeloid and T cell activation, proinflammatory cytokine production, and an interferon response that correlated with behavioral changes extending a month post viral clearance. These sustained transcriptional changes could also be corroborated from tissue isolated from individuals who recovered from COVID-19. These data highlight a molecular mechanism for persistent COVID-19 symptomology and provide a small animal model to explore future therapeutics.
266	D263		MonaSadat Larijania1FatemehAshrafiana1FahimehBagheri AmiribMohammadBanifazlcAnahitaBavandaAfsanehKaramidFatemehAsgari ShokoohaAmitisRamezania	Characterization of long COVID-19 manifestations and its associated factors: A prospective cohort study from Iran	https://doi.org/10.1016/j.micpath.2022.105618	Published	11 June 2022	Study	https://www.sciencedirect.com/science/article/pii/S0882401022002315	Highlights •Post-COVID-19 could possibly initiate long after full recovery and different window time. •Different manifestations of SARS-CoV-2 may not be resolved fully. •According to our findings, no association found between the patients' clinical history and COVID-19 long term side effects. •Unpredictable outcomes post-COVID-19 vaccination draw attentions as well as the viral effects. The prevalence and variety complaints of COVID-19 cases in a long term have been investigated in recent studies. The symptoms over the time are various and unpredictable which may persist several weeks after full recovery. The importance of long-COVID-19 manifestations includes its effect on the recovered cases which requires a rational management based on an accurate guideline to handle post-acute COVID-19 state. The aim of this study was to evaluate the incidence of post-acute COVID-19 syndrome and to identify the associated risk factors as well as to compare new and persistent symptoms at different post-acute phases. Totally 254 individuals from Pasteur Institute of Iran (or/and their relatives) were investigated who had a previously confirmed COVID-19 PCR test. The long-term manifestations of the virus were categorized through a time window as acute, ongoing, post-COVID and persistent phases and the individuals were assessed by the face-to-face or the phone call interview according to their complaints. The data were then statistically analyzed to determine the frequency of the symptoms and also the associated factors in which a p value < 0.05 was considered significant. Except a small asymptotic group of five, 249 cases progressed the symptoms to acute phase among which 64.1% reported at least one symptom in post-acute phase. Neurological sequelae were found as the most frequent symptom (91.6%). Furthermore, there was a significant association between the underlying diseases, age and acute phase symptoms to the post-acute phase syndrome susceptibility (p < 0.05). In conclusion, the increasing number of the reports and studies on long COVID-19 which can hugely affect the life quality should be more investigated and explored in terms of the pathophysiology to achieve appropriate treatments in time. The clusters of symptoms, specially a combination of neurological signs, presenting over months after the recovery impose a huge difficulty to the recovered population.
267	D264		Chengliang Yang Hedi Zhao Scott J Tebbutt	A glimpse into long COVID and symptoms	https://doi.org/10.1016/S2213-2600(22)00217-X	Published	June 10, 2022	CORRESPONDENCE	https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00217-X/fulltext	Long COVID has significant implications for individuals, health-care systems, and society. Those affected might have reduced functional capacity and cognitive and physical limitations, ultimately resulting in reduced autonomy and increased dependency on caregivers and other societal supports. Hence, more comprehensive understanding of long COVID would aid policymakers and health-care systems in developing, implementing, and evaluating future policies and health resource planning reflective of the population's needs. In The Lancet Respiratory Medicine, Lixue Huang and colleagues1 addressed this topic in a longitudinal follow-up of patients after SARS-CoV-2 infection during the early phase of the COVID-19 pandemic (between January, 2020, and May, 2021). To date, this study has the longest duration of follow-up for post-COVID-19 outcomes in patients who survived hospitalisation for COVID-19. Still, many questions remain about the reported symptoms of long COVID, and the people who continue to live with it. Persistent physical symptoms attributed to COVID-19 might not be specific to SARS-CoV-2 infection.2 Knowledge of previous SARS-CoV-2 infection might increase a person's likelihood of experiencing persistent physical symptoms—either by affecting perception of symptoms that might have predated the infection or by promoting maladaptive health behaviours, such as reducing physical activity or dietary exclusion, in an effort to improve health.2 It is therefore crucial to delineate individual symptom manifestations before and after infection, in addition to the overall dynamics of COVID-19 symptomatology in infected populations during this pandemic. Huang and colleagues1 stated that their questionnaires included the SARS-CoV-2 vaccination survey, blood specimens for complete blood count, renal function, liver function, lipid test, and routine urine;1 however, the results of these laboratory studies were omitted. Furthermore, whether self-reported symptoms of chest pain and palpitations were corroborated by objective clinical and diagnostic findings was unclear. It might be useful to have a separate analysis of respondents with or without chronic diseases such as chronic kidney disease or chronic obstructive pulmonary disease to delineate whether these affect the degree of symptomatology. The omicron variant of SARS-CoV-2 (B.1.1.529 and its sublineages) has a higher risk of reinfection compared with the other variants.3 Reinfection information of relevance to these patients could help clarify the effect of long COVID among survivors. COVID-19 survivors at 2 years had more problems with fatigue, muscle weakness, sleep difficulties, dizziness, headache, and myalgia than COVID-19 survivors at 1 year.1 There is increasing evidence for brain-related injuries in patients with COVID-19.4, 5 Even mild COVID-19 is linked to brain damage, which might provide insight into neurological or cognitive symptoms such as difficulty concentrating, trouble sleeping, memory loss, or confusion associated with long COVID.4 This might be one of the particularly relevant issues in long COVID pathogenesis,6 warranting further investigation. Moreover, many of these symptoms might be further exacerbated by physical deconditioning or sedentary behaviours, a history of smoking or alcohol consumption, pregnancy, or an overall shift to work-from-home structures. Furthermore, it would be important to capture not only the symptom presence, but the degree of impairment associated with these symptoms, whether it might be due to loss of work productivity or increased health-care use. It would be important to address not only the symptoms, but also the associations with various contributing factors to better characterise the populations at risk. This information would allow for better generalisation and the proposal of future strategies to mitigate the effects of long COVID.
268	D265		Lixue Huang Xiaoying Gu Hui Zhang Bin Cao	A glimpse into long COVID and symptoms – Authors' reply	https://doi.org/10.1016/S2213-2600(22)00212-0	Published	June 10, 2022	CORRESPONDENCE	https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00212-0/fulltext	In our study, we described the dynamics of long COVID symptoms in COVID-19 survivors with various disease severities, which was one of our main research objectives.1 In their Correspondence, Chengliang Yang and colleagues noted that delineating individual symptom manifestations at pre-infection and post-infection timepoints is important because some physical symptoms might have been present before SARS-CoV-2 infection. We agree with Yang and colleagues on this matter, and their suggestion that this information could help to find excess symptom burden post-SARS-CoV-2 infection. In our study, to address the problem that some symptoms might have been present before COVID-19, sequelae symptoms were defined as those that were newly occurring and persistent, or worse than the status before getting COVID-19, and could not be explained by an alternative disease. The sequelae symptoms observed in our study, including the physical symptoms mentioned by Yang and colleagues, might not be specific to SARS-CoV-2 infection, which was acknowledged as a limitation in our published Article.1 It is not only quite challenging to distinguish whether the observed physical symptoms were direct effects of COVID-19 or not, but also the degree of impairment related to these symptoms. To the best of our knowledge, no validated symptom questionnaire was available at the time of our study. There are also several limitations of self-reported symptom surveys, including information bias and difficulty of objective diagnosis of subjective symptoms (eg, chest pain and palpitations). We mentioned the potential information bias of using self-report symptom questionnaires in our Article.1 We did laboratory tests at three follow-up visits, including complete blood count, renal function, liver function, lipid test, and routine urine. The laboratory findings of 1164 COVID-19 survivors who completed 6-month and 12-month follow-up visits were shown in the appendix (table S5) of our previously published Article.2 Most survivors showed normal ranges for the laboratory indicators. Due to data insufficiency before COVID-19, it was difficult to interpret the observed laboratory abnormalities among some participants at follow-up because some results might have been new or persistent; thus, we did not show laboratory findings in our 2-year follow-up study. As for SARS-CoV-2 vaccination, of the 1294 COVID-19 survivors who participated in face-to-face interviews at the 2-year follow-up, 1054 (81·5%) were vaccinated, and 705 (54·5%) received at least two doses. The 2-year follow-up was completed on Jan 10, 2022, which, to our knowledge, predated the emergence of the first case of COVID-19 caused by omicron (B.1.1.529) in Wuhan. We cannot provide reinfection information of omicron with data already obtained, but we hope to answer related questions in a future follow-up study. Specific abnormalities after mild SARS-CoV-2 infection could be helpful to uncover the pathogenesis of long COVID, including brain damage,3 increased risk of cardiovascular event,4 or diabetes.5 There are several hypotheses related to the pathogenesis of long COVID, including persistent virus or viral antigens and RNA in tissues that drive chronic inflammation, the triggering of autoimmunity after acute viral infection, dysbiosis of the microbiome or virome, and unrepaired tissue damage.6 There is still a long way to go to fully understand the pathogenesis of COVID-19; and once more knowledge is accumulated, this new evidence might also apply to the study of inflammatory processes that are involved in other respiratory infections.
269	D266		Diana Araja *ORCID,Uldis Berkis andModra MurovskaORCID	COVID-19 Pandemic-Revealed Consistencies and Inconsistencies in Healthcare: A Medical and Organizational View	https://doi.org/10.3390/healthcare10061018	Published	31 May 2022	Study	https://www.mdpi.com/2227-9032/10/6/1018/htm	The circumstances of the Coronavirus disease caused by the SARS-CoV-2 virus (COVID-19) pandemic have had a significant impact on global and national developments, affecting the existence of society in all its expressions, as well as the lives of people themselves. In the context of the pandemic, increased attention has been focused on acute measures, but the ending of the pandemic is expected as a resolution of the related healthcare problems. However, there are several indicators that the COVID-19 pandemic might induce long-term consequences for individual and public health. Some of the consequences are inferred and predictable, but there are also areas of medicine that have been indirectly affected by the pandemic, and these consequences have not yet been sufficiently explored. This study is focused on drawing attention to some of the COVID-19 pandemic consistencies and the pandemic-revealed inconsistencies in healthcare. Content analysis and statistical analysis were applied to achieve the aim of the study. The main findings of the study address chronic disease burden (particularly, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)), healthcare governance and organizational issues, and the synergy between health policy perspectives and innovative solutions in practice. The study provides insight into the particular healthcare issues affected by the COVID-19 pandemic, such as the increase in mortality in some diagnoses besides COVID-19 and the possible emergence of a new type of resistance—vaccine-resistance—contemporaneously supporting the identification of the tendencies and currently unnoticed indirect consistencies and inconsistencies revealed by the pandemic.
270	D267		Diana Duong	The evolving picture of long COVID	https://doi.org/10.1503/cmaj.1096004	Published	June 19, 2022	Article	https://www.cmaj.ca/content/194/24/E850	Some big remaining questions Researchers have to account for a large number of factors as both COVID-19 and the global pandemic response evolves. People exposed to SARS-CoV-2 in the spring of 2020 — before vaccines, variants, and new therapeutics — may not experience the same long-haul symptoms as those exposed during the later Delta and Omicron waves. There also needs to be more understanding of the mechanism of the disease, which could open a door to potential treatment, says Alain Piché, a microbiologist, infectious disease physician, and director of a post-COVID clinic in Sherbrooke. “At this point, we really need new drugs or known drugs that will be effective against long COVID, because I’m seeing so many patients that have a huge impairment on their daily lives,” he says. “They cannot work, they cannot take care of themselves, they need somebody around, they forget things, they cannot concentrate, they cannot live a normal life anymore. Unfortunately, these patients are severely impaired and this is too common. I’ve seen so many of these patients and there are few things that we can do to help them besides trying to ease some of the symptoms.” Piché hopes that studies like Cheung’s RECLAIM study as well as several others around the world — which hopefully will be available within the next year to 18 months — will provide much-needed answers.
271	D268		Daniel Munblit, PhD * Timothy Nicholson, PhD * Athena Akrami, PhD Christian Apfelbacher, PhD Jessica Chen, BSc Wouter De Groote, PhD Janet V Diaz, MD Sarah L Gorst, PhD Nicola Harman, PhD Alisa Kokorina, BSc Piero Olliaro, PhD Callum Parr, BSc Jacobus Preller, MD Nicoline Schiess, MD Jochen Schmitt, MD Nina Seylanova, MD Frances Simpson, MSc Allison Tong, PhD Prof Dale M Needham, MD * Paula R Williamson, PhD *	A core outcome set for post-COVID-19 condition in adults for use in clinical practice and research: an international Delphi consensus study	https://doi.org/10.1016/S2213-2600(22)00169-2	Published	June 14, 2022	Article	https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00169-2/fulltext	Health consequences that persist beyond the acute infection phase of COVID-19, termed post-COVID-19 condition (also commonly known as long COVID), vary widely and represent a growing global health challenge. Research on post-COVID-19 condition is expanding but, at present, no agreement exists on the health outcomes that should be measured in people living with the condition. To address this gap, we conducted an international consensus study, which included a comprehensive literature review and classification of outcomes for post-COVID-19 condition that informed a two-round online modified Delphi process followed by an online consensus meeting to finalise the core outcome set (COS). 1535 participants from 71 countries were involved, with 1148 individuals participating in both Delphi rounds. Eleven outcomes achieved consensus for inclusion in the final COS: fatigue; pain; post-exertion symptoms; work or occupational and study changes; survival; and functioning, symptoms, and conditions for each of cardiovascular, respiratory, nervous system, cognitive, mental health, and physical outcomes. Recovery was included a priori because it was a relevant outcome that was part of a previously published COS on COVID-19. The next step in this COS development exercise will be to establish the instruments that are most appropriate to measure these core outcomes. This international consensus-based COS should provide a framework for standardised assessment of adults with post-COVID-19 condition, aimed at facilitating clinical care and research worldwide.
272	D269		Hans Henri P.KlugeaNatasha AzzopardiMuscataContribution from -SatishMishraaSusanneNielsenaFlorianTilleaDinaPfeiferaLongCOVID EuropebManojSivana	Call for action: Health services in the European region must adopt integrated care models to manage Post-Covid-19 Condition	https://doi.org/10.1016/j.lanepe.2022.100435	Published	22 June 2022	Article	https://www.sciencedirect.com/science/article/pii/S2666776222001296?via%3Dihub	Success in this pandemic is not only developing new diagnostics, treatments and vaccinations to prevent hospitalisations and deaths, but also ensuring provision of accessible, affordable and individualised long-term rehabilitative care, thereby reducing disease burden and restoring best quality of life for the affected population. In a call for action, the recommendation is to: •Build capacity for early identification and recognition of symptoms of Post-Covid-19 Condition. •Strengthen primary health care to manage Post-Covid-19 Condition when medically indicated, and to be the point of referral for more severe cases. •Acknowledge the need for individualized long-term rehabilitative care for persons with Post-Covid-19 Condition. •Strengthen the health system to be able to provide an individualised multidisciplinary care pathway in which patient's multi-system symptoms and rehabilitation needs are assessed and managed, informed by real world outcome data and patient experience.
273	D270		Toluwalase Awoyemi, Ujunwa Ebili, Abiola Olusanya, Kayode E. Ogunniyi, Adedolapo V. Adejumo	Twitter Sentiment Analysis of Long COVID Syndrome	https://doi.org/10.7759/cureus.25901	Published	June 13, 2022	Study	https://www.cureus.com/articles/99095-twitter-sentiment-analysis-of-long-covid-syndrome	Background Long COVID syndrome originated as a patient phrased terminology which was initially used to describe a group of vague symptoms that persisted after recovering from COVID-19. However, it has moved from a patient lingo to a recognized pathological entity which refers to a group of symptoms that lasts weeks or months after the COVID-19 illness. The novelty of this condition, the inadequacy of research on long COVID syndrome, and its origin as a patient-coined terminology necessitated exploring the disease's sentiments and conversations by analyzing publicly available tweets. Method Tweets were extracted using the Twarc2 tool for tweets in the English language with the keywords (long COVID syndrome, long COVID, post-COVID syndrome, post-acute sequelae of SARS-CoV-2, long-term COVID, long haulers, and chronic COVID syndrome) between March 25, 2022, and April 1, 2022. The analyses included frequency of the keywords, sentiment analysis, and topic modeling to identify and explore discussion topics over time. A natural language approach and the latent Dirichlet allocation algorithm were used to determine the most shared tweet topics, categorize clusters, and identify themes based on keyword analysis. Results The search yielded 62,232 tweets. The tweets were reduced to 10,670 tweets after removing the duplicates. The vast majority of the tweets originated from the United States of America (38%), United Kingdom (30%), and Canada (13%), with the most common hashtags being #longcovid (36%) and #covid (6.36%), and the most frequently used word being people (1.05%). The top three emotions detected by our analysis were trust (11.68%), fear (11.26%), and sadness (9.76%). The sentiment analysis results showed that people have comparable levels of positivity (19.90%) and negativity (18.39%) towards long COVID. Conclusions Our analysis revealed comparable sentiments about long COVID syndrome, albeit slightly positive. Most tweets connoted trust (positive), fear (negative), and sadness (negative). These emotions were linked with concerns about the infection, pandemic, chronic disability, and governmental policies. We believe this study would be important in guiding information dissemination and governmental policy implementation necessary in tackling long COVID syndrome.
274	D271		Christina PagelChristina Pagel	The covid waves continue to come	https://doi.org/10.1136/bmj.o1504	Published	17 June 2022	Opinion	https://www.bmj.com/content/377/bmj.o1504	Omicron continues to drive waves of covid infections, writes Christina Pagel, but let’s not give up trying to control transmission We are just over five months into 2022 and have already seen two record highs of coronavirus infection in England, with population prevalence peaking at 7% in early January (omicron BA.1) and 8% in late March (omicron BA.2).1 After eight weeks of declining prevalence, infections have started to increase again with the rise of yet another set of omicron variants. Instead of just one new variant, we currently have four: BA.2.12.1 (dominant in the US), BA.4 and BA.5 (dominant in South Africa), and BA.5.1 (dominant in Portugal). Together, these four variants became dominant in England in early June,2 and it looks as if BA.5 and BA.5.1 will likely win out to become the overall dominant variants.3 So what does this mean for the shorter and longer term? In the short term, we will see another wave of infections here, likely peaking at the end of June/early July. South Africa’s BA.4/5 wave has now passed, with fewer hospital admissions and deaths than in their BA.1 wave in December. Portugal’s BA.5 wave looks to have just peaked, with a similar magnitude of deaths and hospital admissions to their first omicron BA.1 wave. While omicron BA.2 became dominant in both South Africa and Portugal, it did not result in a second large wave of infections.4 It did, however, in England and we will be the first (but not the last) big country to have a BA.4/5 wave after having had two previous omicron waves (BA.1 and BA.2). This means that we might get some additional protection from the high number of infections we had in March, which will reduce the size of this coming wave. Nonetheless, a significant proportion of the country will get sick, especially as the population’s immunity from boosters is waning. While omicron might be somewhat less severe than delta, and people have higher immunity through vaccination and previous infection, it is not mild. At a population level, its sheer transmissibility more than compensates for any reduction in experienced disease severity or symptoms for the individual. For instance, in the five months of the omicron era since 1 January 2022, almost 20 000 people have died with covid-19 mentioned on their death certificate.5 Almost exactly the same number of people had it mentioned on their death certificate in the six months that delta was dominant in England in 2021—but we have just started yet another omicron wave and so deaths from this variant will rise still further.
275	D272		McSpedon, Corinne	Long COVID: What We Know Now	https://doi.org/10.1097/01.NAJ.0000842232.15530.f1	Published	June 23 2022	Article	https://journals.lww.com/ajnonline/Fulltext/2022/07000/Long_COVID__What_We_Know_Now.18.aspx	A growing population struggles with ongoing health problems. An overview of this emerging health issue—and what's being done to study and address it.
276	D273		Lisa Langnickel, Johannes Darms, Katharina Heldt, Denise Ducks, Juliane Fluck	Continuous development of the semantic search engine preVIEW: from COVID-19 to long COVID	https://doi.org/10.1093/database/baac048	Published	01 July 2022	Study	https://academic.oup.com/database/article/doi/10.1093/database/baac048/6625658	preVIEW is a freely available semantic search engine for Coronavirus disease (COVID-19)-related preprint publications. Currently, it contains >43 800 documents indexed with >4000 semantic concepts, annotated automatically. During the last 2 years, the dynamic situation of the corona crisis has demanded dynamic development. Whereas new semantic concepts have been added over time—such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of interest—the service has been also extended with several features improving the usability and user friendliness. Most importantly, the user is now able to give feedback on detected semantic concepts, i.e. a user can mark annotations as true positives or false positives. In addition, we expanded our methods to construct search queries. The presented version of preVIEW also includes links to the peer-reviewed journal articles, if available. With the described system, we participated in the BioCreative VII interactive text-mining track and retrieved promising user-in-the-loop feedback. Additionally, as the occurrence of long-term symptoms after an infection with the virus SARS-CoV-2—called long COVID—is getting more and more attention, we have recently developed and incorporated a long COVID classifier based on state-of-the-art methods and manually curated data by experts. The service is freely accessible under https://preview.zbmed.de
277	D274		Olalekan Lee Aiyegbusi Applied Health Research	A core outcome set for post-COVID-19 condition in adults for use in clinical practice and research: an international Delphi consensus study	https://doi.org/10.1016/S2213-2600(22)00169-2	Published	14 Jun 2022	Study	https://research.birmingham.ac.uk/en/publications/a-core-outcome-set-for-post-covid-19-condition-in-adults-for-use-	Health consequences that persist beyond the acute infection phase of COVID-19, termed post-COVID-19 condition (also commonly known as long COVID), vary widely and represent a growing global health challenge. Research on post-COVID-19 condition is expanding but, at present, no agreement exists on the health outcomes that should be measured in people living with the condition. To address this gap, we conducted an international consensus study, which included a comprehensive literature review and classification of outcomes for post-COVID-19 condition that informed a two-round online modified Delphi process followed by an online consensus meeting to finalise the core outcome set (COS). 1535 participants from 71 countries were involved, with 1148 individuals participating in both Delphi rounds. Eleven outcomes achieved consensus for inclusion in the final COS: fatigue; pain; post-exertion symptoms; work or occupational and study changes; survival; and functioning, symptoms, and conditions for each of cardiovascular, respiratory, nervous system, cognitive, mental health, and physical outcomes. Recovery was included a priori because it was a relevant outcome that was part of a previously published COS on COVID-19. The next step in this COS development exercise will be to establish the instruments that are most appropriate to measure these core outcomes. This international consensus-based COS should provide a framework for standardised assessment of adults with post-COVID-19 condition, aimed at facilitating clinical care and research worldwide.
278	D275		Shankar, R Perera, B Roy, A Courtenay, K Laugharne, R Sivan, M	Post-COVID syndrome and adults with intellectual disability: another vulnerable population forgotten?	http://dx.doi.org/10.1192/bjp.2022.89	Published	June 29, 2022	Editorial	https://pearl.plymouth.ac.uk/handle/10026.1/19356	An area of interest presently is the lingering symptoms after COVID-19, i.e. post-COVID-19 syndrome (PCS). Specifics of diagnosis and management of PCS are emerging. However, vulnerable populations such as those with intellectual disabilities, who were disproportionately affected by the pandemic, risk being ‘left behind’ from these considerations.
279	D276		Marie Norredam Sally Hayward Anna Deal Charles Agyemang Sally Hargreaves	Understanding and addressing long-COVID among migrants and ethnic minorities in Europe	https://doi.org/10.1016/j.lanepe.2022.100427	Published	June 29, 2022	Comment	https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(22)00121-1/fulltext	Several European countries have observed an increasing number of patients with long-term health consequences of COVID-19, popularly termed long-COVID. In the UK alone, recent numbers have shown around 860,000 people with self-reported long-COVID at least 12 weeks after infection, symptoms of which include persistent fatigue, neurological difficulties such as depression, headache, and memory loss as well as cardiopulmonary symptoms including cough, dyspnea and chest pain.1 A wealth of evidence suggests that migrants and ethnic minorities have been disproportionally impacted by COVID-19, in terms of cases, hospitalisations, deaths and mental health outcomes in many European countries.2,3 In addition, emerging data have suggested inequities in the delivery of vaccines to these populations.4 We here describe migrants and ethnic minorities combined because these groups overlap and share common characteristics including socioeconomic and psychosocial vulnerabilities. The term ‘migrants’ is used as an umbrella term encompassing all the different subgroups of people who immigrated including asylum seekers, undocumented immigrants etc. The extent to which migrants and ethnic minorities are impacted by long-COVID is, however, not known, despite an increasing literature identifying a number of relevant risk factors for long-COVID including older age, disease severity, comorbidities and admission to Intensive Care Units.1,5 The few studies on long-COVID that do include data on migrants and ethnic minorities suggest that they are disproportionately impacted by long-COVID, but data are lacking in European countries and beyond.6,7 One UK study found that among 100 patients assessed by telephone interview 4-8 weeks after discharge from admission for a severe COVID-19 infection, those belonging to Black, Asian, and minority ethnic groups were more likely to experience dyspnea than White individuals (42.1% versus 25%) whereas rates of Post Traumatic Stress Disorder (PTSD) were similar.6 A US study based on 711 telephone interviews done among individuals at least 2 months after a positive test result for COVID-19 found that individuals reporting as Black were at higher risk of having ‘any long-COVID symptom’ and specifically dyspnea and arthralgia/myalgia compared to other ethnic groups including those reporting as White.7 These ethnicity datasets are highly heterogeneous and rarely disaggregated by migrant status, making it difficult to assess the impact on more recent arrivals from overseas, who may have a range of unique risk factors for worse health outcomes, including restricted access to health and vaccination systems.8,9
280	D277		National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Care Services; Laura Aiuppa Denning and Erin Hammers Forstag, Rapporteurs	Long COVID Examining Long-Term Health Effects of COVID-19 and Implications for the Social Security Administration: Proceedings of a Workshop		Published	June 2022	Book	https://nap.nationalacademies.org/catalog/26619/long-covid-examining-long-term-health-effects-of-covid-19	Long COVID' refers to the wide range of long-lasting symptoms experienced by some patients after a SARS-CoV-2 infection. The most common symptoms include fatigue, headache, brain fog, shortness of breath, hair loss, and pain. At this time, there are many knowledge gaps related to Long COVID, including the prevalence of the condition, the impact of the symptoms on survivors' ability to function, and the long-term course of the condition. While many individuals with Long COVID recover within one year, others experience little or no decrease in symptom severity over time. Long COVID symptoms can affect a person's ability to work and otherwise function in daily life, so people with the condition may need to utilize programs such as Social Security Disability Insurance (SSDI) and the Supplemental Security Income Program (SSI). The Social Security Administration (SSA), which administers both of these programs, requested that the National Academies of Sciences, Engineering, and Medicine host a public workshop to discuss research into the long-term health effects of COVID-19, their impacts on individuals and populations, and how the SSDI and SSI programs can support individuals who suffer disability as a result of Long COVID. This publication summarizes the presentation and discussion of the workshop.
281	D278		B Patterson J Ruppenkamp F Richards R Debnath AC El Khoury JK DeMartino B Bookhart C Holy P Coplan	EE211 Cost of Long COVID Following Severe Disease - a US Healthcare Database Analysis	https://doi.org/10.1016/j.jval.2022.04.460	Published	July 01, 2022	Study	https://www.valueinhealthjournal.com/article/S1098-3015(22)00661-1/fulltext	Objectives Continued morbidity following Coronavirus disease 2019 (COVID-19), or long COVID (LC), is defined by the World Health Organization (WHO) as conditions lasting > 2 months and identified 3 months after COVID-19 onset. LC might be particularly prevalent in severe COVID-19 patients. The impact of LC on healthcare costs is unknown. Methods Patients with severe/critical COVID-19 (first date =index) from April 1, 2020, onwards, with ≥ 6 months of continuous enrollment pre- and post-index, in IBM® MarketScan® Commercial and Medicare Supplemental databases, were identified. Severe disease was defined as admissions with respiratory distress/failure, with or without organ/neurological dysfunction or shock/tachypnea/tachycardia/hypoxemia. Variables for all patients included demographics, comorbidities (Elixhauser index (EI) and all 31 Elixhauser disease domains), and COVID-19 signs/symptoms. Disease duration was defined as follows: from 5 days before positive test to last related visit/prescription. A ≤ 35-day gap between visits/prescription was allowed. LC was defined as disease duration ≥ 5 months. All-cause (with any diagnostic code) and disease-specific costs (with COVID-19 related diagnostic codes) for patients with and without LC (non-LC) were estimated from index to end of disease duration or last available date (for ongoing disease), using generalized linear model with gamma distribution and log link. Results 13.7% (95%CI: 13.5%-13.9%) with severe/critical COVID-19 had LC. Average available duration of LC for costing analyses was 213.1 days (95%CI: 207.8-218.3). In contrast, non-LC duration of disease averaged 53.6 days (95%CI: 53.1-54.2) Between LC and non-LC patients, all-cause costs significantly increased in commercially-insured and Medicare patients by respectively $58,445 (95%CI: $49,453-$67,437 – from $46,912 (non-LC) to $105,357 (LC)) and $34,940 (95%CI: $28,990-$40,889 – from $29,491 (non-LC) to 64,412 (LC)). Conclusion As observed over 213 days, all-cause cost of COVID-19 almost doubled in severe COVID-19 patients with LC vs without LC. These costs are expected to further increase with increased follow-up time.
282	D279		Tom Lawton Nisreen A Alwan	The UK COVID-19 Inquiry must examine the foundations of pandemic decision making	https://doi.org/10.1016/S0140-6736(22)01332-0	Published	July 18, 2022	Article	https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01332-0/fulltext	First, long COVID is not centred in the Terms of Reference. The chronic illness burden created by mass SARS-CoV-2 infection is the living legacy of this pandemic and needs to be a priority area for the UK COVID-19 Inquiry. At the start of the pandemic in 2020, data were available about clinical outcomes in severe acute respiratory syndrome3 and early reports from COVID-19 survivors4 pointed to longer-term sequelae with potentially serious effects for individuals and the population. On the basis of data up to August, 2021, at least one in nine of those infected with SARS-COV-2 reported experiencing long COVID at 12 weeks from onset of infection.5 Population estimates from the UK's Office for National Statistics (ONS), as of June 4, 2022, point to an estimated burden of 2 million people living with long COVID for more than 4 weeks (3% of the population), of whom 105 000 are aged 2–16 years and 95 000 are aged 17–24 years.6 A Bank of England publication in May, 2022, stated that the UK workforce has shrunk by 440 000 people (1·3%) since the final quarter of 2019 and is 2·5% below the January, 2020 forecast, and that the share of the population aged 16–64 years who are outside the workforce because of long-term sickness is a record high, with a particularly sharp rise among women.7 This could at least partly be due to long COVID.7 The UK COVID-19 Inquiry has the potential to enhance our understanding of what has so far happened during the pandemic. This should be an opportunity to learn valuable lessons that could have global relevance, and hopefully improve any response to future pandemics. But there is a need for the Inquiry to examine the principles that underpinned the UK's responses if it is to have a meaningful, lasting impact. An opaque culture, which has signs of being driven by political convenience, has pervaded many aspects of the UK's pandemic response. The Inquiry must examine and be able to challenge the underlying culture and assumptions that shaped the UK Government's pandemic policies.
283	D280		Karin Magnusson1 Aleksandra Turkiewicz2 Signe Flottorp1 Martin Englund	Development of long-covid, or prevalent complaints in general?	https://doi.org/10.21203/rs.3.rs-1684643/v1	pre-print	18 Jul 2022	Study	https://www.researchsquare.com/article/rs-1684643/v1	Objectives: To study the prevalence and patterns of typical post-covid complaints in ~2.3 million persons with and without confirmed COVID-19. Methods: In a Nation-wide population-based prospective cohort study, we studied all persons aged 18-70 years living in Norway and who tested positive (n=75 979), negative (n=1 167 582) and who were not tested for SARS-CoV-2 (n=1 084 578) from August 1st 2020 to August 1st 2021 (non-hospitalized from -2 to +14 days from test date), who were, or were not vaccinated against COVID-19. Our main outcome measures were the period prevalence of single-occurring or different combinations of complaints based on medical records: 1) Pulmonary (dyspnea and/or cough), 2) Neurological (concentration problems, memory loss), and/or 3) General complaints (fatigue). Results: In persons testing positive, 64 (95% confidence interval: 54 to 73) and 122 (111 to 113) more persons per 10 000 persons had pulmonary complaints 5-6 months after the test compared to 10 000 persons testing negative or untested, respectively. The corresponding difference in prevalence of general complaints (fatigue) was 181 (168 to 195) and 224 (211 to 238) per 10 000, and of neurological complaints 5 (2 to 8) and 9 (6-13) per 10 000. Overlap between complaints was rare. Conclusions: Post-covid complaints were only slightly more prevalent in persons with than without confirmed COVID-19. Still, long-covid may pose a substantial burden to healthcare systems in the future given the lasting high incidence of symptomatic COVID-19 in both vaccinated and unvaccinated individuals.
284	D281		Dasom I. Ham	Long-Haulers and Labor Market Outcomes	https://doi.org/10.21034/iwp.60	pre-print	Jul 2022	Study	https://ideas.repec.org/p/fip/fedmoi/94528.html	There have been growing concerns about long-haulers or individuals with long-term COVID-19 health complications (long-haul COVID). While the medical field has been investigating the health complications, there has been limited research on the relationship between long-haul COVID and labor market outcomes. To investigate this relationship, I used the University of Southern California Understanding America Study COVID-19 longitudinal survey to provide a snapshot of mid-2021. I first find about 24.1% of individuals who have had COVID are long-haulers and 25.9% of long-haulers reported that their long-haul COVID affected employment or work hours. I then find that a majority of these affected long-haulers remained employed and in same employment type. But I find that their mean change in work hours and paycheck declined. Afterwards, I tested whether long-haul COVID is associated with negative changes in labor market outcomes. When I combined long-haulers who reported that their health complications did or did not affect work, I failed to find that long-haulers are less likely to be employed relative to individuals without prior COVID infection. But, when I discern long-haulers by whether long-haul COVID affected work, I find that long-haulers who reported long-haul COVID affected work are 10 percentage points less likely to be employed and, on average, work 50% fewer hours than individuals without prior COVID infection. In contrast, I failed to find evidence that affected long-haulers receive a lower paycheck earning relative to individuals without prior COVID infection. Lastly, when comparing these affected long-haulers against similar individuals, I find evidence that they are more impacted in their employed status and work hours. Due to limitations, future data collection and research would provide a more robust picture.
285	D282		Nick Mayer; Bernardo Meza-Torres; Cecilia Okusi; Gayathri Delanerolle; Martin Chapman; Wenjuan Wang; Sneha Anand; Michael Feher; Jack Macartney; Rachel Byford; Mark Joy; Piers Gatenby; Vasa Curcin; Trisha Greenhalgh; Brendan Delaney; Simon de Lusignan	Developing a long covid phenotype for post-acute COVID-19 in a national primary care sentinel cohort: an observational retrospective database analysis	https://doi.org/10.2196/36989	Published	Jul 21, 2022	Study	https://preprints.jmir.org/preprint/36989/accepted	Background: Following COVID-19 up to 40% of people have ongoing health problems, referred to as “post-acute COVID-19” or long covid (LC). LC varies from a single persisting symptom to a complex multi-system disease. Research has flagged that this condition is under recorded in primary care record; and seeks to better define its clinical characteristics and management. Phenotypes provide a standard method for case definition and identification from routine data and are usually machine processable. A LC phenotype can underpin research into this condition. Objective: To develop a phenotype for long COVID-19 to inform the epidemiology and future research into this condition. We will compare clinical symptoms in people with long COVID-19 before and after their index infection. We will also compare people recoded as having acute infection with those with LC who have been hospitalised with those who are not. Methods: We used data from the Primary Care Sentinel Cohort (PCSC) of the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database. The PCSC is recruited to be nationally representative of the English population. We developed a long LC phenotype using our established three-step ontological method: (1) Ontological step: Defining the reasoning process underpinning the phenotype; (2) Coding step: Exploring what clinical terms are available; (3) Logical extract model: testing performance. We created version of this phenotype using Protégé in the ontology web language (OWL) for Bioportal and using Phenoflow. We used the phenotype to compare people with long COVID-19 with: (1) Their symptoms in the year prior to acquiring COVID-19; and (2) People with acute COVID-19. We also compared hospitalised people with long COVID-19 with those not hospitalised. We compared socio-demographic details (age, gender, ethnicity, socioeconomic-status, obesity and smoking), comorbidities (cardiometabolic, respiratory and mental health) and Office of National Statistics (ONS) defined long covid symptoms between groups. We used descriptive statistics and logistic regression. Results: The long covid phenotype, available in Bioportal and Phenoflow, formats that differentiates people hospitalised with LC from people who are not, and where there no index infection is identified. The PCSC (N=7.4 million) includes 428,479 patients with an acute COVID-19 diagnosis confirmed by a laboratory test and 10,772 patients with clinically diagnosed COVID-19. We have before and after symptoms related to LC for hospitalized and community strata. 7,471 (1.74%;95CI=1.70-1.78) people were coded as having LC, 1,009 (13.5%;95CI=12.7-14.3) had a hospital admission related to acute COVID-19, 6,462 (86.5%;95CI=85.7-87.3) were not admitted to hospital of whom 2,728 had no COVID-19 index date recorded. 15.6% (95CI=14.7-16.5) of people with LC were hospitalised compared to 4.9% (95CI=4.8-5.0, p<0.0001) with uncomplicated COVID-19. Conclusions: Our long covid phenotype identifies LC cases and enables us to conduct a comparison between LC and defined comparator groups. Clinical Trial: Not applicable
286	D283		Fern Davies, Ilora Finlay, Helen Howson, Nicholas Rich	Recommendations for a voluntary Long COVID Registry	https://doi.org/10.1177%2F01410768221114964	Published	July 26, 2022	Article	https://journals.sagepub.com/doi/full/10.1177/01410768221114964	Long COVID has had a profound impact on the lives and health of many people around the globe.1 Estimates of the number of people affected vary, but on the 6th May 2022, the Office of National Statistics (ONS) identified that there were 1.8 million (2.8%) people living in private households in the UK alone who were experiencing self-reported long COVID symptoms.2 The same data identified that symptoms adversely affect the day-to-day activities of 1.2 million people in the UK.2 However, the long-term consequences of SARS-CoV-2 infection and the subsequent impact on public health are still largely unknown and present a major challenge to health and care systems moving forward. A mechanism to facilitate long-term monitoring of long COVID is therefore essential to support research, service improvement and enhance understanding of the disease as it evolves. In response to this, the aim of this commentary is to outline key recommendations for a voluntary Long COVID Registry in Wales. In this paper, five key recommendations are highlighted that should be considered in the development of a Long COVID Registry. These include: 1) a dual purpose of research and service improvement; 2) experiential co-design with end-users; 3) recruitment of a self-referred population and inclusion of a control group; 4) utilisation of digital infrastructures and 6) a prudent and integrated approach.
287	D284		GiovanniGuaraldiabJovanaMilicaMatteoCesaricLeonardLeibovicidFedericaMandreoliePaoloMissierfRenzoRozzinigAnna MariaCattelanhFedericoMottaaCristinaMussiniabAndreaCossarizzai	The interplay of post-acute COVID-19 syndrome and aging: a biological, clinical and public health approach	https://doi.org/10.1016/j.arr.2022.101686	Published	30 July 2022	Review	https://www.sciencedirect.com/science/article/pii/S1568163722001283	Highlights •PACS is a condition of growing interest for clinical and public health reasons. •PACS occurs even in individuals with mild or asymptomatic acute SARS COV-2 infection. •PACS is likely driven by a vicious cycle of inflammaging and immunosenescence. •This altered immune-metabolic condition may affect aging trajectories. •Aging trajectoris may be depicted by the relationship between frailty and resilience. Abstract The post-acute COVID-19 syndrome (PACS) is characterized by the persistence of fluctuating symptoms over three months from the onset of the possible or confirmed COVID-19 acute phase. Current data suggests that at least 10% of people with previously documented infection may develop PACS, and up to 50–80% of prevalence is reported among survivors after hospital discharge. This viewpoint will discuss various aspects of PACS, particularly in older adults, with a specific hypothesis to describe PACS as the expression of a modified aging trajectory induced by SARS CoV-2. This hypothesis will be argued from biological, clinical and public health view, addressing three main questions: (i) does SARS-CoV-2-induced alterations in aging trajectories play a role in PACS?; (ii) do people with PACS face immuno-metabolic derangements that lead to increased susceptibility to age-related diseases?; (iii) is it possible to restore the healthy aging trajectory followed by the individual before pre-COVID?. A particular focus will be given to the well-being of people with PACS that could be assessed by the intrinsic capacity model and support the definition of the healthy aging trajectory.
288	D285		Burhan Fatih Kocyigit & Ahmet Akyol	The relationship between COVID-19 and fibromyalgia syndrome: prevalence, pandemic effects, symptom mechanisms, and COVID-19 vaccines	https://doi.org/10.1007/s10067-022-06279-9	Published	08 July 2022	Article	https://link.springer.com/article/10.1007/s10067-022-06279-9	On March 11, 2020, the World Health Organization, realizing the level of spread worldwide and the severity of the condition, accepted coronavirus disease 19 (COVID-19) as a pandemic. Subsequently, quarantine conditions were implemented around the world, and these triggered particular results. Like all other individuals, fibromyalgia syndrome (FMS) patients were affected by these conditions. The stress load in pandemic conditions, difficulties in accessing healthcare services, changes in exercise compliance, variations in physiotherapy programs, and remote work conditions all had an impact on FMS patients. Although general expectations were negative, some FMS patients were able to manage the pandemic conditions and even turn them in their favor. This is thought to be due to this patient group having established strategies to cope with stress in the pre-pandemic period, and they had sufficient ability to adapt to changing situations. FMS-related symptoms occur in a subset of individuals following COVID-19. One of the factors is the increased psychological burden after COVID-19. There is evidence that neuroinflammatory pathways affect neuroplasticity in the central nervous system and trigger the onset of FMS-related symptoms. Among the probable mechanisms are alterations in inflammatory and anti-inflammatory pathways. Changes in the autonomic nervous system with the effect of SARS-CoV-2 may induce the emergence of FMS-related symptoms. FMS and COVID-19 can coexist, and FMS may create a tendency to vaccine hesitancy. Future studies should focus on elucidating FMS-related symptoms occurring post-COVID-19. There is a need to determine distinctions between the FMS clinical status that emerged following COVID-19 and the regular patient group in terms of diagnosis, treatment, and follow-up. Key Points • Conflicting results have been observed in studies investigating the impacts of COVID-19 on FMS patients. In addition to studies revealing unfavorable effects, there are also articles reporting a steady course and even positive impacts. • No significant difference was detected between the groups with and without a diagnosis of FMS in terms of hospitalization and mortality outcomes related to COVID-19. • Several mechanisms have been proposed to explain the onset of FMS-related symptoms following COVID-19. During periods of lock-down and self-isolation, individuals are influenced biopsychosocially. Activation of some inflammatory pathways, changes in plasticity-central sensitization, and alterations in pain pathways are also plausible explanations.
289	D286		Darja ReuschkeORCID Icon &Donald HoustonORCID Icon	The impact of Long COVID on the UK workforce	https://doi.org/10.1080/13504851.2022.2098239	Published	06 Jul 2022	Study	https://www.tandfonline.com/doi/full/10.1080/13504851.2022.2098239	COVID-19 is more likely to lead to Long COVID among persons of working age. We outline the first estimates of the impact of Long Covid on employment in the UK. Using estimates of cumulative prevalence of Long COVID, activity-limiting Long COVID in the working-age population and of economic inactivity and job loss resulting from Long COVID, we provide evidence of the profound impact of Long COVID on national labour supply. Since the start of the pandemic, cumulatively 2.9 million people of working age (7% of the total) in the UK have had, or still have, Long COVID. This figure will continue to rise due to very high infection rates in the Omicron wave. Since the beginning of the pandemic, economic inactivity due to long-term sickness has risen by 120,900 among the working-age population, fuelling the UK’s current labour shortage. An estimated 80,000 people have left employment due to Long COVID. We argue that governments need to tackle the twin challenges to public health and labour supply and provide employment protection and financial support for individuals and firms affected by Long COVID.
290	D287		Jennifer Abbasi	The US Now Has a Research Plan for Long COVID—Is It Enough?	https://doi.org/10.1001/jama.2022.14536	Published	August 12, 2022	Article	https://jamanetwork.com/journals/jama/article-abstract/2795468	More than 2 years after patients with lingering health problems coined the term Long COVID, the US government has unveiled a research plan to understand, prevent, and treat the broad range of persistent and sometimes debilitating disease symptoms that are now known to affect many people after initial SARS-CoV-2 infection. The National Research Action Plan on Long COVID, released this August 3, has been met with a mixture of enthusiasm and disappointment. What Is Long COVID? A new US government research plan presents an interim definition of Long COVID. It broadly defines Long COVID as signs, symptoms, and conditions that continue or develop after initial COVID-19 or SARS-CoV-2 infection. The plan defines the signs, symptoms, and conditions as follows: Are present 4 weeks or more after the initial phase of infection May be multisystemic May present with a relapsing-remitting pattern and progression or worsening over time, with the possibility of severe and life-threatening events even months or years after infection The plan emphasizes that Long COVID is not 1 single condition. Instead, it represents many potentially overlapping entities that likely have different biological causes and different risk factors and outcomes. Adapted from the National Research Action Plan on Long COVID. Department of Health and Human Services; August 2022.
291	D288		Mohammad Hossein Taghrir, Hossein Akbarialiabad, Ashkan Abdollahi, Nasrollah Ghahramani, Bahar Bastani, Shahram Paydar, Babak Razani, John Mwangi, Ali A. Asadi-Pooya, Jamshid Roozbeh, Leila Malekmakan, Manasi Kumar**	Inequity and disparities mar existing global research evidence on Long COVID	https://doi.org/10.1177%2F17579759221113276	Published	August 12, 2022	Article	https://journals.sagepub.com/doi/abs/10.1177/17579759221113276	Since the pandemic began in December 2019, SARS-Cov2 has accentuated the wide gap and disparities in socioeconomic and healthcare access at individual, community, country, and regional levels. More than two years into the current pandemic, up to three-fourths of the patients are reporting continued signs and symptoms beyond the acute phase of COVID-19, and Long COVID portends to be a major challenge in the future ahead. With a comprehensive overview of the literature, we found that most studies concerning long COVID came from high and upper-middle income countries, and people of low-income and lower-and-middle income regions and vulnerable groups with comorbid conditions have been neglected. Apart from the level of income, there is a significant geographical heterogeneity in investigating the Post-Acute Sequelae of COVID-19 (PASC) or what we call now, long COVID. We believe that these recognizing health disparities is crucial from equity perspective and is the first step toward global health promotion.
292	D289		Nikhil Mayor 1 Bernardo Meza-Torres 2, 3 Cecilia Okusi 4 Gayathri Delanerolle 4 Martin Chapman 5 Wenjuan Wang 5 Sneha Anand 4 Michael Feher 2 Jack Macartney 2 Rachel Byford 2 Mark Joy 2 Piers Gatenby 1 Vasa Curcin 5 Trisha Greenhalgh 2 Brendan Delaney 4 Simon de Lusignan 2, 6 Author	Developing a Long COVID Phenotype for Postacute COVID-19 in a National Primary Care Sentinel Cohort: Observational Retrospective Database Analysis	https://doi.org/10.2196/36989	Published	11.8.2022	Study	https://publichealth.jmir.org/2022/8/e36989	Background: Following COVID-19, up to 40% of people have ongoing health problems, referred to as postacute COVID-19 or long COVID (LC). LC varies from a single persisting symptom to a complex multisystem disease. Research has flagged that this condition is underrecorded in primary care records, and seeks to better define its clinical characteristics and management. Phenotypes provide a standard method for case definition and identification from routine data and are usually machine-processable. An LC phenotype can underpin research into this condition. Objective: This study aims to develop a phenotype for LC to inform the epidemiology and future research into this condition. We compared clinical symptoms in people with LC before and after their index infection, recorded from March 1, 2020, to April 1, 2021. We also compared people recorded as having acute infection with those with LC who were hospitalized and those who were not. Methods: We used data from the Primary Care Sentinel Cohort (PCSC) of the Oxford Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database. This network was recruited to be nationally representative of the English population. We developed an LC phenotype using our established 3-step ontological method: (1) ontological step (defining the reasoning process underpinning the phenotype, (2) coding step (exploring what clinical terms are available, and (3) logical extract model (testing performance). We created a version of this phenotype using Protégé in the ontology web language for BioPortal and using PhenoFlow. Next, we used the phenotype to compare people with LC (1) with regard to their symptoms in the year prior to acquiring COVID-19 and (2) with people with acute COVID-19. We also compared hospitalized people with LC with those not hospitalized. We compared sociodemographic details, comorbidities, and Office of National Statistics–defined LC symptoms between groups. We used descriptive statistics and logistic regression. Results: The long-COVID phenotype differentiated people hospitalized with LC from people who were not and where no index infection was identified. The PCSC (N=7.4 million) includes 428,479 patients with acute COVID-19 diagnosis confirmed by a laboratory test and 10,772 patients with clinically diagnosed COVID-19. A total of 7471 (1.74%, 95% CI 1.70-1.78) people were coded as having LC, 1009 (13.5%, 95% CI 12.7-14.3) had a hospital admission related to acute COVID-19, and 6462 (86.5%, 95% CI 85.7-87.3) were not hospitalized, of whom 2728 (42.2%) had no COVID-19 index date recorded. In addition, 1009 (13.5%, 95% CI 12.73-14.28) people with LC were hospitalized compared to 17,993 (4.5%, 95% CI 4.48-4.61; P<.001) with uncomplicated COVID-19. Conclusions: Our LC phenotype enables the identification of individuals with the condition in routine data sets, facilitating their comparison with unaffected people through retrospective research. This phenotype and study protocol to explore its face validity contributes to a better understanding of LC.
293	D290		World Bank	Long COVID The Extended Effects of the Pandemic on Labor Markets in Latin America and the Caribbean	https://doi.org/10.1596/37682	Published	July 2022	Article	https://elibrary.worldbank.org/doi/epdf/10.1596/37682	More than a year on from the start of the Coronavirus (COVID-19) pandemic and with massive vaccination campaigns underway, over a quarter of the adult population in Latin America and the Caribbean (LAC) who had a job before the pandemic were still not working. Of these, over half left the labor force entirely. Women, young people, older workers, and individuals with low educational attainment levels have been disproportionately affected by this crisis. In many cases, workers have become discouraged or unable to return to work, exiting the labor market altogether. The exit of workers from the labor market was simultaneously accompanied by entry from inactivity into the labor force at unprecedented levels during the pandemic, suggesting that further examination at the country level is required to understand the role of government transfers and care work as determinants of people’s activity choices. Still, as of mid-2021, inactivity rates remained higher than before the pandemic in most countries.
294	D291		Lin Zhang1J. Paulo Moreira2,3,Yan Xi	What is Long COVID-19?Clarifying Definitions and Symptoms	https://doi.org/10.56226/ihr.v1i2.28	Published	8 August 2022	Review	https://internationalhealthcarereview.com/index.php/home/article/view/28/4	Background:What is the definition of Long COVID-19? What are its currently acknowledged symptoms? As this is a new condition suspected to be evolving as a potentially post-Pandemic new disease, it becomes relevant to clarify the current definitions of Long COVID-19. The article puts together the most recent definitions and briefly discusses points of common understanding and points of uncertainty.Objectives:The main aim of the article is to clarify the definitions and symptoms of Long COVID-19 as international evidence defines them. This is relevant to support health professionals and interested parties to access a structured clarification of the disease at this stage of knowledge. Supporting evidence-based intervention is the fundamental objective of the article.Methods:The Rapid Literature Reviewis a form of evidence synthesis that providestimely information for decision making and evidence-based practice compared with standard systematic reviews. The review used the following sources: Web of Science and PubMed,.The Search used the keywords ‘Long Covid-19’, ‘Definitions’ and ‘Symptoms’ and limited to articles published between January 2021 and June 2022.There were two reviewers to selectarticles based on the inclusion/exclusion criteria(keywords defined and time span of publications).Both reviewers appraised criticallyand rigorously within the criteria defined and a summary was produced.Results:Six articles were identified as relevant for the objectives of this article. These were individually evaluated on the contribution to clarifying definitions and symptoms of Long COVID-19. Definitions seem to follow the initial definition made available in a publication from World Health Organization. However, the follow-up articles seem to add additional interpretations and associated symptoms.Main Contribution to Evidence-Based Practice:The article puts together the recent evolution of the definition of Long COVID-19 and associated symptoms to support clinical decision-making and evidence-based practice.
295	D292		Rachel L. Levine	Addressing the Long-term Effects of COVID-19	http://jamanetwork.com/article.aspx?doi=10.1001/jama.2022.14089	Published	August 3, 2022	Article	https://jamanetwork.com/journals/jama/article-abstract/2795139	The COVID-19 pandemic is the most significant medical and public health challenge the US has encountered in the last 100 years. As of July 26, 2022, an estimated 90 million cases of COVID-19 have been reported in the US, with an estimated 1 million COVID-19–related deaths. The current number of SARS-CoV-2 infections is difficult to estimate accurately, considering that many individuals with positive self-test results do not seek care or report their infection. At the same time, new coronavirus variants continue to emerge, with Omicron subvariants such as BA.5 and BA.4 now identified as the dominant circulating strains. From the start of the pandemic, infected individuals exhibited different patterns of recovery. Some patients partnered with other groups of patients with similar or overlapping sets of symptoms and voiced their concerns to health care professionals, allowing recognition of what has been referred to as “Long COVID.”1 In defining Long COVID, 2 perspectives need to be balanced: the need to learn more and avoid premature definitions that inappropriately exclude patients in need of care, and the need to establish interim definitions to enable access to health care and disability services as the science of Long COVID continues to emerge. Long COVID and associated conditions as well as the longer-term sequelae of the pandemic will continue to affect patients and families. The medical and public health community have made dedicated efforts during the last 2½ years to stopping the spread of this deadly coronavirus and have implemented prevention methods, developed treatments, and released vaccines that have been central to reducing initial COVID-19 infections and preventing Long COVID. It is important to focus a new lens on the pandemic and direct much-needed attention to Long COVID. Taking care of affected patients presents challenges given the incompleteness of research, the lack of sufficient diagnostics support, and pervasive problems with access to services. The provisions in the presidential memo are important elements for mounting an effective approach for addressing the long-term effects of COVID.
296	D293		UKCDR	COVID-19 FUNDED RESEARCH PROJECTS IN FOCUS		Published	July 2022	Article	https://www.ukcdr.org.uk/wp-content/uploads/2022/07/UPDATED-UKCDR-0722-Tracker-Highlights-Long-Covid-250722-1.pdf	As the coronavirus pandemic evolves, there is increased interest in the emerging phenomenon, now commonly referred to as “long COVID”, which encompasses a wide spectrum of persistent and newly emerging multisystemic symptoms following COVID-19 infection. These include cough, fatigue, shortness of breath, alterations in taste and smell, depression and mood disturbances (1). Cardiac, pulmonary and renal sequalae may also follow COVID-19 infections. To date, there is a lack of consensus on a clear definition, diagnosis, clinical characterization and management, rehabilitation and appropriate support for sufferers in addition to difficulties in ascertaining its prevalence (1) (2) (3). Here, we present the scope of funded research activity focused on long COVID, drawing on evidence from the July 2022 update of the Living Mapping Review (LMR) of COVID-19 funded research projects and the UKCDR/GLOPID-R.
297	D294		Jannathul Firdous, Nang Thinn Thinn Htike, Alia Afiqah Binti Zainudin, Azizah Haziqah Binti Azizah Ariffin, Mohamad Aidel Mukhriz Bin Mohd Burhan, Nurin Zahirah Binti Zulhisham	Impacts on post-COVID-19 sequelae: A systemic Review	http://dx.doi.org/10.7324/JAPS.2022.121003	Published	Jul 31, 2022	Review	https://japsonline.com/abstract.php?article_id=3742&sts=2	Concerns on whether or not coronavirus disease 2019 (COVID-19) can cause long-term impact are rising since many aspects of the disease are still under investigation. This systemic review was carried out to recognize the post- COVID-19 sequelae infection in various body systems and to analyze the comorbidities in survivors who suffered long-term impacts. The choice of words used to search is “post-COVID-19,” “COVID-19,” and “SARS-CoV-2 infection.” A total of 1,282 articles were extracted. Reports suggested that a wide range of sequelae were faced by the survivors which affected various systems, mainly the respiratory, gastrointestinal, nervous, cardiovascular, and musculoskeletal systems, while rarely affect other systems such as the endocrine, vascular, renal, and urogenital systems. Comorbidities are involved in determining the harshness of sequelae and the persistence of symptoms of post-severe acute respiratory syndrome coronavirus-2 infection. COVID-19 survivors may present with different symptoms and conditions that vary from mild symptoms to severe and rare conditions. It is crucial to understand the sequelae of post-COVID-19 for prevention and help to establish pandemic control strategies and rehabilitation needs.
298	D295		Blake Hereth, postdoctoral fellow1, Paul Tubig, assistant professor2, Ashton Sorrels, graduate student3, Anna Muldoon, graduate student4, Kelly Hills, graduate student1, Nicholas G Evans, associate professor1	Long covid and disability: a brave new world	https://doi.org/10.1136/bmj-2021-069868	Published	01 August 2022	Article	https://www.bmj.com/content/378/bmj-2021-069868.full	Nicholas Evans and colleagues argue that long covid needs to be better recognised, understood, and supported, and should stimulate a rethink of our approach to disability. Key messages - The rise of long covid has created millions of new people with disabilities who will have to navigate the post-pandemic world - The need for change to support people with disabilities predated the pandemic - Long covid needs to be legally recognised as disabling through clinical research and practice - The state must support people with long covid through expanded or reformed infrastructure and policy and by changing social norms - Such changes will benefit all disabled people and wider society
299	D296		Sandro Galea	The Post–COVID-19 Case for Primary Care	https://doi.org/10.1001/jamahealthforum.2022.3096	Published	July 28, 2022	Article	https://jamanetwork.com/journals/jama-health-forum/fullarticle/2794949	As the pandemic moves to a stage that occasions reflection, scholarship is emerging about how we may rethink primary care in the postpandemic moment, with a focus on innovations in service delivery, digital medicine, and payment structures. These efforts to reconsider primary care delivery are indeed important and should be encouraged. A broader public conversation that clarifies and elevates the role of primary care can make an important contribution to a national reconsideration of the centrality of primary care.
300	D297		Celina Silvia Stafie 1ORCID,Sorina Mihaela Solomon 2,,Irina-Georgeta Sufaru 2,ORCID,Maria Manaila 3,Ingrid Ioana Stafie 3,Gabriela Melinte 3,Bianca Simionescu 4 andLetitia Leustean 5	Pathogenic Connections in Post-COVID Conditions: What Do We Know in the Large Unknown? A Narrative Review	https://doi.org/10.3390/v14081686	Published	30 July 2022	Review	https://www.mdpi.com/1999-4915/14/8/1686/htm	The coronavirus 2019 (COVID-19) disease has long-term effects, known as post-COVID conditions (PCC) or long-COVID. Post-COVID-19 syndrome is defined by signs and symptoms that occur during or after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection which persist for more than 12 weeks and cannot be supported by an alternative diagnosis. The cardiovascular damage caused by COVID-19 in the severe forms of the disease is induced by severe systemic inflammation, considered to be one of the causes of myocardial lesions, with increased levels of circulating cytokines and toxic response mediators. We have focused on conditions that can induce long-COVID-19, or multisystem inflammatory syndrome in adults or children (MIS-C/MIS-A), with an emphasis on endocrinological and metabolic disorders. Although described less frequently in children than in adults, long-COVID syndrome should not be confused with MIS-C, which is an acute condition characterized by multisystem involvement and paraclinical evidence of inflammation in a pediatric patient who tested positive for SARS-CoV-2. At the same time, we mention that the MIS-A symptoms remit within a few weeks, while the duration of long-COVID is measured in months. Long-COVID syndrome, along with its complications, MIS-A and MIS-C, represents an important challenge in the medical community. Underlying comorbidities can expose both COVID-19 adult and pediatric patients to a higher risk of negative outcomes not only during, but in the aftermath of the SARS-CoV-2 infection as well.
301	D298		Eleni Gavriilaki Styliani Kokoris	COVID-19 sequelae: can long-term effects be predicted?	https://doi.org/10.1016/S1473-3099(22)00529-1	Published	August 25, 2022	Comment	https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(22)00529-1/fulltext	In this context, the study by Jeremy Werner Deuel and colleagues,10 reported in The Lancet Infectious Diseases, explores sequelae after SARS-CoV-2 infection in young adults (median age 21 years [IQR 21–23]). Deuel and colleagues did a longitudinal cohort study of 501 mainly young male adults (464 [93%]) undertaking a comprehensive test battery designed to evaluate physical and psychosocial outcomes after COVID-19. All participants at the time of the study had not received a dose of any COVID-19 vaccine and were members of the Swiss Armed Forces. Increased BMI, dyslipidaemia, and decreased physical endurance 6 months after COVID-19 were suggestive of a higher risk of developing metabolic disorders and possible cardiovascular complications. These findings might support the hypothesis of endothelial dysfunction as a primary driver of COVID-19 sequelae. Obesity, dyslipidaemia, and low physical activity are known risk factors for future cardiovascular complications, characterised by endothelial dysfunction. Cardiovascular risk factors can be modified through lifestyle changes and medications. More importantly, novel vascular and biochemical markers have been discovered over the last decade that can better predict cardiovascular risk.11 In conclusion, although no accurate prediction models exist for who will develop severe COVID-19 or sequelae, risk factors of vascular damage have emerged as important predictors. Large and high-quality studies are needed utilising multidisciplinary teams not only from different medical specialties but also from computational scientists that could suggest novel predictive models for the development of COVID-19 sequelae.
302	D299		Sateesh M.SakhamuriaSatishJankiebLexley M.Pinto Pereirac	Calling on Latin America and the Caribbean countries to recognise the disability from long COVID	https://doi.org/10.1016/j.lana.2022.100362	Published	26 August 2022	Article	https://www.sciencedirect.com/science/article/pii/S2667193X2200179X?via%3Dihub	Long COVID sufferers voiced the term on social media after being stigmatised, denied access to medical/specialist services or diagnosis, and feeling “fobbed off,” hoping their burden of devastating debilitation would stop being dismissed.1 This multi-dimensional disability is characterised by diverse health-related challenges embracing physical, mental, and cognitive issues, affecting daily activities, social, family, and employment relationships. Considering its life-changing impact on disabling resumption of normalcy, mentation, and work capacity, the 2006 United Nations Convention on the Rights of Persons with Disabilities qualifies it as a disability.2 An impending enormous influx of new entrants to the disability community is signalled by adverse health issues for six months or more in half of COVID-19 survivors from a large systemic review of 57 reports.3 The longest longitudinal cohort of COVID-19 patients, studied two years post-hospitalisation in Wuhan, found that 11% who did not return to work had decreased physical function or were unwilling to do so.4 As of early 2022 long COVID has distressed 23 million Americans, driving an approximate million people jobless, causing yet unknown significant public health, social, and economic outcomes. The Americas have probably been the hardest hit by COVID-19 globally. By the fourth week of May 2022, the Latin America and the Caribbean countries (LAC) were contributing an enormous cumulative COVID-19 global burden with about 13% of reported acute cases and 27% of confirmed deaths, despite having only 8% of the world's population.6 Brazil, Argentina, Columbia, Mexico, and Chile are worst affected, contributing more than 80% of the LACs burden. During the pandemic, LAC suffered the worst economic decline in two hundred years, devastating the region's society, economics, and health systems. Extrapolating Long COVID's estimated global prevalence of 43% (irrespective of hospitalization or disease severity)7 to the LAC signifies a current prevalence of more than 29 million cases of this new emergent pandemic. Prioritising disability is a global public health and human rights issue. Interestingly, the recent Global Disability Summit discussed interventional measures for long COVID but did not acknowledge it as a disability.8 Besides the exemplary initiative of the United States in recognising long COVID as a disability,9 neither international nor regional responses to disability benefit policies and employee protection after long COVID are forthcoming. The American commitment to long COVID recovery is bolstered by the National Institute of Health (September 2021) $470 million award to the RECOVERY (Researching COVID to Enhance Recovery) collaborative research proposal on mechanisms and management of long COVID10 and the Biden Administration's first-ever interagency national research action plan (April 2022) committing $20 million to investigate optimum health care for long COVID sufferers. Though the United States has a robust and historical relationship with the LAC region straddling economic, defence, cultural, and social spheres, government responses in most LAC countries have not used the model to recognise the disability from long COVID or the needs of sufferers. Priorities at different strata for LAC to address the suffering, needs, and disability inflicted by long COVID are presented in Table 1. Governments can pioneer policies to encourage mutual employer-employee work output, thereby improving opportunities for long COVID sufferers, avoiding discrimination against the disabled, and motivating occupational rehabilitation, which will promote cost savings and reforms for the disability workforce. National funding for scientific scrutiny into the mysteries of long COVID will boost research and surveillance.
303	D300		Elise Paul, Daisy Fancourt	OP30 Do stressors increase the risk of long COVID? A longitudinal study of adversity worries and experiences in the two months prior to COVID-19 infection and the development of long COVID in 1,962 UK adults	http://dx.doi.org/10.1136/jech-2022-SSMabstracts.30	Published	August 26, 2022	Study	https://jech.bmj.com/content/76/Suppl_1/A15.1	Abstract Background - Long COVID is increasingly recognised as public health burden. Ongoing inflammatory processes have been found to underlie the post-acute sequalae, as in other viral infections. Psychological stress can trigger increases in circulating markers of inflammation, with higher inflammation in turn associated with a greater propensity for developing chronic illness. However, research on risk factors for long COVID has focused almost entirely on demographic and infection-related characteristics, to the exclusion of psychosocial predictors such as stress immediately preceding the index infection. Research on whether stressors predict the development of specific long COVID symptoms is also needed, because some long COVID symptoms may be more debilitating than others and have different risk factors. Methods - Data from 1,962 UK adults who had previously been infected with COVID-19 and who took part in the UCL COVID-19 Social Study were analysed. The number of adverse experiences (e.g., job loss) and the number of adversity worries measured within the two months prior to COVID-19 infection were used to predict the development of self-reported long COVID and the presence of three specific long COVID symptoms (difficulty with mobility, cognition, and self-care). Logistic regression analyses controlled for a range of COVID-19 infection characteristics, socio-demographics, and health-related factors. Results - One in five who had been infected with COVID-19 had either been diagnosed with or believed themselves to have had long COVID. Odds of self-reported long COVID increased by 1.31 (95% confidence interval [CI]: 1.04 to 1.64) for each additional worry about adversity in the two months prior to COVID-19 infection. The number of adversity experiences corresponded with increased odds of difficulty with self-care (e.g., dressing, washing all over) by 1.68 (95% CI: 1.08 to 2.61). Discussion - Results suggest a central role of stress in the time preceding the acute COVID-19 infection for the development of long COVID and point to the importance of prioritising and monitoring COVID-19 patients who have been affected by stress for ongoing care and prevention. A more comprehensive understanding of whether psychosocial circumstances in the time period leading up to infection could aid in identifying early in the disease who is most likely to be negatively impacted due to ongoing symptoms.
304	D301		Charmaine van Eeden,Mohammed S. Osman &Jan Willem Cohen Tervaert	Fatigue in ANCA-associated vasculitis (AAV) and systemic sclerosis (SSc): similarities with Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A critical review of the literature	https://doi.org/10.1080/1744666X.2022.2116002	Published	31 Aug 2022	Review	https://www.tandfonline.com/doi/abs/10.1080/1744666X.2022.2116002	Introduction Persistent debilitating fatigue is a frequent complaint in patients with systemic autoimmune rheumatic diseases (SARDs). Fatigue is, however, frequently overlooked in the clinic, and patients who successfully achieve remission of their disease, often still have a lowered quality of life due to its persistence. How similar is this fatigue to Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), what is this fatigue associated with, and what tools/approaches (if any), have resulted in the improvement of fatigue in these patients is poorly defined. Areas covered Similarities between the pathophysiology of ME/CFS, systemic sclerosis (SSc) and primary systemic vasculitides (PSV) are discussed, followed by an in-depth review of the prevalence and correlates of fatigue in these diseases. The authors reviewed literature from MEDLINE, APA PsycInfo, Embase, and CINAHL. Expert opinion Persistent fatigue is a prominent feature in SARDs and may not be associated with components commonly associated with disease activity and/or progression. Immune and metabolic commonalities exist between ME/CFS, SSc, and PSVs – suggesting that common pathways inherent to the diseases and fatigue may be present. We suggest that patients with features of ME/CFS need to be identified by treating physicians, as they may require alternative approaches to therapy to improve their quality of life.
305	D302		LarryAuaCristianCapotescubGilEyalcGabrielleFinestonec	Long covid and medical gaslighting: Dismissal, delayed diagnosis, and deferred treatment	https://doi.org/10.1016/j.ssmqr.2022.100167	Published	7 September 2022	Article	https://www.sciencedirect.com/science/article/pii/S2667321522001299	Highlights •Long Covid patients use language of gaslighting to describe physicians interactions. •Online survey shows experiences of dismissal, delayed diagnosis, and deferred treatment. •Medical gaslighting likely exacerbated by social inequalities in the United States. Abstract While we know a lot more about Long Covid today, patients who were infected with Covid-19 early on in the pandemic and developed Long Covid had to contend with medical professionals who lacked awareness of the potential for extended complications from Covid-19. Long Covid patients have responded by labeling their contentious interactions with medical professionals, organizations, and the broader medical system as “gaslighting.” We argue that the charge of medical gaslighting can be understood as a form of ontological politics. Not only do patients demand that their version of reality be recognized, but they also blame the experts who hold gatekeeping power over their medical care for producing a distorted version of said reality. By analyzing results from an online survey of Long Covid patients active on social media in the United States (n = 334), we find that experiences of contention and their reframing as “gaslighting” were common amongst our respondents. In short answer responses about their experience obtaining medical care for Long Covid, our respondents described encountering medical professionals who dismissed their experience, leading to lengthy diagnostic odysseys and lack of treatment options for Long Covid. Even though we are limited by characteristics of our sample, there is good reason to believe that these experiences and their contentious reframing as medical gaslighting are exacerbated by gender, class, and racial inequalities.
306	D303		Simon Haunhorst, Wilhelm Bloch, Heiko Wagner, Claudia Ellert, Karsten Krüger, Daniel C Vilser, Kathrin Finke, Philipp Reuken, Mathias W Pletz, Andreas Stallmach, Christian Puta	Long COVID: a narrative review of the clinical aftermaths of COVID-19 with a focus on the putative pathophysiology and aspects of physical activity	https://doi.org/10.1093/oxfimm/iqac006	Published	16 September 2022	Review	https://academic.oup.com/ooim/advance-article/doi/10.1093/oxfimm/iqac006/6701971	The pandemic coronavirus disease 2019 (COVID-19) can cause multi-systemic symptoms that can persist beyond the acute symptomatic phase. The post-acute sequelae of COVID-19 (PASC), also referred to as Long COVID, describe the persistence of symptoms and/or long-term complications beyond four weeks from the onset of the acute symptoms and are estimated to affect at least 20% of the individuals infected with SARS-CoV-2 regardless of their acute disease severity. The multi-faceted clinical picture of Long COVID encompasses a plethora of undulating clinical manifestations impacting various body systems such as fatigue, headache, attention disorder, hair loss, and exercise intolerance. The physiological response to exercise testing is characterized by a reduced aerobic capacity, cardiocirculatory limitations, dysfunctional breathing patterns, and an impaired ability to extract and use oxygen. Still, to this day, the causative pathophysiological mechanisms of Long COVID remain to be elucidated, with long-term organ damage, immune system dysregulation, and endotheliopathy being among the hypotheses discussed. Likewise, there is still a paucity of treatment options and evidence-based strategies for the management of the symptoms. In sum, this review explores different aspects of Long COVID and maps the literature on what is known about its clinical manifestations, potential pathophysiological mechanisms, and treatment options.
307	D304		Howard Bauchner	It's Time To Create A National Long COVID Compensation Program	https://www.healthaffairs.org/do/10.1377/forefront.20220914.188014	Published	September 16, 2022	Article	https://www.healthaffairs.org/content/forefront/s-time-create-national-long-covid-compensation-program	In the face of this daunting challenge, the US should look to the example of a very successful national program of care. In 1986, after years of debate, Congress created the National Vaccine Injury Compensation Program (NVICP) to ensure a stable supply of vaccines, protect vaccine manufactures from liability claims, and fairly compensate individuals who had very rare medical consequences associated with vaccines. The new law added a tax to each vaccine administered, pooled the funds, and created a system to compensate individuals injured by a vaccine. It is a no-fault system, involving both HHS and the Department of Justice (DOJ). A claimant, or a representative of the claimant, presents evidence that they have been harmed by a vaccine, medical experts in HHS determine if the claimant meets edibility criteria and the case is referred to the DOJ, and the “vaccine courts” for adjudication. To help claimants, the program created a vaccine injury table listing which vaccines are associated with which specific injury. Since 1988, more than 5,000 claims, mostly related to the influenza vaccine, have been awarded. This program has protected manufacturers from liability claims and therefore reduced the risk of entering the market, a key step to ensuring a stable vaccine supply and spurring the development and introduction of new vaccines. Virtually every public health group acknowledges this mechanism has allowed for one of the great public health success stories in the US: very high sustained vaccination rates in all children, regardless of socioeconomic status, race, or ethnicity. With this model in mind, the US should create the NLCCP. Several entities could contribute to such a fund, including pharmaceutical and other companies that have reaped substantial profit since the pandemic began; and health and disability insurers, who would benefit from such a program. Policy makers might also consider adding an additional tax to vaccines to fund the program. Rather than having disability insurers process claims, many of which will likely be contentious, a group of experts—perhaps lawyers, perhaps clinical authorities, perhaps both—should be charged with determining whether individuals meet pre-specified diagnostic criteria and the corresponding award amounts. (This approach would echo that of the National Vaccine Injury Compensation Program.) Importantly, those without disability insurance could also file claims, an option that should help minimize disparities in care and compensation. The same group of experts could also determine which treatments for long COVID should be supported by either the program or health insurers. These determinations would be based upon recommendations from professional medical groups and have the added benefit of relieving health insurers of the challenge of making these decisions.
308	D305		Robert Leaman1 , Rezarta Islamaj1 , Alexis Allot1 , Qingyu Chen1 , W. John Wilbur1 , and Zhiyong Lu1,2,*	Comprehensive identification of Long Covid articles with human-in-theloop machine learning		Pre-print	September 2022	Study	https://arxiv.org/ftp/arxiv/papers/2209/2209.08124.pdf	Highlights • We propose a semi-automated classification framework for creating scientific literature collections with reduced need for human labels. • Our framework integrates automated classifiers of varying accuracy to provide a reliable classification for each article and flags articles where human effort is needed. • We use our framework to identify PubMed articles on Long Covid, also known as post-acute sequelae of SARS-CoV-2. • As of November 2021, we identify 5,645 articles relevant to Long Covid – 75.8% of which do not mention Long Covid by name – and have collected 496 synonymous terms for Long Covid. A significant percentage of COVID-19 survivors experience ongoing multisystemic symptoms that often affect daily living, a condition known as Long Covid or post-acute-sequelae of SARS-CoV-2 infection. However, identifying Long Covid articles is challenging since articles refer to the condition using a variety of less common terms or refrain from naming it at all. We developed an iterative human-in-the-loop machine learning framework designed to effectively leverage the data available and make the most efficient use of human labels. Specifically, our approach combines data programming with active learning into a robust ensemble model. Evaluating our model on a holdout set demonstrates over three times the sensitivity of other methods. We apply our model to PubMed to create the Long Covid collection, and demonstrate that (1) most Long Covid articles do not refer to Long Covid by any name (2) when the condition is named, the name used most frequently in the biomedical literature is Long Covid, and (3) Long Covid is associated with disorders in a wide variety of body systems. The Long Covid collection is updated weekly and is searchable online at the LitCovid portal: https://www.ncbi.nlm.nih.gov/research/coronavirus/docsum?filters=e_condition.LongCovid
309	D306		Brian Owens	How “long covid” is shedding light on postviral syndromes	https://doi.org/10.1136/bmj.o2188	Published	21 September 2022	Article	https://www.bmj.com/content/378/bmj.o2188	The global burden of long covid has put a spotlight on the long neglected mystery of postviral syndromes. Brian Owens asks what’s changing. Unanswered questions Finding a common cause of the various syndromes would be a breakthrough in postviral syndrome research. Several hypotheses have been put forward, including persistent but undetected infections, autoimmune responses, dysregulation of the microbiome, and tissue damage.4 But Andrew Lloyd of the University of New South Wales mostly dismisses those ideas. “The lessons we’ve learned from other post-infection syndromes is that it is not a persistent infection, not immunological, not a simple psychological disorder,” he says. Among researchers who study these illnesses, including long covid, the smart money is now on some kind of disorder of the central nervous system,5 he explains. And since there’s no clear evidence of any major structural problems in the brain, this suggests that the disorder lies at the cellular and protein level. “There is some circumstantial evidence to support that,” he says. “But nothing concrete yet.” Treatments Alba Azola, co-director of the Post-Acute Covid-19 Team at Johns Hopkins University School of Medicine in Baltimore, USA, has been treating patients with lingering covid-19 symptoms since April 2020. At first, the patients with long covid seemed to have a lot in common with people with postural orthostatic tachycardia syndrome (POTS), a blood circulation disorder characterised by elevated heart rate and other symptoms brought on by standing up, as fatigue and brain fog are also common symptoms of that condition. So Azola, a physical and rehabilitation physician, along with a team of physiotherapists, started treating these patients using the same protocols as for POTS, focusing on things such as diet and exercise. But after about three months it was clear that this exercise focused treatment regimen was not working. The team realised that long covid was more like ME/CFS, says Azola, and began drawing on ideas from that area instead. This meant focusing on managing and conserving energy levels and understanding which triggers can bring on fatigue, to get off what she calls the “corona-coaster,” where patients start to feel better, become more active, and then crash. She says that, in the absence of a reliable treatment or cure, patients need to learn to live with the condition by being selective with their energy and what they invest it in, which can be as simple as using a chair in the shower to avoid unnecessary exertion. “I learned all of this from the ME/CFS community,” she says.
310	D307		Ethan B. Jansen,Spencer N. Orvold,Cynthia L. Swan,Anthony Yourkowski,Brittany M. Thivierge,Magen E. Francis,Anni Ge,Melissa Rioux,Joseph Darbellay,John G. Howland,Alyson A. Kelvin	After the virus has cleared—Can preclinical models be employed for Long COVID research?	https://doi.org/10.1371/journal.ppat.1010741	Published	September 7, 2022	Review	https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1010741	Abstract Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) can cause the life-threatening acute respiratory disease called COVID-19 (Coronavirus Disease 2019) as well as debilitating multiorgan dysfunction that persists after the initial viral phase has resolved. Long COVID or Post-Acute Sequelae of COVID-19 (PASC) is manifested by a variety of symptoms, including fatigue, dyspnea, arthralgia, myalgia, heart palpitations, and memory issues sometimes affecting between 30% and 75% of recovering COVID-19 patients. However, little is known about the mechanisms causing Long COVID and there are no widely accepted treatments or therapeutics. After introducing the clinical aspects of acute COVID-19 and Long COVID in humans, we summarize the work in animals (mice, Syrian hamsters, ferrets, and nonhuman primates (NHPs)) to model human COVID-19. The virology, pathology, immune responses, and multiorgan involvement are explored. Additionally, any studies investigating time points longer than 14 days post infection (pi) are highlighted for insight into possible long-term disease characteristics. Finally, we discuss how the models can be leveraged for treatment evaluation, including pharmacological agents that are currently in human clinical trials for treating Long COVID. The establishment of a recognized Long COVID preclinical model representing the human condition would allow the identification of mechanisms causing disease as well as serve as a vehicle for evaluating potential therapeutics. Author summary Not everyone who develops COVID-19 (Coronavirus Disease 2019) recovers completely after 5 days, 14 days, or even 12 weeks. People who experience continuing or new symptoms such as fatigue, difficulty breathing, joint pain, heart dysfunction, and memory issues are now recognized as having “Long COVID” or Post-Acute Sequelae of COVID-19 (PASC). Although Long COVID has been estimated to affect 30% to 75% of recovering COVID-19 patients in some studies, the illness is poorly understood, leaving us unable to properly support patients in their recovery. Here, we summarize COVID-19 and Long COVID in people then discuss the potential utility of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) animal models to address problems of Long COVID. We review SARS-CoV-2 infection and disease manifestations in mice, Syrian hamsters, ferrets, and nonhuman primates (NHPs). Specifically, the virology, pathology, immune responses, and multiorgan involvement are summarized. These models are rationally examined for their use in understanding the complexities of the multiorgan involvement during Long COVID and the potential for their use in screening therapeutics such as anti-inflammatory drugs, which are currently used for treating other diseases. The aim of this review is to highlight Long COVID preclinical animal models that could be used for Long COVID research and to screen for pharmacological interventions.
311	D308		Puja Mehta, Ivan O. Rosas & Mervyn Singer	Long Covid: where we stand and challenges ahead	https://doi.org/10.1038/s41418-022-01052-6	Published	07 September 2022	Review	https://www.nature.com/articles/s41418-022-01052-6	Post-acute sequelae of SARS-CoV-2 (PASC), also known as Post-Covid Syndrome, and colloquially as Long Covid, has been defined as a constellation of signs and symptoms which persist for weeks or months after the initial SARS-CoV-2 infection. PASC affects a wide range of diverse organs and systems, with manifestations involving lungs, brain, the cardiovascular system and other organs such as kidney and the neuromuscular system. The pathogenesis of PASC is complex and multifactorial. Evidence suggests that seeding and persistence of SARS-CoV-2 in different organs, reactivation, and response to unrelated viruses such as EBV, autoimmunity, and uncontrolled inflammation are major drivers of PASC. The relative importance of pathogenetic pathways may differ in different tissue and organ contexts. Evidence suggests that vaccination, in addition to protecting against disease, reduces PASC after breakthrough infection although its actual impact remains to be defined. PASC represents a formidable challenge for health care systems and dissecting pathogenetic mechanisms may pave the way to targeted preventive and therapeutic approaches. Facts PASC is a frequent legacy of acute SARS-CoV-2 infection, affecting over 10% of patients with different signs and symptoms across a wide range of organs and systems. The most frequent manifestations of PASC, in addition to compromised lung functions, include: neurocognitive alterations; alterations of cardiovascular functions and increased risk of acute events; fatigue. The SARS-CoV-2 virus seeds and persists in different organs and tissues. The pathogenesis of PASC is multifactorial and includes: virus seeding and persistence in different organs; activation and response to unrelated viruses (e.g., EBV); autoimmunity; uncontrolled inflammation. Biomarkers of clinical PASC include levels of IgG, cytokines, chemokines, PTX3, and interferons. Vaccination reduces PASC after breakthrough infection. Open questions Occurrence, mechanism, and significance of SARS-CoV-2 persistence in different organs. Mechanisms, targets, and significance of autommune reactions. Role of other viruses. Impact of host genetics and microbiome. Actual impact of vaccination in people who get breakthrough infections and its duration. Occurrence and severity of PASC after infection with future variants. Preventive and therapeutic approaches.
312	D309		F.AlghamdiaR.OwenbR.E.M.AshtonbA.D.ObotibaaR.M.MeertensaE.HydecM.A.FaghybK.M.KnappaP.RogersdW.D.Straina	Post-acute COVID syndrome (long COVID): What should radiographers know and the potential impact for imaging services	https://doi.org/10.1016/j.radi.2022.08.009	Published	13 September 2022	Review	https://www.sciencedirect.com/science/article/pii/S1078817422001195	Objectives The COVID-19 pandemic caused an unprecedented health crisis resulting in over 6 million deaths worldwide, a figure, which continues to grow. In addition to the excess mortality, there are individuals who recovered from the acute stages, but suffered long-term changes in their health post COVID-19, commonly referred to as long COVID. It is estimated there are currently 1.8 million long COVID sufferers by May 2022 in the UK alone. The aim of this narrative literature review is to explore the signs, symptoms and diagnosis of long COVID and the potential impact on imaging services. Key findings Long COVID is estimated to occur in 9.5% of those with two doses of vaccination and 14.6% if those with a single dose or no vaccination. Long COVID is defined by ongoing symptoms lasting for 12 or more weeks post acute infection. Symptoms are associated with reductions in the quality of daily life and may involve multisystem manifestations or present as a single symptom. Conclusion The full impact of long COVID on imaging services is yet to be realised, but there is likely to be significant increased demand for imaging, particularly in CT for the assessment of lung disease. Educators will need to include aspects related to long COVID pathophysiology and imaging presentations in curricula, underpinned by the rapidly evolving evidence base. Implications for practice Symptoms relating to long COVID are likely to become a common reason for imaging, with a particular burden on Computed Tomography services. Planning, education and updating protocols in line with a rapidly emerging evidence base is going to be essential.
313	D310		Arthur A. Mirin,Mary E. Dimmock &Leonard A. JasonORCID Icon	A preliminary estimate of the economic impact of long COVID in the United States	https://doi.org/10.1080/21641846.2022.2124064	Published	13 Sep 2022	Article	https://www.tandfonline.com/doi/abs/10.1080/21641846.2022.2124064	Post-Acute Sequelae of SARS CoV-2 infection (PASC), more commonly referred to as Long COVID, is one of the most daunting health-care grand challenges facing the United States today. Affecting millions of Americans, Long COVID extracts a huge cost both socially and economically. In this article, we provide a preliminary estimate of the annual income loss and medical costs due to Long COVID in the United States. With many Long COVID patients either meeting the diagnostic criteria for myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) or exhibiting symptoms consistent with ME/CFS, we utilize ME/CFS to help guide our estimates. Based on the nearly 86 million documented US COVID survivors as of June 25, 2022, and considering a range of 5% to 20% of those survivors currently afflicted with Long COVID, we estimate annual medical costs to range from $43 billion to $172 billion, and lost income to range from $101 billion to $430 billion. This corresponds to an annual economic impact (exclusive of costs of disability services, social services, and lost income on the part of caretakers) ranging from roughly $140 billion to $600 billion.
314	D311		Kieran L. Quinn, Gabrielle M. Katz, Pavlos Bobos, Beate Sander, Candace D. McNaughton, Angela M. Cheung, Margaret S. Herridge, Clare L. Atzema, Karen B. Born, Christine Chan, Vincent Chien, David M. Kaplan, Jeffrey Kwong, Susan Leung, Linda Mah, Sharmistha Mishra, Andrew M. Morris, Christopher J. Mushquash, Karen Palmer, Alexandra Rendely, Arthur S. Slutsky, Rosa Stalteri, Fahad A. Razak	Understanding the Post COVID-19 Condition (Long COVID) in Adults and the Expected Burden for Ontario	https://doi.org/10.47326/ocsat.2022.03.65.1.0	Published	September 7, 2022	Study	https://covid19-sciencetable.ca/sciencebrief/understanding-the-post-covid-19-condition-long-covid-in-adults-and-the-expected-burden-for-ontario/	Key Message The post COVID-19 condition is a complex and heterogeneous syndrome that develops in people with prior SARS-CoV-2 infection. More than 100 symptoms have been reported in people with the post COVID-19 condition, and these appear to be associated with reduced quality of life, reduced function, and impairments in people’s ability to work and care for themselves. There remains significant uncertainty in the definition, magnitude of prevalence, causes, risk factors, prevention, and prognosis of the post COVID-19 condition, as well as its impact on people’s quality of life, function, and ability to work. Nonetheless, the reported range of these effects in the published literature suggests that the post COVID-19 condition poses substantial health risks to adults across a diverse range of outcomes that have the potential to impart a considerable burden on individuals and healthcare systems. More contemporary evidence in the era of widespread vaccination and emerging variants resulting in less severe illness than earlier variants suggests that the post COVID-19 condition may now be less frequent following SARS-CoV-2 infection. Still, a proactive and comprehensive strategy to manage the post COVID-19 condition needs to be developed by health systems and policy makers. This strategy should include substantial investments in research and health system resources to mitigate the long-term health, social, and economic impacts of the post COVID-19 condition in Ontario. Summary Background The post COVID-19 condition is a complex and heterogeneous syndrome that can develop in people with prior SARS-CoV-2 infection. The goal of this Science Brief is to identify and support the healthcare care needs of adults living with the post COVID-19 condition and their caregivers, and to inform health system and social resource planning to be able to meet those needs. Questions How has the post COVID-19 condition been defined? What are the potential underlying causes of the post COVID-19 condition? What is the prevalence of the post COVID-19 condition? What are the symptoms and sequelae of the post COVID-19 condition? Who is at risk of developing the post COVID-19 condition, and can this risk be mitigated? What is the impact of the post COVID-19 condition on functional limitations, health system utilization, and utilization of long-term disability and unemployment benefits? How are healthcare systems delivering care to people with the post COVID-19 condition? What barriers exist to providing clinical support to those with the post COVID-19 condition? What are the current knowledge gaps about the post COVID-19 condition? Findings The post COVID-19 condition is variably defined as the persistence of symptoms or sequelae occurring at least 4 or 12 weeks after probable or confirmed SARS-CoV-2 infection. Combined evidence estimates the prevalence of new or persistent symptoms at 4 or more weeks from SARS-CoV-2 infection to be 43% (54% among hospitalized persons, including those admitted to the intensive care unit, and 34% among those who are not hospitalized) and between 10-20% at 12 or more weeks, depending on the definition and data used to inform those estimates. Data from more recent pandemic time periods suggests a much lower overall prevalence. The five most frequently observed individual symptoms were fatigue (23%, 95% confidence interval (CI) 17-30), memory deficits (14%, 95% CI 10-19), shortness of breath (13%, 95% CI 0.11-0.15), sleep problems (11%, 95% CI 5-23), and joint pain (10%, 95% CI 4-22). The systemic nature of the condition is believed to be related to viral persistence, inflammation, autoimmunity, and/or coagulopathy. More than 100 symptoms have been reported in people with the post COVID-19 condition, and these appear to be associated with reduced function, impairments in people’s ability to work and care for themselves, poor quality of life, and high healthcare use. Vaccination against COVID-19 with one or two doses of vaccine prior to SARS-CoV-2 infection was associated with a reduction of approximately 50% in the risk of developing lingering symptoms at either time point. The benefits of vaccination in reducing the development of the post COVID-19 condition were also observed in people who were vaccinated after SARS-CoV-2 infection, as well as potentially in those with established post COVID–19 condition. High-quality care for people with the post COVID-19 condition is limited by a lack of proven therapies, potential inequities in care that are driven by limited access to primary and specialized care, and inconsistent application of insurance policies for reimbursement. There is also variable use of and lack of diagnostic and physician fee codes to track and evaluate care delivery and outcomes at a population level. Interpretation The post COVID-19 condition poses substantial health risks across a diverse range of outcomes that may result in a considerable burden for Ontarians, the economy, and the healthcare system. More contemporary evidence in the era of widespread vaccination and emerging variants resulting in less severe illness than earlier variants suggests that the post COVID-19 condition may now be less frequent following SARS-CoV-2 infection. Due to limitations in the quality of available published evidence, however, there remains significant uncertainty in the definition, prevalence, causes, risk factors, prevention, and prognosis of the post COVID-19 condition, as well as its impact on people’s quality of life, function, and ability to work. There is also considerable uncertainty about the magnitude of these potential effects. Nonetheless, a proactive and comprehensive strategy to manage the post COVID-19 condition needs to be developed by health systems and policymakers. This strategy should include substantial investments in research and health system resources to mitigate the long-term health, social, and economic impacts of the post COVID-19 condition in Ontario.
315	D312	AXD	Afagh Garjani, View ORCID ProfileRodden M. Middleton, View ORCID ProfileRichard Nicholas, View ORCID ProfileNikos Evangelou	Recovery From COVID-19 in Multiple Sclerosis A Prospective and Longitudinal Cohort Study of the United Kingdom Multiple Sclerosis Register	https://doi.org/10.1212/NXI.0000000000001118	Published	November 30, 2021	Study	https://nn.neurology.org/content/9/1/e1118	Background and Objectives To understand the course of recovery from coronavirus disease 2019 (COVID-19) among patients with multiple sclerosis (MS) and to determine its predictors, including patients' pre–COVID-19 physical and mental health status. Methods This prospective and longitudinal cohort study recruited patients with MS who reported COVID-19 from March 17, 2020, to March 19, 2021, as part of the United Kingdom MS Register (UKMSR) COVID-19 study. Participants used online questionnaires to regularly update their COVID-19 symptoms, recovery status, and duration of symptoms for those who fully recovered. Questionnaires were date stamped for estimation of COVID-19 symptom duration for those who had not recovered at their last follow-up. The UKMSR holds demographic and up-to-date clinical data on participants as well as their web-based Expanded Disability Status Scale (web-EDSS) and Hospital Anxiety and Depression Scale (HADS) scores. The association between these factors and recovery from COVID-19 was assessed using multivariable Cox regression analysis. Results Of the 7,977 patients with MS who participated in the UKMSR COVID-19 study, 599 reported COVID-19 and prospectively updated their recovery status. Twenty-eight hospitalized participants were excluded. At least 165 participants (29.7%) had long-standing COVID-19 symptoms for ≥4 weeks and 69 (12.4%) for ≥12 weeks. Participants with pre–COVID-19 web-EDSS scores ≥7, participants with probable anxiety and/or depression (HADS scores ≥11) before COVID-19 onset, and women were less likely to report recovery from COVID-19. Discussion Patients with MS are affected by postacute sequelae of COVID-19. Preexisting severe neurologic impairment or mental health problems appear to increase this risk. These findings can have implications in tailoring their post–COVID-19 rehabilitation.	to Zotero
316	D313	AXD	Jana L Hirschtick, Andrea R Titus, Elizabeth Slocum, Laura E Power, Robert E Hirschtick, Michael R Elliott, Patricia McKane, Nancy L Fleischer	Population-Based Estimates of Post-acute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection (PASC) Prevalence and Characteristics	https://doi.org/10.1093/cid/ciab408	Published	19 May 2021	Study	https://academic.oup.com/cid/article/73/11/2055/6276644	Background Emerging evidence suggests many people have persistent symptoms after acute coronavirus disease 2019 (COVID-19) illness. Our objective was to estimate the prevalence and correlates of post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC). Methods We used a population-based probability survey of adults with COVID-19 in Michigan. Living noninstitutionalized adults aged ≥18 in the Michigan Disease Surveillance System with COVID-19 onset through mid-April 2020 were eligible for selection (N = 28 000). Among 2000 selected, 629 completed the survey between June–December 2020. We estimated PASC prevalence, defined as persistent symptoms ≥30 (30-day COVID-19) or ≥60 (60-day COVID-19) days post–COVID-19 onset, overall and by sociodemographic and clinical factors. We used modified Poisson regression to produce adjusted prevalence ratios (aPRs) for potential risk factors. Results The analytic sample (n = 593) was predominantly female (56.1%), aged ≥45 years (68.2%), and non-Hispanic White (46.3%) or Black (34.8%). Thirty- and 60-day COVID-19 were highly prevalent (52.5% and 35.0%), even among nonhospitalized respondents (43.7% and 26.9%) and respondents reporting mild symptoms (29.2% and 24.5%). Respondents reporting very severe (vs mild) symptoms had 2.25 times higher prevalence of 30-day COVID-19 (aPR, 2.25; 95% CI, 1.46–3.46) and 1.71 times higher prevalence of 60-day COVID-19 (aPR, 1.71; 95% CI: 1.02–2.88). Hospitalized (vs nonhospitalized) respondents had ~40% higher prevalence of both 30-day (aPR, 1.37; 95% CI: 1.12–1.69) and 60-day (aPR, 1.40; 95% CI: 1.02–1.93) COVID-19. Conclusions PASC is highly prevalent among cases reporting severe initial symptoms and, to a lesser extent, cases reporting mild and moderate symptoms.	to Zotero
317	D314		Rachel L. Levine	Addressing the Long-term Effects of COVID-19	https://doi.org/10.1001/jama.2022.14089	Published	August 3, 2022	Viewpoint	https://jamanetwork.com/journals/jama/fullarticle/2795139	Conclusions Long COVID and associated conditions as well as the longer-term sequelae of the pandemic will continue to affect patients and families. The medical and public health community have made dedicated efforts during the last 2½ years to stopping the spread of this deadly coronavirus and have implemented prevention methods, developed treatments, and released vaccines that have been central to reducing initial COVID-19 infections and preventing Long COVID. It is important to focus a new lens on the pandemic and direct much-needed attention to Long COVID. Taking care of affected patients presents challenges given the incompleteness of research, the lack of sufficient diagnostics support, and pervasive problems with access to services. The provisions in the presidential memo are important elements for mounting an effective approach for addressing the long-term effects of COVID.
318	D315		Nina Smyth ,Nisreen A. Alwan ,Rebecca Band,Ashish Chaudhry,Carolyn A. Chew-Graham,Dipesh Gopal,Monique Jackson,Tom Kingstone,Alexa Wright,Damien Ridge	Exploring the lived experience of Long Covid in black and minority ethnic groups in the UK: Protocol for qualitative interviews and art-based methods	https://doi.org/10.1371/journal.pone.0275166	Published	October 3, 2022	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0275166	Some people experience prolonged symptoms following an acute COVID-19 infection including fatigue, chest pain and breathlessness, headache and cognitive impairment. When symptoms persist for over 12 weeks following the initial infection, and are not explained by an alternative diagnosis, the term post-COVID-19 syndrome is used, or the patient-defined term of Long Covid. Understanding the lived experiences of Long Covid is crucial to supporting its management. However, research on patient experiences of Long Covid is currently not ethnically diverse enough. The study aim is to explore the lived experience of Long Covid, using qualitative interviews and art-based methods, among people from ethnically diverse backgrounds (in the UK), to better understand wider systems of support and healthcare support needs. Co-created artwork will be used to build on the interview findings. A purposive sampling strategy will be used to gain diverse experiences of Long Covid, sampling by demographics, geographic locations and experiences of Long Covid. Individuals (aged >18 years) from Black and ethnic minority backgrounds, who self-report Long Covid symptoms, will be invited to take part in a semi-structured interview. Interviews will be analysed thematically. A sub-sample of participants will be invited to co-create visual artwork to further explore shared narratives of Long Covid, enhance storytelling and increase understanding about the condition. A patient advisory group, representing diversity in ethnicity and experiences of Long Covid, will inform all research stages. Stakeholder workshops with healthcare professionals and persons, systems or networks important to people’s management of Long Covid, will advise on the integration of findings to inform management of Long Covid. The study will use patient narratives from people from diverse ethnic backgrounds, to raise awareness of Long Covid and help inform management of Long Covid and how wider social systems and networks may inform better healthcare service access and experiences.
319	D316		Jonathan Koss 1 Author Orcid Image ; Sabine Bohnet-Joschko 1 Author Orcid Image	Social Media Mining of Long-COVID Self-Medication Reported by Reddit Users: Feasibility Study to Support Drug Repurposing	https://doi.org/10.2196/39582	Published	3.10.2022	Study	https://formative.jmir.org/2022/10/e39582/	Background: Since the beginning of the COVID-19 pandemic, over 480 million people have been infected and more than 6 million people have died from COVID-19 worldwide. In some patients with acute COVID-19, symptoms manifest over a longer period, which is also called “long-COVID.” Unmet medical needs related to long-COVID are high, since there are no treatments approved. Patients experiment with various medications and supplements hoping to alleviate their suffering. They often share their experiences on social media. Objective: The aim of this study was to explore the feasibility of social media mining methods to extract important compounds from the perspective of patients. The goal is to provide an overview of different medication strategies and important agents mentioned in Reddit users’ self-reports to support hypothesis generation for drug repurposing, by incorporating patients’ experiences. Methods: We used named-entity recognition to extract substances representing medications or supplements used to treat long-COVID from almost 70,000 posts on the “/r/covidlonghaulers” subreddit. We analyzed substances by frequency, co-occurrences, and network analysis to identify important substances and substance clusters. Results: The named-entity recognition algorithm achieved an F1 score of 0.67. A total of 28,447 substance entities and 5789 word co-occurrence pairs were extracted. “Histamine antagonists,” “famotidine,” “magnesium,” “vitamins,” and “steroids” were the most frequently mentioned substances. Network analysis revealed three clusters of substances, indicating certain medication patterns. Conclusions: This feasibility study indicates that network analysis can be used to characterize the medication strategies discussed in social media. Comparison with existing literature shows that this approach identifies substances that are promising candidates for drug repurposing, such as antihistamines, steroids, or antidepressants. In the context of a pandemic, the proposed method could be used to support drug repurposing hypothesis development by prioritizing substances that are important to users.
320	D317	ME	Wolfgang Hausotter	Long- und Post-COVID versus Chronic Fatigue Syndrome Chronische Erschöpfungssyndrome im Vergleich	https://doi.org/10.1007/s15202-022-5508-1	Published	04 October 2022	Article	https://link.springer.com/article/10.1007/s15202-022-5508-1	Das Chronic Fatigue Syndrome ist seit vielen Jahren bekannt und fasst die immer wieder beschriebene Symptomatik der chronischen Müdigkeit und vorzeitigen Erschöpfbarkeit mit den verschiedenen Begleitbeschwerden zusammen. Eine überzeugende Erklärung für das Syndrom fand sich bislang nicht. Wird CFS nun mit dem erst seit zwei Jahren beobachteten Post-COVID-Syndrom verglichen, ergeben sich eklatante Parallelen. So ist die Symptomatik bei CFS und Post-COVID-19 im Grunde identisch. Wie beim Post-COVID-Syndrom wird auch beim CFS seit Jahrzehnten ein Zusammenhang mit einer Virusinfektion etwa Epstein-Barr- oder Herpesvirus diskutiert, ohne dass dahingehend ein wissenschaftlicher Konsens erzielt werden konnte. Ebenso wurde die Möglichkeit einer psychischen Ursache über eine längere Zeit erwogen, jedoch konnte sie in den meisten Fällen nicht überzeugend belegt werden. Im Vergleich dazu besteht beim Post-COVID-Syndrom ein enger zeitlicher Zusammenhang mit der akuten SARS-CoV-2-Infektionskrankheit und dadurch eine allgemeine wissenschaftliche Übereinstimmung hinsichtlich einer viralen Genese. Die neu aufgetretene Infektion COVID-19 lässt daher die lange bekannte Krankheitsentität CFS in neuem Licht erscheinen. Obgleich bisher kein allgemein anerkannter Beweis für eine Virusgenese vorliegt, ist es naheliegend, diese frühere Theorie für die Entstehung eines CFS wieder aufzugreifen. Eine ausschließlich psychische Genese kann dann wohl nicht mehr angenommen werden. Psychische Störungen sind dementsprechend eher als Folgeerscheinungen zu werten - der erlebten Beeinträchtigung, der Hilflosigkeit, der Einschränkung sozialer Kontakte, der negativen Emotionen und Kognitionen durch die ständige Müdigkeit und Erschöpfung im Sinne eines biopsychosozialen Krankheitsmodells. Fazit für die Praxis Das seit Jahrzehnten bekannte und umstrittene Chronic Fatigue Syndrome, wofür bis heute, trotz zweifellos im Einzelfall, schwerwiegender subjektiver Beeinträchtigung, keine objektiven Nachweise bestehen, hat seit zwei Jahren im Rahmen der COVID-19-Erkrankung außerordentliche Parallelen im Long- und Post-COVID-Syndrom gefunden. Frühere Diskussionen über eine mögliche Virusgenese sind dadurch wieder aktuell geworden, sodass die Annahme einer rein seelischen Störung nicht mehr überzeugt - obgleich nach wie vor entsprechende allgemein akzeptierte Belege dafür fehlen.
321	D318		DavidRussellaNaomi J.SpencebJo-Ana D.ChasecTatumSchwartzaChrista M.TumminellodErinBouldin	Support amid uncertainty: Long COVID illness experiences and the role of online communities	https://doi.org/10.1016/j.ssmqr.2022.100177	Published	4 October 2022	Interview Study	https://www.sciencedirect.com/science/article/pii/S2667321522001391	Highlights •Long COVID is experienced as a complex and unpredictable illness. •Uncertainty surrounding Long COVID was heightened early in the pandemic. •Many with Long COVID experienced medical gaslighting in healthcare interactions. •Online communities for Long COVID provided validation of illness and social support. Abstract Long COVID is characterized by persistent and debilitating long-term symptoms from COVID-19. Many persons with Long COVID began gathering in online communities during the early phases of the pandemic to share their illness experiences. This qualitative interview study explored the subjective experiences of 20 persons with Long COVID recruited from five online communities. Their understandings of illness and associated implications for social relationships with family and friends, healthcare professionals, and online community members were explored. Three themes were identified from our analysis, including (1) complex and unpredictable illness experienced amid an evolving understanding of the pandemic; (2) frustration, dismissal, and gaslighting in healthcare interactions; and (3) validation and support from online communities. These findings highlight the significant uncertainty that persons with Long COVID navigated, the features of their often dismaying healthcare experiences, and the ways in which online communities aided them in understanding their illness.
322	D319		VerónicaTíscar-GonzálezabcdSheilaSánchez-GómezefAnaLafuente MartínezeAnaPeña SerranoeMartaTwose LópezeSofíaDíaz AlonsoeMartaBartolomé-RupérezgJanirePortuondo-JiménezahIñakiZorrilla-Martínezefi	Vivencias e impacto en la calidad de vida de personas con COVID persistenteExperiences and impact on the quality of life of people with long COVID	https://doi.org/10.1016/j.gaceta.2022.102247	Published	1 October 2022	Study	https://www.sciencedirect.com/science/article/pii/S0213911122001285?via%3Dihub	Objective To explore the experiences of people with persistent COVID in the Basque Country more than a year after the start of the pandemic, in order to understand the health and social impact it has, as well as to detect possible areas for improvement in the care that these people receive in order to develop health programms to support their recovery. Method Qualitative phenomenological study. In-depth interviews will be carried out as a data collection technique until saturation of the discourse. Patients of legal age who present persistent COVID symptomatology with an evolution time of more than 12 weeks were included. Contact with the patients was made through the Basque Long COVID Collective. The interviews were carried out and recorded through the ZOOM application. After the literal transcription of the interviews, the thematic analysis will be carried out, identifying the first units of meaning and assigning codes that will later be grouped into the different categories. Results 20 patients participated. A total of three main categories emerged from the analysis of the discourses: 1) affecting/impacting patients’ quality of life; 2) identifying improvements in healthcare; and 3) comforting aspects. Conclusions This study shows the significant impact on the quality of life suffered by these people. It is necessary to design health policies that favour a personalised, comprehensive and multidisciplinary approach to these patients.
323	D320		KaiFischeraJ. JamesReadebW. BenediktSchmal	What cannot be cured must be endured: The long-lasting effect of a COVID-19 infection on workplace productivity	https://doi.org/10.1016/j.labeco.2022.102281	Published	6 October 2022	Study	https://www.sciencedirect.com/science/article/pii/S0927537122001713	Highlights •We estimate the causal effect of a COVID-19 infection on individual productivity. •We identify a population effect as all true infections are identified. •We find a persistent deterioration for more than half a year after an infection. •Other respiratory infections do not have the same effect. •Individual productivity is negatively affected by infections of colleagues. Abstract The COVID-19 pandemic has triggered economic shock waves across the globe. Exploiting a natural experiment, this paper estimates how being infected with the virus shapes individual-level productivity after having recovered. Studying the performance of professional athletes in Germany and Italy and applying a staggered difference-in-differences design, we find that individual performance drops by around 6 percent after a previously infected athlete returns to the pitch. This striking deterioration remains persistent over time – amounting to 5% eight months after the infection. The effect increases with age and infection severity, and is spread disproportionally over the course of a match. We detect no productivity effects for other respiratory infections. We take these findings as first evidence that the pandemic might cause long-lasting effects on worker productivity and economic growth.
324	D321		Sabina Mirza	Supporting staff with long COVID and making reasonable adjustments	https://doi.org/10.1038/s41404-022-1739-2	Published	10 October 2022	Article	https://www.nature.com/articles/s41404-022-1739-2	The Equality and Human Rights Commission (EHRC) has clarified that not all people with long COVID will be classed as disabled under the Equality Act 2010.2 Whether a person's long COVID will be considered a disability, will depend on the severity and duration of the symptoms. This issue was recently considered at the preliminary employment tribunal hearing of Burke v Turning Point Scotland.3 The Tribunal found that Mr Burke's 'post viral fatigue syndrome' in which he experienced substantial and long-term side effects arising from him contracting COVID-19 in November 2020, was a disability. This decision does not automatically mean that every person suffering from long COVID will be classed as a disabled person, and each case will need to be reviewed separately and assessed on its own facts. It is advisable for you to carefully consider whether a staff member who reports suffering from long COVID, meets the definition of disability under the Equality Act 2010. If so your statutory duty to make 'reasonable adjustments' in the workplace will apply to them. So, if you agreed for a staff member with COVID related long term heart problems to undertake some duties at home, then if this medical condition is recognised as a disability, it would be difficult to justify why this working arrangement could not continue for that staff member as a 'reasonable' adjustment. A staff member with long COVID could be discriminated against if their symptoms are not recognised in line with the definition of disability under the Equality Act. If the employer fails to implement reasonable adjustments, the staff member could pursue a disability discrimination claim. Therefore, it is advisable for you to apply the same considerations to a staff member with long COVID as you would for a staff member with any long-term health condition or disability. There is no cap on the award a judge can give for disability discrimination so it is always better to take a cautious position. Furthermore a discrimination claim, whether successful or not (especially if related to COVID-19) is likely to generate negative publicity for a dental practice. It may also create irreparable damage to your dental practices image and patient base, where some of your patients will have disabilities or suffer from long COVID. ' The onus is on the employer to show any adjustments implemented are reasonable when a disabled person is placed at a substantial disadvantage. Sometimes, it can be difficult to determine what is considered 'reasonable'.'
325	D322	CPET	Matthew S. Durstenfeld, MD, MAS1,2; Kaiwen Sun, MD1; Peggy Tahir, MLIS, MA3; Michael J. Peluso, MD, MHS, MPhil, DTMH1,4; Steven G. Deeks, MD1,4; Mandar A. Aras, MD, PhD1,5; Donald J. Grandis, MD1,5; Carlin S. Long, MD1,5; Alexis Beatty, MD1,5,6; Priscilla Y. Hsue, MD1,2	Use of Cardiopulmonary Exercise Testing to Evaluate Long COVID-19 Symptoms in Adults A Systematic Review and Meta-analysis	https://doi.org/10.1001/jamanetworkopen.2022.36057	Published	October 12, 2022	Systematic Review and Meta-analysis	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2797203	Key Points Question Is exercise capacity reduced more than 3 months after SARS-CoV-2 infection among those with long COVID-19 (LC) symptoms compared with recovered individuals without symptoms, and what patterns of limitations on cardiopulmonary exercise testing (CPET) are common? Findings In this systematic review and meta-analysis of 38 studies comprising 2160 participants, exercise capacity was reduced by 4.9 mL/kg/min among individuals with symptoms consistent with LC compared with individuals without symptoms more than 3 months after SARS-CoV-2 infection. Findings among individuals with exertional intolerance suggest that deconditioning, dysfunctional breathing, chronotropic incompetence, and abnormal peripheral oxygen extraction and/or use may contribute to reduced exercise capacity. Meaning These findings suggest that CPET may provide insight into the mechanisms for reduced exercise capacity among individuals with LC. Abstract Importance Reduced exercise capacity is commonly reported among individuals with COVID-19 symptoms more than 3 months after SARS-CoV-2 infection (long COVID-19 [LC]). Cardiopulmonary exercise testing (CPET) is the criterion standard to measure exercise capacity and identify patterns of exertional intolerance. Objectives To estimate the difference in exercise capacity among individuals with and without LC symptoms and characterize physiological patterns of limitations to elucidate possible mechanisms of LC. Data Sources A search of PubMed, EMBASE, Web of Science, preprint servers, conference abstracts, and cited references was performed on December 20, 2021, and again on May 24, 2022. A preprint search of medrxiv.org, biorxiv.org, and researchsquare.com was performed on June 9, 2022. Study Selection Studies of adults with SARS-CoV-2 infection more than 3 months earlier that included CPET-measured peak oxygen consumption (V̇o2) were screened independently by 2 blinded reviewers; 72 (2%) were selected for full-text review, and 35 (1%) met the inclusion criteria. An additional 3 studies were identified from preprint servers. Data Extraction and Synthesis Data extraction was performed by 2 independent reviewers according to the PRISMA reporting guideline. Data were pooled using random-effects models. Main Outcomes and Measures Difference in peak V̇o2 (in mL/kg/min) among individuals with and without persistent COVID-19 symptoms more than 3 months after SARS-CoV-2 infection. Results A total of 38 studies were identified that performed CPET on 2160 individuals 3 to 18 months after SARS-CoV-2 infection, including 1228 with symptoms consistent with LC. Most studies were case series of individuals with LC or cross-sectional assessments within posthospitalization cohorts. Based on a meta-analysis of 9 studies including 464 individuals with LC symptoms and 359 without symptoms, the mean peak V̇o2 was −4.9 (95% CI, −6.4 to −3.4) mL/kg/min among those with symptoms with a low degree of certainty. Deconditioning and peripheral limitations (abnormal oxygen extraction) were common, but dysfunctional breathing and chronotropic incompetence were also described. The existing literature was limited by small sample sizes, selection bias, confounding, and varying symptom definitions and CPET interpretations, resulting in high risk of bias and heterogeneity. Conclusions and Relevance The findings of this systematic review and meta-analysis study suggest that exercise capacity was reduced more than 3 months after SARS-CoV-2 infection among individuals with symptoms consistent with LC compared with individuals without LC symptoms, with low confidence. Potential mechanisms for exertional intolerance other than deconditioning include altered autonomic function (eg, chronotropic incompetence, dysfunctional breathing), endothelial dysfunction, and muscular or mitochondrial pathology.
326	D323		I Nagyova	Long COVID and NCDs: the Elephant in the Room: Iveta Nagyova	https://doi.org/10.1093/eurpub/ckac129.140	Published	25 October 2022	Article	https://academic.oup.com/eurpub/article/32/Supplement_3/ckac129.140/6766365	Issue/problem COVID-19 has now emerged as a public health concern that not only disrupted healthcare services of people living with non-communicable diseases (NCDs) but likely also increase the burden of NCDs. Description of the problem Before the pandemic, SDG target 3.4, which calls for a reduction in premature mortality from NCDs by one third by 2030, was expected to be achieved by 17.5% of countries, and a further of 23% could achieve the target with a slight acceleration in decline. Currently, most countries are off track due to disruption of healthcare services for people with NCDs, overstretched health systems, and fewer resources than before the pandemic. In addition, only around one in four people who had COVID-19 reported feeling fully recovered within a year of being discharged from hospital. The adverse health effects from long COVID range from ‘invisible symptoms’ such as fatigue and difficulty concentrating, to neurological and neuropsychiatric symptoms, respiratory and cardiovascular problems, and metabolic disease. Results The COVID-19 pandemic has shown that siloed programmes are increasingly unfit, and the bidirectional relationships between communicable diseases and NCDs underscore the need to dismantle disease-specific silos, emphasising reforms and investments that improve a wide range of health outcomes. Cost-effective, feasible, and relevant interventions that target both physical and mental health impairments are urgently required. Lessons By 2030, ministries of health would need to contribute about 20% of their budgets to high-priority NCD interventions. Protecting current investments and scaling up cost-effective public health interventions is especially crucial in the context of long haul COVID and NCDs. Policy makers and planners will need concrete guidance for making progress on SDG target 3.4, often with overburdened health systems and scarcer resources.
327	D324		Organised by: EUPHA-CHR, Chair persons: Sarah Cuschieri (Malta), Julian Mamo (EUPHA-CHR)	3.D. Workshop: An urgent need to fully understand Long Covid-19 and its sequela	https://doi.org/10.1093/eurpub/ckac129.135	Published	25 October 2022	Article	https://academic.oup.com/eurpub/article/32/Supplement_3/ckac129.135/6765873	Introduction Covid-19 has been a pandemic for the past two years. From early on, it became obvious that some of the individuals surviving the infection continued to experience symptoms beyond the acute phase of the infection or else developed symptoms after the acute infection. Multiple terminologies describing this phenomenon started to appear with ‘Long Covid’ being a popular nomenclature. It soon became evident that Long Covid can affect almost all the body's systems with a plethora of associated symptoms, while new symptoms keep on emerging across time. These persistent symptoms are noted to act differently among different individuals, irrelevant whether they were previously healthy or previously suffering from any chronic disease/s. Indeed, while some experienced persistent symptoms for a couple of weeks, some had persistent symptoms for months. The variations in the severity of symptoms are another feature that became evident among Long Covid sufferers. The year 2021 saw the approval of different Covid-19 vaccines and the initiation of vaccination rollouts across Europe. As the vaccine population coverage progressed, it was anticipated that the lower viral infectivity rate will also decrease the occurrence of Long Covid-19 among the vaccinated as compared to the unvaccinated. Yet breakthrough Covid-19 infections still occurred along with the development of Long Covid-19 among vaccinated, especially as new variants emerged and immunity waned. Long Covid-19 is still a relatively new condition with unspecified pathophysiology and unknown long-term disability trajectory. Therefore, it is imperative that this condition is put into the spotlight to comprehend this pandora's box while trying to prevent its occurrence and the associated sequela. Aim Considering the fluidly of this condition with speculations that Long Covid might be the new chronic disease of this decade, this workshop is set to provide a multidisciplinary platform for emerging evidence on Long Covid originating from across Europe. In fact, the presentations in this workshop will tackle various aspects pertaining to Long Covid. The first presentation will provide evidence on the different risk factors and symptoms of Long Covid. The second presentation will discuss the association of multimorbidity and socio-economic factors as risk factors of Long-Covid. The third presentation will bring forward the perspectives of those suffering from the condition and the need for an integration of health care targeting both Long Covid and chronic diseases. While the fourth presentation will discuss the burden of Long-Covid symptoms and its impact on the quality of life. Finally, the bidirectional relationship between Long Covid-19 and NCDs along with the required public health action will be discussed. This will be followed by a discussion between the presenters and the audience. Key messages • Long Covid-19 is a common occurrence among healthy and chronic diseases population alike with a plethora of contributing risk factors. • An integrated healthcare plan is required to decrease the impact of Long Covid-19 on the population while simultaneously managing other underlying conditions and diseases.
328	D325		Joanna Dietzel	Long-COVID, Post-COVID und Chronic Fatigue – Symptom, Syndrom, Diagnose Long-COVID, post-COVID, and chronic fatigue—symptom, syndrome, diagnosis	https://doi.org/10.1007/s42212-022-00508-7	Published	24 October 2022	Review	https://link.springer.com/article/10.1007/s42212-022-00508-7	Einleitung Langsam lässt sich die neue Terminologie besser überblicken, die sich im Laufe der Coronaepidemie entwickelt hat und die postakute Phasen betrifft oder die postinfektiösen, chronifizierten Folgeerkrankungen umschreibt. Zwar gibt es weiterhin begriffliche Überlappungen, wie in der wissenschaftlichen Literatur aus der frühen Phase der Pandemie, aber Unterschiede zwischen den Termini und Gemeinsamkeiten mit bereits bekannten Krankheitsbildern wie der myalgischen Encephalomyelitis/Chronic Fatigue (CFS/ME) werden immer deutlicher. Sobald das Virus im PCR-Test nicht mehr nachweisbar ist, darf die Arbeitnehmer*in wieder an den Arbeitsplatz zurück, mit dem Genesenenstatus waren in den Hochphasen der Pandemie Privilegien verbunden. Ein wesentlicher Anteil aller Infizierten aber, nämlich etwa 10 %, haben im Anschluss an die Phase, in der der Antigen- oder PCR-Test positiv war, weiterhin Krankheitszeichen, vergleichbar mit der akuten Phase einer Corona oder z. B. einer Grippeinfektion: Muskelschmerzen, Abgeschlagenheit, Konzentrationsstörungen, Atemstörungen [1]. Die Symptome sind oft so ausgeprägt, dass sich eine wochen- bis monatelange Arbeitsunfähigkeit anschließt; es wird in europäischen Gesundheitsministerien von einer Long-COVID-Krise gesprochen. Im Folgenden werden die Termini Long-COVID, Post-COVID und Chronic Fatigue definiert, angelehnt an die Vorschläge der großen Fachgesellschaften und der WHO.
329	D326		Mun-Keat Looi, Elisabeth Mahase	Has covid-19 become milder?	https://doi.org/10.1136/bmj.o2516	Published	27 October 2022	Article	https://www.bmj.com/content/379/bmj.o2516.full	Deaths and hospital admissions are falling, so does this mean that the virus is less severe? The BMJ asks the experts Is covid-19 really getting milder? The short answer is no. Covid-19 is still a deadly disease, having killed almost 1.1 million people in 2022 at the time of writing. There remains a high risk of hospital admission and death for anyone without prior immunity. With some populations still largely unexposed to the virus, such as in China, and variation in the types of vaccines used in different places, it would be cavalier to call covid-19 anything but serious. “It’s really hard to compare the severe disease aspects of [variants] because the immunity of our population is so different,” says Steve Griffin, associate professor at the University of Leeds. “When people call omicron mild, yes, there’s probably a lesser tendency for it to go deep in the lungs. But if you think about the clinical impact of it, because of its massive prevalence, even though it’s got a lower chance of causing the sorts of severe disease we’re talking about with acute covid-19, the actual clinical impact is still very, very marked.” David Strain, senior clinical lecturer at the University of Exeter Medical School, points out that covid-19 tends to make other diseases worse. “It doesn’t matter what those other diseases are,” he told The BMJ in August 2022. “Patients who’ve got longstanding Crohn’s disease are coming in with exacerbations of their Crohn’s or their coeliac or their arthritis.” Monica Verduzco Gutierrez, professor and chair of the Department of Rehabilitation Medicine at the Long School of Medicine in San Antonio, Texas, also emphasises that even mild covid-19 could cause long covid, with lingering symptoms and debility. She adds that we’ve yet to fully understand the impact of reinfections. A study of the health records of six million people held by the US Department of Veteran Affairs, released as a preprint in June,1 suggested that people who had a second or third covid-19 infection had considerably higher rates of heart disease, kidney disorders, and other health problems during the first 30 days of infection, as well as in the months that followed, than people who had been infected only once.
330	D327		Chih-ChengLaiaChi-KueiHsubMuh-YongYencPing-IngLeedWen-ChienKoefPo-RenHsuehghij	Long COVID: An inevitable sequela of SARS-CoV-2 infection	https://doi.org/10.1016/j.jmii.2022.10.003	Published	15 October 2022	Review	https://www.sciencedirect.com/science/article/pii/S1684118222001864	At present, there are more than 560 million confirmed cases of the coronavirus disease 2019 (COVID-19) worldwide. Although more than 98% of patients with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection can survive acute COVID, a significant portion of survivors can develop residual health problems, which is termed as long COVID. Although severe COVID-19 is generally associated with a high risk of long COVID, patients with asymptomatic or mild disease can also show long COVID. The definition of long COVID is inconsistent and its clinical manifestations are protean. In addition to general symptoms, such as fatigue, long COVID can affect many organ systems, including the respiratory, neurological, psychosocial, cardiovascular, gastrointestinal, and metabolic systems. Moreover, patients with long COVID may experience exercise intolerance and impaired daily function and quality of life. Long COVID may be caused by SARS-CoV-2 direct injury or its associated immune/inflammatory response. Assessment of patients with long COVID requires comprehensive evaluation, including history taking, physical examination, laboratory tests, radiography, and functional tests. However, there is no known effective treatment for long COVID. Based on the limited evidence, vaccines may help to prevent the development of long COVID. As long COVID is a new clinical entity that is constantly evolving, there are still many unknowns, and further investigation is warranted to enhance our understanding of this disease.
331	D328		Jayesh Cherusseri 1ORCID,Claire Mary Savio 2ORCID,Mohammad Khalid 1,3,ORCID,Vishal Chaudhary 4,5,,Arshid Numan 1,3,Sreekanth J. Varma 6ORCID,Amrutha Menon 7 andAjeet Kaushik 8,9	SARS-CoV-2-on-Chip for Long COVID Management	https://doi.org/10.3390/bios12100890	Published	18 October 2022	Review	https://www.mdpi.com/2079-6374/12/10/890/htm	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a “wicked evil” in this century due to its extended progression and huge human mortalities. Although the diagnosis of SARS-CoV-2 viral infection is made simple and practical by employing reverse transcription polymerase chain reaction (RT-PCR) investigation, the process is costly, complex, time-consuming, and requires experts for testing and the constraints of a laboratory. Therefore, these challenges have raised the paradigm of on-site portable biosensors on a single chip, which reduces human resources and enables remote access to minimize the overwhelming burden on the existing global healthcare sector. This article reviews the recent advancements in biosensors for long coronavirus disease (COVID) management using a multitude of devices, such as point-of-care biosensors and lab-on-chip biosensors. Furthermore, it details the shift in the paradigm of SARS-CoV-2-on-chip biosensors from the laboratory to on-site detection with intelligent and economical operation, representing near-future diagnostic technologies for public health emergency management.
332	D329		Stefanos G. Sakellaropoulos, Muhammad Ali, Athanasios Papadis, Muhemin Mohammed, Andreas Mitsis, Zaza Zivzivadze	Is Long COVID Syndrome a Transient Mitochondriopathy Newly Discovered: Implications of CPET	https://doi.org/10.14740/cr1419	Published	13, Oct. 2022	Article	https://cardiologyres.org/index.php/Cardiologyres/article/view/1419	The new outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has an impact worldwide, primarily as a medical emergency. Even that the total constellation is considered as a pandemic of acute respiratory disease, coronavirus disease 2019 (COVID-19) gives rise to dysfunction in multiple organs (e.g., brain, lungs, heart, muscles) that impairs cardiopulmonary (CP) function. Parallel to the CP consequences of COVID-19 is a significant reduction in physical activity. Cardiopulmonary exercise testing (CPET) is daily used in clinical practice to define prognosis, provide risk stratification and treatment strategy. As such, the significance of CPET is crucial concerning clinical assessments of COVID-19 patients. Furthermore, new studies aim at understanding the effects of SARS-CoV-2 infection in long term. Multiple studies have investigated the cardiopulmonary function and impairment of exercise endurance in such patients, as well as a possible prolonged physical impairment. With this review, we summarize the COVID-19-associated pathophysiology for the Long COVID (LC) syndrome as well as the importance of performing CPET.
333	D330		Ana Paula Andrade Barreto ,Marcio Andrade Barreto Filho ,Lucimeire Cardoso Duarte ,Thiago Cerqueira-Silva,Aquiles Camelier,Natalia Machado Tavares,Manoel Barral-Netto,Viviane Boaventura ,Marcelo Chalhoub Coelho Lima ,on behalf of the CPC study group	Metabolic disorders and post-acute hospitalization in black/mixed-race patients with long COVID in Brazil: A cross-sectional analysis	https://doi.org/10.1371/journal.pone.0276771	Published	October 31, 2022	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0276771	Background Although low-middle income countries have been disproportionately affected by the COVID-19 pandemic, there is scarce information about the impact of long COVID on their population. This study aimed to evaluate long COVID symptomatology, complications (hospital readmission and metabolic disorders), and main clinical features that impact Quality of Life (QoL). Methods This cross-sectional study provides a detailed clinical and laboratory picture of individuals who presented residual symptoms after mild to severe acute COVID-19. Between Aug-2020 to Sep-2021, long COVID patients were evaluated in a reference center for long COVID in Bahia State, Brazil. The EQ-5D-5L questionnaire accessed QoL. Results A total of 1164 (52 ±13.4 years, 57% female, 88% black/mixed-race) were evaluated 2.3 [IQR = 1.6–3.7] months after mild (n = 351, 30.2%), moderate (338, 29.0%) or severe (475, 40.8%) acute illness. Dyspnea (790, 67.9%), fatigue (738, 63.5%), and chest pain (525, 42.9%) were the most frequent residual symptoms regardless of acute severity, affecting the QoL of 88.9% of patients (n/N—826/925), mainly the domains of anxiety/depression and pain/discomfort. High levels of HbA1c were detected for 175 out of 664 patients (26.6%), 40% of them without a previous diagnosis of diabetes mellitus. Of note, hospital admission one-to-three months after the acute phase of disease was required for 51 (4.4%) patients. Conclusion In this majority-black/mixed-race population, long COVID was associated with post-acute hospitalization, newly diagnosed diabetes mellitus, and decreased QoL, particularly in women and regardless of disease severity of acute infection, suggesting important implications for health care system.
334	D331		Sedina Lewis, Public Health Specialist Tha Han, Consultant in Public Health Anthony Wakhisi, Public Health Intelligence Lead	Health Needs Assessment Long COVID		Published	August 2022	Guide	https://www.haveringdata.net/wp-content/uploads/2022/10/Havering-Long-COVID-needs-assessment-Final.pdf
335	D332		Ziyad Al-Aly, Anupam Agarwal, Nisreen Alwan & Valerie A. Luyckx	Long COVID: long-term health outcomes and implications for policy and research	https://doi.org/10.1038/s41581-022-00652-2	Published	01 November 2022	Article	https://www.nature.com/articles/s41581-022-00652-2	Long COVID, which refers to post-acute and chronic sequelae of SARS-CoV-2 infection, can affect nearly every organ system and all demographic groups. The high and growing toll of long COVID calls for an urgent need to understand how to prevent and treat it. Governments and health systems must address the care needs of people with long COVID.
336	D333		Aurelie Fischer 1 Author Orcid Image ; Abir Elbeji 1 Author Orcid Image ; Gloria Aguayo 1 Author Orcid Image ; Guy Fagherazzi 1 Author Orcid Image	Recommendations for Successful Implementation of the Use of Vocal Biomarkers for Remote Monitoring of COVID-19 and Long COVID in Clinical Practice and Research	https://doi.org/10.2196/40655	Published	15.11.2022	Article	https://i-jmr.org/2022/2/e40655/	The COVID-19 pandemic accelerated the use of remote patient monitoring in clinical practice or research for safety and emergency reasons, justifying the need for innovative digital health solutions to monitor key parameters or symptoms related to COVID-19 or Long COVID. The use of voice-based technologies, and in particular vocal biomarkers, is a promising approach, voice being a rich, easy-to-collect medium with numerous potential applications for health care, from diagnosis to monitoring. In this viewpoint, we provide an overview of the potential benefits and limitations of using voice to monitor COVID-19, Long COVID, and related symptoms. We then describe an optimal pipeline to bring a vocal biomarker candidate from research to clinical practice and discuss recommendations to achieve such a clinical implementation successfully.
337	D334		A.M.MalkovaY.Shoenfeld	Autoimmune autonomic nervous system imbalance and conditions: Chronic fatigue syndrome, fibromyalgia, silicone breast implants, COVID and post-COVID syndrome, sick building syndrome, post-orthostatic tachycardia syndrome, autoimmune diseases and autoimmune/inflammatory syndrome induced by adjuvants	https://doi.org/10.1016/j.autrev.2022.103230	Published	5 November 2022	Review	https://www.sciencedirect.com/science/article/abs/pii/S1568997222002002	Chronic fatigue syndrome (CFS), fibromyalgia, silicone breast implants syndrome (SBIs), COVID and post-COVID syndrome (PCS), sick building syndrome (SBS), post-orthostatic tachycardia syndrome (POTS), autoimmune diseases and autoimmune/inflammatory syndrome induced by adjuvants (ASIA) are frequently accompanied by clinical symptoms characteristic for dysautonomia: severe fatigue, dizziness, fogginess, memory loss, dry mouth and eyes, hearing dysfunction, tachycardia etc. The recent discovery of an imbalance of autoantibodies against G protein-coupled receptors (GPCR) in some autoimmune diseases, post-COVID syndrome, SBIs allowed researchers to assume the novel mechanism in these conditions - autoimmune autonomic nervous system imbalance. In this review, all data published on an imbalance of autoantibodies against GPCR, clinical symptoms and pathogenic mechanisms in CFS, Fibromyalgia, SBIs, COVID and PCS, SBS, POTS, and some autoimmune diseases were analyzed. Possible criteria to diagnose the autoimmune autonomic nervous system imbalance were created.
338	D335		M.TalmatkadiP.FoulquiéA.DéguilhemS.RennerL.ChâteauneufA.MebarkiN.TexierS.Schuck	Création d'un algorithme d'identification d'expériences vécues par des patients ou leurs proches à partir de messages issus des réseaux sociaux : un cas d'usage sur le COVID long	https://doi.org/10.1016/j.respe.2022.09.045	Published	4 November 2022	Study	https://www.sciencedirect.com/science/article/pii/S0398762022008021	Introduction La pandémie de COVID-19 a entrainé une masse d'informations sur les réseaux sociaux et forums provenant de multiples acteurs : gouvernements, journalistes ou encore citoyens. Parmi ces messages, de nombreux patients se sont saisis de ces outils pour partager leurs symptômes et se regrouper en communauté, comme c'est le cas des patients atteints de COVID long avec le hashtag #aprèsJ20. Un algorithme de traitement automatique du langage naturel capable d'identifier les messages constituant des expériences de santé vécues par des patients ou des proches permettrait d'exploiter ces données de vie réelle dans un objectif de santé publique. Méthodes A partir de différentes sources, 12 430 messages issus de forums et réseaux sociaux (Twitter, Facebook) ont été extraits sur différentes pathologies : cancer (sans précision d'une localisation), diabète, maladie de Fabry, COVID-19, sevrage tabagique. Ces messages ont été manuellement analysées et codifiées en trois catégories selon la nature de l'internaute : patient/aidant ou proche/répondant. Sur la base de ce « gold standard », un modèle de « machine learning » a été créé et entrainé, couplé avec des champs lexicaux marqueurs d'expériences vécues (par exemple, la présence d'un récit à la première personne ou du champ lexical de la famille). Deux modèles Xgboost ont été choisis permettant de déterminer en premier lieu si l'internaute est un proche de malade ou non, puis dans un second temps, si c'est un patient ou non. Pour être validé, ce modèle a été appliqué sur des messages spécifiques au COVID long. Une sélection aléatoire de ces messages couplée à une annotation par trois annotateurs a permis de mesurer les performances du modèle. Résultats Après application de l'algorithme d'identification d'expériences vécues par des patients ou des proches, 700 messages ont été revus et annotés sur le COVID long. Les catégories patients et aidants ont été regroupées en raison des nombreux cas de formes familiales de COVID long rapportés sur les réseaux sociaux. Les performances du modèle ont permis de mesurer une sensibilité de 96 %, une spécificité de 76 %, une « accuracy » à 87 % et une précision de 84 %. Conclusion Un algorithme identifiant les expériences vécues par des patients ou des proches au sein des messages issus des réseaux sociaux facilite leur utilisation comme données de vie réelle. Les bonnes performances de l'algorithme, notamment sur les formes longues de COVID-19, permettent un suivi prospectif de ces patients dans un objectif de santé publique. Une future version du modèle devra intégrer la possibilité d'identifier au sein d'un même message la présence d'expériences à la fois de patients et de proches, notamment en cas de formes familiales (”mon fils et moi avons un covid long ”).
339	D336		Fern Davies , Ilora Finlay, Nick Rich, Helen Howsen	Recommendations for a Long COVID Registry: A Prudent and Integrated Approach	http://doi.org/10.5334/ijic.ICIC22256	Published	04 Nov 2022	Research	https://www.ijic.org/articles/abstract/10.5334/ijic.ICIC22256/	Introduction: Long COVID has had a profound impact on the lives and health of many people around the globe, with 1.5 million (2.4%) people in the UK alone experiencing self-reported symptoms. Whilst the prevalence and long-term consequences of SARS-CoV-2 infection remain largely unknown, modelling suggests a significant increase of long COVID patients and consequent challenge for the health and care system during the next stage of the pandemic. In response to this, the Bevan Commission were asked to make recommendations on how to set about establishing a voluntary registry for long COVID in Wales, in order to undertake long-term monitoring of the disease. Aims and Methods: The aim of this research was to understand the UK context for setting up a voluntary long COVID registry and to make recommendations for a long COVID registry in Wales. A multi-stakeholder advisory board of twenty-five members was established, with a diverse range of expertise. Patient representatives were recruited to engage in the process of co-production, as aligned with the prudent healthcare principles . A qualitative and inductive methodology was adopted, supported by a multi-methods approach. This included exploratory desktop research, observations of four advisory board meetings and expert interviews. The multiple methods identified above contributed to the findings of this work and key recommendations. Key Findings: The main findings indicate that there are no known voluntary long COVID registries that have been launched within the UK. However, the advisory board unanimously agreed the importance of a registry in Wales (or similar mechanism) for long-term monitoring of the disease and to facilitate research and service improvement. Digital infrastructure and linkages were identified as essential in the development of a registry, yet findings suggested a current disconnect and need for enhanced co-ordination and interoperability between resources, databases and organisations. The need for co-production with end-users of a Long COVID Registry, such as healthcare professionals and patient groups, was an enduring finding during advisory board meetings, as was the need to promote equity of access and inclusion of a self-referred population. Findings from the patient representatives specifically identified a feeling of abandonment and described care as ‘disjointed’, particularly when referred to multiple healthcare professionals, specialities and resources. This promotes the need for a prudent and integrated approach to make effective use of available resources and to derive optimal value from a Long COVID Registry in Wales. Conclusion: To conclude, this research identifies the importance of an integrated and multidisciplinary approach to improve the monitoring and management of long COVID and in turn address anticipated health system challenges. This approach should be central to inform the development of a Long COVID Registry within Wales. Digital infrastructure and linkages are key solutions to harness the technological capabilities within Wales and optimise the success of a registry. Implications for applicability/transferability, sustainability, and limitations: This research has informed health policy decisions related to the effective care and research of long COVID in Wales. It also provides valuable recommendations for voluntary disease registries moving forward. However, it should be acknowledged that the research is only representative of one geographical context and healthcare system.
340	D337		Ann M. O’Hare, MA, MD1,2,3; Elizabeth K. Vig, MD, MPH2,3; Theodore J. Iwashyna, MD, PhD4; Alexandra Fox, PhD5; Janelle S. Taylor, PhD6; Elizabeth M. Viglianti, MD7; Catherine R. Butler, MD, MA1,2,3; Kelly C. Vranas, MD, MCR8,9; Mark Helfand, MD, MPH8,9; Anaïs Tuepker, PhD, MPH8,9; Shannon M. Nugent, PhD8,9; Kara A. Winchell, MA8; Ryan J. Laundry, BS1; C. Barrett Bowling, MD, MSPH10,11; Denise M. Hynes, RN, PhD8,9,12; Matthew L. Maciejewski, PhD13,14,15; Amy S. B. Bohnert, PhD16,17; Emily R. Locke, MPH1,5; Edward J. Boyko, MD, MPH2,3,5; George N. Ioannou, BMBCh, MS1,2,3,5; for the VA COVID Observational Research Collaboratory (CORC)	Complexity and Challenges of the Clinical Diagnosis and Management of Long COVID	http://jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2022.40332	Published	November 3, 2022	Qualitative analysis	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2798146	Key Points Question What themes pertaining to long COVID can be identified in qualitative analysis of health records from the Department of Veterans Affairs health system? Findings This qualitative study including health records from 200 randomly sampled veterans identified 2 dominant themes: (1) clinical uncertainty: it was often unclear whether particular symptoms were due to long COVID, given the medical complexity and functional limitations of many patients and absence of specific markers for this condition, which led to ongoing monitoring, diagnostic testing, and referral; and (2) care fragmentation: post–COVID-19 care processes were often siloed from other care and could be burdensome to patients. Meaning These findings highlight the complexity of diagnosing and managing long COVID in clinical settings. Abstract Importance There is increasing recognition of the long-term health effects of SARS-CoV-2 infection (sometimes called long COVID). However, little is yet known about the clinical diagnosis and management of long COVID within health systems. Objective To describe dominant themes pertaining to the clinical diagnosis and management of long COVID in the electronic health records (EHRs) of patients with a diagnostic code for this condition (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code U09.9). Design, Setting, and Participants This qualitative analysis used data from EHRs of a national random sample of 200 patients receiving care in the Department of Veterans Affairs (VA) with documentation of a positive result on a polymerase chain reaction (PCR) test for SARS-CoV-2 between February 27, 2020, and December 31, 2021, and an ICD-10 diagnostic code for long COVID between October 1, 2021, when the code was implemented, and March 1, 2022. Data were analyzed from February 5 to May 31, 2022. Main Outcomes and Measures A text word search and qualitative analysis of patients’ VA-wide EHRs was performed to identify dominant themes pertaining to the clinical diagnosis and management of long COVID. Results In this qualitative analysis of documentation in the VA-wide EHR, the mean (SD) age of the 200 sampled patients at the time of their first positive PCR test result for SARS-CoV-2 in VA records was 60 (14.5) years. The sample included 173 (86.5%) men; 45 individuals (22.5%) were identified as Black and 136 individuals (68.0%) were identified as White. In qualitative analysis of documentation pertaining to long COVID in patients’ EHRs 2 dominant themes were identified: (1) clinical uncertainty, in that it was often unclear whether particular symptoms could be attributed to long COVID, given the medical complexity and functional limitations of many patients and absence of specific markers for this condition, which could lead to ongoing monitoring, diagnostic testing, and specialist referral; and (2) care fragmentation, describing how post–COVID-19 care processes were often siloed from and poorly coordinated with other aspects of care and could be burdensome to patients. Conclusions and Relevance This qualitative study of documentation in the VA EHR highlights the complexity of diagnosing long COVID in clinical settings and the challenges of caring for patients who have or are suspected of having this condition.
341	D338		Lin Zhang, Jie Lei, Jintao Zhang, Longlong Yin, Yanjiao Chen, Yan Xi & Joaquim Paulo Moreira	Undiagnosed Long COVID-19 in China Among Non-vaccinated Individuals: Identifying Persistent Symptoms and Impacts on Patients' Health-Related Quality of Life	https://doi.org/10.1007/s44197-022-00079-9	Published	24 November 2022	Study	https://link.springer.com/article/10.1007/s44197-022-00079-9	Is Long COVID-19 under-diagnosed? The definition of this new condition has received many contributions, and it is still under development as a great variety of symptoms have been associated to it. This study explores the possibility that there are non-diagnosed cases among individuals who have been infected by SARS-CoV-2 and have not been vaccinated. The long-term symptoms identified among a sample 255 individuals have been associated to Long COVID-19 by recent literature. The study relates these symptoms to risk factors and health-related quality of life (HRQoL) negative impacts. The individuals were screened 1 year after discharge to explore its potential relation to Long COVID-19. Patients diagnosed with COVID-19 and discharged from designated hospitals in a Chinese province between January and April 2020 were included in this study. They received computed tomography (CT) scans one month after discharge. One year after discharge, patients were invited to physical examination and interviewed with questionnaire on health-related quality of life (HRQoL) and post-COVID-19 symptoms. Tobit regression and Logistic regression were applied to evaluate the risk factors for health utility value and pain/discomfort and anxiety/depression. One year after discharge, 39.61% patients complained of several of the symptoms associated to Long COVID-19. More than half had abnormal chest CT. Previous studies focused on the post-COVID-19 symptoms and chest CT findings of patients, but few studies have assessed the COVID-19-associated risk factors for health-related quality of life.
342	D339		MarijaPantelicDPhilabNidaZiauddeenPhDcdMarkBoyesPhDefMargaret EO'HaraPhDgClaireHastieBScgProfNisreen AAlwanPhDcdh	The prevalence of stigma in a UK community survey of people with lived experience of long COVID	https://doi.org/10.1016/S0140-6736(22)02294-2	Published	24 November 2022	Study	https://www.sciencedirect.com/science/article/abs/pii/S0140673622022942	Background Stigma can be experienced as perceived or actual disqualification from social and institutional acceptance on the basis of one or more physical, health-related, behavioural, or other attributes deemed to be undesirable. Long COVID is a predominantly multisystem condition that occurs in people with a history of SARS-CoV-2 infection, often resulting in functional disability, which limits day-to-day activities. We aimed to quantify the burden of stigma experienced in a community-based sample of people with lived experience of long COVID. Methods Data from the follow-up of a long COVID longitudinal online survey was used. The survey was coproduced with people living with long COVID. 13 questions on stigma were included to develop a Long COVID Stigma Scale capturing three domains: enacted (overt experiences of discrimination due to long COVID), internalised (internalising negative associations with long COVID and accepting them as self-applicable), and anticipated (expectation of bias or poor treatment by others) stigma. Data were collected through a social media survey with convenience non-probability sampling. Findings 966 (47·9%) of 2016 participants from the UK completed the follow-up survey and 888 responded to the questions on stigma. The mean age of respondents was 48·3 years (SD 10·7), and 84·6% identified as female. Roughly half (n=460, 50·4%) reported having a formal, clinical, long COVID diagnosis, and of these, 440 responded to the questions on stigma. The prevalence of people experiencing overall stigma at least sometimes was 95·4% (n=847), prevalence of enacted stigma was 62·7% (n=557), internalised stigma was 86·4% (n=767), and anticipated stigma was 90·8% (n=806). Prevalence of stigma was higher in respondents with a formal diagnosis of long COVID (97·5%; n=429) than in those without (93·2%; n=413). Interpretation This study highlights widespread and multilayered stigmas experienced by people living with long COVID in the UK, which presents a serious public health concern. The broader literature on stigmatised health conditions consistently suggests that stigma drives people away from health services, contributes to psychological distress, and compromises long-term physical outcomes. The higher proportion experiencing stigma in those with clinical diagnosis of long COVID might be indicative of stigma within the health-care system. Findings from this study should be taken into consideration within clinical practice and health care, social care, employment, and education policies.
343	D340		Ilduara Pintos-Pascual1*, Victor Moreno-Torres1,2, Fatima Ibánez-Estéllez1, Pilar Corrales-Rodriguez1, Ana Treviño2, Manuel Corpas3, Octavio Corral2, Vicente Soriano2, and Carmen de Mendoza1	Is SARS-CoV-2 the only cause of long-COVID?	https://doi.org/10.24875/AIDSRev.22000025	Published	03-11-2022	Article	https://www.aidsreviews.com/resumen.php?id=1616	Around 10% of adults infected with SARS-CoV-2 that survive a first episode of COVID-19 appear to experience long-term clinical manifestations. The signs and symptoms of this post-acute COVID-19 syndrome (PACS) include fatigue, dyspnea, joint pain, myalgia, chest pain, cough, anosmia, dysgeusia, headache, depression, anxiety, memory loss, concentration difficulties, and insomnia. These sequelae remind the constellation of clinical manifestations previously recognized as myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS). This condition has been described following distinct infectious events, mostly acute viral illnesses. In this way, the pathophysiology of PACS might overlap with mechanisms involved in other post-infectious fatigue syndromes. The risk of PACS is more frequent in women than men. Additional host genetic factors could be involved. There is a dysregulation of multiple body organs and systems, involving the immune system, the coagulation cascade, endocrine organs, autonomic nervous system, microbiota–gut–brain axis, hypothalamic–pituitary–adrenal axis, hypothalamic–pituitary–thyroid axis, etc. Hypothetically, an abnormal response to certain infectious agents could trigger the development of postinfectious fatigue syndromes.
344	D341		Mawuena Binka, Braeden Klaver, Georgine Cua, Alyson W Wong, Chad Fibke, Héctor A Velásquez García, Prince Adu, Adeera Levin, Sharmistha Mishra, Beate Sander, Hind Sbihi, Naveed Z Janjua	An Elastic Net Regression Model for Identifying Long COVID Patients Using Health Administrative Data: A Population-Based Study	https://doi.org/10.1093/ofid/ofac640	Published	24 November 2022	Study	https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofac640/6845426	Background Long COVID patients experience persistent symptoms after acute SARS-CoV-2 infection. Healthcare utilization data could provide critical information on the disease burden of long COVID for service planning, however, not all patients are diagnosed or assigned long COVID diagnostic codes. We developed an algorithm to identify individuals with long COVID using population-level health administrative data from British Columbia (BC), Canada. Methods An elastic net penalized logistic regression model was developed to identify long COVID patients based on demographic characteristics, pre-existing conditions, COVID-19-related data, and all symptoms/conditions recorded 28-183 days after the COVID-19 symptom onset/reported (index) date of known long COVID patients (N = 2,430) and a control group (N = 24,300); selected from all adult COVID-19 cases in BC with an index date on/before October 31, 2021 (N = 168,111). Known long COVID cases were diagnosed in a clinic and/or had the ICD-10-CA code for “Post COVID-19 condition” in their records. Results The algorithm retained known symptoms/conditions associated with long COVID, demonstrating high sensitivity (86%), specificity (86%), and area under the receiver operator curve (93%). It identified 25,220 (18%) long COVID patients among the remaining 141,381 adult COVID-19 cases; over ten times the number of known cases. Known and predicted long COVID patients had comparable demographic and health-related characteristics. Conclusions Our algorithm identified long COVID patients with a high level of accuracy. This large cohort of long COVID patients will serve as a platform for robust assessments on the clinical course of long COVID, and provide much needed concrete information for decision-making.
345	D342		Ronald W.DamantaLiamRourkeaYingCuibGrace Y.LamaMaeve P.SmithaDesi P.FuhraJaqueline K.TayaRhea A.VarugheseaCheryl R.LarattaaAngelaLauaEric Y.WongaMichael K.SticklandaGiovanniFerraraa	Reliability and validity of the post COVID-19 condition stigma questionnaire: A prospective cohort study	https://doi.org/10.1016/j.eclinm.2022.101755	Published	25 November 2022	Study	https://www.sciencedirect.com/science/article/pii/S2589537022004849	Background Many of the 10–20% percent of COVID-19 survivors who develop Post COVID-19 Condition (PCC, or Long COVID) describe experiences suggestive of stigmatization, a known social determinant of health. Our objective was to develop an instrument, the Post COVID-19 Condition Stigma Questionnaire (PCCSQ), with which to quantify and characterise PCC-related stigma. Methods We conducted a prospective cohort study to assess the reliability and validity of the PCCSQ. Patients referred to our Post COVID-19 Clinic in the Canadian City of Edmonton, Alberta between May 29, 2021 and May 24, 2022 who met inclusion criteria (attending an academic post COVID-19 clinic; age ≥18 years; persistent symptoms and impairment at ≥ 12 weeks since PCR positive acute COVID-19 infection; English-speaking; internet access; consenting) were invited to complete online questionnaires, including the PCCSQ. Analyses were conducted to estimate the instrument's reliability, construct validity, and association with relevant instruments and defined health outcomes. Findings Of the 198 patients invited, 145 (73%) met inclusion criteria and completed usable questionnaires. Total Stigma Score (TSS) on the PCCSQ ranged from 40 to 174/200. The mean (SD) was 103.9 (31.3). Cronbach's alpha was 0.97. Test-retest reliability was 0.92. Factor analysis supported a 6-factor latent construct. Subtest reliabilities were >0.75. Individuals reporting increased TSS occurred across all demographic groups. Increased risk categories included women, white ethnicity, and limited educational opportunities. TSS was positively correlated with symptoms, depression, anxiety, loneliness, reduced self-esteem, thoughts of self-harm, post-COVID functional status, frailty, EQ5D5L score, and number of ED visits. It was negatively correlated with perceived social support, 6-min walk distance, and EQ5D5L global rating. Stigma scores were significantly increased among participants reporting employment status as disabled. Interpretation Our findings suggested that the PCCSQ is a valid, reliable tool with which to estimate PCC-related stigma. It allows for the identification of patients reporting increased stigma and offers insights into their experiences.
346	D343		Rónan Astin,Amitava Banerjee,Mark R. Baker,Melanie Dani,Elizabeth Ford,James H. Hull,Phang Boon Lim,Melitta McNarry,Karl Morten,Oliver O'Sullivan,Etheresia Pretorius,Betty Raman,Demetris S. Soteropoulos,Maxime Taquet,Catherine N. Hall	Long COVID: mechanisms, risk factors and recovery	https://doi.org/10.1113/EP090802	Published	22 November 2022	Review	https://physoc.onlinelibrary.wiley.com/doi/10.1113/EP090802	New Findings What is the topic of this review? The emerging condition of long COVID, its epidemiology, pathophysiological impacts on patients of different backgrounds, physiological mechanisms emerging as explanations of the condition, and treatment strategies being trialled. The review leads from a Physiological Society online conference on this topic. What advances does it highlight? Progress in understanding the pathophysiology and cellular mechanisms underlying Long COVID and potential therapeutic and management strategies. Abstract Long COVID, the prolonged illness and fatigue suffered by a small proportion of those infected with SARS-CoV-2, is placing an increasing burden on individuals and society. A Physiological Society virtual meeting in February 2022 brought clinicians and researchers together to discuss the current understanding of long COVID mechanisms, risk factors and recovery. This review highlights the themes arising from that meeting. It considers the nature of long COVID, exploring its links with other post-viral illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome, and highlights how long COVID research can help us better support those suffering from all post-viral syndromes. Long COVID research started particularly swiftly in populations routinely monitoring their physical performance – namely the military and elite athletes. The review highlights how the high degree of diagnosis, intervention and monitoring of success in these active populations can suggest management strategies for the wider population. We then consider how a key component of performance monitoring in active populations, cardiopulmonary exercise training, has revealed long COVID-related changes in physiology – including alterations in peripheral muscle function, ventilatory inefficiency and autonomic dysfunction. The nature and impact of dysautonomia are further discussed in relation to postural orthostatic tachycardia syndrome, fatigue and treatment strategies that aim to combat sympathetic overactivation by stimulating the vagus nerve. We then interrogate the mechanisms that underlie long COVID symptoms, with a focus on impaired oxygen delivery due to micro-clotting and disruption of cellular energy metabolism, before considering treatment strategies that indirectly or directly tackle these mechanisms. These include remote inspiratory muscle training and integrated care pathways that combine rehabilitation and drug interventions with research into long COVID healthcare access across different populations. Overall, this review showcases how physiological research reveals the changes that occur in long COVID and how different therapeutic strategies are being developed and tested to combat this condition.
347	D344		Maciej Debski,Vasiliki Tsampasian,Shawn Haney,Katy Blakely,Samantha Weston,Eleana Ntatsaki,Mark Lim,Susan Madden,Aris Perperoglou,Vassilios S. Vassiliou	Post-COVID-19 syndrome risk factors and further use of health services in East England	https://doi.org/10.1371/journal.pgph.0001188	Published	November 30, 2022	Study	https://journals.plos.org/globalpublichealth/article?id=10.1371/journal.pgph.0001188	Post-COVID syndrome, defined as symptoms persisting for more than twelve weeks after the diagnosis of COVID-19, has been recognised as a new clinical entity in the context of SARS-CoV-2 infection. This study was conducted to characterise the burden and predictors for post-COVID-19 syndrome in the local population. It was a community-based web-survey study conducted in Norfolk, East England, UK. We sent the survey to patients with confirmed COVID-19 infection by real-time polymerase chain reaction by December 6th, 2020. Questions related to the pre-COVID and post-COVID level of symptoms and further healthcare use. Baseline characteristics were collected from the primary care records. Logistic regression analysis was conducted to establish predictors for post-COVID-19 syndrome and further healthcare utilisation. Of 6,318 patients, survey responses were obtained from 1,487 participants (23.5%). Post-COVID-19 syndrome symptoms were experienced by 774 (52.1%) respondents. Male sex compared to female sex was a factor protective of post-COVID symptoms; relative risk (RR) 0.748, 95% confidence interval (CI), 0.605–0.924. Body mass index was associated with a greater risk of developing post-COVID-19 symptoms (RR 1.031, 95% CI, 1.016–1.047, for 1 kg/m2). A total of 378 (25.4%) people used further health services after their index COVID-19 infection, of whom 277 (73.2%) had post-COVID symptoms. Male sex was negatively associated with the use of further health services (RR 0.618, 95% CI, 0.464–0.818) whereas BMI was positively associated (RR 1.027, 95% CI, 1.009–1.046). Overall, post-COVID-19 symptoms increased the probability of using health services with RR 3.280, 95% CI, 2.540–4.262. This survey of a large number of people previously diagnosed with COVID-19 across East England shows a high prevalence of self-reported post-COVID-19 syndrome. Female sex and BMI were associated with an increased risk of post-COVID-19 syndrome and further utilisation of healthcare.
348	D345		Anna Herminghaus Marcin F. Osuchowski	How sepsis parallels and differs from COVID-19	https://doi.org/10.1016/j.ebiom.2022.104355	Published	December 02, 2022	Article	https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00537-0/fulltext	There is a striking parallel between bacterial sepsis and COVID-19 phenotypes: the long-term sequelae. In both patient groups, the hospital discharge does not equal full recovery, but it is frequently followed by protracted, incapacitating consequences. While in bacterial sepsis, the post-discharge complications are referred to as post-sepsis syndrome and/or Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS), whereas, in SARS-CoV-2 infected patients, they are known as “long-COVID”. Long-COVID is not very different from post-sepsis syndrome. The most common persistent symptoms include fatigue, muscle pain, poor sleep, cardiac and cognitive disturbances (e.g. arrhythmias, short-term memory loss).7 Remarkably, a new, troubling difference exists: unlike in sepsis, long-COVID is frequently diagnosed in mildly SARS-CoV-2 infected patients (i.e. no hospital stay).8 The presence of the “long-phenotype” in both illnesses strongly indicates a severe and protracted deregulation of the immune-inflammatory (with clear immunosuppression features) and organ homeostasis. In the context of the slowly subsiding severe COVID-19 manifestations, we should re-focus on the long-term sequalae to evaluate a potential risk of increase in chronic debilitations in individuals, repeatedly exposed to the virus, as SARS-CoV-2 becomes seasonal/endemic. A comparison of the pre-clinical research in sepsis and COVID-19 brings several important lessons. A subjective (and largely undeserved) disappointment in pre-clinical bacterial sepsis studies has not been shared by COVID-19 modeling. On the contrary, despite logistic challenges, modeling of SARS-COV-2 infection has demonstrated its robust utility. One of the key advantages of pre-clinical COVID-19 research is the rich palette of species (including non-human primates), while >90% of bacterial sepsis studies are performed in mice and rats. A multi-species approach considerably enhances reproducibility and translatability concurrently reducing idiosyncratic findings. Animal COVID-19 models were well-predictive of both successes (e.g. anti-SARS-CoV-2 monoclonal antibodies, remdesivir, vaccines) and failures (e.g. hydroxychloroquine, lopinavir/ritonavir) of clinically-tested substances.9 Given intuitive drive for benefits, the latter should not be underappreciated; “negative” findings hold a valuable life-/time and cost-saving potential. Notably, anti-TNF treatment in a clinically relevant mouse model of cecal ligation and puncture sepsis predicted failure of that therapy three years before the failed clinical trials.10 A clear pre-clinical parallel for sepsis and COVID-19 models exist: they both can be employed to cover identical research niches: i) mild-to-severe disease phenotypes, ii) defined cohort targeting, iii) selected pathophysiological insights (e.g. compartmentalization of responses). Furthermore, long-term sequalae can be effectively investigated in both bacterial sepsis and COVID-19 models.
349	D346		Guo, Yi; Wang, Hao; Xiao, Mingzhong; Guan, Xin; Lei, Yanshou; Diao, Tingyue; Long, Pinpin; Zeng, Rui; Lai, Xuefeng; Cai, Hao; You, Yutong; Wen, Yuying; Li, Wenhui; Wang, Xi; Wang, Yufei; Chen, Qinlin; Yang, Yuchan; Qiu, Yutong; Chen, Jishuai; Zeng, Huidan; Ni, Wei; Zhao, Youyun; Ouyang, Kani; Wang, Jingzhi; Wang, Qi; Liu, Li; Song, Lulu; Wang, Youjie; Guo, Huan; Li, Xiaodong; Wu, Tangchun; Yuan, Yu	Long-term outcomes of COVID-19 convalescents: An 18.5-month longitudinal study in Wuhan	https://doi.org/10.1186/s41256-022-00283-x	Published	2022-12-01	Study	https://doi.org/10.1186/s41256-022-00283-x	COVID-19 is a serious threat to human health and development. The acute burden of the pandemic includes more than 18.2 million deaths worldwide, and is unprecedented in modern times. This represents only a fraction of the total burden, as it excludes infection sequelae. An effective global strategic paradigm has been missing throughout the pandemic. The ‘flattening the curve’ approach neglected the importance of infection sequelae, and being centered on healthcare capacity was conceptually contrary to a people-centered health system. In March 2022, the World Health Organization revised its pandemic approach, importantly shifting emphasis away from managing transmission and towards prevention. Despite limitations, this now recognizes the role of infection sequelae, whose impact is becoming clearer in both variety and scale. Drawing on the foundational concepts of Sun Tzu and Carl von Clausewitz, most country approaches do not qualify as strategies, but rather as operational plans. They are also largely ineffective, neglecting infection sequelae, viral evolution dangers and other parameters. The purpose of this article is to summarize the evidence on COVID-19 infection sequelae, and alongside other contextual parameters use this to motivate that infection should be prevented. This is then used to answer the question: What is an effective strategy against COVID-19?
350	D347		Demir, Ismail; Aydin, Sukru; Cengiz, Deniz Ugur	The short-term effect of COVID-19 on the cochleovestibular system in pediatric patients	https://doi.org/10.1016/j.ijid.2022.12.008	Published	2022-12-09	Study	https://www.ijidonline.com/article/S1201-9712(22)00642-7/fulltext	Publisher: Elsevier PMID: 36509334 Highlights •Most participants had an improved physical and psychological health status •We observed sequelae symptoms in 45.2% of participants at 18.5 months •We observed abnormal chest CT patterns in about 30% of participants at 18.5 months •The convalescents still had mild depression or anxiety disorders at the last visit Long-term outcomes of COVID-19 convalescents: An 18.5-month longitudinal study in Wuhan Abstract Objective To describe the full scope of long-term outcomes and the ongoing pathophysiological alterations among the COVID-19 survivor. Methods We established a longitudinal cohort of 208 COVID-19 convalescents and followed them at 3.3 (IQR: 1.3, 4.4, visit 1), 9.2 (IQR: 9.0, 9.6, visit 2), and 18.5 (IQR: 18.2, 19.1, visit 3) months after infection, respectively. Serial changes in multiple physical and psychological outcomes were comprehensively characterized. We additionally explored the potential risk factors of SARS-CoV-2 antibody response and sequelae symptoms. Results We observed continuous improvement of sequelae symptoms, lung function, chest CT, 6-minute walk test, and the Borg dyspnoea scale, whereas sequelae symptoms (at least one) and abnormal chest CT patterns still existed in 45.2% and about 30% of the patients at 18.5 months, respectively. Both anxiety and depression disorders were alleviated for the convalescents, although the depression status was sustained for a longer duration. Conclusions Most COVID-19 convalescents had an overall improved physical and psychological health status, whereas sequelae symptoms, residual lesions on lung function, exercise impairment, and mental health disorders were still observed in a small proportion of the participants at 18.5 months after infection. Implementing appropriate preventive and management strategies for the ever-growing COVID-19 population is warranted.
351	D348		Khalife, Jade	Effective strategies against COVID-19 and the importance of infection sequelae	https://doi.org/10.1093/occmed/kqac119	Published	2022-12-08	Study	https://doi.org/10.1093/occmed/kqac119	The COVID-19 pandemic has given rise to an increasing number of patients with ‘long COVID’. Long COVID is the persistence of symptoms for weeks or months after an infection by SARS-CoV-2. It often impacts on the professional life of affected people.The aim of this study is to understand the experiences and needs of people with long COVID in relation to their return to work.A qualitative study, combining individual interviews and online forum discussions, was performed early 2021, as part of a larger mixed method study on the needs of long COVID patients in Belgium.One hundred and thirty-four people participated in the study. Participants described various clinical symptoms precluding their return to work. They also face sceptical reactions from employers and colleagues and a lack of support from the social welfare system to facilitate their return to work. These barriers have various impacts, including psychological ones, likely to compromise the professional future of long COVID patients.While the analysis of patients’ experiences shows variation in long COVID patients’ experiences with return to work, it may help occupational physicians and healthcare practitioners to better take up their crucial role in the return to work of long COVID patients, including raising employers’ and colleagues’ awareness of the specific difficulties related to long COVID.
352	D349		Baskett, William I; Qureshi, Adnan I; Shyu, Daniel; Armer, Jane M; Shyu, Chi-Ren	COVID-Specific Long-Term Sequelae in Comparison to Common Viral Respiratory Infections: An Analysis of 17,487 Infected Adult Patients	https://doi.org/10.1093/ofid/ofac683	Published	2022-12-21	Study	https://doi.org/10.1093/ofid/ofac683	better understanding of long-term health effects after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become one of the healthcare priorities in the current pandemic. We analyzedlarge and diverse patient cohort to study health effects related to SARS-CoV-2 infection occurring more than one month post-infection.We analyzed 17,487 patients who received diagnoses for SARS-CoV-2 infection in a total of 122 healthcare facilities in the United States prior to April, 14,2022. Patients were propensity score matched with patients diagnosed with the common cold, influenza, or viral pneumonia from March 1, 2020, to April 1, 2021. For each outcome, SARS-CoV-2 was compared to a generic Viral Respiratory Infection (VRI) by predicting diagnoses in the period between 30 and 365 days post-infection. Both COVID-19 and VRI patients were propensity score matched with patients with no record of COVID-19 or VRI and the same methodology was applied. Diagnoses where COVID-19 infection was a significant positive predictor in both COVID-19 vs VRI and COVID-19 vs Control comparisons were considered COVID-19-specific effects.Compared to common VRIs, SARS-CoV-2 was associated with diagnoses palpitations, hair loss, fatigue, chest pain, dyspnea, joint pain, and obesity in the post-infectious period.We identify that some diagnoses commonly described as “long COVID” do not appear significantly more frequent post-COVID-19 infection compared to other common VRIs. We also identify sequelae which are specifically associated with a prior SARS-CoV-2 infection.
353	D350		Ishii, Shinya; Sugiyama, Aya; Ito, Noriaki; Miwata, Kei; Kitahara, Yoshihiro; Okimoto, Mafumi; Kurisu, Akemi; Abe, Kanon; Imada, Hirohito; Akita, Tomoyuki; Kubo, Tatsuhiko; Nagasawa, Akira; Nakanishi, Toshio; Takafuta, Toshiro; Kuwabara, Masao; Tanaka, Junko	The role of discrimination in the relation between COVID-19 sequelae, psychological distress, and work impairment in COVID-19 survivors	https://doi.org/10.1038/s41598-022-26332-6	Published	2022-12-23	Study	https://www.nature.com/articles/s41598-022-26332-6	Perceived discrimination and work impairment are commonly observed in COVID-19 survivors, but their relationship has not been well understood. We aimed to evaluate the role of discrimination in the development of psychological distress and work impairment in COVID-19 survivors. From April 2020 to November 2021, 309 patients were recruited at two designated COVID-19 hospitals in Japan. Participants completed a standardized questionnaire including COVID-19 sequelae, psychological distress, impairments in work performance and perceived discrimination. The majority of participants (62.5%) experienced one or more COVID-19 sequelae. Psychological distress was observed in 36.9% and work impairment in 37.9%. In multivariate logistic regression analyses, COVID-19 sequelae and discrimination were associated with both psychological distress and work impairment. Mediation analysis demonstrated that the direct effect of sequelae on work impairment was non-significant after accounting for psychological distress, suggesting that the effect of sequelae on work impairment was mainly mediated through psychological distress. These findings were replicated in a subgroup analysis limited to patients with mild COVID-19. We conclude that discrimination plays an important role in the development of psychological distress and work impairment, and that both discrimination and psychological distress should be targets of intervention in COVID-19 survivors.
354	D351		Lapteva, E. S.; Ariev, A. L.; Arieva, G. T.; Tsutsunawa, M. R.; Diachkova-Gerceva, D. C.	On the Role of Geriatric Services in the Diagnosis and Monitoring of Outcomes of Post-Covid Syndrome (Review)	https://doi.org/10.1134/S2079057022040105	Published	2022-12-01	Review	https://doi.org/10.1134/S2079057022040105	In addition to the rapid spread of the pandemic in waves across the globe today, there is a growing problem called “long-COVID-19,” a term that describes the long-term effects of the novel coronavirus infection COVID-19. How the disease proceeds after “recovery,” including long-term physical and psychological health consequences, and the future of COVID-19 survivors remains largely unclear. This is especially true for older age groups. This article summarizes the experience of foreign studies aimed at determining the duration and clarifying the nature of multi-organ complications after suffering from COVID-19, as well as ways of the long-term rehabilitation of patients in older age groups with post-COVID syndrome.
355	D352		Kohn, Laurence; Dauvrin, Marie; Detollenaere, Jens; Primus-de-Jong, Célia; Maertens de Noordhout, Charline; Castanares-Zapatero, Diego; Cleemput, Irina; Van den Heede, Koen	Difficultés rencontrées par les patients COVID long dans le système de santé belge	https://doi.org/10.3917/spub.225.0663	Published	2022	Study	https://www.cairn.info/revue-sante-publique-2022-5-page-663.htm	Introduction : Suite à une infection COVID-19, bon nombre de personnes ont ressenti divers symptômes pendant plusieurs semaines et mois, et ce, même après une phase aiguë légère. Ces personnes atteintes de « COVID long » se sont trouvées confrontées au système de soins de santé, non sans difficultés.But de l’étude : Afin de mieux comprendre leurs expériences, nous avons complété les informations obtenues via une enquête en ligne par une approche qualitative mixte, comprenant 33 entretiens individuels et les discussions de 101 participants à un forum durant le mois de mars 2021.Résultats : Plusieurs lacunes ont été mises en évidence lors des contacts des patients « COVID long » avec le système de santé, comme l’absence d’écoute ou d’empathie de certains professionnels de la santé, d’approche systématique ou proactive lors du bilan diagnostique, ou encore l’absence de coordination interdisciplinaire. Les patients se sentent incompris et se voient obligés de développer leurs propres stratégies afin d’établir un diagnostic ou un traitement. Le malaise des patients les ont amenés à remettre en question la valeur de la médecine et à recourir à des thérapies non conventionnelles afin de soulager leurs symptômes, parfois à un prix élevé.Conclusions : Mieux informer le corps médical quant à la manifestation de la maladie et aux prises en charge possibles, y compris les possibilités de remboursement, permettrait de le sensibiliser et de lui donner les outils pour répondre aux besoins des patients « COVID long ». Évaluer de manière globale le patient via un « bilan interdisciplinaire » est nécessaire.
356	D353		Suran, Melissa	HHS Releases New Report on Long COVID Experiences	https://doi.org/10.1001/jama.2022.20052	Published	2022-12-27	Article	https://doi.org/10.1001/jama.2022.20052	The US Department of Health and Human Services (HHS) published a report highlighting the experiences of patients with long COVID. Between 5% and 30% of people who had COVID-19 may develop long COVID conditions, and about 1 million individuals aren’t in the workforce “at any given time” because of related symptoms, according to an HHS statement. It also notes that researchers have documented more than 50 long COVID conditions that affect nearly all organ systems. “Long COVID isn’t one condition,” Deputy Assistant Secretary for Science and Medicine Michael Iademarco, MD, MPH, said in the statement. “The Health+ Long COVID Report allows us to hear directly from patients so we can better understand the complexities of this multisystemic condition and enrich our understanding and response to Long COVID and its associated conditions.” A literature review, 4 workshops, and interviews with more than 60 people about long COVID served as the report’s foundation. Participants were recruited from a diverse group to include those who had long COVID as well as caregivers and health care professionals. Researchers then synthesized common themes that emerged to paint a picture of shared long COVID experiences. The report—commissioned by HHS and produced by Coforma, an independent research agency—also explores how and why the effects of long COVID can vary from person to person and ways in which individuals with related conditions can improve their quality of life and care. It points out that related conditions likely disproportionately affect historically underserved communities. “Long COVID will be around long after the pandemic subsides,” the report concludes. “We can reduce the severity and breadth of that impact, however, if we act collectively and urgently.”
357	D354		Moretti, Chiara; Collaro, Concetta; Terzoni, Cristina; Colucci, Gennaro; Copelli, MariaRosa; Sarli, Leopoldo; Artioli, Giovanna	Dealing with uncertainty. A qualitative study on the illness’ experience in patients with Long-COVID in Italy	https://doi.org/10.23750/abm.v93i6.14059	Published	2022-12-16	Study	https://mattioli1885journals.com	number: 6 Abstract. Background and goals: An unknown proportion of people who had COVID-19 infection continue to experience symptoms such as fatigue, breathlessness, joint or muscle pain, difficulty sleeping, and brain fog. These symptoms have a significant impact on the quality of life. Long-COVID is a new multisystem disease still under investigation. This research aims to explore the illness experienced by patients suffering from Long-COVID in Italy. Research Design and Methods: Qualitative methodology with semi- structured interviews. Participants were recruited on the Facebook patient group between October 2021 and January 2022. Partici-pants had been experiencing symptoms for at least three months following confirmed COVID-19 infection. Interviews were conducted by video call, recorded and transcribed with consent. The thematic analysis method has been chosen to infer data from textual material. Results: 17 interviews with women with Long-COVID have been analysed. The main themes include: a total change of life due to the symptomatology, loss ofautonomy that affects social, family and professional life; social isolation, a sense of abandonment often in-creased by stigma, the difficulty of being believed and achieving diagnosis; difficulty in managing symptoms and accessing to care services; living with uncertainty caused by the lack of institutional, social, professional, familial and medical support. Conclusions: Intervention programs, both institutional and social-health policies should be developed for patients with Long-COVID. The impact of symptoms could be reduced by develop-ing standards and protocols, and by ensuring access to care and to multi-disciplinary rehabilitation. Further development of knowledge on Long-COVID is essential.
358	D355		Guzman-Esquivel, Jose; Mendoza-Hernandez, Martha A.; Guzman-Solorzano, Hannah P.; Sarmiento-Hernandez, Karla A.; Rodriguez-Sanchez, Iram P.; Martinez-Fierro, Margarita L.; Paz-Michel, Brenda A.; Murillo-Zamora, Efren; Rojas-Larios, Fabian; Lugo-Trampe, Angel; Plata-Florenzano, Jorge E.; Delgado-Machuca, Marina; Delgado-Enciso, Ivan	Clinical Characteristics in the Acute Phase of COVID-19 That Predict Long COVID: Tachycardia, Myalgias, Severity, and Use of Antibiotics as Main Risk Factors, While Education and Blood Group B Are Protective	https://doi.org/10.3390/healthcare11020197	Published	1/1/2023	Study	https://www.mdpi.com/2227-9032/11/2/197	Background: Risk factors for developing long COVID are not clearly established. The present study was designed to determine if any sign, symptom, or treatment of the acute phase, or personal characteristics of the patient, is associated with the development of long COVID. Methods: A cohort study was carried out, randomly selecting symptomatic COVID-19 patients and not vaccinated. The severity of the acute illness was assessed through the number of compatible COVID-19 symptoms, hospitalizations, and the symptom severity score using a 10-point visual analog scale. Results: After multivariate analysis, a severity score ≥8 (RR 2.0, 95%CI 1.1–3.5, p = 0.022), hospitalization (RR 2.1, 95%CI 1.0–4.4, p = 0.039), myalgia (RR 1.9, 95%CI 1.08–3.6, p = 0.027), tachycardia (RR 10.4, 95%CI 2.2–47.7, p = 0.003), and use of antibiotics (RR 2.0, 95%CI 1.1–3.5, p = 0.022), was positively associated with the risk of having long COVID. Higher levels of education (RR 0.6, 95%CI 0.4–0.9, p = 0.029) and type positive B blood group (B + AB, RR 0.44, 95%CI 0.2–0.9, p = 0.044) were protective factors. The most important population attributable fractions (PAFs) for long COVID were myalgia (37%), severity score ≥8 (31%), and use of antibiotics (27%). Conclusions: Further studies in diverse populations over time are needed to expand the knowledge that could lead us to prevent and/or treat long COVID.
359	D356		Lippi, Giuseppe; Sanchis‑Gomar, Fabian; Henry, Brandon M.	COVID-19 and its long-term sequelae: what do we know in 2023?	https://doi.org/10.20452/pamw.16402	Published	1/9/2023	Review	https://www.mp.pl/paim/issue/article/16402	Post‑viral syndrome is a well‑known medical condition characterized by different levels of physical, cogni‑tive, and emotional impairment that may persist with fluctuating severity after recovering from an acute viral infection. Unsurprisingly, COVID‑19 may also be accompanied by medium- and long‑term clinical sequelae after recovering from a SARS‑CoV‑2 infection. Although many clinical definitions have been provided, “long‑ COVID” can be defined as a condition occurring in patients with a history of SARS‑CoV‑2 infection, developing 3 months from the symptoms onset, persisting for at least 2 months, and not explained by alternative diagnoses. According to recent global analyses, the cumulative prevalence of long‑ COVID seems to range between 9% and 63%, and is up to 6‑ fold higher than that of similar postv iral infection conditions. Long‑COVID primarily encompasses the presence of at least 1 symptom, such as fatigue, dyspnea, cognitive impairment / brain fog, postexertional malaise, memory issues, musculoskel‑etal pain / spasms, cough, sleep disturbances, tachycardia / palpitations, altered smell / taste perception, headache, chest pain, and depression. The most important demographic and clinical predictors to date are female sex, older age, cigarette smoking, pre‑existing medical conditions, lack of COVID‑19 vac‑cination, infection with pre‑Omicron SARS‑CoV‑2 variants, number of acute phase symptoms, viral load, severe / critical COVID‑19 illness, as well as invasive mechanical ventilation. Concerning the care for long‑ COVID patients, the greatest challenge is the fact that this syndrome cannot be considered a single clinical entity, and thus it needs an integrated multidisciplinary management, specifically tailored to the type and severity of symptoms.
360	D357		Jacobs, Elizabeth T.; Catalfamo, Collin J.; Colombo, Paulina M.; Khan, Sana M.; Austhof, Erika; Cordova-Marks, Felina; Ernst, Kacey C.; Farland, Leslie V.; Pogreba-Brown, Kristen	Pre-existing conditions associated with post-acute sequelae of COVID-19	https://doi.org/10.1016/j.jaut.2022.102991	Published	2/1/2023	Study	https://www.sciencedirect.com/science/article/pii/S0896841122001998	Highlights •Post-acute sequelae of COVID-19 (PASC) has been increasingly observed to occur in patients who have been infected with SARS-CoV-2. •To date, it is not known which comorbidities may increase an individual's risk of developing PASC. •This study shows that those with autoimmune diseases were more likely to develop PASC than those without these comorbidities. Abstract Post-acute sequelae of COVID-19 (PASC) are conditions that occur or remain at least 28 days after SARS-CoV-2 infection. While some risk factors for PASC have been identified, little is known about pre-existing conditions that render one susceptible to developing PASC. Data from participants (n = 1224) in a longitudinal COVID-19 cohort study in Arizona were used to investigate comorbid conditions associated with PASC. After adjustment of the models for age, BMI, gender, race, and smoking, the following pre-existing conditions were statistically significantly associated with the development of PASC: asthma (OR = 1.54; 95% CI = 1.10–2.15); chronic constipation (OR = 4.29; 95% CI = 1.15–16.00); reflux (OR = 1.54; 95% CI = 1.01–2.34); rheumatoid arthritis (OR = 3.69; 95%CI = 1.15–11.82); seasonal allergies (OR = 1.56; 95% CI = 1.22–1.98); and depression/anxiety (OR = 1.72; 95% CI = 1.17–2.52). When grouping conditions together, statistically significant associations with PASC were observed for respiratory (OR = 1.47; 95% CI = 1.06–2.14); gastrointestinal (OR = 1.62; 95% CI = 1.16–2.26), and autoimmune conditions (OR = 4.38; 95% CI = 1.59–12.06). After adjustment for severity of acute SARS-CoV-2 infection and depression/anxiety, seasonal allergies (OR = 1.48; 95% CI 1.15–1.91) and autoimmune disease (OR = 3.78; 95% CI - 1.31-10.91) remained significantly associated with risk for PASC. These findings indicate that numerous pre-existing conditions may be associated with an increased risk for the development of PASC. Patients with these conditions should consider taking extra steps to avoid infection.
361	D358		Barker, Kristin Kay; Whooley, Owen; Madden, Erin F.; Ahrend, Emily E.; Greene, R. Neil	The long tail of COVID and the tale of long COVID: Diagnostic construction and the management of ignorance	https://doi.org/10.1111/1467-9566.13599	Published	12/29/2022	Article	https://onlinelibrary.wiley.com/doi/abs/10.1111/1467-9566.13599	We bring together insights from the sociology of diagnosis and the sociology of ignorance to examine the early diagnostic unfolding of ‘Long COVID’ (LC). Originally described by patient activists, researchers set out to ponder its unwieldy clinical boundaries. Using a scoping review method in tandem with qualitative content analytic techniques, we analyse medicine’s initial struggles to construct a LC diagnosis. Paying attention to the dynamics of ignorance, we highlight three consequential conceptual manoeuvres in the early classifications of LC: causal agnosticism concerning the relationship between COVID-19 and LC, evasion of lumping LC with similar conditions; and the predictable splitting off of medically explainable cases from the LC designation. These manoeuvres are not maleficent, inept or unreasonable. They are practical but impactful responses to the classificatory dilemmas present in the construction of diagnoses amidst ignorance. Although there are unique aspects to LC, we suggest that its early fate is nevertheless emblematic of medicine’s diagnostic standardisation processes more generally. To varying degrees, diagnoses are ignorance management strategies; they create a pathway through the uncertainty at the core of disease realities. However, while diagnoses circumscribe some types of ignorance, they produce others through the creation of blind spots and paths not taken.
362	D359		Berg, Selina Kikkenborg; Palm, Pernille	Playing catch with long COVID – Understanding a new disease	https://doi.org/10.1016/j.lanepe.2022.100568	Published	2/1/2023	Article	https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(22)00264-2/fulltext	publisher: Elsevier PMID: 36597517 This study from the CLoCk study by Pereira et al. is a large-scale English, matched longitudinal cohort study of children and adolescents 11–17 years of age reporting symptoms and well-being.3 The included children and adolescents were all tested and those with confirmed SARS-CoV-2 infection were compared to those SARS-CoV-2 PCR-negative. The study shows that across all time points, adverse symptoms were generally more common in test-positive compared to test-negative children and adolescents. Symptoms presentation at time of testing e.g. shortness of breaths was 5.4% higher after 12 months and tiredness was 13.8% higher at 12 months in positive compared to negative. More new-onset long-COVID symptoms were also found at 6 and 12 months in the SARS-CoV-2 positive group. Overall wellbeing is better among SARS-CoV-2 positives which is in line with previous research.5,6 Specific symptoms and quality of life issues presenting at 6 months and 12 months shows varying patterns of differences between groups, suggesting that multiple factors influencing symptoms developing during the follow up time. The authors should be applauded for carrying out a large, well-planned study that also includes a control group. Further that the participants were asked to report symptoms at multiple times at 0,3,6 and 12 months posttest. A mayor concern is, however, a large drop out. Only 5086 of the 127,896 in the initial invited group responded to the final questionnaire after 12 months. Therefore, the results are indicative rather than conclusive due to lack of generalizability, and selection bias. It is a strength that the children and adolescents were asked to answer themselves not using parent proxy.7 Even when planning a study carefully some problems are interfering with the data. One problem is the changing variants questioning if the results are transferable for the Omicron variant. Another major issue is the offer to vaccinate during the follow up period. The authors make a note in the methods section, that 66% in both groups received vaccination between 6 and 12 months, However, the impact on the results are not discussed. E.g., late onset of headache and dizziness could be related to vaccines.8,9 Measuring symptoms of long COVID over time is very complex as it is impossible to control for interfering symptoms. Also, the long COVID symptoms being so unspecific and similar to symptoms that occur from varies reasons such as other viral infections, stress reactions after long school hours, after sport, and for the girls hormonal symptoms. In this study symptom burden decrease only to increase with new onset symptoms over time. The fluctuational patters is described before in long COVID4,6 however, it cannot be ruled out that new symptoms are connected to e.g. vaccines or other viral infections. So even when designing with a control group, it is difficult to control for extrinsic factors. Also a vulnerability to comorbid disease is suggested and might explain new onset symptoms long after the initial COVID-19 diagnose.10 Previous studies including our study the LongCOVIDKidsDK shows age and gender differences with girls presenting more symptoms after puberty than boys and with more symptoms among adolescents than younger children.6 The authors don't address this important issue and should be encouraged to look more into this. The overall take home message is that most children seem to recover quickly. However, some experience long lasting symptoms and difference between groups are found up to 12 months after the initial diagnosis. Behind these numbers is probable hidden a smaller group that are affected significantly by long-lasting symptoms. General practitioners and pediatricians should be aware of the potential burden in children. Furthermore, we still lack public accept and see skepticism from some health professionals, despite mounting evidence of long COVID. More clinical research is now needed to investigate the biological mechanisms and develop effective preventional strategies and treatments.
363	D360		Ogungbe, Oluwabunmi; Slone, Sarah; Alharthi, Abeer; Tomiwa, Tosin; Kumbe, Baridosia; Bergman, Alanna; McNabb, Katherine; Wright, Rhonda Smith; Farley, Jason E.; Himmelfarb, Cheryl R. Dennison; Cooper, Lisa A.; Post, Wendy S.; Davidson, Patricia M.; Commodore-Mensah, Yvonne	“Living like an empty gas tank with a leak”: Mixed methods study on post-acute sequelae of COVID-19	https://doi.org/10.1371/journal.pone.0279684	Published	12/30/2022	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0279684	Background The burden and presentation of post-acute sequela of SARS-CoV-2 infection (PASC) are a developing major public health concern. Objectives To characterize the burden of PASC in community-dwelling individuals and understand the experiences of people living with PASC. Methods This mixed-methods study of COVID-19 positive community-dwelling persons involved surveys and in-depth interviews. Main outcome was self-report of possible PASC symptoms 3 weeks or longer after positive COVID-19 test. In-depth interviews were guided by a semi-structured interview guide with open-ended questions and probes based on emerging literature on PASC and the impact of COVID-19. Results With a survey response rate of 70%, 442 participants were included in this analysis, mean (SD) age 45.4 (16.2) years, 71% female, 12% Black/African American. Compared to those with no PASC symptoms, persons who reported PASC symptoms were more likely to be older (mean age: 46.5 vs. 42; p = 0.013), female (74.3% vs. 61.2%; p = 0.010), to have pre-existing conditions (49.6% vs. 34%; p = 0.005), and to have been hospitalized for COVID-19 (14.2% vs. 2.9%; p = 0.002). About 30% of the participants experienced severe fatigue; the proportion of persons reporting severe fatigue was 7-fold greater in those with PASC symptoms (Adjusted Prevalence Ratio [aPR] 6.73, 95%CI: 2.80–16.18). Persons with PASC symptoms were more likely to report poor quality of life (16% vs. 5%, p<0.001) and worse mental health functioning (Mean difference: -1.87 95%CI: -2.38, -1.37, p<0.001). Themes from in-depth interviews revealed PASC was experienced as debilitating. Conclusions In this study, the prevalence of PASC among community-dwelling adults was substantial. Participants reported considerable coping difficulties, restrictions in everyday activities, invisibility of symptoms and experiences, and impediments to getting and receiving PASC care.
364	D361		Himmels, Jan Peter	Post COVID-19 condition and new onset diseases after COVID-19		Published	12/1/2022	Review	https://fhi.brage.unit.no/fhi-xmlui/bitstream/handle/11250/3040161/Himmels-2022-Pos.pdf?sequence=1	Current evidence suggests that patients who have been hospitalised or undergone non-invasive ventilation due to severe COVID-19 experience similar long-term consequences as patients who have been exposed to similar treatment due to other RTIs. These findings support the current rehabilitation practise of providing similar care to patients post-COVID as after other severe RTIs. Controlled studies also found that most symptoms reported by COVID-19-patients were also reported in the uninfected general population, albeit to a lesser extent. The symptoms that are most specific for COVID-19 seems to be altered smell and taste and neurological diagnoses, although with equally common reporting of dyspnoea and fatigue. Most reported symptoms and new onset diseases are also seen in the follow-up period of other RTIs. Symptom burden appears to decrease over time, but we do not know if or when these symptoms might disappear. The data also reflect that many of the reported symptoms are prevalent in non-infected populations. Although the evidence base is growing and steadily becomes more trustworthy, some aspects remain uncertain. Our findings continue to reflect long term symptoms in patients who were infected early in the pandemic. New virus variants causing milder disease will likely reduce the overall risk and burden of long-term symptoms. Therapeutic advancements and vaccination impact outcomes and probably lead to milder courses of disease, contributing to a further reduction in the prevalence and burden of long-term symptoms. Studies on consequences of breakthrough infections, and comparative studies on vaccinated versus non vaccinated populations are already pointing in the directions of fewer long-term symptoms. Persons with asymptomatic COVID-19, or those not tested are not well researched.
365	D362		Davis, Hannah E.; McCorkell, Lisa; Vogel, Julia Moore; Topol, Eric J.	Long COVID: major findings, mechanisms and recommendations	https://doi.org/10.1038/s41579-022-00846-2	Published	2023-01-13	Review	https://www.nature.com/articles/s41579-022-00846-2	Long COVID is an often debilitating illness that occurs in at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. More than 200 symptoms have been identified with impacts on multiple organ systems. At least 65 million individuals worldwide are estimated to have long COVID, with cases increasing daily. Biomedical research has made substantial progress in identifying various pathophysiological changes and risk factors and in characterizing the illness; further, similarities with other viral-onset illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome have laid the groundwork for research in the field. In this Review, we explore the current literature and highlight key findings, the overlap with other conditions, the variable onset of symptoms, long COVID in children and the impact of vaccinations. Although these key findings are critical to understanding long COVID, current diagnostic and treatment options are insufficient, and clinical trials must be prioritized that address leading hypotheses. Additionally, to strengthen long COVID research, future studies must account for biases and SARS-CoV-2 testing issues, build on viral-onset research, be inclusive of marginalized populations and meaningfully engage patients throughout the research process.
366	D363		Leitzke, Marco	Is the post-COVID-19 syndrome a severe impairment of acetylcholine-orchestrated neuromodulation that responds to nicotine administration?	https://doi.org/10.1186/s42234-023-00104-7	Published	2023-01-18	Article	https://doi.org/10.1186/s42234-023-00104-7	Following a SARS-CoV-2 infection, many individuals suffer from post-COVID-19 syndrome. It makes them unable to proceed with common everyday activities due to weakness, memory lapses, pain, dyspnea and other unspecific physical complaints. Several investigators could demonstrate that the SARS-CoV-2 related spike glycoprotein (SGP) attaches not only to ACE-2 receptors but also shows DNA sections highly affine to nicotinic acetylcholine receptors (nAChRs). The nAChR is the principal structure of cholinergic neuromodulation and is responsible for coordinated neuronal network interaction. Non-intrinsic viral nAChR attachment compromises integrative interneuronal communication substantially. This explains the cognitive, neuromuscular and mood impairment, as well as the vegetative symptoms, characterizing post-COVID-19 syndrome. The agonist ligand nicotine shows an up to 30-fold higher affinity to nACHRs than acetylcholine (ACh). We therefore hypothesize that this molecule could displace the virus from nAChR attachment and pave the way for unimpaired cholinergic signal transmission. Treating several individuals suffering from post-COVID-19 syndrome with a nicotine patch application, we witnessed improvements ranging from immediate and substantial to complete remission in a matter of days.
367	D364		Van Wambeke, Erika; Bezler, Cécile; Kasprowicz, Anne-Marie; Charles, Anne-Laure; Andres, Emmanuel; Geny, Bernard	Two-Years Follow-Up of Symptoms and Return to Work in Complex Post-COVID-19 Patients	https://doi.org/10.3390/jcm12030741	Published	2023-01-01	Study	https://www.mdpi.com/2077-0383/12/3/741	Introduction: Many COVID-19 patients present with severe long-lasting symptoms. They might benefit from a coordination team to manage such complex situations, but late efficacy still needs to be determined. Population and Methods: Out of 105 contacts, 45 patients had two phone consultations separated by personalized support 15 and 22 months, respectively, after COVID infection. Self-reported symptoms, feelings of improvement and ability to return to work allowed us to determine the efficacy of the therapeutic strategy proposed. Results: Unlike what was expected, many post-COVID-19 patients directly contacted the coordination team and had significant pre-existing comorbidities. Despite exercise, respiratory, olfactory rehabilitations, cognition/speech therapy and/or psychological support, the more frequent self-reported symptoms (fatigue, neurocognitive disorders, muscles and joint pain) did not resolve. However, dyspnea, anxiety and chest pain were significantly reduced. Finally, 2/3 of the patients felt some degree of improvement and returned to work either partially or fully, but 1/3 remained complaining of symptoms and out of work as late as 22 months after COVID occurrence. All patients greatly appreciated the second phone consultation. Conclusions: In such complex situations, besides early and adapted rehabilitations and psychological help allowing better symptom management, relatively simple actions such as a phone call might be very useful to reduce patients’ feelings of abandonment.
368	D365		Shelton, A Teresa	Epstein-Barr Virus Testing-to-Treatment in Long COVID Patients: A Review and Recommendation		Published	2023-01-18	Review	https://digitalshowcase.lynchburg.edu/dmscjournal/vol5/iss1/101	Incidence rates are increasing worldwide of symptoms persisting for several months or longer after Coronavirus 19 (COVID-19, SARS-Co-2) acute infection known as the post-acute sequelae of COVID-19 (PASC, long COVID). Research demonstrates Epstein-Barr virus (EBV) latent reactivation in hospitalized patients with COVID-19 carries a higher mortality rate when untreated. A critical link between EBV and long COVID symptoms connects the hyperinflammatory cascade and immune dysfunction common to both viral conditions. A clinical review of emerging literature justifies the rationale for testing and treatment of EBV in cases of PASC. Current World Health Organization (WHO) Post-COVID Care Center (PCCC) clinical guidelines for outpatient treatment of long COVID and Multisystem Inflammatory Syndrome (MIS) involve multiple specialty provider access yet exclude viral co-infection screening and treatment for EBV. No patented therapy for EBV exists, and the literature review reveals profound evidence for a Federal Drug Administration (FDA) approved treatment for EBV infection. To reduce long COVID symptoms, a proposed evaluation and treatment plan for future research of EBV reactivation in PASC patients is merited. Primary care and PCCC clinics need a standardized therapy for EBV and PASC co-infection to improve patient outcomes.
369	D366		Quinn, Kieran L.; Razak, Fahad; Cheung, Angela M.	Diagnosing post-COVID-19 condition (long COVID) in adults	https://doi.org/10.1503/cmaj.220818	Published	2023-01-17	Review	https://www.cmaj.ca/content/195/2/E78	About 1.4 million people in Canada have been affected by long COVID The 2022 Canadian COVID-19 Antibody and Health Survey reported that nearly 15% of adults in Canada with suspected or confirmed SARS-CoV-2 infection had symptoms beyond 3 months.2 Females (18.0%) were more likely than males (11.6%) to report lingering symptoms.2 A 2022 meta-analysis and systematic review of early pandemic experiences with more severe variants reported an overall global prevalence of 43%, which differed among people who were admitted to hospital (54%) and those who were not (34%).3 Consequently, contemporary prevalence may be far lower owing to high vaccination rates, evolving therapies and less virulent variants, resulting in less severe disease overall.3 Long COVID is systemic in nature This may be related to the expression of angiotensin-converting-enzyme 2 (ACE2) receptors in different organ systems, through which SARS-CoV-2 enters a cell.4 Several pathophysiological mechanisms may contribute differentially to long COVID, including cellular damage, persistent inflammation or viremia, autoimmunity and a procoagulant state.4 Long COVID can affect most organ systems in the body The condition has substantial effects on patients’ daily well-being and functioning.3,4 More than 100 symptoms have been reported in people with long COVID, and female sex appears to be an independent risk factor. The most common potentially modifiable symptoms include fatigue (23%–63%), anxiety and depression (23%–46%), dyspnea (11%–43%), sleep disturbances (11%–31%) and palpitations (6%–22%).3,4 Many people with long COVID have lingering symptoms Although many people recover from long COVID, some continue to have symptoms and are unable to return to full-time work at 1 year after infection.2,5 In a 2022 longitudinal cohort study5 involving 1192 people who were admitted to hospital in Wuhan, China, and who survived COVID-19, 68% had at least 1 symptom at 6 months after infection, which decreased to 55% at 2 years. A total of 21% of people who were previously employed had not returned to work,5 and the same proportion of people in Canada reported that their symptoms often or always limited their daily activities.2 publisher: CMAJ section: Practice PMID: 36649955
370	D367		Quinn, Kieran L.; Razak, Fahad; Cheung, Angela M.	Assessing common and potentially modifiable symptoms of post-COVID-19 condition (long COVID) in adults	https://doi.org/10.1503/cmaj.220823	Published	2023-01-17	Review	https://www.cmaj.ca/content/195/2/E76	Fatigue is the most common symptom of long COVID Fatigue is associated with diminished activity tolerance and postexertional malaise and symptom exacerbation. Providers should assess its frequency, severity, duration, impact, and alleviating and exacerbating factors (physical, cognitive and psychological), as well as sleep hygiene and effect on daily activities. To rule out other causes, a comprehensive history, physical examination and routine bloodwork including hemoglobin and thyroid-stimulating hormone are important.1 People with long COVID frequently experience anxiety or depression It is important to validate a person’s psychological experience during long COVID and screen for symptoms of anxiety and depression, which are common. Providers should explore isolation, stress and any underlying drivers of psychological symptoms, with a focus on potential impairment in function.1 Assessment of dyspnea on exertion should explore a physical examination and oxygen saturation monitoring during a walk test2 In people with normoxia and mild acute illness, dyspnea may be due to weak respiratory muscles and cardiac or noncardiac diseases. A limited set of routine investigations, in addition to pulmonary function and natriuretic peptide tests, may be useful in differentiating people with post-viral reactive airway disease from weak respiratory muscles and cardiac disease. For more severe dyspnea, residual lung abnormalities (e.g., fibrosis) or cardiac disease may explain the dyspnea requiring specific investigations, such as chest radiograph, echocardiography and a 6-minute walk test.2 Evaluation of sleep disturbances should explore sleep pattern, duration, quality, frequency of awakenings and whether the person feels refreshed after waking Special attention needs to be paid to the use of alcohol, cannabis, caffeine and sleep medications by people with long COVID. Severe acute illness may warrant a sleep study as the need for supplemental oxygen owing to nocturnal hypoxemia was reported in 6.6% of people who were admitted to hospital 60 days after acute COVID-19, which may persist beyond 90 days.3 Investigation of palpitations should include orthostatic vital signs and a 12-lead electrocardiogram Cardiac dysautonomia has been associated with long COVID.4 Postural orthostatic tachycardia syndrome can be diagnosed with orthostatic vital signs and a 10-minute stand test.5 Holter monitoring may help distinguish inappropriate sinus tachycardia (the most common arrhythmia associated with long COVID) from other arrhythmias.5 publisher: CMAJ section: Practice PMID: 36649958
371	D368		Khosla, Seema; Cheung, Joseph; Gurubhagavatula, Indira; Medicine, on behalf of the COVID-19 Task Force of the American Academy of Sleep	Sleep Assessment in Long COVID Clinics: A Necessary Tool for Effective Management	https://doi.org/10.1212/CPJ.0000000000200079	Published	2023-02-01	Study	https://cp.neurology.org/content/13/1/e200079	As we adapt to SARS-CoV-2, it has become apparent that the acute illness is not the only threat from this virus. Long COVID has emerged as a potentially disabling condition with multiple varied symptoms. We propose that querying patients about their sleep may allow for the assessment of a sleep-related disorder that is amenable to treatment. In addition, hypersomnolence is a prominent feature and may mimic other organic hypersomnias; therefore, inquiring about COVID-19 infection in sleepy patients is suggested.
372	D369		Saigle, Victoria	“My family doctor didn’t know how to help me”: a teenager’s perspective on being diagnosed with long COVID	https://doi.org/10.1503/cmaj.221846	Published	2023-01-17	Article	https://www.cmaj.ca/content/195/2/E84	Around the 3-month mark, my mom found a study that was enrolling long COVID patients. We had a phone call with the study group and did blood work. When we saw the [study] doctor in person, they said I had symptoms that a lot of long COVID patients have. The study was one of the only ones that would accept me — I was 16 at the time. I liked knowing that there was something they could help me with; it wasn’t just like, “Oh, you’re sick.” It was, “We’ll help you through it.” The long COVID team is great. They listen. For a while, I had been crashing every 4 days. I’d feel good for a few days and then, by around day 4, I’d need to sleep for 18 hours. The long COVID clinic explained that, as I started feeling better, I’d have to take baby steps. If I didn’t, I’d get so fatigued that my body would start to shut down and tell me I needed to stop and rest. They also recommended that I take a higher dose of ferritin because my levels were still low. Long COVID affected me a lot last year and a bit this year. I stopped doing basically everything — fastpitch, rugby and school. I didn’t see anybody. The only thing that I did was work, but I wasn’t working as much as I used to. Now, I’m still tired but I don’t need to take a nap every few days. However, I’m not at the level that I was before having COVID. — Interviewee preferred to remain anonymous publisher: CMAJ section: Humanities PMID: 36649954
373	D370		Saigle, Victoria	A patient’s perspective on long COVID: improvement month to month not week to week	https://doi.org/10.1503/cmaj.221816	Published	2023-01-17	Article	https://www.cmaj.ca/content/195/2/E83	I got COVID in early January of 2022. It lasted 10 days and then in mid-to-late February, I got additional symptoms. It started with a lack of appetite, dizziness and extreme fatigue, and then psychological symptoms, like anxiety and depression. The nausea, lack of appetite and weight loss were the most concerning. At its worst, walking around the house or to the end of the driveway was difficult. I slept 16–18 hours a day. In mid-to-late March, I saw my primary care doctor and other specialists to try to figure out what was wrong. Initially, they were thinking something else was going on, maybe an autoimmune disease or cancer. I had lost 30 pounds in 3 to 4 weeks. I saw a gastroenterologist and an internal medicine specialist, had a CT scan of my chest and abdomen, an upper GI scope and a whole bunch of blood work, as well as an abdominal ultrasound and an echocardiogram. After all of the tests were done, long COVID kind of became a diagnosis of exclusion. In early May 2022, I got an appointment at a long COVID clinic. My wife had heard of the clinic and we emailed them directly. No one that I had seen up to that point was willing to do anything else. I felt like I was stuck. The long COVID clinic had the benefit of a 3 and a half month history and all the medical tests that showed essentially nothing. They took a thorough history, did some more tests and said it fit with long COVID. One thing they talked about was the importance of pacing and setting a level of activity I could achieve without pushing myself. It was relearning what I could manage and then slowly building up my activity. Other than time and rest, that’s probably the most important concept that I had to get my head around. I see improvement month to month, not week to week, which I’m still coming to terms with. The nausea and the poor appetite disappeared first, and after 4 or 5 months my weight returned. The fatigue, lightheadedness, dizziness and my exercise tolerance are still works in progress. I was off work for 4 or 5 months. I work as a large animal vet. It’s a physically demanding job with long hours. At that time, my work involved night work and getting called in at irregular hours. I have not returned to that, but I now work about 60% of a normal week. My employer was super supportive and I couldn’t ask for more. My work, my wife and my family are my rocks that helped me get through this. Before this, I had no significant problems and took no medications. I felt like a healthy 52-year-old man. It’s been really difficult to be that sick and not have an accepted hypothesis about what’s going on. I understand that sometimes we don’t know, but it’s important to see a path forward. In the summer, I spoke with people who also went through long COVID. Finding a way for patients to talk to others with the disease would be a huge help. The psychological part of long COVID could also be discussed more. I am on medication now, but at times I got the feeling that there was a temptation to explain all of my symptoms as being psychological. The uncertainty, lack of experience with long COVID and the dearth of clinicians to treat me resulted in extreme difficulty accessing any disability insurance. It has been very hard to get the details of my symptoms and their effects into my records in sufficient measure for insurers to feel it is worthy of a claim. — Patient wished to remain anonymous publisher: CMAJ section: Humanities PMID: 36649950
374	D371		Huerne, Katherine; Filion, Kristian B.; Grad, Roland; Ernst, Pierre; Gershon, Andrea S.; Eisenberg, Mark J.	Epidemiological and Clinical Perspectives of Long COVID Syndrome	https://doi.org/10.1016/j.ajmo.2023.100033	Published	2023-01-18	Review	https://www.sciencedirect.com/science/article/pii/S2667036423000031	UNSTRUCTURED ABSTRACT Long COVID, or post-acute COVID-19 syndrome, is characterized by multi-organ symptoms lasting 2+ months after initial COVID-19 virus infection. This review presents the current state of evidence for long COVID syndrome, including the global public health context, incidence, prevalence, cardiopulmonary sequelae, physical and mental symptoms, recovery time, prognosis, risk factors, rehospitalization rates, and the impact of vaccination on long COVID outcomes. Results are presented by clinically relevant subgroups. Overall, 10-35% of COVID survivors develop long COVID, with common symptoms including fatigue, dyspnea, chest pain, cough, depression, anxiety, post-traumatic stress disorder, memory loss, and difficulty concentrating. Delineating these issues will be crucial to inform appropriate post-pandemic health policy and protect the health of COVID-19 survivors, including potentially vulnerable or underrepresented groups. Directed to policymakers, health practitioners, and the general public, we provide recommendations and suggest avenues for future research with the larger goal of reducing harms associated with long COVID syndrome.
375	D372		N3C Consortium; RECOVER Consortium; Reese, Justin T.; Blau, Hannah; Casiraghi, Elena; Bergquist, Timothy; Loomba, Johanna J.; Callahan, Tiffany J.; Laraway, Bryan; Antonescu, Corneliu; Coleman, Ben; Gargano, Michael; Wilkins, Kenneth J.; Cappelletti, Luca; Fontana, Tommaso; Ammar, Nariman; Antony, Blessy; Murali, T. M.; Caufield, J. Harry; Karlebach, Guy; McMurry, Julie A.; Williams, Andrew; Moffitt, Richard; Banerjee, Jineta; Solomonides, Anthony E.; Davis, Hannah; Kostka, Kristin; Valentini, Giorgio; Sahner, David; Chute, Christopher G.; Madlock-Brown, Charisse; Haendel, Melissa A.; Robinson, Peter N.; Spratt, Heidi; Visweswaran, Shyam; Flack, Joseph Eugene; Yoo, Yun Jae; Gabriel, Davera; Alexander, G. Caleb; Mehta, Hemalkumar B.; Liu, Feifan; Miller, Robert T.; Wong, Rachel; Hill, Elaine L.; Thorpe, Lorna E.; Divers, Jasmin	Generalisable long COVID subtypes: Findings from the NIH N3C and RECOVER programmes	https://doi.org/10.1016/j.ebiom.2022.104413	Published	2023-01-01	Study	http://www.scopus.com/inward/record.url?scp=85144488606&partnerID=8YFLogxK	Background: Stratification of patients with post-acute sequelae of SARS-CoV-2 infection (PASC, or long COVID) would allow precision clinical management strategies. However, long COVID is incompletely understood and characterised by a wide range of manifestations that are difficult to analyse computationally. Additionally, the generalisability of machine learning classification of COVID-19 clinical outcomes has rarely been tested. Methods: We present a method for computationally modelling PASC phenotype data based on electronic healthcare records (EHRs) and for assessing pairwise phenotypic similarity between patients using semantic similarity. Our approach defines a nonlinear similarity function that maps from a feature space of phenotypic abnormalities to a matrix of pairwise patient similarity that can be clustered using unsupervised machine learning. Findings: We found six clusters of PASC patients, each with distinct profiles of phenotypic abnormalities, including clusters with distinct pulmonary, neuropsychiatric, and cardiovascular abnormalities, and a cluster associated with broad, severe manifestations and increased mortality. There was significant association of cluster membership with a range of pre-existing conditions and measures of severity during acute COVID-19. We assigned new patients from other healthcare centres to clusters by maximum semantic similarity to the original patients, and showed that the clusters were generalisable across different hospital systems. The increased mortality rate originally identified in one cluster was consistently observed in patients assigned to that cluster in other hospital systems. Interpretation: Semantic phenotypic clustering provides a foundation for assigning patients to stratified subgroups for natural history or therapy studies on PASC. Funding: NIH (TR002306/OT2HL161847-01/OD011883/HG010860), U.S.D.O.E. (DE-AC02-05CH11231), Donald A. Roux Family Fund at Jackson Laboratory, Marsico Family at CU Anschutz.
376	D373		Dotan, Arad; Shoenfeld, Yehuda	Editorial for “Post COVID-19 Syndrome in Patients with Asymptomatic/Mild Form”	https://doi.org/10.3390/pathogens12020167	Published	2023-02-01	Editorial	https://www.mdpi.com/2076-0817/12/2/167	Due to the unclear criteria for PCS prevention, diagnosis, management tactics, and contributing factors, Anna Malkova et al. conducted a review analysis of publications about COVID-19 in online databases from December 2019 to September 2021 [7]. This analysis looked at research on post-COVID-19 syndrome in patients with asymptomatic and mild SARS-CoV-2 infections. The inclusion criteria were asymptomatic or mild forms of COVID-19 diagnosed with a PCR test, the development of PCS symptoms a minimum of 1 month after, and the description of the developed PCS symptoms. Unfortunately, only a small number of published papers had described the type of PCS manifestations; thus, this study could not follow the PRISMA guidelines. Nevertheless, 11 studies were reviewed, which included the sum of 13,637 SARS-CoV-2-infected patients. PCS developed among approximately 30–60% of patients with asymptomatic or mild forms of COVID-19, and the most common symptoms were fatigue, shortness of breath, cough, anosmia, and ageusia. In addition, other signs of central nervous system damage were reported, including headaches and brain fog. Furthermore, a meta-analysis that defined PCS as ranging from 14 to 110 days after the viral infection estimated that 80% of the infected patients with SARS-CoV-2 developed one or more long-term symptoms [8]. Notably, females had a higher risk of developing PCS in comparison to males, with an approximately 1.25 ratio (on average, 60% of PCS patients were females). These results highlight the immense importance of further research in sufficient therapeutic agents for PCS manifestations. In addition, current evidence suggests that the severity and mortality of COVID-19 are higher in males than in females, whereas females are at an increased risk of COVID-19 reinfection and the development of PCS [9]. These conflicting risks between the severity and mortality of COVID-19 compared to the development of PCS could be explained by the generally more aggressive immune system of females [10,11]. Differences between the sexes are well studied in numerous infectious diseases, as well as in response to vaccinations [9,12]. Sex-specific expression patterns of proteins that mediate virus binding and entry and divergent reactions of the immune and endocrine systems, particularly the hypothalamic–pituitary–adrenal axis, in response to acute stress might explain the higher severity of COVID-19 in men [9]. Additionally, as enhanced immunoreactivity in females provides better protection against infections, it contributes to enhanced autoreactivity, thereby contributing to the induction of more autoimmune manifestations and diseases than in males, such as SLE, multiple sclerosis, rheumatoid arthritis, and numerous others [11,13,14]. Furthermore, COVID-19 has been shown to be associated with many autoantibodies, as well as autoimmune manifestations [10,15,16,17,18]. Thus, the PCS course of the disease may have at least a partial autoimmune factor; otherwise, it would not be logical that females would be at an elevated risk. Importantly, as the severity of COVID-19 is higher in males than in females, it could be assumed that the difference in the risk of PCS is not primarily due to the severity of the COVID-19 infection. The possible association between the described PCS symptoms and brain damage that occurs during an SARS-CoV-2 infection suggests that PCS patients commonly have a clinical presentation similar to that of encephalomyelitis/chronic fatigue syndrome (ME/CFS): severe fatigue, sleep disorders, cognitive impairments, and different manifestations of autonomic dysfunction exacerbated in physical exercise [8,10]. Furthermore, close to 20 distinct autoantibodies which target the GPCR of the nervous system and renin-angiotensin system-related molecules were found to be significantly associated with the clinical severity of COVID-19 [10]. Additionally, these autoantibodies were elevated in a subset of ME/CFS patients, specifically, the β2 adrenergic and M3 and M4 cholinergic receptor antibodies, as well as in other similar disorders [19,20,21]. Thus, autoimmune-mediated autonomic nervous system dysfunction, referred to as dysautonomia, may contribute to the disease course of PCS, which is similar to ME/CFS [10,21,22,23]. Notably, supervised and moderate physical exercise was shown to stabilize the autonomic nervous system. Thus, it may also be beneficial for PCS patients. Additionally, therapeutic options such as immunomodulatory and immunosuppressive therapy could benefit some PCS patients, whereas plasmapheresis and IVIG could be considered in severe cases [1,10,22,23] number: 2 publisher: Multidisciplinary Digital Publishing Institute
377	D374		Prasada Kabekkodu, Shama; Chakrabarty, Sanjiban; Jayaram, Pradyumna; Mallya, Sandeep; Thangaraj, Kumarasamy; Singh, Keshav K; Satyamoorthy, Kapaettu	Severe acute respiratory syndrome coronaviruses contributing to mitochondrial dysfunction: Implications for post-COVID complications	https://doi.org/10.1016/j.mito.2023.01.005	Published	2023-03-01	Review	https://www.sciencedirect.com/science/article/pii/S1567724923000053	Highlights •Mitochondria are vital cellular organelles linked to the production of ATP, biosynthesis of fatty acids, calcium signaling, regulation of cell cycle, apoptosis, and innate immune response among others. •Several RNA viruses target mitochondria leading to abnormal anterograde and retrograde grade signaling to facilitate growth and survival. •Mitochondria plays a role in controlling immunity against SARS-CoV-2, and its infection leads to alteration in both structure and function of the mitochondria. •SARS-CoV participates in stress response, apoptosis pathways and mitochondrial fusion in host cells. •Research concentrating on SARS-CoV-2 modulation of essential mitochondrial activities should close the gap in COVID-19 prevention and treatment. Abstract Mitochondria play a central role in oxidative phosphorylation (OXPHOS), bioenergetics linked with ATP production, fatty acids biosynthesis, calcium signaling, cell cycle regulation, apoptosis, and innate immune response. Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) infection manipulates the host cellular machinery for its survival and replication in the host cell. The infectiaon causes perturbed the cellular metabolism that favours viral replication leading to mitochondrial dysfunction and chronic inflammation. By localizing to the mitochondria, SARS CoV proteins increase reactive oxygen species (ROS) levels, perturbation of Ca2+ signaling, changes in mtDNA copy number, mitochondrial membrane potential (MMP), mitochondrial mass, and induction of mitophagy. These proteins also influence the fusion and fission kinetics, size, structure, and distribution of mitochondria in the infected host cells. This results in compromised bioenergetics, altered metabolism, and innate immune signaling, and hence can be a key player in determining the outcome of SARS-CoV infection. SARS-CoV infection contributes to stress and activates apoptotic pathways. This review summarizes how mitochondrial function and dynamics are affected by SARS-CoV and how the mitochondria-SARS-CoV interaction benefits viral survival and growth by evading innate host immunity. We also highlight how the SARS-CoV-mediated mitochondrial dysfunction contributes to post-COVID complications. Besides, a discussion on targeting virus-mitochondria interactions as a therapeutic strategy is presented.
378	D375		Levine, Kristin S.; Leonard, Hampton L.; Blauwendraat, Cornelis; Iwaki, Hirotaka; Johnson, Nicholas; Bandres-Ciga, Sara; Ferrucci, Luigi; Faghri, Faraz; Singleton, Andrew B.; Nalls, Mike A.	Virus exposure and neurodegenerative disease risk across national biobanks	https://doi.org/10.1016/j.neuron.2022.12.029	Published	2023-01-19	Study	https://www.cell.com/neuron/abstract/S0896-6273(22)01147-3	Highlights •Identified 45 pairs of viral exposures associated with increased risk of NDDs •Replicated 22 of the viral exposures/NDD pairings •Replicated the previously reported Epstein-Barr and multiple sclerosis association •Follow-up shows significantly elevated risk of NDD years after viral exposure Summary With recent findings connecting the Epstein-Barr virus to an increased risk of multiple sclerosis and growing concerns regarding the neurological impact of the coronavirus pandemic, we examined potential links between viral exposures and neurodegenerative disease risk. Using time series data from FinnGen for discovery and cross-sectional data from the UK Biobank for replication, we identified 45 viral exposures significantly associated with increased risk of neurodegenerative disease and replicated 22 of these associations. The largest effect association was between viral encephalitis exposure and Alzheimer’s disease. Influenza with pneumonia was significantly associated with five of the six neurodegenerative diseases studied. We also replicated the Epstein-Barr/multiple sclerosis association. Some of these exposures were associated with an increased risk of neurodegeneration up to 15 years after infection. As vaccines are currently available for some of the associated viruses, vaccination may be a way to reduce some risk of neurodegenerative disease. publisher: Elsevier PMID: 36669485
379	D376		Nepotchatykh, Evguenia; Caraus, Iurie; Elremaly, Wesam; Leveau, Corinne; Elbakry, Mohamed; Godbout, Christian; Rostami-Afshari, Bita; Petre, Diana; Khatami, Nasrin; Franco, Anita; Moreau, Alain	Circulating microRNA expression signatures accurately discriminate myalgic encephalomyelitis from fibromyalgia and comorbid conditions	https://doi.org/10.1038/s41598-023-28955-9	Published	2023-02-02	Study	https://www.nature.com/articles/s41598-023-28955-9	Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and fibromyalgia (FM) are two chronic complex diseases with overlapping symptoms affecting multiple systems and organs over time. Due to the absence of validated biomarkers and similarity in symptoms, both disorders are misdiagnosed, and the comorbidity of the two is often unrecognized. Our study aimed to investigate the expression profiles of 11 circulating miRNAs previously associated with ME/CFS pathogenesis in FM patients and individuals with a comorbid diagnosis of FM associated with ME/CFS (ME/CFS + FM), and matched sedentary healthy controls. Whether these 11 circulating miRNAs expression can differentiate between the two disorders was also examined. Our results highlight differential circulating miRNAs expression signatures between ME/CFS, FM and ME/CFS + FM, which also correlate to symptom severity between ME/CFS and ME/CFS + FM groups. We provided a prediction model, by using a machine-learning approach based on 11 circulating miRNAs levels, which can be used to discriminate between patients suffering from ME/CFS, FM and ME/CFS + FM. These 11 miRNAs are proposed as potential biomarkers for discriminating ME/CFS from FM. The results of this study demonstrate that ME/CFS and FM are two distinct illnesses, and we highlight the comorbidity between the two conditions. Proper diagnosis of patients suffering from ME/CFS, FM or ME/CFS + FM is crucial to elucidate the pathophysiology of both diseases, determine preventive measures, and establish more effective treatments.
380	D377		Samper-Pardo, M.; Oliván-Blázquez, B.; Magallón-Botaya, R.; Méndez-López, F.; Bartolomé-Moreno, C.; León-Herrera, S.	The emotional well-being of Long COVID patients in relation to their symptoms, social support and stigmatization in social and health services: a qualitative study	https://doi.org/10.1186/s12888-022-04497-8	Published	2023-01-25	Study	https://doi.org/10.1186/s12888-022-04497-8	Background Long COVID patients have experienced a decline in their quality of life due to, in part but not wholly, its negative emotional impact. Some of the most prevalent mental health symptoms presented by long COVID patients are anxiety, depression, and sleep disorders. As such, the need has arisen to analyze the personal experiences of these patients to understand how they are managing their daily lives while dealing with the condition. The objective of this study is to increase understanding about the emotional well-being of people diagnosed with long COVID. Methods A qualitative design was created and carried out using 35 patients, with 17 participants being interviewed individually and 18 of them taking part in two focus groups. The participating patients were recruited in November and December 2021 from Primary Health Care (PHC) centers in the city of Zaragoza (Northern Spain) and from the Association of Long COVID Patients in Aragon. The study topics were emotional well-being, social support networks, and experience of discrimination. All an inductive thematic content analyses were performed iteratively using NVivo software. Results The Long COVID patients identified low levels of self-perceived well-being due to their persistent symptoms, as well as limitations in their daily lives that had been persistent for many months. Suicidal thoughts were also mentioned by several patients. They referred to anguish and anxiety about the future as well as a fear of reinfection or relapse and returning to work. Many of the participants reported that they have sought the help of a mental health professional. Most participants identified discriminatory situations in health care. Conclusions It is necessary to continue researching the impact that Long COVID has had on mental health, as well as to provide Primary Health Care professionals with evidence that can guide the emotional treatment of these patients
381	D378		Kaufmann, Julia; Gould, Odette; Lloyd, Vett	Seeking Care for Long COVID: A Narrative Analysis of Canadian Experiences	https://doi.org/10.1177/23743735231151770	Published	2023-01-01	Study	https://doi.org/10.1177/23743735231151770	The goal of this study was to explore the experiences of individuals seeking care for long COVID-19 in the Canadian healthcare system. Recorded virtual interviews were carried out with 8 participants and narrative analysis was used to examine the stories produced and identify the central narratives that defined participants? experiences. Care-seeking experiences were characterized by (1) often debilitating multi-system symptoms for which little information about prognosis was available and no effective treatments were provided, (2) compounded by the frustration of trying to convince family, friends, and health care practitioners of the legitimacy of their illness, (3) access to medical care was severely limited by the global pandemic and associated higher thresholds for care, (4) like others suffering from complex, multi-system conditions, people with long COVID are often struggling with a health-care system ill-suited for dealing with long-term and possibly chronic conditions. To make system-level improvements to better serve those with chronic conditions, it is critical that we understand the care-seeking experiences of chronic illness patients, including the unique experiences of those with long COVID.
382	D379		N3C Consortium; RECOVER Consortium; Reese, Justin T.; Blau, Hannah; Casiraghi, Elena; Bergquist, Timothy; Loomba, Johanna J.; Callahan, Tiffany J.; Laraway, Bryan; Antonescu, Corneliu; Coleman, Ben; Gargano, Michael; Wilkins, Kenneth J.; Cappelletti, Luca; Fontana, Tommaso; Ammar, Nariman; Antony, Blessy; Murali, T. M.; Caufield, J. Harry; Karlebach, Guy; McMurry, Julie A.; Williams, Andrew; Moffitt, Richard; Banerjee, Jineta; Solomonides, Anthony E.; Davis, Hannah; Kostka, Kristin; Valentini, Giorgio; Sahner, David; Chute, Christopher G.; Madlock-Brown, Charisse; Haendel, Melissa A.; Robinson, Peter N.; Spratt, Heidi; Visweswaran, Shyam; Flack, Joseph Eugene; Yoo, Yun Jae; Gabriel, Davera; Alexander, G. Caleb; Mehta, Hemalkumar B.; Liu, Feifan; Miller, Robert T.; Wong, Rachel; Hill, Elaine L.; Thorpe, Lorna E.; Divers, Jasmin	Generalisable long COVID subtypes: Findings from the NIH N3C and RECOVER programmes	https://doi.org/10.1016/j.ebiom.2022.104413	Published	2023-01-01	Article	http://www.scopus.com/inward/record.url?scp=85144488606&partnerID=8YFLogxK	Background: Stratification of patients with post-acute sequelae of SARS-CoV-2 infection (PASC, or long COVID) would allow precision clinical management strategies. However, long COVID is incompletely understood and characterised by a wide range of manifestations that are difficult to analyse computationally. Additionally, the generalisability of machine learning classification of COVID-19 clinical outcomes has rarely been tested. Methods: We present a method for computationally modelling PASC phenotype data based on electronic healthcare records (EHRs) and for assessing pairwise phenotypic similarity between patients using semantic similarity. Our approach defines a nonlinear similarity function that maps from a feature space of phenotypic abnormalities to a matrix of pairwise patient similarity that can be clustered using unsupervised machine learning. Findings: We found six clusters of PASC patients, each with distinct profiles of phenotypic abnormalities, including clusters with distinct pulmonary, neuropsychiatric, and cardiovascular abnormalities, and a cluster associated with broad, severe manifestations and increased mortality. There was significant association of cluster membership with a range of pre-existing conditions and measures of severity during acute COVID-19. We assigned new patients from other healthcare centres to clusters by maximum semantic similarity to the original patients, and showed that the clusters were generalisable across different hospital systems. The increased mortality rate originally identified in one cluster was consistently observed in patients assigned to that cluster in other hospital systems. Interpretation: Semantic phenotypic clustering provides a foundation for assigning patients to stratified subgroups for natural history or therapy studies on PASC. Funding: NIH (TR002306/OT2HL161847-01/OD011883/HG010860), U.S.D.O.E. (DE-AC02-05CH11231), Donald A. Roux Family Fund at Jackson Laboratory, Marsico Family at CU Anschutz.
383	D380		Dotan, Arad; Shoenfeld, Yehuda	Editorial for “Post COVID-19 Syndrome in Patients with Asymptomatic/Mild Form”	https://doi.org/10.3390/pathogens12020167	Published	2023-02-01	Editorial	https://www.mdpi.com/2076-0817/12/2/167	The possible association between the described PCS symptoms and brain damage that occurs during an SARS-CoV-2 infection suggests that PCS patients commonly have a clinical presentation similar to that of encephalomyelitis/chronic fatigue syndrome (ME/CFS): severe fatigue, sleep disorders, cognitive impairments, and different manifestations of autonomic dysfunction exacerbated in physical exercise [8,10]. Furthermore, close to 20 distinct autoantibodies which target the GPCR of the nervous system and renin-angiotensin system-related molecules were found to be significantly associated with the clinical severity of COVID-19 [10]. Additionally, these autoantibodies were elevated in a subset of ME/CFS patients, specifically, the β2 adrenergic and M3 and M4 cholinergic receptor antibodies, as well as in other similar disorders [19,20,21]. Thus, autoimmune-mediated autonomic nervous system dysfunction, referred to as dysautonomia, may contribute to the disease course of PCS, which is similar to ME/CFS [10,21,22,23]. Notably, supervised and moderate physical exercise was shown to stabilize the autonomic nervous system. Thus, it may also be beneficial for PCS patients. Additionally, therapeutic options such as immunomodulatory and immunosuppressive therapy could benefit some PCS patients, whereas plasmapheresis and IVIG could be considered in severe cases [1,10,22,23]. number: 2 publisher: Multidisciplinary Digital Publishing Institute
384	D381		Kudoh, Ryohei; Komiya, Kosaku; Shinohara, Aya; Kageyama, Takaaki; Hiramatsu, Kazufumi; Kadota, Jun-ichi	Marital status and post-COVID-19 conditions	https://doi.org/10.1016/j.resinv.2023.01.001	Published	2023-03-01	Study	https://www.sciencedirect.com/science/article/pii/S2212534523000084	Although studies have investigated the factors associated with psychological post-COVID-19 symptoms, the impact of marital status on symptom development has not been fully determined. This study conducts a questionnaire survey to investigate the association between marital status and the proportion of patients with post-COVID-19 symptoms in 749 cases as valid responses. Depressive state and memory impairment were more frequently seen in the no-spouse group when each symptom was compared according to marital status. Particularly in individuals in the 40s who had minor COVID-19 illness, this trend was noted. Single patients with mild COVID-19 illness may need proactive psychological support.
385	D382		Cooper, Emily; Lound, Adam; Atchison, Christina J.; Whitaker, Matthew; Eccles, Caroline; Cooke, Graham S.; Elliott, Paul; Ward, Helen	Awareness and perceptions of Long COVID among people in the REACT programme: Early insights from a pilot interview study	https://doi.org/10.1371/journal.pone.0280943	Published	2023-01-26	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0280943	Background Long COVID is a patient-made term describing new or persistent symptoms experienced following SARS-CoV-2 infection. The Real-time Assessment of Community Transmission-Long COVID (REACT-LC) study aims to understand variation in experiences following infection, and to identify biological, social, and environmental factors associated with Long COVID. We undertook a pilot interview study to inform the design, recruitment approach, and topic guide for the REACT-LC qualitative study. We sought to gain initial insights into the experience and attribution of new or persistent symptoms and the awareness or perceived applicability of the term Long COVID. Methods People were invited to REACT-LC assessment centres if they had taken part in REACT, a random community-based prevalence study, and had a documented history of SARS-CoV-2 infection. We invited people from REACT-LC assessment centres who had reported experiencing persistent symptoms for more than 12 weeks to take part in an interview. We conducted face to face and online semi-structured interviews which were transcribed and analysed using Thematic Analysis. Results We interviewed 13 participants (6 female, 7 male, median age 31). Participants reported a wide variation in both new and persistent symptoms which were often fluctuating or unpredictable in nature. Some participants were confident about the link between their persistent symptoms and COVID-19; however, others were unclear about the underlying cause of symptoms or felt that the impact of public health measures (such as lockdowns) played a role. We found differences in awareness and perceived applicability of the term Long COVID. Conclusion This pilot has informed the design, recruitment approach and topic guide for our qualitative study. It offers preliminary insights into the varied experiences of people living with persistent symptoms including differences in symptom attribution and perceived applicability of the term Long COVID. This variation shows the value of recruiting from a nationally representative sample of participants who are experiencing persistent symptoms.
386	D383		Hitch, Danielle; Deféin, Elle; Lloyd, Melanie; Rasmussen, Bodil; Haines, Kimberley; Garnys, Eleanor	Beyond the case numbers: Social determinants and contextual factors in patient narratives of recovery from COVID-19	https://doi.org/10.1016/j.anzjph.2022.100002	Published	2023-02-01	Study	https://www.sciencedirect.com/science/article/pii/S1326020022000024	Objective This study aimed to describe and contextualise COVID-19 recovery from the perspective of patient-lived experience, to inform the evolving public health response to the pandemic. Methods Narrative interviews were completed with 37 adult Australians between six and 10 months following their COVID-19 diagnosis. Verbatim transcripts were analysed thematically and trustworthiness was supported by multiple strategies to ensure rigour. Results Three themes were identified: 1) trajectories of recovery, 2) back to ‘some sort of normal’ and 3) the importance of work. Resumed participation in activities of daily life, the influence of social determinants of health and the impact of contextual factors were prominent features in the recovery narratives. Conclusions The COVID-19 pandemic presents both challenges and opportunities for public health systems to formulate appropriate responses and make improvements. Behind the case numbers, patient narratives described the uncertainty, diversity and multiple pathways to recovery that need to inform public health policy. Implications for public health Looking beyond the case numbers reveals a complex landscape characterised by uncertainty, diversity and multiple pathways to recovery. The pandemic presents challenges and opportunities for public health in Australia and New Zealand, lived experience expertise is crucial to the formulation of an effective response.
387	D384		Marks, David F	Treatment Harms to Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome	https://doi.org/10.33140/ABBSR.06.01.01	Published	2023-01-19	Review	https://www.opastpublishers.com/open-access-articles/treatment-harms-to-patients-with-myalgic-encephalomyelitischronic-fatigue-syndrome.pdf	Despite evidence of physiological and cellular abnormalities in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS), the dominant therapeutic approach has been cognitive behaviour therapy (CBT) and graded exercise therapy (GET). Patients report distress and dissatisfaction following healthcare encounters based on GET and CBT. A significant body of research suggests that CBT and GET are harmful for many patients with ME/CFS. These findings raise ethical concerns and suggest that more collaborative working between scientists, therapists and patients would be helpful in making scientific progress in this difficult field.
388	D385		Herminghaus, Anna; Osuchowski, Marcin F.	How sepsis parallels and differs from COVID-19	https://doi.org/10.1016/j.ebiom.2022.104355	Published	2022-12-01	Article	https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00537-0/fulltext	There is a striking parallel between bacterial sepsis and COVID-19 phenotypes: the long-term sequelae. In both patient groups, the hospital discharge does not equal full recovery, but it is frequently followed by protracted, incapacitating consequences. While in bacterial sepsis, the post-discharge complications are referred to as post-sepsis syndrome and/or Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS), whereas, in SARS-CoV-2 infected patients, they are known as “long-COVID”. Long-COVID is not very different from post-sepsis syndrome. The most common persistent symptoms include fatigue, muscle pain, poor sleep, cardiac and cognitive disturbances (e.g. arrhythmias, short-term memory loss).7 Remarkably, a new, troubling difference exists: unlike in sepsis, long-COVID is frequently diagnosed in mildly SARS-CoV-2 infected patients (i.e. no hospital stay).8 The presence of the “long-phenotype” in both illnesses strongly indicates a severe and protracted deregulation of the immune-inflammatory (with clear immunosuppression features) and organ homeostasis. In the context of the slowly subsiding severe COVID-19 manifestations, we should re-focus on the long-term sequalae to evaluate a potential risk of increase in chronic debilitations in individuals, repeatedly exposed to the virus, as SARS-CoV-2 becomes seasonal/endemic. A comparison of the pre-clinical research in sepsis and COVID-19 brings several important lessons. A subjective (and largely undeserved) disappointment in pre-clinical bacterial sepsis studies has not been shared by COVID-19 modeling. On the contrary, despite logistic challenges, modeling of SARS-COV-2 infection has demonstrated its robust utility. One of the key advantages of pre-clinical COVID-19 research is the rich palette of species (including non-human primates), while >90% of bacterial sepsis studies are performed in mice and rats. A multi-species approach considerably enhances reproducibility and translatability concurrently reducing idiosyncratic findings. Animal COVID-19 models were well-predictive of both successes (e.g. anti-SARS-CoV-2 monoclonal antibodies, remdesivir, vaccines) and failures (e.g. hydroxychloroquine, lopinavir/ritonavir) of clinically-tested substances.9 Given intuitive drive for benefits, the latter should not be underappreciated; “negative” findings hold a valuable life-/time and cost-saving potential. Notably, anti-TNF treatment in a clinically relevant mouse model of cecal ligation and puncture sepsis predicted failure of that therapy three years before the failed clinical trials.10 A clear pre-clinical parallel for sepsis and COVID-19 models exist: they both can be employed to cover identical research niches: i) mild-to-severe disease phenotypes, ii) defined cohort targeting, iii) selected pathophysiological insights (e.g. compartmentalization of responses). Furthermore, long-term sequalae can be effectively investigated in both bacterial sepsis and COVID-19 models. Given that bacterial sepsis and COVID-19 parallels heavily intertwine with contrasts, it is critical to carefully dissect them into defined, manageable pieces of pathophysiological evidence (eg, by a given system, compartment) before any further therapeutic action is recommended. Equally important is that we avoid a reflexive transplantation of ready-to-use preconceptions (eg, “cytokine storm”) from an existing disease while dealing with any new entity. Well-designed pre-clinical studies can aid in a translationally valid verification of virtually any of the above concepts at the fraction of time/costs required for a clinical trial execution. publisher: Elsevier PMID: 36470836
389	D386		Xu, Wangzi; Cao, Yu; Wu, Lin	No Causal Effects Detected in COVID-19 and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Two Sample Mendelian Randomization Study	https://doi.org/10.3390/ijerph20032437	Published	2023-01-01	Study	https://www.mdpi.com/1660-4601/20/3/2437	New clinical observational studies suggest that Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a sequela of COVID-19 infection, but whether there is an exact causal relationship between COVID-19 and ME/CFS remains to be verified. To investigate whether infection with COVID-19 actually causes ME/CFS, this paper obtained pooled data from the Genome Wide Association Study (GWAS) and analyzed the relationship between COVID susceptibility, hospitalization and severity of COVID and ME/CFS, respectively, using two-sample Mendelian randomization (TSMR). TSMR analysis was performed by inverse variance weighting (IVW), weighted median method, MR-Egger regression and weighted mode and simple mode methods, respectively, and then the causal relationship between COVID-19 and ME/CFS was further evaluated by odds ratio (OR). Eventually, we found that COVID-19 severity, hospitalization and susceptibility were all not significantly correlated with ME/CFS (OR:1.000,1.000,1.000; 95% CI:0.999–1.000, 0.999–1.001, 0.998–1.002; p = 0.333, 0.862, 0.998, respectively). We found the results to be reliable after sensitivity analysis. These results suggested that SARS-CoV-2 infection may not significantly contribute to the elevated risk of developing CFS, and therefore ME/CFS may not be a sequela of COVID-19, but may simply present with symptoms similar to those of CFS after COVID-19 infection, and thus should be judged and differentiated by physicians when diagnosing and treating the disease in clinical practice.
390	D387		Pink, Isabell; Welte, Tobias	Risiko und Häufigkeit von Long-COVID	https://doi.org/10.1007/s11298-022-3104-5	Published	2023-02-01	Article	https://doi.org/10.1007/s11298-022-3104-5	Fazit für die Praxis Wahrscheinlich leiden 10-20% aller SARS-CoV-2-infizierten Patient*innen unter Long-COVID-Beschwerden. Die Beschwerden sind mannigfaltig und in der Intensität häufig im zeitlichen Verlauf regredient. Es gibt keine pathognomonischen Befunde oder laborchemischen Parameter für Long-COVID. Die häufigsten Beschwerden sind Fatigue, Dyspnoe, Anosmie und Ageusie sowie Kopfschmerzen, Gelenkschmerzen, Husten, kognitive Einschränkungen und Schlafstörungen. Vor allem das weibliche Geschlecht, > 5 Symptome während COVID-19 und ein höherer COVID-19-Schweregrad sind mögliche Prädiktoren für Long-COVID. Hospitalisierte Patientinnen und Patienten und solche mit massiver Erschöpfung und Belastungsintoleranz sollten einer stationären Rehabilitationsmaßnahme zugeführt werden. Patientinnen und Patienten mit kardiovaskulären Komplikationen während der Akuterkrankung oder Notwendigkeit einer intensivstationären Behandlung sollten sechs bis zwölf Wochen nach COVID-19 eine kardiologische Diagnostik erhalten, da das Risiko kardiovaskulärer Komplikationen für diese Patientengruppe unabhängig von Long-COVID auch ein Jahr nach der Infektion erhöht ist.
391	D388		Yan, Michael Zhipeng; Yang, Ming; Lai, Ching-Lung	Post-COVID-19 Syndrome Comprehensive Assessment: From Clinical Diagnosis to Imaging and Biochemical-Guided Diagnosis and Management	https://doi.org/10.3390/v15020533	Published	2023-02-01	Review	https://www.mdpi.com/1999-4915/15/2/533	The COVID-19 outbreak was first reported in 2019, causing massive morbidity and mortality. The majority of the COVID-19 patients survived and developed Post-COVID-19 Syndrome (PC19S) of varying severity. Currently, the diagnosis of PC19S is achieved through history and symptomatology that cannot be explained by an alternative diagnosis. However, the heavy reliance on subjective reporting is prone to reporting errors. Besides, there is no unified diagnostic assessment tool to classify the clinical severity of patients. This leads to significant difficulties when managing patients in terms of public resource utilization, clinical progression monitorization and rehabilitation plan formulation. This narrative review aims to review current evidence of diagnosis based on triple assessment: clinical symptomatology, biochemical analysis and imaging evidence. Further assessment tools can be developed based on triple assessment to monitor patient’s clinical progression, prognosis and intervals of monitoring. It also highlights the high-risk features of patients for closer and earlier monitoring. Rehabilitation programs and related clinical trials are evaluated; however, most of them focus on cardiorespiratory fitness and psychiatric presentations such as anxiety and depression. Further research is required to establish an objective and comprehensive assessment tool to facilitate clinical management and rehabilitation plans.
392	D389		Perlis, Roy H.; Lunz Trujillo, Kristin; Safarpour, Alauna; Santillana, Mauricio; Ognyanova, Katherine; Druckman, James; Lazer, David	Association of Post–COVID-19 Condition Symptoms and Employment Status	https://doi.org/10.1001/jamanetworkopen.2022.56152	Published	2023-02-15	Study	https://doi.org/10.1001/jamanetworkopen.2022.56152	Key Points Question Is post–COVID-19 condition (PCC), also known as long COVID, associated with differences in employment status that might suggest functional impairment? Findings Among 15 308 individuals with prior COVID-19 infection, those with PCC were less likely to be employed full-time and more likely to be unemployed. These differences persisted after adjustment for demographic differences between those with and without PCC. Meaning These findings suggest that individuals with PCC are less likely to be working and to be working full time. Abstract Importance Little is known about the functional correlates of post–COVID-19 condition (PCC), also known as long COVID, particularly the relevance of neurocognitive symptoms. Objective To characterize prevalence of unemployment among individuals who did, or did not, develop PCC after acute infection. Design, Setting, and Participants This survey study used data from 8 waves of a 50-state US nonprobability internet population-based survey of respondents aged 18 to 69 years conducted between February 2021 and July 2022. Main Outcomes and Measures The primary outcomes were self-reported current employment status and the presence of PCC, defined as report of continued symptoms at least 2 months beyond initial month of symptoms confirmed by a positive COVID-19 test. Results The cohort included 15 308 survey respondents with test-confirmed COVID-19 at least 2 months prior, of whom 2236 (14.6%) reported PCC symptoms, including 1027 of 2236 (45.9%) reporting either brain fog or impaired memory. The mean (SD) age was 38.8 (13.5) years; 9679 respondents (63.2%) identified as women and 10 720 (70.0%) were White. Overall, 1418 of 15 308 respondents (9.3%) reported being unemployed, including 276 of 2236 (12.3%) of those with PCC and 1142 of 13 071 (8.7%) of those without PCC; 8229 respondents (53.8%) worked full-time, including 1017 (45.5%) of those with PCC and 7212 (55.2%) without PCC. In survey-weighted regression models excluding retired respondents, the presence of PCC was associated with a lower likelihood of working full-time (odds ratio [OR], 0.71 [95% CI, 0.63-0.80]; adjusted OR, 0.84 [95% CI, 0.74-0.96]) and with a higher likelihood of being unemployed (OR, 1.45 [95% CI, 1.22-1.73]; adjusted OR, 1.23 [95% CI, 1.02-1.48]). The presence of any cognitive symptom was associated with lower likelihood of working full time (OR, 0.70 [95% CI, 0.56-0.88]; adjusted OR, 0.75 [95% CI, 0.59-0.84]). Conclusions and Relevance PCC was associated with a greater likelihood of unemployment and lesser likelihood of working full time in adjusted models. The presence of cognitive symptoms was associated with diminished likelihood of working full time. These results underscore the importance of developing strategies to treat and manage PCC symptoms.
393	D390		Davisse-Paturet, Camille; Orri, Massimiliano; Legleye, Stéphane; Florence, Aline-Marie; Hazo, Jean-Baptiste; Warszawski, Josiane; Falissard, Bruno; Geoffroy, Marie-Claude; Melchior, Maria; Rouquette, Alexandra; Group, the EPICOV study	Suicidal ideation following self-reported COVID-19-like symptoms or serology-confirmed SARS-CoV-2 infection in France: A propensity score weighted analysis from a cohort study	https://doi.org/10.1371/journal.pmed.1004171	Published	2023-02-14	Study	https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004171	Background A higher risk of suicidal ideation associated with self-report of Coronavirus Disease 2019 (COVID-19)-like symptoms or COVID-19 infection has been observed in cross-sectional studies, but evidence from longitudinal studies remains limited. The aims of this study were 2-fold: (1) to explore if self-reported COVID-19-like symptoms in 2020 were associated with suicidal ideation in 2021; (2) to explore if the association also existed when using a biological marker of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in 2020. Methods and findings A total of 52,050 participants from the French EpiCov cohort were included (median follow-up time = 13.7 months). In terms of demographics, 53.84% were women, 60.92% were over 45 years old, 82.01% were born in mainland France from parents born in mainland France, and 59.38% completed high school. COVID-19-like symptoms were defined as participant report of a sudden loss of taste/smell or fever alongside cough, shortness of breath, or chest oppression, between February and November 2020. Symptoms were self-reported at baseline in May 2020 and at the first follow-up in Autumn 2020. Serology-confirmed SARS-CoV-2 infection in 2020 was derived from Spike protein ELISA test screening in dried-blood-spot samples. Samples were collected from October 2020 to March 2021, with 94.4% collected in 2020. Suicidal ideation since December 2020 was self-reported at the second follow-up in Summer 2021. Associations of self-reported COVID-19-like symptoms and serology-confirmed SARS-CoV-2 infection in 2020 with suicidal ideation in 2021 were ascertained using modified Poisson regression models, weighted by inverse probability weights computed from propensity scores. Among the 52,050 participants, 1.68% [1.54% to 1.82%] reported suicidal ideation in 2021, 9.57% [9.24% to 9.90%] had a serology-confirmed SARS-CoV-2 infection in 2020, and 13.23% [12.86% to 13.61%] reported COVID-19-like symptoms in 2020. Self-reported COVID-19-like symptoms in 2020 were associated with higher risks of later suicidal ideation in 2021 (Relative Riskipw [95% CI] = 1.43 [1.20 to 1.69]), while serology-confirmed SARS-CoV-2 infection in 2020 was not (RRipw = 0.89 [0.70 to 1.13]). Limitations of this study include the use of a single question to assess suicidal ideation, the use of self-reported history of mental health disorders, and limited generalizability due to attrition bias. Conclusions Self-reported COVID-19-like symptoms in 2020, but not serology-confirmed SARS-CoV-2 infection in 2020, were associated with a higher risk of subsequent suicidal ideation in 2021. The exact role of SARS-CoV-2 infection with respect to suicide risk has yet to be clarified. Including mental health resources in COVID-19-related settings could encourage symptomatic individuals to care for their mental health and limit suicidal ideation to emerge or worsen.
394	D391		Iwasaki, Akiko; Putrino, David	Why we need a deeper understanding of the pathophysiology of long COVID	https://doi.org/10.1016/S1473-3099(23)00053-1	Published	2023-02-14	Article	https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(23)00053-1/fulltext	The main disease hypotheses for the root causes of long COVID include viral persistence (infectious virus, viral RNA, or viral proteins), autoimmunity triggered by the infection, reactivation of latent viruses, and inflammation-triggered chronic changes leading to tissue dysfunction and damage (figure). There is growing and compelling evidence that SARS-CoV-2 infects and produces its RNA and proteins in a wide range of cell types in tissues, including the gastrointestinal, respiratory, cardiovascular, lymphoid, endocrine, urogenital, ocular, skin, muscular, and peripheral nervous system and CNS tissues.2 Circulating spike proteins are observed in 60% of patients with long COVID between 2 and 12 months after infection.3 Although the presence of viral RNA and proteins do not necessarily indicate persistent infection, viral RNA can trigger innate immune responses and viral proteins might cause tissue damage and stimulate persistent activation of lymphocytes, which lead to chronic inflammation. In people with long COVID, assessment of autoantibodies to human exoproteome using rapid extracellular antigen profiling revealed no significant differences from people without long COVID.4 However, autoantibodies to intracellular antigens5 or autoreactive T cells might have a role in long COVID. There is also emerging evidence for latent herpesviruses reactivation in people with long COVID. Reactivation of latent Epstein-Barr virus, but not the acute mononucleosis infection, is found in people with long COVID,4, 6 and Epstein-Barr virus viraemia at the time of acute COVID is predictive for long COVID.5 Local inflammatory response to SARS-CoV-2 in one organ can cause lasting alterations in distant tissues and organs. In a mouse model, even mild lung-restricted COVID-19 (in which the infectious virus became undetectable within a week) was found to induce prolonged changes in the CNS, including microglial activation, oligodendrocyte loss, and reduced myelination, for up to 7 weeks after infection.7 Beyond these potential root causes, many secondary pathological changes have been observed in people with long COVID, including the formation of micro-clots and platelet activation,8 reduced cortisol,4, 5 and mitochondrial dysfunction.9 Despite the multifactorial pathogenesis, available data show that long COVID is an organic post-acute infection syndrome (PAIS) with clear physiological dysfunction that is often not consistently apparent using standard medical diagnostic tests. This discrepancy highlights the need for a new generation of more sensitive testing procedures for people with PAIS. Although it is not known whether pre-existing psychological diagnoses might influence the risk of long COVID (eg, by affecting the host endocrine and immune systems), it is neither productive nor clinically or scientifically valid to classify long COVID as a psychosomatic condition. As avoiding COVID-19 becomes increasingly difficult, we argue that deep biological analyses will identify biomarkers for long COVID and possibly identify distinct endotypes driven by different root causes so that the risk of contracting long COVID is better defined. Biomarker identification will not only be crucial for identifying predisposing factors but also allow us to implement safer, evidence-based policies. Similarly, molecular, cellular, and physiological analyses will inform precision interventions that target the root causes of each long COVID endotype. For example, persistent viral infection could be targeted by antivirals; long COVID driven by autoimmune disease could be treated using monoclonal antibodies that target lymphocytes or drugs that block cytokines and cytokine signalling; and, if the reactivation of herpesviruses contributes to disease, targeting such viruses using antivirals or vaccines could be considered. Diagnostic criteria considering the root causes to prevent and treat long COVID will require large longitudinal studies. If therapeutic targeting of root causes is not feasible, the downstream pathological changes of long COVID could still be treated. publisher: Elsevier
395	D392		Suran, Melissa	Long COVID Linked With Unemployment in New Analysis	https://doi.org/10.1001/jama.2023.0157	Published	2023-02-15	Editorial	https://doi.org/10.1001/jama.2023.0157	Although COVID-19’s designation as a national and public health emergency is nearing its end in the US, post–COVID-19 condition, also known as long COVID, seems to be sticking around. Now, new research adds to evidence that long COVID may be affecting the workforce. A survey-based study of more than 15 000 people with prior COVID-19, published in JAMA Network Open, found that those with self-reported long COVID symptoms were more likely to be unemployed.The employment research builds on an October study focused on the prevalence of long COVID. Both analyses used the same US data set derived from an internet survey called the COVID States Project. Despite its name, the survey casts a wide net of questions related to behavior and beliefs, including many items unrelated to COVID-19. Respondents are also asked about their political stances and social networks, for example. This means the survey doesn’t introduce bias about the illness, Roy Perlis, MD, MSc, lead author of both studies, said in an interview with JAMA.
396	D393		Pike, Jamison	Direct Medical Costs Associated With Post–COVID-19 Conditions Among Privately Insured Children and Adults	https://doi.org/10.5888/pcd20.220292	Published	2023-02-09	Study	https://www.cdc.gov/pcd/issues/2023/22_0292.htm	Introduction SARS-CoV-2, the virus that causes COVID-19, has caused more than 100.2 million infections and more than 1 million deaths in the US as of November 2022, yet information on the economic burden associated with post–COVID-19 conditions is lacking. We estimated the possible economic burden associated with post–COVID-19 conditions by comparing direct medical costs among patients younger than 65 years with and without COVID-19 in the postacute period. Methods Commercially insured children and adults with a COVID-19 diagnosis (cases) during April–August 2020 were matched to those without COVID-19 (controls) on a 1:4 ratio. Direct medical costs represented 1-, 3-, and 6-month total expenditures per person starting 31 days after the diagnosis date. We used a 2-part model to evaluate cost differences among individuals with and without COVID-19, adjusted for patient characteristics. Results Costs were higher among cases compared with controls. Direct medical costs among child cases were 1.82, 1.72, and 1.70 times higher than controls over 1, 3, and 6 months, respectively. Direct medical costs among adult cases were 1.69, 1.54, and 1.46 times higher than costs among controls over 1, 3, and 6 months, respectively. Relative differences in costs were highest among adults aged 50 to 64 years. In a subset of people with COVID-19, costs were higher among hospitalized cases compared with nonhospitalized cases. Conclusion Our findings suggest a considerable economic burden of COVID-19 even after the resolution of acute illness, highlighting the importance of prevention and mitigation measures to reduce the economic impact of COVID-19 on the US health care system.
397	D394		Ferrara, Francesco; Zovi, Andrea; Masi, Marta; Langella, Roberto; Trama, Ugo; Boccellino, Mariarosaria; Vitiello, Antonio	Long COVID could become a widespread post-pandemic disease? A debate on the organs most affected	https://doi.org/10.1007/s00210-023-02417-5	Published	2023-02-11	Article	https://doi.org/10.1007/s00210-023-02417-5	Long COVID is an emerging problem in the current health care scenario. It is a syndrome with common symptoms of shortness of breath, fatigue, cognitive dysfunction, and other conditions that have a high impact on daily life. They are fluctuating or relapsing states that occur in patients with a history of SARS-CoV-2 infection for at least 2 months. They are usually conditions that at 3 months after onset cannot be explained by an alternative diagnosis. Currently very little is known about this syndrome. A thorough review of the literature highlights that the cause is attributable to deposits of tau protein. Massive phosphorylation of tau protein in response to SARS-CoV-2 infection occurred in brain samples from autopsies of people previously affected with COVID-19. The neurological disorders resulting from this clinical condition are termed tauopathies and can give different pathological symptoms depending on the involved anatomical region of the brain. Peripheral small-fiber neuropathies are also evident among patients with Long COVID leading to fatigue, which is the main symptom of this syndrome. Certainly more research studies could confirm the association between tau protein and Long COVID by defining the main role of tau protein as a biomarker for the diagnosis of this syndrome that is widespread in the post-pandemic period.
398	D395		Epsi, Nusrat J.; Powers, John H.; Lindholm, David A.; Mende, Katrin; Malloy, Allison; Ganesan, Anuradha; Huprikar, Nikhil; Lalani, Tahaniyat; Smith, Alfred; Mody, Rupal M.; Jones, Milissa U.; Bazan, Samantha E.; Colombo, Rhonda E.; Colombo, Christopher J.; Ewers, Evan C.; Larson, Derek T.; Berjohn, Catherine M.; Maldonado, Carlos J.; Blair, Paul W.; Chenoweth, Josh; Saunders, David L.; Livezey, Jeffrey; Maves, Ryan C.; Edwards, Margaret Sanchez; Rozman, Julia S.; Simons, Mark P.; Tribble, David R.; Agan, Brian K.; Burgess, Timothy H.; Pollett, Simon D.; Group, for the EPICC COVID-19 Cohort Study	A machine learning approach identifies distinct early-symptom cluster phenotypes which correlate with hospitalization, failure to return to activities, and prolonged COVID-19 symptoms	https://doi.org/10.1371/journal.pone.0281272	Published	2023-02-09	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0281272	Background Accurate COVID-19 prognosis is a critical aspect of acute and long-term clinical management. We identified discrete clusters of early stage-symptoms which may delineate groups with distinct disease severity phenotypes, including risk of developing long-term symptoms and associated inflammatory profiles. Methods 1,273 SARS-CoV-2 positive U.S. Military Health System beneficiaries with quantitative symptom scores (FLU-PRO Plus) were included in this analysis. We employed machine-learning approaches to identify symptom clusters and compared risk of hospitalization, long-term symptoms, as well as peak CRP and IL-6 concentrations. Results We identified three distinct clusters of participants based on their FLU-PRO Plus symptoms: cluster 1 (“Nasal cluster”) is highly correlated with reporting runny/stuffy nose and sneezing, cluster 2 (“Sensory cluster”) is highly correlated with loss of smell or taste, and cluster 3 (“Respiratory/Systemic cluster”) is highly correlated with the respiratory (cough, trouble breathing, among others) and systemic (body aches, chills, among others) domain symptoms. Participants in the Respiratory/Systemic cluster were twice as likely as those in the Nasal cluster to have been hospitalized, and 1.5 times as likely to report that they had not returned-to-activities, which remained significant after controlling for confounding covariates (P < 0.01). Respiratory/Systemic and Sensory clusters were more likely to have symptoms at six-months post-symptom-onset (P = 0.03). We observed higher peak CRP and IL-6 in the Respiratory/Systemic cluster (P < 0.01). Conclusions We identified early symptom profiles potentially associated with hospitalization, return-to-activities, long-term symptoms, and inflammatory profiles. These findings may assist in patient prognosis, including prediction of long COVID risk.
399	D396		Gottschalk, Carl Gunnar; Peterson, Daniel; Armstrong, Jan; Knox, Konstance; Roy, Avik	Potential molecular mechanisms of chronic fatigue in long haul COVID and other viral diseases	https://doi.org/10.1186/s13027-023-00485-z	Published	2023-02-07	Review	https://doi.org/10.1186/s13027-023-00485-z	Historically, COVID-19 emerges as one of the most devastating diseases of humankind, which creates an unmanageable health crisis worldwide. Until now, this disease costs millions of lives and continues to paralyze human civilization's economy and social growth, leaving an enduring damage that will take an exceptionally long time to repair. While a majority of infected patients survive after mild to moderate reactions after two to six weeks, a growing population of patients suffers for months with severe and prolonged symptoms of fatigue, depression, and anxiety. These patients are no less than 10% of total COVID-19 infected individuals with distinctive chronic clinical symptomatology, collectively termed post-acute sequelae of COVID-19 (PASC) or more commonly long-haul COVID. Interestingly, Long-haul COVID and many debilitating viral diseases display a similar range of clinical symptoms of muscle fatigue, dizziness, depression, and chronic inflammation. In our current hypothesis-driven review article, we attempt to discuss the molecular mechanism of muscle fatigue in long-haul COVID, and other viral diseases as caused by HHV6, Powassan, Epstein–Barr virus (EBV), and HIV. We also discuss the pathological resemblance of virus-triggered muscle fatigue with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
400	D397		Zhang, Yongkang; Hu, Hui; Fokaidis, Vasilios; V, Colby Lewis; Xu, Jie; Zang, Chengxi; Xu, Zhenxing; Wang, Fei; Koropsak, Michael; Bian, Jiang; Hall, Jaclyn; Rothman, Russell L.; Shenkman, Elizabeth A.; Wei, Wei-Qi; Weiner, Mark G.; Carton, Thomas W.; Kaushal, Rainu	Identifying environmental risk factors for post-acute sequelae of SARS-CoV-2 infection: An EHR-based cohort study from the recover program	https://doi.org/10.1016/j.envadv.2023.100352	Published	2023-04-01	Study	https://www.sciencedirect.com/science/article/pii/S2666765723000121	Highlights •The first study to identify environmental risk factors for Long-COVID. •Comprehensive COVID-19 patient data linked with environmental characteristics. •Nearly 200 exposome factors across three domains were examined. •Air pollutions and neighborhood deprivation are important risk factors. •Significant heterogeneity of risk factors across geographic regions. Abstract Post-acute sequelae of SARS-CoV-2 infection (PASC) affects a wide range of organ systems among a large proportion of patients with SARS-CoV-2 infection. Although studies have identified a broad set of patient-level risk factors for PASC, little is known about the association between “exposome”—the totality of environmental exposures and the risk of PASC. Using electronic health data of patients with COVID-19 from two large clinical research networks in New York City and Florida, we identified environmental risk factors for 23 PASC symptoms and conditions from nearly 200 exposome factors. The three domains of exposome include natural environment, built environment, and social environment. We conducted a two-phase environment-wide association study. In Phase 1, we ran a mixed effects logistic regression with 5-digit ZIP Code tabulation area (ZCTA5) random intercepts for each PASC outcome and each exposome factor, adjusting for a comprehensive set of patient-level confounders. In Phase 2, we ran a mixed effects logistic regression for each PASC outcome including all significant (false positive discovery adjusted p-value < 0.05) exposome characteristics identified from Phase I and adjusting for confounders. We identified air toxicants (e.g., methyl methacrylate), particulate matter (PM2.5) compositions (e.g., ammonium), neighborhood deprivation, and built environment (e.g., food access) that were associated with increased risk of PASC conditions related to nervous, blood, circulatory, endocrine, and other organ systems. Specific environmental risk factors for each PASC condition and symptom were different across the New York City area and Florida. Future research is warranted to extend the analyses to other regions and examine more granular exposome characteristics to inform public health efforts to help patients recover from SARS-CoV-2 infection.
401	D398		Wang, Siwen; Li, Yanping; Yue, Yiyang; Yuan, Changzheng; Kang, Jae Hee; Chavarro, Jorge E.; Bhupathiraju, Shilpa N.; Roberts, Andrea L.	Adherence to Healthy Lifestyle Prior to Infection and Risk of Post–COVID-19 Condition	https://doi.org/10.1001/jamainternmed.2022.6555	Published	2023-02-06	Study	https://doi.org/10.1001/jamainternmed.2022.6555	Question Is a healthy lifestyle (healthy body mass index, never smoking, high-quality diet, moderate alcohol intake, regular exercise, and adequate sleep) prior to SARS-CoV-2 infection protective of post–COVID-19 condition (PCC)? Findings In this prospective cohort study of 1981 women who reported a positive SARS-CoV-2 test from April 2020 to November 2021, adherence to a healthy lifestyle prior to infection was inversely associated with risk of PCC in a dose-dependent manner. Compared with those who did not have any healthy lifestyle factors, those with 5 or 6 had half the risk of PCC. Meaning Preinfection healthy lifestyle was associated with a substantially decreased risk of PCC. Abstract Importance Few modifiable risk factors for post–COVID-19 condition (PCC) have been identified. Objective To investigate the association between healthy lifestyle factors prior to SARS-CoV-2 infection and risk of PCC. Design, Setting, and Participants In this prospective cohort study, 32 249 women in the Nurses’ Health Study II cohort reported preinfection lifestyle habits in 2015 and 2017. Healthy lifestyle factors included healthy body mass index (BMI, 18.5-24.9; calculated as weight in kilograms divided by height in meters squared), never smoking, at least 150 minutes per week of moderate to vigorous physical activity, moderate alcohol intake (5 to 15 g/d), high diet quality (upper 40% of Alternate Healthy Eating Index–2010 score), and adequate sleep (7 to 9 h/d). Main Outcomes and Measures SARS-CoV-2 infection (confirmed by test) and PCC (at least 4 weeks of symptoms) were self-reported on 7 periodic surveys administered from April 2020 to November 2021. Among participants with SARS-CoV-2 infection, the relative risk (RR) of PCC in association with the number of healthy lifestyle factors (0 to 6) was estimated using Poisson regression and adjusting for demographic factors and comorbidities. Results A total of 1981 women with a positive SARS-CoV-2 test over 19 months of follow-up were documented. Among those participants, mean age was 64.7 years (SD, 4.6; range, 55-75); 97.4% (n = 1929) were White; and 42.8% (n = 848) were active health care workers. Among these, 871 (44.0%) developed PCC. Healthy lifestyle was associated with lower risk of PCC in a dose-dependent manner. Compared with women without any healthy lifestyle factors, those with 5 to 6 had 49% lower risk (RR, 0.51; 95% CI, 0.33-0.78) of PCC. In a model mutually adjusted for all lifestyle factors, BMI and sleep were independently associated with risk of PCC (BMI, 18.5-24.9 vs others, RR, 0.85; 95% CI, 0.73-1.00, P = .046; sleep, 7-9 h/d vs others, RR, 0.83; 95% CI, 0.72-0.95, P = .008). If these associations were causal, 36.0% of PCC cases would have been prevented if all participants had 5 to 6 healthy lifestyle factors (population attributable risk percentage, 36.0%; 95% CI, 14.1%-52.7%). Results were comparable when PCC was defined as symptoms of at least 2-month duration or having ongoing symptoms at the time of PCC assessment. Conclusions and Relevance In this prospective cohort study, pre-infection healthy lifestyle was associated with a substantially lower risk of PCC. Future research should investigate whether lifestyle interventions may reduce risk of developing PCC or mitigate symptoms among individuals with PCC or possibly other postinfection syndromes.
402	D399		de Andrade, Evandro Carvalho; Pinheiro, Luana Ibiapina C. C.; Pinheiro, Plácido Rogério; Nunes, Luciano Comin; Pinheiro, Mirian Calíope Dantas; Pereira, Maria Lúcia Duarte; de Abreu, Wilson Correia; Filho, Raimir Holanda; Simão Filho, Marum; Pinheiro, Pedro Gabriel C. D.; Nunes, Rafael Espíndola Comin	Hybrid model for early identification post-Covid-19 sequelae	https://doi.org/10.1007/s12652-023-04555-3	Published	2023-02-06	Study	https://doi.org/10.1007/s12652-023-04555-3	Artificial Intelligence techniques based on Machine Learning algorithms, Neural Networks and Naïve Bayes can optimise the diagnostic process of the SARS-CoV-2 or Covid-19. The most significant help of these techniques is analysing data recorded by health professionals when treating patients with this disease. Health professionals' more specific focus is due to the reduction in the number of observable signs and symptoms, ranging from an acute respiratory condition to severe pneumonia, showing an efficient form of attribute engineering. It is important to note that the clinical diagnosis can vary from asymptomatic to extremely harsh conditions. About 80% of patients with Covid-19 may be asymptomatic or have few symptoms. Approximately 20% of the detected cases require hospital care because they have difficulty breathing, of which about 5% may require ventilatory support in the Intensive Care Unit. Also, the present study proposes a hybrid approach model, structured in the composition of Artificial Intelligence techniques, using Machine Learning algorithms, associated with multicriteria methods of decision support based on the Verbal Decision Analysis methodology, aiming at the discovery of knowledge, as well as exploring the predictive power of specific data in this study, to optimise the diagnostic models of Covid-19. Thus, the model will provide greater accuracy to the diagnosis sought through clinical observation.
403	D400		Tan, Hao; Liu, Jiayan; Zeng, Fanrui	China needs a scientific long COVID recovery-support platform	https://doi.org/10.1016/S0140-6736(23)00138-1	Published	2023-02-04	Article	https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00138-1/fulltext	Post-COVID-19 condition (also known as long COVID) emerged as a major public health problem in the post-pandemic era.1 Timely and sufficient information guidance and support are crucial for an effective response to long COVID. With China likely to end its zero-COVID strategy in the future,2, 3 it seems inevitable that long COVID will become a major concern for China. According to the longest follow-up study so far, more than 55% of COVID-19 patients in Wuhan (China) still have symptoms 2 years later.4 As the most populous country in the world, China is at acute risk of national crisis on account of long COVID. However, there is currently no publicly available authoritative platform to explain long COVID symptoms in China, and the public does not have access to reliable scientific information, leading to little awareness and scientific knowledge of long COVID. The absence of authoritative sources of information or official, well-informed platforms to support patients with long COVID could prolong and exacerbate the symptoms of long COVID and contribute to psychological distress due to the absence of timely guidance. In addition, China has insufficient medical resources (the number of physicians in China is only 0·198% of the total population, which is nearly half the proportion in high-income countries, according to World Bank data in 2017). The dearth of medical resources and absence of an official recovery-support platform could lead to patients with long COVID not receiving timely health guidance during recovery, and the Government and related workers being unable to respond effectively to long COVID.
404	D401		Loreche, Arianna Maever; Pepito, Veincent Christian F.; Dayrit, Manuel M.	Long Covid: A call for global action	https://doi.org/10.1002/puh2.69	Published	1905-07-15	Article	https://onlinelibrary.wiley.com/doi/abs/10.1002/puh2.69	The COVID-19 pandemic has resulted in another global health crisis with millions of individuals with Long Covid experiencing disability, worse health-related quality of life, and productivity and income losses. Despite its impact on population health outcomes, health systems, and the economy, there remains a need for a global consensus on its standard definition, diagnostic approaches, and treatment plans to manage symptoms. In many low- and middle-income countries (LMICs), there are limited published estimates on Long Covid, limited studies on its diagnostics and therapeutics, and limited media and news coverage. We advocate for a global action plan and necessary investments on Long Covid research and treatment, meaningful involvement of patients and cooperation between high-income countries and LMICs, stronger and more effective public health communication surrounding the risks of Long Covid, and support toward financial risk protection as advocated by Universal Health Care.
405	D402		Russell, Clark D.; Lone, Nazir I.; Baillie, J. Kenneth	Comorbidities, multimorbidity and COVID-19	https://doi.org/10.1038/s41591-022-02156-9	Published	2023-02-01	Review	https://www.nature.com/articles/s41591-022-02156-9	The influence of comorbidities on COVID-19 outcomes has been recognized since the earliest days of the pandemic. But establishing causality and determining underlying mechanisms and clinical implications has been challenging—owing to the multitude of confounding factors and patient variability. Several distinct pathological mechanisms, not active in every patient, determine health outcomes in the three different phases of COVID-19—from the initial viral replication phase to inflammatory lung injury and post-acute sequelae. Specific comorbidities (and overall multimorbidity) can either exacerbate these pathological mechanisms or reduce the patient’s tolerance to organ injury. In this Review, we consider the impact of specific comorbidities, and overall multimorbidity, on the three mechanistically distinct phases of COVID-19, and we discuss the utility of host genetics as a route to causal inference by eliminating many sources of confounding. Continued research into the mechanisms of disease-state interactions will be crucial to inform stratification of therapeutic approaches and improve outcomes for patients.
406	D403		National COVID-19 Health and Research Advisory Committee	Advice 29: Update on Long COVID		Published	2022-04-26	Recommendations and Reports	https://www.nhmrc.gov.au/sites/default/files/2023-02/NCHRAC-Advice-29-Update-on-Long-COVID.pdf	Clinical Care • Long COVID is a complex condition that can impact multiple organs; people with the condition can display a variety of signs and symptoms. • In addition to physical symptoms, there is evidence that the experience of continued poor health has a clinically observable psychological impact in those with Long COVID. • Consensus on a case definition for Long COVID is required to ensure consistent and appropriate diagnosis and treatment for individuals. • Development of a case definition should occur in collaboration with people with lived experience of Long COVID to ensure the criteria are meaningful and relevant to the Australian context.
407	D404		Lafkas, Sara McPhee; Christensen, Marin; Madsen, Susan R.	The Impact of COVID-19 on Women and Work: Career Advancement Challenges	https://doi.org/10.3390/merits3010011	Published	2023-03-01	Study	https://www.mdpi.com/2673-8104/3/1/11	The COVID-19 pandemic upended countless lives all over the world. Considerable research has shown that women’s career progression has been more negatively impacted by the pandemic than men’s, especially in the wake of school closures and increased childcare responsibilities. In order to understand more deeply the impact of the pandemic on women’s careers, a large mixed-method survey was conducted in Utah, a western state in the United States. This article reports on the responses of 2564 respondents to one of three open-ended questions taken from the overall survey, namely: “How has the pandemic impacted your career advancement experiences and opportunities over the short term and longer term?” The article frames the findings of this question by outlining workplace conditions and structures that contributed to women not advancing prior to the pandemic and applies the lenses of identity theory and systems psychodynamic theory to illustrate tendencies for workers and organizations to maintain the gendered dynamics that impede women’s career advancement. Findings included 59.1 percent of respondents who described a negative effect on their career advancement caused by the pandemic. Overarching themes and sub-themes were identified from these negative effects. Overarching themes included: (1) “Everything is on hold”; (2) “Lost or relinquished opportunity”; (3) “Reevaluation of Career”; and (4) “Experiences by Characteristics.” The latter theme highlighted unique experiences women faced versus men and manifested the gendered dynamics identified by identity and psychodynamic theories. Findings highlighted the importance of making workplace changes such as more flexible work and/or hybrid work arrangements, improved leave policies, the provision of childcare and other support services, and government policies that eliminate gendered barriers to women’s career advancement.
408	D405		Plebani, Mario	COVID-19 and Biomarkers: The Contribution of the Journal	https://doi.org/10.3390/jcm12051853	Published	2023-01-01	Article	https://www.mdpi.com/2077-0383/12/5/1853	Three years after coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization (WHO), several features of the pathogenesis and innate immune response to SARS-CoV-2 (severe acute respiratory syndrome coronavirus disease 2) have now been clarified. Several studies have highlighted the crucial interplay among inflammation, thrombosis, cardiovascular diseases, multi-visceral manifestations, and SARS-CoV-2 infection, namely, linking the roles of cytokines, neutrophil extracellular traps (NETs), nucleosomes, histones, and the coagulation cascade. Although dramatic improvements have been achieved in better understanding the pathophysiology of the disease, the mechanisms of innate immune response and more appropriate therapeutic treatments, reliable and accurate biomarkers for the early risk stratification and clinical management of COVID-19 patients are still lacking. A series of papers recently published in the Journal have provided new insights into some interesting and potentially useful biomarkers in COVID-19. The first paper is by Simon T-P et al., who evaluated the prognostic value of bioactive adrenomedullin (bio-ADM) in critically ill patients with COVID-19. The rationale of the study, as underlined by the authors, is that “endothelial cell infection, inflammation and activation with the subsequent interruption of endothelial barrier function have been described in COVID-19 patients and adrenomedullin (ADM) has been shown to play a key role in regulating vascular hyper- permeability and endothelial stability/integrity in patients with severe infection” [1]. number: 5 publisher: Multidisciplinary Digital Publishing Institute
409	D406		Fialho, Maria Fernanda Pessano; Brum, Evelyne Silva; Oliveira, Sara Marchesan	Could the fibromyalgia syndrome be triggered or enhanced by COVID-19?	https://doi.org/10.1007/s10787-023-01160-w	Published	2023-02-27	Article	https://doi.org/10.1007/s10787-023-01160-w	Fibromyalgia (FM) is a complex disease with an uncertain aetiology and intricate pathophysiology. Although its genesis is not fully explained, potential environmental factors, such as viral infections might trigger FM or worsen patients' clinical outcomes. The SARS-CoV-2 virus may affect central and peripheral nervous systems, leading to musculoskeletal, neurological, and psychological disturbances. These symptoms might persist at least 12 months beyond the recovery, often referred to as post-COVID syndrome, which resembles FM syndrome. In this sense, we argued the potential consequences of COVID-19 exclusively on FM syndrome. First, we have described post-COVID syndrome and its painful symptoms. Afterwards, we argued whether FM syndrome could be triggered or enhanced by COVID-19 infection or by numerous and persistent stressors imposed daily by the pandemic setting (isolation, uncertainty, depression, mental stress, generalized anxiety, and fear of the virus). In addition, we have demonstrated similarities between pathophysiological mechanisms and cardinal symptoms of FM and COVID-19, speculating that SARS-CoV-2 might represent a critical mediator of FM or an exacerbator of its symptoms once both syndromes share similar mechanisms and complaints. Therefore, pharmacologic and non-pharmacological approaches commonly used to treat FM could serve as strategic therapies to attenuate painful and neurological manifestations of post-COVID syndrome. Although it is still theoretical, clinicians and researchers should be alert of patients who develop symptoms similar to FM or those who had their FM symptoms increased post-COVID to manage them better.
410	D407		Deng, Yamin; Han, Shasha; Liu, Jue; Guo, Li; Feng, Luzhao; Liao, Yilan; Peng, Zhixing; Ren, Lili; Yang, Weizhong; Wang, Jianwei	The risks of death and hospitalizations associated with SARS-CoV-2 Omicron declined after lifting testing and quarantining measures	https://doi.org/10.1016/j.jinf.2023.02.033	Published	2023-02-27	Study	https://www.journalofinfection.com/article/S0163-4453(23)00118-4/fulltext	We reported the estimated infection–fatality ratio (IFR) and infection-hospitalization ratio (IHR) after lifting non-pharmaceutical interventions using a mathematical compartment model that accounted for unascertained infections. China lifted the testing and quarantining measures against SARS-CoV-2 Omicron on 7 December 2022. One online survey study conducted on December 27-30, 2022, in Macao, China, reported 70% of the population infection rates.1 This concurrence of the surge of Omicron infection and the excess winter mortality among old adults has sparked a widespread susception of an increasing medical burden of the disease after the lifting. However, a well-known problem with web surveys is selection bias, which could lead to unreliable survey outcomes.2 It is unclear which statistical techniques 3 were used to address the problem. Moreover, the authors noted that unascertained infections were difficult to count in the survey. The risks of death and hospitalization provide an alternative way of converting COVID-19 mortality into an estimate of infections and further into the requirement of hospital resources, and a reverse way to convert the requirement of hospital resources into an estimate of infections and further into COVID-19 mortality, which together comprises a self-checking robust way to qualify for the medical burdens of Omicron variants. Thus, a better understanding of the changes in IFR and IHR after lifting testing measures is needed. We highlighted the difference between IFR—a metric quantifying the likelihood of people dying once infected,4 and the case-fatality ratio (CFR) with the infections being replaced by the ascertained infections. Because of the great uncertainty surrounding the number of infections after the lifting, estimates of the IFR and IHR that rely on detected cases are likely to be misleading. Our age-specific and all-age estimation of the IFR and IHR showed that the risk of death and hospitalizations among people infected with Omicron declined after the lifting, with considerably lower values than reported CFR and CHR. Understanding these changes in IFR and IHR has direct implications for quantifying the need for medical resources, especially when great uncertainty surrounds the number of infections after the lifting. Although our analysis shows relatively stable IFRs and IHRs across different periods, it is key to remark that most Omicron infections recorded in our data occurred in seasons other than winter. We were not able to evaluate the differences in risks across seasons, but our findings present a basis for future comparison. The finding has profound implications for understanding the medical burden of pathology and informing medical resource allocations, which should take into consideration the impact of case ascertaining measures and the limitation in data collection. publisher: Elsevier PMID: 36858179
411	D408		Abenavoli, Ludovico; Gentile, Ivan	COVID-19: Where We Are and Where We Are Going	https://doi.org/10.3390/diseases11010040	Published	2023-03-01	Article	https://www.mdpi.com/2079-9721/11/1/40	The impact of COVID-19 on global health has been colossal. By the end of 2021, there were reports of over 672 million cumulative confirmed cases and 6.8 million deaths from COVID-19 [1], and these statistics continue to increase. However, these figures almost certainly constitute an underestimation of the true number of cases and deaths. The pandemic has put health systems under pressure in both developing and high-income countries [2,3]. With this in mind, national health systems are expected to be able to answer to the following questions: how do we manage the current epidemic? How do we realize measures to prevent future epidemics? How do we maximize health gain and health equity in the long term? Since 2019, the rapid availability of new vaccines and new antiviral treatments has considerably altered the evolution of the pandemic [4]. However, from a medical research perspective, the pandemic represents a transitional moment in human history. In the last three years, extensive scientific research has been conducted on COVID-19, causing a delaying in research breakthroughs for other diseases. Moreover, the pandemic exacerbated the health of those affected by noncommunicable diseases by delaying and disrupting their diagnoses, treatments and follow-up appointments [5]. In addition, the indirect impact of COVID-19 on the changes of livelihoods, education systems and social protection is relevant, and these changes open up several challenges. However, it is important to underline the aims of the COVID-19 pandemic research, which should include effectiveness, efficiency and equity. From a clinical point of view, we have gained a great deal of experience on this topic. In fact, COVID-19 is now considered not only a respiratory illness, but a complex disorder that affects the cardiovascular, gastrointestinal, and urinary systems [6,7,8]. In addition, several neurological manifestations have been observed in patients with SARS-CoV-2 infection [9]. Some examples include dysgeusia, hyposmia, encephalitis, meningitis, and acute cerebrovascular disease, most likely due to direct infection of the brain, induced hyperinflammatory response, hypercoagulation, and immune-mediated processes [10]. Long COVID-19 represents a new medical challenge. Currently, there is no consensus regarding the management of this complex condition, which causes the onset of several manifestations associated with different tissues. There is no definitive accepted treatment, but therapies focused on specific symptoms are commonly prescribed [11]. For this reason, a multidisciplinary approach to improving the management of patients with long COVID-19 is suggested [12,13]. number: 1 publisher: Multidisciplinary Digital Publishing Institute
412	D409		Scharf, Rüdiger E.; Anaya, Juan-Manuel	Post-COVID Syndrome in Adults—An Overview	https://doi.org/10.3390/v15030675	Published	2023-03-01	Review	https://www.mdpi.com/1999-4915/15/3/675	This article provides an overview of various aspects related to post-COVID syndrome. Apart from its prevalence, symptoms and sequelae, risk determinants, and psychosocial implications, the pathogenesis of post-COVID condition is discussed in more detail. A focus on thrombo-inflammation in SARS-CoV-2 infection, the role of neutrophil extracellular traps, and the prevalence of venous thromboembolism is made. Moreover, COVID-19 and post-COVID syndrome in immunocompromising conditions, and the impact of vaccination on the prevention and treatment of post-COVID symptoms are reviewed. Autoimmunity is a hallmark of post-COVID syndrome, and, therefore, is another focus of this article. Thus, misdirected cellular and humoral immune responses can enhance the risk of latent autoimmunity in post-COVID syndrome. Facing the high prevalence of COVID-19 cases worldwide, it can be assumed that autoimmune disorders will increase globally over the next few years. Recent advances in identifying genetically determined variants may open the avenue for a better understanding of the susceptibility to and severity of SARS-CoV-2 infection and post-COVID syndrome.
413	D410		Alwan, Nisreen A.	Healing Long Covid: a marathon not a sprint	https://doi.org/10.1016/S0140-6736(23)00408-7	Published	2023-03-04	Article	https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00408-7/fulltext	I have been immersed in Long Covid both personally and professionally since the summer of 2020. I experienced the condition myself, wrote and spoke about it on various national and international platforms, and did research trying to understand its features and effects. Now there is a handbook about the condition that I was eager to read, even though it is written mainly from the individual patient's point of view rather than the population-level perspective that I often see things through and advocate for as a public health professional. publisher: Elsevier
414	D411		Scholz, Urte; Bierbauer, Walter; Lüscher, Janina	Social Stigma, Mental Health, Stress, and Health-Related Quality of Life in People with Long COVID	https://doi.org/10.3390/ijerph20053927	Published	2023-01-01	Study	https://www.mdpi.com/1660-4601/20/5/3927	A considerable amount of people who have been infected with SARS-CoV-2 experience ongoing symptoms, a condition termed long COVID. This study examined nuanced experiences of social stigma in people with long COVID and their associations with perceived stress, depressive symptoms, anxiety, and mental and physical health-related quality of life (hrqol). A total of N = 253 participants with long COVID symptoms (mean age = 45.49, SD = 12.03; n = 224, 88.5% women) completed a cross-sectional online survey on overall social stigma and the subfacets enacted and perceived external stigma, disclosure concerns, and internalized stigma. Data were analysed using multiple regression and controlling for overall burden of consequences of long COVID, overall burden of symptoms of long COVID, and outcome-specific confounders. In line with our preregistered hypotheses, total social stigma was related to more perceived stress, more depressive symptoms, higher anxiety, and lower mental hrqol, but—in contrast to our hypothesis—it was unrelated to physical hrqol after controlling for confounders. The three subscales of social stigma resulted in differential associations with the outcomes. Social stigma experiences go hand in hand with worse mental health in people with long COVID. Future studies should examine potential protective factors to buffer the effects of social stigma on people’s well-being.
415	D412		Blanchflower, David; Bryson, Alex	Long Covid in the United States		pre-print	2023-02-01	Study	http://www.nber.org/papers/w30988.pdf	Long COVID in the United States Although yet to be clearly identified as a clinical condition, there is immense concern at the health and wellbeing consequences of long COVID. Using data collected from nearly half a million Americans in the period June 2022-December 2022 in the US Census Bureau’s Household Pulse Survey (HPS), we find 14 percent reported suffering long COVID at some point, half of whom reported it at the time of the survey. Its incidence varies markedly across the United States – from 11 percent in Hawaii to 18 percent in West Virginia – and is higher for women than men, among Whites compared with Blacks and Asians, and declines with rising education and income. It peaks in midlife in the same way as negative affect. Ever having had long COVID is strongly associated with negative affect (anxiety, depression, worry and a lack of interest in things). The effect is larger among those who currently report long COVID, especially if they report severe symptoms. In contrast, those who report having had short COVID report higher wellbeing than those who report never having had COVID. Long COVID is also strongly associated with physical mobility problems, and with problems dressing and bathing. It is also associated with mental problems as indicated by recall and understanding difficulties. Again, the associations are strongest among those who currently report long COVID, while those who said they had had short COVID have fewer physical and mental problems than those who report never having had COVID. Vaccination is associated with lower negative affect, including among those who reported having had long COVID.
416	D413		Thurner, Carolin; Stengel, Andreas	Long-COVID syndrome: physical–mental interplay in the spotlight	https://doi.org/10.1007/s10787-023-01174-4	Published	2023-03-09	Review	https://doi.org/10.1007/s10787-023-01174-4	Patients suffering from Long-COVID syndrome experience a variety of different symptoms on a physical, but also on a psychological and social level. Previous psychiatric conditions such as depression and anxiety have been identified as separate risk factors for developing Long-COVID syndrome. This suggests a complex interplay of different physical and mental factors rather than a simple cause–effect relationship of a specific biological pathogenic process. The biopsychosocial model provides a foundation for understanding these interactions and integrating them into a broader perspective of the patient suffering from the disease instead of the individual symptoms, pointing towards the need of treatment options on a psychological as well as social level besides biological targets. This leads to our conclusion, that the biopsychosocial model should be the underlying philosophy of understanding, diagnosing and treating patients suffering from Long-COVID syndrome, moving away from the strictly biomedical understanding suspected by many patients, treaters and the media while also reducing the stigma still associated with the suggestion of a physical–mental interplay.
417	D414		Yang, Chengliang; Tebbutt, Scott J.	Long COVID: the next public health crisis is already on its way	https://doi.org/10.1016/j.lanepe.2023.100612	Published	2023-03-10	Article	https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(23)00030-3/fulltext	In the current issue of The Lancet Regional Health - Europe, Wahlgren and colleagues report on a longitudinal follow-up of COVID-19 patients who were hospitalized during the first pandemic wave (between March and May 2020) in Sweden,2 one of the longest follow-up studies of hospitalized COVID-19 patients to date. Using a 37-point questionnaire, patients reported that cognition, sensorimotor impairments and fatigue were their most common persistent symptoms; up to 84% of patients still had problems affecting their daily lives 24 months after acute infection. Approximately half of the cohort who were on sick leave associated with LC at 4 months after infection remained on sick leave at 24 months, with health risks such as hospitalization for cardiovascular disease.2 Similarly, a UK study confirmed that COVID-19 infection, including LC, was associated with increased short- and long-term risk of cardiovascular disease and death, particularly in those who had severe COVID.3 Nevertheless, many questions remain regarding the reported symptoms of LC, the effectiveness of COVID-19 vaccines against LC, and the vulnerable population for LC. To date, more than 200 LC symptoms have been reported. In Wahlgren's study cohort, up to 11% (19/165) of patients' mental health was affected by psychiatric disorders.2 Importantly, indications of cognitive impairment, sensorimotor disorders, and fatigue are generally based on patient self-report, which is less objective than clinician diagnoses and might not be uniform and accurate across the study population. Persistent physical symptoms after the acute COVID-19 phase may not be due to SARS-CoV-2 infection, as some symptoms may have already been present before COVID-19.4 A Spanish group compared the differences in LC symptoms between hospitalized and non-hospitalized patients two years after acute infection. Their cross-sectional study showed that 59.7% of hospitalized patients and 67.5% of non-hospitalized patients had at least one LC symptom two years after infection.5 However, neither the Wahlgren nor Spanish studies included healthy controls, limiting their ability to separate effects independently with COVID-19 from those associated with matched control populations.2,5 Indeed, few studies examining LC have used an uninfected control group, and the clinical presentation of LC patients, including symptoms, physical assessment, mental health and psychotherapy, and diagnostic investigation, remains incompletely characterized in most published studies. From a clinical viewpoint, LC patients require precise medical assessment to prevent pre-existing or unrelated symptoms from being erroneously attributed to COVID-19 infection, and to identify pathophysiologic mechanisms for targeted symptom relief. Currently, objective clinical measures are limited, and biomarkers are urgently needed to close the diagnostic gap for LC. In Wahlgren's study, 91% of patients received more than two doses of COVID-19 vaccine, but the vaccine type was unknown.2 Whether or not vaccination, particularly with inactivated virus, protects against LC symptoms, remains controversial. A recent national cohort study from Israel evaluated clinical sequelae in vaccinated patients with mild COVID-19 up to one year post-infection, compared to uninfected and unvaccinated SARS-CoV-2-infected patients as controls. This study concluded that vaccinated mild patients with a breakthrough SARS-CoV-2 infection had reduced risk of lingering dyspnea compared to unvaccinated individuals, while risks for other adverse health outcomes were comparable.6 A Hong Kong study found that those who received two doses of BNT162b2 (mRNA vaccine) had higher levels of protection against severe COVID-19 than those who received two doses of CoronaVac (inactive virus vaccine), especially in older age groups.7 Researchers in Malaysia compared the duration of protection using BNT162b2 and CoronaVac vaccines, and found protection diminished more rapidly after two doses of CoronaVac, especially against mild and moderate COVID-19.8 Turkish researchers reported that participants receiving a third dose of BNT162b2 had significantly increased neutralizing antibody titers compared to a third dose of CoronaVac.9 Surprisingly, a recent Chinese study showed that patients with breakthrough infection who had received three doses of inactivated virus COVID-19 vaccine had significantly lower titers of neutralizing antibodies to Omicron BA.2, BA.4 and BA.5 variants compared to patients with breakthrough infection who had received two doses of inactivated virus vaccine.10 These results suggest that repeated inactivated virus vaccination back-boosts prior memory and dampens immune responses to new antigenically-related but different viral strains,10 likely due to stronger immune imprinting against the ancestral strain and suppression of the neutralizing antibody response against new Omicron variants. A recent study from the United States suggests current COVID-19 vaccines (including WA1/BA.5 bivalent mRNA vaccine) are ineffective against BQ and XBB Omicron due to the superiority of these subvariants in evading antibodies.11 Emerging SARS-CoV-2 variants such as XBB 1.5 and evidence of waning vaccine efficacy due to immune escape pose significant potential barriers to control of the COVID-19 pandemic. According to a World Health Organization (WHO) report, only 30.61% of people worldwide have received booster vaccines.12 Number of people at risk of developing LC might be greater than earlier predictions, especially in unvaccinated populations in lower-income countries, post-COVID-19 patients living in socioeconomically deprived areas, and seriously ill and vulnerable patients.12,13 The increasing prevalence of LC threatens healthcare systems worldwide and seriously affects socioeconomic recovery. Strategies are urgently needed to address this developing public health crisis. publisher: Elsevier
418	D415		Tabassum, Farah; Selke, Moira Sarah A.; MacQuarrie, Maureen; Stein, Eleanor	Lessons for Long COVID from Myalgic Encephalomyelitis (ME) care		Published	2023-03-28	Article	https://www.cmaj.ca/content/lessons-long-covid-myalgic-encephalomyelitis-me-care, /content/lessons-long-covid-myalgic-encephalomyelitis-me-care	We thank Quinn et al. for their three timely articles on long COVID. Our comments are mostly directed towards the treating article(1) but also aim to bring awareness to the existing body of literature regarding myalgic encephalomyelitis (ME), which is a disease that shares many overlapping symptoms with long COVID and most commonly also arises in a post-infectious setting. Quinn et al. raise the similarities between long COVID and ME but unfortunately limit the comparison to the section on the mental health consequences of long COVID.(1) Beyond the potential mental health sequelae, parallels between long COVID and ME symptomatology have been written about, starting early on in the pandemic, and it is now apparent that about half of individuals with long COVID meet ME diagnostic criteria.(2) Much of the experience gained from the research and care of people with ME may be both relevant and significant for long COVID. It is noted in the article by Quinn et al. that cognitive behavioural therapy (CBT) for the treatment of fatigue is controversial.(1) We wish to highlight however, that within the context of ME, the use of CBT as a treatment for fatigue is not recommended.(3,4) The NICE ME/CFS guidelines, referenced in the article(5) which Quinn et al. cite, were updated in October 2021 and note that CBT is only to be offered as general support for those with ME/CFS to “... reduce the distress associated with having a chronic illness,” and/or to manage comorbid mood disorder, but not as a cure.(3) This is in keeping with the approaches used in any chronic disabling condition, in order to address comorbid mental health disorders and provide coping strategies for living with a chronic disease. Post-exertional malaise (PEM), sometimes referred to as post-exertional symptom exacerbation, is the hallmark feature of ME(4) and can be found in long COVID.(2) Based on experience with ME, the “structured and symptom-guided” return to activity suggested by Quinn et al.(1) needs to be clarified, as the term “structured” can be problematic. A “structured” rehabilitation program(1) should not be confused with strategies founded in graded exercise therapy (GET). GET, as defined in the 2021 NICE ME/CFS guidelines as utilizing “fixed incremental increases in the time spent being physically active” is not to be undertaken(3). It should be noted that activity of any nature, for some, may exacerbate symptoms and could even result in relapses with long-term consequences.(3,4) The WHO COVID-19 Clinical management: living guidance document contains similar cautions for long COVID. A “symptom - guided” rehabilitation program is in keeping with concepts of pacing, and should be emphasized. Pacing, which Quinn et al. do reference,(1) is a quintessential management strategy for PEM well founded in the ME field of practice(4) with tools readily available for practitioners and patients, such as through the Bateman Horne Center and Workwell Foundation websites.
419	D416		Tate, Warren P.; Walker, Max O. M.; Peppercorn, Katie; Blair, Anna L. H.; Edgar, Christina D.	Towards a Better Understanding of the Complexities of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID	https://doi.org/10.3390/ijms24065124	Published	2023-01-01	Review	https://www.mdpi.com/1422-0067/24/6/5124	Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition arising in susceptible people, predominantly following viral infection, but also other stressful events. The susceptibility factors discussed here are both genetic and environmental although not well understood. While the dysfunctional physiology in ME/CFS is becoming clearer, understanding has been hampered by different combinations of symptoms in each affected person. A common core set of mainly neurological symptoms forms the modern clinical case definition, in the absence of an accessible molecular diagnostic test. This landscape has prompted interest in whether ME/CFS patients can be classified into a particular phenotype/subtype that might assist better management of their illness and suggest preferred therapeutic options. Currently, the same promising drugs, nutraceuticals, or behavioral therapies available can be beneficial, have no effect, or be detrimental to each individual patient. We have shown that individuals with the same disease profile exhibit unique molecular changes and physiological responses to stress, exercise and even vaccination. Key features of ME/CFS discussed here are the possible mechanisms determining the shift of an immune/inflammatory response from transient to chronic in ME/CFS, and how the brain and CNS manifests the neurological symptoms, likely with activation of its specific immune system and resulting neuroinflammation. The many cases of the post viral ME/CFS-like condition, Long COVID, following SARS-CoV-2 infection, and the intense research interest and investment in understanding this condition, provide exciting opportunities for the development of new therapeutics that will benefit ME/CFS patients.
420	D417		Yu, Zhebin; Ekström, Sandra; Bellander, Tom; Ljungman, Petter; Pershagen, Göran; Eneroth, Kristina; Kull, Inger; Bergström, Anna; Georgelis, Antonios; Stafoggia, Massimo; Gruzieva, Olena; Melén, Erik; Almqvist, Catarina; Andersson, Niklas; Ballardini, Natalia; Bergström, Anna; Björkander, Sophia; Brodin, Petter; Castel, Anna; Ekström, Sandra; Georgelis, Antonios; Hammarström, Lennart; Pan-Hammarström, Qiang; Hallberg, Jenny; Jansson, Christer; Kere, Maura; Kull, Inger; Lauber, André; Lövquist, Alexandra; Melén, Erik; Mjösberg, Jenny; Mogensen, Ida; Palmberg, Lena; Pershagen, Göran; Roxhed, Niclas; Schwenk, Jochen	Ambient air pollution exposure linked to long COVID among young adults: a nested survey in a population-based cohort in Sweden	https://doi.org/10.1016/j.lanepe.2023.100608	Published	2023-03-07	Study	https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(23)00026-1/fulltext	Background Post COVID-19 conditions, also known as long COVID, are of public health concern, but little is known about their underlying risk factors. We aimed to investigate associations of air pollution exposure with long COVID among Swedish young adults. Methods We used data from the BAMSE (Children, Allergy, Environment, Stockholm, Epidemiology [in Swedish]) cohort. From October 2021 to February 2022 participants answered a web-questionnaire focusing on persistent symptoms following acute SARS-CoV-2 infection. Long COVID was defined as symptoms after confirmed infection with SARS-CoV-2 lasting for two months or longer. Ambient air pollution levels (particulate matter ≤2.5 μm [PM2.5], ≤10 μm [PM10], black carbon [BC] and nitrogen oxides [NOx]) at individual-level addresses were estimated using dispersion modelling. Findings A total of 753 participants with SARS-CoV-2 infection were included of whom 116 (15.4%) reported having long COVID. The most common symptoms were altered smell/taste (n = 80, 10.6%), dyspnea (n = 36, 4.8%) and fatigue (n = 34, 4.5%). Median annual PM2.5 exposure in 2019 (pre-pandemic) was 6.39 (interquartile range [IQR] 6.06–6.71) μg/m3. Adjusted Odds Ratios (95% confidence intervals) of PM2.5 per IQR increase were 1.28 (1.02–1.60) for long COVID, 1.65 (1.09–2.50) for dyspnea symptoms and 1.29 (0.97–1.70) for altered smell/taste. Positive associations were found for the other air pollutants and remained consistent across sensitivity analyses. Associations tended to be stronger among participants with asthma, and those having had COVID during 2020 (versus 2021). Interpretation Ambient long-term PM2.5 exposure may affect the risk of long COVID in young adults, supporting efforts for continuously improving air quality. publisher: Elsevier
421	D418		Spence, Naomi J; Russell, David; Bouldin, Erin D; Tumminello, Christa M; Schwartz, Tatum	Getting back to normal? Identity and role disruptions among adults with Long COVID	https://doi.org/10.1111/1467-9566.13628	Published	2023-03-01	Study	https://doi.org/10.1111/1467-9566.13628	Long COVID is a novel chronic illness with a variety of symptoms that people who have labelled themselves 'long-haulers' experience for an extended duration following a COVID-19 infection. We draw on in-depth interviews conducted in March-April 2021 with 20 working-aged adults in the U.S. who self-identified as long-haulers to understand the consequences for identities. The results demonstrate that Long COVID has important consequences for identities and sense of self. Long-haulers described experiencing three stages of biographical disruptions: realising their illness experience as misaligned with sense of self and embodied, age-based expectations; facing challenges to identities and changes in social roles; and reconciling illness and identity in the context of an uncertain prognosis. It remains unclear how long-haulers will resolve biographical disruptions and identity conflicts, especially as scientific insights about this novel condition emerge. Such outcomes may depend largely on whether Long COVID remains a contested illness or medical knowledge progresses to improve their quality of life. For now, healthcare providers may approach Long COVID holistically to address the identity disruptions that long-haulers face as they manage the consequences of this chronic illness.
422	D419		Song, Zirui; Giuriato, Mia	Demographic And Clinical Factors Associated With Long COVID	https://doi.org/10.1377/hlthaff.2022.00991	Published	2023-03-01	Study	https://www.healthaffairs.org/doi/abs/10.1377/hlthaff.2022.00991	Risk factors for postacute sequelae of SARS-CoV-2 infection (“long COVID”) in community-dwelling populations remain poorly understood. Large-scale data, follow-up, comparison groups, and a consensus definition of long COVID are often lacking. Using data from the OptumLabs Data Warehouse on a nationwide sample of commercial and Medicare Advantage enrollees from the period January 2019 through March 2022, we examined demographic and clinical factors associated with long COVID, using two definitions of people who suffer symptoms long after they were first diagnosed with COVID-19 (“long haulers”). We identified 8,329 long haulers using the narrow definition (diagnosis code), 207,537 long haulers using the broad definition (symptom based), and 600,161 non–long haulers (comparison group). On average, long haulers were older and more likely female, with more comorbidities. Among narrow-definition long haulers, the leading risk factors for long COVID included hypertension, chronic lung disease, obesity, diabetes, and depression. Their time between initial COVID-19 diagnosis and diagnosis of long COVID averaged 250 days, with racial and ethnic differences. Broad-definition long haulers exhibited similar risk factors. Distinguishing long COVID from the progression of underlying conditions can be challenging, but further study may advance the evidence base related to the identification, causes, and consequences of long COVID.
423	D420		Matsuda, Yui; Tokumasu, Kazuki; Otsuka, Yuki; Sunada, Naruhiko; Honda, Hiroyuki; Sakurada, Yasue; Nakano, Yasuhiro; Hasegawa, Toru; Obika, Mikako; Ueda, Keigo; Otsuka, Fumio	Symptomatic Characteristics of Hypozincemia Detected in Long COVID Patients	https://doi.org/10.3390/jcm12052062	Published	2023-01-01	Study	https://www.mdpi.com/2077-0383/12/5/2062	Objectives: The aim of this study was to determine the characteristics of hypozincemia in long COVID patients. Methods: This study was a single-center retrospective observational study for outpatients who visited the long COVID clinic established in a university hospital during the period from 15 February 2021 to 28 February 2022. Characteristics of patients with a serum zinc concentration lower than 70 μg/dL (10.7 μmol/L) were compared with characteristics of patients with normozincemia. Results: In a total of 194 patients with long COVID after excluding 32 patients, hypozincemia was detected in 43 patients (22.2%) including 16 male patients (37.2%) and 27 female patients (62.8%). Among various parameters including the background characteristics of the patients and medical histories, the patients with hypozincemia were significantly older than the patients with normozincemia (median age: 50 vs. 39 years). A significant negative correlation was found between serum zinc concentrations and age in male patients (R = −0.39; p < 0.01) but not in female patients. In addition, there was no significant correlation between serum zinc levels and inflammatory markers. General fatigue was the most frequent symptom in both male patients with hypozincemia (9 out of 16: 56.3%) and female patients with hypozincemia (8 out of 27: 29.6%). Patients with severe hypozincemia (serum zinc level lower than 60 μg/dL) had major complaints of dysosmia and dysgeusia, which were more frequent complaints than general fatigue. Conclusions: The most frequent symptom in long COVID patients with hypozincemia was general fatigue. Serum zinc levels should be measured in long COVID patients with general fatigue, particularly in male patients.
424	D421		Tanne, Janice Hopkins	Covid-19: US studies show racial and ethnic disparities in long covid	https://doi.org/10.1136/bmj.p535	Published	2023-03-06	Article	https://www.bmj.com/content/380/bmj.p535	Black and Hispanic Americans are more likely than white Americans to have symptoms of long covid and some people who had covid early in the epidemic may have long covid but not be diagnosed as such because of coding changes, show studies funded by the National Institutes of Health.123 Long covid was defined by the Centers for Disease Control and Prevention in December 2022, and includes general symptoms as well as respiratory, cardiovascular, neurological, digestive, and other symptoms.4 Mitchell Elkind, professor of neurology and epidemiology at Columbia University Medical Center in New York and chief clinical officer of the American Heart Association, said, “New evidence suggests that there may be important differences in how long covid manifests in different racial and ethnic groups. Further research is needed to understand better the mechanisms for these differences in symptoms and access to care, and also if diagnostic codes assigned by clinicians …
425	D422		Quinn, Kieran L.; Razak, Fahad; Cheung, Angela M.	Diagnostiquer le syndrome post-COVID-19 (COVID-19 de longue durée) chez l’adulte	https://doi.org/10.1503/cmaj.220818-f	Published	2023-03-06	Article	https://www.cmaj.ca/content/195/9/E346	La COVID-19 de longue durée est un syndrome systémique Cette caractéristique serait associée à l’expression dans différents organes des récepteurs de l’enzyme de conversion de l’angiotensine 2 (ECA2), utilisés par le SRAS-CoV-2 pour pénétrer dans les cellules4. Plusieurs mécanismes pathophysiologiques pourraient contribuer à la COVID-19 de longue durée, notamment les lésions cellulaires, la persistance de l’inflammation ou de la virémie, l’auto-immunité et un état procoagulant4. La COVID-19 de longue durée peut toucher la plupart des systèmes organiques Le syndrome bouleverse le fonctionnement et le bien-être des patients au quotidien3,4. Plus de 100 symptômes de la COVID-19 de longue durée ont été déclarés. Par ailleurs, le sexe féminin semble être un facteur de risque indépendant. Les symptômes les plus fréquents qui peuvent être traités comprennent la fatigue (23 %–63 %), l’anxiété et la dépression (23 %–46 %), la dyspnée (11 %–43 %), les troubles du sommeil (11 %–31 %) et les palpitations (6 %–22 %)3,4. Beaucoup de personnes atteintes de la COVID-19 de longue durée ont des symptômes persistants De nombreuses personnes guérissent de la COVID-19 de longue durée, mais certaines continuent de souffrir de symptômes au point de ne pas pouvoir reprendre une activité à temps plein au bout de 1 an2,5. Une étude longitudinale de cohorte publiée en 20225 a suivi 1192 personnes hospitalisées à Wuhan (Chine) ayant survécu à la COVID-19: 68 % présentaient au moins 1 symptôme 6 mois après l’infection; cette proportion avait diminué à 55 % après 2 ans. Parmi les participants qui occupaient auparavant un emploi, 21 % n’avaient pas repris le travail5, ce qui correspond à la proportion de personnes au Canada ayant déclaré que leurs symptômes restreignaient souvent ou toujours leurs activités quotidiennes2. publisher: CMAJ section: Pratique PMID: 36878549
426	D423		Nobili, Alessandro; D’Avanzo, Barbara; Tettamanti, Mauro; Galbussera, Alessia Antonella; Remuzzi, Giuseppe; Fortino, Ida; Leoni, Olivia; Harari, Sergio; Mannucci, Pier Mannuccio	Post-COVID condition: dispensation of drugs and diagnostic tests as proxies of healthcare impact	https://doi.org/10.1007/s11739-023-03228-5	Published	2023-03-21	Study	https://doi.org/10.1007/s11739-023-03228-5	With the goal to increase knowledge on the healthcare impact of the post-COVID-19 condition we exploited the administrative claims database of Lombardy, the largest Italian region and the first after China to be heavily hit by the SARS-CoV-2 pandemic in February–May 2020. We chose to employ the dispensation of drugs and diagnostic tests as proxies of the impact of the post-COVID condition in 46,574 cases who recovered from COVID-19 and were negative at PCR testing within June 20, 2020. Data were obtained throughout the 18-month post-negativization period until December 2021 and results on the use of drugs and diagnostic tests were compared with those accrued in the same cases during the pre-COVID period in July–December 2019. After an increase in the first semester after SARS-CoV-2 negativization (July–December 2020), trends in the dispensation of drugs according to the broad ATC classes and of diagnostic tests decreased or remained substantially stable. However, dispensation of drugs for acid related disorders (A02), diabetes (A10), heparins (B01AB), direct oral anticoagulants (B01AP), antipsychotics (N05A), antidepressants (N06A) and for obstructive airways diseases (R03) was still higher than in the pre-COVID period. These findings, based upon drug and diagnostic test dispensation as proxies of the healthcare impact of the post-COVID condition, show that in a substantial proportion of recovered cases the post-COVID condition is active and clinically relevant 18 months after the acute disease. The findings also provide indirect evidence of the body organs and systems more compromised in the post-COVID period.
427	D424		Salisbury, Helen	Helen Salisbury: Unexplained symptoms aren’t always long covid	https://doi.org/10.1136/bmj.p654	Published	2023-03-21	Article	https://www.bmj.com/content/380/bmj.p654	On busy days in general practice I often long for straightforward presentations—the sort where the patient seems to have read a medical textbook, as the history and symptoms fit so neatly with the examination findings. Diagnosis and management are simple, the patient is helped, and I feel useful. An added bonus is that the consultation is likely to be achievable within the allotted time (I might even fit in a cup of tea). However, especially now that we’ve passed many of general practice’s more predictable elements to other healthcare workers, most of our work isn’t so tidy. Sometimes the symptoms suggest sciatica, but the examination findings are much more in keeping with arthritis (does the patient have both?), or the various elements of a patient’s history don’t seem to fit together to make any physiological or pathological sense. How we respond to presentations that we don’t immediately understand makes a difference to us and the patient. At my best, I engage with such cases with empathy and enthusiasm, working with the patient to reach a diagnosis. I share my uncertainty and the various possibilities—ranging from the “likely and harmless” to the “unlikely but definitely needs excluding”—and discuss how we might investigate or who we might ask for advice. As long as I attend to the patient’s immediate needs (time off work, analgesia, or other symptom control) I can demonstrate that, although I don’t know the answers, I do take the questions seriously. When I’m stressed and rushed, it takes effort to muster this enthusiasm and suppress that feeling of “heart sink” that comes when I feel as though I have little to offer. Long covid throws this problem into sharp relief. Two million patients in the UK have persistent symptoms after covid infection, and 1.2 million have had these symptoms for over a year.1 Fatigue, breathlessness, muscle ache, and loss of smell are the most common symptoms, but there’s a very long list of possible effects involving almost every system and part of the body.2 Currently, we have an incomplete understanding of what’s happening and little in the way of effective treatment. As the vast majority of people in the UK have now had at least one episode of covid infection, a real concern is that patients or their doctors may attribute symptoms too readily to long covid and so miss other conditions.3 In our practice we’ve recently diagnosed two cases of lung cancer, which might have presented sooner if the persistent cough and malaise hadn’t been misinterpreted as the lingering effects of covid infection. When the patient opens with, “I’ve not been right ever since I had covid,” we must take care to exclude other diagnoses before we blame the virus. publisher: British Medical Journal Publishing Group section: Opinion PMID: 36944437
428	D425		Szabo, Sandor; Zayachkivska, Oksana; Hussain, Alamdar; Muller, Veronika	What is really ‘Long COVID’?	https://doi.org/10.1007/s10787-023-01194-0	Published	2023-03-25	Article	https://doi.org/10.1007/s10787-023-01194-0	The previous acute respiratory diseases caused by viruses originating from China or the middle east (e.g., SARS, MERS) remained fast developing short diseases without major sequalae or any long-lasting complications. The new COVID-19, on the other hand, not only that it rapidly spread over the world, but some patients never fully recovered or even if they did, a few weeks later started to complain not only of shortness of breath, if any, but general weakness, muscle pains and ‘brain fog’, i.e., fuzzy memories. Thus, these signs and symptoms were eventually labelled ‘long COVID’, for which the most widely used definition is ‘new signs and symptoms occurring 4–8 weeks after recovering from acute stage of COVID-19’. The other most frequent manifestations associated with long COVID include headache, loss of memory, smell and of hair, nausea, and vomiting. Thus, long COVID is not a simple disease, but complex disorder of several organ systems malfunctioning; hence, it is probably more appropriate to call this a syndrome. The pathogenesis of long COVID syndrome is poorly understood, but initial and persistent vascular endothelial injury that often triggers the formation of microthrombi that if dislodged as emboli, damage several organs, especially in the brain, heart and kidney, by creating microinfarcts. The other major contributory mechanistic factor is the persistent cytokine storm that may last longer in long COVID patients than in others, probably triggered by aggregates of SARS-Co-2 discovered recently in the adrenal cortex, kidney and brain. The prevalence of long COVID is relatively high, e.g., initially varied 3–30%, and recent data indicate that 2.5% of UK population suffers from this syndrome, while in the US 14.7% of acute COVID-19 patients continued to have symptoms longer than 2 months. Thus, the long COVID syndrome deserves to be further investigated, both from clinical and basic research perspectives.
429	D426		Morgan, Jules	Long COVID? What is that?	https://doi.org/10.1016/S2213-2600(23)00126-1	Published	2023-03-24	Article	https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00126-1/fulltext	Some people do not believe long COVID (also known as post-COVID-19 condition) is real. In fact, patients have reported that there are even doctors who sit in this camp, who might dismiss their symptoms as psychosomatic, or do not know how to recognise or treat long COVID. It is complicated, even for researchers. People might not have had severe symptoms when infected with SARS-CoV-2 virus, they might be young, without a significant medical history or risk factors. Although studies suggest around 10–20% of individuals who did not have severe acute disease might develop long COVID symptoms, the number of people who are facing long-term effects is hard to quantify. There are common symptoms, such as fatigue, shortness of breath on exertion, and cognitive and executive dysfunction, but the list is extensive and changeable, and many experience problems with multiple organs. People with long COVID are asking “Why me?” and “When will it end?” publisher: Elsevier PMID: 36972723
430	D427		Sherif, Zaki A; Gomez, Christian R; Connors, Thomas J; Henrich, Timothy J; Reeves, William Brian; RECOVER Mechanistic Pathway Task Force	Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC)	https://doi.org/10.7554/eLife.86002	Published	2023-03-22	Review	https://doi.org/10.7554/eLife.86002	COVID-19, with persistent and new onset of symptoms such as fatigue, post-exertional malaise, and cognitive dysfunction that last for months and impact everyday functioning, is referred to as Long COVID under the general category of post-acute sequelae of SARS-CoV-2 infection (PASC). PASC is highly heterogenous and may be associated with multisystem tissue damage/dysfunction including acute encephalitis, cardiopulmonary syndromes, fibrosis, hepatobiliary damages, gastrointestinal dysregulation, myocardial infarction, neuromuscular syndromes, neuropsychiatric disorders, pulmonary damage, renal failure, stroke, and vascular endothelial dysregulation. A better understanding of the pathophysiologic mechanisms underlying PASC is essential to guide prevention and treatment. This review addresses potential mechanisms and hypotheses that connect SARS-CoV-2 infection to long-term health consequences. Comparisons between PASC and other virus-initiated chronic syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome will be addressed. Aligning symptoms with other chronic syndromes and identifying potentially regulated common underlining pathways may be necessary for understanding the true nature of PASC. The discussed contributors to PASC symptoms include sequelae from acute SARS-CoV-2 injury to one or more organs, persistent reservoirs of the replicating virus or its remnants in several tissues, re-activation of latent pathogens such as Epstein–Barr and herpes viruses in COVID-19 immune-dysregulated tissue environment, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation dysregulation, dysfunctional brainstem/vagus nerve signaling, dysautonomia or autonomic dysfunction, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. The individualized nature of PASC symptoms suggests that different therapeutic approaches may be required to best manage specific patients.
431	D428		Tsampasian, Vasiliki; Elghazaly, Hussein; Chattopadhyay, Rahul; Debski, Maciej; Naing, Thin Kyi Phyu; Garg, Pankaj; Clark, Allan; Ntatsaki, Eleana; Vassiliou, Vassilios S.	Risk Factors Associated With Post−COVID-19 Condition: A Systematic Review and Meta-analysis	https://doi.org/10.1001/jamainternmed.2023.0750	Published	2023-03-23	Systematic review and meta-analysis	https://doi.org/10.1001/jamainternmed.2023.0750	Key Points Question Which individuals are at risk of developing post−COVID-19 condition (PCC)? Findings This systematic review and meta-analysis of 41 studies including 860 783 patients found that female sex, older age, higher body mass index, smoking, preexisting comorbidities, and previous hospitalization or ICU admission were risk factors significantly associated with developing PCC, and that SARS-CoV-2 vaccination with 2 doses was associated with lower risk of PCC. Meanings The findings of this systematic review and meta-analysis provide a profile of the characteristics associated with increased risk of developing PCC and suggest that vaccination may be protective against PCC. Abstract Importance Post−COVID-19 condition (PCC) is a complex heterogeneous disorder that has affected the lives of millions of people globally. Identification of potential risk factors to better understand who is at risk of developing PCC is important because it would allow for early and appropriate clinical support. Objective To evaluate the demographic characteristics and comorbidities that have been found to be associated with an increased risk of developing PCC. Data sources Medline and Embase databases were systematically searched from inception to December 5, 2022. Study Selection The meta-analysis included all published studies that investigated the risk factors and/or predictors of PCC in adult (≥18 years) patients. Data Extraction and Synthesis Odds ratios (ORs) for each risk factor were pooled from the selected studies. For each potential risk factor, the random-effects model was used to compare the risk of developing PCC between individuals with and without the risk factor. Data analyses were performed from December 5, 2022, to February 10, 2023. Main Outcomes and Measures The risk factors for PCC included patient age; sex; body mass index, calculated as weight in kilograms divided by height in meters squared; smoking status; comorbidities, including anxiety and/or depression, asthma, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, immunosuppression, and ischemic heart disease; previous hospitalization or ICU (intensive care unit) admission with COVID-19; and previous vaccination against COVID-19. Results The initial search yielded 5334 records of which 255 articles underwent full-text evaluation, which identified 41 articles and a total of 860 783 patients that were included. The findings of the meta-analysis showed that female sex (OR, 1.56; 95% CI, 1.41-1.73), age (OR, 1.21; 95% CI, 1.11-1.33), high BMI (OR, 1.15; 95% CI, 1.08-1.23), and smoking (OR, 1.10; 95% CI, 1.07-1.13) were associated with an increased risk of developing PCC. In addition, the presence of comorbidities and previous hospitalization or ICU admission were found to be associated with high risk of PCC (OR, 2.48; 95% CI, 1.97-3.13 and OR, 2.37; 95% CI, 2.18-2.56, respectively). Patients who had been vaccinated against COVID-19 with 2 doses had a significantly lower risk of developing PCC compared with patients who were not vaccinated (OR, 0.57; 95% CI, 0.43-0.76). Conclusions and Relevance This systematic review and meta-analysis demonstrated that certain demographic characteristics (eg, age and sex), comorbidities, and severe COVID-19 were associated with an increased risk of PCC, whereas vaccination had a protective role against developing PCC sequelae. These findings may enable a better understanding of who may develop PCC and provide additional evidence for the benefits of vaccination.
432	D429		Jackson, Sally	Online Health Communities in Controversy over ME/CFS and Long Covid	https://doi.org/10.47368/ejhc.2023.203	Published	2023-03-24	Article	https://ejhc.org/article/view/3559	The condition known variously as myalgic encephalomyelitis, chronic fatigue syndrome, or ME/CFS has been steeped in controversy for 40 years or more. Long Covid, first noticed and named in 2020, has become entangled with the ME/CFS controversy because of striking similarities in the experiences of patients suffering from the two illnesses. Online health communities (OHCs) have played central roles in both controversies, but these are not the kinds of roles that have been so well-documented in prior literature. While prior research has established many ways in which participation in an OHC may benefit or otherwise affect community members themselves, this essay focuses on how OHCs contribute to positional shifts in health controversies that involve other communities as well. Using a framework for understanding health controversies as argumentative polylogues, I show that OHCs arguing with other players have made contributions that are both effective in gaining ground for the OHCs' own goals and in elevating the overall quality of the debate. Further, in some cases these contributions have been so innovative as to suggest surprising future trajectories for OHCs.
433	D430		Pan, Daniel; Pareek, Manish	Toward a Universal Definition of Post–COVID-19 Condition—How Do We Proceed?	https://doi.org/10.1001/jamanetworkopen.2023.5779	Published	2023-04-05	Article	https://doi.org/10.1001/jamanetworkopen.2023.5779	Finally, in our opinion, future observational studies that aim to investigate the prevalence and natural history of PCC must be longitudinal in nature, so that repeated measurements of symptoms and different outcomes are taken over time. Ideally, such studies should also include patients whose symptoms and signs that did not have a disproportionately severe effect on a patient’s quality of life, far beyond what is expected from their initial infection, as a control group so that comparisons can be made to the PCC group, Clearly, PCC is not just signs and symptoms that occur following COVID-19; it is disproportionately prolonged and severe signs and symptoms, indicative of the development of a new condition following an initial infection. Once the natural history of PCC is better defined, treatment for PCC can then be developed more effectively. PCC is a syndrome, not a single disease. Indeed, PCC is most likely to be a manifestation of multiple diseases mediated by different mechanisms. For example, while fatigue and dyspnea may be highly prevalent in patients with PCC, some patients acquire these symptoms due to the development of interstitial lung disease following severe infection; others will have the same symptoms but no clear organ dysfunction and perhaps even mild initial infection. A therapy that could potentially help to improve the symptoms of patients with COVID-19 interstitial lung disease must only be assessed in a trial that targets that subgroup of patients with PCC; if the therapy was targeted at everyone with PCC, where COVID-19 related interstitial lung disease only constitutes a small proportion, the therapy will show no effect and important resources that were used to perform the trial will be wasted. Chaichana and colleagues2 found that much more can be done in the design of future studies for patients with PCC. Observational studies aiming to define the natural history of PCC must be longitudinal in design, with accurately defined control groups, that are inclusive of everyone who has, and will be affected by, the syndrome. These studies must have one unified definition and title of the same syndrome, that is agreed on by patients, clinicians, and academics alike, and have the potential to identify different disease phenotypes. Clinical trials of interventions or drug therapy for PCC can then be tailored specifically to the patients with the characteristics that make a disease phenotype, rather than everyone with PCC syndrome. To treat PCC, we must first develop better studies that can identify what PCC actually is. Only then can we have a more personalized and effective approach to the treatment of those affected.
434	D431		Saunders, Chloe; Sperling, Søren; Bendstrup, Elisabeth	A new paradigm is needed to explain long COVID	https://doi.org/10.1016/S2213-2600(22)00501-X	Published	2023-02-01	Article	https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00501-X/fulltext	We now have adequate data to describe the core symptoms, course, and prevalence of long COVID. Core symptoms include breathing difficulties, muscle pain, anosmia, tingling extremities, and general tiredness. Many of these symptoms are non-specific, but are seen at higher rates in people with long COVID than would be expected in the general population.1 Despite intense research in the area, no clear pathogenesis has been established that can explain the full range of long COVID symptoms.2 Studies have found that patients' symptoms in many cases persist beyond the point at which pathophysiological observations can adequately explain them.3 Symptoms not adequately explained by traditional medical research paradigms are common across medicine and represent the most common diagnosis in some specialities.4 Persistent symptoms are highly prevalent in the general population5 and even within well-defined disease cohorts there is often little association between objective pathophysiology and symptom burden.6 • View related content for this article Coherent and relatable explanatory models are key to engaging patients with appropriate treatment, and act as a model to guide research. This need for explanatory models in long COVID invites various responses. The first response is to continue a search for an all-encompassing pathophysiological mechanism. The second response is to pursue a personalised medicine approach through attempts to cluster clinical phenotypes. We propose a third response that allows for a more complex understanding of the reciprocal relationships between triggers, conditioning mechanisms, and symptoms. Long COVID could be explained as an embodied condition with heterogeneous biological, psychological (experiential), and social (or environmental) factors integrated in complex relationships (figure). These complex relationships in symptom generation and persistence have been most extensively researched by those working in the field of functional disorders.7 Specific linear causal processes within the organs and tissues are not able to explain all physical suffering. For some conditions, it is necessary to approach treatment holistically rather than on an individual pathophysiological basis. Effective treatments and rehabilitation approaches for functional disorders are known,8 and many of them are already employed in long COVID clinics. However, explicit explanatory models that address the need for a multidisciplinary and integrated treatment provision are key to better clinical services. Poorly integrated explanatory models contribute to poor care and stigma for people who are ill in these specific ways. In summary, we highly welcome research into the cellular and physiological mechanisms behind persistent symptoms, including post-viral fatigue. However, it is increasingly clear that simple, causative relationships between pathophysiology and symptoms inadequately explain many diseases and chronic health conditions, including long COVID. There is an available body of literature on the multiple factors involved in the generation, perception, and persistence of functional symptoms, and models through which to integrate these. We are moving into a new era in long COVID research and treatment that would benefit from an integrated paradigm through which to understand human illness. We suggest it is time to break taboos based on a dualistic understanding of physical versus mental illness and bring in existing knowledge about functional somatic symptoms to provide improved explanations and treatments. publisher: Elsevier PMID: 36620963
435	D432		Cornish, Flora; Stelson, Elisabeth A.	Concerns regarding a suggested long COVID paradigm	https://doi.org/10.1016/S2213-2600(23)00095-4	Published	2023-04-01	Article	https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00095-4/fulltext	In Chloe Saunders and colleagues’ Comment,1 they recommend a model (which they term new) in which biological, social, experiential, and psychological factors interact to cause long COVID (also known as post-COVID-19 condition). To us—public health scholars with lived experience of post-COVID-19 condition—the model appears indistinguishable from old biopsychosocial models. For decades, such models have been misused to inaccurately characterise similar conditions, such as myalgic encephalomyelitis (also known as chronic fatigue syndrome), as rooted in patients’ own maladaptive psychological processes.2 The authors claim that a merit of their model is its ability to engage patients. We dispute this claim. Insisting on psychological and social origins of the disease is more likely to disengage patients. We thus caution respiratory medical colleagues against adopting language that treats the psychological as causal. To engage patients, a patient-centred perspective, rather than a physician-centred perspective, calls for listening to patients’ experience. Saunders and colleagues’ model suggests that societal “illness narratives” contribute to patients’ maladjusted thinking (eg, “catastrophising” or “illness perceptions”) and behaviour (“avoidant illness behaviours”), thereby causing their symptoms. However, this does not match patients’ experiences, in which symptoms precede the development of illness narratives. Patients typically report surprise and bafflement at their post-COVID-19 condition symptoms, often believing themselves recovered before having recurrent or new symptoms.3 The very counterintuitive post-exertional malaise (ie, onset of symptoms 24–48 h after overexertion) is very common in post-COVID-19 condition. Patients report wanting and trying to return to daily activities, only to be prevented—contrary to their expectations—by the delayed exacerbation of symptoms.4 In short, the temporal ordering of post-COVID-19 condition events are entirely at odds with the claim that “illness narratives” are causal. This mismatch with patients’ experience is unlikely to engage them. Further, people with post-COVID-19 condition report that some of their greatest challenges in securing clinical, workplace, and family and friend support lies in the dismissal of their condition, reinforced by assumptions that their symptoms are self-generated.5 Even if this is not the intention, biopsychosocial-type models are easily understood as blaming patients’ faulty thinking. We support holistic care but suggest that health professionals can address psychological and social aspects of managing post-COVID-19 condition without needing to make unsubstantiated claims about causes. We recommend clinicians critically reflect on how their own causal models—which are themselves “illness narratives”—contribute to public misunderstanding of post-COVID-19 condition. Health professionals’ illness narratives should support rather than blame patients. publisher: Elsevier PMID: 36997264
436	D433		Schwendinger, Fabian; Knaier, Raphael; Schmidt-Trucksäss, Arno	Concerns regarding a suggested long COVID paradigm	https://doi.org/10.1016/S2213-2600(23)00094-2	Published	2023-04-01	Article	https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00094-2/fulltext	We read with great interest the Comment by Chloe Saunders and colleagues1 that suggested a new paradigm to explain long COVID (also known as post-COVID-19 condition) as an embodied condition with heterogeneous biological, psychological, and social factors that might be interrelated. We value the proposal of transitioning towards an individualised approach for the treatment of patients with post-COVID-19 condition. Due to the multifaceted nature of the condition,2 the universal treatment principle is clearly obsolete in these patients. Incorporating information on experiential, psychological, and social factors in addition to biological findings could be beneficial in providing integral treatment.1 • View related content for this article However, we are afraid the Comment by Saunders and colleagues and the advocated paradigm could be misinterpreted by some readers. The common misconception that post-COVID-19 condition is largely psychological or a consequence of deconditioning is still widely circulating in the general population and even among some professionals. We thus highlight several shortcomings regarding the biological factors in Saunder and colleagues’ main figure and add relevant evidence that could aid the adequate interpretation of their article. Figure thumbnail fx1 View Large Image Copyright © 2023 Picture Alliance/Getty Images Besides those presented in the authors’ main figure, there are indeed important additional factors that have been suggested as contributing to post-COVID-19 condition, including (but not limited to) viral persistence,3 systemic inflammation,3 endothelial dysfunction and vascular damage,3 microclotting,3 mitochondrial dysfunction,4 and altered microbiome.3 These findings have been supported by numerous studies to date; however, these studies must be confirmed through further investigation. All these potential pathophysiological mechanisms should be considered when aiming to explain post-COVID-19 condition in an individual. The authors also present deconditioning as a biological conditioning mechanism for post-COVID-19 condition. Deconditioning is often incorrectly described as the main mechanism of exercise intolerance—a symptom that is frequently present in these patients.5 A review of 32 studies performing cardiopulmonary exercise testing in patients who had had COVID-19 showed that peripheral, followed by cardiovascular, factors and lung diffusion limitations are central to low cardiorespiratory fitness and exercise intolerance.5 Deconditioning should thus be seen as a consequence of persistent organ limitations that prevent the patients from being physically active.5 We hope this correspondence will support the integral model proposed by Saunders and colleagues1 and contribute to the adequate interpretation of their article. publisher: Elsevier PMID: 36997262
437	D434		Palen, Jenny van der	Concerns regarding a suggested long COVID paradigm	https://doi.org/10.1016/S2213-2600(23)00088-7	Published	2023-04-01	Article	https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00088-7/fulltext#%20	Upon reading Chloe Saunders and colleagues’ Comment,1 it is striking how this new paradigm is essentially the old paradigm for medically unexplained symptoms and contested illnesses.2 The authors advance an alleged philosophical problem they call “taboos based on a dualistic understanding of physical versus mental illness”. They assert such “Poorly integrated explanatory models contribute to poor care and stigma for people who are ill in these specific ways.” For the sake of argument, let us consult the lemma dualism: “In the philosophy of mind, dualism is the theory that the mental and the physical—or mind and body or mind and brain—are, in some sense, radically different kinds of things. Because common sense tells us that there are physical bodies, and because there is intellectual pressure towards producing a unified view of the world, one could say that materialist monism is the ‘default option’.”3 • View related content for this article If monism is the default option, pushback against implicitly systemic “dualistic understanding”1 is a non sequitur. In actuality, what Saunders and colleagues seem to oppose is divergence of care pathways across the salient care needs of patients. Although their explanatory model is agnostic on this point, the authors assert some patients “are ill in these specific ways” that demand integrated care—specifically, “effective treatments and rehabilitation approaches for functional disorders”. In effect, this routes patients who are ill in these specific (ie, non-specific) ways along a specific care pathway to specific clinical services and obscures their care needs. Hand poked on a row of wooden dominoes, with the words “COVID19” on the first piece and the words “LONG COVID” on subsequent pieces. View Large Image Copyright © 2023 Jikaboom/Getty Images This paradigm promotes “a non-dualistic approach” to justify special pleading for patients who are allegedly ill in these ontologically distinct but vague ways4 (unlike patients well served by “a dualistic understanding”1). When the authors argue an explanatory model of long COVID (also known as post-COVID-19 condition) cannot succeed “on an individual pathophysiological basis alone” but necessitates “social, experiential, and psychological factors”, they ostensibly subscribe to a pluralistic understanding. However, treatment provision is narrowly defined according to their fixed understanding. An integrated model of post-COVID-19 condition that a priori rejects “simple, causative relationships between pathophysiology and symptoms”, insistent on analysing it as a multifactorial clinical entity with non-linear causal processes, flouts basic principles of parsimony, saliency,5 and incommensurability. Successful integration of epistemically distinct domains, by a single field (of functional disorders), no less, is an extraordinary claim. The authors seem content to endorse an evidence base that has historically failed to deliver on that claim. publisher: Elsevier PMID: 36997263
438	D435		Saunders, Chloe; Sperling, Søren; Bendstrup, Elisabeth	Concerns regarding a suggested long COVID paradigm – Authors' reply	https://doi.org/10.1016/S2213-2600(23)00087-5	Published	2023-04-01	Article	https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00087-5/fulltext	We thank the authors of these three helpful responses to our previously published Comment.1 We welcome Fabian Schwendinger and colleagues highlighting some important factors related to the ongoing immune response that we did not expand upon and for introducing the microbiome. Knowing which factors are necessary and sufficient to understand and treat long COVID (also known as post-COVID-19 condition) across the spectrum is an important goal of a research programme. An exploratory model is needed as the starting point of such a research programme, but scientific models are updated as research progresses.2 Our simple assertion is that post-COVID-19 condition has features of complex illness, best understood by models that can integrate illness mechanisms across domains. There are, of course, existing paradigms that address the complexity of human illness.3, 4 We suggest a paradigm capable of modelling complexity to how we think about post-COVID-19 condition. We understand the concerns of Jenny van der Palen about the historical insufficiency of similarly motivated attempts. However, we cautiously suggest that this is a different moment in history. Advancements in the past 20 years in the science of causal inference promise improved computational models of complexity.5 Such approaches are a route towards personalised precision interventions for complex and heterogeneous illnesses. To benefit, post-COVID-19 condition research must equip itself with a model that can integrate the diverse factors that research is revealing to be meaningful in post-COVID-19 condition, and investigate the likely nature of these relationships,6 without creating a model of redundant complexity. Potential illness mechanisms might be held in balance proportionally to their promise to deliver treatment interventions, as well as on the basis other pragmatic criteria.7 We also suggest that it is equally important to understand how illness mechanisms relate to each other as it is to isolate individual causes. Logic suggests it is at the crossroads of systems, where maintaining reciprocal relationships between illness mechanisms have established themselves, that one will find the most effective interventions.8 • View related content for this article Taking up just on piece of this complex puzzle, we echo Schwendinger and colleagues that cardiorespiratory deconditioning should not be considered the sole cause of exercise intolerance in post-COVID-19 condition.9 Considering the mutually interlocking interactions of illness mechanisms when they occur in the body, it becomes clear that limits of tolerance will not be the same for everyone. Some people will have scarred lungs, whereas others might have developed dysautonomia, mitochondrial changes, or microclots. On top of this, people could have neuroimmune changes strongly altering their responses into one of constant and perpetual illness.10 At the same time, movement-based therapies might be considered as working at the crossroads of multiple pathophysiological processes seen in post-COVID-19 condition.11, 12, 13, 14 In the clinic, different combinations of illness mechanisms (with complex interrelationships) will be relevant for different individuals. As highlighted by Flora Cornish and colleagues in their response, the explanation for symptoms that is co-constructed between a patient and a clinician must relate to the individual's specific symptoms and lived experience, if it is to engage the patient in treatment. We strongly echo Cornish and colleagues that clinicians should not consider only the psychological or social origins of complex illnesses, especially if this is used to dismiss, discharge, or otherwise discriminate against patients. When integrative models of illness are misused to justify blaming patients for their symptoms, this is a misunderstanding of the complex interactions that occur between body, mind, and environment. The shared wish of most health-care professionals, patients, and researchers is that effective treatment and rehabilitation options are developed and made available to help people with post-COVID-19 condition. However, there is a lot at stake in getting these conversations right. In research, models of illness that integrate complexity can paradoxically provide simpler explanations of findings, if they provide a more accurate mirror to the reality of biological functioning.2 In the clinic, our experience is that when integrative explanations are co-constructed with patients, this can clarify—rather than obscure—care needs and expand therapeutic options. publisher: Elsevier PMID: 36997265
439	D436		Verduzco-Gutierrez, Monica	Sequelae of COVID-19 and the need for Post-COVID Rehabilitation	https://doi.org/10.1016/j.pmr.2023.03.001	Published	2023-03-30	Article	https://www.pmr.theclinics.com/article/S1047-9651(23)00017-7/fulltext	The COVID-19 pandemic is defining for our generation. The pandemic has had an unprecedented impact on every aspect of our lives. It has not only affected patients, particularly those from marginalized communities, highlighting healthcare disparities, but has also had long lasting effects on the healthcare workforce for generations to come. One area that has emerged as a significant concern is the growing number of persons who are acquiring new disabilities and therefore there is a need for care from a multidisciplinary team, inclusive of Physical Medicine and Rehabilitation specialists to address those needs throughout the healthcare continuum. This edition of PM&R Clinics explores the various ways in which the pandemic has led to the emergence of new disabilities and how these challenges have been addressed by physical medicine and rehabilitation specialists and their colleagues via post-COVID rehabilitation. We address the impacts of SARS-CoV-2 infection on a person’s health in this edition of PM&R Clinics. These impacts range from acute tissue damage and critical illness polyneuromyopathy in hospitalized patients to the development of Long COVID or post-acute sequelae of SARS-CoV-2 (PASC) in individuals with mild disease. The pandemic also disrupted healthcare services and rehabilitation programs, often making it more difficult for patients to access healthcare, and this will be addressed as well. The pandemic also showed us the need for prehabilitation services, and this is also discussed. A comprehensive understanding of the impact of COVID-19 on individuals who are acquiring new disabilities and have a need for post-COVID rehabilitation is provided by a series of expert authors who have delivered quality care on the front lines, in clinics, and rehabilitation centers. Long COVID, thought to impact 10 to 20 percent of those who had COVID-19, will be the defining illness of our generation. This series offers guidance and recommendations for healthcare professionals to care for persons who may have new challenges and disabilities due to PASC, and ensure they patients have the necessary support and resources to adapt and thrive. publisher: Elsevier
440	D437		Xiao, Weijun; Liu, Xiaoyang; Wang, Hao; Huang, Yiman; Dai, Zhenwei; Si, Mingyu; Fu, Jiaqi; Chen, Xu; Jia, Mengmeng; Leng, Zhiwei; Cui, Dan; Mak, Winnie W. S.; Dong, Liming; Su, Xiaoyou	Mediating role of resilience in the relationship between COVID-19 related stigma and mental health among COVID-19 survivors: a cross-sectional study	https://doi.org/10.1186/s40249-023-01074-3	Published	2023-03-28	Study	https://doi.org/10.1186/s40249-023-01074-3	Background The global coronavirus disease 2019 (COVID-19) has caused many negative effects on physical and mental health of patients who have survived COVID-19. Apart from some long-lasting physical sequelae, those COVID-19 survivors are also suffering stigma and discrimination at different levels around the world. The current study aims to assess the role resilience played in stigma and mental disorders among COVID-19 survivors. Methods The cross-sectional study was carried out among former COVID-19 patients in Jianghan District (Wuhan, China) from June 10 to July 25, 2021. The demographic questions, the Impact of Events Scale-Revised, the Generalized Anxiety Disorder Questionnaire, the Patient Health Questionnaire, the Resilience Style Questionnaire and the Short Version of COVID-19 Stigma Scale of 12 items were used to collect relevant information of the participants. Descriptive analyses, Pearson correlation analysis and Structural Equation Modeling were used to make data description and analysis. Results A total of 1541 out of 1601 COVID-19 survivors (887 females and 654 males) were included in the analysis. Perceived stigma of those COVID-19 survivors correlates significantly with anxiety (r = 0.335, P < 0.001), depression (r = 0.325, P < 0.001) and post-traumatic stress disorder (PTSD) (r = 0.384, P < 0.001). It has a direct effect on COVID-19 survivors’ anxiety (β = 0.326, P < 0.001), depression (β = 0.314, P < 0.001), PTSD (β = 0.385, P < 0.001) and their resilience (β = − 0.114, P < 0.01). Resilience partially mediated the association between perceived stigma and anxiety (β = 0.020, P < 0.01), depression (β = 0.020, P < 0.01), and PTSD (β = 0.014, P < 0.01) among COVID-19 survivors. Conclusion Stigma has a significant negative impact on mental health, while resilience plays a mediator role in the relationship between stigma and mental health among COVID-19 survivors. Based on our study, we suggested that when designing psychological interventions for COVID-19 survivors, consideration should be taken into account to reduce stigma and improve resilience.
441	D438		Katz, Nicole B.; Hunter, Tracey L.; Flores, Laura E.; Silver, Julie K.	Addressing Rehabilitation Healthcare Disparities During the COVID-19 Pandemic and Beyond	https://doi.org/10.1016/j.pmr.2023.03.005	Published	2023-03-30	Review	https://www.pmr.theclinics.com/article/S1047-9651(23)00021-9/fulltext	Key Points •There are disproportionately higher rates of infection, severe illness, and hospitalization from acute COVID-19 infection in people from racial/ethnic minority groups as compared to White/Caucasian individuals, which likely attributes to inequitable post-acute sequelae SARS-CoV-2 and rehabilitation needs. •Individuals with disabilities have been adversely impacted by the COVID-19 pandemic and require specialized rehabilitation treatment plans. •Telemedicine should be further explored as a modality to increase accessibility of healthcare to historically and socially marginalized and underrepresented populations (e.g., individuals with disabilities, people who identify with race/ethnic minority groups, and pediatric, elderly, pregnant people).Publisher: Elsevier
442	D439		Cimolai, Nevio	The Ambiguity of Using the Long COVID Diagnosis		Published	2023-04-26	Article	https://www.cmaj.ca/content/ambiguity-using-long-covid-diagnosis, /content/ambiguity-using-long-covid-diagnosis	The Practice synopsis from Quinn et al. illustrates practical ambiguities for clinical diagnoses of Long COVID.[1] The WHO case definition, if taken literally, would encompass very broad and indeed overwhelming working bases for inclusion. Of past, overarching clinical and syndromic definitions often add to more confusion than not.[2] Outside of attributing disease to former laboratory diagnoses of SARS-CoV-2 infection, there is little other tangible diagnostic confirmation that can be credible at this time. There is the likelihood that overinclusion or overgeneralization has potential to muddle study of those that may particularly have bonafide virus-specific long-term illness. It would be more likely that confounders can be partially avoided by study of more well-defined post-infectious clinical entities rather than using overly inclusive WHO or similar definitions. Furthermore, the authors, although accepting lack of diagnostic standards, continue to project potentially confusing practice points. For example, while citing meta-analysis to project global prevalence, it would be well-known that such meta-analysis would be jeopardized by variable definitions used throughout the world for Long COVID. While expressing doubts of definitive diagnostic criteria, the authors nevertheless venture into mechanisms of pathogenesis (Practice point #3). It is yet another distant projection that any veritable such illness would be affecting most organs (Practice point #4). In Practice point #5, the authors reference Huang et al.[3] The latter details outcomes of patients who were infected during January-May, 2020, and yet it is well-known that laboratory diagnostic methods for confirming infection, which are not concretely detailed in the paper, were largely being honed in January-February of that same year even in China. Whether direct experience or published science, it is well-established that prolonged or intense illnesses can be associated with extended recoveries after non-COVID-19 viral or non-viral illnesses. In context, use of ‘Long COVID’ terminology fares at first glance to be no better than designation of the same as ‘post-viral syndrome’. There is jeopardy in having patients expect, and physicians believe, that any form of prolonged illness after COVID-19 should necessarily extract preliminary cause-and-effect relationship. Assessment and management should be focused on primary care since most patients with Long COVID diagnoses as is will convalesce over weeks to months and with return to pre-infection functioning without much intervention if any. That should not discourage academic and specialist study that could perhaps confirm more precise and differentiated long-term COVID-related diseases whether attributable directly to virus or associated viral illness pathology. Until further elucidated, the issue of ‘d
443	D440		Szabo, Sandor; Gyires, Klara; Zayachkivska, Oksana	Introduction to the ‘long COVID’ special issue	https://doi.org/10.1007/s10787-023-01197-x	Published	2023-04-01	Article	https://doi.org/10.1007/s10787-023-01197-x	Acute respiratory diseases caused by viruses or bacteria usual get resolved quickly and patients recover fast. Namely, even people who survived MERS or the first SARS, caused by another coronavirus, recovered after intensive treatment, and no subacute or chronic sequalae of the disease were noted. COVID-19, induced by the SARS-CoV-2 virus, behaved very differently, since about 3–30% of acute COVID-19 patients complain about shortness of breath, fatigue, headache, ‘brain fog’, muscle weakness and general fatigue more than 4 weeks after the initial infection. Or, even worse, some patients who have completely recovered show up with these nonspecific, multiorgan signs and symptoms. More alarming is the recent recognition that vaccination against SARS-CoV-2 does not offer protection, i.e., it may reduce the risk of long COVID, but it does not eliminate it. Needless to say, the pathogenesis of long COVID is poorly understood and no specific treatment is available; only symptomatic relief that makes both patients and clinicians very frustrated. Because of the wide-spread, worldwide occurrence of the long COVID syndrome (LCS), we organized in 2022 a symposium on long COVID, with international participation, at the Hungarian Academy of Sciences. We then asked participants to prepare short original or review articles on their presentations that appear in this special issue of Inflammopharmacology, thanks to its forward looking editor Prof. Kim Rainsford. Namely, despite of our insufficient understanding of the molecular and cellular mechanisms of LCS, we know that it is a multiorgan inflammatory process, perpetuated by cytokine storm and complicated by multiorgan thrombi. due to the damage of vascular endothelial cells. By disseminating information about the manifestation, clinical and public health aspects, as well as the ‘little we know’ about the pathogenesis of LCS, thanks to the generosity of Inflammopharmacology, we hope this publication will not only generate more data collection about the clinical manifestations and epidemiology of long COVID, but also stimulate more clinical and basic research to better understand and treat more successfully this new syndrome of the twenty-first century.
444	D441		Aquino, Katherine C.; Jarrow, Jane; Vance, Lisa; Rei-Skoff, Ametrine Elizabeth	Long COVID as a chronic illness: giving credibility to support students	https://doi.org/10.1002/dhe.31478	Published	2023-03-26	Article	https://onlinelibrary.wiley.com/doi/abs/10.1002/dhe.31478	The SARS-CoV-2 virus continues to account for millions of short- and long-term conditions that can impact an individual's cognition, breathing, and digestion. Specifically, Long COVID creates long-term health problems, diagnosable if COVID-19 symptoms present after an initial infection. Approximately 15% of U.S. adults with a prior positive COVID-19 diagnosis experience Long COVID symptoms. (See Roy H. Perlis, et al, Prevalence and Correlates of Long COVID Symptoms Among US Adults, 5 JAMA NETW OPEN 10 (October 27, 2022).) Long COVID is plaguing individuals’ ability to return to their typical functioning, including their ability to return to work. (See Katie Bach, New Data Shows Long Covid Is Keeping as Many as 4 Million People Out of Work, BROOKINGS INSTITUTE (August 24, 2022) (https://brook.gs/3xktTkC).)
445	D442		Zang, Chengxi; Zhang, Yongkang; Xu, Jie; Bian, Jiang; Morozyuk, Dmitry; Schenck, Edward J.; Khullar, Dhruv; Nordvig, Anna S.; Shenkman, Elizabeth A.; Rothman, Russell L.; Block, Jason P.; Lyman, Kristin; Weiner, Mark G.; Carton, Thomas W.; Wang, Fei; Kaushal, Rainu	Data-driven analysis to understand long COVID using electronic health records from the RECOVER initiative	https://doi.org/10.1038/s41467-023-37653-z	Published	2023-04-07	Study	https://www.nature.com/articles/s41467-023-37653-z	Recent studies have investigated post-acute sequelae of SARS-CoV-2 infection (PASC, or long COVID) using real-world patient data such as electronic health records (EHR). Prior studies have typically been conducted on patient cohorts with specific patient populations which makes their generalizability unclear. This study aims to characterize PASC using the EHR data warehouses from two large Patient-Centered Clinical Research Networks (PCORnet), INSIGHT and OneFlorida+, which include 11 million patients in New York City (NYC) area and 16.8 million patients in Florida respectively. With a high-throughput screening pipeline based on propensity score and inverse probability of treatment weighting, we identified a broad list of diagnoses and medications which exhibited significantly higher incidence risk for patients 30–180 days after the laboratory-confirmed SARS-CoV-2 infection compared to non-infected patients. We identified more PASC diagnoses in NYC than in Florida regarding our screening criteria, and conditions including dementia, hair loss, pressure ulcers, pulmonary fibrosis, dyspnea, pulmonary embolism, chest pain, abnormal heartbeat, malaise, and fatigue, were replicated across both cohorts. Our analyses highlight potentially heterogeneous risks of PASC in different populations.
446	D443		Espín, Estefanía; Yang, Chengliang; Shannon, Casey P.; Assadian, Sara; He, Daniel; Tebbutt, Scott J.	Cellular and molecular biomarkers of long COVID: a scoping review	https://doi.org/10.1016/j.ebiom.2023.104552	Published	2023-05-01	Review	https://www.sciencedirect.com/science/article/pii/S2352396423001172	Background Long-COVID (LC) encompasses diverse symptoms lasting months after the initial SARS-CoV-2 infection. Symptoms can be debilitating and affect the quality of life of individuals with LC and their families. Although the symptoms of LC are well described, the aetiology of LC remains unclear, and consequently, patients may be underdiagnosed. Identification of LC specific biomarkers is therefore paramount for the diagnosis and clinical management of the syndrome. This scoping review describes the molecular and cellular biomarkers that have been identified to date with potential use for diagnosis or prediction of LC. Methods This review was conducted using the Joanna Briggs Institute (JBI) Methodology for Scoping Reviews. A search was executed in the MEDLINE and EMBASE databases, as well as in the grey literature for original studies, published until October 5th, 2022, reporting biomarkers identified in participants with LC symptoms (from all ages, ethnicities, and sex), with a previous infection of SARS-CoV-2. Non-English studies, cross-sectional studies, studies without a control group, and pre-prints were excluded. Two reviewers independently evaluated the studies, extracted population data and associated biomarkers. Findings 23 cohort studies were identified, involving 2163 LC patients [median age 51.8 years, predominantly female sex (61.10%), white (75%), and non-vaccinated (99%)]. A total of 239 candidate biomarkers were identified, consisting mainly of immune cells, immunoglobulins, cytokines, and other plasma proteins. 19 of the 239 candidate biomarkers identified were evaluated by the authors, by means of receiver operating characteristic (ROC) curves. Interpretation Diverse cellular and molecular biomarkers for LC have been proposed. Validation of candidate biomarkers in independent samples should be prioritized. Modest reported performance (particularly in larger studies) suggests LC may encompass many distinct aetiologies, which should be explored e.g., by stratifying by symptom clusters and/or sex. Funding Dr. Tebbutt has received funding from the Canadian Institutes of Health Research (177747) to conduct this work. The funding source was not involved in this scoping review, or in the decision to submit this manuscript for publication.
447	D444		Majumder, Rajib; Ghosh, Sanmitra; Singh, Manoj K.; Das, Arpita; Roy Chowdhury, Swagata; Saha, Abinit; Saha, Rudra P.	Revisiting the COVID-19 Pandemic: An Insight into Long-Term Post-COVID Complications and Repurposing of Drugs	https://doi.org/10.3390/covid3040037	Published	2023-04-01	Review	https://www.mdpi.com/2673-8112/3/4/37	SARS-CoV-2 is a highly contagious and dangerous coronavirus that has been spreading around the world since late December 2019. Severe COVID-19 has been observed to induce severe damage to the alveoli, and the slow loss of lung function led to the deaths of many patients. Scientists from all over the world are now saying that SARS-CoV-2 can spread through the air, which is a very frightening prospect for humans. Many scientists thought that this virus would evolve during the first wave of the pandemic and that the second wave of reinfection with the coronavirus would also be very dangerous. In late 2020 and early 2021, researchers found different genetic versions of the SARS-CoV-2 virus in many places around the world. Patients with different types of viruses had different symptoms. It is now evident from numerous case studies that many COVID-19 patients who are released from nursing homes or hospitals are more prone to developing multi-organ dysfunction than the general population. Understanding the pathophysiology of COVID-19 and its impact on various organ systems is crucial for developing effective treatment strategies and managing long-term health consequences. The case studies highlighted in this review provide valuable insights into the ongoing health concerns of individuals affected by COVID-19.
448	D445		Tsuchida, Tomoya; Yoshimura, Naohito; Ishizuka, Kosuke; Katayama, Kohta; Inoue, Yoko; Hirose, Masanori; Nakagama, Yu; Kido, Yasutoshi; Sugimori, Hiroki; Matsuda, Takahide; Ohira, Yoshiyuki	Five cluster classifications of long COVID and their background factors: A cross-sectional study in Japan	https://doi.org/10.1007/s10238-023-01057-6	Published	2023-04-07	Study	https://doi.org/10.1007/s10238-023-01057-6	Purpose The long-term symptoms of coronavirus disease 2019 (COVID-19), i.e., long COVID, have drawn research attention. Evaluating its subjective symptoms is difficult, and no established pathophysiology or treatment exists. Although there are several reports of long COVID classifications, there are no reports comparing classifications that include patient characteristics, such as autonomic dysfunction and work status. We aimed to classify patients into clusters based on their subjective symptoms during their first outpatient visit and evaluate their background for these clusters. Methods Included patients visited our outpatient clinic between January 18, 2021, and May 30, 2022. They were aged ≥ 15 years and confirmed to have SARS-CoV-2 infection and residual symptoms lasting at least 2 months post-infection. Patients were evaluated using a 3-point scale for 23 symptoms and classified into five clusters (1. fatigue only; 2. fatigue, dyspnea, chest pain, palpitations, and forgetfulness; 3. fatigue, headache, insomnia, anxiety, motivation loss, low mood, and forgetfulness; 4. hair loss; and 5. taste and smell disorders) using CLUSTER. For continuous variables, each cluster was compared using the Kruskal–Wallis test. Multiple comparison tests were performed using the Dunn’s test for significant results. For nominal variables, a Chi-square test was performed; for significant results, a residual analysis was conducted with the adjusted residuals. Results Compared to patients in other cluster categories, those in cluster categories 2 and 3 had higher proportions of autonomic nervous system disorders and leaves of absence, respectively. Conclusions Long COVID cluster classification provided an overall assessment of COVID-19. Different treatment strategies must be used based on physical and psychiatric symptoms and employment factors.
449	D446		Thompson, S.	Employers must provide better support to workers with long covid	https://doi.org/10.1136/bmj.p800	Published	2023-04-06	Article	https://www.bmj.com/content/381/bmj.p800	People with long covid need to be believed, trusted, and offered flexible workplace adaptations by employers, writes S Thompson There are shining examples of success among people who’ve returned to work with long covid—where employees have been offered slow, flexible phased returns that take months or years, and where the goal is to balance work, life, and illness. In these cases, employees are at the centre of conversations about returning to work and are asked what they need and can honestly manage—not on their best day, but on their worst. Strong collaboration is needed between employee, occupational health, HR, and the employer to make this happen. Any relapses in an employee’s symptoms should be met with swift action to reduce their hours and responsibilities, in turn reducing the length and impact of the relapse. Finding yourself unexpectedly limited physically and/or cognitively because of long covid can be devastating. Yet being unable to work—either because you can’t or your employer refuses to make the adjustments that would allow you to—is a further blow, both financially and emotionally. The key to supporting this group of people is shunning stigma and embracing an open culture of understanding and trust. Many people with long covid are frontline health and other key workers who worked through the worst of the covid-19 pandemic. That they should now be disbelieved or dismissed, instead of supported, is a great injustice. Recognising that each person with long covid is unique, believing them, and personalising adaptations to their symptoms can make it possible, practical, rewarding, and fulfilling for people with long covid to work—it just needs the support of employers to make it happen. publisher: British Medical Journal Publishing Group section: Opinion PMID: 37024137
450	D447		Karpman, Michael; Zuckerman, Stephen; Morriss, Sarah	Health Care Access and Affordability Among US Adults Aged 18 to 64 Years With Self-reported Post–COVID-19 Condition	https://doi.org/10.1001/jamanetworkopen.2023.7455	Published	2023-04-10	Study	https://doi.org/10.1001/jamanetworkopen.2023.7455	Key Points Question Are adults with post–COVID-19 condition (PCC) more likely than other adults to experience health care access and affordability challenges? Findings In this survey study of 9484 US adults aged 18 to 64 years, a statistically higher rate of respondents with self-reported PCC did not obtain needed health care in the past year because of cost compared with adults without PCC. Adults with PCC were also more likely to have unmet needs because of difficulties getting timely appointments or health plan authorization, among other challenges with health care institutions or health insurance. Meaning These findings suggest that improved health care access for adults with PCC may require developing clinical protocols and addressing insurance-related barriers. Abstract Importance Many US adults report having post–COVID-19 condition (PCC), but little is known about their access to health care. Objective To estimate the association of PCC with access and affordability challenges among US adults aged 18 to 64 years. Design, Setting, and Participants This survey study used data from the Health Reform Monitoring Survey, a probability-based internet survey conducted June 17 to July 5, 2022. Participants included a nationally representative sample of 9484 US adults ages 18 to 64 years drawn from the Ipsos KnowledgePanel. Main Outcomes and Measures Self-reported PCC was defined as experiencing symptoms more than 4 weeks after first having COVID-19 that were not explained by another condition or factor. Access and affordability outcomes included having a usual place of care; forgoing care in the past 12 months because of costs, difficulty finding clinicians, or difficulty using health insurance; having problems paying family medical bills in the past 12 months; and having past-due medical debt. Results Of 19 162 panel members recruited for the survey, 9599 individuals completed the survey (completion rate, 50.1%) and 9484 respondents were included in the final analytic sample (4720 females [50.6%, weighted]; mean [SD] age, 41.0 [13.5] years). A total of 3382 respondents (36.4%; 95% CI, 34.7%-38.2%) reported ever being diagnosed with COVID-19, among whom, 833 respondents (22.5%; 95% CI, 20.9%-24.2%) reported currently having PCC. After adjustment for differences in demographic, health, and geographic characteristics, adults with PCC were more likely than 2549 adults with a COVID-19 diagnosis but no report of PCC and 6102 adults never diagnosed with COVID-19 to report unmet health care needs in the past 12 months because of the following challenges: costs (27.0%; 95% CI, 23.2%-30.7% vs 18.3%; 95% CI, 15.9%-20.7% and 17.5%; 95% CI, 15.4%-19.6%) and difficulties finding clinicians accepting new patients (16.4%; 95% CI, 14.3%-18.4% vs 10.1%; 95% CI, 8.8%-11.5% and 10.7%; 95% CI, 9.6%-11.8%), getting a timely appointment (22.0%; 95% CI, 19.3%-24.8% vs 14.4%; 95% CI, 13.2%-15.7% and 13.9%; 95% CI, 12.9%-14.8%), and getting health plan care authorization (16.6%; 95% CI, 14.6%-18.6% vs 10.8%; 95% CI, 9.6%-12.1% and 10.3%; 95% CI, 9.4%-11.2%) (P < .001 for all comparisons). Conclusions and Relevance This study found that adults aged 18 to 64 years with PCC were more likely than other adults to have difficulty getting and paying for health care. These findings suggest that policies aimed at improving access and affordability may focus on accelerating development of treatments and clinical guidelines, training clinicians, and addressing insurance-related administrative and cost barriers.
451	D448		Ramasamy, Akshara; Wang, Chumeng; Brode, W. Michael; Verduzco-Gutierrez, Monica; Melamed, Esther	Immunologic and Autoimmune Related Sequelae of SARS-CoV-2 infection: Clinical Symptoms and Mechanisms of Disease	https://doi.org/10.1016/j.pmr.2023.04.004	Published	2023-04-11	Review	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10086105/	The continued Coronavirus Disease 2019 (COVID-19) pandemic has resulted in over 600 million infections worldwide, with 10-30% of patients experiencing post-acute sequelae of SARS-CoV-2 (PASC). Despite initial signs of COVID-19 as a primarily respiratory disease, it has become clear that there is multi-organ dysfunction that can occur both in the acute stage of SARS-CoV-2 infection and PASC. Mechanistically, it is known that SARS-CoV-2 enters cells through an interaction between angiotensin-converting enzyme 2 receptor and SARS-CoV-2 Spike protein and leads to an acute illness that can last between one to four weeks. Less is known about the exact mechanism of PASC, although several proposed possibilities include direct SARS-CoV-2 tissue invasion, persistent inflammation and rise of autoimmunity, as well as potential persistence of SARS-CoV-2 virus or immunogenicity from residual SARS-CoV-2 RNA. Co-morbid conditions such as pulmonary dysfunction, cardiovascular disease, neuropsychiatric conditions, autoimmunity, hypogammaglobulinemia, and cancers likely contribute to presentation and disease outcomes in both acute SARS-CoV-2 infection and PASC. In this review, we compare evolving information on clinical symptoms, pathophysiology, and co-morbid disease risk factors between acute COVID-19 and PASC.
452	D449		Abbott, Zachary; Summers, William; Niehaus, William	Fatigue in Postacute Sequelae of COVID-19	https://doi.org/10.1016/j.pmr.2023.04.006	Published	2023-04-24	Review	https://www.pmr.theclinics.com/article/S1047-9651(23)00029-3/fulltext	Key Points • According to recent data from the U.S. Census Bureau and CDC’s National Center for Health Statistics (NCHS), 7.5% or 1 in 13 patients diagnosed with COVID-19 reported long-term symptoms • Because of the varied possible etiologies causing PASC symptoms, there does not appear to be a single laboratory evaluation, diagnostic test, or exam finding that will best identify the etiology of PASC symptoms. • At this time, there is continued investigation into which medication, therapy program, diet, infusion, or supplement that would best improve PASC symptoms. Clinics Care Points • Collect a detailed fatigue history that includes information on the wide differential diagnoses that can impact PASC symptoms including the endocrinologic (HPA axis, adrenal gland), inflammatory, cardiac, pulmonary, myofascial, neuropsychiatric (including sleep), and gastrointestinal systems • If not already completed, perform a general work up that includes complete blood count comprehensive metabolic panel, and measurement of phosphorus, thyroid-stimulating hormone, and C-reactive protein. • If needed, refer to clinical sites and providers who have more experience assisting patients with PASC symptoms. publisher: Elsevier
453	D450		Harky, Amer; Ala'Aldeen, Avesta; SundasButt; Duric, Bea; Roy, Sakshi; Zeinah, Mohamed	COVID-19 and Multiorgan Response: The Long-Term Impact	https://doi.org/10.1016/j.cpcardiol.2023.101756	Published	2023-04-22	Article	https://www.sciencedirect.com/science/article/pii/S0146280623001731	In late December 2019, severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) was discovered following a cluster of pneumonia cases in Wuhan, China. During the early stages of the COVID-19 pandemic in 2020, it was unclear how this virus would manifest into a multiorgan impacting disease. After over 750 million cases worldwide, it has become increasingly evident that SARS-CoV-2 is a complex multifaceted disease we continue to develop our understanding of. The pathophysiology of COVID-19 and how it affects these systems has many theories, ranging from direct viral infection via ACE2 receptor binding, to indirect coagulation dysfunction, cytokine storm, and pathological activation of the complement system. Since the onset of the pandemic, disease presentation, management and manifestation have changed significantly. This paper intends to expand on the long-term impacts of COVID-19 on the cardiovascular, respiratory, urinary, gastrointestinal, and vascular systems of the body and the changes in clinical management. It is evident that the pharmacological, non-pharmacological and psychological management of COVID-19 patients require clearer guidelines to improve the survival odds and long-term clinical outcomes of those presenting with severe disease.
454	D451		Regunath, Hariharan; Goldstein, Nir M.; Guntur, Vamsi P.	Long COVID: Where Are We in 2023?		Published	2023-03-01	Article	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10121126/	The term “COVID Long-Hauler” or “Long-Haul COVID” was first created by patients within few months of the onset of the pandemic.1,2 The first publication of persistent symptoms following acute COVID-19 was from Italy in July 2020, where-in, 143 hospitalized patients with acute COVID-19 between April and May 2020, who eventually tested negative by polymerase chain reaction (PCR), were followed for two months as out-patient and 87.4% had at least one persistent symptom.3 The database study from the United States (U.S.) Department of Veterans Affairs (VA) was the first largest study to show that beyond a month of illness, there existed a higher risk for death and healthcare utilization because of a variety of incident respiratory, cardiovascular, neurological, musculoskeletal, gastrointestinal and metabolic disorders.4 Subsequently, multiple other observational studies have been published.5–10 The systematic reviews that followed, were limited by the low quality of such studies, lack of standardized definition and representative biologic markers for the different organ systems involved as a part of this syndrome. To date, “long COVID” remains loosely defined by the Centers for Disease Control and Prevention (CDC) as new-onset, persistent or evolving symptoms that linger beyond four weeks following recovery from a documented acute COVID illness or diagnosis, and characterized by persistent physical or mental health issues.11 The World Health Organization (WHO) uses a longer interval of 12 weeks in the absence of an alternative explanation or diagnosis.12, 13 Consensus continues to be lacking for a unified definition due to wide variations in study criteria, measures, and quality.14 Long COVID, post-COVID conditions, post-acute sequelae of SARS CoV-2 (PASC), chronic COVID-19, ongoing symptomatic COVID-19, post-COVD-19 persistent symptoms, and post COVID-19 syndrome are all merely different terms for a set of continued symptoms that linger after recovery from acute illness. Table 1 displays the different terms, definitions still in use as proposed by organizations and website references.14, 15 Clinically useful and meaningful definitions based on the organ system of greatest involvement, or prolonged manifestations from initial illness (e.g. post-ARDS, lack of pulmonary involvement, minimal URI involvement) are yet to be sorted out.
455	D452		Lippi, Giuseppe; Henry, Brandon; Favresse, Julien; Plebani, Mario	Addressing standardized definitions of post-COVID and long-COVID	https://doi.org/10.1515/cclm-2023-0390	Published	2023-04-19	Article	https://www.degruyter.com/document/doi/10.1515/cclm-2023-0390/html	There is still large confusion and open debate as to what should be defined as a “pathological continuum of symptoms after recovering from an acute SARS-CoV-2 infection”, including confusion over appropriate terminology, such as differentiating between “post-COVID” and “long-COVID”. We are hence providing here a tentative (operative) definition, where we suggest to define “post-COVID” as continuation of signs, symptoms or even radiologic/laboratory abnormalities of an initial SARS-CoV-2 infection, irrespective of their duration, whilst we prefer to reserve the definition of “long-COVID” to those people with persistence of signs, symptoms or even radiologic/laboratory abnormalities of an initial SARS-CoV-2 infection for more than 3 months. We hope that these definitions could help harmonize the classification of patients with any type of post-COVID condition for both clinical and research purposes.
456	D453		Lenz, Christian; Slack, Mary P.E; Shea, Kimberly M.; Reinert, Ralf René; Taysi, Bülent N.; Swerdlow, David L.	Long-Term effects of COVID-19: a review of current perspectives and mechanistic insights	https://doi.org/10.1080/1040841X.2023.2190405	Published	2023-04-19	Review	https://doi.org/10.1080/1040841X.2023.2190405	Although SARS-CoV-2, responsible for COVID-19, is primarily a respiratory infection, a broad spectrum of cardiac, pulmonary, neurologic, and metabolic complications can occur. More than 50 long-term symptoms of COVID-19 have been described, and as many as 80% of patients may develop ≥1 long-term symptom. To summarize current perspectives of long-term sequelae of COVID-19, we conducted a PubMed search describing the long-term cardiovascular, pulmonary, gastrointestinal, and neurologic effects post-SARS-CoV-2 infection and mechanistic insights and risk factors for the above-mentioned sequelae. Emerging risk factors of long-term sequelae include older age (≥65 years), female sex, Black or Asian race, Hispanic ethnicity, and presence of comorbidities. There is an urgent need to better understand ongoing effects of COVID-19. Prospective studies evaluating long-term effects of COVID-19 in all body systems and patient groups will facilitate appropriate management and assess burden of care. Clinicians should ensure patients are followed up and managed appropriately, especially those in at-risk groups. Healthcare systems worldwide need to develop approaches to follow-up and support patients recovering from COVID-19. Surveillance programs can enhance prevention and treatment efforts for those most vulnerable.
457	D454		Zhang, Harrison G.; Honerlaw, Jacqueline P.; Maripuri, Monika; Samayamuthu, Malarkodi Jebathilagam; Beaulieu-Jones, Brendin R.; Baig, Huma S.; L’Yi, Sehi; Ho, Yuk-Lam; Morris, Michele; Panickan, Vidul Ayakulangara; Wang, Xuan; Weber, Griffin M.; Liao, Katherine P.; Visweswaran, Shyam; Tan, Bryce W. Q.; Yuan, William; Gehlenborg, Nils; Muralidhar, Sumitra; Ramoni, Rachel B.; Kohane, Isaac S.; Xia, Zongqi; Cho, Kelly; Cai, Tianxi; Brat, Gabriel A.	Potential pitfalls in the use of real-world data for studying long COVID	https://doi.org/10.1038/s41591-023-02274-y	Published	2023-04-13	Article	https://www.nature.com/articles/s41591-023-02274-y	A further challenge is the definition of cohorts of individuals with long COVID, as the syndrome is defined by a time to presentation and therefore requires an index date from which to observe clinical outcomes. The index date is usually an initial infection date, which may become increasingly difficult to ascertain with the use of at-home testing, the results of which are inconsistently reported in EHRs. Researchers should therefore carry out routine quality controls (such as checking the time period between initial infection and input of the ICD-10 code for long COVID), to better understand the biases present in the data. Researchers should also allow for some flexibility in defining index dates, such as considering an infection time period rather than a single date, which would help to account for delays in billing or data processing. Researchers must remain cognizant of potential biases in patient selection in real-world data; using visits to a long-COVID clinic as a proxy for true disease status is problematic. We found that, on average, only 24.0% of patients assigned the U09.9 code visited a long-COVID clinic, suggesting that the majority of patients sampled were being coded by physicians who do not work at these clinics5. Among patients who met the WHO definition of long COVID, an average of just 35.6% visited a long-COVID clinic, suggesting that many patients are not being seen at these specialty care facilities5. Studies should also account for differential data density and healthcare utilization. We found that individuals who visited a long-COVID clinic were, on average, annotated with more new-onset conditions when compared with individuals who never visited a long-COVID clinic5. Physicians working at long-COVID clinics could be more experienced with the syndrome and therefore document the disease more thoroughly. This contributes to a difference in data density and granularity, which can confound findings if not properly addressed. Studies of long COVID using real-world data must be based on robust and comprehensive clinical data sets. The incorporation of narrative data obtained using natural-language-processing techniques should better capture symptoms, and researchers should take care when using only the ICD-10 code or a visit to a long-COVID clinic as surrogates for disease status. Computational phenotypes (in which data elements are combined, using machine-learning algorithms, to describe a particular disorder) have the potential to account for the longitudinal persistence of symptoms while avoiding the misattribution of conditions that existed prior to initial infection9. Semi-supervised machine-learning algorithms are resistant to some of these challenges, and so may be powerful tools to capture complex underlying temporal patterns in the data using a small number of manually curated labels. Rule-based algorithms may be less suited for the inherent complexity of long COVID10. Real-world data have an important role in supporting research into long COVID, but these pitfalls should be considered so that the most equitable clinical and policy decisions can be informed by population-level studies. publisher: Nature Publishing Group
458	D455		Magnusson, Karin; Turkiewicz, Aleksandra; Flottorp, Signe Agnes; Englund, Martin	Prevalence of long COVID complaints in persons with and without COVID-19	https://doi.org/10.1038/s41598-023-32636-y	Published	2023-04-13	Study	https://www.nature.com/articles/s41598-023-32636-y	We studied the prevalence and patterns of typical long COVID complaints in ~ 2.3 million individuals aged 18–70 years with and without confirmed COVID-19 in a Nation-wide population-based prospective cohort study in Norway. Our main outcome measures were the period prevalence of single-occurring or different combinations of complaints based on medical records: (1) Pulmonary (dyspnea and/or cough), (2) Neurological (concentration problems, memory loss), and/or (3) General complaints (fatigue). In persons testing positive (n = 75 979), 64 (95% confidence interval: 54 to 73) and 122 (111 to 113) more persons per 10 000 persons had pulmonary complaints 5–6 months after the test compared to 10 000 persons testing negative (n = 1 167 582) or untested (n = 1 084 578), respectively. The corresponding difference in prevalence of general complaints (fatigue) was 181 (168 to 195) and 224 (211 to 238) per 10 000, and of neurological complaints 5 (2 to 8) and 9 (6–13) per 10 000. Overlap between complaints was rare. Long COVID complaints were only slightly more prevalent in persons with than without confirmed COVID-19. Still, long COVID may pose a substantial burden to healthcare systems in the future given the lasting high incidence of symptomatic COVID-19 in both vaccinated and unvaccinated individuals.
459	D456		Vasilevskaya, Anna; Mushtaque, Asma; Tsang, Michelle Y.; Alwazan, Batoul; Herridge, Margaret; Cheung, Angela M.; Tartaglia, Maria Carmela	Sex and age affect acute and persisting COVID-19 illness	https://doi.org/10.1038/s41598-023-33150-x	Published	2023-04-13	Study	https://www.nature.com/articles/s41598-023-33150-x	Long COVID is associated with neurological and neuropsychiatric manifestations. We conducted an observational study on 97 patients with prior SARS-CoV-2 infection and persisting cognitive complaints that presented to the University Health Network Memory Clinic between October 2020 and December 2021. We assessed the main effects of sex, age, and their interaction on COVID-19 symptoms and outcomes. We also examined the relative contribution of demographics and acute COVID-19 presentation (assessed retrospectively) on persistent neurological symptoms and cognition. Among our cohort, males had higher hospitalization rates than females during the acute COVID-19 illness (18/35 (51%) vs. 15/62 (24%); P = .009). Abnormal scores on cognitive assessments post-COVID were associated with older age (AOR = 0.84; 95% CI 0.74–0.93) and brain fog during initial illness (AOR = 8.80; 95% CI 1.76–65.13). Female sex (ARR = 1.42; 95% CI 1.09–1.87) and acute shortness of breath (ARR = 1.41; 95% CI 1.09–1.84) were associated with a higher risk of experiencing more persistent short-term memory symptoms. Female sex was the only predictor associated with persistent executive dysfunction (ARR = 1.39; 95% CI 1.12–1.76) and neurological symptoms (ARR = 1.66; 95% CI 1.19–2.36). Sex differences were evident in presentations and cognitive outcomes in patients with long COVID.
460	D457		Srikanth, Sujata; Boulos, Jessica R.; Dover, Tristan; Boccuto, Luigi; Dean, Delphine	Identification and diagnosis of long COVID-19: A scoping review	https://doi.org/10.1016/j.pbiomolbio.2023.04.008	Published	2023-09-01	Review	https://www.sciencedirect.com/science/article/pii/S0079610723000421	Long COVID-19 (LC-19) is a condition that has affected a high percentage of the population that recovered from the initial disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). LC-19 diagnosis is currently poorly defined because of its variable, multisystem, episodic symptoms, and lack of uniformity in the critical time points associated with the disease. Considering the number of cases, workers’ compromised efficiency or inability to return to their duties can affect organizations and impact economies. LC-19 represents a significant burden on multiple levels and effectively reduces quality of life. These factors necessitate the establishment of firm parameters of diagnoses to provide a foundation for ongoing and future studies of clinical characteristics, epidemiology, risk factors, and therapy. In this scoping review, we conducted a literature search across multiple publication sites to identify papers of interest regarding the diagnosis of LC-19. We identified 225 records of interest and categorized them into seven categories. Based on our findings, there are only 11 original papers that outline the diagnostic process in detail with little overlap. This scoping review highlights the lack of consensus regarding the definition and, thereby, the LC-19 diagnosis processes. Due to no clear directive and considering the many unknowns surrounding the natural history of the disease and further recovery/sequelae from COVID-19, continued discussion and agreement on a definition/diagnosis will help future research and management of these patients.
461	D458		Levent-Krauskopff, Sandrine; Guedj, Myriam	Les conséquences psychologiques du COVID long. Effet des incertitudes, des stratégies de coping, du soutien social et de la qualité de vie sur la dépression	https://doi.org/10.1016/j.amp.2023.05.001	Published	2023-05-13	Study	https://www.sciencedirect.com/science/article/pii/S0003448723001592	Résumé Objectifs De nombreuses personnes ont été infectées par le COVID-19 et pour une minorité d’entre elles, des symptômes multi-systémiques, fluctuants et impactant la qualité de vie, ont persisté au-delà de 20jours. Le COVID long a été d’abord défini par les patients eux-mêmes au printemps 2020 pour décrire leurs parcours de non-récupération. Plus précisément, le COVID long est défini comme « une constellation de symptômes physiques et mentaux qui peut persister ou émerger par la suite, façonnant un syndrome multi-systémique et invalidant, qui varie d’un patient à l’autre et qui fluctue dans le temps ». La persistance des symptômes du COVID, la diminution de la qualité de vie, l’incertitude quant à l’avenir, assorties parfois d’un faible soutien social perçu dans l’entourage médical et personnel, ont pu favoriser la survenue d’un trouble dépressif chez les patients atteints de COVID-long. L’objectif de cette recherche a été d’étudier l’effet des symptômes du COVID-long, des incertitudes et de l’altération de la qualité de vie sur les symptômes anxiodépressifs, tout en identifiant l’impact de variables modératrices comme les stratégies de coping et le soutien social. Matériel et méthode Deux cent quatorze participants atteints de COVID long (âgés de 18 à 68 ans, M=44ans, ET=11), dont 93 % de femmes (n=200) et 7 % d’hommes (n=14), ont participé à cette étude quantitative transversale entre les mois d’avril et de juin 2022. Ils ont décrit leurs symptômes et répondu à cinq échelles : l’échelle d’intolérance à l’incertitude (EII), l’échelle des stratégies de coping (WCC), l’échelle de mesure de la qualité de vie (MOS SF-36), l’échelle de soutien social perçu (QSSP), et l’échelle de mesure d’anxiété et de dépression (HADS). Résultats Les participants ont déclaré des symptômes de fatigue 91 % (n=171), de perte de concentration 52 % (n=111), de douleurs 51 % (n=110), de troubles du sommeil 49 % (n=104) et des difficultés de mémorisation 41 % (n=88). En comparaison avec la population générale, ils présentaient une qualité de vie dégradée, ainsi que des scores d’anxiété, de dépression et d’intolérance à l’incertitude élevés. Les scores aux stratégies de coping étaient également supérieurs aux normes relatives à la population générale, et ceux de la satisfaction du soutien social étaient généralement bons. Il est également apparu que les variables de l’intolérance à l’incertitude, de la qualité de vie et de la dépression étaient toutes corrélées entre elles. Par ailleurs, l’analyse de régression a permis de mettre en évidence les prédicteurs de la dépression. Ainsi les domaines de la qualité de vie Bien être émotionnel (β=–0,41, t (199)=–6,23, p<0,01) et Fatigue/énergie (β=–0,16, t (199)=–2,83, p<0,01) étaient des prédicteurs négatifs de la dépression, tout comme le score de coping centré sur le problème (β=–0,14, t (199)=–2,84, p<0,05). Les symptômes de la maladie en lien avec les difficultés de concentration (β=0,27, t (199)=5,16, p<0,01) et ceux impactant les projets (β=0,18, t (199)=3,31, p<0,01) étaient quant à eux des prédicteurs positifs de la dépression. Le deuxième constat de cette étude est que les personnes prises en charge spécifiquement pour leur COVID long présentaient des scores significativement moins élevés d’anxiété et d’intolérance à l’incertitude malgré des scores à certaines dimensions de la qualité de vie plus faibles. Également, les personnes prises en charge dans notre étude développaient davantage de stratégies de coping basées sur le problème et déclaraient davantage de disponibilité et de satisfaction liées au soutien social. Enfin, sur le plan de la qualité de vie, la population prise en charge a exprimé une meilleure santé psychique. Conclusions L’étude a montré, outre l’influence des symptômes du COVID long, de la qualité de vie, et des stratégies de coping sur les symptômes dépressifs, que la prise en charge spécifique des patients atteints de COVID long semble constituer en elle-même un facteur de protection de la dépression et de l’anxiété. Il apparaît donc essentiel que tout patient présentant un COVID long puisse bénéficier d’une prise en charge pluridisciplinaire spécifique à cette pathologie. Objectives Many people were infected by COVID-19 and for a minority of them, symptoms persisted beyond twenty days. These symptoms are multi-systemic, fluctuating, and impact the quality of life. Long COVID was first defined by patients themselves in the spring of 2020 to describe their recovery problems. Specifically, long COVID is defined as “a constellation of physical and mental symptoms which can persist or emerge afterwards, generating a multi-systemic and disabling syndrome, which varies from patient to patient and fluctuates over time”. The persistence of COVID symptoms, the decrease in the quality of life, the uncertainly about the future sometimes accompanied by a low level of social support perceived in the medical and personal entourage may have triggered the occurrence of a depressive disorder in patients with long COVID. The objective of this research was to study the effect of long COVID symptoms, of uncertainty and the impairment of quality of life on the development of depressive symptoms, while identifying the impact of moderating variables such as coping strategies and social support. Materials and methods Two hundred and fourteen participants with long COVID (aged 18–68, M=44, SD=11), including 93 % females (n=200) and 7% males (n=14), participated in this cross-sectional quantitative study between the months of April and June 2022. They described their symptoms and responded to five scales: the Evaluation of Intolerance of Uncertainty Scale (EII), the Coping Strategies Checklist (WCC), the Medical Outcome Study Short Form 36-item health survey (MOS SF-36), the Perceived Social Support Questionnaire (QSSP), and the Hospital Anxiety and Depression Scale (HADS). Results 91% of the participants reported symptoms of fatigue (n=171), 52% a loss of concentration (n=111), 51% pain (n=110), 49 % trouble sleeping (n=104), and 41% memory problems (n=88). Compared with the general population, they presented a poorer quality of life, as well as high scores for anxiety, depression, and intolerance of uncertainty. Scores on coping strategies were also higher than the norms for the general population, and scores on satisfaction with social support were generally good. It was also found that the variables of intolerance of uncertainty, quality of life, and depression all correlated with each other. Furthermore, the regression analysis revealed predictors of depression. The areas of quality of life and emotional well-being (β=–0.41, t(199)=–6.23, P<0.01) and fatigue/energy (β=–0.16, t(199)=–2.83, P<0.01) were negative predictors of depression, as was the problem-focused coping score (β=–0.14, t(199)=–2.84, P<0.05). Symptoms of the disorder related to concentration difficulties (β=0.27, t(199)=5.16, P<0.01) and those impacting projects (β=0.18, t(199)=3.31, P<0.01) were positive predictors of depression. The second finding of this study is that people treated specifically for their long COVID had significantly lower scores for anxiety and intolerance of uncertainty despite lower scores for certain dimensions of quality of life. The individuals who took part in our study also developed more problem-based coping strategies and reported more availability of and satisfaction with social support. Lastly, in terms of quality of life, the treated population expressed better mental health. Conclusions The study showed that, in addition to the effects of long COVID symptoms, quality of life, and coping strategies on the onset of symptoms of depression, the specific treatment of patients with long COVID seemed to constitute in itself a protective factor against depression and anxiety. It therefore would seem essential that any patient suffering from long COVID should receive multidisciplinary care specific to this pathology.
462	D459		Navarro-Olivos, Efraín; Flores-Vargas, Gilberto; Morales-Reyes, Guadalupe Irazú; Plascencia-Roldán, Jéssica Paola; Gallardo-Luna, María de Jesús; Padilla-Raygoza, Nicolás; Navarro-Olivos, Efraín; Flores-Vargas, Gilberto; Morales-Reyes, Guadalupe Irazú; Plascencia-Roldán, Jéssica Paola; Gallardo-Luna, María de Jesús; Padilla-Raygoza, Nicolás	Post-COVID-19 Condition and Its Presence in Mexico	https://doi.org/10.5772/intechopen.111697	Published	2023-05-12	Article	https://www.intechopen.com/online-first/87098	In this chapter, we discuss general information about the post-COVID-19 condition, also known as long COVID. Since it is still under research, many questions remain unanswered. Nevertheless, post-acute complications due to infections have been previously reported for other viruses. Among those complications that remain are anosmia, fatigue, cardiovascular, and pulmonary. The evidence so far suggests that these complications decrease with time. The most worrying persistent symptoms due to COVID-19 are related to neurological damage. Most post-COVID-19 complications can be treated in a standard way, but their impact on life quality is unknown. Finally, we present a rough landscape of long COVID-19 in Mexico and Latin America. More studies are needed to study this condition and its impact on public health.
463	D460		Baroni, Carolina; Potito, Jorge; Perticone, María Eugenia; Orausclio, Paola; Luna, Carlos Marcelo	How Does Long-COVID Impact Prognosis and the Long-Term Sequelae?	https://doi.org/10.3390/v15051173	Published	2023-05-01	Review	https://www.mdpi.com/1999-4915/15/5/1173	Context: We reviewed what has been studied and published during the last 3 years about the consequences, mainly respiratory, cardiac, digestive, and neurological/psychiatric (organic and functional), in patients with COVID-19 of prolonged course. Objective: To conduct a narrative review synthesizing current clinical evidence of abnormalities of signs, symptoms, and complementary studies in COVID-19 patients who presented a prolonged and complicated course. Methods: A review of the literature focused on the involvement of the main organic functions mentioned, based almost exclusively on the systematic search of publications written in English available on PubMed/MEDLINE. Results: Long-term respiratory, cardiac, digestive, and neurological/psychiatric dysfunction are present in a significant number of patients. Lung involvement is the most common; cardiovascular involvement may happen with or without symptoms or clinical abnormalities; gastrointestinal compromise includes the loss of appetite, nausea, gastroesophageal reflux, diarrhea, etc.; and neurological/psychiatric compromise can produce a wide variety of signs and symptoms, either organic or functional. Vaccination is not associated with the emergence of long-COVID, but it may happen in vaccinated people. Conclusions: The severity of illness increases the risk of long-COVID. Pulmonary sequelae, cardiomyopathy, the detection of ribonucleic acid in the gastrointestinal tract, and headaches and cognitive impairment may become refractory in severely ill COVID-19 patients.
464	D461		Szabo, Sandor	The post-COVID stress syndrome: from the three-stage stress response of Hans Selye to COVID-19	https://doi.org/10.1007/s10787-023-01179-z	Published	2023-05-15	Review	https://doi.org/10.1007/s10787-023-01179-z	Stress is the nonspecific response of the body to any demand made upon it, as defined by Hans Selye more than 80 years ago, based on his animal experiments at McGill University in Montreal, Canada. By emphasizing ‘nonspecificity’ he tried to underline that stress response is elicited my several factors, like nowadays in COVID-19, e.g., fear of infection, social isolation, death in family, loss of employment, etc. Thus, COVID-19 has been the largest new human stressor in the twenty-first century. Selye’s studies in rats also revealed 3 stages of stress response: the short initial “alarm reaction” is followed by a longer “stage of resistance”, associated with increased levels of corticosterone that is often terminated by a “stage of exhaustion”, referring to an exhausted adrenal cortex when the secretion of glucocorticoids drops. Fast forward, that is exactly what has been documented in severe cases of infections caused by the SARS-CoV-2 virus: in hospitalized COVID-19 patients initially the blood levels of cortisol not only have been elevated, but only those with high concentration of this natural anti-inflammatory corticosteroid survived vs. those who had low levels of cortisol, suggesting diminished adrenocortical functions. Furthermore, patients with very severe cases of COVID-19 who ended up in intensive care units had significantly low cortisol blood levels, compared to patients with equal severity of diseases due to other causes. Thus, these ‘natural phenomena’ in clinical medicine, unfortunately confirmed Selye’s studies in experimental animals several decades ago. Still, the good news is that astute clinicians empirically recognized this and started to give potent synthetic glucocorticoids such as dexamethasone to severe COVD-19 patients and this beneficial effect of exogenous corticoids has been extensively confirmed in the scientific literature.
465	D462		Kamanzi, Patrick; Mulundu, Gina; Mutale, Keagan; Mumba, Chibamba; Ngalamika, Owen	HIV and inflammatory markers are associated with persistent COVID‐19 symptoms	https://doi.org/10.1002/iid3.859	Published	2023-05-08	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10165949/	Background A proportion of COVID19 survivors may present with long‐COVID, which is persistent symptoms lasting four or more weeks post SARS‐CoV‐2 infection. These symptoms may be mild to severe, and may affect different organ‐systems of the body. Aims The main objective of this study was to determine the demographic, clinical and immunological factors associated with long COVID. Materials & Methods We conducted a nested case control study, with a total of 94 study participants initially included, and 64 participants matched for age and sex for biomarker analyses. Results 32/94 (34.1%) of all the participants had long COVID. Respiratory symptoms were the most common (59.5%) followed by the musculoskeletal symptoms (28.1%). HIV was an independent predictor of long COVID (adjusted odds ratio = 2.7; p = .037). In all the 64 matched cases and controls, IFN‐β was significantly higher among controls than cases. After stratifying by HIV, IL6 was significantly higher among cases than controls in the HIV‐ group (2.06 vs. 0.81 pg/mL; p = .02). On the other hand, IFN‐β was significantly higher among controls than cases in the HIV+ group (251 vs. 0 pg/mL; p = .01). Conclusion HIV infection is a risk factor for long COVID, and inflammatory markers associated with long COVID may be slightly different for HIV− and HIV+ individuals. PMID: null PMCID: PMC10165949
466	D463		Yang, Chengliang; Zhao, Hedi; Espín, Estefanía; Tebbutt, Scott J.	Association of SARS-CoV-2 infection and persistence with long COVID	https://doi.org/10.1016/S2213-2600(23)00142-X	Published	2023-05-10	Article	https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00142-X/fulltext	The presented evidence suggests that the duration of SARS-CoV-2 infection in patients can persist considerably longer than suggested by PCR-negative tests on nasopharyngeal swabs or bronchoalveolar lavage fluids. A US study including 40 947 participants with SARS-CoV-2 reinfection (two or more infections), 443 588 participants with a single SARS-CoV-2 infection, and 5 334 729 participants with no SARS-CoV-2 infection indicated that reinfection further increases risks of death, hospitalisation, and sequelae in multiple organ systems in the acute and post-acute phases.14 Persistent low-grade multisystem injury in both adults and children might result from lingering SARS-CoV-2 infection or reinfection. In another study, the circulating SARS-CoV-2 components, spike protein, and viral RNA fragments persisted for up to 1 year or longer after SARS-CoV-2 acute infection in patients with long COVID, whereas these viral components decreased or were totally absent in convalescent patients with COVID-19, as shown by ddPCR and spike protein ELISA techniques.15 These findings provide further evidence that there might be a correlation between the length of time the virus stays in the body and the risk of long COVID (appendix p 1). Therefore, rapid viral elimination in patients with persistent SARS-CoV-2 virus could be crucial. We summarised the approved and ongoing, but unpublished, randomised trials on the nirmatrelvir with ritonavir (a SARS-CoV-2 main protease inhibitor) treatment for long COVID (appendix p 3) or persistence of SARS-CoV-2 in post-COVID-19 patients (appendix p 4) listed on ClinicalTrials.gov. The results of a recent observational study on nirmatrelvir with ritonavir and long COVID are promising and intriguing, and demand further investigation. The use of nirmatrelvir with ritonavir might eliminate viral reservoirs and alleviate long COVID symptoms. Here we present a pathophysiological model of long COVID based on the persistence of SARS-CoV-2 virus that triggers a dysregulation of the immune system, followed by increased release of inflammatory cytokines and abnormal endothelial damage, ultimately leading to the development of chronic inflammation, vascular damage, hypercoagulability, microthrombosis, and multiorgan symptoms (figure). Anti-SARS-CoV-2 and other applicable therapies might contribute to viral clearance or to the reduction of inflammation to improve long COVID symptoms. Here, we present recommendations and future directions for a more effective response to long COVID (appendix p 5). We believe that a comprehensive understanding of the pathogenesis of long COVID will provide an opportunity for better outcomes for all patients experiencing similar conditions. publisher: Elsevier PMID: 37178694
467	D464		Voruz, Philippe; Assal, Frédéric; Péron, Julie A	The economic burden of the post-COVID-19 condition: Underestimated long-term consequences of neuropsychological deficits	https://doi.org/10.7189/jogh.13.03019	Published	2023-05-05	Article	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10159592/	Thus, it is essential to estimate the economic burden of the post-COVID-19 condition according to its neuropsychological disorders and phenotypes, based on multidisciplinary approaches, and statistically validated simulation analyses, as had been done for other neurological pathologies. The implementation of such interdisciplinary studies for the neuropsychological post-COVID-19 condition could have effects on encouraging the search for the most prominent neuropsychological risk factors on direct and indirect costs (as it has already been done for multiple sclerosis), designing targeted rehabilitation programs (which are currently lacking) based on evidence-based medicine, and developing specific guidelines associating neuropsychological disorders and professional recovery. This would allow employers to reduce the impact of neuropsychological disorders on their employees' productivity and positively impact society by reducing the disability costs of these syndromes and the impact on the patients and their surroundings. An external file that holds a picture, illustration, etc. Object name is jogh-13-03019-Fa.jpg Photo: Anamnesis of a simulated patient suffering from anosognosia following a SARS-CoV-2 infection and schematic explaining potential association between immunological variables and long-term cognitive disorders following a SARS-CoV-2 infection. Source: Extracted from videos produced by the Clinical and Experimental Neuropsychology Laboratory (CENLab) in the framework of the COVID-COG project (NRP 78_Swiss National Science Fondation). Available: https://www.youtube.com/@nrp7854. © CENLab. Used with permission. Finally, based on patient testimonials, a gap exists between empirical evidence of post-COVID-19 symptoms and the knowledge of health care professionals and economists. The scientific community and civil society must work together to develop effective communication channels based on empirical evidence to ensure clear and unbiased transmission of scientific results to all layers of society (e.g. patients and health care professionals, employers, economic entities, insurers) to mitigate the potential global impact of the neuropsychological post-COVID-19 condition. PMID: 37141527 PMCID: PMC10159592
468	D465		Chen, Benjamin; Julg, Boris; Mohandas, Sindhu; Bradfute, Steven B; RECOVER Mechanistic Pathways Task Force	Viral persistence, reactivation, and mechanisms of long COVID	https://doi.org/10.7554/eLife.86015	Published	2023-05-04	Review	https://doi.org/10.7554/eLife.86015	The COVID-19 global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has infected hundreds of millions of individuals. Following COVID-19 infection, a subset can develop a wide range of chronic symptoms affecting diverse organ systems referred to as post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. A National Institutes of Health-sponsored initiative, RECOVER: Researching COVID to Enhance Recovery, has sought to understand the basis of long COVID in a large cohort. Given the range of symptoms that occur in long COVID, the mechanisms that may underlie these diverse symptoms may also be diverse. In this review, we focus on the emerging literature supporting the role(s) that viral persistence or reactivation of viruses may play in PASC. Persistence of SARS-CoV-2 RNA or antigens is reported in some organs, yet the mechanism by which they do so and how they may be associated with pathogenic immune responses is unclear. Understanding the mechanisms of persistence of RNA, antigen or other reactivated viruses and how they may relate to specific inflammatory responses that drive symptoms of PASC may provide a rationale for treatment.
469	D466		Yair Mina, Yoshimi Enose-Akahata, Dima A. Hammoud, Anthony J. Videckis, Sandeep R. Narpala, Sarah E. O'Connell, Robin Carroll, Bob C. Lin, Cynthia Chen McMahan, Govind Nair, Lauren B. Reoma, Adrian B. McDermott, Brian Walitt, Steven Jacobson, David S. Goldstein, Bryan R. Smith, Avindra Nath	Deep Phenotyping of Neurologic Postacute Sequelae of SARS-CoV-2 Infection \| Neurology Neuroimmunology & Neuroinflammation	https://doi.org/10.1212/NXI.0000000000200097	Published	2023-05-05	Study	https://nn.neurology.org/content/10/4/e200097.abstract	Background and Objectives SARS-CoV-2 infection has been associated with a syndrome of long-term neurologic sequelae that is poorly characterized. We aimed to describe and characterize in-depth features of neurologic postacute sequelae of SARS-CoV-2 infection (neuro-PASC). Methods Between October 2020 and April 2021, 12 participants were seen at the NIH Clinical Center under an observational study to characterize ongoing neurologic abnormalities after SARS-CoV-2 infection. Autonomic function and CSF immunophenotypic analysis were compared with healthy volunteers (HVs) without prior SARS-CoV-2 infection tested using the same methodology. Results Participants were mostly female (83%), with a mean age of 45 ± 11 years. The median time of evaluation was 9 months after COVID-19 (range 3–12 months), and most (11/12, 92%) had a history of only a mild infection. The most common neuro-PASC symptoms were cognitive difficulties and fatigue, and there was evidence for mild cognitive impairment in half of the patients (MoCA score <26). The majority (83%) had a very disabling disease, with Karnofsky Performance Status ≤80. Smell testing demonstrated different degrees of microsmia in 8 participants (66%). Brain MRI scans were normal, except 1 patient with bilateral olfactory bulb hypoplasia that was likely congenital. CSF analysis showed evidence of unique intrathecal oligoclonal bands in 3 cases (25%). Immunophenotyping of CSF compared with HVs showed that patients with neuro-PASC had lower frequencies of effector memory phenotype both for CD4+ T cells (p < 0.0001) and for CD8+ T cells (p = 0.002), an increased frequency of antibody-secreting B cells (p = 0.009), and increased frequency of cells expressing immune checkpoint molecules. On autonomic testing, there was evidence for decreased baroreflex-cardiovagal gain (p = 0.009) and an increased peripheral resistance during tilt-table testing (p < 0.0001) compared with HVs, without excessive plasma catecholamine responses. Discussion CSF immune dysregulation and neurocirculatory abnormalities after SARS-CoV-2 infection in the setting of disabling neuro-PASC call for further evaluation to confirm these changes and explore immunomodulatory treatments in the context of clinical trials.
470	D467		Perumal, Rubeshan; Shunmugam, Letitia; Naidoo, Kogieleum; Abdool Karim, Salim S.; Wilkins, Dave; Garzino-Demo, Alfredo; Brechot, Christian; Parthasarathy, Sairam; Vahlne, Anders; Nikolich, Janko Ž.	Long COVID: a review and proposed visualization of the complexity of long COVID	https://doi.org/10.3389/fimmu.2023.1117464	Published	2023-04-20	Review	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10157068/	Post-Acute Sequelae of Severe Acute Respiratory Syndrome Coronavirus – 2 (SARS-CoV-2) infection, or Long COVID, is a prevailing second pandemic with nearly 100 million affected individuals globally and counting. We propose a visual description of the complexity of Long COVID and its pathogenesis that can be used by researchers, clinicians, and public health officials to guide the global effort toward an improved understanding of Long COVID and the eventual mechanism-based provision of care to afflicted patients. The proposed visualization or framework for Long COVID should be an evidence-based, dynamic, modular, and systems-level approach to the condition. Furthermore, with further research such a framework could establish the strength of the relationships between pre-existing conditions (or risk factors), biological mechanisms, and resulting clinical phenotypes and outcomes of Long COVID. Notwithstanding the significant contribution that disparities in access to care and social determinants of health have on outcomes and disease course of long COVID, our model focuses primarily on biological mechanisms. Accordingly, the proposed visualization sets out to guide scientific, clinical, and public health efforts to better understand and abrogate the health burden imposed by long COVID.
471	D468		Bergmans, Rachel S.; Chambers-Peeple, Keiyana; Yu, Christine; Xiao, Lillian Z.; Wegryn-Jones, Riley; Martin, Allie; Dell'Imperio, Samantha; Aboul-Hassan, Deena; Williams, David A.; Clauw, Daniel J.; DeJonckheere, Melissa	‘I'm still here, I'm alive and breathing’: The experience of Black Americans with long COVID	https://doi.org/10.1111/jocn.16733	Published	2023-05-04	Study	https://onlinelibrary.wiley.com/doi/abs/10.1111/jocn.16733	Aims and Objectives In this study, we aimed to characterize the impact of long COVID on quality of life and approaches to symptom management among Black American adults. Background As a novel condition, qualitative evidence concerning long COVID symptoms and their impact on quality of life can inform the refinement of diagnostic criteria and care plans. However, the underrepresentation of Black Americans in long COVID research is a barrier to achieving equitable care for all long COVID patients. Design We employed an interpretive description study design. Methods We recruited a convenience sample of 15 Black American adults with long COVID. We analysed the anonymized transcripts from race-concordant, semi-structured interviews using an inductive, thematic analysis approach. We followed the SRQR reporting guidelines. Results We identified four themes: (1) The impact of long COVID symptoms on personal identity and pre-existing conditions; (2) Self-management strategies for long COVID symptoms; (3) Social determinants of health and symptom management; and (4) Effects on interpersonal relationships. Conclusion Findings demonstrate the comprehensive ramifications of long COVID on the lives of Black American adults. Results also articulate how pre-existing conditions, social risk factors, distrust due to systemic racism, and the nature of interpersonal relationships can complicate symptom management. Relevance to Clinical Practice Care approaches that support access to and implementation of integrative therapies may be best suited to meet the needs of long COVID patients. Clinicians should also prioritize eliminating patient exposure to discrimination, implicit bias, and microaggressions. This is of particular concern for long COVID patients who have symptoms that are difficult to objectively quantify, such as pain and fatigue. No Patient or Public Contribution While patient perspectives and experiences were the focus of this study, patients were not involved with the design or conduct of the study, data analysis or interpretation, or writing the manuscript. What does this paper contribute to the wider global clinical community? This study helps address the underrepresentation of Black Americans in long COVID research. Findings highlight how pre-existing conditions, social risk factors, distrust due to systemic racism, and the nature of interpersonal relationships can complicate the management of long COVID symptoms. _eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/jocn.16733
472	D469		Petry Moecke, D.m.; Kwong, E.; Yao, J.; Turner, J.; Mclean, K.; den Breejen, S.; Cressman, S.; Camp, P.	Rehabilitation Needs of Adult British Columbians With Long COVID		Published	2023-05-01	Study	https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A2167
473	D470		Scholkmann, Felix; May, Christian-Albrecht	COVID-19, post-acute COVID-19 syndrome (PACS, “long COVID”) and post-COVID-19 vaccination syndrome (PCVS, “post-COVIDvac-syndrome”): Similarities and differences	https://doi.org/10.1016/j.prp.2023.154497	Published	2023-06-01	Review	https://www.sciencedirect.com/science/article/pii/S0344033823001978	Worldwide there have been over 760 million confirmed coronavirus disease 2019 (COVID-19) cases, and over 13 billion COVID-19 vaccine doses have been administered as of April 2023, according to the World Health Organization. An infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to an acute disease, i.e. COVID-19, but also to a post-acute COVID-19 syndrome (PACS, “long COVID”). Currently, the side effects of COVID-19 vaccines are increasingly being noted and studied. Here, we summarise the currently available indications and discuss our conclusions that (i) these side effects have specific similarities and differences to acute COVID-19 and PACS, that (ii) a new term should be used to refer to these side effects (post-COVID-19 vaccination syndrome, PCVS, colloquially “post-COVIDvac-syndrome”), and that (iii) there is a need to distinguish between acute COVID-19 vaccination syndrome (ACVS) and post-acute COVID-19 vaccination syndrome (PACVS) – in analogy to acute COVID-19 and PACS (“long COVID”). Moreover, we address mixed forms of disease caused by natural SARS-CoV-2 infection and COVID-19 vaccination. We explain why it is important for medical diagnosis, care and research to use the new terms (PCVS, ACVS and PACVS) in order to avoid confusion and misinterpretation of the underlying causes of disease and to enable optimal medical therapy. We do not recommend to use the term “Post-Vac-Syndrome” as it is imprecise. The article also serves to address the current problem of “medical gaslighting” in relation to PACS and PCVS by raising awareness among the medical professionals and supplying appropriate terminology for disease.
474	D471		Prashar, Jai	Long Covid: conceptualizing the challenges for public health	https://doi.org/10.1093/pubmed/fdac153	Published	2023-05-02	Article	https://doi.org/10.1093/pubmed/fdac153	Long Covid has caused significant disruption to public services, economies and population health worldwide, but no single public health approach has proven effective in its management. This essay was the winning entry for the Faculty of Public Health’s Sir John Brotherston Prize 2022.In this essay, I synthesize existing literature on public health policy in long Covid, and discuss the challenges and opportunities posed by long Covid for the public health profession. The utility of specialist clinics and community care, in the UK and internationally, is examined, as well as key outstanding issues relating to evidence generation, health inequality and defining long Covid. I then use this information to inform a simple conceptual model.The generated conceptual model integrates community- and population-level interventions; key areas of identified policy need at both levels include ensuring equitable access to long Covid care, developing screening programmes for high-risk populations, co-production of research and clinical services with patients, and using interventions to generate evidence.Significant challenges remain in the management of long Covid from a public health policy perspective. Multidisciplinary community-level and population-level interventions should be employed with a view to achieving an equitable and scalable model of care.
475	D472		El-Maradny, Yousra A; Rubio-Casillas, Alberto; Uversky, Vladimir N; Redwan, Elrashdy M	Intrinsic factors behind long-COVID: I. Prevalence of the extracellular vesicles	https://doi.org/10.1002/jcb.30415	Published	2023-05-01	Article	https://doi.org/10.1002/jcb.30415	It can be argued that the severity of COVID-19 has decreased in many countries. This could be a result of the broad coverage of the population by vaccination campaigns, which often reached an almost compulsory status in many places. Furthermore, significant roles were played by the multiple mutations in the body of the virus, which led to the emergence of several new SARS-CoV-2 variants with enhanced infectivity but dramatically reduced pathogenicity. However, the challenges associated with the development of various side effects and their persistence for long periods exceeding 20 months as a result of the SARS-CoV-2 infection, or taking available vaccines against it, are spreading horizontally and vertically in number and repercussions. For example, the World Health Organization announced that there are more than 17 million registered cases of long-COVID (also known as post-COVID syndrome) in the European Union countries alone. Furthermore, by using the PubMed search engine, one can find that more than 10 000 articles have been published focusing exclusively on long-COVID. In light of these enormous and ever-increasing numbers of cases and published articles, most of which are descriptive of the various long-COVID symptoms, the need to know the reasons behind this phenomenon raises several important questions. Is long-COVID caused by the continued presence of the virus or one/several of its components in the recovering individual body for long periods of time, which urges the body to respond in a way that leads to long-COVID development? Or are there some latent and limited reasons related to the recovering patients themselves? Or is it a sum of both? Many observations support a positive answer to the first question, whereas others back the second question but typically without releasing a fundamental reason/signal behind it. Whatever the answer is, it seems that the real reasons behind this widespread phenomenon remain unclear. This report opens a series of articles, in which we will try to shed light on the underlying causes that could be behind the long-COVID phenomenon.
476	D473		Tsilingiris, Dimitrios; Vallianou, Natalia G.; Karampela, Irene; Christodoulatos, Gerasimos Socrates; Papavasileiou, Georgios; Petropoulou, Dimitra; Magkos, Faidon; Dalamaga, Maria	Laboratory Findings and Biomarkers in Long COVID: What Do We Know So Far? Insights Into Epidemiology, Pathogenesis, Therapeutic Perspectives and Challenges	https://doi.org/10.20944/preprints202305.1487.v1	Published	2023-05-22	Review	https://www.preprints.org/manuscript/202305.1487/v1	Long COVID (LC) encompasses a constellation of long-term symptoms experienced by at least 10% of people after the initial SARS-CoV-2 infection, and so far has affected about 65 million people. The etiology of LC remains unclear; however, many pathophysiological pathways may be involved, including viral persistence; chronic, low grade inflammatory response; immune dysregulation and defective immune response; reactivation of latent viruses; autoimmunity; persistent endothelial dysfunction and coagulopathy; gut dysbiosis; hormonal dysregulation, mitochondrial dysfunction; and autonomic nervous system dysfunction. There are no specific tests for the diagnosis of LC, and clinical features including laboratory findings and biomarkers may not specifically relate to LC. Therefore, it is of paramount importance to develop and validate biomarkers that can be employed for the prediction, diagnosis and prognosis of LC and its therapeutic response. Promising candidate biomarkers that are found in some patients are markers of systemic inflammation including acute phase proteins, cytokines and chemokines; biomarkers reflecting SARS-CoV-2 persistence, reactivation of herpesviruses and immune dysregulation; biomarkers of endotheliopathy, coagulation and fibrinolysis; microbiota alterations; diverse proteins and metabolites; hormonal and metabolic biomarkers; as well as cerebrospinal fluid biomarkers. At present, there are only two reviews summarizing relevant biomarkers; however, they do not cover the entire umbrella of current biomarkers or their link to etiopathogenetic mechanisms, and the diagnostic work-up in a comprehensive manner. Herein, we aim to appraise and synopsize the available evidence on the typical laboratory manifestations and candidate biomarkers of LC, their classification based on main LC symptomatology in the frame of the epidemiological and pathogenetic aspects of the syndrome, and furthermore assess limitations and challenges as well as potential implications in candidate therapeutic interventions.
477	D474		Del Carpio-Orantes, Luis; Aguilar-Silva, Andrés	[Intertwined long COVID theories to explain its etiopathogenesis]		Published	2023-05-02	Editorial	https://pubmed.ncbi.nlm.nih.gov/37216305/	This editorial lists the main current theories on long COVID, such as the theory of viral persistence and the one of immunothrombosis associated with deregulation of the immune system; it is discussed as well their interrelation, which finally explains the etiopathogenesis and physiopathology of this new syndrome that afflicts the survivors of COVID-19; it is also discussed the link between viral persistence with the formation of amyloid microthrombi based on the hypothesis that the spike protein causes amyloidogenesis, inducing organic chronic damage that will characterize long COVID.
478	D475		Mattiuzzi, Camilla; Lippi, Giuseppe	Long COVID: An Epidemic within the Pandemic	https://doi.org/10.3390/covid3050057	Published	2023-05-01	Article	https://www.mdpi.com/2673-8112/3/5/57	he use of a uniform, validated and trustworthy definition of the term “long COVID” is certainly the most important issue when it comes to this condition, because the use of different terms can only lead to great confusion. A specific ICD-10-CM (International Classification of Diseases, Tenth Revision, Clinical Modification) code has been developed for recognizing the post-viral clinical syndrome that develops after SARS-CoV-2 infection. Such a diagnosis code U09.9 (post-COVID-19 condition, unspecified) refers specifically to patients presenting suggestive symptoms that are new or persist for at least three months after diagnosis of a SARS-CoV-2 infection and that persist for more than two months without other reasonable explanations [5]. While this definition is certainly reasonable from a clinical standpoint, the spectrum of abnormalities and/or functional impairments that develop after recovering from an acute SARS-CoV-2 infection is broad and not necessarily limited to the—always obvious—clinical signs and symptoms. For this very reason, we recently proposed to also include “radiological/laboratory abnormalities” among the possible changes observed in patients with long COVID [6]. For example, fatigue is a paradigmatic symptom in patients with long COVID (in fact, it is the most common prolonged physical consequence), encompassing a multifactorial pathogenesis [7]. On the other hand, lower than normal hemoglobin levels have been described in a large number of patients after recovering from SARS-CoV-2 infections [8], and this lower hemoglobin level can therefore be considered an important cause of fatigue that could be misrecognized or misdiagnosed, especially when patients have sedentary habits. Nevertheless, anemia should always be considered as a long COVID condition when it develops after an acute SARS-CoV-2 infection. Consequently, anemic patients, whether symptomatic or not, should be classified as having long COVID. Similarly, a variety of fibrotic abnormalities have been reported in patients with long COVID [9]. Although many biological or functional anomalies may remain asymptomatic over a long period of time, they are very likely to become symptomatic with advancing age and physiological decline. Therefore, it seems appropriate to include a set of objectives (i.e., biochemical, metabolic and structural) but still asymptomatic signs of parenchymal injury in the definition of long COVID to allow a more timely and accurate identification of patients at risk of becoming symptomatic in the future.
479	D476		Perumal, Rubeshan; Shunmugam, Letitia; Naidoo, Kogieleum; Wilkins, Dave; Garzino-Demo, Alfredo; Brechot, Christian; Vahlne, Anders; Nikolich, Janko	Biological mechanisms underpinning the development of long COVID	https://doi.org/10.1016/j.isci.2023.106935	Published	2023-06-16	Review	https://www.sciencedirect.com/science/article/pii/S258900422301012X	As COVID-19 evolves from a pandemic to an endemic disease, the already staggering number of people that have been or will be infected with SARS-CoV-2 is only destined to increase, and the majority of humanity will be infected. It is well understood that COVID-19, like many other viral infections, leaves a significant fraction of the infected with prolonged consequences. Continued high number of SARS-CoV-2 infections, viral evolution with escape from post-infection and vaccinal immunity, and reinfections heighten the potential impact of Long COVID. Hence, the impact of COVID-19 on human health will be seen for years to come until more effective vaccines and pharmaceutical treatments become available. To that effect, it is imperative that the mechanisms underlying the clinical manifestations of Long COVID be elucidated. In this article, we provide an in-depth analysis of the evidence on several potential mechanisms of Long COVID and discuss their relevance to its pathogenesis.
480	D477		Deng, Mario C.	An exercise immune fitness test to unravel mechanisms of Post-Acute Sequelae of COVID-19	https://doi.org/10.1080/1744666X.2023.2214364	Published	2023-05-16	Editorial	https://doi.org/10.1080/1744666X.2023.2214364	Within an integrated cardio-respiratory-immunological fitness concept, sequential blood sampling during a standardized brief exercise regime after recovery from acute COVID-19 can be used to improve the understanding of mechanisms of Post-Acute Sequelae of COVID-19 (PASC) Syndrome. Longitudinal follow-up data based on this protocol is posed to provide fine-granular multi-omic mechanistic and predictive information and may allow for incorporation of quantifiable information in the assessment of the disabling socio-economic impact of PASC. In a broader perspective, this integrated cardio-respiratory-immunological fitness concept may be applicable as a predictive paradigm in other debilitating chronic disease conditions such as heart failure. publisher: Taylor & Francis _eprint: https://doi.org/10.1080/1744666X.2023.2214364 PMID: 37190994
481	D478		Wang, Siwen; Huang, Tianyi; Weisskopf, Marc G.; Kang, Jae H.; Chavarro, Jorge E.; Roberts, Andrea L.	Multidimensional Sleep Health Prior to SARS-CoV-2 Infection and Risk of Post–COVID-19 Condition	https://doi.org/10.1001/jamanetworkopen.2023.15885	Published	2023-05-30	Study	https://doi.org/10.1001/jamanetworkopen.2023.15885	Key Points Question Is healthy sleep, both before and during the COVID-19 pandemic, prior to SARS-CoV-2 infection, protective against post–COVID-19 condition (PCC)? Findings In this cohort study of 1979 women who reported testing positive for SARS-CoV-2, adherence to healthy sleep before infection was inversely associated with the risk of PCC. Compared with women who had a prepandemic sleep score of 0 or 1 (least healthy), those who scored 5 (most healthy) had a 30% lower risk of PCC. Meaning These findings suggest that preinfection healthy sleep may be associated with a substantially decreased risk of PCC, indicating a need for further research on sleep health to prevent or improve symptoms of PCC. Abstract Importance The association of multiple healthy sleep dimensions with post–COVID-19 condition (PCC), also known as long COVID, has not been investigated. Objective To examine whether multidimensional sleep health before and during the COVID-19 pandemic, prior to SARS-CoV-2 infection, was associated with the risk of PCC. Design, Setting, and Participants This prospective cohort study (2015-2021) included Nurses’ Health Study II participants who reported testing positive (n = 2303) for SARS-CoV-2 infection in a substudy series of COVID-19–related surveys (n = 32 249) between April 2020 and November 2021. After exclusion for incomplete information about sleep health and nonresponse to a question about PCC, 1979 women were included in the analysis. Exposures Sleep health was measured both before (June 1, 2015, to May 31, 2017) and early (April 1 to August 31, 2020) in the COVID-19 pandemic. Prepandemic sleep score was defined according to 5 dimensions: morning chronotype (assessed in 2015), 7 to 8 hours of sleep per day, low insomnia symptoms, no snoring, and no frequent daytime dysfunction (all assessed in 2017). On the first COVID-19 substudy survey (returned between April and August 2020), average daily sleep duration and sleep quality for the past 7 days were queried. Main Outcomes and Measures SARS-CoV-2 infection and PCC (≥4 weeks of symptoms) were self-reported during 1 year of follow-up. Comparisons were examined between June 8, 2022, and January 9, 2023, using Poisson regression models. Results Of the 1979 participants reporting SARS-CoV-2 infection (mean [SD] age, 64.7 [4.6] years; 1979 [100%] female; and 1924 [97.2%] White vs 55 [2.8%] other races and ethnicities), 845 (42.7%) were frontline health care workers, and 870 (44.0%) developed PCC. Compared with women who had a prepandemic sleep score of 0 or 1 (least healthy), those who scored 5 (most healthy) had a 30% lower risk of developing PCC (multivariable-adjusted relative risk, 0.70; 95% CI, 0.52-0.94; P for trend <.001). Associations did not differ by health care worker status. No or little daytime dysfunction prepandemic and good sleep quality during the pandemic were independently associated with a lower risk of PCC (relative risk, 0.83 [95% CI, 0.71-0.98] and 0.82 [95% CI, 0.69-0.99], respectively). Results were similar when PCC was defined as having 8 or more weeks of symptoms or as having ongoing symptoms at the time of PCC assessment. Conclusions and Relevance The findings indicate that healthy sleep measured prior to SARS-CoV-2 infection, both before and during the COVID-19 pandemic, may be protective against PCC. Future research should investigate whether interventions on sleep health may prevent PCC or improve PCC symptoms.
482	D479		Iv, Edward J. Weldon; Hong, Bradon; Hayashi, Jeffrey; Goo, Connor; Carrazana, Enrique; Viereck, Jason; Liow, Kore; Iv, Edward J. Weldon; Hong, Bradon; Hayashi, Jeffrey; Goo, Connor; Carrazana, Enrique; Viereck, Jason; Liow, Kore	Mechanisms and Severity of Exercise Intolerance Following COVID-19 and Similar Viral Infections: A Comparative Review	https://doi.org/10.7759/cureus.39722	Published	2023-05-30	Review	https://www.cureus.com/articles/153767-mechanisms-and-severity-of-exercise-intolerance-following-covid-19-and-similar-viral-infections-a-comparative-review	Approximately 19% of the population is suffering from “Long COVID”, also known as post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PASC), which often results in exercise intolerance. As COVID infections continue to be common, studying the long-term consequences of coronavirus disease (COVID) on physical function has become increasingly important. This narrative review will aim to summarize the current literature surrounding exercise intolerance following COVID infection in terms of mechanism, current management approaches, and comparison with similar conditions and will aim to define limitations in the current literature. Multiple organ systems have been implicated in the onset of long-lasting exercise intolerance post-COVID, including cardiac impairment, endothelial dysfunction, decreased VO2 max and oxygen extraction, deconditioning due to bed rest, and fatigue. Treatment modalities for severe COVID have also been shown to cause myopathy and/or worsen deconditioning. Besides COVID-specific pathophysiology, general febrile illness as commonly experienced during infection will cause hypermetabolic muscle catabolism, impaired cooling, and dehydration, which acutely cause exercise intolerance. The mechanisms of exercise intolerance seen with PASC also appear similar to post-infectious fatigue syndrome and infectious mononucleosis. However, the severity and duration of the exercise intolerance seen with PASC is greater than that of any of the isolated mechanisms described above and thus is likely a combination of the proposed mechanisms. Physicians should consider post-infectious fatigue syndrome (PIFS), especially if fatigue persists after six months following COVID recovery. It is important for physicians, patients, and social systems to anticipate exercise intolerance lasting for weeks to months in patients with long COVID. These findings underscore the importance of long-term management of patients with COVID and the need for ongoing research to identify effective treatments for exercise intolerance in this population. By recognizing and addressing exercise intolerance in patients with long COVID, clinicians can provide proper supportive interventions, such as exercise programs, physical therapy, and mental health counseling, to improve patient outcomes.
483	D480		Wu, Qiao	Understanding the burden of post-covid-19 condition	https://doi.org/10.1136/bmj.p932	Published	2023-05-31	Editorial	https://www.bmj.com/content/381/bmj.p932	Most patients with persistent covid symptoms after infection recovered between six months and 12 months, but those who did not recover seemed to develop chronic health problems and had very little improvement after month 12. People who were symptomatic at all follow-ups or reported worsened symptoms were more likely to be older and to have pre-existing health problems. This new study identifies remaining uncertainties and indicates where future research is needed.7 Post-covid-19 condition may induce a wide variety of symptoms, each with independent courses and complex inter-relationships. The study did not aim to evaluate all possible symptoms but surveying for more in future studies might show a more complete picture of the experience of post-covid-19 condition. Another recent The BMJ article3 provides a good example. The authors examined 30 postacute covid symptoms and identified 13 combinations of symptom clusters, including patterns of cluster co-occurrence. The most prevalent symptom cluster observed was fatigue, which frequently co-occurred with neurocognitive impairment and chest symptoms. An important limitation of Ballouz and colleagues’ study was its focus on only wild type SARS-CoV-2 in an unvaccinated population. Empirical evidence accounting for vaccination status and later virus strains is emerging. For example, another study8 found that vaccinated individuals with breakthrough infections had a significantly lower risk of persistent dyspnea and hair loss 30-90 days after infection when compared with unvaccinated individuals. Additionally, the risks of developing post-covid-19 condition were not significantly different among people who had an infection with wild type, alpha, or delta variants. Post-covid-19 condition remains a global public health crisis. The design of future treatments, clinical trials, and policy interventions will depend on robust studies based on high quality population level data. Further studies focusing on more recent phases of the pandemic, and accounting for complexities (eg, more virus strains, vaccination statuses, and reinfections), will be particularly valuable. Additionally, in view of the complexity of symptom trajectories and the unique disease burden experienced by each individual patient with post-covid-19 condition, patients should be more closely involved in the design and conduct of these studies going forward. publisher: British Medical Journal Publishing Group section: Editorial PMID: 37257892
484	D481		Gallegos, Miguel; Morgan, Melissa L; Burgos-Videla, Carmen; Caycho-Rodríguez, Tomás; Martino, Pablo; Cervigni, Mauricio	The impact of long Covid on people’s capacity to work	https://doi.org/10.1093/annweh/wxad029	Published	2023-05-30	Article	https://doi.org/10.1093/annweh/wxad029	This commentary addresses the post-COVID-19 syndrome and its implications for workers’ health. Post-COVID-19 syndrome consists of a set of physiological and psychological symptoms resulting from SARS-CoV-2 (COVID-19) infection, which occur continuously for several weeks or months. Therefore, it is an affectation that has multiple consequences for the recovery of people’s health, and compromises the ability to perform daily activities, including work, whether in person or remotely. Although several studies have been published so far, and several long-term consequences on people’s health have been demonstrated, most have not adequately delved into the implications for the health of workers, their families, and the socioeconomic cost for governments. The aim of this paper is to highlight this public health issue and to encourage more specialized research.
485	D482		Thaweethai, Tanayott; Jolley, Sarah E.; Karlson, Elizabeth W.; Levitan, Emily B.; Levy, Bruce; McComsey, Grace A.; McCorkell, Lisa; Nadkarni, Girish N.; Parthasarathy, Sairam; Singh, Upinder; Walker, Tiffany A.; Selvaggi, Caitlin A.; Shinnick, Daniel J.; Schulte, Carolin C. M.; Atchley-Challenner, Rachel; Horwitz, Leora I.; Foulkes, Andrea S.; RECOVER Consortium Authors for the RECOVER Consortium	Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection	https://doi.org/10.1001/jama.2023.8823	Published	2023-05-25	Study	https://doi.org/10.1001/jama.2023.8823	Key Points Question What symptoms are differentially present in SARS-CoV-2–infected individuals 6 months or more after infection compared with uninfected individuals, and what symptom-based criteria can be used to identify postacute sequelae of SARS-CoV-2 infection (PASC) cases? Findings In this analysis of data from 9764 participants in the RECOVER adult cohort, a prospective longitudinal cohort study, 37 symptoms across multiple pathophysiological domains were identified as present more often in SARS-CoV-2–infected participants at 6 months or more after infection compared with uninfected participants. A preliminary rule for identifying PASC was derived based on a composite symptom score. Meaning A framework for identifying PASC cases based on symptoms is a first step to defining PASC as a new condition. These findings require iterative refinement that further incorporates clinical features to arrive at actionable definitions of PASC. Abstract Importance SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals. Objective To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections. Design, Setting, and Participants Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling. Exposure SARS-CoV-2 infection. Main Outcomes and Measures PASC and 44 participant-reported symptoms (with severity thresholds). Results A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months. Conclusions and Relevance A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.
486	D483		Gross, Robert; Lo Re, Vincent, III	Disentangling the Postacute Sequelae of SARS-CoV-2: E Unibus Pluram (From One, Many)	https://doi.org/10.1001/jama.2023.8961	Published	2023-05-25	Editorial	https://doi.org/10.1001/jama.2023.8961	Early in the COVID-19 pandemic, patients and clinicians reported the persistence of initial symptoms and the onset of new symptoms after the acute phase of SARS-CoV-2 infection, collectively referred to as postacute sequelae of SARS-CoV-2 infection (PASC), or more colloquially called long COVID. Persistent anosmia as well as debilitating physical symptoms, such as chronic cough, gastrointestinal symptoms, fatigue, malaise, myalgias, pain, and lack of clarity of thought (“brain fog”), with or without obvious organ dysfunction, were prominent ailments identified by numerous patients after acute COVID-19. This phenomenon has been a major focus of research. Investigators have sought to determine the pathogenesis of illness with a goal of designing effective interventions to mitigate or resolve the symptoms.
487	D484		Clauw, Daniel J.; Calabrese, Leonard	Rheumatology and Long COVID: lessons from the study of fibromyalgia	https://doi.org/10.1136/ard-2023-224250	Published	2023-05-25	Article	https://ard.bmj.com/content/early/2023/05/24/ard-2023-224250	Rheumatology, such as other subspecialties, has both a unique perspective to offer as well as an evolving role to play in the global COVID-19 pandemic. Our field has already contributed meaningfully to the development and repurposing of many of the immune-based therapeutics which are now standard treatments for severe forms of the disease as well as to the understanding of the epidemiology, risk factors and natural history of COVID-19 in immune-mediated inflammatory diseases. Still in evolution is our potential to contribute to burgeoning research efforts in the next phase of the pandemic: the syndrome of postacute sequelae of COVID-19 or Long COVID. While our field brings many assets to the study of Long COVID including our expertise in the investigation of chronic inflammation and autoimmunity, our Viewpoint focuses on the strong similarities between fibromyalgia (FM) and Long COVID. While one can speculate on how embracing and confident practising rheumatologists already are regarding these interrelationships, we assert that in the emerging field of Long COVID the potential lessons from the field of fibromyalgia care and research have been underappreciated and marginalised and most importantly now deserve a critical appraisal.
488	D485		Faghy, Mark A.; Ashton, Ruth EM; Skipper, Lindsay; Kane, Binita	Long COVID – integrated approaches to chronic disease management?	https://doi.org/10.1016/j.amjmed.2023.04.037	Published	2023-05-23	Article	https://www.amjmed.com/article/S0002-9343(23)00332-7/fulltext	This creates an important and timely opportunity to review the approaches taken to support Long COVID patients and more broadly the approach to managing and treating chronic disease. Utilising previous approaches there is a need to develop and implement a substantive pathways that are underpinned with whole system thinking approaches15, and enriched with interdisciplinary consideration and practice. In the context of Long COVID it feels appropriate to convene the relevant specialists to discuss the mechanistic and integrated issues that affect Long COVID patients. Again, acknowledge the broad challenges of Long COVID, it might be prudent to develop assessment services that incorporate objective triaging and monitoring to establish each patient's presentation and increase the understanding between the dynamic and the interrelating cause-effect factors that underpin Long COVID. This information obtained over time (i.e., whilst waiting for an appointment) can be used to direct patients towards the most important appropriate support services. Adopting such approaches will undoubtedly improve patient outcomes and experiences but it represents a step change in thinking that will cause logistical challenges as all parties will need to listen, learn, and collaborate with each other and seek a mutual understanding and approach. Moving towards a coordinated and integrated approach could lead to the design and implementation of efficient and effective services that can address a growing and significant burden to healthcare services which could be considered for adoption more broadly long-term conditions. Long COVID is an unprecedented burden to healthcare systems and patients worldwide, and the long-term impacts for patients and healthcare providers are still to be realised16. The authors acknowledge that the development of Long COVID services is still very much embryonic, however, services are required at pace and scale to support the >2 million people in the UK and >150 million globally living with persistent and debilitating symptom profiles. publisher: Elsevier PMID: 37230401

	A	B	C	D	E	F	G	H	I	J	K	M
1	Ref	PPLC	Authors	Title	DOI	Peer reviewed	Date	type	Link	Keys	Clés

2	MS01		Angelo Carfì, MD1; Roberto Bernabei, MD1; Francesco Landi,	Persistent Symptoms in Patients After Acute COVID-19	https://doi.org/10.1001/jama.2020.12603		July 9, 2020	Research Letter	https://jamanetwork.com/journals/jama/fullarticle/2768351	A letter in the prestigious JAMA on persistent symptoms after acute covid. Small sample, without control group nor study of confounding factors. his study found that in patients who had recovered from COVID-19, 87.4% reported persistence of at least 1 symptom, particularly fatigue and dyspnea.	Une lettre dans JAMA sur les symptômes persistants après une covid aiguë. Faible échantillon, sans groupe contrôle ni étude de facteurs confondants.
3	MS02		Hassaan Ahmed, Kajal Patel, Darren Greenwood, Stephen Halpin,	LONG-TERM CLINICAL OUTCOMES IN SURVIVORS OF CORONAVIRUS OUTBREAKS AFTER HOSPITALISATION OR ICU ADMISSION: A SYSTEMATIC REVIEW AND META-ANALYSIS OF FOLLOW-UP STUDIES	https://doi.org/10.1101/2020.04.16.20067975	pre-print	April 22, 2020.		https://www.medrxiv.org/content/10.1101/2020.04.16.20067975v1	As a comparison with #COVID19, a pre-print meta-analysis (not peer-reviewed) of the long-term sequelae of hospitalized patients affected by the 2 coronaviruses SARS (SARS-CoV, 2003) and MERS (MERS-CoV , 2014-2016).	Pour comparaison avec la #COVID__19, une méta-analyse en pré-print (non évaluée) des séquelles à long terme des patients hospitalisés touchés par les 2 coronavirus SRAS (SARS-CoV, 2003) et MERS (MERS-CoV, 2014-2016).
4	MS03	AXD	Mark W. Tenforde, MD, PhD1; Sara S. Kim, MPH1,2; Christopher J. Lindsell, PhD3	Symptom Duration and Risk Factors for Delayed Return to Usual Health Among Outpatients with COVID-19 in a Multistate Health Care Systems Network — United States, March–June 2020	http://dx.doi.org/10.15585/mmwr.mm6930e1	published opinion	July 31, 2020	Article	https://www.cdc.gov/mmwr/volumes/69/wr/mm6930e1.htm	The US public health agency CDC details the persistence of symptoms of covid (including for young patients) in a study recently published. In a multistate telephone survey of symptomatic adults who had a positive outpatient test result for SARS-CoV-2 infection, 35% had not returned to their usual state of health when interviewed 2–3 weeks after testing. Among persons aged 18–34 years with no chronic medical conditions, one in five had not returned to their usual state of health. Nonhospitalized COVID-19 illness can result in prolonged illness and persistent symptoms, even in young adults and persons with no or few chronic underlying medical conditions. Public health messaging should target populations that might not perceive COVID-19 illness as being severe or prolonged, including young adults and those without chronic underlying medical conditions. Preventative measures, including social distancing, frequent handwashing, and the consistent and correct use of face coverings in public, should be strongly encouraged to slow the spread of SARS-CoV-2.	L'agence américaine de santé publique CDC détaille la persistance des symptômes du covid (y compris chez des patients jeunes) dans une étude publiée ce weekend.
5	MS04		Association française du syndrome de fatigue chronique	FATIGUE POST-COVID19		published opinion	Juin 2020	Communiqué de presse	http://www.asso-sfc.org/documents/an-454-Communique-Post-covid-ASFC.pdf	The French Association of Chronic Fatigue Syndrome (@AssociationSfc) publishes a guide on post-covid fatigue19, discussing the hypothesis of the onset of myalgic encephalomyelitis (ME - chronic fatigue syndrome CFS).	L'Association française du syndrome de fatigue chronique (@AssociationSfc) publie un guide sur la fatigue post-covid19, évoquant l'hypothèse du déclenchement d'une encéphalomyélite myalgique (EM - syndrome de fatigue chronique SFC).
6	MS05		David T Arnold, Fergus W Hamilton, Alice Milne, Anna Morley, Jason Viner, Marie Attwood, et al.	Patient outcomes after hospitalisation with COVID-19 and implications for follow-up; results from a prospective UK cohort.	https://doi.org/10.1136/thoraxjnl-2020-216086	pre-print	August 14, 2020.		https://www.medrxiv.org/content/10.1101/2020.08.12.20173526v1	British prospective longitudinal study (North Bristol NHS Trust) in pre-print (not yet reviewed) on August 14, carried out on 110 patients, 90 days of covid symptoms.	Étude longitudinale prospective anglaise (North Bristol NHS Trust) en pré-print (pas encore relue) le 14 août, effectuée sur 110 patients, #apresJ90 de symptômes covid.
7	MS06		Joseph R. Larsen1,2, Margaret R. Martin3, John D. Martin4, Peter Kuhn2* and James B. Hicks2*	Modeling the Onset of Symptoms of COVID-19	https://doi.org/10.3389/fpubh.2020.00473	published	13 August 2020	ORIGINAL RESEARCH ARTICLE	https://www.frontiersin.org/articles/10.3389/fpubh.2020.00473/full	The most common order of symptoms of covid, in severe and non-severe cases. The first two symptoms of COVID-19, SARS, and MERS are fever and cough. However, the upper GI tract (i.e., nausea/vomiting) seems to be affected before the lower GI tract (i.e., diarrhea) in COVID-19, which is the opposite from MERS and SARS.	L'ordre le plus fréquent des symptômes de la covid, dans les cas sévères et non-sévères.
8	MS07		Eve Garrigues Paul Janvier Yousra Kherabi Vasco Honsel	Post-discharge persistent symptoms and health-related quality of life after hospitalization for COVID-19	https://doi.org/10.1016/j.jinf.2020.08.029	published opinion	August 24, 2020	LETTER TO THE EDITOR	https://www.journalofinfection.com/article/S0163-4453(20)30562-4/fulltext	A letter published 08/24 in Journal of Infection notes symptoms almost 4 months after hospitalization for covid for 120 patients (24 in intensive care unit). Beaujon Hospital (Paris).	Une lettre publiée le 24/08 dans Journal of Infection note les symptômes presque 4 mois après une hospitalisation pour covid pour 120 patients (24 passés en unité de soins intensifs). Hôp. Beaujon (Paris).
9	MS08		CIDRAP	COVID-19 symptoms can persist for months after hospital stay		published opinion	Aug 25, 2020	Article	https://www.cidrap.umn.edu/news-perspective/2020/08/covid-19-symptoms-can-persist-months-after-hospital-stay		_
10	MS09		Vellingiri Balachandar 1, Iyer Mahalaxmi 2, Mohandevi Subramaniam	Follow-up studies in COVID-19 recovered patients - is it mandatory?	https://doi.org/10.1016/j.scitotenv.2020.139021	published	2020 Aug 10	Review	https://www.sciencedirect.com/science/article/abs/pii/S0048969720325389?via%3Dihub		Suivi en Inde
11	MS10		Survivor Corps	COVID-19 “Long Hauler” Symptoms Survey Report			25/07/2021	Survey	https://static1.squarespace.com/static/5e8b5f63562c031c16e36a93/t/5f25b5bfb3f4f86b1bf4d5f5/1596306894541/2020+Survivor+Corps+COVID-19+%27Long+Hauler%27+Symptoms+Survey+Report+%28revised+July+25.1%29.pdf	https://dig.abclocal.go.com/wls/documents/2020/072720-wls-covid-symptom-study-doc.pdf	Suivi "long-hauler" Indiana
12	MS11		Mark W. Tenforde, MD, PhD,corresponding author1 Sara S. Kim, MPH,1,2 Christopher	Symptom Duration and Risk Factors for Delayed Return to Usual Health Among Outpatients with COVID-19 in a Multistate Health Care Systems Network — United States, March–June 2020	https://doi.org/10.15585%2Fmmwr.mm6930e1	published	2020 Jul 31	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392393/		Dans une étude US sur un panel randomisé de patients testés positifs non hospitalisés, l'état de santé antérieur n'est pas revenu au bout d'environ 20 jours pour plus d'un tiers des sondés. Toux, fatigue et essoufflement sont les symptômes les plus cités.
13	MS12		Mandal	‘Long-COVID’: a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19	http://dx.doi.org/10.1136/		21-Sep-20		https://thorax.bmj.com/content/thoraxjnl/early/2020/11/09/thoraxjnl-2020-215818.full.pdf	Initial reports are emerging of significant ongoing symptom burden1 termed ‘Long-COVID’, and of changes in lung function2 and imaging.3	while symptom burden in subjects recovering from hospital admission with COVID-19 had generally improved at early follow-up, 53% reported persistent breathlessness, 34% persistent cough and 69% persistent fatigue. Fifteen per cent were depressed.
14	MS13	Yes	Ladds	Persistent symptoms after Covid-19: qualitative study of 114 “long Covid” patients and draft quality criteria for services	https://doi.org/10.1186/s12913-020-06001-y	Published	14-Oct-20	Published after pre-print https://www.medrxiv.org/content/10.1101/2020.10.13.20211854v1	https://bmchealthservres.biomedcentral.com/articles/10.1186/s12913-020-06001-y	“Long” Covid is the name patients gave to Covid-19 infection that has not got better yet.1 Working definitions of ‘post-acute’ (symptoms beyond 3-4 weeks) and ‘chronic’ (symptoms beyond 12 weeks) Covid-19 are yet to be formally confirmed.23 A positive test for Covid-19 is not a prerequisite for diagnosis of post-acute or chronic disease, since many people were never tested.4 a heavy sense of loss and stigma; difficulty accessing and navigating services; difficulty being taken seriously and achieving a diagnosis; disjointed and siloed care (including inability to access specialist services); variation in standards (e.g. inconsistent criteria for seeing, investigating and referring patients); variable quality of the therapeutic relationship (some participants felt well supported while others felt “fobbed off”); and possible critical events (e.g. deterioration after being unable to access services). Emotional touch points in participants’ experiences informed ideas for improving services.	People with long Covid experience a confusing array of persistent and fluctuating symptoms including cough, breathlessness, fever, sore throat, chest pain, palpitations, cognitive deficits, myalgia, neurological symptoms, skin rashes, and diarrhoea; some also have persistent or intermittent low oxygen saturations.249-13 The cause of persisting symptoms is unknown, but probably involves several different disease mechanisms including an inflammatory reaction with a vasculitic component.14-16 Documented post-acute sequelae include myo- or pericarditis, heart failure, arrhythmias, and thrombo-embolic complications including myocardial infarction, stroke and venous thrombosis.1718
15	MS14		Cirulli	Long-term COVID-19 symptoms in a large unselected population	https://doi.org/10.1101/2020.10.07.20208702	under-review	24-Oct-20		https://www.medrxiv.org/content/10.1101/2020.10.07.20208702v2	The long-term symptoms most enriched in those with COVID-19 are anosmia, ageusia, difficulty concentrating, dyspnea, memory loss, confusion, headache, heart palpitations, chest pain, pain with deep breaths, dizziness, and tachycardia. We additionally observe that individuals who had an initial symptom of dyspnea are significantly more likely to develop long-term symptoms.	_
16	MS15		Maria Skaalum Petersen, Marnar Fríðheim Kristiansen, Katrin Dahl Hanusson,	Long COVID in the Faroe Islands - a longitudinal study among non-hospitalized patients	https://doi.org/10.1093/cid/ciaa1792	published	30 November 2020	Study	https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1792/6012625		Une étude importante sur la prévalence du covid long. Aux Îles Féroé, lors d'une campagne de tests PCR intense entre avril et juin, 187 personnes furent testées positives. 180 d'entre eux (soit 96%) ont accepté un suivi téléphonique jusqu'en août. / La moyenne d'âge est de 40 ans. Seuls 8 furent hospitalisés. Après 4 mois, plus de 50% gardent des symptômes. 33% ont 1 ou 2 symptômes, et 19% en ont 3 ou plus. Les trois symptômes les plus fréquents sont la fatigue prolongée, la perte d'odorat et les douleurs articulaires. /La tranche d'âge intermédiaire (18 à 66 ans) est en proportion la plus touchée. Même si elle est déclarative, cette étude est considérée comme l'une des moins impactées par les biais de sélection. NB : Selon ces données inédites par leur mode de sélection Après 4 mois les symptômes persistants des testés positifs de la tranche 18-34 ans sont : légers : 32% Modérés : 14% Sévères : 11% Après 4 mois, ceux de la tranche 35-49 ans sont : légers : 51% Modérés : 33% Sévères : 8%
17	MS16	Yes	Dominique Salmon MD, PhD , Dorsaf Slama MD , Thomas De Broucker MD , Marina Karmochkine MD ,	Clinical, virological and imaging profile in patients with Persistent or Resurgent forms of COVID-19: a cross-sectional study	https://doi.org/10.1016/j.jinf.2020.12.002	published	2 December 2020	Study	https://www.sciencedirect.com/science/article/pii/S0163445320307623		Une étude française sur une petite cohorte de patients infectés présentant des symptômes post-covid indique que pour la moitié d'entre eux, une période de 2 à 6 semaines s'est écoulée entre la phase aiguë et la réapparition de symptômes. L'étude émet des hypothèses sur le covid long : 1/ - une persistance virale active 2/ - une réponse immunitaire excessive menant à un état auto-inflammatoire chronique chez des personnes prédisposées génétiquement 3/ - le développement d'une encéphalomyélite myalgique, déjà observée pour le SRAS. Enfin, même si la cause de stress post-traumatique n'est pas exclue, l'étude précise que la répétition de troubles neurologiques et cardiothoraciques similaires, parfois objectivés par l'imagerie cardiaque, suggère une réelle entité post-covid.	N001B
18	MS17		Julie Walsh-Messinger, Hannah Manis, Alison Vrabec, Jenna Sizemore, Karyn Bishof, Marcella Debidda	The Kids Are Not Alright: A Preliminary Report of Post-COVID Syndrome in University Students	https://doi.org/10.1101/2020.11.24.20238261	pre-print	November 29, 2020		https://www.medrxiv.org/content/10.1101/2020.11.24.20238261v2	51% of participants who contracted COVID-19 (N=43) experienced symptoms ≥28 days and were classified as having post-COVID syndrome; all but one (96%) were female. During acute illness the post-COVID group, compared to those who fully recovered, experienced significantly more chest pain (64% vs 14%; P=.002), fatigue (86% vs 48%; P=.009), fever (82% vs 48%; P=.02), olfactory impairment (82% vs 52%; P=.04), headaches (32% vs 5%; P<.05), and diarrhea (32% vs 5%; P<.05).	_
19	MS18		Mayssam Nehme, MDOlivia Braillard, MDGabriel Alcoba, MDSigiriya Aebischer Perone, MD	COVID-19 Symptoms: Longitudinal Evolution and Persistence in Outpatient Settings		published	8 December 2020		https://www.acpjournals.org/doi/10.7326/M20-5926		Les résultats de l'étude suisse COVICARE sur la persistance de symptômes covid long à un mois- un mois et demi. L'étude retrouve la symptomatologie déjà décrite ailleurs, même si ses biais de sélection importants empêchent une estimation de prévalence.
20	MS19		Office of National Statistics (GB)	The prevalence of long COVID symptoms and COVID-19 complications		published	16 December 2020	Article	https://www.ons.gov.uk/news/statementsandletters/theprevalenceoflongcovidsymptomsandcovid19complications		L'Office national britannique des statistiques fait un point sur la prévalence des symptômes du covid long et indique que 10% des testés positifs ont des symptômes qui perdurent au delà de 3 mois.
21	MS20	PESE	Hannah E Davis, Gina S Assaf, Lisa McCorkel, Hannah Wei, Ryan J Low, Yochai Reem, Signe Redfield, Jared P Austin, Athena Akrami	Characterizing Long COVID in an International Cohort: 7 Months of Symptoms and Their Impact	https://doi.org/10.1101/2020.12.24.20248802	pre-print	December 26, 2020	Survey	https://www.medrxiv.org/content/10.1101/2020.12.24.20248802v2	Athena Akrami @AthenaAkrami >8k responded to our survey. In this work, we focus on 3762 cases w illness lasting >28 days & onset prior to June 2020, which gives us the chance to characterize symptom profile & time course over 7 months, along w the impact on daily life, work & return to baseline health 1/Of the 3762 respondents, 2454 experienced symptoms for at least 180 days (6 months). 257 respondents (6.8%) recovered after day 28 of illness. In this Long COVID cohort The probability of symptoms lasting beyond 35 weeks was 91.8%. 2/The majority of respondents reported “moderate” symptoms throughout the course. In those who recovered in less than 90 days, the average number of symptoms peaked at week2 (11.35); in those who did not recover in 90 days, the average # of symptoms peaked at month2 (17.16!) 3/Prevalence of 205 symptoms in 10 organ systems was estimated, with 66 symptoms traced over seven months. We had special focus on neurological/psychiatric symptoms (calling them neuropsychiatric) Here's symptom prevalence estimates for non-neuropsychiatric symptoms. 4/and prevalence estimates for neuropsychiatric symptoms in 9 groups: -Cognitive Functioning (>85%) -Memory (>70%) -Speech and Language (~50%) -Sensorimotor symptoms (>90%) -Sleep (~80%) -Headaches (~80%) -Emotion and Mood (~90%) -Taste and Smell (~60%) -Hallucinations (>15%) 5/88.0% of the total respondents (3310) experienced either cognitive dysfunction or memory loss, with substantial impact on daily life, particularly Work. These symptoms had similar impacts across all age groups. 6/To characterize the progression of the 66 symptoms over seven months, we estimated symptom time courses—the probability of experiencing each symptom at each time point, given that recovery has not yet occurred. 7/We also estimated the distribution of onset times for each symptom. White points and error bars show the mean onset time and 95% pointwise confidence intervals. As you can see, some symptoms are most likely to start in the 1st week, whereas others would start later (month 2) 8/To summarize general patterns in the progression of symptoms over time, we used a clustering algorithm to group theses symptms into 3 clusters, according to the shapes of their time courses (i.e. changes in relative amplitude over time, ignoring their overall prevalence) 9/Cluster 1: symptoms with early peak (the first 2 or 3 weeks), then a decreasing trend in probability over time Cluster 2: symptoms w a slow decrease, slow increase, or unchanging probability over time Cluster 3: symptoms w sharp ramp in the first 2 months, then plateau 10/The mean # of organ systems affected in each respondent was 9.08/10. Symptoms in the same organ-based category didn't necessarily cluster together & could appear across clusters Systemic & neuro/cognitive symptoms were most likely to persist from disease onset to month 7 11/Did all respondents test + for COVI19? No. 1730 tested negative & 600 tested positive (RT-PCR). Difference? The median number of days between first experiencing symptoms & being tested was 6 days for those who tested + and 43 days for those who tested -. 12/Out of 205 symptoms, only loss of smell/taste was significantly different between the two groups, after stratifying the data based on comparing populations with equal test times. This is consistent with what we found in our first study. See here: 13/Moreover, symptom probability time courses for participants with confirmed COVID-19 (n=1020, RT-PCR, antigen, or antibody tests) overlapped significantly with probability estimates from the whole population, except again for "Changes in smell/taste". 14/Going back to symptoms, 89.1% of participants reported experiencing either physical or mental Post-Exertional Malaise: "worsening or relapse of symptoms after physical or mental activity" one of the most demoralising features of #LongCOVID / 15Majority of respondents experienced PEM after a few hours or the following day, and it can last for a few days. Physical activity, stress, exercise, and mental activity were the most reported triggers of these relapses. 16/Those who still experience PEM after 6 month, on average experience a lot more symptoms, compared to those w no PEM. PEM is a mandatory symptom for ME/CFS. Intriguingly, among those still experiencing symptoms at month 6 w no PEM, fatigue was still the most common symptom 17/This suggests that while a subset of the #LongCOVID population may meet #MECFS diagnostic criteria, there remains a subpopulation w significant fatigue who do not meet the criteria & therefore the mechanisms of fatigue require further investigation. 18/A total of 2454 (65.2%) respondents were experiencing symptoms for at least 6 months. For this population, the top remaining symptoms after 6 months were primarily a combination of systemic and neurological symptoms. 19/You may wonder, do patients usually have break in their symptoms? Only 164 out of 3762 participants (4.4%) experienced a temporary break in symptoms (to the precision of our study, which is week 1-4, then month 2-7) 20/We also asked participants to answer the Fatigue Assessment Scale (FAS) questionnaire, based on their subjective report during the “past 1 week". Majority of unrecovered respondents fall in "Fatigued" and "Severely Fatigued", compared to recovered. 21/Respondents were also asked, “How would you rate how you feel today, on a scale of 0-100% (with 100% being your pre-COVID baseline)?" Unrecovered participants reported a mean score of 59.2, while recovered participants reported a mean score of 86.5. 22/AND most importantly, 45.2% of respondents reported requiring a reduced work schedule compared to pre-illness. 22.3% were not working due to their health conditions. Unrecovered ones were impacted stronger (68.9% reported reduced work hrs or not working at all). This is HUGE 23/We hope this work would help with valuable future research to answer: What are the biological underpinnings of #LongCOVID & what are potential treatments? What can be done to support the suffers, both medically & through policy, until treatments are identified? @ahandvanish (co-author) "While we had a few thousand more fill in the survey, this paper focuses on 3,762 #longhaulers (sick >28 days) who got sick between Dec-May (to look at an average of ~6 months of data). Some key findings: 1/We looked at 205 symptoms over 10 organs systems (Neuropsychiatric, Pulmonary, Head Ears Eyes Nose Throat (HEENT), Gastrointestinal, Cardiovascular, Musculoskeletal, Immunologic, Dermatologic, Reproductive/Genitourinary/Endocrine). On average, 9 in 10 of these were affected! 2/Of the 205 symptoms, we looked at 74 over time, looking at Weeks 1-4 and Months 2-7. These graphs show the % of respondents who have reached each month who have these symptoms. Some of them go down (fever, dry cough) while others don't. (tho some have fever for months!) 3/(Personal interpretation) there are a few symptoms that seem to increase or happen in later months (months 6+) that more research/investigation is worth looking into: bone ache/burning, tinnitus, hearing loss, and other ear symptoms, and possibly eye/vision symptoms. 4/A very cool graph showing the average onset of these #LongCovid symptoms. 5/~Half of our symptoms were Neuropsychiatric, so we divided them into 9 subgroups. Most of these were common: Cognitive dysfunction (85%), Sensorimotor issues (tremors, tingling, skin burning) (~91%), Sleep issues (79%), Headaches (77%). Memory loss happened to 73%. 6/Our last survey found "brain fog" was common, but what is brain fog (referred to as cognitive dysfunction here) more concretely? We found this to mean: 1. Poor attention/concentration (75% of respondents) 2. Difficulty thinking (70%) 3. Difficulty with executive... 7/3. ...functioning (planning, organizing, figuring out the sequence of actions, abstracting) (58%) 4. Difficulty problem solving/decision making (54%) 5. Slowed thoughts (49%) These still don't capture the full impact of how disorienting it is, so read these quotes! #LongCovid 8/We asked about the impact of this cognitive dysfunction and memory loss of everyday life. The greatest area affected was work (86%), with 29% responding this impact was 'severe'. Other high areas included making serious decisions, communicating thoughts/needs, 9/difficulty having conversations, maintaining medication schedules, following simple instructions, and driving. #LongCovid Memory issues were also high: 73% were affected overall. The most common was short-term memory loss, at 65%. 10/One of the biggest findings to me was that there was no difference on age for the cognitive dysfunction, memory loss, or impact of these on daily life!! These happened as often in the 18-29 year old group as the 70+ group. #LongCovid #longhaulers 11/There were high prevalences of fatigue (98%) and post-exertional malaise (worsening of symptoms after activity) at (89%). These went down over time, but ~73% of respondents in month 7 reported having post-exertional malaise. Charts a-c describe PEM/PENE severity/delay #pwme 12/Cognitive dysfunction, fatigue, & post-exertional malaise are the 1) most common symptoms overall, 2) three most debilitating symptoms reported by patients, & 3) most common persisting symptoms after 6 months (followed closely by sensorimotor & headaches). #LongCovid 13/Relapses happened to >86% of #LongCovid respondents. Physical activity & stress were the most common triggers, followed by exercise & mental activity. Chart e describes relapses as well as symptom timecourses. ~50% said their symptoms got gradually better. 14/This paper includes many lesser known symptoms - even if infrequent, I want to highlight a few of them (Remember, with 80.5 million cases worldwide, & 10% of those (low estimate) with #LongCovid, that's 8 million people. A symptom prevalence of 1% is 800,000 people affected!) 15/Some serious symptoms are happening in #LongCovid: vision loss (1%), hearing loss (9%), new anaphalaxis (4%), new allergies (9%), facial paralysis (3%), suicidality (12%). 20% of respondents have changes in sensitivity to medications!! All doctors need to be aware of these. 16/On reproductive health in #LongCovid - I won't repeat everything but a few new datapoints: 15% of men reported sexual dysfunction. 11% of cis men and 3% of nonbinary respondents reported pain in testicles. 3% of cis men reported a decrease in genital size. 17/Post-menopausal bleeding/spotting happened to 4.5% of cis women over age 49. Early menopause happened to 3% of cis women in their 40s. #LongCovid 26% of people with periods had abnormal periods; 20% had abnormally heavy periods/clotting. 18/The impact of Long COVID is substantial. 68% either required a reduced work schedule or were no longer working due to #LongCovid. For those with symptoms beyond 6 months, they continued to experience an average of 14 symptoms in month 7! 19/A key point - like last time, we accepted all suspected (positive, negative, and untested) #LongCovid patients, and compared the symptoms. Of 203 symptoms, 205 were statistically the same when comparing positive (orange in the chart here) & negative. The only difference 20/was loss of smell & taste, though altered smell/taste, heightened smell/taste, & phantom smell/tastes were all the same between positive & negative. I think the loss of smell/taste may be bc: 1) Our dataset is mostly March or earlier, which was before smell/taste were known 21/2) there may be a testing bias for later months (if you had loss of smell/taste, you were more likely to get tested and therefore test positive) 3) it's also totally possible that in the negative cohort, the virus doesn't stay in the throat as long, for some reason #LongCovid 22/Importantly, the positive cohort was tested at a median of Day 6, and the negative cohort on Day 43 (!!!!) Whenever you hear 'negative test', especially for the spring wave, you should associated that with later or no testing availability. 23/We didn't write too much about treatments in this paper, but we did include "pacing", which stood out with the highest % considering it "significantly helpful" (23%) or "slightly helpful" (19%). (For an understanding of pacing, check out https://meaction.net/stoprestpace/) 24/I could write about insights forever but I'll end there for now. Future papers will include antibody & diagnostic testing, mental health, symptom clustering, socioeconomic impact, & more. Please reach out to us at @patientled with any questions or collaborations! #LongCovid 25/We especially welcome BIPOC #LongCovid researchers who want to work with this data, & we plan to continue distributing this survey to #BIPOC communities. Please reach out if you'd like to collaborate! 26/This was only possible due to the most amazing team ever (all #LongCovid patients):@GinaAssaf @LisaAMcCorkell @herlifeinpixels & @AthenaAkrami (who got us IRB sponsorship at @ucl !) Forever grateful to @itsbodypolitic (our home!), to @long_covid, #pwme, & so many others! 27/We've been working on this for 7 months, immediately after we published our first #LongCovid survey in May, with every spare ounce of energy we have. If you're able, please consider donating: https://gofund.me/f1acbf08 28/ should mention this was in a mostly non-hospitalized cohort (91.6% were not hospitalized). #LongCovid 29/ Tagging @YochaiReemMD who also worked on this paper and is on Twitter now!	> 8000 participants Ici, nous nous concentrons sur 3762 malades plus de 28 j et apparition avant juin 2020, ce qui nous permet de caractériser le profil des symptômes et l'évolution du temps sur 7 m, ainsi que l'impact sur la vie quotidienne, le travail et le retour à santé 1 /Sur les 3762 répondants, 2454 ont présenté des symptômes pendant au moins 180 jours (6 mois). 257 répondants (6,8%) se sont rétablis après le 28e jour de maladie. Dans cette cohorte COVID longue, la probabilité que les symptômes durent au-delà de 35 semaines était de 91,8%. 2 /La majorité des répondants ont signalé des symptômes «modérés» . Chez ceux qui se sont rétablis en moins de 90 j, le nombre moyen de symptômes a culminé à la semaine 2 ; chez ceux qui ne se sont pas rétablis en 90 j, le nombre moyen de symptômes a culminé au mois2 3 /Une prévalence de 205 symptômes dans 10 systèmes organiques a été estimée, avec 66 symptômes tracés sur 7mois. Nous nous sommes particulièrement concentrés sur les symptômes neuro psy. Ici les estimations de la prévalence des symptômes pour les symptômes non neuro psy. 4 /prévalence des symptômes neuropsychiatriques : -Fonctionnement cognitif (> 85%) -Mémoire (> 70%) -Parole et langage (~ 50%) -Symptômes sensorimoteurs (> 90%) -Dormir (~ 80%) -Maux de tête (~ 80%) -Émotion et humeur (~ 90%) -Goût et odeur (~ 60%) -Hallucinations (> 15%) 5 /88,0% du total des répondants (3310) ont connu un dysfonctionnement cognitif ou une perte de mémoire, avec un impact substantiel sur la vie quotidienne, en particulier le travail. Ces symptômes ont eu un impact similaire dans tous les groupes d'âge. 6 /Pour caractériser la progression des 66 symptômes sur sept mois, nous avons estimé l'évolution des symptômes dans le temps - la probabilité de ressentir chaque symptôme à chaque moment , tant que la guérison ne s'est pas encore produite. 7/Nous avons également estimé la distribution des temps d'apparition pour chaque symptôme. Comme vous pouvez le voir, certains symptômes sont plus susceptibles de commencer la 1ère semaine, tandis que d'autres commenceraient plus tard (mois 2) 8 /Pour résumer les tendances générales de la progression des symptômes au fil du temps, nous avons utilisé un algorithme de clustering pour regrouper ces symptômes en 3 groupes, en fonction de leur évolution dans le temps 9 /Gpe 1: symptômes avec pic précoce puis tendance à la baisse de la probabilité au fil du temps Gpe 2: symptômes avec une diminution lente, augmentation lente ou probabilité constante dans le temps Gpe 3: symptômes avec forte rampe au cours des 2 premiers mois, puis plateau 10/Le nombre moyen de systèmes organiques affectés chez chaque répondant était de 9,08 / 10. Les symptômes systémiques et neuro / cognitifs étaient les plus susceptibles de persister, du ébut de la maladie au mois 7 11 /Tous les participants n’ont pas eu un test + 1730 ont été testés négatifs et 600 ont été testés positifs (PCR). Différence? Le nombre médian de jours entre les premiers symptômes et le test était de 6 jours pour ceux qui ont testé + et de 43 jours pour ceux qui ont testé -. 12 / Sur 205 symptômes, seule la perte d'odeur / de goût était significativement différente entre les deux groupes, après stratification des données en comparant les populations à des temps de test égaux. Ceci est cohérent avec ce que nous avons trouvé dans notre première étude. 13 /En outre, le cours des symptômes pour les participants avec COVID19+ (n = 1020, RT-PCR, ou tests d'anticorps) se chevauchaient significativement avec les estimations de probabilité de l'ensemble de la population, sauf encore une fois pour «Changements d'odeur / goût». \ 14Pour en revenir aux symptômes, 89,1% des participants ont déclaré avoir éprouvé un malaise post-effort physique ou mental: «aggravation ou rechute des symptômes après une activité physique ou mentale», l'une des caractéristiques les plus démoralisantes de #LongCOVID / 15La majorité des répondants ont fait l'expérience de MPE après quelques heures ou le lendemain, et cela peut durer quelques jours. L'activité physique, le stress, l'exercice et l'activité mentale étaient les déclencheurs les plus signalés de ces rechutes. 16 / Ceux qui souffrent encore de MPE après 6 m éprouvent plus de symptômes que ceux qui n'en ont pas. Le MPE est un symptôme obligatoire de l'EM / SFC. Pourtant, parmi ceux qui présentaient encore des symptômes au mois 6 sans MPE, la fatigue était tjs le symptôme le plus courant / 17Cela suggère que si un sous-ensemble de la population #LongCOVID peut répondre aux critères de diagnostic #MECFS, il reste une sous-population avec une fatigue importante qui ne répond pas aux critères,dc les mécanismes de la fatigue nécessitent une enquête plus approfondie. 18 /Un total de 2 454 répondants (65,2%) ont éprouvé des symptômes pendant au moins 6 mois. Pour cette population, les principaux symptômes restants après 6 mois étaient principalement une combinaison de symptômes systémiques et neurologiques. 19 /Vous vous demandez peut-être, est-ce que les patients ont généralement des pauses de leurs symptômes ? Seuls 164 participants sur 3762 (4,4%) ont connu une interruption temporaire des symptômes (selon la précision de notre étude, qui est la semaine 1-4, puis le mois 2-7) 20 / Nous avons également demandé aux participants de répondre au questionnaire de l'échelle d'évaluation de la fatigue (FAS). La majorité de « non guéris »se situent dans les catégories «fatigués» et «gravement fatigués», comparativement à ceux qui ont guéri . 21 /A la question: «Comment évalueriez-vous votre santé aujourd'hui, sur une échelle de 0 à 100% (100% étant votre base de référence pré-COVID)?» Les participants non guéris ont rapporté un score moyen de 59,2, alors que les guéris ont rapporté un score moyen de 86,5. 22 /45,2% des répondants ont déclaré ne pas pouvoir travailler autant qu’avant. 22,3% ne pouvaient pas travailler du tout. Les personnes non guéries ont été plus touchées (68,9% ont déclaré avoir réduit leurs heures de travail ou ne pas travailler du tout). C'est énorme 23 / Nous espérons que ce travail contribuera à de précieuses futures recherches sur la physiopatho de #LongCOVID et les traitements potentiels. Que peut-on faire pour aider les victimes, médicalement et par le biais de politiques, jusqu'à ce que des traitements soient identifiés?
22	MS21	Suspected of falsification	Chaolin Huang, Lixue Huang, Yeming Wang, Xia Li, Lili Ren, Xiaoying Gu	6-month consequences of COVID-19 in patients discharged from hospital: a cohort study	https://doi.org/10.1016/S0140-6736(20)32656-8	Published	January 08, 2021	Study	https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32656-8/fulltext		Une étude à Wuhan a suivi une cohorte de 1733 malades de la covid sortis d'hôpital pendant 6 mois. Une large majorité garde des symptômes, dont une faiblesse musculaire générale, des troubles du sommeil, de l'anxiété et dépression. * Suspected of falsification *
23	MS22		Sandra Lopez-Leon, Talia Wegman-Ostrosky, Carol Perelman, Rosalinda Sepulveda, Paulina A Rebolledo, Angelica Cuapio, Sonia Villapol	More than 50 long term effects of COVID-19: a systematic review and meta-analysis	https://doi.org/10.1101/2021.01.27.21250617	Published	01/27/2021	systematic review and meta-analysis	https://www.medrxiv.org/content/10.1101/2021.01.27.21250617v2	The Preferred Reporting Items for Systematic Reviewers and Meta-analysis (PRISMA) reporting guideline was followed. A total of 18,251 publications were identified, of which 15 met the inclusion criteria. The prevalence of 55 long-term effects was estimated, 21 meta-analyses were performed, and 47,910 patients were included. The follow-up time ranged from 15 to 110 days post-viral infection. The age of the study participants ranged between 17 and 87 years. It was estimated that 80% (95% CI 65-92) of the patients that were infected with SARS-CoV-2 developed one or more long-term symptoms.	Une méta-analyse en relecture (pre-print), non publiée à ce jour, estime la prévalence de symptômes de la covid 15 à 110 jours post-infection à 4 patients sur 5. Elle présente une répartition sur 55 manifestations principales.
24	MS23		Chinwe Juliana Iwu, Chidozie Declan Iwu, Charles Shey Wiysonge	The occurrence of long COVID: a rapid review	https://doi.org/10.11604/pamj.2021.38.65.27366	Published	20 Jan 2021	Review	https://www.panafrican-med-journal.com/content/article/38/65/full/		_
25	MS24		Dominik Menges, Tala Ballouz, Alexia Anagnostopoulos, Hélène E. Aschmann, Anja Domenghino, Jan S. Fehr, Milo A. Puhan	Estimating the Burden of Long COVID in the Canton of Zurich: Implications for Healthcare Service Planning	https://doi.org/10.1371/journal.pone.0254523	Pre-print	03/02/2021	Study - intermediate results	https://www.corona-immunitas.ch/en/program/studies/e7-zurich-coronavirus-cohort-study/	Symptoms at diagnosis were reported by 90% of participants, of which 16%, 40%, 30% and 13% reported mild, moderate, severe and very severe symptoms, respectively. 20% of participants were hospitalized within two weeks of the infection. At 6 months, 26% reported not having returned to their normal health state; 31% among males and 21% among females. Furthermore, 23% among the non-hospitalized and 39% among the hospitalized reported not having fully recovered. Half of the participants reported at least one general practitioner visit post-infection. 54% of participants had fatigue in the FAS, and 26% and 32% had DASS-21 scores indicating depression and anxiety, respectively. One fourth had grade 1 dyspnea or higher based on mMRC scores.	Dans les résultats intermédiaires non publiés d'une étude menée dans le canton de Zurich, les patients infectés, dont 90% ont eu une forme initiale symptomatique, sont 26% à ne pas avoir retrouvé leur état de santé après 6 mois. La fatigue selon les critères FAS touche 54% des participants, la dépression et l'anxiété 26 et 32% selon les critères DASS-21, 1/4 ont une dyspnée de grade 1 ou plus selon les scores mMRC. Les auteurs notent que les prévalences peuvent être surestimées à cause d'une part de cas asymptomatiques.	N003
26	MS25		Sofie Bliddal, Karina Banasik, Ole Birger Pedersen, Ioanna Nissen, Lisa Cantwell, Sisse Rye Ostrowski, Kirsten Grønbæk, Claus Henrik Nielsen, Susanne Dam Nielsen, Ulla Feldt-Rasmussen	Acute and persistent symptoms in non-hospitalized PCR-confirmed COVID-19 patients	https://doi.org/10.1101/2021.01.22.21249945	Pre-print	January 25, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.01.22.21249945v1	445 participants were included, of whom 34% were asymptomatic. Most common acute symptoms 41 were fatigue, headache, and sneezing, while fatigue and reduced smell and taste were reported as most severe. 42 Persistent symptoms, most commonly fatigue and memory and concentration difficulties, were reported by 43 36% of 198 symptomatic participants with follow-up >four weeks. Risk factors for persistent symptoms 44 included female sex (women 44% vs. men 24%, odds ratio 2.7, 95%CI:1.4-5.1, p=0.003) and BMI (odds ratio 45 1.1, 95%CI:1.0-1.2, p=0.001).	Dans une étude danoise non encore relue ni publiée, les auteurs ont suivi des patients testés PCR + pour la covid mais n'ayant pas été hospitalisés. Un tiers se révèlent asymptomatiques et parmi les cas symptomatiques, plus d'un tiers témoignent de symptômes persistants aussi bien après 4 semaines que 12 semaines. Les femmes apparaissent comme étant plus touchées, un peu moins de 2 fois plus souvent que les hommes.
27	MS26		Jennifer K. Logue, BS1; Nicholas M. Franko, BS1; Denise J. McCulloch, MD, MPH1; Dylan McDonald, BA1; Ariana Magedson, BS1; Caitlin R. Wolf, BS1; Helen Y. Chu,	Sequelae in Adults at 6 Months After COVID-19 Infection	https://doi.org/10.1001/jamanetworkopen.2021.0830	Published	February 19, 2021	Research Letter	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2776560	The most common persistent symptoms were fatigue (24 of 177 patients [13.6%]) and loss of sense of smell or taste (24 patients [13.6%]). Overall, 23 patients (13.0%) reported other symptoms, including brain fog (4 [2.3%]). A total of 51 outpatients and hospitalized patients (30.7%) reported worse HRQoL compared with baseline vs 4 healthy participants and asymptomatic patients (12.5%); 14 patients (7.9%) reported negative impacts on at least 1 activity of daily living (ADL), the most common being household chores.	Une étude publiée dans JAMA note que près de 30% des patients souffrent encore de symptômes 6 mois après une infection covid. À cette échéance, 13% des patients seraient toujours touchés par de la fatigue, et le même pourcentage par une perte de goût et d'odorat, tandis que 13% rapporteraient d'autres symptômes. 1 à 5% continueraient de souffrir de "brouillard cérébral".	N002
28	MS27		Bhakti Kundlik Lonkar* and Ketakee Prakash Gosavi	A Review on Post COVID-19 Effects		Published	13 February 2021	Review	https://d1wqtxts1xzle7.cloudfront.net/65655321/152.pdf?1612972663=&response-content-disposition=inline%3B+filename%3DA_Review_on_Post_COVID_19_Effects.pdf&Expires=1614283047&Signature=KuK-YCI3gwGMCZSa9k0ivqb1m6di-LnTlJiB2thnsU13Kf1JNUuVQPFHWiFSI2VcmE7jYH2RFpPaPiIaj08GFAw7jY~I-LCwmIhxRrvrLIK0s8PY6kdlhLyIzooxCCMMLs078JABgFxFv4kJG~gwcEdvmpGFDiIPFcbXWmJ~fl9XLXTGoRX862Rfy6-xlGpNNnJ2qfj9rA4reczUvgmCDqHELiRc3kVifbbseBut5kWei8tTIGeE7kDSnXrQcS5ZAC7sKKMgFDrAjZEAf0U~OAvmR-96bFQFROEtqze~mGWO3IxbYkkNP-wcv9DxYHIufOffqKhpt1LhzLlorHCfVw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA	A short review on post covid effects.	Une courte revue d'études sur les effets à long terme de la covid.
29	MS28		Bryan Oronsky, Christopher Larson, Terese C. Hammond, Arnold Oronsky, Santosh Kesari, Michelle Lybeck & Tony R. Reid	A Review of Persistent Post-COVID Syndrome (PPCS)	https://doi.org/10.1007/s12016-021-08848-3	Published	20 February 2021	Review	https://link.springer.com/article/10.1007/s12016-021-08848-3	Inhibiting transforming growth factor beta (TGF-β), an immuno- and a fibrosis modulator, may attenuate these post-COVID sequelae. Current preclinical and clinical efforts are centered on the mechanisms and manifestations of COVID-19 and its presymptomatic and prodromal periods; by comparison, the postdrome, which occurs in the aftermath of COVID-19, which we refer to as persistent post-COVID-syndrome, has received little attention. Potential long-term effects from post-COVID syndrome will assume increasing importance as a surge of treated patients are discharged from the hospital, placing a burden on healthcare systems, patients’ families, and society in general to care for these medically devastated COVID-19 survivors. This review explores underlying mechanisms and possible manifestations of persistent post-COVID syndrome, and presents a framework of strategies for the diagnosis and management of patients with suspected or confirmed persistent post-COVID syndrome.	En comparant les symptômes persistants de la covid au syndrome post-septique (d'autres auteurs, comme le Pr J.-L. Vincent, assimilaient déjà la covid à une septicémie, cf https://www.futuremedicine.com/doi/full/10.2217/fmb-2020-0312), l'équipe du docteur américain Bryan Oronsky émet une hypothèse physiopathologique impliquant une surexpression du facteur de croissance transformant bêta (cytokine TGF-β). L'article formule en conséquence des pistes de traitements, notamment des inhibiteurs de TGF-β, qui pourraient concourir au rétablissement de l'homéostasie immunologique et à l'atténuation des séquelles des malades Covid longs.	N003R2
30	MS29		Suneel Piryani1 , Rano Mal Piryani2*, Ganesh Dangal3	COVID-19 Course of Infection and Disease	https://doi.org/10.46405/ejms.v3i1.308	Published	25 January 2021	Letter to Editor	http://scholar.google.fr/scholar_url?url=https://www.europasianjournals.org/ejms/index.php/ejms/article/download/208/139&hl=fr&sa=X&ei=08JCYM-SC4eUmAGinKG4CA&scisig=AAGBfm2O0Khf_xGE6ef0O4ExiY0JyJr7kA&nossl=1&oi=scholarr	Letter to Editor	Lettre à éditeur
31	MS30		Kent J. Nielsen, Jesper Medom Vestergaard, Vivi Schlünssen, Jens Peter Bonde, Kathrine Agergård Kaspersen, Karin Biering, Ole Carstensen, Thomas Greve, Karoline Kærgaard Hansen, Annett Dalbøge, Esben Meulengracht Flachs, Sanne Jespersen, Mette Lausten Hansen, Susan Mikkelsen, Marianne Kragh Thomsen, Jacob Dvinge Redder, Else Toft Würtz, Lars Østergaard, Christian Erikstrup, Henrik Albert Kolstad	Day by day symptoms following positive and negative PCR tests for SARS-CoV-2 in non-hospitalised health-care workers: a 90-day follow-up study	https://doi.org/10.1101/2021.03.02.21252437	pre-print	March 03, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.03.02.21252437v1	Key messages Reduced sense of taste and smell is present at a highly increased level of 30% during 90 days after testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). Test-positive participants experience dyspnoea persistently more often than test-negative participants but affect only few. The prevalence of cough, sore throat, headache, muscle ache or pain, and fever following a positive test reach the level seen after a negative test within 30 days. Women and participants aged 45 years or older tend to be more susceptible to symptoms following SARS-CoV-2 infection.	Un pré-print (étude non relue ni publiée) avec groupe contrôle remarque dans une cohorte de personnel médical que 5% des personnes infectées (210 patients) rapportent une dyspnée au bout de 30 j, tandis que toux, maux de tête, de gorge, et douleurs musculaires n'ont pas une prévalence significativement élevée. L'anosmie reste le symptôme le plus constant (1/3 des positifs PCR) sur au moins 90 jours.
32	MS31		Yong Huang, Melissa D. Pinto, Jessica L. Borelli, Milad Asgari Mehrabadi, Heather Abrihim, Nikil Dutt, Natalie Lambert, Erika L. Nurmi, Rana Chakraborty, Amir M. Rahmani, Charles A. Downs	COVID Symptoms, Symptom Clusters, and Predictors for Becoming a Long-Hauler: Looking for Clarity in the Haze of the Pandemic	https://doi.org/10.1101/2021.03.03.21252086	pre-print	March 05, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.03.03.21252086v1	27% reported persistent symptoms after 60 days. Women were more likely to become long- haulers, and all age groups were represented with those aged 50 ± 20 years comprising 72% of cases. Presenting symptoms included palpitations, chronic rhinitis, dysgeusia, chills, insomnia, hyperhidrosis, anxiety, sore throat, and headache among others. We identified 5 symptom clusters at day 61+: chest pain-cough, dyspnea-cough, anxiety-tachycardia, abdominal pain- nausea, and low back pain-joint pain. roughly 32% of those reporting symptoms at day 61+ in our study were initially asymptomatic at the time of SARS-CoV-2 testing	Une étude non publiée et non encore relue affirme que les femmes et patients de 30-79 ans sont plus à risque de symptômes persistants de covid. Dans le segment des 27% avec des symptômes à 2 mois, 32% étaient asymptomatiques initialement au moment du test.
33	MS32		Himmels JPW, Qureshi SA, Brurberg KG, Gravningen KM	COVID-19: Long-Term Effects of COVID-19		Published	03.03.2021	SYSTEMATIC REVIEW	https://www.fhi.no/en/publ/2021/Long-Term-Effects-of-COVID-19/	Hospitalised COVID-19 patients report prevailing symptoms long after infection, with a large proportion continuing to experience one or more symptoms at six months of follow-up.	Le Norwegian Institute of Public Health publie une rapide revue d'études sur les effets et séquelles à plus d'un mois de la covid.	N003A
34	MS33		Max Augustin, Philipp Schommers, Melanie Stecher, Felix Dewald, Lutz Gieselmann, Gerd Fätkenheuer, Michael Hallek, Florian Klein, Isabelle Suárez, Clara Lehmann	Recovered not restored: Long-term health consequences after mild COVID-19 in non-hospitalized patients	https://doi.org/10.1101/2021.03.11.21253207	pre-print	March 12, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.03.11.21253207v1	We observed 442 and 353 patients over four and seven months after symptom onset, respectively. Four months post SARS-CoV-2 infection, 8.6% (38/442) of patients presented with shortness of breath, 12.4% (55/442) with anosmia, 11.1% (49/442) with ageusia and 9.7% (43/442) with fatigue. At least one of these characteristic symptoms was present in 27.8% (123/442) and 34.8% (123/353) at month 4 and 7 post-infection, respectively. This corresponds to 12.8% patients with long-lasting symptoms relative to the initial total cohort (123/958).	Dans une étude en peer-review, 12,8% des patients testés positivement suivis ont au moins un symptome après 7 mois. Après 4 mois, 8,6% souffraient d'essoufflement, 12,4% d'anosmie, 9,7% d'asthénie. Un faible taux d'anticoprs igG (immunoglobuline G) apparaît comme corrélé avec le risque de développer des symptômes durables.
35	MS34		Michael J. Peluso, J. Daniel Kelly, Scott Lu, Sarah A. Goldberg, Michelle C. Davidson, Sujata Mathur, Matthew S. Durstenfeld, Matthew A. Spinelli, Steven G. Deeks, Jeffrey N. Martin	Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19	https://doi.org/10.1101/2021.03.11.21252311	pre-print	March 13, 2021	Preliminary results	https://www.medrxiv.org/content/10.1101/2021.03.11.21252311v1.full	Among a cohort of participants enrolled in the post-acute phase of SARS-CoV-2 infection, we found many with persistent physical symptoms through 8 months following onset of COVID-19 with an impact on self-rated overall health.	_
36	MS35		The Writing Committee for the COMEBAC Study Group	Four-Month Clinical Status of a Cohort of Patients After Hospitalization for COVID-19	https://doi.org/10.1001/jama.2021.3331	Published	March 17, 2021	Original Investigation	https://jamanetwork.com/journals/jama/fullarticle/2777787	Four months after hospitalization, in an uncontrolled cohort study of 478 survivors of COVID-19, at least 1 new-onset symptom was reported by telephone interview by 244 patients (51%), including fatigue in 134 of 431 (31%), cognitive symptoms in 86 of 416 (21%), and dyspnea in 78 of 478 (16%). Computed tomographic lung scan abnormalities were reported in 63% of 171 patients assessed at an ambulatory visit, mainly subtle ground-glass opacities. Fibrotic lesions were observed in 19% of these 171 patients.	_
37	MS36		Anne M. Doherty, Gabrielle C. Colleran, Laura Durcan, Alan D. Irvine & Elizabeth Barrett	A pilot study of burnout and long covid in senior specialist doctors	https://doi.org/10.1007/s11845-021-02594-3	Published	13 March 2021	Study	https://link.springer.com/article/10.1007/s11845-021-02594-3	To assess the effect of the ongoing Covid-19 pandemic on Irish doctors by investigating the incidence of burnout and long covid among senior medical staff in Ireland. A total of 114 responses were received. Three-quarters 77% (N = 88) screened positive for burnout on the MBS, with mean score of 5.6 (SD3.3), nearly double the cut-off for burnout. Nearly two-thirds (64%, n = 72) reported that Covid-19 has had an adverse effect on their mental health. One-quarter reported that they or colleagues had experience of ‘long-covid’ secondary to the virus.	_
38	MS37		Anna K. Taylor Tom Kingstone Tracy A. Briggs Catherine A. O'Donnell Helen Atherton David N. Blane Carolyn A. Chew‐Graham	Reluctant pioneer': A qualitative study of doctors' experiences as patients with long COVID	https://doi.org/10.1111/hex.13223	Published	22 March 2021	Study	https://onlinelibrary.wiley.com/doi/10.1111/hex.13223	A qualitative study; interviews with doctors experiencing persistent symptoms were conducted by telephone or video call. Thirteen doctors participated. The following themes are reported: making sense of symptoms, feeling let down, using medical knowledge and connections, wanting to help and be helped, combining patient and professional identity. Experiencing long COVID can be transformative: many expressed hope that good would come of their experiences. Distress related to feelings of being ‘let down’ and the hard work of trying to access care. Participants highlighted that they felt better able to care for, and empathize with, patients with chronic conditions, particularly where symptoms are unexplained.	_
39	MS38		Nida Ziauddeen, Deepti Gurdasani, Margaret E O'Hara, Claire Hastie, Paul Roderick, Guiqing Yao, Nisreen A Alwan	Characteristics of Long Covid: findings from a social media survey	https://doi.org/10.1101/2021.03.21.21253968	pre-print	March 27, 2021	Survey	https://www.medrxiv.org/content/10.1101/2021.03.21.21253968v2	We aimed to explore the initial and ongoing symptoms of Long Covid following SARS-CoV-2 infection and describe its impact on daily life in people who were not admitted to hospital during the first two weeks of the illness. We co-produced a survey with people living with Long Covid. We collected the data through an online survey using convenience non-probability sampling, with the survey posted both specifically on Long Covid support groups and generally on social media. The criteria for inclusion were adults with lab-confirmed (PCR or antibody) or suspected COVID-19 managed in the community (non-hospitalised) in the first two weeks of illness.	_
40	MS39		Matthew Cadd & Maya Nunn	An A-E assessment of post-ICU COVID-19 recovery	https://doi.org/10.1186/s40560-021-00544-w	Published	20 March 2021	Commentary	https://jintensivecare.biomedcentral.com/articles/10.1186/s40560-021-00544-w	A wide range of sequelae contribute to post intensive care syndrome (PICS); from our current knowledge of COVID-19, a few of these have the potential to be more prevalent following critical care admission. Follow-up assessment, diagnosis and treatment in an increasingly virtual setting will provide challenges but also opportunities to develop these services. Here, we propose an A to E approach to consider the potential long-term effects of COVID-19 following critical care admission. Anxiety and other mental health diagnoses - Breathlessness - Central nervous system impairment - Dietary insufficiency and malnutrition - Embolic events	_
41	MS40		Bodunrin Osikomaiya, Olufemi Erinoso, Kikelomo Ololade Wright, Olusegun Ogboye, Akin Osibogun & Akin Abayomi	‘Long COVID’: persistent COVID-19 symptoms in survivors managed in Lagos State, Nigeria	https://doi.org/10.1186/s12879-020-05716-x	Published	25 March 2021	Research article	https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-020-05716-x	A total of 274 patients were enrolled in the study. A majority were within the age group > 35 to ≤49 years (38.3%), and male (66.1%). More than one-third (40.9%) had persistent COVID-19 symptoms after discharge, and 19.7% had more than three persistent COVID-like symptoms. The most persistent COVID-like symptoms experienced were easy fatigability (12.8%), headaches (12.8%), and chest pain (9.8%). Symptomatic COVID-19 disease with moderate severity compared to mild severity was a predictor of persistent COVID-like symptoms after discharge (p < 0.05). Our study identified neurologic symptoms in 39.1% of the COVID-19 survivors reviewed, symptoms such as headaches, insomnia, and attention deficits. These symptoms can potentially preclude a safe and effective return of survivors to usual life.	_
42	MS41		ONS	Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the UK: 1 April 2021		Published	1 April 2021	Survey	https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/prevalenceofongoingsymptomsfollowingcoronaviruscovid19infectionintheuk/1april2021#duration-of-reported-symptoms-following-confirmed-coronavirus-covid-19-infection	1.Main points Over the four-week period ending 6 March 2021, an estimated 1.1 million people in private households in the UK reported experiencing long COVID (symptoms persisting more than four weeks after the first suspected coronavirus (COVID-19) episode that are not explained by something else). The estimates presented in this analysis relate to self-reported long COVID, as experienced by study participants, rather than clinically diagnosed ongoing symptomatic COVID-19 or post-COVID-19 syndrome. There is no universally agreed definition of long COVID, but it covers a broad range of symptoms such as fatigue, muscle pain, and difficulty concentrating. Self-reported long COVID symptoms were adversely affecting the day-to-day activities of 674,000 people in private households in the UK, with 196,000 of these individuals reporting that their ability to undertake their day-to-day activities had been limited a lot. Of people with self-reported long COVID, 697,000 first had (or suspected they had) COVID-19 at least 12 weeks previously, and 70,000 first had (or suspected they had) COVID-19 at least one year previously. Prevalence rates of self-reported long COVID were greatest in people aged 35 to 69 years, females, those living in the most deprived areas, those working in health or social care, and those with a pre-existing, activity-limiting health condition; however, it is not possible to say whether these patterns are because of differences in the risk of coronavirus infection or susceptibility to experiencing long COVID following infection. These estimates provide a measure of the prevalence of self-reported long COVID across the whole population, and reflect both the risk of being infected with coronavirus and the risk of developing long COVID following infection; to investigate the second of these components, we examined the duration of self-reported symptoms following confirmed infection. Among a sample of over 20,000 study participants who tested positive for COVID-19 between 26 April 2020 and 6 March 2021, 13.7% continued to experience symptoms for at least 12 weeks. This was eight times higher than in a control group of participants who are unlikely to have had COVID-19, suggesting that the prevalence of ongoing symptoms following coronavirus infection is higher than in the general population. Of study participants who tested positive for COVID-19, symptom prevalence at 12 weeks post-infection was higher for female participants (14.7%) than male participants (12.7%) and was highest among those aged 25 to 34 years (18.2%).	Dans son rapport de décembre 2020, l'ONS (UK) estimait à 9,9% [95% CI : 6,7% - 14,7%] la proportion de personnes testées positives au SARS-CoV-2 qui continuent de présenter des symptômes 3 mois après l’infection. Une nouvelle estimation parue aujourd'hui sur une plus grande cohorte donne 13,7% (95% CI 10,7% - 17,3%] d'infectés avec des symptômes à +3 mois. Soit 11 points de plus qu'un groupe contrôle a priori non infecté. Ces symptômes persistants à 3 mois sont : L'asthénie (8,3%), les maux de tête (7,2%), la toux (7%), les maux de gorge (4%), l'anosmie/agueusie (3,7%), les douleurs musculaires (5,6%), l'essoufflement (3.4%), la diarrhée (1,7%) et les douleurs abdominales (1,5%). L'ONS évalue à près de 700 000 le nombre de Britanniques souffrant toujours de symptômes plus de 3 mois après leur infection (1,1 million >4 semaines), pour une population de 66,6 millions d'habitants. L'étude est sur une base auto-declarative. Sur un critère de symptômes >4 semaines après l'infection, 420 000 disent n'être pas du tout gênés dans leurs activités quotidiennes, 478 000 l'être un peu, 196 000 l'être beaucoup.	N007
43	MS42		Francisco J.Barrantes	The Unfolding Palette of COVID-19Multisystemic Syndrome and its Neurological Manifestations	https://doi.org/10.1016/j.bbih.2021.100251	Published	3 April 2021	Review	https://www.sciencedirect.com/science/article/pii/S2666354621000545	Highlights •The original severe acute pulmonary syndrome is the main, but not the only manifestation of COVID-19 •One year of basic and clinical research indicate that COVID-19 is a much more complex multisystemic nosological entity •SARS-CoV-2 tropism for vascular endothelium, epithelial mucosae and nervous tissue determines pathophysiological mechanisms	Une analyse invite à considérer la covid comme une entité nosologique (de classification) multi-systémique, et fait une revue d'études très complète du tableau neurologique de la maladie.	N007
44	MS43		Sebastian Havervall, MD1; Axel Rosell, MD1; Mia Phillipson, PhD2; Sara M. Mangsbo, PhD2; Peter Nilsson, PhD3; Sophia Hober, PhD3; Charlotte Thålin, MD, PhD1	Symptoms and Functional Impairment Assessed 8 Months After Mild COVID-19 Among Health Care Workers	https://doi.org/10.1001/jama.2021.5612	Published	April 7, 2021	Research Letter	https://jamanetwork.com/journals/jama/fullarticle/2778528	Approximately 80% of hospitalized patients with COVID-19 report persistent symptoms several months after infection onset.1,2 However, knowledge of long-term outcomes among individuals with mild COVID-19 is scarce, and prevalence data are hampered by selection bias and suboptimal control groups.3,4 This cohort study investigated COVID-19–related long-term symptoms in health care professionals. Comparing seropositive vs seronegative participants, 26% vs 9% reported at least 1 moderate to severe symptom lasting for at least 2 months (RR, 2.9 [95% CI, 2.2-3.8]) and 15% vs 3% reported at least 1 moderate to severe symptom lasting for at least 8 months (RR, 4.4 [95% CI, 2.9-6.7]) (Table). The most common moderate to severe symptoms lasting for at least 2 months in the seropositive group were anosmia, fatigue, ageusia, and dyspnea. Of the seropositive participants, 8% reported that their long-term symptoms moderately to markedly disrupted their work life, compared with 4% of the seronegative participants (RR, 1.8 [95% CI, 1.2-2.9]); 15% reported their long-term symptoms moderately to markedly disrupted their social life, compared with 6% of the seronegative participants (RR, 2.5 [95% CI, 1.8-3.6]); and 12% reported that their long-term symptoms moderately to markedly disrupted their home life, compared with 5% of the seronegative participants (RR, 2.3 [95% CI, 1.6-3.4]) (Figure). Furthermore, 11% of the seropositive participants reported moderate to marked disruption in any Sheehan Disability Scale category as well as having at least 1 moderate to severe symptom lasting for at least 8 months, compared with 2% of the seronegative participants (RR, 4.5 [95% CI, 2.7-7.3]).	Une étude dans JAMA évalue à 15% des patients, sur une cohorte de malades de la covid (testés positifs), qui rapportent au moins un symptôme d'intensité modérée à sévère à 8 mois de l'infection. 8, 15 et 12% considèrent que ces symptômes impactent significativement et respectivement leur vie professionnelle, leur vie sociale et leur vie dans leur foyer.	N010
45	MS44		Ziyad Al-Aly, Yan Xie & Benjamin Bowe	High-dimensional characterization of post-acute sequalae of COVID-19	https://doi.org/10.1038/s41586-021-03553-9	Published	22 April 2021	Study	https://www.nature.com/articles/s41586-021-03553-9	We show that beyond the first 30 days of illness, people with COVID-19 exhibit higher risk of death and health resource utilization. Our high dimensional approach identifies incident sequalae in the respiratory system and several others including nervous system and neurocognitive disorders, mental health disorders, metabolic disorders, cardiovascular disorders, gastrointestinal disorders, malaise, fatigue, musculoskeletal pain, and anemia. We show increased incident use of several therapeutics including pain medications (opioids and non-opioids), antidepressants, anxiolytics, antihypertensives, and oral hypoglycemics and evidence of laboratory abnormalities in multiple organ systems. Analysis of an array of pre-specified outcomes reveals a risk gradient that increased across severity of the acute COVID-19 infection (non-hospitalized, hospitalized, admitted to intensive care). The findings show that beyond the acute illness, substantial burden of health loss — spanning pulmonary and several extrapulmonary organ systems — is experienced by COVID-19 survivors.	La revue Nature publie une très large étude rétrospective avec groupe contrôle sur les séquelles de la covid. Une surmortalité d'environ 60% est rapportée chez les patients qui n'avaient pas été hospitalisés. Ce qui représente 0,8% de mortalité à +6 mois.	N009
46	MS45		Bruno Silva Andrade 1 ,Sérgio Siqueira 1,Wagner Rodrigues de Assis Soares 1,2 ,Preetam Ghosh 7 andDebmalya Barh 8,*	Long-COVID and Post-COVID Health Complications: An Up-to-Date Review on Clinical Conditions and Their Possible Molecular Mechanisms	https://doi.org/10.3390/v13040700	Published	18 April 2021	Review	https://www.mdpi.com/1999-4915/13/4/700/htm	We conducted a comprehensive review of adverse post-COVID health outcomes and potential long-COVID effects. We observed that such adverse outcomes were not localized. Rather, they affected different human systems, including: (i) immune system (e.g., Guillain–Barré syndrome, rheumatoid arthritis, pediatric inflammatory multisystem syndromes such as Kawasaki disease), (ii) hematological system (vascular hemostasis, blood coagulation), (iii) pulmonary system (respiratory failure, pulmonary thromboembolism, pulmonary embolism, pneumonia, pulmonary vascular damage, pulmonary fibrosis), (iv) cardiovascular system (myocardial hypertrophy, coronary artery atherosclerosis, focal myocardial fibrosis, acute myocardial infarction, cardiac hypertrophy), (v) gastrointestinal, hepatic, and renal systems (diarrhea, nausea/vomiting, abdominal pain, anorexia, acid reflux, gastrointestinal hemorrhage, lack of appetite/constipation), (vi) skeletomuscular system (immune-mediated skin diseases, psoriasis, lupus), (vii) nervous system (loss of taste/smell/hearing, headaches, spasms, convulsions, confusion, visual impairment, nerve pain, dizziness, impaired consciousness, nausea/vomiting, hemiplegia, ataxia, stroke, cerebral hemorrhage), (viii) mental health (stress, depression and anxiety). We additionally hypothesized mechanisms of action by investigating possible molecular mechanisms associated with these disease outcomes/symptoms. Overall, the COVID-19 pathology is still characterized by cytokine storm that results to endothelial inflammation, microvascular thrombosis, and multiple organ failures.	Revue d'études très technique des mécanismes pathologiques de la covid et des symptômes de covid long.	N009
47	MS46		Y. Meije, A. Duarte-Borges, X. Sanz, M. Clemente, Ribera A, L. Ortega, R. González-Pérez, R. Cid, J. Pareja, I. Cantero, M. Ariño, T. Sagués, J. LLaberia, A. Ayestarán, N. Fernández-Hidalgo, B. Candás-Estébanez	Long-term outcomes of patients following hospitalization for COVID-19: a prospective observational study	https://doi.org/10.1016/j.cmi.2021.04.002	Published	April 22, 2021	Study	https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(21)00170-1/fulltext	Facility follow-up: 302 patients were enrolled. Median follow-up was 45 days after discharge; 78% (228/294) of patients had COVID-19-related symptoms (53% asthenia, 56% respiratory symptoms) and 40% (122/302) had residual pulmonary radiographic lesions. PaO2/FiO2 <200 was an independent predictor of persistent dyspnea; OR = 1.87 (1.38 to 2.52), (p <0.0001). PaO2/FiO2 >300 was associated with resolution of chest radiographic lesions; OR = 0.56 (0.42 to 0.74), (p <0.0001). Fifty per cent of patients required specific medical follow-up after the first consultation and were transferred to another physician. Telephone follow-up: 294 patients were contacted after a median time follow-up of 7 months. Fifty per cent of patients (147/294) still presented symptoms and 49% (145/294) psychological disorders. Asthenia was identified in 27% (78/294) and dyspnea in 10% (28/294) of patients independently of PaO2/FiO2.	_
48	MS47		Stephen J Gamble	Are There Possible Long-Term Effects Of Covid-19?		Published	May 1, 2021	Article	https://istonline.org.uk/the-tech-magazine/vol-2-no-1/are-there-possible-long-term-effects-of-covid-19/	COVID-19 is a worldwide pandemic caused by the SARS-CoV-2 Corona virus. Following the acute phase of the infection, a number of people exhibit post infection symptoms that may last for a number of months. Evidence is presented that some other viral infections may cause effects which present a number of years after the initial infection either as re-activation of dormant virus or as delayed effects on other systems. There is a growing body of evidence that SARS-CoV-2 may also cause some of these long delayed effects. As this infection has only existed for just over one year, the full extent of these long delayed effects cannot yet be fully evaluated.	_
49	MS48		Marcus Yu Bin Pai Andrew Seung Ho Park Bruno Fu Lon Chen Juliana Takiguti Toma Hong Jin Pai	Health Complications in Patients Recovering from COVID-19: A Narrative Review of Post-COVID Syndrome	https://doi.org/10.9734/jammr/2021/v33i1030916	Published	8 May 2021	Review	https://journaljammr.com/index.php/JAMMR/article/view/30916	Results: Fatigue, myalgia (i.e., muscle pain), sleep disruptions, and mental health issues (e.g., anxiety and depression) are among the most reported post-recovery symptoms in patients recovering from the disease. The etiology and potential management of these health complications are discussed, considering recently published findings from COVID-19 patients as well as previous studies focusing on complications arising from other related pandemics. Conclusion: Patients who have recovered from COVID-19 should be evaluated for signs of fatigue, muscle pain, mental health difficulties, and sleeping difficulties regardless of disease severity. Based on this review of the literature, complete clinical and psychiatric evaluation, and the use of validated indicators of the severity of COVID-19 disease, symptoms are recommended to develop efficient health management approaches that meet patients' needs.	_
50	MS49		Lars Christian Lund, MD, Prof Jesper Hallas, DMSc, Prof Henrik Nielsen, DMSc, Anders Koch, PhD, Stine Hasling Mogensen, PhD, Nikolai Constantin Brun, PhD, Christian Fynbo Christiansen, PhD, Reimar Wernich Thomsen, PhD, Prof Anton Pottegård, DMSc	Post-acute effects of SARS-CoV-2 infection in individuals not requiring hospital admission: a Danish population-based cohort study	https://doi.org/10.1016/S1473-3099(21)00211-5	Published	May 10, 2021	Study	https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00211-5/fulltext	This was a population-based cohort study using the Danish prescription, patient, and health insurance registries. All individuals with a positive or negative RT-PCR test for SARS-CoV-2 in Denmark between Feb 27 and May 31, 2020, were eligible for inclusion. Outcomes of interest were delayed acute complications, chronic disease, hospital visits due to persisting symptoms, and prescription drug use. We used data from non-hospitalised SARS-CoV-2-positive and matched SARS-CoV-2-negative individuals from 2 weeks to 6 months after a SARS-CoV-2 test to obtain propensity score-weighted risk differences (RDs) and risk ratios (RRs) for initiation of 14 drug groups and 27 hospital diagnoses indicative of potential post-acute effects. We also calculated prior event rate ratio-adjusted rate ratios of overall health-care use. This study is registered in the EU Electronic Register of Post-Authorisation Studies (EUPAS37658). Findings 10 498 eligible individuals tested positive for SARS-CoV-2 in Denmark from Feb 27 to May 31, 2020, of whom 8983 (85·6%) were alive and not admitted to hospital 2 weeks after their positive test. The matched SARS-CoV-2-negative reference population not admitted to hospital consisted of 80 894 individuals. Compared with SARS-CoV-2-negative individuals, SARS-CoV-2-positive individuals were not at an increased risk of initiating new drugs (RD <0·1%) except bronchodilating agents, specifically short-acting β2-agonists (117 [1·7%] of 6935 positive individuals vs 743 [1·3%] of 57 206 negative individuals; RD +0·4% [95% CI 0·1–0·7]; RR 1·32 [1·09–1·60]) and triptans (33 [0·4%] of 8292 vs 198 [0·3%] of 72 828; RD +0·1% [0·0–0·3]; RR 1·55 [1·07–2·25]). There was an increased risk of receiving hospital diagnoses of dyspnoea (103 [1·2%] of 8676 vs 499 [0·7%] of 76 728; RD +0·6% [0·4–0·8]; RR 2·00 [1·62–2·48]) and venous thromboembolism (20 [0·2%] of 8785 vs 110 [0·1%] of 78 872; RD +0·1% [0·0–0·2]; RR 1·77 [1·09–2·86]) for SARS-CoV-2-positive individuals compared with negative individuals, but no increased risk of other diagnoses. Prior event rate ratio-adjusted rate ratios of overall general practitioner visits (1·18 [95% CI 1·15–1·22]) and outpatient hospital visits (1·10 [1·05–1·16]), but not hospital admission, showed increases among SARS-CoV-2-positive individuals compared with SARS-CoV-2-negative individuals. Interpretation The absolute risk of severe post-acute complications after SARS-CoV-2 infection not requiring hospital admission is low. However, increases in visits to general practitioners and outpatient hospital visits could indicate COVID-19 sequelae.	_
51	MS50		MaxAugustinMDabc1PhilippSchommersM.D. PhD.acd1MelanieStecherPh.D.ac1FelixDewaldM.D.dLutzGieselmannM.D.dHenningGruellM.D.dCarolaHornM.D.abcKanikaVanshyllaPh.D.dVeronica DiCristanzianoM.D.dLuiseOseboldaMariaRoventaaToqeerRiazaNikolaiTschernosterM.SceJanineAltmuellerM.D.eLeonardRoseM.D.fSusanneSalomonPh.D.dVanessaPriesnerM.D.aJan ChristofferLuersProf.gChristianAlbusProf.hStephanRosenkranzProf.bijBirgitGathofProf.fGerdFätkenheuerProf.acMichaelHallekProf.abklFlorianKleinProf.bdIsabelleSuárezM.D.ac2ClaraLehmannProf.a	Post-COVID syndrome in non-hospitalised patients with COVID-19: a longitudinal prospective cohort study	https://doi.org/10.1016/j.lanepe.2021.100122	Published	18 May 2021	Study	https://www.sciencedirect.com/science/article/pii/S2666776221000995	We present a longitudinal, prospective analysis of health consequences in patients who initially presented with no or minor symptoms of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection. Hence, we focus on mild COVID-19 in non-hospitalised patients. Methods 958 Patients with confirmed SARS-CoV-2 infection were observed from April 6th to December 2nd 2020 for long-term symptoms and SARS-CoV-2 antibodies. We identified anosmia, ageusia, fatigue or shortness of breath as most common, persisting symptoms at month 4 and 7 and summarised presence of such long-term health consequences as post-COVID syndrome (PCS). Predictors of long-term symptoms were assessed using an uni- and multivariable logistic regression model. Findings We observed 442 and 353 patients over four and seven months after symptom onset, respectively. Four months post SARS-CoV-2 infection, 8•6% (38/442) of patients presented with shortness of breath, 12•4% (55/442) with anosmia, 11•1% (49/442) with ageusia and 9•7% (43/442) with fatigue. At least one of these characteristic symptoms was present in 27•8% (123/442) and 34•8% (123/353) at month 4 and 7 post-infection, respectively. A lower baseline level of SARS-CoV-2 IgG, anosmia and diarrhoea during acute COVID-19 were associated with higher risk to develop long-term	Une étude constate que des symptômes de diarrhée et d'anosmie et un niveau faible d'immunoglobuline G (anticorps neutralisant) pendant la phase aiguë sont associés à un risque plus élevé de développer un covid long.	N011
52	MS51		Sarah E Daugherty, senior researcher1, Yinglong Guo, director1, Kevin Heath, national medical director for clinical intelligence and physician2 , Micah C Dasmariñas, data scientist1, Karol Giuseppe Jubilo, data scientist1, Jirapat Samranvedhya, principal data scientist1, Marc Lipsitch, professor3, Ken Cohen	Risk of clinical sequelae after the acute phase of SARS-CoV-2 infection: retrospective cohort study	https://doi.org/10.1136/bmj.n1098	Published	19 May 2021	Study	https://www.bmj.com/content/373/bmj.n1098	Results 14% of adults aged ≤65 who were infected with SARS-CoV-2 (27 074 of 193 113) had at least one new type of clinical sequelae that required medical care after the acute phase of the illness, which was 4.95% higher than in the 2020 comparator group. The risk for specific new sequelae attributable to SARS-Cov-2 infection after the acute phase, including chronic respiratory failure, cardiac arrythmia, hypercoagulability, encephalopathy, peripheral neuropathy, amnesia (memory difficulty), diabetes, liver test abnormalities, myocarditis, anxiety, and fatigue, was significantly greater than in the three comparator groups (2020, 2019, and viral lower respiratory tract illness groups) (all P<0.001). Significant risk differences because of SARS-CoV-2 infection ranged from 0.02 to 2.26 per 100 people (all P<0.001), and hazard ratios ranged from 1.24 to 25.65 compared with the 2020 comparator group. Conclusions The results indicate the excess risk of developing new clinical sequelae after the acute phase of SARS-CoV-2 infection, including specific types of sequelae less commonly seen in other viral illnesses. Although individuals who were older, had pre-existing conditions, and were admitted to hospital because of covid-19 were at greatest excess risk, younger adults (aged ≤50), those with no pre-existing conditions, or those not admitted to hospital for covid-19 also had an increased risk of developing new clinical sequelae. The greater risk for incident sequelae after the acute phase of SARS-CoV-2 infection is relevant for healthcare planning.	Une très vaste étude statistique établit que 14% des personnes âgées de 65 ans et moins, infectées par le SRAS-CoV-2, ont développé au moins un nouveau type de séquelle clinique nécessitant des soins médicaux après la phase aiguë de l'infection.	N011
53	MS52		Tahmina Nasserie, MPH; Michael Hittle, BS; Steven N. Goodman	Assessment of the Frequency and Variety of Persistent Symptoms Among Patients With COVID-19 A Systematic Review	https://doi.org/10.1001/jamanetworkopen.2021.11417	Published	May 26, 2021	Study	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2780376	Key Points Question What are the frequency and variety of persistent symptoms after COVID-19 infection? Findings In this systematic review of 45 studies including 9751 participants with COVID-19, the median proportion of individuals who experienced at least 1persistent symptom was 73%; symptoms occurring most frequently included shortness of breath or dyspnea, fatigue or exhaustion, and sleep disorders or insomnia. However, the studies were highly heterogeneous and needed longer follow-up and more standardized designs. Meaning This systematic review found that COVID-19 symptoms commonly persisted beyond the acute phase of infection, with implications for health-associated functioning and quality of life; however, methodological improvements are needed to reliably quantify these risks.	Une revue systématique dans JAMA, qui rassemble des études aux résultats très hétérogènes et centrées le plus souvent sur des patients hospitalisés, rapporte qu'entre 55 et 80% d'entre eux présente au moins un symptôme persistant à 2 mois.
54	MS53	PESE	Leonard A. Jason, Mohammed F. Islam, Karl Conroy, Joseph Cotler, Chelsea Torres, Mady Johnson & Brianna Mabie	COVID-19 symptoms over time: comparing long-haulers to ME/CFS	https://doi.org/10.1080/21641846.2021.1922140	Published	05 May 2021	Study	https://www.tandfonline.com/doi/full/10.1080/21641846.2021.1922140	Over time, the long-haulers reported an overall reduction of most symptoms including unrefreshing sleep and post-exertional malaise, but an intensification of neurocognitive symptoms. When compared to ME/CFS, the COVID-19 sample was initially more symptomatic for the immune and orthostatic domains but over time, the long-haulers evidenced significantly less severe symptoms than those with ME/CFS, except in the orthostatic domain. Among the COVID-19 long haulers, several neurocognitive symptoms got worse over time, whereas improvements occurred in most other areas.	Comparée à des malades d'encéphalomyélite myalgique (EM), la cohorte de malades du covid long était, dans une étude, initialement plus symptomatique sur les aspects immunitaire et orthostatique, mais au fil du temps, ils ont présenté des symptômes significativement moins graves que ceux atteints d'EM, sauf dans le domaine orthostatique. Les malades du covid long ont également plus de troubles neurologiques à 5 mois qu'aux deux premières semaines de leur maladie.	N011
55	MS54		Naresh Kumar, Dhiraj Wasnik, Harsh Vardhan, MK Daga	Long Term Health Sequelae of COVID-19: A Review		Published	June 1, 2021	Review	http://medical.advancedresearchpublications.com/index.php/MedicineJournal/article/view/584	This review describes the effects of SARS-CoV-2 taking into account the previous experiences with SARS-CoV-2 and the Middle East Respiratory Syndrome (MERS) coronavirus that caused SARS in 2003 and MERS in 2012 respectively. This review aims to update on the long-term sequelae of SARS-CoV-2 infection and highlight the necessity for patient monitoring following the acute stage of infection with SARS-CoV-2 to provide ground for the prevention, diagnosis, and management of these potential long-term sequelae and to complete the natural history of COVID-19.	_
56	MS55		Sarmin Sultana, Mohammad Tanvir Islam, Marium Salwa, Shah M. Zakir Hossain, Md Nazmul Hasan, Abdullah A. Masum, Abed H. Khan, Md Maruf Haque Khan, M Atiqul Haque	Duration and Risk Factors of Post-COVID Symptoms Following Recovery Among the Medical Doctors in Bangladesh	https://doi.org/10.7759/cureus.15351	Published	May 31, 2021	Study	https://www.cureus.com/articles/59394-duration-and-risk-factors-of-post-covid-symptoms-following-recovery-among-the-medical-doctors-in-bangladesh	A large number of coronavirus disease 2019 (COVID-19) recovered patients are suffering from related symptoms. We conducted telephone interviews with 186 COVID-19 recovered medical doctors to determine the post-COVID symptoms, duration, and associated risk factors. About 70% of participants had at least one acute post-COVID symptom, including fatigue (43.0%), sleep disturbance (13.4%), lack of concentration (11.8%), breathing difficulty (10.2%), headache (6.5%), and muscle pain (6.5%). However, about 24% of participants reported having long post-COVID symptoms. Logistic regression analysis showed that female sex (odds ratio {OR}, 2.79; 95% CI, 1.28-6.06; p-value: 0.010) and comorbid conditions (OR, 2.28; 95% CI, 1.08-4.79; p: value, 0.030) are risk factors for the long post-COVID symptoms.	_
57	MS56		Emma Westerlind, Annie Palstam, Katharina S. Sunnerhagen & Hanna C. Persson	Patterns and predictors of sick leave after Covid-19 and long Covid in a national Swedish cohort	https://doi.org/10.1186/s12889-021-11013-2	Published	31 May 2021	Study	https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-021-11013-2	A substantial number of people are on sick leave due to Covid-19. Sick leave may be protracted, and sick leave for long Covid is quite common. The severity of Covid-19 (needing inpatient care), prior sick leave, and age all seem to predict the likelihood of longer sick leave. However, no socioeconomic factor could clearly predict longer sick leave, indicating the complexity of this condition. The group needing long sick leave after Covid-19 seems to be heterogeneous, indicating a knowledge gap.	_
58	MS57		Rosa María Wong-Chew , Edwin Xchel Rodríguez Cabrera , Carlos Alberto Rodríguez Valdez , Diego-Abelardo Álvarez-Hernández logo , Héctor Gallardo-Rincón * , German Fajardo Dolci , Roberto Tapia-Conyer , Rafael Ricardo Valdez Vazquez	Symptom Cluster Analysis of long COVID-19 in Patients Discharged from the Temporary COVID-19 Hospital in Mexico City: A Longitudinal Study	https://doi.org/10.20944/preprints202106.0011.v1	pre-print	1 June 2021	Study	https://www.preprints.org/manuscript/202106.0011/v1	As further research is needed, we conducted a longitudinal observational study to report the prevalence and associated risk factors of long-term health consequences of COVID-19 by symptom clusters in patients discharged from the Temporary COVID-19 Hospital (TCH) in Mexico City. Self-reported clinical symptom data were collected via telephone calls over 90 days post-discharge. Among 4670 patients discharged from the TCH, we identified 45 symptoms across eight symptom clusters (neurological; mood disorders; systemic; respiratory; musculoskeletal; ear, nose, and throat; dermatological; and gastrointestinal). We observed that the neurological, dermatological, and mood disorder symptom clusters persisted in >30% of patients at 90 days post-discharge. Although most symptoms decreased in frequency between day 30 and 90, alopecia and the dermatological symptom cluster significantly increased (p<0·00001). Women were more prone than men to develop long-term symptoms and invasive mechanical ventilation also increased the frequency of symptoms at 30-days post-discharge. Overall, we observed that symptoms often persisted regardless of disease severity. We hope these findings will help promote public health strategies that ensure equity in the access to solutions focused on the long-term consequences of COVID-19.	_
59	MS58		Sherif M Shoucri1, Lawrence Purpura1, Clare DeLaurentis2, Matthew A Adan3, Deborah A Theodore1, Alexandria Lauren Irace3, Karthik Natarajan4, George Hripcsak4, Ruijun Chen4,5, Michael T Yin1, Magdalena E Sobieszczyk1, Delivette Castor1, Jason E Zucker1	Characterising the long-term clinical outcomes of 1190 hospitalised patients with COVID-19 in New York City: a retrospective case series	http://dx.doi.org/10.1136/bmjopen-2021-049488	Published	June 02, 2021	Study	https://bmjopen.bmj.com/content/11/6/e049488.full	Of the 1190 reviewed patients, 929 survived their initial hospitalisation and 261 died. Among survivors, 570 had follow-up encounters (488 at 3 months and 364 at 6 months). An additional 33 patients died in the follow-up period. In the first 3 months after admission, most encounters were telehealth visits (59%). Cardiopulmonary symptoms (35.7% and 28%), especially dyspnoea (22.1% and 15.9%), were the most common reported symptoms at 3-month and 6-month encounters, respectively. Additionally, a large number of patients reported generalised (26.4%) or neuropsychiatric (24.2%) symptoms 6 months after hospitalisation. Patients with severe COVID-19 were more likely to have reduced mobility, reduced independence or a new dialysis requirement in the 6 months after hospitalisation. Conclusions Patients hospitalised with SARS-CoV-2 infection reported persistent symptoms up to 6 months after diagnosis. These results highlight the long-term morbidity of COVID-19 and its burden on patients and healthcare resources.	_
60	MS59		Sanjay Pujari 1, Sunil Gaikwad 1, Abhishek Chitalikar 1, Digamber Dabhade 1, Kedar Joshi 1, Vivek Bele 1	Long-coronavirus disease among people living with HIV in western India: An observational study	https://doi.org/10.1002/iid3.467	Published	2021 Jun 2	Study	https://pubmed.ncbi.nlm.nih.gov/34078004/	Results: Ninety-four PLHIV were screened for long-COVID. Median (interquartile range [IQR]) age was 51 (47-56) years and 73.4% were males. The majority (76.6%) had a history of asymptomatic-mild COVID-19 illness. The prevalence of long-COVID was 43.6% (95% confidence interval [CI], 33.4-54.2). Moderate-severe COVID-19 illness was significantly associated with long-COVID (adjusted odds ratio, 4.7; 95% CI, 1.4-17.9; p = .016). Among individuals with long-COVID, cough (22.3%) and fatigue (19.1%) were the commonest symptoms. The median (IQR) duration for resolution of symptoms was 15 (7-30) days. Ten individuals (10.6%) had persistent symptoms at a median of 109 days since the onset of COVID-19. Conclusion: Long-COVID is common among PLHIV with moderate-severe acute COVID-19 illness. There is a need for integration of long-COVID diagnosis and care services within antiretroviral therapy clinics for PLHIV with COVID-19.	_
61	MS60		Maddalena Peghin, Alvisa Palese, Margherita Venturini, Maria De Martino, Valentina Gerussin, Elena Graziano, Giulia Bontempo, Francesco Marrella, Alberto Tommasini, Martina Fabris, Francesco Curcio, Miriam Isola, Carlo Tascini	Post-COVID-19 symptoms 6 months after acute infection among hospitalized and non-hospitalized patients	https://doi.org/10.1016/j.cmi.2021.05.033	Published	June 06, 2021	Study	https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(21)00281-0/fulltext	A bidirectional prospective study. Interviews investigated symptoms potentially associated with COVID-19 six months after the disease onset of all consecutive adult in- and out-patients with COVID-19 attending Udine Hospital (Italy) from March to May 2020. IgG antibodies against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) were also evaluated six months after the onset of symptoms, at the time of the interview. Results A total of 599 individuals were included (320 female, 53.4%; mean age 53 years, SD 15.8) and interviewed 187 days (22 SD) after the onset. The prevalence of post-COVID-19 syndrome was 40.2% (241/599). The presence of IgG antibodies was significantly associated with the occurrence of post-COVID-19 syndrome (OR 2.56, 95% CI 1.48–4.38, p = 0.001) and median SARS-CoV-2 IgG titres were significantly higher in long-haulers than in patients without symptoms (42.1, IQR 17.1-78.4 vs. 29.1, IQR 12.1-54.2 kAU/L, p = 0.004). Female gender (OR 1.55, 95% CI 1.05–2.27), a proportional increase in the number of symptoms at the onset of COVID-19 (OR 1.81, 95% CI 1.59–2.05) and ICU admission OR 3.10, 95% CI 1.18–8.11) were all independent risk factors for post-COVID-19 syndrome. The same predictors also emerged in a subgroup of 231 patients with the serological follow-up available at the time of the interview alongside the proportional increase in anti-SARS-CoV-2 IgG (OR 1.01, 95% CI 1.00–1.02, p = 0.04). Conclusions Prospective follow-up could be offered to specific subgroups of COVID-10 patients, to identify typical symptoms and persistently high anti-SARS-CoV-2 IgG titers as a means of early detection of post-COVID-19 long-term sequelae.	_
62	MS61		Domingo FR, Waddell LA, Cheung AM, Cooper CL, Belcourt VJ, Zuckermann AME, Corrin T, Ahmad R, Boland L, Laprise C, Idzerda L, Khan A, Garcia AJ	Prevalence of long-term effects in individuals diagnosed with COVID-19: a living systematic review	https://doi.org/10.1101/2021.06.03.21258317	pre-print	06 Jun 2021	Study	https://www.medrxiv.org/content/10.1101/2021.06.03.21258317v1	Of the 2807 unique citations, 36 observational studies met our inclusion criteria. Over 100 post COVID-19 conditions were reported in laboratory-confirmed individuals. Eighty-three percent (95%CI: 65-93%; low certainty ) and 56% (95%CI: 34-75%; very low certainty ) reported persistence or presence of one or more symptoms in the short- and long-term, respectively. The most prevalent symptoms in both periods included: fatigue, general pain or discomfort, sleep disturbances, shortness of breath and anxiety or depression (point estimates ranging from 22-51%; low to very low certainty ).	_
63	MS62		Anna Schandl 1 2 3, Anders Hedman 4 2, Patrik Lyngå 4 2, Sozan Fathi Tachinabad 5, Jessica Svefors 5, Mari Roël 5, Anne Geborek 5, Mikael Andersson Franko 2, Mårten Söderberg 5 2, Eva-Joelsson-Alm 1 2, Pernilla Darlington 5 2	Long-term consequences in critically ill COVID-19 patients: a prospective cohort study	https://doi.org/10.1111/aas.13939	Published	2021 Jun 7	Study	https://pubmed.ncbi.nlm.nih.gov/34097753/	Results: Among 248 ICU patients, 200 patients survived. Of these, 113 patients came for follow-up. Seventy patients (62%) had received invasive ventilation. Most patients reported impaired health-related quality of life. Approximately one third suffered from posttraumatic stress, anxiety and depression. Twenty-six percent had reduced total lung capacity, 34% had reduced 6MWT and 50% worked fulltime. The outcomes were similar regardless of ventilatory support, but invasive ventilation was associated with more bodily pain (MSD -19, 95% CI: -32 to -5) and <80% total lung capacity (OR 4.1, 95% CI: 1.3-16.5).	_
64	MS63		A FAIR Health White Paper	A Detailed Study of Patients with Long-Haul COVID - An Analysis of Private Healthcare Claims		Published	June 15, 2021	Study	https://s3.amazonaws.com/media2.fairhealth.org/whitepaper/asset/A%20Detailed%20Study%20of%20Patients%20with%20Long-Haul%20COVID--An%20Analysis%20of%20Private%20Healthcare%20Claims--A%20FAIR%20Health%20White%20Paper.pdf		_
65	MS64		Paolo Boscolo-Rizzo MD, Francesco Guida MD, Jerry Polesel ScD, Alberto Vito Marcuzzo MD, Vincenzo Capriotti MD, Nicoletta Gardenal MD, Martino Pengo MD, Giancarlo Tirelli MD	Sequelae in adults at 12 months after mild-to-moderate coronavirus disease 2019 (COVID-19)	https://doi.org/10.1002/alr.22832	Published	09 June 2021	Study	https://onlinelibrary.wiley.com/doi/full/10.1002/alr.22832	Patients were considered mild-to-moderately symptomatic if they had less severe clinical symptoms, oxygen saturation (SpO2) ≥ 94%, not requiring hospitalization, and therefore considered suitable for being treated at home. Asymptomatic patients were not included in the study. Of the 496 eligible patients, 354 (71.4%) completed the baseline telephone interview, which was conducted within 3 weeks after the first positive swab performed from March 1, 2020 to March 31, 2020. The median time from onset of symptoms to SARS-CoV-2 testing was 7 days (interquartile range [IQR], 4–12 days). The median age of the study cohort was 47 years (range, 18–76 years). Persistence of at least one symptom at 12 months was reported by 161 patients (53.0%) with the most frequent being "felt tired" (n = 83, 27.3%), followed by "smell or taste impairment" (n = 67, 22.0%), "shortness of breath" (n = 39, 12.8%), and "muscle pain" (n = 28, 9.2%).	Sur une cohorte de 304 patients qui ont accepté pendant un an de répondre à une enquête téléphonique pour le suivi de leurs symptômes de la covid (ni hospitalisés, ni asymptomatiques), sur 496 éligibles initialement, 161 patients déclarent garder au moins un symptôme à un an. Parmi les plus fréquents : fatigue (83), pertes d'odorat (67), essoufflement (39) douleurs musculaires (28). Le fait d'être une femme, d'avoir entre 40 et 54 ans, d'avoir un IMC ≥ 25, d'avoir eu plus de 3, voire plus de 8 symptômes en phase initiale est corrélé avec un plus fort risque de conserver des symptômes.	N011
66	MS65		Rebecca R Taylor 1, Bhavi Trivedi 1, Neena Patel 1, Richa Singh 1, William M Ricketts 2, Katharine Elliott 1, Marcus Yarwood 1, Veronica White 1, Hannah Hylton 1, Ruth Allen 1, Gavin Thomas 1, Vikas Kapil 3, Rachel McGuckin 1, Paul E Pfeffer 4	Post-COVID symptoms reported at asynchronous virtual review and stratified follow-up after COVID-19 pneumonia	https://doi.org/10.7861/clinmed.2021-0037	Published	2021 Jun 8	Study	https://pubmed.ncbi.nlm.nih.gov/34103378/	Patients reviewed after hospitalisation for COVID pneumonia had a median of two ongoing physical health symptoms post-COVID. The most common was fatigue (50.3% of high-risk patients). Symptom burden did not vary significantly by severity of hospitalised COVID pneumonia but was highest in community referrals. Symptoms suggestive of depression, anxiety and post-traumatic stress disorder were common (depression occurred in 24.9% of high-risk patients). Asynchronous virtual review facilitated triage of patients at highest need of face-to-face review.	_
67	MS66		CésarFernández-de-las-PeñasPhD1DomingoPalacios-CeñaPhD1VíctorGómez-MayordomoMD2Lidiane LFlorencioPhD1María L.CuadradoPhD23GustavoPlaza-ManzanoPhD45MarcosNavarro-Santana	Prevalence of Post-COVID-19 Symptoms in Hospitalized and Non-Hospitalized COVID-19 Survivors: A Systematic Review and Meta-Analysis	https://doi.org/10.1016/j.ejim.2021.06.009	Published	16 June 2021	Systematic Review and Meta-Analysis	https://www.sciencedirect.com/science/article/pii/S0953620521002089	Highlights •This meta-analysis quantitively analysed data from 29 peer-reviewed studies and 4 preprints. •The results showed that 63.2%, 71.9% and 45.9% of the sample exhibited ≥one post-COVID symptoms 30, 60, or ≥90days after onset or hospitalization. •Fatigue and dyspnea were the most prevalent symptoms (pooled prevalence from 35% to 60%) depending on the follow-up period •The prevalence of each post-COVID symptom in isolation dropped off 30days after (10-15%) but increased at 60days or longer after (40-60%) onset.	Une méta-analyse évalue la prévalence des symptômes sur le long terme de la covid depuis des études comprenant des malades hospitalisés et non hospitalisés. L'estimation note 46% de patients encore symptomatiques à 3 mois, avec un pic à 2 mois.	N011
68	MS67		Sandra Ekström, Niklas Andersson, Alexandra Lövquist, André Lauber, Antonios Georgelis, Inger Kull, Erik Melén, Anna Bergström	COVID-19 among young adults in Sweden: self-reported long-term symptoms and associated factors	https://doi.org/10.1177%2F14034948211025425	Published	June 19, 2021	Study	https://journals.sagepub.com/doi/abs/10.1177/14034948211025425	The study population includes 1644 participants aged 23–26 years from the Swedish population-based birth cohort BAMSE. From August to November 2020, the participants answered a web questionnaire on COVID-19 symptoms, lifestyle and health. Information on tobacco use was compared against the previous study follow-up in 2016–2019. Results: The prevalence of suspected COVID-19 symptoms was 45.3% (n=742), and 80 of these (10.8%) reported long-term symptoms (⩾4 weeks). There was no significant difference in sociodemographic or lifestyle factors in relation to the duration of suspected COVID-19 symptoms. Rhinitis, migraine and lower self-rated health before the pandemic was more common among participants with long-term symptoms. In addition, there was a tendency for higher prevalences of asthma, chronic bronchitis and depression in this group. The prevalence of smoking decreased from 18.9% before the pandemic to 14.7% during the pandemic, while snuff use increased from 12.7% to 22.4% (P<0.001).	Une étude suédoise qui suit des participants issus d'une cohorte nationale représentative de la population compte 11% des malades avec des symptômes persistants au moins un mois.	N011
69	MS68		Cecilie Delphin Amdal, Madeline Pe, Ragnhild Sørum Falk, Claire Piccinin, Andrew Bottomley, Juan Ignacio Arraras, Anne Sophie Darlington, Kristin Hofsø, Bernard Holzner, Nina Marie Høyning Jørgensen, Dagmara Kulis, Stein Arne Rimehaug, Susanne Singer, Katherine Taylor, Sally Wheelwright & Kristin Bjordal	Health-related quality of life issues, including symptoms, in patients with active COVID-19 or post COVID-19; a systematic literature review	https://doi.org/10.1007/s11136-021-02908-z	Published	19 June 2021	Review	https://link.springer.com/article/10.1007/s11136-021-02908-z	This first comprehensive systematic review provides a detailed overview of the wide range of HRQoL issues experienced by patients with COVID-19 throughout the course of the disease. It demonstrates the devastating impact of the disease and provides critically important information for clinicians, to enable them to better recognize the disease and to provide knowledge important for treatment and follow-up. The results provided the foundation for the international development of a COVID-19 specific patient-reported HRQoL questionnaire.	Une revue systématique d'études entreprend de caractériser tous les impacts sur la qualité de vie liés à la persistance de symptômes de la covid, et s'intéresse aux différences par tranches d'âge et par sexe.	N011
70	MS69		César Fernández-de-las-Peñas, Víctor Gómez-Mayordomo, María L Cuadrado, Domingo Palacios-Ceña, Lidiane L Florencio, Angel L Guerrero, David García-Azorín, Valentín Hernández-Barrera, Lars Arendt-Nielsen	The presence of headache at onset in SARS-CoV-2 infection is associated with long-term post-COVID headache and fatigue: A case-control study	https://doi.org/10.1177%2F03331024211020404	Published	June 16, 2021	Study	https://journals.sagepub.com/doi/full/10.1177/03331024211020404	Overall, 205 patients reporting headache and 410 patients without headache at hospitalisation were assessed 7.3 months (Standard Deviation 0.6) after hospital discharge. Patients with headache at onset presented a higher number of post-COVID symptoms (Incident Rate Ratio: 1.16, 95% CI: 1.03–1.30). Headache at onset was associated with a previous history of migraine (Odd Ratio: 2.90, 95% Confidence Interval: 1.41–5.98) and with the development of persistent tension-type like headache as a new post-COVID symptom (Odd Ratio: 2.65, 95% CI: 1.66–4.24). Fatigue as a long-term symptom was also more prevalent in patients with headache at onset (Odd Ratio: 1.55, 95% CI: 1.07–2.24). No between-group differences in the prevalence of anxiety/depressive symptoms or sleep quality were seen.	_
71	MS70		Malhotra P* , Malhotra V, Gupta U, Sanwariya Y, Pahuja I and Akshay	Post Covid-19 Complications After First Wave in Haryana		Published	18 Jun 2021	Research Article	https://www.researchgate.net/profile/Parveen-Malhotra/publication/352476274_Post_Covid-19_Complications_After_First_Wave_in_Haryana/links/60cac8e092851ca3aca738f2/Post-Covid-19-Complications-After-First-Wave-in-Haryana.pdf	Materials and Methods: It was a cross sectional study con- ducted at Department of Medical Gastroenterology, Post Graduate Institute of Medical Sciences (PGIMS), Rohtak, over a period of two months i.e. from 01.03.2021 to 30.04.2021. The 25,000 confirmed patients of first wave of Covid-19 infection who have recovered six months prior from this illness, belonging to various parts of Haryana were enrolled in the study. 1.4. Results: Out of these twenty-five thousand patients of Covid-19 infection, only Sixty-five (65) i.e. 0.26 % patients developed Post Covid complications. It is pertinent to mention that these patients belonged to first wave of Covid-19 infection in India which started in March, 2020.	_
72	MS71		Bjørn Blomberg, Kristin Greve-Isdahl Mohn, Karl Albert Brokstad, Fan Zhou, Dagrun Waag Linchausen, Bent-Are Hansen, Sarah Lartey, Therese Bredholt Onyango, Kanika Kuwelker, Marianne Sævik, Hauke Bartsch, Camilla Tøndel, Bård Reiakvam Kittang, Bergen COVID-19 Research Group, Rebecca Jane Cox & Nina Langeland	Long COVID in a prospective cohort of home-isolated patients	https://doi.org/10.1038/s41591-021-01433-3	Published	23 June 2021	Study	https://www.nature.com/articles/s41591-021-01433-3	We conducted a long-term follow-up in a prospective cohort study of 312 patients—247 home-isolated and 65 hospitalized—comprising 82% of total cases in Bergen during the first pandemic wave in Norway. At 6 months, 61% (189/312) of all patients had persistent symptoms, which were independently associated with severity of initial illness, increased convalescent antibody titers and pre-existing chronic lung disease. We found that 52% (32/61) of home-isolated young adults, aged 16–30 years, had symptoms at 6 months, including loss of taste and/or smell (28%, 17/61), fatigue (21%, 13/61), dyspnea (13%, 8/61), impaired concentration (13%, 8/61) and memory problems (11%, 7/61). Our findings that young, home-isolated adults with mild COVID-19 are at risk of long-lasting dyspnea and cognitive symptoms highlight the importance of infection control measures, such as vaccination.
73	MS72		Elda Righi, Massimo Mirandola, Fulvia Mazzaferri, Elisa Razzaboni, Amina Zaffagnini, Anna Erbogasto, Ilaria Dalla Vecchia, Nina Auerbach, Federico Ivaldi, Maria Mongardi, Pietro Minuz, Michele Milella, Sara Mehrabi, Oliviero Olivieri, Domenico Girelli, Enrico Polati, Claudio Micheletto & Evelina Tacconelli	Long-Term Patient-Centred Follow-up in a Prospective Cohort of Patients with COVID-19	https://doi.org/10.1007/s40121-021-00461-3	Published	21 June 2021	Study	https://link.springer.com/article/10.1007/s40121-021-00461-3	A total of 448 patients (55% men, median age 56 years) were enrolled. WHO-CPS showed mild, moderate and severe disease in 48%, 42% and 10% of patients at admission and mild disease in all patients at follow-up, respectively. BI and aSGRQ were normal in 96% and 93% patients before COVID-19 but only in 47% and 16% at COVID-19 diagnosis and in 87% and 65% at 6-week follow-up. Male gender was identified by all three assessments as a predictor of impaired general health (BI, OR 2.14, p < 0.0001; aSGRQ, OR 0.53, p = 0.003; WHO-CPS, OR 1.56, p = 0.01). Other predictors included age, ICU admission and comorbidities (e.g. cardiovascular disease and cancer) for BI, hospital admission for aSGRQ, age and presence of comorbidities for WHO-CPS. At 6- and 12-week follow-up, 39% and 20% of patients, respectively, were still reporting symptoms. Fatigue and breathlessness were the most frequently reported symptoms.
74	MS73		Verena Hennig, Wolfgang Schuh, Antje Neubert, Dirk Mielenz, Hans-Martin Jäck, Holm Schneider	Increased risk of chronic fatigue and hair loss following COVID-19 in individuals with hypohidrotic ectodermal dysplasia	https://doi.org/10.21203/rs.3.rs-529105/v1	pre-print	25 Jun, 2021	Study	https://www.researchsquare.com/article/rs-529105/v1	HED appears to be associated with an increased risk of long-term consequences of a SARS-CoV-2 infection. Preventive vaccination against COVID-19 should be recommended for individuals affected by this rare genetic disorder.	_
75	MS74		Sandra Willi,a,b,∗ Renata Lüthold,b Adam Hunt,b Nadescha Viviane Hänggi,b Donikë Sejdiu,b Camila Scaff,b Nicole Bender,b,1 Kaspar Staub,b,c,1 and Patricia Schlagenhaufa,1	COVID-19 sequelae in adults aged less than 50 years: A systematic review	https://dx.doi.org/10.1016%2Fj.tmaid.2021.101995	Published	2021 Feb 22	Review	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898978/	Study types included prospective and retrospective cohort studies, cross-sectional studies and case reports. Sequelae persistence since infection spanned 14 days to three months. Sequelae included persistent fatigue (39–73% of assessed persons), breathlessness (39–74%), decrease in quality of life (44–69%), impaired pulmonary function, abnormal CT findings including pulmonary fibrosis (39–83%), evidence of peri-/perimyo-/myocarditis (3–26%), changes in microstructural and functional brain integrity with persistent neurological symptoms (55%), increased incidence of psychiatric diagnoses (5.8% versus 2.5–3.4% in controls), incomplete recovery of olfactory and gustatory dysfunction (33–36% of evaluated persons).
76	MS75		Anup Bastola 1 ,Richa Nepal 2,* ,Bikesh Shrestha 2,Kijan Maharjan 2,Sanjay Shrestha 2 ,Bimal Sharma Chalise 2 andJenish Neupane 2	Persistent Symptoms in Post-COVID-19 Patients Attending Follow-Up OPD at Sukraraj Tropical and Infectious Disease Hospital (STIDH), Kathmandu, Nepal	https://doi.org/10.3390/tropicalmed6030113	Published	28 June 2021	Study	https://www.mdpi.com/2414-6366/6/3/113/htm	All patients, presenting to the outpatient clinic during the study duration of six weeks, with history of positive reverse transcriptase- polymerase chain reaction for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) at least two weeks prior to presentation, were included. The duration of follow-up ranged from 15 till 150 days with the mean duration of 28 days after diagnosis of COVID-19. Of 118 patients, 43 (36.4%) had a history of mild COVID-19, 15 (12.8%) had moderate, and 60 (50.8%) had severe. At the time of presentation, 97 (82.2%) patients reported that they had at least one persistent/new symptom beyond two weeks from the diagnosis of COVID-19. Dyspnea, fatigue, chest heaviness, and cough were the commonest persistent complaints in 48 (40.7%), 39 (33.1%), 33 (28%), and 32 (27.1%) patients, respectively.	_
77	MS76		Francesca Reyes Domingo, Lisa A Waddell, Angela M. Cheung, Curtis L. Cooper, Veronica J. Belcourt, Alexandra M. E. Zuckermann, Tricia Corrin, Rukshanda Ahmad, Laura Boland, Claudie Laprise, Leanne Idzerda, Anam Khan, Alejandra Jaramillo Garcia	Prevalence of long-term effects in individuals diagnosed with COVID-19: a living systematic review	https://doi.org/10.1101/2021.06.03.21258317	pre-print	June 06, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.06.03.21258317v1	Of the 2807 unique citations, 36 observational studies met our inclusion criteria. Over 100 post COVID-19 conditions were reported in laboratory-confirmed individuals. Eighty-three percent (95%CI: 65-93%; low certainty) and 56% (95%CI: 34-75%; very low certainty) reported persistence or presence of one or more symptoms in the short- and long-term, respectively. The most prevalent symptoms in both periods included: fatigue, general pain or discomfort, sleep disturbances, shortness of breath and anxiety or depression (point estimates ranging from 22-51%; low to very low certainty).	_
78	MS77		Louis Jacob MD-Ph Dabc Ai Koyanagi MD-PhDd Lee Smith Ph De Christian Tanislav MD-PhD f Marcel Konrad PhDg Susannevan der Beckh Karel Kostev PhDh	Prevalence of and factors associated with long-term COVID-19 sick leave in working-age patients followed in general practices in Germany	https://doi.org/10.1016/j.ijid.2021.06.063	Published	2 July 2021	Study	https://www.sciencedirect.com/science/article/pii/S120197122100552X	Highlights •This study included 30,950 patients diagnosed with COVID-19 •The prevalence of long-term sick leave was 5.8%. •Women and elderly individuals had a higher risk of long-term sick leave. •Seven chronical diseases were positively associated with long-term sick leave. This study included 30,950 patients diagnosed with COVID-19 (51.7% women, mean [standard deviation] age 41.5 [13.0] years). The prevalence of long-term sick leave was 5.8%. Female sex, older age, and several conditions (i.e., noninfective enteritis and colitis, reaction to severe stress, and adjustment disorders, atopic dermatitis, mononeuropathies, reflux diseases, diabetes mellitus, and hypertension) were positively and significantly associated with long-term sick leave.
79	MS78		Jennifer M. Radin, PhD, MPH1; Giorgio Quer, PhD1; Edward Ramos, PhD1,2; Katie Baca-Motes, MBA1; Matteo Gadaleta, PhD1; Eric J. Topol, MD1; Steven R. Steinhubl, MD1	Assessment of Prolonged Physiological and Behavioral Changes Associated With COVID-19 Infection	https://doi.org/10.1001/jamanetworkopen.2021.15959	Published	July 7, 2021	Study	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2781687	We found a prolonged physiological impact of COVID-19 infection, lasting approximately 2 to 3 months, on average, but with substantial intraindividual variability, which may reflect various levels of autonomic nervous system dysfunction or potentially ongoing inflammation. Transient bradycardia has been noted in a case study6 approximately 9 to 15 days after symptom onset, which was also seen in our population. Our data suggest that early symptoms and larger initial RHR response to COVID-19 infection may be associated with the physiological length of recovery from this virus.
80	MS79		Neha Chopra, Mohit Chowdhury, Anupam K Singh, Khan MA, Arvind Kumar, Piyush Ranjan, Devashish Desai, Naveet Wig	Clinical predictors of long COVID-19 and phenotypes of mild COVID-19 at a tertiary care centre in India	https://doi.org/10.5582/ddt.2021.01014	Published	June 30, 2021	Study	https://www.jstage.jst.go.jp/article/ddt/15/3/15_2021.01014/_article	Follow up data at 30 days post-discharge was available for 53 patients. Among them, the most common persistent symptom was fatigue (22.6%), followed by cough (9.4%) and myalgias (7.5%). There was a significant association of persistent symptoms with diarrhoea at presentation [OR 14.26 (95% CI 2.30-142.47; p = 0.009] and gap between symptom onset and admission [OR 1.40 (95% CI 1.08-1.93; p = 0.020] on multivariate logistic regression analysis. On cluster analysis, three phenotypes of mild COVID-19 were identified, which may have implications on monitoring and management. There appears to be a positive association of diarrhoea as a presenting manifestation and gap between symptom onset and admission with the persistence of symptoms classified as long COVID-19, even in mild illness. We also identified multiple phenotypes of mild COVID-19 illness, which warrant further exploration.
81	MS80		Jessica Seeßle, Tim Waterboer, Theresa Hippchen, Julia Simon, Marietta Kirchner, Adeline Lim, Barbara Müller, Uta Merle	Persistent symptoms in adult patients one year after COVID-19: a prospective cohort study	https://doi.org/10.1093/cid/ciab611	Published	05 July 2021	Study	https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab611/6315216?login=true	At month 12, only 22.9% of patients were completely free of symptoms and the most frequent symptoms were reduced exercise capacity (56.3%), fatigue (53.1%), dyspnoea (37.5%), concentration problems (39.6%), problems finding words (32.3%), and sleeping problems (26.0%). Females showed significantly more neurocognitive symptoms than males. ANA titres were ≥1:160 in 43.6% of patients at 12 months post COVID-19 symptom onset, and neurocognitive symptom frequency was significantly higher in the group with an ANA titre ≥1:160 compared to <1:160. Compared to patients without symptoms, patients with at least one long COVID symptom at 12 months did not differ significantly with respect to their SARS-CoV-2-antibody levels, but had a significantly reduced physical and mental life quality compared to patients without symptoms. Conclusions Neurocognitive long COVID symptoms can persist at least for one year after COVID-19 symptom onset, and reduce life quality significantly. Several neurocognitive symptoms were associated with ANA titre elevations. This may indicate autoimmunity as cofactor in aetiology of long COVID.
82	MS81		Aiyegbusi, Olalekan Lee; Hughes, Sarah; Turner, Grace; Cruz Rivera, Samantha; McMullan, Christel; Chandan, Joht; Haroon, Shamil; Price, Gary; Davies, Elin Haf ; Nirantharakumar, Krishnarajah; Sapey, Elizabeth; Calvert, Melanie; on behalf of the TLC Study Group	Symptoms, complications and management of long COVID – a review		Published	29 Jun 2021	Review	https://research.birmingham.ac.uk/portal/files/136127534/AiyegbusiOL2021Symptoms.pdf	While the majority of infected individuals recover, a significant proportion continue to experience symptoms and complications after their acute illness. Patients with ‘long COVID’ experience a wide range of physical and mental/psychological symptoms. Pooled prevalence data showed the 10 most prevalent reported symptoms were fatigue, shortness of breath, muscle pain, joint pain, headache, cough, chest pain, altered smell, altered taste, and diarrhoea. Other common symptoms were cognitive impairment, memory loss, anxiety, and sleep disorders. Beyond symptoms and complications, people with long COVID often reported impaired quality of life, mental health and employment issues. These individuals may require multidisciplinary care involving the long-term monitoring of symptoms, to identify potential complications, physical rehabilitation, mental health and social services support.
83	MS82		Mayssam Nehme, MD, Olivia Braillard, MD, François Chappuis, MD, PhD, Delphine S. Courvoisier, PhD, Idris Guessous, MD, PhD, on behalf of the CoviCare Study Team	Prevalence of Symptoms More Than Seven Months After Diagnosis of Symptomatic COVID-19 in an Outpatient Setting	https://doi.org/10.7326/M21-0878	Published	6 July 2021	Study	https://www.acpjournals.org/doi/full/10.7326/M21-0878	Of the 629 participants in the study who completed the baseline interviews, 410 completed follow-up at 7 to 9 months after COVID-19 diagnosis; 39.0% reported residual symptoms. Fatigue (20.7%) was the most common symptom reported, followed by loss of taste or smell (16.8%), dyspnea (11.7%), and headache (10.0%).
84	MS83		Bircan Kayaaslan 1, Fatma Eser 1, Ayse Kaya Kalem 1, Gamze Kaya 2, Betül Kaplan 2, Duygu Kacar 2, Imran Hasanoglu 1, Belgin Coskun 2, Rahmet Guner	Post-covid Syndrome: A Single-Center Questionnaire Study On 1007 Participants Recovered from COVID-19	https://doi.org/10.1002/jmv.27198	Published	2021 Jul 13	Study	https://pubmed.ncbi.nlm.nih.gov/34255355/	A total of 1007 participants, 39.0% had at least one comorbidity, and 47.5% had persistent symptoms. Fatigue/easy fatigability, myalgia, and loss of weight were the most frequent persistent symptoms (overall 29.3%) and followed by respiratory symptoms (25.4%). A total of 235 participants had visited outpatient clinics due to several reasons during the post-COVID-19 period, 17 of them were hospitalized. Severe acute COVID-19, hospitalization, and presence of comorbidity were independent factors for the development of persistent symptoms.	_
85	MS84		Hannah E. Davis 1 Gina S. Assaf 1 Lisa McCorkell 1 Hannah Wei 1 Ryan J. Low 1 Yochai Re'em 1 Signe Redfield Jared P. Austin Athena Akrami	Characterizing long COVID in an international cohort: 7 months of symptoms and their impact	https://doi.org/10.1016/j.eclinm.2021.101019	Published	July 15, 2021	Study	https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00299-6/fulltext	Publication of MS20.
86	MS85		César Fernández-de-las-Peñas, Víctor Gómez-Mayordomo, David García-Azorín, Domingo Palacios-Ceña, Lidiane L. Florencio, Angel L. Guerrero, Valentín Hernández-Barrera & María L. Cuadrado	Previous History of Migraine Is Associated With Fatigue, but Not Headache, as Long-Term Post-COVID Symptom After Severe Acute Respiratory SARS-CoV-2 Infection: A Case-Control Study	https://doi.org/10.3389/fnhum.2021.678472	Published	2021-07-08	Study	https://philpapers.org/go.pl?id=FERPHO	Overall, 57 patients with confirmed diagnosis of migraine and 144 non-migraine controls who had recovered from COVID-19 were assessed at 7.3 months after hospital discharge. The number of post-COVID symptoms in the migraine group was significantly greater than in the non-migraine group. Fatigue was significantly more prevalent in the migraine group. However, no between-groups difference in the prevalence of headache as a post-COVID symptom was detected.ConclusionPatients with a history of migraine who recovered from COVID-19 exhibited more long-term fatigue as post-COVID sequelae than those without migraine. Some of the pathophysiological changes associated with migraine could predispose to the occurrence of post-COVID symptoms.
87	MS86		Sophie A M van Kessel, Tim C Olde Hartman, Peter L B J Lucassen, Cornelia H M van Jaarsveld	Post-acute and long-COVID-19 symptoms in patients with mild diseases: a systematic review	https://doi.org/10.1093/fampra/cmab076	Published	16 July 2021	Review	https://academic.oup.com/fampra/advance-article/doi/10.1093/fampra/cmab076/6322429	In total, nine articles were included in this literature review. The frequency of persistent symptoms in patients after mild COVID-19 infection ranged between 10% and 35%. Symptoms persisting after a mild COVID-19 infection can be distinguished into physical, mental and social symptoms. Fatigue was the most frequently described persistent symptom. Other frequently occurring persistent symptoms were dyspnoea, cough, chest pain, headache, decreased mental and cognitive status and olfactory dysfunction. In addition, it was found that persisting symptoms after a mild COVID-19 infection can have major consequences for work and daily functioning.	_
88	MS87		Thomas MDrakeMBChBaAya MRiadBMedSciaCameron JFairfieldMBChBaConorEganMScaStephen RKnightMBChBaRiinuPiusPhDaHayley EHardwickeLisaNormanPhDaCatherine AShawPhDaKenneth AMcLeanMBChBaA A RogerThompsonPhDhAntoniaHoPhDiOlivia VSwannPhDbkMichaelSullivanMBChBjFelipeSoaresMPhilhKarl AHoldenMBChBelLauraMersonBScmDanielPlotkinBAmLouiseSigfridPhDmThushan Ide SilvaPhDhMichelleGirvanBScfClareJacksonfClark DRussellMBChBcdJakeDunningPhDenProfTomSolomonPhDegoGailCarsonMBChBmProfPieroOlliaroPhDmProfJonathan SNguyen-Van-TamDMpqLanceTurtlePhDeAnnemarie BDochertyPhDaProfPeter JMOpenshawPhDrJ KennethBailliePhDfProfEwen MHarrisonPhDa†Malcolm GSemple	Characterisation of in-hospital complications associated with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol UK: a prospective, multicentre cohort study	https://doi.org/10.1016/S0140-6736(21)00799-6	Published	17 July 2021	Study	https://www.sciencedirect.com/science/article/pii/S0140673621007996	Between Jan 17 and Aug 4, 2020, 80 388 patients were included in the study. Of the patients admitted to hospital for management of COVID-19, 49·7% (36 367 of 73 197) had at least one complication. The mean age of our cohort was 71·1 years (SD 18·7), with 56·0% (41 025 of 73 197) being male and 81·0% (59 289 of 73 197) having at least one comorbidity. Males and those aged older than 60 years were most likely to have a complication (aged ≥60 years: 54·5% [16 579 of 30 416] in males and 48·2% [11 707 of 24 288] in females; aged <60 years: 48·8% [5179 of 10 609] in males and 36·6% [2814 of 7689] in females). Renal (24·3%, 17 752 of 73 197), complex respiratory (18·4%, 13 486 of 73 197), and systemic (16·3%, 11 895 of 73 197) complications were the most frequent. Cardiovascular (12·3%, 8973 of 73 197), neurological (4·3%, 3115 of 73 197), and gastrointestinal or liver (0·8%, 7901 of 73 197) complications were also reported.	_
89	MS88		GillesDarcis1#AntoineBouquegneau2#NathalieMaes3Mariethys3MoniqueHenket4FlorenceLabye5Anne-FrançoiseRousseau6PerrineCanivet7ColinDesir7DorianeCalmes4RaphaelSchils1SophieDe Worm1PhilippeLéonard1PaulMeunier7MichelMoutschen1RenaudLouis4JulienGuiot	Long-term clinical follow up of patients suffering from moderate to severe COVID-19 infection: A monocentric prospective observational cohort study	https://doi.org/10.1016/j.ijid.2021.07.016	Published	14 July 2021	Study	https://www.sciencedirect.com/science/article/pii/S1201971221005725	Highlights •Post-COVID conditions are common •The prevalence of tiredness up to 6 months after COVID-19 is high •The prevalence of shortness of breath up to 6 months after COVID-19 is high •Pulmonary function test improved during follow up •Chest CT-scan at 3 months after discharge showed that most of images were improved	_
90	MS89		ONS	Coronavirus and the social impacts of ‘long COVID’ on people’s lives in Great Britain: 7 April to 13 June 2021		Published	21 July 2021	Study	https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/articles/coronavirusandthesocialimpactsoflongcovidonpeopleslivesingreatbritain/7aprilto13june2021	Over the period 7 April to 13 June 2021, 6.2% of adults said they may have experienced long COVID since the start of the pandemic; this includes 3.6% who said they had experienced long COVID, and 2.6% who said they were unsure if they had experienced long COVID; a further 10.1% reported they had at some point had a positive test for or believed they'd had coronavirus (COVID-19) but had not experienced long COVID.	Sur une base auto-déclarative, l'ONS (office de statistiques britannique) relève dans son rapport de juillet : - 6,2% de la population adulte pensent avoir vécu un covid long depuis le début de la pandémie ; décomposés en 3,6% qui en sont sûrs et 2,6% qui n'en sont pas sûrs. - 10,1% pensent avoir eu la covid (et/ou ont été testés positifs) mais déclarent ne pas avoir eu de covid long.	N012
91	MS90		Diana C. Sanchez-Ramirez 1,* ,Kaylene Normand 1,Yang Zhaoyun 2 andRodrigo Torres-Castro	Long-Term Impact of COVID-19: A Systematic Review of the Literature and Meta-Analysis	https://doi.org/10.3390/biomedicines9080900	Published	27 July 2021	Study	https://www.mdpi.com/2227-9059/9/8/900	This study aimed to explore post COVID-19 effects on patients chest computed tomography (CT), lung function, respiratory symptoms, fatigue, functional capacity, health-related quality of life (HRQoL), and the ability to return to work beyond 3 months post infection. Methods: A systematic search was performed on PubMed, Web of Science, and Ovid MEDLINE on 22 May 2021, to identify studies that reported persistent effects of COVID-19 beyond 3 months follow-up. Data on the proportion of patients who had the outcome were collected and analyzed using a one-group meta-analysis. Results: Data were extracted from 24 articles that presented information on a total of 5323 adults, post-infection, between 3 to 6 months after symptom onset or hospital discharge. The pooled prevalence of CT abnormalities was 59% (95% CI 44–73, I2 = 96%), abnormal lung function was 39% (95% CI 24–55, I2 = 94%), fatigue was 38% (95% CI 27–49, I2 = 98%), dyspnea was 32% (95% CI 24–40, I2 = 98%), chest paint/tightness was 16% (95% CI 12–21, I2 = 94%), and cough was 13%, (95% CI 9–17, I2 = 94%). Decreased functional capacity and HRQoL were found in 36% (95% CI 22–49, I2 = 97%) and 52% (95% CI 33–71, I2 = 94%), respectively. On average, 8 out of 10 of the patients had returned to work or reported no work impairment.	_
92	MS91		Elisa Mantovani, Sara Mariotto, Daniele Gabbiani, Gianluigi Dorelli, Silvia Bozzetti, Angela Federico, Serena Zanzoni, Domenico Girelli, Ernesto Crisafulli, Sergio Ferrari & Stefano Tamburin	Chronic fatigue syndrome: an emerging sequela in COVID-19 survivors?	https://doi.org/10.1007/s13365-021-01002-x	Published	02 August 2021	Study	https://link.springer.com/article/10.1007/s13365-021-01002-x	SARS-CoV-2 survivors may report persistent symptoms that resemble myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We explored (a) ME/CFS-like symptom prevalence and (b) whether axonal, inflammatory, and/or lung changes may contribute to ME/CFS-like symptoms in SARS-CoV-2 survivors through clinical, neuropsychiatric, neuropsychological, lung function assessment, and serum neurofilament light chain, an axonal damage biomarker. ME/CFS-like features were found in 27% of our sample. ME/CFS-like group showed worse sleep quality, fatigue, pain, depressive symptoms, subjective cognitive complaints, Borg baseline dyspnea of the 6-min walking test vs. those without ME/CFS-like symptoms. These preliminary findings raise concern on a possible future ME/CFS-like pandemic in SARS-CoV-2 survivors.	_
93	MS92		Viet-Thi Tran, Raphael Porcher, Isabelle Pane, Philippe Ravaud	Course of long COVID symptoms over time in the ComPaRe long COVID prospective e-cohort	https://doi.org/10.21203/rs.3.rs-753615/v1	pre-print	03 Aug, 2021	Study	https://www.researchsquare.com/article/rs-753615/v1	About 10% of the people infected by the severe acute respiratory syndrome coronavirus 2 are reported to experience “long COVID,” that is, persistence of symptoms several weeks after infection. Day-by-day prevalence of long COVID symptoms was determined from responses to the Long COVID Symptom Tool by 837 patients (3075 person-months) with a confirmed infection and enrolled in the ComPaRe long COVID cohort, a prospective cohort of such patients in France. Nine months after disease onset, 88.7% patients reported persistent symptoms and 70% reported a high burden of disease. Over time, the prevalence progressively decreased for 19/53 symptoms (e.g., loss of taste/smell) and was stable for 29/53 symptoms (e.g., fatigue). For 5/53 symptoms (e.g., memory problems), prevalence increased rapidly over the first two months and then reached a plateau. These findings are important for understanding the underlying etiologies and mechanisms of long COVID.
94	MS93		Bridget M. Kuehn, MSJ	Post–COVID-19 Symptoms Were Worse Than Cancer’s Effects	https://doi.org/10.1001/jama.2021.12353	Published	August 24/31, 2021	Article	https://jamanetwork.com/journals/jama/fullarticle/2783410https://jamanetwork.com/journals/jama/fullarticle/2783410
95	MS94		Laura Catalina Cortes , Joseph Pergolizzi Jr, Sanim Choudhury, Charles Wollmuth, Peter Magnusson, Frank Breve, Giustino Varrassi	Chronic Pain Patients During/after COVID – Effects		pre-print	August 05, 2021	Review	https://www.cureus.com/abstracts/609-chronic-pain-patients-duringafter-covid---effects	With chronic pain affecting 15-30% of people across the globe, SARS-CoV-2 may have the potential to contribute to a rise in this statistic as patients report new onset pain symptoms after being infected with the virus. One study followed COVID-19 patients after being released from their hospital stay and demonstrated that 65.2% of patients reported new-onset pain compared to the control group, (11%, P=0.0001). These patients included those living with chronic pain and those living without pain. When exclusively considering patients without previous chronic pain, results were similar with 70% having new-onset pain and only 20% in control groups. Neuropathic syndromes have also been reported in COVID-19. Pain maybe part of the “long-haulers” syndrome reported with COVID-19.	_
96						From this point on, the survey of studies is no longer as exhaustive as possible. Only those studies which seem to us to bring significant new elements will be listed.
97	MS95		Arne Søraas ,Karl Trygve Kalleberg,John Arne Dahl,Camilla Lund Søraas,Tor Åge Myklebust,Eyvind Axelsen,Andreas Lind,Roar Bævre-Jensen,Silje Bakken Jørgensen,Mette S. Istre,Eyrun F. Kjetland,Giske Ursin	https://doi.org/10.1371/journal.pone.0256142	https://doi.org/10.1371/journal.pone.0256142	Published	August 26, 2021	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256142	Long-COVID-19 is a proposed syndrome negatively affecting the health of COVID-19 patients. We present data on self-rated health three to eight months after laboratory confirmed COVID-19 disease compared to a control group of SARS-CoV-2 negative patients. We followed a cohort of 8786 non-hospitalized patients who were invited after SARS-CoV-2 testing between February 1 and April 15, 2020 (794 positive, 7229 negative). Participants answered online surveys at baseline and follow-up including questions on demographics, symptoms, risk factors for SARS-CoV-2, and self-rated health compared to one year ago. Determinants for a worsening of self-rated health as compared to one year ago among the SARS-CoV-2 positive group were analyzed using multivariate logistic regression and also compared to the population norm. The follow-up questionnaire was completed by 85% of the SARS-CoV-2 positive and 75% of the SARS-CoV-2 negative participants on average 132 days after the SARS-CoV-2 test. At follow-up, 36% of the SARS-CoV-2 positive participants rated their health “somewhat” or “much” worse than one year ago. In contrast, 18% of the SARS-CoV-2 negative participants reported a similar deterioration of health while the population norm is 12%. Sore throat and cough were more frequently reported by the control group at follow-up. Neither gender nor follow-up time was associated with the multivariate odds of worsening of self-reported health compared to one year ago. Age had an inverted-U formed association with a worsening of health while being fit and being a health professional were associated with lower multivariate odds. A significant proportion of non-hospitalized COVID-19 patients, regardless of age, have not returned to their usual health three to eight months after infection.
98	MS96		ONS	Technical article: Updated estimates of the prevalence of post-acute symptoms among people with coronavirus (COVID-19) in the UK: 26 April 2020 to 1 August 2021		Published	16 September 2021	Study	https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/articles/technicalarticleupdatedestimatesoftheprevalenceofpostacutesymptomsamongpeoplewithcoronaviruscovid19intheuk/26april2020to1august2021	Experimental estimates from three approaches to estimating the percentage of people testing positive for coronavirus (COVID-19) and who experience symptoms four or more weeks after infection, broken down by demographic and viral characteristics, using UK Coronavirus Infection Survey data. Main points Experimental estimates of the prevalence of symptoms that remain 12-weeks after coronavirus (COVID-19) infection (commonly referred to as "long COVID") range from 3.0% based on tracking specific symptoms, to 11.7% based on self-classification of long COVID, using data to 1 August 2021. This analysis focusses on the number of Coronavirus Infection Survey (CIS) participants with post-acute symptoms out of those with laboratory-confirmed COVID-19, unlike our monthly prevalence publication where the denominator is the national population (irrespective of infection). Approach 1: Prevalence of any symptom at a point in time after infection. Among study participants with COVID-19, 5.0% reported any of 12 common symptoms 12 to 16 weeks after infection; however, prevalence was 3.4% in a control group of participants without a positive test for COVID-19, demonstrating the relative commonness of these symptoms in the population at any given time. Approach 2: Prevalence of continuous symptoms after infection. Among study participants with COVID-19, 3.0% experienced any of 12 common symptoms for a continuous period of at least 12 weeks from infection, compared with 0.5% in the control group; this estimate of 3.0% is based on a similar approach to the one we published in April 2021 (13.7%), but is substantially lower because of a combination of longer study follow-up time and updated statistical methodology. The corresponding prevalence estimate when considering only participants who were symptomatic at the acute phase of infection was 6.7%. Approach 3: Prevalence of self-reported long COVID. An estimated 11.7% of study participants with COVID-19 would describe themselves as experiencing long COVID (based on self-classification rather than reporting one of the 12 common symptoms) 12 weeks after infection, and may therefore meet the clinical case definition of post-COVID-19 syndrome, falling to 7.5% when considering long COVID that resulted in limitation to day-to-day activities; these percentages increased to 17.7% and 11.8% respectively when considering only participants who were symptomatic at the acute phase of infection. Irrespective of the approach to measurement, post-acute symptom prevalence was highest in females, adults aged 50 to 69 years, people with a pre-existing health condition, and those with signs of high viral load at the time of infection.	L'institut britannique de statistiques, l'ONS, publie une analyse ambitieuse d'estimation de la prévalence du covid long. Selon l'étude, entre 3 et 12% des personnes infectées (y compris asymptomatiques) présentent des symptômes évocateurs 3 mois après une infection de covid. En considérant uniquement les personnes symptomatiques à la phase aiguë de l'infection, les auteurs évaluent une prévalence entre 7% et 18%. L'analyse utilise un groupe contrôle et plusieurs approches statistiques. Elle relève que la tranche d'âge 2-11 ans serait touchée dans une proportion difficile à distinguer d'un groupe contrôle, tandis que les symptômes d'au moins 3 à 4 mois toucherait environ 1,5-2% des infectés (y compris asymptomatiques) parmi les 12-16 ans. Après une infection symptomatique, environ 12% des patients estiment être limités dans leurs activités quotidiennes par leurs symptômes 3 mois après l'infection.	N013
99	MS97		Glenn Melnick, PhD \| June F. O’Leary, PhD	After Their Initial Diagnosis, Many Adult COVID-19 Patients Continue Seeking Medical Care for up to Six Months or More		Published	1 Sep 2021	Study	https://ehrn.org/articles/after-their-initial-diagnosis-many-adult-covid-19-patients-continue-seeking-medical-care-for-up-to-six-months-or-more	Depending on age group, 3-6% of patients first diagnosed during this 5-month window had at least one COVID-19 related health care claim 91-180 days later. These results are consistent with growing evidence suggesting it may take weeks to fully recover from COVID-19, and that 10% or more of patients may continue to experience symptoms for at least 3 months and some as long as 9 months or more.
100	MS98		Bérengère Davin-Casalena, Romain Lutaud, Dimitri Scronias, Valérie Guagliardo and Pierre Verger	French General Practitioners Frequently See Patients with Long-COVID	https://doi.org/10.3122/jabfm.2021.05.210142	Published	September 17, 2021	Study	https://www.jabfm.org/content/34/5/1010	Our study sought to identify the proportion of French GPs dealing with patients with potential long COVID syndrome and their symptoms in an online cross-sectional questionnaire-based survey among a representative national panel of GPs. The majority (53.8%) reported at least 1 patient with COVID-19 and persistent symptoms, and 33% 2 or more such patients. Their most frequent symptoms were respiratory difficulties (60.6%), psychological distress (42.8%), and anosmia-dysgeusia (40.8%). Long COVID syndrome's recognition, management, and rehabilitation are priorities requiring effective coordination between primary and secondary care.	_
101	MS99		Melina Michelen1,2, Lakshmi Manoharan2, Natalie Elkheir3, Vincent Cheng4, Andrew Dagens2, Claire Hastie5, Margaret O'Hara5, Jake Suett6, Dania Dahmash2, Polina Bugaeva7, Ishmeala Rigby2, Daniel Munblit8,9,10, Eli Harriss11, Amanda Burls1, Carole Foote12, Janet Scott13, Gail Carson2, Piero Olliaro2, Louise Sigfrid2, Charitini Stavropoulou	Characterising long COVID: a living systematic review	http://dx.doi.org/10.1136/bmjgh-2021-005427	Published	September 27, 2021	Living systematic review	https://gh.bmj.com/content/6/9/e005427	Results A total of 39 studies were included: 32 cohort, 6 cross-sectional and 1 case–control. Most showed high or moderate risk of bias. None were set in low-income countries and few included children. Studies reported on 10 951 people (48% female) in 12 countries. Most included previously hospitalised people (78%, 8520/10 951). The longest mean follow-up time was 221.7 (SD: 10.9) days post COVID-19 onset. Over 60 physical and psychological signs and symptoms with wide prevalence were reported, most commonly weakness (41%; 95% CI 25% to 59%), general malaise (33%; 95% CI 15% to 57%), fatigue (31%; 95% CI 24% to 39%), concentration impairment (26%; 95% CI 21% to 32%) and breathlessness (25%; 95% CI 18% to 34%). 37% (95% CI 18% to 60%) of patients reported reduced quality of life; 26% (10/39) of studies presented evidence of reduced pulmonary function.	_
102	MS100		Hossein Estiri, Zachary H. Strasser, Gabriel A. Brat, Yevgeniy R. Semenov, The Consortium for Characterization of COVID-19 by EHR (4CE), Chirag J. Patel & Shawn N. Murphy	Evolving phenotypes of non-hospitalized patients that indicate long COVID	https://doi.org/10.1186/s12916-021-02115-0	Published	27 September 2021	Study	https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-021-02115-0	We identified 33 phenotypes among different age/gender cohorts or time windows that were positively associated with past SARS-CoV-2 infection. All identified phenotypes were newly recorded in patients’ medical records 2 months or longer after a COVID-19 RT-PCR test in non-hospitalized patients regardless of the test result. Among these phenotypes, a new diagnosis record for anosmia and dysgeusia (OR 2.60, 95% CI [1.94–3.46]), alopecia (OR 3.09, 95% CI [2.53–3.76]), chest pain (OR 1.27, 95% CI [1.09–1.48]), chronic fatigue syndrome (OR 2.60, 95% CI [1.22–2.10]), shortness of breath (OR 1.41, 95% CI [1.22–1.64]), pneumonia (OR 1.66, 95% CI [1.28–2.16]), and type 2 diabetes mellitus (OR 1.41, 95% CI [1.22–1.64]) is one of the most significant indicators of a past COVID-19 infection. Additionally, more new phenotypes were found with increased confidence among the cohorts who were younger than 65.	_
103	MS101		Maxime Taquet ,Quentin Dercon,Sierra Luciano,John R. Geddes,Masud Husain,Paul J. Harrison	Incidence, co-occurrence, and evolution of long-COVID features: A 6-month retrospective cohort study of 273,618 survivors of COVID-19	https://doi.org/10.1371/journal.pmed.1003773	Published	September 28, 2021	Study	https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1003773	Among COVID-19 survivors (mean [SD] age: 46.3 [19.8], 55.6% female), 57.00% had one or more long-COVID feature recorded during the whole 6-month period (i.e., including the acute phase), and 36.55% between 3 and 6 months. The incidence of each feature was: abnormal breathing (18.71% in the 1- to 180-day period; 7.94% in the 90- to180-day period), fatigue/malaise (12.82%; 5.87%), chest/throat pain (12.60%; 5.71%), headache (8.67%; 4.63%), other pain (11.60%; 7.19%), abdominal symptoms (15.58%; 8.29%), myalgia (3.24%; 1.54%), cognitive symptoms (7.88%; 3.95%), and anxiety/depression (22.82%; 15.49%). All 9 features were more frequently reported after COVID-19 than after influenza (with an overall excess incidence of 16.60% and hazard ratios between 1.44 and 2.04, all p < 0.001), co-occurred more commonly, and formed a more interconnected network. Significant differences in incidence and co-occurrence were associated with sex, age, and illness severity. Besides the limitations inherent to EHR data, limitations of this study include that (i) the findings do not generalize to patients who have had COVID-19 but were not diagnosed, nor to patients who do not seek or receive medical attention when experiencing symptoms of long-COVID; (ii) the findings say nothing about the persistence of the clinical features; and (iii) the difference between cohorts might be affected by one cohort seeking or receiving more medical attention for their symptoms.	_
104	MS102		Destin Groff, BA1; Ashley Sun, BA1; Anna E. Ssentongo, DrPH, MPH1,2; Djibril M. Ba, PhD, MPH2; Nicholas Parsons, MPhil3; Govinda R. Poudel, PhD4; Alain Lekoubou, MD, MSc2,5; John S. Oh, MD2; Jessica E. Ericson, MD, MPH6; Paddy Ssentongo, MD, PhD, MPH2,7; Vernon M. Chinchilli, PhD2	Short-term and Long-term Rates of Postacute Sequelae of SARS-CoV-2 Infection A Systematic Review	https://doi.org/10.1001/jamanetworkopen.2021.28568	Published	October 13, 2021	Review	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2784918	From a total of 2100 studies identified, 57 studies with 250 351 survivors of COVID-19 met inclusion criteria. The mean (SD) age of survivors was 54.4 (8.9) years, 140 196 (56%) were male, and 197 777 (79%) were hospitalized during acute COVID-19. High-income countries contributed 45 studies (79%). The median (IQR) proportion of COVID-19 survivors experiencing at least 1 PASC was 54.0% (45.0%-69.0%; 13 studies) at 1 month (short-term), 55.0% (34.8%-65.5%; 38 studies) at 2 to 5 months (intermediate-term), and 54.0% (31.0%-67.0%; 9 studies) at 6 or more months (long-term). Most prevalent pulmonary sequelae, neurologic disorders, mental health disorders, functional mobility impairments, and general and constitutional symptoms were chest imaging abnormality (median [IQR], 62.2% [45.8%-76.5%]), difficulty concentrating (median [IQR], 23.8% [20.4%-25.9%]), generalized anxiety disorder (median [IQR], 29.6% [14.0%-44.0%]), general functional impairments (median [IQR], 44.0% [23.4%-62.6%]), and fatigue or muscle weakness (median [IQR], 37.5% [25.4%-54.5%]), respectively. Other frequently reported symptoms included cardiac, dermatologic, digestive, and ear, nose, and throat disorders.	_
105	MS103		Eloara Vieira Machado Ferreira1, Rudolf K. F. Oliveira1	Mechanisms of exercise intolerance after COVID-19: new perspectives beyond physical deconditioning	https://dx.doi.org/10.36416/1806-3756/e20210406	Published	Octobre 2021	EDITORIAL	https://www.jornaldepneumologia.com.br/details/3604/en-US/mecanismos-de-intolerancia-ao-exercicio-apos-covid-19--novas-perspectivas-alem-do-descondicionamento-fisico;	Another possible cause for ventilatory inefficiency would be the increase in dead space as a fraction of tidal volume (VD/VT), which may be present in patients with endothelial and/or microvascular injury, poor alveoli perfusion, and/or destruction of the pulmonary vascular bed in fibrotic areas, associated with reduced O2 diffusion through the blood-alveolar barrier. (...) Thus, considering the current pathophysiological knowledge of intolerance mechanisms and the range of systemic manifestations of the acute phase of COVID-19 infection, it would be simplistic for us to consider that all chronic symptoms of the long-COVID-19 syndrome are due to physical deconditioning by inactivity or prolonged hospitalization. The physical deconditioning theory does not explain the presence of persistent symptoms in patients who were affected by mild forms of the disease, many of whom did not even require hospitalization. Similarly, this theory does not explain the dissociation between the severity of hospitalization and the reduction in peak VO2 reported so far, nor does it explain the antagonism of the persistence of symptoms in patients with preserved peak VO2. (4-6) In light of the potential complexity and the lack of knowledge on the post-COVID-19 syndrome, it is unacceptable to be simplistic when attempting to unravel the post-COVID-19 syndrome exercise intolerance mechanisms. More robust scientific evidence is needed before drawing simple conclusions.
106	MS104		Antonella Serafini 1,,Alberto Tagliaferro 2,3, ,Francesco Balbi 1,Alberto Bordo 1,Stefano Bernardi 1,Giorgio Berta 1,Lorenzo Trucco 1,Enrico Perretta 1,Elisa Gualco 1,Patrizia Zoccali 1 andClaudio De Michelis	Screening of a Small Number of Italian COVID-19 Syndrome Survivors by Means of the Fatigue Assessment Scale: Long COVID Prevalence and the Role of Gender	https://doi.org/10.3390/covid1030044	Published	29 October 2021	Study	https://www.mdpi.com/2673-8112/1/3/44/htm	The outcome of the two questionnaires were analyzed separately and compared. Females are more affected by fatigue than males. This results holds for both physical and mental fatigue. All the males’ fatigue scores were reduced at the second control, while 40% of females worsened it. Home-confined patients showed a higher fatigue score at the first check. In the initial stages of the recovery, patients are more affected by physical, rather than mental, fatigue. This is worth of further investigation as well as the reasons leading to a higher initial fatigue score for home cared patients.	_
107	MS105		Anna Crispo, Sabrina Bimonte, Giuseppe Porciello, Cira Antonietta Forte, Gaia Cuomo, Concetta Montagnese, Melania Prete, Maria Grimaldi, Egidio Celentano, Alfonso Amore, Elvio de Blasio, Francesca Pentimalli, Antonio Giordano, Gerardo Botti, Giovanni Baglio, Pierpaolo Sileri, Marco Cascella & Arturo Cuomo	Strategies to evaluate outcomes in long-COVID-19 and post-COVID survivors	https://doi.org/10.1186/s13027-021-00401-3	Published	30 October 2021	Review	https://link.springer.com/article/10.1186/s13027-021-00401-3	This narrative review is aimed at providing an updated overview of the impact of physical, cognitive, and psychological health disorders in COVID-19 survivors, by summarizing the data already published in literature in the last year. Studies cited were found through PubMed searches. We also presented an overview of the post-COVID-19 health consequences on three important aspects: nutritional status, neurological disorders, and physical health. Moreover, to activate a correct health planning policy, a multidisciplinary approach for addressing the post- COVID-19 issue, has been proposed. Finally, the involvement of health professionals is necessary even after the pandemic, to reduce expected post-pandemic psychosocial responses and mental health disorders.	_
108	MS106		Yan Xie, Benjamin Bowe & Ziyad Al-Aly	Burdens of post-acute sequelae of COVID-19 by severity of acute infection, demographics and health status	https://doi.org/10.1038/s41467-021-26513-3	Published	12 November 2021	Study	https://www.nature.com/articles/s41467-021-26513-3	Here we used the healthcare databases of the US Department of Veterans Affairs to build a cohort of 181,384 people with COVID-19 and 4,397,509 non-infected controls and estimated that burden of PASC—defined as the presence of at least one sequela in excess of non-infected controls—was 73.43 (72.10, 74.72) per 1000 persons at 6 months. Burdens of individual sequelae varied by demographic groups (age, race, and sex) but were consistently higher in people with poorer baseline health and in those with more severe acute infection. In sum, the burden of PASC is substantial; PASC is non-monolithic with sequelae that are differentially expressed in various population groups. Collectively, our results may be useful in informing health systems capacity planning and care strategies of people with PASC.
109	MS107		Stephanie A Richard, Simon D Pollett, Charlotte A Lanteri, Eugene V Millar, Anthony C Fries, Ryan C Maves, Gregory C Utz, Tahaniyat Lalani, Alfred Smith, Rupal M Mody, Anuradha Ganesan, Rhonda E Colombo, Christopher J Colombo, David A Lindholm, Cristian Madar, Sharon Chi, Nikhil Huprikar, Derek T Larson, Samantha E Bazan, Caroline English, Edward Parmelee, Katrin Mende, Eric D Laing, Christopher C Broder, Paul W Blair, Josh Chenoweth, Mark P Simons, David R Tribble, Brian K Agan, Timothy H Burgess	COVID-19 outcomes among U.S. Military Health System beneficiaries include complications across multiple organ systems and substantial functional impairment	https://doi.org/10.1093/ofid/ofab556	Published	10 November 2021	Study	https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab556/6425105?login=true	A total of 1,202 participants were enrolled. There were 1,070 laboratory confirmed SARS-CoV-2 cases and 132 SARS-CoV-2 negative participants. In the first month post-symptom onset among the SARS-CoV-2 positive cases, there were 214 hospitalizations, 79% requiring oxygen, 22 ICU admissions, and 9 deaths. Risk factors for COVID-19 associated hospitalization included race (increased for Asian, Black, and Hispanic compared to non-Hispanic White), age (age 45-64 and 65+ compared to <45), and obesity (BMI>=30 compared to BMI<30). Over 2% of survey respondents reported the need for supplemental oxygen and 31% had not returned to normal daily activities at one-month post-symptom onset. Conclusions Older age, reporting Asian, Black or Hispanic race/ethnicity, and obesity are associated with SARS-CoV-2 hospitalization. A proportion of acute SARS-CoV-2 infections require long-term oxygen therapy; the impact of SARS-CoV-2 infection on short-term functional status was substantial. A significant number of MHS beneficiaries had not yet returned to normal activities by one month.
110	MS108		Sumit Mukherjee, Meghana Kshirsagar, Nicholas Becker, Yixi Xu, William B Weeks, Shwetak Patel, Juan Lavista Ferres, Michael L. Jackson	Identifying Long-Term Effects of SARS-CoV-2 and Their Association with Social Determinants of Health in a Cohort of Over One Million COVID-19 Survivors	https://doi.org/10.21203/rs.3.rs-1032897/v1	pre-print	11 Nov, 2021	Study	https://www.researchsquare.com/article/rs-1032897/v1	Among the over 1.37 million COVID patients in our datasets we found 36 out of 1,724 3-digit ICD-10 codes to be statistically significantly increased in the post-COVID period (p-value <0.05). We also found one combination of ICD-10 codes, corresponding to ‘other anemias’ and ‘hypertension’, that was statistically significantly increased in the post-COVID period (p-value <0.05). Our logistic regression-based association analysis with social determinants of health variables, after adjusting for comorbidities and prior conditions, showed that age and gender were significantly associated with the multiple long-term effects. Race was only associated with ‘other sepsis’, income was only associated with ‘Alopecia areata’, while education level was only associated with ‘Maternal infectious and parasitic diseases’ (p-value <0.05).	_
111	MS109		Mattia Bellan, Alessio Baricich, Filippo Patrucco, Patrizia Zeppegno, Carla Gramaglia, Piero Emilio Balbo, Alessandro Carriero, Roberta Rolla, Pier Paolo Sainaghi, Stefano Tricca & Mario Pirisi	Long-term sequelae are highly prevalent one year after hospitalization for severe COVID-19	https://doi.org/10.1038/s41598-021-01215-4	Published	22 November 2021	Study	https://www.nature.com/articles/s41598-021-01215-4	We performed a prospective cohort study on 238 patients previously hospitalized for Covid-19 pneumonia in 2020 who already underwent clinical follow-up 4 months post-Covid-19. 200 consented to participate to a 12-months clinical assessment, including: pulmonary function tests with diffusing lung capacity for carbon monoxide (DLCO); post-traumatic stress (PTS) symptoms evaluation by the Impact of Event Scale (IES); motor function evaluation (by Short Physical Performance Battery and 2 min walking test); chest Computed Tomography (CT). After 366 [363–369] days, 79 patients (39.5%) reported at least one symptom. A DLCO < 80% was observed in 96 patients (49.0%). Severe DLCO impairment (< 60%) was reported in 20 patients (10.2%), related to extent of CT scan abnormalities. Some degree of motor impairment was observed in 25.8% of subjects. 37/200 patients (18.5%) showed moderate-to-severe PTS symptoms. In the time elapsed from 4 to 12 months after hospital discharge, motor function improves, while respiratory function does not, being accompanied by evidence of lung structural damage. Symptoms remain highly prevalent one year after acute illness.	_
112	MS110		Yan-Jie Zhao Wei Bai Zhaohui Su Chee H Ng Yu-Tao Xiang	Long-term effects on survivors with COVID-19	https://doi.org/10.1016/S0140-6736(21)02283-2	Published	November 20, 2021	CORRESPONDENCE	https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02283-2/fulltext	Lixue Huang and colleagues1 reported that patients discharged from hospital with COVID-19 showed good physical and functional recovery 1 year after symptom onset. Because of several concerns with the methods, we contend that the findings should be interpreted cautiously. Quality of life (QOL) was measured using the EuroQol five-dimension five-level (EQ-5D-5L) questionnaire. However, the authors did not seem to use the validated Chinese version of the EQ-5D-5L, nor did they cite relevant studies.2 Additionally, the EQ-5D-5L item on anxiety or depression was used on its own as a major health outcome, which is not appropriate since the EQ-5D-5L item on anxiety or depression has not been validated in Chinese populations. Furthermore, depression and anxiety each consist of a cluster of different symptoms that cannot simply be assessed using one EQ-5D-5L item. The study findings on the anxiety or depression risk factors are therefore tentative.
113	MS111		L.Chiche1H.Faralli2C.Stavris1S.Rebaudet3J.Allemand3F.Cohen4D.Balma5H.Pegliasco6H.Drouet3M.Delord7P.Halfon1F.Retornaz1	Séquelles physiques et psychiques 3–6 mois après la COVID-19 : premiers résultats de la cohorte prospective ALCOVID	https://doi.org/10.1016/j.revmed.2021.10.298	Published	24 November 2021	Study	https://www.sciencedirect.com/science/article/pii/S0248866321010225	les séquelles physiques et psychologiques sont fréquentes 3 à 6 mois après une COVID-19 quelle que soit sa gravité initiale. Les séquelles respiratoires et post-traumatiques pourraient être plus sévères chez les patients ayant nécessité respectivement une oxygénothérapie et de la réanimation. La gravité initiale semble aussi conditionner la réponse sérologique ultérieure.	_
114	MS112		Sudham Chand, MD, Sumit Kapoor, MD, Ali Naqvi, MD, Jyotsana Thakkar, MD, Melissa J. Fazzari, Ph.D, Deborah Orsi, MD, Vladyslav Dieiev, MD, David C. Lewandowski, MD, Peter V. Dicpinigaitis, MD	Long-Term Follow up of Renal and Other Acute Organ Failure in Survivors of Critical Illness Due to Covid-19	https://doi.org/10.1177%2F08850666211062582	Published	December 17, 2021	Study	https://journals.sagepub.com/doi/abs/10.1177/08850666211062582	126 out of 300 (42%) survived to 120-days post-hospital discharge. The median age of survivors was 54 (47-61) years. Seventy-eight (62%) patients developed acute kidney injury (AKI); thirty-five (44.9%) of them required renal replacement therapy (RRT). One hundred-five (83.3%) required invasive mechanical ventilation; ten of them required tracheotomy. 103 (81.7%) completed the telephone questionnaire-based study, at a median (IQR) of 216.5 (200-234.5) days after hospital discharge. 29 (28.2%) patients reported persistent shortness of breath, 24, (23.3%) complained of persistent cough, and persistent anosmia in 9 (8.8%). AKI resolved completely in 58 (74.4%) patients. Of 35 AKI patients who required initiation of RRT during hospitalization, 27 (77%) were liberated from RRT and 20 (57%) had resolution of AKI. Of 20 patients without AKI resolution, 12 developed chronic kidney disease, whereas 8 still require RRT. Thirty-three (32.4%) patients developed post-traumatic stress disorder (PTSD) and 10 (11.8%) reported major depression. Many of the patients (68%) regained baseline functional status. Readmissions occurred in 22.3% patients within first 6 months after discharge.	_
115	MS113		CésarFernández-de-las-PeñasPhD1Oscar J.Pellicer-ValeroMSc2EsperanzaNavarro-PardoPhD3DomingoPalacios-CeñaPhD1Lidiane L.FlorencioPhD1CarlosGuijarroPhD45José D.Martín-GuerreroPhD2	Symptoms Experienced at the Acute Phase of SARS-CoV-2 Infection as Risk Factor of Long-term Post-COVID Symptoms: The LONG-COVID-EXP-CM Multicenter Study	https://doi.org/10.1016/j.ijid.2022.01.007	Published	10 January 2022	Study	https://www.sciencedirect.com/science/article/pii/S1201971222000078	Highlights •This multicentre study included 1,969 COVID-19 hospitalized patients. •A higher number of onset symptoms was associated with more post-COVID symptoms •Dyspnea and headache symptoms at onset are associated with post-COVID symptoms. Results Overall, 1,969 patients (46.5% women, age: 61, SD: 16 years) were randomly assessed at 8.4 months (SD 1.5) after hospital discharge. Female gender (OR1.82, 95%CI 1.57-2.10), number of morbidities (OR1.182, 95%CI 1.08-1.29), number of symptoms at hospital admission (OR1.309, 95%CI 1.15-1.49) and days at the hospital (OR1.01, 95%CI 1.007-1.017) were associated (all, P<0.001) with more long-term post-COVID symptoms. Further, vomiting (OR1.78, 95%CI 1.26-2.52), throat pain (OR1.36, 95%CI 1.02-1.81), diarrhoea (OR1.51, 95%CI 1.25-1.82), dyspnea (OR1.20, 95%CI 1.01-1.41), or headache (OR1.50, 95%CI 1.28-1.75) as symptoms at hospital admission were also associated (all, P<0.01) with a higher number of post-COVID symptoms. Conclusion This multicenter study found that a higher number of symptoms at hospital admission was the most relevant risk factor for developing more post-COVID symptoms, supporting the assumption that a higher symptom load at the acute phase is associated with a greater likelihood of long-term post-COVID symptoms. Female gender (OR1.82, 95%CI 1.57-2.10), number of COVID-19 symptoms at hospital admission (OR1.309, 95%CI 1.15-1.49), number of pre-existing medical co-morbidities (OR1.182, 95%CI 1.08-1.29), and days at hospital (OR1.01, 95%CI 1.007-1.017) were independently associated (all, P<0.001) with more long-term post-COVID symptoms: the higher the number of COVID-19 onset symptoms or the higher the number of co-morbidities, the higher the number of post-COVID symptoms (Figure). No specific co-morbidity (e.g., obesity, hypertension) was associated with a greater number of post-COVID symptoms. Some specific symptoms at the acute phase were also independently associated (all, P<0.01) with a higher number of long-term post-COVID symptoms (Table): vomiting (OR1.78, 95%CI 1.26-2.52), throat pain (OR1.36, 95%CI 1.02-1.81), diarrhoea (OR1.51, 95%CI 1.25-1.82), dyspnea (OR1.20, 95%CI 1.01-1.41), or headache (OR1.50, 95%CI 1.28-1.75).
116	MS114		Marcel Ballin, MSc Jonathan Bergman, BSc Miia Kivipelto, MD, PhD Anna Nordström, MD, PhD Peter Nordström, MD, PhD	Excess Mortality After COVID-19 in Swedish Long-Term Care Facilities	https://doi.org/10.1016/j.jamda.2021.06.010	Published	June 23, 2021	Study	https://www.jamda.com/article/S1525-8610(21)00568-5/fulltext	Results A total of 3731 residents (median age 87 years, 64.5% female) with COVID-19 were matched to 3731 controls without COVID-19. Thirty-day mortality was 39.9% in COVID-19 cases and 5.7% in controls [relative risk 7.05, 95% confidence interval (CI) 6.10-8.14]. In COVID-19 cases, the odds ratio (OR) for 30-day mortality was 2.44 (95% CI 1.57-3.81) in cases aged 80-84 years, 2.99 (95% CI 1.93-4.65) in cases aged 85-89 years, and 3.28 (95% CI 2.11-5.10) in cases aged ≥90 years, as compared with cases aged <70 years. Other risk factors for mortality among COVID-19 cases included male sex (OR, 2.60, 95% CI 2.22-3.05), neuropsychological conditions (OR, 2.18; 95% CI 1.76-2.71), impaired walking ability (OR, 1.45, 95% CI 1.17-1.78), urinary and bowel incontinence (OR 1.51, 95% CI 1.22-1.85), diabetes (OR 1.36, 95% CI 1.14-1.62), chronic kidney disease (OR 1.37, 95% CI 1.11-1.68) and previous pneumonia (OR 1.57, 95% CI 1.32-1.85). Nutritional factors, cardiovascular diseases, and antihypertensive medications were not significantly associated with mortality. Conclusions and Implications In Swedish LTCFs, COVID-19 was associated with a large excess in mortality after controlling for an extensive number of risk factors. Beyond older age and male sex, several prevalent clinical risk factors independently contributed to higher mortality. These findings suggest that reducing transmission of COVID-19 in LTCFs will likely prevent a considerable number of deaths.
117	MS115		Rosie Twomey, PhD, Jessica DeMars, BScPT, MSc, Kelli Franklin, BScPT, MSc, S Nicole Culos-Reed, PhD, Jason Weatherald, MD, James G Wrightson, PhD	Chronic Fatigue and Postexertional Malaise in People Living with Long COVID: An Observational Study	https://doi.org/10.1093/ptj/pzac005	Published	13 January 2022	Study	https://academic.oup.com/ptj/advance-article-abstract/doi/10.1093/ptj/pzac005/6506311	Results After data cleaning, 213 participants were included in the analysis. The total FACIT-F score was 18 (SD = 10) (where the score can range from 0 to 52 and a lower score indicates more severe fatigue), and 71.4% were experiencing chronic fatigue. Postexertional symptom exacerbation affected most participants, and 58.7% met the PEM scoring thresholds used in people living with myalgic encephalomyelitis/chronic fatigue syndrome. Conclusion Long COVID is characterized by chronic fatigue that is clinically relevant and at least as severe as fatigue in several other clinical conditions. PEM is a significant challenge for this patient group. Because of the potential for setbacks and deteriorated function following overexertion, fatigue and postexertional symptom exacerbation must be monitored and reported in clinical practice and in studies involving interventions for people with long COVID. Impact Physical therapists working with people with long COVID should measure and validate the patient’s experience. Postexertional symptom exacerbation must be considered, and rehabilitation needs to be carefully designed based on individual presentation. Beneficial interventions might first ensure symptom stabilization via pacing, a self-management strategy for the activity that helps minimize postexertional malaise.
118	MS116		Chiara Mariani Fabio Borgonovo Amedeo F Capetti Letizia Oreni Maria Vittoria Cossu Martina Pellicciotta Luciana Armiento Simona Bocchio Gianfranco Dedivitiis Angelica Lupo Massimo Galli Giuliano Rizzardini	Persistence of Long-COVID symptoms in a heterogenous prospective cohort	https://doi.org/10.1016/j.jinf.2022.01.024	Published	January 22, 2022	Correspondence	https://www.journalofinfection.com/article/S0163-4453(22)00024-X/fulltext	Palpitations are disproportionate accelerations of the heartbeat during exercise or at rest that resolve slowly. Their estimated median time to resolution (95% CI) was 425 days (282-489). The estimated median time to resolution of anxiety and panic attacks was 391 days (313-NA). The median time to resolution of headache was estimated to be 379 days (264-505). For amnesia and insomnia the slow decay rate currently makes it impossible to foresee a median time of resolution. After one year less than 20% of our patients have resolved memory problems, and only about 15% have resolved insomnia. After median 35 days beyond the onset of COVID-19 phase of the disease 17.3% of the population reported telogen effluvium, the only truly post-COVID symptom, which had a median time to resolution of 299 days. What happens after COVID-19 disease cannot be summarily referred to a simple convalescence period in which symptoms gradually but linearly decrease.
119	MS117		CésarFernández-de-las-Peñas1José D.Martín-Guerrero2IgnacioCancela-Cilleruelo1PalomaMoro-López-Menchero1JorgeRodríguez-Jiménez1Oscar J.Pellicer-Valero2	Exploring the Trajectory Recovery Curve of the number of Post-COVID Symptoms: The LONG-COVID-EXP-CM Multicenter Study	https://doi.org/10.1016/j.ijid.2022.02.010	Published	9 February 2022	Study	https://www.sciencedirect.com/science/article/pii/S1201971222000832	Highlights •This multicentre study included 1,563 COVID-19 hospitalized patients •Almost 50% of patients developed ≥3 post-COVID symptoms 6-months after infection •A trajectory curve reveals overall decrease in the number of post-COVID symptoms Results A total of 1,593 COVID-19 survivors were assessed 8.4 (T1) and 13.2 (T2) months after hospitalization. The mean number of post-COVID symptoms was 2.6 (SD 2.0) at T1 and 1.5 (SD 1.4) at T2. The trajectory curve showed a decrease prevalence trend. The analysis also revealed that 985 (61.8%) subjects reported a greater number (T1>T2), 549 (34.5%) equal number (T1 =T2) and 59 (3.7%) lower number (T1<T2) of post-COVID symptoms in the first (T1: 8.4 months) in comparison with the second (T2: 13.2 months) assessment. Conclusion Current trajectory analysis revealed an overall decrease in the tendency in the number of post-COVID symptoms throughout the two years after the infection.
120	MS118	Cf MS119	Ingrid Torjesen	Covid-19 patients discharged from hospital have “substantially higher risk” of adverse outcomes and need monitoring	https://doi.org/10.1136/bmj.o265	Published	01 February 2022	Article	https://www.bmj.com/content/376/bmj.o265.full	Patients who leave hospital after a stay for covid-19 are far more likely to need to be readmitted or to die than the general population, shows a UK study.1 The researchers said their findings emphasised that patients discharged after covid-19 were likely to pose a “substantial extra burden on healthcare.” The findings support those of a study published in The BMJ in March 2021 that found that patients of all ages discharged after hospital treatment for covid-19 had higher than expected rates of multiorgan dysfunction.2 In the new study, researchers used linked primary care and hospital data in England to evaluate the risks of hospital admission and death among 24 673 patients who were treated in hospital for covid who survived for at least a week after discharge between February and December 2020. They were compared with 123 362 matched controls. Outcomes among the discharged patients were also compared with outcomes in 16 058 people who had been discharged after hospital treatment for influenza between 2017 and 2019. The findings, reported in PLoS Medicine, showed that during a follow-up period of up to 315 days the covid patients were more than twice as likely to need readmission or to die as the general population (fully adjusted hazard ratio 2.22 (95% confidence interval 2.14 to 2.30, P<0.001)) but slightly less likely than the patients who had been admitted to hospital for flu (HR 0.95, 0.91 to 0.98, P=0.004).
121	MS119		Krishnan Bhaskaran ,Christopher T. Rentsch ,George Hickman ,William J. Hulme ,Anna Schultze,Helen J. Curtis,Kevin Wing,Charlotte Warren-Gash,Laurie Tomlinson,Chris J. Bates,Rohini Mathur,Brian MacKenna,Viyaasan Mahalingasivam,Angel Wong,Alex J. Walker,Caroline E. Morton,Daniel Grint,Amir Mehrkar,Rosalind M. Eggo,Peter Inglesby,Ian J. Douglas,Helen I. McDonald,Jonathan Cockburn,Elizabeth J. Williamson,David Evans,John Parry,Frank Hester,Sam Harper,Stephen JW Evans,Sebastian Bacon,Liam Smeeth ,Ben Goldacre	Overall and cause-specific hospitalisation and death after COVID-19 hospitalisation in England: A cohort study using linked primary care, secondary care, and death registration data in the OpenSAFELY platform	https://doi.org/10.1371/journal.pmed.1003871	Published	January 25, 2022	Study	https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1003871	Background There is concern about medium to long-term adverse outcomes following acute Coronavirus Disease 2019 (COVID-19), but little relevant evidence exists. We aimed to investigate whether risks of hospital admission and death, overall and by specific cause, are raised following discharge from a COVID-19 hospitalisation. Methods and findings With the approval of NHS-England, we conducted a cohort study, using linked primary care and hospital data in OpenSAFELY to compare risks of hospital admission and death, overall and by specific cause, between people discharged from COVID-19 hospitalisation (February to December 2020) and surviving at least 1 week, and (i) demographically matched controls from the 2019 general population; and (ii) people discharged from influenza hospitalisation in 2017 to 2019. We used Cox regression adjusted for age, sex, ethnicity, obesity, smoking status, deprivation, and comorbidities considered potential risk factors for severe COVID-19 outcomes. We included 24,673 postdischarge COVID-19 patients, 123,362 general population controls, and 16,058 influenza controls, followed for ≤315 days. COVID-19 patients had median age of 66 years, 13,733 (56%) were male, and 19,061 (77%) were of white ethnicity. Overall risk of hospitalisation or death (30,968 events) was higher in the COVID-19 group than general population controls (fully adjusted hazard ratio [aHR] 2.22, 2.14 to 2.30, p < 0.001) but slightly lower than the influenza group (aHR 0.95, 0.91 to 0.98, p = 0.004). All-cause mortality (7,439 events) was highest in the COVID-19 group (aHR 4.82, 4.48 to 5.19 versus general population controls [p < 0.001] and 1.74, 1.61 to 1.88 versus influenza controls [p < 0.001]). Risks for cause-specific outcomes were higher in COVID-19 survivors than in general population controls and largely similar or lower in COVID-19 compared with influenza patients. However, COVID-19 patients were more likely than influenza patients to be readmitted or die due to their initial infection or other lower respiratory tract infection (aHR 1.37, 1.22 to 1.54, p < 0.001) and to experience mental health or cognitive-related admission or death (aHR 1.37, 1.02 to 1.84, p = 0.039); in particular, COVID-19 survivors with preexisting dementia had higher risk of dementia hospitalisation or death (age- and sex-adjusted HR 2.47, 1.37 to 4.44, p = 0.002). Limitations of our study were that reasons for hospitalisation or death may have been misclassified in some cases due to inconsistent use of codes, and we did not have data to distinguish COVID-19 variants. Conclusions In this study, we observed that people discharged from a COVID-19 hospital admission had markedly higher risks for rehospitalisation and death than the general population, suggesting a substantial extra burden on healthcare. Most risks were similar to those observed after influenza hospitalisations, but COVID-19 patients had higher risks of all-cause mortality, readmission or death due to the initial infection, and dementia death, highlighting the importance of postdischarge monitoring.
122	MS120		Namrata Walia (1), Jessica Olivia Lat (2), Rabeet Tariq (3), Surbhi Tyagi (4), Adam Manzoor Qazi (5), Syeda Wajiha Salari (6), Amina Jafar (7), Tasneem Kousar (8), Sherrie Bieniek (9)	Post-acute sequelae of COVID-19 and the mental health implications	https://doi.org/10.15190/d.2021.19	Published	Dec. 31, 2021	Review	https://discoveriesjournals.org/discoveries/D.2021.04.RA-Namrata.DOI	Post-acute sequelae of COVID-19 (PASC) or more commonly known as Long COVID-19, is the term given to persistent symptoms 12 weeks from the initial presentation of COVID-19 infection. Several multi-organ symptoms have been reported by patients. Some common symptoms include headaches, fatigue, memory impairment and mental health complications such as anxiety and depression. People with previous psychiatric diagnosis are at greater risk of developing longer mental health implications from persistent COVID-19 symptoms. Additionally, healthcare workers are at increased risk of being long haulers leading to burnout and exhaustion. The objective of this review article is to provide comprehensive evidence from existing literature on various symptoms reported by patients experiencing Long COVID-19 and the rate of occurrence of such symptoms in different populations. A long-term disease surveillance is required to further understand the persistent symptoms or the long-term impact of this infection.
123	MS121	ES	Dana Yelin 1,2,*,Ili Margalit 1,2,3 ,Mayssam Nehme 4,Jaume Bordas-Martínez 5,6 ,Francesco Pistelli 7,8 ,Dafna Yahav 2,3,Idris Guessous 4,9,Xavier Durà-Miralles 9,10,Laura Carrozzi 6,Irit Shapira-Lichter 2,11 ,Pauline Vetter 12,Dolores Peleato-Catalan 13,Giusy Tiseo 14,Eytan Wirtheim 15,Laurent Kaiser 12,Carlota Gudiol 6,16,17 ,Marco Falcone 14,Leonard Leibovici	Patterns of Long COVID Symptoms: A Multi-Center Cross Sectional Study	https://doi.org/10.3390/jcm11040898	Published	9 February 2022	Study	https://www.mdpi.com/2077-0383/11/4/898/htm	Background: Long COVID has become a burden on healthcare systems worldwide. Research into the etiology and risk factors has been impeded by observing all diverse manifestations as part of a single entity. We aimed to determine patterns of symptoms in convalescing COVID-19 patients. Methods: Symptomatic patients were recruited from four countries. Data were collected regarding demographics, comorbidities, acute disease and persistent symptoms. Factor analysis was performed to elucidate symptom patterns. Associations of the patterns with patients’ characteristics, features of acute disease and effect on daily life were sought. Results: We included 1027 symptomatic post-COVID individuals in the analysis. The majority of participants were graded as having a non-severe acute COVID-19 (N = 763, 74.3%). We identified six patterns of symptoms: cognitive, pain-syndrome, pulmonary, cardiac, anosmia-dysgeusia and headache. The cognitive pattern was the major symptoms pattern, explaining 26.2% of the variance; the other patterns each explained 6.5–9.5% of the variance. The cognitive pattern was higher in patients who were outpatients during the acute disease. The pain-syndrome pattern was associated with acute disease severity, higher in women and increased with age. The pulmonary pattern was associated with prior lung disease and severe acute disease. Only two of the patterns (cognitive and cardiac) were associated with failure to return to pre-COVID occupational and physical activity status. Conclusion: Long COVID diverse symptoms can be grouped into six unique patterns. Using these patterns in future research may improve our understanding of pathophysiology and risk factors of persistent COVID, provide homogenous terminology for clinical research, and direct therapeutic interventions.
124	MS122	ES	Mohamad SalimAlkodaymiMBBS, MPH1∗∗Osama AliOmraniMBBS, BSc23∗∗Nader A.Fawzy4#Bader AbouShaar4#RaghedAlmamloukMBBS4#MuhammadRiazPhD5#MustafaObeidatMBBS, MBA4YasinObeidatMBBS6DanaGerberiMLS7Rand M.Taha4ZakariaKashourMBBS4TarekKashourMBChB8Elie F.BerbariMD9KhaledAlkattanMD4Imad M.TleyjehMD, MSc491011	Prevalence of post-acute COVID-19 syndrome symptoms at different follow-up periods: A systematic review and meta-analysis	https://doi.org/10.1016/j.cmi.2022.01.014	Published	3 February 2022	Systematic Review	https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(22)00038-6/fulltext	Results After screening 3209 studies, a total of 63 studies were eligible, with a total COVID-19 population of 257,348. The most commonly reported symptoms were fatigue, dyspnea, sleep disorder and concentration difficulty (32%, 25%, 24%, and 22% respectively at 3-<6 months follow-up), effort intolerance, fatigue, sleep disorder and dyspnea (45%, 36%, 29% and 25% respectively at 6-<9 months follow-up), fatigue (37%) and dyspnea (21%) at 9-<12 months and fatigue, dyspnea, sleep disorder, myalgia (41%, 31%, 30%, and 22% respectively at >12 months follow-up). There was substantial between-studies heterogeneity for all reported symptoms prevalence. Meta-regressions identified statistically significant effect modifiers: world region, male gender, diabetes mellitus, disease severity and overall study quality score. Five of six studies including a comparator group consisting of COVID-19 negative cases observed significant adjusted associations between COVID-19 and several long-term symptoms. Conclusions This systematic review found that a large proportion of patients experience PACS 3 to 12 months after recovery from the acute phase of COVD-19. However, available studies of PACS are highly heterogeneous. Future studies need to have appropriate comparator groups, standardized symptoms definitions and measurements and longer follow-up.
125	MS123	ES	Saurabh Mehandru & Miriam Merad	Pathological sequelae of long-haul COVID	https://doi.org/10.1038/s41590-021-01104-y	Published	01 February 2022	Review	https://www.nature.com/articles/s41590-021-01104-y	The world continues to contend with successive waves of coronavirus disease 2019 (COVID-19), fueled by the emergence of viral variants. At the same time, persistent, prolonged and often debilitating sequelae are increasingly recognized in convalescent individuals, named ‘post-COVID-19 syndrome’ or ‘long-haul COVID’. Clinical symptomatology includes fatigue, malaise, dyspnea, defects in memory and concentration and a variety of neuropsychiatric syndromes as the major manifestations, and several organ systems can be involved. The underlying pathophysiological mechanisms are poorly understood at present. This Review details organ-specific sequelae of post-COVID-19 syndromes and examines the underlying pathophysiological mechanisms available so far, elaborating on persistent inflammation, induced autoimmunity and putative viral reservoirs. Finally, we propose diagnostic strategies to better understand this heterogeneous disorder that continues to afflict millions of people worldwide.
126	MS124		Anuradhaa Subramanian, Krishnarajah Nirantharakumar, Sarah Hughes, Puja Myles, Tim Williams, Krishna Gokhale, Tom Taverner, Joht Chandan, Kirsty Brown, Nikita Simms-Williams, Anoop Shah, Megha Singh, Farah Kidy, Kelvin Okoth, Richard Hotham, Nasir Bashir, Neil Cockburn, Siang Lee, Grace Turner, Georgios Gkoutos, Olalekan Lee Aiyegbusi, Christel McMullan, Alastair Denniston, Elizabeth Sapey, Janet Lord, David Wraith, Edward Leggett, Clare Iles, Tom Marshall, Malcolm Price, Steven Marwaha, Elin Davies, Louise Jackson, Jenny Camaradou, Melanie Calvert, Shamil Haroon	Assessment of 115 symptoms for Long COVID (post-COVID-19 condition) and their risk factors in non-hospitalised individuals: a retrospective matched cohort study in UK primary care	10.21203/rs.3.rs-1343889/v1	Pre-print	15 Feb, 2022	Study	https://www.researchsquare.com/article/rs-1343889/v1	The objectives of this study were to assess which symptoms are associated with confirmed SARS CoV-2 beyond 12 weeks post-infection in non-hospitalised individuals, and the risk factors associated with developing persistent symptoms. We undertook a retrospective matched cohort study between 31st January 2020 and 15th April 2021 using data from a large database of UK-based primary care electronic health records, Clinical Practice Research Datalink (CPRD) Aurum. We selected 486,149 adult patients with a confirmed diagnosis of SARS CoV-2 infection that had not been hospitalised within 28 days of the diagnosis (infected cohort). We propensity score matched them to 1,944,580 patients without a coded record of either confirmed or suspected COVID-19 (uninfected cohort). Outcomes were the presence of 115 separate symptoms at ≥12 weeks post-infection, and Long COVID, defined as having at least one of the symptoms included in the World Health Organisation case definition. Separate Cox proportional hazards models were used to estimate adjusted hazard ratios (aHR) for individual symptoms and Long Covid. 62 symptoms were significantly associated with prior exposure to SARS CoV-2 after 12 weeks. The largest adjusted hazard ratios (aHR) were for anosmia (aHR 6.49, 95% CI 5.02 to 8.39), hair loss (3.99, 3.63 to 4.39), sneezing (2.77, 1.40 to 5.50), difficulties with ejaculation (2.63, 1.61 to 4.28), reduced libido (2.36, 1.61 to 3.47), shortness of breath at rest (2.20, 1.57 to 3.08), fatigue (1.92, 1.81 to 2.03), pleuritic chest pain (1.86, 1.41 to 2.46), hoarse voice (1.78, 1.44 to 2.20), and fever (1.75, 1.54 to 1.98). Among the infected cohort, risk factors for Long COVID included younger age (aHR 0.75, 95% CI 0.70 to 0.81, for those aged ≥70 years compared to those aged 18 to 30 years), female sex (1.52, 1.48 to 1.56), belonging to an ethnic minority group (1.14 [1.07 to 1.22] for mixed race, 1.21 [1.10 to 1.34] for black ethnic groups, and 1.06 [1.03 to 1.10] for other ethnic minority groups, compared to white ethnic groups), socioeconomic deprivation (1.11 [1.07 to 1.16] for the most compared to the least socioeconomically deprived quintile), smoking (1.12, 1.08 to 1.15), obesity (1.10, 1.07 to 1.14), and a wide range of comorbidities such as COPD. SARS CoV-2 in non-hospitalised individuals is associated with a plethora of symptoms being reported at ≥12 weeks post-infection, with a higher risk associated with younger age, female sex, ethnic minority groups, socioeconomic deprivation, smoking, obesity, and several comorbidities.
127	MS125		Han, Q.; Zheng, B.; Daines, L.; Sheikh, A.	Long-Term Sequelae of COVID-19: A Systematic Review and Meta-Analysis of One-Year Follow-Up Studies on Post-COVID Symptoms	https://doi.org/10.3390/pathogens11020269	Published	19 February 2022	Systematic review	https://www.sciencedirect.com/science/article/pii/S0013935122002948	Highlights •A long-term WBE was conducted using samples from four WWTP and four hospitals. •WBE was capable of providing 2–7 days of early warning of clinical cases. •The median detection rate of SARS-CoV-2 is one out of 14,300 reported new cases. •Viral loads in influents and effluents of WWTPs were found similar. •The COVID-19 point prevalence according to WBE ranged from 0.02 to 4.6%. Abstract Wastewater-based epidemiology offers a time- and cost-effective way to monitor SARS-CoV-2 spread in communities and therefore represents a complement to clinical testing. WBE applicability has been demonstrated in a number of cases over short-term periods as a method for tracking the prevalence of SARS-CoV-2 and an early-warning tool for predicting outbreaks in the population. This study reports SARS-CoV-2 viral loads from wastewater treatment plants (WWTPs) and hospitals over a 6-month period (June to December 2020). Results show that the overall range of viral load in positive tested samples was between 1.2 × 103 and 3.5 × 106 gene copies/l, unveiling that secondary-treated wastewaters mirrored the viral load of influents. The interpretation suggests that the viral titers found in three out of four WWTPs were associated to clinical COVID-19 surveillance indicators preceding 2–7 days the rise of reported clinical cases. The median wastewater detection rate of SARS-CoV-2 was one out of 14,300 reported new cases. Preliminary model estimates of prevalence ranged from 0.02 to 4.6% for the studied period. This comprehensive statistical and epidemiological analysis demonstrates that the applied wastewater-based approach to COVID-19 surveillance is in general consistent and feasible, although there is room for improvements.
128	MS126		Nicola Spiers	Reassessment of persistent symptoms, self-reported COVID-19 infection and SARS-CoV-2 serology in the SAPRIS-SERO cohort: identifying possible sub-syndromes of Long Covid	https://doi.org/10.1101/2022.02.25.22271499	Pre-print	February 26, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.02.25.22271499v1.full-text	Background Long Covid remains a relatively new phenomenon with emerging understanding. Estimated UK prevalence of Long Covid with three or more symptoms lasting for 12 weeks or more was 2.2% at the end of 2021. The population-based French SAPRIS-SERO cohort has novel information about the pattern of symptoms of Long Covid that has been obscured by controversy around the original paper. Methods Secondary analysis was used to describe and re-interpret the pattern of persistent symptoms by IgG seropositivity and self-reported Long Covid in the SAPRIS-SERO survey. Participants in the cross-sectional analysis were 26 823 individuals from the French population-based CONSTANCES cohort, included between 2012 and 2019, who took part in the nested SAPRIS and SAPRIS-SERO surveys. Between May and November 2020, the Euroimmun enzyme-linked immunosorbent assay was used to detect anti–SARS-CoV-2 antibodies. Surveyed online between December 2020 and January 2021, participants self-reported previous COVID-19 infection and physical symptoms during the previous four weeks that were new since March 2020, and had persisted for at least eight weeks. Results There was similarity of prevalence over the majority of symptoms in those self-reporting COVID-19 infection, regardless of blood test result. Persistent symptoms significantly associated with self-reported COVID-19 infection and common in both groups include respiratory tract symptoms and a group of symptoms that might be related to chronic fatigue, malaise or postural issues. Seropositivity for IgG antibodies did not predict symptoms independently of self-reported Long Covid, except for anosmia. Conclusions There may be three common sub-syndromes of Long Covid, one with persistent anosmia, another with other respiratory tract symptoms and a third, currently under researched, with symptoms relatable to chronic fatigue. Antibody tests are insufficient for case detection while Long Covid remains poorly understood. Key Messages - IgG seropositivity is insufficient to identify potential cases of Long Covid - Persistent anosmia is very strongly associated with IgG seropositivity and may define a subsyndrome of Long Covid - Other potential subsyndromes are those with persistent respiratory symptoms and those with persistent symptoms relatable to fatigue, malaise or postural issues - The Long Covid research effort should be rebalanced towards understanding the fatigue/tiredness subsyndrome.
129	MS127		Anna Irene Vedel Sørensen, View ProfileLampros Spiliopoulos, View ProfilePeter Bager, View ProfileNete Munk Nielsen, View ProfileJørgen Vinsløv Hansen, View ProfileAnders Koch, View ProfileInger Kristine Meder, View ProfileSteen Ethelberg, View ProfileAnders Hviid	Post-acute symptoms, new onset diagnoses and health problems 6 to 12 months after SARS-CoV-2 infection: a nationwide questionnaire study in the adult Danish population	https://doi.org/10.1101/2022.02.27.22271328	Pre-print	February 28, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.02.27.22271328v1.full-text	Background - A considerable number of individuals infected with SARS-CoV-2 continue to experience symptoms after the acute phase. More information on duration and prevalence of these symptoms in non-hospitalized populations is needed. Methods - We conducted a nationwide cross-sectional study including 152 880 individuals aged 15-years or older, consisting of RT-PCR confirmed SARS-CoV-2 cases between September 2020-April 2021 (N=61 002) and a corresponding test-negative control group (N=91 878). Data were collected 6, 9 or 12 months after the test using web-based questionnaires. The questionnaire covered acute and post-acute symptoms, selected diagnoses, sick leave and general health, together with demographics and life style at baseline. Risk differences (RDs) between test-positives and -negatives were reported, adjusted for age, sex, single comorbidities, Charlson comorbidity score, obesity and healthcare-occupation. Findings - Six to twelve months after the test date, the risks of 18 out of 21 physical symptoms were elevated among test-positives and one third (29.6%) of the test-positives experienced at least one physical post-acute symptom. The largest risk differences were observed for dysosmia (RD = 10.92%, 95%CI 10.68-11.21%), dysgeusia (RD=8.68%, 95%CI 8.43-8.93%), fatigue/exhaustion (RD=8.43%, 95%CI 8.14-8.74%), dyspnea (RD=4.87%, 95%CI 4.65-5.09%) and reduced strength in arms/legs (RD=4.68%, 95%CI 4.45-4.89%). More than half (53.1%) of test-positives reported at least one of the following conditions: concentration difficulties (RD=28.34%, 95%CI 27.34-28.78%), memory issues (RD=27.25%, 95%CI 26.80-27.71%), sleep problems (RD=17.27%, 95%CI 16.81-17.73%), mental (RD=32.58%, 95%CI 32.11-33.09%) or physical exhaustion (RD=40.45%, 95%CI 33.99-40.97%), compared to 11.5% of test-negatives. New diagnoses of anxiety (RD=1.15%, 95%CI 0.95-1.34%) or depression (RD=1.00%, 95%CI 0.81-1.19%) were also more common among test-positives. Interpretation - At the population-level, where the majority of test-positives (96.0%) were not hospitalized during acute infection, a considerable proportion experience post-acute symptoms and sequelae 6-12 months after infection.
130	MS128		Kelly K O'BrienDarren A Brown5,6, Colm Bergin7,8, Kristine M Erlandson9, Jaime H Vera10,11, Lisa Avery12,13, Soo Chan Carusone14, Angela M Cheung2,12,15, Susie Goulding16, Richard Harding17, Lisa McCorkell18, Margaret O'Hara19, Larry Robinson20, Catherine Thomson6, Hannah Wei21, Natalie St Clair-Sullivan11, Brittany Torres1, Ciaran Bannan7,8, Niamh Roche22, Ruth Stokes22, Patriic Gayle23, Patricia Solomon	Long COVID and episodic disability: advancing the conceptualisation, measurement and knowledge of episodic disability among people living with Long COVID – protocol for a mixed-methods study	http://dx.doi.org/10.1136/bmjopen-2022-060826	Published	March 07, 2022	Study	https://bmjopen.bmj.com/content/12/3/e060826.abstract	Introduction As the prevalence of Long COVID increases, there is a critical need for a comprehensive assessment of disability. Our aims are to: (1) characterise disability experiences among people living with Long COVID in Canada, UK, USA and Ireland; and (2) develop a patient-reported outcome measure to assess the presence, severity and episodic nature of disability with Long COVID. Methods and analysis In phase 1, we will conduct semistructured interviews with adults living with Long COVID to explore experiences of disability (dimensions, uncertainty, trajectories, influencing contextual factors) and establish an episodic disability (ED) framework in the context of Long COVID (n~10 each country). Using the conceptual framework, we will establish the Long COVID Episodic Disability Questionnaire (EDQ). In phase 2, we will examine the validity (construct, structural) and reliability (internal consistency, test–retest) of the EDQ for use in Long COVID. We will electronically administer the EDQ and four health status criterion measures with adults living with Long COVID, and readminister the EDQ 1 week later (n~170 each country). We will use Rasch analysis to refine the EDQ, and confirm structural and cross-cultural validity. We will calculate Cronbach’s alphas (internal consistency reliability), and intraclass correlation coefficients (test–retest reliability), and examine correlations for hypotheses theorising relationships between EDQ and criterion measure scores (construct validity). Using phase 2 data, we will characterise the profile of disability using structural equation modelling techniques to examine relationships between dimensions of disability and the influence of intrinsic and extrinsic contextual factors. This research involves an academic–clinical–community partnership building on foundational work in ED measurement, Long COVID and rehabilitation.
131	MS129		Nida Ziauddeen ,Deepti Gurdasani,Margaret E. O’Hara,Claire Hastie,Paul Roderick,Guiqing Yao,Nisreen A. Alwan	Characteristics and impact of Long Covid: Findings from an online survey	https://doi.org/10.1371/journal.pone.0264331	Published	March 8, 2022	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0264331	Results We analysed data from 2550 participants with a median duration of illness of 7.6 months (interquartile range (IQR) 7.1–7.9). 26.5% reported lab-confirmation of infection. The mean age was 46.5 years (standard deviation 11 years) with 82.8% females and 79.9% of participants based in the UK. 89.5% described their health as good, very good or excellent before COVID-19. The most common initial symptoms that persisted were exhaustion, chest pressure/tightness, shortness of breath and headache. Cognitive dysfunction and palpitations became more prevalent later in the illness. Most participants described fluctuating (57.7%) or relapsing symptoms (17.6%). Physical activity, stress, and sleep disturbance commonly triggered symptoms. A third (32%) reported they were unable to live alone without any assistance at six weeks from start of illness. 16.9% reported being unable to work solely due to COVID-19 illness. 37.0% reported loss of income due to illness, and 64.4% said they were unable to perform usual activities/duties. Acute systems clustered broadly into two groups: a majority cluster (n = 2235, 88%) with cardiopulmonary predominant symptoms, and a minority cluster (n = 305, 12%) with multisystem symptoms. Similarly, ongoing symptoms broadly clustered in two groups; a majority cluster (n = 2243, 88.8%) exhibiting mainly cardiopulmonary, cognitive symptoms and exhaustion, and a minority cluster (n = 283, 11.2%) exhibiting more multisystem symptoms. Belonging to the more severe multisystem cluster was associated with more severe functional impact, lower income, younger age, being female, worse baseline health, and inadequate rest in the first two weeks of the illness, with no major differences in the cluster patterns when restricting analysis to the lab-confirmed subgroup. Conclusion This is an exploratory survey of Long Covid characteristics. Whilst this is a non-representative population sample, it highlights the heterogeneity of persistent symptoms, and the significant functional impact of prolonged illness following confirmed or suspected SARS-CoV-2 infection. To study prevalence, predictors and prognosis, research is needed in a representative population sample using standardised case definitions.
132	MS130		Chan Sui Ko Adrien Candellier Alexandre Mercier Marie Joseph Cédric Jean-Luc Schmit Lanoix Jean-Philippe Andrejak Claire	Number of initial symptoms is more related to long COVID-19 than acute severity of infection: a prospective cohort of hospitalized patients.	https://doi.org/10.1016/j.ijid.2022.03.006	Published	March 04, 2022	Study	https://www.ijidonline.com/article/S1201-9712(22)00141-2/fulltext	Post-COVID-19 symptoms experienced by many survivors after infection have a further devastating effect. Reports of risk factor of long COVID-19 are rising but data including reliable assessment of persistent symptoms by structured face to face follow up visit are scarce (Halpinet al. 2021). Here we report a study assessing post-COVID-19 associated risk factors in hospitalized patients including those requiring ICU four months after admission. We provide also data about objective measures of COVID-19 severity e.g., oxygen requirement, inflammatory biomarkers and radiological findings. In univariate analysis, women had significantly increased risk (OR = 1.89 95% CI [1.16-3.03], p=0.01) than men. Patient with hypertension (OR = 1.64 95% CI [1.04-2.61], p=0.04) experienced persistent symptoms more frequently. The number of initial symptoms (OR = 1.27 95% CI [1.12-1.45], p<0.001) or patient with five or more initial symptoms showed greater risk for long-COVID-19 (OR = 2.47 95%CI [1.12-3.03]). In multivariate logistic regression, female sex (OR = 1.94 95% CI [1.17-3.22], p=0.01) hypertension (OR = 2.01 95% CI [1.22-3.31], p<0.01) and the number of initial symptoms (OR = 1.35 95% CI [1.17-1.54], p<0.001) remained significantly associated with persistent symptoms (supplementary Table 1). Similarly, in multivariate Poisson regression, the number of persistent symptoms was significatively associated with the number of initial symptoms (adjusted incidence rate ratios, aIRR = 1.16 95% CI [1.11-1.22], p<0.001) as well as female sex (aIRR = 1.56 95% CI [1.29-1.87], p<0.001), hypertension (aIRR = 1.23 95% CI [1.02-1.50], p=0.03) and length of stay in hospital (aIRR = 1.01 95% CI [1.005-1.017], p<0.001)
133	MS131		Kenneth Fiala, Joshua Martens & Alaa Abd-Elsayed	Post-COVID Pain Syndromes	https://doi.org/10.1007/s11916-022-01038-6	Published	10 March 2022	Commentary	https://link.springer.com/article/10.1007/s11916-022-01038-6	COVID-19 has taken the world by storm and there is a growing body of literature on how it can acutely manifest in patients. Now that COVID-19 has been affecting patients for approximately 2 years, we are discovering the potential long-term effects possible after contracting the virus. There appears to be an increase in the number of cases of long-term headaches, chest pain, testicular pain, and chronic pain being reported after COVID-19 infection. It has been postulated that secondary to the COVID-19 pandemic, chronic pain may be expected to rise in both the immediate and long-term [33]. Further analysis of the literature should be conducted in the future to continue to analyze the chronic effects of COVID-19.
134	MS132		Martha Spyridoula Katsarou , Eleni Iasonidou , Alexander Osarogue , Efthymios Kalafatis , Stylianos Gatzonis , Sofia Pappa logo , Athanasia Verentzioti , Maria Stefanatou , Pantelis Gounopoulos , Christos Demponeras , Eleni Konstantinidou , Nikolaos Drakoulis logo , Andreas Asimakos , Archontoula Antonoglou , Aspasia Mavronasou , Stavroula Spetsioti , Anastasia Kotanidou logo , Paraskevi Katsaounou * logo	Collaborative Research for Long COVID Haulers in Greece (Characteristics, Clinical Assessment and Rehabilitation). Non-hospitalized and Hospitalized Long COVID Patients Share Similar Symptom Patterns	https://doi.org/10.20944/preprints202203.0277.v1	Pre-print	21 March 2022	Study	https://www.preprints.org/manuscript/202203.0277/v1	COVID-19 Long Haulers, an estimated 3% to 12% of people infected globally with coronavirus having latter devasting symptoms 12 weeks after the initial infection is on the rise. We conducted a collaborative study with the long covid patient organization in Greece in order to estimate the prevalence, symptoms and problems that adult long haulers experience and then propose a management plan for these patients. Symptoms were obtained from 208 patients using unstructured qualitative free text entries in an anonymized online questionnaire. The majority of respondents (68.8%) were not hospitalized and had been diagnosed more than six months ago with lingering symptoms (66,8%). Eighteen different symptoms (fatigue, tachycardia, shortness of breath, parosmia etc) were mentioned in both hospitalized and community patients. Interestingly, patients with initial mild symptoms suffer from the same persistent symptoms as those who were hospitalized. Awareness of long covid sequelae seems to be low even among medical doctors. Treatment options incorporating targeted rehabilitation programs are either not available or still excluded from the management plan of long covid patients. Since long COVID is a multi-systemic entity, we propose a holistic interventional approach using a multidisciplinary medical team in order to securely and effectively diagnose and treat these specific patients. Academic and medical community must collaborate with long covid patients’ organizations so as to provide personalized medicine.
135	MS133		Michele R.SchaefferabJuthapornCowancdeKathryn M.MilnebfJoseph H.PuyatgNhaVoduccVicenteCorrales-MedinadKim L.LavoiehiAndrewMulloycJulio A.ChirinosjSara J.AbdallahdJordan A.Guenetteab	Cardiorespiratory physiology, exertional symptoms, and psychological burden in post-COVID-19 fatigue	https://doi.org/10.1016/j.resp.2022.103898	Published	29 March 2022	Study	https://www.sciencedirect.com/science/article/pii/S156990482200057X	Highlights •Peak ⩒O2 (ml/kg/min) is lower in survivors with post-COVID-19 fatigue vs. without. •Dyspnoea is elevated during exercise in COVID-19 survivors with fatigue vs. without. •Higher psychological burden may contribute to post-COVID-19 fatigue symptomology. Fatigue is a common, debilitating, and poorly understood symptom post-COVID-19. We sought to better characterize differences in those with and without post-COVID-19 fatigue using cardiopulmonary exercise testing. Despite elevated dyspnoea intensity ratings, V̇O2peak (ml/kg/min) was the only significant difference in the physiological responses to exercise (19.9 ± 7.1 fatigue vs. 24.4 ± 6.7 ml/kg/min non-fatigue, p = 0.04). Consistent with previous findings, we also observed a higher psychological burden in those with fatigue in the context of similar resting cardiopulmonary function. Our findings suggest that lower cardiorespiratory fitness and/or psychological factors may contribute to post-COVID-19 fatigue symptomology. Further research is needed for rehabilitation and symptom management following SARS-CoV-2 infection.
136	MS134		Jin H. Han,Kelsey N. Womack,Mark W. Tenforde,D. Clark Files,Kevin W. Gibbs,Nathan I. Shapiro,Matthew E. Prekker,Heidi L. Erickson,Jay S. Steingrub,Nida Qadir,Akram Khan,Catherine L. Hough,Nicholas J. Johnson,E. Wesley Ely,Todd W. Rice,Jonathan D. Casey,Christopher J. Lindsell,Michelle N. Gong,Vasisht Srinivasan,Nathaniel M. Lewis,Manish M. Patel,Wesley H. Self	Associations between persistent symptoms after mild COVID-19 and long-term health status, quality of life, and psychological distress	https://doi.org/10.1111/irv.12980	Published	28 March 2022	Study	https://onlinelibrary.wiley.com/doi/10.1111/irv.12980	Background We sought to assess whether persistent COVID-19 symptoms beyond 6 months (Long-COVID) among patients with mild COVID-19 is associated with poorer health status, quality of life, and psychological distress. Methods This was a multicenter prospective cohort study that included adult outpatients with acute COVID-19 from eight sites during 2-week sampling periods from April 1 and July 28, 2020. Participants were contacted 6–11 months after their first positive SARS-CoV-2 to complete a survey, which collected information on the severity of eight COVID-19 symptoms using a 4-point scale ranging from 0 (not present) to 3 (severe) at 1 month before COVID-19 (pre-illness) and at follow-up; the difference for each was calculated as an attributable persistent symptom severity score. A total attributable persistent COVID-19 symptom burden score was calculated by summing the attributable persistent severity scores for all eight symptoms. Outcomes measured at long-term follow-up comprised overall health status (EuroQol visual analogue scale), quality of life (EQ-5D-5L), and psychological distress (Patient Health Questionnaire-4). The association between the total attributable persistent COVID-19 burden score and each outcome was analyzed using multivariable proportional odds regression. Results Of the 2092 outpatients with COVID-19, 436 (21%) responded to the survey. The median (IQR) attributable persistent COVID-19 symptom burden score was 2 (0, 4); higher scores were associated with lower overall health status (aOR 0.63; 95% CI: 0.57–0.69), lower quality of life (aOR: 0.65; 95%CI: 0.59–0.72), and higher psychological distress (aOR: 1.40; 95%CI, 1.28–1.54) after adjusting for age, race, ethnicity, education, and income. Conclusions In participants with mild acute COVID-19, the burden of persistent symptoms was significantly associated with poorer long-term health status, poorer quality of life, and psychological distress.
137	MS135		Margherita Schiavi, Stefania Fugazzaro, Anna Bertolini, Monica Denti, Carlotta Mainini, Monia Allisen Accogli, Ginevra Bedogni, Daniele Ghizzoni, Otmen Esseroukh, Cecilia Gualdi & Stefania Costi	“Like before, but not exactly”: the Qualy-REACT qualitative inquiry into the lived experience of long COVID	https://doi.org/10.1186/s12889-022-13035-w	Published	28 March 2022	Study	https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-022-13035-w	Background Post-acute sequelae of SARS-CoV-2 infection (PASC) affect millions of individuals worldwide. Rehabilitation interventions could support individuals during the recovery phase of COVID-19, but a comprehensive understanding of this new disease and its associated needs is crucial. This qualitative study investigated the experience of individuals who had been hospitalized for COVID-19, focusing on those needs and difficulties they perceived as most urgent. Methods This naturalistic qualitative study was part of a single-center mix-method cross-sectional study (REACT) conducted in Italy during the first peak of the SARS-CoV-2 pandemic. The qualitative data collection took place through a telephone interview conducted 3 months after hospital discharge. The experience of individuals discharged after hospitalization for COVID-19 was investigated through the main research question – “Tell me, how has it been going since you were discharged?”. Two secondary questions investigated symptoms, activities, and participation. Data were recorded and transcribed verbatim within 48 h. An empirical phenomenological approach was used by the researchers, who independently analyzed the data and, through consensus, developed an interpretative model to answer the research question. Translation occurred after data was analyzed. Results During the first peak of the COVID-19 pandemic, 784 individuals with COVID-19 were discharged from the hospitals of the Local Health Authority of the Province of Reggio Emilia (Italy); 446 were excluded due to the presence of acute or chronic conditions causing disability other than COVID-19 (n. 339), inability to participate in the study procedures (n. 56), insufficient medical documentation to allow for screening (n. 21), discharge to residential facilities (n. 25), and pregnancy (n. 5). Overall, 150 individuals consented to participate in the REACT study, and 56 individuals (60.7% male, average age 62.8 years ±11.8) were interviewed in June–July 2020, up to data saturation. Persistent symptoms, feelings of isolation, fear and stigma, emotional distress, a fatalistic attitude, and return to (adapted) life course were the key themes that characterized the participants’ experience after hospital discharge. Conclusions The experience as narrated by the participants in this study confirms the persistence of symptoms described in PASC and highlights the sense of isolation and psychological distress. These phenomena may trigger a vicious circle, but the participants also reported adaptation processes that allowed them to gradually return to their life course. Whether all individuals are able to rapidly activate these mechanisms and whether rehabilitation can help to break this vicious circle by improving residual symptoms remain to be seen.
138	MS136		Robineau, Olivier and Wiernik, Emmanuel and Lemogne, Cédric and de Lamballerie, Xavier and Ninove, Laetitia and Blanché, Hélène and Deleuze, Jean-François and Ribet, Céline and Kab, Sofiane and Goldberg, Marcel and Severi, Gianluca and Touvier, Mathilde and Zins, Marie and Carrat, Fabrice	Persistent Symptoms After the First Wave of COVID-19 in Relation to SARS-CoV-2 Serology and Experience of Acute Symptoms: A Nested Survey in a Population-Based Cohort	http://dx.doi.org/10.2139/ssrn.4016549	pre-print	24 Jan 2022	Study	https://papers.ssrn.com/sol3/Delivery.cfm/e37b60e6-007d-4c5e-a222-dfe776deeae5-MECA.pdf?abstractid=4016549&mirid=1	Background: Many patients report persistent symptoms after COVID-19. Our aim was to determine whether some of these symptoms were more associated with past SARS-CoV-2 infection compared to other conditions. Methods: This prospective survey was nested in CONSTANCES, a randomly selected French population-based cohort, started in 2012. All participants being followed-up by internet completed 2 questionnaires during the first wave of the pandemic (April-March 2020) focusing on the acute symptoms of their COVID-19-like illness. Serological tests for SARS-CoV-2 were then performed (May-Nov 2020). Between December 2020 and January 2021, participants completed a third questionnaire about symptoms that had lasted more than 2 months. Participants were classified into four groups according to European Center for Diseases Control (ECDC) criteria for SARS-CoV-2 infection (ECDC+ or ECDC-) and according to serological SARS-CoV-2 test results (Sero+ or Sero-). To compare the risk of each persistent symptom among the groups, logistic regression models were adjusted for age, sex, educational level, comorbidities, and the number of acute symptoms declared during the first wave of the epidemic. A mediation analysis was performed to estimate the direct effect of the infection on symptom persistence and its indirect effect via the initial clinical presentation. Findings: The analysis was performed in 25910 participants. There was a higher risk of persistent persistent dysgeusia/anosmia, dyspnea and asthenia in the ECDC+/Sero+ group than in the ECDC+/Sero- group (OR: 6.83 [4.47-10.42], 1.69 [1.07-2.6] and 1.48 [1.05-2.07], respectively). Abdominal pain, sensitive symptoms or sleep disorders were at lower risk in the ECDC+/Sero+ group than in the ECDC+/Sero- group (0.51 [0.24-0.96], 0.40 [0.16-0.85], and 0.69 [0.49-0.95], respectively). The mediations analysis revealed that the association of infection with each symptom was mainly mediated by ECDC symptoms (proportion mediated range 50%-107%). Conclusion: After COVID-19, persistent symptoms are very similar to those after other similar clinical conditions, apart from greater risk of anosmia, fatigue and dyspnea. The acute clinical presentation drives the risk of persistent symptoms.
139	MS137		Mike K.P. So Amanda M.Y. Chu Agnes Tiwari	Persistent symptoms after SARS-CoV-2 infection: Long-term implications for health and quality of life	https://doi.org/10.1016/j.lanepe.2022.100373	Published	March 29, 2022	Comment	https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(22)00066-7/fulltext	A positive serological result was regarded as “true SARS-CoV-2 infection” though there is the chance of false positives. The study was administrated longitudinally and participants were invited to complete three questionnaires online, around the time when their serological tests were taken, to self-report their symptoms. The third questionnaire was administered from December 2020 to February 2021 to collect information on persistent symptoms, defined as symptoms and effects that last for at least two months after the infection (“post-covid-19 syndrome” and “long-covid”). Using logistic regression models, the authors found a higher chance for people with SARS-CoV-2 infection, compared to those without the infection, in developing dysgeusia/anosmia, dyspnea and asthenia as persistent symptoms. Not only the authors presented useful information on persistent symptoms post COVID-19 in the French population, they have also provided a good reference for persistent symptoms in other populations. A natural extension of the longitudinal study is to consider changes in the severity of symptoms over time, from which we can learn how long the “long covid” will persist. Another future research direction is to investigate relationships among persistent symptoms, which may indicate suitable medical interventions for alleviating or removing the symptoms. Many studies on persistent symptoms or “long covid” focused on physical symptoms which may be directly attributed to SARS-CoV-2 infection.2, 3, 4 Psychological or psychiatric symptoms, such as anxiety, depression, phobic anxiety disorder, however, have received relatively less attention in persistent symptom research despite some evidence pointing to the co-existence of depressive and even psychiatric disorders with the common physical COVID-19 symptoms.5,6 A possible concern is that psychological symptoms are more long-lasting than physical symptoms, and hence may affect health and quality of life for a long period of time. From the healthcare perspective, psychological symptoms can also be alarming as they may not be easily removed by medicine or medical treatments, and may therefore increase the burden for the healthcare and social welfare systems. Interestingly, post COVID-19 physical and psychological symptoms may be related. For example, insomnia can be a symptom of depression, and brain fog could progress to become long-term brain problems. Research has been devoted to the impact of COVID-19 on the brain and neurological diseases.7 There is speculation that after experiencing SARS-CoV-2 infection, people may have higher risk of cognitive decline, though more scientific evidence is needed. We also see mental health consequences from COVID-19 in the literature. For example, after SARS-CoV-2 infection, people are more vulnerable to having psychological distress, poor sleep quality and depression.8 Thus, the impact of the persistent symptoms on psychosocial health post COVID-19 infection should not be underestimated. After the outbreak of the COVID-19 pandemic for more than two years, there is increasing research addressing persistent physical and psychological symptoms and their relationship and joint effects. We hope to see more longitudinal studies involving multiple regions to look into the typical “long-covid” symptoms including persistent psychological symptoms, and their impacts on psychosocial well-being and quality of life. Quantifying symptoms can also save lives in the pandemic.
140	MS138	ES	Viet-Thi Tran, Raphaël Porcher, Isabelle Pane & Philippe Ravaud	Course of post COVID-19 disease symptoms over time in the ComPaRe long COVID prospective e-cohort	https://doi.org/10.1038/s41467-022-29513-z	Published	05 April 2022	Study	https://www.nature.com/articles/s41467-022-29513-z	About 10% of people infected by severe acute respiratory syndrome coronavirus 2 experience post COVID-19 disease. We analysed data from 968 adult patients (5350 person-months) with a confirmed infection enroled in the ComPaRe long COVID cohort, a disease prevalent prospective e-cohort of such patients in France. Day-by-day prevalence of post COVID-19 symptoms was determined from patients’ responses to the Long COVID Symptom Tool, a validated self-reported questionnaire assessing 53 symptoms. Among patients symptomatic after 2 months, 85% still reported symptoms one year after their symptom onset. Evolution of symptoms showed a decreasing prevalence over time for 27/53 symptoms (e.g., loss of taste/smell); a stable prevalence over time for 18/53 symptoms (e.g., dyspnoea), and an increasing prevalence over time for 8/53 symptoms (e.g., paraesthesia). The disease impact on patients’ lives began increasing 6 months after onset. Our results are of importance to understand the natural history of post COVID-19 disease.
141	MS139		Chen Chen, MA, Spencer R. Haupert, BS, Lauren Zimmermann, BSc, Xu Shi, PhD, Lars G. Fritsche, PhD, Bhramar Mukherjee	Global Prevalence of Post COVID-19 Condition or Long COVID: A Meta-Analysis and Systematic Review	https://doi.org/10.1093/infdis/jiac136	Published	16 April 2022	Study	https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiac136/6569364?login=true	Introduction This study aims to examine the worldwide prevalence of post COVID-19 condition, through a systematic review and meta-analysis. Methods PubMed, Embase, and iSearch were searched on July 5, 2021 with verification extending to March 13, 2022. Using a random effects framework with DerSimonian-Laird estimator, we meta-analyzed post COVID-19 condition prevalence at 28+ days from infection. Results 50 studies were included, and 41 were meta-analyzed. Global estimated pooled prevalence of post COVID-19 condition was 0.43 (95% CI: 0.39,0.46). Hospitalized and non-hospitalized patients have estimates of 0.54 (95% CI: 0.44,0.63) and 0.34 (95% CI: 0.25,0.46), respectively. Regional prevalence estimates were Asia— 0.51 (95% CI: 0.37,0.65), Europe— 0.44 (95% CI: 0.32,0.56), and North America— 0.31 (95% CI: 0.21,0.43). Global prevalence for 30, 60, 90, and 120 days after infection were estimated to be 0.37 (95% CI: 0.26,0.49), 0.25 (95% CI: 0.15,0.38), 0.32 (95% CI: 0.14,0.57) and 0.49 (95% CI: 0.40,0.59), respectively. Fatigue was the most common symptom reported with a prevalence of 0.23 (95% CI: 0.17,0.30), followed by memory problems (0.14 [95% CI: 0.10,0.19]). Discussion This study finds post COVID-19 condition prevalence is substantial; the health effects of COVID-19 appear to be prolonged and can exert stress on the healthcare system.
142	MS140		The PHOSP-COVID Collaborative Group	Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study	https://doi.org/10.1016/S2213-2600(22)00127-8	Published	April 23, 2022	Study	https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00127-8/fulltext	Background No effective pharmacological or non-pharmacological interventions exist for patients with long COVID. We aimed to describe recovery 1 year after hospital discharge for COVID-19, identify factors associated with patient-perceived recovery, and identify potential therapeutic targets by describing the underlying inflammatory profiles of the previously described recovery clusters at 5 months after hospital discharge. Methods The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a prospective, longitudinal cohort study recruiting adults (aged ≥18 years) discharged from hospital with COVID-19 across the UK. Recovery was assessed using patient-reported outcome measures, physical performance, and organ function at 5 months and 1 year after hospital discharge, and stratified by both patient-perceived recovery and recovery cluster. Hierarchical logistic regression modelling was performed for patient-perceived recovery at 1 year. Cluster analysis was done using the clustering large applications k-medoids approach using clinical outcomes at 5 months. Inflammatory protein profiling was analysed from plasma at the 5-month visit. This study is registered on the ISRCTN Registry, ISRCTN10980107, and recruitment is ongoing. Findings 2320 participants discharged from hospital between March 7, 2020, and April 18, 2021, were assessed at 5 months after discharge and 807 (32·7%) participants completed both the 5-month and 1-year visits. 279 (35·6%) of these 807 patients were women and 505 (64·4%) were men, with a mean age of 58·7 (SD 12·5) years, and 224 (27·8%) had received invasive mechanical ventilation (WHO class 7–9). The proportion of patients reporting full recovery was unchanged between 5 months (501 [25·5%] of 1965) and 1 year (232 [28·9%] of 804). Factors associated with being less likely to report full recovery at 1 year were female sex (odds ratio 0·68 [95% CI 0·46–0·99]), obesity (0·50 [0·34–0·74]) and invasive mechanical ventilation (0·42 [0·23–0·76]). Cluster analysis (n=1636) corroborated the previously reported four clusters: very severe, severe, moderate with cognitive impairment, and mild, relating to the severity of physical health, mental health, and cognitive impairment at 5 months. We found increased inflammatory mediators of tissue damage and repair in both the very severe and the moderate with cognitive impairment clusters compared with the mild cluster, including IL-6 concentration, which was increased in both comparisons (n=626 participants). We found a substantial deficit in median EQ-5D-5L utility index from before COVID-19 (retrospective assessment; 0·88 [IQR 0·74–1·00]), at 5 months (0·74 [0·64–0·88]) to 1 year (0·75 [0·62–0·88]), with minimal improvements across all outcome measures at 1 year after discharge in the whole cohort and within each of the four clusters. Interpretation The sequelae of a hospital admission with COVID-19 were substantial 1 year after discharge across a range of health domains, with the minority in our cohort feeling fully recovered. Patient-perceived health-related quality of life was reduced at 1 year compared with before hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials.	todo
143	MS141		Imad M.Tleyjehabcd1TarekKashoure1MuhammadRiazf2Samar A.Amergh2NourahAlSwaidanaLailaAlmutairigRabihHalwaniijAbdullahAssirig	Persistent COVID-19 symptoms at least one month after diagnosis: A national survey	https://doi.org/10.1016/j.jiph.2022.04.006	Published	25 April 2022	Study	https://www.sciencedirect.com/science/article/pii/S1876034122000946	Background Post-acute COVID-19 syndrome (PACS) is an important healthcare burden. We examined persistent symptoms in COVID-19 patients at least four weeks after the onset of infection, participants’ return to pre-COVID-19 health status and associated risk factors. Methods Cross-sectional study was conducted (December 2020 to January 2021). A validated online questionnaire was sent to randomly selected individuals aged more than 14 years from a total of 1397,386 people confirmed to have COVID-19 at least 4 weeks prior to the start of this survey. This sample was drawn from the Saudi ministry of health COVID-19 testing registry system. Results Out of the 9507 COVID-19 patients who responded to the survey, 5946 (62.5%) of them adequately completed it. 2895 patients (48.7%) were aged 35–44 years, 64.4% were males, and 91.5% were Middle Eastern or North African. 79.4% experienced unresolved symptoms for at least 4 weeks after the disease onset. 9.3% were hospitalized with 42.7% visiting healthcare facility after discharge and 14.3% requiring readmission. The rates of main reported persistent symptoms in descending order were fatigue 53.5%, muscle and body ache 38.2%, loss of smell 35.0%, joint pain 30.5%, and loss of taste 29.1%. There was moderate correlation between the number of symptoms at the onset and post-four weeks of COVID-19 infection. Female sex, pre-existing comorbidities, increased number of baseline symptoms, longer hospital-stay, and hospital readmission were predictors of delayed return to baseline health state (p < 0.05). Conclusion The symptoms of PACS are prevalent after contracting COVID-19 disease. Several risk factors could predict delayed return to baseline health state.
144	MS142		César Fernández-de-las-Peñas José D. Martín-Guerrero Ignacio Cancela-Cilleruelo Paloma Moro-López-Menchero Oscar J. Pellicer-Valero	Exploring the recovery curve for long-term post-COVID dyspnea and fatigue	https://doi.org/10.1016/j.ejim.2022.03.036	Published	April 28, 2022	Study	https://www.ejinme.com/article/S0953-6205(22)00136-4/fulltext	To the best of our knowledge, this is the first time analyzing the longitudinal curve of recovery of post-COVID dyspnea and fatigue in previously hospitalized COVID-19 survivors. The mosaic plots showed that a large number of patients developed “de novo” dyspnea, whereas fatigue was considered as a “de novo” post-COVID symptom. Despite this, more individuals recovered than those that developed dyspnea “de novo”, explaining the downwards prevalence trend observed. This decrease was, however, less pronounced in the case of post-COVID fatigue, which seems to be a long-lasting symptom. Our prevalence rates of dyspnea and fatigue at the different follow-up periods are similar to those reported in current literature [[3],[4]]; however, we recognized that collecting fatigue as an onset symptom at hospital admission during the first wave of the pandemic was difficult because several subjects confused it with generalized viral-induced myalgias (general tiredness painful sensation). In fact, dyspnea and fever are the most bothersome COVID-19 symptoms self-reported by the patients at hospital admission. Since lungs exhibit high levels of the angiotensin-converting enzyme II (ACE2) and transmembrane serine protease 2 (TMPRSS2) receptors, they are invaded by SARS-CoV-2 virus resulting in pulmonary affectation, and, hence, the development of post-COVID dyspnea and fatigue. The exponential recovery curve identified in our study suggests that post-COVID dyspnea could be present up to four years after the infection. This may be explained to the fact that almost 62% of COVID-19 survivors develop “de novo” dyspnea the following months after hospitalization. Similarly, the huge prevalence of post-COVID fatigue developed after hospitalization would explain the slow recovery curve presented by this symptom. Since recovery of post-COVID fatigue will be longer than expected, this could suggest an enhanced exposure and significant viral load for a prolonged time period. Nevertheless, evidence suggests complex mechanisms underlying post-COVID dyspnea and fatigue. For instance, the systemic immune response against SARS-CoV-2 virus, reflected by significant lower levels of antibodies, has been found to be strongly correlated with more severe post-COVID fatigue [[9]]. Therefore, identifying the risk factors associated with the development of post-COVID dyspnea and fatigue may help to better understand the management of these symptoms [[10]]. An important finding revealed by the mosaic plots is that the development of post-COVID symptoms, in this case dyspnea or fatigue, can appear at any time, e.g., almost 25% individuals without dyspnea at T1 self-reported this symptom at T2, suggesting that longitudinally evolution of post-COVID symptoms should be analyzed patient by patient and not just as the total sample [[8]]. We acknowledge potential weaknesses of the study. First, only hospitalized patients aged around 60-years old were included. Second, we collected self-reported dyspnea and fatigue. Although some tools are used for the assessment of fatigue, all consists of self-reported questionnaires. Third, we focused on these post-COVID symptoms. Interaction between different post-COVID symptoms is common. Future studies investigating the interactions between different post-COVID symptoms during the following years are now needed In conclusion, our tendency analysis revealed that post-COVID dyspnea tend to slowly recover during the three years after SARS-CoV-2 infection, whereas the recovery of post-COVID fatigue is much slower in previously hospitalized COVID-19 survivors and could last several years after the infection.
145	MS143		Daniel A P de Miranda, Sarah V C Gomes, Priscilla S Filgueiras, Camila A Corsini, Nathalie B F Almeida, Raphael A Silva, Maria Izabella V A R C Medeiros, Raquel V R Vilela, Gabriel R Fernandes, Rafaella F Q Grenfell	Long COVID-19 syndrome: a 14-months longitudinal study during the two first epidemic peaks in Southeast Brazil	https://doi.org/10.1093/trstmh/trac030	Published	06 May 2022	Study	https://academic.oup.com/trstmh/advance-article/doi/10.1093/trstmh/trac030/6581500?login=true	Background A growing number of long COVID cases after infection have been reported. By definition, long COVID is the condition whereby affected individuals do not recover for several weeks or months following the onset of symptoms suggestive of COVID-19, the profile and timeline of which remains uncertain. Methods In this work, in-home, outpatient and hospitalized COVID-19 positive patients were monitored for up to 14 mo to establish the prevalence of long COVID symptoms and their correlation with age, pre-existing comorbidities and course of acute infection. The longitudinal study included 646 positive patients who were monitored once a month. Results From the whole population, 50.2% presented with long COVID syndrome. Twenty-three different symptoms were reported. Most frequent were fatigue (35.6%), persistent cough (34.0%), dyspnea (26.5%), loss of smell/taste (20.1%) and frequent headaches (17.3%). Mental disorders (20.7%), change in blood pressure (7.4%) and thrombosis (6.2%) were also reported. Most patients presented with 2–3 symptoms at the same time. Long COVID started after mild, moderate and severe infection in 60, 13 and 27% of cases, respectively, and it was not restricted to specific age groups. Conclusions Older patients tended to have more severe symptoms, leading to a longer post-COVID-19 period. The presence of seven comorbidities was correlated with the severity of infection, and severity itself was the main factor that determined the duration of symptoms in long COVID cases.
146	MS144		Carol Strahm, Marco Seneghini, Sabine Güsewell, Thomas Egger, Onicio Leal-Neto, Angela Brucher, Eva Lemmenmeier, Dorette Meier Kleeb, J Carsten Möller, Philip Rieder, Markus Ruetti, Remus Rutz, Hans-Ruedi Schmid, Reto Stocker, Danielle Vuichard-Gysin, Benedikt Wiggli, Ulrike Besold, Stefan P Kuster, Allison McGeer, Lorenz Risch, Andrée Friedl, Matthias Schlegel, Dagmar Schmid, Pietro Vernazza, Christian R Kahlert, Philipp Kohler	Symptoms Compatible With Long Coronavirus Disease (COVID) in Healthcare Workers With and Without Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection—Results of a Prospective Multicenter Cohort	https://doi.org/10.1093/cid/ciac054	Published	28 January 2022	Study	https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac054/6516835	Background The burden of long-term symptoms (ie, long COVID) in patients after mild COVID-19 is debated. Within a cohort of healthcare workers (HCWs), frequency and risk factors for symptoms compatible with long COVID are assessed. Methods Participants answered baseline (August/September 2020) and weekly questionnaires on SARS-CoV-2 nasopharyngeal swab (NPS) results and acute disease symptoms. In January 2021, SARS-CoV-2 serology was performed; in March, symptoms compatible with long COVID (including psychometric scores) were asked and compared between HCWs with positive NPS, seropositive HCWs without positive NPS (presumable asymptomatic/pauci-symptomatic infections), and negative controls. The effect of time since diagnosis and quantitative anti-spike protein antibodies (anti-S) was evaluated. Poisson regression was used to identify risk factors for symptom occurrence. Results Of 3334 HCWs (median, 41 years; 80% female), 556 (17%) had a positive NPS and 228 (7%) were only seropositive. HCWs with positive NPS more frequently reported ≥1 symptom compared with controls (73% vs 52%, P < .001); seropositive HCWs without positive NPS did not score higher than controls (58% vs 52%, P = .13), although impaired taste/olfaction (16% vs 6%, P < .001) and hair loss (17% vs 10%, P = .004) were more common. Exhaustion/burnout was reported by 24% of negative controls. Many symptoms remained elevated in those diagnosed >6 months ago; anti-S titers correlated with high symptom scores. Acute viral symptoms in weekly questionnaires best predicted long-COVID symptoms. Physical activity at baseline was negatively associated with neurocognitive impairment and fatigue scores. Conclusions Seropositive HCWs without positive NPS are only mildly affected by long COVID. Exhaustion/burnout is common, even in noninfected HCWs. Physical activity might be protective against neurocognitive impairment/fatigue symptoms after COVID-19.
147	MS145		Lara Bull-Otterson, PhD1; Sarah Baca1,2; Sharon Saydah, PhD1; Tegan K. Boehmer, PhD1; Stacey Adjei, MPH1; Simone Gray, PhD1; Aaron M. Harris	Post–COVID Conditions Among Adult COVID-19 Survivors Aged 18–64 and ≥65 Years — United States, March 2020–November 2021	https://doi.org/10.15585/mmwr.mm7121e1	Published	May 26, 2022	Study	https://www.cdc.gov/mmwr/volumes/71/wr/mm7121e1.htm	What is already known about this topic? As more persons are exposed to and infected by SARS-CoV-2, reports of patients who experience persistent symptoms or organ dysfunction after acute COVID-19 and develop post-COVID conditions have increased. What is added by this report? COVID-19 survivors have twice the risk for developing pulmonary embolism or respiratory conditions; one in five COVID-19 survivors aged 18–64 years and one in four survivors aged ≥65 years experienced at least one incident condition that might be attributable to previous COVID-19. What are the implications for public health practice? Implementation of COVID-19 prevention strategies, as well as routine assessment for post-COVID conditions among persons who survive COVID-19, is critical to reducing the incidence and impact of post-COVID conditions, particularly among adults aged ≥65 years.
148	MS146		Bernardo Meza-Torres 1, Gayathri Delanerolle 1, Cecilia Okusi 1, Nikhil Mayer 2, Sneha Anand 1, Jack McCartney 1, Piers Gatenby 2, Ben Glampson 3, Martin Chapman 4, Vasa Curcin 4, Erik Mayer 3, Mark Joy 1, Trisha Greenhalgh 1, Brendan Delaney 5, Simon de Lusignan 6Bernardo Meza-Torres 1, Gayathri Delanerolle 1, Cecilia Okusi 1, Nikhil Mayer 2, Sneha Anand 1, Jack McCartney 1, Piers Gatenby 2, Ben Glampson 3, Martin Chapman 4, Vasa Curcin 4, Erik Mayer 3, Mark Joy 1, Trisha Greenhalgh 1, Brendan Delaney 5, Simon de Lusignan 6	Differences in clinical presentation with long covid following community and hospital infection, and associations with all-cause mortality: English sentinel network database study	https://doi.org/10.2196/37668	Published	2022 May 17	Study	https://pubmed.ncbi.nlm.nih.gov/35605170/	Background: Most studies of long covid (symptoms of COVID-19 beyond 4 weeks) have focused on people hospitalised in their initial illness. Long covid is thought to be under-recorded in UK primary care electronic records. Objective: We sought to determine which symptoms people present to primary care following COVID-19, and whether presentation differs in people who were not hospitalised, and post-long covid mortality. Methods: We used routine data from the nationally representative Primary Care Sentinel Cohort of the Oxford-Royal College of General Practitioners Research and Surveillance Centre (N=7.4million), applying a pre-defined long covid phenotype and grouped by whether the illness index was in hospital or community. We included COVID-19 cases between 1st-March-2020 and 1st-April-2021. We conducted a before and after analysis of pre-specified long covid symptoms identified by the Office of National Statistics, comparing symptoms presented between one and six months after their index infection matched with the same months one year previously. We conducted logistic regression analysis, quoting odds ratios with 95% confidence intervals, reporting differences between those with an index community infection compared to those who had been hospitalised, and separately associations with all-cause mortality. Results: 5.6% (416,505/7,396,702) and 1.8% (7,623/416,505) of patients respectively had a coded diagnosis of COVID-19 and diagnosis or referral for long covid. People coded as having long covid were significantly more likely to have presented the pre-specified symptoms after vs before COVID-19 infection (odds ratios 2.66 [2.46-2.88] for those with index community infection and 2.42 [2.03-2.89] for those hospitalised). Following an index community infection, patients were more likely to present with non-specific symptoms (odds ratio 3.44 [3.00-3.95], P<.001) than following a hospital admission (odds ratio 2.09 [1.56-2.80], P<.001). Mental health sequelae were more commonly associated with hospital admission index infections (odds ratio 2.21 [1.64-2.96]) compared to community (odds ratio 1.36 [1.21-1.53], P<.001). People presenting to primary care following hospital infection were more likely to be male (odds ratio 1.43 [1.25-1.64], P<.001), more socioeconomically deprived (odds ratio 1.42 [1.24-1.63], P<.001); and to have multi-morbidity (odds ratio 1.41 [1.26-1.57], P<.001) than those presenting after an index community infection. All-cause mortality in people with long covid was associated with increasing age; male gender (odds ratio 3.32 [1.34-9.24], P<.01) and higher multi-morbidity score (odds ratio 2.11 [1.34-3.29], P<.001). One or more vaccine doses was associated with reduced odds of mortality (odds ratio 0.10 [0.03-0.35], P<.001). Conclusions: The low percentage of people recorded as having long covid following COVID-19 reflects either low prevalence or under-recording. The characteristics and comorbidities of those presenting with long covid following a community infection are different from those who were hospitalised with their index infection. This study provides insights into the presentation of long covid in primary care and implications for workload.
149	MS147		G.Gavazzi1C.Roubaud-Baudron2J.PLanoix3N.Baclet4C.Arlaud5T.fraisse6M.Paccalin7P.Caraux-Paz8A.Putot9E.Forestier10	Impact de COVID 19 sur le statut fonctionnel des populations françaises les plus âgées : Étude multicentrique COVID-OLD.	https://doi.org/10.1016/j.mmifmc.2022.03.030	Published	31 May 2022	Study	https://www.sciencedirect.com/science/article/pii/S2772743222000484	Introduction L'infection à COVID 19 est une maladie infectieuse sévère dans les populations âgées, induisant des taux de mortalité élevés. Cependant peu d'études ont exploré l'impact de COVID 19 chez les survivants. Les maladies aigues provoquent généralement un déclin fonctionnel de 20 à 50% dans ces populations. L'objectif de notre étude était de mesurer le taux de patients présentant un déclin fonctionnel à 3 mois après la COVID et d'en déterminer les facteurs associés. Matériels et méthodes 60 centres français ont participé à cette étude prospective observationnelle incluant des patients âgés de 70 ans et plus, hospitalisés pour une COVID 19 entre le 04/10/2020 et le 10/12/20 dans des services de maladies infectieuses ou de gériatrie. Le déclin fonctionnel était défini par une perte d'au moins 0,5 sur le score d'activité de la vie quotidienne (ADL = capacité à transférer, manger, aller au toilette,se laver, s'habiller seul et être continent coté /6) ou/et une perte d'au moins 1 sur le score d'activité instrumentale de la vie quotidienne (IADL, cotés sur /8). Les données sociodémographiques, la sévérité du COVID 19, la présentation clinique, les traitements spécifiques et non spécifiques ont été recueillis. Des analyses univariées et multivariées (sans score de propension) ont été réalisées. Les différences entre les 2 vagues ont été déterminées. Résultats Sur les 1083 patients inclus 662 ont eu un suivi avec données complétées. L'âge moyen était de 84 ans. 56% présentaient un déclin fonctionnel à 3 mois, 40% sur les ADLs et 38% pour les IADLs. La perte moyenne était de 1,1 point pour les ADLs et de 1,6 point pour les IADLs. Tous les items des ADL étaient également affectés. La perte fonctionnelle était équivalente durant les 2 vagues. En analyse univariée (n= 545), la perte d'ADL aiguë avant l'hospitalisation, la confusion, la durée du séjour, la chute, l'immobilisation sont des marqueurs prédictifs du déclin fonctionnel à 3 mois. En analyse multivariée (n=415), seuls La perte d'ADL avant l'hospitalisation et la présence d'une confusion au diagnostic sont prédicteurs de la perte fonctionnelle indépendamment des autres variables (gravité immédiate de la COVID, durée d'hospitalisation, de l'âge, sexe, syndrome d'immobilisation, chute, réhospitalisation dans les 3 Mois). Conclusion La majorité de la population survivante à une COVID 19 présente un déclin fonctionnel à 3 mois. La gravité de la perte fonctionnelle avant l'hospitalisation et la confusion au moment du diagnostic sont les 2 prédicteurs indépendants de la gravité immédiate de la COVID et de la durée d'hospitalisation . On ne sait pas ce qui est lié à la comorbidité, à l'absence de réadaptation ou à une longue infection Covid. L'impact de la COVID 19 sur la qualité de vie et les conséquences économiques de cet impact devraient être mesurés.
150	MS148		Pierre Smith, Kristiaan Proesmans, Dieter Van Cauteren, Stefaan Demarest, Sabine Drieskens, Robby De Pauw, Laura Cornelissen, Karin De Ridder & Rana Charafeddine	Post COVID-19 condition and its physical, mental and social implications: protocol of a 2-year longitudinal cohort study in the Belgian adult population	https://doi.org/10.1186/s13690-022-00906-2	Published	04 June 2022	Study	https://link.springer.com/article/10.1186/s13690-022-00906-2	Background Since the onset of the COVID-19 pandemic, most research has focused on the pathophysiology and management of the acute symptoms of COVID-19, yet some people tend to experience symptoms beyond the acute phase of infection, that is, Post COVID-19 condition (PCC). However, evidence on the long-term health impacts of a COVID-19 infection are still scarce. The purpose of this paper is to describe the COVIMPACT study, which aims to set up a cohort of people who have been tested positive for COVID-19 and study the evolution of their physical, mental and social health over the medium (3 months) and long term (two years), and the factors associated with an (un)favorable evolution. Methods COVIMPACT is a longitudinal cohort study organised over a two-years period between April 2021 and April 2023. The eligible population is all people aged 18 years and older, living in Belgium, with a recent COVID-19 infection and contacted by the health authorities for contact tracing. Two questionnaires are used: a baseline questionnaire that aims to assess the initial health status of the participants and their status during the acute phase of the illness, and a follow-up questionnaire that is sent every three months after participants enter into the cohort. A matched non-COVID-19 control group was also selected. As of November 1, 2021, 10,708 people completed the baseline questionnaire (5% of the eligible population) and the follow-up participation rate was 79%. In total, 48% of the cohort participants appeared to fit the proposed case definition of PCC (i.e. report at least one symptom related to their COVID-19 infection three months afterwards). Discussion This study was designed to provide timely information on the short and long term impact of a COVID-19 infection, to stakeholders such as policymakers, health practitioners and people with PCC. Although the follow-up participation rate was good (79%), the participation rate of the eligible population was low (5%). Compared to other studies, this study has a large sample, of non-hospitalised and hospitalised people, who will be followed over a long period of 3 months to two years post infection, and with a global approach to their health.
151	MS149		Marta Rigoni, Emanuele Torri, Giandomenico Nollo, Livia Delle Donne, Sebastiano Rizzardo, Lorenza Lenzi, Andrea Falzone & Susanna Cozzio	“Long COVID” results after hospitalization for SARS-CoV-2 infection	https://doi.org/10.1038/s41598-022-13077-5	Published	10 June 2022	Study	https://www.nature.com/articles/s41598-022-13077-5	Long-term sequelae of symptomatic infection caused by SARS-CoV-2 are largely undiscovered. We performed a prospective cohort study on consecutively hospitalized Sars-CoV-2 patients (March–May 2020) for evaluating COVID-19 outcomes at 6 and 12 months. After hospital discharge, patients were addressed to two follow-up pathways based on respiratory support needed during hospitalization. Outcomes were assessed by telephone consultation or ambulatory visit. Among 471 patients, 80.9% received no respiratory support during hospitalization; 19.1% received non-invasive ventilation (NIV) or invasive mechanical ventilation (IMV). 58 patients died during hospitalization, therefore 413 were enrolled for follow-up. At 6 months, among 355 patients, the 30.3% had any symptoms, 18.0% dyspnea, 6.2% neurological symptoms. Fifty-two out of 105 had major damages in interstitial computed tomography images. NIV/IMV patients had higher probability to suffer of symptoms (aOR = 4.00, 95%CI:1.99–8.05), dyspnea (aOR = 2.80, 95%CI:1.28–6.16), neurological symptoms (aOR = 9.72, 95%CI:2.78–34.00). At 12 months, among 344, the 25.3% suffered on any symptoms, 12.2% dyspnea, 10.1% neurological symptoms. Severe interstitial lesions were present in 37 out of 47 investigated patients. NIV/IMV patients in respect to no respiratory support, had higher probability of experiencing symptoms (aOR = 3.66, 95%CI:1.73–7.74), neurological symptoms (aOR = 8.96, 95%CI:3.22–24.90). COVID-19 patients showed prolonged sequelae up to 12 months, highlighting the need of follow-up pathways for post-COVID-19 syndrome.
152	MS150		Na Zeng, Yi-Miao Zhao, Wei Yan, Chao Li, Qing-Dong Lu, Lin Liu, Shu-Yu Ni, Huan Mei, Kai Yuan, Le Shi, Peng Li, Teng-Teng Fan, Jun-Liang Yuan, Michael V Vitiello, Thomas Kosten, Alexandra L Kondratiuk, Hong-Qiang Sun, Xiang-Dong Tang, Mei-Yan Liu, Ajit Lalvani, Jie Shi, Yan-Ping Bao & Lin Lu	A systematic review and meta-analysis of long term physical and mental sequelae of COVID-19 pandemic: call for research priority and action	https://doi.org/10.1038/s41380-022-01614-7	Published	06 June 2022	Systematic Review	https://www.nature.com/articles/s41380-022-01614-7	The long-term physical and mental sequelae of COVID-19 are a growing public health concern, yet there is considerable uncertainty about their prevalence, persistence and predictors. We conducted a comprehensive, up-to-date meta-analysis of survivors’ health consequences and sequelae for COVID-19. PubMed, Embase and the Cochrane Library were searched through Sep 30th, 2021. Observational studies that reported the prevalence of sequelae of COVID-19 were included. Two reviewers independently undertook the data extraction and quality assessment. Of the 36,625 records identified, a total of 151 studies were included involving 1,285,407 participants from thirty-two countries. At least one sequelae symptom occurred in 50.1% (95% CI 45.4-54.8) of COVID-19 survivors for up to 12 months after infection. The most common investigation findings included abnormalities on lung CT (56.9%, 95% CI 46.2–67.3) and abnormal pulmonary function tests (45.6%, 95% CI 36.3–55.0), followed by generalized symptoms, such as fatigue (28.7%, 95% CI 21.0–37.0), psychiatric symptoms (19.7%, 95% CI 16.1–23.6) mainly depression (18.3%, 95% CI 13.3–23.8) and PTSD (17.9%, 95% CI 11.6–25.3), and neurological symptoms (18.7%, 95% CI 16.2–21.4), such as cognitive deficits (19.7%, 95% CI 8.8–33.4) and memory impairment (17.5%, 95% CI 8.1–29.6). Subgroup analysis showed that participants with a higher risk of long-term sequelae were older, mostly male, living in a high-income country, with more severe status at acute infection. Individuals with severe infection suffered more from PTSD, sleep disturbance, cognitive deficits, concentration impairment, and gustatory dysfunction. Survivors with mild infection had high burden of anxiety and memory impairment after recovery. Our findings suggest that after recovery from acute COVID-19, half of survivors still have a high burden of either physical or mental sequelae up to at least 12 months. It is important to provide urgent and appropriate prevention and intervention management to preclude persistent or emerging long-term sequelae and to promote the physical and psychiatric wellbeing of COVID-19 survivors.
153	MS151		Gunnhild Helmsdal, Katrin Dahl Hanusson, Marnar Fríðheim Kristiansen, Billa Mouritsardóttir Foldbo, Marjun Eivindardóttir Danielsen, Bjarni á Steig, Shahin Gaini, Marin Strøm, Pál Weihe, Maria Skaalum Petersen	Long COVID in the long run - 23 months follow-up study of persistent symptoms	https://doi.org/10.1093/ofid/ofac270	Published	06 June 2022	Study	https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofac270/6603333	Symptoms of long COVID were found in 38% of 170 patients followed median 22.6 months. Most prevalent symptoms were fatigue, affected taste and smell, and difficulties remembering and concentrating. Predictors for long COVID were older age and number of symptoms in the acute phase. Long COVID may take many months, maybe years to resolve.
154	MS152		Quin Healey1, Aziz Sheikh2, Luke Daines2, Eleftheria Vasileiou2	Symptoms and signs of long COVID: A rapid review and meta-analysis	http://dx.doi.org/10.7189/jogh.12.05014	Published	May 2022	Rapid review and meta-analysis	https://jogh.org/2022/jogh-12-05014	Background: Long COVID is defined as symptoms and signs related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that are present at least four weeks following acute infection. These symptoms and signs are poorly characterised but may be associated with significant morbidity. We sought to synthesise the evidence on their incidence to guide future research, policy and practice. Methods: We searched Medline and Embase for longitudinal cohort studies from January 2020 to July 2021 that investigated adults with long COVID at least four weeks after acute infection. Risk of bias was assessed using the Joanna Briggs Institute checklist for cohort studies. Random-effects meta-analyses were performed with subgroup analysis by follow-up time (4-12 vs more than 12 weeks). Results: 19 studies were included, 13 of which included patients hospitalised with COVID-19. The total sample size was 10 643 and the follow-up time ranged from 30 to 340 days. Risk of bias was assessed as high in one study, moderate in two studies and low in the remaining 16 studies. The most common symptoms and signs seen at any time point in long COVID were fatigue (37%; 95% confidence interval (CI) = 23-55), dyspnoea (21%; 95% CI = 14-30), olfactory dysfunction (17%; 95% CI = 9-29), myalgia (12%; 95% CI = 5-25), cough (11%; 95% CI = 6-20) and gustatory dysfunction (10%; 95% CI = 7-17). High heterogeneity was seen for all meta-analyses and the presence of some funnel plot asymmetry may indicate reporting bias. No effect of follow-up time was found for any symptom or sign included in the subgroup analysis. Conclusions: We have summarised evidence from longitudinal cohort studies on the most common symptoms and signs associated with long COVID. High heterogeneity seen in the meta-analysis means pooled incidence estimates should be interpreted with caution. This heterogeneity may be attributable to studies including patients from different health care settings and countries.
155	MS153		Christopher Millet Spandana Narvaneni Sherif Roman George Horani Suhail Chaudhry Patrick Michael Jin Suh Humberto R. Jimenez	Symptoms Persist in Patients Two Years after COVID-19 infection: A Prospective Follow Up Study	https://doi.org/10.1016/j.cmi.2022.06.008	Published	June 16, 2022	Study	https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(22)00321-4/fulltext	This is a prospective, longitudinal, Institutional Review Board approved cohort study consisting of patients diagnosed with COVID-19 infection in March and April of 2020 in the St. Joseph’s Health Network. Individuals with confirmed SARS-CoV-2, who were either hospitalized or tested positive in the outpatient setting, were included. Patients under 18 years of age or those with cognitive impairment were excluded. Informed consent was obtained over telephone and participants were contacted during March and April of 2021 to complete a comprehensive questionnaire to evaluate for persistent symptoms following their initial diagnosis with COVID-19. Patients who reported persistence of symptoms at a one-year follow-up were contacted again at a two year follow-up in March of 2022 to assess for persistence of COVID-19 related symptoms. Logistic regression analysis was performed to identify predictors of symptom persistence and the McNemar test was used to compare the duration of symptoms among those surveyed both years. 500 patients were invited, of which 173 participated, including 91 patients who were previously hospitalized. The mean age was 51.5 years old, with an age range of 18-95, of whom 49.42% were male. The most common ethnicity was Hispanic (46.24%) and the most common comorbidity was hypertension (39.5%)(Table 1.). At 12 months follow up 50.8% of the patients experienced at least one persistent symptom (Figure 1A); the most common symptoms were shortness of breath (25%), fatigue (24%) anxiety (21%), difficulty focusing/brain fog (18%), body aches (18%) and headaches (16%)(Figure 1B.). At 24 months follow up, 23.1% of the patients experienced at least one persistent symptom (Figure 1A); the most common symptoms being shortness of breath (13.2%), fatigue (12.1%), difficulty focusing/brain fog (10.4%), memory loss (9.2%) and anxiety (8.1%)(Figure 1B.) 13 patients were lost to follow up from year 1 to year 2. Two years after infection, 23.1% of patients still experienced at least one persistent symptom. At one and two years follow up, shortness of breath and fatigue were the most common symptoms. In other studies, fatigue and shortness of breath were similarly found to be amongst the most commonly reported symptoms after one year. [1, 2, 3, 4, 5] The symptoms most likely to improve between years one and two were anxiety, headaches, shortness of breath and fatigue. Women were more likely to have persistent symptoms at two years compared to men. Women have been found to experience more persistent symptoms in other studies as well. [4, 5]. To our knowledge this is the first US study to describe the duration and symptomatology of COVID-19 in patients over a two year follow up period. Most patients had reduction and resolution in their symptoms over the two year period, however nearly a quarter of patients still experience persistent symptoms. Study limitations include a small patient sample, self-recall bias, loss of patients to follow up and single center study. The study would have benefited from more frequent follow up intervals to provide a more accurate timeline of symptom recovery. The etiology and treatment of PACS remains poorly defined. With over half a billion people infected worldwide, thousands of new infections daily, and weaning protection from immunization or prior infection, a global public health crisis could be looming. For millions of patients, PACS can significantly impair cognitive function, quality of life and the ability to work at full capacity for years to come. [1, 2, 3, 4] These points highlight the urgent need for larger scale studies to better understand and effectively treat this post viral phenomenon.
156	MS154		Ahmet Naci Emecen, Salih Keskin, Oyku Turunc, Ahmet Furkan Suner, Neslisah Siyve, Ecem Basoglu Sensoy, Fatih Dinc, Oguz Kilinc, Vildan Avkan Oguz, Serdar Bayrak & Belgin Unal	The presence of symptoms within 6 months after COVID-19: a single-center longitudinal study	https://doi.org/10.1007/s11845-022-03072-0	Published	17 June 2022	Study	https://link.springer.com/article/10.1007/s11845-022-03072-0	Background Characterizing the post-COVID health conditions is helpful to direct patients to appropriate healthcare. Aims To describe the presence of symptoms in COVID-19 patients within 6 months after diagnosis and to investigate the associated factors in terms of reporting symptoms. Methods Data of DEU-COVIMER (a telephone interview-based COVID-19 follow-up center established in a tertiary care hospital) was analyzed for SARS-CoV-2 RNA positive participants aged ≥ 18 years from November 1st, 2020, to May 31st, 2021. Symptom frequencies were stratified by demographic and clinical characteristics at one, three, and 6 months after diagnosis. With the patients who had symptoms at baseline, generalized estimating equations were applied to identify the factors associated with reporting of symptoms. Results A total of 5610 patients agreed to participate in the study. Symptom frequency was 37.2%, 21.8%, and 18.2% for the first, third, and sixth months. Tiredness/fatigue, muscle or body aches, and dyspnea/difficulty breathing were the most common symptoms in all time frames. In multivariate analysis, older age, female gender (odds ratio OR 1.74, 95% confidence interval 1.57–1.93), bad economic status (OR 1.37, 1.14–1.65), current smoking (OR 1.15, 1.02–1.29), being fully vaccinated before COVID-19 (OR 0.53, 0.40–0.72), having more health conditions (≥ 3 conditions, OR 1.78, 1.33–2.37), having more symptoms (> 5 symptoms, OR 2.47, 2.19–2.78), and hospitalization (intensive care unit, OR 2.18, 1.51–3.14) were associated with reporting of symptoms. Conclusions This study identifies risk factors for patients who experience post-COVID-19 symptoms. Healthcare providers should appropriately allocate resources prioritizing the patients who would benefit from post-COVID rehabilitation.
157	MS155		Shirley V. Sylvester,Rada Rusu,Biankha Chan,Martha Bellows,Carly O’Keefe &Susan Nicholson	Sex differences in sequelae from COVID-19 infection and in long COVID syndrome: a review	https://doi.org/10.1080/03007995.2022.2081454	Published	20 Jun 2022	Review	https://www.tandfonline.com/doi/full/10.1080/03007995.2022.2081454	Objective We conducted literature reviews to uncover differential effects of sex on sequelae from coronavirus disease 2019 (COVID-19) and on long COVID syndrome. Methods Two authors independently searched OvidSP in Embase, Medline, Biosis, and Derwent Drug File. Publications reporting original, sex-disaggregated data for sequelae of COVID-19 (published before August 2020) and long COVID syndrome (published before June 2021) were included in the reviews. The association between COVID-19 sequelae (i.e. lasting <4 weeks after symptom onset) and sex, and between long COVID syndrome (i.e. lasting >4 weeks after symptom onset) and sex, was determined by odds ratio (OR) and 95% confidence interval (CI) (statistical significance defined by 95% CI not including 1). Results Of 4346 publications identified, 23 and 12 met eligibility criteria for COVID-19 sequelae and long COVID syndrome, respectively. COVID-19 sequelae in the categories of psychiatric/mood (OR = 1.80; 95% CI: 1.35–2.41), ENT (OR = 1.42; 95% CI: 1.39–1.46), musculoskeletal (OR = 1.15; 95% CI: 1.14–1.16), and respiratory (OR = 1.09; 95% CI: 1.08–1.11) were significantly more likely among females (vs. males), whereas renal sequelae (OR = 0.83; 95% CI: 0.75–0.93) were significantly more likely among males. The likelihood of having long COVID syndrome was significantly greater among females (OR = 1.22; 95% CI: 1.13–1.32), with the odds of ENT (OR = 2.28; 95% CI: 1.94–2.67), GI (OR = 1.60; 95% CI: 1.04–2.44), psychiatric/mood (OR = 1.58; 95% CI: 1.37–1.82), neurological (OR = 1.30; 95% CI: 1.03–1.63), dermatological (OR = 1.29; 95% CI: 1.05–1.58), and other (OR = 1.36; 95% CI: 1.25–1.49) disorders significantly higher among females and the odds of endocrine (OR = 0.75; 95% CI: 0.69–0.81) and renal disorders (OR = 0.74; 95% CI: 0.64–0.86) significantly higher among males. Conclusions Sex-disaggregated differences for COVID-19 sequelae and long COVID syndrome were observed. Few COVID-19 studies report sex-disaggregated data, underscoring the need for further sex-based research/reporting of COVID-19 disease.
158	MS156		S. PATIL R. PATIL G. GONDHALI	LONG COVID IN POST-COVID-19 CARE SETTING: PROSPECTIVE, OBSERVATIONAL, AND INTERVENTIONAL STUDY OF 6,000 CASES IN TERTIARY CARE SETTING IN INDIA	https://doi.org/10.1016/j.chest.2022.04.072	Published	June 01, 2022	Study	https://journal.chestnet.org/article/S0012-3692(22)00814-5/fulltext	TOPIC: Chest Infections PURPOSE: our aim of this study is to analyze effects on organ system and its correlation with inflammatory markers and CT severity score. METHODS: observational study, included 6000 COVID-19 indoor cases confirmed with RT-PCR. Retrospective analysis with treatment records, laboratory markers as IL-6, D-dimer, Ferritin, LDH, BSL, HBA1C. All cases undergone thorough interview in 'post covid care' outdoor setting regarding symptomatology, documnted vital signs abnormality, & workup as HBA1C,BSL,TFT,KFT,ECG, chest x-ray,HRCT thorax,BMD,Echocardiography,MRI brain whichever is necessary. Statistical analysis by using Chi square test and ANOVA. RESULTS: Long covid manifestations were documented in 36.06% (2517/6000) post COVID cases, Fatigue 41.95%,dyspnea 35.98%,cough 31.96%,chest discomfort 26.95%,anosmia 8.76%,joint pain & headache 11.96%,dizziness,vertigo&insomnia 22.95% &alopecia 4.18% cases, Lung fibrosis in 16.66%, minimal lung abnormality 23.65%, pulmonary embolism 7.18% cases, palpitations 25.56%, chest pain 11.3%,arrythmias 5.53%,cardiac dysfunction 24.31%,PTSD 28%,Impaired memory with or without poor concentration (brain fog) 24.03%,Anxiety and or depression 6.33%,Reduction in quality of life 33%,Diabetes mellitus-new onset26%,transient34%,uncontrolled27%, Osteoporosis38.08%, thyroid dysfunction12.1%.CT severity score, Intensive care treatment with or without oxygen and or ventilator use & Laboratory parameters (D-dimer,IL-6,LDH,Ferritin) during hospitalization has significant association with long covid manifestations (p<0.00001) CONCLUSIONS: Long covid in underestimated,improperly evaluated and halfheartedly treated during follow-up.All treated cases needs prompt evaluation, more awareness regrding its manifestations and its impact on quality of life is must CLINICAL IMPLICATIONS: COVID-19 are heterogenous lung disease with pulmonary and extrapulmonary manifestations, and occurs irrespective of severity of illness. Timley workup and protoclised evaluation in these cases have positive impact on good symptom control and adequate quality of life.
159	MS157		Alison Jackes *,Michael Malfesi,Eleanor CurnowORCID,Vaibhav Tyagi andCathy Bulley	Living with and Breaking a Cycle of Illness: A Secondary Qualitative Data Analysis of Women’s Experiences with Long COVID	https://doi.org/10.3390/women2020017	Published	17 June 2022	Study	https://www.mdpi.com/2673-4184/2/2/17/htm	Long COVID is an emerging condition, with early evidence suggesting it impacts women at a greater rate than men. As we seek to understand long COVID, it is important to consider the holistic impacts of this condition. Therefore, a qualitative perspective was used to explore the experience of those living with long COVID. Eight people from Scotland, who presented as women and Caucasian, participated in this study. A thematic analysis, from a phenomenological perspective, was conducted on data collected during two semi-structured focus groups. Five central themes emerged including: (1) a prolonged, varied, and debilitating illness; (2) barriers to care; (3) predominantly negative experiences of care; (4) fighting to carry the burden; and (5) looking to the future. These themes are linked through an explanatory theory describing a cycle of illness, the work required to break the cycle, and participant’s aims to regain their health and advocate for their condition. The thematic results are consistent with two prior qualitative studies on long COVID, creating a relatively consistent picture of individuals’ experiences during the pandemic. Additionally, the developed theory shares commonalities with individuals living with chronic illness, providing further insight into participants’ experiences. Long COVID is an emerging condition with an incomplete understanding regarding pathology, epidemiology, and clinical management. There has been limited research into the experiences of those living with this illness. Therefore, this qualitative study sought to explore the experiences and perceptions of individuals who identified with the term long COVID. To meet this aim, data were collected by conducting semi-structured focus groups. A thematic analysis employing a phenomenological perspective revealed five central themes: (1) “It’s completely changed my life”: a prolonged, varied, and debilitating illness; (2) barriers to care, “there’s definitely a gap”; (3) “stay away, stay home”: predominantly negative experiences of care; (4) fighting to carry the burden is “a full-time job”; and (5) looking to the future and “those who come after”. An overarching explanatory theory was then proposed. This theory illustrates how participants found themselves in a cycle of illness where care-seeking behaviors were met with barriers, contributing to negative emotions. To break this cycle, participants undertook diverse activities. This was performed in response to their continued illness and out of concern for future long-COVID patients. Several of the thematic results that emerged in our study were consistent with prior qualitative work on long COVID. Additionally, several components described in our theory were consistent with pre-existing frameworks on chronic illness. As we continue to move forward in the pandemic timeline, understanding the holistic experiences of individuals with long COVID will allow for better illness management and healthcare provision.
160	MS158		TalalAlmasaJahanzebMalikbAbdulla K.AlsubaiaSyed MuhammadJawad ZaidicRaafeIqbaldKashifKhanbMuhammadAlibUzmaIshaqeMajidAlsufyaniaSebastianHadeedaReemaAlsufyaniaReemaAhmedaTusharThakurfMeettyAntonygIshanAntonyaAnhadBhullaraFaridaKotaitaLubabahAl-Ania	Post-acute COVID-19 syndrome and its prolonged effects: An updated systematic review	https://doi.org/10.1016/j.amsu.2022.103995	Published	15 June 2022	Review	https://www.sciencedirect.com/science/article/pii/S2049080122007555	Highlights •Clinical features of post-acute COVID-19 infection can manifest even after 60 days of initial infection. •Prolonged symptoms and signs are being reported in observational studies and case reports every day. Although such symptoms are usually experienced in survivors of critical illness, the post-acute effects of COVID-19 are equally being reported in patients with mild severity of disease who do not require hospitalization. •Necessary future research includes stratification of these post-acute effects with gender, age, and comorbid conditions in acute, subacute, and chronic phases of the disease. Abstract Objective This systematic review aimed at estimating the prevalence of post-acute COVID-19 symptoms in view of published literature that studied prolonged clinical manifestations after recovery from acute COVID-19 infection. Methods Relevant databases were searched for extraction of articles. For data synthesis, based on the distribution of quantitative variables, they were expressed as mean ± standard deviation (SD) or median and interquartile range (IQR). Qualitative variables were presented as frequency (n) and percentages (%). Results Twenty-one articles qualified for the final analysis. The most common persistent clinical manifestations were fatigue (54.11%), dyspnea (24.38%), alopecia (23.21%), hyperhidrosis (23.6%), insomnia (25.98%), anxiety (17.29%), and arthralgia (16.35%). In addition to these symptoms, new-onset hypertension, diabetes, neuropsychiatric disorders, and bladder incontinence were also reported. Conclusion Clinical features of post-acute COVID-19 infection can manifest even after 60 days of initial infection. Multidisciplinary care along with regular follow-up must be provided to such patients.
161	MS159		FNU Shivani, Naina Kumari, Pinky Bai, FNU Rakesh, Muhammad Haseeb, Sunny Kumar, Amna Jamil, Maheen Zaidi, Faizan Shaukat, Amber Rizwan	Long-Term Symptoms of COVID-19: One-Year Follow-Up Study	https://doi.org/10.7759/cureus.25937	Published	June 14, 2022	Study	https://www.cureus.com/articles/91406-long-term-symptoms-of-covid-19-one-year-follow-up-study	Introduction: Persistent and prolonged symptoms, termed as long COVID (coronavirus disease), have been reported in several patients who recovered from the acute phase at different intervals. However, there has been largely unclear data regarding the full range of long-term sequelae of coronavirus disease 2019 (COVID-19) patients. This study aims to evaluate the prevalence of long COVID syndrome. Methods: A long-term research was conducted in the COVID-19 unit of a tertiary care hospital in Pakistan from July 2020 to December 2021 in which 2,000 patients who had recovered from COVID-19 and had been discharged were included in the study. Symptoms were noted at the time of discharge and at follow-up after 12 months. Data were analyzed using Statistical Package for the Social Sciences (SPSS) v. 22.0 (IBM Corporation, Armonk, New York, United States). Results: The mean age of the participants was 43 ± 10 years, 801 (53.8%) males and 688 (46.2%) females. At the time of discharge, the most common symptom was fatigue (26.93%), followed by dyspnea (20.34%) and muscle pain (8.86%). The most common symptom on follow-up was fatigue (6.78%). Conclusion: We strongly emphasize discussing and exploring further knowledge on the post-infection syndrome, with an aim to bring healthcare professionals’ attention to the importance of handling COVID patients, their counseling, warning for alarming signs, and a long-term follow-up with necessary investigations and treatment.
162	MS160		Tore Bonsaksen 1,2,*ORCID,Janni Leung 3ORCID,Daicia Price 4ORCID,Mary Ruffolo 4ORCID,Gary Lamph 5,Isaac Kabelenga 6,Hilde Thygesen 7,8ORCID andAmy Østertun Geirdal 9ORCID	Self-Reported Long COVID in the General Population: Sociodemographic and Health Correlates in a Cross-National Sample	https://doi.org/10.3390/life12060901	Published	15 June 2022	Study	https://www.mdpi.com/2075-1729/12/6/901/htm	We aimed to gain knowledge of possible sociodemographic predictors of long COVID and whether long COVID was associated with health outcomes almost two years after the pandemic outbreak. There were 1649 adults who participated in the study by completing a cross-sectional online survey disseminated openly in Norway, the UK, the USA, and Australia between November 2021 and January 2022. Participants were defined as having long COVID based on self-reports that they had been infected by COVID-19 and were experiencing long-lasting COVID symptoms. Logistic regression analyses were used to examine possible sociodemographic predictors, and multivariate analysis of variance was used to examine whether long COVID status was associated with health outcomes. None of the sociodemographic variables was significantly associated with reporting long COVID. Having long COVID was associated with higher levels of psychological distress, fatigue, and perceived stress. The effect of long COVID on health outcomes was greater among men than among women. In conclusion, long COVID appeared across sociodemographic groups. People with long COVID reported worsened health outcomes compared to those who had had COVID-19 but without long-term symptoms. Men experiencing long COVID appear to be particularly vulnerable to experiencing poorer health outcomes; health services may pay extra attention to potentially unnoticed needs for support among men experiencing long COVID.
163	MS161		Martha-Spyridoula Katsarou 1,2,3,Eleni Iasonidou 2,Alexander Osarogue 4,Efthymios Kalafatis 2,Maria Stefanatou 3,5,Sofia Pappa 6ORCID,Stylianos Gatzonis 3,5,Anastasia Verentzioti 3,5,Pantelis Gounopoulos 7,Christos Demponeras 8,Eleni Konstantinidou 7,Nikolaos Drakoulis 1,3ORCID,Andreas Asimakos 3,9,Archontoula Antonoglou 3,Aspasia Mavronasou 3,9,10,Stavroula Spetsioti 3,9,Anastasia Kotanidou 3,9ORCID andParaskevi Katsaounou 3,9,*ORCID	The Greek Collaborative Long COVID Study: Non-Hospitalized and Hospitalized Patients Share Similar Symptom Patterns	https://doi.org/10.3390/jpm12060987	Published	17 June 2022	Study	https://www.mdpi.com/2075-4426/12/6/987/htm	Long COVID-19 syndrome refers to persisting symptoms (>12 weeks) after the initial coronavirus infection and is estimated to affect 3% to 12% of people diagnosed with the disease globally. Aim: We conducted a collaborative study with the Long COVID patient organization in Greece, in order to estimate the characteristics, symptoms, and challenges these patients confront. Methods: Data were collected from 208 patients using unstructured qualitative free-text entries in an anonymized online questionnaire. Results: The majority of respondents (68.8%) were not hospitalized and reported lingering symptoms (66.8%) for more than six months. Eighteen different symptoms (fatigue, palpitations, shortness of breath, parosmia, etc.) were mentioned in both hospitalized and community patients. Awareness of Long COVID sequelae seems to be low even among medical doctors. Treatment options incorporating targeted rehabilitation programs are either not available or still not included inthe management plan of Long COVID patients. Conclusions: Patients infected with coronavirus with initial mild symptoms suffer from the same persistent symptoms as those who were hospitalized. Long COVID syndrome appears to be a multi-systemic entity and a multidisciplinary medical approach should be adopted in order to correctly diagnose and successfully manage these patients.
164	MS162		Maria Skaalum Petersen 1 Marnar Fríðheim Kristiansen Katrin Dahl Hanusson Billa Mouritsardóttir Foldbo Marjun Eivindardóttir Danielsen Bjarni á Steig Shahin Gaini Marin Strøm Pál Weihe	Prevalence of long COVID in a national cohort: longitudinal measures from disease onset until 8 months follow up	https://doi.org/10.1016/j.ijid.2022.06.031	Published	June 23, 2022	Study	https://www.ijidonline.com/article/S1201-9712(22)00364-2/fulltext	Highlights •39% reported long COVID after median 168 days after the acute phase. •The most prevalent long COVID symptoms were fatigue and taste and smell dysfunction. •It may take months to resolve from COVID. Abstract Objectives -206 Persistence of COVID-19 symptoms in non-hospitalised patients beyond a few months has not been well characterised. In this longitudinal study from the Faroe Islands, we present prevalence of long COVID in mainly non-hospitalised patients who were followed for up to 8 months. Methods All Faroese individuals with confirmed COVID-19 diagnosis from August to December 2020 were invited to participate in this study (n=297). Demographic and clinical characteristics and self-reported symptoms were ascertained prospectively using a detailed questionnaire administered at repeated phone interviews. Results A total of 226 individuals participated at baseline (226/297, 76% participation rate) of which 170 participants had more than 3 months follow-up. Of these, 39% (n=67/170, 95% CI [32-37%]) reported persistent symptoms median (range) 168 (93-231) days after the acute phase and 8% (n=14/170, 95% CI [5-13%]) reported severe persistent symptoms. The most prevalent symptoms were fatigue (16%) and smell (17%) and taste (14%) dysfunction. Long COVID was more common in people reporting daily medication use (OR 2.34, 95% CI [1.02-5.37]). Conclusions Our results show that symptoms may take months to resolve, even among non-hospitalised patients with a mild illness in the acute phase. Continued monitoring for long COVID is needed to evaluate the added risk of a potential public health concern.
165	MS163		Tianqi Yang, Michael Zhipeng Yan, Xingyi Li & Eric H. Y. Lau	Sequelae of COVID-19 among previously hospitalized patients up to 1 year after discharge: a systematic review and meta-analysis	https://doi.org/10.1007/s15010-022-01862-3	Published	24 June 2022	Review	https://link.springer.com/article/10.1007/s15010-022-01862-3	Objective Although complications and clinical symptoms of COVID-19 have been elucidated, the prevalence of long-term sequelae of COVID-19 is less clear in previously hospitalized COVID-19 patients. This review and meta-analysis present the occurrence of different symptoms up to 1 year of follow-up for previously hospitalized patients. Methods We performed a systematic review from PubMed and Web of Science using keywords such as “COVID-19”, “SARS-CoV-2”, “sequelae”, “long-term effect” and included studies with at least 3-month of follow-up. Meta-analyses using random-effects models were performed to estimate the pooled prevalence for different sequelae. Subgroup analyses were conducted by different follow-up time, regions, age and ICU admission. Results 72 articles were included in the meta-analyses after screening 11,620 articles, identifying a total of 167 sequelae related to COVID-19 from 88,769 patients. Commonly reported sequelae included fatigue (27.5%, 95% CI 22.4–33.3%, range 1.5–84.9%), somnipathy (20.1%, 95% CI 14.7–26.9%, range 1.2–64.8%), anxiety (18.0%, 95% CI 13.8–23.1%, range 0.6–47.8%), dyspnea (15.5%, 95% CI 11.3–20.9%, range 0.8–58.4%), PTSD (14.6%, 95% CI 11.3–18.7%, range 1.2–32.0%), hypomnesia (13.4%, 95% CI 8.4–20.7%, range 0.6–53.8%), arthralgia (12.9%, 95% CI 8.4–19.2%, range 0.0–47.8%), depression (12.7%, 95% CI 9.3–17.2%, range 0.6–37.5%), alopecia (11.2%, 95% CI 6.9–17.6%, range 0.0–47.0%) over 3–13.2 months of follow-up. The prevalence of most symptoms reduced after > 9 months of follow-up, but fatigue and somnipathy persisted in 26.2% and 15.1%, respectively, of the patients over a year. COVID-19 patients from Asia reported a lower prevalence than those from other regions. Conclusions This review identified a wide spectrum of COVID-19 sequelae in previously hospitalized COVID-19 patients, with some symptoms persisting up to 1 year. Management and rehabilitation strategies targeting these symptoms may improve quality of life of recovered patients.
166	MS164		César Fernández-de-las-Peñas 1,2,*ORCID,Ignacio Cancela-Cilleruelo 1,Jorge Rodríguez-Jiménez 1,Victor Gómez-Mayordomo 3ORCID,Oscar J. Pellicer-Valero 4ORCID,José D. Martín-Guerrero 4ORCID,Valentín Hernández-Barrera 5,Lars Arendt-Nielsen 2,6 andJuan Torres-Macho 7,8	Associated-Onset Symptoms and Post-COVID-19 Symptoms in Hospitalized COVID-19 Survivors Infected with Wuhan, Alpha or Delta SARS-CoV-2 Variant	https://doi.org/10.3390/pathogens11070725	Published	25 June 2022	Study	https://www.mdpi.com/2076-0817/11/7/725/htm	This study compared associated-symptoms at the acute phase of infection and post-COVID-19 symptoms between individuals hospitalized with the Wuhan, Alpha or Delta SARS-CoV-2 variant. Non-vaccinated individuals hospitalized because of SARS-CoV-2 infection in one hospital during three different waves of the pandemic (Wuhan, Alpha or Delta) were scheduled for a telephone interview. The presence of post-COVID-19 symptoms was systematically assessed. Hospitalization and clinical data were collected from medical records. A total of 201 patients infected with the Wuhan variant, 211 with the Alpha variant and 202 with Delta variant were assessed six months after hospitalization. Patients infected with the Wuhan variant had a greater number of symptoms at hospital admission (higher prevalence of fever, dyspnea or gastrointestinal problems) than those infected with Alpha or Delta variant (p < 0.01). A greater proportion of patients infected with the Delta variant reported headache, anosmia or ageusia as onset symptoms (p < 0.01). The mean number of post-COVID-19 symptoms was higher (p < 0.001) in individuals infected with the Wuhan variant (mean: 2.7 ± 1.3) than in those infected with the Alpha (mean: 1.8 ± 1.1) or Delta (mean: 2.1 ± 1.5) variant. Post-COVID-19 dyspnea was more prevalent (p < 0.001) in people infected with the Wuhan variant, whereas hair loss was higher in those infected with the Delta variant (p = 0.002). No differences in post-COVID-19 fatigue by SARS-CoV-2 variant were found (p = 0.594). Differences in COVID-19 associated onset symptoms and post-COVID-19 dyspnea were observed depending on the SARS-CoV-2 variant. The presence of fatigue was a common post-COVID-19 symptom to all SARS-CoV-2 variants.
167	MS165		Harrison G. Zhang, Arianna Dagliati, Zahra Shakeri Hossein Abad, Xin Xiong, Clara-Lea Bonzel, Zongqi Xia, Bryce W. Q. Tan, Paul Avillach, Gabriel A. Brat, Chuan Hong, Michele Morris, Shyam Visweswaran, Lav P. Patel, Alba Gutiérrez-Sacristán, David A. Hanauer, John H. Holmes, Malarkodi Jebathilagam Samayamuthu, Florence T. Bourgeois, Sehi L’Yi, Sarah E. Maidlow, Bertrand Moal, Shawn N. Murphy, Zachary H. Strasser, Antoine Neuraz, Kee Yuan Ngiam, Ne Hooi Will Loh, Gilbert S. Omenn, Andrea Prunotto, Lauren A. Dalvin, Jeffrey G. Klann, Petra Schubert, Fernando J. Sanz Vidorreta, Vincent Benoit, Guillaume Verdy, Ramakanth Kavuluru, Hossein Estiri, Yuan Luo, Alberto Malovini, Valentina Tibollo, Riccardo Bellazzi, Kelly Cho, Yuk-Lam Ho, Amelia L. M. Tan, Byorn W. L. Tan, Nils Gehlenborg, Sara Lozano-Zahonero, Vianney Jouhet, Luca Chiovato, Bruce J. Aronow, Emma M. S. Toh, Wei Gen Scott Wong, Sara Pizzimenti, Kavishwar B. Wagholikar, Mauro Bucalo, The Consortium for Clinical Characterization of COVID-19 by EHR (4CE), Tianxi Cai, Andrew M. South, Isaac S. Kohane & Griffin M. Weber	International electronic health record-derived post-acute sequelae profiles of COVID-19 patients	https://doi.org/10.1038/s41746-022-00623-8	Published	29 June 2022	Study	https://www.nature.com/articles/s41746-022-00623-8	The risk profiles of post-acute sequelae of COVID-19 (PASC) have not been well characterized in multi-national settings with appropriate controls. We leveraged electronic health record (EHR) data from 277 international hospitals representing 414,602 patients with COVID-19, 2.3 million control patients without COVID-19 in the inpatient and outpatient settings, and over 221 million diagnosis codes to systematically identify new-onset conditions enriched among patients with COVID-19 during the post-acute period. Compared to inpatient controls, inpatient COVID-19 cases were at significant risk for angina pectoris (RR 1.30, 95% CI 1.09–1.55), heart failure (RR 1.22, 95% CI 1.10–1.35), cognitive dysfunctions (RR 1.18, 95% CI 1.07–1.31), and fatigue (RR 1.18, 95% CI 1.07–1.30). Relative to outpatient controls, outpatient COVID-19 cases were at risk for pulmonary embolism (RR 2.10, 95% CI 1.58–2.76), venous embolism (RR 1.34, 95% CI 1.17–1.54), atrial fibrillation (RR 1.30, 95% CI 1.13–1.50), type 2 diabetes (RR 1.26, 95% CI 1.16–1.36) and vitamin D deficiency (RR 1.19, 95% CI 1.09–1.30). Outpatient COVID-19 cases were also at risk for loss of smell and taste (RR 2.42, 95% CI 1.90–3.06), inflammatory neuropathy (RR 1.66, 95% CI 1.21–2.27), and cognitive dysfunction (RR 1.18, 95% CI 1.04–1.33). The incidence of post-acute cardiovascular and pulmonary conditions decreased across time among inpatient cases while the incidence of cardiovascular, digestive, and metabolic conditions increased among outpatient cases. Our study, based on a federated international network, systematically identified robust conditions associated with PASC compared to control groups, underscoring the multifaceted cardiovascular and neurological phenotype profiles of PASC.
168	MS166		Thomas Bahmer Christoph Borzikowsky Wolfgang Lieb Anna Horn Lilian Krist Julia Fricke Carmen Scheibenbogen Klaus F. Rabe Walter Maetzler Corina Maetzler Martin Laudien Derk Frank Sabrina Ballhausen Anne Hermes Olga Miljukov Karl Georg Haeusler Nour Eddine El Mokhtari Martin Witzenrath Jörg Janne Vehreschild Dagmar Krefting Daniel Pape Felipe A. Montellano Mirjam Kohls Caroline Morbach Stefan Störk Jens-Peter Reese Thomas Keil Peter Heuschmann Michael Krawczak 1 Stefan Schreiber 1 on behalf of theNAPKON study group	Severity, predictors and clinical correlates of Post-COVID syndrome (PCS) in Germany: A prospective, multi-centre, population-based cohort study	https://doi.org/10.1016/j.eclinm.2022.101549	Published	July 15, 2022	Study	https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(22)00279-6/fulltext	Background Post-COVID syndrome (PCS) is an important sequela of COVID-19, characterised by symptom persistence for >3 months, post-acute symptom development, and worsening of pre-existing comorbidities. The causes and public health impact of PCS are still unclear, not least for the lack of efficient means to assess the presence and severity of PCS. Methods COVIDOM is a population-based cohort study of polymerase chain reaction (PCR) confirmed cases of SARS-CoV-2 infection, recruited through public health authorities in three German regions (Kiel, Berlin, Würzburg) between November 15, 2020 and September 29, 2021. Main inclusion criteria were (i) a PCR confirmed SARS-CoV-2 infection and (ii) a period of at least 6 months between the infection and the visit to the COVIDOM study site. Other inclusion criteria were written informed consent and age ≥18 years. Key exclusion criterion was an acute reinfection with SARS-CoV-2. Study site visits included standardised interviews, in-depth examination, and biomaterial procurement. In sub-cohort Kiel-I, a PCS (severity) score was developed based upon 12 long-term symptom complexes. Two validation sub-cohorts (Würzburg/Berlin, Kiel-II) were used for PCS score replication and identification of clinically meaningful predictors. This study is registered at clinicaltrials.gov (NCT04679584) and at the German Registry for Clinical Studies (DRKS, DRKS00023742). Findings In Kiel-I (n = 667, 57% women), 90% of participants had received outpatient treatment for acute COVID-19. Neurological ailments (61·5%), fatigue (57·1%), and sleep disturbance (57·0%) were the most frequent persisting symptoms at 6–12 months after infection. Across sub-cohorts (Würzburg/Berlin, n = 316, 52% women; Kiel-II, n = 459, 56% women), higher PCS scores were associated with lower health-related quality of life (EQ-5D-5L-VAS/-index: r = -0·54/ -0·56, all p < 0·0001). Severe, moderate, and mild/no PCS according to the individual participant's PCS score occurred in 18·8%, 48·2%, and 32·9%, respectively, of the Kiel-I sub-cohort. In both validation sub-cohorts, statistically significant predictors of the PCS score included the intensity of acute phase symptoms and the level of personal resilience. Interpretation PCS severity can be quantified by an easy-to-use symptom-based score reflecting acute phase disease burden and general psychological predisposition. The PCS score thus holds promise to facilitate the clinical diagnosis of PCS, scientific studies of its natural course, and the development of therapeutic interventions.
169	MS167		H. Shanthanna,A. M. Nelson,N. Kissoon,S. Narouze	The COVID-19 pandemic and its consequences for chronic pain: a narrative review	https://doi.org/10.1111/anae.15801	Published	18 July 2022	Review	https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/full/10.1111/anae.15801	The COVID-19 pandemic transformed everyday life, but the implications were most impactful for vulnerable populations, including patients with chronic pain. Moreover, persistent pain is increasingly recognised as a key manifestation of long COVID. This narrative review explores the consequences of the COVID-19 pandemic for chronic pain. Publications were identified related to the COVID-19 pandemic influence on the burden of chronic pain, development of new-onset pain because of long COVID with proposed mechanisms and COVID-19 vaccines and pain interventions. Broadly, mechanisms underlying pain due to SARS-CoV-2 infection could be caused by ‘systemic inflammatory-immune mechanisms’, ‘direct neuropathic mechanisms’ or ‘secondary mechanisms due to the viral infection or treatment’. Existing chronic pain populations were variably impacted and social determinants of health appeared to influence the degree of effect. SARS-CoV-2 infection increased the absolute numbers of patients with pain and headache. In the acute phase, headache as a presenting symptom predicted a milder course. New-onset chronic pain was reportedly common and likely involves multiple mechanisms; however, its prevalence decreases over time and symptoms appear to fluctuate. Patients requiring intensive support were particularly susceptible to long COVID symptoms. Some evidence suggests steroid exposure (often used for pain interventions) may affect vaccine efficacy, but there is no evidence of clinical repercussions to date. Although existing chronic pain management could help with symptomatic relief, there is a need to advance research focusing on mechanism-based treatments within the domain of multidisciplinary care.
170	MS168		Anna Irene Vedel Sørensen, Lampros Spiliopoulos, Peter Bager, Nete Munk Nielsen, Jørgen Vinsløv Hansen, Anders Koch, Inger Kristine Meder, Steen Ethelberg & Anders Hviid	A nationwide questionnaire study of post-acute symptoms and health problems after SARS-CoV-2 infection in Denmark	https://doi.org/10.1038/s41467-022-31897-x	Published	21 July 2022	Study	https://www.nature.com/articles/s41467-022-31897-x	A considerable number of individuals infected with SARS-CoV-2 continue to experience symptoms after the acute phase. Here, we report findings from a nationwide questionnaire study in Denmark including 61,002 RT-PCR confirmed SARS-CoV-2 cases and 91,878 test-negative controls aged 15-years or older. Six to twelve months after the test, the risks of 18 out of 21 symptoms were elevated among test-positives. The largest adjusted risk differences (RD) were observed for dysosmia (RD = 10.92%, 95% CI 10.68–11.21%), dysgeusia (RD = 8.68%, 95% CI 8.43–8.93%), fatigue/exhaustion (RD = 8.43%, 95%CI 8.14–8.74%), dyspnea (RD = 4.87%, 95% CI 4.65–5.09%) and reduced strength in arms/legs (RD = 4.68%, 95% CI 4.45–4.89%). During the period from the test and until completion of the questionnaire, new diagnoses of anxiety (RD = 1.15%, 95% CI 0.95–1.34%) or depression (RD = 1.00%, 95% CI 0.81–1.19%) were also more common among test-positives. Even in a population where the majority of test-positives were not hospitalized, a considerable proportion experiences symptoms up to 12 months after infection. Being female or middle-aged increases risks.
171	MS169		Qiao Wu, Jennifer A. Ailshire & Eileen M. Crimmins	Long COVID and symptom trajectory in a representative sample of Americans in the first year of the pandemic	https://doi.org/10.1038/s41598-022-15727-0	Published	08 July 2022	Study	https://www.nature.com/articles/s41598-022-15727-0	People who have COVID-19 can experience symptoms for months. Studies on long COVID in the population lack representative samples and longitudinal data focusing on new-onset symptoms occurring with COVID while accounting for pre-infection symptoms. We use a sample representing the U.S. community population from the Understanding America Study COVID-19 Survey, which surveyed around 8000 respondents bi-weekly from March 2020 to March 2021. Our final sample includes 308 infected individuals who were interviewed one month before, around the time of, and 12 weeks after infection. About 23% of the sample experienced new-onset symptoms during infection which lasted for more than 12 weeks, and thus can be considered as having long COVID. The most common new-onset persistent symptoms among those included in the study were headache (22%), runny or stuffy nose (19%), abdominal discomfort (18%), fatigue (17%), and diarrhea (13%). Long COVID was more likely among obese individuals (OR = 5.44, 95% CI 2.12–13.96) and those who experienced hair loss (OR = 6.94, 95% CI 1.03–46.92), headache (OR = 3.37, 95% CI 1.18–9.60), and sore throat (OR = 3.56, 95% CI 1.21–10.46) during infection. There was a lack of evidence relating risk to age, gender, race/ethnicity, education, current smoking status, or comorbid chronic conditions. This work provides national estimates of long COVID in a representative sample after accounting for pre-infection symptoms.
172	MS170		Aranka V Ballering, MSc Sander K R van Zon, PhD Tim C olde Hartman, PhD Prof Judith G M Rosmalen, PhD	Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study	https://doi.org/10.1016/S0140-6736(22)01214-4	Published	August 06, 2022	Study	https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01214-4/fulltext	Background: Patients often report various symptoms after recovery from acute COVID-19. Previous studies on post-COVID-19 condition have not corrected for the prevalence and severity of these common symptoms before COVID-19 and in populations without SARS-CoV-2 infection. We aimed to analyse the nature, prevalence, and severity of long-term symptoms related to COVID-19, while correcting for symptoms present before SARS-CoV-2 infection and controlling for the symptom dynamics in the population without infection. Methods: This study is based on data collected within Lifelines, a multidisciplinary, prospective, population-based, observational cohort study examining the health and health-related behaviours of people living in the north of the Netherlands. All Lifelines participants aged 18 years or older received invitations to digital COVID-19 questionnaires. Longitudinal dynamics of 23 somatic symptoms surrounding COVID-19 diagnoses (due to SARS-CoV-2 alpha [B.1.1.7] variant or previous variants) were assessed using 24 repeated measurements between March 31, 2020, and Aug 2, 2021. Participants with COVID-19 (a positive SARS-CoV-2 test or a physician's diagnosis of COVID-19) were matched by age, sex, and time to COVID-19-negative controls. We recorded symptom severity before and after COVID-19 in participants with COVID-19 and compared that with matched controls. Findings: 76 422 participants (mean age 53·7 years [SD 12·9], 46 329 [60·8%] were female) completed a total of 883 973 questionnaires. Of these, 4231 (5·5%) participants had COVID-19 and were matched to 8462 controls. Persistent symptoms in COVID-19-positive participants at 90–150 days after COVID-19 compared with before COVID-19 and compared with matched controls included chest pain, difficulties with breathing, pain when breathing, painful muscles, ageusia or anosmia, tingling extremities, lump in throat, feeling hot and cold alternately, heavy arms or legs, and general tiredness. In 12·7% of patients, these symptoms could be attributed to COVID-19, as 381 (21·4%) of 1782 COVID-19-positive participants versus 361 (8·7%) of 4130 COVID-19-negative controls had at least one of these core symptoms substantially increased to at least moderate severity at 90–150 days after COVID-19 diagnosis or matched timepoint. Interpretation: To our knowledge, this is the first study to report the nature and prevalence of post-COVID-19 condition, while correcting for individual symptoms present before COVID-19 and the symptom dynamics in the population without SARS-CoV-2 infection during the pandemic. Further research that distinguishes potential mechanisms driving post-COVID-19-related symptomatology is required. Evidence before this study: We searched PubMed, Google Scholar, and preprint repositories from November, 2019, to February, 2022, for studies published in Dutch or English that investigated the course of post-COVID-19 condition (ie, long COVID) over time, the symptoms associated with post-COVID-19 condition, and the prevalence of post-COVID-19 condition. Furthermore, we searched for studies and policy documents from (global) public health institutes (eg, WHO) that aimed to clinically define post-COVID-19 condition. A formal systematic review was not conducted. Most previous research that assessed the prevalence and symptoms associated with post-COVID-19 condition did not include an adequate control group, and so no adjustments for the prevalence of somatic symptoms in the population without COVID-19 could be made. Additionally, we found no studies that included patients’ symptom prevalence before COVID-19 diagnosis; therefore, the previous studies were unable to assess whether somatic symptoms reported after a COVID-19 diagnosis were already present before SARS-CoV-2 infection. Most research was conducted in a clinical setting, disregarding post-COVID-19 condition in the general population. In the context of these shortcomings, a systematic review estimated that the median proportion of patients with at least one somatic symptom after COVID-19 was 72∙5%. Added value of this study: To our knowledge, this study is the first to include a control group matched for age, sex, and time, enabling us to adjust for symptom presence in the general population and changes herein due to public health measures and seasonal influences. Additionally, the repeated-measures nature of this study enabled us to assess symptom severity in patients with COVID-19 before they had SARS-CoV-2 infection. Therefore, we could assess whether symptom severity was truly increased after a COVID-19 diagnosis, or whether symptoms were a continuation of pre-existing symptoms. Our approach allowed for identification of core symptoms that define post-COVID-19 condition, as these are increased in severity 90–150 days after a COVID-19 diagnosis compared with patient’s pre-existing symptom severity. Implications of all the available evidence: Our unique approach allows us to present the core symptoms, namely chest pain, difficulties with breathing, pain when breathing, painful muscles, ageusia or anosmia, tingling extremities, lump in throat, feeling hot and cold alternately, heavy arms or legs, and general tiredness, which could define post-COVID-19 condition. Additionally, we offer an improved working definition of post-COVID-19 condition and provide a reliable prevalence estimate in the general population corrected for pre-existing symptoms, and symptoms in COVID-19-negative controls. Taking into account the symptoms that increased in severity and could be attributed to COVID-19, while correcting for seasonal fluctuations and non-infectious health aspects of the pandemic on symptom dynamics, we estimated that 12∙7% of patients with COVID-19 in the general population will experience persistent somatic symptoms after COVID-19. Additionally, these core symptoms have major implications for future research, as these symptoms have the highest discriminative ability to distinguish between post-COVID-19 condition and non-COVID-19-related symptoms.
173	MS171		Christopher E Brightling Rachael A Evans	Long COVID: which symptoms can be attributed to SARS-CoV-2 infection?	https://doi.org/10.1016/S0140-6736(22)01385-X	Published	August 06, 2022	Comment	https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2822%2901385-X/fulltext	How many of the symptoms currently attributed to long COVID actually represent pre-existent disease or are unrelated to COVID-19 is uncertain. Symptoms that were present before SARS-CoV-2 infection are often not recorded or assessed by recall. In The Lancet, Aranka V Ballering and colleagues10 report the findings of a longitudinal cohort study conducted in the north of the Netherlands between April, 2020, and August, 2021, where 23 somatic symptoms were assessed using 24 repeated measurements in digital COVID-19 questionnaires. The study was embedded within the large, population-based Lifelines COVID-19 cohort. The main strengths of this study were that participants were their own control, with the pattern and severity of symptoms assessed before and 3–5 months after SARS-CoV-2 infection, and were also compared with a matched control group of COVID-19-negative participants. Of the 76 422 participants, 4231 (5·5%) had COVID-19 and were compared with 8462 matched controls. Participants had a mean age of 53·7 years (SD 12·9), 46 329 (60·8%) were female, and nearly all were of White ethnicity. The proportion of participants who had at least one core symptom of substantially increased severity to at least moderate was 21·4% (381 of 1782) in COVID-19-positive participants versus 8·7% (361 of 4130) in COVID-19-negative controls. Thus, this study found that core symptoms were attributed to COVID-19 in 12·7% of participants, or approximately one in eight. This is a major advance on previous long COVID prevalence estimates, as it includes a matched control group without SARS-CoV-2 infection and accounts for symptoms that were present before infection. The pattern of symptomatology observed by Ballering and colleagues10 was similar to previous reports, with fatigue and breathlessness among the most common symptoms, but other symptoms such as chest pain were more common in people who had COVID-19 than in COVID-19-negative controls. Ballering and colleagues10 propose a core symptom set to be considered as part of the case definition for long COVID. Although an agreed diagnostic core symptom set would inform clinical pathways and research, the study by Ballering and colleagues10 did not fully consider the impact on mental health, it was conducted in one region in the Netherlands, and it did not include an ethnically diverse population; thus the concept of a core symptom set will require further validation. Importantly, the study by Ballering and colleagues10 does not provide new mechanistic insights, which are key to uncovering new therapeutic targets. In other studies, clustering of patient-reported outcomes has identified different severity groups of long COVID and identified increased systemic inflammation in people with very severe long COVID.5, 6 How patient-centred outcomes, together with biomarkers, can further refine long COVID diagnosis and inform precision medicine approaches warrants further consideration. Encouragingly, emerging data from other studies suggest that the proportion of newly infected people developing long COVID is reduced in people who have received vaccination before SARS-CoV-2 infection,11 and might be lower in people infected with the omicron variant than those infected with earlier variants.12 Findings from the ONS survey suggested that vaccination following infection might reduce the symptom burden of long COVID after the first dose, with sustained improvement after a second dose.13 Whether acute treatments for COVID-19 affect the likelihood of developing long COVID or its severity is unknown. Current evidence supports the view that long COVID is common and can persist for at least 2 years after SARS-CoV-2 infection, although severe debilitating disease is present in a minority. The long COVID case definition needs to be further improved, potentially to describe different types of long COVID, of which better mechanistic understanding is crucial. This will lead to personalised multimodality treatments that can be implemented to manage the increasingly high number of people with long COVID.
174	MS172		Murray Dryden, MBBCh Caroline Mudara, MSc Caroline Vika, MSc Prof Lucille Blumberg, DSc hc Natalie Mayet, MPhil-CS Prof Cheryl Cohen, PhD Prof Stefano Tempia, PhD Arifa Parker, MMed Jeremy Nel, MBBCh Rubeshan Perumal, MPH Michelle J Groome, PhD Francesca Conradie, MBBCh Norbert Ndjeka, MMed Louise Sigfrid, PhD Laura Merson Waasila Jassat, MMed	Post-COVID-19 condition 3 months after hospitalisation with SARS-CoV-2 in South Africa: a prospective cohort study	https://doi.org/10.1016/S2214-109X(22)00286-8	Published	September 01, 2022	Study	https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(22)00286-8/fulltext	Background Post COVID-19 condition (PCC), as defined by WHO, refers to a wide range of new, returning, or ongoing health problems in people who have had COVID-19, and it represents a rapidly emerging public health priority. We aimed to establish how this developing condition has affected patients in South Africa and which population groups are at risk. Methods In this prospective cohort study, we used the DATCOV national hospital surveillance system to identify participants aged 18 years or older who had been hospitalised with laboratory-confirmed SARS-CoV-2 infection in South Africa. Participants underwent telephone follow-up assessment at 1 month and 3 months after hospital discharge. Participants were assessed using a standardised questionnaire for the evaluation of symptoms, functional status, health-related quality of life, and occupational status. We used negative binomial regression models to determine factors associated with PCC. Findings Of 241 159 COVID-19 admissions reported to DATCOV between Dec 1, 2020, and Aug 23, 2021, 8309 were randomly selected for enrolment. Of the 3094 patients that we were able to contact, 2410 (77·9%) consented to participate in the study at 1 month after discharge. Of these, 1873 (77·7%) were followed up at 3 months after hospital discharge. Participants had a median age of 52 years (IQR 41–62) and 960 (51·3%) were women. At 3 months of follow-up, 1249 (66·7%) of 1873 participants reported new or persistent COVID-19-related symptoms, compared with 1978 (82·1%) of 2410 at 1 month after hospital discharge. The most common symptoms reported at 3 months were fatigue (50·3%), shortness of breath (23·4%), confusion or lack of concentration (17·5%), headaches (13·8%), and problems seeing or blurred vision (10·1%). On multivariable analysis, the factors associated with persistent symptoms after acute COVID-19 were being female (adjusted incident rate ratio 1·20, 95% CI 1·04–1·38) and admission to an intensive care unit (1·17, 1·01–1·37). Interpretation Most participants in this cohort of individuals previously hospitalised with COVID-19 reported persistent symptoms 3 months after hospital discharge and a significant impact of PCC on their functional and occupational status. The large burden of PCC symptoms identified in this study emphasises the need for a national health strategy. This should include the development of clinical guidelines and training of health-care workers for identifying, assessing, and caring for patients affected by PCC; establishment of multidisciplinary health services; and provision of information and support to people who have PCC.
175	MS173		Pierre Smith Rana Charafeddine Sabine Drieskens Robby De Pauw Karin De Ridder Stefaan Demarest Dieter Van Cauteren	ETUDE COVIMPACT INFECTION COVID-19 ET SES IMPLICATIONS PHYSIQUES, MENTALES ET SOCIALES À LONG TERME Résultats du suivi à 3 et 6 mois suivant l’infection	https://doi.org/10.25608/gyzc-w673	Published	Juin 2022	Study	https://www.sciensano.be/sites/default/files/report_2_final_fr.pdf	Parmi les guides de pratique clinique actuels du COVID de longue durée, ceux du NICE (National Institute for Health and Care Excellence) sont fortement utilisés (NICE, 2020): les symptômes persistent ou se développent plus de 3 mois après l’infection COVID-19 et ne peuvent être expliqués par un autre diagnostic. Sur base de cette définition et dans le cadre de ce rapport sur l’impact d’une infection COVID-19 après 3 et 6 mois, nous avons choisi de travailler avec les deux définitions de cas suivantes de la COVID de longue durée : (1) Trois mois après l’infection, présenter au moins un symptôme lié à l’infection au COVID-19, (2) Six mois après l’infection, présenter encore au moins un symptôme persistant lié à l’infection au COVID-19. Selon ces définitions, 47% des participants déclarent après 3 mois encore avoir au moins un symptôme lié à leur infection, et 32% continuent d’en déclarer après 6 mois. Ces proportions sont similaires à celles observées dans d’autres études. Une métaanalyse a mis en évidence que 46% des personnes présentaient au moins un symptôme lié à l’infection au COVID19 trois mois après celle-ci (Fernández-de-Las-Peñas et al., 2021). Une autre étude a mis en avant que 6 mois après l’infection COVID-19, 30% des participants rapportaient encore au moins un symptôme persistant (Logue et al., 2021). Tous les participants présentant un COVID long ne déclarent pas nécessairement un moins bon état de santé suite à leur infection COVID-19. En effet, environ 30% des participants présentant un COVID de longue durée après 3 et 6 mois se sentent complètement rétablis de leur infection COVID-19. Ce résultat montre que certaines personnes peuvent avoir des symptômes persistants sans forcément se sentir en moins bonne santé suite à leur infection. Sur l’ensemble de l’échantillon, 33% des participants souffrent d’un COVID de longue durée et déclarent ne pas être complètement rétablis de leur infection après 3 mois, et 26% après 6 mois. Les femmes, les personnes avec un plus faible niveau d’éducation, les personnes avec un antécédent de maladie chronique, les personnes en situation d’obésité ou de surpoids, les personnes qui présentaient au moins un symptôme de la COVID-19 en phase aigüe de l’infection et les personnes hospitalisées suite à leur infection sont plus à risque de présenter un COVID de longue durée 3 mois et 6 mois après leur infection. L’âge et le nombre de doses de vaccins COVID-19 au moment de l’infection ne sont pas significativement associé au risque de présenter un COVID de longue durée. La fatigue ou épuisement est le symptôme persistant le plus fréquent chez les personnes présentant un COVID de longue durée à 3 mois (49%) et chez ceux le présentant à 6 mois (50%) après l’infection. Les autres symptômes persistants les plus fréquents sont les maux de tête (27% et 32%), les troubles de la mémoire et concentration (26% et 32%), les douleurs musculaires (22% et 28%), les difficultés respiratoires (21% et 27%) et les troubles du sommeil (19% et 22%). Les personnes avec un COVID de longue durée à 6 mois ont des proportions plus élevées des différents symptômes que ceux avec un COVID de longue durée à 3 mois, à l’exception de la perte de gout et perte d’odorat qui sont moins présents après 6 mois. En comparaison aux personnes ne présentant aucun symptôme de la COVID-19 trois et six mois après leur infection, les personnes présentant un COVID de longue durée à trois et six mois rapportent un score plus faible de qualité de vie liée à la santé, plus de difficultés respiratoires modérées et sévères, un niveau de fatigue plus élevé, plus de limitations fonctionnelles, des prévalences plus élevées d’anxiété et de dépression, et une activité physique diminuée. Nous observons également que l’état de santé globale sur ces différents résultats est plus défavorable pour les personnes qui présentent encore des symptômes persistants à 6 mois que chez ceux qui en présente à 3 mois après l’infection. Le COVID de longue durée a aussi des conséquences négatives sur la situation professionnelle et économique des individus. En comparaison aux personnes ne présentant plus de symptôme, les personnes avec un COVID de longue durée à 3 et 6 mois ont plus souvent été en arrêt maladie, avec un nombre de jours moyen en arrêt maladie plus élevé, et ont plus souvent rapporté une perte financière modérée et sévère due à leur état de santé lié au COVID-19. Cette étude présente un certain nombre de limites et biais potentiels dont il est important de tenir compte. Premièrement, un biais de sélection peut survenir lors de la phase de recrutement car certaines personnes n'ont pas de GSM, elles n'auront donc pas accès au lien par SMS du premier questionnaire (voir 3. Méthodologie). De plus, certaines personnes peuvent ne pas avoir accès à Internet ou les compétences nécessaires pour répondre par Internet. Les analyses ont été pondérées sur base de certaines caractéristiques de la population éligible (l’âge, le sexe, et le fait d’avoir au moins un symptôme en phase aigüe de l’infection) afin de tenir partiellement compte de ce biais de sélection. Aussi, un biais lié aux participants perdus de vue (qui ne répondent plus aux questionnaires ou qui quittent l’étude) peut survenir car les personnes qui présentent des symptômes de la COVID de longue durée sont potentiellement plus susceptibles de continuer à participer et les personnes perdues de vue pourraient plus vraisemblablement être des participants qui n'ont pas / plus de symptôme de la COVID-19, ou au contraire des personnes décédées. Enfin, une autre limite de cette étude et qu’elle n’a pas un groupe contrôle de personnes non infectées par la COVID-19.
176	MS174		Rehab Magdy, Alaa Elmazny, Shaimaa H. Soliman, Eman H. Elsebaie, Sara H. Ali, Ali M. Abdel Fattah, Mahmoud Hassan, Ahmed Yassien, Noha A. Mahfouz, Radwa M. Elsayed, Wael Fathy, Hoda M. Abdel-Hamid, Jehan Mohamed & Mona Hussein	Post-COVID-19 neuropsychiatric manifestations among COVID-19 survivors suffering from migraine: a case–control study	https://doi.org/10.1186/s10194-022-01468-y	Pubished	12 August 2022	Study	https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-022-01468-y	Background The burden of post-coronavirus disease (COVID)-19 symptoms has been increasing and is of great concern in patients with pre-existing chronic medical conditions.This study aimed to delineate the post-COVID-19 neuropsychiatric symptoms among migraine patients compared to the non-migraine control group. Methods Two groups, each of 204 COVID-19 survivors, were enrolled in the study after 3 months of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, one group fulfilling the episodic migraine criteria and the other serving as a matching control group. Subjects were evaluated through an in-person interview for post-COVID-19 neuropsychiatric symptoms, including detailed headache patterns and severity, using the visual analogue scale. Results The Frequency of headache during the acute phase of COVID-19 was more frequent in migraine patients (OR = 1.60, 95%CI = 1.04–2.45, P-value = 0.031). The reported significant post-COVID-19 neuropsychiatric symptoms in migraine patients compared to controls were fatigue (OR = 1.662, 95%CI = 1.064–2.596, P-value = 0.025), anosmia/hyposmia (OR = 2.06, 95%CI = 1.164- 3.645, P-value = 0.012), cacosmia (OR = 2.663, 95%CI = 1.145–6.195, P-value = 0.019), depression (OR = 2.259, 95%CI = 1.284- 3.975, P-value = 0.004), anxiety (OR = 3.267, 95%CI = 1.747- 6.108, P-value ≤ 0.001), insomnia (OR = 2.203, 95%CI = 1.298- 3.739, P-value = 0.003), and headache (OR = 3.148, 95%CI = 1.616–6.136, P-value = ≤ 0.001).While there was no statistically significant difference between migraine patients and controls regarding the post-COVID-19 functional status score (P-value = 0.102). The pattern of post-COVID-19 headache was reported as chronic headache transformation in 17.6% of the migraine group, with the median intensity rate being 5.5 and IQR (3–7). In the control group, 14% experienced chronic headache attributed to systemic viral infection with a median intensity rate of 2 and IQR (2–5), while 12% experienced a new daily persistent headache with a median intensity of 5 and IQR (1–6). Conclusion The study highlighted the importance of follow-up migraine patients upon recovery from COVID-19 infection, being more vulnerable to post-COVID-19 symptoms.
177	MS175		Aranka V Ballering, MSc Sander K R van Zon, PhD Tim C olde Hartman, PhD Prof Judith G M Rosmalen, PhD	Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study	https://doi.org/10.1016/S0140-6736(22)01214-4	Published	August 06, 2022	Study	https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01214-4/fulltext	Background Patients often report various symptoms after recovery from acute COVID-19. Previous studies on post-COVID-19 condition have not corrected for the prevalence and severity of these common symptoms before COVID-19 and in populations without SARS-CoV-2 infection. We aimed to analyse the nature, prevalence, and severity of long-term symptoms related to COVID-19, while correcting for symptoms present before SARS-CoV-2 infection and controlling for the symptom dynamics in the population without infection. Methods This study is based on data collected within Lifelines, a multidisciplinary, prospective, population-based, observational cohort study examining the health and health-related behaviours of people living in the north of the Netherlands. All Lifelines participants aged 18 years or older received invitations to digital COVID-19 questionnaires. Longitudinal dynamics of 23 somatic symptoms surrounding COVID-19 diagnoses (due to SARS-CoV-2 alpha [B.1.1.7] variant or previous variants) were assessed using 24 repeated measurements between March 31, 2020, and Aug 2, 2021. Participants with COVID-19 (a positive SARS-CoV-2 test or a physician's diagnosis of COVID-19) were matched by age, sex, and time to COVID-19-negative controls. We recorded symptom severity before and after COVID-19 in participants with COVID-19 and compared that with matched controls. Findings 76 422 participants (mean age 53·7 years [SD 12·9], 46 329 [60·8%] were female) completed a total of 883 973 questionnaires. Of these, 4231 (5·5%) participants had COVID-19 and were matched to 8462 controls. Persistent symptoms in COVID-19-positive participants at 90–150 days after COVID-19 compared with before COVID-19 and compared with matched controls included chest pain, difficulties with breathing, pain when breathing, painful muscles, ageusia or anosmia, tingling extremities, lump in throat, feeling hot and cold alternately, heavy arms or legs, and general tiredness. In 12·7% of patients, these symptoms could be attributed to COVID-19, as 381 (21·4%) of 1782 COVID-19-positive participants versus 361 (8·7%) of 4130 COVID-19-negative controls had at least one of these core symptoms substantially increased to at least moderate severity at 90–150 days after COVID-19 diagnosis or matched timepoint. Interpretation To our knowledge, this is the first study to report the nature and prevalence of post-COVID-19 condition, while correcting for individual symptoms present before COVID-19 and the symptom dynamics in the population without SARS-CoV-2 infection during the pandemic. Further research that distinguishes potential mechanisms driving post-COVID-19-related symptomatology is required.
178	MS176		Jonathan I. Silverberg ,Israel Zyskind ,Hiam Naiditch,Jason Zimmerman,Aaron E. Glatt,Abraham Pinter,Elitza S. Theel,Michael J. Joyner,D. Ashley Hill,Miriam R. Lieberman,Elliot Bigajer,Daniel Stok,Elliot Frank,Avi Z. Rosenberg	Predictors of chronic COVID-19 symptoms in a community-based cohort of adults	https://doi.org/10.1371/journal.pone.0271310	Published	August 4, 2022	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0271310	Background COVID-19 can cause some individuals to experience chronic symptoms. Rates and predictors of chronic COVID-19 symptoms are not fully elucidated. Objective To examine occurrence and patterns of post-acute sequelae of SARS-CoV2 infection (PASC) symptomatology and their relationship with demographics, acute COVID-19 symptoms and anti-SARS-CoV-2 IgG antibody responses. Methods A multi-stage observational study was performed of adults (≥18 years) from 5 US states. Participants completed two rounds of electronic surveys (May-July 2020; April-May 2021) and underwent testing to anti-SARS-CoV-2 nucleocapsid protein IgG antibody testing. Latent Class Analysis was used to identify clusters of chronic COVID-19 symptoms. Results Overall, 390 adults (median [25%ile, 75%ile] age: 42 [31, 54] years) with positive SARS-CoV-2 antibodies completed the follow-up survey; 92 (24.7%) had ≥1 chronic COVID-19 symptom, with 11-month median duration of persistent symptoms (range: 1–12 months). The most common chronic COVID-19 symptoms were fatigue (11.3%), change in smell (9.5%) or taste (5.6%), muscle or joint aches (5.4%) and weakness (4.6%). There were significantly higher proportions of ≥1 persistent COVID-19 symptom (31.5% vs. 18.6%; Chi-square, P = 0.004), and particularly fatigue (15.8% vs. 7.3%, P = 0.008) and headaches (5.4% vs. 1.0%, P = 0.011) in females compared to males. Chronic COVID-19 symptoms were also increased in individuals with ≥6 acute COVID-19 symptoms, Latent class analysis revealed 4 classes of symptoms. Latent class-1 (change of smell and taste) was associated with lower anti-SARS-CoV-2 antibody levels; class-2 and 3 (multiple chronic symptoms) were associated with higher anti-SARS-CoV-2 antibody levels and more severe acute COVID-19 infection. Limitations Ambulatory cohort with less severe acute disease. Conclusion Individuals with SARS-CoV-2 infection commonly experience chronic symptoms, most commonly fatigue, changes in smell or taste and muscle/joint aches. Female sex, severity of acute COVID-19 infection, and higher anti-SARS-CoV-2 IgG levels were associated with the highest risk of having chronic COVID-19 symptoms.
179	MS177		Michał Chudzik 1,†ORCID,Mateusz Babicki 2,*,†ORCID,Joanna Kapusta 3ORCID,Żaneta Kałuzińska-Kołat 4,5ORCID,Damian Kołat 4,5ORCID,Piotr Jankowski 1ORCID andAgnieszka Mastalerz-Migas	Long-COVID Clinical Features and Risk Factors: A Retrospective Analysis of Patients from the STOP-COVID Registry of the PoLoCOV Study	https://doi.org/10.3390/v14081755	Published	11 August 2022	Study	https://www.mdpi.com/1999-4915/14/8/1755/htm	Despite recovering from the acute phase of coronavirus disease (COVID-19), many patients report continuing symptoms that most commonly include fatigue, cough, neurologic problems, hair loss, headache, and musculoskeletal pain, a condition termed long-COVID syndrome. Neither its etiopathogenesis, nor its clinical presentation or risk factors are fully understood. Therefore, the purpose of this study was to retrospectively evaluate the most common symptoms of long-COVID among patients from the STOP COVID registry of the PoLoCOV study, and to search for risk factors for development of the syndrome. The registry includes patients who presented to the medical center for persistent clinical symptoms following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The analysis included data from initial presentation and at three-month follow-up. Of the 2218 patients, 1569 (70.7%) reported having at least one symptom classified as long-COVID syndrome three months after recovery from the initial SARS-CoV-2 infection. The most common symptoms included chronic fatigue (35.6%\), cough (23.0%), and a set of neurological symptoms referred to as brain fog (12.1%). Risk factors for developing long-COVID syndrome included female gender (odds ratio [OR]: 1.48, 95% confidence intervals [CI] [1.19–1.84]), severe COVID-19 (OR: 1.56, CI: 1.00–2.42), dyspnea (OR: 1.31, CI: 1.02–1.69), and chest pain (OR: 1.48, CI: 1.14–1.92). Long-COVID syndrome represents a significant clinical and social problem. The most common clinical manifestations are chronic fatigue, cough, and brain fog. Given the still-limited knowledge of long-COVID syndrome, further research and observation are needed to better understand the mechanisms and risk factors of the disease.
180	MS178		Zoe O Demko, Tong Yu, Sarika K. Mullapudi, M. Gabriela Varela Heslin, Chamia A. Dorsey, Christine B. Payton, Jeffrey A. Tornheim, Paul W. Blair, Shruti H. Mehta, David L. Thomas, Yukari C. Manabe, Annukka A.R. Antar, the OutSMART Study Team	Post-acute sequelae of SARS-CoV-2 (PASC) impact quality of life at 6, 12 and 18 months post-infection	https://doi.org/10.1101/2022.08.08.22278543	pre-print	August 09, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.08.08.22278543v1.full-text	Little data exist on long COVID outcomes beyond one year. In a cohort enrolled with mild-moderate acute COVID-19, a wide range of symptoms manifest at 6, 12, and 18 months. Endorsing over 3 symptoms associates with poorer quality of life in 5 domains: physical, social, fatigue, pain, and general health. We demonstrate in a prospective observational cohort that a high proportion of individuals with pre-delta variant, non-severe acute COVID-19 continue to report a wide range of symptoms at 6, 12, and 18 months post-infection, and that having multiple symptoms is associated with lower quality of life over a year after infection. This data extend to 18 months previously reported PASC symptoms and associations with QoL measures at earlier time points.[7-11] Fatigue, brain fog, nasal congestion and discharge, headache, sleep disturbances, and body aches were the most common symptoms. Neurological, mood, and systemic symptoms persisted in over half of participants surveyed at 18 months post-COVID-19. Almost one-quarter of participants reported not having returned to their usual pre-COVID health by 18 months, while some reported returning to work and other activities before feeling entirely recovered from COVID-19. Symptomatic participants reported that symptoms interfered with activities up to 18 months post-infection, and several quality of life domains were statistically significantly associated with multi-symptom morbidity. Limitations of this study include the relatively small size of the cohort, the proportion of participants who missed survey timepoints, and attrition over the follow-up period, which may lead to sampling and attrition biases. Strengths of the study include prospective enrollment during acute COVID-19, prolonged follow-up with validated survey instruments, and a primarily non-hospitalized cohort. More research is urgently needed to characterize and address the lasting morbidity associated with long COVID, especially in the face of omicron vaccine-breakthrough cases.
181	MS179		Jacqui Wise	Long covid: Hair loss and sexual dysfunction are among wider symptoms, study finds	https://doi.org/10.1136/bmj.o1887	Published	27 July 2022	Article	https://www.bmj.com/content/378/bmj.o1887	People experiencing long covid have reported a wider set of symptoms than previously thought, including hair loss and sexual dysfunction. Electronic health records of 2.4 million people in the UK from January 2020 to April 2021 were analysed for a study published in Nature Medicine.1 The cohort included 486 149 people with confirmed SARS-CoV-2 infection who were not admitted to hospital, matched with a control group of 1.9 million people with no recorded evidence of coronavirus infection. People who tested positive for the virus reported at least one of 62 symptoms more frequently 12 weeks after initial infection with SARS-CoV-2 than those who had not contracted the virus. The symptoms with the largest adjusted hazard ratios were anosmia (6.49 (95% confidence interval 5.02 to 8.39)), hair loss (3.99 (3.63 to 4.39)), sneezing (2.77 (1.40 to 5.50)) ejaculation difficulty (2.63 (1.61 to 4.28)), reduced libido (2.36 (1.61 to 3.47)), and shortness of breath (2.20 (1.57 to 3.08)). Other common symptoms were chest pain, a hoarse voice, and fever. Shamil Haroon, associate clinical professor in public health at the University of Birmingham and senior author, said, “This research validates what patients have been telling clinicians and policy makers throughout the pandemic, that the symptoms of long covid are extremely broad and cannot be fully accounted for by other factors such as lifestyle risk factors or chronic health conditions. “The symptoms we identified should help clinicians and clinical guideline developers to improve the assessment of patients with long term effects from covid-19 and to subsequently consider how this symptom burden can be best managed.”
182	MS180		George N. Ioannou, BMBCh, MS1,2; Aaron Baraff, MS3; Alexandra Fox, MSIS3; Troy Shahoumian, PhD4; Alex Hickok, MS5; Ann M. O’Hare, MD6,7; Amy S. B. Bohnert, PhD8; Edward J. Boyko, MD, MPH9,10; Matthew L. Maciejewski, PhD11,12,13,14; C. Barrett Bowling, MD, MSPH15,16; Elizabeth Viglianti, MD17,18; Theodore J. Iwashyna, MD, PhD19,20; Denise M. Hynes, MPH, PhD, RN5,19,20	Rates and Factors Associated With Documentation of Diagnostic Codes for Long COVID in the National Veterans Affairs Health Care System	https://doi.org/10.1001/jamanetworkopen.2022.24359	Published	July 29, 2022	Study	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2794788	Key Points Question What are the rates, clinical settings, and factors associated with documentation of care related to COVID-19 at 3 or more months after acute infection? Findings In this cohort study of 198 601 persons with a positive SARS-CoV-2 test, COVID-19 care was documented in 13.5% of individuals 3 or more months after infection during a mean follow-up of 13.5 months and was documented more commonly in older persons, those with higher comorbidity burden, those with more severe acute COVID-19 presentation, and those who were unvaccinated at the time of infection. Meaning These findings provide guidance for health care systems to develop systematic approaches to the evaluation and management of patients who may be experiencing long COVID. Abstract Importance Some persons infected with SARS-CoV-2 experience symptoms or impairments many months after acute infection. Objectives To determine the rates, clinical setting, and factors associated with documented receipt of COVID-19–related care 3 or more months after acute infection. Design, Setting, and Participants This retrospective cohort study used data from the US Department of Veterans Affairs health care system. Participants included persons with a positive SARS-CoV-2 test between February 1, 2020, and April 30, 2021, who were still alive 3 months after infection and did not have evidence of reinfection. Data analysis was performed from February 2020 to December 2021. Exposures Positive SARS-CoV-2 test. Main Outcomes and Measures Rates and factors associated with documentation of COVID-19–related International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes (U07.1, Z86.16, U09.9, and J12.82) 3 or more months after acute infection (hereafter, long-COVID care), with follow-up extending to December 31, 2021. Results Among 198 601 SARS-CoV-2–positive persons included in the study, the mean (SD) age was 60.4 (17.7) years, 176 942 individuals (89.1%) were male, 133 924 (67.4%) were White, 44 733 (22.5%) were Black, and 19 735 (9.9%) were Hispanic. During a mean (SD) follow-up of 13.5 (3.6) months, long-COVID care was documented in a wide variety of clinics, most commonly primary care and general internal medicine (18 634 of 56 310 encounters [33.1%]), pulmonary (7360 of 56 310 encounters [13.1%]), and geriatrics (5454 of 56 310 encounters [9.7%]). Long-COVID care was documented in 26 745 cohort members (13.5%), with great variability across geographical regions (range, 10.8%-18.1%) and medical centers (range, 3.0%-41.0%). Factors significantly associated with documented long-COVID care included older age, Black or American Indian/Alaska Native race, Hispanic ethnicity, geographical region, high Charlson Comorbidity Index score, having documented symptoms at the time of acute infection (adjusted odds ratio [AOR], 1.71; 95% CI, 1.65-1.78) and requiring hospitalization (AOR, 2.60; 95% CI, 2.51-2.69) or mechanical ventilation (AOR, 2.46; 95% CI, 2.26-2.69). Patients who were fully vaccinated at the time of infection were less likely to receive long-COVID care (AOR, 0.78; 95% CI, 0.68-0.90). Conclusions and Relevance Long-COVID care was documented in a variety of clinical settings, with great variability across regions and medical centers and was documented more commonly in older persons, those with higher comorbidity burden, those with more severe acute COVID-19 presentation and those who were unvaccinated at the time of infection. These findings provide support and guidance for health care systems to develop systematic approaches to the evaluation and management of patients who may be experiencing long COVID.
183	MS181		Aurélie Fischer, Lu Zhang, Abir Elbéji, Paul Wilmes, Pauline Oustric, Therese Staub, Petr V Nazarov, Markus Ollert, Guy Fagherazzi	Long COVID Symptomatology After 12 Months and Its Impact on Quality of Life According to Initial Coronavirus Disease 2019 Disease Severity	https://doi.org/10.1093/ofid/ofac397	Published	05 August 2022	Study	https://academic.oup.com/ofid/article/9/8/ofac397/6656444	Background “Long COVID” is characterized by a variety of symptoms and an important burden for affected people. Our objective was to describe long COVID symptomatology according to initial coronavirus disease 2019 (COVID-19) severity. Methods Predi-COVID cohort study participants, recruited at the time of acute COVID-19 infection, completed a detailed 12-month symptom and quality of life questionnaire. Frequencies and co-occurrences of symptoms were assessed. Results Among the 289 participants who fully completed the 12-month questionnaire, 59.5% reported at least 1 symptom, with a median of 6 symptoms. Participants with an initial moderate or severe acute illness declared more frequently 1 or more symptoms (82.6% vs 38.6%, P < .001) and had on average 6.8 more symptoms (95% confidence interval, 4.18–9.38) than initially asymptomatic participants who developed symptoms after the acute infection. Overall, 12.5% of the participants could not envisage coping with their symptoms in the long term. Frequently reported symptoms, such as neurological and cardiovascular symptoms, but also less frequent ones such as gastrointestinal symptoms, tended to cluster. Conclusions Frequencies and burden of symptoms present 12 months after acute COVID-19 infection increased with the severity of the acute illness. Long COVID likely consists of multiple subcategories rather than a single entity. This work will contribute to the better understanding of long COVID and to the definition of precision health strategies.
184	MS182		Bernardo Meza-Torres # 1, Gayathri Delanerolle 1, Cecilia Okusi 1, Nikhil Mayor 2, Sneha Anand 1, Jack Macartney 1, Piers Gatenby 2, Ben Glampson 3, Martin Chapman 4, Vasa Curcin 4, Erik Mayer 3, Mark Joy 1, Trisha Greenhalgh 1, Brendan Delaney 5, Simon de Lusignan 1	Differences in Clinical Presentation With Long COVID After Community and Hospital Infection and Associations With All-Cause Mortality: English Sentinel Network Database Study	https://doi.org/10.2196/37668	Published	2022 Aug 16	Study	https://pubmed.ncbi.nlm.nih.gov/35605170/	Background: Most studies of long COVID (symptoms of COVID-19 infection beyond 4 weeks) have focused on people hospitalized in their initial illness. Long COVID is thought to be underrecorded in UK primary care electronic records. Objective: We sought to determine which symptoms people present to primary care after COVID-19 infection and whether presentation differs in people who were not hospitalized, as well as post-long COVID mortality rates. Methods: We used routine data from the nationally representative primary care sentinel cohort of the Oxford-Royal College of General Practitioners Research and Surveillance Centre (N=7,396,702), applying a predefined long COVID phenotype and grouped by whether the index infection occurred in hospital or in the community. We included COVID-19 infection cases from March 1, 2020, to April 1, 2021. We conducted a before-and-after analysis of long COVID symptoms prespecified by the Office of National Statistics, comparing symptoms presented between 1 and 6 months after the index infection matched with the same months 1 year previously. We conducted logistic regression analysis, quoting odds ratios (ORs) with 95% CIs. Results: In total, 5.63% (416,505/7,396,702) and 1.83% (7623/416,505) of the patients had received a coded diagnosis of COVID-19 infection and diagnosis of, or referral for, long COVID, respectively. People with diagnosis or referral of long COVID had higher odds of presenting the prespecified symptoms after versus before COVID-19 infection (OR 2.66, 95% CI 2.46-2.88, for those with index community infection and OR 2.42, 95% CI 2.03-2.89, for those hospitalized). After an index community infection, patients were more likely to present with nonspecific symptoms (OR 3.44, 95% CI 3.00-3.95; P<.001) compared with after a hospital admission (OR 2.09, 95% CI 1.56-2.80; P<.001). Mental health sequelae were more strongly associated with index hospital infections (OR 2.21, 95% CI 1.64-2.96) than with index community infections (OR 1.36, 95% CI 1.21-1.53; P<.001). People presenting to primary care after hospital infection were more likely to be men (OR 1.43, 95% CI 1.25-1.64; P<.001), more socioeconomically deprived (OR 1.42, 95% CI 1.24-1.63; P<.001), and with higher multimorbidity scores (OR 1.41, 95% CI 1.26-1.57; P<.001) than those presenting after an index community infection. All-cause mortality in people with long COVID was associated with increasing age, male sex (OR 3.32, 95% CI 1.34-9.24; P=.01), and higher multimorbidity score (OR 2.11, 95% CI 1.34-3.29; P<.001). Vaccination was associated with reduced odds of mortality (OR 0.10, 95% CI 0.03-0.35; P<.001). Conclusions: The low percentage of people recorded as having long COVID after COVID-19 infection reflects either low prevalence or underrecording. The characteristics and comorbidities of those presenting with long COVID after a community infection are different from those hospitalized. This study provides insights into the presentation of long COVID in primary care and implications for workload.
185	MS183		Catherine Paterson,Deborah Davis,Michael Roche,Bernie Bissett,Cara Roberts,Murray Turner,Emma Baldock,Imogen Mitchell	What are the long-term holistic health consequences of COVID-19 among survivors? An umbrella systematic review	https://doi.org/10.1002/jmv.28086	Published	24 August 2022	Review	https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.28086	Many people who have survived COVID-19 have experienced negative persistent impacts on health. Impacts on health have included persistent respiratory symptoms, decreased quality of life, fatigue, impaired functional capacity, memory deficits, psychological impacts, and difficulties in returning to paid employment. Evidence is yet to be pooled to inform future directions in research and practice, to determine the physical, psychological, social, and spiritual impacts of the illness which extend beyond the acute phase of COVID-19 survivors. This umbrella review (review of systematic reviews) critically synthesized physical (including abnormal laboratory parameters), psychological, social, and spiritual impacts which extended beyond the acute phase of COVID-19 survivors. The search strategy was based on the sample, phenomena of interest, design, evaluation, research model and all publications were double screened independently by four review authors for the eligibility criteria. Data extraction and quality assessment were conducted in parallel independently. Eighteen systematic reviews were included, which represented a total of 493 publications. Sample sizes ranged from n = 15 to n = 44 799 with a total of n = 295 455 participants. There was incomplete reporting of several significant data points including the description of the severe acute respiratory syndrome coronavirus 2 variant, COVID-19 treatments, and key clinical and demographic data. A number of physical, psychological, and social impacts were identified for individuals grappling with post-COVID condition. The long term sequalae of acute COVID-19 and size of the problem is only beginning to emerge. Further investigation is needed to ensure that those affected by post-COVID condition have their informational, spiritual, psychological, social, and physical needs met in the future.
186	MS184		Mayssam Nehme, Olivia Braillard, François Chappuis, CoviCare Study Team & Idris Guessous	The chronification of post-COVID condition associated with neurocognitive symptoms, functional impairment and increased healthcare utilization	https://doi.org/10.1038/s41598-022-18673-z	Published	25 August 2022	Study	https://www.nature.com/articles/s41598-022-18673-z	Post-COVID condition is prevalent in 10–35% of cases in outpatient settings, however a stratification of the duration and severity of symptoms is still lacking, adding to the complexity and heterogeneity of the definition of post-COVID condition and its oucomes. In addition, the potential impacts of a longer duration of disease are not yet clear, along with which risk factors are associated with a chronification of symptoms beyond the initial 12 weeks. In this study, follow-up was conducted at 7 and 15 months after testing at the outpatient SARS-CoV-2 testing center of the Geneva University Hospitals. The chronification of symptoms was defined as the continuous presence of symptoms at each evaluation timepoint (7 and 15 months). Adjusted estimates of healthcare utilization, treatment, functional impairment and quality of life were calculated. Logistic regression models were used to evaluate the associations between the chronification of symptoms and predictors. Overall 1383 participants were included, with a mean age of 44.3 years, standard deviation (SD) 13.4 years, 61.4% were women and 54.5% did not have any comorbidities. Out of SARS-CoV-2 positive participants (n = 767), 37.0% still had symptoms 7 months after their test of which 47.9% had a resolution of symptoms at the second follow-up (15 months after the infection), and 52.1% had persistent symptoms and were considered to have a chronification of their post-COVID condition. Individuals with a chronification of symptoms had an increased utilization of healthcare resources, more recourse to treatment, more functional impairment, and a poorer quality of life. Having several symptoms at testing and difficulty concentrating at 7 months were associated with a chronification of symptoms. COVID-19 patients develop post-COVID condition to varying degrees and duration. Individuals with a chronification of symptoms experience a long-term impact on their health status, functional capacity and quality of life, requiring a special attention, more involved care and early on identification considering the associated predictors.
187	MS185		Mohammed Samannodi 1,Hassan Alwafi 2,3,Abdallah Y. Naser 4ORCID,Abdullah A. Al Qurashi 5,6,Jumanah T. Qedair 5,6,Emad Salawati 7ORCID,Mohammed A. Almatrafi 8,Rakan Ekram 9,Rahaf I. Bukhari 2,Maryam Dahlawi 2ORCID,Bayan Hafiz 2,Roaa Mandora 2,Ranin K. Alsindi 2,Sarah Tayeb 10 andFaisal Minshawi 11,*ORCID	Determinants of Post-COVID-19 Conditions among SARS-CoV-2-Infected Patients in Saudi Arabia: A Web-Based Cross-Sectional Study	https://doi.org/10.3390/diseases10030055	Published	23 August 2022	Study	https://www.mdpi.com/2079-9721/10/3/55/htm	Background: Large numbers of people infected with COVID-19 developed acute symptoms. Post-COVID-19 conditions have been reported after recovery or discharge from the hospital. However, little is known about the prevalence and possible risk factors of post-COVID-19 conditions in the Saudi community. Here, we describe the incidence of post-COVID-19 conditions among the general population of Saudi Arabia. Methods: We conducted a cross-sectional, nationwide study using an online survey in Saudi Arabia from 1 September 2021 to 28 February 2022. The survey was distributed using social media platforms, such as Twitter, WhatsApp, and Facebook. Patients with SARS-CoV-2 infection were included in the questionnaire adapted from published studies. Result: The study enrolled 7520 individuals who were previously infected with SARS-CoV-2. Most patients in our study were symptomatic and their acute symptoms may persist for more than six days. On the other hand, long-term complications may develop and continue for an extended period (post-COVID-19 conditions). Most of these complications are respiratory, neurological, psychological, or skin related. The proportion of long-term complications reported in this study is 36% among SARS-CoV-2-infected individuals. In addition, being female, old age, number of chronic complications, long-term medication, length of stay in hospital and intensive care unit, and duration of acute symptoms may be significant predictors of post-COVID-19 symptoms. Conclusion: In conclusion, the incidence of post-COVID-19 conditions among the Saudi population was high, which urges further investigation into the risk factors associated with post-COVID-19 symptoms.
188	MS186		Anuradhaa Subramanian,1 Krishnarajah Nirantharakumar,corresponding author1,2,3 Sarah Hughes,1,4,5,6,7 Puja Myles,8 Tim Williams,8 Krishna M. Gokhale,1 Tom Taverner,1 Joht Singh Chandan,1 Kirsty Brown,1,9 Nikita Simms-Williams,1 Anoop D. Shah,10 Megha Singh,1 Farah Kidy,1,11 Kelvin Okoth,1 Richard Hotham,1 Nasir Bashir,12 Neil Cockburn,1 Siang Ing Lee,1 Grace M. Turner,1,4,13 Georgios V. Gkoutos,2,3,14,15,16 Olalekan Lee Aiyegbusi,1,4,5,6,7,15 Christel McMullan,1,4,7,13,17 Alastair K. Denniston,2,3,4,6,15,16 Elizabeth Sapey,16,18,19 Janet M. Lord,13,15,18,20 David C. Wraith,15,21 Edward Leggett,8 Clare Iles,8 Tom Marshall,1 Malcolm J. Price,1,15 Steven Marwaha,22,23 Elin Haf Davies,24 Louise J. Jackson,1 Karen L. Matthews,25 Jenny Camaradou,25 Melanie Calvert,1,2,3,4,5,6,7,13,15,19 and Shamil Haroon1	Symptoms and risk factors for long COVID in non-hospitalized adults	https://doi.org/10.1038%2Fs41591-022-01909-w	Published	2022 Jul 25	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9388369/	Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with a range of persistent symptoms impacting everyday functioning, known as post-COVID-19 condition or long COVID. We undertook a retrospective matched cohort study using a UK-based primary care database, Clinical Practice Research Datalink Aurum, to determine symptoms that are associated with confirmed SARS-CoV-2 infection beyond 12 weeks in non-hospitalized adults and the risk factors associated with developing persistent symptoms. We selected 486,149 adults with confirmed SARS-CoV-2 infection and 1,944,580 propensity score-matched adults with no recorded evidence of SARS-CoV-2 infection. Outcomes included 115 individual symptoms, as well as long COVID, defined as a composite outcome of 33 symptoms by the World Health Organization clinical case definition. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) for the outcomes. A total of 62 symptoms were significantly associated with SARS-CoV-2 infection after 12 weeks. The largest aHRs were for anosmia (aHR 6.49, 95% CI 5.02–8.39), hair loss (3.99, 3.63–4.39), sneezing (2.77, 1.40–5.50), ejaculation difficulty (2.63, 1.61–4.28) and reduced libido (2.36, 1.61–3.47). Among the cohort of patients infected with SARS-CoV-2, risk factors for long COVID included female sex, belonging to an ethnic minority, socioeconomic deprivation, smoking, obesity and a wide range of comorbidities. The risk of developing long COVID was also found to be increased along a gradient of decreasing age. SARS-CoV-2 infection is associated with a plethora of symptoms that are associated with a range of sociodemographic and clinical risk factors.
189	MS187		Dan Cui, Simiao Chen, Luzhao Feng, Mengmeng Jia, Yeming Wang, Weijun Xiao, Yanxia Sun, Qiangru Huang, Libing Ma, Zhiwei Leng, Hao Wang, Bin Cao, Weizhong Yang, Juntao Yang, Chen Wang	Long-term outcomes in COVID-19 patients recovered from the first wave of the pandemic	https://doi.org/10.1093/nsr/nwac192	Published	20 September 2022	Study	https://academic.oup.com/nsr/advance-article/doi/10.1093/nsr/nwac192/6706858	This cross-sectional study evaluated the long-term health effects of coronavirus disease 2019 (COVID-19) in Jianghan District (Wuhan, China). The results showed that 61.4% of COVID-19 patients reported at least one symptom, and 8.8% had depressive symptoms at the 17-month follow-up. The proportion of patients with chest radiographic abnormalities in Fangcang shelter hospitals and designated COVID-19 hospitals was 31.6% and 41.1%, respectively, and the proportion of patients with impaired pulmonary diffusion capacity in these hospitals was 52.8% and 60.9%, respectively. Female sex (odds ratio [OR]=1.48, 95% confidence interval [CI]: 1.16–1.88), severe disease (OR = 1.46, 95% CI: 1.01–2.10), and a higher number of initial symptoms (OR = 1.31, 95% CI: 1.23–1.40) were associated with the development of sequelae symptoms at 17 months. This study involving community-dwelling COVID-19 adults may help determine the long-term effects of COVID-19 during the first pandemic wave. Nonetheless, larger follow-up studies are needed to characterise post-COVID-19 condition.
190	MS188	ME - PESE	Frédérique Retornaz, Stanislas Rebaudet, Chloé Stavris & Yves Jammes	Long-term neuromuscular consequences of SARS-Cov-2 and their similarities with myalgic encephalomyelitis/chronic fatigue syndrome: results of the retrospective CoLGEM study	https://doi.org/10.1186/s12967-022-03638-7	Published	24 September 2022	Study	https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03638-7	Background Patients with long-COVID often complain of continuous fatigue, myalgia, sleep problems, cognitive dysfunction, and post-exertional malaise. No data are available on EMG recording of evoked myopotentials (M-waves) or exercise-induced alterations in long-COVID patients, providing evidence of muscle membrane fatigue. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) develops in more than half of patients after an infectious disease, particularly viral diseases. A large proportion (around 70%) of these patients have neuromuscular disorders with M-wave alterations during and after exercise. Our hypothesis was that M-wave alterations would be also found in long-COVID patients, in association with neuromuscular symptoms, similar to ME/CFS. Methods This retrospective observational ColGEM (Covid LonG Encéphalomyelite Myalgique) study compared 59 patients with long-COVID and 55 ME/CFS patients with a history of severe infection who presented before the COVID pandemic. All of these patients underwent the same protocol consisting of a questionnaire focusing on neural and neuromuscular disorders and M-wave recording in the rectus femoris muscle before, during, and 10 min after a progressive cycling exercise. Maximal handgrip strength (MHGS) and maximal exercise power were also measured. The frequency of symptoms and magnitude of M-wave changes in the two groups were compared using non-parametric and parametric tests. Results The frequency of fatigue, myalgia, sleep problems, cognitive dysfunction, and post-exertional malaise as well as the magnitude of exercise-induced M-wave alterations were the same in the two groups. By contrast, digestive problems were less present in long-COVID. M-wave alterations were greater in ME/CFS patients as in those with long-COVID when the highest muscle strength and highest exercise performance were measured. Conclusions These high clinical and biological similarities between long-COVID and ME/CFS support the hypothesis that SARS-Cov-2 infection can cause ME/CFS symptoms.
191	MS189		TineBovilMScPHaChristian T.WesterMSc.aLasse L.Scheel-HinckeMScPHaKarenAndersen-RanbergMD	Risk factors of post-COVID-19 condition attributed to COVID-19 disease in people aged 50+ in Europe and Israel	https://doi.org/10.1016/j.puhe.2022.09.017	Published	27 September 2022	Study	https://www.sciencedirect.com/science/article/pii/S0033350622002785	Objectives High age, male sex, and pre-existing comorbidities are risk factors for a more severe development of COVID-19, and individuals surviving COVID-19 may experience persistent symptoms afterwards referred to as “Post COVID-19 condition”, which represents a range of symptoms after recovering from COVID-19. This study aims at identifying risk factors of post-COVID-19 conditions among 50+ year olds. Study design We conducted a cross-sectional study based on data from the Survey of Health, Ageing and Retirement in Europe. Methods A multiple logistic regression model was used to investigate age, sex, education, comorbidities, smoking, BMI, and COVID-19 hospitalisation as risk-factors of post-COVID-19 condition. Results Participants aged 70+ (OR 1.61), with medium (OR 2.38) and lower (OR 2.14) educational level have a higher risk of post-COVID-19 conditions. Additionally, when considering the severity of the COVID-19 disease, those who were hospitalised due to COVID-19 had a 26 times higher risk of post-COVID-19 conditions compared to those who were only tested positive (OR 25.9). Conclusions This study supports that health inequalities exist across educational levels with respect to post-COVID-19 conditions, although misclassification may be more common among lower educated participants. The results suggest that policy makers should increase educational interventions towards increasing health literacy.
192	MS190		VeredDaitch12#DanaYelin12#MuhammadAwwad3GiovanniGuaraldi45JovanaMilić5CristinaMussini45MarcoFalcone6GiusyTiseo6LauraCarrozzi7FrancescoPistelli7MayssamNehme8IdrisGuessous89LaurentKaiser10PaulineVetter10JaumeBordas-Martínez11XavierDurà-Miralles1213DoloresPeleato-Catalan14CarlotaGudiol1516IritShapira-Lichter217DonnaAbecasis17LeonardLeibovici18DafnaYahav219IliMargalit1219	Characteristics of long COVID among older adults: a cross-sectional study	https://doi.org/10.1016/j.ijid.2022.09.035	Published	1 October 2022	Study	https://www.sciencedirect.com/science/article/pii/S1201971222005355	Highlights •This study evaluated 2333 individuals at hospital-based COVID recovery clinics. •Older adults are more likely to report on long COVID symptoms. •The most common long COVID symptoms among older adults are fatigue and dyspnea. •Older age does not correlate with long COVID fatigue or dyspnea. •Obesity is an independent risk factors for both long COVID fatigue and dyspnea. Abstract Objective To describe long-COVID symptoms among older adults, and to assess risk factors for two common long-COVID symptoms: fatigue and dyspnea. Methods Multicenter prospective cohort study, conducted in Israel, Switzerland, Spain, and Italy. Included were individuals at least 30 days since COVID-19 diagnosis. We compared long-COVID symptoms between elderly individuals (age>65 years) and younger population (18-65 years); and conducted univariate and multivariable analyses for predictors of long-COVID fatigue and dyspnea. Results 2333 individuals were evaluated at an average of 5 months [146 days (95% CI 142-150)] following COVID-19 onset. Mean age was 51 and 20.5% were>65 years. Older adults were more likely to be symptomatic, with most common symptoms being fatigue (38%) and dyspnea (30%). They were more likely to complain of cough and arthralgia, and have abnormal chest imaging and pulmonary function tests. Independent risk factors for long-COVID fatigue and dyspnea included female gender, obesity, and closer proximity to COVID-19 diagnosis; older age was not an independent predictor. Conclusions Older individuals with long-COVID, have different persisting symptoms, with more pronounced pulmonary impairment. Women and individuals with obesity are at risk. Further research is warranted to investigate the natural history of long-COVID among the elderly population and to assess possible interventions aimed at promoting rehabilitation and well-being.
193	MS191		Antonio S. Menezes Jr., Silvia M. Botelho, Luciana R. Santos, Aline L. Rezende	Acute COVID-19 Syndrome Predicts Severe Long COVID-19: An Observational Study	https://doi.org/10.7759/cureus.29826	Published	October 02, 2022	Study	https://www.cureus.com/articles/116317-acute-covid-19-syndrome-predicts-severe-long-covid-19-an-observational-study	Introduction Tissue damage, chronic dysfunction, and symptoms that last more than 12 weeks are hallmarks of long-term chronic opportunistic viral infection (COVID-19), and the disease may have a permanent, relapsing/remitting, or gradually improving course. This study aimed to determine the risk factors of severe long COVID-19. Methods In October 2021, primary care clinics enrolled consenting 18- to 89-year-olds to complete an online questionnaire on self-diagnosis, clinician diagnosis, testing, symptom presence, and duration of COVID-19. Long COVID-19 was identified if symptoms were beyond 12 weeks. Patients with long-lasting COVID-19 symptoms were assessed using multivariable regression to identify potential predictors of severe long COVID-19. Results Of the 220 respondents, 108 (49%) patients were self- or clinician-diagnosed with COVID-19 or had a confirmed positive laboratory test result. Patients aged >45 years and with at least 15 COVID-19 symptoms were 5.55 and 6.02 times, respectively, more likely to acquire severe long COVID-19. Most patients with severe and moderate post-acute COVID-19 syndrome had no relevant comorbidities (p=0.0402; odds ratio [OR]=0.4; 95% confidence interval [CI]=0.18-0.98). Obesity was a significant predictor (p=0.0307; OR=6.2; 95% CI=1.1-33.2). Conclusion The simultaneous presence of 15 or more COVID-19 symptoms, age >45 years, and obesity were related to a higher probability of severe long COVID-19.
194	MS192		Benjamin A. Abramoff, MD Timothy Dillingham, MD Lily A. Brown, PhD Frank Caldera, MD Mitra McLartney, MD Emily McGinley, MS Liliana E. Pezzin, PhD JD Show less	Psychological and Cognitive Functioning Among Patients Receiving Outpatient Rehabilitation for post-COVID sequelae: An Observational Study	https://doi.org/10.1016/j.apmr.2022.09.013	Published	October 03, 2022	Study	https://www.archives-pmr.org/article/S0003-9993(22)01614-8/fulltext	Objectives To describe the characteristics of individuals receiving outpatient rehabilitation for post-acute sequelae of SARS-CoV-2 infection (PASC). Further, to examine factors associated with variation in their psychological and cognitive functioning and health-related quality of life. Design Observational study. Setting Outpatient COVID-19 recovery clinic at a large, tertiary, urban health system in the U.S. Participants COVID-19 survivors with persistent sequelae (n=324). Interventions Not applicable. Main Outcome Measures Multivariable logistic and linear regression models were used to examine factors associated with COVID survivors’ experience of severe anxiety, severe depression, post-traumatic stress disorder (PTSD), cognitive impairment, and self-reported health-related quality of life. Results About 38% of survivors seeking care for their persistent COVID symptoms suffered from severe anxiety, 31.8% from severe depression, 43% experiencing moderate to severe PTSD symptomology, and 17.5% had cognitive impairment. Their health-related quality of life was substantially lower than that of the general population (-26%) and of persons with other chronic conditions. Poor and African American/Black individuals experienced worse psychological and cognitive sequelae following COVID19 infection, even after controlling for age, gender, initial severity of the acute infection, and time since diagnosis. Conclusions Evidence of consistent disparities in outcomes by the patients’ race and socioeconomic status, even among those with access to post-acute COVID rehabilitation care, are concerning and have significant implications for PASC policy and program development.
195	MS193		Asma S. Albtoosh, Ahmad A. Toubasi, Khaled Al Oweidat, Manar M. Hasuneh, Abdullah H. Alshurafa, Daniah L. Alfaqheri & Randa I. Farah	New symptoms and prevalence of postacute COVID-19 syndrome among nonhospitalized COVID-19 survivors	https://doi.org/10.1038/s41598-022-21289-y	Published	08 October 2022	Study	https://www.nature.com/articles/s41598-022-21289-y	The aim of this study was to assess postacute coronavirus disease 2019 (COVID-19) syndrome (PACS) symptoms according to the onset of the infection while evaluating the effect of COVID-19 vaccination on the symptoms of PACS. We conducted a retrospective single-center cohort study in which nonhospitalized COVID-19 survivors and healthy controls were compared for the occurrence of PACS. The total number of patients in this study was 472. At 6–12 and > 12 months after the infection, COVID-19 survivors had a significantly higher incidence of posttraumatic stress disorder (PTSD) and anxiety than the non-COVID-19 cohort. Furthermore, depression, cognitive deficit, tics, impaired quality of life and general health impairment were significantly more prevalent among COVID-19 survivors at < 6 months, 6–12 months and > 12 months than in the non-COVID-19 cohort. However, respiratory symptoms were significantly more prevalent among COVID-19 survivors only in the first 6 months after infection. In addition, cognitive deficit (OR = 0.15; 95% CI 0.03–0.87) and impaired quality of life (B = − 2.11; 95% CI − 4.21 to − 0.20) were significantly less prevalent among vaccinated COVID-19 survivors than among nonvaccinated survivors. Longitudinal studies are needed to establish the time that should elapse after COVID-19 infection for the symptoms of PACS to appear. Randomized clinical trials are needed to assess the possibility that COVID-19 vaccines might relieve PACS symptoms.
196	MS194		M.C.MassicotteabC.ModeriecdS.MombelliabA.-S.Deshaies-RugamaabC.ThompsonaM.NigamafA.DesautelsafJ.MontplaisiraeN.Gosselinab	Distinguer la narcolepsie de type 2, l’hypersomnie idiopathique, la dépression et la somnolence dans le syndrome post-COVID-19Discriminating narcolepsy type-2, idiopathic hypersomnia, depression and hypersomnolence in post-acute COVID-19 syndrome	https://doi.org/10.1016/j.msom.2022.09.001	Published	8 October 2022	Review	https://www.sciencedirect.com/science/article/abs/pii/S1769449322002655	Central disorders of hypersomnolence, including narcolepsy type-1 and type-2 as well as idiopathic hypersomnia, depression and a subtype of post-acute COVID-19 syndrome might be confused when establishing a diagnosis. This diagnostic challenge can be explained by the presence of excessive daytime sleepiness, a clinical symptom that is observed in all four conditions, an overlap in the phenotypic traits of narcolepsy type-2 and idiopathic hypersomnia, as well as the presence of depressive symptoms observed in central disorders of hypersomnolence and post-acute COVID-19 syndrome subtypes. Considering the importance of a valid diagnostic on treatment's efficacy and future interventions, it is essential to define those conditions with precision. In this review, we will discuss the diagnostic criteria, clinical presentation and current state of knowledge with regards to the pathophysiology of central disorders of hypersomnolence and post-acute COVID-19 syndrome. We will pay particular attention to the characteristics specific to narcolepsy type-2, idiopathic hypersomnia, depressive episodes with hypersomnolence, and post-acute COVID-19 syndrome with drowsiness. While many studies have assessed the ability of different tools used to diagnose central disorders of hypersomnolence, very few have focused on physiological markers. A better understanding and identification of biomarkers specific to narcolepsy type-1 and type-2, idiopathic hypersomnia and post-acute COVID-19 syndrome will reduce the possibility of misdiagnoses and allow the development of optimal treatment plans.	"Les syndromes d’hypersomnolence d’origine centrale (c.-à-d. narcolepsie de type-1, narcolepsie de type-2 et hypersomnie idiopathique), la dépression ainsi qu’un sous-type du syndrome post-COVID-19 peuvent être confondus lors de l’établissement d’un diagnostic. Ce défi diagnostique s’explique par un symptôme clinique caractéristique retrouvé dans les quatre conditions, la somnolence diurne excessive, un chevauchement phénotypique considérable entre la narcolepsie de type-2 et l’hypersomnie idiopathique ainsi qu’une symptomatologie dysphorique pouvant être présente autant dans les hypersomnolences centrales que dans un sous-type du syndrome post-COVID-19. Considérant l’importance d’un diagnostic valide sur l’efficacité des traitements et des interventions futures, il est essentiel de définir précisément ces quatre conditions. Dans cette revue, nous reprendrons les critères diagnostiques, les présentations cliniques et les connaissances actuelles en ce qui a trait à la pathophysiologie de ces troubles en portant une attention particulière aux éléments distinctifs de la narcolepsie de type-2, de l’hypersomnie idiopathique, des épisodes dépressifs avec hypersomnolence et du syndrome post-COVID-19 avec somnolence. Bien que de nombreuses études se soient penchées sur les valeurs diagnostiques des différents outils employés dans l’identification des hypersomnolences centrales, très peu de marqueurs physiologiques ont été identifiés. Une meilleure compréhension de ces conditions cliniques pourrait permettre l’identification de marqueurs objectifs spécifiques à chaque condition réduisant ainsi la possibilité d’une erreur diagnostique et optimisant les plans de traitement."
197	MS195		Ilona Merikanto,Yves Dauvilliers,Frances Chung,Yun Kwok Wing,Luigi De Gennaro,Brigitte Holzinger,Bjørn Bjorvatn,Charles M. Morin,Thomas Penzel,Christian Benedict,Adrijana Koscec Bjelajac,Ngan Yin Chan,Colin A. Espie,Harald Hrubos-Strøm,Yuichi Inoue,Maria Korman,Anne-Marie Landtblom,Damien Léger,Kentaro Matsui,Sergio Mota-Rolim,Michael R. Nadorff,Giuseppe Plazzi,Catia Reis,Juliana Yordanova,Markku Partinen	Sleep symptoms are essential features of long-COVID – Comparing healthy controls with COVID-19 cases of different severity in the international COVID sleep study (ICOSS-II)	https://doi.org/10.1111/jsr.13754	Published	08 October 2022	Survey Study	https://onlinelibrary.wiley.com/doi/10.1111/jsr.13754	Many people report suffering from post-acute sequelae of COVID-19 or “long-COVID”, but there are still open questions on what actually constitutes long-COVID and how prevalent it is. The current definition of post-acute sequelae of COVID-19 is based on voting using the Delphi-method by the WHO post-COVID-19 working group. It emphasizes long-lasting fatigue, shortness of breath and cognitive dysfunction as the core symptoms of post-acute sequelae of COVID-19. In this international survey study consisting of 13,628 subjects aged 18–99 years from 16 countries of Asia, Europe, North America and South America (May–Dec 2021), we show that post-acute sequelae of COVID-19 symptoms were more prevalent amongst the more severe COVID-19 cases, i.e. those requiring hospitalisation for COVID-19. We also found that long-lasting sleep symptoms are at the core of post-acute sequelae of COVID-19 and associate with the COVID-19 severity when COVID-19 cases are compared with COVID-negative cases. Specifically, fatigue (61.3%), insomnia symptoms (49.6%) and excessive daytime sleepiness (35.8%) were highly prevalent amongst respondents reporting long-lasting symptoms after hospitalisation for COVID-19. Understanding the importance of sleep-related symptoms in post-acute sequelae of COVID-19 has a clinical relevance when diagnosing and treating long-COVID.
198	MS196		Dapeng Li,Xuejiao Liao,Zhi Liu,Zhenghua Ma,Jingke Dong,Guoqin Zheng,Mei ZiORCID Icon,Fang Wang,Qing He,Guobao Li,Zheng Zhang &Lei Liu	Healthy Outcomes of Patients with COVID-19 Two Years after the Infection: A Prospective Cohort Study	https://doi.org/10.1080/22221751.2022.2133639	Published	10 Oct 2022	Study	https://www.tandfonline.com/doi/full/10.1080/22221751.2022.2133639	The long-term effect of coronavirus disease 2019 (COVID-19) has been rarely known. This study aimed to investigate healthy outcomes of COVID-19 survivors up to 2 years after the infection. A total of 155 COVID-19 patients, who were discharged from Shenzhen Third People's Hospital from February 2020 to April 2020, were enrolled and followed up until March 4, 2022. COVID-19 survivors received questionnaires of long COVID symptoms and psychological symptoms, pulmonary function tests, chest computed tomography (CT) scans, routine laboratory tests. Two years after infection, 36.6% of patients had at least one symptom of long COVID. Vision impairment and fatigue were the most common symptom. 35.0% of participants still had at least one psychological symptom of anxiety, depression, post-traumatic stress symptoms, and sleep difficulties. Radiographic abnormalities were presented in 50.7% of patients, with the most common features of fibrosis-like lesions and residual ground-glass opacity. Diffuse dysfunction (24.0%) was the main abnormalities of pulmonary function tests. Most laboratory parameters returned to normal range, while persistent abnormalities in kidney and liver function test were observed in a subset of participants after discharge. Two years after COVID-19 infection, persistent symptoms of long COVID and psychological symptoms, as well as abnormalities in pulmonary function test and CT, were still common in a subset of recovering individuals. These findings were limited by the lack of a healthy control group and pre-COVID assessments, which should be confirmed by further large-scale studies.
199	MS197		Claire E. Hastie, David J. Lowe, Andrew McAuley, Andrew J. Winter, Nicholas L. Mills, Corri Black, Janet T. Scott, Catherine A. O’Donnell, David N. Blane, Susan Browne, Tracy R. Ibbotson & Jill P. Pell	Outcomes among confirmed cases and a matched comparison group in the Long-COVID in Scotland study	https://doi.org/10.1038/s41467-022-33415-5	Published	12 October 2022	Study	https://www.nature.com/articles/s41467-022-33415-5	With increasing numbers infected by SARS-CoV-2, understanding long-COVID is essential to inform health and social care support. A Scottish population cohort of 33,281 laboratory-confirmed SARS-CoV-2 infections and 62,957 never-infected individuals were followed-up via 6, 12 and 18-month questionnaires and linkage to hospitalization and death records. Of the 31,486 symptomatic infections,1,856 (6%) had not recovered and 13,350 (42%) only partially. No recovery was associated with hospitalized infection, age, female sex, deprivation, respiratory disease, depression and multimorbidity. Previous symptomatic infection was associated with poorer quality of life, impairment across all daily activities and 24 persistent symptoms including breathlessness (OR 3.43, 95% CI 3.29–3.58), palpitations (OR 2.51, OR 2.36–2.66), chest pain (OR 2.09, 95% CI 1.96–2.23), and confusion (OR 2.92, 95% CI 2.78–3.07). Asymptomatic infection was not associated with adverse outcomes. Vaccination was associated with reduced risk of seven symptoms. Here we describe the nature of long-COVID and the factors associated with it.
200	MS198		Michael A. Horberg, Eric Watson, Mamta Bhatia, Celeena Jefferson, Julia M. Certa, Seohyun Kim, Lily Fathi, Keri N. Althoff, Carolyn Williams & Richard Moore	Post-acute sequelae of SARS-CoV-2 with clinical condition definitions and comparison in a matched cohort	https://doi.org/10.1038/s41467-022-33573-6	Published	12 October 2022	Study	https://www.nature.com/articles/s41467-022-33573-6	Disease characterization of Post-Acute Sequelae of SARS-CoV-2 (PASC) does not account for pre-existing conditions and time course of incidence. We utilized longitudinal data and matching to a COVID PCR-negative population to discriminate PASC conditions over time within our patient population during 2020. Clinical Classification Software was used to identify PASC condition groupings. Conditions were specified acute and persistent (occurring 0-30 days post COVID PCR and persisted 30–120 days post-test) or late (occurring initially 30-120 days post-test). We matched 3:1 COVID PCR-negative COVIDPCR-positive by age, sex, testing month and service area, controlling for pre-existing conditions up to four years prior; 28,118 PCR-positive to 70,293 PCR-negative patients resulted. We estimated PASC risk from the matched cohort. Risk of any PASC condition was 12% greater for PCR-positive patients in the late period with a significantly higher risk of anosmia, cardiac dysrhythmia, diabetes, genitourinary disorders, malaise, and nonspecific chest pain. Our findings contribute to a more refined PASC definition which can enhance clinical care.
201	MS199		KATHRYN W. HENDRICKSON JORIE BUTLER STEPHANIE C STOKES DANIELLE GROAT SAMUEL M BROWN HIRSHBERG ELLIOTTE	PATIENT-REPORTED EXPERIENCES WITH SARS-COV-2: A SURVEY STUDY EXAMINING ACUTE- AND LONG-TERM SYMPTOMS AND HOW THEY RELATE TO AREA OF HOSPITALIZATION AND LONG-TERM DISEASE	https://doi.org/10.1016/j.chest.2022.08.899	Published	October 01, 2022	Study	https://journal.chestnet.org/article/S0012-3692(22)02259-0/fulltext	SESSION TITLE: Post-COVID-19 Outcomes SESSION TYPE: Rapid Fire Original Inv PRESENTED ON: 10/19/2022 11:15 am - 12:15 pm PURPOSE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has caused an influx of hospitalized patients with acute disease, as well as an influx of outpatient visits for long-term symptoms. There is still much to learn about symptom patterns in different patient groups based on age, race, sex, and illness severity. Patients with post-acute COVID-19 syndrome (PACS), colloquially called long-haulers, are another group who may have unique symptom profiles. We conducted this study to characterize patients’ experiences with COVID-19 symptoms in both the acute and long-term phase. METHODS: Participants were recruited using existing research panel through Qualtrics, a national consumer insights platform. Eligible participants included those who reported a positive COVID-19 test sometime in 2021 and sought some type of medical care. In an online survey, participants were asked about the three most bothersome physical symptoms they experienced out of body aches or joint pain, “brain fog”, chest pain, cough, fatigue or feeling tired/weak, fever/chills/sweating, GI issues such as vomiting/diarrhea, headache, loss of taste or smell, shortness of breath, and insomnia. This list of physical symptoms was sourced by qualitative, in-depth interviews with 55 hospitalized and recovered COVID-19 patients. In addition, participants reported basic demographics, hospitalizations, and whether they considered themselves long-haulers. RESULTS: Of these patients, 29.8% considered themselves long-haulers. There were 2570 survey respondents who participated, of which 61% were female, 48% were male, and 1% were nonbinary. The patients were all age 18 years or older with 14% Hispanic/Latino/a/x/or Spanish origin, and 25% were non-white. Of those who sought medical treatment through a hospital, 59% reported that they sought treatment for COVID-19 in the emergency room, 32% were hospitalized, and 9% were hospitalized in the Intensive Care Unit (ICU). The most bothersome symptoms reported overall were cough, fatigue/feeling weak, and body aches. We compared bothersome symptoms by hospitalization location and long-haul status descriptively. For 18% of participants hospitalized in the ICU, the most bothersome symptom was shortness of breath compared to 11% of those hospitalized on the general floor, and 11% of those seen in the emergency room. Among participants who reported that they consider themselves long-haulers, the most common symptom reported most bothersome was cough. CONCLUSIONS: Data indicate that symptom patterns may differ by illness severity, age, and race. Patients who consider themselves long-haulers also have a different symptom pattern from those who do not report long-term symptoms. CLINICAL IMPLICATIONS: Our findings contribute to the understanding of patient experience with COVID-19 symptoms both in the acute and long-term phase.
202	MS200	ME	Frédérique Retornaz, Stanislas Rebaudet, Chloé Stavris & Yves Jammes	Long-term neuromuscular consequences of SARS-Cov-2 and their similarities with myalgic encephalomyelitis/chronic fatigue syndrome: results of the retrospective CoLGEM study	https://doi.org/10.1186/s12967-022-03638-7	Published	24 September 2022	Study	https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03638-7	Background Patients with long-COVID often complain of continuous fatigue, myalgia, sleep problems, cognitive dysfunction, and post-exertional malaise. No data are available on EMG recording of evoked myopotentials (M-waves) or exercise-induced alterations in long-COVID patients, providing evidence of muscle membrane fatigue. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) develops in more than half of patients after an infectious disease, particularly viral diseases. A large proportion (around 70%) of these patients have neuromuscular disorders with M-wave alterations during and after exercise. Our hypothesis was that M-wave alterations would be also found in long-COVID patients, in association with neuromuscular symptoms, similar to ME/CFS. Methods This retrospective observational ColGEM (Covid LonG Encéphalomyelite Myalgique) study compared 59 patients with long-COVID and 55 ME/CFS patients with a history of severe infection who presented before the COVID pandemic. All of these patients underwent the same protocol consisting of a questionnaire focusing on neural and neuromuscular disorders and M-wave recording in the rectus femoris muscle before, during, and 10 min after a progressive cycling exercise. Maximal handgrip strength (MHGS) and maximal exercise power were also measured. The frequency of symptoms and magnitude of M-wave changes in the two groups were compared using non-parametric and parametric tests. Results The frequency of fatigue, myalgia, sleep problems, cognitive dysfunction, and post-exertional malaise as well as the magnitude of exercise-induced M-wave alterations were the same in the two groups. By contrast, digestive problems were less present in long-COVID. M-wave alterations were greater in ME/CFS patients as in those with long-COVID when the highest muscle strength and highest exercise performance were measured. Conclusions These high clinical and biological similarities between long-COVID and ME/CFS support the hypothesis that SARS-Cov-2 infection can cause ME/CFS symptoms.
203	MS201		Arjun M C 1, Arvind Kumar Singh 1, Payel Roy 1, Mythry Ravichandran 1, Srijani Mandal 1, Debkumar Pal 1, Kajal Das 1, G Alekhya 1, Mahalingam Venkateshan 2, Baijayantimala Mishra 3, Binod Kumar Patro 1, Prasanta Raghab Mohapatra 4, Sonu Hangma Subba 1	Long COVID following Omicron wave in Eastern India - A retrospective cohort study	https://doi.org/10.1002/jmv.28214	Published	2022 Oct 12	Study	https://pubmed.ncbi.nlm.nih.gov/36224705/	Background and rationale: Long COVID or Post-acute sequelae of COVID-19 is widely reported but the data of Long COVID after infection with the Omicron variant is limited. This study was conducted to estimate the incidence, characteristics of symptoms and predictors of Long COVID among COVID-19 patients diagnosed during the Omicron wave in Eastern India. Methodology: The cohort of COVID-19 patients included were adults (≥18 years) diagnosed as SARS-CoV-2 positive with Reverse Transcription Polymerase Chain Reaction (RT-PCR). After 28 days of diagnosis; participants were followed up with a telephonic interview to capture data on sociodemographic, clinical history, anthropometry, substance use, COVID-19 vaccination status, acute COVID-19 symptoms, and Long COVID symptoms. The Long COVID symptoms were self-reported by the participants. Logistic regression was used to determine the predictors of Long COVID. Results: The median follow-up of participants was 73 days (Interquartile range (IQR); 67,83). The final analysis had 524 participants data; among them 8.2% (95% Confidence Interval (CI): 6%,10.9%) self-reported Long COVID symptoms. Fatigue (34.9%) was the most common reported symptom followed by cough (27.9%). In multivariable logistic regression only two predictors were statistically significant - number of acute COVID-19 symptoms ≥ five (Adjusted Odds ratio (aOR)=2.95, 95% CI:1.30,6.71) and past history of COVID-19 (aOR=2.66, 95% CI: 1.14,6.22). Conclusion: The proportion of self-reported Long COVID is considerably low among COVID-19 patients diagnosed during the Omicron wave in Eastern India, when compared to estimates during Delta wave in the same setting.
204	MS202		Roy H. Perlis, MD, MSc1,2; Mauricio Santillana, PhD3; Katherine Ognyanova, PhD4; Alauna Safarpour, PhD3,5; Kristin Lunz Trujillo, PhD3,5; Matthew D. Simonson, PhD6; Jon Green, PhD3; Alexi Quintana, BA3; James Druckman, PhD7; Matthew A. Baum, PhD5; David Lazer, PhD3	Prevalence and Correlates of Long COVID Symptoms Among US Adults	https://doi.org/10.1001/jamanetworkopen.2022.38804	Published	October 27, 2022	Study	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2797782	Key Points Question How common are COVID-19 symptoms lasting longer than 2 months, also known as long COVID, among adults in the United States, and which adults are most likely to experience long COVID? Findings In this cross-sectional study of more than 16 000 individuals, 15% of US adults with a prior positive COVID-19 test reported current symptoms of long COVID. Those who completed a primary vaccination series prior to infection were less likely to report long COVID symptoms. Meaning This study suggests that long COVID is prevalent and that the risk varies among individual subgroups in the United States; vaccination may reduce this risk. Abstract Importance - Persistence of COVID-19 symptoms beyond 2 months, or long COVID, is increasingly recognized as a common sequela of acute infection. Objectives To estimate the prevalence of and sociodemographic factors associated with long COVID and to identify whether the predominant variant at the time of infection and prior vaccination status are associated with differential risk. Design, Setting, and Participants - This cross-sectional study comprised 8 waves of a nonprobability internet survey conducted between February 5, 2021, and July 6, 2022, among individuals aged 18 years or older, inclusive of all 50 states and the District of Columbia. Main Outcomes and Measures - Long COVID, defined as reporting continued COVID-19 symptoms beyond 2 months after the initial month of symptoms, among individuals with self-reported positive results of a polymerase chain reaction test or antigen test. Results - The 16 091 survey respondents reporting test-confirmed COVID-19 illness at least 2 months prior had a mean age of 40.5 (15.2) years; 10 075 (62.6%) were women, and 6016 (37.4%) were men; 817 (5.1%) were Asian, 1826 (11.3%) were Black, 1546 (9.6%) were Hispanic, and 11 425 (71.0%) were White. From this cohort, 2359 individuals (14.7%) reported continued COVID-19 symptoms more than 2 months after acute illness. Reweighted to reflect national sociodemographic distributions, these individuals represented 13.9% of those who had tested positive for COVID-19, or 1.7% of US adults. In logistic regression models, older age per decade above 40 years (adjusted odds ratio [OR], 1.15; 95% CI, 1.12-1.19) and female gender (adjusted OR, 1.91; 95% CI, 1.73-2.13) were associated with greater risk of persistence of long COVID; individuals with a graduate education vs high school or less (adjusted OR, 0.67; 95% CI, 0.56-0.79) and urban vs rural residence (adjusted OR, 0.74; 95% CI, 0.64-0.86) were less likely to report persistence of long COVID. Compared with ancestral COVID-19, infection during periods when the Epsilon variant (OR, 0.81; 95% CI, 0.69-0.95) or the Omicron variant (OR, 0.77; 95% CI, 0.64-0.92) predominated in the US was associated with diminished likelihood of long COVID. Completion of the primary vaccine series prior to acute illness was associated with diminished risk for long COVID (OR, 0.72; 95% CI, 0.60-0.86). Conclusions and Relevance - This study suggests that long COVID is prevalent and associated with female gender and older age, while risk may be diminished by completion of primary vaccination series prior to infection.
205	MS203	ME	Nader Salari, Yassaman Khodayari, Amin Hosseinian-Far, Hosna Zarei, Shabnam Rasoulpoor, Hakimeh Akbari & Masoud Mohammadi	Global prevalence of chronic fatigue syndrome among long COVID-19 patients: A systematic review and meta-analysis	https://doi.org/10.1186/s13030-022-00250-5	Published	23 October 2022	Review and Meta-Analysis	https://bpsmedicine.biomedcentral.com/articles/10.1186/s13030-022-00250-5	Background Chronic fatigue syndrome is a persistent and debilitating disorder. According to several studies, chronic fatigue syndrome has been identified among recovered COVID-19 patients as the most common symptom of long COVID. The aim of this systematic review and meta-analysis study was to obtain the prevalence of chronic fatigue syndrome in long COVID cases. Methods In this systematic review and meta-analysis, we analysed reported results of studies that assessed the occurrence of chronic fatigue syndrome among COVID-19 patients four weeks after the onset of symptoms. The study selection was commenced by searching PubMed, Web of Science, Science Direct, Scopus, Embase, and Google scholar using the keywords of Chronic fatigue syndrome, COVID-19, and post-COVID-19 syndrome. The searches were without a lower time limit and until April 2022. Heterogeneity of studies was assessed using the I2 index, and a random effects model was used for analysis. Data analysis was performed within the Comprehensive Meta-Analysis software (version 2). Results The pooled prevalence of chronic fatigue syndrome four weeks after the onset of COVID-19 symptoms, in 52 studies with a sample size of 127,117, was 45.2% (95% CI: 34.1-56.9%). Meta-regression analysis in examining the effects of the two factors of sample size, and year of study on the changes in the overall prevalence, showed that with increasing sample size, and year of study, the prevalence of chronic fatigue syndrome among long COVID patients (p < 0.05). Conclusion Our results show that the overall prevalence of chronic fatigue syndrome as a long COVID symptom is 45.2%. Chronic fatigue after infection with COVID-19 can negatively affect personal and social lives. Given such significant negative consequences caused by the syndrome, it is recommended that health policymakers allocate funds to reduce the adverse effects of this syndrome, by creating programs to support long COVID patients.
206	MS204	ME	C. (Linda) M. C. van Campen * andFrans C. Visser	Orthostatic Intolerance in Long-Haul COVID after SARS-CoV-2: A Case-Control Comparison with Post-EBV and Insidious-Onset Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients	https://doi.org/10.3390/healthcare10102058	Published	17 October 2022	Study	https://www.mdpi.com/2227-9032/10/10/2058/htm	Background: As complaints of long-haul COVID patients are similar to those of ME/CFS patients and as orthostatic intolerance (OI) plays an important role in the COVID infection symptomatology, we compared 14 long-haul COVID patients with 14 ME/CFS patients with a post-viral Ebstein-Barr (EBV) onset and 14 ME/CFS patients with an insidious onset of the disease. Methods: In all patients, OI analysis by history taking and OI assessed during a tilt test, as well as cerebral blood flow measurements by extracranial Doppler, and cardiac index measurements by suprasternal Doppler during the tilt test were obtained in all patients. Results: Except for disease duration no differences were found in clinical characteristics. The prevalence of POTS was higher in the long-haul patients (100%) than in post-EBV (43%) and in insidious-onset (50%) patients (p = 0.0002). No differences between the three groups were present in the prevalence of OI, heart rate and blood pressure changes, changes in cerebral blood flow or in cardiac index during the tilt test. Conclusion: OI symptomatology and objective abnormalities of OI (abnormal cerebral blood flow and cardiac index reduction during tilt testing) are comparable to those in ME/CFS patients. It indicates that long-haul COVID is essentially the same disease as ME/CFS.
207	MS205		Juan C. Pacho-Hernández 1ORCID,César Fernández-de-las-Peñas 2,*ORCID,Stella Fuensalida-Novo 2ORCID,Carmen Jiménez-Antona 2,Ricardo Ortega-Santiago 2ORCID andMargarita Cigarán-Mendez 1	Sleep Quality Mediates the Effect of Sensitization-Associated Symptoms, Anxiety, and Depression on Quality of Life in Individuals with Post-COVID-19 Pain	https://doi.org/10.3390/brainsci12101363	Published	8 October 2022	Study	https://www.mdpi.com/2076-3425/12/10/1363/htm	A better understanding of biological and emotional variables associated with health-related quality of life in people with long-COVID is needed. Our aim was to identify potential direct and indirect effects on the relationships between sensitization-associated symptoms, mood disorders such as anxiety/depressive levels, and sleep quality on health-related quality of life in people suffering from post-COVID-19 pain. One hundred and forty-six individuals who were hospitalized due to COVID-19 during the first wave of the pandemic and suffering from long-term post-COVID-19 pain completed different patient-reported outcome measures (PROMs), including clinical features, symptoms associated with sensitization of the central nervous system (Central Sensitization Inventory), mood disorders (Hospital Anxiety and Depressive Scale), sleep quality (Pittsburgh Sleep Quality Index), and health-related quality of life (paper-based five-level version of EuroQol-5D) in a face-to-face interview conducted at 18.8 (SD 1.8) months after hospitalization. Different mediation models were conducted to assess the direct and indirect effects of the associations among the different variables. The mediation models revealed that sensitization-associated symptoms and depressive levels directly affected health-related quality of life; however, these effects were not statistically significant when sleep quality was included. In fact, the effect of sensitization-associated symptomatology on quality of life (β = −0.10, 95% CI −0.1736, −0.0373), the effect of depressive levels on quality of life (β= −0.09, 95% CI −0.1789, −0.0314), and the effect of anxiety levels on quality of life (β = −0.09, 95% CI −0.1648, −0.0337) were all indirectly mediated by sleep quality. This study revealed that sleep quality mediates the relationship between sensitization-associated symptoms and mood disorders (depressive/anxiety levels) with health-related quality of life in individuals who were hospitalized with COVID-19 at the first wave of the pandemic and reporting post-COVID-19 pain. Longitudinal studies will help to determine the clinical implications of these findings.
208	MS206		Endang Mutiawati 1,2,*,Hendrix Indra Kusuma 3,4,5ORCID,Marhami Fahriani 3,Harapan Harapan 3,6,7ORCID,Syahrul Syahrul 1,2 andNasrul Musadir 1,2	Headache in Post-COVID-19 Patients: Its Characteristics and Relationship with the Quality of Life	https://doi.org/10.3390/medicina58101500	Published	21 October 2022	Study	https://www.mdpi.com/1648-9144/58/10/1500/htm	Little is known on the characteristics of headaches associated with coronavirus disease 2019 (COVID-19) in Indonesia. The objective of this study was to describe the characteristics of headache in post-COVID-19 patients, and its impact on the patients’ quality of life (QoL), as well as to determine the associated determinants of the poor QoL. A cross-sectional study was conducted in Banda Aceh, Indonesia. The demographic characteristics, clinical symptoms of COVID-19, characteristics of headache, and the QoL were collected and assessed. Headache was diagnosed and characterized using the International Classification of Headache Disorders, version 3 (ICHD-3). QoL was assessed using a Short Form 36 Health Survey (SF-36) tool. A logistic regression model was used to investigate the associated determinants of poor QoL in post-COVID-19 patients. A total of 215 post-COVID-19 patients were included in the final analysis, and 21.4% (46/215) of them had a poor QoL due to headache following COVID-19. Those who were unemployed and who contracted COVID-19 less than three months prior to the study had higher odds of having poor QoL compared to those who were employed and who contracted COVID-19 more than three months prior to the study. Low QoL was also related to headache that occurred less than one month after recovering from COVID-19 (compared to that which occurred longer than one month after); had a high frequency; had a combination sensation of pulsating, pressing, fiery, and stabbing pain; had a high severity score; and had additional symptoms accompanying the headache. In conclusion, headache related to COVID-19 is associated with low QoL among post-COVID-19 patients. A guideline on prevention measures of headache on COVID-19 patients, therefore, needs to be established to avoid long-term consequences.
209	MS207	ME	C. (Linda) M. C. van Campen * andFrans C. Visser	Orthostatic Intolerance in Long-Haul COVID after SARS-CoV-2: A Case-Control Comparison with Post-EBV and Insidious-Onset Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients	https://doi.org/10.3390/healthcare10102058	Published	17 October 2022	Study	https://www.mdpi.com/2227-9032/10/10/2058/htm	Background: As complaints of long-haul COVID patients are similar to those of ME/CFS patients and as orthostatic intolerance (OI) plays an important role in the COVID infection symptomatology, we compared 14 long-haul COVID patients with 14 ME/CFS patients with a post-viral Ebstein-Barr (EBV) onset and 14 ME/CFS patients with an insidious onset of the disease. Methods: In all patients, OI analysis by history taking and OI assessed during a tilt test, as well as cerebral blood flow measurements by extracranial Doppler, and cardiac index measurements by suprasternal Doppler during the tilt test were obtained in all patients. Results: Except for disease duration no differences were found in clinical characteristics. The prevalence of POTS was higher in the long-haul patients (100%) than in post-EBV (43%) and in insidious-onset (50%) patients (p = 0.0002). No differences between the three groups were present in the prevalence of OI, heart rate and blood pressure changes, changes in cerebral blood flow or in cardiac index during the tilt test. Conclusion: OI symptomatology and objective abnormalities of OI (abnormal cerebral blood flow and cardiac index reduction during tilt testing) are comparable to those in ME/CFS patients. It indicates that long-haul COVID is essentially the same disease as ME/CFS.
210	MS208		Limor Adler,Sivan Gazit,Yuval Pinto,Galit Perez,Miri Mizrahi Reuveni,Ilan Yehoshua,Robert Hoffman,Joseph Azuri &Tal Patalon	Long-COVID in patients with a history of mild or asymptomatic SARS-CoV-2 infection: a Nationwide Cohort Study	https://doi.org/10.1080/02813432.2022.2139480	Published	31 Oct 2022	Study	https://www.tandfonline.com/doi/full/10.1080/02813432.2022.2139480	Objective Evaluating the prevalence of long-COVID symptoms in patients with a history of mild or asymptomatic infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and the factors associated with developing long-COVID. Design A nationwide cohort study. Using a centralized database, we have identified patients with and without a history of SARS-CoV-2 infection 1–6 months before data collection. Patients were asked to fill out an online questionnaire through text messages. Setting Israeli general practice. Subjects 2755 persons participated in the study in September 2021 (a response rate of 7.5%): 819 with and ,936 without a history of SARS-CoV-2 infection. Main outcome measures We asked patients to provide details about their demographic status, medical history, COVID-related variables and the presence of long-COVID symptoms. Results Most prevalent long-COVID symptoms were decreased smell sensation (35.1% vs. 4.3%, p < 0.001), decreased taste sensation (25.2% vs. 3.2%, p < 0.001), memory disturbances (36.9% vs. 14.4%, p < 0.001), dyspnea (24.2% vs. 10.7%, p < 0.001) and arthralgia (33% vs. 16.3%, p < 0.001). Risk factors associated with long-COVID included female gender, symptomatic COVID-19, overweight or obesity and the presence of dyslipidemia. About 34.6% of participants reported not returning to their baseline health condition after the acute illness. Conclusion Long-COVID is frequently seen following a mild symptomatic COVID-19 infection and, to a lesser extent, following an asymptomatic SARS-CoV-2 infection. Primary care physicians should be aware of these symptoms and consider this option in their differential diagnosis. Health policymakers should expect a significant impact of this syndrome on public health. Key Points Long-COVID has emerged as a significant health problem with a serious impact on normal daily function • Long-COVID symptoms were evident in patients with mild symptomatic disease and in asymptomatic patients to a lesser extent. • Risk factors for having Long-COVID symptoms include female gender, symptomatic disease, increased BMI, and the presence of dyslipidemia. • Fatigue, dyspnea, weakness, decreased libido, weight changes, memory, and sleep disturbances were associated with not returning to the baseline health state.
211	MS209		Coen C.W.G. Bongers,Esmée A. Bakker,Laurien M. Buffart &Maria T.E. Hopman	Impact of a COVID-19 infection on exercise levels of recreational athletes one- and three-months post-infection	https://doi.org/10.1080/02640414.2022.2140919	Published	29 Oct 2022	Study	https://www.tandfonline.com/doi/abs/10.1080/02640414.2022.2140919	We examined the effect of a COVID-19 infection on changes in exercise levels in recreational athletes in the first three months after infection, and identified personal factors associated with a larger change in exercise level and recovery time. Recreational athletes (n=4360) completed an online questionnaire on health and exercise levels. 601 Athletes have had a diagnostically confirmed COVID-19 infection, while 3479 athletes did not (non-COVID-19 group). Exercise levels (in MET-min/week) were examined prior to (2019) and during the COVID-19 pandemic (2020) for the non-COVID-19 group, and in 2019, 1-month pre-COVID-19 infection, 1-month post-COVID-19 infection and 3 months post-COVID-19 infection in the COVID-19 group. Median exercise level at baseline in the COVID-19 group was 3528 (IQR=1488–5760) MET-min/week. One-month post-COVID-19 infection, exercise level dropped 58% (2038 MET-min/week), which partly stabilized to 36% (1256 MET-min/week) below baseline values 3 months post-COVID-19 infection. Moreover, in both the COVID-19 (pre-COVID-19 infection) and non-COVID-19 group exercise levels during the pandemic decreased with ~260 MET-min/week. These results illustrate that even a relatively physically active population of recreational athletes is significantly affected by a COVID-19 infection, particularly those athletes who are overweight. COVID-19 disease burden, age, sex, comorbidities and smoking were not associated with reduced exercise levels.
212	MS210		Anouk Verveen, Elke Wynberg, Hugo D. G. van Willigen, Udi Davidovich, Anja Lok, Eric P. Moll van Charante, Menno D. de Jong, Godelieve de Bree, Maria Prins, Hans Knoop, Pythia T. Nieuwkerk & the RECoVERED Study Group	Health-related quality of life among persons with initial mild, moderate, and severe or critical COVID-19 at 1 and 12 months after infection: a prospective cohort study	https://doi.org/10.1186/s12916-022-02615-7	Published	02 November 2022	Study	https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-022-02615-7	Background Currently, there is limited evidence about the long-term impact on physical, social and emotional functioning, i.e. health-related quality of life (HRQL) after mild or moderate COVID-19 not requiring hospitalization. We compared HRQL among persons with initial mild, moderate or severe/critical COVID-19 at 1 and 12 months following illness onset with Dutch population norms and investigated the impact of restrictive public health control measures on HRQL. Methods RECoVERED, a prospective cohort study in Amsterdam, the Netherlands, enrolled adult participants after confirmed SARS-CoV-2 diagnosis. HRQL was assessed with the Medical Outcomes Study Short Form 36-item health survey (SF-36). SF-36 scores were converted to standard scores based on an age- and sex-matched representative reference sample of the Dutch population. Differences in HRQL over time were compared among persons with initial mild, moderate or severe/critical COVID-19 using mixed linear models adjusted for potential confounders. Results By December 2021, 349 persons were enrolled of whom 269 completed at least one SF-36 form (77%). One month after illness onset, HRQL was significantly below population norms on all SF-36 domains except general health and bodily pain among persons with mild COVID-19. After 12 months, persons with mild COVID-19 had HRQL within population norms, whereas persons with moderate or severe/critical COVID-19 had HRQL below population norms on more than half of the SF-36 domains. Dutch-origin participants had significantly better HRQL than participants with a migration background. Participants with three or more COVID-19 high-risk comorbidities had worse HRQL than part participants with fewer comorbidities. Participants who completed the SF-36 when restrictive public health control measures applied reported less limitations in social and physical functioning and less impaired mental health than participants who completed the SF-36 when no restrictive measures applied. Conclusions Twelve months after illness onset, persons with initial mild COVID-19 had HRQL within population norms, whereas persons with initial moderate or severe/critical COVID-19 still had impaired HRQL. Having a migration background and a higher number of COVID-19 high-risk comorbidities were associated with worse HRQL. Interestingly, HRQL was less impaired during periods when restrictive public health control measures were in place compared to periods without.
213	MS211		Lars Heubner, Paul Leon Petrick, Andreas Güldner, Lea Bartels, Maximillian Ragaller, Martin Mirus, Axel Rand, Oliver Tiebel, Jan Beyer-Westendorf, Martin Rößler, Jochen Schmitt, Thea Koch & Peter Markus Spieth	Extreme obesity is a strong predictor for in-hospital mortality and the prevalence of long-COVID in severe COVID-19 patients with acute respiratory distress syndrome	https://doi.org/10.1038/s41598-022-22107-1	Published	01 November 2022	Study	https://www.nature.com/articles/s41598-022-22107-1	Acute Respiratory Distress Syndrome (ARDS) is common in COVID-19 patients and is associated with high mortality. The aim of this observational study was to describe patients’ characteristics and outcome, identifying potential risk factors for in-hospital mortality and for developing Long-COVID symptoms. This retrospective study included all patients with COVID-19 associated ARDS (cARDS) in the period from March 2020 to March 2021 who were invasively ventilated at the intensive care unit (ICU) of the University Hospital Dresden, Germany. Between October 2021 and December 2021 patients discharged alive (at minimum 6 months after hospital discharge—midterm survival) were contacted and interviewed about persistent symptoms possibly associated with COVID-19 as well as the quality of their lives using the EQ-5D-5L-questionnaire. Long-COVID was defined as the occurrence of one of the symptoms at least 6 months after discharge. Risk factors for mortality were assessed with Cox regression models and risk factors for developing Long-COVID symptoms by using relative risk (RR) regression. 184 Patients were included in this study (male: n = 134 (73%), median age 67 (range 25–92). All patients were diagnosed with ARDS according to the Berlin Definition. 89% of patients (n = 164) had severe ARDS (Horovitz-index < 100 mmHg). In 27% (n = 49) extracorporeal membrane oxygenation was necessary to maintain gas exchange. The median length of in-hospital stay was 19 days (range 1–60). ICU mortality was 51%, hospital mortality 59%. Midterm survival (median 11 months) was 83% (n = 55) and 78% (n = 43) of these patients presented Long-COVID symptoms with fatigue as the most common symptom (70%). Extreme obesity (BMI > 40 kg/m2) was the strongest predictor for in-hospital mortality (hazard ratio: 3.147, confidence interval 1.000–9.897) and for developing Long-COVID symptoms (RR 1.61, confidence interval 1.26–2.06). In-hospital mortality in severe cARDS patients was high, but > 80% of patients discharged alive survived the midterm observation period. Nonetheless, most patients developed Long-COVID symptoms. Extreme obesity with BMI > 40 kg/m2 was identified as independent risk factor for in-hospital mortality and for developing Long-COVID symptoms.
214	MS212		Mayssam Nehme MD, Francois Chappuis MD, PhD, Laurent Kaiser MD, PhD, Frederic Assal MD, PhD & Idris Guessous MD, PhD	The Prevalence, Severity, and Impact of Post-COVID Persistent Fatigue, Post-Exertional Malaise, and Chronic Fatigue Syndrome	https://doi.org/10.1007/s11606-022-07882-x	Published	10 November 2022	Study	https://link.springer.com/article/10.1007/s11606-022-07882-x	Fatigue is the most common and persistent post-COVID symptom. The spectrum of fatigue severity in post-COVID individuals ranges from feeling tired to having severe fatigue, post-exertional malaise, or criteria for chronic fatigue syndrome with an increasing impact on health, functional capacity, and physical activity. Almost half of individuals experiencing fatigue at 6 months after the infection had post-exertional malaise, and 6.2% had criteria for chronic fatigue syndrome, prompting physicians to consider pacing as a management option, in the absence of other treatment options at this stage. SARS-CoV-2 infection was positively associated with fatigue and post-exertional malaise. Results showed that individuals with fatigue were more likely to be vaccinated. This was partially explained by the baseline distribution as older individuals and those with more comorbidities were more likely to get vaccinated. Results compare to recent reviews showing an overlap between post-COVID condition and chronic fatigue syndrome.6 Our study graded post-COVID fatigue by severity in correlation with functional capacity, and showed the high prevalence of post-exertional malaise.
215	MS213		Olivier Robineau, MD, PhD1,2; Marie Zins, MD, PhD3; Mathilde Touvier, MD, PhD4; Emmanuel Wiernik, PhD3; Cedric Lemogne, MD, PhD5; Xavier de Lamballerie, MD, PhD6; Hélène Blanché, PhD7; Jean-François Deleuze, PhD7; Paola Mariela Saba Villarroel, PhD6; Céline Dorival, PhD1; Jerome Nicol, PhD1; Roselyn Gomes-Rima, MPH8; Emmanuelle Correia, PhD8; Mireille Coeuret-Pellicer, MD, MPH3; Nathalie Druesne-Pecollo, PhD4; Younes Esseddik, PhD4; Céline Ribet, PhD3; Marcel Goldberg, MD, PhD3; Gianluca Severi, PhD8,9; Fabrice Carrat, MD, PhD1,10	Long-lasting Symptoms After an Acute COVID-19 Infection and Factors Associated With Their Resolution	https://doi.org/10.1001/jamanetworkopen.2022.40985	Published	November 9, 2022	Study	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2798224	Key Points Question What is the duration of persistent symptoms after SARS-CoV-2 infection, and what factors are associated with their resolution? Findings This cross-sectional study nested in 3 French population-based cohorts found that approximately 10% of individuals with acute COVID-19 infection still had symptoms after 1 year of follow-up. The risk factors associated with the duration of these symptoms vary depending on their persistence. Meaning This study suggests that persistent symptoms after SARS-CoV-2 infection is a public health concern. Abstract Importance - Persistent symptoms after SARS-CoV-2 infection are an emerging public health problem. The duration of these symptoms remains poorly documented. Objective - To describe the temporal dynamics of persistent symptoms after SARS-CoV-2 infection and the factors associated with their resolution. Design, Setting, and Participants - This cross-sectional study involved 53 047 participants from 3 French adult population-based cohorts (CONSTANCES [Consultants des Centres d’Examens de Santé], E3N/E4N, and Nutrinet-Santé) who were included in a nationwide survey about SARS-CoV-2 infection. All participants were asked to complete self-administered questionnaires between April 1 and June 30, 2020. Variables included sociodemographic characteristics, comorbid conditions, COVID-19 diagnosis, and acute symptoms. Blood samples were obtained for serologic analysis between May 1 and November 30, 2020, from patients with SARS-CoV-2 infection defined as enzyme-linked immunosorbent assay immunoglobulin G antispike detection confirmed with a neutralization assay. A follow-up internet questionnaire was completed between June 1 and September 30, 2021, with details on persistent symptoms, their duration, and SARS-CoV-2 infection diagnosis by polymerase chain reaction. Main Outcomes and Measures - Persistent symptoms were defined as symptoms occurring during the acute infection and lasting 2 or more months. Survival models for interval-censored data were used to estimate symptom duration from the acute episode. Multivariable adjusted hazard ratios (HRs) were estimated for age, sex, and comorbid conditions. Factors associated with the resolution of symptoms were assessed. Results - A total of 3972 participants (2531 women [63.7%; 95% CI, 62.2%-65.2%]; mean [SD] age, 50.9 [12.7] years) had been infected with SARS-CoV-2. Of these 3972 participants, 2647 (66.6% [95% CI, 65.1%-68.1%]) reported at least 1 symptom during the acute phase. Of these 2647 participants, 861 (32.5% [95% CI, 30.8%-34.3%]) reported at least 1 persistent symptom lasting 2 or more months after the acute phase. After 1 year of follow-up, the estimated proportion of individuals with complete symptom resolution was 89.9% (95% CI, 88.7%-90.9%) with acute symptoms. Older age (>60 years; HR, 0.78; 95% CI, 0.68-0.90), female sex (HR, 0.64; 95% CI, 0.58-0.70), history of cancer (HR, 0.61; 95% CI, 0.47-0.79), history of tobacco consumption (HR, 0.80; 95% CI, 0.73-0.88), high body mass index (≥30: HR, 0.75; 95% CI, 0.63-0.89), and high number of symptoms during the acute phase (>4; HR, 0.43; 95% CI, 0.39-0.48) were associated with a slower resolution of symptoms. Conclusions and Relevance - In this cross-sectional study, persistent symptoms were still present in 10.1% of infected individuals at 1 year after SARS-CoV-2 infection. Given the high level of cumulative incidence of COVID-19, the absolute prevalent number of people with persistent symptoms is a public health concern.
216	MS214		Mirembe Woodrow, Charles Carey, Nida Ziauddeen, Rebecca Thomas, Athena Akrami, Vittoria Lutje, Darren C Greenwood, Nisreen A Alwan	Systematic review of the prevalence of Long Covid	https://www.medrxiv.org/content/10.1101/2022.11.06.22281979v1.full-text	pre-print	November 07, 2022	Systematic review	https://www.medrxiv.org/content/10.1101/2022.11.06.22281979v1	Background Long Covid occurs in those infected with SARSCoV2 whose symptoms persist or develop beyond the acute phase. We conducted a systematic review to determine the prevalence of persistent symptoms, functional disability or pathological changes in adults or children at least 12 weeks post-infection. Methods We searched MEDLINE (Ovid), Embase (OVID), the Cochrane Covid-19 Study register, WHO ICTRP, medRxiv, Cochrane CENTRAL, MEDLINE (PubMed), ClinicalTrials.gov, and the WHO Global research on coronavirus disease (COVID-19) database from 1st January 2020 to 2nd November 2021, limited to publications in English. We included studies with at least 100 participants. Studies where all participants were critically ill were excluded. Articles were screened independently by two reviewers, with disagreements resolved by a third. Long Covid (primary outcome) was extracted as prevalence of at least one symptom or pathology, or prevalence of the most common symptom or pathology, at 12 weeks or later. Heterogeneity was quantified in absolute terms and as a proportion of total variation and explored across pre-defined subgroups (PROSPERO ID CRD42020218351). Findings In total 120 studies in 130 publications were included. Length of follow-up varied from 12 weeks to over 12 months. Few studies had low risk of bias. All complete and subgroup analyses except one had I2 ≥ 90%, with prevalence of persistent symptoms ranging between 0% and 93%. Studies using routine healthcare records tended to report lower prevalence of persistent symptoms/pathology than self-report. However, studies systematically investigating pathology in all participants at follow up tended to report the highest estimates of all three. Studies of hospitalised cases had generally higher estimates than community-based studies. Interpretation The way in which Long Covid is defined and measured affects prevalence estimation. Given the widespread nature of SARSCoV2 infection globally, the burden of chronic illness is likely to be substantial even using the most conservative estimates. Funding this systematic review received no specific funding. Evidence before this study The chronic effects of COVID19 were accounted for in relation to the health, social and economic impacts at the start of the pandemic in 2020. Long Covid is now established as a serious outcome of infection with SARSCoV2 that influences the daily lives of many. To estimate the population-level burden, the prevalence of prolonged health effects from SARSCoV2 infection needs to be quantified. We conducted a systematic review of published studies to determine the prevalence of persistent symptoms, functional disability or pathological changes in adults or children at least 12 weeks post-infection. Added value of this study We included 120 studies assessing Long Covid symptoms, functional status, or pathology published up to November 2021. There was significant heterogeneity between studies and wide variation in Long Covid prevalence estimates ranging between 0-93%. This is due to differences in Long Covid definition, required threshold of severity or impact on daily activities, study designs, sources of study samples, how the initial infection was defined, number of assessed symptoms and method of assessment. Despite large between-study heterogeneity, the studies with lowest risk of bias estimated prevalence between 3% and 37%. For studies that included comparison of cases to controls, there were significant methodological considerations to the choice of control groups including difficulty ascertaining the absence of exposure (SARSCoV2 infection). The review search timeline meant Long Covid prevalence in vaccinated populations could not be assessed. Implication of all the available evidence Even with the most conservative estimates of prevalence among those infected, the chronic disease burden generated by SARSCoV2 infection seems substantial, particularly in countries where community transmission of SARSCoV2 is high.
217	MS215		Sonja H.Brunvoll1aAnders B.Nygaard1aMorten W.Fagerland2PetterHolland1MereteEllingjord-Dale1John ArneDahl1ArneSøraas1	Post-acute symptoms 3-15 months after COVID-19 among unvaccinated and vaccinated individuals with a breakthrough infection	https://doi.org/10.1016/j.ijid.2022.11.009	Published	12 November 2022	Study	https://www.sciencedirect.com/science/article/pii/S1201971222005963	Highlights •More symptoms in SARS-CoV-2 positive than negative participants ≥3 months post-COVID •Most symptoms no different between vaccinated and unvaccinated positive participants •No difference in EMQ-13 score comparing vaccinated to unvaccinated participants •Less memory problems were reported among vaccinated than unvaccinated participants Abstract Objectives We aimed to describe post-acute sequelae of SARS-CoV-2 infection (PASC) related symptoms 3-15 months after a positive test in SARS-CoV-2 unvaccinated and vaccinated participants with a breakthrough infection. Methods Participants of the Norwegian COVID-19 Cohort, without a positive SARS-CoV-2 test, filled in a questionnaire asking about PASC-related symptoms between November 2020 and January 2021. About a year later, a second questionnaire (which also included the Everyday Memory Questionnaire 13 (EMQ-13)) was filled in by the same participants, most still without a positive SARS-CoV-2 test, but also by unvaccinated and vaccinated participants with a positive test 3-15 months before the questionnaire. Laboratory-confirmed SARS-CoV-2 status (positive or negative swab test determined by reverse transcriptase quantitative polymerase chain reaction) at the time of completing questionnaires was ascertained from the Mandatory Norwegian Surveillance System for Communicable Diseases. Results No differences were found in the self-reported PASC-symptoms dyspnea, fatigue, smell/taste changes or concentration problems, or the EMQ-13 score between unvaccinated and vaccinated participants 3-15 months after the positive test. Less memory problems were reported among vaccinated than unvaccinated participants. Conclusions SARS-CoV-2 vaccines offer minor protection against PASC-symptoms, although less memory problems were reported among the vaccinated than the unvaccinated participants.
218	MS216		Emre Dirican Open the ORCID record for Emre Dirican[Opens in a new window] and Tayibe Bal	COVID-19 disease severity to predict persistent symptoms: a systematic review and meta-analysis	https://doi.org/10.1017/S1463423622000585	Published	10 November 2022	Systematic Review and Meta-Analysis	https://www.cambridge.org/core/journals/primary-health-care-research-and-development/article/covid19-disease-severity-to-predict-persistent-symptoms-a-systematic-review-and-metaanalysis/479FC1E900E22673895FDAC1CF5C12B2	Background: It is unclear, whether the initial disease severity may help to predict which COVID-19 patients at risk of developing persistent symptoms. Aim: The aim of this study was to examine whether the initial disease severity affects the risk of persistent symptoms in post-acute COVID-19 syndrome and long COVID. Methods: A systematic search was conducted using PUBMED, Google Scholar, EMBASE, and ProQuest databases to identify eligible articles published after January 2020 up to and including 30 August 2021. Pooled odds ratio (OR) and confidence intervals (CIs) were calculated using random effects meta-analysis. Findings: After searching a total of 7733 articles, 20 relevant observational studies with a total of 7840 patients were selected for meta-analysis. The pooled OR for persistent dyspnea in COVID-19 survivors with a severe versus nonsevere initial disease was 2.17 [95%CI 1.62 to 2.90], and it was 1.33 [95%CI 0.75 to 2.33] for persistent cough, 1.30 [95%CI 1.06 to 1.58] for persistent fatigue, 1.02 [95%CI 0.73 to 1.40] for persistent anosmia, 1.22 [95%CI 0.69 to 2.16] for persistent chest pain, and 1.30 [95%CI 0.93 to 1.81] for persistent palpitation. Conclusions: Contrary to expectations, we did not observe an association between the initial COVID-19 disease severity and common persistent symptoms except for dyspnea and fatigue. In addition, it was found that being in the acute or prolonged post-COVID phase did not affect the risk of symptoms. Primary care providers should be alert to potential most prevalent persistent symptoms in all COVID-19 survivors, which are not limited to patients with critical–severe initial disease.
219	MS217		César Fernández-de-las-Peñas, PT, PhD1; Jorge Rodríguez-Jiménez, PT, MSc1; Ignacio Cancela-Cilleruelo, PT, MSc1; Angel Guerrero-Peral, MD, PhD2,3; José D. Martín-Guerrero, PhD4; David García-Azorín, MD, PhD2; Ana Cornejo-Mazzuchelli, MD5; Valentín Hernández-Barrera, PhD6; Oscar J. Pellicer-Valero, PhD4*	Post–COVID-19 Symptoms 2 Years After SARS-CoV-2 Infection Among Hospitalized vs Nonhospitalized Patients	https://doi.org/10.1001/jamanetworkopen.2022.42106	Published	November 15, 2022	Study	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2798446	Key Points Question What is the prevalence of post–COVID-19 symptoms among hospitalized and nonhospitalized patients 2 years after acute infection? Findings This cross-sectional study found that the proportion of patients with at least 1 post–COVID-19 symptom 2 years after acute infection was 59.7% for hospitalized patients and 67.5% for those not requiring hospitalization. No significant differences in post–COVID-19 symptoms were seen between hospitalized and nonhospitalized patients. Meaning Similar rates of post–COVID-19 symptoms between hospitalized and nonhospitalized patients suggest that, among all patients who contract COVID-19, these sequelae deserve attention. Abstract Importance Identification of long-term post–COVID-19 symptoms among hospitalized and nonhospitalized patients is needed. Objective To compare the presence of post–COVID-19 symptoms 2 years after acute SARS-CoV-2 infection between hospitalized and nonhospitalized patients. Design, Setting, and Participants A cross-sectional cohort study was conducted at 2 urban hospitals and general practitioner centers from March 20 to April 30, 2020, among 360 hospitalized patients and 308 nonhospitalized patients with acute SARS-CoV-2 infection during the first wave of the pandemic. Follow-up was conducted 2 years later. Main Outcomes and Measures Participants were scheduled for a telephone interview 2 years after acute infection. The presence of post–COVID-19 symptoms was systematically assessed, with particular attention to symptoms starting after infection. Hospitalization and clinical data were collected from medical records. Between-group comparisons and multivariate logistic regressions were conducted. Results A total of 360 hospitalized patients (162 women [45.0%]; mean [SD] age, 60.7 [16.1] years) and 308 nonhospitalized patients (183 women [59.4%]; mean [SD] age, 56.7 [14.7] years) were included. Dyspnea was more prevalent at the onset of illness among hospitalized than among nonhospitalized patients (112 [31.1%] vs 36 [11.7%]; P < .001), whereas anosmia was more prevalent among nonhospitalized than among hospitalized patients (66 [21.4%] vs 36 [10.0%]; P = .003). Hospitalized patients were assessed at a mean (SD) of 23.8 (0.6) months after hospital discharge, and nonhospitalized patients were assessed at a mean (SD) of 23.4 (0.7) months after the onset of symptoms. The number of patients who exhibited at least 1 post–COVID-19 symptom 2 years after infection was 215 (59.7%) among hospitalized patients and 208 (67.5%) among nonhospitalized patients (P = .01). Among hospitalized and nonhospitalized patients, fatigue (161 [44.7%] vs 147 [47.7%]), pain (129 [35.8%] vs 92 [29.9%]), and memory loss (72 [20.0%] vs 49 [15.9%]) were the most prevalent post–COVID-19 symptoms 2 years after SARS-CoV-2 infection. No significant differences in post–COVID-19 symptoms were observed between hospitalized and nonhospitalized patients. The number of preexisting medical comorbidities was associated with post–COVID-19 fatigue (odds ratio [OR], 1.93; 95% CI, 1.09-3.42; P = .02) and dyspnea (OR, 1.91; 95% CI, 1.04-3.48; P = .03) among hospitalized patients. The number of preexisting medical comorbidities (OR, 3.75; 95% CI, 1.67-8.42; P = .001) and the number of symptoms at the onset of illness (OR, 3.84; 95% CI, 1.33-11.05; P = .01) were associated with post–COVID-19 fatigue among nonhospitalized patients. Conclusions and Relevance This cross-sectional study suggested the presence of at least 1 post–COVID-19 symptom in 59.7% of hospitalized patients and 67.5% of nonhospitalized patients 2 years after infection. Small differences in symptoms at onset of COVID-19 were identified between hospitalized and nonhospitalized patients. Post–COVID-19 symptoms were similar between hospitalized and nonhospitalized patients; however, lack of inclusion of uninfected controls limits the ability to assess the association of SARS-CoV-2 infection with overall and specific post–COVID-19 symptoms 2 years after acute infection. Future studies should include uninfected control populations.
220	MS218		Mohammed Samannodi 1,Hassan Alwafi 2,3,Abdallah Y. Naser 4ORCID,Abdullah A. Al Qurashi 5,6,Jumanah T. Qedair 5,6,Emad Salawati 7ORCID,Mohammed A. Almatrafi 8,Rakan Ekram 9,Rahaf I. Bukhari 2,Maryam Dahlawi 2ORCID,Bayan Hafiz 2,Roaa Mandora 2,Ranin K. Alsindi 2,Sarah Tayeb 10 andFaisal Minshawi 11,*ORCID	Determinants of Post-COVID-19 Conditions among SARS-CoV-2-Infected Patients in Saudi Arabia: A Web-Based Cross-Sectional Study	https://doi.org/10.3390/diseases10030055	Published	23 August 2022	Study	https://www.mdpi.com/2079-9721/10/3/55/htm	Background: Large numbers of people infected with COVID-19 developed acute symptoms. Post-COVID-19 conditions have been reported after recovery or discharge from the hospital. However, little is known about the prevalence and possible risk factors of post-COVID-19 conditions in the Saudi community. Here, we describe the incidence of post-COVID-19 conditions among the general population of Saudi Arabia. Methods: We conducted a cross-sectional, nationwide study using an online survey in Saudi Arabia from 1 September 2021 to 28 February 2022. The survey was distributed using social media platforms, such as Twitter, WhatsApp, and Facebook. Patients with SARS-CoV-2 infection were included in the questionnaire adapted from published studies. Result: The study enrolled 7520 individuals who were previously infected with SARS-CoV-2. Most patients in our study were symptomatic and their acute symptoms may persist for more than six days. On the other hand, long-term complications may develop and continue for an extended period (post-COVID-19 conditions). Most of these complications are respiratory, neurological, psychological, or skin related. The proportion of long-term complications reported in this study is 36% among SARS-CoV-2-infected individuals. In addition, being female, old age, number of chronic complications, long-term medication, length of stay in hospital and intensive care unit, and duration of acute symptoms may be significant predictors of post-COVID-19 symptoms. Conclusion: In conclusion, the incidence of post-COVID-19 conditions among the Saudi population was high, which urges further investigation into the risk factors associated with post-COVID-19 symptoms.
221	MS219		Mayssam Nehme MD, Francois Chappuis MD, PhD, Laurent Kaiser MD, PhD, Frederic Assal MD, PhD & Idris Guessous MD, PhD	The Prevalence, Severity, and Impact of Post-COVID Persistent Fatigue, Post-Exertional Malaise, and Chronic Fatigue Syndrome	https://doi.org/10.1007/s11606-022-07882-x	Published	10 November 2022	Study	https://link.springer.com/article/10.1007/s11606-022-07882-x	Overall, 5515 individuals participated in this study (response rate 70.7%), with 5406 participants at 6 months or more after their test date. A total of 1497 (27.7%) participants had a documented positive SARS-CoV-2 test and were ultimately included in the study. The median time for follow-up was 225 days (interquartile range 207–398). Respectively, fatigue was reported by 17.2%, post-exertional malaise by 8.2%, and the presence of criteria for chronic fatigue syndrome by 1.1% of SARS-CoV-2-positive individuals, compared to 8.9%, 3.5%, and 0.5% of SARS-CoV-2-negative individuals. Characteristics are presented in Table 1. Out of SARS-CoV-2-positive participants with fatigue (n = 258), 35.3% had moderate to severe limitations on the ECOG scale, and 83.0% had a score ≥ 4 on the Chalder fatigue scale. The Chalder fatigue scale revealed a mean score of 19 out of 33, SD 5.4, and a mean score of 6.7 out of 11, SD 3.3 using bimodal scoring. After adjusting for age and sex, 47.7% of SARS-CoV-2-positive individuals with fatigue at 6 months or more had the frequency and severity criteria for post-exertional malaise, and 6.2% had criteria for chronic fatigue syndrome. Individuals had a higher prevalence of insomnia, cognitive impairment, headaches, generalized pain, functional impairment, reduced work capacity, and decreased physical activity, after SARS-CoV-2 infection. The prevalence of these sequelae was adjusted for age and sex and was increasingly higher with severe fatigue, with post-exertional malaise, or when criteria for chronic fatigue syndrome were present (Fig. 1). Fatigue is the most common and persistent post-COVID symptom. The spectrum of fatigue severity in post-COVID individuals ranges from feeling tired to having severe fatigue, post-exertional malaise, or criteria for chronic fatigue syndrome with an increasing impact on health, functional capacity, and physical activity. Almost half of individuals experiencing fatigue at 6 months after the infection had post-exertional malaise, and 6.2% had criteria for chronic fatigue syndrome, prompting physicians to consider pacing as a management option, in the absence of other treatment options at this stage. SARS-CoV-2 infection was positively associated with fatigue and post-exertional malaise. Results showed that individuals with fatigue were more likely to be vaccinated. This was partially explained by the baseline distribution as older individuals and those with more comorbidities were more likely to get vaccinated. Results compare to recent reviews showing an overlap between post-COVID condition and chronic fatigue syndrome.6 Our study graded post-COVID fatigue by severity in correlation with functional capacity, and showed the high prevalence of post-exertional malaise. Limitations include the self-reported nature of this follow-up with individuals infected in 2020 and follow-up in 2021, lacking comparisons to individuals infected with other variants. Additionally, this study considered having received at least 2 doses as full vaccination, a concept that continues to evolve with time. Physicians, employers, and insurance companies should address fatigue on a spectrum, accounting for the correlated functional impairment, decreased activity levels, and potentially poorer quality of life.
222	MS220	ME	Nour Shaheen, MDcorresponding authora,* and Ahmed Shaheen, MDa	Long-term sequelae of COVID-19 (myalgic encephalomyelitis): An international cross-sectional study	https://doi.org/10.1097%2FMD.0000000000031819	Published	2022 Nov 11	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9665887/	Background: As a result of prolonged effects on multiple organs, recovery from COVID-19 caused by SARS-CoV-2 cannot be verified. This study seeks to understand chronic and acute long-term symptoms of COVID-19 lasting from a few weeks after diagnosis. The study also aims to gain insight into prevalence of chronic fatigue syndrome/myalgic encephalomyelitis, a potentially comorbid condition for several months after the infection, in addition to taking a broad perspective on rare symptoms that may have developed during or after the infection. Study design: Cross-sectional questionnaire\descriptive study. Methods: The questionnaire was developed to assess the long-term effects of the global pandemic of COVID-19 using DePaul Symptom Questionnaire-2. The DePaul Symptom Questionnaire, Patient Health Questionnaire, and other symptoms that have been introduced by literature review. Discussion: A large cohort of people from all over the world will be examined to understand the differential effects of people who have experienced COVID-19, as well as the potential occurrence of ME. In total, 20,000 COVID patients are expected to be included in the study by Sep 1, 2022. Patients who have experienced COVID-19 will be asked about their persistent symptoms from 1 week up to more than 6 months after catching or recovery from the infection.
223	MS221		Dávid Líška1, Erika Liptaková2, Adriana Babičová3, Ladislav Batalik4,5*, Patrícia Shtin Baňárová6 and Silvia Dobrodenková7	What is the quality of life in patients with long COVID compared to a healthy control group?	https://doi.org/10.3389/fpubh.2022.975992	Published	02 November 2022	Study	https://www.frontiersin.org/articles/10.3389/fpubh.2022.975992/full	Introduction: Many patients have prolonged symptoms after COVID-19 infection, which can affect patient quality of life (QOL). The aim of this study is to determine the quality of life in patients with long COVID, compared with healthy controls. Material and methods: The study was a prospective cross-sectional study using an anonymous online survey. The SF-36 questionnaire was chosen for quality of life measurement. The survey was distributed through the Facebook social media platform targeting groups of patients with long COVID. The control group was made up of physiotherapy and physical education students. Results: There was a significant difference in physical function, with a mean score of 94.9 (±9.4) among the students, compared to long COVID patients with a mean score of 66.2 (±25.4) (p < 0.001). A similar result was found in the physical role (p < 0.001). The overall quality of life score for college students was 578.0 (±111.9), and the overall score for patients with long COVID was 331.9 (±126.9). Conclusions: Patients with long COVID had a lower quality of life compared to the healthy control group, and this was associated with the negative effect of long-COVID. Lower quality of life in patients with long COVID is an important therapeutic goal, which requires attention.
224	MS222		Hi Sun Soh,1,2 and BeLong Cho3,4	Long COVID-19 and Health-Related Quality of Life of Mild Cases in Korea: 3-Months Follow-up of a Single Community Treatment Center	https://doi.org/10.3346/jkms.2022.37.e326	Published	Nov 09, 2022	Survey Study	https://www.jkms.kr/DOIx.php?id=10.3346/jkms.2022.37.e326	Background Severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019 [COVID-19]) survivors mount as the pandemic continues. To date, studies on persistent symptoms and their effects on health-related quality of life (HRQoL) in mild COVID-19 cases have been limited. Methods A prospective online survey was conducted in COVID-19 patients who were admitted to Seongnam Community Treatment Center, an isolation center in South Korea, from November 23rd 2021 to January 2nd 2022. Patients above the age of 19 with no or mild symptoms were included in the study. Total of 147 patients returned to the follow-up survey 3 months after discharge. Baseline demographics, clinical characteristics, symptoms, and EuroQol-5 dimensions-5 levels (EQ-5D-5L) measures were investigated. Results The median (interquartile range [IQR]) interval period between the initial and follow-up survey was 96.0 (93.0–98.0) days. The median (IQR) age of participants was 51.0 (43.0–61.0). During isolation, 131 (89.1%) patients manifested symptoms. On follow-up, 82 (55.8%) participants remained symptomatic. Common symptoms were constitutional (fatigue, myalgia), neurological (memory impairment, hyposmia, hypogeusia, dizziness), and neuropsychiatric (anxiety) symptoms. Participants with remaining neuropsychiatric symptoms reported the lowest EQ-5D-5L index values. Factors associated with persistent symptoms and diminished HRQoL were identified as female sex, metabolic disease, and anxiety during acute COVID-19 phase. Conclusions Cardiopulmonary symptoms improved over time but constitutional, neurological, neuropsychiatric symptoms remained. Patients with neuropsychiatric symptoms (anxiety and insomnia) reported the worst HRQoL. Female sex, metabolic disease, and anxiety during the acute COVID-19 phase were associated with long COVID. Observations of long-term symptoms of COVID-19 with decline in HRQoL and integrated research in COVID-19 survivors are warranted.
225	MS223		Qiangru Huang, MD Mengmeng Jia, PhD Yanxia Sun, PhD Binshan Jiang, BS Dan Cui, MD Luzhao Feng, PhD Weizhong Yang, MD	One-year temporal changes in long COVID prevalence and characteristics: a systematic review and meta-analysis	https://doi.org/10.1016/j.jval.2022.11.011	Published	November 24, 2022	Systematic Review and Meta-analysis	https://www.valueinhealthjournal.com/article/S1098-3015(22)04743-X/pdf	Highlights 1.What is already known about this topic? Long COVID shows multiorgan symptoms and persists for a long period in some post-acute patients. 2.What does the paper add to existing knowledge? Our findings highlight the temporal change in prevalence of 44 specific long COVID symptoms. About two-thirds of the symptoms did not reduce during the 1-year follow-up. The influence of acute phase-related factors for long COVID gradually decreases over time. 3.What insights does the paper provide for informing health care-related decision making? Long COVID may persist longer than expected and more attention should be paid to neuropsychiatric symptoms. Abstract Objectives This study aimed to explore the 1-year temporal change in prevalence, variety, and potential risk factors of long COVID symptoms, and to further predict the prognostic trends of long COVID. Methods We searched electronic databases for related studies published from January 2020 to February 2022, and conducted one group meta-analysis and locally weighted regression explore the monthly temporal change in the prevalence of each long COVID symptom in 1-year follow-up period. Results A total of 137 studies were included in meta-analysis, including 134,093 participants. The temporal change of any long COVID symptom showed a steep decrease initially (from 92% at acute phase to 55% at 1-month follow-up), followed by stabilization at approximately 50% during 1-year follow-up. Six months or more after the acute phase, the odds ratio (OR) of population characteristic factors increased, such as female gender (from 1.62 to 1.82), while the OR value of acute phase-related factors (severe/critical and hospitalization) decreased. As for specific symptoms, about two-thirds of the symptoms did not significantly reduce during the 1-year follow-up, and the neuropsychiatric symptoms showed a higher long-term prevalence (approximately 25%) and longer persistence than physical-symptoms. Conclusions The temporal changes in the prevalence and characteristics speculate that long COVID may persist longer than expected. In particular, we should pay more attention to neuropsychiatric symptoms and other symptoms for which there is no significant downward trend in prevalence. The influence of acute phase-related factors for long COVID gradually decreases over time, while the influence of population characteristic-related gradually increases.
226	MS224		J.BaruchabcC.ZahraacT.CardonaaT.Melilloa	National long COVID impact and risk factors	https://doi.org/10.1016/j.puhe.2022.09.021	Published	23 November 2022	Study	https://www.sciencedirect.com/science/article/pii/S0033350622002839	Objective Our objective was to estimate the prevalence and risk factors for long COVID symptoms among polymerase chain reaction–confirmed COVID-19 patients (hospitalised and community) in Malta. Study design This was a national cross-sectional survey among COVID-19 patients in Malta during 2020. Methods Patients were sent a questionnaire 3–6 months after testing positive. Data were analysed descriptively to estimate symptom prevalence, and multivariable logistic regressions were used to determine the risk factors for long COVID symptoms. Age, sex, initial symptoms, hospitalisation, and healthcare worker status were used as risk factors and symptoms (cough, shortness of breath, fatigue, anxiety, sadness, and memory loss) 2.5 months or more after COVID-19 onset were used as outcomes. Results Of 8446 eligible participants, 2665 (31.55%) responded with a median age of 37 years. Initial symptoms were reported in 82% of responders, and 7.73% were hospitalised. Among the long COVID symptoms, fatigue persisted among most non-hospitalised responders, whereas anxiety, shortness of breath, and sadness were the most common symptoms. Female sex, hospitalisation, and initial symptoms were associated with higher odds of fatigue, shortness of breath, cough, anxiety, sadness, and memory loss as long COVID symptoms. Conclusions Our study is the first to highlight long COVID symptoms and risk factors in Malta, showing that long COVID is common among hospitalised and non-hospitalised patients. These data should increase awareness of long COVID and facilitate support to those affected nationally.
227	MS225		Jorge Vásconez-González 1,,Juan S. Izquierdo-Condoy 1,2ORCID,Raul Fernandez-Naranjo 1 andEsteban Ortiz-Prado 1,3,ORCID	A Systematic Review and Quality Evaluation of Studies on Long-Term Sequelae of COVID-19	https://doi.org/10.3390/healthcare10122364	Published	24 November 2022	Systematic review	https://www.mdpi.com/2227-9032/10/12/2364	COVID-19 made its debut as a pandemic in 2020; since then, more than 607 million cases and at least 6.5 million deaths have been reported worldwide. While the burden of disease has been described, the long-term effects or chronic sequelae are still being clarified. The aim of this study was to present an overview of the information available on the sequelae of COVID-19 in people who have suffered from the infection. A systematic review was carried out in which cohort studies, case series, and clinical case reports were included, and the PubMed, Scielo, SCOPUS, and Web of Science databases were extracted. Information was published from 2020 to 1 June 2022, and we included 26 manuscripts: 9 for pulmonary, 6 for cardiac, 2 for renal, 8 for neurological and psychiatric, and 6 for cutaneous sequelae. Studies showed that the most common sequelae were those linked to the lungs, followed by skin, cutaneous, and psychiatric alterations. Women reported a higher incidence of the sequelae, as well as those with comorbidities and more severe COVID-19 history. The COVID-19 pandemic has not only caused death and disease since its appearance, but it has also sickened millions of people around the globe who potentially suffer from serious illnesses that will continue to add to the list of health problems, and further burden healthcare systems around the world.
228	MS226		Simon B. Larsson, Gustaf Stukát von Feilitzen, Maria E. Andersson, Per Sikora, Magnus Lindh, Rickard Nordén, Staffan Nilsson & Robert Sigström	Self-reported symptom severity, general health, and impairment in post-acute phases of COVID-19: retrospective cohort study of Swedish public employees	https://doi.org/10.1038/s41598-022-24307-1	Published	17 November 2022	Study	https://www.nature.com/articles/s41598-022-24307-1	This study aimed to examine current symptom severity and general health in a sample of primarily non-hospitalized persons with polymerase chain reaction (PCR) confirmed COVID-19 in comparison to PCR negative controls. During the first quarter of 2021, we conducted an online survey among public employees in West Sweden, with a valid COVID-19 test result. The survey assessed past-month severity of 28 symptoms and signs, self-rated health, the WHO Disability Assessment Schedule (WHODAS) 2.0 and illness severity at the time of test. We linked participants’ responses to their SARS-CoV-2 PCR tests results. We compared COVID-19 positive and negative participants using univariable and multivariable regression analyses. Out of 56,221 invited, 14,222 (25.3%) responded, with a response rate of 50% among SARS-CoV-2 positive individuals. Analysis included 10,194 participants (86.4% women, mean age 45 years) who tested positive 4–12 weeks (N = 1425; subacute) and > 12 weeks (N = 1584; postcovid) prior to the survey, and 7185 PCR negative participants who did not believe that they had had COVID-19. Symptoms were highly prevalent in all groups, with worst symptoms in subacute phase participants, followed by postcovid phase and PCR negative participants. The most specific symptom for COVID-19 was loss of smell or taste. Both WHODAS 2.0 score and self-rated health were worst in subacute participants, and modestly worse in postcovid participants than in negative controls. Female gender, older age and acute illness severity had larger effects on self-rated health and WHODAS 2.0 score in PCR positive participants than in PCR negative. Studies with longer follow-up are needed to determine the long-term improvement after COVID-19.
229	MS227		Amélia Déguilhem 1 Author Orcid Image ; Joelle Malaab 1 Author Orcid Image ; Manissa Talmatkadi 1 Author Orcid Image ; Simon Renner 1 Author Orcid Image ; Pierre Foulquié 1 Author Orcid Image ; Guy Fagherazzi 2 Author Orcid Image ; Paul Loussikian 1 Author Orcid Image ; Tom Marty 1 Author Orcid Image ; Adel Mebarki 1 Author Orcid Image ; Nathalie Texier 1 Author Orcid Image ; Stephane Schuck 1 Author Orcid Image	Identifying Profiles and Symptoms of Patients With Long COVID in France: Data Mining Infodemiology Study Based on Social Media	https://doi.org/10.2196/39849	Published	22.11.2022	Study	https://infodemiology.jmir.org/2022/2/e39849	Background: Long COVID—a condition with persistent symptoms post COVID-19 infection—is the first illness arising from social media. In France, the French hashtag #ApresJ20 described symptoms persisting longer than 20 days after contracting COVID-19. Faced with a lack of recognition from medical and official entities, patients formed communities on social media and described their symptoms as long-lasting, fluctuating, and multisystemic. While many studies on long COVID relied on traditional research methods with lengthy processes, social media offers a foundation for large-scale studies with a fast-flowing outburst of data. Objective: We aimed to identify and analyze Long Haulers’ main reported symptoms, symptom co-occurrences, topics of discussion, difficulties encountered, and patient profiles. Methods: Data were extracted based on a list of pertinent keywords from public sites (eg, Twitter) and health-related forums (eg, Doctissimo). Reported symptoms were identified via the MedDRA dictionary, displayed per the volume of posts mentioning them, and aggregated at the user level. Associations were assessed by computing co-occurrences in users’ messages, as pairs of preferred terms. Discussion topics were analyzed using the Biterm Topic Modeling; difficulties and unmet needs were explored manually. To identify patient profiles in relation to their symptoms, each preferred term’s total was used to create user-level hierarchal clusters. Results: Between January 1, 2020, and August 10, 2021, overall, 15,364 messages were identified as originating from 6494 patients of long COVID or their caregivers. Our analyses revealed 3 major symptom co-occurrences: asthenia-dyspnea (102/289, 35.3%), asthenia-anxiety (65/289, 22.5%), and asthenia-headaches (50/289, 17.3%). The main reported difficulties were symptom management (150/424, 35.4% of messages), psychological impact (64/424,15.1%), significant pain (51/424, 12.0%), deterioration in general well-being (52/424, 12.3%), and impact on daily and professional life (40/424, 9.4% and 34/424, 8.0% of messages, respectively). We identified 3 profiles of patients in relation to their symptoms: profile A (n=406 patients) reported exclusively an asthenia symptom; profile B (n=129) expressed anxiety (n=129, 100%), asthenia (n=28, 21.7%), dyspnea (n=15, 11.6%), and ageusia (n=3, 2.3%); and profile C (n=141) described dyspnea (n=141, 100%), and asthenia (n=45, 31.9%). Approximately 49.1% of users (79/161) continued expressing symptoms after more than 3 months post infection, and 20.5% (33/161) after 1 year. Conclusions: Long COVID is a lingering condition that affects people worldwide, physically and psychologically. It impacts Long Haulers’ quality of life, everyday tasks, and professional activities. Social media played an undeniable role in raising and delivering Long Haulers’ voices and can potentially rapidly provide large volumes of valuable patient-reported information. Since long COVID was a self-titled condition by patients themselves via social media, it is imperative to continuously include their perspectives in related research. Our results can help design patient-centric instruments to be further used in clinical practice to better capture meaningful dimensions of long COVID.
230	MS228		IvanVargasaAlexandriaMuenchbMichael A.GrandnercMichael R.IrwindeMichael L.Perlisb	Insomnia symptoms predict longer COVID-19 symptom duration	https://doi.org/10.1016/j.sleep.2022.11.019	Published	23 November 2022	Study	https://www.sciencedirect.com/science/article/pii/S1389945722012278	Highlights •The prevalence of clinical insomnia remained high during the COVID-19 pandemic (>13%). •Insomnia was not related to contracting COVID-19 or experiencing more severe symptoms. •Insomnia was associated with a prolonged recovery from COVID-19 (i.e., more days sick). Abstract Objective /Background: The goal of the present study was to assess the prevalence and incidence of insomnia in the United States during the COVID-19 pandemic, and whether, among those that contracted COVID-19, insomnia predicted worse outcomes (e.g., symptoms of greater frequency, duration, or severity). Methods A nationwide sample of 2980 adults living in the United States were surveyed online at two points during the COVID-19 pandemic (T1 = April–June 2020; T2 = January–March 2021). Insomnia symptoms were assessed at both time points using the Insomnia Severity Index (ISI). The T2 survey also asked questions regarding COVID-19 testing and symptoms. Results The prevalence of insomnia (defined as ISI ≥15) was 15% at T1 and 13% at T2. The incidence rate of insomnia (i.e., new cases from T1 to T2) was 5.6%. Participants with insomnia were not more likely to contract COVID-19 relative to those participants without insomnia. Among those participants in our sample that contracted the virus during the study interval (n = 149), there were no significant group differences in COVID-19 symptom outcomes, with one exception, participants with insomnia were more likely to report a longer symptom duration (insomnia = 24.8 sick days, no insomnia = 16.1 sick days). Conclusions The present study suggests the prevalence of insomnia in the U.S. population remained high during the COVID-19 pandemic. The data also support that insomnia may be related to experiencing more chronic COVID-19 symptoms. These findings have more general implications for the role of sleep and insomnia on immune functioning.
231	MS229		Terence Stephenson, Snehal M. Pinto Pereira, Manjula D. Nugawela, Kelsey McOwat, Ruth Simmons, Trudie Chalder, Tamsin Ford, Isobel Heyman, Olivia V Swann, Lana Fox-Smith, Natalia K Rojas, Emma Dalrymple, Shamez N. Ladhani, Roz Shafran	Long COVID - Six months of prospective follow-up of changes in symptom profiles of non-hospitalised children and young people after SARS-CoV-2 testing: a national matched cohort study		Published	18 Nov 2022	Study	https://kclpure.kcl.ac.uk/portal/en/publications/long-covid--six-months-of-prospective-followup-of-changes-in-symptom-profiles-of-nonhospitalised-children-and-young-people-after-sarscov2-testing(a718e8cb-6970-44f1-befb-dd1fb32385df).html	Background: Little is known about the prevalence and natural trajectory of post-COVID symptoms in young people, despite very high numbers of young people having acute COVID. To date, there has been no prospective follow-up to establish the pattern of symptoms over a 6-month time period. Methods: A non-hospitalised, national sample of 3,395 (1,737 SARS-COV-2 Negative;1,658 SARS65 COV-2 Positive at baseline) children and young people (CYP) aged 11-17 completed questionnaires 3 and 6 months after PCR-confirmed SARS-CoV-2 infection between January and March 2021 and were compared with age, sex and geographically-matched test-negative CYP. Results: Three months after a positive SARS-CoV-2 PCR test, 11 of the 21 most common symptoms reported by >10% of CYP had reduced. There was a further decline at 6 months. By 3 and 6 months the prevalence of chills, fever, myalgia, cough and sore throat of CYP who tested positive for SARS71 CoV-2 reduced from 10-25% at testing to Conclusions: In CYP, the prevalence of specific symptoms reported at time of PCR-testing declined with time. Similar patterns were observed among test-positives and test-negatives and new symptoms were reported six months post-test for both groups suggesting that symptoms are unlikely to exclusively be a specific consequence of SARS-COV-2 infection. Many CYP experienced unwanted symptoms that warrant investigation and potential intervention.
232	MS230		Anna Tisler ,Oliver Stirrup,Heti Pisarev,Ruth Kalda,Tatjana Meister,Kadri Suija,Raivo Kolde,Marko Piirsoo,Anneli Uusküla	Post-acute sequelae of COVID-19 among hospitalized patients in Estonia: Nationwide matched cohort study	https://doi.org/10.1371/journal.pone.0278057	Published	November 23, 2022	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0278057	Background Post-acute COVID-19 sequelae refers to a variety of health complications involving different organ systems that have been described among individuals after acute phase of illness. Data from unselected population groups with long-time follow up is needed to comprehensively describe the full spectrum of post-acute COVID-19 complications. Methods In this retrospective nationwide cohort study, we used data obtained from electronic health record database. Our primary cohort were adults hospitalized with confirmed COVID-19 and matched (age, sex, Charlson Comorbidity Index) unaffected controls from general population. Individuals included from February 2020 until March 2021 were followed up for 12 months. We estimated risks of all-cause mortality, readmission and incidence of 16 clinical sequelae after acute COVID-19 phase. Using a frailty Cox model, we compared incidences of outcomes in two cohorts. Results The cohort comprised 3949 patients older than 18 years who were alive 30 days after COVID-19 hospital admission and 15511 controls. Among cases 40.3% developed at least one incident clinical sequelae after the acute phase of SARS-CoV-2 infection, which was two times higher than in general population group. We report substantially higher risk of all-cause mortality (adjusted hazard ratio (aHR) = 2.57 (95%CI 2.23–2.96) and hospital readmission aHR = 1.73 (95%CI 1.58–1.90) among hospitalized COVID-19 patients. We found that the risks for new clinical sequalae were significantly higher in COVID-19 patients than their controls, especially for dementia aHR = 4.50 (95% CI 2.35–8.64), chronic lower respiratory disease aHR = 4.39 (95% CI 3.09–6.22), liver disease aHR 4.20 (95% CI 2.01–8.77) and other (than ischemic) forms of heart diseases aHR = 3.39 (95%CI 2.58–4.44). Conclusion Our results provide evidence that the post-acute COVID-19 morbidity within the first year after COVID-19 hospitalization is substantial. Risks of all-cause mortality, hospitalisation and majority of clinical sequelae were significantly higher in hospitalized COVID-19 patients than in general population controls and warrant targeted prevention efforts.
233	MS231		Nike Walter 1,2,*ORCID,Markus Rupp 2ORCID,Siegmund Lang 2ORCID,Beate Leinberger 1,Volker Alt 2,Thilo Hinterberger 1 andThomas Loew 1	A Comprehensive Report of German Nationwide Inpatient Data on the Post-COVID-19 Syndrome Including Annual Direct Healthcare Costs	https://doi.org/10.3390/v14122600	Published	22 November 2022	Study	https://www.mdpi.com/1999-4915/14/12/2600	Background: The aim of this study was to provide a comprehensive overview of German nationwide data including (i) the number of hospitalized Post-COVID Syndrome (PCS) cases including in-hospital mortality rates and intensive care unit treatments, (ii) the main common concomitant diagnoses associated with PCS, (iii) the most frequently performed treatment procedures, and (iv) the annual direct healthcare costs. Methods: The incidence was calculated based on annual ICD-10 diagnosis codes “U09.9!, Post-COVID-19 condition”. Data on concomitant diagnoses, treatment procedures, treatment in an intensive care unit (ICU), in-hospital mortality, the proportion of G-DRGs, and cumulative costs were assessed based on the Institute for the Hospital Remuneration System (InEK) data for 2019. Results: A total of 29,808 PCS inpatients could be identified yielding a prevalence of 5.5%. In total, 1330 (4.5%) in-hospital deaths were recorded, and 5140 (17.2%) patients required ICU treatment. The majority of patients (18.6%) were aged 65–74 years. The most common concomitant diagnoses included pneumonia, critical illness polyneuropathy, dyspnea, chronic fatigue syndrome, and pulmonary embolisms. The most frequently performed procedures were computed tomography of the thorax with contrast medium, whole-body plethysmography, and the monitoring of respiration, heart, and circulation. The cost per case of the G-DRG codes that were analyzed ranged from € 620 ± 377 (E64D, Respiratory insufficiency, one day of occupancy) to € 113,801 ± 27,939 (A06B, Ventilation > 1799 h with complex OR procedure). Total cumulative direct healthcare costs of € 136,608,719 were calculated, resulting in mean costs of € 4583 per case. Conclusion: Post-COVID Syndrome is of major public health importance with substantial financial implications. The present article can support stakeholders in health care systems to foresee future needs and adapt their resource management. Consensus diagnostic criteria and rehabilitation guidelines are highly warranted.
234	MS232		Mario GennaroMazzaabcMariagraziaPalladiniabcGaiaVillaaElenaAgnolettoaYasmineHarringtonabcBenedettaVaiabFrancescoBenedettiab	Prevalence of depression in SARS-CoV-2 infected patients: An umbrella review of meta-analyses	https://doi.org/10.1016/j.genhosppsych.2022.12.002	Published	7 December 2022	Umbrella review of meta-analyses	https://www.sciencedirect.com/science/article/pii/S0163834322001438	Objective The COVID-19 pandemic is still spreading worldwide two years after its outbreak. Depression has been reported in around 30% of SARS-CoV-2 infected patients. We aim to synthesize the available meta-analytical evidence in an umbrella review exploring the prevalence of depression during and after SARS-CoV-2 infection. Methods First, we performed a narrative umbrella review including only meta-analyses providing a quantitative summary of the prevalence of depression during or after SARS-CoV-2 infection. Then we extracted the prevalence and sample size from the original studies included in each meta-analysis, and after removing duplicate studies, we performed a random-effects model meta-analysis based on single original study estimates. Heterogeneity, publication bias, leave-one-out sensitivity, and subgroup analyses were performed. Results 14 meta-analyses were included in the umbrella review. The prevalence of depression ranged from 12% to 55% in the presence of high heterogeneity. The meta-analysis based on 85 original studies derived from the included 14 meta-analyses showed a pooled prevalence of depression of 31% (95% CI:25–38%) in the presence of high and significant heterogeneity (Q = 8988; p < 10−6; I2 = 99%) and publication bias (p < 0.001). Conclusion The burden of post-COVID depression substantially exceeds the pre-pandemic prevalence. Health care services for COVID-19 survivors should monitor and treat emergent depression, reducing its potential detrimental long-term effects.
235	MS233		Chen Chen, Spencer R Haupert, Lauren Zimmermann, Xu Shi, Lars G Fritsche, Bhramar Mukherjee	Global Prevalence of Post-Coronavirus Disease 2019 (COVID-19) Condition or Long COVID: A Meta-Analysis and Systematic Review	https://doi.org/10.1093/infdis/jiac136	Published	16 April 2022	Meta-Analysis and Systematic Review	https://academic.oup.com/jid/article/226/9/1593/6569364?login=false	Background This study aims to examine the worldwide prevalence of post-coronavirus disease 2019 (COVID-19) condition, through a systematic review and meta-analysis. Methods PubMed, Embase, and iSearch were searched on July 5, 2021 with verification extending to March 13, 2022. Using a random-effects framework with DerSimonian-Laird estimator, we meta-analyzed post-COVID-19 condition prevalence at 28+ days from infection. Results Fifty studies were included, and 41 were meta-analyzed. Global estimated pooled prevalence of post-COVID-19 condition was 0.43 (95% confidence interval [CI], .39–.46). Hospitalized and nonhospitalized patients had estimates of 0.54 (95% CI, .44–.63) and 0.34 (95% CI, .25–.46), respectively. Regional prevalence estimates were Asia (0.51; 95% CI, .37–.65), Europe (0.44; 95% CI, .32–.56), and United States of America (0.31; 95% CI, .21–.43). Global prevalence for 30, 60, 90, and 120 days after infection were estimated to be 0.37 (95% CI, .26–.49), 0.25 (95% CI, .15–.38), 0.32 (95% CI, .14–.57), and 0.49 (95% CI, .40–.59), respectively. Fatigue was the most common symptom reported with a prevalence of 0.23 (95% CI, .17–.30), followed by memory problems (0.14; 95% CI, .10–.19). Conclusions This study finds post-COVID-19 condition prevalence is substantial; the health effects of COVID-19 seem to be prolonged and can exert stress on the healthcare system.
236	MS234		Hao Zhang, Chengxi Zang, Zhenxing Xu, Yongkang Zhang, Jie Xu, Jiang Bian, Dmitry Morozyuk, Dhruv Khullar, Yiye Zhang, Anna S. Nordvig, Edward J. Schenck, Elizabeth A. Shenkman, Russell L. Rothman, Jason P. Block, Kristin Lyman, Mark G. Weiner, Thomas W. Carton, Fei Wang & Rainu Kaushal	Data-driven identification of post-acute SARS-CoV-2 infection subphenotypes	https://doi.org/10.1038/s41591-022-02116-3	Published	01 December 2022	Study	https://www.nature.com/articles/s41591-022-02116-3	The post-acute sequelae of SARS-CoV-2 infection (PASC) refers to a broad spectrum of symptoms and signs that are persistent, exacerbated or newly incident in the period after acute SARS-CoV-2 infection. Most studies have examined these conditions individually without providing evidence on co-occurring conditions. In this study, we leveraged the electronic health record data of two large cohorts, INSIGHT and OneFlorida+, from the national Patient-Centered Clinical Research Network. We created a development cohort from INSIGHT and a validation cohort from OneFlorida+ including 20,881 and 13,724 patients, respectively, who were SARS-CoV-2 infected, and we investigated their newly incident diagnoses 30–180 days after a documented SARS-CoV-2 infection. Through machine learning analysis of over 137 symptoms and conditions, we identified four reproducible PASC subphenotypes, dominated by cardiac and renal (including 33.75% and 25.43% of the patients in the development and validation cohorts); respiratory, sleep and anxiety (32.75% and 38.48%); musculoskeletal and nervous system (23.37% and 23.35%); and digestive and respiratory system (10.14% and 12.74%) sequelae. These subphenotypes were associated with distinct patient demographics, underlying conditions before SARS-CoV-2 infection and acute infection phase severity. Our study provides insights into the heterogeneity of PASC and may inform stratified decision-making in the management of PASC conditions.
237	MS235		Reinhold Kerbl	Wie häufig ist Long-COVID wirklich? How frequent is long COVID really?	https://doi.org/10.1007/s00112-022-01660-z	Published	01 December 2022	Study	https://link.springer.com/article/10.1007/s00112-022-01660-z	Originalpublikation Global Burden of Disease Long COVID Collaborators, Wulf Hanson S, Abbafati C et al (2022) Estimated global proportions of individuals with persistent fatigue, cognitive, and respiratory symptom clusters following symptomatic COVID-19 in 2020 and 2021. JAMA 328(16):1604–1615. https://doi.org/10.1001/jama.2022.18931 Hintergrund. Die Prävalenz von Long-COVID wird in verschiedenen Studien höchst unterschiedlich angegeben. Sie ist u. a. abhängig von der angewandten Definition, der Art der Studie, der untersuchten Fallzahl, aber auch der jeweiligen Infektionswelle (z. B. Delta vs. Omikron). Insbesondere in Fallserien ohne Kontrollgruppe werden teilweise sehr hohe Prävalenzzahlen berichtet; viele Studien berücksichtigen in ihrer Analyse auch das Vorliegen präexistenter Symptome nicht adäquat. Schließlich werden bis zu 300 verschiedene Symptome mit Long-COVID assoziiert und auch dadurch sehr hohe Prävalenzzahlen erzielt. Eine nunmehr im Journal of the American Medical Association (JAMA) publizierte Modellierungsstudie (Bayes-Metaregression) hat nun versucht, unter Anwendung der WHO-Definition und einheitlicher Kriterien die reale Prävalenz für Long-COVID zu erheben. Methodik. In die Metaregression eingeschlossen wurden 54 Studien aus 22 Ländern, die Gesamtzahl der inkludierten Patienten betrug 1,2 Mio. Für die Einstufung als Long-COVID wurde die WHO-Definition angewandt, die eine Symptomdauer von zumindest 3 Monaten voraussetzt. Berücksichtigt wurden nur Fälle mit vormals symptomatischem Verlauf, asymptomatische SARS-CoV-2-Infektionen wurden nicht eingeschlossen. Weiters wurden nur jene Fälle als „Long-COVID“ eingestuft, die zumindest einen der folgenden 3 Symptomenkomplexe zeigten: andauernde Müdigkeit mit Körperschmerz und Stimmungsschwankungen, kognitive Beeinträchtigung oder anhaltende respiratorische Probleme. Ergebnisse. Insgesamt erfüllten 6,2 % aller Patienten die Kriterien für Long-COVID. Vorherrschende Symptome waren respiratorische Probleme (bei 60,4 %), gefolgt von anhaltender Müdigkeit (51 %) und kognitiven Defiziten (35,4 %). Die Prävalenz war bei Personen nach dem 20. Lebensjahr signifikant höher als bei Personen unter 20 Jahren (Frauen 10,6 % vs. 5,4 %, Männer 5,4 % vs. 2,2 %). Die mittlere Symptomdauer betrug bei im Rahmen der Akuterkrankung hospitalisierten Patienten 9 Monate (Konfidenzintervall 7–12), bei vormals nichthospitalisierten Patienten 4 Monate (Konfidenzintervall 3,6–4,6).
238	MS236		Krishna Mohan Surapaneni 1,2,3,ORCID,Manmohan Singhal 1,ORCID,Sofia Rani Saggu 4ORCID,Ashruti Bhatt 4,Priya Shunmathy 4 andAshish Joshi 2,5,*	A Scoping Review on Long COVID-19: Physiological and Psychological Symptoms Post-Acute, Long-Post and Persistent Post COVID-19	https://doi.org/10.3390/healthcare10122418	Published	30 November 2022	Review	https://www.mdpi.com/2227-9032/10/12/2418	Background: The identification of persistent symptoms of chronic/long COVID-19 is crucial in understanding the management of long haulers of post COVID-19. Methods: Pub Med (Medline) database was scoped for original articles based on a search strategy related to the objectives. The selected articles post-screening were analyzed for variables relating to chronic/long COVID-19. Results were analyzed using descriptive statistics. Results: A total of 33 studies were reviewed. A total of 60% of the studies were observational studies and most of them were from high income countries. Almost half of the studies were in phase 3 of post-COVID-19, i.e., symptoms lasting >24 weeks. Among the physiological and psychological symptoms studied, fatigue, dyspnea, cough, headache, memory loss, depression, brain fog and lack of concentration were found to be the most frequently reported symptoms. Excessive sleep, constipation and neuropathic pain were among the least reported symptoms. Prior hospitalization, the female gender was found to be a risk factor. Limitations were reported by all studies. Conclusions: The major physiological and psychological symptoms of long COVID-19 have been explained with risk factors and its impact on patients’ lifestyles. The findings of this review hope to facilitate clinicians to draw conclusions to manage the long-term effects of post/chronic COVID-19.
239	MS237		Lauren E. Wisk, PhD1,2; Michael A. Gottlieb, MD3; Erica S. Spatz, MD, MHS4,5; Huihui Yu, PhD4,5; Ralph C. Wang, MD, MAS6; Benjamin H. Slovis, MD, MA7; Sharon Saydah, PhD8; Ian D. Plumb, MBBS, MSc8; Kelli N. O’Laughlin, MD, MPH9,10; Juan Carlos C. Montoy, MD, PhD6; Samuel A. McDonald, MD, MS11,12; Zhenqiu Lin, PhD4,5; Jin-Mann S. Lin, PhD13; Katherine Koo, MS-HSM14; Ahamed H. Idris, MD11,15; Ryan M. Huebinger, MD16; Mandy J. Hill, DrPH, MPH16; Nicole L. Gentile, MD, PhD17,18; Anna Marie Chang, MD, MSCE7; Jill Anderson, BSN, RN19; Bala Hota, MD, MPH20; Arjun K. Venkatesh, MD, MBA, MHS5,21; Robert A. Weinstein, MD22,23; Joann G. Elmore, MD, MPH1,2; Graham Nichol, MD, MPH9,19; for the INSPIRE Group	Association of Initial SARS-CoV-2 Test Positivity With Patient-Reported Well-being 3 Months After a Symptomatic Illness	http://jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2022.44486	Published	December 1, 2022	Study	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2799116	Key Points Question How do patient-reported physical, mental, and social well-being compare at 3 months after symptomatic illness among those who tested positive vs negative for SARS-CoV-2 infection? Findings In this cohort study of 1000 US adults with symptomatic illness, poor well-being scores at follow-up were common in both those who tested positive and negative for SARS-CoV-2 infection. Despite some improvements over time, 39.6% of COVID-19–positive and 53.5% of COVID-19–negative patients reported residual symptoms. Meaning These findings emphasize the importance of including a concurrent control group when studying sequelae of COVID-19 illness. Abstract Importance Long-term sequelae after symptomatic SARS-CoV-2 infection may impact well-being, yet existing data primarily focus on discrete symptoms and/or health care use. Objective To compare patient-reported outcomes of physical, mental, and social well-being among adults with symptomatic illness who received a positive vs negative test result for SARS-CoV-2 infection. Design, Setting, and Participants This cohort study was a planned interim analysis of an ongoing multicenter prospective longitudinal registry study (the Innovative Support for Patients With SARS-CoV-2 Infections Registry [INSPIRE]). Participants were enrolled from December 11, 2020, to September 10, 2021, and comprised adults (aged ≥18 years) with acute symptoms suggestive of SARS-CoV-2 infection at the time of receipt of a SARS-CoV-2 test approved by the US Food and Drug Administration. The analysis included the first 1000 participants who completed baseline and 3-month follow-up surveys consisting of questions from the 29-item Patient-Reported Outcomes Measurement Information System (PROMIS-29; 7 subscales, including physical function, anxiety, depression, fatigue, social participation, sleep disturbance, and pain interference) and the PROMIS Short Form–Cognitive Function 8a scale, for which population-normed T scores were reported. Exposures SARS-CoV-2 status (positive or negative test result) at enrollment. Main Outcomes and Measures Mean PROMIS scores for participants with positive COVID-19 tests vs negative COVID-19 tests were compared descriptively and using multivariable regression analysis. Results Among 1000 participants, 722 (72.2%) received a positive COVID-19 result and 278 (27.8%) received a negative result; 406 of 998 participants (40.7%) were aged 18 to 34 years, 644 of 972 (66.3%) were female, 833 of 984 (84.7%) were non-Hispanic, and 685 of 974 (70.3%) were White. A total of 282 of 712 participants (39.6%) in the COVID-19–positive group and 147 of 275 participants (53.5%) in the COVID-19–negative group reported persistently poor physical, mental, or social well-being at 3-month follow-up. After adjustment, improvements in well-being were statistically and clinically greater for participants in the COVID-19–positive group vs the COVID-19–negative group only for social participation (β = 3.32; 95% CI, 1.84-4.80; P < .001); changes in other well-being domains were not clinically different between groups. Improvements in well-being in the COVID-19–positive group were concentrated among participants aged 18 to 34 years (eg, social participation: β = 3.90; 95% CI, 1.75-6.05; P < .001) and those who presented for COVID-19 testing in an ambulatory setting (eg, social participation: β = 4.16; 95% CI, 2.12-6.20; P < .001). Conclusions and Relevance In this study, participants in both the COVID-19–positive and COVID-19–negative groups reported persistently poor physical, mental, or social well-being at 3-month follow-up. Although some individuals had clinically meaningful improvements over time, many reported moderate to severe impairments in well-being 3 months later. These results highlight the importance of including a control group of participants with negative COVID-19 results for comparison when examining the sequelae of COVID-19.
240	MS238		Kokolevich, Zoe Mass; Crowe, Melissa; Mendez, Diana; Biros, Erik; Reznik, Jacqueline Elise	Most Common Long COVID Physical Symptoms in Working Age Adults Who Experienced Mild COVID-19 Infection: A Scoping Review	https://doi.org/10.3390/healthcare10122577	Published	2022-12	Systematic Review	https://www.mdpi.com/2227-9032/10/12/2577	Background: One-third of patients who recover from COVID-19 present with long COVID. Their symptoms are broad, affecting their physical functioning and, ultimately, their quality of life. Many of those individuals who develop long COVID, possibly from a mild COVID-19 infection, are in the 18–65 age group. This prolongation of malaise directly influences national workforce economies. Objectives: To summarise the commonly reported physical symptoms of long COVID in order to inform potential adjustments in healthcare for the employable population. Methods: The Embase, CINAHL, Medline, SCOPUS, and WHO COVID-19 databases were searched. The study selection process was based on the PRISMA guidelines. The extracted data were synthesised and presented narratively. Results: 7403 studies were accessed, comprising 60 cohort studies and 10 case series/studies, representing 289,213 patients who met our criteria. The most frequently reported physical symptoms were fatigue (92%), shortness of breath (SOB) (81.8%), muscle pain (43.6%), and joint pain (34.5%). Conclusions: The range of reported physical symptoms was broad and varied; the main ones being fatigue, breathlessness/SOB, and pain. Similarities observed between long COVID and other post-acute infection syndromes may help formulate protocols to manage and promote recovery for long COVID patients. Inconsistencies were evident, particularly with a lack of adherence to the standardised definitions of long COVID.
241	MS239		Epsi, Nusrat J; Lindholm, David A; Ganesan, Anuradha; Lalani, Tahaniyat; Smith, Alfred G; Mody, Rupal; Jones, Milissa; Bazan, Samantha; Colombo, Rhonda E; Colombo, Christopher; Ewers, Evan C; Larson, Derek; Berjohn, Catherine M; Maves, Ryan C; Fries, Anthony C; Scher, Ann; Byrne, Celia; Rusiecki, Jennifer; Sanchez Edwards, Margaret; Rozman, Julia S; Mende, Katrin; Simons, Mark P; Tribble, David R; Agan, Brian; Burgess, Timothy; Pollett, Simon; Richard, Stephanie A	1066. Precision phenotyping of “long COVID” through machine learning	https://doi.org/10.1093/ofid/ofac492.907	Published	2022-12-01	Study	https://doi.org/10.1093/ofid/ofac492.907	Characterizing, diagnosing, and caring for “long COVID” patients has proven to be challenging due to heterogenous symptoms and broad definitions of these post-acute sequelae. Here, we take a machine learning approach to identify discrete clusters of long COVID symptoms which may define specific long COVID phenotypes. Figure 1: (A) Principal component analysis followed by K-means clustering identified three groups of participants. (B) Heatmap depicting three distinct clusters (high values are in red and low value are in blue); Cluster 1 exhibits sensory symptoms (e.g., loss of smell and/or taste), Cluster 2 exhibits fatigue and difficulty thinking (e.g., changes in ability to think) symptoms, and Cluster 3 exhibits difficulty breathing and exercise intolerance symptoms. (C) Clinical and demographic characteristics of 97 military health system beneficiaries by identified clustersThe Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (EPICC) study is a longitudinal COVID-19 cohort study with data and biospecimens collected from 10 military treatment facilities and online recruitment. Demographic and clinical characteristics were collected using case report forms and surveys completed at enrollment and at 1, 3, 6, 9, and 12 months. For this analysis, we identified those who reported any moderate to severe persistent symptoms on surveys collected 6-months post-COVID-19 symptom onset. Using the survey responses, we applied principal component analysis (PCA) followed by unsupervised machine learning clustering algorithm K-means to identify groups with distinct clusters of symptoms.Of 1299 subjects with 6-month survey responses, 97 (7.47%) reported moderate to severe persistent symptoms. Among these subjects, three clusters were identified using PCA (Figure 1A). Cluster 1 is characterized by sensory symptoms (loss of taste and/or smell), Cluster 2 by fatigue and difficulty thinking, and Cluster 3 by difficulty breathing and exercise intolerance (Figure 1B). More than half of these subjects (57%) were female, 64% were 18-44 years old, and 64% had no comorbidities at enrollment (Figure 1C). Those in the sensory symptom cluster were all outpatients at the time of initial COVID-19 presentation (p < 0.01). The difficulty breathing and exercise intolerance symptom-clusters had a higher proportion of older participants (Age group ≥ 45-64) with more comorbidities (CCI ≥ 1-2).We identified three distinct ‘long COVID’ phenotypes among those with moderate to severe COVID-19 symptoms at 6-months post-symptom onset. With further validation and characterization, this framework may allow more precise classification of long COVID cases, and potentially improve the diagnosis, prognosis, and treatment of post- infectious sequelae.Ryan C. Maves, MD, AiCuris: Grant/Research Support\|Sound Pharmaceuticals: Grant/Research Support\|Trauma Insights, LLC: Advisor/Consultant Julia S. Rozman, n/a, Astra Zeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response Mark P. Simons, PhD, AstraZeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response David R. Tribble, DrPH, AstraZeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response Timothy Burgess, MD, MPH, AstraZeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response Simon Pollett, MBBS, Astra Zeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response.
242	MS240		Kenny, Grace; McCann, Kathleen; O'Brien, Conor; Savinelli, Stefano; O'Broin, Cathal; Tinago, Willard; Yousif, Obada; Lambert, John S; Feeney, Eoin; de Barra, Eoghan; Sadlier, Corinna; Landay, Alan; Doran, Peter; Mallon, Patrick W G	77. Demonstration of stable clusters of symptoms in long COVID	https://doi.org/10.1093/ofid/ofac492.002	Published	2022-12-01	Study	https://doi.org/10.1093/ofid/ofac492.002	Long COVID is a heterogenous condition. We previously demonstrated distinct phenotypes of long COVID, but the impact of later waves caused by SARS-CoV-2 variants on long COVID presentations has not been described.Table 1Dates and variants of COVID-19 waves.We selected individuals with ongoing symptoms > 4 weeks from PCR-confirmed COVID-19 in a multicentre, prospective cohort study. We used multiple correspondence analysis and hierarchical clustering on self-reported symptoms to identify symptom clusters, in individuals recruited during two periods; cohort 1 from March 2020 to April 2021, and cohort 2 from April 2021 to March 2022. We explored differences in symptoms by mapping acute infection to one of four COVID-19 waves in Ireland (table 1) as well as vaccination status, and used Chi2 test to compare symptoms frequencies.Table 2Patient demographics and differences between the two cohorts.Figure 1- Heatmaps demonstrating the symptom clusters in the two cohortsEach line represents an individual, red represents the presence of a symptom, blue represents the absence of a symptom.Demographics are shown in Table 2. Cluster analysis of each cohort demonstrated 3 distinct clusters in both cohorts, which shared similar clinical characteristics; a musculoskeletal/pain symptom cluster, a cardiorespiratory cluster and a third less symptomatic cluster (Figure 1).While symptoms within clusters were similar across both periods, in the cardiorespiratory cluster, the frequency of palpitations decreased (56% vs 16%) and cough increased (14% vs 45%) between reporting periods (both P< 0.01). Furthermore, a greater proportion of palpitations were reported in those with COVID-19 from waves 1 and 2 (35% and 28%) compared to 3 and 4 (both 12%, P< 0.001), and a greater proportion of chest pain in waves 1, 2 and 4 compared to wave 3. There were no differences in other symptoms (Table 3). Additionally there were significantly less palpitations reported in those vaccinated at the time of review (17% vs 31% P=0.002), but not chest pain (30% vs 39% P=0.13). In multivariate analysis, infection in wave 3 and 4 but not vaccination status remained significantly associated with lower reported palpitations (OR (95% CI) 0.28 (0.13–0.97) and 0.5 (0.06–0.87) for waves 3 and 4, both P< 0.05), and wave 3 infection remained independently associated with lower reported chest pain (OR 0.3 (0.25–0.7)).Table 3Proportion of individuals reporting each long COVID symptom depending on timing of acute illness.Three symptom clusters define long COVID across the two cohorts, but characteristics of the cardiorespiratory phenotype have evolved over time with evolution of SARS-CoV-2 variants.All Authors: No reported disclosures.
243	MS241		Logue, Jennifer; Franko, Nicholas M; Kemp, Megan M; McCulloch, Denise J; Chow, Eric J; Chu, Helen Y	284. Post-Acute Sequelae of COVID-19 Two Years After Acute Infection	https://doi.org/10.1093/ofid/ofac492.362	Published	2022-12-01	Study	https://doi.org/10.1093/ofid/ofac492.362	The post-acute sequelae of COVID-19 (PASC) includes a constellation of debilitating symptoms after SARS-CoV-2 infection. Much remains unknown about the long-term health burden of COVID-19. We describe the symptom course and quality of life of adults up to 2 years after mild acute COVID-19.Adults within 30 days of laboratory-confirmed acute COVID-19 were enrolled as cases from January – September 2020 and followed for 2 years. Demographic and symptom data were collected in an enrollment survey and at 6, 12 and 24 months post-infection. Surveys included vaccination status, symptom course, and quality of life assessments (Fatigue Assessment Scale (FAS) and EuroQual visual analog scale (VAS)). A cohort of SARS-CoV-2 uninfected controls was concurrently enrolled and surveyed. We used descriptive statistics to compare cases and controls and defined a p-value < 0.05 as significant.A total of 112 of 239 enrolled cases and 44 of 59 controls completed all surveys. Of the 112 cases, 105 (94%) had mild disease. In the 6, 12 and 24 month surveys, 39 (35%), 48 (43%) and 56 (50%) cases indicated at least one persistent symptom, respectively, compared to 4 (9%), 5 (11%) and 6 (14%) controls (Table 1). In all 3 surveys, fatigue and altered smell or taste were the most common post-infection symptoms among cases (Figure 1). At 2 years, 40 (36%) cases reported symptoms were improving or resolved and 30 (27%) reported symptoms continued to wax and wane. Symptoms improved and worsened for 10 and 4 cases, respectively, following a complete SARS-CoV-2 vaccination. 46% reported seeking medical attention for persistent symptoms and 34% of those employed reported symptoms negatively impacted their ability to work. When compared to controls in the 12 and 24 month surveys, cases had a significantly higher mean FAS score (p-value < 0.001 and 0.01, respectively) and significantly lower VAS score (p-value = 0.01 and < 0.001, respectively).Demographic and Clinical Characteristics of the Study Cohort a. Time since symptom onset in infected cohort and time since enrollment in healthy controlsb. Other race/ethnicity included American Indian or Alaska Native, Black or African American, Native Hawaiian or other Pacific Islander, and more than 1 race.Percentage of participants reporting symptoms at 6-, 12-, and 24-months *Symptoms associated with PASC were reported up to 2 years after infection with significant impacts on quality of life. These findings underscore the healthcare and societal burdens even after recovery from acute infection. As studies seek to identify the underlying mechanisms of PASC, prevention of acute infection remains the mainstay of COVID-19 burden mitigation.Helen Y. Chu, MD, MPH, Cepheid: Reagents\|Ellume: Advisor/Consultant\|Gates Ventures: Grant/Research Support\|Merck: Advisor/Consultant\|Pfizer: Advisor/Consultant.
244	MS242		Arjun, M. C.; Singh, Arvind Kumar; Pal, Debkumar; Das, Kajal; G, Alekhya; Venkateshan, Mahalingam; Mishra, Baijayantimala; Patro, Binod Kumar; Mohapatra, Prasanta Raghab; Subba, Sonu Hangma	Characteristics and predictors of Long COVID among diagnosed cases of COVID-19	https://doi.org/10.1371/journal.pone.0278825	Published	2022-12-20	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0278825	Background Long COVID or long-term symptoms after COVID-19 has the ability to affect health and quality of life. Knowledge about the burden and predictors could aid in their prevention and management. Most of the studies are from high-income countries and focus on severe acute COVID-19 cases. We did this study to estimate the incidence and identify the characteristics and predictors of Long COVID among our patients. Methodology We recruited adult (≥18 years) patients who were diagnosed as Reverse Transcription Polymerase Chain Reaction (RTPCR) confirmed SARS-COV-2 infection and were either hospitalized or tested on outpatient basis. Eligible participants were followed up telephonically after four weeks and six months of diagnosis of SARS-COV-2 infection to collect data on sociodemographic, clinical history, vaccination history, Cycle threshold (Ct) values during diagnosis and other variables. Characteristics of Long COVID were elicited, and multivariable logistic regression was done to find the predictors of Long COVID. Results We have analyzed 487 and 371 individual data with a median follow-up of 44 days (Inter quartile range (IQR): 39,47) and 223 days (IQR:195,251), respectively. Overall, Long COVID was reported by 29.2% (95% Confidence interval (CI): 25.3%,33.4%) and 9.4% (95% CI: 6.7%,12.9%) of participants at four weeks and six months of follow-up, respectively. Incidence of Long COVID among patients with mild/moderate disease (n = 415) was 23.4% (95% CI: 19.5%,27.7%) as compared to 62.5% (95% CI: 50.7%,73%) in severe/critical cases(n = 72) at four weeks of follow-up. At six months, the incidence among mild/moderate (n = 319) was 7.2% (95% CI:4.6%,10.6%) as compared to 23.1% (95% CI:12.5%,36.8%) in severe/critical (n = 52). The most common Long COVID symptom was fatigue. Statistically significant predictors of Long COVID at four weeks of follow-up were—Pre-existing medical conditions (Adjusted Odds ratio (aOR) = 2.00, 95% CI: 1.16,3.44), having a higher number of symptoms during acute phase of COVID-19 disease (aOR = 11.24, 95% CI: 4.00,31.51), two doses of COVID-19 vaccination (aOR = 2.32, 95% CI: 1.17,4.58), the severity of illness (aOR = 5.71, 95% CI: 3.00,10.89) and being admitted to hospital (Odds ratio (OR) = 3.89, 95% CI: 2.49,6.08). Conclusion A considerable proportion of COVID-19 cases reported Long COVID symptoms. More research is needed in Long COVID to objectively assess the symptoms and find the biological and radiological markers.
245	MS243		Kröönström, Linda Ashman; Krause, Johanna; Larsson, Simon B.; Sigström, Robert; Sunnerhagen, Katharina Stibrant	Long-term self-reported health and disability after COVID-19 in public employees	https://doi.org/10.1186/s12889-022-14820-3	Published	2022-12-21	Study	https://doi.org/10.1186/s12889-022-14820-3	Abstract Background Although the symptomatology has been assessed in multiple studies among persons recovering from coronavirus disease 2019 (COVID-19), less is known regarding long-term general health and disability. We aimed to assess long-term self-reported disability in public employees after predominantly mild COVID-19 in comparison with individuals who had negative COVID-19 polymerase chain reaction (PCR) test results. Methods Public employees within Region Västra Götaland were offered tests to identify SARS-CoV-2 infection (n = 56,221) and were invited to complete an online survey that included the World Health Organization Disability Assessment Schedule. Questionnaires were sent out between January 26 and March 5, 2021. A total of 14,222 (25.3%) employees responded, of which 10,194 (18%) were included (women n = 8749, 85.8%). Of these, 7185 (70.5%) participants had a negative PCR test result (controls). A total of 1425 (14%) had a positive PCR result and were categorized in the sub-acute phase (4–12 weeks post COVID-19), and 1584 (15.5%) had a positive PCR test and were categorized in the post COVID-19 phase (> 12 weeks). Results Fifty-two percent of controls rated disability of varying degrees, versus 73% and 64% of participants in the sub-acute and post COVID-19 phase, respectively. Being “emotionally affected” was the most frequently reported disability in the sub-acute phase, the post COVID-19 phase, as well as in controls. The proportion of participants reporting difficulties for 20–30 days was higher in the sub-acute phase than in the post COVID-19 phase (27.9% vs. 21.8%, p < 0.001) as well as in a comparison between participants in the post COVID-19 phase and controls (21.8% vs 14.2%, p < 0.001). Compared with controls, severe disability was more common in the post COVID-19 phase among both women (15.8% vs. 10.7%,), and men (9.8% vs. 6.8%). Conclusions Disability was present in all groups; however, reported disability was greater in the sub-acute phase than in the post COVID-19 phase. The higher levels of disability reported in the COVID-19 patient population may indicate a persisting need for rehabilitation and recovery. In general, women reported a greater degree of disability than men in the sub-acute and post COVID-19 phases.
246	MS244		Robertson, McKaylee M; Qasmieh, Saba A; Kulkarni, Sarah G; Teasdale, Chloe A; Jones, Heidi; McNairy, Margaret; Borrell, Luisa N; Nash, Denis	The epidemiology of long COVID in US adults	https://doi.org/10.1093/cid/ciac961	Published	2022-12-21	Study	https://doi.org/10.1093/cid/ciac961	We estimated the prevalence of long COVID and impact on daily living among a representative sample of adults in the United States (US).We conducted a population-representative survey, June 30-July 2, 2022, of a random sample of 3,042 United States adults aged 18 years or older and weighted to the 2020 US population. Using questions developed by the United Kingdom’s Office of National Statistics, we estimated the prevalence of long COVID, by sociodemographics, adjusting for gender and age.An estimated 7.3% (95% CI: 6.1-8.5%) of all respondents reported long COVID, corresponding to approximately 18,828,696 adults. One-quarter (25.3% [18.2-32.4%]) of respondents with long COVID reported their day-to-day activities were impacted ‘a lot’ and 28.9% had SARS-CoV-2 infection >12 months ago. The prevalence of long COVID was higher among respondents who were female (aPR: 1.84 [1.40-2.42]), had comorbidities (aPR: 1.55 [1.19-2.00]) or were not (versus were) boosted (aPR: 1.67 [1.19-2.34]) or not vaccinated (versus boosted) (aPR: 1.41 (1.05-1.91)).We observed a high burden of long COVID, substantial variability in prevalence of SARS-CoV-2 and risk factors unique from SARS-CoV-2 risk, suggesting areas for future research. Population-based surveys are an important surveillance tool and supplement to ongoing efforts to monitor long COVID.
247	MS245		Khan, Nabeel; Mahmud, Nadim; Patel, Manthankumar; Sundararajan, Ramaswamy; Reinisch, Walter	Incidence of Long COVID and impact of medications on the risk of developing Long COVID in a nationwide cohort of IBD patients	https://doi.org/10.1016/j.cgh.2022.12.017	Published	2022-12-23	Study	https://www.sciencedirect.com/science/article/pii/S1542356522011843
248	MS246		Mizrahi, Barak; Sudry, Tamar; Flaks-Manov, Natalie; Yehezkelli, Yoav; Kalkstein, Nir; Akiva, Pinchas; Ekka-Zohar, Anat; David, Shirley Shapiro Ben; Lerner, Uri; Bivas-Benita, Maytal; Greenfeld, Shira	Long covid outcomes at one year after mild SARS-CoV-2 infection: nationwide cohort study	https://doi.org/10.1136/bmj-2022-072529	Published	1/11/2023	Study	https://www.bmj.com/content/380/bmj-2022-072529	Objectives To determine the clinical sequelae of long covid for a year after infection in patients with mild disease and to evaluate its association with age, sex, SARS-CoV-2 variants, and vaccination status. Design Retrospective nationwide cohort study. Setting Electronic medical records from an Israeli nationwide healthcare organisation. Population 1 913 234 Maccabi Healthcare Services members of all ages who did a polymerase chain reaction test for SARS-CoV-2 between 1 March 2020 and 1 October 2021. Main outcome measures Risk of an evidence based list of 70 reported long covid outcomes in unvaccinated patients infected with SARS-CoV-2 matched to uninfected people, adjusted for age and sex and stratified by SARS-CoV-2 variants, and risk in patients with a breakthrough SARS-CoV-2 infection compared with unvaccinated infected controls. Risks were compared using hazard ratios and risk differences per 10 000 patients measured during the early (30-180 days) and late (180-360 days) time periods after infection. Results Covid-19 infection was significantly associated with increased risks in early and late periods for anosmia and dysgeusia (hazard ratio 4.59 (95% confidence interval 3.63 to 5.80), risk difference 19.6 (95% confidence interval 16.9 to 22.4) in early period; 2.96 (2.29 to 3.82), 11.0 (8.5 to 13.6) in late period), cognitive impairment (1.85 (1.58 to 2.17), 12.8, (9.6 to 16.1); 1.69 (1.45 to 1.96), 13.3 (9.4 to 17.3)), dyspnoea (1.79 (1.68 to 1.90), 85.7 (76.9 to 94.5); 1.30 (1.22 to 1.38), 35.4 (26.3 to 44.6)), weakness (1.78 (1.69 to 1.88), 108.5, 98.4 to 118.6; 1.30 (1.22 to 1.37), 50.2 (39.4 to 61.1)), and palpitations (1.49 (1.35 to 1.64), 22.1 (16.8 to 27.4); 1.16 (1.05 to 1.27), 8.3 (2.4 to 14.1)) and with significant but lower excess risk for streptococcal tonsillitis and dizziness. Hair loss, chest pain, cough, myalgia, and respiratory disorders were significantly increased only during the early phase. Male and female patients showed minor differences, and children had fewer outcomes than adults during the early phase of covid-19, which mostly resolved in the late period. Findings remained consistent across SARS-CoV-2 variants. Vaccinated patients with a breakthrough SARS-CoV-2 infection had a lower risk for dyspnoea and similar risk for other outcomes compared with unvaccinated infected patients. Conclusions This nationwide study suggests that patients with mild covid-19 are at risk for a small number of health outcomes, most of which are resolved within a year from diagnosis.
249	MS247		Gil, Saulo; Gualano, Bruno; de Araújo, Adriana Ladeira; de Oliveira Júnior, Gersiel Nascimento; Damiano, Rodolfo Furlan; Pinna, Fabio; Imamura, Marta; Rocha, Vanderson; Kallas, Esper; Batistella, Linamara Rizzo; Forlenza, Orestes V.; de Carvalho, Carlos R. R.; Busatto, Geraldo Filho; Roschel, Hamilton	Post-acute sequelae of SARS-CoV-2 associates with physical inactivity in a cohort of COVID-19 survivors	https://doi.org/10.1038/s41598-022-26888-3	Published	1/5/2023	Study	https://www.nature.com/articles/s41598-022-26888-3	The aim of this study was to determine whether Post-acute Sequelae of SARS-CoV-2 Infection (PASC) are associated with physical inactivity in COVID-19 survivors. This is a cohort study of COVID-19 survivors discharged from a tertiary hospital in Sao Paulo, Brazil. Patients admitted as inpatients due to laboratory-confirmed COVID-19 between March and August 2020 were consecutively invited for a follow-up in-person visit 6 to 11 months after hospitalization. Ten symptoms of PASC were assessed using standardized scales. Physical activity was assessed by questionnaire and participants were classified according to WHO Guidelines. 614 patients were analyzed (age: 56 ± 13 years; 53% male). Frequency of physical inactivity in patients exhibiting none, at least 1, 1–4, and 5 or more symptoms of PASC was 51%, 62%, 58%, and 71%, respectively. Adjusted models showed that patients with one or more persistent PASC symptoms have greater odds of being physically inactive than those without any persistent symptoms (OR: 1.57 [95% CI 1.04–2.39], P = 0.032). Dyspnea (OR: 2.22 [1.50–3.33], P < 0.001), fatigue (OR: 2.01 [1.40–2.90], P < 0.001), insomnia (OR: 1.69 [1.16–2.49], P = 0.007), post-traumatic stress (OR: 1.53 [1.05–2.23], P = 0.028), and severe muscle/joint pain (OR: 1.53 [95% CI 1.08–2.17], P = 0.011) were associated with greater odds of being physically inactive. This study suggests that PASC is associated with physical inactivity, which itself may be considered as a persistent symptom among COVID-19 survivors. This may help in the early identification of patients who could benefit from additional interventions tailored to combat inactivity (even after treatment of PASC), with potential beneficial impacts on overall morbidity/mortality and health systems worldwide.
250	MS248		Sansone, Donatella; Tassinari, Alice; Valentinotti, Romina; Kontogiannis, Dimitra; Ronchese, Federico; Centonze, Sandro; Maggiore, Adele; Cegolon, Luca; Filon, Francesca Larese	Persistence of Symptoms 15 Months since COVID-19 Diagnosis: Prevalence, Risk Factors and Residual Work Ability	https://doi.org/10.3390/life13010097	Published	1/1/2023	Study	https://www.mdpi.com/2075-1729/13/1/97	Background: A proportion of patients’ ailments may last after recovering from acute COVID-19, with episodic and systemic symptoms of unclear etiology potentially involving different organs. Study aim: The aim of this study was to investigate the persistence of symptoms 15 months since COVID-19 diagnosis in patients referring to the post-COVID-19 clinic in Trieste (north-eastern Italy). Methods: Two-hundred-forty-seven patients were medically examined between 8 December 2020–6 April 2021, after a median time of 49 days since first positive swab test for SARS-CoV-2. After a median time of 15 months since COVID-19 diagnosis, the same patients were contacted over the phone and investigated by standardized questionnaire collecting information on any persisting symptoms and work ability index (WAI). Four multivariable logistic regression models were fitted to investigate factors associated with persistence of any respiratory, neurological, dysautonomic, or psychiatric symptoms at first (median time 49 days since COVID-19 diagnosis) as well as second (median 15 months since COVID-19 diagnosis) follow up. A multiple linear regression was also employed to investigate factors associated with higher mean WAI, assessed only at second follow up. Additionally, factors associated with persistence of symptoms 200+ days since COVID-19 diagnosis between first and second follow-up were investigated by multivariable Generalized Estimating Equation (GEE). Results: At first follow up (median time of 49 days since COVID-19 diagnosis) symptoms more frequently reported were fatigue (80.2%), shortness of breath (69.6%), concentration deficit (44.9%), headache (44.9%), myalgia (44.1%), arthralgia (43.3%), and anosmia (42.1%). At second follow-up (median time of 15 months since COVID-19 diagnosis) 75% patients returned to their baseline status preceding COVID-19. At first follow up males were less likely to experience neurological (OR = 0.16; 95% CI: 0.08; 0.35) as well as psychiatric (OR = 0.43; 95% CI: 0.23; 0.80) symptoms as compared to females. At first follow up, the risk of neurological symptoms increased also linearly with age (OR = 1.04; 95% CI: 1.01; 1.08) and pre-existing depression was a major risk factor for persisting dysautonomic (aOR = 6.35; 95% CI: 2.01; 20.11) as well as psychiatric symptoms (omitted estimate). Consistently, at second follow up only females experience psychiatric symptoms, whereas males exhibited significantly higher mean WAI (RC = 0.50; 95% CI: 0.11; 0.88). Additionally, neurological symptoms at second follow up were more likely in patients with pre-existing comorbidities (OR = 4.31; 95% CI: 1.27; 14.7). Finally, persistence of symptoms lasting 200+ days since COVID-19 diagnosis increased linearly with age (OR = 1.03; 95% CI 1.01–1.05) and were more likely in patients affected by pre-existing depression (OR = 2.68; 95% CI 1.60; 4.49). Conclusions: Following a median time of 15 months since first positive swab test, 75% patients with symptoms returned to their baseline health status preceding COVID-19. Females had a significantly lower WAI and were more likely to experience psychiatric symptoms at second follow up (15 months since COVID-19 diagnosis). Furthermore, the risk of symptoms persisting 200+ days since COVID-19 diagnosis increased with history of depression, endorsing the hypothesis that long-COVID-19 symptoms may be at least partially explained by pre-existing psychological conditions. Patient rehabilitation and psychological support may therefore play a key role in caring patients with the so called long COVID-19 syndrome.
251	MS249		Rosa, Regis Goulart; Cavalcanti, Alexandre Biasi; Azevedo, Luciano César Pontes; Veiga, Viviane Cordeiro; de Souza, Denise; dos Santos, Rosa da Rosa Minho; Schardosim, Raíne Fogliati de Carli; Rech, Gabriela Soares; Trott, Geraldine; Schneider, Daniel; Robinson, Caroline Cabral; Haubert, Tainá Aparecida; Pallaoro, Victoria Emanuele Lobo; Brognoli, Liége Gregoletto; de Souza, Ana Paula; Costa, Lauren Sezerá; Barroso, Bruna Machado; Pelliccioli, Melissa Pezzetti; Gonzaga, Janine; Studier, Nicole dos Santos; Dagnino, Ana Paula Aquistapase; Neto, Juliana de Mesquita; da Silva, Sabrina Souza; Gimenes, Bruna dos Passos; dos Santos, Vanessa Brzoskowski; Estivalete, Gabriel Pozza Muller; Pellegrino, Carolina de Moraes; Polanczyk, Carisi Anne; Kawano-Dourado, Letícia; Tomazini, Bruno Martins; Lisboa, Thiago Costa; Teixeira, Cassiano; Zampieri, Fernando Godinho; Zavascki, Alexandre Prehn; Gersh, Bernard J.; Avezum, Álvaro; Machado, Flávia Ribeiro; Berwanger, Otavio; Lopes, Renato Delascio; Falavigna, Maicon	Association between acute disease severity and one-year quality of life among post-hospitalisation COVID-19 patients: Coalition VII prospective cohort study	https://doi.org/10.1007/s00134-022-06953-1	Published	1/3/2023	Study	https://doi.org/10.1007/s00134-022-06953-1	Purpose To assess the association between acute disease severity and 1-year quality of life in patients discharged after hospitalisation due to coronavirus disease 2019 (COVID-19). Methods We conducted a prospective cohort study nested in 5 randomised clinical trials between March 2020 and March 2022 at 84 sites in Brazil. Adult post-hospitalisation COVID-19 patients were followed for 1 year. The primary outcome was the utility score of EuroQol five-dimension three-level (EQ-5D-3L). Secondary outcomes included all-cause mortality, major cardiovascular events, and new disabilities in instrumental activities of daily living. Adjusted generalised estimating equations were used to assess the association between outcomes and acute disease severity according to the highest level on a modified ordinal scale during hospital stay (2: no oxygen therapy; 3: oxygen by mask or nasal prongs; 4: high-flow nasal cannula oxygen therapy or non-invasive ventilation; 5: mechanical ventilation). Results 1508 COVID-19 survivors were enrolled. Primary outcome data were available for 1156 participants. At 1 year, compared with severity score 2, severity score 5 was associated with lower EQ-5D-3L utility scores (0.7 vs 0.84; adjusted difference, − 0.1 [95% CI − 0.15 to − 0.06]); and worse results for all-cause mortality (7.9% vs 1.2%; adjusted difference, 7.1% [95% CI 2.5%–11.8%]), major cardiovascular events (5.6% vs 2.3%; adjusted difference, 2.6% [95% CI 0.6%–4.6%]), and new disabilities (40.4% vs 23.5%; adjusted difference, 15.5% [95% CI 8.5%–22.5]). Severity scores 3 and 4 did not differ consistently from score 2. Conclusions COVID-19 patients who needed mechanical ventilation during hospitalisation have lower 1-year quality of life than COVID-19 patients who did not need mechanical ventilation during hospitalisation. Take-home message After 1 year of follow-up, patients with more severe COVID-19, defined as need for mechanical ventilation during hospitalisation, had significantly lower health-related quality of life and worse results for mortality, major cardiovascular events, re-hospitalisation, new disabilities in instrumental activities of daily living, anxiety and post-traumatic stress symptoms, and return to work or study than COVID-19 patients who did not need mechanical ventilation during hospitalisation
252	MS250		Aubert, M.; Ohayon, R.; Freymond, N.; Catoire, S.; Couraud, S.; Fontaine-Delaruelle, C.	Exploration cardiorespiratoire à l’effort des patients présentant un syndrome post-COVID	https://doi.org/10.1016/j.rmra.2022.11.097	Published	2023-01-01	Study	https://www.sciencedirect.com/science/article/pii/S1877120322002671	Introduction Les symptômes du syndrome post-COVID, y compris respiratoires, sont souvent inexpliqués par les explorations fonctionnelles respiratoires de repos (EFR), le scanner thoracique et l’échographie cardiaque. L’épreuve d’effort maximale cardiorespiratoire (EFX) permet d’explorer ces symptômes. Méthodes Il s’agit d’une étude rétrospective monocentrique. Les résultats des EFX des patients présentant un syndrome post-COVID avec des EFR normales sont rapportés ainsi que les facteurs favorisant une altération de la VO2pic et un déconditionnement à l’effort. Résultats Cinquante patients ont été inclus, dont 62 % de femmes ; 60 % avaient bénéficié d’une prise en charge initiale ambulatoire. La moyenne de VO2pic était de 20,6mL/min/kg soit 81,1 % de la valeur maximale théorique. Une intolérance à l’effort a été mise en évidence chez 62 % des patients, et un déconditionnement périphérique chez 14 % des patients. La présence d’anomalies au scanner en post-COVID-19, la gravité initiale et l’obésité ne semblaient pas altérer la VO2pic. Conclusion Cette étude met en évidence une proportion significative d’intolérance à l’effort et de déconditionnement périphérique chez 50 patients atteints de syndrome post-COVID avec une fonction respiratoire normale. Cela suggère l’importance de la réhabilitation à l’effort et la nécessité d’études permettant l’analyse des EFX et de l’évolution des symptômes après réhabilitation.
253	MS251		da Costa e Silva, Grazielle Rosa; Moura, Winny Éveny Alves; dos Santos, Kamila Cardoso; Gomes, Davi Oliveira; Bandeira, Gabriela Nolasco; Guimarães, Rafael Alves; Rosso, Claci Fátima Weirich; Bazilio, Gabriela Silvério; Leite, Vanessa Rafaela Milhomem Cruz; Caetano, Karlla Antonieta Amorim; Carneiro, Megmar Aparecida dos Santos; Teles, Sheila Araújo	Long-Term Symptoms after Mild Coronavirus Disease in Healthy Healthcare Professionals: A 12-Month Prospective Cohort Study	https://doi.org/10.3390/ijerph20021483	Published	2023-01-01	Study	https://www.mdpi.com/1660-4601/20/2/1483	The coronavirus disease 2019 (COVID-19) pandemic has changed the course of human history and killed millions of people worldwide. Its long-term consequences remain uncertain. This study aimed to describe the short- and long-term symptoms of COVID-19 among individuals in Goiás, central Brazil, who experienced acute mild or non-symptomatic SARS-CoV-2 infection during the first wave of the pandemic. This prospective cohort study included 110 healthcare workers, 18 safety workers, and 19 administrative support workers, who were followed up for 12 months after the onset of COVID-19. Most participants were healthy adult female healthcare professionals. At the onset of infection, the major symptoms were headache, myalgia, nasal congestion, cough, coryza, anosmia, ageusia, sore throat, fatigue, diarrhea, and dyspnea. Furthermore, 20.3% of the participants had three or more COVID-19 symptoms that persisted for at least 12 months. These included coryza, congestion, hair loss, sore throat, headache, myalgia, cough, memory loss, anosmia, and fatigue. This study revealed a high prevalence of persistent symptoms of COVID-19 in healthy individuals from central Brazil, which may present an additional burden on healthcare services. Further studies are required to investigate the sequelae of COVID-19 over periods greater than 12 months.
254	MS252		Muraro, Ana Paula; Rocha, Roseany; Boing, Alexandra Crispim; Oliveira, Ligia Regina de; Melanda, Francine Nesello; Andrade, Amanda Cristina de Souza	Deaths from post-COVID conditions in Brazil	https://doi.org/10.1590/1413-81232023282.16752022	Published	2023-01-16	Study	https://www.scielosp.org/article/csc/2023.v28n2/331-336/en/	This paper aims to assess the magnitude and profile of deaths from post-COVID conditions in Brazil. Descriptive study based on preliminary data from the 2021 Mortality Information System. Records with ICD code B94.8 as the Basic Cause and with code U09 in some lines of part I or II of the declaration were considered for analysis. The distribution of deaths by geographic region, semester of occurrence, sex, age group, ethnicity/skin color, schooling, and place of occurrence was evaluated. We identified 2,948 deaths from conditions subsequent to COVID-19 were recorded, ranging from 0.5 deaths per 1,000 records in the Northeast Region to 3.6/1,000 in the Midwest Region. More than half occurred among males (58.0%), those aged 60 years or older (66.9%), and whites (51.8%). Conclusion: Deaths from post-COVID conditions had distinct sociodemographic characteristics between regions. publisher: ABRASCO - Associação Brasileira de Saúde Coletiva
255	MS253		Ma, Yirui; Deng, Jie; Liu, Qiao; Du, Min; Liu, Min; Liu, Jue	Long-Term Consequences of Asymptomatic SARS-CoV-2 Infection: A Systematic Review and Meta-Analysis	https://doi.org/10.3390/ijerph20021613	Published	2023-01-01	Review	https://www.mdpi.com/1660-4601/20/2/1613	Little is known about the long-term consequences of asymptomatic infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to review the data available to explore the long-term consequences of asymptomatic SARS-CoV-2 infection in the real world. We searched observational cohort studies that described the long-term health effects of asymptomatic SARS-CoV-2 infections. Random-effects inverse-variance models were used to evaluate the pooled prevalence (PP) and its 95% confidence interval (CI) of long-term symptoms. Random effects were used to estimate the pooled odds ratios (OR) and its 95%CI of different long-term symptoms between symptomatic and asymptomatic infections. Five studies involving a total of 1643 cases, including 597 cases of asymptomatic and 1043 cases of symptomatic SARS-CoV-2 infection were included in this meta-analysis. The PPs of long-term consequences after asymptomatic SARS-CoV-2 infections were 17.13% (95%CI, 7.55–26.71%) for at least one symptom, 15.09% (95%CI, 5.46–24.73%) for loss of taste, 14.14% (95%CI, −1.32–29.61%) for loss of smell, and 9.33% (95%CI, 3.07–15.60) for fatigue. Compared with symptomatic SARS-CoV-2 infection, asymptomatic infection was associated with a significantly lower risk of developing COVID-19-related sequelae (p < 0.05), with 80% lower risk of developing at least one symptom (OR = 0.20, 95%CI, 0.09–0.45), 81% lower risk of fatigue (OR = 0.19, 95%CI, 0.08–0.49), 90% lower risk of loss of taste/smell (OR = 0.10, 95%CI, 0.02–0.58). Our results suggested that there were long-term effects of asymptomatic SARS-CoV-2 infection, such as loss of taste or smell, fatigue, cough and so on. However, the risk of developing long-term symptoms in asymptomatic SARS-CoV-2 infected persons was significantly lower than those in symptomatic SARS-CoV-2 infection cases.
256	MS254		Burton, Christopher; Dawes, Helen; Goodwill, Simon; Thelwell, Michael; Dalton, Caroline	Within and between-day variation and associations of symptoms in Long Covid: Intensive longitudinal study	https://doi.org/10.1371/journal.pone.0280343	Published	2023-01-19	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0280343	Background People with Long Covid (Post Covid-19 Condition) describe multiple symptoms which vary between and within individuals over relatively short time intervals. We aimed to describe the real-time associations between different symptoms and between symptoms and physical activity at the individual patient level. Methods and findings Intensive longitudinal study of 82 adults with self-reported Long Covid (median duration 12–18 months). Data collection involved a smartphone app with 5 daily entries over 14 days and continuous wearing of a wrist accelerometer. Data items included 7 symptoms (Visual Analog Scales) and perceived demands in the preceding period (Likert scales). Activity was measured using mean acceleration in the 3-hour periods preceding and following app data entry. Analysis used within-person correlations of symptoms pairs and both pooled and individual symptom networks derived from graphical vector autoregression. App data was suitable for analysis from 74 participants (90%) comprising 4022 entries representing 77.6% of possible entries. Symptoms varied substantially within individuals and were only weakly autocorrelated. The strongest between-subject symptom correlations were of fatigue with pain (partial coefficient 0.5) and cognitive difficulty with light-headedness (0.41). Pooled within-subject correlations showed fatigue correlated with cognitive difficulty (partial coefficient 0.2) pain (0.19) breathlessness (0.15) and light-headedness (0.12) but not anxiety. Cognitive difficulty was correlated with anxiety and light-headedness (partial coefficients 0.16 and 0.17). Individual participant correlation heatmaps and symptom networks showed no clear patterns indicative of distinct phenotypes. Symptoms, including fatigue, were inconsistently correlated with prior or subsequent physical activity: this may reflect adjustment of activity in response to symptoms. Delayed worsening of symptoms after the highest activity peak was observed in 7 participants. Conclusion Symptoms of Long Covid vary within individuals over short time scales, with heterogenous patterns of symptom correlation. The findings are compatible with altered central symptom processing as an additional factor in Long Covid.
257	MS255		Shanbehzadeh, Sanaz; Zanjari, Nasibeh; Yassin, Marzieh; Yassin, Zeynab; Tavahomi, Mahnaz	Association between long COVID, functional activity, and health-related quality of life in older adults	https://doi.org/10.1186/s12877-023-03757-w	Published	2023-01-23	Study	https://doi.org/10.1186/s12877-023-03757-w	Background Older adults experience persistent symptoms post-COVID-19, termed as Long COVID, affecting their physical and mental health. This study aimed to evaluate the effects of Long COVID, level of physical activity, and functional decline on older adults’ health-related quality of life post-COVID-19. Methods This cross-sectional study was conducted on 121 older adults with 60 to 90 years old post-coronavirus infection. The standardized metrics used in the study were Fatigue Severity Scale, Physical Activity Elderly, SF12, Post-COVID-19 functional status scale, and COVID-19 Yorkshire rehabilitation screening scale. The severity of coronavirus infection was evaluated by changes in chest CT scan images and O2 saturation at hospital admission. Data were analyzed using linear regression analyses. Results The results of regression analysis revealed six factors to be predictors of physical health at 6 months post-COVID-19 (F = 9.046, P < 0.001; explained variance 63%), which the significant factors were fatigue, level of physical activity, worsened pain, difficulties in activities of daily living and cognitive-communication problems. Among these factors, greater fatigue and worsened pain intensity were the strongest predictors. Mental health was associated with days of hospitalization and cognitive-communication problems (F = 2.866, P < 0.001; explained variance 35%). Conclusions Considering the negative impact of fatigue, pain, low physical activity, and cognitive-communication problems on health-related quality of life, early and accurate evaluation and management are required for recovered older adults post-COVID-19.
258	MS256		Vásconez-González, Jorge; Fernandez-Naranjo, Raul; Izquierdo-Condoy, Juan S.; Delgado-Moreira, Karen; Cordovez, Simone; Tello-De-la-Torre, Andrea; Paz, Clara; Castillo, Diana; Izquierdo-Condoy, Nathaly; Carrington, Sarah J; Ortiz-Prado, Esteban	Comparative analysis of long-term self-reported COVID-19 symptoms among pregnant women	https://doi.org/10.1016/j.jiph.2023.01.012	Published	2023-01-20	Study	https://www.sciencedirect.com/science/article/pii/S1876034123000229	Background The negative effects of COVID-19 infections during pregnancy have been amply described, however, the persistent sequels of this infection have not been explored so far. Objective The aim of this study was to describe persisting symptoms after COVID-19 infection in pregnant and non-pregnant women in Ecuador. Methods A cross-sectional analysis based on an online, self-reporting questionnaire was conducted in Ecuador from April to July 2022. Participants were invited by social media, radio, and TV to voluntarily participate in our study. A total of 457 surveys were included in this study. We compared risk factor variables and long-term persisting symptoms of pregnant and non-pregnant women in Ecuador. Results Overall, 247 (54.1%) responders claimed to have long-term symptoms after SARS-CoV-2 infection. Most of these symptoms were reported by non-pregnant women (94.0%). The most common Long-COVID symptoms in pregnant women were fatigue (10.6%), hair loss (9.6%), and difficulty concentrating (6.2%). We found that pregnant women who smoked had a higher risk of suffering fatigue. Conclusions The most frequent Long-COVID symptoms in pregnant women were fatigue, hair loss, and difficulty concentrating. Apparently, the patterns of presentation of long-term sequelae of SARS-CoV-2 infection in pregnant women do not differ significantly from reports available from studies in the general population.
259	MS257		Burton, Christopher; Dawes, Helen; Goodwill, Simon; Thelwell, Michael; Dalton, Caroline	Within and between-day variation and associations of symptoms in Long Covid: Intensive longitudinal study	https://doi.org/10.1371/journal.pone.0280343	Published	2023-01-19	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0280343	Background People with Long Covid (Post Covid-19 Condition) describe multiple symptoms which vary between and within individuals over relatively short time intervals. We aimed to describe the real-time associations between different symptoms and between symptoms and physical activity at the individual patient level. Methods and findings Intensive longitudinal study of 82 adults with self-reported Long Covid (median duration 12–18 months). Data collection involved a smartphone app with 5 daily entries over 14 days and continuous wearing of a wrist accelerometer. Data items included 7 symptoms (Visual Analog Scales) and perceived demands in the preceding period (Likert scales). Activity was measured using mean acceleration in the 3-hour periods preceding and following app data entry. Analysis used within-person correlations of symptoms pairs and both pooled and individual symptom networks derived from graphical vector autoregression. App data was suitable for analysis from 74 participants (90%) comprising 4022 entries representing 77.6% of possible entries. Symptoms varied substantially within individuals and were only weakly autocorrelated. The strongest between-subject symptom correlations were of fatigue with pain (partial coefficient 0.5) and cognitive difficulty with light-headedness (0.41). Pooled within-subject correlations showed fatigue correlated with cognitive difficulty (partial coefficient 0.2) pain (0.19) breathlessness (0.15) and light-headedness (0.12) but not anxiety. Cognitive difficulty was correlated with anxiety and light-headedness (partial coefficients 0.16 and 0.17). Individual participant correlation heatmaps and symptom networks showed no clear patterns indicative of distinct phenotypes. Symptoms, including fatigue, were inconsistently correlated with prior or subsequent physical activity: this may reflect adjustment of activity in response to symptoms. Delayed worsening of symptoms after the highest activity peak was observed in 7 participants. Conclusion Symptoms of Long Covid vary within individuals over short time scales, with heterogenous patterns of symptom correlation. The findings are compatible with altered central symptom processing as an additional factor in Long Covid.
260	MS258		Squillace, Nicola; Cogliandro, Viola; Rossi, Emanuela; Bellelli, Giuseppe; Pozzi, Matteo; Luppi, Fabrizio; Lettino, Maddalena; Strepparava, Maria Grazia; Ferrarese, Carlo; Pollastri, Ester; Ricci, Elena; Bonfanti, Paolo; Bellani, Giacomo; Biondi, Andrea; Cazzaniga, Marina Elena; Citerio, Giuseppe; Contro, Ernesto; Foti, Giuseppe; Valsecchi, Maria Grazia; Rugova, Alban; Beretta, Eleonora Maria; Iannace, Marta; Spolti, Anna; Orsini, Valentina; Malafronte, Cristina; Valagussa, Laura; Ferlicca, Daniela; Bettini, Francesca; Bellin, Valeria; Meroni, Valeria; Calabria, Mariangela; Gatti, Stefano; Bronco, Alfio; Ripa, Claudio; Sosio, Simone; Faverio, Paola; Monzani, Anna; Ferrara, Maria Cristina; Zarcone, Cristina; Ferrarese, Carlo; Beretta, Simone; Salvarani, Valerio; Mauri, Ornella; Da Re, Carolina; Carrer, Andrea; for the STORM Long-COVID Team	A multidisciplinary approach to screen the post-COVID-19 conditions	https://doi.org/10.1186/s12879-023-08006-4	Published	2023-01-24	Study	https://doi.org/10.1186/s12879-023-08006-4	Background Post-COronaVIrus Disease 2019 (COVID-19) conditions (PCC) include multiple symptoms afflicting different organs and systems. To evaluate the frequency and type of them, we described our multidisciplinary approach with preliminary results of the first enrolled patients. Methods We included patients aged ≥ 18 years with hospital admission for confirmed SARS-CoV-2 infection. Symptoms were grouped in five macro groups hereafter referred to as "Symptoms Category" (SC): respiratory SC (dyspnoea or cough), neurological SC (peripheral neuropathies, headache, impaired mobility, behavioural disorders), psychological SC (sleep disorders, mood disorders), muscular SC (arthromyalgia, asthenia), other SC (fever, alopecia, diarrhoea, weight loss, smell and taste alterations, sexual dysfunctions). SC were evaluated at discharge and at follow-up. Association between patients’ characteristics and presence of SC at follow up was estimated by a logistic multivariable regression model. Results From June 2020 to July 2021, we followed up 361 patients: 128 (35.5%) who were previously admitted to Intensive Care Unit (ICU) and 233 patients to ordinary department. The median length of hospital stay was 20 days (Inter-Quartile-Range 13–32). Most patients (317/361, 87.8%) were still symptomatic at discharge, with one third referring three or more SC. At follow up, 67.3% (243/361) of patients still complained at least one SC. Moreover, 159 patients (44%) developed at least one new involved SC during follow up: 116 (72.9%) one SC, 39 (24.5%) two SC, 4 (2.5%) three or more SC. At follow up visit 130 of 361 (36%) were still with SC developed during follow up. At multivariable analysis presence of any SC at follow-up was associated with male gender (Odds Ratio [OR] 3.23, Confidence Interval [CI] 95% 1.46–7.15), ICU admission (OR 2.78, CI 95% 1.29–5.96) and presence of SC at discharge (OR 14.39, CI 95% 6.41–32.32). Conclusions In our sample of patients with severe COVID-19, we found that PCC are highly variable and fluctuating over time; in particular, in about 50% of our patients new SC appear during follow up. Moreover, presence of PCC also in patients without SC at discharge and the variability of symptoms underlining the advisability of our multidisciplinary approach.
261	MS259		O'Mahoney, Lauren L.; Routen, Ash; Gillies, Clare; Ekezie, Winifred; Welford, Anneka; Zhang, Alexa; Karamchandani, Urvi; Simms-Williams, Nikita; Cassambai, Shabana; Ardavani, Ashkon; Wilkinson, Thomas J.; Hawthorne, Grace; Curtis, Ffion; Kingsnorth, Andrew P.; Almaqhawi, Abdullah; Ward, Thomas; Ayoubkhani, Daniel; Banerjee, Amitava; Calvert, Melanie; Shafran, Roz; Stephenson, Terence; Sterne, Jonathan; Ward, Helen; Evans, Rachael A.; Zaccardi, Francesco; Wright, Shaney; Khunti, Kamlesh	The prevalence and long-term health effects of Long Covid among hospitalised and non-hospitalised populations: a systematic review and meta-analysis	https://doi.org/10.1016/j.eclinm.2022.101762	Published	2023-01-01	Study	https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(22)00491-6/fulltext	Background The aim of this study was to systematically synthesise the global evidence on the prevalence of persistent symptoms in a general post COVID-19 population. Methods A systematic literature search was conducted using multiple electronic databases (MEDLINE and The Cochrane Library, Scopus, CINAHL, and medRxiv) until January 2022. Studies with at least 100 people with confirmed or self-reported COVID-19 symptoms at ≥28 days following infection onset were included. Patient-reported outcome measures and clinical investigations were both assessed. Results were analysed descriptively, and meta-analyses were conducted to derive prevalence estimates. This study was pre-registered (PROSPERO-ID: CRD42021238247). Findings 194 studies totalling 735,006 participants were included, with five studies conducted in those <18 years of age. Most studies were conducted in Europe (n = 106) or Asia (n = 49), and the time to follow-up ranged from ≥28 days to 387 days. 122 studies reported data on hospitalised patients, 18 on non-hospitalised, and 54 on hospitalised and non-hospitalised combined (mixed). On average, at least 45% of COVID-19 survivors, regardless of hospitalisation status, went on to experience at least one unresolved symptom (mean follow-up 126 days). Fatigue was frequently reported across hospitalised (28.4%; 95% CI 24.7%–32.5%), non-hospitalised (34.8%; 95% CI 17.6%–57.2%), and mixed (25.2%; 95% CI 17.7%–34.6%) cohorts. Amongst the hospitalised cohort, abnormal CT patterns/x-rays were frequently reported (45.3%; 95% CI 35.3%–55.7%), alongside ground glass opacification (41.1%; 95% CI 25.7%–58.5%), and impaired diffusion capacity for carbon monoxide (31.7%; 95% CI 25.8%–3.2%). Interpretation Our work shows that 45% of COVID-19 survivors, regardless of hospitalisation status, were experiencing a range of unresolved symptoms at ∼ 4 months. Current understanding is limited by heterogeneous study design, follow-up durations, and measurement methods. Definition of subtypes of Long Covid is unclear, subsequently hampering effective treatment/management strategies.Publisher: Elsevier PMID: 36474804
262	MS260		Morioka, S.; Tsuzuki, S.; Maruki, T.; Terada, M.; Miyazato, Y.; Kutsuna, S.; Saito, S.; Shimanishi, Y.; Takahashi, K.; Sanada, M.; Ashida, S.; Akashi, M.; Kuge, C.; Osanai, Y.; Tanaka, K.; Suzuki, M.; Hayakawa, K.; Ohmagari, N.	Epidemiology of post-COVID conditions beyond 1 year: a cross-sectional study	https://doi.org/10.1016/j.puhe.2023.01.008	Published	2023-03-01	Study	https://www.sciencedirect.com/science/article/pii/S0033350623000173	Objective The aim of this study was to investigate the epidemiology of post-COVID conditions beyond 12 months and identify factors associated with the persistence of each condition. Study design This was a cross-sectional questionnaire-based survey. Methods We conducted the survey among patients who had recovered from COVID-19 and visited our institute between February 2020 and November 2021. Demographic and clinical data and data regarding the presence and duration of post-COVID conditions were obtained. We identified factors associated with the persistence of post-COVID conditions using multivariable linear regression analyses. Results Of 1148 surveyed patients, 502 completed the survey (response rate, 43.7%). Of these, 393 patients (86.4%) had mild disease in the acute phase. The proportion of participants with at least one symptom at 6, 12, 18, and 24 months after symptom onset or COVID-19 diagnosis was 32.3% (124/384), 30.5% (71/233), 25.8% (24/93), and 33.3% (2/6), respectively. The observed associations were as follows: fatigue persistence with moderate or severe COVID-19 (β = 0.53, 95% confidence interval [CI] = 0.06–0.99); shortness of breath with moderate or severe COVID-19 (β = 1.39, 95% CI = 0.91–1.87); cough with moderate or severe COVID-19 (β = 0.84, 95% CI = 0.40–1.29); dysosmia with being female (β = −0.57, 95% CI = −0.97 to −0.18) and absence of underlying medical conditions (β = −0.43, 95% CI = −0.82 to −0.05); hair loss with being female (β = −0.61, 95% CI = −1.00 to −0.22), absence of underlying medical conditions (β = −0.42, 95% CI = −0.80 to 0.04), and moderate or severe COVID-19 (β = 0.97, 95% CI = 0.41–1.54); depressed mood with younger age (β = −0.02, 95% CI = −0.04 to −0.004); and loss of concentration with being female (β = −0.51, 95% CI = −0.94 to −0.09). Conclusions More than one-fourth of patients after recovery from COVID-19, most of whom had had mild disease in the acute phase, had at least one symptom at 6, 12, 18, and 24 months after onset of COVID-19, indicating that not a few patients with COVID-19 suffer from long-term residual symptoms, even in mild cases.
263	MS261		Jacobs, Molly M.; Evans, Elizabeth; Ellis, Charles	Racial, ethnic, and sex disparities in the incidence and cognitive symptomology of long COVID-19	https://doi.org/10.1016/j.jnma.2023.01.016	Published	2023-02-13	Study	https://www.sciencedirect.com/science/article/pii/S0027968423000251	Background The pandemic has highlighted and exacerbated health inequities in both acute coronavirus disease 2019 (COVID‐19) and its longer‐term sequelae. Given the heterogeneity in definitions of long COVID and the lack of centralized registries of patients with the disease, little is known about the differential prevalence among racial, ethnic, and sex subgroups. This study examines long COVID among Black, White, Asian, and Hispanic Americans and evaluates differences in the associated cognitive symptomology. Method Data from four releases of the Census Bureau's Household Pulse Survey detailing COVID-19 incidence and the duration and type of symptoms among a nationally representative sample of adults from June 1, 2022, through October 17, 2022, were combined. Binary logistic regression assessed the relative likelihood of long COVID among those who had been diagnosed COVID between racial, ethnic, and sex subgroups. Among those reporting long COVID, differences in the prevalence of difficulty understanding and difficulty remembering were assessed. Empirical models accounted for household, regional, vaccination, and insurance differences between respondents. Two-stage selection models were applied to test the robustness of the results. Results Among respondents who tested positive for COVID-19, Blacks (OR=1.097, CI=1.034-1.163), females (OR=1.849, CI=1.794-1.907), and Hispanics (OR=1.349, CI=1.286-1.414) were more likely to experience long COVID (symptoms lasting for 3 months or longer) compared to Whites, males, and non-Hispanics respectively. However, those with private health insurance (OR=0.634, CI=0.611-0.658) and who received the COVID vaccine (OR=0.901, CI=0.864-0.94) were less likely to have endured COVID symptoms than their counterparts. Symptoms of long COVID varied significantly between population subgroups. Compared to Whites, Blacks were more likely to have trouble remembering (OR=1.878, CI=1.765-1.808) while Hispanics were more likely to report difficult understanding (OR=1.827, CI=1.413, 2.362). Females, compared to males, were less likely to experience trouble understanding (OR=0.664, CI=0.537, 0.821), but more likely to report trouble remembering (OR=1.34, CI=1.237, 1.451). Conclusions Long COVID is more prevalent among Blacks, Hispanics, and females, but each group appears to experience long COVID differently. Therefore, additional research is needed to determine the best method to treat and manage this poorly understood condition.
264	MS262		Paradowska-Nowakowska, Elżbieta; Łoboda, Danuta; Gołba, Krzysztof S.; Sarecka-Hujar, Beata	Long COVID-19 Syndrome Severity According to Sex, Time from the Onset of the Disease, and Exercise Capacity—The Results of a Cross-Sectional Study	https://doi.org/10.3390/life13020508	Published	2023-02-01	Study	https://www.mdpi.com/2075-1729/13/2/508	Symptoms of long COVID-19 syndrome (long COVID-19) are reported by 80% of convalescents up to several months after contracting the coronavirus-19 disease (COVID-19). The study aimed to assess the frequency and correlations of long COVID symptoms with sex, disease severity, time since the onset of the disease, and exercise capacity in a population of Polish convalescents hospitalized as a part of a rehabilitation program after COVID-19. The retrospective analysis was carried out based on medical records concerning reported symptoms, comorbidities, exercise capacity, fatigue and dyspnea on Borg’s scale, arterial oxygen saturation (SpO2), spirometric parameters, chest X-rays/computed tomography scans, systolic pulmonary artery pressure, and left ventricular ejection fraction. The study involved 471 patients aged 63.83 ± 9.93 years who had been hospitalized 191.32 ± 75.69 days from the onset of COVID-19, of which 269 (57.1%) were women. The most common symptoms were fatigue (99.57%), dyspnea (99.36%), and myalgia (97.03%). Women reported more symptoms than men (p < 0.001) and rated their fatigue as more severe (p = 0.021). Patients with depressed moods reported more physical symptoms than others (p < 0.001). Most long COVID symptoms, including dyspnea, fatigue, and depressive symptoms, were found with the same frequency in patients 12–24 weeks and >24 weeks after recovery (p = 0.874, p = 0.400, and p = 0.320, respectively), regardless of acute COVID-19 severity (p = 0.240, p = 0.826, and p = 0.108, respectively). Dyspnea severity correlated with forced vital capacity (FVC) (r = −0.153, p = 0.005), and forced expiratory volume in one second (FEV1) (r = −0.142, p = 0.008). Fatigue severity correlated with impaired FVC and FEV1 (both r = −0.162, p = 0.003). Fatigue and dyspnea inversely correlated with the distance in a six-minute walk test (r = −0.497, p < 0.001, and r = −0.327, p < 0.001). In conclusion, in our cohort, long COVID symptoms are more common in women. Dyspnea/fatigue and depressive symptoms do not tend to subside after an average six-month recovery period. The intensity of perceived fatigue may be exaggerated by the coexistence of neuropsychiatric disorders. Increased fatigue and dyspnea correlate with impaired spirometric parameters and significantly affects convalescents’ exercise capacity.
265	MS263		Jason, Leonard A.; Dorri, Joseph A.	ME/CFS and Post-Exertional Malaise among Patients with Long COVID	https://doi.org/10.3390/neurolint15010001	Published	2023-03-01	Study	https://www.mdpi.com/2035-8377/15/1/1	This study sought to ascertain the prevalence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) among a sample of 465 patients with Long COVID. The participants completed three questionnaires: (1) a new questionnaire measuring both the frequency and severity of 38 common symptoms of COVID and Long COVID, (2) a validated short form questionnaire assessing ME/CFS, and (3) a validated questionnaire measuring post-exertional malaise. The population was predominantly white, female, and living in North America. The mean duration since the onset of COVID-19 symptoms was 70.5 weeks. Among the 465 participants, 58% met a ME/CFS case definition. Of respondents who reported that they had ME/CFS only 71% met criteria for ME/CFS and of those who did not report they had ME/CFS, 40% nevertheless did meet criteria for the disease: both over-diagnosis and under-diagnosis were evident on self-report. This study supports prior findings that ME/CFS occurs with high prevalence among those who have persistent COVID-19 symptoms.
266	MS264		Admon, Andrew J.; Iwashyna, Theodore J.; Kamphuis, Lee A.; Gundel, Stephanie J.; Sahetya, Sarina K.; Peltan, Ithan D.; Chang, Steven Y.; Han, Jin H.; Vranas, Kelly C.; Mayer, Kirby P.; Hope, Aluko A.; Jolley, Sarah E.; Caldwell, Ellen; Monahan, Max L.; Hauschildt, Katrina; Brown, Samuel M.; Aggarwal, Neil R.; Thompson, B. Taylor; Hough, Catherine L.; National Heart, Lung, and Blood Institute PETAL Network	Assessment of Symptom, Disability, and Financial Trajectories in Patients Hospitalized for COVID-19 at 6 Months	https://doi.org/10.1001/jamanetworkopen.2022.55795	Published	2023-02-14	Study	https://doi.org/10.1001/jamanetworkopen.2022.55795	Key Points Question How do symptoms, disabilities, and financial problems evolve in the 6 months after COVID-19-related hospitalization? Findings In this national US cohort study that included 825 adults discharged from 44 hospitals, 75.4% of COVID-19 survivors experienced cardiopulmonary problems at 6 months compared with 67.3% at month 1. Decreases were noted at 6 months in financial problems (from 66.1% to 56.4%) and functional limitations (55.3% to 47.3%). Meaning The findings of this study suggest that symptoms, disabilities, and financial problems remain highly prevalent—with some new problems—in the 6 months after COVID-19 hospitalization. Abstract Importance Individuals who survived COVID-19 often report persistent symptoms, disabilities, and financial consequences. However, national longitudinal estimates of symptom burden remain limited. Objective To measure the incidence and changes over time in symptoms, disability, and financial status after COVID-19–related hospitalization. Design, Setting, and Participants A national US multicenter prospective cohort study with 1-, 3-, and 6-month postdischarge visits was conducted at 44 sites participating in the National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Network's Biology and Longitudinal Epidemiology: COVID-19 Observational (BLUE CORAL) study. Participants included hospitalized English- or Spanish-speaking adults without severe prehospitalization disabilities or cognitive impairment. Participants were enrolled between August 24, 2020, and July 20, 2021, with follow-up occurring through March 30, 2022. Exposure Hospitalization for COVID-19 as identified with a positive SARS-CoV-2 molecular test. Main Outcomes and Measures New or worsened cardiopulmonary symptoms, financial problems, functional impairments, perceived return to baseline health, and quality of life. Logistic regression was used to identify factors associated with new cardiopulmonary symptoms or financial problems at 6 months. Results A total of 825 adults (444 [54.0%] were male, and 379 [46.0%] were female) met eligibility criteria and completed at least 1 follow-up survey. Median age was 56 (IQR, 43-66) years; 253 (30.7%) participants were Hispanic, 145 (17.6%) were non-Hispanic Black, and 360 (43.6%) were non-Hispanic White. Symptoms, disabilities, and financial problems remained highly prevalent among hospitalization survivors at month 6. Rates increased between months 1 and 6 for cardiopulmonary symptoms (from 67.3% to 75.4%; P = .001) and fatigue (from 40.7% to 50.8%; P < .001). Decreases were noted over the same interval for prevalent financial problems (from 66.1% to 56.4%; P < .001) and functional limitations (from 55.3% to 47.3%; P = .004). Participants not reporting problems at month 1 often reported new symptoms (60.0%), financial problems (23.7%), disabilities (23.8%), or fatigue (41.4%) at month 6. Conclusions and Relevance The findings of this cohort study of people discharged after COVID-19 hospitalization suggest that recovery in symptoms, functional status, and fatigue was limited at 6 months, and some participants reported new problems 6 months after hospital discharge.
267	MS265		Fabbri, Andrea; Voza, Antonio; Riccardi, Alessandro; Vanni, Simone; De Iaco, Fabio	Unfavorable Outcome and Long-Term Sequelae in Cases with Severe COVID-19	https://doi.org/10.3390/v15020485	Published	2023-02-01	Review	https://www.mdpi.com/1999-4915/15/2/485	Emerging evidence shows that individuals with COVID-19 who survive the acute phase of illness may experience lingering symptoms in the following months. There is no clear indication as to whether these symptoms persist for a short time before resolving or if they persist for a long time. In this review, we will describe the symptoms that persist over time and possible predictors in the acute phase that indicate long-term persistence. Based on the literature available to date, fatigue/weakness, dyspnea, arthromyalgia, depression, anxiety, memory loss, slowing down, difficulty concentrating and insomnia are the most commonly reported persistent long-term symptoms. The extent and persistence of these in long-term follow-up is not clear as there are still no quality studies available. The evidence available today indicates that female subjects and those with a more severe initial disease are more likely to suffer permanent sequelae one year after the acute phase. To understand these complications, and to experiment with interventions and treatments for those at greater risk, we must first understand the physio-pathological mechanisms that sustain them.
268	MS266		Perisse, Anne; De Cacqueray, François; Delarbre, David; Marsaa, Hélène; Bergmann, Cedric; Da Silva, Virginie; Bronstein, Antoine; Paleiron, Nicolas; Menoud, Nastasia; Cobola, Jacques; Verret, Catherine; Mayet, Aurélie; Bylicki, Olivier	Symptoms of Long-COVID 1-Year After a COVID-19 Outbreak Among Sailors on a French Aircraft Carrier	https://doi.org/10.1016/j.idnow.2023.104673	Published	2023-02-11	Study	https://www.sciencedirect.com/science/article/pii/S2666991923000350	Highlights •Prevalence of Long-COVID symptoms was 53.7%, 55.2% and 54.3% in COVID-positive patients at months 6, 9 and 12. •In COVID-negative patients, prevalence was 31.2%, 23.3% and 40.0% at months 6, 9 and 12. •The main symptoms were concentration difficulties, asthenia and sleep disorders. •Mild COVID-19 patients reported more symptoms than negative patients during the first 9 months. •We should evoke a differential diagnosis in case of symptoms 1 year after mild-COVID. Abstract Objectives While persistent symptoms have been reported after the coronavirus disease-2019 (COVID-19), long-term data on outpatients with mild COVID-19 are lacking. The objective was to describe symptoms persisting for 12 months. Methods This prospective cohort study on 1767 sailors of an aircraft carrier in which a Covid-19 outbreak occurred during a mission in April 2020 described predefined self-reported symptoms of Long-COVID at 6, 9 and 12 months. Logistic-regression analyses were used to identify correlates for Long-COVID at months 6, 9 and 12. Results Among the 641 participants, 619 (35%) completed at least one follow-up questionnaire (413 COVID-positive and 206 COVID-negative). Symptoms of Long-COVID were reported by 53.7%, 55.2% and 54.3% of COVID-positive participants vs. 31.2%, 23.3% and 40.0% in COVID-negative patients, at 6 (p<.002), 9 (p<.002) and 12 months (p=.13), respectively. The most frequent symptoms reported were concentration and memory difficulties, asthenia and sleep disorders. Conclusion In this study more than half of COVID-positive outpatients reported persistent symptoms up to 12 months post-quarantine. These findings suggests that all patients, including those with mild disease, can be affected by Long-COVID. A lack of difference at 12 months with COVID-negative patienys prompts caution. The symptoms of Long-COVID are so non-specific that they may be viewed as the consequence of multiple intercurrent factors.
269	MS267		Han, Emilie; Gyöngyösi, Mariann	Long COVID – eine neue Herausforderung in der Medizin: Fokus auf Schwangerschaft und Stillzeit	https://doi.org/10.1007/s41974-023-00250-5	Published	2023-02-02	Article	https://doi.org/10.1007/s41974-023-00250-5	Long COVID wurde als eine neue Multiorganerkrankung beschrieben, die bei Frauen häufiger auftritt als bei Männern. Schwangere und stillende Frauen sind eine spezielle Untergruppe von Patienten, die bei einer Long-COVID-Erkrankung zu berücksichtigen sind, da bisher die Datenlage nur gering ausfällt. Menstruationsveränderungen werden häufig während oder nach einer akuten Erkrankung mit dem Coronavirus-2019 (COVID-19) beobachtet. Einige Studien stellen zudem einen Zusammenhang zwischen geringen Veränderungen der Zykluslänge und einer COVID-Impfung dar. Schwangere Frauen, die eine symptomatische Infektion mit dem schweren-akuten-Atemwegssyndrom-Coronavirus Typ 2 (SARS-CoV‑2) hatten, können ein höheres Risiko für Komplikationen in der Schwangerschaft, wie Frühgeburt oder Präeklampsie, haben. Darüber hinaus sind mehr Studien notwendig, um die Auswirkungen einer vertikalen Übertragung zu beurteilen. Das wirksamste Mittel gegen die Pandemie sind die verfügbaren COVID-Impfstoffe, da sie eine Infektion verhindern, aber auch Long-COVID-Symptome lindern können. Impfstoffe haben sich sowohl bei schwangeren als auch bei stillenden Frauen als sicher und wirksam erwiesen. Ziel dieses Artikels ist es, die aktuell verfügbaren Daten zu Long COVID bei schwangeren und stillenden Frauen darzustellen und die Risikofaktoren und therapeutischen Möglichkeiten aufzuzeigen. Abstract Long COVID (coronavirus disease) has been described as a new multi-organ disease, which appears to be more prevalent in women than in men. Pregnant and breastfeeding women are a special subgroup of patients to consider with long COVID, as only scarce data have been collected to date. Menstrual changes are commonly observed during or after COVID-19; some studies also attribute slight changes of cycle length to previous inoculation against the virus. Pregnant women who have a symptomatic infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are at a higher risk for adverse outcomes and pregnancy-associated complications. Moreover, more and robust data are required to evaluate vertical transmission. COVID vaccines are the most effective tool against the pandemic, as they prevent infection, but also appear to be able to ease long COVID symptoms. Vaccines have been proven safe and effective in both pregnant and breastfeeding women. This article aims to present current data on long COVID in pregnant and breastfeeding women and elucidate risk factors and possible treatment options.
270	MS268		Khullar, Dhruv; Zhang, Yongkang; Zang, Chengxi; Xu, Zhenxing; Wang, Fei; Weiner, Mark G.; Carton, Thomas W.; Rothman, Russell L.; Block, Jason P.; Kaushal, Rainu	Racial/Ethnic Disparities in Post-acute Sequelae of SARS-CoV-2 Infection in New York: an EHR-Based Cohort Study from the RECOVER Program	https://doi.org/10.1007/s11606-022-07997-1	Published	2023-02-16	Study	https://doi.org/10.1007/s11606-022-07997-1	Background Compared to white individuals, Black and Hispanic individuals have higher rates of COVID-19 hospitalization and death. Less is known about racial/ethnic differences in post-acute sequelae of SARS-CoV-2 infection (PASC). Objective Examine racial/ethnic differences in potential PASC symptoms and conditions among hospitalized and non-hospitalized COVID-19 patients. Design Retrospective cohort study using data from electronic health records. Participants 62,339 patients with COVID-19 and 247,881 patients without COVID-19 in New York City between March 2020 and October 2021. Main Measures New symptoms and conditions 31–180 days after COVID-19 diagnosis. Key Results The final study population included 29,331 white patients (47.1%), 12,638 Black patients (20.3%), and 20,370 Hispanic patients (32.7%) diagnosed with COVID-19. After adjusting for confounders, significant racial/ethnic differences in incident symptoms and conditions existed among both hospitalized and non-hospitalized patients. For example, 31–180 days after a positive SARS-CoV-2 test, hospitalized Black patients had higher odds of being diagnosed with diabetes (adjusted odds ratio [OR]: 1.96, 95% confidence interval [CI]: 1.50—2.56, q<0.001) and headaches (OR: 1.52, 95% CI: 1.11—2.08, q=0.02), compared to hospitalized white patients. Hospitalized Hispanic patients had higher odds of headaches (OR: 1.62, 95% CI: 1.21—2.17, q=0.003) and dyspnea (OR: 1.22, 95% CI: 1.05—1.42, q=0.02), compared to hospitalized white patients. Among non-hospitalized patients, Black patients had higher odds of being diagnosed with pulmonary embolism (OR: 1.68, 95% CI: 1.20—2.36, q=0.009) and diabetes (OR: 2.13, 95% CI: 1.75—2.58, q<0.001), but lower odds of encephalopathy (OR: 0.58, 95% CI: 0.45—0.75, q<0.001), compared to white patients. Hispanic patients had higher odds of being diagnosed with headaches (OR: 1.41, 95% CI: 1.24—1.60, q<0.001) and chest pain (OR: 1.50, 95% CI: 1.35—1.67, q < 0.001), but lower odds of encephalopathy (OR: 0.64, 95% CI: 0.51—0.80, q<0.001). Conclusions Compared to white patients, patients from racial/ethnic minority groups had significantly different odds of developing potential PASC symptoms and conditions. Future research should examine the reasons for these differences.
271	MS269		Wahlgren, Carl; Forsberg, Gustaf; Divanoglou, Anestis; Balkhed, Åse Östholm; Niward, Katarina; Berg, Sören; Levi, Richard	Two-year follow-up of patients with post-COVID-19 condition in Sweden: a prospective cohort study	https://doi.org/10.1016/j.lanepe.2023.100595	Published	2023-02-23	Study	https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(23)00013-3/fulltext	Background Few studies have reported the long-term health effects of COVID-19. The regional population-based Linköping COVID-19 study (LinCoS) included all patients hospitalised due to COVID-19 during the first pandemic wave. Four months post-discharge, over 40% (185/433) experienced persisting symptoms and activity/participation limitations, indicating post-COVID-19 condition (PCC). The present follow-up study aimed to determine the long-term recovery among these patients 24 months post-admission. Methods This prospective cohort study included all patients from LinCoS with PCC at four months post-discharge. We repeated the same structured interview at a 24-month follow-up to identify persisting symptoms and their impact on daily life. Intercurrent health issues were identified by reviewing medical records. Findings Of 185 patients with PCC at 4 months post-discharge, 181 were alive at the 24-month assessment and 165 agreed to participate. Of those, 21% (35/165) had been readmitted to hospital for various causes in the interim period. The majority of patients (139/165, 84%) reported persisting problems affecting everyday life at 24 months. Significant improvements were seen in the prevalence and magnitude of some symptoms/limitations compared with four months post-discharge. Cognitive, sensorimotor, and fatigue symptoms were the most common persisting symptoms at 24 months. No clear difference was evident between individuals treated in the intensive care unit (ICU) and non-ICU-treated individuals. Approximately half of those who were on sick leave related to PCC at four months after infection were on sick leave at 24 months. Interpretation This is one of the first studies to report 2-year outcomes in patients with PCC following COVID-19 hospitalisation. Despite some improvements over time, we found a high prevalence of persisting symptoms and a need for long-term follow-up and rehabilitation post COVID-19 infection. Funding The study was funded by Region Östergötland. publisher: Elsevier
272	MS270		Ranucci, Marco; Baryshnikova, Ekaterina; Anguissola, Martina; Pugliese, Sara; Ranucci, Luca; Falco, Mara; Menicanti, Lorenzo	The Very Long COVID: Persistence of Symptoms after 12–18 Months from the Onset of Infection and Hospitalization	https://doi.org/10.3390/jcm12051915	Published	2023-01-01	Study	https://www.mdpi.com/2077-0383/12/5/1915	According to the World Health Organization’s definition, long COVID is the persistence or development of new symptoms 3 months after the initial infection. Various conditions have been explored in studies with up to one-year follow-up but very few looked further. This prospective cohort study addresses the presence of a wide spectrum of symptoms in 121 patients hospitalized during the acute phase of COVID-19 infection, and the association between factors related to the acute phase of the disease and the presence of residual symptoms after one year or longer from hospitalization. The main results are as follows: (i) post-COVID symptoms persist in up to 60% of the patient population at a mean follow-up of 17 months; (ii) the most frequent symptoms are fatigue and dyspnea, but neuropsychological disturbances persist in about 30% of the patients (iii) when corrected for the duration of follow-up with a freedom-from-event analysis; only complete (2 doses) vaccination at the time of hospital admission remained independently associated with persistence of the major physical symptoms, while vaccination and previous neuropsychological symptoms remained independently associated with persistence of major neuropsychological symptoms.
273	MS271		DeVries, Andrea; Shambhu, Sonali; Sloop, Sue; Overhage, J. Marc	One-Year Adverse Outcomes Among US Adults With Post–COVID-19 Condition vs Those Without COVID-19 in a Large Commercial Insurance Database	https://doi.org/10.1001/jamahealthforum.2023.0010	Published	2023-03-03	Study	https://doi.org/10.1001/jamahealthforum.2023.0010	Key Points Question Do postacute sequelae of SARS-CoV-2 increase risks of 1-year adverse outcomes? Findings In this case-control study of 13 435 US adults with post–COVID-19 condition (PCC) and 26 870 matched adults without COVID-19, the adults with PCC experienced increased risks for a number of cardiovascular outcomes, such as ischemic stroke. During the 12-month follow-up period, 2.8% of the individuals with PCC vs 1.2% of the individuals without COVID-19 died, implying an excess death rate of 16.4 per 1000 individuals. Meaning Individuals with PCC may be at increased risk for adverse outcomes in the year following initial infection. Abstract Importance Many individuals experience ongoing symptoms following the onset of COVID-19, characterized as postacute sequelae of SARS-CoV-2 or post–COVID-19 condition (PCC). Less is known about the long-term outcomes for these individuals. Objective To quantify 1-year outcomes among individuals meeting a PCC definition compared with a control group of individuals without COVID-19. Design, Setting, and Participants This case-control study with a propensity score–matched control group included members of commercial health plans and used national insurance claims data enhanced with laboratory results and mortality data from the Social Security Administration’s Death Master File and Datavant Flatiron data. The study sample consisted of adults meeting a claims-based definition for PCC with a 2:1 matched control cohort of individuals with no evidence of COVID-19 during the time period of April 1, 2020, to July 31, 2021. Exposures Individuals experiencing postacute sequelae of SARS-CoV-2 using a Centers for Disease Control and Prevention–based definition. Main Outcomes and Measures Adverse outcomes, including cardiovascular and respiratory outcomes and mortality, for individuals with PCC and controls assessed over a 12-month period. Results The study population included 13 435 individuals with PCC and 26 870 individuals with no evidence of COVID-19 (mean [SD] age, 51 [15.1] years; 58.4% female). During follow-up, the PCC cohort experienced increased health care utilization for a wide range of adverse outcomes: cardiac arrhythmias (relative risk [RR], 2.35; 95% CI, 2.26-2.45), pulmonary embolism (RR, 3.64; 95% CI, 3.23-3.92), ischemic stroke (RR, 2.17; 95% CI, 1.98-2.52), coronary artery disease (RR, 1.78; 95% CI, 1.70-1.88), heart failure (RR, 1.97; 95% CI, 1.84-2.10), chronic obstructive pulmonary disease (RR, 1.94; 95% CI, 1.88-2.00), and asthma (RR, 1.95; 95% CI, 1.86-2.03). The PCC cohort also experienced increased mortality, as 2.8% of individuals with PCC vs 1.2% of controls died, implying an excess death rate of 16.4 per 1000 individuals. Conclusions and Relevance This case-control study leveraged a large commercial insurance database and found increased rates of adverse outcomes over a 1-year period for a PCC cohort surviving the acute phase of illness. The results indicate a need for continued monitoring for at-risk individuals, particularly in the area of cardiovascular and pulmonary management.
274	MS272		Tran, Bach; Le Vu, Minh Ngoc; Le, Huong Thi; Nguyen, Tu Huu; Boyer, Laurent; Fond, Guillaume; Auquier, Pascal; Latkin, Carl A.; Ho, Roger C. M.; Ho, Cyrus S. H.; Zhang, Melvyn W. B.	Severity and geographical disparities of post-COVID-19 symptoms among the Vietnamese general population: a national evaluation	https://doi.org/10.1038/s41598-023-30790-x	Published	2023-03-17	Study	https://www.nature.com/articles/s41598-023-30790-x	Post-COVID-19 symptoms have become a significant global health concern. This study focused on assessing the prevalence, severity, and care preference of post-COVID-19 symptoms, as well as identifying determinants to inform evidence-based policy on post-COVID-19 in Vietnam. A national cross-sectional study was conducted in May 2022 among 12,361 recovered COVID-19 patients, providing the largest dataset on health status after COVID-19 in Vietnam. The study utilized ordered logistic, Poisson regression, Multilevel linear random-effects models, and Multilevel random effects ordered logistic model to identify factors associated with various aspects of post-COVID-19 conditions. Results showed that the average number of post-COVID-19 symptoms was approximately 3, with fatigue and headache being the most common symptoms. The number of post-COVID-19 symptoms varied by province, decreased with age, and was significantly correlated with the duration of infection. Age, infection period, underlying conditions, telehealth utilization, and geographical location were identified as significant determinants of post-COVID-19 symptoms. The study concluded that improving resource allocation and health-seeking behavior in underserved areas could help address differences in health outcomes and improve post-COVID-19 control in Vietnam.
275	MS273		Bonilla, Hector; Quach, Tom C.; Tiwari, Anushri; Bonilla, Andres E.; Miglis, Mitchell; Yang, Phillip C.; Eggert, Lauren E.; Sharifi, Husham; Horomanski, Audra; Subramanian, Aruna; Smirnoff, Liza; Simpson, Norah; Halawi, Houssan; Sum-ping, Oliver; Kalinowski, Agnieszka; Patel, Zara M.; Shafer, Robert William; Geng, Linda C.	Myalgic Encephalomyelitis/Chronic Fatigue Syndrome is common in post-acute sequelae of SARS-CoV-2 infection (PASC): Results from a post-COVID-19 multidisciplinary clinic	https://doi.org/10.3389/fneur.2023.1090747	Published	1905-07-15	Study	https://www.frontiersin.org/articles/10.3389/fneur.2023.1090747	BackgroundThe global prevalence of PASC is estimated to be present in 0·43 and based on the WHO estimation of 470 million worldwide COVID-19 infections, corresponds to around 200 million people experiencing long COVID symptoms. Despite this, its clinical features are not well-defined.MethodsWe collected retrospective data from 140 patients with PASC in a post-COVID-19 clinic on demographics, risk factors, illness severity (graded as one-mild to five-severe), functional status, and 29 symptoms and principal component symptoms cluster analysis. The Institute of Medicine (IOM) 2015 criteria were used to determine the Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) phenotype.FindingsThe median age was 47 years, 59.0% were female; 49.3% White, 17.2% Hispanic, 14.9% Asian, and 6.7% Black. Only 12.7% required hospitalization. Seventy-two (53.5%) patients had no known comorbid conditions. Forty-five (33.9%) were significantly debilitated. The median duration of symptoms was 285.5 days, and the number of symptoms was 12. The most common symptoms were fatigue (86.5%), post-exertional malaise (82.8%), brain fog (81.2%), unrefreshing sleep (76.7%), and lethargy (74.6%). Forty-three percent fit the criteria for ME/CFS, majority were female, and obesity (BMI > 30 Kg/m2) (P = 0.00377895) and worse functional status (P = 0.0110474) were significantly associated with ME/CFS.InterpretationsMost PASC patients evaluated at our clinic had no comorbid condition and were not hospitalized for acute COVID-19. One-third of patients experienced a severe decline in their functional status. About 43% had the ME/CFS subtype.
276	MS274		Wong, Martin Chi-Sang; Huang, Junjie; Wong, Yuet-Yan; Wong, Grace Lai-Hung; Yip, Terry Cheuk-Fung; Chan, Rachel Ngan-Yin; Chau, Steven Wai-Ho; Ng, Siew-Chien; Wing, Yun-Kwok; Chan, Francis Ka-Leung	Epidemiology, Symptomatology, and Risk Factors for Long COVID Symptoms: Population-Based, Multicenter Study	https://doi.org/10.2196/42315	Published	2023-03-07	Study	https://publichealth.jmir.org/2023/1/e42315	Company: JMIR Public Health and Surveillance Distributor: JMIR Public Health and Surveillance Institution: JMIR Public Health and Surveillance Label: JMIR Public Health and Surveillance publisher: JMIR Publications Inc., Toronto, Canada
277	MS275		Patel, Ajay I.; Yadav, Anju; Patel, Ashok B.; Vyas, Amitkumar J.	Post Covid-19 Women Complications	https://doi.org/10.52711/2349-2996.2023.00017	Published	2023-03-16	Review	https://ajner.com/AbstractView.aspx?PID=2023-13-1-17	Post-covid-19 women complications, Post covid-19 is Clinical symptoms that persist or worsen after acute COVID It is contains both ongoing symptomatic COVID-19 between 4 to 12 weeks or post COVID-19 more than 12 weeks. As of June 2020, given the terminology "post COVID-19". Reported studies are related to complications of the female patient, including effects on the immune system, physiology, or psychological health, and effects on pre-existing diseases, including hypertension, diabetes mellitus, neurodegenerative disease, rheumatoid arthritis, and tuberculosis (TB). However, six months after recovery from COVID-19, complications arise, including cough, fever, breathlessness, muscle aches, joint pain, fatigue, gastrointestinal complaints, anosmia, dyspepsia, sleep difficulties, anxiety or depression, higher stress levels, physical decline, post-activity polypnea, alopecia, chest tightness, palpitations, intestinal blockages, impaired respiratory functions, neurological issues, olfactory dysfunction, cognition, dexterity, conversation, disabilities of sight, or listening. Along with other miscellaneous complications such as Miller-Fisher syndrome. Overall, these reviews summarise studies conducted on pre-existing diseases in female patients after COVID-19, complications in female patients with immune dysfunction, including hormonal imbalances, and CSF-insufficiency in female patients with neurodegeneration complications. It observed high levels of molecular markers such as tau protein (t-tau, p-tau), plasma amyloid-beta (A42), glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neurofilament light chain protein. In Female patients with diabetes mellitus (Type 1 and Type 2) complications reported higher levels of sCr, C-reactive protein, TN-I, white blood cell, and erythrocyte sedimentation rate levels, enzymes, electrolytes, and coagulation factors, and female patients with tuberculosis (TB) complications had lower aggressive angiomyxoma (AAM) and E2 hormone levels.
278	MS276		Wang, Siwen; Farland, Leslie V.; Gaskins, Audrey J.; Mortazavi, Jasmine; Wang, Yi-Xin; Tamimi, Rulla M.; Rich-Edwards, Janet W.; Zhang, Dan; Terry, Kathryn L.; Chavarro, Jorge E.; Missmer, Stacey A.	Association of Laparoscopically-confirmed Endometriosis with Long COVID: A Prospective Cohort Study	https://doi.org/10.1016/j.ajog.2023.03.030	Published	2023-03-25	Study	https://www.sciencedirect.com/science/article/pii/S0002937823001771	Background Women are at greater risk than men of developing chronic inflammatory conditions and of developing ‘long COVID.’ However, few gynecologic health risk factors for long COVID have been identified. Endometriosis is a common gynecological disorder associated with chronic inflammation, immune dysregulation, and comorbid presentation with autoimmune and clotting disorders, all of which are pathophysiologic mechanisms proposed for long COVID. Therefore, we hypothesized that women with a history of endometriosis may be at greater risk of developing long COVID. Objective To investigate the association between history of endometriosis prior to SARS-CoV-2 infection and risk of long COVID. Methods We followed 46,579 women from two ongoing prospective cohort studies: the Nurses’ Health Study II and the Nurses’ Health Study 3, who participated in a series of COVID-19-related surveys administered from April 2020 to November 2022. Laparoscopic diagnosis of endometriosis was documented prospectively in main cohort questionnaires prior to the pandemic (1993–2020) with high validity. SARS-CoV-2 infection (confirmed by antigen, PCR, or antibody test) and CDC-defined long-term COVID-19 symptoms (≥4 weeks) were self-reported during follow-up. Among individuals with SARS-CoV-2 infection, we fit Poisson regression models to assess the associations between endometriosis and risk of long COVID-19 symptoms, with adjustment for potential confounding variables (demographics, body mass index, smoking status, history of infertility, and history of chronic diseases). Results Among 3650 women in our sample with self-reported SARS-CoV-2 infections during follow-up, 386 (10.6%) had a history of endometriosis with laparoscopic confirmation and 1598 (43.8%) reported experiencing long COVID symptoms. The majority of women were Non-Hispanic White (95.4%), with a median age of 59 years (interquartile range=44–65). Women with a history of laparoscopically-confirmed endometriosis had a 22% greater risk of developing long COVID (adjusted RR=1.22, 95% CI=1.05–1.42), compared to those who had never been diagnosed with endometriosis. The association was stronger when we defined long COVID as having symptoms ≥8 weeks (RR=1.28, 95% CI=1.09–1.50). We observed no statistically significant differences in the relationship between endometriosis and long COVID by age, infertility history, or comorbidity with uterine fibroids, although there was a suggestive trend that women <50 years may be at higher risk (<50 years, RR=1.37, 95% CI=1.00–1.88; ≥50 years, RR=1.19, 95% CI=1.01–1.41). Among persons who developed long COVID, women with endometriosis reported on average one additional long-term symptom compared to women without endometriosis. Conclusions and relevance Our findings suggest that those with a history of endometriosis may be at modestly increased risk for long COVID. Health care providers should be aware of endometriosis history when treating patients for signs of persisting symptoms post-SARS-CoV-2 infection. Future studies should investigate the potential biological pathways underlying these associations.
279	MS277		Bostanci, Aysegul; Gazi, Umut; Tosun, Ozgur; Suer, Kaya; Unal Evren, Emine; Evren, Hakan; Sanlidag, Tamer	Long-COVID-19 in Asymptomatic, Non-Hospitalized, and Hospitalized Populations: A Cross-Sectional Study	https://doi.org/10.3390/jcm12072613	Published	2023-01-01	Study	https://www.mdpi.com/2077-0383/12/7/2613	A substantial proportion of coronavirus disease 2019 (COVID-19) survivors continue to suffer from long-COVID-19 (LC) symptoms. Our study aimed to determine the risk factors for LC by using a patient population from Northern Cyprus. Subjects who were diagnosed with severe acute respiratory syndrome-2 (SARS-CoV-2) infection in our university hospital were invited and asked to fill in an online questionnaire. Data from 296 survivors who had recovered from COVID-19 infection at least 28 days prior the study was used in the statistical analysis. For determination of risk factors for “ongoing symptomatic COVID-19 (OSC)” and “Post-COVID-19 (PSC)” syndromes, the patient population was further divided into group 1 (Gr1) and group 2 (Gr2), that included survivors who were diagnosed with COVID-19 within 4-12 weeks and at least three months prior the study, respectively. The number of people with post-vaccination SARS-CoV-2 infection was 266 (89.9%). B.1.617.2 (Delta) (41.9%) was the most common SARS-CoV-2 variant responsible for the infections, followed by BA.1 (Omicron) (34.8%), B.1.1.7 (Alpha) (15.5%), and wild-type SARS-CoV-2 (7.8%). One-hundred-and-nineteen volunteers (40.2%) stated an increased frequency of COVID-19-related symptoms and experienced the symptoms in the week prior to the study. Of those, 81 (38.8%) and 38 (43.7%) were from Gr1 and Gr2 groups, respectively. Female gender, chronic illness, and symptomatic status at PCR testing were identified as risk factors for developing OSC syndrome, while only the latter showed a similar association with PSC symptoms. Our results also suggested that ongoing and persistent COVID-19-related symptoms are not influenced by the initial viral cycle threshold (Ct) values of the SARS-CoV-2, SARS-CoV-2 variant as well as vaccination status and type prior to COVID-19. Therefore, strategies other than vaccination are needed to combat the long-term effect of COVID-19, especially after symptomatic SARS-CoV-2 infection, and their possible economic burden on healthcare settings.
280	MS278		da Silva, Rosilene; de Sarges, Kevin Matheus Lima; Cantanhede, Marcos Henrique Damasceno; da Costa, Flávia Póvoa; dos Santos, Erika Ferreira; Rodrigues, Fabíola Brasil Barbosa; de Nazaré do Socorro de Almeida Viana, Maria; de Meira Leite, Mauro; da Silva, Andréa Luciana Soares; de Brito, Mioni Thieli Magalhães; da Silva Torres, Maria Karoliny; Queiroz, Maria Alice Freitas; Vallinoto, Izaura Maria Vieira Cayres; Henriques, Daniele Freitas; dos Santos, Carla Pinheiro; Viana, Giselle Maria Rachid; Quaresma, Juarez Antônio Simões; Falcão, Luiz Fábio Magno; Vallinoto, Antonio Carlos Rosário; dos Santos, Eduardo José Melo	Thrombophilia and Immune-Related Genetic Markers in Long COVID	https://doi.org/10.3390/v15040885	Published	2023-04-01	Study	https://www.mdpi.com/1999-4915/15/4/885	Aiming to evaluate the role of ten functional polymorphisms in long COVID, involved in major inflammatory, immune response and thrombophilia pathways, a cross-sectional sample composed of 199 long COVID (LC) patients and a cohort composed of 79 COVID-19 patients whose follow-up by over six months did not reveal any evidence of long COVID (NLC) were investigated to detect genetic susceptibility to long COVID. Ten functional polymorphisms located in thrombophilia-related and immune response genes were genotyped by real time PCR. In terms of clinical outcomes, LC patients presented higher prevalence of heart disease as preexistent comorbidity. In general, the proportions of symptoms in acute phase of the disease were higher among LC patients. The genotype AA of the interferon gamma (IFNG) gene was observed in higher frequency among LC patients (60%; p = 0.033). Moreover, the genotype CC of the methylenetetrahydrofolate reductase (MTHFR) gene was also more frequent among LC patients (49%; p = 0.045). Additionally, the frequencies of LC symptoms were higher among carriers of IFNG genotypes AA than among non-AA genotypes (Z = 5.08; p < 0.0001). Two polymorphisms were associated with LC in both inflammatory and thrombophilia pathways, thus reinforcing their role in LC. The higher frequencies of acute phase symptoms among LC and higher frequency of underlying comorbidities might suggest that acute disease severity and the triggering of preexisting condition may play a role in LC development.
281	MS279		Warren-Gash, Charlotte; Lacey, Andrea; Cook, Sarah; Stocker, Dylan; Toon, Samantha; Lelii, Ffion; Ford, Ben; Ireland, Georgina; Ladhani, Shamez N.; Stephenson, Terence; Nguipdop-Djomo, Patrick; Mangtani, Punam; McClenahan, Elliot; McKay, Gillian; Phelan, Jody; Lin, Liang-Yu; Lewin, Alex; Judd, Alison; Davies, Byron; Saib, Anisah; McCrae, James; Kelly, Joe; Diamond, Ian; Rourke, Emma; Dawe, Fiona; Jones, Pete; the COVID-19 Schools Infection Survey 2 Study Group	Post-COVID-19 condition and persisting symptoms in English schoolchildren: repeated surveys to March 2022	https://doi.org/10.1186/s12879-023-08203-1	Published	2023-04-05	Study	https://doi.org/10.1186/s12879-023-08203-1	Background Both post-COVID-19 condition (long COVID) and the presence of persisting symptoms that do not meet formal definitions of post-COVID-19-condition may adversely affect quality of life and function. However, their prevalence among children and young people in England is unclear. Methods We used data from repeated surveys in a large cohort of English schoolchildren from the COVID-19 Schools Infection Survey (SIS) for the school year 2021/22 to describe the weighted prevalence of post-COVID-19-condition and compare persisting symptoms between individuals with a positive SARS-CoV-2 test and those with neither a positive test history nor suspected infection. Results Among 7797 children from 173 schools, 1.8% of primary school pupils (aged 4 to 11 years), 4.5% of secondary school pupils in years 7–11 (aged 11 to 16 years) and 6.9% of those in years 12–13 (aged 16 to 18 years) met a definition of post-COVID-19 condition in March 2022. Specific persisting symptoms such as anxiety or difficulty concentrating were frequently reported regardless of prior infection status and increased with age: 48.0% of primary school pupils, 52.9% of secondary school pupils in years 7–11 and 79.5% in years 12–13 reporting at least one symptom lasting more than 12 weeks. Persisting loss of smell and taste, cardiovascular and some systemic symptoms were more frequently reported by those with a previous positive test. Conclusions We showed that ongoing symptoms were frequently reported by English schoolchildren regardless of SARS-CoV-2 test results and some specific symptoms such as loss of smell and taste were more prevalent in those with a positive test history. Our study emphasises the wide-ranging impacts of the COVID-19 pandemic on the health and wellbeing of children and young people.
282	MS280		Pena-Orbea, Cinthya; Lapin, Brittany; Li, Yadi; Englund, Kristin; Heinzinger, Catherine; Foldvary-Schaefer, Nancy; Mehra, Reena	Sleep Disturbance Severity and Correlates in Post-acute Sequelae of COVID-19 (PASC)	https://doi.org/10.1007/s11606-023-08187-3	Published	2023-04-04	Study	https://doi.org/10.1007/s11606-023-08187-3	INTRODUCTION Post-acute COVID-19 syndrome (PASC) is a global public health crisis in which patients experience lingering and debilitating symptoms beyond 4 weeks after the acute onset of SARS-CoV-2 infection.1 Sleep disturbance has a reported prevalence of 34–50% in PASC,2,3 but only a few studies have identified associated risk factors, and these have primarily described sleep quality and not symptom severity.3,4 Likewise, studies to date have not investigated the interaction of mood disorders and fatigue with sleep disturbance severity or the association of objective sleep study indices in PASC. METHODS Patients with PASC1 were evaluated at the Cleveland Clinic ReCOver Clinic between February 2021 and April 2022. Patients ≥ 18 years old who completed Patient-Reported Outcomes Measurement Information System (PROMIS)5 Sleep Disturbance within 90 days or during their initial ReCOver clinic visit were prospectively examined. Demographics and clinical characteristics were extracted from the COVID-19 Cleveland Clinic Registry. In a subset with pre-infection sleep studies available, Apnea Hypopnea Index (AHI) and hypoxia measures (mean oxygen saturation [SaO2%] and percentage of time spent < 90% oxygen saturation [T90]) were extracted. Patient-reported outcomes collected during the initial ReCOver clinic visit from the Electronic Medical Record included PROMIS Sleep Disturbance, Fatigue, and Global Health (PROMIS-GH) v1.2, Generalized Anxiety Disorder (GAD)-2, Patient Health Questionnaire (PHQ)-2, and the Quality of Life in Neurological Disorders (Neuro-QoL) v1.0 Cognitive Function. PROMIS scores were standardized on a T-scale with mean 50 (SD 10)6, with established cut-points at > 55, > 60, and > 70 for mild, moderate, and severe sleep disturbance respectively.6 Multivariable models were constructed to identify independent predictors of moderate to severe sleep disturbances based on clinically relevant variables determined a priori. Interactions between mood disorders and fatigue using PROMIS Fatigue, PHQ-2, and GAD-2 scores were tested. RESULTS A total of 962 of 1660 patients completed the PROMIS Sleep Disturbance; 565 (58.7%) had normal to mild sleep disturbance and 397 (41.3%) had moderate to severe sleep disturbance with characteristics shown in Table 1. After adjustment (Table 2), Black race (OR = 1.84, 95%CI: 1.10–3.08, p = 0.020), hospitalization for COVID-19 (OR = 1.59, 95%CI: 1.10–2.32, p < 0.015), greater anxiety severity (OR = 1.31, 95%CI: 1.18–1.45, p < 0.001), and moderate to severe fatigue (OR = 2.03, 95%CI: 1.33–3.11, p = 0.001) were significantly associated with moderate to severe sleep disturbance. Statistical interactions of anxiety severity and moderate to severe fatigue were not significant (p = 0.84). Table 1 Patient Characteristics Stratified by Normal/Mild Versus Moderate/Severe Sleep Disturbance Full size table Table 2 Multivariable Logistic Regression Model for Predicting Moderate/Severe Sleep Disturbance Full size table Forty-eight patients had pre-COVID-19 sleep testing conducted 2.6 ± 2.1 years prior to the initial ReCOver Clinic appointment. AHI, the primary measure of obstructive sleep apnea (OSA) severity, was 15.4 ± 18.9 with mean SaO2 of 92 ± 2.3% and a median T90% of 12.1 [2.8,73.3] (Table 1). OSA (AHI:18.7 ± 24.4 vs 12.4 ± 11.8, p = 0.27) and hypoxia measures (mean SaO2%: 91.5 ± 2.8 vs 92.5 ± 1.6, p = 0.14; median T90% 16.5 [3.5, 83.2]vs 9.3 [1.8, 44.3], p = 0.32) were not statistically different between normal to mild and moderate to severe sleep disturbance. DISCUSSION Novel findings include a high prevalence of 41.3% of moderate to severe sleep disturbance in PASC associated with Black race, hospitalization for COVID-19, anxiety severity, and moderate to severe fatigue. There was no significant interaction between anxiety severity and moderate to severe fatigue; further studies are needed to investigate the interplay between mental and sleep disturbances in PASC physiologic pathways. Likewise, there was no association between objective sleep study measures of antecedent sleep apnea and hypoxia with sleep disturbance. This may be explained by the small sample size, testing indication biases, or limitations of sleep study type (i.e., home sleep apnea test), precluding assessment of objective sleep quality or quantity measures. With 58% of PASC patients completing PROMIS Sleep Disturbance, our study may suffer from selection bias. However, we observed that among patients of Black race who did not complete PROMIS Sleep Disturbance, 60% completed mood and fatigue questionnaires. As such, it is possible that the magnitude of association between Black race and moderate to severe sleep disturbances is even stronger. Study findings emphasize the importance of identification of sleep disturbance in PASC considering its impact on patients’ quality of life, daytime functioning, and medical health status. Results inform risk stratification and highlight the need to elucidate contributions of structural racism and socioeconomic inequities to PASC-related sleep disturbances with the goal of developing interventions to reduce PASC disparities.
283	MS281		Zhang, Xiaotong	Chronic Lung Disease as a Risk Factor for Long COVID in Patients Diagnosed with COVID-19: A Retrospective Cohort Study		Published	2023-05-01	Study	https://digitalcommons.unmc.edu/coph_slce/237	Background: Patients with coronavirus disease 2019 (COVID-19) experience a wide range of ongoing symptoms after the acute phase of SARS-CoV-2 infection. Chronic lung disease has been shown to be a potential risk factor for persistent post-COVID conditions (PCC or long COVID). Objective: This study aimed to examine the relationship between chronic lung disease before COVID infection and the incidence of long COVID. Method: We conducted a retrospective cohort study to evaluate the association between chronic lung disease and the incidence of long COVID during a 6-month follow-up period after the acute phase of the infection. Data were sourced from the National COVID Cohort Collaborative (N3C) Data Enclave. Patients included were adults (18-65 years of age), 1) who were confirmed COVID positive during three consecutive SARS-CoV-2 variant dominance periods (Pre-Delta wave from December 29, 2020 to June 14, 2021; Delta wave from June 15, 2021 to November 29, 2021; Omicron wave from November 30, 2021 to June 15, 2022); 2) who completed the 6-month follow-up after acute phase; 3) who were diagnosed with long COVID within 6 months after acute phase but were lost to follow up thereafter. Otherwise, patients who were lost to follow up before the end of follow-up period were excluded. Patients who died from COVID during acute phase were also excluded. We used multivariate logistic regression to evaluate the association between long COVID and chronic lung disease as well as other risk factors. Sensitivity analysis was conducted by removing those who were lost to follow up after long COVID diagnosis. Results: 970,707 patients were included in the study cohort. The overall incidence of long COVID was 1.2%. Chronic lung disease was significantly associated with long COVID (adjusted OR:1.4, 95% CI: 1.34 to 1.47). Reinfection after COVID increased the odds for long COVID by 17% (adjusted OR 1.17, 95% CI: 1.01 to 1.34) among patients with chronic lung disease, but it had no effect on long COVID risk among those without chronic lung disease (adjusted OR: 1.02, 95% CI: 0.93 to 1.12). Cardiomyopathy was also associated with long COVID among patients with chronic lung disease (adjusted OR 1.2, 95% CI: 1.01 to 1.43). Female sex and age of 40-65 years were related to higher odds for long COVID in both subgroups. Sensitivity analysis provided consistent results after removing the patients who were lost to follow up after being diagnosed with long COVID. Conclusion: Underlying chronic lung disease is associated with a higher risk for long COVID during 6 months after acute phase of the infection. Precautions should be taken in this population, especially females, those at the age of 40 to 65 years, those with reinfections post COVID or cardiomyopathy.
284	MS282		Bamps, Laurence; Armenti, Jean-Philippe; Bojan, Mirela; Grandbastien, Bruno; von Garnier, Christophe; Du Pasquier, Renaud; Desgranges, Florian; Papadimitriou-Olivgeris, Matthaios; Alberio, Lorenzo; Preisig, Martin; Schwitter, Jurg; Guery, Benoit; The RegCOVID Study Group	Long-Term Consequences of COVID-19: A 1-Year Analysis	https://doi.org/10.3390/jcm12072673	Published	2023-01-01	Study	https://www.mdpi.com/2077-0383/12/7/2673	Long-lasting symptoms after SARS-CoV-2 infection have been described many times in the literature and are referred to as Long COVID. In this prospective, longitudinal, monocentric, observational study, we collected the health complaints of 474 patients (252 ambulatory and 222 hospitalized) at Lausanne University Hospital 1 year after COVID-19 diagnosis. Using a self-reported health survey, we explored cardiopulmonary, vascular, neurological, and psychological complaints. Our results show that age, Charlson comorbidity index, and smoking habits were associated with hospital admission. Regarding the vascular system, we found that having had thromboembolism before SARS-CoV-2 infection was significantly associated with a higher risk of recurrence of thromboembolism at 1 year. In the neurologic evaluation, the most frequent symptom was fatigue, which was observed in 87.5% of patients, followed by “feeling slowed down”, headache, and smell disturbance in 71.5%, 68.5%, and 60.7% of cases, respectively. Finally, our cohort subjects scored higher overall in the STAI, CESD, Maastricht, and PSQI scores (which measure anxiety, depression, fatigue, and sleep, respectively) than the healthy population. Using cluster analysis, we identified two phenotypes of patients prone to developing Long COVID. At baseline, CCS score, prior chronic disease, stroke, and atrial fibrillation were associated with Long COVID. During COVID infection, mechanical ventilation and five neurological complaints were also associated with Long COVID. In conclusion, this study confirms the wide range of symptoms developed after COVID with the involvement of all the major systems. Early identification of risk factors associated with the development of Long COVID could improve patient follow-up; nevertheless, the low specificity of these factors remains a challenge to building a systematic approach.
285	MS283		Percze, Anna Reka; Nagy, Alexandra; Polivka, Lorinc; Barczi, Eniko; Czaller, Ibolya; Kovats, Zsuzsanna; Varga, Janos Tamas; Ballai, Judit H.; Muller, Veronika; Horvath, Gabor	Fatigue, sleepiness and sleep quality are SARS-CoV-2 variant independent in patients with long COVID symptoms	https://doi.org/10.1007/s10787-023-01190-4	Published	2023-04-05	Study	https://doi.org/10.1007/s10787-023-01190-4	Acute infections with SARS-CoV-2 variants of concerns (VOCs) differ in clinical presentation. Discrepancies in their long-term sequelae, commonly referred to as long COVID, however, remain to be explored. We retrospectively analyzed data of 287 patients presented at the post-COVID care of the Pulmonology Department, Semmelweis University, Budapest, Hungary, and infected with SARS-CoV-2 during a period of 3 major epidemic waves in Hungary (February–July 2021, VOC: B.1.1.7, Alpha, N = 135; August–December 2021, VOC: B.1.617.2, Delta, N = 89; and January–June 2022, VOC: B.1.1.529, Omicron; N = 63), > 4 weeks after acute COVID-19. Overall, the ratio of long COVID symptomatic (LC) and asymptomatic (NS) patients was 2:1. Self-reported questionnaires on fatigue (Fatigue Severity Scale, FSS), sleepiness (Epworth Sleepiness Scale, ESS) and sleep quality (Pittsburgh Sleep Quality Index, PSQI) showed higher scores for LC (4.79 ± 0.12, 7.45 ± 0.33 and 7.46 ± 0.27, respectively) than NS patients (2.85 ± 0.16, 5.23 ± 0.32 and 4.26 ± 0.29, respectively; p < 0.05 for all vs. LC). By comparing data of the three waves, mean FSS and PSQI scores of LC patients, but not ESS scores, exceeded the normal range in all, with no significant inter-wave differences. Considering FSS ≥ 4 and PSQI > 5 cutoff values, LC patients commonly exhibited problematic fatigue (≥ 70%) and poor sleep quality (> 60%) in all three waves. Comparative analysis of PSQI component scores of LC patients identified no significant differences between the three waves. Our findings highlight the importance of concerted efforts to manage both fatigue and sleep disturbances in long COVID patient care. This multifaceted approach should be followed in all cases infected with either VOCs of SARS-CoV-2.
286	MS284		Chilunga, Felix Patience; Appelman, Brent; Vugt, Michele van; Kalverda, Kirsten; Smeele, Patrick; Es, Josien van; Wiersinga, Willem Joost; Rostila, Mikael; Prins, Maria; Stronks, Karien; Norredam, Marie; Agyemang, Charles	Differences in incidence, nature of symptoms, and duration of long COVID among hospitalised migrant and non-migrant patients in the Netherlands: a retrospective cohort study	https://doi.org/10.1016/j.lanepe.2023.100630	Published	2023-04-06	Study	https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(23)00049-2/fulltext	Background Comprehensive data on long COVID across ethnic and migrant groups are lacking. We investigated incidence, nature of symptoms, clinical predictors, and duration of long COVID among COVID-19 hospitalised patients in the Netherlands by migration background (Dutch, Turkish, Moroccan, and Surinamese origin, Others). Methods We used COVID-19 admissions and follow up data (January 2021–July 2022) from Amsterdam University Medical Centers. We calculated long COVID incidence proportions per NICE guidelines by migration background and assessed for clinical predictors via robust Poisson regressions. We then examined associations between migration background and long COVID using robust Poisson regressions and adjusted for derived clinical predictors, and other biologically relevant factors. We also assessed long COVID symptom persistence at one-year post-discharge. Findings 1886 patients were included. 483 patients had long COVID (26%, 95% CI 24–28%) at 12 weeks post-discharge. Symptoms like dizziness, joint pain, insomnia, and headache varied by migration background. Clinical predictors of long COVID were female sex, hospital admission duration, intensive care unit admission, and receiving oxygen, or corticosteroid therapy. Long COVID risk was higher among patients with migration background than Dutch origin patients after adjustments for derived clinical predictors, age, smoking, vaccination status, comorbidities and remdesivir treatment. Only 14% of long COVID symptoms persisted at one-year post-discharge. Interpretation There are significant differences in occurrence, nature of symptoms, and duration of long COVID by migration background. Studies assessing the spectrum of functional limitation and access to post-COVID healthcare are needed to help plan for appropriate and accessible healthcare interventions. publisher: Elsevier
287	MS285		Sedgley, Robert; Winer-Jones, Jessamine; Bonafede, Machaon	Long COVID Incidence in a Large US Ambulatory Electronic Health Record System	https://doi.org/10.1093/aje/kwad095	Published	2023-04-19	Study	https://doi.org/10.1093/aje/kwad095	Estimates of the prevalence of long COVID vary widely. This retrospective cohort study describes the incidence of long COVID symptoms 12-20 weeks post-diagnosis in a US ambulatory care setting and identifies potential risk factors. We identified patients with and without a diagnosis of or positive test for COVID-19 between 1/1/2020 and 3/13/2022 in the Veradigm EHR database. We captured patient demographics, clinical characteristics, and COVID-19 comorbidities in the 12-month baseline period. We compared long COVID symptoms between matched cases and controls 12-20 weeks post-index (COVID-19 diagnosis date [cases] or median visit date [controls]). Multivariable logistic regression was used to examine associations between baseline COVID-19 comorbidities and long COVID symptoms. Among 916,894 patients with COVID-19, 14.8% had at least one long COVID symptom in the 12-20 weeks post-index compared to 2.9% of patients without documented COVID-19. Commonly reported symptoms were joint stiffness (4.5%), cough (3.0%), and fatigue (2.7%). Among patients with COVID-19, the adjusted odds of long COVID symptoms were significantly higher among patients with a baseline COVID-19 comorbidity (odds ratio: 1.91 [95% confidence interval: 1.88-1.95]). In particular, prior diagnosis of cognitive disorders, transient ischemic attack, hypertension, and obesity were associated with higher odds of long COVID symptoms.
288	MS286		Fung, Kin Wah; Baye, Fitsum; Baik, Seo H.; Zheng, Zhaonian; McDonald, Clement J.	Prevalence and characteristics of long COVID in elderly patients: An observational cohort study of over 2 million adults in the US	https://doi.org/10.1371/journal.pmed.1004194	Published	2023-04-17	Study	https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004194	Background Incidence of long COVID in the elderly is difficult to estimate and can be underreported. While long COVID is sometimes considered a novel disease, many viral or bacterial infections have been known to cause prolonged illnesses. We postulate that some influenza patients might develop residual symptoms that would satisfy the diagnostic criteria for long COVID, a condition we call “long Flu.” In this study, we estimate the incidence of long COVID and long Flu among Medicare patients using the World Health Organization (WHO) consensus definition. We compare the incidence, symptomatology, and healthcare utilization between long COVID and long Flu patients. Methods and findings This is a cohort study of Medicare (the US federal health insurance program) beneficiaries over 65. ICD-10-CM codes were used to capture COVID-19, influenza, and residual symptoms. Long COVID was identified by (a) the designated long COVID code B94.8 (code-based definition), or (b) any of 11 symptoms identified in the WHO definition (symptom-based definition), from 1 to 3 months post-infection. A symptom would be excluded if it occurred in the year prior to infection. Long Flu was identified in influenza patients from the combined 2018 and 2019 Flu seasons by the same symptom-based definition for long COVID. Long COVID and long Flu were compared in 4 outcome measures: (a) hospitalization (any cause); (b) hospitalization (for long COVID symptom); (c) emergency department (ED) visit (for long COVID symptom); and (d) number of outpatient encounters (for long COVID symptom), adjusted for age, sex, race, region, Medicare-Medicaid dual eligibility status, prior-year hospitalization, and chronic comorbidities. Among 2,071,532 COVID-19 patients diagnosed between April 2020 and June 2021, symptom-based definition identified long COVID in 16.6% (246,154/1,479,183) and 29.2% (61,631/210,765) of outpatients and inpatients, respectively. The designated code gave much lower estimates (outpatients 0.49% (7,213/1,479,183), inpatients 2.6% (5,521/210,765)). Among 933,877 influenza patients, 17.0% (138,951/817,336) of outpatients and 24.6% (18,824/76,390) of inpatients fit the long Flu definition. Long COVID patients had higher incidence of dyspnea, fatigue, palpitations, loss of taste/smell, and neurocognitive symptoms compared to long Flu. Long COVID outpatients were more likely to have any-cause hospitalization (31.9% (74,854/234,688) versus 26.8% (33,140/123,736), odds ratio 1.06 (95% CI 1.05 to 1.08, p < 0.001)), and more outpatient visits than long Flu outpatients (mean 2.9(SD 3.4) versus 2.5(SD 2.7) visits, incidence rate ratio 1.09 (95% CI 1.08 to 1.10, p < 0.001)). There were less ED visits in long COVID patients, probably because of reduction in ED usage during the pandemic. The main limitation of our study is that the diagnosis of long COVID in is not independently verified. Conclusions Relying on specific long COVID diagnostic codes results in significant underreporting. We observed that about 30% of hospitalized COVID-19 patients developed long COVID. In a similar proportion of patients, long COVID-like symptoms (long Flu) can be observed after influenza, but there are notable differences in symptomatology between long COVID and long Flu. The impact of long COVID on healthcare utilization is higher than long Flu. Author summary Why was this study done? The quoted incidence of long COVID varies widely because of differences in definition and measurement method. Long COVID in the elderly is likely to be underreported because they are less likely to respond to surveys, and symptoms may be confused with other chronic diseases. Lingering ill health after infections is not limited to COVID-19. We postulate that some patients may fit the diagnostic criteria of long COVID after a bout of influenza. We call this condition “long Flu.” Comparing and contrasting long COVID and long Flu may shed light on the understanding of long COVID, a disease still shrouded in mystery. What did the researchers do and find? We used the World Health Organization long COVID definition on 2 million Medicare patients with COVID-19 between April 2020 and June 2021. We applied the same definition to almost 900,000 influenza patients during the 2018 and 2019 Flu seasons to identify long Flu. Long COVID occurred in 16.6% of outpatients and 29.2% of inpatients. The corresponding rates for long Flu were 17% and 24.6%. Using only the designated long COVID code, the estimated rates would be 0.5% and 2.6%, way below the reported rates in most studies. Despite the similar overall incidence rates, long COVID patients suffered with notably different symptoms compared to long Flu patients and were also more likely to access inpatient and outpatient healthcare services. What do these findings mean? The use of designated long COVID diagnostic codes alone is likely to result in gross underreporting of long COVID in this population. Long COVID is associated with greater healthcare utilization than long Flu, suggesting a bigger impact on individual health and well-being, as well as on healthcare expenditure.
289	MS287		Yao, Lan; Wang, Gang; Aleya, Lotfi; Maida, Marcello; Graff, J. Carolyn; Sun, Dianjun; Gu, Weikuan	Was the rate of Long Covid as high as 45%–a scary report with flaw	https://doi.org/10.1016/j.eclinm.2023.101949	Published	2023-05-01	Letter to editor	https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00126-8/fulltext	Long Covid has worried the public as the COVID-19 pandemic continues. We are interested in the report by O'Mahoney et al. on the systematic review and meta-analysis of the prevalence and long-term health effects of Long Covid among hospitalized and non-hospitalized populations.1 We were surprised that 45% of COVID-19 survivors, regardless of hospitalization status, experienced a range of unresolved symptoms at ∼ 4 months. First, these data suggest that a large population worldwide had Long Covid in the past two years up to the end of 2021. The authors collected data from publications until January 2022. Based on the report from World Health Organization (https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---31-August-2021), as of December 26, over 278 million cases were reported globally. If 45% of them have the Long Covid, 130 million people worldwide suffer from Long Covid after 4 months of COVID-19. Secondly, these data are significantly different from public perception. According to the December 15, 2022 report from the Centers for Disease Control and Prevention (https://www.cdc.gov/nchs/covid19/pulse/long-covid.htm), the prevalence of Long Covid was less than 20%. Most importantly, it differs from a credible recent publication.2 Based on the data of 486,149 non-hospitalized individuals, Subramanian and colleagues found that 5.3% of men and 9.8% of women had Long COVID symptoms 12 weeks after the index date.2 As such, we examined the data from the systematic review and found some discrepancies and would like to bring them to public attention. publisher: Elsevier PMID: 37125399
290	MS288		Malesevic, Stefan; Sievi, Noriane A.; Baumgartner, Patrick; Roser, Katharina; Sommer, Grit; Schmidt, Dörthe; Vallelian, Florence; Jelcic, Ilijas; Clarenbach, Christian F.; Kohler, Malcolm	Impaired health-related quality of life in long-COVID syndrome after mild to moderate COVID-19	https://doi.org/10.1038/s41598-023-34678-8	Published	2023-05-12	Study	https://www.nature.com/articles/s41598-023-34678-8	A growing number of patients with SARS-CoV-2 infections experience long-lasting symptoms. Even patients who suffered from a mild acute infection show a variety of persisting and debilitating neurocognitive, respiratory, or cardiac symptoms (Long-Covid syndrome), consequently leading to limitations in everyday life. Because data on health-related quality of life (HRQoL) is scarce, we aimed to characterize the impact of Long-Covid symptoms after a mild or moderate acute infection on HRQoL. In this observational study, outpatients seeking counseling in the interdisciplinary Post-Covid consultation of the University Hospital Zurich with symptoms persisting for more than 4 weeks were included. Patients who received an alternative diagnosis or suffered from a severe acute Covid-19 infection were excluded. St. George’s Respiratory Questionnaire (SGRQ), Euroquol-5D-5L (EQ-5D-5L), and the Short form 36 (SF-36) were distributed to assess HRQoL. 112 patients were included, 86 (76.8%) were female, median (IQR) age was 43 (32.0, 52.5) years with 126 (91, 180) days of symptoms. Patients suffered frequently from fatigue (81%), concentration difficulties (60%), and dyspnea (60%). Patients mostly stated impairment in performing usual activities and having pain/discomfort or anxiety out of the EQ-5D-5L. EQ index value and SGRQ activity score component were significantly lower in females. SF-36 scores showed remarkably lower scores in the physical health domain compared to the Swiss general population before and during the COVID-19 pandemic. Long-Covid syndrome has a substantial impact on HRQoL. Long-term surveillance of patients must provide clarity on the duration of impairments in physical and mental health.
291	MS289		Cazé, Ana B; Cerqueira-Silva, Thiago; Bomfim, Adriele P; de Souza, Gisley L; Azevedo, Amanda CA; Brasil, Michelle QA; Santos, Nara R; Khouri, Ricardo; Dan, Jennifer; Bandeira, Antonio C; Cavalcanti, Luciano PG; Barral-Netto, Manoel; Barral, Aldina; Barbosa, Cynara G; Boaventura, Viviane S	Prevalence and risk factors for long COVID after mild disease: A cohort study with a symptomatic control group	https://doi.org/10.7189/jogh.13.06015	Published	2023-05-12	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173895/	Background There is limited data on the prevalence and risk factors for long COVID and few prospective studies with appropriate control groups and adequate sample sizes. We performed a prospective study to determine the prevalence and risk factors for long COVID. Methods We recruited individuals aged ≥15 years who were clinically suspected of having an acute SARS-CoV-2 infection from September 2020 to April 2021. We collected nasopharyngeal swabs three to five days following symptom onset for analysing using reverse transcriptase polymerase chain reaction (RT-PCR). We also collected clinical and sociodemographic characteristics from both SARS-CoV-2 positive and negative participants using structured questionnaires. We followed-up the participants via telephone interview to assess early outcomes and persistent symptoms. For COVID-19 cases, 5D-3L EuroQol questionnaire was used to assess the impact of symptoms on quality of life. Results We followed 814 participants (412 COVID-19 positive and 402 COVID-19 negative persons). Most (n = 741/814) had mild symptoms. Both groups had similar sociodemographic and clinical characteristics, except for the hospitalization rate (15.8% in the COVID-19 positive vs 1.5% in the COVID-19 negative group). One month after disease onset, 122/412 (29.6%) individuals in the COVID-19 positive (long COVID) and 24 (6%) in the COVID-19 negative group reported residual symptoms. In the long COVID group, fatigue, olfactory disorder, and myalgia were the most frequent symptoms in the acute phase. Compared to recovered individuals, older age and having more than five symptoms during the acute phase were risk factors for long COVID. Quality of life was evaluated in 102 out of 122 cases of long COVID, with 57 (55.9%) reporting an impact in at least one dimension of the European Quality of Life 5 Dimensions 3 Level (EQ-5D-3L) questionnaire. Conclusions In this prospective study consisting predominantly of individuals with mild disease, the persistence of symptoms after an acute respiratory illness was associated with a diagnosis of COVID-19. Polysymptomatic acute disease and older age were risk factors for long COVID.
292	MS290		Chelly, Souhir; Rouis, Sourour; Ezzi, Olfa; Ammar, Asma; Fitouri, Sami; Soua, Asma; Fathallah, Ines; Njah, Mansour; Mahjoub, Mohamed	Symptoms and risk factors for long COVID in Tunisian population	https://doi.org/10.1186/s12913-023-09463-y	Published	2023-05-15	Study	https://doi.org/10.1186/s12913-023-09463-y	Background The COVID-19 pandemic has presented various challenges, one of which is the discovery that after the acute episode, around 30% of patients experience persistent symptoms or develop new ones, now known as long COVID. This new disease has significant social and financial impacts. The objective is to determine the prevalence of long COVID in the Tunisian population and identify its predictive factors. Methods This was a cross-sectional study conducted among Tunisians who were infected with COVID-19 between March 2020 and February 2022. An online self-administered questionnaire was distributed through social media, radio, and television channels over the course of one month (February 2022). Long COVID was defined as the persistence of existing symptoms or the development of new symptoms within three months after onset, lasting for at least two months, and with no differential diagnosis. We performed univariate and multivariate analyses using binary stepwise logistic regression with a significance level set at 5%. Results A total of 1911 patients participated in our study, and the prevalence of long COVID was 46.5%. The two most frequent categories were general and neurological post-COVID syndrome, with a prevalence of 36.7% each. The most commonly observed symptoms were fatigue (63.7%) and memory problems (49.1%). In the multivariate analysis, the predictive factors for long COVID were female gender and age of 60 years or older, while complete anti-COVID vaccination was found to be a protective factor. Conclusions Our study found that complete vaccination was a protective factor against long COVID, while female gender and age of 60 years or older were identified as the main risk factors. These findings are consistent with studies conducted on other ethnic groups. However, many aspects of long COVID remain unclear, including its underlying mechanisms, the identification of which could guide the development of potential effective treatments.
293	MS291		Fong, Siew-Wai; Goh, Yun Shan; Torres-Ruesta, Anthony; Chang, Zi Wei; Chan, Yi-Hao; Neo, Vanessa Kexin; Lee, Bernett; Duan, Kaibo; Amrun, Siti Naqiah; Yeo, Nicholas Kim-Wah; Chen, Hsiuyi V.; Tay, Matthew Zirui; Carissimo, Guillaume; Group, COVID-19 Study; Group, NCID Study; Tan, Seow Yen; Leo, Yee-Sin; Lye, David C.; Renia, Laurent; Young, Barnaby Edward; Ng, Lisa F. P.	Prolonged inflammation in patients hospitalized for coronavirus disease 2019 (COVID-19) resolves 2 years after infection	https://doi.org/10.1002/jmv.28774	Published	2023-05-13	Study	https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.28774	Long-term complications from coronavirus disease 2019 (COVID-19) are concerning, as survivors can develop subclinical multiorgan dysfunction. It is unknown if such complications are due to prolonged inflammation, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination may reduce sequela. We conducted a prospective longitudinal study on hospitalized patients over 24 months. Clinical symptoms were collected by self-reporting during follow-up, along with blood samples for quantification of inflammatory markers and immune cell frequencies. All patients were given one dose of mRNA vaccine at 12−16 months. Their immune profiles at 12 and 24 months were compared. Approximately 37% and 39% of our patients reported post-COVID-19 symptoms at 12 and 24 months, respectively. The proportion of symptomatic patients with more than one symptom decreased from 69% at 12 months to 56% at 24 months. Longitudinal cytokine profiling revealed a cluster of individuals with persistently high inflammatory cytokine levels 12 months after infection. Patients with prolonged inflammation showed elevated terminally differentiated memory T cells in their blood; 54% had symptoms at 12 months. The majority of inflammatory markers and dysregulated immune cells in vaccinated patients recovered to a healthy baseline at 24 months, even though symptoms persisted. Post-COVID-19 symptoms can linger for 2 years after the initial infection and are associated with prolonged inflammation. Prolonged inflammation in hospitalized patients resolves after 2 years. We define a set of analytes associated with persistent inflammation and presence of symptoms, which could be useful biomarkers for identifying and monitoring high-risk survivors.
294	MS292		Zorn, Jule; Vollrath, Shirin; Matits, Lynn; Schönfelder, Martin; Schulz, Sebastian V. W.; Jerg, Achim; Steinacker, Jürgen M.; Bizjak, Daniel A.	Relationship between physical performance and perception of stress and recovery in daily life post COVID-19—An explorative study	https://doi.org/10.1371/journal.pone.0285845	Published	2023-05-15	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0285845	Introduction COVID-19 is a multi-systemic disease which can target the lungs and the cardiovascular system and can also affect parts of the brain for prolonged periods of time. Even healthy athletes without comorbidities can be psychologically affected long-term by COVID-19. Objective This study aimed to investigate athletes’ perceived mental stress and recovery levels in daily life, and their maximal aerobic power, at three different time points, post COVID-19. Methods In total, 99 athletes (62.6% male), who had been infected by COVID-19, filled out the Recovery Stress Questionnaire for Athletes (REST-Q-Sport) and completed cardiopulmonary exercise testing (endpoint maximal aerobic power output (Pmax)) at the initial screening (t1: 4 months after infection). Follow-up assessments occurred three (t2, n = 37) and seven months after t1 (t3, n = 19). Results Subgroup means from the Recovery category were significantly below the reference value of four at all three time points, except “General Recovery” (3.76 (± 0.96), p = 0.275, d = 0.968) at t3.”Overtiredness” (2.34 (± 1.27), p = 0.020, r = 0.224) was significantly above the reference value of two at t1, while all other Stress subgroups were not significantly different from the reference value or were significantly below the maximum threshold of two at t1, t2 and t3. Spearman’s ρ revealed a negative association between Pmax and the subcategories of stress (ρ = -0.54 to ρ = -0.11, p < 0.050), and positive correlations between Pmax and “Somatic Recovery” (ρ = 0.43, p < 0.001) and “General Recovery” (ρ = 0.23, p = 0.040) at t1. Pmax (t1: 3.83 (± 0.99), t2: 3.78 (± 1.14), β = 0.06, p < 0.003) increased significantly from t1 to t2. In addition, REST-Q-Sport indicated a decrease in "Sleep" (t2 = 2.35 (± 0.62), t3 = 2.28(± 0.61), β = -0.18, p < 0.023) at t3, when compared to t2. Conclusion The perceived recovery seems to be negatively affected in post COVID-19 athletes. Physical performance post COVID-19 correlates with both “Emotional and Somatic Stress” and “Somatic and General Recovery”, indicating potential mental and physical benefits of exercise. While it is evident that COVID-19, like other viral infections, may have an influence on physical performance, monitoring stress and recovery perceptions of athletes is critical to facilitate their return-to-sports, while minimizing long-term COVID-19 induced negative effects like the athletic objective and subjective perceived recovery and stress levels.
295	MS293		Roever, Leonardo; Cavalcante, Bruno Raphael Ribeiro; Improta-Caria, Alex Cleber	Long-term consequences of COVID-19 on mental health and the impact of a physically active lifestyle: a narrative review	https://doi.org/10.1186/s12991-023-00448-z	Published	2023-05-11	Study	https://doi.org/10.1186/s12991-023-00448-z	Background Coronavirus-19 disease (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Respiratory viruses damage not only the upper respiratory tract in humans, but also several different organs such as the brain. Some of the neurological consequences of COVID-19 reported are anosmia, headache, stroke, declined cognitive function, and impaired mental health, among others. People who had COVID-19 have a higher risk of sequelae in the central nervous system (CNS). However, it is not known which are all possible sequelae and how long will last the long-term effects of the COVID-19 pandemic on behavioral patterns and quality of life. Aim We intend to address the long-term impacts of COVID-19 on mental health and the relevance of physical exercise during the pandemic. Methods We conducted a literature search using PubMed to find the articles that were related to these themes. Results We found 23,489 papers initially, and then we applied the inclusion/exclusion criteria to narrow down our search to 3617 articles and selected 1380 eligible articles after a thorough reading of titles and abstracts. The findings indicated that COVID-19 impacted general mental health and led many not only hospitalized patients to develop cognitive decline, memory impairment, anxiety, sleep alterations, and depressive-like behavior. Furthermore, the fear of vaccines and their effects had negatively affected mental health and directly impacted mortality rates in unvaccinated COVID-19 patients. Conclusions Preventive measures must be undertaken, such as the vaccination of the entire population, vaccination hesitancy discouragement by creating awareness among individuals, and people’s engagement in a physically active lifestyle, since being physically active is a low-cost and effective measure to restore or inhibit the negative outcomes from COVID-19 on mental health.
296	MS294		Kuodi, Paul; Gorelik, Yanay; Gausi, Blessing; Bernstine, Tomer; Edelstein, Michael	Characterisation of post-COVID syndromes by symptom cluster and time period up to 12 months post-infection: A systematic review and meta-analysis	https://doi.org/10.1016/j.ijid.2023.05.003	Published	2023-05-06	Systematic review and meta-analysis	https://www.sciencedirect.com/science/article/pii/S1201971223005490	Highlights •A subset of individuals continues to report post-COVID symptoms beyond one year •Studies reporting post-COVID symptom clusters remain rare in the literature •We identified, systemic inflammatory, cardiorespiratory, and neurologic clusters •Reporting of post-COVID symptom clusters is key to understanding long COVID Abstract Objectives The objective of this study was to characterise post-COVID condition symptoms and symptom clusters, their duration and prevalence. Methods We conducted a systematic review and random-effects meta-analysis of studies reporting post-COVID-19 symptoms and clusters respectively. We searched MEDLINE (via PubMed), Scopus, Web of Science, Science direct, Google Scholar, EBSCOhost, EMBASE, PsycINFO, Cochrane Library, and Mednar for literature reporting on post-COVID condition up to August 2022. Results In the 76 included studies, we found that although most symptoms were reported less frequently 7-12 months following infection compared to earlier, over 20% of patients reported at least one post-COVID condition-compatible symptoms. In the seven studies reporting post-COVID symptom clusters, neurological clustering was the consistently identified, followed by cardiorespiratory and systemic/inflammatory. Conclusions Post-COVID symptom clustering provides direction for research into the etiology, diagnosis, and management of post-COVID condition. Studies reporting post-COVID symptom clusters remain rare due to focus on individual symptoms reporting. Studies on post-COVID symptom clusters should replace individual symptoms reporting to accelerate our understanding of this emerging public health issue.
297	MS295		Jothi, S.; Claessen, G.; Insel, M.; Kubba, S.; Howden, E.; Carmona, S.-R.; Rischard, F.p.	Post-acute Sequelae of SARS Co-V2 and Chronic Fatigue/Myalgic Encephalitis Share Similar Pathophysiologic Mechanisms of Exercise Limitation		Published	2023-05-01	Study	https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A6470
298	MS296		J. Cirillo1, I. R. Young2, H. Remar1, R. Vakil3, D. Collazo4, A. Witzl5, R. Condos	Comparison of Patient-Reported Post-acute Sequelae SARS-CoV-2 (PASC) Respiratory Symptoms With Pulmonary Function Tests (PFTS) in a Post-COVID Patient Population \| C66. VIRAL INFECTIONS, COVID, AND BEYOND	https://doi.org/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A5620	Published	2023-05-23	Study	https://www.atsjournals.org/doi/epdf/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A5620?role=tab
299	MS297		Eschbach, E.; Parekh, A.; Rapoport, D.m.; Mancini, D.m.; Natelson, B.h.	Dysfunctional Breathing Patterns in Post-Acute Sequelae of SARS-CoV-2 (PASC) Patients Can Be Identified Using Approximate Entropy		Published	2023-05-01	Study	https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A5838
300	MS298		Dierckx, W.; Ides, K.; De Meyer, Y.; Deckers, F.; De Backer, J.; Lavon, B.r.; Franck, E.; De Backer, W.	Pulmonary Vascular Effects of a Personalized Rehab Program in Patients With Post-Acute Sequelae of COVID-19 (PASC)		Published	2023-05-01	Study	https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A5552
301	MS299		Dierckx, W.; Ides, K.; De Meyer, Y.; De Backer, J.; Lavon, B.r.; Franck, E.; De Backer, W.	Changes in Lung Function Following Personalized Pulmonary Rehabilitation Programs in Patients With Post-Acute Sequelae of COVID-19 (PASC)		Published	2023-05-01	Study	https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A2159
302	MS300		Panda, A.; Hough, C.t.; Caldwell, E.; Gage, S.; Hope, A.a.	Fatigue Is Often Associated With Severe Headache, Dyspnea, and Insomnia in Adult Patients With Post-acute Sequelae of SARS-CoV-2 (PASC)		Published	2023-05-01	Study	https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A2826
303	MS301		Witzl, A.; Young, I.r.; Remar, H.j.; Condos, R.	Vaccination Status During Acute COVID-19 Infection as a Predictor for Post-acute Sequelae of COVID-19 (PASC) Symptoms		Published	2023-05-01	Study	https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A1619
304	MS302		Young, I.r.; Remar, H.j.; Cirillo, J.; Vakil, R.; Collazo, D.; Witzl, A.; Condos, R.	Longitudinal Generalized Anxiety Disorder 7-Item (GAD-7) Scale Outcomes as Compared to Other Post-acute Sequelae SARS-CoV-2 (PASC) Symptoms in a Post-COVID Patient Population		Published	2023-05-01	Study	https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A3391
305	MS303		Jothi, S.; Claessen, G.; Insel, M.; Kubba, S.; Howden, E.; Carmona, S.-R.; Rischard, F.p.	Post-acute Sequelae of SARS Co-V2 and Chronic Fatigue/Myalgic Encephalitis Share Similar Pathophysiologic Mechanisms of Exercise Limitation		Published	2023-05-01	Study	https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A6470
306	MS304		Bailey, J.; Phillips, A.; Herzog, K.; Sala, M.a.; Carnethon, M.; Kalhan, R.	Compared to the Wuhan Variant, Infection With Omicron and Delta Variants of SARS-CoV-2 Are Associated With Decreased Odds of Developing Post-Acute Sequelae of COVID-19		Published	2023-05-01	Study	https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A3810
307	MS305		Jolley, S.e.; Gundel, S.; Ringwood, N.; Caldwell, E.; Mayer, K.p.; Palakshappa, J.a.; Rogers, A.; Peltan, I.d.; Qadir, N.; Andrews, J.; Tidswell, M.a.; Biehl, M.; Lynch, D.a.; Burnham, E.l.; Hope, A.a.; Hough, C.t.	One-Year Pulmonary Recovery in Patients Hospitalized for COVID-19		Published	2023-05-01	Study	https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A2905
308	MS306		Litchman, T.d.; Maley, J.h.; Zibrak, J.d.	Characterizing Long COVID in Patients With Respiratory Symptoms Referred to a Multidisciplinary Long COVID Clinic		Published	2023-05-01	Study	https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A2171
309	MS307		Hatte, L.; Preston, P.	Understanding Long COVID in Australia: Shaping Policy and Health Services to Support Long COVID Patients		Published	2023-05-01	Study	https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A1831
310	MS308		Bailey, J.; Lavelle, B.; Miller, J.; Jimenez, M.; Lim, P.; Orban, Z.; Clark, J.; Tomar, R.; Ludwig, A.; Ali, S.; Lank, G.; Zielinski, A.; Mylvaganam, R.; El Muayed, M.; Mutharasan, K.; Liotta, E.; Sznajder, J.i.; Davidson, C.; Koralnik, I.; Sala, M.a.; Northwestern, Medicine Comprehensive COVID Center Investigators	Multidisciplinary Care for Long COVID Syndrome - a Single Center Experience		Published	2023-05-01	Study	https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A4386
311	MS309		A.W. Wong 5, K.C. Tran 4, M. Binka 2, N.Z. Janjua 2, H. Sbihi 2, J.A. Russell 1, C. Carlsten 3, A. Levin 4, C.J. Ryerson	Use of Latent Class Analysis to Identify Distinct Phenotypes of Long COVID \| D14. CUTTING EDGE CONCEPTS IN BEHAVIORAL SCIENCES AND HEALTH SERVICES RESEARCH		Published	2023-05-02	Study	https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A6213
312	MS310		Stalker, G.; Tudas, R.a.; Villacreses, R.; Wilbin, T.; Hamzeh, N.y.; Graham, L.; Blount, R.j.; Zabner, J.; Garg, A.; Cho, J.l.; Comellas, A.p.; Pezzulo, A.	Long-COVID Improves After a Year in 50% of Subjects Enrolled in a Rural Cohort		Published	2023-05-01	Study	https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A4391
313	MS311		Eddy, R.l.; Mummy, D.; Dai, H.; Bechtel, A.; Schmidt, A.; Frizzell, B.; Leipsic, J.a.; Leung, J.m.; Driehuys, B.; Que, L.g.; Sin, D.d.; Castro, M.; Niedbalski, P.j.	129Xe Magnetic Resonance Imaging-based Phenotypes of Long COVID: A Multi-center Evaluation		Published	2023-05-01	Study	https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A6786
314	MS312		Bailey, Joseph; Lavelle, Bianca; Miller, Janet; Jimenez, Millenia; Lim, Patrick H.; Orban, Zachary S.; Clark, Jeffrey R.; Tomar, Ria; Ludwig, Amy; Ali, Sareen T.; Lank, Grace K.; Zielinski, Allison; Mylvaganam, Ruben; Kalhan, Ravi; Muayed, Malek El; Mutharasan, R. Kannan; Liotta, Eric M.; Sznajder, Jacob I; Davidson, Charles; Koralnik, Igor J.; Sala, Marc A.	Multidisciplinary Center Care for Long COVID Syndrome – a Retrospective Cohort Study	https://doi.org/10.1016/j.amjmed.2023.05.002	Published	2023-05-22	Study	https://www.sciencedirect.com/science/article/pii/S0002934323003285	Structured Abstract Background Persistent multi-organ symptoms after COVID-19 have been termed “long COVID” or “post-acute sequelae of SARS-CoV-2 infection” (PASC). The complexity of these clinical manifestations posed challenges early in the pandemic as different ambulatory models formed out of necessity to manage the influx of patients. Little is known about the characteristics and outcomes of patients seeking care at multidisciplinary post-COVID centers. Methods We performed a retrospective cohort study of patients evaluated at our multidisciplinary Comprehensive COVID-19 Center (CCC) in Chicago, IL, between May 2020 and February 2022. We analyzed specialty clinic utilization and clinical test results according to severity of acute COVID-19. Results We evaluated 1802 patients a median of 8 months from acute COVID-19 onset, including 350 post-hospitalization and 1452 non-hospitalized patients. Patients were seen in 2361 initial visits in 12 specialty clinics, with 1151 (48.8%) in neurology, 591 (25%) in pulmonology, and 284 (12%) in cardiology. Among patients tested, 742/878(85%) reported decreased quality of life, 284/553(51%) had cognitive impairment, 195/434(44.9%) had alteration of lung function, 249/299(83.3%) had abnormal CT chest scans, and 14/116(12.1%) had elevated heart rate on rhythm monitoring. Frequency of cognitive impairment and pulmonary dysfunction was associated with severity of acute COVID-19. Non-hospitalized patients with positive SARS-CoV-2 testing had similar findings than those with negative or no test results. Conclusions The CCC experience shows common utilization of multiple specialists by long COVID patients, who harbor frequent neurologic, pulmonary, and cardiologic abnormalities. Differences in post-hospitalization and non-hospitalized groups suggest distinct pathogenic mechanisms of long COVID in these populations.
315	MS313		Mohtasham-Amiri, Zahra; Keihanian, Fatemeh; Rad, Enayatollah Homaie; Shakib, Reza Jafari; Vahed, Leila Kanafi; Kouchakinejad–Eramsadati, Leila; Rezvani, Seyed Mahmoud; Nikkar, Rastin	Long- COVID and general health status in hospitalized COVID-19 survivors	https://doi.org/10.1038/s41598-023-35413-z	Published	2023-05-19	Study	https://www.nature.com/articles/s41598-023-35413-z	Despite advances in clinical research, the long-term effects of COVID-19 on patients are not clear. Many studies revealed persistent long-term signs and symptoms. In a survey study, 259 hospitalized confirmed COVID-19 patients between 18 and 59 years were interviewed. Demographic characteristics and complaints were studied through telephone interviews. Any patient-reported symptoms that continued or developed from 4 weeks up to 12 weeks after the onset of the disease were recorded only if they did not exist prior to infection. The 12-Item General Health Questionnaire was used for screening and assessing mental symptoms and psychosocial well-being. The mean age of participants was 43.8 ± 9.9 years. About 37% had at least one underlying disease. 92.5% showed ongoing symptoms that the most prevalent complications were hair loss (61.4%), fatigue (54.1%), shortness of breath (40.2%), altered smell (34.4%), and aggression (34.4%), respectively. In terms of factors affecting patients' complaints, there were significant differences between age, sex, and underlying disease with long-remaining complications. This study shows a high rate of long COVID-19 conditions that should be considered by physicians, policymakers, and managers.
316	MS314		Ballouz, Tala; Menges, Dominik; Anagnostopoulos, Alexia; Domenghino, Anja; Aschmann, Hélène E.; Frei, Anja; Fehr, Jan S.; Puhan, Milo A.	Recovery and symptom trajectories up to two years after SARS-CoV-2 infection: population based, longitudinal cohort study	https://doi.org/10.1136/bmj-2022-074425	Published	2023-05-31	Study	https://www.bmj.com/content/381/bmj-2022-074425	Objective To evaluate longer term symptoms and health outcomes associated with post-covid-19 condition within a cohort of individuals with a SARS-CoV-2 infection. Design Population based, longitudinal cohort. Setting General population of canton of Zurich, Switzerland. Participants 1106 adults with a confirmed SARS-CoV-2 infection who were not vaccinated before infection and 628 adults who did not have an infection. Main outcome measures Trajectories of self-reported health status and covid-19 related symptoms between months six, 12, 18, and 24 after infection and excess risk of symptoms at six months after infection compared with individuals who had no infection. Results 22.9% (95% confidence interval 20.4% to 25.6%) of individuals infected with SARS-CoV-2 did not fully recover by six months. The proportion of individuals who had an infection who reported not having recovered decreased to 18.5% (16.2% to 21.1%) at 12 months and 17.2% (14.0% to 20.8%) at 24 months after infection. When assessing changes in self-reported health status, most participants had continued recovery (68.4% (63.8% to 72.6%)) or had an overall improvement (13.5% (10.6% to 17.2%)) over time. Yet, 5.2% (3.5% to 7.7%) had a worsening in health status and 4.4% (2.9% to 6.7%) had alternating periods of recovery and health impairment. The point prevalence and severity of covid-19 related symptoms also decreased over time, with 18.1% (14.8% to 21.9%) reporting symptoms at 24 months. 8.9% (6.5% to 11.2%) of participants reported symptoms at all four follow-up time points, while in 12.5% (9.8% to 15.9%) symptoms were alternatingly absent and present. Symptom prevalence was higher among individuals who were infected compared with those who were not at six months (adjusted risk difference 17.0% (11.5% to 22.4%)). Excess risk (adjusted risk difference) for individual symptoms among those infected ranged from 2% to 10%, with the highest excess risks observed for altered taste or smell (9.8% (7.7% to 11.8%)), post-exertional malaise (9.4% (6.1% to 12.7%)), fatigue (5.4% (1.2% to 9.5%)), dyspnoea (7.8% (5.2% to 10.4%)), and reduced concentration (8.3% (6.0% to 10.7%)) and memory (5.7% (3.5% to 7.9%)). Conclusions Up to 18% of individuals who were not vaccinated before infection had post-covid-19 condition up to two years after infection, with evidence of excess symptom risk compared with controls. Effective interventions are needed to reduce the burden of post-covid-19 condition. Use of multiple outcome measures and consideration of the expected rates of recovery and heterogeneity in symptom trajectories are important in the design and interpretation of clinical trials. Study registration Current Controlled Trials ISRCTN14990068Current Controlled Trials ISRCTN18181860
317	MS315		Gottlieb, Michael; Spatz, Erica S; Yu, Huihui; Wisk, Lauren E; Elmore, Joann G; Gentile, Nicole L; Hill, Mandy; Huebinger, Ryan M; Idris, Ahamed H; Kean, Efrat R; Koo, Katherine; Li, Shu-Xia; McDonald, Samuel; Montoy, Juan Carlos C; Nichol, Graham; O’Laughlin, Kelli N; Plumb, Ian D; Rising, Kristin L; Santangelo, Michelle; Saydah, Sharon; Wang, Ralph C; Venkatesh, Arjun; Stephens, Kari A; Weinstein, Robert A; for the INSPIRE Group	Long COVID Clinical Phenotypes Up to Six Months After Infection Identified by Latent Class Analysis of Self-Reported Symptoms	https://doi.org/10.1093/ofid/ofad277	Published	2023-05-31	Study	https://doi.org/10.1093/ofid/ofad277	The prevalence, incidence, and interrelationships of persistent symptoms after SARS-CoV-2 infection (Long COVID) vary. There are limited data on specific phenotypes of persistent symptoms. Using latent class analysis (LCA) modeling, we sought to identify whether specific phenotypes of COVID-19 were present three months and six months after acute infection.This was a multicenter, prospective study of symptomatic adults tested for SARS-CoV-2 with prospectively collected data on general symptoms and fatigue-related symptoms up to six-months post-diagnosis. Using LCA, we identified symptomatically homogenous groups among participants with COVID-19 (COVID-positive) and among others without COVID-19 (COVID-negative) at each time period for both general and fatigue-related symptoms.Among 5,963 baseline participants (4,504 COVID-positive and 1,459 COVID-negative), 4,056 had three-month and 2,856 had six-month data at the time of analysis. We identified four distinct phenotypes of post-COVID conditions at three- and six-months for both general and fatigue-related symptoms; minimal symptom groups represented 70% of participants at three and six months. When compared with the COVID-negative cohort, COVID-positive participants had higher occurrence of loss of taste and smell, as well cognition problems. There was substantial class-switching over time; those in one symptom class at three months were equally likely to remain or enter a new phenotype at six months.We identified distinct classes of post-COVID phenotypes for general and fatigue-related symptoms. Most participants had minimal or no symptoms at three and six months follow-up. Significant proportions of participants changed symptom groups over time, suggesting that symptoms present during the acute illness may differ from prolonged symptoms and that post-COVID conditions may have a more dynamic nature than previously recognized.NCT04610515
318	MS316		Carter, Isabelle; Strohl, Kingman; Rosenberg, David; Patil, Susheel; Torer, Juliane; Griggs, Stephanie; Decker, Michael; May, Anna	0967 Do Pre-existing Sleep Disorders Worsen Long COVID Fatigue and Brain Fog?	https://doi.org/10.1093/sleep/zsad077.0967	Published	2023-05-01	Review	https://doi.org/10.1093/sleep/zsad077.0967	Long COVID is common after COVID-19 infection and leads to functional limitations with most reporting substantial symptom burden from fatigue. Symptoms in sleep disorders are attributed to inflammatory dysregulation and may predispose to fatigue expression. We hypothesize prior diagnoses of sleep disorders are associated with severity of long COVID fatigue.A retrospective EMR review was performed of 210 consecutive adult patients (9/2021 to 2/2022) referred at least 3 months after COVID-19 infection seen in a new community-based long COVID clinic. The intake process collected demographics, past medical history, functional questionnaires, and symptom checklists. Primary outcome was Fatigue Severity Scale (FSS) score. Sleep disorders were evaluated as a composite of self-reported insomnia, sleep disordered breathing, and restless legs syndrome as well as subset analyses of each disorder. Secondary outcome was physical functioning measured by ECOG performance scale. Linear analyses were used for FSS and ECOG analyses. Adjustors included age, sex, body mass index (BMI), and whether patient had COVID-19 hospitalization.Cohort was female (66.2%), aged 51.6±SD14.4 yrs, BMI 29.8 [IQR 26.2, 37.7]). Prior chronic insomnia was present in 9%, sleep disordered breathing in 23%, and RLS in 4%; the pooled history of sleep disorders was 30%. Fatigue was reported in 76% with mean FSS score of 5.44 [interquartile range, IQR: 4.11,6.44]; 48% reported brain fog. The interval between acute COVID infection and clinic evaluation was 10.4±5.34 months and had no association to FSS severity (r = 0.07, p = 0.30). Sleep disorders in aggregate, insomnia, and restless legs syndrome had no associations with fatigue or functional status. Sleep disordered breathing had an association to fatigue in unadjusted (β = 0.68, 95% confidence interval, [CI]:0.13,1.24), but not adjusted models (β = 0.53, 95%CI: -0.06,1.13). Sleep disorders both in aggregate and evaluated individually had no associations to brain fog.A prior history of sleep disorders contributed little to post-COVID fatigue reported in those presenting to a community-based Long COVID clinic.TEAMS institutional award, Department of Medicine, University Hospitals of Cleveland, VA CSRD IK2CX001882
319	MS317		Schilling, Claudia; Nieters, Alexandra; Schredl, Michael; Peter, Raphael S.; Rothenbacher, Dietrich; Brockmann, Stefan O.; Göpel, Siri; Kindle, Gerhard; Merle, Uta; Steinacker, Jürgen M.; Kern, Winfried; Group, the Epidemiology of Long COVID (EPILOC) Phase I. study	Pre-existing sleep problems as a predictor of post-acute sequelae of COVID-19	https://doi.org/10.1111/jsr.13949	Published	2023-05-25	Study	https://onlinelibrary.wiley.com/doi/abs/10.1111/jsr.13949	Several months after COVID-19 many individuals still report persisting symptoms, the so-called ‘post-COVID-19 syndrome’. An immunological dysfunction is one of the main pathophysiological hypotheses. As sleep is central to the functioning of the immune system, we investigated whether self-reported pre-existing sleep disturbance might be an independent risk factor for the development of post-COVID-19 syndrome. A total of 11,710 participants of a cross-sectional survey (all tested positive for severe acute respiratory syndrome coronavirus-2) were classified into probable post-COVID-19 syndrome, an intermediate group, and unaffected participants at an average of 8.5 months after infection. The case definition was based on newly occurring symptoms of at least moderate severity and ≥20% reduction in health status and/or working capacity. Unadjusted and adjusted odds ratios were calculated to investigate the association between pre-existing sleep disturbances and subsequent development of post-COVID-19 syndrome while controlling for a variety of demographic, lifestyle, and health factors. Pre-existing sleep disturbances were found to be an independent predictor of subsequent probable post-COVID-19 syndrome (adjusted odds ratio 2.7, 95% confidence interval 2.27–3.24). Sleep disturbances as part of the post-COVID-19 syndrome were reported by more than half of the participants and appeared to be a new symptom and to occur independent of a mood disorder in most cases. Recognition of disturbed sleep as an important risk factor for post-COVID-19 syndrome should promote improved clinical management of sleep disorders in the context of COVID-19. Further, it may stimulate further research on the effect of improving sleep on the prognosis of COVID-19 long-term sequelae and other post-viral conditions.
320	MS318		Calvache-Mateo, Andrés; Navas-Otero, Alba; Heredia-Ciuró, Alejandro; Matín-Núñez, Javier; Torres-Sánchez, Irene; López-López, Laura; Valenza, Marie Carmen	Post-COVID Patients With New-Onset Chronic Pain 2 Years After Infection: Cross-Sectional Study	https://doi.org/10.1016/j.pmn.2023.04.010	Published	2023-05-22	Study	https://www.sciencedirect.com/science/article/pii/S1524904223000954	Background Although pain is common in non-hospitalized post-COVID-19 syndrome, only a few studies have provided information on the pain experience of these patients. Aim To identify the clinical and psychosocial profile associated with pain in non-hospitalized patients with post-COVID-19 syndrome. Method In this study there were three groups: healthy control group, successfully recovered group, and post-COVID syndrome group. Pain-related clinical profile and pain-related psychosocial variables were collected. Pain-related clinical profile included: pain intensity and interference (Brief Pain Inventory), central sensitization (Central Sensitization Scale), insomnia severity (Insomnia Severity Index), and pain treatment. Pain-related psychosocial variables were: fear of movement and (re)injury (Tampa Scale for Kinesiophobia), catastrophizing (Pain Catastrophizing Scale), depression, anxiety and stress (Depression, Anxiety and Stress Scale), and fear-avoidance beliefs (Fear Avoidance Beliefs Questionnaire). Results In all, 170 participants were included in the study (healthy control group n = 58, successfully recovered group n = 57, and post-COVID syndrome group n = 55). Post-COVID syndrome group obtained significantly worse punctuation in pain-related clinical profile and psychosocial variables than the other two groups (p < .05). Conclusions In conclusion, patients with post-COVID-19 syndrome have experienced high pain intensity and interference, central sensitization, increased insomnia severity, fear of movement, catastrophizing, fear-avoidance beliefs, depression, anxiety, and stress.
321	MS319		Schmidbauer, Lena; Kirchberger, Inge; Goßlau, Yvonne; Warm, Tobias D.; Hyhlik-Dürr, Alexander; Linseisen, Jakob; Meisinger, Christa	The association between the number of symptoms and the severity of Post-COVID-Fatigue after SARS-CoV-2 infection treated in an outpatient setting	https://doi.org/10.1007/s00415-023-11752-9	Published	2023-05-23	Study	https://doi.org/10.1007/s00415-023-11752-9	Background Post-COVID-Fatigue (PCF) is one of the most reported symptoms following SARS-CoV-2 infection. Currently, research on persistent symptoms focuses mainly on severe infections, while outpatients are rarely included in observations. Objective To investigate whether the severity of PCF is related to the number of acute and persistent symptoms due to mild-to-moderate COVID-19 and to compare the most common symptoms during acute infection with the persistent symptoms in PCF patients. Methods A total of 425 participants were examined after COVID-19 treated as an outpatient (median 249 days [IQR: 135; 322] after acute disease) at the site of University Hospital Augsburg, Germany. The Fatigue Assessment Scale (FAS) was used to quantify the severity of PCF. The number of symptoms (maximum 41) during acute infection and persistent symptoms (during the last 14 days before examination) were added up to sum scores. Multivariable linear regression models were used to show the association between the number of symptoms and PCF. Results Of the 425 participants, 37% (n = 157) developed PCF; most were women (70%). The median number of symptoms was significantly higher in the PCF group than in the non-PCF group at both time points. In multivariable linear regression models, both sum scores were associated with PCF (acute symptoms: β-estimate per additional symptom [95%-CI]: 0.48 [0.39; 0.57], p < 0.0001); persistent symptoms: β-estimate per additional symptom [95%-CI]: 1.18 [1.02; 1.34], p < 0.0001). The acute symptoms strongest associated with PCF severity were difficulty concentrating, memory problems, dyspnea or shortness of breath on exertion, palpitations, and problems with movement coordination. Conclusion Each additional symptom that occurs in COVID-19 increases the likelihood of suffering a higher severity of PCF. Further research is needed to identify the aetiology of PCF.

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1	Ref	PPLC	Authors	Title	DOI	Peer reviewed	Date	type	Link	Keys	Clés

2	Ce01		Gemelli	Post-COVID-19 global health strategies: the need for an interdisciplinary approach	https://doi.org/10.1007/s40520-020-01616-x	published	11-Jun-20		https://pubmed.ncbi.nlm.nih.gov/32529595/		_
3	Ce02		Trisha Greenhalgh, Matthew Knight, , Christine A’Court, Maria Buxton, , Laiba Husain	Management of post-acute covid-19 in primary care	https://doi.org/10.1136/bmj.m3026	opinion	August 11, 2020	Practice Pointer	https://www.bmj.com/content/370/bmj.m3026	Suggested care approach for #LongCovid, published August 11 in the BMJ. "About 10% of covid patients show symptoms for more than 3 months" post-acute covid-19 as extending beyond three weeks from the onset of first symptoms and chronic covid-19 as extending beyond 12 weeks. Since many people were not tested, and false negative tests are common,4 we suggest that a positive test for covid-19 is not a prerequisite for diagnosis. Management of covid-19 after the first three weeks is currently based on limited evidence Approximately 10% of people experience prolonged illness after covid-19 Many such patients recover spontaneously (if slowly) with holistic support, rest, symptomatic treatment, and gradual increase in activity Home pulse oximetry can be helpful in monitoring breathlessness Indications for specialist assessment include clinical concern along with respiratory, cardiac, or neurological symptoms that are new, persistent, or progressive	Suggestions d'approche de soins pour les #LongCovid, publiées le 11 août dans le BMJ. "Environ 10% des malades de la covid présentent des symptômes plus de 3 mois"
4	Ce03		Advanced Wellbeing Research Centre (AWRC)	This is the first video in a series that aims to support people who have symptoms of fatigue during their recovery from Covid-19.			14 sept. 2020	videos	https://www.youtube.com/watch?v=CIpXGB-8DWI&feature=youtu.be https://youtu.be/hIGYdjcZi7M	British hospital videos on persistent #LongCovid symptoms The video introduces the team and provides a summary of fatigue and its potential causes The series has been developed by the AWRC at Sheffield Hallam University in partnership with the CRESTA clinic at Newcastle Hospitals Foundation Trust, Newcastle University, and University of Northumbria. The work is part of the RICOVR unit at the AWRC (www.awrc.co.uk).	Vidéo 1 - Intro de présentation de l'équipe du centre de recherches et général sur le syndrôme de fatigue post-virale Vidéo 2 - Gestion de l'énergie et activités quotidiennes Vidéo 3 - Prendre soin de soi pendant la guérison Vidéo 4 - Activité et fatigue Vidéo 5 - Questions et réponses relatives à la guérison du Covid 19.
5	Ce04		Amy M. Lavery, PhD1; Leigh Ellyn Preston, DrPH1; Jean Y. Ko, PhD1; Jennifer R. Chevinsky, MD1; Carla L. DeSisto, PhD1;	Characteristics of Hospitalized COVID-19 Patients Discharged and Experiencing Same-Hospital Readmission — United States, March–August 2020	https://doi.org/10.15585/mmwr.mm6945e2	published	November 9, 2020	Study	https://www.cdc.gov/mmwr/volumes/69/wr/mm6945e2.htm	9% of patients hospitalized for covid need hospital readmission within 2 months, and 1.6% require multiple readmissions, according to a US study conducted between March and August 2020.	9% des patients hospitalisés pour la covid ont besoin d'une réadmission à l'hôpital dans les 2 mois, et 1,6% nécessitent des réadmissions multiples, selon une étude américaine réalisée entre les mois de mars et d'août 2020.
6	Ce004		Saoirse E. O'Sullivan, Carl W. Stevenson, and Steven R. Laviolette	Could Cannabidiol Be a Treatment for Coronavirus Disease-19-Related Anxiety Disorders?	https://doi.org/10.1089/can.2020.0102	opinion	5 Nov 2020	opinion	https://www.liebertpub.com/doi/full/10.1089/can.2020.0102	The journal Cannabis and Cannabinoid Research publishes an article which questions the place of cannabidiol in the treatment of anxiety disorders linked to covid.	La revue Cannabis and Cannabinoid Research publie un article qui s'interroge sur la place du cannabidiol dans le traitement des troubles anxieux liés à la covid
7	Ce005		M Mendelson, J Nel, L Blumberg, S A Madhi, M Dryden, W Stevens, F W D Venter	Long-COVID: An evolving problem with an extensive impact	http://dx.doi.org/10.7196%2FSAMJ.2020.v111i11.15433	published	2020-11-23	Article	http://www.samj.org.za/index.php/samj/article/view/13141		Une étude insiste sur la nécessité d'une approche holistique, multidisciplinaire, pour traiter le sujet du #longcovid. Elle précise qu'il y a de plus en plus d'éléments pour dire que l'infection elle-même est cause de déficiences cognitives persistantes. En traitements, l'étude évoque l'entraînement olfactif, les exercices de contrôle de respiration, un "pacing" progressif pour la réadaptation à l'effort, ainsi que dans certains cas l'implication des professionnels de la santé mentale.
8	Ce006		Helen Humphreys, Laura Kilby, Nik Kudiersky, Robert Copeland	Long Covid and the role of physical activity: a qualitative study	https://doi.org/10.1101/2020.12.03.20243345		December 04, 2020		https://www.medrxiv.org/content/10.1101/2020.12.03.20243345v1	"It is imperative to establish consensus, regarding PA-related advice for people with Long Covid, including the identification of individual phenotypes for whom PA might or might not add value to their recovery"	Un pre-print évoque l'importance de définir des protocoles de reprise d'activités physiques chez lceux qui souffrent de séquelles de la covid.
9	Ce007		Mark Vink 1,* andAlexandra Vink-Niese	Could Cognitive Behavioural Therapy Be an Effective Treatment for Long COVID and Post COVID-19 Fatigue Syndrome? Lessons from the Qure Study for Q-Fever Fatigue Syndrome	https://doi.org/10.3390/healthcare8040552	published	11 December 2020	Review	https://www.mdpi.com/2227-9032/8/4/552	It seems therefore unlikely that CBT will reduce disability or lead to objective improvement in long COVID or in post-COVID-19 fatigue syndrome.	Une revue d'études indique que les thérapies cognitives et comportementales, n'ayant pas fait leur preuve dans des groupes hétérogènes pour l'encéphalomyélite myalgique, sont peu susceptibles d'être efficaces pour l'asthénie du #covidlong.
10	Ce008		Shin Jie Yong	Long-Haul COVID-19: Putative Pathophysiology, Risk Factors, and Treatments	https://doi.org/10.1080/23744235.2021.1924397	pre-print	10 December 2020	Review	https://www.preprints.org/manuscript/202012.0242/v1	cf Ce35	Une revue d'études en preprint décrit les facteurs de risques suspectés du covid long, la physiopathologie et les pistes thérapeutiques. Sont évoqués le rintatolimod, les antihistamines (olopatadine, kétotifène), la clarithromycine et les corticostéroïdes.
11	Ce009		Sumathi Reddy (Wall Street Journal)	Experimental Drugs Aim to Treat Long-Haul Covid Patients People suffering from debilitating symptoms for months after getting sick with Covid could get some relief if drugs prove effective in trials		press article	Dec. 21, 2020	Press Article	https://www.wsj.com/articles/experimental-drugs-aim-to-treat-long-haul-covid-11608569400		Plusieurs médicaments sont prévus à l'essai aux États-Unis pour le covid long : - L'anticorps monoclonal Leronlimab, développé par CytoDyn et qui vise le récepteur CCR5 des lymphocytes T, pour réduire l'inflammation cérébrale (pouvant causer fatigue, brouillard cérébral)---- Zofin, composé dérivé du liquide amniotique, développé par Organicell, vise à la régénération pulmonaire via un processus anti-inflammatoire - LYT-100, développé par PureTech, pour la cicatrisation des lésions pulmonaires---- AIM ImmunoTech développe Ampligen (Rintatolimod), médicament immunomodulateur qui donnerait des résultats encourageants sur des patients atteints d'encéphalomyélite myalgique, et qui cible les symptômes "covid long" y ressemblant.
12	Ce010		M. Alawna, M. Amro, A.A. Mohamed	Aerobic exercises recommendations and specifications for patients with COVID-19: a systematic review	https://doi.org/10.26355/eurrev_202012_24211	published	Dec 2020	Systematic Review	https://www.europeanreview.org/article/24211		Une revue systématique d'études sur les exercices de réadaptation physique post-covid. Les recommandations citées font part de 2 à 3 séances hebdomadaires, à 55-80% VO2max et/ou 60-80% de fréquence cardiaque maximale.
13	Ce011		Sauvant, Céline, Bodet, Colin, MORICLET, Tommy, MANTO, Florence, BARTSCH, Valérie, PIRNAY, Laurence, Kellens, Isabelle, MAES, Nathalie, THYS, Marie, Kaux, Jean-François	Rôle de la médecine physique et réadaptation fonctionnelle dans les suites d’une atteinte au SARS-CoV-2	https://hdl.handle.net/2268/254170	published	Nov-2020	Guideline	https://orbi.uliege.be/handle/2268/254170		_
14	Ce012		American Academy of Pediatrics	COVID-19 Interim Guidance: Return to Sports		published	12/17/2020	Guidance	https://services.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/clinical-guidance/covid-19-interim-guidance-return-to-sports/		_
15	Ce013		George M. Anderson	Fluvoxamine, melatonin and COVID-19	https://doi.org/10.1007/s00213-020-05753-z	Published	04 January 2021	Letter to the editor	https://link.springer.com/article/10.1007/s00213-020-05753-z		Parce que la fluvoxamine peut multiplier par 2 ou 3 les taux plasmatiques nocturnes de mélatonine, elle pourrait aider à la régulation des cycles chronobiologiques, et renforcer des effets anti-oxydants et anti-inflammatoires.
16	Ce014		Ankita Sagar, MD, MPH, FACP; Thomas McGinn	Patient-Centered Care in Post-COVID-19 Recovery		published	January 2021	Article	https://connect.sgim.org/viewdocument/patient-centered-care-in-post-covid		Court article sur la prise en charge de la convalescence des patients covid, par l'institut Northwell de New-York.
17	Ce015		Ricardo Augusto Leoni De Sousa, Alex Cleber Improta-Caria, Roque Aras-Júnior, Edilamar Menezes de Oliveira, Úrsula Paula Reno Soci & Ricardo Cardoso Cassilhas	Physical exercise effects on the brain during COVID-19 pandemic: links between mental and cardiovascular health	https://doi.org/10.1007/s10072-021-05082-9	published	25 January 2021	Review Article	https://link.springer.com/article/10.1007/s10072-021-05082-9		_
18	Ce016		Nicolas Hoertel, Marina Sánchez-Rico, Raphaël Vernet, Nathanaël Beeker, Anne-Sophie Jannot, Antoine Neuraz, Elisa Salamanca, Nicolas Paris, Christel Daniel, Alexandre Gramfort, Guillaume Lemaitre, Mélodie Bernaux, Ali Bellamine, Cédric Lemogne, Guillaume Airagnes, Anita Burgun & Frédéric Limosin	Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study	https://doi.org/10.1038/s41380-021-01021-4	published	04 February 2021	Observationnel study	https://www.nature.com/articles/s41380-021-01021-4	This analysis showed a significant association between antidepressant use and reduced risk of intubation or death (HR, 0.56; 95% CI, 0.43–0.73, p < 0.001). This association remained significant in multiple sensitivity analyses. Exploratory analyses suggest that this association was also significant for SSRI and non-SSRI antidepressants, and for fluoxetine, paroxetine, escitalopram, venlafaxine, and mirtazapine (all p < 0.05).	La piste des ISRS, comme antiviraux et comme anti-inflammatoires pour la covid, dont la fluvoxamine et la fluoxétine, se trouve renforcée par une étude observationnelle en France. Une corrélation est relevée sur une réduction de l'aggravation de l'état.
19	Ce017		Phillip Joseph 1, Carlo Arevalo 2, Rudolf K F Oliveira 3, Mariana Faria-Urbina 4, Donna Felsenstein 5, Anne Louise Oaklander 6, David M Systrom	Insights from Invasive Cardiopulmonary Exercise Testing of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome	https://doi.org/10.1016/j.chest.2021.01.082	published	2021 Feb 9	Study	https://pubmed.ncbi.nlm.nih.gov/33577778/	During exercise, the 160 ME/CFS patients averaged lower RAP (1.9±2 vs. 8.3±1.5; P<0.0001) and peak VO2 (80%±21 vs. 101.4%±17; P<0.0001) than controls. The low-flow tertile had lower peak Qc than the normal and high-flow tertiles (88.4±19% vs. 99.5±23.8% vs. 99.9±19.5% predicted; P<0.01). In contrast, systemic oxygen extraction was impaired in high-flow versus low and normal-flow participants (0.74±0.1% vs. 0.88±0.11 vs. 0.86±0.1; P<0.0001) in association with peripheral left-to-right shunting. Among the 160 ME/CFS patient biopsies, 31% was consistent with SFN (epidermal innervation ≤5.0% of predicted; P < 0.0001). Denervation severity did not correlate with exertional measures.	Le malaise post-effort est un symptôme commun à de nombreux "covid long" et aux malades de l'encéphalomyélite myalgique. Une étude américaine en présente une physiopathologie possible. Les auteurs notent chez ces malades un retour veineux et une extraction périphérique d'oxygène altérés. La pression artérielle droite est inférieure à la moyenne. Pour ceux ayant une neuropathie à petites fibres, les dérégulations induites peuvent provoquer une dilatation microvasculaire, détournant le sang oxygéné des lits capillaires, ce qui réduit le retour cardiaque. Ces dérégulations neurovasculaires périphériques plaident pour une intolérance physiologique à l'effort qui va au-delà du seul déconditionnement. Les auteurs écrivent que leurs observations permettent d'éliminer le déconditionnement physique comme facteur confondant des malaises post-effort, relevé comme incompatible avec le débit cardiaque plus élevé et les faibles pressions de remplissage biventriculaire. "[Pour éviter les malaises post-effort] nous préconisons pour la rééducation physique un programme d'exercices prudents, gradués, pour aider à compenser les limitations cardiovasculaires associées à la maladie."	N001
20	Ce018		Pam R. Taub, Adena Zadourian, Hannah C. Lo, Cameron K. Ormiston, Shahrokh Golshan, and Jonathan C. Hsu	Randomized Trial of Ivabradine in Patients With Hyperadrenergic Postural Orthostatic Tachycardia Syndrome	https://doi.org/10.1016/j.jacc.2020.12.029	published	2021 Feb	RCT	https://www.sciencedirect.com/science/article/pii/S0735109720381316?dgcid=author	There was a significant reduction in heart rate between placebo and ivabradine (p < 0.001). Patients reported significant improvements in QOL with RAND 36-Item Health Survey 1.0 for physical functioning (p = 0.008) and social functioning (p = 0.021). There was a strong trend in reduction of NE levels upon standing with ivabradine (p = 0.056). Patients did not experience any significant side-effects, such as bradycardia or hypotension, with ivabradine.	Un essai clinique randomisé en double aveugle appuie fortement la possibilité que l'ivabradine, un médicament bradycardisant, soit efficace pour atténuer le syndrome de tachycardie orthostatique posturale (POTS en anglais), symptôme assez fréquent chez les malades du covid long, en lien particulier avec la dysautonomie. Ivabradine pour traiter le syndrome de tachycardie orthostatique posturale : Un éditorial dans la revue Journal of the American College of Cardiology, qui publie l'étude de Taub et al. salue une avancée importante dans le traitement de ce syndrome. https://www.jacc.org/doi/10.1016/j.jacc.2020.12.028	N001
21	Ce019		Luxmi Dhoonmoon	Self-management for patients with suspected ‘long COVID’	https://doi.org/10.12968/indn.2021.2.22	Published	18 Feb 2021		https://www.magonlinelibrary.com/doi/abs/10.12968/indn.2021.2.22	Many long COVID patients will require rehabilitation services, which traditionally have long waiting times.7 In light of these new challenges posed on an already stretched healthcare system, nurses should be aware of digital and online health tools they can promote to long COVID patients. Self-management resources should be utilised to ease workload and ensure that patient’s conditions are effectively managed in between face-to-face and virtual consultations for which the wait will be longer than usual. This article will explore the long-term respiratory, neuromuscular, cardiac, chronic wound and mental health effects of COVID-19 and the resources available to support these conditions in the community.	Un article britannique à destination des infirmières fait un rapide tour d'horizon des programmes de rééducation pour les patients atteints de séquelles de la covid.	N003R2
22	Ce020		Victor FigueiredoLeiteMD1Danielle BianchiniRampimMD1Valeria ConceiçãoJorgePT1Maria do CarmoCorreia de LimaPT DPT1Leandro GonçalvesCezarinoPT1Cleber Nunesda RochaMD1Rodrigo BarbosaEsperMD PhD1Prevent Senior COVID-19 Rehabilitation Study	Persistent symptoms and disability after COVID-19 hospitalization: data from a comprehensive telerehabilitation program	https://doi.org/10.1016/j.apmr.2021.03.001	Published	10 March 2021	Study	https://www.sciencedirect.com/science/article/pii/S0003999321002252	Individuals hospitalized due to COVID-19 present high levels of disability, dyspnea, dysphagia, and dependence for both ADLs and IADLs. Those admitted at the ICU presented more advanced disability parameters.	Etude sur les séquelles et les programmes de réadaptation pour des patients âgées (71,8±13,0 ans) covid hospitalisés.
23	Ce021		Manzur Kader, Md. Afzal Hossain, Vijayendar Reddy, Nirmala K. Panagodage Perera	Effects of short-term breathing exercises on respiratory recovery in patients with COVID-19- a quasi-experimental study	https://doi.org/10.21203/rs.3.rs-301294/v1	pre-print	08 Mar, 2021	RESEARCH ARTICLE	https://www.researchsquare.com/article/rs-301294/v1	After 4-5 days of respiratory rehabilitation SpO2 (96.7% ±2.1 vs 90.4% ±1.5), P<0.01), respiratory rate (20.5 ±2.4 vs 23.0 ±2.2) breaths/minute, P<0.01), heart rate (80.5 ±9.2 vs 91.2 ±8.6) beats/minute, P<0.01), and oxygen therapy requirement (0.4 ±0.98 vs 1.4 ±2.0) litre/min, P<0.01) improved in the intervention group compared to the control group. The mean days of hospitalisation for the intervention group and the control group were 7.1 days vs. 14.6 days, respectively.	Un préprint sur les effets d'exercices de respiration à court terme, pour la récupération respiratoire chez les patients hospitalisés atteints de covid.
24	Ce022		Praveen Kumar Kandakurti Sampath Kumar Amaravadi	Management and Rehabilitation of COVID-19: A Physiotherapist Perspective	https://doi.org/10.1615/CritRevPhysRehabilMed.2021037383	Published	2021	Review	http://www.dl.begellhouse.com/journals/757fcb0219d89390,4405326109887885,5aa2c5af68ed4859.html	We conclude that early physiotherapy rehabilitation should be started to avoid post-COVID complications and improve patients' quality of life. The current paper highlights the importance of physiotherapy rehabilitation service for patients with confirmed COVID-19 in the acute hospital setting, including screening to determine indications for physiotherapy, respiratory physiotherapy, exercise interventions, and postdischarge period.	_
25	Ce023		Polly Moffat	Recognising and treating long Covid	https://doi.org/10.12968/prma.2021.31.3.20	Published	12 Mar 2021		https://www.magonlinelibrary.com/doi/abs/10.12968/prma.2021.31.3.20?journalCode=prma	Reports of continuing, long-term symptoms of Covid-19 after patients have recovered from infection have raised concerns among health professionals. What are the characteristics of the condition?	_
26	Ce024		Veronica LourençoWittmeraFlavia MariniParoaHalinaDuarteaVerena KiseCapellinibMarcela CangussuBarbalho-Moulim	Early mobilization and physical exercise in patients with COVID-19: A narrative literature review	https://doi.org/10.1016/j.ctcp.2021.101364	Published	13 March 2021	Review	https://www.sciencedirect.com/science/article/pii/S1744388121000633	Highlights •Mobilization plans must consider disease severity, contraindications and comorbidities. •Early mobilization should start as soon as COVID-19 patients have clinical stability. •Exercise prescription must consider clinical conditions and contraindications. •Most of the studies recommended low-intensity exercise for patients with mild disease. •Telerehabilitation should play a key role for patients in the recovery of COVID-19.	Une revue d'études sur la rééducation après une covid.
27	Ce025		Resat Cinar Malliga R. Iyer George Kunos	Dual inhibition of CB1R and iNOS as a potential novel approach to the pharmacological management of acute and long COVID‐19	https://doi.org/10.1111/bph.15461	Published	26 March 2021	Article	https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.15461	We discuss the potential pathologic function of increased activity of the endocannabinoid (EC)/CB1 receptor (CB1R) system and inducible NO synthase (iNOS). We advocate a polypharmacology approach wherein a single chemical entity simultaneously engages CB1R and iNOS for inhibition as a potential therapeutic strategy for COVID‐19 related health complications.	_
28	Ce026		Emmanuel Coudeyre (Pr) 1 Cédric Cormier 1 Frédéric Costes 2 Marie-Martine Lefevre-Colau 3 Maxime Grolier	Réadaptation musculaire après infection à COVID-19 Muscular rehabilitation post COVID-19 infection	https://doi.org/10.1016/j.monrhu.2021.03.002	Published	24 March 2021	Article	https://www.sciencedirect.com/science/article/pii/S1878622721000412	Severe COVID 19 infection can cause a variety of respiratory and neuro-muscular damage both in the acute phase and at distance from the initial infection. Rehabilitation should be offered at every stages of the infection. Due to a lack of evidence based data, this management is based on published data for severe respiratory infections such as SARS and expert opinion. It should combine muscle strengthening, exercise reconditioning and more specific respiratory physiotherapy for certain patients.	L’infection sévère à COVID 19 peut-être à l’origine d’atteintes respiratoires et neuro-musculaires variées autant à la phase aigüe qu’à distance de l’infection initiale. Une prise en charge rééducative doit être proposée aux différentes phases de l’infection. Par manque de données probantes, cette prise en charge s’appuie sur les données publiées pour les infections respiratoires sévères comme le SARS et l’avis d’experts. Elle doit associer du renforcement musculaire, un reconditionnement à l’effort et une kinésithérapie respiratoire plus spécifique pour certains patients.	N006
29	Ce027		Thomas Hueso , Cécile Pouderoux , Hélène Péré ,Anne-Lise Beaumont ,Laure-Anne Raillon, Florence Ader ,Lucienne Chatenoud ,Déborah Eshagh ,Tali-Anne Szwebel ,Marc Garnier ,France Pirenne ,Pierre Tiberghien ,Karine Lacombe	Convalescent plasma therapy for B-cell–depleted patients with protracted COVID-19	https://doi.org/10.1182/blood.2020008423	Published	November 12, 2020	Study	https://ashpublications.org/blood/article/136/20/2290/463806	Key Points As a proof of concept, COVID-19 convalescent plasma represents an interesting approach in B-cell–depleted patients with protracted COVID-19. COVID-19 convalescent plasma induces a decrease in temperature and inflammatory parameters within 1 week associated with oxygen weaning. Anti-CD20 monoclonal antibodies are widely used for the treatment of hematological malignancies or autoimmune disease but may be responsible for a secondary humoral deficiency. In the context of COVID-19 infection, this may prevent the elicitation of a specific SARS-CoV-2 antibody response. We report a series of 17 consecutive patients with profound B-cell lymphopenia and prolonged COVID-19 symptoms, negative immunoglobulin G (IgG)-IgM SARS-CoV-2 serology, and positive RNAemia measured by digital polymerase chain reaction who were treated with 4 units of COVID-19 convalescent plasma. Within 48 hours of transfusion, all but 1 patient experienced an improvement of clinical symptoms. The inflammatory syndrome abated within a week. Only 1 patient who needed mechanical ventilation for severe COVID-19 disease died of bacterial pneumonia. SARS-CoV-2 RNAemia decreased to below the sensitivity threshold in all 9 evaluated patients. In 3 patients, virus-specific T-cell responses were analyzed using T-cell enzyme-linked immunospot assay before convalescent plasma transfusion. All showed a maintained SARS-CoV-2 T-cell response and poor cross-response to other coronaviruses. No adverse event was reported. Convalescent plasma with anti–SARS-CoV-2 antibodies appears to be a very promising approach in the context of protracted COVID-19 symptoms in patients unable to mount a specific humoral response to SARS-CoV-2.	_
30	Ce028		D Liska, M Andreansky	Rehabilitation and physical activity for COVID-19 patients in the post infection period	https://doi.org/10.4149/bll_2021_052	Published	Avril 2021	Study	https://pubmed.ncbi.nlm.nih.gov/33848179/		_
31	Ce029	PESE	Martine Nurek, Clare Rayner, Anette Freyer, Sharon Taylor, Linn Järte, Nathalie MacDermott, Brendan C. Delaney	Recommendations for the Recognition, Diagnosis, and Management of Patients with Post COVID-19 Condition ('Long COVID'): A Delphi Study	https://dx.doi.org/10.2139/ssrn.3822279	pre-print	8 Apr 2021	Guideline	https://ssrn.com/abstract=3822279	Recommendations pertaining to clinic organisation 1) Consider long covid in patients with a clinical diagnosis of covid-19 as per WHO criteria1 or test-positive history with new or fluctuating symptoms including but not limited to breathlessness, chest pain, palpitations, inappropriate tachycardia, wheeze, stridor, urticaria, abdominal pain, diarrhoea, arthralgia, neuralgia, dysphonia, fatigue including neurocognitive fatigue, cognitive impairment, prolonged pyrexia and neuropathy occurring beyond 4 weeks of initial covid-19. 2) Multispecialty long covid clinics should be led by a doctor with cross-specialty knowledge and experience of managing this condition. 3) Consider individualised investigations, management and rehabilitation planning via a multispecialty long covid assessment service as local services allow. Prioritise physician-led medical assessments and diagnostics initially, and consider allied health professionals including physiotherapy and OT input asadjuncts. 4) It is inappropriate for long covid clinics to be led by mental health specialists e.g., IAPT, clinical or health psychologist. They may be useful in supporting the multispecialty team but do not have the expertise to investigate and manage potential organ damage. 5) All under-18-year-olds need access to similar services run by paediatric specialists with knowledge of how presentations and treatments differ to adults and with close liaison with school. 6) Patients with comorbid mental health difficulties should have equal access to medical care as a patient without mental health difficulties and should not be triaged away from services. Recommendations pertaining to diagnosis of underlying disorder General approach: 7) In someone with long covid, symptoms of possible non-covid-19 related issues should be investigated and referred as per local guidelines. Long covid alone is not a sufficient diagnosis unless other causes have been excluded. 8) Carry out a face-to-face assessment including a thorough history and examination, consider other non-covid-19 related diagnoses, and measure FBC, renal function, CRP, LFT, thyroid function, HbA1c, Vitamin D, Magnesium, B12, folate, ferritin and bone studies. Respiratory: 9) In those with respiratory symptoms, consider CXR at an early stage. Be aware that a normal appearance does not exclude respiratory pathology. 10) Be aware that simple spirometry may be normal but patients may have diffusion defects indicative of scarring, chronic PEs or microthrombi. Consider referral to respiratory for full lung function testing. 11) Measure oxygen saturation at rest and after an age-appropriate brief exercise test in people with breathlessness and refer for investigation if hypoxaemic or if any desaturation on exercise. Cardiac: 12) Consider the possibility of a cardiac cause of breathlessness. 13) Be aware that a normal D-dimer may not exclude thromboembolism, especially in a chronic setting, and referral for investigation is therefore indicated if there is a clinical suspicion of pulmonary emboli. Additionally, be mindful that thromboembolism may occur at any stage during the disease course. 14) In patients with inappropriate tachycardia and/or chest pain, carry out ECG, troponin, Holter monitoring, and echocardiography. Be aware that myocarditis and pericarditis cannot be excluded on echocardiography alone. 15) In patients with chest pain consider a referral to cardiology as cardiac MRI may be indicated in a normal echo to rule out myopericarditis and microvascular angina. 16) In patients with palpitations and/or tachycardia, consider autonomic dysfunction. Others: 17) In patients with urticaria, conjunctivitis, wheeze, inappropriate tachycardia, palpitations, shortness of breath, heartburn, abdominal cramps or bloating, diarrhoea, sleep disturbance, or neurocognitive fatigue,2 consider mast cell disorder. 18) In patients with cognitive difficulties sufficient to interfere with work or social functioning consider neurocognitive assessment. 19) In patients with joint swelling and arthralgia consider a diagnosis of reactive arthritis or new connective tissue disease and investigate and refer as appropriate. Recommendations pertaining to management General approach: 20) For patients with fatigue and worsening symptoms hours to days following an activity emphasise the importance of an initial phase of convalescence followed by careful pacing and rest. 21) Support patients in shifting their mental timeline of recovery to reflect the likely prolonged course, with a possibly long phased return to work. 22) Further support patients with signposting to patient resources. Applicable resources may include: management of post-exertional symptom exacerbation, activity pacing, acupuncture, diagnosis-specific management as relevant. 23) Provide patients with signposting to social prescribing, sickness certification and financial advice. Discuss with the patient whether sickness certification will state long covid as diagnosis. 24) Clinicians should ensure that the occupational status of patients with long covid is recorded (in/out of work, part/full time, student). 25) Follow patients up regularly to monitor progress from a full biopsychosocial and occupational perspective. 26) Encourage reporting of new symptoms (expected) and expectation of waxing-waning course. 27) Consider contributing patient data to research on long covid, using the WHO Case Report Form or similar.3 Management of specific conditions: 28) Patients with cardiac symptoms should be advised to limit their HR to 60% of maximum (usually around 100-110bpm) and investigated with at least ECG and echocardiogram before taking up exercise. Supervised exercise testing should be considered for this patient group as they may have perimyocarditis and exercise carries risk of arrhythmia and worsening cardiac function.4 29) For autonomic dysfunction including PoTS (Postural Orthostatic Tachycardia Syndrome), consider first increased fluids, salts, compression hosiery and specific rehabilitation.5 30) If PoTS and no or inadequate response to non-pharmacological therapy consider beta blocker, Ivabradine or Fludrocortisone (with BP and response monitoring). 31) In patients with possible mast cell disorder, consider a one-month trial of initial medical treatment and dietary advice. Higher than standard dose of antihistamines are commonly used for this indication. If partial effect consider adding second level treatment such as Montelukast, as well as referral to allergy or immunology specialists.6 7 32) Be aware that adverse drug reactions are more common in patients with mast cell disorder, for example to beta lactam antibiotics, NSAIDs, codeine, morphine or buprenorphine. 33) For breathing pattern disorder, consider specialist physiotherapy and/or using alternative therapies such as pranayama breathing and meditation. 34) In patients expressing distress, significant low mood, anxiety or symptoms of PTSD, consider mental health assessment. 35) Over the counter supplementation is common, including vitamin C, D, niacin (nicotinic acid) and quercetin. Be aware of significant drug interactions, such as with niacin or quercetin.	Un guide britannique de recommandations en pre-print (ni relu, ni encore publié) de prise en charge des malades du covid long, liste des conseils retenus par la méthode de Delphes ("Delphi", itérations de consensus par un groupe d'experts structuré). Les recommandations portent sur l'organisation médicale, le diagnostic (notamment respiratoire, cardiaque, systémique) et la prise en charge.
32	Ce030		HAS	HAS - Webinaire : symptômes prolongés de la Covid-19 aiguë chez l'adulte			15 avril 2021	Webinar	https://youtu.be/lqPQbjeOyog		Lors du webinaire de la HAS sur les symptômes prolongés de la covid, le Dr Nicolas Barizien (à 57'05) insiste sur la nécessité de reprendre une petite activité quotidienne au plus tard quelques semaines après la phase aiguë. Il insiste pour faire impérativement précéder la rééducation sportive par une rééducation respiratoire, pour resynchroniser la respiration abdominale et la respiration thoracique. Il indique que, sans ce préalable, le patient risque un retour des dyspnées et une aggravation des symptômes. S'ensuit une réadaptation à l'effort avec de l'endurance douce, puis par "interval training" le retour à la capacité à changer de rythme et passer à des efforts plus soutenus. Le but est d'amener le patient à une activité physique en autonomie à domicile.
33	Ce031		Viet-Thi Tran, Caroline Riveros, Bérangère Clepier, Moïse Desvarieux, Camille Collet, Youri Yordanov, Philippe Ravaud	Development and validation of the long covid symptom and impact tools, a set of patient-reported instruments constructed from patients’ lived experience	https://doi.org/10.1093/cid/ciab352	Published	29 April 2021	Study	https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab352/6252414	The long covid Symptom and Impact Tools (ST and IT) were constructed from the answers to a survey with open-ended questions to 492 patients with long COVID. Validation of the tools involved adult patients with suspected or confirmed COVID-19 and symptoms extending over three weeks after onset. Construct validity was assessed by examining the relations of the ST and IT scores with health related quality of life (EQ-5D-5L), function (PCFS, post-COVID functional scale), and perceived health (MYMOP2).	_
34	Ce032		Kamlesh Khunti, Melanie J. Davies, Mikhail N. Kosiborod & Michael A. Nauck	Long COVID — metabolic risk factors and novel therapeutic management	https://doi.org/10.1038/s41574-021-00495-0	Published	19 April 2021		https://www.nature.com/articles/s41574-021-00495-0	Cardiometabolic conditions, including type 1 and type 2 diabetes mellitus, are associated with severe COVID-19 and long COVID. Interventions to target multiple risk factors, combined with use of novel glucose-lowering agents that improve metabolic function and the key processes that are impaired in COVID-19, should be the preferred therapeutic options for management of people with long COVID.	_
35	Ce033		Enya Daynes, Charlotte Gerlis, Emma Chaplin, Nikki Gardiner, Sally J Singh	Early experiences of rehabilitation for individuals post-COVID to improve fatigue, breathlessness exercise capacity and cognition – A cohort study	https://doi.org/10.1177%2F14799731211015691	Published	May 6, 2021	Study	https://journals.sagepub.com/doi/full/10.1177/14799731211015691	Individuals with lasting symptoms of COVID-19 should be offered a comprehensive recovery programme. 30 individuals (mean[SD] age 58[16]) that completed a 6 week, twice supervised rehabilitation programme demonstrated statistically significant improvements in exercise capacity, respiratory symptoms, fatigue and cognition. Participants improved by 112 m on the Incremental Shuttle Walking Test and 544 seconds on the Endurance Shuttle Walking Test. There were no serious adverse events recorded, and there were no dropouts related to symptom worsening. COVID-19 rehabilitation appears feasible and significantly improves clinical outcomes.	Un article décrit un programme de rééducation et réadaptation physique pour les patients ayant des symptômes persistants de la covid. Il se base sur les conseils donnés par ce site : https://www.yourcovidrecovery.nhs.uk/	N010
36	Ce034		Babita Yadav, Amit Rai, Pallavi Suresh Mundada, Richa Singhal, BCS Rao, Rakesh Rana, Narayanam Srikanth	Safety and Efficacy of Ayurvedic Interventions and Yoga on Long Term Effects of COVID-19: a Structured Summary of a Study Protocol for a Randomized Controlled Trial	https://doi.org/10.21203/rs.3.rs-490926/v1	pre-print	13 May, 2021	Study in progress	https://www.researchsquare.com/article/rs-490926/v1	Participants’ recruitment started on 1st May 2021. Anticipated end of recruitment is August 2021. Protocol number: CCRAS-01 Protocol version number: 1.1, 13th January 2021.	_
37	Ce035		Jaffer Shah, Hani Aiash, Maya Khodor, Sherief Ghozy, Ashraf Sheble, Adel Hassan, Said Abbadi, Khaled Sabry, Amany Abou Zeid, Akram Abdelbary	Integrated multidisciplinary post-COVID-19 care in Egypt	https://doi.org/10.1016/S2214-109X(21)00206-0	Published	May 18, 2021	Correspondance	https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(21)00206-0/fulltext		_
38	Ce036		Shin Jie Yong	Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments	https://doi.org/10.1080/23744235.2021.1924397	Published	22 May 2021	Review	https://www.tandfonline.com/doi/full/10.1080/23744235.2021.1924397	Publication of Ce09	Cf Ce09
39	Ce037		Gutenbrunner, Christoph MD, PhD, FRCP; Nugraha, Boya MS, PhD; Martin, Lidia Teixido	Phase-Adapted Rehabilitation for Acute Coronavirus Disease-19 Patients and Patient With Long-term Sequelae of Coronavirus Disease-19	https://doi.org/10.1097/PHM.0000000000001762	Published	May 2021	Article	https://journals.lww.com/ajpmr/Fulltext/2021/06000/Phase_Adapted_Rehabilitation_for_Acute_Coronavirus.3.aspx?context=LatestArticles	Since the beginning of the COVID-19 pandemic in early 2020, many papers have highlighted the need for the rehabilitation of patients with SARS-CoV-2 infection. Most papers refer to the need for respiratory rehabilitation in the acute phase; however, the fact that the infection also affects other organ systems has to be considered in rehabilitation interventions. Long-term symptoms in many cases severely limit activity and participation and alter quality of life, leading to rehabilitation needs. This article proposes a phase-adapted model of linking the acute, postacute, and long-term symptoms of COVID-19 with the well-established matrix of acute, postacute, and long-term rehabilitation services. A review of currently available recommendations for phase-adapted rehabilitation strategies, including the relevance of prehabilitation within this context, is provided.	_
40	Ce038		Martin Hensher, Mary Rose Angeles, Barbara de Graaff, Julie Campbell, Eugene Athan, Rebecca Haddock	Managing the long term health consequences of COVID-19 in Australia		Published	26/05/2021	Review	https://ahha.asn.au/system/files/docs/publications/deeble_issues_brief_no_40._managing_the_long_term_health_consequence_of_covid-19_in_australia.pdf	Primary prevention of COVID-19 should be prioritised as the most effective means of mitigating the long-term health consequence of infection at population level. However plans must be put in place to allow rapid scaling-up of long-term care were COVID-19 control measures to fail	_
41	Ce039		Zahra Alizadeh1, Nastaran Keyhanian2, Sara Ghaderkhani2, Simin Dashti-Khavidaki3, Raheleh Shokouhi Shoormasti1, and Zahra Pourpak	A Pilot Study on Controlling Coronavirus Disease 2019 (COVID-19) Inflammation Using Melatonin Supplement		Published	10 April 2021		https://ijaai.tums.ac.ir/index.php/ijaai/article/download/3086/1717/	No effective antiviral drugs and vaccines are available for the treatment of patients with severe coronavirus 2019 (COVID-19). Therefore, available, safe, and inexpensive drugs and supplements such as melatonin are among the proposed options for controlling inflammation.	_
42	Ce040		Abdel-Fattah	Long COVID-19 Syndrome Precaution and Management	https://dx.doi.org/10.38125/OAJBS.000286	Published	May 27, 2021	Review	https://biomedscis.com/pdf/OAJBS.ID.000286.pdf	This is a review of COVID-19’s highly effects on almost all the organs and how we precaution and management as the COVID-19 causes many systemic abnormalities like inflammation, endotheliosis, vasoconstriction, hypercoagulability, edema and Lymphocytopenia, with elevated D-dimer, and disseminated intravascular coagulation.	_
43	Ce041	ME - PESE	Alaa Ghali 1,*,Carole Lacout 1,Maria Ghali 2,Aline Gury 1,Estelle Delattre 1,Christian Lavigne 1 andGeoffrey Urbanski 1	Warning Signals of Post-Exertional Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Retrospective Analysis of 197 Patients	https://doi.org/10.3390/jcm10112517	Published	7 June 2021	Study	https://www.mdpi.com/2077-0383/10/11/2517/htm	Post-exertional malaise (PEM), the key feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is characterized by baseline symptom exacerbation after exposure to a stressor, and some patients can experience new or non-typical symptoms. We hypothesized that new or non-typical symptoms occurring long enough before onset of baseline symptom exacerbation could be warning signals predicting PEM. Adult ME/CFS patients who attended the internal medicine department of Angers University Hospital (France) between October 2011 and December 2019 were included in a retrospective medical records review. Patients who experienced one or more new or non-typical symptoms before baseline symptom exacerbation were compared with the rest of the study population for PEM features, epidemiological characteristics, fatigue features, and comorbidities. New or non-typical symptoms preceded baseline symptom exacerbation in 27/197 (13.7%) patients, and the most frequent ones were mood disorders (37%). When compared to the rest of the study population, only PEM intensity was significantly lower in these patients (p = 0.004), even after adjustment for sex and age at disease onset (p = 0.007). New or non-typical symptoms preceding baseline symptom exacerbation in some ME/CFS patients could be warning signals for PEM. Their identification could help preventing PEM occurrences or reducing their intensity leading to improving disease prognosis.	Une étude essaie de définir quels symptômes précurseurs peuvent annoncer un malaise post-effort chez les personnes souffrant d'encéphalomyélite myalgique.	N011
44	Ce042		Funke-Chambour M.a,b · Bridevaux P.-O.c,d · Clarenbach C.F.e · Soccal P.M.d,f · Nicod L.P.g,h · von Garnier C.h	Guidelines Swiss Recommendations for the Follow-Up and Treatment of Pulmonary Long COVID	https://doi.org/10.1159/000517255	Published	17-18 June 2021	Review	https://www.karger.com/Article/FullText/517255	Results: The participants in the survey reached consensus and formulated a strong recommendation for regarding the following points. Patients hospitalized for COVID-19 should have a pulmonary assessment including pulmonary function tests. Symptomatic subjects affected by COVID-19, including those with mild disease, should benefit from a pulmonary follow-up. Persistent respiratory symptoms after COVID-19 should be investigated by a pulmonary follow-up including plethysmography, diffusion capacity measurement, and blood gases analysis. Individuals having suffered from COVID-19 and who present with persistent respiratory symptoms should be offered a rehabilitation. Additional questions were given moderateor weak recommendations for. The panel did not reach sufficient consensus for pharmacological therapy (e.g., therapy specifically targeting lung fibrosis) to formulate recommendations for LC drug treatment. Conclusion: The formulated recommendations should serve as an interim guidance to facilitate diagnosis and treatment of patients with pulmonary LC. As new evidence emerges, these recommendations may need to be adapted.	_
45	Ce043		Philippe Lepere, Bruno Escarguel, Selda Yolartiran, Claude Escarguel	COVID-19: Can early home treatment with Azithromycin alone or with Zinc help prevent hospitalisation, death, and long-COVID-19? A review		pre-print	January 22, 2021	Review	https://www.medrxiv.org/content/10.1101/2020.12.29.20248975v2	Many studies report on outpatient treatment with a combination of AZM + HCQ versus AZM alone, and few studies propose the addition of Zinc (Zn) to AZM. In addition, we identified 5 clinical trials currently recruiting individuals for early outpatient treatment with AZM. However, we failed in identifying any study or clinical trial conducted with family practitioners responding to our question.	_
46	Ce044		Maria Chiara Maccarone, Giacomo Magro, Lucrezia Tognolo & Stefano Masiero	Post COVID-19 persistent fatigue: a proposal for rehabilitative interventions in the spa setting	https://doi.org/10.1007/s00484-021-02158-1	Published	04 June 2021	Correspondence	https://link.springer.com/article/10.1007/s00484-021-02158-1	In conclusion, respecting the hygiene and preventive measures, the spa setting could represent the appropriate environment to take care of post-COVID chronic fatigue, offering adequate and multidisciplinary rehabilitation protocols. Further, prospective trials on this topic are needed to fully evaluate the positive impact of a comprehensive rehabilitative treatment in the spa environment for subjects with post-COVID-19 fatigue	_
47	Ce045		Stefan R. Bornstein, Karin Voit-Bak, Timo Donate, Roman N. Rodionov, Raul R. Gainetdinov, Sergey Tselmin, Waldemar Kanczkowski, Gregor M. Müller, Martin Achleitner, Jun Wang, Julio Licinio, Michael Bauer, Allan H. Young, Sandrine Thuret, Nicole Bechmann & Richard Straube	Chronic post-COVID-19 syndrome and chronic fatigue syndrome: Is there a role for extracorporeal apheresis?	https://doi.org/10.1038/s41380-021-01148-4	Published	17 June 2021	Article	https://www.nature.com/articles/s41380-021-01148-4	This overwhelming phenomenon has not been well defined and has been called “post-COVID syndrome” or “long-COVID” [1]. There are striking similarities to myalgic encephalomyelitis also called chronic fatigue syndrome linked to a viral and autoimmune pathogenesis. In both disorders neurotransmitter receptor antibodies against ß-adrenergic and muscarinic receptors may play a key role. We found similar elevation of these autoantibodies in both patient groups. Extracorporeal apheresis using a special filter seems to be effective in reducing these antibodies in a significant way clearly improving the debilitating symptoms of patients with chronic fatigue syndrome. Therefore, such a form of neuropheresis may provide a promising therapeutic option for patients with post-COVID-19 syndrome. This method will also be effective when other hitherto unknown antibodies and inflammatory mediators are involved.	En faisant le lien avec les thérapies testées pour l'encéphalomyélite myalgique, un article évoque dans Nature la possibilité d'expérimenter l'aphérèse extracorporelle pour les malades du covid long, en visant une diminution des taux d'auto-anticorps.	N011
48	Ce046		Matthew T. Roe, Bray Patrick-Lake & Andrew C. von Eschenbach	Post-COVID-19 Syndrome: Leveraging the Patient Perspective and Technological Innovations to Enable the Delineation of Effective Treatments	https://doi.org/10.1007/s40265-021-01548-4	Published	16 June 2021	Letter to the Editor	https://link.springer.com/article/10.1007/s40265-021-01548-4	A prospective registry that assimilates, aggregates, and curates data collected from both clinician-generated and person-generated sources can fully describe the patient journey for post-COVID survivors, delineate the long-term public health and financial impact of the COVID-19 pandemic after recovery from the acute infection, and serve as a discovery platform for identifying the most promising new and repurposed drugs to treat the long-term consequences of surviving an acute COVID infection	_
49	Ce047		Irfan Ahmed, Aessa Tumi	When is it safe to return to exercise post COVID?		Published	2 November 2020	Article	https://bjgp.org/content/when-it-safe-return-exercise-post-covid	We propose that patients and clinicians alike would benefit from primary care focused “graduated return to exercise” guidelines for the post-acute period of COVID-19.3. These guidelines could help patients to navigate milestones in their recovery, while outlining clear symptom-based criteria for stopping exercise, or when GP’s should refer patients on for further investigation due to a failure to progress during rehabilitation.	_
50	Ce048		CDC	Evaluating and Caring for Patients with Post-COVID Conditions: Interim Guidance		Published	June 14, 2021	Article	https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-index.html	Key Points The term “Post-COVID Conditions” is an umbrella term for the wide range of physical and mental health consequences experienced by some patients that are present four or more weeks after SARS-CoV-2 infection, including by patients who had initial mild or asymptomatic acute infection. Based on current information, many post-COVID conditions can be managed by primary care providers, with the incorporation of patient-centered approaches to optimize the quality of life and function in affected patients. Objective laboratory or imaging findings should not be used as the only measure or assessment of a patient’s well-being; lack of laboratory or imaging abnormalities does not invalidate the existence, severity, or importance of a patient’s symptoms or conditions. Healthcare professionals and patients are encouraged to set achievable goals through shared decision-making and to approach treatment by focusing on specific symptoms (e.g., headache) or conditions (e.g., dysautonomia); a comprehensive management plan focusing on improving physical, mental, and social wellbeing may be helpful for some patients. Understanding of post-COVID conditions remains incomplete and guidance for healthcare professionals will likely change over time as the evidence evolves.
51	Ce049		SCOTT CHEATHAM	WORKING OUT AFTER COVID: RECOMMENDATIONS FOR POST-CORONAVIRUS EXERCISE		Published	July 2021	Article	https://blog.nasm.org/working-out-after-covid	The fitness professional may play a vital role in helping post-COVID-19 clients return to physical activity. COVID-19 can have a significant impact on an individual’s health resulting in possible long-term complications.	_
52	Ce050		G E Ivanova 1 2, A N Bogolepova 1 2, O S Levin 3, N A Shamalov 1 2, D R Khasanova 4, S N Yanishevsky 5, V V Zakharov 6, S E Khatkova 7, L V Stakhovskya 1	[Current issues of treatment and rehabilitation of patients with neurological disorders and the consequences of COVID-19. Resolution of Advisory Board] - Основные направления лечения и реабилитации неврологических проявлений COVID-19. Резолюция совета экспертов	https://doi.org/10.17116/jnevro2021121061145	Published	01/06/2021	Article	https://pubmed.ncbi.nlm.nih.gov/34283545/	To designate such protracted clinical conditions, a new definition was introduced: «Post-COVID-19 Condition». Advisory Board of Neurologists and Rehabilitation Therapists met to, discuss of practical experience and taking into account scientific information about COVID-19, which was available at the time of the meeting, to develop unified approaches for the management of patients with neurological complications and the consequences of a new coronavirus infection. The Advisory Board worked out a resolution in which formulated the tactics of managing patients with neurological manifestations of COVID-19. The substantiation of the importance and expediency of the development and implementation of a special program of clinical examination of patients who have undergone COVID-19, which would include a clinical examination with a detailed assessment of cognitive functions to early identification and diagnosis of neurodegeneration and subsequent therapy, is given.	_
53	Ce051		PieroClavarioa1VincenzoDe Marzobc1RobertaLottibcCristinaBarbaraaAnnalisaPorcileaCarmeloRussoaFedericaBeccariaaMarcoBonaviaaLuigi CarloBottaroaMartaCaltabellottaaFlaviaChioniaMonicaSantangeloaArto J.HautaladRaffaeleGriffoaGianfrancoParatifUgoCorràe2ItaloPorto	Cardiopulmonary exercise testing in COVID-19 patients at 3 months follow-up	https://doi.org/10.1016/j.ijcard.2021.07.033	Published	24 July 2021	Study	https://www.sciencedirect.com/science/article/pii/S0167527321011785	Highlights •Long-term effects of COVID-19 and their sustainability are of the utmost relevance. •At 3-month, 50% of COVID-19 have significant reduction in peak oxygen consumption at CPET. •1/3rd of them has no cardio-pulmonary cause as principal mechanism of CPET impairment. •80% of COVID-19 experienced at least one disabling symptom at 3-month evaluation. •Symptoms are not related with abnormal peak oxygen consumption or functional capacity. Results From 225 patients discharged from March to November 2020, we excluded 12 incomplete/missing cases, 13 unable to perform CPET leading to a final population of 200. Median percent-predicted peak oxygen uptake (%pVO2) was 88% (78.3–103.1). Ninety-nine(49.5%) patients had %pVO2 below, whereas 101(50.5%) above the 85% predicted value (indicating normality). Of 61/99 patients with reduced %pVO2 but normal anaerobic threshold, 9(14.8%) had respiratory, 21(34.4%) cardiac, and 31(50.8%) non-cardiopulmonary limitation of exercise. One-hundred sixty(80.0%) patients complain at least one symptom, without relationship with pVO2. Multivariate linear regression analysis showed percent-predicted forced expiratory volume in one-second(β = 5.29,p = 0.023), percent-predicted diffusing capacity of lungs for carbon monoxide(β = 6.31,p = 0.001), and DLE maximal strength(β = 14.09,p = 0.008) independently associated with pVO2. None adverse event was reported during/after CPET neither the involved health professionals developed COVID-19. Conclusions CPET after COVID-19 is safe and about 1/3rd of COVID-19 survivors show functional capacity limitation mainly explained by muscular impairment, calling for future research to identify patients at higher risk of long-term effects that may benefit from careful surveillance and targeted rehabilitation.	_
54	Ce052		Shelley Lees1, Salla Sariola2, Megan Schmidt-Sane3, Luisa Enria1, Kit-Aun Tan4, Angel Aedo5, Koen Peeters Grietens6,7, David Kaawa-Mafigiri8	Key social science priorities for long-term COVID-19 response	http://dx.doi.org/10.1136/bmjgh-2021-006741	Published	26 Jul 2021	Commentary	https://gh.bmj.com/content/6/7/e006741	The COVID-19 response continues to be driven by epidemiological priorities, and yet, the epidemic and responses are situated within specific political and health system contexts. Social science brings an understanding of context and draws attention to politics, power and social difference. There are four critical social science priorities for COVID-19 research and policy in the long term. First, political-economic insights can support the design of public health measures and elucidate how public health responses are produced by political systems. Second, a better understanding of the political and social structures that relate to vaccine confidence will improve public trust, acceptability, effectiveness and uptake of COVID-19 vaccines and therapeutics. Third, development of social science perspectives on health and governance is vital to inform and untangle the complicated ways in which nationalism interacts with public health measures. Finally, social science inquiry can reveal how individuals and communities perceive, understand and construct COVID-19 risk and severity and seek help. These insights support building trust and good relations between local and international research and programme teams and between communities and researchers that will enhance confidence in the development, research and deployment of vaccines and other COVID-19 control measures.	_
55	Ce053	Ce30	Nurek, Martine; Rayner, Clare; Freyer, Anette; Taylor, Sharon; Järte, Linn; MacDermott, Nathalie; Delaney, Brendan	Recommendations for the recognition, diagnosis, and management of long covid: A Delphi study	https://doi.org/10.3399/BJGP.2021.0265	Published	07 June 2021	Study	https://bjgp.org/content/bjgp/early/2021/07/27/BJGP.2021.0265.full.pdf	Publication of Ce30a
56	Ce054		Zhipeng Yan 1,,† ,Ming Yang 2,† andChing-Lung Lai 1,	Long COVID-19 Syndrome: A Comprehensive Review of Its Effect on Various Organ Systems and Recommendation on Rehabilitation Plans	https://doi.org/10.3390/biomedicines9080966	Published	5 August 2021	Review	https://www.mdpi.com/2227-9059/9/8/966/htm	The majority of people infected with SARS-CoV-2 fully recovered within a few weeks. However, a considerable number of patients of different ages still suffer from long-lasting problems similar to the multi-organ damage in its acute phase of infection, or experience symptoms continuously for a longer term after the recovery. The severity of the primary infection seems not to be associated with the possibility and severity of long-term symptoms. Various unresolved symptoms have been reported in COVID-19 survivors months after hospital discharge. Long COVID-19 Syndrome refers to survivors 4 months after initial symptoms onset. It is important to understand the systemic effects of Long COVID-19 Syndrome, its presentations, and the need for rehabilitations to restore functional recovery in survivors. Government, healthcare workers, and survivor groups should collaborate to establish a self-sustaining system to facilitate follow-up and rehabilitations, with prioritization of resources to more severely Long COVID-19 Syndrome survivors. This review looks into the systemic effects of Long COVID-19 Syndrome in various aspects: respiratory, cardiovascular, hematological, renal, gastrointestinal, neurological, and metabolic effects of Long COVID-19 Syndromes. Recommendations for follow-up and rehabilitations details have been explored to cope with the tremendous Long COVID-19 Syndrome patients.
57	Ce055					From this point on, the survey of studies is no longer as exhaustive as possible. Only those studies which seem to us to bring significant new elements will be listed.
58	Ce056		Gerard Pereira1*, Hunter Gillies1, Sanjay Chanda1, Michael Corbett1, Suzanne D. Vernon2, Tina Milani2 and Lucinda Bateman	Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome	https://doi.org/10.3389/fnsys.2021.698240	Published	01 September 2021	Study	https://www.frontiersin.org/articles/10.3389/fnsys.2021.698240/full	Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multi-symptom disease with widespread evidence of disrupted systems. The authors hypothesize that it is caused by the upregulation of the corticotropin-releasing factor receptor type 2 (CRFR2) in the raphé nuclei and limbic system, which impairs the ability to maintain homeostasis. The authors propose utilizing agonist-mediated receptor endocytosis to downregulate CRFR2. Materials and Methods: This open-label trial tested the safety, tolerability and efficacy of an acute dose of CT38s (a short-lived, CRFR2-selective agonist, with no known off-target activity) in 14 ME/CFS patients. CT38s was subcutaneously-infused at one of four dose-levels (i.e., infusion rates of 0.01, 0.03, 0.06, and 0.20 μg/kg/h), for a maximum of 10.5 h. Effect was measured as the pre-/post-treatment change in the mean 28-day total daily symptom score (TDSS), which aggregated 13 individual patient-reported symptoms. Results: ME/CFS patients were significantly more sensitive to the transient hemodynamic effects of CRFR2 stimulation than healthy subjects in a prior trial, supporting the hypothesized CRFR2 upregulation. Adverse events were generally mild, resolved without intervention, and difficult to distinguish from ME/CFS symptoms, supporting a CRFR2 role in the disease. The acute dose of CT38s was associated with an improvement in mean TDSS that was sustained (over at least 28 days post-treatment) and correlated with both total exposure and pre-treatment symptom severity. At an infusion rate of 0.03 μg/kg/h, mean TDSS improved by −7.5 ± 1.9 (or −25.7%, p = 0.009), with all monitored symptoms improving. Conclusion: The trial supports the hypothesis that CRFR2 is upregulated in ME/CFS, and that acute CRFR2 agonism
59	Ce057		Maria InesMitraniaMichael A.BellioaAllenMeglinbAishaKhancXiuminXucGwendolynHaskellaAlissaArangoaGeorge C.Shapiroa	Treatment of a COVID-19 long hauler with an amniotic fluid-derived extracellular vesicle biologic	https://doi.org/10.1016/j.rmcr.2021.101502	Published	30 August 2021	Study	https://www.sciencedirect.com/science/article/pii/S2213007121001647	Zofin is an acellular biologic that contains the extracellular vesicle (EV) fraction of human amniotic fluid and is under investigation for use as a COVID-19 therapeutic. We obtained FDA and IRB approval to investigate the therapeutic use of Zofin in a single long hauler patient case experiencing prolonged shortness of breath and respiratory impairment. Administration of the EV product was shown to be safe. Furthermore, demonstrated respiratory improvements through chest X ray images and oxygen saturation measurement. The single patient IND studies were completed without any reported adverse events or safety concerns. Further-more, these completed studies demonstrate the feasibility and a therapeutic potential of amniotic fluid-derived EVs for COVID-19 long hauler intervention.
60	Ce058		A. N. Bogolepova, N. A. Osinovskaya, E. A. Kovalenko, E. V. Makhnovich	Fatigue and cognitive impairment in post-COVID syndrome: possible treatment approaches	https://doi.org/10.14412/2074-2711-2021-4-88-93	Published	24.07.2021	Study	https://nnp.ima-press.net/nnp/article/view/1635	Objective: to evaluate the efficacy and safety of Cholytilin (choline alfoscerate) and the combined drug MexiB 6 in patients with post-COVID syndrome and fatigue, ADDs, and CI. Patients and methods. The study included 100 patients aged 22 to 71 years who have had COVID-19 5.4 months ago. Inclusion criterion: cognitive complaints, fatigue, and emotional disturbances. The evaluation included neurological exam, Montreal Cognitive Assessment Scale (MoCA), Frontal Assessment Battery (FAB), 10-words list task, Multidimensional Fatigue Inventory (MFI-20), Hospital Anxiety and Depression Scale (HADS). Study participants were divided into two groups. Patients who had ADDs (anxiety/depression level according to HADS ≥8 points; n=50) were prescribed with MexiB 6 (1 tablet three times per day). Patients with CI (mean MoCA score ≤25 points; n=50) were prescribed with Cholytilin (2 capsules (800 mg) in the morning and 1 capsule (400 mg) at lunchtime). The follow-up period was 60 days. Results and discussion. According to MoCA scores, a decrease in cognition was observed in 58% of participants, while 28% did not notice CI earlier. ADD fere present in 51%, and fatigue — in 100% of patients. We observed a significant reduction in fatigue severity (from 62.42±7.18 to 52.32±16.36 points; p<0.05) in patients prescribed with MexiB 6. The majority of patients noted a significant increase in physical activity, decreased fatigue, improvement of attention and physical well-being, and increased workplace efficiency. We also found a significant decrease in ADDs severity: ADDs either regressed completely (in 42% of participants) or became subclinical (in 48%; р<0.001). CI severity also reduced according to mean МоСА (from 26.60±1.31 to 27.28±1.39 points; p<0.05) and FAB (from 16.98±1.06 to 17.20±0.90 points; p<0.05) scores. In a subgroup of patients with mild CI treated with Cholytilin mean МоСА (from 23.50±0.99 to 26.36±1.34; р<0.001) and FAB (from 16.02±0.91 to 16.96±0.99; р<0.001) scores significantly increased. Complete regression of CI was observed in 74% of participants (р<0.001). We also found a decrease in ADDs (р<0.001) and fatigue (mean MFI-20 scores decreased from 42.28±10.73 to 35.60±8.10; р<0.001) severity in all study participants. Conclusion. Patients who have had COVID-19, regardless of the disease severity, have a high prevalence of fatigue, ADDs and CI, and MexiB 6 and Cholytilin have a potential in their treatment.
61	Ce059	PESE	Maria G. Tanzi, PharmD	CDC releases guidance on caring for ‘COVID long-haulers’	https://doi.org/10.1016/j.ptdy.2021.08.009	Published	September 01, 2021	Article	https://www.pharmacytoday.org/article/S1042-0991(21)00636-8/fulltext	Health care providers can also consider already established symptom management approaches for patients experiencing post-COVID-19 conditions. For example, breathing exercises for dyspnea, OTC or prescription pain relievers for headaches, and activity management (pacing) for post-exertional malaise. CDC reminds clinicians that there is no one-size-fits-all approach, and a treatment plan should always be customized to the patient’s conditions and treatment goals.	_
62	Ce060		Maximilian Andreas Storz	Lifestyle Adjustments in Long-COVID Management: Potential Benefits of Plant-Based Diets	https://doi.org/10.1007/s13668-021-00369-x	Published	10 September 2021	Review	https://link.springer.com/article/10.1007/s13668-021-00369-x	Thus, this review sought to investigate whether a plant-based diet could reduce the burden of long-COVID. Recent Findings The number of clinical trials investigating the role of plant-based nutrition in COVID-19 prevention and management is currently limited. Yet, there is evidence from pre-pandemic observational and clinical studies that a plant-based diet may be of general benefit with regard to several clinical conditions that can also be found in individuals with COVID-19. These include anxiety, depression, sleep disorders, and musculoskeletal pain. Adoption of a plant-based diet leads to a reduced intake in pro-inflammatory mediators and could be one accessible strategy to tackle long-COVID associated prolonged systemic inflammation.	_
63	Ce061		Luke D Liu MD, Deborah L Duricka PhD	Stellate Ganglion Block Successfully Treats Long COVID/PASC: A Case Series	https://doi.org/10.21203/rs.3.rs-873830/v1	pre-print	10 Sep, 2021	Study	https://www.researchsquare.com/article/rs-873830/v1	Most of these symptoms are included in the “sickness behavior response” initiated from the brainstem when levels of circulating pro-inflammatory cytokines are high. Ordinarily a feedback loop prevents excessive production of these cytokines, however the SARS-CoV-2 virus has demonstrated the ability to induce the sympathetic nervous system (SNS), likely due to imbalance between ACE1 and ACE2 activity. Persistent sympathetic drive causes increased cytokine release, which interferes with the feedback loop that ends “sickness behaviors.” The stellate ganglion is a paravertebral collection of sympathetic nerves located in the cervical region that provides a convenient entry point to reduce activity of the SNS using local anesthetic blockade. The stellate ganglion block (SGB) has a well-established safety and efficacy profile for a variety of conditions involving the SNS. In this case report series, we treated three consecutive “Long COVID” patients with SGB. All three patients reported significant and durable improvement in symptoms including fatigue, “brain fog,” and smell and taste derangements. Our findings provide evidence implicating dysautonomia as the main etiology of Long COVID/PASC symptoms and suggest that SGB is an effective intervention for this condition with the potential to change the course of the second COVID pandemic, “Long COVID”/PASC.	_
64	Ce062		Simon Décary, PT, PhD Michèle Dugas, MSc Théo Stefan, MSc Léa Langlois, MSc Becky Skidmore, PhD Anne Bhéreur, MD Annie LeBlanc, PhD	Care Models for Long COVID A Rapid Systematic Review				Review	https://sporevidencealliance.ca/wp-content/uploads/2021/06/Care-Models-for-Long-COVID_Full-Report_2021.06.18.pdf
65	Ce063		Sergey N Gusev1*, Velichko LN2, Bogdanova AV2, Khramenko NI2, Konovalova NV2, Kovtun AV3	Clinical Examples of the Use of Mercureid Drug in Patients with Ischemic Neuropathy of the Optic Nerve That Appeared After Long COVID-19		Published	09-10-2021	Study	https://athenaeumpub.com/clinical-examples-of-the-use-of-mercureid-drug-in-patients-with-ischemic-neuropathy-of-the-optic-nerve-that-appeared-after-long-covid-19/	For these purposes, an innovative multi-target immunotherapy drug, namely, Mercureid, has proven its advantages. Its intake during the period of hospitalization, in combination with vascular drugs, made it possible to achieve remission faster, stabilize the patients’ state, and achieve higher visual functions (synergism of action). As a result, lower dosages of drugs used in combination therapy were required (there was less risk of side effects from their use). After hospital discharge, Mercureid intake as a 3-month monotherapy brought to a complete restoration of vision (it needs reminding that upon inpatient hospital discharge, Right eye 0.01 does not have corrected visual acuity. 3 months later visual acuity became 1.0. Ischemic edema completely resolved. The foci of secondary degeneration were resorbed).	_
66	Ce064		Gilmar Reis, PhD Eduardo Augusto dos Santos Moreira-Silva, PhD Daniela Carla Medeiros Silva, PhD Prof Lehana Thabane, PhD Aline Cruz Milagres, RN Thiago Santiago Ferreira, MD Castilho Vitor Quirino dos Santos Vitoria Helena de Souza Campos Ana Maria Ribeiro Nogueira, MD Alla V Glushchenko, MD Craig R Rayner, FRCPE Prof Eric J Lenze, MD Angela M Reiersen, MD Prof Gordon H Guyatt, MD Prof Edward J Mills	Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial	https://doi.org/10.1016/S2214-109X(21)00448-4	Published	October 27, 2021	Study	https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(21)00448-4/fulltext	Recent evidence indicates a potential therapeutic role of fluvoxamine for COVID-19. In the TOGETHER trial for acutely symptomatic patients with COVID-19, we aimed to assess the efficacy of fluvoxamine versus placebo in preventing hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to a tertiary hospital due to COVID-19. Methods This placebo-controlled, randomised, adaptive platform trial done among high-risk symptomatic Brazilian adults confirmed positive for SARS-CoV-2 included eligible patients from 11 clinical sites in Brazil with a known risk factor for progression to severe disease. Patients were randomly assigned (1:1) to either fluvoxamine (100 mg twice daily for 10 days) or placebo (or other treatment groups not reported here). The trial team, site staff, and patients were masked to treatment allocation. Our primary outcome was a composite endpoint of hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to tertiary hospital due to COVID-19 up to 28 days post-random assignment on the basis of intention to treat. Modified intention to treat explored patients receiving at least 24 h of treatment before a primary outcome event and per-protocol analysis explored patients with a high level adherence (>80%). We used a Bayesian analytic framework to establish the effects along with probability of success of intervention compared with placebo. The trial is registered at ClinicalTrials.gov (NCT04727424) and is ongoing. Findings The study team screened 9803 potential participants for this trial. The trial was initiated on June 2, 2020, with the current protocol reporting randomisation to fluvoxamine from Jan 20 to Aug 5, 2021, when the trial arms were stopped for superiority. 741 patients were allocated to fluvoxamine and 756 to placebo. The average age of participants was 50 years (range 18–102 years); 58% were female. The proportion of patients observed in a COVID-19 emergency setting for more than 6 h or transferred to a teritary hospital due to COVID-19 was lower for the fluvoxamine group compared with placebo (79 [11%] of 741 vs 119 [16%] of 756); relative risk [RR] 0·68; 95% Bayesian credible interval [95% BCI]: 0·52–0·88), with a probability of superiority of 99·8% surpassing the prespecified superiority threshold of 97·6% (risk difference 5·0%). Of the composite primary outcome events, 87% were hospitalisations. Findings for the primary outcome were similar for the modified intention-to-treat analysis (RR 0·69, 95% BCI 0·53–0·90) and larger in the per-protocol analysis (RR 0·34, 95% BCI, 0·21–0·54). There were 17 deaths in the fluvoxamine group and 25 deaths in the placebo group in the primary intention-to-treat analysis (odds ratio [OR] 0·68, 95% CI: 0·36–1·27). There was one death in the fluvoxamine group and 12 in the placebo group for the per-protocol population (OR 0·09; 95% CI 0·01–0·47). We found no significant differences in number of treatment emergent adverse events among patients in the fluvoxamine and placebo groups. Interpretation Treatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19 reduced the need for hospitalisation defined as retention in a COVID-19 emergency setting or transfer to a tertiary hospital.	_
67	Ce065		Betka Sophie, Kannape Oliver Alan, Fasola Jemina, Lance Florian, Cardin Sylvain, Schmid Aline, Similowski Thomas, Soccal Paola Marina, Herbelin Bruno, Adler Dan, Blanke Olaf	Virtual reality exercise to help COVID patients with refractory breathlessness	https://doi.org/10.1101/2021.10.26.21265510	pre-print	October 26, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.10.26.21265510v1	Methods We performed a controlled, randomized, single-blind, cross-over clinical study to evaluate an iVR-based intervention to alleviate refractory breathlessness in patients recovering from COVID-19 pneumonia. The single-site study was conducted at the university hospital of Geneva, Switzerland. Patients reported refractory breathlessness (≥5 on a 10-point dyspnea scale) and had a MoCA score of ≥24. Cross-over groups were randomly assigned, concealed from the referring clinician. Participants received synchronous (intervention) or asynchronous (control) feedback of their breathing, embodied via a gender-matched avatar in iVR. Prior to the first exposure and following both experimental conditions, patients completed questionnaires. Breathing patterns were captured continuously. The COVVR clinical study is registered with ClinicalTrials.gov (NCT04844567) and is now closed. Findings Study enrollment was open between November 2020 and April 2021. A total of 26 patients (27% women; age: mean=57, SD±12) were enrolled; 14 patients were randomly assigned to the “synchronous/asynchronous” sequence, 12 to the “asynchronous/synchronous” sequence. Data was available for all except two (7.7%) of 26 patients. The mean rating of breathing comfort was 0.1 at baseline, 0.8±1.8 for asynchronous, and 1.3±1.4 synchronous feedback (estimated difference of 0.5 (95%CI 0.05 to 1.04; p<0.05) between iVR conditions). Of all patients, 91.2% were satisfied with the intervention (1.8±1.6, t=5.201, p<0.0001, 95%CI 1.173 to inf) and 66.7% perceived it as beneficial for their breathing (0.7±1.9, t=1.806, p<0.05, 95%CI 0.036 to inf). No adverse events were reported. Interpretation Based on these findings, we propose that our iVR-based DTx is a feasible and safe neuro-rehabilitation tool that improves breathing comfort in patients recovering from severe COVID-19 infection.	_
68	Ce066		Stephen A Harrison 1, Seth J Baum 2, Nadege T Gunn 3, Ziad H Younes 4, Anita Kohli 5, Rashmee Patil 6, Margaret J Koziel 7, Harinder Chera 7, Jeff Zhao 7, Manu V Chakravarthy 7	Safety, Tolerability, and Biologic Activity of AXA1125 and AXA1957 in Subjects With Nonalcoholic Fatty Liver Disease	https://doi.org/10.14309/ajg.0000000000001375	Published	2021 Aug 12	Study	https://pubmed.ncbi.nlm.nih.gov/34382947/	Axcella Therapeutics Launches Clinical Program to Develop Treatment for Patients with Long COVID https://www.businesswire.com/news/home/20211026005063/en/	La start-up Axcella Therapeutics va lancer un essai clinique sur son composé, AXA1125, qui vise les modulateurs endogènes du metabolisme et les mitochondries, comme potentiel traitement pour les malades du covid long. Le composé est un mélange d'acides aminés (Leucine 1g - Isoleucine 0,5g - Valine 0,5g - Arginine 1,81g - Glutamine 2g - n-acétyl-cystéine 0,15g). Les résultats sont attendus pour la mi-2022.	N015
69	Ce067		Francisco Mera-Cordero, Sara Bonet Monne, Jesús Almeda Ortega, Ana García-Sangenís, Oriol Cunillera Puèrtolas, Sara Contreras-Martos, Gemma Alvarez Muñoz, Ramon Monfà Escolà, Marina Balanzó Joué, Rosa Morros Pedrós, Betlem Salvador-Gonzalez	Double-blind Placebo-controlled Randomized Clinical Trial to Assess the Efficacy of Montelukast in Mild to Moderate Respiratory Symptoms of Patients With Long COVID E-SPERANZA COVID PROJECT Study Protocol	https://doi.org/10.21203/rs.3.rs-845711/v1	pre-print	29 Oct, 2021	Study	https://www.researchsquare.com/article/rs-845711/v1	Phase III, randomized, double-blind clinical trial. We will include 18 to 80 year-old patients with SARS-CoV-2 infection and mild to moderate respiratory symptoms lasting more than 4 weeks. Participants will be randomly allocated in a 1:1 ratio to the intervention (experimental treatment with 10 mg/day montelukast) or the control group (placebo group), during a 28-day treatment. Follow up will finish 56 days after start of treatment. The primary outcome will be health-related quality of life associated with respiratory symptoms according to the COPD Assessment Test 4 weeks after starting treatment. Secondary outcomes a) Exercise capacity and oxygen saturation (1Min Sit-to-Stand test); b) Post-COVID-19 Functional Status scale; c) Other symptoms: asthenia, headache, mental confusion (brain fog), ageusia and anosmia (Likert scale); d) Use of healthcare resources; e) Mortality; f) Sick leave duration in days g) Side effects of montelukast.	Un médicament utilisé pour l'asthme, le montélukast, pressenti pour de possibles effets antiviraux et anti-inflammatoires, est en essai clinique de phase 3 sur des malades du covid long en Espagne. Le rationnel pour l'utilisation du montélukast pour le covid long se base sur plusieurs études : ▶️https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321662/ ▶️https://www.frontiersin.org/articles/10.3389/fphar.2020.01344/full ▶️https://pubmed.ncbi.nlm.nih.gov/32416408/	N014
70	Ce068		Hazar Abusalamah 1, Jessica M Reel 1, Christopher R Lupfer 2	Pyruvate affects inflammatory responses of macrophages during influenza A virus infection	https://doi.org/10.1016/j.virusres.2020.198088		2020 Sep	Study	https://pubmed.ncbi.nlm.nih.gov/32634445/	We discovered that inclusion of sodium pyruvate in culture media during infection of mouse bone marrow derived macrophages with influenza A virus impaired cytokine production (IL-6, IL-1β, and TNF-α). Sodium pyruvate did not inhibit viral RNA replication. Instead, the addition of sodium pyruvate alters cellular metabolism and diminished mitochondrial reactive oxygen species (ROS) production and lowered immune signaling. Overall, sodium pyruvate affects the immune response produced by macrophages but does not inhibit virus replication.	Le pyruvate de sodium, un médicament qui modifie les réponses inflamamtoires et qui fut testée sur la grippe (https://pubmed.ncbi.nlm.nih.gov/32634445/), est à l'essai sur des malades du covid long dans cet essai clinique (https://clinicaltrials.gov/ct2/show/NCT04871815).	N014E
71	Ce069		Anil Verma Chase E. Hawes Yashavanth Shaan Lakshmanappa Jamin W. Roh Brian A. Schmidt Joseph Dutra William Louie Hongwei Liu Zhong-Min Ma Jennifer K. Watanabe Jodie L. Usachenko Ramya Immareddy Rebecca L. Sammak Rachel Pollard J. Rachel Reader Katherine J. Olstad Lark L. Coffey Pamela A. Kozlowski Dennis J. Hartigan-O’Connor Michel Nussenzweig Koen K.A. Van Rompa John H. Morrison 9 Smita S. Iyer	Monoclonal antibodies protect aged rhesus macaques from SARS-CoV-2-induced immune activation and neuroinflammation	https://doi.org/10.1016/j.celrep.2021.109942	Published	October 18, 2021	Study	https://www.cell.com/cell-reports/fulltext/S2211-1247(21)01415-7	Highlights •Neutralizing monoclonal antibodies (mAbs) block SARS-CoV-2 replication •Neutralizing mAbs prevent SARS-CoV-2-induced interferon-induced chemokines •Neutralizing mAbs limit effector CD4 T cell influx into cerebrospinal fluid nti-viral monoclonal antibody (mAb) treatments may provide immediate but short-term immunity from coronavirus disease 2019 (COVID-19) in high-risk populations, such as people with diabetes and the elderly; however, data on their efficacy in these populations are limited. We demonstrate that prophylactic mAb treatment blocks viral replication in both the upper and lower respiratory tracts in aged, type 2 diabetic rhesus macaques. mAb infusion dramatically curtails severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-mediated stimulation of interferon-induced chemokines and T cell activation, significantly reducing development of interstitial pneumonia. Furthermore, mAb infusion significantly dampens the greater than 3-fold increase in SARS-CoV-2-induced effector CD4 T cell influx into the cerebrospinal fluid. Our data show that neutralizing mAbs administered preventatively to high-risk populations may mitigate the adverse inflammatory consequences of SARS-CoV-2 exposure.
72	Ce070		Heather Vance, Amelita Maslach, Emily Stoneman, Kathryn Harmes, Andrea Ransom, Katharine Seagly and Wendy Furst	Addressing Post-COVID Symptoms: A Guide for Primary Care Physicians	https://doi.org/10.3122/jabfm.2021.06.210254	Published	November 12, 2021	Review	https://www.jabfm.org/content/34/6/1229	Results: A quick-reference guide for management of post-COVID symptoms was created for PCPs. Educational materials were created for clinicians to share with patients. Our article reviews several common complaints including respiratory, cognitive, and neurological symptoms, chronic fatigue, dysautonomia, and anosmia and presents recommendations for management. Conclusions: Data on long-term effects of COVID-19 are still emerging, and rapid dissemination of this data to front-line PCPs is crucial. This table was our effort to make the currently available evidence accessible for our PCPs in a simple, easy-to-use format.	todo
73	Ce071		Vicky van der Togt, Sammie Mcfarland, Marta Esperti, Elizabeth Semper, Sara Citrenbaum & Jeremy S. Rossman	Promotion of non-evidence-based therapeutics within patient-led Long COVID support groups	https://doi.org/10.1038/s41591-021-01589-y	Published	10 December 2021	Correspondence	https://www.nature.com/articles/s41591-021-01589-y	Long COVID support groups began as a patient-led movement, providing safe spaces for patients (including children and their parents and caregivers) to discuss the disease and collectively advocate for awareness, research and support. However, in many groups, individuals and organizations have been promoting experimental treatments, ongoing clinical trials and for-profit treatment plans (examples are included in Table 1). Given the current lack of understanding of the disease etiology of Long COVID and lack of any proven treatment options, patients are desperate for any offered hope. The net result can be an unethical situation that endangers patient health and wellbeing and decreases the integrity and effectiveness of the patient-led movement.	_
74	Ce072		Tim Robbins, Michael Gonevski, Cain Clark, Sudhanshu Baitule, Kavi Sharma, Angel Magar, Kiran Patel, Sailesh Sankar, Ioannis Kyrou, Asad Ali and Harpal S Randeva	Hyperbaric oxygen therapy for the treatment of long COVID: early evaluation of a highly promising intervention	https://doi.org/10.7861/clinmed.2021-0462	Published	November 2021	Study	https://www.rcpjournals.org/content/clinmedicine/21/6/e629	HBOT yielded a statistically significant improvement in the Chalder fatigue scale (p=0.0059; d=1.75 (very large)), global cognition (p=0.0137; d=–1.07 (large)), executive function (p=0.0039; d=–1.06 (large)), attention (p=0.0020; d=–1.2 (very large)), information processing (p=0.0059; d=–1.25 (very large)) and verbal function (p=0.0098; d=–0.92 (large)). Conclusion Long COVID-related fatigue can be debilitating, and may affect young people who were previously in economic employment. The results presented here suggest potential benefits of HBOT, with statistically significant results following 10 sessions.	_
75	Ce073		Jake J.LeeaAndrew M.PetersonabDorinaKallogjeriaPawinaJiramongkolchaiaSaraKukuljanaJohn S.SchneideraCristine N.Klatt-CromwellaAndrew J.DrescheraJoseph D.BrunworthcJay F.Piccirilloa	Smell Changes and Efficacy of Nasal Theophylline (SCENT) irrigation: A randomized controlled trial for treatment of post-viral olfactory dysfunction	https://doi.org/10.1016/j.amjoto.2021.103299	Published	3 December 2021	Study	https://www.sciencedirect.com/science/article/abs/pii/S0196070921004002	Twenty-two patients (n = 12, theophylline; n = 10, placebo) completed the study. Slightly more patients in the theophylline group (33%) reported improved smell compared to the placebo group (30%, difference 3.3%, 95% CI -35.6% to 42.3%). The median differences in pre- and post-treatment UPSIT and QOD-NS change between the two groups were 1 (95% CI -3 to 5) and -10 (95% CI -15 to -4), respectively in favor of theophylline. Three patients receiving theophylline and 2 receiving placebo had clinically meaningful improvements on the UPSIT (difference 5%, 95% CI -30% to 40%). There were no adverse events, and serum theophylline levels were undetectable in 10/10 patients. Conclusions While safe, there were no clinically meaningful differences in olfactory change between the two groups except for olfaction-related quality of life, which was better with theophylline. The imprecise estimates suggest future trials will need substantially larger sample sizes or treatment modifications, such as increasing the theophylline dose, to observe larger treatment effects.	_
76	Ce074		T. A. Kuut, F. Müller, A. Aldenkamp, E. Assmann-Schuilwerve, A. Braamse, S. E. Geerlings, K. B. Gibney, R. A. A. Kanaan, P. Nieuwkerk, T. C. Olde Hartman, D. Pauëlsen, M. Prins, K. Slieker, M. Van Vugt, C. P. Bleeker-Rovers, S. P. Keijmel & H. Knoop	A randomised controlled trial testing the efficacy of Fit after COVID, a cognitive behavioural therapy targeting severe post-infectious fatigue following COVID-19 (ReCOVer): study protocol	https://doi.org/10.1186/s13063-021-05569-y	Published	02 December 2021	Study	https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-021-05569-y	Discussion This is the first trial testing a cognitive behavioural intervention targeting severe fatigue after COVID-19. If Fit after COVID is effective in reducing fatigue severity following COVID-19, this intervention could contribute to alleviating the long-term health consequences of COVID-19 by relieving one of its most prevalent and distressing long-term symptoms.	_
77	Ce075		Авторы: Юрко Е.В., Кучерявченко В.В., Соломенник А.О., Лесная А.С.	Methods of Correction of Neurological Disorders in Patients with Coronavirus Disease (COVID-19)		Published	December 2021	Study	https://xavron.com.ua/en/publications/metody-korekcziyi-nevrologichnyh-porushen-u-pacziyentiv-iz-koronavirusnoyu-hvoroboyu-covid-19/	Neurological manifestations are typical of a new coronavirus disease. The incidence of certain neurological symptoms (impaired consciousness, headache, anxiety, worry, depression) depended on the severity of COVID-19 and was more common in patients with severe disease. The use of edaravon (Xavron), a combination of L-arginine and L-carnitine (Tivorel) and hyperosmolar balanced solution (Rheosorbilact) in the complex therapy of patients with COVID-19 promotes regression of clinical manifestations and normalization of laboratory parameters compared to standard pathogenetics.	_
78	Ce076		Dobri D. Kiprov1, Ahvie Herskowitz1, Daehwan Kim https:// .org/0000-0002-7273-99692, Michael Lieb2, Chao Liu https:// .org/0000-0001-8683-34732, Etsuko Watanabe2, Jan C. Hoffman3, Regina Rohe1, Michael J. Conboy2, Irina M. Conboy https:// .org/0000-0002-4276-06442 Author details	Case Report: Therapeutic and immunomodulatory effects of plasmapheresis in long-haul COVID [version 1; peer review: awaiting peer review]	https://doi.org/10.12688/f1000research.74534.1	pre-print	24 Nov 2021	Study	https://f1000research.com/articles/10-1189	Many patients with COVID-19 experience a range of debilitating symptoms months after being infected, a syndrome termed long-haul COVID. A 68-year-old male presented with lung opacity, fatigue, physical and cognitive weaknesses, loss of smell and lymphocytopenia. After rounds of therapeutic plasma exchange (TPE), the patient returned to normal activities and work. Mechanistically in the patient’s peripheral blood mononuclear cells (PBMCs), markers of inflammatory macrophages diminished and markers of lymphocytes, including natural killer (NK) cells and cytotoxic CD8 T-cells, increased. Circulating inflammatory proteins diminished, while positive regulators of tissue repair increased. This case study suggests that TPE has the capacity to treat long-haul COVID.	_
79	Ce077		L Boglione, G Meli, F Poletti, R Rostagno, R Moglia, M Cantone, M Esposito, C Scianguetta, B Domenicale, F Di Pasquale, S Borrè	Risk factors and incidence of long-COVID syndrome in hospitalized patients: does remdesivir have a protective effect?	https://doi.org/10.1093/qjmed/hcab297	Published	26 November 2021	Study	https://academic.oup.com/qjmed/advance-article-abstract/doi/10.1093/qjmed/hcab297/6443168	Treatment with remdesivir leads to a 35.9% reduction in LCS rate in follow-up. Severity of illness, need of ICU admission and length of hospital stay were factor associated with the persistence of PCS at 6 months of follow-up.	_
80	Ce078		Shin Jie Yong,Shiliang Liu	Proposed subtypes of post-COVID-19 syndrome (or long-COVID) and their respective potential therapies	https://doi.org/10.1002/rmv.2315	Published	09 December 2021	Review	https://onlinelibrary.wiley.com/doi/10.1002/rmv.2315	Depending on the study referred, about 10%–30% (or more) of COVID-19 survivors may develop long-COVID or post-COVID-19 syndrome (PCS), characterised by persistent symptoms (most commonly fatigue, dyspnoea, and cognitive impairments) lasting for 3 months or more after acute COVID-19. While the pathophysiological mechanisms of PCS have been extensively described elsewhere, the subtypes of PCS have not. Owing to its highly multifaceted nature, this review proposes and characterises six subtypes of PCS based on the existing literature. The subtypes are non-severe COVID-19 multi-organ sequelae (NSC-MOS), pulmonary fibrosis sequelae (PFS), myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), postural orthostatic tachycardia syndrome (POTS), post-intensive care syndrome (PICS) and medical or clinical sequelae (MCS). Original studies supporting each of these subtypes are documented in this review, as well as their respective symptoms and potential interventions. Ultimately, the subtyping proposed herein aims to provide better clarity on the current understanding of PCS.	Dans une revue très complète de la littérature concernant les thérapies appliquées sur les malades du covid long, le chercheur Shin Jie Yong catégorise les symptômes et les thérapies proposées pour chacun d'entre eux. Il aborde notamment : 1/ les séquelles non sévères multi-organes de la covid (NSC-MOS) : La revue d'études indique que la rééducation peut être recommandée pour le NSC-MOS en raison de son approche holistique, qui n'a pas besoin d'être adaptée à une physiopathologie spécifique. 2/ les séquelles de la fibrose pulmonaire (PFS) : Il est noté que certains médications sont approuvées, notamment les agents antifibrinolytiques comme le nintédanib et la pirfénidone. Sont également employés la réadaptation pulmonaire avec des exercices de respiration et d'aérobie, des techniques de dégagement des voies respiratoires, un soutien en oxygène et un contrôle nutritionnel. 3/ l'encéphalomyélite myalgique (syndrome de fatigue chronique ME/SFC), Les revues systématiques ont identifié 3 traitements pharmaceutiques (vaccin Staphypan Berna, rintatolimod et coenzyme Q10 + NADH), ainsi que 5 non pharmaceutiques (thérapie cognitivo-comportementale TCC, thérapie par exercices gradués GET, rééducation, acupuncture et abdominoplastie). Shin Jie Yong note que, concernant la TCC et la GET, leur efficacité et même leurs dommages potentiels ont été débattus, suite à des essais cliniques révélés comme faussés et par incompatibilité avec la physiopathologie sous-jacente. L'auteur rappelle que récemment, les instances britanniques NICE ont cessé de recommander la GET et la TCC pour le traitement de l'EM/SFC, bien que la TCC puisse toujours être utilisée pour gérer les symptômes psychologiques des patients. Il indique aussi que la pratique clinique a également suggéré d'utiliser d'autres traitements pharmaceutiques pour traiter des symptômes spécifiques de l'EM/SFC, plutôt que le syndrome lui-même, comme les médicaments contre les troubles du sommeil, la douleur et les antidépresseurs. 4/ le syndrome de tachycardie orthostatique posturale (POTS) : L'article rapporte des études à faible niveau de preuve de traitements pharmaceutiques (c'est-à-dire propranolol, midodrine, ivabradine, fludrocortisone et antihistaminiques) ou non pharmaceutiques (c. exercice vertical). Une étude sur une petite cohorte indique que l'ivabradine soulage la fréquence cardiaque de course plus efficacement que le carvédilol chez des survivants du covid avec des palpitations ou une tachycardie. L'auteur renvoie à d'autres options pharmaceutiques pour le POTS comprennent une solution saline intraveineuse, la pyridostigmine, la clonidine, la méthyldopa, le vérapamil et la droxidopa. Il est noté que cependant, la Heart Rhythm Society recommande d'abord des approches non pharmaceutiques pour le POTS, suivies d'options pharmaceutiques si nécessaire ; et que les thérapies doivent également être personnalisées car il n'y a pas d'approches universellement acceptées pour les POTS. 5/ le syndrome post-soins intensifs (PICS) L'article indique qu'avec une présence d'inflammation chronique, une thrombose ou une fibrose chez les malades du covid long, les antagonistes de ces processus pathologiques peuvent aider. Ces antagonistes comprennent les statines, le dabigatran, les inhibiteurs du système rénine-angiotensine-aldostérone, les inhibiteurs du co-transporteur sodium-glucose-2, l'agoniste du récepteur du peptide-1 semblable au glucagon, la metformine et les inhibiteurs des récepteurs bêta-adrénergiques. Cependant, l'auteur noter que ces médicaments n'ont pas été testés dans des essais cliniques impliquant des patients covid long. Plusieurs études ont souligné les besoins de réadaptation chez les personnes touchées par ce syndrome. Cependant, une méta-analyse a rapporté que la réadaptation physique sur ce syndrome n'améliore pas nécessairement la santé et la qualité mentale entre 6 et 12 mois. D'autres thérapies sont en test (stimulation électrique neuromusculaire, réalité virtuelle et programmes de réadaptation). 6/ les séquelles médicales ou cliniques (MCS) Elles incluent une myriade de mécanismes spécifiques à la maladie, que la covid a créé ou aggravé s'ils étaient préexistants. Les auteurs (@Shin63714105 et Dr Shiliang Liu) concluent que le covid long (ou syndrome post-covid) apparaît désormais comme le syndrome post-viral le plus fréquent à l'échelle mondiale.
81	Ce079		Abdul Mannan Baig	Loss of smell in COVID-19: reasons for variable recovery patterns from anosmia	https://doi.org/10.4103/1673-5374.330625	Published	10-Dec-2021	Letter	https://www.nrronline.org/article.asp?issn=1673-5374;year=2022;volume=17;issue=7;spage=1623;epage=1624;aulast=Baig	Here I debate the possible mechanisms underlying the variable recovery from anosmia in COVID-19 and reasons why it continues in some patients with long-COVID?	_
82	Ce080		Luke D.LiuDeborah L.Duricka	Stellate ganglion block reduces symptoms of Long COVID: A case series	https://doi.org/10.1016/j.jneuroim.2021.577784	Published	8 December 2021	Short Communication	https://www.sciencedirect.com/science/article/pii/S0165572821003118	Highlights •Long COVID symptoms include fatigue, brain fog, anosmia, dysgeusia, orthostatic intolerance. •Long COVIDsymptoms overlap with those of chronic fatigue syndrome (ME/CFS) and POTS. •Reduced cerebral blood flow is a feature of dysautonomia in ME/CFS and POTS. •Stellate ganglion block increases cerebral blood flow and alleviates Long COVID symptoms. •The interaction between nervous and immune systems is involved in Long COVID. After recovering from COVID-19, a significant proportion of symptomatic and asymptomatic individuals develop Long COVID. Fatigue, orthostatic intolerance, brain fog, anosmia, and ageusia/dysgeusia in Long COVID resemble “sickness behavior,” the autonomic nervous system response to pro-inflammatory cytokines (Dantzer et al., 2008). Aberrant network adaptation to sympathetic/parasympathetic imbalance is expected to produce long-standing dysautonomia. Cervical sympathetic chain activity can be blocked with local anesthetic, allowing the regional autonomic nervous system to “reboot.” In this case series, we successfully treated two Long COVID patients using stellate ganglion block, implicating dysautonomia in the pathophysiology of Long COVID and suggesting a novel treatment.	Deux chercheurs de la société Neuroversion, à Anchorage en Alaska, rapportent dans une étude avoir traité 2 malades du covid long par bloc stellaire, une technique qui consiste en l'injection d'un anesthésique local sur le pourtour des nerfs du système sympathique (partie antérieure du cou), avec un supposé effet prolongé sur les nerfs. Les chercheurs indiquent avoir obtenu une diminution des symptômes très notable sur les deux patients traités.
83	Ce081		Esen Sefik, Benjamin Israelow, Haris Mirza, Jun Zhao, Rihao Qu, Eleanna Kaffe, Eric Song, Stephanie Halene, Eric Meffre, Yuval Kluger, Michel Nussenzweig, Craig B. Wilen, Akiko Iwasaki & Richard A. Flavell	A humanized mouse model of chronic COVID-19	https://doi.org/10.1038/s41587-021-01155-4	Published	17 December 2021	Article	https://www.nature.com/articles/s41587-021-01155-4	Here we describe a humanized mouse model of COVID-19 that uses adeno-associated virus to deliver human ACE2 to the lungs of humanized MISTRG6 mice. This model recapitulates innate and adaptive human immune responses to severe acute respiratory syndrome coronavirus 2 infection up to 28 days after infection, with key features of chronic COVID-19, including weight loss, persistent viral RNA, lung pathology with fibrosis, a human inflammatory macrophage response, a persistent interferon-stimulated gene signature and T cell lymphopenia. We used this model to study two therapeutics on immunopathology, patient-derived antibodies and steroids and found that the same inflammatory macrophages crucial to containing early infection later drove immunopathology. This model will enable evaluation of COVID-19 disease mechanisms and treatments.	Une étude dans Nature Biotechnology présente un modèle de souris humanisé pour reproduire les symptômes prolongés de la covid chez l'homme (covid chronique ou covid long). Les souris présentent une perte de poids, la persistance d'un ARN viral, une pathologie pulmonaire avec fibrose, une réaction inflammatoire par activation des macrophages, une signature génique persistante stimulée par interféron ainsi qu'une lymphopénie des lymphocytes T. Ce modèle a permis de tester deux thérapies immunologiques, et fait dire aux auteurs que les glucocorticoïdes (ici la dexaméthasone) ne doivent être envisagés que lorsque les titres viraux sont indétectables, et permettent de réduire la morbidité sur la phase chronique.
84	Ce082		Vicky van der Togt, Sammie Mcfarland, Marta Esperti, Elizabeth Semper, Sara Citrenbaum & Jeremy S. Rossman	Promotion of non-evidence-based therapeutics within patient-led Long COVID support groups	https://doi.org/10.1038/s41591-021-01589-y	Published	17 December 2021	Correspondence	https://www.nature.com/articles/s41591-021-01589-y	Long COVID support groups began as a patient-led movement, providing safe spaces for patients (including children and their parents and caregivers) to discuss the disease and collectively advocate for awareness, research and support. However, in many groups, individuals and organizations have been promoting experimental treatments, ongoing clinical trials and for-profit treatment plans (examples are included in Table 1). Given the current lack of understanding of the disease etiology of Long COVID and lack of any proven treatment options, patients are desperate for any offered hope. The net result can be an unethical situation that endangers patient health and wellbeing and decreases the integrity and effectiveness of the patient-led movement.	_
85	Ce083		Ontario and health care guidelines	Post COVID-19 Condition: Guidance for Primary Care		Published	November 30, 2021	Guidance	https://www.ontariohealth.ca/sites/ontariohealth/files/2021-12/PostCovidConditionsClinicalGuidance_EN.pdf	Assessment and Management of the Post-COVID-19 Condition Content adapted from Centers for Disease Control and Prevention Interim Guidance	_
86	Ce084		Christopher R. Lupfer1, Riley Nadler1, Ronald Amen2, Alain Martin*2	Inhalation of Sodium Pyruvate to Reduce the Symptoms and Severity of Respiratory Diseases Including COVID-19, Long COVID, and Pulmonary Fibrosis	https://doi.org/10.31488/EJRM.121	Published	October 29, 2021	Study	https://europeanjournalofrespiratorymedicine.com/inhalation-of-sodium-pyruvate-to-reduce-the-symptoms-and-severity-of-respiratory-diseases-including-COVID-19-long-COVID-and-pulmonary-fibrosis	Findings: During active COVID-19 infection, N115 decreased viral titers and produced a significant improvement over saline in coughing/sneezing and fatigue. In Long COVID patients, N115 significantly reduced headache, coughing/sneezing and increased SaO2 levels (decreased hypoxemia) and improved breathing (dyspnea). In patients with Pulmonary Fibrosis, there was a significant improvement in all lung functions, compared to baseline, as determined by changes in SaO2, FVC, FEV1, PEF, and FEV1/FVC ratio. Conclusions: N115 is safe and effective at reducing symptoms of active COVID-19 infection and improves disease condition in Long COVID patients. Furthermore, N115 significantly improves lung function in Pulmonary Fibrosis patients. As COVID-19 and Pulmonary Fibrosis are associated with each other, our clinical research demonstrates that N115 is a promising treatment for both and adds to the current 19 human clinical trials where N115 has shown efficacy in thousands of patients, regardless of the etiology of the lung disease (COPD, CF, allergic rhinitis, sinusitis, the flu, COVID-19 infected patients, Long COVID and patients with Pulmonary Fibrosis).	Une étude américaine souligne l'intérêt d'inhalations de pyruvate de sodium chez les malades du covid long pour atténuer les symptômes de maux de tête, de toux et permettre la diminution de l'hypoxémie et de la dyspnée, sur une cohorte de 22 patients. Chez les patients atteints de fibrose pulmonaire, les auteurs notent une amélioration significative de toutes les fonctions pulmonaires, quantifiée par les mesures et ratios SaO2, FVC, FEV1, PEF et FEV1/FVC.
87	Ce085		Etheresia Pretorius, Chantelle Venter, Gert Jacobus Laubscher, Maritha J. Kotze, Kelebogile Moremi, Sunday Oladejo, Liam R. Watson, Kanshu Rajaratnam, Bruce W. Watson, Douglas B. Kell	Combined triple treatment of fibrin amyloid microclots and platelet pathology in individuals with Long COVID/ Post-Acute Sequelae of COVID-19 (PASC) can resolve their persistent symptoms*	https://doi.org/10.21203/rs.3.rs-1205453/v1	pre-print	28 Dec, 2021	Study	https://www.researchsquare.com/article/rs-1205453/v1	A subset of 24 patients was treated with one month of dual antiplatelet therapy (DAPT) (Clopidogrel 75mg/Aspirin 75mg) once a day, as well as a direct oral anticoagulant (DOAC) (Apixiban) 5 mg twice a day. A proton pump inhibitor (PPI) pantoprazole 40 mg/day was also prescribed for gastric protection. Such a regime must only be followed under strict and qualified medical guidance to obviate any dangers, especially haemorrhagic bleeding, and of the therapy as a whole. Thromboelastography (TEG®) was used to assist in determining their clotting status. Each of the 24 treated cases reported that their main symptoms were resolved and fatigue as the main symptom was relieved, and this was also reflected in a decrease of both the fibrin amyloid microclots and platelet pathology scores. Nine patients were genotyped for genetic variation in homocysteine metabolism implicated in hypertension, a common COVID-19 co-morbidity reported in both patients found to be homozygous for the risk-associated MTHFR 677 T-allele. Fibrin amyloid microclots that block capillaries and inhibit the transport of O2 to tissues, accompanied by platelet hyperactivation, provide a ready explanation for the symptoms of Long COVID/PASC. The removal and reversal of these underlying endotheliopathies provide an important treatment option that seems to be highly efficacious, and warrants controlled clinical studies.
88	Ce086		S.Charfeddine12H.Ibn Hadjamor34S.Torjmen12S.Kraiem3R.Hammami12A.Bahloul12N.Kallel25N.Moussa25I.Touil6J.Jdidi27S.Abdesselem(Private cardiologist)48L.Abid12	Sulodexide in the treatment of patients with long COVID 19 symptoms and endothelial dysfunction: The results of TUN-EndCOV study	https://doi.org/10.1016/j.acvdsp.2021.10.007	Published	27 December 2021	Study	https://www.sciencedirect.com/science/article/pii/S1878648021006455	Methods We conducted a prospective multicenter longitudinal case-control study. Endothelial function was evaluated with DTM “E4-Diagnose” Polymath based on the Endothelium Quality Index (EQI). A group of patients with endothelial dysfunction (EQI < 2.0) received sulodexide. All the patients were followed-up 21 days after inclusion. Primary outcomes were defined as endothelial function amelioration (delta EQI) and long COVID-19 symptoms evolution during the follow-up. Results A total of 410 patients were included in this study. Patients were included at an average time of 1.89 ± 1.2 month after COVID-19 infection. At inclusion, 210 (51.2%) patients had an EQI < 2. The median age was 49 ± 13.8 (18–80) years. Among the patients with endothelial dysfunction, only 79 patients received sulodexide. Patients in sulodexide group had lower EQI than the non-medical intervention group (0.94 ± 0.6 vs. 1.52 ± 0.4; P < 10−3). They were more diabetic, hypertensive, had more coronary artery disease and received more long-term medications (aspirin, Bblockers and statins) than the others (P = 0.01, 0.002, 0.01, 0.009, 0.001 and 0.01, respectively). At the 21-days follow-up, patients in sulodexide group presented lower long COVID symptoms especially chest pain, palpitations, fatigue and neuro-cognitive difficulties associated to a significant amelioration of endothelial function (delta EQI 1.26 ± 1.07 vs. 0.22 ± 0.7; P < 10−3). Conclusion Sulodexide in patients with long COVID-19 may be a good intervention to ameliorate chest pain, palpitations, fatigue and neuro-cognitive difficulties associated to endothelial dysfunction.
89	Ce087		Etheresia Pretorius, Chantelle Venter, Gert Jacobus Laubscher, Maritha J. Kotze, Kelebogile Moremi, Sunday Oladejo, Liam R. Watson, Kanshu Rajaratnam, Bruce W. Watson, Douglas B. Kell	Combined triple treatment of fibrin amyloid microclots and platelet pathology in individuals with Long COVID/ Post-Acute Sequelae of COVID-19 (PASC) can resolve their persistent symptoms*	https://doi.org/10.21203/rs.3.rs-1205453/v1	pre-print	28 Dec, 2021	Study	https://www.researchsquare.com/article/rs-1205453/v1	A subset of 24 patients was treated with one month of dual antiplatelet therapy (DAPT) (Clopidogrel 75mg/Aspirin 75mg) once a day, as well as a direct oral anticoagulant (DOAC) (Apixiban) 5 mg twice a day. A proton pump inhibitor (PPI) pantoprazole 40 mg/day was also prescribed for gastric protection. Such a regime must only be followed under strict and qualified medical guidance to obviate any dangers, especially haemorrhagic bleeding, and of the therapy as a whole. Thromboelastography (TEG®) was used to assist in determining their clotting status. Each of the 24 treated cases reported that their main symptoms were resolved and fatigue as the main symptom was relieved, and this was also reflected in a decrease of both the fibrin amyloid microclots and platelet pathology scores. Nine patients were genotyped for genetic variation in homocysteine metabolism implicated in hypertension, a common COVID-19 co-morbidity reported in both patients found to be homozygous for the risk-associated MTHFR 677 T-allele. Fibrin amyloid microclots that block capillaries and inhibit the transport of O2 to tissues, accompanied by platelet hyperactivation, provide a ready explanation for the symptoms of Long COVID/PASC. The removal and reversal of these underlying endotheliopathies provide an important treatment option that seems to be highly efficacious, and warrants controlled clinical studies.
90	Ce088		Rosa María Wong-Chew, Edwin Xchel Rodríguez Cabrera, Carlos Alberto Rodríguez Valdez, Julieta Lomelin-Gascon, Linda Morales-Juárez, Liza Fernanda Contreras, Luis Rafael González de la Cerda, Arturo Juárez Flores, Luis Alberto Martínez-Juarez, Diego-Abelardo Álvarez-Hernández, Héctor Gallardo-Rincón, German Fajardo Dolci, Roberto Tapia-Conyer, Rafael Ricardo Valdez-Vázquez	Does anti-viral treatment in acute COVID infection decrease the risk of developing the Long-COVID Syndrome?	https://doi.org/10.1093/qjmed/hcab319	Published	08 January 2022	Article	https://academic.oup.com/qjmed/article-abstract/114/12/841/6501564	A question that has often been asked is do vaccines prevent Long-COVID Syndrome? And, additionally, does anti-viral treatment of acute coronavirus disease-19 (COVID-19) infections reduce the risk of developing subsequently the Long-COVID Syndrome. We have some early epidemiological evidence that vaccines potentially do reduce the risk of the Long-COVID Syndrome but little evidence to date that specific anti-virals have the potential to also reduce the subsequent risk. In a community population of 1.25 million individuals who downloaded a COVID symptom App, those who had dual vaccinations and experienced breakthrough COVID-19 infection—had significantly reduced disabling symptoms beyond ×28 days compared to unvaccinated individuals.1 In the unvaccinated population, 11% of individuals had persistent symptoms vs. 5% in the vaccinated population.	_
91	Ce089		Kirsty Brown Asma Yahyouche Shamil Haroon Jenny Camaradou Grace Turner	Long COVID and self-management	https://doi.org/10.1016/S0140-6736(21)02798-7	Published	January 22, 2022	Correspondence	https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02798-7/fulltext	People with COVID-19 often have symptoms in the long term (ie, long COVID), including fatigue, breathlessness, and neurocognitive difficulties.1 The disease mechanisms causing long COVID are unknown, and there are no evidence-based treatment options. Clinical guidelines focus on symptom management, and various treatment options are being evaluated.1 The scarcity of advice has often left people with long COVID feeling isolated and frustrated in their search for therapies. Studies have reported a wide range of self-prescribed medications being used for prevention and management of acute COVID-19, including anti-retrovirals, penicillin, vitamin C, traditional medicines, and chloroquine or hydroxychloroquine.2, 3, 4 Self-prescribing practices are unsurprising given the high incidence of and mortality from COVID-19, restricted access to health care during lockdowns, and few treatments and preventive therapies for COVID-19.
92	Ce090	PESE	Miwa K*	Oral Minocycline Challenge as a Potential First-Line Therapy for Myalgic Encephalomyelitis and Long Covid-19 Syndrome		Published	28 Jan 2022	Review	https://acmcasereport.com/wp-content/uploads/2022/01/ACMCR-v8-1710.pdf	Chronic fatigue syndrome characterized by severe disabling fatigue, prolonged post-exertional malaise, and unrefreshing sleep markedly reduces the activities of daily living and impairs the quality of life. Central nervous system dysfunction associated with myalgic encephalomyelitis (ME) has been postulated as the main cause of chronic fatigue syndrome. Recently, oral minocycline therapy has been reported to exert favorable therapeutic effects in some patients with ME, especially in the initial stage of the disease, although many patients discontinued treatment in the first few days because of acute adverse effects such as nausea and/or dizziness. Minocycline appeared to exert a variety of biologic actions against neural inflammation that are independent of their anti-microbial activity, including anti-inflammatory, immunomodulatory, and neuroprotective effects. In recent years, it has been noted that COVID-19 disease may cause persistent signs and symptoms described as post-COVID syndrome or long COVID, in which the clinical presentation is remarkably similar to those seen in patients with ME. A wide range of infectious agents have been suggested to trigger the development of ME, and one of such pathogens may be the COVID-19 virus. Recently, I had a valuable experience of a 22-year-old female patient with a 14-month duration of long COVID who completely recovered from ME-like symptoms after treatment with minocycline. This case suggests that oral minocycline could be an effective first-line therapy for long COVID-19, although a large scale of trial is obviously needed to justify the therapy.
93	Ce091		Gareth Iacobucci	Long covid: “Holistic” approach is best, given range of symptoms, say researchers	https://doi.org/10.1136/bmj.o336	Published	08 February 2022	Article	https://www.bmj.com/content/376/bmj.o336.full	New research on long covid in adults and children supports the multidisciplinary approach to clinical care that is being provided at long covid clinics in England, experts have said. “Long covid seems to be a condition where multiple symptoms are very common,” said Terence Stephenson, Nuffield professor of child health at the UCL Great Ormond Street Institute of Child Health in London, told a Science Media Centre briefing. “I think the services that have been set up in England for young people do address that. They are holistic and comprehensive in their approach, rather than addressing single organs or single problems,” said Stephenson, who is the lead author of the Children and Young People with Long Covid (Clock) study, published in Lancet Adolescent and Child Health.1 “If you have a mixture of symptoms of headache, cough, and dizziness, you probably want to go to a service that can deal with you holistically with all your symptoms,” he added. There are currently around 80 long covid clinics in England that take referrals from primary care for adults or children who are experiencing a range of symptoms that might include brain fog, anxiety, depression, breathlessness, and fatigue.
94	Ce092		Marc Blanchard 1 Author Image ; Lars Backhaus 1 Author Image ; Pedro Ming Azevedo 1 Author Image ; Thomas Hügle 1 Author Image	An mHealth App for Fibromyalgia-like Post–COVID-19 Syndrome: Protocol for the Analysis of User Experience and Clinical Data	https://doi.org/10.2196/32193	Published	4.2.2022	Study	https://www.researchprotocols.org/2022/2/e32193/	Background: Post–COVID-19 syndrome, also referred as “long covid,” describes persisting symptoms after SARS-CoV-2 infection, including myalgia, fatigue, respiratory, or neurological symptoms. Objective symptoms are often lacking, thus resembling a fibromyalgia-like syndrome. Digital therapeutics have shown efficiency in similar chronic disorders such as fibromyalgia, offering specific disease monitoring and interventions such as cognitive behavioral therapy or physical and respiratory exercise guidance. Objective: This protocol aims to study the requirements and features of a new mobile health (mHealth) app among patients with fibromyalgia-like post–COVID-19 syndrome in a clinical trial. Methods: We created a web application prototype for the post–COVID-19 syndrome called “POCOS,” as a web-based rehabilitation tool aiming to improve clinical outcomes. Patients without organ damage or ongoing inflammation will be included in the study. App use will be assessed through user experience questionnaires, focus groups, and clinical data analysis. Subsequently, we will analyze cross-sectional and longitudinal clinical data. Results: The developed mHealth app consists of a clinically adapted app interface with a simplified patient-reported outcome assessment, monitoring of medical interventions, and disease activity as well as web-based instructions for specific physical and respiratory exercises, stress reduction, and lifestyle instructions. The enrollment of participants is expected to be carried out in November 2021. Conclusions: User experience plays an important role in digital therapeutics and needs to be clinically tested to allow further improvement. We here describe this process for a new app for the treatment of the fibromyalgia-like post–COVID-19 syndrome and discuss the relevance of the potential outcomes such as natural disease course and disease phenotypes.
95	Ce093		Nikolay O. Kamenshchikov 1,* ,Lorenzo Berra 2,3 andRyan W. Carroll 3,4	Therapeutic Effects of Inhaled Nitric Oxide Therapy in COVID-19 Patients	https://doi.org/10.3390/biomedicines10020369	Published	3 February 2022	Review	https://www.mdpi.com/2227-9059/10/2/369/htm	The global COVID-19 pandemic has become the largest public health challenge of recent years. The incidence of COVID-19-related acute hypoxemic respiratory failure (AHRF) occurs in up to 15% of hospitalized patients. Antiviral drugs currently available to clinicians have little to no effect on mortality, length of in-hospital stay, the need for mechanical ventilation, or long-term effects. Inhaled nitric oxide (iNO) administration is a promising new non-standard approach to directly treat viral burden while enhancing oxygenation. Along with its putative antiviral affect in COVID-19 patients, iNO can reduce inflammatory cell-mediated lung injury by inhibiting neutrophil activation, lowering pulmonary vascular resistance and decreasing edema in the alveolar spaces, collectively enhancing ventilation/perfusion matching. This narrative review article presents recent literature on the iNO therapy use for COVID-19 patients. The authors suggest that early administration of the iNO therapy may be a safe and promising approach for the treatment of COVID-19 patients. The authors also discuss unconventional approaches to treatment, continuous versus intermittent high-dose iNO therapy, timing of initiation of therapy (early versus late), and novel delivery systems. Future laboratory and clinical research is required to define the role of iNO as an adjunct therapy against bacterial, viral, and fungal infections.
96	Ce094		DebdootBasuaVivek P.ChavdabAnita A.Mehtaa	Therapeutics for COVID-19 and post COVID-19 complications: An update	https://doi.org/10.1016/j.crphar.2022.100086	Published	15 February 2022	Review	https://www.sciencedirect.com/science/article/pii/S2590257122000062	Highlights •With continuous mutation of SARS-CoV-2, there is a strong need for the potent therapeutic agent for covid management. •Effectiveness of repurposed drugs used against COVID-19 till now it's not evident. •List of US-FDA approved drugs for COVID-19 were summarized in the article. •Several new drug molecules and biologics are engineered against SARS-CoV-2. •A consolidated summary of the therapeutic development against SARS-CoV-2 is depicted along with an overview of effective management of postCOVID-19 complications. Abstract Since its inception in late December 2020 in China, novel coronavirus has affected the global socio-economic aspect. Currently, the world is seeking safe and effective treatment measures against COVID-19 to eradicate it. Many established drug molecules are tested against SARS-CoV-2 as a part of drug repurposing where some are proved effective for symptomatic relief while some are ineffective. Drug repurposing is a practical strategy for rapidly developing antiviral agents. Many drugs are presently being repurposed utilizing basic understanding of disease pathogenesis and drug pharmacodynamics, as well as computational methods. In the present situation, drug repurposing could be viewed as a new treatment option for COVID-19. Several new drug molecules and biologics are engineered against SARS-CoV-2 and are under different stages of clinical development. A few biologics drug products are approved by USFDA for emergency use in the covid management. Due to continuous mutation, many of the approved vaccines are not much efficacious to render the individual immune against opportunistic infection of SARS-CoV-2 mutants. Hence, there is a strong need for the cogent therapeutic agent for covid management. In this review, a consolidated summary of the therapeutic developments against SARS-CoV-2 are depicted along with an overview of effective management of post COVID-19 complications.
97	Ce095		Aisha M. Bhaiyat, Efrat Sasson, Zemer Wang, Sherif Khairy, Mouzayan Ginzarly, Umair Qureshi, Moin Fikree & Shai Efrati	Hyperbaric oxygen treatment for long coronavirus disease-19: a case report	https://doi.org/10.1186/s13256-022-03287-w	Published	15 February 2022	Case Report	https://link.springer.com/article/10.1186/s13256-022-03287-w	Two potential mechanisms could be responsible for these long-term unremitting symptoms: hypercoagulability, which increases the risk of blood vessel occlusion, and an uncontrolled continuous inflammatory response. Currently, no known treatment is available for long COVID. One of the options to reverse hypoxia, reduce neuroinflammation, and induce neuroplasticity is hyperbaric oxygen therapy. In this article, we present the first case report of a previously healthy athletic individual who suffered from long COVID syndrome treated successfully with hyperbaric oxygen therapy. Case presentation A previously healthy 55-year-old Caucasian man presented 3 months after severe coronavirus disease 2019 infection with long COVID syndrome. His symptoms included a decline in memory, multitasking abilities, energy, breathing, and physical fitness. After evaluation that included brain perfusion magnetic resonance imaging, diffusion tensor imaging, computerized cognitive tests, and cardiopulmonary test, he was treated with hyperbaric oxygen therapy. Each session included exposure to 90 minutes of 100% oxygen at 2 atmosphere absolute pressure with 5-minute air breaks every 20 minutes for 60 sessions, 5 days per week. Evaluation after completing the treatment showed significant improvements in brain perfusion and microstructure by magnetic resonance imaging and significant improvement in memory with the most dominant effect being on nonverbal memory, executive functions, attention, information procession speed, cognitive flexibility, and multitasking. The improved cognitive functions correlated with the increased cerebral blood flow in brain regions as measured by perfusion magnetic resonance imaging. With regard to physical capacity, there was a 34% increase in the maximum rate of oxygen consumed during exercise and a 44% improvement in forced vital capacity. The improved physical measurements correlated with the regain of his pre-COVID physical capacity. Conclusions We report the first case of successfully treated long COVID symptoms with hyperbaric oxygen therapy with improvements in cognition and cardiopulmonary function. The beneficial effects of hyperbaric oxygen shed additional light on the pathophysiology of long COVID. As this is a single case report, further prospective randomized control studies are needed.
98	Ce096		MohanakrishnanSathyamoorthyaMonicaVerduzco-GutierrezbSwathiVaranasicRobynWarddJohnSpertuseSachinShahcf	Enhanced external counterpulsation for management of symptoms associated with long COVID	https://doi.org/10.1016/j.ahjo.2022.100105	Published	18 February 2022	Study	https://www.sciencedirect.com/science/article/pii/S2666602222000222	Highlights •This cohort of 16 Long COVID patients treated with EECP showed improvements in validated fatigue and cardiovascular markers. •After EECP, patients had enhanced quality of life, allowing them to resume normal daily activities and return to work. •These findings suggest that EECP may be beneficial for the management of Long COVID symptoms and warrants further studies. Results Compared to baseline, the PROMIS Fatigue, SAQ, DASI, and 6MWT improved by 4.63 ± 3.42 (p < 0.001), 21.44 ± 16.54 (p < 0.001), 18.08 ± 13.82 (p < 0.001), and 200.00 ± 180.14 (p = 0.002), respectively. CCS and RDS improved in 63% and 44% of patients, respectively. All patients unable to work prior to EECP were able to return post-therapy. Conclusions and relevance EECP significantly improved validated fatigue and cardiovascular-related markers in patients with Long COVID.
99	Ce097		Leonard Calabrese, Luana Colloca	Long COVID-19 and the Role of the Patient–Clinician Interaction in Symptom Management	https://doi.org/10.1177%2F23743735221077514	Published	February 9, 2022	Research Article	https://journals.sagepub.com/doi/full/10.1177/23743735221077514	We described the physical and psychological impact of Long COVID as well as detailed the neurobiology of the patient–clinician interaction and placebo science. While there are many unknowns we struggle with, placebo effects (and not mere placebo pills) can be potentially exploited as adjuvants for symptom managements. Namely, we recommend: (1) Educating the patient about her experience of sickness to align it with the clinician perspective of treating the symptoms and causes of the disease; (2) conveying awareness about the diagnosis itself of Long COVID and its strong personal dimension; (3) engaging with patients’ perspectives to expunge them of guilt; (4) dispelling fears surrounding the diagnosis of Long COVID; (5) establishing a genuine patient–clinician concordance and alliance to manage Long COVID; and (6) engaging with patients to identify their needs in order to minimize burn out deriving from Long COVID (Table 1). Overall, the reflections presented here are based on current knowledge of Long COVID, the science of placebo effects with a focus on the neurobiology of the patient–clinician relationship with the scope to bridge these two research fields to translate the take-home messages helping patients cope and manage their Long COVID symptoms.
100	Ce098		Michal Botek 1,Jakub Krejčí 1,* ,Michal Valenta 1 ,Andrew McKune 2,3 ,Barbora Sládečková 1,Petr Konečný 4 ,Iva Klimešová 1 andDalibor Pastucha 5	Molecular Hydrogen Positively Affects Physical and Respiratory Function in Acute Post-COVID-19 Patients: A New Perspective in Rehabilitation	https://doi.org/10.3390/ijerph19041992	Published	10 February 2022	Study	https://www.mdpi.com/1660-4601/19/4/1992/htm	Molecular hydrogen (H2) is potentially a novel therapeutic gas for acute post-coronavirus disease 2019 (COVID-19) patients because it has antioxidative, anti-inflammatory, anti-apoptosis, and antifatigue properties. The aim of this study was to determine the effect of 14 days of H2 inhalation on the respiratory and physical fitness status of acute post-COVID-19 patients. This randomized, single-blind, placebo-controlled study included 26 males (44 ± 17 years) and 24 females (38 ± 12 years), who performed a 6-min walking test (6 MWT) and pulmonary function test, specifically forced vital capacity (FVC) and expiratory volume in the first second (FEV1). Symptomatic participants were recruited between 21 and 33 days after a positive polymerase chain reaction test. The experiment consisted of H2/placebo inhalation, 2 × 60 min/day for 14 days. Results showed that H2 therapy, compared with placebo, significantly increased 6 MWT distance by 64 ± 39 m, FVC by 0.19 ± 0.24 L, and, in FEV1, by 0.11 ± 0.28 L (all p ≤ 0.025). In conclusion, H2 inhalation had beneficial health effects in terms of improved physical and respiratory function in acute post-COVID-19 patients. Therefore, H2 inhalation may represent a safe, effective approach for accelerating early function restoration in post-COVID-19 patients.
101	Ce099		Lucinda Bateman, MD Alison C. Bested, MD Hector F. Bonilla, MD Bela V. Chheda, MD Lily Chu, MD, MSHS Jennifer M. Curtin, MD Tania T. Dempsey, MD Mary E. Dimmock, BA Theresa G. Dowell, DNP, MPT Donna Felsenstein, MD David L. Kaufman, MD Nancy G. Klimas, MD Anthony L. Komaroff, MD Charles W. Lapp, MBME, MD Susan M. Levine, MD Jose G. Montoya, MD Benjamin H. Natelson, MD Daniel L. Peterson, MD Richard N. Podell, MD, MPH Irma R. Rey, MD Ilene S. Ruhoy, MD, PhD Maria A. Vera-Nunez, MD, MSBI Brayden P. Yellman, MD	Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management	https://doi.org/10.1016/j.mayocp.2021.07.004	Published	August 25, 2021	Article	https://www.mayoclinicproceedings.org/article/S0025-6196(21)00513-9/fulltext	Despite myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affecting millions of people worldwide, many clinicians lack the knowledge to appropriately diagnose or manage ME/CFS. Unfortunately, clinical guidance has been scarce, obsolete, or potentially harmful. Consequently, up to 91% of patients in the United States remain undiagnosed, and those diagnosed often receive inappropriate treatment. These problems are of increasing importance because after acute COVID-19, a significant percentage of people remain ill for many months with an illness similar to ME/CFS. In 2015, the US National Academy of Medicine published new evidence-based clinical diagnostic criteria that have been adopted by the US Centers for Disease Control and Prevention. Furthermore, the United States and other governments as well as major health care organizations have recently withdrawn graded exercise and cognitive-behavioral therapy as the treatment of choice for patients with ME/CFS. Recently, 21 clinicians specializing in ME/CFS convened to discuss best clinical practices for adults affected by ME/CFS. This article summarizes their top recommendations for generalist and specialist health care providers based on recent scientific progress and decades of clinical experience. There are many steps that clinicians can take to improve the health, function, and quality of life of those with ME/CFS, including those in whom ME/CFS develops after COVID-19. Patients with a lingering illness that follows acute COVID-19 who do not fully meet criteria for ME/CFS may also benefit from these approaches.
102	Ce100		Pedro Cuevas, Antonio Manquillo, Javier Angulo, Guillermo Giménez-Gallego.	Dobesilate: A potential therapy for long-covid?	10.5455/IJMRCR.dobesilate-long-covid	Published	16/04/2021	Study	http://www.mdpub.net/fulltext/172-1633990523.pdf?1646152427	On the basis of the involvement of fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) in inflammation and vascular changes in COVID-19, we hypothesized that Dobesilate, a demonstrated anti-FGF and anti-VEGF drug, might be beneficial for treating COVID-19 patients. We conducted a study and recruited 13 patients with long-COVID syndrome from one centre. Dobesilate (Doxium® 1g, twice a day for 15 days) shows clinical efficacy by improving symptoms in these patients.
103	Ce101		Maziar Malekzadeh Kebria, Peiman Brouki Milan, Noshad Peyravian, Jafar Kiani, Soheil Khatibi & Masoud Mozafari	Stem cell therapy for COVID-19 pneumonia	https://doi.org/10.1186/s43556-021-00067-8	Published	17 February 2022	Review	https://link.springer.com/article/10.1186/s43556-021-00067-8	Researchers have tried different treatments to reduce the side effects of the COVID-19 symptoms. One of the most common and effective treatments now used is steroid therapy to reduce the complications of this disease. Long-term steroid therapy for chronic inflammation following COVID-19 is harmful and increases the risk of secondary infection, and effective treatment remains challenging owing to fibrosis and severe inflammation and infection. Sometimes our immune system can severely damage ourselves in disease. In the past, many researchers have conducted various studies on the immunomodulatory properties of stem cells. This property of stem cells led them to modulate the immune system of autoimmune diseases like diabetes, multiple sclerosis, and Parkinson's. Because of their immunomodulatory properties, stem cell-based therapy employing mesenchymal or hematopoietic stem cells may be a viable alternative treatment option in some patients. By priming the immune system and providing cytokines, chemokines, and growth factors, stem cells can be employed to build a long-term regenerative and protective response. This review addresses the latest trends and rapid progress in stem cell treatment for Acute Respiratory Distress Syndrome (ARDS) following COVID-19.
104	Ce102		Dana Yelin,Charalampos D. Moschopoulos,Ili Margalit,Effrossyni Gkrania-Klotsas,Francesco Landi,Jean-Paul Stahl,Dafna Yahav	ESCMID rapid guidelines for assessment and management of long COVID	https://doi.org/10.1016/j.cmi.2022.02.018	Published	17 Feb, 2022	Guideline	https://www.sciencedirect.com/science/article/abs/pii/S1198743X22000921	Evidence was insufficient to provide any recommendation other than conditional guidance. The panel recommends considering routine blood tests, chest imaging and pulmonary functions tests for patients with persistent respiratory symptoms at 3 months. Other tests should be performed mainly to exclude other conditions according to symptoms. For management, no evidence-based recommendations could be provided. Physical and respiratory rehabilitation should be considered. On the basis of limited evidence, the panel suggests designing high quality prospective clinical studies/trials, including a control group, to further evaluate assessment and management of individuals with persistent symptoms of COVID-19.
105	Ce103		Vink, M.; Vink-Niese, F.	Is It Useful to Question the Recovery Behaviour of Patients with ME/CFS or Long COVID?	https://doi.org/10.3390/healthcare10020392	Published	18 Feb, 2022	Review	https://www.mdpi.com/2227-9032/10/2/392	For the last few decades, medical guidelines have recommended treating patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with graded exercise therapy (GET) and cognitive behavioural therapy (CBT). Moreover, doctors have questioned the recovery behaviour of these patients and stimulated them to follow these treatments so that they would be able to go back to work. In this article, we reviewed trials of GET and CBT for ME/CFS that reported on work status before and after treatment to answer the question of whether doctors should continue to question the recovery behaviour of patients with ME/CFS. Our review shows that more patients are unable to work after treatment than before treatment with CBT and GET. It also highlights the fact that both treatments are unsafe for patients with ME/CFS. Therefore, questioning the recovery behaviour of patients with ME/CFS is pointless. This confirms the conclusion from the British National Institute for Health and Care Excellence (NICE), which has recently published its updated ME/CFS guideline and concluded that CBT and GET are not effective and do not lead to recovery. Studies on CBT and GET for long COVID have not yet been published. However, this review offers no support for their use in improving the recovery of patients with an ME/CFS-like illness after infection with COVID-19, nor does it lend any support to the practice of questioning the recovery behaviour of these patients.
106	Ce104		Ahmadi Hekmatikar, A.H.; Ferreira Júnior, J.B.; Shahrbanian, S.; Suzuki, K.	Functional and Psychological Changes after Exercise Training in Post-COVID-19 Patients Discharged from the Hospital: A PRISMA-Compliant Systematic Review	https://doi.org/10.3390/ijerph19042290	Published	17 Feb, 2022	Systematic review	https://www.mdpi.com/1660-4601/19/4/2290	Because reinfection is still possible in COVID-19 survivors, decreased physical function and increased stress and anxiety can lower immune function. However, the optimal exercise intensity and volume appear to remain unknown. Therefore, the current systematic review aimed to evaluate the effect of resistance or aerobic exercises in post-COVID-19 patients after hospital discharge. We conducted searches in the Scopus, SciELO, PubMed, Web of Science, Science Direct, and Google Scholar databases. Studies that met the following criteria were included: (i) English language, (ii) patients with COVID-19 involved with resistance or aerobic exercise programs after hospital discharge. Out of 381 studies reviewed, seven studies met the inclusion criteria. Evidence shows that exercise programs composed of resistance exercise (e.g., 1–2 sets of 8–10 repetitions at 30–80% of 1RM) along with aerobic exercise (e.g., 5 to 30 min at moderate intensity) may improve the functional capacity and quality of life (reduce stress and mental disorders) in post-COVID-19 patients. In addition, only one study reported reinfection of three subjects involved with the exercise program, suggesting that exercise programs may be feasible for the rehabilitation of the patients. A meta-analysis was not conducted because the included studies have methodological heterogeneities, and they did not examine a control group. Consequently, the results should be generalized with caution.
107	Ce105		Elizabeth Murray1, Henry Goodfellow2, Julia Bindman1, Ann Blandford3, Katherine Bradbury4, Tahreem Chaudhry2, Delmiro Fernandez-Reyes5, Manuel Gomes6, Fiona L Hamilton1, Melissa Heightman7, William Henley8, John R Hurst9, Hannah Hylton10, Stuart Linke11, Paul Pfeffer10, William Ricketts10, Chris Robson12, Richa Singh10, Fiona A Stevenson1, Sarah Walker8, Jonathan Waywell12	Development, deployment and evaluation of digitally enabled, remote, supported rehabilitation for people with long COVID-19 (Living With COVID-19 Recovery): protocol for a mixed-methods study	https://doi.org/10.1136/bmjopen-2021-057408	Published	February 07, 2022	Study	https://bmjopen.bmj.com/content/12/2/e057408	Introduction Long COVID-19 is a distressing, disabling and heterogeneous syndrome often causing severe functional impairment. Predominant symptoms include fatigue, cognitive impairment (‘brain fog’), breathlessness and anxiety or depression. These symptoms are amenable to rehabilitation delivered by skilled healthcare professionals, but COVID-19 has put severe strain on healthcare systems. This study aims to explore whether digitally enabled, remotely supported rehabilitation for people with long COVID-19 can enable healthcare systems to provide high quality care to large numbers of patients within the available resources. Specific objectives are to (1) develop and refine a digital health intervention (DHI) that supports patient assessment, monitoring and remote rehabilitation; (2) develop implementation models that support sustainable deployment at scale; (3) evaluate the impact of the DHI on recovery trajectories and (4) identify and mitigate health inequalities due to the digital divide. Methods and analysis Mixed-methods, theoretically informed, single-arm prospective study, combining methods drawn from engineering/computer science with those from biomedicine. There are four work packages (WP), one for each objective. WP1 focuses on identifying user requirements and iteratively developing the intervention to meet them; WP2 combines qualitative data from users with learning from implementation science and normalisation process theory, to promote adoption, scale-up, spread and sustainability of the intervention; WP3 uses quantitative demographic, clinical and resource use data collected by the DHI to determine illness trajectories and how these are affected by use of the DHI; while WP4 focuses on identifying and mitigating health inequalities and overarches the other three WPs.
108	Ce106		E. Tucker, E. Fraser, A. Pick, R. Rogers, H. Salt, V. Masey	Long COVID rehabilitation: A collaborative approach to managing a new phenomenon	https://doi.org/10.1016/j.physio.2021.12.162	Published	February 01, 2022	Study	https://www.physiotherapyjournal.com/article/S0031-9406(21)00548-4/fulltext	Results: At time of writing, 434 patients had been referred to the Rehabilitation pathway of the Oxfordshire Post COVID Service, of whom 250 assessed and established on rehabilitation strategies. Patients referred are triaged by both leading Acute Trust Consultant and Community Trust AHP to identify the best place of care based on symptoms and functionality, utilising the Post COVID Functional Scale. At assessment, patients share their ‘story’, establish goals and identify most appropriate rehabilitative strategy. Clinicians involved in these processes include Respiratory and Rehabilitation Medicine Consultants, Psychiatrists, Psychologists, CBT Therapists, Physiotherapists and Occupational Therapists. Processes are in place to offer patients an individualised approach to rehabilitation through the use of web based platform, symptom tracking application, development of virtual groups and encouraging use of external resources including ENO Breathe, Your COVID Recovery, NHS Yoga Platforms and we have linked locally with Age UK and Generation Games initiatives. Patient feedback has been actively sought from the outset, ensuring that the patient voice is always heard and listened to. So far, it has been overwhelmingly positive. Conclusion(s): Close collaboration between multiple professions, Trusts and Organisations resulted in seamless care, patient satisfaction and an excellent model of service delivery. Further work is required to support the recognition of health inequalities, with specific focus on BAME communities. We are in the process of collaborating with local GP's, inequality leads and local centres to develop focus groups ensuring that these voices are heard, and plans established to ensure equitable services are accessible to all.
109	Ce107		Lesley J.J.SorilabRonald W.DamantacGrace Y.LamcMaeve P.SmithcJasonWeatheralddJeanBourbeauePaulHernandezfMichael K.Sticklandac	The effectiveness of pulmonary rehabilitation for Post-COVID symptoms: A rapid review of the literature	https://doi.org/10.1016/j.rmed.2022.106782	Published	7 March 2022	Review	https://www.sciencedirect.com/science/article/pii/S0954611122000476	Highlights •Nine studies evaluating the clinical effectiveness of post-COVID pulmonary rehabilitation were identified. •Most studies were small and of low quality. •All studies reported improvements in post-COVID patients who had been hospitalized. •No studies evaluated non-hospitalized patients or long-term outcomes (>3 months). Nine studies evaluating the effectiveness of PR were identified; most were small, experimental or quasi-experimental studies, including 1 RCT, and were primarily of low quality. After attending PR, all studies reported improvements in exercise capacity, pulmonary function, and/or quality of life for individuals with post-COVID symptoms who had been hospitalized for their acute COVID-19 infection. Few studies evaluated changes in post-COVID symptom severity or frequency and, of these, improvements in dyspnea, fatigue, anxiety and depression were observed following PR. Further, no studies evaluated non-hospitalized patients or long-term outcomes beyond 3 months after initiating PR. Conclusions With limited high-quality evidence, any recommendations or practical guidance for PR programmes for those with post-COVID symptoms should consider factors such as feasibility, current PR capacity, and resource constraints.
110	Ce108		Tye, Joe MBA, MHA; Long, Kimberly DHA, MSN, RN, FNP, FACHE; Blake, Nancy PhD, RN, CCRN-K, NEA-BC, NHDP-BC, FAAN, FACHE; Luu, Allison MD, MS; Tye, Annie PhD	Caring for COVID's emotional long haulers	https://doi.org/10.1097/01.NUMA.0000821720.94922.5a	Published	March 2022	Article	https://journals.lww.com/nursingmanagement/Fulltext/2022/03000/Caring_for_COVID_s_emotional_long_haulers.6.aspx	The COVID-19 pandemic has taken a toll on the emotional, psychological, and spiritual well-being of healthcare workers. This article presents 14 strategies nurse leaders can use to help safeguard nurses' mental health. The COVID-19 pandemic is like Halley's Comet, which blazes a path across Earth's sky once every 75 years, pulling a long tail in its wake—a spectacle someone might see once in a lifetime and will never forget. Long after COVID-19 has become an endemic disease, the pandemic will leave behind a long tail of personal grief, emotional trauma, career dislocations, financial problems, anger, and anxiety. People living with long-term health problems associated with COVID-19 are called long haulers. We've borrowed that term to apply to healthcare workers who will experience long-term psychological, emotional, and spiritual pain because of their experiences during the pandemic. They're COVID's emotional long haulers. In her final presidential message for Voice of Nursing Leadership, American Organization for Nursing Leadership (AONL) President Mary Ann Fuchs wrote: “At great personal cost, nurses provided hope, peace, and healing to patients and to each other... Because in times of uncertainty, nurses are there.”1 As the pandemic recedes, we must be there for the caregivers who were there for us as they cope with the likely second pandemic of posttrauma moral and emotional injury.
111	Ce109		Ramamurthy, Lakshmi B; Bhandari, Ridhi,; Kanakpur, Savitha; Thejaswini, P	Outcome of transcutaneous retrobulbar injection of liposomal amphotericin B in post-COVID-19 rhino-orbito-cerebral mucormycosis: Our experience	https://doi.org/10.4103/ijo.IJO_2356_21	Published	March 2022	Study	https://journals.lww.com/ijo/Fulltext/2022/03000/Outcome_of_transcutaneous_retrobulbar_injection_of.66.aspx	Purpose: To assess the outcome and response of transcutaneous retrobulbar injection of amphotericin B (TRAMB) in post-coronavirus disease of 2019 (COVID-19) rhino-orbito-cerebral mucormycosis (ROCM) and to establish a scoring system in guiding treatment modalities. Results: Out of 82 eyes, symptomatic improvement was seen in a major proportion (72%) of patients. A statistically significant improvement in scores was noted in group A (93% improved) with a P value of 0.002, while 68.4% showed improvement in group B (P-value- 0.0001). Group C with severe disease showed minimal improvement in post-injection scores of 41% (P-value 0.086), necessitating surgical intervention. No serious adverse effect of the drug or procedure was noted. Conclusion: Significant improvement in scores of groups A and B highlights TRAMB as an effective and safe treatment modality in mild to moderate ROCM. It is an effective adjunct in severe cases, along with other interventions. Also, the scoring system helps in assessing the severity and guiding in management strategies.
112	Ce110		Nopp S.a · Moik F.a · Klok F.A.b · Gattinger D.c · Petrovic M.c · Vonbank K.d · Koczulla A.R.e,f · Ay C.a · Zwick R.H.c,g	Outpatient Pulmonary Rehabilitation in Patients with Long COVID Improves Exercise Capacity, Functional Status, Dyspnea, Fatigue, and Quality of Life	https://doi.org/10.1159/000522118	Published	February 24, 2022	Study	https://www.karger.com/Article/FullText/522118	Background: COVID-19 survivors face the risk of long-term sequelae including fatigue, breathlessness, and functional limitations. Pulmonary rehabilitation has been recommended, although formal studies quantifying the effect of rehabilitation in COVID-19 patients are lacking. Methods: We conducted a prospective observational cohort study including consecutive patients admitted to an outpatient pulmonary rehabilitation center due to persistent symptoms after COVID-19. The primary endpoint was change in 6-min walk distance (6MWD) after undergoing a 6-week interdisciplinary individualized pulmonary rehabilitation program. Secondary endpoints included change in the post-COVID-19 functional status (PCFS) scale, Borg dyspnea scale, Fatigue Assessment Scale, and quality of life. Further, changes in pulmonary function tests were explored. Results: Of 64 patients undergoing rehabilitation, 58 patients (mean age 47 years, 43% women, 38% severe/critical COVID-19) were included in the per-protocol-analysis. At baseline (i.e., in mean 4.4 months after infection onset), mean 6MWD was 584.1 m (±95.0), and functional impairment was graded in median at 2 (IQR, 2–3) on the PCFS. On average, patients improved their 6MWD by 62.9 m (±48.2, p < 0.001) and reported an improvement of 1 grade on the PCFS scale. Accordingly, we observed significant improvements across secondary endpoints including presence of dyspnea (p < 0.001), fatigue (p < 0.001), and quality of life (p < 0.001). Also, pulmonary function parameters (forced expiratory volume in 1 s, lung diffusion capacity, inspiratory muscle pressure) significantly increased during rehabilitation. Conclusion: In patients with long COVID, exercise capacity, functional status, dyspnea, fatigue, and quality of life improved after 6 weeks of personalized interdisciplinary pulmonary rehabilitation. Future studies are needed to establish the optimal protocol, duration, and long-term benefits as well as cost-effectiveness of rehabilitation.
113	Ce111		Sebastián GarcíaMenéndezabVirna MargaritaMartín GiménezcMichael F.HolickdFrancisco J.BarranteseWalterManuchaab	COVID-19 and neurological sequelae: Vitamin D as a possible neuroprotective and/or neuroreparative agent	https://doi.org/10.1016/j.lfs.2022.120464	Published	7 March 2022	Review	https://www.sciencedirect.com/science/article/pii/S0024320522001643	SARS-CoV-2 infection usually leads to bilateral atypical pneumonia with significant impairment of respiratory function. However, the infectious capacity of SARS-CoV-2 is not limited to the respiratory system, but may also affect other vital organs such as the brain. The central nervous system is vulnerable to cell damage via direct invasion or indirect virus-related effects leading to a neuroinflammatory response, processes possibly associated with a decrease in the activity of angiotensin II converting enzyme (ACE2), the canonical cell-surface receptor for SARS-CoV-2. This enzyme regulates neuroprotective and neuroimmunomodulatory functions and can neutralize both inflammation and oxidative stress generated at the cellular level. Furthermore, there is evidence of an association between vitamin D deficiency and predisposition to the development of severe forms of COVID-19, with its possible neurological and neuropsychiatric sequelae: vitamin D has the ability to down-modulate the effects of neuroinflammatory cytokines, among other anti-inflammatory/immunomodulatory effects, thus attenuating harmful consequences of COVID-19. This review critically analyzes current evidence supporting the notion that vitamin D may act as a neuroprotective and neuroreparative agent against the neurological sequelae of COVID-19.
114	Ce112		Rashudy F. Mahomedradja, Tessa O. van den Beukel, Maaike van den Bos, Steven Wang, Kirsten A. Kalverda, Birgit I. Lissenberg-Witte, Marianne A. Kuijvenhoven, Esther J. Nossent, Majon Muller, Kim C. E. Sigaloff, Jelle Tichelaar & Michiel A. van Agtmael	Prescribing errors in post - COVID-19 patients: prevalence, severity, and risk factors in patients visiting a post - COVID-19 outpatient clinic	https://doi.org/10.1186/s12873-022-00588-7	Published	05 March 2022	Study	https://bmcemergmed.biomedcentral.com/articles/10.1186/s12873-022-00588-7	An acute increase in the number of hospitalized patients has necessitated a rigorous reorganization of hospital care, thereby creating circumstances that previously have been identified as facilitating prescribing errors (PEs), e.g. a demanding work environment, a high turnover of doctors, and prescribing beyond expertise. Hospitalized COVID-19 patients may be at risk of PEs, potentially resulting in patient harm. We determined the prevalence, severity, and risk factors for PEs in post–COVID-19 patients, hospitalized during the first wave of COVID-19 in the Netherlands, 3 months after discharge. Methods This prospective observational cohort study recruited patients who visited a post-COVID-19 outpatient clinic of an academic hospital in the Netherlands, 3 months after COVID-19 hospitalization, between June 1 and October 1 2020. All patients with appointments were eligible for inclusion. The prevalence and severity of PEs were assessed in a multidisciplinary consensus meeting. Odds ratios (ORs) were calculated by univariate and multivariate analysis to identify independent risk factors for PEs. Results Ninety-eight patients were included, of whom 92% had ≥1 PE and 8% experienced medication-related harm requiring an immediate change in medication therapy to prevent detoriation. Overall, 68% of all identified PEs were made during or after the COVID-19 related hospitalization. Multivariate analyses identified ICU admission (OR 6.08, 95% CI 2.16–17.09) and a medical history of COPD / asthma (OR 5.36, 95% CI 1.34–21.5) as independent risk factors for PEs. Conclusions PEs occurred frequently during the SARS-CoV-2 pandemic. Patients admitted to an ICU during COVID-19 hospitalization or who had a medical history of COPD / asthma were at risk of PEs. These risk factors can be used to identify high-risk patients and to implement targeted interventions. Awareness of prescribing safely is crucial to prevent harm in this new patient population.
115	Ce113		Giusto, Elisa DO1; Asplund, Chad A. MD, MPH2	Persistent COVID and a Return to Sport	https://doi.org/10.1249/JSR.0000000000000943	Published	March 2022	Article	https://journals.lww.com/acsm-csmr/Fulltext/2022/03000/Persistent_COVID_and_a_Return_to_Sport.7.aspx	Coronavirus disease (COVID) has become a global pandemic that has widely impacted athletes at all levels of competition. For many athletes infected with COVID, the course is mild or asymptomatic, and most athletes are able to return to play in a matter of weeks. However, 10% to 15% of people infected with COVID will go on to have prolonged COVID symptoms that last for weeks to months and impact their ability to function and exercise. Not much is known about why certain people become “COVID long-haulers,” nor are there any predictive tools to predetermine who may have prolonged symptoms. However, many athletes will suffer from prolonged symptoms that may require further evaluation and may prolong their return to exercise, training, and competition. The purpose of this article is to discuss a framework in which sports medicine and primary care physicians can use to evaluate COVID long-haulers and help them return to sport.
116	Ce114		Salvi, Sundeep Santosh1,; Ghorpade, Deesha1; Dhoori, Sahajal2; Dhar, Raja3; Dumra, Harjit4; Chhajed, Prashant N5; Bhattacharya, Parathasarathi6; Rajan, Sujeet7; Talwar, Deepak8; Christopher, Devasahayam J9; Mohan, Murali10; Udwadia, Zarir11	Role of antifibrotic drugs in the management of post-COVID-19 interstitial lung disease: A review of literature and report from an expert working group	https://doi.org/10.4103/lungindia.lungindia_659_21	Published	March 2022	Review	https://journals.lww.com/lungindia/Fulltext/2022/03000/Role_of_antifibrotic_drugs_in_the_management_of.14.aspx	The EWG recommended that the term post-COVID-19 pulmonary fibrosis is not appropriate because the term “fibrosis” implies a “permanent” nature, which is not the case in most patients with post-COVID-19 fibrotic lung disease. Post-COVID-19 ILD is a more appropriate terminology. Although post-COVID-19 ILD is known to resolve spontaneously in most cases, it does not happen in all patients and is therefore not a completely reversible form of the disease. The burden of post-COVID-19 ILD is estimated to be high and grow with time. The EWG recommended that antifibrotic drugs may be used to prevent pulmonary fibrosis or on compassionate grounds in a specific group of patients. Continued presence of respiratory symptoms and hypoxia, despite 2–4 weeks of treatment with systemic steroids, or presence of honeycombing, traction bronchiectasis, and distorted lung architecture were strong indications to consider the use of antifibrotic drugs. The presence of a high computed tomography score but mild symptoms and normal oxygen saturation are not indications for starting antifibrotic drugs. Although the expert group agreed that antifibrotic drugs should be used in the early course of the disease, the timing varied from immediately (ICU admission) to up to 4 weeks. There was no consensus on how long the antifibrotic drugs be given for, although most members agreed to using them for between 4 and 8 weeks, but less than 6 months, although the duration needs to be decided on a case-to-case basis. Both pirfenidone and nintedanib were equally good, although one-third of the expert group members believed nintedanib was better. Although the anti-inflammatory effects of antifibrotic drugs are known, this was not perceived to be an advantage to use them during the early course of the disease, as the evidence to support this was lacking.
117	Ce115		Huan Chen1,2, Hangyu Shi1,3, Xitong Liu4, Tianheng Sun1,3, Jiani Wu1 and Zhishun Liu1	Effect of Pulmonary Rehabilitation for Patients With Post-COVID-19: A Systematic Review and Meta-Analysis	https://doi.org/10.3389/fmed.2022.837420	Published	21 February 2022	Systematic Review	https://www.frontiersin.org/articles/10.3389/fmed.2022.837420/full	Background: Evidence increasingly suggested that impaired respiratory function remained in about 40% of patients with coronavirus disease 2019 (COVID-19) after discharge, jeopardizing their activities of daily living and quality of life (QoL) in a long term. Pulmonary rehabilitation (PR) can improve exercise capacity and QoL in individuals with chronic lung disease; however, evidence on the effect of PR for patients with post-COIVD-19 was scarce. This study aimed to conduct a systematic review and meta-analysis to evaluate the effect of PR on lung impairment for patients with post-COVID-19 Results: Among 6,000 retrieved studies, 3 studies with 233 patients after COVID-19 were included. The pooled estimate of PR effect on 6-min walk test (6-MWT) (50.41, 95% CI 34.34 to 66.48; p < 0.0001) was in favor of the experiment group with clinical importance. It is found that PR could improve the symptom of dyspnea and QoL; however, its effect on pulmonary function test was inconsistent across studies. The risk of bias of included studies varied, with major concerns on the risk of blinding of participants and interventions performers. Conclusion: The review showed that PR could improve exercise capacity measured by 6-MWT among patients with mild-to-moderate lung impairment after COVID-19. The interpretation of effects on lung function, dyspnea, and QoL should be cautious due to inadequate and conflicting data reported across studies.
118	Ce116		Robert J. Trager, Elise C. Brewka, Christine M. Kaiser, Andrew J. Patterson, Jeffery A. Dusek	Acupuncture in multidisciplinary treatment of post-COVID-19 Syndrome: A Case Report	https://doi.org/10.21203/rs.3.rs-1421933/v1	pre-print	08 Mar, 2022	Case Report	https://www.researchsquare.com/article/rs-1421933/v1	Background: Post-COVID syndrome (PCS) is a complex, multisystem illness that may follow SARS-CoV-2/COVID-19 infection. As there is limited evidence for individual therapies and no singular treatment for PCS, guidelines endorse a multidisciplinary approach. This case describes a post-COVID patient benefiting from acupuncture within a comprehensive approach alongside symptom-titrated physical activity (STPA). Case: A 50-year-old woman presented upon Long-COVID Clinic referral to an outpatient hospital-affiliated acupuncturist with 8 months of fatigue, anosmia, chest pressure, palpitations, and other symptoms following mild assay-confirmed COVID-19. Prior/concurrent medical testing demonstrated multisystem-inflammatory involvement (pericardial effusion, thyroid dysfunction, elevated D-dimers). Cardiology/pulmonology cleared the patient for exercise to tolerance considering serious pathology was absent. The acupuncturist’s Traditional Chinese Medicine impression was of Qi deficiency of the Heart, Lung, Spleen, and Kidney. The patient received 7 sessions of scalp, auricular, and body acupuncture. Physical therapist (PT) led STPA began 1-week post-acupuncture, involving six 30-minute exercise sessions while monitoring heart rate, with as-needed rest. Results: Chest pressure and palpitations resolved after 1 acupuncture treatment. With 6 additional treatments spanning 9 weeks, overlapping with physical therapist-led SPTA, the patient completely recovered and resumed normal exercise habits. Conclusions: In this case, acupuncture appeared to facilitate PCS recovery. However, the independent effects of acupuncture are less clear given the concurrent STPA/exercise therapy, and should be explored using larger study designs. Acupuncture is an attractive potential PCS therapy, considering its holistic approach and that it may be added to a multidisciplinary, guideline-concordant regimen.
119	Ce117		Melitta A McNarry, Ronan M G Berg, James Shelley, Joanne Hudson, Zoe L Saynor, Jamie Duckers, Keir Lewis, Gwyneth A Davies, Kelly A Mackintosh	Inspiratory Muscle Training Enhances Recovery Post COVID-19: A Randomised Controlled Trial	https://doi.org/10.1183/13993003.03101-2021	Published	March 2, 2022	Study	https://erj.ersjournals.com/content/early/2022/02/24/13993003.03101-2021	Methods 281 adults (46.6±12.2 years; 88% female) recovering from self-reported COVID-19 (9.0±4.2 months post-acute infection) were randomised 4:1 to an 8-week IMT or a “usual care” wait list control arm. Health-related quality of life and breathlessness questionnaires (King's Brief Interstitial Lung Disease (KBILD) and Transition Dyspnoea Index (TDI)), respiratory muscle strength and fitness (Chester Step Test) were assessed pre- and post-intervention. The primary endpoint was KBILD total score, with the KBILD subdomains and TDI being key secondary outcomes. Results According to intention to treat (ITT), there was no difference between groups in KBILD total score post-intervention (Control: 59.5±12.4; IMT: 58.2±12.3; p<0.05) but IMT elicited clinically meaningful improvements in the KBILD subdomains of breathlessness (Control: 59.8±12.6; IMT: 62.2±16.2; p<0.05) and chest symptoms (Control: 59.2±18.7; IMT: 64.5±18.2; p<0.05), along with clinically meaningful improvements in breathlessness according to TDI (Control: 0.9±1.7 versus 2.0±2.0; p<0.05). IMT also improved respiratory muscle strength and estimated aerobic fitness. Conclusions IMT may represent an important home-based rehabilitation strategy for wider implementation as part of COVID-19 rehabilitative strategies. Given the diverse nature of long-COVID, further research is warranted on the individual responses to rehabilitation - the withdrawal rate herein highlights that no one strategy is likely to be appropriate for all.
120	Ce118		Felicia Ceban,Alexia Leber,Muhammad Youshay Jawad,Mathew Yu,Leanna M. W. Lui,Mehala Subramaniapillai,Joshua D. Di Vincenzo,Hartej Gill,Nelson B. Rodrigues,Bing Cao,Yena Lee,Kangguang Lin,Rodrigo B. Mansur,Roger Ho,Matthew J. Burke,Joshua D. Rosenblat &Roger S. McIntyre	Registered clinical trials investigating treatment of long COVID: a scoping review and recommendations for research	https://doi.org/10.1080/23744235.2022.2043560	Published	14 Mar 2022	Review	https://www.tandfonline.com/doi/abs/10.1080/23744235.2022.2043560	A considerable proportion of individuals report persistent, debilitating and disparate symptoms despite resolution of acute COVID-19 infection (i.e. long COVID). Numerous registered clinical trials investigating treatment of long COVID are expected to be completed in 2021–2022. The aim of this review is to provide a scope of the candidate treatments for long COVID. A synthesis of ongoing long COVID clinical trials can inform methodologic approaches for future studies and identify key research vistas. Methods Scoping searches were conducted on multiple national and international clinical trial registries. Interventional trials testing treatments for long COVID were selected. The search timeline was from database inception to 28 July 2021. Results This scoping review included 59 clinical trial registration records from 22 countries with a total projected enrolment of 6718. Considerable heterogeneity was exhibited amongst component records with respect to the characterization of long COVID (i.e. name, symptoms- including frequency, intensity, trajectory and duration- mode of ascertainment, and definition of acute phase). In addition, the majority of proposed interventions were non-pharmacological and either targeted multiple long COVID symptoms simultaneously, or focussed on treatment of respiratory/pulmonary sequelae. Multiple interventions targeted inflammation, as well as tissue oxygenation and cellular recovery, and several interventions were repurposed from analogous conditions. Conclusions The results of this scoping review investigating ongoing clinical trials testing candidate treatments for long COVID suggest that a greater degree of definitional stringency and homogeneity is needed insofar as the characterization of long COVID and inclusion/exclusion criteria.
121	Ce119		Eric Asaba,Michael Sy,Roi Charles Pineda,Rebecca Aldrich,Tetsuya Anzai,Peter Bontje,Urša Bratun,Lisette Farias,Maria Kapanadze,Lea Šuc &Elisabet Åkesson	Return to work after COVID-19: an international perspective	https://doi.org/10.1080/14473828.2022.2045819	Published	09 Mar 2022	Research Article	https://www.tandfonline.com/doi/full/10.1080/14473828.2022.2045819	Among individuals who have recovered from COVID-19 around the world, there is a substantial number who would need support in finding their way back to meaningful and productive work. The aims of this paper are to demonstrate the multitude of factors that shape return to work (RTW) practices across and within several countries, and argue for the need to explore RTW from an international perspective during an on-going pandemic, focusing on working age adults who have recovered from COVID-19. Conditions for RTW differ across countries. Occupational therapy has a central role in medical rehabilitation after injury and illness (including COVID-19), but the occupational therapy community has, to the best of our knowledge, yet to raise awareness and advance evidence regarding its role in post-COVID RTW processes. A robust evidence-based knowledge on RTW that can be utilised by occupational therapists during the present and future pandemics is needed.
122	Ce120		Irina Karosanidze 1,Ushangi Kiladze 1,Nino Kirtadze 1,Mikhail Giorgadze 1,Nana Amashukeli 1,Nino Parulava 1,Neli Iluridze 1,Nana Kikabidze 1,Nana Gudavadze 1,Lali Gelashvili 1,Vazha Koberidze 1,Eka Gigashvili 1,Natela Jajanidze 1,Naira Latsabidze 1,Nato Mamageishvili 2,Ramaz Shengelia 2,Areg Hovhannisyan 3 andAlexander Panossian	Efficacy of Adaptogens in Patients with Long COVID-19: A Randomized, Quadruple-Blind, Placebo-Controlled Trial	https://doi.org/10.3390/ph15030345	Published	11 March 2022	Study	https://www.mdpi.com/1424-8247/15/3/345/htm	Currently, no effective treatment of comorbid complications or COVID-19 long-haulers during convalescence is known. This randomized, quadruple-blind, placebo-controlled trial aimed to assess the efficacy of adaptogens on the recovery of patients with Long COVID symptoms. One hundred patients with confirmed positive SARS-CoV-2 test, discharged from COVID Hotel isolation, Intensive Care Unit (ICU), or Online Clinics, and who experienced at least three of nine Long COVID symptoms (fatigue, headache, respiratory insufficiency, cognitive performance, mood disorders, loss of smell, taste, and hair, sweatiness, cough, pain in joints, muscles, and chest) in the 30 days before randomization were included in the study of the efficacy of Chisan®/ADAPT-232 (a fixed combination of adaptogens Rhodiola, Eleutherococcus, and Schisandra) supplementation for two weeks. Chisan® decreased the duration of fatigue and pain for one and two days, respectively, in 50% of patients. The number of patients with lack of fatigue and pain symptoms was significantly less in the Chisan® treatment group than in the placebo group on Days 9 (39% vs. 57%, pain relief, p = 0.0019) and 11 (28% vs. 43%, relief of fatigue, * p = 0.0157). Significant relief of severity of all Long COVID symptoms over the time of treatment and the follow-up period was observed in both groups of patients, notably decreasing the level of anxiety and depression from mild and moderate to normal, as well as increasing cognitive performance in patients in the d2 test for attention and increasing their physical activity and workout (daily walk time). However, the significant difference between placebo and Chisan® treatment was observed only with a workout (daily walk time) and relieving respiratory insufficiency (cough). A clinical assessment of blood markers of the inflammatory response (C-reactive protein) and blood coagulation (D-dimer) did not reveal any significant difference over time between treatment groups except significantly lower IL-6 in the Chisan® treatment group. Furthermore, a significant difference between the placebo and Chisan® treatment was observed for creatinine: Chisan® significantly decreased blood creatinine compared to the placebo, suggesting prevention of renal failure progression in Long COVID. In this study, we, for the first time, demonstrate that adaptogens can increase physical performance in Long COVID and reduce the duration of fatigue and chronic pain. It also suggests that Chisan®/ADAPT-232 might be useful for preventing the progression of renal failure associated with increasing creatinine.
123	Ce121		Győző Szolnoky, MD, PhD, Alejandro José González-Ochoa, MD	Sulodexide: A Benefit for Cardiovascular Sequelae of Long COVID Patients?	https://doi.org/10.1177%2F10760296221084300	Published	March 25, 2022	Article	https://journals.sagepub.com/doi/10.1177/10760296221084300	The elaborate and precise review of Harry N. Magnani didactically demonstrates the complex pathophysiological aspects of coronavirus disease 2019 (COVID-19) emphasizing the roles of vascular endothelial dysfunction and coagulation cascade as key features of disease progression.1 Moreover, this article brings up that glycosaminoglycane (GAG) antithrombotics likely interfere with inflammatory and coagulation activity in an effective fashion.1 Thereafter this postulate has become advocated as the application of sulodexide (Vessel Due F; ALFASIGMA, Italy) (SDX), an unexpensive and orally administrable GAG antithrombotic drug reduced the necessity for both hospital admission and oxygen supplementation in the early phase of SARS-Cov-2 infection under a randomized placebo-controlled out-patient trial.2 Interestingly, these patients also showed lower serum levels of C-reactive protein (CRP) and D-dimer as markers of inflammation and prothrombotic state. Of note, instead of regularly recommended and prescribed 250 RLU twice-daily dose, the clinical trial applied the higher, 500 RLU twice-daily dosing regimen in which an antithrombotic effect was safely achieved in a clinical setting. Conversely, there is still a relatively little but emerging information “long hauler” sufferers who have recovered from the acute presentation and have a negative polymerase chain reaction (PCR) SARS-CoV-2 test yet still continue to have COVID-19 symptoms for weeks or even months later, or those who present cardiovascular complications weeks or months later.
124	Ce122		Aurelian ANGHELESCU Ali-Osman SAGLAM Simona STOICA Gelu ONOSE	Rehabilitation of severe neurological complications post SARS-CoV-2 infection	https://doi.org/10.12680/balneo.2022.491	Published	2022-03-18	Article	https://bioclima.ro/Journal/index.php/BRJ/article/view/82	Medical rehabilitation is a multi-professional / interdisciplinary process aimed at enhancing and restoring functional ability (activity and participation) and quality of life to people with impairments or disabilities. Rehabilitation is applied throughout the continuum of care. COVID-19 patients may develop a myriad of acute medical problems (linked to the virus per se, or as consequences of the invasive procedures), which can cause acute, post-acute and long-term consequences requiring rehabilitation. Information about short and long-term sequelae of COVID-19 indicate an increasing need for rehabilitation. The paper is focused on two main aspects: rehabilitation of the severe neurological disabilities that occurred during the acute phase and continuing in the chronic phase (i.e., different neurological sensory-motor and cognitive deficits secondary to stroke, encephalitis, seizures, encephalopathies). The other main issue is generated by the disruption of regular rehabilitation in people with neurological disabilities and chronic diseases (people living with sequels after stroke, Parkinson's disease, multiple sclerosis) due to quarantine, social isolation, movement restriction, and other healthcare systems ’disruptions. Methods Internet literature search (Lit Covid and PubMed) using the following keywords (Covid-19, Coronavirus, neurological complications, rehabilitation). During 2020-2021 were published 88 papers (in 2020 = 54, and in 2021= 54), with 21 reviewes (2020 = 15; 2021 = 8), and 2 systematic reviews, refearing neuroreabilitation in Covid-19 subacutre and long-term cases. Discussion REH-COVER Cochrane Rehabilitation WHO initiative (“Rapid Living Systematic Reviews Second Edition, called 2020”), contains the main cornerstones for a tailored rehabilitation programme, the best (current) available rehabilitation evidence on recovery interventions, for the patients living with sequelae of COVID-19. Conclusions More than two years since the outbreak of the COVID-19 pandemic, it is obvious that rehabilitation services play a crucial role in post-COVID recovery trajectories. A further achievement of research and evidence focussed on the clinical management, comprehensive treatments, and efficacy need to be targeted on short and long-term (neuro)-rehabilitation service models of care, for COVID-19 survivors.
125	Ce123		Annamária Bardelčíková,Andrej Miroššay,Jindřich Šoltýs,Ján Mojžiš	Therapeutic and prophylactic effect of flavonoids in post-COVID-19 therapy	https://doi.org/10.1002/ptr.7436	Published	18 March 2022	Article	https://onlinelibrary.wiley.com/doi/full/10.1002/ptr.7436	The high incidence of post-covid symptoms in humans confirms the need for effective treatment. Due to long-term complications across several disciplines, special treatment programs emerge for affected patients, emphasizing multidisciplinary care. For these reasons, we decided to look at current knowledge about possible long-term complications of COVID-19 disease and then present the effect of flavonoids, which could help alleviate or eliminate complications in humans after overcoming the COVID-19 infection. Based on articles published from 2003 to 2021, we summarize the flavonoids-based molecular mechanisms associated with the post-COVID-19 syndrome and simultaneously provide a complex view regarding their prophylactic and therapeutic potential. Review clearly sorts out the outcome of post-COVID-19 syndrome according particular body systems. The conclusion is that flavonoids play an important role in prevention of many diseases. We suggest that flavonoids as critical nutritional supplements, are suitable for the alleviation and shortening of the period associated with the post-COVID-19 syndrome. The most promising flavonoid with noteworthy therapeutic and prophylactic effect appears to be quercetin.
126	Ce124		JessieHawkinsChristyHiresLindseyKeenanElizabethDunne	Aromatherapy Blend of Thyme, Orange, Clove Bud, and Frankincense Boosts Energy Levels in Post-COVID-19 Female Patients: A Randomized, Double-Blinded, Placebo Controlled Clinical Trial	https://doi.org/10.1016/j.ctim.2022.102823	Published	25 March 2022	Study	https://www.sciencedirect.com/science/article/pii/S0965229922000255	Highlights •Fatigue is the most common long-haul symptom among women who have recovered from an acute COVID-19 infection. •This randomized, blinded, controlled clinical trial evaluated Longevity essential oil blend for energy boosting effects. •Two weeks of twice-daily inhalation resulted in significant improvements to energy levels as compared to a placebo group. •Aromatherapy provides a non-invasive approach to boosting quality of life among women who have recovered from COVID-19 but still experience low energy. Background A large proportion of individuals who have recovered from an acute COVID-19 infection continue to experience symptoms months later. Post-acute COVID-19 (long-haul COVID-19) can range from serious complications to quality of life symptoms such as fatigue or insomnia. The purpose of this study was to evaluate the potential for inhalation of essential oils to improve energy levels among otherwise healthy female survivors of acute COVID-19 who experience a lack of energy more than five months after recovery. This study was conducted in the United States in late 2021. Method This was a randomized double blind, placebo controlled trial to evaluate the potential for inhalation of Longevity™, a proprietary essential oil blend manufactured by Young Living Essential Oils (Lehi, Utah, USA), on energy levels among female survivors of COVID-19 who continue to experience fatigue more than 5 months recovery from the acute infection. Forty women were randomized to two groups: intervention and placebo. Both groups inhaled the assigned product twice daily for fourteen consecutive days. Fatigue scores were measured using the Multidimensional Fatigue Symptom Inventory (MFSI). Secondary outcomes included scores on each of the MFSI’s ten subscales. Results Individuals who inhaled the essential oil blend for 2 weeks had significantly lower fatigue scores after controlling for baseline scores, employment status, BMI, olfactory function, and time since diagnosis, with a large effect size (F (1,39) = 6.15, p =.020, partial eta squared =.198). Subscale analysis identified subscales of vigor, as well as global, behavioral, general, and mental fatigue as benefiting from the intervention. This study provides evidence that a proprietary aromatherapy blend can significantly improve energy levels among women who are experiencing fatigue after recovering from COVID-19.
127	Ce125		WeiZhenga1He-LiSunbcd1HongCaibcd1QingeZhange1Chee H.NgfYu-TaoXiangbcd	Antidepressants for COVID-19: A systematic review	https://doi.org/10.1016/j.jad.2022.03.059	Published	23 March 2022	Review	https://www.sciencedirect.com/science/article/pii/S0165032722003068	Highlights •Preliminary evidence showed that certain antidepressants appear to have potential as safe, inexpensive, and widely available medications that could improve COVID- 19-related outcomes such as mortality. •The anti-inflammatory properties of antidepressants may be associated with decreased levels of proinflammatory cytokines, including interleukin (IL)-10 and tumor necrosis factor alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1), which are related to the severity of COVID-19. Objective To systematically examine the efficacy and safety of antidepressants for the treatment of coronavirus disease 2019 (COVID-19). Methods A systematic search was performed independently by two researchers based on Chinese Journal Net, WanFang, PsycINFO, Cochrane Library, PubMed, and EMBASE. Results Seven studies (n = 92,947) including three retrospective studies (n = 91,083), two randomized clinical trials (RCTs, n = 1649), two prospective cohort study (n = 215) involving (n = 92,947) patients with COVID-19 were examined. For RCTs, fluvoxamine outperformed placebo in reducing clinical deterioration and hospitalisation for COVID-19 patients. For retrospective studies, antidepressants (2 studies) and fluoxetine (1 study) possibly reduced the risk of mortality in patients with COVID-19. Results from two remaining studies supported the superiority of fluvoxamine in reducing risk of mortality in COVID-19 patients. The two RCTs that examined the safety of fluvoxamine for COVID-19 patients found inconsistent results but no significant group differences in the dropout rate. Conclusion This systematic review found emerging evidence for fluvoxamine in reducing the risk of mortality and hospitalisation in COVID-19 patients, but inconsistent evidence for the safety of fluvoxamine in COVID-19 patients. More studies are needed to determine the efficacy and safety of antidepressants for the treatment of COVID-19.
128	Ce126		ŞevkiAdemaVolkanEyupogluaIbrahim M.IbrahimbIqraSarfrazcAzharRasulcMuhammadAlidAbdo A.Elfikyb	Multidimensional in silico strategy for identification of natural polyphenols-based SARS-CoV-2 main protease (Mpro) inhibitors to unveil a hope against COVID-19	https://doi.org/10.1016/j.compbiomed.2022.105452	Published	29 March 2022	Study	https://www.sciencedirect.com/science/article/pii/S001048252200244X	Highlights •The phenolics were investigated by molecular docking, quantum mechanic and molecular dynamic over SARS-CoV-2 Mpro. •All phenolics that have good binding potency are components of dietary foods can be used for therapeutics against COVID-19. •Diosmin, Rutin, Hesperidin, and Apiin are available phenolics in nature and have inhibition potential SARS-CoV-2 Mpro . SARS-CoV-2, a rapidly spreading new strain of human coronavirus, has affected almost all the countries around the world. The lack of specific drugs against SARS-CoV-2 is a significant hurdle towards the successful treatment of COVID-19. Thus, there is an urgent need to boost up research for the development of effective therapeutics against COVID-19. In the current study, we investigated the efficacy of 81 medicinal plant-based bioactive compounds against SARS-CoV-2 Mpro by using various in silico techniques. The interaction affinities of polyphenolic compounds towards SARS-CoV-2 Mpro was assessed via intramolecular (by Quantum Mechanic), intermolecular (by Molecular Docking), and spatial (by Molecular Dynamic) simulations. Our obtained result demonstrate that Hesperidin, rutin, diosmin, and apiin are most effective compounds agents against SARS-CoV-2 Mpro as compared to Nelfinavir (positive control). This study will hopefully pave a way for advanced experimental research to evaluate the in vitro and in vivo efficacy of these compounds for the treatment of COVID-19.
129	Ce127		TheresaMaitz1DominicParfianowicz1AshleyVojtek1YasothaRajeswaran2Apurva V.Vyas2RahulGupta	COVID-19 Cardiovascular Connection: A Review of Cardiac Manifestations in COVID-19 Infection and Treatment Modalities	https://doi.org/10.1016/j.cpcardiol.2022.101186	Published	26 March 2022	Review	https://www.sciencedirect.com/science/article/pii/S0146280622000834	The coronavirus pandemic has crippled healthcare system since its outbreak in 2020, and has led to over 2.6 million deaths worldwide. Clinical manifestations of COVID-19 range from asymptomatic carrier to severe pneumonia, to life-threatening acute respiratory distress syndrome (ARDS). The early efforts of the pandemic surrounded treating the pulmonary component of COVID-19, however, there has been robust data surrounding the cardiac complications associated with the virus. This is suspected to be from a marked inflammatory response as well as direct viral injury. Arrhythmias, acute myocardial injury, myocarditis, cardiomyopathy, thrombosis, and myocardial fibrosis are some of the observed cardiac complications. There have been high morbidity and mortality rates in those affected by cardiac conditions associated with COVID-19. Additionally, there have been documented cases of patients presenting with typical cardiac symptoms who are subsequently discovered to have COVID-19 infection. In those who test positive for COVID-19, clinical awareness of the significant cardiac components of the virus is pertinent to prevent morbidity and mortality. Unfortunately, treatment and preventative measures developed for COVID-19 have been shown to be also be associated with cardiac complications. This is a comprehensive review of the cardiac complications and manifestations of COVID-19 infection in addition to those associated with both treatment and vaccination.
130	Ce128		Lamyae Benzakour 1,* andGuido Bondolfi 1,2	Update of the Potential Treatments for Psychiatric and Neuropsychiatric Symptoms in the Context of the Post-COVID-19 Condition: Still a Lot of Suffering and Many More Things to Learn	https://doi.org/10.3390/traumacare2020011	Published	24 March 2022	Review	https://www.mdpi.com/2673-866X/2/2/11/htm	The World Health Organization (WHO) has defined a post-COVID-19 condition. Some of these symptoms can be categorized as psychiatric long COVID-19 if they appeared in the aftermath of COVID-19, including depression, anxiety, post-traumatic stress disorder, somatic symptoms disorders such as hyperventilation syndrome, fatigue, cognitive and sleep disorders. Psychiatric and neuropsychiatric post-COVID-19 present mental health specialists with difficult challenges because of its complexity and the multiple ways in which it integrates into a singular somatic context. Methods: We conducted a systematic research paradigm from SARS-CoV-2 using LitCOVID and Web of Science to search management strategies and potential treatments for psychiatric post-COVID-19 symptoms. Results: Management strategies must be based on a multidisciplinary approach to promote the global evaluation of psychiatric and physical symptoms, systematic detection and prevention. Selective serotonin reuptake inhibitors appear to be the best choice to treat post-COVID-19 depression and anxiety disorders, and tofisopam could be helpful for anxiety. Cognitive behavioral therapy techniques adjusted to post-COVID-19 fatigue, functional remediation, extracorporeal apheresis, transcutaneous auricular vagus nerve stimulation, monoclonal antibodies, flavonoids, oxytocin or L-carnitine all represent hypothetical therapeutic avenues that remain to be evaluated in clinical trials. Conclusions: Psychiatric and neuropsychiatric post-COVID-19 symptoms occur frequently and are debilitating. Attention should be paid to this condition and studies undertaken to specify the effective treatments.
131	Ce129		Claudia Cristina Ferreira Vasconcelos, Mariana Beiral Hammerle, Deborah Santos Sales, Fernanda Cristina Rueda Lopes, Patricia Gomes Pinheiro, Elisa Gutman Gouvea, Manuella Caroline Dutra Frazão Alves, Tayane Vasconcellos Pereira, Sergio Luis Schmidt, Regina Maria Papais Alvarenga & Karina Lebeis Pires	Post-COVID-19 olfactory dysfunction: carbamazepine as a treatment option in a series of cases	https://doi.org/10.1007/s13365-022-01066-3	Published	02 April 2022	Case Series	https://link.springer.com/article/10.1007/s13365-022-01066-3	Olfactory dysfunction is reported frequently in patients with coronavirus disease 2019. However, an effective treatment for this dysfunction is unknown. The present study evaluated carbamazepine as a treatment option for olfactory dysfunction based on its use in cases of neuralgia, especially of the V cranial nerve. The study included 10 patients with coronavirus disease with olfactory complaints who were part of a cohort of 172 coronavirus disease patients monitored for late neurological manifestations. Carbamazepine was administered for 11 weeks. The adverse effects reported were drowsiness (9/10) and dizziness (2/10); 9 of the 10 patients reported improved olfactory function after carbamazepine treatment. While the role of carbamazepine in the control of post-coronavirus disease olfactory dysfunction could not be confirmed in this study, the satisfactory response observed in most patients in this series suggests that further studies are warranted.
132	Ce130		Florent Besnier 1,2 ,Béatrice Bérubé 1,3,4,Jacques Malo 1,2,Christine Gagnon 1,Catherine-Alexandra Grégoire 1,Martin Juneau 1,2,François Simard 1,2,Philippe L’Allier 1,2,Anil Nigam 1,2,Josep Iglésies-Grau 1,2,Thomas Vincent 1,Deborah Talamonti 1 ,Emma Gabrielle Dupuy 1,2,Hânieh Mohammadi 1 ,Mathieu Gayda 1,2,* andLouis Bherer 1,2,4	Cardiopulmonary Rehabilitation in Long-COVID-19 Patients with Persistent Breathlessness and Fatigue: The COVID-Rehab Study	https://doi.org/10.3390/ijerph19074133	Published	31 March 2022	Protocol	https://www.mdpi.com/1660-4601/19/7/4133/htm	Background: Cardiopulmonary and brain functions are frequently impaired after COVID-19 infection. Exercise rehabilitation could have a major impact on the healing process of patients affected by long COVID-19. (2) Methods: The COVID-Rehab study will investigate the effectiveness of an eight-week cardiopulmonary rehabilitation program on cardiorespiratory fitness (V˙O2max) in long-COVID-19 individuals. Secondary objectives will include functional capacity, quality of life, perceived stress, sleep quality (questionnaires), respiratory capacity (spirometry test), coagulation, inflammatory and oxidative-stress profile (blood draw), cognition (neuropsychological tests), neurovascular coupling and pulsatility (fNIRS). The COVID-Rehab project was a randomised clinical trial with two intervention arms (1:1 ratio) that will be blindly evaluated. It will recruit a total of 40 individuals: (1) rehabilitation: centre-based exercise-training program (eight weeks, three times per week); (2) control: individuals will have to maintain their daily habits. (3) Conclusions: Currently, there are no specific rehabilitation guidelines for long-COVID-19 patients, but preliminary studies show encouraging results. Clinicaltrials.gov (NCT05035628).
133	Ce131	PESE	Roisin M. Cahalan, PhD, MA, BSc,corresponding author1,2 Ciara Meade, MA,3 and Sarah Mockler2,4	SingStrong—A singing and breathing retraining intervention for respiratory and other common symptoms of long COVID: A pilot study	https://dx.doi.org/10.29390%2Fcjrt-2021-074	Published	2022 Mar 9	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8906430/	Background Management of Long COVID (LC) is hugely challenging for clinicians. This pilot study evaluated a breathing retraining and singing programme (SingStrong for LC) to address common LC symptoms. The study hypothesized that this intervention would improve symptoms impacting disordered breathing and participant wellbeing. Methods The 10-week, bi-weekly online programme was comprised of a 45-min class of mindfulness, breathing retraining, vocal exercises, and singing. Sessions were recorded for non-attenders and conducted by a trained vocal coach experienced in respiratory cohorts. Persons with a confirmed COVID-19 diagnosis and persisting symptoms were invited to participate. Demographic and COVID-19 data were collected, and the DePaul Symptom Questionnaire Short Form (DSQ- SF) and COVID-19 Yorkshire Rehab Screen questionnaires were administered. Post-intervention focus groups were also conducted. Results Of 27 (F = 23(85%)) participants recruited, data from 21 who completed at least 10 (50%) classes were analysed. Participants showed significant pre–post-intervention improvements in all breathlessness symptoms (at rest: P < 0.001; dressing: P = 0.01; stairs: P < 0.001), fatigue (P = 0.03), usual activities (P = 0.04), pain/disability (P = 0.03), voice quality (P = 0.01), and communication/cognition (P = 0.04). Pre–post number of instances meeting DSQ-SF criteria for myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) decreased by a net of nine cases (14.3%). No association between COVID-19 hospitalisation status and diagnosis of ME/CFS was identified. Qualitative feedback from eight participants was overwhelmingly positive with all reporting improvements in breathing and general well-being. Conclusion The SingStrong programme shows promise as a viable treatment option for LC sufferers. Future studies are required to further investigate the efficacy of this intervention.
134	Ce132		Eren Ogut &Kutay Armagan	Evaluation of the Potential Impact of Medical Ozone Therapy on Covid-19: A Review Study	https://doi.org/10.1080/01919512.2022.2065242	Published	19 Apr 2022	Review	https://www.tandfonline.com/doi/abs/10.1080/01919512.2022.2065242	The key objective of this review is to summarize the available information on the effects of medical ozone therapy in COVID-19 and its therapeutic potentials. An electronic literature search was performed using the PubMed, Cochrane, Web of Science, Science Direct, Scopus, Google Scholar, Ovid Medline, J Stage and China Knowledge Resource Integrated (CNKI) databases to September 2021. In total, 1833 articles were identified. Twenty-six articles were selected out of 667 articles. The most preferred and effective administration method for COVID-19 is major autohemotherapy (MAHT), followed by rectal insufflation and minor autohemotherapy (MiAHT). However, other methods, including ozonized oils and ozonated saline, are also used for COVID-19 due to ease of application, prophylactic and therapeutic effects. In studies, 850 patients were treated with ozone therapy as a complementary treatment. The effectiveness of ozone concentrations below 20 μg/mL or above 45 μg/mL for MAHT are yet to be proven in the COVID-19 patient population, and may be less effective. Complementary ozone therapy combined with antivirals increase the activity of antivirals against COVID-19. Large-scale, multicenter randomized clinical trials are needed to be able to isolate the effect of ozone therapy where the clinical variables are distributed more homogeneously. Also, an extended period of follow-up of COVID-19 patients may give more accurate indications about the effectiveness of the treatment in the long term.
135	Ce133		Elnaz Khani & Taher Entezari-Maleki	Fluvoxamine and long COVID-19; a new role for sigma-1 receptor (S1R) agonists	https://doi.org/10.1038/s41380-022-01545-3	Published	06 April 2022	Article	https://www.nature.com/articles/s41380-022-01545-3	We read with interest Hashimoto et al. study about mechanisms of action of fluvoxamine in COVID-19 [1]. As they mentioned, fluvoxamine offers some key mechanisms against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It inhibits acid sphingomyelinase (ASM) activity, the formation of ceramide-enriched membrane domain, and attenuates SARS-CoV-2 cell entry. Interestingly, fluvoxamine acts as a potent sigma-1 receptor (S1R) agonist that may decrease SARS-CoV-2 replication and subsequent endoplasmic reticulum (ER) stress and inflammation. Based on the evidence, S1R agonists prevent inositol requiring enzyme 1α (IRE1) from splicing of mRNA that encodes X-box binding protein-1 (XBP-1). Hence S1R-mediated reduction in XBP1 activation modulates the ER stress response pathway and reduces cytokine storm [2]. XBP1 plays a major role in the reactivation of the Epstein-Barr virus (EBV). It has been indicated that ER stress and unfolded-protein response induce the expression of lytic EBV gene in EBV-infected cells, suggesting a pathway in virus-associated complications [3, 4]. Gold et al. reported that ~70% of patients with long COVID-19 versus 10% of the control group were positive for EBV reactivation according to the early antigen-diffuse immunoglobulin G or EBV viral capsid antigen immunoglobulin M [5]. It has been suggested that more than 50% of patients who recovered from COVID-19 experienced long-term symptoms such as headache, fatigue, anxiety, depression, and cognitive features within 6 months [6]. These findings suggest that most of the long COVID-19 symptoms following the recovery from the acute disease might not be directly affected by SARS-CoV-2 but probably result from COVID-19-associated inflammation and EBV reactivation. Recently, infection with EBV was suggested as the possible leading cause for multiple sclerosis (MS), in which inflammation plays a key role [7]. Given the link between EBV replication and XBP1 activation and modulatory effects of S1R agonists in XBP1 and ER stress response, we proposed that fluvoxamine might have beneficial effects in reducing long-term symptoms of COVID-19. However, further clinical studies are required to confirm this hypothesis.
136	Ce134		Yaeko Hashimoto, Takuji Suzuki & Kenji Hashimoto	Comments to “Fluvoxamine and long COVID-19: a new role for sigma-1 receptor (S1R) agonists” by Khani and Entezari-Maleki	https://doi.org/10.1038/s41380-022-01546-2	Published	06 April 2022	Comment	https://www.nature.com/articles/s41380-022-01546-2	The authors suggest that most of long-lasting symptoms in COVID-19 survivors following the recovery from SARS-CoV-2 infection might not be directly affected by the virus but probably result from SARS-CoV-2-associated inflammation and EBV reactivation [4]. In the issue, Khani and Entezari-Maleki proposed that fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), may be a new therapeutic drug for long-term consequences of COVID-19 survivors [5]. Fluvoxamine has been demonstrated to prevent clinical deterioration in early-stage subjects with COVID-19 [6]. In addition of serotonin transporter inhibition, sigma-1 receptor chaperone in the endoplasmic reticulum (ER) and acid sphingomyelinase might play a role in the mechanisms of beneficial action of fluvoxamine for patients with SARS-CoV-2 infection [6,7,8]. It is also reported that sigma-1 receptor agonists such as fluvoxamine could produce potent anti-inflammatory actions by the prevention of inositol requiring enzyme 1α (IRE1) and X-box binding protein-1 (XBP-1) pathway [9]. Collectively, it is likely that sigma-1 receptor agonists such as fluvoxamine could produce potent anti-inflammatory effects through sigma-1 receptor/IRE1/XBP-1 pathway in the ER [6,7,8,9]. Among the SSRIs, fluvoxamine was the most potent at sigma-1 receptor in the brain [6,7,8]. Given the link between EBV reactivation and XBP-1 [10], it is possible that the potent sigma-1 receptor agonist fluvoxamine may have beneficial effects for long-term consequences in COVID-19 survivors through sigma-1 receptor/IRE1/XBP-1 pathway [4]. Therefore, it is of great interest to examine whether fluvoxamine can improve long-term sequelae in COVID-19 survivors.
137	Ce135		Chun-PaiYangabChing-MaoChangcdeCheng-ChiaYangfCarmine M.PariantegKuan-PinSughij	Long COVID and long chain fatty acids (LCFAs): Psychoneuroimmunity implication of omega-3 LCFAs in delayed consequences of COVID-19	https://doi.org/10.1016/j.bbi.2022.04.001	Published	8 April 2022	Review	https://www.sciencedirect.com/science/article/pii/S0889159122000952	Highlights •SARS-CoV-2 has led to the lasting pandemic of COVID-19 and the post-acute phase sequelae of heterogeneous negative impacts in multiple systems known as the “long COVID.” •The mechanisms of neuropsychiatric complications of long COVID damages from direct CNS viral involvement, unresolved systemic inflammation and oxidative stress, maladaptation of the renin-angiotensin-aldosterone system and coagulation system, dysregulated immunity, the dysfunction of neurotransmitters and HPA axis, and the psychosocial stress imposed by societal changes in response to this pandemic. •Long chain omega-3 PUFAs might have favorable effects on immunity, inflammation, oxidative stress and psychoneuroimmunity at different stages of SARS-CoV-2 infection. •Omega-3 PUFAs and their metabolites, including specialized pro-resolvin mediators, accelerate the process of cleansing chronic inflammation, altering the HPA axis, modulating neurotransmission via lipid rafts and restoring tissue homeostasis, and therefore offer a promising strategy for Long COVID. Abstract The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the lasting pandemic of coronavirus disease 2019 (COVID-19) and the post-acute phase sequelae of heterogeneous negative impacts in multiple systems known as the “long COVID.” The mechanisms of neuropsychiatric complications of long COVID are multifactorial, including long-term tissue damages from direct CNS viral involvement, unresolved systemic inflammation and oxidative stress, maladaptation of the renin-angiotensin-aldosterone system and coagulation system, dysregulated immunity, the dysfunction of neurotransmitters and hypothalamus–pituitaryadrenal (HPA) axis, and the psychosocial stress imposed by societal changes in response to this pandemic. The strength of safety, well-acceptance, and accumulating scientific evidence has now afforded nutritional medicine a place in the mainstream of neuropsychiatric intervention and prophylaxis. Long chain omega-3 polyunsaturated fatty acids (omega-3 or n-3 PUFAs) might have favorable effects on immunity, inflammation, oxidative stress and psychoneuroimmunity at different stages of SARS-CoV-2 infection. Omega-3 PUFAs, particularly EPA, have shown effects in treating mood and neurocognitive disorders by reducing pro-inflammatory cytokines, altering the HPA axis, and modulating neurotransmission via lipid rafts. In addition, omega-3 PUFAs and their metabolites, including specialized pro-resolvin mediators, accelerate the process of cleansing chronic inflammation and restoring tissue homeostasis, and therefore offer a promising strategy for Long COVID. In this article, we explore in a systematic review the putative molecular mechanisms by which omega-3 PUFAs and their metabolites counteract the negative effects of long COVID on the brain, behavior, and immunity.
138	Ce136		Carson, Erin PharmD*; Hemenway, Alice N. PharmD, MPH	A Scoping Review of Pharmacological Management of Postacute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 Infection in 2021	https://doi.org/10.1097/MJT.0000000000001486	Published	April 1, 2022	Review	https://journals.lww.com/americantherapeutics/Abstract/9900/A_Scoping_Review_of_Pharmacological_Management_of.8.aspx	Background: Postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC), or long-COVID, are signs and symptoms that persist after the acute phase of Coronavirus disease 2019 infection has passed. PASC is newly recognized, and research is ongoing to answer questions about pathology, symptoms, diagnosis, and optimal treatment. Areas of Uncertainty: Use of pharmacologic treatment for symptoms of PASC is currently evolving. This scoping review aims to assess medical literature for any evidence supporting or refuting use of any medications to specifically treat PASC. Data Sources: PubMed, EMBASE, Web of Science, and gray literature sources were searched for any study of medication use for PASC. Studies were included if they described medication use in patients with PASC. There were no exclusion criteria based on study type or if results were reported. Studies were divided into completed works and ongoing research. Results: Fifty-two records were included in final analysis from an initial 3524 records found, including 2 randomized controlled trials, 7 prospective, open-label or observational studies, 14 case reports or case series, 1 survey, 1 correspondence, 1 retrospective analysis, and 26 studies in progress. Seven of the 26 completed works investigate ivabradine or beta-blockers, whereas 7 investigate local or systemic corticosteroids. Three investigate multi-ingredient nutritional supplements. The other 9 completed works as well as the 26 studies in progress investigate a wide variety of other treatments including drugs in development, drugs used for other conditions, herbals, supplements, and vitamins. Conclusions: There is limited, but evolving, literature on medication treatment for PASC. Providers who opt to use pharmacologic therapy for PASC need to be vigilant in their knowledge of these evolving data.
139	Ce137		H. Heald, Adriana,b; Perrin, Raymonda; Walther, Andreasc; Stedman, Miked; Hann, Marke; Mukherjee, Annicea; Riste, Lisaa,e,f	Reducing fatigue-related symptoms in Long COVID-19: a preliminary report of a lymphatic drainage intervention	https://doi.org/10.1097/XCE.0000000000000261	Published	April 12, 2022	Study	https://journals.lww.com/cardiovascularendocrinology/Fulltext/2022/06000/Reducing_fatigue_related_symptoms_in_Long.3.aspx?context=LatestArticles	Introduction In the early days of the first global wave of the COVID-19 pandemic, the potential for a postviral syndrome to manifest following COVID-19 infection was first recognized. Here, we present an analysis of a case series of the first 20 patients’ data collected in clinical practice to evaluate the potential of a possible alternative treatment for Long COVID. Methods Face-to-face treatment sessions with Perrin technique practitioners occurred weekly involving effleurage/other manual articulatory techniques. The individuals being treated also undertook daily self-massage along with gentle mobility exercises. Patients recorded symptom severity using the self-report 54-item profile of fatigue-related states (PFRS) before and after treatment. Results The mean age of male patients was 41.8 years (range, 29–53 years), and for female patients, 39.3 years (range, 28–50 years). None of the participants had a prior diagnosis of chronic fatigue syndrome, and all were new attendees to the clinics at the time of initial assessment. The average number of treatment sessions was 9.7 in men and 9.4 in women. The reduction in PFRS scores was 45% in men and 52% in women. The highest subscale scores on average were for fatigue, with the lowest for somatic symptoms. All subscale scores showed, on average, a similar reduction of approximately 50% postintervention, with the reduction in score relating to a decrease in the severity of symptoms. Conclusion Our findings suggest that a specific manual lymphatic drainage intervention may help to reduce fatigue symptoms related to Long COVID. Perhaps preventing acute symptoms through early intervention.
140	Ce138		Arthur Melkumyants 1,2,*,Lyudmila Buryachkovskaya 1,Nikita Lomakin 3,Olga Antonova 1,Julia Docenko 1,Vladimir Ermishkin 1 andVictor Serebruany 4	Effect of Sulodexide on Circulating Blood Cells in Patients with Mild COVID-19	https://doi.org/10.3390/jcm11071995	Published	2 April 2022	Study	https://www.mdpi.com/2077-0383/11/7/1995/htm	Background. Despite the fact that COVID-19 usually manifests with severe pneumonia, there is a growing body of evidence that life-threatening multiorgan damage is caused by vascular and hemostatic abnormalities. Since there is no established therapy, assessing antithrombotics is indeed important. Sulodexide, a compound derived from porcine intestinal mucosa is a mixture of fast-moving heparin fraction (80%) and dermatan sulfate (20%), is approved in Europe and currently in trials for COVID-19 indication. Methods. This single-center, prospective, observational study included 28 patients with mild COVID-19 hospitalized in the Central Clinical Hospital of the Presidential Administration of the Russian Federation. Patients in the control group (n = 14) were treated using routine therapy according to current guidelines, while patients in the experimental group (n = 14) had the routine treatment supplemented with daily intravenous injections of sulodexide in 600-unit doses. Scanning electron microscopy was utilized to examine the blood specimens derived from the cubital vein at admission and at 10 days after hospitalization, which was approximately the average duration of patients’ treatment in the hospital (11.6 ± 0.4 days). Results. Sulodexide significantly (by 40%) diminished the score of circulating endothelial cells, potentially indicating its antiviral endothelium-protective properties. It also prevented the extra activation of the platelets and the formation of erythrocytic sludges. Among patients in the control group, the share of activated platelets rose from 37 ± 5% to 45 ± 6% (p = 0.04) over the course of the study period, whereas among patients in the experimental group, the share of activated platelets remained practically unchanged (43 ± 6% vs. 38 ± 4%, p = 0.22). The score of erythrocytic sludges in the control group remained practically the same (4.8 ± 1.1 at admission vs. 3.9 ± 0.9 after 10 days, p = 0.67), whereas in the experimental group, it significantly decreased (from 5.7 ± 1.7 to 2.4 ± 0.9, p = 0.03). Conclusions. Sulodexide is able to defend endothelium, normalize blood, and, seemingly, prevent thrombosis. Therefore, it may be considered as a promising and effective agent for the treatment of patients with mild COVID-19. Broader randomized trials are needed to assess whether the observed findings will transform into sustained long-term clinical benefit.
141	Ce139		Norman B Gaylis, Angela Ritter, Scott A Kelly, Nader Z Pourhassan, Meenakshi Tiwary, Jonah B Sacha, Scott G Hansen, Christopher Recknor, Otto O Yang	Reduced Cell Surface Levels of C-C Chemokine Receptor 5 and Immunosuppression in Long Coronavirus Disease 2019 Syndrome	https://doi.org/10.1093/cid/ciac226	Published	22 April 2022	Study	https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciac226/6572226	In an exploratory trial treating “long COVID” with the CCR5-binding antibody leronlimab, we observed significantly increased blood cell surface CCR5 in treated symptomatic responders but not in nonresponders or placebo-treated participants. These findings suggest an unexpected mechanism of abnormal immune downmodulation in some persons that is normalized by leronlimab. Clinical Trials Registration. NCT04678830.
142	Ce140		Hannah L.S. Day	Exploring Online Peer Support Groups for Adults Experiencing Long COVID in the United Kingdom: Qualitative Interview Study	https://doi.org/10.2196/37674	Published	Apr 25, 2022	Study	https://preprints.jmir.org/preprint/37674/accepted	Background: Long COVID is an emerging public health concern. A growing number of individuals are experiencing prolonged multifaceted health challenges and accompanying social impacts after COVID-19 infections. Support services in the United Kingdom remain insufficient and fraught with complexity. Responding to persistent gaps in care, patients joined forces in online peer support groups. However, little is known about how these groups impact long COVID patients and their lived experiences of the condition. Objective: The aim of this study is to explore the roles that online peer support groups take on, and the impact they have on patients experiencing and recovering from long COVID in the United Kingdom. In doing so, this study aims to identify ways to inform future long COVID care, including online peer support and broader long COVID care structures. Methods: I conducted 11 semi-structured interviews virtually on Zoom in July 2021. Participants had long COVID, were UK-based, and used long COVID online peer support groups. Topics discussed in interviews included what led participants to these groups, experiences within them, and feelings about the roles that the groups took on. I analyzed the results through manually conducting thematic analysis. Results: Long COVID online peer support groups had numerous roles, significantly impacting users. I identified 7 themes and 19 subthemes through thematic analysis. The identified themes were: (1) professional support, (2) societal awareness, (3) diversity of groups, (4) group format, (5) social connections, (6) engagement behavior, and (7) desired changes. Given the void of professional support, those experiencing long COVID gained some benefit from these groups. However, participants emphasized notable concerns about the all-encompassing roles these groups embody and speculated over potential improvements. Conclusions: If employed appropriately, online peer support groups could be immensely beneficial for patient wellbeing, beyond simply filling gaps in long COVID care. However, it appears many groups take on more than they can manage and become potentially harmful. Through prioritizing patient voices, long COVID care could be restructured to maximize peer support’s benefits within broader care structures.
143	Ce141		Kazuaki Imai 1,Takafumi Yamano 2,Soichiro Nishi 3,Ryushiro Nishi 3,Tatsuro Nishi 3,4,Hiroaki Tanaka 5,Toshiyuki Tsunoda 6,Shohei Yoshimoto 7,Ayaki Tanaka 8,Kenji Hiromatsu 9ORCID,Senji Shirasawa 6,Takashi Nakagawa 10 andKensuke Nishi 2,3,4,*	Epipharyngeal Abrasive Therapy (EAT) Has Potential as a Novel Method for Long COVID Treatment	https://doi.org/10.3390/v14050907	Published	27 April 2022	Study	https://www.mdpi.com/1999-4915/14/5/907/htm	COVID-19 often causes sequelae after initial recovery, referred to collectively as long COVID. Long COVID is considered to be caused by the persistence of chronic inflammation after acute COVID-19 infection. We found that all long COVID patients had residual inflammation in the epipharynx, an important site of coronavirus replication, and some long COVID symptoms are similar to those associated with chronic epipharyngitis. Epipharyngeal abrasive therapy (EAT) is a treatment for chronic epipharyngitis in Japan that involves applying zinc chloride as an anti-inflammatory agent to the epipharyngeal mucosa. In this study, we evaluated the efficacy of EAT for the treatment of long COVID. The subjects in this study were 58 patients with long COVID who were treated with EAT in the outpatient department once a week for one month (mean age = 38.4 ± 12.9 years). The intensities of fatigue, headache, and attention disorder, which are reported as frequent symptoms of long COVID, were assessed before and after EAT using the visual analog scale (VAS). EAT reduced inflammation in the epipharynx and significantly improved the intensity of fatigue, headache, and attention disorder, which may be related to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These results suggest that EAT has potential as a novel method for long COVID treatment.
144	Ce142		Bin Wang, Lei Zhang, Yongqiang Wang, Tong Dai, Ziran Qin, Fangfang Zhou & Long Zhang	Alterations in microbiota of patients with COVID-19: potential mechanisms and therapeutic interventions	https://doi.org/10.1038/s41392-022-00986-0	Published	29 April 2022	Review	https://www.nature.com/articles/s41392-022-00986-0	The global coronavirus disease 2019 (COVID-19) pandemic is currently ongoing. It is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A high proportion of COVID-19 patients exhibit gastrointestinal manifestations such as diarrhea, nausea, or vomiting. Moreover, the respiratory and gastrointestinal tracts are the primary habitats of human microbiota and targets for SARS-CoV-2 infection as they express angiotensin-converting enzyme-2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) at high levels. There is accumulating evidence that the microbiota are significantly altered in patients with COVID-19 and post-acute COVID-19 syndrome (PACS). Microbiota are powerful immunomodulatory factors in various human diseases, such as diabetes, obesity, cancers, ulcerative colitis, Crohn’s disease, and certain viral infections. In the present review, we explore the associations between host microbiota and COVID-19 in terms of their clinical relevance. Microbiota-derived metabolites or components are the main mediators of microbiota-host interactions that influence host immunity. Hence, we discuss the potential mechanisms by which microbiota-derived metabolites or components modulate the host immune responses to SARS-CoV-2 infection. Finally, we review and discuss a variety of possible microbiota-based prophylaxes and therapies for COVID-19 and PACS, including fecal microbiota transplantation (FMT), probiotics, prebiotics, microbiota-derived metabolites, and engineered symbiotic bacteria. This treatment strategy could modulate host microbiota and mitigate virus-induced inflammation.
145	Ce143		Eric Finkelstein, PT, DPT	Vestibular Physical Therapy for the Treatment of Brain Fog From Long COVID—A Case Report	https://doi.org/10.2519/josptcases.2022.10790	Published	April 30, 2022	Case Report	https://www.jospt.org/doi/abs/10.2519/josptcases.2022.10790	Background Individuals with symptoms weeks or months following COVID-19 have been deemed “long haulers” or having long COVID (LC). COVID has a primary effect on the respiratory and cardiovascular systems; however, individuals diagnosed with LC have had a wide array of symptoms that span across all other body systems, including the nervous system. Case Presentation This case study describes the presentation of symptoms and treatment through physical therapy of an individual with LC who presented with cognitive fatigue and brain fog. Outcome and Follow-up The individual demonstrated improvements in cognitive fatigue, brain fog, and concentration as well as improvements in balance and vestibular function. Discussion This case highlights the importance of a thorough examination in individuals with LC as well as the potential role of physical therapy for those suffering from LC.
146	Ce144		Michael J. Peluso1 ORCID Email Khamal Anglin1 Matthew S. Durstenfeld1 Jeffrey N. Martin1 J. Daniel Kelly1 Priscilla Y. Hsue1 Timothy J. Henrich1 Steven G. Deeks1	Effect of oral nirmatrelvir on Long COVID symptoms: a case series	https://doi.org/10.21203/rs.3.rs-1617822/v2	pre-print	05 May, 2022	Case Report	https://www.researchsquare.com/article/rs-1617822/v2	As the SARS-CoV-2 pandemic continues to evolve, efforts to understand variability in COVID-19 recovery, as well as the impact of factors including viral variants, vaccine status, and COVID-19 treatment on the development and persistence of Long COVID symptoms have intensified. We report three cases that demonstrate that variability in the timing of nirmatrelvir therapy may be associated with different outcomes and underscores the need for systematic study of antiviral therapy for this disease condition.
147	Ce145		Mohamed H. Abdelazim, Ahmed H. Abdelazim, Wael F. Ismaiel, Mahmoud E. Alsobky, Ahmed Younes, Abdelgawad M. Hadeya, Sherif Ramzy & Mohammed Shahin	Effect of intra-nasal nitrilotriacetic acid trisodium salt in lowering elevated calcium cations and improving olfactory dysfunction in COVID-19 patients	https://doi.org/10.1007/s00405-022-07424-5	Published	14 May 2022	Study	https://link.springer.com/article/10.1007/s00405-022-07424-5	Purpose An association between COVID-19 and olfactory dysfunction has been noted in many patients worldwide. The olfactory adaptation process leads to an increase in intracellular calcium cation levels. Nitrilotriacetic acid trisodium salt has high selective chelation for calcium cations from olfactory mucus. The aim of this work is to test the effect of an intranasal nitrilotriacetic acid trisodium salt to lower the elevated calcium cations in COVID-19 patients with relevant symptoms of olfactory dysfunction. Methods Fifty-eight COVID-19 adult patients with relevant symptoms of olfactory dysfunction were enrolled in a prospective randomized controlled trial. They received a nasal spray containing either 0.9% sodium chloride or 2% nitrilotriacetic acid trisodium salt. Olfactory function was assessed before and after treatment using the Sniffin’ Sticks test. Quantitative analysis of calcium cation concentration in nasal secretions was performed using a carbon paste ion-selective electrode. Results After the application of nitrilotriacetic acid trisodium salt compared to sodium chloride, a significant improvement from functional anosmia to healthy normosmia with significant decrease in calcium cation concentration was observed. Conclusions Further collaborative research is needed to fully investigate the effect of an intranasal nitrilotriacetic acid trisodium salt in the treatment of olfactory disorders.
148	Ce146		Summer Rolin, Ashley Chakales & Monica Verduzco-Gutierrez	Rehabilitation Strategies for Cognitive and Neuropsychiatric Manifestations of COVID-19	https://doi.org/10.1007/s40141-022-00352-9	Published	14 May 2022	Review	https://link.springer.com/article/10.1007/s40141-022-00352-9	Purpose of Review Extrapulmonary manifestations of COVID-19 are abundant, including after recovery of acute SARS-CoV-2 infection. This review seeks to explore the cognitive and neuropsychiatric manifestations of COVID-19 and post-acute sequelae of SARS-CoV-2 (PASC), including Long COVID syndromes. Furthermore, the review will discuss rehabilitation strategies for the emerging neurological consequences of COVID-19 to help those experiencing long-term effects of COVID-19. Recent Findings There is emerging evidence depicting the neural involvement of COVID-19. Health priorities have shifted from understanding pathogenesis and treatment of pulmonary symptoms to targeting the acute and chronic sequelae of COVID-19, including cognitive and neuropsychiatric symptoms. The sequelae of COVID-19 often co-occur with other medical problems and is best managed by assessment and care across multiple disciplines. Symptoms following infection are similar to those found by other syndromes and disorders that disrupt the central nervous system. Summary The acute and chronic sequelae of COVID-19 have become major targets of current health care providers given its significant public health impact, inclusive of cognitive and neuropsychiatric sequelae. Assessment and referral to rehabilitation based on each individual’s needs and symptoms can decrease morbidity and improve quality of life. Intervention Cognitive remediation and rehabilitation has been established as an effective treatment for ongoing sequelae of brain injury [34]. Common interventions that can be applied to PASC patients include compensatory strategies based on areas of deficit and training in metacognitive strategies and are outlined in recently published consensus guidance statements, which can be referenced [33]. Tele-rehabilitation, including home-based exercises tailored to the patients’ needs, can be implemented based on demonstrated areas of cognitive deficit [35]. Telemedicine services may not be available based on factors such as access to reliable internet connections, technology, and availability of providers. Thus, in-person therapies may be warranted, and these limitations should be particularly considered when treating patients from disparate health populations. Exercise programs have been applied as a means to improve cognition, and cardiovascular exercise has been found to improve attention, processing speed, executive functioning, and memory [36]. Application-based exercise programs in other rehabilitation populations have been found to improve exercise engagement, but not functional outcomes such as motor ability and cognition [37]. In PASC patients, rehabilitation exercise programs focusing on resistance, endurance, and balance training, which include an education and pacing element, have yielded gains in cognition [38]. Improvements in symptoms of fatigue and breathlessness [38] have also been found, as well as an improvement in overall functional status [39]. Thus, it is recommended that exercise programs be applied that are in-person or virtual, and include education on pacing and psychoeducation of symptoms, as well as physical exertion.
149	Ce147		Shamil Haroon,corresponding author1 Krishnarajah Nirantharakumar,1,2 Sarah E Hughes,1,3 Anuradhaa Subramanian,1 Olalekan Lee Aiyegbusi,1,3 Elin Haf Davies,4 Puja Myles,5 Tim Williams,5 Grace Turner,1 Joht Singh Chandan,1 Christel McMullan,1 Janet Lord,6 David C Wraith,7 Kirsty McGee,6 Alastair K Denniston,8 Thomas Taverner,1 Louise J Jackson,1 Elizabeth Sapey,6 George Gkoutos,9 Krishna Gokhale,1 Edward Leggett,5 Clare Iles,5 Christopher Frost,4 Gary McNamara,4 Amy Bamford,8 Tom Marshall,1 Dawit T Zemedikun,1 Gary Price,10 Steven Marwaha,11 Nikita Simms-Williams,1 Kirsty Brown,1 Anita Walker,1 Karen Jones,1 Karen Matthews,10 Jennifer Camaradou,10 Michael Saint-Cricq,10 Sumita Kumar,10 Yvonne Alder,10 David E Stanton,10 Lisa Agyen,10 Megan Baber,10 Hannah Blaize,10 and Melanie Calvert1,2	Therapies for Long COVID in non-hospitalised individuals: from symptoms, patient-reported outcomes and immunology to targeted therapies (The TLC Study)	http://dx.doi.org/10.1136/bmjopen-2021-060413	Published	April 26, 2022	Protocol	https://bmjopen.bmj.com/content/12/4/e060413	Introduction: Individuals with COVID-19 frequently experience symptoms and impaired quality of life beyond 4–12 weeks, commonly referred to as Long COVID. Whether Long COVID is one or several distinct syndromes is unknown. Establishing the evidence base for appropriate therapies is needed. We aim to evaluate the symptom burden and underlying pathophysiology of Long COVID syndromes in non-hospitalised individuals and evaluate potential therapies. Methods and analysis: A cohort of 4000 non-hospitalised individuals with a past COVID-19 diagnosis and 1000 matched controls will be selected from anonymised primary care records from the Clinical Practice Research Datalink, and invited by their general practitioners to participate on a digital platform (Atom5). Individuals will report symptoms, quality of life, work capability and patient-reported outcome measures. Data will be collected monthly for 1 year. Statistical clustering methods will be used to identify distinct Long COVID-19 symptom clusters. Individuals from the four most prevalent clusters and two control groups will be invited to participate in the BioWear substudy which will further phenotype Long COVID symptom clusters by measurement of immunological parameters and actigraphy. We will review existing evidence on interventions for postviral syndromes and Long COVID to map and prioritise interventions for each newly characterised Long COVID syndrome. Recommendations will be made using the cumulative evidence in an expert consensus workshop. A virtual supportive intervention will be coproduced with patients and health service providers for future evaluation. Individuals with lived experience of Long COVID will be involved throughout this programme through a patient and public involvement group. Strengths and limitations of this study The study will generate a nationally representative cohort of individuals with Long COVID recruited from primary care. We will recruit controls matched on a wide range of demographic and clinical factors to assess differences in symptoms between people with Long COVID and similar individuals without a history of COVID-19. We will use a newly developed electronic patient-reported outcome measure (Symptom Burden Questionnaire) for Long COVID to comprehensively assess a wide range of symptoms highlighted by existing literature, patients and clinicians. Immunological, proteomic, genetic and wearable data captured in the study will allow deep phenotyping of Long COVID syndromes to help better target therapies. A limitation is that a significant proportion of non-hospitalised individuals affected by COVID-19 in the first wave of the pandemic will lack confirmatory testing and will be excluded from recruitment to the study.
150	Ce148		Talha Burki	The future of Paxlovid for COVID-19	https://doi.org/10.1016/S2213-2600(22)00192-8	Published	May 24, 2022	Article	https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00192-8/fulltext	In comments to Bloomberg published on May 3, 2022, Pfizer chief executive officer Albert Bourla suggested that patients who experience a relapse of symptoms after finishing a course of the company's COVID-19 antiviral, Paxlovid, should take a second course of the drug. Yet the emergency use authorisation issued by the US Food and Drug Administration (FDA) stipulates that Paxlovid is “not authorized for use longer than five consecutive days”. On May 4, John Farley, director of the Office of Infectious Diseases at the FDA, reiterated this message. “There is no evidence of benefit at this time for a longer course of treatment...or repeating a treatment course of Paxlovid in patients with recurrent COVID-19 symptoms following completion of a treatment course”, stated Farley. The US Government pays around US$530 for each 5-day course of Paxlovid. The drug is a combination of ritonavir plus the novel protease inhibitor PF-07321332. The emergency use authorisation was granted late last year, on the strength of results from the phase 2–3 trial showing that Paxlovid reduces the risk of hospitalisation or death for high-risk patients by 88%, compared with the placebo, if given within 5 days of symptom onset. The trial only recruited unvaccinated individuals. But three-quarters of the UK population and two-thirds of the US population are now fully vaccinated against COVID-19. Whether or not antivirals will relieve long COVID hinges on the extent to which the condition is attributable to viral persistence. “At the moment, there is not enough evidence to support antiviral therapy for long COVID”, stressed Summers. “There have been reports that the genetic material from the virus has lingered in the guts of previously infected people, but we still do not know if this is live virus.” She added that symptoms of long COVID, such as blood clots and cardiovascular effects are indicative of a dysregulated host immune response, rather than viral persistence. “There could be some deep tissue persistence of hard-to-find virus that is driving a dysregulated inflammatory immune response”, countered Peluso. “I think there is enough compelling preliminary data to study this systematically.” The issue will only be resolved in large scale studies. 6 months have now elapsed since the FDA authorisation of Paxlovid, yet supplies to low-income settings remain suboptimal. “We have to work harder to ensure equitable access across the world”, said Summers. “It worries me that we could potentially be giving antiviral therapy for COVID-19 to patients in the UK or USA who are at low risk of hospitalisation, and who have been fully vaccinated, while there are large numbers of people who need them but have no access to these drugs.”
151	Ce149		Huan Yang, Sam J. George, Dane A. Thompson, Harold A. Silverman, Téa Tsaava, Aisling Tynan, Valentin A. Pavlov, Eric H. Chang, Ulf Andersson, Michael Brines, Sangeeta S. Chavan & Kevin J. Tracey	Famotidine activates the vagus nerve inflammatory reflex to attenuate cytokine storm	https://doi.org/10.1186/s10020-022-00483-8	Published	16 May 2022	Study	https://molmed.biomedcentral.com/articles/10.1186/s10020-022-00483-8	Background Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and clinical studies suggest famotidine, a histamine 2 receptor (H2R) antagonist widely used to treat gastroesophageal reflux disease, attenuates the clinical course of COVID-19. Because evidence is lacking for a direct antiviral activity of famotidine, a proposed mechanism of action is blocking the effects of histamine released by mast cells. Here we hypothesized that famotidine activates the inflammatory reflex, a brain-integrated vagus nerve mechanism which inhibits inflammation via alpha 7 nicotinic acetylcholine receptor (α7nAChR) signal transduction, to prevent cytokine storm. Methods The potential anti-inflammatory effects of famotidine and other H2R antagonists were assessed in mice exposed to lipopolysaccharide (LPS)-induced cytokine storm. As the inflammatory reflex is integrated and can be stimulated in the brain, and H2R antagonists penetrate the blood brain barrier poorly, famotidine was administered by intracerebroventricular (ICV) or intraperitoneal (IP) routes. Results Famotidine administered IP significantly reduced serum and splenic LPS-stimulated tumor necrosis factor (TNF) and IL-6 concentrations, significantly improving survival. The effects of ICV famotidine were significantly more potent as compared to the peripheral route. Mice lacking mast cells by genetic deletion also responded to famotidine, indicating the anti-inflammatory effects are not mast cell-dependent. Either bilateral sub-diaphragmatic vagotomy or genetic knock-out of α7nAChR abolished the anti-inflammatory effects of famotidine, indicating the inflammatory reflex as famotidine’s mechanism of action. While the structurally similar H2R antagonist tiotidine displayed equivalent anti-inflammatory activity, the H2R antagonists cimetidine or ranitidine were ineffective even at very high dosages. Conclusions These observations reveal a previously unidentified vagus nerve-dependent anti-inflammatory effect of famotidine in the setting of cytokine storm which is not replicated by high dosages of other H2R antagonists in clinical use. Because famotidine is more potent when administered intrathecally, these findings are also consistent with a primarily central nervous system mechanism of action.
152	Ce150		April S. Caravaca, Alessandro L. Gallina, Laura Tarnawski, +6, Vladimir S. Shavva, Romain A. Colas, Jesmond Dalli, Stephen G. Malin, Henrik Hult, Hildur Arnardottir, and Peder S. Olofsson	Vagus nerve stimulation promotes resolution of inflammation by a mechanism that involves Alox15 and requires the α7nAChR subunit	https://doi.org/10.1073/pnas.2023285119	Published	May 27, 2022	Study	https://www.pnas.org/doi/10.1073/pnas.2023285119	Significance Resolution of inflammation is an active process that restores tissue homeostasis and prevents the development of chronic inflammatory diseases. The mechanisms that regulate resolution of inflammation are only partially understood. Here, we showed that activation of the vagus nerve accelerated resolution of inflammation. Electrical stimulation of the vagus nerve in vivo increased levels of select specialized proresolving mediators in inflammation. Experiments in genetic mouse models revealed that the mechanism involved 12/15-lipoxgenase (Alox15), a key enzyme for biosynthesis of the identified mediators, and required the α7-nicotinic acetylcholine receptor subunit. The findings indicate that electrical signals in the vagus nerve activate a cholinergic signal promoting Alox15-dependent lipid mediator biosynthesis and accelerating resolution of inflammation, providing additional insights into neural regulation of inflammation. Abstract Nonresolving inflammation underlies a range of chronic inflammatory diseases, and therapeutic acceleration of resolution of inflammation may improve outcomes. Neural reflexes regulate the intensity of inflammation (for example, through signals in the vagus nerve), but whether activation of the vagus nerve promotes the resolution of inflammation in vivo has been unknown. To investigate this, mice were subjected to electrical vagus nerve stimulation (VNS) or sham surgery at the cervical level followed by zymosan-induced peritonitis. The duration of inflammation resolution was significantly reduced and efferocytosis was significantly increased in mice treated with VNS as compared with sham. Lipid mediator (LM) metabololipidomics revealed that mice treated with VNS had higher levels of specialized proresolving mediators (SPMs), particularly from the omega-3 docosahexaenoic (DHA) and docosapentaenoic (n-3 DPA) metabolomes, in peritoneal exudates. VNS also shifted the ratio between proinflammatory and proresolving LMs toward a proresolving profile, but this effect by VNS was inverted in mice deficient in 12/15-lipoxgenase (Alox15), a key enzyme in this SPM biosynthesis. The significant VNS-mediated reduction of neutrophil numbers in peritoneal exudates was absent in mice deficient in the cholinergic α7-nicotinic acetylcholine receptor subunit (α7nAChR), an essential component of the inflammatory reflex. Thus, VNS increased local levels of SPM and accelerated resolution of inflammation in zymosan-induced peritonitis by a mechanism that involves Alox15 and requires the α7nAChR.
153	Ce151		Joseph Colombo 1,,Michael I. Weintraub 2,,Ramona Munoz 1,Ashish Verma 1,Ghufran Ahmad 1,Karolina Kaczmarski 1,Luis Santos 3 andNicholas L. DePace 1	Long COVID and the Autonomic Nervous System: The Journey from Dysautonomia to Therapeutic Neuro-Modulation through the Retrospective Analysis of 152 Patients	https://doi.org/10.3390/neurosci3020021	Published	23 May 2022	Study	https://www.mdpi.com/2673-4087/3/2/21/htm	Introduction. The severity and prevalence of Post-Acute COVID-19 Sequela (PACS) or long-COVID syndrome (long COVID) should not be a surprise. Long-COVID symptoms may be explained by oxidative stress and parasympathetic and sympathetic (P&S) dysfunction. This is a retrospective, hypothesis generating, outcomes study. Methods. From two suburban practices in northeastern United States, 152 long COVID patients were exposed to the following practices: (1) first, they were P&S tested (P&S Monitor 4.0; Physio PS, Inc., Atlanta, GA, USA) prior to being infected with COVID-19 due to other causes of autonomic dysfunction; (2) received a pre-COVID-19 follow-up P&S test after autonomic therapy; (3) then, they were infected with COVID-19; (4) P&S tested within three months of surviving the COVID-19 infection with long-COVID symptoms; and, finally, (5) post-COVID-19, follow-up P&S tested, again, after autonomic therapy. All the patients completed autonomic questionnaires with each test. This cohort included 88 females (57.8%), with an average age of 47.0 years (ranging from 14 to 79 years), and an average BMI of 26.9 #/in2. Results. More pre-COVID-19 patients presented with sympathetic withdrawal than parasympathetic excess. Post-COVID-19, these patients presented with this ratio reversed and, on average, 49.9% more autonomic symptoms than they did pre-COVID-19. Discussion. Both parasympathetic excess and sympathetic withdrawal are separate and treatable autonomic dysfunctions and autonomic treatment significantly reduces the prevalence of autonomic symptoms. Conclusion. SARS-CoV-2, via its oxidative stress, can lead to P&S dysfunction, which, in turn, affects the control and coordination of all systems throughout the whole body and may explain all of the symptoms of long-COVID syndrome. Autonomic therapy leads to positive outcomes and patient quality of life may be restored.
154	Ce152		Salma Charfeddine,corresponding author 1 , 2 , * Hassen Ibnhadjamor, 3 Jihen Jdidi, 2 , 4 Slim Torjmen, 2 , 5 Salma Kraiem, 3 Amine Bahloul, 1 , 2 Ahmed Makni, 1 , 2 Nesrine Kallel, 2 , 5 Nedia Moussa, 2 , 5 Mariem Boudaya, 2 , 6 Imen Touil, 7 Aiman Ghrab, 2 , 8 Jamel Elghoul, 2 , 9 Zeineb Meddeb, 10 Yamina Thabet, 10 Kais Ben Salem, 11 Faouzi Addad, 12 Kamel Bouslama, 10 Sami Milouchi, 2 , 8 Rania Hammami, 1 , 2 Salem Abdessalem, 13 and Leila Abid 1 , 2	Sulodexide Significantly Improves Endothelial Dysfunction and Alleviates Chest Pain and Palpitations in Patients With Long-COVID-19: Insights From TUN-EndCOV Study	https://doi.org/10.3389%2Ffcvm.2022.866113	Published	2022 May 12	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133483/	Objective Non-respiratory long-coronavirus disease 2019 (COVID-19) symptoms are mainly related to a long-lasting endothelial dysfunction and microcirculation impairment. We hypothesized that Sulodexide, a purified glycosaminoglycan mixture with a beneficial endothelial effect in arterial and venous peripheral diseases, may be effective in a subset of patients with long COVID-19. Approach and Results We conducted a multicenter prospective quasi-experimental study. A total of 290 patients from the TUN-EndCOV study with long-COVID-19 symptoms and endothelial dysfunction were included. The endothelial function was clinically assessed using a post-occlusive reactive hyperemia protocol with finger thermal monitoring device. Endothelial quality index (EQI) was assessed at inclusion and at 21 days later. The study population was assigned to a sulodexide group (144 patients) or a no-medical treatment group (146 patients). Clinical characteristics were similar at inclusion in the two groups. Fatigue, shortness of breath, and chest pain were the most common symptoms, respectively, 54.5, 53.8, and 28.3%. At 21 days, the sulodexide group improved significantly better than the no-medical treatment group in chest pain (83.7 vs. 43.6%, p < 10−3), palpitations (85.2 vs. 52.9%, p = 0.009), and endothelial function [median delta-EQI 0.66 (0.6) vs. 0.18 (0.3); p < 10−3]. Endothelial function improvement was significantly correlated with chest pain and palpitations recovery (AUC, i.e., area under the curve = 0.66, CI [0.57– 0.75], p = 0.001 and AUC = 0.60, CI [0.51– 0.69], p = 0.03, respectively). Conclusion Sulodexide significantly improves long-lasting post-COVID-19 endothelial dysfunction and alleviates chest pain and palpitations.
155	Ce153		Dario Cerasola, 1 , † Christiano Argano, 2 , 3 , 4 , † and Salvatore Corraocorresponding author 2 , 3 , 4 , *	Lessons From COVID-19: Physical Exercise Can Improve and Optimize Health Status	https://doi.org/10.3389%2Ffmed.2022.834844	Published	2022 May 13	Article	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9136917/	The outbreak of Coronavirus Disease 2019 (COVID-19) has caused increasing challenges for healthcare systems globally. The disease spread rapidly from Wuhan to the rest of the world, involving more than 400 million individuals and including more than 5 million deaths. In dealing with the pandemic, China and other countries took protective measures such as promoting social distancing, canceling public gatherings, closing schools, quarantining, and imposing lockdowns. All these measures lead to physical inactivity. Being physically inactive has significant repercussions on the status of physical and mental wellbeing, and it is associated with anxiety, stress, increased chronic disease risk, and worsening of chronic conditions. In this sense, the relevance of maintaining a healthy lifestyle through physical exercise has been outlined by the World Health Organization (WHO). The aim of this mini review is to discuss the importance of physical activity in the context of the COVID-19 pandemic, highlighting the benefits of physical activity and exercise that could be potentially effective treatment strategies for comorbid chronic conditions, long covid syndrome (LCS), and symptoms such as depression and anxiety.
156	Ce154		Manabu Ohyama 1, Kiichi Matsudo 2, Toru Fujita 2	Management of hair loss after severe acute respiratory syndrome coronavirus 2 infection: Insight into the pathophysiology with implication for better management	https://doi.org/10.1111/1346-8138.16475	Published	2022 May 27	Review	https://pubmed.ncbi.nlm.nih.gov/35633047/	Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared a pandemic by the World Health Organization, and COVID-19 continues to have a major impact on society. Numerous studies have reported impaired health sequelae after COVID-19 recovery, one of which is hair loss. Individuals with hair loss experience a substantial mental burden, which potentially hinders their social life. However, few studies have systematically analyzed the details including hair loss. Therefore, we conducted a narrative review using PubMed on the frequency, associated comorbidities, disease characteristics, and treatment of hair loss after SARS-CoV-2 infection (HLASCI). Two search strings were used to identify 28 articles. Of note, most of the literature identified on COVID-19 sequelae reported an emergence/occurrence of hair loss. HLASCI is speculated to be composed of a heterogeneous population, with the onset or exacerbation of telogen effluvium (TE), anagen effluvium, androgenetic alopecia (AGA), and alopecia areata (AA) reported as possible underlying mechanisms. Among these, acute TE is thought to be the primary cause of HLASCI, with COVID-19 treatment and TE improvement being considered crucial for HLASCI management. An association between COVID-19 and AA exacerbation has also been implicated with still insufficient evidence. Spontaneous recovery of TE can be expected once infection reduces; however, faster improvement in symptoms is expected to reduce the mental and social burden of patients. An additional search string identified 11 articles about TE treatment which suggested that the use of minoxidil may be beneficial. Topical minoxidil has been widely used for AGA patients, who have been speculated to exhibit poor resistance to SARS-CoV-2. Topical minoxidil may provide relief from HLASCI, but future clinical research is warranted to confirm this observation.
157	Ce155		Ali Nouraeinejad	A proposal to apply brain injury recovery treatments for cognitive impairment in COVID-19 survivors	https://doi.org/10.1080/00207454.2022.2084091	Published	30 May 2022	Article	https://www.tandfonline.com/doi/abs/10.1080/00207454.2022.2084091	There is still little information about the nature and broader prevalence of cognitive problems during post-infection in COVID-19 survivors. This is also the case for pathobiological findings related to these complications. In the meantime, there is mounting alarm regarding potential long-term outcomes of COVID-19, with descriptions of ‘long COVID’ symptoms keeping up into the chronic stage, which include ‘brain fog’. The cognitive impairment or brain fog creates many difficulties in daily activities and makes problems for those who wish to successfully return to their job. The author proposes to apply brain injury recovery treatments for cognitive impairment in COVID-19 survivors.
158	Ce156		ManabuNankakuPT, PhDaRyosukeIkeguchiMD, PhDabTomokiAoyamaMD, PhDcGakutoKitamuraPT, MSaAyumiOtagakiPT, BSaRyotaHamadaPT, MSaTakumaYuriOTR, PhDaShuichiMatsudaMD, PhDab	A first view of the effect of a trial of early mobilization on the muscle strength and activities of daily living in mechanically ventilated patients with COVID-19	https://doi.org/10.1016/j.arrct.2022.100201	Published	10 June 2022	Study	https://www.sciencedirect.com/science/article/pii/S2590109522000258	Objective To retrospectively investigate the effect of early mobilization on the muscle strength and activities of daily living in patients with coronavirus disease 2019 (COVID-19) under mechanical ventilation. Design This was a single-center, retrospective, observational study. Setting Inpatient rehabilitation care in Japan Participants The study subjects were divided based on the onset of mobilization: under mechanical ventilation (n =17; aged 68.5 ± 11.9, 13 male) and after extubation (n =11; aged 59.7 ± 7.1, 6 male). Interventions Mobilization, including dangle sitting, standing, walking, and muscle strengthening exercises Main Outcome Measures The outcome measures were Barthel Index, Medical Research Council Manual Muscle Test (MRC), and intensive care unit (ICU) Mobility Scale. Results The difference in the Barthel Index, MRC, and ICU Mobility Scale scores pre- and post-intervention were not statistically significant between the two groups, but all significantly improved after the intervention. Conclusion This small sample size study found no difference in the functional recovery of patients with severe COVID-19 who underwent early mobilization under mechanical ventilation relative to when it was begun after extubation.
159	Ce157		J. Kesavadev S. Shijin A. Shankar G. Krishnan A. Basanth R.S. Joshi A. Raveendran I. Rajalakshmy Y. Unes S. Jothydev	IDF21-0234 The Virtual COVID In-patient (VCIP) Care and Post Covid Symptoms: a Comparison with Conventional Care	https://doi.org/10.1016/j.diabres.2022.109326	Published	April 01, 2022	Study	https://www.diabetesresearchclinicalpractice.com/article/S0168-8227(22)00138-3/fulltext	Background: VCIP is a home based interventional economic model wherein a consenting patient will remain in their home and consult the VCIP team via audio-video consultations to treat COVID-19 in a manner similar to inpatient care. While the widely prevalent home-based care that is currently available is often limited to monitoring of vital signs, the VCIP program described here involves active therapeutic intervention. Aim: We assessed the impact of VCIP in the management of COVID and post COVID symptoms. Method: Since September 2020, our center has been practicing VCIP for our patients with diabetes, already enrolled in our hospital, to treat COVID and Post COVID symptoms. This is a retrospective analysis of the data of 243 COVID-19 positive patients who enrolled in VCIP. A 24/7 dedicated WhatsApp group of patients, their relatives, doctors, nurses, dietitian and a psychologist was created for remote monitoring of temperature, blood pressure, blood glucose, respiratory and pulse rate along with the symptoms and then to follow up them for 4-6 months post-COVID. The vital parameters and general wellbeing of patients are monitored once every 4 hrs. Contrary to conventional domiciliary care, in VCIP, lab investigations, corticosteroids and other interventions were carried out as and when necessary, at home for the successful management of COVID-19. For patients with diabetes on insulin, the dosages were titrated based on SMBG values or real time CGM. We also assessed the post-COVID symptoms in these patients. Results: Out of 243 patients who availed of the VCIP facility, all 243 of them recovered. However, 2 hospitalizations were there, one, due to the impending fear of death and the other one, due to intolerance to oral corticosteroids, yielding a 99.5% success rate in preventing hospitalization. There was a wide range of post-COVID-19 symptoms and illnesses experienced by <10% of the patients, which was very low compared to patients in conventional care, including headache(5%), generalized itching(7%), fatigue(20%), vertigo(<1%), urticaria(<1%), exacerbation of sinusitis(<1%), insomnia(15%), and bacterial infection(30%). The patients recovered from these symptoms within 2-3 months. Some patients who experienced more severe complications such as atrial fibrillation and ventricular ectopics (<1%) picked up in Apple watch ECG was referred to a cardiologist for evaluation. The arrhythmias disappeared spontaneously with clinical improvement in the majority of the patients. Discussion: VCIP when compared to hospitalizations have proven to be cost effective, with significantly better immediate outcomes. With regular and structured teleconsultations and lab assessments, patients likely to deteriorate are identified quite early and treatment initiated without wasting any time. The comorbidities were also aggressively managed. The significantly less occurrence of post Covid symptoms in the VCIP group compared to hospitalized patients could have resulted from these early interventions.
160	Ce158		Pieter C. Goeminne, MD, PhD Grant Waterer, MBBS, PhD	Post-COVID Care Untying the Covidian Knot	https://doi.org/10.1016/j.chest.2022.02.036	Published	June 01, 2022	Editorial	https://journal.chestnet.org/article/S0012-3692(22)00403-2/fulltext	What then are the key questions that we need answers to so as to design appropriate, evidence-based post-COVID-19 care pathways in our health systems? First, are there any interventions in the acute phase of COVD-19 that reduce the risk of long-term complications? A recent analysis by Antonelli and colleagues12 showed that patients who had received two doses of vaccination had lower odds of developing post-COVID-19 syndrome (OR, 0.51; 95% CI, 0.32-0.82; P = .006). Because no other acute therapy has been shown to reduce post-COVID complications, this further emphasizes the need for vaccination campaigns. There is an urgent need to look at the impact of all current acute therapies on the long-term effects of COVID-19, including steroids, anti-IL-6 agents, anti-spike protein monoclonal antibodies, and the newer antivirals. What is the most cost-effective and accurate diagnostic pathway to detect chronic organ damage from COVID-19, and does detection make a difference to therapy? Aside from long COVID-19 prevention, further research on its pathophysiology, identification, risk factors, diagnosis, treatment, and management is needed. As pointed out by Valley and colleagues,9 because there are a wide array of presentations with and without obvious organ pathology, multidisciplinary teams are crucial to address post-COVID-19 syndrome. Does early intervention based on early diagnosis make a difference in patient outcomes or should we wait for patients to self-refer? Data from a broad group of patients with COVID-19 showed that patients who experienced more than five symptoms in the first week were more likely to develop post-COVID-19 syndrome (OR, 3.95; CI, 3.10-5.04). They also found that individuals with post-COVID-19 syndrome were more likely to have required hospital assessment.5 Looking further into the hospitalized patients, the recent PHOSP-COVID study found that factors associated with post-COVID-19 syndrome were female sex, two or more comorbidities, and more severe acute illness (WHO classes 7-9), whereas age groups < 30 and > 70 years had a better recovery. They also found four clusters of severity, with differences in severity regarding mental and physical health impairment.7 Although validating risk factors for post-COVID-19 syndrome is potentially useful, without effective interventions shown to improve outcomes, they remain an academic exercise rather than a clinically useful one. A few attempts have already been made to formulate practical recommendations to tackle post-COVID-19 syndrome care, suggesting a multidisciplinary one-stop clinic to screen, diagnose, and treat patients with specialist expertise and interdisciplinary collaboration.13 Models have been developed and put into practice, such as the Multidisciplinary NHS COVID-19 service, with the establishment of a three-tier model.14 These approaches need confirmation and validation but provide a great basis to start further research. In the post-COVID world, the extent to which these clinics could be delivered virtually while achieving the same or better outcomes will undoubtedly be a major focus of study.15 We also should not forget lessons already learned in other analogous conditions. Post critical-illness syndrome is well recognized, and there has been extensive research into its pathology, diagnosis, and avenues of treatment.16 Although there is certainly a larger variety of pathologies and symptomatology reported post-COVID-19, lessons already learnt around the importance of exercise, nutrition, and psychological support should not have to be rediscovered. In summary, specific guidelines are needed for all what entails post-COVID-19 care, but the evidence base for such recommendations is scant. In the absence of evidence, not surprisingly, a broad range of approaches are being taken across the United States (Valley et al9) and indeed the world. Although we are approaching some understanding of who is most at risk, the best approach to screening for pathology and which treatments (if any) modify long-term outcomes remains to be defined. Further well-designed research studies are urgently required for what is already a major health problem and likely to be so for some years to come.
161	Ce159		Santangelo Letizia , Ginestra Angelo	PHYSIOTHERAPEUTIC REHABILITATION IN THE TREATMENT OF THE POST COVID-19 PATIENT		Published	June 2022	Study	https://jahc.eu/wp-content/uploads/2022/03/JAHC2201-01.pdf	In the coronavirus emergency physiotherapy has had and continues to have a very important role in taking care of patients who, recovered from the disease, need an individualized path of recovery of respiratory and motor rehabilitation, to prevent complications of all kinds and, in general, improve the quality of life. This study is the result of an accurate research conducted by means of the main research databases, including PubMed. For the drafting of the study, many studies were selected and included, including a position paper by AIPO (Italian Association of Hospital Pneumologists), ARIR (Association of Rehabilitators of Respiratory Insuffi ciency) and SIP (Italian Society of Pneumology) on respiratory rehabilitation, which accurately describes the different phases of treatment provided for each patient, based on the degree of severity of the pathology they suffer from, the SIAARTI recommendations for the management of the critical patient, reviews (SIMG) on physical rehabilitation, the results of a Delphi trial on pulmonary rehabilitation, indications for respiratory physiotherapy by ARIR in collaboration with AIFI (Italian Association of Physiotherapists), but also systematic reviews, some of which focus on the care of elderly patients, meta-analyses and randomised controlled clinical trials. In addition, the research group drew on the experience of a motor reconditioning programme of the U.O. of Rehabilitation Medicine of the Azienda Ospedaliera Marche Nord and on a clinical case of the Istituto Scientifi co Maugeri of Bari.
162	Ce160		Matteo Tosato, MD, PhD Francesca Ciciarello, MD Maria Beatrice Zazzara, MD Cristina Pais, MD Giulia Savera, MSc Anna Picca, PhD Vincenzo Galluzzo, MD Hélio José Coelho-Júnior, PhD Riccardo Calvani, PhD Emanuele Marzetti, MD, PhD Francesco Landi, MD, PhD	Nutraceuticals and Dietary Supplements for Older Adults with Long COVID	https://doi.org/10.1016/j.cger.2022.04.004	Published	June 20, 2022	Review	https://www.geriatric.theclinics.com/article/S0749-0690(22)00022-2/fulltext	Key points •Long-term persistence of COVID-19–related symptoms after SARS-CoV-2 infection impacts quality of life. •Several mechanisms may be involved in the persistence of COVID-19 symptoms, including chronic inflammation, immunometabolic processes, endothelial dysfunction, and gut dysbiosis. •Bioactive foods, supplements, and nutraceuticals may be used for the management of long-term COVID-19 clinical sequelae.
163	Ce161		Bashar W Badran1 Sarah M Huffman1 Morgan Dancy1 Christopher W Austelle1 Marom Bikson2 Steven A Kautz1 Mark S George1	A pilot randomized controlled trial of supervised, at-home, self-administered transcutaneous auricular vagus nerve stimulation (taVNS) to manage long COVID symptoms	https://doi.org/10.21203/rs.3.rs-1716096/v1	pre-print	21 Jun, 2022	Study	https://www.researchsquare.com/article/rs-1716096/v1	Background Although the coronavirus disease 19 (COVID-19) pandemic has now impacted the world for over two years, the persistent secondary neuropsychiatric effects are still not fully understood. These “long COVID” symptoms, also referred to as post-acute sequelae of SARS-CoV-2 infection (PASC), can persist for months after infection without any effective treatments. Long COVID involves a complex heterogenous symptomology and can lead to disability and limit work. Long COVID symptoms may be due to sustained inflammatory responses and prolonged immune response after infection. Interestingly, vagus nerve stimulation (VNS) may have anti-inflammatory effects, however, until recently, VNS could not be self-administered, at-home, noninvasively. Methods We created a double-blind, noninvasive transcutaneous auricular VNS (taVNS) system that can be self-administered at home with simultaneous remote monitoring of physiological biomarkers and video supervision by study staff. Subsequently, we carried out a pilot (n = 13) randomized, sham-controlled, trial with this system for four weeks to treat nine predefined long covid symptoms (anxiety, depression, vertigo, anosmia, ageusia, headaches, fatigue, irritability, brain fog). No in-person patient contact was needed, with informed consent, trainings, ratings, and all procedures being conducted remotely during the pandemic (2020–2021) and equipment being shipped to individuals’ homes. This trial was registered onClinicalTrials.gov under the identifier: NCT04638673. Results Four-weeks of at-home self-administered taVNS (two, one-hour sessions daily, delivered at suprathreshold intensities) was feasible and safe. Although our trial was not powered to determine efficacy as an intervention in a heterogenous population, the trends in the data suggest taVNS may have a mild to moderate effect in reducing mental fatigue symptoms in a subset of individuals. This innovative study demonstrates the safety and feasibility of supervised self-administered taVNS under a fully contactless protocol and suggests that future studies can safely investigate this novel form of brain stimulation at-home for a variety of neuropsychiatric and motor recovery applications.
164	Ce162		I.Lassouli1M.Benzakour2K.Echchilali3M.M.Moudatir3H.El Kabli3I.Lassouli1M.Benzakour2K.Echchilali3M.M.Moudatir3H.El Kabli3	Vascularite rétinienne post-Covid-19 et Molnupiravir	https://doi.org/10.1016/j.revmed.2022.03.121	Published	15 June 2022	Study	https://www.sciencedirect.com/science/article/pii/S0248866322002053	Introduction Le coronavirus du syndrome respiratoire aigu sévère 2 (SARS-CoV-2) est une nouvelle souche de coronavirus, a été détectée en fin décembre 2019 à Wuhan la capitale de la Chine centrale province du Hubei. Il a comme organe cible les poumons induisant une inflammation aiguë pouvant évoluer vers des troubles respiratoires et défaillance multiviscérale. Le spectre complet des présentations n’est pas entièrement élucidé car la pandémie est toujours en cours de progression. Les manifestations oculaires liées à la COVID-19 sont rares, dominées par la conjonctivite et la kératoconjonctivite, quelques rares cas de vascularite rétinienne ont été décrits. Le Molnupiravir est le premier antiviral oral appartenant au groupe des inhibiteurs de l’ARN polymérase qui a démontré un avantage significatif dans la réduction des hospitalisations ou des décès dans les cas légers de COVID-19. Nous rapportons un cas d’une vascularite rétinienne bilatérale post-infection au SARS-CoV 2 et qui a bien répondu au Molnupiravir chez une femme âgée de 30 ans suivie pour maladie de Takayasu. Observation Il s’agit d’une patiente âgée de 30 ans, non vaccinée contre le COVID-19, suivie pour maladie de Takayasu classe 5 évoluant depuis 2013 et retenue selon les critères ACR 1990. Admise pour bilan étiologique d’une vascularite rétinienne (VR) bilatérale évoluant depuis 20 jours avant son hospitalisation et concomitante à une infection SARS COV 2 confirmée. L’examen ophtalmologique initial objectivait une actuité visuelle à 3/10 à droit et 9/10 à gauche, le segment antérieur et le tonus intraoculaire étaient sans particularités et au fond d’œil (FO) des foyers de vascularite rétinienne avec des infiltrats blanchâtres et décollement séreux rétinien (DSR) en bilatérale. L’angiographie rétinienne à la fluoresceine retrouvait une vascularite active périmaculaire au niveau droit et normale au niveau gauche. La tomographie par cohérence optique (OCT) objectivait un DSR fovéolaire en bilatérale. Le bilan biologique complet comportant la recherche d’auto-immunité et de maladies infectieuses était négatif, même sa maladie n’était pas en poussée. Sur le plan thérapeutique, elle a été mise initialement sous corticothérapie 1 mg/kg/jour pendant 10 jours, l’évolution fut marquée par l’aggravation de l’acuité visuelle à 1/10 en bilatérale avec apparition au FO des plaques hémorragiques et persistance du DSR en bilatérale. En l’absence d’autre étiologie retrouvée et devant l’aggravation sous corticothérapie, la vascularite rétinienne a été attribuée au SARS COV2. Elle a été mise sous Molnupiravir à raison de 8 comprimés par jour pendant 5 jours avec bonne évolution, l’examen ophtalmologique de contrôle objectivait un acuité visuelle à 9/10 à droit et à 10/10 à gauche avec au FO remaniement maculaire séquelle de résorption du DSR sans oedème maculaire ni signes de vascularite rétinienne. Conclusion L’ARN viral du COVID-19 a été détecté dans la rétine des patients atteints et des publications récentes mettent en évidence la possibilité d’une microangiopathie rétinienne chez les patients dont l’infection au COVID-19 est confirmée. L’efficacité directe du Molnupiravir dans les vascularites rétiniennes post-COVID-19 est probable, elle doit encore être évaluée dans le cadre d’essais cliniques.
165	Ce163		Pallav Sengupta & Sulagna Dutta	N-acetyl cysteine as a potential regulator of SARS-CoV-2-induced male reproductive disruptions	https://doi.org/10.1186/s43043-022-00104-8	Published	15 June 2022	Review	https://link.springer.com/article/10.1186/s43043-022-00104-8	Background The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19), has shown its persistent pandemic strength. This viral infectivity, kinetics, and the mechanisms of its actions in human body are still not completely understood. In addition, the infectivity and COVID-19 severity reportedly differ with patient’s gender with men being more susceptible to the disease. Thus, different studies have also suggested the adverse impact of COVID-19 on male reproductive functions, mainly emphasizing on high expressions of angiotensin-converting enzyme 2 (ACE2) in the testes that allows the viral entry into the cells. Main body The N-acetylcysteine (NAC), a potent therapeutic agent of COVID-19, may be effective in reducing the impairing impacts of this disease on male reproductive functions. NAC acts as mucolytic agent by reducing sulfide bonds in the cross-linked glycoprotein matrix in mucus owing to its free sulfhydryl group. Since NAC also breaks the viral disulfide bonds required for the host cell invasion, it may help to prevent direct SARS-CoV-2 invasion into the testicular cells as well. NAC also acts as a potent anti-inflammatory and antioxidant, directly scavenging reactive oxygen species (ROS) and regulating the redox state by maintaining the thiol pool being a precursor of cysteine (an essential substrate for glutathione synthesis). Since it is suggested that male reproductive impairment in COVID-19 patient may be caused by secondary immune responses owing to systemic inflammation and OS, the anti-inflammatory and antioxidant properties of NAC explained above may attribute in protecting the male reproduction functions from these COVID-19-mediated damages. Conclusion This article explains the mechanisms how NAC treatment for COVID-19 may prevent the infection-mediated disruptions in male reproduction.
166	Ce164		Kiran Pohar Manhas, PhD, Petra O’Connell, MHA, Jacqueline Krysa, PhD, Isabel Henderson, Chester Ho, MD, Elisavet Papathanassoglou, PhD	Development of a Novel Care Rehabilitation Pathway for Post-COVID Conditions (Long COVID) in a Provincial Health System in Alberta, Canada	https://doi.org/10.1093/ptj/pzac090	Published	29 June 2022	Study	https://academic.oup.com/ptj/advance-article/doi/10.1093/ptj/pzac090/6619487?login=true	Objective. The purpose of this study was to describe the development and composition of a codesigned, multidisciplinary, integrated, systematic rehabilitation framework for post-COVID conditions (PCC) that spans the care continuum to streamline and standardize rehabilitation services to support persons with PCC in Alberta, Canada. Methods. A collaborative, consensus-based approach was used, involving 2 iterative provincial taskforces in a Canadian provincial health system. The first taskforce (59 multidisciplinary stakeholders) sought to clarify the requisite facets of a sustainable, provincially coordinated rehabilitation approach for post-COVID rehabilitation needs, based on available research evidence. The second taskforce (129 multidisciplinary stakeholders) translated that strategy and criteria into an operational framework for provincial implementation. Both taskforces sought to align with operational realities of the provincial health system. Results. The summation of this collaborative, consensus approach resulted in the Provincial Post COVID-19 Rehabilitation Response Framework (PCRF). The PCRF includes 3 care pathways across the care continuum, specifically targeting in-hospital care, continuing care, and community-based care, with 3 key elements: (1) the use of specific symptom screening and assessment tools to systematically identify PCC symptoms and functional impairments; (2) pathways to determine patients’ rehabilitation trajectory and to guide their transition between care settings; and, (3) self-management and education resources for patients and providers. Conclusion. The PCRF aligns with international mandates for novel codesigned, multidisciplinary approaches to systematically address PCC and its myriad manifestations across the care continuum. The PCRF allows for local adaptation and highlights equity considerations allowing for further spread and scale provincially, nationally, and internationally.
167	Ce165		Suresh, Harshini; Nagaraja, Manjunatha S.	A study of clinical profile, sequelae of COVID, and satisfaction of inpatient care at a government COVID care hospital in Karnataka	https://doi.org/10.4103/jfmpc.jfmpc_1754_21	Published	Jun 1, 2022	Study	https://journals.lww.com/jfmpc/Fulltext/2022/06000/A_study_of_clinical_profile,_sequelae_of_COVID,.67.aspx	Background: Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2 virus has increased the morbidity and mortality across the world. The most common symptoms are fever, dry cough, tiredness, and the least common symptoms are aches and pains, sore throat, diarrhoea, conjunctivitis, headache and loss of taste or smell. In this current pandemic, the number of COVID-19 survivors being discharged from the hospital is increasing day by day and the long-term effect among the survivors is also increasing. Fatigue and dyspnea were the most reported Post COVID symptoms. The presence of these symptoms is also known as “Long COVID”. COVID-19 disease has not only affected the physical health but also the mental health of the patients which also had led to decrease in their quality of life. Material and Methods: A retrospective cross-sectional study was conducted among 35 patients who were admitted in District hospital in Mysuru during the month of October 2020. Purposive Sampling was adopted for selecting the patients. Data was collected through telephone after their discharge. Data were entered in Microsoft Excel sheet and analysed using SPSS trial version 23. Descriptive statistics such as percentages and proportions were calculated. To see the association between the variables, Chi-square test, Fischer’s exact test was used. P < 0.05 was taken as statistically significant. Results: The mean age of the study participants was 49.1 years. Majority of them had fever (68.6%) followed by Myalgia (65.7%), cough (60%), fatigue (42.9%), headache (37.1%) Majority of the patients had no symptoms after discharge (65.7%). After being discharged from the hospital, 22.9% of patients had difficulty in sleeping, 17.1% had loss of taste/smell and fatigue, 8.6% of them had breathlessness and 5.7% of the patients had a change in voice and loss of appetite. Conclusion: With the increasing number of cases across the world, we will most likely face an ongoing wave of COVID-19 sequelae. To Prevent this, an extensive rehabilitation program is necessary for patients during hospitalization and after discharge.
168	Ce166		Alexander M. Matheson1,2, Marrissa J. McIntosh1,2, Harkiran K. Kooner1,2, Justin Lee3, Vedanth Desaigoudar1,2, Elianna Bier4, Bastiaan Driehuys4, Sarah Svenningsen5, Giles E. Santyr6,7, Miranda Kirby8, Mitchell S. Albert9,10,11, Yurii Shepelytskyi9,10, Vira Grynko9,10, Alexei Ouriadov12, Mohamed Abdelrazek13, Inderdeep Dhaliwal14, J. Michael Nicholson14, Grace Parraga1,2,3,13,14 See fewer authors	Oxaloacetate Treatment For Mental And Physical Fatigue In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID fatigue patients: a non-randomized controlled clinical trial	https://doi.org/10.1186/s12967-022-03488-3	Published	28 June 2022	Study	https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03488-3	Background There is no approved pharmaceutical intervention for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS). Fatigue in these patients can last for decades. Long COVID may continue to ME/CFS, and currently, it is estimated that up to 20 million Americans have significant symptoms after COVID, and the most common symptom is fatigue. Anhydrous Enol-Oxaloacetate, (AEO) a nutritional supplement, has been anecdotally reported to relieve physical and mental fatigue and is dimished in ME/CFS patients. Here, we examine the use of higher dosage AEO as a medical food to relieve pathological fatigue. Methods ME/CFS and Long-COVID patients were enrolled in an open label dose escalating “Proof of Concept” non-randomized controlled clinical trial with 500 mg AEO capsules. Control was provided by a historical ME/CFS fatigue trial and supporting meta-analysis study, which showed average improvement with oral placebo using the Chalder Scale of 5.9% improvement from baseline. At baseline, 73.7% of the ME/CFS patients were women, average age was 47 and length of ME/CFS from diagnosis was 8.9 years. The Long-COVID patients were a random group that responded to social media advertising (Face Book) with symptoms for at least 6 months. ME/CFS patients were given separate doses of 500 mg BID (N = 23), 1,000 mg BID (N = 29) and 1000 mg TID (N = 24) AEO for six weeks. Long COVID patients were given 500 mg AEO BID (N = 22) and 1000 mg AEO (N = 21), again over a six-week period. The main outcome measure was to compare baseline scoring with results at 6 weeks with the Chalder Fatigue Score (Likert Scoring) versus historical placebo. The hypothesis being tested was formulated prior to data collection. Results 76 ME/CFS patients (73.7% women, median age of 47) showed an average reduction in fatigue at 6 weeks as measured by the “Chalder Fatigue Questionnaire” of 22.5% to 27.9% from baseline (P < 0.005) (Likert scoring). Both physical and mental fatigue were significantly improved over baseline and historical placebo. Fatigue amelioration in ME/CFS patients increased in a dose dependent manner from 21.7% for 500 mg BID to 27.6% for 1000 mg Oxaloacetate BID to 33.3% for 1000 mg TID. Long COVID patients’ fatigue was significantly reduced by up to 46.8% in 6-weeks. Conclusions Significant reductions in physical and metal fatigue for ME/CFS and Long-COVID patients were seen after 6 weeks of treatment. As there has been little progress in providing fatigue relief for the millions of ME/CFS and Long COVID patients, anhydrous enol oxaloacetate may bridge this important medical need. Further study of oxaloacetate supplementation for the treatment of ME/CFS and Long COVID is warranted.
169	Ce167		Andrew G. Pliszka, B.S.A.	Modafinil: A Review and Its Potential Use in the Treatment of Long COVID Fatigue and Neurocognitive Deficits	https://doi.org/10.1176/appi.ajp-rj.2022.170402	Published	28 Jun 2022	Drug Review	https://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp-rj.2022.170402	Key Points/Clinical Pearls Long COVID refers to a constellation of persistent symptoms, most commonly fatigue and “brain fog,” often reported by individuals who have recovered from acute COVID-19 infection. Modafinil is an eugeroic agent with a favorable safety profile and a low abuse potential, which has been approved for treating fatigue in narcolepsy and shift-work sleep disorder and shown to safely treat fatigue in populations with poststroke fatigue, multiple sclerosis, and HIV/AIDs neurocognitive dysfunction. Modafinil could be a safe and effective agent in treating fatigue and neurocognitive deficits in patients with long COVID. Modafinil is a eugeroic agent approved for treating fatigue in narcolepsy and shift-work sleep disorder. It has been shown to have antioxidant effects preclinically and clinical efficacy in treating neurocognitive symptoms. This article describes findings from a literature review that focused on modafinil’s mechanisms of action and its possible role in treating the fatigue and neurocognitive deficits of long COVID. PubMed was searched with the following key terms: “COVID-19-neuropsychiatric,” “long COVID,” modafinil,” “modafinil-fatigue,” “modafinil-inflammation,” and “modafinil–antioxidant.” Coronavirus disease 2019 (COVID-19), the illness caused by severe acute respiratory syndrome–associated coronavirus type-2 (SARS-CoV-2) infection, has resulted in worldwide morbidity and mortality. Although the majority of COVID-19 infections result in mild disease, 5% of severe cases can lead to critical illness (1). A portion of recovered patients report persistent or new symptoms, even when polymerase chain reaction (PCR) test results are negative. “Long COVID” is a constellation of symptoms that includes fatigue, “brain fogginess,” autonomic dysfunction, headache, loss of smell or taste, cough, depression, low-grade fevers, palpitations, dizziness, muscle pain, and joint pains. One study reported that 87% of hospitalized COVID-19 patients endorsed the persistence of at least one symptom 60 days after discharge, the most common being fatigue (53.1%) (2). Evidence suggests a neuropsychiatric component of coronavirus infection. Among patients hospitalized for SARS and Middle East respiratory syndrome, 30% to 40% reported neuropsychiatric symptoms during the acute illness, and 10%–20% reported persistent neuropsychiatric symptoms after recovery (3). COVID-19 infections involve increased serum levels of proinflammatory cytokines, which can cross the blood-brain barrier, promoting local inflammation resulting in neurotoxicity (4). Neuroinflammation’s relationship to neuropsychiatric disease and symptomatology is well established, illustrated by data demonstrating increased levels of inflammatory cytokines in depressed patients. These effects are thought to be mediated through down-regulation of monoamine neurotransmission and neurotropic factors (5). There is limited literature regarding treatment of either the symptoms or the pathophysiology of long COVID. Established therapies targeted to the patient’s presentation are currently recommended (6), and immune modulation therapies have been recommended to target the inflammatory aspect of the disease (7). Evidence shows that depressed patients with abnormally elevated inflammation are less likely to respond to classical monoamine reuptake inhibitor therapy (8). Given the inflammatory nature of COVID-19 neuropathology, one could hypothesize a similar trend among long COVID patients.
170	Ce168		Kamran Abbasi	Long covid and apheresis: a miracle cure sold on a hypothesis of hope	https://doi.org/10.1136/bmj.o1733	Published	14 July 2022	Article	https://www.bmj.com/content/378/bmj.o1733	A new BMJ investigation with ITN News finds that people are spending their life savings on apheresis, a treatment that claims to clear microthrombi from blood (doi:10.1136/bmj.o1671).20 There are no trials, only hypotheses. There is no research evidence of benefit, only anecdotal reports and the blind faith of vulnerable people seeking a miracle cure. We all need hope, but hope can sometimes be a dangerous thing.
171	Ce169		SilviaCompagnoaStefanoPalermiabValentinaPescatoreaEricaBruginaMarziaSartobRuggeroMarinaValliCalzavaraaManueleNizzettocMorenoScevoladAccursoAloicAlessandroBiffieCarloZanellaaGiovanniCarrettafSilviaGallofFrancoGiadaa	Physical and psychological reconditioning in long COVID syndrome: Results of an out-of-hospital exercise and psychological - based rehabilitation program	https://doi.org/10.1016/j.ijcha.2022.101080	Published	16 July 2022	Study	https://www.sciencedirect.com/science/article/pii/S2352906722001294	Background Long Covid Syndrome (LCS) is used to describe signs and symptoms that continue or develop after acute COVID-19 infection. Natural history and treatment of this syndrome are still poorly understood, even if evidences suggest the potential role of physical rehabilitation in improving symptoms in these patients. Aim of the study The aim of the present study was to evaluate effectiveness, safety and feasibility of an out-of-hospital multidisciplinary rehabilitation (MDR) program, based both on physical and psychological reconditioning, in reducing symptoms and improving physical fitness and psychological parameters in patients with LCS. Methods Thirty consecutive patients with LCS (18 males, mean age 58 years) underwent an accurate medical screening process including anthropometric and muscular strength evaluation, cardiopulmonary exercise test, quality of life (QoL) and psychological appraisal before and after a MDR program. Results At baseline, all LCS patients were strongly symptomatic and showed severe impairments in physical performance, QoL and psychological parameters. No adverse effects and dropouts were observed during the exercise training sessions. After the MDR program, COVID-19 residual symptoms significantly decreased, and significant improvements in upper and lower limb muscular strength, cardiopulmonary parameters, perceived physical and mental health, depression and anxiety were observed. Conclusions The present study confirms the severe physical and psychological impairment of patients with LCS and suggests that a MDR program is effective, safe and feasible in these patients and could promote their physical and psychological recovery.
172	Ce170		Andrey A. Lobanov, Irina A. Grishechkina, Sergei V. Andronov, Gleb N. Barashkov, Andrey I. Popov, Anatoliy D.Fesyun, Elena P. Ivanova, Maria Chiara Maccarone, Stefano Masiero	Can aquatic exercises contribute to the improvement of the gait stereotype function in patients with Long COVID outcomes?	https://doi.org/10.4081/ejtm.2022.10698	Published	2022-07-14	Study	https://www.pagepressjournals.org/index.php/bam/article/view/10698	A variety of rehabilitation programmes can be offered to Long COVID patients, specifically physical training. Indeed 90% of these patients reports impairments of verticalization, stability and spatial orientation, making difficult exercise in the gym. The aim of our study was to assess the effectiveness and safety of aquatic exercise techniques as part of a comprehensive rehabilitation program for patients with Long COVID. The first of a two-stage program involved development of aquatic exercises technique, which was evaluated in 12 patients with impaired upright posture control before and after exercising by "Habilect" video gait analysis system. During the second phase, effectiveness and safety of aqua exercises were tested in water pool as part of a comprehensive rehabilitation programme conducted in 23 patients with Long COVID outcomes. Physical examination, 6-minute step test, Euro-QL-5D questionnaire, Borg scale, laser Doppler flowmetry, cardiointervalography, and spirometry were performed before and after the aquatic exercises program. After the training with aquatic exercises, indices of deviations of the main body axes of the head and the body mass centre ameliorated, as well as direction of body movement vector decreased (p<0.05). This study demonstrated a statistically significant improvement in exercise tolerance in both groups, as measured by the 6-minute step test after rehabilitation. The comparison group averaged 236.7 metres [126; 380] (T=8, p=0.047) after the rehabilitation course and the intervention group averaged 233.71 metres [150; 320] (T=8.0, p=0.047). When tested with the Euro-QL-5D questionnaire, a post-treatment improvement was noted in the comparison group on the anxiety/depression subscale (3 [3;3] (T=0, p=0.043)). In the intervention group, laser Doppler flowmetry revealed a statistically significant increase in microcirculation (6.36 standard units after rehabilitation) [5.54; 8.17] (T=7.0, p=0.004), and a decrease of oxidative metabolism index of 6.89 standard units. [4.76; 6.96] (T=4.0, p=0.03). No serious adverse events were reported. In conclusion, the developed aquatic exercises technique seems to contribute to recovery of impaired upright posture and motor function, normalizing the walking pattern.
173	Ce171		Chaitanya R Patil,Nilesh A Dhamne,Prasad K Tanawade,Namrata B Mestri	Megestrol Acetate in the Treatment of Post COVID-19 Fatigue in a Patient of Advanced Cancer: A Case Report and Mini Review of Literature	https://doi.org/10.1055/s-0042-1742616	Published	2022-04-14	Case Report	https://www.ijmpo.org/ejournals/topic/megestrol-acetate-in-the-treatment-of-post-covid-19-fatigue-in-a-patient-of-advanced-cancer-a-case-report-and-mini-review-of-literature	Megestrol acetate is one of the pharmacological agents used for cancer-associated fatigue. To date, there are no studies on its use in the treatment of post-COVID-19 (coronavirus disease 2019) fatigue. So, we report a case of metastatic carcinoma lung with a partial response with three cycles of palliative chemotherapy. He was contracted with mild COVID-19 infection post three cycles of his chemotherapy. Post this episode, fatigue was his main and most troublesome symptom. After a thorough clinical history, physical examination, and investigations, type 2 post-COVID-19 syndrome was diagnosed. After explaining the risks and benefits, we started the patient on low-dose megestrol acetate (160 mg/d per oral) with low to moderate benefits. However, upon increasing the dose to 480 mg/d, the benefit on the subjective quality of life was significant. Studies with a larger sample and randomized controlled trials have to be conducted to substantiate the hypothesis and actual effect of megestrol acetate in the treatment of post-COVID-19 fatigue.
174	Ce172		RaffaeleIzzoa1ValentinaTrimarcob1PasqualeMonecTeresitaAloèdMassimo CapraMarzanieAntonioDianafGiovanniFaziogMarioMallardohMauroManiscalcoiGiuseppeMarazzijNunziaMessinakSimoneMininnilChiaraMussimGirolamoPelaianAlfioPennisioPierachilleSantuspFrancescoScarpelliqFrancescoTursir…BrunoTrimarcoa	Combining L-Arginine with Vitamin C Improves Long-COVID Symptoms: The Nationwide Multicenter LINCOLN Study	https://doi.org/10.1016/j.phrs.2022.106360	Published	19 July 2022	Study	https://www.sciencedirect.com/science/article/pii/S104366182200305X	HIGHLIGHTS •We hypothesized that a supplementation combining L-Arginine (to improve endothelial function) and Vitamin C (to reduce oxidation) could have beneficial effects in Long-COVID. •We designed a nationwide multicenter clinical study, in which we administered to COVID-19 survivors a survey assessing several symptoms that have been associated with Long-COVID. •1390 patients – divided in two groups L-Arginine + Vitamin C vs multivitaminic combinations (alternative treatment) – completed the study. •After 1-month treatment, patients in the L-Arginine + Vitamin C group had significantly lower scores compared to the alternative treatment group. ABSTRACT Introduction Recent evidence suggests that oxidative stress and endothelial dysfunction play critical roles in the pathophysiology of COVID-19 and Long-COVID. We hypothesized that a supplementation combining L-Arginine (to improve endothelial function) and Vitamin C (to reduce oxidation) could have favorable effects on Long-COVID symptoms. Methods We designed a nationwide multicenter clinical study (LINCOLN: L-Arginine and Vitamin C improves Long-COVID), in which a survey assessing several symptoms that have been associated with Long-COVID was administered to COVID-19 survivors; effort perception was measured using the Borg scale. Patients were divided in two groups, with a 2:1 ratio: the first group included patients treated with L-Arginine + Vitamin C, whereas the second group was treated with a multivitamin combination (alternative treatment). Before administering the survey, patients completed 30 days of treatment. Results 1590 patients were initially enrolled, of which 1390 completed the study. Following a 30-day treatment with L-Arginine + Vitamin C, the survey revealed that patients in this treatment group had significantly lower scores compared to the other group. There were no other significant differences between the two groups. When examining effort perception, we observed a significantly lower value (p<0.0001) in patients receiving L-Arginine + Vitamin C compared to the alternative-treatment arm. Conclusions Taken together, our findings indicate that the supplementation with L-Arginine + Vitamin C has beneficial effects in Long-COVID, in terms of reducing its typical symptoms and improving effort perception.
175	Ce173		Beatriz Carpallo-Porcar,Laura Romo-Calvo,Sara Pérez-Palomares,Carolina Jiménez-Sánchez ,Pablo Herrero,Natalia Brandín-de la Cruz,Sandra Calvo	Efficacy of an asynchronous telerehabilitation program in post-COVID-19 patients: A protocol for a pilot randomized controlled trial	https://doi.org/10.1371/journal.pone.0270766	Published	July 19, 2022	Protocol	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0270766	Background About 40% of patients who have had COVID-19 still have symptoms three months later whereas a 10% may experience physical and/or psychological consequences two years later. Therefore, it is necessary to perform preventive interventions when patients are discharged from the hospital to decrease the aforementioned sequelae. The purpose of this pilot-controlled trial will be to determine the efficacy of a rehabilitation program on functional status and psychosocial factors for post-COVID-19 patients when it is delivered through a tele-care platform versus a booklet-based rehabilitation. Methods The estimated sample size will be of 50 participants who have been discharged after COVID-19 and have a level of fatigue equal or greater than 4 on the Fatigue Severity Scale. The primary outcome will be the severity of fatigue. Participants will be randomly allocated to an “asynchronous telerehabilitation group” or to a “booklet-based rehabilitation group”. Treatment in both groups will be the same and will consist of a combination of therapeutic exercise and an educative program. Treatment outcomes will be evaluated the last day of the intervention and at three- and six-months follow-up. Discussion The telerehabilitation intervention appears to be a viable and efficacy option in decreasing severe fatigue and other fitness variables such as strength and aerobic capacity, similar to other traditional rehabilitation formats such as through an explanatory booklet.
176	Ce174		Edith L. Graham, Igor J. Koralnik & Eric M. Liotta	Therapeutic Approaches to the Neurologic Manifestations of COVID-19	https://doi.org/10.1007/s13311-022-01267-y	Published	21 July 2022	Article	https://link.springer.com/article/10.1007/s13311-022-01267-y	As of May 2022, there have been more than 527 million infections with severe acute respiratory disease coronavirus type 2 (SARS-CoV-2) and over 6.2 million deaths from Coronavirus Disease 2019 (COVID-19) worldwide. COVID-19 is a multisystem illness with important neurologic consequences that impact long-term morbidity and mortality. In the acutely ill, the neurologic manifestations of COVID-19 can include distressing but relatively benign symptoms such as headache, myalgias, and anosmia; however, entities such as encephalopathy, stroke, seizures, encephalitis, and Guillain–Barre Syndrome can cause neurologic injury and resulting disability that persists long after the acute pulmonary illness. Furthermore, as many as one-third of patients may experience persistent neurologic symptoms as part of a Post-Acute Sequelae of SARS-CoV-2 infection (Neuro-PASC) syndrome. This Neuro-PASC syndrome can affect patients who required hospitalization for COVID-19 or patients who did not require hospitalization and who may have had minor or no pulmonary symptoms. Given the large number of individuals affected and the ability of neurologic complications to impair quality of life and productivity, the neurologic manifestations of COVID-19 are likely to have major and long-lasting personal, public health, and economic consequences. While knowledge of disease mechanisms and therapies acquired prior to the pandemic can inform us on how to manage patients with the neurologic manifestations of COVID-19, there is a critical need for improved understanding of specific COVID-19 disease mechanisms and development of therapies that target the neurologic morbidities of COVID-19. This current perspective reviews evidence for proposed disease mechanisms as they inform the neurologic management of COVID-19 in adult patients while also identifying areas in need of further research.
177	Ce175		Lavanya Visvabharathy Zachary S. Orban1 Igor J. Koralnik1	Treatment of Long COVID with nirmatrelvir/ritonavir and tocilizumab in a patient with rheumatoid arthritis and SARS-CoV-2 antigen persistence: a case report	https://doi.org/10.21203/rs.3.rs-1879380/v1	pre-print	22 Jul, 2022	Case Report	https://www.researchsquare.com/article/rs-1879380/v1	Background Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC) in ~ 30% of all infected individuals. Here, we present a case of PASC in a patient with rheumatoid arthritis characterized by viral persistence in the nasopharynx for 6 months after acute infection. We demonstrate transient disappearance of antigen persistence and decreased antiviral and autoimmune T cell responses after nirmatrelvir/ritonavir and tocilizumab treatment. Case Presentation: A 37-year-old female with a 7-year history of rheumatoid arthritis enrolled in a COVID-19 research study was found to continuously test SARS-CoV-2 antigen positive in the nasopharynx for 6 months after acute infection. She simultaneously presented with new-onset PASC symptoms including chronic occipital headache and periods of intense fatigue 8 weeks after acute infection. The patient was prescribed nirmatrelvir/ritonavir to treat SARS-CoV-2 persistence at 3.5 months post-acute infection and observed a reduction in PASC symptoms 3 weeks after completing antiviral treatment. After resurgence of PASC symptoms, she stopped treatment with tocilizumab for rheumatoid arthritis to attempt complete SARS-CoV-2 viral clearance. The severity of the patient’s PASC symptoms subsequently increased, and she developed new-onset brain fog in addition to previous symptoms, which resolved after resumption of tocilizumab treatment. Assessment of adaptive immune responses demonstrated that nirmatrelvir/ritonavir and tocilizumab treatment decreased antiviral and autoreactive T cell activation. After resuming tocilizumab treatment, the patient’s PASC symptoms were significantly reduced, but nasopharyngeal antigen positivity remained. Conclusions These data suggest that nirmatrelvir/ritonavir should be considered in the treatment of PASC in patients who have SARS-CoV-2 antigen persistence, though care must be taken to monitor the patient for symptom resurgence or viral reactivation. In addition, the IL-6 inhibitor tocilizumab may ameliorate PASC symptoms in patients with persistent headache, fatigue, and brain fog.
178	Ce176		Aaron M. Gusdon1, Nauder Faraday2, John S. Aita3 , Sunil Kumar4, Ishan Mehta5 HuiMahn A. Choi1 , Jeffery L. Cleland6, Keith Robinson7, Louise D. McCullough8 , Derek K. Ng9 Rangaramanujam M. Kannan10, Sujatha Kannan	Dendrimer nanotherapy for severe COVID-19 attenuates inflammation and neurological injury markers and improves outcomes in a phase2a clinical trial	https://doi.org/10.1126/scitranslmed.abo2652	Published	20 Jul 2022	Study	https://www.science.org/doi/10.1126/scitranslmed.abo2652	A dendrimer nanotherapy for COVID-19 OP-101, a hydroxyl-polyamidoamine dendrimer–N-acetyl cysteine conjugate, that specifically targets activated macrophages was evaluated in patients with severe COVID-19 in a phase 2a clinical trial. A single intravenous infusion of OP-101 was well tolerated and reduced the risk of death or mechanical ventilation at 30 and 60 days after treatment when compared to placebo. OP-101 treatment was associated with decreased serum concentrations of proinflammatory markers as well as markers of neurological injury (neurofilament light chain and glial fibrillary acidic protein). OP-101 may have potential for treating systemic hyperinflammation in severe COVID-19. Abstract Hyperinflammation triggered by SARS-CoV-2 is a major cause of disease severity, with activated macrophages implicated in this response. OP-101, a hydroxyl-polyamidoamine dendrimer–N-acetylcysteine conjugate that specifically targets activated macrophages, improves outcomes in preclinical models of systemic inflammation and neuroinflammation. In this multicenter, randomized, double-blind, placebo-controlled, adaptive phase 2a trial, we evaluated safety and preliminary efficacy of OP-101 in patients with severe COVID-19. Twenty-four patients classified as having severe COVID-19 with a baseline World Health Organization seven-point ordinal scale of ≥5 were randomized to receive a single intravenous dose of placebo (n = 7 patients) or OP-101 at 2 (n = 6), 4 (n = 6), or 8 mg/kg (n = 5 patients). All study participants received standard of care, including corticosteroids. OP-101 at 4 mg/kg was better than placebo at decreasing inflammatory markers; OP-101 at 4 and 8 mg/kg was better than placebo at reducing neurological injury markers, (neurofilament light chain and glial fibrillary acidic protein). Risk for the composite outcome of mechanical ventilation or death at 30 and 60 days after treatment was 71% (95% CI: 29%, 96%) for placebo and 18% (95% CI: 4%, 43%; P = 0.021) for the pooled OP-101 treatment arms. At 60 days, 3 of 7 patients given placebo and 14 of 17 OP-101–treated patients were surviving. No drug-related adverse events were reported. These data show that OP-101 was well tolerated and may have potential to treat systemic inflammation and neuronal injury, reducing morbidity and mortality in hospitalized patients with severe COVID-19.
179	Ce177		A. E. Tereshin, V. V. Kiryanova & D. A. Reshetnik	Correction of Mitochondrial Dysfunction in the Complex Rehabilitation of COVID-19 Patients	https://doi.org/10.1007/s11055-022-01269-5	Published	22 July 2022	Study	https://link.springer.com/article/10.1007/s11055-022-01269-5	Objective. To study the efficacy of courses of i.v., Cytoflavin in combination with the standard rehabilitation program for postcovid syndrome for correction of postcovid asthenia. Materials and methods. Follow-up investigations were carried out in 45 patients with postcovid syndrome at the second stage of rehabilitation. Patients were divided into two groups of comparable sex and age. The volume of lung damage was also similar in both groups, at 25–80%. The 24 patients making up the comparison group received standard postcovid rehabilitation: pulsed magnetotherapy, inhalation therapy, aeroionotherapy, infrared laser therapy, courses of aerobic training, rational psychotherapy, and successive drug therapy. The 21 patients of the study group additionally received intravenous Cytoflavin daily for 10 days. The dynamics of increases in scores on the Rehabilitation Routing Scale, the Hamilton Depression Rating Scale (HDRS), the Asthenic Status Scale, and the 6-minute walk test at admission and discharge were also monitored. Results and conclusions. Addition of courses of intravenous Cytoflavin to the complex rehabilitation program for postcovid syndrome significantly improved the general functional state of the body, decreased levels of depression and asthenization, and increased physical exercise tolerance.
180	Ce178		Mateja Janković Makek1, Zdravko Babić2, Barbara Barun3 , Nikolina Bašić-Jukić4 Ervina Bilić3, Fran Borovečki3, Venija Cerovečki5, Rok Čivljak6, Viktor Domislović7 ,Ivo Darko Gabrić2, Mario Habek3, Irzal Hadžibegović8, Nenad Jakšić9, Tajana JalušićGlunčić1 , Željko Krznarić7, Ivica Lukšić10, Đivo Ljubičić11, Darko Marčinko9, Alemka Markotić6 , Ante Marušić12, Porin Perić13, Željka Petelin Gadže3 , Delfa Radić Krišto14, Gzim Redžepi15, Davor Sporiš16, Miroslav Samaržija	Overview and management of different post-COVID conditions	https://doi.org/10.21857/mwo1vc32oy	Published	30 June 2022	Review	https://hrcak.srce.hr/file/407088	Coronavirus disease 2019 (COVID-19) pandemic resulted in global healthcare crises and strained health resources, both in the acute and chronic phase of the disease. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged symptoms after acute COVID-19. These reports and studies have helped contribute to the recognition of post-COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of different manifestations of post-COVID conditions and propose a framework for the identification of patients at higher risk for post- COVID and their coordinated management through dedicated COVID-19 outpatient clinics.
181	Ce179		Bumi Herman ,Martin Chi-sang Wong ,Pramon Viwattanakulvanid	Vaccination status, favipiravir, and micronutrient supplementation roles in post-COVID symptoms: A longitudinal study	https://doi.org/10.1371/journal.pone.0271385	Published	July 21, 2022	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0271385	Introduction Post-COVID symptoms are the new concern in the COVID-19 pandemic, where recovered patients experience residual symptoms affecting their quality of life. Therefore, it is imperative to evaluate the role of complete vaccination, prescribed medication, and micronutrients during COVID episodes in the occurrence of post-COVID symptoms. Method A longitudinal evaluation of Indonesia’s recovered COVID-19 patients was performed using the data collected from July 2021 and extracted in mid-February 2022. All participants were confirmed with a Real-Time Polymerase Chain Reaction test (PCR) and/or antigen test. This study collected demography and comorbidities information, symptoms and treatment of COVID-19, and collection of self-reported post-COVID symptoms every 30 days within 90 days after diagnosis/onset. Exposures of interest include vaccination status, Favipiravir administration, Vitamin C, Vitamin D, and Zinc. A Generalized Estimating Equation (GEE) was used to evaluate the longitudinal effect of exposures, presented with adjusted odds ratios and its 95% confidence interval. Results A total of 923 participants (18.2% fully-vaccinated) were involved in the study, with 79.7% being non-hospitalized. Only 25.7% did not develop any residual symptoms within 90 days. Fatigue was the most reported post-COVID symptom in each measurement time (39.5%, 16.3%, and 7.3%). Full-vaccination was effective against chronic cough (aOR 0.527, 95% CI 0.286–0.971), chronic headache (aOR 0.317, 95% CI 0.163–0.616), and chronic arthritis (aOR 0.285, 95% CI 0.116–0.703). The combination of micronutrient supplementations and Favipiravir gave no significant effect on all post-COVID symptoms. However, early initiation of Favipiravir and delaying vitamin D administration were associated with arthritis. Conclusion Full vaccination of COVID-19 prevents the disease and the development of residual symptoms when infected with SARS-COV-2. Hence, it is crucial to reconsider the prescription of micronutrient supplementation or adjust the dose of Favipiravir in the current guideline.
182	Ce180		Ícaro de A. T. Pires, MD, Sara T. Steffens, MD, Aurenzo G. Mocelin, MD, Debora E. Shibukawa, MD, Letícia Leahy, MD, Fernanda L. Saito, MD, Nicole T. Amadeu, MD, Natália M. D. Lopes, MSc, PhD, Ellen C. D. Garcia, MSc, PhD, Maria L. Albanese, MD, Laura F. De Mari, MD, Isabel M. Ferreira, MD, César A. Veiga, MSc, PhD, Yasser Jebahi, MD, PhD, Herton Coifman, MD, Marco A. Fornazieri, MD, PhD, Rogério Hamerschmidt, MD, PhD	Intensive Olfactory Training in Post-COVID-19 Patients: A Multicenter Randomized Clinical Trial	https://doi.org/10.1177%2F19458924221113124	Published	July 21, 2022	Study	https://journals.sagepub.com/doi/10.1177/19458924221113124	Background Olfactory dysfunction (OD)—including anosmia and hyposmia—is a common symptom of COVID-19. Previous studies have identified olfactory training (OT) as an important treatment for postinfectious OD; however, little is known about its benefits and optimizations after SARS-CoV-2 infection. Objective This study aimed to assess whether olfactory training performance can be optimized using more fragrances over a shorter period of time in patients with persistent OD after COVID-19. In addition, we determined the presence of other variables related to OD and treatment response in this population. Methods This multicenter randomized clinical trial recruited 80 patients with persistent OD and prior COVID-19 infection for less than 3 months. The patients were divided into 2 groups receiving either 4 or 8 essences over 4 weeks. Subjective assessments and the University of Pennsylvania Smell Identification Test (UPSIT) were performed before and after the treatment. Results Significant olfactory improvement was measured subjectively and using the UPSIT in both groups; however, no significant differences between the groups were observed. Additionally, the presence of olfactory fluctuations was associated with higher UPSIT scores. Conclusion These data suggest that training intensification by increasing the number of essences for 4 weeks does not show superiority over the classical method. Moreover, fluctuant olfaction seems to be related to a higher score on the UPSIT.
183	Ce181		Loredana Raciti 1ORCID,Rosaria De Luca 2,Gianfranco Raciti 1,Francesca Antonia Arcadi 2 andRocco Salvatore Calabrò 2,*ORCID	The Use of Palmitoylethanolamide in the Treatment of Long COVID: A Real-Life Retrospective Cohort Study	https://doi.org/10.3390/medsci10030037	Published	14 July 2022	Study	https://www.mdpi.com/2076-3271/10/3/37/htm	COVID-19 can cause symptoms that last weeks or months after the infection has gone, with a significant impairment of quality of life. Palmitoylethanolamide (PEA) is a naturally occurring lipid mediator that has an entourage effect on the endocannabinoid system mitigating the cytokine storm. The aim of this retrospective study is to evaluate the potential efficacy of PEA in the treatment of long COVID. Patients attending the Neurological Out Clinic of the IRCCS Centro Neurolesi Bonino-Pulejo (Messina, Italy) from August 2020 to September 2021 were screened for potential inclusion in the study. We included only long COVID patients who were treated with PEA 600 mg two times daily for about 3 months. All patients performed the post-COVID-19 Functional Status (PCFS) scale. Thirty-three patients (10 males, 43.5%, mean age 47.8 ± 12.4) were enrolled in the study. Patients were divided into two groups based on hospitalization or home care observation. A substantial difference in the PCFS score between the two groups at baseline and after treatment with PEA were found. We found that smoking was a risk factor with an odds ratio of 8.13 CI 95% [0.233, 1.167]. Our findings encourage the use of PEA as a potentially effective therapy in patients with long COVID.
184	Ce182		Shruti Gupta, MD1,2; Jake J. Lee, MD, MSCI1; Amber Perrin, BA1; Amish Khan, BS3; Harrison J. Smith, MD4; Nyssa Farrell, MD5; Dorina Kallogjeri, MD, MPH1; Jay F. Piccirillo, MD1	Efficacy and Safety of Saline Nasal Irrigation Plus Theophylline for Treatment of COVID-19–Related Olfactory Dysfunction The SCENT2 Phase 2 Randomized Clinical Trial	https://doi.org/10.1001/jamaoto.2022.1573	Published	July 7, 2022	Study	https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2793987	Key Points Question Is the use of theophylline added to saline nasal irrigation efficacious and safe for treatment of COVID-19–related olfactory dysfunction? Findings In this phase 2 randomized clinical trial of 51 adults with chronic COVID-19–related olfactory dysfunction, the number of participants who self-reported improvement in their olfactory function after using theophylline nasal irrigation was 16% higher than those receiving placebo (59% vs 43%). The theophylline arm had 24% more participants with a clinically meaningful change in their objective smell identification test score. Meaning The use of theophylline added to saline nasal irrigations may result in clinically beneficial improvements in smell function compared with saline irrigation alone. Abstract Importance Recent studies suggest that theophylline added to saline nasal irrigation (SNI) can be an effective treatment for postviral olfactory dysfunction (OD), a growing public health concern during the COVID-19 pandemic. Objective To evaluate the efficacy and safety of theophylline added to SNI compared with placebo for COVID-19–related OD. Design, Setting, and Participants This triple-blinded, placebo-controlled, phase 2 randomized clinical trial was conducted virtually between March 15 and August 31, 2021. Adults residing in Missouri or Illinois were recruited during this time period if they had OD persisting for 3 to 12 months following suspected COVID-19 infection. Data analysis was conducted from October to December 2021. Interventions Saline sinus rinse kits and bottles of identical-appearing capsules with either 400 mg of theophylline (treatment) or 500 mg of lactose powder (control) were mailed to consenting study participants. Participants were instructed to dissolve the capsule contents into the saline rinse and use the solution to irrigate their nasal cavities in the morning and at night for 6 weeks. Main Outcomes and Measures The primary outcome was the difference in the rate of responders between the treatment and the control arms, defined as a response of at least slightly better improvement in the Clinical Global Impression-Improvement scale posttreatment. Secondary outcome measures included changes in the University of Pennsylvania Smell Identification Test (UPSIT), the Questionnaire for Olfactory Disorders, the 36-Item Short Form Health Survey on general health, and COVID-19–related questions. Results A total of 51 participants were enrolled in the study; the mean (SD) age was 46.0 (13.1) years, and 36 (71%) participants were women. Participants were randomized to SNI with theophylline (n = 26) or to SNI with placebo (n = 25). Forty-five participants completed the study. At the end of treatment, 13 (59%) participants in the theophylline arm reported at least slight improvement in the Clinical Global Impression-Improvement scale (responders) compared with 10 (43%) in the placebo arm (absolute difference, 15.6%; 95% CI, −13.2% to 44.5%). The median difference for the UPSIT change between baseline and 6 weeks was 3.0 (95% CI, −1.0 to 7.0) for participants in the theophylline arm and 0.0 (95% CI, −2.0 to 6.0) for participants in the placebo arm. Mixed-model analysis revealed that the change in UPSIT scores through study assessments was not statistically significantly different between the 2 study arms. Eleven (50%) participants in the theophylline arm and 6 (26%) in the placebo arm had a change of 4 or more points in UPSIT scores from baseline to 6 weeks. The difference in the rate of responders as measured by the UPSIT was 24% (95% CI, −4% to 52%) in favor of theophylline. Conclusions and Relevance This randomized clinical trial suggests that the clinical benefit of theophylline nasal irrigations on olfaction in participants with COVID-19–related OD is inconclusive, though suggested by subjective assessments. Larger studies are warranted to investigate the efficacy of this treatment more fully.
185	Ce183		Madlen Davies	Long covid patients travel abroad for expensive and experimental “blood washing”	https://doi.org/10.1136/bmj.o1671	Published	12 July 2022	Article	https://www.bmj.com/content/378/bmj.o1671.full	Patients with long covid are travelling to private clinics in Cyprus, Germany, and Switzerland for blood filtering apheresis and anticoagulation drugs. Experts question whether these invasive treatments should be offered without sufficient evidence. Madlen Davies reports
186	Ce184		Alicia Gonzalez-Martinez, Ángel Luis Guerrero-Peral, Susana Arias-Rivas, Lorenzo Silva, Álvaro Sierra, Ana Beatriz Gago-Veiga & David García-Azorín	Amitriptyline for post-COVID headache: effectiveness, tolerability, and response predictors	https://doi.org/10.1007/s00415-022-11225-5	Published	12 July 2022	Study	https://link.springer.com/article/10.1007/s00415-022-11225-5	Background Headache is one of the most frequently reported symptoms in post-COVID patients. The clinical phenotype of COVID-19 headache combines phenotypic features of both tension-type headache (TTH) and migraine. We aimed to assess the effectiveness, side effects and predictors of amitriptyline (AMT) response in a real-world study setting. Methods We performed an observational multicentric study with a retrospective cohort. All consecutive patients with confirmed COVID-19 infection who received AMT for post-COVID headache from March 2020 to May 2021 were included. Response was evaluated by the reduction in the number of headache days per month (HDM) between weeks 8 and 12, compared with the baseline. We explored which variables were associated with a higher probability of response to AMT. Results Forty-eight patients were eligible for the study, 40/48 (83.3%) females, aged 46.85 (SD: 13.59) years. Patients had history of migraine 15/48 (31.3%) or TTH 5/48 (10.4%). The mean reduction of HDM was 9.6 (SD: 10.9; 95% CI 6.5, 12.7) days. Only 2/48 (5%) of patients discontinued AMT due to poor tolerability. History of TTH (10.9, 95% CI 1.3, 20.6) and nausea (− 8.5, 95% CI − 14.6, − 2.5) were associated with AMT response. Conclusions This study provides real-world evidence of the potential benefit of AMT in patients with post-COVID-19 headache, especially in patients with history of TTH and without concomitant nausea.
187	Ce185		Fabiola Cardoso Diniz, 1 , 2 , 3 Alan Roger Hipkiss, 4 and Gustavo Costa Ferreiracorresponding author 1 , 2 , 5 , *	The Potential Use of Carnosine in Diabetes and Other Afflictions Reported in Long COVID Patients	https://doi.org/10.3389%2Ffnins.2022.898735	Published	2022 Jun 22	Article	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9257001/	Carnosine is a dipeptide expressed in both the central nervous system and periphery. Several biological functions have been attributed to carnosine, including as an anti-inflammatory and antioxidant agent, and as a modulator of mitochondrial metabolism. Some of these mechanisms have been implicated in the pathophysiology of coronavirus disease-2019 (COVID-19). COVID-19 is caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The clinical manifestation and recovery time for COVID-19 are variable. Some patients are severely affected by SARS-CoV-2 infection and may experience respiratory failure, thromboembolic disease, neurological symptoms, kidney damage, acute pancreatitis, and even death. COVID-19 patients with comorbidities, including diabetes, are at higher risk of death. Mechanisms underlying the dysfunction of the afflicted organs in COVID-19 patients have been discussed, the most common being the so-called cytokine storm. Given the biological effects attributed to carnosine, adjuvant therapy with this dipeptide could be considered as supportive treatment in patients with either COVID-19 or long COVID.
188	Ce186		Shani Zilberman-Itskovich, Merav Catalogna, Efrat Sasson, Karin Elman-Shina, Amir Hadanny, Erez Lang, Shachar Finci, Nir Polak, Gregory Fishlev, Calanit Korin, Ran Shorer, Yoav Parag, Marina Sova & Shai Efrati	Hyperbaric oxygen therapy improves neurocognitive functions and symptoms of post-COVID condition: randomized controlled trial	https://doi.org/10.1038/s41598-022-15565-0	Published	12 July 2022	Study	https://www.nature.com/articles/s41598-022-15565-0	Post-COVID-19 condition refers to a range of persisting physical, neurocognitive, and neuropsychological symptoms after SARS-CoV-2 infection. The mechanism can be related to brain tissue pathology caused by virus invasion or indirectly by neuroinflammation and hypercoagulability. This randomized, sham-control, double blind trial evaluated the effect of hyperbaric oxygen therapy (HBOT or HBO2 therapy) on post-COVID-19 patients with ongoing symptoms for at least 3 months after confirmed infection. Seventy-three patients were randomized to receive daily 40 session of HBOT (n = 37) or sham (n = 36). Follow-up assessments were performed at baseline and 1–3 weeks after the last treatment session. Following HBOT, there was a significant group-by-time interaction in global cognitive function, attention and executive function (d = 0.495, p = 0.038; d = 0.477, p = 0.04 and d = 0.463, p = 0.05 respectively). Significant improvement was also demonstrated in the energy domain (d = 0.522, p = 0.029), sleep (d = − 0.48, p = 0.042), psychiatric symptoms (d = 0.636, p = 0.008), and pain interference (d = 0.737, p = 0.001). Clinical outcomes were associated with significant improvement in brain MRI perfusion and microstructural changes in the supramarginal gyrus, left supplementary motor area, right insula, left frontal precentral gyrus, right middle frontal gyrus, and superior corona radiate. These results indicate that HBOT can induce neuroplasticity and improve cognitive, psychiatric, fatigue, sleep and pain symptoms of patients suffering from post-COVID-19 condition. HBOT’s beneficial effect may be attributed to increased brain perfusion and neuroplasticity in regions associated with cognitive and emotional roles.
189	Ce187		Robin Green1 Julia Rybkina Nithin Jacob Brenda Colella David Gold Donna Stewart Lesley Ruttan Liesel-Ann Meusel Mary Pat McAndrews Susan Abbey	Self-Managing Symptoms of Long COVID: an Education and Strategies Research Protocol	https://doi.org/10.21203/rs.3.rs-1894964/v1	pre-print	11 Aug, 2022	Study	https://www.researchsquare.com/article/rs-1894964/v1	Post-acute sequelae of SARS-COV-2 (PASC) is growing in prevalence, and involves symptoms originating from the central neurological, cardiovascular, respiratory, gastrointestinal, autonomic nervous, or immune systems. There are non-specific symptoms such as fatigue, headaches, and brain fog, which cannot be ascribed to a single system/organ. PASC places a notable strain on our healthcare system, which is already laden with a large number of acute-COVID-19 patients. Furthermore, it impedes social, academic and vocational functioning, and impacts family life, relationships, and work/financial life. The treatment for PASC needs to target this non-specific etiology and wide-ranging sequelae. In conditions similar to PASC, such as “chemo brain”, and prolonged symptoms of concussion, the non-specific symptoms have shown to be effectively managed through education and strategies for self-management and Mindfulness interventions. However, such interventions have yet to be empirically evaluated in PASC to our knowledge. In response to this gap, we have developed a virtual education intervention synthesized by psychiatrists and clinical psychologists for the current study. We will undertake a two-phase randomized controlled trial to determine the feasibility (Phase 1; N = 90) and efficacy (Phase 2; sample sized based on phase 1 results) of the novel 8 week education and self-management strategies group compared to a mindfulness skills program, both delivered virtually. Main outcomes include confidence/ability to self-manage symptoms, quality of life, and healthcare utilization. This study stands to mitigate the deleterious intrusiveness of symptoms on everyday life in patients with PASC, and may also help to reduce the impact of PASC on the healthcare system.
190	Ce188		Sergey Tselmin , Ulrich Julius , Natalia Jarzebska , RomanN. Rodionov	COVID-19 and Therapeutic Apheresis	https://doi.org/10.1055/a-1864-9482	Published	09 August 2022	Review	https://www.thieme-connect.com/products/ejournals/abstract/10.1055/a-1864-9482	The COVID-19 pandemic, caused by the SARS-CoV-2 virus, is an unprecedented challenge for the global community. The pathogenesis of COVID-19, its complications and long term sequelae (so called Long/Post-COVID) include, in addition to the direct virus-induced tissues injury, multiple secondary processes, such as autoimmune response, impairment of microcirculation, and hyperinflammation. Similar pathological processes, but in the settings of neurological, cardiovascular, rheumatological, nephrological, and dermatological diseases can be successfully treated by powerful methods of Therapeutic Apheresis (TA). We describe here the rationale and the initial attempts of TA treatment in severe cases of acute COVID-19. We next review the evidence for the role of autoimmunity, microcirculatory changes and inflammation in pathogenesis of Long/Post COVID and the rationale for targeting those pathogenic processes by different methods of TA. Finally, we discuss the impact of COVID-19 pandemic on patients, who undergo regular TA treatments due to their underlying chronic conditions, with the specific focus on the patients with inherited lipid diseases being treated at the Dresden University Apheresis Center.
191	Ce189		Gaurav Chauhan, Aman Upadhyay, Suchit Khanduja, Trent Emerick	Stellate Ganglion Block for Anosmia and Dysgeusia Due to Long COVID	https://doi.org/10.7759/cureus.27779	Published	August 08, 2022	Case Report	https://www.cureus.com/articles/106516-stellate-ganglion-block-for-anosmia-and-dysgeusia-due-to-long-covid	Anosmia and parosmia refer to the loss or dysfunction of smell, respectively. Dysgeusia refers to taste disturbance. The coronavirus disease 2019 (COVID-19) pandemic and the subsequent phenomenon of Long COVID syndrome have been associated with an increased incidence of anosmia and dysgeusia. Smell and taste disturbances associated with COVID-19 are usually self-limiting but can persist for longer periods in some cases. Imbalances of the autonomic nervous system, especially dysregulation of the sympathetic system, are implicated in the persistence of anosmia and dysgeusia post-COVID-19 infection. Stellate ganglion block (SGB) can diminish the increased sympathetic activity and potentially resolve anosmia and dysgeusia occurring due to Long COVID. The authors report the successful resolution of persistent anosmia and dysgeusia due to Long COVID in a female patient after she underwent SGB.
192	Ce190		Muchtaridi Muchtaridi 1,*ORCID,Siti Rafa Amirah 1,Jacko Abiwaqash Harmonis 1 andEmmy Hainida Khairul Ikram 2ORCID	Role of Nuclear Factor Erythroid 2 (Nrf2) in the Recovery of Long COVID-19 Using Natural Antioxidants: A Systematic Review	https://doi.org/10.3390/antiox11081551	Published	10 August 2022	Review	https://www.mdpi.com/2076-3921/11/8/1551/htm	Coronavirus disease 2019 (COVID-19) is an infectious disease with approximately 517 million confirmed cases, with the average number of cases revealing that patients recover immediately without hospitalization. However, several other cases found that patients still experience various symptoms after 3–12 weeks, which is known as a long COVID syndrome. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can activate nuclear factor kappa beta (NF-κβ) and unbind the nuclear factor erythroid 2-related factor 2 (Nrf2) with Kelch-like ECH-associated protein 1 (Keap1), causing inhibition of Nrf2, which has an important role in antioxidant response and redox homeostasis. Disrupting the Keap1–Nrf2 pathway enhances Nrf2 activity, and has been identified as a vital approach for the prevention of oxidative stress and inflammation. Hence, natural antioxidants from various sources have been identified as a promising strategy to prevent oxidative stress, which plays a role in reducing the long COVID-19 symptoms. Oxygen-rich natural antioxidant compounds provide an effective Nrf2 activation effect that interact with the conserved amino acid residues in the Keap1-binding pocket, such as Ser602, Ser363, Ser508, and Ser555. In this review, the benefits of various natural antioxidant compounds that can modulate the Nrf2 signaling pathway, which is critical in reducing and curing long COVID-19, are highlighted and discussed.
193	Ce191		Leah Conti, Rosa Kim, Amnon A. Berger, Lianne Ryan, Jonathan Eskander	Icosapent Ethyl (VASCEPA®) in the treatment of prolonged post-infectious COVID-19 symptoms		Published	August 2022	Case Report	https://www.cureus.com/publish/articles/92742-icosapent-ethyl-vascepa-in-the-treatment-of-prolonged-post-infectious-covid-19-symptoms/preview?token=K_GvFLfprFB2cyqJukEg&utm_campaign=added_as_coauthor&utm_medium=email&utm_source=author_mailer	COVID-19, the SARS-CoV-2 disease, is a pandemic with devastating effects. Two years into the pandemic, few therapeutic options are available to treat the spectrum of disease. More recently a prolonged post-infectious syndrome, or “long COVID” has been described. This is a post-viral syndrome that persists after the acute infection, without any current available treatment. Emerging evidence attribute this syndrome to ongoing inflammatory response following resolution of acute symptoms. An omega-three fatty acid derivative used in the treatment of hypertriglyceridemia, Icosapent Ethyl (IPE, VASCEPA®), was previously shown to reduce cardiovascular risk, likely via immunomodulatory effects. Following previous publications in treatment of severe acute COVID-19, we present three cases of resolution of long-COVID after treatment with IPE.
194	Ce192		Hansen, Kristoffer Skaalum and Mogensen, Trine Hyrup and Agergaard, Jane and Schiøttz-Christensen, Berit and Østergaard, Lars Jørgen and Vibholm, Line Khalidan and Leth, Steffen	Coenzyme Q10 as Treatment of Post COVID-19 Condition	http://dx.doi.org/10.2139/ssrn.4178044	pre-print	1 Aug 2022	Trial	https://deliverypdf.ssrn.com/delivery.php?ID=466101127096068118004096017107017109028027010042065026093045039119019036059025067074127043001044014042091098031005098067070004076001031016105099052016092007118015037119081113091122104118116122125126054094010014019119087094107019010031064031023031103092064070066098004006106073021119064087107&EXT=pdf&INDEX=TRUE	Background Post COVID-19 condition (PCC) is defined as symptoms lasting more than 12 weeks after developing COVID-19. Evidence of mitochondrial dysfunction has been reported in peripheral blood mononuclear cells obtained from patients with COVID-19. We hypothesized that PCC is caused by prolonged mitochondrial dysfunction. Given that coenzyme Q10 (CoQ10) can improve mitochondrial function, we examined whether high-dose CoQ10 can reduce the number and/or severity of PCC-related symptoms. Methods In this placebo-controlled, double-blind, 2x2 crossover interventional trial, participants were recruited from two centres at Aarhus University Hospital and Gødstrup Hospital, Denmark. They were randomly assigned to receive either oral capsules of CoQ10 in a dose of 500 mg/day or placebo for six weeks, with crossover treatment after a four-week washout period. The ED-5Q and a PCC symptom specific questionnaire were completed by the participants at 5 visits during the 20-week study period. The primary endpoint was the change in the number and/or severity of PCC-related symptoms after the six-week intervention compared to placebo. Participants who completed the two-dosing period were included in the primary analysis, while all participants receiving one dose were included in safety assessment. Findings From May 25th, 2021, to September 22nd, 2021, 121 participants underwent randomization, and 119 completed both dosing periods – 59 and 60 in group A and B, respectively. At baseline, the mean PCC-related symptom score was 43·06 (95% CI: 40·18;45·94), and the mean EQ-5D health index was 0·66 (95% CI: 0·64;0·68). The difference between CoQ10 and placebo was not significant with respect to either the change in EQ-5D health index (with a mean difference of 0·01; 95% CI:0·02;0·04; p=0·45) or the change in PCC-related symptom score (with a mean difference of -1·18; 95% CI: -3·54;1·17; p=0·32). Interpretation We conclude that CoQ10 treatment does not appear to significantly reduce the number or severity of PCC-related symptoms when compared to placebo. Funding Placebo and CoQ10 capsules were provided by Pharma Nord, and the trial was supported by grants from the Novo Nordisk Foundation (NNF21OC0066984). This trial is registered with EudraCT, 2020-005961-16 and ClinicalTrials.gov, NCT04960215. The trial is completed.
195	Ce193		Mária Orendáčová ,Eugen Kvašňák,Jana Vránová	Effect of neurofeedback therapy on neurological post-COVID-19 complications (A pilot study)	https://doi.org/10.1371/journal.pone.0271350	Published	July 27, 2022	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0271350	Objective Anxiety, fatigue and depression are common neurological manifestations after COVID-19. So far, post-COVID complications were treated by rehabilitation, oxygen therapy and immunotherapy. Effects of neurofeedback on post-COVID complications and their potential interrelatedness have not been studied yet. In this pilot study, we investigated the effectiveness of neurofeedback (Othmer method) for treatment of fatigue, anxiety, and depression after COVID-19. Methods 10 participants met inclusion criteria for having positive anamnesis of at least one of the following complications following COVID-19: fatigue, anxiety, and depression which were measured by questionnaires. ANOVA was used for calculating differences in questionnaire score before and after neurofeedback. Pearson’s correlation coefficient was used to calculate correlations between anxiety, depression and fatigue. Results After five neurofeedback sessions, there came to significant reduction of severity of post-COVID anxiety and depression persisting for at least one month. Effect of neurofeedback on fatigue was insignificant. Severity of anxiety, fatigue and depression as well as reductions in depression and fatigue were positively correlated with each other. Conclusion These findings showed effectiveness neurofeedback for reducing anxiety and depression after COVID-19 and for studying correlations between neurological complications after COVID-19. However, since our pilot clinical trial was open-label, it is hard to differentiate between neurofeedback-specific and unspecific effects on our participants. Future randomized controlled trials with more robust sample are necessary to investigate feasibility of neurofeedback for post-COVID neurological complications. The study has identification number trial ID ISRCTN49037874 in ISRCTN register of clinical trials (Retrospectively registered).
196	Ce194		Diana Araja, Angelika Krumina, Uldis Berkis, Zaiga Nora-Krukle and Modra Murovska	The Advantages of an Integrative Approach in the Primary Healthcare of Post-COVID-19 and ME/CFS Patients	https://doi.org/10.5772/intechopen.106013	Published	August 18th, 2022	Article	https://www.intechopen.com/online-first/82708	The coronavirus disease caused by the SARS-CoV-2 virus (COVID-19) pandemic has changed not only global epidemiological and economic developments but also the lives of every individual, with particular severity for patients. The number of acute illness cases grew rapidly, significantly increasing the workload of hospitals, and simultaneously, new chronic diseases emerged, such as persistent post-COVID-19 syndrome (PPCS), with unclear etiology, symptoms, and complexity—similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Accordingly, the burden of chronic diseases poses new long-term challenges for primary healthcare and requires new approaches to patient care. This chapter provides insight into the integrative approach to healthcare and focuses on potentially new solutions by implementing an integrative attitude to the treatment of post-COVID-19 and ME/CFS patients in primary healthcare. Integrative health coaching contributes the holistic approach to patients’ overall health and resilience through cognitive practice and patient active engagement. The findings of this chapter can enrich the person-centered approach and healthcare system strengthening through holistic measures and systems thinking.
197	Ce195		Albert Garcia-Quintanilla, Mario Rivera-Izquierdo2,3, Meritxell Garcia-Quintanilla4	Impact of evening carbohydrate intake on the resolution of persistent night sweats in patients with long COVID: a case series	https://doi.org/10.12688/f1000research.124505.1	pre-print	18 Aug 2022	Study	https://f1000research.com/articles/11-950	Up to 25% of patients with long COVID experience persistent night sweats. However, in most cases they remain untreated until they disappear on their own. Since SARS-CoV-2 is known to disrupt glucose homeostasis, we hypothesized that impaired mitochondria would result in faster glycogen depletion at night due to reduced ATP production yield, inducing adrenaline production ultimately leading to the onset of persistent night sweats. To test our hypothesis we investigated whether incorporating carbohydrates into the diet of three non-diabetic patients with long COVID before bedtime would have any effect decreasing their night sweats. Remarkably, after one week with the dietary intervention, the patients reported that their night sweats had completely disappeared. Therefore, we propose carbohydrate supplementation as an affordable solution for night sweats in long COVID patients.
198	Ce196		Dr BroughNicola1AbelSally2PriddleLucy3	A service evaluation of a community project combining psychoeducation and mind-body complementary approaches to support those with Long Covid in the UK	https://doi.org/10.1016/j.eujim.2022.102182	Published	21 August 2022	Study	https://www.sciencedirect.com/science/article/pii/S187638202200083X	Introduction : Post covid-19 syndrome or Long Covid has been estimated to impact 1.3 million individuals in the UK. This study evaluates the outcomes of delivering a complementary Long Covid support service using psycho-educational and mind-body approaches within a community setting. Methods : This study utilised quantitative methods to evaluate the outcomes of implementing a complementary approach to Long Covid support. The service offered a package of care including group sessions combining psychoeducation and mind-body complementary approaches and optional 1:2:1 sessions (physiotherapy and craniosacral therapy (CST)). Screening for the service and health information was obtained using the Covid-19-Yorkshire Rehabilitation Screening tool (C-19 YRS). The impact of the service was assessed using the patient reported outcome measure: Warwick Holistic Health Questionnaire (WHHQ-18), and a survey was designed for general evaluation and feedback about the service from participants. Results : N=25 participants engaged with the service. The C-19YRS proved to be a useful tool to screen service users. The WHHQ-18 highlighted a positive group change (n=16) in participants’ mental, physical, emotional, and spiritual wellbeing: mean group score at the start = 33.7 (SD=12.5), mean group score at the follow up = 39.5 (SD=10.8). In the feedback from the service evaluation, participants reported that the service was useful in supporting them with their health challenges because of Long Covid and was delivered to the standard expected. Conclusion : In conclusion the psycho-educational and mind-body complementary approaches used within this service were well received and the measures used to evaluate were suitable for a service delivered within a community setting.
199	Ce197		Maxime Taquet, Paul J Harrison	Exposure to phenytoin associates with a lower risk of post-COVID cognitive deficits: a cohort study	https://doi.org/10.1093/braincomms/fcac206	Published	16 August 2022	Study	https://academic.oup.com/braincomms/article/4/4/fcac206/6668727?login=false	Post-COVID cognitive deficits (often referred to as ‘brain fog’) are common and have large impacts on patients’ level of functioning. No specific intervention exists to mitigate this burden. This study tested the hypothesis, inspired by recent experimental research, that post-COVID cognitive deficits can be prevented by inhibiting receptor-interacting protein kinase. Using electronic health record data, we compared the cognitive outcomes of propensity score-matched cohorts of patients with epilepsy taking phenytoin (a commonly used receptor-interacting protein kinase inhibitor) versus valproate or levetiracetam at the time of COVID-19 diagnosis. Patients taking phenytoin at the time of COVID-19 were at a significantly lower risk of cognitive deficits in the 6 months after COVID-19 infection than a matched cohort of patients receiving levetiracetam (hazard ratio 0.78, 95% confidence interval 0.63–0.97, P = 0.024) or valproate (hazard ratio 0.73, 95% confidence interval 0.58–0.93, P = 0.011). In secondary analyses, results were robust when controlling for subtype of epilepsy, and showed specificity to cognitive deficits in that similar associations were not seen with other ‘long-COVID’ outcomes such as persistent breathlessness or pain. These findings provide pharmacoepidemiological support for the hypothesis that receptor-interacting protein kinase signaling is involved in post-COVID cognitive deficits. These results should prompt empirical investigations of receptor-interacting protein kinase inhibitors in the prevention of post-COVID cognitive deficits.
200	Ce198		Maria Angela Barletta, Gerardo Marino, Barbara Spagnolo, Francesco Paolo Bianchi, Paola Chiara Francesca Falappone, Luca Spagnolo & Pietro Gatti	Coenzyme Q10 + alpha lipoic acid for chronic COVID syndrome	https://doi.org/10.1007/s10238-022-00871-8	Published	22 August 2022	Study	https://link.springer.com/article/10.1007/s10238-022-00871-8	Chronic COVID syndrome is characterized by chronic fatigue, myalgia, depression and sleep disturbances, similar to chronic fatigue syndrome (CFS) and fibromyalgia syndrome. Implementations of mitochondrial nutrients (MNs) with diet are important for the clinical effects antioxidant. We examined if use of an association of coenzyme Q10 and alpha lipoic acid (Requpero®) could reduce chronic covid symptoms. The Requpero study is a prospective observational study in which 174 patients, who had developed chronic-covid syndrome, were divided in two groups: The first one (116 patients) received coenzyme Q10 + alpha lipoic acid, and the second one (58 patients) did not receive any treatment. Primary outcome was reduction in Fatigue Severity Scale (FSS) in treatment group compared with control group. complete FSS response was reached most frequently in treatment group than in control group. A FSS complete response was reached in 62 (53.5%) patients in treatment group and in two (3.5%) patients in control group. A reduction in FSS core < 20% from baseline at T1 (non-response) was observed in 11 patients in the treatment group (9.5%) and in 15 patients in the control group (25.9%) (p < 0.0001). To date, this is the first study that tests the efficacy of coenzyme Q10 and alpha lipoic acid in chronic Covid syndrome. Primary and secondary outcomes were met. These results have to be confirmed through a double blind placebo controlled trial of longer duration.
201	Ce199		Sarah Wolf, Ingrid Zechmeister-Koss & Judit Erdös	Possible long COVID healthcare pathways: a scoping review	https://doi.org/10.1186/s12913-022-08384-6	Published	23 August 2022	Review	https://bmchealthservres.biomedcentral.com/articles/10.1186/s12913-022-08384-6	Background Individuals of all ages and with all degrees of severity of the coronavirus disease (COVID) can suffer from persisting or reappearing symptoms called long COVID. Long COVID involves various symptoms, such as shortness of breath, fatigue, or organ damage. The growing number of long COVID cases places a burden on the patients and the broader economy and, hence, has gained more weight in political decisions. This scoping review aimed to give an overview of recommendations about possible long COVID healthcare pathways and requirements regarding decision-making and communication for healthcare professionals. Methods A systematic search in four databases and biweekly update-hand searches were conducted. In addition to guidelines and reviews, expert opinions in consensus statements or clinical perspectives were also considered. Data were systematically extracted and subsequently narratively and graphically summarised. Results Fourteen references, five guidelines, four reviews, one consensus paper, and four clinical perspectives were included. The evidence recommended that most long COVID-related healthcare should be in primary care. Patients with complex symptoms should be referred to specialized long COVID outpatient assessment clinics. In contrast, patients with one dominant symptom should be directed to the respective specialist for a second assessment. Depending on the patients’ needs, further referral options include, e.g. rehabilitation or non-medical health services. Self-management and good communication between healthcare professionals and patients are crucial aspects of the long COVID management recommendations. Conclusions The quality of the included guidelines and reviews is limited in the methods applied due to the novelty of this topic and the associated urgency for research. Hence, an update review with more rigorous data is recommended. Furthermore, the systematic collection of real-world data on long COVID surveillance needs to be set up soon to gather further information on the duration and severity of long COVID and thereby facilitate long COVID care planning.
202	Ce200		Masoumeh Hosseinpoor MD,Mona Kabiri PhD,Mohsen Rajati Haghi MD,Toktam Ghadam Soltani MD,Alireza Rezaei MD,Atiyeh Faghfouri MD,Zahra Poustchian Gholkhatmi MD,Mehdi Bakhshaee MD	Intranasal Corticosteroid Treatment on Recovery of Long-Term Olfactory Dysfunction Due to COVID-19	https://doi.org/10.1002/lary.30353	Published	25 August 2022	Study	https://onlinelibrary.wiley.com/doi/full/10.1002/lary.30353	Background and Aims Olfactory dysfunction is a recognized manifestation in patients infected with Coronavirus Disease 2019 (COVID-19). This investigation aimed to assess the effect of mometasone furoate intranasal spray on the improvement of smell dysfunction in post-COVID-19 patients. Materials and Methods This randomized placebo-controlled trial included 80 non-hospitalized adult patients who had persistent anosmia or severe microsmia for more than 4 weeks due to COVID-19 infection. The participants were randomly allocated to the intervention or placebo group to receive mometasone furoate nasal spray or sodium chloride intranasal spray during 4 weeks of follow-up, respectively. The patients' olfactory dysfunction was assessed in terms of visual analog scale (VAS), and smell test score according to the modified version of the University of Pennsylvania smell identification test for the Iranian population. Results A total of 70 participants completed the follow-up period and were analyzed in this study. By comparing the olfactory scores including smell test and VAS scores, no significant differences were found between case and control groups at baseline, 2, and 4 weeks intervals. However, the change of both olfactory scores at pre to post-treatment intervals and 2–4 weeks was significantly higher in the mometasone group relative to the placebo group. At post-treatment, the frequency of anosmia was 22.9% reduced in the case group compared to the control group. Conclusion Overall, there was no significant difference in olfactory dysfunction between the two groups during follow-up. However, based on the significant between-group difference in terms of olfactory scores changes, it seems that the nasal corticosteroids may be a positive effect on the recovery process of patients who received more than 2 weeks.
203	Ce201		NorbertoPericoMDa†MonicaCortinovisBiotechDa†ProfFredySuterMDb†ProfGiuseppeRemuzziMDab	Home as the new frontier for the treatment of COVID-19: the case for anti-inflammatory agents	https://doi.org/10.1016/S1473-3099(22)00433-9	Published	26 August 2022	Review	https://www.sciencedirect.com/science/article/pii/S1473309922004339	COVID-19, caused by SARS-CoV-2, is characterised by a broad spectrum of symptom severity that requires varying amounts of care according to the different stages of the disease. Intervening at the onset of mild to moderate COVID-19 symptoms in the outpatient setting would provide the opportunity to prevent progression to a more severe illness and long-term complications. As early disease symptoms variably reflect an underlying excessive inflammatory response to the viral infection, the use of anti-inflammatory drugs, especially non-steroidal anti-inflammatory drugs (NSAIDs), in the initial outpatient stage of COVID-19 seems to be a valuable therapeutic strategy. A few observational studies have tested NSAIDs (especially relatively selective COX-2 inhibitors), often as part of multipharmacological protocols, for early outpatient treatment of COVID-19. The findings from these studies are promising and point to a crucial role of NSAIDs for the at-home management of people with initial COVID-19 symptoms.
204	Ce202		Chia Siang Kow, Dinesh Sangarran Ramachandram & Syed Shahzad Hasan	Hyperbaric oxygen therapy to reverse post-COVID cognitive impairment	https://doi.org/10.1007/s10072-022-06365-5	Published	26 August 2022	Comment	https://link.springer.com/article/10.1007/s10072-022-06365-5	The authors did not discuss the clinical implications of these findings in the article. Since the study [1] highlights the central role of hypoxemia in the pathophysiology of post-COVID cognitive impairment in patients with COVID-19, we believe the intervention to post-COVID cognitive impairment should be based on the improvement of tissue oxygenation, which can be directly achieved by oxygen therapy. Early oxygen therapy in patients with COVID-19 may be beneficial to prevent the development of post-COVID cognitive impairment, but most commonly, patients with COVID-19 receive oxygen therapy in the later stage of the disease upon presentation in the healthcare facilities, where tissue hypoxia has already occurred [2]. Therefore, the research focus should be placed on restoration of tissue oxygenation after the development of tissue hypoxia, which can be achieved with hyperbaric oxygen therapy. Hyperbaric oxygen therapy involves inhaling 100% oxygen at pressures exceeding 1 atmosphere absolute (ATA), which aims to enhance the amount of oxygen dissolved in the body tissues. Even before the COVID-19 pandemic, evidence has been accumulated about the neuroplasticity effects of hyperbaric oxygen therapy, where the combined action of hyperoxia and hyperbaric pressure can improve tissue oxygenation by activating both oxygen- and pressure-sensitive genes [3]. It is evidenced that hyperbaric oxygen therapy, which explicitly utilizes the hyperoxic-hypoxic paradox through constant fluctuation in both pressure and oxygen concentrations, can induce gene expression and metabolic pathways involved in brain tissue regeneration. These pathways can promote neurogenesis and angiogenesis in injured brain tissue. Hyperbaric oxygen therapy has been trialed in patients with COVID-19 with some success. In a case report [4] of a patient with post-COVID cognitive impairment, hyperbaric oxygen therapy led to improvements in brain perfusion and integrity of white matter brain microstructure, which are indicative of angiogenesis and neurogenesis, respectively. The patient also demonstrated improvement in cognitive performance after hyperbaric oxygen therapy [4]. Recently, a small-scale randomized controlled trial [5] of hyperbaric oxygen therapy in patients suffering from post-COVID-19 condition adds to the growing positive evidence of the intervention. There was a significant group-by-time interaction in the cognitive performance in patients randomized to hyperbaric oxygen therapy compared to patients randomized to sham therapy, which was accompanied by significant improvement in brain MRI perfusion and microstructural changes in frontal, parietal, and limbic regions of the brain involved in cognitive roles [5]. Based on the discovery that hypoxemia is the main driver of post-COVID cognitive impairment in patients with COVID-19, we believe larger scale trials should be performed to investigate the use of hyperbaric oxygen therapy in patients suffering from post-COVID cognitive impairment, especially when evidence to date has been reassuring. In fact, interventions for the post-COVID condition should not be sidelined since the post-COVID condition has been associated with deterioration in the quality of life, particularly the frail elderly patients who are more susceptible to post-COVID cognitive impairment [6].
205	Ce203		Nicola Veronese 1ORCID,Roberta Bonica 1,Sergio Cotugno 2,Ottavia Tulone 1,Michele Camporeale 2,Lee Smith 3ORCID,Mike Trott 4ORCID,Olivier Bruyere 5ORCID,Luigi Mirarchi 1,Giuseppina Rizzo 1,Davide Fiore Bavaro 1ORCID,Mario Barbagallo 1ORCID,Ligia J. Dominguez 1,6,Claudia Marotta 7,Andrea Silenzi 7ORCID,Emanuele Nicastri 8ORCID,Annalisa Saracino 2 andFrancesco Di Gennaro 2,*ORCID	Interventions for Improving Long COVID-19 Symptomatology: A Systematic Review	https://doi.org/10.3390/v14091863	Published	24 August 2022	Systematic Review	https://www.mdpi.com/1999-4915/14/9/1863/htm	Introduction: Although the understanding of several aspects of long COVID-19 syndrome is increasing, there is limited literature regarding the treatment of these signs and symptoms. The aim of our systematic review was to understand which therapies have proved effective against the symptoms of long COVID-19. Methods: A systematic search for randomized controlled or clinical trials in several databases was conducted through 15 May 2022. Specific inclusion criteria included: (1) intervention studies, either randomized controlled (RCTs) or clinical trials; (2) diagnosis of long COVID-19, according to the World Health Organization criteria; (3) presence of long COVID-19 for at least 12 weeks after SARS-CoV-2 infection. Results: We initially found 1638 articles to screen. After removing 1602 works based on their title/abstract, we considered 35 full texts, and among them, two intervention studies were finally included. The first RCT focused on the greater improvement of treatment combining olfactory rehabilitation with oral supplementation with Palmitoylethanolamide and Luteolin in patients with olfactory dysfunction after COVID-19. The second study evaluated the positive impact of aromatherapy vs. standard care in adult females affected by fatigue. Conclusion: Our systematic review found only two intervention studies focused on patients affected by long COVID-19. More intervention studies are needed to investigate potentially positive interventions for long COVID-19 symptoms.
206	Ce204		Candace W. Burton,Charles A. Downs,Thomas Hughes,Natalie Lambert,Heather L. Abrahim,Maria Giraldo Herrera,Yong Huang,Amir Rahmani,Jung-Ah Lee,Rana Chakraborty,Melissa D. Pinto	A novel conceptual model of trauma-informed care for patients with post-acute sequelae of SARS-CoV-2 illness (PASC)	https://doi.org/10.1111/jan.15426	Published	29 August 2022	DISCUSSION PAPER-METHODOLOGY	https://onlinelibrary.wiley.com/doi/10.1111/jan.15426	Aim This paper proposes a novel, trauma-informed, conceptual model of care for Post-Acute Sequelae of COVID-19 illness (PASC). Design This paper describes essential elements, linkages and dimensions of the model that affect PASC patient experiences and the potential impact of trauma-informed care on outcomes. Data sources PASC is a consequence of the global pandemic, and a new disease of which little is known. Our model was derived from the limited available studies, expert clinical experience specific to PASC survivors and publicly available social media narratives authored by PASC survivors. Implications for nursing The model provides a critical and novel framework for the understanding and care of persons affected by PASC. This model is aimed at the provision of nursing care, with the intention of reducing the traumatic impacts of the uncertain course of this disease, a lack of defined treatment options and difficulties in seeking care. The use of a trauma-informed care approach to PASC patients can enhance nurses' ability to remediate and ameliorate both the traumatic burden of and the symptoms and experience of the illness. Conclusion Applying a trauma-informed perspective to care of PASC patients can help to reduce the overall burden of this complex condition. Owing to the fundamentally holistic perspective of the nursing profession, nurses are best positioned to implement care that addresses multiple facets of the PASC experience. Impact The proposed model specifically addresses the myriad ways in which PASC may affect physical as well as mental and psychosocial dimensions of health. The model particularly seeks to suggest means of supporting patients who have already experienced a life-threatening illness and are now coping with its long-term impact. Since the scope of this impact is not yet defined, trauma-informed care for PASC patients is likely to reduce the overall health and systems burdens of this complex condition.
207	Ce205		Leah Shaffer	Lots of long COVID treatment leads, but few are proven	https://doi.org/10.1073/pnas.2213524119	Published	September 1, 2022	Article	https://www.pnas.org/doi/full/10.1073/pnas.2213524119	Lingering virus particles, microclots, and faulty immune signaling are likely culprits for many long-hauler symptoms. Anticoagulants, immune regulators, and antivirals show early promise.
208	Ce206		Hui Zhang Bin Cao	Post-infection rehabilitation of COVID-19 patients: Findings and prospects	https://doi.org/10.1016/j.lanepe.2022.100496	Published	September 01, 2022	Comment	https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(22)00192-2/fulltext	In the current issue of The Lancet Regional Health – Europe, Berentschot and colleagues provided results of a prospective multicenter cohort study (CO-FLOW) in the Netherlands revealing the changes of physical function across four different rehabilitation pathways within 12 months after discharge. The median age of patients enrolled in this study was 60 years, nearly 97% received supplemental oxygen, 40.7% were treated in ICU and 70.4% treated with steroids during hospitalization, indicating high risk for long COVID and rehabilitation training needs.6 Different from previous studies, this study not only focused on the rehabilitation of cardiopulmonary function, but also focused on changes in muscle strength and mobility. Among the three dimensions of assessed physical function, cardiorespiratory fitness and muscle strength improved most significantly within the first 6 months after discharge, suggesting that the first 6-month post-discharge is the optimal recovery period for COVID-19 patients. The findings also confirmed their hypothesis that patients who require more intensive rehabilitation have more impaired physical function at 3 months after hospital discharge and that these differences in physical function reduce over time. Although the improvement of physical function from 6-month to 1-year was not significant, it continued to improve till to 1-year, which means that the functional status requires longer follow-up observation. Physical function, HRQoL, symptom, disability, activities of daily living and return to work have been identified as important recovery targets for long COVID rehabilitation, and a comprehensive assessment should be conducted before and after rehabilitation to provide more evidence for developing an appropriate plan for patients with long COVID or other illnesses.7,8 The current study was an interim analysis and approximately one-third of enrolled patients completed 3 visits; however, it is unclear which characteristics of patients should be treated by medical professionals and whether rehabilitation is feasible and beneficial for mild patients, who also reportedly have sequelae of long COVID. With the prevalence of the Omicron variants, the number of severe or critical COVID-19 patients has decreased, and the trajectory of rehabilitation may differ from that found in current study, so well-designed prospective cohort or randomized research focusing on recovery outcome of COVID-19 patients with various variants or severities is needed in the future to address the above gaps. In the context of limited medical resources, identifying patients who need rehabilitation treatment and classify them into appropriate rehabilitation sites will benefit for improving patients function level and allocating medical resources rationally. Due to the similarities between long COVID and other post-acute infection syndromes and PICS, appropriate control group needs to be considered in future study design to better elucidate the recovery characteristics of COVID-19 patients.9 In addition to focusing on the characteristics of patients with improved physical function, more attention should be paid to those patients without improvement or even declined continuously, and further study is crucial to uncover the underlying mechanism of long COVID in the future.
209	Ce207		Vengadesh Letchumanan1, Angel Yun-Kuan Thye1, Jodi Woan-Fei Law1, Priyia Pusparajah2, Sivakumar Thurairajasingam3, Loh Teng-Hern Tan3, Learn-Han Lee1	IDDF2022-ABS-0207 The potential use of probiotics in alleviating psychological symptoms of long covid-19	http://dx.doi.org/10.1136/gutjnl-2022-IDDF.63	Published	September 02, 2022	Review	https://gut.bmj.com/content/71/Suppl_2/A57.1.abstract	Background Neuropsychiatric implications could result from disease or brain damage due to direct central nervous system (CNS) infection or indirect effects on the CNS through an immune response. Symptoms of long COVID-19 can persist up to 1-year post-hospitalization. Rates surged for anxiety, depression, and post-traumatic stress in COVID-19 survivors. There is mounting evidence that probiotics could alleviate mental illnesses, which led to research on the application of probiotics as a potential COVID-19 prevention and treatment. This study explores the psychiatric manifestations, particularly anxiety, depression, and post-traumatic stress disorder (PTSD) post COVID-19 infection and the potential of probiotics as an adjunct treatment for COVID-19. Methods Based on PRISMA guidelines, predefined MESH terms ‘COVID-19’ OR ‘long COVID’ AND ‘depression’ OR ‘psychological’ OR ‘anxiety’ OR ‘cognitive’ OR ‘neuropsychiatric’ OR ‘stress’ OR ‘mental health’ was used in databases (PubMed, Web of Science, Ovid Medline) to perform systematic literature searches. Google Scholar was also used. Studies reporting on the psychological sequelae among confirmed COVID-19 infected patients were included. Animal studies, studies without COVID-19 infected patients, and studies without evaluating psychological aspects, including reviews, commentaries/perspectives, conference abstracts, and editorials were excluded. Results 73 studies in accordance with the inclusion criteria out of 391 articles were selected for qualitative analysis. The studies reported anxiety, depression, and PTSD are the persistent symptoms in COVID-19 survivors. Cytokine dysregulation is associated with these psychiatric illnesses presented by the patients. Hence, probiotic supplementation aids in stimulating and modulating the immune system and decreases inflammation. Its efficacy in improving mental illness has been proven in clinical trials. The proposed mechanisms in which probiotics exert its positive effects on the psychiatric symptoms of COVID-19 patients include modulating the kynurenine pathway, neurotransmitter production and the role of SCFAs in decreasing neuroinflammation, maintaining the gut and the blood-brain barrier’s integrity (IDDF2022-ABS-0207 Figure 1. Illustration of mechanisms of probiotics in the management of psychiatric symptoms in Covid19 patients). Conclusions A potential connection exists between the psychiatric sequelae of COVID-19 and the gut microbiome. These findings also provide insights on probiotics as a potential adjunctive treatment to conventional psychotropic medications in alleviating psychiatric sequelae post COVID-19.
210	Ce208		Amaya Jimeno-Almazán,Francisco Franco-López,Ángel Buendía-Romero,Alejandro Martínez-Cava,José Antonio Sánchez-Agar,Bernardino J. Sánchez-Alcaraz Martínez,Javier Courel-Ibáñez,Jesús G. Pallarés	Rehabilitation for post-COVID-19 condition through a supervised exercise intervention: A randomized controlled trial	https://doi.org/10.1111/sms.14240	Published	15 September 2022	Study	https://onlinelibrary.wiley.com/doi/10.1111/sms.14240	Purpose The aim of the study was to compare the outcomes of patients with post-COVID-19 condition undergoing supervised therapeutic exercise intervention or following the self-management WHO (World Health Organization) rehabilitation leaflet. Methods A randomized controlled trial was carried out that included 39 participants with post-COVID-19 condition who had a chronic symptomatic phase lasting >12 weeks. Comprehensive medical screening, patient-reported symptoms, and cardiorespiratory fitness and muscular strength were assessed. Patients were randomly assigned to a tailored multicomponent exercise program based on concurrent training for 8 weeks (two supervised sessions per week comprised resistance training combined with aerobic training [moderate intensity variable training], plus a third day of monitored light intensity continuous training), or to a control group which followed the WHO guidelines for rehabilitation after COVID-19. Results After follow-up, there were changes in physical outcomes in both groups, however, the magnitude of the change pre–post intervention favored the exercise group in cardiovascular and strength markers: VO2max +5.7%, sit-to-stand −22.7% and load-velocity profiles in bench press +6.3%, and half squat +16.9%, (p < 0.05). In addition, exercise intervention resulted in a significantly better quality of life, less fatigue, less depression, and improved functional status, as well as in superior cardiovascular fitness and muscle strength compared to controls (p < 0.05). No adverse events were observed during the training sessions. Conclusion Compared to current WHO recommendations, a supervised, tailored concurrent training at low and moderate intensity for both resistance and endurance training is a more effective, safe, and well-tolerated intervention in post-COVID-19 conditions.
211	Ce209		Steenblock C1, Walther R1, Tselmin S2, Jarzebska N3, Voit-Bak K4, Toepfner N5, Siepmann T6, Passauer J1, Hugo C7, Wintermann G8, Julius U9, Babir M10, Khan TZ10, Puhan MA11, Straube R4, Hohenstein B1, Bornstein SR12, Rodionov R13	Long Covid and Apheresis - Where are we Standing?	https://doi.org/10.1055/a-1945-9694	Published	16 Sep 2022	Study	https://europepmc.org/article/med/36113501	A continual increase in cases of Long Covid constitutes a medical and socioeconomic challenge to health systems around the globe. While the true extent of this problem cannot yet be fully evaluated, recent data suggests that up to 20% of people with confirmed with SARS-CoV-2 suffer from clinically relevant symptoms of Long Covid several weeks to months after the acute phase. The clinical presentation is highly variable with the main symptoms being chronic fatigue, dyspnea and cognitive symptoms. Extracorporeal apheresis has been suggested to alleviate symptoms of Long Covid. Thus, numerous patients are currently treated with apheresis. However, at present there is no data from randomized controlled trials available to confirm the efficacy. Therefore, physicians rely on the experience of practitioners and centers performing this treatment. Here, we summarize clinical experience on extracorporeal apheresis in patients with Long Covid from centers across Germany.
212	Ce210		Trisha Greenhalgh, professor of primary care health sciences1, Manoj Sivan, associate professor in rehabilitation medicine2, Brendan Delaney, professor of medical informatics and decision making3, Rachael Evans, associate professor in respiratory medicine, associate professor in respiratory medicine4, Ruairidh Milne	Long covid—an update for primary care	https://doi.org/10.1136/bmj-2022-072117	Published	22 September 2022	Practice Pointer	https://www.bmj.com/content/378/bmj-2022-072117	What you need to know Long covid (prolonged symptoms following covid-19 infection) is common The mainstay of management is supportive, holistic care, symptom control, and detection of treatable complications Many patients can be supported effectively in primary care by a GP with a special interest
213	Ce211		Mark Vink markvink.md@outlook.com and Alexandra Vink-Niese	Graded exercise therapy for myalgic encephalomyelitis/chronic fatigue syndrome is not effective and unsafe. Re-analysis of a Cochrane review	https://doi.org/10.1177/2055102918805187	Published	October 8, 2018	Review	https://journals.sagepub.com/doi/10.1177/2055102918805187	The analysis of the 2017 Cochrane review reveals flaws, which means that contrary to its findings, there is no evidence that graded exercise therapy is effective. Because of the failure to report harms adequately in the trials covered by the review, it cannot be said that graded exercise therapy is safe. The analysis of the objective outcomes in the trials provides sufficient evidence to conclude that graded exercise therapy is an ineffective treatment for myalgic encephalomyelitis/chronic fatigue syndrome.
214	Ce212		Reinfeld, Samuel	Can bupropion treat COVID-19–induced brain fog? A case series	https://doi.org/10.1097/YIC.0000000000000436	Published	September 15, 2022	Case Series	https://journals.lww.com/intclinpsychopharm/Fulltext/9900/Can_bupropion_treat_COVID_19_induced_brain_fog__A.23.aspx	COVID-19–induced neurocognitive complications that include brain fog have affected a large portion of individuals who survived COVID-19. These symptoms can include inattention, mental fatigue, forgetfulness, amotivation, and distractibility. This can cause significant anxiety and depression, which may worsen disease progression. To date, there are no known specific treatments that target COVID-19-related brain fog. Here, two patients are presented that develop symptoms of brain fog that persisted after they recovered from an acute COVID-19 infection. Both had memory impairment, mental exhaustion, and inattention with associated depressed mood. They were given bupropion extended release and though varied with dosing and time to resolution, they recovered dramatically. The dopamine and norepinephrine reuptake inhibitor is known to have effects on the brain that may treat symptoms of brain fog including blocking hippocampal cell loss, increased neural activity in the cingulate cortex, and decreasing proinflammatory cytokines. Bupropion may be a possible option for those suffering from this growing and debilitating post-COVID-19 complication.
215	Ce213		Anne Schrimpf,corresponding author * Annett Braesigk, Stefan Lippmann, and Markus Bleckwenn	Management and treatment of long COVID symptoms in general practices: An online-based survey	https://doi.org/10.3389%2Ffpubh.2022.937100	Published	2022 Sep 13	Survey	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9513068/	Independent from initial severity, many patients develop persistent symptoms after infection with SARS-CoV-2, described as long COVID syndrome. Most of these patients are treated by general practitioners (GPs). As evidence-based treatment recommendations are still sparse, GPs must make their therapy decisions under uncertainty. We investigated (1) the most frequently observed long COVID symptoms in general practices and (2) GPs' applied treatment and rehabilitation plans for these symptoms. In total, 143 German GPs participated in an online-based survey between 05/2021 and 07/2021. We found that each GP practice was treating on average 12 patients with long COVID symptoms. Most frequently seen symptoms were fatigue and reduced performance. Current therapy options were rated as poor and loss of smell and taste, fatigue, or lack of concentration were perceived to be especially difficult to treat. The use of drug and non-drug therapies and specialist referrals focused primarily on physiological and less on psychosomatic/psychological rehabilitation and followed guidelines of similar conditions. Our results provide first insights into how GPs approach a newly emerging condition in the absence of guidelines, evidence-based recommendations, or approved therapies, and might inform about GP preparedness in future pandemics. Our results also emphasize a gap between the current knowledge of the long COVID manifestation and knowledge about effective rehabilitation.
216	Ce214		Hayley Wright 1 Author Orcid Image ; Andrew Turner 1 Author Orcid Image ; Stuart Ennis 2, 3, 4 Author Orcid Image ; Carol Percy 5 Author Orcid Image ; Garry Loftus 6 Author Orcid Image ; Wendy Clyne 7 Author Orcid Image ; Gabriela Matouskova 6 Author Orcid Image ; Faith Martin 1 Author Orcid Image	Digital Peer-Supported Self-Management Intervention Codesigned by People With Long COVID: Mixed Methods Proof-of-Concept Study	https://doi.org/10.2196/41410	Published	14.10.2022	Study	https://formative.jmir.org/2022/10/e41410	Background: There are around 1.3 million people in the United Kingdom with the devastating psychological, physical, and cognitive consequences of long COVID (LC). UK guidelines recommend that LC symptoms be managed pragmatically with holistic support for patients’ biopsychosocial needs, including psychological, emotional, and physical health. Self-management strategies, such as pacing, prioritization, and goal setting, are vital for the self-management of many LC symptoms. Objective: This paper describes the codevelopment and initial testing of a digital intervention combining peer support with positive psychology approaches for self-managing the physical, emotional, psychological, and cognitive challenges associated with LC. The objectives of this study were to (1) codesign an intervention with and for people with LC; (2) test the intervention and study methods; (3) measure changes in participant well-being, self-efficacy, fatigue, and loneliness; and (4) understand the types of self-management goals and strategies used by people with LC. Methods: The study used a pre-post, mixed methods, pragmatic, uncontrolled design. Digital intervention content was codeveloped with a lived-experience group to meet the needs uncovered during the intervention development and logic mapping phase. The resulting 8-week digital intervention, Hope Programme for Long COVID, was attended by 47 participants, who completed pre- and postprogram measures of well-being, self-efficacy, fatigue, and loneliness. Goal-setting data were extracted from the digital platform at the end of the intervention. Results: The recruitment rate (n=47, 83.9%) and follow-up rate (n=28, 59.6%) were encouraging. Positive mental well-being (mean difference 6.5, P<.001) and self-efficacy (mean difference 1.1, P=.009) improved from baseline to postcourse. All goals set by participants mapped onto the 5 goal-oriented domains in the taxonomy of everyday self-management strategies (TEDSS). The most frequent type of goals was related to activity strategies, followed by health behavior and internal strategies. Conclusions: The bespoke self-management intervention, Hope Programme for Long COVID, was well attended, and follow-up was encouraging. The sample characteristics largely mirrored those of the wider UK population with LC. Although not powered to detect statistically significant changes, the preliminary data show improvements in self-efficacy and positive mental well-being. Our next trial (ISRCTN: 11868601) will use a nonrandomized waitlist control design to further examine intervention efficacy.
217	Ce215		Vijay HaddaORCID Icon,Tejas M SuriORCID Icon,Hariharan Iyer,Avinash Jain,Saurabh MittalORCID Icon,Karan MadanORCID Icon,Anant MohanORCID Icon,Ashu Seith Bhalla,Girish Sindhwani,Naveen Dutt,Kavitha Venkatnarayan,Alok Nath,Sahajal DhooriaORCID Icon,Rohit Kumar,Vikas Marwah,Saurabh Karmakar,Dhruva Chaudhry,Irfan Ismail Ayub,Dharm Prakash Dwivedi,Pawan TiwariORCID Icon,Parvaiz Koul,Ajoy Kumar Behera,Puneet Saxena,Amitabha Sengupta,Prasanta R MohapatraORCID Icon,Abhishek Goyal,Devasahayam J Christopher &Randeep Guleria show less	A Delphi consensus statement for the management of post-COVID interstitial lung disease	https://doi.org/10.1080/17476348.2022.2128770	Published	30 Sep 2022	Review	https://www.tandfonline.com/doi/full/10.1080/17476348.2022.2128770?scroll=top&needAccess=true	Introduction As millions of people worldwide recover from COVID-19, a substantial proportion continue to have persistent symptoms, pulmonary function abnormalities, and radiological findings suggestive of post-COVID interstitial lung disease (ILD). To date, there is limited scientific evidence on the management of post-COVID ILD, necessitating a consensus-based approach. Areas covered A panel of experts in pulmonology and thoracic radiology was constituted. Key questions regarding the management of post-COVID ILD were identified. A search was performed on PubMed and EMBASE and updated till 1 March 2022. The relevant literature regarding the epidemiology, pathophysiology, diagnosis and treatment of post-COVID ILD was summarized. Subsequently, suggestions regarding the management of these patients were framed, and a consensus was obtained using the Delphi approach. Those suggestions which were approved by over 80% of the panelists were accepted. The final document was approved by all panel members. Expert opinion Dedicated facilities should be established for the care of patients with post-COVID ILD. Symptom screening, pulmonary function testing, and thoracic imaging have a role in the diagnosis. The pharmacologic and non-pharmacologic options for the management of post-COVID ILD are discussed. Further research into the pathophysiology and management of post-COVID ILD will improve our understanding of this condition. Article highlights Post-COVID interstitial lung disease (ILD) is a common sequela among patients hospitalized with acute COVID-19. Symptom screening, pulmonary function testing, and thoracic imaging have a role in the diagnosis and follow-up for post-COVID ILD. To date, there is limited scientific evidence on the management of post-COVID ILD. This document uses the Delphi method to offer consensus-based suggestions on the diagnosis and management of post-COVID ILD.
218	Ce216		Svetlana Blitshteyn MD,Jonathan H. Whiteson MD,Benjamin Abramoff MD, MS,Alba Azola MD,Matthew N. Bartels MD, MPH,Ratna Bhavaraju-Sanka MD,Tae Chung MD,Talya K. Fleming MD,Ellen Henning PhD,Mitchell G. Miglis MD, FAAN,Sarah Sampsel MPH,Julie K. Silver MD,Jenna Tosto PT, DPT, NCS,Monica Verduzco-Gutierrez MD,David Putrino PT, PhD	Multi-disciplinary collaborative consensus guidance statement on the assessment and treatment of autonomic dysfunction in patients with post-acute sequelae of SARS-CoV-2 infection (PASC)	https://doi.org/10.1002/pmrj.12894	Published	28 September 2022	Guidance	https://onlinelibrary.wiley.com/doi/10.1002/pmrj.12894	SUMMARY Individuals with PASC commonly present with symptoms of autonomic dysfunction and should undergo a clinical evaluation for autonomic disorders. A comprehensive treatment program including non-pharmacologic, pharmacologic, and rehabilitative interventions is often needed to manage autonomic dysfunction and improve functional status. This guidance statement is designed to help clinicians currently treating individuals with PASC-related autonomic disorders by presenting evidence-based recommendations as well as recommendations based on the collective experience of the PASC Collaborative. FUTURE DIRECTIONS Although COVID vaccines may decrease the risk of PASC, breakthrough cases of COVID and subsequent PASC have been reported in fully vaccinated individuals, as well as observed in clinical practice.116, 117 It is important to note that a number of patients with PASC experience temporary or permanent improvement in symptoms after immunization with COVID vaccines.118-120 In an early post-vaccination study to assess changes in the trajectory of long COVID symptoms in adults infected with SARS-CoV-2, the incidence of symptoms decreased after both the first and second vaccination doses. This study suggests that vaccination may reduce the burden of both SARS-CoV-2 and PASC in adults.121 In contrast, a retrospective cohort study did not find COVID vaccines to be protective against PASC in breakthrough cases.122 Although further studies are needed to determine whether COVID vaccines decrease the incidence of PASC in vaccinated individuals after breakthrough infection, vaccination remains one of the most important public health measures to mitigate the pandemic. These PASC Collaborative guidance statements are preliminary. Studies that investigate autonomic dysfunction in patients with post-COVID symptoms are needed to determine what subset of patients with PASC have autonomic dysfunction. At this time, it is unknown whether post-COVID autonomic disorders are similar to those that can arise after other viral infections or whether these represent a distinct phenotype unique to SARS-CoV-2 virus. Future studies are also needed to determine the biomarkers as well as appropriate diagnostic, prognostic, and therapeutic approaches to patients with post-COVID autonomic dysfunction. Specialized rehabilitation programs, non-pharmacologic management (including individualized dietary and exercise regimens), and pharmacologic treatment (including immunotherapy), require further investigation in clinical trials. As new studies emerge, the PASC Collaborative may require a re-evaluation of the assessment and treatment clinical recommendations in order to provide the most up-to-date evidence-based patient care for individuals with PASC.
219	Ce217		Laura A. Malone MD, PhD,Amanda Morrow MD,Yuxi Chen MD,Donna Curtis MD, MPH,Sarah D. de Ferranti MD, MPH,Monika Desai MD,Talya K. Fleming MD,Therese M. Giglia MD, FAHA,Trevor A. Hall PsyD, ABPdN,Ellen Henning PhD,Sneha Jadhav MD,Alicia M. Johnston MD,Dona Rani C. Kathirithamby MD,Christina Kokorelis MD,Catherine Lachenauer MD,Lilun Li MD,Henry C. Lin MD,Tran Locke MD,Carol MacArthur MD,Michelle Mann MD,Sharon A. McGrath-Morrow MD,Rowena Ng PhD,Laurie Ohlms MD,Sarah Risen MD,S. Christy Sadreameli MD, MHS,Sarah Sampsel MPH,S. Kristen Sexson Tejtel MD, PhD, MPH,Julie K. Silver MD,Tregony Simoneau MD,Rasha Srouji DNP,Sanjeev Swami MD,Souraya Torbey MD,Monica Verduzco Gutierrez MD,Cydni Nicole Williams MD, MCR,Lori Allison Zimmerman M.D.,Louise Elaine Vaz MD, MPH …	Multi-disciplinary collaborative consensus guidance statement on the assessment and treatment of postacute sequelae of SARS-CoV-2 infection (PASC) in children and adolescents	https://doi.org/10.1002/pmrj.12890	Published	28 September 2022	Guidance	https://onlinelibrary.wiley.com/doi/10.1002/pmrj.12890	CONCLUSIONS PASC in children and adolescents is increasing in recognition. Some children may have only one or two symptoms of PASC, whereas others may have a constellation of symptoms.86 Research is ongoing to better understand the pathogenesis behind PASC in both children and adults and optimal treatment approaches. Guidance regarding the evaluation and treatment of PASC in children and adolescents may change as further research is done to provide evidence-based recommendations, including the National Institutes of Health Recover trial.116, 117 It is important to note that not all the symptoms regarding PASC may be attributed to SARS-CoV-2 alone as recent studies have reported a high prevalence of symptoms similar to PASC in children who serve as healthy negative controls. This speaks to the impact of the pandemic as a co-contributor to some symptoms.3, 4, 118 Finally, given the demonstrated variability in COVID-19 outcomes secondary to social inequalities in health, researchers and clinicians must remain vigilant and address pediatric PASC in the context of preserving health equity, noting that particular vulnerable groups and populations may be disproportionately affected by the effects of the pandemic and systemic barriers to optimal health.
220	Ce218		Jennifer A. Frontera ,Lorna E. Thorpe,Naomi M. Simon,Adam de Havenon,Shadi Yaghi,Sakinah B. Sabadia,Dixon Yang,Ariane Lewis,Kara Melmed,Laura J. Balcer,Thomas Wisniewski,Steven L. Galetta	Post-acute sequelae of COVID-19 symptom phenotypes and therapeutic strategies: A prospective, observational study	https://doi.org/10.1371/journal.pone.0275274	Published	September 29, 2022	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0275274	Background Post-acute sequelae of COVID-19 (PASC) includes a heterogeneous group of patients with variable symptomatology, who may respond to different therapeutic interventions. Identifying phenotypes of PASC and therapeutic strategies for different subgroups would be a major step forward in management. Methods In a prospective cohort study of patients hospitalized with COVID-19, 12-month symptoms and quantitative outcome metrics were collected. Unsupervised hierarchical cluster analyses were performed to identify patients with: (1) similar symptoms lasting ≥4 weeks after acute SARS-CoV-2 infection, and (2) similar therapeutic interventions. Logistic regression analyses were used to evaluate the association of these symptom and therapy clusters with quantitative 12-month outcome metrics (modified Rankin Scale, Barthel Index, NIH NeuroQoL). Results Among 242 patients, 122 (50%) reported ≥1 PASC symptom (median 3, IQR 1–5) lasting a median of 12-months (range 1–15) post-COVID diagnosis. Cluster analysis generated three symptom groups: Cluster1 had few symptoms (most commonly headache); Cluster2 had many symptoms including high levels of anxiety and depression; and Cluster3 primarily included shortness of breath, headache and cognitive symptoms. Cluster1 received few therapeutic interventions (OR 2.6, 95% CI 1.1–5.9), Cluster2 received several interventions, including antidepressants, anti-anxiety medications and psychological therapy (OR 15.7, 95% CI 4.1–59.7) and Cluster3 primarily received physical and occupational therapy (OR 3.1, 95%CI 1.3–7.1). The most severely affected patients (Symptom Cluster 2) had higher rates of disability (worse modified Rankin scores), worse NeuroQoL measures of anxiety, depression, fatigue and sleep disorder, and a higher number of stressors (all P<0.05). 100% of those who received a treatment strategy that included psychiatric therapies reported symptom improvement, compared to 97% who received primarily physical/occupational therapy, and 83% who received few interventions (P = 0.042). Conclusions We identified three clinically relevant PASC symptom-based phenotypes, which received different therapeutic interventions with varying response rates. These data may be helpful in tailoring individual treatment programs.
221	Ce219		Tamaradel Corral1Raúl FaberoGarrido2GustavoPlaza-Manzano3CésarFernández-de-las-Peñas4^MarcosNavarro-Santana5IbaiLópez-de-Uralde-Villanueva1	Home-based respiratory muscle training on quality of life and exercise tolerance in long-term post-COVID-19: Randomized controlled trial	https://doi.org/10.1016/j.rehab.2022.101709	Published	30 September 2022	Trial	https://www.sciencedirect.com/science/article/pii/S1877065722000811	Highlights •Respiratory muscle training increased quality of life in long-term COVID. •Respiratory muscle training had no impact on exercise tolerance. •Respiratory muscle training increased expiratory muscle function. •Inspiratory and respiratory muscle training improved inspiratory muscle function. •Inspiratory and respiratory muscle training improved lower limb muscle strength. Abstract Objective To evaluate the effects of a home-based respiratory muscle training programme (inspiratory [IMT] or inspiratory/expiratory muscles [RMT]) supervised by telerehabilitation on quality of life and exercise tolerance in individuals with long-term post-COVID-19 symptoms. The secondary objective was to evaluate the effects of these programmes on respiratory muscle function, physical and lung function, and psychological state. Methods 88 individuals with long-term symptoms of fatigue and dyspnoea after COVID-19 diagnosis were randomly (1:1 ratio) assigned to IMT, IMTsham, RMT or RMTsham groups for an 8-week intervention (40min/day, 6 times/week). Primary outcomes were quality of life (EuroQol-5D questionnaire) and exercise tolerance (Ruffier test). Secondary outcomes were respiratory muscle function (inspiratory/expiratory muscle strength; inspiratory muscle endurance), physical function (lower and upper limb strength [1-min Sit-to-Stand and handgrip force]), lung function (forced spirometry), and psychological status (anxiety/depression levels and post-traumatic stress disorder). All outcomes were measured pre-, intermediate- (4th week), and post-intervention. Results At post-intervention, there was a statistically significant and large (d>0.90) improvement in quality of life, but not in exercise tolerance, in the RMT group compared with the RMTsham group. Both of the real training groups produced a statistically significant and large increase in inspiratory muscle strength and endurance (d≥0.80) and in lower limb muscle strength (d≥0.77) compared with the 2 sham groups. Expiratory muscle strength and peak expiratory flow showed a statistically significant and large (d≥0.87) increase in the RMT group compared with the other 3 groups. Conclusion Only an 8-week supervised home-based RMT programme was effective in improving quality of life, but not exercise tolerance, in individuals with long-term post-COVID-19 symptoms. In addition, IMT and RMT programmes were effective in improving respiratory muscle function and lower limb muscle strength, but had no impact on lung function and psychological status.
222	Ce220		Yoonjung Kim,1 Seong Eun Kim,2 Tark Kim,3 Ki Wook Yun,4 So Hee Lee,5 Eunjung Lee,6 Jun-Won Seo,7 Young Hee Jung,8 and Yong Pil Chong9	Preliminary Guidelines for the Clinical Evaluation and Management of Long COVID	https://doi.org/10.3947/ic.2022.0141	Published	Jul 21, 2022	Guidelines	https://icjournal.org/search.php?where=aview&id=10.3947/ic.2022.0141&code=0086IC&vmode=FULL	Long-lasting coronavirus disease 2019 (COVID-19) symptoms beyond 12 weeks, the so-called ‘long COVID’ have been increasingly reported worldwide. Long COVID can be manifested in various forms, and there is an increasing demand for proper assessment and management. However, it is challenging when trying to determine the best-practice standards of care based on the current evidence because there is no internationally agreed clinical definition or clear treatment pathway. Therefore, the present guidelines have been drafted to provide advice on diagnosis and management based on the latest updated available evidence and the consensus of expert opinion. So far, no standard test and drug treatment can be strongly recommended for patients with long COVID because of a lack of evidence. The present guidelines provide advice based on 12 key questions, including appropriate interventions for long COVID that can be used in clinical practice. Continuous careful observation and studies related to long COVID are needed for the long-term impact of COVID-19 and proper management for long COVID to be determined.
223	Ce221		Grace Russell University of the West of England AD Thomas University of the West of England Alexander Nenov University of the West of England John T Hancock	The Influence of Molecular Hydrogen Therapies in Managing the Symptoms of Acute and Chronic COVID-19	https://doi.org/10.18103/mra.v10i9.3036	Published	Sep 20, 2022	Review	https://esmed.org/MRA/mra/article/view/3036	Coronavirus Infectious Disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) that emerged as a novel pathogen of global concern in the latter stages of 2019. COVID-19 is a highly contagious disease which can be transmitted through aerosol droplets and surface-to-host contact. Both symptomology and the severity of disease can vary wildly between individuals, from asymptomatic but infectious, to those that require critical care. Due to the neoteric emergence of SARS-CoV-2, current treatment strategies are not yet well developed and rely on the repurposing of such medications as antiviral, corticosteroid, immunosuppressant and oxygen (O2) therapies. However, the minimal efficacy of these interventions is concerning. In addition to the acute infection that prevails, it is estimated that up to 30% of adults who contract COVID-19 develop chronic symptoms lasting longer than 12 weeks. It is also estimated that 15% of children aged 2-16 years have developed long-lasting sequelae associated with SARS-CoV-2 infection. According to recent clinical data, molecular hydrogen (H2) and oxy-hydrogen (H2/O2) therapies successfully remediated the debilitating effects of SARS-CoV-2 infection in adults. By acting as an effective anti-inflammatory and antioxidative agent, it is reported that H2 administration can improve recovery through abatement of the hyperinflammatory cytokine cascade and reduction of inhalation resistance in patients with mild-moderate disease symptoms. In this review, the authors investigate the clinical and empirical evidence relating to treating the symptoms of both acute and chronic COVID-19 with H2-containing therapeutics.
224	Ce222		Beatriz A. Cavendish 1 Alisson Lima 1 Laiss Bertola Leigh Charvet Marom Bikson Andre R. Brunoni 2 Kallene S. Vidal 2	Combination of transcranial direct current stimulation with online cognitive training improves symptoms of Post-acute Sequelae of COVID-19: A case series	https://doi.org/10.1016/j.brs.2022.09.008	Published	October 03, 2022	Study	https://www.brainstimjrnl.com/article/S1935-861X(22)00212-1/fulltext	Dear editor, Given that there is accumulating evidence that one third of patients who develop COVID-19 experience enduring cognitive dysfunction with cumulative symptoms, there is an urgent need to develop treatment alternatives for Post-Acute Sequelae of Sars-Cov2 (PASC) [[1]]. Cross-sectional studies addressing the incidence of psychiatric and cognitive abnormalities in COVID-19 patients provided initial evidence on the occurrence of delirium, encephalopathy, persisting cognitive impairment, insomnia, psychotic and mood symptoms [[2]]. In this context, transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation intervention with potential as a PASC treatment as it modulates brain vascular function [[3]] and enhance ongoing synaptic plasticity [[4]], which can result in modulation of neural circuits underlying neurological, cognitive, and psychiatric disorders [[5]]. tDCS has been trialed in non-COVID-19 samples [[6]] and combined with cognitive tasks to boost neurorehabilitation and improve cognitive performance [[7]]. Therefore, this combination is a rational candidate for the treatment of PASC neuropsychiatric symptoms. Here, we investigated the effects of this combined intervention in a case series of four patients with long COVID cognitive symptoms clinically evaluated using the Assessment of PASC inventory (A-PASC, Supplementary Materials Fig. 1) [[8]]. This is a pilot study that preceded an ongoing, double-blinded, randomized controlled trial comparing the effects of cognitive training combined with sham or active tDCS at University of São Paulo, Brazil. Although this pilot study was not powered to show efficacy, several trends were observed: 1) An improvement in depression symptoms (QIDS); 2) A decrease of self-reported cognitive and emotional symptoms and functional abilities (A-PASC inventory); 3) An improvement in processing speed (FDT) and self-reported executive functioning (BDEFS); 4) An improvement in delayed and immediate recall (RAVLT). To conclude, this case series suggest that tDCS combined with cognitive training might improve PASC cognitive symptoms, a condition with no currently available treatments. Notwithstanding, we could not exclude that this improvement occurred due to other factors, such as placebo effects, learning effects, and natural history of disease. Therefore, further randomized, controlled trials are warranted.
225	Ce223		Bjørn IngulfsvannHagenabAnnersLerdalbArneSøraascNils IngeLandrødRagnhildBødMilada CvancarovaSmåstuenbJacquelineBeckereJanStubberudbd	Cognitive rehabilitation in post-COVID-19 condition: A study protocol for a randomized controlled trial	https://doi.org/10.1016/j.cct.2022.106955	Published	5 October 2022	Trial	https://www.sciencedirect.com/science/article/pii/S1551714422002816	Background Post-COVID-19 condition is frequently comprised of persistent cognitive sequela, including deficits in attention and executive functions (EFs), which can act as a barrier for regaining pre-illness functional levels. Goal Management Training (GMT) is a cognitive rehabilitation (CR) intervention for improving attention and EFs that has received empirical support in studies of other patient groups. The present study aims to determine the efficacy of GMT for improving everyday attention and EFs in adults who experience persistent cognitive deficits after COVID-19. Methods This study protocol describes an open-label randomized controlled trial comparing the efficacy of GMT to a wait list control condition (WL), for improving persistent (> 2 months) cognitive sequela in post-COVID-19 condition. The study aims to recruit 240 participants aged 18 to 65 years with a history of SARS-CoV-2 infection and perceived attentional and EF difficulties in daily life. Participants will be block randomized (computer-algorithm) to either group-based GMT (n = 120) or WL (n = 120). GMT will be internet-delivered to groups of six participants in six two-hour sessions delivered once a week. The primary outcome will be the Metacognition Index of the Behavior Rating Inventory of Executive Function – Adult Version, a self-report measure assessing everyday EF difficulties, specifically metacognition, at six months post-treatment. Secondary outcomes include performance-based neurocognitive measures, and tertiary outcomes include rating scales of cognition, emotional health, quality of life, and fatigue. Conclusion Study findings could contribute to providing an evidence-based treatment option for symptoms that are frequent and debilitating following a prevalent condition.
226	Ce224		James Melrose1,2,3,*, Margaret M. Smith1	Natural and Semi-Synthetic Flavonoid Anti-SARS-CoV-2 Agents for the Treatment of Long COVID-19 Disease and Neurodegenerative Disorders of Cognitive Decline	https://doi.org/10.31083/j.fbe1404027	Published	9 October 2022	Review	https://www.imrpress.com/journal/FBE/14/4/10.31083/j.fbe1404027/htm	The aim of this review is to highlight the beneficial attributes of flavonoids, a diverse family of widely-distributed polyphenolic phytochemicals that have beneficial cell and tissue protective properties. Phytochemicals are widely distributed in plants, herbs and shrubs used in traditional complimentary medical formulations for centuries. The bioactive components that convey beneficial medicinal effects in these complex herbal preparations are now being identified using network pharmacology and molecular docking procedures that identify their molecular targets. Flavonoids have anti-oxidant, anti-inflammatory, antiviral, antibacterial and anti-cancer properties that have inspired the development of potent multifunctional derivatised flavonoids of improved efficacy. The antiviral properties of flavonoids and the emergence of the severe acute respiratory syndrome (SARS-CoV-2) pandemic has resulted in a resurgence of interest in phytochemicals in the search for efficacious compounds that can prevent viral infection or replication, with many promising plant compounds identified. Promising semi-synthetic flavonoid derivatives have also been developed that inhibit multiple pathological neurodegenerative processes; these offer considerable promise in the treatment of diseases of cognitive decline. Clinical trials are currently being undertaken to evaluate the efficacy of dietary supplements rich in flavonoids for the treatment of virally-mediated diseases. Such trials are expected to identify flavonoids with cell and tissue protective properties that can be harnessed in biomedical applications that may serve as supportive adjunctive procedures to conventional anti-viral drug therapies against diseases such as COVID-19.
227	Ce225	ME	Neal C. Goldberg,Sabrina Poirier,Allison Kanas,Lisa McCorkell,Carrie Anna McGinn,Yochai Re’em,Kathi Kuehnel,Nina Muirhead,Tahlia Ruschioni,Susan Taylor-Brown &Leonard A. Jason	A new clinical challenge: supporting patients coping with the long-term effects of COVID-19	https://doi.org/10.1080/21641846.2022.2128576	Published	10 Oct 2022	Article	https://www.tandfonline.com/doi/full/10.1080/21641846.2022.2128576	Mental Health Practitioners (MHPs) have a unique opportunity to provide resources and support to those suffering from Long COVID (LC), the post infectious illness that often follows an acute SARS-CoV-2 infection. In working with these individuals, MHPs can learn from the experiences of patients with another post-infectious disease known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS was once thought to be a psychologically mediated disorder caused by deconditioning and the fear of exertion following a precipitating event such as a viral infection. Research now shows that LC and ME/CFS are biomedical, multisystem, complex physiologic diseases. This article provides a framework to MHPs for the treatment of LC patients using knowledge derived from three decades of research on ME/CFS.
228	Ce226		Taku Harada,Kathryn Schmitz,Charles W. Helsper,Grace Campbell,Larissa Nekhlyudov	Long-COVID and long-term cancer survivorship—Shared lessons and opportunities	https://doi.org/10.1111/ecc.13712	Published	24 September 2022	Commentary	https://onlinelibrary.wiley.com/doi/10.1111/ecc.13712	As of 2022, close to 90 million persons in the United States, 243 million persons in Europe and 585 million worldwide have been infected with the novel SARS-CoV-2 (COVID-19) virus and survived. Estimates vary but suggest that up to 50% may experience long-term sequelae, termed ‘Long-COVID’. While Long-COVID is a new condition, the phenomenon of disabling long-term effects following an illness requiring ongoing surveillance and management is not. In this commentary, we discuss how Long-COVID parallels the experiences of long-term cancer survivors, highlight shared challenges and offer opportunities to improve research and clinical care for both growing populations of patients as well as other long-term chronic, disabling conditions.
229	Ce227		Maha F. Alenazy 1,Haya I. Aljohar 2ORCID,Ashwag R. Alruwaili 3ORCID,Maha H. Daghestani 4,Mona A. Alonazi 5ORCID,Ranyah S. Labban 6,Afaf K. El-Ansary 7 andHanan A. Balto 8,*	Gut Microbiota Dynamics in Relation to Long-COVID-19 Syndrome: Role of Probiotics to Combat Psychiatric Complications	https://doi.org/10.3390/metabo12100912	Published	27 September 2022	Review	https://www.mdpi.com/2218-1989/12/10/912/htm	Increasing numbers of patients who recover from COVID-19 report lasting symptoms, such as fatigue, muscle weakness, dementia, and insomnia, known collectively as post-acute COVID syndrome or long COVID. These lasting symptoms have been examined in different studies and found to influence multiple organs, sometimes resulting in life-threating conditions. In this review, these symptoms are discussed in connection to the COVID-19 and long-COVID-19 immune changes, highlighting oral and psychiatric health, as this work focuses on the gut microbiota’s link to long-COVID-19 manifestations in the liver, heart, kidney, brain, and spleen. A model of this is presented to show the biological and clinical implications of gut microbiota in SARS-CoV-2 infection and how they could possibly affect the therapeutic aspects of the disease. Probiotics can support the body’s systems in fighting viral infections. This review focuses on current knowledge about the use of probiotics as adjuvant therapies for COVID-19 patients that might help to prevent long-COVID-19 complications.
230	Ce228		Felipe Contreras-Briceño 1,2,3,4,*ORCID,Maximiliano Espinosa-Ramírez 1ORCID,Dmitry Rozenberg 5,6ORCID andW. Darlene Reid 7,8ORCID	Eccentric Training in Pulmonary Rehabilitation of Post-COVID-19 Patients: An Alternative for Improving the Functional Capacity, Inflammation, and Oxidative Stress	https://doi.org/10.3390/biology11101446	Published	1 October 2022	Narrative Review	https://www.mdpi.com/2079-7737/11/10/1446/htm	Simple Summary Exercise is the cornerstone of pulmonary rehabilitation (PR) programs. Although all exercise has concentric (CONC, where the muscle groups shorten to produce force) and eccentric (ECC, characterized by lengthening muscle during its muscle contraction) contractions or components, usually PR is focus on CONC as the main training modality. Data show that this exercise modality increases cardiopulmonary stress, eliciting higher ventilation and consequently exacerbating dyspnoea, been more stressful for patients with chronic respiratory diseases (e.g., COPD and interstitial lung diseases). Similarly, higher cardiopulmonary stress has been associated with more oxidative stress. This aspect has been proposed as the central pathophysiological mechanism involved in the functional limitation of post-COVID-19 patients with moderate-to-severe damage associated with SARS-CoV-2 infection and prolonged hospital stay. Thus, traditional PR programs with CONC as a primary exercise modality can exacerbate dyspnoea and leg fatigue in these patients, repercussing in early exercise intolerance and diminishing the adherence to PR. On the other hand, ECC training has increased the locomotor muscle mass without significant cardiopulmonary stress, improving functional capacity and self-autonomy. This review discusses the mechanism that supports aerobic ECC exercise as a novel alternative to conventional CONC exercise included in traditional PR for post-COVID-19 patients. Abstract The purpose of this narrative review is to highlight the oxidative stress induced in COVID-19 patients (SARS-CoV-2 infection), describe longstanding functional impairments, and provide the pathophysiologic rationale that supports aerobic eccentric (ECC) exercise as a novel alternative to conventional concentric (CONC) exercise for post-COVID-19 patients. Patients who recovered from moderate-to-severe COVID-19 respiratory distress demonstrate long–term functional impairment. During the acute phase, SARS-CoV-2 induces the generation of reactive oxygen species that can be amplified to a “cytokine storm”. The resultant inflammatory and oxidative stress process causes organ damage, particularly in the respiratory system, with the lungs as the tissues most susceptible to injury. The acute illness often requires a long-term hospital stay and consequent sarcopenia. Upon discharge, muscle weakness compounded by limited lung and cardiac function is often accompanied by dyspnea, myalgia, anxiety, depression, and sleep disturbance. Consequently, these patients could benefit from pulmonary rehabilitation (PR), with exercise as a critical intervention (including sessions of strength and endurance or aerobic exercises). Unfortunately, conventional CONC exercises induce significant cardiopulmonary stress and increase inflammatory and oxidative stress (OS) when performed at moderate/high intensity, which can exacerbate debilitating dyspnoea and muscle fatigue post-COVID-19. Eccentric training (ECC) is a well–tolerated alternative that improves muscle mass while mitigating cardiopulmonary stress in patients with COPD and other chronic diseases. Similar benefits could be realized in post-COVID-19 patients. Consequently, these patients could benefit from PR with exercise as a critical intervention.
231	Ce229		M. V. Kiselevskiy, N. Yu. Anisimova, M. I. Bilan, A. I. Usov, N. E. Ustyuzhanina, A. A. Petkevich, I. Zh. Shubina, G. E. Morozevich & N. E. Nifantiev	Prospects for the Use of Marine Sulfated Fucose-Rich Polysaccharides in Treatment and Prevention of COVID-19 and Post-COVID-19 Syndrome	https://doi.org/10.1134/S1068162022060152	Published	29 October 2022	Review	https://link.springer.com/article/10.1134/S1068162022060152	Symptoms of the new coronavirus infection that appeared in 2019 (COVID-19) range from low fever and fatigue to acute pneumonia and multiple organ failure. The clinical picture of COVID-19 is heterogeneous and involves most physiological systems; therefore, drugs with a wide spectrum of mechanism of action are required. The choice of the treatment strategy for post-COVID-19 syndrome is still a challenge to be resolved. Polysaccharides with a high fucose content derived from seaweed and marine animals can form the basis for the subsequent development of promising agents for the treatment of COVID-19 and post-COVID-19 syndrome. This class of biopolymers is characterized by a variety of biological activities, including antiviral, antithrombotic, anticoagulant, hemo-stimulating, anti-inflammatory and immune-regulatory. Low molecular weight derivatives of these polysaccharides, as well as synthetic oligosaccharides with a sufficient amount and sulfation type may be considered as the most promising compounds due to their better bioavailability, which undoubtedly increases their therapeutic potential.
232	Ce230		Soha G. Elsheikh, Sally S. El-Mosallamy, Yasmin M. Fayez & Abeer M. E. Hassan	Smart stability indicating spectrophotometric methods for determination of modafinil: the promising treatment for post-covid neurological syndrome	https://doi.org/10.1186/s13065-022-00869-z	Published	21 October 2022	Article	https://bmcchem.biomedcentral.com/articles/10.1186/s13065-022-00869-z	Modafinil (MDF) is one of the neurostimulants with a potential effect in the COVID-19 ICU ventilated patients and post-COVID neurological syndrome treatment. Four rapid, simple and cost-effective stability indicating spectrophotometric methods were used for estimation of MDF in the presence of its acidic degradation product, namely; ratio difference (RD), first derivative of the ratio spectra (1DD), mean centering (MCR) and ratio subtraction method (RS). These methods were validated according to ICH guidelines and all methods revealed a good linearity in concentration range of (5-30 µg/mL) in addition to a good accuracy and precision with mean percentage recovery of 99.97 ± 0.305 for (RD), 100.10 ± 0.560 for (1DD), 100.02 ± 0.483 for (MCR) & 99.18 ± 1.145 for (RS) method. Specificity of the proposed methods was assessed and MDF was determined in the presence of up to 80% of its acidic degradation product for RD, 1DD, MCR and RS methods. The proposed methods were successfully applied for the determination of MDF in bulk powder and its tablet dosage form with mean percentage recovery of 100.33 ± 0.915 for (RD), 100.62 ± 0.985 for (1DD), 99.70 ± 0.379 for (MCR) and 100.21 ± 0.313 for (RS) method. The results obtained were statistically compared with those of official HPLC method and showed no significant difference with relevance accuracy and precision.
233	Ce231		Melissa Suran, PhD, MSJ	VA Guidebook on Long COVID	https://doi.org/10.1001/jama.2022.15484	Published	October 25, 2022	Guidelines	https://jamanetwork.com/journals/jama/article-abstract/2797585 https://www.publichealth.va.gov/n-coronavirus/docs/Whole-Health-System-Approach-to-Long-COVID_080122_FINAL.pdf	The Department of Veterans Affairs (VA) published a new guidebook on caring for veterans with long COVID. Titled the Whole Health System Approach to Long COVID, the guidebook provides information about signs, symptoms, and treatments for the illness. The guidebook also includes metrics, such as surveys, to assess autonomic symptoms. “From the first day of the pandemic, VA’s clinicians and researchers have been on the front lines—saving lives and learning how to treat COVID-19 and long COVID,” VA Secretary Denis McDonough, MSFS, said in a statement. “This guidebook packages up the best practices we’ve learned about treating long COVID, and it will help health care providers across America improve the lives of Veterans and non-Veterans alike.” The guidebook’s whole health approach can be implemented to personalize a plan that considers individual goals, needs, and values. Moreover, this approach may help clinicians assess and manage long COVID symptoms and subsequent conditions. Clinicians can also use the whole health approach to prioritize treatment based on patient needs.
234	Ce232		Gita Shafiee, Tohid Arastou, Ramin Heshmat, Ahmad Reza Jamshidi, Bagher Larijani & Seyed Masoud Arzaghi	Post COVID-19 neuropsychiatric complications and therapeutic role for TNF-α inhibitors: a case series study	https://doi.org/10.1007/s40200-022-01138-5	Published	15 October 2022	Case Series	https://link.springer.com/article/10.1007/s40200-022-01138-5	Background The post-COVID syndrome is the various physical and neuropsychiatric symptoms after the acute phase of COVID-19. The understanding of pathophysiology of this syndrome and its treatment need to further studies. This study aimed to present three cases of neuropsychiatric symptoms after COVID-19 and effective treatments in these patients. Case presentation Three patients with new or progressively neuropsychiatric symptoms such as seizures, attention difficulties, insomnia, confusion and etc., were referred to our clinic about 8 months after severe COVID-19 infection. The patients were assessed with extensive workup includes a neurological exam, brain MRI, LORETA scan, and biochemical and levels of inflammatory serum markers. All patients had elevated levels of TNF-α, poor neurological exam, and abnormal reports of MRI or LORETA scan. Diagnosis of post- COVID neuropsychiatric complications was made for the patients.TNF inhibition with Adalimumab (40 mg/weekly for a month) was initiated for the patients and led to a dramatic improvement of all symptoms. Conclusions To our knowledge, this report is the first case series study that suggests TNF inhibitors in the treatment of post-COVID-19 syndrome, especially neuropsychological complications. However, future studies should evaluate the best therapeutic options for this syndrome.
235	Ce233		Clara Douin 1,*,Kevin Forton 2ORCID,Michel Lamotte 2,Alexis Gillet 2ORCID andPhilippe Van de Borne 2ORCID	Benefits of Cardio-Pulmonary Rehabilitation in Moderate to Severe Forms of COVID-19 Infection	https://doi.org/10.3390/healthcare10102044	Published	17 October 2022	Study	https://www.mdpi.com/2227-9032/10/10/2044/htm	Our aim was to evaluate the benefits of cardio-pulmonary rehabilitation on severe to moderate COVID-19 patients. 25 discharged COVID-19 patients underwent a cardio-pulmonary test (CPET), a spirometry test and a measure of carbon monoxide lung diffusion capacity (DLCO) at the beginning of their rehabilitation program and after 23 ± 5 rehabilitation sessions. This rehabilitation program combined interval training exercises on a bike and resistance exercises for major muscle groups. We then compared their progress in rehabilitation to that obtained with cardiac patients. At the beginning of their rehabilitation program, COVID-19 patients presented a reduced physical capacity with a maximal aerobic capacity (VO2 max) at 71% of predicted value, a maximal workload at 70% of predicted value and an exercise hyperventilation measured by a higher VE/VCO2 slope. Exercise was mainly limited by muscle deconditioning. After rehabilitation, the VO2 max and maximal workload increased in COVID 19 patients by 18% and 26%, respectively. In patients with ischemic heart disease the post-rehabilitation gains in VO2 max and maximal workload were 22% and 25%, respectively. Moreover, exercise hyperventilation decreased by 10% in both groups. On the other hand, the intrinsic pulmonary function of COVID 19 patients improved following natural recovery. In conclusion, even if cardio-pulmonary rehabilitation is probably not the only parameter which explains the partial recovery of moderate to severe COVID-19 patients, it certainly helps to improve their physical capacity and reduce exercise hyperventilation.
236	Ce234		MeravCatalognaaEfratSassonaAmirHadannyabYoavParagaShaniZilberman-ItskovichabShaiEfratiabc	Effects of hyperbaric oxygen therapy on functional and structural connectivity in post-COVID-19 condition patients: A randomized, sham-controlled trial	https://doi.org/10.1016/j.nicl.2022.103218	Published	3 October 2022	Trial	https://www.sciencedirect.com/science/article/pii/S2213158222002832	Highlights •Resting state fMRI can detect longitudinal changes in post-COVID-19 patients. •Effects of HBOT on cognitive recovery is most evident in internetwork connectivity. •Emotional recovery correlated with alternation in the amygdala and insula networks. •Structural efficacy enhancement of the amygdala circuit reflects lower psychiatric scores. Abstract Introduction Post-COVID-19 condition refers to a range of persisting physical, neurocognitive, and neuropsychological symptoms after SARS-CoV-2 infection. Abnormalities in brain connectivity were found in recovered patients compared to non-infected controls. This study aims to evaluate the effect of hyperbaric oxygen therapy (HBOT) on brain connectivity in post-COVID-19 patients. Methods In this randomized, sham-controlled, double-blind trial, 73 patients were randomized to receive 40 daily sessions of HBOT (n = 37) or sham treatment (n = 36). We examined pre- and post-treatment resting-state brain functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) scans to evaluate functional and structural connectivity changes, which were correlated to cognitive and psychological distress measures. Results The ROI-to-ROI analysis revealed decreased internetwork connectivity in the HBOT group which was negatively correlated to improvements in attention and executive function scores (p < 0.001). Significant group-by-time interactions were demonstrated in the right hippocampal resting state function connectivity (rsFC) in the medial prefrontal cortex (PFWE = 0.002). Seed-to-voxel analysis also revealed a negative correlation in the brief symptom inventory (BSI-18) score and in the rsFC between the amygdala seed, the angular gyrus, and the primary sensory motor area (PFWE = 0.012, 0.002). Positive correlations were found between the BSI-18 score and the left insular cortex seed and FPN (angular gyrus) (PFWE < 0.0001). Tractography based structural connectivity analysis showed a significant group-by-time interaction in the fractional anisotropy (FA) of left amygdala tracts (F = 7.81, P = 0.007). The efficacy measure had significant group-by-time interactions (F = 5.98, p = 0.017) in the amygdala circuit. Conclusions This study indicates that HBOT improves disruptions in white matter tracts and alters the functional connectivity organization of neural pathways attributed to cognitive and emotional recovery in post-COVID-19 patients. This study also highlights the potential of structural and functional connectivity analysis as a promising treatment response monitoring tool.
237	Ce235		Kazuaki Imai 1,Takafumi Yamano 2,Soichiro Nishi 3,Ryushiro Nishi 3,Tatsuro Nishi 3,4,Hiroaki Tanaka 5,Toshiyuki Tsunoda 6,Shohei Yoshimoto 7,Ayaki Tanaka 8,Kenji Hiromatsu 9ORCID,Senji Shirasawa 6,Takashi Nakagawa 10 andKensuke Nishi 2,3,4,*ORCID	Epipharyngeal Abrasive Therapy (EAT) Has Potential as a Novel Method for Long COVID Treatment	https://doi.org/10.3390/v14050907	Published	27 April 2022	Study	https://www.mdpi.com/1999-4915/14/5/907/htm	COVID-19 often causes sequelae after initial recovery, referred to collectively as long COVID. Long COVID is considered to be caused by the persistence of chronic inflammation after acute COVID-19 infection. We found that all long COVID patients had residual inflammation in the epipharynx, an important site of coronavirus replication, and some long COVID symptoms are similar to those associated with chronic epipharyngitis. Epipharyngeal abrasive therapy (EAT) is a treatment for chronic epipharyngitis in Japan that involves applying zinc chloride as an anti-inflammatory agent to the epipharyngeal mucosa. In this study, we evaluated the efficacy of EAT for the treatment of long COVID. The subjects in this study were 58 patients with long COVID who were treated with EAT in the outpatient department once a week for one month (mean age = 38.4 ± 12.9 years). The intensities of fatigue, headache, and attention disorder, which are reported as frequent symptoms of long COVID, were assessed before and after EAT using the visual analog scale (VAS). EAT reduced inflammation in the epipharynx and significantly improved the intensity of fatigue, headache, and attention disorder, which may be related to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These results suggest that EAT has potential as a novel method for long COVID treatment.
238	Ce236		Jessica DeMars, Darren A. Brown, Ippokratis Angelidis, Fiona Jones, Francis McGuire, Kelly K. O’Brien, Daria Oller, Sue Pemberton, Rachel Tarrant, Monica Verduzco-Gutierrez & Douglas P. Gross	What is Safe Long COVID Rehabilitation?	https://doi.org/10.1007/s10926-022-10075-2	Published	31 October 2022	Editorial	https://link.springer.com/article/10.1007/s10926-022-10075-2	Long COVID is a term coined and preferred by people with the condition that describes persistent effects of Coronavirus Disease (COVID-19) [1]. Long COVID is known by other names including “Post COVID-19 Condition” (World Health Organization (WHO)[2] and “Post-Acute Sequelae of COVID-19” (United States). Long COVID is estimated to affect more than 145 million people around the globe[3] and results in wide diversity of symptoms,[4] episodic disability,[5] reduced quality of life,[6] and work loss,[7] irrespective of hospitalisation or acute disease severity [8]. Improved understanding of appropriate health care and rehabilitation interventions to reduce the burden of Long COVID have been identified as an international research priority.[9]. In September 2022, the patient-led association Long COVID Physio organized the two-day online Long COVID Physio International Forum, bringing lived experiences to Long COVID, disability, rehabilitation, and research. Long COVID Physio is an international, patient-led association of physiotherapists (physical therapists) living with Long COVID and allies, working internationally across peer support, education, research, and advocacy [10]. At the Forum, a discussion session was held to address the question, “What is Safe Long COVID Rehabilitation?” This topic was of critical importance given that some have experienced complications such as acute events, symptom exacerbation, or deterioration following traditional approaches to rehabilitation (i.e., involving progressive loading, physical or cognitive activity, or exercise), as well as perceived lack of support from health care providers who at times question the validity of symptom reports. The discussion session involved people living with Long COVID, clinicians, and researchers with expertise and experiences related to Long COVID rehabilitation. The 10 speakers involved in this session met in advance of the Forum to share experiences and ideas, identify potential themes for discussion, and deliberate proposed recommendations. These were then presented to the international community at the Forum where themes and recommendations were discussed, debated, solidified, and are presented in this editorial (summary available in Table 1). 1) Safe Long COVID rehabilitation should include identifying red flags or complications where commencing rehabilitation could cause an acute event or deterioration. 2) Safe Long COVID rehabilitation should be personalized. 3) Safe Long COVID rehabilitation should be founded within accurate expectations. 4) Long COVID rehabilitation should be psychologically safe and supportive.
239	Ce237		Mohanakrishnan Sathyamoorthy, Rajkumar Sevak, Monica Verduzco-Gutierrez, Juan Cabrera, Marielisa Lopez and Sachin A Shah	Abstract 14980: Enhanced External Counterpulsation Improves Cognitive Function in Long Covid Patients		Published	30 Oct 2022	Study	https://www.ahajournals.org/doi/abs/10.1161/circ.146.suppl_1.14980	INTRODUCTION: Enhanced External Counterpulsation (EECP) has been described to help Long Covid related cardiovascular (e.g. chest pain, fatigue) and neurocognitive (e.g. brain fog) symptoms. We sought to determine whether EECP improves cognitive function. Methods: A retrospective evaluation of a contemporary consecutive patient cohort referred to Flow Therapy for management of Long Covid. All patients subjectively reporting brain fog were assessed using the BrainCheck tool to determine degree of cognitive impairment pre- and post EECP therapy. BrainCheck is an FDA-approved, web-based battery of standardized neuropsychological tests that includes the Trail Making Test (Trails A, Trails B) for assessing executive function (cognitive flexibility), the Digit Symbol Substitution Test (DSST) for assessing attention and processing speed, the Stroop Test for assessing executive function (response inhibition), and the List Learning Test for immediate/delayed verbal memory evaluation. BrainCheck scores have a normative mean of 100±15 with a clinically meaningful change ranging from 12-21 depending on age. Change from baseline to post-EECP were assessed using the paired student’s t-test. Results: A total of 51 Long Covid patients were included (49.3±11.0 years, 60.8% female, 22% had CAD) with the average duration since Covid diagnosis being 9.9±6.1months. No patients were excluded. All patients completed 25-35 sessions of EECP. Baseline BrainCheck composite score was 88.0±22.1 which significantly improved to 100.1±16.4 post-EECP (+11.9±18.7, p<0.001). When limiting to baseline score under 85 (n=20; baseline average 66.7±17.6) the improvement was +26.0±20.9 (p<0.001). EECP therapy improved the patients’ performance across cognitive domains, as indicated by significant enhancements in scores from baseline in Trails A (+6.1±19.7), Trails B (+5.0±11.8), DSST (+12.9±24.1) and Stroop Test (+11.2±19.1) (all p-values<0.05). Conclusion: This is the first evaluation showing significant improvement in Long Covid related cognitive impairment post-EECP therapy. Further study is needed to determine if the mechanistic basis may include EECP induced improved cerebral perfusion, change in endothelial function, or a yet unelucidated pathway.
240	Ce238		Simon Décary,corresponding author a Wouter De Groote, b Chiara Arienti, c Carlotte Kiekens, d Paolo Boldrini, e Stefano Giuseppe Lazzarini, c Michèle Dugas, f Théo Stefan, f Léa Langlois, f Frédérique Daigle, a Florian Naye, a Annie LeBlanc, f and Stefano Negrini g	Scoping review of rehabilitation care models for post COVID-19 condition	https://doi.org/10.2471%2FBLT.22.288105	Published	2022 Oct 3	Review	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9589389/	Objective To systematically map the current evidence about the characteristics of health systems, providers and patients to design rehabilitation care for post coronavirus disease 2019 (COVID-19) condition. Methods We conducted a scoping review by searching the databases: MEDLINE®, Embase®, Web of Science, Cochrane COVID-19 Registry and Cochrane Central Register of Controlled Trials, from inception to 22 April 2022. The search strategy included terms related to (i) post COVID-19 condition and other currently known terminologies; (ii) care models and pathways; and (iii) rehabilitation. We applied no language or study design restrictions. Two pairs of researchers independently screened title, abstracts and full-text articles and extracted data. We charted the evidence according to five topics: (i) care model components and functions; (ii) safe delivery of rehabilitation; (iii) referral principles; (iv) service delivery settings; and (v) health-care professionals. Findings We screened 13 753 titles and abstracts, read 154 full-text articles, and included 37 articles. The current evidence is conceptual and expert based. Care model components included multidisciplinary teams, continuity or coordination of care, people-centred care and shared decision-making between clinicians and patients. Care model functions included standardized symptoms assessment, telehealth and virtual care and follow-up system. Rehabilitation services were integrated at all levels of a health system from primary care to tertiary hospital-based care. Health-care workers delivering services within a multidisciplinary team included mostly physiotherapists, occupational therapists and psychologists. Conclusion Key policy messages include implementing a multilevel and multiprofessional model; leveraging country health systems’ strengths and learning from other conditions; financing rehabilitation research providing standardized outcomes; and guidance to increase patient safety.
241	Ce239		Kristoffer S.HansenabTrine H.MogensenabJaneAgergaardaBeritSchiøttz-ChristensenacLarsØstergaardabLine K.VibholmaeSteffenLethabde	High-dose coenzyme Q10 therapy versus placebo in patients with post COVID-19 condition: A randomized, phase 2, crossover trial	https://doi.org/10.1016/j.lanepe.2022.100539	Published	2 November 2022	Trial	https://www.sciencedirect.com/science/article/pii/S2666776222002356	Background Post COVID-19 condition (PCC) is defined as symptoms lasting more than 12 weeks after developing COVID-19. Evidence of mitochondrial dysfunction has been reported in peripheral blood mononuclear cells obtained from patients with COVID-19. We hypothesized that PCC is caused by prolonged mitochondrial dysfunction. Given that coenzyme Q10 (CoQ10) can improve mitochondrial function, we examined whether high-dose CoQ10 can reduce the number and/or severity of PCC-related symptoms. Methods In this placebo-controlled, double-blind, 2 × 2 crossover interventional trial, participants were recruited from two centres at Aarhus University Hospital and Gødstrup Hospital, Denmark. They were randomly assigned to receive either oral capsules of CoQ10 in a dose of 500 mg/day or placebo for 6 weeks, with crossover treatment after a 4-week washout period. The ED-5Q and a PCC-symptom specific questionnaire were completed by the participants at 5 visits during the 20-week study period. The primary endpoint was the change in the number and/or severity of PCC-related symptoms after the 6-week intervention compared to placebo. Participants who completed the two-dosing period were included in the primary analysis, while all participants receiving one dose were included in safety assessment. Findings From May 25th, 2021, to September 22nd, 2021, 121 participants underwent randomization, and 119 completed both dosing periods – 59 and 60 in group A and B, respectively. At baseline, the mean PCC-related symptom score was 43.06 (95% CI: 40.18; 45.94), and the mean EQ-5D health index was 0.66 (95% CI: 0.64; 0.68). The difference between CoQ10 and placebo was not significant with respect to either the change in EQ-5D health index (with a mean difference of 0.01; 95% CI: −0.02; 0.04; p = 0.45) or the change in PCC-related symptom score (with a mean difference of −1.18; 95% CI: −3.54; 1.17; p = 0.32). Interpretation Based on self-reported data, CoQ10 treatment does not appear to significantly reduce the number or severity of PCC-related symptoms when compared to placebo. However, we observed a significant spontaneous improvement on both scores regardless of treatment during 20 weeks observation.
242	Ce240		Hythem Sidky, View ORCID ProfileDavid K. Sahner, View ORCID ProfileAndrew T. Girvin, View ORCID ProfileNathan Hotaling, Sam G. Michael, Michael G. Kurilla, Ken Gersing the N3C consortium	Assessing the Effect of Selective Serotonin Reuptake Inhibitors in the Prevention of Post-Acute Sequelae of COVID-19	https://doi.org/10.1101/2022.11.09.22282142	pre-print	November 10, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.11.09.22282142v1.full-text	Importance Post-acute sequelae of COVID-19 (PASC) produce significant morbidity, prompting evaluation of interventions that might lower risk. Selective serotonin reuptake inhibitors (SSRIs) potentially could modulate risk of PASC via their central hypothesized immunomodulatory, and/or antiplatelet properties and therefore have been hypothesized to be of potential benefit in patients with PASC, although clinical data are lacking. Objectives The main objective was to evaluate whether SSRIs with agonist activity at the sigma-1 receptor lower the risk of PASC, since agonism at this receptor may serve as a mechanism by which SSRIs attenuate an inflammatory response. A secondary objective was to determine whether potential benefit could be traced to sigma-1 agonism by evaluating the risk of PASC among recipients of SSRIs that are not S1R agonists. Design Retrospective study leveraging real-world clinical data within the National COVID Cohort Collaborative (N3C), a large centralized multi-institutional de-identified EHR database. Presumed PASC was defined based on a computable PASC phenotype trained on the U09.9 ICD-10 diagnosis code to more comprehensively identify patients likely to have the condition, since the ICD code has come into wide-spread use only recently. Setting Population-based study at US medical centers. Participants Adults (≥ 18 years of age) with a confirmed COVID-19 diagnosis date between October 1, 2021 and April 7, 2022 and at least one follow up visit 45 days post-diagnosis. Of the 17 933 patients identified, 2021 were exposed at baseline to a S1R agonist SSRI, 1328 to a non-S1R agonist SSRI, and 14 584 to neither. Exposures Exposure at baseline (at or prior to COVID-19 diagnosis) to an SSRI with documented or presumed agonist activity at the S1R (fluvoxamine, fluoxetine, escitalopram, or citalopram), an SSRI without agonist activity at S1R (sertraline, an antagonist, or paroxetine, which does not appreciably bind to the S1R), or none of these agents. Main Outcome and Measurement Development of PASC based on a previously validated XGBoost-trained algorithm. Using inverse probability weighting and Poisson regression, relative risk (RR) of PASC was assessed. Results A 26% reduction in the RR of PASC (0.74 [95% CI, 0.63-0.88]; P = 5 × 10−4) was seen among patients who received an S1R agonist SSRI compared to SSRI unexposed patients and a 25% reduction in the RR of PASC was seen among those receiving an SSRI without S1R agonist activity (0.75 [95% CI, 0.62 - 0.90]; P = 0.003) compared to SSRI unexposed patients. Conclusions and Relevance SSRIs with and without reported agonist activity at the S1R were associated with a significant decrease in the risk of PASC. Future prospective studies are warranted. Question Do Selective Serotonin Reuptake Inhibitors with and without agonist activity at the sigma-1 receptor (S1R) prevent Post-Acute Sequelae of COVID-19? Findings In this retrospective study leveraging real-world clinical data that included 17 933 patients, a 28% reduction in risk of PASC was observed for S1R agonist SSRIs and a 25% reduction in risk of PASC was observed for non-S1R agonist SSRIs, both versus controls, using a computable phenotype to define PASC. Meaning SSRIs may play a role in managing the long term disease burden of COVID-19. Future prospective studies are warranted to confirm these findings and evaluate potential mechanisms of action.
243	Ce241		Ying Jie Chee,Bingwen Eugene Fan,Barnaby Edward Young,Rinkoo Dalan,David Chien Lye	Clinical trials on the pharmacological treatment of long COVID: a systematic review	https://doi.org/10.1002/jmv.28289	Published	08 November 2022	Review	https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.28289	Background The post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC), also known as post-acute coronavirus disease 19 (COVID-19) or the long COVID syndrome (long COVID) is an emerging public health concern. A substantial proportion of individuals may remain symptomatic months after initial recovery. An updated review of published and ongoing trials focusing on managing long COVID will help identify gaps and address the unmet needs of patients suffering from this potentially debilitating syndrome. Methods A comprehensive literature search was conducted on the international databases and clinical trial registries from inception to 31 July 2022. Results This review included 6 published trials and 54 trial registration records. There is significant heterogeneity in the characterization of long COVID and ascertainment of primary outcomes. Most of the trials are focused on individual symptoms of long COVID or isolated organ dysfunction, classified according to cardiovascular, respiratory and functional capacity, neurological and psychological, fatigue, and olfactory dysfunction. Most of the interventions are related to the mechanisms causing the individual symptoms. Although the 6 published trials showed significant improvement in the symptoms or organ dysfunction studied, these initial studies lack internal and external validity limiting the generalizability. Conclusions This review provides an update of the pharmacological agents that could be used to treat long COVID. Further standardization of the diagnostic criteria, inclusion of participants with concomitant chronic cardiometabolic diseases and standardization of outcomes will be essential in future clinical trials.
244	Ce242		NICE	COVID-19 rapid guideline: managing the longterm effects of COVID-19		Published	03.11.2022	Guidelines	https://www.nice.org.uk/guidance/ng188/resources/covid19-rapid-guideline-managing-the-longterm-effects-of-covid19-pdf-51035515742
245	Ce243		VivianaVersaceaPaolaOrtelliaSabrinaDeziaDavideFerrazzoliaAlessiaAlibardiaIleniaBoniniaMichaelEnglbRobertoMaestricMartinaAssognadValentinaAjelloeElkePucks-FaesfLeopoldSaltuariaLucaSebastianelliaMarkusKoflerf1GiacomoKochdg1	Co-Ultramicronized Palmitoylethanolamide/Luteolin normalizes GABAB-ergic activity and cortical plasticity in long COVID-19 syndrome	https://doi.org/10.1016/j.clinph.2022.10.017	Published	11 November 2022	Study	https://www.sciencedirect.com/science/article/pii/S1388245722009385	Highlights •Long Covid patients with fatigue and cognitive problems show impairment of cortical GABAB activity and reduced plasticity in primary motor cortex. •Co-ultramicronized palmitoylethanolamide with luteolin (PEA-LUT) 700+70 mg bid for 8 weeks restores GABAB neurotransmission and cortical plasticity. •PEA-LUT is a candidate for the treatment of long Covid patients. Abstract Objective Transcranial magnetic stimulation (TMS) studies showed that patients with cognitive dysfunction and fatigue after COVID-19 exhibit impaired cortical GABAB-ergic activity, as revealed by reduced long-interval intracortical inhibition (LICI). Aim of this study was to test the effects of co-ultramicronized palmitoylethanolamide/luteolin (PEA-LUT), an endocannabinoid-like mediator able to enhance GABA-ergic transmission and to reduce neuroinflammation, on LICI. Methods Thirty-nine patients (26 females, mean age 49.9 ± 11.4 years, mean time from infection 296.7 ± 112.3 days) suffering from persistent cognitive difficulties and fatigue after mild COVID-19 were randomly assigned to receive either PEA-LUT 700mg + 70mg or PLACEBO, administered orally bid for eight weeks. The day before (PRE) and at the end of the treatment (POST), they underwent TMS protocols to assess LICI. We further evaluate short-latency afferent inhibition (SAI) and long-term potentiation (LTP)-like cortical plasticity. Results Patients treated with PEA-LUT but not with PLACEBO showed a significant increase of LICI and LTP-like cortical plasticity. SAI remained unaffected. Conclusions Eight weeks of treatment with PEA-LUT restore GABAB activity and cortical plasticity in long Covid patients. Significance This study confirms altered physiology of the motor cortex in long Covid and indicates PEA-LUT as a candidate for the treatment of this post-viral condition.
246	Ce244		DaniloBuonsenso	Pharmacological trials for long COVID: First light at the end of the tunnel	https://doi.org/10.1016/j.lanepe.2022.100544	Published	10 November 2022	Article	https://www.sciencedirect.com/science/article/pii/S266677622200240X?via%3Dihub	Fourth, it is unlikely that a single intervention can be effective in treating such a complex systemic condition. Recent research considers long COVID to be a complex disease in which multiple different mechanisms triggered by the initial infection in a susceptible host, may play significant roles.8 Indeed, immunological imbalances, chronic endothelitis with circulating micro-clots, and intestinal dysbiosis have been documented in patients with long COVID.8 Therefore, it is crucial that trials involving a multipharmacological approach are implemented. Finally, with the increasing number of cases different phenotypes of long COVID have been identified,7 as has also been described in Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS),9 a similar post-viral condition. It is possible that patients with specific phenotypes of long COVID (e.g. those with prevalent cardio-respiratory, gastrointestinal, musculoskeletal or neurocognitive impairments) may benefit from different interventions, and therefore trials should focus on defining better inclusion criteria to select patients according to their predominant symptomatology. Hopefully, this trial will open a new era in long COVID care, which will probably also indirectly benefit the millions of neglected patients with ME/CFS. Importantly, there is clear evidence that long COVID can also affect children, although it is less frequent and usually less severe compared to adult long COVID, and efforts should be made to develop similar trials in children.7,10 The huge positive medical and psychological impact that trials can have on the long COVID community, will hopefully lead governments, public and private funders, and policy makers, to follow the path opened by Hansen and colleagues to conduct pharmacological trials for patients with Long Covid.
247	Ce245		SB Mistry1, AK Banerjee2	‘Endgame’ – Long term impacts of COVID-19 P229 Cardiopulmonary exercise testing in patients with long covid	http://dx.doi.org/10.1136/thorax-2022-BTSabstracts.361	Published	November 11, 2022	Trial	https://thorax.bmj.com/content/77/Suppl_1/A206.abstract	Objective Examine the relationship between symptoms and exercise physiological parameters in patients with long covid. Methods Patients with long covid symptoms 6–12 months after covid19 infection referred to the long covid clinic were invited for Cardiopulmonary Exercise Testing (CPET). None had required ventilatory support during covid19 infection. All patients had normal transthoracic echocardiograms and normal resting flow-volume curves and gas transfer measurements. All patients underwent standard cycle ergometer symptom-limited CPET. Treatment guided by the CPET was offered and follow-up CPET was performed at 3 months. Results 32 patients had a first CPET. The commonest symptoms were breathlessness (30/32), fatigue (26/32), cough (7/32), ‘brain fog’ (6/32) and chest pain (5/32). The main CPET physiological abnormalities were a borderline low peak oxygen uptake (mean 82.5% predicted), a low anaerobic threshold (AT, mean 47.6% of predicted maximal oxygen uptake) and a low oxygen uptake/work rate slope (mean 9.4 ml/min/W). The oxygen pulse curve flattened early in exercise, but peak oxygen pulse was normal (mean 88.9%). 20 patients underwent a second CPET. 14 patients had improved symptoms: breathlessness (11/20), fatigue (9/20), cough (2/20), ‘brain fog’ (3/20) and chest pain (0/20). Symptom improvement was associated with a rise in peak oxygen uptake (to mean 85.3% predicted) and oxygen pulse (to mean 94.1% predicted) although both remained within the normal range. The AT remained low (mean 46.4% predicted maximal oxygen uptake). The ventilatory equivalent for carbon dioxide (VE/VCO2) was normal 28.6 L/L at AT. 6 patients with unchanged symptoms had a reduction in oxygen pulse to mean 81.5% predicted compared to the first CPET but a rise in VE/VCO2 to 33.7 L/L at AT. Conclusions Long covid is associated with impaired peak oxygen uptake, AT and oxygen pulse. This suggests an oxygen delivery or uptake disorder or deconditioning. The transthoracic echocardiograms were normal suggesting a disorder at the muscle level. A targeted treatment programme based on CPET improves symptoms and physiological parameters in long covid patients. ConclusionsPatients with unchanged symptoms after 3 months of treatment had persistent physiological abnormalities but appeared to develop features of dysfunctional breathing syndrome.
248	Ce246		Pinar Mesci ,Janaina S. de Souza ,Laura Martin-Sancho ,Angela Macia ,Aurian Saleh,Xin Yin,Cedric Snethlage,Jason W. Adams,Simoni H. Avansini,Roberto H. Herai,Angels Almenar-Queralt,Yuan Pu,Ryan A. Szeto,Gabriela Goldberg,Patrick T. Bruck,Fabio Papes,Sumit K. Chanda,Alysson R. Muotri	SARS-CoV-2 infects human brain organoids causing cell death and loss of synapses that can be rescued by treatment with Sofosbuvir	https://doi.org/10.1371/journal.pbio.3001845	Published	November 3, 2022	Study	https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001845	The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which was rapidly declared a pandemic by the World Health Organization (WHO). Early clinical symptomatology focused mainly on respiratory illnesses. However, a variety of neurological manifestations in both adults and newborns are now well-documented. To experimentally determine whether SARS-CoV-2 could replicate in and affect human brain cells, we infected iPSC-derived human brain organoids. Here, we show that SARS-CoV-2 can productively replicate and promote death of neural cells, including cortical neurons. This phenotype was accompanied by loss of excitatory synapses in neurons. Notably, we found that the U.S. Food and Drug Administration (FDA)-approved antiviral Sofosbuvir was able to inhibit SARS-CoV-2 replication and rescued these neuronal alterations in infected brain organoids. Given the urgent need for readily available antivirals, these results provide a cellular basis supporting repurposed antivirals as a strategic treatment to alleviate neurocytological defects that may underlie COVID-19- related neurological symptoms.
249	Ce247		D Boiskin, G Jayasekera	P220 Thoracic mobilisation techniques combined with stretches improves thoracic compliance and respiratory rate in long COVID	http://dx.doi.org/10.1136/thorax-2022-BTSabstracts.352	Published	November 11, 2022	Study	https://thorax.bmj.com/content/77/Suppl_1/A201.2.abstract	Background A number of patients with COVID-19 experience prolonged symptoms, known as ‘Long COVID’. Fatigue, dyspnoea and chest wall tightness are common symptoms. These symptoms limit exercise tolerance and cause anxiety. They require thorough and costly investigations that do not always provide a pathway to traditional treatments. We present the impact of thoracic mobilisation, a combination of stretches and general advice on abdominal breathing on long COVID symptoms. Methods Consecutive adult long COVID patients attending a general respiratory physiotherapy clinic with breathlessness and chest wall tightness were included. All patients were assessed for thoracic expansion using a cloth tape, measuring at T6 level from resting expiration to maximum inspiration. Resting respiratory rate (RR) was also measured as breaths per minute (bpm). All patients were then treated with a single application of thoracic mobilisation techniques (muscle energy techniques and/or rib stacking) and combinations of muscle stretches including serratus anterior, pectoralis minor and diaphragm stretches. General advice regarding abdominal breathing was also demonstrated. Results Thirty four consecutive long COVID patients were included (mean age 52 y, 16♂). Nine patients (26%) had pre-existing respiratory co-morbidities including asthma, COPD and sleep-disordered breathing and 12 patients (35%) had no past medical history. Prior to intervention mean thoracic expansion was 1.92 cm (±1.15) and mean RR was 17.6 bpm (±5.1). After intervention, thoracic expansion improved to 3.89 cm (±1.32) and RR to 11.2 bpm (±4.6). There were significant improvements in both thoracic expansion and respiratory rate (p<0.0001). Conclusion Normal thoracic expansion is approximately 3.5 – 7 cm. This group of long COVID patients displayed suboptimal thoracic expansion at T6. This appears to have had an effect on resting respiratory rate. Post mobilisation both thoracic expansion and resting respiratory rate improved. This is likely due to improved thoracic compliance with mobilisations and stretches, reducing the work of breathing in these patients. The addition of simple breathing advice, rather than longer breathing re-education sessions helped to further reduce and correct respiratory rate. A single application of thoracic mobilisation techniques combined with stretches and simple advice on breathing can improve thoracic expansion and resting respiratory rate in long COVID.
250	Ce248		J Gallois1, N McWirter2, A Windith2, D Barber1, S Pilsworth1, D Wat1	P225 Pulmonary Rehabilitation in Long COVID – The impact of social deprivation and treatment delay on outcomes	http://dx.doi.org/10.1136/thorax-2022-BTSabstracts.357	Published	November 11, 2022	Study	https://thorax.bmj.com/content/77/Suppl_1/A204.1.abstract	Introduction Post COVID-19 syndrome (Long COVID) is a new and emerging condition which affects up to 2.2 million patients in the UK as of April 2022. Physical deconditioning is a hallmark of Long COVID. Pulmonary Rehabilitation (PR) is a well-established treatment for many chronic respiratory diseases to improve physical conditioning. Delays in starting PR and socioeconomic factors could play a role in completion rate and efficacy. The validity of PR in Post COVID-19 Syndrome has not yet been clearly defined. Methods We performed a retrospective observational study of patients undergoing PR between June 2020 and April 2021 for Post Covid-19 Syndrome to evaluate the change in exercise tolerance, as well as the effects of the Index of Multiple Deprivation (IMD) score and delay between infection and PR on patients’ outcomes. Completion was defined as attainment of patient’s pre-PR defined personal goals. Pre- and Post-PR 6-minute Walk test (6MWT) results were used to measure exercise tolerance. Results 86 patients participated in PR during the study period with 30 (34.9%) patients completing the program with a mean age of 59 years. The mean number of sessions attended was 10.6 (range 2–19). The number of sessions did not correlate with improvement in 6MWT. Completion of PR was associated with a statistically significant improvement of 6MWT distance (figure 1) using Wilcoxon rank test (p < 0.001). The mean delay between infection and starting PR was 200 days. IMD decile and time between diagnosis of COVID infection and starting PR did not have any influence on the change in 6MWT results. Conclusions This study is a real-world delivery of PR in patients with Post COVID-19 syndrome, illustrating the improvements in physical conditioning. Unlike previous studies in the COPD population, socioeconomic status and the delays in starting PR did not affect the outcome of PR.1 As such this PR should be offered to any eligible patients following COVID-19 infection to improve their physical fitness.
251	Ce249		MA Faghy1, REM Ashton1, R Owen1, J Yates1, C Thomas1, T Maden-Wilkinson2, S Kumar3, R Gururaj3, C Ozemek4, R Arena4, T Bewick5	P227 Reduced respiratory muscle strength, lung function, and functional status and symptomology in patients referred to Long COVID clinics, an observational cohort analysis	http://dx.doi.org/10.1136/thorax-2022-BTSabstracts.359	Published	November 11, 2022	Study	https://thorax.bmj.com/content/77/Suppl_1/A205.1.abstract	Introduction One in ten people will develop Long COVID (LC) following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite broad-ranging and episodic symptomology, there are no data that demonstrate changes in functional status (FS), respiratory muscle strength and lung function over time. We conducted a sixteen-week cohort observation of LC patients to determine changes in FS, respiratory muscle strength and lung function. Method Sixty-six patients (n=48 females, mean age 51 ± 10 years, n=8 hospitalised, mean time post-infection 6.2 ± 1.8 months) were recruited from LC clinics in the United Kingdom (CPMS ID: 52331). Patients completed five face-to-face visits (day 0, 28, 56, 84 and 110 ± 3 days) and bi-weekly telephone consultations (day 14, 42, 70 and 98 ± 3 days). FS was assessed via the post-COVID functional status scale (PCFS) and the six-minute walk test (6MWT). Maximum inspiratory (MIP) and expiratory (MEP) respiratory muscle pressure and lung function (forced vital capacity (FVC) and forced expired volume in one second (FEV1) were assessed during face-to-face visits according to published standards. Results PCFS was 2.7 ± 0.4 AU, P=0.02 at baseline and improved at 16-weeks (2.1 ±1.1 AU) and still highlighted impaired FS. 6MWT was 322 ± 133 meters at baseline and improved at 16 weeks (430 ± 150 meters, P<0.01) but remained lower than normative values for healthy age-matched controls. MIP was 77 ± 21 cmH2O at baseline (86% predicted) and was unchanged post 16 weeks (88 ± 25 cmH2O, 92% predicted, P>0.05). Baseline MEP was 115 ± 41 cmH2O (96% and was unchanged post-16-weeks (119 ± 48 cmH2O, 92% predicted, P>0.05). Lung function data were below predicted values and unchanged over 16 weeks (baseline FVC: 3.10 ± 0.53 L.s-1, 72% predicted, post 16 weeks: 3.16 ± 0.34 L.s-1, 73% predicted, P>0.05 and baseline FEV1: 2.68 ± 0.39 L.s-1, 85% predicted, post 16 weeks: 2.75 ± 0.36 L.s-1, 85% predicted). Conclusion LC patients demonstrate reduced respiratory muscle strength and lung function which could be associated with reduced FS and should be addressed via specific rehabilitation approaches.
252	Ce250		Daniel P. Cardinali 1,Gregory M. Brown 2 andSeithikurippu R. Pandi-Perumal 3,*ORCID	Possible Application of Melatonin in Long COVID	https://doi.org/10.3390/biom12111646	Published	7 November 2022	Review	https://www.mdpi.com/2218-273X/12/11/1646	Clinical sequelae and symptoms for a considerable number of COVID-19 patients can linger for months beyond the acute stage of SARS-CoV-2 infection, “long COVID”. Among the long-term consequences of SARS-CoV-2 infection, cognitive issues (especially memory loss or “brain fog”), chronic fatigue, myalgia, and muscular weakness resembling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are of importance. Melatonin may be particularly effective at reducing the signs and symptoms of SARS-CoV-2 infection due to its functions as an antioxidant, anti-inflammatory, and immuno-modulatory agent. Melatonin is also a chronobiotic medication effective in treating delirium and restoring the circadian imbalance seen in COVID patients in the intensive care unit. Additionally, as a cytoprotector, melatonin aids in the prevention of several COVID-19 comorbidities, including diabetes, metabolic syndrome, and ischemic and non-ischemic cardiovascular diseases. This narrative review discusses the application of melatonin as a neuroprotective agent to control cognitive deterioration (“brain fog”) and pain in the ME/CFS syndrome-like documented in long COVID. Further studies on the therapeutic use of melatonin in the neurological sequelae of SARS-CoV-2 infection are warranted.
253	Ce251		PattonMcClellandM.D.aBruceGrayD.O.	Cilostazol as a Treatment for COVID Toes: A Case Report	https://doi.org/10.1016/j.avsg.2022.10.013	Published	25 November 2022	Case Report	https://www.sciencedirect.com/science/article/pii/S0890509622007348	Highlights 1)Pictorial diagnosis of COVID toes 2)Simple medication to improve symptomatology 3)The association of a viral illness with a “vascular vasospastic condition” Abstract During the Coronavirus Disease 2019 (COVID-19) pandemic, skin lesions resembling those seen in pernio (chilblains) have been observed in patients with COVID-19 infection. The term “COVID toes” has been used when there is toe involvement. We describe the case of a fully vaccinated, 56-year-old woman with no prior diagnosis of COVID-19 who developed pernio-like lesions many months after being vaccinated. Her skin lesions resolved after treatment with cilostazol, suggesting that this medication may be a viable treatment for pernio in the setting of COVID-19 infection.
254	Ce252		ArmanFesharaki-ZadehabNaomiLoweaAmy F.T.Arnstenc	Clinical experience with the α2A-adrenoceptor agonist, guanfacine, and N-acetylcysteine for the treatment of cognitive deficits in “Long-COVID19”	https://doi.org/10.1016/j.nerep.2022.100154	Published	25 November 2022	Study	https://www.sciencedirect.com/science/article/pii/S2667257X22001000	Highlights •Combined treatment with the α2A-adrenoceptor agonist, guanfacine, and the anti-oxidant, N-acetylcysteine (NAC) reduced the cognitive deficits (“brain fog”) associated with long-COVID19 in eight out of twelve patients. •Two patients stopped treatment due to hypotension and/or dizziness, common side effects of guanfacine, and two patients were lost to follow-up. •The remaining eight patients reported improved working memory, concentration and executive function, including the resumption of normal workloads. •One patient temporarily stopped guanfacine due to a hypotensive episode and reported a return of cognitive deficits that abated with resumed guanfacine treatment. •Although placebo-controlled trials will be needed to demonstrate efficacy, the established safety of guanfacine and NAC suggests they may be immediately useful in treating the cognitive deficits of long-COVID19. Abstract Background Prolonged cognitive deficits (“brain fog”) following COVID19 infection (long-COVID) are common and debilitating, yet there are currently no approved treatments. Cognitive impairment particularly targets the working memory and executive functions of the prefrontal cortex (PFC). The PFC has unusual neurotransmission and neuromodulation that render it vulnerable to stressors, and basic research has identified mechanisms that protect PFC connections. Based on the basic neuroscience data, we tried a combined open label treatment to bolster prefrontal function: the α2A-adrenoceptor agonist, guanfacine, which strengthens prefrontal connectivity, and the anti-oxidant, N- acetylcysteine (NAC), which protects mitochondria and reduces kynurenic acid blockade of NMDA receptors. Case report Twelve patients with “brain fog” including difficulties in executive functions were treated with guanfacine (1mg, PO bedtime for the first month, increased to 2mg after 1 month, if well-tolerated) and 600 mg NAC daily. Guanfacine+NAC improved cognitive abilities in eight of the twelve patients; four patients discontinued therapy, two for unspecified reasons and two due to hypotension and/or dizziness, common side effects of guanfacine. Those who stayed on guanfacine+NAC reported improved working memory, concentration, and executive functions, including a resumption of normal workloads. One patient briefly stopped taking guanfacine due to a hypotensive episode and reported a return of cognitive deficits that abated with resumed guanfacine treatment. Conclusion Although placebo-controlled trials will be needed to more rigorously demonstrate efficacy, as these agents have established safety, they may be immediately helpful in treating the large number of patients suffering from prolonged cognitive deficits following COVID19 infection.
255	Ce253		Fedor M. Zurabov 1,*ORCID,Ekaterina A. Chernevskaya 2ORCID,Natalia V. Beloborodova 2ORCID,Alexander Yu. Zurabov 1,Marina V. Petrova 2,Mikhail Ya. Yadgarov 2ORCID,Valentina M. Popova 1,Oleg E. Fatuev 2,Vladislav E. Zakharchenko 2,Marina M. Gurkova 1,Ekaterina A. Sorokina 2,Egor A. Glazunov 1,Tatiana A. Kochetova 1ORCID,Victoria V. Uskevich 1ORCID,Artem N. Kuzovlev 2 andAndrey V. Grechko 2	Bacteriophage Cocktails in the Post-COVID Rehabilitation	https://doi.org/10.3390/v14122614	Published	23 November 2022	Study	https://digitalcommons.wku.edu/ijesab/vol14/iss2/139/	Increasing evidence suggests that gut dysbiosis is associated with coronavirus disease 2019 (COVID-19) infection and may persist long after disease resolution. The excessive use of antimicrobials in patients with COVID-19 can lead to additional destruction of the microbiota, as well as to the growth and spread of antimicrobial resistance. The problem of bacterial resistance to antibiotics encourages the search for alternative methods of limiting bacterial growth and restoring the normal balance of the microbiota in the human body. Bacteriophages are promising candidates as potential regulators of the microbiota. In the present study, two complex phage cocktails targeting multiple bacterial species were used in the rehabilitation of thirty patients after COVID-19, and the effectiveness of the bacteriophages against the clinical strain of Klebsiella pneumoniae was evaluated for the first time using real-time visualization on a 3D Cell Explorer microscope. Application of phage cocktails for two weeks showed safety and the absence of adverse effects. An almost threefold statistically significant decrease in the anaerobic imbalance ratio, together with an erythrocyte sedimentation rate (ESR), was detected. This work will serve as a starting point for a broader and more detailed study of the use of phages and their effects on the microbiome.
256	Ce254		Joan Stephenson, PhD1	Report on Long COVID Urges Actions to Address Needs of Patients, Caregivers	http://jamanetwork.com/article.aspx?doi=10.1001/jamahealthforum.2022.5254	Published	December 6, 2022	Editorial	https://jamanetwork.com/journals/jama-health-forum/fullarticle/2799427	To address this issue, the report urges sending clinicians the latest information on findings, testing, and treatments in the form of “Long COVID digests,” as well as enlisting academic partners to launch an “expansive outreach campaign” to train clinicians about long COVID and suggested care pathways through in-person and virtual presentations. In the longer term, it advised medical schools to increase training on long COVID and other infection-associated chronic conditions. Other recommendations, based on experiences reported by patients, are aimed at nonclinicians. For example, the report said that educators and employers should develop and support accommodations that allow people with long COVID to continue to study and work. The report also stresses that people with long COVID and those who care for them “feel marginalized, misunderstood, and isolated by a general public that is impatient for a return to business as usual.” It urged public messaging campaigns in multiple languages and formats to increase the public’s literacy and awareness regarding long COVID and said that government agency leaders should be encouraged “to amplify and share that Long COVID is real and a serious public health issue.”
257	Ce255		Mashfee H. Khan, Kennedy P. Kirkpatrick, Yi Deng, Krishna B. Shah	Stellate Ganglion Block for Long COVID Symptom Management: A Case Report	https://doi.org/10.7759/cureus.32295	Published	December 07, 2022	Case Report	https://www.cureus.com/articles/127985-stellate-ganglion-block-for-long-covid-symptom-management-a-case-report	Stellate ganglion block (SGB) is gaining increasing acceptance as a treatment modality for various medical conditions. It works by blocking neuronal transmissions which in turn alleviates sympathetically-driven disease processes. Many of the prolonged sequelae of long COVID are thought to be mediated by dysregulation of the autonomic nervous system, and SGB is being investigated as a potential option for symptomatic management of long COVID. This case report demonstrates the efficacy of SGB in a previously healthy patient for the management of long COVID symptoms including fatigue, post-exertional malaise, shortness of breath, and gastrointestinal symptoms.
258	Ce256		Antonio Cimellaro 1,*ORCID,Desirée Addesi 1,Michela Cavallo 1,Francesco Spagnolo 1,Edoardo Suraci 1,Raffaella Cordaro 1,Ines Spinelli 1,Francesco Passafaro 2,Manuela Colosimo 3,Medea Pintaudi 4,Carmelo Pintaudi 1 andon behalf of the CATAnzaro LOng COVID (CATALOCO) Study Group †	Monoclonal Antibodies and Antivirals against SARS-CoV-2 Reduce the Risk of Long COVID: A Retrospective Propensity Score-Matched Case–Control Study	https://doi.org/10.3390/biomedicines10123135	Published	5 December 2022	Study	https://www.mdpi.com/2227-9059/10/12/3135	Long COVID is a complex condition affecting quality of life, with limited therapeutic options. We investigated the occurrence of long COVID in subjects receiving early therapy with monoclonal antibodies (mAbs) or antivirals to reduce the risk of COVID-19 progression. In this retrospective study we enrolled 737 adult patients (aged 65.16 ± 13.46; 361F), who experienced COVID-19 between January 2021 and March 2022. Antiviral or mAbs were administered to symptomatic patients who did not require oxygen therapy or hospital admission for SARS-CoV-2 infection, and who were at high risk of progression to severe disease, as identified by age > 65 years or the presence of comorbidities. Long COVID, defined as newly or persistent long-term symptoms 4 weeks after the onset of the acute illness, was reported in 204 cases (28%). Age (OR 1.03; p < 0.001), gender (OR 1.88; p < 0.001) and at least three comorbidities (OR 3.49; p = 0.049) were directly associated with long COVID; conversely, vaccination (OR 0.59; p = 0.005) and mAbs/antivirals (OR 0.44; p = 0.002) were independently associated with a reduced risk of long COVID. At a propensity-score-matched analysis, the mAbs/antivirals group had a significantly lower occurrence of long COVID in comparison with untreated controls (11% vs. 34%; p = 0.001). In conclusion, mAbs and antivirals administered against the progression of COVID-19 were associated with a reduced risk of long COVID.
259	Ce257		Katie Chadd, Sophie Chalmers, Kate Harrall, Kathryn Moyse, Gemma Clunie	An evaluation of speech and language therapy services for people with long COVID in the UK: a call for integrated care		Published	30 November 2022	Study	https://www.emerald.com/insight/content/doi/10.1108/JICA-07-2022-0038/full/html	Purpose Long COVID is a complex and highly heterogeneous condition with a variable symptom profile, and calls have been made for an integrated care approach to be taken for its management. To date, no studies have explored speech and language therapy services or needs associated with long COVID. This service evaluation aimed to gauge the level of demand on speech and language therapy services for individuals with long COVID in the UK; their clinical needs, the organisational arrangements of services and the barriers and facilitators of delivering quality care. Design/methodology/approach A service evaluation was undertaken via distribution of an online survey to speech and language therapists (SLTs) receiving referrals for individuals with long COVID. Analysis was completed using descriptive statistics, with thematic analysis to evaluate qualitative data. Findings One hundred and eleven SLTs responded. Eighty-six percent were seeing individuals with long COVID in their “everyday” service, in uni- or multi-disciplinary teams, without any “dedicated” resource. Dysphagia and dysphonia were the most reported symptoms. Most respondents (66.7%) indicated the individuals they were seeing were of working age, and that an individuals' speech and language therapy needs were impacting their wellbeing. Perceived barriers to quality care included fragmented and non-integrated care pathways. Multi-disciplinary and integrated working was a key enabler. Originality/value This study provides novel insights into the current speech and language therapy needs of and care pathways for individuals with long COVID in the UK SLTs have unique expertise and are integral to supporting individuals with long COVID and should be a part of integrated care teams.
260	Ce258	VP	Yan Xie, Taeyoung Choi, View ORCID ProfileZiyad Al-Aly	Nirmatrelvir and the Risk of Post-Acute Sequelae of COVID-19	https://doi.org/10.1101/2022.11.03.22281783	pre-print	November 05, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.11.03.22281783v1.full-text	Long Covid – the disease encompassing the post-acute sequelae of SARS-CoV-2 (PASC) —affects millions of people around the world. Prevention of PASC is an urgent public health priority. In this work, we aimed to examine whether treatment with nirmatrelvir in the acute phase of COVID-19 is associated with reduced risk of post-acute sequelae. We used the healthcare databases of the US Department of Veterans Affairs to identify users of the health system who had a SARS-CoV-2 positive test between March 01, 2022 and June 30, 2022, were not hospitalized on the day of the positive test, had at least 1 risk factor for progression to severe COVID-19 illness and survived the first 30 days after SARS-CoV-2 diagnosis. We identify those who were treated with oral nirmatrelvir within 5 days after the positive test (n=9217) and those who received no COVID-19 antiviral or antibody treatment during the acute phase of SARS-CoV-2 infection (control group, n= 47,123). Inverse probability weighted survival models were used to estimate the effect of nirmatrelvir (versus control) on a prespecified panel of 12 post-acute COVID-19 outcomes and reported as hazard ratio (HR) and absolute risk reduction (ARR) in percentage at 90 days. Compared to the control group, treatment with nirmatrelvir was associated with reduced risk of PASC (HR 0.74 95% CI (0.69, 0.81), ARR 2.32 (1.73, 2.91)) including reduced risk of 10 of 12 post-acute sequelae in the cardiovascular system (dysrhythmia and ischemic heart disease), coagulation and hematologic disorders (deep vein thrombosis, and pulmonary embolism), fatigue, liver disease, acute kidney disease, muscle pain, neurocognitive impairment, and shortness of breath. Nirmatrelvir was also associated with reduced risk of post-acute death (HR 0.52 (0.35, 0.77), ARR 0.28 (0.14, 0.41)), and post-acute hospitalization (HR 0.70 (0.61, 0.80), ARR 1.09 (0.72, 1.46)). Nirmatrelvir was associated with reduced risk of PASC in people who were unvaccinated, vaccinated, and boosted, and in people with primary SARS-CoV-2 infection and reinfection. In sum, our results show that in people with SARS-CoV-2 infection who had at least 1 risk factor for progression to severe COVID-19 illness, treatment with nirmatrelvir within 5 days of a positive SARS-CoV-2 test was associated with reduced risk of PASC regardless of vaccination status and history of prior infection. The totality of findings suggests that treatment with nirmatrelvir during the acute phase of COVID-19 reduces the risk of post-acute adverse health outcomes.
261	Ce259		Marasco, Giovanni; Cremon, Cesare; Barbaro, Maria Raffaella; Cacciari, Giulia; Falangone, Francesca; Kagramanova, Anna; Bordin, Dmitry; Drug, Vasile; Miftode, Egidia; Fusaroli, Pietro; Mohamed, Salem Youssef; Ricci, Chiara; Bellini, Massimo; Rahman, Mohammed Masudur; Melcarne, Luigi; Santos, Javier; Lobo, Beatriz; Bor, Serhat; Yapali, Suna; Akyol, Deniz; Sapmaz, Ferdane Pirincci; Urun, Yonca Yilmaz; Eskazan, Tugce; Celebi, Altay; Kacmaz, Huseyin; Ebik, Berat; Binicier, Hatice Cilem; Bugdayci, Mehmet Sait; Yağcı, Munkhtsetseg Banzragch; Pullukcu, Husnu; Kaya, Berrin Yalınbas; Tureyen, Ali; Hatemi, İbrahim; Koc, Elif Sitre; Sirin, Goktug; Calıskan, Ali Riza; Bengi, Goksel; Alıs, Esra Ergun; Lukic, Snezana; Trajkovska, Meri; Hod, Keren; Dumitrascu, Dan; Pietrangelo, Antonello; Corradini, Elena; Simren, Magnus; Sjölund, Jessica; Tornkvist, Navkiran; Ghoshal, Uday C.; Kolokolnikova, Olga; Colecchia, Antonio; Serra, Jordi; Maconi, Giovanni; Giorgio, Roberto De; Danese, Silvio; Portincasa, Piero; Sabatino, Antonio Di; Maggio, Marcello; Philippou, Elena; Lee, Yeong Yeh; Salvi, Daniele; Venturi, Alessandro; Borghi, Claudio; Zoli, Marco; Gionchetti, Paolo; Viale, Pierluigi; Stanghellini, Vincenzo; Barbara, Giovanni	Post COVID-19 irritable bowel syndrome	https://doi.org/10.1002/mco2.196	Published	44903	Study	https://onlinelibrary.wiley.com/doi/abs/10.1002/mco2.196	COVID-19 caused by SARS-CoV-2 infection affects humans not only during the acute phase of the infection, but also several weeks to 2 years after the recovery. SARS-CoV-2 infects a variety of cells in the human body, including lung cells, intestinal cells, vascular endothelial cells, olfactory epithelial cells, etc. The damages caused by the infections of these cells and enduring immune response are the basis of long COVID. Notably, the changes in gene expression caused by viral infection can also indirectly contribute to long COVID. We summarized the occurrences of both common and uncommon long COVID, including damages to lung and respiratory system, olfactory and taste deficiency, damages to myocardial, renal, muscle, and enduring inflammation. Moreover, we provided potential treatments for long COVID symptoms manifested in different organs and systems, which were based on the pathogenesis and the associations between symptoms in different organs. Importantly, we compared the differences in symptoms and frequency of long COVID caused by breakthrough infection after vaccination and infection with different variants of concern, in order to provide a comprehensive understanding of the characteristics of long COVID and propose improvement for tackling COVID-19.
262	Ce260		Jimeno-Almazán, Amaya; Buendía-Romero, Ángel; Martínez-Cava, Alejandro; Franco-López, Francisco; Sánchez-Alcaraz, Bernardino; Courel-Ibáñez, Javier; Pallarés, Jesús G.	Effects of a concurrent training, respiratory muscle exercise and self-management recommendations on recovery from post-COVID-19 conditions: the RECOVE trial	https://doi.org/10.3390/life12122057	Published	2022-12	Study	https://www.mdpi.com/2075-1729/12/12/2057	Vaccines against SARS-CoV-2 have saved millions of lives and played an important role in containing the COVID-19 pandemic. Vaccination against SARS-CoV-2 is also associated with reduced disease severity and, perhaps, with COVID-19 symptom burden. In this narrative review, we present, in a clinically relevant question-and-answer manner, the evidence regarding the association between vaccination against SARS-CoV-2 and long COVID-19. We discuss how the mechanism of action of vaccines could interplay with the pathophysiology of post-COVID-19 condition. Furthermore, we describe how specific factors, such as the number of vaccine doses and the type of SARS-CoV-2 variants, may affect post-COVID-19 condition. We also discuss the role of timing for vaccination in relation to the onset of long COVID-19 symptoms, as it seems to affect the frequency and severity of the condition. Additionally, we describe the potential modifying effect of age, as well as the association of type and level of immune response with long COVID-19. We also describe how system-specific long COVID-19 sequelae, namely neurocognitive-psychologic symptoms and cardiovascular pathology, could be altered by vaccination. Last, we address the question of whether seasonal influenza vaccination has a meaningful impact on the frequency of long COVID-19.
263	Ce261		Kohn, L; Dauvrin, M; Detollenaere, J; Primus-de Jong, C; Maertens de Noordhout, C; Castanares-Zapatero, D; Cleemput, I; Van den Heede, K	Long COVID and return to work: a qualitative study	https://doi.org/10.1152/japplphysiol.00489.2022	Published	2022-12-08	Study	https://journals.physiology.org/doi/abs/10.1152/japplphysiol.00489.2022	The aim of this study was to determine the effectiveness of physical exercise, respiratory muscle training and the self-management WHO recommendations leaflet on the recovery of physical fitness, quality of life and symptom status in people with post COVID-19 conditions. Eighty non-hospitalized adults with a post-COVID-19 condition were randomly assigned to one of four 8-week parallel intervention groups: multicomponent exercise program based on concurrent training- CT (n= 20; 3 resistance and endurance supervised sessions per week at low-moderate intensity); b) inspiratory muscle training- RM (n= 17; 2 standardized daily sessions); c) a combination of both of the above- CTRM (n= 23); d) control group- CON (n= 20; following the WHO guidelines for post-COVID-19 related illness rehabilitation). No significant differences between groups were detected at baseline. While no significant differences between interventions were detected in the VO2max, significant individual improvements were identified in the CT (7.5%; ES=0.38) and CTRM (7.8%; ES=0.28) groups. Lower body muscle strength significantly improved in the CT and CTRM (14.5-32.6%; ES=0.27-1.13) groups compared to RM and CON (-0.3-11.3%; ES=0.19-0.00). The CT and CTRM groups improved significantly for dyspnea and fatigue, as did the health status. In addition, significant differences between interventions were described in fatigue and depression scales favouring CT and CTRM interventions. An individualized and supervised concurrent training with or without respiratory muscle training was safer and more effective than self-care recommendations and inspiratory muscle training alone, to regain cardiovascular and muscular fitness, improve symptom severity and health status in outpatients with post-COVID-19 conditions.
264	Ce262		Nevalainen, Olli P O; Horstia, Saana; Laakkonen, Sanna; Rutanen, Jarno; Mustonen, Jussi; Kalliala, Ilkka; Ansakorpi, Hanna; Kreivi, Hanna-Riikka; Kuutti, Pauliina; Paajanen, Juuso; Parkkila, Seppo; Paukkeri, Erja-Leena; Perola, Markus; Pourjamal, Negar; Renner, Andreas; Rosberg, Tuomas; Rutanen, Taija; Savolainen, Joni; Haukka, Jari K; Guyatt, Gordon H; Tikkinen, Kari A	1126. Effect of Remdesivir on Recovery, Quality of Life, and Long-COVID Symptoms One Year after Hospitalization for COVID-19 Infection: A Randomized Controlled SOLIDARITY Finland Trial	https://doi.org/10.1093/ofid/ofac492.965	Published	2022-12-01	Trial	https://doi.org/10.1093/ofid/ofac492.965	Coronavirus disease 2019 (COVID-19) patients frequently suffer from long-term sequelae, often called “long COVID” or “post COVID-19 condition”. Remdesivir, given in early disease, decreases the risk of hospitalization and potentially mortality. No randomized trials have thus far published long-term follow-up data on any COVID-19 drug treatment. We investigated the effects of remdesivir on a range of patient-important outcomes at one year.Between July 2020 and January 2021, an open-label randomized multicenter trial in Finland recruited 208 adult patients from 11 Finnish hospitals. Patients were randomly assigned (1:1 ratio) to standard of care (SoC)with remdesivir (median duration of remdesivir treatment 5 days) or SoC alone. Primary outcomes were self-reported recovery, exertional dyspnea, fatigue, and quality of life at one year. Secondary outcomes were overall mortality and several potential long-COVID symptoms.At one year, 5 (4.4%) of 114 patients in the remdesivir and 5 (5.3%) of 94 in the SoC group had died (RR 0.82, 95% CI 0.25-2.76; absolute difference: -0.9%, 95% CI -7.9-5.3); 181 (92% of survivors) completed the follow-up. Self-reported recovery (fully or largely) occurred in 85% in remdesivir and in 86% in SoC (RR 0.94, 0.47-1.90; absolute difference: -0.9%, 95% CI -11%-10%). Exertional dyspnea occurred in 5% in remdesivir and 8% in SoC (OR 0.61, 95% CI 0.20-1.85; absolute difference -3.3%, 95% CI -12%-4.4%). We found no convincing difference between remdesivir and SoC groups in quality of life or symptom outcomes (p > 0.05 for all). Of the 21 potential long-COVID symptoms, patients often reported moderate or major bother from fatigue (26%), joint pain (22%), persistent respiratory mucus (21%), and problems with memory (19%) and attention/concentration (18%) (Figure).Bother from potential long-COVID symptoms at one year from COVID-19 hospitalization between the standard of care and standard of care plus remdesivir groups. After a one-year follow-up of hospitalized patients (with a very high participation rate), approximately one in four reported substantial bother from fatigue, and one in six reported that they had not recovered well from COVID-19. We found no convincing evidence of a remdesivir effect, but confidence intervals were wide and included possible substantial benefit and substantial harm.Hanna-Riikka Kreivi, MD, PhD, Pfizer: Advisor/Consultant\|Roche: Advisor/Consultant Tuomas Rosberg, MD, PhD, AstraZeneca: Honoraria\|Boehringer-Ingelheim: Honoraria\|GSK: Honoraria.
265	Ce263		Monk, Phillip D; Evans, Rachael A; Tear, Victoria J; Brookes, Jody L; Batten, Toby; Mankowski, Marcin; Djukanovic, Ratko; Holgate, Stephen T; Brightling, Chris; Wilkinson, Tom	LB1533. Impact of Treatment of Hospitalised COVID-19 Patients With Inhaled Interferon Beta-1a (SNG001) on Long COVID Symptoms: Results From the SPRINTER trial	https://doi.org/10.1093/ofid/ofac492.1879	Published	2022-12-01	Trial	https://doi.org/10.1093/ofid/ofac492.1879	People with post-COVID conditions can have a wide range of symptoms lasting months and it can affect as many as one in five infected people. Interferon beta (IFN-β) is key in host defence against viruses but can be suppressed by virus or host factors locally at the site of infection. Inhalation of SNG001 (IFN-β-1a nebuliser solution) aims to restore lung IFN-β levels. SPRINTER (NCT04732949) was a RCT of inhaled interferon beta in hospitalised COVID-19. There was no effect of SNG001 on the primary endpoints of time to discharge or recovery most likely due to improvements in the standard of care. However, there was an encouraging signal for the key secondary endpoint of prevention of progression to severe disease or death (ITT 26% relative risk reduction [RRR]; Odds Ratio [95% CI]: 0.71 [0.44, 1.15]; Per Protocol 36% RRR; OR 0.63 [0.35, 1.13]). Post hoc analyses showed enhanced effects favouring SNG001 in subgroups at higher risk of progression. We report on the impact of SNG001 on long COVID symptoms in SPRINTER.Patients requiring low-flow oxygen were randomized to receive SNG001 (314) or placebo (309) once daily for 14 days, plus standard-of-care. Long COVID symptoms were assessed as a secondary endpoint at follow-up visits via telephone/video call on Day 60 and Day 90. The following patient reported outcome (PRO) measures were also assessed: General Anxiety Disorder 7 Questionnaire (GAD-7), Patient Health Questionnaire-9 (PHQ-9), Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Scale and Brief Pain Inventory (Short Form).When compared to placebo, SNG001 reduced the relative risk of common symptoms of long COVID (fatigue/malaise [RRR=35.4%]; dyspnoea [RRR=28.3%]; loss of smell and/or taste [RRR=61.4%]). Analysis of the PROs is ongoing.Assessment of COVID symptoms at Day 60 and 90 follow up visits Effect of SNG001 treatment on long COVID symptoms Long COVID can leave patients with lingering cognitive, respiratory, and functional symptoms months after a SARS-CoV-2 infection. Given the shift from pandemic to endemic status for COVID-19 and the need for new treatments then these findings, suggesting SNG001 may be impacting common long COVID symptoms, provide additional support for the further investigation of SNG001.Phillip D. Monk, PhD, Synairgen Plc (Employed by Synairgen Research Ltd which is a subsidiary of Synairgen Plc, Stocks/Bonds): Board Member\|Synairgen Plc (Employed by Synairgen Research Ltd which is a subsidiary of Synairgen Plc, Stocks/Bonds): Stocks/Bonds Victoria J. Tear, PhD, Synairgen Plc (Employed by Synairgen Research Ltd which is a subsidiary of Synairgen Plc, Stocks/Bonds): Stocks/Bonds Jody L. Brookes, BSc, Synairgen Plc (Employed by Synairgen Research Ltd which is a subsidiary of Synairgen Plc, Stocks/Bonds): Stocks/Bonds Marcin Mankowski, MD, MFPM (Dis), CytoDyn: Advisor/Consultant\|Entasis: Advisor/Consultant\|ImmuPharma: Advisor/Consultant\|Menarini: Advisor/Consultant\|Pfizer: Advisor/Consultant\|Synairgen: Advisor/Consultant\|Venatorx: Advisor/Consultant Ratko Djukanovic, MD, Synairgen: Advisor/Consultant\|Synairgen: Honoraria\|Synairgen: Stocks/Bonds Stephen T. Holgate, FMedSci, MD, Synairgen: Board Member\|Synairgen: Non executive board director, patent on inhaled interferon beta\|Synairgen: Stocks/Bonds chris brightling, FMedSci, Synairgen: Advisor/Consultant\|Synairgen: Grant/Research Support Tom Wilkinson, PhD, PhD, AZ: Grant/Research Support\|AZ: Honoraria\|My mhealth: Board Member\|My mhealth: Ownership Interest\|My mhealth: Stocks/Bonds\|Synairgen: Grant/Research Support\|Synairgen: Honoraria.
266	Ce264		Writing Committee for the REMAP-CAP Investigators	Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial	https://doi.org/10.1001/jama.2022.23257	Published	2022-12-16	Trial	https://doi.org/10.1001/jama.2022.23257	Key Points Question What is the effect of treatment for critically ill patients with COVID-19 on longer-term mortality, disability, and health-related quality of life? Findings In this bayesian adaptive randomized clinical platform trial that included 4869 critically ill patients with COVID-19, the probability was high that IL-6 receptor antagonists and antiplatelet agents improved survival at 6 months (posterior probabilities of superiority of >99.9% and 95.0%, respectively). Long-term outcomes were not improved with therapeutic anticoagulation (11.5%), convalescent plasma (54.7%), or lopinavir-ritonavir (31.9%) and were worsened with hydroxychloroquine (posterior probability of harm, 96.8%). Corticosteroids did not improve long-term outcomes, although enrollment had been terminated early in response to external evidence. Meaning Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, there was a high likelihood of improved 180-day mortality among patients treated with IL-6 receptor antagonists and antiplatelet agents. Abstract Importance The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. Objective To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. Design, Setting, and Participants Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. Interventions Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). Main Outcomes and Measures The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. Results Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies. Conclusions and Relevance Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.
267	Ce265		Lechien, Jerome R.; Le Bon, Serge D.; Saussez, Sven	Platelet-rich plasma injection in the olfactory clefts of COVID-19 patients with long-term olfactory dysfunction	https://doi.org/10.1007/s00405-022-07788-8	Published	2022-12-15	Trial	https://doi.org/10.1007/s00405-022-07788-8	Abstract Objective To investigate safety, feasibility, and effectiveness of platelet-rich plasma (PRP) injection into the olfactory clefts of COVID-19 patients with persistent olfactory dysfunction (OD). Methods From March 2022 to July 2022, COVID-19 patients with persistent OD were consecutively recruited to benefit from PRP injection into the olfactory clefts. Patient pain, annoyance, time of procedure, and adverse events were evaluated. Olfactory function was evaluated at baseline and 2-month post-injection with the olfactory disorder questionnaire (ODQ) and threshold, discrimination, and identification (TDI) test. Results Eighty-seven patients with anosmia (N = 30), hyposmia (N = 40), or parosmia (N = 17) with a mean OD duration of 15.7 months completed the evaluations. The PRP injection was successfully performed in all patients with a mean procedure time of 18.4 ± 3.4 min. The adverse events included transient epistaxis (N = 31), parosmia related to xylocaine spray (N = 10), and vasovagal episode (N = 2). The injection procedure was evaluated as somewhat or moderately painful by 41 (47%) and 22 (25%) patients, respectively. Thirty-seven patients were assessed after 2 months post-injection. The mean ODQ and TDI scores significantly improved from baseline to 2-month post-injection (p < 0.01). The olfactory improvement occurred after a mean of 3.6 ± 1.9 weeks. Conclusion The injection of PRP into the olfactory clefts is safe and associated with adequate patient-reported outcomes. The findings of this preliminary study suggest possible efficacy on subjective and psychophysical evaluations, but future randomized controlled studies are needed to determine the superiority of PRP injection over placebo.
268	Ce266		Fernández-Lázaro, Diego; Santamaría, Gema; Sánchez-Serrano, Nerea; Lantarón Caeiro, Eva; Seco-Calvo, Jesús	Efficacy of Therapeutic Exercise in Reversing Decreased Strength, Impaired Respiratory Function, Decreased Physical Fitness, and Decreased Quality of Life Caused by the Post-COVID-19 Syndrome	https://doi.org/10.3390/v14122797	Published	2022-12	Review	https://www.mdpi.com/1999-4915/14/12/2797	In the current global scenario, many COVID-19 survivors present a severe deterioration in physical strength, respiratory function, and quality of life due to persistent symptoms and post-acute consequences of SARS-CoV-2 infection. These alterations are known as post-COVID-19 syndrome for which there is no specific and effective treatment for their management. Currently, therapeutic exercise strategies (ThEx) are effective in many diseases by reducing the appearance of complications and side effects linked to treatment, and are consequently of great relevance. In this study, we review the effect of ThEX in reversing decreased strength, impaired respiratory function, decreased physical fitness, and decreased quality of life (QoL) caused by post-COVID-19 syndrome. A literature search was conducted through the electronic databases, Medline (PubMed), SciELO and Cochrane Library Plus for this structured narrative review for studies published from database retrieval up till 12 December 2022. A total of 433 patients with post-COVID-19 syndrome condition (60% women) were included in the nine studies which met the inclusion/exclusion criteria. Overall, post-COVID-19 syndrome patients who followed a ThEx intervention showed improvements in strength, respiratory function, physical fitness and QoL, with no exercise-derived side effects. Thus, ThEx based on strength, aerobic and respiratory training could be an adjuvant non-pharmacological tool in the modulation of post-COVID-19 syndrome.
269	Ce267		Russell, Peije; Esser, Lars; Hagemeyer, Christoph E.; Voelcker, Nicolas H.	The potential impact of nanomedicine on COVID-19-induced thrombosis	https://doi.org/10.1038/s41565-022-01270-6	Published	2022-12-19	Review	https://www.nature.com/articles/s41565-022-01270-6	Extensive reports of pulmonary embolisms, ischaemic stroke and myocardial infarctions caused by coronavirus disease 2019 (COVID-19), as well as a significantly increased long-term risk of cardiovascular diseases in COVID-19 survivors, have highlighted severe deficiencies in our understanding of thromboinflammation and the need for new therapeutic options. Due to the complexity of the immunothrombosis pathophysiology, the efficacy of treatment with conventional anti-thrombotic medication is questioned. Thrombolytics do appear efficacious, but are hindered by severe bleeding risks, limiting their use. Nanomedicine can have profound impact in this context, protecting delicate (bio)pharmaceuticals from degradation en route and enabling delivery in a targeted and on demand manner. We provide an overview of the most promising nanocarrier systems and design strategies that may be adapted to develop nanomedicine for COVID-19-induced thromboinflammation, including dual-therapeutic approaches with antiviral and immunosuppressants. Resultant targeted and side-effect-free treatment may aid greatly in the fight against the ongoing COVID-19 pandemic.
270	Ce268		Uehara, Laura; Corrêa, João Carlos Ferrari; Ritti, Raphael; Leite, Paulo; de Faria, Deivide Rafael Gomes; Pacheco-Barrios, Kevin; Castelo-Branco, Luis; Fregni, Felipe; Corrêa, Fernanda Ishida	Transcutaneous auricular vagus nerve stimulation effects on inflammatory markers and clinical evolution of patients with COVID-19: a pilot randomized clinical trial	https://doi.org/10.1080/17434440.2022.2154147	Published	2022-11-02	Trial	https://doi.org/10.1080/17434440.2022.2154147	Objective To evaluate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on inflammatory markers and clinical outcomes in patients with COVID-19.Methods A randomized blinded pilot study was carried out with 21 individuals hospitalized with COVID-19 who received 14 sessions of active (a-taVNS) or sham taVNS (s-taVNS). The level of interleukin-6 (IL-6), interleukin-10 (IL-10), cortisol, and C-reactive protein (CRP) in plasma and clinical evolution pre- and post-intervention were evaluated. The memory and attention levels were evaluated 14 days after the end of the treatment.Results After treatment, significant intragroup differences were found in the CRP (p = 0.01), IL-6 (p = 0.01), and cortisol (p = 0.01) levels; however, in the comparison between the groups, only the CRP level was statistically lower for the a-taVNS (p = 0.04). The impression of improvement in memory and attention was greater in the a-taVNS than in the s-taVNS (p = 0.01, p = 0.04, respectively). There was no difference between the other clinical outcomes.Conclusions taVNS is a viable and safe intervention in the acute care of patients with COVID-19, which can modulate their inflammatory profile and improve cognitive symptoms. However, improvements in overall clinical outcomes were not detected. Larger sample sizes and longer follow-ups are needed to confirm the anti-inflammatory and clinical effects of taVNS in patients with COVID-19.Trials Registry The Brazilian Registry of Clinical Trials (RBR–399t4g5).
271	Ce269		Ora, Josuel; Calzetta, Luigino; Frugoni, Chiara; Puxeddu, Ermanno; Rogliani, Paola	Expert guidance on the management and challenges of long-COVID syndrome: a systematic review	https://doi.org/10.1080/14656566.2022.2161365	Published	2022-12-21	Systematic Review	https://doi.org/10.1080/14656566.2022.2161365	Introduction Long-COVID is the condition characterised by the permanence of symptoms beyond 4 weeks after initial infection. It affects 1 out of 5 people and is loosely related to the severity of acute infection and pathological mechanisms which are yet to be understood.Areas covered This article looks at currently available or under-study therapies for long-COVID syndrome. It particularly gives focus to ongoing trials and review the underlying mechanisms. A comprehensive literature search was performed on PubMed and clincaltrial.gov of clinical trials concerning the management of long-COVID syndrome.Expert opinion “Long-COVID” syndrome is a new emergency characterized by several symptoms such as fatigue, dyspnoea, cognitive and attention disorders, sleep disorders, post-traumatic stress disorder, muscle pain, and concentration problems. Despite the many guidelines available to date, there are no established treatments of long-COVID. Pharmacological research is studying known drugs that act on the reduction or modulation of systemic inflammation, or innovative drugs used in similar pathologies. Rehabilitation now seems to be the safest treatment to offer, whereas we will have to wait for the pharmacological research trials in progress as well as plan new trials based on a better understanding of the pathogenic mechanisms.
272	Ce270		Negro, Roberto W. Dal; Turco, Paola; Povero, Massimiliano	Nebivolol: an effective option against long-lasting dyspnoea following COVID-19 pneumonia - a pivotal double-blind, cross-over controlled study	https://doi.org/10.4081/mrm.2022.886	Published	2022-12-23	Study	https://www.mrmjournal.org/mrm/article/view/886	Background: Pulmonary microvascular occlusions can aggravate SARS-CoV-2 pneumonia and result in a variable decrease in capillary blood volume (Vc). Dyspnoea may persist for several weeks after hospital discharge in many patients who have "radiologically recovered" from COVID-19 pneumonia. Dyspnoea is frequently "unexplained" in these cases because abnormalities in lung vasculature are understudied. Furthermore, even when they are identified, therapeutic options are still lacking in clinical practice, with nitric oxide (NO) supplementation being used only for severe respiratory failure in the hospital setting. Nebivolol is the only selective β1 adrenoceptor antagonist capable of inducing nitric oxide-mediated vasodilation by stimulating endothelial NO synthase via β3 agonism. The purpose of this study was to compare the effect of nebivolol versus placebo in patients who had low Vc and complained of dyspnoea for several weeks after COVID-19 pneumonia. Methods: Patients of both genders, aged ≥18 years, non-smokers, who had a CT scan that revealed no COVID-related parenchymal lesions but still complained of dyspnoea 12-16 weeks after hospital discharge, were recruited. Spirometrical volumes, blood haemoglobin, SpO2, simultaneous diffusing capacity for carbon monoxide (CO) and NO (DLCO and DLNO, respectively), DLNO/DLCO ratio, Vc and exhaled NO (eNO) were measured together with their dyspnoea score (DS), heart frequency (HF), and blood arterial pressure (BAP). Data were collected before and one week after both phosphorus (P) and nitrogen (N) (2.5 mg od) double-blind cross-over administered at a two-week interval. Data were statistically compared, and p<0.05 assumed as statistically significant.Results: Eight patients (3 males) were investigated. In baseline, their mean DS was 2.5±0.6 sd, despite the normality of lung volumes. DLCO and DLNO mean values were lower than predicted, while mean DLNO/DLCO ratio was higher. Mean Vc proved substantially reduced. Placebo did not modify any variable (all p=ns) while N improved DLCO and Vc significantly (+8.5%, p<0.04 and +17.7%, p<0.003, respectively). Also eNO was significantly increased (+17.6%, p<0.002). Only N lowered the dyspnoea score (-76%, p<0.001). Systolic and diastolic BAP were slightly lowered (-7.5%, p< 0.02 and -5.1% p< 0.04, respectively), together with HF (-16.8%, p<0.03).Conclusions: The simultaneous assessment of DLNO, DLCO, DLNO/DLCO ratio, and Vc confirmed that long-lasting dyspnoea is related to hidden abnormalities in the lung capillary vasculature. These abnormalities can persist even after the complete resolution of parenchymal lesions regardless of the normality of lung volumes. Nebivolol, but not placebo, improves DS and Vc significantly. The mechanism suggested is the NO-mediated vasodilation via the β3 adrenoceptor stimulation of endothelial NO synthase. This hypothesis is supported by the substantial increase of eNO only assessed after nebivolol. As the nebivolol tolerability in these post-COVID normotensive patients was very good, the therapeutic use of nebivolol against residual and symptomatic signs of long-COVID can be suggested in out-patients.
273	Ce271		Tartibian, Bakhtyar; Khayat, Sirwan Mohammad Amini; Maleki, Behzad Hajizadeh; Chehrazi, Mohammad	The Effects of Exercise Training on Recovery of Biochemical and Hematological Outcomes in Patients Surviving COVID-19: A Randomized Controlled Assessor-Blinded Trial	https://doi.org/10.1186/s40798-022-00546-4	Published	2022-12-23	Trial	https://doi.org/10.1186/s40798-022-00546-4	Abstract Background No previous research has investigated the direct effects of exercise interventions on COVID-19 outcomes. The aim is to investigate the effect of 8 weeks of home-based moderate-intensity continuous training (MICT), resistance training (RT), and combined aerobic and resistance training (CET) on biochemical and hematologic markers associated with COVID-19 symptoms and severity in COVID-19 survivors. Methods A total of 547 male and female COVID-19 survivors were screened, and 296 (aged 20–93 years) were randomly assigned in a 1:1:1:1 ratio to one of four groups: MICT (n = 74), RT (n = 74), CET (n = 74), or non-exercise (NON-EX, n = 74). Blood samples were taken at baseline, at week 4, and week 8 after training. Results After the intervention, compared with the NON-EX group, all 3 MICT, RT, and CET interventions caused significant improvements in the levels of creatine kinase (CK), lactate dehydrogenase (LDH), C-reactive protein (CRP), troponin-I, d-dimer, creatinine, urea, potassium (K), sodium (Na), white blood cell (WBC), neutrophils, lymphocytes, red blood cells (RBC), platelets, hemoglobin, and hematocrit concentrations (P < 0.05). CET was effectively superior to MICT and RT in the improvements in the biochemical and hematological variables studied (P < 0.05). Conclusions Overall, the present study demonstrates that long-term MICT plus RT interventions have a synergistic effect in accelerating and enhancing the recovery in patients surviving COVID-19. Trial registration IRCT20160605028270N3, 6 September 2020. Key Points No prior studies have investigated the direct impact of exercise interventions on COVID-19 outcomes. Regular exercise training accelerates and improves recovery in COVID-19 survivors. Eight weeks of aerobic training, resistance training, or combined aerobic and resistance training improved considerably the biochemical and hematologic indicators associated with COVID-19 symptoms and severity. Combined aerobic and resistance training was substantially more effective in improving these biomarkers and indicators than aerobic training alone and resistance training alone.
274	Ce272		Noda, Yoshihiro; Sato, Akiko; Shichi, Misaki; Sato, Ayano; Fujii, Kyoshiro; Iwasa, Mio; Nagano, Yasuhiro; Kitahata, Ryosuke; Osawa, Ryota	Real world research on transcranial magnetic stimulation treatment strategies for neuropsychiatric symptoms with Long-COVID in Japan	https://doi.org/10.1016/j.ajp.2022.103438	Published	2022-12-28	Study	https://www.sciencedirect.com/science/article/pii/S1876201822004361	Highlights • We developed the novel TMS therapeutic approach for patients with long-COVID. • The novel TMS treatment could improve depressive symptoms of long-COVID. • The novel TMS treatment could alleviate subjective chronic fatigue of long-COVID. • The novel TMS treatment could restore subjective cognitive decline of long-COVID. Abstract The number of patients suffering from long-COVID is currently increasing rapidly, even after the acute symptoms of COVID-19 have improved. The objective of this study was to investigate the effects of a pilot transcranial magnetic stimulation (TMS) treatment on neuropsychiatric symptoms caused by long-COVID. In this study, we examined the efficacy of the TMS treatment protocol, which has been established to be effective in depression, by applying it to patients who sought TMS treatment for neuropsychiatric symptoms caused by long-COVID at TMS clinics in Tokyo, Japan in the context of real world TMS registry study in Japan. Of the 23 patients (13 females) with long-COVID included in this case series, the main neuropsychiatric symptoms were chronic fatigue (n=12) and cognitive dysfunction (n=11), but most patients also showed mild depressive symptoms. The mean Montgomery-Åsberg Depression Rating Scale score before TMS treatment was 21.2 but improved to 9.8 after treatment. Similarly, the Performance Status score, which assesses the degree of fatigue, improved from 5.4 to 4.2, and the Perceived Deficits Questionnaire–Depression 5-item score, which reflects cognitive function, improved from 10.0 to 6.3. There were no serious adverse events, although a few patients complained of pain at the stimulation site during the TMS as a side effect. Despite the limitations of this open-label pilot study, the TMS protocol implemented in this study may have beneficial effects on neuropsychiatric symptoms caused by long-COVID, including depressive symptoms, chronic fatigue, and cognitive impairment. These preliminary findings warrant further validation in randomized controlled trials.
275	Ce273		Suran, Melissa	VA Finds Nirmatrelvir Associated With Lower Risk of Long COVID	https://doi.org/10.1001/jama.2022.20051	Published	2022-12-27	Study	https://doi.org/10.1001/jama.2022.20051	The antiviral therapy nirmatrelvir, 1 of the medications used in Paxlovid, may mitigate the development of long COVID conditions, according to an observational study by the US Department of Veterans Affairs (VA). The study was posted to the preprint server medRxiv in early November and had not yet been peer-reviewed. In the study of medical records from veterans who tested positive for SARS-CoV-2, about 9200 patients took oral nirmatrelvir within 5 days of their diagnosis while about 47 000 did not receive antiviral or antibody treatment during the first 30 days of infection. All patients had at least 1 risk factor for developing severe COVID-19. None were hospitalized on the day they tested positive, and all survived for at least 30 days. About 3 months after diagnosis, patients who received nirmatrelvir were 26% less likely to develop long COVID conditions such as blood clots, fatigue, heart disease, kidney disease, liver disease, muscle pain, neurocognitive impairment, and shortness of breath. Such conditions occurred less often among these patients regardless of their vaccination status and prior history of SARS-CoV-2 infection. Nirmatrelvir use was also associated with a 30% and 48% reduction in postacute hospitalization and death, respectively. However, the drug wasn’t associated with a lower risk of new-onset diabetes or cough. “This treatment could be an important asset to address the serious issue of long COVID,” the study’s corresponding author, Ziyad Al-Aly, MD, director of the Clinical Epidemiology Center at the VA St Louis Health Care System, said in a statement.
276	Ce274		Haque, Azizul; Pant, Anudeep B.	Long Covid: Untangling the Complex Syndrome and the Search for Therapeutics	https://doi.org/10.3390/v15010042	Published	2023-01	Review	https://www.mdpi.com/1999-4915/15/1/42	Long Covid can affect anyone who has previously had acute COVID-19. The root causes of this syndrome are still unknown, and no effective therapeutics are available. This complex syndrome, with a wide array of symptoms, is still evolving. Given the dire situation, it is important to identify the causes of Long Covid and the changes occurring within the immune system of affected patients to figure out how to treat it. The immune system intersects with the persistent viral fragments and blood clots that are implicated in this syndrome; understanding how these complex systems interact may help in untangling the puzzling physiopathology of Long Covid and identifying mitigation measures to provide patients some relief. In this paper, we discuss evidence-based findings and formulate hypotheses on the mechanisms underlying Long Covid’s physiopathology and propose potential therapeutic options.
277	Ce275		Tanashyan, Marine M.; Мовсесовна, Танашян Маринэ; Raskurazhev, Anton A.; Алексеевич, Раскуражев Антон; Kuznetsova, Polina I.; Игоревна, Кузнецова Полина; Bely, Petr A.; Александрович, Белый Петр; Zaslavskaya, Kira Ia; Яковлевна, Заславская Кира	Prospects and possibilities for the treatment of patients with long COVID-19 syndrome	https://doi.org/10.26442/00403660.2022.11.201981	Published	2022-12-26	Study	https://doi.org/10.26442/00403660.2022.11.201981	Aim. To study the efficacy and safety of a drug product based on the succinic acid complex with trimethylhydrazine used to treat patients with asthenic syndrome after a new coronavirus infection (COVID-19).Materials and methods. A prospective, multicenter, comparative, randomized, double-blind, placebo-controlled study of the safety and efficacy of sequential therapy with Brainmax® enrolled 160 patients 12–16 weeks after coronavirus infection (no more than 12 months). The study was conducted at 6 healthcare centers in different regions of the Russian Federation. At the enrollment, clinical and neurological examination and the following tests were performed: complete blood count, urinalysis, blood chemistry, coagulation test, pulse oximetry, electrocardiography, glomerular filtration rate calculation (according to Cockcroft–Gault formula) were performed. Also, the patients were assessed using the following tools: VAS headache rating scale, MFI-20 asthenia scale, PSQI index, FAS-10 fatigue assessment scale, Dizziness Handicap Inventory (DHI), MoCA-test for cognitive impairment assessment, Beck Anxiety Inventory, Kérdö Autonomic Index.Results. The primary endpoint was the mean reduction in the MFI-20 asthenia scale score after the therapy (Visit 5, 41st day of therapy) compared to data from Visit 0 (beginning of therapy). A clinically significant advantage of the study drug versus the placebo was demonstrated, with a median absolute change in the MFI-20 score of -19.5 [-27; -11] points in the Brainmax® drug group and -3 [-7; 1] score in the placebo group (p<0.001). A significant sleep quality improvement according to the PSQI index was shown in the study group: by -2.5 [-4; -1] points versus no improvement in the placebo group (0 [-3; 0], p<0,001). Significant differences were also noted for the following secondary endpoints: PSQI sleep quality scale, FAS-10 fatigue assessment scale, DHI, and Beck Anxiety and Depression Inventory. There was also a decrease in patients' complaints of cognitive deterioration according to the CGI scale.Conclusion. Our study clearly demonstrated the efficacy and high safety profile of Brainmax® in a representative sample of patients with the post-COVID syndrome.
278	Ce276		Valverde-Martínez, María Ángeles; López-Liria, Remedios; Martínez-Cal, Jesús; Benzo-Iglesias, María Jesús; Torres-Álamo, Lucía; Rocamora-Pérez, Patricia	Telerehabilitation, A Viable Option in Patients with Persistent Post-COVID Syndrome: A Systematic Review	https://doi.org/10.3390/healthcare11020187	Published	1/1/2023	Review	https://www.mdpi.com/2227-9032/11/2/187	The number of patients with post-COVID-19 syndrome continues to increase considerably, having serious healthcare, social and economic repercussions. The objective of this study is to describe the effectiveness of telerehabilitation to alleviate the symptoms of post-COVID-19 syndrome. A systematic review was conducted using the information available on four databases (PubMed, Medline, Scielo and PEDRo) on these patients until November 2022. The MeSH search terms were: Post-COVID syndrome, Post-COVID-19, Long COVID, Telerehabilitation, Physiotherapy, Rehabilitation, Virtual, Home care. Six articles were included which provided information on 140 patients, detailing their symptomatology, assessment, treatment and monitoring. The variables measured were dyspnea, fatigue, physical performance and quality of life. All studies included aerobic and anaerobic exercises. Most notable among the techniques used were rib cage expansion exercises, respiratory control and thoracic cage stretching, patient education, Mindfulness and virtual reality games to address physical, mental and relaxation aspects. The use of telerehabilitation could be an effective tool for the treatment of persistent symptoms after suffering from COVID-19. It has been shown in these studies that patients improve both their physical performance and their quality of life.
279	Ce277		Ostrowska, Małgorzata; Rzepka-Cholasińska, Alicja; Pietrzykowski, Łukasz; Michalski, Piotr; Kosobucka-Ozdoba, Agata; Jasiewicz, Małgorzata; Kasprzak, Michał; Kryś, Jacek; Kubica, Aldona	Effects of Multidisciplinary Rehabilitation Program in Patients with Long COVID-19: Post-COVID-19 Rehabilitation (PCR SIRIO 8) Study	https://doi.org/10.3390/jcm12020420	Published	1/1/2023	Study	https://www.mdpi.com/2077-0383/12/2/420	Up to 80% of COVID-19 survivors experience prolonged symptoms known as long COVID-19. The aim of this study was to evaluate the effects of a multidisciplinary rehabilitation program in patients with long COVID-19. The rehabilitation program was composed of physical training (aerobic, resistance, and breathing exercises), education, and group psychotherapy. After 6 weeks of rehabilitation in 97 patients with long COVID-19, body composition analysis revealed a significant decrease of abdominal fatty tissue (from 2.75 kg to 2.5 kg; p = 0.0086) with concomitant increase in skeletal muscle mass (from 23.2 kg to 24.2 kg; p = 0.0104). Almost 80% of participants reported dyspnea improvement assessed with the modified Medical Research Council scale. Patients’ physical capacity assessed with the 6 Minute Walking Test increased from 320 to 382.5 m (p < 0.0001), the number of repetitions in the 30 s Chair Stand Test improved from 13 to 16 (p < 0.0001), as well as physical fitness in the Short Physical Performance Battery Test from 14 to 16 (p < 0.0001). The impact of fatigue on everyday functioning was reduced in the Modified Fatigue Impact Scale from 37 to 27 (p < 0.0001). Cardiopulmonary exercise test did not show any change. The multidisciplinary rehabilitation program has improved body composition, dyspnea, fatigue and physical capacity in long COVID-19 patients.
280	Ce278		Khondakar, Kamil Reza; Kaushik, Ajeet	Role of Wearable Sensing Technology to Manage Long COVID	https://doi.org/10.3390/bios13010062	Published	1/1/2023	Review	https://www.mdpi.com/2079-6374/13/1/62	Long COVID consequences have changed the perception towards disease management, and it is moving towards personal healthcare monitoring. In this regard, wearable devices have revolutionized the personal healthcare sector to track and monitor physiological parameters of the human body continuously. This would be largely beneficial for early detection (asymptomatic and pre-symptomatic cases of COVID-19), live patient conditions, and long COVID monitoring (COVID recovered patients and healthy individuals) for better COVID-19 management. There are multitude of wearable devices that can observe various human body parameters for remotely monitoring patients and self-monitoring mode for individuals. Smart watches, smart tattoos, rings, smart facemasks, nano-patches, etc., have emerged as the monitoring devices for key physiological parameters, such as body temperature, respiration rate, heart rate, oxygen level, etc. This review includes long COVID challenges for frequent monitoring of biometrics and its possible solution with wearable device technologies for diagnosis and post-therapy of diseases.
281	Ce279		Herman, Bumi; Bruni, Andrea; Zain, Ekachaeryanti; Dzulhadj, Azhar; Oo, Aye Chan; Viwattanakulvanid	Post-COVID depression and its multiple factors, does Favipiravir have a protective effect? A longitudinal study of indonesia COVID-19 patients	https://doi.org/10.1371/journal.pone.0279184	Published	12/30/2022	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0279184	Background Coronavirus disease (COVID-19) not only has a long-term effect on its survivors, it also affects their quality of life, including inducing depression as a possible manifestation of central nervous system disruption. Favipiravir shows promising efficacy as an antiviral drug for the treatment of COVID-19. However, its effect on the sequelae of COVID-19 has not been explored. Therefore, this study aims to assess the impact of Favipiravir and address the factors associated with post-COVID depression in Indonesia. Method This cohort study conducted a post-COVID-19 survey on Indonesian patients who were diagnosed by using real-time polymerase chain reaction (RT-PCR) and antigen tests until January 2022. An online questionnaire was distributed to obtain information on demographics, comorbidities, health behavior, symptoms, and treatment. The propensity technique was used to allocate the participants into the favipiravir and nonrecipient groups (1:1). The Patient Health Questionnaire-9 (PHQ-9) was used for outcome measurement. The cohort was followed up biweekly for 60 days after onset/diagnosis to determine the occurrence of depression. Cox regression analysis with an adjusted odds ratio and 95% confidence interval was used to estimate the effect of favipiravir on post-COVID-19 depression. Results The data included the information of 712 participants, of whom 18.54% had depression within 60 days after onset/diagnosis. Depression was higher in the nonrecipient group (21.06%) than in the favipiravir group (16.01%). After adjustment by other factors, favipiravir prescription was found to be associated with depression (aOR 0.488, 95% CI 0.339–0.701 p < 0.001). In accordance with the PHQ-9 subset, favipiravir exerted a significant protective effect against depressive mood and loss of interest. However, patients living alone were prone to experiencing loss of interest (aOR 2.253, 95% CI 1.329–3.818, p = 0.003). Conclusion The data obtained in this preliminary survey suggested that favipiravir may be useful for preventing post-COVID depression. However, further study is needed. Moreover, the provision of mental health support, particularly to those who live alone, must be ensured. Trial registration Registry NCT05060562.
282	Ce280		Khan, Amish M.; Piccirillo, Jeffrey; Kallogjeri, Dorina; Piccirillo, Jay F.	Efficacy of Combined Visual-Olfactory Training With Patient-Preferred Scents as Treatment for Patients With COVID-19 Resultant Olfactory Loss: A Randomized Clinical Trial	https://doi.org/10.1001/jamaoto.2022.4112	Published	12/29/2022	Trial	https://doi.org/10.1001/jamaoto.2022.4112	Key Points Question Does bimodal visual-olfactory training with patient-preferred scents improve olfaction vs unimodal olfactory training with physician-assigned scents in individuals with COVID-19 postviral olfactory loss? Findings In this randomized clinical trial that included 275 adults, the marginal mean difference for change in the UPSIT scores preintervention to postintervention between participants randomized to patient-preferred vs physician-assigned scents was 0.73, and between participants randomized to bimodal visual-olfactory vs unimodal olfactory training was 1.10. These were both insignificant differences. Meaning No clinically meaningful improvement in UPSIT score was observed among individuals who underwent olfactory training, with no added benefit from bimodal visual-olfactory training or patient-preferred scents. Abstract Importance The number of olfactory dysfunction cases has increased dramatically because of the COVID-19 pandemic. Identifying therapies that aid and accelerate recovery is essential. Objective To determine the efficacy of bimodal visual-olfactory training and patient-preferred scents vs unimodal olfactory training and physician-assigned scents in COVID-19 olfactory loss. Design, Setting, and Participants This was a randomized, single-blinded trial with a 2-by-2 factorial design (bimodal, patient preferred; unimodal, physician assigned; bimodal, physician assigned; unimodal, patient preferred) and an independent control group. Enrollment occurred from February 1 to May 27, 2021. Participants were adults 18 to 71 years old with current olfactory loss defined as University of Pennsylvania Smell Identification Test (UPSIT) score less than 34 for men and less than 35 for women and duration of 3 months or longer. Olfactory loss was initially diagnosed within 2 weeks of COVID-19 infection. Interventions Participants sniffed 4 essential oils for 15 seconds with a 30-second rest in between odors for 3 months. Participants in the physician-assigned odor arms trained with rose, lemon, eucalyptus, and clove. Participants randomized to the patient-preferred arms chose 4 of 24 available scents. If assigned to the bimodal arm, participants were shown digital images of the essential oil they were smelling. Main Outcomes and Measures The primary end point was postintervention change in UPSIT score from baseline; measures used were the UPSIT (validated, objective psychometric test of olfaction), Clinical Global Impressions Impression–Improvement (CGI-I; self-report improvement scale), and Olfactory Dysfunction Outcomes Rating (ODOR; olfaction-related quality-of-life questionnaire). Results Among the 275 enrolled participants, the mean (SD) age was 41 (12) years, and 236 (86%) were female. The change in UPSIT scores preintervention to postintervention was similar between the study arms. The marginal mean difference for change in UPSIT scores preintervention to postintervention between participants randomized to patient-preferred vs physician-assigned olfactory training was 0.73 (95% CI, −1.10 to 2.56), and between participants randomized to bimodal vs unimodal olfactory training was 1.10 (95% CI, −2.92 to 0.74). Five (24%) participants in the control arm had clinically important improvement on UPSIT compared with 18 (53%) in the bimodal, patient-preferred arm for a difference of 29% (95% CI, 4%-54%). Four (19%) participants in the control group self-reported improvement on CGI-I compared with 12 (35%) in the bimodal, patient-preferred arm for a difference of 16% (95% CI, −7% to 39%). The mean change in ODOR score preintervention to postintervention was 11.6 points (95% CI, 9.2-13.9), which was not deemed clinically important nor significantly different between arms. Conclusions and Relevance Based on the change in UPSIT scores, this randomized clinical trial did not show any difference between intervention arms, but when exploring within-patient change in UPSIT as well as self-reported impression of improvement, active interventions were associated with larger improvement than controls with a potential advantage of bimodal intervention. While not definitive, these results suggest that patients with COVID-19 olfactory loss may benefit from bimodal visual-olfactory training with patient-preferred scents. Trial Registration ClinicalTrials.gov Identifier: NCT04710394
283	Ce281		Kitala, Diana; Łabuś, Wojciech; Kozielski, Jerzy; Strzelec, Przemysław; Nowak, Mariusz; Knefel, Grzegorz; Dyjas, Piotr; Materniak, Krzysztof; Kosmala, Jolanta; Pająk, Jolanta; Czop, Jolanta; Janda-Kalus, Barbara; Marona, Barbara; Nowak-Wróżyna, Anna; Gierek, Marcin; Szczegielniak, Jan; Kucharzewski, Marek	Preliminary Research on the Effect of Hyperbaric Oxygen Therapy in Patients with Post-COVID-19 Syndrome	https://doi.org/10.3390/jcm12010308	Published	1/1/2023	Study	https://www.mdpi.com/2077-0383/12/1/308	Negative consequences and medical complications of COVID-19 can persist for up to several months after initial recovery. These consequences can include stroke, diabetes, decreased lung diffusing capacity, sleep apnea, pulmonary fibrosis, arrhythmia, myocarditis, fatigue, headaches, muscle aches, heart rate fluctuations, sleep problems, memory problems, nervousness, anxiety, and other neurological disorders. Thirty-one patients who reported symptoms related to previous COVID-19 disease of both sexes were enrolled in the initial program. The patients underwent compression sessions in a multiplace hyperbaric chamber. Each patient underwent a cycle of 15 compressions. Before the first session, each participant completed a venous blood gas test, a Fullerton test, and two spirometry tests (one before the Fullerton test and one after the test). Patients completed psychotechnical tests, a questionnaire on quality of life (Polish version of EQ-5D-5L), and a questionnaire on specific symptoms accompanying the disease and post-infection symptoms. The results showed significant improvements in areas such as quality of life, endurance and strength, some spirometric parameters, the anion gap and lactate levels, working memory, and attention in the group of treated patients. In contrast, there were no changes in pH, pO2, pCO2, glucose, and excess alkaline values. A follow-up interview confirmed that the beneficial effects were maintained over time. Considering the results obtained, including the apparent improvement in the patient’s clinical condition, it can be concluded that the use of 15 compression sessions was temporarily associated with a noticeable improvement in health and performance parameters as well as improvement in certain blood gas parameters.
284	Ce282		Cavigli, Luna; Fusi, Chiara; Focardi, Marta; Mandoli, Giulia Elena; Pastore, Maria Concetta; Cameli, Matteo; Valente, Serafina; Zorzi, Alessandro; Bonifazi, Marco; D’Andrea, Antonello; D’Ascenzi, Flavio	Post-Acute Sequelae of COVID-19: The Potential Role of Exercise Therapy in Treating Patients and Athletes Returning to Play	https://doi.org/10.3390/jcm12010288	Published	1/1/2023	Review	https://www.mdpi.com/2077-0383/12/1/288	Post-acute sequelae of coronavirus disease 19 (COVID-19) (PASC) describe a wide range of symptoms and signs involving multiple organ systems occurring after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, representing a growing health problem also in the world of sport and the athletic population. Patients with PASC have new, returning, or persisting symptoms four or more weeks after the infection. Among the most frequent symptoms, patients complain of fatigue, dyspnea, exercise intolerance, and reduced functional capacity that interfere with everyday life activity. The role of exercise programs in PASC patients will be identified, and upcoming studies will establish the magnitude of their benefits. However, the benefits of exercise to counteract these symptoms are well known, and an improvement in cardiopulmonary fitness, functional status, deconditioning, and quality of life can be obtained in these patients, as demonstrated in similar settings. Based on this background, this review aims to summarise the current evidence about the PASC syndrome and the benefit of exercise in these patients and to provide a practical guide for the exercise prescription in PASC patients to help them to resume their functional status, exercise tolerance, prior activity levels, and quality of life, also considering the athletic population and their return to play and sports competitions.
285	Ce283		Fawzy, Nader A.; Shaar, Bader Abou; Taha, RandM.; Arabi, Tarek Z.; Sabbah, Belal N.; Alkodaymi, Mohamad S.; Omrani, Osama A.; Makhzoum, Tariq; Almahfoudh, Najwa E.; Al-Hammad, Qasem A.; Hejazi, Wed; Obeidat, Yasin; Osman, Naden; Al-Kattan, Khaled M.; Berbari, Elie F.; Tleyjeh, Imad M.	A Systematic Review of Trials Currently Investigating Therapeutic Modalities for Post-Acute COVID-19 Syndrome and Registered on World Health Organization International Clinical Trials Platform	https://doi.org/10.1016/j.cmi.2023.01.007	Published	2023-01-13	Review	https://www.sciencedirect.com/science/article/pii/S1198743X23000095	Background Post-acute coronavirus 2019 (COVID-19) syndrome (PACS) is a well-recognized complex systemic disease that is associated with substantial morbidity. There is a paucity of established interventions to treat patients with this syndrome. Objectives To systematically review registered trials currently investigating therapeutic modalities for PACS. Data sources Search was conducted up to the 16th of September 2022 using the COVID-19 section of the World Health Organization (WHO) Internal Clinical Trials Registry Platform. Study eligibility criteria, participants, and interventions Interventional clinical trials of any sample size examining any therapeutic modality targeting persistent symptoms among individuals after diagnosis with COVID-19. Methods Data on trial characteristics and intervention characteristics were collected and summarized. Results After screening 17125 trials, 388 trials from 42 countries were eligible. 331 trials tested mono-therapeutic strategies, while 39 trials included a combination of interventions. Among the 824 primary outcomes identified, there were more than 300 different outcomes. Rehabilitation was the most employed class of intervention with 169 trials. We encountered 76 trials examining pharmacological agents of various classes with the most common agent being colchicine. Complementary and alternative medicine encompassed 64 trials exploring Traditional Chinese Medicine, Ayurveda, homeopathic medications, naturopathic medications, vitamins, dietary supplements, and botanicals. Psychotherapeutic and educational interventions were also employed with 12 and 4 trials, respectively. Other interventions including transcranial current direct stimulation, transcutaneous auricular vagus nerve stimulation, general electrical stimulation, cranial electrotherapy stimulation, various stem cell interventions, and oxygen therapy interventions were also employed. Conclusion We identified 388 registered trials with a high degree of heterogeneity exploring 144 unique interventions for PACS. Most target general alleviation of symptoms. There is a need for further high-quality and methodologically robust PACS treatment trials conducted with standardization of outcomes while following WHO’s recommendation for uniform evaluation and treatment.
286	Ce284		Hausswirth, Christophe; Schmit, Cyril; Rougier, Yann; Coste, Alexandre	Positive Impacts of a Four-Week Neuro-Meditation Program on Cognitive Function in Post-Acute Sequelae of COVID-19 Patients: A Randomized Controlled Trial	https://doi.org/10.3390/ijerph20021361	Published	2023-01-01	Study	https://www.mdpi.com/1660-4601/20/2/1361	Study objective: Long COVID patients can experience high levels of impairment in their cognitive function and mental health. Using a parallel randomized control trial, we evaluated the effectiveness of a neuro-meditation program to reduce cognitive impairment in patients with long COVID. Methods: A total of 34 patients with long COVID were randomized to an intervention group (G-Int; n = 17) or a control group (G-Con; n = 17) and 15 healthy participants were constitutive of a normative group (G-Nor). The intervention consisted of ten 30-min sessions of Rebalance® over a period of five weeks. Each session included sound therapy and coach-guided meditation associated with light stimulations (i.e., chromotherapy). Primary outcomes were performance on five computerized cognitive tasks (choice response time, pattern comparison, Simon, pursuit rotor task, and Corsi block-tapping task), mental and physical fatigue (Chalder fatigue scale), perceived stress (perceived stress scale) and mood (profiles of mood states). Secondary outcomes were anxiety and depressive symptoms (hospital anxiety and depression scale), muscular pain, joint pain, and headaches using visual analog scales (VAS) as well as sleep quality (Spiegel sleep questionnaire). Assessments were conducted at baseline and at 1–2 and 7–8 days of follow-up. Results: Compared to healthy subjects, long COVID patients showed significant differences at baseline on all the self-report questionnaires, and a Rebalance® program improved all the subjective reports, as well as cognitive performances, especially on reaction time-based tasks. In particular, only the G-Int group revealed shortened reaction times in the choice reaction time (RTbaseline = 593 ± 121 ms vs. RTpost2 = 521 ± 86 ms, p < 0.001), Simon (RTbaseline = 539 ± 123 ms vs. RTpost2 = 494 ± 134 ms, p < 0.01), and pattern comparison tasks (RTbaseline = 1244 ± 315 ms vs. RTpost2 = 1079 ± 213 ms, p < 0.001). Conclusions) Initial evidence suggests that neuro-meditation reduces cognitive impairment and improves physical and mental fatigue, muscle and joint pain, symptoms of depression and anxiety, mood disturbances as well as sleep quality. The Rebalance® program hence constitutes a promising non-pharmacological intervention for the treatment of long-term psychological/cognitive outcomes of COVID-19.
287	Ce285		Berraies, A.; Sleiman, C.; Rabut, H.	Réhabilitation respiratoire dans la dyspnée chronique en post-COVID : expérience du service de pneumologie de Chartres	https://doi.org/10.1016/j.rmra.2022.11.095	Published	2023-01-01	Study	https://www.sciencedirect.com/science/article/pii/S1877120322002658	Introduction Certains patients gardent des séquelles plusieurs mois après une infection pulmonaire à SARS-CoV-2 indépendamment de la sévérité initiale de la maladie. La dyspnée, la fatigue et le retentissement psychologique sont les principaux symptômes rapportés. De plus en plus de données montrent l’intérêt de la réhabilitation respiratoire (RR) dans la dyspnée chronique post-COVID. Méthodes Nous rapportons les résultats de la RR en post-COVID à Chartres. Depuis septembre 2020, nous accueillons dans notre unité de RR ambulatoire des patients souffrant de dyspnée persistante en post-COVID pendant 6 semaines à raison de 3 séances hebdomadaires. Nous évaluons leur fonction respiratoire, leurs capacités à l’effort par un test de levers de chaise de 1 minute (TLC1) et une épreuve d’effort cardiorespiratoire (EFX) ainsi qu’une épreuve d’endurance et différents questionnaires. Résultats Quarante-six patients ont participé au programme avec un âge moyen de 55 ans (24–79 ans). Le sex-ratio est de 0,39. Parmi ces patients, 65 % ont été hospitalisés (30 patients) dont les 2/3 en réanimation et 28 % ont nécessité la ventilation mécanique. Le délai moyen de la RR était de 7,6 mois (3–24 mois). Treize patients (28 %) ont une restriction avec une CPT moyenne à 64 %. La DLCO était abaissée chez 58 % des patients avec une moyenne de 66 %. Dix-neuf patients (41 %) avaient des anomalies au scanner au moment de la réhabilitation dont 68 % avaient une fibrose. La VO2 moyenne était de 68 % (31–83 %). Un syndrome d’hyperventilation a été retrouvé chez 52 % des patients. L’anxiété et la dépression étaient présentes chez respectivement 74 % et 43 % des patients. Après réhabilitation, l’endurance est multipliée par 3 en moyenne (1,5 et 7,1). Amélioration du TLC1 chez 69 % des patients. L’anxiété s’améliore chez le tiers des patients et la dépression chez la moitié. Le syndrome d’hyperventilation a régressé dans 54 % des cas. Conclusion Comme pour les pathologies respiratoires chroniques, la RR permet d’améliorer les capacités à l’effort mais également le syndrome d’hyperventilation et le retentissement psychologique particulièrement importants dans cette pathologie.
288	Ce286		Steinmetz, Anke; Bahlmann, Susanne; Bergelt, Corinna; Bröker, Barbara M.; Ewert, Ralf; Felix, Stephan B.; Flöel, Agnes; Fleischmann, Robert; Hoffmann, Wolfgang; Holtfreter, Silva; Nauck, Matthias; Riemann, Katja; Scheer, Christian; Stahl, Dana; Vogelgesang, Antje; Völker, Uwe; Wiesmann, Ulrich; Klinger-König, Johanna; Walk, René; Grabe, Hans J.; Gross, Stefan; Lehnert, Kristin; Fielitz, Jens; Dörr, Marcus	The Greifswald Post COVID Rehabilitation Study and Research (PoCoRe)–Study Design, Characteristics and Evaluation Tools	https://doi.org/10.3390/jcm12020624	Published	2023-01-01	Protocol	https://www.mdpi.com/2077-0383/12/2/624	(1) Background: COVID-19 is often associated with significant long-term symptoms and disability, i.e., the long/post-COVID syndrome (PCS). Even after presumably mild COVID-19 infections, an increasing number of patients seek medical help for these long-term sequelae, which can affect various organ systems. The pathogenesis of PCS is not yet understood. Therapy has so far been limited to symptomatic treatment. The Greifswald Post COVID Rehabilitation Study (PoCoRe) aims to follow and deeply phenotype outpatients with PCS in the long term, taking a holistic and comprehensive approach to the analysis of their symptoms, signs and biomarkers. (2) Methods: Post-COVID outpatients are screened for symptoms in different organ systems with a standardized medical history, clinical examination, various questionnaires as well as physical and cardiopulmonary function tests. In addition, biomaterials are collected for the analysis of immunomodulators, cytokines, chemokines, proteome patterns as well as specific (auto)antibodies. Patients are treated according to their individual needs, adhering to the current standard of care. PoCoRe’s overall aim is to optimize diagnostics and therapy in PCS patients.
289	Ce287		Shoaib, Shoaib; Ansari, Mohammad Azam; Kandasamy, Geetha; Vasudevan, Rajalakshimi; Hani, Umme; Chauhan, Waseem; Alhumaidi, Maryam S.; Altammar, Khadijah A.; Azmi, Sarfuddin; Ahmad, Wasim; Wahab, Shadma; Islam, Najmul	An Attention towards the Prophylactic and Therapeutic Options of Phytochemicals for SARS-CoV-2: A Molecular Insight	https://doi.org/10.3390/molecules28020795	Published	2023-01-01	Review	https://www.mdpi.com/1420-3049/28/2/795	The novel pathogenic virus was discovered in Wuhan, China (December 2019), and quickly spread throughout the world. Further analysis revealed that the pathogenic strain of virus was corona but it was distinct from other coronavirus strains, and thus it was renamed 2019-nCoV or SARS-CoV-2. This coronavirus shares many characteristics with other coronaviruses, including SARS-CoV and MERS-CoV. The clinical manifestations raised in the form of a cytokine storm trigger a complicated spectrum of pathophysiological changes that include cardiovascular, kidney, and liver problems. The lack of an effective treatment strategy has imposed a health and socio-economic burden. Even though the mortality rate of patients with this disease is lower, since it is judged to be the most contagious, it is considered more lethal. Globally, the researchers are continuously engaged to develop and identify possible preventive and therapeutic regimens for the management of disease. Notably, to combat SARS-CoV-2, various vaccine types have been developed and are currently being tested in clinical trials; these have also been used as a health emergency during a pandemic. Despite this, many old antiviral and other drugs (such as chloroquine/hydroxychloroquine, corticosteroids, and so on) are still used in various countries as emergency medicine. Plant-based products have been reported to be safe as alternative options for several infectious and non-infectious diseases, as many of them showed chemopreventive and chemotherapeutic effects in the case of tuberculosis, cancer, malaria, diabetes, cardiac problems, and others. Therefore, plant-derived products may play crucial roles in improving health for a variety of ailments by providing a variety of effective cures. Due to current therapeutic repurposing efforts against this newly discovered virus, we attempted to outline many plant-based compounds in this review to aid in the fight against SARS-CoV-2.
290	Ce288		Mullard, Jordan C. R.; Kawalek, Jessica; Parkin, Amy; Rayner, Clare; Mir, Ghazala; Sivan, Manoj; Greenhalgh, Trisha	Towards evidence-based and inclusive models of peer support for long covid: A hermeneutic systematic review	https://doi.org/10.1016/j.socscimed.2023.115669	Published	2023-03-01	Review	https://www.sciencedirect.com/science/article/pii/S0277953623000242	Since the first wave of COVID-19 in March 2020 the number of people living with post-COVID syndrome has risen rapidly at global pace, however, questions still remain as to whether there is a hidden cohort of sufferers not accessing mainstream clinics. This group are likely to be constituted by already marginalised people at the sharp end of existing health inequalities and not accessing formal clinics. The challenge of supporting such patients includes the question of how best to organise and facilitate different forms of support. As such, we aim to examine whether peer support is a potential option for hidden or hardly reached populations of long COVID sufferers with a specific focus on the UK, though not exclusively. Through a systematic hermeneutic literature review of peer support in other conditions (57 papers), we evaluate the global potential of peer support for the ongoing needs of people living with long COVID. Through our analysis, we highlight three key peer support perspectives in healthcare reflecting particular theoretical perspectives, goals, and understandings of what is ‘good health’, we call these: biomedical (disease control/management), relational (intersubjective mutual support) and socio-political (advocacy, campaigning & social context). Additionally, we identify three broad models for delivering peer support: service-led, community-based and social media. Attention to power relations, social and cultural capital, and a co-design approach are key when developing peer support services for disadvantaged and underserved groups. Models from other long-term conditions suggest that peer support for long COVID can and should go beyond biomedical goals and harness the power of relational support and collective advocacy. This may be particularly important when seeking to reduce health inequalities and improve access for a potentially hidden cohort of sufferers.
291	Ce289		Di Stadio, Arianna; Bernitsas, Evanthia; La Mantia, Ignazio; Brenner, Michael J.; Ralli, Massimo; Vaira, Luigi Angelo; Colizza, Andrea; Cavaliere, Carlo; Laudani, Matteo; Frohman, Teresa C.; De Vincentiis, Marco; Frohman, Elliot M.; Altieri, Marta	Targeting Neuroinflammation to Alleviate Chronic Olfactory Dysfunction in Long COVID: A Role for Investigating Disease-Modifying Therapy (DMT)?	https://doi.org/10.3390/life13010226	Published	2023-01-01	Study	https://www.mdpi.com/2075-1729/13/1/226	Chronic olfactory dysfunction after SARS-CoV-2 infection occurs in approximately 10% of patients with COVID-19-induced anosmia, and it is a growing public health concern. A regimen of olfactory training and anti-neuroinflammatory therapy with co-ultramicronized palmitoylethanolamide with luteolin (um-PEA-LUT) has shown promising results in clinical trials; however, approximately 15% of treated patients do not achieve full recovery of a normal olfactory threshold, and almost 5% have no recovery. Disease-modifying therapies (DMTs), which are used to treat autoimmune neuroinflammation in multiple sclerosis (MS), have not been studied for treating persistent inflammation in refractory post-COVID-19 smell disorder. This study evaluated COVID-19-related smell loss and MS-related smell loss, comparing the responses to different therapies. Forty patients with MS and 45 reporting post-COVID-19 olfactory disorders were included in the study. All patients underwent nasal endoscopy and were evaluated by using validated Sniffin’ Sticks testing. The patients with long COVID were treated for three months with um-PEA-LUT plus olfactory training. The patients with MS were treated with DMTs. Olfactory functions before and after treatment were analyzed in both groups. At the experimental endpoint, 13 patients in the COVID-19 group treated with um-PEA-LUT had residual olfactory impairment versus 10 patients in the MS group treated with DMTs. The severity of the persistent olfactory loss was lower in the MS group, and the patients with MS treated with IFN-beta and glatiramer acetate had the preservation of olfactory function. These data provide a rationale for considering prospective trials investigating the efficacy of DMTs for post-COVID-19 olfactory disorders that are refractory to um-PEA-LUT with olfactory training. This study is the first to consider the role of DMT in treating refractory post-viral olfactory loss in patients with long COVID.
292	Ce290		Liu, Ting-Hui; Wu, Jheng-Yan; Huang, Po-Yu; Tsai, Ya-Wen; Lai, Chih-Cheng	The effect of nirmatrelvir plus ritonavir on the long-term risk of epilepsy and seizure following COVID-19: A retrospective cohort study including 91,528 patients	https://doi.org/10.1016/j.jinf.2023.01.014	Published	2023-01-13	Study	https://www.journalofinfection.com/article/S0163-4453(23)00017-8/fulltext	In summary, the results of this large retrospective cohort study suggest that non-hospitalized COVID-19 patients receiving NMV-r may have a lower long-term risk of epilepsy and seizure compared to those who did not receive anti-viral agents. This finding suggests that NMV-r may be effective in reducing the risk of post-acute COVID-19 sequelae, including epilepsy and seizure. Our findings were based on analyzing a large database involving multination, multi-institution, and multi-races. To minimize the potential effects of possible confounding factors, we exclude the patients with prior history of epilepsy or seizure, and the baseline characteristics were well-matched between groups. Therefore, our findings are generalizable, and the level of evidence is robust. Our findings, in combination with those from a previous observational study,4 demonstrating the preventive effect of NMV-r on ten post-acute sequelae, suggest a potential role for NMV-r in preventing long COVID. These findings are extremely important because no effective measure can prevent the development of long COVID during this pandemic. If NMV-r can provide clinical benefits for acute COVID-19 and reduce the risk of post-acute sequelae, it may be worth considering changing clinical practice to encourage the use of NMV-r for patients with SARS-CoV-2 infection.Publisher: Elsevier PMID: 36649824
293	Ce291		Hansen, Kristoffer Skaalum; Leth, Steffen	Coenzyme Q10 therapy in patients with post COVID-19 condition – Authors’ response	https://doi.org/10.1016/j.lanepe.2022.100571	Published	2023-02-01	Study	https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(22)00267-8/fulltext	A subgroup analysis on a cohort with BMI less than 26 was performed. The number of participants with BMI <26 was 51. In this sub-cohort, mean BMI was now 23.8, mean age 46 years and 39 (76.5%) were female. Group A and B consisted of 25 and 28 participants, respectively, and were still well-balanced. There was no significant difference between the subgroup of participants with BMI <26 and the original cohort with regards to baseline parameters (other than BMI). There was no significant difference in reduction of PCC symptom score (−0.002 (95% CI -3.64; 3.66), P = 0.99) or increase in EQ-5D health index (−0.006 (95% CI -0.44; 0.032), P = 0.75) when comparing CoQ10 and placebo with a mixed-effect linear regression model in this subgroup. A subsequent analysis on symptom clusters did not show any significant difference between CoQ10 and placebo (Fig. 1). Importantly, subgroup analysis results should be interpreted with caution due to the risk of false positive by multiple comparisons and – especially in this case – limited power after reduction of the number of observations. Thus, larger cohort studies are needed to establish a connection between mitochondrial dysfunction in PCC and the involvement of interleukins. publisher: Elsevier
294	Ce292		Dannouf, Khaleedah	Management of Long COVID in the Primary Care Setting		Published	2023-01-18	Review	https://digitalshowcase.lynchburg.edu/dmscjournal/vol5/iss1/55	Long COVID is a relatively new syndrome of uncertain chronicity. The syndrome presents in multiple fashions with one or more coronavirus-2 (COVID-19) symptoms persisting, reactivating, or beginning 12 weeks or more after the initial COVID-19 infection. Increasing survival rates from COVID-19 mean a growing number of patients at risk for developing long COVID. With more than 93 million confirmed COVID-19 cases in the United States by September 9, 2022, the likelihood of a primary care clinician treating patients with long COVID is significant. Clinicians must be poised to identify, treat and recognize when to refer care for their long COVID patients. This article reviews the etiology, complications, putative pathophysiology, diagnosis, differentials, treatments, and future direction of long COVID in managing primary care patients with previously mild-moderate COVID-19 illnesses.
295	Ce293		Quinn, Kieran L.; Cheung, Angela M.; Razak, Fahad	Treating common and potentially modifiable symptoms of post-COVID-19 condition (long COVID) in adults	https://doi.org/10.1503/cmaj.220824	Published	2023-01-17	Review	https://www.cmaj.ca/content/195/2/E80	Fatigue and postexertional malaise associated with long COVID should be treated with titrated structured activity and energy conservation strategies1 To avoid precipitating postexertional malaise, patients should be advised to begin a structured and symptom-guided return to activity program, tailored to their severity of fatigue. The 4 Ps (pacing; prioritizing which activities need to get done on specific days and which activities can be postponed; positioning to modify activities to make them easier to perform [e.g., while sitting]; and planning) is a helpful framework to educate people about how to apply physical, emotional and cognitive energy conservation strategies.1 Guideline-directed use of psychosocial interventions and medications can be used to treat mental health complications of long COVID Anxiety, depression and posttraumatic stress disorder are among the most common mental health manifestations of long COVID and may be treated according to relevant guidelines in people with these conditions, which are similar to recommendations among people with myalgic encephalomyelitis (ME).2 The use of cognitive behavioural therapy for the treatment of fatigue is controversial and not currently endorsed by the ME Association.2 Breathing exercises, body positioning and pulmonary rehabilitation may improve dyspnea2 In people with mild dyspnea, pursed lip or deep breathing exercises may improve symptoms. Persistent hypoxemia is not a common manifestation of long COVID and may be caused by severe lung disease or organizing pneumonia. Its presence should prompt referral to a respirologist and consideration of pulmonary rehabilitation.2,3 People with sleep disturbances should receive counselling on sleep hygiene, relaxation techniques and stimulus control2 Sleep disturbances may be a result of their SARS-CoV-2 infection or the negative effects of the pandemic.2 They can be managed using cognitive behavioural therapy or 1 of the following medications currently available in Canada: eszopiclone, zolpidem or doxepin.4 Specific guidelines exist for the treatment of palpitations and tachycardia with particular causes Current recommendations for the treatment of inappropriate sinus tachycardia and postural orthostatic tachycardia syndrome include behavioural modifications, oral fluids, salt, compression stockings, β-blockers, ivabradine and midodrine.5 publisher: CMAJ section: Practice PMID: 36649947
296	Ce294		Bompani, Nicole; Bertella, Laura; Barbieri, Valentina; Scarabel, Luca; Scarpina, Federica; Perucca, Laura; Rossi, Paolo	The predictive role of fatigue and neuropsychological components on functional outcomes in COVID-19 after a multidisciplinary rehabilitation program	https://doi.org/10.1177/03000605221148435	Published	2023-01-01	Study	https://doi.org/10.1177/03000605221148435	ObjectiveTo verify the impact of altered cognitive functioning and higher levels of mental fatigue, both reported after coronavirus disease 2019 (COVID-19), on rehabilitation treatment outcomes.MethodsIn this real-practice retrospective pre?post intervention cohort study, cognitive functioning, measured through standardized neuropsychological measures, and individual levels of fatigue, depression and anxiety symptoms, were evaluated at admission to a rehabilitation program in individuals who had been hospitalized for COVID-19. The rehabilitation program effectiveness was measured through the Functional Independence Measure.ResultsAmong the patient sample (n?=?66), 87.88% reported experiencing high levels of fatigue at admission, while 16.67% reported depressive symptoms, and 22.73% reported anxiety symptoms. After rehabilitation, the sample displayed a significant decrease in the level of disability, in both the motor and cognitive subscales. Neuropsychological and psychological functioning did not play a predictive role. The 45 patients who received mechanical ventilation during intensive care, representing 68.18% of the sample, benefited more from rehabilitation treatment.ConclusionsThe results support the importance of an early rehabilitation program after COVID-19 infection, independent of the initial neuropsychological and psychological functioning. Respiratory assistance may represent a crucial factor for short-term neuropsychological disease after-effects. Future studies on the long-term neuropsychological effect of COVID-19 infection on individual levels of disability are necessary.
297	Ce295		Jimeno-Almazán, Amaya; Buendía-Romero, Ángel; Martínez-Cava, Alejandro; Franco-López, Francisco; Sánchez-Alcaraz, Bernardino Javier; Courel-Ibáñez, Javier; Pallarés, Jesús G.	Effects of a concurrent training, respiratory muscle exercise, and self-management recommendations on recovery from post-COVID-19 conditions: the RECOVE trial	https://doi.org/10.1152/japplphysiol.00489.2022	Published	2023-01-01	Study	https://journals.physiology.org/doi/full/10.1152/japplphysiol.00489.2022	The aim of this study was to determine the effectiveness of physical exercise, respiratory muscle training, and the self-management World Health Organization (WHO) recommendations leaflet on the recovery of physical fitness, quality of life, and symptom status in people with post-COVID-19 conditions. Eighty nonhospitalized adults with a post-COVID-19 condition were randomly assigned to one of four 8-wk parallel intervention groups: 1) multicomponent exercise program based on concurrent training (CT, number of subjects (n) = 20; 3 resistance and endurance supervised sessions per week at low-moderate intensity); 2) inspiratory muscle training (RM, n = 17; 2 standardized daily sessions); 3) a combination of both of the above (CTRM, n = 23); and 4) control group (CON, n = 20; following the WHO guidelines for post-COVID-19-related illness rehabilitation). No significant differences between groups were detected at baseline. Although no significant differences between interventions were detected in the V̇o2max, significant individual improvements were identified in the CT (7.5%; effect size, ES = 0.28) and CTRM (7.8%; ES = 0.36) groups. Lower body muscle strength significantly improved in the CT and CTRM (14.5%–32.6%; ES = 0.27–1.13) groups compared with RM and CON (−0.3% to 11.3%; ES = 0.10–0.19). The CT and CTRM groups improved significantly for dyspnea and fatigue, as did the health status. In addition, significant differences between interventions were described in fatigue and depression scales favoring CT and CTRM interventions. An individualized and supervised concurrent training with or without inspiratory muscle training was safe and more effective than self-care recommendations and inspiratory muscle training alone, to regain cardiovascular and muscular fitness, improve symptom severity, and health status in outpatients with post-COVID-19 conditions. NEW & NOTEWORTHY Eight weeks of concurrent training, with or without inspiratory muscle exercise, was better than WHO “Support for Rehabilitation: Self-Management after COVID-19-Related Illness” recommendations or inspiratory muscle training alone to improve cardiopulmonary fitness, strength, and symptom severity, in a safe and effective manner. The RECOVE trial proved the benefits and utility of a supervised exercise program in people with post-COVID-19 conditions after mild COVID-19 in an ambulatory setting. publisher: American Physiological Society
298	Ce296		Santana, Kelly; França, Eduardo; Sato, João; Silva, Ana; Queiroz, Maria; de Farias, Julia; Rodrigues, Danniely; Souza, Iara; Ribeiro, Vanessa; Caparelli-Dáquer, Egas; Teixeira, Antonio L.; Charvet, Leigh; Datta, Abhishek; Bikson, Marom; Andrade, Suellen	Non-invasive brain stimulation for fatigue in post-acute sequelae of SARS-CoV-2 (PASC)	https://doi.org/10.1016/j.brs.2023.01.1672	Published	2023-01-01	Study	https://www.sciencedirect.com/science/article/pii/S1935861X23016741	Highlights •Ten sessions of HD tDCS and rehabilitation program decreases symptoms associated with post-acute sequelae of COVID-19 (PASC). •M1 HD tDCS modulates fatigue, anxiety, and quality of life on PASC-related fatigue. •HD tDCS might be used as adjuvant therapeutic tool for PASC-related fatigue. Abstract Background and purpose: Fatigue is among the most common persistent symptoms following post-acute sequelae of Sars-COV-2 infection (PASC). The current study investigated the potential therapeutic effects of High-Definition transcranial Direct Current Stimulation (HD-tDCS) associated with rehabilitation program for the management of PASC-related fatigue. Methods Seventy patients with PASC-related fatigue were randomized to receive 3 mA or sham HD-tDCS targeting the left primary motor cortex (M1) for 30 min paired with a rehabilitation program. Each patient underwent 10 sessions (2 sessions/week) over five weeks. Fatigue was measured as the primary outcome before and after the intervention using the Modified Fatigue Impact Scale (MFIS). Pain level, anxiety severity and quality of life were secondary outcomes assessed, respectively, through the McGill Questionnaire, Hamilton Anxiety Rating Scale (HAM-A) and WHOQOL. Results Active HD-tDCS resulted in significantly greater reduction in fatigue compared to sham HD-tDCS (mean group MFIS reduction of 22.11 points vs 10.34 points). Distinct effects of HD-tDCS were observed in fatigue domains with greater effect on cognitive (mean group difference 8.29 points; effect size 1.1; 95% CI 3.56–13.01; P < .0001) and psychosocial domains (mean group difference 2.37 points; effect size 1.2; 95% CI 1.34–3.40; P < .0001), with no significant difference between the groups in the physical subscale (mean group difference 0.71 points; effect size 0.1; 95% CI 4.47–5.90; P = .09). Compared to sham, the active HD-tDCS group also had a significant reduction in anxiety (mean group difference 4.88; effect size 0.9; 95% CI 1.93–7.84; P < .0001) and improvement in quality of life (mean group difference 14.80; effect size 0.7; 95% CI 7.87–21.73; P < .0001). There was no significant difference in pain (mean group difference −0.74; no effect size; 95% CI 3.66–5.14; P = .09). Conclusion An intervention with M1 targeted HD-tDCS paired with a rehabilitation program was effective in reducing fatigue and anxiety, while improving quality of life in people with PASC.
299	Ce297		Wang, Samuel S. Y.; Xu, Chuanhui	Hydroxychloroquine: is there a role in long COVID?	https://doi.org/10.1007/s10067-023-06514-x	Published	2023-01-25	Article	https://doi.org/10.1007/s10067-023-06514-x	HCQ could be explored as a potential therapeutic agent in long COVID for a few reasons. First, a persistent residual virus may drive the unremitting inflammatory response in long COVID [5]. HCQ is an immunomodulatory drug by inhibits toll-like receptor (TLR) 7/9 sensing virus [6]. HCQ inhibits TLR signaling by altering the pH of endosomes involved in TLR processing and/or preventing TLR7/9 from binding to their respective ligands (RNA and DNA) [7]. HCQ can also exert its immunomodulatory effects through the inhibition of nucleic acid sensor cyclic GMP-AMP (cGAMP) synthase (cGAS) by interfering with cGAS binding to cytosolic DNA. cGAS stimulator of IFN genes (STING) pathway is a major source of the type I interferon (IFN) response, and through inhibition of this pathway, it can reduce the production of pro-inflammatory cytokines, including type I IFN [7]. HCQ is able to inhibit cytokine production in various immune cells, for example, the production of IL-1, IL-6, TNF, and IFNγ by mononuclear cells and the production of TNF, IFNα, and IL-6 by plasmacytoid dendritic cells and natural killer cells [7]. Therefore, HCQ may dampen the unremitting hyperinflammatory response seen in long COVID by suppressing TLR 7/9 activation, pro-inflammatory cytokine release, and also subsequent immune activation. Second, long COVID has been associated with autoantibodies [5]. HCQ might address this problem through the prevention of MHC class II-mediated autoantigen presentation through inhibition of lysosomal activity [7]. HCQ inhibits the degradation of cargo derived externally (via endocytosis or phagocytosis) or internally (via the autophagy pathway) in autolysosomes by increasing the pH of endosomal compartments, impairing the maturation of lysosomes and autophagosomes, and inhibit auto-antigen presentation along the lysosomal pathway [7]. Another postulated mechanism of long COVID is a sustained endotheliopathy due to microthrombi; it was noted that in patients with long COVID, their plasma vWF antigen and propeptide levels correlated inversely with exercise capacity [8]. HCQ is well-proven to reduce thromboembolic events in SLE and improve endothelial dysfunction [9]. Assuming that the ongoing endotheliopathy is associated with immune-mediated microthromboses, HCQ could potentially improve endothelial dysfunction that is also found in the pathogenesis of long COVID. Lastly, HCQ is safe and widely used in rheumatology for patients with SLE, and rheumatoid arthritis, which are prototypes of chronic inflammatory/autoimmune disease. Hence, should long COVID be defined as a disease of a prolonged and dysregulated inflammatory state HCQ might be a suitable immunomodulatory agent to dampen and alter the hyperinflammatory response, given the above mechanisms of HCQ and the current understanding of the pathophysiology of long COVID. It may be worthwhile to consider exploring treatment options/trials to evaluate the effectiveness and mechanisms of action of HCQ in long COVID patients. Ideally, a double-blind, randomized placebo-controlled trial should be carried out in patients with long COVID treated with HCQ and placebo. The outcome measures could be patient-reported outcomes, inflammatory markers, and endothelial function. This should be the future research agenda, and we are looking forward to it (Table 1).
300	Ce298		Klocke, Carina; Valentini, Jan; Stolz, Regina; Gaßner, Lena; Joos, Stefanie; Förster, Christian	Patients’ Experiences With Therapeutic Approaches for Post-COVID Syndrome: Results of a Crowdsourced Research Survey	https://doi.org/10.1370/afm.2898	Published	2023-01-01	Study	https://www.annfammed.org/content/21/1/73	Some patients develop multiple protracted sequelae after infection with SARS-CoV-2, collectively known as post-COVID syndrome or long COVID. To date, there is no evidence showing benefit of specific therapies for this condition, and patients likely resort to self-initiated therapies. We aimed to obtain information about therapies used by and needs of this population via inductive crowdsourcing research. Patients completed an online questionnaire about their symptoms and experiences with therapeutic approaches. Responses of 499 participants suggested few approaches (eg, mind-body medicine, respiratory therapy) had positive effects and showed a great need for patient-centered communication (eg, more recognition of this syndrome). Our findings can help design clinical studies and underscore the importance of the holistic approach to care provided by family medicine.
301	Ce299		Jimeno-Almazán, Amaya; Buendía-Romero, Ángel; Martínez-Cava, Alejandro; Franco-López, Francisco; Sánchez-Alcaraz, Bernardino Javier; Courel-Ibáñez, Javier; Pallarés, Jesús G.	Effects of a concurrent training, respiratory muscle exercise, and self-management recommendations on recovery from post-COVID-19 conditions: the RECOVE trial	https://doi.org/10.1152/japplphysiol.00489.2022	Published	2023-01-01	Study	https://journals.physiology.org/doi/full/10.1152/japplphysiol.00489.2022	The aim of this study was to determine the effectiveness of physical exercise, respiratory muscle training, and the self-management World Health Organization (WHO) recommendations leaflet on the recovery of physical fitness, quality of life, and symptom status in people with post-COVID-19 conditions. Eighty nonhospitalized adults with a post-COVID-19 condition were randomly assigned to one of four 8-wk parallel intervention groups: 1) multicomponent exercise program based on concurrent training (CT, number of subjects (n) = 20; 3 resistance and endurance supervised sessions per week at low-moderate intensity); 2) inspiratory muscle training (RM, n = 17; 2 standardized daily sessions); 3) a combination of both of the above (CTRM, n = 23); and 4) control group (CON, n = 20; following the WHO guidelines for post-COVID-19-related illness rehabilitation). No significant differences between groups were detected at baseline. Although no significant differences between interventions were detected in the V̇o2max, significant individual improvements were identified in the CT (7.5%; effect size, ES = 0.28) and CTRM (7.8%; ES = 0.36) groups. Lower body muscle strength significantly improved in the CT and CTRM (14.5%–32.6%; ES = 0.27–1.13) groups compared with RM and CON (−0.3% to 11.3%; ES = 0.10–0.19). The CT and CTRM groups improved significantly for dyspnea and fatigue, as did the health status. In addition, significant differences between interventions were described in fatigue and depression scales favoring CT and CTRM interventions. An individualized and supervised concurrent training with or without inspiratory muscle training was safe and more effective than self-care recommendations and inspiratory muscle training alone, to regain cardiovascular and muscular fitness, improve symptom severity, and health status in outpatients with post-COVID-19 conditions. NEW & NOTEWORTHY Eight weeks of concurrent training, with or without inspiratory muscle exercise, was better than WHO “Support for Rehabilitation: Self-Management after COVID-19-Related Illness” recommendations or inspiratory muscle training alone to improve cardiopulmonary fitness, strength, and symptom severity, in a safe and effective manner. The RECOVE trial proved the benefits and utility of a supervised exercise program in people with post-COVID-19 conditions after mild COVID-19 in an ambulatory setting. publisher: American Physiological Society
302	Ce300		Müller, Thomas; Riederer, Peter; Kuhn, Wilfried	Aminoadamantanes: from treatment of Parkinson’s and Alzheimer’s disease to symptom amelioration of long COVID-19 syndrome?	https://doi.org/10.1080/17512433.2023.2176301	Published	2023-02-01	Article	https://doi.org/10.1080/17512433.2023.2176301	Introduction The aminoadamantanes amantadine and memantine are well known. They mainly act as N-methyl-D-aspartate antagonists. Areas covered The antiviral drug amantadine moderately ameliorates impaired motor behavior in patients with Parkinson’s disease. Memantine provides beneficial effects on memory function in patients with advanced Alzheimer’s disease already treated with acetylcholine esterase inhibitors. Both compounds counteract impaired monoamine neurotransmission with associated symptoms, such as depression. They improve vigilance, lack of attention and concentration, fatigue syndromes according to clinical findings in patients with chronic neurodegenerative processes. Their extrasynaptic N-methyl-D-Aspartate receptor blockade weakens a prolonged influx of Ca2+ ions as the main responsible components of neuronal excitotoxicity. This causes neuronal dying and associated functional deficits. Expert opinion We suggest aminoadamantanes as future therapies for amelioration of short- and long-term consequences of a COVID 19 infection. Particularly the extended-release amantadine formulations will be suitable. They showed better clinical efficacy compared with the conventional available compounds. Amantadine may particularly be suitable for amelioration of fatigue or chronic exhaustion, memantine for improvement of cognitive deficits. Clinical research in patients, who are affected by the short- and long-term consequences of a COVID 19 infection, is warranted to confirm these still hypothetical putative beneficial effects of aminoadamantanes. Plain Language Summary The drugs amantadine and memantine are known as aminoadamantanes. Amantadine improves motor skills in patients with Parkinson’s disease. It also reduces fatigue in individuals suffering from multiple sclerosis. Memantine improves memory dysfunction linked to Alzheimer’s disease. Aminoadamantanes affect communication between nerve cells by supporting neurotransmission of monoamines. Clinical studies have found that these drugs benefit patients with chronic neurodegenerative diseases, who have depression, fatigue, loss of attention or concentration deficits. These brain function problems may also appear to some extent due to COVID-19 infection. We suggest that aminoadamantanes could improve these problems in COVID-19 patients in both the short and long term. Clinical research is needed to confirm this hypothesis. Article highlights The aminoadamantanes, amantadine, and memantine, antagonize the neuronal N-methyl-D-aspartate receptor function and modify neurotransmission of monoamines. Amantadine ameliorates impaired motor behavior in patients with Parkinson’s disease and improves fatigue syndromes Memantine is well known for beneficial effects for some aspects of cognition and behavior, particularly in dementia. COVID-19 infections may worsen alertness, attention, cognitive abilities, and mood as short- and long-term consequences. Therefore, amantadine and memantine may be beneficial for the treatment of long-covid syndrome We suggest that intake of either amantadine or memantine as therapy for mental consequences of COVID-19 infections, but we emphasize that future clinical trials are needed to confirm these hypothetical considerations. publisher: Taylor & Francis _eprint: https://doi.org/10.1080/17512433.2023.2176301 PMID: 36726198
303	Ce301		Cavalcante, Tahissa Frota; Lourenço, Caroline Evaristo; Ferreira, José Erivelton de Souza Maciel; Oliveira, Lídia Rocha; Neto, João Cruz; Amaro, Josemberg Pereira; Moreira, Rafaella Pessoa	Models of Support for Caregivers and Patients with the Post-COVID-19 Condition: A Scoping Review	https://doi.org/10.3390/ijerph20032563	Published	2023-01-01	Review	https://www.mdpi.com/1660-4601/20/3/2563	Background: In December 2019, an outbreak of the coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), occurred in the city of Wuhan, China. On 30 January 2020, the World Health Organization declared the outbreak a public health emergency of international concern. In October 2021, with the advancement of the disease, the World Health Organization defined the post-COVID-19 condition. The post-COVID-19 condition occurs in individuals with a history of probable or confirmed infection with SARS-CoV-2, usually 3 months after the onset of the disease. The chronicity of COVID-19 has increased the importance of recognizing caregivers and their needs. Methods: We conducted a scoping review following international guidelines to map the models of support for caregivers and patients with the post-COVID-19 condition. The searches were conducted in electronic databases and the grey literature. The Population, Concept, and Context framework was used: Population: patients with the post-COVID-19 condition and caregivers; Concept: models of caregiver and patient support; and Context: post-COVID-19 condition. A total of 3258 records were identified through the electronic search, and 20 articles were included in the final sample. Results: The studies approached existing guidelines and health policies for post-COVID-19 condition patients and support services for patients and home caregivers such as telerehabilitation, multidisciplinary care, hybrid models of care, and follow-up services. Only one study specifically addressed the home caregivers of patients with this clinical condition. Conclusions: The review indicates that strategies such as telerehabilitation are effective for training and monitoring the patient–family dyad, but the conditions of access and digital literacy must be considered.
304	Ce302		Wilmshurst, Peter; Bewley, Susan; Murray, Patricia	Hyperbaric oxygen therapy for the treatment of long COVID	https://doi.org/10.7861/clinmed.Let.23.1.2	Published	2023-01-01	Article	https://www.rcpjournals.org/content/clinmedicine/23/1/99.2	A number of other hyperbaric facilities offer private HBOT for treatment of diseases for which there is neither evidence of efficacy nor a plausible hypothesis for a therapeutic mechanism. These include Alzheimer's disease, autism, cancers, depression, HIV/AIDS, Lyme disease and Parkinson's disease. Some facilities provide HBOT for multiple sclerosis although 12 randomised trials have identified no clinically significant benefit.2 This report states that 10 patients received 10 sessions of HBOT at 2.4 atmospheres. Only one author, who works at the Midlands Diving Chamber, treated the patients and he performed the pre- and post-treatment assessments of fatigue and cognitive scoring. The remaining 10 authors, who work at the University Hospitals Coventry and Warwickshire NHS Trust, analysed the data (which we estimate should have taken one person one day). The article reports that HBOT yielded significant improvements in fatigue scale, global cognition, executive function, attention, information processing and verbal function. The authors conclude that the results suggest potential benefits of HBOT in the treatment of long COVID. We believe it is unacceptable that this experimental non-comparative efficacy trial had ethics approval only for the data analysis. It did not have ethics approval for the exposure of patients to the unproven use of HBOT in a clinical trial. If the patients were not told that they were participating in a research clinical trial, they did not give adequately informed consent. HBOT involves risks of barotrauma to lungs and ears, and oxygen-induced pulmonary pneumonitis and neurological toxicity. The latter causes convulsions with the risk of aspiration for patients wearing a face mask or hood in the hyperbaric chamber. The trial was not blinded for either patients or the treating doctor, who performed the assessment in the private facility. Whether the research was funded by the subjects paying for ‘private treatment’ is not stated. Placebo effects are likely as HBOT facilities are highly technical. Patients are locked in a hyperbaric chamber and usually wear a mask or hood. They experience pressure sensations in their ears and temperature alterations as ambient pressure in the chamber changes. The Midlands Diving Chamber now cites this paper on its website as evidence of efficacy of HBOT in long COVID to attract paying customers.3 We believe that Clinical Medicine should publish an expression of concern about this paper whilst the journal investigates whether there was ethical approval for the actual research and not just the analysis. If there was not, the article should be retracted.Publisher: Royal College of Physicians section: Letters to the editor PMID: 36697009
305	Ce303		Marshall-Andon, Tess; Walsh, Sebastian; Berger-Gillam, Tara; Pari, Anees Ahmed Abdul	Systematic review of post-COVID-19 syndrome rehabilitation guidelines	https://doi.org/10.1136/ihj-2021-000100	Published	2023-02-01	Review	https://ihj.bmj.com/content/4/1/e000100	Introduction Post-COVID-19 syndrome is associated with significant health and potential socioeconomic burden. Due to its novel nature, there is a lack of clarity over best practice for the rehabilitation of patients with ongoing or new symptoms following acute COVID-19 infection. We conducted a systematic review of clinical and service guidelines for post-COVID-19 syndrome rehabilitation. Methods This review was registered on PROSPERO and is reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included guidelines formally published or endorsed by a recognised professional body, covering rehabilitation of people with symptoms following resolution of acute COVID-19 infection. We searched Medline, Embase, PsycINFO, CINAHL, Web of Science, NHS Evidence, MedRxiv, PsyArXiv and Google for terms related to COVID-19, rehabilitation and guideline. Two reviewers independently screened articles for inclusion, data extracted and quality assessed using the AGREE II and AGREE-REX tools for clinical guidelines and the AGREE-HS tool for service guidelines. We included guidelines of sufficient quality in a narrative synthesis. Results We identified 12 790 articles, of which 37 guidelines (19 clinical only, 7 service only and 11 combined clinical and service) were included. Guidelines covered a range of countries, rehabilitation types, populations and rehabilitation settings. Synthesis of clinical guidelines (n=4) was structured following the patient pathway, from identification, to assessment, treatment and discharge, with consideration of specific patient groups. Synthesis of service guidelines (n=8) was structured according to the Donabedian framework. Discussion Though the available post-COVID-19 syndrome rehabilitation guidelines were generally of poor quality, there was a high degree of consensus regarding the breadth of symptoms, the need for holistic assessment by a broad multidisciplinary team and person-centred care. There was less clarity on management options, measuring outcomes and discharge criteria. PROSPERO registration number CRD42021236049.
306	Ce304		Conti, Valeria; Corbi, Graziamaria; Sabbatino, Francesco; De Pascale, Domenico; Sellitto, Carmine; Stefanelli, Berenice; Bertini, Nicola; De Simone, Matteo; Liguori, Luigi; Di Paola, Ilenia; De Bernardo, Maddalena; Tesse, Angela; Rosa, Nicola; Pagliano, Pasquale; Filippelli, Amelia	Long COVID: Clinical Framing, Biomarkers, and Therapeutic Approaches	https://doi.org/10.3390/jpm13020334	Published	2023-02-01	Review	https://www.mdpi.com/2075-4426/13/2/334	More than two years after the onset of the COVID-19 pandemic, healthcare providers are facing an emergency within an emergency, the so-called long COVID or post-COVID-19 syndrome (PCS). Patients diagnosed with PCS develop an extended range of persistent symptoms and/or complications from COVID-19. The risk factors and clinical manifestations are many and various. Advanced age, sex/gender, and pre-existing conditions certainly influence the pathogenesis and course of this syndrome. However, the absence of precise diagnostic and prognostic biomarkers may further complicate the clinical management of patients. This review aimed to summarize recent evidence on the factors influencing PCS, possible biomarkers, and therapeutic approaches. Older patients recovered approximately one month earlier than younger patients, with higher rates of symptoms. Fatigue during the acute phase of COVID-19 appears to be an important risk factor for symptom persistence. Female sex, older age, and active smoking are associated with a higher risk of developing PCS. The incidence of cognitive decline and the risk of death are higher in PCS patients than in controls. Complementary and alternative medicine appears to be associated with improvement in symptoms, particularly fatigue. The heterogeneous nature of post-COVID symptoms and the complexity of patients with PCS, who are often polytreated due to concomitant clinical conditions, suggest a holistic and integrated approach to provide useful guidance for the treatment and overall management of long COVID.
307	Ce305		Duñabeitia, Jon Andoni; Mera, Francisco; Baro, Óscar; Jadad-Garcia, Tamen; Jadad, Alejandro R.	Personalized Computerized Training for Cognitive Dysfunction after COVID-19: A Before-and-After Feasibility Pilot Study	https://doi.org/10.3390/ijerph20043100	Published	2023-01-01	Study	https://www.mdpi.com/1660-4601/20/4/3100	The current pilot study was set to evaluate the feasibility and potential benefit of a personalized computerized cognitive training (CCT) intervention to improve cognitive function among people living with post-acute sequelae of COVID-19 (PASC). Seventy three adults who self-reported cognitive dysfunction more than 3 months after a diagnosis of COVID-19 took part in an 8-week training study. Participants’ general cognitive function was assessed before they completed as many cognitive daily training sessions as they wished during an 8-week period, using a personalized CCT application at home. At the end of this period, participants repeated the general cognitive function assessment. The differences between the scores at 8 weeks and baseline in five cognitive domains (attention, memory, coordination, perception, reasoning), complemented with analyses of the changes based on the participants’ age, training time, self-reported health level at baseline and time since the initial COVID-19 infection. Participants had significant cognitive dysfunction and self-reported negative health levels at baseline. Most of the participants obtained higher scores after CCT in each of the domains as compared with baseline. The magnitude of this score increase was high across domains. It is concluded that a self-administered CCT based on gamified cognitive tasks could be an effective way to ameliorate cognitive dysfunction in persons with PASC. The ClinicalTrials.gov identifier is NCT05571852.
308	Ce306		Mey, Jacob T.; Kirwan, John P.; Axelrod, Christopher L.	The Role of Nutrition in Mitigating the Effects of COVID-19 from Infection through PASC	https://doi.org/10.3390/nu15040866	Published	2023-01-01	Review	https://www.mdpi.com/2072-6643/15/4/866	The expansive and rapid spread of the SARS-CoV-2 virus has resulted in a global pandemic of COVID-19 infection and disease. Though initially perceived to be acute in nature, many patients report persistent and recurrent symptoms beyond the infectious period. Emerging as a new epidemic, “long-COVID”, or post-acute sequelae of coronavirus disease (PASC), has substantially altered the lives of millions of people globally. Symptoms of both COVID-19 and PASC are individual, but share commonality to established respiratory viruses, which include but are not limited to chest pain, shortness of breath, fatigue, along with adverse metabolic and pulmonary health effects. Nutrition plays a critical role in immune function and metabolic health and thus is implicated in reducing risk or severity of symptoms for both COVID-19 and PASC. However, despite the impact of nutrition on these key physiological functions related to COVID-19 and PASC, the precise role of nutrition in COVID-19 infection and PASC onset or severity remains to be elucidated. This narrative review will discuss established and emerging nutrition approaches that may play a role in COVID-19 and PASC, with references to the established nutrition and clinical practice guidelines that should remain the primary resources for patients and practitioners.
309	Ce307		Di Nicola, Marco; Pepe, Maria; Montanari, Silvia; Spera, Maria Chiara; Panaccione, Isabella; Simonetti, Alessio; Sani, Gabriele	Vortioxetine improves physical and cognitive symptoms in patients with post-COVID-19 major depressive episodes	https://doi.org/10.1016/j.euroneuro.2023.02.006	Published	2023-05-01	Study	https://www.sciencedirect.com/science/article/pii/S0924977X23000238	Major Depressive Episodes (MDE) following COVID-19 are frequent, can have a characteristic clinical picture, and are associated with immune-inflammatory changes. Vortioxetine is known to improve physical and cognitive performance in patients with depression and shows anti-inflammatory and anti-oxidative activities. This study aimed to retrospectively evaluate the effects of vortioxetine after 1 and 3 months of treatment in 80 patients (44.4% males, 54±17.2 years) with post-COVID-19 MDE. The primary outcome was improvement in physical and cognitive symptoms measured by specific items of Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale (HARS), Short Form-36 Health Survey Questionnaire (SF-36), Digit Symbol Substitution Test (DSST), Perceived Deficits Questionnaire for Depression (PDQ-D5). Changes in mood, anxiety, anhedonia, sleep, and quality of life were also investigated, as well as the underlying inflammatory status. Results show that, alongside reduction of depressive symptoms (HDRS, p<0.001), vortioxetine (mean dose: 10.1±4.1 mg/day) significantly improved physical features (all measurements p<0.001) and cognitive functioning (DDST, p=0.02; PDQ-D5, p<0.001) throughout treatment. We also observed significant reductions in inflammatory indexes. Therefore, vortioxetine might be a favorable therapeutic choice in post-COVID-19 patients with MDE because of its beneficial effects on physical complaints and cognition, features that appear to be specifically affected in relation to SARS-CoV-2 infection, and its good safety/tolerability profile. High prevalence and clinical and socioeconomic implications of COVID-19 consequences are a major public health concern and developing tailored, safe interventions is crucial to promote full functional recovery.
310	Ce308		Barnes, Henry W.; Demirdjian, Sally; Haddock, Naomi L.; Kaber, Gernot; Martinez, Hunter A.; Nagy, Nadine; Karmouty-Quintana, Harry; Bollyky, Paul L.	Hyaluronan in the pathogenesis of acute and post-acute COVID-19 infection	https://doi.org/10.1016/j.matbio.2023.02.001	Published	2023-02-01	Review	https://www.sciencedirect.com/science/article/pii/S0945053X23000112	Highlights •Hyaluronan (HA) is abundant in the sputum and serum of patients with COVID-19 acute respiratory distress syndrome (ARDS). •There are suggestions that HA may also be present in post-acute SARS-CoV-2 infection (PASC), also known as “long COVID”. •It may be possible to target HA in the lung therapeutically. Oral 4-MU has recently been shown to inhibit HA synthesis in the lung of healthy human patients and is under evaluation in a clinical trial in china in COVID-19. Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged as the cause of a global pandemic. Infection with SARS-CoV-2 can result in COVID-19 with both acute and chronic disease manifestations that continue to impact many patients long after the resolution of viral replication. There is therefore great interest in understanding the host factors that contribute to COVID-19 pathogenesis. In this review, we address the role of hyaluronan (HA), an extracellular matrix polymer with roles in inflammation and cellular metabolism, in COVID-19 and critically evaluate the hypothesis that HA promotes COVID-19 pathogenesis. We first provide a brief overview of COVID-19 infection. Then we briefly summarize the known roles of HA in airway inflammation and immunity. We then address what is known about HA and the pathogenesis of COVID-19 acute respiratory distress syndrome (COVID-19 ARDS). Next, we examine potential roles for HA in post-acute SARS-CoV-2 infection (PASC), also known as “long COVID” as well as in COVID-associated fibrosis. Finally, we discuss the potential therapeutics that target HA as a means to treat COVID-19, including the repurposed drug hymecromone (4-methylumbelliferone). We conclude that HA is a promising potential therapeutic target for the treatment of COVID-19.
311	Ce309		Akanchise, Thelma; Angelova, Angelina	Potential of Nano-Antioxidants and Nanomedicine for Recovery from Neurological Disorders Linked to Long COVID Syndrome	https://doi.org/10.3390/antiox12020393	Published	2023-02-01	Article	https://www.mdpi.com/2076-3921/12/2/393	Long-term neurological complications, persisting in patients who cannot fully recover several months after severe SARS-CoV-2 coronavirus infection, are referred to as neurological sequelae of the long COVID syndrome. Among the numerous clinical post-acute COVID-19 symptoms, neurological and psychiatric manifestations comprise prolonged fatigue, “brain fog”, memory deficits, headache, ageusia, anosmia, myalgias, cognitive impairments, anxiety, and depression lasting several months. Considering that neurons are highly vulnerable to inflammatory and oxidative stress damages following the overproduction of reactive oxygen species (ROS), neuroinflammation and oxidative stress have been suggested to dominate the pathophysiological mechanisms of the long COVID syndrome. It is emphasized that mitochondrial dysfunction and oxidative stress damages are crucial for the pathogenesis of neurodegenerative disorders. Importantly, antioxidant therapies have the potential to slow down and prevent disease progression. However, many antioxidant compounds display low bioavailability, instability, and transport to targeted tissues, limiting their clinical applications. Various nanocarrier types, e.g., liposomes, cubosomes, solid lipid nanoparticles, micelles, dendrimers, carbon-based nanostructures, nanoceria, and other inorganic nanoparticles, can be employed to enhance antioxidant bioavailability. Here, we highlight the potential of phytochemical antioxidants and other neuroprotective agents (curcumin, quercetin, vitamins C, E and D, melatonin, rosmarinic acid, N-acetylcysteine, and Ginkgo Biloba derivatives) in therapeutic strategies for neuroregeneration. A particular focus is given to the beneficial role of nanoparticle-mediated drug-delivery systems in addressing the challenges of antioxidants for managing and preventing neurological disorders as factors of long COVID sequelae.
312	Ce310		Colzato, Lorenza S.; Elmers, Julia; Beste, Christian; Hommel, Bernhard	A Prospect to Ameliorate Affective Symptoms and to Enhance Cognition in Long COVID Using Auricular Transcutaneous Vagus Nerve Stimulation	https://doi.org/10.3390/jcm12031198	Published	2023-01-01	Article	https://www.mdpi.com/2077-0383/12/3/1198	Long COVID, the postviral disorder caused by COVID-19, is expected to become one of the leading causes of disability in Europe. The cognitive consequences of long COVID have been described as “brain fog” and characterized by anxiety and depression, and by cognitive deficits. Long COVID is assumed to be a complex condition arising from multiple causes, including persistent brainstem dysfunction and disrupted vagal signaling. We recommend the potential application of auricular transcutaneous vagus nerve stimulation (atVNS) as an ADD-ON instrument to compensate for the cognitive decline and to ameliorate affective symptoms caused by long COVID. This technique enhances vagal signaling by directly activating the nuclei in the brainstem, which are hypoactive in long COVID to enhance mood and to promote attention, memory, and cognitive control—factors affected by long COVID. Considering that atVNS is a non-pharmacological intervention, its ADD-ON to standard pharmaceutical agents will be useful for non-responders, making of this method a suitable tool. Given that atVNS can be employed as an ecological momentary intervention (EMI), we outline the translational advantages of atVNS in the context of accelerating the cognitive and affective recovery from long COVID.
313	Ce311		Souissi, Amine; Dergaa, Ismail; Romdhani, Mohamed; Ghram, Amine; Irandoust, Khadijeh; Chamari, Karim; Saad, Helmi Ben	Can melatonin reduce the severity of post-COVID-19 syndrome?	https://doi.org/10.17179/excli2023-5864	Published	2023-02-02	Review	https://www.excli.de/index.php/excli/article/view/5864	This short review aimed at (i) providing an update on the health benefits associated with melatonin supplementation, while (ii) considering future potential research directions concerning melatonin supplementation use relative to Coronavirus disease of 2019 (COVID-19). A narrative review of the literature was undertaken to ascertain the effect of exogenous melatonin administration on humans. Night-time melatonin administration has a positive impact on human physiology and mental health. Indeed, melatonin (i) modulates the circadian components of the sleep-wake cycle; (ii) improves sleep efficiency and mood status; (iii) improves insulin sensitivity; and (iv) reduces inflammatory markers and oxidative stress. Melatonin has also remarkable neuroprotective and cardioprotective effects and may therefore prevent deterioration caused by COVID-19. We suggest that melatonin could be used as a potential therapy in the post-COVID-19 syndrome, and therefore call for action the research community to investigate on the potential use of exogenous melatonin to enhance the quality of life in patients with post-COVID-19 syndrome.
314	Ce312		Buchhorn, Reiner	Therapeutic Approaches to Dysautonomia in Childhood, with a Special Focus on Long COVID	https://doi.org/10.3390/children10020316	Published	2023-02-01	Study	https://www.mdpi.com/2227-9067/10/2/316	Background: Dysautonomia seems to be important for the pathophysiology of psychosomatic diseases and, more recently, for long COVID. This concept may explain the clinical symptoms and could help open new therapeutic approaches. Methods: We compared our data from an analysis of heart rate variability (HRV) in an active standing test in 28 adolescents who had developed an inappropriate sinus tachycardia (IST, n = 13) or postural orthostatic tachycardia syndrome (POTS, n = 15) after contracting COVID-19 disease and/or vaccination with 64 adolescents from our database who developed dysautonomia due to psychosomatic diseases prior to the COVID-19 pandemic. We prove the effects of our treatment: omega-3 fatty acid supplementation (O3-FA, n = 18) in addition to propranolol (low dose, up to 20-20-0 mg, n = 32) or ivabradine 5-5-0 mg (n = 17) on heart rate regulation and heart rate variability (HRV). Results: The HRV data were not different between the adolescents with SARS-CoV-2-related disorders and the adolescents with dysautonomia prior to the pandemic. The heart rate increases in children with POTS while standing were significantly lower after low-dose propranolol (27.2 ± 17.4 bpm**), ivabradine (23.6 ± 8.12 bpm), and O-3-FA (25.6 ± 8.4 bpm). The heart rate in children with IST while lying/standing was significantly lower after propranolol (81.6 ± 10.1 bpm/101.8 ± 18.8), ivabradine (84.2 ± 8.4 bpm/105.4 ± 14.6), and O-3-FA (88.6 ± 7.9 bpm/112.1/14.9*). Conclusions: The HRV data of adolescents with dysautonomia after COVID-19 disease/vaccination are not significantly different from a historical control of adolescents with dysautonomia due to psychosomatic diseases prior to the pandemic. Low-dose propranolol > ivabradine > omega-3 fatty acids significantly decrease elevated heart rates in patients with IST and the heart rate increases in patients with POTS and may be beneficial in these children with dysautonomia.
315	Ce313		Chandan, Joht Singh; Brown, Kirsty R.; Simms-Williams, Nikita; Bashir, Nasir Z.; Camaradou, Jenny; Heining, Dominic; Turner, Grace M.; Rivera, Samantha Cruz; Hotham, Richard; Minhas, Sonica; Nirantharakumar, Krishnarajah; Sivan, Manoj; Khunti, Kamlesh; Raindi, Devan; Marwaha, Steven; Hughes, Sarah E.; McMullan, Christel; Marshall, Tom; Calvert, Melanie J.; Haroon, Shamil; Aiyegbusi, Olalekan Lee	Non-Pharmacological Therapies for Post-Viral Syndromes, Including Long COVID: A Systematic Review	https://doi.org/10.3390/ijerph20043477	Published	2023-01-01	Review	https://www.mdpi.com/1660-4601/20/4/3477	Background: Post-viral syndromes (PVS), including Long COVID, are symptoms sustained from weeks to years following an acute viral infection. Non-pharmacological treatments for these symptoms are poorly understood. This review summarises the evidence for the effectiveness of non-pharmacological treatments for PVS. Methods: We conducted a systematic review to evaluate the effectiveness of non-pharmacological interventions for PVS, as compared to either standard care, alternative non-pharmacological therapy, or placebo. The outcomes of interest were changes in symptoms, exercise capacity, quality of life (including mental health and wellbeing), and work capability. We searched five databases (Embase, MEDLINE, PsycINFO, CINAHL, MedRxiv) for randomised controlled trials (RCTs) published between 1 January 2001 to 29 October 2021. The relevant outcome data were extracted, the study quality was appraised using the Cochrane risk-of-bias tool, and the findings were synthesised narratively. Findings: Overall, five studies of five different interventions (Pilates, music therapy, telerehabilitation, resistance exercise, neuromodulation) met the inclusion criteria. Aside from music-based intervention, all other selected interventions demonstrated some support in the management of PVS in some patients. Interpretation: In this study, we observed a lack of robust evidence evaluating the non-pharmacological treatments for PVS, including Long COVID. Considering the prevalence of prolonged symptoms following acute viral infections, there is an urgent need for clinical trials evaluating the effectiveness and cost-effectiveness of non-pharmacological treatments for patients with PVS. Registration: The study protocol was registered with PROSPERO [CRD42021282074] in October 2021 and published in BMJ Open in 2022.
316	Ce314		Adamová, Andrea; Laskov, Olga; Biačková, Nina; Novák, Tomáš; Voráčková, Veronika; Renka, Jiří; Klírová, Monika	Transcranial Direct Current Stimulation (TDCS) As A Therapeutic Intervention For Post-Acute Neuropsychiatric Sequelae Of SARS-COV-2	https://doi.org/10.1016/j.brs.2023.01.394	Published	2023-01-01	Study	https://www.brainstimjrnl.com/article/S1935-861X(23)00396-0/fulltext	Background: There is a significant lack of effective treatment strategies for post-acute sequelae of SARS-Cov-2 (PASC). Neuropsychiatric (NP) symptoms, including functional impairment, emotional, and cognitive dysregulation, are among the most common manifestations of PASC. Non-invasive brain stimulation (NIBS) could represent a treatment method for post-acute and chronic stages of COVID-19. The first clinical results indicate the therapeutic potential of transcranial direct current stimulation (tDCS) in influencing NP symptoms of PASC associated with the advantage of portable devices with the possibility of home use. Methods: A four-week, double-blind, randomized, placebo-controlled, parallel study was used to compare the efficacy (response to the treatment, effect duration) and safety of a 4-week active prefrontal cortex (PFC) tDCS (20 tDCS applications with anode placement at F3; 2 mA, 30 min/tDCS session) to placebo-tDCS in the treatment of NP symptoms of PASC. Patients were clinically assessed by “The Fatigue Impact Scale“ (FIS) and “The post-COVID-19 Symptoms Assessment Questionnaire“ (A-PASC), at baseline, after two weeks, and at the end of four weeks of treatment. Results: 15 out of 34 enrolled patients were included in the Intention-to-treat (ITT) analysis. The treatment groups did not differ in age, gender, and at baseline FIS and A-PASC. PFC-tDCS (did not) showed better improvement (as assessed by FIS and A_PASC) compared to sham tDCS after four weeks. However, the study is still in progress and the results will be updated. No major side effects were observed during and after the treatment. publisher: Elsevier
317	Ce315		Vidal, Kallene; Cavendish, Beatriz; Lima, Alisson Lima; Bertola, Laiss; Charveth, Leigh; Bikson, Marom; Brunoni, Andre	Combination of transcranial direct current stimulation with online cognitive training improves symptoms of Post-acute Sequelae of COVID-19: a case series	https://doi.org/10.1016/j.brs.2023.01.348	Published	2023-01-01	Study	https://www.brainstimjrnl.com/article/S1935-861X(23)00350-9/fulltext	Post-Acute Sequelae of COVID-19 (PASC) has been associated with cognitive impairment and complains in up to 90% of individuals after the infection by COVID 19. In this context, there is an urgent need to develop treatments for this disorder. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation intervention that can modulate neuronal excitability and improve PASC neurocognitive symptoms. Here, we investigated the effects of this intervention in a case series of four patients with cognitive symptoms using the Assessment of PASC (A-PASC) inventory. The intervention consisted of 20-minute, 2mA, 20 daily sessions of bilateral prefrontal (anodal-left/cathodal-right) tDCS (1x1 Mini-CT, Soterix Medical, New York, NY) plus online cognitive training using the BrainHQ platform (Posit Science, San Francisco, Glenn Smith). Several neuropsychological domains were assessed at baseline and endpoint. After treatment ,all participants described cognitive and emotional complaints decreasing. The neuropsychological assessment showed that the participants performed better for delayed and immediate recall in the verbal episodic memory task. They showed an improving trend in lexicon assessment, and in phonemic verbal fluency. The same was observed for the sustained attention task. Also, the participants showed a trend in becoming faster and more accurate in processing speed, and in executive function (inhibitory control, cognitive flexibility and time management). These are preliminary results from a pilot study that preceded an ongoing, double-blinded, randomized controlled trial comparing the effects of cognitive training combined with sham or active tDCS at University of São Paulo, Brazil. publisher: Elsevier
318	Ce316		Biačková, Nina; Klírová, Monika; Voráčková, Veronika; Adamová, Andrea; Novák, Tomáš; Renka, Jiří; Laskov, Olga	Treatment of cognitive symptoms in post-COVID-19 syndrome – a transcranial direct current stimulation (tDCS) approach	https://doi.org/10.1016/j.brs.2023.01.391	Published	2023-01-01	Study	https://www.brainstimjrnl.com/article/S1935-861X(23)00393-5/fulltext	Background: Despite the acute infection's remission, COVID-19 is associated with clinically severe residual symptoms (i.e., post-COVID-19 syndrome). One of the most prevalent and incapacitating symptoms of the syndrome is fatigue, accompanied by cognitive impairment. Very few therapy options are effective for post-acute SARS-Cov-2 sequelae (PASC). There is a possibility that non-invasive brain stimulation methods could become successful and convenient treatment options for post-acute and chronic COVID-19. There are already the first clinical results for the use of transcranial direct current stimulation (tDCS) in the therapy of PASC. Our goal was to study the potential tDCS effect on cognitive impairment in patients with PASC. Methods: We present a four-week, double-blind, randomized, placebo-controlled, parallel study with a 4-week active dorsolateral prefrontal cortex (DLPFC) tDCS (20 tDCS applications; anode on the F3; 2 mA, 30 min/tDCS session). Patients were evaluated with tests measuring attention (digit span forward), working memory (digit span backward), and psychomotor speed (digit symbol substitution test) at baseline, after two weeks, and at the end of four weeks of treatment. The tests were chosen according to previous studies on the assessment of cognitive function in patients after COVID-19. Results: 15 out of 34 enrolled patients were included in Intention-to-treat (ITT) analysis. The treatment groups did not differ in age, gender, and baseline cognitive tests. There wasn’t a significant difference in cognitive tests results between active DLPFC tDCS and sham tDCS after four weeks. However, the study is still in progress and the results will be updated. No major side effects were observed during and after the treatment. publisher: Elsevier
319	Ce317		Seeley, Marie-Claire; Hooper, Matthew; Tan, Jason; Wells, Rachel; Gallagher, Celine; Lau, Dennis H.	Plasma exchange improves cognitive function in long-COVID related postural orthostatic tachycardia syndrome and autoimmune neurological dysfunction: Seeley et al. Plasmapheresis in long-COVID	https://doi.org/10.1016/j.amjmed.2023.01.043	Published	2023-02-21	Study	https://www.amjmed.com/article/S0002-9343(23)00100-6/fulltext
320	Ce318		Fang, Chao; Baz, Sarah; Carpentieri, JD; Sheard, Laura; Newlands, Fiona; Shafran, Roz	Understanding and supporting the long-term effects of COVID-19: A report from the Qualitative Long COVID Research Network in the United Kingdom		Published	2033-02-01	Guidelines	https://www.convalescence.ac.uk/wp-content/uploads/2023/02/Briefing-report.pdf
321	Ce319		Mińko, Alicja; Turoń-Skrzypińska, Agnieszka; Rył, Aleksandra; Szylińska, Aleksandra; Denisewicz, Iwona; Rotter, Iwona	Effects of Comprehensive Rehabilitation on Pulmonary Function in Patients Recovering from COVID-19	https://doi.org/10.3390/ijerph20053985	Published	2023-01-01	Study	https://www.mdpi.com/1660-4601/20/5/3985	The aim of this study is to evaluate the effect of inpatient rehabilitation on pulmonary function in patients recovering from COVID-19, a multifaceted disease caused by the SARS-CoV-2 virus. This aspect of recovery is crucial, as pneumonia associated with this disease can cause lung-function abnormalities with varying degrees of hypoxemia. This study involved 150 patients qualified for inpatient rehabilitation following SARS-CoV-2 infection. Functional assessment of the lungs was performed by spirometry. The mean age of patients was 64.66 (±11.93) years, and the mean body mass index (BMI) was 29.16 (±5.68). The tests showed a statistically significant improvement in spirometric parameters. The rehabilitation program based on aerobic, strength, and endurance exercises improved lung-function parameters in the long term. The improvement in spirometric parameters in patients after COVID-19 may be related to body mass index (BMI).
322	Ce320		Torres-Castro, Rodrigo; Núñez-Cortés, Rodrigo; Larrateguy, Santiago; Alsina-Restoy, Xavier; Barberà, Joan Albert; Gimeno-Santos, Elena; García, Agustin Roberto; Sibila, Oriol; Blanco, Isabel	Assessment of Exercise Capacity in Post-COVID-19 Patients: How Is the Appropriate Test Chosen?	https://doi.org/10.3390/life13030621	Published	2023-03-01	Review	https://www.mdpi.com/2075-1729/13/3/621	There is a wide range of sequelae affecting COVID-19 survivors, including impaired physical capacity. These sequelae can affect the quality of life and return to work of the active population. Therefore, one of the pillars of following-up is the evaluation of physical capacity, which can be assessed with field tests (such as the six-minute walk test, the one-minute standing test, the Chester step test, and the shuttle walking test) or laboratory tests (such as the cardiopulmonary exercise test). These tests can be performed in different contexts and have amply demonstrated their usefulness in the assessment of physical capacity both in post-COVID-19 patients and in other chronic respiratory, metabolic, cardiologic, or neurologic diseases. However, when traditional tests cannot be performed, physical function can be a good substitute, especially for assessing the effects of an intervention. For example, the Short Physical Performance Battery assessment and the Timed Up and Go assessment are widely accepted in older adults. Thus, the test should be chosen according to the characteristics of each subject.
323	Ce321		Sasaki, Nobuyuki; Yamatoku, Masato; Tsuchida, Tomoya; Sato, Hiroyuki; Yamaguchi, Keiichiro	Effect of Repetitive Transcranial Magnetic Stimulation on Long Coronavirus Disease 2019 with Fatigue and Cognitive Dysfunction	https://doi.org/10.2490/prm.20230004	Published	1905-07-15	Study		Objectives: There is no established treatment for chronic fatigue and various cognitive dysfunctions (brain fog) caused by long coronavirus disease 2019 (COVID-19). We aimed to clarify the effectiveness of repetitive transcranial magnetic stimulation (rTMS) for treating these symptoms.Methods: High-frequency rTMS was applied to occipital and frontal lobes in 12 patients with chronic fatigue and cognitive dysfunction 3 months after severe acute respiratory syndrome coronavirus 2 infection. Before and after ten sessions of rTMS, Brief Fatigue Inventory (BFI), Apathy Scale (AS), and Wechsler Adult Intelligence Scale-fourth edition (WAIS4) were determined and N-isopropyl-p-[123I]iodoamphetamine single photon emission computed tomography (SPECT) was performed.Results: Twelve subjects completed ten sessions of rTMS without adverse events. The mean age of the subjects was 44.3 ± 10.7 years, and the mean duration of illness was 202.4 ± 114.5 days. BFI, which was 5.7 ± 2.3 before the intervention, decreased significantly to 1.9 ± 1.8 after the intervention. The AS was significantly decreased after the intervention from 19.2 ± 8.7 to 10.3 ± 7.2. All WAIS4 sub-items were significantly improved after rTMS intervention, and the full-scale intelligence quotient increased from 94.6 ± 10.9 to 104.4 ± 13.0. Hypoperfusion in the bilateral occipital and frontal lobes observed on SPECT improved in extent and severity after ten sessions of rTMS.Conclusions: Although we are still in the early stages of exploring the effects of rTMS, the procedure has the potential for use as a new non-invasive treatment for the symptoms of long COVID.
324	Ce322		Sadeghdoust, Mohammadamin; Aligolighasemabadi, Farnaz; Dehesh, Tania; Taefehshokr, Nima; Sadeghdoust, Adel; Kotfis, Katarzyna; Hashemiattar, Amirhossein; Ravandi, Amir; Aligolighasemabadi, Neda; Vakili, Omid; Grabarek, Beniamin; Staszkiewicz, Rafał; Łos, Marek J.; Mokarram, Pooneh; Ghavami, Saeid	The Effects of Statins on Respiratory Symptoms and Pulmonary Fibrosis in COVID-19 Patients with Diabetes Mellitus: A Longitudinal Multicenter Study	https://doi.org/10.1007/s00005-023-00672-1	Published	2023-02-28	Study	https://doi.org/10.1007/s00005-023-00672-1	The aim of this prospective cohort study was to explore the effect of statins on long-term respiratory symptoms and pulmonary fibrosis in coronavirus disease 2019 (COVID-19) patients with diabetes mellitus (DM). Patients were recruited from three tertiary hospitals, categorized into Statin or Non-statin groups, and assessed on days 0, 28, and 90 after symptoms onset to record the duration of symptoms. Pulmonary fibrosis was scored at baseline and follow-up time points by high-resolution computed tomography scans. Each group comprised 176 patients after propensity score matching. Data analysis revealed that the odds of having cough and dyspnea were significantly higher in the Non-statin group compared to the Statin group during the follow-up period. Overall, there was no significant difference in the change in pulmonary fibrosis score between groups. However, Non-statin patients with > 5 years of DM were more likely to exhibit a significantly higher fibrosis score during the follow-up period as compared to their peers in the Statin group. Our results suggest that the use of statins is associated with a lower risk of developing chronic cough and dyspnea in diabetic patients with COVID-19, and may reduce pulmonary fibrosis associated with COVID-19 in patients with long-term (> 5 years) DM.
325	Ce323		Sova, Milan; Sovova, Eliska; Ozana, Jaromir; Moravcova, Katarina; Sovova, Marketa; Jelinek, Libor; Mizera, Jan; Genzor, Samuel	Post-COVID Syndrome and Cardiorespiratory Fitness—26-Month Experience of Single Center	https://doi.org/10.3390/life13030684	Published	2023-03-01	Study	https://www.mdpi.com/2075-1729/13/3/684	Introduction: Persistent post-COVID syndrome, also referred to as long COVID, is a pathologic entity that involves persistent physical, medical, and cognitive sequelae following COVID-19. Decreased fitness has repeatedly been reported in numerous studies dealing with post-COVID syndrome, however, it is still not fully clear which groups of patients may be more susceptible for persisting symptoms. Aim: The aim of our study was to evaluate the number of post-COVID patients with cardiac symptoms, where these patients were evaluated by CPET and the results compared with a control group of patients. Methods: Follow-up of patients in post-COVID outpatient clinic from 1 March 2020 to 31 May 2022. Inclusion criteria were positive PCR test for SARS-CoV-2 and age 18–100. The initial examination was performed 4–12 weeks after the disease onset. All patients with possible cardiac symptoms had completed cardiopulmonary exercise testing. The control group was randomly selected from a database of clients in 2019, with the preventive reason for evaluation. Results: From 1 March 2020 to 31 May 2022, 2732 patients (45.7% males) were evaluated with a mean age of 54.6 ± 14.7. CPET was indicated only in 97 patients (3.5%). Seventy-four patients (26 male) achieved the exercise maximum and a comparison were made with a control group (same age (p = 0.801), BMI (p = 0.721), and sex ratio). No significant dependence between the parameter VO2 max mL/kg/min and post-COVID disability was demonstrated (p = 0.412). Spearman’s correlation analysis did not show a significant relationship between the parameter VO2 max mL/kg/min and the severity of COVID-19 (p = 0.285). Conclusions: Cardiac symptoms occurred in only a small percentage of patients in our study. There is a need for further studies that would objectively evaluate the effect of COVID-19 disease on the patient’s health.
326	Ce324		Patterson, Bruce K.; Yogendra, Ram; Guevara-Coto, Jose; Mora-Rodriguez, Rodrigo A.; Osgood, Eric; Bream, John; Parikh, Purvi; Kreimer, Mark; Jeffers, Devon; Rutland, Cedric; Kaplan, Gary; Zgoda, Michael	Case series: Maraviroc and pravastatin as a therapeutic option to treat long COVID/Post-acute sequelae of COVID (PASC)	https://doi.org/10.3389/fmed.2023.1122529	Published	2023-02-08	Case Series	https://www.frontiersin.org/articles/10.3389/fmed.2023.1122529	Post-acute sequelae of COVID (PASC), or long COVID, is a multisystem complication of SARS-CoV-2 infection that continues to debilitate millions worldwide thus highlighting the public health importance of identifying effective therapeutics to alleviate this illness. One explanation behind PASC may be attributed to the recent discovery of persistent S1 protein subunit of SARS-CoV-2 in CD16+ monocytes up to 15 months after infection. CD16+ monocytes, which express both CCR5 and fractalkine receptors (CX3CR1), play a role in vascular homeostasis and endothelial immune surveillance. We propose targeting these receptors using the CCR5 antagonist, maraviroc, along with pravastatin, a fractalkine inhibitor, could disrupt the monocytic-endothelial-platelet axis that may be central to the etiology of PASC. Using five validated clinical scales (NYHA, MRC Dyspnea, COMPASS-31, modified Rankin, and Fatigue Severity Score) to measure 18 participants’ response to treatment, we observed significant clinical improvement in 6 to 12 weeks on a combination of maraviroc 300 mg per oral twice a day and pravastatin 10 mg per oral daily. Subjective neurological, autonomic, respiratory, cardiac and fatigue symptoms scores all decreased which correlated with statistically significant decreases in vascular markers sCD40L and VEGF. These findings suggest that by interrupting the monocytic-endothelial-platelet axis, maraviroc and pravastatin may restore the immune dysregulation observed in PASC and could be potential therapeutic options. This sets the framework for a future double-blinded, placebo-controlled randomized trial to further investigate the drug efficacy of maraviroc and pravastatin in treating PASC.
327	Ce325		Zulbaran-Rojas, Alejandro; Lee, Myeounggon; Bara, Rasha O.; Flores-Camargo, Areli; Spitz, Gil; Finco, M. G.; Bagheri, Amir Behzad; Modi, Dipaben; Shaib, Fidaa; Najafi, Bijan	Electrical stimulation to regain lower extremity muscle perfusion and endurance in patients with post-acute sequelae of SARS CoV-2: A randomized controlled trial	https://doi.org/10.14814/phy2.15636	Published	1905-07-15	Trial	https://onlinelibrary.wiley.com/doi/abs/10.14814/phy2.15636	Muscle deconditioning and impaired vascular function in the lower extremities (LE) are among the long-term symptoms experienced by COVID-19 patients with a history of severe illness. These symptoms are part of the post-acute sequelae of Sars-CoV-2 (PASC) and currently lack evidence-based treatment. To investigate the efficacy of lower extremity electrical stimulation (E-Stim) in addressing PASC-related muscle deconditioning, we conducted a double-blinded randomized controlled trial. Eighteen (n = 18) patients with LE muscle deconditioning were randomly assigned to either the intervention (IG) or the control (CG) group, resulting in 36 LE being assessed. Both groups received daily 1 h E-Stim on both gastrocnemius muscles for 4 weeks, with the device functional in the IG and nonfunctional in the CG. Changes in plantar oxyhemoglobin (OxyHb) and gastrocnemius muscle endurance (GNMe) in response to 4 weeks of daily 1 h E-Stim were assessed. At each study visit, outcomes were measured at onset (t0), 60 min (t60), and 10 min after E-Stim therapy (t70) by recording ΔOxyHb with near-infrared spectroscopy. ΔGNMe was measured with surface electromyography at two time intervals: 0–5 min (Intv1) and: 55–60 min (Intv2). Baseline OxyHb decreased in both groups at t60 (IG: p = 0.046; CG: p = 0.026) and t70 (IG = p = 0.021; CG: p = 0.060) from t0. At 4 weeks, the IG's OxyHb increased from t60 to t70 (p < 0.001), while the CG's decreased (p = 0.003). The IG had higher ΔOxyHb values than the CG at t70 (p = 0.004). Baseline GNMe did not increase in either group from Intv1 to Intv2. At 4 weeks, the IG's GNMe increased (p = 0.031), whereas the CG did not change. There was a significant association between ΔOxyHb and ΔGNMe (r = 0.628, p = 0.003) at 4 weeks in the IG. In conclusion, E-Stim can improve muscle perfusion and muscle endurance in individuals with PASC experiencing LE muscle deconditioning.
328	Ce326		Foss, Violeta; Maddie, Nicole; Frankini, Elisabeth; Landman, Scott; Maccagnano, Jennifer; Yao, Sheldon	Covid-19 Fatigue: Diagnosis and Treatment for the Osteopathic Physician	https://doi.org/10.33181/13090	Published	2023-03-08	Review	https://www.ofpjournal.com/index.php/ofp/article/view/843	The novel coronavirus disease 2019 (COVID-19) has given rise to a global pandemic, as well as a multitude of long-term sequelae that continue to perplex physicians around the world, including in the United States. Among the most common and impactful long-haul symptoms experienced by survivors is COVID-19 fatigue. This review will use long COVID-19, post-acute COVID-19 syndrome (PCS), and Post-Acute Sequelae of COVID-19 (PASC) as synonymous terms to refer to the chronic symptomatology; chronic fatigue associated with PASC will be referred to as COVID-19 fatigue. While the knowledge and research on the exact pathophysiological mechanisms involved in the disease is still limited, parallels have been drawn between fatigue as a component of long COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Current studies suggest applying principles of pathophysiology, diagnosis, and treatment similar to those for ME/CFS in order to aid in managing chronic fatigue in COVID-19 survivors, particularly in the primary care setting. The osteopathic family physician can use the proposed pharmacologic agents, along with osteopathic manipulative treatment (OMT), as therapeutic modalities that can be tailored to each patient’s unique case. Nevertheless, research on proven successful treatments is still scarce. For that reason, it is essential that COVID-19 fatigue is recognized early, especially since its longitudinal impacts may be debilitating for many. This review of the available literature on COVID-19 fatigue aims to help provide quality care and lessen the disease burden experienced by patients.
329	Ce327		Calvani, Riccardo; Gervasoni, Jacopo; Picca, Anna; Ciciarello, Francesca; Galluzzo, Vincenzo; Coelho-Júnior, Hélio José; Di Mario, Clara; Gremese, Elisa; Lomuscio, Sara; Paglionico, Anna Maria; Santucci, Lavinia; Tolusso, Barbara; Urbani, Andrea; Marini, Federico; Marzetti, Emanuele; Landi, Francesco; Tosato, Matteo	Effects of l-Arginine Plus Vitamin C Supplementation on l-Arginine Metabolism in Adults with Long COVID: Secondary Analysis of a Randomized Clinical Trial	https://doi.org/10.3390/ijms24065078	Published	2023-01-01	Study	https://www.mdpi.com/1422-0067/24/6/5078	Altered l-arginine metabolism has been described in patients with COVID-19 and has been associated with immune and vascular dysfunction. In the present investigation, we determined the serum concentrations of l-arginine, citrulline, ornithine, monomethyl-l-arginine (MMA), and symmetric and asymmetric dimethylarginine (SDMA, ADMA) in adults with long COVID at baseline and after 28-days of l-arginine plus vitamin C or placebo supplementation enrolled in a randomized clinical trial, compared with a group of adults without previous history of SARS-CoV-2-infection. l-arginine-derived markers of nitric oxide (NO) bioavailability (i.e., l-arginine/ADMA, l-arginine/citrulline+ornithine, and l-arginine/ornithine) were also assayed. Partial least squares discriminant analysis (PLS–DA) models were built to characterize systemic l-arginine metabolism and assess the effects of the supplementation. PLS–DA allowed discrimination of participants with long COVID from healthy controls with 80.2 ± 3.0% accuracy. Lower markers of NO bioavailability were found in participants with long COVID. After 28 days of l-arginine plus vitamin C supplementation, serum l-arginine concentrations and l-arginine/ADMA increased significantly compared with placebo. This supplement may therefore be proposed as a remedy to increase NO bioavailability in people with long COVID.
330	Ce328		Quinn, Kieran L.; Cheung, Angela M.; Razak, Fahad	Traiter les symptômes courants et potentiellement modifiables du syndrome post-COVID-19 (COVID-19 de longue durée) chez l’adulte	https://doi.org/10.1503/cmaj.220824-f	Published	2023-03-06	Article	https://www.cmaj.ca/content/195/9/e350	Un plan de reprise progressive des activités et une stratégie de conservation d’énergie sont indiqués pour traiter la fatigue et la malaise post-effort associés à la COVID-19 de longue durée1 Afin d’éviter le déclenchement d’épisodes de malaise post-effort, il faut conseiller aux patients de suivre un programme de reprise des activités structuré fondé sur les symptômes et le niveau de fatigue. Ils doivent apprendre à appliquer des stratégies physiques, émotionnelles et cognitives de conservation d’énergie, en particulier les 4 principes consistant à doser les activités au niveau d’énergie, à accorder la priorité aux activités les plus importantes (en déterminant celles qui doivent être exécutées le jour même et celles qui peuvent être retardées), à adopter une bonne posture pour modifier les activités et les rendre plus faciles à accomplir (p. ex., en position assise), et à planifier leur horaire1. Des interventions psychosociales et des médicaments conformes aux lignes directrices peuvent être prescrits pour traiter les complications de santé mentale de la COVID-19 de longue durée L’anxiété, la dépression et le trouble de stress post-traumatique font partie des manifestations de santé mentale les plus fréquentes de la COVID-19 de longue durée et peuvent être pris en charge en suivant les lignes directrices existantes, qui sont similaires à celles relatives à l’encéphalomyélite myalgique2. Le traitement de la fatigue par la thérapie cognitivo-comportementale est controversé et n’est pas approuvé par la ME Association2. Des exercices de respiration, le positionnement du corps et la réadaptation pulmonaire peuvent atténuer la dyspnée2 Des exercices de respiration profonde ou avec la bouche à demi fermée peuvent atténuer les symptômes de dyspnée légère. L’hypoxémie persistante n’est pas une manifestation fréquente de la COVID-19 de longue durée, mais elle peut être provoquée par une pneumopathie grave ou une pneumonie organisée. Il faut donc orienter rapidement les patients concernés vers un pneumologue et envisager le recours à des services de réadaptation pulmonaire2,3. Des conseils sur l’hygiène du sommeil, les techniques de relaxation et le contrôle des stimuli sont utiles pour les personnes atteintes de troubles du sommeil2 Les troubles du sommeil sont parfois secondaires à l’infection par le SRAS-CoV-2 ou aux effets négatifs de la pandémie2. Ils peuvent être pris en charge par une thérapie cognitivo-comportementale ou l’un des traitements offerts au Canada: eszopiclone, zolpidem ou doxépine4. Des lignes directrices précises existent pour différentes causes de palpitations et tachycardie Les recommandations actuelles pour traiter la tachycardie sinusale inappropriée et le syndrome de tachycardie orthostatique posturale (STOP) comprennent les modifications comportementales, l’apport liquidien, le sel, les bas de contention, les bêtabloquants, l’ivabradine et la midodrine5. publisher: CMAJ section: Pratique PMID: 36878541
331	Ce329		Heining, Dominic	Non-pharmacological therapies for post-viral syndromes, including long COVID: a systematic review.	https://doi.org/10.3390/ijerph20043477	Published	2023-02-16	Review	https://rwt.dspace-express.com/handle/20.500.12687/1443	Background: Post-viral syndromes (PVS), including Long COVID, are symptoms sustained from weeks to years following an acute viral infection. Non-pharmacological treatments for these symptoms are poorly understood. This review summarises the evidence for the effectiveness of non-pharmacological treatments for PVS. Methods: We conducted a systematic review to evaluate the effectiveness of non-pharmacological interventions for PVS, as compared to either standard care, alternative non-pharmacological therapy, or placebo. The outcomes of interest were changes in symptoms, exercise capacity, quality of life (including mental health and wellbeing), and work capability. We searched five databases (Embase, MEDLINE, PsycINFO, CINAHL, MedRxiv) for randomised controlled trials (RCTs) published between 1 January 2001 to 29 October 2021. The relevant outcome data were extracted, the study quality was appraised using the Cochrane risk-of-bias tool, and the findings were synthesised narratively. Findings: Overall, five studies of five different interventions (Pilates, music therapy, telerehabilitation, resistance exercise, neuromodulation) met the inclusion criteria. Aside from music-based intervention, all other selected interventions demonstrated some support in the management of PVS in some patients. Interpretation: In this study, we observed a lack of robust evidence evaluating the non-pharmacological treatments for PVS, including Long COVID. Considering the prevalence of prolonged symptoms following acute viral infections, there is an urgent need for clinical trials evaluating the effectiveness and cost-effectiveness of non-pharmacological treatments for patients with PVS.
332	Ce330		Saif-Ur-Rahman, K. M.; Kothari, Kavita; Sadlier, Corinna; Moriarty, Frank; Movsisyan, Ani; Whelan, Sean; Taneri, Petek E.; Blair, Matthew; Guyatt, Gordon; Devane, Declan	Effect of pharmacological interventions for the treatment of people with post-COVID-19 condition: A rapid review	https://doi.org/10.1002/cesm.12001	Published	1905-07-15	Review	https://onlinelibrary.wiley.com/doi/abs/10.1002/cesm.12001	Objective Little is known about the treatment of post-coronavirus disease 2019 (COVID-19) condition (PCC). This article examines the effectiveness of pharmacological interventions for treating people with PCC. Methods We searched Medline, EMBASE, ClinicalTrials. gov, and the International Clinical Trials Registry Platform. Two independent review authors screened citations, extracted data, and assessed the quality of the included studies. Due to heterogeneity in participants, interventions, and outcomes, we synthesized data narratively. We assessed the certainty of evidence using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). Participants People with PCC. Interventions Pharmacological interventions include corticosteroids, ivabradine, and inhaled hydrogen. Outcome Measures Olfactory function, sinus tachycardia, respiratory function. Results We identified 5 completed studies and 41 ongoing studies. Oral corticosteroids and olfactory training had higher olfactory scores after 10 weeks (MD: 5.60, 95% confidence interval [CI]: 1.41 to 9.79). Patients allocated oral corticosteroid, and nasal irrigation demonstrated improved recovery of olfactory function compared with the control group at 40 days (median 60, interquartile range [IQR]: 40 vs. median 30, IQR: 25, p = 0.024). Patients allocated to topical corticosteroid nasal spray and olfactory training had improved recovery of olfactory function after 2 weeks (median 7, IQR: 5−10 vs. median 5, IQR: 2−8, p = 0.08). Participants allocated to ivabradine had a greater mean reduction in heart rate compared with participants randomized to carvedilol (MD: −4.24, 95% CI: −10.09 to 1.61). Participants allocated to inhaled hydrogen therapy had an improved vital capacity (MD: 0.20, 95% CI: 0.07 to 0.33), forced expiratory volume (MD: 0.19, 95% CI: 0.04 to 0.34), 6-minute walk test (MD: 55.0, 95% CI: 36.04 to 73.96). Conclusions The evidence is of low to very low certainty about the effect of all pharmacological interventions investigated for the treatment of people with PCC. There is currently a significant body of research underway that could expand the evidence to inform treatment decisions on pharmacological interventions for PCC.
333	Ce331		Hashimoto, Kenji	Overview of the potential use of fluvoxamine for COVID-19 and long COVID	https://doi.org/10.1007/s44192-023-00036-3	Published	2023-03-21	Review	https://doi.org/10.1007/s44192-023-00036-3	Coronavirus disease 2019 (COVID-19) has presented a serious worldwide threat to public health since its emergence in late 2019. From a safety point of view, drug repurposing has received particular attention. Several clinical studies have demonstrated that the use of fluvoxamine, a selective serotonin reuptake inhibitor with potent sigma-1 receptor agonism, in the early-stage of infection might be associated with the prevention of clinical deterioration in individuals with SARS-CoV-2 infection, although several reports have shown that a low dose of fluvoxamine may be ineffective. There is increasing evidence that SARS-CoV-2 can cross the blood–brain barrier, resulting in a number of psychiatric and neurologic symptoms in COVID-19 survivors. Importantly, about half of COVID-19 survivors experience a variety of long-term sequelae, including psychiatric and neurologic symptoms, known as long COVID. In this priority review, the author presents an overview of the potential use of fluvoxamine in the treatment of COVID-19 and long COVID.
334	Ce332		Veliz, Philip T.; Zhou, Weijiao; Smith, Sheree; Larson, Janet L.	Substance Use and the Self-Management of Persistent Symptoms of COVID-19	https://doi.org/10.1080/10826084.2023.2184208	Published	2023-03-21	Study	https://doi.org/10.1080/10826084.2023.2184208	Background: Understanding the self-management practices of persistent symptoms of SARS-Cov-2 (COVID-19) is critical given the misinformation that has been presented about this disease in the U.S. The purpose of this descriptive study is to assess the self-management of persistent symptoms of COVID-19 with commonly used and misused substances (i.e., alcohol, marijuana and commonly prescribed medications) among adults in the U.S. Methods: The data for this study comes from a cross-sectional survey of U.S. adults that was designed to broadly assess symptom burden, persistent symptom patterns, self-efficacy for symptom management and self-management strategies among people who experienced persistent/Long COVID. Multiple logistic regression analyses were used to assess how symptom length of COVID-19 was associated with the use of several substances to manage these persistent symptoms. Results: The analysis found that adults who had COVID-19 symptoms that persisted for 13 weeks or longer had higher rates of using alcohol (27.3%), marijuana (30.9%) and prescription tranquilizers (21.4%) to manage these symptoms when compared to their adult peers who had COVID-19 symptoms persist for only 4 weeks or less. For instance, the odds of indicating the use of marijuana (AOR = 4.21 95% CI = 1.68,10.5) to manage COVID-19 related symptoms was roughly four times higher for respondents who had COVID-19 symptoms persist for 13 weeks or longer when compared to respondents whose COVID-19 symptoms persisted for only 4 weeks or less. Conclusion: The findings suggest that screening of substance use disorders should be considered among healthcare providers who are treating adults who have persistent symptoms of COVID-19.
335	Ce333		Kazama, Itsuro	Brain Leukocytes as the Potential Therapeutic Target for Post-COVID-19 Brain Fog	https://doi.org/10.1007/s11064-023-03912-0	Published	2023-03-23	Article	https://doi.org/10.1007/s11064-023-03912-0	After recovering from the acute phase of coronavirus disease 2019 (COVID-19), many patients struggle with additional symptoms of long COVID during the chronic phase. Among them, the neuropsychiatric manifestations characterized by a short-term memory loss and inability to concentrate are called “brain fog”. Recent studies have revealed the involvement of “chronic neuro-inflammation” in the pathogenesis of brain fog following COVID-19 infection. In the COVID-related brain fog, similarly to neurodegenerative disorders caused by neuro-inflammation, brain leukocytes, such as microglia and lymphocytes, are hyperactivated, suggesting the overexpression of delayed rectifier K+-channels (Kv1.3) within the cells. In our previous patch-clamp studies, drugs, such as antihistamines, statins, nonsteroidal anti-inflammatory drugs, antibiotics and anti-hypertensive drugs, suppressed the Kv1.3-channel activity and reduced the production of pro-inflammatory cytokines. Additionally, newer generation antihistamines, antibiotics and corticosteroids strongly stabilize mast cells that directly activate microglia in the brain. Taking such pharmacological properties of these commonly used drugs into account, they may be useful in the treatment of COVID-related brain fog, in which the enhanced innate and adaptive immune responses are responsible for the pathogenesis.
336	Ce334		Galluzzo, Vincenzo; Zazzara, Maria Beatrice; Ciciarello, Francesca; Tosato, Matteo; Martone, Anna Maria; Pais, Cristina; Savera, Giulia; Calvani, Riccardo; Picca, Anna; Marzetti, Emanuele; Landi, Francesco; on behalf of Gemelli Against COVID-19 Post-Acute Care Team	Inadequate Physical Activity Is Associated with Worse Physical Function in a Sample of COVID-19 Survivors with Post-Acute Symptoms	https://doi.org/10.3390/jcm12072517	Published	2023-01-01	Study	https://www.mdpi.com/2077-0383/12/7/2517	Background—Patients affected by Long COVID often report shorter times spent doing physical activity (PA) after COVID-19. The aim of the present study was to evaluate potential associations between PA levels and parameters of physical function in a cohort of COVID-19 survivors with post-acute symptoms, with a particular focus on individuals aged 65 and older. Materials and methods—PA levels before and after COVID-19 were assessed in a sample of patients that had recovered from COVID-19 and were admitted to a post-acute outpatient service at the Fondazione Policlinico Universitario Agostino Gemelli IRCCS (Rome, Italy). Participation in PA was operationalized as the engagement in leisure-time PA for at least 150 min per week in the last 3 months. Self-rated health and measures of physical performance and muscle strength were assessed. Results—Mean age of 1846 participants was 55.2 ± 14.4 years and 47% were women. Before COVID-19, inactivity was detected in 47% of the whole study population; only 28% maintained pre-COVID-19 PA engagement. Inactivity was more frequent in women. The stopping of physical activity was associated with increased BMI and CRP levels, lower vitamin D levels and a higher prevalence of post-COVID-19 fatigue, dyspnea, arthralgia, and myalgia. Active participants had higher handgrip strength and performed better on both the six-minute walking test (6MWT) and at the one-minute sit-to-stand test (1MSTST). In particular, at the 6MWT, participants 65 and older that were still active after COVID-19 walked 32 m more than sedentary peers. Moreover, the distance covered was 28 m more than those who were active only before COVID-19 (p = 0.05). Formerly active subjects performed similarly at the 6MWT to inactive participants. PA was associated with better self-rated health. Conclusions—Our findings reveal that inactivity is frequent in the post-acute COVID-19 phase. Stopping physical activity after COVID-19 results in measures of performance that are comparable to those who were never active. Relevant differences in the distance covered at the 6MWT were found between older active subjects and their sedentary peers.
337	Ce335		Hsu, Wan-Hsuan; Shiau, Bo-Wen; Tsai, Ya-Wen; Wu, Jheng-Yan; Liu, Ting-Hui; Chuang, Min-Hsiang; Lai, Chih-Cheng	The effect of molnupiravir on post-acute outcome of COVID-19 survivors	https://doi.org/10.1016/j.jinf.2023.03.016	Published	2023-03-21	Article	https://www.journalofinfection.com/article/S0163-4453(23)00145-7/fulltext	Our study included 3600 patients for each cohort and we performed the final outcome analysis using these 7200 patients. We found that molnupiravir could reduce post-acute all-cause hospitalization or mortality among COVID-19 survivors. This finding was consistent with our previous study, in which patients receiving nirmatrelvir plus ritonavir could have a lower risk of all-cause hospitalization or mortality (HR, 0.543; 95% CI, 0.495-0.597) 30 to 180 days after a documented COVID-19 diagnosis.4 Both findings indicated that the novel oral anti-viral agents, including molnupiravir and nirmatrelvir plus ritonavir, are able to provide further clinical benefits for COVID-19 survivors during the post-acute phase. These findings suggested the promising effects of antivirals in the prevention of post-acute COVID-19 complications. The association between molnupiravir and the post-acute outcome of patients with COVID-19 in this study could be explained by the following reasons. A significant portion of patients surviving acute COVID-19 would experience the post-acute sequelae of COVID-19 or long COVID, which was caused by SARS-CoV-2 direct injury or its associated immune/inflammatory response.6 However, early antiviral treatment may help facilitate the virological eradication and reduce further inflammatory or immunologic response. Thus, the risk of post-acute complications after SARS-CoV-2 infection could be reduced by anti-viral therapies.5, 7 With the TriNetX Research Network, our study was able to recruit cohort members from the large population-based database of over 120 HCOs. Propensity score matching was used to reduce confounding variables despite the retrospective nature of the database. However, our findings should be interpreted with the following limitations. First, our acquired data may be subjected to residual confounding variables such as vaccination status, COVID-19 severity, SARS-CoV-2 variants, and the use of other anti-COVID-19 treatments that were not listed in the cohort construction, particularly for corticosteroids and interleukin-6 blockade agents. Secondly, as with all coding-based studies, our results are susceptible to misdiagnosis, inaccurate coding, and errors in documentation. Hence, further study is warranted to clarify these issues. In conclusion, in addition to the clinical benefit of molnupiravir for acute COVID-19,2, 3 our study demonstrated the extended effect of molnupiravir in reducing the risks of all-cause hospitalization and mortality in the post-acute phase following SARS-CoV-2 infection. publisher: Elsevier PMID: 36958635
338	Ce336		Minutolo, Antonella; Petrone, Vita; Fanelli, Marialaura; Maracchioni, Christian; Giudice, Martina; Teti, Elisabetta; Coppola, Luigi; Sorace, Chiara; Iannetta, Marco; Tony Miele, Martino; Bernardini, Sergio; Mastino, Antonio; Sinibaldi Vallebona, Paola; Balestrieri, Emanuela; Andreoni, Massimo; Sarmati, Loredana; Grelli, Sandro; Garaci, Enrico; Matteucci, Claudia	Thymosin alpha 1 restores the immune homeostasis in lymphocytes during Post-Acute sequelae of SARS-CoV-2 infection	https://doi.org/10.1016/j.intimp.2023.110055	Published	2023-05-01	Study	https://www.sciencedirect.com/science/article/pii/S1567576923003764	Highlights •Tα1 modulates the differentiation of T cells in PASC. •Tα1 reduces the exhaustion of CD8 + T cells. •Tα1 specifically reduces inflammation in activated lymphocytes. •Higher immunomodulation by Tα1 in individuals with specific systemic and psychiatric PASC symptoms. Abstract The complex alterations of the immune system and the immune-mediated multiorgan injury plays a key role in host response to SARS-CoV-2 infection and in the pathogenesis of COVID-19, being also associated with adverse outcomes. Thymosin alpha 1 (Tα1) is one of the molecules used in the treatment of COVID-19, as it is known to restore the homeostasis of the immune system during infections and cancer. The use of Tα1 in COVID-19 patients had been widely used in China and in COVID-19 patients, it has been shown to decrease hospitalization rate, especially in those with greater disease severity, and reduce mortality by restoring lymphocytopenia and more specifically, depleted T cells. Persistent dysregulation with depletion of naive B and T cell subpopulations and expansion of memory T cells suggest a chronic stimulation of the immune response in individuals with post-acute sequelae of SARS-CoV-2 infection (PASC). Our data obtained from an ex vivo study, showed that in PASC individuals with a chronically altered immune response, Tα1 improve the restoration of an appropriate response, most evident in those with more severe illness and who need respiratory support during acute phase, and in those with specific systemic and psychiatric symptoms of PASC, confirming Tα1 treatment being more effective in compromised patients. The results obtained, along with promising reports on recent trials on Tα1 administration in patients with COVID-19, offer new insights into intervention also for those patients with long-lasting inflammation with post-infectious symptoms, some of which have a delayed onset.
339	Ce337		Schmidt, F.; Azar, C.; Goektas, O.	Treatment of Olfactory Disorders After SARS – CoViD 2 Virus Infection	https://doi.org/10.1177/01455613231168487	Published	2023-03-28	Study	https://doi.org/10.1177/01455613231168487	ObjectiveThe benefit of a nasal corticosteroid in the treatment of persistent post-infectious smell disorders is not as clear in previous studies as is assumed for olfactory training. This study would therefore like to describe the treatment strategies using the example of a persistent olfactory dysfunction as a result of a proven infection with SARS-CoViD-2-virus.MethodsTwenty patients (average age of 33.9 ± 11.9 years) with hyposmia were included in this study from December 2020 to July 2021. Every second patient received additionally a nasal corticosteroid. The two resulting randomized groups of equal size were screened with the TDI test, a 20-item taste powder test for the assessment of retronasal olfaction and otorhinolaryngological examination. The patients were asked to train twice daily using a standardized odor training kit and followed up after 2 months and 3 months, respectively.ResultsWe documented a significant overall improvement in olfactory ability over the investigation period in both groups. While the TDI score steadily increased on average under the combination therapy, the rise under olfactory training alone was initially steeper. This short-term interaction effect over mean two months was not statistically significant. According to Cohen, however, a moderate effect (eta2 = 0.055, Cohen`s d = 0.5) can still be assumed. This effect could be explained by a possibly higher compliance at the beginning of the sole olfactory training due to the lack of further drug treatment offers. When the training intensity decreases, the recovery of the sense of smell stagnates. Adjunctive therapy ultimately outweighs this short-term benefit.ConclusionsThe results reinforce the recommendation of early and consistent olfactory training on patients with dysosmia due to COVID-19. For continuous improvement of the sense of smell, an accompanying topical treatment seems at least to be worth consideration. The results should be optimized with larger cohorts and using new objective olfactometric methods.
340	Ce338		Imam, Mohamed S.; Abdelazim, Mohamed H.; Abdelazim, Ahmed H.; Ismaiel, Wael F.; Gamal, Mohammed; Abourehab, Mohammed A. S.; Alghamdi, Saleh; Alghamdi, Mohamed A.; Ghoneim, Mohammed M.; Elwany, Samy	Efficacy of pentasodium diethylenetriamine pentaacetate in ameliorating anosmia post COVID-19	https://doi.org/10.1016/j.amjoto.2023.103871	Published	2023-07-01	Trial	https://www.sciencedirect.com/science/article/pii/S0196070923000856	Highlights •Reports demonstrated a relationship between anosmia and COVID-19 •Olfactory dysfunction causes an increase in intracellular calcium concentration. •Pentasodium diethylenetriamine pentaacetate (DTPA) can decrease the concentration of calcium in the nasal secretion. •Intranasal DTPA could be effective in treating anosmia. Abstract Background COVID-19 has been frequently demonstrated to be associated with anosmia. Calcium cations are a mainstay in the transmission of odor. One of their documented effects is feedback inhibition. Thus, it has been advocated that reducing the free intranasal calcium cations using topical chelators such as pentasodium diethylenetriamine pentaacetate (DTPA) could lead to restoration of the olfactory function in patients with post-COVID-19 anosmia. Methodology This is a randomized controlled trial that investigated the effect of DTPA on post-COVID-19 anosmia. A total of 66 adult patients who had confirmed COVID-19 with associated anosmia that continued beyond three months of being negative for SARS-CoV-2 infection. The included patients were randomly allocated to the control group that received 0.9 % sodium chloride-containing nasal spray or the interventional group that received 2 % DTPA-containing nasal spray at a 1:1 ratio. Before treatment and 30 days post-treatment, the patients' olfactory function was evaluated using Sniffin' Sticks, and quantitative estimation of the calcium cations in the nasal mucus was done using a carbon paste ion-selective electrode test. Results Patients in the DTPA-treated group significantly improved compared to the control group in recovery from functional anosmia to hyposmia. Additionally, they showed a significant post-treatment reduction in the calcium concentration compared to the control group. Conclusion This study confirmed the efficacy of DTPA in treating post-COVID-19 anosmia.
341	Ce339		Quinn, Kieran L.; Lam, Grace Y.; Walsh, Jillian F.; Bhéreur, Anne; Brown, Adam D.; Chow, Chung Wai; Christie Chung, Kit Yan; Cowan, Juthaporn; Crampton, Noah; Décary, Simon; Falcone, Emilia L.; Graves, Lorraine; Gross, Douglas P.; Hanneman, Kate; Harvey, Paula J.; Holmes, Sheila; Katz, Gabrielle M.; Parhizgar, Parinaz; Sharkawy, Abdu; Tran, Karen C.; Waserman, Susan; Zannella, Vanessa E.; Cheung, Angela M.	Cardiovascular Considerations in the Management of People with Suspected Long COVID	https://doi.org/10.1016/j.cjca.2023.04.003	Published	2023-04-06	Review	https://www.sciencedirect.com/science/article/pii/S0828282X23003033	Approximately 15% of adult Canadians with SARS-CoV-2 infection develop lingering symptoms beyond 12 weeks post-acute infection, known as post-COVID condition or long COVID. Some of the commonly reported long COVID cardiovascular symptoms include fatigue, shortness of breath, chest pain, and palpitations. Suspected long-term cardiovascular complications of SARS-CoV-2 infection may present as a constellation of symptoms that can be challenging for clinicians to diagnose and treat. When assessing patients with these symptoms, clinicians need to keep in mind Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), post-exertional malaise and post-exertional symptom exacerbation (PEM/PESE), cardiac dysautonomia such as Inappropriate Sinus Tachycardia (IST), and Postural Orthostatic Tachycardia Syndrome (POTS), and occasionally Mast Cell Activation Syndrome (MCAS). This paper summarizes the globally evolving evidence around management of cardiac sequelae of long COVID. In addition, this review includes a Canadian perspective, consisting of a panel of expert opinions from experienced clinicians across Canada who have been involved in management of long COVID. The objective of this review is to offer some practical guidance to cardiologists and generalist clinicians regarding diagnostic and treatment approaches for adult patients with suspected long COVID who continue to experience unexplained cardiac symptoms.
342	Ce340		Bertuccio, Paola; Degli Antoni, Melania; Minisci, Davide; Amadasi, Silvia; Castelli, Francesco; Odone, Anna; Quiros-Roldan, Eugenia	The impact of early therapies for COVID-19 on death, hospitalization and persisting symptoms: a retrospective study	https://doi.org/10.1007/s15010-023-02028-5	Published	2023-04-06	Study	https://doi.org/10.1007/s15010-023-02028-5	Purpose Oral antivirals (nirmatrelvir/ritonavir and molnupiravir), intravenous short treatment of remdesivir and anti-SARS-CoV-2 monoclonal antibodies (mAbs) have been used for early COVID-19 treatments in high risk of disease progression patients. The term long COVID has been used to refer to a range of new, returning, or ongoing symptoms after SARS-CoV-2 infection. Little is known about the impact of such therapies on long COVID. Methods This is a retrospective observational study, including all outpatients evaluated from April 2021 to March 2022 in Brescia, Lombardy, northern Italy. Patients were stratified in three groups: (a) treated with mAbs, (b) treated with antivirals drugs and (c) controls (patients eligible for a or b who refused treatment). Data were collected at baseline and at month 1 and 3 (data on self-reported symptoms were collected using a telephone-administered questionnaire). We assessed early COVID-19 therapies effectiveness in preventing hospitalization, death at 1 or 3 months and persisting symptoms at 3 months after the onset of SARS-CoV-2 infection. Results A total of 649 patients were included in the study, of which 242 (37.3%) were treated with mAbs, 197 (30.3%) with antiviral drugs and 210 (32.4%) were not treated. Patients most frequently reported cerebro-cardiovascular diseases (36.7%) followed by obesity (22%). Overall, 29 patients (4.5%) died or were hospitalized at 1 or 3-month follow-up. Death or hospitalization was positively associated with older ages, with a significant linear trend (OR 3.05; 95% CI 1.16–8.06, for patients aged 80 or more years compared to those aged less than 65). Data on long COVID at 3 months were available for 323 (49.8%) patients. A positive association emerged for females compared to men, with an OR of 2.14 (95% CI 1.30–3.53) for any symptoms. Conversely, inverse associations were found for treatment groups as compared to the control one, with significant estimates among patients treated with antiviral drugs for any symptoms (OR 0.43, 95% CI 0.21–0.87) and patients treated with mAbs for any neuro-behavioral symptoms (OR 0.48, 95% CI 0.25–0.92). Conclusions We report beneficial effect of early use of anti-SARS-CoV-2 antivirals and mAbs on long COVID.
343	Ce341		Seid, Abubeker Alebachew; Mohammed, Ahmed Adem; Hasen, Aragaw Asfaw	Progressive muscle relaxation exercises in patients with COVID-19: Systematic review and meta-analysis	https://doi.org/10.1097/MD.0000000000033464	Published	2023-04-07	Systematic review and meta-analysis	https://journals.lww.com/md-journal/Fulltext/2023/04070/Progressive_muscle_relaxation_exercises_in.60.aspx	Background: Patients with COVID-19 will experience high levels of anxiety and depression and poor levels of sleep and quality of life (QoL) due to isolation treatment and uncertain outcomes. Progressive muscle relaxation (PMR) exercises show promising treatment effects on mental health and sleep problems and overall QoL in COVID-19 patients. This study aimed to evaluate the efficacy and safety of PMR exercises in patients with COVID-19. Methods: Both experimental and non-experimental studies related to PMR and COVID-19 were systematically searched in the PubMed, Cochrane Library, PEDro and HINARI databases for studies published from the occurrence of the pandemic to December 2022. Study selection, methodological quality assessment and data extraction were carried out by 2 independent authors. Efficacy outcomes were evaluated for sleep quality, anxiety, depression, and QoL. The safety outcomes were evaluated based on adverse events reported. Review manager (RevMan 5.4, Cochrane collaboration) was used for the data analysis. Results: Four studies with 227 subjects were included in this systematic review. The pooled results indicated that PMR interventions improved the sleep quality score standardized mean difference (SMD): −0.23; 95% confidence interval (CI): −0.54, 0.07; P = .13, level of anxiety SMD: −1.35; 95% CI −2.38, −0.32; P = .01 compared to the usual care. Depression level, disease severity and QoL were also improved following PMR interventions. Only 1 study reported worsening of 1 patient clinical status while all other studies did not report any adverse events during the interventions. Conclusions: PMR interventions can improve the sleep quality, anxiety, depression, disease severity and QoL in patients with mild to moderate COVID-19 in a short-term period compared to the usual care. However, there was indecision about the safety and long-term effects of PMR.
344	Ce342		Heitmann, Juliane; Kreutz, Julian; Aldudak, Sümeya; Schieffer, Elisabeth; Schieffer, Bernhard; Schäfer, Ann-Christin	A practical approach for the treatment of post-COVID symptoms	https://doi.org/10.1007/s00059-023-05177-3	Published	2023-04-23	Case Report	https://doi.org/10.1007/s00059-023-05177-3	For the past 3 years, our daily lives have been largely dictated by the coronavirus disease 2019 (COVID-19) pandemic. In many people, this infectious disease leads to long-lasting symptoms, which can vary greatly in form and intensity between individuals. This report describes the case of a young patient who had no health restrictions until she came into contact with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As part of a post-COVID syndrome, she not only temporarily lost her ability to work, but was also no longer able to manage her daily life independently. A crucial therapeutic approach, in this case, was the use of heparin-induced extracorporeal LDL/fibrinogen precipitation (H.E.L.P.) apheresis.
345	Ce343		Wacks, Michael; Wortley, Elizabeth; Gregorowski, Anna; Segal, Terry Y.; Whittaker, Elizabeth	Fifteen-minute consultation: Managing post-COVID-19 syndrome (long COVID) in children and young people	https://doi.org/10.1136/archdischild-2022-324950	Published	2023-04-20	Article	https://ep.bmj.com/content/early/2023/04/20/archdischild-2022-324950	Post-COVID-19 syndrome is a new condition that can have a major impact on the physical and mental well-being of children and young people, affecting their ability to access activities including education. Paediatricians and general practitioners need to be able to assess and manage patients with this condition; making the diagnosis, excluding serious pathology, managing comorbidities and accessing appropriate management are crucial. This 15 minute consultation presents an approach to history taking, examination, investigations, management principles and referrals.
346	Ce344		Bachmeier, Beatrice E.; Hölzle, Salome; Gasser, Mohamed; van den Akker, Marjan	How do German General Practitioners Manage Long-/Post-COVID? A Qualitative Study in Primary Care	https://doi.org/10.3390/v15041016	Published	2023-04-01	Study	https://www.mdpi.com/1999-4915/15/4/1016	Background: Many patients with ongoing complaints after a SARS-CoV-2 infection are treated in primary care. Existing medical guidelines on how to diagnose and treat Long-/Post-COVID are far from being comprehensive. This study aims to describe how German general practitioners (GPs) deal with this situation, what problems they experience when managing such patients, and how they solve problems associated with the diagnosis and treatment of Long-/Post-COVID. Methods and Findings: We conducted a qualitative study and interviewed 11 GPs. The most commonly described symptoms were ongoing fatigue, dyspnea, chest tightness and a decrease in physical capacity. The most common way to identify Long-/Post-COVID was by exclusion. Patients suffering from Long-/Post-COVID were generally treated by their GPs and rarely referred. A very common non-pharmacological intervention was to take a wait-and-see approach and grant sick leave. Other non-pharmacological interventions included lifestyle advices, physical exercise, acupuncture and exercises with intense aromas. Pharmacological treatments focused on symptoms, like respiratory symptoms or headaches. Our study’s main limitations are the small sample size and therefore limited generalizability of results. Conclusions: Further research is required to develop and test pharmaceutical and non-pharmaceutical interventions for patients with Long-/Post-COVID. In addition, strategies to prevent the occurrence of Long-/Post-COVID after an acute infection with SARS-CoV-2 have to be developed. The routine collection of data on the diagnosis and management of Long-/Post-COVID may help in the formulation of best practices. It is up to policymakers to facilitate the necessary implementation of effective interventions in order to limit the huge societal consequences of large groups of patients suffering from Long-/Post-COVID.
347	Ce345		Rinn, Robin; Gao, Lingling; Schoeneich, Sarah; Dahmen, Alina; Kumar, Vinayak Anand; Becker, Petra; Lippke, Sonia	Digital Interventions for Treating Post-COVID or Long-COVID Symptoms: Scoping Review	https://doi.org/10.2196/45711	Published	2023-04-17	Review	https://www.jmir.org/2023/1/e45711	Background: Patients with post-COVID/long-COVID symptoms need support, and health care professionals need to be able to provide evidence-based patient care. Digital interventions can meet these requirements, especially if personal contact is limited. Objective: We reviewed evidence-based digital interventions that are currently available to help manage physical and mental health in patients with post-COVID/long-COVID symptoms. Methods: A scoping review was carried out summarizing novel digital health interventions for treating post-COVID/long-COVID patients. Using the PICO (population, intervention, comparison, outcome) scheme, original studies were summarized, in which patients with post-COVID/long-COVID symptoms used digital interventions to help aid recovery. Results: From all scanned articles, 8 original studies matched the inclusion criteria. Of the 8 studies, 3 were “pretest” studies, 3 described the implementation of a telerehabilitation program, 1 was a post-COVID/long-COVID program, and 1 described the results of qualitative interviews with patients who used an online peer-support group. Following the PICO scheme, we summarized previous studies. Studies varied in terms of participants (P), ranging from adults in different countries, such as former hospitalized patients with COVID-19, to individuals in disadvantaged communities in the United Kingdom, as well as health care workers. In addition, the studies included patients who had previously been infected with COVID-19 and who had ongoing symptoms. Some studies focused on individuals with specific symptoms, including those with either post–COVID-19 or long-term symptoms, while other studies included patients based on participation in online peer-support groups. The interventions (I) also varied. Most interventions used a combination of psychological and physical exercises, but they varied in duration, frequency, and social dimensions. The reviewed studies investigated the physical and mental health conditions of patients with post-COVID/long-COVID symptoms. Most studies had no control (C) group, and most studies reported outcomes (O) or improvements in physiological health perception, some physical conditions, fatigue, and some psychological aspects such as depression. However, some studies found no improvements in bowel or bladder problems, concentration, short-term memory, unpleasant dreams, physical ailments, perceived bodily pain, emotional ailments, and perceived mental health. Conclusions: More systematic research with larger sample sizes is required to overcome sampling bias and include health care professionals’ perspectives, as well as help patients mobilize support from health care professionals and social network partners. The evidence so far suggests that patients should be provided with digital interventions to manage symptoms and reintegrate into everyday life, including work. Company: Journal of Medical Internet Research Distributor: Journal of Medical Internet Research Institution: Journal of Medical Internet Research Label: Journal of Medical Internet Research publisher: JMIR Publications Inc., Toronto, Canada
348	Ce346		Chuang, Hung-Jui; Lin, Chia-Wei; Hsiao, Ming-Yen; Wang, Tyng-Guey; Liang, Huey-Wen	Long COVID and rehabilitation	https://doi.org/10.1016/j.jfma.2023.03.022	Published	2023-04-13	Review	https://www.sciencedirect.com/science/article/pii/S0929664623001079	Coronavirus disease 2019 (COVID-19) has caused tremendous morbidity and mortality worldwide. The large number of post-COVID survivors has drawn attention to the management of post-COVID condition, known as long COVID. This review examines current knowledge of long COVID, regarding its epidemiology, mechanism, and clinical presentations in both adults and children. We also review the rehabilitation principles, modules, and effects, and share Taiwan's efforts to provide a top-down, nationwide care framework for long COVID patients. Dyspnea, chronic cough, and fatigue are the most commonly reported symptoms in the first 6 months after infection, but cognitive impairment and psychological symptoms may persist beyond this time. Several possible mechanisms behind these symptoms were proposed, but remained unconfirmed. These symptoms negatively impact individuals' function, activities, participation and quality of life. Rehabilitation is a key element of management to achieve functional improvement. Early management should start with comprehensive evaluation and identification of red flags. Exercise-based therapy, an essential part of management of long COVID, can be conducted with different modules, including telerehabilitation. Post-exertional symptom exacerbation and orthostatic hypotension should be carefully monitored during exercise. Randomized control trials with a large sample size are needed to determine the optimal timing, dosage, and modules.
349	Ce347		Finnigan, Lucy E. M.; Cassar, Mark Philip; Koziel, Margaret James; Pradines, Joel; Lamlum, Hanan; Azer, Karim; Kirby, Dan; Montgomery, Hugh; Neubauer, Stefan; Valkovič, Ladislav; Raman, Betty	Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised controlled phase 2a pilot study	https://doi.org/10.1016/j.eclinm.2023.101946	Published	2023-04-14	Study	https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00123-2/fulltext	Background ‘Long COVID’ describes persistent symptoms, commonly fatigue, lasting beyond 12 weeks following SARS-CoV-2 infection. Potential causes include reduced mitochondrial function and cellular bioenergetics. AXA1125 has previously increased β-oxidation and improved bioenergetics in preclinical models along with certain clinical conditions, and therefore may reduce fatigue associated with Long COVID. We aimed to assess the efficacy, safety and tolerability of AXA1125 in Long COVID. Methods Patients with fatigue-dominant Long COVID were recruited in this single-centre, double-blind, randomised controlled phase 2a pilot study completed in the UK. Patients were randomly assigned (1:1) using an Interactive Response Technology to receive either AXA1125 or matching placebo in a clinical-based setting. Each dose (33.9 g) of AXA1125 or placebo was administered orally in a liquid suspension twice daily for four weeks with a two-week follow-up period. The primary endpoint was the mean change from baseline to day 28 in the phosphocreatine (PCr) recovery rate following moderate exercise, assessed by 31P-magnetic resonance spectroscopy (MRS). All patients were included in the intention to treat analysis. This trial was registered at ClinicalTrials.gov, NCT05152849. Findings Between December 15th 2021, and May 23th 2022, 60 participants were screened, and 41 participants were randomised and included in the final analysis. Changes in skeletal muscle phosphocreatine recovery time constant (τPCr) and 6-min walk test (6MWT) did not significantly differ between treatment (n = 21) and placebo group (n = 20). However, treatment with AXA1125 was associated with significantly reduced day 28 Chalder Fatigue Questionnaire [CFQ-11] fatigue score when compared with placebo (least squares mean difference [LSMD] −4.30, 95% confidence interval (95% CI) −7.14, −1.47; P = 0.0039). Eleven (52.4%, AXA1125) and four (20.0%, placebo) patients reported treatment-emergent adverse events; none were serious or led to treatment discontinuation. Interpretation Although treatment with AXA1125 did not improve the primary endpoint (τPCr-measure of mitochondrial respiration), when compared to placebo, there were significant improvements in fatigue-based symptoms among patients living with Long COVID following a four-week treatment period. Further multicentre studies are needed to validate our findings in a larger cohort of patients with fatigue-dominant Long COVID. publisher: Elsevier
350	Ce348		Thomas-Purcell, Kamilah; Davenport, Rosemary; Ayala, Victoria; Purcell, Donrie; Ownby, Raymond L.	Chronic Disease Self-Management of Post-Acute Sequelae of COVID-19 Among Older Adults: A Mixed-Methods Analysis	https://doi.org/10.2147/CIA.S393732	Published	2023-04-14	Study	https://www.dovepress.com/chronic-disease-self-management-of-post-acute-sequelae-of-covid-19-amo-peer-reviewed-fulltext-article-CIA	Introduction: Approximately 20– 30% of individuals who contract acute coronavirus disease (COVID-19) infection develop longer term complications of their initial infection, referred to as Post-Acute Sequelae of SARS-CoV-2 infection (PASC). PASC is characterized by chronic, varying symptomatology. Methods: Using a mixed methods study design, we aimed to gain insight into individuals’ experience with PASC, including cognitive issues, fatigue, and sleep disturbances. We explored whether our previously developed application (app), aimed at improving self-management skills among individuals with chronic diseases, is relevant for individuals with PASC and gained information to adapt the app for individuals with PASC. The study included 19 individuals, aged 40 years and older, recruited from our research participant database, Nova Southeastern University clinics, and community locations. We included this age range because older adults are more likely to have comorbid conditions, allowing us to better understand the impact of COVID-19 infection in these individuals. Participants completed seven standardized self-report questionnaires online, and an individual semi-structured interview via videoconferencing. Quantitative data were assessed using descriptive statistics and calculating individuals’ scores in relation to norms. Qualitative data were analyzed using a thematic analysis approach. Triangulation of the data was accomplished by calculating correlations between participants’ responses on self-report scales and themes found in semi-structured interviews. Results: Themes included disruption of everyday life, diverse physical symptoms, and cognitive problems including brain fog, fatigue, coping, and emotional upset. Quantitative analysis demonstrated that participants experienced high levels of fatigue, negative mood, cognitive problems, and overall reduction in health-related quality of life (HRQOL). Correlation analyses revealed that individual interview responses were related to participants’ self-report of symptoms on standard questionnaires. Discussion: Findings indicate that self-report questionnaires may reflect the experience of individuals with PASC and its impact. Additionally, further efforts to expand our prior mobile app are warranted among individuals with PASC.
351	Ce349		Oliveira, Karla Cybele Vieira de; Ferreira, Ana Paula de Lima; Silva, Diana de Andrade; Monteiro, Janaína dos Santos; Silva, Kennedy Victor; Lucena, Larissa Coutinho de; Araújo, Maria das Graças Rodrigues de	The impact of post-COVID multicomponent rehabilitation	https://doi.org/10.1590/fm.2023.36112	Published	2023-05-15	Study	https://www.scielo.br/j/fm/a/BssyDbNrSdCRjRzGmtXtnRs/	Abstract Introduction Post-COVID-19 syndrome is characterized by chronic fatigue and myalgia, among other symptoms, which can limit activities of daily living. Physical therapy protocols with multicomponent exercises combine strength, resistance, balance and gait, producing sig-nificant improvements in functional mobility. Objective Evaluate whether multicomponent rehabilitation is effective in improving functional mobility and quality of life in individuals with post-COVID-19 syndrome. Methods Randomized controlled trial with 59 volunteers, divided into an intervention (IG) and control group (CG), all of whom underwent initial assessment (T0). The IG performed 24 sessions over 12 weeks and the CG did not undergo training. Functional mobility was analyzed using the 6-minute walk test (6MWT) and the Berg balance scale, while the SF-36 questionnaire assessed quality of life. Results In the 6MWT, the IG covered 464.40 + 81.26 meters (T0) and 518.60 + 82.68 meters (T4). The IG Berg scale scores were 48.00 + 4.00 (T0) and 51.90 + 4.26 (T4). In terms of quality of life, the IG obtained mean scores of 96.26 + 10.14 (T0) and 102.60 + 5.53 (T4). None of these measures was statistically significant. Conclusion Individuals who underwent the multicomponent phys-iotherapy protocol showed statistically nonsignificant increases in the variables studied.
352	Ce350		Nikolich, Janko Ž.; Rosen, Clifford J.	Toward Comprehensive Care for Long Covid	https://doi.org/10.1056/NEJMp2304550	Published	2023-05-09	Article	https://doi.org/10.1056/NEJMp2304550	RECOVER is a building block for ultimately establishing the clinical definition of long Covid. We believe that over and above this research effort, the country needs additional structures that can provide the capacity for clinicians, patients, caregivers, advocacy groups, employers, and government officials to learn about, adapt, and implement interventions, therapeutics, and other best practices to combat long Covid. We suggest that this effort include several key features. First, it should support people with long Covid by coordinating clinical care and rehabilitation, reducing health care disparities, and addressing ongoing and complex medical and psychosocial needs, with a particular focus on patients who currently receive fragmented care or no care at all. Such support could be provided by means of national long Covid centers of excellence. This program could begin by building out some centers involved in RECOVER so that they not only collect data and follow participants, but also provide comprehensive care for those patients and others with long Covid. RECOVER serves a cross section of underserved communities through research centers in both urban and rural areas and can act as a bridge to care provision for these patients. Second, we need to define, continuously improve, and implement standards of care and best practices, built on evidence obtained through a coordinated exchange of information. Third, we can leverage innovative methods for disseminating information and providing support in order to educate clinicians, patients, and communities; broaden access to high-quality care; and further reduce disparities. And fourth, we will need to develop and implement workforce training programs for clinicians caring for patients with long Covid. To implement such an ambitious program, we strongly urge Congress to consider appropriating funding in fiscal year 2024 for the Health Resources and Services Administration to competitively select centers of excellence in long Covid care by leveraging and expanding the initial investment in RECOVER hubs and other federally supported long Covid activities. In addition, such centers could support and leverage, both nationally and throughout their states, greater educational initiatives from the CDC and the WHO for both clinicians and patients. Some examples include continuing education programs, grand rounds, and the Project ECHO (Extension for Community Healthcare Outcomes) model, a scalable and effective way of using electronic media to inform and facilitate changes in health and education for clinicians. These efforts should focus on symptom complexes, potential complications, and management strategies. We need to demystify the disease and empower affected people, involving them actively in their own care and in education and training. We also recommend that insurance providers reexamine criteria for disability claims and urge employers to gain a better understanding of this disorder and its wide-ranging implications. Most important, we need to put people and communities, not diseases, at the center of our health systems and empower them to take charge of their own health rather than be passive recipients of services. If the prevalence of long Covid is indeed between 5 and 15%, we will continue to face an enormous challenge to our national health and our health care system moving forward. Innovative approaches will be needed to care for patients with long Covid, and these need to be backed by education, research, and support at all levels. It’s about time. publisher: Massachusetts Medical Society _eprint: https://doi.org/10.1056/NEJMp2304550
353	Ce351		Diem, Lara; Höfle, Oliver; Fregolente, Livia; Hoepner, Robert	The Role of Neurorehabilitation in Post-COVID-19 Syndrome	https://doi.org/10.3390/ctn7020013	Published	2023-06-01	Article	https://www.mdpi.com/2514-183X/7/2/13	Post-COVID-19 syndrome is an ongoing challenge for healthcare systems as well as for society. The clinical picture of post-COVID-19 syndrome is heterogeneous, including fatigue, sleep disturbances, pain, hair loss, and gastrointestinal symptoms such as chronic diarrhea. Neurological complaints such as fatigue, cognitive impairment, and sleep disturbances are common. Due to the short timeframe of experience and small amount of evidence in this field, the treatment of post-COVID-19 syndrome remains a challenge. Currently, therapeutic options for post-COVID-19 syndrome are limited to non-pharmaceutical interventions and the symptomatic therapy of respective symptoms. In this article, we summarize the current knowledge about therapeutic options for the treatment of neurological symptoms of post-COVID-19 syndrome.
354	Ce352		Barshikar, Surendra; Laguerre, Martin; Gordon, Patricia; Lopez, Marielisa	Integrated Care Models for Long Coronavirus Disease	https://doi.org/10.1016/j.pmr.2023.03.007	Published	2023-05-08	Article	https://www.pmr.theclinics.com/article/S1047-9651(23)00023-2/fulltext	Key points • The wide range of persistent symptoms in long COVID requires a coordinated response from multiple medical specialties. • Formalized models of care systems and multidisciplinary collaborations began in early 2021 as health care providers recognized the needs of the affected population. • Multidisciplinary models largely exist in academic centers and larger cities; however, most care for PASC patients is provided by the primary care providers. Introduction As of July 2022, there have been more than 540 million confirmed cases of coronavirus disease (severe acute respiratory syndrome coronavirus 2 [SARS CoV-2], coronavirus disease 2019 [COVID-19]) during the global pandemic.1 Severe acute cases of SARS-CoV-2 respiratory illness continue to strain communities, health care systems, and nations. Evidence-based medical treatments have greatly improved patient outcomes; however, a growing population of survivors with persisting long-term complications has been recognized. This syndrome has been labeled as long COVID or the Post-Acute Sequelae of SARS CoV-2 (PASC).2,3 There is no single accepted definition of PASC. However, PASC is characterized by persistent and/or delayed symptoms or complications beyond 4 weeks of symptom onset or 3 months after a confirmed SARS CoV-2 infection.3 The population that experiences PASC is extremely heterogeneous, from those initially asymptomatic with no prior comorbidities to those with preexisting respiratory conditions and prolonged intensive care unit (ICU) stays. The exact prevalence of PASC in the population is unknown with reports of patients with PASC ranging from 10% to 81% of confirmed cases.4 Given this large population, treatment resource, health care needs, and social costs will continue to be a growing burden on already exhausted health care systems.5
355	Ce353		Kuut, Tanja A; Müller, Fabiola; Csorba, Irene; Braamse, Annemarie; Aldenkamp, Arnoud; Appelman, Brent; Assmann-Schuilwerve, Eleonoor; Geerlings, Suzanne E; Gibney, Katherine B; Kanaan, Richard A A; Mooij-Kalverda, Kirsten; Olde Hartman, Tim C; Pauëlsen, Dominique; Prins, Maria; Slieker, Kitty; van Vugt, Michele; Keijmel, Stephan P; Nieuwkerk, Pythia; Rovers, Chantal P; Knoop, Hans	Efficacy of cognitive behavioral therapy targeting severe fatigue following COVID-19: results of a randomized controlled trial	https://doi.org/10.1093/cid/ciad257	Published	2023-05-08	Study	https://doi.org/10.1093/cid/ciad257	Background Severe fatigue following COVID-19 is prevalent and debilitating. This study investigated the efficacy of cognitive behavioral therapy (CBT) for severe fatigue following COVID-19. Methods A multicenter, 2-arm randomized controlled trial was conducted in the Netherlands with patients being severely fatigued 3-12 months following COVID-19. Patients (n = 114) were randomly assigned (1:1) to CBT or care as usual (CAU). CBT, targeting perpetuating factors of fatigue, was provided for 17 weeks. The primary outcome was the overall mean difference between CBT and CAU on the fatigue severity subscale of the Checklist Individual Strength, directly post CBT or CAU (T1), and after six months (T2). Secondary outcomes were differences in proportions of patients meeting criteria for severe and/or chronic fatigue, differences in physical and social functioning, somatic symptoms and problems concentrating between CBT and CAU. Results Patients were mainly non-hospitalized and self-referred. Patients who received CBT were significantly less severely fatigued across follow-up assessments than patients receiving CAU (-8.8, (95% confidence interval (CI)) -11.9 to -5.8); P < 0.001), representing a medium Cohen’s d effect size (0.69). The between-group difference in fatigue severity was present at T1 -9.3 (95% CI -13.3 to -5.3) and T2 -8.4 (95% CI -13.1 to -3.7). All secondary outcomes favored CBT. Eight adverse events were recorded during CBT, and 20 during CAU. No serious adverse events were recorded. Conclusions Among patients, who were mainly non-hospitalized and self-referred, CBT was effective in reducing fatigue. The positive effect was sustained at six month follow-up.
356	Ce354		Shabaan, Alshaimaa Ahmed; Kassem, Islam; Mahrous, Aliaa Ibrahium; aboulmagd, Inass; Badrah, Mai; Attalla, Mohamed; Refahee, Shaimaa Mohsen	Diode laser in management of loss of taste sensation in patients with post-COVID syndrome: a randomized clinical trial	https://doi.org/10.1186/s12903-023-02952-w	Published	2023-05-06	Study	https://doi.org/10.1186/s12903-023-02952-w	Objective Loss of taste (ageusia) is a symptom observed following recovery from COVID-19 infection. The loss of taste and smell sensation may negatively affect patients’ quality of life (QoL). The present study aimed to evaluate the effectiveness of the Diode Laser in managing loss of taste sensation in patients with post-COVID syndrome versus the placebo. Material and method The study sample was 36 patients who complained of persistent loss of taste sensation following COVID-19. The patients were randomly assigned to one of the two groups according to the received treatment: Group I (laser treatment) and Group II (light treatment), with each patient receiving a diode laser treatment or placebo from the same operator. Taste sensation was subjectively measured after treatment for four weeks. Results The results demonstrated a significant difference between both groups regarding taste restoration after one month (p = 0.041), with Group II having a significantly higher percentage of cases 7 (38.9%) with partial taste restoration. In contrast, a significantly higher proportion of Group I 17 cases (94.4%) had complete taste restoration (p < 0.001). Conclusion The present study concluded that using a Diode laser 810 nm aided in a more rapid recovery from loss of taste dysfunction.
357	Ce355		Moukayed, Meis	A Narrative Review on the Potential Role of Vitamin D3 in the Prevention, Protection, and Disease Mitigation of Acute and Long COVID-19	https://doi.org/10.1007/s13668-023-00471-2	Published	2023-05-05	Review	https://doi.org/10.1007/s13668-023-00471-2	Purpose of Review The coronavirus disease 2019 (COVID-19) pandemic has challenged global health systems and economies from January 2020. COVID-19 caused by the infectious severe acute respiratory syndrome coronavirus (SARS-CoV-2) has acute respiratory and cardiometabolic symptoms that can be severe and lethal. Long-term physiological and psychological symptoms, known as long COVID-19, persist affecting multiple organ systems. While vaccinations support the fight against SARS-CoV-2, other effective mechanisms of population protection should exist given the presence of yet unvaccinated and at-risk vulnerable groups, global disease comorbidities, and short-lived vaccine responses. The review proposes vitamin D3 as a plausible molecule for prevention, protection, and disease mitigation of acute and long COVID-19. Recent Findings Epidemiological studies have shown that individuals who were deficient in vitamin D3 had worse COVID-19 health outcomes and mortality rates. Higher doses of vitamin D3 supplementation may improve health and survivorship in individuals of various age groups, comorbidities, and severity of disease symptoms. Summary Vitamin D3’s biological effects can provide protection and repair in multiple organ systems affected by SARS-CoV-2. Vitamin D3 supplementation can potentially support disease-mitigation in acute and long COVID-19.
358	Ce356		Jelinek, C.; Orozco-Bersoza, L.; Pini, S.; Melloy, S.; O'Connell, S.; Shaikh, H.; Collins, E.g.; Laghi, F.	A Home-based, Remotely Monitored Program to Improve Physical Activity in Patients With Long COVID		Published	2023-05-01	Study	https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A2169
359	Ce357		Achleitner, Martin; Steenblock, Charlotte; Dänhardt, Juliane; Jarzebska, Natalia; Kardashi, Romina; Kanczkowski, Waldemar; Straube, Richard; Rodionov, Roman N.; Bornstein, Nitzan; Tselmin, Sergey; Kaiser, Frank; Bucher, Ronald; Barbir, Mahmoud; Wong, Ma-Li; Voit-Bak, Karin; Licinio, Julio; Bornstein, Stefan R.	Clinical improvement of Long-COVID is associated with reduction in autoantibodies, lipids, and inflammation following therapeutic apheresis	https://doi.org/10.1038/s41380-023-02084-1	Published	2023-05-02	Study	https://www.nature.com/articles/s41380-023-02084-1	In the aftermath of the COVID-19 pandemic, we are witnessing an unprecedented wave of post-infectious complications. Most prominently, millions of patients with Long-Covid complain about chronic fatigue and severe post-exertional malaise. Therapeutic apheresis has been suggested as an efficient treatment option for alleviating and mitigating symptoms in this desperate group of patients. However, little is known about the mechanisms and biomarkers correlating with treatment outcomes. Here, we have analyzed in different cohorts of Long-Covid patients specific biomarkers before and after therapeutic apheresis. In patients that reported a significant improvement following two cycles of therapeutic apheresis, there was a significant reduction in neurotransmitter autoantibodies, lipids, and inflammatory markers. Furthermore, we observed a 70% reduction in fibrinogen, and following apheresis, erythrocyte rouleaux formation and fibrin fibers largely disappeared as demonstrated by dark field microscopy. This is the first study demonstrating a pattern of specific biomarkers with clinical symptoms in this patient group. It may therefore form the basis for a more objective monitoring and a clinical score for the treatment of Long-Covid and other postinfectious syndromes.
360	Ce358		Landhuis, Esther Wei-Yun	How Primary Care Physicians Can Recognize and Treat Long COVID	https://doi.org/10.1001/jama.2023.6604	Published	2023-05-23	Article	https://doi.org/10.1001/jama.2023.6604	There are not enough long COVID specialty clinics to meet patient need, Ziyad Al-Aly, MD, chief of research and education service at the Veterans Affairs (VA) St Louis Health Care System, said in an interview. “We’re going to have to figure out a way to make sure the larger community of physician assistants, nurse practitioners, and primary care clinicians is educated to recognize and treat [long COVID].” There’s also an urgent need for research. Last August, the US Department of Health and Human Services launched a research action plan for long COVID that includes the National Institutes of Health–funded Researching COVID to Enhance Recovery, or RECOVER, Initiative. Some have criticized RECOVER as inadequate and slow—to the extent that its principal investigators recently published a Call to Action urging Congress to include $37.5 million in fiscal year 2024 to speed research and disseminate learnings to other physicians. The first RECOVER clinical trials are expected to launch in the coming months, a spokesperson from the National Heart, Lung, and Blood Institute told JAMA in an email, and will evaluate multiple interventions focused on 5 symptom types: viral persistence, autonomic dysfunction, sleep disturbances, cognitive dysfunction, and exercise intolerance or fatigue. Details of the interventions will appear on ClinicalTrials.gov once finalized, the spokesperson said. Until results from those and other clinical trials arrive, guidance on managing long COVID in patients is available from the CDC, the VA, and the American Academy of Physical Medicine and Rehabilitation. Experts interviewed for this story offered some basic guidance for primary care physicians: Believe the patient. “Say it out loud. They need to hear it,” Palacio said of patients with long COVID symptoms, who are often not believed. If their physician says, “‘I believe you, and I will work with you to try to make you better even though I know very little about this,’ stress levels go down.” Go beyond symptoms. Physicians are accustomed to checking off symptoms, but it’s also important to ask, “’How often do these occur?’ and ‘How do they affect your ability to carry out normal daily activities?’” Bateman said. “When you can’t perform physically and cognitively, it starts to really be disabling.” Address fatigue. “If patients stop overexerting themselves, they start to feel better. It’s as simple as that,” Brode said. Physicians should discuss with patients “what they can honestly do in their daily activities.” Look to familiar conditions. According to the CDC, long COVID can share symptoms with ME/CFS, fibromyalgia, posttreatment Lyme disease syndrome, dysautonomia, and mast cell activation syndrome. Approaches to managing these conditions can help some patients with long COVID. For example, POTS can be alleviated with fluids, compression garments, and graded horizontal exercise. Primary care physicians “should be willing to think outside the box and use their medical training to provide sensible, supportive care,” Bateman said.
361	Ce359		Morgan, Sandra; Visovsky, Constance; Thomas, Bini; Klein, Aimee B.; Ji, Ming; Schwab, Lauren; Coury, Jillian	Home-Based Pilot Pulmonary Program for Dyspneic Patients Post-COVID-19	https://doi.org/10.1177/10547738231170496	Published	2023-06-01	Study	https://doi.org/10.1177/10547738231170496	It is estimated that at least 10% of people who have had COVID-19 will experience ongoing symptoms such as shortness of breath, fatigue, and cognitive disturbances. Pulmonary exercise has demonstrated improved dyspnea outcomes in other respiratory conditions. Thus, the purpose of this study was to assess the efficacy of a home-based pulmonary rehabilitation program in post-COVID-19 survivors who continue to experience dyspnea. This was a longitudinal, single group pilot study in which 19 patients received a home-based expiratory muscle strength training program over 12 weeks. Outcomes measured at baseline, 6 weeks, and 12 weeks included pulmonary symptoms, functional performance, thoracic expansion, forced expiratory volume, and expiratory resistance measures. Significant improvements were found in pulmonary symptoms (p < .001), functional performance (p = .014), and progressive expiratory resistance capabilities (p < .001). A home-based pulmonary program may be an inexpensive strategy for post-COVID-19 survivors who continue to experience dyspnea.
362	Ce360		Galvin, Vaughna; Cheek, Dennis J.; Zhang, Yan; Collins, Gregory; Gaskin, David	Short Communication: Stellate Ganglion Blockade for Persistent Olfactory and Gustatory Symptoms Post-COVID-19	https://doi.org/10.2147/LRA.S402197	Published	2023-05-03	Study	https://www.dovepress.com/short-communication-stellate-ganglion-blockade-for-persistent-olfactor-peer-reviewed-fulltext-article-LRA	One hundred ninety-five patients presenting with post-COVID symptomology, including parosmia and dysgeusia, underwent reversible stellate ganglion blockade. Stellate ganglion blockade was performed at an outpatient facility, and patients were evaluated via survey at seven days post-injection. Of the 195 participants, ages ranged from 18– 69 years of age with the breakdown of sexes being females n = 157 and males n = 38. The most significant finding was a reported improvement in olfaction post-injection in 87.4% of subjects. The effectiveness of this novel treatment for post-COVID is promising and warrants further investigation.
363	Ce361		Andrade, Sancler	Cognitive strategies and metacognition in occupational therapy for a long COVID-19 patient: a single case report	https://doi.org/10.1590/2526-8910.ctoRE265434642	Published	2023-05-22	Case Report	https://www.scielo.br/j/cadbto/a/56B6TCcVFxNbJ8sWL59KDdH/?lang=en	Abstract Introduction The impact of COVID-19 on occupational and cognitive functioning deserves further exploration since clinicians have observed long COVID and neurological manifestations of COVID-19 long after the remission of respiratory symptoms. Patients with long COVID represent an underexplored population in need of quality occupational therapy interventions. Objectives (a) present an experience report on occupational therapy for assessment and intervention with this population in a hospital setting; (b) demonstrate how perceived occupational performance and health behavior can be improved by the adoption of cognitive strategies and strategies for changing habits. Method This was a single-case study of a long COVID patient in a hospital setting. A description of the framework for assessment and treatment is provided. The patient received a total of nine sessions focused on the use of cognitive strategies and metacognition. The data were analyzed descriptively. Results After exploring guided interventions, the client could create new habits and routines and have perceived occupational performance. Conclusion This experience report presents a framework for assessing and intervening in long COVID that highlights neurocognition. Prospective studies should evaluate if the effects of the proposed awareness assessment and treatment guidelines are reproducible in other settings and if this approach could be helpful for other COVID-19 survivors.
364	Ce362		Vontetsianos, A.; Chynkiamis, N.; Anagnostopoulou, C.; Vogiatzis, I.; Kaltsakas, G.; Koutsoukou, A.; Koulouris, N.; Kosmas, E.	Effect of hybrid rehabilitation on exercise tolerance and peripheral muscle strength in patients with long COVID-19 syndrome	https://doi.org/10.1183/23120541.LSC-2023.182	Published	2023-03-09	Study	https://openres.ersjournals.com/content/9/suppl_10/182	Background: Exercise tolerance and quadriceps strength (QF) are reduced in patients with long COVID-19 syndrome several months after the acute phase of the disease. The effect of pulmonary rehabilitation (PR) on exercise tolerance and QF is inconclusive. Aim: To investigate the effect of a hybrid PR program, combining outpatient and home-based PR, on exercise capacity and QF in long COVID-19 syndrome. Methods: 38 patients (age (mean±SD): 57±12 yrs.) with excessive fatigue due to long COVID-19 syndrome (FACIT score (26±10) were allocated to PR (n=24) or usual care (UC) (n=14) groups, 132±75 days from hospital discharge. PR consisted of 8 outpatient sessions (twice weekly for 4 weeks), and 24 home- based sessions (3 times/week for 8 weeks). Patients in the UC were instructed to be physically active. Exercise tolerance was assessed by a ramp incremental CPET to the limit of tolerance. QF was assessed via an isometric strength test. Results: Exercise tolerance was increased in the PR group (by 18±9 Watt, p<0.05) leading to greater oxygen consumption (by 2.3±1.6 ml/min/kg, p<0.05) following the completion of the PR programme. Leg fatigue at peak exercise was reduced by a clinically significant margin (1.0±3.0, Borg). Finally, QF was increased in the PR group (by 4.3±4.6 kg, p<0.05). There were no significant differences in the UC group. The change in exercise tolerance and oxygen consumption were positively associated with the change in QF when all patients were included in the analysis (r=0.315 (p=0.054) and r=0.353 (p=0.041), respectively). Conclusions: A hybrid PR programme improves exercise tolerance and QF in patients with long COVID-19 syndrome.
365	Ce363		MCCarthy, Matthew W.	Metformin as a potential treatment for COVID-19	https://doi.org/10.1080/14656566.2023.2215385	Published	2023-05-17	Study	https://doi.org/10.1080/14656566.2023.2215385	Introduction Early treatment for SARS-CoV-2 infection is essential to limit the clinical progression of COVID-19. However, limited therapeutic options are available for standard-risk patients, including those under age 50 who have received the primary series of COVID-19 vaccination as well as a bivalent booster. Areas covered Metformin is a widely used, inexpensive antihyperglycemic for the treatment of diabetes mellitus type 2 as well as polycystic ovarian syndrome, with a well-described safety profile. Expert opinion Although the mechanism of action has not been fully elucidated, metformin is known to alter glucose metabolism and is under investigation as an antiviral agent, demonstrating in vitro and in vivo activity against SARS-CoV-2. Recent work suggests metformin may also serve as a therapeutic option for patients with COVID-19 as well as those with post-acute sequelae of SARS-CoV-2 infection, known more commonly as ‘long COVID-19.’ This manuscript examines what is known about metformin for the treatment of COVID-19 and explores how this drug may be used in the future to address the SARS-CoV-2 pandemic. KEYWORDS: MetforminSARS-CoV-2antiviralCOVID-19diabetes mellitus Previous article View latest articles Next article Article highlights Metformin is a widely used, inexpensive medication used for the treatment of diabetes, mellitus type 2, and polycystic ovarian syndrome. Metformin exerts its effects in humans through a variety of mechanisms. Metformin inhibits the mTOR pathway via AMP-kinase signaling, through the activation of tumor suppressor gene p53, inhibition of hypoxia inducible factor (HIF)-1α, and reduction of reactive oxygen species. Metformin has antiviral and anti-inflammatory properties and may serve as a therapeutic option for outpatients infected with SARS-CoV-2 Metformin may also serve as a therapeutic option for patients with post-acute sequelae of SARS-CoV-2 infection (PASC). publisher: Taylor & Francis _eprint: https://doi.org/10.1080/14656566.2023.2215385 PMID: 37194484
366	Ce364		Samper-Pardo, M.; León-Herrera, S.; Oliván-Blázquez, B.; Méndez-López, F.; Domínguez-García, M.; Sánchez-Recio, R.	Effectiveness of a telerehabilitation intervention using ReCOVery APP of long COVID patients: a randomized, 3-month follow-up clinical trial	https://doi.org/10.1038/s41598-023-35058-y	Published	2023-05-16	Study	https://www.nature.com/articles/s41598-023-35058-y	The main objective of this study is to analyze the clinical efficacy of telerehabilitation in the recovery of Long COVID patients through ReCOVery APP for 3 months, administered in the Primary Health Care context. The second objective is to identify significant models associated with an improvement in the study variables. An open-label randomized clinical trial was conducted using two parallel groups of a total of 100 Long COVID patients. The first group follows the treatment as usual methods established by their general practitioner (control group) and the second follows the same methods and also uses ReCOVery APP (intervention group). After the intervention, no significant differences were found in favour of the group intervention. Regarding adherence, 25% of the participants made significant use of the APP. Linear regression model establishes that the time of use of ReCOVery APP predicts an improvement in physical function (b = 0.001; p = 0.005) and community social support (b = 0.004; p = 0.021). In addition, an increase in self-efficacy and health literacy also contribute to improving cognitive function (b = 0.346; p = 0.001) and reducing the number of symptoms (b = 0.226; p = 0.002), respectively. In conclusion, the significant use of ReCOVery APP can contribute to the recovery of Long COVID patients.
367	Ce365		Michi, Teresa; Mattana, Chiara; Menga, Luca S.; Bocci, Maria Grazia; Cesarano, Melania; Rosà, Tommaso; Gualano, Maria Rosaria; Montomoli, Jonathan; Spadaro, Savino; Tosato, Matteo; Rota, Elisabetta; Landi, Francesco; Cutuli, Salvatore L.; Tanzarella, Eloisa S.; Pintaudi, Gabriele; Piervincenzi, Edoardo; Bello, Giuseppe; Tonetti, Tommaso; Rucci, Paola; De Pascale, Gennaro; Maggiore, Salvatore M.; Grieco, Domenico Luca; Conti, Giorgio; Antonelli, Massimo; Maviglia, Riccardo; Mercurio, Giovanna; De Santis, Paolo; Pennisi, Mariano Alberto; Anzellotti, Gian Marco; Torrini, Flavia; Rubino, Carlotta; Morena, Tony C.; Gennenzi, Veronica; Postorino, Stefania; Vargas, Joel; Filetici, Nicoletta; Settanni, Donatella; Durante, Miriana; Cascarano, Laura; Di Muro, Mariangela; Scarascia, Roberta; Bitondo, Maria Maddalena; Murdolo, Martina; Mele, Alessandro; Silva, Serena; Zaccone, Carmelina; Pozzana, Francesca; Maccaglia, Alessio; Savino, Martina; Potalivo, Antonella; Ceccaroni, Francesca; Scavone, Angela; Lombardi, Gianmarco; Bello, Giuseppe; Montini, Luca; Dell’Anna, Antonio Maria; Volta, Carlo Alberto; Ranieri, Vito M.; Falò, Giulia; Carelli, Simone; Natalini, Daniele; Berardi, Cecilia; Delle Cese, Luca; Vetrugno, Luigi; Balzani, Eleonora; for the Gemelli COVID-ICU study group	Long-term outcome of COVID-19 patients treated with helmet noninvasive ventilation vs. high-flow nasal oxygen: a randomized trial	https://doi.org/10.1186/s40560-023-00669-0	Published	2023-05-19	Trial	https://doi.org/10.1186/s40560-023-00669-0	Background Long-term outcomes of patients treated with helmet noninvasive ventilation (NIV) are unknown: safety concerns regarding the risk of patient self-inflicted lung injury and delayed intubation exist when NIV is applied in hypoxemic patients. We assessed the 6-month outcome of patients who received helmet NIV or high-flow nasal oxygen for COVID-19 hypoxemic respiratory failure. Methods In this prespecified analysis of a randomized trial of helmet NIV versus high-flow nasal oxygen (HENIVOT), clinical status, physical performance (6-min-walking-test and 30-s chair stand test), respiratory function and quality of life (EuroQoL five dimensions five levels questionnaire, EuroQoL VAS, SF36 and Post-Traumatic Stress Disorder Checklist for the DSM) were evaluated 6 months after the enrollment. Results Among 80 patients who were alive, 71 (89%) completed the follow-up: 35 had received helmet NIV, 36 high-flow oxygen. There was no inter-group difference in any item concerning vital signs (N = 4), physical performance (N = 18), respiratory function (N = 27), quality of life (N = 21) and laboratory tests (N = 15). Arthralgia was significantly lower in the helmet group (16% vs. 55%, p = 0.002). Fifty-two percent of patients in helmet group vs. 63% of patients in high-flow group had diffusing capacity of the lungs for carbon monoxide < 80% of predicted (p = 0.44); 13% vs. 22% had forced vital capacity < 80% of predicted (p = 0.51). Both groups reported similar degree of pain (p = 0.81) and anxiety (p = 0.81) at the EQ-5D-5L test; the EQ-VAS score was similar in the two groups (p = 0.27). Compared to patients who successfully avoided invasive mechanical ventilation (54/71, 76%), intubated patients (17/71, 24%) had significantly worse pulmonary function (median diffusing capacity of the lungs for carbon monoxide 66% [Interquartile range: 47–77] of predicted vs. 80% [71–88], p = 0.005) and decreased quality of life (EQ-VAS: 70 [53–70] vs. 80 [70–83], p = 0.01). Conclusions In patients with COVID-19 hypoxemic respiratory failure, treatment with helmet NIV or high-flow oxygen yielded similar quality of life and functional outcome at 6 months. The need for invasive mechanical ventilation was associated with worse outcomes. These data indicate that helmet NIV, as applied in the HENIVOT trial, can be safely used in hypoxemic patients. Trial registration Registered on clinicaltrials.gov NCT04502576 on August 6, 2020
368	Ce366		Lejay, Noémie; Salvioni Chiabotti, Paolo; Ducrot, Aurélie; Allali, Gilles; Nehme, Mayssam	[Pharmacological trials evaluating treatment options for neuropsychiatric symptoms in post-COVID. A narrative review]	https://doi.org/10.53738/REVMED.2023.19.827.984	Published	2023-05-17	Review	https://pubmed.ncbi.nlm.nih.gov/37195115/	Post-COVID prevalence's is estimated at 10 % in the general population. The neuropsychiatric symptoms, which are frequent (up to 30 %), can severely affect the quality of life of patients affected by this condition, notably by significantly reducing their working ability. To date, no pharmacologic treatment is available for post-COVID, apart from symptomatic treatments. A large number of pharmacological clinical trials for post-COVID are underway since 2021. A number of these trials targets neuropsychiatric symptoms, based on the various underlying pathophysiological hypotheses. The objective of this narrative review is to provide an overview of these ongoing trials targeting neuropsychiatric symptoms in post-COVID.
369	Ce367		Sánchez-Solís, Alejandra Margarita; Peláez-Hernández, Viridiana; Santiago-Fuentes, Laura Mercedes; Luna-Rodríguez, Guadalupe Lizzbett; Reyes-Lagos, José Javier; Orea-Tejeda, Arturo	Induced Relaxation Enhances the Cardiorespiratory Dynamics in COVID-19 Survivors	https://doi.org/10.3390/e25060874	Published	2023-06-01	Study	https://www.mdpi.com/1099-4300/25/6/874	Most COVID-19 survivors report experiencing at least one persistent symptom after recovery, including sympathovagal imbalance. Relaxation techniques based on slow-paced breathing have proven to be beneficial for cardiovascular and respiratory dynamics in healthy subjects and patients with various diseases. Therefore, the present study aimed to explore the cardiorespiratory dynamics by linear and nonlinear analysis of photoplethysmographic and respiratory time series on COVID-19 survivors under a psychophysiological assessment that includes slow-paced breathing. We analyzed photoplethysmographic and respiratory signals of 49 COVID-19 survivors to assess breathing rate variability (BRV), pulse rate variability (PRV), and pulse–respiration quotient (PRQ) during a psychophysiological assessment. Additionally, a comorbidity-based analysis was conducted to evaluate group changes. Our results indicate that all BRV indices significantly differed when performing slow-paced breathing. Nonlinear parameters of PRV were more appropriate for identifying changes in breathing patterns than linear indices. Furthermore, the mean and standard deviation of PRQ exhibited a significant increase while sample and fuzzy entropies decreased during diaphragmatic breathing. Thus, our findings suggest that slow-paced breathing may improve the cardiorespiratory dynamics of COVID-19 survivors in the short term by enhancing cardiorespiratory coupling via increased vagal activity.
370	Ce368		Momtazmanesh, Sara; Ansari, Sahar; Izadi, Zahra; Shobeiri, Parnian; Vatankhah, Venus; Seifi, Arash; Ghiasvand, Fereshteh; Bahrami, Mahboobeh; Salehi, Mohammdreza; Noorbala, Ahmad Ali; Akhondzadeh, Shahin	Effect of famotidine on cognitive and behavioral dysfunctions induced in post-COVID-19 infection: A randomized, double-blind, and placebo-controlled study	https://doi.org/10.1016/j.jpsychores.2023.111389	Published	2023-05-31	Trial	https://www.sciencedirect.com/science/article/pii/S0022399923002465	Highlights •Post-COVID-19 complications persist in near 1/3 of the patients. •Cognitive impairment and neuropsychiatric disorders are the most common complications. •Few have assessed therapies for neuropsychiatric disorders caused by post-COVID-19 infection. •A short-term treatment with famotidine improved cognitive functioning in post-COVID-19 infection. Abstract Objectives This is an investigation of the efficacy and safety of famotidine, a selective histamine H2 receptor antagonist, on improvement of cognitive impairment, depression and anxiety symptoms developing post-COVID-19, in a 12-week, randomized controlled trial. Methods A total of 50 patients with a confirmed diagnosis of COVID-19 and a score ≤ 23 on the Mini-Mental State Examination (MMSE) test or a score ≤ 22 on the Montreal Cognitive Assessment (MoCA) were randomly assigned to either the famotidine (40 mg twice daily) or the placebo group. Changes in MMSE scores at weeks 6 and 12 were the primary outcome, while changes in other scales were the secondary outcomes. Participants and evaluators were blinded. Results At weeks 6 and 12, patients in the famotidine group had significantly higher MMSE scores (p = 0.014, p < 0.001, respectively). Regarding the MoCA scale, the famotidine group had a significantly higher score at weeks 6 and 12 (p = 0.001, p < 0.001, respectively). Considering the HAM-D scale (Hamilton Depression Rating Scale), at weeks 6 and 12, the famotidine group experienced a larger reduction (p = 0.009, p = 0.02, respectively). Additionally, comparison of the HAM-A scale scores (Hamilton Anxiety Rating Scale) at weeks 6 and 12 showed a statistically significant larger reduction in the famotidine group (p = 0.04, p = 0.02, respectively). The two groups did not differ in the frequency of adverse effects. Conclusion Our study supports safety and efficacy of famotidine in treating cognitive impairment, depression and anxiety symptoms induced by COVID-19.
371	Ce369		Cerfoglio, Serena; Capodaglio, Paolo; Rossi, Paolo; Verme, Federica; Boldini, Gabriele; Cvetkova, Viktoria; Ruggeri, Graziano; Galli, Manuela; Cimolin, Veronica	Tele-Rehabilitation Interventions for Motor Symptoms in COVID-19 Patients: A Narrative Review	https://doi.org/10.3390/bioengineering10060650	Published	2023-06-01	Review	https://www.mdpi.com/2306-5354/10/6/650	The COVID-19 pandemic brought new challenges to global healthcare systems regarding the care of acute patients and the delivery of rehabilitation programs to post-acute or chronic patients. Patients who survive severe forms of COVID-19 often report incomplete healing and long-term symptoms. The need of these patients for rehabilitation has been recognized as a public health problem. In this context, the application of tele-rehabilitation has been explored to reduce the burden on healthcare systems. The purpose of this narrative review is to present an overview of the state of the art regarding the application of remote motor rehabilitation programs for paucisymptomatic acute and post-acute COVID-19 patients, with a focus on the motor aspects of tele-rehabilitation. Following an extensive search on PubMed, the Web of Science, and Scopus, specific studies have been reviewed and compared in terms of study objectives and participants, experimental protocols and methods for home-based interventions, functional assessment, and rehabilitation outcomes. Overall, this review suggests the feasibility and the effectiveness of tele-rehabilitation as a promising tool to complement face-to-face rehabilitation interventions. However, further improvements are needed to overcome the limitations and the current lack of knowledge in the field.
372	Ce370		Tomisti, Luca; Angelotti, Francesca; Lenzi, Mirco; Amadori, Francesco; Sarteschi, Giovanni; Porcu, Anna; Capria, Anna-Lisa; Bertacca, Gloria; Lombardi, Stefania; Bianchini, Guido; Vincenti, Antonella; Cesta, Novella	Efficacy of Convalescent Plasma to Treat Long-Standing COVID-19 in Patients with B-Cell Depletion	https://doi.org/10.3390/life13061266	Published	2023-06-01	Case Report	https://www.mdpi.com/2075-1729/13/6/1266	The use of antivirals, corticosteroids, and IL-6 inhibitors has been recommended by the WHO to treat COVID-19. CP has also been considered for severe and critical cases. Clinical trials on CP have shown contradictory results, but an increasing number of patients, including immunocompromised ones, have shown benefits from this treatment. We reported two clinical cases of patients with prolonged COVID-19 infection and B-cell depletion who showed rapid clinical and virological recovery after the administration of CP. The first patient in this study was a 73-year-old female with a history of follicular non-Hodgkin lymphoma previously treated with bendamustine followed by maintenance therapy with rituximab. The second patient was a 68-year-old male with chronic obstructive pulmonary disease, bipolar disorder, alcoholic liver disease, and a history of mantellar non-Hodgkin lymphoma treated with rituximab and radiotherapy. After the administration of CP, both patients showed a resolution of symptoms, improvement of their clinical conditions, and a negative result of the nasopharyngeal swab test. The administration of CP might be effective in resolving symptoms and improving clinical and virological outcomes in patients with B-cell depletion and prolonged SARS-CoV2 infections.
373	Ce371		Melamed, Esther; Rydberg, Leslie; Ambrose, Anne Felicia; Bhavaraju-Sanka, Ratna; Fine, Jeffrey S.; Fleming, Talya K.; Herman, Eric; Phipps Johnson, Jamie L.; Kucera, Jennifer Ryan; Longo, Michele; Niehaus, William; Oleson, Christina V.; Sampsel, Sarah; Silver, Julie K.; Smith, Martha M.; Verduzco-Gutierrez, Monica	Multidisciplinary collaborative consensus guidance statement on the assessment and treatment of neurologic sequelae in patients with post-acute sequelae of SARS-CoV-2 infection (PASC)	https://doi.org/10.1002/pmrj.12976	Published	2023-03-29	Guidelines	https://onlinelibrary.wiley.com/doi/abs/10.1002/pmrj.12976	Despite the prevalence of neurological sequelae of COVID-19 infection and emerging data on longevity of symptoms, limited guidance exists regarding the assessment and treatment of neurologic sequelae in patients with PASC. The AAPM&R Multi-Disciplinary PASC Collaborative (PASC Collaborative), consisting of experts in PM&R, neurology, internal medicine, family practice, pediatric specialties, cardiology, physical therapy, occupational therapy, social work among other disciplines, was convened to address the pressing need for guidance in the care of patients with PASC. The PASC Collaborative is following an iterative, modified Delphi process to achieve consensus on assessment and treatment recommendations for a series of consensus guidance statements focused on the most prominent PASC symptoms. These recommendations and guidance are informed by experts from established PASC centers with experience in managing individuals across the spectrum of sequelae experienced by patients with PASC.8-10, 13, 14 There is an intentional focus on health equity as disparities in care and outcomes are critically important to address. Beyond patient care, the hope is that a broadened understanding of current patient care practices will help identify areas of future research. A full description of the methodology has been published previously.15 We acknowledge that the definition of PASC is evolving, and there are various factors that contribute to diagnosis and management. Literature available at the time of our consensus process suggested that PASC be defined as the persistence of symptoms beyond 4 weeks from the onset of acute infection.16 Alternative definitions of PASC include symptoms lasting longer than 3 months.17 The World Health Organization released a definition of “post-COVID condition,” including describing the timing as “usually 3 months from the onset of COVID-19” and lasting “for at least 2 months.”18 Based on patient feedback during our consensus process, we agree that earlier evaluation, diagnosis, and management can improve access to beneficial interventions. For the purposes of this guidance statement, we recommend expanded assessment if symptoms are not improving 1 month after acute symptom onset. At present, scientific evidence regarding effective assessment and treatment of PASC is limited, which prevents the creation of evidence-based clinical guidelines. This consensus guidance statement is intended to reflect current practice in patient assessment, testing, and treatments based on expert opinion from health care professionals who care for PASC patients regularly. It is intended as a resource and concise point of reference geared toward clinicians in different specialties caring for PASC patients. The recommendations should not preclude clinical judgment and must be applied in the context of the specific patient, with adjustments for patient preferences, comorbidities, and other factors. _eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1002/pmrj.12976
374	Ce372		Widmann, Catherine Nichols; Kolano, Juliana; Peper, Martin	Improving Neuropsychological Rehabilitation for COVID-19 Patients	https://doi.org/10.1024/1016-264X/a000373	Published	2023-06-01	Guidelines	https://econtent.hogrefe.com/doi/full/10.1024/1016-264X/a000373	: Cognitive sequelae after recovery from an initial COVID-19 disease are present in a subset of affected individuals, coalescing around several important issues such as effects of age, COVID-19 disease severity, comorbidities, and other factors. Some neuropsychological symptoms appear more common among certain patient populations. Comorbidities may complicate neuropsychological assessment as well. Hence, we need a guideline-based evaluation to guide neuropsychological rehabilitation. Drawing from the recent revision of the German National Guideline for the Long- and Post-COVID Syndrome and current advances in international guidance on neuropsychological assessment, this article provides practical and scientifically informed recommendations for the neuropsychological assessment of individuals recovering from coronavirus-related diseases.
375	Ce373		Hasting, Anna S.; Herzig, Sabine; Obrig, Hellmuth; Schroeter, Matthias L.; Villringer, Arno; Thöne-Otto, Angelika I. T.	The Leipzig Treatment Program for Interdisciplinary Diagnosis and Therapy of Neurocognitive Post-COVID Symptoms	https://doi.org/10.1024/1016-264X/a000376	Published	2023-06-01	Study	https://econtent.hogrefe.com/doi/full/10.1024/1016-264X/a000376	: This study introduces a 3-week group program designed for patients with neurocognitive post-COVID-19 syndrome (PCS). The program represents a combination of evidence-based components of neurorehabilitation and cognitive behavioral therapy (CBT). Following a detailed assessment, we develop a personalized bio-psycho-social model that integrates perceived complaints and identifies modifiable and influencing factors. We employed physiotherapeutic, cognitive, and communicative training methods to improve patients’ awareness of energy limits and implement compensatory strategies, including pacing and mindfulness techniques. N = 33 patients completed the program between June 2021 and November 2022. A pre-post comparison of questionnaire-based self-assessments revealed significant positive effects on mood, self-efficacy, and participation but not on fatigue symptoms. The study provides recommendations for the neuropsychological treatment of patients with PCS.
376	Ce374		Albiach, C; Dominguez, E; Lopez, L; Sastre, C; Minguez, S; Nunez, J; Palau Sampio, P	Effect of a home-based inspiratory muscle training program on functional capacity in post-discharged patients with long COVID: The InsCOVID trial	https://doi.org/10.1093/eurjpc/zwad125.022	Published	2023-06-01	Study	https://doi.org/10.1093/eurjpc/zwad125.022	Type of funding sources: Public Institution(s). Main funding source(s): Sociedad Española de Cardiología.Fatigue and exercise intolerance are the most common symptoms in patients with long COVID.This study aimed to evaluate whether a home-based inspiratory muscle training (IMT) program improves maximal functional capacity in patients long COVID after a previous admission due to SARS-CoV-2 pneumonia.This study was a single-centre, blinded assessor, randomised controlled trial. Twenty-six patients with long COVID and a previous admission due to SARS-CoV-2 pneumonia were randomly assigned to receive either a 12-week program of IMT or usual care alone. The physiotherapist and participants were not blinded. Patients allocated to the IMT arm were instructed to train at home twice daily using a threshold inspiratory muscle trainer and to maintain diaphragmatic breathing during the training session. The usual care arm received no intervention.The primary endpoint was changes in peak oxygen consumption (peakVO2). Secondary endpoints were changes in quality of life (QoL), ventilatory efficiency and chronotropic response during exercise (evaluated by chronotropic index-CIx- formula). We used linear mixed regression analysis for evaluating changes in primary and secondary endpoints.The median (interquartile range) age of the sample and time to first visit after discharge were 52 (42-59) years and 405 (301-435) days, respectively. A total of 11 (42.3%) were female. At baseline, the median of peakVO2, ventilatory efficiency and CIx were 17.4 (15.6-21.1) mL/kg/min, 29 (24.5-33.3), and 0.64 (0.54-0.87), respectively. The IMT arm improved their peakVO2 significantly compared to usual care (+Δ 4.46 mL/kg/min, 95% CI 3.10 to 5.81; p<0.001). Similar positive findings were found when evaluating changes for CIx and some QoL dimensions. We did not find significant changes in ventilatory efficiency.In long COVID patients with a previous admission due to SARS-CoV-2 pneumonia, IMT was associated with marked improvement in exercise capacity and QoL.
377	Ce375		Freda, Colette	Biofeedback and Anxiety Reduction: An Occupational Therapy Intervention for Persons with Long Covid		Published	2023-01-01	Study	https://encompass.eku.edu/otdcapstones/113	Background: People who acquire Covid 19 may have symptoms lasting over three months, called Long Covid. It is estimated that one in five people in the United States has Long Covid. Unpleasant symptoms of Long Covid are many including anxiety. People with Long Covid have a difficult time engaging in everyday activities and have a poor quality of life. Occupational therapy practitioners using heart rate variability (HRV) biofeedback may help decrease anxiety in the Long Covid population. There is limited research on occupational therapy and HRV biofeedback. Purpose: The problem the study addressed was to investigate the use of HRV biofeedback therapy delivered by an occupational therapy practitioner and its effectiveness to decrease anxiety levels in people with Long Covid. The research aimed to discover if HRV biofeedback decreased anxiety and increased the quality of life in persons with Long Covid. Methods: This study was quasi-experimental in the form of a pre-test-post-test design. Each participant was administered two pre-tests/posttests, the Generalized Anxiety Disorder (GAD) and the Quality of Life Scale (QOLS). Each participant received eight biofeedback sessions. Results: The results of this study found that HRV biofeedback demonstrated potential in decreasing anxiety and improving quality of life in persons with Long Covid. This study yielded a low sample size; therefore, more data needs to be collected in order to determine if the results are statistically significant. A minimal clinical difference of a 4-point change is considered clinically meaningful. Ten out of eleven participants in this study reported a decrease in anxiety based on the post-test outcome measures of the GAD-7 which is considered clinically meaningful. An increase of 8-9 points in the QOLS is considered a 60% improvement in quality of life. Nine out of eleven participants reported an improvement in their quality of life and as a group mean score, which was found to be clinically meaningful. Conclusions: The results of this pilot study appear promising for the use of HRV biofeedback to reduce anxiety and improve QOLS in persons with Long Covid. The study will continue to collect data until there are sufficient participants to perform paired-sample t-tests to determine the statistical significance of pre-test/post-test scores for both the GAD-7 and the QOLS.

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1	Ref	PPLC	Authors	Title	DOI	Peer reviewed	Date	type	Link	Keys	Clés

2	I01		Fan Wu, Aojie Wang, Mei Liu, Qimin Wang, Jun Chen, Shuai Xia, Yun Ling,	Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications	https://doi.org/10.1101/2020.03.30.20047365	pre-print	April 20, 2020	Study	https://www.medrxiv.org/content/10.1101/2020.03.30.20047365v2		Une mauvaise régulation des anticorps neutralisants pourrait expliquer d'autres symptômes.
3	I02		Rajani Dube1, Subhranshu Sekhar Kar2	COVID-19 in pregnancy: the foetal perspective—a systematic review	http://dx.doi.org/10.1136/bmjpo-2020-000859	Published	November 1, 2020	Original research	https://bmjpaedsopen.bmj.com/content/4/1/e000859		Selon une revue de la littérature, le risque de bébé mort-né chez les mères infectées par la covid est à 0,99% et celui des morts néonatales à 0,55%. Cependant, cette majoration du risque (> x2) aurait des causes indirectes et non liées à l'infection. L'infection au SARS-CoV-2 de la mère ne semble pas présenter de caractère tératogène. Le risque de transmission congénitale du virus est faible, entre 0,63 et 3% selon les études répertoriées dont certaines ont des biais de sélection.
4	I03		N.Haddad1S.Oro2C.Ram-Wolff3M.Bagot34L.Rousset1S.Dalac5L.Laroche1E.Maubec1Groupe	COVID-19 et lymphomes cutanés	https://doi.org/10.1016/j.annder.2020.09.237	Published	25 Nov 2020	Study	https://www.sciencedirect.com/science/article/pii/S0151963820306335		Les lymphomes cutanés primitifs à cellules B ou T (mycosis fongoïde), type de cancer du système lymphatique, sont décrits comme facteur de risque de covid sévère.
5	I04		Carel W. le Roux	COVID-19 alters thinking and management in metabolic diseases	https://doi.org/10.1038/s41574-020-00449-y	Published	25 November 2020	Article	https://www.nature.com/articles/s41574-020-00449-y		Les maladies métaboliques, sont décrites comme facteur de risque de covid sévère.
6	I004		Muge Cevik, MRCP Matthew Tate, MRCP Ollie Lloyd, MRCP Alberto Enrico Maraolo, MD Jenna Schafers, MRCP Antonia Ho, PhD	SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis	https://doi.org/10.1016/S2666-5247(20)30172-5	Published	November 19, 2020	Systematic review et méta-analyse	https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(20)30172-5/abstract		Une méta-analyse dans The Lancet (SRAS+MERS+SARS-CoV2, de 2003 à juin 2020) conclut que si l'excrétion d'ARN viral peut durer 126j dans les selles, aucun virus vivant de SARS-CoV-2 n'est présent dans les échantillons respiratoires après 9j de symptômes. "La transmission de la covid par voie respiratoire ne serait plus possible après 9 jours de symptômes, ce qui rendrait alors les tests PCR inutiles". La contagiosité serait plus courte pour les asymptomatiques. La possibilité de transmission par les selles est jugée incertaine.
7	I005	Yes	Eric Y. Wang, Tianyang Mao, Jon Klein, Yile Dai, John D. Huck, Feimei Liu, Neil S. Zheng, Ting Zhou, Patrick Wong, Akiko Iwasaki, Aaron M. Ring	Diverse Functional Autoantibodies in Patients with COVID-19	https://doi.org/10.1101/2020.12.10.20247205	pre-print	December 12, 2020		https://www.medrxiv.org/content/10.1101/2020.12.10.20247205v2	One of the co-authors : "New exciting collaboration work with @Aaronmring lab reveals diverse and functional autoantibodies in #COVID patients. Our findings provide clues for why COVID affects many organs, induce range of symptoms that are long lasting. A large fraction of #COVID patients had autoantibodies to multiple self antigens. The more severe the disease, more autoantibodies they had. So what are the targets of these autoantibodies? It turns out to be many. Some antibodies bound to interferons, chemokine and cytokines, while others bound to proteins expressed on the surface of immune and non-immune cells. ... These autoantibodies to IFN-I are likely functional - people who have them were unable to control viral load, compared to those without - matched for comparable average age, sex, and disease severity.	_
8	I006	Questionable methodology	Bruce Patterson, Jose Guevara-Coto, Ram Yogendra, Edgar B. Francisco, emily long, Amruta Pise, Hallison Rodrigues, Purvi Parikh, Javier Mora, Rodrigo A. Mora-Rodriguez	Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning	https://doi.org/10.1101/2020.12.16.423122	pre-print	December 22, 2020	New Results	https://www.biorxiv.org/content/10.1101/2020.12.16.423122v1		Le quotient : S1= (interférons γ (IFNγ) + interleukine 2 (IL-2)) / protéines CCL4 (MIP-1β) si supérieur à 0,4, permettrait de distinguer 97% des patients covid long sans faux positifs, selon un pre-print qui a utilisé un réseau neuronal...Ce qui signifie que les "covids longs" auraient un profil immunitaire efficace pour éliminer le virus mais sans les signaux de recrutement appropriés pour attirer les lymphocytes T activés. Cohorte de 144 patients, dont 64 covids longs et 25 sévères. De la même façon, la différence de taux : S2 = (10*IL-10 + IL-6) – (IL-2 + IL-8) si supérieur à 0, distinguerait les patients à covid sévère avec une sensibilité de 88% et une spécificité de 96%.Pour les patients à covid sévère, l'écart S2 traduit l'inflammation excessive, ainsi que l'activation dérégulée des lymphocytes T. L'étude a été menée par la société IncellDx, par analyse du plasma et isolation des cellules mononuclées du sang périphérique.
9	I007		Catherine J. Reynolds1,, Leo Swadling2,, Joseph M. Gibbons3,, Corinna Pade3,, Melanie P. Jensen4, Maria	Discordant neutralizing antibody and T cell responses in asymptomatic and mild SARS-CoV-2 infection	https://doi.org/10.1126/sciimmunol.abf3698	Published	23 Dec 2020	RESEARCH ARTICLE	https://immunology.sciencemag.org/content/5/54/eabf3698/		Une étude note des anomalies chez des malades asymptomatiques ou bénins de la covid, avec des réponses en anticorps et lymphocytes T parfois discordantes.
10	I008		Laura Bergamaschi, Federica Mescia, Lorinda Turner, Aimee Hanson, Prasanti Kotagiri, Benjamin J. Dunmore, Helene Ruffieux, Aloka De Sa, Oisin Huhn, Mark R. Wills,	Early immune pathology and persistent dysregulation characterise severe COVID-19	https://doi.org/10.1101/2021.01.11.20248765	pre-print	January 15, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.01.11.20248765v1	"Viral load does not correlate with the development of this pathological response, but does with its subsequent severity. Immune recovery is complex, with profound persi=stent cellular abnormalities correlating with a change in the nature of the inflammatory response, where signatures characteristic of increased oxidative phosphorylation and reactive-oxygen species-associated inflammation replace those driven by TNF and IL-6. These late immunometabolic inflammatory changes and unresolved immune cell defects, if persistent, may contribute to “long COVID”."	La façon dont le système immunitaire réagit dès l'infection covid, au plus tard aux premiers symptômes, permettrait de prédire une évolution bénigne ou non, selon une étude très qualitative encore non relue ni publiée. Selon ses auteurs, il n'y aurait pas de lien entre la charge virale aux premiers stades et la progression vers une maladie inflammatoire (covid sévère ou long). Mais une réponse immunitaire tardive serait signe d'une future évolution négative. Selon l'étude, une évolution vers un "covid long" peut résulter de modifications immuno-métaboliques inflammatoires tardives et d'altérations persistantes de certaines cellules immunitaires.
11	I009		Petter Brodin	Immune determinants of COVID-19 disease presentation and severity	https://doi.org/10.1038/s41591-020-01202-8	published	13 January 2021	Perspective	https://www.nature.com/articles/s41591-020-01202-8		Un article rappelle que le covid long est l'un des syndromes liés à la covid encore mal compris, avec le MIS-C (syndrome inflammatoire multisystémique chez l’enfant) et le MIS-A (le syndrome similaire chez l'adulte), et interroge le lien entre les 3.	N004
12	I010		Alisa Pavel, Giusy del Giudice, Antonio Federico, Antonio Di Lieto, Pia A S Kinaret, Angela Serra, Dario Greco	Integrated network analysis reveals new genes suggesting COVID-19 chronic effects and treatment	https://doi.org/10.1093/bib/bbaa417	Published	11 February 2021	Study	https://academic.oup.com/bib/advance-article/doi/10.1093/bib/bbaa417/6132618	•Integrated molecular network analysis can help to clarify the pathogenesis of complex diseases and suggest novel drug targets. •By mapping SARS-CoV-2 first physical interactors and COVID-19 downstream differentially expressed genes on the integrated human molecular network, we identified a new set of intermediate genes. •The newly discovered set of intermediate genes underlies important aspects of COVID-19 pathogenesis and long-term consequences, pointing to lung tissue remodelling and fibrosis. • We highlighted immuno-modulatory and anti-angiogenic drugs targeting multiple genes in each and every relevant set: physical interactors, intermediate and downstream effectors.	Compilant plusieurs bases de données, une étude identifie des gènes susceptibles de favoriser une covid plus grave, et particulièrement les séquelles persistantes. Elle liste des médicaments qui pourraient atténuer ces prédispositions.	N002N
13	I011		Xiao-Lin Jiang, Guo-Lin Wang, Xiang-Na Zhao, Fei-Hu Yan, Lin Yao, Zeng-Qiang Kou, Sheng-Xiang Ji, Xiao-Li Zhang, Cun-Bao Li, Li-Jun Duan, Yan Li, Yu-Wen Zhang, Qing Duan, Tie-Cheng Wang, En-Tao Li, Xiao Wei, Qing-Yang Wang, Xue-Feng Wang, Wei-Yang Sun, Yu-Wei Gao, Dian-Min Kang, Ji-Yan Zhang & Mai-Juan Ma	Lasting antibody and T cell responses to SARS-CoV-2 in COVID-19 patients three months after infection	https://doi.org/10.1038/s41467-021-21155-x	Published	09 February 2021	Study	https://www.nature.com/articles/s41467-021-21155-x	Our results thus provide critical evidence that IgG, NAb, and T cell responses persist in the majority of patients for at least 3–4 months after infection.	Cette étude indique que les anticorps neutralisants, d'autres comme l'immunoglobulines de type G, ainsi que les lymphocytes T restent présents chez une majorité de patients 3 à 4 mois après une infection de covid.
14	I012		Erfan Taherifard,Ehsan Taherifard,Hamed Movahed &Mohammad Reza Mousavi	Hematologic autoimmune disorders in the course of COVID-19: a systematic review of reported cases	https://doi.org/10.1080/16078454.2021.1881225	Published	17 Feb 2021	Systematic Review	https://www.tandfonline.com/doi/full/10.1080/16078454.2021.1881225	the most common hematologic autoimmune disorder was ITP in 55 cases (58%) followed by autoimmune hemolytic anemia (AIHA) in 22 cases (23%). Other hematologic autoimmune disorders observed in the literature include antiphospholipid syndrome (APLS) in 10 individuals, thrombotic thrombocytopenic purpura (TTP) in 3 individuals, Evans syndrome in 3 individuals and autoimmune neutropenia in one individual	Dans une revue d'études s'intéressant aux affections auto-immunes hématologiques qui sont parfois consécutives à la covid, une équipe de chercheurs remarquent que le purpura thrombopénique immunologique (une destruction périphérique des plaquettes dans le cadre d'un processus auto-immun médié par des autoanticorps) est le trouble le plus fréquent. Le second trouble en prévalence est l'anémie hémolytique autoimmune (les anticorps s'attaquant aux globules rouges).
15	I013		Javier García-Abellán, Sergio Padilla, Marta Fernández-González, José A. García, Vanesa Agulló, María Andreo, Sandra Ruiz, Antonio Galiana, Félix Gutiérrez, Mar Masiá	Long-term clinical, virological and immunological outcomes in patients hospitalized for COVID-19: antibody response predicts long COVID	https://doi.org/10.1101/2021.03.08.21253124	pre-print	March 08, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.03.08.21253124v1.article-info	Gender, severity of illness and weaker antibody responses, but not viral shedding, were associated with long-COVID.	Sur 146 patients covid hospitalisés, une étude non relue et non publiée note que 7,8% des patients rapportent des symptômes persistants modérés/sévères à 6 mois. Le sexe féminin et un faible taux d'anticorps Spike-IgG augmente le risque de symptômes à 6 mois. Aucune association n'est constatée avec une excrétion virale prolongée.
16	I014		N. Winchester, BS1, C. Calabrese, DO2, L.H. Calabrese, DO2	The intersection of COVID-19 and autoimmunity: What is our current	https://doi.org/10.20411/pai.v6i1.417	Published	March 8, 2021	Study	https://www.paijournal.com/index.php/paijournal/article/download/417/325	The purpose of this review was not to provide a systematic review of this literature but rather to pose critical questions regarding the intersections of COVID-19 and autoimmunity and attempt to address them with a critical synthesis of select works that may provide insight or direction - at least for the moment.	Un article assez technique explore le lien entre les maladies auto-immune et la covid, et se demande comment celle-ci pourrait déclencher une maladies inflammatoire à médiation immunitaire.	N003A
17	I015		Florence WJ Chioh, Siew-Wai Fong, Barnaby E Young, Kan-Xing Wu, Anthony Siau, Shuba Krishnan, Yi-Hao Chan, Guillaume Carissimo, Louis LY Teo, Fei Gao, Ru San Tan, Liang Zhong, Angela S Koh, Seow-Yen Tan, Paul A Tambyah, Laurent Renia, Lisa FP Ng, David C Lye, Christine Cheung	Convalescent COVID-19 patients are susceptible to endothelial dysfunction due to persistent immune activation	https://doi.org/10.7554/eLife.64909	Published	Mar 23, 2021	Research Article	https://elifesciences.org/articles/64909	We found elevated levels of circulating endothelial cells (CECs), a biomarker of vascular injury, in COVID-19 convalescents compared to healthy controls. In particular, those with pre-existing conditions (e.g., hypertension, diabetes) had more pronounced endothelial activation hallmarks than non-COVID-19 patients with matched cardiovascular risk. Several proinflammatory and activated T lymphocyte-associated cytokines sustained from acute infection to recovery phase, which correlated positively with CEC measures, implicating cytokine-driven endothelial dysfunction. Notably, we found higher frequency of effector T cells in our COVID-19 convalescents compared to healthy controls. The activation markers detected on CECs mapped to counter receptors found primarily on cytotoxic CD8+ T cells, raising the possibility of cytotoxic effector cells targeting activated endothelial cells.	Une étude note un taux élevé de cellules endothéliales circulantes (CEC), un biomarqueur des lésions vasculaires, chez les convalescents de la covid par rapport aux témoins sains. Elle repère notamment des cytokines associées aux lymphocytes T pro-inflammatoires qui se maintiennent pendant la phase de récupération, impliquant un dysfonctionnement endothélial induit par celles-ci.	N006
18	I016		Ales Macela andKlara Kubelkova	Why Does SARS-CoV-2 Infection Induce Autoantibody Production?	https://doi.org/10.3390/pathogens10030380	Published	22 March 2021	Opinion	https://www.mdpi.com/2076-0817/10/3/380	SARS-CoV-2 infection induces the production of autoantibodies, which is significantly associated with complications during hospitalization and a more severe prognosis in COVID-19 patients. Such a response of the patient’s immune system may reflect (1) the dysregulation of the immune response or (2) it may be an attempt to regulate itself in situations where the non-infectious self poses a greater threat than the infectious non-self. Of significance may be the primary virus-host cell interaction where the surface-bound ACE2 ectoenzyme plays a critical role. Here, we present a brief analysis of recent findings concerning the immune recognition of SARS-CoV-2, which, we believe, favors the second possibility as the underlying reason for the production of autoantibodies during COVID-19.	Une analyse qualitative tente de comprendre pourquoi la covid entraîne une production d'auto-anticorps. Les auteurs appuient l'hypothèse que le corps entre dans une tentative de se réguler dans une situation où le soi non-infectieux représente une menace plus grande que le non-soi infectieux.	N006
19	I017		Rohan Ameratunga 1 2 3, See-Tarn Woon 2, Anthony Jordan 1, Hilary Longhurst 1 4, Euphemia Leung 5, Richard Steele 2 6, Klaus Lehnert 7, Russell Snell 7, Anna E S Brooks	Perspective: Diagnostic laboratories should urgently develop T cell assays for SARS-CoV-2 infection	https://doi.org/10.1080/1744666x.2021.1905525	Published	2021 Mar 22	Perspective Article	https://pubmed.ncbi.nlm.nih.gov/33745411/	The role of T cells in acute illness is uncertain but long-term protection against the virus may rely on memory T cell responses. Measuring memory T cell responses is important for retrospective confirmation of cases, who may have been infected early in the pandemic before reliable RT-qPCR tests were available and whose SARS-CoV-2 antibodies may have become undetectable.	Dans la mesure où les anticorps suite à une infection à la covid peuvent parfois rapidement disparaître, voire être très peu présents même en première phase, un article plaide pour le développement rapide de tests de lymphocytes T pour déceler une infection passée.	N006
20	I018		Kwang Su Kim ,Keisuke Ejima ,Shoya Iwanami,Yasuhisa Fujita,Hirofumi Ohashi,Yoshiki Koizumi,Yusuke Asai,Shinji Nakaoka,Koichi Watashi,Kazuyuki Aihara,Robin N. Thompson,Ruian Ke,Alan S. Perelson ,Shingo Iwami	A quantitative model used to compare within-host SARS-CoV-2, MERS-CoV, and SARS-CoV dynamics provides insights into the pathogenesis and treatment of SARS-CoV-2	https://doi.org/10.1371/journal.pbio.3001128	Published	March 22, 2021		https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001128	These findings suggest the difficulty of controlling SARS-CoV-2 infection by antivirals. We further used the viral dynamics model to predict the efficacy of potential antiviral drugs that have different modes of action. The efficacy was measured by the reduction in the viral load area under the curve (AUC). Our results indicate that therapies that block de novo infection or virus production are likely to be effective if and only if initiated before the viral load peak (which appears 2–3 days after symptom onset), but therapies that promote cytotoxicity of infected cells are likely to have effects with less sensitivity to the timing of treatment initiation. Furthermore, combining a therapy that promotes cytotoxicity and one that blocks de novo infection or virus production synergistically reduces the AUC with early treatment. Our unique modeling approach provides insights into the pathogenesis of SARS-CoV-2 and may be useful for development of antiviral therapies.	Une étude soutient l'idée que le contrôle de la covid est très délicat par des antiviraux. Elle affirme que seule une thérapie commencée avant le maximum de charge virale (soit 2 ou 3 jours après le début des symptômes) peut être efficace. L'alternative serait de conjuguer l'action avec une thérapie ciblant les cellules infectés en favorisant les effets cytotoxiques.	N006
21	I019		Quan-Xin Long, Yan-Jun Jia, Xin Wang, Hai-Jun Deng, Xiao-Xia Cao, Jun Yuan, Liang Fang, Xu-Rong Cheng, Chao Luo, An-Ran He, Xiao-Jun Tang, Jie-li Hu, Yuan Hu, Ni Tang, Xue-Fei Cai, De-Qiang Wang, Jie Hu, Jing-Fu Qiu, Bei-Zhong Liu, Juan Chen & Ai-long Huang	Immune memory in convalescent patients with asymptomatic or mild COVID-19	https://doi.org/10.1038/s41421-021-00250-9	Published	25 March 2021	Article	https://www.nature.com/articles/s41421-021-00250-9	Here, we systematically evaluated the SARS-CoV-2-specific memory B cell and T cell responses in healthy controls and individuals recovered from asymptomatic or symptomatic infection approximately 6 months prior.	_
22	I020		Lauren Eggert,Ziyuan He,William Collins,Alexandra Lee,Gopal Dhondalay,Shirley Jiang,Jessica Fitzpatrick,Theo Snow,Benjamin Pinsky,Maja Artandi,Linda Barman,Rajan Puri,Richard Wittman,Andra Blomkalns,Shu Cao,Ruth O'Hara,Neera Ahuja,Manisha Desai,Sayantani Sindher,Kari Nadeau,Sharon Chinthrajah	Asthma phenotypes, associated comorbidities, and long-term symptoms in COVID-19	https://doi.org/10.22541/au.161661725.56823358/v1	pre-print	March 24, 2021	Study	https://www.authorea.com/users/403836/articles/515192-asthma-phenotypes-associated-comorbidities-and-long-term-symptoms-in-covid-19	Asthma is not a risk factor for more severe COVID-19 disease. Allergic asthmatics were half as likely to be hospitalized with COVID-19 compared to non-allergic asthmatics. Lower levels of eosinophil counts (allergic biomarkers) were associated with more severe COVID-19 disease trajectory. Recovery was similar among asthmatics and non-asthmatics with over 50% of patients reporting ongoing lower respiratory symptoms three months post-infection.	Selon une étude, l'asthme n'apparaît pas comme un facteur de comorbidités pour une covid sévère, les allergies athmatiques pourraient même entrainer un risque moindre de complications.
23	I021		Halima A.Shuwa111Tovah N.Shaw1211Sean B.Knight13KellyWemyss1Flora A.McClure1LaurencePearmain45IanPrise1ChristopherJagger1David J.Morgan1SabaKhan1OliverBrand1Elizabeth R.Mann16AndrewUstianowski7Nawar DiarBakerly3PaulDark510Christopher E.Brightling8SeemaBrij	Alterations in T and B cell function persist in convalescent COVID-19 patients	https://doi.org/10.1016/j.medj.2021.03.013	Published	31 March 2021		https://www.sciencedirect.com/science/article/pii/S266663402100115X	We report that the alterations in B cell subsets observed in acute COVID-19 patients were largely recovered in convalescent patients. In contrast, T cells from convalescent patients displayed continued alterations with persistence of a cytotoxic program evident in CD8+ T cells as well as elevated production of type 1 cytokines and interleukin-17 (IL-17). Interestingly, B cells from patients with acute COVID-19 displayed an IL-6/IL-10 cytokine imbalance in response to Toll-like receptor activation, skewed toward a pro-inflammatory phenotype. Whereas the frequency of IL-6+ B cells was restored in convalescent patients irrespective of clinical outcome, the recovery of IL-10+ B cells was associated with the resolution of lung pathology. Highlights . Lymphocytes were examined during COVID-19 and at up to 6 months of convalescence . B cell changes seen during acute COVID-19 were largely restored in convalescence . T cells from convalescent COVID-19 patients displayed persistent changes . Lymphocyte signatures defined 3 convalescent patient groups, one with poorer outcomes	Chez les malades de la covid présentant des symptômes persistants, une étude montre une activité cytotoxique des lymphocytes T CD8, et une production élevée de cytokines de type 1 et d'interleukine 17 (IL-17).	N010
24	I022		Jean-Baptiste Dalmas	Éosinopénie et COVID-19		Published	10 avril 2021	Mémoire d'étudiant	https://hal-obspm.ccsd.cnrs.fr/MEM-UNIV-AMU/dumas-03193755v1		_
25	I023		Elena Ortona, Danilo Buonsenso, Angelo Carfi, Walter Malorni & The Long Covid Kids study group	Long COVID: an estrogen-associated autoimmune disease?	https://doi.org/10.1038/s41420-021-00464-6	Published	13 April 2021	Comment	https://www.nature.com/articles/s41420-021-00464-6	Organ damage caused by an excessive inflammatory response activated by the virus, but also an autoimmune reaction “unmasked” by the virus itself, perhaps due to molecular mimicry with some components of our body, could be responsible for the symptoms of Long COVID5. The autoimmune hypothesis could justify the higher incidence of this syndrome in women. In fact, the immune response for both genetic and hormonal factors is stronger in women than in men and this represents a double-edged sword: the outcome of acute COVID-19 is more severe in men but autoimmune reactions are more frequent in women6,7. Hence, the study of the appearance of autoantibodies in patient serum and the characterization of the specificity of these autoantibodies could be an important goal to begin to identify personalized and specific treatments also based on the sex of patients affected by Long COVID.	_
26	I024		Yu Zuo, Srilakshmi Yalavarthi, Sherwin Navaz, Claire Hoy, Hui Shi, Alyssa Harbaugh, Kelsey Gockman, Melanie Zuo, Jacqueline A. Madison, Yogendra Kanthi, Jason S. Knight	Autoantibodies stabilize neutrophil extracellular traps in COVID-19	https://doi.org/10.1101/2021.03.31.21254692	pre-print	April 05, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.03.31.21254692v1	The release of neutrophil extracellular traps (NETs) by hyperactive neutrophils is recognized to play an important role in the thromboinflammatory milieu inherent to severe presentations of COVID-19. At the same time, a variety of functional autoantibodies have been observed in individuals with severe COVID-19 where they likely contribute to immunopathology. Here, we aimed to determine the extent to which autoantibodies might target NETs in COVID-19 and, if detected, to elucidate their potential functions and clinical associations. We measured global anti-NET activity in 171 individuals hospitalized with COVID-19 alongside 48 healthy controls. We found high anti-NET activity in the IgG and IgM fractions of approximately 40% and 50% of patients, respectively. There was a strong correlation between anti-NET IgG and anti-NET IgM, with high anti-NET antibody levels in general associating with circulating markers of NETs such as myeloperoxidase-DNA complexes and calprotectin. Clinically, anti-NET antibodies tracked with impaired oxygenation efficiency and elevated levels of circulating D-dimer. Furthermore, patients who required mechanical ventilation had higher levels of anti-NET antibodies than those who did not require oxygen supplementation. Mechanistically, anti-NET antibodies of the IgG isotype impaired the ability of DNases in healthy serum to degrade NETs. In summary, these data reveal high levels of anti-NET antibodies in individuals hospitalized with COVID-19, where they likely impair NET clearance and thereby potentiate SARS-CoV-2 mediated thromboinflammation.	_
27	I025		GerdWallukatabBettinaHohbergercKatrinWenzelbJuliaFürstdSaraSchulze-RothebAnneWallukatbAnne-SophieHönickebJohannesMüller	Functional autoantibodies against G-protein coupled receptors in patients with persistent post-COVID-19 symptoms	https://doi.org/10.1016/j.jtauto.2021.100100	Published	16 April 2021	Study	https://www.sciencedirect.com/science/article/pii/S2589909021000204	Highlights •Sera from post-COVID syndrome patients contained functionally active autoantibodies which target G-protein coupled receptors. •The list included pathogenic autoantibodies targeting the nociception receptor, the β2-and α1-adrenoceptors, angiotensin II AT1-, muscarinic M2-, MAS-, and ETA-receptors. •Included syndromes were of neurological and cardiological origin, or a combination of both. •This type of pathogenic autoantibody and specific autoantibody pattern were described before the first appearance of SARS-CoV2 in distinct neurological deficits and cardiovascular diseases.	Une étude renforce l'hypothèse que des symptômes de covid long pourrait traduire l'installation d'une maladie auto-immune. Elle relève la présence d'autoanticorps pathogènes fonctionnellement actifs (fAAB) ciblant les récepteurs couplés aux protéines G (GPCR-fAAB) chez les malades à distance de l'infection. Un tel processus était, par le passé, déjà identifié comme favorisant des symptômes neurologiques et cardiaques, par une perturbation d'équilibre de mécanismes neuronaux et vasculaires.Selon les auteurs, ces éléments suggèrent qu'une combinaison de cofacteurs ischémiques ou inflammatoires, mais également d'autoanticorps, peut maintenir notamment un processus inflammatoire cardiaque.	N009
28	I026		Liang Cheng, Zijun Zhu, Chao Wang, Ping Wang, Yongqun Oliver He, and Xue Zhang	COVID-19 induces lower levels of IL-8, IL-10, and MCP-1 than other acute CRS-inducing diseases	https://doi.org/10.1073/pnas.2102960118	Published	May 10, 2021	Letter	https://www.pnas.org/content/118/21/e2102960118	Overall, our MR analysis shows that COVID-19 induced lower levels of IL-8, IL-10, and MCP-1 than other acute diseases in CRS patients, suggesting a critical COVID-19 pathogenesis mechanism, that is, lowering the levels of these three cytokines in COVID-19 patients with CRS compared with the levels in those patents with other acute CRS-inducing diseases including bacterial sepsis, ARDS, and burns.	En comparaison avec d'autres maladies provoquant des orages de cytokines, la covid se distingue selon une étude par des niveaux plus faibles des trois cytokines suivantes : IL-8, IL-10 et MCP-1.	N010
29	I027		Andreas Wack	Monocyte and dendritic cell defects in COVID-19	https://doi.org/10.1038/s41556-021-00685-y	Published	10 May 2021	Article	https://www.nature.com/articles/s41556-021-00685-y	Regarding therapeutic options, the results of this study suggest that boosting the pathways found to be impaired in patients with severe disease may be beneficial. IFN therapies have been hotly debated, and several versions have been tested with mixed results and controversial interpretations; this may not come as a surprise, given that both loss of IFN function and excessive IFNs were linked to severe COVID-19 (refs. 7,8,10). What seems clear is that IFN therapy may be most beneficial if given early, as later intervention may lead to complications due to the pro-inflammatory and anti-proliferative effects associated with IFNs6,10,14,15. In addition, whether or not patients with moderate disease should be regarded as prototypes of a successful antiviral response is unclear, as it could be argued that they still require hospital assistance and do not clear the virus with only minimal clinical symptoms, which is the assumed course of infection for many people infected by SARS-CoV-2 who remain below the clinical radar. Through the present study and many others, a coherent picture of severe COVID-19 is slowly emerging, and more work will be required to add higher resolution in time and space to the complex evolution of the immune response and its protective and pathogenic effects in COVID-19.	_
30	I028		Chung-HsiangLiab1Hsin-YingClair Chiouc1Ming-HongLindChang-HungKuoeYu-ChihLinfgYi-ChingLinhij2Chih-HsingHungklmn2Chao-HungKuo	Immunological Map in COVID-19	https://doi.org/10.1016/j.jmii.2021.04.006	Published	12 May 2021	Review	https://www.sciencedirect.com/science/article/pii/S1684118221000967	We constructed a brief summary comparison of SARS-CoV-2, SARS-CoV, and MERS-CoV infections regarding their immunological changes. In addition, we further investigated the immunological differences between severe and nonsevere COVID-19 cases, and we searched for possible immunological predictors of the patient outcome by reviewing case series studies to date. Possible immunological predictors of a poor outcome are leukocytosis, neutrophilia, lymphopenia (both CD4 and CD8 T cells), an increased neutrophil-to-lymphocyte ratio (NLR), and increased levels of pro-inflammatory cytokines (IL-6 and TNF-α), Th1 cytokines (IL-2 and IFN-γ), regulatory T cell cytokines (IL-10) and Th17 cytokines (IL-17). A more precise immunological map needs to be established, which may assist in diagnosing this disease and facilitate immunological precision medicine treatment.	_
31	I029		Shengli Ma, Fan Zhang, Fengxia Zhou, Hui Li, Wenyu Ge, Rui Gan, Huan Nie, Biao Li, Yindong Wang, Meng Wu, Duo Li, Dongmei Wang, Zheng Wang, Yuhong You & Zhiwei Huang	Metagenomic analysis reveals oropharyngeal microbiota alterations in patients with COVID-19	https://doi.org/10.1038/s41392-021-00614-3	Published	13 May 2021	Study	https://www.nature.com/articles/s41392-021-00614-3	Here, we present the oropharyngeal microbiota characteristics identified by shotgun metagenomic sequencing analyses of oropharynx swab specimens from 31 COVID-19 patients, 29 influenza B patients, and 28 healthy controls. Our results revealed a distinct oropharyngeal microbiota composition in the COVID-19 patients, characterized by enrichment of opportunistic pathogens such as Veillonella and Megasphaera and depletion of Pseudopropionibacterium, Rothia, and Streptococcus. Based on the relative abundance of the oropharyngeal microbiome, we built a microbial classifier to distinguish COVID-19 patients from flu patients and healthy controls with an AUC of 0.889, in which Veillonella was identified as the most prominent biomarker for COVID-19 group. Several members of the genus Veillonella, especially Veillonella parvula which was highly enriched in the oropharynx of our COVID-19 patients, were also overrepresented in the BALF of COVID-19 patients, indicating that the oral cavity acts as a natural reservoir for pathogens to induce co-infections in the lungs of COVID-19 patients. We also found the increased ratios of Klebsiella sp., Acinetobacter sp., and Serratia sp. were correlated with both disease severity and elevated systemic inflammation markers (neutrophil–lymphocyte ratio, NLR), suggesting that these oropharynx microbiota alterations may impact COVID-19 severity by influencing the inflammatory response. Moreover, the oropharyngeal microbiome of COVID-19 patients exhibited a significant enrichment in amino acid metabolism and xenobiotic biodegradation and metabolism. In addition, all 26 drug classes of antimicrobial resistance genes were detected in the COVID-19 group, and were significantly enriched in critical cases. In conclusion, we found that oropharyngeal microbiota alterations and functional differences were associated with COVID-19 severity.	Une publication dans Nature note des modifications spécifiques du microbiote dans le milieu oropharyngé des malades de la covid. Ces altérations pourraient selon les auteurs avoir un impact sur la réponse inflammatoire.	N011
32	I030		Sílvia Guerrero Caballeroa,*, Sonia Bilbao Fernándezb	Persistencia del virus SARS-CoV-2 como causa etiológica de la sintomatología de larga duración en pacientes con COVID-19 persistente - Persistence of the SARS-CoV-2 virus as etiological cause of long-term symptoms in persistent COVID-19 patients	http://dx.doi.org/10.24038/mgyf.2021.027		6 de mayo de 2021		http://mgyf.org/persistencia-virus-sars-cov-2-causa-etiologica-sintomatologia-larga-duracion-en-pacientes-con-covid-19-persistente/	At present, there are significant gaps in knowledge regarding the COVID-19, result of infection due to SARS-CoV-2 virus, since a very short period of time has passed since its appearance. This viral infection has presented with a wide range of clinical manifestations whose severity has varied greatly among the patients: persons who have required hospitalization, very ill patients with fatal consequences, subjects with long-term symptoms and others who are asymptomatic. From the research group of Long COVID ACTS (patients with persistent symptoms of COVID-19) we have focused on the development of a scientific hypothesis in order to not rule out (and even strengthen) research projects based on the persistence of the SARS-CoV-2 virus as etiological cause of the symptoms in patients who present Persistent/Long COVID clinical symptoms (CP/LC).	_
33	I031		David T. Arnold, MBChB, BSc, Alice Milne, MSc, Emma Samms, Louise Stadon, BSc, Nick A. Maskell, DM, Fergus W. Hamilton	Symptoms After COVID-19 Vaccination in Patients With Persistent Symptoms After Acute Infection: A Case Series	https://doi.org/10.7326/M21-1976	Published	25 May 2021	Letter	https://www.acpjournals.org/doi/10.7326/M21-1976	Participants were telephoned a median of 30 days after vaccination (IQR, 26 to 36 days) to investigate changes in symptoms and quality of life. Among the 159 symptoms reported before vaccination, 37 (23.2%) had improved, 9 (5.6%) had worsened, and 113 (71.1%) were unchanged (Figure). There was no significant worsening in quality-of-life metrics before versus after vaccination (t test P > 0.1 for all SF-36 comparisons).	Dans une étude qui présente des limitations (cohorte d'une trentaine de patients et pas de double aveugle), davantage de malades du covid long observent une amélioration de leurs symptômes et quelques uns moins nombreux une dégradation. Les vaccins étaient Pfizer et AstraZeneca, aucun avantage de l'un sur l'autre n'est mesuré.	N010
34	I032		Chansavath Phetsouphanh, David Darley, Anette Howe, C. Mee Ling Munier, Sheila K Patel, Jenifer A Juno, Louise M Burrell, Stephen J Kent, Gregory J Dore, Anthony D Kelleher, Gail Matthews	Immunological dysfunction persists for 8 months following initial mild-moderate SARS-CoV-2 infection	https://doi.org/10.1101/2021.06.01.21257759	pre-print	June 03, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.06.01.21257759v1.full-text	Here we studied a prospective cohort of individuals with long COVID (the ADAPT study) compared to age/gender matched subjects without long COVID, healthy donors and individuals infected with other non-SARS CoV2 human coronaviruses (the ADAPT-C study). We found an elevated diffuse serum inflammatory cytokine profile in symptomatic long COVID subjects that was maintained at 8 months post-infection and was not observed in asymptomatic COVID-19 survivors. This inflammatory profile consisted of 15 cytokines that positively correlated; revealing an apparent diffuse, potentially coordinated, low level up regulation of a spectrum of immune and inflammatory mediators. In addition, we found an absence of subsets of un-activated naїve T and B cells in peripheral blood of long COVID subjects, that did not reconstitute over time. In contrast, individual serum cytokines from the interferon I and III classes, T cell activation markers and plasma ACE2, while elevated in the serum of people previously infected with SARS-CoV-2 were not further elevated in subjects with long COVID symptoms. This work defines immunological parameters associated with long COVID and suggests future opportunities to prevention and treatment.	Une étude en pre-print note des modifications et dérégulations immunologiques particulières à 8 mois chez des patients covid long avec une phase initiale modérée.
35	I033		Sanjay Pujari 1, Sunil Gaikwad 1, Abhishek Chitalikar 1, Digamber Dabhade 1, Kedar Joshi 1, Vivek Bele 1	Long-coronavirus disease among people living with HIV in western India: An observational study	https://doi.org/10.1002/iid3.467	Published	2021 Jun 2	Study	https://pubmed.ncbi.nlm.nih.gov/34078004/	Long-COVID is common among PLHIV with moderate-severe acute COVID-19 illness. There is a need for integration of long-COVID diagnosis and care services within antiretroviral therapy clinics for PLHIV with COVID-19.	_
36	I034		Jacob K. Files,1 Sanghita Sarkar,1 Timothy R Fram.,1 Sushma Boppana,1 Sarah Sterrett,1 Kai Qin,1 Anju Bansal,1 Dustin M. Long,2 Steffanie Sabbaj,1 James J. Kobie,1 Paul A. Goepfert,1 and Nathan Erdmann1	Duration of post-COVID-19 symptoms are associated with sustained SARS-CoV-2 specific immune responses	https://doi.org/10.1172/jci.insight.151544	Published	June 18, 2021	Study	https://insight.jci.org/articles/view/151544	We investigated longitudinal peripheral blood samples in 50 individuals with previously confirmed SARS-CoV-2 infection, including 20 who experienced prolonged duration of COVID-19 symptoms (lasting more than 30 days; median=74 days) compared to 30 who had symptom resolution in 20 days or less. Individuals with prolonged symptom duration maintained antigen-specific T-cell response magnitudes to SARS-CoV-2 spike protein in CD4+ and cTfh populations during late convalescence while those without persistent symptoms demonstrated an expected decline. The prolonged group also displayed increased IgG avidity to SARS-CoV-2 S-protein. Significant correlations between symptom duration and both SARS-CoV-2-specific T cells and antibodies were observed. Activation and exhaustion markers were evaluated in multiple immune cell types, revealing few phenotypic differences between prolonged and recovered groups suggesting that prolonged symptom duration is not due to persistent systemic inflammation. These findings demonstrate that SARS-CoV-2-specific immune responses are maintained in patients suffering from prolonged post-COVID-19 symptom duration in contrast to those with resolved symptoms and may suggest the persistence of viral antigens as an underlying etiology.	Une étude américaine note que les malades du covid long conservent des taux élevés de lymphocytes T spécifiques de l'antigène de la protéine Spike du SARS-CoV-2, tout comme une activité similaire des immunoglobulines de type G. Ces résultats appuient la possibilité que des réponses immunitaires spécifiques au SARS-CoV-2 sont maintenues chez les malades du covid long, et pourraient suggérer la persistance d'antigènes viraux comme étiologie sous-jacente, appuyant l'hypothèse de réservoirs viraux.	N011
37	I035	Questionable methodology (preprin I07)	Bruce Patterson1*, Jose Guevara-Coto2, Ram Yogendra3, Edgar Francisco1, Emily Long1, Amruta Pise1, Hallison Rodrigues1, Purvi Parikh4, Javier Mora5 and Rodrigo A. Mora-Rodríguez5	Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning	https://doi.org/10.3389/fimmu.2021.700782	Published	10 Jun 2021	Study	https://www.frontiersin.org/articles/10.3389/fimmu.2021.700782/abstract	Publication of pre-print I07. Cf above.
38	I036		Bruce Patterson, Edgar B. Francisco, Ram Yogendra, Emily Long, Amruta Pise, Hallison Rodrigues, Eric Hall, onica Herrera, Purvi Parikh, Jose Guevara-Coto, Xaiolan Chang, Jonah B Sacha, Rodrigo Rodriguez, Javier Mora	Persistence of SARS CoV-2 S1 Protein in CD16+ Monocytes in Post-Acute Sequelae of COVID-19 (PASC) Up to 15 Months Post-Infection	https://doi.org/10.1101/2021.06.25.449905	pre-print	June 25, 2021	Study	https://www.biorxiv.org/content/10.1101/2021.06.25.449905v1	To be linked to I35.
39	I037		Hannah Zacharias a Shirish Dubey ab Gouri Koduric David D'Cruz d	Rheumatological complications of Covid 19	https://doi.org/10.1016/j.autrev.2021.102883	Published	5 July 2021	Review	https://www.sciencedirect.com/science/article/pii/S1568997221001567	Results We found a number of reports of inflammatory arthritis after SARS-CoV-2 infection. SLE and renal disease have been described, and vasculitis also appears to be a common complication. Rhabdomyolysis and myositis has also been reported in a number of patients. We also found some evidence of large vessel vasculitis in ‘long COVID’ patients. Conclusions This review highlights a number of important complications such as inflammatory arthritis, lupus-like disease, myostis and vasculitis following SARS-CoV-2 infection.	Une revue d'études sur les rhumatismes et arthrites causées par la covid. Les auteurs rapportent les arthrites inflammatoires, les troubles du tissu conjonctif, les vascularites (à petits, gros vaisseaux, et à IgA), les manifestations cutanées, les atteintes du système nerveux central, et les syndromes inflammatoires multi-systémiques.	N014E
40	I038		Rolf F. Barth, MD; L. Maximillian Buja, MD; Alison L. Barth, PhD; David E. Carpenter, MA; Anil V. Parwani, MD, PhD	A Comparison of the Clinical, Viral, Pathologic, and Immunologic Features of Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and Coronavirus 2019 (COVID-19) Diseases	https://doi.org/10.5858/arpa.2020-0820-SA	Published	July 07 2021	Review	https://meridian.allenpress.com/aplm/article/doi/10.5858/arpa.2020-0820-SA/467552/A-Comparison-of-the-Clinical-Viral-Pathologic-and	The SARS and MERS epidemics have been limited, involving 7,500 and 2,500 individuals, respectively. In contrast, COVID-19 has resulted in a worldwide pandemic with over 177 million cases and 3.9 million deaths as of June 15, 2021, and fatality rates ranging from <0.1% to ~10% depending upon the country. Ending on a positive note, the development of a number of vaccines, at least six of which now are in clinical use, should mitigate and eventually control the devastating COVID-19 pandemic.
41	I039		Xu C, Fan J, Luo Y, Zhao Z, Tang P, Yang G, Pan Y, Guo S, Liu Y, Xiong Y, Xie W, Long X	Prevalence and Characteristics of Rheumatoid-Associated Autoantibodies in Patients with COVID-19	https://doi.org/10.2147/JIR.S312090	Published	12 July 2021	Study	https://www.dovepress.com/prevalence-and-characteristics-of-rheumatoid-associated-autoantibodies-peer-reviewed-fulltext-article-JIR	Rheumatoid-associated autoantibodies were detected in 20.16% of patients (26/129) following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition, IgM-RF was primarily present in critically ill patients, while IgA-RF was mainly present in mild patients. Five patients were able to track for several months to monitor dynamic changes of these antibodies. Rheumatoid factor antibodies peaks in the later phase of the disease and last for longer time. Anti-Jo-1 antibody was found in one of the five patients. Conclusion: This was the case series report that rheumatoid-associated autoantibodies are present in patients with COVID-19. The clinical significance of these antibodies was not fully understood and needed further characterization. These autoantibodies are related to the severity of the patient’s disease and exist for a long time in the patient’s body, while their impact on the patient’s health is unknown.
42	I040		Carolina Lucas, Chantal B. F. Vogels, Inci Yildirim, Jessica E. Rothman, Peiwen Lu, Valter Monteiro, Jeff R. Gelhausen, Melissa Campbell, Julio Silva, Alexandra Tabachikova, M. Catherine Muenker, Mallery I. Breban, Joseph R. Fauver, Subhasis Mohanty, Jiefang Huang, Yale SARS-CoV-2 Genomic Surveillance Initiative, Claire Pearson, Anthony Muyombwe, Randy Downing, Jafar Razeq, Mary Petrone, Isabel Ott, Anne Watkins, Chaney Kalinich, Tara Alpert, Anderson Brito, Rebecca Earnest, Steven Murphy, Caleb Neal, Eva Laszlo, Ahmad Altajar, Irina Tikhonova, Christopher Castaldi, Shrikant Mane, Kaya Bilguvar, Nicholas Kerantzas, David Ferguson, Wade Schulz, Marie Landry, David Peaper, Albert C. Shaw, Albert I. Ko, Saad B. Omer, Nathan D. Grubaugh, Akiko Iwasaki	Impact of circulating SARS-CoV-2 variants on mRNA vaccine-induced immunity in uninfected and previously infected individuals	https://doi.org/10.1101/2021.07.14.21260307	pre-print	July 18, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.07.14.21260307v1	We analysed the development of anti-SARS-CoV-2 antibody and T cell responses in previously infected (recovered) or uninfected (naive) individuals that received mRNA vaccines to SARS-CoV-2. While previously infected individuals sustained higher antibody titers than uninfected individuals post-vaccination, the latter reached comparable levels of neutralization responses to the ancestral strain than previously infected individuals 7 days after the second vaccine dose. T cell activation markers measured upon spike or nucleocapsid peptide in vitro stimulation showed a progressive increase after vaccination in the time-points analysed. Comprehensive analysis of plasma neutralization using 16 authentic isolates of distinct locally circulating SARS-CoV-2 variants revealed a range of reduction in the neutralization capacity associated with specific mutations in the spike gene: lineages with E484K and N501Y/T (e.g., B.1.351 and P.1) had the greatest reduction, followed by lineages with L452R (e.g., B.1.617.2) or with E484K (without N501Y/T). While both groups retained neutralization capacity against all variants, plasma from previously infected vaccinated individuals displayed overall better neutralization capacity when compared to plasma from uninfected individuals that also received two vaccine doses, pointing to vaccine boosters as a relevant future strategy to alleviate the impact of emerging variants on antibody neutralizing activity.	_
43	I041		MiriamMerad1234ArunaSubramanian5Taia T.Wang	An aberrant inflammatory response in severe COVID-19	https://doi.org/10.1016/j.chom.2021.06.018	Published	14 July 2021	Forum	https://www.sciencedirect.com/science/article/pii/S1931312821003000	Severe COVID-19 arises from the convergence of inadequate pre-existing immunity and a host response that damages, rather than repairs, tissues. We outline clinical presentations of COVID-19 that are likely driven by dysregulated host immunity, discuss potential mechanisms underlying pathological responses, and highlight important areas for basic research on this topic.	_
44	I042		Javier García-Abellán, Sergio Padilla, Marta Fernández-González, José A. García, Vanesa Agulló, María Andreo, Sandra Ruiz, Antonio Galiana, Félix Gutiérrez & Mar Masiá	Antibody Response to SARS-CoV-2 is Associated with Long-term Clinical Outcome in Patients with COVID-19: a Longitudinal Study	https://doi.org/10.1007/s10875-021-01083-7	Published	17 July 2021	Study	https://link.springer.com/article/10.1007/s10875-021-01083-7	Of 146 patients (60% male, median age 64 years) followed-up, 20.6% required hospital readmission and 5.5% died. At 2 months and 6 months, 9.6% and 7.8% patients, respectively, reported moderate/severe persistent symptoms. SARS-CoV-2 RT-PCR was positive in NPS in 11.8% (median Ct = 38) and 3% (median Ct = 36) patients at 2 months and 6 months, respectively, but no reinfections were demonstrated. Antibody titers gradually waned, with seroreversion occurring at 6 months in 27 (27.6%) patients for N-IgG and in 6 (6%) for S-IgG. Adjusted 2-month predictors of the highest CSQ scores (OR [95%CI]) were lower peak S-IgG (0.80 [0.66–0.94]) and higher WHO severity score (2.57 [1.20–5.86]); 6-month predictors were lower peak S-IgG (0.89 [0.79–0.99]) and female sex (2.41 [1.20–4.82]); no association was found with prolonged viral RNA shedding. Conclusions Long-COVID is associated with weak anti-SARS-CoV-2 antibody response, severity of illness, and female gender. Late clinical events and persistent symptoms in the medium and long term occur in a significant proportion of patients hospitalized for COVID-19.	Une étude sur le profil immunologique de 146 malades du covid long montre une positivité aux tests PCR qui peut être maintenue sur 1 ou 2 mois, voire davantage, et une corrélation avec une baisse rapide des anticorps neutralisants S. Une séroreversion est intervenue à 6 mois pour plus d'un quart des patients pour les anticorps N-IgG, et pour 6% des patients concernant les S-IgG.	N012
45	I043		Vinod Nikhra	SARS-CoV-2 Infection, COVID-19, and Long Covid: Saga of Erratic Immune Response, Waning Immunity, and Immune System Failure	http:// .org/0000-0003-0859-5232	Published	July 2021	REVIEW ARTICLE	https://www.researchgate.net/profile/Vinod-Nikhra/publication/353170583_SARS-CoV-2_Infection_COVID-19_and_Long_Covid_Saga_of_Erratic_Immune_Response_Waning_Immunity_and_Immune_System_Failure/links/60ebb03ab8c0d5588cee6286/SARS-CoV-2-Infection-COVID-19-and-Long-Covid-Saga-of-Erratic-Immune-Response-Waning-Immunity-and-Immune-System-Failure.pdf	The role of the vaccine in protecting Long Covid manifestations is being assumed, though not backed by large clinical studies (41).
46	I044		William David Strain Ondine Sherwood Amitava Banerjee Vicky van der Togt Lyth Hishmeh Jeremy Rossman	The Impact of COVID Vaccination on Symptoms of Long COVID. An International Survey of People with Lived Experience of Long COVID		pre-print	17 Jun 2021	Study	https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3868856	Results: 900 people participated in the questionnaire, of whom 45 had pre-existing myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) but no evidence of COVID infection and a further 43 did not complete the survey in full. The demographics and symptomology of the remaining 812 people were similar to Office of National Statistics. Following vaccination, 57.9% of participants reported improvements in symptoms, 17.9% reported deterioration and the remainder no change. There was considerable individual variation in responses. Larger improvements in symptom severity scores were seen in those receiving the mRNA vaccines compared to adenoviral vector vaccines.
47	I045		Moriah Bergwerk, M.B., B.S., Tal Gonen, B.A., Yaniv Lustig, Ph.D., Sharon Amit, M.D., Marc Lipsitch, Ph.D., Carmit Cohen, Ph.D., Michal Mandelboim, Ph.D., Einav Gal Levin, M.D., Carmit Rubin, N.D., Victoria Indenbaum, Ph.D., Ilana Tal, R.N., Ph.D., Malka Zavitan, R.N., M.A., Neta Zuckerman, Ph.D., Adina Bar-Chaim, Ph.D., Yitshak Kreiss, M.D., and Gili Regev-Yochay	Covid-19 Breakthrough Infections in Vaccinated Health Care Workers	https://doi.org/10.1056/NEJMoa2109072	Published	July 28, 2021	Study	https://www.nejm.org/doi/full/10.1056/NEJMoa2109072	Among 1497 fully vaccinated health care workers for whom RT-PCR data were available, 39 SARS-CoV-2 breakthrough infections were documented. Neutralizing antibody titers in case patients during the peri-infection period were lower than those in matched uninfected controls (case-to-control ratio, 0.361; 95% confidence interval, 0.165 to 0.787). Higher peri-infection neutralizing antibody titers were associated with lower infectivity (higher Ct values). Most breakthrough cases were mild or asymptomatic, although 19% had persistent symptoms (>6 weeks). The B.1.1.7 (alpha) variant was found in 85% of samples tested. A total of 74% of case patients had a high viral load (Ct value, <30) at some point during their infection; however, of these patients, only 17 (59%) had a positive result on concurrent Ag-RDT. No secondary infections were documented.	Une étude israélienne relève que si la vaccination réduit bien le risque d'infection de façon conséquente, elle ne supprime pas la possibilité de développer un covid long en cas d'infection post-vaccinale. Sur 11453 soignants du centre hospitalier de Ramat Gan, complètement vaccinés au Pfizer, 39 ont été infectés au SARS-CoV-2 malgré leur vaccination, a priori tous par des non-vaccinés. 13 d'entre eux ont eu une infection asymptomatique, les 26 autres des symptômes légers. 31% de tous les soignants infectés ont déclaré avoir des symptômes résiduels 14 jours après leur diagnostic. Six semaines après leur diagnostic, 19% ont rapporté des symptômes de covid long : une perte d'odorat prolongée, une toux persistante, de la fatigue, une dyspnée ou une myalgie. Neuf employés (23 %) ont pris un congé au-delà des 10 jours de quarantaine requis, et parmi ces soignants 4 ont repris le travail dans les 2 semaines. Un employé n'était pas encore revenu après 6 semaines.	N012
48	I046		Daisy Massey;1 Diana Berrent;2 Athena Akrami;3,4 Gina Assaf;4 Hannah Davis;4 Karen Harris;4 Lisa McCorkell;4 Aaron M Ring;5 Wade L Schulz;1,6 Hannah Wei;4 Harlan M Krumholz;1,7,8 Akiko Iwasaki;5,9	Change in Symptoms and Immune Response in People with Post-Acute Sequelae of SARS-Cov-2 Infection (PASC) After SARS-Cov-2 Vaccination	https://doi.org/10.1101/2021.07.21.21260391	pre-print	July 28, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.07.21.21260391v2	As such, we are conducting a study that measures the changes in PASC symptoms after vaccination. We are collecting baseline self-report and biospecimens for immune assays and then are following up with participants to collect the same data at 2-weeks, 6-weeks, and 12-weeks post-vaccination (first dose). Immune assays using blood specimens will include B-cell, T-cell, and myeloid cell panels; evaluation of T-cell responsiveness to SARS-CoV-2 peptides and antigen specific response; autoantibody screening (of IgG, IgM, and IgA antibodies that attack human proteins); and TCR sequencing and antigen mapping of CD8+ T-cells. Mucosal immunity will be measured using saliva specimens. The study aims to provide answers for people with PASC, especially regarding the causes of their symptoms and how the vaccine may affect them, and clues for PASC treatment.
49	I047	Cf D88	Kevin Roe	A role for T-cell exhaustion in Long COVID-19 and severe outcomes for several categories of COVID-19 patients	https://doi.org/10.1002/jnr.24917	Published	19 July 2021	Review	https://onlinelibrary.wiley.com/doi/full/10.1002/jnr.24917	It is now hypothesized that these differences in mortality rates and symptoms could be caused by a SARS-CoV-2 virus infection acting together with one or more latent pathogen infections in certain patients, through mutually beneficial induced immune cell dysfunctions, including T-cell exhaustion. A latent pathogen infection likely to be involved is the protozoan parasite Toxoplasma gondii, which infects approximately one third of the global human population. Furthermore, certain infections and cancers that cause T-cell exhaustion can also explain the more severe outcomes of other COVID-19 patients having several disease and cancer comorbidities.
50	I048		Raghava S. Ambadapoodi1∗; Fnu Deepti1∗; Javaria Anwer1∗; Rafael Fernandez-Botran2†	Post-Acute Sequelae of COVID-19 (PASC): Association with Inflammation and Autoimmunity		Published	July 27, 2021	Review	https://ir.library.louisville.edu/cgi/viewcontent.cgi?article=1213&context=jri	The exact causes for the symptoms observed in patients with PASC remain to be adequately characterized, but are likely to be associated with multiple factors, including residual disease and/or inflammation, organ damage, effects of hospitalization and/or prolonged ventilation, as well as effects of social isolation and stress. This mini-review discusses evidence that may link both inflammatory and auto-immune processes in the pathophysiology of PASC.	_
51	I049		Tarek A-Z K Gaber, Abdul Ashish, Alison Unsworth & Jane Martindale	Are mRNA Covid 19 vaccines safe in Long Covid patients? A Health Care Workers perspective		pre-print	August 2021	Study	https://www.bjmp.org/content/are-mrna-covid-19-vaccines-safe-long-covid-patients-health-care-workers-perspective	Method: A short questionnaire was sent to users of a long covid service supporting an NHS Trust staff in Wigan 2 weeks following the conclusion of a mRNA vaccine first dose roll out. The questionnaire explored acceptance and compliance with the vaccine and any change in the symptoms at least 2 weeks following the vaccination. Results: 77 HCW were offered the vaccine. 10 respondents declined mainly because of concerns regarding worsening long covid symptoms. 67% of respondents did not experience any change in symptoms whilst 21% experienced improvement of symptoms. 12% experienced worsening of symptoms. Conclusion: mRNA vaccines can influence long covid symptoms. However, patients seemed to be twice as likely to experience improvement than worsening of symptoms.
52	I050		Michael J.Peluso16Amelia N.Deitchman26LeonelTorres136Nikita S.Iyer3Sadie E.Munter3Christopher C.Nixon3JoannaDonatelli3CassandraThanh3SakiTakahashi1JillHakim1KeirstinneTurcios1OwenJanson1RebeccaHoh1VivaTai1YanelHernandez1Emily A.Fehrman1Matthew A.Spinelli1MonicaGandhi1…Timothy J.Henrich	Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symptoms	https://doi.org/10.1016/j.celrep.2021.109518	Published	10 August 2021	Study	https://www.sciencedirect.com/science/article/pii/S2211124721009487	We describe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell responses, soluble markers of inflammation, and antibody levels and neutralization capacity longitudinally in 70 individuals with PCR-confirmed SARS-CoV-2 infection. Participants represent a spectrum of illness and recovery, including some with persistent viral shedding in saliva and many experiencing post-acute sequelae of SARS-CoV-2 infection (PASC). T cell responses remain stable for up to 9 months. Whereas the magnitude of early CD4+ T cell immune responses correlates with severity of initial infection, pre-existing lung disease is independently associated with higher long-term SARS-CoV-2-specific CD8+ T cell responses. Among participants with PASC 4 months following coronavirus disease 2019 (COVID-19) symptom onset, we observe a lower frequency of CD8+ T cells expressing CD107a, a marker of degranulation, in response to Nucleocapsid (N) peptide pool stimulation, and a more rapid decline in the frequency of N-specific interferon-γ-producing CD8+ T cells. Neutralizing antibody levels strongly correlate with SARS-CoV-2-specific CD4+ T cell responses. Highlights •The magnitude of early CD4+ T cell responses correlates with severity of COVID-19 •Prior lung disease correlates with higher SARS-CoV-2-specific CD8+ T cell responses •PASC is associated with a decline in N-specific interferon-γ-producing CD8+ T cells •Neutralizing capacity correlates with SARS-CoV-2-specific CD4+ T cell responses
53	I051		Feargal J. Ryan, Christopher M. Hope, Makutiro G. Masavuli, Miriam A. Lynn, Zelalem A. Mekonnen, Arthur Eng Lip Yeow, Pablo Garcia-Valtanen, Zahraa Al-Delfi, Jason Gummow, Catherine Ferguson, Stephanie O’Connor, Benjamin AJ Reddi, David Shaw, Chuan Kok-Lim, Jonathan M. Gleadle, Michael R. Beard, Simon C. Barry, Branka Grubor-Bauk, David J. Lynn	Long-term perturbation of the peripheral immune system months after SARS-CoV-2 infection	https://doi.org/10.1101/2021.07.30.21261234	pre-print	August 03, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.07.30.21261234v1	Increasing evidence suggests immune dysregulation in individuals recovering from SARS- CoV-2 infection. We have undertaken an integrated analysis of immune responses at a transcriptional, cellular, and serological level at 12, 16, and 24 weeks post-infection (wpi) in 69 individuals recovering from mild, moderate, severe, or critical COVID-19. Anti-Spike and anti-RBD IgG responses were largely stable up to 24wpi and correlated with disease severity. Deep immunophenotyping revealed significant differences in multiple innate (NK cells, LD neutrophils, CXCR3+ monocytes) and adaptive immune populations (T helper, T follicular helper and regulatory T cells) in COVID-19 convalescents compared to healthy controls, which were most strongly evident at 12 and 16wpi. RNA sequencing suggested ongoing immune and metabolic dysregulation in convalescents months after infection. Variation in the rate of recovery from infection at a cellular and transcriptional level may explain the persistence of symptoms associated with long COVID in some individuals.
54	I052						From this point on, the survey of studies is no longer as exhaustive as possible. Only those studies which seem to us to bring significant new elements will be listed.
55	I053		Michela Antonelli, PhD, Rose S Penfold, BMBCh, Jordi Merino, PhD, Carole H Sudre, PhD, Erika Molteni, PhD, Sarah Berry, PhD, Liane S Canas, PhD, Mark S Graham, PhD, Kerstin Klaser, MSc, Marc Modat, PhD, Benjamin Murray, MSc, Eric Kerfoot, PhD, Liyuan Chen, MSc, Jie Deng, PhD, Marc F Österdahl, MBBS, Nathan J Cheetham, PhD, David A Drew, PhD, Long H Nguyen, MD, Joan Capdevila Pujol, PhD, Christina Hu, MA, Somesh Selvachandran, MSc, Lorenzo Polidori, MS, Anna May, MSc, Jonathan Wolf, MA, Prof Andrew T Chan, MD, Prof Alexander Hammers, PhD, Prof Emma L Duncan, PhD, Prof Tim D Spector, PhD, Prof Sebastien Ourselin, PhD *, Claire J Steves	Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study	https://doi.org/10.1016/S1473-3099(21)00460-6	Published	September 01, 2021	Study	https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00460-6/fulltext	Between Dec 8, 2020, and July 4, 2021, 1 240 009 COVID Symptom Study app users reported a first vaccine dose, of whom 6030 (0·5%) subsequently tested positive for SARS-CoV-2 (cases 1), and 971 504 reported a second dose, of whom 2370 (0·2%) subsequently tested positive for SARS-CoV-2 (cases 2). In the risk factor analysis, frailty was associated with post-vaccination infection in older adults (≥60 years) after their first vaccine dose (odds ratio [OR] 1·93, 95% CI 1·50–2·48; p<0·0001), and individuals living in highly deprived areas had increased odds of post-vaccination infection following their first vaccine dose (OR 1·11, 95% CI 1·01–1·23; p=0·039). Individuals without obesity (BMI <30 kg/m2) had lower odds of infection following their first vaccine dose (OR 0·84, 95% CI 0·75–0·94; p=0·0030). For the disease profile analysis, 3825 users from cases 1 were included in cases 3 and 906 users from cases 2 were included in cases 4. Vaccination (compared with no vaccination) was associated with reduced odds of hospitalisation or having more than five symptoms in the first week of illness following the first or second dose, and long-duration (≥28 days) symptoms following the second dose. Almost all symptoms were reported less frequently in infected vaccinated individuals than in infected unvaccinated individuals, and vaccinated participants were more likely to be completely asymptomatic, especially if they were 60 years or older.	Selon une étude britannique, les chances d'avoir des symptômes qui se prolongent pendant 28 jours ou plus, après une infection de covid post-vaccinale, seraient approximativement réduites de moitié en ayant reçu deux doses de vaccin. La diminution de risque sur la population générale est estimée à 0,51 [CI 0,32-0,82], et même 0,21 [0,08-0,59] pour la tranche des 18-59 ans, c'est-à-dire de fortes chances de voir le risque diminuer bien davantage que de moitié. La réduction de symptômes prolongés sur une plus longue durée que 28 jours n'est pas analysée dans l'étude, faute de recul encore suffisant (données collectées jusqu'au 18 juillet 2021).	N013
56	I054		Lavanya Visvabharathy, Barbara Hanson, Zachary Orban, Patrick H. Lim, Nicole Palacio, Rishi Jain, Eric Michael Liotta, Pablo Penaloza-MacMaster, Igor J. Koralnik	Neuro-COVID long-haulers exhibit broad dysfunction in T cell memory generation and responses to vaccination	https://doi.org/10.1101/2021.08.08.21261763	pre-print	August 09, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.08.08.21261763v2.full-text	Here, we report that neuro-PASC patients have a specific signature composed of humoral and cellular immune responses that are biased towards different structural proteins compared to healthy COVID convalescents. Interestingly, the severity of cognitive deficits or quality of life markers in neuro-PASC patients are associated with reduced effector molecule expression in memory T cells. Furthermore, we demonstrate that T cell responses to SARS-CoV-2 mRNA vaccines are aberrantly elevated in longitudinally sampled neuro-PASC patients compared with healthy COVID convalescents. These data provide a framework for the rational design of diagnostics and predictive biomarkers for long-COVID disease, as well as a blueprint for improved therapeutics.
57	I055		John P Haran 1, Evan Bradley 1, Abigail L Zeamer 2, Lindsey Cincotta 1, Marie-Claire Salive 1, Protiva Dutta 1, Shafik Mutaawe 1, Otuwe Anya 1, Mario Meza-Segura 2, Ann M Moormann 3, Doyle V Ward 2, Beth A McCormick 2, Vanni Bucci 2	Inflammation-type dysbiosis of the oral microbiome associates with the duration of COVID-19 symptoms and long-COVID	https://doi.org/10.1172/jci.insight.152346	Published	2021 Aug 17	Study	https://insight.jci.org/articles/view/152346	The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the pandemic Coronavirus Disease 2019 (COVID-19) and now many face the burden of prolonged symptoms-long-lasting COVID-19 symptoms or "long-COVID". Long-COVID is thought to be linked to immune dysregulation due to harmful inflammation, with the exact causes being unknown. Given the role of the microbiome in mediating inflammation, we aimed to examine the relationship between the oral microbiome and the duration of long-COVID symptoms. Tongue swabs were collected from patients presenting with symptoms concerning for COVID-19. Confirmed infections were followed until resolution of all symptoms. Bacterial composition was determined by metagenomic sequencing. We used random forest modeling to identify microbiota and clinical covariates that associated with long-COVID symptoms. Of the patients followed, 63% (17/27) developed ongoing symptomatic COVID-19 and 37% (10/27) went on to long-COVID. Patients with prolonged symptoms had significantly higher abundances of microbiota that induce inflammation, such as members of the genera Prevotella and Veillonella. Of note are species that produce lipopolysaccharides and the similarity of long-COVID patients' oral microbiome to those of patients with chronic fatigue syndrome. All together, we our findings suggest an association with the oral microbiome and long-COVID revealing the possibility that dysfunction of the oral microbiome may contribute to this draining disease.
58	I056		John M. Arthur ,J. Craig Forrest ,Karl W. Boehme ,Joshua L. Kennedy,Shana Owens,Christian Herzog,Juan Liu,Terry O. Harville	Development of ACE2 autoantibodies after SARS-CoV-2 infection	https://doi.org/10.1371/journal.pone.0257016	Published	September 3, 2021	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257016	Activation of the immune system is implicated in the Post-Acute Sequelae after SARS-CoV-2 infection (PASC) but the mechanisms remain unknown. Angiotensin-converting enzyme 2 (ACE2) cleaves angiotensin II (Ang II) resulting in decreased activation of the AT1 receptor and decreased immune system activation. We hypothesized that autoantibodies against ACE2 may develop after SARS-CoV-2 infection, as anti-idiotypic antibodies to anti-spike protein antibodies. Methods and findings We tested plasma or serum for ACE2 antibodies in 67 patients with known SARS-CoV-2 infection and 13 with no history of infection. None of the 13 patients without history of SARS-CoV-2 infection and 1 of the 20 outpatients that had a positive PCR test for SARS-CoV-2 had levels of ACE2 antibodies above the cutoff threshold. In contrast, 26/32 (81%) in the convalescent group and 14/15 (93%) of patients acutely hospitalized had detectable ACE2 antibodies. Plasma from patients with antibodies against ACE2 had less soluble ACE2 activity in plasma but similar amounts of ACE2 protein compared to patients without ACE2 antibodies. We measured the capacity of the samples to inhibit ACE2 enzyme activity. Addition of plasma from patients with ACE2 antibodies led to decreased activity of an exogenous preparation of ACE2 compared to patients that did not have antibodies. Conclusions Many patients with a history of SARS-CoV-2 infection have antibodies specific for ACE2. Patients with ACE2 antibodies have lower activity of soluble ACE2 in plasma. Plasma from these patients also inhibits exogenous ACE2 activity. These findings are consistent with the hypothesis that ACE2 antibodies develop after SARS-CoV-2 infection and decrease ACE2 activity. This could lead to an increase in the abundance of Ang II, which causes a proinflammatory state that triggers symptoms of PASC.	Des chercheurs de la University of Arkansas for Medical Sciences (UAMS) publient une étude sur des auto-anticorps au récepteur ACE2 qui pourraient selon eux être déclencheurs du covid long. La présence de ces anticorps est relevée sur 26 des 32 malades convalescents de la covid, et sur 14 des 15 malades ayant été hospitalisés. Les anticorps sont suspectés être de type anti-idiotypique et d'inhiber l'activité enzymatique des récepteurs ACE2. Pour les auteurs, il s'agit d'un mécanisme assimilable à celui d'autres virus qui déclenchent des auto-anticorps et provoquent des maladies auto-immunes. Les effets positifs après la vaccination de malades du covid long s'expliqueraient par le fait que le vaccin incite le système immunitaire à équilibrer les anticorps idiotypiques et anti-idiotypiques pour le contrôle homéostatique. Ces élément seraient en cohérence avec une théorie de l'immunologiste danois Niels Kaj Jerne (https://pubmed.ncbi.nlm.nih.gov/4142565/). Les échantillons étant anonymisés, une corrélation avec les symptômes du covid long n'a pas pu être déterminée. Les résultats pourraient ouvrir la voie à des traitements. D'une part avec les bloqueurs des récepteurs de l'angiotensine, qui sont des molécules relativement sûres et largement utilisées, ainsi que la piste des inhibiteurs de l'ECA. Une thérapie plus ciblée sur le mécanisme d'inhibition de l'enzyme de conversion de l'angiotensine serait également possible selon l'équipe de recherche.	N013
59	I057		Kangyun Wu,1 Kenji Kamimoto,2 Yong Zhang,1 Kuangying Yang,1 Shamus P. Keeler,1 Benjamin J. Gerovac,1 Eugene V. Agapov,1 Stephen P. Austin,1 Jennifer Yantis,1 Kelly A. Gissy,1 Derek E. Byers,1 Jennifer Alexander-Brett,1 Christy M. Hoffmann,1 Matthew Wallace,1 Michael E. Hughes,1 Erika C. Crouch,3 Samantha A. Morris,2 and Michael J. Holtzman	Basal-epithelial stem cells cross an alarmin checkpoint for post-viral lung disease	https://doi.org/10.1172/JCI149336	Published	August 24, 2021	Study	https://www.jci.org/articles/view/149336	Here we identify a pattern of imbalance marked by basal epithelial cell growth and differentiation that replaces normal airspaces in a mouse model of progressive post-viral lung disease due to Sendai virus. Single-cell and lineage-tracing technologies identify a distinct subset of basal epithelial stem cells (basal-ESCs) that extend into gas-exchange tissue to form long-term bronchiolar-alveolar remodeling regions. Moreover, this cell subset is selectively expanded by crossing a cell growth and survival checkpoint linked to the nuclear-localized alarmin IL-33 that is independent of IL-33-receptor signaling and instead connected to autocrine chromatin accessibility. This mechanism creates an activated stem-progenitor cell lineage with potential for physiological or pathological function. Thus, conditional loss of Il33 gene function in basal epithelial cells disrupts homeostasis of the epithelial barrier at skin and gut sites but also markedly attenuates post-viral disease in the lung based on down-regulation of remodeling and inflammation. We thereby identify a basal-ESC strategy to deploy innate-immune machinery that appears to overshoot the primordial goal of self-defense. The findings reveal new targets to stratify and correct chronic and often deadly post-viral disease.
60	I058		Yukai Jing, Li Luo, Ying Chen, Lisa S. Westerberg, Peng Zhou, Zhiping Xu, Andrés A. Herrada, Chan-Sik Park, Masato Kubo, Heng Mei, Yu Hu, Pamela Pui-Wah Lee, Bing Zheng, Zhiwei Sui, Wei Xiao, Quan Gong, Zhongxin Lu & Chaohong Liu	SARS-CoV-2 infection causes immunodeficiency in recovered patients by downregulating CD19 expression in B cells via enhancing B-cell metabolism	https://doi.org/10.1038/s41392-021-00749-3	Published	22 September 2021	Study	https://www.nature.com/articles/s41392-021-00749-3	The SARS-CoV-2 infection causes severe immune disruption. However, it is unclear if disrupted immune regulation still exists and pertains in recovered COVID-19 patients. In our study, we have characterized the immune phenotype of B cells from 15 recovered COVID-19 patients, and found that healthy controls and recovered patients had similar B-cell populations before and after BCR stimulation, but the frequencies of PBC in patients were significantly increased when compared to healthy controls before stimulation. However, the percentage of unswitched memory B cells was decreased in recovered patients but not changed in healthy controls upon BCR stimulation. Interestingly, we found that CD19 expression was significantly reduced in almost all the B-cell subsets in recovered patients. Moreover, the BCR signaling and early B-cell response were disrupted upon BCR stimulation. Mechanistically, we found that the reduced CD19 expression was caused by the dysregulation of cell metabolism. In conclusion, we found that SARS-CoV-2 infection causes immunodeficiency in recovered patients by downregulating CD19 expression in B cells via enhancing B-cell metabolism, which may provide a new intervention target to cure COVID-19.
61	I059		Leonard B.WeinstockM.D. FACGaJill B.BrookMAbArthur S.WaltersMDcAshleighGorisRN, BSN, MPH, CIC, FAPICdLawrence B.AfrinMDeGerhard J.MolderingsMDf	Mast cell activation symptoms are prevalent in Long-COVID	https://doi.org/10.1016/j.ijid.2021.09.043	Published	23 September 2021	Study	https://www.sciencedirect.com/science/article/pii/S1201971221007517	•Mast cell activation symptoms (MCAS) were increased in Long-COVID patients •Long-COVID patients had similar severity of numerous MCAS symptoms •Aberrant mast cells induced by SARS-CoV-2 infection is the likely triggering factor •MC-directed therapy could help treat Long-COVID patients
62	I060		Tran, Viet-Thi and Perrodeau, Elodie and Saldanha, Julia and Pane, Isabelle and Ravaud, Philippe	Efficacy of COVID-19 Vaccination on the Symptoms of Patients With Long COVID: A Target Trial Emulation Using Data From the ComPaRe e-Cohort in France		pre-print	29 Sep 2021	Study	https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3932953	Findings: In total, 455 patients were allocated to the vaccination group and 455 to the control group; 545 (60·1%) had confirmed infections, and 81 (8·9%) had been hospitalized during their acute COVID-19. By 120 days, vaccination reduced the long COVID symptoms (mean (SD) ST score in the vaccination group 13·0 (9·4) vs. 14·8 (9·8) in the control group; mean difference: -1·8, 95% CI -2·5 to -1·0) and doubled the rate of patients in complete remission (remission rate 16·6% vs 7·5%, HR: 1·97, 95% CI 1·23 to 3·15). Furthermore, vaccination reduced both disease impact on patients’ lives (mean (SD) IT score 24.3 (16·7) vs 27·6 (16·7); mean difference: -3·3, 95% CI -6·2 to -0·5) and the proportion of patients with an unacceptable symptom state (38.9% vs 46.4%, risk difference -7·5%, 95% CI -14·4 to -0·5). In the vaccination group, two (0·4%) patients reported serious adverse events leading to hospitalisation. Interpretation: COVID-19 vaccination lowers the severity and life impact of long COVID at 120 days among patients with persistent symptoms.
63	I061		Rogan A. Grant, Luisa Morales-Nebreda, Nikolay S. Markov, Suchitra Swaminathan, Melissa Querrey, Estefany R. Guzman, Darryl A. Abbott, Helen K. Donnelly, Alvaro Donayre, Isaac A. Goldberg, Zasu M. Klug, Nicole Borkowski, Ziyan Lu, Hermon Kihshen, Yuliya Politanska, Lango Sichizya, Mengjia Kang, Ali Shilatifard, Chao Qi, Jon W. Lomasney, A. Christine Argento, Jacqueline M. Kruser, Elizabeth S. Malsin, Chiagozie O. Pickens, Sean B. Smith, James M. Walter, Anna E. Pawlowski, Daniel Schneider, Prasanth Nannapaneni, Hiam Abdala-Valencia, Ankit Bharat, Cara J. Gottardi, G. R. Scott Budinger, Alexander V. Misharin, Benjamin D. Singer, Richard G. Wunderink	Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia	https://doi.org/10.1038/s41586-020-03148-w	pre-print	11 January 2021	Study	https://www.nature.com/articles/s41586-020-03148-w	Here we investigate SARS-CoV-2 pathobiology by characterizing the immune response in the alveoli of patients infected with the virus. We collected bronchoalveolar lavage fluid samples from 88 patients with SARS-CoV-2-induced respiratory failure and 211 patients with known or suspected pneumonia from other pathogens, and analysed them using flow cytometry and bulk transcriptomic profiling. We performed single-cell RNA sequencing on 10 bronchoalveolar lavage fluid samples collected from patients with severe coronavirus disease 2019 (COVID-19) within 48 h of intubation. In the majority of patients with SARS-CoV-2 infection, the alveolar space was persistently enriched in T cells and monocytes. Bulk and single-cell transcriptomic profiling suggested that SARS-CoV-2 infects alveolar macrophages, which in turn respond by producing T cell chemoattractants. These T cells produce interferon-γ to induce inflammatory cytokine release from alveolar macrophages and further promote T cell activation. Collectively, our results suggest that SARS-CoV-2 causes a slowly unfolding, spatially limited alveolitis in which alveolar macrophages containing SARS-CoV-2 and T cells form a positive feedback loop that drives persistent alveolar inflammation.
64	I062	VP	Esen Sefik, Rihao Qu, Eleanna Kaffe, Jun Zhao, Caroline Junqueira, Haris Mirza, Ricky Brewer, Ailin Han, Holly Steach, Benjamin Israelow, Y. Grace Chen, Stephanie Halene, Akiko Iwasaki, Eric Meffre, Michel Nussenzweig, Judy Lieberman, Craig B. Wilen, Yuval Kluger, Richard A. Flavell	Viral replication in human macrophages enhances an inflammatory cascade and interferon driven chronic COVID-19 in humanized mice	https://doi.org/10.1101/2021.09.27.461948	pre-print	September 27, 2021	Study	https://www.biorxiv.org/content/10.1101/2021.09.27.461948v1	Chronic COVID-19 is characterized by persistent viral RNA and sustained interferon (IFN) response which is recapitulated and required for pathology in SARS-CoV-2 infected MISTRG6-hACE2 humanized mice. As in the human disease, monocytes, and macrophages in SARS-CoV-2 infected MISTRG6-hACE2 are central to disease pathology. Here, we describe SARS-CoV-2 uptake in tissue resident human macrophages that is enhanced by virus specific antibodies. SARS-CoV-2 replicates in these human macrophages as evidenced by detection of double-stranded RNA, subgenomic viral RNA and expression of a virally encoded fluorescent reporter gene; and it is inhibited by Remdesivir, an inhibitor of viral replication. Although early IFN deficiency leads to enhanced disease, blocking either viral replication with Remdesivir or the downstream IFN stimulated cascade by injecting anti-IFNAR2 in vivo in the chronic stages of disease attenuates many aspects of the overactive immune-inflammatory response, especially the inflammatory macrophage response, and most consequentially, the chronic disease itself.	Dans un pre-print (non publié à ce jour) présenté par l'équipe du Pr. A. Iwasaki, l'hypothèse d'une persistance virale pour expliquer l'un des mécanismes du covid long est remise sur le devant de la scène. Selon l'étude, le SARS-CoV-2 pourrait persister dans l'organisme à l'intérieur des macrophages (type de globule blanc), continuer à s'y répliquer et provoquer une inflammation persistante. Le traitement de ce covid chronique par des antiviraux (dont le remdesivir) apparaît probant sur le modèle murin humanisé. Le mécanisme d'entrée dans les cellules serait constitutif d'une facilitation de l'infection par des anticorps (Antibody-dependant enhancement, ADE en anglais). Il ne concernerait pas les vaccins à ARNm selon plusieurs immunologues.
65	I063		Lechien JR, Hopkins C, Vaira LA, Saussez S.	SARS-CoV-2 vaccination may help patients with persistent COVID-19 smell dysfunction	https://doi.org/10.1177%2F01455613211044770	Published	September 26, 2021	Study	https://journals.sagepub.com/doi/10.1177/01455613211044770	According to these findings and our clinical observations, we believe that the persistence of OD in COVID-19 patients could be related to the persistence of the virus in the olfactory region, which induces a chronic inflammatory reaction characterized by the destruction of re-infected cells throughout the recovery process, that is, neuroepithelium cells, sustentacular cells and olfactory neurons. Interestingly, it has been supported that inflammation may suppress regeneration of the olfactory stem cells.11 In this way, we believe that the administration of vaccine may stimulate the local and systemic immune response against the virus, ‘cleaning’ the olfactory region from the remaining viruses, allowing the regeneration of stem cells. Future controlled studies are needed to compare the evolution of olfactory outcomes of patients with persistent OD according to the vaccine status of patients. Recent studies have shown that SARS-CoV-2 can be detected in immunologically privileged tissues, such as the testicles, without significant immune response.12 Further studies are needed to test the hypothesis that the olfactory bulb could be considered as an additional anatomical region not exposed to a significant immune response, allowing for persistence of SARS-CoV-2.
66	I064		Paul Glynne1, Natasha Tahmasebi2, Vanya Gant3, Rajeev Gupta	Long COVID following mild SARS-CoV-2 infection: characteristic T cell alterations and response to antihistamines	http://dx.doi.org/10.1136/jim-2021-002051	Published	October 5, 2021	Study	https://jim.bmj.com/content/early/2021/10/05/jim-2021-002051	Anecdotal reports of gradual clinical responses to histamine receptor antagonists (HRAs) suggest a histamine-dependent mechanism that is distinct from anaphylaxis, possibly mediated by T cells, which are also regulated by histamine. T cell perturbations have been previously reported in post-viral syndromes, but the T cell landscape in patients who have recovered from mild COVID-19 and its relationship to both long COVID symptoms and any symptomatic response to HRA remain underexplored. We addressed these questions in an observational study of 65 individuals who had recovered from mild COVID-19. Participants were surveyed between 87 and 408 days after the onset of acute symptoms; none had required hospitalization, 16 had recovered uneventfully, and 49 had developed long COVID. Symptoms were quantified using a structured questionnaire and T cell subsets enumerated in a standard diagnostic assay. Patients with long-COVID had reduced CD4+ and CD8+ effector memory (EM) cell numbers and increased PD-1 (programmed cell death protein 1) expression on central memory (CM) cells, whereas the asymptomatic participants had reduced CD8+ EM cells only and increased CD28 expression on CM cells. 72% of patients with long COVID who received HRA reported clinical improvement, although T cell profiling did not clearly distinguish those who responded to HRA. This study demonstrates that T cell perturbations persist for several months after mild COVID-19 and are associated with long COVID symptoms.	Une étude britannique note que les patients atteints de covid long ont un nombre réduit de lymphocytes T CD4+ et CD8+, ainsi qu'une expression accrue de protéines PD-1. Cette étude montre selon les auteurs que les perturbations des lymphocytes T persistent pendant plusieurs mois après une covid légère et sont associées à des symptômes de covid long.	N014E
67	I065		Ryan C. Thompson, Nicole W. Simons, Lillian Wilkins, Esther Cheng, Diane Marie Del Valle, Gabriel E. Hoffman, Brian Fennessy, Konstantinos Mouskas, Nancy J. Francoeur, Jessica S. Johnson, , Robert Sebra, Miriam Merad, Sacha Gnjatic, Eric E. Schadt, Alexander W. Charney, Noam D. Beckmann	Acute COVID-19 gene-expression profiles show multiple etiologies of long-term sequelae	https://doi.org/10.1101/2021.10.04.21264434	pre-print	October 05, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.10.04.21264434v1.full-text	Here, a transcriptome-wide investigation of this new condition was performed in a large cohort of acutely infected patients followed clinically into the post-acute period. Gene expression signatures of post-acute sequelae were already present in whole blood during the acute phase of infection, with both innate and adaptive immune cells involved. Plasma cells stood out as driving at least two distinct clusters of sequelae, one largely dependent on circulating antibodies against the SARS-CoV-2 spike protein and the other antibody-independent. Altogether, multiple etiologies of post-acute sequelae were found concomitant with SARS-CoV-2 infection, directly linking the emergence of these sequelae with the host response to the virus.	_
68	I066		Maya M.L. Poon, Ksenia Rybkina, Yu Kato, Masaru Kubota, Rei Matsumoto, Nathaniel I. Bloom, Zeli Zhang, Kathryn M. Hastie, Alba Grifoni, Daniela Weiskopf, Steven B. Wells, Basak B. Ural, Nora Lam, Peter A. Szabo, Pranay Dogra, Yoon S. Lee, Bradley, Marissa C, Brusko, Maigan A, Brusko, Todd M, Saphire, Erica O, Connors, Thomas J, Sette, Alessandro, Crotty, Shane, Farber, Donna L	SARS-CoV-2 infection generates tissue-localized immunological memory in humans	https://doi.org/10.1126/sciimmunol.abl9105	Published	7 Oct 2021	Study	https://www.science.org/doi/10.1126/sciimmunol.abl9105	Here, we report from examination of SARS-CoV-2 seropositive organ donors (ages 10 – 74) that CD4+ T, CD8+ T, and B cell memory generated in response to infection is present in bone marrow, spleen, lung, and multiple lymph nodes (LNs) for up to 6 months post-infection. Lungs and lung-associated LNs were the most prevalent sites for SARS-CoV-2-specific memory T and B cells, with significant correlations between circulating and tissue-resident memory T and B cells in all sites. We further identified SARS-CoV-2-specific germinal centers in the lung-associated LNs up to 6 months post-infection. SARS-CoV-2-specific follicular helper T cells were also abundant in lung-associated LNs and lungs. Together, the results indicate local tissue coordination of cellular and humoral immune memory against SARS-CoV-2 for site-specific protection against future infectious challenges.
69	I067		Maxime Taquet, Quentin Dercon, Paul J Harrison	Six-month sequelae of post-vaccination SARS-CoV-2 infection: a retrospective cohort study of 10,024 breakthrough infections	https://doi.org/10.1101/2021.10.26.21265508	pre-print	October 28, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.10.26.21265508v2	Among 10,024 vaccinated individuals with SARS-CoV-2 infection, 9479 were matched to unvaccinated controls. Receiving at least one COVID-19 vaccine dose was associated with a significantly lower risk of respiratory failure, ICU admission, intubation/ventilation, hypoxaemia, oxygen requirement, hypercoagulopathy/venous thromboembolism, seizures, psychotic disorder, and hair loss (each as composite endpoints with death to account for competing risks; HR 0.70-0.83, Bonferroni-corrected p<.05), but not other outcomes, including long-COVID features, renal disease, mood, anxiety, and sleep disorders. Receiving 2 vaccine doses was associated with lower risks for most outcomes. Associations between prior vaccination and outcomes of SARS-CoV-2 infection were marked in those < 60 years-old, whereas no robust associations were observed in those ≥ 60 years-old.	_
70	I068		RAPHAEL CARAPITORICHARD LIJULIE HELMSCHRISTINE CARAPITOSHARVARI GUJJAVÉRONIQUE ROLLIRAONY GUIMARAESJOSE MALAGON-LOPEZPERRINE SPINNHIRNY[...]SEIAMAK BAHRAM	Identification of driver genes for critical forms of COVID-19 in a deeply phenotyped young patient cohort	https://doi.org/10.1126/scitranslmed.abj7521	Published	26 Oct 2021	Study	https://www.science.org/doi/10.1126/scitranslmed.abj7521	The cohort included 47 “critical” (in the intensive care unit under mechanical ventilation) and 25 “non-critical” (in a non-critical care ward) patients with COVID-19 and 22 healthy individuals. The analyses included whole-genome sequencing, whole-blood RNA sequencing, plasma and blood mononuclear cells proteomics, cytokine profiling, and high-throughput immunophenotyping. An ensemble of machine learning, deep learning, quantum annealing, and structural causal modeling were employed. Patients with critical COVID-19 were characterized by exacerbated inflammation, perturbed lymphoid and myeloid compartments, increased coagulation, and viral cell biology. Among differentially expressed genes, we observed up-regulation of the metalloprotease ADAM9. This gene signature was validated in a second independent cohort of 81 critical and 73 recovered patients with COVID-19, and were further confirmed at the transcriptional and protein level as well as by proteolytic activity. Ex vivo ADAM9 inhibition decreased severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uptake and replication in human lung epithelial cells. In conclusion, within a young, otherwise healthy, cohort of individuals with COVID-19, we provide the landscape of biological perturbations in vivo where a unique gene signature differentiated critical from non-critical patients. We further identified ADAM9 as a driver of disease severity and a candidate therapeutic target.
71	I069		Benjamin A. Krishna, Eleanor Y. Lim, Lenette Mactavous, NIHR BioResource Team, Paul Lyons, Rainer Doffinger, John Bradley, Kenneth G. C. Smith, John Sinclair, Nicholas J. Matheson, Paul J. Lehner, Mark R. Wills, Nyaradzai Sithole	Retrospective diagnosis of SARS-CoV-2 infection in patients with Long COVID by measuring specific T cell mediated IL-2 release.	https://doi.org/10.21203/rs.3.rs-989434/v1	pre-print	21 Oct, 2021	Study	https://www.researchsquare.com/article/rs-989434/v1	Given the diagnostic conundrum of Long COVID, we set out to design a SARS-CoV-2 specific T cell assay, to follow up a cohort of undifferentiated mostly non-hospitalised patients with Long COVID for up to 13 months. Here, we show that IL-2 release from SARS-CoV-2-specific memory T cells shows >75% sensitivity and >88% specificity in identifying individuals with confirmed SARS-CoV-2 infection >6 months after a positive PCR test.	_
72	I070		Stuart Stewart Louise Newson Tracy A Briggs Dimitris Grammatopoulos Lawrence Young Paramjit Gill	Long COVID risk - a signal to address sex hormones and women's health	https://doi.org/10.1016/j.lanepe.2021.100242	Published	November 02, 2021	Article	https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(21)00228-3/fulltext	From a biological perspective, we propose the asymmetry in risk and outcomes between sexes, and an overlap of symptoms of Long COVID [[3]] with those of perimenopause and menopause [[6]] point towards sex hormone differences as targets for further investigation. Furthermore, the higher prevalence of Long COVID in women under the age of 50 years [[2]] is an important and supporting clue as the mean age of natural menopause (in the UK) is 51 years [[6]]. Oestrogen and androgen receptors are ubiquitous, present in almost all tissues in the body, evidencing the widespread and important roles of sex hormones [[7]], well beyond their obvious roles in the reproductive system. Viral-induced sex hormone dysfunction resulting in early menopause, menstruation abnormalities and miscarriage are documented in HIV and Hepatitis B and C infections [[8]]. In the context of viral infections, sex hormone dysfunction may be related to multisystem disruption or due to organ-specific effects [[8]]. The role of sex hormones in COVID-19 infection are now beginning to emerge. A recent study [[9]] highlights important clinical and immunological differences between sexes in acute COVID-19 infection; women had lower mortality, lower levels of inflammation, higher lymphocyte counts, and faster antibody responses than men.	todo
73	I071		Krishna, Benjamin A. and Lim, Eleanor Y. and Mactavous, Lenette and Team, NIHR BioResource and Lyons, Paul A. and Doffinger, Rainer and Bradley, John and Smith, KGC and Sinclair, John and Matheson, Nicholas J. and Lehner, Paul and Wills, Mark R. and Sithole, Nyarie	Retrospective Diagnosis of SARS-CoV-2 Infection in Patients with Long COVID by Measuring Specific T Cell Mediated IL-2 Release.	http://dx.doi.org/10.2139/ssrn.3947817	pre-print	27 Oct 2021	Study	https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3947817	Given the diagnostic conundrum of Long COVID, we set out to design a SARS-CoV-2 specific T cell assay, to follow up a cohort of undifferentiated mostly non-hospitalised patients with Long COVID for up to 13 months. Here, we show that IL-2 release from SARS-CoV-2-specific memory T cells shows >75% sensitivity and >88% specificity in identifying individuals with confirmed SARS-CoV-2 infection >6 months after a positive PCR test.
74	I072		Leo Swadling, Mariana O. Diniz, Nathalie M. Schmidt, Oliver E. Amin, Aneesh Chandran, Emily Shaw, Corinna Pade, Joseph M. Gibbons, Nina Le Bert, Lucy van Dorp, Francois Balloux, Áine McKnight, Mahdad Noursadeghi, Antonio Bertoletti & Mala K. Maini	Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2	https://doi.org/10.1038/s41586-021-04186-8	Published	10 November 2021	Study	https://www.nature.com/articles/s41586-021-04186-8	Individuals with potential exposure to SARS-CoV-2 do not necessarily develop PCR or antibody positivity, suggesting some may clear sub-clinical infection before seroconversion. T-cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections1–3. We hypothesised that pre-existing memory T-cell responses, with cross-protective potential against SARS-CoV-24–11, would expand in vivo to support rapid viral control, aborting infection. We measured SARS-CoV-2-reactive T-cells, including those against the early transcribed replication transcription complex (RTC)12,13, in intensively monitored healthcare workers (HCW) remaining repeatedly negative by PCR, antibody binding, and neutralisation (seronegative HCW, SN-HCW). SN-HCW had stronger, more multispecific memory T-cells than an unexposed pre-pandemic cohort, and more frequently directed against the RTC than the structural protein-dominated responses seen post-detectable infection (matched concurrent cohort). SN-HCW with the strongest RTC-specific T-cells had an increase in IFI27, a robust early innate signature of SARS-CoV-214, suggesting abortive infection. RNA-polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and SARS-CoV-2 clades. RNA-polymerase was preferentially targeted (amongst regions tested) by T-cells from pre-pandemic cohorts and SN-HCW. RTC epitope-specific T-cells cross-recognising HCoV variants were identified in SN-HCW. Enriched pre-existing RNA-polymerase-specific T-cells expanded in vivo to preferentially accumulate in the memory response after putative abortive compared to overt SARS-CoV-2 infection. Our data highlight RTC-specific T-cells as targets for vaccines against endemic and emerging Coronaviridae.	_
75	I073		SARAH C. VICK MARIE FRUTOSO FLORIAN MAIR ANDREW J. KONECNYEVAN GREENECAITLIN R. WOLF JENNIFER K. LOGUE NICHOLAS M. FRANKO JIM BOONYARATANAKORNKIT RAPHAEL GOTTARDO JOSHUA T. SCHIFFER HELEN Y. CHUMARTIN PRLIC AND JENNIFER M. LUND	A regulatory T cell signature distinguishes the immune landscape of COVID-19 patients from those with other respiratory infections	https://doi.org/10.1126/sciadv.abj0274	Published	10 Nov 2021	Study	https://www.science.org/doi/10.1126/sciadv.abj0274	We compare the immune signature from hospitalized SARS-CoV-2–infected patients to patients hospitalized prepandemic with influenza or respiratory syncytial virus (RSV). Our in-depth profiling indicates that the immune landscape in SARS-CoV-2 patients is largely similar to flu or RSV patients. Unique to patients infected with SARS-CoV-2 who had the most critical clinical disease were changes in the regulatory T cell (Treg) compartment. A Treg signature including increased frequency, activation status, and migration markers was correlated COVID-19 severity. These findings are relevant as Tregs are considered for therapy to combat the severe inflammation seen in COVID-19 patients. Likewise, having defined the overlapping immune landscapes in SARS-CoV-2, existing knowledge of flu and RSV infections could be leveraged to identify common treatment strategies.
76	I074		I. V. Sarvilina, O. A. Gromova, A. V. Naumov	Pathobiochemical pathways of redox imbalance in the neurological long-term effects of COVID-19 and the role of chondroitin sulfate in the redox status restoration	https://doi.org/10.14412/2074-2711-2021-5-109-115	Published	November 2021	Review	https://nnp.ima-press.net/nnp/article/view/1674/0	The review examines the epidemiology and clinical manifestations of COVID-19 long-term neurological effects, main pathobiochemical mechanisms, and integrated circuits of redox status impairment in COVID-19, such as the decrease of adenosine triphosphate production, fatty acids levels, acylcarnitine, and amino acids, impairment of oxidative phosphorylation and glycolysis, hypometabolic state, redox imbalance with the increase of peroxides and superoxides, isoprostanes, the decrease of α-tocopherol, substances reacting with thiobarbituric acid, increased nitrosative stress with the increase of inducible synthase of nitric oxide, nitric oxide, peroxynitrite, and nitrate. Neuroprotective approaches aimed at suppressing excitotoxicity, oxidative stress, and neuroinflammation are presented. Recent data on the relationship between mechanisms of chondroitin sulfate and its derivatives (chondroitin sulfate glycoprotein disaccharide) neuroprotective effects and characteristics of their chemical structure are analyzed. The mechanism of action and neuroprotective effects of chondroitin sulfate and its derivatives in fatigue syndrome in patients with SARS-CoV2 infection are discussed (regulation of the PKC/PI3K/Akt activity, the increase of heme oxygenase-1 level, the decrease of reactive oxygen species). The position that chondroitin sulfate and its derivatives can become promising drugs to prevent the long-term neurological effects of COVID-19 is reasoned.	_
77	I075		Ziyad Al-Aly, Benjamin Bowe, Yan Xie	Long Covid after Breakthrough COVID-19: the post-acute sequelae of breakthrough COVID-19	https://doi.org/10.21203/rs.3.rs-1062160/v1	pre-print	15 Nov, 2021	Study	https://www.researchsquare.com/article/rs-1062160/v1	We show that compared to people with no evidence of COVID-19, beyond the first 30 days of illness, people with breakthrough COVID-19 exhibit a higher risk of death and broad array of incident post-acute sequelae in the pulmonary system, as well as extrapulmonary sequelae that include cardiovascular disorders, coagulation disorders, gastrointestinal disorders, general disorders (e.g., fatigue), kidney disorders, mental health disorders, metabolic disorders, musculoskeletal disorders, and neurologic disorders. People with breakthrough COVID-19 exhibited lower risk of death (HR 0.65 (0.55, 0.76); burden -12.97 (-16.58, -8.74); negative values denote reduced burden in breakthrough COVID-19 relative to COVID-19) and lower risk of post-acute sequelae (HR 0.87 (0.83, 0.92); burden -30.60 (-42.25, -18.49)) compared to those with COVID-19 and no prior history of vaccination (Figure 4 and Supplementary Table 9). Comparatively, the risk of post-acute sequelae in the cardiovascular, coagulation, metabolic, and pulmonary organ systems, as well as risk of fatigue, was lower in people with breakthrough COVID-19 vs those with COVID-19 without prior vaccination. Lower risk was not statistically significant in kidney, gastrointestinal, mental health, and neurologic organ systems. None of the outcomes exhibited a higher risk among people with breakthrough COVID-19 compared to those with COVID-19 without prior vaccination.
78	I076		JihaneEl KhalifaNourMekkiLydiaDeschampsVincentDescamps	Récidive des « COVID toes » après un nouveau contage avec le SARS-CoV-2	https://doi.org/10.1016/j.fander.2021.09.206	Published	19 November 2021	Study	https://www.sciencedirect.com/science/article/pii/S2667062321004839	Nos 4 observations témoignent de la possibilité de récidive lors d’un nouveau contage témoignant de l’absence de réelle immunité spécifique et même la possibilité de développer une forme plus symptomatique. Il est probable que la sévérité clinique soit la conséquence de la balance entre l’importance de l’inoculum viral et de la capacité à développer une réponse immunitaire innée. Ainsi chez le 4e patient, le contage étant liée à sa partenaire avec vraisemblablement une charge virale de l’inoculum supérieure à celle du premier contage. Ceci confirme que les patients ayant eu un « COVID toes » justifient d’une vaccination car ces patients ne sont pas dans la majorité des cas immunisés.	todo
79	I077		Heidi Ledford	Do vaccines protect against long COVID? What the data say Vaccines reduce the risk of developing COVID-19 — but studies disagree on their protective effect against long COVID.	https://doi.org/10.1038/d41586-021-03495-2	Published	23 November 2021	Article	https://www.nature.com/articles/d41586-021-03495-2	Vaccines reduce the risk of long COVID by lowering the chances of contracting COVID-19 in the first place. But for those who do experience a breakthrough infection, studies suggest that vaccination might only halve the risk of long COVID — or have no effect on it at all.	todo
80	I078		Maxime Taquet, Quentin Dercon, Paul J Harrison	Six-month sequelae of post-vaccination SARS-CoV-2 infection: a retrospective cohort study of 10,024 breakthrough infections	https://doi.org/10.1101/2021.10.26.21265508	pre-print	November 08, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.10.26.21265508v3.full-text	Receiving at least one COVID-19 vaccine dose was associated with a significantly lower risk of respiratory failure, ICU admission, intubation/ventilation, hypoxaemia, oxygen requirement, hypercoagulopathy/venous thromboembolism, seizures, psychotic disorder, and hair loss (each as composite endpoints with death to account for competing risks; HR 0.70-0.83, Bonferroni-corrected p<.05), but not other outcomes, including long-COVID features, renal disease, mood, anxiety, and sleep disorders. Receiving 2 vaccine doses was associated with lower risks for most outcomes. Associations between prior vaccination and outcomes of SARS-CoV-2 infection were marked in those < 60 years-old, whereas no robust associations were observed in those ≥ 60 years-old. In summary, COVID-19 vaccination is associated with lower risk of several, but not all, COVID-19 sequelae in those with breakthrough SARS-CoV-2 infection. These benefits of vaccination were clear in younger people but not in the over-60s. The findings may inform service planning, contribute to forecasting public health impacts of vaccination programmes, and highlight the need to identify additional interventions for COVID-19 sequelae.	_
81	I079		Kevin Roe	The role of polyspecific T-cell exhaustion in severe outcomes for COVID-19 patients having latent pathogen infections such as Toxoplasma gondii	https://doi.org/10.1016/j.micpath.2021.105299	Published	20 November 2021	Article	https://www.sciencedirect.com/science/article/pii/S0882401021005738	Highlights •COVID-19 patients exhibit mortality rate differences probably from latent pathogen infections. •Toxoplasma gondii infects about one third of the global human population and it is likely involved. •Latent pathogens have different genetic strains & different effects on later pathogen infections. •Drug treatments affect pathogen infections causing immune dysfunctions, e.g. T-cell exhaustion. •"Polyspecific T-cell exhaustion" enables concurrent multiple pathogen T-cell exhaustion. The aims and purposes of this paper include providing explanations for the contradictions between these studies and introducing a significant new category of T-cell exhaustion. Latent pathogens can have different genetic strains with great differences in their effects on a second pathogen infection. Furthermore, depending on the timing and effectiveness of drug treatments, pathogen infections that become latent may or may not later induce immune cell dysfunctions, including T-cell exhaustion. Concurrent multiple pathogen T-cell exhaustion is herein called "polyspecific T-cell exhaustion."	_
82	I080		Elaine Holmes, Julien Wist, Reika Masuda, Samantha Lodge, Philipp Nitschke, Torben Kimhofer, Ruey Leng Loo, Sofina Begum, Berin Boughton, Rongchang Yang, Aude-Claire Morillon, Sung-Tong Chin, Drew Hall, Monique Ryan, Sze-How Bong, Melvin Gay, Dale W. Edgar, John C. Lindon, Toby Richards, Bu B. Yeap, Sven Pettersson, Manfred Spraul, Hartmut Schaefer, Nathan G. Lawler, Nicola Gray, Luke Whiley, and Jeremy K. Nicholson*	Incomplete Systemic Recovery and Metabolic Phenoreversion in Post-Acute-Phase Nonhospitalized COVID-19 Patients: Implications for Assessment of Post-Acute COVID-19 Syndrome	https://doi.org/10.1021/acs.jproteome.1c00224	Published	May 19, 2021	Article	https://pubs.acs.org/doi/abs/10.1021/acs.jproteome.1c00224	We present a multivariate metabotyping approach to assess the functional recovery of nonhospitalized COVID-19 patients and the possible biochemical sequelae of “Post-Acute COVID-19 Syndrome”, colloquially known as long-COVID. Blood samples were taken from patients ca. 3 months after acute COVID-19 infection with further assessment of symptoms at 6 months. Some 57% of the patients had one or more persistent symptoms including respiratory-related symptoms like cough, dyspnea, and rhinorrhea or other nonrespiratory symptoms including chronic fatigue, anosmia, myalgia, or joint pain. Plasma samples were quantitatively analyzed for lipoproteins, glycoproteins, amino acids, biogenic amines, and tryptophan pathway intermediates using Nuclear Magnetic Resonance (NMR) spectroscopy and mass spectrometry. Metabolic data for the follow-up patients (n = 27) were compared with controls (n = 41) and hospitalized severe acute respiratory syndrome SARS-CoV-2 positive patients (n = 18, with multiple time-points). Univariate and multivariate statistics revealed variable patterns of functional recovery with many patients exhibiting residual COVID-19 biomarker signatures. Several parameters were persistently perturbed, e.g., elevated taurine (p = 3.6 × 10–3 versus controls) and reduced glutamine/glutamate ratio (p = 6.95 × 10–8 versus controls), indicative of possible liver and muscle damage and a high energy demand linked to more generalized tissue repair or immune function. Some parameters showed near-complete normalization, e.g., the plasma apolipoprotein B100/A1 ratio was similar to that of healthy controls but significantly lower (p = 4.2 × 10–3) than post-acute COVID-19 patients, reflecting partial reversion of the metabolic phenotype (phenoreversion) toward the healthy metabolic state. Plasma neopterin was normalized in all follow-up patients, indicative of a reduction in the adaptive immune activity that has been previously detected in active SARS-CoV-2 infection. Other systemic inflammatory biomarkers such as GlycA and the kynurenine/tryptophan ratio remained elevated in some, but not all, patients. Correlation analysis, principal component analysis (PCA), and orthogonal-partial least-squares discriminant analysis (O-PLS-DA) showed that the follow-up patients were, as a group, metabolically distinct from controls and partially comapped with the acute-phase patients. Significant systematic metabolic differences between asymptomatic and symptomatic follow-up patients were also observed for multiple metabolites. The overall metabolic variance of the symptomatic patients was significantly greater than that of nonsymptomatic patients for multiple parameters (χ2p = 0.014). Thus, asymptomatic follow-up patients including those with post-acute COVID-19 Syndrome displayed a spectrum of multiple persistent biochemical pathophysiology, suggesting that the metabolic phenotyping approach may be deployed for multisystem functional assessment of individual post-acute COVID-19 patients.	todo
83	I081		Winston A. Haynes, Kathy Kamath, Joel Bozekowski, Elisabeth Baum-Jones, Melissa Campbell, Arnau Casanovas-Massana, Patrick S. Daugherty, Charles S. Dela Cruz, Abhilash Dhal, Shelli F. Farhadian, Lynn Fitzgibbons, John Fournier, Michael Jhatro, Gregory Jordan, Jon Klein, Carolina Lucas, Debra Kessler, Larry L. Luchsinger, Brian Martinez, M. Catherine Muenker, Lauren Pischel, Jack Reifert, Jaymie R. Sawyer, Rebecca Waitz, Elsio A. Wunder Jr., Minlu Zhang, Yale IMPACT Team, Akiko Iwasaki, Albert Ko & John C. Shon	High-resolution epitope mapping and characterization of SARS-CoV-2 antibodies in large cohorts of subjects with COVID-19	https://doi.org/10.1038/s42003-021-02835-2	Published	22 November 2021	Study	https://www.nature.com/articles/s42003-021-02835-2	Since traditional epitope identification tools are dependent upon pre-defined peptide sequences, they are not readily adaptable to diverse viral proteomes. The Serum Epitope Repertoire Analysis (SERA) platform leverages a high diversity random bacterial display library to identify proteome-independent epitope binding specificities which are then analyzed in the context of organisms of interest. When evaluating immune response in the context of SARS-CoV-2, we identify dominant epitope regions and motifs which demonstrate potential to classify mild from severe disease and relate to neutralization activity. We highlight SARS-CoV-2 epitopes that are cross-reactive with other coronaviruses and demonstrate decreased epitope signal for mutant SARS-CoV-2 strains. Collectively, the evolution of SARS-CoV-2 mutants towards reduced antibody response highlight the importance of data-driven development of the vaccines and therapies to treat COVID-19.	todo
84	I082		M.ScherlingerL.PijnenburgE.ChatelusJ.SibiliaJ.E.GottenbergL.ArnaudR.Felten	Effet de la vaccination anti-SARS-CoV-2 sur les symptômes prolongés post-Covid : résultat de l’enquête nationale VAXILONG	https://doi.org/10.1016/j.rhum.2021.10.350	Published	26 November 2021	Study	https://www.sciencedirect.com/science/article/abs/pii/S1169833021006098	L’absence d’effet de la vaccination va à l’encontre de l’hypothèse de persistance virale dans le COVID-long, d’autant que l’immunogénicité vaccinale y semble normale. Par ailleurs, des données suggèrent que la vaccination diminue le risque de développer un COVID-long [2]. Conclusion La vaccination anti-SARS-CoV-2 ne semble pas influencer les symptômes de COVID-long rapportés par les patients.	_
85	I083		Pilar Brito-Zerón 1, Nihan Acar-Denizli 2, Vasco C Romão 3, Berkan Armagan 4, Raphaèle Seror 5, Francesco Carubbi 6, Sheila Melchor 7, Roberta Priori 8, Valeria Valim 9, Soledad Retamozo 10, Sandra G Pasoto 11, Virginia Fernandes Moça Trevisani 12, Benedikt Hofauer 13, Antonia Szántó 14, Nevsun Inanc 15, Gabriela Hernández-Molina 16, Agata Sebastian 17, Elena Bartoloni 18, Valerie Devauchelle-Pensec 19, Miriam Akasbi 20, Federico Giardina 21, Matilde Bandeira 3, Antoni Sisó-Almirall 22, Manuel Ramos-Casals 23	Post-COVID-19 syndrome in patients with primary Sjögren's syndrome after acute SARS-CoV-2 infection	PMID: 34874821.	Published	2021 Nov 22	Study	https://pubmed.ncbi.nlm.nih.gov/34874821/	This is the first study that analyses the frequency and characteristics of post-COVID-19 syndrome in patients affected by a systemic autoimmune disease. We found that 57% of patients with pSS affected by COVID-19 remain symptomatic after a mean follow-up of 5 months. The risk of developing post-COVID-19 syndrome in patients who required hospitalisation was 8-times higher than in non-hospitalised patients, with baseline raised CRP levels and the use of hydroxychloroquine being independent risk factors for post-COVID-19.
86	I084		Sabrina Kral 1 Chiara Banfi 1 Tobias Niedrist Nazanin Sareban Christian Guelly Lisa Kriegl Stefanie Schiffmann Christoph Zurl Markus Herrmann Ivo Steinmetz Peter Schlenke Andrea Berghold Robert Krause	Long-lasting immune response to a mild course of PCR-confirmed SARS-CoV-2 infection: A cohort study	https://doi.org/10.1016/j.jinf.2021.08.030	Published	August 21, 2021	Study	https://www.journalofinfection.com/article/S0163-4453(21)00419-9/fulltext	Taken together, our results indicate a strong and persistent immune response against SARS-CoV-2 infection in individuals who recovered from a mild course of COVID-19 for up to 8 months post infection. Importantly, our findings are in line with a recent study10 that used the very same quantitative anti-RBD antibody assay as we did and reported a robust and persistent antibody response after six months post infection. The titre at the baseline visit and its change through time was modulated by the time lag between infection and sampling. In line with Wells et al., we found that individuals without core symptoms developed immunity against COVID-19, although to a lower degree than individuals showing core symptoms, and it persisted through time.
87	I085		Daniel Ayoubkhani, Charlotte Bermingham, Koen B. Pouwels, Myer Glickman, Vahé Nafilyan, Francesco Zaccardi, Kamlesh Khunti, Nisreen A. Alwan, A. Sarah Walker	Changes in the trajectory of Long Covid symptoms following COVID-19 vaccination: community-based cohort study	https://doi.org/10.1101/2021.12.09.21267516	pre-print	December 09, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.12.09.21267516v1.full-text	Results Median follow-up was 141 days from first vaccination (among all participants) and 67 days from second vaccination (84% of participants). First vaccination was associated with an initial 12.8% decrease (95% confidence interval: −18.6% to −6.6%) in the odds of Long Covid, but increasing by 0.3% (−0.6% to +1.2%) per week after the first dose. Second vaccination was associated with an 8.8% decrease (−14.1% to −3.1%) in the odds of Long Covid, with the odds subsequently decreasing by 0.8% (−1.2% to −0.4%) per week. There was no statistical evidence of heterogeneity in associations between vaccination and Long Covid by socio-demographic characteristics, health status, whether hospitalised with acute COVID-19, vaccine type (adenovirus vector or mRNA), or duration from infection to vaccination. Conclusions The likelihood of Long Covid symptoms reduced after COVID-19 vaccination, and the improvement was sustained over the follow-up period after the second dose. Vaccination may contribute to a reduction in the population health burden of Long Covid, though longer follow-up time is needed. Summary box What is already known on this topic COVID-19 vaccines are effective at reducing rates of SARS-CoV-2 infection, transmission, hospitalisation, and death The incidence of Long Covid may be reduced if infected after vaccination, but the relationship between vaccination and pre-existing long COVID symptoms is unclear, as published studies are generally small and with self-selected participants What this study adds The likelihood of Long Covid symptoms reduced after COVID-19 vaccination, and the improvement was sustained over the follow-up period after the second dose There was no evidence of differences in this relationship by socio-demographic characteristics, health-related factors, vaccine type, or duration from infection to vaccination Although causality cannot be inferred from this observational evidence, vaccination may contribute to a reduction in the population health burden of Long Covid; further research is needed to understand the biological mechanisms that may ultimately contribute to the development of therapeutics for Long Covid	_
88	I086		Daniel Chertow, Sydney Stein, Sabrina Ramelli, Alison Grazioli, Joon-Yong Chung, Manmeet Singh, Claude Kwe Yinda, Clayton Winkler, James Dickey, Kris Ylaya, Sung Hee Ko, Andrew Platt, Peter Burbelo, Martha Quezado, Stefania Pittaluga, Madeleine Purcell, Vincent Munster, Frida Belinky, Marcos Ramos-Benitez, Eli Boritz, Daniel Herr, Joseph Rabin, Kapil Saharia, Ronson Madathil, Ali Tabatabai, Shahabuddin Soherwardi, Michael McCurdy, Karin Peterson, Jeffrey Cohen, Emmie de Wit, Kevin Vannella, Stephen Hewitt, David Kleiner	SARS-CoV-2 infection and persistence throughout the human body and brain	https://doi.org/10.21203/rs.3.rs-1139035/v1	pre-print	20 Dec, 2021	Study	https://www.researchsquare.com/article/rs-1139035/v1	COVID-19 is known to cause multi-organ dysfunction1-3 in acute infection, with prolonged symptoms experienced by some patients, termed Post-Acute Sequelae of SARS-CoV-2 (PASC)4-5. However, the burden of infection outside the respiratory tract and time to viral clearance is not well characterized, particularly in the brain3,6-14. We performed complete autopsies on 44 patients with COVID-19 to map and quantify SARS-CoV-2 distribution, replication, and cell-type specificity across the human body, including brain, from acute infection through over seven months following symptom onset. We show that SARS-CoV-2 is widely distributed, even among patients who died with asymptomatic to mild COVID-19, and that virus replication is present in multiple extrapulmonary tissues early in infection. Further, we detected SARS-CoV-2 RNA in multiple anatomic sites, including regions throughout the brain, for up to 230 days following symptom onset. Despite extensive distribution of SARS-CoV-2 in the body, we observed a paucity of inflammation or direct viral cytopathology outside of the lungs. Our data prove that SARS-CoV-2 causes systemic infection and can persist in the body for months.	Il apparaît de plus en plus que le SARS-CoV-2 est un virus dont le corps ne se débarrasse peut-être jamais (pour au moins une part des infectés) complètement. Vers des pistes thérapeutiques ? Un article de @MarcGozlan sur son blog de @lemondefr https://www.lemonde.fr/blog/realitesbiomedicales/2021/12/24/covid-19-le-sars-cov-2-peut-persister-dans-le-corps-pendant-des-mois-et-disseminer-precocement-dans-le-cerveau/ Dans cette étude, non encore relue et publiée et relue, 44 autopsies ont été réalisées sur des individus décédés de complications de la covid, jusqu'à 7 mois après l'infection, avec une moyenne de 35 jours. 95% d'entre eux présentaient une comorbidité, le plus souvent de l’hypertension artérielle, de l’obésité ou une maladie respiratoire chronique. Cependant, deux sont décédés sans formes sévère (par embolie pulmonaire tardive et par complications fatales liées à une comorbidité). Les 44 autopsiés sans exception conservaient des virions de SARS-CoV-2 dans de très nombreux sites anatomiques. L'ARN du SARS-CoV-2 a même été détecté dans le cerveau des six individus décédés tardivement, dont un décédé 7 mois après l'infection. Pour 5 d'entre eux, le virus était disséminé dans tous le système nerveux central. Les chercheurs ont noté que chez certains patients, le virus s'était diversifié en différents variants selon la zone infectée (avec par ex un profil différent dans le cerveau et dans les poumons. L'ARN viral était également présent à l’intérieur de globules blancs (leucocytes mononucléés) dans la rate, l'appendice et l'épithélium du côlon, ce qui traduit des virions soit replicatifs, soit phagocytés dans des macrophages. Au total, l'ARN viral semble persister au long cours : * dans l'endothélium vasculaire (couche de la paroi de tous les vaisseaux sanguins), * le cerveau pour 6 individus sur les 44 de la cohorte, dans le tissu cérébral dans 10 des 11 cas analysés, * le poumon, les bronches, les fosses nasales (cornets nasaux) ; pour 43 des 44 cas autopsiques, l'ARN viral a été détecté dans le tissu respiratoire, * le cœur (cellules musculaires, endothélium, muscles lisses des vaisseaux), dans le péricarde (enveloppe entourant le cœur), * dans le tissu cardiovasculaire dans 35 cas sur 44, * les ganglions lymphatiques intra-thoraciques (le tissu lymphoïde dans 38 cas), * l'humeur aqueuse et tissu oculaire dans 22 cas, * l'intestin grêle et les glandes surrénales, * le tissu de l’appareil reproducteur dans 17 cas, * le muscle, la peau et le tissu nerveux périphérique dans 30 cas, La réplication virale était encore active chez une majorité de cas, dans tous les tissus, et même chez 42% des individus décédés plus de 30 jours après les premiers symptômes. En détail, de l'ARN viral était retrouvé dans : * les cellules endocrines de la thyroïde et glandulaires du pancréas,* cellules de l’appareil reproducteur (cellules de Leydig et de Sertoli dans les testicules, cellules germinales dans les tubes séminifères, * l'épithélium glandulaire de l'endomètre, les cellules musculaires du muscle utérin,* les myocytes (cellules du muscle squelettique),* l'épithélium de l’œsophage, les cellules du foie (dont les hépatocytes et l'épithélium des canaux biliaires), les amas lymphoïdes du côlon,* les cellules des tubules rénaux et vaisseaux des glomérules où a lieu la formation de l'urine primitive, élaborée à partir du sang filtré,* les neurones, les cellules gliales, l'endothélium des vaisseaux cérébraux dans tous les lobes cérébraux, * le cervelet (neurones, cellules de Purkinje, endothélium vasculaire). Les chercheurs ont observé une atteinte alvéolaire diffuse au niveau pulmonaire et, au niveau cardiaque, des infiltrats inflammatoires dans le myocarde. De minuscules caillots sanguins (micro-thrombi) ont été décrits, de même qu'un appauvrissement du nombre de lymphocytes (lymphodépletion) dans les ganglions lymphatiques et dans la rate. Peu de changements morphologiques ont été observés à l’examen histologique du cerveau. Les auteurs notent qu'il y a peu d'inflammation significative hormis l'appareil pulmonaire. Pour les auteurs, ces examens montrent que le virus peut se disséminer très précocement dans le corps, dont le cerveau, dès la première semaine. Comme des études précédentes l'avaient montré, le virus peut entrer dans le cerveau, et probablement en franchissant la barrière hémato-encéphalique. Les auteurs concluent que le covid long pourrait notamment s'expliquer par cette persistance virale. L'étude a été menée par une équipe des Instituts américains de la santé (NIH). Les interprétations de la récente étude, qui analyse 44 autopsies de victimes de la covid et qui note une forte et persistante dissémination du virus dans le corps, sont critiquées par plusieurs experts. Notamment par l'immunologiste Andrew Croxford, qui explique pourquoi selon lui il n'est pas possible d'en tirer des conclusions sur le covid long. Il tient à rappeler que les malades avaient presque tous des comorbidités, que beaucoup ont été intubés, qu'il s'agit de malades non vaccinés et que l'essentiel étaient soit immunodéprimés, soit ont reçu des glucocorticoïdes (à même de favoriser la progression du virus). Pour Andrew Croxford, cette étude ne permet absolument pas de dire qu'une telle dissémination virale intervient fréquemment chez les personnes vaccinées ou les personnes sans comorbidités.
89	I087		Marc Scherlinger 1,2,3,* , Luc Pijnenburg 1,2, Emmanuel Chatelus 1,2, Laurent Arnaud 1,2,4, Jacques-Eric Gottenberg 1,2,5, Jean Sibilia 1,2,4 and Renaud Felten	Effect of SARS-CoV-2 Vaccination on Symptoms from Post-Acute Sequelae of COVID-19: Results from the Nationwide VAXILONG Study	https://doi.org/10.3390/vaccines10010046	pre-print	30 December 2021	Study	https://www.mdpi.com/2076-393X/10/1/46/htm	We conducted a nationwide online study among adult patients with PASC as defined by symptoms persisting over 4 weeks following a confirmed or probable COVID-19, without any identified alternative diagnosis. Information concerning PASC symptoms, vaccine type and scheme and its effect on PASC symptoms were studied. Results: 620 questionnaires were completed and 567 satisfied the inclusion criteria and were analyzed. The respondents’ median age was 44 (IQR 25–75: 37–50) and 83.4% were women. The initial infection was proven in 365 patients (64%) and 5.1% had been hospitalized to receive oxygen. A total of 396 patients had received at least one injection of SARS-CoV-2 vaccine at the time of the survey, after a median of 357 (198–431) days following the initially-reported SARS-CoV-2 infection. Among the 380 patients who reported persistent symptoms at the time of SARS-CoV-2 vaccination, 201 (52.8%) reported a global effect on symptoms following the injection, corresponding to an improvement in 21.8% and a worsening in 31%. There were no differences based on the type of vaccine used. After a complete vaccination scheme, 93.3% (28/30) of initially seronegative patients reported a positive anti-SARS-CoV-2 IgG. A total of 170 PASC patients had not been vaccinated. The most common reasons for postponing the SARS-CoV-2 vaccine were fear of worsening PASC symptoms (55.9%) and the belief that vaccination was contraindicated because of PASC (15.6%). Conclusion: Our study suggests that SARS-CoV-2 vaccination is well tolerated in the majority of PASC patients and has good immunogenicity. Disseminating these reassuring data might prove crucial to increasing vaccine coverage in patients with PASC.
90	I088		Jing Sun, MD, MPH, PhD1; Qulu Zheng, MS1; Vithal Madhira, MS2; Amy L. Olex, MS3; Alfred J. Anzalone, MS4; Amanda Vinson, MD5; Jasvinder A. Singh, MD6,7; Evan French, BS3; Alison G. Abraham, PhD8; Jomol Mathew, PhD9; Nasia Safdar, MD, PhD10; Gaurav Agarwal, MD, MSPH11; Kathryn C. Fitzgerald, ScD1,12; Namrata Singh, MD13; Umit Topaloglu, PhD14; Christopher G. Chute, MD, DrPH, MPH1,15; Roslyn B. Mannon, MD16; Gregory D. Kirk, MD, MPH, PhD1,17; Rena C. Patel, MD, MPH18;	Association Between Immune Dysfunction and COVID-19 Breakthrough Infection After SARS-CoV-2 Vaccination in the US	http://jamanetwork.com/article.aspx?doi=10.1001/jamainternmed.2021.7024	Published	December 28, 2021	Study	https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2787643	A total of 664 722 patients in the N3C sample were included. These patients had a median (IQR) age of 51 (34-66) years and were predominantly women (n = 378 307 [56.9%]). Overall, the incidence rate for COVID-19 breakthrough infection was 5.0 per 1000 person-months among fully vaccinated persons but was higher after the Delta variant became the dominant SARS-CoV-2 strain (incidence rate before vs after June 20, 2021, 2.2 [95% CI, 2.2-2.2] vs 7.3 [95% CI, 7.3-7.4] per 1000 person-months). Compared with partial vaccination, full vaccination was associated with a 28% reduced risk for breakthrough infection (adjusted IRR [AIRR], 0.72; 95% CI, 0.68-0.76). People with a breakthrough infection after full vaccination were more likely to be older and women. People with HIV infection (AIRR, 1.33; 95% CI, 1.18-1.49), rheumatoid arthritis (AIRR, 1.20; 95% CI, 1.09-1.32), and solid organ transplant (AIRR, 2.16; 95% CI, 1.96-2.38) had a higher rate of breakthrough infection. Conclusions and Relevance This cohort study found that full vaccination was associated with reduced risk of COVID-19 breakthrough infection, regardless of the immune status of patients. Despite full vaccination, persons with immune dysfunction had substantially higher risk for COVID-19 breakthrough infection than those without such a condition. For persons with immune dysfunction, continued use of nonpharmaceutical interventions (eg, mask wearing) and alternative vaccine strategies (eg, additional doses or immunogenicity testing) are recommended even after full vaccination.
91	I089		Svetlana P. Chapoval & Achsah D. Keegan	Perspectives and potential approaches for targeting neuropilin 1 in SARS-CoV-2 infection	https://doi.org/10.1186/s10020-021-00423-y	Published	27 December 2021	Review	https://molmed.biomedcentral.com/articles/10.1186/s10020-021-00423-y	This perspective focuses on the contribution of the recently discovered interaction of SARS-CoV-2 Spike protein with neuropilin 1 (NRP1) receptor, NRP1 as a virus entry receptor for SARS-CoV-2, its role in different physiologic and pathologic conditions, and the potential to target the Spike–NRP1 interaction to combat virus infectivity and severe disease manifestations. NRP1 has been shown to participate in the entry of SARS-CoV-2 into cells. Importantly, recent ‘omic’ analyses revealed a significant upregulation of NRP-1 in biological samples from COVID-19 patients compared to healthy controls (Xiong et al. 2020). Moreover, the increased levels of one NRP1 ligand, VEGF165, in bronchial alveolar lavage fluid from COVID-19 patients were also reported (Xiong et al. 2020). VEGF165 is a physiological ligand for the b1b2 pocket in NRP-1 (Moutal et al. 2021). Spike protein, the major surface antigen of SARS-CoV-2, could block VEGF165/NRP-1 signaling. Noteworthy, Sema3A and Sema4A also bind NRP-1 but into a1a2 pocket (Fig. 1). Nevertheless, Sema3A or Sema4A binding may modify the ability of NRP-1 to interact with Spike. The multiple roles of these ligand-receptor interactions in SARS-CoV-2 infection of different cells, tissues, and organs need to be further evaluated. This is an emerging field in research as the roles of NRP1 in different diseases are not well established. Nevertheless, published studies point to NRP1 as potential player in SARS-CoV-2 infection and recently developed approaches for NRP1 targeting provide a foundation for designing novel anti-viral therapies.
92	I090	I33: pre-print ES	Chansavath Phetsouphanh, David R. Darley, Daniel B. Wilson, Annett Howe, C. Mee Ling Munier, Sheila K. Patel, Jennifer A. Juno, Louise M. Burrell, Stephen J. Kent, Gregory J. Dore, Anthony D. Kelleher & Gail V. Matthews	Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection	https://doi.org/10.1038/s41590-021-01113-x	Published	13 January 2022	Study	https://www.nature.com/articles/s41590-021-01113-x	A proportion of patients surviving acute coronavirus disease 2019 (COVID-19) infection develop post-acute COVID syndrome (long COVID (LC)) lasting longer than 12 weeks. Here, we studied individuals with LC compared to age- and gender-matched recovered individuals without LC, unexposed donors and individuals infected with other coronaviruses. Patients with LC had highly activated innate immune cells, lacked naive T and B cells and showed elevated expression of type I IFN (IFN-β) and type III IFN (IFN-λ1) that remained persistently high at 8 months after infection. Using a log-linear classification model, we defined an optimal set of analytes that had the strongest association with LC among the 28 analytes measured. Combinations of the inflammatory mediators IFN-β, PTX3, IFN-γ, IFN-λ2/3 and IL-6 associated with LC with 78.5–81.6% accuracy. This work defines immunological parameters associated with LC and suggests future opportunities for prevention and treatment.	todo
93	I091		SØREN R. PALUDAN AND TRINE H. MOGENSEN	Innate immunological pathways in COVID-19 pathogenesis	https://doi.org/10.1126/sciimmunol.abm5505	Published	7 Jan 2022	Review	https://www.science.org/doi/10.1126/sciimmunol.abm5505	Coronavirus disease 2019 (COVID-19) is a disease characterized by a profound dysregulation of the innate immune system. This knowledge has emerged from the large body of single-cell omics studies of patients with COVID-19, which have provided one of the most detailed cellular atlases of a human disease ever. However, we are only beginning to understand the innate immunological pathways that govern host defense and immunopathology in COVID-19. In this review, we discuss the emerging understanding of how SARS-CoV-2 and host-derived molecules activate specific pattern recognition receptors to elicit protective interferon responses and pathological cytokine responses, with particular focus on acute infection of the lung and lung pathophysiology in critical COVID-19. In addition, we discuss how these pathways are modulated by virus-host interactions and host stress-sensing pathways. In-depth understanding of the disease mechanisms will likely uncover specific molecular targets for the treatment of COVID-19 and other emerging viral infections. In addition, it will reveal the fine balance between beneficial protective versus pathological disease causing immune responses.
94	I092		Paul Kuodi, Yanay Gorelik, Hiba Zayyad, Ofir Wertheim, Karine Beiruti Wiegler, Kamal Abu Jabal, Amiel Dror, Saleh Nazzal, Daniel Glikman, Michael Edelstein	Association between vaccination status and reported incidence of post-acute COVID-19 symptoms in Israel: a cross-sectional study of patients tested between March 2020 and November 2021	https://doi.org/10.1101/2022.01.05.22268800	pre-print	January 17, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.01.05.22268800v2	Long COVID is a post-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection syndrome characterised by not recovering for several weeks or months following the acute episode. The effectiveness of COVID-19 vaccines against long-term symptoms of COVID-19 is not well understood. We determined whether vaccination was associated with the incidence of reporting long-term symptoms post-SARS-CoV-2 infection Methods: We invited individuals who were PCR tested for SARS-CoV-2 infection at participating hospitals between March 2020-November 2021 to fill an online questionnaire that included baseline demographics, details of their acute episode and information about symptoms they were currently experiencing. Using binomial regression, we compared vaccinated individuals with those unvaccinated and those uninfected in terms of self-reported symptoms post-acute infection. Results: We included 951 infected and 2437 uninfected individuals. Of the infected, 637(67%) were vaccinated. The most commonly reported symptoms were; fatigue (22%), headache (20%), weakness (13%), and persistent muscle pain (10%). After adjusting for follow-up time and baseline symptoms, those who received two doses less likely than unvaccinated individuals to report any of these symptoms by 64%, 54%, 57%, and 68% respectively, (Risk ratios 0.36, 0.46, 0.43, 0.32, p<0.04 in the listed sequence). Those who received two doses were no more likely to report any of these symptoms than individuals reporting no previous SARS-CoV-2 infection. Conclusions: Vaccination with at least two doses of COVID-19 vaccine was associated with a substantial decrease in reporting the most common post-acute COVID-19 symptoms, bringing it back to baseline. Our results suggest that, in addition to reducing the risk of acute illness, COVID-19 vaccination may have a protective effect against long COVID.	Selon la version 2 d'un preprint d'une équipe israélienne (non encore revue par les pairs ni publiée), la vaccination avec 2 doses de Pfizer pourrait protéger très largement d'un covid long consécutif à une infection post-vaccinale. La prevalence de symptômes prolongées ne présente pas, pour cette cohorte, de différences significatives entre les double-vaccinés et les participants non infectés, ce qui suggère une protection forte d'un schéma vaccinal complet sur le covid long.
95	I093		Benjamin Charvet, Joanna Brunel, Justine Pierquin, Mathieu Iampietro, Didier Decimo, Nelly Queruel, Alexandre Lucas, Maria del Mar Encabo-Berzosa, Izaskun Arenaz, Tania Perez Marmolejo, Francina Valezka Bolanos Morales, Arturo Ivan Gonzalez Gonzalez, Armando Castorena Maldonado, Cesar Luna Rivero, Cyrille Mathieu, Patrick Kury, Jose Flores-Rivera, Santiago Avila Rios, Gonzalo Salgado Montes de Oca, Jon Schoorlemmer, Branka Horvat, Herve JF Perron	SARS-CoV-2 induces human endogenous retrovirus type W envelope protein expression in blood lymphocytes and in tissues of COVID-19 patients.	https://doi.org/10.1101/2022.01.18.21266111	pre-print	January 18, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.01.18.21266111v1	As viral infections may activate human endogenous retroviral elements (HERV), we studied the effect of SARS-CoV-2 on HERV-W and HERV-K envelope (ENV) expression, known to be involved in immunological and neurological pathogenesis of human diseases. Our results have showed that the exposure to SARS-CoV-2 virus activates early HERV-W and K transcription but only HERV-W ENV protein expression, in an infection- and ACE2-independent way within peripheral blood mononuclear cell cultures from one-third of healthy donors. Moreover, HERV-W ENV protein was significantly increased in serum and plasma of COVID-19 patients, correlating with its expression in CD3+ lymphocytes and with disease severity. Finally, HERV-W ENV was found expressed in post-mortem tissues of lungs, heart, brain olfactory bulb and nasal mucosa from acute COVID-19 patients in cell-types relevant for COVID-19-associated pathogenesis within affected organs, but different from those expressing of SARS-CoV-2 antigens. Altogether, the present study revealed that SARS-CoV-2 can induce HERV-W ENV expression in cells from individuals with symptomatic and severe COVID-19. Our data suggest that HERV-W ENV is likely to be involved in pathogenic features underlying symptoms of acute and post-acute COVID. It highlights the importance to further understand patients genetic susceptibility to HERV-W activation and the relevance of this pathogenic element as a prognostic marker and a therapeutic target in COVID-19 associated syndromes.
96	I094		Samu N. Kurki, Jonas Kantonen, Karri Kaivola, Laura Hokkanen, Mikko I. Mäyränpää, Henri Puttonen, FinnGen, Juha Martola, Minna Pöyhönen, Mia Kero, Jarno Tuimala, Olli Carpén, Anu Kantele, Olli Vapalahti, Marjaana Tiainen, Pentti J. Tienari, Kai Kaila, Johanna Hästbacka & Liisa Myllykangas	APOE ε4 associates with increased risk of severe COVID-19, cerebral microhaemorrhages and post-COVID mental fatigue: a Finnish biobank, autopsy and clinical study	https://doi.org/10.1186/s40478-021-01302-7	Published	23 December 2021	Study	https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-021-01302-7	Apolipoprotein E ε4 allele (APOE4) has been shown to associate with increased susceptibility to SARS-CoV-2 infection and COVID-19 mortality in some previous genetic studies, but information on the role of APOE4 on the underlying pathology and parallel clinical manifestations is scarce. Here we studied the genetic association between APOE and COVID-19 in Finnish biobank, autopsy and prospective clinical cohort datasets. In line with previous work, our data on 2611 cases showed that APOE4 carriership associates with severe COVID-19 in intensive care patients compared with non-infected population controls after matching for age, sex and cardiovascular disease status. Histopathological examination of brain autopsy material of 21 COVID-19 cases provided evidence that perivascular microhaemorrhages are more prevalent in APOE4 carriers. Finally, our analysis of post-COVID fatigue in a prospective clinical cohort of 156 subjects revealed that APOE4 carriership independently associates with higher mental fatigue compared to non-carriers at six months after initial illness. In conclusion, the present data on Finns suggests that APOE4 is a risk factor for severe COVID-19 and post-COVID mental fatigue and provides the first indication that some of this effect could be mediated via increased cerebrovascular damage. Further studies in larger cohorts and animal models are warranted.
97	I095	ES	Carlo Cervia, Yves Zurbuchen, Patrick Taeschler, Tala Ballouz, Dominik Menges, Sara Hasler, Sarah Adamo, Miro E. Raeber, Esther Bächli, Alain Rudiger, Melina Stüssi-Helbling, Lars C. Huber, Jakob Nilsson, Ulrike Held, Milo A. Puhan & Onur Boyman	Immunoglobulin signature predicts risk of post-acute COVID-19 syndrome	https://doi.org/10.1038/s41467-021-27797-1	Published	25 January 2022	Study	https://www.nature.com/articles/s41467-021-27797-1	Following acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) a significant proportion of individuals develop prolonged symptoms, a serious condition termed post-acute coronavirus disease 2019 (COVID-19) syndrome (PACS) or long COVID. Predictors of PACS are needed. In a prospective multicentric cohort study of 215 individuals, we study COVID-19 patients during primary infection and up to one year later, compared to healthy subjects. We discover an immunoglobulin (Ig) signature, based on total IgM and IgG3 levels, which – combined with age, history of asthma bronchiale, and five symptoms during primary infection – is able to predict the risk of PACS independently of timepoint of blood sampling. We validate the score in an independent cohort of 395 individuals with COVID-19. Our results highlight the benefit of measuring Igs for the early identification of patients at high risk for PACS, which facilitates the study of targeted treatment and pathomechanisms of PACS.	todo
98	I096		ONS	Self-reported long COVID after two doses of a coronavirus (COVID-19) vaccine in the UK: 26 January 2022		Published	26 January 2022	Study	https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/selfreportedlongcovidaftertwodosesofacoronaviruscovid19vaccineintheuk/26january2022	Odds ratios for symptoms reported at least 12 weeks after coronavirus (COVID-19) infection, comparing Coronavirus (COVID-19) Infection Survey participants who had received two doses of a COVID-19 vaccine before infection with those who were unvaccinated. Main points In a sample of UK adults aged 18 to 69 years, receiving two doses of a coronavirus (COVID-19) vaccine at least two weeks before a first test-confirmed COVID-19 infection was associated with a 41.1% decrease in the odds of self-reported long COVID at least 12 weeks later, relative to socio-demographically similar study participants who were not vaccinated when infected (Figure 1). This analysis was based on data to 30 November 2021, and longer follow-up time is needed to assess the impact of booster doses and the Omicron variant; furthermore, the observational nature of the analysis means that we cannot say whether COVID-19 vaccination caused subsequent changes in the likelihood of self-reported long COVID. Long COVID symptoms of any severity were reported by 9.5% of double-vaccinated study participants, compared with 14.6% of socio-demographically similar participants who were unvaccinated when infected; the corresponding estimates for long COVID symptoms severe enough to result in limitation to day-to-day activities were 5.5% and 8.7% respectively. There was no statistical evidence that the relationship between vaccination status at the time of infection and the likelihood of subsequently reporting long COVID symptoms differed by whether participants received adenovirus vector (Oxford/AstraZeneca) or mRNA (Pfizer/BioNTech or Moderna) vaccines.
99	I097		Qin Liu,1,2,3,4 Joyce Wing Yan Mak ,1,2,3 Qi Su,1,2,3 Yun Kit Yeoh ,1,5 Grace Chung-Yan Lui,2,6 Susanna So Shan Ng,2 Fen Zhang ,1,2,3 Amy Y L Li,1,2,3Wenqi Lu,1,2,3 David Shu-Cheong Hui, 6 Paul KS Chan,1,5 Francis K L Chan ,1,2,3Siew C Ng	Gut microbiota dynamics in a prospective cohort of patients with post-acute COVID-19 syndrome	http://dx.doi.org/10.1136/gutjnl-2021-325989	Published	January 26, 2022	Study	https://gut.bmj.com/content/early/2022/01/05/gutjnl-2021-325989	What is already known on this subject? ► Persistent symptoms after the convalescence period in patients with COVID-19 have been reported. ► Emerging evidence supports the potential role of gut dysbiosis in the severity of COVID-19 infection. ► The long-term impact of SARS-CoV-2 on the gut microbiome after the acute infection and whether gut microbiota composition affects risk of persistent symptoms in recovered patients with different severity of COVID-19 infection is unknown. What are the new findings? ► Our results show that an individual’s gut microbiome profile may affect their susceptibility to long-term complications of COVID-19. ► Gut microbiome pattern reflects different symptoms in patients with post-acute COVID-19 syndrome (PACS). ► Distinct gut microbiota composition at admission is associated with occurrence of PACS at 6 months. How might it impact on clinical practice in the foreseeable future? ► These findings provide new insights into the intricate association between the gut microbiome and the long-term sequelae after COVID-19 infection. ► Microbiome-based profiling might be used as a tool in early risk stratification for occurrence of post-acute COVID-19 syndrome. Background Long-term complications after COVID-19 are common, but the potential cause for persistent symptoms after viral clearance remains unclear. Objective To investigate whether gut microbiome composition is linked to post-acute COVID-19 syndrome (PACS), defined as at least one persistent symptom 4 weeks after clearance of the SARS-CoV-2 virus. Methods We conducted a prospective study of 106 patients with a spectrum of COVID-19 severity followed up from admission to 6 months and 68 non-COVID-19 controls. We analysed serial faecal microbiome of 258 samples using shotgun metagenomic sequencing, and correlated the results with persistent symptoms at 6 months. Results At 6 months, 76% of patients had PACS and the most common symptoms were fatigue, poor memory and hair loss. Gut microbiota composition at admission was associated with occurrence of PACS. Patients without PACS showed recovered gut microbiome profile at 6 months comparable to that of non-COVID-19 controls. Gut microbiome of patients with PACS were characterised by higher levels of Ruminococcus gnavus, Bacteroides vulgatus and lower levels of Faecalibacterium prausnitzii. Persistent respiratory symptoms were correlated with opportunistic gut pathogens, and neuropsychiatric symptoms and fatigue were correlated with nosocomial gut pathogens, including Clostridium innocuum and Actinomyces naeslundii (all p<0.05). Butyrate-producing bacteria, including Bifidobacterium pseudocatenulatum and Faecalibacterium prausnitzii showed the largest inverse correlations with PACS at 6 months. Conclusion These findings provided observational evidence of compositional alterations of gut microbiome in patients with long-term complications of COVID-19. Further studies should investigate whether microbiota modulation can facilitate timely recovery from post-acute COVID-19 syndrome.
100	I098	ES	YapengSu12328DanYuan1428Daniel G.Chen1528Rachel H.Ng14KaiWang1JongchanChoi1SarahLi1SungaHong1RongyuZhang14JingyiXie16Sergey A.Kornilov1KelseyScherler1Ana JimenaPavlovitch-Bedzyk7ShenDong8ChristopherLausted1InyoulLee1ShannonFallen1Chengzhen L.Dai1…James R.Heath	Multiple Early Factors Anticipate Post-Acute COVID-19 Sequelae	https://doi.org/10.1016/j.cell.2022.01.014	Published	25 January 2022	Study	https://www.cell.com/cell/fulltext/S0092-8674(22)00072-1	Highlights Longitudinal multiomics associate PASC with autoantibodies, viremia and comorbidities Reactivation of latent viruses during initial infection may contribute to PASC Subclinical autoantibodies negatively correlate with anti-SARS-CoV-2 antibodies Gastrointestinal PASC uniquely present with post-acute expansion of cytotoxic T cells Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk-factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data, and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific autoantibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.
101	I099		Nabin K Shrestha, Patrick C Burke, Amy S Nowacki, Paul Terpeluk, Steven M Gordon	Necessity of COVID-19 Vaccination in Persons Who Have Already Had COVID-19	https://doi.org/10.1093/cid/ciac022	Published	13 January 2022	Study	https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac022/6507165	Results Among 52238 employees, 4718 (9%) were previously infected, and 36922 (71%) were vaccinated by the study’s end. Cumulative incidence of COVID-19 was substantially higher throughout for those previously uninfected who remained unvaccinated than for all other groups, lower for the vaccinated than unvaccinated, and lower for those previously infected than those not. Incidence of COVID-19 increased dramatically in all groups after the Omicron variant emerged. In multivariable Cox proportional hazards regression, both prior COVID-19 and vaccination were independently associated with significantly lower risk of COVID-19. Among previously infected subjects, a lower risk of COVID-19 overall was not demonstrated, but vaccination was associated with a significantly lower risk of symptomatic COVID-19 in both the pre-Omicron (HR 0.60, 95% CI 0.40–0.90) and Omicron (HR 0.36, 95% CI 0.23–0.57) phases. Conclusions Both previous infection and vaccination provide substantial protection against COVID-19. Vaccination of previously infected individuals does not provide additional protection against COVID-19 for several months, but after that provides significant protection at least against symptomatic COVID-19.
102	I100		Priya Venkatesan	Do vaccines protect from long COVID?	https://doi.org/10.1016/S2213-2600(22)00020-0	Published	January 20, 2022	Article	https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00020-0/fulltext	The data on long COVID are worrying, particularly during the current increase in global cases of COVID-19 infection. There are, however, encouraging emerging data that individuals who are vaccinated against COVID-19 are less likely to report long COVID symptoms. For example, a case-control study of 1·2 million users of a COVID symptom tracker app in the UK showed that there were lower odds of symptoms lasting 28 days or more in individuals who had received two vaccine doses (odds ratio 0·51 [95% CI 0·32–0·82]; p=0·0060)—ie, the risk of developing long COVID was reduced by around 50% in those who were double vaccinated. Wilder-Smith said “Even if COVID-19 did not cause deaths, the high morbidity as a result of this viral infection would justify vaccinating all. The reasons for vaccination beyond the most pressing need to avert severe disease and deaths are manifold, but foremost it is to prevent long COVID.” De Soyza added “Ideally preventing both acute severe COVID through vaccination and also reducing the chances of long COVID represents an additional driver to support people to get vaccinated.”
103	I101		PabloPánicoPatriciaOstrosky-WegmanAna MaríaSalazar	The potential role of COVID-19 in the induction of DNA damage	https://doi.org/10.1016/j.mrrev.2022.108411	Published	21 January 2022	Article	https://www.sciencedirect.com/science/article/pii/S1383574222000011	In some individuals, COVID-19 can cause a wide array of symptoms, affecting several organs, such as the lungs, heart, bowels, kidneys and brain, causing multiorgan failure, sepsis and death. These effects are related in part to direct viral infection of these organs, immunological deregulation, a hypercoagulatory state and the potential for development of cytokine storm syndrome. Since the appearance of COVID-19 is recent, the long-term effects on the health of recovered patients remain unknown. In this review, we focused on current evidence of the mechanisms of DNA damage mediated by coronaviruses. Data supports that these viruses can induce DNA damage, genomic instability, and cell cycle deregulation during their replication in mammalian cells. Since the induction of DNA damage and aberrant DNA repair mechanisms are related to the development of chronic diseases such as cancer, diabetes, neurodegenerative disorders, and atherosclerosis, it will be important to address similar effects and outcomes in recovered COVID-19 patients.
104	I102	VP	Luis AntonioDíazMD1+TamaraGarcía-SalumPh.D2+EduardoFuentes-LópezPh.D3+DiegoReyesMD4JavierOrtizMD4JavierChahuanMD1JorgeLevicanPh.D2Leonardo I.AlmonacidPh.D2Gonzalo H.ValenzuelaMD2EileenSerranocPh.D2SigallBudnik5VicenteGandara5AndreaGallardo5María FranciscaSeydewitz5MarcelaFerrésMD2ColombaCofréMD6ManuelÁlvarezMD1CarolinaPavezMD1…ArnoldoRiquelmeMD M.Med.Ed Full Professor13	High prevalence of SARS-CoV-2 detection and prolonged viral shedding in stools: A Systematic Review and Cohort StudyElevada detección de SARS-CoV-2 y prolongada excreción viral en deposiciones: Estudio de cohorte y revisión sistemática	https://doi.org/10.1016/j.gastrohep.2021.12.009	Published	22 January 2022	Study	https://www.sciencedirect.com/science/article/pii/S0210570522000012	Results: We included 32 patients; mean age was 43.7;17.7 years, 43.8% were female, and 40.6% reported gastrointestinal symptoms. Twenty-five percent (8/32) of patients had detectable viral RNA in stools. The median clearance time in stools of the cohort was 11[10-15] days. Systematic review included 30 studies (1,392 patients) with stool samples. Six studies were performed in children and 55% were male. The pooled prevalence of viral detection in stools was 34.6% (twenty-four studies, 1,393 patients; 95%CI:25.4-45.1); heterogeneity was high (I2:91.2%, Q:208.6; p=<0.001). A meta-regression demonstrates an association between female-gender and lower presence in stools (p=0.004). The median clearance time in stools was 22 days (nineteen studies, 140 patients; 95%CI:19–25). After 34 days, 19.9% (95%CI:11.3-29.7) of patients have a persistent detection in stools. Conclusions: Detection of SARS-CoV-2 in stools is a frequent finding. The clearance of SARS-CoV-2 in stools is prolonged and it takes longer than nasopharyngeal secretions.
105	I103		Artem Pliss, Andrey N. Kuzmin, Paras N. Prasad, and Supriya D. Mahajan	Mitochondrial Dysfunction: A Prelude to Neuropathogenesis of SARS-CoV-2	https://doi.org/10.1021/acschemneuro.1c00675	Published	January 20, 2022	Article	https://pubs.acs.org/doi/10.1021/acschemneuro.1c00675	The neuropathology of SARS-CoV-2 is increasingly attributed to mitochondrial dysfunction of brain microglia cells. However, the changes in biochemical content of mitochondria that drive the progression of neuro-COVID remain poorly understood. Here we introduce a Raman microspectrometry approach that enables the molecular profiling of single cellular organelles to characterize the mitochondrial molecular makeup in the infected microglia cells. We found that microglia treated with either spike protein or heat-inactivated SARS-CoV-2 trigger a dramatic reduction in mtDNA content and an increase in phospholipid saturation levels. At the same time, no significant changes were detected in Golgi apparatus and in lipid droplets, the organelles that accommodate biogenesis and storage of lipids. We hypothesize that transformations in mitochondria are caused by increased synthesis of reactive oxygen species in these organelles. Our findings call for the development of mitochondria-targeted therapeutic approaches to limit neuropathology associated with SARS-CoV-2.
106	I104		Reka Varnai 1 ,Tihamer Molnar 2,* ,Laszlo Zavori 3 ,Margit Tőkés-Füzesi 4,Zsolt Illes 5,Andrea Kanizsai 6 andPeter Csecsei 7	Serum Level of Anti-Nucleocapsid, but Not Anti-Spike Antibody, Is Associated with Improvement of Long COVID Symptoms	https://doi.org/10.3390/vaccines10020165	Published	21 January 2022	Article	https://www.mdpi.com/2076-393X/10/2/165/htm	Previous reports have suggested the role of an unsatisfactory immune response and impaired viral clearance in the pathogenesis of long COVID syndrome. We focused on potential associations between post-vaccination changes of antibody titers and the severity of long COVID symptoms and factors influencing the state of remission observed in patients with long COVID after vaccination. Methods: The severity of long COVID symptoms and serum anti-SARS-CoV-2 spike (S-Ig) and nucleocapsid (NC-Ig) levels were assessed in 107 post-COVID subjects at two time points: at baseline, and 17–24 weeks later. Besides, vaccination status was also assessed. Symptoms were evaluated based on the Chalder fatigue scale (CFQ-11) and visual analogue scale (VAS). Results: Serum level of S-Ig and NC-Ig at baseline were significantly higher in the patients with non-severe fatigue than those with severe fatigue, and this difference remained significant at follow-up in the case of NC-Ig. NC-Ig level above median was as an independent predictor for complete remission at follow-up. The difference in NC-Ig levels in subgroup analyses (severe fatigue vs. non-severe fatigue; complete remission vs. incomplete remission or progression) was found to be significant only in patients who received vaccination. Conclusions: The immune response against the SARS-CoV-2 nucleocapsid may play a more important role than the spike in the course of long-term COVID syndrome.
107	I105		César Fernández-de-las-Peñas 1,2,* ,José D. Martín-Guerrero 3 ,Óscar J. Pellicer-Valero 3 ,Esperanza Navarro-Pardo 4 ,Víctor Gómez-Mayordomo 5 ,María L. Cuadrado 5,6,José A. Arias-Navalón 7 ,Margarita Cigarán-Méndez 8,Valentín Hernández-Barrera 9 andLars Arendt-Nielsen 2,10	Female Sex Is a Risk Factor Associated with Long-Term Post-COVID Related-Symptoms but Not with COVID-19 Symptoms: The LONG-COVID-EXP-CM Multicenter Study	https://doi.org/10.3390/jcm11020413	Published	14 January 2022	Study	https://www.mdpi.com/2077-0383/11/2/413/htm	This multicenter cohort study investigated the differences between coronavirus disease 2019 (COVID-19) related symptoms and post-COVID symptoms between male and female COVID-19 survivors. Clinical and hospitalization data were collected from hospital medical records in a sample of individuals recovered from COVID-19 at five public hospitals in Spain. A predefined list of post-COVID symptoms was systematically assessed, but patients were free to report any symptom. Anxiety/depressive levels and sleep quality were also assessed. Adjusted multivariate logistic regressions were used to identify the association of sex with post-COVID related-symptoms. A total of 1969 individuals (age: 61, SD: 16 years, 46.4% women) were assessed 8.4 months after discharge. No overall significant sex differences in COVID-19 onset symptoms at hospital admission were found. Post-COVID symptoms were present in up to 60% of hospitalized COVID-19 survivors eight months after the infection. The number of post-COVID symptoms was 2.25 for females and 1.5 for males. After adjusting by all variables, female sex was associated with ≥3 post-COVID symptoms (adj OR 2.54, 95%CI 1.671–3.865, p < 0.001), the presence of post-COVID fatigue (adj OR 1.514, 95%CI 1.040–2.205), dyspnea (rest: adj OR 1.428, 95%CI 1.081–1.886, exertion: adj OR 1.409, 95%CI 1.109–1.791), pain (adj OR 1.349, 95%CI 1.059–1.720), hair loss (adj OR 4.529, 95%CI 2.784–7.368), ocular problems (adj OR 1.981, 95%CI 1.185–3.312), depressive levels (adj OR 1.606, 95%CI 1.002–2.572) and worse sleep quality (adj OR 1.634, 95%CI 1.097–2.434). Female sex was a risk factor for the development of some long-term post-COVID symptoms including mood disorders. Healthcare systems should consider sex differences in the management of long haulers.
108	I106		C. Lazor-Blanchet, P. Zygoura, U. Dafni, F. Lamoth, Z. Tsourti, M.A. Lobritz, J. Regina, B. Grandbastien, C. Fenwick, G. Pantaleo, T. Calandra, S.d Meylan	Low neutralizing antibody titers after asymptomatic or non-severe SARS-CoV-2 infection over a 6-month assessment period	https://doi.org/10.1016/j.jinf.2022.02.001	Published	February 05, 2022	Letter to Editor	https://www.journalofinfection.com/article/S0163-4453(22)00062-7/fulltext	Highlights •Patients with asymptomatic and mild SARS-CoV-2 infections are at risk of re-infection within the same year •Neutralizing capacity remains more stable over time than do anti-S IgG titers.
109	I107		NicoleBechmannPhDabProfAndreasBarthelMDacProfAndreasSchedlPhDadProfStephanHerzigPhDeProfZsuzsannaVargaMDfProfCatherineGebhardMDghProfManuelMayrPhDaiConstanzeHantelPhDakProfFelixBeuschleinMDklProfChristianWolfrumPhDmProfNikolaosPerakakisMDaProfLucillaPostonPhDnCynthia LAndoniadouPhDaoRichardSiowPhDijProfRaul RGainetdinovMDqAradDotanMDrProfYehudaShoenfeldMDrsProfGeltrudeMingroneMDptuProfStefan RBornsteinMDap	Sexual dimorphism in COVID-19: potential clinical and public health implications	https://doi.org/10.1016/S2213-8587(21)00346-6	Published	1 February 2022	Personal View	https://www.sciencedirect.com/science/article/pii/S2213858721003466	Current evidence suggests that severity and mortality of COVID-19 is higher in men than in women, whereas women might be at increased risk of COVID-19 reinfection and development of long COVID. Differences between sexes have been observed in other infectious diseases and in the response to vaccines. Sex-specific expression patterns of proteins mediating virus binding and entry, and divergent reactions of the immune and endocrine system, in particular the hypothalamic–pituitary–adrenal axis, in response to acute stress might explain the higher severity of COVID-19 in men. In this Personal View, we discuss how sex hormones, comorbidities, and the sex chromosome complement influence these mechanisms in the context of COVID-19. Due to its role in the severity and progression of SARS-CoV-2 infections, we argue that sexual dimorphism has potential implications for disease treatment, public health measures, and follow-up of patients predisposed to the development of long COVID. We suggest that sex differences could be considered in future pandemic surveillance and treatment of patients with COVID-19 to help to achieve better disease stratification and improved outcomes.
110	I108		RavindraGaneshMBBS, MDaStephanie L.GrachMD, MSdAditya K.GhoshMDeDennis M.BierleMDaBradley R.SalonenMDaNerissa M.CollinsMDaAvni Y.JoshiMD, MSbNeal D.BoederJr.MDaChristopher V.AnstineMDaMichael R.MuellerMD, MSaElizabeth C.WightMDaIvana T.CroghanPhDaAndrew D.BadleyMDcRickey E.CarterPhDfRyan T.HurtMD, PhDa	The Female-Predominant Persistent Immune Dysregulation of the Post-COVID Syndrome	https://doi.org/10.1016/j.mayocp.2021.11.033	Published	5 February 2022	Study	https://www.sciencedirect.com/science/article/pii/S0025619621008880	Results Most of the patients seen in our clinic were female (75%; 81/108), and the median age at presentation was 46 years (interquartile range, 37 to 55 years). All had post-acute sequelae of SARS-CoV-2 infection, with 6 clinical phenotypes being identified: fatigue predominant (n=69), dyspnea predominant (n=23), myalgia predominant (n=6), orthostasis predominant (n=6), chest pain predominant (n=3), and headache predominant (n=1). The fatigue-predominant phenotype was more common in women, and the dyspnea-predominant phenotype was more common in men. Interleukin 6 (IL-6) was elevated in 61% of patients (69% of women; P=.0046), which was more common than elevation in C-reactive protein and erythrocyte sedimentation rate, identified in 17% and 20% of cases, respectively. Conclusion In our PCOCC, we observed several distinct clinical phenotypes. Fatigue predominance was the most common presentation and was associated with elevated IL-6 levels and female sex. Dyspnea predominance was more common in men and was not associated with elevated IL-6 levels. IL-6 levels were more likely than erythrocyte sedimentation rate and C-reactive protein to be elevated in patients with post-acute sequelae of SARS-CoV-2 infection.
111	I109		Dr. Carolina Diamandis,Olga Ivanova,Adrian Tudor Corresponding Author	From pandemic Covid-19 to endemic Sars-2 Omicron Disease: is Long Covid still an issue?	https://doi.org/10.22541/au.164364370.07687372/v1	pre-print	January 31, 2022	Review	https://www.authorea.com/doi/full/10.22541/au.164364370.07687372	Abstract For many patients with severe Covid-19 disease of the pre-Omicron era, recovery is far from over with the end of acute symptoms. The authors of this paper have reviewed the currently available studies and conclude that Long-Covid appears to be a serious, sometimes even life-threatening syndrome. However, it seems to have good prospects for full recovery with multidisciplinary and evidence-based post-treatment care, which is, however, still lacking in Europe and North America. The Omicron variant appears to be a game changer in this regard as well. So far it seems that Long Covid is no common consequence of Sars-2-Omicron Disease.
112	I110		Sara Ahmad Assiri Raad M. M. Althaqafi Taif University Khaled Alswat Ahmed Abdullah Alghamdi	Post COVID-19 Vaccination-Associated Neurological Complications	http://dx.doi.org/10.2147/NDT.S343438	Published	February 2022	Study	https://www.researchgate.net/publication/358272064_Post_COVID-19_Vaccination-Associated_Neurological_Complications	Purpose: Neurological sequelae after COVID-19 vaccination are rare. We investigated the possible pathogenesis behind the development of neurological complications within a short period after Saudi residents received a COVID-19 vaccine. Patients and Methods: We evaluated 18 patients who recently received a COVID-19 vaccine (Comirnaty and Vaxzevria vaccines) and presented with neurological complications to the Saudi German Hospitals in Jeddah, Saudi Arabia. Neurologists assessed the patients’ clinical presentation, radiological investigations, and laboratory findings. Results: Three patients who received the first dose of the Vaxzevria vaccine experienced severe cerebral venous thrombosis, two of them were complicated by intracranial hemorrhage. Their laboratory investigations showed very high d-dimers and severe thrombocytopenia, which have been linked to higher mortality and poor outcome. Ischemic stroke occurred in eight cases (44.4%) with a predominance in older male patients. Three patients presented with seizures, two had optic neuritis. Guillain–Barré syndrome (GBS) and Miller Fisher syndrome (MFS) occurred in two male patients following vaccination with Comirnaty. Conclusion: Neurological complications after COVID-19 vaccinations are very rare, and only a few cases have been reported worldwide. The shared pathophysiological basis between COVID-19 viral infection and COVID-19 vaccines stands behind the very rare neurological complications resulting from the hypercoagulable state triggered by the general inflammatory condition. We suspect some differences in the pathogenesis of ischemic stroke caused by COVID-19 infection and COVID-19 vaccines, which render COVID-19 vaccine-associated ischemic stroke more responsive to treatment. To date, no definitive association between the vaccine and GBS has been proven by any strong evidence, but it has recently been added as a very rare side effect of the Janssen COVID-19 vaccine. No possible links of Miller Fisher syndrome to COVID-19 vaccines have been reported before the one reported in this study. Keywords: vaccine, ischemic stroke, cerebral venous thrombosis, seizures, optic neuritis.
113	I111		Yang Yang, Minghui Yang, Yun Peng, Yanhua Liang, Jinli Wei, Li Xing, Liping Guo, Xiaohe Li, Jie Li, Jun Wang, Mianhuan Li, Zhixiang Xu, Mingxia Zhang, Fuxiang Wang, Yi Shi, Jing Yuan & Yingxia Liu	Longitudinal analysis of antibody dynamics in COVID-19 convalescents reveals neutralizing responses up to 16 months after infection	https://doi.org/10.1038/s41564-021-01051-2	Published	07 February 2022	Article	https://www.nature.com/articles/s41564-021-01051-2	Elucidating the dynamics of the neutralizing antibody (nAb) response in coronavirus disease 2019 (COVID-19) convalescents is crucial in controlling the pandemic and informing vaccination strategies. Here we measured nAb titres across 411 sequential plasma samples collected during 1–480 d after illness onset or laboratory confirmation (d.a.o.) from 214 COVID-19 convalescents, covering the clinical spectrum of disease and without additional exposure history after recovery or vaccination against SARS-CoV-2, using authentic SARS-CoV-2 microneutralization (MN) assays. Forty-eight samples were also tested for neutralizing activities against the circulating variants using pseudotyped neutralization assay. Results showed that anti-RBD IgG and MN titres peaked at ~120 d.a.o. and subsequently declined, with significantly reduced nAb responses found in 91.67% of COVID-19 convalescents (≥50% decrease in current MN titres compared with the paired peak MN titres). Despite this decline, majority of the COVID-19 convalescents maintained detectable anti-RBD IgG and MN titres at 400–480 d.a.o., with undetectable neutralizing activity found in 14.41% (16/111) of the mild and 50% (5/10) of the asymptomatic infections at 330–480 d.a.o. Persistent antibody-dependent immunity could provide protection against circulating variants after one year, despite significantly decreased neutralizing activities against Beta, Delta and Mu variants. In conclusion, these data show that despite a marked decline in neutralizing activity over time, nAb responses persist for up to 480 d in most convalescents of symptomatic COVID-19, whereas a high rate of undetectable nAb responses was found in convalescents from asymptomatic infections.
114	I112		Jin-Gyu Cheong, Arjun Ravishankar, Siddhartha Sharma, Christopher N. Parkhurst, Djamel Nehar-Belaid, Sai Ma, Lucinda Paddock, Benoit Fatou, Onur Karakaslar, Asa Thibodeau, Michael J. Bale, Vinay K. Kartha, Jim K Yee, Minh Yen Mays, Louise Leyre, Alexia Martinez de Paz, Andrew W. Daman, Sergio Alvarez Mullett, Lexi Robbins, Elyse LaFond, Karissa Weidman, View ProfileSabrina Racine-Brzostek, He S. Yang, David Price, Brad Jones, Edward J. Schenck, Robert J. Kaner, Amy Chadburn, Zhen Zhao, View ProfileHanno Steen, Virginia Pascual, Jason Buenrostro, Rachel E. Niec, Lindsay Lief, Duygu Ucar, View ProfileSteven Z. Josefowicz	Epigenetic Memory of COVID-19 in Innate Immune Cells and Their Progenitors	https://doi.org/10.1101/2022.02.09.479588	pre-print	February 10, 2022	Study	https://www.biorxiv.org/content/10.1101/2022.02.09.479588v1.full	Severe coronavirus disease 2019 (COVID-19) is characterized by systemic inflammation and can result in protracted symptoms. Robust systemic inflammation may trigger persistent changes in hematopoietic cells and innate immune memory through epigenetic mechanisms. We reveal that rare circulating hematopoietic stem and progenitor cells (HSPC), enriched from human blood, match the diversity of HSPC in bone marrow, enabling investigation of hematopoiesis and HSPC epigenomics. Following COVID-19, HSPC retain epigenomic alterations that are conveyed, through differentiation, to progeny innate immune cells. Epigenomic changes vary with disease severity, persist for months to a year, and are associated with increased myeloid cell differentiation and inflammatory or antiviral programs. Epigenetic reprogramming of HSPC may underly altered immune function following infection and be broadly relevant, especially for millions of COVID-19 survivors. One Sentence Summary Transcriptomic and epigenomic analysis of blood reveal sustained changes in hematopoiesis and innate immunity after COVID-19.
115	I113		Lydia L.Shook12Elinor L.Sullivan345Jamie O.Lo678Roy H.Perlis9Andrea G.Edlow12	COVID-19 in pregnancy: implications for fetal brain development	https://doi.org/10.1016/j.molmed.2022.02.004	Published	14 February 2022	Review	https://www.sciencedirect.com/science/article/pii/S1471491422000454	Highlights •SARS-CoV-2 infection in pregnancy is known to confer a risk of increased morbidity and mortality for the mother, but data are lacking regarding the impact of maternal SARS-CoV-2 infection on the developing fetal brain. •Placental and fetal infection with SARS-CoV-2 have been rare to date; SARS-CoV-2 infection in pregnancy appears most likely to impact fetal brain development via maternal and placental immune activation. •Maternal, placental, and fetal immune activation have been observed in SARS-CoV-2 infection during pregnancy, and adverse neurodevelopmental outcomes have been reported in early follow-up studies of offspring. •Maternal and placental immune activation may impact the placenta and developing fetal brain via induction of immune activation and pro-inflammatory cytokine production, dysregulation of serotonin/other neurotransmitter signaling, and increased oxidative stress. Abstract The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy on the developing fetal brain is poorly understood. Other antenatal infections such as influenza have been associated with adverse neurodevelopmental outcomes in offspring. Although vertical transmission has been rarely observed in SARS-CoV-2 to date, given the potential for profound maternal immune activation, impact on the developing fetal brain is likely. Here we review evidence that SARS-CoV-2 and other viral infections during pregnancy can result in maternal, placental and fetal immune activation, and ultimately in offspring neurodevelopmental morbidity. Finally, we highlight the need for cellular models of fetal brain development to better understand potential short- and long-term impacts of maternal SARS-CoV-2 infection on the next generation.
116	I114		MarySmallCharles N.SerhanStephaniaLibrerosRobertNshimiyimana	E-series Resolvin Metabolome, Biosynthesis and Critical Role of Stereochemistry of Specialized Pro-Resolving Mediators (SPMs) in Inflammation-Resolution: Preparing SPMs for Long COVID-19, Human Clinical Trials, and Targeted Precision Nutrition	https://doi.org/10.1016/j.smim.2022.101597	Published	16 February 2022	Review	https://www.sciencedirect.com/science/article/pii/S1044532322000148	The COVID-19 pandemic has raised international awareness of the importance of rigorous scientific evidence and the havoc caused by uncontrolled excessive inflammation. Here we consider the evidence on whether the specialized pro-resolving mediators (SPMs) are ready to meet this challenge as well as targeted metabololipidomics of the resolution-inflammation metabolomes. Specific stereochemical mechanisms in the biosynthesis of SPMs from omega-3 essential fatty acids give rise to unique local-acting lipid mediators. SPMs possess stereochemically defined potent bioactive structures that are high-affinity ligands for cognate G protein-coupled surface receptors that evoke the cellular responses required for efficient resolution of acute inflammation. The SPMs biosynthesized from the major omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are coined Resolvins (resolution phase interaction products; E series and D-series), Protectins and Maresins (macrophage mediators in resolving inflammation). Their biosynthesis and stereochemical assignments are established and confirmed as well as their functional roles on innate immune cells and adaptive immune cells (both lymphocyte T-cell subsets and B-cells). The resolution of a protective acute inflammatory response is governed mainly by phagocytes that actively clear apoptotic cells, debris, blood clots and pathogens. These resolution phase functions of the acute inflammatory response are enhanced by SPMs, which together prepare the inflammatory loci for homeostasis and stimulate tissue regeneration via activating stem cells and the biosynthesis of novel cys-SPMs (e.g. MCTRs, PCTRs and RCTRs). These cys-SPMs also activate regeneration, are organ protective and stimulate resolution of local inflammation. Herein, we review the biosynthesis and functions of the E-series resolvins, namely resolvin E1 (the first n-3 resolvin identified), resolvin E2, resolvin E3 and resolvin E4 biosynthesized from their precursor eicosapentaenoic acid (EPA), and the critical role of total organic synthesis in confirming SPM complete stereochemistry, establishing their potent functions in resolution of inflammation, and novel structures. The physical properties of each biologically derived SPM, i.e., ultra-violet (UV) absorbance, chromatographic behavior, and tandem mass spectrometry (MS2) fragmentation, were matched to SPMs biosynthesized and prepared by stereospecific total organic synthesis. We briefly review this approach, also used with the endogenous D-series resolvins, protectins and maresins confirming their potent functions in resolution of inflammation, that paves the way for their rigorous evaluation in human tissues and clinical trials. The assignment of complete stereochemistry for each of the E and D series Resolvins, Protectins and Maresins was a critical and required step that enabled human clinical studies as in SPM profiling in COVID-19 infections and experimental animal disease models that also opened the promise of resolution physiology, resolution pharmacology and targeted precision nutrition as new areas for monitoring health and disease mechanisms.
117	I115		Denise Goh1 Jeffrey Chun Tatt Lim1 Sonia Bilbao Fernández2 Justina Nadia Lee1 Craig Ryan Joseph1 Zhen Wei Neo1 Sílvia Guerrero2 Mai Chan Lau1 Joe Yeong Poh Sheng1	Persistence of residual SARS-CoV-2 viral antigen and RNA in tissues of patients with long COVID-19	https://doi.org/10.21203/rs.3.rs-1379777/v1	pre-print	22 Feb, 2022	Study	https://www.researchsquare.com/article/rs-1379777/new/v1	Since we have previously reported residual viral antigens in tissues of convalescent patients, we now aim to assess the presence of such antigens in post-convalescent tissues. Here, we established the presence of residual virus within the appendix and breast tissue of 2 patients who exhibited LC symptoms, 175 to 462 days upon positive diagnosis, using immunohistological techniques. We observed positive staining for viral nucleocapsid protein (NP) in the appendix, and tumour-adjacent region of the breast, but not within the tumour via multiplex immunohistochemistry. Notably, with RNAscope, both positive-sense and negative-sense (replicative intermediate) viral RNA were detected. As a single-stranded virus, SARS-CoV-2, have to produce a replicative intermediate as a template to synthesize new genomic RNAs. Thus, the detection of negative-sense viral RNA suggests ongoing viral replication. While viral RNA and antigen from gastrointestinal and stool samples of convalescent patients has been extensively reported, we believe this is the first study to detect viable virus. Furthermore, our positive finding in the breast tissue also corroborated with recent reports that immunocompromised patients had also experienced LC symptoms and persistent viral replication. Overall, our findings, along with emerging LC studies, question the possibility of the gastrointestinal tract functioning as a reservoir.
118	I116		Daniel Ayoubkhani, View ProfileMatthew L Bosworth, Sasha King, View ProfileKoen B Pouwels, View ProfileMyer Glickman, View ProfileVahe Nafilyan, View ProfileFrancesco Zaccardi, View ProfileKamlesh Khunti, View ProfileNisreen A Alwan, View ProfileAnn Sarah Walker	Risk of Long Covid in people infected with SARS-CoV-2 after two doses of a COVID-19 vaccine: community-based, matched cohort study	https://doi.org/10.1101/2022.02.23.22271388	pre-print	February 24, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.02.23.22271388v1	Participants who were double-vaccinated ≥14 days before infection were 1:1 propensity-score matched, based on socio-demographic characteristics and time from infection to follow-up for Long Covid, to those unvaccinated at time of infection. We estimated adjusted odds ratios (aOR) of Long Covid symptoms ≥12 weeks post-infection, comparing double-vaccinated with unvaccinated (reference group) participants. Results: The study sample comprised 3,090 double-vaccinated participants (mean age 49 years, 54% female, 92% white, median follow-up from infection 96 days) and matched control participants. Long Covid symptoms were reported by 294 double-vaccinated participants (prevalence 9.5%) compared with 452 unvaccinated participants (14.6%), corresponding to an aOR for Long Covid symptoms of 0.59 (95% CI: 0.50 to 0.69). There was no evidence of heterogeneity by adenovirus vector versus messenger ribonucleic acid vaccines (p=0.25). Conclusions: COVID-19 vaccination is associated with reduced risk of Long Covid, emphasising the need for public health initiatives to increase population-level vaccine uptake. Longer follow-up is needed, as is the assessment of further vaccine doses and the Omicron variant.
119	I117		Tomonari Sumi, Kouji Harada	Immune Response To SARS-Cov-2 In Severe And Long COVID-19	https://doi.org/10.21203/rs.3.rs-1348061/v1	pre-print	17 Feb, 2022	Article	https://www.researchsquare.com/article/rs-1348061/v1	Here, we developed a mathematical model of the immune response to SARS-CoV-2 and revealed that typical age-related risk factors such as only a several 10 % decrease in innate immune cell activity and inhibition of type-I interferon signaling by autoantibodies drastically increased the viral load. It was reported that the numbers of certain dendritic cell subsets remained less than half those in healthy donors even seven months after infection. Hence, the inflammatory response was ongoing. Our model predicted the persistent DC reduction and showed that certain patients with severe and even mild symptoms could not effectively eliminate the virus and could potentially develop long COVID.
120	I118		Elisabeth Mahase	Covid-19: Vaccinated people are less likely to get long covid, review finds	https://doi.org/10.1136/bmj.o407	Published	16 February 2022	Article	https://www.bmj.com/content/376/bmj.o407.short	People who had been fully vaccinated against covid-19 were around half as likely to develop long covid symptoms as people who had received only one vaccine dose or were unvaccinated, the UK Health Security Agency has said.1 The agency conducted a rapid review of evidence, including 15 UK and international studies up to January 2022. Being vaccinated was defined as having two doses of the Pfizer-BioNTech, Oxford-AstraZeneca, or Moderna vaccine or one dose of the Janssen vaccine. The review found that vaccine effectiveness against most post-covid symptoms in adults was highest in people over 60 and lowest in those aged 19 to 35. Around 2% of the UK population have reported symptoms of long covid (or “post-covid syndrome”), which can last for more than four weeks after the initial SARS-CoV-2 infection. The most common symptoms are fatigue, shortness of breath, and muscle or joint pain.
121	I119		Panagiotis Giannos,Konstantinos Prokopidis	Gut dysbiosis and long COVID-19: Feeling gutted	https://doi.org/10.1002/jmv.27684	Published	28 February 2022	Article	https://onlinelibrary.wiley.com/doi/10.1002/jmv.27684	Emerging evidence has suggested that the pathology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may in part be explained by microbial species,1 contributing to the inflammatory phenotype commonly seen in patients with coronavirus disease (COVID-19).2, 3 Indeed, dysbiosis of the gut microbiota has been associated with poor clinical outcomes in mechanically ventilated COVID-19 patients. Specifically, Wu et al. observed elevated Granulicatella and Rothia mucilaginosa in the gut microbiome of COVID-19 hospitalized patients when compared to healthy individuals.4 Additionally, increased Burkholderia cepacia complex, Staphylococcus epidermidis, Mycoplasma hominis, and Mycroplasma orale species have been observed in severely ill COVID-19 patients as opposed to mildly affected ones.5 These findings hint at a possible yet prominent link between gut microbiota and SARS-CoV-2 repercussions, which may also be related to the imminent occurrence of long-term COVID-19 complications. Contemporary research has revealed a disruption of the gut microbiota in stool samples of SARS-CoV-2 patients that may explain the well-described cytokine storm-induced ramifications post-infection.6 Interestingly, fecal transplantation may regenerate gut microbiota diversity, bolstering the respiratory system of patients suffering from COVID-19.7 Considering that long-term complications following recovery from SARS-CoV-2 persistently exhibit a damaged microbial microenvironment compared to uninfected controls,8 these changes may hint at alterations in the patients' microbiome. We describe recently published data on the relationship of the long COVID-19 phenomenon with gut microbiota dysbiosis, providing a mechanistic insight. Our aim is to raise awareness of the impact SARS-CoV-2 imposes on public health that in part may be explained through a gut-lung axis cascade. The depletion of immunomodulatory microbiota from severe SARS-CoV-2 infection may prolong physiological repercussions (i.e., lung injury) during long COVID-19, induced by systemic inflammation.9 The recent study by Chen et al. showed significant reductions of microbial diversity in patients with COVID-19 during a 6-month follow-up, as opposed to the aseptic group.10 Particularly, following acute (30 days) and prolonged (3 months) SARS-CoV-2 recovery, suppression of anti-inflammatory bacteria such as Faecalibacterium prausnitzii, Eubacterium rectale, and Bifidobacterium adolescentis, and enrichment of pathogens, including Rothia, Erysipelatoclostridium, Ruminococcus gnavus, Ruminococcus torques, and Bacteroides dorei have been observed.8, 11 These changes may underlie the association between lower gut microbiota diversity and higher C-reactive protein levels in long COVID-19 patients (Figure 1).
122	I120		Yasue Sakurada 1,Naruhiko Sunada 1,Hiroyuki Honda 1,Kazuki Tokumasu 1,Yuki Otsuka 1 ,Yasuhiro Nakano 1 ,Yoshihisa Hanayama 1,Masanori Furukawa 2,Hideharu Hagiya 1 andFumio Otsuka	Serial Changes of Long COVID Symptoms and Clinical Utility of Serum Antibody Titers for Evaluation of Long COVID	https://doi.org/10.3390/jcm11051309	Published	27 February 2022	Study	https://www.mdpi.com/2077-0383/11/5/1309/htm	In February 2021, we established an outpatient clinic in a university hospital for patients with long COVID and started medical treatment for sequelae that persisted one month or more after infection. Methods: To determine the key factors that affect the onset and clinical course of sequelae, a retrospective analysis was performed at Okayama University Hospital (Japan) between February and July 2021. We focused on changes in the numbers of symptoms and the background of the patients during a three-month period from the first outpatient visit. We also examined the relationship with SARS-CoV-2 antibody titers. Results: Information was obtained from medical records for 65 patients. The symptoms of sequelae were diverse, with more than 20 types. The most frequent symptoms were general malaise, dysosmia, dysgeusia, sleeplessness, and headache. These symptoms improved in about 60% of the patients after 3 months. Patients who required hospitalization and had a poor condition in the acute phase and patients who received oxygen/dexamethasone therapy had higher antibody titers at the time of consultation. Patients with antibody titers ≥200 U/mL showed significantly fewer improvements in long COVID symptoms in 1 month, but they showed improvements at 3 months after the first visit. Conclusion: Long COVID symptoms were improved at 3 months after the initial visit in more than half of the patients. Serum antibody titers were higher in patients who experienced a severe acute phase, but the serum antibody titers did not seem to be directly related to the long-term persistence of long COVID symptoms.
123	I121		Daniel Ayoubkhani, View ProfileMatthew L. Bosworth, Sasha King, View ProfileKoen B. Pouwels, View ProfileMyer Glickman, View ProfileVahé Nafilyan, View ProfileFrancesco Zaccardi, View ProfileKamlesh Khunti, View ProfileNisreen A. Alwan, View ProfileA. Sarah Walker	Risk of Long Covid in people infected with SARS-CoV-2 after two doses of a COVID-19 vaccine: community-based, matched cohort study	https://doi.org/10.1101/2022.02.23.22271388	pre-print	February 24, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.02.23.22271388v1.full-text	Background It is unclear whether receiving two COVID-19 vaccinations before SARS-CoV-2 infection reduces the risk of developing Long Covid symptoms. We examined whether the likelihood of symptoms 12 weeks after infection differed by vaccination status. Methods We included COVID-19 Infection Survey participants aged 18-69 years who tested positive for SARS-CoV-2 between 26 April 2020 and 30 November 2021; we excluded participants who, before their first test-confirmed infection, had suspected COVID-19 or Long Covid symptoms, or were single-vaccinated. Participants who were double-vaccinated ≥14 days before infection were 1:1 propensity-score matched, based on socio-demographic characteristics and time from infection to follow-up for Long Covid, to those unvaccinated at time of infection. We estimated adjusted odds ratios (aOR) of Long Covid symptoms ≥12 weeks post-infection, comparing double-vaccinated with unvaccinated (reference group) participants. Results The study sample comprised 3,090 double-vaccinated participants (mean age 49 years, 54% female, 92% white, median follow-up from infection 96 days) and matched control participants. Long Covid symptoms were reported by 294 double-vaccinated participants (prevalence 9.5%) compared with 452 unvaccinated participants (14.6%), corresponding to an aOR for Long Covid symptoms of 0.59 (95% CI: 0.50 to 0.69). There was no evidence of heterogeneity by adenovirus vector versus messenger ribonucleic acid vaccines (p=0.25). Conclusions COVID-19 vaccination is associated with reduced risk of Long Covid, emphasising the need for public health initiatives to increase population-level vaccine uptake. Longer follow-up is needed, as is the assessment of further vaccine doses and the Omicron variant.
124	I122		Xu-Rui Shen, Rong Geng, Qian Li, Ying Chen, Shu-Fen Li, Qi Wang, Juan Min, Yong Yang, Bei Li, Ren-Di Jiang, Xi Wang, Xiao-Shuang Zheng, Yan Zhu, Jing-Kun Jia, Xing-Lou Yang, Mei-Qin Liu, Qian-Chun Gong, Yu-Lan Zhang, Zhen-Qiong Guan, Hui-Ling Li, Zhen-Hua Zheng, Zheng-Li Shi, Hui-Lan Zhang, Ke Peng & Peng Zhou	ACE2-independent infection of T lymphocytes by SARS-CoV-2	https://doi.org/10.1038/s41392-022-00919-x	Published	11 March 2022	Study	https://www.nature.com/articles/s41392-022-00919-x	SARS-CoV-2 induced marked lymphopenia in severe patients with COVID-19. However, whether lymphocytes are targets of viral infection is yet to be determined, although SARS-CoV-2 RNA or antigen has been identified in T cells from patients. Here, we confirmed that SARS-CoV-2 viral antigen could be detected in patient peripheral blood cells (PBCs) or postmortem lung T cells, and the infectious virus could also be detected from viral antigen-positive PBCs. We next prove that SARS-CoV-2 infects T lymphocytes, preferably activated CD4 + T cells in vitro. Upon infection, viral RNA, subgenomic RNA, viral protein or viral particle can be detected in the T cells. Furthermore, we show that the infection is spike-ACE2/TMPRSS2-independent through using ACE2 knockdown or receptor blocking experiments. Next, we demonstrate that viral antigen-positive T cells from patient undergone pronounced apoptosis. In vitro infection of T cells induced cell death that is likely in mitochondria ROS-HIF-1a-dependent pathways. Finally, we demonstrated that LFA-1, the protein exclusively expresses in multiple leukocytes, is more likely the entry molecule that mediated SARS-CoV-2 infection in T cells, compared to a list of other known receptors. Collectively, this work confirmed a SARS-CoV-2 infection of T cells, in a spike-ACE2-independent manner, which shed novel insights into the underlying mechanisms of SARS-CoV-2-induced lymphopenia in COVID-19 patients.
125	I123		Tomoya Tsuchida,Masanori Hirose,Yoko Inoue,Hiroyuki Kunishima,Takehito Otsubo,Takahide Matsuda	Relationship between changes in symptoms and antibody titers after a single vaccination in patients with Long COVID	https://doi.org/10.1002/jmv.27689	Published	02 March 2022	Study	https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.27689	This study evaluated postvaccination changes in symptoms and antibody titers in patients with Long COVID. Patients visiting the outpatient department specializing in Long COVID at our hospital were enrolled. Changes in symptoms were evaluated before and 14–21 days after first vaccination. Antibody titers were measured using ARCHITECT SARS-CoV-2 IgG II Quant at the same time. This study included 42 patients (median age: 45 years; 17 [40.5%] men). Median pre- and postvaccination antibody titers were 456 and 28,963 AU/ml, respectively. Postvaccination symptoms (fatigue, joint pain, and taste and olfactory abnormalities) were relieved, worsened, and unchanged in 7 (16.7%), 9 (21.4%), and 26 (61.9%) patients, respectively. Ratios of pre- and postvaccination antibody titers were 53, 40, and 174 in the unchanged, relief, and worsened groups, respectively. The worsened group had the significantly highest antibody titer ratio (p = 0.02). The higher increased rate of the antibody titer in the worsened group than in the nonworsened group suggests an excessive immune response to vaccination associated with worsening of sequelae. Although patients with Long COVID should be vaccinated, additional concerns should be addressed.
126	I124		Francisco Tejerina, Pilar Catalan, Cristina Rodriguez-Grande, Javier Adan, Carmen Rodriguez-Gonzalez, Patricia Muñoz, Teresa Aldamiz, Cristina Diez, Leire Perez, Chiara Fanciulli, Dario Garcia de Viedma	Post-COVID-19 syndrome. SARS-CoV-2 RNA detection in plasma, stool, and urine in patients with persistent symptoms after COVID-19	https://doi.org/10.1186/s12879-022-07153-4	Published	03 March 2022	Study	https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-022-07153-4	Methods We evaluated patients with symptoms that persisted for at least 4 weeks after COVID-19. Epidemiological and clinical data were collected. Blood tests, including inflammatory markers, were conducted, and imaging studies made if deemed necessary. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription polymerase chain reaction (RT-PCR) in plasma, stool, and urine were performed. Patients were offered antiviral treatment (compassionate use). Results We evaluated 29 patients who reported fatigue, muscle pain, dyspnea, inappropriate tachycardia, and low-grade fever. Median number of days from COVID-19 to positive RT-PCR in extra-respiratory samples was 55 (39–67). Previous COVID-19 was mild in 55% of the cases. Thirteen patients (45%) had positive plasma RT-PCR results and 51% were positive in at least one RT-PCR sample (plasma, urine, or stool). Functional status was severely reduced in 48% of the subjects. Eighteen patients (62%) received antiviral treatment. Improvement was seen in most patients (p = 0.000) and patients in the treatment group achieved better outcomes with significant differences (p = 0.01). Conclusions In a cohort of COVID-19 patients with persistent symptoms, 45% of them have detectable plasma SARS-CoV-2 RNA. Our results indicate possible systemic viral persistence in these patients, who may benefit of antiviral treatment strategies.
127	I125	ES	MIRIAM MERAD CATHERINE A. BLISH FEDERICA SALLUSTO AND AKIKO IWASAKI	The immunology and immunopathology of COVID-19	https://doi.org/10.1126/science.abm8108	Published	10 Mar 2022	Review	https://www.science.org/doi/full/10.1126/science.abm8108	Considerable research effort has been made worldwide to decipher the immune response triggered upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, identify the drivers of severe and fatal COVID-19, and understand what leads to the prolongation of symptoms after disease resolution. We review the results of almost 2 years of COVID-19 immunology research and discuss definitive findings and remaining questions regarding our understanding of COVID-19 pathophysiology. We discuss emerging understanding of differences in immune responses seen in those with and without Long Covid syndrome, also known as post-acute sequelae of SARS-CoV-2. We hope that the knowledge gained from this COVID-19 research will be applied in studies of inflammatory processes involved in critical and chronic illnesses, which remain a major unmet need.
128	I126		Yaniv Lustig, Ph.D, Ella Mendelson, Ph.D, Michal Mandelboim, Ph.D, Asaf Biber, MD, Einav G Levin, MD, Carmit Cohen, DVM, Ph.D, Gili Regev-Yochay, MD, Eli Schwartz	Existence of immunological memory response in true sero-negative individuals post COVID-19 molecular diagnosis	https://doi.org/10.1093/cid/ciac196	Published	10 March 2022	Study	https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac196/6546613	Approximately 1-8% of individuals do not develop antibodies following SARS-CoV-2 infection (sero-negatives). One BNT162b2 dose resulted in potent humoral response in 14 sero-negatives and 15 sero-positives, significantly higher than the response of 15 naïve-individuals, to two doses suggesting that COVID-19 provoked a memory response in individuals without detectable antibodies.
129	I127		Zheng Quan Toh, PhD1,2; Jeremy Anderson, BSc1,2; Nadia Mazarakis, PhD1; Melanie Neeland, PhD1,2; Rachel A. Higgins, BBiomed1; Karin Rautenbacher, BAppSc3; Kate Dohle, BSc1; Jill Nguyen, BSc1; Isabella Overmars, MPH1; Celeste Donato, PhD1,2; Sohinee Sarkar, PhD1,2; Vanessa Clifford, PhD4; Andrew Daley, PhD4; Suellen Nicholson, BSc5; Francesca L. Mordant, MSc6; Kanta Subbarao, MBBS6,7; David P. Burgner, PhD1,2,4; Nigel Curtis, MD1,2,4; Julie E. Bines, MD1,2,8; Sarah McNab, MD1,4; Andrew C. Steer, PhD1,2,4; Kim Mulholland, MD1,2,9; Shidan Tosif, PhD1,2,4; Nigel W. Crawford, MD1,2,4; Daniel G. Pellicci, PhD1,2,6; Lien Anh Ha Do, PhD1,2; Paul V. Licciardi, PhD1,2	Comparison of Seroconversion in Children and Adults With Mild COVID-19	https://doi.org/10.1001/jamanetworkopen.2022.1313	Published	March 9, 2022	Study	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2789845	Question - What proportion of children with mild SARS-CoV-2 infection undergo seroconversion compared with adults? Findings In this cohort study of 57 children and 51 adults, the proportion of children with seroconversion to SARS-CoV-2 was half that found in adults despite similar viral load. Meaning - These findings suggest that serology may provide a less reliable marker of prior SARS-CoV-2 infection in children and support strategies to protect children against COVID-19, including vaccination. Abstract Importance The immune response in children with SARS-CoV-2 infection is not well understood. Objective - To compare seroconversion in nonhospitalized children and adults with mild SARS-CoV-2 infection and identify factors that are associated with seroconversion. Design, Setting, and Participants - This household cohort study of SARS-CoV-2 infection collected weekly nasopharyngeal and throat swabs and blood samples during the acute (median, 7 days for children and 12 days for adults [IQR, 4-13] days) and convalescent (median, 41 [IQR, 31-49] days) periods after polymerase chain reaction (PCR) diagnosis for analysis. Participants were recruited at The Royal Children’s Hospital, Melbourne, Australia, from May 10 to October 28, 2020. Participants included patients who had a SARS-CoV-2–positive nasopharyngeal or oropharyngeal swab specimen using PCR analysis. Main Outcomes and Measures - SARS-CoV-2 immunoglobulin G (IgG) and cellular (T cell and B cell) responses in children and adults. Seroconversion was defined by seropositivity in all 3 (an in-house enzyme-linked immunosorbent assay [ELISA] and 2 commercial assays: a SARS-CoV-2 S1/S2 IgG assay and a SARS-CoV-2 antibody ELISA) serological assays. Results - Among 108 participants with SARS-CoV-2–positive PCR findings, 57 were children (35 boys [61.4%]; median age, 4 [IQR, 2-10] years) and 51 were adults (28 women [54.9%]; median age, 37 [IQR, 34-45] years). Using the 3 established serological assays, a lower proportion of children had seroconversion to IgG compared with adults (20 of 54 [37.0%] vs 32 of 42 [76.2%]; P < .001). This result was not associated with viral load, which was similar in children and adults (mean [SD] cycle threshold [Ct] value, 28.58 [6.83] vs 24.14 [8.47]; P = .09). In addition, age and sex were not associated with seroconversion within children (median age, 4 [IQR, 2-14] years for both seropositive and seronegative groups; seroconversion by sex, 10 of 21 girls [47.6%] vs 10 of 33 boys [30.3%]) or adults (median ages, 37 years for seropositive and 40 years for seronegative adults [IQR, 34-39 years]; seroconversion by sex, 18 of 24 women [75.0%] vs 14 of 18 men [77.8%]) (P > .05 for all comparisons between seronegative and seropositive groups). Symptomatic adults had 3-fold higher SARS-CoV-2 IgG levels than asymptomatic adults (median, 227.5 [IQR, 133.7-521.6] vs 75.3 [IQR, 36.9-113.6] IU/mL), whereas no differences were observed in children regardless of symptoms. Moreover, differences in cellular immune responses were observed in adults compared with children with seroconversion. Conclusions and Relevance - The findings of this cohort study suggest that among patients with mild COVID-19, children may be less likely to have seroconversion than adults despite similar viral loads. This finding has implications for future protection after SARS-CoV-2 infection in children and for interpretation of serosurveys that involve children. Further research to understand why seroconversion and development of symptoms are potentially less likely in children after SARS-CoV-2 infection and to compare vaccine responses may be of clinical and scientific importance.
130	I128		Jialu Huang 1,Yubo Ding 2,Jingwei Yao 2,Minghui Zhang 1,Yu Zhang 1,Zhuoyi Xie 1 andJianhong Zuo	Nasal Nanovaccines for SARS-CoV-2 to Address COVID-19	https://doi.org/10.3390/vaccines10030405	Published	8 March 2022	Review	https://www.mdpi.com/2076-393X/10/3/405/htm	COVID-19 is still prevalent around the globe. Although some SARS-CoV-2 vaccines have been distributed to the population, the shortcomings of vaccines and the continuous emergence of SARS-CoV-2 mutant virus strains are a cause for concern. Thus, it is vital to continue to improve vaccines and vaccine delivery methods. One option is nasal vaccination, which is more convenient than injections and does not require a syringe. Additionally, stronger mucosal immunity is produced under nasal vaccination. The easy accessibility of the intranasal route is more advantageous than injection in the context of the COVID-19 pandemic. Nanoparticles have been proven to be suitable delivery vehicles and adjuvants, and different NPs have different advantages. The shortcomings of the SARS-CoV-2 vaccine may be compensated by selecting or modifying different nanoparticles. It travels along the digestive tract to the intestine, where it is presented by GALT, tissue-resident immune cells, and gastrointestinal lymph nodes. Nasal nanovaccines are easy to use, safe, multifunctional, and can be distributed quickly, demonstrating strong prospects as a vaccination method for SARS-CoV-2, SARS-CoV-2 variants, or SARS-CoV-n. SARS-CoV-2 nasal vaccines are being developed, and nine of them are in clinical trials. SARS-CoV-2 vaccines include inactivated vaccines, live attenuated vaccines, protein subunit vaccines, nucleic acid vaccines, viral vector-based vaccines, and other vaccines [39]. Inactivated vaccines are prepared using chemical stress or heat stress. In the process of heat stress or chemical stress, inactivated vaccines may lose immunogenicity, so these vaccines often need to be mixed with adjuvants. So far, a total of 28 inactivated vaccines for SARS-CoV-2 have been recorded by the WHO, of which 17 have entered clinical trials, and only one inactivated nasal vaccine has entered a phase I trial (NCT04871737) [40]. Live attenuated vaccines are vaccines made by removing or attenuating parts of the virus. Live attenuated vaccines have appropriate immunogenicity, although live attenuated vaccines require a long time to construct a suitable attenuated virus strain, and the constructed virus strain may undergo virulence reversal at any time. Only eight live attenuated vaccines have been recorded by the WHO. Among the eight vaccines, two nasal vaccines have entered clinical trials (NCT04798001, NCT04619628). Due to the long development time, live attenuated vaccines are not the preferred vaccine for SARS-CoV-2. Viral vector-based vaccines, on the other hand, are vital in the development of SARS-CoV-2 vaccines. This method is to insert antigens into existing successful and safe viral vectors (adenovirus, HIV, etc.) and enter the host through the viral vectors. It is easy for the viral vector to enter the host, causing a stronger host immune response and cross-reaction. In total, 70 viral vector-based vaccines have been recorded by the WHO and 26 viral vector-based vaccines have entered clinical trials, three of which are nasal vaccines (ChiCTR2000037782, discontinued test NCT04679909, NCT04751682, NCT04954287). Nucleic acid vaccines directly introduce the exogenous gene (DNA or RNA), transferring the antigen protein to the host cell to produce the antigen through the expression system of the host cell. The antigens can be recognized by the host immune system to produce anti-SARS-CoV-2 antibodies to achieve the purpose of prevention and treatment. Nucleic acid vaccines can select antigenic determinants by modifying the target gene carried by the gene expression vector. Moreover, the vaccine recipients can benefit from long-term immunity once vaccinated. A total of 76 nucleic acid vaccines have been recorded by the WHO, of which 36 have entered clinical trials. Among them, nasal mRNA vaccines can induce strong mucosal immunity and systemic immunity [41,42]. Protein subunit vaccines are made from one or more immunologically active fragments of SARS-CoV-2. Protein subunit vaccines discard some of the epitopes of SARS-CoV-2, whose immune effect is low and improves the effective antigen utilization efficiency of SARS-CoV-2. It needs to be used together with an adjuvant. In total, 122 protein subunit vaccines have been recorded by the WHO, and 47 have entered clinical trials, including two kinds of nasal protein subunit vaccines (RPCEC0000, IRCT20201214049709N2). All the SARS-CoV-2 vaccines data are from the WHO [23].
131	I129		Morley D.Hollenberg123MurrayEpstein4	The innate immune response, microenvironment proteinases, and the COVID-19 pandemic: pathophysiologic mechanisms and emerging therapeutic targets	https://doi.org/10.1016/j.kisu.2021.12.001	Published	18 March 2022	Review	https://www.sciencedirect.com/science/article/pii/S2157171621000630	The coronavirus disease 2019 (COVID-19) pandemic, causing considerable mortality and morbidity worldwide, has fully engaged the biomedical community in attempts to elucidate the pathophysiology of COVID-19 and develop robust therapeutic strategies. To this end, the predominant research focus has been on the adaptive immune response to COVID-19 infections stimulated by mRNA and protein vaccines and on the duration and persistence of immune protection. In contrast, the role of the innate immune response to the viral challenge has been underrepresented. This overview focuses on the innate immune response to COVID-19 infection, with an emphasis on the roles of extracellular proteases in the tissue microenvironment. Proteinase-mediated signaling caused by enzymes in the extracellular microenvironment occurs upstream of the increased production of inflammatory cytokines that mediate COVID-19 pathology. These enzymes include the coagulation cascade, kinin-generating plasma kallikrein, and the complement system, as well as angiotensin-generating proteinases of the renin–angiotensin system. Furthermore, in the context of several articles in this Supplement elucidating and detailing the trajectory of diverse profibrotic pathways, we extrapolate these insights to explore how fibrosis and profibrotic pathways participate importantly in the pathogenesis of COVID-19. We propose that the lessons garnered from understanding the roles of microenvironment proteinases in triggering the innate immune response to COVID-19 pathology will identify potential therapeutic targets and inform approaches to the clinical management of COVID-19. Furthermore, the information may also provide a template for understanding the determinants of COVID-19–induced tissue fibrosis that may follow resolution of acute infection (so-called “long COVID”), which represents a major new challenge to our healthcare systems.
132	I130		MaddalenaPeghin12MariaDe Martino3AlvisaPalese4ValentinaGerussi1GiuliaBontempo1ElenaGraziano12EricaVisintini4Denise D’Elia1FabianaDellai1FrancescoMarrella1MartinaFabris5FrancescoCurcio5AssuntaSartor5MiriamIsola3CarloTascini1	Post-COVID-19 syndrome and humoral response association after one year in vaccinated and unvaccinated patients	https://doi.org/10.1016/j.cmi.2022.03.016	Published	23 March 2022	Study	https://www.sciencedirect.com/science/article/pii/S1198743X22001550	Objectives To describe the impact of vaccination and the role of humoral responses on post-coronavirus disease 2019 (COVID-19) syndrome one year after the onset of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods A prospective study. Interviews investigated post-COVID-19 syndrome 6 and 12 months after the disease onset of all adult in- and outpatients with COVID-19 attending Udine Hospital (March–May 2020). Vaccination status and two different serological assays to distinguish between response to vaccination (receptor-binding domain –RBD SARS-CoV-2 IgG) and/or natural infection (non-RBD- SARS-CoV-2 IgG) were also assessed. Results 479 individuals (52.6% female, mean age 53 years) were interviewed 13.5 months (0.6 SD) after acute infection. Post-COVID-19 syndrome was observed in 47.2% (226/479) of patients after one year. There were no significant differences in the worsening of post-COVID 19 symptoms (22.7% vs 15.8%, p = 0.209) among vaccinated (n=132) and unvaccinated (n=347) patients. The presence of non-RBD SARS-CoV-2 IgG induced by natural infection showed a significant association with post-COVID-19 syndrome (OR 1.35, 95% CI 1.11–1.64, p = 0.003), and median non-RBD SARS-CoV-2 IgG titres were significantly higher in long-haulers than in patients without symptoms 22 (IQR 9.7–37.2) vs 14.1 (IQR 5.4–31.3) kAU/L, p = 0.009) after one year. In contrast, the presence of RBD SARS-CoV-2 IgG was not associated with the occurrence of post-COVID-19 syndrome (>2500 U/mL vs 0.9–2500 U/mL, OR 1.36, 95% CI 0.62–3.00, p = 0.441) and RBD SARS-CoV-2 IgG titres were similar in long-haulers than in patients without symptoms (50% values > 2500 U/mL vs 55.6% values > 2500 U/mL, p = 0.451) Conclusions The SARS-CoV-2 vaccination is not associated with the emergence of post-COVID-19 symptoms over one year after acute infection. The persistence of high serological titres response induced by natural infection but not by vaccination, may play a role in long-COVID-19.
133	I131		Miguel Galán1†, Lorena Vigón1†, Daniel Fuertes2, María Aránzazu Murciano-Antón3, Guiomar Casado-Fernández1, Susana Domínguez-Mateos3, Elena Mateos1,4, Fernando Ramos-Martín1, Vicente Planelles5, Montserrat Torres1, Sara Rodríguez-Mora1,4, María Rosa López-Huertas1,4*‡ and Mayte Coiras1	Persistent Overactive Cytotoxic Immune Response in a Spanish Cohort of Individuals With Long-COVID: Identification of Diagnostic Biomarkers	https://doi.org/10.3389/fimmu.2022.848886	Published	25 March 2022	Study	https://www.frontiersin.org/articles/10.3389/fimmu.2022.848886/full?s=03	The underlying mechanisms for Long-COVID are still undefined, but a sustained inflammatory response caused by the persistence of SARS-CoV-2 in organ and tissue sanctuaries or resemblance with an autoimmune disease are within the most considered hypotheses. In this study, we analyzed the usefulness of several demographic, clinical, and immunological parameters as diagnostic biomarkers of Long-COVID in one cohort of Spanish individuals who presented signs and symptoms of this syndrome after 49 weeks post-infection, in comparison with individuals who recovered completely in the first 12 weeks after the infection. We determined that individuals with Long-COVID showed significantly increased levels of functional memory cells with high antiviral cytotoxic activity such as CD8+ TEMRA cells, CD8±TCRγδ+ cells, and NK cells with CD56+CD57+NKG2C+ phenotype. The persistence of these long-lasting cytotoxic populations was supported by enhanced levels of CD4+ Tregs and the expression of the exhaustion marker PD-1 on the surface of CD3+ T lymphocytes. With the use of these immune parameters and significant clinical features such as lethargy, pleuritic chest pain, and dermatological injuries, as well as demographic factors such as female gender and O+ blood type, a Random Forest algorithm predicted the assignment of the participants in the Long-COVID group with 100% accuracy. The definition of the most accurate diagnostic biomarkers could be helpful to detect the development of Long-COVID and to improve the clinical management of these patients.
134	I132		Julien Ramillon, Xavier de Lamballerie, Olivier Robineau, Helene Blanché, Gianluca Severi, Mathilde Touvier, Marie Zins, Fabrice Carrat, View ProfileNathanaël Lapidus, the SAPRIS-SERO study group	Humoral response, associated symptoms and profile of patients infected by SARS-CoV-2 with taste or smell disorders in the SAPRIS multicohort study	https://doi.org/10.1101/2022.02.01.22270250	pre-print	February 02, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.02.01.22270250v1.full	Objectives Taste or smell disorders have been reported as strongly associated with COVID-19 diagnosis. We aimed to identify subject characteristics, symptom associations, and humoral response intensity associated with taste or smell disorders. Patients and methods We used data from SAPRIS, a study based on a consortium of five prospective cohorts gathering 279,478 participants in the French general population. In the analysis, we selected participants who were presumably infected by SARS-CoV-2 during the first epidemic wave. Results The analysis included 3,439 patients with a positive ELISA-Spike. Sex (OR = 1.28 [95% CI 1.05-1.58] for women), smoking (OR = 1.54 [95% CI 1.13-2.07]), consumption of more than 2 drinks of alcohol a day (OR = 1.37 [95% CI 1.06-1.76]) were associated with a higher probability of taste or smell disorders. The relationship between age and taste or smell disorders was non-linear. Serological titers were associated with taste or smell disorders: OR = 1.31 [95% CI 1.26-1.36], OR = 1.37 [95% CI 1.33-1.42] and OR = 1.34 [95% CI 1.29-1.39] for ELISA-Spike, ELISA-Nucleocapsid and seroneutralization, respectively. Among participants with taste or smell disorders, 90% reported a wide variety of other symptoms whereas 10% reported no other symptom or only rhinorrhea. Conclusion Among patients with a positive ELISA-Spike test, women, smokers and people drinking more than 2 drinks a day were more likely to develop taste or smell disorders. This symptom was strongly associated with a humoral response. The overwhelming majority of patients with taste or smell disorders experienced a wide variety of symptoms.
135	I133		Edda Russo, Lavinia Curini, Alessio Fabbrizzi & Amedeo Amedei	SARS-CoV-2 and Microbiota	https://doi.org/10.1007/978-981-16-8957-4_14	Published	26 March 2022	Article	https://link.springer.com/chapter/10.1007/978-981-16-8957-4_14	This infectious disease is triggered by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and at lung level, like as intestine, there are different bacterial populations, named microbiota, that have a significant influence on the host’s immunological homeostasis. But, to date, our understanding of bacterial flora and its symbiotic connection with immunological processes in the context of SARS-CoV-2 is, however, incomplete. A disturbed bacterial flora combined with too many opportunistic infections can trigger a cascade of inflammatory reactions dysregulating the immune system and resulting in multi-organ damage. The involvement of the lung and intestinal microbiota in immune regulation of SARS-CoV-2 infection via multiple pathways will be discussed in this chapter. In addition, diet and lifestyle have a huge impact on the microbiota-inflammation crosstalk affecting both frequency and timing of this viral infection. So, in the last section we focus on the microbiota function in COVID-19, with an emphasis on immunological activation by the lung and gut bacteria and potential future therapies based on probiotic administration, able to regulate the microbiota–immunity axis.
136	I134		LiGuoPhDabGengWangMSabdYemingWangMDeQiaoZhangPhDaLiliRenPhDabXiaoyingGuPhDeTingxuanHuangMSadJingchuanZhongMSaYingWangMSaXinmingWangMSaLixueHuangMDeLiuhuiXuBSaConghuiWangPhDaLanChenBSaXiaXiaoPhDaYanchunPengPhDfgJulian CKnightPhDghTaoDongPhDfg…JianweiWangPhDab†	SARS-CoV-2-specific antibody and T-cell responses 1 year after infection in people recovered from COVID-19: a longitudinal cohort study	https://doi.org/10.1016/S2666-5247(22)00036-2	Published	23 March 2022	Study	https://www.sciencedirect.com/science/article/pii/S2666524722000362	Background The memory immune response is crucial for preventing reinfection or reducing disease severity. However, the robustness and functionality of the humoral and T-cell response to SARS-CoV-2 remains unknown 12 months after initial infection. The aim of this study is to investigate the durability and functionality of the humoral and T-cell response to the original SARS-CoV-2 strain and variants in recovered patients 12 months after infection. Methods In this longitudinal cohort study, we recruited participants who had recovered from COVID-19 and who were discharged from the Wuhan Research Center for Communicable Disease Diagnosis and Treatment at the Chinese Academy of Medical Sciences, Wuhan, China, between Jan 7 and May 29, 2020. Patients received a follow-up visit between Dec 16, 2020, and Jan 27, 2021. We evaluated the presence of IgM, IgA, and IgG antibodies against the SARS-CoV-2 nucleoprotein, Spike protein, and the receptor-binding domain 12 months after initial infection, using ELISA. Neutralising antibodies against the original SARS-CoV-2 strain, and the D614G, beta (B.1.351), and delta (B.1.617.2) variants were analysed using a microneutralisation assay in a subset of plasma samples. We analysed the magnitude and breadth of the SARS-CoV-2-specific memory T-cell responses using the interferon γ (IFNγ) enzyme-linked immune absorbent spot (ELISpot) assay and intracellular cytokine staining (ICS) assay. The antibody response and T-cell response (ie, IFN-γ, interleukin-2 [IL-2], and tumour necrosis factor α [TNFα]) were analysed by age and disease severity. Antibody titres were also analysed according to sequelae symptoms. Findings We enrolled 1096 patients, including 289 (26·4%) patients with moderate initial disease, 734 (67·0%) with severe initial disease, and 73 (6·7%) with critical initial disease. Paired plasma samples were collected from 141 patients during the follow-up visits for the microneutralisation assay. PBMCs were collected from 92 of 141 individuals at the 12-month follow-up visit, of which 80 were analysed by ELISpot and 92 by ICS assay to detect the SARS-CoV-2-specific memory T-cell responses. N-IgG (899 [82·0%]), S-IgG (1043 [95·2%]), RBD-IgG (1032 [94·2%]), and neutralising (115 [81·6%] of 141) antibodies were detectable 12 months after initial infection in most individuals. Neutralising antibodies remained stable 6 and 12 months after initial infection in most individuals younger than 60 years. Multifunctional T-cell responses were detected for all SARS-CoV-2 viral proteins tested. There was no difference in the magnitude of T-cell responses or cytokine profiles in individuals with different symptom severity. Moreover, we evaluated both antibody and T-cell responses to the D614G, beta, and delta viral strains. The degree of reduced in-vitro neutralising antibody responses to the D614G and delta variants, but not to the beta variant, was associated with the neutralising antibody titres after SARS-CoV-2 infection. We also found poor neutralising antibody responses to the beta variant; 83 (72·2%) of 115 patients showed no response at all. Moreover, the neutralising antibody titre reduction of the recovered patient plasma against the delta variant was similar to that of the D614G variant and lower than that of the beta variant. By contrast, T-cell responses were cross-reactive to the beta variant in most individuals. Importantly, T-cell responses could be detected in all individuals who had lost the neutralising antibody response to SARS-CoV-2 12 months after the initial infection. Interpretation SARS-CoV-2-specific neutralising antibody and T-cell responses were retained 12 months after initial infection. Neutralising antibodies to the D614G, beta, and delta viral strains were reduced compared with those for the original strain, and were diminished in general. Memory T-cell responses to the original strain were not disrupted by new variants. This study suggests that cross-reactive SARS-CoV-2-specific T-cell responses could be particularly important in the protection against severe disease caused by variants of concern whereas neutralising antibody responses seem to reduce over time. Evidence before this study We searched PubMed on Nov 2, 2021, using the following search terms [(“SARS-CoV-2” OR “COVID-19” OR “Coronavirus Disease 2019 Virus” OR “2019 Novel Coronavirus”) AND (“Adaptive Immunity” OR “Adoptive Immunity” OR “Immunity, Cellular” OR “Cellular Immunity” OR “Humoral Immunity” OR “Immunity, Humoral”)], with no date or language restrictions, and identified 793 results. Studies identified by the search reported that SARS-CoV-2-specific antibodies gradually decreased over several months. However, analyses of lymphocytes from COVID-19-convalescent individuals indicate that B cells and CD4 or CD8 T cells play an important role in mediating memory responses after natural infection. Therefore, it is important to explore these pathways to improve vaccination efficacy. The longest study spanned 12 months. However, the characteristics of adaptive immunity in patients 12 months after they contracted COVID-19 was not well understood. Given the rapid emergence of variants of concern, the ability of immunological memory to protect previously infected individuals from new variants has been examined, but no firm conclusions were reached. Added value of this study To our knowledge, this is the first comprehensive evaluation on the durability and robustness of antibody and T-cell responses against the SARS-CoV-2 original strain and its variants in recovered patients 1 year after natural infection without repeat exposure or vaccination in Wuhan, China. Our findings show that robust antibody and T-cell immunity against SARS-CoV-2 is present in the majority of recovered patients 12 months after moderate-to-critical infection. Total SARS-CoV-2-specific T-cell responses remain effective against variants, but neutralising antibodies diminish by 12 months. Implications of all the available evidence These data have important implications for vaccine efficacy against SARS-CoV-2 variants; the presence of cellular immune responses to SARS-CoV-2 variants and patients who lost their neutralising antibody responses provide additional important information on broad B-cell and T-cell immunity for future vaccine strategies targeting SARS-CoV-2. In particular, when neutralising antibody responses are reduced, cross-reactive SARS-CoV-2-specific T-cell responses could be important in protection against severe disease caused by variants of concern. Continuous surveillance is required to assess the duration of infection-induced immunity and the antibody and T-cell responses to these variants.
137	I135		Jacek M.Witkowskia1TamasFulopbEwaBrylc	Immunosenescence and COVID-19	https://doi.org/10.1016/j.mad.2022.111672	Published	8 April 2022	Article	https://www.sciencedirect.com/science/article/pii/S0047637422000549	Highlights •Aging is associated with increasing severity and mortality rates of COVID-19. •The ability of immune system to fight SARS-CoV-2 depends in part on immunosenescence and inflammaging. •Immunosenescence and inflammaging are the consequence of prior challenges called immunobiography. •SARS-CoV-2 infection bears on individual immunobiography and might accelerate immunosenescence. Ageing is associated with modified function of both innate and adaptive immunity. It is believed that changes occurring in ageing immune system are responsible for increased severity and deadliness of COVID-19 in the elderly. Although supported by statistics and epidemiology, these finding do not compute at the mechanistic level as depending solely on chronological and biological ageing. The phenomena describing changes in the aging immune system are immunosenescence and inflammageing, which develop in time depending on challenges to the individual immune system (immunobiography). Thus, “richer” immunobiography (in addition to other factors, including genetic, epigenetics or metabolic) may adversely affect the reactivity to the SARS-CoV-2 not only at later decades of life, but also earlier, in young and middle-aged individuals. On the other hand, infection with SARS-CoV-2 is affecting the function of both innate and adaptive branches of the immune system, adding to the individual immunobiography. Summarizing, immunosenescence and inflammaging may aggravate, but also may be aggravated by SARS-CoV-2 infection.
138	I136		C Mohan Rao, Pragyan Rout, Ashwini P. Pattnaik, Nipa Singh, Aarthi Rajendran, Shubhransu Patro	The Microbial Profile and Resistance Pattern of Pathogens Isolated From Long COVID Pneumonia Patients and Their Correlation to Clinical Outcome: Our Experience From a Tertiary Care Hospital	https://doi.org/10.7759/cureus.23644	Published	March 30, 2022	Study	https://www.cureus.com/articles/90127-the-microbial-profile-and-resistance-pattern-of-pathogens-isolated-from-long-covid-pneumonia-patients-and-their-correlation-to-clinical-outcome-our-experience-from-a-tertiary-care-hospital	Background Coronavirus disease 2019 (COVID-19) patients with persistent symptoms for at least four weeks in spite of being reverse transcriptase-polymerase chain reaction (RTPCR) negative for COVID infection are defined as long COVID (wherein pulmonary involvement is seen in a significant proportion of cases). The history of prolonged use of corticosteroids, broad-spectrum antibiotics, and associated comorbid conditions in these patients increases the possibility of infection with multidrug-resistant microbial strains. It may lead to a grave prognosis, hence appropriate microbiological evaluation and management at the earliest can have a better outcome. Methods A retrospective observational study was carried out among long COVID patients admitted to the Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India, a tertiary care hospital. Eighty-four patients admitted to the ICU or non-ICU ward in the hospital from April to October 2021 were included in the study. Antibiotics, as prescribed by our hospital antibiotic policy, were administered wherever required and were subsequently changed according to culture and sensitivity reports of the samples (sputum, endotracheal aspirates, or blood). An analysis of the antibiotic sensitivity patterns of the pathogens isolated was performed. The outcome after optimum medical management was assessed for survivors, discharge, or death. Results Out of the total of 84 patients, 41 samples (sputum, endotracheal aspirates or blood) were collected and sent for culture, of which 32 (78.1%) were found to be culture positive for pathogens. Among the pathogens isolated, there were 22 (69%) drug-resistant and 10 (31%) sensitive organisms. Among the 22 resistant pathogen isolates, 18 were Gram-negative species, the most common species being Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumanii; two were Gram-positive species, one each from Staphylococcus aureus and Enterococcus faecalis, and three were Candida tropicalis. Of five deaths reported among 22 cases with resistant isolates, extensively drug-resistant (XDR), multi-drug resistance (MDR), and pan drug resistance (PDR) strains were detected in three, one, and one cases, respectively, and were harboured by K. pneumoniae, P. aeruginosa, and A. baumanii. Of the total eight deaths, there were two deaths among the 43 patients who received an empiric antibiotic in the wards, and six deaths were reported in the ICU. Despite raised biomarkers of inflammation, comorbid illnesses, renal impairment, and immunocompromised states, there was 91% survival and discharge, which was statistically significant (p-value = 0.00). Conclusion To conclude, K. pneumoniae, P. aeruginosa, A. baumanii, C. tropicalis, S. aureus, and E. faecalis were the most commonly isolated organisms among long COVID pneumonia cases, of which some were MDR, PDR and XDR strains. Early microbiological evaluation with targeted, proper antimicrobial usage along with optimized medical management and, wherever needed, critical care support in the ICU may lead to a better prognostic outcome in those groups of patients.
139	I137		Rachel M. Gittelman,1 Enrico Lavezzo,2 Thomas M. Snyder,1 H. Jabran Zahid,3 Cara L. Carty,1 Rebecca Elyanow,1 Sudeb C. Dalai,1 Ilan Kirsch,1 Lance Baldo,1 Laura Manuto,2 Elisa Franchin,2 Claudia Del Vecchio,2 Monia Pacenti,4 Caterina Boldrin,4 Margherita Cattai,4 Francesca Saluzzo,5 Andrea Padoan,6 Mario Plebani,6 Fabio Simeoni,7 Jessica Bordini,8 Nicola I. Lorè,5 Dejan Lazarević,7 Daniela Maria Cirillo,5 Paolo Ghia,9 Stefano Toppo,2 Jonathan M. Carlson,3 Harlan S. Robins,1 Andrea Crisanti,10 and Giovanni Tonon7	Longitudinal analysis of T-cell receptor repertoires reveals shared patterns of antigen-specific response to SARS-CoV-2 infection	https://doi.org/10.1172/jci.insight.151849	Published	April 19, 2022	Study	https://insight.jci.org/articles/view/151849	T cells play a prominent role in orchestrating the adaptive immune response to viral diseases and are a key component in understanding variability in SARS-CoV-2 infection severity and immunity. How the T cell response to SARS-CoV-2 infection and vaccination relates to clinical presentation, other components of the immune response, and subsequent immunity remains poorly understood. A population-based swab survey of the municipality of Vo’, Italy, conducted after the initial SARS-CoV-2 outbreak, uncovered a high frequency of asymptomatic infected individuals and their role in transmission. We sampled the T-cell receptor repertoire structure of the entire Vo’ population 2 months after the initial survey and followed up positive cases at 9 and 15 months post infection. We found that 97.0% (98/101) of cases had elevated levels of T-cell receptors associated with SARS-CoV-2 antigens at 2 months. T-cell frequency (depth) was increased in individuals with more severe disease. Both depth and diversity (breadth) of the T-cell receptor repertoire were also positively associated with neutralizing antibody titers, driven mostly by helper CD4+ T cells directed towards antigens from spike protein. At the later time points, detection of SARS-CoV-2 associated T cells remained high, with 90.7% (78/96) and 86.2% (25/29) of individuals having detectable signal at 9 and 15 months, respectively. Notably, at 9 months, T-cell signal was detectable in 84.6% (22/26) of cases who were initially asymptomatic. Forty-three individuals had been vaccinated by month fifteen, all presenting with a positive T-cell signal and showing a significant increase in T cells, specifically directed against spike protein. Taken together, these results demonstrate the central role of the T-cell response in mounting a comprehensive immune defense against SARS-CoV-2 that persists out to 15 months.
140	I138		Rebecca Elyanow,1 Thomas M. Snyder,1 Sudeb C. Dalai,1 Rachel M. Gittelman,1 Jim Boonyaratanakornkit,2 Anna Wald,2 Stacy Selke,3 Mark H. Wener,2 Chihiro Morishima,3 Alexander L. Greninger,3 Michael Gale Jr.,4 Tien-Ying Hsiang,4 Lichen Jing,2 Michael R. Holbrook,5 Ian M. Kaplan,1 H. Jabran Zahid,6 Damon H. May,1 Jonathan M. Carlson,6 Lance Baldo,1 Thomas Manley,1 Harlan S. Robins,1 and David M. Koelle3	T-cell receptor sequencing identifies prior SARS-CoV-2 infection and correlates with neutralizing antibodies and disease severity	https://doi.org/10.1172/jci.insight.150070	Published	April 19, 2022	Study	https://insight.jci.org/articles/view/150070	BACKGROUND. Measuring the immune response to SARS-CoV-2 enables assessment of past infection and protective immunity. SARS-CoV-2 infection induces humoral and T-cell responses, but these responses vary with disease severity and individual characteristics. METHODS. A T-cell receptor (TCR) immunosequencing assay was conducted using small-volume blood samples from 302 individuals recovered from COVID-19. Correlations between the magnitude of the T-cell response and neutralizing antibody (nAb) titers or indicators of disease severity were evaluated. Sensitivity of T-cell testing was assessed and compared to serologic testing. RESULTS. SARS-CoV-2–specific T-cell responses were significantly correlated with nAb titers and clinical indicators of disease severity, including hospitalization, fever, and difficulty breathing. Despite modest declines in depth and breadth of T-cell responses during convalescence, high sensitivity was observed until at least 6 months after infection, with overall sensitivity ~5% greater than serology tests for identifying prior SARS-CoV-2 infection. Improved performance of T-cell testing was most apparent in recovered, non-hospitalized individuals sampled >150 days after initial illness, suggesting greater sensitivity than serology at later timepoints and in individuals with less severe disease. T-cell testing identified SARS-CoV-2 infection in 68% (55/81) of samples with undetectable nAb titers (<1:40) and in 37% (13/35) of samples negative by 3 antibody assays. CONCLUSION. These results support TCR-based testing as a scalable, reliable measure of past SARS-CoV-2 infection with clinical value beyond serology.
141	I139		Xue Cao, Wenjuan Li, Ting Wang, Dongzhi Ran, Veronica Davalos, Laura Planas-Serra, Aurora Pujol, Manel Esteller, Xiaolin Wang & Huichuan Yu	Accelerated biological aging in COVID-19 patients	https://doi.org/10.1038/s41467-022-29801-8	Published	19 April 2022	Article	https://www.nature.com/articles/s41467-022-29801-8	Chronological age is a risk factor for SARS-CoV-2 infection and severe COVID-19. Previous findings indicate that epigenetic age could be altered in viral infection. However, the epigenetic aging in COVID-19 has not been well studied. In this study, DNA methylation of the blood samples from 232 healthy individuals and 413 COVID-19 patients is profiled using EPIC methylation array. Epigenetic ages of each individual are determined by applying epigenetic clocks and telomere length estimator to the methylation profile of the individual. Epigenetic age acceleration is calculated and compared between groups. We observe strong correlations between the epigenetic clocks and individual’s chronological age (r > 0.8, p < 0.0001). We also find the increasing acceleration of epigenetic aging and telomere attrition in the sequential blood samples from healthy individuals and infected patients developing non-severe and severe COVID-19. In addition, the longitudinal DNA methylation profiling analysis find that the accumulation of epigenetic aging from COVID-19 syndrome could be partly reversed at late clinic phases in some patients. In conclusion, accelerated epigenetic aging is associated with the risk of SARS-CoV-2 infection and developing severe COVID-19. In addition, the accumulation of epigenetic aging from COVID-19 may contribute to the post-COVID-19 syndrome among survivors.
142	I140	ES	AravindNatarajan12∗SoumayaZlitni12∗Erin F.Brooks2∗Summer E.Vance2∗AlexDahlen3HaleyHedlin3Ryan M.ParkAlvinHan4Danica T.Schmidtke4RenuVerma5Karen B.Jacobson5JulieParsonnet67Hector F.Bonilla6UpinderSingh5Benjamin A.Pinsky58Jason R.Andrews5PrasannaJagannathan46Ami S.Bhatt12	Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA suggest prolonged gastrointestinal infection	https://doi.org/10.1016/j.medj.2022.04.001	Published	13 April 2022	Study	https://www.sciencedirect.com/science/article/pii/S2666634022001672	Highlights 1.Approximately half of COVID-19 patients shed fecal RNA in the week after infection 2.4% patients with COVID-19 shed fecal viral RNA 10 months after diagnosis. 3.Presence of fecal SARS-CoV-2 RNA is associated with gastrointestinal symptoms. 4.SARS-CoV-2 likely infects gastrointestinal tissue. Abstract Background COVID-19 manifests with respiratory, systemic, and gastrointestinal (GI) symptoms.1,2 SARS-CoV-2 RNA is detected in respiratory and fecal samples, and recent reports demonstrate viral replication in both the lung and intestinal tissue.3–5 Although much is known about early fecal RNA shedding, little is known about the long term shedding, especially in those with mild COVID-19. Furthermore, most reports of fecal RNA shedding do not correlate these findings with GI symptoms.6 Methods We analyze the dynamics of fecal RNA shedding up to 10 months after COVID-19 diagnosis in 113 individuals with mild to moderate disease. We also correlate shedding with disease symptoms. Findings Fecal SARS-CoV-2 RNA is detected in 49.2% [95% Confidence interval = 38.2%-60.3%] of participants within the first week after diagnosis. Whereas there was no ongoing oropharyngeal SARS-CoV-2 RNA shedding in subjects at and after 4 months, 12.7% [8.5%-18.4%] of participants continued to shed SARS-CoV-2 RNA in the feces at 4 months after diagnosis and 3.8% [2.0%-7.3%] shed at 7 months. Finally, we find that GI symptoms (abdominal pain, nausea, vomiting) are associated with fecal shedding of SARS-CoV-2 RNA. Conclusions The extended presence of viral RNA in feces, but not respiratory samples, along with the association of fecal viral RNA shedding with GI symptoms suggest that SARS-CoV-2 infects the GI tract, and that this infection can be prolonged in a subset of individuals with COVID-19.
143	I141	ES	LeilaMobasheriaMohammad HosseinNasirpourbElhamMasoumicdAfsaneh FooladyAzarnaminyeMozhdehJafarifgSeyed-AlirezaEsmaeilifg	SARS-CoV-2 triggering autoimmune diseases	https://doi.org/10.1016/j.cyto.2022.155873	Published	20 April 2022	Review	https://www.sciencedirect.com/science/article/pii/S1043466622000825	Highlight •SARS-CoV-2, the cause of the pandemic coronavirus disease, causes dysregulation of an immune response. •Infection of respiratory epithelium by virus triggers both innate and acquired immunity that led to the immune system's hyperactivation. •Therefore, triggering chronic inflammation can contribute to autoimmune disease. •Post-Covid-19 autoimmunity may be due to molecular mimicry, bystander activation of T cells, transient immunosuppression, and pro-inflammatory cytokines, which might complicate SARS-CoV-2 vaccination. Autoimmunity, hyperstimulation of the immune system, can be caused by a variety of reasons. Viruses are thought to be important environmental elements that contribute to the development of autoimmune antibodies. It seems that viruses cause autoimmunity with mechanisms such as molecular mimicry, bystander activation of T cells, transient immunosuppression, and inflammation, which has also been seen in post-Covid-19 autoimmunity. Infection of respiratory epithelium by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) dysregulates the immune response, triggers both innate and acquired immunity that led to the immune system's hyperactivation, excessive cytokine secretion known as “cytokine storm,” and finally acute respiratory distress syndrome (ARDS) associated with high mortality. Any factor in the body that triggers chronic inflammation can contribute to autoimmune disease, which has been documented during the Covid-19 pandemic. It has been observed that some patients produce autoantibody and autoreactive CD4+ and CD8+ T cells, leading to the loss of self-tolerance. However, there is a scarcity of evidence defining the precise molecular interaction between the virus and the immune system to elicit autoreactivity. Here, we present a review of the relevant immunological findings in Covid-19 and the current reports of autoimmune disease associated with the disease.
144	I142		Fernández-de-las-Peñas C.a,b · Ryan-Murua P.c · Rodríguez-Jiménez J.a · Palacios-Ceña M.a · Arendt-Nielsen L.b,d · Torres-Macho J.c,e	Serological Biomarkers at Hospital Admission Are Not Related to Long-Term Post-COVID Fatigue and Dyspnea in COVID-19 Survivors	https://doi.org/10.1159/000524042	Published	April 05, 2022	Study	https://www.karger.com/Article/FullText/524042	Objective: The aim of this study was to investigate the association between serological biomarkers at the acute phase of infection at hospital admission with the development of long-term post-COVID fatigue and dyspnea. Methods: A cohort study including patients hospitalized due to COVID-19 in one urban hospital of Madrid (Spain) during the first wave of the outbreak (from March 20 to June 30, 2020) was conducted. Hospitalization data, clinical data, and eleven serological biomarkers were systematically collected at hospital admission. Patients were scheduled for an individual telephone interview after hospital discharge for collecting data about the presence of post-COVID fatigue and dyspnea. Results: A total of 412 patients (age: 62 years, standard deviation: 15 years; 47.5% women) were assessed with a mean of 6.8 and 13.2 months after discharge. The prevalence of post-COVID fatigue and dyspnea was 72.8% and 17.2% at 6 months and 45.4% and 13.6% at 12 months after hospital discharge, respectively. Patients exhibiting post-COVID fatigue at 6 or 12 months exhibited a lower hemoglobin level, higher lymphocyte count, and lower neutrophil and platelets counts (all, p < 0.05), whereas those exhibiting post-COVID dyspnea at 6 or 12 months had a lower platelet count and lower alanine transaminase, aspartate transaminase, and lactate dehydrogenase (LDH) levels (all, p < 0.05) than those not developing post-COVID fatigue or dyspnea, respectively. The multivariate regression analyses revealed that a lower platelet count and lower LDH levels were associated but just explaining 4.5% of the variance, of suffering from post-COVID fatigue and dyspnea, respectively. Conclusion: Some serological biomarkers were slightly different in patients exhibiting post-COVID fatigue or dyspnea, but they could not explain the long-COVID problems in those patients.
145	I143		Lucía Beltrán-Camacho, Sara Eslava-Alcón, Marta Rojas-Torres, Daniel Sánchez-Morillo, Mª Pilar Martinez-Nicolás, Victoria Martín-Bermejo, Inés García de la Torre, Esther Berrocoso, Juan Antonio Moreno, Rafael Moreno-Luna & Mª Carmen Durán-Ruiz	The serum of COVID-19 asymptomatic patients up-regulates proteins related to endothelial dysfunction and viral response in circulating angiogenic cells ex-vivo	https://doi.org/10.1186/s10020-022-00465-w	Published	09 April 2022	Study	https://molmed.biomedcentral.com/articles/10.1186/s10020-022-00465-w	Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has already caused 6 million deaths worldwide. While asymptomatic individuals are responsible of many potential transmissions, the difficulty to identify and isolate them at the high peak of infection constitutes still a real challenge. Moreover, SARS-CoV-2 provokes severe vascular damage and thromboembolic events in critical COVID-19 patients, deriving in many related deaths and long-hauler symptoms. Understanding how these processes are triggered as well as the potential long-term sequelae, even in asymptomatic individuals, becomes essential. Methods We have evaluated, by application of a proteomics-based quantitative approach, the effect of serum from COVID-19 asymptomatic individuals over circulating angiogenic cells (CACs). Healthy CACs were incubated ex-vivo with the serum of either COVID-19 negative (PCR −/IgG −, n:8) or COVID-19 positive asymptomatic donors, at different infective stages: PCR +/IgG − (n:8) and PCR −/IgG + (n:8). Also, a label free quantitative approach was applied to identify and quantify protein differences between these serums. Finally, machine learning algorithms were applied to validate the differential protein patterns in CACs. Results Our results confirmed that SARS-CoV-2 promotes changes at the protein level in the serum of infected asymptomatic individuals, mainly correlated with altered coagulation and inflammatory processes (Fibrinogen, Von Willebrand Factor, Thrombospondin-1). At the cellular level, proteins like ICAM-1, TLR2 or Ezrin/Radixin were only up-regulated in CACs treated with the serum of asymptomatic patients at the highest peak of infection (PCR + /IgG −), but not with the serum of PCR −/IgG + individuals. Several proteins stood out as significantly discriminating markers in CACs in response to PCR or IgG + serums. Many of these proteins particiArticle title: Kindly check and confirm the edit made in the article title.pate in the initial endothelial response against the virus. Conclusions The ex vivo incubation of CACs with the serum of asymptomatic COVID-19 donors at different stages of infection promoted protein changes representative of the endothelial dysfunction and inflammatory response after viral infection, together with activation of the coagulation process. The current approach constitutes an optimal model to study the response of vascular cells to SARS-CoV-2 infection, and an alternative platform to test potential inhibitors targeting either the virus entry pathway or the immune responses following SARS-CoV-2 infection.
146	I144	ES	Zhongfang Wang, Xiaoyun Yang, Xinyue Mei, Yumin Zhou, Zhiqiang Tang, Guichang Li, Jiaying Zhong, Mengqiu Yu, Mingzhu Huang, Xiaoling Su, Bijia Lin, Pengxing Cao, Ji Yang & Pixin Ran	SARS-CoV-2-specific CD4+ T cells are associated with long-term persistence of neutralizing antibodies	https://doi.org/10.1038/s41392-022-00978-0	Published	23 April 2022	Study	https://www.nature.com/articles/s41392-022-00978-0	Understanding the decay and maintenance of long-term SARS-CoV-2 neutralizing antibodies in infected or vaccinated people and how vaccines protect against other SARS-CoV-2 variants is critical for assessing public vaccination plans. Here, we measured different plasm antibody levels 2 and 12 months after disease onset, including anti-RBD, anti-N, total neutralizing antibodies, and two neutralizing-antibody clusters. We found that total neutralizing antibodies declined more slowly than total anti-RBD and anti-N IgG, and the two neutralizing-antibody clusters decayed even more slowly than total neutralizing antibodies. Interestingly, the level of neutralizing antibodies at 12 months after disease onset was significantly lower than that at 2 months but more broadly neutralized SARS-CoV-2 variants, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Lambda (C.37). Significant immune escape by the Omicron variant (B.1.1.529) was also observed 2 months post-recovery. Furthermore, we revealed that a high percentage of virus-specific CD4+ T cells and cTfh1 were associated with a slower decline in humoral immunity, accompanied by higher levels of CXCR3 ligands such as CXCL9 and CXCL10, higher frequency of cTfh1, and lower levels of cTfh2 and cTfh17. Our data highlight the importance of coordinating T-cell and humoral immunity to achieve long-term protective immunity.
147	I145		RYAN W. NELSON YUEZHOU CHEN OLIVIA L. VENEZIARICHARD M. MAJERUS DANIEL S. SHIN MGH COVID-19 COLLECTION & PROCESSING TEAM†MARY N. CARRINGTON XU G. YU DUANE R. WESEMANN JAMES J. MOON AND ANDREW D. LUSTER	SARS-CoV-2 epitope-specific CD4+ memory T cell responses across COVID-19 disease severity and antibody durability	https://doi.org/10.1126/sciimmunol.abl9464	Published	21 Apr 2022	Study	https://www.science.org/doi/10.1126/sciimmunol.abl9464	CD4+ T cells are central to long-term immunity against viruses through the functions of T helper-1 (Th1) and T follicular helper (Tfh) cell subsets. To better understand the role of these subsets in COVID-19 immunity, we conducted a longitudinal study of SARS-CoV-2-specific CD4+ T cell and antibody responses in convalescent subjects who seroconverted during the first wave of the pandemic in Boston, Massachusetts, United States, across a range of COVID-19 disease severities. Analyses of spike (S) and nucleocapsid (N) epitope-specific CD4+ T cells using peptide and major histocompatibility complex class II (peptide:MHCII) tetramers demonstrated expanded populations of T cells recognizing the different SARS-CoV-2 epitopes in most subjects compared to pre-pandemic controls. Individuals who experienced a milder disease course not requiring hospitalization had a greater percentage of circulating Tfh (cTfh) and Th1 cells among SARS-CoV-2-specific cells. Analysis of SARS-CoV-2-specific CD4+ T cells responses in a subset of individuals with sustained anti-S antibody responses following viral clearance also revealed an increased proportion of memory cTfh cells. Our findings indicate efficient early disease control also predicts favorable long-term adaptive immunity.
148	I146		Arezoo Faramarzi 1, Reza Safaralizadeh 1, Narges Dastmalchi 2, Shahram Teimourian 3	Epigenetic-related effects of COVID-19 on the human cells	https://doi.org/10.2174/1871526522666220420093029	Published	2022 Apr 20	Article	https://pubmed.ncbi.nlm.nih.gov/35450534/	Epigenetics related to the various pathways which show long-term impacts on the gene expression patterns without alterations in nucleotide sequences. Over the last decade, epigenetics advanced significantly in the science of biology, oncology, innate immunity as well as pathogens and infectious diseases. In the present review, we aimed to review the relationships between covid19 and epigenetic alterations of the infected cells. Corona virus is one of the known infectious diseases causes respiratory infection, such as pneumonia, and coughing while in animal, it causes diarrhea and upper respiratory disorders. This virus could be transmitted human to human or human to animal with droplets, it translocate via membrane ACE-2 exopeptidase in to the host cells. In conclusion, hypomethylation of Angiotensin II Converting Enzyme (ACE II) possibly upregulates its expression, which will enhance the possibility of SARS-CoV-2 infection.
149	I147		Hussein Kadhem Al-Hakeim, Haneen Tahseen Al-Rubaye, Dhurgham Shihab Al-Hadrawi, Abbas F. Almulla, Michael Maes	Long-COVID post-viral chronic fatigue syndrome and affective symptoms are associated with oxidative damage, lowered antioxidant defenses and inflammation: a proof of concept and mechanism study	https://doi.org/10.1101/2022.04.25.22274251	pre-print	April 27, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.04.25.22274251v1.full-text	The immune-inflammatory response during the acute phase of COVID-19, as assessed using peak body temperature (PBT) and peripheral oxygen saturation (SpO2), predicts the severity of chronic fatigue, depression and anxiety (“physio-affective”) symptoms three to four months later. The present study was performed to characterize whether the effects of SpO2 and PBT on the physio-affective phenome of Long COVID are mediated by immune, oxidative and nitrosative stress (IO&NS) pathways. This study assayed SpO2 and PBT during acute COVID-19, and C-reactive protein (CRP), malondialdehyde (MDA), protein carbonyls (PCs), myeloperoxidase (MPO), nitric oxide (NO), zinc, and glutathione peroxidase (Gpx) in 120 Long COVID individuals and 36 controls. Cluster analysis showed that 31.7% of the Long COVID patients had severe abnormalities in SpO2, body temperature, increased oxidative toxicity (OSTOX) and lowered antioxidant defenses (ANTIOX), and increased total Hamilton Depression (HAMD) and Anxiety (HAMA) and Fibromylagia-Fatigue (FF) scores. Around 60% of the variance in the physio-affective phenome of Long COVID (a factor extracted from HAMD, HAMA and FF scores) was explained by OSTOX/ANTIOX ratio, PBT and SpO2. Increased PBT predicted increased CRP and lowered ANTIOX and zinc levels, while lowered SpO2 predicted lowered Gpx and increased NO production. Both PBT and SpO2 strongly predict OSTOX/ATIOX during Long COVID. In conclusion, the impact of acute COVID-19 on the physio-affective symptoms of Long COVID is partly mediated by OSTOX/ANTIOX, especially lowered Gpx and zinc, increased MPO and NO production and lipid peroxidation-associated aldehyde formation. Post-viral physio-affective symptoms have an inflammatory origin and are partly mediated by neuro-oxidative toxicity.
150	I148	ES	Bin Wang, Lei Zhang, Yongqiang Wang, Tong Dai, Ziran Qin, Fangfang Zhou & Long Zhang	Alterations in microbiota of patients with COVID-19: potential mechanisms and therapeutic interventions	https://doi.org/10.1038/s41392-022-00986-0	Published	29 April 2022	Review	https://www.nature.com/articles/s41392-022-00986-0	The global coronavirus disease 2019 (COVID-19) pandemic is currently ongoing. It is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A high proportion of COVID-19 patients exhibit gastrointestinal manifestations such as diarrhea, nausea, or vomiting. Moreover, the respiratory and gastrointestinal tracts are the primary habitats of human microbiota and targets for SARS-CoV-2 infection as they express angiotensin-converting enzyme-2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) at high levels. There is accumulating evidence that the microbiota are significantly altered in patients with COVID-19 and post-acute COVID-19 syndrome (PACS). Microbiota are powerful immunomodulatory factors in various human diseases, such as diabetes, obesity, cancers, ulcerative colitis, Crohn’s disease, and certain viral infections. In the present review, we explore the associations between host microbiota and COVID-19 in terms of their clinical relevance. Microbiota-derived metabolites or components are the main mediators of microbiota-host interactions that influence host immunity. Hence, we discuss the potential mechanisms by which microbiota-derived metabolites or components modulate the host immune responses to SARS-CoV-2 infection. Finally, we review and discuss a variety of possible microbiota-based prophylaxes and therapies for COVID-19 and PACS, including fecal microbiota transplantation (FMT), probiotics, prebiotics, microbiota-derived metabolites, and engineered symbiotic bacteria. This treatment strategy could modulate host microbiota and mitigate virus-induced inflammation.
151	I149		Carlo Brogna 1,,†,Barbara Brogna 2ORCID,Domenico Rocco Bisaccia 1,Francesco Lauritano 1,Giuliano Marino 3,Luigi Montano 4,Simone Cristoni 5,Marina Prisco 6ORCID andMarina Piscopo 6,,†ORCID	Could SARS-CoV-2 Have Bacteriophage Behavior or Induce the Activity of Other Bacteriophages?	https://doi.org/10.3390/vaccines10050708	Published	29 April 2022	Review	https://www.mdpi.com/2076-393X/10/5/708/htm	SARS-CoV-2 has become one of the most studied viruses of the last century. It was assumed that the only possible host for these types of viruses was mammalian eukaryotic cells. Our recent studies show that microorganisms in the human gastrointestinal tract affect the severity of COVID-19 and for the first time provide indications that the virus might replicate in gut bacteria. In order to further support these findings, in the present work, cultures of bacteria from the human microbiome and SARS-CoV-2 were analyzed by electron and fluorescence microscopy. The images presented in this article, in association with the nitrogen (15N) isotope-labeled culture medium experiment, suggest that SARS-CoV-2 could also infect bacteria in the gut microbiota, indicating that SARS-CoV-2 could act as a bacteriophage. Our results add new knowledge to the understanding of the mechanisms of SARS-CoV-2 infection and fill gaps in the study of the interactions between SARS-CoV-2 and non-mammalian cells. These findings could be useful in suggesting specific new pharmacological solutions to support the vaccination campaign.
152	I150		Mari E. K. Niemi, Mark J. Daly & Andrea Ganna	The human genetic epidemiology of COVID-19	https://doi.org/10.1038/s41576-022-00478-5	Published	02 May 2022	Review	https://www.nature.com/articles/s41576-022-00478-5	Human genetics can inform the biology and epidemiology of coronavirus disease 2019 (COVID-19) by pinpointing causal mechanisms that explain why some individuals become more severely affected by the disease upon infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Large-scale genetic association studies, encompassing both rare and common genetic variants, have used different study designs and multiple disease phenotype definitions to identify several genomic regions associated with COVID-19. Along with a multitude of follow-up studies, these findings have increased our understanding of disease aetiology and provided routes for management of COVID-19. Important emergent opportunities include the clinical translatability of genetic risk prediction, the repurposing of existing drugs, exploration of variable host effects of different viral strains, study of inter-individual variability in vaccination response and understanding the long-term consequences of SARS-CoV-2 infection. Beyond the current pandemic, these transferrable opportunities are likely to affect the study of many infectious diseases.
153	I151		Cristina Cerrada-Romero, Judith Berastegui-Cabrera, Pedro Camacho-Martínez, Josune Goikoetxea-Aguirre, Patricia Pérez-Palacios, Sonia Santibáñez, María José Blanco-Vidal, Adoración Valiente, Jorge Alba, Regino Rodríguez-Álvarez, Álvaro Pascual, José Antonio Oteo, José Miguel Cisneros, Jerónimo Pachón, Inmaculada Casas-Flecha, Elisa Cordero, Francisco Pozo & Javier Sánchez-Céspedes	Excretion and viability of SARS-CoV-2 in feces and its association with the clinical outcome of COVID-19	https://doi.org/10.1038/s41598-022-11439-7	Published	05 May 2022	Study	https://www.nature.com/articles/s41598-022-11439-7	The main objective was to evaluate the viability of the SARS-CoV-2 viral particles excreted in stools. In addition, we aimed to identify clinical factors associated with the detection of SARS-CoV-2 RNA in feces, and to determine if its presence is associated with an unfavorable clinical outcome, defined as intensive care unit (ICU) admission and/or death. A prospective multicenter cohort study of COVID-19 adult patients, with confirmed SARS-CoV-2 infection by RT-PCR assay in nasopharyngeal (NP) swabs admitted to four hospitals in Spain, from March 2020 to February 2021. Sixty-two adult COVID-19 patients had stool samples collected at admission and/or during the follow up, with a total of 79 stool samples. SARS-CoV-2 RNA was detected in stool samples from 27 (43.5%) out of the 62 patients. Replicative virus, measured by the generation of cytopathic effect in cell culture and subsequent RT-PCR confirmation of a decrease in the Ct values, was not found in any of these stool samples. Fecal virus excretion was not associated with the presence of gastrointestinal symptoms, or with differences in the evolution of COVID-19 patients. Our results suggest that SARS-CoV-2 replicative capacity is null or very limited in stool samples, and thus, the fecal–oral transmission of SARS-CoV-2 as an alternative infection route is highly unlikely. In our study, the detection of SARS-CoV-2 RNA in feces at the beginning of the disease is not associated with any clinical factor nor with an unfavorable clinical outcome.
154	I152		Dejan Jakimovski 1ORCID,Karen Zakalik 2,Samreen Awan 2,Katelyn S. Kavak 2,Penny Pennington 2,David Hojnacki 2,Channa Kolb 2,Alexis A. Lizarraga 2,Svetlana P. Eckert 2ORCID,Rosila Sarrosa 3,Kamath Vineetha 3,Keith Edwards 3 andBianca Weinstock-Guttman 2,*ORCID	COVID-19 Vaccination in Multiple Sclerosis and Inflammatory Diseases: Effects from Disease-Modifying Therapy, Long-Term Seroprevalence and Breakthrough Infections	https://doi.org/10.3390/vaccines10050695	Published	28 April 2022	Study	https://www.mdpi.com/2076-393X/10/5/695/htm	Background: To determine the effect of disease-modifying therapies (DMT) on humoral postvaccine seroconversion, long-term humoral response, and breakthrough COVID-19 infections in persons with multiple sclerosis (PwMS) and other neuroinflammatory disorders. Methods: A total of 757 PwMS and other neuroinflammatory disorders were recruited in two MS centers and vaccinated with one of the FDA-approved vaccines (BNT162b2, mRNA-1273, Ad26.COV2.S). The primary outcomes are the rate of humoral postvaccine seroconversion and anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) immunoglobulin G (IgG) differences between patients on different DMTs. Secondary measures include breakthrough infections and humoral response after six months. Other outcomes include differences in vaccine response between SARS-CoV-2 vaccines and the effects of age and comorbidities on the vaccine response. Results: A total of 465 (68.4%) PwMS and 55 (74.3%) patients with neuroinflammatory diseases were seropositive at 4–12 weeks after vaccination. A significant difference in seroconversion based on the DMT used at the time of vaccination (p < 0.001) was observed, with the lowest rates seen in patients treated with anti-CD20 antibodies (23.2%) and sphingosine-1-phosphate modulators (S1P) (30.8%). In seropositive patients, there was a significant decrease in anti-SARS IgG from mean 20.0 to 4.7 at six months (p = 0.004). Thirty-nine patients had breakthrough infection, but only two seronegative patients required hospitalization. mRNA vaccines resulted in significantly greater seroconversion compared to Ad26.COV2.S (p < 0.001). Older age and presence of cardiovascular comorbidities were associated with lower anti-SARS IgG (p = 0.021 and p = 0.003, respectively) Conclusions: PwMS and neuroinflammatory disorders treated with anti-CD20 and S1P medications have lower humoral response after anti-SARS-CoV-2 vaccination, even after booster dose. Waning of the humoral response puts vaccinated PwMS at a greater risk of COVID-19 breakthrough.
155	I153		Hussein Kadhem Al-Hakeim1 Haneen Tahseen Al-Rubaye2 Dhurgham Shihab Al-Hadrawi3 Abbas F. Almulla4 Michael Maes5	Long-COVID post-viral chronic fatigue and affective symptoms are associated with oxidative damage, lowered antioxidant defenses and inflammation: a proof of concept and mechanism study.	https://doi.org/10.21203/rs.3.rs-1610917/v1	pre-print	02 May, 2022	Study	https://www.researchsquare.com/article/rs-1610917/v1	The immune-inflammatory response during the acute phase of COVID-19, as assessed using peak body temperature (PBT) and peripheral oxygen saturation (SpO2), predicts the severity of chronic fatigue, depression and anxiety (“physio-affective”) symptoms three to four months later. The present study was performed to characterize whether the effects of SpO2 and PBT on the physio-affective phenome of Long COVID are mediated by immune, oxidative and nitrosative stress (IO&NS) pathways. This study assayed SpO2 and PBT during acute COVID-19, and C-reactive protein (CRP), malondialdehyde (MDA), protein carbonyls (PCs), myeloperoxidase (MPO), nitric oxide (NO), zinc, and glutathione peroxidase (Gpx) in 120 Long COVID individuals and 36 controls. Cluster analysis showed that 31.7% of the Long COVID patients had severe abnormalities in SpO2, body temperature, increased oxidative toxicity (OSTOX) and lowered antioxidant defenses (ANTIOX), and increased total Hamilton Depression (HAMD) and Anxiety (HAMA) and Fibromylagia-Fatigue (FF) scores. Around 60% of the variance in the physio-affective phenome of Long COVID (a factor extracted from HAMD, HAMA and FF scores) was explained by OSTOX/ANTIOX ratio, PBT and SpO2. Increased PBT predicted increased CRP and lowered ANTIOX and zinc levels, while lowered SpO2 predicted lowered Gpx and increased NO production. Both PBT and SpO2 strongly predict OSTOX/ATIOX during Long COVID. In conclusion, the impact of acute COVID-19 on the physio-affective symptoms of Long COVID is partly mediated by OSTOX/ANTIOX, especially lowered Gpx and zinc, increased MPO and NO production and lipid peroxidation-associated aldehyde formation. Post-viral physio-affective symptoms have an inflammatory origin and are partly mediated by neuro-oxidative toxicity.
156	I154		Ibrahim Shnawa	Postinfection-Postvaccination autoimmune neural long covid	http://dx.doi.org/10.9734/jpri/2022/v34i36A36175	Published	02 May 2022	Article	https://www.researchgate.net/publication/360317846_Postinfection-Postvaccination_autoimmune_neural_long_covid	Normal human subject can have baseline auto-antibodies and auto-reactive immune cells constituting the normal physiological autoimmune state. On, post- sars-cov-2 infection and post-vaccination periods either the virus built in spike protein in case of post-infection . Or the peptide expressed from the spike protein sequence within the human COVID -19 mRNA vaccines have an auto-reacting epitopes within the human vaccinee cells. Both of the virus spike protein and vaccinee cells are bearing either pan-sharing molecular mimicking or mono-specific molecular mimicking epitopes that initiate on continual exposure to the immune system cells mediating an autoimmune responses. Such responses may cause an immune conversion of the antibody and /or auto-reactive immune cells levels from the baseline limits to the clinically indicative levels of auto-antibody and/or auto-reacting cells. The immune conversion state may pose to an autoimmune tissue injuries as single or multiple organs defects expressing the patho-biologic features of autoimmune long COVID-19.This mechanistic view to the long Covid-19 is parallel with inclusion of long COVID-19 on the list of autoimmune registry 2021.Some workers holds the believe that autoimmune long COVID-19 is an auto-antibody mediated condition .Other workers are of the opinion that both auto-antibody and auto-reacting immune cells may be involved in, Though there is still existing some debate .A literature show case analysis of neural autoimmune long COVID-19 was tempted .A laboratory animal model for Post-infection-Post-vaccination autoimmune long COVID-19 was suggested .Both of these disease entities are being over-lapping.
157	I155		Nermine Abdelwahab, MD # Nicholas E Ingraham, MD # Nguyen Nguyen Lianne Siegel, PhD Greg Silverman Himanshu Shekhar Sahoo Serguei Pakhomov, PhD Leslie R Morse, DO Joanne Billings, MD MPH Michael G. Usher, MD PhD Tanya E. Melnik, MD Christopher J. Tignanelli, MD Farha Ikramuddin, MD MHA	Predictors of Post-Acute Sequelae of COVID-19 Development and Rehabilitation: A Retrospective Study	https://doi.org/10.1016/j.apmr.2022.04.009	Published	May 12, 2022	Study	https://www.archives-pmr.org/article/S0003-9993(22)00397-5/fulltext	Main outcome measure Descriptive analyses were conducted across the entire cohort along with an adult subgroup analysis. A logistic regression was performed to assess factors associated with PASC development and rehabilitation utilization. Results In an analysis of 19,792 patients, the frequency of PASC was 42.8% in the adult population. Patients with PASC compared to those without had a higher utilization of rehabilitation services (8.6% vs 3.8%, p<0.001). Risk factors for rehabilitation utilization in patients with PASC included younger age (OR 0.99, 95% CI 0.98-1.00; p=0.01). In addition to several comorbidities and demographics factors, risk factors for rehabilitation utilization solely in the inpatient population included male sex (OR 1.24, 95% CI 1.02-1.50; p=0.03) with patients on angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers three months prior to COVID-19 infections having a decreased risk of needing rehabilitation (OR 0.80, 95% CI 0.64-0.99; p=0.04). Conclusion Patients with PASC had higher rehabilitation utilization. We identified several clinical and demographic factors associated with the development of PASC and rehabilitation utilization.
158	I156		Laurence Pearmain, Nicholas Scott, Sean B Knight, Oliver Brand, David J Morgan, Chris Jagger, Saba Khan, Pamela Hackney, Lara Smith, Madhvi Menon, Joanne E Konkel, Halima A Shuwa, Miriam Franklin, Verena Kästele, Sarah Harbach, Seema Brij, Andrew Ustianowski, Alexander G Mathoudiakis, Christopher E Brightling, Pilar Rivera Ortega, Nawar Diar Bakerly, Paul Dark, Kathryn Gray, Graham M Lord, Timothy W Felton, Circo, Karen Piper Hanley, Angela Simpson, John R Grainger, Tracy Hussell, Elizabeth R Mann	Monocyte migratory signatures identify acute and convalescent COVID-19 patients, and are associated with long COVID-19 symptoms	https://doi.org/10.1183/23120541.LSC-2022.172	Published	May 9, 2022	Study	https://openres.ersjournals.com/content/8/suppl_8/172.abstract	Background: Monocytes regulate the development and resolution of lung injury. We previously demonstrated dysregulation of blood monocytes in hospitalised COVID-19 patients. It is unknown whether monocyte abnormalities persist after discharge and their clinical significance to long COVID symptoms Aims: We aimed to assess if monocyte dysfunction in COVID-19 is associated with long COVID symptoms. Methods: Clinical data were collected from 72 patients with acute COVID-19 pneumonitis, 147 COVID-19 convalescent patients (range 8-36 weeks), and 38 healthy controls. Blood monocytes were characterised by flow cytometry. Results: Monocytes from hospitalised, acute COVID-19 patients aberrantly expressed adhesion/migration molecules, including increased monocyte chemoattractant protein 1, chemokine receptor CXCR6 and adhesion molecules integrinβ7, PSGL-1. Notably chemokine receptor CXCR2 (decreased) and CD62L (increased) expression stratified with acute COVID-19 severity. In convalescence, increased monocyte CXCR6 and PSGL1 persisted; associating with patient breathlessness. Cyclo-oxygenase 2 expression was decreased on monocytes during acute COVID-19, stratifying with disease severity, and remained low during convalescence in patients with persistent fatigue. TNFα monocyte production was enhanced in patients with mild disease during the acute phase, and in patients without long COVID symptoms. Conlusions: Persistent changes in monocytes during COVID-19 convalescence are associated with long COVID symptoms, where traditional tests of lung recovery are not. Targeting aberrant monocyte phenotypes throughout the COVID-19 time-course has biomarker & immunomodulatory therapy promise.
159	I157		Buonsenso, Danilo 1 ; Piazza, Michele 2 ; Boner, Attilio L. 2 ; Bellanti, Joseph A. 3 ;	Long COVID: A proposed hypothesis-driven model of viral persistence for the pathophysiology of the syndrome	https://doi.org/10.2500/aap.2022.43.220018	Published	1 mai 2022	Article	https://www.ingentaconnect.com/content/ocean/aap/2022/00000043/00000003/art00003	Background: Long COVID (coronavirus disease 2019) syndrome includes a group of patients who, after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibit lingering mild-to-moderate symptoms and develop medical complications that can have lasting health problems. In this report, we propose a model for the pathophysiology of the long COVID presentation based on increased proinflammatory cytokine production that results from the persistence of the SARS-CoV-2 virus or one of its molecular components. Associated with this hyperproduction of inflammatory cytokines is a heightened activity of nuclear factor κ B (NF-κB) and p38 mitogen-activated protein kinase signaling pathways that regulate cytokine production. Objective: The purpose of the present report was to review the causes of long COVID syndrome and suggest ways that can provide a basis for a better understanding of the clinical symptomatology for the of improved diagnostic and therapeutic procedures for the condition. Methods: Extensive research was conducted in medical literature data bases by applying terms such as “long COVID” associated with “persistence of the SARS-CoV-2 virus” “spike protein' “COVID-19” and “biologic therapies.” Results and Conclusions: In this model of the long COVID syndrome, the persistence of SARS-CoV-2 is hypothesized to trigger a dysregulated immune system with subsequent heightened release of proinflammatory cytokines that lead to chronic low-grade inflammation and multiorgan symptomatology. The condition seems to have a genetic basis, which predisposes individuals to have a diminished immunologic capacity to completely clear the virus, with residual parts of the virus persisting. This persistence of virus and resultant hyperproduction of proinflammatory cytokines are proposed to form the basis of the syndrome.
160	I158		Daniel Ayoubkhani, Charlotte Bermingham, Koen B Pouwels, Myer Glickman, Vahé Nafilyan, Francesco Zaccardi, Kamlesh Khunti, , Nisreen A Alwan	Trajectory of long covid symptoms after covid-19 vaccination: community based cohort study	https://doi.org/10.1136/bmj-2021-069676	Published	18 May 2022	Study	https://www.bmj.com/content/377/bmj-2021-069676	Objective: To estimate associations between covid-19 vaccination and long covid symptoms in adults with SARS-CoV-2 infection before vaccination. Design: Observational cohort study. Setting: Community dwelling population, UK. Participants: 28 356 participants in the Office for National Statistics COVID-19 Infection Survey aged 18-69 years who received at least one dose of an adenovirus vector or mRNA covid-19 vaccine after testing positive for SARS-CoV-2 infection. Main outcome measure; Presence of long covid symptoms at least 12 weeks after infection over the follow-up period 3 February to 5 September 2021. Results: Mean age of participants was 46 years, 55.6% (n=15 760) were women, and 88.7% (n=25 141) were of white ethnicity. Median follow-up was 141 days from first vaccination (among all participants) and 67 days from second vaccination (83.8% of participants). 6729 participants (23.7%) reported long covid symptoms of any severity at least once during follow-up. A first vaccine dose was associated with an initial 12.8% decrease (95% confidence interval −18.6% to −6.6%, P<0.001) in the odds of long covid, with subsequent data compatible with both increases and decreases in the trajectory (0.3% per week, 95% confidence interval −0.6% to 1.2% per week, P=0.51). A second dose was associated with an initial 8.8% decrease (95% confidence interval −14.1% to −3.1%, P=0.003) in the odds of long covid, with a subsequent decrease by 0.8% per week (−1.2% to −0.4% per week, P<0.001). Heterogeneity was not found in associations between vaccination and long covid by sociodemographic characteristics, health status, hospital admission with acute covid-19, vaccine type (adenovirus vector or mRNA), or duration from SARS-CoV-2 infection to vaccination. Conclusions: The likelihood of long covid symptoms was observed to decrease after covid-19 vaccination and evidence suggested sustained improvement after a second dose, at least over the median follow-up of 67 days. Vaccination may contribute to a reduction in the population health burden of long covid, although longer follow-up is needed.
161	I159		Manoj Sivan, Trisha Greenhalgh, Ruairidh Milne, Brendan Delaney	Are vaccines a potential treatment for long covid?	https://doi.org/10.1136/bmj.o988	Published	18 May 2022	Article	https://www.bmj.com/content/377/bmj.o988.full	Benefits are possible, but we need more evidence and a mechanism of action. The mechanisms underpinning changes in long covid symptoms after vaccination are not fully understood. However, as Ayoubkhani and colleagues suggest, vaccination can increase antibody titres and potentially eliminate viral reservoirs.2 Given the small numbers of patients reported to benefit (an 8.8% reduction in odds of long covid after two vaccine doses) and the uncertainty around the true effect of vaccines relative to natural recovery, a clear explanation for how vaccines might reduce the multisystem manifestations of long covid is still lacking. Particularly for people already well past the stage of systemic inflammatory responses, and those with end organ damage from covid-19, such as lung fibrosis. Several plausible mechanisms underlying long covid are currently being investigated, including the persistence of viral antigens and abnormalities in T cells, platelets, vascular endothelium, and clotting factors. People with long covid need timely investigation, management, and rehabilitation in specialist clinics, including identification of thrombotic phenomena, cardiac dysrhythmias, and dysautonomia. Vaccination to reduce risk of reinfection remains important for people with long covid, and evidence so far suggests that benefits are likely to outweigh any harms. Three outcomes are possible after vaccination: no change in symptoms (most likely), improvement (best case), or deterioration (worst case).1 Unfortunately, many unknowns remain about the long term prognosis of long covid, including the effect of booster vaccines or recurrent covid-19. More research is needed on the link between antibody titres and symptoms over time before we can hope to predict the effects of vaccination on individuals.
162	I160		Ngai Sze Wong, Shui Shan Lee, Denise P. C. Chan, Timothy C. M. Li, Tracy H. Y. Ho, Fion W. L. Luk, Kai Ming Chow, Eugene Y. K. Tso, Eng-Kiong Yeoh, Samuel Y. S. Wong, David S. C. Hui & Grace C. Y. Lui	Trajectory patterns of SARS-CoV-2 neutralising antibody response in convalescent COVID-19 patients	https://doi.org/10.1038/s43856-022-00119-2	Published	19 May 2022	Study	https://www.nature.com/articles/s43856-022-00119-2	Background The adaptive immune responses of COVID-19 patients contributes to virus clearance, restoration of health and protection from re-infection. The patterns of and the associated characteristics with longitudinal neutralising antibody (NAb) response following SARS-CoV-2 infection are important in their potential association with the population risks of re-infection. Methods This is a longitudinal study with blood samples and clinical data collected in adults aged 18 or above following diagnosis of SARS-CoV-2 infection. NAb levels were measured by the SARS-CoV-2 surrogate virus neutralisation test (sVNT). Anonymous clinical and laboratory data were matched with surveillance data for each subject for enabling analyses and applying latent class mixed models for trajectory delineation. Logistic regression models were performed to compare the characteristics between the identified classes. Results In 2020–2021, 368 convalescent patients in Hong Kong are tested for NAb. Their seroconversion occur within 3 months in 97% symptomatic patients, the level of which are maintained at 97% after 9 months. The NAb trajectories of 200 symptomatic patients are classified by the initial response and subsequent trend into high-persistent and waning classes in latent class mixed models. High-persistent (15.5%) class patients are older and most have chronic illnesses. Waning class patients (84.5%) are largely young adults who are mildly symptomatic including 2 who serorevert after 10 months. Conclusions Characteristic sub-class variabilities in clinical pattern are noted especially among patients with waning NAb. The heterogeneity of the NAb trajectory patterns and their clinical association can be important for informing vaccination strategy to prevent re-infection.
163	I161	I75 now published in Nature Medicine	Ziyad Al-Aly, Benjamin Bowe, Yan Xie	Long COVID after breakthrough SARS-CoV-2 infection	https://doi.org/10.1038/s41591-022-01840-0	Published	25 May 2022	Study	https://www.nature.com/articles/s41591-022-01840-0	The post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection—also referred to as Long COVID—have been described, but whether breakthrough SARS-CoV-2 infection (BTI) in vaccinated people results in post-acute sequelae is not clear. In this study, we used the US Department of Veterans Affairs national healthcare databases to build a cohort of 33,940 individuals with BTI and several controls of people without evidence of SARS-CoV-2 infection, including contemporary (n = 4,983,491), historical (n = 5,785,273) and vaccinated (n = 2,566,369) controls. At 6 months after infection, we show that, beyond the first 30 days of illness, compared to contemporary controls, people with BTI exhibited a higher risk of death (hazard ratio (HR) = 1.75, 95% confidence interval (CI): 1.59, 1.93) and incident post-acute sequelae (HR = 1.50, 95% CI: 1.46, 1.54), including cardiovascular, coagulation and hematologic, gastrointestinal, kidney, mental health, metabolic, musculoskeletal and neurologic disorders. The results were consistent in comparisons versus the historical and vaccinated controls. Compared to people with SARS-CoV-2 infection who were not previously vaccinated (n = 113,474), people with BTI exhibited lower risks of death (HR = 0.66, 95% CI: 0.58, 0.74) and incident post-acute sequelae (HR = 0.85, 95% CI: 0.82, 0.89). Altogether, the findings suggest that vaccination before infection confers only partial protection in the post-acute phase of the disease; hence, reliance on it as a sole mitigation strategy may not optimally reduce long-term health consequences of SARS-CoV-2 infection. The findings emphasize the need for continued optimization of strategies for primary prevention of BTI and will guide development of post-acute care pathways for people with BTI. We examined the risk of death and post-acute sequelae in those with BTI versus several controls of people without evidence of SARS-CoV-2 infection, including (1) a contemporary control of people exposed to the same broader forces of the pandemic (lockdowns and economic, social and environmental stressors); (2) a historical control from a pre-pandemic era that represents a baseline unaffected by the disruptions of the pandemic; and (3) a vaccinated control group. The results show two key findings: (1) Long COVID, including increased risks of death and myriad post-acute sequelae in the pulmonary and extrapulmonary organ systems, also manifests in vaccinated individuals who experience a BTI; and (2) the range of post-acute sequelae in various organ systems in BTI does not appear to be different than COVID-19 without prior vaccination. Our analyses of BTI versus SARS-CoV-2 infection without prior vaccination show that, comparatively, the magnitude of the risks of death and post-acute sequelae was lower in people with BTI versus those with SARS-CoV-2 infection who had not been previously vaccinated for it. These results show that, although vaccination may partially reduce the risks of post-acute death and disease, to most optimally reduce this burden requires continued emphasis on primary prevention of breakthrough SARS-CoV-2 infection as a goal of public health policy. Although the absolute rates are smaller than in those with SARS-CoV-2 infection without prior vaccination, given the scale of the pandemic and the potential for breakthrough cases to continue to accumulate, the overall burden of death and disease after BTI will likely be substantial, will further add to the toll of this pandemic and will represent an additional strain on already overwhelmed health systems. In planning and development of health resources, governments and health systems should take into account the care needs of people with post-acute sequelae after BTI. Our analyses suggest that this risk reduction (of post-acute sequelae) was most pronounced in recipients of BNT162b2 and mRNA-1273 vaccines (compared to Ad26.COV2.S). Although these results recapitulate evidence of vaccine effectiveness in the acute phase of COVID-19, the mechanism or mechanisms underlying this carry-through effect of risk reduction from the acute to the post-acute phase of the disease is not entirely clear. One putative interpretation of these results is that vaccine-induced reduction in severity of the acute infection may then translate into less long-term risk of post-acute health outcomes. In other analyses, we also show that the reduced risk of post-acute sequelae in people with BTIs was partially eroded in people with immunocompromised status, suggesting a putative immune-related mechanism in the expression of post-acute sequelae that may be influenced by vaccination. We also show that the risk of post-acute sequelae is higher in people with BTI than in people with seasonal influenza—a well-characterized respiratory viral illness. This extends previous evidence showing that the risk of post-acute sequelae in people with SARS-CoV-2 infection was higher than those with seasonal influenza and again emphasizes the importance of prevention of both SARS-CoV-2 infection and BTI1.
164	I162		Katherine M. Littlefield, Renée O. Watson, Jennifer M. Schneider, Charles P. Neff, Eiko Yamada, Min Zhang, Thomas B. Campbell, Michael T. Falta, Sarah E. Jolley, Andrew P. Fontenot, Brent E. Palmer	SARS-CoV-2-specific T cells associate with inflammation and reduced lung function in pulmonary post-acute sequalae of SARS-CoV-2	https://doi.org/10.1371/journal.ppat.1010359	Published	May 26, 2022	Article	https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1010359	As of January 2022, at least 60 million individuals are estimated to develop post-acute sequelae of SARS-CoV-2 (PASC) after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While elevated levels of SARS-CoV-2-specific T cells have been observed in non-specific PASC, little is known about their impact on pulmonary function which is compromised in the majority of these individuals. This study compares frequencies of SARS-CoV-2-specific T cells and inflammatory markers with lung function in participants with pulmonary PASC and resolved COVID-19 (RC). Compared to RC, participants with respiratory PASC had between 6- and 105-fold higher frequencies of IFN-γ- and TNF-α-producing SARS-CoV-2-specific CD4+ and CD8+ T cells in peripheral blood, and elevated levels of plasma CRP and IL-6. Importantly, in PASC participants the frequency of TNF-α-producing SARS-CoV-2-specific CD4+ and CD8+ T cells, which exhibited the highest levels of Ki67 indicating they were activity dividing, correlated positively with plasma IL-6 and negatively with measures of lung function, including forced expiratory volume in one second (FEV1), while increased frequencies of IFN-γ-producing SARS-CoV-2-specific T cells associated with prolonged dyspnea. Statistical analyses stratified by age, number of comorbidities and hospitalization status demonstrated that none of these factors affect differences in the frequency of SARS-CoV-2 T cells and plasma IL-6 levels measured between PASC and RC cohorts. Taken together, these findings demonstrate elevated frequencies of SARS-CoV-2-specific T cells in individuals with pulmonary PASC are associated with increased systemic inflammation and decreased lung function, suggesting that SARS-CoV-2-specific T cells contribute to lingering pulmonary symptoms. These findings also provide mechanistic insight on the pathophysiology of PASC that can inform development of potential treatments to reduce symptom burden.
165	I163		Krista L.Newell1Adam T.Waickman121	Inflammation, immunity, and antigen persistence in post-acute sequelae of SARS-CoV-2 infection	https://doi.org/10.1016/j.coi.2022.102228	Published	24 May 2022	Review	https://www.sciencedirect.com/science/article/pii/S0952791522000759	Highlights •PASC impacts 7-10% of convalescent COVID-19 patients. •PASC is associated with persistent inflammation after acute SARS-CoV-2 infection. •The antigens or other immune stimuli driving PASC are still unclear. •PASC severity and duration is reduced by SARS-CoV-2 vaccination. SARS-CoV-2 infection is known to result in a range of symptoms with varying degrees of acute phase severity. In a subset of individuals an equally diverse collection of long-term sequelae has been reported after convalescence. As survivorship and therefore the number of individuals with “long-COVID” continues to grow, an understanding of the prevalence, origins, and mechanisms of post-acute sequelae manifestation is critically needed. Here, we will explore proposed roles of the anti-SARS-CoV-2 immune response in the onset, severity, and persistence of SARS-CoV-2 post-acute sequelae. We discuss the potential roles of persistent virus and autoantigens in this syndrome, as well as the contributions of unresolved inflammation and tissue injury. Furthermore, we highlight recent evidence demonstrating the potential benefits of vaccination and immunity in the resolution of post-acute symptoms.
166	I164		Sreus A.G. NaiduORCID Icon,Roger A. ClemensORCID Icon &A. Satyanarayan NaiduORCID Icon	SARS-CoV-2 Infection Dysregulates Host Iron (Fe)-Redox Homeostasis (Fe-R-H): Role of Fe-Redox Regulators, Ferroptosis Inhibitors, Anticoagulants, and Iron-Chelators in COVID-19 Control	https://doi.org/10.1080/19390211.2022.2075072	Published	22 May 2022	Review	https://www.tandfonline.com/doi/abs/10.1080/19390211.2022.2075072	Severe imbalance in iron metabolism among SARS-CoV-2 infected patients is prominent in every symptomatic (mild, moderate to severe) clinical phase of COVID-19. Phase-I – Hypoxia correlates with reduced O2 transport by erythrocytes, overexpression of HIF-1α, altered mitochondrial bioenergetics with host metabolic reprogramming (HMR). Phase-II – Hyperferritinemia results from an increased iron overload, which triggers a fulminant proinflammatory response – the acute cytokine release syndrome (CRS). Elevated cytokine levels (i.e. IL6, TNFα and CRP) strongly correlates with altered ferritin/TF ratios in COVID-19 patients. Phase-III – Thromboembolism is consequential to erythrocyte dysfunction with heme release, increased prothrombin time and elevated D-dimers, cumulatively linked to severe coagulopathies with life-threatening outcomes such as ARDS, and multi-organ failure. Taken together, Fe-R-H dysregulation is implicated in every symptomatic phase of COVID-19. Fe-R-H regulators such as lactoferrin (LF), hemoxygenase-1 (HO-1), erythropoietin (EPO) and hepcidin modulators are innate bio-replenishments that sequester iron, neutralize iron-mediated free radicals, reduce oxidative stress, and improve host defense by optimizing iron metabolism. Due to its pivotal role in ‘cytokine storm’, ferroptosis is a potential intervention target. Ferroptosis inhibitors such as ferrostatin-1, liproxstatin-1, quercetin, and melatonin could prevent mitochondrial lipid peroxidation, up-regulate antioxidant/GSH levels and abrogate iron overload-induced apoptosis through activation of Nrf2 and HO-1 signaling pathways. Iron chelators such as heparin, deferoxamine, caffeic acid, curcumin, α-lipoic acid, and phytic acid could protect against ferroptosis and restore mitochondrial function, iron-redox potential, and rebalance Fe-R-H status. Therefore, Fe-R-H restoration is a host biomarker-driven potential combat strategy for an effective clinical and post-recovery management of COVID-19.
167	I165		Zion Congrave-Wilson 1,†ORCID,Wesley A. Cheng 1,†ORCID,Yesun Lee 1,Stephanie Perez 1,Lauren Turner 1,Carolyn Jennifer Marentes Ruiz 1,Shirley Mendieta 1ORCID,Adam Skura 1ORCID,Jaycee Jumarang 1ORCID,Jennifer Del Valle 1ORCID,John Kubale 2ORCID,Emma Kaitlynn Allen 3ORCID,Paul G. Thomas 3ORCID,Aubree Gordon 2ORCID andPia S. Pannaraj 1,4,*	Twelve-Month Longitudinal Serology in SARS-CoV-2 Naïve and Experienced Vaccine Recipients and Unvaccinated COVID-19-Infected Individuals	https://doi.org/10.3390/vaccines10050813	Published	20 May 2022	Study	https://www.mdpi.com/2076-393X/10/5/813/htm	Longitudinal data comparing SARS-CoV-2 serology in individuals following infection and vaccination over 12 months are limited. This study compared the magnitude, decay, and variability in serum IgG, IgA, and neutralizing activity induced by natural infection (n = 218) or mRNA vaccination in SARS-CoV-2 naïve (n = 143) or experienced (n = 122) individuals over time using enzyme-linked immunosorbent assays and an in vitro virus neutralization assay. Serological responses were found to be highly variable after natural infection compared with vaccination but durable through 12 months. Antibody levels in vaccinated, SARS-CoV-2 naïve individuals peaked by 1 month then declined through 9 months, culminating in non-detectable SARS-CoV-2-specific serum IgA. Individuals with both infection and vaccination showed SARS-CoV-2-specific IgG and IgA levels that were more robust and slower to decline than the other groups; neutralizing activity remained highest in this group at 9 months past vaccination. These data reinforce the benefit of vaccination after SARS-CoV-2 recovery.
168	I166		Dominique GRANDJEAN,Caroline ELIE,Capucine GALLET,Clotilde JULIEN,Vinciane ROGER,Loïc DESQUILBET,Guillaume ALVERGNAT,Séverine DELARUE,Audrey GABASSI,Marine MINIER,Laure CHOUPEAUX,Solen KERNEIS,Constance DELAUGERRE,Jérôme LE GOFF,Jean-Marc TRELUYER	Diagnostic accuracy of non-invasive detection of SARS-CoV-2 infection by canine olfaction	https://doi.org/10.1371/journal.pone.0268382	Published	June 1, 2022	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0268382	Background Throughout the COVID-19 pandemic, testing individuals remains a key action. One approach to rapid testing is to consider the olfactory capacities of trained detection dogs. Methods Prospective cohort study in two community COVID-19 screening centers. Two nasopharyngeal swabs (NPS), one saliva and one sweat samples were simultaneously collected. The dog handlers (and the dogs…) were blinded with regards to the Covid status. The diagnostic accuracy of non-invasive detection of SARS-CoV-2 infection by canine olfaction was assessed as compared to nasopharyngeal RT-PCR as the reference standard, saliva RT-PCR and nasopharyngeal antigen testing. Results 335 ambulatory adults (143 symptomatic and 192 asymptomatic) were included. Overall, 109/335 participants tested positive on nasopharyngeal RT-PCR either in symptomatic (78/143) or in asymptomatic participants (31/192). The overall sensitivity of canine detection was 97% (95% CI, 92 to 99) and even reached 100% (95% CI, 89 to 100) in asymptomatic individuals compared to NPS RT-PCR. The specificity was 91% (95% CI, 72 to 91), reaching 94% (95% CI, 90 to 97) for asymptomatic individuals. The sensitivity of canine detection was higher than that of nasopharyngeal antigen testing (97% CI: 91 to 99 versus 84% CI: 74 to 90, p = 0.006), but the specificity was lower (90% CI: 84 to 95 versus 97% CI: 93 to 99, p = 0.016). Conclusions Non-invasive detection of SARS-CoV-2 infection by canine olfaction could be one alternative to NPS RT-PCR when it is necessary to obtain a result very quickly according to the same indications as antigenic tests in the context of mass screening.
169	I167		Rita Rubin	From Positive to Negative to Positive Again—The Mystery of Why COVID-19 Rebounds in Some Patients Who Take Paxlovid	https://doi.org/10.1001/jama.2022.9925	Published	June 8, 2022	Article	https://jamanetwork.com/journals/jama/fullarticle/2793357	Ho likely is one of very few people who’ve relapsed after taking nirmatrelvir/ritonavir and then sequenced their own virus both the first and second time around. (At least 1 other leading virologist, Peter Hotez, MD, PhD, of the Baylor College of Medicine, has revealed that he also experienced a post-Paxlovid relapse.) Both of Ho’s sequences were identical, ruling out a couple of possible explanations for his relapse, he said. It couldn’t have been due to a stroke of bad luck—a second SARS-CoV-2 infection just as he was getting over his first one. And it couldn’t have resulted from the virus becoming resistant to nirmatrelvir. If either were the case, the virus pair wouldn’t have been identical. Scientists have proposed a few other possible explanations for rebounds after nirmatrelvir/ritonavir treatment. “Question number 1 in my mind is the timing. I think maybe we’re giving it too early,” del Rio said. Perhaps, Wachter speculated, “If you get started right away, maybe you suppress the virus [and] the immune system doesn’t rev up in the way it normally would.” He and others have also suggested that 5 days might not be a long enough treatment course. “All these theories are total handwaving,” Wachter acknowledged. To answer the outstanding questions about relapses, “I’m not sure we need a clinical trial in the classical definition,” del Rio said. “We need post-approval data.” It’s being collected, he said, but the findings probably won’t be available for months. For now, there is no evidence that additional treatment with nirmatrelvir/ritonavir is needed when a rebound is suspected after a 5-day course, according to both the CDC’s advisory and FDA official Farley’s recent update. Despite all the questions about the rebound phenomenon, “the biggest challenge we’re having with the drug is it’s not being used as frequently as it should,” del Rio said. “Primary care physicians are freaked out about the drug-drug interactions.” The people in whom COVID-19 is most likely to progress to a serious or even deadly infection are also the ones most likely to be taking multiple medications, he noted. One thing is for sure, testing is more important than ever, given the availability of effective treatments for COVID-19, Cohen said. “I see a sea change in the management of respiratory infections.” Nobody says, “Oh, I think I have a cold” anymore, he explained. “If we’re going to treat people with COVID, we need to know if they have COVID.”
170	I168		Alexandra Flemming	Vaccines only partially protect against Long COVID	https://doi.org/10.1038/s41577-022-00749-6	Published	10 June 2022	Article	https://www.nature.com/articles/s41577-022-00749-6	COVID-19 vaccines have proven very successful in protecting against severe disease. However, they only provide partial protection against infection, and an increasing number of individuals suffer breakthrough infections (BTIs) after vaccination. Al-Aly and colleagues investigated the vast US department of Veterans Affairs national health-care database to determine the level of protection vaccines provide against post-acute COVID-19 sequelae (‘Long COVID’). They found that individuals with BTIs, compared with unvaccinated individuals, had a lower risk of death and Long COVID between of 1–6 months post-infection, particularly when comparing patients who had been hospitalized with COVID-19. However, the overall protection of the vaccine from Long COVID was only ~15%, which means that the burden of Long COVID is likely to be substantial even in fully vaccinated populations. Therefore, vaccination alone may not be enough to mitigate the long-term health consequences of SARS-CoV-2 infection.
171	I169		Juan-Manuel Anaya,María Herrán,Santiago Beltrán &Manuel Rojas	Is post-COVID syndrome an autoimmune disease?	https://doi.org/10.1080/1744666X.2022.2085561	Published	14 Jun 2022	Perspective	https://www.tandfonline.com/doi/abs/10.1080/1744666X.2022.2085561	Article highlights - Post-COVID syndrome (PCS) is a heterogeneous condition characterized by persistent inflammation and autoimmunity. - PCS shares similarities with other post-infectious conditions but may last longer (> 6 months). - The overlap between post-care syndromes and PCS may hinder differential diagnosis while suggesting clinical subphenotypes of PCS. - In addition to an autoimmune-mediated mechanism, endotheliopathy, coagulopathy, autonomic, endocrine, neurological dysfunction, and viral persistence may contribute to PCS. - Based on population data and new health and social care frameworks, personalized medicine should be considered to deal with PCS. Post-COVID syndrome (PCS) is recognized as a new entity in the context of SARS-CoV-2 infection. Though its pathogenesis is not completely understood, persistent inflammation from acute illness and the development of autoimmunity play a critical role in its development. Areas covered The mechanisms involved in the emergence of PCS, their similarities with post-viral and post-care syndromes, its inclusion in the spectrum of autoimmunity and possible targets for its treatment. Expert opinion An autoimmune phenomenon plays a major role in most causative theories explaining PCS. There is a need for both PCS definition and classification criteria (including severity scores). Longitudinal and controlled studies are necessary to better understand this new entity, and to find what additional factors participate into its development. With the high prevalence of COVID-19 cases worldwide, together with the current evidence on latent autoimmunity in PCS, we may observe an increase of autoimmune diseases (ADs) in the coming years. Vaccination’s effect on the development of PCS and ADs will also receive attention in the future. Health and social care services need to develop a new framework to deal with PCS.
172	I170		Raffaele Pagliuca, Maria Grazia Cupido, Giacomo Mantovani, Maura Bugada, Giulia Matteucci, Arturo Caffarelli, Federico Bellotti, Raffaella Cocchieri, Antonio Dentale, Federica Lozzi, Paola Malagoli, Pasquale Morabito, Gianluca Serra & Candida Andreati	Absence of negativization of nasal swab test and frailty as risk factors for mortality in elderly COVID-19 patients admitted in long-term care facilities	https://doi.org/10.1007/s41999-022-00657-x	Published	04 June 2022	Study	https://link.springer.com/article/10.1007/s41999-022-00657-x	Aim: Focus of prognostic factors in elderly covid19 patients admitted in long term unit. Findings: Nasal swab test at discharge, infection, age and frailty represented risk factors associated with increased mortality. Message: Absence of negativization of nasal swab test is the major risk factor for mortality. Methods A limited amount of data is now available on prognostic factors and mortality among elderly people resident in Long-Term Care facilities and in post-acute units. These populations (in particular those with underlying chronic medical conditions) seem to have higher risk of morbidity and mortality related to COVID-19 disease, but further evidence is needed. The aim of our study is to investigate the impact of some well-known prognostic factors in elderly patients (≥ 65 years) with COVID-19 admitted in the Long-Term Care setting in AUSL Ferrara, Italy. We performed binary regression logistic analysis for some variables (demographic data, clinical data including nasal swab test (NST) at discharge and frailty assessments) to find potential predictors of mortality. We subsequently tested statistically significant variables using Kaplan–Meier curves and Cox-regression models to find survival outcomes and related hazard ratio. Results Risk factors associated with increased mortality resulted NST at discharge, infection, age and frailty. At a further secondary analysis carried out between NST at discharge, age and clinical frailty scale (CFS) < 5, we found a positive correlation between NST at discharge and CFS < 5. Kaplan–Meier curves showed a statistically significant difference regarding frailty and NST at discharge but not for age. Conclusion Our study showed that absence of negativization of NST at discharge and frailty are strong predictors for mortality in elderly COVID-19 patients admitted in Long-Term Care facilities, while age and the comorbidity burden are less important.
173	I171		Svitlana Zubchenko, Iryna Kril, Olena Nadizhko, Oksana Matsyura & Valentyna Chopyak	Herpesvirus infections and post-COVID-19 manifestations: a pilot observational study	https://doi.org/10.1007/s00296-022-05146-9	Published	01 June 2022	Study	https://link.springer.com/article/10.1007/s00296-022-05146-9	The global spread of SARS-CoV-2 points to unrivaled mutational variation of the virus, contributing to a variety of post-COVID sequelae in immunocompromised subjects and high mortality. Numerous studies have reported the reactivation of "sluggish" herpes virus infections in COVID-19, which exaggerate the course of the disease and complicate with lasting post-COVID manifestations CMV, EBV, HHV6). This study aimed to describe clinical and laboratory features of post-COVID manifestations accompanied by the reactivation of herpes virus infections (CMV, EBV, HHV6). 88 patients were recruited for this study, including subjects with reactivation of herpes viruses, 68 (72.3%) (main group) and 20 (27.7%) subjects without detectable DNA of herpesviruses (control group): 46 (52.3%) female and 42 (47.7%) male; median age was 41.4 ± 6.7 years. Patients with post-COVID manifestations presented with reactivation of EBV in 42.6%, HHV6 in 25.0%, and EBV plus HHV6 in 32.4%. Compared with controls, patients with herpes virus infections presented with more frequent slight fever temperature, headache, psycho-neurological disorders, pulmonary abnormalities and myalgia (p < 0.01), activation of liver enzymes, elevated CRP and D-dimer, and suppressed cellular immune response (p ≤ 0.05). Preliminary results indicate a likely involvement of reactivated herpes virus infections, primarily EBV infections in severe COVID-19 and the formation of the post-COVID syndrome. Patients with the post-COVID syndrome and reactivation of EBV and HHV6 infections are at high risk of developing various pathologies, including rheumatologic diseases.
174	I172		Nadia M. Hamdy, Fatma H. Shaker, Xianquan Zhan & Emad B. Basalious	Tangled quest of post-COVID-19 infection-caused neuropathology and what 3P nano-bio-medicine can solve?	https://doi.org/10.1007/s13167-022-00285-2	Published	02 June 2022	Review	https://link.springer.com/article/10.1007/s13167-022-00285-2	COVID-19-caused neurological problems are the important post-CoV-2 infection complications, which are recorded in ~ 40% of critically ill COVID-19 patients. Neurodegeneration (ND) is one of the most serious complications. It is necessary to understand its molecular mechanism(s), define research gaps to direct research to, hopefully, design new treatment modalities, for predictive diagnosis, patient stratification, targeted prevention, prognostic assessment, and personalized medical services for this type of complication. Individualized nano-bio-medicine combines nano-medicine (NM) with clinical and molecular biomarkers based on omics data to improve during- and post-illness management or post-infection prognosis, in addition to personalized dosage profiling and drug selection for maximum treatment efficacy, safety with least side-effects. This review will enumerate proteins, receptors, and enzymes involved in CoV-2 entrance into the central nervous system (CNS) via the blood–brain barrier (BBB), and list the repercussions after that entry, ranging from neuroinflammation to neurological symptoms disruption mechanism. Moreover, molecular mechanisms that mediate the host effect or viral detrimental effect on the host are discussed here, including autophagy, non-coding RNAs, inflammasome, and other molecular mechanisms of CoV-2 infection neuro-affection that are defined here as hallmarks of neuropathology related to COVID-19 infection. Thus, a couple of questions are raised; for example, “What are the hallmarks of neurodegeneration during COVID-19 infection?” and “Are epigenetics promising solution against post-COVID-19 neurodegeneration?” In addition, nano-formulas might be a better novel treatment for COVID-19 neurological complications, which raises one more question, “What are the challenges of nano-bio-based nanocarriers pre- or post-COVID-19 infection?” especially in the light of omics-based changes/challenges, research, and clinical practice in the framework of predictive preventive personalized medicine (PPPM / 3P medicine).
175	I173		Noha Sharafeldin, Vithal Madhira, Qianqian Song, Benjamin Bates, Amit Kumar Mitra, Feifan Liu, Timothy Bergquist, Jing Su, Fang-Chi Hsu, Umit Topaloglu	Long COVID-19 in patients with cancer: Report from the National COVID Cohort Collaborative (N3C).	https://doi.org/10.1200/JCO.2022.40.16_suppl.1540	Published	June 02, 2022	Study	https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.1540	Background: Post-acute sequelae of SARS-CoV-2 or long COVID, is characterized by persistence of symptoms and/or emergence of new symptoms post COVID-19 infection. As evidence accumulates and national initiatives arise to address this increasingly prevalent syndrome, characterization of specific patient groups is still lacking including patients with cancer. Using a nationally representative sample of over 4.3M COVID-19 patients from the National COVID Cohort Collaborative (N3C), we aim to describe characteristics of patients with cancer and long COVID. Methods: We employed two approaches to identify long COVID patients within N3C: i) patients presenting to a long COVID clinic at four N3C sites and ii) patients diagnosed using the recently introduced ICD-10 code: U09.9 Post COVID-19 condition, unspecified. We included patients with at least one positive COVID-19 diagnosis between 1/1/2020 and 2/3/2022. Patients had to survive at least 90 days from the date of their COVID-19 diagnosis. Analyses were performed in the N3C Data Enclave on the Palantir platform. Results: A total of 1700 adult patients with long COVID were identified from the N3C cohort; 634 (37.3%) were cancer patients and 1066 were non-cancer controls. The most common represented cancers were skin (21.9%), breast (17.7%), prostate (8.3%), lymphoma (8.0%) and leukemia (5.7%). Median age of long-COVID cancer patients was 64 years (Interquartile Range: 54-72), 48.6% were 65 years or older, 60.4% females, 76.8% non-Hispanic White, 12.3% were Black, and 3% Hispanic. A total of 41.1% were current or former smokers, 27.7% had an adjusted Charlson Comorbidity Index score of 0, 18.6% score of 1 and 11.2% score of 2. A total of 57.2% were hospitalized for their initial COVID-19 infection, the average length of stay in the hospital was 9.6 days (SD: 16.7 days), 9.1% required invasive ventilation, and 13% had acute kidney injury during hospitalization. The most common diagnosis among the non-cancer long COVID patients was asthma (26%), diabetes (17%), chronic kidney disease (12%), heart failure (9.4%), and chronic obstructive pulmonary disease (7.8%). Among long COVID patients, compared to non-cancer controls, cancer patients were more likely to be older (OR = 2.4, 95%CI: 1.1-5.4, p = 0.03), have comorbidities (OR = 4.3, 95%CI: 2.9-6.2, p < 0.0001), and to be hospitalized for COVID-19 (OR = 1.3, 95%CI: 1.0-1.7, p = 0.05), adjusting for sex, race/ethnicity, body mass index and smoking history. Conclusions: In a nationally representative sample of long COVID patients, there was a relative overrepresentation of patients with cancer. Compared to non-cancer controls, cancer patients were older, more likely to have more comorbidities and to be hospitalized for COVID-19 warranting further investigation to identify risk factors for long COVID in patients with cancer.
176	I174		Viola Popov, Mihaela Andreescu, Catalina Pirvu, Andra Grigorie, Oana Constantin, Andreea Calen, Mihaela Dana Badoiu Niculae, Adriana Badea, Ana Rus, Lelia Iliescu	The importance of the long Covid-19 in the evolution of patients with neoplasms.	https://doi.org/10.1200/JCO.2022.40.16_suppl.e18647		June 02, 2022		https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.e18647	Background: Patients with comorbidities especially those with oncological diseases could have severe COVID-19 outcomes. OBJECTIVE: The aim of this study was to evaluate the role of prolonged positivity of SARS-Cov2 in evolution of patients with various neoplasia. Methods: We analysed clinical and laboratory (hematological parameters and inflammatory markers: interleukin-6 and ferritin) data of COVID-19 patients admitted in intensive care unit (ICU) Department of our hospital, during 2020-2021 and presented in medical history solid tumors or haematological neoplasia . The cohort of patients included 78 patients with severe and critical form of COVID-19, 31 patients with solid tumors and 47 patients with hematologic malignancies. We consider long COVID-19 all cases with SARS Cov2 positivity more than 14 days. Results: The frequency of long COVID-19 was quite equal between patients groups with solid tumors and hematologic malignancies, incidence rate 1:2, the incidence rate differences was 1:18, p = 0.75. Long COVID-19 was observed in 60% cases with favourable evolution, Chi-squared 5.35%, p = 0.02, these patients had moderate form and was admitted in hospital in 1 or more days after the onset, median value 3 (min 1, max 55) compared with patients with normal duration of positivity of SARS-Cov2 test- median value 2 (min 1, max 8), p = 0.01. The Kaplan Meyer survival analyses indicated long COVID-19 as predictive factor for unfavourable evolution, Chi-squared 17.97, p < 0.0001. Although we have not obtain significant differences, we observed more severe lymphopenia in patient without long COVID-19, probably because a part of these patients group died in the first 14 days of COVID-19 (0.765 (min 0.04, max 297.64) vs. 1.01 (min 0.09, max 254.35), p = 0.09). The rest of hematological and biochemistry parameters was not significant different between groups. Infectious and thrombotic complication was most frequent in patients with long COVID-19, Chi squared 8.6, p = 0.003. Conclusions: Long Covid-19 is predictable for unfavourable evolution and is associated with sepsis and thrombotic complication. This diagnosis is frequent in patients who was admitted in hospital after the onset of COVID-19 symptoms, early treatment of COVID-19 in oncological patients being very important for favourable evolution.
177	I175		Guang-Ying Cui, Ben-Chen Rao, Zhao-Hai Zeng, Xue-Mei Wang, Tong Ren, Hai-Yu Wang, Hong Luo, Hong-Yan Ren, Chao Liu, Su-Ying Ding, Jun-Jie Tan, Zhen-Guo Liu, Ya-Wen Zou, Zhi-Gang Ren & Zu-Jiang Yu	Characterization of oral and gut microbiome and plasma metabolomics in COVID-19 patients after 1-year follow-up	https://doi.org/10.1186/s40779-022-00387-y	Published	17 June 2022	Study	https://link.springer.com/article/10.1186/s40779-022-00387-y	Background Due to the outbreak and rapid spread of coronavirus disease 2019 (COVID-19), more than 160 million patients have become convalescents worldwide to date. Significant alterations have occurred in the gut and oral microbiome and metabonomics of patients with COVID-19. However, it is unknown whether their characteristics return to normal after the 1-year recovery. Methods We recruited 35 confirmed patients to provide specimens at discharge and one year later, as well as 160 healthy controls. A total of 497 samples were prospectively collected, including 219 tongue-coating, 129 stool and 149 plasma samples. Tongue-coating and stool samples were subjected to 16S rRNA sequencing, and plasma samples were subjected to untargeted metabolomics testing. Results The oral and gut microbiome and metabolomics characteristics of the 1-year convalescents were restored to a large extent but did not completely return to normal. In the recovery process, the microbial diversity gradually increased. Butyric acid-producing microbes and Bifidobacterium gradually increased, whereas lipopolysaccharide-producing microbes gradually decreased. In addition, sphingosine-1-phosphate, which is closely related to the inflammatory factor storm of COVID-19, increased significantly during the recovery process. Moreover, the predictive models established based on the microbiome and metabolites of patients at the time of discharge reached high efficacy in predicting their neutralizing antibody levels one year later. Conclusions This study is the first to characterize the oral and gut microbiome and metabonomics in 1-year convalescents of COVID-19. The key microbiome and metabolites in the process of recovery were identified, and provided new treatment ideas for accelerating recovery. And the predictive models based on the microbiome and metabolomics afford new insights for predicting the recovery situation which benefited affected individuals and healthcare.
178	I176		Abhishek Thakur, Gaurav Sharma, Vishnu Nayak Badavath, Venkatesan Jayaprakash, Kenneth M. Merz Jr., Galia Blum, and Orlando Acevedo	Primer for Designing Main Protease (Mpro) Inhibitors of SARS-CoV-2	https://doi.org/10.1021/acs.jpclett.2c01193	Published	June 21, 2022	Study	https://pubs.acs.org/doi/10.1021/acs.jpclett.2c01193	The COVID-19 outbreak has been devastating, with hundreds of millions of infections and millions of deaths reported worldwide. In response, the application of structure–activity relationships (SAR) upon experimentally validated inhibitors of SARS-CoV-2 main protease (Mpro) may provide an avenue for the identification of new lead compounds active against COVID-19. Upon the basis of information gleaned from a combination of reported crystal structures and the docking of experimentally validated inhibitors, four “rules” for designing potent Mpro inhibitors have been proposed. The aim here is to guide medicinal chemists toward the most probable hits and to provide guidance on repurposing available structures as Mpro inhibitors. Experimental examination of our own previously reported inhibitors using the four “rules” identified a potential lead compound, the cathepsin inhibitor GB111-NH2, that was 2.3 times more potent than SARS-CoV-2 Mpro inhibitor N3.
179	I177		Sandra Ekstedt, Krzysztof Piersiala, Marianne Petro, Agneta Karlsson, Åsa Kågedal, Susanna Kumlien Georén & Lars Olaf Cardell Sandra Ekstedt, Krzysztof Piersiala, Marianne Petro, Agneta Karlsson, Åsa Kågedal, Susanna Kumlien Georén & Lars Olaf Cardell	A prolonged innate systemic immune response in COVID-19	https://doi.org/10.1038/s41598-022-13986-5	Published	15 June 2022	Article	https://www.nature.com/articles/s41598-022-13986-5	Despite the introduction of vaccines, COVID-19 still affects millions of people worldwide. A better understanding of pathophysiology and the discovery of novel therapies are needed. One of the cells of interest in COVID-19 is the neutrophil. This cell type is being recruited to a site of inflammation as one of the first immune cells. In this project, we investigated a variety of neutrophils phenotypes during COVID-19 by measuring the expression of markers for migration, maturity, activation, gelatinase granules and secondary granules using flow cytometry. We show that neutrophils during COVID-19 exhibit altered phenotypes compared to healthy individuals. The activation level including NETs production and maturity of neutrophils seem to last longer during COVID-19 than expected for innate immunity. Neutrophils as one of the drivers of severe cases of COVID-19 are considered as potential treatment targets. However, for a successful implementation of treatment, there is a need for a better understanding of neutrophil functions and phenotypes in COVID-19. Our study answers some of those questions.
180	I178		Jacqui Wise	Covid-19: Long covid risk is lower with omicron than delta, researchers find	https://doi.org/10.1136/bmj.o1500	Published	17 June 2022	Article	https://www.bmj.com/content/377/bmj.o1500	The risk of developing long covid is lower among people with the omicron variant of SARS-CoV-2 than with delta, shows an analysis of self reported data to the UK ZOE covid app.1 Researchers from King’s College London looked at data logged by 56 003 adults who tested positive between 20 December 2021 and 9 March 2022, when the omicron variant was dominant. They compared these with 41 361 who tested positive between 1 June 2021 and 27 November 2021, when the delta variant was most common. Among the cases in the omicron period, 2501 people (4.5%) reported they had experienced long covid, defined as having new or ongoing symptoms four weeks or more after they had tested positive. This compared with 4469 (10.8%) of people in the delta period, according to the analysis, published as a letter in the Lancet. Overall the study found a reduction in odds of long covid with the omicron variant versus the delta variant of between 0.24 and 0.5, depending on age and time since vaccination. But because far more people have been infected during the omicron wave than during the delta wave, the total number with long covid will be higher. Earlier this month the Office for National Statistics estimated that the number of people experiencing long covid increased from 1.3 million in January 2022 to two million on 1 May 2022.23 Lead researcher Claire Steves said, “The omicron variant appears substantially less likely to cause long covid than previous variants—but still, one out of every 23 people who catches covid-19 goes on to have symptoms for more than four weeks. “Given the numbers of people affected, it’s important that we continue to support them at work, at home, and within the NHS.” Slightly more women than men log onto the ZOE app, and fewer people from the most deprived areas, so the samples are not fully generalisable to the UK population. But the researchers said the samples were similar in both study periods, allowing comparison. The researchers said the strength of the study was the prospective logging of a wide range of symptoms. Limitations included no direct resting of infectious variants and no objective measures of illness duration. There were also insufficient data to estimate the odds of long covid in unvaccinated people, and the study did not estimate effects in children.
181	I179		Zoe Swank, View ORCID ProfileYasmeen Senussi, Galit Alter, View ORCID ProfileDavid R. Walt	Persistent circulating SARS-CoV-2 spike is associated with post-acute COVID-19 sequelae	https://doi.org/10.1101/2022.06.14.22276401	pre-print	June 16, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.06.14.22276401v1.full-text	The diagnosis and management of post-acute sequelae of COVID-19 (PASC) poses an ongoing medical challenge. Identifying biomarkers associated with PASC would immensely improve the classification of PASC patients and provide the means to evaluate treatment strategies. We analyzed plasma samples collected from a cohort of PASC and COVID-19 patients (n = 63) to quantify circulating viral antigens and inflammatory markers. Strikingly, we detect SARS-CoV-2 spike antigen in a majority of PASC patients up to 12 months post-diagnosis, suggesting the presence of an active persistent SARS-CoV-2 viral reservoir. Furthermore, temporal antigen profiles for many patients show the presence of spike at multiple time points over several months, highlighting the potential utility of the SARS-CoV-2 full spike protein as a biomarker for PASC.
182	I180		Benjamin A. Krishna Eleanor Y. Lim Lenette Mactavous NIHR BioResource Team Paul A. Lyons Rainer Doffinger John R. Bradley Kenneth G.C. Smith John Sinclair Nicholas J. Matheson Paul J. Lehner Mark R. Wills Nyaradzai Sithole	Evidence of previous SARS-CoV-2 infection in seronegative patients with long COVID	https://doi.org/10.1016/j.ebiom.2022.104129	Published	June 27, 2022	Study	https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00310-3/fulltext	Background There is currently no consensus on the diagnosis, definition, symptoms, or duration of COVID-19 illness. The diagnostic complexity of Long COVID is compounded in many patients who were or might have been infected with SARS-CoV-2 but not tested during the acute illness and/or are SARS-CoV-2 antibody negative. Methods Given the diagnostic conundrum of Long COVID, we set out to investigate SARS-CoV-2-specific T cell responses in patients with confirmed SARS-CoV-2 infection and/or Long COVID from a cohort of mostly non-hospitalised patients. Findings We discovered that IL-2 release (but not IFN-γ release) from T cells in response to SARS-CoV-2 peptides is both sensitive (75% +/−13%) and specific (88%+/−7%) for previous SARS-CoV-2 infection >6 months after a positive PCR test. We identified that 42–53% of patients with Long COVID, but without detectable SARS-CoV-2 antibodies, nonetheless have detectable SARS-CoV-2 specific T cell responses. Interpretation Our study reveals evidence (detectable T cell mediated IL-2 release) of previous SARS-CoV-2 infection in seronegative patients with Long COVID.
183	I181		Elena Azzolini, MD, PhD1; Riccardo Levi, MSc2; Riccardo Sarti, MSc2; Chiara Pozzi, PhD1; Maximiliano Mollura, MSc3; Alberto Mantovani, MD1; Maria Rescigno, PhD1	Association Between BNT162b2 Vaccination and Long COVID After Infections Not Requiring Hospitalization in Health Care Workers	https://doi.org/10.1001/jama.2022.11691	Published	July 1, 2022	Study	https://jamanetwork.com/journals/jama/fullarticle/2794072	Survivors of COVID-19 may present with long-lasting symptoms.1 Some factors have been associated with the development of post-COVID conditions (also referred to as “long COVID”),2 including hospitalization.3 A study of older US veterans showed 15% reduction of long COVID after vaccination; however, study limitations included the low number of women and suboptimal vaccination schedules.4 Methods The study was approved by the Humanitas Research Hospital institutional review board. Each participant provided written informed consent. We conducted an observational cohort study from March 2020 to April 2022 in individuals working in 9 Italian health care facilities.5,6 Polymerase chain reaction (PCR) tests for SARS-CoV-2 were conducted every week (in COVID wards) or 2 weeks (in other wards) for hospital personnel, or if they developed symptoms or were exposed to cases. All health care workers were required to receive 3 doses of vaccine (BNT162b2), with the first and second doses administered in January-February 2021 and the booster dose in November-December 2021. Between February and April 2022, each participant completed a survey including demographics, comorbidities, a list of SARS-CoV-2–related symptoms at the time of infection and their duration (survey in the Supplement), and vaccination status. We defined long COVID as reporting at least 1 SARS-CoV-2–related symptom with a duration of more than 4 weeks. Hospitalized individuals were excluded to avoid bias related to severe disease, as were individuals with a date of infection less than 28 days before the survey. We included asymptomatic infections in the acute infection group (they could not have long COVID by definition) to avoid overestimating the prevalence of long COVID. The analysis was restricted to health care workers who were tested every 1 or 2 weeks with complete demographic data and a documented positive result for SARS-CoV-2 between March 2020 and March 2022. By the date of infection, we divided the patients into 3 groups corresponding to the peaks in our data and circulation of variants of concern in Italy (wave 1, February-September 2020 [wild-type variant]; wave 2, October 2020-July 2021 [Alpha]; and wave 3, August 2021-March 2022 [Delta and Omicron]) (eFigure in the Supplement). A multivariable logistic regression model was used to assess the relationship between long COVID and characteristics, including participant sex, age, SARS-CoV-2 infection, wave, and vaccination status 14 days prior to infection. Time since second vaccination was assessed among vaccinated individuals. The Clopper-Pearson method was used to calculate 95% CIs and the Mann-Whitney U test or the t test for continuous variables and the χ2-test for categorical variables to calculate P values. The significance threshold was defined as P < .05 (2-sided). Analyses were done in Python, version 3.8.3. Results Of 2560 participants, 739 individuals (29%) had COVID-19 (89 asymptomatic), of whom 229 (31.0%; 95% CI, 27.7%-34.5%) had long COVID (Table 1). The prevalence of long COVID varied across the pandemic waves, from 48.1% (95% CI, 39.9%-56.2%) in wave 1 to 35.9% (95% CI, 30.5%-41.6%) in wave 2 to 16.5% (95% CI, 12.4%-21.4%) in wave 3. The number of vaccine doses was associated with lower long COVID prevalence: 41.8% (95% CI, 37.0%-46.7%) in unvaccinated patients, 30.0% (95% CI, 6.7%-65.2%) with 1 dose, 17.4% (95% CI, 7.8%-31.4%) with 2 doses, and 16.0% (95% CI, 11.8%-21.0%) with 3 doses. Older age, higher body mass index, allergies, and obstructive lung disease were associated with long COVID. With a reference group of unvaccinated females in wave 1 with no allergies or comorbidities (Table 2), male sex (odds ratio [OR], 0.65; 95% CI, 0.44-0.98, P = .04), 2 vaccine doses (OR, 0.25; 95% CI, 0.07-0.87, P = .03), and 3 vaccine doses (OR, 0.16; 95% CI, 0.03-0.84, P = .03) were associated with a lower probability of long COVID. Older age (OR, 1.23; 95% CI, 1.01-1.49, P = .04), allergies (OR, 1.50; 95% CI, 1.06-2.11, P = .02), and an increasing number of comorbidities (OR, 1.32; 95% CI, 1.04-1.68, P = .03) were associated with a higher probability. No statistically significant association with infection wave was found. Among vaccinated individuals (n = 265), time between the second vaccination dose and infection was not associated with long COVID (OR, 0.66; 95% CI, 0.34-1.29). Discussion In this longitudinal observational study conducted among health care workers with SARS-CoV-2 infections not requiring hospitalization, 2 or 3 doses of vaccine, compared with no vaccination, were associated with lower long COVID prevalence. Study limitations include that symptoms and duration were self-reported, and causality cannot be inferred.
184	I182		Anna Vicco ,Francesca Caccuri ,Serena Messali,Adriana Vitiello,Aron Emmi,Claudia Del Vecchio,Alberto Reale,Arnaldo Caruso,Giancarlo Ottaviano,Carla Mucignat,Cristina Parolin,Angelo Antonini ,Arianna Calistri Anna Vicco ,Francesca Caccuri ,Serena Messali,Adriana Vitiello,Aron Emmi,Claudia Del Vecchio,Alberto Reale,Arnaldo Caruso,Giancarlo Ottaviano,Carla Mucignat,Cristina Parolin,Angelo Antonini ,Arianna Calistri	Genomic surveillance of SARS-CoV-2 in patients presenting neurological manifestations	https://doi.org/10.1371/journal.pone.0270024	Published	June 30, 2022	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0270024	During the first wave of infections, neurological symptoms in Coronavirus Disease 2019 (COVID-19) patients raised particular concern, suggesting that, in a subset of patients, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could invade and damage cells of the central nervous system (CNS). Indeed, up to date several in vitro and in vivo studies have shown the ability of SARS-CoV-2 to reach the CNS. Both viral and/or host related features could explain why this occurs only in certain individuals and not in all the infected population. The aim of the present study was to evaluate if onset of neurological manifestations in COVID-19 patients was related to specific viral genomic signatures. To this end, viral genome was extracted directly from nasopharyngeal swabs of selected SARS-CoV-2 positive patients presenting a spectrum of neurological symptoms related to COVID-19, ranging from anosmia/ageusia to more severe symptoms. By adopting a whole genome sequences approach, here we describe a panel of known as well as unknown mutations detected in the analyzed SARS-CoV-2 genomes. While some of the found mutations were already associated with an improved viral fitness, no common signatures were detected when comparing viral sequences belonging to specific groups of patients. In conclusion, our data support the notion that COVID-19 neurological manifestations are mainly linked to patient-specific features more than to virus genomic peculiarities.
185	I183		Michelle D Cherne 1, Andrew B Gentry 2, Anna Nemudraia 1, Artem Nemudryy 1, Jodi F Hedges 1, Heather Walk 1, Karlin Blackwell 1, Deann T Snyder 1, Maria Jerome 1, Wyatt Madden 1 3, Marziah Hashimi 1, T Andrew Sebrell 1, David B King 2, Raina K Plowright 1, Mark A Jutila 1, Blake Wiedenheft 1, Diane Bimczok	SARS-CoV-2 is detected in the gastrointestinal tract of asymptomatic endoscopy patients but is unlikely to pose a significant risk to healthcare personnel	https://doi.org/10.1016/j.gastha.2022.06.002	Published	2022 Jun 24	Study	https://pubmed.ncbi.nlm.nih.gov/35765598/	Background and aims: Recent evidence suggests that the gut is an additional target for SARS-CoV-2 infection. However, whether SARS-CoV-2 spreads via gastrointestinal secretions remains unclear. To determine the prevalence of gastrointestinal SARS-CoV-2 infection in asymptomatic subjects, we analyzed gastrointestinal biopsy and liquid samples from endoscopy patients for the presence of SARS-CoV-2. Methods: We enrolled 100 endoscopic patients without known SARS-CoV-2 infection (cohort A) and 12 patients with a previous COVID-19 diagnosis (cohort B) in a cohort study performed at a regional hospital. Gastrointestinal biopsies and fluids were screened for SARS-CoV-2 by PCR, immunohistochemistry and virus isolation assay, and the stability of SARS-CoV-2 in gastrointestinal liquids in vitro was analyzed. Results: SARS-CoV-2 RNA was detected by PCR in the colonic tissue of 1/100 patients in cohort A. In cohort, B, three colonic liquid samples tested positive for SARS-CoV-2 by PCR, and viral nucleocapsid protein was detected in the epithelium of the respective biopsy samples. However, no infectious virions were recovered from any samples. In vitro exposure of SARS-CoV-2 to colonic liquid led to a 4-log fold reduction of infectious SARS-CoV-2 within 1 hour (P ≤ 0.05). Conclusions: Overall, the persistent detection of SARS-CoV-2 in endoscopy samples after resolution of COVID-19 points to the gut as a long-term reservoir for SARS-CoV-2. Since no infectious virions were recovered and SARS-CoV-2 was rapidly inactivated in the presence of colon liquids, it is unlikely that performing endoscopic procedures is associated with a significant infection risk due to undiagnosed asymptomatic or persistent gastrointestinal SARS-CoV-2 infections.
186	I184		Oya Ozlem Eren-Kutsoylu, Ozgur Appak, Arzu Nazli-Zeka, Gokcen Omeroglu-Simsek, Nil Tekin, Basak Bayram, Ayca Arzu Sayiner, Nesim Tanglay & Vildan Avkan-Oguz	Evaluation of SARS-CoV-2 antibody persistence and viral spread in stool: a long-term care experience before COVID-19 vaccination	https://doi.org/10.1007/s11845-022-03095-7	Published	12 July 2022	Study	https://link.springer.com/article/10.1007/s11845-022-03095-7	Background Due to elderly residents, nursing homes/assisted living facilities were the most affected places in COVID-19 pandemic. Besides symptomatic patients, asymptomatic patients were detected during routine screening. Aim This study aims to determine the factors that affect antibody response and viral shedding in stool samples after natural exposure to the virus in residents and staff who recovered from COVID-19 before the vaccine was available. Methods This prospective cross-sectional study was conducted at the nation’s highest-capacity Residential and Nursing Home. Blood samples were collected between December 15, 2020 and January 15, 2021 from participating residents and staff for anti-SARS-CoV-2 antibody testing. Stool samples were obtained for SARS-CoV-2 PCR testing 2 months after COVID-19. The Social Sciences (SPSS) program version 15.0 was used for statistical analysis. The Mann–Whitney U test compared SARS‐CoV‐2 antibody concentration between two groups. Results Four hundred sixty-four (52.3%) residents and 424 (47.7%) staff participated. Entirely 259 (29.2%) participants were anti-SARS-CoV-2 IgG (+) and 255 (28.7%) were SARS-CoV-2 PCR (+). Both antibody and PCR positivity was detected in 196 (76.9%). In PCR (−) group, 63 (10.0%) participants were SARS-CoV‐2 IgG (+). Antibody titers were found highest in SARS-CoV-2 PCR (+) male residents. SARS-CoV-2 IgG titers were significantly high in SARS-CoV-2 PCR (+) and hospitalized participants regardless of age. Stool samples were obtained from 61(23.9%) participants and were found negative. Conclusion A durable SARS-CoV‐2 IgG antibody response was monitored at least 9 months after the participants were diagnosed with COVID-19. SARS-CoV-2 antibody positivity was detected 76.9% in PCR (+) and 10.0% in PCR (−) participants. Knowing the duration of detectable antibodies is an important finding for developing disease prevention and public health strategies.
187	I185		Laracy, Justin C.a,b; Kamboj, Minia,b; Vardhana, Santosha A.c,d	https://journals.lww.com/co-infectiousdiseases/Abstract/2022/08000/Long_and_persistent_COVID_19_in_patients_with.3.aspx	https://doi.org/10.1097/QCO.0000000000000841	Published	Jul 5, 2022	Review	https://journals.lww.com/co-infectiousdiseases/Abstract/2022/08000/Long_and_persistent_COVID_19_in_patients_with.3.aspx	Purpose of review Cancer patients, especially those with hematologic malignancies, are at increased risk for coronavirus disease 2019 (COVID-19)-related complications and mortality. We describe the incidence, clinical characteristics, risk factors, and outcomes of persistent COVID-19 infection in patients with hematologic malignancies. Recent findings The syndrome of persistent COVID-19 in patients with hematologic malignancies manifests as a chronic protracted illness marked by waxing and waning or progressive respiratory symptoms and prolonged viral shedding. Immunosuppressed patients with lymphoid malignancies may serve as partially immune reservoirs for the generation of immune-evasive viral escape mutants. Summary Persistent COVID-19 infection is a unique concern in patients with hematologic malignancies. While vaccination against severe acute respiratory syndrome coronavirus 2 has reduced the overall burden of COVID-19 in patients with hematologic cancers, whether vaccination or other novel treatments for COVID-19 prevent or alleviate this syndrome remains to be determined.
188	I186		Aqsa Mumtaz 1,Abdul Ahad Ehsan Sheikh 2,Amin Moazzam Khan 3ORCID,Subaina Naeem Khalid 3ORCID,Jehanzaeb Khan 4,Adeel Nasrullah 5ORCID,Shazib Sagheer 6 andAbu Baker Sheikh 4,*ORCID	COVID-19 Vaccine and Long COVID: A Scoping Review	https://doi.org/10.3390/life12071066	Published	16 July 2022	Review	https://www.mdpi.com/2075-1729/12/7/1066/htm	As the COVID-19 pandemic progresses, changing definitions and therapeutics regarding the post-acute sequela of COVID-19, particularly long COVID, have become a subject of great interest and study. The study aims to describe the pathophysiology and discuss different therapeutic agents currently available for long COVID. Another objective is to assess comparative efficacy between different types of vaccines on symptoms of long COVID. A preliminary search was conducted using Ovid Medline, Embase, medRxiv, and NIH COVID-19 portfolios. A total of 16 studies were included in our review. Despite some of the data showing variable results, most of the vaccinated patients reported improvement in long COVID symptoms with no significant difference between various types of vaccines. Further trials are needed to better identify the comparative efficacy of vaccines for long COVID and ascertain other therapeutic modalities.
189	I187		Lisa M James, Apostolos P Georgopoulos	At the Root of 3 “Long” Diseases: Persistent Antigens Inflicting Chronic Damage on the Brain and Other Organs in Gulf War Illness, Long-COVID-19, and Chronic Fatigue Syndrome	https://doi.org/10.1177%2F26331055221114817	Published	July 22, 2022	Article	https://journals.sagepub.com/doi/full/10.1177/26331055221114817	Several foreign antigens such as those derived from viruses and bacteria have been linked to long-term deleterious effects on the brain and other organs; yet, health outcomes subsequent to foreign antigen exposure vary depending in large part on the host’s immune system, in general, and on human leukocyte antigen (HLA) composition, in particular. Here we first provide a brief description of 3 conditions characterized by persistent long-term symptoms, namely long-COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and Gulf War Illness (GWI), followed by a brief overview of the role of HLA in the immune response to foreign antigens. We then discuss our Persistent Antigen (PA) hypothesis and highlight associations between antigen persistence due to HLA-antigen incongruence and chronic health conditions in general and the 3 “long” diseases above in particular. This review is not intended to cover the breadth and depth of symptomatology of those diseases but is specifically focused on the hypothesis that the presence of persistent antigens underlies their pathogenesis.
190	I188		V. Lammi,1 H.M. Ollila,1,	Tackling Long COVID using international host genetics research collaboration	https://doi.org/10.1016%2Fj.sleep.2022.05.184	Published	2022 Jul 21	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9300219/	Introduction: While the world is still fighting the spread and casualties of the acute disease caused by SARS-CoV-2 virus, there is also a need for mitigating the long-term effects of this pandemic. WHO has estimated that 10-20% of coronavirus disease 2019 (COVID-19) patients suffer from lingering symptoms, termed Long COVID (Post-acute sequelae of COVID-19, PASC / Post COVID-19 conditions). Various symptoms have been reported in virtually all organs, with debilitating fatigue, exercise intolerance, cognitive dysfunction, anxiety, depression, loss of smell or taste, and sleep difficulties among the most prevalent. Several pathophysiological mechanisms ranging from prolonged infection to tissue damage and autoimmunity have been proposed. Studying human genetic variants predisposing to Long COVID can provide hypothesis-free information on the underlying biology. Materials and methods: We have established an open world-wide collaboration for elucidating genetic risk factors for Long COVID. Currently, the Long COVID Host Genetics Initiative comprises 46 studies across 23 countries with genotype data combined to questionnaire information of symptoms and/or electronic health record (EHR) data of diagnoses. Using questionnaire data, we have defined Long COVID as ‘any symptoms that cannot be explained by alternative diagnoses, or impact on everyday functioning, 3 months after the onset of COVID’. With EHR data, we have used specific diagnosis codes for Post COVID-19 conditions (ICD-10: U09) or Coronavirus as the cause of other diseases (B97.2). In the first data freeze, we have data from 11 studies from 8 countries, with 1,534 Long COVID cases and 800,353 controls, of which 96,692 have had COVID but not Long COVID. Each contributing study has performed genome-wide association analyses (GWAS) comparing Long COVID to individuals who have recovered from COVID within 3 months, and to population controls. Also lifestyle measures and other diagnoses have been broadly assessed in some of the participating cohorts. This allowed us to examine the phenotypic associations with Long COVID using logistic regression. Results: GWAS of individual cohorts have suggested potential variants associated with Long COVID but without genome-wide statistical significance. We are currently running meta-analyses to increase statistical power by combining data from these studies. Using registry follow-up of 12 months in the FinnGen study after the beginning of the COVID-19 pandemic in Finland identified 2,018 participants with a PCR-verified SARS-CoV-2 infection. 50 (2.5%) of them had received a diagnosis for long COVID. Long COVID associated with autoimmune diseases (p = 0.026, OR[se] = 2.15[1.41]) but not with depression (p = 0.71, OR[se] = 1.20[1.75]) or asthma (p = 0.43, OR[se] = 1.55[1.74]). Conclusions: Our findings indicate that Long COVID may be related to autoimmunity. The joint effort of the international Long COVID Host Genetics Initiative combining phenotypic and genetic data will allow us to identify genetic risk factors and test causality between autoimmunity and Long COVID.
191	I189		William J. Pandori,Lindsey E. Padgett,Ahmad Alimadadi,Norma A. Gutierrez,Daniel J. Araujo,Christine J. Huh,Claire E. Olingy,Huy Q. Dinh,Runpei Wu,Pandurangan Vijayanand,Serena J. Chee,Christian H. Ottensmeier,Catherine C. Hedrick	Single-cell immune profiling reveals long-term changes in myeloid cells and identifies a novel subset of CD9+ monocytes associated with COVID-19 hospitalization	https://doi.org/10.1002/JLB.4COVA0122-076R	Published	22 July 2022	Study	https://jlb.onlinelibrary.wiley.com/doi/full/10.1002/JLB.4COVA0122-076R	Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in severe immune dysfunction, hospitalization, and death. Many patients also develop long-COVID-19, experiencing symptoms months after infection. Although significant progress has been made in understanding the immune response to acute SARS-CoV-2 infection, gaps remain in our knowledge of how innate immunity influences disease kinetics and severity. We hypothesized that cytometry by time-of-flight analysis of PBMCs from healthy and infected subjects would identify novel cell surface markers and innate immune cell subsets associated with COVID-19 severity. In this pursuit, we identified monocyte and dendritic cell subsets that changed in frequency during acute SARS-CoV-2 infection and correlated with clinical parameters of disease severity. Subsets of nonclassical monocytes decreased in frequency in hospitalized subjects, yet increased in the most severe patients and positively correlated with clinical values associated with worse disease severity. CD9, CD163, PDL1, and PDL2 expression significantly increased in hospitalized subjects, and CD9 and 6-Sulfo LacNac emerged as the markers that best distinguished monocyte subsets amongst all subjects. CD9+ monocytes remained elevated, whereas nonclassical monocytes remained decreased, in the blood of hospitalized subjects at 3–4 months postinfection. Finally, we found that CD9+ monocytes functionally released more IL-8 and MCP-1 after LPS stimulation. This study identifies new monocyte subsets present in the blood of COVID-19 patients that correlate with disease severity, and links CD9+ monocytes to COVID-19 progression.
192	I190		Yu-Si Luo1,2†, www.frontiersin.orgLei Luo3†, www.frontiersin.orgWei Li4, www.frontiersin.orgYan Chen5, www.frontiersin.orgGuo-Feng Wu1, www.frontiersin.orgFang Chen2, www.frontiersin.orgHu-Yan Shen2, www.frontiersin.orgHong-Man Li6, www.frontiersin.orgMing-Yang Guo2, www.frontiersin.orgSha Yin3, www.frontiersin.orgKe Zhang2* and www.frontiersin.orgZhong-Shan Cheng7*	Evaluation of a Functional Single Nucleotide Polymorphism of the SARS-CoV-2 Receptor ACE2 That Is Potentially Involved in Long COVID	https://doi.org/10.3389/fgene.2022.931562	Published	18 July 2022	Article	https://www.frontiersin.org/articles/10.3389/fgene.2022.931562/full	Since the occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, SARS-CoV-2 has led to a global coronavirus disease 2019 (COVID-19) pandemic. A better understanding of the SARS-CoV-2 receptor ACE2 at the genetic level would help combat COVID-19, particularly for long COVID. We performed a genetic analysis of ACE2 and searched for its common potential single nucleotide polymorphisms (SNPs) with minor allele frequency >0.05 in both European and Chinese populations that would contribute to ACE2 gene expression variation. We thought that the variation of the ACE2 expression would be an important biological feature that would strongly affect COVID-19 symptoms, such as “brain fog”, which is highlighted by the fact that ACE2 acts as a major cellular receptor for SARS-CoV-2 attachment and is highly expressed in brain tissues. Based on the human GTEx gene expression database, we found rs2106809 exhibited a significant correlation with the ACE2 expression among multiple brain and artery tissues. This expression correlation was replicated in an independent European brain eQTL database, Braineac. rs2106809G also displays significantly higher frequency in Asian populations than in Europeans and displays a protective effect (p = 0.047) against COVID-19 hospitalization when comparing hospitalized COVID-19 cases with non-hospitalized COVID-19 or SARS-CoV-2 test-negative samples with European ancestry from the UK Biobank. Furthermore, we experimentally demonstrated that rs2106809G could upregulate the transcriptional activity of ACE2. Therefore, integrative analysis and functional experiment strongly support that ACE2 SNP rs2106809 is a functional brain eQTL and its potential involvement in long COVID, which warrants further investigation.
193	I191		Soumya Arun, Abbie Storan, Bethan Myers	Mast cell activation syndrome and the link with long COVID	https://doi.org/10.12968/hmed.2022.0123	Published	26 Jul 2022	Article	https://www.magonlinelibrary.com/doi/abs/10.12968/hmed.2022.0123	Mast cells are innate immune cells found in connective tissues throughout the body, most prevalent at tissue-environment interfaces. They possess multiple cell-surface receptors which react to various stimuli and, after activation, release many mediators including histamine, heparin, cytokines, prostaglandins, leukotrienes and proteases. In mast cell activation syndrome, excessive amounts of inflammatory mediators are released in response to triggers such as foods, fragrances, stress, exercise, medications or temperature changes. Diagnostic markers may be difficult to assess because of their rapid degradation; these include urinary N-methyl histamine, urinary prostaglandins D2, DM and F2α and serum tryptase (which is stable) in the UK. Self-management techniques, medications and avoiding triggers may improve quality of life. Treatments include mast cell mediator blockers, mast cell stabilisers and anti-inflammatory agents. ‘Long COVID’ describes post-COVID-19 syndrome when symptoms persist for more than 12 weeks after initial infection with no alternative diagnosis. Both mast cell activation syndrome and long COVID cause multiple symptoms. It is theorised that COVID-19 infection could lead to exaggeration of existing undiagnosed mast cell activation syndrome, or could activate normal mast cells owing to the persistence of viral particles. Other similarities include the relapse-remission cycle and improvements with similar treatments. Importantly, however, aside from mast cell disorders, long COVID could potentially be attributed to several other conditions.
194	I192	COA	Helen Fogarty,Soracha E. Ward,Liam Townsend,Ellie Karampini,Stephanie Elliott,Niall Conlon,Jean Dunne,Rachel Kiersey,Aifric Naughton,Mary Gardiner,Mary Byrne,Colm Bergin,Jamie M. O’Sullivan,Ignacio Martin-Loeches,Parthiban Nadarajan,Ciaran Bannan,Patrick W. Mallon,Gerard F. Curley,Roger J. S. Preston,Aisling M. Rehill,Ross I. Baker,Cliona Ni Cheallaigh,James S. O’Donnell,	Sustained VWF-ADAMTS13 axis imbalance and endotheliopathy in Long COVID syndrome is related to immune dysfunction	https://doi.org/10.1111/jth.15830	Published	25 July 2022	Study	https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.15830	Background Prolonged recovery is common after SARs-CoV-2 infection, however the pathophysiological mechanisms underpinning Long COVID syndrome remain unknown. VWF-ADAMTS13 imbalance, dysregulated angiogenesis and immuno-thrombosis are hallmarks of acute COVID-19. We hypothesized that VWF-ADAMTS13 imbalance persists in convalescence together with EC activation and angiogenic disturbance. Additionally, we postulate that ongoing immune cell dysfunction may be linked to sustained EC and coagulation activation. Patients and Methods Fifty patients were reviewed at a minimum of 6 weeks following acute COVID-19. ADAMTS13, WPB proteins and angiogenesis-related proteins were assessed and clinical evaluation and immunophenotyping performed. Comparisons were made with healthy controls (n=20) and acute COVID-19 patients (n=36). Results ADAMTS13 levels were reduced (p=0.009) and the VWF/ADAMTS13 ratio was increased in convalescence (p=0.0004). Levels of Platelet Factor 4 (PF4), a putative protector of VWF, were also elevated (p=0.0001). A non-significant increase in WPB proteins Angiopoietin-2 (Ang-2) and Osteoprotegerin (OPG) was observed in convalescent patients and WPB markers correlated with EC parameters. Enhanced expression of 21 angiogenesis-related proteins was observed in convalescent COVID-19. Finally, immunophenotyping revealed significantly elevated intermediate monocytes and activated CD4+ and CD8+ T cells in convalescence, which correlated with thrombin generation and endotheliopathy markers, respectively. Conclusion Our data provide insights into sustained EC activation, dysregulated angiogenesis and VWF/ADAMTS13 axis imbalance in convalescent COVID-19. In keeping with the pivotal role of immuno-thrombosis in acute COVID-19, our findings support the hypothesis that abnormal T cell and monocyte populations may be important in the context of persistent EC activation and hemostatic dysfunction during convalescence.
195	I193		Bruce K. Patterson1Email Edgar B. Francisco2 Ram Yogendra3 Emily Long4 Amruta Pise2 Christopher Beaty2 Eric Osgood5 John Bream6 Mark Kreimer7 Richard Vander Heide8 Jose Guevara-Coto9 Rodrigo Mora10 Javier Mora1	SARS-CoV-2 S1 Protein Persistence in SARS-CoV-2 Negative Post-Vaccination Individuals with Long COVID/ PASC-Like Symptoms	https://doi.org/10.21203/rs.3.rs-1844677/v1	pre-print	12 Jul, 2022	Study	https://www.researchsquare.com/article/rs-1844677/v1	Background We sought to determine the immunologic abnormalities in patients following SARS-CoV-2 vaccines who experience post-acute sequelae of COVID-19 (PASC)-like symptoms > 4 weeks post vaccination. In addition, we investigated whether the potential etiology was similar to PASC. Design: We enrolled 50 post-vaccination individuals who experience PASC-like symptoms, 10 healthy individuals, and 35 individuals post-vaccination without symptoms. We performed multiplex cytokine/chemokine profiling with machine learning as well as SARS-CoV-2 S1 protein detection on monocyte subsets using flow cytometry and mass spectrometry. Results We determined that post-vaccination individuals with PASC-like symptoms had similar symptoms to PASC patients. When analyzing their immune profile, post-vaccination individuals had statistically significant elevations of sCD40L, CCL5, IL-6, and IL-8. SARS-CoV-2 S1 and S2 protein were detected in CD16 + monocytes using flow cytometry and mass spectrometry on sorted cells. Conclusions Post-vaccination individuals with PASC-like symptoms exhibit markers of platelet activation and pro-inflammatory cytokine production which may be driven by the persistence of SARS-CoV-2 S1 protein persistence in intermediate and non-classical monocytes.
196	I194		Xiaolin Jia,1,2 Shu Cao,1,3 Alexandra S. Lee,1,3 Monali Manohar,1,3 Sayantani B. Sindher,1,3 Neera Ahuja,1,2 Maja Artandi,1,4 Catherine A. Blish,1,5,6,7 Andra L. Blomkalns,8 Iris Chang,1,3 William J. Collins,1,2,3 Manisha Desai,1,3,9 Hena Naz Din,1,3 Evan Do,1,3 Andrea Fernandes,1,3 Linda N. Geng,1,4 Yael Rosenberg-Hasson,1,3 Megan Ruth Mahoney,1,4 Abigail L. Glascock,5 Lienna Y. Chan,5 Sharon Y. Fong,5 CLIAHUB Consortium,10 Chan Zuckerberg Biohub,5 Maira Phelps,5 Olivia Raeber,1,3 Stanford COVID-19 Biobank Study Group,10 Natasha Purington,1,3,9 Katharina Röltgen,11 Angela J. Rogers,1,12 Theo Snow,1,3 Taia T. Wang,1,6,7 Daniel Solis,11 Laura Vaughan,1,4 Michelle Verghese,11 Holden Maecker,13 Richard Wittman,1,4 Rajan Puri,1,4 Amy Kistler,5 Samuel Yang,8 Scott D. Boyd,1,3,11 Benjamin A. Pinsky,6,11 Sharon Chinthrajah,1,3 and Kari C. Nadeau1,3,12,13	Anti-nucleocapsid antibody levels and pulmonary comorbid conditions are linked to post–COVID-19 syndrome	https://doi.org/10.1172/jci.insight.156713	Published	July 8, 2022	Study	https://insight.jci.org/articles/view/156713	BACKGROUND. Prolonged symptoms after SARS-CoV-2 infection are well documented. However, which factors influence development of long-term symptoms, how symptoms vary across ethnic groups, and whether long-term symptoms correlate with biomarkers are points that remain elusive. METHODS. Adult SARS-CoV-2 reverse transcription PCR–positive (RT-PCR–positive) patients were recruited at Stanford from March 2020 to February 2021. Study participants were seen for in-person visits at diagnosis and every 1–3 months for up to 1 year after diagnosis; they completed symptom surveys and underwent blood draws and nasal swab collections at each visit. RESULTS. Our cohort (n = 617) ranged from asymptomatic to critical COVID-19 infections. In total, 40% of participants reported at least 1 symptom associated with COVID-19 six months after diagnosis. Median time from diagnosis to first resolution of all symptoms was 44 days; median time from diagnosis to sustained symptom resolution with no recurring symptoms for 1 month or longer was 214 days. Anti-nucleocapsid IgG level in the first week after positive RT-PCR test and history of lung disease were associated with time to sustained symptom resolution. COVID-19 disease severity, ethnicity, age, sex, and remdesivir use did not affect time to sustained symptom resolution. CONCLUSION. We found that all disease severities had a similar risk of developing post–COVID-19 syndrome in an ethnically diverse population. Comorbid lung disease and lower levels of initial IgG response to SARS-CoV-2 nucleocapsid antigen were associated with longer symptom duration.
197	I195		Yunsung Lee, Espen Riskedal, Karl Trygve Kalleberg, Mette Istre, Andreas Lind, Fridtjof Lund-Johansen, Olaug Reiakvam, Arne V. L. Søraas, Jennifer R. Harris, John Arne Dahl, Cathrine L. Hadley & Astanand Jugessur	EWAS of post-COVID-19 patients shows methylation differences in the immune-response associated gene, IFI44L, three months after COVID-19 infection	https://doi.org/10.1038/s41598-022-15467-1	Published	07 July 2022	Study	https://www.nature.com/articles/s41598-022-15467-1	Although substantial progress has been made in managing COVID-19, it is still difficult to predict a patient’s prognosis. We explored the epigenetic signatures of COVID-19 in peripheral blood using data from an ongoing prospective observational study of COVID-19 called the Norwegian Corona Cohort Study. A series of EWASs were performed to compare the DNA methylation profiles between COVID-19 cases and controls three months post-infection. We also investigated differences associated with severity and long-COVID. Three CpGs—cg22399236, cg03607951, and cg09829636—were significantly hypomethylated (FDR < 0.05) in COVID-19 positive individuals. cg03607951 is located in IFI44L which is involved in innate response to viral infection and several systemic autoimmune diseases. cg09829636 is located in ANKRD9, a gene implicated in a wide variety of cellular processes, including the degradation of IMPDH2. The link between ANKRD9 and IMPDH2 is striking given that IMPDHs are considered therapeutic targets for COVID-19. Furthermore, gene ontology analyses revealed pathways involved in response to viruses. The lack of significant differences associated with severity and long-COVID may be real or reflect limitations in sample size. Our findings support the involvement of interferon responsive genes in the pathophysiology of COVID-19 and indicate a possible link to systemic autoimmune diseases.
198	I196	PESE	Jon Klein, Jamie Wood, Jillian Jaycox, Peiwen Lu, Rahul M. Dhodapkar, Jeff R. Gehlhausen, Alexandra Tabachnikova, Laura Tabacof, Amyn A. Malik, Kathy Kamath, Kerrie Greene, Valter Silva Monteiro, Mario Peña-Hernandez, Tianyang Mao, Bornali Bhattacharjee, Takehiro Takahashi, Carolina Lucas, Julio Silva, Dayna Mccarthy, Erica Breyman, Jenna Tosto-Mancuso, Yile Dai, Emily Perotti, Koray Akduman, Tiffany J. Tzeng, Lan Xu, Inci Yildirim, Harlan M. Krumholz, John Shon, Ruslan Medzhitov, Saad B. Omer, David van Dijk, Aaron M. Ring, David Putrino, Akiko Iwasaki	Distinguishing features of Long COVID identified through immune profiling	https://doi.org/10.1101/2022.08.09.22278592	pre-print	August 10, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.08.09.22278592v1.full-text	SARS-CoV-2 infection can result in the development of a constellation of persistent sequelae following acute disease called post-acute sequelae of COVID-19 (PASC) or Long COVID1–3. Individuals diagnosed with Long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions1–3; however, the basic biological mechanisms responsible for these debilitating symptoms are unclear. Here, 215 individuals were included in an exploratory, cross-sectional study to perform multi-dimensional immune phenotyping in conjunction with machine learning methods to identify key immunological features distinguishing Long COVID. Marked differences were noted in specific circulating myeloid and lymphocyte populations relative to matched control groups, as well as evidence of elevated humoral responses directed against SARS-CoV-2 among participants with Long COVID. Further, unexpected increases were observed in antibody responses directed against non-SARS-CoV-2 viral pathogens, particularly Epstein-Barr virus. Analysis of circulating immune mediators and various hormones also revealed pronounced differences, with levels of cortisol being uniformly lower among participants with Long COVID relative to matched control groups. Integration of immune phenotyping data into unbiased machine learning models identified significant distinguishing features critical in accurate classification of Long COVID, with decreased levels of cortisol being the most significant individual predictor. These findings will help guide additional studies into the pathobiology of Long COVID and may aid in the future development of objective biomarkers for Long COVID.
199	I197		Paul Farrell	Review 2: "Impact of Pre-Existing Chronic Viral Infection and Reactivation on the Development of Long COVID"	https://doi.org/10.1162/2e3983f5.67d7e320	Published	Aug 11, 2022	Study Review	https://rapidreviewscovid19.mitpress.mit.edu/pub/mjjeglr7/release/1	Reviewers were mixed on the overall reliability of this preprint. There is agreement that the study results are supported by the data, but some concern over the suggested explanation for the results. Although descriptive, this is a well presented, valuable and worthwhile study. Minor points to be addressed: Table 1 is good but it does not allow the reader to know the distribution of the preexisting conditions in the patient cohort (were they all in different people, did the same 54 HIV+ people have most of the conditions etc?). It would be helpful to also have a more comprehensive supplementary table showing the distribution of the conditions in the patient population. Since only some of the patients have raised antibodies to EBV, should the title of the paper be “Evidence of recent EBV reactivation in some individuals experiencing long COVID” ? The current title seems to imply that they all have raised EBV antibodies.
200	I198	PESE	Rohrhofer J 1 #, Graninger M 2#, Lettenmaier L 1, Schweighardt J 1, Gentile SA 1, Koidl L 1, Ret D 1, 3, Stingl M 4, Puchhammer-Stöckl E 2#*, Untersmayr E 1#	Association between EBV reactivation and development of Long-COVID fatigue	http://dx.doi.org/10.1111/all.15471	Published	8 August 2022	Study	https://onlinelibrary.wiley.com/doi/epdf/10.1111/all.15471	To the Editor,Post-viral fatigue after S ARS-CoV-2 infection is a major concern in the ongoing COVID-19 pandemic. Up to 10% of patients develop Long-C O VID1, a syndrome defined by the National Institute for Health and Care Excellence as post-infectious long-term symptoms for more than 12 weeks, which cannot be explained by alternative pathologies1. While some Long-COVID symptoms, like shortness of breath or chest pain, might be associated with organdamage, the origin of post COVID fatigue, including debilitating fatigue and impaired memory and concentration, remains unclear. Several viruses were associated with post-viral fatigue, such as Epstein-Barr-Virus (EBV) or influenza viruses. Also, Myalgic encephalomyelitis / chronic fatigue syndrome, a WHO defined independent disease, may develop, amongst other triggers, after viral infections. However, the mechanisms leading to post-viral fatigue syndrome in overall and especially in Long-C O VID are unresolved 2. So far a higher frequency of EBV viremia was observed only in acute severe C O VID-19 infections 3. In the present prospective study, we analysed whether Long-C O VID fatigue may be triggered by SARS-CoV-2 persistence in the gastrointestinal or respirator y tract after acute disease 2, or by C O VID-19 associated reactivation of EBV. We tested for SARS-CoV-2 RNA in stool and throat washings, and for EBV D NA in stool, throat washings and blood by real time PCR (EBV) and real time RT-PCR (SARS-CoV-2) as described before 4,5. The exper imental procedures were performed with permission of the human ethics committee of the Medical University of Vienna (vote number: 2281/2020). All patients provided written informed consent. Samples were collected between 74 and 471 days (median: 235 days) after beginning of acute S ARS-CoV-2 infection in 30 Long-C O VIDpatients characterized by persistent fatigue, post-exertional malaise (PEM), autonomic dysfunction and/or orthostatic intolerance. Twenty age- and sex-matched patients, who have fully recovered after the S ARS-CoV-2 infection, were recruited for control pur poses. Samples were collected between 106 and 571 days (median: 275 days) after beginning of acute SARS-CoV-2 infection. All patients had mild infections, were not hospitalized and infected between spring 2020 and autumn 2021. We further analyzed virus-specific antibodies including SARS-CoV-2 IgA and IgG with commercial ELISA assays (Euroimmun, Germany). As Long-C O VID patients showed a higher frequency of positive titers for specific EBV antibodies compared to controls in earlier studies 6, the patients’ EBV IgM and IgG were tested by a commercial microarray (ViraMed, Germany). Demographic data as well as inclusion and exclusion criteria are depicted in Suppl. Table 1. More detailed information on the methodological procedures are listed in the supplementary information.At time point of sampling, SARS-CoV-2 RNA was detectable neither in throat washing nor stool in any of the study participants by real time RT-PCR. SARS-CoV-2 antibody titers (IgA and Ig G) did not differ between the cohorts (Suppl. Fig. 1). Most study participants had been vaccinated after COVID-19 disease prior to sampling (24/30 in Long-C O VID patients, 17/20 in controls). EBV real time PCR was negative in all blood or stool samples. However, EBV DNA was detected in throat washings in 15/30 (50%) of Long-C O VID patients while only in 4/20 (20%) of non-Long-C O VID patients who had recovered from their SARS-CoV-2 infection (p= 0.0411). EB V load levels were not significantly different between the two cohorts in EBV-specific real time PCR positive samples (Figure 1). All patients of both groups, except one patient in the fully convalescent COVID-19 group (SARS-CoV-2 – LC),had past EB V infections, as confirmed by EBV IgG seropositive and I g M seronegative status at the time of investigation, thus the EBV r eplication observed was due to EB V reactivationrather than primary infection. EBV specific antibody titers as assessed by microarray in blood were not different between the groups. (Suppl. Fig. 2) Taken together, SARS-CoV-2 persistence could not be detected in our study participants up to 10 weeks after infection, but EB V reactivation in the throat was more common in patientswith Long-C O VID fatigue, also months after acute S ARS-CoV-2 infection, compared to convalescent SARS-CoV-2 patients. This suggests that EBV replication may be a co-factor in a sub-group of patients developing Long-C O VID fatigue. However, contributing factors, such as HLA-subtype depending answers to latent EBV infection, have not been evaluated in this study and represent limitations. Earlier reports of differences in the EBV antibody profile of Long-C O VID patients6 could not be confirmed, possibly due to the small sample sizeanalyzed in our study. Further and larger studies are needed to clarify the impact and mechanism of EBV-associated Long-COVID fatigue.
201	I199		Icaro Bonyek-Silva1,2,3,4, Thiago Cerqueira-Silva1,2, Sara Nunes1,2, Antônio Fernando Araújo Machado5, Márcio Rivison Silva Cruz5, Blenda Pereira1,2, Leilane Estrela1, Jéssica Silva1,2, Ananda Isis1, Aldina Barral1,2,6, Pablo Rafael Silveira Oliveira7, Ricardo Khouri1,2, C. Henrique Serezani8, Cláudia Brodskyn1,2,6, Juliana Ribeiro Caldas5,9,10, Manoel Barral-Netto1,2,6, Viviane Boaventura1,2† and Natalia Machado Tavares	Prediabetes Induces More Severe Acute COVID-19 Associated With IL-6 Production Without Worsening Long-Term Symptoms	https://doi.org/10.3389/fendo.2022.896378	Published	08 July 2022	Study	https://www.frontiersin.org/articles/10.3389/fendo.2022.896378/full	Aims: Pre-existing conditions, such as age, hypertension, obesity, and diabetes, constitute known risk factors for severe COVID-19. However, the impact of prediabetes mellitus (PDM) on COVID-19 severity is less clear. This study aimed to evaluate the influence of PDM in the acute and long-term phases of COVID-19. Materials and methods: We compared inflammatory mediators, laboratory and clinical parameters and symptoms in COVID-19 patients with prediabetes (PDM) and without diabetes (NDM) during the acute phase of infection and at three months post-hospitalization. Results: Patients with PDM had longer hospital stays and required intensive care unit admission more frequently than NDM. Upon hospitalization, PDM patients exhibited higher serum levels of interleukin 6 (IL-6), which is related to reduced partial pressure of oxygen (PaO2) in arterial blood, oxygen saturation (SpO2) and increased COVID-19 severity. However, at three months after discharge, those with PDM did not exhibit significant alterations in laboratory parameters or residual symptoms; however, PDM was observed to influence the profile of reported symptoms. Conclusions: PDM seems to be associated with increased risk of severe COVID-19, as well as higher serum levels of IL-6, which may constitute a potential biomarker of severe COVID-19 risk in affected patients. Furthermore, while PDM correlated with more severe acute-phase COVID-19, no long-term worsening of sequelae was observed.
202	I200		Zhu Yang , Di Wu, Shanxin Lu, +9 , Yang Qiu, Zhengyi Hua, Fancheng Tan, Cixiong Zhang, Lei Zhang, Ding-Yu Zhang, Xi Zhou Zongwei Cai , You Shang you_shanghust@163.com, and Shu-Hai Lin	Plasma metabolome and cytokine profile reveal glycylproline modulating antibody fading in convalescent COVID-19 patients	https://doi.org/10.1073/pnas.2117089119	Published	August 9, 2022	Study	https://www.pnas.org/doi/full/10.1073/pnas.2117089119	Significance Using absolute quantification of both cytokines and metabolites from the plasmas of convalescent COVID-19 patients, machine-learning approaches identified that a combination of cytokines and metabolites can clearly discriminate convalescent patients with rapidly faded antibodies (CO) from ordinary convalescents with antibodies (CA). We found glycylproline (gly-pro) accumulation in CO individuals compared with the CA group. Intriguingly, gly-pro contributes to the rapid fading of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–specific antibodies, whereas the inhibitor of its producing enzyme dipeptidyl peptidase 4, an antidiabetic drug, can counteract the gly-pro–down-regulated SARS-CoV-2-specific antibodies under physiological conditions. Therefore, our findings point to a novel mechanism for gly-pro–suppressed immune responses upon SARS-CoV-2 infection and provide therapeutic potentials for maintaining neutralizing antibody levels. Abstract The COVID-19 pandemic has incurred tremendous costs worldwide and is still threatening public health in the “new normal.” The association between neutralizing antibody levels and metabolic alterations in convalescent patients with COVID-19 is still poorly understood. In the present work, we conducted absolutely quantitative profiling to compare the plasma cytokines and metabolome of ordinary convalescent patients with antibodies (CA), convalescents with rapidly faded antibodies (CO), and healthy subjects. As a result, we identified that cytokines such as M-CSF and IL-12p40 and plasma metabolites such as glycylproline (gly-pro) and long-chain acylcarnitines could be associated with antibody fading in COVID-19 convalescent patients. Following feature selection, we built machine-learning–based classification models using 17 features (six cytokines and 11 metabolites). Overall accuracies of more than 90% were attained in at least six machine-learning models. Of note, the dipeptide gly-pro, a product of enzymatic peptide cleavage catalyzed by dipeptidyl peptidase 4 (DPP4), strongly accumulated in CO individuals compared with the CA group. Furthermore, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination experiments in healthy mice demonstrated that supplementation of gly-pro down-regulates SARS-CoV-2–specific receptor-binding domain antibody levels and suppresses immune responses, whereas the DPP4 inhibitor sitagliptin can counteract the inhibitory effects of gly-pro upon SARS-CoV-2 vaccination. Our findings not only reveal the important role of gly-pro in the immune responses to SARS-CoV-2 infection but also indicate a possible mechanism underlying the beneficial outcomes of treatment with DPP4 inhibitors in convalescent COVID-19 patients, shedding light on therapeutic and vaccination strategies against COVID-19.
203	I201		Cristina Solé, Sandra Domingo, Xavier Vidal & Josefina Cortés-Hernández	Humoral and cellular response in convalescent COVID-19 lupus patients	https://doi.org/10.1038/s41598-022-17334-5	Published	12 August 2022	Study	https://www.nature.com/articles/s41598-022-17334-5	In SLE, underlying immune dysregulation and immunosuppression may increase the susceptibility to COVID-19 and impair the humoral and adaptive response. We aimed to characterize COVID-19 infection, identifying susceptibility and severity risk factors, assessing the presence of SARS-CoV-2 IgG antibodies and analyzing the cellular response. We established a prospective cohort of lupus patients to estimate the COVID-19 incidence compared to the reference general population. Data were collected via telephone interviews and medical record review. SARS-CoV-2 IgG antibodies were measured cross-sectionally as part of routine surveillance. Longitudinal changes in antibody titers and immunological profile from convalescent COVID-19 patients were evaluated at 6, 12 and 24 week after symptom onset. From immunological studies, PBMCs from convalescent patients were extracted and analyzed by flow cytometry and gene expression analysis. We included 725 patients, identifying 29 with PCR-confirmed COVID-19 infection and 16 with COVID-19-like symptoms without PCR-testing. Of the 29 confirmed cases, 7 had severe disease, 8 required hospital admission (27.6%), 4 intensive care, and 1 died. COVID-19 accumulated incidence was higher in lupus patients. Health care workers and anti-SSA/Ro52 antibody positivity were risk factors for COVID-19 susceptibility, and hypocomplementemia for severity. SARS-CoV-2 IgG antibodies were detected in 8.33% of patients. Three fourths of confirmed COVID-19 cases developed antibodies. High prednisone doses were associated with lack of antibody response. Antibody titers declined over time (39%). Convalescent patients at week 12 after symptom onset displayed a CD8+T cell reduction and predominant Th17 with a mild Th2 response, more pronounced in severe COVID-19 disease. Longitudinal immune response analysis showed a progressive sustained increase in CD8+ T and B memory cells with a decrease of Th17 signaling. Lupus patients are at higher risk of COVID-19 infection and new susceptibility and severity risk factors were identified. Lupus patients were able to mount humoral and cellular responses despite immunosuppressive therapy.
204	I202		Juan Zhao,Madison Schank,Ling Wang,Xindi Dang,Dechao Cao,Sushant Khanal,Lam N.T. Nguyen,Yi Zhang,Xiao Y. Wu,James L. Adkins,Benjamin J. Pelton,Jinyu Zhang,Shunbin Ning,Mohamed El Gazzar,Jonathan P. Moorman,Zhi Q. Yao	Plasma biomarkers for systemic inflammation in COVID-19 survivors	https://doi.org/10.1002/prca.202200031	Published	05 August 2022	Study	https://onlinelibrary.wiley.com/doi/full/10.1002/prca.202200031	Background While the majority of COVID-19 patients fully recover from the infection and become asymptomatic, a significant proportion of COVID-19 survivors experience a broad spectrum of symptoms lasting weeks to months post-infection, a phenomenon termed “post-acute sequelae of COVID-19 (PASC).” The aim of this study is to determine whether inflammatory proteins are dysregulated and can serve as potential biomarkers for systemic inflammation in COVID-19 survivors. Methods We determined the levels of inflammatory proteins in plasma from 22 coronavirus disease 2019 (COVID-19) long haulers (COV-LH), 22 COVID-19 asymptomatic survivors (COV-AS), and 22 healthy subjects (HS) using an Olink proteomics assay and assessed the results by a beads-based multiplex immunoassay. Results Compared to HS, we found that COVID-19 survivors still exhibited systemic inflammation, as evidenced by significant changes in the levels of multiple inflammatory proteins in plasma from both COV-LH and COV-AS. CXCL10 was the only protein that significantly upregulated in COV-LH compared with COV-AS and HS. Conclusions Our results indicate that several inflammatory proteins remain aberrantly dysregulated in COVID-19 survivors and CXCL10 might serve as a potential biomarker to typify COV-LH. Further characterization of these signature inflammatory molecules might improve the understanding of the long-term impacts of COVID-19 and provide new targets for the diagnosis and treatment of COVID-19 survivors with PASC.
205	I203		Muhammad G. Saleh ORCID logo, Linda Chang, Huajun Liang, Meghann C. Ryan, Eric Cunningham, Jonathan Garner, Eleanor Wilson, Andrea R. Levine, Shyamasundaran Kottilil and Thomas Ernst	Ongoing oxidative stress in individuals with post-acute sequelae of COVID-19	https://doi.org/10.1515/nipt-2022-0006	Published	August 15, 2022	Study	https://www.degruyter.com/document/doi/10.1515/nipt-2022-0006/html	Objectives Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is associated with lower plasma glutathione (GSH) levels due to oxidative stress. However, plasma levels may not reflect brain GSH levels. Individuals with post-acute sequelae of COVID-19 (PASC) have a higher prevalence of cognitive fatigue, which might be related to altered brain γ-aminobutyric-acid (GABA) levels. Hence, our study aims to measure the brain GSH and GABA levels in PASC. Methods 29 PASC participants and 24 uninfected controls were recruited for this study. Each was evaluated with detailed neuropsychiatric assessments and an edited proton MRS (Hadamard Encoding and Reconstruction of Mega-Edited Spectroscopy, HERMES) method to measure GABA and GSH concentrations in predominantly grey matter (GM) and predominantly white matter (WM) brain frontal voxels. Results PASC participants were 219 ± 137 days since their COVID-19 diagnosis. Nine individuals with PASC were hospitalized. Compared to controls, individuals with PASC had similar levels of GABA in both brain regions, but lower GSH and greater age-related GSH decline in the frontal GM region. Conclusions The lower-than-normal frontal GM GSH level in participants with PASC suggest that they have ongoing oxidative stress in the brain, and that older individuals may be even more vulnerable to oxidative stress.
206	I204		Marta Bertran1, Snehal M Pinto Pereira2, Manjula D Nugawela3, Terence Stephenson3, Roz Shafran3, Tamsin Ford4, Marta Buszewicz5, Elizabeth Whittaker6, Isobel Heyman3, Terry Y Segal 7, Emma Dalrymple3, Shamez N Ladhani	Association between parents experiencing ongoing problems from COVID-19 and adolescents reporting LONG COVID six months after a positive or negative SARS-CoV-2 PCR-test: prospective, national cohort study in England		pre-print	August 14, 2022	Study	https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4192732	Abstract In a national cohort of 12,788 adolescents, those reporting parents experiencing ongoing problems from COVID-19 had 1.79-fold (95%CI: 1.58-2.02) higher odds of experiencing LONG COVID 6 months after a SARS-CoV-2 PCR-test than those reporting parents without ongoing symptoms, independent of age, sex, deprivation and SARS-CoV-2 infection status. Funding: This work was supported by the Department of Health and Social Care, in their capacity as the National Institute for Health Research (NIHR), and by the UK Research and Innovation (UKRI) who have awarded funding grant number COVLT0022. All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. SMPP is supported by a UK Medical Research Council Career Development Award (ref: MR/P020372/1).
207	I205		Michael J. Peluso, Tyler-Marie Deveau, Sadie E. Munter, Dylan Ryder, Amanda Buck, Gabriele Beck-Engeser, Fay Chan, Scott Lu, Sarah A. Goldberg, Rebecca Hoh, Viva Tai, Leonel Torres, Nikita S. Iyer, Monika Deswal, Lynn H. Ngo, Melissa Buitrago, Antonio Rodriguez, Jessica Y. Chen, Brandon C. Yee, Ahmed Chenna, John W. Winslow, Christos J. Petropoulos, Amelia N. Deitchman, Joanna Hellmuth, Matthew A. Spinelli, Matthew S. Durstenfeld, Priscilla Y. Hsue, J. Daniel Kelly, Jeffrey N. Martin, Steven G. Deeks, Peter W. Hunt, Timothy J. Henrich	Impact of Pre-Existing Chronic Viral Infection and Reactivation on the Development of Long COVID	https://doi.org/10.1101/2022.06.21.22276660	pre-print	July 22, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.06.21.22276660v2.full-text	The presence and reactivation of chronic viral infections such as Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human immunodeficiency virus (HIV) have been proposed as potential contributors to Long COVID (LC), but studies in well-characterized post-acute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited. In a cohort of 280 adults with prior SARS-CoV-2 infection, we observed that LC symptoms such as fatigue and neurocognitive dysfunction at a median of 4 months following initial diagnosis were independently associated with serological evidence of recent EBV reactivation (early antigen-D [EA-D] IgG positivity) or high nuclear antigen IgG levels, but not with ongoing EBV viremia. Evidence of EBV reactivation (EA-D IgG) was most strongly associated with fatigue (OR 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR 0.52) and tended to have less severe (>5 symptoms reported) LC (OR 0.44). Overall, these findings suggest differential effects of chronic viral co-infections on the likelihood of developing LC and predicted distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted. SUMMARY The authors found that Long COVID symptoms in a post-acute cohort were associated with serological evidence of recent EBV reactivation and pre-existing HIV infection when adjusted for participant factors, sample timing, comorbid conditions and prior hospitalization, whereas underlying CMV infection was associated with a decreased risk of Long COVID.
208	I206		ShuangLiuaYasuyukiSuzukiabcErikaTakemasaaRyusukeWatanabeaMasakiMogia	Mast cells promote viral entry of SARS-CoV-2 via formation of chymase/spike protein complex	https://doi.org/10.1016/j.ejphar.2022.175169	Published	31 July 2022	Study	https://www.sciencedirect.com/science/article/pii/S0014299922004307	The pulmonary pathological findings associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) result from the release of multiple proinflammatory cytokines, which causes the subsequential damage of the lungs. The current study was undertaken to investigate the responses of mast cells to viral inoculation and their contribution to host defenses from the point of view of viral entry. Pseudovirions, in which the spike glycoprotein of SARS-CoV-2 was incorporated, triggered activation of mast cells, and a mast cell-derived chymase, MCP2, formed a complex with spike protein, which promoted protease-dependent viral entry. According to the quantification results of viral entry, 10 μM quercetin, a mast cell stabilizer, potentially potently inhibited 41.3% of viral entry, while 100 μM chymostatin, which served as a chymase inhibitor, suppressed 52.1% of viral entry, compared to non-treated cells. Study using mast cell-deficient mice showed that the absence of mast cells may influence early viral loading in the upper respiratory tract, which consequently increases the risk of viral invasion into the lower respiratory system. Furthermore, mast cell-deficient mice exhibited ongoing infection in the late phase post-viral inoculation, while clearance of virus-positive cells was observed in wild-type mice. In conclusion, mast cells act as a multifaceted immune modulator that is equipped with both protective effects and pathogenic influences on viral entry of SARS-CoV-2. The utility of mast cell stabilizers and chymase inhibitors in the treatment of SARS-CoV-2-induced acute respiratory syndrome should be optimized regarding the infection stage and the risk of cytokine storm.
209	I207	VP	Daniel Benharroch* and Karen Nalbandyan	Sars-Cov-2 Persistent Infection May Evolve into Malignancy, Possibly Curbed by Vaccination: A Hypothesis	https://doi.org/10.47363/JIRR/2022(2)114	Published	July 13, 2022	Review	https://onlinescientificresearch.com/articles/sarscov2-persistent-infection-may-evolve-into-malignancy-possibly-curbed-by-vaccination-a-hypothesis.pdf	The three coronavirus variant infections which evolve onto severe respiratory conditions, have occasionally been associated with persistence. The viral RNA might be solely affected, or else, new symptoms might represent the only disease manifestations, often systemic and neurological. At times, it may associate with variable immunity. A persistent COVID-19 may initiate a “long COVID” episode. It has been hypothesized that, pending an expanded follow-up, the persistence of the SARS-CoV-2 might advance into a cancer: TMPRSS2 gene might develop into prostate cancer, while ground glass lung opacities might lead to lung cancer. In contrast, vaccines may impede the development of a malignancy. Among these, the BCG vaccine predominates, together with the MMR vaccine; mumps and measles being possibly responsible for tumor handicap. It is too early to discern a similar role for COVID-19 with anti-SARSCoV-2 vaccines, as they may relate to cancer.
210	I208		Paul Kuodi, Yanay Gorelik, Hiba Zayyad, Ofir Wertheim, Karine Beiruti Wiegler, Kamal Abu Jabal, Amiel A. Dror, Saleh Nazzal, Daniel Glikman & Michael Edelstein	Association between BNT162b2 vaccination and reported incidence of post-COVID-19 symptoms: cross-sectional study 2020-21, Israel	https://doi.org/10.1038/s41541-022-00526-5	Published	26 August 2022	Study	https://www.nature.com/articles/s41541-022-00526-5	The effectiveness of Coronavirus disease 2019 (COVID-19) vaccines against the long-term COVID-19 symptoms expressed by a substantial proportion of patients is not well understood. We determined whether vaccination with the BNT162b2 mRNA vaccine was associated with incidence of reporting long-term symptoms post-SARS-CoV-2 infection. We invited individuals PCR-tested for SARS-CoV-2 infection at participating hospitals between March 2020 and November 2021 to fill an online questionnaire that included information about demographics, acute COVID-19 episode and symptoms they were currently experiencing. Using binomial regression, we compared vaccinated individuals with those unvaccinated and those uninfected, in terms of post-acute self-reported symptoms. Of the 951 infected, 637(67%) were vaccinated. In the study population, the most prevalent symptoms were: fatigue (22%), headache (20%), weakness of limbs (13%), and persistent muscle pain (10%). After adjusting for age, time from beginning of symptoms to responding to the survey, and baseline symptoms, those who received two vaccine doses were less likely than unvaccinated individuals to report any of these symptoms (fatigue, headache, weakness of limbs, persistent muscle pain) by 62%, 50%, 62%, and 66% respectively, (Risk ratios 0.38, 0.50, 0.38, 0.34, p < 0.04 in the listed sequence). Compared to the 2447 included individuals who never reported SARS-CoV-2 infection, double-vaccinated participants were no more likely to report any of the mentioned symptoms. Vaccination with 2+ doses of BNT162b2 was associated with a reduced risk of reporting most of the common post-acute COVID-19 symptoms. Our results suggest that BNT162b2 vaccination may have a protective effect against longer term COVID-19 symptoms.
211	I209		Kin IsraelNotarteaJesus AlfonsoCatahaybJacqueline VeronicaVelascocAdrielPastranacAbbygail ThereseVercFlos CarmeliPangilinancPrincess JuneirePeligrocMichaelCasimirocJonathan JaimeGuerrerodMa. Margarita LeticiaGellacocGiuseppeLippieBrandon MichaelHenryfCésarFernández-de-las-Peñasg	Impact of COVID-19 vaccination on the risk of developing long-COVID and on existing long-COVID symptoms: A systematic review	https://doi.org/10.1016/j.eclinm.2022.101624	Published	27 August 2022	Systematic review	https://www.sciencedirect.com/science/article/pii/S2589537022003546	Background Although COVID-19 vaccination decreases the risk of severe illness, it is unclear whether vaccine administration may impact the prevalence of long-COVID. The aim of this systematic review is to investigate the association between COVID-19 vaccination and long-COVID symptomatology. Methods MEDLINE, CINAHL, PubMed, EMBASE, and Web of Science databases, as well as medRxiv and bioRxiv preprint servers were searched up to June 20, 2022. Peer-reviewed studies or preprints monitoring multiple symptoms appearing after acute SARS-CoV-2 infection either before or after COVID-19 vaccination collected by personal, telephone or electronic interviews were included. The methodological quality of the studies was assessed using the Newcastle-Ottawa Scale. Findings From 2584 studies identified, 11 peer-reviewed studies and six preprints were included. The methodological quality of 82% (n=14/17) studies was high. Six studies (n=17,256,654 individuals) investigated the impact of vaccines before acute SARS-CoV-2 infection (vaccine-infection-long-COVID design). Overall, vaccination was associated with reduced risks or odds of long-COVID, with preliminary evidence suggesting that two doses are more effective than one dose. Eleven studies (n=36,736 COVID-19 survivors) investigated changes in long-COVID symptoms after vaccination (infection-long-COVID-vaccine design). Seven articles showed an improvement in long-COVID symptoms at least one dose post-vaccination, while four studies reported no change or worsening in long-COVID symptoms after vaccination. Interpretation Low level of evidence (grade III, case-controls, cohort studies) suggests that vaccination before SARS-CoV-2 infection could reduce the risk of subsequent long-COVID. The impact of vaccination in people with existing long-COVID symptoms is still controversial, with some data showing changes in symptoms and others did not. These assumptions are limited to those vaccines used in the studies.
212	I210		Sara Díaz-Salazar,Raquel Navas,Laura Sainz-Maza,Patricia Fierro,Meryam Maamar,Arancha Artime,Héctor Basterrechea,Benedetta Petitta,Stefanie Pini,José Manuel OlmosORCID Icon,Carmen RamosORCID Icon,Emilio ParienteORCID Icon &José Luis Hernández	Blood group O is associated with post-COVID-19 syndrome in outpatients with a low comorbidity index	https://doi.org/10.1080/23744235.2022.2115548	Published	27 Aug 2022	Study	https://www.tandfonline.com/doi/abs/10.1080/23744235.2022.2115548	Background ABO blood group system modulates the inflammatory response and has been implicated in COVID-19. Group O protects against SARS-CoV-2 infection, but there are no data regarding post-COVID-19 syndrome (PCS). Our aim was to assess this possible association. Methods Case–control study in a community setting, with subjects who had experienced mild COVID-19. Cases were PCS+, controls were PCS-, and the exposure variable, group O. We collected age, sex, BMI, smoking, comorbidities, inflammatory markers, anti-SARS-CoV-2 IgG antibodies, blood type and clinical data. Five composite inflammatory indices were developed. Multivariate analyses were performed. Results We analysed 121 subjects (56.2% women), mean age 45.7 ± 16 years. Blood group frequencies were 41.5%, 7.9%, 5.9%, and 44.5% for A, B, AB and O, respectively. Thirty-six patients were PCS+, without significant differences between cases and controls. Compared to non-O, a higher prevalence of PCS (p = .036), and number of symptoms of PCS (p = .017) were noted in group O. Concerning biomarkers, PCS + and PCS- showed no differences in A, B, and AB groups. In contrast, group O PCS + patients had significantly lower albumin-to-globulin ratio and higher lymphocyte count, fibrinogen, CRP levels, and higher percentages of 3 composite indices, than PCS- subjects. Group O showed a 6-fold increased risk of PCS, compared to non-O (adjusted OR = 6.25 [95%CI, 1.6-23]; p = .007). Conclusions Group O has shown a consistent relationship with PCS, characterised by a more intense inflammatory burden than the other blood groups. Blood group O could be part of the immunological link between acute COVID-19 and PCS.
213	I211		C. Kedor, H. Freitag, L. Meyer-Arndt, K. Wittke, L. G. Hanitsch, T. Zoller, F. Steinbeis, M. Haffke, G. Rudolf, B. Heidecker, T. Bobbert, J. Spranger, H. D. Volk, C. Skurk, F. Konietschke, F. Paul, U. Behrends, J. Bellmann-Strobl & C. Scheibenbogen	A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity	https://doi.org/10.1038/s41467-022-32507-6	Published	30 August 2022	Study	https://www.nature.com/articles/s41467-022-32507-6	A subset of patients has long-lasting symptoms after mild to moderate Coronavirus disease 2019 (COVID-19). In a prospective observational cohort study, we analyze clinical and laboratory parameters in 42 post-COVID-19 syndrome patients (29 female/13 male, median age 36.5 years) with persistent moderate to severe fatigue and exertion intolerance six months following COVID-19. Further we evaluate an age- and sex-matched postinfectious non-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome cohort comparatively. Most post-COVID-19 syndrome patients are moderately to severely impaired in daily live. 19 post-COVID-19 syndrome patients fulfill the 2003 Canadian Consensus Criteria for myalgic encephalomyelitis/chronic fatigue syndrome. Disease severity and symptom burden is similar in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome and non-COVID-19/myalgic encephalomyelitis/chronic fatigue syndrome patients. Hand grip strength is diminished in most patients compared to normal values in healthy. Association of hand grip strength with hemoglobin, interleukin 8 and C-reactive protein in post-COVID-19 syndrome/non-myalgic encephalomyelitis/chronic fatigue syndrome and with hemoglobin, N-terminal prohormone of brain natriuretic peptide, bilirubin, and ferritin in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome may indicate low level inflammation and hypoperfusion as potential pathomechanisms.
214	I212		Vladimir V. Klimov	Allergies in COVID-19 and Post-COVID Syndrome	https://doi.org/10.1007/978-3-031-04309-3_10	Published	02 September 2022	Article	https://link.springer.com/chapter/10.1007/978-3-031-04309-3_10	This chapter focuses on the immunity and atopic allergies in COVID and post-COVID syndrome. The pandemic SARS-CoV-2 infection has added to our knowledge about immune reactions and responses, uncommon clinical situations, risk factors for poor outcomes, and promoted novel treatment approaches. We consider the process of viral entry in a host cell and how Th2-cytokines can inhibit it, and corticosteroids suppress SARS-CoV-2 replication. There are controversial data concerning atopic allergies, mainly asthma, during COVID-19, and multifactorial influence on disease outcomes and residual changes. Systematic reviews, meta-analyses, and online surveys allow us a vision of the whole panorama.
215	I213		Mohd Arish,Wei Qian,Harish Narasimhan,Jie Sun	COVID-19 immunopathology: From acute diseases to chronic sequelae	https://doi.org/10.1002/jmv.28122	Published	03 September 2022	Review	https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.28122	The clinical manifestation of coronavirus disease 2019 (COVID-19) mainly targets the lung as a primary affected organ, which is also a critical site of immune cell activation by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, recent reports also suggest the involvement of extrapulmonary tissues in COVID-19 pathology. The interplay of both innate and adaptive immune responses is key to COVID-19 management. As a result, a robust innate immune response provides the first line of defense, concomitantly, adaptive immunity neutralizes the infection and builds memory for long-term protection. However, dysregulated immunity, both innate and adaptive, can skew towards immunopathology both in acute and chronic cases. Here we have summarized some of the recent findings that provide critical insight into the immunopathology caused by SARS-CoV-2, in acute and post-acute cases. Finally, we further discuss some of the immunomodulatory drugs in preclinical and clinical trials for dampening the immunopathology caused by COVID-19.
216	I214		Bellanti, Joseph A.	The long COVID syndrome: A conundrum for the allergist/immunologist	https://doi.org/10.2500/aap.2022.43.220059	Published	25 September 2022	Article	https://www.ingentaconnect.com/content/ocean/aap/2022/00000043/00000005/art00007	Background: The long coronavirus disease 2019 (COVID-19) syndrome includes a group of patients who, after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibit lingering mild-to-moderate symptoms and develop medical complications that can have lasting health problems. Objective: The purpose of this report was to examine the current body of evidence that deals with the relationship of COVID-19 infection with the long COVID syndrome to define the possible immunologic mechanisms involved in the pathogenesis of long COVID and to describe potential strategies for the diagnosis and clinical management of the condition. Methods: Extensive research was conducted in medical literature data bases by applying terms such as long COVID, post‐COVID-19 condition, pathogenesis of long COVID, management of the long COVID syndrome. Results: The post-COVID conditions, a more recent and less anxiety-inducing term for the patient than long COVID or “long haul,” is an umbrella term for a wide range of physical and mental health symptoms similar to those seen in patients with the myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), experienced by some patients and are present ≥ 4 weeks after SARS-CoV-2 infection. Although the precise reason why long COVID develops is unknown, one of the major causes is thought to be related to chronic inflammation with overproduction of inflammatory cytokines responsible for the symptoms of the disorder. Conclusion: Long COVID is a growing burden for millions of patients, health-care providers, and global health-care systems, and is a particular challenge for the allergist/immunologist. Many survivors of COVID-19 struggle with multiple symptoms, increased disability, reduced function, and poor quality of life. The allergist/immunologist can assist the total health-care team's efforts in providing a comprehensive and coordinated approach to the management of these patients by promoting comprehensive vaccination and rehabilitation and social services that focus on improving physical, mental, and social well-being, and by establishing partnerships with specialists and other health-care professionals who can provide behavioral, lifestyle, and integrative approaches that may have much to offer in helping patients cope with their symptoms.
217	I215		Bailey Brooks 1,2ORCID,Christina Tancredi 2,Yufeng Song 2,Alemu Tekewe Mogus 2,Meei-Li W. Huang 3ORCID,Haiying Zhu 3,Tuan L. Phan 4,5,Harrison Zhu 5,6ORCID,Alexandra Kadl 7,8,Judith Woodfolk 7,9,Keith R. Jerome 3,10 andSteven L. Zeichner 2,9,*	Epstein–Barr Virus and Human Herpesvirus-6 Reactivation in Acute COVID-19 Patients	https://doi.org/10.3390/v14091872	Published	25 August 2022	Study	https://www.mdpi.com/1999-4915/14/9/1872/htm	Beyond their pulmonary disease, many COVID-19 patients experience a complex constellation of characteristics, including hyperinflammatory responses, autoimmune disorders, and coagulopathies. However, the pathogenesis of these aspects of COVID-19 is obscure. More than 90% of people are latently infected with the lymphotropic herpesviruses Epstein–Barr Virus (EBV) and/or Human Herpesvirus-6 (HHV-6). Some of the inflammatory features of COVID-19 resemble clinical syndromes seen during EBV and HHV-6 infection, and these latent viruses can be reactivated by inflammatory mediators. We hypothesized that EBV and HHV-6 reactivation might be a common feature of early COVID-19, particularly in patients with more inflammation. We tested for EBV and HHV-6 reactivation in 67 patients acutely hospitalized with COVID-19 using previously validated quantitative PCR assays on the plasma. In our cohort, we found that 15/67 (22.4%) patients had detectable EBV and 3/67 (4.5%) had detectable HHV-6. This frequency of activation is somewhat more than the frequency reported for some healthy cohorts, such as blood donors and other healthy control cohorts. There was no association between EBV or HHV-6 and markers indicative of more inflammatory disease. We conclude that EBV and HHV-6 activation at about day 7 of hospitalization occurred in a modest fraction of our cohort of COVID-19 patients and was not associated with high levels of inflammation. In the modest fraction of patients, EBV and HHV-6 reactivation could contribute to some features of acute disease and pre-disposition to post-acute sequelae in a subset of patients.
218	I216		César Fernández-de-las-Peñas 1,*ORCID,Ricardo Ortega-Santiago 1,Stella Fuensalida-Novo 1ORCID,José D. Martín-Guerrero 2ORCID,Oscar J. Pellicer-Valero 2ORCID andJuan Torres-Macho 3,4ORCID	Differences in Long-COVID Symptoms between Vaccinated and Non-Vaccinated (BNT162b2 Vaccine) Hospitalized COVID-19 Survivors Infected with the Delta Variant	https://doi.org/10.3390/vaccines10091481	Published	6 September 2022	Study	https://www.mdpi.com/2076-393X/10/9/1481/htm	This study compared differences in the presence of post-COVID symptoms among vaccinated and non-vaccinated COVID-19 survivors requiring hospitalization due to the Delta (B.1.617.2) variant. This cohort study included hospitalized subjects who had survived SARS-CoV-2 infection (Delta variant) from July to August 2021 in an urban hospital in Madrid, Spain. Individuals were classified as vaccinated if they received full administration (i.e., two doses) of BNT162b2 (“Pfizer-BioNTech”) vaccines. Other vaccines were excluded. Those with just one dose of the BNT162b2 vaccine were considered as non-vaccinated. Patients were scheduled for a telephone interview at a follow-up around six months after infection for assessing the presence of post-COVID symptoms with particular attention to those symptoms starting after acute infection and hospitalization. Anxiety/depressive levels and sleep quality were likely assessed. Hospitalization and clinical data were collected from medical records. A total comprising 109 vaccinated and 92 non-vaccinated COVID-19 survivors was included. Vaccinated patients were older and presented a higher number of medical comorbidities, particular cardiorespiratory conditions, than non-vaccinated patients. No differences in COVID-19 onset symptoms at hospitalization and post-COVID symptoms six months after hospital discharge were found between vaccinated and non-vaccinated groups. No specific risk factor for any post-COVID symptom was identified in either group. This study observed that COVID-19 onset-associated symptoms and post-COVID symptoms six-months after hospitalization were similar between previously hospitalized COVID-19 survivors vaccinated and those non-vaccinated. Current data can be applied to the Delta variant and those vaccinated with BNT162b2 (Pfizer-BioNTech) vaccine.
219	I217	VP	Denise Goh1†, Jeffrey Chun Tatt Lim1†, Sonia Bilbao Fernaíndez2†, Craig Ryan Joseph1, Sara Gil Edwards3, Zhen Wei Neo1, Justina Nadia Lee1, Sílvia Guerrero Caballero2, Mai Chan Lau1 and Joe Poh Sheng Yeong	Case report: Persistence of residual antigen and RNA of the SARS-CoV-2 virus in tissues of two patients with long COVID	https://doi.org/10.3389/fimmu.2022.939989	Published	05 September 2022	Case Report	https://www.frontiersin.org/articles/10.3389/fimmu.2022.939989/full	The World Health Organization has defined long COVID-19 (LC) as a condition that occurs in individuals with a history of SARS-CoV-2 infection who exhibit persistent symptoms after its acute phase that last for at least two months and cannot be explained by an alternative diagnosis. Since we had previously reported residual viral antigens in tissues of convalescent patients, we aimed to assess the presence of such antigens in long COVID tissues. Here, we established the presence of the residual virus in the appendix, skin, and breast tissues of 2 patients who exhibited LC symptoms 163 and 426 days after symptom onset. With multiplex immunohistochemistry, we detected viral nucleocapsid protein in all three tissues. The nucleocapsid protein was further observed to colocalize with macrophage marker CD68, suggesting that immune cells were direct targets of SARS-CoV-2. Additionally, using RNAscope, the presence of viral RNA was also detected. Our positive finding in the breast tissue is corroborated by the recent reports of immunocompromised patients experiencing LC symptoms and persistent viral replication. Overall, our findings and emerging LC studies raise the possibility that the gastrointestinal tract may function as a reservoir for SARS-CoV-2.
220	I218		Miklós Fagyas, Béla Nagy Jr., Arnold Péter Ráduly, Ivetta Siket Mányiné, Lilla Mártha, Gábor Erdősi, Sándor Sipka Jr., Enikő Enyedi, Attila Ádám Szabó, Zsófia Pólik, János Kappelmayer, Zoltán Papp, Attila Borbély, Tamás Szabó, József Balla, György Balla, Péter Bai, Attila Bácsi & Attila Tóth	The majority of severe COVID-19 patients develop anti-cardiac autoantibodies	https://doi.org/10.1007/s11357-022-00649-6	Published	16 September 2022	Study	https://link.springer.com/article/10.1007/s11357-022-00649-6	Severe cases of COVID-19 are characterized by an inflammatory burst, which is accompanied by multiorgan failure. The elderly population has higher risk for severe or fatal outcome for COVID-19. Inflammatory mediators facilitate the immune system to combat viral infection by producing antibodies against viral antigens. Several studies reported that the pro-inflammatory state and tissue damage in COVID-19 also promotes autoimmunity by autoantibody generation. We hypothesized that a subset of these autoantibodies targets cardiac antigens. Here we aimed to detect anti-cardiac autoantibodies in severe COVID-19 patients during hospitalization. For this purpose, 104 COVID-19 patients were recruited, while 40 heart failure patients with dilated cardiomyopathy and 20 patients with severe aortic stenosis served as controls. Patients were tested for anti-cardiac autoantibodies, using human heart homogenate as a bait. Follow-up samples were available in 29 COVID-19 patients. Anti-cardiac autoantibodies were detected in 68% (71 out of 104) of severe COVID-19 patients. Overall, 39% of COVID-19 patients had anti-cardiac IgG autoantibodies, while 51% had anti-cardiac autoantibodies of IgM isotype. Both IgG and IgM anti-cardiac autoantibodies were observed in 22% of cases, and multiple cardiac antigens were targeted in 38% of COVID-19 patients. These anti-cardiac autoantibodies targeted a diverse set of myocardial proteins, without apparent selectivity. As controls, heart failure patients (with dilated cardiomyopathy) had similar occurrence of IgG (45%, p = 0.57) autoantibodies, while significantly lower occurrence of IgM autoantibodies (30%, p = 0.03). Patients with advanced aortic stenosis had significantly lower number of both IgG (11%, p = 0.03) and IgM (10%, p < 0.01) type anti-cardiac autoantibodies than that in COVID-19 patients. Furthermore, we detected changes in the anti-cardiac autoantibody profile in 7 COVID-19 patients during hospital treatment. Surprisingly, the presence of these anti-cardiac autoantibodies did not affect the clinical outcome and the prevalence of the autoantibodies did not differ between the elderly (over 65 years) and the patients younger than 65 years of age. Our results demonstrate that the majority of hospitalized COVID-19 patients produce novel anti-cardiac IgM autoantibodies. COVID-19 also reactivates resident IgG autoantibodies. These autoantibodies may promote autoimmune reactions, which can complicate post-COVID recuperation, contributing to post-acute sequelae of COVID-19 (long COVID).
221	I219		Shahrooz AminMozaffariaAliSalehibElnazMousavicBurhan AbdullahZamandAli EslambolNassajeFarnooshEbrahimzadehfHadiNasiriaZahraValedkarimiaAliAdilighGhazalehAsemaniaMortezaAkbariia	SARS-CoV-2-associated gut microbiome alteration; a new contributor to colorectal cancer pathogenesis	https://doi.org/10.1016/j.prp.2022.154131	Published	16 September 2022	Review	https://www.sciencedirect.com/science/article/pii/S0344033822003752	The emergence of a novel coronavirus, COVID-19, in December 2019 led to a global pandemic with more than 170 million confirmed infections and more than 6 million deaths (by July 2022). Studies have shown that infection with SARS-CoV-2 in cancer patients has a higher mortality rate than in people without cancer. Here, we have reviewed the evidence showing that gut microbiota plays an important role in health and is linked to colorectal cancer development. Studies have shown that SARS-CoV-2 infection leads to a change in gut microbiota, which modify intestinal inflammation and barrier permeability and affects tumor-suppressor or oncogene genes, proposing SARS-CoV-2 as a potential contributor to CRC pathogenesis
222	I220		Javier García-Abellán, 1 , 2 , 3 Marta Fernández, 1 , 3 Sergio Padilla, 1 , 2 , 3 José Alberto García, 1 , 3 Vanesa Agulló, 1 , 3 Valle Lozano, 4 Nuria Ena, 1 Lidia García-Sánchez, 1 Félix Gutiérrez,corresponding author 1 , 2 , 3 , * , † and Mar Masiácorresponding author 1	Immunologic phenotype of patients with long-COVID syndrome of 1-year duration	https://doi.org/10.3389%2Ffimmu.2022.920627	Published	2022 Aug 24	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9451924/	Background The pathophysiology of long-COVID remains unknown, and information is particularly limited for symptoms of very long duration. We aimed to assess the serological, T-cell immune responses and ANA titers of patients with long-COVID-19 syndrome of 1-year duration. Methods Prospective, longitudinal study of hospitalized COVID-19 patients followed-up for 12 months. Sequential blood samples and COVID-19 symptom questionnaires (CSQ) were obtained, and humoral and cellular immune responses, antinuclear antibodies (ANA) and inflammation biomarkers were analyzed. Results Of 154 patients discharged from hospital, 72 non-vaccinated with available CSQ in all visits were included. Of them, 14 (19.4%) reported persistent symptoms both at 6-months and 12-months, mainly asthenia (15.3%), myalgia (13.9%), and difficulty concentrating/memory loss (13.9%). Symptomatic patients were more frequently women, smokers, showed higher WHO severity score, and a trend to higher ICU admission. In the adjusted analysis, long-COVID syndrome was associated with lower frequency of detectable neutralizing antibodies (adjusted hazard ratio [aHR] 0.98; 95% confidence interval [CI], 0.97-0.99) and lower SARS-CoV-2-S1/S2 titers (aHR [95%CI] 0.14 [0.03–0.65]). T-cell immune response measured with a SARS-CoV-2-interferon-γ release assay was not different between groups. There was a higher frequency of positive ANA titers (≥160) in symptomatic patients (57.1% vs 29.3%, p=0.04), that was attenuated after adjustment aHR [95% CI] 3.37 [0.84-13.57], p=0.087. Levels of C-reactive protein and D-dimer were higher during follow-up in symptomatic patients, but with no differences at 12 months. Conclusion Patients with 1-year duration long-COVID-19 syndrome exhibit a distinct immunologic phenotype that includes a poorer SARS-CoV-2 antibody response, low-degree chronic inflammation that tends to mitigate, and autoimmunity.
223	I221		Soumya Arun, Abbie Storan, Bethan Myers	Mast cell activation syndrome and the link with long COVID	https://doi.org/10.12968/hmed.2022.0123	Published	26 Jul 2022	Review	https://www.magonlinelibrary.com/doi/abs/10.12968/hmed.2022.0123	Mast cells are innate immune cells found in connective tissues throughout the body, most prevalent at tissue-environment interfaces. They possess multiple cell-surface receptors which react to various stimuli and, after activation, release many mediators including histamine, heparin, cytokines, prostaglandins, leukotrienes and proteases. In mast cell activation syndrome, excessive amounts of inflammatory mediators are released in response to triggers such as foods, fragrances, stress, exercise, medications or temperature changes. Diagnostic markers may be difficult to assess because of their rapid degradation; these include urinary N-methyl histamine, urinary prostaglandins D2, DM and F2α and serum tryptase (which is stable) in the UK. Self-management techniques, medications and avoiding triggers may improve quality of life. Treatments include mast cell mediator blockers, mast cell stabilisers and anti-inflammatory agents. ‘Long COVID’ describes post-COVID-19 syndrome when symptoms persist for more than 12 weeks after initial infection with no alternative diagnosis. Both mast cell activation syndrome and long COVID cause multiple symptoms. It is theorised that COVID-19 infection could lead to exaggeration of existing undiagnosed mast cell activation syndrome, or could activate normal mast cells owing to the persistence of viral particles. Other similarities include the relapse-remission cycle and improvements with similar treatments. Importantly, however, aside from mast cell disorders, long COVID could potentially be attributed to several other conditions.
224	I222		Michael J Peluso, Anthea Mitchell, Chung Yu Wang, Saki Takahashi, Rebecca Hoh, Viva Tai, Matthew S Durstenfeld, Priscilla Y Hsue, J Daniel Kelly, Jeffrey N Martin, Michael R Wilson, Bryan Greenhouse, Steven G Deeks, Joseph L DeRisi, Timothy J Henrich	Low Prevalence of Interferon-α Autoantibodies in People Experiencing Long COVID Symptoms	https://doi.org/10.1093/infdis/jiac372	Published	12 September 2022	Study	https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiac372/6696027	Interferon (IFN)-specific autoantibodies have been implicated in severe COVID-19 and have been proposed as a potential driver of the persistent symptoms characterizing Long COVID, a type of post-acute sequelae of SARS-CoV-2 infection (PASC). We report than only two of 215 SARS-CoV-2 convalescent participants tested over 394 timepoints, including 121 people experiencing Long COVID symptoms, had detectable IFN-α2 antibodies. Both had been hospitalized during the acute phase of the infection. These data suggest that persistent anti-IFN antibodies, although a potential driver of severe COVID-19, are unlikely to contribute to Long COVID symptoms in the post-acute phase of the infection.
225	I223		Rupert Donald Holms	Long COVID (PASC) Is Maintained by a Self-Sustaining Pro-Inflammatory TLR4/RAGE-Loop of S100A8/A9 > TLR4/RAGE Signalling, Inducing Chronic Expression of IL-1b, IL-6 and TNFa: Anti-Inflammatory Ezrin Peptides as Potential Therapy	https://doi.org/10.3390/immuno2030033	Published	8 September 2022	Review	https://www.mdpi.com/2673-5601/2/3/33/htm	Long COVID, also referred to as Post-Acute Sequelae of COVID (PASC), is probably triggered during SARS-CoV-2 infection and acute COVID-19 by SARS-CoV-2 Spike-protein binding and hyper-activating the cell-membrane expressed Receptor for Advance Glycation End-products (mRAGE) and Toll-Like Receptor 4 (TLR4). SARS-CoV-2 infects lung monocytes by Spike binding to mRAGE (not ACE2). During acute COVID-19, high levels of IL-6 hyper-stimulate S100A8/A9 expression and secretion. Although no viral protein nor mRNA can be detected in half of long COVID (PASC) patients, there is a significant elevation of serum levels of IL-1b, IL-6, TNFa, and S100A8/A9. It appears that a pathological pro-inflammatory feedback loop (the TLR4/RAGE-loop) is established during acute COVID-19, which is maintained by S100A8/A9 > RAGE/TLR4 chronic inflammatory signalling, even after SARS-CoV-2 has been cleared from the body. During long COVID/PASC, Ca2+-binding protein S100A8/A9 chronically stimulates TLR4/RAGE-signalling to induce chronic expression of IL-1b, IL-6 and TNFa. Secreted IL-6 binds to its IL-6R receptor on the surface of other cells and signals via STAT3 and C/EBPb for more S100A8/A9 expression. Secreted IL-1b binds to its receptor IL-1R on other cells, and signals via NFkB for more mRAGE and TLR4 expression. New S100A8/A9 can bind and activate cell-surface mRAGE and TLR4 to stimulate expression of more IL-1b, IL-6 and TNFa. This process establishes a pathogenic pro-inflammatory TLR4/RAGE-loop: IL-1b + IL-6 > IL-1R + IL-6R > TLR4/mRAGE + S100A8/A9 > IL-1b + IL-6, which generates multi-organ inflammation that persists in the blood vessels, the brain, the liver, the heart, the kidneys, the gut and the musculo-skeletal system, and is responsible for all the complex pathologies associated with long COVID/PASC. Chronic expression of IL-1, IL-6 and TNFa is critical for the maintenance of the TLR4/RAGE-loop and persistence of long COVID/PASC. Ezrin peptides are inhibitors of IL-1, IL-6, IL-8 and TNFa expression, so are now being investigated as potential therapy for long COVID/PASC. There is preliminary anecdotal evidence of symptomatic relief (not confirmed yet by formal clinical trials) from a few long COVID/PASC patient volunteers, after treatment with ezrin peptide therapy.
226	I224		Gabriella Captur 1 James C. Moon 1 Constantin-Cristian Topriceanu George Joy Leo Swadling Jenny Hallqvist Ivan Doykov Nina Patel Justyna Spiewak Tomas Baldwin Matt Hamblin Katia Menacho Marianna Fontana Thomas A. Treibel Charlotte Manisty Ben O'Brien Joseph M. Gibbons Corrina Pade Tim Brooks Daniel M. Altmann Rosemary J. Boyton Áine McKnight Mala K. Maini Mahdad Noursadeghi Kevin Mills 2 Wendy E. Heywood	Plasma proteomic signature predicts who will get persistent symptoms following SARS-CoV-2 infection	https://doi.org/10.1016/j.ebiom.2022.104293	Published	September 28, 2022	Study	https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00475-3/fulltext	Background The majority of those infected by ancestral Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) during the UK first wave (starting March 2020) did not require hospitalisation. Most had a short-lived mild or asymptomatic infection, while others had symptoms that persisted for weeks or months. We hypothesized that the plasma proteome at the time of first infection would reflect differences in the inflammatory response that linked to symptom severity and duration. Methods We performed a nested longitudinal case-control study and targeted analysis of the plasma proteome of 156 healthcare workers (HCW) with and without lab confirmed SARS-CoV-2 infection. Targeted proteomic multiple-reaction monitoring analysis of 91 pre-selected proteins was undertaken in uninfected healthcare workers at baseline, and in infected healthcare workers serially, from 1 week prior to 6 weeks after their first confirmed SARS-CoV-2 infection. Symptom severity and antibody responses were also tracked. Questionnaires at 6 and 12 months collected data on persistent symptoms. Findings Within this cohort (median age 39 years, interquartile range 30–47 years), 54 healthcare workers (44% male) had PCR or antibody confirmed infection, with the remaining 102 (38% male) serving as uninfected controls. Following the first confirmed SARS-CoV-2 infection, perturbation of the plasma proteome persisted for up to 6 weeks, tracking symptom severity and antibody responses. Differentially abundant proteins were mostly coordinated around lipid, atherosclerosis and cholesterol metabolism pathways, complement and coagulation cascades, autophagy, and lysosomal function. The proteomic profile at the time of seroconversion associated with persistent symptoms out to 12 months. Data are available via ProteomeXchange with identifier PXD036590. Interpretation Our findings show that non-severe SARS-CoV-2 infection perturbs the plasma proteome for at least 6 weeks. The plasma proteomic signature at the time of seroconversion has the potential to identify which individuals are more likely to suffer from persistent symptoms related to SARS-CoV-2 infection.
227	I225		Daniel Ayoubkhani, Matthew L Bosworth, Sasha King, Koen B Pouwels, Myer Glickman, Vahé Nafilyan, Francesco Zaccardi, Kamlesh Khunti, Nisreen A Alwan, A Sarah Walker	Risk of Long COVID in People Infected With Severe Acute Respiratory Syndrome Coronavirus 2 After 2 Doses of a Coronavirus Disease 2019 Vaccine: Community-Based, Matched Cohort Study	https://doi.org/10.1093/ofid/ofac464	Published	12 September 2022	Study	https://academic.oup.com/ofid/article/9/9/ofac464/6696170	We investigated long COVID incidence by vaccination status in a random sample of UK adults from April 2020 to November 2021. Persistent symptoms were reported by 9.5% of 3090 breakthrough severe acute respiratory syndrome coronavirus 2 infections and 14.6% of unvaccinated controls (adjusted odds ratio, 0.59 [95% confidence interval, .50–.69]), emphasizing the need for public health initiatives to increase population-level vaccine uptake.
228	I226		Eva Schulte1	68. UNTANGLING GENETIC RISK FACTORS OF LONG COVID: WORK OF THE INTERNATIONAL COVID-19 HOST GENETICS INITIATIVE	https://doi.org/10.1016%2Fj.euroneuro.2022.07.155	Published	2022 Sep 23	International Initiative	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9502139/	Background: WHO has published a clinical definition of the post COVID-19 condition, “Long COVID”, as a condition occurring “usually 3 months from the onset of COVID-19 with symptoms” “that cannot be explained by an alternative diagnosis”. Debilitating fatigue, exercise intolerance, cognitive dysfunction, disturbed sleep, anxiety, and depression are among the most prevalent symptoms, making the Long COVID phenotype of special interested to mental health professionals. Methods: We have established an open global collaboration for elucidating genetic risk factors of Long COVID. The Long COVID Host Genetics Initiative currently comprises 46 studies across 23 countries with genotype data combined with Long COVID phenotype definitions based on questionnaire information on symptoms and/or electronic health record (EHR) data. For the first data freeze, contributing studies (N=11) performed genome-wide association analyses (GWAS) comparing Long COVID (N=1,588) to individuals who have recovered from COVID within 3 months (N=96,714), and to population controls (N=800,478). Results: GWAS of individual cohorts have suggested potential variants associated with Long COVID but short of genome-wide statistical significance. We are currently running meta-analyses combining data from these studies. Further, data from individual studies have further detailed associations with other phenotypes in individuals with Long COVID. For example, in the FinnGen sample from Finland with 2,018 participants with a PCR-verified SARS-CoV-2 infection, and 50 (2.4%) with a Long COVID diagnosis, Long COVID associated with previous autoimmune diseases (p = 0.026, OR[se] = 2.15 [1.41]) but not with depression (p = 0.71, OR [se] = 1.20 [1.75]) or asthma (p = 0.43, OR[se] = 1.55 [1.74]). Data from the currently ongoing second GWAS data freeze and corresponding meta-analyses will be presented at the meeting. Discussion: Current global GWAS efforts for Long COVID seem promising in that they can further inform the underlying disease pathophysiology through genetics. Although no locus of genome-wide significance has been identified to date, the global collaboration in the COVID-19 Host Genetics Initiative allows us–through stark increases in sample sizes in the ongoing meta-analyses–to assume that this will change in the near future. The identification of genetic risk factors for COVID-19 is important because it furthers understanding about the underlying pathophysiology of the disorder, which is currently only incompletely understood, and because it could, in the future, aid in identifying at-risk individuals.
229	I227		Gabriella Captur 1James C. Moon 1 Constantin-Cristian Topriceanu George Joy Leo Swadling Jenny Hallqvist Ivan Doykov Nina Patel Justyna Spiewak Tomas Baldwin Matt Hamblin Katia Menacho Marianna Fontana Thomas A. Treibel Charlotte ManistyBen O'Brien Joseph M. Gibbons Corrina Pade Tim Brooks Daniel M. Altmann Rosemary J. Boyton Áine McKnight Mala K. Maini Mahdad Noursadeghi Kevin Mills 2 Wendy E. Heywood	Plasma proteomic signature predicts who will get persistent symptoms following SARS-CoV-2 infection	https://doi.org/10.1016/j.ebiom.2022.104293	Published	September 28, 2022	Study	https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00475-3/fulltext	Background The majority of those infected by ancestral Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) during the UK first wave (starting March 2020) did not require hospitalisation. Most had a short-lived mild or asymptomatic infection, while others had symptoms that persisted for weeks or months. We hypothesized that the plasma proteome at the time of first infection would reflect differences in the inflammatory response that linked to symptom severity and duration. Methods We performed a nested longitudinal case-control study and targeted analysis of the plasma proteome of 156 healthcare workers (HCW) with and without lab confirmed SARS-CoV-2 infection. Targeted proteomic multiple-reaction monitoring analysis of 91 pre-selected proteins was undertaken in uninfected healthcare workers at baseline, and in infected healthcare workers serially, from 1 week prior to 6 weeks after their first confirmed SARS-CoV-2 infection. Symptom severity and antibody responses were also tracked. Questionnaires at 6 and 12 months collected data on persistent symptoms. Findings Within this cohort (median age 39 years, interquartile range 30–47 years), 54 healthcare workers (44% male) had PCR or antibody confirmed infection, with the remaining 102 (38% male) serving as uninfected controls. Following the first confirmed SARS-CoV-2 infection, perturbation of the plasma proteome persisted for up to 6 weeks, tracking symptom severity and antibody responses. Differentially abundant proteins were mostly coordinated around lipid, atherosclerosis and cholesterol metabolism pathways, complement and coagulation cascades, autophagy, and lysosomal function. The proteomic profile at the time of seroconversion associated with persistent symptoms out to 12 months. Data are available via ProteomeXchange with identifier PXD036590. Interpretation Our findings show that non-severe SARS-CoV-2 infection perturbs the plasma proteome for at least 6 weeks. The plasma proteomic signature at the time of seroconversion has the potential to identify which individuals are more likely to suffer from persistent symptoms related to SARS-CoV-2 infection.
230	I228		Sophia Stromberg1, Bridget A. Baxter2, Gregory Dooley2, Stephanie M. LaVergne2, Emily Gallichotte3, Taru Dutt3, Madison Tipton2, Kailey Berry2, Jared Haberman2, Nicole Natter2, Tracy L. Webb4, Kim McFann5, Marcela Henao-Tamayo3, Greg Ebel3, Sangeeta Rao4, Julie Dunn5 and Elizabeth P. Ryan2	Relationships between plasma fatty acids in adults with mild, moderate, or severe COVID-19 and the development of post-acute sequelae	https://doi.org/10.3389/fnut.2022.960409	Published	14 September 2022	Study	https://www.frontiersin.org/articles/10.3389/fnut.2022.960409/full	Background: SARS-CoV-2 has infected millions across the globe. Many individuals are left with persistent symptoms, termed post-acute sequelae of COVID-19 (PASC), for months after infection. Hyperinflammation in the acute and convalescent stages has emerged as a risk factor for poor disease outcomes, and this may be exacerbated by dietary inadequacies. Specifically, fatty acids are powerful inflammatory mediators and may have a significant role in COVID-19 disease modulation. Objective: The major objective of this project was to pilot an investigation of plasma fatty acid (PFA) levels in adults with COVID-19 and to evaluate associations with disease severity and PASC. Methods and procedures: Plasma from adults with (N = 41) and without (N = 9) COVID-19 was analyzed by gas chromatography-mass spectrometry (GC-MS) to assess differences between the concentrations of 18 PFA during acute infection (≤14 days post-PCR + diagnosis) in adults with varying disease severity. Participants were grouped based on mild, moderate, and severe disease, alongside the presence of PASC, a condition identified in patients who were followed beyond acute-stage infection (N = 23). Results: Significant differences in PFA profiles were observed between individuals who experienced moderate or severe disease compared to those with mild infection or no history of infection. Palmitic acid, a saturated fat, was elevated in adults with severe disease (p = 0.04), while behenic (p = 0.03) and lignoceric acid (p = 0.009) were lower in adults with moderate disease. Lower levels of the unsaturated fatty acids, γ-linolenic acid (GLA) (p = 0.03), linoleic (p = 0.03), and eicosapentaenoic acid (EPA) (p = 0.007), were observed in adults with moderate disease. Oleic acid distinguished adults with moderate disease from severe disease (p = 0.04), and this difference was independent of BMI. Early recovery-stage depletion of GLA (p = 0.02) and EPA (p = 0.0003) was associated with the development of PASC. Conclusion: Pilot findings from this study support the significance of PFA profile alterations during COVID-19 infection and are molecular targets for follow-up attention in larger cohorts. Fatty acids are practical, affordable nutritional targets and may be beneficial for modifying the course of disease after a COVID-19 diagnosis. Moreover, these findings can be particularly important for overweight and obese adults with altered PFA profiles and at higher risk for PASC.
231	I229		Maria P.YavropoulouaGeorge C.TsokosbGeorge P.Chrousosc1Petros P.Sfikakisa1	Protracted stress-induced hypocortisolemia may account for the clinical and immune manifestations of Long COVID	https://doi.org/10.1016/j.clim.2022.109133	Published	29 September 2022	Comment	https://www.sciencedirect.com/science/article/pii/S1521661622002145	About one out of eight people to convalesce from COVID-19 suffer from the so called Long COVID, a syndrome of non-specific symptoms with unclear pathogenesis. In a recent study published in Cell Long COVID participants reporting respiratory symptoms had low cortisol levels. In an as yet unpublished analysis from Yale University low plasma cortisol levels discriminated Long COVID from asymptomatic convalescent or healthy non-infected controls. Although various immune perturbations were present in Long COVID, low levels of cortisol were prominent and strikingly, depression and anxiety were increased. It has become clear that Long COVID features may be similar to those described in myalgic encephalomyelitis/chronic fatigue syndrome, post-SARS sickness syndrome, and various chronic stress syndromes which have been linked to hypocortisolemia. Notably, lack of response of the hypothalamic–pituitary–adrenal axis to hypocortisolemia shows a suppressed axis in Long COVID. We suggest that the inability of hypothalamic–pituitary–adrenal axis to recover after the acute illness, perhaps due to protracted stress in predisposed individuals, may represent the pathogenetic basis of the Long COVID-associated clinical and immunological manifestations.
232	I230		John Kee, Samuel Thudium, David M. Renner, Karl Glastad, Katherine Palozola, Zhen Zhang, Yize Li, Yemin Lan, Joseph Cesare, Andrey Poleshko, Anna A. Kiseleva, Rachel Truitt, Fabian L. Cardenas-Diaz, Xianwen Zhang, Xuping Xie, Darrell N. Kotton, Konstantinos D. Alysandratos, Johnathan A. Epstein, Pei-Yong Shi, Wenli Yang, Edward Morrisey, Benjamin A. Garcia, Shelley L. Berger, Susan R. Weiss & Erica Korb	SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry	https://doi.org/10.1038/s41586-022-05282-z	Published	05 October 2022	Study	https://www.nature.com/articles/s41586-022-05282-z	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and caused the devastating global pandemic of coronavirus disease 2019 (COVID-19), in part because of its ability to effectively suppress host cell responses1,2,3. In rare cases, viral proteins dampen antiviral responses by mimicking critical regions of human histone proteins4,5,6,7,8, particularly those containing post-translational modifications required for transcriptional regulation9,10,11. Recent work has demonstrated that SARS-CoV-2 markedly disrupts host cell epigenetic regulation12,13,14. However, how SARS-CoV-2 controls the host cell epigenome and whether it uses histone mimicry to do so remain unclear. Here we show that the SARS-CoV-2 protein encoded by ORF8 (ORF8) functions as a histone mimic of the ARKS motifs in histone H3 to disrupt host cell epigenetic regulation. ORF8 is associated with chromatin, disrupts regulation of critical histone post-translational modifications and promotes chromatin compaction. Deletion of either the ORF8 gene or the histone mimic site attenuates the ability of SARS-CoV-2 to disrupt host cell chromatin, affects the transcriptional response to infection and attenuates viral genome copy number. These findings demonstrate a new function of ORF8 and a mechanism through which SARS-CoV-2 disrupts host cell epigenetic regulation. Further, this work provides a molecular basis for the finding that SARS-CoV-2 lacking ORF8 is associated with decreased severity of COVID-19.
233	I231		Clemens A. Schmitt, Tamar Tchkonia, Laura J. Niedernhofer, Paul D. Robbins, James L. Kirkland & Soyoung Lee	COVID-19 and cellular senescence	https://doi.org/10.1038/s41577-022-00785-2	Published	05 October 2022	Article	https://www.nature.com/articles/s41577-022-00785-2	The clinical severity of coronavirus disease 2019 (COVID-19) is largely determined by host factors. Recent advances point to cellular senescence, an ageing-related switch in cellular state, as a critical regulator of SARS-CoV-2-evoked hyperinflammation. SARS-CoV-2, like other viruses, can induce senescence and exacerbates the senescence-associated secretory phenotype (SASP), which is comprised largely of pro-inflammatory, extracellular matrix-degrading, complement-activating and pro-coagulatory factors secreted by senescent cells. These effects are enhanced in elderly individuals who have an increased proportion of pre-existing senescent cells in their tissues. SASP factors can contribute to a ‘cytokine storm’, tissue-destructive immune cell infiltration, endothelialitis (endotheliitis), fibrosis and microthrombosis. SASP-driven spreading of cellular senescence uncouples tissue injury from direct SARS-CoV-2-inflicted cellular damage in a paracrine fashion and can further amplify the SASP by increasing the burden of senescent cells. Preclinical and early clinical studies indicate that targeted elimination of senescent cells may offer a novel therapeutic opportunity to attenuate clinical deterioration in COVID-19 and improve resilience following infection with SARS-CoV-2 or other pathogens.
234	I232		Marta Bertran Snehal M Pinto Pereira Manjula D Nugawela Terence Stephenson Roz Shafran Tamsin Ford Marta Buszewicz Elizabeth Whittaker Isobel Heyman Terry Y Segal Emma Dalrymple Shamez N Ladhani	The relationship between Post COVID symptoms in young people and their parents	https://doi.org/10.1016/j.jinf.2022.10.005	Published	October 07, 2022	Letter to the Editor	https://www.journalofinfection.com/article/S0163-4453(22)00560-6/fulltext	We read with interest the recent study on risk factors for long COVID. 1 Similar risk factors, including female gender, older age and higher number of symptoms, have been reported in children and young people (CYP). 2 In England, the CLoCk study was established to investigate long COVID in a cohort of >30,000 CYP aged 11–17 years with PCR-confirmed SARS-CoV-2 infection and a contemporaneous PCR-negative group, matched by age, sex, geography and time. 3 Outcomes at 3 months follow-up have been published. 4 Anecdotal information suggested many CYP with ongoing symptoms had other household members with symptoms after COVID-19. We hypothesised that CYP reporting long COVID were more likely to have a parent with ongoing symptoms.
235	I233		Gaber El-Saber Batiha, Hayder M. Al-kuraishy, Ali I. Al-Gareeb & Nermeen N. Welson	Pathophysiology of Post-COVID syndromes: a new perspective	https://doi.org/10.1186/s12985-022-01891-2	Published	09 October 2022	Review	https://virologyj.biomedcentral.com/articles/10.1186/s12985-022-01891-2	Most COVID-19 patients recovered with low mortality; however, some patients experienced long-term symptoms described as “long-COVID” or “Post-COVID syndrome” (PCS). Patients may have persisting symptoms for weeks after acute SARS-CoV-2 infection, including dyspnea, fatigue, myalgia, insomnia, cognitive and olfactory disorders. These symptoms may last for months in some patients. PCS may progress in association with the development of mast cell activation syndrome (MCAS), which is a distinct kind of mast cell activation disorder, characterized by hyper-activation of mast cells with inappropriate and excessive release of chemical mediators. COVID-19 survivors, mainly women, and patients with persistent severe fatigue for 10 weeks after recovery with a history of neuropsychiatric disorders are more prone to develop PCS. High D-dimer levels and blood urea nitrogen were observed to be risk factors associated with pulmonary dysfunction in COVID-19 survivors 3 months post-hospital discharge with the development of PCS. PCS has systemic manifestations that resolve with time with no further complications. However, the final outcomes of PCS are chiefly unknown. Persistence of inflammatory reactions, autoimmune mimicry, and reactivation of pathogens together with host microbiome alterations may contribute to the development of PCS. The deregulated release of inflammatory mediators in MCAS produces extraordinary symptoms in patients with PCS. The development of MCAS during the course of SARS-CoV-2 infection is correlated to COVID-19 severity and the development of PCS. Therefore, MCAS is treated by antihistamines, inhibition of synthesis of mediators, inhibition of mediator release, and inhibition of degranulation of mast cells.
236	I234		Kevin Roe	SARS-CoV-2 and Toxoplasma gondii shared symptoms suggest muscle cells and neurons are their chronic infection reservoirs	https://doi.org/10.1007/s13577-022-00809-y	Published	10 October 2022	Letter to the Editor	https://link.springer.com/article/10.1007/s13577-022-00809-y	In conclusion, the post-infection symptoms of Long COVID/PASC are sometimes experienced after active SARS-CoV-2 virus infections. Long COVID/PASC exhibits several neurological and muscular symptoms that substantially parallel T. gondii infection symptoms. T. gondii is known to use central nervous system neurons and muscle cells to maintain chronic infections. It is therefore plausible that in some cases SARS-CoV-2 and T. gondii both use central nervous system neurons and muscle cells as reservoirs to maintain chronic infections. There may also be other pathways without a chronic infection viral reservoir that could explain the remaining Long COVID/PASC cases that lack SARS-CoV-2 antigens.
237	I235		Charles-Edouard Luyt, Sonia Burrel, David Mokrani, Marc Pineton de Chambrun, Domitille Luyt, Juliette Chommeloux, Vincent Guiraud, Nicolas Bréchot, Matthieu Schmidt, Guillaume Hekimian, Alain Combes & David Boutolleau	Herpesviridae lung reactivation and infection in patients with severe COVID-19 or influenza virus pneumonia: a comparative study	https://doi.org/10.1186/s13613-022-01062-0	Published	24 September 2022	Study	https://annalsofintensivecare.springeropen.com/articles/10.1186/s13613-022-01062-0	Background Lung reactivations of Herpesviridae, herpes simplex virus (HSV) and cytomegalovirus (CMV) have been reported in COVID-19 patients. Whether or not those viral reactivations are more frequent than in other patients is not known. Methods Retrospective monocentric cohort study of 145 patients with severe COVID-19 pneumonia requiring invasive mechanical ventilation and who were tested for HSV and CMV in bronchoalveolar lavage performed during fiberoptic bronchoscopy for ventilator-associated pneumonia suspicion. Rates of HSV and CMV lung reactivations, and HSV bronchopneumonitis were assessed and compared with an historical cohort of 89 patients with severe influenza pneumonia requiring invasive mechanical ventilation. Results Among the 145 COVID-19 patients included, 50% and 42% had HSV and CMV lung reactivations, respectively, whereas among the 89 influenza patients, 63% and 28% had HSV and CMV lung reactivations, respectively. Cumulative incidence of HSV lung reactivation (taking into account extubation and death as competing events) was higher in influenza than in COVID-19 patients (p = 0.03), whereas the rate of HSV bronchopneumonitis was similar in both groups (31% and 25%, respectively). Cumulative incidence of CMV lung reactivation (taking into account extubation and death as competing events) was similar in COVID-19 and influenza patients (p = 0.07). Outcomes of patients with HSV or CMV lung reactivations were similar to that of patients without, whatever the underlying conditions, i.e., in COVID-19 patients, in influenza patients, or when all patients were grouped. Conclusions HSV and CMV lung reactivations are frequent in COVID-19 patients, but not more frequent than in patients with influenza-associated severe pneumonia, despite a higher severity of illness at intensive care unit admission of the latter and a longer duration of mechanical ventilation of the former. Although no impact on outcome of HSV and CMV lung reactivations was detected, the effect of antiviral treatment against these Herpesviridae remains to be determined in these patients.
238	I236		Vamsi P. Guntur 1,2,†,Travis Nemkov 3,†ORCID,Esther de Boer 1,2,Michael P. Mohning 1,2,David Baraghoshi 4ORCID,Francesca I. Cendali 3ORCID,Inigo San-Millán 5,6,7,Irina Petrache 1,2,‡ORCID andAngelo D’Alessandro 3	Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC)	https://doi.org/10.3390/metabo12111026	Published	26 October 2022	Study	https://www.mdpi.com/2218-1989/12/11/1026/htm	Exercise intolerance is a major manifestation of post-acute sequelae of severe acute respiratory syndrome coronavirus infection (PASC, or “long-COVID”). Exercise intolerance in PASC is associated with higher arterial blood lactate accumulation and lower fatty acid oxidation rates during graded exercise tests to volitional exertion, suggesting altered metabolism and mitochondrial dysfunction. It remains unclear whether the profound disturbances in metabolism that have been identified in plasma from patients suffering from acute coronavirus disease 2019 (COVID-19) are also present in PASC. To bridge this gap, individuals with a history of previous acute COVID-19 infection that did not require hospitalization were enrolled at National Jewish Health (Denver, CO, USA) and were grouped into those that developed PASC (n = 29) and those that fully recovered (n = 16). Plasma samples from the two groups were analyzed via mass spectrometry-based untargeted metabolomics and compared against plasma metabolic profiles of healthy control individuals (n = 30). Observational demographic and clinical data were retrospectively abstracted from the medical record. Compared to plasma of healthy controls or individuals who recovered from COVID-19, PASC plasma exhibited significantly higher free- and carnitine-conjugated mono-, poly-, and highly unsaturated fatty acids, accompanied by markedly lower levels of mono-, di- and tricarboxylates (pyruvate, lactate, citrate, succinate, and malate), polyamines (spermine) and taurine. Plasma from individuals who fully recovered from COVID-19 exhibited an intermediary metabolic phenotype, with milder disturbances in fatty acid metabolism and higher levels of spermine and taurine. Of note, depletion of tryptophan—a hallmark of disease severity in COVID-19—is not normalized in PASC patients, despite normalization of kynurenine levels—a tryptophan metabolite that predicts mortality in hospitalized COVID-19 patients. In conclusion, PASC plasma metabolites are indicative of altered fatty acid metabolism and dysfunctional mitochondria-dependent lipid catabolism. These metabolic profiles obtained at rest are consistent with previously reported mitochondrial dysfunction during exercise, and may pave the way for therapeutic intervention focused on restoring mitochondrial fat-burning capacity.
239	I237		Sarah E Turbett, MD, Christopher H Tomkins-Tinch, BS, Melis N Anahtar, MD, PhD, Caitlin M Dugdale, MD, Emily P Hyle, MD, MSc, Erica S Shenoy, MD, PhD, Bennett Shaw, BS, Kenechukwu Egbuonu, BS, Kathryn A Bowman, MD, Kimon C Zachary, MD, Gordon C Adams, BA, David C Hooper, MD, Edward T Ryan, MD, Regina C LaRocque, MD, MPH, Ingrid V Bassett, MD, MPH, Virginia A Triant, MD, MPH, Katherine J Siddle, PhD, Eric Rosenberg, MD, PhD, Pardis C Sabeti, MD, DPhil, Stephen F Schaffner, PhD, Bronwyn L MacInnis, PhD, Jacob E Lemieux, MD, PhD, Richelle C Charles, MD	Distinguishing SARS-CoV-2 persistence and reinfection: A retrospective cohort study	https://doi.org/10.1093/cid/ciac830	Published	21 October 2022	Study	https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac830/6765222	Background SARS-CoV-2 reinfection is poorly understood, partly because few studies have systematically applied genomic analysis to distinguish reinfection from persistent RNA detection related to initial infection. We aimed to evaluate the characteristics of SARS-CoV-2 reinfection and persistent RNA detection using independent genomic, clinical, and laboratory assessments. Methods All individuals at a large academic medical center who underwent a SARS-CoV-2 nucleic acid amplification test (NAAT) ≥ 45 days after an initial positive test, with both tests between March 14th and December 30th, 2020, were analyzed for potential reinfection. Inclusion criteria required having ≥2 positive NAATs collected ≥45 days apart with a cycle threshold (Ct) value <35 at repeat testing. For each included subject, likelihood of reinfection was assessed by viral genomic analysis of all available specimens with a Ct value <35, structured Ct trajectory criteria, and case-by-case review by infectious diseases physicians. Results Among 1,569 individuals with repeat SARS-CoV-2 testing ≥45 days after an initial positive NAAT, 65 (4%) met cohort inclusion criteria. Viral genomic analysis characterized mutations present, and was successful for 14/65 (22%) subjects. Six subjects had genomically-supported reinfection and eight subjects had genomically-supported persistent RNA detection. Compared to viral genomic analysis, clinical and laboratory assessments correctly distinguished reinfection from persistent RNA detection in 12/14 (86%) subjects but missed 2/6 (33%) genomically-supported reinfections. Conclusion Despite good overall concordance with viral genomic analysis, clinical and Ct value-based assessments failed to identify 33% of genomically-supported reinfections. Scaling-up genomic analysis for clinical use would improve detection of SARS-CoV-2 reinfections.
240	I238		Arjun MC1, Singh AK1, Roy P1, Ravichandran M1, Mandal S1, Pal D1, Das K1, Gajjala A1, Venkateshan M2, Mishra B3, Patro BK1, Mohapatra PR4, Subba SH1	Long COVID following Omicron wave in Eastern India-A retrospective cohort study.	https://doi.org/10.1002/jmv.28214	Published	12 Oct 2022	Study	https://europepmc.org/article/med/36224705	Long coronavirus disease (COVID) or postacute sequelae of coronavirus disease of 2019 (COVID-19) is widely reported but the data of long COVID after infection with the Omicron variant is limited. This study was conducted to estimate the incidence, characteristics of symptoms, and predictors of long COVID among COVID-19 patients diagnosed during the Omicron wave in Eastern India. The cohort of COVID-19 patients included were adults (≥18 years) diagnosed as severe acute respiratory syndrome coronavirus 2 positive with Reverse Transcription Polymerase Chain Reaction. After 28 days of diagnosis; participants were followed up with a telephonic interview to capture data on sociodemographic, clinical history, anthropometry, substance use, COVID-19 vaccination status, acute COVID-19 symptoms, and long COVID symptoms. The long COVID symptoms were self-reported by the participants. Logistic regression was used to determine the predictors of long COVID. The median follow-up of participants was 73 days (Interquartile range; 67-83). The final analysis had 524 participants' data; among them 8.2% (95% Confidence Interval [CI]: 6%-10.9%) self-reported long COVID symptoms. Fatigue (34.9%) was the most common reported symptom followed by cough (27.9%). In multivariable logistic regression only two predictors were statistically significant-number of acute COVID-19 symptoms ≥ five (Adjusted odds ratio (aOR) = 2.95, 95% CI: 1.30-6.71) and past history of COVID-19 (aOR = 2.66, 95% CI: 1.14-6.22). The proportion of self-reported long COVID is considerably low among COVID-19 patients diagnosed during the Omicron wave in Eastern India when compared with estimates during Delta wave in the same setting.
241	I239		EthanDavittaColinDavittbMonty B.MazerceSathya S.AretidRichard S.HotchkissabKenneth E.Remybcde	COVID-19 disease and immune dysregulation	https://doi.org/10.1016/j.beha.2022.101401	Published	15 October 2022	Review	https://www.sciencedirect.com/science/article/pii/S1521692622000561	The SARS-CoV-2 virus has complex and divergent immune alterations in differing hosts and over disease evolution. Much of the nuanced COVID-19 disease immune dysregulation was originally dominated by innate cytokine changes, which has since been replaced with a more complex picture of innate and adaptive changes characterized by simultaneous hyperinflammatory and immunosuppressive phenomena in effector cells. These intricacies are summarized in this review as well as potential relevance from acute infection to a multisystem inflammatory syndrome commonly seen in children. Additional consideration is made for the influence of variant to variant host cellular changes and the impact of potential vaccination upon these phenotypes. Finally, therapeutic benefit for immune alterations are discussed.
242	I240		Yasuhiro Nakano 1ORCID,Yuki Otsuka 1ORCID,Hiroyuki Honda 1,Naruhiko Sunada 1,Kazuki Tokumasu 1ORCID,Yasue Sakurada 1,Yui Matsuda 1,Toru Hasegawa 1,Kanako Ochi 2,Hideharu Hagiya 1ORCID,Hitomi Kataoka 1,Keigo Ueda 1 andFumio Otsuka 1,*ORCID	Transitional Changes in Fatigue-Related Symptoms Due to Long COVID: A Single-Center Retrospective Observational Study in Japan	https://doi.org/10.3390/medicina58101393	Published	5 October 2022	Study	https://www.mdpi.com/1648-9144/58/10/1393/htm	Background and Objectives: Changes in post COVID-19 condition (PCC) characteristics caused by viral variants have yet to be clarified. We aimed to characterize the differences between clinical backgrounds and manifestations in long COVID patients who were infected with the Delta variant and those who were infected with the Omicron variants. Materials and Methods: This study was a single-center retrospective observational study for patients who visited our COVID-19 aftercare outpatient clinic (CAC) established in Okayama University Hospital (Japan) during the period from 15 February 2021 to 15 July 2022. We classified the onset of COVID-19 in the patients into three groups, the preceding, Delta-dominant, and Omicron-dominant periods, based on the prevalent periods of the variants in our prefecture. Results: In a total of 353 patients, after excluding 8 patients, 110, 130, and 113 patients were classified into the preceding, Delta-dominant, and Omicron-dominant periods, respectively. Patients infected in the Omicron-dominant period had significantly fewer hospitalizations, milder illnesses, more vaccinations and earlier visit to the CAC than did patients infected in the Delta-dominant period. Patients infected in the Omicron-dominant period had significantly lower frequencies of dysosmia (12% vs. 45%, p < 0.01), dysgeusia (14% vs. 40%, p < 0.01) and hair loss (7% vs. 28%, ** p < 0.01) but had higher frequencies of fatigue (65% vs. 50%, * p < 0.05), insomnia (26% vs. 13%, * p < 0.05) and cough (20% vs. 7%, ** p < 0.01) than did patients infected in the Delta-dominant period. Conclusions: The transitional changes in long COVID symptoms caused by the two variants were characterized.
243	I241		Maria J Monroy-Iglesias , Kathryn Tremble, Beth Russell, Charlotte Moss , Saoirse Dolly, Ailsa Sita-Lumsden, Alessio Cortellini, David James Pinato, Anne Rigg, Sophia N Karagiannis & Mieke Van Hemelrijck	Long-term effects of COVID-19 on cancer patients: the experience from Guy's Cancer Centre	https://doi.org/10.2217/fon-2022-0088	Published	29 Sep 2022	Study	https://www.futuremedicine.com/doi/10.2217/fon-2022-0088	Background: Few studies have investigated the long-term effects of COVID-19 on cancer patients. Materials & methods: The authors conducted a telephone survey on the long-term symptoms of cancer patients from Guy's Cancer Centre. They compared patients whose symptoms occurred/got worse over 4 weeks after COVID-19 diagnosis (classified as long COVID) with patients who did not develop symptoms or whose symptoms occurred/got worse in the first 4 weeks after diagnosis. Results: The authors analyzed responses from 80 patients with a previous COVID-19 diagnosis; 51.3% (n = 41) developed long COVID. The most common symptoms were fatigue, breathlessness and cognitive impairment. Conclusion: Findings suggest that over half of the cancer population will experience long-term effects after their initial COVID-19 diagnosis. Further studies are required to validate the findings of this study.
244	I242		Marialaura Fanelli 1,Vita Petrone 1,Margherita Buonifacio 1,Elisabetta Delibato 2,Emanuela Balestrieri 1,Sandro Grelli 1,3,Antonella Minutolo 1ORCID andClaudia Matteucci 1,*	Multidistrict Host–Pathogen Interaction during COVID-19 and the Development Post-Infection Chronic Inflammation	https://doi.org/10.3390/pathogens11101198	Published	18 October 2022	Review	https://www.mdpi.com/2076-0817/11/10/1198/htm	Due to the presence of the ACE2 receptor in different tissues (nasopharynx, lung, nervous tissue, intestine, liver), the COVID-19 disease involves several organs in our bodies. SARS-CoV-2 is able to infect different cell types, spreading to different districts. In the host, an uncontrolled and altered immunological response is triggered, leading to cytokine storm, lymphopenia, and cellular exhaustion. Hence, respiratory distress syndrome (ARDS) and systemic multi-organ dysfunction syndrome (MODS) are established. This scenario is also reflected in the composition of the microbiota, the balance of which is regulated by the interaction with the immune system. A change in microbial diversity has been demonstrated in COVID-19 patients compared with healthy donors, with an increase in potentially pathogenic microbial genera. In addition to other symptoms, particularly neurological, the occurrence of dysbiosis persists after the SARS-CoV-2 infection, characterizing the post-acute COVID syndrome. This review will describe and contextualize the role of the immune system in unbalance and dysbiosis during SARS-CoV-2 infection, from the acute phase to the post-COVID-19 phase. Considering the tight relationship between the immune system and the gut–brain axis, the analysis of new, multidistrict parameters should be aimed at understanding and addressing chronic multisystem dysfunction related to COVID-19.
245	I243		César Fernández-de-las-Peñas 1,2,ORCID,Lars Arendt-Nielsen 2,3,Gema Díaz-Gil 4ORCID,Francisco Gómez-Esquer 4ORCID,Antonio Gil-Crujera 4ORCID,Stella M. Gómez-Sánchez 4ORCID,Silvia Ambite-Quesada 1ORCID,María A. Palomar-Gallego 4ORCID,Oscar J. Pellicer-Valero 5ORCID andRocco Giordano 2,ORCID	Genetic Association between ACE2 (rs2285666 and rs2074192) and TMPRSS2 (rs12329760 and rs2070788) Polymorphisms with Post-COVID Symptoms in Previously Hospitalized COVID-19 Survivors	https://doi.org/10.3390/genes13111935	Published	24 October 2022	Study	https://www.mdpi.com/2073-4425/13/11/1935/htm	The aim of the study was to identify the association between four selected COVID-19 polymorphisms of ACE2 and TMPRSS2 receptors genes with the presence of long-COVID symptomatology in COVID-19 survivors. These genes were selected as they associate with the entry of the SARS-CoV-2 virus into the cells, so polymorphisms could be important for the prognoses of long-COVID symptoms. Two hundred and ninety-three (n = 293, 49.5% female, mean age: 55.6 ± 12.9 years) individuals who had been previously hospitalized due to COVID-19 were included. Three potential genotypes of the following single nucleotide polymorphisms (SNPs) were obtained from non-stimulated saliva samples of participants: ACE2 (rs2285666), ACE2 (rs2074192), TMPRSS2 (rs12329760), TMPRSS2 (rs2070788). Participants were asked to self-report the presence of any post-COVID defined as a symptom that started no later than one month after SARS-CoV-2 acute infection and whether the symptom persisted at the time of the study. At the time of the study (mean: 17.8, SD: 5.2 months after hospital discharge), 87.7% patients reported at least one symptom. Fatigue (62.8%), pain (39.9%) or memory loss (32.1%) were the most prevalent post-COVID symptoms. Overall, no differences in long-COVID symptoms were dependent on ACE2 rs2285666, ACE2 rs2074192, TMPRSS2 rs12329760, or TMPRSS2 rs2070788 genotypes. The four SNPs assessed, albeit previously associated with COVID-19 severity, do not predispose for developing long-COVID symptoms in people who were previously hospitalized due to COVID-19 during the first wave of the pandemic
246	I244		Karen Giménez-Orenga1†, Justine Pierquin2†, Joanna Brunel2, Benjamin Charvet2, Eva Martín-Martínez3, Hervé Perron2,4† and Elisa Oltra5,6†	HERV-W ENV antigenemia and correlation of increased anti-SARS-CoV-2 immunoglobulin levels with post-COVID-19 symptoms	https://doi.org/10.3389/fimmu.2022.1020064	Published	27 October 2022	Study	https://www.frontiersin.org/articles/10.3389/fimmu.2022.1020064/full	Due to the wide scope and persistence of COVID-19´s pandemic, post-COVID-19 condition represents a post-viral syndrome of unprecedented dimensions. SARS-CoV-2, in line with other infectious agents, has the capacity to activate dormant human endogenous retroviral sequences ancestrally integrated in human genomes (HERVs). This activation was shown to relate to aggravated COVID-19 patient´s symptom severity. Despite our limited understanding of how HERVs are turned off upon infection clearance, or how HERVs mediate long-term effects when their transcription remains aberrantly on, the participation of these elements in neurologic disease, such as multiple sclerosis, is already settling the basis for effective therapeutic solutions. These observations support an urgent need to identify the mechanisms that lead to HERV expression with SARS-CoV-2 infection, on the one hand, and to answer whether persistent HERV expression exists in post-COVID-19 condition, on the other. The present study shows, for the first time, that the HERV-W ENV protein can still be actively expressed long after SARS-CoV-2 infection is resolved in post-COVID-19 condition patients. Moreover, increased anti-SARS-CoV-2 immunoglobulins in post-COVID-19 condition, particularly high anti-SARS-CoV-2 immunoglobulin levels of the E isotype (IgE), seem to strongly correlate with deteriorated patient physical function (r=-0.8057, p<0.01). These results indicate that HERV-W ENV antigenemia and anti-SARS-CoV-2 IgE serology should be further studied to better characterize post-COVID-19 condition pathogenic drivers potentially differing in subsets of patients with various symptoms. They also point out that such biomarkers may serve to design therapeutic options for precision medicine in post-COVID-19 condition.
247	I245		Laura C. Chambers, PhD, MPH and Francesca L. Beaudoin, MD, PhD, MS	A Longitudinal Study of COVID-19 Sequelae and Immunity	https://doi.org/10.7326/L22-0330	Published	1 November 2022	Study	https://www.acpjournals.org/doi/full/10.7326/L22-0330	TO THE EDITOR: Sneller and colleagues' article (1) received controversial coverage on social media for the authors' conclusions that extensive diagnostic evaluation did not identify a cause of postacute sequelae of SARS-CoV-2 infection (PASC) and that persons with a history of anxiety disorder are at increased risk for PASC. Although we may be apt to dismiss such critiques in the age of misinformation, it is worth further examination lest we draw erroneous inferences about anxiety and PASC. The authors' primary analyses included 189 participants with a history of COVID-19 (104 with PASC and 85 without). Ignoring power lost because of (appropriate) correction of the false discovery rate, the study sample was sufficiently powered to detect an odds ratio of 4.6 (assuming 5% prevalence of the characteristic among control participants). An effect size of this magnitude is large and probably unreasonable given that PASC may represent multiple distinct conditions with different causes and risk factors. Exploratory immunologic and virologic evaluations included an even smaller subset of participants, further limiting power. The noted absence of associations may be true or simply due to limited power. Of note, the study measured prevalent PASC at study enrollment, which occurred approximately 5 months after COVID-19 onset. Given that some patients experience symptom resolution within 5 months (2), participants with resolved PASC at enrollment would have been misclassified as control participants “without PASC,” biasing results toward the null. The design was also subject to recall and selection bias that would have been mitigated with a prospective design or different sampling scheme. It is not surprising that persons with a history of anxiety who believed they had PASC might have been more apt to volunteer for a study about PASC. The authors acknowledge the limitations of self-referral, but it is also important to highlight how this sample differs from the general population. For example, 48% of participants had an advanced degree versus 13% of the U.S. population (3). Finally, analyses of risk factors for PASC were unadjusted, so associations may have been confounded by measured (such as female sex is associated with both PASC and anxiety disorders) and unmeasured (such as genetics) characteristics (4). This study contributes much-needed data on PASC and highlights critical areas for future research. However, we must not draw broad conclusions from a small study with important limitations, and appropriate messaging around the science is critical. Patients with PASC already experience stigma and difficulty accessing care (5); our early work on PASC should not exacerbate this.
248	I246		Javier Jurado Velez, Nita Kanney, Sadeep Shrestha and Bertha Hidalgo	Abstract 14914: Post-Acute Sequelae of SARS-CoV-2 and Mortality Among Individuals With Breakthrough Infections in Alabama	https://doi.org/10.1161/circ.146.suppl_1.14914	Published	30 Oct 2022	Study	https://www.ahajournals.org/doi/abs/10.1161/circ.146.suppl_1.14914	Introduction: While breakthrough SARS-CoV-2 infections were expected among vaccinated individuals, less is known about the incidence of post-acute SARS-CoV-2 sequelae (PASC) and mortality among vaccinated individuals. Methods: A retrospective analysis of Alabama Health System electronic health record (EHR) data was performed for 4,274 individuals with vaccination, clinical, medical, and mortality information between December 2020 and December 2021. The study population consisted of patients who had documented evidence of vaccination (e.g., two doses of Pfizer-BioNTech, two doses of Moderna, or a single dose of Janssen/Johnson & Johnson vaccines). Results: Out of 4,274 individuals with EHR data in our cohort, 2,177 were female (51%), with a mean age equal to 56 ± 16.2; 1,245 individuals had received one or more doses of a COVID-19 vaccine. There were 640 COVID-19 related deaths, of which were 265 women (41%), 487 (76%) had obesity/overweight, and 133 patients (21%) that had an organ transplant or had a history of cancer. A greater percentage of unvaccinated individuals had documented COVID-19 deaths compared to individuals who were vaccinated (N=57, 5% and 583, 19%, respectively). The odds of mortality were lower among those who were vaccinated, compared to those who were unvaccinated (OR = 0.2, 95% CI = 0.15, 0.27). Sensitivity analyses showed that mortality among vaccinated individuals comprised of 6% (13) of patients with 1 dose, 5% (42) of patients with 2 doses, and <1% (2) of patients with 3 doses. One hundred and eighteen individuals had a PASC diagnosis, with 57% (67) of patients having received at least 1 dose. PASC occurred in 6% (13) of patients with 1 dose, 10% (84) of patients with 2 doses, and 3% (6) of patients with 3 doses. The odds of having PASC were higher among those vaccinated, compared to those unvaccinated (OR = 3.32, 95% CI = 2.29, 4.81). Among those who were vaccinated and had PASC (N=67), a greater proportion were female than male (69% compared to 31%, respectively). Conclusions: At least 1 dose of a COVID-19 vaccine provided a lower odds of mortality in individuals with a breakthrough infection; however, in our population, vaccinated individuals had equal odds of post-acute SARS-CoV-2 sequelae (PASC) as unvaccinated individuals.
249	I247		Marianna Spatola, Nadège Nziza, Wonyeong Jung, Yixiang Deng, Dansu Yuan, View ORCID ProfileAlessandro Dinoto, View ORCID ProfileSilvia Bozzetti, View ORCID ProfileVanessa Chiodega, Sergio Ferrari, View ORCID ProfileDouglas A Lauffenburger, View ORCID ProfileSara Mariotto, View ORCID ProfileGalit Alter	Neurologic sequalae of COVID-19 are determined by immunologic imprinting from previous Coronaviruses	https://doi.org/10.1101/2022.11.07.22282030	pre-print	November 10, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.11.07.22282030v1.full-text	Coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health emergency. Although SARS-CoV-2 is primarily a respiratory pathogen, extra-respiratory organs, including the central nervous system (CNS), can also be affected. Neurologic symptoms have been observed not only during acute SARS-CoV-2 infection, but also at distance from respiratory disease, also known as long-COVID or neurological post-acute sequelae of COVID-19 (neuroPASC). The pathogenesis of neuroPASC is not well understood, but hypotheses include SARS-CoV-2-induced immune dysfunctions, hormonal dysregulations, and persistence of SARS-CoV-2 reservoirs. In this study, we used a high throughput systems serology approach to dissect the humoral response to SARS-CoV-2 (and other common Coronaviruses - 229E, HKU1, NL63, OC43) in the serum and cerebrospinal fluid (CSF) from 112 infected individuals who developed or did not develop neuroPASC. Unique SARS-CoV-2 humoral profiles were observed in the CSF of neuroPASC. All antibody isotypes (IgA, IgM, IgA) and subclasses (IgA1-2; IgG1-4) were detected in serum, whereas CSF was characterized by focused IgG1 (and absence of IgM). These data argue in favor of compartmentalized brain-specific responses against SARS-CoV-2 through selective transfer of antibodies from the serum to the CSF across the blood-brain-barrier, rather than intrathecal synthesis, where more diversity in antibody classes/subclasses would be expected. Moreover, compared to individuals who did not develop post-acute neurological complications following infection (n=94), those with neuroPASC (n=18) exhibited attenuated systemic antibody responses against SARS-CoV-2, characterized by decreased capacity to activate antibody-dependent complement deposition (ADCD), NK cell activation (ADNKA) and to bind Fcγ receptors. However, surprisingly, neuroPASC showed significantly expanded antibody responses to other common Coronaviruses, including 229E, HKU1, NL63, and OC43. This biased humoral activation across coronaviruses was particularly enriched in neuroPASC individuals with poor outcome, suggesting an original antigenic sin (or immunologic imprinting), where pre-existing immune responses against related viruses shape the response to current infection, as a key prognostic marker of neuroPASC disease. Overall, these findings point to a pathogenic role for compromised anti-SARS-CoV-2 responses in the CSF, likely resulting in incomplete virus clearance from the brain and persistent neuroinflammation, in the development of post-acute neurologic complications of SARS-CoV-2 infection.
250	I248		Benjamin Bowe, Yan Xie & Ziyad Al-Aly	Acute and postacute sequelae associated with SARS-CoV-2 reinfection	https://doi.org/10.1038/s41591-022-02051-3	Published	10 November 2022	Study	https://www.nature.com/articles/s41591-022-02051-3	First infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with increased risk of acute and postacute death and sequelae in various organ systems. Whether reinfection adds to risks incurred after first infection is unclear. Here we used the US Department of Veterans Affairs’ national healthcare database to build a cohort of individuals with one SARS-CoV-2 infection (n = 443,588), reinfection (two or more infections, n = 40,947) and a noninfected control (n = 5,334,729). We used inverse probability-weighted survival models to estimate risks and 6-month burdens of death, hospitalization and incident sequelae. Compared to no reinfection, reinfection contributed additional risks of death (hazard ratio (HR) = 2.17, 95% confidence intervals (CI) 1.93–2.45), hospitalization (HR = 3.32, 95% CI 3.13–3.51) and sequelae including pulmonary, cardiovascular, hematological, diabetes, gastrointestinal, kidney, mental health, musculoskeletal and neurological disorders. The risks were evident regardless of vaccination status. The risks were most pronounced in the acute phase but persisted in the postacute phase at 6 months. Compared to noninfected controls, cumulative risks and burdens of repeat infection increased according to the number of infections. Limitations included a cohort of mostly white males. The evidence shows that reinfection further increases risks of death, hospitalization and sequelae in multiple organ systems in the acute and postacute phase. Reducing overall burden of death and disease due to SARS-CoV-2 will require strategies for reinfection prevention.
251	I249		Qin Liu, Qi Su, Fen Zhang, Hein M. Tun, Joyce Wing Yan Mak, Grace Chung-Yan Lui, Susanna So Shan Ng, Jessica Y. L. Ching, Amy Li, Wenqi Lu, Chenyu Liu, Chun Pan Cheung, David S. C. Hui, Paul K. S. Chan, Francis Ka Leung Chan & Siew C. Ng	Multi-kingdom gut microbiota analyses define COVID-19 severity and post-acute COVID-19 syndrome	https://doi.org/10.1038/s41467-022-34535-8	Published	10 November 2022	Study	https://www.nature.com/articles/s41467-022-34535-8	Our knowledge of the role of the gut microbiome in acute coronavirus disease 2019 (COVID-19) and post-acute COVID-19 is rapidly increasing, whereas little is known regarding the contribution of multi-kingdom microbiota and host-microbial interactions to COVID-19 severity and consequences. Herein, we perform an integrated analysis using 296 fecal metagenomes, 79 fecal metabolomics, viral load in 1378 respiratory tract samples, and clinical features of 133 COVID-19 patients prospectively followed for up to 6 months. Metagenomic-based clustering identifies two robust ecological clusters (hereafter referred to as Clusters 1 and 2), of which Cluster 1 is significantly associated with severe COVID-19 and the development of post-acute COVID-19 syndrome. Significant differences between clusters could be explained by both multi-kingdom ecological drivers (bacteria, fungi, and viruses) and host factors with a good predictive value and an area under the curve (AUC) of 0.98. A model combining host and microbial factors could predict the duration of respiratory viral shedding with 82.1% accuracy (error ± 3 days). These results highlight the potential utility of host phenotype and multi-kingdom microbiota profiling as a prognostic tool for patients with COVID-19.
252	I250		Veronica Dioverti, Sonsoles Salto-Alejandre & Ghady Haidar	Immunocompromised Patients with Protracted COVID-19: a Review of “Long Persisters”	https://doi.org/10.1007/s40472-022-00385-y	Published	12 November 2022	Review	https://link.springer.com/article/10.1007/s40472-022-00385-y	Purpose of Review Certain immunocompromised individuals are at risk for protracted COVID-19, in which SARS-CoV-2 leads to a chronic viral infection. However, the pathogenesis, diagnosis, and management of this phenomenon remain ill-defined. Recent Findings Herein, we review key aspects of protracted SARS-CoV-2 infection in immunocompromised individuals, or the so-called long persisters, and describe the clinical presentation, risk factors, diagnosis, and treatment modalities of this condition, as well as intra-host viral evolution. Based on the available data, we also propose a framework of criteria with which to approach this syndrome. Summary Protracted COVID-19 is an uncharacterized syndrome affecting patients with B-cell depletion; our proposed diagnostic approach and definitions will inform much needed future research.
253	I251		Benjamin Bowe, Yan Xie & Ziyad Al-Aly	Acute and postacute sequelae associated with SARS-CoV-2 reinfection	https://doi.org/10.1038/s41591-022-02051-3	Published	10 November 2022	Study	https://www.nature.com/articles/s41591-022-02051-3	First infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with increased risk of acute and postacute death and sequelae in various organ systems. Whether reinfection adds to risks incurred after first infection is unclear. Here we used the US Department of Veterans Affairs’ national healthcare database to build a cohort of individuals with one SARS-CoV-2 infection (n = 443,588), reinfection (two or more infections, n = 40,947) and a noninfected control (n = 5,334,729). We used inverse probability-weighted survival models to estimate risks and 6-month burdens of death, hospitalization and incident sequelae. Compared to no reinfection, reinfection contributed additional risks of death (hazard ratio (HR) = 2.17, 95% confidence intervals (CI) 1.93–2.45), hospitalization (HR = 3.32, 95% CI 3.13–3.51) and sequelae including pulmonary, cardiovascular, hematological, diabetes, gastrointestinal, kidney, mental health, musculoskeletal and neurological disorders. The risks were evident regardless of vaccination status. The risks were most pronounced in the acute phase but persisted in the postacute phase at 6 months. Compared to noninfected controls, cumulative risks and burdens of repeat infection increased according to the number of infections. Limitations included a cohort of mostly white males. The evidence shows that reinfection further increases risks of death, hospitalization and sequelae in multiple organ systems in the acute and postacute phase. Reducing overall burden of death and disease due to SARS-CoV-2 will require strategies for reinfection prevention.
254	I252		Sindhu Vangeti, Sivakumar Periasamy, Peifang Sun, Corey A. Balinsky, Avinash S. Mahajan, Natalia A. Kuzmina, Alessandra Soares-Schanoski, Elizabeth Cooper, Charmagne Beckett, Jan Marayag, Amethyst Marrone, Edgar Nunez, Yongchao Ge, Chad K. Porter, Carl W. Goforth, Stephen E. Lizewski, Rhonda Lizewski, Vihasi Jani, Victor A. Sugiharto https://orcid.org/0000-0002-9505-7303, Megan Schilling, Xuechen B. Yu, Nada Marjanovic, Mary Catherine George, Alexander Bukreyev, Stuart C. Sealfon stuart.sealfon@mssm.edu, Andrew G. Letizia andrew.g.letizia.mil@mail.mil, Irene Ramos	Serum Fc-Mediated Monocyte Phagocytosis Activity Is Stable for Several Months after SARS-CoV-2 Asymptomatic and Mildly Symptomatic Infection	https://doi.org/10.1128/spectrum.01837-22	Published	14 November 2022	Study	https://journals.asm.org/doi/10.1128/spectrum.01837-22	We investigated the temporal profile of multiple components of the serological response after asymptomatic or mildly symptomatic SARS-CoV-2 infection, in a cohort of 67 previously SARS-CoV-2 naive young adults, up to 8.5 months after infection. We found a significant decrease of spike IgG and neutralization antibody titers from early (11 to 56 days) to late (4 to 8.5 months) time points postinfection. Over the study period, S1-specific IgG levels declined significantly faster than that of the S2-specific IgG. Further, serum antibodies from PCR-confirmed participants cross-recognized S2, but not S1, of the betacoronaviruses HKU1 and OC43, suggesting a greater degree of cross-reactivity of S2 among betacoronaviruses. Antibody-Dependent Natural Killer cell Activation (ADNKA) was detected at the early time point but significantly decreased at the late time point. Induction of serum Antibody-Dependent Monocyte Phagocytosis (ADMP) was detected in all the infected participants, and its levels remained stable over time. Additionally, a reduced percentage of participants had detectable neutralizing activity against the Beta (50%), Gamma (61 to 67%), and Delta (90 to 94%) variants, both early and late postinfection, compared to the ancestral strain (100%). Antibody binding to S1 and RBD of Beta, Gamma, Delta (1.7 to 2.3-fold decrease), and Omicron (10 to 16-fold decrease) variants was also significantly reduced compared to the ancestral SARS-CoV-2 strain. Overall, we found variable temporal profiles of specific components and functionality of the serological response to SARS-CoV-2 in young adults, which is characterized by lasting, but decreased, neutralizing activity and antibody binding to S1, stable ADMP activity, and relatively stable S2-specific IgG levels. IMPORTANCE Adaptive immunity mediated by antibodies is important for controlling SARS-CoV-2 infection. While vaccines against COVID-19 are currently widely distributed, a high proportion of the global population is still unvaccinated. Therefore, understanding the dynamics and maintenance of the naive humoral immune response to SARS-CoV-2 is of great importance. In addition, long-term responses after asymptomatic infection are not well-characterized, given the challenges in identifying such cases. Here, we investigated the longitudinal humoral profile in a well-characterized cohort of young adults with documented asymptomatic or mildly symptomatic SARS-CoV-2 infection. By analyzing samples collected preinfection, early after infection and during late convalescence, we found that, while neutralizing activity decreased over time, high levels of serum S2 IgG and Antibody-Dependent Monocyte Phagocytosis (ADMP) activity were maintained up to 8.5 months after infection. This suggests that a subset of antibodies with specific functions could contribute to long-term protection against SARS-CoV-2 in convalescent unvaccinated individuals.
255	I253		Stefanie N. Bernas,Henning Baldauf,Ruben Real,Jürgen Sauter,Jan Markert,Sarah Trost,Kristin Tausche,Uta Behrends,Alexander H. Schmidt,Johannes Schetelig	Post-COVID-19 condition in the German working population: A cross-sectional study of 200k registered stem cell donors	https://doi.org/10.1111/joim.13587	Published	13 November 2022	Study	https://onlinelibrary.wiley.com/doi/abs/10.1111/joim.13587	Background The SARS-CoV-2 pandemic has strained health systems worldwide, and infection numbers continue to rise. While previous data have already shown that many patients suffer from symptoms for months after an acute infection, data on risk factors and long-term outcomes are incomplete, particularly for the working population. Objectives We aimed to provide information on the prevalence of post COVID-19 conditions in a subset of the German working-age population (18-61 years old) and to analyze risk-factors. Methods We conducted an online survey with a health questionnaire among registered potential stem cell donors with or without a self-reported history of PCR-confirmed SARS-CoV-2 infection. Logistic regression models were used to examine the risks of severity of acute infection, sex, age, body mass index, diabetes mellitus and arterial hypertension medication on post COVID-19 symptoms. Results 199,377 donors reported evaluable survey questionnaires: 12,609 cases had a history of SARS-CoV-2 infection and 186,768 controls had none. Overall, cases reported physical, cognitive and psychological complaints more frequently compared to controls. Increased rates of complaints persisted throughout 15 months post infection, e.g. 28.4/19.3% of cases/controls reported fatigue (p<0.0001) and 9.5/3.6% of cases/controls reported loss of concentration (p<0.0001). No significant differences were observed in the frequency of reported symptoms between three- and 15-months post-infection. Multivariate analysis revealed a strong influence of the severity of the acute SARS-CoV-2 infection episode and age on the risk for post-COVID-19 conditions. Conclusion We report the prevalence of post-COVID-19 conditions in mainly unvaccinated individuals with SARS-CoV-2 infections between February 2020 and August 2021. Severity of the acute course and age were major risk factors. Vaccinations may reduce the risk of post-COVID-19 conditions by reducing the risk for severe infections.
256	I254		V. Rossini,V. Tolosa-Enguis,C. Frances-Cuesta &Y. Sanz	Gut microbiome and anti-viral immunity in COVID-19	https://doi.org/10.1080/10408398.2022.2143476	Published	16 Nov 2022	Review	https://www.tandfonline.com/doi/full/10.1080/10408398.2022.2143476	SARS-CoV-2 mainly affects the respiratory system, but the gastrointestinal tract is also a target. Prolonged gut disorders, in COVID-19 patients, were correlated with decreased richness and diversity of the gut microbiota, immune deregulation and delayed viral clearance. Although there are no definitive conclusions, ample evidence would suggest that the gut microbiome composition and function play a role in COVID-19 progression. Microbiome modulation strategies for population stratification and management of COVID-19 infection are under investigation, representing an area of interest in the ongoing pandemic. In this review, we present the existing data related to the interaction between gut microbes and the host’s immune response to SARS-CoV-2 and discuss the implications for current disease management and readiness to face future pandemics.
257	I255		Pierre Dudouet, Philippe Colson, Sarah Aherfi, Anthony Levasseur, Mamadou Beye, Jeremy Delerce, Emilie Burel, Philippe Lavrard, Wahiba Bader, Jean-Christophe Lagier, Pierre-Edouard Fournier, Bernard La Scola & Didier Raoult	SARS-CoV-2 quasi-species analysis from patients with persistent nasopharyngeal shedding	https://doi.org/10.1038/s41598-022-22060-z	Published	04 November 2022	Study	https://www.nature.com/articles/s41598-022-22060-z	At the time of a new and unprecedented viral pandemic, many questions are being asked about the genomic evolution of SARS-CoV-2 and the emergence of different variants, leading to therapeutic and immune evasion and survival of this genetically highly labile RNA virus. The nasopharyngeal persistence of infectious virus beyond 17 days proves its constant interaction with the human immune system and increases the intra-individual mutational possibilities. We performed a prospective high-throughput sequencing study (ARTIC Nanopore) of SARS-CoV-2 from so-called "persistent" patients, comparing them with a non-persistent population, and analyzing the quasi-species present in a single sample at time t. Global intra-individual variability in persistent patients was found to be higher than in controls (mean 5.3%, Standard deviation 0.9 versus 4.6% SD 0.3, respectively, p < 0.001). In the detailed analysis, we found a greater difference between persistent and non-persistent patients with non-severe COVID 19, and between the two groups infected with clade 20A. Furthermore, we found minority N501Y and P681H mutation clouds in all patients, with no significant differences found both groups. The question of the SARS-CoV-2 viral variants’ genesis remains to be further investigated, with the need to prevent new viral propagations and their consequences, and quasi-species analysis could be an important key to watch out.
258	I256		Lucy Kundura1*, Renaud Cezar2, Sonia André3, Mauricio Campos-Mora4, Claire Lozano5, Thierry Vincent5, Laurent Muller6, Jean-Yves Lefrant6, Claire Roger6, Pierre-Géraud Claret7, Sandra Duvnjak8, Paul Loubet9, Albert Sotto9, Tu-Ahn Tran10, Jérôme Estaquier3,11† and Pierre Corbeau	Low perforin expression in CD8+ T lymphocytes during the acute phase of severe SARS-CoV-2 infection predicts long COVID	https://doi.org/10.3389/fimmu.2022.1029006	Published	20 October 2022	Study	https://www.frontiersin.org/articles/10.3389/fimmu.2022.1029006/full	T cell cytotoxicity plays a major role in antiviral immunity. Anti-SARS-CoV-2 immunity may determine acute disease severity, but also the potential persistence of symptoms (long COVID). We therefore measured the expression of perforin, a cytotoxic mediator, in T cells of patients recently hospitalized for SARS-CoV-2 infection. We recruited 54 volunteers confirmed as being SARS-CoV-2-infected by RT-PCR and admitted to Intensive Care Units (ICUs) or non-ICU, and 29 age- and sex-matched healthy controls (HCs). Amounts of intracellular perforin and granzyme-B, as well as cell surface expression of the degranulation marker CD107A were determined by flow cytometry. The levels of 15 cytokines in plasma were measured by Luminex. The frequency of perforin-positive T4 cells and T8 cells was higher in patients than in HCs (9.9 ± 10.1% versus 4.6 ± 6.4%, p = 0.006 and 46.7 ± 20.6% vs 33.3 ± 18.8%, p = 0.004, respectively). Perforin expression was neither correlated with clinical and biological markers of disease severity nor predictive of death. By contrast, the percentage of perforin-positive T8 cells in the acute phase of the disease predicted the onset of long COVID one year later. A low T8 cytotoxicity in the first days of SARS-CoV-2 infection might favor virus replication and persistence, autoimmunity, and/or reactivation of other viruses such as Epstein-Barr virus or cytomegalovirus, paving the way for long COVID. Under this hypothesis, boosting T cell cytotoxicity during the acute phase of the infection could prevent delayed sequelae.
259	I257		Kamille Fogh https://orcid.org/0000-0002-6669-6894 kamille.fogh.01@regionh.dk, Tine Graakjær Larsen, Cecilie B. Hansen, Rasmus B. Hasselbalch, Alexandra R. R. Eriksen, Henning Bundgaard, Ruth Frikke-Schmidt, Linda M. Hilsted, Lars Østergaard, Isik S. Johansen, Ida Hageman, Peter Garred https://orcid.org/0000-0002-2876-8586, Kasper Iversen	Self-Reported Long COVID and Its Association with the Presence of SARS-CoV-2 Antibodies in a Danish Cohort up to 12 Months after Infection	https://doi.org/10.1128/spectrum.02537-22	Published	9 November 2022	Study	https://journals.asm.org/doi/10.1128/spectrum.02537-22	The majority of long coronavirus disease (COVID) symptoms are not specific to COVID-19 and could be explained by other conditions. The present study aimed to explore whether Danish individuals with a perception that they suffer from long COVID have antibodies against the nucleocapsid antigen, as a proxy for detecting previous infection. The study was conducted in February and March 2021, right after the second surge of the COVID-19 pandemic in Denmark. All members of the social media group on Facebook “Covidramte med senfølger” (“long COVID sufferers'') above the age of 17 years and living in Denmark were invited to participate in a short electronic questionnaire about long COVID risk factors and symptoms. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N) protein was detected in blood samples as a proxy for natural SARS-CoV-2 infection. The final study population comprised 341 participants (90.6% females) who completed blood sampling and answered the questionnaire. A total of 232 (68%) were seropositive (median age, 49.5 years; interquartile range [IQR], 41 to 55 years; 90.1% females). There was no significant difference between sexes and serostatus. Seronegative and seropositive individuals had a similar burden of symptoms that could be attributed to long COVID. Time since perceived COVID-19 was significantly longer in the group of seronegative individuals than the seropositive ones (P < 0.001). This study suggests that long-COVID sufferers are mostly women and showed that a third of the participants did not have detectable anti-N-protein antibodies. It emphasizes the importance of early confirmation of COVID-19, as this study indicates an overlap between long-COVID symptoms and symptoms that are possibly of another origin. IMPORTANCE This cohort study included questionnaire data as well as anti-nucleocapsid antibody analysis, allowing us to determine whether participants were seropositive due to vaccination or natural infection. The study emphasizes the importance of early confirmation of COVID-19, as antibodies recede with time, and it indicates an overlap between long COVID symptoms and symptoms possibly of another origin.
260	I258		Bhupesh K. Prusty1*, Francesca Kasimir1, Danny Toomey2, Zheng Liu1, Agnes Kaiping1 and Maria Eugenia Ariza3	Tissue specific signature of HHV-6 infection in ME/CFS	https://doi.org/10.3389/fmolb.2022.1044964	Published	05 Dec 2022	Study	https://www.frontiersin.org/articles/10.3389/fmolb.2022.1044964/abstract?s=31	First exposure to various human herpesviruses (HHVs) including HHV-6, HCMV and EBV does not cause a life-threatening disease. In fact, most individuals are frequently unaware of their first exposure to such pathogens. These herpesviruses acquire lifelong latency in the human body where they show minimal genomic activity required for their survival. We hypothesized that it is not the latency itself but a timely, regionally restricted viral reactivation in a sub-set of host cells that plays a key role in disease development. HHV-6 (HHV-6A and HHV-6B) and HHV-7 are unique HHVs that acquire latency by integration of the viral genome into sub-telomeric region of human chromosomes. HHV-6 reactivation has been linked to Alzheimer’s Disease, Chronic Fatigue Syndrome, and many other diseases. However, lack of viral activity in commonly tested biological materials including blood or serum strongly suggests tissue specific localization of active HHV-6 genome. Here in this paper, we attempted to analyze active HHV-6 transcripts in postmortem tissue biopsies from a small cohort of ME/CFS patients and matched controls by fluorescence in situ hybridization using a probe against HHV-6 microRNA (miRNA), miR-aU14. Our results show abundant viral miRNA in various regions of the human brain and associated neuronal tissues including the spinal cord that is only detected in ME/CFS patients and not in controls. Our findings provide evidence of tissue-specific active HHV-6 and EBV infection in ME/CFS, which along with recent work demonstrating a possible relationship between herpesvirus infection and ME/CFS, provide grounds for renewed discussion on the role of herpesviruses in ME/CFS.
261	I259		Michael J. Peluso, Tyler-Marie Deveau, Sadie E. Munter, Dylan Ryder, Amanda Buck, Gabriele Beck-Engeser, Fay Chan, Scott Lu, Sarah A. Goldberg, Rebecca Hoh, Viva Tai, Leonel Torres, Nikita S. Iyer, Monika Deswal, Lynn H. Ngo, Melissa Buitrago, Antonio Rodriguez, Jessica Y. Chen, Brandon C. Yee, Ahmed Chenna, John W. Winslow, Christos J. Petropoulos, Amelia N. Deitchman, Joanna Hellmuth, Matthew A. Spinelli, Matthew S. Durstenfeld, Priscilla Y. Hsue, J. Daniel Kelly, Jeffrey N. Martin, Steven G. Deeks, Peter W. Hunt, Timothy J. Henrich	Impact of Pre-Existing Chronic Viral Infection and Reactivation on the Development of Long COVID	https://doi.org/10.1101/2022.06.21.22276660	pre-print	July 22, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.06.21.22276660v2.full-text	The presence and reactivation of chronic viral infections such as Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human immunodeficiency virus (HIV) have been proposed as potential contributors to Long COVID (LC), but studies in well-characterized post-acute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited. In a cohort of 280 adults with prior SARS-CoV-2 infection, we observed that LC symptoms such as fatigue and neurocognitive dysfunction at a median of 4 months following initial diagnosis were independently associated with serological evidence of recent EBV reactivation (early antigen-D [EA-D] IgG positivity) or high nuclear antigen IgG levels, but not with ongoing EBV viremia. Evidence of EBV reactivation (EA-D IgG) was most strongly associated with fatigue (OR 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR 0.52) and tended to have less severe (>5 symptoms reported) LC (OR 0.44). Overall, these findings suggest differential effects of chronic viral co-infections on the likelihood of developing LC and predicted distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted. SUMMARY The authors found that Long COVID symptoms in a post-acute cohort were associated with serological evidence of recent EBV reactivation and pre-existing HIV infection when adjusted for participant factors, sample timing, comorbid conditions and prior hospitalization, whereas underlying CMV infection was associated with a decreased risk of Long COVID.
262	I260		Partha Chattopadhyay1,2, Kriti Khare1,2†, Manish Kumar2,3†, Pallavi Mishra1†, Alok Anand4†, Ranjeet Maurya1,2, Rohit Gupta1, Shweta Sahni3, Ayushi Gupta4, Saruchi Wadhwa3, Aanchal Yadav1,2, Priti Devi1,2, Kishore Tardalkar5, Meghnad Joshi5, Tavpritesh Sethi4 and Rajesh Pandey1,2*	Single-cell multiomics revealed the dynamics of antigen presentation, immune response and T cell activation in the COVID-19 positive and recovered individuals	https://doi.org/10.3389/fimmu.2022.1034159	Published	02 December 2022	Study	https://www.frontiersin.org/articles/10.3389/fimmu.2022.1034159/full	Introduction: Despite numerous efforts to describe COVID-19's immunological landscape, there is still a gap in our understanding of the virus's infections after-effects, especially in the recovered patients. This would be important to understand as we now have huge number of global populations infected by the SARS-CoV-2 as well as variables inclusive of VOCs, reinfections, and vaccination breakthroughs. Furthermore, single-cell transcriptome alone is often insufficient to understand the complex human host immune landscape underlying differential disease severity and clinical outcome. Methods: By combining single-cell multi-omics (Whole Transcriptome Analysis plus Antibody-seq) and machine learning-based analysis, we aim to better understand the functional aspects of cellular and immunological heterogeneity in the COVID-19 positive, recovered and the healthy individuals. Results: Based on single-cell transcriptome and surface marker study of 163,197 cells (124,726 cells after data QC) from the 33 individuals (healthy=4, COVID-19 positive=16, and COVID-19 recovered=13), we observed a reduced MHC Class-I-mediated antigen presentation and dysregulated MHC Class-II-mediated antigen presentation in the COVID-19 patients, with restoration of the process in the recovered individuals. B-cell maturation process was also impaired in the positive and the recovered individuals. Importantly, we discovered that a subset of the naive T-cells from the healthy individuals were absent from the recovered individuals, suggesting a post-infection inflammatory stage. Both COVID-19 positive patients and the recovered individuals exhibited a CD40-CD40LG-mediated inflammatory response in the monocytes and T-cell subsets. T-cells, NK-cells, and monocyte-mediated elevation of immunological, stress and antiviral responses were also seen in the COVID-19 positive and the recovered individuals, along with an abnormal T-cell activation, inflammatory response, and faster cellular transition of T cell subtypes in the COVID-19 patients. Importantly, above immune findings were used for a Bayesian network model, which significantly revealed FOS, CXCL8, IL1β, CST3, PSAP, CD45 and CD74 as COVID-19 severity predictors. Discussion: In conclusion, COVID-19 recovered individuals exhibited a hyper-activated inflammatory response with the loss of B cell maturation, suggesting an impeded post-infection stage, necessitating further research to delineate the dynamic immune response associated with the COVID-19. To our knowledge this is first multi-omic study trying to understand the differential and dynamic immune response underlying the sample subtypes.
263	I261		Michael J. Peluso,1 Tyler-Marie Deveau,2 Sadie E. Munter,2 Dylan M. Ryder,2 Amanda M. Buck,2 Gabriele Beck-Engeser,2 Fay Chan,2 Scott Lu,3 Sarah A. Goldberg,3 Rebecca Hoh,1 Viva Tai,1 Leonel Torres,2 Nikita S. Iyer,2 Monika Deswal,1 Lynn H. Ngo,1 Melissa Buitrago,1 Antonio E. Rodriguez,1 Jessica Y. Chen,1 Brandon C. Yee,4 Ahmed Chenna,5 John W. Winslow,5 Christos J. Petropoulos,5 Amelia N. Deitchman,6 Joanna Hellmuth,7 Matthew A. Spinelli,1 Matthew S. Durstenfeld,8 Priscilla Y. Hsue,8 John Daniel Kelly,3 Jeffrey N. Martin,3 Steven G. Deeks,1 Peter W. Hunt,2 and Timothy J. Henrich2	Impact of pre-existing chronic viral infection and reactivation on the development of long COVID	https://doi.org/10.1172/JCI163669	Published	December 1, 2022	Study	https://www.jci.org/articles/view/163669	BACKGROUND. The presence and reactivation of chronic viral infections such as Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human immunodeficiency virus (HIV) have been proposed as potential contributors to Long COVID (LC), but studies in well-characterized post-acute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited. METHODS. In a cohort of 280 adults with prior SARS-CoV-2 infection, we assessed the presence and types of LC symptoms and prior medical history (including COVID-19 history and HIV status), and performed serological testing for EBV and CMV using a commercial laboratory. We used covariate-adjusted binary logistic regression models to identify independent associations between variables and LC symptoms. RESULTS. We observed that LC symptoms such as fatigue and neurocognitive dysfunction at a median of 4months following initial diagnosis were independently associated with serological evidence suggesting recent EBV reactivation (early antigen-D [EA-D] IgG positivity) or high nuclear antigen (EBNA) IgG levels, but not with ongoing EBV viremia. Serological evidence suggesting recent EBV reactivation (EA-D IgG) was most strongly associated with fatigue (OR 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR 0.52). CONCLUSION. Overall, these findings suggest differential effects of chronic viral co-infections on the likelihood of developing LC and predicted distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted.
264	I262		César Fernández-de-las-Peñas 1,2,*ORCID,Kin Israel Notarte 3ORCID,Princess Juneire Peligro 4,Jacqueline Veronica Velasco 4ORCID,Miguel Joaquín Ocampo 4,Brandon Michael Henry 5,Lars Arendt-Nielsen 2,6,Juan Torres-Macho 7,8 andGustavo Plaza-Manzano 9ORCID	Long-COVID Symptoms in Individuals Infected with Different SARS-CoV-2 Variants of Concern: A Systematic Review of the Literature	https://doi.org/10.3390/v14122629	Published	25 November 2022	Systematic Review	https://www.mdpi.com/1999-4915/14/12/2629	The association of SARS-CoV-2 variants with long-COVID symptoms is still scarce, but new data are appearing at a fast pace. This systematic review compares the prevalence of long-COVID symptoms according to relevant SARS-CoV-2 variants in COVID-19 survivors. The MEDLINE, CINAHL, PubMed, EMBASE and Web of Science databases, as well as the medRxiv and bioRxiv preprint servers, were searched up to 25 October 2022. Case-control and cohort studies analyzing the presence of post-COVID symptoms appearing after an acute SARS-CoV-2 infection by the Alpha (B.1.1.7), Delta (B.1.617.2) or Omicron (B.1.1.529/BA.1) variants were included. Methodological quality was assessed using the Newcastle–Ottawa Scale. From 430 studies identified, 5 peer-reviewed studies and 1 preprint met the inclusion criteria. The sample included 355 patients infected with the historical variant, 512 infected with the Alpha variant, 41,563 infected with the Delta variant, and 57,616 infected with the Omicron variant. The methodological quality of all studies was high. The prevalence of long-COVID was higher in individuals infected with the historical variant (50%) compared to those infected with the Alpha, Delta or Omicron variants. It seems that the prevalence of long-COVID in individuals infected with the Omicron variant is the smallest, but current data are heterogeneous, and long-term data have, at this stage, an obviously shorter follow-up compared with the earlier variants. Fatigue is the most prevalent long-COVID symptom in all SARS-CoV-2 variants, but pain is likewise prevalent. The available data suggest that the infection with the Omicron variant results in fewer long-COVID symptoms compared to previous variants; however, the small number of studies and the lack of the control of cofounders, e.g., reinfections or vaccine status, in some studies limit the generality of the results. It appears that individuals infected with the historical variant are more likely to develop long-COVID symptomatology.
265	I263		Huan-ping Zhang,Yuan-li Sun,Yan-fen Wang,Duygu Yazici,Dilek Azkur,Ismail Ogulur,Ahmet Kursat Azkur,Zhao-wei Yang,Xiao-xue Chen,Ai-Zhi Zhang,Jia-qian Hu,Guang-Hui Liu,Mübeccel Akdis,Cezmi A. Akdis,Ya-dong Gao	Recent developments in the immunopathology of COVID-19	https://doi.org/10.1111/all.15593	Published	24 November 2022	Review	https://onlinelibrary.wiley.com/doi/10.1111/all.15593	There has been an important change in the clinical characteristics and immune profile of Coronavirus disease 2019 (COVID-19) patients during the pandemic thanks to the extensive vaccination programs. Here, we highlight recent studies on COVID-19, from the clinical and immunological characteristics to the protective and risk factors for severity and mortality of COVID-19. The efficacy of the COVID-19 vaccines and potential allergic reactions after administration are also discussed. The occurrence of new variants of concerns such as Omicron BA.2, BA.4, and BA.5 and the global administration of COVID-19 vaccines have changed the clinical scenario of COVID-19. Multisystem inflammatory syndrome in children (MIS-C) may cause severe and heterogeneous disease but with a lower mortality rate. Perturbations in immunity of T cells, B cells, and mast cells, as well as autoantibodies and metabolic reprogramming may contribute to the long-term symptoms of COVID-19. There is conflicting evidence about whether atopic diseases, such as allergic asthma and rhinitis, are associated with a lower susceptibility and better outcomes of COVID-19. At the beginning of pandemic, the European Academy of Allergy and Clinical Immunology (EAACI) developed guidelines that provided timely information for the management of allergic diseases and preventive measures to reduce transmission in the allergic clinics. The global distribution of COVID-19 vaccines and emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with reduced pathogenic potential dramatically decreased the morbidity, severity, and mortality of COVID-19. Nevertheless, breakthrough infection remains a challenge for disease control. Hypersensitivity reactions (HSR) to COVID-19 vaccines are low compared to other vaccines, and these were addressed in EAACI statements that provided indications for the management of allergic reactions, including anaphylaxis to COVID-19 vaccines. We have gained a depth knowledge and experience in the over 2 years since the start of the pandemic, and yet a full eradication of SARS-CoV-2 is not on the horizon. Novel strategies are warranted to prevent severe disease in high-risk groups, the development of MIS-C and long COVID-19.
266	I264		Chiara Ambaglio,1,* Marina Marchetti, PhD,1,* Simone V Benatti,2,* Carmen J Tartari, PhD,1,* Cinzia Giaccherini,1,* Laura Russo,1,* Sara Gamba, MD,1,* Cristina Verzeroli,1,* Silvia Bolognini,1,* Chiara Ticozzi,1,* Francesca Schieppati, MD,1,* Serena Venturelli,2,* Luca Barcella, MD,1,* Marco Rizzi,2,* and Anna Falanga, MD1,3	Role of Hemostatic Biomarkers for the Identification of Patients with LONG-COVID19 Syndrome: Results from the 'Accordi' Study	https://doi.org/10.1182%2Fblood-2022-162206	Published	2022 Nov 15	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9665220/	Introduction: Hemostatic alterations of patients with acute Covid-19 are well described, while post-Covid-19 clinical and laboratory consequences are less clear. Survivors of Covid-19 exhibit a complex array of symptoms, whose underlying pathology is still to be elucidated. The term 'long-Covid' is used to describe this condition developing after acute Covid-19. Materials and Methods: After the first wave of the pandemic, we started an ad hoc multidisciplinary follow-up project for Covid-19 patients discharged from our Institution (ACCORDI STUDY). The program was run from July to November 2020. Patients were reassessed one time for clinical, instrumental, and laboratory parameters. Blood samples were collected from each participant for the measurement of hemostatic biomarkers. Here we present the first interim analysis of the biomarkers study. The laboratory study included complete blood cell count, liver and renal functional tests, LDH, C-reactive protein, fibrinogen, D-dimer (DD), von Willebrand factor antigen (vWF:Ag), thrombomodulin (TM), tissue plasminogen activator (tPA) and plasminogen activator inhibitor PAI-1, prothrombin fragment 1+2 (F1+2). Results: A cohort of 1471 (554F/917M) patients was recruited in the ACCORDI program with a median age of 60 (19-93). The median time from Covid-19 onset was 107 days (range 65-142). At the onset of disease, patients had the following symptoms: cardiopulmonary (94%), flu-like (91%), respiratory (82%), and neurological (57%). At the follow-up visit, cardiopulmonary symptoms persisted in 88%, flu-like in 64%, respiratory in 42%, and neurological in 13%. No differences in symptoms' distribution were present in relation to age and gender at either disease onset or follow-up visit. Based on the time of symptom persistence, 771 (53%) patients were classified as long-Covid, while the remaining 700 (47%) were symptoms-free. The median age of long-Covid patients was 59 (range 38-80) years, 55% male, with cardiopulmonary as the prevalent symptoms. In a subgroup of 468 patients [322M/146F, age range 65 (38-83) years], 231 long-Covid and 237 symptoms-free, an interim analysis of hemostatic biomarker test results was performed. The analysis (Table 1) showed that, compared to symptoms-free subjects, long-Covid patients had significantly (p<0.05) higher levels of vWF:Ag and PAI-1. In addition, among subjects evaluated within 12 weeks from disease onset, the symptomatic subjects (n=48) had significantly higher levels of PAI-1 and TM (p<0.05) than the symptoms-free ones (n=78), whereas, among subjects evaluated after 12 weeks of disease onset (n=184), i.e. the post-Covid syndrome patients, had significantly (p<0.05) higher levels of vWF:Ag as compared to symptoms-free subjects (n=159). No significant differences were observed in the levels of tPA, DD, fibrinogen, F1+2 of symptomatic vs asymptomatic individuals. In a model of logistic regression analysis corrected for age and gender, having at least one among TM and PAI-1 biomarkers above the 75th percentile within 12 weeks from the disease onset, was significantly associated with a diagnosis of long-Covid (OR 2.425; 95% CI:1.037-5.671; p=0.041). Conclusions: In conclusion, in this study cohort, patients with long-Covid syndrome are characterized by the persistence of cardiopulmonary symptoms. Preliminary results on hemostatic biomarkers analysis show that endothelial (TM and vWF:Ag) and fibrinolytic (PAI) biomarkers are associated with long-Covid symptoms and may be useful for the identification of affected subjects.
267	I265		LorenzThurneraNatalieFadleaEviRegitzaKlaus-DieterPreussaFrankNeumannaOnurCetinaClaudiaSchormannaMarie-ChristinHoffmannaChristianHerrbParastooKheiroddincTorben MillardRixeckerbRobertBalsbdSylvianeMullereBernhardThurnerfChristophKesselgMichaelKabeschcMoritzBewarderaKristinaHeyneaChristianLenschb1Igor AgeKosa1	Autoantibodies against SUMO1-DHX35 in long-COVID	https://doi.org/10.1016/j.jtauto.2022.100171	Published	20 November 2022	Study	https://www.sciencedirect.com/science/article/pii/S2589909022000326	Highlights •IgG autoantobodies against SUMO1-DHX35 occur in a subset of patients with long-COVID. •Lysine 53 was identified as SUMOylation site of DHX35 •SUMOylation of DHX-35 is a necessary prerequisite for reactivity of autoantibodies Abstract Long COVID is a collection of symptoms as a late sequelae of SARS-CoV-2 infection. It often includes mental symptoms such as cognitive symptoms, persisting loss of smell and taste, in addition to exertional dyspnea. A role of various autoantibodies (autoAbs) has been postulated in long-COVID and is being further investigated. With the goal of identifying potentially unknown autoAbs, we screened plasma of patients with long COVID on in-house post-translationally modified protein macroarrays including citrullinated, SUMOylated and acetylated membranes. SUMO1ylated isoform DEAD/H (Asp-Glu-Ala-Asp/His) box helicase 35 (SUMO1-DHX35) was identified as only candidate antigen. In adult patients with long COVID, IgG autoAbs against SUMO1-DHX35 of IgG class were found in seven of 71 (9.8%) plasma samples, of IgM and IgG class in one of 69 (1.4%) samples, not in 200 healthy adult controls, not in 442 healthy children, and 146 children after SARS-CoV-2 infection. All autoAb-positive seven patients were female. AutoAb titers ranged between 200 to up to 400 By point mutagenesis and expression of FLAG-tagged mutants of DHX35 in HEK293 cells, and subsequent SUMOylation of purified constructs, lysine 53 was identified as a unique, never yet identified, SUMOylation site. The autoAbs had no reactivity against the non-SUMO1ylated mutant (K53R) of DHX35. To summarize, autoAbs against SUMO1-DHX35 were identified in adult female patients with long-COVID. Further studies are needed to verify the frequency of occurrence. The function of DHX35 has not yet been determined and there is no available information in relation to disease implication. The molecular mechanism causing the SUMOylation, the potential functional consequences of this post-translational modification on DHX35, and a potential pathogenicity of the autoAbs against SUMO1-DHX35 in COVID-19 and other possible contexts remain to be elucidated.
268	I266		AsimaKarimaTahirMuhammadbM. ShahidIqbalcRizwanQaisara	Elevated plasma CAF22 are incompletely restored six months after COVID-19 infection in older men	https://doi.org/10.1016/j.exger.2022.112034	Published	21 November 2022	Study	https://www.sciencedirect.com/science/article/pii/S0531556522003436?ref=pdf_download&fr=RR-2&rr=775595db0de8f124	Highlights •Covid-19 infection is associated with sarcopenia in old age. •Muscle weakness and elevated plasma CAF22 occur one week after COVID-19 infection. •Muscle strength and CAF22 are partly restored six months after COVID-19 infection. •COVID-19 may cause muscle loss by degrading neuromuscular junctions. •Evaluation and prevention of muscle loss may help treat COVID-19 infection. Abstract Introduction The long-term complications of COVID-19 appear as significant health problems. However, the long-term muscle decline in these patients is poorly characterized. Methods We investigated the age-related muscle decline, termed sarcopenia, before and following the COVID-19 infection in older male patients (n = 87). We evaluated handgrip strength (HGS) and functional capacity (short physical performance battery; SPPB) in COVID-19 patients 7–42 days before and one week and 6-month after COVID-19 infection. We used ELISA tests to measure plasma c-terminal agrin fragment-22 (CAF22), c-reactive protein (CRP), and 8-isoprostanes as markers of degraded neuromuscular junctions, inflammation, and oxidative stress, respectively. Results Before the COVID-19 infection, 54 patients were non-sarcopenic, and 25 patients were sarcopenic, while eight patients subsequently developed sarcopenia. All patients exhibited reduced HGS and SPPB, while elevated CAF22, CRP, and 8-isoprostane levels one week post-COVID-19 infection (all p < 0.05). At six months post-COVID-19 infection, the HGS, SPPB, CAF22, CRP, and 8-isoprostanes were partly restored to baseline levels (all p < 0.05). Correlation analysis revealed that the plasma CAF22 had a significant correlation with HGS, SPPB, and COVID-19 disease severity. CAF22 also demonstrated significant areas under the curves in diagnosing sarcopenia at all three time-points. Conclusion Altogether, the muscle detriment due to COVID-19 persists six months post-infection, and plasma CAF22 may be helpful to detect muscle and functional decline in these patients. Timely evaluation and intervention of sarcopenia may be critical in COVID-19 treatment.
269	I267		Mahdi Taghadosi,Elham Safarzadeh,Ali Asgarzadeh,Seyed Askar Roghani,Afsaneh Shamsi,Cyrus Jalili,Shirin Assar,Parviz Soufivand,Mehran Pournazari,Parisa Feizollahi,Mohammad Hossein Nicknam,Vahid Asghariazar,Siavash Vaziri,Hossein Shahriari,Asadollah Mohammadi	Partners in crime: Autoantibodies complicit in COVID-19 pathogenesis	https://doi.org/10.1002/rmv.2412	Published	05 December 2022	Review	https://onlinelibrary.wiley.com/doi/10.1002/rmv.2412	Autoantibodies (AABs) play a critical role in the pathogenesis of autoimmune diseases (AIDs) and serve as a diagnostic and prognostic tool in assessing these complex disorders. Viral infections have long been recognized as a principal environmental factor affecting the production of AABs and the development of autoimmunity. COVID-19 has primarily been considered a hyperinflammatory syndrome triggered by a cytokine storm. In the following, the role of maladaptive B cell response and AABs became more apparent in COVID-19 pathogenesis. The current review will primarily focus on the role of extrafollicular B cell response, Toll-like receptor-7 (TLR-7) activation, and neutrophil extracellular traps (NETs) formation in the development of AABs following SARS-CoV-2 infection. In the following, this review will clarify how these AABs dysregulate immune response to SARS-CoV-2 by disrupting cytokine function and triggering neutrophil hyper-reactivity. Finally, the pathologic effects of these AABs will be further described in COVID-19 associate clinical manifestations, including venous and arterial thrombosis, a multisystem inflammatory syndrome in children (MIS-C), acute respiratory distress syndrome (ARDS), and recently described post-acute sequelae of COVID-19 (PASC) or long-COVID.
270	I268		Alistair V. W. Nunn 1,*ORCID,Geoffrey W. Guy 2,Wolfgang Brysch 3 andJimmy D. Bell 1ORCID	Understanding Long COVID; Mitochondrial Health and Adaptation—Old Pathways, New Problems	https://doi.org/10.3390/biomedicines10123113	Published	2 December 2022	Review	https://www.mdpi.com/2227-9059/10/12/3113	Many people infected with the SARS-CoV-2 suffer long-term symptoms, such as “brain fog”, fatigue and clotting problems. Explanations for “long COVID” include immune imbalance, incomplete viral clearance and potentially, mitochondrial dysfunction. As conditions with sub-optimal mitochondrial function are associated with initial severity of the disease, their prior health could be key in resistance to long COVID and recovery. The SARs virus redirects host metabolism towards replication; in response, the host can metabolically react to control the virus. Resolution is normally achieved after viral clearance as the initial stress activates a hormetic negative feedback mechanism. It is therefore possible that, in some individuals with prior sub-optimal mitochondrial function, the virus can “tip” the host into a chronic inflammatory cycle. This might explain the main symptoms, including platelet dysfunction. Long COVID could thus be described as a virally induced chronic and self-perpetuating metabolically imbalanced non-resolving state characterised by mitochondrial dysfunction, where reactive oxygen species continually drive inflammation and a shift towards glycolysis. This would suggest that a sufferer’s metabolism needs to be “tipped” back using a stimulus, such as physical activity, calorie restriction, or chemical compounds that mimic these by enhancing mitochondrial function, perhaps in combination with inhibitors that quell the inflammatory response.
271	I269		Ekaterina Pisareva, Stephanie Badiou, Lucia Mihalovičová, Alexia Mirandola, Brice Pastor, Andrei Kudriavtsev, Marie Berger, Camille Roubille, Pierre Fesler, Kada Klouche, Jean-Paul Cristol, Alain R. Thierry	Persistence of neutrophil extracellular traps and anticardiolipin auto-antibodies in post-acute phase COVID-19 patients	https://doi.org/10.1002/jmv.28209	Published	13 October 2022	Study	https://onlinelibrary.wiley.com/doi/10.1002/jmv.28209	In the early phase of the pandemic, we were among the first to postulate that neutrophil extracellular traps (NETs) play a key role in COVID-19 pathogenesis. This exploratory prospective study based on 279 individuals showed that plasma levels of neutrophil elastase, myeloperoxidase and circulating DNA of nuclear and mitochondrial origins in nonsevere (NS), severe (S) and postacute phase (PAP) COVID-19 patients were statistically different as compared to the levels in healthy individuals, and revealed the high diagnostic power of these NETs markers in respect to the disease severity. The diagnostic power of NE, MPO, and cir-nDNA as determined by the Area Under Receiver Operating Curves (AUROC) was 0.95, 097, and 0.64; 0.99, 1.0, and 0.82; and 0.94, 1.0, and 0.93, in NS, S, and PAP patient subgroups, respectively. In addition, a significant fraction of NS, S as well as of PAP patients exhibited aCL IgM/IgG and anti-B2GP IgM/IgG positivity. We first demonstrate persistence of these NETs markers in PAP patients and consequently of sustained innate immune response imbalance, and a prolonged low-level pro-thrombotic potential activity highlighting the need to monitor these markers in all COVID-19 PAP individuals, to investigate postacute COVID-19 pathogenesis following intensive care, and to better identify which medical resources will ensure complete patient recovery.	TO Zotero
272	I270		Thompson, Ryan C.; Simons, Nicole W.; Wilkins, Lillian; Cheng, Esther; Del Valle, Diane Marie; Hoffman, Gabriel E.; Cervia, Carlo; Fennessy, Brian; Mouskas, Konstantinos; Francoeur, Nancy J.; Johnson, Jessica S.; Lepow, Lauren; Le Berichel, Jessica; Chang, Christie; Beckmann, Aviva G.; Wang, Ying-chih; Nie, Kai; Zaki, Nicholas; Tuballes, Kevin; Barcessat, Vanessa; Cedillo, Mario A.; Yuan, Dan; Huckins, Laura; Roussos, Panos; Marron, Thomas U.; Glicksberg, Benjamin S.; Nadkarni, Girish; Heath, James R.; Gonzalez-Kozlova, Edgar; Boyman, Onur; Kim-Schulze, Seunghee; Sebra, Robert; Merad, Miriam; Gnjatic, Sacha; Schadt, Eric E.; Charney, Alexander W.; Batchelor, Craig; Beckmann, Noam D.	Molecular states during acute COVID-19 reveal distinct etiologies of long-term sequelae	https://doi.org/10.1186/s10020-022-00583-5	Published	2022-12-12	Study	https://doi.org/10.1186/s10020-022-00583-5	Background Multisystem Inflammatory Syndrome in Children (MIS-C) is a life-threatening complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which manifests as a hyper inflammatory process with multiorgan involvement in predominantly healthy children in the weeks following mild or asymptomatic coronavirus disease 2019 (COVID-19). However, host monogenic predisposing factors to MIS-C remain elusive. Methods Herein, we used whole exome sequencing (WES) on 16 MIS-C Brazilian patients to identify single nucleotide/InDels variants as predisposition factors associated with MIS-C. Results We identified ten very rare variants in eight genes (FREM1, MPO, POLG, C6, C9, ABCA4, ABCC6, and BSCL2) as the most promising candidates to be related to a higher risk of MIS-C development. These variants may propitiate a less effective immune response to infection or trigger the inflammatory response or yet a delayed hyperimmune response to SARS-CoV-2. Protein–Protein Interactions (PPIs) among the products of the mutated genes revealed an integrated network, enriched for immune and inflammatory response mechanisms with some of the direct partners representing gene products previously associated with MIS-C and Kawasaki disease (KD). In addition, the PPIs direct partners are also enriched for COVID-19-related gene sets. HLA alleles prediction from WES data allowed the identification of at least one risk allele in 100% of the MIS-C patients. Conclusions This study is the first to explore host MIS-C-associated variants in a Latin American admixed population. Besides expanding the spectrum of MIS-C-associated variants, our findings highlight the relevance of using WES for characterising the genetic interindividual variability associated with COVID-19 complications and ratify the presence of overlapping/convergent mechanisms among MIS-C, KD and COVID-19, crucial for future therapeutic management.
273	I271		Tofarides, Andreas G.; Christaki, Eirini; Milionis, Haralampos; Nikolopoulos, Georgios K.	Effect of Vaccination against SARS-CoV-2 on Long COVID-19: A Narrative Review	https://doi.org/10.1038/s41591-022-02107-4	Published	2022-12-08	Study	https://www.nature.com/articles/s41591-022-02107-4	Post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are debilitating, clinically heterogeneous and of unknown molecular etiology. A transcriptome-wide investigation was performed in 165 acutely infected hospitalized individuals who were followed clinically into the post-acute period. Distinct gene expression signatures of post-acute sequelae were already present in whole blood during acute infection, with innate and adaptive immune cells implicated in different symptoms. Two clusters of sequelae exhibited divergent plasma-cell-associated gene expression patterns. In one cluster, sequelae associated with higher expression of immunoglobulin-related genes in an anti-spike antibody titer-dependent manner. In the other, sequelae associated independently of these titers with lower expression of immunoglobulin-related genes, indicating lower non-specific antibody production in individuals with these sequelae. This relationship between lower total immunoglobulins and sequelae was validated in an external cohort. Altogether, multiple etiologies of post-acute sequelae were already detectable during SARS-CoV-2 infection, directly linking these sequelae with the acute host response to the virus and providing early insights into their development.
274	I272		He, Shi-ting; Wu, Kexin; Cheng, Zixuan; He, Mengjie; Hu, Ruolan; Fan, Ning; Shen, Lin; Li, Qirui; Fan, Huahao; Tong, Yigang	Long COVID: The latest manifestations, mechanisms, and potential therapeutic interventions	https://doi.org/10.1038/s41577-022-00815-z	Published	2022-12-09	Study	https://www.nature.com/articles/s41577-022-00815-z	Tissue-resident memory T (TRM) cells were originally identified as a tissue-sequestered population of memory T cells that show lifelong persistence in non-lymphoid organs. That definition has slowly evolved with the documentation of TRM cells having variable terms of tissue residency combined with a capacity to return to the wider circulation. Nonetheless, reductionist experiments have identified an archetypical population of TRM cells showing intrinsic permanent residency in a wide range of non-lymphoid organs, with one notable exception: the lungs. Despite the fact that memory T cells generated during a respiratory infection are maintained in the circulation, local TRM cell numbers in the lung decline concomitantly with a decay in T cell-mediated protection. This Perspective describes the mechanisms that underpin long-term T cell lodgement in non-lymphoid tissues and explains why residency is transient for select TRM cell subsets. In doing so, it highlights the unusual nature of memory T cell egress from the lungs and speculates on the broader disease implications of this process, especially during infection with SARS-CoV-2.
275	I273		Nehme, Mayssam; Vetter, Pauline; Chappuis, François; Kaiser, Laurent; Guessous, Idris; the CoviCare Study team	Prevalence of post-COVID Condition 12 Weeks after Omicron Infection Compared to Negative Controls and Association with Vaccination Status	https://doi.org/10.1093/cid/ciac947	Published	2022-12-15	Study	https://doi.org/10.1093/cid/ciac947	Post-COVID symptoms can persist several months after SARS-CoV-2 infection. Little is known, however, about the prevalence of post-COVID condition following infections from Omicron variants and how this varies according to vaccination statusThis study evaluates the prevalence of symptoms and functional impairment 12 weeks after an infection by Omicron variants (BA.1 and BA.2) compared to negative controls tested during the same period.Outpatient individuals tested positive or negative for COVID-19 infection between December 2021 and February 2022 at the Geneva University Hospitals were followed 12 weeks after their test date.Overall, 11.7% of Omicron cases had symptoms 12 weeks after the infection compared to 10.4% of individuals who tested negative during the same period (p < 0.001), and symptoms were much less common in vaccinated vs non-vaccinated individuals with Omicron infection (9.7% vs 18.1%, p < 0.001). There were no significant differences in functional impairment at 12 weeks between Omicron cases and negative controls even after adjusting for multiple potential confounders.The differential prevalence of post-COVID symptoms and functional impairment attributed to Omicron BA.1 and BA.2 infection is low when compared to negative controls. Vaccination is associated with lower prevalence of post-COVID symptoms.
276	I274		Thompson, JY; Nnate, DA; Mussad, M; Carroll, S; Buck, P; Strain, WD; Banerjee, A; Van de Velde, N	EPH155 A Systematic Review of the Impact of Vaccination on Long COVID	https://doi.org/10.1016/j.jval.2022.09.1076	Published	2022-12	Systematic Review	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9747389/	PMID: null PMCID: PMC9747389 Objectives Coronavirus disease 2019 (COVID-19) has multisystem effects, with a myriad of symptoms that may persist beyond four weeks (i.e., “long COVID”) but may be amenable to vaccination. This review systematically synthesised evidence to evaluate the health and economic burden of long COVID, specifically its relationship to vaccines. Go to: Methods Relevant databases were searched for experimental randomized controlled trials (RCTs) and non-interventional studies. No language restrictions were applied. Estimates from 29 studies were narratively synthesised from Canada (2), United States (6), Australia (1), United Kingdom (9), France (2), India (2), Europe (1), Indonesia (1), Israel (1), Egypt (1), and international (3). Of the 29 studies identified, only 11 studies considered fully vaccinated vs partially vaccinated or unvaccinated groups before they were infected. Most studies were conducted among community-dwelling individuals (n=20), four among hospitalized patients, and five in either setting. Seven studies considered participants that were vaccinated post-infection. In comparison, eleven studies did not provide adequate information about vaccination status. Go to: Results Of the 29 studies, 17 explored the relationship between vaccination and symptoms of long-COVID; 1 study reported worsening of symptoms, 11 studies reported improvement of symptoms, and 5 reported no difference in symptom profile following vaccination. Only two studies provided information on the economic benefit of vaccination strategies. Go to: Conclusions The COVID-19 and long COVID evidence base is evolving, and additional data may be presented at the conference. Data collected to date suggest that the prevalence of long COVID is a crude approximation, which underestimates the burden of the disease and the impact of vaccines and findings may also be limited by the reporting and quality of eligible studies. Furthermore, we would not be able to evaluate the impact of risk aversion via adherence to public health guidelines or non-pharmacological interventions due to measurement error, thereby increasing the possibility of bias.
277	I275		Thompson, J. Y.; Nnate, D. A.; Mussad, M.; Carroll, S.; Buck, P.; Strain, W. D.; Banerjee, A.; Velde, N. Van de	EPH155 A Systematic Review of the Impact of Vaccination on Long COVID	https://doi.org/10.1016/j.jval.2022.09.1076	Published	2022-12-01	Systematic Review	https://www.valueinhealthjournal.com/article/S1098-3015(22)03281-8/fulltext	publisher: Elsevier Objectives Coronavirus disease 2019 (COVID-19) has multisystem effects, with a myriad of symptoms that may persist beyond four weeks (i.e., “long COVID”) but may be amenable to vaccination. This review systematically synthesised evidence to evaluate the health and economic burden of long COVID, specifically its relationship to vaccines. Methods Relevant databases were searched for experimental randomized controlled trials (RCTs) and non-interventional studies. No language restrictions were applied. Estimates from 29 studies were narratively synthesised from Canada (2), United States (6), Australia (1), United Kingdom (9), France (2), India (2), Europe (1), Indonesia (1), Israel (1), Egypt (1), and international (3). Of the 29 studies identified, only 11 studies considered fully vaccinated vs partially vaccinated or unvaccinated groups before they were infected. Most studies were conducted among community-dwelling individuals (n=20), four among hospitalized patients, and five in either setting. Seven studies considered participants that were vaccinated post-infection. In comparison, eleven studies did not provide adequate information about vaccination status. Results Of the 29 studies, 17 explored the relationship between vaccination and symptoms of long-COVID; 1 study reported worsening of symptoms, 11 studies reported improvement of symptoms, and 5 reported no difference in symptom profile following vaccination. Only two studies provided information on the economic benefit of vaccination strategies. Conclusions The COVID-19 and long COVID evidence base is evolving, and additional data may be presented at the conference. Data collected to date suggest that the prevalence of long COVID is a crude approximation, which underestimates the burden of the disease and the impact of vaccines and findings may also be limited by the reporting and quality of eligible studies. Furthermore, we would not be able to evaluate the impact of risk aversion via adherence to public health guidelines or non-pharmacological interventions due to measurement error, thereby increasing the possibility of bias.
278	I276		Stein, Sydney R.; Ramelli, Sabrina C.; Grazioli, Alison; Chung, Joon-Yong; Singh, Manmeet; Yinda, Claude Kwe; Winkler, Clayton W.; Sun, Junfeng; Dickey, James M.; Ylaya, Kris; Ko, Sung Hee; Platt, Andrew P.; Burbelo, Peter D.; Quezado, Martha; Pittaluga, Stefania; Purcell, Madeleine; Munster, Vincent J.; Belinky, Frida; Ramos-Benitez, Marcos J.; Boritz, Eli A.; Lach, Izabella A.; Herr, Daniel L.; Rabin, Joseph; Saharia, Kapil K.; Madathil, Ronson J.; Tabatabai, Ali; Soherwardi, Shahabuddin; McCurdy, Michael T.; Peterson, Karin E.; Cohen, Jeffrey I.; de Wit, Emmie; Vannella, Kevin M.; Hewitt, Stephen M.; Kleiner, David E.; Chertow, Daniel S.	SARS-CoV-2 infection and persistence in the human body and brain at autopsy	https://doi.org/10.1038/s41586-022-05542-y	Published	2022-12	Study	https://www.nature.com/articles/s41586-022-05542-y	Coronavirus disease 2019 (COVID-19) is known to cause multi-organ dysfunction1–3 during acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with some patients experiencing prolonged symptoms, termed post-acute sequelae of SARS-CoV-2 (refs. 4,5). However, the burden of infection outside the respiratory tract and time to viral clearance are not well characterized, particularly in the brain3,6–14. Here we carried out complete autopsies on 44 patients who died with COVID-19, with extensive sampling of the central nervous system in 11 of these patients, to map and quantify the distribution, replication and cell-type specificity of SARS-CoV-2 across the human body, including the brain, from acute infection to more than seven months following symptom onset. We show that SARS-CoV-2 is widely distributed, predominantly among patients who died with severe COVID-19, and that virus replication is present in multiple respiratory and non-respiratory tissues, including the brain, early in infection. Further, we detected persistent SARS-CoV-2 RNA in multiple anatomic sites, including throughout the brain, as late as 230 days following symptom onset in one case. Despite extensive distribution of SARS-CoV-2 RNA throughout the body, we observed little evidence of inflammation or direct viral cytopathology outside the respiratory tract. Our data indicate that in some patients SARS-CoV-2 can cause systemic infection and persist in the body for months.
279	I277		Ogura, Hideki; Gohda, Jin; Lu, Xiuyuan; Yamamoto, Mizuki; Takesue, Yoshio; Son, Aoi; Doi, Sadayuki; Matsushita, Kazuyuki; Isobe, Fumitaka; Fukuda, Yoshihiro; Huang, Tai-Ping; Ueno, Takamasa; Mambo, Naomi; Murakami, Hiromoto; Kawaguchi, Yasushi; Inoue, Jun-ichiro; Shirai, Kunihiro; Yamasaki, Sho; Hirata, Jun-Ichi; Ishido, Satoshi	Dysfunctional Sars-CoV-2-M protein-specific cytotoxic T lymphocytes in patients recovering from severe COVID-19	https://doi.org/10.1038/s41467-022-34655-1	Published	2022-12-16	Study	https://www.nature.com/articles/s41467-022-34655-1	Although the importance of virus-specific cytotoxic T lymphocytes (CTL) in virus clearance is evident in COVID-19, the characteristics of virus-specific CTLs related to disease severity have not been fully explored. Here we show that the phenotype of virus-specific CTLs against immunoprevalent epitopes in COVID-19 convalescents might differ according to the course of the disease. We establish a cellular screening method that uses artificial antigen presenting cells, expressing HLA-A24:02, the costimulatory molecule 4-1BBL, SARS-CoV-2 structural proteins S, M, and N and non-structural proteins ORF3a and nsp6/ORF1a. The screen implicates SARS-CoV-2 M protein as a frequent target of IFNγ secreting CD8+ T cells, and identifies M198–206 as an immunoprevalent epitope in our cohort of HLA-A24:02 positive convalescent COVID-19 patients recovering from mild, moderate and severe disease. Further exploration of M198–206-specific CD8+ T cells with single cell RNA sequencing reveals public TCRs in virus-specific CD8+ T cells, and shows an exhausted phenotype with less differentiated status in cells from the severe group compared to cells from the moderate group. In summary, this study describes a method to identify T cell epitopes, indicate that dysfunction of virus-specific CTLs might be an important determinant of clinical outcomes.
280	I278		Lu, Scott; Anglin, Khamal; Tassetto, Michel; Garcia-Knight, Miguel; Pineda-Ramirez, Jesus; Sanchez, Ruth Diaz; Zhang, Amethyst; Romero, Mariela; Goldberg, Sarah A; Chen, Jessica Y; Donohue, Kevin; Davidson, Michelle; Lugtu, Kara; Yee, Brandon; Chenna, Ahmed; Winslow, John; Petropoulos, Christos J; Briggs-Hagen, Melissa; Peluso, Michael J; Andino, Raul; Midgley, Claire; Martin, Jeffrey; Saydah, Sharon; Kelly, Dan; Deeks, Steve	1048. Biological Determinants of Post-Acute Sequelae of SARS-CoV-2	https://doi.org/10.1093/ofid/ofac492.889	Published	2022-12-01	Study	https://doi.org/10.1093/ofid/ofac492.889	The biological determinants of post-acute sequelae of SARS-CoV-2 infection (PASC), defined as the persistence or recurrence of symptoms not explained by an alternative medical diagnosis, are poorly understood. We assessed viral and immunological determinants during acute SARS-CoV-2 infection for an association with PASC at 4 to 8 months.From September 2020 to February 2022, symptomatic non-hospitalized individuals with laboratory-confirmed SARS-CoV-2 infection were identified within 5 days of symptom onset. We used anterior nasal biospecimens to measure the magnitude and duration of RNA and infectious viral shedding as well as blood samples to measure soluble markers of inflammation during the acute phase (first 28 days post-enrollment). PASC was defined as self-report of 1 or more COVID-19 attributed symptoms between 4 and 8 months after initial illness. We compared virologic and inflammatory markers, GFAP (a marker of neuronal damage) and neutralizing antibody levels from the acute phase between those with and without PASC using Mann-Whitney U tests or repeated measures mixed effects linear models.Among 71 SARS-CoV-2-positive participants with a completed follow-up visit between 4 to 8 months, we included 69 with virologic data and 61 with inflammatory marker data. Median age was 37 (IQR: 29 to 48) Overall, 16/72 (23%) reported at least one qualifying PASC symptom. Report of PASC was associated with >9 days of RNA shedding (p=0.04); all participants stopped RNA shedding by day 20. During acute illness, those with subsequent PASC had increased levelsof INF-alpha, INF-gamma, IP-10, IL-10, and MCP-1; these differences were greatest in the early period and normalized over 2 to 3 weeks post-illness onset. Compared to those without PASC, during the acute illness those with PASC had increased levels of GFAP and decreased levels of neutralizing antibodies but these differences were not statistically significant.We found indications that viral and immunological factors during acute illness may be associated with PASC, suggesting acute immunologic response to SARS-CoV-2 may have longer term effects and play a role in PASC. Further understanding of the clinically significance of these observations is needed.Ahmed Chenna, PhD, LabCorp: Employee John Winslow, PhD, Labcorp-Monogram Bioscience: Issued patents on VeraTag immunoassay-not applicable to present work\|Labcorp-Monogram Bioscience: Employee\|Labcorp-Monogram Biosciences: Issued patents on VeraTag immunoassay-not applicable to present work\|Labcorp-Monogram Biosciences: Employee of Labcorp-Monogram Biosciences Christos J. Petropoulos, PhD, Labcorp-Monogram Biosciences: employee, corporate officer\|Labcorp-Monogram Biosciences: Stocks/Bonds.
281	I279		McDonald, Dylan; Logue, Jennifer; Franko, Nicholas M; Kemp, Megan M; McCulloch, Denise J; Chow, Eric J; Chu, Helen Y	1054. Comparison of Post-Acute COVID-19 Symptoms in Infected Individuals Pre- and Post-Vaccination	https://doi.org/10.1093/ofid/ofac492.895	Published	2022-12-01	Study	https://doi.org/10.1093/ofid/ofac492.895	A constellation of debilitating symptoms, known as post-acute sequelae of COVID-19 (PASC), has been described in those in those with prior SARS-CoV-2 infection. While SARS-CoV-2 vaccination remains an effective way to prevent severe illness, PASC in individuals infected after vaccination is not well characterized.A cohort of adults with laboratory confirmed SARS-CoV-2 infection were enrolled as cases and longitudinally followed between March 2020-March 2022 in the greater Seattle region. Demographic and acute illness surveys capturing baseline symptoms, infection severity and medical care were administered at enrollment (Table). Controls with no history of SARS-CoV-2 infection were concurrently followed.Symptom surveys were given at 6 months post-infection. Vaccination status was self-reported. We defined PASC as the presence of one or more symptoms that persisted for at least 4 weeks after acute SARS-CoV-2 infection. Table.Demographic and Illness Characteristics of Study ParticipantsDays since illness onset refers to the days passed since infection date. *Comorbidities included hypertension, diabetes mellitus, chronic obstructive pulmonary disease, cardiovascular disease, chronic liver disease, chronic kidney disease, HIV, current use of immunosuppressants or diagnosis of cancer.Of 369 cases and 93 controls 57% (median age 44.7 years; 59.3% female) and 30% (median age 50.0 years; 50.0% female), completed the 6-month survey, respectively (Table). A total of 174 cases were infected prior to vaccination and 35 were post-vaccination.A total of 58 (28%) cases reported symptoms at 6 months, compared to 5 (18%) controls (Figure). In participants infected pre-vaccination, 32% reported PASC symptoms, compared to 6% of those infected post-vaccination (Figure; P=0.001). Our study found that the proportion of individuals reporting PASC at 6 months after infection was significantly higher among those infected before SARS-CoV-2 vaccination than those who were infected after. This suggests that timing of vaccination relative to SARS-CoV-2 infection may be associated with the development of PASC symptoms. Symptoms were still reported among many individuals with PASC who were vaccinated after their infection. Further research is required to understand the underlying mechanisms of PASC, and to characterize PASC in those infected after vaccination and with variant of concerns.Helen Y. Chu, MD, MPH, Cepheid: Reagents\|Ellume: Advisor/Consultant\|Gates Ventures: Grant/Research Support\|Merck: Advisor/Consultant\|Pfizer: Advisor/Consultant.
282	I280		LaVergne, Stephanie; LaVergne, Stephanie; Dutt, Taru; McFann, Kim; Baxter, Bridget; Webb, Tracy; Berry, Kailey; Stomberg, Sophia; Dunn, Julie; Henao-Tamayo, Marcela; Ryan, Elizabeth	78. Longitudinal Analysis of T cells in COVID-19 Survivors with Post-Acute Sequelae of COVID-19 Reveals Associations between Individual Symptoms and Inflammatory Indexes	https://doi.org/10.1093/ofid/ofac492.003	Published	2022-12-01	Study	https://doi.org/10.1093/ofid/ofac492.003	Many individuals infected with SARS-CoV-2 are left with persistent symptoms of COVID-19. Post-acute sequelae of COVID-19 (PASC) can affect quality of life and functionality. The mechanism underlying PASC is unknown but elevated inflammatory markers several months post infection have been found in those with PASC.Individuals diagnosed with COVID-19 were evaluated longitudinally for PASC and persistent symptoms. CD4+ and CD8+ cellular markers and intracellular cytokines were assessed at each follow-up time point and analyzed by individual PASC symptoms reported.Participants who reported persistent dyspnea, forgetfulness, confusion, and chest pain had significantly higher levels of CD8+Ki67+ cells. Those with dyspnea also had significantly higher levels of CD8+CD38+, CD8+Granzyme B+, and CD8+IL10+ cells. Those who suffered from forgetfulness, chest pain, and joint pain had significantly higher levels of CD4+CD25+ cells.Table 1Baseline participant characteristics and demographic data.Figure 1Differences in CD8 T cell markers and inflammatory cytokines in participants reporting symptoms of: a) dyspnea (N=20) and without dyspnea (N=104), b) fatigue (N=35) and without fatigue (N=89), c) confusion (N=17) and without confusion (N=107), d) difficulty concentrating (DC) (N=26) and without difficulty concentrating (N= 98), and e) forgetfulness or absent-mindedness (N=28) and without forgetfulness or absent-mindedness (N=96). *p<0.05.Figure 2Inflammatory indexes measured at 15–44, 45–89, 90–174, and > 175 days post PCR by symptom: A) dyspnea B) fatigue C) confusion D) DC=difficulty concentrating E) forgetfulness.These findings suggest continued CD8+ T cell and CD4+CD25+ T cell activation and response following SARS-CoV-2 infection in patients with PASC. An increase in T regulatory cells suggests an ongoing attempt to control host inflammation in a subset of these patients. These results shed further light on continued immune system activation and chronic inflammation as a link to symptoms in COVID-19 survivors suffering from PASC.All Authors: No reported disclosures.
283	I281		Klimova, Elena M.; Bozhkov, Anatoly I.; Lavinska, Olena V.; Drozdova, Larisa A.; Kurhuzova, Nataliia I.	Low molecular weight cytotoxic components (DAMPs) form the post-COVID-19 syndrome	https://doi.org/10.1016/j.imbio.2022.152316	Published	2023-01-01	Study	https://www.sciencedirect.com/science/article/pii/S0171298522001425	Highlights • The duration of post-COVID-19 symptoms is associated with neutrophil dysfunction and the formation of a specific humoral immunological pattern that performs an adaptive function and at the same time provides additional DAMPs production. • The DAMPs formed in the body of SARS-CoV-2 infection are not species-specific. • The possibility of modeling post-COVID-19 manifestations in an experiment on rats is shown. • The preliminary administaration of the biologically active substance MF into the body “modifies” the subsequent adaptive response of the body to the actions of cytotoxic components of the patient's serum in such a way that the studied parameters are similar or close to the control values. Abstract We studied the role of cytotoxic components (DAMPs) formed in the body of patients with COVID-19 in ensuring the long-term preservation of post-COVID-19 manifestations and the possibility of creating an experimental model by transferring DAMPs to rats. In patients with post-COVID-19 syndrome (PCS) 2 months after SARS-CoV-2 infection we determined the presence of cytotoxic components in the blood serum (Terasaki test, Dunaliella viridis test and content of DAMPs). In post-COVID-19 syndrome patients with a high content of serum cytotoxic oligopeptide fraction (selective group, n = 16) we determined the number of leukocytes, lymphocytes, neutrophil granulocytes and monocytes in the blood, the content of C-reactive protein (CRP), the concentration of C3 and C4 complement components and circulating immune complexes, the serum content of IL-6, IL −10, IL-18, TNF-α, phagocytic activity of neutrophils, presence of neutrophil traps and autoantibodies ANA. It has been shown that in patients with PCS, there are components with cytotoxicity in the blood serum, form specific immunopathological patterns, which are characterized by: an increased content of CRP, complement system components C3 and C4 and cytokines (TNF-α, IL-6, IL-10, IL-18) activation, the formation of a wide range of autoantibodies ANA, the low efficiency of endocytosis in oxygen-independent phagocytosis; their phagocytic activity reaches its functional limit, and against this background, activation of neutrophil traps occurs, which can contribute to further induction of DAMPs. This self-sustaining cell-killing activation provided long-term preservation of PCS symptoms. The transfer of blood serum components from selective group patients with PCS to rats was accompanied by the appearance of cytotoxic components in them which induced sensitization and immunopathological reactions. Preventive administration of a biologically active substance with polyfunctional properties MF to experimental animals “corrected” the initial functional state of the body's immune-metabolic system and eliminated or facilitated immuno-inflammatory reactions.
284	I282		Maher, Allison K.; Burnham, Katie L.; Jones, Emma M.; Tan, Michelle M. H.; Saputil, Rocel C.; Baillon, Laury; Selck, Claudia; Giang, Nicolas; Argüello, Rafael; Pillay, Clio; Thorley, Emma; Short, Charlotte-Eve; Quinlan, Rachael; Barclay, Wendy S.; Cooper, Nichola; Taylor, Graham P.; Davenport, Emma E.; Dominguez-Villar, Margarita	Transcriptional reprogramming from innate immune functions to a pro-thrombotic signature by monocytes in COVID-19	https://doi.org/10.1038/s41467-022-35638-y	Published	2022-12-26	Study	https://www.nature.com/articles/s41467-022-35638-y	Although alterations in myeloid cells have been observed in COVID-19, the specific underlying mechanisms are not completely understood. Here, we examine the function of classical CD14+ monocytes in patients with mild and moderate COVID-19 during the acute phase of infection and in healthy individuals. Monocytes from COVID-19 patients display altered expression of cell surface receptors and a dysfunctional metabolic profile that distinguish them from healthy monocytes. Secondary pathogen sensing ex vivo leads to defects in pro-inflammatory cytokine and type-I IFN production in moderate COVID-19 cases, together with defects in glycolysis. COVID-19 monocytes switch their gene expression profile from canonical innate immune to pro-thrombotic signatures and are functionally pro-thrombotic, both at baseline and following ex vivo stimulation with SARS-CoV-2. Transcriptionally, COVID-19 monocytes are characterized by enrichment of pathways involved in hemostasis, immunothrombosis, platelet aggregation and other accessory pathways to platelet activation and clot formation. These results identify a potential mechanism by which monocyte dysfunction may contribute to COVID-19 pathology.
285	I283		Behura, Assirbad; Naik, Lincoln; Patel, Salina; Das, Mousumi; Kumar, Ashish; Mishra, Abtar; Nayak, Dev Kiran; Manna, Debraj; Mishra, Amit; Dhiman, Rohan	Involvement of epigenetics in affecting host immunity during SARS-CoV-2 infection	https://doi.org/10.1016/j.bbadis.2022.166634	Published	2023-03-01	Article	https://www.sciencedirect.com/science/article/pii/S0925443922003052	Highlights •SARS-CoV-2 regulates the epigenetic machinery of the host. •miRNAs and virulent proteins help in hijacking the primary immune response. •The host epigenetic landscape regulates SARS-CoV-2 mediated cytokine storm. •Vitamins and minerals control SARS-CoV-2 infection by regulating the epigenetic module. •Treatment approaches targeting epigenetic mechanisms can potentially combat COVID-19. Abstract Coronavirus disease 19 (COVID-19) is caused by a highly contagious RNA virus Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2), originated in December 2019 in Wuhan, China. Since then, it has become a global public health concern and leads the disease table with the highest mortality rate, highlighting the necessity for a thorough understanding of its biological properties. The intricate interaction between the virus and the host immune system gives rise to diverse implications of COVID-19. RNA viruses are known to hijack the host epigenetic mechanisms of immune cells to regulate antiviral defence. Epigenetics involves processes that alter gene expression without changing the DNA sequence, leading to heritable phenotypic changes. The epigenetic landscape consists of reversible modifications like chromatin remodelling, DNA/RNA methylation, and histone methylation/acetylation that regulates gene expression. The epigenetic machinery contributes to many aspects of SARS-CoV-2 pathogenesis, like global DNA methylation and receptor angiotensin-converting enzyme 2 (ACE2) methylation determines the viral entry inside the host, viral replication, and infection efficiency. Further, it is also reported to epigenetically regulate the expression of different host cytokines affecting antiviral response. The viral proteins of SARS-CoV-2 interact with various host epigenetic enzymes like histone deacetylases (HDACs) and bromodomain-containing proteins to antagonize cellular signalling. The central role of epigenetic factors in SARS-CoV-2 pathogenesis is now exploited as promising biomarkers and therapeutic targets against COVID-19. This review article highlights the ability of SARS-CoV-2 in regulating the host epigenetic landscape during infection leading to immune evasion. It also discusses the ongoing therapeutic approaches to curtail and control the viral outbreak.
286	I284		Fernández-de-las-Peñas, César; Arendt-Nielsen, Lars; Díaz-Gil, Gema; Gil-Crujera, Antonio; Gómez-Sánchez, Stella M.; Ambite-Quesada, Silvia; Palomar-Gallego, Maria A.; Pellicer-Valero, Oscar J.; Giordano, Rocco	ACE1 rs1799752 Polymorphism is not Associated with Long-COVID Symptomatology in Previously Hospitalized COVID-19 Survivors	https://doi.org/10.1016/j.jinf.2022.12.026	Published	2022-12-27	Study	https://www.journalofinfection.com/article/S0163-4453(22)00752-6/fulltext	publisher: Elsevier PMID: 36584771 Viral mechanisms of infection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent responsible of the coronavirus disease, 2019 (COVID-19), suggest the involvement of surface receptor for S1 of the angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine-2 (TMPRSS2) receptors [[1]]. Single studies have found that single nucleotide polymorphisms (SNP), e.g., ACE2 rs2285666, ACE2 rs2074192, or TMPRSS2 rs12329760, seem to be potentially associated with severity of COVID-19; however, current evidence is still not conclusive [[2]]. Another potential SNP that could be implicated in various clinical diseases (e.g., renal damage, pneumonia, ischemic stroke) and also immunological reaction (i.e., cytokine storm) induced by SARS-CoV-2 is ACE1 rs1799752 [[3]]. In fact, evidence suggests that the D allele of this SNP is associated with higher severity of SARS-CoV-2 [[4]]. Although ACE2, TMPRSS2 and ACE1 receptors are highly expressed in the lungs and respiratory tract, these receptors are also present in several other tissues explaining the heterogeneity clinical presentation of COVID-19. Accordingly, it could be proposed that these receptors are potentially also associated with the presence of symptoms after the acute phase of the infection, i.e., long-COVID. Mariani et al have recently observed that post-COVID symptoms are present for up to one year in a heterogeneous population [[5]]. Additionally, a recent meta-analysis reported that post-COVID fatigue can be present in up to 51% of COVID-19 survivors [[6]]. Our group has recently identified that ACE2 rs2285666, ACE2 rs2074192, TMPRSS2 rs12329760 and TMPRSS2 rs2070788 polymorphisms do not predispose for long-COVID symptoms in previously hospitalized COVID-19 survivors [[7]]. We present here a secondary analysis, genetic part of THE LONG COVID EXPERIENCE STUDY [[7]], of the potential association between ACE1 rs1799752 polymorphism and the presence of long-COVID symptomatology. Briefly, unstimulated whole saliva samples were collected from 288 COVID-19 survivors who were hospitalized at three urban hospitals in Madrid (Spain) during the first wave of the pandemic (March-May 2020). All participants provided written informed consent. The study was approved by the Institutional Ethics Committees of all involved institutions (HSO25112020; URJC0907202015920; HUFA20/126; HUIL/092-20). Genotyping collection and procedures have been previously published [[7]]. Identification of each possible genotype of ACE1 rs1799752 polymorphism was conducted by using specific fluorescent dyes. The ACE1 rs1799752 is an insertion/deletion of an Alu repeat sequence that is interrogated using a pair of assays. The possible variants of the ACE1 rs1799752 (the mutant Alu insertion allele -I allele- and the wild type of deletion allele -D allele-) SNP lead to the following genotypes (D/D, D/I, I/I) derived from the sequence: CCCATTTCTCTAGACCTGCTGCCT [-/ALU] ATACAGTCACTTTTATGTGGTTTC Demographic, medical comorbidities, and hospitalization data were collected from hospital medical records. Post-COVID symptomatology was collected during a face-to-face appointment conducted by experienced healthcare professionals at 17.8 (SD 5.2) months after hospitalization [[7]]. Dyspnea at exertion (n=196, 68%) and fatigue (n=181, 63%) were the most prevalent post-COVID symptoms in the total sample. Other post-COVID symptoms included pain (n=117, 40.6%), memory loss (n=92, 32%) or hair loss (n=77, 26.7%). The genotype distribution (D/D genotype n=109, 37%; D/I genotype n=173, 60%; I/I genotype n=6, 3%) deviated from that expected based on the Hardy-Weinberg equilibrium, a result also extensively found in published COVID-19 studies. Overall, no significant differences in long-COVID symptoms were observed depending on the genotypes of ACE1 rs1799752 SNP (Table). No sex differences in the genotype distribution (P=0.723) were either found. TablePre-Infection data and post-COVID symptoms according to the ACE1 rs1799752 Polymorphism Genotype (n=288) The results of this secondary analysis reveal that ACE1 rs1799752 polymorphism does not predispose to developing long-COVID symptoms when evaluated in previously hospitalized COVID-19 survivors. Current results would agree with our previous report on ACE2 and TMPRSS2 polymorphisms [[7]]. The lack of association between these SNPs and long-COVID could be explained by the significant gene variability existing (i.e., ethnic differences) across populations [[8]]. Further, the lack of relationship among SNPs associated with COVID-19 severity and the presence of long-COVID reinforce the idea that the severity of the disease is not associated with the development of post-COVID symptoms since the presence of these symptoms is similar between hospitalized and non-hospitalized patients [[9]]. Similarly, the D allele of the ACE1 rs1799752 polymorphism has been associated with a higher risk of hospitalization in patients with co-morbidities at the acute phase of the infection since these individuals are at a higher risk for developing acute respiratory distress syndrome (ARDS) [[10]]. In our study, no differences in previous medical co-morbidities depending on the ACE1 rs1799752 genotype were observed. Some limitations of the current data should be recognized. First, only previously hospitalized COVID-19 survivors were included, therefore, the role of these SNPs in non-hospitalized patients is yet to be invetigated. Second, it could be possible that larger samples could identify genotype differences, accordingly, our data should be considered exploratory. Population-based cohort studies and a whole genome SNPs analysis might help to validate current results and identify other genes potentially related to long-COVID symptoms.
287	I285		Altmann, Daniel M.	The COVID-19 immunology masterclass enters its third year	https://doi.org/10.1038/s41590-022-01393-x	Published	1/5/2023	Article	https://www.nature.com/articles/s41590-022-01393-x	publisher: Nature Publishing Group The other topic within this throwing down of the gauntlet to immunology researchers and funders is the huge challenge of long COVID, often correctly referred to as the ‘pandemic within the pandemic’. We cannot accurately count how many on the planet have experienced COVID-19 infection, but estimate that around one-tenth suffer persistent symptoms — the lives of a significant minority of these remain changed at two and half years and counting. This is a disease process that is destroying lives and has potential to destroy health services and damage economies, imposing a societal disease burden as large as that of rheumatic or cardiac disease. Most agree that defining an etiology, whatever the mix of autoimmunity, immunopathology, endotheliitis, viral persistence and hypercoagulation, lies within the remit of immunologists. Given the huge successes over past decades of translational immunology across areas from cancer to autoimmune disease, there is reason for optimism that with knowledge of long-COVID mechanisms, the well-stocked immunology toolkit would have the wherewithal to supply solutions. We just need the resources to fight this next battle. So, as immunologists return to the day job and rightly go back to the countless research questions that occupied us prior to the end of 2019, let us also keep reminding ourselves of the only half-done COVID-19 job and the need for us, with the help of appropriate funding, to now show what can be achieved if we really let rip with all that hard-fought immunological knowledge.
288	I286		Adnot, S.; Bernard, D.; Lipskaia, L.; Trottein, F.	La sénescence cellulaire, nouvelle cible des infections virales respiratoires : du virus influenza au SARS-CoV-2	https://doi.org/10.1016/j.banm.2022.11.011	Published	1/4/2023	Review	https://www.sciencedirect.com/science/article/pii/S0001407922003727	Résumé L’accumulation de cellules sénescentes dans les tissus est un processus clé du vieillissement et des maladies chroniques liées à l’âge, notamment les maladies pulmonaires telles la bronchopneumopathie chronique obstructive, la fibrose pulmonaire, ou le cancer. Ces dernières années ont permis d’élargir le spectre des maladies respiratoires associées à une sénescence cellulaire, en particulier les infections pulmonaires aiguës virales, au premier rang desquelles la maladie à coronavirus 2019 (COVID19), particulièrement sévère chez le sujet âgé ou atteint de comorbidités. L’infection par le virus influenza qui frappe plus sévèrement les âges extrêmes de la vie est également associée à une forte sénescence pulmonaire. La sénescence cellulaire représente potentiellement une cible originale pour s’attaquer à ces maladies, bien que ses mécanismes spécifiques restent largement incompris. De nouvelles approches thérapeutiques à visée anti-sénescente sont ainsi proposées au cours des infections pulmonaires virales sévères, dans un but de prévention des effets aigus et/ou, à plus long terme, des séquelles pulmonaires. Summary The accumulation of senescent cells in tissues is a key process of aging and age-related diseases, including lung diseases such as chronic obstructive pulmonary disease, lung fibrosis, or cancer. In recent years, the spectrum of respiratory diseases associated with cellular senescence has been broadened, in particular acute viral pulmonary infections, foremost among which is coronavirus disease 2019 (COVID19), which is particularly severe in the elderly or in subjects with comorbidities. Influenza virus infection, which strikes more severely at the extreme ages of life, is also associated with severe pulmonary senescence. Cellular senescence potentially represents an original target for attacking these diseases, although its specific mechanisms remain largely misunderstood. New anti-senescent therapeutic approaches are thus proposed during severe viral pulmonary infections, with the aim of preventing acute effects and/or, in the longer term, pulmonary sequelae.
289	I287		Torres-Ruiz, Jiram; Lomelín-Gascón, Julieta; Lira Luna, Jaquelin; Vargas- Castro, Ana Sofia; Pérez-Fragoso, Alfredo; Nuñez-Aguirre, Miroslava; Alcalá-Carmona, Beatriz; Absalón-Aguilar, Abdiel; Balderas-Miranda, Jennifer T.; Maravillas-Montero, José Luis; Mejía-Domínguez, Nancy R.; Núñez-Álvarez, Carlos; Llorente, Luis; Romero-Ramírez, Sandra; Sosa-Hernández, Victor Andrés; Cervantes-Díaz, Rodrigo; Juárez-Vega, Guillermo; Meza-Sánchez, David; Rull-Gabayet, Marina; Martínez-Juárez, Luis Alberto; Morales, Linda; López-López, Lizeth Naomi; Negrete-Trujillo, José Adrián; Falcón-Lezama, Jorge Abelardo; Valdez-Vázquez, Rafael Ricardo; Gallardo-Rincón, Héctor; Tapia-Conyer, Roberto; Gómez-Martín, Diana	Novel clinical and immunological features associated with persistent post-acute sequelae of COVID-19 after six months of follow-up: a pilot study	https://doi.org/10.1080/23744235.2022.2158217	Published	2023-01-13	Study	https://doi.org/10.1080/23744235.2022.2158217	Background Currently, there is scant information regarding the features associated to the persistence of post-COVID-19 syndrome, which is the main aim of the present study.Methods A cohort study of 102 COVID-19 patients was conducted. The post-COVID-19 symptoms were assessed by a standardised questionnaire. Lymphocyte immunophenotyping was performed by flow cytometry and chemokines/cytokines, neutrophil extracellular traps, the tripartite motif 63, anti-cellular, and anti-SARS-CoV-2 IgG antibodies were addressed in serum. The primary outcome was the persistence of post-COVID-19 syndrome after six months follow-up.Results Thirteen patients (12.7%) developed the primary outcome and had a more frequent history of post-COVID-19 syndrome 3 months after infection onset (p = .044), increased levels of IL-1α (p = .011) and IP-10 (p = .037) and increased CD57 expression in CD8+ T cells (p = .003). There was a trend towards higher levels of IFN-γ (p = .051), IL-1β (p = .062) and IL-6 (p = .087). The history of post COVID-19 in the previous 3 months, obesity, baseline serum MIP-1α and IP-10, and CD57 expression in CD8+ T cells were independently associated with the persistence of post-COVID-19 syndrome.Conclusion Our data suggest an important relationship between a pro-inflammatory state mediated through metabolic pathways related to obesity and increased cellular senescence as a key element in the persistence of post-COVID-19 syndrome at six months of follow-up.
290	I288		Abel, T.; Gueant-Rodriguez, R. M.; Regnault, V.; Gueant, J. L.; Chaouat, A.; Chabot, F.; Valentin, S.	Rôle prédictif des marqueurs de l’activation des neutrophiles dans les complications respiratoires résiduelles des pneumonies à SARS-CoV-2	https://doi.org/10.1016/j.rmra.2022.11.353	Published	2023-01-01	Study	https://www.sciencedirect.com/science/article/pii/S1877120322005237	Introduction L’infection par le SARS-CoV-2 s’exprime au niveau respiratoire par des formes très diverses allant de l’absence de symptômes à un syndrome de détresse respiratoire aiguë. Ces différences sont expliquées par différents mécanismes physiopathologiques. Notamment, certains marqueurs impliqués dans la régulation de l’immunité innée (élastase des polynucléaires neutrophiles, myélopéroxydase-DNA et histone-DNA) sont associés à la gravité de l’atteinte respiratoire à la phase aiguë de l’infection [1]. Les conséquences à court et moyen terme de l’infection sont maintenant bien connues. Cependant, l’évolution de l’immunité innée des neutrophiles à distance de l’infection n’est pas bien décrite. Ainsi, l’objectif était de décrire l’évolution de ces biomarqueurs dans les six mois suivants une infection sévère à SARS-CoV-2 et de les comparer avec les données de sujets sains. Méthodes Nous avons recueilli les données cliniques, biologiques, fonctionnelles et radiologiques de patients lors du suivi à trois et six mois d’une hospitalisation pour une infection sévère à SARS-CoV-2 au CHRU de Nancy entre mars et décembre 2020. Les données biologiques de sujets sains, antérieures à la pandémie à SARS-CoV-2 ont également été colligées. Résultats Sur les 98 patients inclus, 82 ont été réévalués à trois mois et 66 à six mois de la sortie d’hospitalisation. L’âge médian était de 65,5 [56–73] avec 72 (73,5 %) hommes et un indice de masse corporelle médian de 27,8 [24,6–31,0] kg/m2. À la première réévaluation, 65 patients (66,3 %) avaient des séquelles respiratoires de l’infection à SARS-CoV-2 (Tableau 1). Le taux médian d’élastase des neutrophiles à trois mois était de 419,5 [269,3–629,0] ng/mL et 504,0 [234,8–811,0] ng/mL à six mois, significativement plus élevé que chez les sujets sains 32,8 [21,0–78,5] ng/mL (p<0,0001) ng/mL. Les taux de myéloperoxydase-DNA et d’histones-DNA sont également significativement plus élevés à six mois de l’infection que chez les sujets sains (p<0,0001) (Tableau 1). À trois mois, on ne notait pas de différence significative du taux de ces biomarqueurs entre patients gardant ou non des séquelles respiratoires. Conclusion Les patients ayant présenté une infection sévère à SARS-CoV-2 conservent une élévation significative du taux d’élastase des neutrophiles, de myélopéroxydase-DNA et d’histone-DNA dans le suivi jusqu’à 6 mois par rapport à des sujets sains. Ces résultats préliminaires pourraient suggérer une implication de l’immunité innée dans la persistance de séquelles respiratoire et ouvrir la voie à de nouvelles thérapeutiques spécifiques.
291	I289		Sin, Don D.	Is long COVID an autoimmune disease?	https://doi.org/10.1183/13993003.02272-2022	Published	2023-01-01	Article	https://erj.ersjournals.com/content/61/1/2202272	Extract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the novel coronavirus disease of 2019 (COVID-19), has, to date (27 December, 2022), infected over 662 million people and been directly responsible for 6.6 million deaths worldwide [1]. Millions of patients who have recovered from COVID-19 continue to experience one or more COVID-19-related symptoms, including fatigue, intractable headaches, exertional dyspnoea, olfactory and taste disturbances, myalgia and cognitive dysfunction (also called “brain fog”) for many weeks to months following their acute illness [2]. Tweetable abstract @ERSpublications click to tweetThe findings from the study reported by Mukherjee and co-workers suggest that autoreactive antibodies may be responsible for driving the inflammatory process that persist in patients with long COVID https://bit.ly/3hAnDkt
292	I290		Giannitrapani, Lydia; Mirarchi, Luigi; Amodeo, Simona; Licata, Anna; Soresi, Maurizio; Cavaleri, Francesco; Casalicchio, Salvatore; Ciulla, Gregorio; Ciuppa, Maria Elena; Cervello, Melchiorre; Barbagallo, Mario; Veronese, Nicola; the COMEPA Group	Can Baseline IL-6 Levels Predict Long COVID in Subjects Hospitalized for SARS-CoV-2 Disease?	https://doi.org/10.3390/ijms24021731	Published	2023-01-01	Study	https://www.mdpi.com/1422-0067/24/2/1731	The immune response to infection plays a crucial role in the pathogenesis of COVID-19, but several patients develop a wide range of persistent symptoms, which is becoming a major global health and economic burden. However, reliable indicators are not yet available to predict the persistence of symptoms typical of the so-called long COVID. Our study aims to explore an eventual role of IL-6 levels as a marker of long COVID. Altogether, 184 patients admitted to the COVID Medicine Unit of the University Hospital in Palermo, Italy, from the 1st of September 2020, were analyzed. Patients were divided into two groups according to the IL-6 serum levels (normal or elevated), considering the serum IL-6 levels measured during the first four days of hospitalization. In our study, higher serum IL-6 levels were associated with a doubled higher risk of long COVID (OR = 2.05; 95% CI: 1.04–4.50) and, in particular, they were associated with a higher incidence of mobility decline (OR = 2.55; 95% CI: 1.08–9.40) and PTSD (OR = 2.38; 95% CI: 1.06–8.61). The analysis of our case series confirmed the prominent role of IL-6 levels in response to SARS-CoV-2 infection, as predictors not only of COVID-19 disease severity and unfavorable outcomes, but also long COVID development trends.
293	I291		Prasada Kabekkodu, Shama; Chakrabarty, Sanjiban; Jayaram, Pradyumna; Mallya, Sandeep; Thangaraj, Kumarasamy; Singh, Keshav K; Satyamoorthy, Kapaettu	Severe acute respiratory syndrome coronaviruses contributing to mitochondrial dysfunction: Implications for post-COVID complications	https://doi.org/10.1016/j.mito.2023.01.005	Published	2023-03-01	Review	https://www.sciencedirect.com/science/article/pii/S1567724923000053	Highlights •Mitochondria are vital cellular organelles linked to the production of ATP, biosynthesis of fatty acids, calcium signaling, regulation of cell cycle, apoptosis, and innate immune response among others. •Several RNA viruses target mitochondria leading to abnormal anterograde and retrograde grade signaling to facilitate growth and survival. •Mitochondria plays a role in controlling immunity against SARS-CoV-2, and its infection leads to alteration in both structure and function of the mitochondria. •SARS-CoV participates in stress response, apoptosis pathways and mitochondrial fusion in host cells. •Research concentrating on SARS-CoV-2 modulation of essential mitochondrial activities should close the gap in COVID-19 prevention and treatment. Abstract Mitochondria play a central role in oxidative phosphorylation (OXPHOS), bioenergetics linked with ATP production, fatty acids biosynthesis, calcium signaling, cell cycle regulation, apoptosis, and innate immune response. Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) infection manipulates the host cellular machinery for its survival and replication in the host cell. The infectiaon causes perturbed the cellular metabolism that favours viral replication leading to mitochondrial dysfunction and chronic inflammation. By localizing to the mitochondria, SARS CoV proteins increase reactive oxygen species (ROS) levels, perturbation of Ca2+ signaling, changes in mtDNA copy number, mitochondrial membrane potential (MMP), mitochondrial mass, and induction of mitophagy. These proteins also influence the fusion and fission kinetics, size, structure, and distribution of mitochondria in the infected host cells. This results in compromised bioenergetics, altered metabolism, and innate immune signaling, and hence can be a key player in determining the outcome of SARS-CoV infection. SARS-CoV infection contributes to stress and activates apoptotic pathways. This review summarizes how mitochondrial function and dynamics are affected by SARS-CoV and how the mitochondria-SARS-CoV interaction benefits viral survival and growth by evading innate host immunity. We also highlight how the SARS-CoV-mediated mitochondrial dysfunction contributes to post-COVID complications. Besides, a discussion on targeting virus-mitochondria interactions as a therapeutic strategy is presented.
294	I292		Zhu, JingJing; Wilding, John P. H.; Hu, Ji	Adipocytes in obesity: A perfect reservoir for SARS-CoV-2?	https://doi.org/10.1016/j.mehy.2023.111020	Published	2023-02-01	Article	https://www.sciencedirect.com/science/article/pii/S0306987723000166	Research evidence suggests that adipocytes in obesity might facilitate SARS-CoV-2 replication, for it was only found in adipose tissue of individuals with overweight or obesity but not lean individuals who died from COVID-19. As lipid metabolism is key to adipocyte function, and viruses are capable of exploiting and manipulating lipid metabolism of host cells for their own benefit of infection, we hypothesize that adipocytes could not only impair host immune defense against viral infection, but also facilitate SARS-CoV-2 entry, replication and assembly as a reservoir to boost the viral infection in obesity. The latter of which could mainly be mediated by SARS-CoV-2 hijacking the abnormal lipid metabolism in the adipocytes. If these were to be confirmed, an approach to combat COVID-19 in people with obesity by taking advantage of the abnormal lipid metabolism in adipocytes might be considered, as well as modifying lipid metabolism of other host cells as a potential adjunctive treatment for COVID-19.
295	I293		Parodi, Josefina B.; Indavere, Agustín; Bobadilla Jacob, Pamela; Toledo, Guillermo C.; Micali, Rubén G.; Waisman, Gabriel; Masson, Walter; Epstein, Eduardo D.; Huerin, Melina S.	Impact of COVID-19 vaccination in post-COVID cardiac complications	https://doi.org/10.1016/j.vaccine.2023.01.052	Published	2023-01-27	Study	https://www.sciencedirect.com/science/article/pii/S0264410X23000841	Highlights •1883 vaccinated and unvaccinated post-COVID patients evaluated by echocardiogram. •2.92% presented pathological TTE findings consistent with post-COVID cardiac injury. •Unvaccinated patients presented more cardiac injury than vaccinated (4.1% vs 1.3%) •15% of the patients reported persistent symptoms at the post-COVID control. •Complete vaccination was associated with 48% reduction in risk of long-COVID symptoms. Abstract Background After the acute infection, COVID-19 can produce cardiac complications as well as long-COVID persistent symptoms. Although vaccination against COVID-19 represented a clear reduction in both mortality and ICU admissions, there is very little information on whether this was accompanied by a decrease in the prevalence of post-COVID cardiac complications. The aim of this study was to analyze the relationship between COVID-19 vaccination and the prevalence of post-COVID cardiac injury assessed by echocardiogram, and long-COVID persistent cardiac symptoms. Methods: All patients who consulted for post-COVID evaluation 14 days after discharge from acute illness were included. Patients with heart disease were excluded. The relationship between complete vaccination scheme (at least two doses applied with 14 days or more since the last dose) and pathological echocardiographic findings, as well as the relationship of vaccination with persistent long-COVID symptoms, were evaluated by multivariate analysis, adjusting for age, sex and clinical variables that would have shown significant differences in univariate analysis. Results: From 1883 patients, 1070 patients (56.8%) suffered acute COVID-19 without a complete vaccination scheme. Vaccination was associated with lower prevalence of cardiac injury (1.35% versus 4.11%, adjusted OR 0.33; 95% CI 0.17–0.65, p=0.01). In addition, vaccinated group had a lower prevalence of persistent long-COVID symptoms compared to unvaccinated patients (10.7% versus 18.3%, adjusted OR 0.52; 95% CI 0.40–0.69, p<0.001). Conclusion: Vaccination against COVID-19 was associated with lower post-COVID cardiac complications and symptoms, reinforcing the importance of fully vaccinating the population.
296	I294		Rabaan, Ali A.; Aljeldah, Mohammed; Shammari, Basim R. Al; Alsubki, Roua A.; Alotaibi, Jawaher; Alhashem, Yousef N.; Alali, Neda A.; Sulaiman, Tarek; Alsalem, Zainab; Bajunaid, Huda A.; Garout, Mohammed; Alsaffar, Heba A.; Almuthree, Souad A.; Hudhaiah, Doha; Alzaher, Azhar M.; Alshaikh, Fatimah A.; Alshengeti, Amer; Najim, Mustafa A.; Farahat, Ramadan Abdelmoez; Mohapatra, Ranjan K.	Epigenetic Targets and Pathways Linked to SARS-CoV-2 Infection and Pathology	https://doi.org/10.3390/microorganisms11020341	Published	2023-02-01	Review	https://www.mdpi.com/2076-2607/11/2/341	The scale at which the SARS-CoV-2/COVID-19 pandemic has spread remains enormous. Provided the genetic makeup of the virus and humans is readily available, the quest for knowing the mechanism and epidemiology continues to prevail across the entire scientific community. Several aspects, including immunology, molecular biology, and host-pathogen interaction, are continuously being dug into for preparing the human race for future pandemics. The exact reasons for vast differences in symptoms, pathophysiological implications of COVID-infections, and mortality differences remain elusive. Hence, researchers are also looking beyond traditional genomics, proteomics, and transcriptomics approach, especially entrusting the environmental regulation of the genetic landscape of COVID–human interactions. In line with these questions lies a critical process called epigenetics. The epigenetic perturbations in both host and parasites are a matter of great interest to unravel the disparities in COVID-19 mortalities and pathology. This review provides a deeper insight into current research on the epigenetic landscape of SARS-CoV-2 infection in humans and potential targets for augmenting the ongoing investigation. It also explores the potential targets, pathways, and networks associated with the epigenetic regulation of processes involved in SARS-CoV-2 pathology.
297	I295		Cron, Randy Q.	Immunologic prediction of long COVID	https://doi.org/10.1038/s41590-022-01396-8	Published	2023-02-01	Article	https://www.nature.com/articles/s41590-022-01396-8	In addition to the acute phase of SARS-CoV-2 infection, a significant percentage of patients experience a prolonged illness with varying symptomatology. Longitudinal SARS-CoV-2 patient-centric immunologic, inflammatory and metabolic data collection has allowed the generation of a composite signature to predict recovery.
298	I296		Ruffieux, Hélène; Hanson, Aimee L.; Lodge, Samantha; Lawler, Nathan G.; Whiley, Luke; Gray, Nicola; Nolan, Tui H.; Bergamaschi, Laura; Mescia, Federica; Turner, Lorinda; de Sa, Aloka; Pelly, Victoria S.; Kotagiri, Prasanti; Kingston, Nathalie; Bradley, John R.; Holmes, Elaine; Wist, Julien; Nicholson, Jeremy K.; Lyons, Paul A.; Smith, Kenneth G. C.; Richardson, Sylvia; Bantug, Glenn R.; Hess, Christoph	A patient-centric modeling framework captures recovery from SARS-CoV-2 infection	https://doi.org/10.1038/s41590-022-01380-2	Published	2023-02-01	Study	https://www.nature.com/articles/s41590-022-01380-2	The biology driving individual patient responses to severe acute respiratory syndrome coronavirus 2 infection remains ill understood. Here, we developed a patient-centric framework leveraging detailed longitudinal phenotyping data and covering a year after disease onset, from 215 infected individuals with differing disease severities. Our analyses revealed distinct ‘systemic recovery’ profiles, with specific progression and resolution of the inflammatory, immune cell, metabolic and clinical responses. In particular, we found a strong inter-patient and intra-patient temporal covariation of innate immune cell numbers, kynurenine metabolites and lipid metabolites, which highlighted candidate immunologic and metabolic pathways influencing the restoration of homeostasis, the risk of death and that of long COVID. Based on these data, we identified a composite signature predictive of systemic recovery, using a joint model on cellular and molecular parameters measured soon after disease onset. New predictions can be generated using the online tool http://shiny.mrc-bsu.cam.ac.uk/apps/covid-19-systemic-recovery-prediction-app, designed to test our findings prospectively.
299	I297		Bogard, Gemma; Barthelemy, Johanna; Hantute-Ghesquier, Aline; Sencio, Valentin; Brito-Rodrigues, Patricia; Séron, Karin; Robil, Cyril; Flourens, Anne; Pinet, Florence; Eberlé, Delphine; Trottein, François; Duterque-Coquillaud, Martine; Wolowczuk, Isabelle	SARS-CoV-2 infection induces persistent adipose tissue damage in aged golden Syrian hamsters	https://doi.org/10.1038/s41419-023-05574-w	Published	2023-02-01	Study	https://www.nature.com/articles/s41419-023-05574-w	Coronavirus disease 2019 (COVID-19, caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2)) is primarily a respiratory illness. However, various extrapulmonary manifestations have been reported in patients with severe forms of COVID-19. Notably, SARS-CoV-2 was shown to directly trigger white adipose tissue (WAT) dysfunction, which in turn drives insulin resistance, dyslipidemia, and other adverse outcomes in patients with COVID-19. Although advanced age is the greatest risk factor for COVID-19 severity, published data on the impact of SARS-CoV-2 infection on WAT in aged individuals are scarce. Here, we characterized the response of subcutaneous and visceral WAT depots to SARS-CoV-2 infection in young adult and aged golden hamsters. In both age groups, infection was associated with a decrease in adipocyte size in the two WAT depots; this effect was partly due to changes in tissue’s lipid metabolism and persisted for longer in aged hamsters than in young-adult hamsters. In contrast, only the subcutaneous WAT depot contained crown-like structures (CLSs) in which dead adipocytes were surrounded by SARS-CoV-2-infected macrophages, some of them forming syncytial multinucleated cells. Importantly, older age predisposed to a unique manifestation of viral disease in the subcutaneous WAT depot during SARS-CoV-2 infection; the persistence of very large CLSs was indicative of an age-associated defect in the clearance of dead adipocytes by macrophages. Moreover, we uncovered age-related differences in plasma lipid profiles during SARS-CoV-2 infection. These data suggest that the WAT’s abnormal response to SARS-CoV-2 infection may contribute to the greater severity of COVID-19 observed in elderly patients.
300	I298		Xue, Pei; Merikanto, Ilona; Chung, Frances; Morin, Charles M.; Espie, Colin; Bjorvatn, Bjørn; Cedernaes, Jonathan; Landtblom, Anne-Marie; Penzel, Thomas; De Gennaro, Luigi; Holzinger, Brigitte; Matsui, Kentaro; Hrubos-Strøm, Harald; Korman, Maria; Leger, Damien; Mota-Rolim, Sérgio; Bolstad, Courtney J.; Nadorff, Michael; Plazzi, Giuseppe; Reis, Catia; Chan, Rachel Ngan Yin; Wing, Yun Kwok; Yordanova, Juliana; Bjelajac, Adrijana Koscec; Inoue, Yuichi; Partinen, Markku; Dauvilliers, Yves; Benedict, Christian	Persistent short nighttime sleep duration is associated with a greater post-COVID risk in fully mRNA-vaccinated individuals	https://doi.org/10.1038/s41398-023-02334-4	Published	2023-02-01	Study	https://www.nature.com/articles/s41398-023-02334-4	Short nighttime sleep duration impairs the immune response to virus vaccination, and long nighttime sleep duration is associated with poor health status. Thus, we hypothesized that short (<6 h) and long (>9 h) nighttime sleepers have a higher post-COVID risk than normal nighttime sleepers, despite two doses of mRNA vaccine (which has previously been linked to lower odds of long-lasting COVID-19 symptoms). Post-COVID was defined as experiencing at least one core COVID-19 symptom for at least three months (e.g., shortness of breath). Multivariate logistic regression adjusting for age, sex, BMI, and other factors showed in 9717 respondents (age span 18–99) that two mRNA vaccinations lowered the risk of suffering from post-COVID by about 21% (p < 0.001). When restricting the analysis to double-vaccinated respondents (n = 5918), short and long sleepers exhibited a greater post-COVID risk than normal sleepers (adjusted OR [95%-CI], 1.56 [1.29, 1.88] and 1.87 [1.32, 2.66], respectively). Among respondents with persistent sleep duration patterns during the pandemic compared to before the pandemic, short but not long sleep duration was significantly associated with the post-COVID risk (adjusted OR [95%-CI], 1.59 [1.24, 2.03] and 1.18 [0.70, 1.97], respectively). No significant association between sleep duration and post-COVID symptoms was observed in those reporting positive SARS-CoV-2 test results (n = 538). Our findings suggest that two mRNA vaccinations against SARS-CoV-2 are associated with a lower post-COVID risk. However, this protection may be less pronounced among those sleeping less than 6 h per night. Our findings warrant replication in cohorts with individuals with confirmed SARS-CoV-2 infection.
301	I299		Vojdani, Aristo; Vojdani, Elroy; Saidara, Evan; Maes, Michael	Persistent SARS-CoV-2 Infection, EBV, HHV-6 and Other Factors May Contribute to Inflammation and Autoimmunity in Long COVID	https://doi.org/10.3390/v15020400	Published	2023-02-01	Review	https://www.mdpi.com/1999-4915/15/2/400	A novel syndrome called long-haul COVID or long COVID is increasingly recognized in a significant percentage of individuals within a few months after infection with SARS-CoV-2. This disorder is characterized by a wide range of persisting, returning or even new but related symptoms that involve different tissues and organs, including respiratory, cardiac, vascular, gastrointestinal, musculo-skeletal, neurological, endocrine and systemic. Some overlapping symptomatologies exist between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Very much like with long ME/CFS, infections with herpes family viruses, immune dysregulation, and the persistence of inflammation have been reported as the most common pattern for the development of long COVID. This review describes several factors and determinants of long COVID that have been proposed, elaborating mainly on viral persistence, reactivation of latent viruses such as Epstein–Barr virus and human herpesvirus 6 which are also associated with the pathology of ME/CFS, viral superantigen activation of the immune system, disturbance in the gut microbiome, and multiple tissue damage and autoimmunity. Based on these factors, we propose diagnostic strategies such as the measurement of IgG and IgM antibodies against SARS-CoV-2, EBV, HHV-6, viral superantigens, gut microbiota, and biomarkers of autoimmunity to better understand and manage this multi-factorial disorder that continues to affect millions of people in the world.
302	I300		Fogh, Kamille; Garred, Peter; Hansen, Cecilie B.; Iversen, Kasper K.	Reply to Brandt et al., “Antibodies to Nucleocapsid Are Not Diagnostic for Long COVID”	https://doi.org/10.1128/spectrum.00065-23	Published	2023-02-14	Article	https://journals.asm.org/doi/10.1128/spectrum.00065-23	The first question posed by Brandt et al. concerns the small number of respondents (less than 5%) and skewed gender distribution. We had a target population of 8,000 members of the social media group, but likely due to logistics, as blood samples could only be taken at 3 different hospitals in Denmark, our study population ended up with 350 participants, which is 5% of the target population. We did not anticipate that the entire target group would participate. In total, 926 social media users expressed an interest in participating, and 350 (38%) of them had a blood sample taken, with sampling bias as a limitation. As stated in the article’s limitations section, participation bias cannot be ruled out because members of the social media group were more often women than men. The second question posed by Brandt et al. concerns the long-term persistence of nucleocapsid protein (N protein). According to Brandt et al., 30 to 40% of patients will not have persisting antibodies at the time of recruitment, and antibody decay is faster with mild COVID. In our study, we are looking at observations and measuring the qualitative outcome (seropositive or seronegative) rather than the quantitative outcome. The presence of SARS-CoV-2 N protein total Ig was determined using Roche electrochemiluminescence and a COBAS analyzer system, as mentioned in the article. This assay has been shown to be reliable, with a specificity of 98.1% compared to prepandemic samples and a sensitivity of 99.1% in patients with a confirmed PCR-positive test 14 days after symptom start (2). There was no significant difference in assay sensitivity by disease severity. Thus, the gray area of whether we oversee true-positive samples appears to be negligible. According to a published study, detectable N protein can be found up to 6 months after infection, with an increasing tendency due to improved affinity (3). The same system was used in an unpublished study of hospital employees from our group who were mostly infected but not hospitalized. In this study, N protein was found in 90% of previously infected participants after 12 months. It should be noted that N protein seropositivity and decline over time may vary between different studies, as other studies have shown around 80% seropositivity 9 months after virologically confirmed SARS-CoV-2 infection (4). The third question posed by Brandt et al. concerns the inclusion of PCR test-positive patients in the characterization of long COVID. Brandt et al. mention that 90% of the participants reported a previous PCR test, and the inclusion of the PCR result could be used as a reliable factor in the characterization of long COVID. Unfortunately, the questionnaire design only allowed participants to report the most recent PCR test, which was not always related to the first reported infection with SARS-CoV-2. As a result, we chose not to include self-reported PCR test results. publisher: American Society for Microbiology
303	I301		Reyes-Long, Samuel; Cortés-Altamirano, Jose Luis; Bandala, Cindy; Avendaño-Ortiz, Karina; Bonilla-Jaime, Herlinda; Bueno-Nava, Antonio; Ávila-Luna, Alberto; Sánchez-Aparicio, Pedro; Clavijo-Cornejo, Denise; Dotor-LLerena, Ana Lilia; Cabrera-Ruiz, Elizabeth; Alfaro-Rodríguez, Alfonso	Role of the MicroRNAs in the Pathogenic Mechanism of Painful Symptoms in Long COVID: Systematic Review	https://doi.org/10.3390/ijms24043574	Published	2023-01-01	Review	https://www.mdpi.com/1422-0067/24/4/3574	The ongoing pandemic of COVID-19 has caused more than 6.7 million tragic deaths, plus, a large percentage of people who survived it present a myriad of chronic symptoms that last for at least 6 months; this has been named as long COVID. Some of the most prevalent are painful symptoms like headache, joint pain, migraine, neuropathic-like pain, fatigue and myalgia. MicroRNAs are small non-coding RNAs that regulate genes, and their involvement in several pathologies has been extensively shown. A deregulation of miRNAs has been observed in patients with COVID-19. The objective of the present systematic review was to show the prevalence of chronic pain-like symptoms of patients with long COVID and based on the expression of miRNAs in patients with COVID-19, and to present a proposal on how they may be involved in the pathogenic mechanisms of chronic pain-like symptoms. A systematic review was carried out in online databases for original articles published between March 2020 to April 2022; the systematic review followed the PRISMA guidelines, and it was registered in PROSPERO with registration number CRD42022318992. A total of 22 articles were included for the evaluation of miRNAs and 20 regarding long COVID; the overall prevalence of pain-like symptoms was around 10 to 87%, plus, the miRNAs that were commonly up and downregulated were miR-21-5p, miR-29a,b,c-3p miR-92a,b-3p, miR-92b-5p, miR-126-3p, miR-150-5p, miR-155-5p, miR-200a, c-3p, miR-320a,b,c,d,e-3p, and miR-451a. The molecular pathways that we hypothesized to be modulated by these miRNAs are the IL-6/STAT3 proinflammatory axis and the compromise of the blood–nerve barrier; these two mechanisms could be associated with the prevalence of fatigue and chronic pain in the long COVID population, plus they could be novel pharmacological targets in order to reduce and prevent these symptoms.
304	I302		Yin, Kailin; Peluso, Michael J.; Thomas, Reuben; Shin, Min-Gyoung; Neidleman, Jason; Luo, Xiaoyu; Hoh, Rebecca; Anglin, Khamal; Huang, Beatrice; Argueta, Urania; Lopez, Monica; Valdivieso, Daisy; Asare, Kofi; Ibrahim, Rania; Ständker, Ludger; Lu, Scott; Goldberg, Sarah A.; Lee, Sulggi A.; Lynch, Kara L.; Kelly, J. Daniel; Martin, Jeffrey N.; Münch, Jan; Deeks, Steven G.; Henrich, Timothy J.; Roan, Nadia R.	Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2	https://doi.org/10.1101/2023.02.09.527892	pre-print	2023-02-10	Study	https://www.biorxiv.org/content/10.1101/2023.02.09.527892v1	Long COVID (LC), a type of post-acute sequelae of SARS-CoV-2 infection (PASC), occurs after at least 10% of SARS-CoV-2 infections, yet its etiology remains poorly understood. Here, we used multiple “omics” assays (CyTOF, RNAseq, Olink) and serology to deeply characterize both global and SARS-CoV-2-specific immunity from blood of individuals with clear LC and non-LC clinical trajectories, 8 months following infection and prior to receipt of any SARS-CoV-2 vaccine. Our analysis focused on deep phenotyping of T cells, which play important roles in immunity against SARS-CoV-2 yet may also contribute to COVID-19 pathogenesis. Our findings demonstrate that individuals with LC exhibit systemic inflammation and immune dysregulation. This is evidenced by global differences in T cell subset distribution in ways that imply ongoing immune responses, as well as by sex-specific perturbations in cytolytic subsets. Individuals with LC harbored increased frequencies of CD4+ T cells poised to migrate to inflamed tissues, and exhausted SARS-CoV-2-specific CD8+ T cells. They also harbored significantly higher levels of SARS-CoV-2 antibodies, and in contrast to non-LC individuals, exhibited a mis-coordination between their SARS-CoV-2-specific T and B cell responses. Collectively, our data suggest that proper crosstalk between the humoral and cellular arms of adaptive immunity has broken down in LC, and that this, perhaps in the context of persistent virus, leads to the immune dysregulation, inflammation, and clinical symptoms associated with this debilitating condition.
305	I303		Craddock, Vaughn; Mahajan, Aatish; Spikes, Leslie; Krishnamachary, Balaji; Ram, Anil K.; Kumar, Ashok; Chen, Ling; Chalise, Prabhakar; Dhillon, Navneet K.	Persistent circulation of soluble and extracellular vesicle-linked Spike protein in individuals with postacute sequelae of COVID-19	https://doi.org/10.1002/jmv.28568	Published	2023-02-09	Study	https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.28568	SARS-CoV-2, the causative agent of COVID-19 disease, has resulted in the death of millions worldwide since the beginning of the pandemic in December 2019. While much progress has been made to understand acute manifestations of SARS-CoV-2 infection, less is known about post-acute sequelae of COVID-19 (PASC). We investigated the levels of both Spike protein (Spike) and viral RNA circulating in patients hospitalized with acute COVID-19 and in patients with and without PASC. We found that Spike and viral RNA were more likely to be present in patients with PASC. Among these patients, 30% were positive for both Spike and viral RNA; whereas, none of the individuals without PASC were positive for both. The levels of Spike and/or viral RNA in the PASC+ve patients were found to be increased or remained the same as in the acute phase; whereas, in the PASC−ve group, these viral components decreased or were totally absent. Additionally, this is the first report to show that part of the circulating Spike is linked to extracellular vesicles without any presence of viral RNA in these vesicles. In conclusion, our findings suggest that Spike and/or viral RNA fragments persist in the recovered COVID-19 patients with PASC up to 1 year or longer after acute SARS-CoV-2 infection.
306	I304		Peluso, Michael J.; Deveau, Tyler-Marie; Munter, Sadie E.; Ryder, Dylan; Buck, Amanda; Beck-Engeser, Gabriele; Chan, Fay; Lu, Scott; Goldberg, Sarah A.; Hoh, Rebecca; Tai, Viva; Torres, Leonel; Iyer, Nikita S.; Deswal, Monika; Ngo, Lynn H.; Buitrago, Melissa; Rodriguez, Antonio; Chen, Jessica Y.; Yee, Brandon C.; Chenna, Ahmed; Winslow, John W.; Petropoulos, Christos J.; Deitchman, Amelia N.; Hellmuth, Joanna; Spinelli, Matthew A.; Durstenfeld, Matthew S.; Hsue, Priscilla Y.; Kelly, J. Daniel; Martin, Jeffrey N.; Deeks, Steven G.; Hunt, Peter W.; Henrich, Timothy J.	Chronic viral coinfections differentially affect the likelihood of developing long COVID	https://doi.org/10.1172/JCI163669	Published	2023-02-01	Study	https://www.jci.org/articles/view/163669	BACKGROUND. The presence and reactivation of chronic viral infections, such as EBV, CMV, and HIV, have been proposed as potential contributors to long COVID (LC), but studies in well-characterized postacute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited. METHODS. In a cohort of 280 adults with prior SARS-CoV-2 infection, we assessed the presence and types of LC symptoms and prior medical history (including COVID-19 history and HIV status) and performed serological testing for EBV and CMV using a commercial laboratory. We used covariate-adjusted binary logistic regression models to identify independent associations between variables and LC symptoms. RESULTS. We observed that LC symptoms, such as fatigue and neurocognitive dysfunction, at a median of 4 months following initial diagnosis were independently associated with serological evidence suggesting recent EBV reactivation (early antigen–diffuse IgG positivity) or high nuclear antigen (EBNA) IgG levels but not with ongoing EBV viremia. Serological evidence suggesting recent EBV reactivation (early antigen–diffuse IgG positivity) was most strongly associated with fatigue (OR = 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR = 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR = 0.52). CONCLUSION. Overall, these findings suggest differential effects of chronic viral coinfections on the likelihood of developing LC and association with distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted.Publisher: American Society for Clinical Investigation PMID: 0
307	I305		Watanabe, Atsuyuki; Iwagami, Masao; Yasuhara, Jun; Takagi, Hisato; Kuno, Toshiki	Protective effect of COVID-19 vaccination against long COVID syndrome: A systematic review and meta-analysis	https://doi.org/10.1016/j.vaccine.2023.02.008	Published	2023-02-08	Review	https://www.sciencedirect.com/science/article/pii/S0264410X23001342	Highlights •The effects of COVID-19 vaccination on long COVID remains inconclusive. •Vaccination before SARS-CoV-2 infection was associated with a lower risk of long COVID. •Vaccination after SARS-CoV-2 infection was not associated with symptomatic changes of long COVID. •Vaccination before SARS-CoV-2 infection can be recommended to reduce long COVID. Abstract Background The relationship between coronavirus disease 2019 (COVID-19) vaccination and long COVID has not been firmly established. We conducted a systematic review and meta-analysis to evaluate the association between COVID-19 vaccination and long COVID. Methods PubMed and EMBASE databases were searched on September 2022 without language restrictions (CRD42022360399) to identify prospective trials and observational studies comparing patients with and without vaccination before severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. We also included studies reporting symptomatic changes of ongoing long COVID following vaccination among those with a history of SARS-CoV-2 infection. Odds ratios (ORs) for each outcome were synthesized using a random-effects model. Symptomatic changes after vaccination were synthesized by a one-group meta-analysis. Results Six observational studies involving 536,291 unvaccinated and 84,603 vaccinated (before SARS-CoV-2 infection) patients (mean age, 41.2–66.6; female, 9.0–67.3%) and six observational studies involving 8,199 long COVID patients (mean age, 40.0 to 53.5; female, 22.2–85.9%) who received vaccination after SARS-CoV-2 infection were included. Two-dose vaccination was associated with a lower risk of long COVID compared to no vaccination (OR, 0.64; 95% confidence interval [CI], 0.45–0.92) and one-dose vaccination (OR, 0.60; 95% CI, 0.43–0.83). Two-dose vaccination compared to no vaccination was associated with a lower risk of persistent fatigue (OR, 0.62; 95% CI, 0.41–0.93) and pulmonary disorder (OR, 0.50; 95% CI, 0.47–0.52). Among those with ongoing long COVID symptoms, 54.4% (95% CI, 34.3–73.1%) did not report symptomatic changes following vaccination, while 20.3% (95% CI, 8.1–42.4%) experienced symptomatic improvement after two weeks to six months of COVID-19 vaccination. Conclusions COVID-19 vaccination before SARS-CoV-2 infection was associated with a lower risk of long COVID, while most of those with ongoing long COVID did not experience symptomatic changes following vaccination.
308	I306		Feng, Allan; Yang, Emily Y.; Moore, Andrew Reese; Dhingra, Shaurya; Chang, Sarah Esther; Yin, Xihui; Pi, Ruoxi; Mack, Elisabeth K. M.; Völkel, Sara; Geßner, Reinhard; Gündisch, Margrit; Neubauer, Andreas; Renz, Harald; Tsiodras, Sotirios; Fragkou, Paraskevi C.; Asuni, Adijat A.; Levitt, Joseph E.; Wilson, Jennifer G.; Leong, Michelle; Lumb, Jennifer H.; Mao, Rong; Pinedo, Kassandra; Roque, Jonasel; Richards, Christopher M.; Stabile, Mikayla; Swaminathan, Gayathri; Salagianni, Maria L.; Triantafyllia, Vasiliki; Bertrams, Wilhelm; Blish, Catherine A.; Carette, Jan E.; Frankovich, Jennifer; Meffre, Eric; Nadeau, Kari Christine; Singh, Upinder; Wang, Taia T.; Prak, Eline T. Luning; Herold, Susanne; Andreakos, Evangelos; Schmeck, Bernd; Skevaki, Chrysanthi; Rogers, Angela J.; Utz, Paul J.	Autoantibodies are highly prevalent in non–SARS-CoV-2 respiratory infections and critical illness	https://doi.org/10.1172/jci.insight.163150	Published	2023-02-08	Study	https://insight.jci.org/articles/view/163150	The widespread presence of autoantibodies in acute infection with SARS-CoV-2 is increasingly recognized, but the prevalence of autoantibodies in non–SARS-CoV-2 infections and critical illness has not yet been reported. We profiled IgG autoantibodies in 267 patients from 5 independent cohorts with non–SARS-CoV-2 viral, bacterial, and noninfectious critical illness. Serum samples were screened using Luminex arrays that included 58 cytokines and 55 autoantigens, many of which are associated with connective tissue diseases (CTDs). Samples positive for anti-cytokine antibodies were tested for receptor blocking activity using cell-based functional assays. Anti-cytokine antibodies were identified in > 50% of patients across all 5 acutely ill cohorts. In critically ill patients, anti-cytokine antibodies were far more common in infected versus uninfected patients. In cell-based functional assays, 11 of 39 samples positive for select anti-cytokine antibodies displayed receptor blocking activity against surface receptors for Type I IFN, GM-CSF, and IL-6. Autoantibodies against CTD-associated autoantigens were also commonly observed, including newly detected antibodies that emerged in longitudinal samples. These findings demonstrate that anti-cytokine and autoantibodies are common across different viral and nonviral infections and range in severity of illness. publisher: American Society for Clinical Investigation PMID: 0
309	I307		Gerhards, Catharina; Kittel, Maximilian; Ast, Volker; Bugert, Peter; Froelich, Matthias F.; Hetjens, Michael; Haselmann, Verena; Neumaier, Michael; Thiaucourt, Margot	Humoral SARS-CoV-2 Immune Response in COVID-19 Recovered Vaccinated and Unvaccinated Individuals Related to Post-COVID-Syndrome	https://doi.org/10.3390/v15020454	Published	2023-02-01	Study	https://www.mdpi.com/1999-4915/15/2/454	Background: The duration of anti-SARS-CoV-2-antibody detectability up to 12 months was examined in individuals after either single convalescence or convalescence and vaccination. Moreover, variables that might influence an anti-RBD/S1 antibody decline and the existence of a post-COVID-syndrome (PCS) were addressed. Methods: Forty-nine SARS-CoV-2-qRT-PCR-confirmed participants completed a 12-month examination of anti-SARS-CoV-2-antibody levels and PCS-associated long-term sequelae. Overall, 324 samples were collected. Cell-free DNA (cfDNA) was isolated and quantified from EDTA-plasma. As cfDNA is released into the bloodstream from dying cells, it might provide information on organ damage in the late recovery of COIVD-19. Therefore, we evaluated cfDNA concentrations as a biomarker for a PCS. In the context of antibody dynamics, a random forest-based logistic regression with antibody decline as the target was performed and internally validated. Results: The mean percentage dynamic related to the maximum measured value was 96 (±38)% for anti-RBD/S1 antibodies and 30 (±26)% for anti-N antibodies. Anti-RBD/S1 antibodies decreased in 37%, whereas anti-SARS-CoV-2-anti-N antibodies decreased in 86% of the subjects. Clinical anti-RBD/S1 antibody decline prediction models, including vascular and other diseases, were cross-validated (highest AUC 0.74). Long-term follow-up revealed no significant reduction in PCS prevalence but an increase in cognitive impairment, with no indication for cfDNA as a marker for a PCS. Conclusion: Long-term anti-RBD/S1-antibody positivity was confirmed, and clinical parameters associated with declining titers were presented. A fulminant decrease in anti-SARS-CoV-2-anti-N antibodies was observed (mean change to maximum value 30 (±26)%). Anti-RBD/S1 antibody titers of SARS-CoV-2 recovered subjects boosted with a vaccine exceeded the maximum values measured after single infection by 235 ± 382-fold, with no influence on preexisting PCS. PCS long-term prevalence was 38.6%, with an increase in cognitive impairment compromising the quality of life. Quantified cfDNA measured in the early post-COVID-19 phase might not be an effective marker for PCS identification.
310	I308		Williams, Elizabeth SCP; Martins, Thomas B.; Shah, Kevin S.; Hill, Harry R.; Coiras, Mayte; Spivak, Adam M.; Planelles, Vicente	Cytokine Deficiencies in Patients with Long-COVID		Published	2022-11-18	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894377/	Up to half of individuals who contract SARS-CoV-2 develop symptoms of long-COVID approximately three months after initial infection. These symptoms are highly variable, and the mechanisms inducing them are yet to be understood. We compared plasma cytokine levels from individuals with long-COVID to healthy individuals and found that those with long-COVID had 100% reductions in circulating levels of Interferon Gamma (IFNγ) and Interleukin-8 (IL-8). Additionally, we found significant reductions in levels of IL-6, IL-2, IL-17, IL-13, and IL-4 in individuals with long-COVID. We propose immune exhaustion as the driver of long-COVID, with the complete absence of IFNγ and IL-8preventing the lungs and other organs from healing after acute infection, and reducing the ability to fight off subsequent infections, both contributing to the myriad of symptoms suffered by those with long-COVID.
311	I309		Frasca, Loredana; Ocone, Giuseppe; Palazzo, Raffaella	Safety of COVID-19 Vaccines in Patients with Autoimmune Diseases, in Patients with Cardiac Issues, and in the Healthy Population	https://doi.org/10.3390/pathogens12020233	Published	2023-02-01	Review	https://www.mdpi.com/2076-0817/12/2/233	The coronavirus disease 2019 (COVID-19) has been a challenge for the whole world since the beginning of 2020, and COVID-19 vaccines were considered crucial for disease eradication. Instead of producing classic vaccines, some companies pointed to develop products that mainly function by inducing, into the host, the production of the antigenic protein of SARS-CoV-2 called Spike, injecting an instruction based on RNA or a DNA sequence. Here, we aim to give an overview of the safety profile and the actual known adverse effects of these products in relationship with their mechanism of action. We discuss the use and safety of these products in at-risk people, especially those with autoimmune diseases or with previously reported myocarditis, but also in the general population. We debate the real necessity of administering these products with unclear long-term effects to at-risk people with autoimmune conditions, as well as to healthy people, at the time of omicron variants. This, considering the existence of therapeutic interventions, much more clearly assessed at present compared to the past, and the relatively lower aggressive nature of the new viral variants.
312	I310		Lavi, Yael; Vojdani, Aristo; Halpert, Gilad; Sharif, Kassem; Ostrinski, Yuri; Zyskind, Israel; Lattin, Miriam T.; Zimmerman, Jason; Silverberg, Jonathan I.; Rosenberg, Avi Z.; Shoenfeld, Yehuda; Amital, Howard	Dysregulated Levels of Circulating Autoantibodies against Neuronal and Nervous System Autoantigens in COVID-19 Patients	https://doi.org/10.3390/diagnostics13040687	Published	2023-01-01	Study	https://www.mdpi.com/2075-4418/13/4/687	Background: COVID-19 is a heterogenous disease resulting in long-term sequela in predisposed individuals. It is not uncommon that recovering patients endure non-respiratory ill-defined manifestations, including anosmia, and neurological and cognitive deficit persisting beyond recovery—a constellation of conditions that are grouped under the umbrella of long-term COVID-19 syndrome. Association between COVID-19 and autoimmune responses in predisposed individuals was shown in several studies. Aim and methods: To investigate autoimmune responses against neuronal and CNS autoantigens in SARS-CoV-2-infected patients, we performed a cross-sectional study with 246 participants, including 169 COVID-19 patients and 77 controls. Levels of antibodies against the acetylcholine receptor, glutamate receptor, amyloid β peptide, alpha-synucleins, dopamine 1 receptor, dopamine 2 receptor, tau protein, GAD-65, N-methyl D-aspartate (NMDA) receptor, BDNF, cerebellar, ganglioside, myelin basic protein, myelin oligodendrocyte glycoprotein, S100-B, glial fibrillary acidic protein, and enteric nerve were measured using an Enzyme-Linked Immunosorbent Assay (ELISA). Circulating levels of autoantibodies were compared between healthy controls and COVID-19 patients and then classified by disease severity (mild [n = 74], severe [n = 65], and requiring supplemental oxygen [n = 32]). Results: COVID-19 patients were found to have dysregulated autoantibody levels correlating with the disease severity, e.g., IgG to dopamine 1 receptor, NMDA receptors, brain-derived neurotrophic factor, and myelin oligodendrocyte glycoprotein. Elevated levels of IgA autoantibodies against amyloid β peptide, acetylcholine receptor, dopamine 2 receptor, myelin basic protein, and α-synuclein were detected in COVID-19 patients compared with healthy controls. Lower IgA autoantibody levels against NMDA receptors, and IgG autoantibodies against glutamic acid decarboxylase 65, amyloid β peptide, tau protein, enteric nerve, and S100-B were detected in COVID-19 patients versus healthy controls. Some of these antibodies have known clinical correlations with symptoms commonly reported in the long COVID-19 syndrome. Conclusions: Overall, our study shows a widespread dysregulation in the titer of various autoantibodies against neuronal and CNS-related autoantigens in convalescent COVID-19 patients. Further research is needed to provide insight into the association between these neuronal autoantibodies and the enigmatic neurological and psychological symptoms reported in COVID-19 patients
313	I311		Bamidis, Anna D; Koehler, Philipp; Di Cristanziano, Veronica; Rasche, Kurt; Demirel, Baris; Bacher, Petra; Hallek, Michael; Kochanek, Matthias; Klein, Florian; Hofmann, Silke C; Wesselmann, Ulrich; Kofler, David M	First manifestation of adult-onset Still's disease after COVID-19	https://doi.org/10.1016/S2665-9913(21)00072-2	Published	2021-05-01	Case Report	https://linkinghub.elsevier.com/retrieve/pii/S2665991321000722	Adult-onset Still's disease (AOSD) is a rare inflammatory disorder that usually affects young adults, with a bimodal peak at ages 15–25 years and 36–46 years. The disease is characterised by fever of more than 39°C, transient skin rash, leucocytosis, arthralgia, arthritis, or a combination of these symptoms.1 In addition to at least two of the aforementioned major criteria, the Yamaguchi criteria for the diagnosis of AOSD require the presence of minor criteria—ie, sore throat, lymphadenopathy, hepatomegaly or splenomegaly, abnormal liver function tests, and negative tests for antinuclear antibodies and rheumatoid factor.1 Infections, malignancies, and other rheumatic diseases need to be excluded. The cytokine interleukin (IL)-1 has a central role in the pathogenesis of AOSD and inhibition of IL-1β by monoclonal antibodies, and blockade of the IL-1 receptor by antagonists significantly ameliorates the disease.2 IL-1 drives the intense innate immune response by activating neutrophils, macrophages, and mast cells, and by leading to overexpression of several proinflammatory cytokines, including IL-6, IL-8, IL-17, IL-18, and TNF.3 Viral or bacterial infections have been proposed as potential trigger, but the exact mechanisms underlying AOSD onset remain largely unknown.4 SARS-CoV-2 emerged in late 2019, causing the COVID-19 pandemic. AOSD and COVID-19 share several clinical and laboratory features, including systemic inflammation, unremitting fever, high serum ferritin, and a potentially life-threatening cytokine release syndrome. Data obtained from single-cell analysis revealed IL-1β-associated inflammasome signatures and a significant expansion of CD14-positive, IL-1β-positive monocytes in the peripheral blood of patients with severe COVID-19.5, 6 Thus, AOSD and the severe immune over-reaction which occurs in some patients with COVID-19 might be triggered by the same mechanisms. Here, we report a case of severe AOSD manifestations emerging in a patient suffering from long-term sequelae of COVID-19 for 6 months. In Germany, in March, 2020, a 29-year-old White woman with no notable medical history developed signs of SARS-CoV-2 infection including sore throat, headache, anosmia, ageusia, generalised weakness, shortness of breath, diarrhoea, and chilblain-like skin eruptions of the toes. The patient tested positive for SARS-CoV-2 by RT-PCR from a nasopharyngeal swab. There was no need for therapy or hospitalisation. RT-PCR tests for SARS-CoV-2 were negative on day 15 after the onset of first symptoms. The patient continued to have elevated temperatures of up to 38·0°C for another 8 days.
314	I312		Karbalaeimahdi, Mohammad; Farajnia, Safar; Bargahi, Nasrin; Ghadiri-Moghaddam, Farzaneh; Rasouli Jazi, Hamid Reza; Bakhtiari, Nasim; Ghasemali, Samaneh; Zarghami, Nosratollah	The Role of Interferons in Long Covid Infection	https://doi.org/10.1089/jir.2022.0193	Published	2023-02-01	Review	https://www.liebertpub.com/doi/10.1089/jir.2022.0193	Although the new generation of vaccines and anti-COVID-19 treatment regimens facilitated the management of acute COVID-19 infections, concerns about post-COVID-19 syndrome or Long Covid are rising. This issue can increase the incidence and morbidity of diseases such as diabetes, and cardiovascular, and lung infections, especially among patients suffering from neurodegenerative disease, cardiac arrhythmias, and ischemia. There are numerous risk factors that cause COVID-19 patients to experience post-COVID-19 syndrome. Three potential causes attributed to this disorder include immune dysregulation, viral persistence, and autoimmunity. Interferons (IFNs) are crucial in all aspects of post-COVID-19 syndrome etiology. In this review, we discuss the critical and double-edged role of IFNs in post-COVID-19 syndrome and how innovative biomedical approaches that target IFNs can reduce the occurrence of Long Covid infection.
315	I313		Joung, Sandy; Weber, Brittany; Wu, Min; Liu, Yunxian; Tang, Amber B.; Driver, Matthew; Sternbach, Sarah; Wynter, Timothy; Hoang, Amy; Barajas, Denisse; Kao, Yu Hung; Khuu, Briana; Bravo, Michelle; Masoom, Hibah; Tran, Teresa; Sun, Nancy; Botting, Patrick G.; Claggett, Brian L.; Prostko, John C.; Frias, Edwin C.; Stewart, James L.; Robertson, Jackie; Kwan, Alan C.; Torossian, Mariam; Pedraza, Isabel; Sterling, Carina; Goldzweig, Caroline; Oft, Jillian; Zabner, Rachel; Fert-Bober, Justyna; Ebinger, Joseph E.; Sobhani, Kimia; Cheng, Susan; Le, Catherine N.	Serological response to vaccination in post-acute sequelae of COVID	https://doi.org/10.1186/s12879-023-08060-y	Published	2023-02-16	Study	https://doi.org/10.1186/s12879-023-08060-y	Background Individuals with post-acute sequelae of COVID (PASC) may have a persistence in immune activation that differentiates them from individuals who have recovered from COVID without clinical sequelae. To investigate how humoral immune activation may vary in this regard, we compared patterns of vaccine-provoked serological response in patients with PASC compared to individuals recovered from prior COVID without PASC. Methods We prospectively studied 245 adults clinically diagnosed with PASC and 86 adults successfully recovered from prior COVID. All participants had measures of humoral immunity to SARS-CoV-2 assayed before or after receiving their first-ever administration of COVID vaccination (either single-dose or two-dose regimen), including anti-spike (IgG-S and IgM-S) and anti-nucleocapsid (IgG-N) antibodies as well as IgG-S angiotensin-converting enzyme 2 (ACE2) binding levels. We used unadjusted and multivariable-adjusted regression analyses to examine the association of PASC compared to COVID-recovered status with post-vaccination measures of humoral immunity. Results Individuals with PASC mounted consistently higher post-vaccination IgG-S antibody levels when compared to COVID-recovered (median log IgG-S 3.98 versus 3.74, P < 0.001), with similar results seen for ACE2 binding levels (median 99.1 versus 98.2, P = 0.044). The post-vaccination IgM-S response in PASC was attenuated but persistently unchanged over time (P = 0.33), compared to in COVID recovery wherein the IgM-S response expectedly decreased over time (P = 0.002). Findings remained consistent when accounting for demographic and clinical variables including indices of index infection severity and comorbidity burden. Conclusion We found evidence of aberrant immune response distinguishing PASC from recovered COVID. This aberrancy is marked by excess IgG-S activation and ACE2 binding along with findings consistent with a delayed or dysfunctional immunoglobulin class switching, all of which is unmasked by vaccine provocation. These results suggest that measures of aberrant immune response may offer promise as tools for diagnosing and distinguishing PASC from non-PASC phenotypes, in addition to serving as potential targets for intervention.
316	I314		Bhatia-Dey, Naina; Csoka, Antonei B.; Heinbockel, Thomas	Chemosensory Ability and Sensitivity in Health and Disease: Epigenetic Regulation and COVID-19	https://doi.org/10.3390/ijms24044179	Published	2023-01-01	Review	https://www.mdpi.com/1422-0067/24/4/4179	Throughout the animal kingdom, our two chemical senses, olfaction and gustation, are defined by two primary factors: genomic architecture of the organisms and their living environment. During the past three years of the global COVID-19 pandemic, these two sensory modalities have drawn much attention at the basic science and clinical levels because of the strong association of olfactory and gustatory dysfunction with viral infection. Loss of our sense of smell alone, or together with a loss of taste, has emerged as a reliable indicator of COVID-19 infection. Previously, similar dysfunctions have been detected in a large cohort of patients with chronic conditions. The research focus remains on understanding the persistence of olfactory and gustatory disturbances in the post-infection phase, especially in cases with long-term effect of infection (long COVID). Also, both sensory modalities show consistent age-related decline in studies aimed to understand the pathology of neurodegenerative conditions. Some studies using classical model organisms show an impact on neural structure and behavior in offspring as an outcome of parental olfactory experience. The methylation status of specific odorant receptors, activated in parents, is passed on to the offspring. Furthermore, experimental evidence indicates an inverse correlation of gustatory and olfactory abilities with obesity. Such diverse lines of evidence emerging from basic and clinical research studies indicate a complex interplay of genetic factors, evolutionary forces, and epigenetic alterations. Environmental factors that regulate gustation and olfaction could induce epigenetic modulation. However, in turn, such modulation leads to variable effects depending on genetic makeup and physiological status. Therefore, a layered regulatory hierarchy remains active and is passed on to multiple generations. In the present review, we attempt to understand the experimental evidence that indicates variable regulatory mechanisms through multilayered and cross-reacting pathways. Our analytical approach will add to enhancement of prevailing therapeutic interventions and bring to the forefront the significance of chemosensory modalities for the evaluation and maintenance of long-term health.
317	I315		Zavori, Laszlo; Molnar, Tihamer; Varnai, Reka; Kanizsai, Andrea; Nagy, Lajos; Vadkerti, Bence; Szirmay, Balazs; Schwarcz, Attila; Csecsei, Peter	Cystatin-c May Indicate Subclinical Renal Involvement, While Orosomucoid Is Associated with Fatigue in Patients with Long-COVID Syndrome	https://doi.org/10.3390/jpm13020371	Published	2023-02-01	Study	https://www.mdpi.com/2075-4426/13/2/371	Long-COVID syndrome is associated with high healthcare costs, but its pathophysiology is not yet fully understood. Inflammation, renal impairment or disturbance of the NO system emerge as potential pathogenetic factors. We aimed to investigate the relationship between symptoms of long-COVID syndrome and serum levels of cystatin-c (CYSC), orosomucoid (ORM), l-arginine, symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA). A total of 114 patients suffering from long-COVID syndrome were included in this observational cohort study. We found that serum CYSC was independently associated with the anti-spike immunoglobulin (S-Ig) serum level (OR: 5.377, 95% CI: 1.822–12.361; p = 0.02), while serum ORM (OR: 9.670 (95% CI: 1.34–9.93; p = 0.025) independently predicted fatigue in patients with long-COVID syndrome, both measured at baseline visit. Additionally, the serum CYSC concentrations measured at the baseline visit showed a positive correlation with the serum SDMA levels. The severity of abdominal and muscle pain indicated by patients at the baseline visit showed a negative correlation with the serum level of L-arginine. In summary, serum CYSC may indicate subclinical renal impairment, while serum ORM is associated with fatigue in long-COVID syndrome. The potential role of l-arginine in alleviating pain requires further studies.
318	I316		Ballouz, Tala; Menges, Dominik; Kaufmann, Marco; Amati, Rebecca; Frei, Anja; Wyl, Viktor von; Fehr, Jan S.; Albanese, Emiliano; Puhan, Milo A.	Post COVID-19 condition after Wildtype, Delta, and Omicron SARS-CoV-2 infection and prior vaccination: Pooled analysis of two population-based cohorts	https://doi.org/10.1371/journal.pone.0281429	Published	2023-02-22	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0281429	Background Post COVID-19 condition (PCC) is an important complication of SARS-CoV-2 infection, affecting millions worldwide. This study aimed to evaluate the prevalence and severity of post COVID-19 condition (PCC) with novel SARS-CoV-2 variants and after prior vaccination. Methods We used pooled data from 1350 SARS-CoV-2-infected individuals from two representative population-based cohorts in Switzerland, diagnosed between Aug 5, 2020, and Feb 25, 2022. We descriptively analysed the prevalence and severity of PCC, defined as the presence and frequency of PCC-related symptoms six months after infection, among vaccinated and non-vaccinated individuals infected with Wildtype, Delta, and Omicron SARS-CoV-2. We used multivariable logistic regression models to assess the association and estimate the risk reduction of PCC after infection with newer variants and prior vaccination. We further assessed associations with the severity of PCC using multinomial logistic regression. To identify groups of individuals with similar symptom patterns and evaluate differences in the presentation of PCC across variants, we performed exploratory hierarchical cluster analyses. Results We found strong evidence that vaccinated individuals infected with Omicron had reduced odds of developing PCC compared to non-vaccinated Wildtype-infected individuals (odds ratio 0.42, 95% confidence interval 0.24–0.68). The odds among non-vaccinated individuals were similar after infection with Delta or Omicron compared to Wildtype SARS-CoV-2. We found no differences in PCC prevalence with respect to the number of received vaccine doses or timing of last vaccination. The prevalence of PCC-related symptoms among vaccinated, Omicron-infected individuals was lower across severity levels. In cluster analyses, we identified four clusters of diverse systemic, neurocognitive, cardiorespiratory, and musculoskeletal symptoms, with similar patterns across variants. Conclusion The risk of PCC appears to be lowered with infection by the Omicron variant and after prior vaccination. This evidence is crucial to guide future public health measures and vaccination strategies.
319	I317		Patel, Maitray A.; Knauer, Michael J.; Nicholson, Michael; Daley, Mark; Van Nynatten, Logan R.; Cepinskas, Gediminas; Fraser, Douglas D.	Organ and cell-specific biomarkers of Long-COVID identified with targeted proteomics and machine learning	https://doi.org/10.1186/s10020-023-00610-z	Published	2023-02-21	Study	https://doi.org/10.1186/s10020-023-00610-z	Background Survivors of acute COVID-19 often suffer prolonged, diffuse symptoms post-infection, referred to as “Long-COVID”. A lack of Long-COVID biomarkers and pathophysiological mechanisms limits effective diagnosis, treatment and disease surveillance. We performed targeted proteomics and machine learning analyses to identify novel blood biomarkers of Long-COVID. Methods A case–control study comparing the expression of 2925 unique blood proteins in Long-COVID outpatients versus COVID-19 inpatients and healthy control subjects. Targeted proteomics was accomplished with proximity extension assays, and machine learning was used to identify the most important proteins for identifying Long-COVID patients. Organ system and cell type expression patterns were identified with Natural Language Processing (NLP) of the UniProt Knowledgebase. Results Machine learning analysis identified 119 relevant proteins for differentiating Long-COVID outpatients (Bonferonni corrected P < 0.01). Protein combinations were narrowed down to two optimal models, with nine and five proteins each, and with both having excellent sensitivity and specificity for Long-COVID status (AUC = 1.00, F1 = 1.00). NLP expression analysis highlighted the diffuse organ system involvement in Long-COVID, as well as the involved cell types, including leukocytes and platelets, as key components associated with Long-COVID. Conclusions Proteomic analysis of plasma from Long-COVID patients identified 119 highly relevant proteins and two optimal models with nine and five proteins, respectively. The identified proteins reflected widespread organ and cell type expression. Optimal protein models, as well as individual proteins, hold the potential for accurate diagnosis of Long-COVID and targeted therapeutics.
320	I318		Brandt, C. T.; Wiese, L.; Christiansen, K. M.; Agergaard, J.	Antibodies to Nucleocapsid Are Not Diagnostic for Long COVID	https://doi.org/10.1128/spectrum.04900-22	Published	2023-02-21	Letter to editor	https://journals.asm.org/doi/10.1128/spectrum.04900-22	Studying the long-term effects of COVID-19 (long COVID) among members of a Facebook group dedicated to individuals who suspect they may have sequelae from COVID-19 is innovative (1). The study by Fogh et al. emphasizes the importance of thorough investigation of patients with symptoms resembling long COVID to rule out other causes of malaise. Fogh et al. used antibodies against the nucleocapsid antigen as a proxy for detecting previous COVID infection among Danish individuals with a perception that they suffer from long COVID. The finding that 32% of the participants did not have detectable antinucleocapsid antibodies leads to the conclusion that their symptoms were most likely not related to COVID-19. The low number of respondents—below 5%—is likely to have introduced a bias of uncertain significance besides skewed gender distribution. The acquired data do, however, only to a limited extent support the study conclusions. The study premises where Facebook group members with negative screening to SARS-CoV-2 nucleocapsid protein are considered not to have had COVID is challenging since 30 to 40% of patients will not have persisting antibodies at the time of recruitment (2). Furthermore, patients with mild COVID have an antibody response with an even more rapid decay (2, 3). The results presented by Fogh et al. confirm these results by showing significantly increased time from COVID in seronegative individuals compared to seropositive (317 versus 214 days). Close to 90% of the included group members had COVID PCR tests performed. These results could be included as confirmative data for infection as a more reliable indicator of COVID disease status. All available data are important in order to characterize long COVID, and a positive SARS-CoV-2 test is part of the long COVID diagnosis. It is important to use test-positive patients when we characterize long COVID symptoms and search for new treatment options for long COVID patients. Footnote For the author reply, see https://doi.org/10.1128/spectrum.00065-23. publisher: American Society for Microbiology
321	I319		Hernández-Aceituno, Ana; García-Hernández, Abigail; Larumbe-Zabala, Eneko	COVID-19 long-term sequelae: Omicron versus Alpha and Delta variants	https://doi.org/10.1016/j.idnow.2023.104688	Published	2023-02-28	Study	https://www.sciencedirect.com/science/article/pii/S2666991923000507	Highlights •The Omicron variant was associated with a lower risk of COVID-19long-term sequelae. •Severity of illness indicators increased the risk (ICU length of stay and antiviral or immunomodulatory treatment). •Vaccination, age, sex, and comorbidities were not found to predict risk of sequelae. Abstract Background The study aimed to assess the association between three predominant SARS-CoV-2 variants (Alpha, Delta, and Omicron) and the risk of developing long COVID (persistence of physical, medical, and cognitive symptoms more than 4 weeks after infection), post-COVID-19 syndrome (symptoms extending beyond 12 weeks), and viral persistence (testing positive beyond 4 weeks despite clinical resolution). Methods Retrospective study of 325 patients hospitalized for COVID-19 with genomic sequencing information. For each SARS-CoV-2 variant, sample characteristics, frequency of symptoms, and long-term sequelae were compared using Chi-squared test, Fisher’s exact test, Kruskal-Wallis test, and Dunn's test as appropriate. Odds ratios (OR) were calculated using logistic regression models to assess the association of risk factors and sequelae. Results The adjusted model showed that the Omicron (vs Alpha) variant (OR, 0.30; 95% CI 0.16–0.56), admission to ICU (OR, 1.14; 95% CI 1.05–1.23), and being treated with antiviral or immunomodulatory drugs (OR, 2.01; 95% CI 1.23–3.27) predicted long COVID and post-COVID-19 syndrome. Viral persistence showed no difference between variants. Conclusions The Omicron variant was associated with significantly lower odds of developing long-term sequelae from COVID-19 compared with previous variants, while severity of illness indicators increased the risk. Vaccination status, age, sex, and comorbidities were not found to predict sequelae development. This information has implications for both health managers and clinicians when deciding on the appropriate clinical management and subsequent outpatient follow-up of these patients. More studies with non-hospitalized patients are still necessary.
322	I320		Sher, Emina Karahmet; Ćosović, Adnan; Džidić-Krivić, Amina; Farhat, Esma Karahmet; Pinjić, Emma; Sher, Farooq	Covid-19 a triggering factor of autoimmune and multi-inflammatory diseases	https://doi.org/10.1016/j.lfs.2023.121531	Published	2023-04-15	Review	https://www.sciencedirect.com/science/article/pii/S0024320523001650	SARS-CoV-2 virus has attracted a lot of attention globally due to the autoimmune and inflammatory processes that were observed during the development of Covid-19 disease. Excessive activation of immune response and triggering of autoantibodies synthesis as well as an excessive synthesis of inflammatory cytokines and the onset of cytokine storm has a vital role in the disease outcome and the occurring autoimmune complications. This scenario is reminiscent of infiltration of lymphocytes and monocytes in specific organs and the increased production of autoantibodies and chemoattractants noted in other inflammatory and autoimmune diseases. The main goal of this study is to investigate the complex inflammatory processes that occur in Covid-19 disease and to find similarities with other inflammatory diseases such as multiple sclerosis (MS), acute respiratory distress syndrome (ARDS), rheumatoid arthritis (RA) and Kawasaki syndrome to advance existing diagnostic and therapeutic protocols. The therapy with Interferon-gamma (IFN-γ) and the use of S1P receptor modulators showed promising results. However, there are many unknowns about these mechanisms and possible novel therapies. Therefore, the inflammation and autoimmunity triggered by Covid-19 should be further investigated to improve existing diagnostic procedures and therapeutic protocols for Covid-19.
323	I321		Huang, Mengwen; Pan, Xingchao; Wang, Xinling; Ren, Qingfei; Tong, Bei; Dong, Xianchi; Ge, Gaoxiang; Lu, Lu; Jiang, Shibo; Chen, Jianfeng	Lymphocyte integrins mediate entry and dysregulation of T cells by SARS-CoV-2	https://doi.org/10.1038/s41392-023-01348-0	Published	2023-02-27	Study	https://www.nature.com/articles/s41392-023-01348-0	T-cell infection by SARS-CoV-2 and associated immune responses are correlated with disease severity and prognosis of COVID-19. Lymphopenia is associated with increased disease severity in COVID-19. Significantly lower circulating T and B cell counts were observed in patients who died from COVID-19 compared with survivors. Moreover, SARS-CoV-2 infection causes aberrant lymphocyte activation and dysfunction. COVID-19 patients displayed hyperactivated T cells which are prone to apoptosis and dysregulated cytokine responses.1 Some evidence suggests the infection of lymphocytes by SARS-CoV-2, including colocalization of SARS-CoV-2 spike (S) protein and lymphocytes in lung tissues of COVID-19 patients and strands of SARS-CoV-2 sub-genomes in immune cells from bronchoalveolar lavage fluid (BALF) and sputum samples of severe COVID-19 patients.2 Angiotensin-converting enzyme 2 (ACE2) and some other reported S protein receptors are barely expressed in lymphocytes. Some recent studies suggest that integrins may act as SARS-CoV-2 receptors, shedding light on the dysregulation of lymphocyte functions by SARS-CoV-2. However, a clear-cut mechanism underlying the crosstalk between SARS-CoV-2 and lymphocyte integrins remains elusive. Lymphopenia and cytokine storm are associated with disease severity in most COVID-19 patients. Our data showed that the binding of S-RBD to integrins on T cells not only suppressed T cell proliferation but also promoted T cell activation and proinflammatory cytokine secretion. The dysregulation of T cells by S-RBD binding may therefore result in aberrant T cell immune responses and increase the severity of COVID-19. In summary, our study demonstrates that integrins act as SARS-CoV-2 receptors on T cells and mediate entry and dysregulation of T cells by SARS-CoV-2. Blocking S-RBD‒integrin interaction may be a strategy for preventing SARS-CoV-2 entry into T cells and associated immune dysregulation in COVID-19 patients. number: 1 publisher: Nature Publishing Group
324	I322		Edwards, Frances; Hamilton, Fergus W.	Impact of covid-19 vaccination on long covid	https://doi.org/10.1136/bmjmed-2022-000470	Published	2023-02-01	Article	https://bmjmedicine.bmj.com/content/2/1/e000470	> Some beneficial effects are likely but estimating the size of the effect currently remains a challenge Vaccines have had an important role in reducing mortality and morbidity from the covid-19 pandemic, with an estimated 14.4 million lives saved globally over the first year of vaccination. Where do these data leave us with vaccines and long covid? Given new and existing evidence, covid-19 vaccination is likely to have some beneficial effect on long covid through reducing case severity as well as incidence. However, estimating the size of the effect (and the effect of further vaccine doses) remains a challenge in observational data. The evidence of benefit after infection is much more unclear and harder to interpret given the current rate of seropositivity and vaccine uptake in many countries. While these studies are encouraging, trials comparing vaccination with placebo in patients with long covid (as defined by WHO criteria) are required to definitively recommend for or against vaccination to improve symptoms of long covid. Until then, vaccination should continue to be based on the most up-to-date evidence available for the prevention of covid-19 related infection, hospital admission, and death. publisher: BMJ Specialist Journals section: Editorial
325	I323		Taylor, Luke	Covid-19: Vaccination reduces severity and duration of long covid, study finds	https://doi.org/10.1136/bmj.p491	Published	2023-03-01	Article	https://www.bmj.com/content/380/bmj.p491	Vaccination against covid-19 reduces both the severity and the duration of long covid, a study published in BMJ Medicine has found.1 The paper adds to the evidence that patients infected with SARS CoV-2 who experience persistent covid-19 symptoms should be encouraged to be vaccinated against the virus, the authors said. Lasting covid-19 symptoms that persist more than three months after infection affect an estimated one in 10 people in the UK. The condition can end a patient’s social life and put them out of work because of the many associated symptoms, ranging from breathlessness and muscle pain to brain fog and headaches. An estimated two million to four million people in the US are out of work because of long covid, costing $170bn-$230bn (£141bn-£191bn; €159bn-€215bn) a year in lost wages.2 One of the remaining questions over the poorly understood condition is whether covid-19 vaccination affects recovery, which is made more difficult by the fact …
326	I324		Lee, A. Ram; Woo, Jin Seok; Lee, Seon-Yeong; Lee, Yeon Su; Jung, Jooyeon; Lee, Chae Rim; Park, Sung-Hwan; Cho, Mi-La	SARS-CoV-2 spike protein promotes inflammatory cytokine activation and aggravates rheumatoid arthritis	https://doi.org/10.1186/s12964-023-01044-0	Published	2023-03-02	Study	https://doi.org/10.1186/s12964-023-01044-0	Background Coronavirus disease 2019 (COVID-19) induces inflammation, autoantibody production, and thrombosis, which are common symptoms of autoimmune diseases, including rheumatoid arthritis (RA). However, the effect of COVID-19 on autoimmune disease is not yet fully understood. Methods This study was performed to investigate the effects of COVID-19 on the development and progression of RA using a collagen-induced arthritis (CIA) animal model. Human fibroblast-like synoviocytes (FLS) were transduced with lentivirus carrying the SARS-CoV-2 spike protein gene in vitro, and the levels of inflammatory cytokine and chemokine expression were measured. For in vivo experiments, CIA mice were injected with the gene encoding SARS-CoV-2 spike protein, and disease severity, levels of autoantibodies, thrombotic factors, and inflammatory cytokine and chemokine expression were assessed. In the in vitro experiments, the levels of inflammatory cytokine and chemokine expression were significantly increased by overexpression of SARS-CoV-2 spike protein in human FLS. Results The incidence and severity of RA in CIA mice were slightly increased by SARS-CoV-2 spike protein in vivo. In addition, the levels of autoantibodies and thrombotic factors, such as anti-CXC chemokine ligand 4 (CXCL4, also called PF4) antibodies and anti-phospholipid antibodies were significantly increased by SARS-CoV-2 spike protein. Furthermore, tissue destruction and inflammatory cytokine level in joint tissue were markedly increased in CIA mice by SARS-CoV-2 spike protein. Conclusions The results of the present study suggested that COVID-19 accelerates the development and progression of RA by increasing inflammation, autoantibody production, and thrombosis.
327	I325		Tran, Viet-Thi; Perrodeau, Elodie; Saldanha, Julia; Pane, Isabelle; Ravaud, Philippe	Efficacy of first dose of covid-19 vaccine versus no vaccination on symptoms of patients with long covid: target trial emulation based on ComPaRe e-cohort	https://doi.org/10.1136/bmjmed-2022-000229	Published	2023-02-01	Study	https://bmjmedicine.bmj.com/content/2/1/e000229	Objective To evaluate the effect of covid-19 vaccination on the severity of symptoms in patients with long covid. Design Target trial emulation based on ComPaRe e-cohort. Data source ComPaRe long covid cohort, a nationwide e-cohort (ie, a cohort where recruitment and follow-up are performed online) of patients with long covid, in France. Methods Adult patients (aged ≥18 years) enrolled in the ComPaRe cohort before 1 May 2021 were included in the study if they reported a confirmed or suspected SARS-CoV-2 infection, symptoms persistent for >3 weeks after onset, and at least one symptom attributable to long covid at baseline. Patients who received a first covid-19 vaccine injection were matched with an unvaccinated control group in a 1:1 ratio according to their propensity scores. Number of long covid symptoms, rate of complete remission of long covid, and proportion of patients reporting an unacceptable symptom state at 120 days were recorded. Results 910 patients were included in the analyses (455 in the vaccinated group and 455 in the control group). By 120 days, vaccination had reduced the number of long covid symptoms (mean 13.0 (standard deviation 9.4) in the vaccinated group v 14.8 (9.8) in the control group; mean difference −1.8, 95% confidence interval −3.0 to −0.5) and doubled the rate of patients in remission (16.6% v 7.5%, hazard ratio 1.93, 95% confidence interval 1.18 to 3.14). Vaccination reduced the effect of long covid on patients' lives (mean score on the impact tool 24.3 (standard deviation 16.7) v 27.6 (16.7); mean difference −3.3, 95% confidence interval −5.7 to −1.0) and the proportion of patients with an unacceptable symptom state (38.9% v 46.4%, risk difference −7.4%, 95% confidence interval −14.5% to −0.3%). In the vaccinated group, two (0.4%) patients reported serious adverse events requiring admission to hospital. Conclusion In this study, covid-19 vaccination reduced the severity of symptoms and the effect of long covid on patients' social, professional, and family lives at 120 days in those with persistent symptoms of infection.
328	I326		Qi, Furong; Li, Dapeng; Zhang, Zheng	The kinetics of chemokine autoantibodies in COVID-19	https://doi.org/10.1038/s41590-023-01455-8	Published	2023-03-15	Article	https://www.nature.com/articles/s41590-023-01455-8	First, it will be of importance to validate the presence of chemokine autoantibody patterns in a larger population, although the authors have validated their observation in two additional cohorts. Longitudinal follow-up of cohorts should be conducted to explore whether the elevation of chemokine autoantibodies that are associated with the absence of long COVID are already present in the acute phase or the early recovery stages and to further study their predictive value. In addition, it is not clear whether various patterns of chemokine autoantibodies can be defined in patients with long COVID with different organ-specific symptoms (for example, respiratory symptoms versus neurological symptoms), given the heterogeneity of symptoms, and even in long-term sequelae caused by other viral infections. Second, it remains to be determined what drives the elevation of these autoantibodies in patients with favorable outcomes. A simple model would be that chemokines proportionally induce autoantibodies, but such a correlation was not found by Muri et al4. This may be partly owing to different sampling times and the variable half-lives for the chemokines and the autoantibodies in plasma. It will be important to determine whether the level of chemokine autoantibodies in the blood correlates with the amount of chemokines in the tissues. In autoimmune diseases, chemokines at autoimmune sites could cause the breakthrough of B cell tolerance to generate autoantibodies against the dominant chemokine at these sites9. A subset of patients with COVID-19 and individuals with long COVID can present inflammation- and autoimmune-related symptoms10. However, the chemokine autoantibody signature in COVID-19 is different from that in the autoimmune diseases that authors have investigated here. Future studies should elaborately investigate the mechanisms underlying the elevated chemokine autoantibodies in individuals post-COVID-19 infection without long COVID. Third, given that the chemokine autoantibodies associated with long COVID are involved in sustaining lymphocyte recruitment, understanding the kinetics of these lymphocytes could help to clarify the mechanisms underlying the various COVID-19 outcomes. Research in the dynamics of antibody-producing cells and T cells through single-cell transcriptomic analysis might lead to better understanding of these complex regulatory mechanisms8. Considering that naturally arising chemokine autoantibodies associated with COVID-19 may be beneficial in regulating inflammatory responses, the development of targeted therapies to the chemokine system will be critical in the treatment of long COVID. publisher: Nature Publishing Group
329	I327		Schloss, John V.	Nutritional deficiencies that may predispose to long COVID	https://doi.org/10.1007/s10787-023-01183-3	Published	2023-03-15	Review	https://doi.org/10.1007/s10787-023-01183-3	Multiple nutritional deficiencies (MND) confound studies designed to assess the role of a single nutrient in contributing to the initiation and progression of disease states. Despite the perception of many healthcare practitioners, up to 25% of Americans are deficient in five-or-more essential nutrients. Stress associated with the COVID-19 pandemic further increases the prevalence of deficiency states. Viral infections compete for crucial nutrients with immune cells. Viral replication and proliferation of immunocompetent cells critical to the host response require these essential nutrients, including zinc. Clinical studies have linked levels of more than 22 different dietary components to the likelihood of COVID-19 infection and the severity of the disease. People at higher risk of infection due to MND are also more likely to have long-term sequelae, known as Long COVID.
330	I328		Worku, Dominic	Multisystem Inflammatory Syndrome in Adults (MIS-A) and SARS-CoV2: An Evolving Relationship	https://doi.org/10.3390/biomed3010016	Published	2023-03-01	Article	https://www.mdpi.com/2673-8430/3/1/16	The SARS-CoV2 pandemic is the most significant global health emergency of the last century. While the pathophysiology of SARS-CoV2 is understood, the early and long-term outcomes of natural infection are increasingly being recognised. Multisystem inflammatory syndrome (MIS) represents a manifestation of the extreme immune dysfunction that SARS-CoV2 infection heralds and has been described in both children (MIS-C) and adults (MIS-A). Here, we discuss current knowledge of MIS-A and the vast questions that remain unanswered.
331	I329		Hackenbruch, Christopher; Maringer, Yacine; Tegeler, Christian M.; Walz, Juliane S.; Nelde, Annika; Heitmann, Jonas S.	Elevated SARS-CoV-2-Specific Antibody Levels in Patients with Post-COVID Syndrome	https://doi.org/10.3390/v15030701	Published	2023-03-01	Study	https://www.mdpi.com/1999-4915/15/3/701	With the routine use of effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, the number of life-threatening coronavirus disease 2019 (COVID-19) courses have largely been reduced. However, multiple COVID-19 convalescents, even after asymptomatic to moderate disease, suffer from post-COVID syndrome, with relevant limitations in daily life. The pathophysiologic mechanisms of post-COVID syndrome are still elusive, with dysregulation of the immune system suggested as a central mechanism. Here, we assessed COVID-19 post-infectious symptoms (5–6 months after PCR-confirmed acute infection) together with the humoral immune response against SARS-CoV-2 in non-hospitalized COVID-19 convalescents, early (5–6 weeks) and late (5–6 months) after their first positive SARS-CoV-2 PCR result. Convalescents reporting several post-infectious symptoms (>3) showed higher anti-spike and anti-nucleocapsid antibody levels 5–6 weeks after PCR-confirmed infection with the latter remained increased 5–6 months after positive PCR. Likewise, a higher post-infectious symptom score was associated with increased antibody levels. Of note, convalescents displaying neuro-psychiatric symptoms such as restlessness, palpitations, irritability, and headache, as well as general symptoms such as fatigue/reduced power had higher SARS-CoV-2-specific antibody levels compared with asymptomatic cases. The increased humoral immune response in convalescents with post-COVID syndrome might be useful for the detection of individuals with an increased risk for post-COVID syndrome.
332	I330		Gioia, Ubaldo; Tavella, Sara; Martínez-Orellana, Pamela; Cicio, Giada; Colliva, Andrea; Ceccon, Marta; Cabrini, Matteo; Henriques, Ana C.; Fumagalli, Valeria; Paldino, Alessia; Presot, Ettore; Rajasekharan, Sreejith; Iacomino, Nicola; Pisati, Federica; Matti, Valentina; Sepe, Sara; Conte, Matilde I.; Barozzi, Sara; Lavagnino, Zeno; Carletti, Tea; Volpe, Maria Concetta; Cavalcante, Paola; Iannacone, Matteo; Rampazzo, Chiara; Bussani, Rossana; Tripodo, Claudio; Zacchigna, Serena; Marcello, Alessandro; d’Adda di Fagagna, Fabrizio	SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence	https://doi.org/10.1038/s41556-023-01096-x	Published	2023-03-09	Article	https://www.nature.com/articles/s41556-023-01096-x	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the RNA virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Although SARS-CoV-2 was reported to alter several cellular pathways, its impact on DNA integrity and the mechanisms involved remain unknown. Here we show that SARS-CoV-2 causes DNA damage and elicits an altered DNA damage response. Mechanistically, SARS-CoV-2 proteins ORF6 and NSP13 cause degradation of the DNA damage response kinase CHK1 through proteasome and autophagy, respectively. CHK1 loss leads to deoxynucleoside triphosphate (dNTP) shortage, causing impaired S-phase progression, DNA damage, pro-inflammatory pathways activation and cellular senescence. Supplementation of deoxynucleosides reduces that. Furthermore, SARS-CoV-2 N-protein impairs 53BP1 focal recruitment by interfering with damage-induced long non-coding RNAs, thus reducing DNA repair. Key observations are recapitulated in SARS-CoV-2-infected mice and patients with COVID-19. We propose that SARS-CoV-2, by boosting ribonucleoside triphosphate levels to promote its replication at the expense of dNTPs and by hijacking damage-induced long non-coding RNAs’ biology, threatens genome integrity and causes altered DNA damage response activation, induction of inflammation and cellular senescence.
333	I331		Kahlert, Christian R; Strahm, Carol; Güsewell, Sabine; Cusini, Alexia; Brucher, Angela; Goppel, Stephan; Möller, Elisabeth; Möller, J Carsten; Ortner, Manuela; Ruetti, Markus; Stocker, Reto; Vuichard-Gysin, Danielle; Besold, Ulrike; McGeer, Allison; Risch, Lorenz; Friedl, Andrée; Schlegel, Matthias; Vernazza, Pietro; Kuster, Stefan P; Kohler, Philipp; SURPRISE Study Group	Post-acute sequelae after SARS-CoV-2 infection by viral variant and vaccination status: a multicenter cross-sectional study	https://doi.org/10.1093/cid/ciad143	Published	2023-03-11	Study	https://doi.org/10.1093/cid/ciad143	Disentangling the effects of SARS-CoV-2 variants and vaccination on the occurrence of post-acute sequelae of SARS-CoV-2 (PASC) is crucial to estimate and reduce the burden of PASC.We performed a cross-sectional analysis (May/June 2022) within a prospective multicenter healthcare worker (HCW) cohort in North-Eastern Switzerland. HCW were stratified by viral variant and vaccination status at time of their first positive SARS-CoV-2 nasopharyngeal swab. HCW without positive swab and with negative serology served as controls. The sum of eighteen self-reported PASC symptoms was modeled with univariable and multivariable negative-binomial regression to analyse the association of mean symptom number with viral variant and vaccination status.Among 2’912 participants (median age 44 years, 81.3% female), PASC symptoms were significantly more frequent after wild-type infection (estimated mean symptom number 1.12, p<0.001; median time since infection 18.3 months), after Alpha/Delta infection (0.67 symptoms, p<0.001; 6.5 months), and after Omicron BA.1 infections (0.52 symptoms, p=0.005; 3.1 months) compared to uninfected controls (0.39 symptoms). After Omicron BA.1 infection, the estimated mean symptom number was 0.36 for unvaccinated individuals, compared to 0.71 with 1-2 vaccinations (p=0.028) and 0.49 with ≥3 prior vaccinations (p=0.30). Adjusting for confounders, only wild-type (adjusted rate ratio [aRR] 2.81, 95% confidence interval [CI] 2.08-3.83) and Alpha/Delta infection (aRR 1.93, 95% CI 1.10-3.46) were significantly associated with the outcome.Previous infection with pre-Omicron variants was the strongest risk factor for PASC symptoms among our HCW. Vaccination prior to Omicron BA.1 infection was not associated with a clear protective effect against PASC symptoms in this population.
334	I332		Opsteen, Skye; Files, Jacob K.; Fram, Tim; Erdmann, Nathan	The role of immune activation and antigen persistence in acute and long COVID	https://doi.org/10.1177/10815589231158041	Published	2023-03-06	Review	https://doi.org/10.1177/10815589231158041	In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered the global coronavirus disease 2019 (COVID-19) pandemic. Although most infections cause a self-limited syndrome comparable to other upper respiratory viral pathogens, a portion of individuals develop severe illness leading to substantial morbidity and mortality. Furthermore, an estimated 10%?20% of SARS-CoV-2 infections are followed by post-acute sequelae of COVID-19 (PASC), or long COVID. Long COVID is associated with a wide variety of clinical manifestations including cardiopulmonary complications, persistent fatigue, and neurocognitive dysfunction. Severe acute COVID-19 is associated with hyperactivation and increased inflammation, which may be an underlying cause of long COVID in a subset of individuals. However, the immunologic mechanisms driving long COVID development are still under investigation. Early in the pandemic, our group and others observed immune dysregulation persisted into convalescence after acute COVID-19. We subsequently observed persistent immune dysregulation in a cohort of individuals experiencing long COVID. We demonstrated increased SARS-CoV-2-specific CD4+ and CD8+ T-cell responses and antibody affinity in patients experiencing long COVID symptoms. These data suggest a portion of long COVID symptoms may be due to chronic immune activation and the presence of persistent SARS-CoV-2 antigen. This review summarizes the COVID-19 literature to date detailing acute COVID-19 and convalescence and how these observations relate to the development of long COVID. In addition, we discuss recent findings in support of persistent antigen and the evidence that this phenomenon contributes to local and systemic inflammation and the heterogeneous nature of clinical manifestations seen in long COVID.
335	I333		Dhawan, Manish; Rabaan, Ali A.; Alwarthan, Sara; Alhajri, Mashael; Halwani, Muhammad A.; Alshengeti, Amer; Najim, Mustafa A.; Alwashmi, Ameen S. S.; Alshehri, Ahmad A.; Alshamrani, Saleh A.; AlShehail, Bashayer M.; Garout, Mohammed; Al-Abdulhadi, Saleh; Al-Ahmed, Shamsah H.; Thakur, Nanamika; Verma, Geetika	Regulatory T Cells (Tregs) and COVID-19: Unveiling the Mechanisms, and Therapeutic Potentialities with a Special Focus on Long COVID	https://doi.org/10.3390/vaccines11030699	Published	2023-03-01	Review	https://www.mdpi.com/2076-393X/11/3/699	The COVID-19 pandemic has caused havoc all around the world. The causative agent of COVID-19 is the novel form of the coronavirus (CoV) named SARS-CoV-2, which results in immune system disruption, increased inflammation, and acute respiratory distress syndrome (ARDS). T cells have been important components of the immune system, which decide the fate of the COVID-19 disease. Recent studies have reported an important subset of T cells known as regulatory T cells (Tregs), which possess immunosuppressive and immunoregulatory properties and play a crucial role in the prognosis of COVID-19 disease. Recent studies have shown that COVID-19 patients have considerably fewer Tregs than the general population. Such a decrement may have an impact on COVID-19 patients in a number of ways, including diminishing the effect of inflammatory inhibition, creating an inequality in the Treg/Th17 percentage, and raising the chance of respiratory failure. Having fewer Tregs may enhance the likelihood of long COVID development in addition to contributing to the disease’s poor prognosis. Additionally, tissue-resident Tregs provide tissue repair in addition to immunosuppressive and immunoregulatory activities, which may aid in the recovery of COVID-19 patients. The severity of the illness is also linked to abnormalities in the Tregs’ phenotype, such as reduced expression of FoxP3 and other immunosuppressive cytokines, including IL-10 and TGF-beta. Hence, in this review, we summarize the immunosuppressive mechanisms and their possible roles in the prognosis of COVID-19 disease. Furthermore, the perturbations in Tregs have been associated with disease severity. The roles of Tregs are also explained in the long COVID. This review also discusses the potential therapeutic roles of Tregs in the management of patients with COVID-19.
336	I334		Amiama-Roig, Ana; Pérez-Martínez, Laura; Rodríguez Ledo, Pilar; Verdugo-Sivianes, Eva M.; Blanco, José-Ramón	Should We Expect an Increase in the Number of Cancer Cases in People with Long COVID?	https://doi.org/10.3390/microorganisms11030713	Published	2023-03-01	Review	https://www.mdpi.com/2076-2607/11/3/713	The relationship between viral infections and the risk of developing cancer is well known. Multiple mechanisms participate in and determine this process. The COVID-19 pandemic caused by the SARS-CoV-2 virus has resulted in the deaths of millions of people worldwide. Although the effects of COVID-19 are limited for most people, a large number of people continue to show symptoms for a long period of time (long COVID). Several studies have suggested that cancer could also be a potential long-term complication of the virus; however, the causes of this risk are not yet well understood. In this review, we investigated arguments that could support or reject this possibility.
337	I335		Liu, Ziqi; Yin, Ziqiao; Mi, Zhilong; Guo, Binghui	Long-COVID Inducement Mechanism Based on the Path Module Correlation Coefficient	https://doi.org/10.3390/math11061368	Published	2023-01-01	Study	https://www.mdpi.com/2227-7390/11/6/1368	As the number of COVID-19 cases increases, the long-COVID symptoms become the focus of clinical attention. Based on the statistical analysis of long-COVID symptoms in European and Chinese populations, this study proposes the path module correlation coefficient, which can estimate the correlation between two modules in a network, to evaluate the correlation between SARS-CoV-2 infection and long-COVID symptoms, providing a theoretical support for analyzing the frequency of long-COVID symptoms in European and Chinese populations. The path module correlation coefficients between specific COVID-19-related genes in the European and Chinese populations and genes that may induce long-COVID symptoms were calculated. The results showed that the path module correlation coefficients were completely consistent with the frequency of long-COVID symptoms in the Chinese population, but slightly different in the European population. Furthermore, the cathepsin C (CTSC) gene was found to be a potential COVID-19-related gene by a path module correlation coefficient correction rate. Our study can help to explore other long-COVID symptoms that have not yet been discovered and provide a new perspective to research this syndrome. Meanwhile, the path module correlation coefficient correction rate can help to find more species-specific genes related to COVID-19 in the future.
338	I336		Byambasuren, Oyungerel; Stehlik, Paulina; Clark, Justin; Alcorn, Kylie; Glasziou, Paul	Effect of covid-19 vaccination on long covid: systematic review	https://doi.org/10.1136/bmjmed-2022-000385	Published	2023-02-01	Review	https://bmjmedicine.bmj.com/content/2/1/e000385	Objective To determine the effect of covid-19 vaccination, given before and after acute infection with the SARS-CoV-2 virus, or after a diagnosis of long covid, on the rates and symptoms of long covid. Design Systematic review. Data sources PubMed, Embase, and Cochrane covid-19 trials, and Europe PubMed Central (Europe PMC) for preprints, from 1 January 2020 to 3 August 2022. Eligibility criteria for selecting studies Trials, cohort studies, and case-control studies reporting on patients with long covid and symptoms of long covid, with vaccination before and after infection with the SARS-CoV-2 virus, or after a diagnosis of long covid. Risk of bias was assessed with the ROBINS-I tool. Results 1645 articles were screened but no randomised controlled trials were found. 16 observational studies from five countries (USA, UK, France, Italy, and the Netherlands) were identified that reported on 614 392 patients. The most common symptoms of long covid that were studied were fatigue, cough, loss of sense of smell, shortness of breath, loss of taste, headache, muscle ache, difficulty sleeping, difficulty concentrating, worry or anxiety, and memory loss or confusion. 12 studies reported data on vaccination before infection with the SARS-CoV-2 virus, and 10 showed a significant reduction in the incidence of long covid: the odds ratio of developing long covid with one dose of vaccine ranged from 0.22 to 1.03; with two doses, odds ratios were 0.25-1; with three doses, 0.16; and with any dose, 0.48-1.01. Five studies reported on vaccination after infection, with odds ratios of 0.38-0.91. The high heterogeneity between studies precluded any meaningful meta-analysis. The studies failed to adjust for potential confounders, such as other protective behaviours and missing data, thus increasing the risk of bias and decreasing the certainty of evidence to low. Conclusions Current studies suggest that covid-19 vaccines might have protective and therapeutic effects on long covid. More robust comparative observational studies and trials are needed, however, to clearly determine the effectiveness of vaccines in preventing and treating long covid. Protocol registration Open Science Framework https://osf.io/e8jdy.
339	I337		Muri, Jonathan; Cecchinato, Valentina; Cavalli, Andrea; Shanbhag, Akanksha A.; Matkovic, Milos; Biggiogero, Maira; Maida, Pier Andrea; Moritz, Jacques; Toscano, Chiara; Ghovehoud, Elaheh; Furlan, Raffaello; Barbic, Franca; Voza, Antonio; De Nadai, Guendalina; Cervia, Carlo; Zurbuchen, Yves; Taeschler, Patrick; Murray, Lilly A.; Danelon-Sargenti, Gabriela; Moro, Simone; Gong, Tao; Piffaretti, Pietro; Bianchini, Filippo; Crivelli, Virginia; Podešvová, Lucie; Pedotti, Mattia; Jarrossay, David; Sgrignani, Jacopo; Thelen, Sylvia; Uhr, Mario; Bernasconi, Enos; Rauch, Andri; Manzo, Antonio; Ciurea, Adrian; Rocchi, Marco B. L.; Varani, Luca; Moser, Bernhard; Bottazzi, Barbara; Thelen, Marcus; Fallon, Brian A.; Boyman, Onur; Mantovani, Alberto; Garzoni, Christian; Franzetti-Pellanda, Alessandra; Uguccioni, Mariagrazia; Robbiani, Davide F.	Autoantibodies against chemokines post-SARS-CoV-2 infection correlate with disease course	https://doi.org/10.1038/s41590-023-01445-w	Published	2023-03-06	Study	https://www.nature.com/articles/s41590-023-01445-w	Infection with severe acute respiratory syndrome coronavirus 2 associates with diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse coronavirus disease 2019 (COVID-19) outcomes. Here we discovered that antibodies against specific chemokines were omnipresent post-COVID-19, were associated with favorable disease outcome and negatively correlated with the development of long COVID at 1 yr post-infection. Chemokine antibodies were also present in HIV-1 infection and autoimmune disorders, but they targeted different chemokines compared with COVID-19. Monoclonal antibodies derived from COVID-19 convalescents that bound to the chemokine N-loop impaired cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising chemokine antibodies may modulate the inflammatory response and thus bear therapeutic potential.
340	I338		Horne, Benjamin Davies; Knowlton, Kirk U.; Le, Viet T.; Bair, Tami L.; May, Heidi Thomas; Knight, Stacey; Anderson, Jeffrey L.	Is exposure to epstein-barr virus a risk factor for long-covid?	https://doi.org/10.1016/S0735-1097(23)02228-3	Published	2023-03-07	Study	https://www.jacc.org/doi/full/10.1016/S0735-1097%2823%2902228-3	Background A viral etiology to chronic fatigue syndrome (CFS) has long been postulated, and Epstein-Barr Virus (EBV) was the first CFSassociated virus. CFS and Long-COVID share features, potentially implicating a similar etiology. This study evaluated if EBV exposure is associated with post-COVID syndrome (Long-COVID). Methods Intermountain Healthcare electronic health records were queried to identify patients diagnosed with COVID-19 and tested for EBV between March 6, 2020 and April 13, 2022. A subsequent diagnosis of Long-COVID (ICD-10 U09.9) was evaluated using survival methods. Results Overall, 296,959 patients had COVID-19 and 590 had concurrent EBV test results [207 (35.1%) were EBV positive]. Subjects averaged 27.4±18.4 years of age (range: 0-86); 57.6% were female. Hospitalization occurred in 61 subjects (10.3%) within 30 days of COVID-19 diagnosis, with 17 (2.9%) requiring intensive care. Long-COVID was found in 29 (4.9%) subjects (just 10 were among the 61 hospitalized for COVID-19), with 15 (7.2%) EBV positive (Figure) and 14 (3.7%) EBV negative (HR=2.09, 95% CI=1.01, 4.34; p=0.042). EBV risk remained in multivariable analyses. Race, hyperlipidemia, and tobacco use also predicted Long-COVID, with histories of anticoagulant and vitamin D use were protective. Conclusion In a large prospectively-collected registry, EBV positivity was associated with an elevated risk of Long-COVID. This suggests that EBV may be a predisposing risk factor for or co-precipitant of Long-COVID. publisher: American College of Cardiology Foundation
341	I339		Abu Hamdh, Bayan; Nazzal, Zaher	A prospective cohort study assessing the relationship between long-COVID symptom incidence in COVID-19 patients and COVID-19 vaccination	https://doi.org/10.1038/s41598-023-30583-2	Published	2023-03-25	Study	https://www.nature.com/articles/s41598-023-30583-2	Current studies about the long-term effects of COVID-19 show a wide range of symptoms. This prospective cohort study aimed to find the incidence of long-COVID symptoms and the associated risk factors. We followed 669 confirmed COVID-19 patients. Sociodemographic and clinical data were extracted from medical records and collected via semi-structured telephone interviews on days 10, 30, 60, and 90. The incidence of long-COVID symptoms was 41.6% (95% CI 37.8–45.4%). Females [aOR = 1.5 (95% CI 1.1–2.3)], the elderly [aOR = 4.9 (95% CI 2.0–11.3)], and those who required hospitalization [aOR = 5.0 (95% CI 1.3–3.7)] were at a higher risk of developing long-COVID. Patients with dyspnea at day 10 [aOR: 2.4 (95% CI 1.6–3.7] and fatigue at day 60 [aOR: 3.1 (95% CI 1.5–6.3] were also at risk. While non-vaccinated patients were almost seven times more likely to report long-COVID symptoms than vaccinated patients [aOR: 6.9 (95% CI 4.2–11.3)]. In conclusion, long-COVID was common among COVID-19 patients, with higher rates among females, older age groups, hospitalized patients, and those with dyspnea and fatigue, while vaccination provided protection. Interventions should educate health professionals, raise general public awareness about the risks and consequences of Long COVID, and the value of vaccination.
342	I340		Ceban, Felicia; Kulzhabayeva, Dana; Rodrigues, Nelson B.; Di Vincenzo, Joshua D.; Gill, Hartej; Subramaniapillai, Mehala; Lui, Leanna M. W.; Cao, Bing; Mansur, Rodrigo B.; Ho, Roger C.; Burke, Matthew J.; Rhee, Taeho Greg; Rosenblat, Joshua D.; McIntyre, Roger S.	COVID-19 Vaccination for the Prevention and Treatment of Long COVID: A Systematic Review and Meta-analysis	https://doi.org/10.1016/j.bbi.2023.03.022	Published	2023-03-27	Systematic review and meta-analysis	https://www.sciencedirect.com/science/article/pii/S088915912300079X	Highlights •At least one dose of a SARS-CoV-2 vaccine was associated with a protective effect against long COVID. •Long COVID trajectory following vaccination was mixed, with most patients reporting no changes. •Evidence supports SARS-CoV-2 vaccination for the prevention of long COVID. Abstract Empirical evidence addressing the association between SARS-CoV-2 vaccination and long COVID would guide public health priorities and inform personal health decisions. Herein, the co-primary objectives are to determine the differential risk of long COVID in vaccinated versus unvaccinated patients, and the trajectory of long COVID following vaccination. Of 2775 articles identified via systematic search, 17 were included, and 6 were meta-analyzed. Meta-analytic results determined that at least one vaccine dose was associated with a protective effect against long COVID (OR 0.539, 95% CI 0.295-0.987, p = 0.045, N= 257 817). Qualitative analysis revealed that trajectories of pre-existing long COVID following vaccination were mixed, with most patients reporting no changes. The evidence herein supports SARS-CoV-2 vaccination for the prevention of long COVID, and recommends long COVID patients adhere to standard SARS-CoV-2 vaccination schedules.
343	I341		Xie, Yan; Choi, Taeyoung; Al-Aly, Ziyad	Association of Treatment With Nirmatrelvir and the Risk of Post–COVID-19 Condition	https://doi.org/10.1001/jamainternmed.2023.0743	Published	2023-03-23	Study	https://doi.org/10.1001/jamainternmed.2023.0743	Key Points Question Is treatment with nirmatrelvir in the acute phase of SARS-CoV-2 infection associated with a lower risk of post–COVID-19 condition (PCC)? Findings In this cohort study of 281 793 people with SARS-CoV-2 infection who had at least 1 risk factor for progression to severe COVID-19 illness, compared with 246 076 who had no treatment, nirmatrelvir use in the acute phase (n = 35 717) was associated with reduced risk of PCC, including reduced risk of 10 of 13 post–acute sequelae in various organ systems, as well as reduced risk of post–acute death and post–acute hospitalization. Nirmatrelvir was associated with reduced risk of PCC in people who were unvaccinated, vaccinated, and boosted, and in people with primary SARS-CoV-2 infection and reinfection. Meaning In people with SARS-CoV-2 infection and at least 1 risk factor for progression to severe COVID-19 illness, treatment with nirmatrelvir during the acute phase of COVID-19 was associated with reduced risk of PCC. Abstract Importance Post–COVID-19 condition (PCC), also known as long COVID, affects many individuals. Prevention of PCC is an urgent public health priority. Objective To examine whether treatment with nirmatrelvir in the acute phase of COVID-19 is associated with reduced risk of PCC. Design, Setting, and Participants This cohort study used the health care databases of the US Department of Veterans Affairs (VA) to identify patients who had a SARS-CoV-2 positive test result between January 3, 2022, and December 31, 2022, who were not hospitalized on the day of the positive test result, who had at least 1 risk factor for progression to severe COVID-19 illness, and who had survived the first 30 days after SARS-CoV-2 diagnosis. Those who were treated with oral nirmatrelvir within 5 days after the positive test (n = 35 717) and those who received no COVID-19 antiviral or antibody treatment during the acute phase of SARS-CoV-2 infection (control group, n = 246 076) were identified. Exposures Treatment with nirmatrelvir or receipt of no COVID-19 antiviral or antibody treatment based on prescription records. Main Outcomes and Measures Inverse probability weighted survival models were used to estimate the association of nirmatrelvir (vs control) with post–acute death, post–acute hospitalization, and a prespecified panel of 13 post–acute COVID-19 sequelae (components of PCC) and reported in relative scale as relative risk (RR) or hazard ratio (HR) and in absolute scale as absolute risk reduction in percentage at 180 days (ARR). Results A total of 281 793 patients (mean [SD] age, 61.99 [14.96]; 242 383 [86.01%] male) who had a positive SARS-CoV-2 test result and had at least 1 risk factor for progression to severe COVID-19 illness were studied. Among them, 246 076 received no COVID-19 antiviral or antibody treatment during the acute phase of SARS-CoV-2 infection, and 35 717 received oral nirmatrelvir within 5 days after the positive SARS-CoV-2 test result. Compared with the control group, nirmatrelvir was associated with reduced risk of PCC (RR, 0.74; 95% CI, 0.72-0.77; ARR, 4.51%; 95% CI, 4.01-4.99), including reduced risk of 10 of 13 post–acute sequelae (components of PCC) in the cardiovascular system (dysrhythmia and ischemic heart disease), coagulation and hematologic disorders (pulmonary embolism and deep vein thrombosis), fatigue and malaise, acute kidney disease, muscle pain, neurologic system (neurocognitive impairment and dysautonomia), and shortness of breath. Nirmatrelvir was also associated with reduced risk of post–acute death (HR, 0.53; 95% CI, 0.46-0.61); ARR, 0.65%; 95% CI, 0.54-0.77), and post–acute hospitalization (HR, 0.76; 95% CI, 0.73-0.80; ARR, 1.72%; 95% CI, 1.42-2.01). Nirmatrelvir was associated with reduced risk of PCC in people who were unvaccinated, vaccinated, and boosted, and in people with primary SARS-CoV-2 infection and reinfection. Conclusions and Relevance This cohort study found that in people with SARS-CoV-2 infection who had at least 1 risk factor for progression to severe disease, treatment with nirmatrelvir within 5 days of a positive SARS-CoV-2 test result was associated with reduced risk of PCC across the risk spectrum in this cohort and regardless of vaccination status and history of prior infection; the totality of findings suggests that treatment with nirmatrelvir during the acute phase of COVID-19 may reduce the risk of post–acute adverse health outcomes.
344	I342		Kurian, Shilia Jacob; Mathews, Sara Poikayil; Paul, Abin; Viswam, Subeesh K.; Nagri, Shivashankara Kaniyoor; Miraj, Sonal Sekhar; Karanth, Shubhada	Association of serum ferritin with severity and clinical outcome in COVID-19 patients: An observational study in a tertiary healthcare facility	https://doi.org/10.1016/j.cegh.2023.101295	Published	2023-05-01	Study	https://cegh.net/article/S2213-3984(23)00082-9/fulltext	Highlights •Evidence show hyperferritinemia has been associated with higher disease severity and adverse clinical outcomes in COVID-19. •Median ferritin levels were significantly high in moderate to severe COVID-19 infection compared to mild infection. •Median ferritin levels were notably high in patients with COVID-19-related complications than those without complications. • Patients with more than 287.4 ng/ml ferritin value have greater chances of developing moderate to severe COVID-19 infections. Abstract Background Ferritin, an intracellular protein, has a pivotal role in immune dysregulation. Hyperferritinemia has been associated with higher disease severity and adverse clinical outcomes in COVID-19, including mortality. We aimed to study the association of serum ferritin levels with disease severity and clinical outcomes and its severity prediction potential in COVID-19 patients. Methods This retrospective study included 870 adult patients with symptomatic COVID-19 infection hospitalized between July 1, 2020 to December 21, 2020. All the patients had a positive polymerase chain reaction test result of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Results The median age was 55 (IQR:40, 65) years with a male predominance [66.32% (n = 577)], among 870 COVID-19. Of these, 413 (47.47%) had mild COVID-19, and 457 (52.53%) had moderate plus severe COVID-19 disease. Median ferritin levels were significantly high in moderate to severe COVID-19 infection compared to mild [545.8 (326.0, 1046.0) vs 97.3 (52.65–155.5) (p = 0.001)], and in patients who developed a complication compared to without complications [380 (177.05, 863.15) vs 290 (110.9, 635) (p = 0.002). A slight elevation in median ferritin levels was observed in patients who had an ICU stay than non-ICU [326 (129.8, 655) vs 309 (119.1, 684) (p = 0.872)]. The cut-off for ferritin was identified at >287.4 ng/ml for mild versus moderate plus severe COVID-19 infections. Conclusion Moderate to severe COVID-19 patients have elevated ferritin levels. Patients with more than 287.4 ng/ml ferritin value would have greater chances of developing moderate to severe COVID-19 infections. publisher: Elsevier PMID: 37012977
345	I343		Santa Cruz, André; Mendes-Frias, Ana; Azarias-da-Silva, Marne; André, Sónia; Oliveira, Ana Isabel; Pires, Olga; Mendes, Marta; Oliveira, Bárbara; Braga, Marta; Lopes, Joana Rita; Domingues, Rui; Costa, Ricardo; Silva, Luís Neves; Matos, Ana Rita; Ângela, Cristina; Costa, Patrício; Carvalho, Alexandre; Capela, Carlos; Pedrosa, Jorge; Castro, António Gil; Estaquier, Jérôme; Silvestre, Ricardo	Post-acute sequelae of COVID-19 is characterized by diminished peripheral CD8+β7 integrin+ T cells and anti-SARS-CoV-2 IgA response	https://doi.org/10.1038/s41467-023-37368-1	Published	2023-03-30	Study	https://www.nature.com/articles/s41467-023-37368-1	Several millions of individuals are estimated to develop post-acute sequelae SARS-CoV-2 condition (PASC) that persists for months after infection. Here we evaluate the immune response in convalescent individuals with PASC compared to convalescent asymptomatic and uninfected participants, six months following their COVID-19 diagnosis. Both convalescent asymptomatic and PASC cases are characterised by higher CD8+ T cell percentages, however, the proportion of blood CD8+ T cells expressing the mucosal homing receptor β7 is low in PASC patients. CD8 T cells show increased expression of PD-1, perforin and granzyme B in PASC, and the plasma levels of type I and type III (mucosal) interferons are elevated. The humoral response is characterized by higher levels of IgA against the N and S viral proteins, particularly in those individuals who had severe acute disease. Our results also show that consistently elevated levels of IL-6, IL-8/CXCL8 and IP-10/CXCL10 during acute disease increase the risk to develop PASC. In summary, our study indicates that PASC is defined by persisting immunological dysfunction as late as six months following SARS-CoV-2 infection, including alterations in mucosal immune parameters, redistribution of mucosal CD8+β7Integrin+ T cells and IgA, indicative of potential viral persistence and mucosal involvement in the etiopathology of PASC.
346	I344		Fedorchenko, Yuliya; Zimba, Olena	Long COVID in autoimmune rheumatic diseases	https://doi.org/10.1007/s00296-023-05319-0	Published	2023-03-30	Review	https://doi.org/10.1007/s00296-023-05319-0	Consequences of Corona Virus Disease-19 (COVID-19) in patients with rheumatic diseases (RDs) are clinically diverse. SARS-CoV-2 infection has been associated with various autoimmune and rheumatic manifestations over the past three years. Emerging evidence points to the possibility of Long COVID predisposition in rheumatic patients due to the changes in immune regulatory response. The aim of this article was to overview data on the pathobiology of Long COVID in patients with RDs. Related risk factors, clinical characteristics, and prognosis of Long COVID in RDs were analyzed. Relevant articles were retrieved from Medline/PubMed, Scopus, and Directory of Open Access Journals (DOAJ). Diverse mechanisms of viral persistence, chronic low-grade inflammation, lasting production of autoantibodies, endotheliopathy, vascular complications, and permanent tissue damage have been described in association with Long COVID. Patients with RDs who survive COVID-19 often experience severe complications due to the immune disbalance resulting in multiple organ damage. Regular monitoring and treatment are warranted in view of the accumulating evidence.
347	I345		Hulme, John	COVID-19 and Diarylamidines: The Parasitic Connection	https://doi.org/10.3390/ijms24076583	Published	2023-01-01	Review	https://www.mdpi.com/1422-0067/24/7/6583	As emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants (Omicron) continue to outpace and negate combinatorial vaccines and monoclonal antibody therapies targeting the spike protein (S) receptor binding domain (RBD), the appetite for developing similar COVID-19 treatments has significantly diminished, with the attention of the scientific community switching to long COVID treatments. However, treatments that reduce the risk of “post-COVID-19 syndrome” and associated sequelae remain in their infancy, particularly as no established criteria for diagnosis currently exist. Thus, alternative therapies that reduce infection and prevent the broad range of symptoms associated with ‘post-COVID-19 syndrome’ require investigation. This review begins with an overview of the parasitic–diarylamidine connection, followed by the renin-angiotensin system (RAS) and associated angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSSR2) involved in SARS-CoV-2 infection. Subsequently, the ability of diarylamidines to inhibit S-protein binding and various membrane serine proteases associated with SARS-CoV-2 and parasitic infections are discussed. Finally, the roles of diarylamidines (primarily DIZE) in vaccine efficacy, epigenetics, and the potential amelioration of long COVID sequelae are highlighted.
348	I346		Sumantri, Stevent; Rengganis, Iris	Immunological dysfunction and mast cell activation syndrome in long COVID	https://doi.org/10.5415/apallergy.0000000000000022	Published	2023-03-01	Review	https://journals.lww.com/apallergy/Fulltext/2023/03000/Immunological_dysfunction_and_mast_cell_activation.8.aspx	At least 65 million people around the world suffer from long COVID-19, with the majority of cases occurring in the productive age (36–50 years old). Individuals with long COVID-19 are confounded with multiple organ system dysfunctions, long-term organ injury sequelae, and a decreased quality of life. There is an overlapping of risk factors between long COVID-19 and other postviral infection syndromes, so advances in research could also benefit other groups of patients. Long COVID-19 is the consequence of multiple immune system dysregulation, such as T-cell depletion, innate immune cell hyperactivity, lack of naive T and B cells, and elevated signature of pro-inflammatory cytokines, together with persistent severe acute respiratory syndrome-coronavirus 2 reservoir and other consequences of acute infection. There is an activated condition of mast cells in long COVID-19, with abnormal granulation and excessive inflammatory cytokine release. A study by Weinstock et al. indicates that patients with long COVID-19 suffer the same clinical syndrome as patients with mast cell activation syndrome (MCAS). Diagnosis and treatment of MCAS in patients with long COVID-19 will provide further symptomatic relief, and manage mast cell-mediated hyperinflammation states, which could be useful in the long-term control and recovery of such patients.
349	I347		Savchenko, Andrei A.; Kudryavtsev, Igor V.; Isakov, Dmitry V.; Sadowski, Ivan S.; Belenyuk, Vasily D.; Borisov, Alexandr G.	Recombinant Human Interleukin-2 Corrects NK Cell Phenotype and Functional Activity in Patients with Post-COVID Syndrome	https://doi.org/10.3390/ph16040537	Published	2023-04-01	Study	https://www.mdpi.com/1424-8247/16/4/537	Post-COVID syndrome develops in 10–20% of people who have recovered from COVID-19 and it is characterized by impaired function of the nervous, cardiovascular, and immune systems. Previously, it was found that patients who recovered from infection with the SARS-CoV-2 virus had a decrease in the number and functional activity of NK cells. The aim of the study was to assess the effectiveness of recombinant human IL-2 (rhIL-2) administered to correct NK cell phenotype and functional activity in patients with post-COVID syndrome. Patients were examined after 3 months for acute COVID-19 of varying severity. The phenotype of the peripheral blood NK cells was studied by flow cytometry. It was found that disturbances in the cell subset composition in patients with post-COVID syndrome were characterized by low levels of mature (p = 0.001) and cytotoxic NK cells (p = 0.013), with increased release of immature NK cells (p = 0.023). Functional deficiency of NK cells in post-COVID syndrome was characterized by lowered cytotoxic activity due to the decreased count of CD57+ (p = 0.001) and CD8+ (p < 0.001) NK cells. In the treatment of patients with post-COVID syndrome with recombinant IL-2, peripheral blood NK cell count and functional potential were restored. In general, the effectiveness of using rhIL-2 in treatment of post-COVID syndrome has been proven in patients with low levels of NK cells.
350	I348		Tannous, Jonika; Pan, Alan P.; Potter, Thomas; Bako, Abdulaziz T.; Dlouhy, Katharine; Drews, Ashley; Sostman, Henry Dirk; Vahidy, Farhaan S.	Real-world effectiveness of COVID-19 vaccines and anti-SARS-CoV-2 monoclonal antibodies against postacute sequelae of SARS-CoV-2: analysis of a COVID-19 observational registry for a diverse US metropolitan population	https://doi.org/10.1136/bmjopen-2022-067611	Published	2023-04-01	Study	https://bmjopen.bmj.com/content/13/4/e067611	Objectives We evaluated the effectiveness of COVID-19 vaccines and monoclonal antibodies (mAbs) against postacute sequelae of SARS-CoV-2 infection (PASC). Design and setting A retrospective cohort study using a COVID-19 specific, electronic medical record-based surveillance and outcomes registry from an eight-hospital tertiary hospital system in the Houston metropolitan area. Analyses were replicated across a global research network database. Participants We identified adult (≥18) patients with PASC. PASC was defined as experiencing constitutional (palpitations, malaise/fatigue, headache) or systemic (sleep disorder, shortness of breath, mood/anxiety disorders, cough and cognitive impairment) symptoms beyond the 28-day postinfection period. Statistical analysis We fit multivariable logistic regression models and report estimated likelihood of PASC associated with vaccination or mAb treatment as adjusted ORs with 95% CIs. Results Primary analyses included 53 239 subjects (54.9% female), of whom 5929, 11.1% (95% CI 10.9% to 11.4%), experienced PASC. Both vaccinated breakthrough cases (vs unvaccinated) and mAb-treated patients (vs untreated) had lower likelihoods for developing PASC, aOR (95% CI): 0.58 (0.52–0.66), and 0.77 (0.69–0.86), respectively. Vaccination was associated with decreased odds of developing all constitutional and systemic symptoms except for taste and smell changes. For all symptoms, vaccination was associated with lower likelihood of experiencing PASC compared with mAb treatment. Replication analysis found identical frequency of PASC (11.2%, 95% CI 11.1 to 11.3) and similar protective effects against PASC for the COVID-19 vaccine: 0.25 (0.21–0.30) and mAb treatment: 0.62 (0.59–0.66). Conclusion Although both COVID-19 vaccines and mAbs decreased the likelihood of PASC, vaccination remains the most effective tool for the prevention of long-term consequences of COVID-19.
351	I349		Hansen, Cecilie Bo; Dvoncova, Kristina; Pérez-Alós, Laura; Fogh, Kamille; Madsen, Johannes Roth; Garred, Caroline Hartwell; Jarlhelt, Ida; Nielsen, Pernille Brok; Petersen, Steffan Svejgaard; Fjordager, Charlotte Gandsø; Lauritsen, Klara Tølbøll; Hilsted, Linda; Boding, Lasse; Iversen, Kasper Karmark; Hyveled, Liselotte; Garred, Peter	SARS-CoV-2 antibody dynamics over time and risk factors associated with infection and long COVID-19 symptoms in large working environments	https://doi.org/10.1111/joim.13637	Published	2023-04-01	Study	https://doi.org/10.1111/joim.13637	BackgroundFactors influencing SARS-CoV-2 antibody dynamics, transmission, waning and long COVID-19 symptomatology are still not fully understood.MethodsIn the Danish section of the Novo Nordisk Group, we performed a prospective seroepidemiological study during the first and second waves of the COVID-19 pandemic. All employees and their household members (>18 years) were invited to participate in a baseline (June-August 2020), 6-month follow-up (December 2020-January 2021), and 12-month follow-up (August 2021) sampling. In total, 18,614 accepted and provided at least one blood sample and completed a questionnaire regarding socioeconomic background, health status, previous SARS-CoV-2 infection, and persistent symptoms. Total antibody and specific IgM, IgG and IgA levels against recombinant receptor binding domain were tested.ResultsAt baseline, the SARS-CoV-2-antibody seroprevalence was 3.9%. At 6-month follow-up, the seroprevalence was 9.1%, while at 12-month follow-up, the seroprevalence was 94.4% (after the vaccine roll-out). Male sex and younger age (18-40 years) were significant risk factors for seropositivity. From baseline to the 6-month sampling, we observed a substantial waning of IgM, IgG and IgA levels (p ConclusionThe study provides a comprehensive insight into SARS-CoV-2 antibody seroprevalence following infection and vaccination, waning, persistent COVID-19 symptomatology and risk factors for seropositivity in large working environments.
352	I350		Sen, Parikshit; R, Naveen; Nune, Arvind; Day, Jessica; Joshi, Mrudula; Agarwal, Vikas; Aggarwal, Rohit; Gupta, Latika	Post-COVID-19 condition in patients with autoimmune rheumatic diseases: the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study	https://doi.org/10.1016/S2665-9913(23)00066-8	Published	2023-05-01	Study	https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(23)00066-8/fulltext	Literature regarding post-COVID-19 condition in patients with autoimmune rheumatic diseases is scarce. One large, global study reported that post-COVID-19 condition developed in nearly one in ten people with systemic autoimmune rheumatic diseases and outlined the demographics of individuals with post-COVID-19 condition.6 Regional database studies have reported that belonging to a minority ethnic group, including Black and Hispanic, is a risk factor for post-COVID-19 condition—a finding that we could not replicate in our data. The presence of comorbidities has been more consistently identified as a risk factor for the condition in published reports.7, 8 Notably, in our analysis, patients with severe COVID-19 who required oxygen supplementation, intensive care, or advanced treatment appeared to be at higher risk of developing post-COVID-19 condition than patients who did not, which is consistent with data from a single-centre study.9 Our finding of poorer physical health outcomes in individuals who develop the condition further aligns with previous studies on long-term outcomes of COVID-19 (eg 10). Our study is one of few to study risk factors for post-COVID-19 condition in patients with diverse rheumatic and non-rheumatic autoimmune diseases, including patients from understudied regions of Africa and South America. A strength of the study was the relatively high rate of completion of the survey (62%). The study also had limitations, including the self-reported nature of the questionnaire, which could result in recall and reporting bias, and underrepresentation of some groups because of convenience sampling. However, we have tried to minimise these limitations through the inclusion of patients from the outpatient clinics, the inclusion of control groups, and the analysis of stratified subsets. We did not confirm SARS-CoV-2 serology or vaccine immunogenicity, nor did we explore the full symptomatology, severity, and the duration of post-COVID-19 condition, which might be an avenue for future exploration. Given the limitations of screening for the condition with the WHO definition, caution is warranted in deriving strong conclusions in the absence of more well accepted diagnostic criteria. We studied risk factors for post-COVID-19 condition in a relatively small subgroup of patients with autoimmune rheumatic diseases, and additional characterisation of the condition and its risk factors in the general population is needed in larger-structured cohorts. Our study provides information on risk factors for post-COVID-19 condition that might help to inform local guidelines. We found that individuals with autoimmune rheumatic diseases are at greater risk of developing post-COVID-19 condition than are healthy individuals. Associated comorbid conditions and advanced treatment or admission to an intensive care unit for severe COVID-19 confer a heightened risk of post-COVID-19 condition. Referring people with autoimmune rheumatic diseases and a recent SARS-CoV-2 infection for post-exposure treatment in a timely way is imperative, particularly in the presence of the identified risk factors, to facilitate close monitoring and multidisciplinary management in anticipation of poorer physical and mental outcomes. publisher: Elsevier
353	I351		Jarupan, Muttharat; Jantarabenjakul, Watsamon; Jaruampornpan, Peera; Subchartanan, Jarujan; Phasomsap, Chayapa; Sritammasiri, Taweesak; Cartledge, Sapphire; Suchartlikitwong, Pintip; Anugulruengkitt, Suvaporn; Kawichai, Surinda; Puthanakit, Thanyawee	Long COVID and Hybrid Immunity among Children and Adolescents Post-Delta Variant Infection in Thailand	https://doi.org/10.3390/vaccines11050884	Published	2023-05-01	Study	https://www.mdpi.com/2076-393X/11/5/884	This study aimed to assess long COVID, and describe immunogenicity against Omicron variants following BNT162b2 vaccination. A prospective cohort study was conducted among children (aged 5–11) and adolescents (aged 12–17) who had SARS-CoV-2 infection from July to December 2021 (Delta predominant period). Long COVID symptoms were assessed by questionnaires at 3 months after infection. Immunogenicity was evaluated by using a surrogate virus-neutralizing antibody test (sVNT) against the Omicron variant. We enrolled 97 children and 57 adolescents. At 3 months, 30 children (31%) and 34 adolescents (60%) reported at least one long COVID symptom, with respiratory symptoms prevailing (25% children and 32% adolescents). The median time from infection to vaccination was 3 months in adolescents and 7 months in children. At 1 month following vaccination, in children who received one-dose and two-dose BNT162b2 vaccines, the median (IQR) sVNT against Omicron was 86.2% inhibition (71.1–91.8) and 79.2% inhibition (61.5–88.9), respectively (p = 0.26). Among adolescents who received one-dose and two-dose BNT162b2 vaccines, the median (IQR) sVNT against Omicron was 64.4% inhibition (46.8–88.8) and 68.8% inhibition (65.0–91.2) (p = 0.64). Adolescents had a higher prevalence of long COVID than children. Immunogenicity against the Omicron variant after vaccination was high and did not vary between one or two doses of the vaccine in either children or adolescents.
354	I352		Price, Jillian Kallman; Gerber, Lynn H.; Stepanova, Maria; Avila, Leyla de; Weinstein, Ali A.; Pham, Huong; Nader, Fatema; Afendy, Mariam; Terra, Kathy; Austin, Patrick; Keo, Wisna’odom; Racila, Andrei; Estep, James Michael; Gerber, Suzannah; Verma, Manisha; Golabi, Pegah; Lam, Brian P.; Younossi, Zobair	Post-Acute SARS-CoV-2 Symptoms are Fewer, Less Intense Over Time in People Treated with Mono-Clonal Antibodies for Acute Infection	https://doi.org/10.2147/IJGM.S406571	Published	2023-04-24	Study	https://www.dovepress.com/post-acute-sars-cov-2-symptoms-are-fewer-less-intense-over-time-in-peo-peer-reviewed-fulltext-article-IJGM	Introduction: Many with post-acute SARS-CoV-2 (PASC) have persistent symptoms impacting physical and cognitive function, decreased health and health-related life quality. Monoclonal antibody (mAb) treatment was available to acutely infected patients which might improve these outcomes. Purpose: To compare patient perception of PASC symptoms for those receiving bamlanivimab or casirivimab and imdevimab (mAbs) to those not receiving this treatment (non-mAbs). To compare changes between these groups in symptoms, function and quality of life over a 6-month follow-up. Patients and Methods: Consented adults > 28 days post-infection with positive SARS-CoV-2 qPCR or antigen test and SARS-CoV-2 infection between March of 2020 and July of 2022 were enrolled. This prospective, repeated measure observational study reports baseline through 6-month follow-up. Extensive sociodemographic data, detailed medical history, COVID-19 symptom history, and standardized measures of well-being, depression, anxiety, stigma, cognition, symptom assessment, distress, and health status were collected. Results: 323 participants [101 mAb, 221 non-mAb, 52.7± 15.5 years, 47.7% male, body mass index (BMI) 31.4± 8.4] were analyzed. Fewer symptoms at baseline were reported in mAb versus non-mAb participants (1.06± 1.31 vs 1.78± 2.15, respectively p=0.0177) 6 months: (0.911± 1.276 mAb vs.1.75± 2.22 non-mAb, p=0.0427). Both groups showed significant within-group decreases in symptom number (52 to 21 mAb, 126 to 63 non-mAb) and symptom burden (p=0.0088 mAb, p< 0.00001 non-mAb). mAb patients had significantly shorter infection-to-baseline interval (days) (120.4± 55.3 mAb vs 194.0± 89.3 non-mAb, p< 0.00001); less frequent history of myocardial infarction (0.0 vs 3.9%, p=0.0464); headache (2.0% vs.11.8%, p=0.0046), rash (3.1% vs 9.9%, p=0.0377), and miscellaneous muscle complaints (2.0% vs 12.3%, p=0.0035), plus significantly better 6-month mood. (2.2% vs 13.2%, p=0.0390). Conclusion: mAb treated participants had reduced symptom burden and consistently reported fewer symptoms than non-mAb at all time points despite less time since acute illness. Both groups reported a statistically significant decrease in symptoms by 6-month visit with no statistically significant differences between them at follow-up. publisher: Dove Press
355	I353		Yin, Jing-Xian; Agbana, Yannick Luther; Sun, Zhi-Shan; Fei, Si-Wei; Zhao, Han-Qing; Zhou, Xiao-Nong; Chen, Jun-Hu; Kassegne, Kokouvi	Increased interleukin-6 is associated with long COVID-19: a systematic review and meta-analysis	https://doi.org/10.1186/s40249-023-01086-z	Published	2023-04-24	Review	https://doi.org/10.1186/s40249-023-01086-z	Background Coronavirus disease 2019 (COVID-19) can involve persistence, sequelae, and other clinical complications that last weeks to months to evolve into long COVID-19. Exploratory studies have suggested that interleukin-6 (IL-6) is related to COVID-19; however, the correlation between IL-6 and long COVID-19 is unknown. We designed a systematic review and meta-analysis to assess the relationship between IL-6 levels and long COVID-19. Methods Databases were systematically searched for articles with data on long COVID-19 and IL-6 levels published before September 2022. A total of 22 published studies were eligible for inclusion following the PRISMA guidelines. Analysis of data was undertaken by using Cochran's Q test and the Higgins I-squared (I2) statistic for heterogeneity. Random-effect meta-analyses were conducted to pool the IL-6 levels of long COVID-19 patients and to compare the differences in IL-6 levels among the long COVID-19, healthy, non-postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (non-PASC), and acute COVID-19 populations. The funnel plot and Egger's test were used to assess potential publication bias. Sensitivity analysis was used to test the stability of the results. Results An increase in IL-6 levels was observed after SARS-CoV-2 infection. The pooled estimate of IL-6 revealed a mean value of 20.92 pg/ml (95% CI = 9.30–32.54 pg/ml, I2 = 100%, P < 0.01) for long COVID-19 patients. The forest plot showed high levels of IL-6 for long COVID-19 compared with healthy controls (mean difference = 9.75 pg/ml, 95% CI = 5.75–13.75 pg/ml, I2 = 100%, P < 0.00001) and PASC category (mean difference = 3.32 pg/ml, 95% CI = 0.22–6.42 pg/ml, I2 = 88%, P = 0.04). The symmetry of the funnel plots was not obvious, and Egger’s test showed that there was no significant small study effect in all groups. Conclusions This study showed that increased IL-6 correlates with long COVID-19. Such an informative revelation suggests IL-6 as a basic determinant to predict long COVID-19 or at least inform on the “early stage” of long COVID-19.
356	I354		Chen, Yi-Chen; Ho, Chung-Han; Liu, Ting-Hui; Wu, Jheng-Yan; Huang, Po-Yu; Tsai, Ya-Wen; Lai, Chih-Cheng	Long-term risk of herpes zoster following COVID-19: A retrospective cohort study of 2 442 686 patients	https://doi.org/10.1002/jmv.28745	Published	2023-04-18	Study	https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.28745	The long-term risk of herpes zoster (HZ) after recovery from a SARS-CoV-2 infection is unclear. This retrospective cohort study assessed the risk of HZ in patients following a COVID-19 diagnosis. This retrospective, propensity score-matched cohort study was based on the multi-institutional research network TriNetX. The risk of incident HZ in patients with COVID-19 was compared with that of those not infected with SARS-CoV-2 during a 1-year follow-up period. Hazard ratios (HRs) and 95% confidence intervals (CIs) of HZ and its subtypes were calculated. This study identified 1 221 343 patients with and without COVID-19 diagnoses with matched baseline characteristics. During the 1-year follow-up period, patients with COVID-19 had a higher risk of HZ compared with those without COVID-19 (HR: 1.59; 95% CI: 1.49–1.69). In addition, compared with the control group patients, those with COVID-19 had a higher risk of HZ ophthalmicus (HR: 1.31; 95% CI: 1.01–1.71), disseminated zoster (HR: 2.80; 95% CI: 1.37–5.74), zoster with other complications (HR: 1.46; 95% CI: 1.18–1.79), and zoster without complications (HR: 1.66; 95% CI: 1.55–1.77). Kaplan–Meier curve analysis (log-rank p < 0.05) results indicated that the risk of HZ remained significantly higher in patients with COVID-19 compared with those without COVID-19. Finally, the higher risk of HZ in the COVID-19 cohort compared with that in the non-COVID-19 cohort remained consistent across subgroup analyses regardless of vaccine status, age, or sex. The risk of HZ within a 12-month follow-up period was significantly higher in patients who had recovered from COVID-19 compared with that in the control group. This result highlights the importance of carefully monitoring HZ in this population and suggests the potential benefit of the HZ vaccine for patients with COVID-19.
357	I355		Basaran, M. Mert; Hazar, Merve; Aydın, Mehtap; Uzuğ, Gülsüm; Özdoğan, İlkima; Pala, Emin; Aydın Dilsiz, Sevtap; Basaran, Nursen	Effects of COVID-19 Disease on DNA Damage, Oxidative Stress and Immune Responses	https://doi.org/10.3390/toxics11040386	Published	2023-04-01	Study	https://www.mdpi.com/2305-6304/11/4/386	Coronavirus disease 2019 (COVID-19) has posed a great threat to public health and has caused concern due to its fatal consequences over the last few years. Most people with COVID-19 show mild-to-moderate symptoms and recover without the need for special treatment, while others become seriously ill and need medical attention. Additionally, some serious outcomes, such as heart attacks and even stroke, have been later reported in patients who had recovered. There are limited studies on how SARS-CoV-2 infection affects some molecular pathways, including oxidative stress and DNA damage. In this study, we aimed to evaluate DNA damage, using the alkaline comet assay, and its relationship with oxidative stress and immune response parameters in COVID-19-positive patients. Our results show that DNA damage, oxidative stress parameters and cytokine levels significantly increased in SARS-CoV-2-positive patients when compared with healthy controls. The effects of SARS-CoV-2 infection on DNA damage, oxidative stress and immune responses may be crucial in the pathophysiology of the disease. It is suggested that the illumination of these pathways will contribute to the development of clinical treatments and to reduce adverse effects in the future.
358	I356		Goetzl, Edward J.; Yao, Pamela J.; Kapogiannis, Dimitrios	Prediction of Post-Acute-Sequelae of COVID-19 by Cargo Protein Biomarkers of Blood Total Extracellular Vesicles in Acute COVID-19	https://doi.org/10.1016/j.amjmed.2023.03.026	Published	2023-04-17	Study	https://www.sciencedirect.com/science/article/pii/S0002934323002589	Background SARS-CoV-2 invades mitochondria of infected cells resulting in disordered metabolism, mitophagy and abnormal levels of mitochondrial proteins in extracellular vesicles. Blood extracellular vesicle SARS-CoV-2 proteins and mitochondrial proteins were quantified in COVID-19 to assess possible roles as biomarkers. Methods Total extracellular vesicles were precipitated from blood of age- and gender-matched participants with no infection (n=10), acute COVID-19 (n=16), post-acute sequelae of COVID-19 (PASC or long-COVID) (n=30) or post-acute COVID without PASC (n=8) and their extracted proteins quantified by enzyme-linked immunosorbent assays (ELISAs). Results Total extracellular vesicle levels of S1(RBD) protein were significantly higher in acute infections than in uninfected controls, post-acute infection without PASC and PASC. Total extracellular vesicle levels of N protein were significantly higher in PASC than in uninfected controls, acute infections and post-acute infection without PASC. Neither acute levels of S1(RBD) or N proteins predicted progression to PASC. Levels of neither SARS-CoV-2 protein in established PASC correlated with neuropsychiatric manifestations. Significant decreases in total extracellular vesicle levels of the mitochondrial proteins MOTS-c, VDAC-1 and humanin, as well as elevations of levels of SARM-1, were observed in acutely infected patients who would develop PASC. Significant decreases in total extracellular vesicle levels of MOTS-c and humanin, but not VDAC-1, as well as elevations of total extracellular vesicle levels of SARM-1, were characteristic of PASC patients with neuropsychiatric manifestations. Conclusions Total extracellular vesicle levels of SARS-CoV-2 proteins in COVID-19 indicate intracellular presence of SARS-CoV-2. Abnormal total extracellular vesicles levels of mitochondrial proteins in acute infections predict a high risk of PASC and later in established PASC are indicative of neuropsychiatric manifestations.
359	I357		Ren, Zhigang; Liu, Shanshuo; Wang, Qiong; Rao, Benchen; Zeng, Zhaohai; Xu, Yakun; Wang, Haiyu; Luo, Hong; Gou, Jianjun; Yu, Zujiang	Alterations of the oral and gut mycobiome and cytokines during long-term follow-up of COVID-19 convalescents	https://doi.org/10.1038/s41392-023-01417-4	Published	2023-04-17	Study	https://www.nature.com/articles/s41392-023-01417-4	A large number of COVID-19 patients experience body-specific conditions such as fatigue, sleep disturbances, anxiety, depression, and dyspnea after the disease has subsided, which is called “long COVID-19”.1 Studies have confirmed reduced microbial diversity, enrichment of opportunistic pathogens and depletion of beneficial symbiotic bacteria in patients with COVID-19.2,3 Long-term dysregulation of the microbiota has also been observed in recovered patients.4 Nevertheless, long-term fungal microbiota follow-up was still blank. The microecology is closely associated with altered immune status and physical health and may be a potential cause of symptoms. We collected tongue coating, feces, and serum samples from 35 COVID-19 confirmed patients who were recovery (CPR0) and followed up for 1 year (CPR1) and 90 age- and sex-matched healthy controls (HC) for internal transcribed spacer (ITS) sequencing (Supplementary Fig. 1, Supplementary Table S1). The blood routine, liver and kidney function, and cytokines of CPR1 and HC were all within the normal range, but a few indicators were different, and most of them in the HC group were lower (Supplementary Tables S2–3). During COVID-19 recovery, the α diversity of oral (Fig. 1a) and fecal (Fig. 1b) fungal microbiota increased to varying degrees, but did not fully return to normal levels after 1 year. The Venn diagram indicated the shared and unique operational taxonomy units (OTUs) between the three groups (Fig. 1c, d). In the β diversity analysis, non-metric multidimensional scale (NMDS) analysis and principal coordinate analysis (PCoA) revealed that the oral (Fig. 1e, f) and fecal (Fig. 1g, h) fungal microbiota of CPR1 group was between CPR0 and HC, and tended to converge to the latter, and the difference between groups was statistically significant. Fig. 1 figure 1 Alterations of the oral and gut mycobiome and cytokines of COVID-19 convalescents after 1-year follow-up. a As estimated by the Shannon index, the α diversity of oral mycobiome gradually increased. b As estimated by the Simpson index, the α diversity of gut mycobiome gradually increased. c With a total of 2912 OTUs found and 271 OTUs shared between the three groups in oral, the HC group had 1560 unique OTUs, significantly higher than the CPR0 and CPR1 groups. d 631 OTUs of a total of 6811 OTUs were shared between the three groups, while 5021 OTUs appeared only in the HC group. The NMDS (e) and PCoA (f) analysis indicated the oral fungal taxonomic composition was conspicuously different in the three groups, and CPR1 gradually approached HC. The NMDS (g) and PCoA (h) analysis showed the gut fungal taxonomic composition was conspicuously different in the three groups, and CPR1 gradually approached HC. Composition of gut mycobiome at the phylum (i) and genus (j) levels in different groups. Comparison of fecal mycobiome at the phylum (k), genus (l) and species (m) levels among three groups. (n) Compared with the CPR0-H group, the POD value of the CPR0-L group in tongue coating samples increased significantly and achieved great diagnostic results in the training set, with an AUC value of 0.8095 (o) (P < 0.05). p Compared with the CPR0-H group, the POD value of the CPR0-L group in fecal samples increased significantly and achieved great diagnostic results in the training set, with an AUC value of 0.9667 (q) (P < 0.05). r Gradual recovery of the cytokines among three groups. OTUs operational taxonomy units; HC healthy controls, CPR0 confirmed patients recover at discharge, CPR1 confirmed patients recover 1 year, NMDS non-metric multidimensional scale analysis, PCoA principal coordinate analysis, POD probability of disease, AUC area under the curve. Data were represented as mean ± SEM. P < 0.05, P < 0.01, **P < 0.001. ns not significant Full size image When analyzing the average composition and comparison of oral and fecal fungal microbiome at different levels (Supplementary Data S1–10), we found that the dominant phylum of oral and fecal fungi was the same, which were Ascomycota, Basidiomycota and Mucoromycota (Fig. 1i). At the genus level, Zanclospora, Aspergillus, Acrodictys, Entorrhiza and Candida were co-dominant genera, Malassezia, Actinomucor, Cladosporium and Blumeria were more abundant in the oral cavity, and Ascomycota_gen_Incertae_ Sedis and Saccharomyces were more abundant in feces (Fig. 1j). In the between-group differential fungal analysis at the phylum level, the abundance of Ascomycota in the oral cavity gradually increased and Mucoromycota in feces (Fig. 1k) gradually decreased during disease recovery. At the genus level, there were 21 genera in oral cavity and 11 genera in feces gradually increased, while 8 genera in oral cavity and 11 genera in feces (Fig. 1l) gradually decreased. Tuber, Chrysosphaeria, and Angustimassarina gradually increased in abundance in both environments, while Actinomucor, Rhodotorula, and Micor decreased. At the species level, the abundance of 25 species in the oral cavity and 13 species in the feces gradually increased, and the abundance of 13 species in oral cavity and 13 species in feces (Fig. 1m) gradually decreased. The heatmap can visualize the abundance of different OTUs between three groups of fungal microbes during disease recovery (Supplementary Fig. 2). Linear discriminant analysis (LDA) effect size (LEfSe) was used to compare the phylogenetic distribution of fungal microorganisms in three groups. We set LDA score (log10)>3 to select differential species, and compared with CPR0 and HC, the number of species significantly enriched in tongue samples in CPR1 was the smallest. Nevertheless, the CPR0 group had the largest number of species significantly enriched in fecal samples, more than the CPR1 group and HC group. Interestingly, we found that the CPR0 group had Dipodascus, Candida, Rhodotorula, Mucor, Cladosporium and Actinomucor as the dominant fungi in both tongue and fecal samples (Supplementary Data S11–12). Candida causes opportunistic infections when immunocompromised and is the most cited COVID-19-associated fungal infections. Cladosporium infections can develop into diseases such as pneumonia if not treated promptly. The MetaCyc database was used to determine possible enrichment pathways for fungal influences on COVID-19. We found that oral and fecal fungi were enriched in tryptophan degradation, guanosine nucleotides degradation, pantothenate and coenzyme A biosynthesis, and sucrose biosynthesis in CPR0 group. Nevertheless, guanosine nucleotides biosynthesis was observed in feces in the CPR1 group. We also found that the amino acid and nucleotide degradation pathways were more enriched in the CPR0 group, while the synthesis pathways were more obvious in the CPR1 group, which was like that in the HC group (Supplementary Data S13–14). We selected patients with complete clinical information and samples from both CPR0 and CPR1 to establish the prediction model, and finally included 16 patients who provided oral samples and 11 patients who provided fecal samples. After 1-year follow-up, neutralizing antibody inhibition rates below 70% were classified as CPR0-L group, and those above 70% were divided to CPR0-H group. Subsequently, a random forest model was constructed and a five-fold cross-validation was carried out. Finally, 3 oral fungal biomarkers and 18 fecal fungal biomarkers were determined (Supplementary Data S15–16). The probability of disease (POD) index of the CPR0-L group was significantly higher than that of the CPR0-H group in both samples (Fig. 1n, p). The area under the curve (AUC) of the oral prediction model was 0.8095 (95% CI: 0.5261-1, P = 0.0418) (Fig. 1o) and the AUC of the fecal prediction model was 0.9667 (95% CI: 0.8743-1, P = 0.0087) (Fig. 1q). Most cytokines, such as IL-1b, MIP-3a, IL-5, and IL-10, tended to decline during disease recovery, while IL-8 concentrations gradually increased (Fig. 1r, Supplementary Data S17). To explore the relationship between fungal flora and immunity during COVID-19 recovery, key oral and fecal fungi and cytokines that showed increasing or decreasing trend among CPR0, CPR1 and HC with statistical difference were selected for Spearman correlation analysis (Supplementary Table S3). In the association analysis between 37 oral OTUs, 23 fecal OTUs and 11 cytokines (Supplementary Fig. 3), IL-8 and MIP-1b were negatively correlated with other cytokines, and were negatively correlated with OTU5, OTU50, OTU67, OTU119, OTU157 in oral fungal microorganisms and OTU5, OTU19, OTU29, OTU69, OTU8088 in fecal fungal microorganisms. In the association analysis of 18 oral fungal OTUs and 8 fecal fungal OTUs with 10 clinical indicators, we found that neutralizing antibody and IgG were negatively correlated with monocytes and total bile acids, and positively correlated with albumin. In addition, OTU5 in oral fungal microorganisms was positively correlated with SARS-CoV-2 binding IgG and IgM during disease recovery. In the association analysis of fungi and bacteria, we found that OTU4, OTU12, OTU19, OTU69, OTU5910 in fecal fungi were negatively correlated with key bacteria (Supplementary Data S18–20). This confirmed that bacteria in the gastrointestinal tract may limit fungal colonization and invasion. In this study, we reported for the first time that oral and gut fungal microbiome diversity was restored 1 year after discharge from COVID-19 patients, and cytokine concentrations associated with inflammatory storms were gradually reduced. Moreover, the CPR1 neutralizing antibody prediction models based on oral and intestinal fungal flora obtained excellent prediction effects. Spearman correlation analysis also showed significant correlations between oral fungi and bacteria, fecal fungi and bacteria, cytokines, and clinical indicators. However, there are certain shortcomings in this study. Although the predictive model achieves high efficiency, the sample size is small, and large sample validation is required before clinical practice. In addition, the study is observational and requires more in-depth design experiments to validate the findings.
360	I358		Allan-Blitz, Lao-Tzu; Akbari, Omid; Kojima, Noah; Saavedra, Edwyn; Chellamuthu, Prithivi; Denny, Nicholas; MacMullan, Melanie A.; Hess, Victoria; Shacreaw, Maria; Brobeck, Matthew; Turner, Frederick; Slepnev, Vladimir I.; Ibrayeva, Albina; Klausner, Jeffrey D.	Unique immune and inflammatory cytokine profiles may define long COVID syndrome	https://doi.org/10.1007/s10238-023-01065-6	Published	2023-04-16	Study	https://doi.org/10.1007/s10238-023-01065-6	Purpose Long COVID is estimated to occur in 5–10% of individuals after acute SARS-CoV-2 infection. However, the pathophysiology driving the disease process is poorly understood. Methods We evaluated urine and plasma inflammatory and immune cytokine profiles in 33 individuals with long COVID compared to 33 who were asymptomatic and recovered, and 34 without prior infection. Results Mean urinary leukotriene E4 was significantly elevated among individuals with long COVID compared to asymptomatic and recovered individuals (mean difference 774.2 pg/mL; SD 335.7) and individuals without prior SARS-CoV-2 infection (mean difference 503.1 pg/ml; SD 467.7). Plasma chemokine ligand 6 levels were elevated among individuals with long COVID compared to individuals with no prior SARS-CoV-2 infection (mean difference 0.59 units; SD 0.42). We found no significant difference in angiotensin-converting enzyme 2 antibody levels. Plasma tumor necrosis factor receptor-associated factor 2 (TRAF2) levels were reduced among individuals with long COVID compared to individuals who were asymptomatic and recovered (mean difference = 0.6 units, SD 0.46). Similarly, the mean level of Sarcoma Homology 2-B adapter protein 3 was 3.3 units (SD 1.24) among individuals with long COVID, lower than 4.2 units (SD 1.1) among individuals with recovered, asymptomatic COVID. Conclusion Our findings suggest that further studies should be conducted to evaluate the role of leukotriene E4 as a potential biomarker for a diagnostic test. Furthermore, based on reductions in TRAF2, long COVID may be driven in part by impaired TRAF2-dependent immune-mediated inflammation and potentially immune exhaustion.
361	I359		Fudge, Jared B.	Long COVID immune phenotypes identified for blockade	https://doi.org/10.1038/s41587-023-01765-0	Published	2023-04-01	Article	https://www.nature.com/articles/s41587-023-01765-0	Symptoms of severe long COVID may include lung fibrosis, and a precise, detailed profile of associated immunopathology has been missing until now. Writing in Proceedings of the National Academy of Sciences USA, Cui et al. use published single-cell transcriptomics data from human lung-tissue samples to explore the onset of fibrosis, alongside a new humanized mouse model for long COVID. A series of unique immune hallmarks serve as a basis to investigate potential therapeutic strategies for the ever-growing cohort of patients with long COVID. Leukocytes and pulmonary fibroblasts from patients with long COVID had unique gene-expression profiles compared to those from healthy, matched control individuals. Pathways related to the pro-inflammatory cytokine and anti-inflammatory myokine interleukin-6 (IL-6) were upregulated in alveolar macrophages from these patients, consistent with previous reports of cytokine storms. Neutrophils and lung fibroblasts were enriched for profibrotic pathways and associated with increased deposition of extracellular matrix proteins. Immunofluorescence assays validated the enrichment of proteins involved in innate immune activation and profibrosis pathways in lung tissue from patients with long COVID, probably mediated by the transcription factor JUN. Next, the authors developed a humanized mouse model of SARS-CoV-2 infection. Fibrosis symptoms appeared in 75% of treated mice four weeks after exposure. Neutrophil and macrophage recruitment further recapitulated patient pathology in the mouse model. Treatments using anti-IL-6 and anti-CD47 antibodies were administered for two weeks, and this was sufficient to restore lung morphology, reduce fibrosis and ameliorate recruitment of neutrophils and macrophages to the affected tissue. This study pinpoints the role of fibrosis and inflammation pathways in initial long-COVID pathology and offers clinical targets related to the innate immune response. number: 4 publisher: Nature Publishing Group
362	I360		Guiot, Julien; Henket, Monique; Remacle, Claire; Cambier, Maureen; Struman, Ingrid; Winandy, Marie; Moermans, Catherine; Louis, Edouard; Malaise, Michel; Ribbens, Clio; Louis, Renaud; Njock, Makon-Sébastien	Systematic review of overlapping microRNA patterns in COVID-19 and idiopathic pulmonary fibrosis	https://doi.org/10.1186/s12931-023-02413-6	Published	2023-04-15	Review	https://doi.org/10.1186/s12931-023-02413-6	Background Pulmonary fibrosis is an emerging complication of SARS-CoV-2 infection. In this study, we speculate that patients with COVID-19 and idiopathic pulmonary fibrosis (IPF) may share aberrant expressed microRNAs (miRNAs) associated to the progression of lung fibrosis. Objective To identify miRNAs presenting similar alteration in COVID-19 and IPF, and describe their impact on fibrogenesis. Methods A systematic review of the literature published between 2010 and January 2022 (PROSPERO, CRD42022341016) was conducted using the key words (COVID-19 OR SARS-CoV-2) AND (microRNA OR miRNA) or (idiopathic pulmonary fibrosis OR IPF) AND (microRNA OR miRNA) in Title/Abstract. Results Of the 1988 references considered, 70 original articles were appropriate for data extraction: 27 studies focused on miRNAs in COVID-19, and 43 on miRNAs in IPF. 34 miRNAs were overlapping in COVID-19 and IPF, 7 miRNAs presenting an upregulation (miR-19a-3p, miR-200c-3p, miR-21-5p, miR-145-5p, miR-199a-5p, miR-23b and miR-424) and 9 miRNAs a downregulation (miR-17-5p, miR-20a-5p, miR-92a-3p, miR-141-3p, miR-16-5p, miR-142-5p, miR-486-5p, miR-708-3p and miR-150-5p). Conclusion Several studies reported elevated levels of profibrotic miRNAs in COVID-19 context. In addition, the balance of antifibrotic miRNAs responsible of the modulation of fibrotic processes is impaired in COVID-19. This evidence suggests that the deregulation of fibrotic-related miRNAs participates in the development of fibrotic lesions in the lung of post-COVID-19 patients. What is already known on this topic An emerging complications of SARS-CoV-2 infection is pulmonary fibrosis. In this study, we speculate that patients with COVID-19 and idiopathic pulmonary fibrosis (IPF) may share aberrant expressed miRNAs associated to the progression of lung fibrosis. What this study adds This is the first review to identify miRNAs presenting similar alteration in COVID-19 and IPF. Interestingly, these miRNAs are key regulators of fibrosis processes. The deregulation of these fibrotic-related miRNAs may participate in the development of fibrotic lesions in the lung of post-COVID-19 patients. How this study might affect research, practice or policy The study of these miRNAs may help to decipher molecular pathways involved in the development of lung fibrosis in post-COVID-19 patients.
363	I361		di Filippo, Luigi; Frara, Stefano; Nannipieri, Fabrizio; Cotellessa, Alice; Locatelli, Massimo; Rovere Querini, Patrizia; Giustina, Andrea	Low Vitamin D Levels Are Associated With Long COVID Syndrome in COVID-19 Survivors	https://doi.org/10.1210/clinem/dgad207	Published	2023-04-13	Study	https://doi.org/10.1210/clinem/dgad207	Context Long COVID is an emerging syndrome affecting 50% to 70% of COVID-19 survivors that still lacks predicting factors. Objective Due to the extraskeletal effects of vitamin D, we retrospectively assessed the association between 25(OH) vitamin D levels and long COVID in COVID-19 survivors 6 months after hospitalization. Methods Long COVID was defined according to NICE guidelines. Fifty long COVID and 50 non–long-COVID subjects matched on a 1:1 basis were enrolled from an outpatient clinic post-COVID cohort seen from August to November 2020. Therapies/comorbidities affecting calcium/vitamin D/bone metabolism, and/or admission to the intensive care unit during hospitalization were exclusion criteria. 25(OH) Vitamin D was measured at hospital admission and 6 months after discharge. Results We observed lower 25(OH) vitamin D levels, evaluated at follow-up, in subjects with long COVID than those without (20.1 vs 23.2 ng/mL, P = .03). Regarding the affected health areas evaluated in the entire cohort, we observed lower 25(OH) vitamin D levels in those with neurocognitive symptoms at follow-up (n = 7) than those without (n = 93) (14.6 vs 20.6 ng/mL, P = .042). In patients presenting vitamin D deficiency (<20 ng/mL), both at admission and at follow-up (n = 42), those affected by long COVID (n = 22) presented lower 25(OH) vitamin D levels at follow-up than those not affected (n = 20) (12.7 vs 15.2 ng/mL, P = .041). In multiple regression analyses, lower 25(OH) vitamin D levels at follow-up were the only variable significantly associated with long COVID in our cohort (P = .008, OR 1.09, CI 1.01-1.16). Conclusion COVID-19 survivors with long COVID have lower 25(OH) vitamin D levels than matched patients without long COVID. Our data suggest that vitamin D levels should be evaluated in COVID-19 patients after hospital discharge. The role of vitamin D supplementation as a preventive strategy of COVID-19 sequelae should be tested in randomized controlled trials.
364	I362		Nguyen, Nhu Ngoc; Nguyen, Y. Ngoc; Hoang, Van Thuan; Million, Matthieu; Gautret, Philippe	SARS-CoV-2 Reinfection and Severity of the Disease: A Systematic Review and Meta-Analysis	https://doi.org/10.3390/v15040967	Published	2023-04-01	Systematic review and meta-analysis	https://www.mdpi.com/1999-4915/15/4/967	Since the discovery of SARS-CoV-2, changes in genotype and reinfection with different variants have been observed in COVID-19-recovered patients, raising questions around the clinical pattern and severity of primary infection and reinfection. In this systematic review, we summarize the results of 23 studies addressing SARS-CoV-2 reinfections. A total of 23,231 reinfected patients were included, with pooled estimated reinfection rates ranging from 0.1 to 6.8%. Reinfections were more prevalent during the Omicron variant period. The mean age of reinfected patients was 38.0 ± 6. years and females were predominant among reinfected patients (M/F = 0.8). The most common symptoms during the first and second infection were fever (41.1%), cough (35.7% and 44.6%), myalgia (34.5% and 33.3%), fatigue (23.8% and 25.6%), and headaches (24.4% and 21.4%). No significant differences of clinical pattern were observed between primary infection and reinfection. No significant differences in the severity of infection were observed between primary infection and reinfection. Being female, being a patient with comorbidities, lacking anti-nucleocapsid IgG after the first infection, being infected during the Delta and Omicron wave, and being unvaccinated were associated with a higher risk of reinfection. Conflicting age-related findings were found in two studies. Reinfection with SARS-CoV-2 suggests that natural immunity is not long-lasting in COVID-19 patients.
365	I363		Liang, Weifeng; Gu, Ming; Zhu, Lingxiang; Yan, Ziqi; Schenten, Dominik; Herrick, Shelby; Li, Hongmin; Samrat, Subodh Kumar; Zhu, Jiapeng; Chen, Yin	The main protease of SARS-CoV-2 downregulates innate immunity via a translational repression	https://doi.org/10.1038/s41392-023-01418-3	Published	2023-04-13	Study	https://www.nature.com/articles/s41392-023-01418-3	SARS-CoV-2 is the etiological cause of COVID-19. RIG-I-like receptor (RLR) signaling pathway appeared to be responsible for SARS-CoV-2 induced IFN,1 a major antiviral pathway. IFN deficiency2,3 was identified to be a significant risk factor of severe COVID-19, highlighting an important role of IFN in the defense against SARS-CoV-2 and in the pathogenesis of severe COVID-19. Since SARS-CoV-2 is highly susceptible to IFN treatment,3,4 it has to evade host IFN-mediated immune surveillance to establish an active infection, To identify viral regulators of IFN, we designed a screening strategy, in which MAVS, the common adaptor protein, was overexpressed to initiate the downstream IFN signaling. Each viral protein encoded by SARS-CoV-2 was introduced into the system to examine its effect on MAVS-IFN signaling. We found that NSP5, the main protease of SARS-CoV-2, is among the five viral proteins (NSP1, 3, 5, ORF6, and 8) that significantly repressed MAVS-IFN (Supplementary Fig. 1a). In contrast, NSP5 (C145A), an enzymatic inactive NSP5, could not inhibit MAVS-induced ISRE reporter activity (Supplementary Fig. 1b). Furthermore, NSP5 was able to inhibit IFN promoter reporter (PRDIII) and this inhibition was mostly restored by a protease inhibitor of NSP5 (GC376) (Supplementary Fig. 1c). Next, we extended the study of reporter assay (Supplementary Fig. 1) to cellular RLR signaling pathway. MAVS overexpression induced MAVS aggregation (a pre-requisite for MAVS activation) and STAT1 phosphorylation (Fig. 1c), confirming that MAVS overexpression indeed activated the downstream IFN pathway. We further tested if overexpression of upstream RNA sensors (MDA5 and RIG-I) or downstream signaling proteins (TBK1 and IRF3) could also activate IFN pathway. Indeed, an overexpression of MDA5 (Fig. 1a), RIG-I (Fig. 1b), TBK1 (Fig. 1d) and IRF3 (Fig. 1e) robustly induced STAT1 phosphorylation. At the mRNA level, we tested MAVS (Fig. 1f) or TBK1 (Fig. 1g) overexpression and found that both could increase the expression of selected interferon stimulated genes (or ISGs) (e.g. IFNβ, and ISG15). The cellular protease activity of transfected NSP5 was verified by flipGFP model system (Supplementary Fig. 2), in which an inactive flipGFP could be activated by a specific cleavage of NSP5 recognition site. Indeed, transfected NSP5, but not NSP5 (C145A), elicited a strong protease activity as demonstrated by a robust GFP signal (Supplementary Fig. 2). Consistent with the results from the reporter gene assay (Supplementary Fig. 1), co-transfection with NSP5, but not with NSP5 (C145A), significantly repressed STAT1 activation (Fig. 1a-e, Supplementary Fig. 3) and MAVS aggregation (Fig. 1c). Additionally, increased expressions of ISGs (IFNβ and ISG15) were almost completely repressed by NSP5, but not by NSP5 (C145A) (Fig. 1f, g). We also tested two other common IFN stimuli: poly (I:C) and Sendai virus (SeV) infection. Indeed, their downstream IFN signaling pathways were also repressed by NSP5, but not by NSP5 (C145A) (Supplementary Fig. 4a, b). Taken together, NSP5 significantly repressed RLR pathway in a protease-dependent manner. In summary, we have discovered a novel translational mechanism that is likely responsible for NSP5-mediated IFN repression. eIF4G, a key component of translational initiation complex, was identified to be a specific NSP5 substrate in vitro as well as in a cell model of SARS-CoV-2 infection. Ectopic eIF4G expression was able to partly rescue NSP5-mediated repression of RLR-IFN pathway. Our finding provides a unique angle to the research of innate immunity against SARS-CoV-2 infection. Since IFN repression is a major mechanism of viral evasion and a determinant of severe COVID-19, our finding may reveal a new target (eIF4G) for research on COVID-19 pathogenesis. number: 1 publisher: Nature Publishing Group
366	I364		Kriebs, Anna	SARS-CoV-2-induced loss of CHK1 causes DNA damage	https://doi.org/10.1038/s43587-023-00414-0	Published	2023-04-14	Article	https://www.nature.com/articles/s43587-023-00414-0	SARS-CoV-2 infection promotes cellular phenotypes that are associated with aging, such as senescence and proinflammatory cytokine release. However, the molecular pathways that link SARS-CoV-2 with these phenotypes are not fully understood. Now, a study by Ubaldo Gioia, Sara Tavella and colleagues shows that SARS-CoV-2 infection leads to a loss of CHK1, which causes a shortage in dNTP and impairs DNA replication, thus initiating a DNA damage response (DDR), inflammation and senescence. Credit: Zhengshun tang/Moment/Getty “The idea of a mechanism clicked in my head when I attended an RNA conference in the earliest days of the pandemic, before any lockdown”, says corresponding author Fabrizio d’Adda di Fagagna. “Narry Kim from Seoul National University showed her preliminary results from nanopore RNA sequencing of infected cells. Staggeringly, two out of three sequenced RNAs were of viral origin! Such an amount of RNA synthesis immediately meant to me that the cell was getting into trouble: where would the cell find three times the amount of rNTP than normally needed?” The researchers began by infecting human cells with SARS-CoV-2. They observed that SARS-CoV-2 infection causes DNA damage and an altered DDR associated with a proinflammatory phenotype and senescence; it was also associated with a downregulation of effector kinase CHK1. As loss of CHK1 is sufficient to cause replication stress and DNA damage accumulation, the team measured dNTP levels and cell cycle progression. They observed that SARS-CoV-2 infection decreases dNTP concentrations and impairs S-phase progression. Deoxynucleotide supplementation in the culture medium of infected cells reduces DDR activation, DNA damage accumulation and proinflammatory cytokine expression. “Our study shows that SARS-CoV-2 infections causes the degradation of CHK1, thus reducing ribonucleoside-diphosphate reductase subunit M2 (RRM2) expression and ribonucleotide reductase (RNR) activity and thereby shifting the balance of cellular nucleotide metabolism in favor of rNTP and in disfavor of dNTP. This generates DNA damage”, explains d’Adda di Fagagna. “In addition, DNA damage repair is impaired: surprisingly, 53BP1 foci cannot assemble. This is because they depend on the function of damage-induced long noncoding RNA (dilncRNA) generated at sites of DNA damage. We discovered that viral N protein binds to dilncRNA and blocks 53BP1 condensation.” The researchers also measured the DDR markers 53BP1, CHK1 and RRM2 in lungs from mice infected with SARS-CoV-2 and in lung and nasal mucosa sections from patients who died of COVID-19. These results are consistent with their in vitro data. “Key to this study was the collaboration with experts in the field, like Alessandro Marcello’s group, to perform all real viral infections (no pseudoviruses)”, continues d’Adda di Fagagna. “Also essential was access to infected tissues form mice and patients, and a great pathologist, Claudio Tripodo, who assessed DDR in these tissues.” In future studies, the authors note it will be interesting to establish whether the mechanisms they uncovered contribute to long-COVID pathology. Overall, this study sheds light on the mechanisms that underlie the cellular effects of SARS-CoV-2 infection, particularly DNA damage, inflammation and senescence. publisher: Nature Publishing Group
367	I365		Gioia, Ubaldo; Tavella, Sara; Martínez-Orellana, Pamela; Cicio, Giada; Colliva, Andrea; Ceccon, Marta; Cabrini, Matteo; Henriques, Ana C.; Fumagalli, Valeria; Paldino, Alessia; Presot, Ettore; Rajasekharan, Sreejith; Iacomino, Nicola; Pisati, Federica; Matti, Valentina; Sepe, Sara; Conte, Matilde I.; Barozzi, Sara; Lavagnino, Zeno; Carletti, Tea; Volpe, Maria Concetta; Cavalcante, Paola; Iannacone, Matteo; Rampazzo, Chiara; Bussani, Rossana; Tripodo, Claudio; Zacchigna, Serena; Marcello, Alessandro; d’Adda di Fagagna, Fabrizio	SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence	https://doi.org/10.1038/s41556-023-01096-x	Published	2023-04-01	Study	https://www.nature.com/articles/s41556-023-01096-x	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the RNA virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Although SARS-CoV-2 was reported to alter several cellular pathways, its impact on DNA integrity and the mechanisms involved remain unknown. Here we show that SARS-CoV-2 causes DNA damage and elicits an altered DNA damage response. Mechanistically, SARS-CoV-2 proteins ORF6 and NSP13 cause degradation of the DNA damage response kinase CHK1 through proteasome and autophagy, respectively. CHK1 loss leads to deoxynucleoside triphosphate (dNTP) shortage, causing impaired S-phase progression, DNA damage, pro-inflammatory pathways activation and cellular senescence. Supplementation of deoxynucleosides reduces that. Furthermore, SARS-CoV-2 N-protein impairs 53BP1 focal recruitment by interfering with damage-induced long non-coding RNAs, thus reducing DNA repair. Key observations are recapitulated in SARS-CoV-2-infected mice and patients with COVID-19. We propose that SARS-CoV-2, by boosting ribonucleoside triphosphate levels to promote its replication at the expense of dNTPs and by hijacking damage-induced long non-coding RNAs’ biology, threatens genome integrity and causes altered DNA damage response activation, induction of inflammation and cellular senescence.
368	I366		Basaran, M. Mert; Hazar, Merve; Aydın, Mehtap; Uzuğ, Gülsüm; Özdoğan, İlkima; Pala, Emin; Aydın Dilsiz, Sevtap; Basaran, Nursen	Effects of COVID-19 Disease on DNA Damage, Oxidative Stress and Immune Responses	https://doi.org/10.3390/toxics11040386	Published	2023-04-01	Study	https://www.mdpi.com/2305-6304/11/4/386	Coronavirus disease 2019 (COVID-19) has posed a great threat to public health and has caused concern due to its fatal consequences over the last few years. Most people with COVID-19 show mild-to-moderate symptoms and recover without the need for special treatment, while others become seriously ill and need medical attention. Additionally, some serious outcomes, such as heart attacks and even stroke, have been later reported in patients who had recovered. There are limited studies on how SARS-CoV-2 infection affects some molecular pathways, including oxidative stress and DNA damage. In this study, we aimed to evaluate DNA damage, using the alkaline comet assay, and its relationship with oxidative stress and immune response parameters in COVID-19-positive patients. Our results show that DNA damage, oxidative stress parameters and cytokine levels significantly increased in SARS-CoV-2-positive patients when compared with healthy controls. The effects of SARS-CoV-2 infection on DNA damage, oxidative stress and immune responses may be crucial in the pathophysiology of the disease. It is suggested that the illumination of these pathways will contribute to the development of clinical treatments and to reduce adverse effects in the future.
369	I367		Augustin, Max; Heyn, Ferdinand; Ullrich, Stella; Sandaradura de Silva, Ute; Albert, Marie-Christine; Linne, Viktoria; Schlotz, Maike; Schommers, Philipp; Pracht, Elisabeth; Horn, Carola; Suarez, Isabelle; Simonis, Alexander; Picard, Lea Katharina; Zoufaly, Alexander; Wenisch, Christoph; Fätkenheuer, Gerd; Gruell, Henning; Klein, Florian; Hallek, Michael; Walczak, Henning; Rybniker, Jan; Theobald, Sebastian J.; Lehmann, Clara	Immunological fingerprint in coronavirus disease-19 convalescents with and without post-COVID syndrome	https://doi.org/10.3389/fmed.2023.1129288	Published	2023-04-24	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10165999/	Background Symptoms lasting longer than 12 weeks after severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection are called post-coronavirus disease (COVID) syndrome (PCS). The identification of new biomarkers that predict the occurrence or course of PCS in terms of a post-viral syndrome is vital. T-cell dysfunction, cytokine imbalance, and impaired autoimmunity have been reported in PCS. Nevertheless, there is still a lack of conclusive information on the underlying mechanisms due to, among other things, a lack of controlled study designs. Methods Here, we conducted a prospective, controlled study to characterize the humoral and cellular immune response in unvaccinated patients with and without PCS following SARS-CoV-2 infection over 7 months and unexposed donors. Results Patients with PCS showed as early as 6 weeks and 7 months after symptom onset significantly increased frequencies of SARS-CoV-2-specific CD4+ and CD8+ T-cells secreting IFNγ, TNF, and expressing CD40L, as well as plasmacytoid dendritic cells (pDC) with an activated phenotype. Remarkably, the immunosuppressive counterparts type 1 regulatory T-cells (TR1: CD49b/LAG-3+) and IL-4 were more abundant in PCS+. Conclusion This work describes immunological alterations between inflammation and immunosuppression in COVID-19 convalescents with and without PCS, which may provide potential directions for future epidemiological investigations and targeted treatments. PMID: 37168268 PMCID: PMC10165999
370	I368		El-Akkad, S.-E.-D.; Shao, S.; Tran, K.c.w.; Russell, J.a.; Carlsten, C.; Ryerson, C.j.; Levin, A.; Wong, A.w.	COVID-19 Vaccination Is Not Associated With Abnormal Patient Reported Outcome Measures in Patients With Long-COVID: A Prospective Cohort Study		Published	2023-05-01	Study	https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A3846
371	I369		Di, Filippo Luigi; Frara, Stefano; Nannipieri, Fabrizio; Cotellessa, Alice; Locatelli, Massimo; Rovere-Querini, Patrizia; Giustina, Andrea	Low 25(OH) vitamin D levels are associated with Long COVID syndrome in COVID-19 survivors	https://doi.org/10.1530/endoabs.90.EP150	Published	2023-05-02	Study	https://www.endocrine-abstracts.org/ea/0090/ea0090ep150	Low vitamin D levels were consistently reported as a risk factor for worse outcomes in hospitalized COVID-19 patients. Emerging evidences suggest that in 50–70% of COVID-19 survivors several post-COVID symptoms can be observed up to 3 months after acute-disease, representing a novel clinical condition defined Long-COVID syndrome. To date, the predisposing factors for this syndrome are still poorly understood. We retrospectively aimed at evaluating the influence of 25(OH) vitamin D levels on Long-COVID occurrence in patients previously hospitalized for COVID-19, re-assessed 6-months after discharge. Long-COVID was defined based on the National Institute for Health and Care Excellence-guidelines and approximately 500 patients were re-evaluated after the first pandemic-wave. While excluding patients with therapies/comorbidities affecting bone metabolism, and/or those admitted in ICU during hospitalization, only 50 Long-COVID patients were eligible for enrolment and compared in an age, sex, comorbidities and acute-disease characteristics-matched 1:1 ratio with non-Long-COVID patients. 25(OH) vitamin D was measured at hospital-admission and after 6-months. Median 25(OH) vitamin D levels were 14.7 and 20.6 ng/ml, at hospital-admission and at 6-month follow-up, respectively. At admission, vitamin D deficiency (25(OH) vitamin D <20 ng/ml) was found in 71 patients, and, at 6-month follow-up, in 46 patients. We observed lower 25(OH) vitamin D levels, evaluated at follow-up visit, in Long-COVID group than those without (20.1 vs 23.2 ng/ml, P=0.03). No statistically significant differences were observed regarding prevalence of vitamin D deficiency between those with and without Long-COVID. Regarding the different affected health areas evaluated in the entire cohort, we observed lower 25(OH) vitamin D levels in those with neurocognitive symptoms at 6-month visit (n.7) as compared to those without (n.93) (14.6 vs 20.6 ng/ml, P=0.042). In patients presenting vitamin D deficiency both at admission and at follow-up (n.42), those affected by Long-COVID (n.22) were characterized by lower 25(OH) vitamin D levels, evaluated at follow-up, compared to those not affected (n.20) (12.7 vs 15.2 ng/ml, P=0.041). In multiple regression analyses, lower 25(OH) vitamin D levels, evaluated at follow-up, resulted as the only variable significantly associated with the Long-COVID occurrence (P=0.016, OR 1.08-CI 1.01-1.15). In conclusion, COVID-19 survivors with Long-COVID have lower 25(OH) vitamin D levels as compared to matched patients without Long-COVID. Moreover, lower vitamin D resulted as an independent risk factor for the occurrence of this syndrome. Our data suggest that evaluating vitamin D levels in COVID-19 patients after hospital discharge and improving their vitamin D status when needed may be helpful in reducing the burden of COVID-19 sequelae. ISSN: 1470-3947, 1479-6848
372	I370		Ambrus, Mira; Fodor, Eszter; Berki, Timea; Müller, Veronika; Uhlár, Ádám; Hornyák, István; Lacza, Zsombor	Professional Athletes Maintain High TNF-Alpha or IFN-Gamma Related Inflammatory Status after Recovering from COVID-19 Infection without Developing a Neutralizing Antibody Response	https://doi.org/10.3390/sports11050097	Published	2023-05-01	Study	https://www.mdpi.com/2075-4663/11/5/97	Introduction: Professional athletes are endangered by COVID-19 and belong to the high-risk population due to their lifestyle. To obtain information on the behavior of COVID-19 in professional athletes, serological, cytokine, and virus neutralization capacities were analyzed. Materials and methods: Hungarian national teams participated in international sports events during the early phases of the COVID-19 epidemic in 2020. Altogether, 29 professional athletes volunteered to donate plasma. Their serological status was evaluated by IgA, IgM, and IgG ELISAs and the highest virus neutralization titer in an in vitro live tissue assay. Plasma cytokine patterns were analyzed with a Bioplex multiplex ELISA system. Results: Surprisingly, only one athlete (3%) had anti-SARS-CoV-2 IgG, while IgA was more common (31%). Neither plasma showed direct virus neutralization in a titer over 1:10; hence, they were not suitable for reconvalescent treatment. The ‘cytokine storm’ markers IL-6 and IL-8 were at baseline levels. In contrast, either the TNF-alpha-related cytokines or the IFN-gamma-associated cytokines were elevated. There was a strong negative correlation between the TNF-alpha- or IFN-gamma-related cytokines. Conclusions: Professional athletes are susceptible to the SARS-CoV-2 infection without developing long-term immunity through neutralizing immunoglobulins. Elevated secretory and cellular immunity markers indicate that these systems are probably responsible for virus elimination in this subpopulation.
373	I371		Baalbaki, N.; Cornelissen, M.; Drunen, C. Van; Houweling, L.; Noij, L.; Werken, M. Van De; Korneliusz, G.; Zee, A. Maitland-Van Der	Activated -inflammatory states of airway cells in Long COVID	https://doi.org/10.1183/23120541.LSC-2023.124	Published	2023-03-09	Study	https://openres.ersjournals.com/content/9/suppl_10/124	Introduction: Long COVID is described as the persistence of symptoms following acute COVID-19 for >12 weeks and occurs in about 30% of all cases. Nasal epithelium is a primary target for SARS-CoV-2 and involved in the early phase immune response. Aims: To assess the role of nasal epithelium and a local tissue micro-environment in long COVID. Methods: Phenotype and function of nasal epithelium and innate lymphoid cells(ILC) were analyzed from long COVID patients and healthy controls(HC) using quantitative polymerase chain reaction, transepithelial resistance, scratch assays and flow cytometry. Long COVID samples were collected from Precision Medicine for more Oxygen (P4O2)– COVID-19 participants at 3-6 months post-COVID. Nasal epithelium was cultured at air-liquid-interface and exposed to viral mimic poly(I:C). Results: An activated inflammatory state of nasal epithelium in long COVID (n=10) compared to HC(n=5) was found. In nasal epithelium, the relative gene expression of pro-inflammatory cytokines, including interleukin (IL)6, IL8, CXCL10, CCL5, TNFA and IL1B, was increased at baseline and after 24-hour exposure to poly(I:C). Furthermore, increased frequencies of IFN-gamma producing ILCs were found in the blood of long COVID patients, that in vitro produced more IFN-gamma after exposure to epithelium-derived IL-1beta compared to HC. Ex vivo, this inflammatory state resulted in a reduced barrier function and increased regeneration potential of long COVID nasal epithelium. Conclusions: In Long COVID, epithelium-derived IL-1beta is potentially a key mediator in shaping the inflammatory airway tissue micro-environment by inducing IFN-gamma production in immune cells and consequently disturbing the epithelial barrier function.
374	I372		Barco, N. Mendoza; Cruz, T.; Lledó, G.; Perea, L.; Albacar, N.; Hernandez-Gonzalez, F.; Agustí, A.; Sellarés, J.; Sibila, O.; Faner, R.	Persistence of specific T-cell response in patients with Long COVID and pulmonary sequelae	https://doi.org/10.1183/23120541.LSC-2023.207	Published	2023-03-09	Study	https://openres.ersjournals.com/content/9/suppl_10/207	Background: A significant proportion of patients that survive COVID19 may develop LongCOVID or pulmonary sequelae(DLCO<80%).The mechanisms underlying these alterations are not described.Objectives:To determine if there is an association of the virus specific T cell response and the presence of LongCOVID or pulmonary sequelae at 12 months of convalescence. Methods: T lymphocytes were stimulated with specific SARSCoV2 peptides(N and S) in 40 patients (11 with LongCOVID, 17 pulmonary sequelae) at 12 months postCOVID.Tcell populations and IFNg production in stimulated lymphocytes were measured by flow cytometry. Lung function was measured at 6 and 12 months to evaluate the progression. Results: After comparing the prevalence of SARSCoV2 specific T cells(>2%IFNg+Tcells) across study groups at 12 months we observed that:1)50% of the recovered patients presented an in vitro Tcell response against SARSCoV2;2)72% of the patients with LongCOVID and 82% of the patients with lung sequelae responded.Th1 cells were increased in patients with LongCOVID in response to both peptides.Patients with pulmonary sequelae only presented an increase in Th1 in response to the S peptide. An in-depth characterization of the T lymphocytes in patients with LongCOVID,showed reduced expression of HLADR in CD4/CD8 T cells, and overall reduction of the frequencies of Th1 response.The frequency of CD4 HLADR,Th1,Th17,Th1/17 correlated with the change in DLCO in patients with pulmonary sequelae. Conclusions: Patients with LongCOVID or pulmonary sequelae have an increased persistence of virus specific Tcell response after 12 months. Findings suggest the presence of long-term altered immune profile in patients with LongCOVID.
375	I373		Patil, S. V.; Patil, S.; Toshniwal, S.; Gondhali, G.; Patil, R.; Acharya, A.; Patil, D.	“Clinical and immunological phenotypes” in ‘Long COVID’: The tsunami of multisystem syndrome of this decade!	https://doi.org/10.1183/23120541.LSC-2023.1	Published	2023-03-09	Study	https://openres.ersjournals.com/content/9/suppl_10/1	Background: Clinical presentation and immunological patterns are different in all three waves & still evolving. Methods: Prospective,observational study done in all three waves of COVID-19 pandemic & enrolled 8000 symptomatic, RT PCR confirmed cases in post COVID Unit. Clinical & immunological phenotypes were categorised in four types, Duration of illness (DOI) classified into transient or evolved, persistent, progressive, Topographical classification into vague or nonspecific and systemic or organic as per involvement of organ systems, Treatment responsive classified as per response into easy to treat and difficult to treat or refractory to treatment & Fourth is according genetic makeup patterns or strain patterns observed in first, second and third wave as pulmonary, extrapulmonary and pulmonary-extrapulmonary combo. Investigated with LDH, Uric acid, CRP, D-dimer, antinuclear antibody & retrospective analysis of antigenic cross reactivity/mimicry, markers as IL-6, Ferritin and interventions required during hospitalization including follow up HRCT thorax. Results: Clinical phenotypes as per DOI & Topographical phenotypes has documented significant association with immunological markers (p<0.00001) Treatment response phenotypes has documented significant association with DOI before hospitalisation, interventions required and inflammatory marker (p<0.00001) Clinical phenotypes in three waves has documented significant association with four pathophysiological pathways (p<0.00001) Conclusion: Clinical-Immunological Phenotypes of ‘Long COVID’ can be predicted at entry point, and sequential titers of inflammatory marker has 'vital role' during management in post covid care setting.
376	I374		Bellinghausen, C.; Grünewaldt, A.; Khodamoradi, Y.; Du, W.; Azem, T.; Lask, C.; Vehreschild, M.; Rohde, G.	Serum markers of chronic inflammation and pulmonary remodelling in patients with long COVID up to one year after infection	https://doi.org/10.1183/23120541.LSC-2023.42	Published	2023-03-09	Study	https://openres.ersjournals.com/content/9/suppl_10/42	Clinical sequelae following COVID19 can persist months after initial infection and significantly affect patients’ quality of life. The pathomechanisms and predictors for their course remain unclear. Here, we explored markers of systemic inflammation and pulmonary damage, and their association with clinical characteristics in patients with long COVID. Outpatients presenting with persisting symptoms after SARS-CoV2 infection were prospectively recruited. Serum markers of inflammation and pulmonary damage, and their association with symptom burden, clinical and lung function parameters were assessed for up to one year after infection. We included data from 235 patients (median age 48 [IQR 38-56] y, 65% female) during 503 visits. Acute COVID19 had mostly been mild to moderate, yet symptom burden at inclusion was high, with fatigue (81.7%) and shortness of breath (75.3%) being most common. FEV1% was below 80% in 11.6% of visits. Maximum inspiratory muscle strength (MIP) was impaired during 54.5% of visits, and negatively correlated with fatigue (ρ=-0.16, p=0.001) and cumulative symptom scores (ρ=-0.14, p=0.024). Levels of IL8, IL1β, IL10, TGFβ, surfactant protein D, and club cell protein 16 (CC16) showed little to no change over time and did not differ depending on severity of acute COVID19. CC16 levels were lower in patients with fatigue (7.1 [IQR 5.2-8.9] vs. 7.7 [IQR 6.4-10.8] ng/ml, p=0.008), and negatively correlated with symptom scores (ρ=-0.16, p=0.025). Our results confirm the high burden and heterogeneity of symptoms in patients with long COVID. Lack of anti-inflammatory proteins such as CC16 associated with symptoms may represent a pathogenetic factor.
377	I375		Hoang, Huy-Dung; Naeli, Parisa; Alain, Tommy; Jafarnejad, Seyed Mehdi	Mechanisms of impairment of interferon production by SARS-CoV-2	https://doi.org/10.1042/BST20221037	Published	2023-05-18	Review	https://doi.org/10.1042/BST20221037	Interferons (IFNs) are crucial components of the cellular innate immune response to viral infections. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown a remarkable capacity to suppress the host IFN production to benefit viral replication and spread. Thus far, of the 28 known virus-encoded proteins, 16 have been found to impair the host's innate immune system at various levels ranging from detection and signaling to transcriptional and post-transcriptional regulation of expression of the components of the cellular antiviral response. Additionally, there is evidence that the viral genome encodes non-protein-coding microRNA-like elements that could also target IFN-stimulated genes. In this brief review, we summarise the current state of knowledge regarding the factors and mechanisms by which SARS-CoV-2 impairs the production of IFNs and thereby dampens the host's innate antiviral immune response.
378	I376		Knight, S.; Menon, M.; Pott, B.; Hussell, T.; Bakerly, N.; Williams, T.; Grainger, J.; Konkel, J.; Mann, E.; Simpson, A.; Pearmain, L.; Mathioudakis, A.; Lowman, G.; Sarda, S.; Turkoglu, A.; Pickle, L.; Toro, M.	Resolution of inflammation in long COVID	https://doi.org/10.1183/23120541.LSC-2023.30	Published	2023-03-09	Study	https://openres.ersjournals.com/content/9/suppl_10/30	As the cases of severe COVID-19 decline, long COVID is emerging as the major complication of SARS CoV2 infection. We have reasoned that the dysregulated immune response characterising acute COVID-19 is unlikely to resolve in an orderly fashion and that persistence of some features may be present in patients with long COVID. We have extended our landmark acute COVID-19 studies [1, 2], following up 53 patients one year into convalescence. This unique cohort includes 30 people who are fully recovered and 23 with long COVID. All have been evaluated by multi-parameter flow cytometry and a subset have had B cell receptor repertoire sequencing. The main perturbations of B/T cell phenotypes in acute COVID-19 resolve, however, there was an unexpected peak in the complementarity determining region of the B cell receptor repertoire in long COVID patients. Interestingly, the consensus sequence is an 82% match to spike protein monoclonal antibody sequences (Figure 1) and only present in IgM and IgD receptors. This implies that patients with long COVID have a different humoral response to those with a full recovery from acute COVID-19. References: [1] Mann ER, Menon M, Knight SB, et al. Longitudinal immune profiling reveals key myeloid signatures associated with COVID-19. Sci Immunol. 2020;5(51). [2] Shuwa HA, Shaw TN, Knight SB, et al. Alterations in T and B cell function persist in convalescent COVID-19 patients. Med (N Y). 2021;2(6):720-35 e4.
379	I377		Neves, Pablo Fabiano Moura das; Quaresma, Juarez Antônio Simões; Queiroz, Maria Alice Freitas; Silva, Camilla Costa; Maia, Enzo Varela; Oliveira, João Sergio de Sousa; Neves, Carla Manuela Almeida das; Mendonça, Suellen da Silva; Falcão, Aline Semblano Carreira; Melo, Giovana Salomão; Santos, Isabella Boechat Faria; Sousa, Jorge Rodrigues de; Santos, Eduardo José Melo dos; Vasconcelos, Pedro Fernando da Costa; Vallinoto, Antonio Carlos Rosário; Falcão, Luiz Fábio Magno	Imbalance of Peripheral Temperature, Sympathovagal, and Cytokine Profile in Long COVID	https://doi.org/10.3390/biology12050749	Published	2023-05-01	Study	https://www.mdpi.com/2079-7737/12/5/749	Simple Summary In this study, we looked at how persistent inflammation affects peripheral body temperature and sympathovagal balance in individuals with long COVID. Increased temperature and reduced heart rate variability were directly related to the increase in inflammatory cytokines and reduction in anti-inflammatory cytokines. We identified a possible “molecular signature” for long COVID, characterised by a Th17 inflammatory profile with a reduced anti-inflammatory response, resulting in alterations in homeostatic functions and sympathovagal balance. Abstract A persistent state of inflammation has been reported during the COVID-19 pandemic. This study aimed to assess short-term heart rate variability (HRV), peripheral body temperature, and serum cytokine levels in patients with long COVID. We evaluated 202 patients with long COVID symptoms categorized them according to the duration of their COVID symptoms (≤120 days, n = 81; >120 days, n = 121), in addition to 95 healthy individuals selected as controls. All HRV variables differed significantly between the control group and patients with long COVID in the ≤120 days group (p < 0.05), and participants in the long COVID ≤120 days group had higher temperatures than those in the long COVID >120 days group in all regions analysed (p < 0.05). Cytokine analysis showed higher levels of interleukin 17 (IL-17) and interleukin 2 (IL-2), and lower levels of interleukin 4 (IL-4) (p < 0.05). Our results suggest a reduction in parasympathetic activation during long COVID and an increase in body temperature due to possible endothelial damage caused by the maintenance of elevated levels of inflammatory mediators. Furthermore, high serum levels of IL-17 and IL-2 and low levels of IL-4 appear to constitute a long-term profile of COVID-19 cytokines, and these markers are potential targets for long COVID-treatment and prevention strategies.
380	I378		Espindola, M.; Hohman, M.; Sá, Y.; Garcia, S.; Creyns, B.; Coelho, A. L.; Yao, C.; Chiang, G.; Parimon, T.; Strip, B.; Chen, P.; Hogaboam, C.	Biomarker identification in fatal and post-acute sequelae of SARS-CoV-2 (PASC) lungs leads to epigenetic targeting in PASC-related fibrosis	https://doi.org/10.1183/23120541.LSC-2023.201	Published	2023-03-09	Study	https://openres.ersjournals.com/content/9/suppl_10/201	A percentage of COVID-19 affected patients develop post-acute sequalae of SARS-CoV-2, with evidence that SARS-CoV-2 causes ARDS leading to lung fibrosis (PASC-Fibrosis) that shares similarities with idiopathic pulmonary fibrosis (IPF). Herein, we addressed the hypothesis that fatal COVID-19, PASC, and IPF share key biomarkers of interest in lung fibrosis. Autopsy and explanted lung samples were subjected to histopathological and immunohistochemical (IHC) analysis for key biomarkers of interest in fibrosis. PASC-fibrosis-derived 2D and 3D cell cultures were treated with BRD4 inhibitors to evaluate proliferation and differentiation of fibroblasts, airway epithelial cells and lung bronchospheres. Single-cell RNA sequencing determined altered immune subpopulations. PASC-Fibrosis survivors had diffuse interstitial fibrosis, with organization into a non-specific interstitial fibrosis (NSIP) pattern. Transcriptomic analysis from fatal COVID-19 lungs showed BRD4, GDF15, IFNα2 and IL11 pathways markedly active. These findings were confirmed by IHC on PASC-fibrosis, with increased expression in myeloid cells. Altered frequencies in lung PASC-fibrosis subpopulations included loss of FABP4+ and increase of MERTK+SSP1+ macrophages and monocytes. Pharmacological inhibition of PASC-Fibrosis lung cultures and bronchospheres with BRD4 inhibitors limited outgrowth and differentiation of fibroblasts, airway epithelial cells and the formation of lung bronchospheres. In conclusion, shared profibrotic pathways among COVID-19 and chronic fibrotic ILDs provides the impetus to further explore treatment strategies to chronically ventilated COVID-19 patients.
381	I379		Boekel, Laura; Atiqi, Sadaf; Leeuw, Maureen; Hooijberg, Femke; Besten, Yaëlle R.; Wartena, Rosa; Steenhuis, Maurice; Vogelzang, Erik; Webers, Casper; Boonen, Annelies; Gerritsen, Martijn; Lems, Willem F.; Tas, Sander W.; Vollenhoven, Ronald F. van; Voskuyl, Alexandre E.; Horst-Bruinsma, Irene van der; Nurmohamed, Mike; Rispens, Theo; Wolbink, Gertjan	Post-COVID condition in patients with inflammatory rheumatic diseases: a prospective cohort study in the Netherlands	https://doi.org/10.1016/S2665-9913(23)00127-3	Published	2023-05-31	Study	https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(23)00127-3/fulltext	Background Studies on long-term consequences of COVID-19, commonly referred to as post-COVID condition, in patients with inflammatory rheumatic diseases are scarce and inconclusive. Furthermore, classifying patients with inflammatory rheumatic diseases as having post-COVID condition is complicated because of overlapping symptoms. Therefore, we investigated the risk of post-COVID condition and time until recovery, and compared the prevalence of symptoms seen in post-COVID condition, between patients with inflammatory rheumatic diseases and healthy controls, with and without a history of COVID-19. Methods In this substudy we used data from an ongoing prospective cohort study in the Netherlands. All adult patients with inflammatory rheumatic diseases from the Amsterdam Rheumatology and Immunology Center in Amsterdam, the Netherlands, were invited to participate in the study between April 26, 2020, and March 1, 2021. All patients were asked, but not obliged, to recruit their own control participant of the same sex, of comparable age (< 5 years), and without an inflammatory rheumatic disease. Demographic and clinical data, including data on the occurrence of SARS-CoV-2 infections, were collected via online questionnaires. On March 10, 2022, all study participants received a questionnaire on the occurrence, onset, severity, and duration of persistent symptoms during the first 2 years of the COVID-19 pandemic, independent of their history of SARS-CoV-2 infection. Additionally, we prospectively monitored a subset of participants who had a PCR or antigen confirmed SARS-CoV-2 infection in the 2-month period surrounding the questionnaire in order to assess COVID-19 sequelae. In line with WHO guidelines, post-COVID condition was defined as persistent symptoms that lasted at least 8 weeks, started after the onset and within 3 months of a PCR or antigen-confirmed SARS-CoV-2 infection, and could not be explained by an alternative diagnosis. Statistical analyses included descriptive statistics, logistic regression analyses, logistic-based causal mediation analyses, and Kaplan-Meier survival analyses for time until recovery from post-COVID condition. In exploratory analyses, E-values were calculated to investigate unmeasured confounding. Findings A total of 1974 patients with inflammatory rheumatic disease (1268 [64%] women and 706 [36%] men; mean age 59 years [SD 13]) and 733 healthy controls (495 [68%] women and 238 [32%] men; mean age 59 years [12]) participated. 468 (24%) of 1974 patients with inflammatory rheumatic disease and 218 (30%) of 733 healthy controls had a recent SARS-CoV-2 omicron infection. Of those, 365 (78%) of 468 patients with inflammatory rheumatic disease and 172 (79%) of 218 healthy controls completed the prospective follow-up COVID-19 sequelae questionnaires. More patients than controls fulfilled post-COVID condition criteria: 77 (21%) of 365 versus 23 (13%) of 172 (odds ratio [OR] 1·73 [95% CI 1·04–2·87]; p=0·033). The OR was attenuated after adjusting for potential confounders (adjusted OR 1·53 [95% CI 0·90–2·59]; p=0·12). Among those without a history of COVID-19, patients with inflammatory diseases were more likely to report persistent symptoms consistent with post-COVID condition than were healthy controls (OR 2·52 [95% CI 1·92–3·32]; p<0·0001). This OR exceeded the calculated E-values of 1·74 and 1·96. Recovery time from post-COVID condition was similar for patients and controls (p=0·17). Fatigue and loss of fitness were the most frequently reported symptoms in both patients with inflammatory rheumatic disease and healthy controls with post-COVID condition. Interpretation Post-COVID condition after SARS-CoV-2 omicron infections was higher in patients with inflammatory rheumatic disease than in healthy controls based on WHO classification guidelines. However, because more patients with inflammatory rheumatic disease than healthy controls without a history of COVID-19 reported symptoms that are commonly used to define a post-COVID condition during the first 2 years of the pandemic, it is likely that the observed difference in post-COVID condition between patients and controls might in part be explained by clinical manifestations in the context of underlying rheumatic diseases. This highlights the limitations of applying current criteria for post-COVID condition in patients with inflammatory rheumatic disease, and suggests it might be appropriate for physicians to keep a nuanced attitude when communicating the long-term consequences of COVID-19. publisher: Elsevier
382	I380		Calabrese, Leonard H.	Long COVID in inflammatory rheumatic diseases—what's in a name?	https://doi.org/10.1016/S2665-9913(23)00134-0	Published	2023-05-31	Article	https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(23)00134-0/fulltext	The impact of COVID-19 from the perspective of disease severity and overall mortality appears to be subsiding; however, what the future holds in terms of the post-COVID condition, commonly referred to as long COVID, remains uncertain. Although the effect of acute COVID-19 on patients with immune-mediated inflammatory diseases and inflammatory rheumatic diseases in particular has been extensively investigated, it is somewhat surprising that we still know relatively little regarding whether patients with immune-mediated inflammatory diseases are more or less susceptible to experiencing long COVID and, if it does occur, whether it is similar or different in severity and clinical expression to patients without immune-mediated inflammatory diseases. In The Lancet Rheumatology, Laura Boekel and colleagues1 have contributed considerably to efforts to address unanswered questions regarding long COVID in patients with inflammatory rheumatic diseases by reporting on an extension of a prospective cohort study that was originally designed to assess the severity of incident COVID-19 in patients with inflammatory rheumatic diseases and healthy controls in the Netherlands. Boekel and colleagues further exploited the original data, which was utilised to assess the frequency and characteristics of long COVID sequelae. Employing an assessment tool in line with WHO guidelines defining long COVID,2 they were able to explore prevalent and incident symptomatology in those with and without inflammatory rheumatic diseases, both with and without a history of COVID-19. Their top line results revealed that patients with inflammatory rheumatic diseases were more likely than healthy controls to experience new onset and persistent long COVID (21% vs 13%; odds ratio [OR] 1·73 [95% CI 1·04–2·87]; p=0·033), yet this was attenuated after adjusting for potential confounders (adjusted OR 1·53 [95% CI 0·90–2·59]; p=0·12). They also documented that symptoms of long COVID and recovery time were similar between patients with inflammatory rheumatic diseases and healthy controls. Thus, based on this first prospective and controlled investigation, the impact of long COVID on patients with inflammatory rheumatic diseases might be greater than in healthy controls, but appears likely to be similar in clinical expression and natural history when comparing the two groups. • View related content for this article Beyond these observations, and perhaps of even more importance, is the exploratory analysis revealing that patients with inflammatory rheumatic diseases, but without a history of COVID-19, were more likely to report common long COVID symptoms during the first 2 years of the pandemic than were healthy controls without a history of COVID-19. Most studies, including the study by Boekel and colleagues, rely on WHO guidelines2 which define long COVID as any symptom lasting 8 weeks (and starting after the onset of and within 3 months of a SARS-CoV-2 infection) that cannot be explained by an alternative diagnosis. Among the most prevalent symptoms identified in the current study, in those both with and without inflammatory rheumatic diseases or COVID-19, were fatigue, loss of fitness, difficulties with concentration, sleep disturbances, and pain. Such symptoms are common among patients with inflammatory rheumatic diseases, especially in those with concomitant fibromyalgia,3, 4 and thus might confound efforts to identify affected patients on the basis of one unexplained symptom. At the same time it must also be emphasised that these limitations of case definition should not in any way diminish the reality of those suffering from long COVID, but rather should serve to remind us that at this stage of the pandemic we unfortunately still lack validated classification criteria for long COVID and of the importance of including non-SARS-CoV-2 infected controls in all studies. From a wider perspective, beyond the epidemiologic challenges of studying long COVID in patients with inflammatory rheumatic diseases, are the challenges of studying long COVID in the general population using clinical signs and symptoms. An assertion from a recent review5 that the number of symptoms which might occur in the wake of COVID-19 might exceed 200 should raise concern regarding the challenges of specificity when attempting to use the presence of medically unexplained symptoms to assign causality. Previous data from multiple studies in the pre-COVID era using community surveys showed that respondents reported a median of five symptoms in the past week, with 23% of the population reporting ten or more symptoms including the variable presence of fatigue, headache, sleep disturbances, dizziness, and back pain, which are largely medically unexplained.6, 7 Such symptomatology might constitute a reservoir of distress in our daily lives, challenging their utility in assigning causality from an infection with the magnitude of the global prevalence of COVID-19. Validated classification criteria for long COVID that can be used for comparative epidemiologic investigations and biomarker discovery are now urgently required. The field of rheumatology has extensive experience in the development of disease-state classification criteria for disorders that are complex and have many overlapping features with long COVID that could serve as a model for such efforts. For now it appears that long COVID, while an important reality affecting the lives of millions of individuals, remains incompletely defined and still in search of becoming a nosologically defined disease state. publisher: Elsevier
383	I381		Mohandas, Sindhu; Jagannathan, Prasanna; Henrich, Timothy J; Sherif, Zaki A; Bime, Christian; Quinlan, Erin; Portman, Michael A; Gennaro, Marila; Rehman, Jalees; RECOVER Mechanistic Pathways Task Force	Immune mechanisms underlying COVID-19 pathology and post-acute sequelae of SARS-CoV-2 infection (PASC)	https://doi.org/10.7554/eLife.86014	Published	2023-05-26	Review	https://doi.org/10.7554/eLife.86014	With a global tally of more than 500 million cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections to date, there are growing concerns about the post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Recent studies suggest that exaggerated immune responses are key determinants of the severity and outcomes of the initial SARS-CoV-2 infection as well as subsequent PASC. The complexity of the innate and adaptive immune responses in the acute and post-acute period requires in-depth mechanistic analyses to identify specific molecular signals as well as specific immune cell populations which promote PASC pathogenesis. In this review, we examine the current literature on mechanisms of immune dysregulation in severe COVID-19 and the limited emerging data on the immunopathology of PASC. While the acute and post-acute phases may share some parallel mechanisms of immunopathology, it is likely that PASC immunopathology is quite distinct and heterogeneous, thus requiring large-scale longitudinal analyses in patients with and without PASC after an acute SARS-CoV-2 infection. By outlining the knowledge gaps in the immunopathology of PASC, we hope to provide avenues for novel research directions that will ultimately lead to precision therapies which restore healthy immune function in PASC patients.
384	I382		Sahni, Dimple; Singh, Parvinder; kaur, Rajwant; Aggarwal, Sangeeta; kaur, Amandeep	Rising Incidence of Post Covid Rhinocerebral Mucormycosis: An Otolaryngologists Prospective	https://doi.org/10.1007/s12070-023-03886-z	Published	2023-05-29	Study	https://doi.org/10.1007/s12070-023-03886-z	Mucormycosis or grimmer popular name, “black fungus” has evolved public concern in context of covid-19 pandemic, Covid Associated Mucormycosis (CAM) seen in Covid-19 pandemic and as a post covid sequelae. The present study was conducted to find out the incidence of the Mucormycosis, and to study its association with post-covid status and co-morbidities. A retrospective study conducted at tertiary care centre over a period of four months, involving all patients with mucormycosis of the paranasal sinuses suffering from or having a history of coronavirus disease. 59 patients had CAM, 47 patients had rhino-orbital Mucormycosis, followed by nasal and paranasal Mucormycosis in 8 patients, 3 patients with rhino-orbital-cerebral Mucormycosis, and one patient with pulmonary Mucormycosis. Diabetes mellitus was present in all 59 patients, 60.41% who had HbA1c > 10 (range 7–15), and 39.58% had HbA1c < 10 with range 6–13. Only 8.33% had controlled diabetes status, uncontroled hypertension and diabetes was seen in 34.02%. All patients were started with IV amphotericin B anti-fungal drug, and followed by oral posaconazole. Depending upon the extent of the disease surgical debridement was done in 52 patients. All patients had history of steroid intake. 7 mortality was there. Uncontrolled diabetes, over-zealous use of steroids, uncontrolled underlying primary disease or co-morbidities, prolonged hospitalization in intensive care unit or normal wards, and hyperventilation all these factors together aggravated the CAM. So it’s proper management based on, prompt diagnosis, reversal of predisposing condition with proper medical and aggressive surgical debridement remain the corner stone for this deadly CAM.
385	I383		Jahankhani, Kasra; Ahangari, Fatemeh; Adcock, Ian M.; Mortaz, Esmaeil	Possible cancer-causing capacity of COVID-19: Is SARS-CoV-2 an oncogenic agent?	https://doi.org/10.1016/j.biochi.2023.05.014	Published	2023-10-01	Review	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10202899/	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown diverse life-threatening effects, most of which are considered short-term. In addition to its short-term effects, which has claimed many millions of lives since 2019, the long-term complications of this virus are still under investigation. Similar to many oncogenic viruses, it has been hypothesized that SARS-CoV-2 employs various strategies to cause cancer in different organs. These include leveraging the renin angiotensin system, altering tumor suppressing pathways by means of its nonstructural proteins, and triggering inflammatory cascades by enhancing cytokine production in the form of a “cytokine storm” paving the way for the emergence of cancer stem cells in target organs. Since infection with SARS-CoV-2 occurs in several organs either directly or indirectly, it is expected that cancer stem cells may develop in multiple organs. Thus, we have reviewed the impact of coronavirus disease 2019 (COVID-19) on the vulnerability and susceptibility of specific organs to cancer development. It is important to note that the cancer-related effects of SARS-CoV-2 proposed in this article are based on the ability of the virus and its proteins to cause cancer but that the long-term consequences of this infection will only be illustrated in the long run.
386	I384		Moynan, David; Barkat, Rizwan; Avramovic, Gordana; Morley, Deirdre; O'Kelly, Brendan; Lambert, John S.	The reactivation of herpesviruses in severe COVID-19; a retrospective analysis of a critical care cohort	https://doi.org/10.1016/j.clinpr.2023.100232	Published	2023-07-01	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10204275/	While this study is limited in its retrospective design, we have found that the reactivation of CMV (22.3%), EBV (26%), and HSV/VZV (9%) in this cohort is in line with what has previously been documented (Saade et al., 2021). CMV infection in particular was associated with invasive ventilation and longer ventilation times, as previously described (Niitsu et al., 2021, Gatto et al., 2022). However, contrary to results from other studies, there was no association with lymphopaenia and CMV infection, although the measurement of a single nadir lymphocyte count likely underestimates the time spent in a lymphopenic state. Furthermore, while not fully elucidated, the reactivation of latent viral infections is certainly multifactorial. The cytokine storm caused by SARS-CoV-2 infection is thought to induce herpesvirus reactivation via TNF-alpha and IL-6 among others, while the transcripts of SARS-CoV-2 are thought to interact with herpesvirus elements directly (Chen et al., 2022). Viral reactivation is not exclusive to SARS-CoV-2 infection, with herpesvirus reactivation documented prior to the onset of the pandemic in critically unwell patients in the ICU (Coşkun et al., 2017). As seen in our study, it is often associated with higher CRP values, mechanical ventilation and lymphopaenia. However, recent data from a non-critical care cohort has implicated EBV reactivation in the pathophysiology of long-COVID. In a study by Gold et al that investigated the prevalence of EBV reactivation in a long-COVID cohort, as defined by a positive titre for EBV EA-D IgG or EBV VCA IgM, 66.7% of long-term long-COVID patients were found to be positive for EBV reactivation (Gold et al., 2021). With many of these patients documented as asymptomatic to their initial infection, it strengthens the argument that SARS-CoV-2 infection itself plays a role in viral reactivation, independent of disease severity. In conclusion, we believe that the reactivation of herpesviruses in the setting of SARS-CoV-2 infection warrants further research, with the virus itself capable of stimulating other infections and potentially contribute to an enhanced disease severity and a protracted symptom course, as seen in long-COVID. PMID: 37251495 PMCID: PMC10204275

	A	B	C	D	E	F	G	H	I	J	K	M
1	Ref	PPLC	Authors	Title	DOI	Peer reviewed	Date	type	Link	Keys	Clés

2	CaV01	ENDO	Valentina O. Puntmann, MD, PhD1; M. Ludovica Carerj, MD1,2; Imke Wieters, MD3; et al	Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19)	https://doi.org/10.1001/jamacardio.2020.3557	Published	July 27, 2020	Original Investigation	https://jamanetwork.com/journals/jamacardiology/fullarticle/2768916	A study in JAMA Cardiology highlights the frequent cardiovascular sequelae in people who have been affected by covid, even without hospitalization. Nevertheless, a group of cardiologists warns against misinterpretations of cardiac abnomalies : https://cvctcardiobrief.com/letter-warns-against-clinical-role-for-cardiac-mri-in-asymptomatic-covid-patients/ In this cohort study including 100 patients recently recovered from COVID-19 identified from a COVID-19 test center, cardiac magnetic resonance imaging revealed cardiac involvement in 78 patients (78%) and ongoing myocardial inflammation in 60 patients (60%), which was independent of preexisting conditions, severity and overall course of the acute illness, and the time from the original diagnosis	Une étude dans JAMA Cardiology souligne les fréquentes séquelles cardio-vasculaires chez les personnes ayant été touchées par le covid, même sans hospitalisation. Cependant, un collectif de cardiologues publient une lettre mettant en garde contre les interprétations hâtives des anomalies aux images et déconseillent les IRM sur les patients asymptomatiques. https://cvctcardiobrief.com/letter-warns-against-clinical-role-for-cardiac-mri-in-asymptomatic-covid-patients/
3	CaV02	No	Diana Lindner, PhD1,2; Antonia Fitzek, MD3; Hanna Bräuninger, MS1,2; et al	Association of Cardiac Infection With SARS-CoV-2 in Confirmed COVID-19 Autopsy Cases	https://doi.org/10.1001/jamacardio.2020.3551	Published	July 27, 2020	Brief Report	https://jamanetwork.com/journals/jamacardiology/fullarticle/2768914	Another study (JAMA Cardiology) examines the cardiac damages observed during autopsies of patients who died from covid, and the viral load of SARS-CoV-2 RNA in the myocardium.	Une autre étude (JAMA Cardiology) s'intéresse aux atteintes cardiaques constatées lors d'autopsies de patients morts du covid, et de la charge virale d'ARN SARS-CoV-2 dans le myocarde.
4	CaV03	?	By ELIZABETH COONEY	Covid-19 infections leave an impact on the heart, raising concerns about lasting damage		Opinion	July 27, 2020	Editorial	https://www.statnews.com/2020/07/27/covid19-concerns-about-lasting-heart-damage/	An article from the US health news site STAT reviews these two studies from JAMA Cardiology. "biomarker evidence pointing to heart lesions typical of those seen after a heart attack" "It is premature to say whether the heart damage seen in patients recovering from covid is transient or permanent, but cardiologists are concerned."	Un article du site d'information américain consacré à la santé STAT revient sur ces deux études du JAMA Cardiology. "des preuves de biomarqueurs mettant en évidence des lésions cardiaques typiques de celles observées après une crise cardiaque" "Il est trop tôt pour dire si les lésions cardiaques observées chez les patients en convalescence du covid sont transitoires ou permanentes, mais les cardiologues sont inquiets"
5	CaV04	?	Juan A. Pérez-Bermejo, Serah Kang, Sarah J. Rockwood, Camille R. Simoneau,	SARS-CoV-2 infection of human iPSC-derived cardiac cells predicts novel cytopathic features in hearts of COVID-19 patients	https://doi.org/10.1101/2020.08.25.265561	pre-print	September 12, 2020	New Results	https://www.biorxiv.org/content/10.1101/2020.08.25.265561v2	Very qualitative study (https://biorxiv.org/content/10.1101/2020.08.25.265561v1) not yet peer-reviewed, which can explain the MRIs of cardiac attacks, from JAMA Cardiology (https://jamanetwork.com/journals/jamacardiology/fullarticle/2768916, end of July). Infection and spread of the virus in cardiomyocytes (contractile cells).	Étude très qualitative (biorxiv.org/content/10.110…) non encore relue, qui peut expliquer les IRM d'atteintes cardiaques du JAMA Cardiology (jamanetwork.com/journals/jamac…, fin juillet). Infection et propagation du virus dans les cardiomyocytes (cellules contractiles).
6	CaV05		Rocio Eiros, Manuel Barreiro-Perez, Ana Martin-Garcia, Julia Almeida, Eduardo Villacorta,	Pericarditis and myocarditis long after SARS-CoV-2 infection: a cross-sectional descriptive study in health-care workers	https://doi.org/10.1101/2020.07.12.20151316	pre-print	July 14, 2020	cross-sectional descriptive study	https://www.medrxiv.org/content/10.1101/2020.07.12.20151316v1	Myocarditis (inflammation of the heart) and pericarditis due to covid, even for asymptomatic patients, worry cardiologists, and raise fears of an increase in the incidence of heart failure. Detectable by cardiac MRI, myocarditis "is often cured without incident". "It is accompanied by symptoms such as shortness of breath, chest pain, fever and fatigue, but can also be asymptomatic."	Les myocardites (inflammation du cœur) et péricardites dues à la covid, même chez des asymptomatiques, inquiètent les cardiologues, et fait craindre une hausse de l'incidence des insuffisances cardiaque. Détectables par IRM cardiaque, les myocardites "se guérissent souvent sans incident". "Elle s'accompagnent de symptômes tels que l'essoufflement, les douleurs thoraciques, de la fièvre et de la fatigue, mais peuvent aussi être asymptomatiques."
7	CaV06	ENDO	Richard C. Becker	Anticipating the long-term cardiovascular effects of COVID-19	https://doi.org/10.1007/s11239-020-02266-6	Published	03 September 2020	Editorial	https://link.springer.com/article/10.1007/s11239-020-02266-6	What we know so far about the cardiac impacts of covid: a very comprehensive editorial by renowned cardiologist Richard Becker, to be put in the hands of all practitioners who follow #LongCovid patients.	Ce que l'on sait à ce jour des impacts cardiaques de la covid : un éditorial très complet du cardiologue réputé Richard Becker, à mettre dans les mains de tous les praticiens qui suivent des patients #LongCovid.
8	CaV07		Alessandro Di Minno, Pasquale Ambrosino, Ilenia Calcaterra, Matteo Nicola Dario Di Minno	COVID-19 and Venous Thromboembolism: A Meta-analysis of Literature Studies	https://doi.org/10.1055/s-0040-1715456	Published	03 September 2020	Review Article	https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0040-1715456	Venous thromboembolic disorders	Troubles thromboemboliques veineux
9	CaV08		Eric J. Topol	COVID-19 can affect the heart	https://doi.org/10.1126/science.abe2813	Published	23 Oct 2020	PERSPECTIVE	https://science.sciencemag.org/content/370/6515/408	Synthetic article by the well-known American cardiologist @EricTopol on the current state of knowledge concerning heart attacks linked to covid.	Article synthétique du très renommé cardiologue américain @EricTopol sur l'état actuel des connaissances concernant les atteintes cardiaques liées à la covid.
10	CaV09		Robert O. Bonow, MD, MS1,2; Patrick T. O’Gara, MD3,4; Clyde W. Yancy, MD, MSc1,4	Cardiology and COVID-19	https://doi.org/10.1001/jama.2020.15088	Published	September 22/29, 2020	Viewpoint	https://jamanetwork.com/journals/jama/fullarticle/2770858	JAMA publishes abstracts of specialists on different aspects of covid pathologies. Cardiological: https://jamanetwork.com/journals/jama/fullarticle/2770858 "There remain important unknowns regarding the intermediate and long-term sequelae of COVID-19 infection"	Le JAMA publie des synthèses de spécialistes sur différents aspects des pathologies covid. Cardiologiques "There remain important unknowns regarding the intermediate and long-term sequelae of COVID-19 infection"
11	CaV007		Gennaro Giustino, MD,a,∗∗ Lori B. Croft, MD,a,∗ Giulio G. Stefanini, MD, PhD,b,∗∗ Renato Bragato, MD,b	Characterization of Myocardial Injury in Patients With COVID-19	https://doi.org/10.1016%2Fj.jacc.2020.08.069	Published	2020 Oct 26	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588179/	A technical article which details myocardial damage in patients with covid.	Un article technique qui détaille les atteintes du myocarde chez les malades de la covid.
12	CaV008	Yes	Daniel Brito, Scott Meester, Naveena Yanamala, Heenaben B. Patel, Brenden J. Balcik,	High Prevalence of Pericardial Involvement in College Student Athletes Recovering From COVID-19	https://doi.org/10.1016/j.jcmg.2020.10.023	Published	Nov 25, 2020	Clinical Research	https://www.jacc.org/doi/10.1016/j.jcmg.2020.10.023	In a cohort of 160 young athletes affected by covid, 48 of whom had extensive cardiac examinations, a West Virginia study to appear in JACC: Cardiovascular Imaging finds heart damage in 27 patients.	Dans une cohorte de 160 jeunes athlètes touchés par la covid dont 48 ont eu des examens cardiaques poussés, une étude en Virginie-Occidentale à paraître dans JACC: Cardiovascular Imaging constate des lésions cardiaques pour 27 patients.
13	CaV009	ENDO	Bingwen Eugene Fan, Thirugnanam Umapathi, Karen Chua, Yew Woon Chia	Delayed catastrophic thrombotic events in young and asymptomatic post COVID-19 patients	https://doi.org/10.1007/s11239-020-02332-z	Published	07 November 2020	Case Letter to the Editor	https://link.springer.com/article/10.1007/s11239-020-02332-z	Four cases in Singapore of severe delayed vascular damage, avg. 38 years old, who were asymptomatic, including 3 without risk factors.	Quatre cas à Singapour de graves dégâts vasculaires différés, moy. 38 ans, qui étaient asymptomatiques dont 3 sans facteur de risques.
14	CaV010	ENDO	Yu Zuo1, Shanea K. Estes1, Ramadan A. Ali1, Alex A. Gandhi1	Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19	https://doi.org/10.1126/scitranslmed.abd3876	Published	18 Nov 2020	RESEARCH ARTICLE	https://stm.sciencemag.org/content/12/570/eabd3876	The cycle of inflammation and coagulation that creates blood clots in covid patients, linked to autoantibodies and similar to Hughes syndrome, better understood thanks to a 🇺🇲 study. The reaction causes thrombosis, pulmonary embolism and stroke. The team is launching a clinical trial (https://clinicaltrials.gov/ct2/show/NCT04391179) on dipyridamole, an anticoagulant showing promise for blocking this specific type of inflammation.	Le cycle d'inflammation et de coagulation qui crée des caillots sanguins chez des malades covid, lié à des auto-anticorps et proche du syndrome de Hughes, mieux compris grâce à une étude 🇺🇲. La réaction provoque thromboses, embolies pulmonaires et AVC. L'équipe lance un essai clinique (clinicaltrials.gov/ct2/show/NCT04…) sur le dipyridamole, anticoagulant prometteur pour bloquer ce type spécifique d’inflammation.
15	CaV011		Kathleen M. Capaccione Jay S. Leb Belinda D'souza	Acute myocardial infarction secondary to COVID-19 infection: A case report and review of the literature	https://doi.org/10.1016/j.clinimag.2020.11.030	Published	November 14, 2020	Case report and review	https://www.clinicalimaging.org/article/S0899-7071(20)30462-9/fulltext#%20	An unprecedented case of acute coronary syndrome (obstruction of a coronary artery, precursor of myocardial infarction) following a covid infection, reported by a New York team, supplemented by a review of the literature on this subject.	Un cas inédit de syndrome coronarien aigu (obstruction d'une artère coronaire, précurseur d'infarctus du myocarde) consécutif à une infection covid, rapporté par une équipe new-yorkaise, complété d'une revue de la littérature sur ce sujet.
16	CaV012		Marijke Linschoten, Sanne Peters, Maarten van Smeden, ...	Cardiac complications in patients hospitalised with COVID-19	https://doi.org/10.1177%2F2048872620974605	Published	November 21, 2020	Research Article	https://journals.sagepub.com/doi/full/10.1177/2048872620974605	A very large international study (CAPACITY-COVID) intended to quantify the incidence of cardiac complications, on a cohort of patients with a median age of 67 (63% men.), found 20% of deaths and 11.6% of cardiac complications during hospitalization.	Une très large étude internationale (CAPACITY-COVID) destinée à quantifier l'incidence des complications cardiaques, sur une cohorte de patients de médiane 67 ans (63% h.), relève 20% de décès et 11,6% de complications cardiaques pendant l'hospitalisation.
17	CaV013		Moutal, Aubin1; Martin, Laurent F.2,; Boinon, Lisa1,; Gomez, Kimberly	SARS-CoV-2 Spike protein co-opts VEGF-A/Neuropilin-1 receptor signaling to induce analgesia	https://doi.org/10.1097/j.pain.0000000000002097	Published	October 01, 2020	RESEARCH PAPER	https://journals.lww.com/pain/Abstract/9000/SARS_CoV_2_Spike_protein_co_opts.98244.aspx		Une étude avance l'hypothèse que la protéine Spike du SARS-CoV-2 pourrait bloquer sur l'endothélium vasculaire A (VEGF-A) les récepteurs de neuropiline-1 (NRP-1), et donc inhiber la douleur. Les auteurs évoque une douleur "mise en sourdine" ("silencing").
18	CaV014		Puneet Kaur Randhawa1 , Kaylyn Scanlon1 , Jay Rappaport2 and Manish K. Gupta	Modulation of Autophagy by SARS-CoV-2: A Potential Threat for Cardiovascular System	https://doi.org/10.3389/fphys.2020.611275	Published	30 November 2020	Mini-review article	https://www.frontiersin.org/articles/10.3389/fphys.2020.611275/full		Une revue de la littérature sur les effets cardiovasculaires de la covid, et l'impact du dérèglement de l'autophagie par le virus.
19	CaV015		Geraldine Martorella, Suzanne Fredericks, Julie Sanders, Rochelle Wynne	Breaking pandemic chain reactions: telehealth psychosocial support in cardiovascular disease during COVID-19	https://doi.org/10.1093/eurjcn/zvaa011	Published	01 December 2020	Editorial	https://academic.oup.com/eurjcn/advance-article/doi/10.1093/eurjcn/zvaa011/6013085		La possibilité de lésions cardiaques provoquées par la covid, associée aux conditions socio-économiques de la crise, majorent le risque de maladies cardiovasculaires, selon une étude qui met en avant des thérapies de santé mentale et la télémédecine.
20	CaV016		Young Joo Suh, Hyunsook Hong, Hasti Robbie, Soon Ho Yoon	Pulmonary Embolism and Deep Vein Thrombosis in COVID-19: A Systematic Review and Meta-Analysis	https://doi.org/10.1148/radiol.2020203557	Published	Dec 15 2020	Systematic Review and Meta-Analysis	https://pubs.rsna.org/doi/10.1148/radiol.2020203557		_
21	CaV017		Patrick S. Buckley, MD and Catherine A. Logan MD, MBA, MSPT	COVID-19 Related Cardiology for the Sports Medicine Physician		Published	Dec 2020	Opinion	https://www.sportsmed.org/aossmimis/STOP/Downloads/Posts/CardiacCovid_Buckley_Logan.pdf		Un article d'opinion de médecins du sport sur les risques pour les athlètes avec la covid, qui renvoit notamment à ce guide : https://jamanetwork.com/journals/jamacardiology/fullarticle/2772399 ainsi qu'à ce guide de retour à l'activité sportive : https://services.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/clinical-guidance/covid-19-interim-guidance-return-to-sports/
22	CaV018		Linghua Fu, Xiao Liu, Yuhao Su, Jianyong Ma, Kui Hong	Prevalence and impact of cardiac injury on COVID‐19: A systematic review and meta‐analysis	https://doi.org/10.1002/clc.23540	Published	31 December 2020	Systematic review and meta‐analysis	https://onlinelibrary.wiley.com/doi/full/10.1002/clc.23540		Une méta-analyse retrouve un quart de patients hospitalisés pour covid avec des lésions cardiaques, avec une forte corrélation entre l'importance de ces lésions et le risque létal.
23	CaV019			COVID-19 vasculitis and novel vasculitis mimics	https://doi.org/10.1016/S2665-9913(20)30420-3	Published	07/01/2021		https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(20)30420-3/fulltext		suggèrent que ce mécanisme représente une nouvelle vascularite-like liée au COVID-19 qui pourrait conduire à des accidents vasculaires cérébraux cryptogéniques à travers les territoires à plusieurs vaisseaux, à une lésion rénale aiguë avec hématurie, à une vascularite cutanée mimétique, à une ischémie intestinale et à d'autres manifestations ischémiques d'organes.
24	CaV020		Kurz David J., Eberli Franz R.	Cardiovascular aspects of COVID-19	https://doi.org/10.4414/smw.2020.20417	Published	31.12.2020	Review	https://smw.ch/article/doi/smw.2020.20417		Dans la Swiss Medical Weekly, une revue d'études particulièrement documentée évalue et analyse les conséquences possibles cardio-vasculaires de la covid. Les principaux mécanismes d'attaque du virus y sont documentés, notamment avec le rôle du système rénine-angiotensine-aldostérone, la susceptibilité aux antécédents cardiaques et les mécanismes à long terme des lésions cardiaques.
25	CaV021		DAVE FORNELL	The Long-term Cardiovascular Impact of COVID-19		Published	January 22, 2021	Opinion	https://www.dicardiology.com/article/long-term-cardiovascular-impact-covid-19		Un article d'opinion décrit les séquelles cardiovasculaires de la covid et détaille les orientations que la recherche prend et devra prendre sur le sujet.
26	CaV022		Visesha Kakarla, Naoki Kaneko, May Nour, Kasra Khatibi, Fanny Elahi, David S Liebeskind, Jason D Hinman	Pathophysiologic mechanisms of cerebral endotheliopathy and stroke due to Sars-CoV-2	https://doi.org/10.1177%2F0271678X20985666	Published	February 2, 2021	Review Article	https://journals.sagepub.com/doi/full/10.1177/0271678X20985666	Cerebrovascular events have emerged as a central feature of the clinical syndrome associated with Sars-CoV-2 infection. This increase in infection-related strokes is marked by atypical presentations including stroke in younger patients and a high rate of hemorrhagic transformation after ischemia. A variety of pathogenic mechanisms may underlie this connection. Efforts to identify synergism in the pathophysiology underlying stroke and Sars-CoV-2 infection can inform the understanding of both conditions in novel ways. In this review, the molecular cascades connected to Sars-CoV-2 infection are placed in the context of the cerebral vasculature and in relationship to pathways known to be associated with stroke. Cytokine-mediated promotion of systemic hypercoagulability is suggested while direct Sars-CoV-2 infection of cerebral endothelial cells may also contribute. Endotheliopathy resulting from direct Sars-CoV-2 infection of the cerebral vasculature can modulate ACE2/AT1R/MasR signaling pathways, trigger direct viral activation of the complement cascade, and activate feed-forward cytokine cascades that impact the blood-brain barrier. All of these pathways are already implicated as independent mechanisms driving stroke and cerebrovascular injury irrespective of Sars-CoV-2. Recognizing the overlap of molecular pathways triggered by Sars-CoV-2 infection with those implicated in the pathogenesis of stroke provides an opportunity to identify future therapeutics targeting both Sars-CoV-2 and stroke thereby reducing the impact of the global pandemic.	Une revue d'études s'intéresse à la physiopathologie des endothéliopathies cérébrales et des AVC consécutifs à la covid. Elle décrit de possibles mécanismes viraux et inflammatoires qui entrent en jeu à la frontière cerveau / système sanguin.	N002
27	CaV023		Marketa Kubankova, Bettina Hohberger, Jakob Hoffmanns, Julia Fuerst, Martin Hermann, Jochen Guck, Martin Krater	Physical phenotype of blood cells is altered in COVID-19	https://doi.org/10.1101/2021.02.12.429482	pre-print	February 12, 2021	New Results	https://www.biorxiv.org/content/10.1101/2021.02.12.429482v1	"We found significant changes in erythrocyte deformability, lymphocyte stiffness, monocyte size, and neutrophil size and deformability. While some of these changes recovered to normal values after hospitalization, others persisted for months after hospital discharge, evidencing the long-term imprint of COVID-19 on the body." "neutrophil alterations observed in our recovered cohort were induced after the successful displacement of the virus by the immune system. This might be indicative for SARS-CoV-2 causing long-term immunological signals or even targeting bone marrow stem cells, as viral RNA was found post-mortem in patient bone marrow" "These alterations could be connected with long term symptoms of the recovered patients"	Sur une cohorte assez réduite, une étude allemande en relecture (pre-print) note chez les patients guéris de la phase aiguë de la covid des altérations des globules rouges et des granulocytes neutrophiles qui pourraient avoir des effets à long terme. Des changements dans la déformabilité érythrocytaire ainsi que celle des neutrophiles et de leur taille, se retrouvent avec des écarts statistiquement significatifs, sur une médiane de 7 mois après l'infection au SARS-CoV-2.
28	CaV024	ENDO	Mi Zhou,Chun-Ka Wong ,Ka-Chun Un ,Yuk-Ming Lau,Jeffrey Chun-Yin Lee,Frankie Chor-Cheung Tam,Yee-Man Lau,Wing-Hon Lai,Anthony Raymond Tam,Yat-Yin Lam,Polly Pang,Teresa Tong,Milky Tang, [ ... ],Chung-Wah Siu	Cardiovascular sequalae in uncomplicated COVID-19 survivors	https://doi.org/10.1371/journal.pone.0246732	Published	February 11, 2021	RESEARCH ARTICLE	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246732	The mean age was 46.5 ± 18.6 years; 53.6% were men. All were classified with non-severe disease without overt cardiac manifestations and did not require intensive care. Median hospitalization stay was 17 days and median duration from discharge to screening was 11 days. Cardiac abnormalities were detected in 42.3% including sinus bradycardia (29.9%), newly detected T-wave abnormality (8.2%), elevated troponin level (6.2%), newly detected atrial fibrillation (1.0%), and newly detected left ventricular systolic dysfunction with elevated NT-proBNP level (1.0%). Significant sinus bradycardia with heart rate below 50 bpm was detected in 7.2% COVID-19 survivors, which appeared to be self-limiting and recovered over time.	Première étude systémique d'évaluation cardio-vasculaire pour détecter les atteintes cardiaques subcliniques et/ou latentes parmi des cas hospitalisés de la covid non sévères. Les atteintes non directement perceptibles sont fréquentes, parfois seulement révélées par IRM cardiaque (CRM).	N002N
29	CaV025		Ehsan Zaboli1 , Roya Ghasemian2 , Mahdi Abounoori3 , Mohammad Zahedi4 , Seyyed Abbas Hashemi * 5	Deep Vein Thrombosis Associated With COVID-19	http://pbr.mazums.ac.ir/article-1-360-en.html	Published	2020	Case Report	http://pbr.mazums.ac.ir/article-1-360-en.html	Deep vein thrombosis (DVT) is a devastating condition that usually involves the lower extremities. The typical course of DVT is associated with an episode of enormous limb swelling and pain. In this case report, we aimed to present one of the COVID-19 possible complications: DVT in a 38 years old man infected with SARS-CoV-2. A 38 years old man presented with leg pain. He had a dry cough and fatigue suspicious symptoms of COVID-19.	Un cas rapporté de thrombose veineuse profonde consécutif à une infection de covid.
30	CaV026	ENDO	Tushar Kotecha, Daniel S Knight, Yousuf Razvi, Kartik Kumar, Kavitha Vimalesvaran, George Thornton, Graham D Cole, Marianna Fontana	Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance	https://doi.org/10.1093/eurheartj/ehab075	Published	18 February 2021	Study	https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab075/6140994	Multi-organ involvement in COVID-19 is recognized, with many patients having troponin release indicative of acute myocardial injury.6–11 Here, in a multicentre study across six acute hospitals, we show that myocardial injury during acute COVID-19 infection requiring acute hospital admission is associated with a CMR abnormality in approximately half of patients, with three patterns of injury being observed: non-infarct, myocarditis-pattern injury (27%), ischaemic pathology (22%), and non-ischaemic non-specific scar (5%). Dual pathology with ischaemic and non-ischaemic features was observed in 6%. The different patterns of abnormalities found suggest multiple possible underlying mechanisms including myocarditis (with limited extent and no functional consequence), MI (type 1 or type 2), and inducible myocardial ischaemia.	Dans une étude multicentrique, une équipe montre que les lésions myocardiques (avec niveau élevé de troponine) chez les patients covid hospitalisés sont associées à une anomalie visible à l'IRM cardiovasculaire chez environ la moitié d'entre eux.	N003A
31	CaV027	ENDO	Alan D.KayeMD, PhD(Professor, Provost, Allyson L.Spence, MariahMayerlecNitishSardana, Claire M.Clay, Matthew R.EngMD,Markus M.LuediMDgPh.DMichelle A.Carroll Turpin, Richard D.Urman, Elyse M.Cornett	The impact of COVID-19 infection on the cardiovascular system: an evidence-based analysis of risk factors and outcomes	https://doi.org/10.1016/j.bpa.2021.02.003	Published	1 March 2021	Analysis	https://www.sciencedirect.com/science/article/pii/S1521689621000082	In this evidence-based review, we discuss risk factors of cardiovascular involvement in COVID-19 infection, pathophysiology of COVID-19-related cardiovascular infection and injury, COVID-19 effects on the cardiovascular system and corresponding treatments, and hematologic effects of COVID-19 and COVID-19 in heart transplant patients.	Une revue des facteurs de risque cardiovasculaire pour la covid, de la physiopathologie des blessures cardiovasculaires liées, des atteintes hématologiques et sur le système cardiovasculaire, et enfin évocation des traitements correspondants. La dysfonction endothéliale est présentée comme un élément parmi plusieurs autres de dommages vasculaires pouvant être causés par le SARS-CoV-2.	N003A
32	CaV028	ENDO	Federica Catapano, Livia Marchitelli, Giulia Cundari, Francesco Cilia, Giuseppe Mancuso, Giacomo Pambianchi, Nicola Galea, Paolo Ricci, Carlo Catalano & Marco Francone	Role of advanced imaging in COVID-19 cardiovascular complications	https://doi.org/10.1186/s13244-021-00973-z	Published	24 February 2021	Critical Review	https://insightsimaging.springeropen.com/articles/10.1186/s13244-021-00973-z	Present article aims to review the value of advanced multimodality imaging in patients with suspected SARS-CoV-2-related cardiovascular involvement and its essential role in risk stratification and tailored treatment strategies. Based on our experience, we also sought to suggest possible diagnostic algorithms for the rationale utilization of advanced imaging tools, such as cardiac CT and CMR, avoiding unnecessary examinations and diagnostic delays.	Une étude examine la valeur de l'imagerie multimodale avancée chez les patients avec des séquelles cardiovasculaires liées à la covid. Les auteurs suggèrent des algorithmes de diagnostic possibles pour justifier l'utilisation d'outils d'imagerie avancés.	N004
33	CaV029		Satish R. Raj, Amy C. Arnold, Alexandru Barboi, Victoria E. Claydon, Jacqueline K. Limberg, Vera-Ellen M. Lucci, Mohammed Numan, Amanda Peltier, Howard Snapper, Steven Vernino	Long-COVID postural tachycardia syndrome: an American Autonomic Society statement		Published	19 March 2021	Review Article	https://link.springer.com/article/10.1007/s10286-021-00798-2	There is much that is not known about Long-COVID POTS. While not exhaustive, the list includes: 1. Natural history of Long-COVID POTS. Is this a self-limiting disorder that will resolve in several months, or one that will last for years? 2. Underlying pathophysiology of Long-COVID POTS. 3. Are patients with Long-COVID POTS different from patients with POTS unrelated to COVID-19? 4. Best treatments for Long-COVID POTS.	Une analyse américaine s'intéresse au syndrome de tachycardie posturale (PoTS) dans le cadre de la covid. Elle évalue toutes les inconnues actuelles liées à ce symptôme de la covid et esquisse des hypothèses explicatives.	N006
34	CaV030		Dr. Lázaro Alfonso Pérez Cabrera. * Dra. Natalia L. Planas Sliuntiaeva. ** Dr. Ronald Aroche Aportela	Miocarditis post Covid-19 a propósito de un caso tratado con Jusvinza Post Covid-19 myocarditiscase treated with Jusvinza		Published	Mars 2021	Case Report	https://aniversariocimeq2021.sld.cu/index.php/ac2021/Cimeq2021/paper/viewFile/91/43	or https://aniversariocimeq2021.sld.cu/index.php/ac2021/Cimeq2021/paper/view/91 SARSCov 2 disease (Covid-19) manifests with a broad spectrum of clinical presentation, ranging from asymptomatic disease to severe respiratory failure, myocardial injury, and death. As more patients recover from the acute stage, reports of cardiovascular manifestations such as: heart failure, arrhythmias, myocarditis, among others that could be considered as a disease sequel, increase. Existing reports of coronavirus myocarditis are scarce, but it appears that more heart damage occurs in patients affected by Covid-19 than by other coronaviruses. A 50-year-old patient is presented, with a history of Covid-19 diagnosed 23 days ago, who comes in due to palpitations. In the emergency room the exam revealed arrhythmic heart sounds and elevated heart rate, corroborating atrial fibrillation in the electrocardiogram with rapid ventricular response, accompanied by increased cardiac enzymes. He was diagnosed as Post Covid-19 myocarditis and was admitted to intensive care unit, antiarrhythmic and immunomodulatory treatment with Jusvinza was started.	_
35	CaV031		LeylaHazaraMineKarahanaEsraVuralbSedatAvaaSeyfettinErdemaMehmet EminDursunaUğurKeklikçi	Macular vessel density in patients recovered from COVID-19 disease	https://doi.org/10.1016/j.pdpdt.2021.102267	Published	27 March 2021	Study	https://www.sciencedirect.com/science/article/pii/S1572100021000934	Highlights •COVID-19, lead to vasculopathy and retinal vascular pathologies. •The ability of OCTA to provide vascular mapping of separate layers is an important advantage. •Very limited report is available about superficial and deep capillary plexus in patients with COVID 19 disease. •Vascular densities of both superficial and deep capillary network are affected in COVID 19 disease. •Foveal avascular zone is not affected in patients who have recovered from mild to moderate COVID-19 disease.	Une étude s'intéresse aux vasculopathies consécutives à la covid qui peuvent affecter la vision. La mesure de densité vasculaire rétinienne maculaire peut être étudiée par tomographie par cohérence optique (TCO), qui permet une cartographie vasculaire de couches séparées. L'étude explique que la covid peut affecter le réseau capillaire superficiel et profond de l'oeil, même si la zone avasculaire fovéale n'est pas affectée chez les patients qui se sont rétablis d'une covid légère à modérée.	N006
36	CaV032		Carole Émile	Risque thrombotique de la Covid-19	https://dx.doi.org/10.1016%2FS0992-5945(21)00048-9	Published	2021 mars 29		https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006242/	La fréquence des embolies pulmonaires au cours de la Covid-19 est élevée, voisine de 20 %. La physiopathologie des événements thromboemboliques est complexe et reste mal connue, notamment pour les thromboses artérielles. Une prophylaxie anti-thrombotique est proposée chez les patients hospitalisés en l’absence de risque hémorragique, à doses habituelles ou élevées, ainsi que chez les patients à domicile en cas de réduction de la mobilité associée à un facteur de risque.	_
37	CaV033	ENDO	Aldo Bonaventura, Alessandra Vecchié, Lorenzo Dagna, Kimberly Martinod, Dave L. Dixon, Benjamin W. Van Tassell, Francesco Dentali, Fabrizio Montecucco, Steffen Massberg, Marcel Levi & Antonio Abbate	Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19	https://doi.org/10.1038/s41577-021-00536-9	Published	06 April 2021	Article	https://www.nature.com/articles/s41577-021-00536-9	Here, we propose that SARS-CoV-2 infection induces a process known as immunothrombosis, in which activated neutrophils and monocytes interact with platelets and the coagulation cascade, leading to intravascular clot formation in small and larger vessels. Microthrombotic complications may contribute to acute respiratory distress syndrome (ARDS) and other organ dysfunctions. Therapeutic strategies aimed at reducing immunothrombosis may therefore be useful. Several antithrombotic and immunomodulating drugs have been proposed as candidates to treat patients with SARS-CoV-2 infection.	Un article de recherche très qualitatif dans Nature explore l'hypothèse physiopathologique des micro-thromboses consécutives à une infection de SARS-CoV-2. L'étude pose l'idée que la covid entraîne un processus d'immunothrombose, dans lequel les neutrophiles et les monocytes activés interagissent avec les plaquettes et la cascade de la coagulation, conduisant à la formation de caillots intravasculaires dans des petits vaisseaux mais aussi de plus grande taille. L'étude y voit un impact sur les conséquences à long terme de la covid.	N007
38	CaV034		Fuad-Tahsin Abbas, Wayne State University School Of Medicine	The Ticking Time Bomb: COVID-19's hidden, long-term impact: permanent cardiovascular disease		Published	March 31, 2021		https://digitalcommons.wayne.edu/covidinfographics/38/		_
39	CaV035		Bingwen Eugene Fan , Christine Cheung	Post COVID-19 Arterial Thromboembolism: A Clear and Present Danger	https://doi.org/10.1055/s-0041-1728717	Published	15 avril 2021	Letter to the Editor	https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0041-1728717	The evidence of persistent endothelial dysfunction in post COVID-19 patients, including those with either no or minimal symptoms during initial infection, raises pressing concerns about the potential long-term cardiovascular effects. Besides arterial thromboembolism, COVID-19 survivors developing endothelial dysfunction may experience chronic cardiovascular complications such as heart failure, sudden cardiac death, arrhythmias (especially atrial fibrillation), accelerated arteriosclerosis,[21] pulmonary hypertension,[22] and arterial aneurysms.[23] Moreover, the incidence of vascular events due to endothelial dysfunction from COVID-19 in survivors is likely to be exacerbated by comorbidities such as hypertension and diabetes. Immunomodulatory therapy targeting thromboinflammation in COVID-19,[24] such as tocilizumab (anti–interleukin-6 receptor monoclonal antibodies) or the use of high-dose steroid therapy, may have benefits in reducing the inflammatory cascade in COVID-19 and endotheliitis in at-risk patients, and requires further evaluation.	Un article note que les preuves d'un dysfonctionnement endothélial persistant chez les patients postcovid, y compris les paucisymptomatiques en phase initiale, soulèvent des inquiétudes quant aux effets cardiovasculaires potentiels à long terme. Les auteurs remarquent que l'incidence des événements vasculaires dus au dysfonctionnement endothélial lié à la covid est susceptible d'être exacerbée par des comorbidités telles que l'hypertension et le diabète. Ils suggèrent qu'une thérapie immunomodulatrice ciblant la thromboinflammation (citant le tocilizumab), ou une corticothérapie à haute dose, peuvent présenter des avantages pour réduire les effets inflammatoires et l'endothélite chez les patients à risque.	N011
40	CaV036		Sabrine Zieda Mariem Messelmani Manel Akkari Hajer Derbali Malek Mansour Jamel Zaouali Ridha Mrissa	Accident vasculaire cérébral inaugural d’une infection COVID-19 : étude de 9 cas	https://doi.org/10.1016/j.neurol.2021.02.294	Published	11 April 2021	Study	https://www.sciencedirect.com/science/article/pii/S0035378721003362		_
41	CaV037		RichardChocronaBaptisteDuceaubNicolasGendroncNacimEzzouhairidLinaKhidereAntoninTrimaillefGuillaumeGoudoteOrianneWeizmangJean MarcAlsachThibaultPommieriOlivierBoryjJoffreyCellierkAurélienPhilippecLauraGenestelIannisBen AbdallahhVassiliPanagidesmSalmaEl BattihWassimaMarsounPhilippeJuvinjAntoineDeneyoEmmanuelMessaspSabirAttouqBenjaminPlanquetterDelphineMikasPascaleGaussemtCharlesFauveluJean-LucDiehlvTheoPezelwTristanMiraultpWillySutterbOlivierSanchezrGuillaumeBonnetbArielCohenx1David M.Smadjac1forthe Critical COVID-19 France investigators	D-dimer at hospital admission for COVID-19 are associated with in-hospital mortality, independent of venous thromboembolism: Insights from a French multicenter cohort studyLes D-dimères à l’admission pour COVID-19 sont associés à la mortalité hospitalière indépendamment du risque de thrombose veineuse	https://doi.org/10.1016/j.acvd.2021.02.003	Published	9 March 2021	Study	https://www.sciencedirect.com/science/article/pii/S1875213621000516	Highlights •COVID-19 has been associated with micro- and macrothrombotic events. •D-dimer measurement on admission is recommended in patients with COVID-19. •The optimum D-dimer cut-off has been a matter of debate. •We identified > 1128 ng/mL as the optimum cut-off to predict in-hospital mortality. •This cut-off predicts mortality independent of venous thromboembolism occurrence.	_
42	CaV038		Liam Townsend Helen Fogarty Adam Dyer Ignacio Martin‐Loeches Ciaran Bannan Parthiban Nadarajan Colm Bergin Cliona O’Farrelly Niall Conlon Nollaig M. Bourke Soracha E. Ward Mary Byrne Kevin Ryan Niamh O’Connell Jamie M. O’Sullivan Cliona Ni Cheallaigh James S. O’Donnell	Prolonged elevation of D‐dimer levels in convalescent COVID‐19 patients is independent of the acute phase response	https://doi.org/10.1111/jth.15267	Published	15 February 2021	BRIEF REPORT	https://onlinelibrary.wiley.com/doi/full/10.1111/jth.15267	ESSENTIALS Persistent fatigue, breathlessness, and reduced exercise tolerance following acute COVID‐19 infection has been termed long COVID syndrome. We observed sustained elevated D‐dimer levels in 25% of patients reviewed a minimum of 6 weeks following initial diagnosis. Although D‐dimers remained elevated, other coagulation and inflammation markers had returned to normal in the majority of patients. Despite ongoing symptoms and elevated D‐dimers, computed tomography pulmonary angiogram screening in eight patients failed to demonstrate pulmonary embolism. Further adequately powered studies will be required to elucidate the mechanisms underlying elevated D‐dimer levels during COVID‐19 convalescence.	Des niveaux accrus de D-dimères (marqueurs de coagulation) sont observés chez un quart des personnes infectées par le SARS-CoV-2 jusqu'à 4 mois après l'infection. L'étude lie ces examens à la pathogenèse du covid long.	N014E
43	CaV039		Nathaniel Moulson, Bradley J. Petek, Jonathan A. Drezner, Kimberly G. Harmon, Stephanie A. Kliethermes, Manesh R. Patel, and Aaron L. Baggish	SARS-CoV-2 Cardiac Involvement in Young Competitive Athletes	https://doi.org/10.1161/CIRCULATIONAHA.121.054824		17 Apr 2021		https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.054824	Among 19,378 athletes tested for SARS-CoV-2 infection, 3018 (mean age 20 years [SD,1 year]; 32% female) tested positive and underwent cardiac evaluation. A total of 2820 athletes underwent at least one element of cardiac 'triad' testing [12-lead electrocardiography (ECG), troponin, and/or transthoracic echocardiography(TTE)] followed by cardiac magnetic resonance (CMR) if clinically indicated. In contrast, primary screening CMR was performed in 198 athletes. Abnormal findings suggestive of SARS-CoV-2 cardiac involvement were detected by ECG (21/2999,0.7%), cardiac troponin (24/2719,0.9%), and TTE (24/2556,0.9%). Definite, probable, or possible SARS-COV-2 cardiac involvement was identified in 21/3018 (0.7%) athletes, including 15/2820 (0.5%) who underwent clinically indicated CMR (n=119) and 6/198 (3.0%) who underwent primary screening CMR. Accordingly, the diagnostic yield of CMR for SARS-COV-2 cardiac involvement was 4.2 times higher for a clinically indicated CMR (15/119,12.6%) versus a primary screening CMR (6/198,3.0%). After adjustment for race and sex, predictors of SARS-CoV-2 cardiac involvement included cardiopulmonary symptoms (OR:3.1,95% CI:1.2,7.7) or at least one abnormal triad test (OR:37.4,95% CI:13.3,105.3). Five (0.2%) athletes required hospitalization for non-cardiac complications of SARS-CoV-2. During clinical surveillance (median follow-up 113 days [IQR=90,146]), there was one (0.03%) adverse cardiac event likely unrelated to SARS-CoV-2 infection.	Chez les jeunes athlètes, les complications et séquelles cardiovasculaires semblent relativement rare. L'âge et les facteurs de comorbidité comme un terrain auto-immun favorable pourraient jouer.
44	CaV040	ENDO	Mina K. Chung,corresponding author1,2,3 David A. Zidar,3,4 Michael R. Bristow,5 Scott J. Cameron,1,2,3 Timothy Chan,1,2,3 Clifford V. Harding, III,3 Deborah H. Kwon,1,2,3 Tamanna Singh,1,2,3 John C. Tilton,3 Emily J. Tsai,6 Nathan R. Tucker,7,8 John Barnard,1,2 and Joseph Loscalzo	COVID-19 and Cardiovascular Disease From Bench to Bedside	https://dx.doi.org/10.1161%2FCIRCRESAHA.121.317997	Published	2021 Apr 16	Review	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048382/	Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can infect the heart, vascular tissues, and circulating cells through ACE2 (angiotensin-converting enzyme 2), the host cell receptor for the viral spike protein. Acute cardiac injury is a common extrapulmonary manifestation of COVID-19 with potential chronic consequences. This update provides a review of the clinical manifestations of cardiovascular involvement, potential direct SARS-CoV-2 and indirect immune response mechanisms impacting the cardiovascular system, and implications for the management of patients after recovery from acute COVID-19 infection.	Les lésions cardiaques aiguës sont une manifestation extrapulmonaire courante de la covid avec des conséquences chroniques potentielles, décrit une revue d'études qui répertorie les impacts cardio-vasculaires à long terme de la maladie.	N014E
45	CaV041	ENDO	Paul C Evans, G Ed Rainger, Justin C Mason, Tomasz J Guzik, Elena Osto, Zania Stamataki, Desley Neil, Imo E Hoefer, Maria Fragiadaki, Johannes Waltenberger, Christian Weber, Marie-Luce Bochaton-Piallat, Magnus Bäck	Endothelial dysfunction in COVID-19: a position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science	https://doi.org/10.1093/cvr/cvaa230	Published	04 August 2020		https://academic.oup.com/cardiovascres/article/116/14/2177/5880580	[We] provide a Position Statement on the importance of the endothelium in the underlying pathophysiology behind the clinical presentation in COVID-19 and identify key questions for future research to address. We propose that endothelial biomarkers and tests of function (e.g. flow-mediated dilatation) should be evaluated for their usefulness in the risk stratification of COVID-19 patients. A better understanding of the effects of SARS-CoV-2 on endothelial biology in both the micro- and macrovasculature is required, and endothelial function testing should be considered in the follow-up of convalescent COVID-19 patients for early detection of long-term cardiovascular complications.	Le Council on Basic Cardiovascular Science de la Société européenne de cardiologie recommande : "Nous proposons que les biomarqueurs endothéliaux et les tests de fonction endothéliale (par exemple la dilatation à médiation par le flux) soient évalués pour leur utilité dans la stratification du risque des patients COVID-19. Une meilleure compréhension des effets du SRAS-CoV-2 sur la biologie endothéliale à la fois dans le domaine micro et macro-vasculaire est nécessaire, et des tests de la fonction endothéliale doivent être envisagés dans le suivi des patients convalescents COVID-19 pour la détection précoce des complications cardiovasculaires de la maladie à long terme."
46	CaV042	ENDO	Peter Libby, Thomas Lüscher	COVID-19 is, in the end, an endothelial disease	https://doi.org/10.1093/eurheartj/ehaa623	Published	03 September 2020		https://academic.oup.com/eurheartj/article/41/32/3038/5901158	This essay explores the hypothesis that COVID-19, particularly in the later complicated stages, represents an endothelial disease. Cytokines, protein pro-inflammatory mediators, serve as key danger signals that shift endothelial functions from the homeostatic into the defensive mode. The endgame of COVID-19 usually involves a cytokine storm, a phlogistic phenomenon fed by well-understood positive feedback loops that govern cytokine production and overwhelm counter-regulatory mechanisms. The concept of COVID-19 as an endothelial disease provides a unifying pathophysiological picture of this raging infection, and also provides a framework for a rational treatment strategy at a time when we possess an indeed modest evidence base to guide our therapeutic attempts to confront this novel pandemic.	_
47	CaV043	ENDO	Zsuzsanna Varga,a Andreas J Flammer,b Peter Steiger,c Martina Haberecker,a Rea Andermatt,c Annelies S Zinkernagel,d Mandeep R Mehra,e Reto A Schuepbach,c Frank Ruschitzka,b and Holger Moch	Endothelial cell infection and endotheliitis in COVID-19	https://dx.doi.org/10.1016%2FS0140-6736(20)30937-5	Published	2020 Apr 21	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172722/	Our findings show the presence of viral elements within endothelial cells and an accumulation of inflammatory cells, with evidence of endothelial and inflammatory cell death. These findings suggest that SARS-CoV-2 infection facilitates the induction of endotheliitis in several organs as a direct consequence of viral involvement (as noted with presence of viral bodies) and of the host inflammatory response. In addition, induction of apoptosis and pyroptosis might have an important role in endothelial cell injury in patients with COVID-19. COVID-19-endotheliitis could explain the systemic impaired microcirculatory function in different vascular beds and their clinical sequelae in patients with COVID-19. This hypothesis provides a rationale for therapies to stabilise the endothelium while tackling viral replication, particularly with anti-inflammatory anti-cytokine drugs, ACE inhibitors, and statins.7, 8, 9, 10, 11 This strategy could be particularly relevant for vulnerable patients with pre-existing endothelial dysfunction, which is associated with male sex, smoking, hypertension, diabetes, obesity, and established cardiovascular disease, all of which are associated with adverse outcomes in COVID-19.	Dans The Lancet, des chercheurs rapportent que le recrutement de cellules immunitaires lors d'une covid, soit par infection virale directe de l'endothélium, soit à médiation immunitaire, peut entraîner un dysfonctionnement endothélial généralisé associé à l'apoptose (mort cellulaire). Cela renforce selon les auteurs l'intérêt de thérapies comprenant des médicaments anti-inflammatoires anti-cytokines, des inhibiteurs de l'ACE2 et des statines.	N014E
48	CaV044	ENDO	Florence WJ Chioh, Siew-Wai Fong, Barnaby E Young, Kan-Xing Wu, Anthony Siau, Shuba Krishnan, Yi-Hao Chan, Guillaume Carissimo, Louis LY Teo, Fei Gao, Ru San Tan, Liang Zhong, Angela S Koh, Seow-Yen Tan, Paul A Tambyah, Laurent Renia, Lisa FP Ng, David C Lye, Christine Cheung	Convalescent COVID-19 patients are susceptible to endothelial dysfunction due to persistent immune activation	https://doi.org/10.7554/eLife.64909	Published	Mar 23, 2021	Research Article	https://elifesciences.org/articles/64909	We found elevated levels of circulating endothelial cells (CECs), a biomarker of vascular injury, in COVID-19 convalescents compared to healthy controls. In particular, those with pre-existing conditions (e.g., hypertension, diabetes) had more pronounced endothelial activation hallmarks than non-COVID-19 patients with matched cardiovascular risk. Several proinflammatory and activated T lymphocyte-associated cytokines sustained from acute infection to recovery phase, which correlated positively with CEC measures, implicating cytokine-driven endothelial dysfunction. Notably, we found higher frequency of effector T cells in our COVID-19 convalescents compared to healthy controls. The activation markers detected on CECs mapped to counter receptors found primarily on cytotoxic CD8+ T cells, raising the possibility of cytotoxic effector cells targeting activated endothelial cells.	Une étude note un taux élevé de cellules endothéliales circulantes (CEC), un biomarqueur des lésions vasculaires, chez les convalescents de la covid par rapport aux témoins sains. Elle repère notamment des cytokines associées aux lymphocytes T pro-inflammatoires qui se maintiennent pendant la phase de récupération, impliquant un dysfonctionnement endothélial induit par celles-ci.	N009
49	CaV045	ENDO	Douglas Alexandre do Espírito Santo, Anna Cristina Bertoldi Lemos & Carlos Henrique Miranda	In vivo demonstration of microvascular thrombosis in severe COVID-19	https://doi.org/10.1007/s11239-020-02245-x	Published	13 August 2020	Study	https://link.springer.com/article/10.1007/s11239-020-02245-x	We report preliminary results of an in vivo evaluation of sublingual microcirculation in thirteen patients with severe COVID-19 requiring mechanical ventilation. We observed multiple filling defects moving within the microvessels indicative of thrombi in most of the cases 11/13 (85%). Microthrombi in pulmonary circulation is a common finding in autopsies of severe COVID-19 patients. In vivo evaluation of sublingual microcirculation of severe COVID-19 patients showed multiple filling defects moving within the microvessels indicative of thrombi in most of the cases. This is the first imaging documentation of microvascular thrombosis in living severe COVID-19 patients. The clinical relevance of microvascular thrombosis in COVID-19 requires further research.	_
50	CaV046	ENDO	Alexandros Rovas # 1, Irina Osiaevi # 1, Konrad Buscher 1, Jan Sackarnd 2, Phil-Robin Tepasse 3, Manfred Fobker 4, Joachim Kühn 5, Stephan Braune 6, Ulrich Göbel 7, Gerold Thölking 1 8, Andreas Gröschel 9, Hermann Pavenstädt 1, Hans Vink 10, Philipp Kümpers	Microvascular dysfunction in COVID-19: the MYSTIC study	https://doi.org/10.1007/s10456-020-09753-7	Published	2020 Oct 14	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556767/	Pre-clinical and autopsy studies have fueled the hypothesis that a dysregulated vascular endothelium might play a central role in the pathogenesis of ARDS and multi-organ failure in COVID-19. COVID-19 patients showed an up to 90% reduction in vascular density, almost exclusively limited to small capillaries (diameter 4–6 µm), and also significant reductions of VRBC. Especially, patients on mechanical ventilation showed severe glycocalyx damage as indicated by higher PBR values (i.e., thinner glycocalyx) and increased blood levels of shed glycocalyx constituents. Several markers of endothelial dysfunction were increased and correlated with disease severity in COVID-19. PBR (AUC 0.75, p = 0.01), ADAMTS13 (von Willebrand factor-cleaving protease; AUC 0.74, p = 0.02), and vascular endothelial growth factor A (VEGF-A; AUC 0.73, p = 0.04) showed the best discriminatory ability to predict 60-day in-hospital mortality. Conclusions Our data clearly show severe alterations of the microcirculation and the endothelial glycocalyx in patients with COVID-19. Future therapeutic approaches should consider the importance of systemic vascular involvement in COVID-19.	(Étude qui se concentre sur la fonction endothéliale pour comprendre les atteintes vasculaires.)
51	CaV047	ENDO	Gerlando Natalello,a,⁎ Giacomo De Luca,b Laura Gigante,a Corrado Campochiaro,b Enrico De Lorenzis,a,c Lucrezia Verardi,a Annamaria Paglionico,a Luca Petricca,a Anna Maria Martone,f Stefania Calvisi,d Marco Ripa,e Giulio Cavalli,b Emanuel Della-Torre,b Moreno Tresoldi,d Francesco Landi,f Silvia Laura Bosello,a Elisa Gremese,a and Lorenzo Dagna	Nailfold capillaroscopy findings in patients with coronavirus disease 2019: Broadening the spectrum of COVID-19 microvascular involvement	https://dx.doi.org/10.1016%2Fj.mvr.2020.104071	Published	2020 Sep 17	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494493/	Increasing evidence points to endothelial dysfunction as a key pathophysiological factor in coronavirus disease-2019 (COVID-19). No specific methods have been identified to predict, detect and quantify the microvascular alterations during COVID-19. Our aim was to assess microvasculature through nailfold videocapillaroscopy (NVC) in COVID-19 patients. Methods We performed NVC in patients with a confirmed diagnosis of COVID-19 pneumonia. Elementary alterations were reported for each finger according to a semi-quantitative score. Capillary density, number of enlarged and giant capillaries, number of micro-hemorrhages and micro-thrombosis (NEMO score) were registered. Results We enrolled 82 patients (mean age 58.8 ± 13.2 years, male 68.3%) of whom 28 during the hospitalization and 54 after recovery and hospital discharge. At NVC examination we found abnormalities classifiable as non-specific pattern in 53 patients (64.6%). Common abnormalities were pericapillary edema (80.5%), enlarged capillaries (61.0%), sludge flow (53.7%), meandering capillaries and reduced capillary density (50.0%). No pictures suggestive of scleroderma pattern have been observed. Acute COVID-19 patients, compared to recovered patients, showed a higher prevalence of hemosiderin deposits as a result of micro-hemorrhages (P = .027) and micro-thrombosis (P < .016), sludge flow (P = .001), and pericapillary edema (P < .001), while recovered patients showed a higher prevalence of enlarged capillaries (P < .001), loss of capillaries (P = .002), meandering capillaries (P < .001), and empty dermal papillae (P = .006). Conclusion COVID-19 patients present microvascular abnormalities at NVC. Currently ill and recovered subjects are characterized by a different distribution of elementary capillaroscopic alterations, resembling acute and post-acute microvascular damage. Further studies are needed to assess the clinical relevance of NVC in COVID-19.	Cette étude préconise d'utiliser la vidéo-capillaroscopie, qui enregistre nombre de microhémorragies et de micro-thromboses (score NEMO), pendant et après une hospitalisation.
52	CaV048		Elliot Akama-Garren, Praveen Anand, Tudor Cristea-Platon, Patrick Lenehan, Emily Lindemer, Sairam Bade, Saran Liukasemsarn, John C. O’Horo, Ryan T. Hurt, Amy W. Williams, Gregory J. Gores, Andrew D. Badley, Samir Awasthi, Venky Soundararajan	Hair loss in females and thromboembolism in males are significantly enriched in post-acute sequelae of COVID (PASC) relative to recent medical history	https://doi.org/10.1101/2021.01.03.20248997	Pre-print	April 13, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.01.03.20248997v2	Through comparison of the frequency of 10,039 signs and symptoms before and after diagnosis, we identified an increase in hypertensive chronic kidney disease (OR 47.3, 95% CI 23.9-93.6, p=3.50×10−9), thromboembolism (OR 3.84, 95% CI 3.22-4.57, p=1.18×10−4), and hair loss (OR 2.44, 95% CI 2.15-2.76, p=8.46×10−3) in COVID-19 patients three to six months after diagnosis. The sequelae associated with long COVID were notably different among male vs female patients and patients above vs under 55 years old, with the hair loss enrichment found primarily in females and the thromboembolism enrichment in males.	_
53	CaV049		Nishant R. Tiwari 1 Sanat Phatak Vivek R. Sharma Sanjay K. Agarwal	COVID-19 and thrombotic microangiopathies	https://doi.org/10.1016/j.thromres.2021.04.012	Published	April 19, 2021	REVIEW ARTICLE	https://www.thrombosisresearch.com/article/S0049-3848(21)00297-8/fulltext	Highlights •COVID – 19 infection can be associated with and complicated by the presence of thrombotic microangiopathies (TMAs). •Available evidence points to higher incidence of TMAs in seriously ill COVID-19 infected patients. •Treatment strategies for various TMAs including TPE, Eculizumab and immunosuppression in carefully selected patients can be lifesaving. •Retrospective studies for defining the incidence of TMAs in and RCTs for guiding the therapy of such patients are required.	_
54	CaV050		Louie F. Dy, Ryan C. V. Lintao, Cynthia P. Cordero, Ian Theodore G. Cabaluna & Leonila F. Dans	Prevalence and prognostic associations of cardiac abnormalities among hospitalized patients with COVID-19: a systematic review and meta-analysis	https://doi.org/10.1038/s41598-021-87961-x	Published	19 April 2021	Review	https://www.nature.com/articles/s41598-021-87961-x	This study aims to estimate the proportion of COVID-19 patients with cardiac abnormalities and to determine the association between the cardiac abnormalities in COVID-19 patients and disease severity and mortality. Pooled prevalence of cardiac abnormalities in 20 studies was calculated to be 0.31 [95% Confidence Intervals (CI) of (0.23; 0.41)], with statistically significant heterogeneity (percentage of variation or I-squared statistic I2 = 97%, p < 0.01). Pooled analysis of 19 studies showed an overall odds ratio (OR) of 6.87 [95%-CI (3.92; 12.05)] for cardiac abnormalities associated with disease severity and mortality, with statistically significant heterogeneity (I2 = 85%, between-study variance or tau-squared statistic τ2 = 1.1485, p < 0.01). Due to the high uncertainty in the pooled prevalence of cardiac abnormalities and the unquantifiable magnitude of risk (although an increased risk is certain) for severity or mortality among COVID-19 patients, much more long-term prognostic studies are needed to check for the long-term complications of COVID-19 and formalize definitive criteria of “COVID-19 associated cardiomyopathy”.	Une analyse reprenant les données de plusieurs études suggère que les atteintes cardiaques chez les patients hospitalisées pour la covid peuvent concerner un quart des malades. Elles multiplieraient par 7 le risque de décès.	N011
55	CaV051		Santiago Garcia, Payam Dehghani, Cindy Grines, Laura Davidson, Keshav R. Nayak, Jacqueline Saw, Ron Waksman, John Blair, Bagai Akshay, Ross Garberich, David A. Wood, Frederick G. Welt, Jay Giri, Ehtisham Mahmud, Timothy D. Henry	Initial Findings From the North American COVID-19 Myocardial Infarction Registry		Published	2021 Apr	Study	https://www.jacc.org/doi/abs/10.1016/j.jacc.2021.02.055	The coronavirus disease 2019 (COVID-19) pandemic has impacted many aspects of ST-segment elevation myocardial infarction (STEMI) care, including timely access to primary percutaneous coronary intervention (PPCI). As of December 6, 2020, 1,185 patients were included in the NACMI registry (230 COVID+ patients, 495 PUIs, and 460 control patients). COVID+ patients were more likely to have minority ethnicity (Hispanic 23%, Black 24%) and had a higher prevalence of diabetes mellitus (46%) (all p < 0.001 relative to PUIs). COVID+ patients were more likely to present with cardiogenic shock (18%) but were less likely to receive invasive angiography (78%) (all p < 0.001 relative to control patients). Among COVID+ patients who received angiography, 71% received PPCI and 20% received medical therapy (both p < 0.001 relative to control patients). The primary outcome occurred in 36% of COVID+ patients, 13% of PUIs, and 5% of control patients (p < 0.001 relative to control patients). Conclusions COVID+ patients with STEMI represent a high-risk group of patients with unique demographic and clinical characteristics. PPCI is feasible and remains the predominant reperfusion strategy, supporting current recommendations. Related pocast: https://www.jacc.org/do/10.1016/podcast-jacc-77-16-3/full/	_
56	CaV052		LÁZARO ALFONSO PÉREZ CABRERA, NATALIA L. PLANAS SLIUNTIAEVA, RONALD AROCHE APORTELA	Miocarditis post COVID-19: a propósito de un caso tratado con Jusvinza		Published	2021-04-28	Article	http://www.revcimeq.sld.cu/index.php/imq/article/view/716	La enfermedad causada por el coronavirus SARSCoV-2 (Covid - 19) se manifiesta por un amplio espectro en su presentación clínica, que va de la enfermedad asintomática hasta la insuficiencia respiratoria grave, lesión miocárdica y muerte. A medida que una mayor cantidad de pacientes se recuperan de la etapa aguda, aumentan los reportes de manifestaciones clínicas cardiovasculares como: insuficiencia cardíaca, arritmias, miocarditis, entre otras, que podrían ser consideradas como secuelas de la enfermedad. Los reportes existentes sobre miocarditis por coronavirus son escasos, pero al parecer se producen mayores daños cardiacos en los pacientes afectados por SARSCoV-2 que por otros coronavirus. Se presenta un paciente de 50 años, que acude por presentar palpitaciones, con el antecedente de Covid-19 diagnosticada hace 23 días. En urgencias se constatan, ruidos cardíacos arrítmicos y frecuencia cardiaca elevada, corroborándose en electrocardiograma fibrilación auricular con respuesta ventricular rápida, acompañado de una elevación de las enzimas cardíacas. Se diagnóstica como miocarditis Post Covid-19, se ingresa en cuidados intensivos y se comienza tratamiento antiarrítmico e inmunomodulador con Jusvinza.	_
57	CaV053		Rachel E. Szeghy Valesha M. Province Nina L. Stute Marc A. Augenreich Laurel K. Koontz Jonathon L. Stickford Abigail S. L. Stickford Stephen M. Ratchford	Carotid stiffness, intima media thickness, and aortic augmentation index among adults with SARS‐CoV‐2	https://doi.org/10.1113/EP089481	Published	26 April 2021	Study	https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/EP089481	New Findings What is the central question of this study? This study sought to investigate whether carotid stiffness and cIMT, as well as aortic augmentation index, are altered in young adults 3–4 weeks following contraction of SARS‐CoV‐2 compared with young healthy adults. What is the main finding and its importance? The main findings were carotid stiffness, Young's modulus, and aortic augmentation index were greater in young adults who tested positive for SARS‐CoV‐2 compared with healthy young adults. These findings provide additional evidence for detrimental effects of SARS‐CoV‐2 on young adult vasculature, which may have implications for cardiovascular health.	Une étude sur 15 patients de 20 ans, 3 à 4 semaines après un test positif au SARS-CoV-2, constate une modification importante de l’état des artères par rapport à un groupe contrôle. Une rigidité plus nette et une moindre élasticité est notée. Notamment, l'artère carotide présente une capacité de gonflement inférieure à 27% et une élasticité moindre de 22%. L'artère aortique est également atteinte. Les auteurs estiment que l'augmentation constatée du module d'élasticité de Young, de plus d'un écart-type, pourrait représenter un surrisque supérieur à 15% de développer de l'hypertension dans les 3 ans si l'élasticité ne s'améliore pas. L'index d'augmentation AIx (heightened radial artery) correspond en moyenne à celui de sujets 10 and plus âgés. L'article précise enfin que la persistance à long terme de ces altérations demeure inconnue.	N009
58	CaV054		Samantha M. Morrissey, Anne E. Geller, Xiaoling Hu, David Tieri, Chuanlin Ding, Christopher K. Klaes, Elizabeth A. Cooke, Silvia M. Uriarte, Corey T. Watson, Jiapeng Huang, and Jun Yan	A specific low-density neutrophil population correlates with hypercoagulation and disease severity in hospitalized COVID-19 patients	https://doi.org/10.1172/jci.insight.148435	Published	May 10, 2021	Study	https://insight.jci.org/articles/view/148435	SARS coronavirus 2 (SARS-CoV-2) is a novel viral pathogen that causes a clinical disease called coronavirus disease 2019 (COVID-19). Although most COVID-19 cases are asymptomatic or involve mild upper respiratory tract symptoms, a significant number of patients develop severe or critical disease. Patients with severe COVID-19 commonly present with viral pneumonia that may progress to life-threatening acute respiratory distress syndrome (ARDS). Patients with COVID-19 are also predisposed to venous and arterial thromboses that are associated with a poorer prognosis. The present study identified the emergence of a low-density inflammatory neutrophil (LDN) population expressing intermediate levels of CD16 (CD16Int) in patients with COVID-19. These cells demonstrated proinflammatory gene signatures, activated platelets, spontaneously formed neutrophil extracellular traps, and enhanced phagocytic capacity and cytokine production. Strikingly, CD16Int neutrophils were also the major immune cells within the bronchoalveolar lavage fluid, exhibiting increased CXCR3 but loss of CD44 and CD38 expression. The percentage of circulating CD16Int LDNs was associated with D-dimer, ferritin, and systemic IL-6 and TNF-α levels and changed over time with altered disease status. Our data suggest that the CD16Int LDN subset contributes to COVID-19–associated coagulopathy, systemic inflammation, and ARDS. The frequency of that LDN subset in the circulation could serve as an adjunct clinical marker to monitor disease status and progression.	_
59	CaV055		Saikat Mitra 1, Ryan Ruiyang Ling, Isabelle Xiaorui Yang, Wynne Hsing Poon, Chuen Seng Tan, Paul Monagle, Graeme MacLaren, Kollengode Ramanathan	Severe COVID-19 and coagulopathy: A systematic review and meta-analysis	https://doi.org/10.47102/annals-acadmedsg.2020420	Published	2021 Apr	Review	https://pubmed.ncbi.nlm.nih.gov/33990820/	Methods: We conducted a systematic review of the literature (until 1 June 2020) to assess CIC and disease severity during the early COVID-19 pandemic. Primary outcomes were pooled mean differences in platelet count, D-dimer level, prothrombin time, activated partial thromboplastin time (aPTT) and fibrinogen level between non-severe and severe patients, stratified by degree of hypoxaemia or those who died. The risk factors for CIC were analysed. Random-effects meta-analyses and meta-regression were performed using R version 3.6.1, and certainty of evidence was rated using the Grading of Recommendation, Assessment, Development, and Evaluation approach. Results: Of the included 5,243 adult COVID-19 patients, patients with severe COVID-19 had a significantly lower platelet count, and higher D-dimer level, prothrombin time and fibrinogen level than non-severe patients. Pooled mean differences in platelet count (-19.7×109 /L, 95% confidence interval [CI] -31.7 to -7.6), D-dimer level (0.8μg/mL, 95% CI 0.5–1.1), prothrombin time (0.4 second, 95% CI 0.2–0.6) and fibrinogen level (0.6g/L, 95% CI 0.3–0.8) were significant between the groups. Platelet count and D-dimer level were significant predictors of disease severity on meta-regression analysis. Older men had higher risks of severe coagulopathic disease. Conclusion: Significant variability in CIC exists between non-severe and severe patients, with platelet count and D-dimer level correlating with disease severity. Routine monitoring of all coagulation parameters may help to assess CIC and decide on the appropriate management. This systematic review and meta-analysis demonstrated significant variability of the coagulation parameters in non-severe versus severe COVID-19. COVID-19 patients manifest a dynamic coagulation profile with the progression of disease severity. Both platelet count and D-dimer level significantly correlated with the severity.	_
60	CaV056		Sujin Kang, Toshio Tanaka, Hitomi Inoue, Chikako Ono, Shoji Hashimoto, Yoshiyuki Kioi, Hisatake Matsumoto, Hiroshi Matsuura, Tsunehiro Matsubara, Kentaro Shimizu, Hiroshi Ogura, Yoshiharu Matsuura, and Tadamitsu Kishimoto	Reply to Cheng et al.: COVID-19 induces lower extent of cytokines, but damages vascular endothelium by IL-6 signaling	https://doi.org/10.1073/pnas.2105040118	Published	May 25, 2021	Reply	https://www.pnas.org/content/118/21/e2105040118	The IL-6 concentrations in patients with COVID-19 are significantly lower than those in patients with sepsis or ARDS patients (2, 3). COVID-19 patients were heterogeneous, from critical to severe cases, in the primary analysis, with a broad range of IL-6 concentrations, from 6.5 pg/mL to 357.2 pg/mL (3). Notably, severe acute respiratory syndrome coronavirus 2 infection causes pulmonary endothelial injury and increases IL-6 production by endothelial cells (4). Moreover, several in vitro data from multiple studies indicate that IL-6 trans-signaling in vascular endothelial cells can induce the production of IL-6, IL-8, and MCP-1. The extent to which severe COVID-19 causes endothelial injury can depend on the site of insult and the basis of systemic inflammatory profiles (5, 6). Importantly, the levels of acute-phase proteins such as C-reactive protein, which is induced by IL-6, and D-dimer were elevated in patients with COVID-19, and the concentrations of these proteins were comparable between patients with COVID-19 and those with sepsis. Increasing IL-6 levels might function in endothelial activation and the coagulation cascade in pulmonary tissue; this possibility supports the findings of recent clinical trials indicating that IL-6 signaling-inhibiting therapeutics are beneficial for treating severe cases of COVID-19 (7, 8).	_
61	CaV057	Questionable methodology	Lize M. Grobbelaar, Chantelle Venter, Mare Vlok, Malebogo Ngoepe, Gert Jacobus Laubscher, Petrus Johannes Lourens, Janami Steenkamp, Douglas B. Kell, Etheresia Pretorius	SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: Implications for microclot formation in COVID-19	https://doi.org/10.1101/2021.03.05.21252960	pre-print	March 08, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.03.05.21252960v1	Here we suggest that, in part, the presence of spike protein in circulation may contribute to the hypercoagulation in COVID-19 positive patients and may cause substantial impairment of fibrinolysis. Such lytic impairment may result in the persistent large microclots we have noted here and previously in plasma samples of COVID-19 patients. This observation may have important clinical relevance in the treatment of hypercoagulability in COVID-19 patients.	_
62	CaV058		Sebastian Fridman, Maria Bres Bullrich, Amado Jimenez-Ruiz, Pablo Costantini, Palak Shah, Caroline Just, Daniel Vela-Duarte, Italo Linfante, Athena Sharifi-Razavi, Narges Karimi, Rodrigo Bagur, Derek B. Debicki, Teneille E. Gofton, David A. Steven, Luciano A. Sposato	Stroke risk, phenotypes, and death in COVID-19 Systematic review and newly reported cases	https://doi.org/10.1212/WNL.0000000000010851	Published	December 15, 2020	Study	https://n.neurology.org/content/95/24/e3373	The proportions of patients with COVID-19 with stroke (1.8%, 95% confidence interval [CI] 0.9%–3.7%) and in-hospital mortality (34.4%, 95% CI 27.2%–42.4%) were exceedingly high. Mortality was 67% lower in patients <50 years of age relative to those >70 years of age (odds ratio [OR] 0.33, 95% CI 0.12–0.94, p = 0.039). Large vessel occlusion was twice as frequent (46.9%) as previously reported and was high across all age groups, even in the absence of risk factors or comorbid conditions. A clinical phenotype characterized by older age, a higher burden of comorbid conditions, and severe COVID-19 respiratory symptoms was associated with the highest in-hospital mortality (58.6%) and a 3 times higher risk of death than the rest of the cohort (OR 3.52, 95% CI 1.53–8.09, p = 0.003).	_
63	CaV059		Curt J. Daniels, Saurabh Rajpal, Joel T. Greenshields, Geoffrey L. Rosenthal, Eugene H. Chung, Michael Terrin, Jean Jeudy, Scott E. Mattson, Ian H. Law, James Borchers, Richard Kovacs, Jeffrey Kovan, Sami F. Rifat, Christopher J. Kratochvil, Lawrence D. Rink, for the Big Ten COVID-19 Cardiac Registry Investigators	Prevalence of Clinical and Subclinical Myocarditis in Competitive Athletes With Recent SARS-CoV-2 Infection Results From the Big Ten COVID-19 Cardiac Registry	http://jamanetwork.com/article.aspx?doi=10.1001/jamacardio.2021.2065	Published	May 27, 2021	Study	https://jamanetwork.com/journals/jamacardiology/fullarticle/2780548	In this cohort study of 1597 US competitive collegiate athletes undergoing comprehensive cardiovascular testing, the prevalence of clinical myocarditis based on a symptom-based screening strategy was only 0.31%. Screening with cardiovascular magnetic resonance imaging increased the prevalence of clinical and subclinical myocarditis by a factor of 7.4 to 2.3%. These cardiac magnetic resonance imaging findings provide important data on the prevalence of clinical and subclinical myocarditis in college athletes recovering from symptomatic and asymptomatic COVID-19 infections. At present, we do not know the natural history or the short- and long-term implications to an athlete with COVID-19 clinical or subclinical myocarditis. To address these concerns, we must find ways to minimize the variability in performance among academic centers to diagnose myocarditis, perhaps through standardized evidence-based diagnostic algorithms and testing protocols, and when indicated, standardization of CMR protocols and interpretation.	Sur 1597 athlètes américains testés positifs à la covid, 2,3% avaient une myocardite clinique ou subclinique selon une étude. Les patients pour qui des symptômes étaient visibles représentaient 0,3%.	N011
64	CaV060		Farnaz Farshidfar, Navid Koleini, and Hossein Ardehali	Cardiovascular complications of COVID-19		Published	June 2021	Review	https://df6sxcketz7bb.cloudfront.net/manuscripts/148000/148980/jci.insight.148980.v1.pdf	The presence of pre-existing cardiovascular disease increases mortality in COVID-19 patients, and cardiovascular injuries, including myocarditis, cardiac rhythm abnormalities, endothelial cell injury, thrombotic events, and myocardial interstitial fibrosis, are observed in some COVID-19 patients. The underlying pathophysiology of COVID-19-associated cardiovascular complications is not fully understood, although direct viral infection of myocardium and cytokine storm have been suggested as possible mechanisms of myocarditis. In this review, we summarize available data on SARS- 2 CoV-2-related cardiac damage and discuss potential mechanisms of cardiovascular implications of this rapidly spreading virus.	_
65	CaV061		Ian Paterson 1, Krishnan Ramanathan 2, Rakesh Aurora 3, David Bewick 4, Chi-Ming Chow 5, Brian Clarke 6, , Larry Sterns 18, Ricky Turgeon 19, Sean Virani 20, Kenny K Wong 21, Shelley Zieroth 22	Long COVID-19: A Primer for Cardiovascular Health Professionals On Behalf of the CCS Rapid Response Team	https://doi.org/10.1016/j.cjca.2021.05.011	Published	2021 Jun 3	Guidance	https://pubmed.ncbi.nlm.nih.gov/34090980/	It is now widely recognized that COVID-19 illness can be associated with significant intermediate and potentially longer-term physical limitations. The term “Long COVID-19” is used to define any patient with persistent symptoms after acute COVID-19 (i.e. after 4 weeks). It is postulated that cardiac injury may be linked to symptoms that persist following resolution of acute infection, as part of this syndrome. The Canadian Cardiovascular Society Rapid Response Team has generated this document to provide guidance to health care providers on the optimal management of patients with suspected cardiac complications of Long COVID-19.	_
66	CaV062		Jenna Stephanie O'Sullivan1, Andrew Lyne2 and Carl J Vaughan1	COVID-19-induced postural orthostatic tachycardia syndrome treated with ivabradine	http://dx.doi.org/10.1136/bcr-2021-243585	Published	June 14, 2021	Case Report	https://casereports.bmj.com/content/14/6/e243585	Evaluation revealed a resting sinus tachycardia and criteria for postural orthostatic tachycardia syndrome were met. After non-pharmacological interventions failed to yield symptomatic improvement, ivabradine was commenced. This intervention was followed by a substantial improvement in the patient’s exercise tolerance and energy levels and an objective reduction in supine and standing heart rate.	_
67	CaV063		Marketa Kubankova, Bettina Hohberger, Jakob Hoffmanns, Julia Fuerst, Martin Hermann, Jochen Guck, Martin Krater	Physical phenotype of blood cells is altered in COVID-19	Publication of CaV26 https://doi.org/10.1016/j.bpj.2021.05.025	Published	June 2, 2021	New Results	https://www.sciencedirect.com/science/article/pii/S0006349521004549	"We found significant changes in erythrocyte deformability, lymphocyte stiffness, monocyte size, and neutrophil size and deformability. While some of these changes recovered to normal values after hospitalization, others persisted for months after hospital discharge, evidencing the long-term imprint of COVID-19 on the body." "neutrophil alterations observed in our recovered cohort were induced after the successful displacement of the virus by the immune system. This might be indicative for SARS-CoV-2 causing long-term immunological signals or even targeting bone marrow stem cells, as viral RNA was found post-mortem in patient bone marrow" "These alterations could be connected with long term symptoms of the recovered patients"	Sur une cohorte assez réduite, une étude allemande note chez les patients guéris de la phase aiguë de la covid des altérations des globules rouges et des granulocytes neutrophiles qui pourraient avoir des effets à long terme. Des changements dans la déformabilité érythrocytaire ainsi que celle des neutrophiles et de leur taille, se retrouvent avec des écarts statistiquement significatifs, sur une médiane de 7 mois après l'infection au SARS-CoV-2.	N014E
68	CaV064		David M. Smadja, Steven J. Mentzer, Michaela Fontenay, Mike A. Laffan, Maximilian Ackermann, Julie Helms, Danny Jonigk, Richard Chocron, Gerald B. Pier, Nicolas Gendron, Stephanie Pons, Jean-Luc Diehl, Coert Margadant, Coralie Guerin, Elisabeth J. M. Huijbers, Aurélien Philippe, Nicolas Chapuis, Patrycja Nowak-Sliwinska, Christian Karagiannidis, Olivier Sanchez, Philipp Kümpers, David Skurnik, Anna M. Randi & Arjan W. Griffioen	COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects	https://doi.org/10.1007/s10456-021-09805-6	Published	28 June 2021	Review	https://link.springer.com/article/10.1007/s10456-021-09805-6	Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is presenting as a systemic disease associated with vascular inflammation and endothelial injury. Severe forms of SARS-CoV-2 infection induce acute respiratory distress syndrome (ARDS) and there is still an ongoing debate on whether COVID-19 ARDS and its perfusion defect differs from ARDS induced by other causes. Beside pro-inflammatory cytokines (such as interleukin-1 β [IL-1β] or IL-6), several main pathological phenomena have been seen because of endothelial cell (EC) dysfunction: hypercoagulation reflected by fibrin degradation products called D-dimers, micro- and macrothrombosis and pathological angiogenesis. Direct endothelial infection by SARS-CoV-2 is not likely to occur and ACE-2 expression by EC is a matter of debate. Indeed, endothelial damage reported in severely ill patients with COVID-19 could be more likely secondary to infection of neighboring cells and/or a consequence of inflammation. Endotheliopathy could give rise to hypercoagulation by alteration in the levels of different factors such as von Willebrand factor. Other than thrombotic events, pathological angiogenesis is among the recent findings. Overexpression of different proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) or placental growth factors (PlGF) have been found in plasma or lung biopsies of COVID-19 patients. Finally, SARS-CoV-2 infection induces an emergency myelopoiesis associated to deregulated immunity and mobilization of endothelial progenitor cells, leading to features of acquired hematological malignancies or cardiovascular disease, which are discussed in this review. Altogether, this review will try to elucidate the pathophysiology of thrombotic complications, pathological angiogenesis and EC dysfunction, allowing better insight in new targets and antithrombotic protocols to better address vascular system dysfunction. Since treating SARS-CoV-2 infection and its potential long-term effects involves targeting the vascular compartment and/or mobilization of immature immune cells, we propose to define COVID-19 and its complications as a systemic vascular acquired hemopathy.	La covid est une 𝗵𝗲́𝗺𝗼𝗽𝗮𝘁𝗵𝗶𝗲 (𝗺𝗮𝗹𝗮𝗱𝗶𝗲 𝗱𝘂 𝘀𝗮𝗻𝗴) 𝘃𝗮𝘀𝗰𝘂𝗹𝗮𝗶𝗿𝗲 𝘀𝘆𝘀𝘁𝗲́𝗺𝗶𝗾𝘂𝗲 acquise, résume un groupe de chercheurs français dans le journal Angiogenesis. L'étude explore la physiopathlogie de la covid et note que l'infection induit une myélopoïèse d'urgence associée à une immunité dérégulée et à une mobilisation des cellules progénitrices endothéliales, conduisant à des caractéristiques de malignités hématologiques acquises ou de maladies cardiovasculaires.	N014E
69	CaV065		Anna Giulia Falchi Sergio Leonardi Giovanni Cappa Stefano Perlini	Subclinical pericarditis long after SARS-CoV-2 infection: a case report	https://doi.org/10.4081/ecj.2021.9782	Published	2021-06-28	Case Report	https://www.pagepressjournals.org/index.php/ecj/article/view/9782	We describe a rare complication of COVID-19 long after infection in a 76-years-old man presented to the Emergency Department with dyspnea and palpitations. A 12-lead Electrocardiogram (ECG) showed sinus tachycardia PR depression in the inferior leads associated with an apparent pseudo ST elevation. In the absence of elevation of inflammatory indices, considering the lack of symptoms neither NSAIDs nor colchicine were prescribed, and the patient was referred for clinical follow-up. After ten days ECG documented initial reduction of the widespread concave STE and PR depression, and the 1-month follow- up visit, the patient was asymptomatic with unremarkable physical examination, and a 12-lead ECG showed almost complete normalization of the ST and PR segments.	_
70	CaV066		Clement C. E. Lee,Kashan Ali,David Connell,Ify R. Mordi ,Jacob George ,Elizabeth MSL Lang andChim C. Lang *	COVID-19-Associated Cardiovascular Complications	https://doi.org/10.3390/diseases9030047	Published	29 June 2021	Review	https://www.mdpi.com/2079-9721/9/3/47/htm	Coronavirus disease 2019 (COVID-19) has been reported to cause cardiovascular complications such as myocardial injury, thromboembolic events, arrhythmia, and heart failure. Multiple mechanisms—some overlapping, notably the role of inflammation and IL-6—potentially underlie these complications. The reported cardiac injury may be a result of direct viral invasion of cardiomyocytes with consequent unopposed effects of angiotensin II, increased metabolic demand, immune activation, or microvascular dysfunction. Thromboembolic events have been widely reported in both the venous and arterial systems that have attracted intense interest in the underlying mechanisms. These could potentially be due to endothelial dysfunction secondary to direct viral invasion or inflammation. Additionally, thromboembolic events may also be a consequence of an attempt by the immune system to contain the infection through immunothrombosis and neutrophil extracellular traps. Cardiac arrhythmias have also been reported with a wide range of implicated contributory factors, ranging from direct viral myocardial injury, as well as other factors, including at-risk individuals with underlying inherited arrhythmia syndromes. Heart failure may also occur as a progression from cardiac injury, precipitation secondary to the initiation or withdrawal of certain drugs, or the accumulation of des-Arg9-bradykinin (DABK) with excessive induction of pro-inflammatory G protein coupled receptor B1 (BK1). The presenting cardiovascular symptoms include chest pain, dyspnoea, and palpitations. There is currently intense interest in vaccine-induced thrombosis and in the treatment of Long COVID since many patients who have survived COVID-19 describe persisting health problems. This review will summarise the proposed physiological mechanisms of COVID-19-associated cardiovascular complications.
71	CaV067		Sanjay R Agarwala1, Mayank Vijayvargiya2 and Prashant Pandey2	Avascular necrosis as a part of ‘long COVID-19’	http://dx.doi.org/10.1136/bcr-2021-242101	Published	July 02, 2021	Case report	https://casereports.bmj.com/content/14/7/e242101	We report a series of three cases in which patients developed AVN of the femoral head after being treated for COVID-19 infection. The mean dose of prednisolone used in these cases was 758 mg (400–1250 mg), which is less than the mean cumulative dose of around 2000 mg steroid, documented in the literature as causative for AVN. Patients were symptomatic and developed early AVN presentation at a mean of 58 days after COVID-19 diagnosis as compared with the literature which shows that it generally takes 6 months to 1 year to develop AVN post steroid exposure.
72	CaV068		Lee Stoner1, 2, *(), Mark Faghy2, 3, 4, Ryan Conners2, 5	COVID-19 infection and cardiometabolic complications: short- and long-term treatment and management considerations	https://doi.org/10.31083/j.rcm2202031	Published	30 June 2021	Review	https://rcm.imrpress.com/EN/10.31083/j.rcm2202031	Below we pose some of the many questions of interest to chronic disease management (summarized in Fig. 1), with an emphasis on cardiometabolic disease, during and following COVID-19. On behalf of HL-PIVOT (Healthy Living for Pandemic Event Protection) and Exercise is Medicine® (EIM) Underserved & Community Health, this special issue aims to expand the discourse related to the short- and long-term impact of COVID19 on individual and public health. Below we pose some of the many topics of interest to chronic disease management, with an emphasis on cardiometabolic disease. during and following COVID-19. The intention of this section is to ignite interest in this special issue and spur continued discourse from authors across the biomedical spectrum.
73	CaV069		Fatih Akkaya,1 Feyza Nur Topçu Yenerçağ,2 Ahmet Kaya,1 Yusuf Ziya Şener,corresponding author3 and Ali Bağcı4	Long term effects of mild severity COVID‑19 on right ventricular functions	https://dx.doi.org/10.1007%2Fs10554-021-02340-x	Published	2021 Jul 12	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274467/	The aim of our study was to evaluate the right ventricular functions of mild severity COVID-19 patients 3 months after, and compare them to the right ventricular functions of healthy volunteers. For this single-center study, data from 105 patients who were treated for mild severity COVID-19 between September 15, 2020 and December 31, 2020 were collected. 105 age and sex matched healthy subjects were included in the study. Right ventricular (RV) functions were evaluated using conventional two-dimensional (2D) echocardiography and 2D speckle-tracking echocardiography (STE) for all patients. 2D-E parameters indicating RV functions were compared between the two groups. RV diamaters, systolic pulmonary artery pressure (sPAP) and RV myocardial performance index (RV MPI) were significantly higher in the COVID-19 patients compared to control group (p < 0.05). Tricuspid annular plane systolic motion (TAPSE), right ventricular fractional area change (RVFAC) and RV S’ were significantly lower in the COVID-19 group compared to control group (p < 0.05). RV global longitudinal strain (RV-GLS) (− 19.6 ± 5.2 vs. − 15.1 ± 3.4, p < 0.001) and RV free wall longitudinal strain RV-FWLS (− 19.6 ± 5.2 vs. − 17.2 ± 4.4, p < 0.001) values were significantly lower in the COVID-19 group than the control group. There was a significant negative correlation between RV-FWLS, RV-GLS and C-reactive protein (CRP), neutrophil to lymphocyte ratio (NLR), d-dimer, ferritin, platelet to lymphocyte ratio (PLR) in patients with mild severity COVID-19. This results suggested that RV-GLS and RV-FWLS decreased in the long term (third month) follow-up of patients treated for mild severity COVID-19 disease. Subclinical RV dysfunction may be observed in patients after mild severity COVID-19.
74	CaV070		Katherine Chenevey, William Murdoch, A. Vincent Songco	COVID-19-Induced Cardiomyopathy in a Young Nulliparous Woman	https://doi.org/10.7759/cureus.16516	Published	July 20, 2021	Case Report	https://www.cureus.com/articles/64043-covid-19-induced-cardiomyopathy-in-a-young-nulliparous-woman	A young nulliparous woman presented with new-onset heart failure several weeks after an asymptomatic coronavirus disease 2019 (COVID-19) infection. Investigation revealed non-ischemic cardiomyopathy without apical ballooning. A literature review demonstrates other reported cases of COVID-19-induced cardiomyopathy; however, our patient was demographically unique from previously described cases, presented later, and did not have Takotsubo-like findings. Our patient continued to have evidence of cardiac remodeling and a reduced ejection fraction months after presentation. This case highlights the importance of surveilling for the post-infectious sequelae of COVID-19, along with the wide demographic range of patients susceptible to such outcomes.	_
75	CaV071		Jayanta Kumar Biswal, Sujit Kumar Mohanty, Satya Narayan Behera, Santanu Kumar Swain, Ashok Kumar Sahoo	Acute Limb Ischemia: A Catastrophic COVID-19 Sequel Leading to Amputation	https://doi.org/10.7759/cureus.16456	Published	July 18, 2021	Case Report	https://www.cureus.com/articles/64302-acute-limb-ischemia-a-catastrophic-covid-19-sequel-leading-to-amputation	A positive-sense single-stranded ribonucleic acid (RNA) virus causes the novel coronavirus illness 2019 (COVID-19). COVID-19 symptoms range from mild to moderate to severe and very severe. Fever, cough, headache, anosmia, ageusia, body ache, and diarrhoea are mild to moderate grade symptoms, whereas systemic involvements (pneumonia, myocarditis, stroke, and other coagulation abnormalities) are more serious. Except for a few patients who have mild complaints of cough and shortness of breath, the majority of patients are recuperating entirely from the viral infection. Patients with severe to very severe illnesses experience significant lung damage and fibrosis. These are the patients who are more likely to experience extrapulmonary complications after COVID-19. The disease's aberrant presentation may be related to systemic involvement and a hypercoagulable condition with micro and macro-angiopathy. Acute limb ischemia is one of the symptoms of the hypercoagulable condition. Its presentation can be in the form of chilblains, bullae, acral cyanosis, bruising, blood blisters, dry gangrene, or life-threatening acute limb ischemia. Unfortunately, most patients have to undergo amputation due to a delay in presentation or rapidly progressing disease. Here we present a case series of two COVID-19 infected patients who were initially discharged from the hospital after proper treatment but developed acute limb ischemia within the home isolation period and their treatment strategy.	_
76	CaV072		Damsara Nandadeva 1, Benjamin E Young 1, Brandi Y Stephens 1, Ann-Katrin Grotle 1, Rachel J Skow 1, Angela J Middleton 2, Florence P Haseltine 3, Paul J Fadel 1	Blunted peripheral but not cerebral vasodilator function in young otherwise healthy adults with persistent symptoms following COVID-19	https://doi.org/10.1152/ajpheart.00368.2021	Published	2021 Jul 23	Study	https://pubmed.ncbi.nlm.nih.gov/34296966/	Recent findings suggest that COVID-19 causes vascular dysfunction during the acute phase of the illness in otherwise healthy young adults. To date, no studies have investigated the longer-term effects of COVID-19 on vascular function. Herein, we hypothesized that young, otherwise healthy adults who are past the acute phase of COVID-19 would exhibit blunted peripheral (brachial artery flow-mediated dilation (FMD) and reactive hyperemia) and cerebral vasodilator function (cerebral vasomotor reactivity to hypercapnia; CVMR) and increased central arterial stiffness. Sixteen young adults who were at least 4 weeks past a COVID-19 diagnosis and 12 controls who never had COVID-19 were studied. Eight COVID subjects were symptomatic (SYM) and 8 were asymptomatic (ASYM) at the time of testing. FMD and reactive hyperemia were not different between COVID and Control groups. However, FMD was lower in SYM (3.8 ± 0.6%) compared to ASYM (6.8 ± 0.9%; P = 0.007) and Control (6.8 ± 0.6%; P = 0.003) with no difference between ASYM and Control. Similarly, peak blood velocity following cuff release was lower in SYM (47 ± 8 cm/s) compared to ASYM (64 ± 19 cm/s; P = 0.025) and Control (61 ± 14 cm/s; P = 0.036). CVMR and arterial stiffness were not different between any groups. In summary, peripheral macro- and microvascular function, but not cerebral vascular function or central arterial stiffness were blunted in young adults symptomatic beyond the acute phase of COVID-19. In contrast, those who were asymptomatic had similar vascular function compared to controls who never had COVID.	Une étude relève que la vasodilatation macrovasculaire et microvasculaire périphérique est considérablement émoussée chez les jeunes adultes encore symptomatiques du covid au-delà de la phase aiguë. Les chercheurs réalisent ces mesures par la technique de la dilatation liée au flux (FMD : Flow mediated-dilatation) de l'artère brachiale.	N014E
77	CaV073		Arthur Melkumyants, Ludmila Buryachkovskaya, Nikita Lomakin, Olga Antonova, Victor Serebruany	Mild COVID-19 and Impaired Cell-Endothelial Crosstalk: Considering Long-Term Antithrombotics and Vascular Protection? COVID and vascular-endothelial injury	https://doi.org/10.1055/a-1551-9911	Published	16 July 2021		https://www.thieme-connect.com/products/ejournals/abstract/10.1055/a-1551-9911	We analyzed blood erythrocytes (RBC), endotheliocytes, and echinocytes by electron microscopy and flow cytometry in patients with confirmed COVID-19 (n=31) and matched controls (n=32) on admission and at hospital discharge. Results All patients experienced mild disease, none required pulmonary support, and all survived. Admission number of circulating endotheliocytes was significantly (40-100 times) higher in COVID-19 patients. Cells were massively damaged by multiple fenestrae in membranes with diameter comparable to the size of supercapsid in SARS CoV-2 virus. COVID-19 also provoked formation of stacked aggregated RBC capable to clog microvascular bed and to diminish oxygen supply. In some patients, such abnormalities persisted at hospital discharge revealing remaining penetration of COVID-19 intracellular where it may be replicated and returned to circulation. Conclusion Cell-endothelial injury cause blood vessels denuded; their increased permeability resulted in tissue edema, inflammation, platelet activation, and augmented thrombosis. Such sequelae can provoke long-term delayed vascular complications following COVID-19. Controlled outcome-driven trials are urgently needed for exploring optimal antithrombotic and vascular protection strategies following even mild COVID-19.	_
78	CaV074		Umit Arslan MD, Ferhat Borulu MD, İbrahim Sarac MD, Bilgehan Erkut Prof	Chronic intracardiac thrombus, a long-term complication of COVID-19: Case reports	https://doi.org/10.1111/jocs.15836	Published	26 July 2021	Case Report	https://onlinelibrary.wiley.com/doi/full/10.1111/jocs.15836	Our study describes two patients who recovered from COVID-19 and presented with chronic intracardiac thrombus. To date, reports of intracardiac thrombosis in COVID-19 patients with normal cardiac anatomy and function are rare and may cause major cardiovascular complications. Therefore, patients are recommended standard prophylactic anticoagulation doses for at least 3 months during and after the illness. In addition, patients must follow up with monthly echocardiography to check for cardiac thrombus.	_
79	CaV075		Arthur Melkumyants, Ludmila Buryachkovskaya, Nikita Lomakin, Olga Antonova, Victor Serebruany	Mild COVID-19 and Impaired Cell-Endothelial Crosstalk: Considering Long-Term Antithrombotics and Vascular Protection? COVID and vascular-endothelial injury	https://doi.org/10.1055/a-1551-9911	Published	16 July 2021	Study	https://www.thieme-connect.com/products/ejournals/abstract/10.1055/a-1551-9911	We analyzed blood erythrocytes (RBC), endotheliocytes, and echinocytes by electron microscopy and flow cytometry in patients with confirmed COVID-19 (n=31) and matched controls (n=32) on admission and at hospital discharge. Results All patients experienced mild disease, none required pulmonary support, and all survived. Admission number of circulating endotheliocytes was significantly (40-100 times) higher in COVID-19 patients. Cells were massively damaged by multiple fenestrae in membranes with diameter comparable to the size of supercapsid in SARS CoV-2 virus. COVID-19 also provoked formation of stacked aggregated RBC capable to clog microvascular bed and to diminish oxygen supply. In some patients, such abnormalities persisted at hospital discharge revealing remaining penetration of COVID-19 intracellular where it may be replicated and returned to circulation. Conclusion Cell-endothelial injury cause blood vessels denuded; their increased permeability resulted in tissue edema, inflammation, platelet activation, and augmented thrombosis. Such sequelae can provoke long-term delayed vascular complications following COVID-19. Controlled outcome-driven trials are urgently needed for exploring optimal antithrombotic and vascular protection strategies following even mild COVID-19.	_
80	CaV076		Victor Arévalos ,Luis Ortega-Paz ,Diego Fernandez-Rodríguez,Víctor Alfonso Jiménez-Díaz,Jordi Bañeras Rius,Gianluca Campo,Miguel Rodríguez-Santamarta,Armando Pérez de Prado,Antonio Gómez-Menchero,José Francisco Díaz Fernández,Claudia Scardino,Nieves Gonzalo,Alberto Pernigotti,Fernando Alfonso,Ignacio Jesús Amat-Santos,Antonio Silvestro,Alfonso Ielasi,José María de la Torre,Gabriela Bastidas,Josep Gómez-Lara,Manel Sabaté,Salvatore Brugaletta	Long-term effects of coronavirus disease 2019 on the cardiovascular system, CV COVID registry: A structured summary of a study protocol	https://doi.org/10.1371/journal.pone.0255263	Published	July 29, 2021	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255263	The primary outcome will be cardiovascular mortality at 1 year. The secondary outcomes will be acute myocardial infarction, stroke, heart failure hospitalization, pulmonary embolism, and serious cardiac arrhythmias, at 1 year. Outcomes will be compared between the two groups. Events will be adjudicated by an independent clinical event committee. Conclusion The results of this registry will contribute to a better understanding of the long-term cardiovascular implications of the COVID19.	_
81	CaV077		Ioannis Katsoularis, MD † Osvaldo Fonseca-Rodríguez, PhD † Paddy Farrington, PhD Krister Lindmark, PhD Anne-Marie Fors Connolly	Risk of acute myocardial infarction and ischaemic stroke following COVID-19 in Sweden: a self-controlled case series and matched cohort study	https://doi.org/10.1016/S0140-6736(21)00896-5	Published	July 29, 2021	Study	https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00896-5/fulltext	86 742 patients with COVID-19 were included in the SCCS study, and 348 481 matched control individuals were also included in the matched cohort study. When day of exposure was excluded from the risk period in the SCCS, the IRR for acute myocardial infarction was 2·89 (95% CI 1·51–5·55) for the first week, 2·53 (1·29–4·94) for the second week, and 1·60 (0·84–3·04) in weeks 3 and 4 following COVID-19. When day of exposure was included in the risk period, IRR was 8·44 (5·45–13·08) for the first week, 2·56 (1·31–5·01) for the second week, and 1·62 (0·85–3·09) for weeks 3 and 4 following COVID-19. The corresponding IRRs for ischaemic stroke when day of exposure was excluded from the risk period were 2·97 (1·71–5·15) in the first week, 2·80 (1·60–4·88) in the second week, and 2·10 (1·33–3·32) in weeks 3 and 4 following COVID-19; when day of exposure was included in the risk period, the IRRs were 6·18 (4·06–9·42) for the first week, 2·85 (1·64–4·97) for the second week, and 2·14 (1·36–3·38) for weeks 3 and 4 following COVID-19. In the matched cohort analysis excluding day 0, the odds ratio (OR) for acute myocardial infarction was 3·41 (1·58–7·36) and for stroke was 3·63 (1·69–7·80) in the 2 weeks following COVID-19. When day 0 was included in the matched cohort study, the OR for acute myocardial infarction was 6·61 (3·56–12·20) and for ischaemic stroke was 6·74 (3·71–12·20) in the 2 weeks following COVID-19. Interpretation Our findings suggest that COVID-19 is a risk factor for acute myocardial infarction and ischaemic stroke. This indicates that acute myocardial infarction and ischaemic stroke represent a part of the clinical picture of COVID-19, and highlights the need for vaccination against COVID-19.	_
82	CaV078		Sanjay R Agarwala Orthopaedics, PD Hinduja National Hospital, Mumbai, Maharashtra, India PubMed articlesGoogle scholar articles Mayank Vijayvargiya Orthopaedics, PD Hinduja National Hospital and Medical Research Centre, Mumbai, Maharashtra, India PubMed articlesGoogle scholar articles Prashant Pandey	Avascular necrosis as a part of ‘long COVID-19’	http://dx.doi.org/10.1136/bcr-2021-242101	Published	July 02, 2021	Study	https://casereports.bmj.com/content/14/7/e242101	We report a series of three cases in which patients developed AVN of the femoral head after being treated for COVID-19 infection. The mean dose of prednisolone used in these cases was 758 mg (400–1250 mg), which is less than the mean cumulative dose of around 2000 mg steroid, documented in the literature as causative for AVN. Patients were symptomatic and developed early AVN presentation at a mean of 58 days after COVID-19 diagnosis as compared with the literature which shows that it generally takes 6 months to 1 year to develop AVN post steroid exposure.	_
83	CaV079		Helen Fogarty,Liam Townsend,Hannah Morrin,Azaz Ahmad,Claire Comerford,Ellie Karampini,Hanna Englert,Mary Byrne,Colm Bergin,Jamie M. O’Sullivan,Ignacio Martin-Loeches,Parthiban Nadarajan,Ciaran Bannan,Patrick W. Mallon,Gerard F. Curley,Roger J.S. Preston,Aisling M. Rehill,Dennis McGonagle,Cliona Ni Cheallaigh,Ross I. Baker,Thomas Renné,Soracha E. Ward,James S. O’ Donnell	Persistent Endotheliopathy in the Pathogenesis of Long COVID Syndrome	https://doi.org/10.1111/jth.15490	Published	10 August 2021	BRIEF REPORT	https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.15490	Persistent symptoms including breathlessness, fatigue and decreased exercise tolerance have been reported in patients after acute SARS-CoV-2 infection. The biological mechanisms underlying this ‘Long COVID’ syndrome remain unknown. However, autopsy studies have highlighted the key roles played by pulmonary endotheliopathy and microvascular immunothrombosis in acute COVID-19. We hypothesized that endothelial cell activation may be sustained in convalescent COVID-19 patients and contribute to Long COVID pathogenesis. Patients and Methods Fifty patients were reviewed at a median of 68 days following SARS-CoV-2 infection. In addition to clinical workup, acute phase markers, EC activation and NETosis parameters and thrombin generation were assessed. Results Thrombin generation assays revealed significantly shorter lag times (p<0.0001, 95% CI -2.57– -1.02min), increased endogenous thrombin potential (ETP) (p=0.04, 95% CI 15–416nM/min) and peak thrombin (p<0.0001, 95% CI 39–93nM) in convalescent COVID-19 patients. These pro-thrombotic changes were independent of ongoing acute phase response or active NETosis. Importantly, EC biomarkers including VWF:Ag, VWF propeptide (VWFpp) and Factor VIII (FVIII:C) were significantly elevated in convalescent COVID-19 compared to controls (p=0.004, 95% CI 0.09–0.57IU/ml; p=0.009, 95% CI 0.06–0.5IU/ml; p=0.04, 95% CI 0.03–0.44IU/ml, respectively). In addition, plasma soluble thrombomodulin (sTM) levels were significantly elevated in convalescent COVID-19 (p=0.02, 95% CI 0.01–2.7ng/ml). Sustained endotheliopathy was more frequent in older, comorbid patients and those requiring hospitalization. Finally, both plasma VWF:Ag and VWFpp levels correlated inversely with 6-minute walk tests. Conclusions Collectively, our findings demonstrate that sustained endotheliopathy is common in convalescent COVID-19 and raise the intriguing possibility that this may contribute to Long COVID pathogenesis.
84	CaV080						From this point on, the survey of studies is no longer as exhaustive as possible. Only those studies which seem to us to bring significant new elements will be listed.
85	CaV081		Damsara Nandadeva, 1 Benjamin E. Young, 1 Brandi Y. Stephens, 1 Ann-Katrin Grotle, 1 Rachel J. Skow, 1 Angela J. Middleton, 2 Florence P. Haseltine, 3 and Paul J. Fadel	Blunted peripheral but not cerebral vasodilator function in young otherwise healthy adults with persistent symptoms following COVID-19	https://dx.doi.org/10.1152%2Fajpheart.00368.2021	Published	1 September 2021	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384473/	Recent findings suggest that COVID-19 causes vascular dysfunction during the acute phase of the illness in otherwise healthy young adults. To date, to our knowledge, no studies have investigated the longer-term effects of COVID-19 on vascular function. Herein, we hypothesized that young, otherwise healthy adults who are past the acute phase of COVID-19 would exhibit blunted peripheral [brachial artery flow-mediated dilation (FMD) and reactive hyperemia] and cerebral vasodilator function (cerebral vasomotor reactivity to hypercapnia; CVMR) and increased central arterial stiffness. Sixteen young adults who were at least 4 wk past a COVID-19 diagnosis and 12 controls who never had COVID-19 were studied. Eight subjects with COVID-19 were symptomatic (SYM) and eight were asymptomatic (ASYM) at the time of testing. FMD and reactive hyperemia were not different between COVID and control groups. However, FMD was lower in SYM (3.8 ± 0.6%) compared with ASYM (6.8 ± 0.9%; P = 0.007) and control (6.8 ± 0.6%; P = 0.003) with no difference between ASYM and control. Similarly, peak blood velocity following cuff release was lower in SYM (47 ± 8 cm/s) compared with ASYM (64 ± 19 cm/s; P = 0.025) and control (61 ± 14 cm/s; P = 0.036). CVMR and arterial stiffness were not different between any groups. In summary, peripheral macrovascular and microvascular function, but not cerebral vascular function or central arterial stiffness were blunted in young adults symptomatic beyond the acute phase of COVID-19. In contrast, those who were asymptomatic had similar vascular function compared with controls who never had COVID-19. This study was the first to investigate the persistent effects of COVID-19 on vascular function in otherwise healthy young adults. We demonstrated that peripheral macrovascular and microvascular vasodilation was significantly blunted in young adults still symptomatic from COVID-19 beyond the acute phase (>4 wk from diagnosis), whereas those who become asymptomatic have similar vascular function compared with controls who never had COVID-19. In contrast, cerebral vascular function and central arterial stiffness were unaffected irrespective of COVID-19 symptomology.
86	CaV082		Pierre Dudouet Serge Cammilleri Eric Guedj Alexis Jacquier Didier Raoult Carole Eldin	Aortic [18F] FDG-PET/CT hypermetabolism in patients with long COVID: a retrospective study	https://doi.org/10.1016/j.cmi.2021.09.020	Published	26 September 2021	LETTER TO THE EDITOR	https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(21)00542-5/fulltext	To resume, we retrospectively found aortic hypermetabolism in 10 out of 47 patients with long COVID who had a 18F-FDG PET/CT scan, with more frequent chest pain in this group (6/10; 60% vs 7/37; 19%, p=0.017). The high proportion of aortic hypermetabolism in our cohort (21%) makes us think that this phenomenon is not incidental. To have an idea of the prevalence of incidental finding of thoracic aortic hypermetabolism, we compared thoracic aortic uptakes between our long COVID patients, and a non-COVID-19 control group of 20 randomly selected patients with negative SARS-CoV-2 RT-PCR and serology, who had 18 F-FDG PET/CT scan for oncologic indications. No patient of this control group had visually detected aortic hypermetabolism and comparative analysis with non-parametric Kruskall-Wallis test showed significant differences in mean aortic SUVmax between our 10 patients with aortic hypermetabolism and non-COVID-19 control group (3.36, SD 0.63 and 2.15 (SD 0.59), respectively; p< 0.0001).	Une lettre faisant part de résultats en imagerie #TEP métabolique corps-entier au 18FDG, publiée dans Clinical Microbiology & Infection en collaboration avec l’IHU Méditerranée Infection, portant sur 47 patients souffrant de COVID long et 20 sujets contrôles non-COVID : - 21% d’inflammation des gros vaisseaux (aortite) vs 0% dans le groupe contrôle non-COVID - Une association significative entre l’hypermétabolisme aortique et douleurs thoraciques chez les patients avec COVID long (douleurs thoraciques 3 fois plus fréquentes en cas d’hypermétabolisme aortique par rapport aux patients post-COVID avec TEP négatif)	N014E
87	CaV083	Questionable methodology	Etheresia Pretorius, Mare Vlok, Chantelle Venter, Johannes A. Bezuidenhout, Gert Jacobus Laubscher, Janami Steenkamp & Douglas B. Kell	Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin	https://doi.org/10.1186/s12933-021-01359-7	Published	23 August 2021	Study	https://cardiab.biomedcentral.com/articles/10.1186/s12933-021-01359-7	We use techniques including proteomics and fluorescence microscopy to study plasma samples from healthy individuals, individuals with Type 2 Diabetes Mellitus (T2DM), with acute COVID-19, and those with Long COVID/PASC symptoms. Results We show that plasma samples from Long COVID/PASC still contain large anomalous (amyloid) deposits (microclots). We also show that these microclots in both acute COVID-19 and Long COVID/PASC plasma samples are resistant to fibrinolysis (compared to plasma from controls and T2DM), even after trypsinisation. After a second trypsinization, the persistent pellet deposits (microclots) were solubilized. We detected various inflammatory molecules that are substantially increased in both the supernatant and trapped in the solubilized pellet deposits of acute COVID-19 and Long COVID/PASC, versus the equivalent volume of fully digested fluid of the control samples and T2DM. Of particular interest was a substantial increase in α(2)-antiplasmin (α2AP), various fibrinogen chains, as well as Serum Amyloid A (SAA) that were trapped in the solubilized fibrinolytic-resistant pellet deposits. Conclusions Clotting pathologies in both acute COVID-19 infection and in Long COVID/PASC might benefit from following a regime of continued anticlotting therapy to support the fibrinolytic system function.	todo ------ les échantillons de plasma de Long COVID/PASC contiennent toujours de gros dépôts anormaux (amyloïdes) (microcaillots).
88	CaV084		Francesco Carubbi 1,2,*,† ,Alessia Alunno 1,† ,Silvia Leone 1,Nicoletta Di Gregorio 1,2,Bernardina Mancini 1,2,Angelo Viscido 1 ,Rita Del Pinto 1 ,Sabrina Cicogna 2,3,Davide Grassi 1 andClaudio Ferri 1	Pericarditis after SARS-CoV-2 Infection: Another Pebble in the Mosaic of Long COVID?	https://doi.org/10.3390/v13101997	Published	4 October 2021	Study	https://www.mdpi.com/1999-4915/13/10/1997/htm	Here, we reported a series of 7 patients developing pericarditis after a median of 20 days from clinical and virological recovery from SARS-CoV-2 infection. We excluded specific identifiable causes of pericarditis, hence we speculate that these cases can be contextualized within the clinical spectrum of long COVID. All our patients were treated with a combination of colchicine and either ASA or NSAIDs, but four of them did not achieve a clinical response. When switched to glucocorticoids, these four patients recovered with no recurrence during drug tapering. Based on this observation and on the latency of pericarditis occurrence (a median of 20 days after a negative nasopharyngeal swab), could be suggested that post-COVID pericarditis may be linked to ongoing inflammation sustained by the persistence of viral nucleic acid without virus replication in the pericardium. Therefore, glucocorticoids may be a suitable treatment option in patients not responding or intolerant to conventional therapy and who require to counteract the pericardial inflammatory component rather than direct an acute viral injury to the pericardial tissue.	_
89	CaV085		Jae Kyu Ryu, Elif G. Sozmen, Karuna Dixit, Mauricio Montano, Yusuke Matsui, Yixin Liu, Ekram Helmy, Thomas J. Deerinck, Zhaoqi Yan, Renaud Schuck, Rosa Meza Acevedo, Collin M. Spencer, Reuben Thomas, Alexander R. Pico, Scott S. Zamvil, Kara L. Lynch, Mark H. Ellisman, Warner C. Greene, Katerina Akassoglou	SARS-CoV-2 spike protein induces abnormal inflammatory blood clots neutralized by fibrin immunotherapy	https://doi.org/10.1101/2021.10.12.464152	pre-print	October 13, 2021	Study	https://www.biorxiv.org/content/10.1101/2021.10.12.464152v1	Here we report that the Spike protein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the blood coagulation factor fibrinogen and induces structurally abnormal blood clots with heightened proinflammatory activity. SARS-CoV-2 Spike virions enhanced fibrin-mediated microglia activation and induced fibrinogen-dependent lung pathology. COVID-19 patients had fibrin autoantibodies that persisted long after acute infection. Monoclonal antibody 5B8, targeting the cryptic inflammatory fibrin epitope, inhibited thromboinflammation. Our results reveal a procoagulant role for the SARS-CoV-2 Spike and propose fibrin-targeting interventions as a treatment for thromboinflammation in COVID-19. One-Sentence Summary SARS-CoV-2 spike induces structurally abnormal blood clots and thromboinflammation neutralized by a fibrin-targeting antibody.	_
90	CaV086		G Artemyeva, A Kalinskaya, O Dukhin, A Lebedeva, A Rozin, A Shpektor, E Vasilieva	Long-term post-discharge coagulation abnormalities in patients with moderate to severe COVID-19	https://doi.org/10.1093/eurheartj/ehab724.3428	Published	14 October 2021	Study	https://academic.oup.com/eurheartj/article/42/Supplement_1/ehab724.3428/6392448	In the deferred period (2–5 months) of COVID-19 the fibrinolysis process remains still active whereas the process of clot formation is mostly suppressed. Endothelial function assessed via the FMD test is within the normal range in the post COVID period.	_
91	CaV087		C Espejo, H Mejia-Renteria, A Travieso, N Gonzalo, S Fernandez, M L Capote, O Vedia, L Wang, I Nunez-Gil, J M Grande Ingelmo, I Fernandez Rozas, C Olmos, D Vivas, J Escaned	Myocardial ischaemia of non-obstructive origin as a cause of new onset anginal chest pain in the long COVID syndrome	https://doi.org/10.1093/eurheartj/ehab724.1078	Published	14 October 2021	Study	https://academic.oup.com/eurheartj/article/42/Supplement_1/ehab724.1078/6392359?login=true	Myocardial ischaemia of non-obstructive origin is common in patients with chest pain and LCS. Vasomotor abnormalities related to endothelial dysfunction occurred in 82% of patients, frequently associated to impaired microvascular vasodilation or high microvascular resistance. Stratified medical treatment led to significant improvement in angina stability and frequency.	_
92	CaV088	ES	Benjamin A. Satterfield, Deepak L. Bhatt & Bernard J. Gersh	Cardiac involvement in the long-term implications of COVID-19	https://doi.org/10.1038/s41569-021-00631-3	Published	22 October 2021	Perspective	https://www.nature.com/articles/s41569-021-00631-3	In this Perspectives article, we highlight what is known about the cardiovascular sequelae in survivors of COVID-19 and discuss important questions that need to be addressed in prospective studies to understand and mitigate these lasting cardiovascular consequences, including in post-acute COVID-19 syndrome. Of note, the manifestations of acute cardiovascular injury associated with SARS-CoV-2 infection are diverse, including acute myocardial infarction, myocarditis, stress cardiomyopathy, pericarditis, arrhythmias, multisystem inflammatory syndrome in both adults (MIS-A) and children (MIS-C), stroke, macrothrombotic disease including arterial and venous thromboembolism, microthrombotic disease and bleeding diathesis2,3,4 (Fig. 1). The pathogenic mechanisms underlying these clinical manifestations are not well understood and are likely to be multifactorial, including primary causes such as elevated local (endotheliitis) and systemic (cytokine storm) inflammation, resulting in coagulopathy, myocardial infarction, stroke, MIS-A, MIS-C and arrhythmias, direct viral cytopathic effects possibly resulting in myocarditis, and autoantibodies5,6,7. In addition, hypoxaemia can occur secondary to lung injury, and myocardial oedema can develop secondary to the inflammatory states mentioned above5,6,7.	Review Cardiaque. Dans Nature Reviews Cardiology, une riche synthèse sur les dommages et séquelles cardiaques de la covid pouvant être à l'origine de symptômes du covid long. Les vascularites/aortites, récemment objectivées par PET-SCAN, ne sont cependant pas ici évoquées.	N014
93	CaV089		Rossana Rauti, Meishar Shahoha, Yael Leichtmann-Bardoogo, Rami Nasser, Eyal Paz, Rina Tamir, Victoria Miller, Tal Babich, Kfir Shaked, Avner Ehrlich, Konstantinos Ioannidis, Yaakov Nahmias, Roded Sharan, Uri Ashery, Ben Meir Maoz	Effect of SARS-CoV-2 proteins on vascular permeability	https://doi.org/10.7554/eLife.69314	pre-print	Oct 25, 2021	Research Article	https://elifesciences.org/articles/69314	It affects several vital organs, seemingly through a pathological effect on endothelial cells. The SARS-CoV-2 genome encodes 29 proteins, whose contribution to the disease manifestations, and especially endothelial complications, is unknown. We cloned and expressed 26 of these proteins in human cells and characterized the endothelial response to overexpression of each, individually. Whereas most proteins induced significant changes in endothelial permeability, nsp2, nsp5_c145a (catalytic dead mutant of nsp5), and nsp7 also reduced CD31, and increased von Willebrand factor expression and IL-6, suggesting endothelial dysfunction. Using propagation-based analysis of a protein–protein interaction (PPI) network, we predicted the endothelial proteins affected by the viral proteins that potentially mediate these effects. We further applied our PPI model to identify the role of each SARS-CoV-2 protein in other tissues affected by coronavirus disease (COVID-19). While validating the PPI network model, we found that the tight junction (TJ) proteins cadherin-5, ZO-1, and β-catenin are affected by nsp2, nsp5_c145a, and nsp7 consistent with the model prediction. Overall, this work identifies the SARS-CoV-2 proteins that might be most detrimental in terms of endothelial dysfunction, thereby shedding light on vascular aspects of COVID-19.
94	CaV090		HernanMejia-RenteriaaAlejandroTraviesoaAdamSagirbEduardoMartínez-GómezaAngelaCarrascosa-GranadaaTakumiToyacIván J.Núñez-GilaVicenteEstradaaAmirLermancJavierEscaneda	In-vivo evidence of systemic endothelial vascular dysfunction in COVID-19	https://doi.org/10.1016/j.ijcard.2021.10.140	Published	24 October 2021	Study	https://www.sciencedirect.com/science/article/pii/S0167527321016946	Highlights •Endothelium-mediated vasodilator function is markedly reduced in COVID-19 post-infection stage compared to active infection and controls. •These findings suggest that endothelial vascular dysfunction may be a chronic complication of the SARS-CoV-2 infection. •This study opens new venues to investigate the clinical implication of vascular endothelial dysfunction in post-COVID syndrome using non-invasive techniques. This study suggests a deleterious effect of SARS-CoV-2 infection on systemic vascular endothelial function. By a measure of endothelium-mediated dilation of peripheral arteries.
95	CaV091		Yogesh Acharya, Aqeel Alameer, Gavin Calpin, Maha Alkhattab & Sherif Sultan	A comprehensive review of vascular complications in COVID-19	https://doi.org/10.1007/s11239-021-02593-2	Published	01 November 2021	Review	https://link.springer.com/article/10.1007/s11239-021-02593-2	This study aims to review the available literature pertinent to vascular complications in COVID-19. A systematic search was performed using PubMed and Google Scholar to identify all relevant studies based on our study objective. Multiple studies have reported widespread systemic inflammation and procoagulant/hypercoagulable state in COVID-19, including thrombotic microangiopathy, endothelial dysfunction, bleeding disorder, and thrombosis. However, large specialised studies on vascular complications are lacking despite current evidence indicating dysfunctional coagulation pathways. Furthermore, there are no clear and definitive recommendations regarding thromboprophylaxis or full therapeutic anticoagulation in COVID-19. Several studies have reported hypercoagulability and vascular complications as important predictors of patient outcome in COVID-19.	_
96	CaV092		Giovanna Pelà 1,2,* ,Matteo Goldoni 1 ,Chiara Cavalli 1,Felice Perrino 1,Sara Tagliaferri 1 ,Annalisa Frizzelli 1,3,Pier Anselmo Mori 4,Maria Majori 4,Marina Aiello 1,3 ,Nicola Sverzellati 1,5,Massimo Corradi 1 andAlfredo Chetta 1,3	Long-Term Cardiac Sequelae in Patients Referred into a Diagnostic Post-COVID-19 Pathway: The Different Impacts on the Right and Left Ventricles	https://doi.org/10.3390/diagnostics11112059	Published	6 November 2021	Study	https://www.mdpi.com/2075-4418/11/11/2059/htm	This monocentric cohort study included 160 consecutive patients who had been discharged from the ward or from the outpatient clinic after a diagnosis of COVID-19 and subsequently referred for a follow-up visit. Clinical features’ data about the acute phase along with information about the follow-up visit, including ECG and Echocardiographic parameters, were recorded. At an average follow-up of 5 months, echocardiography showed morpho-functional characteristics of both right (RV) and left (LV) ventricles, such as RV dilation, increased pressure in the pulmonary circulation, and bi-ventricular systolic–diastolic dysfunction. When examined using multivariate analysis, independent of age, sex, and co-morbidities, RV and LV changes were significantly associated with chest High-Resolution computed tomography score and hemodynamic Instability (HI), and with C-reactive protein, respectively. Our results suggest that COVID-19 may impact RV and LV differently. Notably, the extent of the pneumonia and HI may affect RV, whereas the inflammatory status may influence LV. A long-term follow-up is warranted to refine and customize the most appropriate therapeutic strategies.
97	CaV093		Helen Fogarty,Ellie Karampini,Andrew S. O’Donnell,Soracha E. Ward,Jamie M O’Sullivan,James S. O’Donnell	More on Persistent Endotheliopathy in the Pathogenesis of Long COVID Syndrome	https://doi.org/10.1111/jth.15578	Published	04 November 2021	Study	https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.15578	These findings provide further evidence that sustained endotheliopathy and coagulopathy are both common in patients following acute COVID-19 [2-5]. The longitudinal data presented provide additional insights into the duration of specific aspects of COVID-19-induced hemostatic dysfunction. Previous studies have reported elevated D-dimer levels in 25% of patients in the first few months post-SARS-CoV-2 infection [2, 5]. Notwithstanding differences in patient cohorts and study design, von Meijenfeldt et al show that these elevated D-dimer levels after acute COVID appear to normalize by 4 months [1]. Given that convalescent COVID-19 patients commonly present with respiratory symptoms, this observation has important clinical implications with respect to the utility of D-dimer testing in pulmonary embolism testing algorithms.	todo
98	CaV094		Salma Charfeddine1,2*, Hassen Ibn Hadj Amor3, Jihen Jdidi2,4, Slim Torjmen1,2, Salma Kraiem3, Rania Hammami1,2, Amine Bahloul1,2, Nesrine Kallel2,5, Nedia Moussa2,5, Imen Touil6, Aiman Ghrab7, Jamel Elghoul2,8, Zineb Meddeb9, Yamina Thabet9, Samir Kammoun1,2, Kamel Bouslama9, Sami Milouchi2,7, Salem Abdessalem10 and Leila Abid1,2	Long COVID 19 Syndrome: Is It Related to Microcirculation and Endothelial Dysfunction? Insights From TUN-EndCOV Study	https://doi.org/10.3389/fcvm.2021.745758	Published	30 November 2021	Study	https://www.frontiersin.org/articles/10.3389/fcvm.2021.745758/full	Our study focused on the evaluation of endothelial quality index (EQI) by finger thermal monitoring with E4 diagnosis Polymath in a large cohort of long COVID-19 patients to determine whether long-covid 19 symptoms are associated with endothelial dysfunction. This is a cross-sectional multicenter observational study with prospective recruitment of patients. A total of 798 patients were included in this study. A total of 618 patients (77.4%) had long COVID-19 symptoms. The mean EQI was 2.02 ± 0.99 IC95% [1.95–2.08]. A total of 397 (49.7%) patients had impaired EQI. Fatigue, chest pain, and neuro-cognitive difficulties were significantly associated with endothelium dysfunction with an EQI <2 after adjustment for age, sex, diabetes, hypertension, dyslipidemia, coronary heart disease, and the severity of acute COVID-19 infection. In multivariate analysis, endothelial dysfunction (EQI <2), female gender, and severe clinical status at acute COVID-19 infection with a need for oxygen supplementation were independent risk factors of long COVID-19 syndrome. Long COVID-19 symptoms, specifically non-respiratory symptoms, are due to persistent endothelial dysfunction. These findings allow for better care of patients with long COVID-19 symptoms.	todo
99	CaV095		Jozica Šikić 1,2,* ,Zrinka Planinić 1 ,Vid Matišić 2 ,Tea Friščić 1,Vilim Molnar 2,Dorijan Jagačić 2,Lovro Vujičić 2,Neven Tudorić 2,Lana Postružin Gršić 3,Đivo Ljubičić 2,4 andDragan Primorac	COVID-19: The Impact on Cardiovascular System	https://doi.org/10.3390/biomedicines9111691	Published	15 November 2021	Review	https://www.mdpi.com/2227-9059/9/11/1691/htm	SARS-CoV-2 has been circulating in population worldwide for the past year and a half, and thus a vast amount of scientific literature has been produced in order to study the biology of the virus and the pathophysiology of COVID-19, as well as to determine the best way to prevent infection, treat the patients and eliminate the virus. SARS-CoV-2 binding to the ACE2 receptor is the key initiator of COVID-19. The ability of SARS-CoV-2 to infect various types of cells requires special attention to be given to the cardiovascular system, as it is commonly affected. Thorough diagnostics and patient monitoring are beneficial in reducing the risk of cardiovascular morbidity and to ensure the most favorable outcomes for the infected patients, even after they are cured of the acute disease. The multidisciplinary nature of the fight against the COVID-19 pandemic requires careful consideration from the attending clinicians, in order to provide fast and reliable treatment to their patients in accordance with evidence-based medicine principles. In this narrative review, we reviewed the available literature on cardiovascular implications of COVID-19; both the acute and the chronic.
100	CaV096		Giandomenico Bisaccia 1,† ,Fabrizio Ricci 1,2,3,*,† ,Vittoria Recce 1,Antonio Serio 1,Giovanni Iannetti 4,Anwar A. Chahal 5,6,7,8 ,Marcus Ståhlberg 9,Mohammed Yunus Khanji 8,10,11,Artur Fedorowski 2,9,† andSabina Gallina 1,†	Post-Acute Sequelae of COVID-19 and Cardiovascular Autonomic Dysfunction: What Do We Know?	https://doi.org/10.3390/jcdd8110156	Published	15 November 2021	Review	https://www.mdpi.com/2308-3425/8/11/156/htm	Post-acute sequelae of SARS-CoV-2 (PASC), or long COVID syndrome, is emerging as a major health issue in patients with previous SARS-CoV-2 infection. Symptoms commonly experienced by patients include fatigue, palpitations, chest pain, dyspnea, reduced exercise tolerance, and “brain fog”. Additionally, symptoms of orthostatic intolerance and syncope suggest the involvement of the autonomic nervous system. Signs of cardiovascular autonomic dysfunction appear to be common in PASC and are similar to those observed in postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia. In this review, we report on the epidemiology of PASC, discuss current evidence and possible mechanisms underpinning the dysregulation of the autonomic nervous system, and suggest nonpharmacological and pharmacological interventions to treat and relieve symptoms of PASC-associated dysautonomia.	_
101	CaV097		Vallejo Camazón N1, Teis A2, Martínez Membrive MJ1, Llibre C1, Bayés-Genís A1, Mateu L3	Long COVID-19 and microvascular disease-related angina	https://doi.org/10.1016/j.rec.2021.10.010	Published	28 Oct 2021	Study	https://www.sciencedirect.com/science/article/pii/S1885585721003224	However, many patients report persistent symptoms after recovery, a condition known as persistent or long-coronavirus disease 2019 (COVID-19) syndrome. In some series, chest pain has been described in ∼20% of patients with long-COVID-19 syndrome,1 but the mechanisms for these symptoms have not been adequately explored. Some of these patients have angina-like chest pain. Adenosine stress perfusion cardiac magnetic resonance (CMR) imaging is a useful noninvasive diagnostic tool for assessing myocardial perfusion and distinguishing epicardial from microvascular impairment according to perfusion patterns.2 CMR could play a role in the evaluation of this syndrome. These first consecutive cases in this observational study strongly suggest that coronary microvascular ischemia is the underlying mechanism of angina-like persistent chest pain in patients who have recovered from COVID-19. As noted, the patients reported here are part of a broader study (ANGI-Covid) in which special CMR sequences for noninvasive quantification of myocardial perfusion and coronary flow reserve are also being studied and evaluated in these patients. Future work will have to elucidate the incidence and prevalence and compare these data with controls. However, at this point, we believe the results provided are of clinical importance.	todo
102	CaV098		Iana Simova, Denislava Hristova, Hristina Tzanovska, Denis Nikolov, Diliana Iakova, Anyuta Ivanova, Maria-Magdalena Pintova, Pavlin Pavlov, Ognyan Matkov, Todor Samardjiev, Vladimir Kornovski, Jordan Krasnaliev, Todor Kundurzhiev, Nikolay Dimitrov and Toni Vekov	Post COVID-19 Conditions and the Cardiovascular System	https://doi.org/10.5772/intechopen.99197	Published	December 8th 2021	Review	https://www.intechopen.com/chapters/77664	The cardiovascular system is one of the key targets for the Post COVID-19 syndrome, given the pathogenesis of the virus and prevalence of ACE-2 receptors. According to our initial personal experience via the campaign “Life after COVID” of the Bulgarian Cardiac Institute, a substantial proportion of patients having suffered from COVID-19 develop long-term cardiovascular consequences. They could range from rhythm disorder and blood pressure variation, through impairment of myocardial mechanics and heart failure, and to acute vascular manifestations of Post COVID-19 conditions, such as acute coronary syndrome, acute pulmonary embolism, and acute limb ischemia. These cardiovascular complications require special and dedicated medical attention, and we could share our personal experience on the matter.	_
103	CaV099		S.Charfeddine12H.Ibnhadjamor34S.Torjmen12S.Kraiem3R.Hammami12A.Bahloul12N.Kallel25N.Moussa25I.Touil6S.Milouchi27J.Elghoul28Z.Meddeb49Y.Thabet9J.Jdidi210K.Bouslema45S.Abdesselem(Private cardiologist)411L.Abid12	Endothelial dysfunction is the key of long COVID-19 symptoms: The results of TUN-EndCOV study	https://doi.org/10.1016/j.acvdsp.2021.10.004	Published	27 December 2021	Study	https://www.sciencedirect.com/science/article/pii/S187864802100642X	A total of 798 patients were included in this study. Patients were included at an average time of 68.93 ± 43.1 days. The mean EQI was 2.02 ± 0.99 [0–5]. A total of 397 (49.7%) patients had poor or very poor EQI and 211 (26.4%) patients had very poor EQI. The median age was 49.94 ± 14.2 (18–80) years. A total of 618 patients (77.4%) had long COVID-19 symptoms. Patients with long COVID-19 symptoms had a reduced EQI (1.99 ± 0.97 vs. 2.09 ± 1.05, P = 0.24). Among long COVID-19 symptoms, fatigue was the most common symptom reported in 42.2%. Fatigue and chest pain were significantly associated to the endothelial dysfunction (P = 0.04 and 0.001 respectively). Patients with chest pain had significantly lower EQI (1.74 ± 1.0 vs. 2.09 ± 0.9, P ≤ 10−3) and LVGLS (−16.35 ± 3.0 vs. −17.16 ± 2.5, P = 0.04). Conclusion Long COVID-19 symptoms specifically chest pain and fatigue are due to persistent poor endothelial quality index. These findings allow a better care of patients with long COVID-19 symptoms.
104	CaV100		I.Hassen1S.Charfeddine2K.Salma1T.Imen3T.Slim2H.Rania2A.Bahloul2K.Nesrine4M.Nadia4S.Milouchi5G.Jamel6M.Zeinab7T.Yemina7J.Jihen8B.Kamel7A.Salem(Private cardiologist)9L.Abid2	Left ventricular global longitudinal strain alteration in young patient and correlation with post-COVID syndrome (TUN END COV Study)	https://doi.org/10.1016/j.acvdsp.2021.09.120	Published	27 December 2021	Study	https://www.sciencedirect.com/science/article/pii/S187864802100478X	Patients and methods A prospective multicentric study including a total of 630 patients diagnosed with COVID-19, 2 weeks to one month after recovering from COVID-19. Young patients without any medical history other than recent SARS-CoV2 infection are selected. A meticulous interrogation and clinical examination as well as an echocardiography are performed in all of patients. In addition to symptoms, we assessed echocardiographic parameters including initial left ventricular global longitudinal strain (initial SLG: SLGi) and after one month (SLG control: SLGc). Results Mean SLGi was −18.1 ± 2.4 in study group (−19.6 ± 1.5; P < 0.001). Forty-two patients (52.5%) had initially altered strain versus 38 patients (47.5%) with normal strain. The threshold value for SLG in our study has been established using ROC curve which was −17.95% with sensibility (52.5%) and specificity (83.7%). we found a statistically significative correlation between the initial alteration of SLG and persistent symptoms in multivariate test: dyspnea (P < 0.002); chest pain (P = 0.031). At one month of follow-up, 87.5% of patients improved their SLG. And there was a correlation between control GS value (mean SLGc was −18.91 ± 3.33; P = 0.002) associated with a marked improvement in symptoms (P = 0.001). Conclusion We reported here an original case series of SLG alteration induced by SARS-CoV2 infection that is correlated with the presence of chest pain and dyspnea. However, this affection seems to be spontaneously significantly reversible and associated with significant clinical improvement.
105	CaV101		Xi Liu, Yan-Zi Wen, Zi-Liang Huang, Xia Shen, Jun-Hao Wang, Yi-Hai Luo, Wen-Xin Chen, Zhao-Rong Lun, Hui-Bin Li, Liang-Hu Qu, Hong Shan, Ling-Ling Zheng	SARS-CoV-2 Causes a Significant Stress Response Mediated by Small RNAs in the Blood of COVID-19 Patients	https://doi.org/10.1016/j.omtn.2021.12.034	Published	29 December 2021	Study	https://www.cell.com/molecular-therapy-family/nucleic-acids/pdf/S2162-2531(21)00337-1.pdf	SARS-CoV-2 has had a serious impact on the world. In this study, small RNAs from the blood of COVID-19 patients with moderate or severe symptoms were extracted for high-throughput sequencing and analysis. Interestingly, the levels of a special group of tRNA-derived small RNAs (tsRNAs) were found to be dramatically upregulated after SARS-CoV-2 infection, particularly in COVID-19 patients with severe symptoms. In particular, the 3'CCA tsRNAs from Gly-tRNA were highly consistent with the inflammation indicator C-reactive protein (CRP). In addition, we found that the majority of significantly changed microRNAs (miRNAs) were associated with endoplasmic reticulum (ER)/unfolded protein response (UPR) sensors, which may lead to the induction of proinflammatory cytokine and immune responses. This study found that SARS-CoV-2 infection caused significant changes in the levels of stress44 associated small RNAs in patient blood and their potential functions. Our research revealed that the cells of COVID-19 patients undergo tremendous stress and respond, which can be reflected or regulated by sncRNAs, thus providing potential thought for therapeutic intervention in COVID-19 by modulating small RNA levels or activities.
106	CaV102		Elsi S. Tryfou, Peggy M. Kostakou, Christos G. Chasikidis, Vassilios S. Kostopoulos, Ioannis I. Serafetinidis, Efterpi K. Ferdianaki, Constantinos Mihas, Christoforos D. Olympios & Nikos T. Kouris	Biventricular myocardial function in Covid-19 recovered patients assessed by speckle tracking echocardiography: a prospective cohort echocardiography study	https://doi.org/10.1007/s10554-021-02498-4	Published	23 December 2021	Study	https://link.springer.com/article/10.1007/s10554-021-02498-4	The aim of our study was to evaluate prospectively cardiac involvement in patients after the recovery from Covid-19, using two-dimensional speckle tracking echocardiography. 100 Covid-19 recovered patients with preserved left ventricular ejection fraction, were included, divided based upon clinical manifestation into two groups, those who were treated ambulant and those who were hospitalized. All patients underwent echocardiographic evaluation after their recovery. Although overall LV systolic function expressed by EF was normal, left ventricular global longitudinal strain (LVGLS) was significantly lower in Covid-19 recovered patients (33.28 ± 9.4 days after diagnosis) compared to controls (− 18.47 ± − 2.4 vs. − 21.07 ± − 1.76% respectively, p < 0.0001). Εspecially the lateral wall longitudinal strain (LATLS) and posterior wall longitudinal strain (POSTLS) were significantly reduced in all patients compared to controls (− 17.77 ± − 3.48 vs. − 20.97 ± − 2.86%, p < 0.0001 and − 19.52 ± − 5.3 vs. − 22.23 ± − 2.65%, p = 0.01). right ventricular global longitudinal strain (RVGLS) was significantly diminished only in the hospitalized group of Covid-19 recovered patients, compared to controls (− 18.17 ± − 3.32 vs. − 26.03 ± − 4.55% respectively, p < 0.0001). LVGLS is affected in almost all individuals after Covid-19 infection independently of the infection severity, with LATLS being the most sensitive marker of LV impairment and with POSTLS to follow. RV shows impaired GLS in severely ill patients highlighting RVGLS as a helpful tool of prognosis. Recovered patients from Covid-19 infection have to be monitored for a long time, since the term “long Covid disease” might also include the cardiac function.
107	CaV103		Lesley Kavi	Postural tachycardia syndrome and long COVID: an update	https://doi.org/10.3399/bjgp22X718037	Published	December 31, 2021	Editorial	https://bjgp.org/content/72/714/8.full	Autonomic dysregulation causes inadequate vasoconstriction when standing, resulting in blood pooling within the splanchnic vasculature and limbs, and consequent reduced venous return to the heart. An excessive compensatory tachycardia and increased plasma noradrenaline levels contribute to symptoms, the commonest of which are fatigue, palpitations, light-headedness, headache, and nausea.3,4 See Table 1 for a list of symptoms. If not adequately treated, PoTS can become a debilitating disorder that can lead to significant disability and impaired quality of life. Exercise intolerance resulting in prolonged post-exercise fatigue is a common symptom of both PoTS and long COVID, and may hinder ability to engage in an exercise regimen.5 The role of physical activity including exercise in severely exercise-intolerant patients remains unclear and should be undertaken with great caution. Physiotherapists and occupational therapists treating patients with long COVID and PoTS should be familiar with managing these conditions. Like long COVID, PoTS severity can fluctuate unpredictably, making rehabilitation and return to work challenging. Medication that was recommended pre-pandemic for PoTS is being prescribed in long COVID PoTS when self-management measures are insufficient to control symptoms.5 Although unlicensed for use in PoTS, many of these drugs such as propranolol, ivabradine, midodrine, fludrocortisone, pyridostigmine, clonidine, and methyldopa are familiar to GPs through use in other conditions and may be prescribed provided that the General Medical Council’s guidance for good practice in prescribing unlicensed medicines is followed. Where possible, withdraw drugs that can exacerbate symptoms such as those that lower blood pressure or induce tachycardia.
108	CaV104		Maria-Luiza Luchian 1,* ,Andreea Motoc 1,Stijn Lochy 1,Julien Magne 2,3,Dries Belsack 4,Johan De Mey 4,Bram Roosens 1 ,Karen Van den Bussche 1 ,Sven Boeckstaens 1,Hadischat Chameleva 5,Jolien Geers 1,Laura Houard 1 ,Tom De Potter 5,Sabine Allard 6 ,Caroline Weytjens 1,Steven Droogmans 1 andBernard Cosyns 1	Subclinical Myocardial Dysfunction in Patients with Persistent Dyspnea One Year after COVID-19	https://doi.org/10.3390/diagnostics12010057	Published	28 December 2021	Study	https://www.mdpi.com/2075-4418/12/1/57/htm	We investigated the presence of subclinical cardiac dysfunction, assessed by transthoracic echocardiography (TTE), in recovered COVID-19 patients with or without dyspnea, after exclusion of previous cardiopulmonary diseases. A total of 310 consecutive COVID-19 patients were prospectively included. Of those, 66 patients (mean age 51.3 ± 11.1 years, almost 60% males) without known cardiopulmonary diseases underwent one-year follow-up consisting of clinical evaluation, spirometry, chest computed tomography, and TTE. From there, 23 (34.8%) patients reported dyspnea. Left ventricle (LV) ejection fraction was not significantly different between patients with or without dyspnea (55.7 ± 4.6 versus (vs.) 57.6 ± 4.5, p = 0.131). Patients with dyspnea presented lower LV global longitudinal strain, global constructive work (GCW), and global work index (GWI) compared to asymptomatic patients (−19.9 ± 2.1 vs. −21.3 ± 2.3 p = 0.039; 2183.7 ± 487.9 vs. 2483.1 ± 422.4, p = 0.024; 1960.0 ± 396.2 vs. 2221.1 ± 407.9, p = 0.030). GCW and GWI were inversely and independently associated with dyspnea (p = 0.035, OR 0.998, 95% CI 0.997–1.000; p = 0.040, OR 0.998, 95% CI 0.997–1.000). Persistent dyspnea one-year after COVID-19 was present in more than a third of the recovered patients. GCW and GWI were the only echocardiographic parameters independently associated with symptoms, suggesting a decrease in myocardial performance and subclinical cardiac dysfunction.
109	CaV105		Radu Tanacli, 1 , 2 Patrick Doeblin, 1 Collin Götze, 1 Victoria Zieschang, 1 Alessandro Faragli, 1 , 2 Christian Stehning, 3 Grigorios Korosoglou, 4 Jennifer Erley, 1 Jakob Weiss, 1 , 5 Alexander Berger, 1 Felix Pröpper, 1 Fridolin Steinbeis, 6 Titus Kühne, 1 , 7 Franziska Seidel, 1 , 7 Dominik Geisel, 8 Thula Cannon Walter-Rittel, 8 Philipp Stawowy, 1 , 5 Martin Witzenrath, 6 Karin Klingel, 9 Sophie Van Linthout, 5 , 10 Burkert Pieske, 1 , 2 , 5 Carsten Tschöpe, 2 , 5 , 10 , † and Sebastian Kelle 1 , 2 , 5 , * , †	COVID-19 vs. Classical Myocarditis Associated Myocardial Injury Evaluated by Cardiac Magnetic Resonance and Endomyocardial Biopsy	https://dx.doi.org/10.3389%2Ffcvm.2021.737257	Published	2021 Dec 24	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8739473/	Methods: In total, 32 patients with persistent cardiac symptoms after a COVID-19 infection, 22 patients with acute classic myocarditis not related to COVID-19, and 16 healthy volunteers were included in this study and underwent a comprehensive baseline CMR scan. Of these, 10 patients post COVID-19 and 13 with non-COVID-19 myocarditis underwent a follow-up scan. In 10 of the post-COVID-19 and 15 of the non-COVID-19 patients with myocarditis endomyocardial biopsy (EMB) with histological, immunohistological, and molecular analysis was performed. Results: In total, 10 (31%) patients with COVID-19 showed evidence of myocardial injury, eight (25%) presented with myocardial oedema, eight (25%) exhibited global or regional systolic left ventricular (LV) dysfunction, and nine (28%) exhibited impaired right ventricular (RV) function. However, only three (9%) of COVID-19 patients fulfilled updated CMR–Lake Louise criteria (LLC) for acute myocarditis. Regarding EMB, none of the COVID-19 patients but 87% of the non-COVID-19 patients with myocarditis presented histological findings in keeping with acute or chronic inflammation. COVID-19 patients with severe disease on the WHO scale presented with reduced biventricular longitudinal function, increased RV mass, and longer native T1 times compared with those with only mild or moderate disease. Conclusions: In our cohort, CMR and EMB findings revealed that SARS-CoV-2 infection was associated with relatively mild but variable cardiac involvement. More symptomatic COVID-19 patients and those with higher clinical care demands were more likely to exhibit chronic inflammation and impaired cardiac function compared to patients with milder forms of the disease.
110	CaV106		Gordon T. Snowden, Nick D. Clement, Shenqi Zhang, Qingyun Xue, A. Hamish R. W. Simpson	Orthopaedic long COVID - the unknown unknowns are we facing a pandemic of avascular necrosis following COVID-19?	https://doi.org/10.1302/2046-3758.111.BJR-2021-0505	Published	11 Jan 2022	Article	https://online.boneandjoint.org.uk/doi/full/10.1302/2046-3758.111.BJR-2021-0505	The detrimental effects of steroids are well documented, and the link between these drugs and the occurrence of femoral head avascular necrosis (AVN) is increasingly recognized.9,10 AVN involves progressive destruction of bone as a result of compromise of bone vasculature,11,12 death of osteocytes and fat cells, and alteration of bone architecture. Following the SARS epidemic in 2003, high rates of femoral head AVN (up to 23%) were noted in patients recovering from the condition who had received steroid treatment.13 The link between COVID-19 and AVN in those who have received steroids has been reported.14 If the rates of AVN reach the heights of those reported following SARS, then orthopaedic services may be subject to a pandemic of AVN, and result in a significant increase in the burden of musculoskeletal disease in the community.
111	CaV107		Maciej Koźlik 1,* ,Adrianna Błahuszewska 2 andMaciej Kaźmierski 1	Cardiovascular System during SARS-CoV-2 Infection	https://doi.org/10.3390/ijerph19031184	Published	21 January 2022	Review	https://www.mdpi.com/1660-4601/19/3/1184/htm	SARS-CoV-2 virus can not only damage the respiratory system but may also pose a threat to other organs, such as the heart or vessels. This review focuses on cardiovascular complications of COVID-19, including acute cardiac injury, arrhythmias, biomarkers, accompanying comorbidities and outcomes in patients diagnosed with SARS-CoV-2 infection. The research was conducted on the databases: PubMed, Springer, ScienceDirect, UpToDate, Oxford Academic, Wiley Online Library, ClinicalKey. Fifty-six publications from 1 November 2020 till 15 August 2021 were included in this study. The results show that cardiac injury is present in about 1 in 4 patients with COVID-19 disease, and it is an independent risk factor, which multiplies the death rate several times in comparison to infected patients without myocardial injury. New-onset cardiac injury occurs in nearly every 10th patient of the COVID-19-suffering population. Comorbidities (such as hypertension, cardiovascular disease and diabetes) severely deteriorate the outcome. Therefore, patients with SARS-CoV-2 infection should be carefully assessed in terms of cardiac medical history and possible cardiological complications.
112	CaV108		Yan Xie, Evan Xu, Benjamin Bowe & Ziyad Al-Aly	Long-term cardiovascular outcomes of COVID-19	https://doi.org/10.1038/s41591-022-01689-3	Published	7 February 2022	Study	https://www.nature.com/articles/s41591-022-01689-3	We show that, beyond the first 30 d after infection, individuals with COVID-19 are at increased risk of incident cardiovascular disease spanning several categories, including cerebrovascular disorders, dysrhythmias, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure and thromboembolic disease. These risks and burdens were evident even among individuals who were not hospitalized during the acute phase of the infection and increased in a graded fashion according to the care setting during the acute phase (non-hospitalized, hospitalized and admitted to intensive care). Our results provide evidence that the risk and 1-year burden of cardiovascular disease in survivors of acute COVID-19 are substantial. Care pathways of those surviving the acute episode of COVID-19 should include attention to cardiovascular health and disease.	todo
113	CaV109		Lale Dinc Asarcikli, Mert İlker Hayiroglu, Altug Osken, Kivanc Keskin, Zeynep Kolak & Tolga Aksu	Heart rate variability and cardiac autonomic functions in post-COVID period	https://doi.org/10.1007/s10840-022-01138-8	Published	01 February 2022	Study	https://link.springer.com/article/10.1007/s10840-022-01138-8	Results Time domain indices of HRV analysis (standard deviation of normal RR intervals in 24 h (SDNN 24 h) and root mean square of successive RR interval differences (RMSSD)) were significantly higher in post-COVID patients (p < 0.05 for all). Among frequency domain indices, high frequency and low frequency/high frequency ratio was significantly higher in post-COVID patients (p = 0.037 and p = 0.010, respectively). SDNN >60 ms [36 (60.0%) vs. 12 (36.4%), p = 0.028)] and RMSSD >40 ms [31 (51.7%) vs. 7 (21.2%), p = 0.003)] were more prevalent in post-COVID patients. Logistic regression models were created to evaluate parasympathetic overtone in terms of SDNN >60 ms and RMSSD >40 ms. After covariate adjustment, post-COVID patients were more likely to have SDNN >60 msn (OR: 2.4, 95% CI:1.2–12.8) and RMSSD >40 ms (OR: 2.5, 95% CI: 1.4–9.2). Conclusion This study revealed parasympathetic overtone and increased HRV in patients with history of COVID-19. This may explain the unresolved orthostatic symptoms occurring in post-COVID period which may be associated with autonomic imbalance.
114	CaV110		JS.TascaG.BianchiAGirardelloA.LucchiniC.Cappelli	Atteinte cardiaque chez les athlètes infectés par le SARS COV-2 - Cardiac involvement in athletes infected by SARS COV-2 disease	https://doi.org/10.1016/j.scispo.2021.05.009	Published	7 February 2022	Article	https://www.sciencedirect.com/science/article/pii/S0765159722000314	News: The COVID-19 pandemic has resulted in the inevitable cancellation of most sports activities, practiced at both a professional and amateur level, in order to minimize the risk of spreading the infection. Since the number of athletes who tested positive was rather high, the potential cardiac involvement in this peculiar population of subjects contracting the disease in a mild (asymptomatic, slightly symptomatic) or moderate form, has recently raised concerns following the observation of cases of recorded myocardial damage, myocarditis, arrhythmias and a first reported case of Sudden Cardiac Death (SCD) in a 27-year-old professional basketball player. Several studies even seem to confirm the possibility of permanent impairment of the cardiorespiratory system following the infection. Medical history, biomarkers, electrocardiographical and cardiac imaging features appear to be crucial in distinguishing cardiovascular alterations related to COVID-19 infection from typical adaptations to exercise related to athletes’ heart. Prospects and Projects: Clarifications and prospective data based on long-term follow-ups on larger populations of athletes are still needed to exclude the development of myocardial damage capable of negatively affecting prognosis and increasing cardiovascular risk in athletes recovered from COVID-19 in asymptomatic (simple positivity to SARS-COV-2) or in a mild form.
115	CaV111		E Yaroslavskaya, D Krinochkin, N Shirokov, E Gultyaeva, N Osokina, E Gorbatenko, T Petelina	One-year cardiac follow-up of COVID-19 pneumonia: dynamics of right heart echocardiographic parameters three months and one year after discharge	https://doi.org/10.1093/ehjci/jeab289.348	Published	04 February 2022	Study	https://academic.oup.com/ehjcimaging/article/23/Supplement_1/jeab289.348/6522650?login=true	Purpose To compare EchoCG parameters of right heart in patients with proven COVID-19 pneumonia 3 months and one year after discharge. Methods A total of 116 patients with confirmed COVID-19 pneumonia were included from April 2020 to July 2021. All patients underwent clinical examination including transthoracic EchoCG 3 months ±2 weeks and one year ±3 weeks after discharge. Mean age of patients was 49.0 ± 14.4 years (19-84 years), females were 49.6%. During hospitalization, chest computed tomography (CT) detected mild lesions in 31.3%, moderate lesions in 33.3%, severe lesions in 29.3% and critical lesions in 6.1%. Results The rate of resolution of lung abnormalities according to CT was 55.9%. Mean body mass index was 28.7 ± 5.8 kg/m2 3 months after discharge, and it significantly increased to one year after discharge – 29.4 ± 6.1 kg/m2 (p < 0,001). The mean anteroposterior right ventricular (RV) diameter index decreased over the observation period (13.5 ± 1.9 vs 13.0 ± 1.5 mm/m2, p <0.001), as well as the indices of end-diastolic and end-systolic RV area (8.0 ± 1.8 vs 7.5 ± 1.5 cm2/m2 and 3.8 ± 1.1 vs 3.3 ± 0.8 cm2/m2, respectively, both p < 0.001). The basal RV diameter increased (30.4 ± 5.4 versus 31.1 ± 4.1 mm, p = 0.045), the mid-cavitary RV diameter did not change (25.8 ± 5.4 and 25.8 ± 4.2 mm, p = 0.852), and the base to apex RV length decreased (69.5 ± 8.8 vs 63.9 ± 8.3 mm, p < 0.001). Basal and mid RV sphericity indices (RVSI) increased (0.44 ± 0.07 vs 0.49 ± 0.07 and 0.37 ± 0.07 vs 0.41 ± 0.07, respectively, both p < 0.001). The systolic excursion of the fibrous ring of the tricuspid valve (TAPSE) (22.7 ± 3.2 and 22.8 ± 2.3 mm, p = 0.637) and the tricuspid annular peak systolic velocity S" did not change significantly (10.4 ± 2.6 and 10,1 ± 3.0 cm/s, p = 0.289). The fraction of change in the RV area (FAC RV) increased (52.6 ± 8.2 vs 55.0 ± 8.9%, p = 0.019). The right ventricular outflow tract velocity time integral (RVOT VTI) decreased (18.1 ± 4.0 vs 16.4 ± 3.7 cm, p < 0.001). There were tendencies to increase in the systolic pulmonary artery pressure (PAPs) (22.5 ± 7.1 and 23.3 ± 6.3 mm Hg, p = 0.076) and to increase of the right atrium (RA) long axis dimension (48.7 ± 6.5 vs 49.5 ± 6.3 mm, p = 0.074). Conclusions Compared to three months after discharge, in patients one year after COVID-19 pneumonia EchoCG showed the anteroposterior RV diameter and the end-diastolic RV area decreased, the FAC RV increased. However, increase of the basal and mid RVSI, decrease in the RVOT VTI and tendencies to increase of the PAPs and the RA long axis dimension was observed. A subgroup analysis is planned depending on the severity of lung damage during hospitalization.
116	CaV112		M Akbulut, TS Tan, DM Gerede, V Kozluca, I Dincer	Evaluation of cardiac function by two-dimensional speckle tracking echocardiography in uncomplicated COVID-19 survivors	https://doi.org/10.1093/ehjci/jeab289.155	Published	04 February 2022	Study	https://academic.oup.com/ehjcimaging/article/23/Supplement_1/jeab289.155/6522343	COVID-19 is a multi-systemic infectious disease. Nearly 20-30% of hospitalized patients have evidence of acute myocardial involvement, portending a poorer prognosis. However, not much is known about the long-term cardiac effects of the disease. Also, there is a growing concern about the cardiac sequelae of COVID-19 among survivors. In this study, we aimed to investigate the long-term cardiac effects in patients with prior mild-moderate COVID-19 infection, using both conventional and speckle tracking echocardiographic imaging modalities. A total number of 58 patients who have been diagnosed with COVID-19 within the previous six months and 20 age-, sex- and risk factor-matched healthy adults were included. All patients underwent a comprehensive echocardiographic examination. Both conventional and two-dimensional speckle tracking echocardiographic measurements were done. Also, serum cardiac biomarkers were obtained on the day of echocardiographic examination. Compared with healthy controls, COVID-19 survivors had similar left and right ventricular systolic function at six months. Also, left and right atrial peak systolic strain values did not differ between the groups. Long-term cardiac sequelae of COVID-19 infection are still widely unknown, resulting in concern among survivors. This study is valuable in putting forth the unaffected systolic and diastolic myocardial function on long-term in uncomplicated COVID-19 cases and may decrease the survivors’ anxiety and the number of unnecessary applications to cardiology clinics.
117	CaV113		Mitchell G. Miglis, Nicholas Larsen & Srikanth Muppidi	Inappropriate sinus tachycardia in long-COVID and other updates on recent autonomic research	https://doi.org/10.1007/s10286-022-00854-5	Published	07 February 2022	Editorial	https://link.springer.com/article/10.1007/s10286-022-00854-5	As the COVID-19 pandemic continues to affect hundreds of millions of people worldwide, autonomic complications are being recognized with increasing frequency in both the acute and chronic form of the illness, the latter now designated as post-acute sequelae of SARS-CoV-2 (PASC), colloquially termed long-COVID. Tachycardia is a common symptom of PASC, and some patients may be diagnosed with postural tachycardia syndrome (POTS) or inappropriate sinus tachycardia (IST). While post-COVID POTS has garnered more attention from the scientific and popular press, IST may be equally or more common and has been reported in survivors of the prior SARS coronavirus pandemic [1]. The etiology of IST is unknown; however, the proposed mechanisms overlap with those of POTS, including increased sympathetic and/or reduced cardiovagal activity.
118	CaV114	ES	Douglas B. Kell Gert Jacobus Laubscher; Etheresia Pretorius	A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications	https://doi.org/10.1042/BCJ20220016	Published	February 23 2022	Review	https://academic.oup.com/jmp/article-abstract/21/3/303/902332	Post-acute sequelae of COVID (PASC), usually referred to as ‘Long COVID’ (a phenotype of COVID-19), is a relatively frequent consequence of SARS-CoV-2 infection, in which symptoms such as breathlessness, fatigue, ‘brain fog’, tissue damage, inflammation, and coagulopathies (dysfunctions of the blood coagulation system) persist long after the initial infection. It bears similarities to other post-viral syndromes, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Many regulatory health bodies still do not recognize this syndrome as a separate disease entity, and refer to it under the broad terminology of ‘COVID’, although its demographics are quite different from those of acute COVID-19. A few years ago, we discovered that fibrinogen in blood can clot into an anomalous ‘amyloid’ form of fibrin that (like other β-rich amyloids and prions) is relatively resistant to proteolysis (fibrinolysis). The result, as is strongly manifested in platelet-poor plasma (PPP) of individuals with Long COVID, is extensive fibrin amyloid microclots that can persist, can entrap other proteins, and that may lead to the production of various autoantibodies. These microclots are more-or-less easily measured in PPP with the stain thioflavin T and a simple fluorescence microscope. Although the symptoms of Long COVID are multifarious, we here argue that the ability of these fibrin amyloid microclots (fibrinaloids) to block up capillaries, and thus to limit the passage of red blood cells and hence O2 exchange, can actually underpin the majority of these symptoms. Consistent with this, in a preliminary report, it has been shown that suitable and closely monitored ‘triple’ anticoagulant therapy that leads to the removal of the microclots also removes the other symptoms. Fibrin amyloid microclots represent a novel and potentially important target for both the understanding and treatment of Long COVID and related disorders.
119	CaV115		Betty Raman, David A. Bluemke, Thomas F. Lüscher, Stefan Neubauer	Long COVID: post-acute sequelae of COVID-19 with a cardiovascular focus	https://doi.org/10.1093/eurheartj/ehac031	Published	18 February 2022	Review	https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehac031/6529562	Cardiopulmonary symptoms including chest pain, shortness of breath, fatigue, and autonomic manifestations such as postural orthostatic tachycardia are common and associated with significant disability, heightened anxiety, and public awareness. A range of cardiovascular (CV) abnormalities has been reported among patients beyond the acute phase and include myocardial inflammation, myocardial infarction, right ventricular dysfunction, and arrhythmias. Pathophysiological mechanisms for delayed complications are still poorly understood, with a dissociation seen between ongoing symptoms and objective measures of cardiopulmonary health. COVID-19 is anticipated to alter the long-term trajectory of many chronic cardiac diseases which are abundant in those at risk of severe disease. In this review, we discuss the definition of long COVID and its epidemiology, with an emphasis on cardiopulmonary symptoms. We further review the pathophysiological mechanisms underlying acute and chronic CV injury, the range of post-acute CV sequelae, and impact of COVID-19 on multiorgan health. We propose a possible model for referral of post-COVID-19 patients to cardiac services and discuss future directions including research priorities and clinical trials that are currently underway to evaluate the efficacy of treatment strategies for long COVID and associated CV sequelae.
120	CaV116		Berenice Martínez-Salazar1,2†, Melle Holwerda2†, gChiara Stüdle3†, Indre Piragyte2,4†, Nadia Mercader2,4,5,6, Britta Engelhardt3, Robert Rieben2* and Yvonne Döring1,2,7,8*	COVID-19 and the Vasculature: Current Aspects and Long-Term Consequences	https://doi.org/10.3389/fcell.2022.824851	Published	15 February 2022	Review	https://www.frontiersin.org/articles/10.3389/fcell.2022.824851/full	Early on during this pandemic, it became apparent that SARS-CoV-2 was not only restricted to infecting the respiratory tract, but the virus was also found in other tissues, including the vasculature. Individuals with underlying pre-existing co-morbidities like diabetes and hypertension have been more prone to develop severe illness and fatal outcomes during COVID-19. In addition, critical clinical observations made in COVID-19 patients include hypercoagulation, cardiomyopathy, heart arrythmia, and endothelial dysfunction, which are indicative for an involvement of the vasculature in COVID-19 pathology. Hence, this review summarizes the impact of SARS-CoV-2 infection on the vasculature and details how the virus promotes (chronic) vascular inflammation. We provide a general overview of SARS-CoV-2, its entry determinant Angiotensin-Converting Enzyme II (ACE2) and the detection of the SARS-CoV-2 in extrapulmonary tissue. Further, we describe the relation between COVID-19 and cardiovascular diseases (CVD) and their impact on the heart and vasculature. Clinical findings on endothelial changes during COVID-19 are reviewed in detail and recent evidence from in vitro studies on the susceptibility of endothelial cells to SARS-CoV-2 infection is discussed. We conclude with current notions on the contribution of cardiovascular events to long term consequences of COVID-19, also known as “Long-COVID-syndrome”. Altogether, our review provides a detailed overview of the current perspectives of COVID-19 and its influence on the vasculature.
121	CaV117		Annamaria Russo 1,Ester Tellone 2,* ,Davide Barreca 2,* ,Silvana Ficarra 2 andGiuseppina Laganà 2	Implication of COVID-19 on Erythrocytes Functionality: Red Blood Cell Biochemical Implications and Morpho-Functional Aspects	https://doi.org/10.3390/ijms23042171	Published	16 February 2022	Review	https://www.mdpi.com/1422-0067/23/4/2171/htm	In this review, the hematological changes are evaluated, with particular focus on the morphology and metabolic aspects of erythrocytes. Changes in the functionality of such cells may, in fact, help provide important information about disease severity and progression. The viral infection causes significant damage to the blood cells that are altered in size, rigidity, and distribution width. Lower levels of hemoglobin and anemia have been reported in several studies, and an alteration in the concentration of antioxidant enzymes has been shown to promote a dangerous state of oxidative stress in red blood cells. Patients with severe COVID-19 showed an increase in hematological changes, indicating a progressive worsening as COVID-19 severity progressed. Therefore, monitored hematological alterations in patients with COVID-19 may play an important role in the management of the disease and prevent the risk of a severe course of the disease. Finally, monitored changes in erythrocytes and blood, in general, may be one of the causes of the condition known as Long COVID.
122	CaV118		Gille-Johnson, Patrik MD, PhD; Kessler, Irene; Tehrani, Sara	Impaired Microvascular Function in Patients With Critical COVID-19	https://doi.org/10.1097/CCE.0000000000000643	Published	February 2022	Study	https://journals.lww.com/ccejournal/Fulltext/2022/02000/Impaired_Microvascular_Function_in_Patients_With.15.aspx	MAIN RESULTS: Patients with critical COVID-19 had higher basal skin perfusion during both the acute (34 ± 9 perfusion unit; p = 0.0003) and the postinfectious phase (29 ± 8 perfusion unit; p = 0.04), compared with noncoronavirus disease controls (23 ± 7 perfusion unit). In addition, endothelial-dependent and endothelial-independent vasodilation were reduced in patients with critical COVID-19 during the acute disease phase (p < 0.001 for both), whereas no significant differences between patients and controls were found during the postinfectious phase. In patients with severe COVID-19, basal skin perfusion and endothelial-dependent vasodilatation were not significantly changed, whereas endothelial-independent vasodilatation was reduced (p = 0.02) compared with controls. CONCLUSIONS: Changes in skin microcirculation in patients with critical COVID-19 indicate that the infection induces a systemic microvascular impairment with persisting long-term effects on the microvascular function.
123	CaV119		William T. Gunning 1,* ,Paula M. Kramer 1,Jacob A. Cichocki 1,Beverly L. Karabin 2,Sadik A. Khuder 2 andBlair P. Grubb	Platelet Storage Pool Deficiency and Elevated Inflammatory Biomarkers Are Prevalent in Postural Orthostatic Tachycardia Syndrome	https://doi.org/10.3390/cells11050774	Published	23 February 2022	Study	https://www.mdpi.com/2073-4409/11/5/774/htm	A significant number of postural orthostatic tachycardia syndrome (POTS) patients have platelet delta granule storage pool deficiency (δ-SPD). The etiology of POTS is unknown but a number of laboratories, including ours, have reported elevations of G-protein-coupled adrenergic receptor and muscarinic acetylcholine receptor autoantibodies in POTS patients, detected by a variety of techniques, suggesting that the disorder is an autoimmune condition. Thus, it could also be considered an inflammatory disease. In a pilot study, we investigated a limited number of platelet-related cytokines and chemokines and discovered many that were elevated. This case–control study validates our pilot study results that POTS patients have an activated innate immune system. Plasma of 35 POTS patients and 35 patients with unexplained bleeding symptoms and categorized as “non-POTS” subjects was analyzed by multiplex flow cytometry to quantify 16 different innate immune system cytokines and chemokines. Electron microscopy was used to quantify platelet dense granules. Ten of 16 biomarkers of inflammation were elevated in plasma from POTS patients compared to non-POTS subjects, with most of the differences extremely significant, with p values < 0.0001. Of particular interest were elevations of IL-1β and IL-18 and decreased or normal levels of type 1 interferons in POTS patients, suggesting that the etiology of POTS might be autoinflammatory. All POTS patients had δ-SPD. With a growing body of evidence that POTS is an autoimmune disease and having elevations of the innate immune system, our results suggest a potential T-cell-mediated autoimmunity in POTS characteristic of a mixed-pattern inflammatory disease similar to rheumatoid arthritis.
124	CaV120		Chi-Ju Hsu, Wen-Chin Lin, Yu-Ching Chou, Chuen-Mi Yang, Hsueh-Ling Wu, Yun-Hsiang Cheng, Ping-Cheng Liu, Jia-Yu Chang, Hsing-Yu Chen, Jun-Ren Sun	Dynamic Changes of the Blood Chemistry in Syrian Hamsters Post-Acute COVID-19	https://doi.org/10.1128/spectrum.02362-21	Published	23 February 2022	Study	https://journals.asm.org/doi/10.1128/spectrum.02362-21	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that causes coronavirus disease 2019 (COVID-19). However, the long-term health consequences of COVID-19 are not fully understood. We aimed to determine the long-term lung pathology and blood chemistry changes in Syrian hamsters infected with SARS-CoV-2. Syrian hamsters (Mesocricetus auratus) were inoculated with 105 PFU of SARS-CoV-2, and changes post-infection (pi) were observed for 20 days. On days 5 and 20 pi, the lungs were harvested and processed for pathology and viral load count. Multiple blood samples were collected every 3 to 5 days to observe dynamic changes in blood chemistry. Infected hamsters showed consistent weight loss until day 7 pi At day 5 pi, histopathology of the lungs showed moderate to severe inflammation and the virus could be detected. These results indicate that SARS-CoV-2 has an acute onset and recovery course in the hamster infection model. During the acute onset, blood triglyceride levels increased significantly at day 3 pi During the recovery course, uric acid and low-density lipoprotein levels increased significantly, but the total protein and albumin levels decreased. Together, our study suggests that SARS-CoV-2 infection in hamsters not only causes lung damage but also causes long-term changes in blood biochemistry during the recovery process.
125	CaV121		Vignesh Chidambaram Amudha Kumar Giuseppe Calcaterra Jawahar L. Mehta	Persistent cardiac injury – An important component of long COVID-19 syndrome	https://doi.org/10.1016/j.ebiom.2022.103892	Published	February 23, 2022	Study	https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00076-7/fulltext	As the COVID-19 pandemic goes on, we continue to identify the long-term complications or symptoms among patients who recovered from this infection, be it mild or severe.1 These complications are collectively recognized as “COVID-19 long-hauler syndrome”.1 It is crucial to understand the factors leading to the development of these long-term sequelae to identify, prevent and manage them using appropriate interventions. Acute cardiac injury (ACI), marked by elevation of troponin levels in the blood over the 99th percentile, is an important phenomenon shown to occur in nearly 30% of patients admitted to the hospital with COVID-19 infection.2 ACI has been shown to be associated with an elevated risk of critical illness, increased duration of hospital stay and mortality.2,3 Multiple processes, both ischaemic and non-ischaemic, have been shown to contribute to the development of ACI in COVID-19 patients. The most important among them is the direct myocardial injury caused by SARS-CoV-2.4 Tavazzi et al. demonstrated direct viral infection in the interstitial cells of the myocardium on endomyocardial biopsy, accompanied by low-grade inflammation.4 But to date, there has been no demonstration of COVID-19 genome in the cardiac tissue in patients with clinical myocarditis. Other mechanisms postulated to increase myocardial injury include systemic inflammation, vascular endothelial damage, cardiomyocyte apoptosis, abnormal myocardial strain, microthrombi formation and supply-demand mismatch (Figure 1).2 The precise mechanisms of myocardial injury in patients with COVID-19 are still unclear. It is also unknown if the myocardial injury is a direct effect of the virus or a response to systemic inflammation or both. As we continue to obtain long-term data on COVID-19 survivors, it is imperative to look at how the patients with troponin elevation during their hospital admission fair after discharge. We read with interest the article by Lu et al.5 on the importance of persistent cardiac injury in patients with previous COVID-19 and the factors associated with its development. Among the 673 patients who developed ACI and had a follow-up visit, 371 patients (55.1%) had persistent elevation in troponin levels over a median follow-up of 2.5 months. The authors have made a significant case that COVID-19 is associated with persistent cardiac injury in some patients even after the primary infection has resolved. This highlights the long-term cardiac involvement in patients with COVID-19 in the convalescent period. The clinical relevance of these persistently elevated troponin levels on left ventricular function and other cardiovascular outcomes is still to be determined. A retrospective study from the SWEDEHEART database showed that, among 48,482 COVID 19 patients with elevated cardiac troponin levels (>99 percentile) without a diagnosis of acute coronary syndrome, 7529 patients (15.4%) developed long-term major adverse cardiac events, defined as the composite of all-cause mortality, myocardial infarction, readmission for heart failure, or stroke, over a median follow-up of 4.9 years.6 Kotecha et al. performed cardiac magnetic resonance (CMR) studies in 148 patients with severe COVID-19 and persistent troponin elevation at a median of 68 days post-discharge and observed late gadolinium enhancement and/or ischaemia in 54% of patients.7 Though multiple studies have shown a high frequency of abnormalities on CMR within 1-2 months following SARS-CoV-2 infection, Joy et al. demonstrated that the CMR features are similar in patients with mild COVID-19 illness compared with seronegative healthy individuals, 6 months after SARS-CoV-2 infection.8 However, the long-term CMR abnormalities and their clinical relevance remain to be ascertained.9 Even when the COVID-19 infection has resolved and the individual is no longer infective, he/she might still harbor SARS-CoV-2 RNA in various tissues in the body for up to 230 days.10 This could be one of the mechanisms leading to persistent cardiac injury.10 There are yet major gaps in our understanding of the mechanisms by which SARS-CoV-2 affects the blood vessels and the myocardium, and in turn affects the development of important clinical syndromes like atherosclerosis and heart failure. Although most of current treatment measures have concentrated on the management of acute illness, multiple trials on the use of various medications and their effects on outcomes in patients with COVID-19 are ongoing.9 Prospective studies are essential to better appreciate the lasting cardiovascular consequences of the long COVID-19 syndrome. It is important to formulate the surveillance guidelines among select groups of patients to identify electrophysiologic, morphologic and functional abnormalities. Consideration should be given for advanced imaging such as CMR, particularly in high-risk patients during follow-up. In that context, whether persistent elevation of troponin points towards a high risk of development of long-term cardiac complications and whether elevated troponin levels is a useful and cost-effective method of screening is to be tested. Optimal screening guidelines for patients after recovery from COVID-19 should be determined to prevent cardiovascular complications in a vast majority of the population.
126	CaV122		Reika Masuda, Samantha Lodge, Luke Whiley, Nicola Gray, Nathan Lawler, Philipp Nitschke, Sze-How Bong, Torben Kimhofer, Ruey Leng Loo, Berin Boughton, Annie X. Zeng, Drew Hall, Hartmut Schaefer, Manfred Spraul, Girish Dwivedi, Bu B. Yeap, Tammo Diercks, Ganeko Bernardo-Seisdedos, José M. Mato, John C. Lindon, Elaine Holmes, Oscar Millet, Julien Wist, and Jeremy K. Nicholson	Exploration of Human Serum Lipoprotein Supramolecular Phospholipids Using Statistical Heterospectroscopy in n-Dimensions (SHY-n): Identification of Potential Cardiovascular Risk Biomarkers Related to SARS-CoV-2 Infection	https://doi.org/10.1021/acs.analchem.1c05389	Published	March 1, 2022	Study	https://pubs.acs.org/doi/full/10.1021/acs.analchem.1c05389	SARS-CoV-2 infection causes a significant reduction in lipoprotein-bound serum phospholipids give rise to supramolecular phospholipid composite (SPC) signals observed in diffusion and relaxation edited 1H NMR spectra. To characterize the chemical structural components and compartmental location of SPC and to understand further its possible diagnostic properties, we applied a Statistical HeterospectroscopY in n-dimensions (SHY-n) approach. This involved statistically linking a series of orthogonal measurements made on the same samples, using independent analytical techniques and instruments, to identify the major individual phospholipid components giving rise to the SPC signals. Thus, an integrated model for SARS-CoV-2 positive and control adults is presented that relates three identified diagnostic subregions of the SPC signal envelope (SPC1, SPC2, and SPC3) generated using diffusion and relaxation edited (DIRE) NMR spectroscopy to lipoprotein and lipid measurements obtained by in vitro diagnostic NMR spectroscopy and ultrahigh-performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS). The SPC signals were then correlated sequentially with (a) total phospholipids in lipoprotein subfractions; (b) apolipoproteins B100, A1, and A2 in different lipoproteins and subcompartments; and (c) MS-measured total serum phosphatidylcholines present in the NMR detection range (i.e., PCs: 16.0,18.2; 18.0,18.1; 18.2,18.2; 16.0,18.1; 16.0,20.4; 18.0,18.2; 18.1,18.2), lysophosphatidylcholines (LPCs: 16.0 and 18.2), and sphingomyelin (SM 22.1). The SPC3/SPC2 ratio correlated strongly (r = 0.86) with the apolipoprotein B100/A1 ratio, a well-established marker of cardiovascular disease risk that is markedly elevated during acute SARS-CoV-2 infection. These data indicate the considerable potential of using a serum SPC measurement as a metric of cardiovascular risk based on a single NMR experiment. This is of specific interest in relation to understanding the potential for increased cardiovascular risk in COVID-19 patients and risk persistence in post-acute COVID-19 syndrome (PACS).
127	CaV123	doublon CaV114	Douglas B. Kell ORCHID logo ; Gert Jacobus Laubscher; Etheresia Pretorius ORCHID logo	A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications	https://doi.org/10.1042/BCJ20220016	Published	February 23 2022	Review	https://portlandpress.com/biochemj/article/479/4/537/230829	Post-acute sequelae of COVID (PASC), usually referred to as ‘Long COVID’ (a phenotype of COVID-19), is a relatively frequent consequence of SARS-CoV-2 infection, in which symptoms such as breathlessness, fatigue, ‘brain fog’, tissue damage, inflammation, and coagulopathies (dysfunctions of the blood coagulation system) persist long after the initial infection. It bears similarities to other post-viral syndromes, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Many regulatory health bodies still do not recognize this syndrome as a separate disease entity, and refer to it under the broad terminology of ‘COVID’, although its demographics are quite different from those of acute COVID-19. A few years ago, we discovered that fibrinogen in blood can clot into an anomalous ‘amyloid’ form of fibrin that (like other β-rich amyloids and prions) is relatively resistant to proteolysis (fibrinolysis). The result, as is strongly manifested in platelet-poor plasma (PPP) of individuals with Long COVID, is extensive fibrin amyloid microclots that can persist, can entrap other proteins, and that may lead to the production of various autoantibodies. These microclots are more-or-less easily measured in PPP with the stain thioflavin T and a simple fluorescence microscope. Although the symptoms of Long COVID are multifarious, we here argue that the ability of these fibrin amyloid microclots (fibrinaloids) to block up capillaries, and thus to limit the passage of red blood cells and hence O2 exchange, can actually underpin the majority of these symptoms. Consistent with this, in a preliminary report, it has been shown that suitable and closely monitored ‘triple’ anticoagulant therapy that leads to the removal of the microclots also removes the other symptoms. Fibrin amyloid microclots represent a novel and potentially important target for both the understanding and treatment of Long COVID and related disorders.
128	CaV124		EvangelosOikonomouab1NektariosSouvaliotisaaStamatiosLampsasaaGerasimosSiasosabGaryphalliaPoulakoucPanagiotisTheofilisbTheodore G.PapaioannoubAnna-BettinaHaidichdGeorgiaTsaousieVasileiosNtousopouloscVissariaSakkacGeorgiosCharalambousfVasilikiRapticSylviaRaftopoulougKonstantinosSyrigoscCostasTsioufisbDimitrisTousoulisbManolisVavuranakisa	Endothelial dysfunction in acute and long standing COVID−19: A prospective cohort study	https://doi.org/10.1016/j.vph.2022.106975	Published	3 March 2022	Study	https://www.sciencedirect.com/science/article/pii/S1537189122000246	Background Coronavirus disease-19 (COVID-19) is implicated by active endotheliitis, and cardiovascular morbidity. The long-COVID-19 syndrome implications in atherosclerosis have not been elucidated yet. We assessed the immediate, intermediate, and long-term effects of COVID-19 on endothelial function. Results Seventy-three patients diagnosed with COVID-19 (37% admitted in ICU) were recruited. FMD was significantly (p < 0.001) impaired in the COVID-19 group (1.65 ± 2.31%) compared to the control (6.51 ± 2.91%). ICU-treated subjects presented significantly impaired (p = 0.001) FMD (0.48 ± 1.01%) compared to those treated in the medical ward (2.33 ± 2.57%). During hospitalization, FMD was inversely associated with Interleukin-6 and Troponin I (p < 0.05 for all). Although, a significant improvement in FMD was noted during the follow-up (acute: 1.75 ± 2.19% vs. 1 month: 4.23 ± 2.02%, vs. 6 months: 5.24 ± 1.62%; p = 0.001), FMD remained impaired compared to control (6.48 ± 3.08%) at 1 month (p < 0.001) and 6 months (p = 0.01) post-hospital discharge. Conclusion COVID-19 patients develop a notable endothelial dysfunction, which is progressively improved over a 6-month follow-up but remains impaired compared to healthy controls subjects. Whether chronic dysregulation of endothelial function following COVID-19 could be accompanied by a residual risk for cardiovascular and thrombotic events merits further research.
129	CaV125		Nan Liu,Hui Long,Jianhua Sun,Huan Li,Yunting He,Qiang Wang,Kai Pan,Yongliang Tong,Bingshun Wang,Qingming Wu,Likun Gong	New laboratory evidence for the association between endothelial dysfunction and COVID-19 disease progression	https://doi.org/10.1002/jmv.27693	Published	05 March 2022	Study	https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.27693	There is growing evidence that ACE2 is highly expressed on endothelial cells, endothelial dysfunction plays a critical role in COVID-19 disease progression, but laboratory evidence is still lacking. This study established a multicenter retrospective cohort of 966 COVID-19 patients from three hospitals in Wuhan, China. We found that male (62.8% vs 46.5%), old age (72 (17) vs 60.5 (21)), and coexisting chronic diseases (88.5% vs 60.0%) were associated with poor clinical prognosis in COVID-19. Furthermore, the deteriorated patients exhibited more severe multi-organ damage, coagulation dysfunction, and extensive inflammation. Additionally, a cross-sectional study including 41 non-COVID-19 controls and 39 COVID-19 patients assayed endothelial function parameters in plasma and showed that COVID-19 patients exhibited elevated VCAM-1 (odds ratio, 1.000; 95% CI, 1.000-1.000; P=0.002), E-selectin (odds ratio, 1.000; 95% CI, 1.000-1.001; P<0.001), tPA (odds ratio, 1.024; 95% CI, 1.014-1.035; P<0.001), and decreased PAI-1 (odds ratio, 0.995; 95% CI, 0.990-1.000; P=0.059). Moreover, VCAM-1 was positively correlated with D-dimer (R=0.544, P<0.001); tPA was positively correlated with D-dimer (R=0.800, P<0.001) and BUN (R=0.638, P<0.001). Our findings further confirm the strong association between endothelial dysfunction and poor prognosis of COVID-19, which offers a rationale for targeting endothelial dysfunction as a therapeutic strategy for COVID-19.
130	CaV126		Christoph C. Kaufmann 1,*,Amro Ahmed 1,Achim Leo Burger 1,Marie Muthspiel 1,Bernhard Jäger 1,2,Johann Wojta 3,4,5 andKurt Huber 1,2,5	Biomarkers Associated with Cardiovascular Disease in COVID-19	https://doi.org/10.3390/cells11060922	Published	8 March 2022	Review	https://www.mdpi.com/2073-4409/11/6/922/htm	While the respiratory system is the primary target of disease manifestation, COVID-19 has been shown to also affect several other organs, making it a rather complex, multi-system disease. As such, cardiovascular involvement has been a topic of discussion since the beginning of the COVID-19 pandemic, primarily due to early reports of excessive myocardial injury in these patients. Treating physicians are faced with multiple challenges in the management and early triage of patients with COVID-19, as disease severity is highly variable ranging from an asymptomatic infection to critical cases rapidly deteriorating to intensive care treatment or even fatality. Laboratory biomarkers provide important prognostic information which can guide decision making in the emergency department, especially in patients with atypical presentations. Several cardiac biomarkers, most notably high-sensitive cardiac troponin (hs-cTn) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), have emerged as valuable predictors of prognosis in patients with COVID-19. The purpose of this review was to offer a concise summary on prognostic cardiac biomarkers in COVID-19 and discuss whether routine measurements of these biomarkers are warranted upon hospital admission.
131	CaV127	CPET	Pasquale Ambrosino 1,*,† ,Paolo Parrella 2,†,Roberto Formisano 1,Giovanni Perrotta 1,Silvestro Ennio D’Anna 3,Marco Mosella 3,Antimo Papa 1,‡ andMauro Maniscalco	Cardiopulmonary Exercise Performance and Endothelial Function in Convalescent COVID-19 Patients	https://doi.org/10.3390/jcm11051452	Published	7 March 2022	Study	https://www.mdpi.com/2077-0383/11/5/1452/htm	Background: Endothelial dysfunction has been proposed as the common pathogenic background of most manifestations of coronavirus disease 2019 (COVID-19). Among these, some authors also reported an impaired exercise response during cardiopulmonary exercise testing (CPET). We aimed to explore the potential association between endothelial dysfunction and the reduced CPET performance in COVID-19 survivors. Methods: 36 consecutive COVID-19 survivors underwent symptom-limited incremental CPET and assessment of endothelium-dependent flow-mediate dilation (FMD) according to standardized protocols. Results: A significantly higher FMD was documented in patients with a preserved, as compared to those with a reduced, exercise capacity (4.11% ± 2.08 vs. 2.54% ± 1.85, p = 0.048), confirmed in a multivariate analysis (β = 0.899, p = 0.038). In the overall study population, FMD values showed a significant Pearson’s correlation with two primary CPET parameters, namely ventilation/carbon dioxide production (VE/VCO2) slope (r = −0.371, p = 0.026) and end-tidal carbon dioxide tension (PETCO2) at peak (r = 0.439, p = 0.007). In multiple linear regressions, FMD was the only independent predictor of VE/VCO2 slope (β = −1.308, p = 0.029) and peak PETCO2 values (β = 0.779, p = 0.021). Accordingly, when stratifying our study population based on their ventilatory efficiency, patients with a ventilatory class III-IV (VE/VCO2 slope ≥ 36) exhibited significantly lower FMD values as compared to those with a ventilatory class I-II. Conclusions: The alteration of endothelial barrier properties in systemic and pulmonary circulation may represent a key pathogenic mechanism of the reduced CPET performance in COVID-19 survivors. Personalized pharmacological and rehabilitation strategies targeting endothelial function may represent an attractive therapeutic option.
132	CaV128		He Li ,Yixiang Deng ,Zhen Li,Ander Dorken Gallastegi,Christos S. Mantzoros,Galit H. Frydman,George E. Karniadakis	Multiphysics and multiscale modeling of microthrombosis in COVID-19	https://doi.org/10.1371/journal.pcbi.1009892	Published	March 7, 2022	Study	https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1009892	Because of the infectious nature of SARS-CoV-2, patients’ fresh blood samples are limited to access for in vitro experimental investigations. Herein, we employ a novel multiscale and multiphysics computational framework to perform predictive modeling of the pathological thrombus formation in the microvasculature using data from patients with COVID-19. This framework seamlessly integrates the key components in the process of blood clotting, including hemodynamics, transport of coagulation factors and coagulation kinetics, blood cell mechanics and adhesive dynamics, and thus allows us to quantify the contributions of many prothrombotic factors reported in the literature, such as stasis, the derangement in blood coagulation factor levels and activities, inflammatory responses of endothelial cells and leukocytes to the microthrombus formation in COVID-19. Our simulation results show that among the coagulation factors considered, antithrombin and factor V play more prominent roles in promoting thrombosis. Our simulations also suggest that recruitment of WBCs to the endothelial cells exacerbates thrombogenesis and contributes to the blockage of the blood flow. Additionally, we show that the recent identification of flowing blood cell clusters could be a result of detachment of WBCs from thrombogenic sites, which may serve as a nidus for new clot formation. These findings point to potential targets that should be further evaluated, and prioritized in the anti-thrombotic treatment of patients with COVID-19. Altogether, our computational framework provides a powerful tool for quantitative understanding of the mechanism of pathological thrombus formation and offers insights into new therapeutic approaches for treating COVID-19 associated thrombosis. Author summary Emerging clinical evidence suggests that thrombosis in the microvasculature of patients with Coronavirus disease 2019 (COVID-19) plays an essential role in dictating the disease progression. We employ a novel multiphysics and multiscale computational framework to investigate the underlying mechanism of the pathological formation of microthrombi and circulating cell clusters in COVID-19. We quantify the contributions of many prothrombotic factors reported in the literature, such as stasis, the derangement in blood coagulation factor levels and activities, inflammatory responses of endothelial cells and leukocytes to the microthrombus formation in COVID-19, through which we identify the potential targets that should be further evaluated, and prioritized in the anti-thrombotic treatment of patients with COVID-19.
133	CaV129		Jennifer Abbasi	The COVID Heart—One Year After SARS-CoV-2 Infection, Patients Have an Array of Increased Cardiovascular Risks	https://doi.org/10.1001/jama.2022.2411	Published	March 2, 2022	Study	https://jamanetwork.com/journals/jama/fullarticle/2789793	An analysis of data from nearly 154 000 US veterans with SARS-CoV-2 infection provides a grim preliminary answer to the question: What are COVID-19’s long-term cardiovascular outcomes? The study, published in Nature Medicine by researchers at the Veterans Affairs (VA) St Louis Health Care System, found that in the year after recovering from the illness’s acute phase, patients had increased risks of an array of cardiovascular problems, including abnormal heart rhythms, heart muscle inflammation, blood clots, strokes, myocardial infarction, and heart failure. What’s more, the heightened risks were evident even among those who weren’t hospitalized with acute COVID-19.
134	CaV130		Michael Tarasev, Sabrina Mota, Xiufeng Gao, Marta Ferranti, Aliya U. Zaidi, Bryan Hannan, Patrick Hines	Possible Role of P-selectin Adhesion in Long-COVID: A Comparative Analysis of a Long-COVID Case Versus an Asymptomatic Post-COVID Case	https://doi.org/10.1101/2022.03.09.22271297	pre-print	March 12, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.03.09.22271297v1.full-text	The pathophysiology of Long-COVID remains to be established. Functional P-selectin activity, implicated in COVID-19 sequalae, was measured between two convalescent COVID-19 subjects, one with (Long-COVID subject) and another without Long-COVID symptoms. Methods - Flow adhesion of whole blood or isolated white blood cells to P-selectin (FA-WB-Psel and FA-WBC-Psel) was measured using a standardized microfluidics clinical assay; impedance aggregometry with a collagen agonist was measured using model 590 Chrono-Log impedance aggregometer; standard laboratory assays were performed to evaluate changes in blood chemistries. Results - For both subjects, hemoglobin, WBC, platelet counts, electrolytes and ferritin were within normal reference ranges, with FA-WB-Psel significantly elevated compared to healthy controls (p< 0.01). In vitro treatment of whole blood samples with crizanlizumab (anti-p-selectin monoclonal antibody) within the clinical dose range (10 μg/ml) mL) inhibited FA-WB-Psel only in samples from asymptomatic post-COVID subject, with the Long-COVID subject sample requiring close to 5-fold elevated dose to achieve a response. Pronounced inhibition of P-selectin adhesion of isolated leukocytes was observed for both subjects in autologous platelet-poor plasma and buffer. Impedance aggregometry showed greater baseline platelet aggregation to collagen in the Long-COVID sample, although both samples responded similarly to aspirin-induced platelet inhibition. Conclusions - Presented results suggest that elevated platelet activation in Long-COVID subject may be associated with increased P-Selectin activity. The results are discussed in terms of possible use on P-selectin inhibition therapies in treating Long-COVID.
135	CaV131		Sara Díaz-Salazar, Raquel Navas, Laura Sainz-Maza, Patricia Fierro, Meryam Maamar, Arancha Artime, Héctor Basterrechea, Benedetta Petitta, Carlota Lamadrid, Lucía Pedraja, Claudia Gándara-Samperio, Stefanie Pini, View ProfileJosé Manuel Olmos, View ProfileCarmen Ramos, View ProfileEmilio Pariente, View ProfileJosé Luis Hernández	Blood group O and post-COVID-19 syndrome	https://doi.org/10.1101/2022.03.10.22272197	pre-print	March 17, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.03.10.22272197v3.full-text	The ABO blood group system modulates the inflammatory response and has been involved in COVID-19. O-group protects against SARS-CoV-2 infection, but there are no data regarding post-COVID-19 syndrome (PCS). Our aim was to assess this possible association. Subjects and methods - Case-control study in a community setting, with subjects who had experienced mild COVID-19. Cases were PCS+, controls were PCS-, and the exposure variable, O-group. Epidemiological data (age, sex, BMI, smoking, comorbidities), laboratory parameters (inflammatory markers, IgG antibodies, blood type) and clinical data were collected. Composite inflammatory indices were developed. Multivariate analyses were performed. Results - We analyzed 121 subjects (56.2% women), mean age 45.7 ± 16 years. Blood group frequencies were 43.3%, 7.7%, 5.7%, and 43.3% for A, B, AB and O, respectively. Thirty-six patients were PCS+. There were no significant differences between cases and controls. Compared to non-O, a higher prevalence of PCS (p=0.036), number of symptoms (p=0.017) and myalgia (p=0.030) were noted in O-group. Concerning inflammatory markers, PCS+ and PCS-showed no differences in A, B, and AB groups. In contrast, O-group PCS+ patients had significantly higher lymphocyte count, higher levels of fibrinogen and CRP, and higher percentages of 3 composite indices, than PCS-subjects. The O-group showed a 4-fold increased risk of PCS compared to non-O (adjusted OR=4.20 [95%CI, 1.2-14]; p=0.023). Conclusion - An increased risk of PCS has shown to be associated with O-group, after controlling for confounders. In O-group subjects with PCS, slightly albeit significant, raised levels of fibrinogen, CRP, and lymphocyte count, have been demonstrated.
136	CaV132		Shokrollah Elahi	Hematopoietic responses to SARS-CoV-2 infection	https://doi.org/10.1007/s00018-022-04220-6	Published	13 March 2022	Review	https://link.springer.com/article/10.1007/s00018-022-04220-6	Under physiological conditions, hematopoietic stem and progenitor cells (HSPCs) in the bone marrow niches are responsible for the highly regulated and interconnected hematopoiesis process. At the same time, they must recognize potential threats and respond promptly to protect the host. A wide spectrum of microbial agents/products and the consequences of infection-induced mediators (e.g. cytokines, chemokines, and growth factors) can have prominent impact on HSPCs. While COVID-19 starts as a respiratory tract infection, it is considered a systemic disease which profoundly alters the hematopoietic system. Lymphopenia, neutrophilia, thrombocytopenia, and stress erythropoiesis are the hallmark of SARS-CoV-2 infection. Moreover, thrombocytopenia and blood hypercoagulability are common among COVID‐19 patients with severe disease. Notably, the invasion of erythroid precursors and progenitors by SARS-CoV-2 is a cardinal feature of COVID-19 disease which may in part explain the mechanism underlying hypoxia. These pieces of evidence support the notion of skewed steady-state hematopoiesis to stress hematopoiesis following SARS-CoV-2 infection. The functional consequences of these alterations depend on the magnitude of the effect, which launches a unique hematopoietic response that is associated with increased myeloid at the expense of decreased lymphoid cells. This article reviews some of the key pathways including the infectious and inflammatory processes that control hematopoiesis, followed by a comprehensive review that summarizes the latest evidence and discusses how SARS-CoV-2 infection impacts hematopoiesis.
137	CaV133		Filippo Crea	European Society of Cardiology guidance for the management of cardiovascular disease during the pandemic and a focus on long COVID	https://doi.org/10.1093/eurheartj/ehac087	Published	17 February 2022	Guidance	https://academic.oup.com/eurheartj/article/43/11/1017/6547843?login=true	This focus issue on COVID-19 opens with two guidance documents produced by the Task Force for the management of COVID-19 of the European Society of Cardiology.6,7 The aim of this two-part series is to provide practical knowledge and guidance to aid clinicians in the diagnosis and management of cardiovascular disease (CVD) in association with COVID-19. The authors point out that they have reviewed the available evidence and have organized the resulting information into two parts. The first focuses on the epidemiology, pathophysiology, and diagnosis of CV conditions that may be manifest in patients with COVID-19. The second part addresses the topics of care pathways, treatment, and follow-up of CV conditions in patients with COVID-19. The Task Force concludes that these documents provide a summary of current knowledge and guidance to practising clinicians managing patients with CVD and COVID-19. The recommendations are mainly the result of observations and personal experience from healthcare providers. Therefore, the information provided may be subject to change with increasing knowledge, evidence from prospective studies, and changes in the pandemic. Likewise, the guidance provided in the document should not interfere with recommendations provided by local and national healthcare authorities.
138	CaV134		Ismaheel O. Lawal, Mankgopo M. Kgatle, Kgomotso Mokoala, Abubakar Farate & Mike M. Sathekge	Cardiovascular disturbances in COVID-19: an updated review of the pathophysiology and clinical evidence of cardiovascular damage induced by SARS-CoV-2	https://doi.org/10.1186/s12872-022-02534-8	Published	09 March 2022	Review	https://bmccardiovascdisord.biomedcentral.com/articles/10.1186/s12872-022-02534-8	Severe acute respiratory coronavirus-2 (SARS-Co-2) is the causative agent of coronavirus disease-2019 (COVID-19). COVID-19 is a disease with highly variable phenotypes, being asymptomatic in most patients. In symptomatic patients, disease manifestation is variable, ranging from mild disease to severe and critical illness requiring treatment in the intensive care unit. The presence of underlying cardiovascular morbidities was identified early in the evolution of the disease to be a critical determinant of the severe disease phenotype. SARS-CoV-2, though a primarily respiratory virus, also causes severe damage to the cardiovascular system, contributing significantly to morbidity and mortality seen in COVID-19. Evidence on the impact of cardiovascular disorders in disease manifestation and outcome of treatment is rapidly emerging. The cardiovascular system expresses the angiotensin-converting enzyme-2, the receptor used by SARS-CoV-2 for binding, making it vulnerable to infection by the virus. Systemic perturbations including the so-called cytokine storm also impact on the normal functioning of the cardiovascular system. Imaging plays a prominent role not only in the detection of cardiovascular damage induced by SARS-CoV-2 infection but in the follow-up of patients’ clinical progress while on treatment and in identifying long-term sequelae of the disease.
139	CaV135		Sina Bohnacker, Franziska Hartung, Fiona Henkel, Alessandro Quaranta, Johan Kolmert, Alina Priller, Minhaz Ud-Dean, Johanna Giglberger, Luisa M. Kugler, Lisa Pechtold, Sarah Yazici, Antonie Lechner, Johanna Erber, Ulrike Protzer, Paul Lingor, Percy Knolle, Adam M. Chaker, Carsten B. Schmidt-Weber, Craig E. Wheelock & Julia Esser-von Bieren	Mild COVID-19 imprints a long-term inflammatory eicosanoid- and chemokine memory in monocyte-derived macrophages	https://doi.org/10.1038/s41385-021-00482-8	Published	15 March 2022	Study	https://www.nature.com/articles/s41385-021-00482-8	Monocyte-derived macrophages (MDM) drive the inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and they are a major source of eicosanoids in airway inflammation. Here we report that MDM from SARS-CoV-2-infected individuals with mild disease show an inflammatory transcriptional and metabolic imprint that lasts for at least 5 months after SARS-CoV-2 infection. MDM from convalescent SARS-CoV-2-infected individuals showed a downregulation of pro-resolving factors and an increased production of pro-inflammatory eicosanoids, particularly 5-lipoxygenase-derived leukotrienes. Leukotriene synthesis was further enhanced by glucocorticoids and remained elevated at 3–5 months, but had returned to baseline at 12 months post SARS-CoV-2 infection. Stimulation with SARS-CoV-2 spike protein or LPS triggered exaggerated prostanoid-, type I IFN-, and chemokine responses in post COVID-19 MDM. Thus, SARS-CoV-2 infection leaves an inflammatory imprint in the monocyte/ macrophage compartment that drives aberrant macrophage effector functions and eicosanoid metabolism, resulting in long-term immune aberrations in patients recovering from mild COVID-19.
140	CaV136		Writing Committee, Ty J. Gluckman, Nicole M. Bhave, Larry A. Allen, Eugene H. Chung, Erica S. Spatz, Enrico Ammirati, Aaron L. Baggish, Biykem Bozkurt, William K. Cornwell, Kimberly G. Harmon, Jonathan H. Kim, Anuradha Lala, Benjamin D. Levine, Matthew W. Martinez, Oyere Onuma, Dermot Phelan, Valentina O. Puntmann, Saurabh Rajpal, Pam R. Taub, and Amanda K. Verma	2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19 in Adults: Myocarditis and Other Myocardial Involvement, Post-Acute Sequelae of SARS-CoV-2 Infection, and Return to Play: A Report of the American College of Cardiology Solution Set Oversight Committee EXPERT CONSENSUS DECISION PATHWAY	https://doi.org/10.1016/j.jacc.2022.02.003	Published	Mar 16, 2022	EXPERT CONSENSUS DECISION PATHWAY	https://www.jacc.org/doi/full/10.1016/j.jacc.2022.02.003	The novel coronavirus disease 2019 (COVID-19) pandemic has had an unprecedented impact worldwide. In the United States alone, more than 78 million cases have been reported, with greater than 948,000 deaths attributed directly to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as of the writing of this ECDP.2 Among patients hospitalized for COVID-19, various abnormalities in cardiac testing (eg, electrocardiographic abnormalities, elevated cardiac biomarkers)3-5 and a wide range of cardiovascular complications (eg, myocardial injury, thrombosis, arrhythmia) have been reported.4-7 For some patients infected with SARS-CoV-2, cardiac symptoms (eg, chest pain, shortness of breath, fatigue, and palpitations) persist, lasting months after the initial illness.8,9 Laboratory and imaging evidence of myocardial injury and involvement has also been observed in both symptomatic and asymptomatic individuals,4,10,11 as well as after receipt of the COVID-19 mRNA vaccine.12 For clinicians treating these individuals, a growing number of questions exist related to evaluation and management of these conditions, as well as safe resumption of physical activity. To help gather further insights, the ACC held a virtual Heart House Roundtable in May 2021, bringing together experts in the following areas: 1) myocarditis; 2) post-acute sequelae of SARS-CoV-2 infection (PASC); and 3) sports cardiology. This ECDP represents a key output from that meeting and is intended to serve as a resource for clinicians caring for these patients, largely in the outpatient setting. More specifically, this document attempts to address commonly asked questions regarding the care of adults (aged ≥18 years) with cardiac symptoms (eg, chest pain, dyspnea, palpitations, syncope) after SARS-CoV-2 infection. In the absence of robust clinical trial data, it is intended to provide practical guidance related to evaluation and management.
141	CaV137	ME - PESE	Milan Haffke, Helma Freitag, Gordon Rudolf, Martina Seifert, Wolfram Doehner, Nadja Scherbakov, Leif Hanitsch, Kirsten Wittke, Sandra Bauer, Frank Konietschke, Friedemann Paul, Judith Bellmann-Strobl, Claudia Kedor, Carmen Scheibenbogen & Franziska Sotzny	Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS)	https://doi.org/10.1186/s12967-022-03346-2	Published	22 March 2022	Study	https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03346-2	Background Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS. Methods We studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs). 14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS. Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs. In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers. Results Five of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding. A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs. Conclusion A subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups.
142	CaV138		Mauro Giacca & Ajay M. Shah	The pathological maelstrom of COVID-19 and cardiovascular disease	https://doi.org/10.1038/s44161-022-00029-5	Published	16 March 2022	Review	https://www.nature.com/articles/s44161-022-00029-5	Coronavirus disease 2019 (COVID-19) is a consequence of infection of the upper and lower respiratory tract with severe acute respiratory syndrome coronavirus 2 but often becomes a systemic disease, with important involvement of other organs. A bidirectional relationship exists between COVID-19 and cardiovascular disease. On the one hand, preexisting comorbidities, in particular high prevalence of cardiovascular risk factors such as hypertension and diabetes and chronic cardiovascular conditions predispose to severe disease. On the other hand, biomarkers of myocardial injury are frequently raised in patients with COVID-19, along with arrhythmia and heart failure. Localized thrombosis is a common finding in the lungs but can also increase the occurrence of thrombotic events systemically. Thrombosis is consequent to different pathogenic mechanisms, which include endothelial dysfunction and immunothrombosis. Thrombocytopenia is common in patients with COVID-19 and alterations in platelet function participate in the pro-thrombotic phenotype. Involvement of the cardiovascular system in COVID-19 has important consequences during recovery from infection and the development of long COVID.
143	CaV139		Francesco Nappi 1,*,† ,Omar Giacinto 2,†,Omar Ellouze 3,Antonio Nenna 2 ,Sanjeet Singh Avtaar Singh 4 ,Massimo Chello 2 ,Assine Bouzguenda 3 andXavier Copie 5	Association between COVID-19 Diagnosis and Coronary Artery Thrombosis: A Narrative Review	https://doi.org/10.3390/biomedicines10030702	Published	18 March 2022	Review	https://www.mdpi.com/2227-9059/10/3/702/htm	Coronavirus disease 2019 is characterized by its severe respiratory effects. Data early on indicated an increased risk of mortality in patients with cardiovascular comorbidities. Early reports highlighted the multisystem inflammatory syndrome, cytokine storm, and thromboembolic events as part of the disease processes. The aim of this review is to assess the association between COVID-19 and its thrombotic complications, specifically related to the cardiovascular system. The role of neutrophil extracellular traps (NETs) is explored in the pathogenesis of the disease. The structure and anatomy of the virus are pivotal to its virulence in comparison to other α and β Coronaviridae (HCoV-229E, HCoV-OC43, HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1). In particular, the host interaction and response may explain the variability of severity in patients. Angio tensin-converting enzyme 2 (ACE2) activation may be implicated in the cardiovascular and throm bogenic potential of the disease. The virus may also have direct effects on the endothelial lining affecting hemostasis and resulting in thrombosis through several mechanisms. Dipyridamole may have a therapeutic benefit in NET suppression. Therapeutic avenues should be concentrated on the different pathophysiological steps involving the virus and the host.
144	CaV140		Michael S. Nirenberg,Luis Requena,Carlos Santonja,Gregory T. Smith,Steve A. McClain	Histopathology of Persistent Long COVID Toe: A Case Report	https://doi.org/10.1111/cup.14240	Published	02 April 2022	Case Report	https://onlinelibrary.wiley.com/doi/10.1111/cup.14240	During the 2020 coronavirus (SARS-CoV-2) pandemic, several cutaneous lesions were identified, including: pseudo-chilblain, vesicular, urticarial, maculopapular, and livedo/necrosis. A 59-year-old obese man with probable COVID-19 developed painful cyanosis with histopathologic capillary thrombosis of toes, and the cyanosis persisted for nearly 22 months. Shortly after initial exposure to family members with documented SARS-CoV-2, he developed upper respiratory symptoms, yet his anti-SARS-CoV-2 antibody and nasal swab RT-PCR tests were repeatedly negative. Two family members were hospitalized and one of them succumbed with documented SARS-CoV-2 pneumonia within ten days of exposure. Biopsy of the distal toe 16 weeks after initial exposure demonstrated papillary dermal capillary thrombosis with endothelial swelling, telangiectasia, and peri-eccrine lymphocytic infiltrates resembling pernio. Overall, this is the first case of biopsy of “long COVID toe” following presumed SARS-Cov-2 exposure, with demonstration of thrombotic vasculopathy, toe cyanosis, and pernio-like pathology.
145	CaV141		Mohamed O. Mohamed & Amitava Banerjee	Long COVID and cardiovascular disease: a learning health system approach	https://doi.org/10.1038/s41569-022-00697-7	Published	24 March 2022	Article	https://www.nature.com/articles/s41569-022-00697-7	Cardiovascular disease is both a risk factor and potential outcome of the direct, indirect and long-term effects of COVID-19. A recent analysis in >150,000 survivors of COVID-19 demonstrates an increased 1-year risk of numerous cardiovascular diseases. Preventing and managing this new disease burden presents challenges to health systems and requires a learning health system approach. To summarize, bidirectional relationships exist between CVD and COVID-19. Multimorbidity and CVD are key considerations in patients with long COVID, who require multidisciplinary and integrated care. Long COVID, including cardiovascular complications, has potentially far-reaching implications for health system resources, including staffing, infrastructure and funding. The knowledge gaps in basic research, clinical evidence and patient care need to be addressed together to enable effective and timely management of long COVID. Future pandemic planning and preparedness should include modelling and consideration of CVDs and noncommunicable diseases, as well as potential long-term disease sequelae.
146	CaV142		Pietro Enea Lazzerini, Franco Laghi-Pasini, Mohamed Boutjdir & Pier Leopoldo Capecchi	Inflammatory cytokines and cardiac arrhythmias: the lesson from COVID-19	https://doi.org/10.1038/s41577-022-00714-3	Published	28 March 2022	Article	https://www.nature.com/articles/s41577-022-00714-3	Although inflammatory cytokines are implicated in the pathogenesis of cardiac arrhythmias, inflammation is still largely overlooked in the current management of heart rhythm disorders. Now, COVID-19, a systemic inflammatory disease, causes an unexpectedly high prevalence of arrhythmic events, emphasizing the relevance of inflammation in the pathogenesis of cardiac arrhythmias. Conclusion COVID-19 has provided us with the unique opportunity to observe how systemic cytokine release increases arrhythmic risk. It is increasingly evident that a very similar increase of arrhythmic events is also found in other inflammatory conditions. Although some clinical studies show beneficial effects of targeting inflammation and inflammatory cytokines to reduce arrhythmic risk1, this field is still largely unexplored. Notably, a large meta-analysis of randomized controlled trials recently demonstrated that therapy with glucocorticoid and/or IL-6 receptor antagonist significantly reduced short-term mortality in patients with severe COVID-19, including cardiovascular death10. Therefore, it is important to consider inflammation as an essential contributor to cardiac arrhythmic events, especially given that its clinical impact is likely to be relevant in conditions beyond COVID-19.
147	CaV143		Luca Santoro 1,†,Lorenzo Falsetti 2,† ,Vincenzo Zaccone 2,*,Antonio Nesci 1,Matteo Tosato 3 ,Bianca Giupponi 4,Maria Cristina Savastano 5 ,Gianluca Moroncini 6,Antonio Gasbarrini 7,8,Francesco Landi 3,8,Angelo Santoliquido 1,8	Impaired Endothelial Function in Convalescent Phase of COVID-19: A 3 Month Follow Up Observational Prospective Study	https://doi.org/10.3390/jcm11071774	Published	23 March 2022	Study	https://www.mdpi.com/2077-0383/11/7/1774/htm	Endothelial dysfunction has a role in acute COVID-19, contributing to systemic inflammatory syndrome, acute respiratory distress syndrome, and vascular events. Evidence regarding COVID-19 middle- and long-term consequences on endothelium are still lacking. Our study aimed to evaluate if COVID-19 severity could significantly affect the endothelial function after three months from the acute phase. Methods: We assessed endothelial function in outpatients with previous COVID-19 three months after negative SARS-CoV-2 molecular test by measuring flow-mediated dilation (FMD) in patients categorized according to a four-variable COVID-19 severity scale (“home care”; “hospital, no oxygen”; “hospital, oxygen”; “hospital requiring high-flow nasal canula, non-invasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation”). FMD difference among COVID-19 severity categories was assessed with analysis of variance; we further clarified the relationship between FMD and previous COVID-19 severity with multivariate logistic models. Results: Among 658 consecutive COVID-19 subjects, we observed a significant linear trend of FMD reduction with the increase of the COVID-19 category (p < 0.0001). The presence of endothelial dysfunction was more frequent among hospitalized patients (78.3%) with respect to home-care patients (21.7%; p < 0.0001). COVID-19 severity was associated with increased endothelial dysfunction risk (OR: 1.354; 95% CI: 1.06–1.71; p = 0.011) at multivariate binary logistic analysis. FMD showed a significant direct correlation with PaO2 (p = 0.004), P/F ratio (p = 0.004), FEV1 (p = 0.008), and 6MWT (p = 0.0001). Conclusions: Hospitalized COVID-19 subjects showed an impaired endothelial function three months after the acute phase that correlated with pulmonary function impairment. Further studies are needed to evaluate if these subjects are at higher risk of developing pulmonary disease or future cardiovascular events.
148	CaV144		Ioannis Katsoularis, Osvaldo Fonseca-Rodríguez, Paddy Farrington, Hanna Jerndal, Erling Häggström Lundevaller, Malin Sund, Krister Lindmark, Anne-Marie Fors Connolly	Risks of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19: nationwide self-controlled cases series and matched cohort study	https://doi.org/10.1136/bmj-2021-069590	Published	06 April 2022	Study	https://www.bmj.com/content/377/bmj-2021-069590	Objective To quantify the risk of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19. Design Self-controlled case series and matched cohort study. Setting National registries in Sweden. Participants 1 057 174 people who tested positive for SARS-CoV-2 between 1 February 2020 and 25 May 2021 in Sweden, matched on age, sex, and county of residence to 4 076 342 control participants. Main outcomes measures Self-controlled case series and conditional Poisson regression were used to determine the incidence rate ratio and risk ratio with corresponding 95% confidence intervals for a first deep vein thrombosis, pulmonary embolism, or bleeding event. In the self-controlled case series, the incidence rate ratios for first time outcomes after covid-19 were determined using set time intervals and the spline model. The risk ratios for first time and all events were determined during days 1-30 after covid-19 or index date using the matched cohort study, and adjusting for potential confounders (comorbidities, cancer, surgery, long term anticoagulation treatment, previous venous thromboembolism, or previous bleeding event). Results Compared with the control period, incidence rate ratios were significantly increased 70 days after covid-19 for deep vein thrombosis, 110 days for pulmonary embolism, and 60 days for bleeding. In particular, incidence rate ratios for a first pulmonary embolism were 36.17 (95% confidence interval 31.55 to 41.47) during the first week after covid-19 and 46.40 (40.61 to 53.02) during the second week. Incidence rate ratios during days 1-30 after covid-19 were 5.90 (5.12 to 6.80) for deep vein thrombosis, 31.59 (27.99 to 35.63) for pulmonary embolism, and 2.48 (2.30 to 2.68) for bleeding. Similarly, the risk ratios during days 1-30 after covid-19 were 4.98 (4.96 to 5.01) for deep vein thrombosis, 33.05 (32.8 to 33.3) for pulmonary embolism, and 1.88 (1.71 to 2.07) for bleeding, after adjusting for the effect of potential confounders. The rate ratios were highest in patients with critical covid-19 and highest during the first pandemic wave in Sweden compared with the second and third waves. In the same period, the absolute risk among patients with covid-19 was 0.039% (401 events) for deep vein thrombosis, 0.17% (1761 events) for pulmonary embolism, and 0.101% (1002 events) for bleeding. Conclusions The findings of this study suggest that covid-19 is a risk factor for deep vein thrombosis, pulmonary embolism, and bleeding. These results could impact recommendations on diagnostic and prophylactic strategies against venous thromboembolism after covid-19.
149	CaV145		Ahmed Ibrahim Ahmed, Jean Michel Saad, Yushui Han, Maan Malahfji, Faisal Nabi, John J. Mahmarian, William A. Zoghbi, and Mouaz H. Al-Mallah	CORONARY MICROVASCULAR HEALTH IN PATIENTS WITH PRIOR COVID-19 INFECTION: IMPLICATIONS FOR LONG-COVID SYNDROME		Published	2022 Mar	Study	https://www.jacc.org/doi/full/10.1016/S0735-1097%2822%2902813-3	Background: SARS-CoV-2 infection has been shown to directly infect coronary vascular endothelium, causing inflammation and plaque instability. We aimed to assess the vascular health of patients with prior COVID-19 using Positron emission tomography (PET) derived coronary flow reserve (CFR). Methods: A prospective cohort of consecutive patients with PCR confirmed prior COVID-19 infection undergoing clinically indicated PET myocardial perfusion imaging were included and compared to patients with no prior COVID19. CFR was determined by PET and microvascular dysfunction (CMD) was defined as CFR<2. Results: The study population consisted of 2316 patients (4.4% prior COVID 19, 52% male, mean age 67±12 years, 55% hypertensive, 32% diabetic, 41% dyslipidemia). The mean duration between COVID19 diagnosis and PET was 191 (±131) days. CMD was more prevalent in those with prior COVID19 (58% vs 46%, p=0.012). After adjusting for baseline and clinical characteristics, patients with prior COVID19 had statistically significant higher odds of CMD (OR 1.8, p=0.008). Results were consistent in subgroups of patients with no clinical risk factors and normal stress tests. Conclusion: Our analysis shows that patients with prior COVID19 have higher rates of CMD. This may in part explain the long-COVID symptoms. The prognostic implications of these findings need to be determined.
150	CaV146		Christopher Werlein, Maximilian Ackermann, Harshit R. Shah, Helge Stark, Florian Laenger, Tim Salditt, Tobias Welte, Johann Bauersachs, Axel Haverich, Saskia von Stillfried, Mark Kuehnel, Roman Buelow, Peter Boor, Stephen M. Black, Steven J. Mentzer, and Danny Jonigk	INFLAMMATION AND VASCULAR REMODELING IN COVID-19 HEARTS		Published	2022 Mar	Study	https://www.jacc.org/doi/full/10.1016/S0735-1097%2822%2902814-5	Background: Cardiac involvement in COVID-19 infection is a common clinical finding and can determine the clinical outcome; however the underlying pathomechanisms are largely unknown. Methods: We performed a comprehensive analysis of heart-tissue samples of 24 autopsies with confirmed COVID-19 disease and compared them to samples of age-matched Influenza A (n=16) as well as conventional viral myocarditis cases (n=8) and control tissue (n=9). We employed conventional histopathology, microvascular corrosion casting, scanning electron microscopy, phase-contrast synchrotron x-ray tomography, direct multiplexed measurements of gene expression, multiplexed immunohistochemistry (MPX) and Synchrotron radiation tomographic microscopy. Results: On conventional histopathology, none of the COVID-19 samples fulfilled the criteria for lymphocytic myocarditis; however quantification via MPX showed a significant increase in perivascular CD11b/Tie2+-macrophages in COVID-19 over hospitalisation time. Ultrastructurally, an altered microvascularity, an increase of intussusceptive angiogenesis as well as multifocal ultrastructurally detectable thrombi (uTh) could be demonstrated, unapparent in conventional morphology. On a molecular level, COVID-19 hearts displayed a distinct expression pattern coding mainly for angiogenesis and epithelial-mesenchymal transition (EMT) and lesser for inflammation. Conclusion: Cardiac involvement in COVID-19 is not a conventional viral myocarditis but a rather qualitative than quantitative increase in CD11b+/Tie2+ monocytes/ macrophages contributing to cardiac neoangiogenesis and remodeling in COVID-19 cardiomyopathy. COVID-19 cardiomyopathy is substantially underappreciated upon light-microscopy observation and requires a multimodal approach. Our comparative morphological and transcriptional data indicate that the neovascularization by intussusceptive angiogenesis is the main driver for a specific COVID-19 induced cardiac response facilitated by interactions between the incorporation of blood-borne CD11b+/Tie2+ monocytes/macrophages and damaged and activated endothelial cells in COVID-19 hearts.
151	CaV147		Vishal Khetpal, Julia Berkowitz, Lan Jiang, Shilpa Vijayakumar, Khansa Ahmad, Justin Echouffo Tcheugui, Anupama Menon, Daithi S. Heffernan, Gaurav Choudhary, James Rudolph, Wen-Chih Wu, and Sebhat Erqou	LONG-TERM OUTCOMES OF VETERANS WITH A DIAGNOSIS OF HEART FAILURE AFTER CORONAVIRUS-2019 (COVID-19) INFECTION		Published	2022 Mar	Study	https://www.jacc.org/doi/full/10.1016/S0735-1097%2822%2903146-1	Background: Patients with heart failure (HF) are at risk for continued symptoms after recovery from acute COVID-19, termed in a growing body of literature as ‘long COVID’. However, limited data have examined whether COVID-19 is associated with higher long-term risk for mortality and hospital admission for HF patients. Methods: We conducted a retrospective cohort study of HF patients using Veterans’ Affairs (VA) data from February 1, 2020, to July 31, 2021. Patients with a diagnosis of HF, defined by ICD-10 codes in the year prior to study entry, and COVID-19 infection during the study period were age-, sex- and race-matched with HF patients without COVID-19 infection. We calculated 90-, 180- and 270-day hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause mortality and hospital admissions using Cox-regression models with adjustment for comorbidities. To assess for long-term sequelae of infection, only outcomes taking place beyond the first 30 days after diagnosis of COVID-19 infection were included in analyses. Results: Analyses included 85,818 (mean [SD]; 72.5 [10.3] years, 97.6% male, 71.7% White) HF patients. Compared with the subset of HF patients without COVID-19 infection (n=71,515), the subset of HF patients with COVID-19 infection (n=14,303) had significantly higher risk of 90-, 180-, and 270-day mortality, with exclusion of events taking place within the first 30 days of COVID-19 diagnosis (adjusted HR [95% CIs]: 2.15 [1.96-2.37], 1.63 [1.53-1.75], 1.48 [1.39-1.57], respectively). HF patients with COVID-19 infection also had significantly higher 90-, 180-, and 270-day hospital admission rates with exclusion of events taking place within the first 30 days of COVID-19 diagnosis (adjusted HR [95% CIs]: 1.73 [1.56-1.92], 1.51 [1.42-1.60], 1.44 [1.37-1.52], respectively). Conclusion: COVID-19 is associated with higher long-term all-cause mortality rate and hospital admission rates for HF patients persisting beyond the acute phase of infection.
152	CaV148		Sameer M. Jamal, David Landers, Zoltan G. Turi, Steven M. Hollenberg, Taya V. Glotzer, Jana Tancredi, and Joseph E. Parrillo	NEUROCARDIOGENIC SYNCOPE DURING HEAD-UP TILT TABLE (HUTT) TESTING IN PATIENTS WITH POST-ACUTE SEQUELA OF COVID-19 (PASC): A PROSPECTIVE EVALUATION		Published	2022 Mar	Study	https://www.jacc.org/doi/full/10.1016/S0735-1097%2822%2903106-0	Background: There is increasing recognition of “Long COVID” or Post-Acute Sequela of COVID-19 (PASC) occurring well after recovery from the initial acute illness. Symptoms may include palpitations, fatigue, and perceived heart rate increase upon standing or on minimal exertion. Somewhat less commonly, patients experience syncope. Autonomic dysfunction may explain these findings, and we have previously shown orthostatic intolerance (OI) on head-up tilt table (HUTT) in 22 of 24 prospectively studied subjects with PASC symptoms. Our objective was to investigate if autonomic dysfunction causes neurocardiogenic syncope on HUTT in PASC patients. Methods: This was an IRB approved, prospective, longitudinal, observational study. We included PASC patients complaining of tachycardia with standing or minimal activity, palpitations, and fatigue with exertion. Patients with an alternate medical explanation for these symptoms, pre-existing autonomic dysfunction, or history of syncope prior to PASC symptom development were excluded. Subjects underwent HUTT testing using a standard protocol. OI, postural orthostatic tachycardia syndrome (POTS), and neurocardiogenic syncope were classically defined. Results: HUTT was performed on 24 consecutive patients (4 males, mean age 43 years), reporting PASC symptoms for 6 + 4 months. Three demonstrated pure neurocardiogenic syncope. Four demonstrated POTS, with 1 progressing to neurocardiogenic syncope. Fifteen developed OI after sublingual nitroglycerin, and five of these subjects progressed to neurocardiogenic syncope. Neurocardiogenic syncope occurred in 9 of 24 (38%) PASC patients during HUTT testing. Conclusion: Neurocardiogenic syncope was demonstrated in 38% of PASC study patients. Our findings suggest autonomic dysfunction contributes to PASC symptom development. In patients with PASC, OI is commonly seen on HUTT.
153	CaV149		Rachana Raghupathy, Umar Khalid, Sathwika Thodeti, Brandon M. Mikolich, Tahir Kuraan, and J Ronald Mikolich	PREVALENCE OF RIGHT AND LEFT VENTRICULAR DYSFUNCTION AMONG PATIENTS WITH POST-COVID INFLAMMATORY HEART DISEASE		Published	2022 Mar	Study	https://www.jacc.org/doi/full/10.1016/S0735-1097%2822%2903057-1	Background: Recently published data suggests that inflammatory heart disease (IHD) is more prevalent in COVID-19 patients than initially expected. There have been reports of greater than expected right ventricular (RV) dysfunction during the post COVID-19 recovery period. This study was designed to assess and compare the prevalence of RV hypokinesis and LV hypokinesis in patients with post COVID-19 related IHD using CMR, which is the “gold” standard for ejection fraction assessment, given its full field of view and spatial resolution. Also, CMR is not limited by intercostal space size, obesity or breast artifact. Methods: An institutional cardiac imaging database was queried for all patients with post-COVID-19 IHD documented by CMR. IHD was defined as pericarditis and/or myocarditis using the recent Lake Louise criteria, including T1 and T2 relaxation mapping. Left ventricular global ejection fraction (LVEF) and right ventricular ejection fraction (RVEF) were computed using PRECESSION software (Heart IT) for each patient with post-COVID-19 IHD. The prevalence of RV dysfunction (EF<40%) and LV dysfunction (EF<55%) were computed and statistically analyzed using an unpaired t-test. Results: Query of the institutional cardiac imaging database identified 109 patients with post-COVID IHD using state of the art CMR pulse sequences. All had excellent CMR visualization of the RV. Of these 109 patients, 61 (56.0%) were females and 47 (44.0%) were male. Of the 109 post-COVID patients with IHD, 90 (82.6%) showed evidence of RV hypokinesis on CMR with RVEF<40%. Only 25 (22.9%) showed evidence of LV hypokinesis on CMR with LVEF<55. There was a statistically significant difference between the prevalence of RV hypokinesis and LV hypokinesis (p-value < 0.001) among patients with post-COVID IHD. Conclusion: These data demonstrate a significantly higher prevalence of RV dysfunction in post-COVID patients with IHD using CMR imaging with both T1 and T2 relaxation mapping to detect myocardial and pericardial edema/inflammation. If a patient with symptoms of post-COVID IHD has a 2-D echo which does not fully visualize the RV structures, this study suggests that CMR should be considered to assess the RVEF.
154	CaV150		Karina Janice Guadalupe Díaz-Resendiz,Alma Betsaida Benitez-Trinidad,Carlos Eduardo Covantes-Rosales,Gladys Alejandra Toledo-Ibarra,Pablo Cesar Ortiz-Lazareno,Daniel Alberto Girón-Pérez,Adela Yolanda Bueno-Durán,Daniela Alejandra Pérez-Díaz,Rocío Guadalupe Barcelos-García,Manuel Iván Girón-Pérez … See fewer authors	Loss of mitochondrial membrane potential (ΔΨm) in leucocytes as post-COVID-19 sequelae	https://doi.org/10.1002/JLB.3MA0322-279RRR	Published	31 March 2022	Study	https://jlb.onlinelibrary.wiley.com/doi/full/10.1002/JLB.3MA0322-279RRR	The mitochondrial membrane potential (ΔΨm) is a parameter often used to determine mitochondrial function; therefore, it can be used to determine the integrity and functionality of cells. A decrement of ΔΨm is implicated in several inflammatory-related pathologies, such phenomena can be related to COVID-19 infection. The present work aimed to compare the ΔΨm in leucocytes (human PBMCs; HPBMC) isolated from healthy control (HC) subjects, patients with COVID-19 (C-19), recovered subjects at 40 ± 13 (R1) and 335 ± 20 (R2) days after infection (dai). Obtained data showed that ΔΨm decreased in HPBMC of subjects with C-19, R1, and R2 compared with HC. When analyzing the ΔΨm data by sex, in females, a significant decrease was observed in R1 and R2 groups versus HC. Regarding men, a significant decrease of ΔΨm was observed in R1, with respect to HC, contrary to R2 group, who reestablished this parameter. Obtained results suggest that the loss of ΔΨm could be related to the long-COVID.
155	CaV151		Sandeep A. Saha MD, MS, FHRS, Andrea M. Russo MD, FHRS, Mina K. Chung MD, FHRS, Thomas F. Deering MD, FHRS, Dhanunjaya Lakkireddy MD, FHRS & Rakesh Gopinathannair MD, MA, FHRS	COVID-19 and Cardiac Arrhythmias: a Contemporary Review	https://doi.org/10.1007/s11936-022-00964-3	Published	19 April 2022	Review	https://link.springer.com/article/10.1007/s11936-022-00964-3	Purpose of Review A significant proportion of patients infected by the severe acute respiratory syndrome-coronavirus (SARS-CoV2) (COVID-19) also have disorders affecting the cardiac rhythm. In this review, we provide an in-depth review of the pathophysiological mechanisms underlying the associated arrhythmic complications of COVID-19 infection and provide pragmatic, evidence-based recommendations for the clinical management of these conditions. Recent Findings Arrhythmic manifestations of COVID-19 include atrial arrhythmias such as atrial fibrillation or atrial flutter, sinus node dysfunction, atrioventricular conduction abnormalities, ventricular tachyarrhythmias, sudden cardiac arrest, and cardiovascular dysautonomias including the so-called long COVID syndrome. Various pathophysiological mechanisms have been implicated, such as direct viral invasion, hypoxemia, local and systemic inflammation, changes in ion channel physiology, immune activation, and autonomic dysregulation. The development of atrial or ventricular arrhythmias in hospitalized COVID-19 patients has been shown to portend a higher risk of in-hospital death. Summary Arrhythmic complications from acute COVID-19 infection are commonly encountered in clinical practice, and COVID-19 patients with cardiac complications tend to have worse clinical outcomes than those without. Management of these arrhythmias should be based on published evidence-based guidelines, with special consideration of the acuity of COVID-19 infection, concomitant use of antimicrobial and anti-inflammatory drugs, and the transient nature of some rhythm disorders. Some manifestations, such as the long COVID syndrome, may lead to residual symptoms several months after acute infection. As the pandemic evolves with the discovery of new SARS-CoV2 variants, development and use of newer anti-viral and immuno-modulator drugs, and the increasing adoption of vaccination, clinicians must remain vigilant for other arrhythmic manifestations that may occur in association with this novel but potentially deadly disease.
156	CaV152		Fabian Heinrich 1,,† ,Kevin Roedl 2,† ,Dominik Jarczak 2 ,Hanna-Lisa Goebels 1,Axel Heinemann 1,Ulrich Schäfer 3,Frank Ludwig 4,Martin Bachmann 5,Berthold Bein 6,Christian Friedrich Weber 7,Karsten Sydow 8,Marc Bota 9 ,Hans-Richard Paschen 10,Andreas de Weerth 11,Carsten Veit 12,Oliver Detsch 13,Philipp-Alexander Brand 14,Stefan Kluge 2,Benjamin Ondruschka 1,‡ andDominic Wichmann 2,,‡	New Insights in the Occurrence of Venous Thromboembolism in Critically Ill Patients with COVID-19—A Large Postmortem and Clinical Analysis	https://doi.org/10.3390/v14040811	Published	14 April 2022	Study	https://www.mdpi.com/1999-4915/14/4/811/htm	Critically ill COVID-19 patients are at high risk for venous thromboembolism (VTE), namely deep vein thrombosis (DVT) and/or pulmonary embolism (PE), and death. The optimal anticoagulation strategy in critically ill patients with COVID-19 remains unknown. This study investigated the ante mortem incidence as well as postmortem prevalence of VTE, the factors predictive of VTE, and the impact of changed anticoagulation practice on patient survival. We conducted a consecutive retrospective analysis of postmortem COVID-19 (n = 64) and non-COVID-19 (n = 67) patients, as well as ante mortem COVID-19 (n = 170) patients admitted to the University Medical Center Hamburg-Eppendorf (Hamburg, Germany). Baseline patient characteristics, parameters related to the intensive care unit (ICU) stay, and the clinical and autoptic presence of VTE were evaluated and statistically compared between groups. The occurrence of VTE in critically ill COVID-19 patients is confirmed in both ante mortem (17%) and postmortem (38%) cohorts. Accordingly, comparing the postmortem prevalence of VTE between age- and sex-matched COVID-19 (43%) and non-COVID-19 (0%) cohorts, we found the statistically significant increased prevalence of VTE in critically ill COVID-19 cohorts (p = 0.001). A change in anticoagulation practice was associated with the statistically significant prolongation of survival time (HR: 2.55, [95% CI 1.41–4.61], p = 0.01) and a reduction in VTE occurrence (54% vs. 25%; p = 0.02). In summary, in the autopsy as well as clinical cohort of critically ill patients with COVID-19, we found that VTE was a frequent finding. A change in anticoagulation practice was associated with a statistically significantly prolonged survival time.
157	CaV153		Manuela De Michele, Joshua Kahan , Irene Berto, Oscar G. Schiavo , Marta Iacobucci , Danilo Toni ,* Alexander E. Merkler	Cerebrovascular Complications of COVID-19 and COVID-19 Vaccination	https://doi.org/10.1161/CIRCRESAHA.122.319954	Published	April 23, 2022	Review	https://www.ahajournals.org/doi/pdf/10.1161/CIRCRESAHA.122.319954	The risk of stroke and cerebrovascular disease complicating infection with SARS-CoV-2 has been extensively reported since the onset of the pandemic. The striking efforts of many scientists in cooperation with regulators and governments worldwide have rapidly brought the development of a large landscape of vaccines against SARS-CoV-2. The novel DNA and mRNA vaccines have offered great flexibility in terms of antigen production and led to an unprecedented rapidity in effective and safe vaccine production. However, as mass vaccination has progressed, rare but catastrophic cases of thrombosis have occurred in association with thrombocytopenia and antibodies against PF4 (platelet factor 4). This catastrophic syndrome has been named vaccine-induced immune thrombotic thrombocytopenia. Rarely, ischemic stroke can be the symptom onset of vaccine-induced immune thrombotic thrombocytopenia or can complicate the course of the disease. In this review, we provide an overview of stroke and cerebrovascular disease as a complication of the SARS-CoV-2 infection and outline the main clinical and radiological characteristics of cerebrovascular complications of vaccinations, with a focus on vaccine-induced immune thrombotic thrombocytopenia. Based on the available data from the literature and from our experience, we propose a therapeutic protocol to manage this challenging condition. Finally, we highlight the overlapping pathophysiologic mechanisms of SARS-CoV-2 infection and vaccination leading to thrombosis.
158	CaV154		Rachel E. Szeghy, Nina L. Stute, Valesha M. Province, Marc A. Augenreich, Jonathon L. 4 Stickford, Abigail S.L. Stickford, Stephen M. Ratchford	Six-Month Longitudinal Tracking of Arterial Stiffness and Blood Pressure 2 in Young Adults Following SARS-CoV-2 Infection Short Title: Improvement From SARS-CoV-2: Arterial Stiffness	-	Published	April 23, 2022	Study	https://journals.physiology.org/doi/pdf/10.1152/japplphysiol.00793.2021	Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can increase arterial stiffness 3-4 weeks following infection, even among young, healthy adults. However, the long-term impacts of SARS-CoV-2 infection on cardiovascular health and the duration of recovery remains unknown. Purpose: The purpose of this study was to elucidate potential long lasting effects of SARS-CoV-2 infection on markers of arterial stiffness among young adults during the six months following infection. Methods: Assessments were performed at months 1, 2, 3, 4, and ~6 following SARS-CoV-2 infection. Doppler ultrasound was utilized to measure carotid-femoral pulse wave velocity (cfPWV) and carotid stiffness, and arterial tonometry was used to measure central blood pressures and aortic augmentation index at a heart rate of 75 beats∙min-1 (AIx@HR75). Vascular (VCAM-1) and intracellular (ICAM-1) adhesion molecules were analyzed as circulating markers of arterial stiffness. Results: From months 1-6, a significant reduction in cfPWV was observed (month1: 5.70±0.73m·s-1; month6: 4.88±0.65m·s-1 31 ; p<0.05) without any change in carotid stiffness measures. Reductions in systolic blood pressure (month1: 123±8mmHg; month6: 112±11mmHg) and mean arterial pressure (month1: 97±6mmHg; month6: 86±7mmHg) were observed (p<0.05), although AIx@HR75 did not change over time. The month1-6 change in cfPWV and MAP were correlated (r=0.894; p<0.001). A reduction in VCAM-1 was observed at month 3 compared with month 1 (month1: 5575±2242pg·ml-1; month3: 4636±1621pg·ml-1 37 ; p<0.05) without a change in ICAM-1. Conclusion: A reduction in cfPWV was related with MAP, and some indicators of arterial stiffness remain elevated for several months following SARS-CoV-2 infection, possibly contributing to prolonged recovery and increased cardiovascular health risks.
159	CaV155		Paul J. Hanson, Felicia Liu-Fei, Coco Ng, Taylor A. Minato, Chi Lai, Al Rohet Hossain, Rebecca Chan, Bobby Grewal, Harpreet Rai, Jeremy Hirota, Daniel R. Anderson, Stanley J. Radio & Bruce M. McManus	Characterization of COVID-19-associated cardiac injury: evidence for a multifactorial disease in an autopsy cohort	https://doi.org/10.1038/s41374-022-00783-x	Published	18 April 2022	Study	https://www.nature.com/articles/s41374-022-00783-x	As the coronavirus disease 2019 (COVID-19) pandemic evolves, much evidence implicates the heart as a critical target of injury in patients. The mechanism(s) of cardiac involvement has not been fully elucidated, although evidence of direct virus-mediated injury, thromboembolism with ischemic complications, and cytokine storm has been reported. We examined suggested mechanisms of COVID-19-associated heart failure in 21 COVID-19-positive decedents, obtained through standard autopsy procedure, compared to clinically matched controls and patients with various etiologies of viral myocarditis. We developed a custom tissue microarray using regions of pathological interest and interrogated tissues via immunohistochemistry and in situ hybridization. Severe acute respiratory syndrome coronavirus 2 was detected in 16/21 patients, in cardiomyocytes, the endothelium, interstitial spaces, and percolating adipocytes within the myocardium. Virus detection typically corresponded with troponin depletion and increased cleaved caspase-3. Indirect mechanisms of injury—venous and arterial thromboses with associated vasculitis including a mixed inflammatory infiltrate—were also observed. Neutrophil extracellular traps (NETs) were present in the myocardium of all COVID-19 patients, regardless of injury degree. Borderline myocarditis (inflammation without associated myocyte injury) was observed in 19/21 patients, characterized by a predominantly mononuclear inflammatory infiltrate. Edema, inflammation of percolating adipocytes, lymphocytic aggregates, and large septal masses of inflammatory cells and platelets were observed as defining features, and myofibrillar damage was evident in all patients. Collectively, COVID-19-associated cardiac injury was multifactorial, with elevated levels of NETs and von Willebrand factor as defining features of direct and indirect viral injury.
160	CaV156		R.SiglerB.ChenA.BhartiS.Aslam	Long COVID-19 in Heart Transplant Recipients	https://doi.org/10.1016/j.healun.2022.01.682	Published	7 April 2022	Study	https://www.sciencedirect.com/science/article/pii/S1053249822007008	Purpose The goal of this study was to assess the frequency and common symptoms of post-acute COVID-19 syndrome (Long COVID-19) in heart transplant recipients (HTR). Methods After obtaining IRB approval, we conducted telephone surveys of HTR (n=30) who had tested positive for SARS-CoV-2 to evaluate their experience with acute COVID-19 illness and assess symptoms of Long COVID-19. Symptoms at onset and also beyond 6, 12, and 24 weeks of the initial diagnosis were recorded. Additionally, medical charts were reviewed for detailed information regarding transplant history, immunosuppression, COVID-19 management and hospitalization, and COVID-19 vaccination status. Results As noted in Table 1, among the 30 participants, 10 (33%) had symptoms consistent with Long COVID-19. Those with Long COVID-19 were more symptomatic during acute illness, with 40% of patients reporting cough, fevers or chills, and headaches, compared with 15%, 25%, and 20% respectively in those without Long COVID-19. Emergency department visits at initial illness (80% vs. 20%) and admission to the intensive care unit were more frequent (60% vs. 5%) in the Long COVID-19. Symptoms of Long COVID-19 lasted for a median of 9 weeks with 30% reporting ongoing symptoms at week 24. The most common persistent symptoms were depression, confusion, and difficulty concentrating. Conclusion This study is an early investigation of a complex syndrome of Long COVID-19 in transplant patients. Long COVID-19 is not well described in the transplant setting. HTR at our center with Long COVID-19 were sicker at their initial COVID-19 diagnosis and had more emergency room visits, hospital admissions, and longer hospital stays than those without subsequent Long COVID-19. Although, recall bias could affect participants’ ability to remember details and symptoms, this would have impacted both groups similarly as the time since COVID-19 diagnosis to study enrollment was similar between the two groups. These are preliminary findings and the study is currently ongoing.
161	CaV157		Ioannis Katsoularis, cardiologist, internist, and doctoral student1, Osvaldo Fonseca-Rodríguez, senior research assistant of epidemiology and statistics2, Paddy Farrington, professor emeritus of statistics3, Hanna Jerndal, doctoral student and medical intern2, Erling Häggström Lundevaller, associate professor of statistics4, Malin Sund, professor of general surgery5 6, Krister Lindmark, associate professor of cardiology1, Anne-Marie Fors Connolly	Risks of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19: nationwide self-controlled cases series and matched cohort study	https://doi.org/10.1136/bmj-2021-069590	Published	06 April 2022	Study	https://www.bmj.com/content/377/bmj-2021-069590	Abstract Objective - To quantify the risk of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19. Design Self-controlled case series and matched cohort study. Setting National registries in Sweden. Participants - 1 057 174 people who tested positive for SARS-CoV-2 between 1 February 2020 and 25 May 2021 in Sweden, matched on age, sex, and county of residence to 4 076 342 control participants. Main outcomes measures - Self-controlled case series and conditional Poisson regression were used to determine the incidence rate ratio and risk ratio with corresponding 95% confidence intervals for a first deep vein thrombosis, pulmonary embolism, or bleeding event. In the self-controlled case series, the incidence rate ratios for first time outcomes after covid-19 were determined using set time intervals and the spline model. The risk ratios for first time and all events were determined during days 1-30 after covid-19 or index date using the matched cohort study, and adjusting for potential confounders (comorbidities, cancer, surgery, long term anticoagulation treatment, previous venous thromboembolism, or previous bleeding event). Results - Compared with the control period, incidence rate ratios were significantly increased 70 days after covid-19 for deep vein thrombosis, 110 days for pulmonary embolism, and 60 days for bleeding. In particular, incidence rate ratios for a first pulmonary embolism were 36.17 (95% confidence interval 31.55 to 41.47) during the first week after covid-19 and 46.40 (40.61 to 53.02) during the second week. Incidence rate ratios during days 1-30 after covid-19 were 5.90 (5.12 to 6.80) for deep vein thrombosis, 31.59 (27.99 to 35.63) for pulmonary embolism, and 2.48 (2.30 to 2.68) for bleeding. Similarly, the risk ratios during days 1-30 after covid-19 were 4.98 (4.96 to 5.01) for deep vein thrombosis, 33.05 (32.8 to 33.3) for pulmonary embolism, and 1.88 (1.71 to 2.07) for bleeding, after adjusting for the effect of potential confounders. The rate ratios were highest in patients with critical covid-19 and highest during the first pandemic wave in Sweden compared with the second and third waves. In the same period, the absolute risk among patients with covid-19 was 0.039% (401 events) for deep vein thrombosis, 0.17% (1761 events) for pulmonary embolism, and 0.101% (1002 events) for bleeding. Conclusions - The findings of this study suggest that covid-19 is a risk factor for deep vein thrombosis, pulmonary embolism, and bleeding. These results could impact recommendations on diagnostic and prophylactic strategies against venous thromboembolism after covid-19.
162	CaV158		Samit M. Shah,Natalija Odanovic,Steffne Kunnirickal,Attila Feher,Steven E. Pfau,Erica S. Spatz	Chest pain and coronary endothelial dysfunction after recovery from COVID-19: A case series	https://doi.org/10.1002/ccr3.5612	Published	08 April 2022	Case Series	https://onlinelibrary.wiley.com/doi/full/10.1002/ccr3.5612	Endothelial cell damage related to coronavirus disease 2019 (COVID-19) has been described in multiple vascular beds, and many survivors of COVID-19 report chest pain. This case series describes two previously healthy middle-aged individuals who survived COVID-19 and were subsequently found to have symptomatic coronary endothelial dysfunction months after initial infection.
163	CaV159		Harneet Bhatti, Andres Cordova Sanchez, Rajat Dhungana, Christos Carvounis, Avneet Singh	Left Ventricular Global Longitudinal Strain in Patients With COVID-19 Infection	https://doi.org/10.7759/cureus.23986	Published	April 09, 2022	Study	https://www.cureus.com/articles/86618-left-ventricular-global-longitudinal-strain-in-patients-with-covid-19-infection	Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2, is an ongoing pandemic that has affected millions globally. Many infected patients have been noted to have cardiovascular damage. Prior to the development of clinical symptoms, the use of transthoracic echocardiography, specifically with measurements of left ventricular global longitudinal strain (LVGLS), may provide an additional prognostic marker for patients infected with COVID-19. We sought to determine whether patients with COVID-19 and reduced LVGLS have an increased risk for mortality. The mean LVGLS was determined to be significantly lower in the non-survivors compared to the survivors (−11.6 ± 1.8 vs −15.4 ± 0.74, p<0.05). It should be noted, however, that even those that survived were found to have reduced LVGLS (<−18.5%). A multivariate logistic regression analysis was also performed that demonstrated a relationship between reduced LVGLS and an increased risk for mortality. Overall, our data indicate that COVID-19 patients may have subclinical left ventricular dysfunction, and that critically ill patients may have a greater decline in cardiac dysfunction.
164	CaV160		Bingwen Eugene Fan,Shiun Woei Wong,Christina Lai Lin Sum,Gek Hsiang Lim,Bernard PuiLam Leung,Chuen Wen Tan,Kollengode Ramanathan,Rinkoo Dalan,Christine Cheung,Xin Rong Lim,Mucheli Shravan Sadasiv,David Chien Lye,Barnaby Edward Young,Eng Soo Yap,Yew Woon Chia	Hypercoagulability, endotheliopathy, and inflammation approximating 1 year after recovery: Assessing the long-term outcomes in COVID-19 patients	https://doi.org/10.1002/ajh.26575	Published	28 April 2022	Study	https://onlinelibrary.wiley.com/doi/10.1002/ajh.26575	Sustained hypercoagulability and endotheliopathy are present in convalescent COVID-19 patients for up to 4 months from recovery. The hemostatic, endothelial, and inflammatory profiles of 39 recovered COVID-19 patients were evaluated up to 16 months after recovery from COVID-19. These values were compared with a control group of healthy volunteers (n = 124). 39 patients (71.8% males, median age 43 years) were reviewed at a mean of 12.7 ± 3.6 months following recovery. One patient without cardiovascular risk factors had post COVID-19 acute ischaemic limb. Elevated D-dimer and Factor VIII levels above normal ranges were noted in 17.9% (7/39) and 48.7% (19/39) of patients respectively, with a higher median D-dimer 0.34 FEU μg/mL (IQR 0.28, 0.46) (p < .001) and Factor VIII 150% (IQR 171, 203) (p = .004), versus controls. Thrombin generation (Thromboscreen) showed a higher median endogenous thrombin potential (ETP) of 1352 nM*min (IQR 1152, 1490) (p = .002) and a higher median peak height of 221.4 nM (IQR 170.2, 280.4) (p = 0.01) and delayed lag time 2.4 min (1.42–2.97) (p = 0.0002) versus controls. Raised vWF:Ag and ICAM-1 levels were observed in 17.9% (7/39) and 7.7% (3/39) of patients respectively, with a higher median VWF:Ag 117% (IQR 86, 154) (p = 0.02) and ICAM-1 54.1 ng/mL (IQR 43.8, 64.1) (p = .004) than controls. IL-6 was noted to be raised in 35.9% (14/39) of patients, with a higher median IL-6 of 1.5 pg/mL (IQR 0.6, 3.0) (p = 0.004) versus controls. Subgroup analysis stratifying patients by COVID-19 severity and COVID-19 vaccination preceding SARS-CoV-2 infection did not show statistically significant differences. Hypercoagulability, endothelial dysfunction, and inflammation are still detectable in some patients approximately 1 year after recovery from COVID-19.
165	CaV161		Charalambos Vlachopoulos MD, Dimitrios Terentes-Printzios MD, Paraskevi Katsaounou MD, Eirini Solomou MD, Vasiliki Gardikioti MD, Dimitrios Exarchos MD, Dimitrios Economou MD, Georgia Christopoulou MD, Antonios-Dimosthenis Kalkinis MD, Pavlos Kafouris MD, Alexios Antonopoulos MD, Georgios Lazaros MD, Anastasia Kotanidou MD, Ioannis Datseris MD, Konstantinos Tsioufis MD & Constantinos Anagnostopoulos	Time-related aortic inflammatory response, as assessed with 18F-FDG PET/CT, in patients hospitalized with severely or critical COVID-19: the COVAIR study	https://doi.org/10.1007/s12350-022-02962-1	Published	02 May 2022	Study	https://link.springer.com/article/10.1007/s12350-022-02962-1	Aim Arterial involvement has been implicated in the coronavirus disease of 2019 (COVID-19). Fluorine 18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging is a valuable tool for the assessment of aortic inflammation and is a predictor of outcome. We sought to prospectively assess the presence of aortic inflammation and its time-dependent trend in patients with COVID-19. Methods Between November 2020 and May 2021, in this pilot, case-control study, we recruited 20 patients with severe or critical COVID-19 (mean age of 59 ± 12 years), while 10 age and sex-matched individuals served as the control group. Aortic inflammation was assessed by measuring 18F-FDG uptake in PET/CT performed 20-120 days post-admission. Global aortic target to background ratio (GLA-TBR) was calculated as the sum of TBRs of ascending and descending aorta, aortic arch, and abdominal aorta divided by 4. Index aortic segment TBR (IAS-TBR) was designated as the aortic segment with the highest TBR. Results There was no significant difference in aortic 18F-FDG PET/CT uptake between patients and controls (GLA-TBR: 1.46 [1.40-1.57] vs. 1.43 [1.32-1.70], respectively, P = 0.422 and IAS-TBR: 1.60 [1.50-1.67] vs. 1.50 [1.42-1.61], respectively, P = 0.155). There was a moderate correlation between aortic TBR values (both GLA and IAS) and time distance from admission to 18F-FDG PET-CT scan (Spearman’s rho = − 0.528, P = 0.017 and Spearman’s rho = − 0.480, p = 0.032, respectively). Patients who were scanned less than or equal to 60 days from admission (n = 11) had significantly higher GLA-TBR values compared to patients that were examined more than 60 days post-admission (GLA-TBR: 1.53 [1.42-1.60] vs. 1.40 [1.33-1.45], respectively, P = 0.016 and IAS-TBR: 1.64 [1.51-1.74] vs. 1.52 [1.46-1.60], respectively, P = 0.038). There was a significant difference in IAS- TBR between patients scanned ≤ 60 days and controls (1.64 [1.51-1.74] vs. 1.50 [1.41-1.61], P = 0.036). Conclusion This is the first study suggesting that aortic inflammation, as assessed by 18F-FDG PET/CT imaging, is increased in the early post COVID phase in patients with severe or critical COVID-19 and largely resolves over time. Our findings may have important implications for the understanding of the course of the disease and for improving our preventive and therapeutic strategies.
166	CaV162		Diana L. Tobler, Alix J. Pruzansky, Sahar Naderi, Andrew P. Ambrosy & Justin J. Slade	Long-Term Cardiovascular Effects of COVID-19: Emerging Data Relevant to the Cardiovascular Clinician	https://doi.org/10.1007/s11883-022-01032-8	Published	04 May 2022	Review	https://link.springer.com/article/10.1007/s11883-022-01032-8	Purpose of Review COVID-19 is now a global pandemic and the illness affects multiple organ systems, including the cardiovascular system. Long-term cardiovascular consequences of COVID-19 are not yet fully characterized. This review seeks to consolidate available data on long-term cardiovascular complications of COVID-19 infection. Recent Findings Acute cardiovascular complications of COVID-19 infection include myocarditis, pericarditis, acute coronary syndrome, heart failure, pulmonary hypertension, right ventricular dysfunction, and arrhythmia. Long-term follow-up shows increased incidence of arrhythmia, heart failure, acute coronary syndrome, right ventricular dysfunction, myocardial fibrosis, hypertension, and diabetes mellitus. There is increased mortality in COVID-19 patients after hospital discharge, and initial myocardial injury is associated with increased mortality. Summary Emerging data demonstrates increased incidence of cardiovascular illness and structural changes in recovered COVID-19 patients. Future research will be important in understanding the clinical significance of these structural abnormalities, and to determine the effect of vaccines on preventing long-term cardiovascular complications.
167	CaV163		Zainab AlDuhailibabSimonOczkowskicdKamilPolokeJakubFronczekeWojciechSzczeklikeJoshuaPiticarucManoj J.MammenfFayezAlshamsigJohnEikelboomhiEmilie P.Belley-CotehiWaleedAlhazzanicd	Venous and Arterial Thrombosis in COVID-19: An updated Narrative Review	https://doi.org/10.1016/j.jiph.2022.05.003	Published	14 May 2022	Review	https://www.sciencedirect.com/science/article/pii/S187603412200123X	Hospitalized patients with coronavirus disease 2019 (COVID-19), particularly those admitted to the intensive care unit (ICU) are at high risk of morbidity and mortality. Several observational studies have described hemostatic derangements and thrombotic complications in patients with COVID-19. The aim of this review article is to summarize the current evidence on pathologic findings, pathophysiology, coagulation and hemostatic abnormalities, D-dimer’s role in prognostication epidemiology and risk factors of thrombotic complications, and the role of prophylactic and therapeutic anticoagulation in patients with COVID-19. While existing evidence is limited in quality, COVID-19 appears to increase micro-and macro-vascular thrombosis rates in hospitalized and critically ill patients, which may contribute to the burden of disease. D-dimer can be used for risk stratification of hospitalized patients, but its role to guide anticoagulation therapy remains unclear. Evidence of higher quality is needed to address the role of therapeutic anticoagulation or high-intensity venous thromboembolism prophylaxis in COVID-19 patients. Take-home points •The prevalence of venous thromboembolism (VTE) in hospitalized COVID-19 patients is high, therefore, clinicians should have a high index of suspicion. •The pathophysiology of thrombosis is likely related to a combination of SARS-CoV-2 direct endothelial injury and dysregulated inflammation causing coagulation activation. •The current evidence on the value of D-dimer guided therapy is limited. •The rate of VTE post-hospital discharge is very low, supporting the safety of current discharge practice without VTE prophylaxis in most patients. •The role of higher-intensity VTE prophylaxis or therapeutic anticoagulation in critically ill COVID-19 patients without documented or suspected VTE remains uncertain. •Therapeutic anticoagulation in hospitalized non-critically ill patients with COVID-19 may improve outcomes but more research is warranted.
168	CaV164		Pretorius E, Venter C, Laubscher GJ, Kotze MJ, Oladejo S, Watson LR, Rajaratnam K, Watson BW, Kell DB	Prevalence of symptoms, comorbidities, fibrin amyloid microclots and platelet pathology in individuals with Long COVID/ Post-Acute Sequelae of COVID-19 (PASC)	https://doi.org/10.21203/rs.3.rs-1205453/v2	pre-print	09 May 2022	Study	https://europepmc.org/article/ppr/ppr490705	Background: Fibrin(ogen) amyloid microclots and platelet hyperactivation previously reported as a novel finding in South African patients with the coronavirus 2019 disease (COVID-19) and Long COVID/Post-Acute Sequelae of COVID-19 (PASC), might form a suitable set of foci for the clinical treatment of the symptoms of long COVID/PASC. A Long COVID/PASC Registry was subsequently established as an online platform where patients can report Long COVID/PASC symptoms and previous comorbidities. Methods: : In this study, we report on the comorbidities and persistent symptoms, using data obtained from 845 South African Long COVID/PASC patients. By using a previously published scoring system for fibrin amyloid microclots and platelet pathology, we also analysed blood samples from 80 patients, and report the presence of significant fibrin amyloid microclots and platelet pathology in all cases. Results: : Hypertension, high cholesterol levels (dyslipidaemia), cardiovascular disease and type 2 diabetes mellitus (T2DM) were found to be the most important comorbidities. The gender balance (70% female) and the most commonly reported Long COVID/PASC symptoms (fatigue, brain fog, loss of concentration and forgetfulness, shortness of breath, as well as joint and muscle pains) were comparable to those reported elsewhere. These findings confirmed that our sample was not atypical. Microclot and platelet pathologies were associated with Long COVID/PASC symptoms that persisted after the recovery from acute COVID-19. Conclusions: : Fibrin amyloid microclots that block capillaries and inhibit the transport of O 2 to tissues, accompanied by platelet hyperactivation, provide a ready explanation for the symptoms of Long COVID/PASC. Removal and reversal of these underlying endotheliopathies provide an important treatment option that urgently warrants controlled clinical studies to determine efficacy in patients with a diversity of comorbidities impacting on SARS-CoV-2 infection and COVID-19 severity. We suggest that our platelet and clotting grading system provides a simple and cost-effective diagnostic method for early detection of long COVID/PASC as a major determinant of effective treatment regimens, including those focusing on reducing clot burden and platelet hyperactivation.
169	CaV165		Sofia Romagnoli,Agnese SbrolliniORCID,Ilaria Marcantoni,Micaela MorettiniORCID andLaura Burattini *ORCID	Review on Cardiorespiratory Complications after SARS-CoV-2 Infection in Young Adult Healthy Athletes	https://doi.org/10.3390/ijerph19095680	Published	6 May 2022	Review	https://www.mdpi.com/1660-4601/19/9/5680/htm	This review analyzes scientific data published in the first two years of the COVID-19 pandemic with the aim to report the cardiorespiratory complications observed after SARS-CoV-2 infection in young adult healthy athletes. Fifteen studies were selected using PRISMA guidelines. A total of 4725 athletes (3438 males and 1287 females) practicing 19 sports categories were included in the study. Information about symptoms was released by 4379 (93%) athletes; of them, 1433 (33%) declared to be asymptomatic, whereas the remaining 2946 (67%) reported the occurrence of symptoms with mild (1315; 45%), moderate (821; 28%), severe (1; 0%) and unknown (809; 27%) severity. The most common symptoms were anosmia (33%), ageusia (32%) and headache (30%). Cardiac magnetic resonance identified the largest number of cardiorespiratory abnormalities (15.7%). Among the confirmed inflammations, myocarditis was the most common (0.5%). In conclusion, the low degree of symptom severity and the low rate of cardiac abnormalities suggest that the risk of significant cardiorespiratory involvement after SARS-CoV-2 infection in young adult athletes is likely low; however, the long-term physiologic effects of SARS-CoV-2 infection are not established yet. Extensive cardiorespiratory screening seems excessive in most cases, and classical pre-participation cardiovascular screening may be sufficient.
170	CaV166		Laura P.M.H. de Rooij, Lisa M. Becker and Peter Carmeliet	A Role for the Vascular Endothelium in Post–Acute COVID-19?	https://doi.org/10.1161/CIRCULATIONAHA.122.059231	Published	16 May 2022	Article	https://www.ahajournals.org/doi/abs/10.1161/CIRCULATIONAHA.122.059231	While the war against acute coronavirus disease 2019 (COVID-19) is still raging, reports of a long-lasting post-COVID-19 syndrome are surging. "Long COVID" progressed from a mere oddity to an acknowledged public health issue worldwide. A formal definition of post-acute COVID-19 syndrome (ie, long COVID) is evolving, and for the purposes of this review, we consider as persistent symptoms or complications lasting more than 30 days after severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) infection. Symptoms of long COVID involve multiple organs and include shortness of breath, wae storiess breath fatigue, chest pain, loss of taste and/or smell, and nitive dysfunction. Studies investigating the incidence of long COVID report broad heterogeneity (likely attrib and cog utable to variations in study cohorts and long COVID definition/symptoms), and its manifestation may from 30% to a staggering 280% of all SARS-CoV-2 infected patients. Although there is reduce the risk of developing long COVID, nation may reduce the risk of here is hope that vacci studies remain inconclusive thus far. Breakthrough infections frequently occur in vaccinated people and may unfortunately still cause an escalation in long COVID cases. Detection and treatment of long COVID is challenging because the molecular underpinnings of the condition remain largely unknown.
171	CaV167		Jorge H. Ulloa 1 Oscar Y. Moreno Rocha 1 Paula Pinto 1 Maria C. Consuegra Sebastian Cifuentes 2 Andrés Figueroa 1 Antonio Solano 1 Javier Bravo 1 Jairo Ramirez	Post–COVID-19 Arterial Thrombosis: A Systematic Review	https://doi.org/10.1016/j.jvs.2022.03.158	Published	19 May 2022	Review	https://www.jvascsurg.org/article/S0741-5214(22)00652-8/fulltext	Objectives COVID-19 (coronavirus disease 2019) is associated with coagulation defects, including endothelial dysfunction, inflammation, hypoxia, cytokine release, and hypercoagulability. We aimed to summarize the available cases of arterial peripheral thrombosis in the setting of post–COVID-19 infection and the use of biomarkers and related pharmacologic therapies to describe the better medical and surgical treatments based on the reported outcomes. Methods We executed a systematic review following the 2020 PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. We searched PubMed, Embase, Scopus, and the Cochrane Library for studies reported from March 2020 to September 2021 with serologic confirmation of a resolved SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection. Related questions regarding high-yield end points included the location of the thrombosis, amputation, reintervention rates, mortality, anticoagulant therapy, and biomarkers. Results Of the 398 matching results, 23 reports met the inclusion criteria of post–COVID-19 thrombosis, arterial, venous, peripheral, and cured. The literature review included 12 case reports, 3 incidence reports, 3 literature reviews, 2 meta-analyses, 1 observational cohort study, and 2 prospective analyses. The overall presentation consisted of peripheral arterial thrombosis (33.3%), venous thrombosis (63.2%), and mixed events (3.5%). Most of the studies had used low-molecular-weight heparin monotherapy as a part of the medical management. There was no difference in the use of clopidogrel and aspirin as antiplatelet agents. Other pharmacologic alternatives were nonfractionated heparin, enoxaparin, warfarin, rivaroxaban, and apixaban. Open thrombectomy was the most common procedure used for COVID-19 thrombosis complications (40%), with mortality of 27.2%, followed by endovascular thrombectomy (15%), amputation (12.5%), exploratory laparotomy (5%), and endarterectomy (2.5%). We found 38 reported biomarkers, which were classified into seven categories related to an inflammatory process, coagulation time, clotting factors, cardiorespiratory function, kidney function, metabolic profile, and autoimmunity. An initial D-dimer level >1.250 ng/mL might identify COVID-19 patients at risk of arterial thrombotic events. Additional end points were associated with increased creatinine, interleukin-6, interferon gamma-induced protein-10, D-dimer, and C-reactive protein levels. Conclusions COVID-19 infection is associated with a high risk of arterial and venous post-thrombotic complications, with a variable clinical and anatomic presentation, high mortality, and high amputation risk. Microcirculatory alterations can be reflected by a panel of biomarkers. The medical and surgical management of these patients could depend on the availability of resources regarding the context of medical attention. Nevertheless, considering the highly inflammatory context, endovascular interventions with less systemic stress should be considered in addition to thromboprophylaxis measures.
172	CaV168		Justin J. Frere & Benjamin R. tenOever	Cardiometabolic syndrome — an emergent feature of Long COVID?	https://doi.org/10.1038/s41577-022-00739-8	Published	24 May 2022	Comment	https://www.nature.com/articles/s41577-022-00739-8	Large-scale clinical studies on the post-infectious impacts of SARS-CoV-2 have suggested that patients who have recovered from acute infection have increased risk for cardiometabolic syndrome-associated morbidities such as diabetes, chronic kidney disease and heart failure. Initial studies have taken the first steps towards unravelling the molecular processes that may be driving these findings, including the role of immune and inflammatory factors, but a comprehensive aetiology remains unclear. Given that cardiometabolic syndrome progression in patients with Long COVID may pose a significant global health and economic burden post pandemic, there is an emergent need to identify therapeutic targets and treatment options.
173	CaV169		Pascal Bauer, Lutz Kraushaar, Oliver Dörr, Stanislav Keranov, Holger Nef, Christian W. Hamm & Astrid Most	Vascular alterations among male elite athletes recovering from SARS-CoV-2 infection	https://doi.org/10.1038/s41598-022-12734-z	Published	23 May 2022	Study	https://www.nature.com/articles/s41598-022-12734-z	SARS-CoV-2 may affect the cardiovascular system and vascular impairment has been reported in healthy young adults recovering from COVID-19. However, the impact of SARS-CoV-2 infection on the vascular function of elite athletes is unknown. We examined 30 healthy male elite athletes (age 25.8 ± 4.6 years) pre-season and at a 6-month follow-up (182 ± 10 days). Vascular function and central blood pressure were calculated using transfer function-based analysis of peripheral arterial waveforms obtained by oscillometry. We performed a two-way repeated-measures ANOVA on the biomarker data, with SARS-CoV-2 status as the between-groups factor and time as the within-groups factor. Subjects who tested positive for SARS-CoV-2 were studied 18 ± 4 days after their positive testing date at follow-up. Of 30 athletes, 15 tested positive for SARS-CoV-2 after the first examination and prior to the follow-up. None had severe COVID-19 or reported any persisting symptoms. The results of the two-way repeated measures ANOVA revealed that there was no significant main effect of COVID-19 on any of the investigated biomarkers. However, there was a significant interaction between the effects of SARS-CoV-2 exposure and time on augmentation index (Aix) (p = 0.006) and augmentation index normalized to a heart rate of 75 beats per minute (Aix@75), (p = 0.0018). The observation of an interaction effect on Aix and Aix@75 in the absence of any main effect indicates a cross-over interaction. Significant vascular alterations in male elite athletes recovering from COVID-19 were observed that suggest vascular impairment. Whether these alterations affect athletic performance should be evaluated in future studies.
174	CaV170		Gabriela Trifan & Fernando D. Testai	Neurological Manifestations of Myocarditis	https://doi.org/10.1007/s11910-022-01203-9	Published	19 May 2022	Review	https://link.springer.com/article/10.1007/s11910-022-01203-9	Purpose of Review The present review discusses the neurological complications associated with myocarditis of different etiologies. Recent Findings Myocarditis can be idiopathic or caused by different conditions, including toxins, infections, or inflammatory diseases. Clinical findings are variable and range from mild self-limited shortness of breath or chest pain to hemodynamic instability which may result in cardiogenic shock and death. Several neurologic manifestations can be seen in association with myocarditis. Tissue remodeling, fibrosis, and myocyte dysfunction can result in heart failure and arrhythmias leading to intracardiac thrombus formation and cardioembolism. In addition, peripheral neuropathies, status epilepticus, or myasthenia gravis have been reported in association with specific types of myocarditis. Summary Multiple studies suggest the increasing risk of neurologic complications in patients with myocarditis. Neurologists should maintain a high suspicion of myocarditis in cases presenting with both cardiovascular and neurological dysfunction without a clear etiology.
175	CaV171		Fizzah A.ChoudryKrishnaraj S.RathodAndreasBaumbachAnthonyMathurDaniel A.Jones	Long-term outcomes of COVID-19 associated ST-elevation myocardial infarction treated with primary PCI	https://doi.org/10.1016/j.carrev.2022.05.029	Published	25 May 2022	Study	https://www.sciencedirect.com/science/article/pii/S1553838922002809	Coronavirus disease 2019 (COVID-19) is known to significantly increase the risk of arterial thrombosis (1*). In patients with type I or ST-elevation myocardial infarction (STEMI) who have COVID-19 infection there is data to suggest a poorer in-hospital outcome compared with patients who are COVID negative and suffer from STEMI (with higher thrombus burden, increased incidence of delayed presentation, cardiogenic shock, left ventricular (LV) dysfunction and need for intensive care) [1], [2], [3], [4], [5]. However, there is a paucity of comparative long-term outcome data in this cohort of patients. Here we examine the characteristics and long terms outcomes of a cohort of COVID positive STEMI patients treated with primary percutaneous coronary intervention (PCI) comparing long-term outcomes with a COVID negative group from the first and second waves of the pandemic. Results Over a 1-year period between 01/03/2020 and 01/03/2021, 101 consecutive patients with COVID-19 presenting with confirmed STEMI and 465 confirmed STEMI patients without COVID 19 infection were included (Table 1). Of patients with COVID-19, 12 had established infection undergoing inpatient treatment at time of presentation whereas the remaining 89 were first diagnosed at the time of STEMI presentation.
176	CaV172		A.Menard1L.Meddeb1M.Chine2A.Meilhac3P.Rossi2F.Thuny3	Symptômes cardiaques en Post Covid : bilan cardiaque ? Pour qui ? Quand ? Comment ?	https://doi.org/10.1016/j.mmifmc.2022.03.025	Published	31 May 2022	Study	https://www.sciencedirect.com/science/article/pii/S2772743222000435	Introduction Dans le contexte de pandémie de Sars-Cov-19 avec des atteintes cardiovasculaires mal caractérisées, nous réalisons depuis mai 2020 une étude prospective, observationnelle, de cohorte centrée sur une évaluation et un suivi cardiovasculaire systématique chez des patients, quel que soit leur profil cardiovasculaire, ayant survécu à un épisode de Covid-19 modéré ou sévère (IDRCB: 2020-A01576-33) Matériels et méthodes A S4, S24 et S48 d'une infection avec PCRSars-Cov-19 positive, les patients inclus bénéficient d'une consultation clinique de cardiologie avec 1) ECG 2)Prélèvement sanguin troponine T, NT-proBNP, D-Dimères, bilan d'hémostase 3)Échocardiographie trans-thoracique (ETT) + écho-doppler veineux « 3 points » à 1 et 12 mois 4)IRM cardiaque et Angioscanner thoracique selon les recommandations internationales. Nous proposons ici une analyse intermédiaire de nos résultats après 18 mois du début de l'etude. Résultats 124 patients ont été inclus, avec un sex ratio de 1/2, d'âge médian de 55 ans, 58% avec une comorbidité à risque de forme sévère dont 38% de pathologie cardio-vasculaire, tabagisme actif dans 13% des cas .La prise en charge initiale était en ambulatoire (42.2%)en hospitalisation conventionnelle(37.8%) ou en soins intensif/réanimation(20%). Une maladie chronique a décompensé chez 24.4%des patients ou a été découverte chez 7% et 8% ont présenté une maladie thrombo-embolique et 2 patients une pericardite et 3 un trouble du rythme en phase aigüe. Dans le suivi, la présence de signes cardiologiques (douleur thoracique, syncope, palpitation, dyspnée de classe III ou IV NYHA, signes congestifs d'insuffisance cardiaque gauche ou droite, frottement péricardique, anomalies ECG du segment ST, des ondes T, élargissement du QRS, bloc atrio-ventriculaire du 2ème ou 3ème degré) était retrouvée chez 33% des patients à S4, 28% àS12, 22% àS24 et 14% à S48. Une ETT a été réalisée chez 60 patients et anormale chez 12 (20%) avec hypokinésie septale (8) une pericardite (2) ou HVG (2), une IRM cardiaque chez 41 patients et anormale chez 12 (29%) avec 10 myocardites et 2 péricardites. Tous les holter-ECG étaient normaux (4/4). Entre S4 etS12, 28% des patients avaient des D-Dimeres élevés (>0,5) et 25% une anomalie de la tropo/ NT-proBNP. Tous les patients avec une elevation des DDimeres avec une imagerie cardiaque anormale. Aucun lien n'est retrouvé entre le degré de sévérité initial, les co morbidités et les complications cardio-vasculaires post Covid sur le long terme. Conclusion Notre étude retrouve une importante prévalence des symptômes cardiaques même si ces derniers semblent disparaitre spontanément après 1 an de suivi. Nous ne disposons pas, à ce jour, de stratégie rentable pour exclure une pathologie CV sévére (myocadite pericardite) mais les consensus d'expert (https://doi.org/10.1093/eurheartj/ehac031) considèrent comme raisonnable de dépister les personnes à haut risque d'atteinte cardiaque ou avec un nouveau diagnostic CVpost-COVID-19 ainsi que les athlètes.
177	CaV173		Michael Hultström, Robert Frithiof, Jonathan Grip, Linnea Lindelöf, Olav Rooijackers, Sara Pigazzini, Mari Niemi, Mattia Cordioli, Lindo Nkambule, Tomislav Maricic, Kristina Nilsson Ekdahl, Bo Nilsson, Miklós Lipcsey, Hugo Zeberg & Oskar Eriksson	Genetic determinants of mannose-binding lectin activity predispose to thromboembolic complications in critical COVID-19	https://doi.org/10.1038/s41590-022-01227-w	Published	27 May 2022	Study	https://www.nature.com/articles/s41590-022-01227-w	A recent study demonstrated that the complement recognition protein mannose-binding lectin (MBL) can bind to glycosylated SARS-CoV-2 spike protein. Binding activated complement in a spike-dependent manner and inhibited severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in in vitro models1. Furthermore, genetic variants near or in the MBL2 gene that encodes MBL in humans were suggested as being associated with COVID-19 requiring hospitalization. In the present study, we carried out genetic and biochemical analyses of MBL activity in plasma in a multicenter cohort of critically ill COVID-19 patients and interrogated the publicly available summary statistics from the COVID-19 Human Genetics Initiative (COVID-19 HGI)2. We found no evidence that genetic variants that determine activity of the MBL pathway are associated with hospitalization or intensive care admission due to SARS-CoV-2 infection. Instead, we demonstrated that MBL2 haplotypes determine risk for thrombotic complications in critically ill COVID-19 patients. Specifically, genetically determined MBL activity confers risk for pulmonary embolism in a U-shaped manner, where haplotypes associated with intermediate MBL activity are protective. Our results demonstrate a complement-dependent mechanism for COVID-19-associated thrombosis and provide an example of how genetic variation in the innate immune system modulates thrombosis risk. The unique polymorphic nature of the MBL2 locus, with a high frequency of naturally occurring knockouts devoid of functional MBL, allows for an assessment of the role of MBL activity in observational studies. We show that genetically determined MBL deficiency does not influence the risk of COVID-19 requiring hospitalization or admission to intensive care. Instead, our results demonstrate that the interaction between genetic variation in the MBL2 gene and SARS-CoV-2 infection determines thrombosis risk in critically ill patients, a finding with important clinical implications given the high rate of thrombotic complications in COVID-19 patients.
178	CaV174		Ioana Mădălina Zota 1ORCID,Cristian Stătescu 1ORCID,Radu Andy Sascău 1,Mihai Roca 1,Larisa Anghel 1,Alexandra Maștaleru 1,Maria Magdalena Leon-Constantin 1,Cristina Mihaela Ghiciuc 2,ORCID,Sebastian Romica Cozma 3ORCID,Lucia Corina Dima-Cozma 1,Irina Mihaela Esanu 1, andFlorin Mitu 1ORCID	Acute and Long-Term Consequences of COVID-19 on Arterial Stiffness—A Narrative Review	https://doi.org/10.3390/life12060781	Published	25 May 2022	Review	https://www.mdpi.com/2075-1729/12/6/781/htm	The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing global coronavirus (COVID-19) pandemic. Although initially viewed as an acute respiratory illness, COVID-19 is clearly a complex multisystemic disease with extensive cardiovascular involvement. Emerging evidence shows that the endothelium plays multiple roles in COVID-19 physiopathology, as both a target organ that can be directly infected by SARS-CoV-2 and a mediator in the subsequent inflammatory and thrombotic cascades. Arterial stiffness is an established marker of cardiovascular disease. The scope of this review is to summarize available data on the acute and long-term consequences of COVID-19 on vascular function. COVID-19 causes early vascular aging and arterial stiffness. Fast, noninvasive bedside assessment of arterial stiffness could optimize risk stratification in acute COVID-19, allowing for early escalation of treatment. Vascular physiology remains impaired at least 12 months after infection with SARS-CoV-2, even in otherwise healthy adults. This raises concerns regarding the extent of arterial remodeling in patients with preexisting vascular disease and the potential development of a persistent, chronic COVID-19 vasculopathy. Long-term follow up on larger cohorts is required to investigate the reversibility of COVID-19-induced vascular changes and their associated prognostic implications.
179	CaV175		Oleksandr Dmytrenko 1ORCID andKory J. Lavine 1,2,3,*ORCID	Cardiovascular Tropism and Sequelae of SARS-CoV-2 Infection	https://doi.org/10.3390/v14061137	Published	25 May 2022	Review	https://www.mdpi.com/1999-4915/14/6/1137/htm	The extrapulmonary manifestation of coronavirus disease-19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), became apparent early in the ongoing pandemic. It is now recognized that cells of the cardiovascular system are targets of SARS-CoV-2 infection and associated disease pathogenesis. While some details are emerging, much remains to be understood pertaining to the mechanistic basis by which SARS-CoV-2 contributes to acute and chronic manifestations of COVID-19. This knowledge has the potential to improve clinical management for the growing populations of patients impacted by COVID-19. Here, we review the epidemiology and pathophysiology of cardiovascular sequelae of COVID-19 and outline proposed disease mechanisms, including direct SARS-CoV-2 infection of major cardiovascular cell types and pathogenic effects of non-infectious viral particles and elicited inflammatory mediators. Finally, we identify the major outstanding questions in cardiovascular COVID-19 research.
180	CaV176		Massimo Nunes1 Arneaux Kruger1 Amy Proal2 Douglas Kell3 Etheresia Pretorius1	The occurrence of hyperactivated platelets and fibrinaloid microclots in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)	https://doi.org/10.21203/rs.3.rs-1727226/v1	pre-print	08 Jun, 2022	Study	https://www.researchsquare.com/article/rs-1727226/v1	We have previously demonstrated that platelet poor plasma (PPP) obtained from patients with LongCovid/Post-Acute Sequelae of COVID-19 (PASC) is characterized by a hypercoagulable state reflected in hyperactivated platelets and the presence of considerable numbers of fibrin(ogen) amyloid microclots or fibrinaloid microclots. Due to substantial overlap in symptoms and aetiology between PASC and ME/CFS, we investigated whether coagulopathies, platelet hyperactivation and/or fibrin amyloid formation differed between individuals exhibiting ME/CFS and gender- and age-matched healthy controls. ME/CFS patients were statistically far more hypercoagulable as judged by thromboelastography of both whole blood and platelet-poor plasma. The area of plasma images containing fibrinaloid microclots was commonly more than 10-fold greater in untreated platelet-poor plasma from individuals with ME/CFS than in that of healthy controls. A similar difference was found when the plasma samples were treated with thrombin. Using fluorescently labelled PAC-1, which recognizes glycoprotein IIb/IIIa, and CD62P, which binds P-selectin, we observed massive hyperactivation and spreading of platelets in samples from individuals with ME/CFS. Using a quantitative scoring system, this was found to have a score of 2.72 ± 1.24 vs 1.00 (activation with pseudopodia formation) for healthy controls. We conclude that ME/CFS is accompanied by substantial and measurable changes in coagulability, platelet hyperactivation, and fibrinaloid microclot formation. However, fibrinaloid microclot load was not as prevalent as was previously noted in PASC. Fibrinaloid microclots, in particular can provide a ready explanation, via (temporary) blockage of microcapillaries and hence ischaemia, for many of the symptoms, such as fatigue, seen in patients with ME/CFS. The discovery of these biomarkers pointing to significant and systemic endothelial inflammation, represents an important development in ME/CFS research. It also points at novel treatment strategies using known drugs and/or nutraceuticals that target systemic vascular pathology and endothelial inflammation.
181	CaV177		Andrea Izquierdo-Marquisá,corresponding author 1 , 2 , * Hector Cubero-Gallego, 1 , 3 Álvaro Aparisi, 1 , 3 Beatriz Vaquerizo, 1 , 2 , 3 , 4 and Núria Ribas-Barquet 1 , 2 , 4	Myocardial Injury in COVID-19 and Its Implications in Short- and Long-Term Outcomes	https://doi.org/10.3389%2Ffcvm.2022.901245	Published	2022 May 26	Review	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9204594/	COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still a pandemic with high mortality and morbidity rates. Clinical manifestation is widely variable, including asymptomatic or mild respiratory tract illness to severe pneumonia and death. Myocardial injury is a significant pathogenic feature of COVID-19 and it is associated with worse in-hospital outcomes, mainly due to a higher number of hospital readmissions, with over 50% mortality. These findings suggest that myocardial injury would identify COVID-19 patients with higher risk during active infection and mid-term follow-up. Potential contributors responsible for myocardial damage are myocarditis, vasculitis, acute inflammation, type 1 and type 2 myocardial infarction. However, there are few data about cardiac sequelae and its long-term consequences. Thus, the optimal screening tool for residual cardiac sequelae, clinical follow-up, and the benefits of a specific cardiovascular therapy during the convalescent phase remains unknown. This mini-review explores the different mechanisms of myocardial injury related to COVID-19 and its short and long-term implications.
182	CaV178		Raul DMitraniaNitikaDabasaJarrahAlfadhliaMaureen HLoweryaThomas MBestbJoshua MHareacRobert JMyerburgaJeffrey JGoldbergera	Long-Term Cardiac Surveillance and Outcomes of COVID-19 Patients	https://doi.org/10.1016/j.tcm.2022.06.003	Published	16 June 2022	Article	https://www.sciencedirect.com/science/article/pii/S1050173822000871	Acute cardiac manifestions of COVID-19 have been well described, while chronic cardiac sequelae remain less clear. Various studies have shown conflicting data on the prevalence of new or worsening cardiovascular disease, myocarditis or cardiac dysrhythmias among patients recovered from COVID-19. Data are emerging that show that patients recovering from COVID-19 have an increased incidence of myocarditis and arrhythmias after recovery from COVID-19 compared with the control groups without COVID-19. The incidence of myocarditis after COVID-19 infection is low but is still significantly greater than the incidence of myocarditis from a COVID-19 vaccine. There have been several studies of athletes who underwent a variety of screening protocols prior to being cleared to return to exercise and competition. The data show possible, probable or definite myocarditis or cardiac injury among 0.4-3.0% of the athletes studied. Recent consensus statements suggest that athletes with full recovery and absence of cardiopulmonary symptoms may return to exercise and competition without cardiovascular testing. In conclusion, patients with COVID-19 may be expected to have an increased risk of cardiovascular disease, myocarditis or arrhythmias during the convalescent phase. Fortunately, the majority of patients, including athletes may return to their normal activity after recovery from COVID 19, in the absence of persisting cardiovascular symptoms.
183	CaV179		M.Pineton De Chambrun1P.Barhoum1K.Dorgham2M.Kerneis3Q.Moyon4P.Quentric4J.L.Charuel5M.Schmidt1G.Lebreton6C.E.Luyt1M.Miyara5Z.Amoura4A.Combes1G.Gorochov7G.Hekimian1	Hétérogénéité phénotypique des myocardites fulminantes induites par la COVID-19 chez l’adulte	https://doi.org/10.1016/j.revmed.2022.03.316	Published	15 June 2022	Study	https://www.sciencedirect.com/science/article/pii/S0248866322004003	Introduction L’infection par le SARS-CoV-2 peut induire chez l’adulte un syndrome inflammatoire multisystémique (MIS-A). La myocardite fulminante est l’une des complications les plus graves du MIS-A. Des critères internationaux ont été établis par le Center for Disease Control and Prevention américain (US-CDC) pour faciliter son diagnostic. Cependant, certains patients présentant une myocardite fulminante dans un contexte de la COVID-19 ne répondent pas aux critères de l’US-CDC, suggérant l’existence de plusieurs phénotypes de myocardites fulminantes associées à la COVID-19. L’objectif de cette étude était de comparer les caractéristiques cliniques et l’évolution des myocardites fulminantes induites par la COVID-19 selon qu’elles répondent, ou non, aux critères du MIS-A établis par l’US-CDC. Patients et méthodes Etude rétrospective monocentrique incluant toutes les myocardites fulminantes induites par la COVID-19 admises dans un service de Médecine Intensive-Réanimation entre mars 2020 et juin 2021. Le critère de jugement principal était la mortalité intra-hospitalière. Résultats Pendant la durée de l’étude, 38 patients ont été admis en réanimation pour une myocardite fulminante (homme 66 %, âge moyen à l’admission ± DS 32 ± 15 ans) induite par la COVID-19. Les traitements des défaillances d’organes reçus par les patients étaient : dobutamine 79 %, noradrénaline 60 %, ventilation invasive 50 %, ECMO-VA 42 % et épuration extra-rénale 29 %. La mortalité intra-hospitalière était de 13 %. Vingt-cinq patients (66 %) répondaient aux critères du MIS-A (MIS-A + ). Les patients MIS-A- présentaient : un délai plus court entre le début de la COVID-19 et la survenue de la myocardite ; une fraction d’éjection du ventricule gauche plus basse ; une plus grande fréquence des défaillance d’organes et avaient un risque plus important de recevoir une ECMO-VA (92 % vs. 16 %, p < 0,0001). La mortalité intra-hospitalière était plus élevée chez les MIS-A- (31 % vs. 4 %). Les MIS-A+ présentaient des taux circulants plus élevées d’IL-17, d’IL-22 et de TNFa alors que les MIS-A- présentaient des taux circulants plus important d’IFNa2 et d’IL-8. De plus, les anticorps anti-ARN polymérases III étaient présents chez 54 % des patients MIS-A- mais chez aucun patient MIS-A+. Conclusion Les critères de MIS-A permettent d’identifier deux phénotypes au sein des myocardites fulminantes induites par la COVID-19. Les patients MIS-A+ et MIS-A- ont une présentation clinique, un pronostic et un profil immunologique très différents. Différencier ces deux entités semble important pour leurs traitements et pour mieux en comprendre la physiopathologie.
184	CaV180		Akash Srinivasan 1ORCID,Felyx Wong 1ORCID,Liam S. Couch 2 andBrian X. Wang 3,ORCIDAkash Srinivasan 1ORCID,Felyx Wong 1ORCID,Liam S. Couch 2 andBrian X. Wang 3,ORCID	Cardiac Complications of COVID-19 in Low-Risk Patients	https://doi.org/10.3390/v14061322	Published	17 June 2022	Review	https://www.mdpi.com/1999-4915/14/6/1322/htm	The coronavirus disease 2019 (COVID-19) pandemic has resulted in over 6 million deaths and significant morbidity across the globe. Alongside common respiratory symptoms, COVID-19 is associated with a variety of cardiovascular complications in the acute and post-acute phases of infection. The suggested pathophysiological mechanisms that underlie these complications include direct viral infection of the myocardium via the angiotensin-converting enzyme 2 (ACE2) protein and a cytokine release syndrome that results in indirect inflammatory damage to the heart. Patients with pre-existing cardiovascular disease and co-morbidities are generally more susceptible to the cardiac manifestations of COVID-19. However, studies have identified a variety of complications in low-risk individuals, including young adults and children. Myocarditis and paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS) are among the adverse events reported in the acute phase of infection. Furthermore, patients have reported cardiac symptoms persisting beyond the acute phase in post-COVID syndrome. This review summarises the acute and chronic cardiac consequences of COVID-19 in low-risk patients, explores the pathophysiology behind them, and discusses new predictive factors for poor outcomes.
185	CaV181		Vincenzo Nuzzi, Eva Del Mestre, Alessia Degrassi, Daniel I. Bromage, Paolo Manca, Susan Piper, Jessica Artico, Piero Gentile, Paul A. Scott, Mario Chiatto, Marco Merlo, Nilesh Pareek, Mauro Giacca, Gianfranco Sinagra, Theresa A. McDonagh & Antonio Cannata	Cardiovascular Damage in COVID-19: What We Know Two Years Later	https://doi.org/10.1007/s11886-022-01730-4	Published	25 June 2022	Review	https://link.springer.com/article/10.1007/s11886-022-01730-4	Purpose of the Review The Coronavirus disease 2019 (COVID-19) pandemic has profoundly influenced cardiological clinical and basic research in the past two years. In the present review, we summarize the current knowledge on myocardial involvement in COVID-19, providing an overview on the incidence, the pathogenetic mechanisms, and the clinical implications of cardiac injury in this setting. Recent Findings The possibility of heart involvement in patients with COVID-19 has received great attention since the beginning of the pandemic. After more than two years, several steps have been taken in understanding the mechanisms and the incidence of cardiac injury during COVID-19 infection. Similarly, studies globally have clarified the implications of co-existing heart disease and COVID-19. Summary Severe COVID-19 infection may be complicated by myocardial injury. To date, a direct damage from the virus has not been demonstrated. The presence of myocardial injury should be systematically assessed for a prognostication purpose and for possible therapeutic implications.
186	CaV182		Pratima Chowdary	COVID-19 coagulopathy – what should we treat?	https://doi.org/10.1113/EP089404	Published	22 June 2022	Review	https://physoc.onlinelibrary.wiley.com/doi/full/10.1113/EP089404	New Findings What is the topic of this review? Overview of the coagulation abnormalities, including elevated D-dimers widely reported with COVID-19, often labelled as COVID coagulopathy. What advances does it highlight? The review highlights the changes in bronchoalveolar haemostasis due to apoptosis of alveolar cells, which contributes to acute lung injury and acute respiratory distress syndrome; the pathophysiological mechanisms, including endothelial dysfunction and damage responsible for thrombosis of pulmonary microcirculation and potential contribution to the hypoxaemia of COVID-19 acute lung injury; and changes in coagulation proteins responsible for the hypercoagulability and increased risk of thrombosis in other venous and arterial beds. The rationale for anticoagulation and fibrinolytic therapies is detailed, and potential confounders that might have led to less than expected improvement in the various randomised controlled trials are considered. Abstract Coronavirus disease 19 (COVID-19) causes acute lung injury with diffuse alveolar damage, alveolar–capillary barrier disruption, thrombin generation and alveolar fibrin deposition. Clinically, hypoxaemia is associated with preserved lung compliance early in the disease, suggesting the lack of excessive fluid accumulation typical of other lung injuries. Notably, autopsy studies demonstrate infection of the endothelium with extensive capillary thrombosis distinct from the embolic thrombi in pulmonary arteries. The inflammatory thrombosis in pulmonary vasculature secondary to endothelial infection and dysfunction appears to contribute to hypoxaemia. This is associated with elevated D-dimers and acquired hypercoagulability with an increased risk of deep vein thrombosis. Hypercoagulability is secondary to elevated plasma tissue factor levels, von Willebrand factor, fibrinogen, reduced ADAMTS-13 with platelet activation and inhibition of fibrinolysis. Multi-platform randomised controlled studies of systemic therapeutic anticoagulation with unfractionated and low molecular mass heparins demonstrated a survival benefit over standard care with full-dose anticoagulation in patients with non-severe disease who require supplemental oxygen, but not in severe disease requiring ventilatory support. Late intervention and the heterogeneous nature of enrolled patients can potentially explain the apparent lack of benefit in severe disease. Improvement in oxygenation has been demonstrated with intravenous fibrinolytics in small studies. Inhaled anticoagulants, thrombolytic agents and non-specific proteolytic drugs in clinical trials for decreasing alveolar fibrin deposition might benefit early disease. Essentially, COVID-19 is a multi-system disorder with pulmonary vascular inflammatory thrombosis that requires an interdisciplinary approach to combination therapies addressing both inflammation and intravascular thrombosis or alveolar fibrin deposits to improve outcomes.
187	CaV183		Yicheng Yang, Zhiyao Wei, Changming Xiong & Haiyan Qian	Direct mechanisms of SARS-CoV-2-induced cardiomyocyte damage: an update	https://doi.org/10.1186/s12985-022-01833-y	Published	25 June 2022	Review	https://virologyj.biomedcentral.com/articles/10.1186/s12985-022-01833-y	Myocardial injury induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is reportedly related to disease severity and mortality, attracting attention to exploring relevant pathogenic mechanisms. Limited by insufficient evidence, myocardial injury caused by direct viral invasion of cardiomyocytes (CMs) is not fully understood. Based on recent studies, endosomal dependence can compensate for S protein priming to mediate SARS-CoV-2 infection of CMs, damage the contractile function of CMs, trigger electrical dysfunction, and tip the balance of the renin–angiotensin–aldosterone system to exert a myocardial injury effect. In this review, we shed light on the direct injury caused by SARS-CoV-2 to provide a comprehensive understanding of the cardiac manifestations of coronavirus disease 2019 (COVID-19).
188	CaV184		O Shchudro, L Konopkina, T Pertseva, L Botvinikova, K Bielosludtseva	The role of NT-proBNP in patients discharged after COVID-19 pneumonia	https://doi.org/10.1093/eurjcn/zvac060.019	Published	02 July 2022	Study	https://academic.oup.com/eurjcn/article-abstract/21/Supplement_1/zvac060.019/6627402	Aims The long-term health effects after SARS-CoV-2 infection remain poorly understood. The aim of our study was to define the cardiac disorders in the early postCOVID period. Methods and resuts Was observed 85 patients (40 (47,1%) men, 45 (52,9%) women, average age – 44,2 (39,3; 47,1)) on 48,3 (45,0; 56,2) days after the onset of the first symptoms of COVID-19. The main group were divided into 3 subgroups: 1 – 39 patients after moderate COVID-19 pneumonia, 2 – 36 patients after severe COVID-19 pneumonia, 3 – 10 patients after critical COVID-19 pneumonia. The subgroups were comparable in gender and age. All patients before COVID-19 were virtually healthy and had no history of cardiovascular disease, including arrhythmias. All patients underwent general clinical methods of examination, determination of SpO2, echocardiography and measured NT-proBNP concentration in serum. In 100% patients was the level of SpO2 more than 95% (average 97,5 (96,3; 98,8)%) and preserved left ventricular ejection fraction (LVEF) (average 62,3 (60,2; 74,3)%). In patients after moderate COVID-19 pneumonia, the level of NT-proBNP was significantly lower (79,4 (59,9; 75,3) pg/ml) than in patients after severe (145,0 (66,9; 170,9) pg/ml) and critical (149,7 (79,3; 138,5) pg/ml) COVID-19 pneumonia (p < 0,01). But concentration NT-proBNP in patients after severe and critical COVID-19 pneumonia didn’t differ significantly (p > 0,05). Conclusions Patients after severe and critical COVID-19 pneumonia are at risk for developing cardiac disorders in the early postCOVID period. Determining the level of NT-proBNP, and not just performing echocardiography, after discharged in such patients will help to customize the most appropriate therapeutic strategies.
189	CaV185		Cameron K.OrmistonBSabIwonaŚwiątkiewiczMD, PhDacPam R.TaubMDa	Postural Orthostatic Tachycardia Syndrome as a Sequela of COVID-19	https://doi.org/10.1016/j.hrthm.2022.07.014	Published	16 July 2022	Review	https://www.sciencedirect.com/science/article/pii/S1547527122021853	Postural Orthostatic Tachycardia Syndrome (POTS) is a complex, multisystem disorder characterized by orthostatic intolerance and tachycardia and may be triggered by viral infection. Recent reports indicate 2-14% of COVID-19 survivors develop POTS and 9-61% experience POTS-like symptoms, such as tachycardia, orthostatic intolerance, fatigue, and cognitive impairment within 6-8 months following a SARS-CoV-2 infection. Pathophysiological mechanisms of Post-COVID-19 POTS are not well understood. Current hypotheses include autoimmunity related to SARS-CoV-2 infection, autonomic dysfunction, direct toxic injury by SARS-CoV-2 to the autonomic nervous system, and invasion of the central nervous system by SARS-CoV-2. Practitioners should actively assess for POTS in patients with post-acute COVID syndrome symptoms. Given symptoms of Post-COVID-19 POTS are predominantly chronic orthostatic tachycardia, lifestyle modifications in combination with the use of heart rate-lowering medications along with other pharmacotherapies should be considered. For example, ivabradine or beta-blockers in combination with compression stockings and increasing salt and fluid intake has shown potential. Treatment teams should be multidisciplinary, including physicians of various specialties, nurses, psychologists, and physiotherapists. Additionally, more resources to adequately care for this patient population are urgently needed given the increased demand for autonomic specialists and clinics since the start of the COVID-19 pandemic. Considering our limited understanding of Post-COVID-19 POTS, further research on topics such as its natural history, pathophysiological mechanisms, and ideal treatment is warranted. This review evaluates the current literature available on the associations between COVID-19 and POTS, possible mechanisms, patient assessment, treatments, and future directions to improving our understanding of Post-COVID-19 POTS.
190	CaV186		Emma Rezel-Potts,Abdel Douiri,Xiaohui Sun,Phillip J. Chowienczyk,Ajay M. Shah,Martin C. Gulliford Emma Rezel-Potts,Abdel Douiri,Xiaohui Sun,Phillip J. Chowienczyk,Ajay M. Shah,Martin C. Gulliford	Cardiometabolic outcomes up to 12 months after COVID-19 infection. A matched cohort study in the UK	https://doi.org/10.1371/journal.pmed.1004052	Published	July 19, 2022	Study	https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004052	Background Acute Coronavirus Disease 2019 (COVID-19) has been associated with new-onset cardiovascular disease (CVD) and diabetes mellitus (DM), but it is not known whether COVID-19 has long-term impacts on cardiometabolic outcomes. This study aimed to determine whether the incidence of new DM and CVDs are increased over 12 months after COVID-19 compared with matched controls. Methods and findings We conducted a cohort study from 2020 to 2021 analysing electronic records for 1,356 United Kingdom family practices with a population of 13.4 million. Participants were 428,650 COVID-19 patients without DM or CVD who were individually matched with 428,650 control patients on age, sex, and family practice and followed up to January 2022. Outcomes were incidence of DM and CVD. A difference-in-difference analysis estimated the net effect of COVID-19 allowing for baseline differences, age, ethnicity, smoking, body mass index (BMI), systolic blood pressure, Charlson score, index month, and matched set. Follow-up time was divided into 4 weeks from index date (“acute COVID-19”), 5 to 12 weeks from index date (“post-acute COVID-19”), and 13 to 52 weeks from index date (“long COVID-19”). Net incidence of DM increased in the first 4 weeks after COVID-19 (adjusted rate ratio, RR 1.81, 95% confidence interval (CI) 1.51 to 2.19) and remained elevated from 5 to 12 weeks (RR 1.27, 1.11 to 1.46) but not from 13 to 52 weeks overall (1.07, 0.99 to 1.16). Acute COVID-19 was associated with net increased CVD incidence (5.82, 4.82 to 7.03) including pulmonary embolism (RR 11.51, 7.07 to 18.73), atrial arrythmias (6.44, 4.17 to 9.96), and venous thromboses (5.43, 3.27 to 9.01). CVD incidence declined from 5 to 12 weeks (RR 1.49, 1.28 to 1.73) and showed a net decrease from 13 to 52 weeks (0.80, 0.73 to 0.88). The analyses were based on health records data and participants’ exposure and outcome status might have been misclassified. Conclusions In this study, we found that CVD was increased early after COVID-19 mainly from pulmonary embolism, atrial arrhythmias, and venous thromboses. DM incidence remained elevated for at least 12 weeks following COVID-19 before declining. People without preexisting CVD or DM who suffer from COVID-19 do not appear to have a long-term increase in incidence of these conditions. Author summary Why was this study done? ➢ Acute Coronavirus Disease 2019 (COVID-19) may be associated with cardiovascular complications and disorders of blood glucose. ➢ It is not known whether patients recovering from COVID-19 remain at increased risk of cardiovascular disease (CVD) or diabetes mellitus (DM). ➢ This study aimed to find out whether new diagnoses of DM and CVDs are increased over 12 months after COVID-19 compared with matched control patients who did not have COVID-19. What did the researchers do and find? ➢ We analysed electronic records for 428,650 COVID-19 patients who were matched with 428,650 control patients and followed up to January 2022. We evaluated new diagnoses of DM and CVD up to 12 months after COVID-19 infection. We compared COVID-19 patients with controls and adjusted for baseline differences in risk. ➢ DM diagnoses were increased by 81% in acute COVID-19 and remained elevated by 27% from 4 to 12 weeks after the infection. ➢ Acute COVID-19 was associated with a 6-fold increase in cardiovascular diagnoses overall, including an 11-fold increase in pulmonary embolism, a 6-fold increase in atrial arrythmias, and a 5-fold increase in venous thromboses. CVD diagnoses declined from 4 to 12 weeks after COVID-19 and returned to baseline levels or below from 12 weeks to 1 year after the infection. What do these findings mean? ➢ Acute COVID-19 is associated with increased risk of cardiovascular disorders, but risk generally returns to background levels soon after the infection. ➢ The risk of new DM remains increased for at least 12 weeks following COVID-19 before declining. ➢ Patients recovering from COVID-19 should be advised to consider measures to reduce diabetes risk including healthy diet and taking exercise. ➢ People without preexisting CVD or DM who suffer from COVID-19 do not appear to have a long-term increase in incidence of these conditions.
191	CaV187		Jessica Nye, PhD	Are Amyloid Fibrin Microclots Central to Long COVID?		Published	July 8, 2022	Article	https://www.hematologyadvisor.com/home/topics/thrombotic-disorders/covid-amyloid-fibrin-micro-clots-central-treatment-risk/	Analysis of patient blood samples found that microclots and platelet pathologies were present in all 80 patients. Using a spreading, clumping, and microclot scoring system, 30 of the 80 patients were found to have moderate activation.6 One of the possible treatments will be to prevent microclots from forming and to prevent platelet hyperactivation. Oral anticoagulants or nutraceuticals might be an option to investigate, and some clinicians have embarked upon clinician-initiated treatment regimens that include such treatments.11 However, such treatment regimens should be tested in randomized controlled trials to determine dosage, as well as efficacy in large patient populations. Various adjuvant medications may also assist in patient symptom relief and other research groups have suggested a combination of statins and antihistamines.6,11 Going forward there are still many aspects of SARS-CoV-2 infections that remain elusive. Prof Kell explained that symptoms of COVID-19 can persist for months, or even longer ¾ much as with myalgic encephalomyelitis/chronic fatigue syndrome ¾ after recovery and viral clearance. This suggests that there may be a replicating viral reservoir remaining long term, in some cases. Finding that reservoir ¾ most likely in the gut microbiome that may well contain microbial hosts for the virus ¾ should be the next mystery to investigate.
192	CaV188		Kyya, Yulian; Barnett, Olga; Halkevych, Marta; Labinska, Olha	RED BLOOD CELL COLOUR VARIATION AS A MARKER OF CALCIUM DISTRIBUTION: WHAT ROLE DOES IT HAVE IN HEART FAILURE PATIENTS WITH HYPERTENSION AND LONG COVID?	https://doi.org/10.1097/01.hjh.0000837240.96681.96	Published	Jun 1, 2022	Study	https://journals.lww.com/jhypertension/Abstract/2022/06001/RED_BLOOD_CELL_COLOUR_VARIATION_AS_A_MARKER_OF.487.aspx	Objective: Red blood cell (RBC) role is both passive action, oxygen delivery to the tissues as well as carbon dioxide to the lungs and active action involvement in the regulation of vascular tone. The aim was to investigate pathophysiological and ultrastructural changes of RBC in heart failure (HF) patients with hypertension (HT) and long Covid. Design and method: In total 12 patients with HF of Coronary Artery Disease origin, HT, and long Covid were examined. Mean age of patients was 62 ± 5.8 years. The control group consisted of 10 apparently healthy people. The functional state and ultrastructure of RBC were studied using electron microscopy. Results: During ultrastructure examination, structural pathologies of RBC in HF patients with HT and long Covid were revealed. RBC anisocytosis and poikilocytosis as structural damage variations in size and shape were found respectively. Reticulocytes were found much more often in HF patients with HT and long Covid than in the control group. In healthy control group, RBC had a typical discoid shape. In the presence of long Covid, both calcification as a marker of RBC apoptosis and destruction was also detected (Fig.1). Neutrophil extracellular traps (NETs) were found in RBC surrounding (Fig.1). Conclusions: Altered RBC function has important implications for HF patients with HT and long Covid. RBC has been shown to induce endothelial cell dysfunction and to increase cardiac injury as well as increased inflammatory processes in long Covid. The presence of HF, HT and long Covid leads to RBC calcification and activation of blood cell apoptosis. Prognostic role of RBC calcium distribution in combination with other important prognostic measures, such as biomarkers like Thrombospondin - 1, NT-proBNP and ST2 is subject of interest and requires further research.
193	CaV189		Petra Barhoum, Marc Pineton de Chambrun, Karim Dorgham, Mathieu Kerneis, Sonia Burrel, Paul Quentric, Christophe Parizot, Juliette Chommeloux, Nicolas Bréchot, Quentin Moyon, Guillaume Lebreton, Samia Boussouar, Matthieu Schmidt, Hans Yssel, Lucie Lefevre, Makoto Miyara, Jean-Luc Charuel, Stéphane Marot, Anne-Geneviève Marcelin, Charles-Edouard Luyt, Pascal Leprince, Zahir Amoura, Gilles Montalescot, Alban Redheuil, Alain Combes, Guy Gorochov, and Guillaume Hékimian	Phenotypic Heterogeneity of Fulminant COVID-19--Related Myocarditis in Adults	https://doi.org/10.1016/j.jacc.2022.04.056	Published	July 18, 2022	Study	https://www.jacc.org/doi/full/10.1016/j.jacc.2022.04.056	Background Adults who have been infected with SARS-CoV-2 can develop a multisystem inflammatory syndrome (MIS-A), including fulminant myocarditis. Yet, several patients fail to meet MIS-A criteria, suggesting the existence of distinct phenotypes in fulminant COVID-19–related myocarditis. Objectives This study sought to compare the characteristics and clinical outcome between patients with fulminant COVID-19–related myocarditis fulfilling MIS-A criteria (MIS-A+) or not (MIS-A−). Methods A monocentric retrospective analysis of consecutive fulminant COVID-19–related myocarditis in a 26-bed intensive care unit (ICU). Results Between March 2020 and June 2021, 38 patients required ICU admission (male 66%; mean age 32 ± 15 years) for suspected fulminant COVID-19–related myocarditis. In-ICU treatment for organ failure included dobutamine 79%, norepinephrine 60%, mechanical ventilation 50%, venoarterial extracorporeal membrane oxygenation 42%, and renal replacement therapy 29%. In-hospital mortality was 13%. Twenty-five patients (66%) met the MIS-A criteria. MIS-A− patients compared with MIS-A+ patients were characterized by a shorter delay between COVID-19 symptoms onset and myocarditis, a lower left ventricular ejection fraction, and a higher rate of in-ICU organ failure, and were more likely to require mechanical circulatory support with venoarterial extracorporeal membrane oxygenation (92% vs 16%; P < 0.0001). In-hospital mortality was higher in MIS-A− patients (31% vs 4%). MIS-A+ had higher circulating levels of interleukin (IL)-22, IL-17, and tumor necrosis factor-α (TNF-α), whereas MIS-A− had higher interferon-α2 (IFN-α2) and IL-8 levels. RNA polymerase III autoantibodies were present in 7 of 13 MIS-A− patients (54%) but in none of the MIS-A+ patients. Conclusion MIS-A+ and MIS-A− fulminant COVID-19–related myocarditis patients have 2 distinct phenotypes with different clinical presentations, prognosis, and immunological profiles. Differentiating these 2 phenotypes is relevant for patients’ management and further understanding of their pathophysiology.
194	CaV190		Rachel E. Szeghy, Nina L. Stute, Valesha M. Province, Marc A. Augenreich, Jonathon L. Stickford, Abigail S. L. Stickford, and Stephen M. Ratchford	Six-month longitudinal tracking of arterial stiffness and blood pressure in young adults following SARS-CoV-2 infection	https://doi.org/10.1152/japplphysiol.00793.2021	Published	17 May 2022	Study	https://journals.physiology.org/doi/full/10.1152/japplphysiol.00793.2021	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can increase arterial stiffness 3–4 wk following infection, even among young, healthy adults. However, the long-term impacts of SARS-CoV-2 infection on cardiovascular health and the duration of recovery remain unknown. The purpose of this study was to elucidate potential long-lasting effects of SARS-CoV-2 infection on markers of arterial stiffness among young adults during the 6 mo following infection. Assessments were performed at months 1, 2, 3, 4, and ∼6 following SARS-CoV-2 infection. Doppler ultrasound was used to measure carotid-femoral pulse wave velocity (cfPWV) and carotid stiffness, and arterial tonometry was used to measure central blood pressures and aortic augmentation index at a heart rate of 75 beats·min−1 (AIx@HR75). Vascular (VCAM-1) and intracellular (ICAM-1) adhesion molecules were analyzed as circulating markers of arterial stiffness. From months 1–6, a significant reduction in cfPWV was observed (month 1: 5.70 ± 0.73 m·s−1; month 6: 4.88 ± 0.65 m·s−1; P < 0.05) without any change in carotid stiffness measures. Reductions in systolic blood pressure (month 1: 123 ± 8 mmHg; month 6: 112 ± 11 mmHg) and mean arterial pressure (MAP; month 1: 97 ± 6 mmHg; month 6: 86 ± 7 mmHg) were observed (P < 0.05), although AIx@HR75 did not change over time. The month 1–6 change in cfPWV and MAP were correlated (r = 0.894; P < 0.001). A reduction in VCAM-1 was observed at month 3 compared with month 1 (month 1: 5,575 ± 2,242 pg·mL−1; month 3: 4,636 ± 1,621 pg·mL−1; P < 0.05) without a change in ICAM-1. A reduction in cfPWV was related with MAP, and some indicators of arterial stiffness remain elevated for several months following SARS-CoV-2 infection, possibly contributing to prolonged recovery and increased cardiovascular health risks. NEW & NOTEWORTHY We sought to investigate potential long-lasting effects of SARS-CoV-2 infection on markers of arterial stiffness among young adults for 6 mo following infection. Carotid femoral pulse wave velocity was significantly reduced while carotid stiffness measures remained unaltered over the 6-mo period. These findings suggest several months of recovery from infection may be necessary for young adults to improve various markers of arterial stiffness, possibly contributing to cardiovascular health and recovery among those infected with SARS-CoV-2.
195	CaV191		Larisa G.TereshchenkoMD, PhDabAdamBishopBSaNoraFisher-CampbellBAaJacquelineLeveneDOaCraig C.MorrisMDaHetalPatelMScacErynnBeesonMDaJessica A.BlankMDaJG N.BradnerBSaMichelleCoblensBAaJacob W.CorpronBSaJenna M.DavisonMPHaKathleenDennyBAaMary S.EarpBSaSimeonFloreaaHowardFreemanMDaOliviaFusonBSaFlorian H.GuillotBSaKazi T.HaqPhDaMorrisKimMDaClintonKolsethMDaOliviaKrolBScLisaLinBSaLiatLitwinMDaAneeqMalikMDaEvanMitchellBSaAmanMohapatraBSacCassandraMullenMDaChad DNixMScaAyodeleOyeyemiMDaChristineRutlenMD, MPHaAshley E.TamBAaIngaVan BurenBAaJessicaWallaceBAaAkramKhanMDd	Risk of Cardiovascular Events After COVID-19	https://doi.org/10.1016/j.amjcard.2022.06.023	Published	15 July 2022	Study	https://www.sciencedirect.com/science/article/pii/S0002914922006555	We aimed to determine absolute and relative risks of either symptomatic or asymptomatic SARS-CoV-2 infection for late cardiovascular (CV) events and all-cause mortality. We conducted a retrospective double cohort study of patients with either symptomatic or asymptomatic SARS-CoV-2 infection (COVID-19+ cohort) and its documented absence (COVID-19− cohort). The study investigators drew a simple random sample of records from all patients under the Oregon Health & Science University Healthcare (n = 65,585), with available COVID-19 test results, performed March 1, 2020 to September 13, 2020. Exclusion criteria were age <18 years and no established Oregon Health & Science University care. The primary outcome was a composite of CV morbidity and mortality. All-cause mortality was the secondary outcome. The study population included 1,355 patients (mean age 48.7 ± 20.5 years; 770 women [57%], 977 White non-Hispanic [72%]; 1,072 ensured [79%]; 563 with CV disease history [42%]). During a median 6 months at risk, the primary composite outcome was observed in 38 of 319 patients who were COVID-19+ (12%) and 65 of 1,036 patients who were COVID-19− (6%). In the Cox regression, adjusted for demographics, health insurance, and reason for COVID-19 testing, SARS-CoV-2 infection was associated with the risk for primary composite outcome (hazard ratio 1.71, 95% confidence interval 1.06 to 2.78, p = 0.029). Inverse probability-weighted estimation, conditioned for 31 covariates, showed that for every patient who was COVID-19+, the average time to all-cause death was 65.5 days less than when all these patients were COVID-19−: average treatment effect on the treated −65.5 (95% confidence interval −125.4 to −5.61) days, p = 0.032. In conclusion, either symptomatic or asymptomatic SARS-CoV-2 infection is associated with an increased risk for late CV outcomes and has a causal effect on all-cause mortality in a late post-COVID-19 period.
196	CaV192		Ryota Urata, Koji Ikeda, Ekura Yamazaki, Daisuke Ueno, Akiko Katayama, Masaharu Shin-Ya, Eriko Ohgitani, Osam Mazda & Satoaki Matoba	Senescent endothelial cells are predisposed to SARS-CoV-2 infection and subsequent endothelial dysfunction	https://doi.org/10.1038/s41598-022-15976-z	Published	25 July 2022	Study	https://www.nature.com/articles/s41598-022-15976-z	The coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains to spread worldwide. COVID-19 is characterized by the striking high mortality in elderly; however, its mechanistic insights remain unclear. Systemic thrombosis has been highlighted in the pathogenesis of COVID-19, and lung microangiopathy in association with endothelial cells (ECs) injury has been reported by post-mortem analysis of the lungs. Here, we experimentally investigated the SARS-CoV-2 infection in cultured human ECs, and performed a comparative analysis for post-infection molecular events using early passage and replicative senescent ECs. We found that; (1) SARS-CoV-2 infects ECs but does not replicate and disappears in 72 hours without causing severe cell damage, (2) Senescent ECs are highly susceptible to SARS-CoV-2 infection, (3) SARS-CoV-2 infection alters various genes expression, which could cause EC dysfunctions, (4) More genes expression is affected in senescent ECs by SARS-CoV-2 infection than in early passage ECs, which might causes further exacerbated dysfunction in senescent ECs. These data suggest that sustained EC dysfunctions due to SARS-CoV-2 infection may contribute to the microangiopathy in the lungs, leading to deteriorated inflammation and thrombosis in COVID-19. Our data also suggest a possible causative role of EC senescence in the aggravated disease in elder COVID-19 patients.
197	CaV193		Husam M. Salah, Marat Fudim, Shawn T. O’Neil, Amin Manna, Christopher G. Chute & Melissa C. Caughey	Post-recovery COVID-19 and incident heart failure in the National COVID Cohort Collaborative (N3C) study	https://doi.org/10.1038/s41467-022-31834-y	Published	15 July 2022	Study	https://www.nature.com/articles/s41467-022-31834-y	Cardiac involvement has been noted in COVID-19 infection. However, the relationship between post-recovery COVID-19 and development of de novo heart failure has not been investigated in a large, nationally representative population. We examined post-recovery outcomes of 587,330 patients hospitalized in the United States (257,075 with COVID-19 and 330,255 without), using data from the National COVID Cohort Collaborative study. Patients hospitalized with COVID-19 were older (51 vs. 46 years), more often male (49% vs. 42%), and less often White (61% vs. 69%). Over a median follow up of 367 days, 10,979 incident heart failure events occurred. After adjustments, COVID-19 hospitalization was associated with a 45% higher hazard of incident heart failure (hazard ratio = 1.45; 95% confidence interval: 1.39–1.51), with more pronounced associations among patients who were younger (P-interaction = 0.003), White (P-interaction = 0.005), or who had established cardiovascular disease (P-interaction = 0.005). In conclusion, COVID-19 hospitalization is associated with increased risk of incident heart failure.
198	CaV194		Zainab Mahmoud 1 Lauren East 1 Marye Gleva Pamela K. Woodard Kory Lavine Amanda K. Verma	Cardiovascular symptom phenotypes of post-acute sequelae of SARS-CoV-2	https://doi.org/10.1016/j.ijcard.2022.07.018	Published	July 13, 2022	Study	https://www.internationaljournalofcardiology.com/article/S0167-5273(22)01086-5/fulltext	Highlights: •Cardiovascular post-acute sequelae occur in some patients after acute COVID-19 infection •The most common symptoms are chest pain, palpitations, and dyspnea on exertion •Patients were found to have a significant burden of sinus tachycardia that correlated with symptoms •Elevated blood pressures compared to pre-COVID-19 infection were also seen •Cardiac imaging showed reduced strain, increased left ventricular volume, and myocardial involvement on cardiac MRI Abstract Background Acute COVID-19 infection has been shown to have significant effects on the cardiovascular system. Post-acute sequelae of SARS-CoV-2 (PASC) are being identified in patients; however, the cardiovascular effects are yet to be well-defined. The Post-COVID Cardiology Clinic at Washington University evaluates and treats patients with ongoing cardiovascular PASC. Objectives This investigation aims to describe the phenotypes of cardiovascular symptoms of PASC in patients presenting to the Post-COVID Cardiology Clinic, including their demographics, symptoms, and the clinical phenotypes observed. Methods This was a retrospective analysis of symptoms, clinical findings, and test results from the first 100 consecutive adult patients who presented to the Post-COVID Cardiology Clinic at Washington University in St. Louis, between September 2020 to May 2021 with cardiovascular symptoms following COVID-19 infection. Results The population (n = 100) had a mean age of 46.3 years and was 81% female. Most patients had mild acute illness, with only 23% of patients requiring hospitalization during acute COVID-19 infection. The most commonly reported PASC symptoms were chest pain (66%), palpitations (59%), and dyspnea on exertion (56%). Of those presenting with these symptoms, 74/98 patients (75.5%) were found to have a significant blood pressure elevation, considerable sinus tachycardia burden, reduced global longitudinal strain, increased indexed left-ventricular end-diastolic volume (LVEDVi) by echocardiogram, and/or cMRI findings consistent with possible active or healing myocarditis. Conclusions Our findings highlight clinical phenotypes of the cardiovascular manifestations of PASC. Further studies are needed to evaluate the pathophysiology, treatment options and long-term outcomes for these patients.
199	CaV195		Stefanie Lip1, Linsay Mccallum1,2, Christian Delles1, John D McClure1, Tomasz Guzik1, Colin Berry1, Rhian Touyz1,3 and Sandosh Padmanabhan1	Rationale and Design for the LOnger-term effects of SARS-CoV-2 INfection on blood Vessels And blood pRessure (LOCHINVAR): an observational phenotyping study	http://dx.doi.org/10.1136/openhrt-2022-002057	Published	June 24, 2022	Protocol	https://openheart.bmj.com/content/9/1/e002057	Introduction COVID-19 may lead to long-term endothelial consequences including hypertension, stroke and myocardial infarction. A pilot study ‘COVID-19 blood pressure endothelium interaction study’, which found that patients with normal blood pressure (BP) at the time of hospital admission with COVID-19 showed an 8.6 mm Hg higher BP ≥12 weeks after recovery, compared with a group without COVID-19. The ‘LOnger-term effects of SARS-CoV-2 INfection on blood Vessels And blood pRessure’(LOCHINVAR) study is designed to provide definitive evidence of the long-term impact of COVID-19 on BP. Methods and analysis The LOCHINVAR study is an observational clinical phenotyping study comparing longitudinal BP change between individuals with and without COVID-19 infection. 150 participants (30–60 years) with no history of hypertension and not on BP lowering medications will be recruited to the study to attend three visits (baseline, 12 months, 18 months). Cases will be patients who were admitted to the Queen Elizabeth University Hospital (QEUH), Glasgow, UK, with suspected/confirmed COVID-19 until 31 December 2021 and who were alive at discharge. Controls will be those who have never had confirmed COVID-19 infection. All participants will undergo clinical and vascular phenotyping studies which will include 24-hour ambulatory BP monitoring systolic BP (ABPM SBP), brachial flow-mediated dilatation urine and blood samples to assess the renin-angiotensin system, vascular inflammation and immune status. The primary outcome is the change in systolic 24-hour ABPM (ABPM SBP) between the cases and controls. Sample size was calculated to detect a mean difference of 5 mm Hg ABPM SBP at 80% power.
200	CaV196		Maria Pia Borrelli Adelaide Buora Paolo Frigatti	The long haul COVID-19 arterial thrombosis	https://doi.org/10.1016/j.thromres.2022.07.008	Published	July 26, 2022	Letter to the Editor	https://www.thrombosisresearch.com/article/S0049-3848(22)00324-3/fulltext	The presence of a coexisting hypercoagulable state associated with Covid-19 infection has gained attention and several studies have already described acute limb ischemia (ALI) and peripheral arterial disease in critically ill patients, as well as coronary artery disease and ischemic stroke as manifestations usually associated with respiratory distress. Actually no information is currently available on how long inflammation and thrombotic derangements can last after recovery from Covid-19 symptoms and which patients are prone to develop acute arterial thrombosis. Considering the high rates of in-hospital thrombosis in Covid-19 patients, an aggressive thromboprophylaxis is recommended during hospitalization [[7]]. The International Society on Thrombosis and Haemostasis recommend to administer low molecular-weight heparin (LMWH) to all patients who need to be hospitalized for Covid-19 infection, unless contraindicated [[8]]. Beyond its anticoagulant action, heparin has also anti-inflammatory, cytoprotective and anti-viral effects: in fact it is able to bind to Sars-CoV-2 and block replication of the virus [[9]]. Besides LMWH and UFH, direct oral anticoagulants, antiplatelet drugs and fibrinolytic agents are also useful in management of Covid-19 patients. Abciximab (ReoPro) is a monoclonal antibody against the GPIIb/IIIa receptor, inhibiting platelet aggregation and thrombus formation. Evidence from the coronary literature suggest its use to enhance microperfusion likely because of prevention of downstream microembolization and platelet aggregation. The PROMPT Study, a randomized pilot trial [[10]], has demonstrated that in patients with ALI who underwent urokinase thrombolysis an adjunctive abciximab infusion resulted in faster thrombus dissolution and improved amputation free-survival. Our rationale for using adjunctive intra-arterial infusion of abciximab in Covid-19 patients with ALI was based on the histologic analysis of thrombi extracted in these kind of patients, which revealed platelet-fibrin thrombi and not just simple clot. Although prophylactic anticoagulation in active Covid-19 patients is largely accepted, there is no agreement on the dosage to be employed. Furthermore, whether and how long the pro-thrombotic state of Covid-19 persists after symptoms resumption is unknown and the utility of post-discharge tromboprophylaxis is debated. Our analysis underlines that delayed arterial thrombotic sequela of Covid-19 can also occur in susceptible patients after the index infection. From this perspective, vascular screening and followup should be discussed both during and after Covid-19 systemic symptoms resumption, to detect vascular manifestations which could be silent during viral infection. A better understanding of the coagulopathy in Covid-19 could have an essential role to guide prevention and treatment of arterial thromboembolic events, both during and after the viral infection. Further investigations are required to establish the type, dose and duration of anticoagulant/antiplatelet therapy not just during but also after Covid-19 infection.
201	CaV197		Irina Osiaevi, Arik Schulze, Georg Evers, Kimon Harmening, Hans Vink, Philipp Kümpers, Michael Mohr & Alexandros Rovas	Persistent capillary rarefication in long COVID syndrome	https://doi.org/10.1007/s10456-022-09850-9	Published	11 August 2022	Study	https://link.springer.com/article/10.1007/s10456-022-09850-9	Background Recent studies have highlighted Coronavirus disease 2019 (COVID-19) as a multisystemic vascular disease. Up to 60% of the patients suffer from long-term sequelae and persistent symptoms even 6 months after the initial infection. Methods This prospective, observational study included 58 participants, 27 of whom were long COVID patients with persistent symptoms > 12 weeks after recovery from PCR-confirmed SARS-CoV-2 infection. Fifteen healthy volunteers and a historical cohort of critically ill COVID-19 patients (n = 16) served as controls. All participants underwent sublingual videomicroscopy using sidestream dark field imaging. A newly developed version of Glycocheck™ software was used to quantify vascular density, perfused boundary region (PBR-an inverse variable of endothelial glycocalyx dimensions), red blood cell velocity (VRBC) and the microvascular health score (MVHS™) in sublingual microvessels with diameters 4–25 µm. Measurements and main results Although dimensions of the glycocalyx were comparable to those of healthy controls, a µm-precise analysis showed a significant decrease of vascular density, that exclusively affected very small capillaries (D5: − 45.16%; D6: − 35.60%; D7: − 22.79%). Plotting VRBC of capillaries and feed vessels showed that the number of capillaries perfused in long COVID patients was comparable to that of critically ill COVID-19 patients and did not respond adequately to local variations of tissue metabolic demand. MVHS was markedly reduced in the long COVID cohort (healthy 3.87 vs. long COVID 2.72 points; p = 0.002). Conclusions Our current data strongly suggest that COVID-19 leaves a persistent capillary rarefication even 18 months after infection. Whether, to what extent, and when the observed damage might be reversible remains unclear.
202	CaV198		Weijie Wang Chi-Yen Wang Shiow-Ing Wang 1 James Cheng-Chung Wei	Long-term cardiovascular outcomes in COVID-19 survivors among non-vaccinated population: A retrospective cohort study from the TriNetX US collaborative networks	https://doi.org/10.1016/j.eclinm.2022.101619	Published	August 11, 2022	Study	https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(22)00349-2/fulltext	Background The long-term cardiovascular outcomes in COVID-19 survivors remain largely unclear. The aim of this study was to investigate the long-term cardiovascular outcomes in COVID-19 survivors. Methods This study used the data from the US Collaborative Network in TriNetX. From a cohort of more than 42 million records between 1 January 2019 and 31 March 2022, a total of 4,131,717 participants who underwent SARS-CoV-2 testing were recruited. Study population then divided into two groups based on COVID-19 test results. To avoid reverse causality, the follow-up initiated 30 days after the test, and continued until 12 months. Hazard ratios (HRs) and 95% Confidence intervals (CIs) of the incidental cardiovascular outcomes were calculated between propensity score–matched patients with versus without SARS-CoV-2 infection. Subgroup analyses on sex, and age group were also conducted. Sensitivity analyses were performed using different network, or stratified by hospitalization to explore the difference of geography and severity of COVID-19 infection. Findings The COVID-19 survivors were associated with increased risks of cerebrovascular diseases, such as stroke (HR [95% CI] = 1.618 [1.545-1.694]), arrhythmia related disorders, such as atrial fibrillation (HR [95% CI] = 2.407 [2.296-2.523]), inflammatory heart disease, such as myocarditis (HR [95% CI] =4.406 [2.890-6.716]), ischemic heart disease(IHD), like ischemic cardiomyopathy (HR [95% CI] = 2.811 [2.477-3.190]), other cardiac disorders, such as heart failure (HR [95% CI] =2.296 [2.200-2.396]) and thromboembolic disorders (e.g. pulmonary embolism: HR [95% CI] =2.648 [2.443-2.870]). The risks of two composite endpoints, major adverse cardiovascular event (HR [95% CI] = 1.871 [1.816–1.927]) and any cardiovascular outcome (HR [95% CI] = 1.552 [1.526–1.578]), were also higher in the COVID-19 survivors than in the controls. Moreover, the survival probability of the COVID-19 survivors dramatically decreased in all the cardiovascular outcomes. The risks of cardiovascular outcomes were evident in both male and female COVID-19 survivors. Furthermore, the risk of mortality was higher in the elderly COVID-19 survivors (age ≥ 65 years) than in the young ones. Sensitivity analyses presented roughly similar results globally. Furthermore, the impact of COVID-19 on cardio-related outcomes appeared to be more pronounced in inpatients than in outpatients. Interpretation The 12-month risk of incidental cardiovascular diseases is substantially higher in the COVID-19 survivors than the non-COVID-19 controls. Clinicians and patients with a history of COVID-19 should pay attention to their cardiovascular health in long term.
203	CaV199		Edward M. Conway, Nigel Mackman, Ronald Q. Warren, Alisa S. Wolberg, Laurent O. Mosnier, Robert A. Campbell, Lisa E. Gralinski, Matthew T. Rondina, Frank L. van de Veerdonk, Karin M. Hoffmeister, John H. Griffin, Diane Nugent, Kyung Moon & James H. Morrissey	Understanding COVID-19-associated coagulopathy	https://doi.org/10.1038/s41577-022-00762-9	Published	05 August 2022	Article	https://www.nature.com/articles/s41577-022-00762-9	COVID-19-associated coagulopathy (CAC) is a life-threatening complication of SARS-CoV-2 infection. However, the underlying cellular and molecular mechanisms driving this condition are unclear. Evidence supports the concept that CAC involves complex interactions between the innate immune response, the coagulation and fibrinolytic pathways, and the vascular endothelium, resulting in a procoagulant condition. Understanding of the pathogenesis of this condition at the genomic, molecular and cellular levels is needed in order to mitigate thrombosis formation in at-risk patients. In this Perspective, we categorize our current understanding of CAC into three main pathological mechanisms: first, vascular endothelial cell dysfunction; second, a hyper-inflammatory immune response; and last, hypercoagulability. Furthermore, we pose key questions and identify research gaps that need to be addressed to better understand CAC, facilitate improved diagnostics and aid in therapeutic development. Finally, we consider the suitability of different animal models to study CAC.
204	CaV200		Mirawati, D. K., Budianto, P., Danuaji, R., Subandi, S., Ristinawati, I., & Prabaningtyas, H. R.	Long-COVID neurological symptoms are associated with D-dimer levels in COVID-19 patients	https://doi.org/10.18051/UnivMed.2022.v41.169-175	Published	Aug 13, 2022	Study	https://univmed.org/ejurnal/index.php/medicina/article/view/1246	Background Coronavirus disease 2019 (COVID-19) is a disease designated as a global pandemic by the WHO that can manifest clinically as neurological disorders that can occur in the acute phase or after the acute phase (long COVID-19), such as headache, myalgia, anosmia, and cognitive impairment. These neurological disorders as symptoms of long COVID-19 are presumably caused by hypercoagulable conditions characterized by an increase in D-dimer level. This study aims to determine the correlation of long COVID-19 neurological symptoms with hypercoagulable conditions and the role of D-dimer as a biomarker of long COVID-19 neurological symptoms. Methods This was a cross-sectional study involving 31 patients with long COVID-19 symptoms. Admitted long COVID-19 cases with recorded D-dimer levels and definitive outcomes were included consecutively. Long COVID-19 neurological symptoms were collected. D-dimer level was measured using immunofluorescence assay and reported in fibrinogen equivalent units (ìg/mL). The correlation between D-dimer levels and neurological clinical manifestations was assessed by using ordinal regression analysis. The p-value of <0.05 was considered statistically significant. Results The mean age of the subjects was 38.81 ± 11.58 years and 18 (58.06%) were female. Long COVID neurological symptoms comprised myalgia, anosmia and cephalgia, and most subjects complained of myalgia (80.65%). On multivariable analysis, long-COVID-19 neurological symptoms were significantly correlated with D-dimer [odds ratio (OR) = 1.05; p=0.020]. Conclusion The number of neurological long COVID symptoms were significantly correlated with level of D-Dimer. Ultimately, more clarity is needed on the neurological impact of COVID-19, its diagnosis, and its treatment.
205	CaV201		Sebastián Garcia-Zamora, José M. Picco, Augusto J. Lepori, Marcela I. Galello, Ariel K. Saad, Miguel Ayón, Nancy Monga-Aguilar, Issam Shehadeh, Carlos F. Manganiello, Cintia Izaguirre, Luciano N. Fallabrino, Matias Clavero, Flavia Mansur, Sebastián Ghibaudo, Daniela Sevilla, Cesar A. Cado, Mauricio Priotti, Kiera Liblik, Natalio Gastaldello & Pablo M. Merlo	Abnormal echocardiographic findings after COVID-19 infection: a multicenter registry	https://doi.org/10.1007/s10554-022-02706-9	Published	13 August 2022	Study	https://link.springer.com/article/10.1007/s10554-022-02706-9	The Coronavirus Disease 2019 (COVID-19) pandemic has transformed health systems worldwide. There is conflicting data regarding the degree of cardiovascular involvement following infection. A registry was designed to evaluate the prevalence of echocardiographic abnormalities in adults recovered from COVID-19. We prospectively evaluated 595 participants (mean age 45.5 ± 14.9 years; 50.8% female) from 10 institutions in Argentina and Brazil. Median time between infection and evaluation was two months, and 82.5% of participants were not hospitalized for their infection. Echocardiographic studies were conducted with General Electric equipment; 2DE imaging and global longitudinal strain (GLS) of both ventricles were performed. A total of 61.7% of the participants denied relevant cardiovascular history and 41.8% had prolonged symptoms after resolution of COVID-19 infection. Mean left ventricular ejection fraction (LVEF) was 61.0 ± 5.5% overall. In patients without prior comorbidities, 8.2% had some echocardiographic abnormality: 5.7% had reduced GLS, 3.0% had a LVEF below normal range, and 1.1% had wall motion abnormalities. The right ventricle (RV) was dilated in 1.6% of participants, 3.1% had a reduced GLS, and 0.27% had reduced RV function. Mild pericardial effusion was observed in 0.82% of participants. Male patients were more likely to have new echocardiographic abnormalities (OR 2.82, p = 0.002). Time elapsed since infection resolution (p = 0.245), presence of symptoms (p = 0.927), or history of hospitalization during infection (p = 0.671) did not have any correlation with echocardiographic abnormalities. Cardiovascular abnormalities after COVID-19 infection are rare and usually mild, especially following mild infection, being a low GLS of left and right ventricle, the most common ones in our registry. Post COVID cardiac abnormalities may be more frequent among males.
206	CaV202		Helen Fogarty,Soracha E. Ward,Liam Townsend,Ellie Karampini,Stephanie Elliott,Niall Conlon,Jean Dunne,Rachel Kiersey,Aifric Naughton,Mary Gardiner,Aisling M. Rehill,Ross I. Baker,Cliona Ni Cheallaigh,James S. O'Donnell,	Sustained VWF-ADAMTS-13 axis imbalance and endotheliopathy in long COVID syndrome is related to immune dysfunction	https://doi.org/10.1111/jth.15830	Published	25 July 2022	Study	https://onlinelibrary.wiley.com/doi/10.1111/jth.15830	Background Prolonged recovery is common after acute SARS-CoV-2 infection; however, the pathophysiological mechanisms underpinning Long COVID syndrome remain unknown. VWF/ADAMTS-13 imbalance, dysregulated angiogenesis, and immunothrombosis are hallmarks of acute COVID-19. We hypothesized that VWF/ADAMTS-13 imbalance persists in convalescence together with endothelial cell (EC) activation and angiogenic disturbance. Additionally, we postulate that ongoing immune cell dysfunction may be linked to sustained EC and coagulation activation. Patients and methods Fifty patients were reviewed at a minimum of 6 weeks following acute COVID-19. ADAMTS-13, Weibel Palade Body (WPB) proteins, and angiogenesis-related proteins were assessed and clinical evaluation and immunophenotyping performed. Comparisons were made with healthy controls (n = 20) and acute COVID-19 patients (n = 36). Results ADAMTS-13 levels were reduced (p = 0.009) and the VWF-ADAMTS-13 ratio was increased in convalescence (p = 0.0004). Levels of platelet factor 4 (PF4), a putative protector of VWF, were also elevated (p = 0.0001). A non-significant increase in WPB proteins Angiopoietin-2 (Ang-2) and Osteoprotegerin (OPG) was observed in convalescent patients and WPB markers correlated with EC parameters. Enhanced expression of 21 angiogenesis-related proteins was observed in convalescent COVID-19. Finally, immunophenotyping revealed significantly elevated intermediate monocytes and activated CD4+ and CD8+ T cells in convalescence, which correlated with thrombin generation and endotheliopathy markers, respectively. Conclusion Our data provide insights into sustained EC activation, dysregulated angiogenesis, and VWF/ADAMTS-13 axis imbalance in convalescent COVID-19. In keeping with the pivotal role of immunothrombosis in acute COVID-19, our findings support the hypothesis that abnormal T cell and monocyte populations may be important in the context of persistent EC activation and hemostatic dysfunction during convalescence. Essentials - Reduced plasma ADAMTS-13 levels and an increased VWF/ADAMTS13 ratio are common in convalescentCOVID-19 patients. - Levels of Platelet Factor 4, a putative VWF protector, are elevated in convalescent COVID-19 patients compared to healthy controls. - Elevated levels of pro-angiogenic proteins, including Weibel Palade Body constituents Angiopoietin-2 and Osteoprotegerin, are observed in a subset of patients. - Intermediate monocytes and activated CD4+ and CD8+ T cell subsets are increased in convalescent COVID-19 and correlate with thrombin generation and endotheliopathy markers, respectively.
207	CaV203		Saima May Sidik	Heart disease after COVID: what the data say		Published	02 August 2022	Editorial	https://www.nature.com/articles/d41586-022-02074-3	Some studies suggest that the risk of cardiovascular problems, such as a heart attack or stroke, remains high even many months after a SARS-CoV-2 infection clears up. Researchers are starting to pin down the frequency of these issues and what is causing the damage.
208	CaV204		Ahmed Ibrahim Ahmed, Jean Michel Saad, Yushui Han, Fares Alahdab, Maan Malahfji, Faisal Nabi, John J. Mahmarian, John P. Cooke, William A. Zoghbi, and Mouaz H. Al-Mallah	Coronary Microvascular Health in Patients With Prior COVID-19 Infection: IMPLICATIONS FOR LONG-COVID SYNDROME	https://doi.org/10.1016/j.jcmg.2022.07.006	Published	Aug 17, 2022	Study	https://www.jacc.org/doi/10.1016/j.jcmg.2022.07.006	Background: SARS-CoV-2 infection has been shown to directly infect coronary vascular endothelium, causing inflammation and plaque instability. We aimed to assess the vascular health of patients with prior COVID-19 using Positron emission tomography (PET) derived coronary flow reserve (CFR). Methods: A prospective cohort of consecutive patients with PCR confirmed prior COVID-19 infection undergoing clinically indicated PET myocardial perfusion imaging were included and compared to patients with no prior COVID19. CFR was determined by PET and microvascular dysfunction (CMD) was defined as CFR<2. Results: The study population consisted of 2316 patients (4.4% prior COVID 19, 52% male, mean age 67±12 years, 55% hypertensive, 32% diabetic, 41% dyslipidemia). The mean duration between COVID19 diagnosis and PET was 191 (±131) days. CMD was more prevalent in those with prior COVID19 (58% vs 46%, p=0.012). After adjusting for baseline and clinical characteristics, patients with prior COVID19 had statistically significant higher odds of CMD (OR 1.8, p=0.008). Results were consistent in subgroups of patients with no clinical risk factors and normal stress tests. Conclusion: Our analysis shows that patients with prior COVID19 have higher rates of CMD. This may in part explain the long-COVID symptoms. The prognostic implications of these findings need to be determined.
209	CaV205	VP	Vaughn Craddock, Aatish Mahajan, Balaji Krishnamachary, Leslie Spikes, Prabhakar Chalise, View ORCID ProfileNavneet K. Dhillon	Persistent Presence of Spike protein and Viral RNA in the Circulation of Individuals with Post-Acute Sequelae of COVID-19	https://doi.org/10.1101/2022.08.07.22278520	pre-print	August 09, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.08.07.22278520v1.full-text	SARS-CoV-2, the causative agent of COVID-19 disease has resulted in the death of millions worldwide since the beginning of the pandemic in December 2019. While much progress has been made to understand acute manifestations of SARS-CoV-2 infection, less is known about post-acute sequelae of COVID-19 (PASC). We investigated the levels of circulating SARS-CoV-2 components, Spike protein and viral RNA, in patients hospitalized with acute COVID-19 and in patients with and without PASC. In hospitalized patients with acute COVID-19 (n=116), we observed a positive correlation of Spike protein with D-dimer, length of hospitalization, and peak WHO score while viral RNA correlated with a tissue injury marker, lactate dehydrogenase (LDH). When comparing patients with post-COVID symptoms (n=33) and patients without (n=14), we found that Spike protein and viral RNA were more likely to be present in patients with PASC and in some cases at higher levels compared to acute COVID-19 patients. We also observed that the percent positivity of circulating viral RNA increased in the PASC positive individuals compared to acute COVID-19 group while Spike protein positivity remained the same. Additionally, we report that part of the circulating Spike protein is linked to extracellular vesicles without any presence of viral RNA in these vesicles. In conclusion, our findings suggest that Spike protein and/or viral RNA fragments persist in the recovered COVID-19 patients with PASC, regardless of their presence or absence during the acute COVID-19 phase. These results may help in understanding the reason(s) for why patients experience PASC symptoms and may offer potential therapeutic targets.
210	CaV206	VP	Manuela De Michele, Giulia d’Amati, Martina Leopizzi, Marta Iacobucci, Irene Berto, Svetlana Lorenzano, Laura Mazzuti, Ombretta Turriziani, Oscar G. Schiavo & Danilo Toni	Evidence of SARS-CoV-2 spike protein on retrieved thrombi from COVID-19 patients	https://doi.org/10.1186/s13045-022-01329-w	Published	16 August 2022	Study	https://jhoonline.biomedcentral.com/articles/10.1186/s13045-022-01329-w	The pathophysiology of COVID-19-associated coagulopathy is complex and not fully understood. SARS-CoV-2 spike protein (SP) may activate platelets and interact with fibrin(ogen). We aimed to investigate whether isolated SP can be present in clots retrieved in COVID-19 patients with acute ischemic stroke (by mechanical thrombectomy) and myocardial infarction. In this pilot study, we could detect SP, but not nucleocapsid protein, on platelets of COVID-19 patients’ thrombi. In addition, in all three COVID-19 thrombi analyzed for molecular biology, no SARS-CoV-2 RNA could be detected by real-time polymerase chain reaction. These data could support the hypothesis that free SP, besides the whole virus, may be the trigger of platelet activation and clot formation in COVID-19.
211	CaV207		Jasimuddin Ahamed1 and Jeffrey Laurence2	Long COVID endotheliopathy: hypothesized mechanisms and potential therapeutic approaches	https://doi.org/10.1172/JCI161167	Published	August 1, 2022	Review	https://www.jci.org/articles/view/161167	SARS-CoV-2–infected individuals may suffer a multi–organ system disorder known as “long COVID” or post-acute sequelae of SARS-CoV-2 infection (PASC). There are no standard treatments, the pathophysiology is unknown, and incidence varies by clinical phenotype. Acute COVID-19 correlates with biomarkers of systemic inflammation, hypercoagulability, and comorbidities that are less prominent in PASC. Macrovessel thrombosis, a hallmark of acute COVID-19, is less frequent in PASC. Female sex at birth is associated with reduced risk for acute COVID-19 progression, but with increased risk of PASC. Persistent microvascular endotheliopathy associated with cryptic SARS-CoV-2 tissue reservoirs has been implicated in PASC pathology. Autoantibodies, localized inflammation, and reactivation of latent pathogens may also be involved, potentially leading to microvascular thrombosis, as documented in multiple PASC tissues. Diagnostic assays illuminating possible therapeutic targets are discussed.
212	CaV208		Cheng-I. Wu, MD Peter J. Schwartz, MD, FHRS Michael J. Ackerman, MD, PhD Arthur A.M. Wilde, MD, PhD, FHRS	COVID-19 vaccination in patients with long QT syndrome	https://doi.org/10.1016/j.hroo.2022.07.011	Published	August 02, 2022	Article	https://www.heartrhythmopen.com/article/S2666-5018(22)00168-4/fulltext	Patients with long QT syndrome (LQTS) face potential threats from COVID-19 vaccination. Fever is one of the issues that is not uncommon after vaccination, and it usually takes place within 2 days. In particular, patients with type 2 LQTS based on trafficking-deficient variants are probably vulnerable to arrhythmogenicity under febrile conditions. Furthermore, myocarditis is one of the rare complications that is possibly associated with acquired QT prolongation and puts patients with LQTS at risk of life-threatening arrhythmia. Moreover, postural orthostatic tachycardia syndrome is another rare condition that, perhaps, poses LQTS patients susceptible to life-threatening arrhythmia when QT interval does not shorten optimally during tachycardia. In this review, we recommended prudent measurements to beneficially reduce the risk for patients with LQTS when vaccination or booster doses are eligible. Key Findings ▪Patients with type 2 long QT syndrome (LQTS) are probably vulnerable to arrhythmogenicity under febrile conditions. ▪In the extremely rare event that an LQTS patient experiences myocarditis following either the infection itself or the vaccination, monitoring the QTc seems a reasonable precaution. ▪If patients with type 1 LQTS have any sign of postural orthostatic tachycardia syndrome after COVID-19 vaccination, monitoring the electrocardiogram may be reasonable in the initial phase.
213	CaV209		Timothy L Wiemken, Ph.D, Leah J McGrath, Ph.D, Kathleen M Andersen, Ph.D, Farid Khan, MPH, Deepa Malhotra, MS MBA, Tamuno Alfred, Ph.D, Jennifer L Nguyen, ScD MPH, Laura Puzniak, Ph.D, Elizabeth Thoburn, MPH, Luis Jodar, Ph.D, John M McLaughlin, PhD	COVID-19 severity and risk of subsequent cardiovascular events	https://doi.org/10.1093/cid/ciac661	Published	19 August 2022	Study	https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac661/6671924	Background Little is known about the relationship between COVID-19 severity and subsequent risk of experiencing a cardiovascular event (CVE) after COVID-19 recovery. We evaluated this relationship in a large cohort of US adults. Methods Using a claims database, we performed a retrospective cohort study of adults diagnosed with COVID-19 between April 1, 2020 and May 31, 2021. We evaluated the association between COVID-19 severity and risk of CVE >30 days after COVID-19 diagnosis using inverse probability of treatment weighted competing risks regression. Severity was based on level of care required for COVID-19 treatment: intensive care unit (ICU) admission, non-ICU hospitalization, or outpatient care only. Results 1,357,518 COVID-19 patients were included (2% ICU, 3% non-ICU hospitalization, and 95% outpatient only). Compared to outpatients, there was an increased risk of any CVE for patients requiring ICU admission (adjusted hazard ratio [HR]: 1.80 [95%CI: 1.71−1.89]) or non-ICU hospitalization (HR: 1.28 [1.24−1.33]). Risk of subsequent hospitalization for CVE was even higher (HR: 3.47 [3.20–3.76] for ICU and HR: 1.96 [1.85–2.09] for non-ICU hospitalized vs. outpatient only). Conclusions COVID-19 patients hospitalized or requiring critical care had a significantly higher risk of experiencing and being hospitalized for post-COVID-19 CVE than patients with milder COVID-19 who were managed solely in the outpatient setting even after adjusting for differences between these groups. These findings underscore the continued importance of preventing SARS-CoV-2 infection from progressing to severe illness to reduce potential long-term cardiovascular complications.
214	CaV210		Georgios Mavraganis,Maria-Angeliki Dimopoulou,Dimitrios Delialis,Dimitrios Bampatsias,Raphael Patras,Alexandros Sianis,Eleni Maneta,Kimon Stamatelopoulos,Georgios Georgiopoulos	Clinical implications of vascular dysfunction in acute and convalescent COVID-19: a systematic review	https://doi.org/10.1111/eci.13859	Published	20 August 2022	Systematic Review	https://onlinelibrary.wiley.com/doi/abs/10.1111/eci.13859	Background Accumulating evidence suggests that endothelial dysfunction is implicated in the pathogenesis and severity of coronavirus disease 2019 (COVID-19). In this context, vascular impairment in COVID-19 might be associated with clinical manifestations and could refine risk stratification in these patients. Methods This systematic review aims to synthesize current evidence on the frequency and the prognostic value of vascular dysfunction during acute and post-recovery COVID-19. After systematically searching the MEDLINE, clinicaltrials.gov and the Cochrane Library from 1/12/19 until 05/03/22, we identified 24 eligible studies with laboratory confirmed COVID-19 and a thorough examination of vascular function. Flow mediated dilation (FMD) was assessed in 5 and 12 studies in acute and post-recovery phase respectively; pulse wave velocity (PWV) was the marker of interest in 3 studies in the acute and 4 studies in the post-recovery phase. Results All studies except for one in the acute and in the post-recovery phase showed positive association between vascular dysfunction and COVID-19 infection. Endothelial dysfunction in 2 studies and increased arterial stiffness in 3 studies were related to inferior survival in COVID-19. Discussion Overall, a detrimental effect of COVID-19 on markers of endothelial function and arterial stiffness that could persist even for months after the resolution of the infection and provide prognostic value was congruent across published studies. Further research is warranted to elucidate clinical implications of this association.
215	CaV211		Narendra N. Khanna,Mahesh Maindarkar,Anudeep Puvvula,Sudip Paul ,Mrinalini Bhagawati ,Puneet Ahluwalia,Zoltan Ruzsa ,Aditya Sharma Smiksha Munjral,Raghu Kolluri,Padukone R. Krishnan,Inder M. Singh,John R. Laird,Mostafa Fatemi ,Azra Alizad,Surinder K. Dhanjil,Luca Saba,Antonella Balestrieri,Gavino Faa ,Kosmas I. Paraskevas	Vascular Implications of COVID-19: Role of Radiological Imaging, Artificial Intelligence, and Tissue Characterization: A Special Report	https://doi.org/10.3390/jcdd9080268	Published	15 August 2022	Study	https://www.mdpi.com/2308-3425/9/8/268/htm	The SARS-CoV-2 virus has caused a pandemic, infecting nearly 80 million people worldwide, with mortality exceeding six million. The average survival span is just 14 days from the time the symptoms become aggressive. The present study delineates the deep-driven vascular damage in the pulmonary, renal, coronary, and carotid vessels due to SARS-CoV-2. This special report addresses an important gap in the literature in understanding (i) the pathophysiology of vascular damage and the role of medical imaging in the visualization of the damage caused by SARS-CoV-2, and (ii) further understanding the severity of COVID-19 using artificial intelligence (AI)-based tissue characterization (TC). PRISMA was used to select 296 studies for AI-based TC. Radiological imaging techniques such as magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound were selected for imaging of the vasculature infected by COVID-19. Four kinds of hypotheses are presented for showing the vascular damage in radiological images due to COVID-19. Three kinds of AI models, namely, machine learning, deep learning, and transfer learning, are used for TC. Further, the study presents recommendations for improving AI-based architectures for vascular studies. We conclude that the process of vascular damage due to COVID-19 has similarities across vessel types, even though it results in multi-organ dysfunction. Although the mortality rate is ~2% of those infected, the long-term effect of COVID-19 needs monitoring to avoid deaths. AI seems to be penetrating the health care industry at warp speed, and we expect to see an emerging role in patient care, reduce the mortality and morbidity rate.
216	CaV212		Jyotpal Singh,Lanishen Bhagaloo,Eric Sy,Andrea J. Lavoie,Payam Dehghani,Holly A. Bardutz,Cameron S. Mang,Josef Buttigieg,J. Patrick Neary	Cardiac impairments in postacute COVID-19 with sustained symptoms: A review of the literature and proof of concept	https://doi.org/10.14814/phy2.15430	Published	22 August 2022	Review	https://physoc.onlinelibrary.wiley.com/doi/10.14814/phy2.15430	Although acute COVID-19 is known to cause cardiac damage in some cases, there is still much to learn about the duration and relative permanence of the damage that may occur. Long COVID is a condition that can occur when COVID-19 symptoms remain in the postviral acute period. Varying accounts of long COVID have been described across the literature, however, cardiac impairments are sustained in many individuals and cardiovascular assessment is now considered to be an expected follow-up examination. The purpose of this review and proof of concept is to summarize the current research related to the assessment of cardiac function, including echocardiography and blood biomarker data, during the follow-up period in patients who recovered from COVID-19. Following a literature review, it was found that right ventricular dysfunction along with global longitudinal strain and diastolic dysfunction are common findings. Finally, more severe acute myocardial injury during the index hospitalization appears to exacerbate cardiac function. The available literature implies that cardiac function must be monitored in patients recovered from COVID-19 who remain symptomatic and that the impairments and severity vary from person-to-person. The proof-of-concept analysis of patients with cardiac disease and respiratory disease in comparison to those with sustained symptoms from COVID-19 suggests elevated systolic time interval in those with sustained symptoms from COVID-19, thus reducing heart performance indices. Future research must consider the details of cardiac complications during the acute infection period and relate this to the cardiac function in patients with long COVID during mid- and long-term follow-up.
217	CaV213		Ignas Badaras and Agnė Laučytė-Cibulskienė	Vascular Aging and COVID-19	https://doi.org/10.1177/00033197221121007	Published	August 28, 2022	Article	https://journals.sagepub.com/doi/full/10.1177/00033197221121007	Vascular age is determined by functional and structural changes in the arterial wall. When measured by its proxy, pulse wave velocity, it has been shown to predict cardiovascular and total mortality. Disconcordance between chronological and vascular age might represent better or worse vascular health. Cell senescence is caused by oxidative stress and sustained cell replication. Senescent cells acquire senescence-associated secretory phenotype. Oxidative stress, endothelial dysfunction, dysregulation of coagulation and leucocyte infiltration are observed in the aging endothelium. All of these mechanisms lead to increased vascular calcification and stiffness. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can involve the vascular endothelium. It enters cells using angiotensin-converting enzyme 2 (ACE-2) receptors, which are abundant in endothelial cells. The damage this virus does to the endothelium can be direct or indirect. Indirect damage is caused by hyperinflammation. Direct damage results from effects on ACE-2 receptors. The reduction of ACE-2 levels seen during coronavirus disease 2019 (COVID-19) infection might cause vasoconstriction and oxidative stress. COVID-19 and vascular aging share some pathways. Due to the novelty of the virus, there is an urgent need for studies that investigate its long-term effects on vascular health.
218	CaV214		Suzana E. Tanni Carolina R. Tonon Mariana Gatto Gustavo A.F. Mota Marina P. Okoshi	Post-COVID-19 syndrome: Cardiovascular manifestations	https://doi.org/10.1016/j.ijcard.2022.08.054	Published	August 31, 2022	Editorial	https://www.internationaljournalofcardiology.com/article/S0167-5273(22)01265-7/fulltext	In this issue of International Journal of Cardiology, Mahmoud et al. [[9]] present a valuable study analyzing cardiovascular changes in patients with post-acute sequelae of SARS-CoV-2 infection. The authors performed a retrospective analysis from medical records of 100 consecutive adult patients referred to the Post-COVID Cardiology Clinic at Washington University School of Medicine in St. Louis, Missouri, USA, between September 2020 and May 2021. The Clinic had been established to evaluate and treat individuals with previous or new cardiovascular symptoms following acute COVID-19. Baseline data were collected from a chart review of previous visits when available. Cardiovascular symptoms, vital signs, treatments, and follow-up were evaluated. Laboratory analyzes included inflammatory and cardiac biomarkers, electrocardiogram, Holter monitoring, and transthoracic echocardiogram (TTE).
219	CaV215	PESE	Douglas B. Kell ORCID logo ; Etheresia Pretorius ORCID logo	The potential role of ischaemia–reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implications	https://doi.org/10.1042/BCJ20220154	Published	August 31 2022	Review	https://portlandpress.com/biochemj/article/479/16/1653/231696/The-potential-role-of-ischaemia-reperfusion-injury	Ischaemia–reperfusion (I–R) injury, initiated via bursts of reactive oxygen species produced during the reoxygenation phase following hypoxia, is well known in a variety of acute circumstances. We argue here that I–R injury also underpins elements of the pathology of a variety of chronic, inflammatory diseases, including rheumatoid arthritis, ME/CFS and, our chief focus and most proximally, Long COVID. Ischaemia may be initiated via fibrin amyloid microclot blockage of capillaries, for instance as exercise is started; reperfusion is a necessary corollary when it finishes. We rehearse the mechanistic evidence for these occurrences here, in terms of their manifestation as oxidative stress, hyperinflammation, mast cell activation, the production of marker metabolites and related activities. Such microclot-based phenomena can explain both the breathlessness/fatigue and the post-exertional malaise that may be observed in these conditions, as well as many other observables. The recognition of these processes implies, mechanistically, that therapeutic benefit is potentially to be had from antioxidants, from anti-inflammatories, from iron chelators, and via suitable, safe fibrinolytics, and/or anti-clotting agents. We review the considerable existing evidence that is consistent with this, and with the biochemical mechanisms involved.
220	CaV216		Dr. xing chang, Dr. Nur Izzah Ismail, Dr. Attaur Rahman, Prof. Dachun Xu, Prof. Renee Wan Yi Chan, Prof. Sang-Ging Ong, and Prof. SANG-BING ONG	Long COVID-19 and the heart: is cardiac mitochondria the missing link?	https://doi.org/10.1089/ars.2022.0126	Published	2 Sep 2022	Article	https://www.liebertpub.com/doi/abs/10.1089/ars.2022.0126	Significance: Although COVID-19 has now gradually been categorized as an endemic, the long-term effect of COVID-19 in causing multi-organ disorders, including a perturbed cardiovascular system, is beginning to gain attention. Nonetheless, the underlying mechanism triggering post-COVID-19 cardiovascular dysfunction remains enigmatic. Are cardiac mitochondria the key to mediating cardiac dysfunction post-SARS-CoV-2 infection? Recent Advances: Cardiovascular complications post-SARS-CoV-2 infection include myocarditis, myocardial injury, microvascular injury, pericarditis, acute coronary syndrome, and arrhythmias (fast or slow). Different types of myocardial damage or reduced heart function can occur after a lung infection or lung injury. Myocardial/coronary injury or decreased cardiac function is directly associated with increased mortality after hospital discharge in patients with COVID-19. The incidence of adverse cardiovascular events increases even in recovered COVID-19 patients. Disrupted cardiac mitochondria post-infection have been postulated to lead to cardiovascular dysfunction in the COVID-19 patients. Further studies are crucial to unravel the association between SARS-CoV-2 infection, mitochondrial dysfunction and ensuing cardiovascular disorders. Critical Issues: The relationship between COVID-19 and myocardial injury or cardiovascular dysfunction has not been elucidated. In particular, the role of the cardiac mitochondria in this association remains to be determined. Future Directions: Elucidating the cause of cardiac mitochondrial dysfunction post-SARS-CoV-2 infection may allow a deeper understanding of long COVID-19 and resulting cardiovascular disorders, thus providing a potential therapeutic target
221	CaV217		Valentina O. Puntmann, Simon Martin, Anastasia Shchendrygina, Jedrzej Hoffmann, Mame Madjiguène Ka, Eleni Giokoglu, Byambasuren Vanchin, Niels Holm, Argyro Karyou, Gerald S. Laux, Christophe Arendt, Philipp De Leuw, Kai Zacharowski, Yascha Khodamoradi, Maria J. G. T. Vehreschild, Gernot Rohde, Andreas M. Zeiher, Thomas J. Vogl, Carsten Schwenke & Eike Nagel	Long-term cardiac pathology in individuals with mild initial COVID-19 illness	https://doi.org/10.1038/s41591-022-02000-0	Published	05 September 2022	Study	https://www.nature.com/articles/s41591-022-02000-0	Cardiac symptoms are increasingly recognized as late complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in previously well individuals with mild initial illness, but the underlying pathophysiology leading to long-term cardiac symptoms remains unclear. In this study, we conducted serial cardiac assessments in a selected population of individuals with Coronavirus Disease 2019 (COVID-19) with no previous cardiac disease or notable comorbidities by measuring blood biomarkers of heart injury or dysfunction and by performing magnetic resonance imaging. Baseline measurements from 346 individuals with COVID-19 (52% females) were obtained at a median of 109 days (interquartile range (IQR), 77–177 days) after infection, when 73% of participants reported cardiac symptoms, such as exertional dyspnea (62%), palpitations (28%), atypical chest pain (27%) and syncope (3%). Symptomatic individuals had higher heart rates and higher imaging values or contrast agent accumulation, denoting inflammatory cardiac involvement, compared to asymptomatic individuals. Structural heart disease or high levels of biomarkers of cardiac injury or dysfunction were rare in symptomatic individuals. At follow-up (329 days (IQR, 274–383 days) after infection), 57% of participants had persistent cardiac symptoms. Diffuse myocardial edema was more pronounced in participants who remained symptomatic at follow-up as compared to those who improved. Female gender and diffuse myocardial involvement on baseline imaging independently predicted the presence of cardiac symptoms at follow-up. Ongoing inflammatory cardiac involvement may, at least in part, explain the lingering cardiac symptoms in previously well individuals with mild initial COVID-19 illness.
222	CaV218		Stefano Rigo, Vasile Urechie, Andre Diedrich, Luis E Okamoto, Italo Biaggioni and Cyndya A Shibao	Abstract 022: Impaired Parasympathetic Cardiac Modulation In Long-COVID Postural Tachycardia Syndrome	https://doi.org/10.1161/hyp.79.suppl_1.022	Published	7 Sep 2022	Study	https://www.ahajournals.org/doi/abs/10.1161/hyp.79.suppl_1.022	About 1 out of 10 patients infected with Sars-CoV2 have persistent symptoms beyond 4 weeks and some of them meet diagnostic criteria for postural tachycardia syndrome (Long-COVID POTS). The pathophysiology of Long-COVID POTS is unknown, but autonomic dysfunction may play a role. We hypothesize Long-COVID POTS patients have impaired cardiovascular autonomic reflexes and cardiac sympathovagal balance. We conducted a case-control study with patients recruited from the Vanderbilt Autonomic Dysfunction Center and an historical population of healthy controls. Hemodynamic parameters were measured before and during 75° head up tilt. Supine ECG and finger blood pressure were continuously measured for spontaneous heart rate variability analysis. The Low Frequency (0.04-0.15Hz, LFRR) and High Frequency (0.15-0.4 Hz, HFRR) oscillatory modulations of sino-atrial node discharge were computed. We included 14 Long-COVID POTS patients and 15 controls matched by age (34±11 vs 28±7; p=0.09) and BMI (26.1±5.3 vs 23.0±2.6; p=0.06). As expected, the orthostatic HR increase was higher in Long-COVID POTS compared to controls (40±18 vs 21±1, p<0.05). Spectral analysis of heart rate variability in 9 patients and 15 controls (Figure) showed that Long-COVID POTS had reduced HFRR (363±420 vs 933±1000 ms2; p<0.05) and similar LFRR (798±596 vs 962±1075 ms2; p=0.68), resulting in a greater LF/HF ratio (3.7±2.9 vs 1.4±1.3; p<0.05). Patients with Long-COVID POTS have reduced markers of cardiovagal modulation, but normal cardiac sympathetic activation. Our results suggest that parasympathetic dysfunction contributes to the pathophysiology of Long-COVID POTS.
223	CaV219		Amanda Verma,Tarun Ramayya,Anand Upadhyaya,Ines Valenta,Maureen Lyons,Jonas Marschall,Farrokh Dehdashti,Robert J. Gropler,Pamela K. Woodard,Thomas Hellmut Schindler	Post COVID-19 syndrome with impairment of flow-mediated epicardial vasodilation and flow reserve	https://doi.org/10.1111/eci.13871	Published	09 September 2022	Study	https://onlinelibrary.wiley.com/doi/full/10.1111/eci.13871	Aims The aim of this study is to evaluate whether post-acute sequelae of COVID-19 cardiovascular syndrome (PASC-CVS) is associated with alterations in coronary circulatory function. Materials and Methods In individuals with PASC-CVS but without known cardiovascular risk factors (n = 23) and in healthy controls (CON, n = 23), myocardial blood flow (MBF) was assessed with 13N-ammonia and PET/CT in mL/g/min during regadenoson-stimulated hyperemia, at rest, and the global myocardial flow reserve (MFR) was calculated. MBF was also measured in the mid and mid-distal myocardium of the left ventricle (LV). The Δ longitudinal MBF gradient (hyperemia minus rest) as a reflection of an impairment of flow-mediated epicardial vasodilation, was calculated. Results Resting MBF was significantly higher in PASC-CVS than in CON (1.29 ± 0.27 vs. 1.08 ± 0.20 ml/g/min, p ≤ .024), while hyperemic MBFs did not differ significantly among groups (2.46 ± 0.53 and 2.40 ± 0.34 ml/g/min, p = .621). The MFR was significantly less in PASC-CVS than in CON (1.97 ± 0.54 vs. 2.27 ± 0.43, p ≤ .031). In addition, there was a Δ longitudinal MBF gradient in PASC-CVS, not observed in CON (−0.17 ± 0.18 vs. 0.04 ± 0.11 ml/g/min, p < .0001). Conclusions Post-acute sequelae of COVID-19 cardiovascular syndrome may be associated with an impairment of flow-mediated epicardial vasodilation, while reductions in coronary vasodilator capacity appear predominantly related to increases in resting flow in women deserving further investigations.
224	CaV220		Miroslawa Gorecka, Nicholas Jex, Sharmaine Thirunavukarasu, Amrit Chowdhary, Joanna Corrado, Jennifer Davison, Rachel Tarrant, Ana-Maria Poenar, Noor Sharrack, Amy Parkin, Manoj Sivan, Peter P. Swoboda, Hui Xue, Vassilios Vassiliou, Peter Kellman, Sven Plein, Stephen J. Halpin, Alexander D. Simms, John P. Greenwood & Eylem Levelt	Cardiovascular magnetic resonance imaging and spectroscopy in clinical long-COVID-19 syndrome: a prospective case–control study	https://doi.org/10.1186/s12968-022-00887-9	Published	12 September 2022	Study	https://link.springer.com/article/10.1186/s12968-022-00887-9	Background The underlying pathophysiology of post-coronavirus disease 2019 (long-COVID-19) syndrome remains unknown, but increased cardiometabolic demand and state of mitochondrial dysfunction have emerged as candidate mechanisms. Cardiovascular magnetic resonance (CMR) provides insight into pathophysiological mechanisms underlying cardiovascular disease and 31-phosphorus CMR spectroscopy (31P-CMRS) allows non-invasive assessment of the myocardial energetic state. The main aim of the study was to assess whether long COVID-19 syndrome is associated with abnormalities of myocardial structure, function, perfusion and energy metabolism. Methods Prospective case–control study. A total of 20 patients with a clinical diagnosis of long COVID-19 syndrome (seropositive) and no prior underlying cardiovascular disease (CVD) and 10 matching healthy controls underwent 31P-CMRS and CMR at 3T at a single time point. All patients had been symptomatic with acute COVID-19, but none required hospital admission. Results Between the long COVID-19 syndrome patients and matched contemporary healthy controls there were no differences in myocardial energetics (phosphocreatine to ATP ratio), in cardiac structure (biventricular volumes), function (biventricular ejection fractions, global longitudinal strain), tissue characterization (T1 mapping and late gadolinium enhancement) or perfusion (myocardial rest and stress blood flow, myocardial perfusion reserve). One patient with long COVID-19 syndrome showed subepicardial hyperenhancement on late gadolinium enhancement imaging compatible with prior myocarditis, but no accompanying abnormality in cardiac size, function, perfusion, extracellular volume fraction, native T1, T2 or cardiac energetics. Conclusions In this prospective case–control study, the overwhelming majority of patients with a clinical long COVID-19 syndrome with no prior CVD did not exhibit any abnormalities in myocardial energetics, structure, function, blood flow or tissue characteristics.
225	CaV221		Arneaux Kruger, Mare Vlok, Simone Turner, Chantelle Venter, Gert Jacobus Laubscher, Douglas B. Kell & Etheresia Pretorius	Proteomics of fibrin amyloid microclots in long COVID/post-acute sequelae of COVID-19 (PASC) shows many entrapped pro-inflammatory molecules that may also contribute to a failed fibrinolytic system	https://doi.org/10.1186/s12933-022-01623-4	Published	21 September 2022	Study	https://cardiab.biomedcentral.com/articles/10.1186/s12933-022-01623-4	Background Post-acute sequelae of COVID-19 (PASC), also now known as long COVID, has become a major global health and economic burden. Previously, we provided evidence that there is a significant insoluble fibrin amyloid microclot load in the circulation of individuals with long COVID, and that these microclots entrap a substantial number of inflammatory molecules, including those that might prevent clot breakdown. Scientifically, the most challenging aspect of this debilitating condition is that traditional pathology tests such as a serum CRP (C-reactive protein) may not show any significant abnormal inflammatory markers, albeit these tests measure only the soluble inflammatory molecules. Elevated, or abnormal soluble biomarkers such as IL-6, D-Dimer or fibrinogen indicate an increased risk for thrombosis or a host immune response in COVID-19. The absence of biomarkers in standard pathology tests, result in a significant amount of confusion for patients and clinicians, as patients are extremely sick or even bed-ridden but with no regular identifiable reason for their disease. Biomarkers that are currently available cannot detect the molecules present in the microclots we identified and are therefore unable to confirm their presence or the mechanisms that drive their formation. Methods Here we analysed the protein content of double-digested microclots of 99 long COVID patients and 29 healthy controls. The patients suffering from long COVID reported their symptoms through a questionnaire completed by themselves or their attending physician. Results Our long COVID cohort’s symptoms were found to be in line with global findings, where the most prevalent symptoms were constant fatigue (74%,) cognitive impairment (71%) and depression and anxiety (30%). Our most noteworthy findings were a reduced level of plasma Kallikrein compared to our controls, an increased level of platelet factor 4 (PF4) von Willebrand factor (VWF), and a marginally increased level of α-2 antiplasmin (α-2-AP). We also found a significant presence of antibodies entrapped inside these microclots. Conclusion Our results confirm the presence of pro-inflammatory molecules that may also contribute to a failed fibrinolysis phenomenon, which could possibly explain why individuals with long COVID suffer from chronic fatigue, dyspnoea, or cognitive impairment. In addition, significant platelet hyperactivation was noted. Hyperactivation will result in the granular content of platelets being shed into the circulation, including PF4. Overall, our results provide further evidence of both a failed fibrinolytic system in long COVID/PASC and the entrapment of many proteins whose presence might otherwise go unrecorded. These findings might have significant implications for individuals with pre-existing comorbidities, including cardiovascular disease and type 2 diabetes.
226	CaV222		Valentina Puntmann and Eike Nagel	Lingering cardiac involvement in previously well people after mild COVID-19	https://doi.org/10.1038/s41591-022-02002-y	Published	26 September 2022	Study	https://www.nature.com/articles/s41591-022-02002-y	Serial heart MRI scans conducted in previously well people with mild initial COVID-19 illness suggest that lingering cardiac symptoms may be explained, at least in part, by ongoing mild cardiac inflammation.
227	CaV223		DurreAdenaSufianZaheerbRohitKumarcSwatiRajdTaibaKhaneShilpiVarshneyf	Beyond COVID-19 and SARS-CoV-2, cardiovascular outcomes of “long covid” from a pathological perspective – a look back and road ahead	https://doi.org/10.1016/j.prp.2022.154144	Published	29 September 2022	Review	https://www.sciencedirect.com/science/article/pii/S0344033822003880	With the decrease in severity of COVID-19 there is a sense of relief in the general population. However, there has been an increased incidence of cardiovascular and other organ complications post-infection, which have raised concerns about long COVID. The term “long COVID” was first used by Perego on social media to denote the persistence of symptoms weeks or months after initial SARS-CoV-2 infection and the term ‘long haulers’ was first described by Watson and by Yong to identify post-COVID conditions. There has been an increased incidence of sudden cardiac death and MI post-COVID-19 in healthy individuals, sports persons and prominent movie stars. Potential mechanisms contributing to the pathophysiology of post-acute COVID-19 may include 1) Damage to tissues and cells that are important for blood flow, so clotting of blood is increased. 2) Persistence of fragments of virus or its sub-particles/ protein material in a wide range of body sites and, 3) an immune system gone haywire. As the majority of countries across the globe are easing coronavirus precautionary measures, there is an urgent need by health care organizations and policymakers worldwide to generate awareness by educating the public at large, about the ill effects of long-COVID and varied types of post-acute sequelae of COVID-19.
228	CaV224		Pin Li, Yi Lee, Qasim Jehangir, Chun-Hui Lin, Geetha Krishnamoorthy, Anupam A. Sule, Abdul R. Halabi, Kiritkumar Patel, Laila Poisson & Girish B. Nair	SARS-COV-ATE risk assessment model for arterial thromboembolism in COVID-19	https://doi.org/10.1038/s41598-022-18510-3	Published	28 September 2022	Study	https://www.nature.com/articles/s41598-022-18510-3	Patients with SARS-CoV-2 infection are at an increased risk of cardiovascular and thrombotic complications conferring an extremely poor prognosis. COVID-19 infection is known to be an independent risk factor for acute ischemic stroke and myocardial infarction (MI). We developed a risk assessment model (RAM) to stratify hospitalized COVID-19 patients for arterial thromboembolism (ATE). This multicenter, retrospective study included adult COVID-19 patients admitted between 3/1/2020 and 9/5/2021. Among 3531 patients from the training cohort, 15.5% developed acute in-hospital ATE, including stroke, MI, and other ATE, compared to 13.4% in the validation cohort. The 16-item final score was named SARS-COV-ATE (Sex: male = 1, Age [40–59 = 2, > 60 = 4], Race: non-African American = 1, Smoking = 1 and Systolic blood pressure elevation = 1, Creatinine elevation = 1; Over the range: leukocytes/lactate dehydrogenase/interleukin-6, B-type natriuretic peptide = 1, Vascular disease (cardiovascular/cerebrovascular = 1), Aspartate aminotransferase = 1, Troponin-I [> 0.04 ng/mL = 1, troponin-I > 0.09 ng/mL = 3], Electrolytes derangement [magnesium/potassium = 1]). RAM had a good discrimination (training AUC 0.777, 0.756–0.797; validation AUC 0.766, 0.741–0.790). The validation cohort was stratified as low-risk (score 0–8), intermediate-risk (score 9–13), and high-risk groups (score ≥ 14), with the incidence of ATE 2.4%, 12.8%, and 33.8%, respectively. Our novel prediction model based on 16 standardized, commonly available parameters showed good performance in identifying COVID-19 patients at risk for ATE on admission.
229	CaV225		ManuelSerranoaGerardEspinosabAntonioSerranoaRicardCerverab	COVID-19 and the antiphospholipid syndrome	https://doi.org/10.1016/j.autrev.2022.103206	Published	3 October 2022	Review	https://www.sciencedirect.com/science/article/pii/S1568997222001768	Highlights •Coagulopathy secondary to COVID-19 occurs in the context of an uncontrolled inflammatory response, reminiscent of APS, especially in its catastrophic form. •During the first days of infection, there is an aPL-independent mechanism secondary to SARS-CoV2 infection. •The aPL carriers would have an additional later risk of thrombosis. Abstract Coronavirus disease 2019 (COVID-19) has resulted in a global pandemic. Most COVID-19 patients are asymptomatic or have flu-like symptoms. However, around 15% of the patients may have severe disease, including unilateral or bilateral pneumonia with acute respiratory distress syndrome and progressive hypoxemia that may require mechanical ventilation assistance. A systemic inflammatory response syndrome occurs in the most severe forms of COVID-19, with multiorgan involvement which can be life threatening caused by a cytokine storm. Although what best characterizes COVID-19 are the manifestations of the respiratory system, it has been shown that it also acts at the cardiovascular level, producing coagulation abnormalities, which causes thrombotic events mainly in the arteries/arterioles, microcirculation and venous system, and potentially increased mortality risk. This multiorgan vascular disease overlaps with other known microangiopathies, such as thrombotic microangiopathy or paroxysmal nocturnal hemoglobinuria, where complement overactivation plays an important role in the pathophysiology of thrombosis. Furthermore, coagulopathy secondary to COVID-19 occurs in the context of an uncontrolled inflammatory response, reminiscent of APS, especially in its catastrophic form. This review summarizes the current knowledge regarding the relationship between COVID-19 and the APS.
230	CaV226		Maitray A. Patel, Michael J. Knauer, Michael Nicholson, Mark Daley, Logan R. Van Nynatten, Claudio Martin, Eric K. Patterson, Gediminas Cepinskas, Shannon L. Seney, Verena Dobretzberger, Markus Miholits, Brian Webb & Douglas D. Fraser	Elevated vascular transformation blood biomarkers in Long-COVID indicate angiogenesis as a key pathophysiological mechanism	https://doi.org/10.1186/s10020-022-00548-8	Published	10 October 2022	Study	https://link.springer.com/article/10.1186/s10020-022-00548-8	Background Long-COVID is characterized by prolonged, diffuse symptoms months after acute COVID-19. Accurate diagnosis and targeted therapies for Long-COVID are lacking. We investigated vascular transformation biomarkers in Long-COVID patients. Methods A case–control study utilizing Long-COVID patients, one to six months (median 98.5 days) post-infection, with multiplex immunoassay measurement of sixteen blood biomarkers of vascular transformation, including ANG-1, P-SEL, MMP-1, VE-Cad, Syn-1, Endoglin, PECAM-1, VEGF-A, ICAM-1, VLA-4, E-SEL, thrombomodulin, VEGF-R2, VEGF-R3, VCAM-1 and VEGF-D. Results Fourteen vasculature transformation blood biomarkers were significantly elevated in Long-COVID outpatients, versus acutely ill COVID-19 inpatients and healthy controls subjects (P < 0.05). A unique two biomarker profile consisting of ANG-1/P-SEL was developed with machine learning, providing a classification accuracy for Long-COVID status of 96%. Individually, ANG-1 and P-SEL had excellent sensitivity and specificity for Long-COVID status (AUC = 1.00, P < 0.0001; validated in a secondary cohort). Specific to Long-COVID, ANG-1 levels were associated with female sex and a lack of disease interventions at follow-up (P < 0.05). Conclusions Long-COVID patients suffer prolonged, diffuse symptoms and poorer health. Vascular transformation blood biomarkers were significantly elevated in Long-COVID, with angiogenesis markers (ANG-1/P-SEL) providing classification accuracy of 96%. Vascular transformation blood biomarkers hold potential for diagnostics, and modulators of angiogenesis may have therapeutic efficacy.
231	CaV227		S Lampsas, E Oikonomou, N Souvaliotis, A Goliopoulou, G A Papamikroulis, A Anastasiou, P Theofilis, G Zakynthinos, I Gialamas, P Pantelidis, M A Gounaridi, A Tsatsaragkou, G Siasos, D Tousoulis, M Vavuranakis	Impaired heart rate variability one and six months post acute COVID-19	https://doi.org/10.1093/eurheartj/ehac544.402	Published	03 October 2022	Study	https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.402/6743966	Background Long COVID-19 syndrome is an increasingly recognized problem. Post-infectious cardiac autonomic dysfunction is commonly reported. This study aims to evaluate autonomic dysfunction by means of Heart rate variability (HRV) on post-COVID-19 patients. Methods Hospitalized patients for COVID-19 (either at the medical ward or Intensive Care Unit (ICU)) were followed up at 1 and 6 months after hospital discharge. Medical history and clinical information were collected. HRV was assessed by 24-hour ambulatory electrocardiography Holter, with the measure of the standard deviation of normal RR intervals in 24 h, ms (SDNN). The comparison was conducted with age and sex-matched non-COVID-19 controls. Results Thirty-four patients hospitalized with COVID-19 (20.6% admitted in ICU) were examined 1-month and 6-months post-hospital discharge. SDNN was significantly (p<0.001) reduced in the COVID-19 group (111±23 ms) compared to the control subjects (152±24 ms) 1-month after discharge. Subgroup analysis between COVID-19 group revealed that ICU subjects presented significantly (p<0.001) reduced SDNN compared to the medical ward, respectively (83±20 ms vs. 118±17 ms). At 6-months, an improvement was noted at SDNN 24h (6-month: 133±24 vs. control: 151±24 ms, p=0.004; 1-month: 111±23 ms vs. 6-month: 133±24 ms, p<0.001). Also at 6-months, ICU subjects noted significantly (p=0.003) reduced SDNN 24h compared to medical ward subjects (107±17 ms vs. 140±20 ms). On the 6-months follow-up, 32% of the subjects had “long-COVID-19” symptoms. Subjects with long COVID-19 symptoms had low SDNN values (“long-COVID-19”: 112±17 ms vs. non-“long-COVID-19”: 142±20 ms, p=0.001) Conclusion Patients hospitalized for COVID-19 have reduced SDNN, at one month post-hospital discharge which is improved at the six months follow-up. These findings emphasize the increased sympathetic drive activity in the post-acute COVID-19 phase and imply a link between autonomic dysfunction and long COVID-19.
232	CaV228		V Arevalos Rivas, L Ortega-Paz, D Fernandez-Rodriguez, V A Jimenez-Diaz, J Baneras Rius, G Campo, J F Diaz, C Scardino, M Rodriguez-Santamarta, N Gonzalo, A Perginotti, F Alfonso, I Amat-Santos, M Sabate, S Brugaletta	Long-term effects of coronavirus disease 2019 on the cardiovascular system: the CV COVID-19 registry	https://doi.org/10.1093/eurheartj/ehac544.2859	Published	03 October 2022	Study	https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.2859/6745820	Background Patients with COVID-19 have an increased risk of cardiovascular adverse events during the acute phase. However, the long-term cardiovascular outcomes are unknown. Objective We aimed to determine the long-term effects of COVID-19 in the cardiovascular system. Methods This is a multicenter, observational, retrospective registry conducted at 17 centers in Spain and Italy. Consecutive patients older than 18 years who underwent a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) for SARS-CoV2 in the participating institutions were included. Patients were classified into two groups, according to the results of the RT-PCR: COVID-19 positive or negative. The primary outcome was cardiovascular (CV) death at 1-year. The secondary outcomes included acute myocardial infarction, stroke, heart failure hospitalization, pulmonary embolism, and serious cardiac arrhythmias at 1-year. Outcomes were compared between the two groups. An independent clinical event committee adjudicated events. Results A total of 4427 patients were included, 3578 (80.8%) patients with COVID-19 and 849 (19.2%) without COVID-19. COVID-19 patients were older, had a higher rate of classical cardiovascular risk factors, except for active smoking, and had fewer comorbidities. At a median time of 13.5 (IQR 11.8–15.8) months, after an adjustment by baseline characteristics, there was no difference in CV death (1.4% vs. 1.1%; HR 1.03 [0.49–2.18]; p=0.941) between patients with COVID-19 and without. However, COVID-19 patients experienced higher rate of venous thromboembolism (VTE) (3.9% vs. 0.6%, HR 6.11 [2.46–15.16]; p=0.001), major bleeding (2.9% vs. 0.5%, HR 5.38 [1.95–14.84]; p=0.001), and serious cardiac arrhythmias (2.6% vs. 0.9%, HR 2.25 [1.07–4.73]; p=0.033). During follow-up, between discharge and end of follow-up, COVID-19 patients did not experience a higher risk of adverse cardiovascular outcomes (composite of CV death, any MI, ischemic stroke, systemic arterial thrombosis, VTE, heart failure hospitalization, or any serious arrhythmia) compared to patients without (HR 0.80; [0.53–1.21]; p=0.298). Conclusions At 1-year follow-up, COVID-19 was not associated with an increased risk of cardiovascular death but with a higher risk of VTE events, major bleeding, and serious cardiac arrhythmias. COVID-19 was not associated with a higher risk of adverse cardiovascular events during follow-up.
233	CaV229		Suo-wen Xu, Iqra Ilyas & Jian-ping Weng	Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies	https://doi.org/10.1038/s41401-022-00998-0	Published	17 October 2022	Review	https://www.nature.com/articles/s41401-022-00998-0	The fight against coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is still raging. However, the pathophysiology of acute and post-acute manifestations of COVID-19 (long COVID-19) is understudied. Endothelial cells are sentinels lining the innermost layer of blood vessel that gatekeep micro- and macro-vascular health by sensing pathogen/danger signals and secreting vasoactive molecules. SARS-CoV-2 infection primarily affects the pulmonary system, but accumulating evidence suggests that it also affects the pan-vasculature in the extrapulmonary systems by directly (via virus infection) or indirectly (via cytokine storm), causing endothelial dysfunction (endotheliitis, endothelialitis and endotheliopathy) and multi-organ injury. Mounting evidence suggests that SARS-CoV-2 infection leads to multiple instances of endothelial dysfunction, including reduced nitric oxide (NO) bioavailability, oxidative stress, endothelial injury, glycocalyx/barrier disruption, hyperpermeability, inflammation/leukocyte adhesion, senescence, endothelial-to-mesenchymal transition (EndoMT), hypercoagulability, thrombosis and many others. Thus, COVID-19 is deemed as a (micro)vascular and endothelial disease. Of translational relevance, several candidate drugs which are endothelial protective have been shown to improve clinical manifestations of COVID-19 patients. The purpose of this review is to provide a latest summary of biomarkers associated with endothelial cell activation in COVID-19 and offer mechanistic insights into the molecular basis of endothelial activation/dysfunction in macro- and micro-vasculature of COVID-19 patients. We envisage further development of cellular models and suitable animal models mimicking endothelial dysfunction aspect of COVID-19 being able to accelerate the discovery of new drugs targeting endothelial dysfunction in pan-vasculature from COVID-19 patients.
234	CaV230		F Santoro, N Di Nunno, A Centola, R Cetera, V Le Rose, J Perez-Villacastin, A Fernandez-Ortiz, I Nunez Gil, N D Brunetti	Long-term mayor adverse cardiovascular events after COVID-19 infection: a clinical score from a cohort of 2575 patients enrolled in the multicenter international HOPE 2 registry	https://doi.org/10.1093/eurheartj/ehac544.1334	Published	03 October 2022	Study	https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.1334/6744487	Background Long-term consequences of COVID-19 infection are still partly known. According to some studies several patients may experience long term symptoms; however, predictors of long-term mayor adverse cardiovascular events among (MACE) patients with previous COVID-19 infection are . Aim of the study To derive a simple clinical score for risk prediction of long-term MACE among patients with previous covid-19 infection. Methods 2575 consecutive patients were enrolled in a multicenter, international registry (HOPE-2) from February 2020 to April 2021, and followed-up at long-term. A risk score was developed using a stepwise multivariable regression analysis. Results Out of 2575 patients enrolled in the HOPE-2 registry, 1481 (58%) were male, with mean age of 60±16 years. At long-term follow-up overall rate of MACE was 7.9% (202 of 2545 pts, 3.3% death, 2.4% inflammatory myocardial disease, 1.3% arterial thrombosis, 0.7% venous thrombosis). After multivariable regression analysis, independent predictors of MACE were used to derive a simple prognostic score: The HOPE-2 prognostic score may be calculated by giving: ½ point for every 10 years of age, 2 points for previous cardiovascular disease, 1 point for increased troponin serum levels during hospitalization, 2.5 points for heart failure and 3 points for sepsis during hospitalization, −1.5 points for vaccination at follow-up. Score accuracy at receiver operating characteristic curve analysis was 0.81. Stratification into 3 risk groups (0–2, 3–5, and >5 points) classified into low, intermediate and high risk. The observed MACE rates were 0.5% for low-risk patients, 4% for intermediate-risk patients, and 19.5% for high-risk patients (log-Rank p<0.001, Figure 1). Conclusions The HOPE-2 prognostic score may be useful for long-term risk stratification in patients with previous COVID-19 infection. High-risk patients may require a strict cardiological follow-up.
235	CaV231		M Camera, M Brambilla, P Canzano, A Becchetti, M Conti, P G Agostoni, M Pengo, E Tortorici, M E Mancini, D Andreini, A Bonomi, G F Parati	Long COVID-19 syndrome: association of cardiopulmonary impairment with a persistent platelet activation	https://doi.org/10.1093/eurheartj/ehac544.3038	Published	03 October 2022	Study	https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.3038/6746301	Background A considerable proportion of patients do not fully recover from COVID-19 infection and report symptoms that persist beyond the initial phase of infection: this condition is defined long-COVID-19 syndrome (LCS). LCS can involve lungs as well as several extrapulmonary organs, including the cardiovascular system. The risk and 1-year burden of cardiovascular diseases (CVD) is increased in COVID-19 survivors, even in subjects at low risk of CVD. Recently, we documented that acute COVID-19 infection induces altered platelet activation state characterized by a prothrombotic phenotype and by the formation of platelet-leukocyte aggregates (PLA), that may be involved in the pulmonary microthrombi found in autoptic specimens. No data are yet available on the contribution of platelet activation to residual pulmonary impairment and procoagulant potential in LCS patients. Purpose To study platelet activation status, microvesicle (MV) profile, platelet thrombin generation capacity (pTGC) in LCS patients enrolled at 6 months after resolution of the acute phase (6mo-FU), compared to acute COVID-19 infection patients. Methods 6mo-FU COVID-19 patients (n=24) with established LCS were enrolled at Centro Cardiologico Monzino. Residual pulmonary impairment was assessed by Cardiopulmonary Exercise Testing (CPET) and 64-rows-CT scan evaluation. Platelet activation (P-selectin, Tissue Factor [TF] and PLA) and MV profile were assessed by flow cytometry; pTGC by calibrated automated thrombogram. 46 patients enrolled during acute COVID-19 infection and 46 healthy subjects (HS) were used for comparison. Results Dispnea in LCS patients was confirmed by CPET showing compromised alveolus-capillary membrane diffusion and residual pulmonary impairment. TF+-platelet and -MV levels were 3-fold (1.5% [1.2–2.9] vs 2.4% [1.6–5.7]) and 2-fold (217/μl [137–275] vs 435/μl [275–633]) lower at 6mo-FU compared to acute phase, being comparable to HS. pTGC behaved similarly. At 6mo-FU, the MV profile, in terms of total number and cell origin, returned to physiological levels. Conversely, although lower than that measured in acute phase, a 2.5-fold higher platelet P-selectin expression (6.9% [3–13.5] vs 11.7% [5.2–18.9]) and PLA formation (35.5% [27.4–46.8] vs 67.7% [45.7–85.3]) was observed at 6mo-FU compared to HS. Interestingly, a significant correlation between PLA formation and residual pulmonary impairment was observed (r=−0.423; p=0.02). Conclusion These data strengthen the hypothesis that the presence of PLA in the bloodstream, and thus also in the pulmonary microcirculation, may contribute to support pulmonary dysfunction still observed in LCS patients.
236	CaV232		R A Xuereb, A Gatt, K Vella, R G Xuereb, C J Barbara, S Fava, C J Magri	Long COVID syndrome: a case-control study	https://doi.org/10.1093/eurheartj/ehac544.2836	Published	03 October 2022	Study	https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.2836/6745876	Background Cardiovascular complications are rapidly emerging as a major threat in COVID-19 infection. Nonetheless, the mechanisms underlying the disproportionate effect of SARS-CoV-2 infection on patients with cardiovascular comorbidities remain incompletely understood. Purpose To assess whether COVID-19 infection has an adverse clinical outcome at medium-term follow-up. Methods A case-control study was performed. Cases were subjects who were diagnosed with COVID-19 infection following nasopharyhngeal swabbing. Controls were age- and gender-matched subjects who were not found to be infected with COVID-19 following swabbing and were negative on testing for COVID-19 IgG antibodies. All participants were submitted a standardised questionnaire regarding past medical history. Baseline blood investigations were taken including N-terminal pro–B-type natriuretic peptide (NT-proBNP) and troponin levels. High-sensitivity C-reactive protein (hsCRP) was taken as marker of inflammation and von Willebrand factor (vWF) was taken as marker of endothelial dysfunction. Results 270 subjects were recruited, comprising 174 cases and 96 controls. Of the latter, 21 were found to be COVID-19 IgG positive and were excluded from the analysis. Hence, the study cohort comprised 174 cases and 75 controls. The mean age of the participants was 46.1±13.8 years. The median follow-up was of 173.5 days (IQR 129–193.25 days). There was no statistically significant difference in the baseline demographics between cases and controls with regards age, gender as well as cardiovascular risk factors and underlying medical conditions. Regarding symptomatology at follow-up, there was a statistically significant difference between the groups in deterioration in general condition (p<0.001), shortness of breath (SOB) (p=0.008), fatigue (p=0.044), arthralgia (p<0.001), abnormal taste (p<0.001) and anosmia (p<0.001), all being more frequent in subjects with prior COVID-19 infection. At follow-up, the blood investigations showed that only hsCRP was statistically significantly higher in the cases as compared to the controls (p=0.03, Figure 1). Correlation analysis consequently revealed a negative correlation in both troponin (p=0.013, r=−0.19) and vWF levels (p=0.026, r=−0.169) with time. Finally, the association between the cases experiencing dyspnoea and the blood investigations at follow-up was assessed. Multivariate analysis revealed that COVID-19 positive cases experiencing dyspnoea have significantly higher white cell count (WCC) (OR 1.22, 95% CI 1.02–1.46, p=0.029) and troponin levels (OR 1.15, 95% CI 1.02–1.29, p=0.015) and lower haemoglobin levels at follow-up (OR 0.66, 95% CI 0.5–0.86, p<0.002), Figure 2. Conclusion Patients previously infected with COVID-19 have persistent symptomatology at medium-term follow-up. The role of troponin, together with markers of inflammation and endothelial dysfunction at long-term follow-up merit further investigation.
237	CaV233		P Rasmus, J D Kasprzak, M Chudzik, A Lipert	Anxiety and depression among ambulatory and hospitalized patients with cardiovascular long-COVID-19 presentation referred to cardiology consultation after COVID-19 infection	https://doi.org/10.1093/eurheartj/ehac544.2426	Published	03 October 2022	Study	https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.2426/6746291	Introduction COVID-19 is connected with varying degrees of emotional stress. Patients (pts) who are hospitalized with severe COVID-19 (C19) are located in single rooms without a permanent attendant to prevent contamination. All personnel serving these pts come into contact with patients with personal full-body protective garment. Ambulatory C19 pts, usually with less severe presentation, are treated in more comfortable conditions. Purpose To evaluate the impact of the psychosocial changing conditions on individuals' psyche and to analyse the differences in terms of experienced anxiety and depression among the ambulatory and hospital patients referred to post-C19 cardiology consultation. Methods The study involved 388 pts with persistent cardiovascular symptoms, including 198 ambulatory patients (130 females and 68 males) and 190 hospital patients (128 females and 62 males) referred to the cardiology consultation (mean age 4.9±12.9 and 50.5±14.4 years, respectively). The data were collected using the specially designed questionnaire related to descriptive characteristics of the patients and to standardized questionnaires: the State-Trait Anxiety Inventory (STAI) and Beck's Depression Inventory (BDI). Results Abnormal psychological metrics was common in the study pts. Indicators of anxiety were lower in the ambulatory than in hospitalized pts (p<0.001). Depression level was also lower in the ambulatory pts (p<0.001). The same differences were statistically significant in both female and male pts subsets. However, anxiety and depression were more pronounced among female than male pts. Very strong positive correlation was observed between anxiety - state and depression among ambulatory patients, both females and males (p<0.05). Conclusions C19 convalescents with persistent symptoms of presumed cardiovascular origin present with abnormal psychological traits including increased anxiety and depression especially in individuals requiring hospital treatment. For this reason, it is necessary to plan the interventions particularly in hospitalized pts to reduce their anxiety and depression levels and to create psychological support programs.
238	CaV234		M Chudzik, M Banach, J Lewek, J Kapusta, A Bielecka-Dabrowa, P Jankowski	Independent predictors of long-COVID in patients without comorbidities. Data from the Polish long-COVID cardiovascular (PoLoCOV-CVD) study	https://doi.org/10.1093/eurheartj/ehac544.2392	Published	03 October 2022	Study	https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.2392/6745656	Coronavirus disease 2019 (COVID-19) is a serious respiratory disease that results from infection with a newly discovered coronavirus (SARS-COV-2). Patients recovering from SARS-COV2 infection complain of persisting symptoms which may lead to chronic fatigue syndrome and as well as many other complications. The vast majority of COVID-19 patients remaining in isolation/quarantine, due to the mild course of the disease, do not require hospitalization. There are many studies describing the course and complications of patients hospitalized due to COVID-19. There is little published data on how nonhospitalized patients get sick and what are the early and late complications of SARS-CoV-2 infection. Little is also known about Long-COVID (LC) in patients without comorbidities. Therefore, the aim of our analysis was to assess the predictors of long-lasting symptoms in patients without comorbidities suffering from COVID-19. Methods Patients ≥18 years of age diagnosed with COVID-19, were examined after full recovery (resolution of clinical symptoms, minimum 14 days after last symptoms). Patient information, course of the disease with symptoms, post-COVID-19 complaints were collected within 4–8 weeks after the COVID-19 recovery. We followed patients for at least 3 months. Patients were ordered the following tests: 12-lead ECG, 24-hour Holter ECG monitoring, 24-hour Holter blood pressure monitoring, Echocardiographic of the Heart assessment, Biochemical tests: lipid profile, glucose or glycosylated hemoglobin level, D-dimers. In patients with indications, the following were additionally performed: Magnetic resonance imaging of the heart, Computed tomography angiography (CTA) of pulmonary vessels, Angio CT of coronary vessels or other diagnostic tests. Results We identified 701 consecutive patients without comorbidities of whom 488 pts completed 3 month follow-up. Comparisons were made between LC group (n=218) and non-LC group (n=270). The demographic and laboratory characteristics of the studied group are presented in Table 1. Patients with severe course of acute phase of COVID-19 developed LC more often (72 vs. 28%, p<0.001). Significant differences regarding sex, weight, height, body mass index were observed. Patients with LC more often presented with dyspnoea, significant fatigue, chest pain, leg muscle pain, headache, arthralgia and chills. No statistically significant difference was observed regarding laboratory tests, 24-hour systolic and diastolic BP and echocardiographic parameters. LC group had higher 24-hour heart rate (77 [72–83] vs. 75 [70–81], p=0.021). Multivariate regression analysis showed that LC patients had higher BMI (odds ratio 1.057, 95% confidence intervals 1.016–1.100) and almost twice as often had a severe course (1.736, 1.071–2.814) and presented with arthralgia in the acute phase (1.901, 1.225–2.950). Conclusions Severe course of COVID-19, BMI, and arthralgia are independently related to long-COVID in patients without comorbidities.
239	CaV235		J Lewek, B Sosnowska, W Adach, K Gryglewska, A Bielecka-Dabrowa, M Maciejewski, M Banach	Post-COVID-19 cardiovascular complications and their association with clinical characteristics, symptoms and comorbidities – the LATE-COVID study	https://doi.org/10.1093/eurheartj/ehac544.2335	Published	03 October 2022	Study	https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.2335/6746129	Background Among many complications of coronavirus disease 2019 (COVID-19) there is a wide range of cardiovascular (CV) problems ranging from mild to severe ones. Even asymptomatic patients and those with mild course of COVID-19 may develop severe CV complications. Factors leading to such state have not been extensively studied so far. Purpose We aimed to assess which factors were linked to the severe complications of COVID-19. Methods We included 200 consecutive patients admitted to the Department of Cardiology and Adult Congenital Heart Diseases of the Polish Mother's Memorial Research Institute (PMMHRI) due to post-Covid cardiovascular complications. SARS-CoV2 infection was confirmed with real-life PCR testing. Laboratory tests, 24-hour ECG monitoring and echocardiography were performed in all patients from the investigated group. For the purposes of our study severe complications were defined as: myocarditis, a decrease of ejection fraction >10% from the pre-disease value, thromboembolic complications, angina pectoris requiring myocardial revascularization and the new onset of atrial fibrillation of supraventricular tachycardia. Some patients presented more than one of the above. Statistical analysis was performed using the software Statistica v.13 (TIBCO Software Inc., Palo Alto, CA, USA). Data were presented as mean ±SD or median (25th-75th percentile) for continuous variables and as proportions for categorical variables. Comparisons between groups were performed using Student's t-test for independent variables and the Mann-Whitney U test or χ2 test with Yates's correction, as appropriate. For all calculations p-values <0.05 were considered statistically significant. Results Finally, we included 200 consecutive patients (aged 54±16 years, 76 males – 38%), hospitalized for COVID-19 complications after a median 3 (2–6) months following the acute phase of infection. On admission patients presented with dyspnea (23%), impairment of exercise tolerance (47%), chest pain (32%), increase in blood pressure (29%), palpitations (25%), weight loss (13%), brain fog (6%), general malaise (11%), headache (5%), limb pain (13%), swelling (14%). Severe complications of COVID-19 were diagnosed in 31 patients (16%).Taking into consideration symptoms, the presence of severe COVID-19 complications was significantly associated with dyspnoea and deterioration of exercise tolerance. In comparison to patients with mild complications, severe ones were linked to age (the older patients, the higher risk), previous history of heart failure and diabetes mellitus. We did not observe statistically significant differences in severity of complications depending on smoking status (Tables 1 and 2). Conclusions Previous history of heart failure and diabetes mellitus as well as symptoms (dyspnoea and deterioration of exercise tolerance) along with older age are related to more severe complications following COVID-19.
240	CaV236		R A Xuereb, R G Xuereb, C Barbara, S Fava, C J Magri	COVID-19 and the autonomic nervous system	https://doi.org/10.1093/eurheartj/ehac544.2422	Published	03 October 2022	Study	https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.2422/6746061	Background COVID-19 infection has been shown to have an adverse impact on the cardiovascular system. Cardiac injury, as indicated by elevated cardiac troponin and NT-proBNP levels have been confirmed in COVID-19 cases. There is still ambivalent data on the effect of left ventricular function. Cases of left ventricular impairment, persistent hypotension, acute myopericarditis, myocarditis, arrhythmia and heart failure have been reported in the short term, but there is a significant lacuna when it comes to medium and long-term follow-up of subjects previously infected with COVID-19. Purpose To assess any residual myocardial and autonomic injury in subjects previously infected with COVID-19 at a median follow-up of 5 months. Methods A case-control study was performed. Cases were randomly selected subjects who were previously diagnosed with COVID-19 infection following nasopharyngeal swabbing. Controls were subjects who had not been found to be infected with COVID-19 following swabbing and were negative for COVID-19 IgG antibodies. All participants were submitted a standardised questionnaire regarding past medical history. Blood investigations were taken including NT-proBNP and troponin I levels. In addition, all participants underwent 24-hour ambulatory blood pressure monitoring (ABPM) and 24-hour ECG monitoring. The latter was used to assess both for underlying arrhythmias as well as heart rate variability (HRV), a measure of autonomic regulation of the heart. All data was analysed using SPSS version 23.0. Results The study comprised 259 subjects, whereby cases included 174 participants while 75 subjects were age- and gender-matched controls. The study cohort was relatively young with a mean age of 46.1±13.8 years. The median follow-up was of approximately 5 months (median 173.5 days, IQR 129–193.25 days). There was no statistically significant difference between cases and controls with regards cardiovascular risk factors and underlying medical conditions. Likewise, there was no difference in blood investigations, including troponin I and NT-proBNP levels at 5-months follow-up. No difference was noted between the two groups in both awake and asleep blood pressure (BP) readings, as well as dipping BP status. No significant arrhythmias were noted in both groups on 24-hour ECG monitoring. However, when assessing for heart rate variability, it was shown that subjects who had been previously infected with COVID-19 exhibited lower root-mean square differences of successive R-R intervals (RMSSD), p=0.028. This indicates poor vagus nerve-mediated autonomic control of the heart. Conclusion Subjects previously infected with COVID-19 exhibited lower HRV as exhibited by low RMSSD as compared to controls. Reduced HRV is a known biomarker for mortality and sudden death in cardiac disease. The possible long-term implications of reduced HRV in subjects previously infected with COVID-19 merits further investigation.
241	CaV237		M L Luchian, A Motoc, B Roosens, J Magne, K Van Den Bussche, H Chameleva, T De Potter, L Houard, S Droogmans, B Cosyns	The impact of long COVID on myocardial work performance	https://doi.org/10.1093/eurheartj/ehac544.012	Published	03 October 2022	Study	https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.012/6743492	Background Long COVID emerged as a new condition, following the acute episode of coronavirus disease 2019 (COVID-19),exerting a significant impact on patients' quality of life [1]. Several studies involving COVID-19 survivors emphasized the presence of cardiac abnormalities following the acute infection. However, data on possible mechanisms associated to long COVID remain limited. Clinical applications of myocardial work (MW) analysis, assessed by transthoracic echocardiography (TTE) have expended recently, showing an additional value in detecting cardiac dysfunction compared to standard parameters such as left ventricle ejection fraction (LVEF) or global longitudinal strain (GLS) in various pathologies, including COVID-19 [2]. Nevertheless, its potential role in detecting subclinical cardiac dysfunction in long COVID remained unexplored. Purpose We assessed the association between subclinical cardiac dysfunction evaluated by global work index (GWI) and global constructive work (GCW) and long COVID. Methods We included 310 COVID-19 patients hospitalized between March and April 2020. All patients were invited to a systematic one-year follow-up, including clinical evaluation, TTE with MW assessment, chest-computed tomography and spirometry. 140 patients completed the follow-up. Normal values for GWI and GCW were defined as 1926±247 mmHg% and 2224±229 mmHg% [3]. The primary endpoint was long COVID, characterized by a cluster of symptoms such as fatigue or dyspnea more than 3 months after the acute infection, without any other explanation. Results 140 patients (57.1±13.9 years, 90 (64.3%) males) had a mean follow-up of 337.1±34.5 days.The mean values of LVEF, GWI and GCW were 55.2±3.2%, 2105.9±403.3 mmHg% and 2377.8±446.2 mmHg%. 83 (61%) patients had long COVID. No significant differences in terms of comorbidities, clinical evaluation and COVID-19 severity were found between patients with and without long COVID. GCW (2276.7±410.3 vs 2516.5±458.6, p=0.006) and GWI (2008.5±358.9 vs 2242.2±427.0, p=0.003) were the only TTE parameters different between patients with and without long COVID. Multivariable regression analysis showed that GWI <1926 mmHg% (OR 6.095; CI: 2.024–18.355, p=0.001) and GCW <2224 mmHg% (OR 3.205; CI: 1.181–8.694, p=0.022) were the only MW parameters independently associated with long COVID, irrespective of age or the severity of the acute infection, at one year. In a subgroup analysis of 77 patients without previous cardiovascular diseases, long COVID was diagnosed in 45 (58.4%)patients. GWI <1926 mmHg% (OR 8.015; CI: 2.149–29.887, p=0.002) remained independently associated with long COVID at 1 year follow-up. Conclusions Long COVID, frequently observed in recovered COVID-19 patients may indicate the presence of subclinical cardiac dysfunction, reflected by a decrease of the left ventricle performance, assessed by GWI and GCW.Long-term follow-up including cardiac screening should be performed in order to identify patients at risk who would benefit from cardiac rehabilitation programs.
242	CaV238		J Niebauer, C Binder, A Iscel, S Klenk, C Capelle, M Kahr, S Cadjo, M Lichtenauer, A Toma, A Zoufaly, S Hoffman, S Charwat-Resl, C Krestan, C Wenisch, D Bonderman	Cardiopulmonary long-term effects in patients after hospitalization due to COVID-19 infection	https://doi.org/10.1093/eurheartj/ehac544.249	Published	03 October 2022	Study	https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.249/6743527	Background Multiple studies have described acute effects of the Covid-19 infection on the heart, but little is known about the long-term cardiac and pulmonary effects and complications after recovery. The aim of this analysis was to deliver a comprehensive report of symptoms and possible long-term impairments after hospitalization because of Covid-19 infection as well as to try to identify predictors for Long-Covid. Methods This was a prospective, multicenter registry study. Patients with verified Covid-19 infection, who were treated as in-patients at our dedicated Covid hospital (Clinic Favoriten), have been included in this study. In all patients, testing was performed approximately 6 months post discharge. During the study visit the following tests and investigations were performed: detailed patient history and clinical examination, transthoracic echocardiography, electrocardiography, cardiac magnetic resonance imaging (MRI), chest computed tomography (CT) scan, lung function test and a comprehensive list of laboratory parameters including cardiac bio markers. Results Between July 2020 and October 2021, 150 patients were recruited. Sixty patients (40%) were female and the average age was 53.5±14.5 years. Of all patients, 92% had been admitted to our general ward and 8% had a severe course of disease, requiring admission to our intensive care unit. Six months after discharge the majority of patients still experienced symptoms and 75% fulfilled the criteria for Long-Covid. Only 24% were completely asymptomatic (figure 1). Echocardiography detected reduced global longitudinal strain (GLS) in 11%. Cardiac MRI revealed pericardial effusion in 18%. Furthermore, cardiac MRI showed signs of former peri- or myocarditis in 4%. Pulmonary CT scans identified post-infectious residues, such as bilateral ground glass opacities and fibrosis in 22%. Exertional dyspnea was associated with either reduced forced vital capacity measured during pulmonary function tests in 11%, with reduced GLS and/or diastolic dysfunction, thus providing evidence for a cardiac and/or pulmonary cause. Independent predictors for Long-Covid were markers of a more severe disease course like length of in-hospital stay, admission to an intensive care unit, type of ventilation as well as higher NT-proBNP and/or troponin levels. Conclusion Even 6 months after recovery from Covid-19 infection, the majority of previously hospitalized patients still suffer from at least one symptom, such as chronic fatigue and/or exertional dyspnea. While there was no association between fatigue and cardiopulmonary abnormalities, impaired lung function, reduced GLS and/or diastolic dysfunction were significantly more prevalent in patients presenting with exertional dyspnea. On chest CT approximately one fifth of all patients showed post infectious changes in chest CT including evidence for myo- and pericarditis as well as accumulation of pericardial effusions.
243	CaV239		L Simonini, S Sbrana, I Foffa, M Baroni, G Catapano, D Chiappino, C Grigoratos, C Marrone, P Losi, F Mannucci, S Salvadori, G Todiere, E Valenti, L Ait-Ali, G D Aquaro	Relationships between plasma cytokine balance and cardiac magnetic resonance imaging in long-term post-COVID follow-up: a cross-sectional preliminary study	https://doi.org/10.1093/eurheartj/ehac544.245	Published	03 October 2022	Study	https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.245/6744716	Background COVID-19 infection can lead to a constellation of long-lasting post-infectious sequelae, including myocardial dysfunction, whose outcome is strongly affected by a fine-tuned balance between pro- and anti-inflammatory systemic immune responses. Plasma cytokines are key mediators of this immunological balance. In this preliminary study we evaluated the cross-sectional association between the circulating levels of the main pro- and anti-inflammatory cytokines and cardiac magnetic resonance (CMR) abnormalities. Methods 71 subjects (59% female, mean age 52±14) with previous diagnosis of COVID-19 infection were enrolled at our institution for MULTICOVID protocol, comprehensive of CMR and biomarkers assessment performed >3 months and <1 year following the first negative swab test. CMR protocols consisted of conventional sequences (cine, T2-weighted imaging, and late gadolinium enhancement [LGE]) and quantitative mapping sequences (T1, T2, and extracellular volume [ECV] mapping). Plasma levels of cytokines TNF-α, IL-1β, IL-1α, IFN-α2, IL-6, IL-8, IL-13, IL-10, IL-17A, IL-18, IP-10, MIG and MCP-1 were quantified by Multiplex Immunoassays on the Luminex technology platform. Soluble cardiologic and biochemical biomarkers were measured by routine laboratory analysis. Results After a median of 9 (IQR 6–11) months following negative swab, CMR was normal in 48 subjects, while in 23 (32%) it revealed tissue characterization abnormalities (myocardial late enhancement and/or edema). By multivariate regression analysis (adjusted for age, sex, vaccination, severity degrees of the initial COVID disease, presence of comorbidities, smoke, time interval between COVID diagnosis and CMR assessment) the cytokine ratio TNF-α/(IL-10+IL-13) was independently associated (OR=2.89, 95% CI 1.19–7.04, p=0.02) with CMR abnormalities. Interestingly, the cumulative pro-/anti-inflammatory cytokine ratio (IL-1β+TNF-α+IFN-α2+IL-6+IL-17A+IL-8)/(IL-10+IL-13) showed a positive (OR=1.70, 95% CI: 1.04–2.75) and significant (p=0.03) association with CMR imaging aspects. Also, the ratio IFN-α2/(IL-10+IL-13), although without achieving a complete statistical significance (p=0.09), was associated positively with CMR findings. Conclusions The preliminary results of this cross-sectional study suggest that the systemic inflammatory environment, long-lasting unbalanced towards a prevalent cytokine-driven pro-inflammatory condition following COVID infection, could affect the development of CMR-detectable myocardial edema and fibrosis in long-term post-COVID subjects.
244	CaV240		T L F Sousa, M J N N Alves, M D T Melo, A L P Albuquerque, J G Martins, L F B Botelho	Evaluation of myocardial work in patients recovered from the severe form of COVID-19	https://doi.org/10.1093/eurheartj/ehac544.073	Published	03 October 2022	Study	https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.073/6743486	Background/Introduction The impact of COVID-19 goes beyond its acute form, and can lead to the persistence of symptoms and the emergence of systemic disorders, defined as Post-Covid or Long-Covid. Purpose Assess the late impact on the cardiorespiratory system of patients recovered from severe Covid. Methods We performed cross-sectional study that included patients over 18 years of age who recovered from the severe form of COVID-19 after at least 60 days of their discharge. Patients and healthy controls were enrolled to perform transthoracic echocardiography (TTE) and cardiopulmonary exercise testing (CPET). Results A total of 52 patients and 24 controls were enrolled. The standard TTE parameters (end diastolic diameters, left ventricular ejection fraction, diastolic function and right ventricular systolic function) showed no difference when compared to the control group. When analyzing the myocardial work, there was a higher Wasted MW (GWW): 135 mmHg% vs 84.5 mmHg% (p=0.002), with lower MW Efficiency (GWE): 94 vs. 96 (p=0.003); as well as lower values of global strain: cases = 18.6% vs. 20.1% (p=0.009). No differences were found in the Constructive MW (GWC) and MW Global Index (GWI). In the CPET data we found lower peak values for the VO2: 24 ml/kg/min vs. 32.75 ml/kg/min (p<0.001); for the Heart Rate: 162 bpm vs. 175 bpm (p<0.001); for the Ventilation: 79.3 L/min vs. 109.85 L/min (p<0.001) and Respiratory Exchange Ratio: 1.12 vs. 1.19 (p=0.004). There was no difference in the maximum load reached, neither in the oxygen pulse values and in the Ve/CO2 slope. In relation to the oxygen kinetics, there was a significant reduction in OUES%: 85% vs. 98% (p=0.03); as well as an extended T½: 112 s vs. 88.5 s (p<0.001); and a slowing of the fall in heart rate in recovery time, as measured by the Heart Rate decay: −17.32 bpm vs. −22.08 bpm (p=0.005). Conclusion Patients recovered from the severe form of COVID-19 had higher GWW with lower efficiency (GWE). Such findings, added to changes in oxygen kinetics during exercise, may point to a possible cardiocirculatory mechanism associated with decreased aerobic capacity.
245	CaV241		P Theofilis, E Oikonomou, S Lampsas, G Siasos, K Tsioufis, D Tousoulis	Endothelial dysfunction in the post-COVID-19 period: a meta-analysis	https://doi.org/10.1093/eurheartj/ehac544.2833	Published	03 October 2022	Meta-Analysis	https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.2833/6746530	Background Coronavirus disease (COVID)-19 is an entity characterized by a cytokine storm and profound endotheliitis. Although several reports have pointed to the presence of endothelial dysfunction in the acute phase, data is accumulating regarding a possible prolonged adverse effect of COVID-19 on endothelial function. Purpose This systematic review and meta-analysis aims to evaluate the degree of endothelial impairment, assessed by flow-mediated dilation (FMD) of the brachial artery, in individuals recovering from COVID-19. Methods We conducted a systematic literature search for studies assessing FMD between in patients post-COVID-19 and controls. Exclusion criteria consisted of the absence of a control group, measurement of FMD only during the acute phase of the disease, and not reporting FMD in % change. Effect sizes were pooled via random-effect model and the results are expressed as uncorrected standardized mean difference (SMD), using the Cohen's d as the effect size metric, with 95% confidence intervals (CI). Between-study heterogeneity was assessed through the calculation of I2. Subgroup analysis according to follow-up duration and the presence of cardiovascular risk factor-matched controls was also carried out. Results Database search identified 51 studies. Following the application of the exclusion criteria, 7 studies were included in the meta-analysis (post-COVID-19: 342 subjects, Control: 273 subjects). Compared to controls, patients post-COVID-19 had significantly lower FMD% values (SMD: −1.06, 95% CI: −1.74 to −0.38, p<0.01, I2: 86%) (Figure 1). Results remained unaffected after exclusion of any single study using the leave-one-out method. Subgroup analysis revealed no significant differences in FMD between post-COVID-19 patients and controls according to follow-up duration or the presence of cardiovascular risk factor-matched control group. Conclusion Flow-mediated dilation of the brachial artery, indicative of endothelial dysfunction, was significantly reduced in post-COVID-19 subjects compared to non-infected controls. This finding may be an alarming sign towards a higher risk of incident cardiovascular events.
246	CaV242		M Klinceva, L V Veljanovska-Kiridzievska, P Z Zafirovska, E I Idoski, V A Ampova-Sokolov, T A Angjusheva, I M Milev, S I Idrizi, I N Neshkovski, Z M Mitrev	Post COVID-19 cardiac magnetic resonance findings among inpatients vs outpatients	https://doi.org/10.1093/eurheartj/ehac544.250	Published	03 October 2022	Study	https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.250/6743526	Background Myocardial injury and myopericarditis constitute an important complication after viral infection. The prevalence of myocardial injury among patients that survived COVID – 19 infections and its causes are still not clear. The purpose of this study is to estimate whether there is a difference in the prevalence of cardiac magnetic findings between patients treated in a hospital vs patients treated at an outpatient clinic. Methods We evaluated 360 cardiac magnetic resonance examinations, performed from 1st of June 2020 until the 31st of August, 2021. Out of them, 141 patients (39%) underwent cardiac magnetic resonance due to persistent symptoms after a SARS-CoV-2 infection. A conventional CMR protocol was performed to rule out myocarditis. Revised 2018 Lake Louise Criteria were used to diagnose myocarditis. All scans were performed by Phillips Medical Systems Ingenia 1.5T. T1 native values were estimated elevated when mapping values measured above 1030ms, T2 mapping values were estimated elevated when greater than 55 ms. Mid wall or subepicardial late gadolinium enhancement, pericardial effusions and extracardiac findings were evaluated. Chi-square test was used. Results Out of 141 patients, 78 patients (55%) had at least one cardiac magnetic resonance finding: either increased T1 (22%), T2 mapping (7%), T2 STIR (1.4%), left gadolinium enhancement (30%), small pericardial effusion (26%) or lung parenchymal changes (12%) after COVID-19. Twenty out of 141 patients (14%) fulfilled the criteria for myocarditis. Out of these 20 patients, 14 patients (70%) received treatment at an outpatient clinic, while 6 patients (30%) were treated from COVID-19 in a hospital (p<0.053). The most prevalent symptoms were effort intolerance and palpitations (50% and 26% respectively). There was no statistical difference in myocarditis prevalence, between hospitalized patients treated with or without corticosteroids (p=0.65), as well as between patients treated with hemodiafiltration (Oxiris filter) and patients without hemodiafiltration (p=0.95). Also, there was no statistical difference between T1 mapping among the inpatients and outpatients (p=0.58), as well as the severity of the clinical picture (p=0.72). There was no statistical difference between the in- and outpatient groups according to age (p=0.46). None of these patients had signs of fulminant myocarditis. Conclusion The prevalence of myopericardial and/or lung involvement after SARS-CoV-2 infection is present in every other cardiac magnetic resonance examination performed for persistent symptoms after a survived COVID-19. Myocarditis after SARS-CoV-2 infection develops regardless of the severity of the symptoms or the treatment method. We can conclude that we have to look for the reasons for myocarditis, beyond the clinical picture and the treatment strategies.
247	CaV243		Renin Chang 1 Cheuk-Kwan Sun 1 Yao-Min Hung	Concerns about Long-term cardiovascular outcomes in COVID-19 survivors among non-vaccinated population: A retrospective cohort study from the TriNetX US collaborative networks	https://doi.org/10.1016/j.eclinm.2022.101701	Published	October 20, 2022	Correspondance	https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(22)00431-X/fulltext	A recent study of eClinicalMedicine found that COVID-19 survivors, compared with non-COVID-19 controls, had a significantly higher risk of cardiovascular events within 12-month follow-up.1 This study offered timely information to readers. However, we have several concerns. First, this study excluded patients who died within 30 days of the index date, a method that could lead to a Neyman bias that tends to distort survival analyses.2 Thus, critically ill patients who had new cardiovascular events within 30 days of the diagnosis of COVID-19 were intentionally excluded, which may lead to an underestimation or overestimation of the true risk of cardiovascular events. Second, this study conducted by the TriNetX EHR database is retrospective and observational, and the authors have mentioned the possibility of residual unmeasured confounders such as smoking, exercise, or family history of cardiovascular disease. We recommend a self-matched study design, which may reduce the interference caused by unmeasured confounders.3 Third, as the investigators recognized, there may be inaccuracies in this study caused by the diagnosis and coding of myocardial injury or myocarditis into myocardial infarction and vice versa. Here, we would like to emphasize the importance of reporting case ascertainment, providing positive predictive rates or performing sensitivity analyses (using a rigorous definition of cardiovascular outcomes rather than just ICD-10) to make study results more reliable. Although vaccination and antiviral therapy have produced positive results,4 further research is needed to prevent sequelae such as long-term cardiovascular events among COVID-19 survivors.
248	CaV244		R. Hira T. Siddiqui J. Baker S. Ranada A. Soroush K. Karalasingham H. Ahmad C. Morillo R. Sheldon S. Raj	OBJECTIVE CARDIOVASCULAR AUTONOMIC ABNORMALITIES IN POST-ACUTE SEQUELAE OF COVID-19 (PASC): OVERALL AND SEX-BASED PREVALENCE	https://doi.org/10.1016/j.cjca.2022.08.085	Published	October 01, 2022	Study	https://www.onlinecjc.ca/article/S0828-282X(22)00619-5/fulltext	Background The novel coronavirus has negatively impacted the health and economy of Canada and the world. While most patients recover, many patients are left with residual symptoms even several months after resolution of the acute illness (“Post-Acute Sequalae of COVID-19” [PASC]; or “Long COVID). Symptoms can include fatigue, light-headedness, and achycardia/palpitations, which are common in cardiovascular autonomic disorders such as Postural Orthostatic Tachycardia Syndrome (POTS), Initial Orthostatic Hypotension (IOH), Orthostatic Hypotension (OH), and Inappropriate Sinus Tachycardia (IST). Currently, we do not know the prevalence of objective autonomic abnormalities in patients with PASC, nor if there are sex differences. We aimed to determine the prevalence of objective autonomic abnormalities, and whether there was a sex-difference, among patients with PASC. Methods and Results Patients with PASC (n=61; F=49; Age=45±11 years) underwent autonomic function testing with beat-to-beat hemodynamics for 10 min supine followed by a 10 min active stand 397±131 days after their COVID infection. Patients were evaluated for hemodynamic criterion for POTS (ΔHR≥30 bpm within 10 min), IOH (transient ΔSBP≥40mmHg within 45s), OH (ΔSBP≥20mmHg within 3 min), and IST (supine HR>100 bpm). Categorical data were analyzed with a Fisher’s Exact test. The POTS criterion was met in 18 (30%) patients with PASC, while the IOH criterion was met in 40 (66%) patients. The IST and OH criteria were each seen in 1 patient. Overall, 44 (72%) patients met the criterion for at least 1 of these disorders. When analyzed by sex, the POTS criterion was met in 18 (37%) females, but no males (P=0.01). IOH criterion was met in females (69%) and males (50%; P=0.2) at a similar frequency. The single OH and IST patients were female. Overall, there was a non-significant trend for more females (78%) than males (50%; P=0.06) meeting the criterion for at least 1 of these disorders. Conclusion Many patients with PASC have objective evidence of autonomic cardiovascular abnormalities. The most common abnormality is IOH, followed by POTS. IOH will be missed unless an active standing protocol is used. POTS was much more common in females than males, but IOH was evenly split between sexes. Overall, there is a trend toward increased frequency of autonomic cardiovascular disorders in females than males. On behalf of the Canadian Long Covid Autonomic Network (CaLoCAN).
249	CaV245		Zahra Raisi-Estabragh1,2, Jackie Cooper1, Ahmed Salih1, Betty Raman3, Aaron Mark Lee1, Stefan Neubauer3, Nicholas C. Harvey4,5, http://orcid.org/0000-0003-4622-5160Steffen E. Petersen	Cardiovascular disease and mortality sequelae of COVID-19 in the UK Biobank	http://dx.doi.org/10.1136/heartjnl-2022-321492	Published	24 October 2022	Study	https://heart.bmj.com/content/early/2022/09/21/heartjnl-2022-321492	Objective To examine association of COVID-19 with incident cardiovascular events in 17 871 UK Biobank cases between March 2020 and 2021. Methods COVID-19 cases were defined using health record linkage. Each case was propensity score-matched to two uninfected controls on age, sex, deprivation, body mass index, ethnicity, diabetes, prevalent ischaemic heart disease (IHD), smoking, hypertension and high cholesterol. We included the following incident outcomes: myocardial infarction, stroke, heart failure, atrial fibrillation, venous thromboembolism (VTE), pericarditis, all-cause death, cardiovascular death, IHD death. Cox proportional hazards regression was used to estimate associations of COVID-19 with each outcome over an average of 141 days (range 32–395) of prospective follow-up. Results Non-hospitalised cases (n=14 304) had increased risk of incident VTE (HR 2.74 (95% CI 1.38 to 5.45), p=0.004) and death (HR 10.23 (95% CI 7.63 to 13.70), p<0.0001). Individuals with primary COVID-19 hospitalisation (n=2701) had increased risk of all outcomes considered. The largest effect sizes were with VTE (HR 27.6 (95% CI 14.5 to 52.3); p<0.0001), heart failure (HR 21.6 (95% CI 10.9 to 42.9); p<0.0001) and stroke (HR 17.5 (95% CI 5.26 to 57.9); p<0.0001). Those hospitalised with COVID-19 as a secondary diagnosis (n=866) had similarly increased cardiovascular risk. The associated risks were greatest in the first 30 days after infection but remained higher than controls even after this period. Conclusions Individuals hospitalised with COVID-19 have increased risk of incident cardiovascular events across a range of disease and mortality outcomes. The risk of most events is highest in the early postinfection period. Individuals not requiring hospitalisation have increased risk of VTE, but not of other cardiovascular-specific outcomes.
250	CaV246		Ian M. Kronish & Ari Shechter	COVID-19 and the amplification of cardiovascular risk by psychological distress	https://doi.org/10.1038/s44161-022-00153-2	Published	24 October 2022	Comment	https://www.nature.com/articles/s44161-022-00153-2	The COVID-19 pandemic has unleashed a tidal wave of psychological distress. Here we discuss the biobehavioral mechanisms through which psychological distress amplifies the adverse effects of SARS-CoV-2 infection on cardiovascular outcomes. We also examine how the stress of caring for patients with COVID-19 increases cardiovascular risk in healthcare workers.
251	CaV247		C. (Linda) M. C. van Campen *ORCID andFrans C. Visser	Long-Haul COVID Patients: Prevalence of POTS Are Reduced but Cerebral Blood Flow Abnormalities Remain Abnormal with Longer Disease Duration	https://doi.org/10.3390/healthcare10102105	Published	21 October 2022	Study	https://www.mdpi.com/2227-9032/10/10/2105/htm	Background: Postural orthostatic tachycardia syndrome (POTS) has been described early after the onset of the COVID-19 infection, but also orthostatic hypotension (OH). In the present study, we hypothesized that orthostatic intolerance decreases over time. Methods: In 29 long-haul COVID-19 (LHC) patients, a tilt test was performed, including measurements of cerebral blood flow (CBF) by extracranial Doppler. The time interval between the onset of infection and the tilt test varied between 3 and 28 months. Results: In the first 12 months after the infection, 71% of the LHC patients showed POTS and after 24 months none of them. In the first 12 months, 29% of patients had a normal heart rate and blood pressure response (normHRBP) and after 24 months 75% (distribution of POTS, OH, and a normHRBP over time: p < 0.0001). Linear regression showed that, over time, there was a decrease in the abnormal CBF during the tilt (p = 0.024) but remained abnormal. Conclusion: In LHC patients, hemodynamic abnormalities of a tilt test change over time. Patients studied early after the onset of the disease mainly exhibit POTS, but patients studied later in the time course mainly show a normHRBP or OH. In addition, the abnormal CBF reduction improves over time, but CBF remains abnormal.
252	CaV248		Rute Pires 1ORCID,Miguel Pedrosa 2,Maria Marques 3,4,*,Margarida Goes 3,4ORCID,Henrique Oliveira 5,6ORCID andHélder Godinho 1	Cardiometabolic Risk after SARS-CoV-2 Virus Infection: A Retrospective Exploratory Analysis	https://doi.org/10.3390/jpm12111758	Published	24 October 2022	Study	https://www.mdpi.com/2075-4426/12/11/1758/htm	Objective: The aim of this study is to characterize the cardiometabolic risk of individuals who were infected with the SARS-CoV-2 virus and subsequently admitted to a hospital in a major city in mainland Portugal. Methods: This is a retrospective exploratory study using a sample of 102 patients, with data analysis including descriptive statistics, nonparametric measures of association between variables based on Spearman’s rank-order correlation, a logistic regression model for predicting the likelihood that an individual might eventually pass away, and a multiple linear regression model to predict a likely increase in the number of days an infected patient remained in the hospital. Results: About 62.7% of the individuals required intensive care on the second day of hospitalization, remaining 14.2 days in the intensive care unit (ICU) on average. The likelihood that an individual might eventually pass away due to SARS-CoV-2 virus infection increases for the older than younger ones and increases even more if he/she suffers from cardiometabolic disorders such as obesity, especially cardiovascular disease. Older individuals and those with obesity and hypertension remained more days in the ICU. Conclusions: A later age and the prevalence of cardiometabolic disorders severely affect the care pathway of individuals infected with the SARS-CoV-2 virus.
253	CaV249		Austin Culver, Peter Ju, Daniel Kim, Brandon Benefield, Li-Yueh Hsu, Suvai Gunasekaran, Michael Ison, Ravi Kalhan, Bradley D Allen, Michael Markl, Clyde Yancy and Daniel C Lee	Abstract 11734: Myocardial Perfusion Reserve Quantified by Stress Cardiovascular Magnetic Resonance Imaging is Reduced in Long COVID Patients Presenting With Chest Pain		Published	30 Oct 2022	Study	https://www.ahajournals.org/doi/abs/10.1161/circ.146.suppl_1.11734	Introduction: Chest pain is common in patients with Post-acute Sequelae of SARS-CoV-2 (PASC), also known as long COVID, but the mechanism is unknown. Hypothesis: We hypothesized that PASC patients with chest pain have impaired myocardial perfusion reserve (MPR) measured by stress perfusion cardiovascular magnetic resonance (CMR) imaging. Methods: We retrospectively identified the first 30 consecutive patients who underwent clinically ordered adenosine stress perfusion CMR for chest pain persisting >4 weeks after SARS-CoV-2 infection (PASC). Patients with a history of coronary artery disease (CAD) or left ventricular ejection fraction (LVEF) <50% were excluded. Patients without a history of SARS-CoV-2 infection who had a normal clinically ordered perfusion CMR served as controls. A previously-described automated pixel-wise quantitative perfusion tool was used to calculate stress and rest myocardial blood flow (MBF) in mL/min/g, and MPR as the ratio of stress MBF/rest MBF. The cutoff for reduced MPR was >2 SD below mean MPR for controls. Results: In 30 PASC (67% female, age 43±13) and 13 controls (54% female, age 50±12), with LVEF (61±6% vs 59±8%), native T1 (1001±49 vs 992±57 ms), T2 (49.5±3.7 vs 48.0±3.3 ms), and ECV (24.6±2.9 vs 24.6±2.6%) were similar (p>0.2 for all). Prior pericarditis (n=2) or prior myocarditis (n=3) were infrequent, with no acute disease by CMR. PASC patients had significantly lower global MPR than controls (1.54±0.25 vs. 2.20±0.36, p<0.001), and 16/30 (53%) PASC patients had reduced MPR (<1.49). Clinical ischemia evaluation revealed obstructive CAD in only 2 PASC patients. Conclusions: In PASC patients with chest pain undergoing stress perfusion CMR, global MPR is frequently reduced and is significantly lower than in patients with normal clinical perfusion CMR and no history of SARS-CoV-2 infection. This study raises the possibility that microvascular dysfunction is an important cause of chest pain in patients with long COVID.
254	CaV250		Ali Mahdi, Ulrika Reistam, Jannike Nickander, Artur Fedorowski, Liyew Desta, Malin Nygren-Bonnier, Michael Runold, Judith Bruchfeld, John Pernow and Marcus Stahlberg	Abstract 12760: Microvascular Endothelial Dysfunction in Postural Orthostatic Tachycardia Syndrome Associated With Post-Acute Sequelae of COVID-19		Published	30 Oct 2022	Study	https://www.ahajournals.org/doi/abs/10.1161/circ.146.suppl_1.12760	Introduction: Post-acute sequelae of COVID-19 (PASC) is a novel clinical syndrome. We have previously reported that PASC patients can develop postural orthostatic tachycardia syndrome (POTS) and that COVID-19 induce microvascular endothelial dysfunction in acutely ill, hospitalized patients, that persist up to four months post discharge. Whether microvascular endothelial dysfunction contributes to POTS pathophysiology in PASC remains unclear. Hypothesis: Patients with PACS combined with POTS have impaired microvascular endothelial function. Methods: PASC patients (n=44) with mild SARS-CoV-2 infection (not hospitalized) were recruited from the post-COVID multidisciplinary clinic at Karolinska University Hospital. PASC diagnosis was based on the WHO PASC criteria. POTS was diagnosed in 21 patients (PASC + POTS) while 23 had a negative head-up tilt test (PASC - POTS). Age- and gender-matched healthy subjects (n=15) served as controls. Microvascular endothelial function was quantified as reactive hyperemia index (RHI) determined from the changes in pulse amplitude tonometry before and after a 5 min episode of arterial occlusion. Stress-perfusion cardiac magnetic resonance imaging (cMRI) with adenosine was performed in a subset of patients. Results: Mean age was 42±11 years and 95 % were women among PACS patients. Time from COVID-19 symptom onset to study inclusion was 18±3 months. RHI was significantly lower in PASC + POTS than in healthy controls and PASC - POTS (Figure 1). The prevalence of cardiac microvascular dysfunction on cMRI did not differ between the PASC groups (8% in PASC + POTS vs. 13% in PASC - POTS, p=1.00). All subjects with microvascular dysfunction on cMRI except one had a RHI below the cutoff (1.67) indicating microvascular dysfunction. Conclusions: Microvascular endothelial dysfunction is common in patients with PACS-associated POTS and may cause stress-induced myocardial ischemia up to 18 months after a mild primary infection.
255	CaV251		Melanie Walker, Emma M Federico, Douglas B Kell, Christopher Dupont, Amy Proal and Etheresia Pretorius	Abstract 15637: Detection and Characterization of Fibrin/Amyloid Microclots in Patients With Post-Acute Sequelae of Covid-19		Published	30 Oct 2022	Study	https://www.ahajournals.org/doi/abs/10.1161/circ.146.suppl_1.15637	LongCovid or Post-Acute Sequelae of COVID-19 (PASC) is a diagnosis given to patients who experience a wide range of debilitating chronic symptoms after infection with SARS-CoV-2. The majority of individuals are PCR negative, indicating microbiological recovery. There are currently few LongCovid/PASC blood-based biomarkers. We used fluorescence microcopy to identify unique fibrin/amyloid micro-thrombosis and hyperactivated platelets in individuals with PASC. These fibrin/amyloid microclots may impede blood flow to tissue. Methods: Whole blood was collected in citrate tubes from 30 matched healthy subjects and 30 PASC subjects. Platelet poor plasma (PPP) was prepared by centrifugation and stored at -80 °C. PPP was then exposed to thioflavin T (ThT), a fluorescence marker known to bind to and open hydrophobic areas on damaged amyloidogenic protein. Samples were viewed with fluorescence microscopy using a 63x/1.4 Oil DIC M27 objective (excitation wavelength 450nm-488nm, emission 499nm- 529nm). After a double-trypsin PPP digestion method, proteomic analysis of the PPP samples was performed. Results: Significant microclot load was observed in the PPP of participants with PASC compared to healthy participants (Fig. 1). Proteomic analysis revealed the presence of inflammatory molecules within digested microclots. Conclusion: Preliminary results suggest that the presence of microclots in PPP may be used as a diagnostic biomarker for the PASC. Characterization of inflammatory molecules and antibodies trapped within microclots might provide insight into the pathogenesis of PASC and serve as a basis for novel treatment strategies or preventative medicine. Figure: Representative specimens A) Microclots in healthy plasma. B) Microclots in PASC plasma.
256	CaV252		Mark C Beatty and Amanda K Verma	Abstract 11491: Clinical Time Course of Post-Acute Sequelae of SARS-CoV-2 Cardiovascular Syndrome		Published	30 Oct 2022	Study	https://www.ahajournals.org/doi/abs/10.1161/circ.146.suppl_1.11491	Introduction: Post-acute sequelae of SARS-CoV-2 cardiovascular syndrome (PASC-CVS) is a heterogeneous disorder of post-COVID syndrome that involves a wide range of cardiovascular symptoms including palpitations, chest pain, dyspnea and dizziness. The clinical time-course of PASC-CVS is not well characterized. We sought to understand predictors of time to symptom improvement for patients with PASC-CVS. Methods: Patients with PASC-CVS undergoing evaluation in a dedicated post-COVID cardiology clinic were recruited after informed consent. Information was obtained from chart review and included demographics, comorbidities, symptoms, time of infection to time of presentation to the clinic and time to improvement in symptoms. A multivariate linear regression model was used to determine predictors of time to improvement. Results: A total of 144 consecutive patients were included that had complete records available for review. Average age was 46 years, 74% were female and 94% were Caucasian. Comorbities included obesity (49%), mental health disorder (25%), hypertension (24%), hyperlipidemia (24%), pulmonary disease (18%), type II diabetes (9%), atrial arrhythmia (5%) and coronary artery disease (3%). Time from infection to presentation (p <0.001), chest pain (p 0.002) and dyspnea (<0.001) demonstrated significant associations with time to improvement of symptoms and were used in the multivariate regression model (F 27.8, p<0.001). The time to presentation predicted the longest time to symptom improvement, followed by dyspnea, chest pain, and dizziness. Conclusions: This analysis of a large group of PASC-CVS patients suggests those who wait longer to seek care for PASC-CVS symptoms may have longer duration of post-COVID symptoms. Additionally, specific symptoms may take longer to improve than others. Patients with PASC-CVS should therefore consider early medical care to mitigate symptoms and reduce duration of post-COVID syndrome.
257	CaV253		Khan O. Mohammad, Andrew Lin & Jose B. Cruz Rodriguez	Cardiac Manifestations of Post-Acute COVID-19 Infection	https://doi.org/10.1007/s11886-022-01793-3	Published	02 November 2022	Review	https://link.springer.com/article/10.1007/s11886-022-01793-3	Purpose of Review There is emerging evidence that the post-acute and chronic phases of COVID-19 infection are associated with various significant cardiovascular sequelae. Recent Findings Long COVID has been shown to be associated with multiple cardiovascular sequelae including direct myocardial injury, arrhythmias, and cardiomyopathies. Hypotheses on the mechanism of myocardial injury include direct viral infiltration and autoimmune dysregulation. Long COVID is associated with persistent cardiac ischemia in patients with no previous history of coronary disease, atrial and ventricular arrhythmias, and the development of new-onset heart failure in previously healthy patients. Onset of long COVID may be related to severity of the initial SARS-CoV2 infection. Cardiac MRI is a valuable tool in assessing myocarditis and the development of cardiomyopathies in the setting of long COVID. Summary Both patients with and without pre-existing cardiovascular disease are at risk of developing myocardial injury in the setting of long COVID. Future studies will elucidate both cardiovascular mortality and cardiac rehabilitation in the post-acute and chronic phases of COVID-19.
258	CaV254		Darius A. Gerlach, Andrea Maier, Jorge Manuel, Anja Bach, Alex Hoff, Jan‐Niklas Hönemann, Karsten Heusser, Dirk Voit, Jens Frahm, Jens Jordan and Jens Tank	Real‐Time Magnetic Resonance Imaging to Study Orthostatic Intolerance Mechanisms in Human Beings: Proof of Concept	https://doi.org/10.1161/JAHA.122.026437	Published	27 Oct 2022	Proof‐of‐concept study	https://www.ahajournals.org/doi/10.1161/JAHA.122.026437	Background Discerning the mechanisms driving orthostatic symptoms in human beings remains challenging. Therefore, we developed a novel approach combining cardiac and cerebral real‐time magnetic resonance imaging, beat‐to‐beat physiological monitoring, and orthostatic stress testing through lower‐body negative pressure (LBNP). We conducted a proof‐of‐concept study in a patient with severe orthostatic hypotension. Methods and Results We included a 46‐year‐old man with pure autonomic failure. Without and during −30 mmHg LBNP, we obtained 3T real‐time magnetic resonance imaging of the cardiac short axis and quantitative flow measurements in the pulmonary trunk and middle cerebral artery. Blood pressure was 118/74 mmHg during supine rest and 58/35 mmHg with LBNP. With LBNP, left ventricular stroke volume decreased by 44.6%, absolute middle cerebral artery flow by 37.6%, and pulmonary trunk flow by 40%. Conclusions Combination of real‐time magnetic resonance imaging, LBNP, and continuous blood pressure monitoring provides a promising new approach to study orthostatic intolerance mechanisms in human beings.
259	CaV255		Sarah Schlick 1,†,Marianna Lucio 2,†,Gerd Wallukat 3,Alexander Bartsch 1ORCID,Adam Skornia 1,Jakob Hoffmanns 1,Charlotte Szewczykowski 1,Thora Schröder 1,Franziska Raith 1,Lennart Rogge 1,Felix Heltmann 1,Michael Moritz 1,Lorenz Beitlich 1,Julia Schottenhamml 1,Martin Herrmann 4,5ORCID,Thomas Harrer 4,5ORCID,Marion Ganslmayer 6,Friedrich E. Kruse 1,Robert Lämmer 1ORCID,Christian Mardin 1,,‡ andBettina Hohberger 1,,‡	Post-COVID-19 Syndrome: Retinal Microcirculation as a Potential Marker for Chronic Fatigue	https://doi.org/10.3390/ijms232213683	Published	8 November 2022	Study	https://www.mdpi.com/1422-0067/23/22/13683	Post-COVID-19 syndrome (PCS) is characterized by persisting sequelae after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). PCS can affect patients with all COVID-19 disease severities. As previous studies have revealed impaired blood flow as a provoking factor triggering PCS, it was the aim of the present study to investigate the potential association between self-reported chronic fatigue and retinal microcirculation in patients with PCS, potentially indicating an objective biomarker. A prospective study was performed, including 201 subjects: 173 patients with PCS and 28 controls. Retinal microcirculation was visualized by OCT angiography (OCT-A) and quantified using the Erlangen-Angio-Tool as macula and peripapillary vessel density (VD). Chronic fatigue (CF) was assessed according to the variables of Bell’s score, age and gender. VDs in the superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP) were analyzed, considering the repetitions (12 times). Seropositivity for autoantibodies targeting G protein-coupled receptors (GPCR-AAbs) was determined by an established cardiomyocyte bioassay. Taking account of the repetitions, a mixed model was performed to detect possible differences in the least square means between the different groups included in the analysis. An age effect in relation to VD was observed between patients and controls (p < 0.0001). Gender analysis showed that women with PCS showed lower VD levels in the SVP compared to male patients (p = 0.0015). The PCS patients showed significantly lower VDs in the ICP as compared to the controls (p = 0.0001 (CI: 0.32; 1)). Moreover, considering PCS patients, the mixed model revealed a significant difference between those with chronic fatigue (CF) and those without CF with respect to VDs in the SVP (p = 0.0033 (CI: −4.5; −0.92)). The model included variables of age, gender and Bell’s score, representing a subjective marker for CF. Consequently, retinal microcirculation might serve as an objective biomarker in subjectively reported chronic fatigue in patients with PCS.
260	CaV256		Jaroslav Pelisek ORCID logo ; Benedikt Reutersberg; Urs F Greber; Alexander Zimmermann	Vascular dysfunction in COVID-19 patients: update on SARS-CoV-2 infection of endothelial cells and the role of long non-coding RNAs	https://doi.org/10.1042/CS20220235	Published	November 11 2022	Review	https://portlandpress.com/clinsci/article/136/21/1571/232077/Vascular-dysfunction-in-COVID-19-patients-update	Although COVID-19 is primarily a respiratory disease, it may affect also the cardiovascular system. COVID-19 patients with cardiovascular disorder (CVD) develop a more severe disease course with a significantly higher mortality rate than non-CVD patients. A common denominator of CVD is the dysfunction of endothelial cells (ECs), increased vascular permeability, endothelial-to-mesenchymal transition, coagulation, and inflammation. It has been assumed that clinical complications in COVID-19 patients suffering from CVD are caused by SARS-CoV-2 infection of ECs through the angiotensin-converting enzyme 2 (ACE2) receptor and the cellular transmembrane protease serine 2 (TMPRSS2) and the consequent dysfunction of the infected vascular cells. Meanwhile, other factors associated with SARS-CoV-2 entry into the host cells have been described, including disintegrin and metalloproteinase domain-containing protein 17 (ADAM17), the C-type lectin CD209L or heparan sulfate proteoglycans (HSPG). Here, we discuss the current data about the putative entry of SARS-CoV-2 into endothelial and smooth muscle cells. Furthermore, we highlight the potential role of long non-coding RNAs (lncRNAs) affecting vascular permeability in CVD, a process that might exacerbate disease in COVID-19 patients.
261	CaV257		Pasquale AmbrosinoORCID Icon,Stefano Sanduzzi ZamparelliORCID Icon,Marco Mosella,Roberto FormisanoORCID Icon,Antonio MolinoORCID Icon,Giorgio Alfredo SpedicatoORCID Icon,Antimo PapaORCID Icon,Andrea MottaORCID Icon,Matteo Nicola Dario Di MinnoORCID Icon &Mauro ManiscalcoORCID Icon show less	Clinical assessment of endothelial function in convalescent COVID-19 patients: a meta-analysis with meta-regressions	https://doi.org/10.1080/07853890.2022.2136403	Published	16 Nov 2022	Meta-Analysis	https://www.tandfonline.com/doi/full/10.1080/07853890.2022.2136403	Background Endothelial dysfunction has been proposed to play a key role in the pathogenesis of coronavirus disease 2019 (COVID-19) and its post-acute sequelae. Flow-mediated dilation (FMD) is recognized as an accurate clinical method to assess endothelial function. Thus, we performed a meta-analysis of the studies evaluating FMD in convalescent COVID-19 patients and controls with no history of COVID-19. Methods A systematic literature search was conducted in the main scientific databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Using the random effects method, differences between cases and controls were expressed as mean difference (MD) with 95% confidence intervals (95% CI). The protocol was registered on PROSPERO with reference number CRD42021289684. Results Twelve studies were included in the final analysis. A total of 644 convalescent COVID-19 patients showed significantly lower FMD values as compared to 662 controls (MD: −2.31%; 95% CI: −3.19, −1.44; p < 0.0001). Similar results were obtained in the sensitivity analysis of the studies that involved participants in either group with no cardiovascular risk factors or history of coronary artery disease (MD: −1.73%; 95% CI: −3.04, −0.41; p = 0.010). Interestingly, when considering studies separately based on enrolment within or after 3 months of symptom onset, results were further confirmed in both short- (MD: −2.20%; 95% CI: −3.35, −1.05; p < 0.0001) and long-term follow-up (MD: −2.53%; 95% CI: −4.19, −0.86; p = 0.003). Meta-regression models showed that an increasing prevalence of post-acute sequelae of COVID-19 was linked to a higher difference in FMD between cases and controls (Z-score: −2.09; p = 0.037). Conclusions Impaired endothelial function can be documented in convalescent COVID-19 patients, especially when residual clinical manifestations persist. Targeting endothelial dysfunction through pharmacological and rehabilitation strategies may represent an attractive therapeutic option. Key messages The mechanisms underlying the post-acute sequelae of coronavirus disease 2019 (COVID-19) have not been fully elucidated. Impaired endothelial function can be documented in convalescent COVID-19 patients for up to 1 year after infection, especially when residual clinical manifestations persist. Targeting endothelial dysfunction may represent an attractive therapeutic option in the post-acute phase of COVID-19.
262	CaV258		Paul Baum, Lisa Do, Lea Deterding, Julia Lier, Ines Kunis, Dorothee Saur, Joseph Classen, Hubert Wirtz & Ulrich Laufs	Cardiac function in relation to functional status and fatigue in patients with post-COVID syndrome	https://doi.org/10.1038/s41598-022-24038-3	Published	15 November 2022	Study	https://www.nature.com/articles/s41598-022-24038-3	Patients with Post-COVID syndrome (PCS) are frequently referred for cardiologic evaluation. We assessed cardiac function and biomarkers in relation to functional status and fatigue in patients with PCS. This prospective single-center cohort study included 227 patients with persisting symptoms after COVID-19 infection. Most frequent complaints were fatigue (70%), dyspnea (56%), neurocognitive symptoms (34%) and chest pain (28%). Standardized questionnaires were used to assess Post-COVID-Functional-Scale (PCFS) and fatigue (MFI-20). The fatigue severity was inversely related to age and did not correlate with cardiovascular diseases, echocardiographic findings, or biomarkers. Similarly, mild to moderate functional impairment (PCFS 1–3) did not correlate with cardiovascular alterations. However, the subgroup of patients with significant functional impairment (PCFS = 4) had more frequent cardiovascular comorbidities, biomarkers and impaired global longitudinal strain (GLS). Patients with elevated troponin T showed abnormal GLS, reduced left ventricular ejection fraction and impaired tricuspid annular plane systolic excursion. The majority of patients with PCS shows a normal cardiac function. Only the small subgroup of patients with severe functional impairment and patients with elevated troponin T is at risk for impaired cardiac function and likely to benefit from specialized care by a cardiologist.
263	CaV259		Lukas Fiedler 1,2,†ORCID,Lukas J. Motloch 1,†,Peter Jirak 1,Ruslan Gumerov 3,Paruir Davtyan 3,Diana Gareeva 3,Irina Lakman 3,4ORCID,Alexandr Tataurov 5,Gulnaz Lasinova 3,Valentin Pavlov 6,Laurenz Hauptmann 1ORCID,Kristen Kopp 1ORCID,Uta C. Hoppe 1,Michael Lichtenauer 1,Rudin Pistulli 7ORCID,Anna-Maria Dieplinger 8,9,† andNaufal Zagidullin	Investigation of hs-TnI and sST-2 as Potential Predictors of Long-Term Cardiovascular Risk in Patients with Survived Hospitalization for COVID-19 Pneumonia	https://doi.org/10.3390/biomedicines10112889	Published	10 November 2022	Study	https://www.mdpi.com/2227-9059/10/11/2889	Introduction: COVID-19 survivors reveal an increased long-term risk for cardiovascular disease. Biomarkers like troponins and sST-2 improve stratification of cardiovascular risk. Nevertheless, their prognostic value for identifying long-term cardiovascular risk after having survived COVID-19 has yet to be evaluated. Methods: In this single-center study, admission serum biomarkers of sST-2 and hs-TnI in a single cohort of 251 hospitalized COVID-19 survivors were evaluated. Concentrations were correlated with major cardiovascular events (MACE) defined as cardiovascular death and/or need for cardiovascular hospitalization during follow-up after hospital discharge [FU: 415 days (403; 422)]. Results: MACE was a frequent finding during FU with an incidence of 8.4% (cardiovascular death: 2.8% and/or need for cardiovascular hospitalization: 7.2%). Both biomarkers were reliable indicators of MACE (hs-TnI: sensitivity = 66.7% & specificity = 65.7%; sST-2: sensitivity = 33.3% & specificity = 97.4%). This was confirmed in a multivariate proportional-hazards analysis: besides age (HR = 1.047, 95% CI = 1.012–1.084, p = 0.009), hs-TnI (HR = 4.940, 95% CI = 1.904–12.816, p = 0.001) and sST-2 (HR = 10.901, 95% CI = 4.509–29.271, p < 0.001) were strong predictors of MACE. The predictive value of the model was further improved by combining both biomarkers with the factor age (concordance index hs-TnI + sST2 + age = 0.812). Conclusion: During long-term FU, hospitalized COVID-19 survivors, hs-TnI and sST-2 at admission, were strong predictors of MACE, indicating both proteins to be involved in post-acute sequelae of COVID-19.
264	CaV260		Elamein Yousif, Sarah Premraj	A Review of Long COVID With a Special Focus on Its Cardiovascular Manifestations	https://doi.org/10.7759/cureus.31933	Published	November 27, 2022	Review	https://www.cureus.com/articles/124983-a-review-of-long-covid-with-a-special-focus-on-its-cardiovascular-manifestations	Abstract The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has been the cause of the century’s worst pandemic so far: coronavirus disease 2019 (COVID-19). It has led to unprecedented mortality and morbidity, resulting in devastating consequences worldwide. The acute manifestations of COVID-19 including respiratory as well as multisystem involvement have been causes of great concern among physicians. However, the long-term effects of the coronavirus have left many patients battling with chronic symptoms, ranging from extreme fatigue to cardiomyopathy. In this article, we review the chronic manifestations of COVID-19 with a focus on cardiovascular manifestations. We discuss the pathophysiology, post-acute sequelae, clinical manifestations, approach to the laboratory diagnosis of cardiovascular manifestations of long COVID, and a proposed multidisciplinary treatment method. We also explore the relationship between vaccination and the long COVID syndrome. Introduction & Background According to the WHO’s weekly report of coronavirus disease 2019 (COVID-19) on October 30, 2022, over 627 million confirmed cases and over 6.5 million deaths have been reported globally [1]. Although the incidence of new cases is on the decline, the long-term sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have sparked a growing interest among clinicians and researchers. This is due to the fact that survivors of COVID-19 have now been reported to have a higher risk of mortality, and health loss due to a wide spectrum of pulmonary and extra-pulmonary manifestations [2]. In this review, we discuss the definition of post-acute sequelae of COVID-19 (PASC), the epidemiology, pathophysiology, clinical characteristics, and proposed management strategies. Our review touches briefly on the wide spectrum of long COVID while paying special attention to its cardiovascular manifestations.
265	CaV261		Thomas A. Dewland & Gregory M. Marcus	SARS-CoV-2 infection and cardiac arrhythmias	https://doi.org/10.1038/s44161-022-00166-x	Published	23 November 2022	Comment	https://www.nature.com/articles/s44161-022-00166-x	Although cardiac arrhythmias have been observed and described during and after SARS-CoV-2 infection, rigorous studies designed to untangle the complex relationship between this proinflammatory illness and arrhythmogenesis are limited. Despite a pervasive opinion to the contrary, there is presently no definitive data to establish a causal, viral-specific association between COVID-19 and incident arrhythmia.
266	CaV262		Thiago A. Laranjeira, Antonio S. Menezes Jr.	A Systematic Review of Post-COVID Electrocardiographic Changes in Young Athletes	https://doi.org/10.7759/cureus.31829	Published	November 23, 2022	Review	https://www.cureus.com/articles/124860-a-systematic-review-of-post-covid-electrocardiographic-changes-in-young-athletes	Post-coronavirus disease (COVID) syndrome involves the presentation of various new, returning, or ongoing symptoms, more than four weeks after COVID-19 infection. Post-infectious myocarditis is a potential sequela, associated with greater arrhythmogenic potential. Thus, it is an outcome that should be considered in athletes. An undiagnosed heart condition associated with adrenergic stimulus caused by high-intensity exercises can lead to sudden cardiac death. Electrocardiography (ECG) plays a role in cardiac screening for potential cardiac changes associated with myocarditis. Therefore, this study aimed to evaluate the occurrence of electrocardiographic alterations in athletes during the post-COVID period. A systematic review of longitudinal observational studies in the PubMed, LILACS, and CENTRAL databases that evaluated athletes in the post-COVID period with ECG was performed. A total of four articles involving 5371 patients were included in the analysis. The athletes mostly presented with mild asymptomatic or symptomatic COVID-19. A low prevalence of electrocardiographic alterations suggestive of cardiac involvement by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in this population. Electrocardiographic abnormalities indicative of myocarditis are uncommon in young athletes throughout the post-COVID era. However, anomalies that may signify and need further cardiovascular testing were found.
267	CaV263		LeenAlblaihedMBBS, MHAaWilliam J.BradyMDbTareqAl-SalamahMBBS, MPHcAmalMattuMDa	Dysrhythmias associated with COVID-19: Review and management considerations	https://doi.org/10.1016/j.ajem.2022.12.004	Published	5 December 2022	Review	https://www.sciencedirect.com/science/article/pii/S0735675722007446	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), is known to affect the cardiovascular system. Cardiac manifestations in COVID-19 can be due to direct damage to the myocardium and conduction system as well as by the disease's effect on the various organ systems. These manifestations include acute coronary syndrome, ST- segment elevations, cardiomyopathy, and dysrhythmias. Some of these dysrhythmias can be detrimental to the patient. Therefore, it is important for the emergency physician to be aware of the different arrhythmias associated with COVID-19 and how to manage them. This narrative review discusses the pathophysiology underlying the various arrhythmias associated with COVID-19 and their management considerations.
268	CaV264		Zachary V.RezlerBHScabEmmaKoBMScbElaineJinBHScbMishaIshtiaqBHScabChristinaPapaioannoubHelenaKimBHScbKyobinHwangaYu-Hsin (Sophy)LinBSccJakeColauttiBHScabKaren M.DavisonMSc, PhDcVidhiThakkarMSc, PhDac	The impact of COVID-19 on the cardiovascular health of emerging adults aged 18-25: findings from a scoping review	https://doi.org/10.1016/j.cjcpc.2022.11.005	Published	1 December 2022	Review	https://www.sciencedirect.com/science/article/pii/S277281292200118X	There is limited knowledge regarding the cardiovascular impact of coronavirus disease 2019 (COVID-19) on emerging adults aged 18-25, a group which disproportionately contracts COVID-19. To guide future cardiovascular disease (CVD) research, policy, and practice, a scoping review was conducted to: i) examine the impact of the COVID-19 pandemic on the cardiovascular health of emerging adults; and ii) identify strategies to screen for and manage COVID-19-related cardiovascular complications in this age group. A comprehensive search strategy was applied to several academic databases and grey literature sources. An updated search yielded 6738 articles, 147 of which were extracted and synthesized. Reports identified COVID-19-associated cardiac abnormalities, vascular alterations, and multisystem inflammatory syndrome in emerging adults; based on data from student-athlete samples, prevalence estimates of myocarditis and cardiac abnormalities were 0.5-3% and 0-7%, respectively. Obesity, hypertension, CVD, congenital heart disease, and marginalization are potential risk factors for severe COVID-19, related cardiovascular complications, and mortality in this age group. As a screening modality for COVID-19-associated cardiac involvement, it is recommended that cardiac magnetic resonance imaging be indicated by a positive cardiac history and/or abnormal ‘triad’ testing (cardiac troponin, electrocardiogram, and transthoracic echocardiogram) to improve diagnostic utility. To foster long-term cardiovascular health among emerging adults, cardiorespiratory fitness, health literacy and education, and telehealth accessibility should be priorities of health policy and clinical practice. Ultimately, surveillance data from the broader emerging adult population will be crucial to assess the long-term cardiovascular impact of both COVID-19 and vaccination, guide screening and management protocols, and inform CVD prevention efforts.
269	CaV265		Dini, Frank Lloyd; Baldini, Umberto; Bytyçi, Ibadete; Pugliese, Nicola Riccardo; Bajraktari, Gani; Henein, Michael Y.	Acute pericarditis as a major clinical manifestation of long COVID-19 syndrome	https://doi.org/10.3390/medicina58121807	Published	2022-12	Study	https://www.mdpi.com/1648-9144/58/12/1807	Following COVID-19 infection, a substantial proportion of patients suffer from persistent symptoms known as Long COVID. Among the main symptoms are fatigue, cognitive dysfunction, muscle weakness and orthostatic intolerance (OI). These symptoms also occur in myalgic encephalomyelitis/chronic fatigue (ME/CFS). OI is highly prevalent in ME/CFS and develops early during or after acute COVID-19 infection. The causes for OI are unknown and autonomic dysfunction is hypothetically assumed to be the primary cause, presumably as a consequence of neuroinflammation. Here, we propose an alternative, primary vascular mechanism as the underlying cause of OI in Long COVID. We assume that the capacitance vessel system, which plays a key role in physiologic orthostatic regulation, becomes dysfunctional due to a disturbance of the microvessels and the vasa vasorum, which supply large parts of the wall of those large vessels. We assume that the known microcirculatory disturbance found after COVID-19 infection, resulting from endothelial dysfunction, microthrombus formation and rheological disturbances of blood cells (altered deformability), also affects the vasa vasorum to impair the function of the capacitance vessels. In an attempt to compensate for the vascular deficit, sympathetic activity overshoots to further worsen OI, resulting in a vicious circle that maintains OI. The resulting orthostatic stress, in turn, plays a key role in autonomic dysfunction and the pathophysiology of ME/CFS.
270	CaV266		Wirth, Klaus J.; Löhn, Matthias	Orthostatic Intolerance after COVID-19 Infection: Is Disturbed Microcirculation of the Vasa Vasorum of Capacitance Vessels the Primary Defect?	https://doi.org/10.1016/j.ijcard.2022.12.019	Published	2022-12-09	Study	https://www.internationaljournalofcardiology.com/article/S0167-5273(22)01891-5/fulltext	Publisher: Elsevier PMID: 36513284 Highlights •Acute pericarditis is an important manifestation of long COVID-19 syndrome. •Thickened and bright pericardial layers with small effusions was the most frequent finding. •History of autoimmune and allergic disorders, and palpitations/arrhythmias were risk factors. Abstract Background The long COVID-19 syndrome has been recently described and some reports have suggested that acute pericarditis represents important manifestation of long COVID-19 syndrome. The aim of this study was to identify the prevalence and clinical characteristics of patients with long COVID-19, presenting with acute pericarditis. Methods We retrospectively included 180 patients (median age 47 years, 62% female) previously diagnosed with COVID-19, exhibiting persistence or new-onset symptoms ≥12 weeks from a negative naso-pharyngeal SARS CoV2 swamp test. The original diagnosis of COVID-19 infection was determined by a positive swab. All patients had undergone a thorough physical examination. Patients with suspected heart involvement were referred to a complete cardiovascular evaluation. Echocardiography was performed based on clinical need and diagnosis of acute pericarditis was achieved according to current guidelines. Results Among the study population, shortness of breath/fatigue was reported in 52%, chest pain/discomfort in 34% and heart palpitations/arrhythmias in 37%. Diagnosis of acute pericarditis was made in 39 patients (22%). Mild-to-moderate pericardial effusion was reported in 12, while thickened and bright pericardial layers with small effusions (< 5 mm) with or without comet tails arising from the pericardium (pericardial B-lines) in 27. Heart palpitations/arrhythmias (OR:3.748, p = 0.0030), and autoimmune disease and allergic disorders (OR:4.147, p = 0.0073) were independently related to the diagnosis of acute pericarditis, with a borderline contribution of less likelihood of hospitalization during COVID-19 (OR: 0.100, p = 0.0512). Conclusion Our findings suggest a high prevalence of acute pericarditis in patients with long COVID-19 syndrome. Autoimmune and allergic disorders, and palpitations/arrhythmias were frequently associated with pericardial disease.
271	CaV267		Carbone, Francis R.	Unique properties of tissue-resident memory T cells in the lungs: implications for COVID-19 and other respiratory diseases	https://doi.org/10.1016/j.cjca.2022.12.003	Published	2022-12-12	Study	https://www.sciencedirect.com/science/article/pii/S0828282X22010923	Background Acute myocarditis has been described as a relatively rare cardiovascular complication of COVID-19 infection. However, data regarding the risk of myocarditis during the post-acute phase of COVID-19 are scant. We assess the risk of incident myocarditis in COVID-19 survivors within one year from the index infection by a systematic review and meta-analysis of the available data. Methods Data were obtained searching MEDLINE and Scopus for all studies published at any time up to September 1, 2022, and reporting the long-term risk of incident myocarditis in COVID-19 survivors. Myocarditis risk data were pooled using the Mantel–Haenszel random effects models with Hazard ratio (HR) as the effect measure with 95% confidence interval (CI). Heterogeneity among studies was assessed using Higgins and Thomson I2 statistic. Results Overall, 20.875.843 patients (mean age 56.1 years, 59.1% males) were included in this analysis. Of them, 1.245.167 survived to COVID-19 infection. Over a mean follow-up of 9.5 months, myocarditis occurred to 0.21 [95% CI: 0.13- 0.42) out of 1000 patients survived to COVID-19 infection compared to 0.09 [95% CI: 0.07-0.12] out of 1000 control subjects. Pooled analysis revealed that recovered COVID-19 patients presented an increased risk of incident myocarditis (HR: 5.16, 95% CI: 3.87-6.89, p<0.0001, I2=7.9%) within one year from the index infection. The sensitivity analysis confirmed yielded results. Conclusion Our findings suggest that myocarditis represents a relatively rare but important post-acute COVID-19 sequelae.
272	CaV268		Abdulla, Maheeba; Mohammed, Nafeesa; AlQamish, Jehad; Mosli, Mahmoud	Inflammatory bowel disease and COVID-19 outcomes: a meta-analysis	https://doi.org/10.1016/j.cjca.2022.12.002	Published	2022-12-09	Study	https://www.sciencedirect.com/science/article/pii/S0828282X22010911	Background Many COVID-19 patients are left with symptoms several months after resolution of the acute illness (“Post-Acute Sequalae of COVID-19” [PASC]). We aimed to determine the prevalence of objective hemodynamic cardiovascular autonomic abnormalities (CAA), explore sex differences, and assess the prevalence of CAA among hospitalized vs non-hospitalized PASC patients. Methods Patients with PASC (n=70; F=56; 42 years 95% CI [40,48]) completed standard autonomic tests, including an active stand test 399 days [338,455] after their COVID-19 infection. Clinical autonomic abnormalities were evaluated. Results Most patients with PASC met the criteria for at least one CAA (51; 73%; F=43). The Postural Orthostatic Tachycardia Syndrome hemodynamic criterion (POTSHR) of a heart rate increase of >30bpm within 5-10mins of standing was seen in 21 patients (30%; F=20; p=0.037 [by sex]). The Initial Orthostatic Hypotension hemodynamic criterion (IOH40) of a transient SBP change of >40mmHg in the first 15s of standing was seen in 43 (61%) patients and equally among females and males (63% vs. 57%; p=0.7). Only 9 (13%) patients were hospitalized; hospitalized vs. non-hospitalized patients had similar frequencies of abnormalities (67% vs. 74%; p=0.7). Conclusions Patients with PASC have evidence of CAA, most commonly IOH40, which will be missed unless an active stand test is used. Females have increased frequency of POTSHR, but IOH40 is equally prevalent between sexes. Finally, even non-hospitalized “mild” infections can result in long-term CAA.
273	CaV269		Hira, Rashmin; Baker, Jacquie R.; Siddiqui, Tanya; Ranada, Shaun I.; Soroush, Ateyeh; Karalasingham, Kavithra; Ahmad, Hyeqa; Mavai, Vibhuti; Ayala Valani, Luciano Martin; Ambreen, Sakina; Bourne, Kate M.; Lloyd, Matthew G.; Morillo, Carlos A.; Sheldon, Robert S.; Raj, Satish R.	Objective Hemodynamic Cardiovascular Autonomic Abnormalities in Post-Acute Sequelae of COVID-19	https://doi.org/10.1016/j.cjca.2022.12.002	Published	2022-12-09	Study	https://www.sciencedirect.com/science/article/pii/S0828282X22010911	Background: The long-term sequela of COVID-19 on young people is still unknown. This systematic review explored the effect of COVID-19 on lung imaging and function, cardiorespiratory symptoms, fatigue, exercise capacity and functional capacity in children and adolescents ≥ 3 months after infection. Methods: A systemic search was completed in the electronic databases of PubMed, Web of Science and Ovid MEDLINE on 27 May 2022. Data on the proportion of participants who had long-term effects were collected, and one-group meta-analysis were used to estimate the pooled prevalence of the outcomes studied. Results: 17 articles met the inclusion criteria, presented data on 124,568 children and adolescents. The pooled prevalence of abnormalities in lung imaging was 10% (95% CI 1–19, I2 = 73%), abnormal pulmonary function was 24% (95% CI 4–43, I2 = 90%), chest pain/tightness was 6% (95% CI 3–8, I2 = 100%), heart rhythm disturbances/palpitations was 6% (95% CI 4–7, I2 = 98%), dyspnea/breathing problems was 16% (95% CI 14–19, I2 = 99%), and fatigue was 24% (95% CI 20–27, I2 = 100%). Decreased exercise capacity and functional limitations were found in 20% (95% CI 4–37, I2 = 88%) and 48% (95% CI 25–70, I2 = 91%) of the participants studied, respectively. Conclusion: Children and adolescents may have persistent abnormalities in lung imaging and function, cardiorespiratory symptoms, fatigue, and decreased functional capacity between 3 to 12 months after infection. More research is needed to understand the long-term effect of COVID-19 on young people, and to clarify its causes and effective management.
274	CaV270		Constantinescu-Bercu, Adela; Kessler, Anna; Groot, Rens de; Dragunaite, Bertina; Heightman, Melissa; Hillman, Toby; Price, Laura C.; Brennan, Ewan; Sivera, Raphael; Vanhoorelbeke, Karen; Singh, Deepak; Scully, Marie	Analysis of thrombogenicity under flow reveals new insights into the prothrombotic state of patients with post-COVID syndrome	https://doi.org/10.1016/j.jtha.2022.10.013	Published	2022-12-12	Study	https://www.jthjournal.org/article/S1538-7836(22)07182-3/fulltext	publisher: Elsevier Essentials • Post-COVID syndrome is an emerging condition linked to an uncharacterized prothrombotic state. • We studied thrombogenicity using a range of tests, including a novel microfluidic assay. • Post-COVID syndrome can lead to increased platelet recruitment and larger thrombi under flow. • The median time of 23 months from symptom onset suggests potential long-term thrombogenicity. Abstract Background Post-COVID syndrome (PCS) affects millions of people worldwide, causing a multitude of symptoms and impairing quality of life months or even years after acute COVID-19. A prothrombotic state has been suggested; however, underlying mechanisms remain to be elucidated. Objectives To investigate thrombogenicity in PCS using a microfluidic assay, linking microthrombi, thrombin generation, and the von Willebrand factor (VWF):a Disintegrin and Metalloproteinase with a Thrombospondin Type 1 motif, member 13 (ADAMTS13) axis. Methods Citrated blood was perfused through microfluidic channels coated with collagen or an antibody against the VWF A3 domain, and thrombogenicity was monitored in real time. Thrombin generation assays were performed and α(2)-antiplasmin, VWF, and ADAMTS13 activity levels were also measured. Results We investigated thrombogenicity in a cohort of 21 patients with PCS with a median time following symptoms onset of 23 months using a dynamic microfluidic assay. Our data show a significant increase in platelet binding on both collagen and anti-VWF A3 in patients with PCS compared with that in controls, which positively correlated with VWF antigen (Ag) levels, the VWF(Ag):ADAMTS13 ratio (on anti-VWF A3), and inversely correlated with ADAMTS13 activity (on collagen). Thrombi forming on collagen presented different geometries in patients with PCS vs controls, with significantly increased thrombi area mainly attributable to thrombi length in the patient group. Thrombi length positively correlated with VWF(Ag):ADAMTS13 ratio and thrombin generation assay results, which were increased in 55.5% of patients. α(2)-Antiplasmin levels were normal in 89.5% of patients. Conclusion Together, these data present a dynamic assay to investigate the prothrombotic state in PCS, which may help unravel the mechanisms involved and/or establish new therapeutic strategies for this condition.
275	CaV271		Szoltysek-Boldys, Izabela; Zielinska-Danch, Wioleta; Loboda, Danuta; Wilczek, Jacek; Gibinski, Michal; Paradowska-Nowakowska, Elzbieta; Golba, Krzysztof S.; Sarecka-Hujar, Beata	Photoplethysmographic Measurement of Arterial Stiffness in Polish Patients with Long-COVID-19 Syndrome—The Results of a Cross-Sectional Study	https://doi.org/10.3390/diagnostics12123189	Published	2022-12	Study	https://www.mdpi.com/2075-4418/12/12/3189	The coronavirus disease 2019 (COVID-19) is associated with an increase in the incidence of cardiovascular diseases (CVD) that persists even several months after the onset of infection. COVID-19 may also have an impact on arterial stiffness, which is a risk factor for CVD. We aimed to analyze if and to what extent arterial stiffness measured by photoplethysmography differed among COVID-19 convalescents depending on the acute phase severity and time elapsed since disease onset. A total of 225 patients (mean age 58.98 ± 8.57 years, 54.7% women) were analyzed after COVID-19 hospitalization at the Cardiac Rehabilitation Department of the Ustron Health Resort (Poland). In the entire study population, no differences were found in the mean values of stiffness index (SI) and reflection index (RI) depending on the severity of the acute COVID-19 and the time since the onset of the disease. There were no differences in the heart rate (HR) according to the severity of acute COVID-19; the mean HR was higher in patients who had COVID-19 less than 12 weeks before the study than in convalescents more than 24 weeks after the acute disease (p = 0.002). The mean values of SI and RI were higher in men than in women (p < 0.001), while the heart rate (HR) was similar in both sexes (p = 0.286). However, multiple linear regression analyses after adjusting for factors influencing arterial stiffness, i.e., sex, age, body mass index, smoking status, hypertension, diabetes, the severity of the acute COVID-19, and the time from the disease onset, confirmed that age, sex, time from disease onset, and diabetes are the most important determinants that could influence arterial stiffness.
276	CaV272		Moscucci, Federica; Gallina, Sabina; Bucciarelli, Valentina; Aimo, Alberto; Pelà, Giovanna; Cadeddu-Dessalvi, Christian; Nodari, Savina; Maffei, Silvia; Meloni, Antonella; Deidda, Martino; Mercuro, Giuseppe; Pedrinelli, Roberto; Penco, Maria; Sciomer, Susanna; Vittoria Mattioli, Anna	Impact of COVID-19 on the cardiovascular health of women: a review by the Italian Society of Cardiology Working Group on ‘gender cardiovascular diseases’	https://doi.org/10.2459/JCM.0000000000001398	Published		Review	https://journals.lww.com/jcardiovascularmedicine/Fulltext/9900/Impact_of_COVID_19_on_the_cardiovascular_health_of.81.aspx	The coronavirus disease 19 (COVID-19), due to coronavirus 2 (SARS-CoV-2) infection, presents with an extremely heterogeneous spectrum of symptoms and signs. COVID-19 susceptibility and mortality show a significant sex imbalance, with men being more prone to infection and showing a higher rate of hospitalization and mortality than women. In particular, cardiovascular diseases (preexistent or arising upon infection) play a central role in COVID-19 outcomes, differently in men and women. This review will discuss the potential mechanisms accounting for sex/gender influence in vulnerability to COVID-19. Such variability can be ascribed to both sex-related biological factors and sex-related behavioural traits. Sex differences in cardiovascular disease and COVID-19 involve the endothelial dysfunction, the innate immune system and the renin-angiotensin system (RAS). Furthermore, the angiotensin-converting enzyme 2 (ACE2) is involved in disease pathogenesis in cardiovascular disease and COVID-19 and it shows hormone-dependent actions. The incidence of myocardial injury during COVID-19 is sex-dependent, predominantly in association with a greater degree of inflammation and coagulation disorders among men. Its pathogenesis is not fully elucidated, but the main theories foresee a direct role for the ACE2 receptor, the hyperimmune response and the RAS imbalance, which may also lead to isolated presentation of COVID-19-mediated myopericarditis. Moreover, the latest evidence on cardiovascular diseases and their relationship with COVID-19 during pregnancy will be discussed. Finally, authors will analyse the prevalence of the long-covid syndrome between the two sexes and its impact on the quality of life and cardiovascular health.
277	CaV273		Ruberg, Frederick L.; Baggish, Aaron L.; Hays, Allison G.; Jerosch-Herold, Michael; Kim, Jiwon; Ordovas, Karen G.; Reddy, Gautham; Shenoy, Chetan; Weinsaft, Jonathan W.; Woodard, Pamela K.	Utilization of cardiovascular magnetic resonance (CMR) imaging for resumption of athletic activities following COVID-19 infection: an expert consensus document on behalf of the American Heart Association Council on Cardiovascular Radiology and Intervention (CVRI) Leadership and endorsed by the Society for Cardiovascular Magnetic Resonance (SCMR)	https://doi.org/10.1186/s12968-022-00907-8	Published	2022-12-21	Review	https://doi.org/10.1186/s12968-022-00907-8	The global pandemic of coronavirus disease 2019 (COVID-19) caused by infection with severe acute respiratory suyndrome coronavirus 2 (SARS-CoV-2) is now entering its 4th year with little evidence of abatement. As of December 2022, the World Health Organization Coronavirus (COVID-19) Dashboard reported 643 million cumulative confirmed cases of COVID-19 worldwide and 98 million in the United States alone as the country with the highest number of cases. While pneumonia with lung injury has been the manifestation of COVID-19 principally responsible for morbidity and mortality, myocardial inflammation and systolic dysfunction though uncommon are well-recognized features that also associate with adverse prognosis. Given the broad swath of the population infected with COVID-19, the large number of affected professional, collegiate, and amateur athletes raises concern regarding the safe resumption of athletic activity (return to play, RTP) following resolution of infection. A variety of different testing combinations that leverage the electrocardiogram, echocardiography, circulating cardiac biomarkers, and cardiovascular magnetic resonance (CMR) imaging have been proposed and implemented to mitigate risk. CMR in particular affords high sensitivity for myocarditis but has been employed and interpreted non-uniformly in the context of COVID-19 thereby raising uncertainty as to the generalizability and clinical relevance of findings with respect to RTP. This consensus document synthesizes available evidence to contextualize the appropriate utilization of CMR in the RTP assessment of athletes with prior COVID-19 infection to facilitate informed, evidence-based decisions, while identifying knowledge gaps that merit further investigation.
278	CaV274		Ståhlberg, Marcus; Fedorowski, Artur	Cardiovascular autonomic abnormalities in patients with Post-acute Sequalae of COVID-19: don’t miss that target!	https://doi.org/10.1016/j.cjca.2022.12.021	Published	2022-12-28	Editorial	https://www.onlinecjc.ca/article/S0828-282X(22)01117-5/fulltext	publisher: Elsevier PMID: 36586481 A massive and sustained world-wide spread of the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has triggered a pandemic that has lasted for three years now and generated > 600 million reported cases around the globe. It has been increasingly evident that a substantial portion of patients who develop Corona Virus Disease 2019 (COVID-19) do not recover completely but rather experience lingering symptoms for months to years. This novel clinical syndrome is has been termed Long COVID or Post-acute Sequalae of COVID-19 (PASC), and has been defined by the World Health Organization as ongoing symptoms beyond three months from the acute illness due to confirmed or suspected SARS-CoV-2 infection that cannot be explained by other diseases1. The prevalence of PASC in patients with COVID-19 varies based on definition and setting and has been reported to be between 68% in hospitalized 2 and 13% in non-hospitalized patients 3. It’s beyond any doubt that this novel clinical syndrome has profound negative effects on individual patients, healthcare sectors and whole societies. Case reports and smaller observational cohort studies have indicated that PASC can be associated with cardiovascular (CV) autonomic dysfunction including postural orthostatic tachycardia syndrome (POTS), inappropriate sinus tachycardia (IST), and orthostatic hypotension (OH)4, 5, 6, 7. This is important since CV dysautonomias are conditions that often can be successfully treated with substantial symptom improvement, while virtually no evidence exists for effective treatment of PASC itself. The prevalence of CV autonomic dysfunction in PASC remains largely unknown but is important to comprehend since it will highlight dysautonomia as a specific sequalae of acute COVID-19, establish pre-test likelihood and guide the development of diagnostic work-up protocols for unsorted PASC patients. Cardiovascular dysautonomia is common in PACS: more women but no difference between hospitalized and non-hospitalized patients Hira and colleagues should be complimented for the effort to determine the occurrence of cardiovascular autonomic abnormalities in PACS patients. In their study published in this issue8, 70 PASC patients completed a thorough investigation including active standing test, autonomic function testing (quantitative sudomotor axon reflex testing, deep breathing, and Valsalva maneuver) as well as symptom reports at a median of 399 days after a primary PCR-confirmed SARS-CoV-2 infection. A majority of included patients were females (80%) and did not require hospital treatment during the acute COVID-19 disease (87%). However, comorbidities, disease history and current medications as well as the exact inclusion criteria were not detailed. The authors report a high prevalence of CV dysautonomia in the overall cohort (73%), with the most prevalent abnormality being initial orthostatic hypotension (61%) and POTS (30%). Inappropriate sinus tachycardia was uncommon (1.4%) but it should be emphasized that prolonged ECG monitoring was not a part of study protocol, thus reducing the diagnostic accuracy for this specific abnormality.9 Moreover, tilt testing and 24-hour ambulatory blood pressure monitoring were not performed, which potentially may have affected the detection rate of delayed orthostatic hypotension and vasovagal syncope susceptibility, common dysautonomic conditions.7,10,11 POTS was found more frequently in females (36%) compared to males (7%, p=0.0037), and the overall prevalence of cardiovascular dysautonomia was similar in hospitalized and non-hospitalized patients which implies that initial disease severity is not a risk factor for developing dysautonomia in PASC patients. Strengths and weaknesses of the study The study has several strengths. Previous data on the prevalence of specific forms of CV dysautonomia in PASC relied mostly on case reports, case series, smaller observational studies, and symptom questionnaires. In contrast, the current paper includes a fairly large patient cohort that are well characterized in terms of hemodynamic response to active standing test, and by other autonomic tests as well as by presence and severity of symptoms common in dysautonomia. Patients were evaluated on average one year after the primary SARS-CoV-2 infection which is important when interpreting the results. Persistence of CV dysautonomia long time after initial infection suggests that these symptoms and hemodynamic findings are in many unlikely to resolve shortly after the initial infection. One might suspect that the number of patients affected by CV autonomic abnormalities may have been higher at three or six months after acute illness but that some may have recovered before the evaluation one year after. It is also our clinical experience that symptoms and hemodynamic findings during orthostatic tests may change over a longer follow-up period. Therefore, an important study limitation is that testing for CV dysautonomia was performed only once. In general, to describe accurately prevalence of a disease in population, a larger number of evaluated subjects is needed. The study by Hira and colleagues is therefore limited by the relatively small number of included patients. It is additionally difficult to draw conclusions on sex differences (only 20% males) and importance of hospitalization (only 13% were hospitalized) as these subgroups were even smaller. Furthermore, most patients were recruited from referral centers (dedicated PASC centers and/or dysautonomia clinics) which likely makes the study population highly selected. Consequently, it’s difficult to extrapolate these findings onto general PASC population. One can assume that patients evaluated at these centers experienced longer PASC duration and more severe functional impairment compared with an average PASC patient thus biasing the study toward a sicker population. Therefore, the prevalence numbers reported by Hira and colleagues should be interpreted with caution as representative for specialized post-COVID centers, not the general PASC population. The proportions of POTS, for instance, reported here are however in line with our personal experience from a similar tertiary center, and find support in previous reports.12 Importantly, the present study included only Caucasians from the same geographical region and hence, studies in other races and geographical regions are needed to establish the global impact of CV dysautonomia on PASC. Two other aspects we wish to highlight as important when interpreting these results are that 80% of patients were evaluated before COVID-19 vaccination and that data on when the initial COVID-19 disease occurred were not presented. First, COVID-19 vaccination itself can induce prolonged symptoms and physical findings consistent with CV dysautonomia although POTS is diagnosed at a much lower rate after vaccination than after contracting the virus13. Second, the SARS-CoV-2 has mutated several times during the pandemic, and it is unknown whether different SARS-CoV-2 strains are more prone to trigger CV dysautonomia. Thus, the prevalence of dysautonomia in PASC population may change after vaccination or according to the viral strand causing the primary infection. However, we consider it unlikely that these factors would have a decisive effect on the overall incidence of autonomic disturbances in the study. Conclusion Although some limitations exist, the study constitutes an important contribution to our understanding of the role of cardiovascular autonomic dysfunction in the post-COVID condition. Patients were systematically evaluated and majority were diagnosed with at least one objective, symptomatic and potentially treatable autonomic abnormality. These findings highlight the need for specialized autonomic clinics and imply that a high suspicion of cardiovascular dysautonomia should be raised in patients not recovering swiftly from acute COVID-19.
279	CaV275		Matsumoto, Chisa; Shibata, Shigeru; Kishi, Takuya; Morimoto, Satoshi; Mogi, Masaki; Yamamoto, Koichi; Kobayashi, Kazuo; Tanaka, Masami; Asayama, Kei; Yamamoto, Eiichiro; Nakagami, Hironori; Hoshide, Satoshi; Mukoyama, Masashi; Kario, Kazuomi; Node, Koichi; Rakugi, Hiromi	Long COVID and hypertension-related disorders: a report from the Japanese Society of Hypertension Project Team on COVID-19	https://doi.org/10.1038/s41440-022-01145-2	Published	2022-12-27	Review	https://www.nature.com/articles/s41440-022-01145-2	The coronavirus disease 2019 (COVID-19) affects infected patients even after the acute phase and impairs their health and quality of life by causing a wide variety of symptoms, referred to as long COVID. Although the evidence is still insufficient, hypertension is suspected to be a potential risk factor for long COVID, and the occurrence of cardiovascular diseases seems to be a key facet of multiple conditions observed in long COVID. Nonetheless, there are few reports that comprehensively review the impacts of long COVID on hypertension and related disorders. As a sequel to our previous report in 2020 which reviewed the association of COVID-19 and hypertension, we summarize the possible influences of long COVID on hypertension-related organs, including the cardiovascular system, kidney, and endocrine system, as well as the pathophysiological mechanisms associated with the disorders in this review. Given that the clinical course of COVID-19 is highly affected by age and sex, we also review the impacts of these factors on long COVID. Lastly, we discuss areas of uncertainty and future directions, which may lead to better understanding and improved prognosis of clinical problems associated with COVID-19.
280	CaV276		Zuin, Marco; Rigatelli, Gianluca; Roncon, Loris; Pasquetto, Gianpaolo; Bilato, Claudio	Risk of incident heart failure after COVID-19 recovery: a systematic review and meta-analysis	https://doi.org/10.1007/s10741-022-10292-0	Published	2022-12-27	Study	https://doi.org/10.1007/s10741-022-10292-0	Patients recovered from COVID-19 have an increased incidence of cardiovascular disease and heart structural changes. The aim of the present manuscript is to assess the risk of incident heart failure (HF) after COVID-19 infection. Data were obtained searching MEDLINE and Scopus for all studies published at any time up to September 1, 2022 reporting the risk of incident HF in COVID-19 recovered patients. The cumulative post-COVID-19 incidence and risk of incident HF were pooled using a random effects model and presented with the corresponding 95% confidence interval (CI). Statistical heterogeneity was measured using the Higgins I2 statistic. Overall, 21,463,173 patients (mean age 54.5 years, 58.7% males) were analyzed. Among them, 1,628,424 had confirmed COVID-19 infection while the remaining 19,834,749 represented the controls. The mean length of follow-up was 9.2 months. A random effect model revealed a pooled incidence of post COVID-19 HF in 1.1% of cases (95% CI: 0.7–1.6, I2: 99.8%). Moreover, recovered COVID-19 patients showed an increased risk of incident HF (HR: 1.90, 95% CI: 1.54–3.24, p < 0.0001, I2 = 96.5%) in the same follow-up period. Meta-regression showed a direct relationship for the risk of incident HF using age (p = 0.001) and hypertension (HT) (p = 0.02) as moderators, while an inverse association was observed when the follow-up length was adopted as moderating variable (p = 0.01). COVID-19 survivors had an additional 90% risk of developing HF after COVID-19 infection in the long-term period. This risk was directly related with age and previous history of HT especially in the early post-acute phase of the infection.
281	CaV277		Płazak, Wojciech; Drabik, Leszek	SARS-CoV-2 infection and SLE: endothelial dysfunction, atherosclerosis, and thrombosis	https://doi.org/10.1007/s10067-022-06497-1	Published	2023-01-09	Review	https://doi.org/10.1007/s10067-022-06497-1	Abstract An increased risk of atherosclerotic and thrombotic complications characterizes connective tissue diseases. Endothelial dysfunction is the basis for the initiation and progression of atherosclerosis and thrombosis. We present systemic lupus erythematosus (SLE) as a model rheumatic disease with endothelial dysfunction and discuss its mechanisms, factors that influence the early onset and rapid progression of atherosclerosis, and the increased risk of thromboembolic events. We focus on established methods to improve endothelium function, including statins, antiplatelet, and antithrombotic therapy. Hypercoagulable and hypofibrinolitic states and a hyperinflammatory response characterize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Several pathogenic mechanisms are typical for an acute phase of Covid-19 post-Covid syndrome and connective tissue diseases: endothelial dysfunction, elevated antiphospholipid antibody titer, activation of the complement system, and formation of extracellular neutrophil traps (NET). The current review discusses the mechanisms underlying SLE and the COVID-19 in the context of endothelial function, atherosclerosis, and thrombosis (Graphical abstract). Key Points • The pathophysiology of systemic lupus erythematosus (SLE) and Covid-19 shows some similarities, such as endothelial cell activation and dysfunction, the activation of complementary systems, the presence of antiphospholipid antibodies, and the formation of extracellular neutrophil traps. • Autoimmunity in both diseases creates the basis for hyperinflammatory, hypercoagulable, and hypofibrinolitic states and their thromboembolic complications. • This paper presents our perspective on the mechanisms behind the cardiovascular manifestations of SLE and COVID-19, with a particular emphasis on endothelial dysfunction. Graphical abstract Covid-19 and systemic lupus erythematosus—potential similarities in pathophysiology. Figures of the panel illustrate the clinical manifestations of endothelial dysfunction, atherosclerosis, and thromboembolism, including coronary artery disease ([A] coronary angiography with left anterior descending artery stenosis and [B] scintigraphy with reduced perfusion in the myocardial apical segments), stroke ([C] carotid angiography, left carotid artery occlusion) and pulmonary embolism ([D]computed tomography with thrombus in the right pulmonary artery).
282	CaV278		Martingano, Daniel; Santana, Eddie; Mehta, Prutha; Ngyuen, Ashley; Al-Dulaimi, Marwa; Robertson, Katie; Menefee, Christopher; Ouyang, Andrea; Herben, Camilla; Singh, Shailini; Marecheau, Jacqueline; Dribus, Benjamin F.	Effect of Respiratory and Anticoagulation Medications on Long Covid in the Postpartum Period	https://doi.org/10.1016/j.ajog.2022.11.254	Published	2023-01-01	Study	https://www.ajog.org/article/S0002-9378(22)01138-3/fulltext	publisher: Elsevier Objective Long Covid (LC) is a collective term referring to the persistence of symptoms and complications related to those acquiring an acute SARS-CoV-2 infection. This study sought to evaluate the potential benefits of certain medications often employed empirically in the management of LC for pregnant patients in the 3rd trimester and postpartum periods. Study Design We conducted a multi-center, prospective observational study from 7/2021 to 7/2022 comparing all pregnant women diagnosed with SARS-CoV-2 infection (CoV-2) in the 3rd trimester through 6 weeks postpartum. The primary outcomes included the development of LC and improvement following treatment. Patients with preexisting respiratory, hematological, or neurological disorders or preterm delivery < 37 weeks-gestation, were excluded. Medications including any CoV-2 antiviral treatment, enoxaparin, aspirin, inhaled corticosteroids with or without a long-acting beta blocker, theophylline, leukotriene receptor antagonists, and 1st generation antihistamines were included as covariates. Primary outcomes were determined by patient-reported symptoms and provider interpretation in the immediate postpartum, 1-week postpartum (1P), and 6-week postpartum (6P) periods. Results The study included 444 patients diagnosed with LC. 291 (65.6%) patients received enoxaparin at time of diagnosis continued weekly until 6 weeks postpartum. Patients who received enoxaparin were less likely to report LC at the 1P and 6P visits (39.2% v. 54.9%, p = 0.02). LC was not significantly different when comparing patients who received antiviral therapies to those who did not. Patients with LC were more likely to report improvement when taking aspirin 325mg (19.8% v. 11.3%, p = 0.003) or when taking theophylline (22.9% v. 14.2%, p = 0.01). After adjusting for confounding factors these differences remained significant. Conclusion These findings suggest that treatments targeting the circulatory system may prove more useful for LC in the 3rd trimester and postpartum period than other types of medications.
283	CaV279		Durrington, Paul	Blood lipids after COVID-19 infection	https://doi.org/10.1016/S2213-8587(22)00389-8	Published	2023-01-06	Commentary	https://www.thelancet.com/journals/landia/article/PIIS2213-8587(22)00389-8/fulltext	publisher: Elsevier PMID: 36623516 The report by Xu and colleagues3 raises fundamental questions about the origins of dyslipidaemia in general. We know that the acute effect of infection or serious illnesses from other causes is to lower LDL cholesterol, sometimes profoundly.4, 5 At the same time there is a tendency for triglycerides to rise and for HDL cholesterol to decrease. LDL cholesterol is usually restored to premorbid concentrations as the acute illness abates, but in chronic inflammation the increase in triglyceride and decreased HDL persists probably due to the effect of inflammatory cytokines.4, 5 Although the aetiology of long COVID remains speculative, clear evidence that a state of chronic inflammation can persist even in asymptomatic survivors is accruing.6, 7 During such inflammation, the composition and functional capacity of HDL also changes and it has thus been called pro-inflammatory or pro-atherogenic HDL. Serum amyloid A, released during inflammation, interferes with the ability of HDL to protect LDL from pro-atherogenic modifications such as oxidation and glycation. Furthermore, decreases in apolipoprotein A1 in HDL reduce its capacity to receive excess tissue cholesterol, which is believed to occur through the ATP binding cassette A1 and to be an important early phase of reverse cholesterol transport.5 • View related content for this article The effects of chronic inflammation on lipoprotein metabolism have been extensively investigated in obesity. Adipose tissue, particularly when it is centrally located (metabolic syndrome), contains inflammatory cells that release cytokines causing dyslipidaemia. Reversal by bariatric surgery restores triglyceride and HDL metabolism towards normality, but has little effect on LDL cholesterol.8 Persisting effects on LDL after the apparent resolution of inflammation are unexplained and remind us just how imperfect our knowledge is of what determines LDL cholesterol concentrations in adulthood. Recently, because of their potential to lower LDL cholesterol by pharmacological inhibition, interest has sparked in two factors that influence the balance between LDL catabolism and production. These are proprotein convertase subtilisin or kexin type 9 (PCSK9), which has a major effect on hepatic receptor-mediated LDL catabolism9 and angiopoietin-like protein 3 (ANGPTL3), which regulates the production of LDL from its precursor very low density lipoprotein.10 It has been hypothesised that both can increase during inflammation.9, 10, 11 We clearly need to learn more about how cholesterol metabolism is permanently imprinted by nutrition and infection or inflammation.
284	CaV280		Krug, Ethan; Geckeler, Keara C.; Frishman, William H.	Cardiovascular Manifestations of Long COVID: A Review	https://doi.org/10.1097/CRD.0000000000000520	Published	2023-01-06	Review	https://journals.lww.com/cardiologyinreview/Abstract/9900/Cardiovascular_Manifestations_of_Long_COVID__A.65.aspx	The acute phase of severe acute respiratory syndrome coronavirus 2 [coronavirus disease (COVID)] infection has many well-documented cardiovascular manifestations, however, the long-term sequelae are less understood. In this focused review, we explore the risk factors, character, and rates of cardiovascular events in patients with Long COVID, which is defined as symptoms occurring more than 4 weeks following initial infection. Research has identified increased rates of cerebrovascular disease, dysrhythmias, ischemic and inflammatory heart disease, cardiopulmonary symptoms, and thrombotic events among those with Long COVID, though the risk rates and potential mechanisms behind each cardiovascular event vary. Finally, we discuss the current gaps in the literature as well as how COVID compares to other viral infections when it comes to causing long-term cardiovascular sequelae.
285	CaV281		Ortega-Paz, Luis; Arévalos, Victor; Fernández-Rodríguez, Diego; Jiménez-Díaz, Víctor; Bañeras, Jordi; Campo, Gianluca; Rodríguez-Santamarta, Miguel; Díaz, José Francisco; Scardino, Claudia; Gómez-Álvarez, Zaira; Pernigotti, Alberto; Alfonso, Fernando; Amat-Santos, Ignacio J.; Silvestro, Antonio; Rampa, Lorenzo; Hernández, José M. de la Torre; Bastidas, Gabriela; Gómez-Lara, Josep; Bikdeli, Behnood; García-García, Hector M.; Angiolillo, Dominick J.; Rodés-Cabau, Josep; Sabaté, Manel; Brugaletta, Salvatore; Investigators, on behalf of the CV COVID-19 registry	One-year cardiovascular outcomes after coronavirus disease 2019: The cardiovascular COVID-19 registry	https://doi.org/10.1371/journal.pone.0279333	Published	2022-12-30	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0279333	Background The long-term cardiovascular (CV) outcomes of COVID-19 have not been fully explored. Methods This was an international, multicenter, retrospective cohort study conducted between February and December 2020. Consecutive patients ≥18 years who underwent a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) for SARS-CoV2 were included. Patients were classified into two cohorts depending on the nasopharyngeal swab result and clinical status: confirmed COVID-19 (positive RT-PCR) and control (without suggestive symptoms and negative RT-PCR). Data were obtained from electronic records, and clinical follow-up was performed at 1-year. The primary outcome was CV death at 1-year. Secondary outcomes included arterial thrombotic events (ATE), venous thromboembolism (VTE), and serious cardiac arrhythmias. An independent clinical event committee adjudicated events. A Cox proportional hazards model adjusted for all baseline characteristics was used for comparing outcomes between groups. A prespecified landmark analysis was performed to assess events during the post-acute phase (31–365 days). Results A total of 4,427 patients were included: 3,578 (80.8%) in the COVID-19 and 849 (19.2%) control cohorts. At one year, there were no significant differences in the primary endpoint of CV death between the COVID-19 and control cohorts (1.4% vs. 0.8%; HRadj 1.28 [0.56–2.91]; p = 0.555), but there was a higher risk of all-cause death (17.8% vs. 4.0%; HRadj 2.82 [1.99–4.0]; p = 0.001). COVID-19 cohort had higher rates of ATE (2.5% vs. 0.8%, HRadj 2.26 [1.02–4.99]; p = 0.044), VTE (3.7% vs. 0.4%, HRadj 9.33 [2.93–29.70]; p = 0.001), and serious cardiac arrhythmias (2.5% vs. 0.6%, HRadj 3.37 [1.35–8.46]; p = 0.010). During the post-acute phase, there were no significant differences in CV death (0.6% vs. 0.7%; HRadj 0.67 [0.25–1.80]; p = 0.425), but there was a higher risk of deep vein thrombosis (0.6% vs. 0.0%; p = 0.028). Re-hospitalization rate was lower in the COVID-19 cohort compared to the control cohort (13.9% vs. 20.6%; p = 0.001). Conclusions At 1-year, patients with COVID-19 experienced an increased risk of all-cause death and adverse CV events, including ATE, VTE, and serious cardiac arrhythmias, but not CV death. Study registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT04359927.
286	CaV282		Kusumawardhani, Nuraini Yasmin; Putra, Iwan Cahyo Santosa; Kamarullah, William; Afrianti, Rien; Pramudyo, Miftah; Iqbal, Mohammad; Prameswari, Hawani Sasmaya; Achmad, Chaerul; Tiksnadi, Badai Bhatara; Akbar, Mohammad Rizki	Cardiovascular Disease in Post-Acute COVID-19 Syndrome: A Comprehensive Review of Pathophysiology and Diagnosis Approach	https://doi.org/10.31083/j.rcm2401028	Published	2023-01-13	Review	https://www.imrpress.com/journal/RCM/24/1/10.31083/j.rcm2401028	Long COVID or post-acute Coronavirus disease 2019 (COVID-19), a malady defined by the persistence of COVID-19 symptoms for weeks or even months, is expected to affect the lives of millions of individuals worldwide significantly. Cardiopulmonary symptoms such as chest discomfort, shortness of breath, fatigue, and autonomic manifestations such as postural orthostatic tachycardia syndrome, and arrhythmias are prevalent and widely recognized. A variety of cardiovascular problems, including myocardial inflammation, myocardial infarction, ventricular dysfunction, and endothelial dysfunction, have been described in individuals following the initial acute phase. With over 10,000 published publications on COVID-19 and the cardiovascular system, presenting an unbiased thorough analysis of how SARS-CoV-2 affects the system is essentially challenging. This review will provide an overview of frequent cardiovascular manifestations, emphasizing consequences, proposed pathophysiology, and clinical diagnostic manifestation strategy.
287	CaV283		Kumar, Rahul; Aktay-Cetin, Öznur; Craddock, Vaughn; Morales-Cano, Daniel; Kosanovic, Djuro; Cogolludo, Angel; Perez-Vizcaino, Francisco; Avdeev, Sergey; Kumar, Ashok; Ram, Anil Kumar; Agarwal, Stuti; Chakraborty, Ananya; Savai, Rajkumar; Perez, Vinicio de Jesus; Graham, Brian B.; Butrous, Ghazwan; Dhillon, Navneet K.	Potential long-term effects of SARS-CoV-2 infection on the pulmonary vasculature: Multilayered cross-talks in the setting of coinfections and comorbidities	https://doi.org/10.1371/journal.ppat.1011063	Published	2023-01-12	Review	https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1011063	The Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its sublineages pose a new challenge to healthcare systems worldwide due to its ability to efficiently spread in immunized populations and its resistance to currently available therapies. COVID-19, although targeting primarily the respiratory system, is also now well established that later affects every organ in the body. Most importantly, despite the available therapy and vaccine-elicited protection, the long-term consequences of viral infection in breakthrough and asymptomatic individuals are areas of concern. In the past two years, investigators accumulated evidence on how the virus triggers our immune system and the molecular signals involved in the cross-talk between immune cells and structural cells in the pulmonary vasculature to drive pathological lung complications such as endothelial dysfunction and thrombosis. In the review, we emphasize recent updates on the pathophysiological inflammatory and immune responses associated with SARS-CoV-2 infection and their potential long-term consequences that may consequently lead to the development of pulmonary vascular diseases.
288	CaV284		Zanini, Giada; Selleri, Valentina; Roncati, Luca; Coppi, Francesca; Nasi, Milena; Farinetti, Alberto; Manenti, Antonio; Pinti, Marcello; Mattioli, Anna Vittoria	Vascular “Long COVID”: A New Vessel Disease?	https://doi.org/10.1177/00033197231153204	Published	2023-01-18	Review	https://doi.org/10.1177/00033197231153204	Vascular sequelae following (SARS-CoV-2 coronavirus disease) (COVID)-19 infection are considered as ?Long Covid (LC)? disease, when occurring 12 weeks after the original infection. The paucity of specific data can be obviated by translating pathophysiological elements from the original Severe Acute Respiratory Syndrome-Corona Virus (SARS-CoV-2) infection (In a microcirculatory system, a first ?endotheliitis,? is often followed by production of ?Neutrophil Extracellular Trap,? and can evolve into a more complex leukocytoklastic-like and hyperimmune vasculitis. In medium/large-sized vessels, this corresponds to endothelial dysfunction, leading to an accelerated progression of pre-existing atherosclerotic plaques through an increased deposition of platelets, circulating inflammatory cells and proteins. Associated dysregulated immune and pro-coagulant conditions can directly cause thrombo-embolic arterial or venous complications. In order to implement appropriate treatment, physicians need to consider vascular pathologies observed after SARS-Cov-2 infections as possible ?LC? disease.
289	CaV285		Wan, Eric Yuk Fai; Mathur, Sukriti; Zhang, Ran; Yan, Vincent Ka Chun; Lai, Francisco Tsz Tsun; Chui, Celine Sze Ling; Li, Xue; Wong, Carlos King Ho; Chan, Esther Wai Yin; Yiu, Kai Hang; Wong, Ian Chi Kei	Association of COVID-19 with short- and long-term risk of cardiovascular disease and mortality: a prospective cohort in UK Biobank	https://doi.org/10.1093/cvr/cvac195	Published	2023-01-19	Study	https://doi.org/10.1093/cvr/cvac195	This study aims to evaluate the short- and long-term associations between COVID-19 and development of cardiovascular disease (CVD) outcomes and mortality in the general population.A prospective cohort of patients with COVID-19 infection between 16 March 2020 and 30 November 2020 was identified from UK Biobank, and followed for up to 18 months, until 31 August 2021. Based on age (within 5 years) and sex, each case was randomly matched with up to 10 participants without COVID-19 infection from two cohorts—a contemporary cohort between 16 March 2020 and 30 November 2020 and a historical cohort between 16 March 2018 and 30 November 2018. The characteristics between groups were further adjusted with propensity score-based marginal mean weighting through stratification. To determine the association of COVID-19 with CVD and mortality within 21 days of diagnosis (acute phase) and after this period (post-acute phase), Cox regression was employed. In the acute phase, patients with COVID-19 (n = 7584) were associated with a significantly higher short-term risk of CVD {hazard ratio (HR): 4.3 [95% confidence interval (CI): 2.6– 6.9]; HR: 5.0 (95% CI: 3.0–8.1)} and all-cause mortality [HR: 81.1 (95% CI: 58.5–112.4); HR: 67.5 (95% CI: 49.9–91.1)] than the contemporary (n = 75 790) and historical controls (n = 75 774), respectively. Regarding the post-acute phase, patients with COVID-19 (n = 7139) persisted with a significantly higher risk of CVD in the long-term [HR: 1.4 (95% CI: 1.2–1.8); HR: 1.3 (95% CI: 1.1– 1.6)] and all-cause mortality [HR: 5.0 (95% CI: 4.3–5.8); HR: 4.5 (95% CI: 3.9–5.2) compared to the contemporary (n = 71 296) and historical controls (n = 71 314), respectively.COVID-19 infection, including long-COVID, is associated with increased short- and long-term risks of CVD and mortality. Ongoing monitoring of signs and symptoms of developing these cardiovascular complications post diagnosis and up till at least a year post recovery may benefit infected patients, especially those with severe disease.
290	CaV286		Ashton, Ruth E.; Philips, Bethan E.; Faghy, Mark	The acute and chronic implications of the COVID-19 virus on the cardiovascular system in adults: A systematic review	https://doi.org/10.1016/j.pcad.2023.01.003	Published	2023-01-20	Review	https://www.sciencedirect.com/science/article/pii/S003306202300004X	Despite coronavirus disease 2019 (COVID-19) primarily being identified as a respiratory illness, some patients who seemingly recovered from initial infection, developed chronic multi-system complications such as cardiovascular (CV), pulmonary and neurological issues leading to multiple organ injuries. However, to date, there is a dearth of understanding of the acute and chronic implications of a COVID-19 infection on the CV system in adults. A systematic review of the literature was conducted according to PRISMA guidelines and prospectively registered via Prospero (ID: CRD42022360444). The MEDLINE Ovid, Cochrane Library and PubMed databases were searched from inception to August 2022. The search strategy keywords and MeSH terms used included: 1) COVID; 2) coronavirus; 3) long COVID; 4) cardiovascular; and 5) cardiovascular disease. Reference lists of all relevant systematic reviews identified were searched for additional studies. A total of 11,332 records were retrieved from database searches, of which 310 records were duplicates. A further 9887 were eliminated following screening of titles and abstracts. After full-text screening of 1135 articles, 9 manuscripts were included for review. The evidence of CV implications post-COVID-19 infection is clear, and this must be addressed with appropriate management strategies that recognise the acute and chronic nature of cardiac injury in COVID-19 patients. Efficacious management strategies will be needed to address long standing issues and morbidity.
291	CaV287		Gyöngyösi, Mariann; Alcaide, Pilar; Asselbergs, Folkert W; Brundel, Bianca J J M; Camici, Giovanni G; Martins, Paula da Costa; Ferdinandy, Péter; Fontana, Marianna; Girao, Henrique; Gnecchi, Massimiliano; Gollmann-Tepeköylü, Can; Kleinbongard, Petra; Krieg, Thomas; Madonna, Rosalinda; Paillard, Melanie; Pantazis, Antonis; Perrino, Cinzia; Pesce, Maurizio; Schiattarella, Gabriele G; Sluijter, Joost P G; Steffens, Sabine; Tschöpe, Carsten; Van Linthout, Sophie; Davidson, Sean M	Long COVID and the cardiovascular system—elucidating causes and cellular mechanisms in order to develop targeted diagnostic and therapeutic strategies: a joint Scientific Statement of the ESC Working Groups on Cellular Biology of the Heart and Myocardial and Pericardial Diseases	https://doi.org/10.1093/cvr/cvac115	Published	2022-07-25	Review	https://doi.org/10.1093/cvr/cvac115	Long COVID has become a world-wide, non-communicable epidemic, caused by long-lasting multiorgan symptoms that endure for weeks or months after SARS-CoV-2 infection has already subsided. This scientific document aims to provide insight into the possible causes and therapeutic options available for the cardiovascular manifestations of long COVID. In addition to chronic fatigue, which is a common symptom of long COVID, patients may present with chest pain, ECG abnormalities, postural orthostatic tachycardia, or newly developed supraventricular or ventricular arrhythmias. Imaging of the heart and vessels has provided evidence of chronic, post-infectious perimyocarditis with consequent left or right ventricular failure, arterial wall inflammation, or microthrombosis in certain patient populations. Better understanding of the underlying cellular and molecular mechanisms of long COVID will aid in the development of effective treatment strategies for its cardiovascular manifestations. A number of mechanisms have been proposed, including those involving direct effects on the myocardium, microthrombotic damage to vessels or endothelium, or persistent inflammation. Unfortunately, existing circulating biomarkers, coagulation, and inflammatory markers, are not highly predictive for either the presence or outcome of long COVID when measured 3 months after SARS-CoV-2 infection. Further studies are needed to understand underlying mechanisms, identify specific biomarkers, and guide future preventive strategies or treatments to address long COVID and its cardiovascular sequelae.
292	CaV288		Yong, Shin Jie; Halim, Alice; Halim, Michael; Liu, Shiliang; Aljeldah, Mohammed; Al Shammari, Basim R.; Alwarthan, Sara; Alhajri, Mashael; Alawfi, Abdulsalam; Alshengeti, Amer; Khamis, Faryal; Alsalman, Jameela; Alshukairi, Abeer N.; Abukhamis, Nujoud A.; Almaghrabi, Fatimah S.; Almuthree, Souad A.; Alsulaiman, Abdulrahman M.; Alshehail, Bashayer M.; Alfaraj, Amal H.; Alhawaj, Shorouq A.; Mohapatra, Ranjan K.; Rabaan, Ali A.	Inflammatory and vascular biomarkers in post-COVID-19 syndrome: A systematic review and meta-analysis of over 20 biomarkers	https://doi.org/10.1002/rmv.2424	Published	2023-01-27	Study	https://onlinelibrary.wiley.com/doi/abs/10.1002/rmv.2424	Severe acute respiratory syndrome coronavirus 2 may inflict a post-viral condition known as post-COVID-19 syndrome (PCS) or long-COVID. Studies measuring levels of inflammatory and vascular biomarkers in blood, serum, or plasma of COVID-19 survivors with PCS versus non-PCS controls have produced mixed findings. Our review sought to meta-analyse those studies. A systematic literature search was performed across five databases until 25 June 2022, with an updated search on 1 November 2022. Data analyses were performed with Review Manager and R Studio statistical software. Twenty-four biomarkers from 23 studies were meta-analysed. Higher levels of C-reactive protein (Standardized mean difference (SMD) = 0.20; 95% CI: 0.02–0.39), D-dimer (SMD = 0.27; 95% CI: 0.09–0.46), lactate dehydrogenase (SMD = 0.30; 95% CI: 0.05–0.54), and leukocytes (SMD = 0.34; 95% CI: 0.02–0.66) were found in COVID-19 survivors with PCS than in those without PCS. After sensitivity analyses, lymphocytes (SMD = 0.30; 95% CI: 0.12–0.48) and interleukin-6 (SMD = 0.30; 95% CI: 0.12–0.49) were also significantly higher in PCS than non-PCS cases. No significant differences were noted in the remaining biomarkers investigated (e.g., ferritin, platelets, troponin, and fibrinogen). Subgroup analyses suggested the biomarker changes were mainly driven by PCS cases diagnosed via manifestation of organ abnormalities rather than symptomatic persistence, as well as PCS cases with duration of <6 than ≥6 months. In conclusion, our review pinpointed certain inflammatory and vascular biomarkers associated with PCS, which may shed light on potential new approaches to understanding, diagnosing, and treating PCS.
293	CaV289		Reis Carneiro, Diogo; Rocha, Isabel; Habek, Mario; Helbok, Raimund; Sellner, Johann; Struhal, Walter; Wenning, Gregor; Fanciulli, Alessandra	Clinical presentation and management strategies of cardiovascular autonomic dysfunction following a COVID-19 infection – A systematic review	https://doi.org/10.1111/ene.15714	Published	2023-01-24	Review	https://onlinelibrary.wiley.com/doi/abs/10.1111/ene.15714	Background Cardiovascular autonomic dysfunction may reportedly occur after a coronavirus-disease-2019 (COVID-19) infection, but the available evidence is scattered. Here we sought to understand the acute and mid-term effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on cardiovascular autonomic function. Methods We performed a systematic PubMed, Embase, Web of Science, medRxiv, and bioRxiv search for cases of cardiovascular autonomic dysfunction during an acute SARS-CoV-2 infection or post-COVID-19 condition. The clinical-demographic characteristics of individuals in the acute versus post-COVID-19 phase were compared. Results We screened 6470 titles and abstracts. Fifty-four full-length articles were included in the data synthesis. One-hundred and thirty-four cases were identified: 81 during the acute SARS-CoV-2 infection (24 thereof diagnosed by history) and 53 in the post-COVID-19 phase. Post-COVID-19 cases were younger than those with cardiovascular autonomic disturbances in the acute SARS-CoV-2 phase (42 vs. 51 years old, p = 0.002) and were more frequently women (68% vs. 49%, p = 0.034). Reflex syncope was the most common cardiovascular autonomic disorder in the acute phase (p = 0.008) and postural orthostatic tachycardia syndrome (POTS) the most frequent diagnosis in individuals with post-COVID-19 orthostatic complaints (p < 0.001). Full recovery was more frequent in individuals with acute versus post-COVID-19 onset of cardiovascular autonomic disturbances (43% vs. 15%, p = 0.002). Conclusions There is evidence from the scientific literature about different types of cardiovascular autonomic dysfunction developing during and after COVID-19. More data about the prevalence of autonomic disorders associated with a SARS-CoV-2 infection are needed to quantify its impact on human health.
294	CaV290		Shrestha, Abhigan Babu; Mehta, Aashna; Pokharel, Pashupati; Mishra, Aakash; Adhikari, Lukash; Shrestha, Sajina; Yadav, Randhir Sagar; Khanal, Surakshya; Sah, Ranjit; Nowrouzi-Kia, Behdin; Padhi, Bijaya Kumar; Chattu, Vijay Kumar	Long COVID Syndrome and Cardiovascular Manifestations: A Systematic Review and Meta-Analysis	https://doi.org/10.3390/diagnostics13030491	Published	2023-01-01	Systematic review and meta-analysis	https://www.mdpi.com/2075-4418/13/3/491	(1) Background: Long COVID syndrome is a significant cause of morbidity in COVID-19 patients who remain symptomatic with varied clinical presentations beyond three weeks. Furthermore, the relevance of considering cardiovascular outcomes in post-COVID-19 syndrome is important in the current COVID-19 pandemic; (2) Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed for this systematic review and meta-analysis. Systematic searches were conducted from multiple databases without language restrictions until October 8, 2022, to find studies evaluating cardiovascular outcomes such as arrhythmias, myocardium and pericardium diseases, coronary vessel disease, and thromboembolic disorders in post-COVID cases. The pooled odds ratio (OR), and standard mean difference (SMD) with their corresponding 95% confidence intervals (CI) were computed to find the association; (3) Results: Altogether, seven studies with a total of 8,126,462 (cases: 1,321,305; controls: 6,805,157) participants were included in the meta-analysis. Pooled odds ratios of cardiovascular outcomes were significantly higher in post-COVID cases (OR > 1, p < 0.05) than in controls. However, the mortality (OR: 4.76, p = 0.13), and heart rate variability (SMD: −0.06, p = 0.91) between cases and controls were not statistically significant; (4) Conclusions: Significant cardiovascular sequelae in long COVID syndrome highlight the importance of careful cardiac monitoring of COVID-19 patients in the post-COVID phase to address cardiovascular complications as soon as possible; larger-scale prospective studies are required for accurate estimation.
295	CaV291		Huseynov, Aydin; Akin, Ibrahim; Duerschmied, Daniel; Scharf, Rüdiger E.	Cardiac Arrhythmias in Post-COVID Syndrome: Prevalence, Pathology, Diagnosis, and Treatment	https://doi.org/10.3390/v15020389	Published	2023-02-01	Review	https://www.mdpi.com/1999-4915/15/2/389	An increase in post-COVID patients with late sequelae of acute COVID-19 infection is emerging as an ongoing challenge for physicians and healthcare professionals. Since the beginning of the pandemic, it has rapidly become evident that the acute infection is not limited to the respiratory tract but that several organs, including the cardiovascular system, can be affected. Moreover, in a significant proportion of patients (ranging from about 10 to up to 50%) with former COVID-19, cardiopulmonary symptoms such as dyspnea, palpitations, restricted physical capacity, and cardiac arrhythmias can persist weeks and months after the acute SARS-CoV-2 infection. The spectrum of COVID-19-associated arrhythmias is rather wide, most likely due to various pathomechanisms. In this article, the prevalence of cardiac arrhythmias and underlying pathologies are reviewed, including direct myocardial injury and abnormal consequences with an impact on cardiac electric instability. The hyperinflammatory reaction of the host immune system is specifically considered. Moreover, several distinct rhythm disorders occurring in post-COVID patients are discussed with regard to their clinical management.
296	CaV292		Doğan, Hasan; Kara, Aslı; Çankaya, Erdem; Balkan, Eda; Gürbüz, Muhammet Ali; Kızılkaya, Murat; Aykaç, Merve	Clinical Investigation of Leukocyte DNA Damage in COVID-19 Patients	https://doi.org/10.3390/cimb45020062	Published	2023-02-01	Study	https://www.mdpi.com/1467-3045/45/2/62	This prospective cross-sectional study aimed to evaluate leukocyte DNA damage in coronavirus disease (COVID-19) patients. In this study, 50 COVID-19-positive patients attending the Erzurum City Hospital Internal Medicine Outpatient Clinic and 42 control group patients were included. DNA damage was detected in living cells through leukocyte isolation in 50 COVID-19-positive patients using the comet assay method. DNA tail/head (olive) moments were evaluated and compared. White blood cells (WBC), red blood cells (RBC), hemoglobin (HGB), neutrophils (NEU), lymphocytes (LYM), eosinophils (EO), monocytes (MONO), basophils (BASO), platelets (PLT), and the neutrophil/lymphocyte ratio (NLR) were analyzed. The RBC, lymphocyte, eosinophil, and monocyte means were significantly higher in the control group (p < 0.05), whereas the HGB and neutrophile means were significantly higher in the study group (p < 0.05). There were significant negative correlations between COVID-19 and RBC (r = −0.863), LYM (r = −0.542), EO (r = −0.686), and MONO (r = −0.385). Meanwhile, there were significant positive correlations between COVID-19 and HGB (r = 0.863), NEU (r = 0.307), tail moment (r = 0.598), and olive moment (r = 0.582). Both the tail and olive moment mean differences were significantly higher in the study group, with higher ranges (p < 0.05). COVID-19 infection caused statistically significant increases in both the tail and olive damage percentage in patients, causing DNA damage. Lastly, the NLR rate was associated with the presence and progression of COVID-19.
297	CaV293		ZeinElabdeen, Shimaa Gamal; Sherif, Abdelsalam; Kandil, Nader Talaat; Altabib, Abdalaali Mohammed Omar; abdelrashid, Mahmoud Abdelaziz	Left atrial longitudinal strain analysis in long Covid-19 syndrome	https://doi.org/10.1007/s10554-023-02801-5	Published	2023-02-14	Study	https://doi.org/10.1007/s10554-023-02801-5	It is known that during the active course of Coronavirus disease 2019 (COVID-19), myocardial injury has an established pathological base, while its myocardial injury post-recovery is still obscured.The aim of this study was to evaluate the longitudinal left atrial strain (LAS) using speckle tracking echocardiography (STE) in COVID-19-recovered patients who are previously healthy without confounder comorbidities to detect the potential cardiac dysfunction.200 patients were prospectively included and examined 4?12 weeks after recovery from COVID-19 infection. 137 participants with comorbidities or previous history of cardiopulmonary disease were excluded from the analysis. A total of 63 patients who fulfilled our inclusion criteria were recruited into two groups according to thepresence or absence of persistent dyspnoea and exercise intolerance. Clinical, laboratory & comprehensive echocardiographic examinations were done for all. We observed that 31.7% of the previously healthy individuals developed dyspnoea & exercise intolerance post-COVID-19 infection. There were significantly impaired LAS parameters in the symptomatic group (LA reservoir, contraction & conduit strain, 22.7%, -6.6% & -16.1% versus 40%, -12%, and ? 27% in the asymptomatic group with P < 0.000). Only LA reservoir strain and LA stiffness can independently predict the development of dyspnoea & exercise intolerance post-COVID-19 at cut-off values of 30% & 24.5% respectively with a sensitivity of 90% and a specificity of 91%, P < 0.001. These impaired LAS parameters could explain the developed symptoms post-COVID-19 recovery, even before disturbed conventional diastolic echocardiographic parameters.LAS parameters are significantly associated with the developed exertional dyspnoea & exercise intolerance post-COVID-19. LA reservoir strain & LA stiffness could provide a simple, easily available tool that points to early LV diastolic dysfunction and may direct the therapy in this subset of the population.
298	CaV294		Akhtar, Zubair; Trent, Mallory; Moa, Aye; Tan, Timothy C; Fröbert, Ole; MacIntyre, C Raina	The impact of COVID-19 and COVID vaccination on cardiovascular outcomes	https://doi.org/10.1093/eurheartjsupp/suac123	Published	2023-02-15	Review	https://doi.org/10.1093/eurheartjsupp/suac123	COVID-19 is an independent risk factor for cardiovascular disease. COVID-19 vaccination may prevent this, but in some cases, COVID-19 vaccination may cause myocarditis or pericarditis. Patients with COVID-19 may present with non-specific symptoms that have a cardiac origin. This review examines the cardiovascular complications of COVID-19 infection and the impact of COVID-19 vaccination. COVID-19 cardiovascular complications include myocardial injury, pericarditis, coagulopathy, myocardial infarction, heart failure, arrhythmias, and persistent post-acute risk of adverse cardiovascular outcomes. Diagnostic and referral pathways for non-specific symptoms, such as dyspnoea and fatigue, remain unclear. COVID-19 vaccination is cardioprotective overall but is associated with myopericarditis in young males, though at a lower rate than following SARS-CoV-2 infection. Increased awareness among primary care physicians of potential cardiovascular causes of non-specific post-COVID-19 symptoms, including in younger adults, such as fatigue, dyspnoea, and chest pain, is essential. We recommend full vaccination with scheduled booster doses, optimal management of cardiovascular risk factors, rapid treatment of COVID-19, and clear diagnostic, referral, and management pathways for patients presenting with non-specific symptoms to rule out cardiac complications.
299	CaV295		Willems, Loes H.; Jacobs, Lotte M. C.; Groh, Laszlo A.; ten Cate, Hugo; Spronk, Henri M. H.; Wilson-Storey, Boden; Hannink, Gerjon; van Kuijk, Sander M. J.; Ghossein-Doha, Chahinda; Nagy, Magdi; Thijssen, Dick H. J.; van Petersen, André S.; Warlé, Michiel C.	Vascular Function, Systemic Inflammation, and Coagulation Activation 18 Months after COVID-19 Infection: An Observational Cohort Study	https://doi.org/10.3390/jcm12041413	Published	2023-01-01	Study	https://www.mdpi.com/2077-0383/12/4/1413	Introduction: Among its effect on virtually all other organs, COVID-19 affects the cardiovascular system, potentially jeopardizing the cardiovascular health of millions. Previous research has shown no indication of macrovascular dysfunction as reflected by carotid artery reactivity, but has shown sustained microvascular dysfunction, systemic inflammation, and coagulation activation at 3 months after acute COVID-19. The long-term effects of COVID-19 on vascular function remain unknown. Materials and Methods: This cohort study involved 167 patients who participated in the COVAS trial. At 3 months and 18 months after acute COVID-19, macrovascular dysfunction was evaluated by measuring the carotid artery diameter in response to cold pressor testing. Additionally, plasma endothelin-1, von Willebrand factor, Interleukin(IL)-1ra, IL-6, IL-18, and coagulation factor complexes were measured using ELISA techniques. Results: The prevalence of macrovascular dysfunction did not differ between 3 months (14.5%) and 18 months (11.7%) after COVID-19 infection (p = 0.585). However, there was a significant decrease in absolute carotid artery diameter change, 3.5% ± 4.7 vs. 2.7% ± 2.5, p—0.001, respectively. Additionally, levels of vWF:Ag were persistently high in 80% of COVID-19 survivors, reflecting endothelial cell damage and possibly attenuated endothelial function. Furthermore, while levels of the inflammatory cytokines interleukin(IL)-1RA and IL-18 were normalized and evidence of contact pathway activation was no longer present, the concentrations of IL-6 and thrombin:antithrombin complexes were further increased at 18 months versus 3 months (2.5 pg/mL ± 2.6 vs. 4.0 pg/mL ± 4.6, p = 0.006 and 4.9 μg/L ± 4.4 vs. 18.2 μg/L ± 11.4, p < 0.001, respectively). Discussion: This study shows that 18 months after COVID-19 infection, the incidence of macrovascular dysfunction as defined by a constrictive response during carotid artery reactivity testing is not increased. Nonetheless, plasma biomarkers indicate sustained endothelial cell activation (vWF), systemic inflammation (IL-6), and extrinsic/common pathway coagulation activation (FVII:AT, TAT) 18 months after COVID-19 infection.
300	CaV296		Carbone, Roberto G.; Puppo, Francesco	Pericarditis in long COVID-19	https://doi.org/10.1016/j.ijcard.2023.01.087	Published	2023-02-06	Editorial	https://www.internationaljournalofcardiology.com/article/S0167-5273(23)00170-5/fulltext	In summary the investigation by Llyod Dini et al. [[1]] confirms the data reported in the literature showing that pericarditis is a major cardiac complication in COVID-19 infection. However large prospective clinical trials are required for a more accurate assessment of the incidence of pericarditis in acute and long COVID-19 infection. publisher: Elsevier PMID: 36758864
301	CaV297		Parhizgar, Parinaz; Yazdankhah, Nima; Rzepka, Anna M.; Chung, Kit Yan Christie; Ali, Irfan; Lai, Rachel; Russell, Victoria; Cheung, Angela M.	Beyond acute COVID-19: A review of long-term cardiovascular outcomes	https://doi.org/10.1016/j.cjca.2023.01.031	Published	2023-02-06	Review	https://www.sciencedirect.com/science/article/pii/S0828282X23000776	Statistics Canada estimates that approximately 1.4 million Canadians suffer from long COVID. While cardiovascular changes during acute SARS-CoV-2 infection are well documented, long-term cardiovascular sequelae are less understood. In this review, we sought to characterize adult cardiovascular outcomes seen in the months following acute COVID-19 illness. Our search identified reports of outcomes including cardiac dysautonomia, myocarditis, ischemic injuries, and ventricular dysfunction. Even in patients without overt cardiac outcomes, subclinical changes have been observed. Cardiovascular sequelae following SARS-CoV-2 infection can stem from exacerbation of pre-existing conditions, ongoing inflammation, or as a result of damage occurring during acute infection. For example, myocardial fibrosis has been reported months after hospital admission for COVID-19 illness, and may be a consequence of myocarditis and myocardial injury during acute disease. In turn, myocardial fibrosis can contribute to further outcomes including dysrhythmias and heart failure. Severity of acute infection may be a risk factor for long-term cardiovascular consequences, however, cardiovascular changes have also been reported in young, healthy individuals who had asymptomatic or mild acute disease. Although evolving evidence suggests that prior SARS-CoV-2 infection may be a risk factor for cardiovascular disease, there is heterogeneity in existing evidence, and some studies are marred by both measured and unmeasured confounders. Many investigations have also been limited by relatively short follow up. Future studies should focus on longer term outcomes (beyond 1 year) and identifying the prevalence of outcomes in different populations based on acute and long COVID disease severity.
302	CaV298		Moulson, Nathaniel; Petek, Bradley J.; Baggish, Aaron L.; Harmon, Kimberly G.; Kliethermes, Stephanie A.; Patel, Manesh R.; Churchill, Timothy W.; Drezner, Jonathan A.	The Cardiac Effects of COVID-19 on Young Competitive Athletes: Results from the Outcomes Registry for Cardiac Conditions in Athletes (ORCCA)	https://doi.org/10.3390/jcdd10020072	Published	2023-02-01	Review	https://www.mdpi.com/2308-3425/10/2/72	The Outcomes Registry for Cardiac Conditions in Athletes (ORCCA) study is a large-scale prospective investigation evaluating the cardiovascular effects and outcomes of SARS-CoV-2 infection on young competitive athletes. This review provides an overview of the key results from the ORCCA study. Results from the ORCCA study have provided important insights into the clinical impact of SARS-CoV-2 infection on the cardiovascular health of young competitive athletes and informed contemporary screening and return to sport practices. Key results include defining a low prevalence of both cardiac involvement and adverse cardiovascular outcomes after SARS-CoV-2 infection and evaluating the utility of a return-to-play cardiac evaluation. Future aims of the ORCCA study include the longer-term evaluation of cardiovascular outcomes among athletes post-SARS-CoV-2 infection and the transition to investigating outcomes in young athletes with potentially high-risk genetic or structural cardiac diagnoses.
303	CaV299		Espinosa-Gonzalez, Ana B.; Master, Harsha; Gall, Nicholas; Halpin, Stephen; Rogers, Natalie; Greenhalgh, Trisha	Orthostatic tachycardia after covid-19	https://doi.org/10.1136/bmj-2022-073488	Published	2023-02-24	Article	https://www.bmj.com/content/380/bmj-2022-073488	### What you need to know Patients with long covid—defined by the National Institute for Health and Care Excellence (NICE) as signs and symptoms that persist for more than four weeks (and especially more than 12 weeks) following acute covid-1912—may present in primary care with symptoms of palpitations (tachycardia) triggered by standing or minimal exertion.3 These may be accompanied by dizziness, breathlessness, chest pain, sweating, bloating, fatigue, and other symptoms which may be caused by a dysfunction of the autonomic nervous system (dysautonomia).45678910111213 Patients can find these symptoms debilitating and they can affect function and mood. Limited evidence, variable diagnostic criteria, uncertainty around cause and pathogenesis, and the absence of licensed medications, have all contributed to making this a difficult condition to diagnose and manage. In this practice pointer, we offer an overview of orthostatic tachycardia following covid-19, including a summary of the key steps for diagnosis and management. Prevalence estimates vary depending on sample and setting, but indicate that about 25% of long covid patients may have dysautonomia14 and 2-14% will develop orthostatic tachycardia (postural orthostatic tachycardia syndrome) six to eight months after infection.341516Box 1 provides more information on these conditions. The assessment and management is summarised in the infographic. Box 1 ### Dysautonomia and postural orthostatic tachycardia syndromes The autonomic nervous system is responsible for the unconscious regulation of many physiological processes, including heart rate, blood pressure, respiration, and digestion. The broad category of “dysautonomia” encompasses several conditions, from the intermittent “faint” (neurocardiogenic syncope) through more pervasive dysregulation (postural … RETURN TO TEXT
304	CaV300		Han, Lefei; Zhao, Shi; Li, Siyuan; Gu, Siyu; Deng, Xiaobei; Yang, Lin; Ran, Jinjun	Excess cardiovascular mortality across multiple COVID-19 waves in the United States from March 2020 to March 2022	https://doi.org/10.1038/s44161-023-00220-2	Published	2023-03-01	Study	https://www.nature.com/articles/s44161-023-00220-2	The COVID-19 pandemic has limited the access of patients with cardiovascular diseases to healthcare services, causing excess deaths. However, a detailed analysis of temporal variations of excess cardiovascular mortality during the COVID-19 pandemic has been lacking. Here we estimate time-varied excess cardiovascular deaths (observed deaths versus expected deaths predicted by the negative binomial log-linear regression model) in the United States. From March 2020 to March 2022 there were 90,160 excess cardiovascular deaths, or 4.9% more cardiovascular deaths than expected. Two large peaks of national excess cardiovascular mortality were observed during the periods of March–June 2020 and June–November 2021, coinciding with two peaks of COVID-19 deaths, but the temporal patterns varied by state, age, sex and race and ethnicity. The excess cardiovascular death percentages were 5.7% and 4.0% in men and women, respectively, and 3.6%, 8.8%, 7.5% and 7.7% in non-Hispanic White, Black, Asian and Hispanic people, respectively. Our data highlight an urgent need for healthcare services optimization for patients with cardiovascular diseases in the COVID-19 era.
305	CaV301		Philip, Bejoy; Mukherjee, Prerona; Khare, Yuti; Ramesh, Pranav; Zaidi, Sara; Sabry, Haytham; Harky, Amer	COVID-19 and its long-term impact on the cardiovascular system	https://doi.org/10.1080/14779072.2023.2184800	Published	2023-03-01	Review	https://doi.org/10.1080/14779072.2023.2184800	Introduction TheSARS-CoV-2 virus caused a pandemic affecting healthcare deliveryglobally. Despite the presentation of COVID-19 infection beingfrequently dominated by respiratory symptoms; it is now notorious tohave potentially serious cardiovascular sequelae. This articleexplores current data to provide a comprehensive overview of thepathophysiology, cardiovascular risk factors, and implications ofCOVID-19. Areas covered Inherentstructure of SARS-CoV-2, and its interaction with both ACE-2 andnon-ACE-2 mediated pathways have been implicated in the developmentof cardiovascular manifestations, progressively resulting in acuterespiratory distress syndrome, multiorgan failure, cytokine releasesyndrome, and subsequent myocardial damage. The interplay betweenexisting and de novo cardiac complications must be noted. Forindividuals taking cardiovascular medications, pharmacologicinteractions are a crucial component. Short-term cardiovascularimpacts include arrhythmia, myocarditis, pericarditis, heart failure,and thromboembolism, whereas long-term impacts include diabetes andhypertension. To identify suitable studies, a PubMed literaturesearch was performed including key words such as ‘Covid 19,’‘Cardiovascular disease,’ ‘Long covid,’ etc. Expert opinion Moresophisticated planning and effective management for cardiologyhealthcare provision is crucial, especially for accommodatingchallenges associated with Long-COVID. With the potential applicationof AI and automated data, there are many avenues and sequelae thatcan be approached for investigation. Plain Language Summary Deemed the pandemic of the century, COVID-19 is an illness affecting multiple organ systems. Although the virus is best known for its lung-related complications, its adverse effects on the heart and blood vessels are now becoming more apparent. Rapidly mutating and evolving, its unique structure enables it to undergo interactions with various proteins in the body, resulting in complications of both the heart itself and blood vessels throughout the body. Numerous risk factors have been identified to facilitate these manifestations, including existing heart disease, medication usage, and age. Research has shown that certain drug interactions induce disturbances of the heart rhythm and function. In addition to this, they can also exacerbate preexisting heart-related complications, resulting in severe manifestations. The effects on the heart and blood vessels can be divided into acute and chronic complications. Acute complications include heart failure, rhythm disturbances, heart muscle weakness, and inflammation. In addition to this, chronic complications such as high blood pressure and the new onset of diabetes could also be a consequence. Further research is necessary to improve and enhance both our understanding of the virus and our ability to anticipate heart-related symptoms early on. publisher: Taylor & Francis _eprint: https://doi.org/10.1080/14779072.2023.2184800 PMID: 36856339
306	CaV302		Zharkikh, Elena V.; Loktionova, Yulia I.; Fedorovich, Andrey A.; Gorshkov, Alexander Y.; Dunaev, Andrey V.	Assessment of Blood Microcirculation Changes after COVID-19 Using Wearable Laser Doppler Flowmetry	https://doi.org/10.3390/diagnostics13050920	Published	2023-01-01	Study	https://www.mdpi.com/2075-4418/13/5/920	The present work is focused on the study of changes in microcirculation parameters in patients who have undergone COVID-19 by means of wearable laser Doppler flowmetry (LDF) devices. The microcirculatory system is known to play a key role in the pathogenesis of COVID-19, and its disorders manifest themselves long after the patient has recovered. In the present work, microcirculatory changes were studied in dynamics on one patient for 10 days before his disease and 26 days after his recovery, and data from the group of patients undergoing rehabilitation after COVID-19 were compared with the data from a control group. A system consisting of several wearable laser Doppler flowmetry analysers was used for the studies. The patients were found to have reduced cutaneous perfusion and changes in the amplitude–frequency pattern of the LDF signal. The obtained data confirm that microcirculatory bed dysfunction is present in patients for a long period after the recovery from COVID-19.
307	CaV303		Czeisler, Mark É.; Ibrahim, Said A.	Cardiovascular Risks in Patients With Post–COVID-19 Condition	https://doi.org/10.1001/jamahealthforum.2022.4664	Published	2023-03-03	Article	https://doi.org/10.1001/jamahealthforum.2022.4664	Post–COVID-19 condition (PCC) following SARS-CoV-2 infection (also known as long COVID) describes a variety of symptoms and health conditions, including both direct and indirect effects of the virus. The constellation of symptoms was initially identified by members of the public on social media in May 2020.1 As recurrent waves of COVID-19 have led to large numbers of infections and reinfections, PCC has garnered increased attention from policy makers, clinicians, and the public. To date, more than 200 signs and symptoms and 50 health conditions have been identified in PCC.2 In a US Centers for Disease Control and Prevention study, new-onset symptoms consistent with PCC were reported by 38.2% of adults with and 16.0% of adults without prior SARS-CoV-2 infection—greater than a 2-fold increased risk after prior infection.3 Beyond impaired health and suffering, the enormous medical spending and earning losses attributable to PCC in the US may measure in the trillions of dollars.4 Therefore, PCC is a defining challenge for health care systems. A study in this issue of JAMA Health Forum by DeVries and colleagues directly addresses this evolving public health challenge.5 The study of US adults in a large commercial insurance database describes markedly increased risks of adverse cardiovascular events and excess all-cause mortality in the postacute phase of COVID-19. These findings, together with increasing evidence of long-term consequences of SARS-CoV-2 infections spanning a wide range of organ systems,6 call for enhanced and extended health monitoring of individuals with SARS-CoV-2 infections and raise questions about public health goals at this stage of the pandemic. DeVries and colleagues used propensity score matching on a comprehensive set of variables in commercial insurance claims to compare a cohort of 13 435 persons who had experienced PCC symptoms with a cohort of 26 870 persons without evidence of COVID-19.5 Additional analyses were conducted among persons who had experienced PCC and been hospitalized within a month of SARS-CoV-2 infection. For both analyses, claims-based utilization tied to cardiovascular disorders, chronic respiratory disorders, and mortality over 12 months were compared between cohorts. Between 1 month and 12 months postinfection, individuals who had experienced COVID-19 exhibited increased incident cardiovascular disease relative to those who had not, including more than a doubling in the relative risk (RR) of pulmonary embolism or deep vein thrombosis (8.0% vs 2.2%; RR, 3.64), cardiac arrhythmias (29.5% vs 12.5%; RR, 2.35), and ischemic stroke (3.9% vs 1.8%; RR, 2.17). Individuals with SARS-CoV-2 infections also experienced a comparable relative increase in all-cause mortality (2.8% vs 1.2%) during the 12-month follow-up period. Even greater increases in the RRs of these adverse outcomes were observed among individuals hospitalized within a month of SARS-CoV-2 infection. The findings of DeVries and colleagues5 extend those of several recently published studies of postacute cardiovascular sequelae of SARS-CoV-2 infection. Other notable studies identifying a prolonged increased risk of incident cardiovascular disease between 1 month and 12 months following SARS-CoV-2 infection include those by Xie and colleagues7 and Wang and colleagues.8 However, their findings may be less generalizable; the former study reported on a cohort that was more than 90% male with a mean age older than 60 years, and the latter study analyzed a cohort that excluded persons who had received COVID-19 vaccines. DeVries and colleagues build on these studies by demonstrating findings of similar magnitude in a cohort that was 58% female with a mean age of 50 years and had representation across US racial and ethnic groups and geographic regions.5 Perhaps the most comparable published study is an analysis of UK Biobank participants by Raisi-Estabragh and colleagues, which primarily highlighted markedly increased cardiovascular and mortality risks among individuals hospitalized within 30 days of infection.9 The authors also reported sustained elevated risks of venous thromboembolism and of heart failure similar to those of DeVries and colleagues5 across the overall study cohort (ie, both hospitalized and nonhospitalized participants). However, contrary to the spectrum of cardiovascular-specific risk outcomes reported by DeVries and colleagues, Raisi-Estabragh and colleagues reported that the only postacute cardiovascular-specific risk outcome for nonhospitalized participants was venous thromboembolism.9 This difference could be related to the shorter follow-up interval in the UK Biobank study compared with the study by DeVries and colleagues.5
308	CaV304		Ranucci, Marco; Baryshnikova, Ekaterina; Anguissola, Martina; Pugliese, Sara; Falco, Mara; Menicanti, Lorenzo	The Long Term Residual Effects of COVID-Associated Coagulopathy	https://doi.org/10.3390/ijms24065514	Published	2023-01-01	Study	https://www.mdpi.com/1422-0067/24/6/5514	During the acute phase of COVID-19, many patients experience a complex coagulopathy characterized by a procoagulant pattern. The present study investigates the persistence of hemostatic changes in post-COVID patients at a long-term follow up, and the link with the persistence of physical and neuropsychological symptoms. We completed a prospective cohort study on 102 post-COVID patients. Standard coagulation and viscoelastic tests were performed, along with an assessment of persistent symptoms and recording of acute phase details. A procoagulant state was adjudicated in the presence of fibrinogen > 400 mg/dL, or D-dimer > 500 ng/mL, or platelet count > 450,000 cells/µL, or a maxim clot lysis at viscoelastic test < 2%. A procoagulant state was identified in 75% of the patients at 3 months follow up, 50% at 6 months, and 30% at 12–18 months. Factors associated with the persistence of a procoagulant state were age, severity of the acute phase, and persistence of symptoms. Patients with major physical symptoms carry a procoagulant state relative risk of 2.8 (95% confidence interval 1.17–6.7, p = 0.019). The association between persistent symptoms and a procoagulant state raises the hypothesis that an ongoing process of thrombi formation and/or persistent microthrombosis may be responsible for the main physical symptoms in long-COVID patients.
309	CaV305		Mabila, Sithembile; Patel, Deven; Fan, Michael; Stahlman, Shauna; Seliga, Nicholas; Nowak, Gosia; Wells, Natalie	Post –acute sequalae of COVID-19 and cardiac outcomes in U. S. military members	https://doi.org/10.1016/j.ijcrp.2023.200183	Published	2023-06-01	Study	https://www.sciencedirect.com/science/article/pii/S2772487523000168	Post –acute sequalae of COVID-19 (PASC) among U.S. military members remains unexplored. A cohort study of U. S. military members who had a COVID-19 test result, with the specimen collected between March 1, 2020 and November 30, 2021 was conducted. Demographic, inpatient and outpatient data including cardiac event diagnoses were extracted from electronic medical records and compared COVID-19 test-positive and COVID-19 test-negative service members. We used univariate and multivariable logistic regression methods to determine the effect PASC on select cardiac events. Among 997,785 service members, 15,779 (1.6%) were diagnosed with a cardiac event. In fully adjusted models, PASC was significantly associated with increased odds of any cardiac event [OR =1.64 (95% CI: 1.57, 1.71]. PASC was associated with increased odds of myocarditis [OR = 5.86 (95% CI: 4.22, 8.15)], pericarditis [OR =3.08 (95% CI: 2.31, 4.11)], syncope [OR =1.52 (95% CI: 1.41, 1.63)], tachycardia [OR =1.72 (95% CI: 1.56, 1.89)], heart failure [OR =2.15 (95% CI: 1.76, 2.63)], bradycardia [OR =1.71 (95% CI: 1.50, 1.96)], and atrial fibrillation [OR =1.33(95% CI: 1.02, 1.74)] in fully adjusted models. In a sensitivity analysis of military members with no history of cardiac events, PASC was still significantly associated with increased odds of any cardiac event [OR =1.75 (95% CI: 1.67, 1.84)]. In conclusion, we observed a significant association between PASC and cardiac outcomes including; myocarditis, pericarditis, and heart failure. These associations were observed in a relatively young and healthy population and among those without pre-existing cardiac diagnoses.
310	CaV306		Ball, Erin E.; Weiss, Christopher M.; Liu, Hongwei; Jackson, Kenneth; Keel, M. Kevin; Miller, Christopher J.; Van Rompay, Koen K. A.; Coffey, Lark L.; Pesavento, Patricia A.	Severe Acute Respiratory Syndrome Coronavirus 2 Vasculopathy in a Syrian Golden Hamster Model	https://doi.org/10.1016/j.ajpath.2023.02.013	Published	2023-03-10	Study	https://www.sciencedirect.com/science/article/pii/S0002944023000822	Clinical evidence of vascular dysfunction and hypercoagulability as well as pulmonary vascular damage and microthrombosis are frequently reported in severe cases of human coronavirus disease 2019 (COVID-19). Syrian golden hamsters recapitulate histopathologic pulmonary vascular lesions reported in patients with COVID-19. Here, special staining techniques and transmission electron microscopy further define vascular pathologies in a Syrian golden hamster model of human COVID-19. The results show that regions of active pulmonary inflammation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are characterized by ultrastructural evidence of endothelial damage with platelet marginalization and both perivascular and subendothelial macrophage infiltration. SARS-CoV-2 antigen/RNA was not detectable within affected blood vessels. Taken together, these findings suggest that the prominent microscopic vascular lesions in SARS-CoV-2–inoculated hamsters are likely due to endothelial damage followed by platelet and macrophage infiltration.
311	CaV307		Sewanan, Lorenzo R.; Clerkin, Kevin J.; Tucker, Nathan R.; Tsai, Emily J.	How Does COVID-19 Affect the Heart?	https://doi.org/10.1007/s11886-023-01841-6	Published	2023-03-01	Review	https://doi.org/10.1007/s11886-023-01841-6	Purpose of Review Cardiac consequences occur in both acute COVID-19 and post-acute sequelae of COVID-19 (PASC). Here, we highlight the current understanding about COVID-19 cardiac effects, based upon clinical, imaging, autopsy, and molecular studies. Recent Findings COVID-19 cardiac effects are heterogeneous. Multiple, concurrent cardiac histopathologic findings have been detected on autopsies of COVID-19 non-survivors. Microthrombi and cardiomyocyte necrosis are commonly detected. Macrophages often infiltrate the heart at high density but without fulfilling histologic criteria for myocarditis. The high prevalences of microthrombi and inflammatory infiltrates in fatal COVID-19 raise the concern that recovered COVID-19 patients may have similar but subclinical cardiac pathology. Molecular studies suggest that SARS-CoV-2 infection of cardiac pericytes, dysregulated immunothrombosis, and pro-inflammatory and anti-fibrinolytic responses underlie COVID-19 cardiac pathology. The extent and nature by which mild COVID-19 affects the heart is unknown. Imaging and epidemiologic studies of recovered COVID-19 patients suggest that even mild illness confers increased risks of cardiac inflammation, cardiovascular disorders, and cardiovascular death. The mechanistic details of COVID-19 cardiac pathophysiology remain under active investigation. Summary The ongoing evolution of SARS-CoV-2 variants and vast numbers of recovered COVID-19 patients portend a burgeoning global cardiovascular disease burden. Our ability to prevent and treat cardiovascular disease in the future will likely depend on comprehensive understanding of COVID-19 cardiac pathophysiologic phenotypes.
312	CaV308		Yar, Aria; Uusitalo, Valtteri; Vaara, Satu M.; Holmström, Miia; Vuorinen, Aino-Maija; Heliö, Tiina; Paakkanen, Riitta; Kivistö, Sari; Syväranta, Suvi; Hästbacka, Johanna	Cardiac magnetic resonance -detected myocardial injury is not associated with long-term symptoms in patients hospitalized due to COVID-19	https://doi.org/10.1371/journal.pone.0282394	Published	2023-03-08	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0282394	Background Long-term symptoms are frequent after coronavirus disease 2019 (COVID-19). We studied the prevalence of post-acute myocardial scar on cardiac magnetic resonance imaging (CMR) in patients hospitalized due to COVID-19 and its association with long-term symptoms. Materials and methods In this prospective observational single-center study, 95 formerly hospitalized COVID-19 patients underwent CMR imaging at the median of 9 months after acute COVID-19. In addition, 43 control subjects were imaged. Myocardial scar characteristic of myocardial infarction or myocarditis were noted from late gadolinium enhancement images (LGE). Patient symptoms were screened using a questionnaire. Data are presented as mean ± standard deviation or median (interquartile range). Results The presence of any LGE was higher in COVID-19 patients (66% vs. 37%, p<0.01) as was the presence of LGE suggestive of previous myocarditis (29% vs. 9%, p = 0.01). The prevalence of ischemic scar was comparable (8% vs. 2%, p = 0.13). Only two COVID-19 patients (7%) had myocarditis scar combined with left ventricular dysfunction (EF <50%). Myocardial edema was not detected in any participant. The need for intensive care unit (ICU) treatment during initial hospitalization was comparable in patients with and without myocarditis scar (47% vs. 67%, p = 0.44). Dyspnea, chest pain, and arrhythmias were prevalent in COVID-19 patients at follow-up (64%, 31%, and 41%, respectively) but not associated with myocarditis scar on CMR. Conclusions Myocardial scar suggestive of possible previous myocarditis was detected in almost one-third of hospital-treated COVID-19 patients. It was not associated with the need for ICU treatment, greater symptomatic burden, or ventricular dysfunction at 9 months follow-up. Thus, post-acute myocarditis scar on COVID-19 patients seems to be a subclinical imaging finding and does not commonly require further clinical evaluation.
313	CaV309		Nunes, Jean M.; Kell, Douglas B.; Pretorius, Etheresia	Cardiovascular and haematological pathology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A role for viruses	https://doi.org/10.1016/j.blre.2023.101075	Published	2023-03-20	Review	https://www.sciencedirect.com/science/article/pii/S0268960X2300036X	ME/CFS is a debilitating chronic condition that often develops after viral or bacterial infection. Insight from the study of Long COVID/Post Acute Sequelae of COVID-19 (PASC), the post-viral syndrome associated with SARS-CoV-2 infection, might prove to be useful for understanding pathophysiological mechanisms of ME/CFS. Disease presentation is similar between the two conditions, and a subset of Long COVID patients meet the diagnostic criteria for ME/CFS. Since Long COVID is characterized by significant vascular pathology – including endothelial dysfunction, coagulopathy, and vascular dysregulation – the question of whether or not the same biological abnormalities are of significance in ME/CFS arises. Cardiac abnormalities have for a while now been documented in ME/CFS cohorts, with recent studies demonstrating major deficits in cerebral blood flow, and hence vascular dysregulation. A growing body of research is demonstrating that ME/CFS is accompanied by platelet hyperactivation, anomalous clotting, a procoagulant phenotype, and endothelial dysfunction. Endothelial damage and dysregulated clotting can impair substance exchange between blood and tissues, and result in hypoperfusion, which may contribute to the manifestation of certain ME/CFS symptoms. Here we review the ME/CFS literature to summarize cardiovascular and haematological findings documented in patients with the condition, and, in this context, briefly discuss the potential role of previously-implicated pathogens. Overall, cardiac and haematological abnormalities are present within ME/CFS cohorts. While atherosclerotic heart disease is not significantly associated with ME/CFS, suboptimal cardiovascular function defined by reduced cardiac output, impaired cerebral blood flow, and vascular dysregulation are, and these abnormalities do not appear to be influenced by deconditioning. Rather, these cardiac abnormalities may result from dysfunction in the (autonomic) nervous system. Plenty of recently published studies are demonstrating significant platelet hyperactivity and endothelial dysfunction in ME/CFS, as well as anomalous clotting processes. It is of particular importance to determine to what extent these cardiovascular and haematological abnormalities contribute to symptom severity, and if these two systems can be targeted for therapeutic purposes. Viral reservoirs of herpesviruses exist in ME/CFS, and most likely contribute to cardiovascular and haematological dysfunction directly or indirectly. This review highlights the potential of studying cardiac functioning, the vasculature, and coagulation system in ME/CFS.
314	CaV310		Podrug, Mario; Koren, Pjero; Dražić Maras, Edita; Podrug, Josip; Čulić, Viktor; Perissiou, Maria; Bruno, Rosa Maria; Mudnić, Ivana; Boban, Mladen; Jerončić, Ana	Long-Term Adverse Effects of Mild COVID-19 Disease on Arterial Stiffness, and Systemic and Central Hemodynamics: A Pre-Post Study	https://doi.org/10.3390/jcm12062123	Published	2023-01-01	Study	https://www.mdpi.com/2077-0383/12/6/2123	COVID-19-associated vascular disease complications are primarily associated with endothelial dysfunction; however, the consequences of disease on vascular structure and function, particularly in the long term (>7 weeks post-infection), remain unexplored. Individual pre- and post-infection changes in arterial stiffness as well as central and systemic hemodynamic parameters were measured in patients diagnosed with mild COVID-19. As part of in-laboratory observational studies, baseline measurements were taken up to two years before, whereas the post-infection measurements were made 2–3 months after the onset of COVID-19. We used the same measurement protocol throughout the study as well as linear and mixed-effects regression models to analyze the data. Patients (N = 32) were predominantly healthy and young (mean age ± SD: 36.6 ± 12.6). We found that various parameters of arterial stiffness and central hemodynamics—cfPWV, AIx@HR75, and cDBP as well as DBP and MAP—responded to a mild COVID-19 disease. The magnitude of these responses was dependent on the time since the onset of COVID-19 as well as age (pregression_models ≤ 0.013). In fact, mixed-effects models predicted a clinically significant progression of vascular impairment within the period of 2–3 months following infection (change in cfPWV by +1.4 m/s, +15% in AIx@HR75, approximately +8 mmHg in DBP, cDBP, and MAP). The results point toward the existence of a widespread and long-lasting pathological process in the vasculature following mild COVID-19 disease, with heterogeneous individual responses, some of which may be triggered by an autoimmune response to COVID-19.
315	CaV311		Lee, Joanna; Kothari, Aditi S.; Bhatt, Gaurang; Gupta, Navneet; Ali, Ahmed Elsaid; Najam, Nadia; Mazroua, Muhammad; Mansoor, Taha; Amal, Tanya; Elsaban, Mariam; Deo, Rohan; Bansal, Vikas; Kashyap, Rahul	Cardiac complications among long covid patients: a systematic review and meta-analysis	https://doi.org/10.1016/S0735-1097(23)02559-7	Published	2023-03-07	Review	https://www.jacc.org/doi/full/10.1016/S0735-1097%2823%2902559-7	Background Long COVID is a novel phenomenon of persistent or new symptoms affecting multiple organ systems including the cardiovascular system. The long-term implications of long COVID, particularly its cardiac complications remain uncertain. We performed a systematic review and meta-analysis of studies that reported cardiac complications among long COVID patients. Methods We searched PUBMED, EMBASE, and SCOPUS databases and included 982 eligible studies from January 2020 to July 2022. After applying exclusion criteria, 74 studies were included for the detailed review. The meta-analysis included cohort and case control studies comparing the cardiac complications among long COVID vs. control. Total 11 studies were eligible for meta-analysis on full text review. It was registered on PROSPERO with the ID CRD42022338488. Results A total of 5,885,453 patients were included, and a total of 449,599 patients had cardiac complications (18,956 patients in long COVID-19 arm and 430,272 patients in control arm). The unadjusted odds of cardiac complications in long COVID-19 were significantly higher (OR 2.35, p=0.01) with high heterogeneity (I2=91%). We performed sensitivity analysis by excluding study by Galloway et al to reduce the heterogeneity and the odds of cardiac complications remained same with moderate heterogeneity (OR 2.57, p=<0.001, I2=51%). Conclusion Patients with long COVID have significantly higher odds of developing cardiac complications compared to those who do not. publisher: American College of Cardiology Foundation
316	CaV312		Howick, James; Saric, Petar; Elwazir, Mohamed; Gersh, Bernard J.; Bois, John P.	Cardiac sequelae of long-covid	https://doi.org/10.1016/S0735-1097(23)02684-0	Published	2023-03-07	Study	https://www.jacc.org/doi/full/10.1016/S0735-1097%2823%2902684-0	Background Cardiac injury from COVID-19 is likely the result of a bidirectional interaction with various pathophysiologic mechanisms coupled with modifying factors such as delayed presentation resulting in several clinical outcomes. The spectrum of long-term cardiovascular sequelae and incidence of structural cardiac damage remains unclear. Methods Advanced Text Explorer was utilized to search for COVID-19 long-haulers, defined as symptoms lasting greater than 4 weeks after initial infection, who presented to Cardiology Clinics at Mayo from April 2020 to March 2022. Additional patients diagnosed with COVID with possible cardiac sequelae seen in Chest Pain Clinic, Infectious Disease, and Radiology departments were also manually assessed for potential inclusion. These patients were evaluated for ongoing symptoms including chest pain, fatigue, dyspnea, palpitations, and syncope thought to represent cardiac sequelae related to COVID-19. All patients were manually reviewed to verify long-haul status and to determine whether these symptoms were indeed due to cardiovascular effects from COVID-19 versus a different etiology. Results 78,202 unique patients were diagnosed with COVID-19 at Mayo Clinic from April 2020 to March 2022. 336 (0.4%) long-haulers evaluated by Cardiology for ongoing symptoms that may represent cardiac sequelae from COVID were identified. 216 (61.6%) of these patients were vaccinated and 42 (12.5%) had severe initial infection receiving inpatient treatment for COVID prior to developing long-haul symptoms. 116 (34.5%) likely had symptoms from a cardiac cause and 220 (65.5%) were non-cardiac. Of the 116 with a cardiac etiology, 76 (22.6%) were thought to have symptoms largely driven by COVID; 59 with new cardiac disease and 17 with worsening of existing disease secondary to COVID. There were 7 cases of myocarditis, 5 suspected cases of endothelial dysfunction, and 31 cases of autonomic dysfunction/POTS. Conclusion In a sample of COVID-19 long-haulers with possible cardiac symptoms, the incidence of true structural cardiac sequelae as an explanation is rare. publisher: American College of Cardiology Foundation
317	CaV313		May, Heidi Thomas; Knight, Stacey; Horne, Benjamin Davies; Bair, Tami L.; Anderson, Jeffrey L.; Le, Viet T.; Muhlestein, J. Brent; Knowlton, Kirk U.	A comparison of cardiovascular outcomes among sars-cov-2 positive patients, sars-cov-2 negative patients, and a historical cohort	https://doi.org/10.1016/S0735-1097(23)02286-6	Published	2023-03-07	Study	https://www.jacc.org/doi/full/10.1016/S0735-1097%2823%2902286-6	Background Recovery from a SARS-CoV-2 infection varies among individuals. Some report symptoms for weeks or months after the acute infection, and in some, new symptoms emerge. Symptoms range from mild to incapacitating and can involve multiple organ systems. Such symptoms and damage have been termed post-acute sequelae of SARS-CoV-2 infection (PASC). COVID-19 infection has been shown to affect the cardiovascular (CV) system, but whether symptoms and organ damage have yet resulted in an increase in diagnoses and events has not been entirely determined. Methods Outpatients >18 yrs with 30-days survival testing positive for SARS-CoV-2 were matched to SARS-CoV-2 negative and historical patients by age (±1 yrs), sex, and index month seen. Pts were followed for 6-month and 1-year CV outcomes occurring >30 days after index. Results The baseline characteristics of the 444,474 (148,158/group) pts are shown in Table 1. Event rates were low and generally similar between the groups after adjustment, with chest pain being significantly greater in SARS-CoV-2 positive pts (Table 2 and 3). Conclusion This study found chest pain to be more common among SARS-CoV-2 positive pts, but no other increases in CV outcomes. It may be that the lasting effects of infection on the CV system are hard to quantify in terms of diagnoses or other events in the short-term and won't be realized until longer follow-up. Therefore, ongoing CV outcome monitoring will be critical in determining the true effect of a SARS-CoV-2 infection on CV disease. publisher: American College of Cardiology Foundation
318	CaV314		Fontana, Gregory Paul; Egloff, Shanna Arnold; Kar, Kar Saibal; Lakkireddy, Dhanunjaya R.; Huneycutt, David; Misch, Amanda; Williamson, Weldon Kent; Sands, Kenneth; Manoukian, Steven Vahe	Trends in long-term cardiovascular-related hospital admissions after covid-19 hospitalization	https://doi.org/10.1016/S0735-1097(23)02839-5	Published	2023-03-07	Study	https://www.jacc.org/doi/full/10.1016/S0735-1097%2823%2902839-5	Background Evidence exists that cardiovascular (CV) disease risk is increased in patients following COVID-19 (C19) infection and these risks may be sustained and manifest long after symptoms have resolved (long-COVID syndrome). This study sought to assess trends and timing of long-term CV-related admissions following C19 hospitalization and identify associated risks. Methods A retrospective multisite observational cohort study of a large private U.S. hospital network was performed of patients >18 years of age who survived an index C19 hospitalization (>24 hours) between 3/2/2020 and 7/31/2021, allowing for 1-year follow-up for CV-related admissions. Autoregressive integrated moving average (ARIMA) models were used to assess trends and compare expected vs. observed CV admissions for those having prior C19 hospitalization. Independent effects of clinicodemographics at time of C19 index hospitalization on future CV admission were assessed using multivariable logistic regression models with intent to expand models to include comorbidities as well as facility and C19 admission attributes. Results The C19 cohort (n=134,235) was compared to total monthly CV admission diagnoses from 2016 to 2021. Deep vein thrombosis, cardiac arrest, atrial fibrillation, and cardiogenic shock were concentrated within 30 days of C19 discharge. In contrast, stroke, myocardial infarction (MI), hypertension (HTN), and heart valve disorders peaked from 180 to 365+ days after C19 admission. HTN and cardiomyopathy accounted for 50% of all CV inpatient diagnoses. The largest peak in CV admissions occurred 8 months past the C19 delta wave; a pattern that remained consistent for stroke and MI. Current smoking, Black race, and age >50 years were associated with increased odds of having a CV-related admission; male sex, Asian race, and Hispanic ethnicity were associated with reduced odds. Conclusion In the year following admission for C19 infection, CV hospital admissions are elevated and exhibit a bimodal distribution. Numerous subgroups exist which are at increased risk of CV admission following C19 admission; greater understanding of these populations will aid in CV evaluation, surveillance and follow-up. publisher: American College of Cardiology Foundation
319	CaV315		Puntmann, Valentina O.; Nagel, Eike	Toward Better Understanding of Cardiac Involvement Post COVID∗	https://doi.org/10.1016/j.jcmg.2023.02.004	Published	2023-03-23	Editorial	https://www.sciencedirect.com/science/article/pii/S1936878X23000980	Owing to the new disease entity and wide spectrum of potential myocardial involvement that may be seen with COVID-19, the 2022 American College of Cardiology Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19 in Adults1 focused on myocarditis and other forms of inflammatory cardiac involvement and provides the following definitions: •Myocarditis: Condition defined by the presence of cardiac symptoms (eg, chest pain, dyspnea, palpitations, syncope), an elevated cardiac troponin (cTn), and abnormal electrocardiographic, echocardiographic, CMR, and/or histopathologic findings on biopsy or postmortem evaluation in the absence of flow-limiting coronary artery disease. •Myocardial involvement: Condition defined by abnormal myocardium manifest by electrocardiographic, echocardiographic, CMR, and/or histopathologic findings, with or without symptoms and with or without an elevated cTn. •Myocardial injury: Condition defined by a cTn level above the 99th percentile upper reference limit. We urge the CMR field to use this classification, as it may help to underpin the many faces of heterogeneous clinical presentation because of SARS-CoV-2 infection, and by that help to better understand some of the highly variable prevalences. The technical issues to diagnosis of post-COVID cardiac involvement by CMR aside, the management of the complex condition requires dedicated expert knowledge and a multidisciplinary approach. In summary, our understanding of cardiac involvement post COVID-19 continues to evolve and remains an important issue both for clinicians as well as for researchers. The use of CMR is relevant to better understand patients with symptoms or abnormal ECG or laboratory values post COVID-19. However, for routine use, more standardization of imaging and reporting is required.
320	CaV316		Tijmes, Felipe Sanchez; Marschner, Constantin; Thavendiranathan, Paaladinesh; Hanneman, Kate	Magnetic Resonance Imaging of Cardiovascular Manifestations Following COVID-19	https://doi.org/10.1002/jmri.28677	Published	2023-03-23	Review	https://onlinelibrary.wiley.com/doi/abs/10.1002/jmri.28677	Globally, over 650 million people have had COVID-19 due to infection with the SARS-Cov-2 virus. Cardiac complications in the acute infectious and early recovery phase were recognized early in the pandemic, including myocardial injury and inflammation. With a decrease in the number of acute COVID-19 related deaths, there has been increased interest in postacute sequela of COVID-19 (PASC) and other longer-term cardiovascular complications. A proportion of patients recovered from COVID-19 have persistent cardiac symptoms and are at risk of cardiovascular disease. Cardiovascular imaging, including MRI, plays an important role in the detection of cardiovascular manifestations of COVID-19 in both the acute and longer-term phases after COVID-19. The purpose of this review is to highlight the role of cardiovascular imaging in the diagnosis and risk stratification of patients with acute and chronic cardiovascular manifestations of COVID-19 with a focus on cardiac MRI. Evidence Level 4. Technical Efficacy Stage 3.
321	CaV317		Ferreira, Vanessa M.; Plein, Sven; Wong, Timothy C.; Tao, Qian; Raisi-Estabragh, Zahra; Jain, Supriya S.; Han, Yuchi; Ojha, Vineeta; Bluemke, David A.; Hanneman, Kate; Weinsaft, Jonathan; Vidula, Mahesh K.; Ntusi, Ntobeko A. B.; Schulz-Menger, Jeanette; Kim, Jiwon	Cardiovascular magnetic resonance for evaluation of cardiac involvement in COVID-19: recommendations by the Society for Cardiovascular Magnetic Resonance	https://doi.org/10.1186/s12968-023-00933-0	Published	2023-03-27	Recommendations	https://doi.org/10.1186/s12968-023-00933-0	Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic that has affected nearly 600 million people to date across the world. While COVID-19 is primarily a respiratory illness, cardiac injury is also known to occur. Cardiovascular magnetic resonance (CMR) imaging is uniquely capable of characterizing myocardial tissue properties in-vivo, enabling insights into the pattern and degree of cardiac injury. The reported prevalence of myocardial involvement identified by CMR in the context of COVID-19 infection among previously hospitalized patients ranges from 26 to 60%. Variations in the reported prevalence of myocardial involvement may result from differing patient populations (e.g. differences in severity of illness) and the varying intervals between acute infection and CMR evaluation. Standardized methodologies in image acquisition, analysis, interpretation, and reporting of CMR abnormalities across would likely improve concordance between studies. This consensus document by the Society for Cardiovascular Magnetic Resonance (SCMR) provides recommendations on CMR imaging and reporting metrics towards the goal of improved standardization and uniform data acquisition and analytic approaches when performing CMR in patients with COVID-19 infection.
322	CaV318		Simone Turner	Rapid flow cytometric analysis of fibrin amyloid microclots in Long COVID	https://doi.org/10.2139/ssrn.4405265	Published	2023-03-29	Study	https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4405265	Long COVID has become a significant global health and economic burden, yet there are currently no established diagnostic tools to identify which patients might benefit from specific treatments. One of the major pathophysiological factors contributing to Long COVID is the presence of hypercoagulability; this results in insoluble amyloid microclots that are resistant to fibrinolysis. Our previous research using fluorescence microscopy has demonstrated a significant amyloid microclot load in Long COVID patients. However, this approach lacked statistical robustness, objectivity, and rapid throughput. In the current study, we have used imaging flow cytometry for the first time to show significantly increased concentration and size of these microclots. We identified notable variations in size and fluorescence between microclots in Long COVID and those of controls even using a 20x objective. By combining cell imaging and the high-event-rate nature of a conventional flow cytometer, imaging flow cytometry can eliminate erroneous results and increase accuracy in gating and analysis beyond what pure quantitative measurements from conventional flow cytometry can provide. Although imaging flow cytometry was used in our study, our results suggest that the signals indicating the presence of microclots should be easily detectable using a conventional flow cytometer. Flow cytometry is a more widely available technique which has been used in pathology laboratories for decades, rendering it a potentially more suitable and accessible method for detecting microclots in individuals suffering from both Long COVID and other conditions with similar pathology, such as myalgic encephalomyelitis. DOI: 10.21203/rs.3.rs-2731434/v1
323	CaV319		Émile, Carole	Atteintes myocardiques au cours de la Covid-19, utilité des biomarqueurs cardiaques	https://doi.org/10.1016/S0992-5945(23)00050-8	Published	2023-03-01	Article	https://www.sciencedirect.com/science/article/pii/S0992594523000508	La Covid-19 est une pandémie sans précédent, par son ampleur, sa gravité et ses conséquences sociétales. Dans nos hôpitaux, elle a conduit à un afflux massif de patients, une saturation des capacités des services de réanimation et la création d’unités spécialisées. Les patients les plus sévères avaient des marqueurs biologiques très perturbés, en faveur d’une atteinte multiviscérale et, parmi ceux-ci, une augmentation des CK-MB, de la troponine et du BNP, stigmates d’une atteinte myocardique. À retenir 20 % des patients qui développent une forme sévère de la Covid-19 ont une atteinte myocardique (troponine [I ou T] supérieure au 99e percentile de la limite supérieure de référence). Une troponine élevée est associée à un mauvais pronostic et permet d’identifier les patients à risque, nécessitant une prise en charge intensive. Toutefois, dans la majorité des cas, l’élévation de la troponine n’est pas associée à une atteinte coronarienne aiguë, mais reflète de nombreuses atteintes cardiaques ou à retentissement cardiaque. Les patients qui ont développé une forme sévère de la Covid-19, mais également une forme modérée, ont un risque cardiovasculaire à un an augmenté. Enfin, dans plus de 50 % des cas d’atteintes myocardiques, la troponine reste élevée plusieurs mois après l’infection, ce qui pourrait expliquer ce risque cardio-vasculaire plus important.
324	CaV320		Kalinskaya, Anna; Vorobyeva, Daria; Rusakovich, George; Maryukhnich, Elena; Anisimova, Alexandra; Dukhin, Oleg; Elizarova, Antonina; Ivanova, Oxana; Bugrova, Anna; Brzhozovskiy, Alexander; Kononikhin, Alexey; Nikolaev, Evgeny; Vasilieva, Elena	Targeted Blood Plasma Proteomics and Hemostasis Assessment of Post COVID-19 Patients with Acute Myocardial Infarction	https://doi.org/10.3390/ijms24076523	Published	2023-01-01	Study	https://www.mdpi.com/1422-0067/24/7/6523	The molecular mechanisms underlying cardiovascular complications after the SARS-CoV-2 infection remain unknown. The goal of our study was to analyze the features of blood coagulation, platelet aggregation, and plasma proteomics in COVID-19 convalescents with AMI. The study included 66 AMI patients and 58 healthy volunteers. The groups were divided according to the anti-N IgG levels (AMI post-COVID (n = 44), AMI control (n = 22), control post-COVID (n = 31), and control (n = 27)). All participants underwent rotational thromboelastometry, thrombodynamics, impedance aggregometry, and blood plasma proteomics analysis. Both AMI groups of patients demonstrated higher values of clot growth rates, thrombus size and density, as well as the elevated levels of components of the complement system, proteins modifying the state of endothelium, acute-phase and procoagulant proteins. In comparison with AMI control, AMI post-COVID patients demonstrated decreased levels of proteins connected to inflammation and hemostasis (lipopolysaccharide-binding protein, C4b-binding protein alpha-chain, plasma protease C1 inhibitor, fibrinogen beta-chain, vitamin K-dependent protein S), and altered correlations between inflammation and fibrinolysis. A new finding is that AMI post-COVID patients opposite the AMI control group, are characterized by a less noticeable growth of acute-phase proteins and hemostatic markers that could be explained by prolonged immune system alteration after COVID-19.
325	CaV321		Nandadeva, Damsara; Skow, Rachel J.; Stephens, Brandi Y.; Grotle, Ann-Katrin; Georgoudiou, Stephanie; Barshikar, Surendra; Seo, Yaewon; Fadel, Paul J.	Cardiovascular and Cerebral Vascular Health in Females with Post-Acute Sequelae of COVID-19 (PASC)	https://doi.org/10.1152/ajpheart.00018.2023	Published	2023-03-31	Study	https://journals.physiology.org/doi/abs/10.1152/ajpheart.00018.2023	Many individuals who had COVID-19 develop detrimental persistent symptoms; a condition known as post-acute sequelae of COVID-19 (PASC). Despite the elevated risk of cardiovascular disease following COVID-19, limited studies have examined vascular function in PASC with equivocal results reported. Moreover, the role of PASC symptom burden on vascular health has not been examined. We tested the hypothesis that peripheral and cerebral vascular function would be blunted, and central arterial stiffness would be elevated in patients with PASC compared to age-matched controls. Furthermore, we hypothesized that impairments in vascular health would be greater in those with higher PASC symptom burden. Resting blood pressure (BP; brachial and central), brachial artery flow-mediated dilation (FMD), forearm reactive hyperemia, carotid-femoral pulse wave velocity (PWV), and cerebral vasodilator function were measured in 12 females with PASC and 11 age matched female controls without PASC. The severity of persistent symptoms in those with PASC was reported on a scale of 1-10 (higher score: greater severity). Brachial BP (e.g., systolic BP, 126±19 vs.109±8 mmHg; P=0.010), central BP (P<0.050) and PWV (7.1±1.2 vs. 6.0±0.8 m/s; P=0.015) were higher in PASC compared to controls. However, FMD, reactive hyperemia, and cerebral vasodilator function were not different between groups (P>0.050 for all). Total symptom burden was not correlated with any measure of cardiovascular health (P>0.050 for all). Collectively, these findings indicate that BP and central arterial stiffness are elevated in females with PASC, whereas peripheral and cerebral vascular function appear to be unaffected; effects that appear independent of symptom burden.
326	CaV322		Singh, Inderjit; Leitner, Brooks P.; Wang, Yiwei; Zhang, Hanming; Joseph, Phillip; Lutchmansingh, Denyse D.; Gulati, Mridu; Possick, Jennifer D.; Damsky, William; Hwa, John; Heerdt, Paul M.; Chun, Hyung J.	Proteomic profiling demonstrates inflammatory and endotheliopathy signatures associated with impaired cardiopulmonary exercise hemodynamic profile in Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome	https://doi.org/10.1002/pul2.12220	Published	2023-04-01	Study	https://onlinelibrary.wiley.com/doi/abs/10.1002/pul2.12220	Approximately 50% of patients who recover from the acute SARS-CoV-2 experience Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome. The pathophysiological hallmark of PASC is characterized by impaired system oxygen extraction (EO2) on invasive cardiopulmonary exercise test (iCPET). However, the mechanistic insights into impaired EO2 remain unclear. We studied 21 consecutive iCPET in PASC patients with unexplained exertional intolerance. PASC patients were dichotomized into mildly reduced (EO2peak-mild) and severely reduced (EO2peak-severe) EO2 groups according to the median peak EO2 value. Proteomic profiling was performed on mixed venous blood plasma obtained at peak exercise during iCPET. PASC patients as a group exhibited depressed peak exercise aerobic capacity (peak VO2; 85 ± 18 vs. 131 ± 45% predicted; p = 0.0002) with normal systemic oxygen delivery, DO2 (37 ± 9 vs. 42 ± 15 mL/kg/min; p = 0.43) and reduced EO2 (0.4 ± 0.1 vs. 0.8 ± 0.1; p < 0.0001). PASC patients with EO2peak-mild exhibited greater DO2 compared to those with EO2peak-severe [42.9 (34.2–41.2) vs. 32.1 (26.8–38.0) mL/kg/min; p = 0.01]. The proteins with increased expression in the EO2peak-severe group were involved in inflammatory and fibrotic processes. In the EO2peak-mild group, proteins associated with oxidative phosphorylation and glycogen metabolism were elevated. In PASC patients with impaired EO2, there exist a spectrum of PASC phenotype related to differential aberrant protein expression and cardio-pulmonary physiologic response. PASC patients with EO2peak-severe exhibit a maladaptive physiologic and proteomic signature consistent with persistent inflammatory state and endothelial dysfunction, while in the EO2peak-mild group, there is enhanced expression of proteins involved in oxidative phosphorylation-mediated ATP synthesis along with an enhanced cardiopulmonary physiological response.
327	CaV323		Gomes, Shayane Martins Rodrigues; Brito, Andréia Carolinne de Souza; Manfro, Wânia Ferraz Pereira; Ribeiro-Alves, Marcelo; Ribeiro, Roberto Stefan de Almeida; Cal, Mariana Soares da; Lisboa, Vinicius da Cunha; Abreu, Daniel Paiva Barros de; Castilho, Leda dos Reis; Porto, Luís Cristóvão de Moares Sobrino; Mafort, Thiago Thomáz; Lopes, Agnaldo José; Silva, Silvia Amaral Gonçalves da; Dutra, Patrícia Maria Lourenço; Rodrigues, Luciana Silva	High levels of pro-inflammatory SARS-CoV-2-specific biomarkers revealed by in vitro whole blood cytokine release assay (CRA) in recovered and long-COVID-19 patients	https://doi.org/10.1371/journal.pone.0283983	Published	2023-04-05	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0283983	Background Cytokines induced by SARS-CoV-2 infection play a crucial role in the pathophysiology of COVID-19 and hyperinflammatory responses have been associated with poor clinical outcomes, with progression to severe conditions or long-term subacute complications named as long-COVID-19. Methods In this cross-sectional study, we aimed to evaluate a set of antigen-specific inflammatory cytokines in blood from recovered COVID-19 individuals or who suffered a post-acute phase of SARS-CoV-2 infection compared to healthy individuals with no history of COVID-19 exposition or infection. Interferon-gamma (IFN-γ), IFN-γ-induced protein 10 (IP-10), tumor necrosis factor (TNF), IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, and IL-17A were quantified by multiplex cytometric bead assay and enzyme-linked immunosorbent assay after stimulation of whole blood with recombinant Spike protein from SARS-CoV-2. Additionally, all participants have evaluated for anti-(S) protein-specific IgG antibodies. Clinical specimens were collected within two months of COVID-19 diagnosis. Results A total of 47 individuals were enrolled in the study, a median age of 43 years (IQR = 14.5), grouped into healthy individuals with no history of infection or exposure to SARS-CoV-2 (unexposed group; N = 21); and patients from the Health Complex of the Rio de Janeiro State University (UERJ), Brazil, who were SARS-CoV-2 positive by RT-PCR (COVID-19 group)–categorized as recovered COVID-19 (N = 11) or long-COVID-19 (N = 15). All COVID-19 patients presented at least one signal or symptom during the first two weeks of infection. Six patients were hospitalized and required invasive mechanical ventilation. Our results showed that COVID-19 patients had significantly higher levels of IFN-γ, TNF, IL-1β, IL-2, IL-6, IL-8, and IP-10 than the unexposed group. The long-COVID-19 group has presented significantly high levels of IL-1β and IL-6 compared to unexposed individuals, but not from recovered COVID-19. A principal-component analysis demonstrated 84.3% of the total variance of inflammatory-SARS-CoV-2 response in the first two components, and it was possible to stratify IL-6, TNF, IL-1β, IL-10, and IL-2 as the top-five cytokines which are candidates to discriminate COVID-19 group (including long-COVID-19 subgroup) and healthy unexposed individuals. Conclusion We revealed important S protein-specific differential biomarkers in individuals affected by COVID-19, bringing new insights into the inflammatory status or SARS-CoV-2 exposition determination.
328	CaV324		Martins-Gonçalves, Remy; Hottz, Eugenio D.; Bozza, Patricia T.	Acute to post-acute COVID-19 thromboinflammation persistence: Mechanisms and potential consequences	https://doi.org/10.1016/j.crimmu.2023.100058	Published	2023-01-01	Review	https://www.sciencedirect.com/science/article/pii/S2590255523000045	Concerns for the long-term effects of COVID-19 infection have grown due to frequently reported persisting symptoms that can affect multiple systems for longer than 4 weeks after initial infection, a condition known as long-COVID-19 or post-acute COVID-19 syndrome (PACS). Even nonhospitalized survivors have an elevated risk for the development of thromboinflammatory-associated events, such as ischemic stroke and heart failure, pulmonary embolism and deep vein thrombosis. Recent findings point to the persistence of many mechanisms of hypercoagulability identified to be associated with disease severity and mortality in the acute phase of the disease, such as sustained inflammation and endotheliopathy, accompanied by abnormal fibrin generation and impaired fibrinolysis. Platelets seem to be central to the sustained hypercoagulable state, displaying hyperreactivity to stimuli and increased adhesive capacity. Platelets also contribute to elevated levels of thromboinflammatory mediators and pro-coagulant extracellular vesicles in individuals with ongoing PACS. Despite new advances in the understanding of mechanisms sustaining thromboinflammation in PACS, little is known about what triggers this persistence. In this graphical review, we provide a schematic representation of the known mechanisms and consequences of persisting thromboinflammation in COVID-19 survivors and summarize the hypothesized triggers maintaining this prothrombotic state.
329	CaV325		Sattar, Yasar; Taha, Amro; Patel, Neel; Victor, Varun; Titus, Anoop; Aziz, Shazia; Gonuguntla, Karthik; Thyagaturu, Harshith; Atti, Lalitsiri; Micho, Tarec; Almas, Talal; Tarun, Tushar; Alraies, M. Chadi; Balla, Sudarshan	Cardiovascular outcomes of type 2 myocardial infarction among COVID-19 patients: a propensity matched national study	https://doi.org/10.1080/14779072.2023.2200933	Published	2023-04-10	Study	https://doi.org/10.1080/14779072.2023.2200933	Background Myocardial infarction Type II (T2MI) is a prevalent cause of troponin elevation secondary to a variety of conditions causing stress/demand mismatch. The impact of T2MI on outcomes in patients hospitalized with COVID-19 is not well studied.Methods The Nationwide Inpatient Sample database from the year 2020 was queried to identify COVID-19 patients with T2MI during the index hospitalization. Clinical Modification (ICD-10-CM) codes ‘U07.1’ and ‘I21.A1’ were used as disease identifiers for COVID-19 and T2MI respectively. Multivariate adjusted Odds ratio (aOR) and propensity score matching (PSM) was done to compare outcomes among COVID patients with and without T2MI. The primary outcome was in-hospital mortality.Results A total of 1,678,995 COVID-19-weighted hospitalizations were identified in the year 2020, of which 41,755 (2.48%) patients had T2MI compared to 1,637,165 (97.5%) without T2MI. Patients with T2MI had higher adjusted odds of in-hospital mortality (aOR 1.44, PSM 32.27%, 95% CI 1.34–1.54) sudden cardiac arrest (aOR 1.29, PSM 6.6%, 95% CI 1.17–1.43) and CS (aOR 2.16, PSM 2.73%, 95% CI 1.85–2.53) compared to patients without T2MI. The rate of coronary angiography (CA) in T2MI with COVID was 1.19%, with significant use of CA among patients with T2MI complicated by CS compared to those without CS (4% vs 1.1%, p < 0.001). Additionally, COVID-19 patients with T2MI had an increased prevalence of sepsis compared to COVID-19 without T2MI (48% vs 24.1%, p < 0.001).Conclusion COVID-19 patients with T2MI had worse cardiovascular outcomes with significantly higher in-hospital mortality, SCA, and CS compared to those without T2MI. Long-term mortality and morbidity among COVID-19 patients who had T2MI will need to be clarified in future studies.
330	CaV326		Krinsky, Nitzan; Sizikov, Sofia; Nissim, Sivan; Dror, Adi; Sas, Anna; Prinz, Hodaya; Pri-Or, Ester; Perek, Shay; Raz-Pasteur, Ayelet; Lejbkowicz, Izabella; Cohen-Matsliah, Sivan Ida; Almog, Ronit; Chen, Nikanor; Kurd, Ramzi; Jarjou'i, Amir; Rokach, Ariel; Ben-Chetrit, Eli; Schroeder, Avi; Caulin, Aleah F.; Yost, Christian Con; Schiffman, Joshua D.; Goldfeder, Mor; Martinod, Kimberly	NETosis induction reflects COVID-19 severity and Long COVID: insights from a two-center patient cohort study in Israel	https://doi.org/10.1016/j.jtha.2023.02.033	Published	2023-04-11	Study	https://www.jthjournal.org/article/S1538-7836(23)00274-X/fulltext	Background COVID-19 severity and its late complications continue to be poorly understood. Neutrophil extracellular traps (NETs) form in acute COVID-19, likely contributing to morbidity and mortality. This study evaluated immunothrombosis markers in a comprehensive cohort of acute and recovered COVID-19 patients, including the association of NETs with LongCOVID. Methods One-hundred-seventy-seven patients were recruited from clinical cohorts at two Israeli centers: acute COVID-19 (mild/moderate, severe/critical), convalescent COVID-19 (recovered and Long COVID), along with 54 non-COVID controls. Plasma was examined for markers of platelet activation, coagulation, and NETs. Ex vivo NETosis induction capability was evaluated after neutrophil incubation with patient plasma. Results Soluble P-selectin, Factor VIII, von Willebrand factor, and platelet factor 4 were significantly elevated in COVID-19 patients versus controls. Myeloperoxidase (MPO)-DNA complex levels were increased only in severe COVID-19 and did not differentiate between COVID-19 severities or correlate with thrombotic markers. NETosis induction levels strongly correlated with illness severity/duration, platelet activation markers, and coagulation factors, and were significantly reduced upon dexamethasone treatment and recovery. Long COVID patients maintained higher NETosis induction, but not NET fragments, compared to recovered convalescent patients. Conclusions Increased NETosis induction can be detected in Long COVID patients. NETosis induction appears to be a more sensitive NET measurement than MPO-DNA levels in COVID-19, differentiating between disease severity and Long COVID patients. Ongoing NETosis induction capability in Long COVID may provide insights into pathogenesis and serve as a surrogate marker for persistent pathology. This study emphasizes the need to explore neutrophil-targeted therapies in acute and chronic COVID-19. publisher: Elsevier PMID: 37054916
331	CaV327		Balas, Reka Borka; Meliț, Lorena Elena; Mărginean, Cristina Oana	COVID-19 and Cardiac Implications—Still a Mystery in Clinical Practice	https://doi.org/10.31083/j.rcm2405125	Published	2023-04-24	Review	https://www.imrpress.com/journal/RCM/24/5/10.31083/j.rcm2405125	Although initially the evolution of Coronavirus disease 2019 (COVID-19) seemed less severe in pediatric patients, in the three years since the beginning of the pandemics, several severe cases have been described, pediatric inflammatory multisystem syndrome (PIMS) has been defined, pathogenesis is being continuously studied, and many aspects regarding the long-term evolution and multi-organ damage are still unexplained. Cardiac injuries in COVID-19 represent most-likely the second cause of mortality associated with the infection. A wide-spectrum of cardiac abnormalities were reported to be associated with COVID-19 in children including ventricular dysfunction, acute myocardial dysfunction, arrhythmias, conduction abnormalities, coronary artery dilation or aneurysms, and less common pericarditis and valvulitis. Risk factors for severe COVID-19 in children should be identified, laboratory tests and imaging techniques should be performed to reveal cardiac injury as soon as possible. The aim of this review was to highlight the great value of repeated cardiological monitoring in patients with COVID-19, underlining also the peculiarities in terms of pediatric population. This review is looking for answers on questions like ‘Why do some, but not all, patients with COVID-19 develop cardiac injury or severe hyperinflammatory status?’, ‘Which factors are involved in triggering COVID-19 associated cardiac injury?’, ‘What are the mechanisms involved in the etiology of cardiac injury?’, ‘Is there a clear relationship between hyperinflammation and cardiac injury?’, ‘Is hyperinflammatory status the pre-stage of cardiac injury in COVID-19 patients?’ which still lack clear answers. The understanding of mechanisms involved in the development of COVID-19 associated cardiac injury might shed light on all the above-mentioned mysteries and might increase the likelihood of favorable evolution even in severe cases.
332	CaV328		González-Hermosillo G, J. Antonio; Galarza, Esteban Jorge; Fermín, Onasis Vicente; González, José Manuel Núñez; Tostado, Lucia Mariel Félix Álvarez; Lozano, Marco Antonio Estrada; Rabasa, Claudia Ruíz; Martínez Alvarado, María del Rocio	Exaggerated blood pressure elevation in response to orthostatic challenge, a post-acute sequelae of SARS-CoV-2 infection (PASC) after hospitalization	https://doi.org/10.1016/j.autneu.2023.103094	Published	2023-07-01	Study	https://www.sciencedirect.com/science/article/pii/S1566070223000231	Highlights •Head-up tilt may unmask an exaggerated blood pressure response after COVID-19. •Renin-angiotensin imbalance enhancing sympathetic tone may be the mechanism. •Preclinical hypertension could be a sequelae of COVID-19. Abstract Objective Post-acute sequelae of SARS-COV-2 (PASC) are emerging as a major health challenge. Orthostatic intolerance secondary to autonomic failure has been found in PASC patients. This study investigated the effect of COVID-19 after recovery on blood pressure (BP) during the orthostatic challenge. Research design and methods Thirty-one out of 45 patients hospitalized due to COVID-19-related pneumonia that developed PASC and did not have hypertension at discharge were studied. They underwent a head-up tilt test (HUTT) at 10.8 ± 1.9 months from discharge. All met the PASC clinical criteria, and an alternative diagnosis did not explain the symptoms. This population was compared with 32 historical asymptomatic healthy controls. Results Exaggerated orthostatic blood pressure response (EOPR)/orthostatic hypertension (OHT) was detected in 8 out of 23 (34.7 %) patients, representing a significantly increased prevalence (7.67-fold increase p = 0.009) compared to 2 out of 32 (6.4 %) asymptomatic healthy controls matched by age, who underwent HUTT and were not infected with SARS-CoV-2. Conclusions This prospective evaluation in patients with PASC revealed abnormal blood pressure rise during the orthostatic challenge, suggesting of autonomic dysfunction in a third of the studied subjects. Our findings support the hypothesis that EOPR/OHT may be a phenotype of neurogenic hypertension. Hypertension in PASC patients may adversely affect the cardiovascular burden in the world.
333	CaV329		Lorente-Ros, Marta; Das, Subrat; Elias, Joseph; Frishman, William H; Aronow, Wilbert S	Cardiovascular Manifestations of the Long COVID Syndrome	https://doi.org/10.1097/crd.0000000000000552	Published	2023-04-01	Review	https://doi.org/10.1097/CRD.0000000000000552	While most coronavirus 2019 (COVID-19) survivors have had complete resolution of symptoms, a significant proportion have suffered from incomplete recovery. Cardiopulmonary symptoms, such as dyspnea, chest pain, and palpitations are responsible for a substantial symptom burden in COVID-19 survivors. Studies have revealed persistent myocardial injury with late gadolinium enhancement and myocardial scar on cardiac magnetic resonance in a significant proportion of patients. Evidence of myocardial edema, active inflammation, left ventricular dysfunction, and right ventricular dysfunction, is limited to a minority of patients. Large observational studies of COVID-19 survivors have indicated an increased risk of cardiovascular disease compared to the general population, including the risk of coronary artery disease, cardiomyopathy, and arrhythmias. Management of long COVID is focused on supportive therapy to reduce systemic inflammation. Patients with high cardiovascular risk, namely, those who had cardiovascular complications during acute illness, patients who have new onset cardiopulmonary symptoms in the postinfectious period, and competitive athletes, should be evaluated by a cardiovascular specialist. Management of cardiovascular sequelae is currently based on general expert guideline recommendations given the lack of evidence specific to long COVID syndrome. In this review, we outline the cardiovascular manifestations of long COVID, the current evidence supporting cardiac abnormalities in the postinfectious period, and the recommended management of these patients.
334	CaV330		Cecchetto, Antonella; Torreggiani, Gianpaolo; Guarnieri, Gabriella; Vianello, Andrea; Baroni, Giulia; Palermo, Chiara; Bertagna De Marchi, Leonardo; Lorenzoni, Giulia; Bartolotta, Patrizia; Bertaglia, Emanuele; Donato, Filippo; Aruta, Patrizia; Iliceto, Sabino; Mele, Donato	Subclinical Myocardial Injury in Patients Recovered from COVID-19 Pneumonia: Predictors and Longitudinal Assessment	https://doi.org/10.3390/jcdd10040179	Published	2023-04-01	Study	https://www.mdpi.com/2308-3425/10/4/179	(1) Background: Emerging data regarding patients recovered from COVID-19 are reported in the literature, but cardiac sequelae have not yet been clarified. To quickly detect any cardiac involvement at follow-up, the aims of the research were to identify: elements at admission predisposing subclinical myocardial injury at follow up; the relationship between subclinical myocardial injury and multiparametric evaluation at follow-up; and subclinical myocardial injury longitudinal evolution. (2) Methods and Results: A total of 229 consecutive patients hospitalised for moderate to severe COVID-19 pneumonia were initially enrolled, of which 225 were available for follow-up. All patients underwent a first follow-up visit, which included a clinical evaluation, a laboratory test, echocardiography, a six-minute walking test (6MWT), and a pulmonary functional test. Of the 225 patients, 43 (19%) underwent a second follow-up visit. The median time to the first follow-up after discharge was 5 months, and the median time to the second follow-up after discharge was 12 months. Left ventricular global longitudinal strain (LVGLS) and right ventricular free wall strain (RVFWS) were reduced in 36% (n = 81) and 7.2% (n = 16) of the patients, respectively, at first the follow-up visit. LVGLS impairment showed correlations with patients of male gender (p 0.008, OR 2.32 (95% CI 1.24–4.42)), the presence of at least one cardiovascular risk factor (p < 0.001, OR 6.44 (95% CI 3.07–14.9)), and final oxygen saturation (p 0.002, OR 0.99 (95% CI 0.98–1)) for the 6MWTs. Subclinical myocardial dysfunction had not significantly improved at the 12-month follow-ups. (3) Conclusions: in patients recovered from COVID-19 pneumonia, left ventricular subclinical myocardial injury was related to cardiovascular risk factors and appeared stable during follow-up.
335	CaV331		Soysal, G. G.; Kimyon, S.; Mete, A.; Güngör, K.	Evaluation of the retina with optical coherence tomography angiography (OCTA) in patients with coronavirus (COVID-19) infection	https://doi.org/10.1016/j.jfo.2023.02.006	Published	2023-04-17	Study	https://www.sciencedirect.com/science/article/pii/S0181551223002280	Purpose The goal of this study is to compare the optical coherence tomography angiography (OCTA) findings in Coronavirus (COVID-19) positive adult and pediatric patients with those of healthy volunteers with the same demographic characteristics. Methods The right eye of 157 adults infected with covid, 168 healthy adult volunteers, 40 children (6–18 years of age) infected with covid, and 44 healthy children (6–18 years of age) were included in this prospective study. All participants underwent ophthalmological examination and OCTA. The OCTA findings were evaluated. Results Deep nasal density (DND), deep inferior density (DID), and deep parafoveal density (DPD) were significantly lower in the pediatric covid-affected group (PCAG) than in the pediatric healthy control group (PHCG) (P=0.034, P=0.029, P=0.022 respectively). On the other hand, radial peripapillary capillary vessel density (RPCVD) intra-disc measurements were significantly higher in the PCAG compared to the PHCG (P=0.025). There was no significant difference between the OCTA measurements of the adult covid-affected group (ACAG) and the adult healthy control group (AHCG). Conclusion In our study, significant differences were found in OCTA measurements between the covid group and the healthy control group in children. Retinal microvascular changes may occur in patients with covid infection, and these patients might be followed for long-term retinal changes. Résumé Objectif L’objectif de cette étude est de comparer les résultats de l’angiographie par tomographie à cohérence optique (OCTA) de patients adultes et pédiatriques positifs au coronavirus (COVID-19) avec des volontaires sains présentant les mêmes caractéristiques démographiques. Méthodes L’œil droit de 157 adultes infectés par la covid, 168 volontaires adultes sains, 40 enfants (6–18 ans) infectés par la covid et 44 enfants sains (6–18 ans) ont été inclus dans cette étude prospective. Tous les participants ont subi un examen ophtalmologique et une OCTA a été réalisée. Les résultats de l’OCTA ont été évalués. Résultats La densité nasale profonde (DND), la densité inférieure profonde (DID) et la densité parafovéale profonde (DPD) étaient significativement plus faibles dans le groupe pédiatrique atteint de la covid (PCAG) que dans le groupe témoin sain (PHCG) (p=0,034, p=0,029, p=0,022 respectivement). D’autre part, les mesures de la densité des vaisseaux capillaires péripapillaires radiaux (RPCVD) à l’intérieur du disque étaient significativement plus élevées dans le PCAG que dans le PHCG (p=0,025). Il n’y avait pas de différence significative entre les mesures OCTA du groupe d’adultes atteints de la covid (ACAG) et du groupe de contrôle adulte sain (AHCG). Conclusion Dans notre étude, des différences significatives ont été trouvées dans les mesures OCTA entre le groupe covid et le groupe de contrôle sain chez les enfants. Des changements microvasculaires rétiniens peuvent se produire chez les patients atteints d’une infection de la covid, et ces patients peuvent être suivis pour des changements rétiniens à long terme.
336	CaV332		Machado, Nicolle R.; Dias, Karina T.; Cortes, Bryan F.S.; Rodrigues, Stephen F.	Effect of coronaviruses on blood vessel permeability: potential therapeutic targets	https://doi.org/10.1177/17534666231162252	Published	2023-01-01	Study	https://doi.org/10.1177/17534666231162252	Coronavirus-induced diseases have afflicted humanity for several decades. This scenario was aggravated by the emergence of the coronavirus disease 2019 (named COVID-19) in Wuhan, China, in December 2019. Since then, COVID-19 has killed millions of people worldwide, probably the most devastating pandemic since HIV/AIDS. This review aimed to bring together important updated aspects related to coronavirus-induced diseases and the enhanced vascular permeability observed mainly in the lungs of affected people. The dysregulated vascular permeability in the lungs is of fundamental importance for coronaviruses-caused morbidity and mortality. Thus, as described in this review, it is a target of new and old drugs.
337	CaV333		Kersten, Johannes; Schellenberg, Jana; Jerg, Achim; Kirsten, Johannes; Persch, Hasema; Liu, Yuefei; Steinacker, Jürgen M.	Strain Echocardiography in Acute COVID-19 and Post-COVID Syndrome: More than Just a Snapshot	https://doi.org/10.3390/biomedicines11041236	Published	2023-04-01	Review	https://www.mdpi.com/2227-9059/11/4/1236	Speckle-tracking echocardiography (STE) has become an established, widely available diagnostic method in the past few years, making its value clear in cases of COVID-19 and the further course of the disease, including post-COVID syndrome. Since the beginning of the pandemic, many studies have been published on the use of STE in this condition, enabling, on the one hand, a better understanding of myocardial involvement in COVID-19 and, on the other, a better identification of risk to patients, although some questions remain unanswered in regard to specific pathomechanisms, especially in post-COVID patients. This review takes a closer look at current findings and potential future developments by summarising the extant data on the use of STE, with a focus on left and right ventricular longitudinal strain.
338	CaV334		Turner, Simone; Khan, M. Asad; Putrino, David; Woodcock, Ashley; Kell, Douglas B.; Pretorius, Etheresia	Long COVID: pathophysiological factors and abnormalities of coagulation	https://doi.org/10.1016/j.tem.2023.03.002	Published	2023-06-01	Study	https://www.cell.com/trends/endocrinology-metabolism/abstract/S1043-2760(23)00055-3	Highlights Long COVID has a multifactorial nature with multiple pathophysiological factors at play. Viral factors, host factors (including systemic inflammation, and metabolic, endocrine, and endothelial dysfunction) and downstream impacts (tissue damage from the initial infection, hypoxia, dysbiosis, and autonomic nervous system dysfunction) are key elements underpinning the condition. Various factors culminate in the long-term persistence of the disorder (i.e., a thrombotic endothelialitis characterized by endothelial inflammation, hyperactivated platelets, and fibrinaloid microclots). We suggest a multipronged treatment agenda for Long COVID treatment trials, incorporating drugs targeting all potential mechanisms, including viral persistence, autoimmunity, immune dysregulation, and gut dysbiosis; with endothelialitis and coagulation abnormalities as two priorities. Abstract Acute COVID-19 infection is followed by prolonged symptoms in approximately one in ten cases: known as Long COVID. The disease affects ~65 million individuals worldwide. Many pathophysiological processes appear to underlie Long COVID, including viral factors (persistence, reactivation, and bacteriophagic action of SARS CoV-2); host factors (chronic inflammation, metabolic and endocrine dysregulation, immune dysregulation, and autoimmunity); and downstream impacts (tissue damage from the initial infection, tissue hypoxia, host dysbiosis, and autonomic nervous system dysfunction). These mechanisms culminate in the long-term persistence of the disorder characterized by a thrombotic endothelialitis, endothelial inflammation, hyperactivated platelets, and fibrinaloid microclots. These abnormalities of blood vessels and coagulation affect every organ system and represent a unifying pathway for the various symptoms of Long COVID. publisher: Elsevier PMID: 37080828
339	CaV335		Nicolai, Leo; Kaiser, Rainer; Stark, Konstantin	Thrombo-inflammation in Long COVID – the elusive key to post-infection sequelae?	https://doi.org/10.1016/j.jtha.2023.04.039	Published	2023-05-11	Review	https://www.sciencedirect.com/science/article/pii/S1538783623004002	Long COVID is a public health emergency affecting millions of people worldwide, characterized by heterogenous symptoms across multiple organs systems. Here, we discuss the current evidence linking thrombo-inflammation to Post-acute sequelae of COVID-19 (PASC). Studies have found persistence of vascular damage with increased circulating markers of endothelial dysfunction, coagulation abnormalities with increased thrombin generation capacity, and abnormalities in platelet counts in PASC. Neutrophil phenotype resembles acute COVID-19 with an increase in activation and NETosis. These insights are potentially linked by elevated platelet-neutrophil aggregate formation. This hypercoagulable state in turn can lead to microvascular thrombosis, evidenced by microclots and elevated D-Dimer in the circulation, as well as perfusion abnormalities in the lung and brain of Long COVID patients. Also, COVID-19 survivors suffer from an increased rate of arterial and venous thrombotic events. We discuss three important, potentially intertwined hypotheses, that might contribute to thromboinflammation in Long COVID: Lasting structural changes, most prominently endothelial damage, caused during initial infection, a persistent viral reservoir, and immunopathology driven by a misguided immune system. Lastly, we outline the necessity for large, well-characterized clinical cohorts and mechanistic studies to clarify the contribution of thromboinflammation to Long COVID.
340	CaV336		Koupenova, Milka; Chung, Mina K.; Bristow, Michael R.	COVID-19 and the Cardiovascular System: Requiem for a Medical Minotaur	https://doi.org/10.1161/CIRCRESAHA.123.322935	Published	2023-05-12	Article	https://www.ahajournals.org/doi/full/10.1161/CIRCRESAHA.123.322935	Sophisticated imaging methodology has contributed enormously to our understanding of how a respiratory viral infection caused by SARS-CoV-2 may seriously impact cardiovascular disease. Cardiac magnetic resonance imaging is instrumental in the detection of myocardial injury and the clinical diagnosis of myocarditis in COVID-19 patients, in addition to the evaluation of coronary microvascular dysfunction particularly in patients recovered from COVID-19 infection. In this compendium, Holby et al14 provide an overview of the multimodality imaging that has been used to diagnose and evaluate COVID-19. As we dive deeper into the mechanisms of disease, murine models and mouse adaptable strains have proved valuable, which is briefly discussed by Sciaudone et al.5 However, mice including those that express human ACE2, lack a full set of sequelae presented by human COVID-19. In that sense the usefulness of iPS-derived systems, particularly cardiomyocytes, are also reviewed by Satta et al,15 including the benefits and limitations in advancements in microfluidics, organ-on-a-chip and human stem-cell derived models to study SARS-CoV-2 infection in the physiological organ microenvironment. Overall, many tools have been developed in COVID-19 investigations, and we are beginning to understand the unique roles of these model systems.Three years following the onset of the pandemic, we have gained a vast amount of knowledge as to how one virus as small as 100 µm can collapse an entire multiorgan system. We can now conclusively say that certain respiratory coronaviruses increase the risk of macrothrombotic events, organ microthrombosis, myocardial injury including myocarditis, and arrhythmias. We have learned there are factors, such as hypertension, atrial fibrillation, heart failure, diabetes and obesity, that predispose to cardiac involvement in COVID-19. We have increased our understanding of how the immune response to SARS-CoV-2 may contribute to the pathophysiology of CVD in addition to its roles in inflammation and thrombosis signaling. Nevertheless, we have just scratched the surface and many questions remain unanswered. For instance, what are the exact mechanisms that cannot be controlled by anticoagulation and antiplatelet therapy that contribute to treatment-refractory macro- and microthrombosis; what are the precise mechanisms that underline myocardial injury in cases where myocarditis is not detected, what are the factors responsible for development of prolonged fatigue and other symptoms that underlie long-COVID/PASC, and in CV research and training should there be a greater emphasis on immunology and infectious disease? History has shown that pandemics will continue to occur, and the more we understand how viruses and infections in general impact human cardiovascular pathophysiology, the better prepared we will be for the next outbreak, which may occur sooner rather than later in this age of global connectivity. Areas where we will need to do better include recognizing and preventing the consequences of cardiovascular clinical risks, understanding and avoiding postinfection sequelae, and designing better therapeutic agents and vaccines. We as a community must continue to address the remaining questions and elucidate the relevant mechanisms; only then will we be able to more effectively confront the next Minotaur of infectious impact on cardiovascular disease.
341	CaV337		Singh, Tamanna K.; Zidar, David A.; McCrae, Keith; Highland, Kristin B.; Englund, Kristin; Cameron, Scott J.; Chung, Mina K.	A Post-Pandemic Enigma: The Cardiovascular Impact of Post-Acute Sequelae of SARS-CoV-2	https://doi.org/10.1161/CIRCRESAHA.122.322228	Published	2023-05-12	Review	https://www.ahajournals.org/doi/abs/10.1161/CIRCRESAHA.122.322228	COVID-19 has become the first modern-day pandemic of historic proportion, affecting >600 million individuals worldwide and causing >6.5 million deaths. While acute infection has had devastating consequences, postacute sequelae of SARS-CoV-2 infection appears to be a pandemic of its own, impacting up to one-third of survivors and often causing symptoms suggestive of cardiovascular phenomena. This review will highlight the suspected pathophysiology of postacute sequelae of SARS-CoV-2, its influence on the cardiovascular system, and potential treatment strategies. publisher: Lippincott Williams & Wilkins Hagerstown, MD
342	CaV338		Lopes, Leilani A.; Agrawal, Devendra K.	Thromboembolism in the Complications of Long COVID-19	https://doi.org/	Published	2023-04-20	Review	http://www.fotunejournals.com/thromboembolism-in-the-complications-of-long-covid19.html	SARS-CoV-2 is a +ssRNA helical coronavirus responsible for the global pandemic caused by coronavirus disease 19 (COVID-19). Classical clinical symptoms from primary COVID-19 when symptomatic include cough, fever, pneumonia or even ARDS; however, they are limited primarily to the respiratory system. Long-COVID-19 sequalae is responsible for many pathologies in almost every organ system and may be present in up to 30% of patients who have developed COVID-19. Our review focuses on how long-COVID-19 (3 -24 weeks after primary symptoms) may lead to an increased risk for stroke and thromboembolism. Patients who were found to be primarily at risk for thrombotic events included critically ill and immunocompromised patients. Additional risk factors for thromboembolism and stroke included diabetes, hypertension, respiratory and cardiovascular disease, and obesity. The etiology of how long-COVID-19 leads to a hypercoagulable state are yet to be definitively elucidated. However, anti-phospholipid antibodies and elevated D-dimer are present in many patients who develop thromboembolism. In addition, chronic upregulation and exhaustion of the immune system may lead to a pro-inflammatory and hypercoagulable state, increasing the likelihood for induction of thromboembolism or stroke. This article provides an up-to-date review on the proposed etiologies for thromboembolism and stroke in patients with long-COVID-19 and to assist health care providers in examining patients who may be at a higher risk for developing these pathologies.
343	CaV339		Chouairi, Fouad; Pinsker, Bret; Miller, P. Elliott; Fudim, Marat	Effects of COVID-19 on heart failure admissions	https://doi.org/10.1016/j.ahj.2023.05.001	Published	2023-05-06	Study	https://www.sciencedirect.com/science/article/pii/S0002870323001114	Despite significant investigation into the effects of COVID-19 on cardiovascular disease, there is a paucity of national data specifically examining its effects on heart failure (HF) hospitalizations. Previous cohort study data demonstrate worsened outcomes in HF patients with recent COVID-19 infection. To better understand this association, this study aimed to utilize a nationally representative database to examine demographics, outcomes, and health care utilization in hospitalizations for HF with a codiagnosis of COVID-19.
344	CaV340		Sayegh, Michael N.; Goins, Allie E.; Hall, Mary Ann Kirkconnell; Shin, Yoo Mee; Sayegh, Michael N.; Goins, Allie E.; Hall, Mary Ann Kirkconnell; Shin, Yoo Mee	Presentations, Diagnosis, and Treatment of Post-COVID Viral Myocarditis in the Inpatient Setting: A Narrative Review	https://doi.org/10.7759/cureus.39338	Published	2023-05-22	Review	https://www.cureus.com/articles/153448-presentations-diagnosis-and-treatment-of-post-covid-viral-myocarditis-in-the-inpatient-setting-a-narrative-review	While coronavirus disease 2019 (COVID-19) infection rates have declined, and mortality outcomes have improved with vaccines, targeted antiviral therapies, and improved care practices over the course of the pandemic, post-acute sequelae of SARS CoV-2 infection (PASC, also referred to as “long COVID”) has emerged as a significant concern, even among individuals who appear to have fully recovered from their initial infection. Acute COVID-19 infection is associated with myocarditis and cardiomyopathies, but the prevalence and presentation of post-infectious myocarditis are unclear. We provide a narrative review of post-COVID myocarditis, including symptoms and signs, physical exam findings, diagnosis, and treatment strategies. Post-COVID myocarditis has a wide range of presentations, from very mild symptoms to severe ones that can include sudden cardiac death. Several studies have noted what appears to be a bimodal distribution of affected patients, with individuals under age 16 (particularly males) most affected, followed by those over age 50. The gold standard of diagnosis for myocarditis is endomyocardial biopsy and cardiac magnetic resonance imaging with a confirmed diagnosis of COVID-19. However, if these are not available, other studies such as electrocardiogram, echocardiography, and inflammatory markers can guide clinicians to diagnose post-COVID myocarditis when appropriate. Treatment is largely supportive and may include oxygen therapy, intravenous hydration, diuretics, steroids, and antivirals. Post-COVID myocarditis is rare but important to recognize as more patients present with this condition in the inpatient setting.
345	CaV341		Diekman, Sarah; Chung, Tae	Post-acute sequelae of SARS-CoV-2 syndrome presenting as postural orthostatic tachycardia syndrome	https://doi.org/10.15441/ceem.22.409	Published	2023-01-30	Review	http://www.ceemjournal.org/journal/view.php?doi=10.15441/ceem.22.409	What is already known Postural orthostatic tachycardic syndrome (POTS) is increasingly recognized among patients with post-acute sequelae of SARS-CoV-2 syndrome (PASC). What is new in the current study We have reviewed all the case reports and prospective studies of POTS or dysautonomia among patients with PASC. The novel SARS-CoV-2 emerged in 2019, and the global COVID-19 pandemic continues into 2022. It has been known that a subset of patients develops chronic, debilitating symptoms after otherwise complete recovery from acute infection of COVID-19. Multiple terms have been used to describe this constellation of symptoms, including long COVID, long-haul COVID, and postacute sequelae of SARS-CoV-2 syndrome (PASC). PASC is broadly defined as a wide range of new, returning, or ongoing symptoms at least four weeks after infection. Those patients are often seen in emergency departments after acute COVID-19 infection, but their symptoms are not adequately managed because the underlying pathophysiology of PASC is not well understood. Among patients with PASC, postural orthostatic tachycardic syndrome (POTS) has been increasingly recognized. POTS is one of the most common forms of autonomic dysfunction and defined by a sustained orthostatic tachycardia during active standing or head-up tilt test in the absence of orthostatic hypotension or other cardiopulmonary diseases. Because POTS is a treatable condition, it is important to recognize POTS among PASC patients. Herein, we reviewed the current literature on POTS and dysautonomia in PASC in order to better understand the overlap and distinction between these pathologies. publisher: The Korean Society of Emergency Medicine
346	CaV342		Gotelli, E.; Ingegnoli, F.; Angelis, R. De; Guiducci, S.; Giuggioli, D.; Pizzorni, C.; Riccieri, V.; Sebastiani, M.; Sulli, A.; Smith, V.; Cutolo, M.	Ab1310 Utilization and Attitudes Towards Nailfold Videocapillaroscopy for the Assessment of Microvascular Status in Patients with Long-Covid: A Multicenter Online Survey	https://doi.org/10.1136/annrheumdis-2023-eular.3345	Published	2023-06-01	Study	https://ard.bmj.com/content/82/Suppl_1/1883.3	Background Human SARS-CoV-2 infection is responsible for a large variety of clinical manifestations related to Coronavirus disease-19 (COVID-19) [1]. SARS-CoV-2 can induce microvascular damage, that can be safely detected by nailfold videocapillaroscopy (NVC), as recently demonstrated [2-4]. Virus-induced endothelial dysfunction has been implicated in the pathogenesis of both active infection and long-COVID clinical manifestations (the last as persistence of disease symptoms after at least three months from onset) [5]. The study group on capillaroscopy and microcirculation in rheumatic diseases of the Italian Society of Rheumatology (CAPSIR) carried out an internal survey on the interest of the Italian Centers that perform NVC in participating in a detailed capillaroscopic and clinical data collection in long-COVID patients. Objectives To carry out an Italian multicenter cognitive survey on the interest in collecting NVC and clinical data of patients affected by long-COVID with or without previous rheumatological diseases. Methods The steering committee of the CAPSIR study group formulated a cognitive questionnaire, entitled “Study on the role of capillaroscopy in patients with long-COVID” (CAPSIR_2 Study), consisting of 27 open or multiple-choice questions. A Google Form of the questionnaire was emailed to all the member of the study group between September and October 2022. Data are reported with a descriptive analysis. Results The online questionnaire was completed by 41 CAPSIR members, belonging to 33 different Italian centers. Of note, 63% of participants had already experienced NVC in patients with long-COVID. The primary indication to perform the NVC was the onset of a new Raynaud’s phenomenon (46% of cases) and the requests come mainly from General Practitioners (33% of cases). In 2/3 of the cases, patients with long-COVID and previous rheumatic diseases, who underwent NVC examination, represented less than 20% of the total. It should be noted that always in 2/3 of the cases there was no preferential channel for the study of the microcirculation in patients affected by long-COVID nor a NVC investigation prior to the SARS-CoV-2 infection. According to the previous experience of the participants in the interview, the most important NVC parameters considered to be evaluated in long-COVID patients were number of capillaries per linear millimeter (24% of cases), presence of hemorrhages (34% of cases) and giant capillaries (22% of capillaries). All participants (100%) therefore agreed to participate in a further collection of NVC and clinical data in this cohort of patients. Conclusion This survey highlighted the interest of Italian Rheumatologists in assessing by NVC the COVID-related microvascular involvement. A consensus has emerged that future research is needed. After this pilot survey, the second part of the CAPSIR_2 Study will concern the collection/analysis before and after the SARS-CoV-2 infection of NVC and clinical data in patients with primary and secondary (to rheumatic diseases) Raynaud’s phenomenon and affected by long-COVID versus adequate controls. The aim is to investigate if the presence/severity of the microvascular damage might be involved in the pathogenesis of the clinical manifestations observed in COVID-19 patients after the active infection. CAPSIR_2 Study will be open to all Italian rheumatological centers that participated in the previous national CAPSIR_1 Project [6]. References [1]Fernandes Q et al. Ann Med. 2022;54:524-540.[2]Cutolo M et al. Nat Rev Rheumatol. 2021;17:665-677.[3]Sulli A et al. Microvasc Res 2022;142:104361.[4]Natalello G et al. Microvasc Res. 2021;133:104071.[5]Charfeddine S et al. Front Cardiovasc Med. 2021;8:745758.[6]Ingegnoli F et al. Reumatismo. 2022;74. Acknowledgements Authors wrote the abstract on behalf of the study group on capillaroscopy and microcirculation in rheumatic diseases of the Italian Society of Rheumatology (SIR) - CAPSIR.CAPSIR Study Group thanks the EULAR Study Group of Microcirculation in Rheumatic Diseases for the continuous cultural support. Disclosure of Interests None Declared.
347	CaV343		Hovornyan, A; Ilashchuk, T O	Analysis of long-term cardiovascular outcomes of COVID-19. Artificial Intelligence model for risk evaluation	https://doi.org/10.1093/eurjpc/zwad125.328	Published	2023-06-01	Study	https://doi.org/10.1093/eurjpc/zwad125.328	Type of funding sources: None.The COVID-19 pandemic has caused a serious worldwide health crisis with wide-reaching consequences. According to current studies, COVID-19 may contribute to the emergence of various problems, including cardiovascular disorders [1-3]. However, there are currently no strategies for predicting the cardiovascular post-acute COVID-19 consequences, nor is there any scientific examination of these effects [3]. This knowledge gap must be filled in order to improve post-acute COVID-19 care [4].To conduct a 12-month follow-up longitudinal observation study to explore potential long-term cardiovascular outcomes of COVID-19 and develop an AI-based model to predict them.We included 328 COVID-19 patients who were admitted to the hospital between February and April 2021. The average age of the studied population was 56.1, while 51% of the population was male. Patients with severe comorbidities, major adverse cardiovascular events (MACE) in anamnesis, and intra-hospital mortality were not included. After discharge, patients were monitored for 12 months. The data were randomly divided into derivation (n=201), validation (n=81), and external cohort (n=47). The obtained data include clinical data, results of laboratory and instrumental investigations, and medical records during the 1-year period. Our AI model is a convolutional neural network (CNN) consisting of sigmoid-activation-function neurons, trained by using outcome results, received in follow-ups, and evaluated on the external cohort.Due to the analysis of clinical data, higher levels of C-reactive protein, D-dimer, neutrophil/lymphocyte ratio, and lower levels of thyrotropin were associated with a higher 12-month risk of cardiovascular consequences. The longitudinal study showed that 16.4% of patients experienced MACE (8.5% - myocardial infarction, 5.2% - cerebrovascular disorders, 2.7% - pulmonary embolism) leading to cardiovascular death in 2.4% of the studied population. The total count of cardiovascular complications was 25.9% including first-detected hypertension, arrhythmias, heart failure etc.The derivation and validation datasets were used for the training of the CNN. The ROC analysis indicated that our AI model had a high predictive value for cardiovascular events during follow-up (AUC=0.891, 95% CI=0.869–0.913, p<0.001, sensitivity 92.4%, specificity 90.1%). The external cohort data analysis showed accurate results in 41/47 patients (87.2% accuracy), which significantly outperformed any other known methods of cardiovascular outcomes prediction during 12 months after COVID-19.Cardiovascular health in COVID-19 survivors needs special attention since COVID-19 is linked to an elevated risk of post-acute cardiovascular consequences. Long-term outcomes for COVID-19 can be predicted using AI-driven models.
348	CaV344		Noniashvili, M; Tamar Saralidze, T S; Tamar Svanidze, T S; Tamar Kandashvili, T K; David Malidze, D M	Cardiovascular pathologies in post-covid syndrome	https://doi.org/10.1093/eurjpc/zwad125.337	Published	2023-06-01	Study	https://doi.org/10.1093/eurjpc/zwad125.337	Type of funding sources: None.Problems of cardiovascular system and kidney function often follows the disease of Covid-19. Our aim was revealing and evaluation of cardiovascular disorders and kidney problems in patients who recovered from Covid-19.46 patients with Covid-19 infection, aged 29 to 64, were examined upon entering the clinic and after 2 months in outpatient department. (38 were women and 8 men, average age was 46, 1+_10.3 years). Along with clinical laboratory examination, echocardiography and ECG-Holter monitoring was performed in dynamic. Daily proteinuria, creatinine clearance and glomerular filtration rate were calculated. Patients who previously had arterial hypertension or any other disease of the cardiovascular system were not included in the study.Results of the study: Among the complaints that patients revealed 2 months after clinical onset of Covid-19, most frequent was discomfort and stinging pain in precordial area without irradiation that was not related to physical exertion. Cardialgia was observed in acute period and after two months in 30% and 25% of patients, respectively. 15% of patients revealed shortness of breath and palpitations during slight physical exertion in the acute period, while at repeated examination the specified symptom remained in 6%.Special attention was paid in our study to the dynamics of blood pressure. 24% of patients had elevated blood pressure at baseline. Blood pressure readings was increased in 28% of patients after 14 days. The average values of blood pressure during two months were 135, 5+_14.3 mmHg - systolic and 89.7+_10.7 mmHg- diastolic. After 2 months 26% of patients maintained arterial hypertention (AH) within the first stage. According to echocardiographic data, ventricular diastolic dysfunction was observed in 58% of patients in acute period and in 44% after two months. There were no signs of myocardial systolic dysfunction in dynamics.During the initial examination, diminished creatinine clearance (<90ml/min) and glomerular filtration rate (<90ml/min/1.73m2) disorders were observed in 42% and 62% of patients, respectively and microalbuminuria in 69% of patients. After 2 months microalbuminuria was maintained in 60% of patients, while decreased renal function (creatinine clearance and GFR) was observed in 33% of patients.Cardialgia, AH and signs of diastolic dysfunction were the main clinical manifestations of cardiovascular system dysfunction. The data of our study shows that probability of the formation of AH is highly increased after Covid-19 infection. Long-lasting microalbuminuria and a decrease in the renal filtering capabilities can also be revealed in every third patient after Covid-19 infection.The results of the study indicate the necessity of the monitoring of the patients after Covid-19 for timely diagnosis of AH and kidney disfunction to prevent development of unexpected cardiovascular events and kidney failure.
349	CaV345		Hira, Rashmin; Siddiqui, Tanya; Baker, Jacquie; Bourne, Kate; Ranada, Shaun; Soroush, Ateyeh; Karalasingham, Kavithra; Ahmad, Hyeqa; Morillo, Carlos; Sheldon, Robert; Raj, Satish	Objective cardiovascular autonomic abnormalities persist over time in patients with Post-Acute Sequelae of COVID-19 (PASC)	https://doi.org/10.1152/physiol.2023.38.S1.5735031	Published	2023-05-01	Study	https://journals.physiology.org/doi/abs/10.1152/physiol.2023.38.S1.5735031	BACKGROUND: The novel coronavirus (SARS-CoV-2) has negatively impacted the health and economy of the world. While most patients recover, many are suffering from symptoms several months after resolution of the acute illness (“Post-Acute Sequalae of COVID-19” [PASC]). Symptoms include fatigue, light-headedness, and tachycardia/palpitations, similar to symptoms of cardiovascular autonomic disorders such as Postural Orthostatic Tachycardia Syndrome (POTS), Initial Orthostatic Hypotension (IOH), Orthostatic Hypotension (OH), and Inappropriate Sinus Tachycardia (IST). We have previously shown a high prevalence of autonomic abnormalities among PASC patients. We currently do not know if these autonomic abnormalities are chronic and persist in PASC patients over time. OBJECTIVE: We aimed to determine if the autonomic abnormalities seen in patients after COVID-19 infection are persistent or transient, by comparing hemodynamic criterion between baseline and follow-up visits. We hypothesize that patients will recover, and abnormalities will not persist between the visits. METHODS: PASC patients (n=64; F=51; 46±12y) completed baseline visits 411±133 days after their initial COVID-19 infection and follow-up visits 97±9 days later. Patients underwent autonomic function testing with beat-to-beat hemodynamics during 10min supine rest followed by a 10min active stand. Patients were evaluated for hemodynamic criterion for POTS (↑HR≥30bpm within 10min), IOH (transient ↓SBP≥40mmHg within 15s), OH (↓SBP≥20mmHg within 3min), and IST (supine HR>100bpm). Categorical data were analyzed with a McNemar’s test. RESULTS: 19 (30%) participants met POTS criterion at baseline vs. 15 (23%) at follow-up (p=0.1). 43 (67%) participants met IOH criterion at baseline vs. 37 (58%) at follow-up (p=0.08). The OH criterion was seen in 2 (3.1%) vs 5 (7.8%) patients (p=0.2) and IST was seen in 1 patient at both visits (1.6%). Overall, 48 (75%) patients met the hemodynamic criterion for at least one autonomic disorder at baseline and 43 (67%) patients met at least one criterion at follow-up (p=0.09). CONCLUSION: Many patients with PASC have evidence of cardiovascular autonomic abnormalities, most commonly IOH, followed by POTS. The prevalence of these abnormalities does not decrease over time. These findings suggest patients with PASC are not recovering from autonomic complications due to their COVID-19 infections. Treatment and management strategies for autonomic abnormalities are needed to improve the quality of life for these patients. Funding: Canadian Institutes of Health Research (CIHR) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
350	CaV346		Hupin, D; Pichot, V; Back, M; Nygren Bonnier, M; Reistam, U; Runold, M; Bruchfeldt, J; Barthelemy, J C; Stahlberg, M; Fedorowski, A; Nickander, J	Diagnostic value of 24-h ECG recording in Long COVID patients with postural orthostatic tachycardia syndrome	https://doi.org/10.1093/europace/euad122.626	Published	2023-06-01	Study	https://doi.org/10.1093/europace/euad122.626	Type of funding sources: None.Cardiovascular autonomic dysfunction (CVAD) is a major complication for a large proportion of Long COVID (LC) patients. The main phenotype of CVAD is postural orthostatic tachycardia syndrome (POTS), commonly observed as a sequalae of COVID infection, thus defining a subset of LC patients. POTS is a cardiovascular autonomic disorder characterized by an excessive heart rate (HR) increase and symptoms of orthostatic intolerance when assuming upright posture, occurring predominantly in young and middle-aged women. Since the start of COVID-19 pandemic it has been observed that up to 30% of patients with post-COVID-19 syndrome develop POTS with such symptoms as tachycardia, orthostatic intolerance, fatigue, and cognitive impairment. The heterogeneity of POTS symptoms makes the diagnosis and appropriate management of POTS more difficult and one of the first steps for clinicians is to develop and test relevant diagnostic methods for POTS.Patients with persistent symptoms, 3 months after an acute SARS-CoV-2 infection were referred to the multi-disciplinary LC unit at a hospital in Sweden. Consecutive patients seen at this unit from 2021 to 2022 underwent a 24-h ECG recording. LC patients with POTS verified by active standing test and/or head-up tilt testing were prospectively enrolled in the study database and were compared with LC patients without POTS according to 3 specific analyses based on 24-h ECG recording : (1) cardiac autonomic activity expressed by heart rate variability, HRV (SDNN and RMSSD in ms) parameters, (2) awakening HR increase (HR mean 10 min before vs. 30 min after awakening) and (3) HR spikes (number/h if at least over than 30 bpm and at least during 30 s). Control group consisted of healthy subjects from 24-h ECG recordings database (HRV analysis) of a hospital in France. Data were expressed as mean (± standard deviation, SD) and frequencies (%).A total of 120 LC patients (mean age: 42.7 +/-9.97 y, 88% women) and 100 healthy subjects (mean age: 46.4 +/-10.2 y, 82% women) were included. LC with POTS (42%) was associated with (1) a decrease in most HRV parameters (mean SDNN: 86.8 +/-24.3 vs. 108.7 +/-24.1 ms, p=0.03), and the most reduced components were those related to the parasympathetic tone (mean RMSSD: 34,5 +/-20.4 vs. 45.6 +/-22.1 ms, p=0.04), (2) an abrupt and sustained increase in HR during the first 30 min after awakening (+30%, p<0.05) and (3) a higher number of HR spikes per h (1.4 +/-0.8 vs. 0.8 +/-0.7/h, p<0.001) compared with healthy subjects (HRV) and LC patients without POTS (awakenings and HR peaks) respectively.A triple analysis of 24-h ECG recordings revealed presence of autonomic dysfunction in LC patients with POTS compared with those without POTS. This novel analysis may be introduced in the clinic for screening and therapy monitoring.

	A	B	C	D	E	F	G	H	I	J	K	M
1	Ref	PPLC	Authors	Title	DOI	Peer reviewed	Date	type	Link	Keys	Clés

2	L01		BMJ	Long term respiratory complications of covid-19	https://doi.org/10.1136/bmj.m3001	opinion	August 3, 2020	editorial	https://www.bmj.com/content/370/bmj.m3001	An editorial in the BMJ notes that, like with SARS and MERS diseases, covid-19 is likely to cause respiratory symptoms in many patients that persist for at least several months.	Un éditorial dans BMJ remarque que, comme pour les maladies SRAS et MERS, la covid-19 est susceptible d'entraîner chez de nombreux patients des symptômes respiratoires persistants au moins plusieurs mois.
3	L02		Brian Shaw, Mahyar Daskareh & Ali Gholamrezanezhad	The lingering manifestations of COVID-19 during and after convalescence: update on long-term pulmonary consequences of coronavirus disease 2019 (COVID-19)	https://doi.org/10.1007/s11547-020-01295-8	Published	October 1, 2020	Article	https://link.springer.com/article/10.1007/s11547-020-01295-8	A review of the literature on the pulmonary sequelae of covid. The authors recommend regular checks and examinations of lung function.	Une revue de la littérature sur les séquelles pulmonaires de la covid. Les auteurs conseillent des contrôles et examens réguliers de la fonction pulmonaire.
4	L03		Ahmadreza Zarifian Mohammad Ghasemi Nour Arash Akhavan Rezayat	Chest CT findings of coronavirus disease 2019 (COVID-19): A comprehensive meta-analysis of 9907 confirmed patients	https://doi.org/10.1016/j.clinimag.2020.10.035	Published	October 24, 2020	CARDIOTHORACIC IMAGING	https://www.clinicalimaging.org/article/S0899-7071(20)30402-2/fulltext	A meta-analysis of lung scans of covid patients lists abnormalities by prevalence of onset: ground glass infiltrates with / without union, crosslinks, air bronchograms, pleural thickening and bronchial wall thickening.	Une méta-analyse de scans pulmonaires de patients covid répertorie les anomalies par prévalence d'apparition : infiltrats en verre dépoli avec/sans consolidation, réticulations, bronchogrammes aériens, épaississements pleuraux et des parois bronchiques.
5	L04		Jenny C. NGAI Fanny W. KO Susanna S. NG Kin‐Wang	The long‐term impact of severe acute respiratory syndrome on pulmonary function, exercise capacity and health status	https://doi.org/10.1111/j.1440-1843.2010.01720.x	Published	29 March 2010	Study	https://onlinelibrary.wiley.com/doi/10.1111/j.1440-1843.2010.01720.x		_
6	L05		Jonathan E Aviv1*, Sujana Chandrasekhar2 and Byron Thomashow3	Covid-19 Era Post Viral Vagal Neuropathy Presenting as Persistent Shortness of Breath with Normal Pulmonary Imaging	https://dx.doi.org/10.19080/IJOPRS.2020.04.555641	Published	October 06, 2020	Opinion	https://juniperpublishers.com/ijoprs/IJOPRS.MS.ID.555641.php	A team of New York doctors indicates having detected, for a cohort of a few long covid patients with persistent shortness of breath despite normal pulmonary imaging, post-viral vagal neuropathy. It would be revealed by a dysfunction of the vocal cords, and could be cured by respiratory rehabilitation and a modification of the diet (in particular by the exclusion of acidic foods).	Une équipe de médecins new-yorkais indique avoir détecté, pour une cohorte de quelques patients covid long avec un essoufflement persistant malgré une imagerie pulmonaire normale, une neuropathie vagale post-virale. Elle serait révélée par un dysfonctionnement des cordes vocales, et pourrait être soignée par rééducation respiratoire et une modification du régime alimentaire (notamment par l'exclusion d'aliments acides).
7	L06		Srikanth Kasturi, Arvind Muthirevula, Rohan R Chinthareddy	Delayed COVID-19 sequel - A challenging case of recurrent spontaneous pneumothorax	https://doi.org/10.21203/rs.3.rs-100043/v1	pre-print	20 Nov, 2020	Case report	https://www.researchsquare.com/article/rs-100043/v1	A study of a case of pneumothorax in a 55-year-old man, exceptional for its delayed appearance (30 days after a covid hospitalization, which lasted 35 days) which the authors attribute to persistent inflammation, and to lung damage and lesions.	Une étude d'un cas de pneumothorax chez un homme de 55 ans, exceptionnel par son aspect différé (30 j après une hospitalisation covid, qui avait duré 35j) que les auteurs attribuent à une inflammation persistante, et à des atteintes et lésions pulmonaires.
8	L07		Bram van den Borst, MD, PhD, Jeannette B Peters, PhD, Monique Brink, MD, PhD,	Comprehensive health assessment three months after recovery from acute COVID-19	https://doi.org/10.1093/cid/ciaa1750	Published	21 November 2020	Study	https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1750/5998118		En pratiquant des tomodensitométries thoraciques haute résolution (0,5 mm), une étude montre, 3 mois après, une récupération encourageante des capacités respiratoires des malades hospitalisés, malgré des anomalies résiduelles du parenchyme pulmonaire. L'étude néerlandaise remarque une part non négligeable de patients non hospitalisés qui gardent des séquelles importantes sur différents aspects, toujours à 3 mois, comme pour certains un échec au test de marche de 6 min.
9	L08		University of Sheffield	Hidden damage to lungs from Covid-19 revealed in new study from University of Sheffield		New imagery	1 December 2020	New imagery	https://www.sheffield.ac.uk/news/hidden-damage-lungs-covid-19-revealed-new-study-university-sheffield		En faisant inhaler du xénon hyperpolarisé (¹²⁹Xe) aux patients pendant les IRM pulmonaires, les équipes de l'Université de Sheffield pensent tenir une technique révolutionnaire pour mieux repérer les lésions causées par la covid, quand les autres scans IRM classiques semblent normaux. Cette technique pourrait répondre à certains paradoxes du #covidlong.
10	L09		Federico Giovannoni & Francisco J. Quintana	SARS-CoV-2-induced lung pathology: AHR as a candidate therapeutic target	https://doi.org/10.1038/s41422-020-00447-9	Published	01 December 2020	Article	https://www.nature.com/articles/s41422-020-00447-9		Un article dans Nature décrit une piste thérapeutique pour les atteintes pulmonaires de la covid, qui consiste à cibler par un antagoniste (CH223191) le récepteur d'aryl hydrocarbone (AhR), perçu comme facteur pro-viral. L'article de Nature cite notamment une étude publiée le mois dernier. https://www.nature.com/articles/s41422-020-00435-z
11	L10		Paul Hofman, Marie-Christine Copin	Les lésions histologiques pulmonaires associées à l’infection par le Sars-CoV-2 Histological pulmonary features due to the Sars-CoV-2	https://doi.org/10.1016/S1773-035X(20)30391-9	Published	January 2021	Article	https://www.sciencedirect.com/science/article/pii/S1773035X20303919		Une revue d'articles répertorie les lésions tissulaires pulmonaires dues à la covid et note qu'une maladie vasculaire se traduisant par des thrombi sur des vaisseaux de calibre varié est souvent observée au niveau pulmonaire.
12	L11		Revue des maladies respiratoires - Actualités	Résultats préliminaires d'études Pneumopathie à SARS-CoV-2: évolution fonctionnelle à 3 mois et corrélation avec les anomalies radiologiques (étude post Covid M3) Fonction pulmonaire à 3 mois des patients survivants à la réanimation du SARS-CoV-2 Pneumonie à SARS-COV-2 en réanimation : quelles séquelles respiratoires chez les patients guéris de la COVID-19 ? Bilan COVID à 3 mois : retour d’expérience par le trinôme médical, paramédical et AMA Impact cardiorespiratoire de l’infection à SARS-CoV-2 : données à 3 mois Prévalence du trouble de diffusion après infection à SARS-CoV-2 : comparaison entre les normes CECA/ERS 1993 et GLI Récupération respiratoire à distance d’une pneumonie sévère à SARS-CoV-2 (COVID-19) : résultats préliminaires de l’étude de cohorte multicentrique prospective RE2COVERI		Published	Janvier 2021	Preliminary results from studies	https://www.sciencedirect.com/science/article/abs/pii/S1877120320306376 https://www.sciencedirect.com/science/article/abs/pii/S1877120320306479 https://www.sciencedirect.com/science/article/abs/pii/S1877120320302706 https://www.sciencedirect.com/science/article/abs/pii/S1877120320302391 https://www.sciencedirect.com/science/article/abs/pii/S1877120320302676 https://www.sciencedirect.com/science/article/abs/pii/S1877120320306406 https://www.sciencedirect.com/science/article/abs/pii/S1877120320306418		Dans le numéro de janvier 2021 de la Revue des maladies respiratoires - Actualités, plusieurs résultats intermédiaires d'études sur les séquelles pulmonaires de la covid à 3 mois sont publiées.
13	L12		James P Hayes	Considering the long-term respiratory effects of Covid-19	https://doi.org/10.1093/occmed/kqaa224	Published	22 January 2021	Editorial	https://academic.oup.com/occmed/advance-article/doi/10.1093/occmed/kqaa224/6105804		Un éditorial dans Occupational Medicine décrit les séquelles pulmonaires qui peuvent se retrouver chez des malades covid, aussi bien modérés que sévères, et se traduisent par des opacités en verre dépoli, des atélectasies et divers stades de dysfonctionnement pulmonaire, obstructif ou restrictif. L'éditorial rappelle que le NIHR (agence de recherche médicale britannique) estime que le covid long et l'ensemble des symptômes persistants pourraient en réalité recouvrir jusqu'à 4 syndromes différents.
14	L13		Bavaharan Rajalingam1, Ethirajan Narayanan2, Praveen Nirmalan3, Kamalanthan Muthukrishnan4, Vivek Sundaram5, Saravanan Kumaravelu6, Mukundhan Gopalan7, Senthil Jeyapal8, Baskaran Rajalingam9, Vijay Khanna10, Praveen Dhoss11, Gopinath	Pattern recognition of high-resolution computer tomography (HRCT) chest to guide clinical management in patients with mild to moderate COVID-19		Published	23-Jan-2021	Study	https://www.ijri.org/text.asp?2021/31/5/110/307734		_
15	L14		Srikanth Kasturi, Arvind Muthirevula, Rohan Reddy Chinthareddy & Vijay Cholenahalli Lingaraju	Delayed recurrent spontaneous pneumothorax post-recovery from COVID-19 infection	https://doi.org/10.1007/s12055-021-01145-w	Published	02 February 2021	Case Report	https://link.springer.com/article/10.1007/s12055-021-01145-w	We present a case of delayed recurrent spontaneous pneumothorax, presenting 4 weeks after recovery from COVID-19 in a previously healthy middle-aged gentleman, for which uniportal video-assisted thoracoscopic surgery (VATS) pleurectomy was performed, but the cause of pneumothorax could not be ascertained.	Un cas de pneumothorax retardé et attribué à l'infection (4 semaines après une guérison de phase aiguë de la covid).	N004
16	L15		J.R. Blanco, M.J. Cobos-Ceballos, F. Navarro, I. Sanjoaquin, F. Arnaiz de las RevillasE. Bernal, L. Buzon-Martin, 0, M. Viribay, L. Romero, S. Espejo-Pérez, B. Valencia, 0, D. Ibañez, D. Ferrer-Pargada, D. Malia, F.G. Gutierrez-Herrero, J. Olalla, B. Jurado-Gamez, J. Ugedo	Pulmonary long-term consequences of COVID-19 infections after hospital discharge	https://doi.org/10.1016/j.cmi.2021.02.019	Published	March 01, 2021	ORIGINAL ARTICLE	https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(21)00101-4/fulltext	In summary, this study has shown that a high proportion of severely affected COVID-19 patients show impairment in DLCO measurements in the first few months after symptoms onset. Although its long-term impact is still unknown, DLCO could be considered a useful tool to identify individuals at risk for pulmonary sequelae.	Une publication étudie les pertes de capacité pulmonaire de diffusion du monoxyde de carbone (DLCO) sur le long terme après une infection au SARS-CoV-2.	N004
17	L16		Naybandi Atashi S, Naderpour Z, Goharimpghadam K, Saeedi M.	An Eight-week Follow-up Study in Patients With COVID-19 Respiratory Failure: Delayed Recovery or Lung Sequel	https://doi.org/10.18502/crcp.v5iS1.6240	Published	2021-03-07	CASE REPORT	https://crcp.tums.ac.ir/index.php/crcp/article/view/411	CT imaging techniques have an important role in the primary diagnosis of pneumonia secondary to COVID-19; moreover, the level of pulmonary involvement in CT scan is one of the criteria for disease severity in the acute phase of COVID-19 pneumonia. Still, the role of CT scan in the follow-up period is unknown.	Une présentation de 4 cas de patients avec des séquelles pumlonaires de la covid suivis sur 8 semaines.
18	L17		Laura Fabbri, Samuel Moss, Fasihul Khan, Wenjie Chi, Jun Xia, Karen Robinson, Alan Smyth, Gisli Jenkins, Iain Stewart	Post-viral parenchymal lung disease of COVID-19 and viral pneumonitis: A systematic review and meta-analysis	https://doi.org/10.1101/2021.03.15.21253593	pre-print	March 17, 2021	Systematic review and meta-analysis	https://www.medrxiv.org/content/10.1101/2021.03.15.21253593v1	On follow up CT scans, the overall estimated proportion was 0·56 (95%CI 0·44 to 0·66, I2= 94·44%) for inflammatory changes, and 0·40 (95%CI 0·29 to 0·52, I2=95·19%) for fibrotic findings. In SARS-CoV-2 specifically, proportions were estimated at 0·43 (95%CI 0·32 to 0·56, I2=94.60%) and 0·30 (95%CI 0·19 to 0·43, I2=94.89%) for inflammatory and fibrotic findings, respectively. Overall proportion for restrictive impairment was 0·19 (95%CI 0·12 to 0·27, I2=94·46%), DLCO reduction was estimated at 0·45 (95%CI 0·38 to 0·52, I2=90·10). Elevated radiological and functional estimates persisted across follow-up times.	_
19	L18		MaurizioBalbiabCaterinaConticGianlucaImericAnnaCarolidAlessandraSuraceabAndreaCorsiabElisaMercanzinabAlbertoArrigonieGiuliaVilladFabianoDi MarcocfPietro AndreaBonaffiniabSandroSironi	Post-discharge chest CT findings and pulmonary function tests in severe COVID-19 patients	https://doi.org/10.1016/j.ejrad.2021.109676	Published	20 March 2021	Study	https://www.sciencedirect.com/science/article/pii/S0720048X2100156X	Highlights •Severe COVID-19 survivors can still have chest CT abnormalities after discharge, even beyond three months after the disease onset •The percentage of compromised lung volume on CT correlates with pulmonary function tests and dyspnea severity •Pulmonary function tests indicate an impairment of diffusion capacity and a tendency toward restrictive physiology in most cases. An underlying pulmonary vasculopathy is possibly implied in a minor proportion of patients	_
20	L19		Hiroaki Ogata Taisuke Nakagawa Soichiro Sakoda Akiko Ishimatsu Kazuhito Taguchi Masako Kadowaki Atsushi Moriwaki Makoto Yoshida	Nintedanib treatment for pulmonary fibrosis after coronavirus disease 2019	https://doi.org/10.1002/rcr2.744	Published	30 March 2021	Case Report	https://onlinelibrary.wiley.com/doi/10.1002/rcr2.744	A 78‐year‐old Japanese woman with no smoking history suffered from near‐fatal coronavirus disease 2019 (COVID‐19) requiring four‐week invasive mechanical ventilation, with subsequent radiological features of pulmonary fibrosis. Although methylprednisolone gradually improved her respiratory condition, her oxygenation and exercise tolerance had drastically deteriorated, necessitating high‐flow nasal cannula oxygen therapy. In parallel with tapering systemic steroid, the patient was treated with nintedanib. Three months later, the patient was able to walk with a walking aid using oxygen at 4 L/min. The present case is an indication that nintedanib might provide a novel therapeutic approach for managing post‐COVID‐19 fibrosis, although further studies are warranted.	_
21	L20		Federico Mento, Tiziano Perrone, Anna Fiengo, Francesco Tursi, Veronica Narvena Macioce, Andrea Smargiassi, Riccardo Inchingolo & Libertario Demi	Limiting the areas inspected by lung ultrasound leads to an underestimation of COVID-19 patients’ condition	https://doi.org/10.1007/s00134-021-06407-0	Published	11 May 2021	Correspondence	https://link.springer.com/article/10.1007/s00134-021-06407-0	In a recent work, we compared the impact of different imaging protocols in the evaluation of COVID-19 patients by LUS and found that a minimum of 10 areas was necessary to avoid a significant underestimation of the patient’s condition. Results show a 43, 63, and 80% agreement with our fourteen-area protocol for protocols 1, 2 and 3, respectively, when inspecting the data for bilateral large consolidations and/or areas of white lung (large hyperechoic bands). Moreover, a 77, 87, and 87% agreement was found for protocols 1, 2, and 3, respectively, when inspecting the data for bilateral small or large consolidations and/or areas of white lung. These results would imply an underestimation, according to the classification presented in [1], of HighLUS patients as IntLUS patients. Moreover, as previously reported in [3], these results confirm the importance of the basal areas for a correct evaluation of LUS data from COVID-19 patients.	_
22	L21		Elia Bari 1 ,Ilaria Ferrarotti 2,Laura Saracino 3,Sara Perteghella 1,4 ,Maria Luisa Torre 1,4,* ,Luca Richeldi 5 andAngelo Guido Corsico	Mesenchymal Stromal Cell Secretome for Post-COVID-19 Pulmonary Fibrosis: A New Therapy to Treat the Long-Term Lung Sequelae?	https://doi.org/10.3390/cells10051203	Published	14 May 2021	Article	https://www.mdpi.com/2073-4409/10/5/1203/htm	Available antifibrotic therapies, namely nintedanib and pirfenidone, might have a role in attenuating profibrotic pathways in SARS-CoV-2 infection but are not economically sustainable by national health systems and have critical adverse effects. It is our opinion that the mesenchymal stem cell secretome could offer a new therapeutic approach in treating COVID-19 fibrotic lungs through its anti-inflammatory and antifibrotic factors.	Un article évoque la thérapie par sécrétome des cellules mésenchymateuses stromales pour traiter les fibroses pulmonaires, séquelles à long terme de la covid. Les auteurs évoquent un avantage par rapport aux thérapies antifibrotiques habituellement disponibles, à savoir le nintédanib et la pirfénidone, qui pourraient jouer un rôle dans l'atténuation des voies profibrotiques dans l'infection par le SARS-CoV-2, mais ne sont pas économiquement viables et ont des effets indésirables critiques.	N011
23	L22		Pallab Chakraborty * and Kaustav Chakraborty	Anti-Fibrotic Agents Could Be the Game Changer for Post‑COVID Pulmonary Fibrosis Treatment – A Mini Review	https://doi.org/10.20944/preprints202105.0423.v1	pre-print	18 May 2021	Review	https://www.preprints.org/manuscript/202105.0423/v1	Due to COVID-19, dysregulated immune response and wound repair mainly in elderly patients causes this secondary pulmonary fibrosis. Thus using anti-fibrotic agents could be meaningful in these circumstances although their efficacy in treating COVID-19 is subject to more detailed laboratory research works. In this review article you will get to know about the lung fibrosis generation due to COVID-19 infection, about anti-fibrotic agents and the currents challenges of this field.	_
24	L23		James T. Grist1,2,3,4, Mitchell Chen3, Guilhem J. Collier5, Betty Raman2, Gabriele AbuEid3, Anthony McIntyre3, Violet Matthews3, Emily Fraser7, Ling-Pei Ho6,7, Jim M. Wild5, Fergus Gleeson	Hyperpolarized 129Xe MRI Abnormalities in Dyspneic Participants 3 Months after COVID-19 Pneumonia: Preliminary Results	https://doi.org/10.1148/radiol.2021210033	Published	May 25 2021	Study	https://pubs.rsna.org/doi/10.1148/radiol.2021210033	9 patients (mean age 57±7 years, Male = 6) and 5 volunteers (29 ± 3 years, Female = 5) were enrolled. Patient mean time from hospital discharge was 169, range 116-254 days. There was a difference in RBC:TP between patients and controls (0.3 ± 0.1 versus 0.5 ± 0.1, respectively, p = 0.001, effect size = 1.36). There was significant difference between the RBC and gas phase spectral full width at half maximum (FWHM) between volunteers and patients (median ± 95 % confidence interval, 567 ± 1 vs 507 ± 81, p = 0.002 and 104 ± 2 vs 122 ± 17, p = 0.004, respectively). Results were reproducible with Intraclass Correlation Coefficients of 0.82 and 0.88 for patients and volunteers respectively. Participants had normal or near normal CT scans, mean 7/25, range 0-10/25. Conclusion Xe MRI showed alveolar-capillary diffusion limitation in all 9 post COVID-19 pneumonia patients despite normal or nearly normal CT scans.	Une étude à Oxford sur 9 patients suggère que l'IRM au xénon hyperpolarisée peut être un mode d'imagerie potentiellement utile chez les patients atteints de covid et dyspnéiques 3 mois après la phase aigue ou la sortie de l'hôpital.	N011
25	L24		YohAritaM.D., Ph.D.aShoheiYamamotoM.D.aManabuNagataM.D., Ph.D.bNobuyukiOgasawaraM.D.aShinjiHasegawaM.D., Ph.D.a	Long COVID presenting with intermittent fever after COVID-19 pneumonia	https://doi.org/10.1016/j.radcr.2021.05.081	Published	4 June 2021	Case Report	https://www.sciencedirect.com/science/article/pii/S1930043321003769	A 72-year-old man presented to our hospital with a fever. Chest computed tomography showed typical coronavirus disease 2019 (COVID-19) pneumonia. The fever normalized after a few days, and the pneumonia was alleviated. However, the intermittent fever subsequently re-occurred and persisted for over a month. Various tests, including blood tests, culture tests, and image evaluations, were performed. However, the conclusion was that long COVID was the cause of the intermittent fever as an exclusion diagnosis. Many patients suffer from persistent symptoms of COVID-19, but the symptoms and their durations vary. Here we report a case of prolonged fever after COVID-19 pneumonia.	_
26	L25		Alberto Fortini, Arianna Torrigiani, Serena Sbaragli, Aldo Lo Forte, Andrea Crociani, Paolo Cecchini, Giulia Innocenti Bruni & Antonio Faraone	COVID-19: persistence of symptoms and lung alterations after 3–6 months from hospital discharge	https://doi.org/10.1007/s15010-021-01638-1	Published	06 June 2021	Study	https://link.springer.com/article/10.1007/s15010-021-01638-1	Results 22% of patients reported no residual symptoms, 28.8% 1 or 2 symptoms and 49.2% 3 or more symptoms. The most frequently symptoms were fatigue, exertional dyspnea, insomnia, and anxiety. Among the inflammatory and coagulation parameters, only the median value of fibrinogen was slightly above normal. A deep vein thrombosis was detected in 1 patient (1.7%). Thoracic US detected mild pulmonary changes in 15 patients (25.4%), 10 of which reported exertional dyspnea. DLCO was mildly or moderately reduced in 19 patients (37.2%), 13 of which complained of exertional dyspnea. Conclusion These results highlight that a substantial percentage of COVID-19 patients (77.8%) continue to complain of symptoms 3–6 months after hospital discharge. Exertional dyspnea was significantly associated with the persistence of lung US abnormalities and diffusing capacity alterations. Extended follow-up is required to assess the long-term evolution of postacute sequelae of COVID-19.	_
27	L26		Saeki, Takuya RPT, MSc1,2; Ogawa, Fumihiro MD, PhD3; Matsumiya, Mina RPT2; Yamamura, Mei RPT2; Oritsu, Hideyuki RPT2; Nonogaki, Manabu MD1; Uesugi, Jo RPT2; Takeuchi, Ichiro MD, PhD3; Nakamura, Takeshi	Long Term Decreased Exercise Capacity of COVID-19 Patients Who Received Mechanical Ventilation in Japan A Case Series	https://doi.org/10.1097/PHM.0000000000001803		May 28, 2021	Cases Report	https://journals.lww.com/ajpmr/Abstract/9000/Long_Term_Decreased_Exercise_Capacity_of_COVID_19.97657.aspx	However, the 6MWD of the four patients remained shorter than those of healthy persons of the same age at 6 months after admission to the hospital. Furthermore, the minimum SpO2 during the 6-minute walking test remained below 96%. It is possible that patients who receive mechanical ventilation due to COVID-19-associated ARDS have decreased long-term exercise capacity, despite muscle power and activities of daily living recovering completely.	_
28	L27		Vinod Nikhra	Pulmonary Involvement in COVID-19 and'Long Covid': The Morbidity, Complications and Sequelae	https://doi.org/10.29328/journal.jprr.1001022	Published	June 15, 2021	Study	https://www.heighpubs.org/jprr/jprr-aid1022.php	Pulmonary Involvement in COVID-19 and ‘Long Covid’: The Morbidity, Complications and Sequelae	_
29	L28		Sonay Aydina 1 Edhem Unver b 1 Erdal Karavasa 1 Seven Yalcin b1 Mecit Kantarci ac2	Computed tomography at every step: Long coronavirus disease	https://doi.org/10.1016/j.resinv.2021.05.014	Published	29 June 2021	Study	https://www.sciencedirect.com/science/article/pii/S221253452100112X	Highlights •Persistent long COVID symptoms of shortness of breath, chest pain, cough, and muscle weakness are correlated with CT severity values. •CT severity is related with more persistent symptoms than laboratory parameters. •Knowing the relationsgip between CT severity and long COVID can help to identify risky patients and create follow up programs to support these cases. Levels of C-reactive protein and fibrinogen, anemia, and female sex were associated with some of the persistent symptoms., the severity of the disease seen on CT was a successful predictor for the disease severity/prognosis and was also correlated with prolonged COVID infection and more persistent symptoms.
30	L29		Shengding Zhang, Wenxue Bai, Junqing Yue, Lu Qin, Cong Zhang, Shuyun Xu, Xiansheng Liu, Wang Ni & Min Xie	Eight months follow-up study on pulmonary function, lung radiographic, and related physiological characteristics in COVID-19 survivors	https://doi.org/10.1038/s41598-021-93191-y	Published	05 July 2021	Study	https://www.nature.com/articles/s41598-021-93191-y	At follow-up, severe cases had higher incidences of persistent symptoms, DLCO impairment, and higher abnormal CT score as compared with mild cases. CT score at follow-up was positively correlated with age, LDH level, cumulative days of oxygen treatment, total dosage of glucocorticoids used, and CT peak score during hospitalization. DLCO% at follow-up was negatively correlated with cumulative days of oxygen treatment during hospitalization. DLCO/VA% at follow-up was positively correlated with BMI, and TNF-α level. Among the three groups categorized as survivors with normal DLCO, abnormal DLCO but normal DLCO/VA, and abnormal DLCO and DLCO/VA, survivors with abnormal DLCO and DLCO/VA had the lowest serum IL-2R, IL-8, and TNF-α level, while the survivors with abnormal DLCO but normal DLCO/VA had the highest levels of inflammatory cytokines during hospitalization. Altogether, COVID-19 had a greater long-term impact on the lung physiology of severe cases. The long-term radiological abnormality maybe relate to old age and the severity of COVID-19. Either absent or excess of inflammation during COVID-19 course would lead to the impairment of pulmonary diffusion function.
31	L30		Salem AM, Al Khathlan N, Alharbi AF, Alghamdi T, AlDuilej S, Alghamdi M, Alfudhaili M, Alsunni A, Yar T, Latif R, Rafique N, Al Asoom L, Sabit H	The Long-Term Impact of COVID-19 Pneumonia on the Pulmonary Function of Survivors	https://doi.org/10.2147/IJGM.S319436	Published	9 July 2021	Study	https://www.dovepress.com/the-long-term-impact-of-covid-19-pneumonia-on-the-pulmonary-function-o-peer-reviewed-fulltext-article-IJGM	Significant reduction in total lung capacity (TLC), forced vital capacity (FVC), forced expiratory volume (FEV1), FEV1/FEV, and diffusing capacity for carbon monoxide (DLCO) was observed in post-COVID-19 subjects compared to controls. Restrictive lung impairment was observed in 50% of post-COVID-19 cases (n = 10) compared to 20% in the control group (n = 6, P = 0.026). In addition, mild diffusion defect was detected in 35% (n = 7) of the post-COVID-19 group compared to 23.3% (n = 7) in the controls (P = 0.012). Conclusion: COVID-19 pneumonia has an impact on the lung functions in terms of restrictive lung impairment and mild diffusion defect after three months from recovery.	_
32	L31		NiclaOrzesa1LauraPiniab1GuidoLeviaSilviaUccelliaFrancescaCettoloaClaudioTantucci	A prospective evaluation of lung function at three and six months in patients with previous SARS-COV-2 pneumonia	https://doi.org/10.1016/j.rmed.2021.106541	Published	10 July 2021	Study	https://www.sciencedirect.com/science/article/pii/S095461112100247X	Highlights •After COVID-19 pneumonia, nearly 50% of patients fully recovered lung function. •Most of those with abnormal pulmonary function tests at 3 months improved later. •However, only another 29% reached normal values at 6 months. •Lung function recovery is faster at first and occurs more slowly thereafter. •More than one-third of patients keep abnormal lung function tests at 6 months.	_
33	L32		Nannan Shi, Chao Huang, Qi Zhang, Chunzi Shi, Fengjun Liu, Fengxiang Song, Qinguo Hou, Jie Shen, Fei Shan, Xiaoming Su, Cheng Liu, Zhiyong Zhang, Lei Shi & Yuxin Shi	Longitudinal trajectories of pneumonia lesions and lymphocyte counts associated with disease severity among convalescent COVID-19 patients: a group-based multi-trajectory analysis	https://doi.org/10.1186/s12890-021-01592-6	Published	13 July 2021	Study	https://bmcpulmmed.biomedcentral.com/articles/10.1186/s12890-021-01592-6	We characterised four distinct trajectory subgroups. (1) Group 1 (13.9%), pneumonia increased until a peak lesion percentage of 1.9% (IQR 0.7–4.4) before absorption. The slightly decreased lymphocyte rapidly recovered to the top half of the normal range. (2) Group 2 (44.7%), the peak lesion percentage was 7.2% (IQR 3.2–12.7). The abnormal lymphocyte count restored to normal soon. (3) Group 3 (26.0%), the peak lesion percentage reached 14.2% (IQR 8.5–19.8). The lymphocytes continuously dropped to 0.75 × 109/L after one day post-onset before slowly recovering. (4) Group 4 (15.4%), the peak lesion percentage reached 41.4% (IQR 34.8–47.9), much higher than other groups. Lymphopenia was aggravated until the lymphocytes declined to 0.80 × 109/L on the fourth day and slowly recovered later. Patients in the higher order groups were older and more likely to have hypertension and diabetes (all P values < 0.05), and have more severe disease. Conclusions Our findings provide new insights to understand the heterogeneous natural courses of COVID-19 patients and the associations of distinct trajectories with disease severity, which is essential to improve the early risk assessment, patient monitoring, and follow-up schedule.
34	L33		Rebecca C. Robey, Katie Kemp, Philip Hayton, Dalia Mudawi, Ran Wang, Melanie Greaves, Veronica Yioe, Pilar Rivera-Ortega, Cristina Avram & Nazia Chaudhuri	Pulmonary Sequelae at 4 Months After COVID-19 Infection: A Single-Centre Experience of a COVID Follow-Up Service	https://doi.org/10.1007/s12325-021-01833-4	Published	18 July 2021	Study	https://link.springer.com/article/10.1007/s12325-021-01833-4	A total of 221 patients were followed-up: all patients who had been admitted to ICU (n = 44) and 38 of 177 (21%) non-ICU patients who had persistent symptoms and/or persistent radiographic changes on chest X-ray at their initial 8-week follow-up visit required further pulmonary function testing and thoracic imaging. An overall prevalence of PFT abnormalities were seen in around 24% of the entire cohort and radiological evidence of fibrosis was seen in around 7% of the entire cohort at 4 months after discharge.	_
35	L34		Carlos Toufen JuniorPaulo Manuel Pêgo-Fernandes	COVID-19: long-term respiratory consequences	https://doi.org/10.1590/1516-3180.2021.139526052021	Published	16 July 2021	Editorial	https://www.scielo.br/j/spmj/a/VHR5DZBxcb6Gh5z5wjWb36Q/?lang=en	Although COVID-19 was initially identified as a pneumonia-like illness, its pathophysiology in severe cases can include destruction of lung epithelial cells, thrombosis, hypercoagulation and vascular leakage. These events lead to acute respiratory distress syndrome (ARDS).	_
36	L35		Ranju T Dhawan, FRCR Deepa Gopalan, FRCR Luke Howard, DPhil Angelito Vicente, BSc Mirae Park, MRCP Kavina Manalan, MRCP Ingrid Wallner, BSc Prof Peter Marsden, PhD Surendra Dave, MSc Howard Branley, MD Georgina Russell, MRCP Nishanth Dharmarajah, MSc Prof Onn M Kon	Beyond the clot: perfusion imaging of the pulmonary vasculature after COVID-19	https://doi.org/10.1016/S2213-2600(20)30407-0	Published	November 17, 2020	Article	https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30407-0/fulltext	Although the long-term outcomes of COVID-19 are not known, should pulmonary vascular sequelae prove to be clinically significant, these have the potential to become a public health problem. In this Personal View, we propose a proactive follow-up strategy to evaluate residual clot burden, small vessel injury, and potential haemodynamic sequelae. A nuanced and physiological approach to follow-up imaging that looks beyond the clot, at the state of perfusion of lung tissue, is proposed as a key triage tool, with the potential to inform therapeutic strategies.	_
37	L36		Damiano Caruso1, Gisella Guido1, Marta Zerunian1, Tiziano Polidori1, Elena Lucertini1, Francesco Pucciarelli1, Michela Polici1, Carlotta Rucci1, Benedetta Bracci1, Matteo Nicolai1, Antonio Cremona1, Chiara De Dominicis1, Andrea Laghi1	Postacute Sequelae of COVID-19 Pneumonia: 6-month Chest CT Follow-up	https://doi.org/10.1148/radiol.2021210834	Published	Jul 27 2021		https://pubs.rsna.org/doi/10.1148/radiol.2021210834	One-hundred-eighteen patients, with both baseline and six-month follow-up Chest CT, were included in the study (62 female, mean age 65±12 years). At follow-up Chest CT, 85/118 (72%) patients showed fibrotic-like changes and 49/118 (42%) showed GGOs. Baseline LSS (>14), QCCT (≤3.75L and ≤80%) showed an excellent performance in predicting fibrotic-like changes at Chest CT follow-up. In the multivariable analysis, AUC was .89 (95%CI .77-.96) for the clinical model, .81 (95%CI .68-.9) for the radiological model and .92 (95%CI .81-.98)for the combined model. Conclusion At six-month follow-up Chest CT, 72% of patients showed late sequelae, in particular fibrotic-like changes. Baseline LSS and QCCT of well-aerated lung showed an excellent performance in predicting fibrotic-like changes at six-month Chest CT (AUC>.88). Male sex, cough, lymphocytosis and QCCT well-aerated lung were significant predictors of fibrotic-like changes at six-month with an inverse correlation (AUC .92).	_
38	L37		AshleyDiazBS1DanielBujnowskiBS2PhillipMcMullenMD, PhD3MariaLysandrouBA1VijayalakshmiAnanthanarayananMD4Aliya N.HusainMBBS3RichardFreemanMD, MBA5Wickii T.VigneswaranMD, MBA5Mark K.FergusonMD6JessicaDoningtonMD6Maria LuciaMadariagaMD6Zaid M.Abdelsattar	Pulmonary parenchymal changes in COVID-19 survivors	https://doi.org/10.1016/j.athoracsur.2021.06.076	Published	31 July 2021	Study	https://www.sciencedirect.com/science/article/pii/S0003497521013072	Results Eleven COVID-19 survivors with asymptomatic (n=4), moderate (n=4), and severe (n=3) COVID-19 infections underwent elective lung resection at a median 68.5 days (range 24-142) after COVID-19 diagnosis. The most common operation was lobectomy (75%). On histopathological examination, no differences were identified between the lung parenchyma of COVID-19 survivors and controls across all compartments examined. Conversely, patients in the end-stage COVID-19 group showed fibrotic diffuse alveolar damage with intra-alveolar macrophages, organizing pneumonia, and focal interstitial emphysema. Conclusions In this first study to examine the lung parenchyma of COVID-19 survivors, we did not find distinct post-acute histopathological changes to suggest permanent pulmonary damage. These results are reassuring for COVID-19 survivors who recover and become asymptomatic.	_
39		PESE - CPET	Inderjit Singh, MD FRCP Phillip Joseph, MD Paul M. Heerdt, MD PhD Marjorie Cullinan, RT Denyse D. Lutchmansingh, MBBS Mridu Gulati, MD MPH Jennifer D. Possick, MD David M. Systrom, MD Aaron B. Waxman	Persistent Exertional Intolerance after COVID-19: Insights from Invasive Cardiopulmonary Exercise Testing.	https://doi.org/10.1016/j.chest.2021.08.010	Published	August 10, 2021	Study	https://journal.chestnet.org/article/S0012-3692(21)03635-7/fulltext	Study Design and Methods This study examined the systemic and pulmonary hemodynamics, ventilation, and gas exchange in 10 post-COVID-19 patients without cardio-pulmonary disease during invasive cardiopulmonary exercise testing (iCPET) and compared the results to 10 age- and sex matched controls. These data were then used to define potential reasons for exertional limitation in the post-COVID-19 cohort. Results Post-COVID-19 patients exhibited markedly reduced peak exercise aerobic capacity (VO2) compared to controls (70±11%predicted vs. 131±45%predicted; p<0.0001). This reduction in peak VO2 was associated with impaired systemic oxygen extraction (i.e., narrow CaVO2/CaO2) compared to controls (0.49±0.1 vs. 0.78±0.1, p<0.0001) despite a preserved peak cardiac index (7.8±3.1 vs. 8.4±2.3 L/min, p>0.05). Additionally, post-COVID-19 patients demonstrated greater ventilatory inefficiency (i.e., abnormal VE/VCO2 slope: 35±5 vs. 27±5, p=0.01) compared to controls without an increase in dead space ventilation. Interpretation Post-COVID-19 patients without cardiopulmonary disease demonstrate a marked reduction in peak VO2 from a peripheral rather than a central cardiac limit along with an exaggerated hyper-ventilatory response during exercise.	En cherchant à comprendre l'intolérance à l'exercice de certains malades du covid long, une étude dans Chest Journal remarque que les patients rétablis de la covid (sans complications cardio-pulmonaires) présentent une capacité aérobique maximale réduite, avec une extraction systémique de l'oxygène altérée et une pente d'efficacité ventilatoire anormale. L'effet est attribué à une limite cardiaque périphérique plutôt que centrale, ainsi qu'une réponse hyperventilatoire exagérée pendant l'exercice.	N014E
40	L38		Grace Y. Lam, A. Dean Befus, Ronald W. Damant, Giovanni Ferrara, Desi P. Fuhr, Michael K. Stickland, Rhea A. Varughese, Eric Y. Wong & Maeve P. Smith	Exertional intolerance and dyspnea with preserved lung function: an emerging long COVID phenotype?	https://doi.org/10.1186/s12931-021-01814-9	Published	06 August 2021	Letter to the Editor	https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-021-01814-9	There is now a growing recognition of the longer-term sequelae of this infection, termed “long COVID”. However, little is known about this condition. Here, we describe a distinct phenotype seen in a subset of patients with long COVID who have reduced exercise tolerance as measured by the 6 min walk test. They are associated with significant exertional dyspnea, reduced health-related quality of life and poor functional status. However, surprisingly, they do not appear to have any major pulmonary function abnormalities or increased burden of neurologic, musculoskeletal or fatigue symptoms.	?
41							From this point on, the survey of studies is no longer as exhaustive as possible. Only those studies which seem to us to bring significant new elements will be listed.
42	L39		Inderjit Singh, MD Phillip Joseph, MD Paul M. Heerdt, MD, PhD Marjorie Cullinan, RT Denyse D. Lutchmansingh, MBBS Mridu Gulati, MD, MPH Jennifer D. Possick, MD David M. Systrom, MD Aaron B. Waxman, MD, PhD	Persistent Exertional Intolerance After COVID-19 Insights From Invasive Cardiopulmonary Exercise Testing	https://doi.org/10.1016/j.chest.2021.08.010	Published	August 10, 2021	Study	https://journal.chestnet.org/article/S0012-3692(21)03635-7/fulltext	This study examined the systemic and pulmonary hemodynamics, ventilation, and gas exchange in 10 patients who recovered from COVID-19 and were without cardiopulmonary disease during invasive cardiopulmonary exercise testing (iCPET) and compared the results with those from 10 age- and sex-matched control participants. These data then were used to define potential reasons for exertional limitation in the cohort of patients who had recovered from COVID-19. Results The patients who had recovered from COVID-19 exhibited markedly reduced peak exercise aerobic capacity (oxygen consumption [VO2]) compared with control participants (70 ± 11% predicted vs 131 ± 45% predicted; P < .0001). This reduction in peak VO2 was associated with impaired systemic oxygen extraction (ie, narrow arterial-mixed venous oxygen content difference to arterial oxygen content ratio) compared with control participants (0.49 ± 0.1 vs 0.78 ± 0.1; P < .0001), despite a preserved peak cardiac index (7.8 ± 3.1 L/min vs 8.4±2.3 L/min; P > .05). Additionally, patients who had recovered from COVID-19 demonstrated greater ventilatory inefficiency (ie, abnormal ventilatory efficiency [VE/VCO2] slope: 35 ± 5 vs 27 ± 5; P = .01) compared with control participants without an increase in dead space ventilation. Interpretation Patients who have recovered from COVID-19 without cardiopulmonary disease demonstrate a marked reduction in peak VO2 from a peripheral rather than a central cardiac limit, along with an exaggerated hyperventilatory response during exercise.
43	L40		Salman Siddiqui Christopher E Brightling	Pathological disease in the lung periphery after acute COVID-19	https://doi.org/10.1016/S2213-2600(21)00378-7	Published	September 07, 2021	COMMENT	https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00378-7/fulltext	First, there is little evidence to show a meaningful persistent impairment in the large or small conducting airways, although longer-term studies that incorporate imaging in a more mixed population, including patients who were ventilated, are required. Second, there might be pulmonary capillary disease alone (particularly given the common vascular effects of COVID-19 infection), in which case DLCO might decrease, consistent with the abnormal DLCO levels that have been identified across several studies. This fall in DLCO might be associated with parenchymal destruction, in which case the total lung capacity, FVC, and residual volume would also decrease. However, without more detailed reporting of the carbon monoxide transfer coefficient and alveolar volume—the two components that define the single-breath carbon monoxide diffusion test—it is difficult to dissect fully the pathological abnormality in the lung periphery in long COVID. An exploratory hyperpolarised 129Xenon MRI study in patients approximately 6 months after acute COVID-19 infection showed striking reductions in the ratio of 129Xe in red blood cells to tissue plasma, despite near-normal CT imaging and preserved lung function.10 These observations further support the notion that damage to the alveolar–capillary interface might be a hallmark of the longer-term pathogenesis of COVID-19 lung disease.
44	L41		Konstantina Kitsou, Anastasia Kotanidou, Dimitrios Paraskevis , Timokratis Karamitros, Aris Katzourakis, Richard Tedder, Tara Hurst, , Spyros Sapounas, Athanassios Kotsinas, Vassilis Gorgoulis , Vana Spoulou, Sotirios Tsiodras, Pagona Lagiou, and Gkikas Magiorkinis	Upregulation of Human Endogenous Retroviruses in Bronchoalveolar Lavage Fluid of COVID-19 Patients	https://doi.org/10.1128/Spectrum.01260-21	Published	06 October 2021	Study	https://journals.asm.org/doi/10.1128/Spectrum.01260-21	Given that human endogenous retroviruses (HERVs) are known to be activated during and participate in inflammatory processes, we examined whether HERV dysregulation signatures are present in COVID-19 patients. By comparing transcriptomes of bronchoalveolar lavage fluid (BALF) of COVID-19 patients and healthy controls, and peripheral blood monocytes (PBMCs) from patients and controls, we have shown that HERVs are intensely dysregulated in BALF of COVID-19 patients compared to those in BALF of healthy control patients but not in PBMCs. In particular, upregulation in the expression of specific HERV families was detected in BALF samples of COVID-19 patients, with HERV-FRD being the most highly upregulated family among the families analyzed. In addition, we compared the expression of HERVs in human bronchial epithelial cells (HBECs) without and after senescence induction in an oncogene-induced senescence model in order to quantitatively measure changes in the expression of HERVs in bronchial cells during the process of cellular senescence. This apparent difference of HERV dysregulation between PBMCs and BALF warrants further studies in the involvement of HERVs in inflammatory pathogenetic mechanisms as well as exploration of HERVs as potential biomarkers for disease progression. Furthermore, the increase in the expression of HERVs in senescent HBECs in comparison to that in noninduced HBECs provides a potential link for increased COVID-19 severity and mortality in aged populations.
45	L42		Felice D’Agnillo†, Kathie-Anne Walters†, Yongli Xiao‡, Zong-Mei Sheng‡, Kelsey Scherler, Jaekeun Park, ,Charles A. BlattiIII Ruoqing Zhu, Lisa Gatzke, Colleen Bushell, Matthew J. Memoli, Steven J. O’Day, Trevan D. Fischer, Terese C. Hammond, Raymond C. Lee, J. Christan Cash, Matthew E. Powers, , Grant E. O’Keefe, Kelly J. Butnor, Amy V. Rapkiewicz, William D. Travis, Scott P. Layne, John C. Kash, Jeffery K. Taubenberger	Lung epithelial and endothelial damage, loss of tissue repair, inhibition of fibrinolysis, and cellular senescence in fatal COVID-19	https://doi.org/10.1126/scitranslmed.abj7790	Published	14 Oct 2021	Study	https://www.science.org/doi/10.1126/scitranslmed.abj7790	Lung autopsy samples from 18 patients with fatal COVID-19, with symptom onset-to-death times ranging from 3 to 47 days, and antemortem plasma samples from 6 of these cases were evaluated using deep sequencing of SARS-CoV-2 RNA, multiplex plasma protein measurements, and pulmonary gene expression and imaging analyses. Prominent histopathological features in this case series included progressive diffuse alveolar damage with excessive thrombosis and late onset pulmonary tissue and vascular remodeling. Acute damage at the alveolar-capillary barrier was characterized by the loss of surfactant protein expression with injury to alveolar epithelial cells, endothelial cells, respiratory epithelial basal cells, and defective tissue repair processes. Other key findings included impaired clot fibrinolysis with increased concentrations of plasma and lung plasminogen activator inhibitor-1 (PAI-1), and modulation of cellular senescence markers, including p21 and sirtuin-1, in both lung epithelial and endothelial cells. Together, these findings further define the molecular pathological features underlying the pulmonary response to SARS-CoV-2 infection and provide important insights into signaling pathways that may be amenable to therapeutic intervention.
46	L43		BenoitBouteleuxaPaulineHenrotbcRachelErnstaLéoGrassiondChantalRaherison-SemjendeFabienBeaufilsbcMaévaZysmanbd1MathieuDelormeaf1	Respiratory rehabilitation for Covid-19 related persistent dyspnoea: A one-year experience	https://doi.org/10.1016/j.rmed.2021.106648	Published	13 October 2021	Study	https://www.sciencedirect.com/science/article/pii/S0954611121003565	Most prevalent symptoms were dyspnoea (n = 35(90%)) and fatigue (n = 30(77%)). Hyperventilation syndrome was highly frequent (n = 12(34%)). 29(74%) patients presented with prolonged functional sequelae, which was associated with younger age (43 ± 14 vs. 50 ± 10yr; p = 0.002), greater prevalence of hyperventilation syndrome (n = 12(41%) vs. 0(0%); p = 0.255) and poorer quality of life (VQ-11; 31 ± 10 vs. 23 ± 9; p = 0.030). Over the course of rehabilitation, exertional dyspnoea, 6-min walking distance, 3-min sit-to-stand test, hyperventilation syndrome prevalence and quality of life significantly improved. Conclusion Hyperventilation is frequent in long Covid and may explain persistent dyspnoea as well as altered quality of life. Our data support screening of hyperventilation syndrome and functional impairment in mild Covid-19 out-patients as both of these components may improve with ambulatory rehabilitation. •COVID-19 out patients without severe initial manifestation may have prolonged sequelae. •Main symptoms in COVID-19 out patients are dyspnoea and fatigue. •Prevalence of hyperventilation syndrome is substantial in Covid-19 out patients. •Respiratory rehabilitation may improve dysfunctional breathing, functional capacities and quality of life.	_
47	L44		Larissa Lipskaia 1 2, Pauline Maisonnasse 3 4, Charles Fouillade 5 6 7, Valentin Sencio 8, Quentin Pascal 4, Jean-Michel Flaman 9, Emmanuelle Born 10 11, Arturo London-Vallejo 5 6 7, Roger Le Grand 3 4, David Bernard 9, François Trottein 12, Serge Adnot 13	Evidence that SARS-CoV-2 Induces Lung-Cell Senescence: Potential Impact on COVID-19 Lung Disease	https://doi.org/10.1165/rcmb.2021-0205le	Published	2021 Oct 14	Study	https://pubmed.ncbi.nlm.nih.gov/34648725/	Cell senescence is usually viewed as a response to chronic stressors that severely impedes healthy aging and promotes age-related noncommunicable diseases (11). Here, BALF cells from patients with severe COVID-19 expressed high levels of senescent-cell markers. This original observation was confirmed in a macaque COVID-19 model: early massive senescent lung-cell accumulation occurred in areas of severe COVID-19-related lung damage. Moreover, senescent cells persisted in the lungs over time, and many of them appeared concomitantly with the development of long-term lung alterations including remodeling of the alveolar septa and pulmonary vessels. Given the deleterious effect of cell senescence on tissue repair and inflammation, these results suggest that senescent-cell accumulation may contribute to the early lung alterations caused by SARS-CoV-2 infection and, potentially, to the post-viral lung pathology seen in a substantial proportion of patients (12). Most ECs in thrombosed vessels were senescent, suggesting a causal relationship between EC senescence and vascular thrombosis. Thus, counteracting the cell-senescence process or eliminating senescent lung cells might lessen lung damage severity. This may be of therapeutic importance since strategies are now proposed to control senescence in various lung diseases, as well as in ARDS due to other causes (13,14). A recent study in mice showed that lung inflammation caused by a mouse -oronavirus was markedly reduced by senolytic treatment, which also decreased mortality in old mice (7). These findings also support senescence as a major mechanism in the pathogenesis of COVID-19 and of other viral infections (15) and suggest that senescent lung-cell persistence after virus clearance may contribute to post-viral lung disease, namely emphysema or fibrosis.
48	L45		Behnam Rabiee,Liesl S. Eibschutz,Shadi Asadollahi,Amit Gupta,Shahram Akhlaghpoor &Ali Gholamrezanezhad	The Role of Imaging Techniques in Understanding and Evaluating the Long-term Pulmonary Effects of COVID-19	https://doi.org/10.1080/17476348.2021.2001330	Published	03 Nov 2021	Review	https://www.tandfonline.com/doi/abs/10.1080/17476348.2021.2001330	Article highlights - Many COVID-19 patients suffer from long-term sequelae months after initial disease recovery. - Imaging plays a pivotal role in the non-invasive assessment of the extent of pulmonary involvement during long-term follow-up. - Although the diagnostic utility is suboptimal due to limited field of view in lungs and operator expertise dependency, the feasibility, affordability, and lack of ionizing radiation associated with lung ultrasonography create a potential niche for this imaging modality in certain patient populations, such as pregnant women and those in low-income countries. - Although useful in initial presentation and readily available, CXR is not optimal for long-term follow-up of COVID-19 due to limited sensitivity in detecting the primary abnormality and evolving changes. - Chest CT can be very useful in long-term follow-up, due to its high contrast and spatial resolution in assessing lung tissue. - Main Chest CT findings include residual ground-glass opacities, scar, and organizing pneumonia, along with fibrotic change as evidenced by interstitial septal thickening and honeycombing. - Abnormal findings have reported on chest CT months after COVID-19 recovery. - While MRI is not utilized routinely for lung imaging, low field MRI not only shows relatively higher signal intensity of the lung parenchyma, but also is comparable to CT regarding image acquisition, and thus may be useful in investigating the long-term pathophysiological findings of COVID-19. - Although not practical for daily clinical practice of medicine (due to radiation burden, costs, and time-consuming imaging protocols), 18F-FDG-PET/CT can also be useful in detection of the extra-pulmonary COVID-19 infection and may be beneficial in long-term follow-up of both pulmonary and systemic sequelae of this disease in certain cases. - V/Q SPECT-CT scans may have great utility in diagnosing small vessel obstruction, identifying parenchymal damage, and monitoring COVID-19 survivors struggling with persistent dyspnea.	_
49	L46		Max J Biondi, Phillip Joseph, Mridu Gulati, Jennifer Possick, Denyse Lutchmansingh, Marjorie Cullinan, Paul M Heerdt, Inderjit Singh	Abstract 6991: Impaired Systemic Oxygen Extraction Relates to Reduced Exercise Capacity in Post-COVID-19 Long Hauler Syndrome		Published	08 November 2021	Case Reports	https://www.ahajournals.org/doi/abs/10.1161/circ.144.suppl_1.6991	Results: All patients had normal biventricular and valvular function on resting echocardiogram, no evident parenchymal lung disease on CT, and normal PFTs. Resting mean pulmonary arterial pressure was ≤20 mmHg for all patients with pulmonary vascular resistance <3 Woods units. At maximum exercise, all patients exhibited normal respiratory, cardiac output (% predicted), and total pulmonary vascular resistance responses, but demonstrated clearly depressed aerobic capacity (peak VO2 <80% predicted). Reduced peak VO2 was associated with impaired systemic O2 extraction as indicated by an arterial-venous O2 content difference (adjusted for hemoglobin) of <80% (Figure 1). Conclusion: This case series provides preliminary evidence that reduced peak aerobic capacity among long haulers is primarily attributable to a peripheral (i.e., impaired systemic O2 extraction), rather than central cardiopulmonary, limitation. These results suggest that systemic microcirculatory dysfunction contributes to exercise limitation.	_
50	L47		Jong Hyuk Lee, Jae-Joon Yim, Jimyung Park	Impaired Diffusion Capacity and Pulmonary Fibrosis after Recovery from COVID-19: A Systematic Review and Meta-Analysis	https://doi.org/10.21203/rs.3.rs-1089533/v1	pre-print	22 Nov, 2021	Systematic Review	https://www.researchsquare.com/article/rs-1089533/v1	Results: Of the 8159 studies identified, 29 met our eligibility criteria. Among these studies, 25 and 20 had data on follow-up pulmonary function testing and chest computed tomography (CT), respectively. Impaired diffusion capacity (<80% of predicted values or lower limit of normal) was the most common pulmonary abnormality (pooled prevalence 34%, 95% CI 27%–41%). When classified according to the severity of index infection, patients with severe COVID-19 were more likely to display impaired diffusion capacity than those with non-severe COVID-19 (pooled odds ratio 2.97, 95% CI 2.10–4.20). On follow-up chest CT, pulmonary fibrosis was found in 26% (95% CI 17%–36%) of the patients. Conclusions: A substantial number of patients recovering from COVID-19 displayed impaired diffusion capacity and pulmonary fibrosis. The severity of index COVID-19 was associated with impaired diffusion capacity, highlighting the importance of respiratory follow-up in patients recovering from severe COVID-19.	_
51	L48		Luigi Angelo Vaira, MD, Giovanni Salzano, MD, Serge Le Bon, MD, Angelantonio Maglio, MD, Marzia Petrocelli, MD, Younes Steffens, MD, Enrica Ligas, MSN, Fabio Maglitto, MD, Jerome R. Lechien, MD, PhD, Sven Saussez, MD, PhD, Alessandro Vatrella, MD, Francesco Antonio Salzano, MD, Paolo Boscolo-Rizzo, MD, Claire Hopkins, FRSC (ORLHNS), DM (Oxon), Giacomo De Riu	Levels of end-tidal carbon dioxide are low despite normal respiratory rate in individuals with Long COVID	https://doi.org/10.1088/1752-7163/ac3c18	Published	22 November 2021	Letter	https://iopscience.iop.org/article/10.1088/1752-7163/ac3c18	In total, 82 patients with Long COVID completed the assessment (Table 1). The most common comorbidities reported were anxiety (n=19, 23%), asthma (n=11, 13%), depression (n=10, 12%) and inflammatory bowel disease (n=7, 9%). Six (7%) patients were hospitalized during acute COVID-19 infection, one (1%) patient had a pulmonary embolism, and three (3%) patients had subsequently developed pulmonary fibrosis. The median and interquartile range (IQR) for ETCO2 were 32 and 8 mmHg respectively (Table 1). The median (IQR) RR was 13 (6) breaths per minute. ETCO2 was below 35mmHg in 61 (74%) patients. The level of ETCO2 and RR were moderately negatively correlated (r=-0.4, p<0.01). In summary, the ETCO2 levels observed were lower than the expected range of 35 to 45 mmHg, despite on average, RR falling within the normal range. It is apparent that hypocapnia is present in the absence of hyperventilation in patients with Long COVID following less severe acute infection, potentially contributing to or as a manifestation of the underlying pathophysiology. The possible causes of hypocapnia in this cohort may include increases in baseline respiration rate compared to pre-COVID-19 infection, disruption of the autonomic nervous system that may also be the cause of many Long COVID symptoms, or organ damage that may not be detectable on routine clinical imaging and assessment.
52	L49		Andrea Vianello logo, Gabriella Guarnieri, Fausto Braccioni, Sara Lococo, Beatrice Molena, Antonella Cecchetto, Chiara Giraudo, Leonardo Bertagna De Marchi, Marco Caminati and Gianenrico Senna	The pathogenesis, epidemiology and biomarkers of susceptibility of pulmonary fibrosis in COVID-19 survivors	https://doi.org/10.1515/cclm-2021-1021	Published	November 16, 2021	Review	https://www.degruyter.com/document/doi/10.1515/cclm-2021-1021/html	Pulmonary fibrosis (PF), a pathological outcome of chronic and acute interstitial lung diseases associated to compromised wound healing, is a key component of the “post-acute COVID-19 syndrome” that may severely complicate patients’ clinical course. Although inconclusive, available data suggest that more than a third of hospitalized COVID-19 patients develop lung fibrotic abnormalities after their discharge from hospital. The pathogenesis of PF in patients recovering from a severe acute case of COVID-19 is complex, and several hypotheses have been formulated to explain its development. An analysis of the data that is presently available suggests that biomarkers of susceptibility could help to identify subjects with increased probability of developing PF and may represent a means to personalize the management of COVID-19’s long-term effects. Our review highlights the importance of both patient-related and disease-related contributing risk factors for PF in COVID-19 survivors and makes it definitely clear the possible use of acute phase and follow-up biomarkers for identifying the patients at greatest risk of developing this disease.
53	L50		Sarah Halawa, Soni S. Pullamsetti, Charles R. M. Bangham, Kurt R. Stenmark, Peter Dorfmüller, Maria G. Frid, Ghazwan Butrous, Nick W. Morrell, Vinicio A. de Jesus Perez, David I. Stuart, Kevin O’Gallagher, Ajay M. Shah, Yasmine Aguib & Magdi H. Yacoub	Potential long-term effects of SARS-CoV-2 infection on the pulmonary vasculature: a global perspective	https://doi.org/10.1038/s41569-021-00640-2	Published	06 December 2021	Review	https://www.nature.com/articles/s41569-021-00640-2	The lungs are the primary target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, with severe hypoxia being the cause of death in the most critical cases. Coronavirus disease 2019 (COVID-19) is extremely heterogeneous in terms of severity, clinical phenotype and, importantly, global distribution. Although the majority of affected patients recover from the acute infection, many continue to suffer from late sequelae affecting various organs, including the lungs. The role of the pulmonary vascular system during the acute and chronic stages of COVID-19 has not been adequately studied. A thorough understanding of the origins and dynamic behaviour of the SARS-CoV-2 virus and the potential causes of heterogeneity in COVID-19 is essential for anticipating and treating the disease, in both the acute and the chronic stages, including the development of chronic pulmonary hypertension. Both COVID-19 and chronic pulmonary hypertension have assumed global dimensions, with potential complex interactions. In this Review, we present an update on the origins and behaviour of the SARS-CoV-2 virus and discuss the potential causes of the heterogeneity of COVID-19. In addition, we summarize the pathobiology of COVID-19, with an emphasis on the role of the pulmonary vasculature, both in the acute stage and in terms of the potential for developing chronic pulmonary hypertension. We hope that the information presented in this Review will help in the development of strategies for the prevention and treatment of the continuing COVID-19 pandemic.
54	L51		Tøri Vigeland Lerum, Niklas Nyboe Maltzahn, Pål Aukrust, Marius Trøseid, Katerina Nezvalova Henriksen, Trine Kåsine, Anne-Ma Dyrhol-Riise, Birgitte Stiksrud, Mette Haugli, Bjørn Blomberg, Bård Reiakvam Kittang, Asgeir Johannessen, Raisa Hannula, Saad Aballi, Anders Benjamin Kildal, Ragnhild Eiken, Tuva Børresdatter Dahl, Fridtjof Lund-Johansen, Fredrik Müller, Jezabel Rivero Rodriguez, Carin Meltzer, Gunnar Einvik, Thor Ueland, Inge Christoffer Olsen, NOR-SOLIDARITY Consortium, Andreas Barratt-Due, Trond Mogens Aaløkken & Ole Henning Skjønsberg	Persistent pulmonary pathology after COVID-19 is associated with high viral load, weak antibody response, and high levels of matrix metalloproteinase-9	https://doi.org/10.1038/s41598-021-02547-x	Published	01 December 2021	Study	https://www.nature.com/articles/s41598-021-02547-x	he association between pulmonary sequelae and markers of disease severity, as well as pro-fibrotic mediators, were studied in 108 patients 3 months after hospital admission for COVID-19. The COPD assessment test (CAT-score), spirometry, diffusion capacity of the lungs (DLCO), and chest-CT were performed at 23 Norwegian hospitals included in the NOR-SOLIDARITY trial, an open-labelled, randomised clinical trial, investigating the efficacy of remdesivir and hydroxychloroquine (HCQ). Thirty-eight percent had a CAT-score ≥ 10. DLCO was below the lower limit of normal in 29.6%. Ground-glass opacities were present in 39.8% on chest-CT, parenchymal bands were found in 41.7%. At admission, low pO2/FiO2 ratio, ICU treatment, high viral load, and low antibody levels, were predictors of a poorer pulmonary outcome after 3 months. High levels of matrix metalloproteinase (MMP)-9 during hospitalisation and at 3 months were associated with persistent CT-findings. Except for a negative effect of remdesivir on CAT-score, we found no effect of remdesivir or HCQ on long-term pulmonary outcomes. Three months after hospital admission for COVID-19, a high prevalence of respiratory symptoms, reduced DLCO, and persistent CT-findings was observed. Low pO2/FiO2 ratio, ICU-admission, high viral load, low antibody levels, and high levels of MMP-9 were associated with a worse pulmonary outcome.
55	L52		Nhu Ngoc Nguyen Van Thuan Hoang Thi Loi Dao Line Meddeb Jean-Christophe Lagier Matthieu Million Didier Raoult Philippe Gautret	Long-term persistence of symptoms of dyspnoea in COVID-19 patients	https://doi.org/10.1016/j.ijid.2021.11.035	Published	November 26, 2021	Short Communication	https://www.ijidonline.com/article/S1201-9712(21)00882-1/fulltext	Highlights •Out of 838 contacted patients, 496 (59.2%) answered the questionnaire. •123/496 (24.8%) patients reported persistent dyspnoea. •Age ≥ 45 years old is associated with persistent dyspnoea.
56	L53		Chiara Colarusso 1,Angelantonio Maglio 2 ,Michela Terlizzi 1,Carolina Vitale 2,Antonio Molino 3,Aldo Pinto 1,Alessandro Vatrella 2 andRosalinda Sorrentino 1,*	Post-COVID-19 Patients Who Develop Lung Fibrotic-like Changes Have Lower Circulating Levels of IFN-β but Higher Levels of IL-1α and TGF-β	https://doi.org/10.3390/biomedicines9121931	Published	17 December 2021	Study	https://www.mdpi.com/2227-9059/9/12/1931/htm	The purpose of this study was to identify blood biomarkers to predict PC patients undergoing pulmonary fibrosis. Patients and Methods: We analyzed blood samples of healthy, anti-SARS-CoV-2 vaccinated (VAX) subjects and PC patients who were stratified according to the severity of the disease and chest computed tomography (CT) scan data. Results: The inflammatory C reactive protein (CRP), complement complex C5b-9, LDH, but not IL-6, were higher in PC patients, independent of the severity of the disease and lung fibrotic areas. Interestingly, PC patients with ground-glass opacities (as revealed by chest CT scan) were characterized by higher plasma levels of IL-1α, CXCL-10, TGF-β, but not of IFN-β, compared to healthy and VAX subjects. In particular, 19 out of 23 (82.6%) severe PC and 8 out of 29 (27.6%) moderate PC patients presented signs of lung fibrosis, associated to lower levels of IFN-β, but higher IL-1α and TGF-β. Conclusions: We found that higher IL-1α and TGF-β and lower plasma levels of IFN-β could predict an increased relative risk (RR = 2.8) of lung fibrosis-like changes in PC patients.
57	L54		Joseph M. Rohr, MD, PhD, Heather Strah, MD, David Berkheim, MD, Aleem Siddique, MBBS, Stanley J. Radio, MD, Benjamin J. Swanson, MD, PhD	Pulmonary Hypertensive Changes Secondary to COVID-19 Pneumonia in a Chronically SARS-CoV-2-Infected Bilateral Lung Explant	https://doi.org/10.1177%2F10668969211064208	Published	December 13, 2021	Case Report	https://journals.sagepub.com/doi/abs/10.1177/10668969211064208	We performed a bilateral lung transplant on a 31-year-old male patient for chronic hypoxic respiratory failure, severe pulmonary hypertension and radiographically identified pulmonary fibrosis five months after an acute COVID-19 infection. The explant demonstrated moderate pulmonary vascular remodeling with intimal thickening and medial hypertrophy throughout, consistent with pulmonary hypertension. The parenchyma demonstrated an organizing lung injury in the proliferative phase, with severe fibrosis, histiocytic proliferation, type II pneumocyte hyperplasia, and alveolar loss consistent with known COVID-19 pneumonia complications. This report highlights a novel histologic finding in severe, chronic COVID-19. Although the findings in acute COVID-19 pneumonia have been well-examined at autopsy, the chronic course of this complex disease is not yet understood. The case presented herein suggests that COVID-induced pulmonary hypertension may become more common as more patients survive severe SARS-CoV-2-related pneumonia.	_
58	L55		panelPaul M.Heerdt1BenShelley2InderjitSingh	Impaired systemic oxygen extraction long after mild COVID-19: potential perioperative implications	https://doi.org/10.1016/j.bja.2021.12.036	Published	27 December 2021	Correspondence	https://www.sciencedirect.com/science/article/abs/pii/S0007091221008564
59	L56	VP	Olivia M. Patania, Shiho Chiba, Peter J. Halfmann, Masato Hatta, Tadashi Maemura, Kristen A. Bernard, Yoshihiro Kawaoka, LaTasha K. Crawford	Pulmonary lesions induced by SARS-CoV-2 infection in domestic cats	https://doi.org/10.1177%2F03009858211066840	Published	December 29, 2021	Study	https://journals.sagepub.com/doi/10.1177/03009858211066840	Our objective was to describe histologic lung lesions and viral loads following experimental SARS-CoV-2 infection in 11 cats. Microscopic evaluation at 3, 6, 10, or 28 days postinoculation (DPI) identified mild to moderate patchy interstitial pneumonia, bronchiolar epithelial damage, and occlusive histiocytic bronchiolitis. Based on immunohistochemistry, alveolar septal thickening was due to CD204-positive macrophages, fewer B and T lymphocytes, type II pneumocytes, and capillary proliferation with a relative dearth of fibrosis. In blood vessel endothelium, there was reactive hypertrophy or vacuolar degeneration and increased MHC II expression at all time points. Unexpectedly, one cat from the 28 DPI group had severe subacute regionally extensive lymphohistiocytic pneumonia with multifocal consolidation, vasculitis, and alveolar fibrin. Reverse transcriptase-quantitative polymerase chain reaction identified SARS-CoV-2 RNA within the lung at 3 and 6 DPI, and viral RNA was below the limit of detection at 10 and 28 DPI, suggesting that pulmonary lesions persist beyond detection of viral RNA. These findings clarify our comparative understanding of disease induced by SARS-CoV-2 and suggest that cats can serve as an informative model to study post-acute pulmonary sequelae.	Les chats infectés par la covid peuvent subir des lésions pulmonaires persistantes, pouvant amener à une détérioration de la fonction pulmonaire, selon une étude dans Veterinary Pathology.
60	L57		Chad S. Clancy, Carl Shaia, Vincent Munster, Emmie de Wit, David Hawman, Atsushi Okumura, Heinz Feldmann, Greg Saturday, Dana Scott	Histologic pulmonary lesions of SARS-CoV-2 in 4 nonhuman primate species: An institutional comparative review	https://doi.org/10.1177%2F03009858211067468	Published	December 29, 2021	Study	https://journals.sagepub.com/doi/full/10.1177/03009858211067468	Nonhuman primate models have previously been shown to be valuable in evaluation of emerging respiratory coronaviruses with pandemic potential (ie, SARS-CoV and Middle East respiratory syndrome coronavirus). In this article, we review the pulmonary histopathologic characteristics and immunohistochemical evaluation of experimental SARS-CoV-2 infection in the rhesus macaque, pigtail macaque, African green monkey, and squirrel monkey. Our results indicate that all evaluated nonhuman primate species developed variably severe histopathologic changes typical of coronavirus respiratory disease characterized by interstitial pneumonia with or without syncytial cell formation, alveolar fibrin, and pulmonary edema that progressed to type II pneumocyte hyperplasia. Lesion distribution was multifocal, frequently subpleural, and often more severe in lower lung lobes. However, squirrel monkeys showed the least severe and least consistent lesions of the evaluated nonhuman primates. Additionally, our results highlight the disparate physical relationship between viral antigen and foci of pulmonary lesions. While classic respiratory coronaviral lesions were observed in the lungs of all nonhuman primates evaluated, none of the primates exhibited severe lesions or evidence of diffuse alveolar damage and therefore are unlikely to represent the severe form of SARS-CoV-2 infection observed in fatal human cases.	Certains primates, notamment le Macaque rhésus, le Grivet d'Éthiopie, le Macaque à queue de cochon, le Singe-écureuil, peuvent, à différents niveaux selon les espèces, souffrir de lésions pulmonaires lorsqu'ils sont infectées au SARS-CoV-2.
61	L58		E.M.Jutant1O.Meyrignac2A.Beurnier3X.Jais1T.Pham4L.Morin5A.Boucly1S.Bulifon1F.Samy6A.Harrois6M.Jevnikar1N.Noël7J.Pichon1A.Roche1A.Seferian1S.Soliman2J.Duranteau6L.Becquemont8X.Monnet4O.Sitbon1M.F.Bellin2M.Humbert1L.Savale1D.Montani1	Symptômes respiratoires et anomalies radiologiques dans le COVID long	https://doi.org/10.1016/j.rmra.2021.11.203	Published	25 December 2021	Study	https://www.sciencedirect.com/science/article/pii/S1877120321008132	Résultats Parmi les 478 patients, 78 (16,3 %) ont signalé une dyspnée et 23 (4,8 %) une toux, apparues depuis la COVID-19. Les patients présentant une dyspnée d’apparition récente étaient significativement plus jeunes (56,1 ± 12,3 versus 61,9 ± 16,6 ans), avaient eu une COVID-19 plus sévère (admission en USI 56,4 % versus 24,5 %) et un antécédent d’embolie pulmonaire pendant la COVID-19 plus fréquente (18,0 % versus 6,8 %) (tous les p ≤ 0,001) que les patients sans nouvelle dyspnée et parmi eux 23 (29,5 %) avaient un score de Nijmegen > 22. Parmi les patients réévalués en HDJ, la prévalence des lésions fibrosantes pulmonaires était de 19,3 %, avec une étendue lésionnelle < 25 % dans 97 % des cas. Les patients présentant des lésions fibrosantes étaient plus âgés (61 ± 11 versus 56 ± 14 ans, p = 0,03), plus fréquemment pris en charge en USI (87,9 versus 47,4 %, p < 0,001) et avaient une capacité pulmonaire totale inférieure (74,1 ± 13,7 versus 84,9 ± 14,8 %, p < 0,001) et une DLCO plus basse (73,3 ± 17,9 versus 89,7 ± 22,8 %, p < 0,001). L’association d’une nouvelle dyspnée, de lésions fibrosantes et d’une DLCO < 70 % était rarement observée (8/478 patients). Conclusion La dyspnée d’apparition récente et les lésions fibrosantes pulmonaire peu étendues sont fréquentes 4 mois après COVID-19 mais l’association d’une dyspnée avec des lésions fibrosantes et des troubles de la diffusion est rarement retrouvée.
62	L59		Bo Xu 1 Fu-qiang Ma 1 Cong He 1 Zi-qi Wu Cun-yu Fan He-rong Mao Ji-xian Zhang Min Yang Zuo-wei Hu	Incidence and affecting factors of pulmonary diffusing capacity impairment with COVID-19 survivors 18 months after discharge in Wuhan, China	https://doi.org/10.1016/j.jinf.2021.12.020	Published	December 25, 2021	Study	https://www.journalofinfection.com/article/S0163-4453(21)00642-3/fulltext	In this study, we discovered the factors affecting COVID-19 patients’ PDCI. The multivariate logistic regression analysis showed that gender, Hb, PLT, MVV and the disease severity levels were correlated with the declined pulmonary diffusing capacity. Furthermore, we found that the incidence of PDCI in female patients was significantly higher than that of males, which are in agreement with the previous studies on COVID-19 patients 1 year after discharge.3,5 In the acute phase, PLT activation and aggregation of COVID-19 patients were increased.6,7 Histopathological assessment on the autopsy of COVID-19 cases revealed presence of PLT-involved inflammatory microvascular thrombosis in the patients’ lungs, kidneys and hearts, confirming that respiratory failure of COVID-19 patients was connected with inflammatory thrombosis.8, 9, 10 Our study also showed that pulmonary diffusing capacity was negatively correlated with PLT, that is, the diffusing capacity would be obviously impaired when PLTs were at the normal high value, and pulmonary diffusing capacity would be greatly improved when PLTs were at the normal low value. Moreover, our findings exhibited that after the correction of hemoglobin that affected pulmonary diffusing capacity, the normal high value of hemoglobin was positively correlated with diffusing capacity of the lungs, which could be probably associated with the enhanced capacity of oxygen-carrying of hemoglobin when increased, and with the improved gas exchange in the lungs. However, FVC and MVV of most COVID-19 survivors with PDCI were normal, which is consistent with other scholars’ findings2. It should be noted that severity of the disease was closely linked to the survivors’ PDCI as shown in Table 2. As a cross-sectional study, limitations of this study still exist, and the baseline data are insufficient about the survivors’ pulmonary functions prior to the onset of COVID-19. In summary, our study revealed that 57.92% of COVID-19 patients had PDCI, which was correlated with gender, PLTs, hemoglobin, MVV and severity of COVID-19. The potential factors affecting pulmonary diffusing capacity of COVID-19 patients and the complicated mechanisms behind remain to be further investigated in the future.
63	L60	CPET	Paul M. Heerdt Ben Shelley Inderjit Singh	Impaired systemic oxygen extraction long after mild COVID-19: potential perioperative implications	https://doi.org/10.1016/j.bja.2021.12.036	Published	December 27, 2021	Correspondence	https://www.bjanaesthesia.org/article/S0007-0912(21)00856-4/fulltext	Singh and colleagues4 performed invasive cardiopulmonary exercise testing (iCPET) on 10 patients (mean age 48 yr, range: 28 to 79 yr, 9/10 female) with persistent exertional limitation 11 (1) months following mild COVID-19. None of the patients had abnormalities evident on chest computed tomographic imaging, pulmonary function testing, or resting echocardiogram, and all had normal haemoglobin levels. Study results were compared to a matched control group of 10 patients with normal exercise capacity and no history of COVID-19. As shown in table 1, relative to control patients at rest, DO2 was the same for post-COVID-19 patients but VO2 and systemic EO2 were modestly reduced. At peak exercise, when functional reserve mechanisms normally increase both DO2 and EO2, the difference in VO2 and EO2 between control and post-COVID-19 patients was more profound. Importantly, this disparity occurred despite a peak exercise response for heart rate and DO2 that was similar for both groups. These results indicate that exercise capacity was primarily limited by impaired systemic EO2 of such severity that what should have been an adequate increase in DO2 was insufficient to allow for an increase in VO2. While patients who are deconditioned can exhibit impaired EO2 with exercise12, preservation of the capacity to increase heart rate and cardiac output adequately at peak exercise in post-COVID-19 patients makes deconditioning a less likely singular explanation for their exercise limitation. In fact, several patients included in the study had already completed supervised exercise rehabilitation programs by the time of their iCPET. The lack of objective evidence for the presence of other factors such as anaemia, impaired cardiac or pulmonary function, or superimposed non-COVID infection suggests a possible microvascular/molecular abnormality. It is worth noting the overlap between the clinical presentations of patients with post-COVID-19 exercise limitation and patients with myalgic encephalitis/chronic fatigue syndrome13. The causal hypothesis of myalgic encephalitis/chronic fatigue syndrome has also been linked to preceding infection including human herpes virus, enterovirus, influenzae, Epstein-Barr virus (EBV), and Borrelia burgdorferi14, 15. Given the broad heterogeneity of symptoms associated with COVID-19, the complexity of accurately measuring EO2, and the fact that a substantial number of people have undoubtedly experienced mild but undiagnosed SARS-CoV-2 infection1, it is difficult (if not impossible) to define the incidence, much less the consequences, of impaired EO2 reserve following mild COVID-19 in the surgical population. Ultimately, we agree with Silvapulle and colleagues2, that at present the best approach to perioperative risk assessment in post-COVID-19 patients is tangible, objective evaluation of multiorgan sequelae. Nonetheless, clinicians should be aware that a deficit may exist that can mimic impaired tissue DO2 despite normal cardiopulmonary function and haemoglobin level, and potentially enhance the adverse consequences of perioperative hypoxaemia, anaemia, or impaired tissue perfusion. We are just beginning to learn of the long-term sequelae of even mild COVID-19, underscoring the need to be vigilant to the potential for a broader perioperative impact of prior SARS-CoV-2 infection.
64	L61	VP	Akmaljon Odilov 1,* ,Alexey Volkov 1,2 ,Adhamjon Abdullaev 3 ,Tatiana Gasanova 4 ,Tatiana Lipina 5 andIgor Babichenko 1	COVID-19: Multiorgan Dissemination of SARS-CoV-2 Is Driven by Pulmonary Factors	https://doi.org/10.3390/v14010039	Published	26 December 2021	Study	https://www.mdpi.com/1999-4915/14/1/39/htm	SARS-CoV-2 VL in the lungs, heart, liver, kidneys, brain, spleen and lymph nodes have been measured by RT qPCR using the following formula: NSARS-CoV−2/NABL1 × 100. Dissemination of SARS-CoV-2 in 30.5% of cases was mono-organ, and in 63.9% of cases, it was multi-organ. The average SARS-CoV-2 VL in the exudative phase of diffuse alveolar damage (DAD) was 60 times higher than in the proliferative phase. The SARS-CoV-2 VL in the lungs ranged from 0 to 250,281 copies. The “pulmonary factors” of SARS-CoV-2 multi-organ dissemination are the high level of SARS-CoV-2 VL (≥4909) and the exudative phase of DAD. The frequency of SARS-CoV-2 dissemination to lymph nodes was 86.9%, heart–56.5%, spleen–52.2%, liver–47.8%, kidney–26%, and brain–13%. We found no link between the SARS-CoV-2 VL level in the liver, kidneys, and heart and the serum level of CPK, LDH, ALP, ALT, AST and Cr of COVID-19 patients. Isolated detection of SARS-CoV-2 RNA in the myocardium of COVID-19 patients who died from heart failure is possible. The pathogenesis of COVID-19-associated multi-organ failure requires further research in a larger cohort of patients.
65	L62		Akmaljon Odilov 1,* ,Alexey Volkov 1,2 ,Adhamjon Abdullaev 3 ,Tatiana Gasanova 4 ,Tatiana Lipina 5 andIgor Babichenko 1	COVID-19: Multiorgan Dissemination of SARS-CoV-2 Is Driven by Pulmonary Factors	https://doi.org/10.3390/v14010039	Published	26 December 2021	Study	https://www.mdpi.com/1999-4915/14/1/39/htm	Multi-organ failure is one of the common causes of fatal outcome in COVID-19 patients. However, the pathogenetic association of the SARS-CoV-2 viral load (VL) level with fatal dysfunctions of the lungs, liver, kidneys, heart, spleen and brain, as well as with the risk of death in COVID-19 patients remains poorly understood. SARS-CoV-2 VL in the lungs, heart, liver, kidneys, brain, spleen and lymph nodes have been measured by RT qPCR using the following formula: NSARS-CoV−2/NABL1 × 100. Dissemination of SARS-CoV-2 in 30.5% of cases was mono-organ, and in 63.9% of cases, it was multi-organ. The average SARS-CoV-2 VL in the exudative phase of diffuse alveolar damage (DAD) was 60 times higher than in the proliferative phase. The SARS-CoV-2 VL in the lungs ranged from 0 to 250,281 copies. The “pulmonary factors” of SARS-CoV-2 multi-organ dissemination are the high level of SARS-CoV-2 VL (≥4909) and the exudative phase of DAD. The frequency of SARS-CoV-2 dissemination to lymph nodes was 86.9%, heart–56.5%, spleen–52.2%, liver–47.8%, kidney–26%, and brain–13%. We found no link between the SARS-CoV-2 VL level in the liver, kidneys, and heart and the serum level of CPK, LDH, ALP, ALT, AST and Cr of COVID-19 patients. Isolated detection of SARS-CoV-2 RNA in the myocardium of COVID-19 patients who died from heart failure is possible. The pathogenesis of COVID-19-associated multi-organ failure requires further research in a larger cohort of patients.
66	L63		James T. Grist, Guilhem J. Collier, Huw Walters, Mitchell Chen, Gabriele Abu Eid, Aviana Laws, Violet Matthews, Kenneth Jacob, Susan Cross, Alexandra Eves, Marianne Durant, Anthony Mcintyre, Roger Thompson, Rolf F. Schulte, Betty Raman, Peter A. Robbins, Jim M. Wild, Emily Fraser, Fergus Gleeson	The Investigation of Pulmonary Abnormalities using Hyperpolarised Xenon Magnetic Resonance Imaging in Patients with Long-COVID	https://doi.org/10.1101/2022.02.01.22269999	pre-print	February 02, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.02.01.22269999v1	Methods Eleven non-hospitalised Long-COVID (NHLC, 4 male), 12 post-hospitalised COVID-19 (PHC, 10 male) patients were recruited from a Post-COVID Assessment clinic, and thirteen healthy controls (6 female) were recruited to undergo Hyperpolarized Xenon Magnetic Resonance Imaging (Hp-XeMRI). NHLC and PHC participants underwent contemporaneous CT, Hp-XeMRI, lung function tests, 1-minute sit-to-stand test and breathlessness questionnaires. Statistical analysis included group and pair-wise comparisons between patients and controls, and correlations between patient clinical and imaging data. Results NHLC and PHC patients were 287 ± 79 [range 190-437] and 149 ± 68 [range 68-269] days from infection, respectively. All NHLC patients had normal CT scans, and the PHC had normal or near normal CT scans (0.3/25 ± 0.6 [range 0-2] and 7/25 ± 5 [range 4-8], respectively). There was a significant difference in TLco (%) between NHLC and PHC patients (76 ± 8 % vs 86 ± 8%, respectively, p = 0.04) but no differences in other measurements of lung function. There were significant differences in RBC:TP mean between volunteers (0.45 ± 0.07, range [0.33-0.55]) and PHC (0.31 ± 0.11, [range 0.16-0.37]) and NHLC (0.35 ± 0.09, [range 0.26-0.58]) patients, but not between NHLC and PHC (p = 0.26). Conclusion There are RBC:TP abnormalities in NHLC and PHC patients, with NHLC patients also demonstrating lower TLco than PHC patients despite their having normal CT scans. These abnormalities are present many months after the initial infection.
67	L64	about L63	NIHR	Lung abnormalities found in long COVID patients with breathlessness		Published	29/01/2022	Article	https://www.nihr.ac.uk/news/lung-abnormalities-found-in-long-covid-patients-with-breathlessness/29798	Researchers have identified abnormalities in the lungs of long COVID patients with breathlessness but whose other tests are normal. The EXPLAIN study is using hyperpolarised xenon MRI scans to investigate possible lung damage in long COVID patients who experience breathlessness and were not hospitalised when they had COVID-19. These early results suggest that COVID-19 may result in persistent impairment in gas transfer and underlying lung abnormalities. However, the extent to which these abnormalities contribute to breathlessness is currently unclear. In the initial results, published on the medRxiv pre-print server, the long COVID patients had abnormal hyperpolarised xenon MRI scans, indicating ‘significantly impaired gas transfer’ from the lungs to the bloodstream. However their CT scans showed normal results. The pilot study involves teams in Oxford, Sheffield, Cardiff and Manchester and is funded by the NIHR. It is one of 19 studies that have received nearly £40 million investment from NIHR to improve understanding of long COVID, from diagnosis and treatment through to rehabilitation and recovery. The research is also supported by the NIHR Oxford Biomedical Research Centre.
68	L65		Erkan Celik ,Christian Nelles,Jonathan Kottlors,Philipp Fervers,Lukas Goertz,Daniel Pinto dos Santos,Tobias Achenbach,David Maintz,Thorsten Persigehl	Quantitative determination of pulmonary emphysema in follow-up LD-CTs of patients with COVID-19 infection	https://doi.org/10.1371/journal.pone.0263261	Published	February 3, 2022	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0263261	Methods Consecutive patients with proven COVID-19 infection and a follow-up CT were retrospectively reviewed. The severity of pulmonary involvement was classified as mild, moderate and severe. Total lung volume, emphysema volume and the ratio of emphysema/-to-lung volume were quantified semi-automatically and compared inter-individually between initial and follow-up CT and to a control group of healthy, age- and sex-matched patients. Lung density was further assessed by drawing circular regions of interest (ROIs) into non-affected regions of the upper lobes. Results A total of 32 individuals (mean age: 64 ± 13 years, 12 females) with at least one follow-up CT (mean: 52 ± 66 days, range: 5–259) were included. In the overall cohort, total lung volume, emphysema volume and the ratio of lung-to-emphysema volume did not differ significantly between the initial and follow-up scans. In the subgroup of COVID-19 patients with > 30 days of follow-up, the emphysema volume was significantly larger as compared to the subgroup with a follow-up < 30 days (p = 0.045). Manually measured single ROIs generally yielded lower attenuation values prior to COVID-19 pneumonia, but the difference was not significant between groups (all p > 0.05). Conclusion COVID-19 patients with a follow-up CT >30 days showed significant emphysematous lung alterations. These findings may help to explain the long-term effect of COVID-19 on pulmonary function and warrant validation by further studies.
69	L66		Fuxiaonan Zhao, Qingwen Ma, Qing Yue, Huaiyong Chen	SARS-CoV-2 Infection and Lung Regeneration	https://doi.org/10.1128/cmr.00188-21	Published	02 February 2022	Review	https://journals.asm.org/doi/full/10.1128/cmr.00188-21	The lung is the primary site of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced immunopathology whereby the virus enters the host cells by binding to angiotensin-converting enzyme 2 (ACE2). Sophisticated regeneration and repair programs exist in the lungs to replenish injured cell populations. However, known resident stem/progenitor cells have been demonstrated to express ACE2, raising a substantial concern regarding the long-term consequences of impaired lung regeneration after SARS-CoV-2 infection. Moreover, clinical treatments may also affect lung repair from antiviral drug candidates to mechanical ventilation. In this review, we highlight how SARS-CoV-2 disrupts a program that governs lung homeostasis. We also summarize the current efforts of targeted therapy and supportive treatments for COVID-19 patients. In addition, we discuss the pros and cons of cell therapy with mesenchymal stem cells or resident lung epithelial stem/progenitor cells in preventing post-acute sequelae of COVID-19. We propose that, in addition to symptomatic treatments being developed and applied in the clinic, targeting lung regeneration is also essential to restore lung homeostasis in COVID-19 patients.
70	L67		Cheng Wang, Haidong Li, Sa Xiao, Zimeng Li, Xiuchao Zhao, Junshuai Xie, Chaohui Ye, Liming Xia, Xin Lou & Xin Zhou	Abnormal dynamic ventilation function of COVID-19 survivors detected by pulmonary free-breathing proton MRI	https://doi.org/10.1007/s00330-022-08605-w	Published	19/02/2022	Study	https://link.springer.com/article/10.1007/s00330-022-08605-w	Objectives To visualize and quantitatively assess regional lung function of survivors of COVID-19 who were hospitalized using pulmonary free-breathing 1H MRI. Methods A total of 12 healthy volunteers and 27 COVID-19 survivors (62.4 ± 8.1 days between infection and image acquisition) were recruited in this prospective study and performed chest 1H MRI acquisitions with free tidal breathing. Then, conventional Fourier decomposition ventilation (FD-V) and global fractional ventilation (FVGlobal) were analyzed. Besides, a modified PREFUL (mPREFUL) method was developed to adapt to COVID-19 survivors and generate dynamic ventilation maps and parameters. All the ventilation maps and parameters were analyzed using Student’s t-test. Pearson’s correlation and a Bland-Altman plot between FVGlobal and mPREFUL were analyzed. Results There was no significant difference between COVID-19 and healthy groups regarding a static FD-V map (0.47 ± 0.12 vs 0.42 ± 0.08; p = .233). However, mPREFUL demonstrated lots of regional high ventilation areas (high ventilation percentage (HVP): 23.7% ± 10.6%) existed in survivors. This regional heterogeneity (i.e., HVP) in survivors was significantly higher than in healthy volunteers (p = .003). The survivors breathed deeper (flow-volume loop: 5375 ± 3978 vs 1688 ± 789; p = .005), and breathed more air in respiratory cycle (total amount: 62.6 ± 19.3 vs 37.3 ± 9.9; p < .001). Besides, mPREFUL showed both good Pearson’s correlation (r = 0.74; p < .001) and Bland-Altman consistency (mean bias = −0.01) with FVGlobal. Conclusions Dynamic ventilation imaging using pulmonary free-breathing 1H MRI found regional abnormity of dynamic ventilation function in COVID-19 survivors.
71	L68		Tomás Franquet, Ana Giménez, Loren Ketai, Sandra Mazzini, Andrea Rial, Virginia Pomar & Pere Domingo	Air trapping in COVID-19 patients following hospital discharge: retrospective evaluation with paired inspiratory/expiratory thin-section CT	https://doi.org/10.1007/s00330-022-08580-2	Published	28 February 2022	Study	https://link.springer.com/article/10.1007/s00330-022-08580-2	The study reports our experience with paired inspiration/expiration thin-section computed tomographic (CT) scans in the follow-up of COVID-19 patients with persistent respiratory symptoms. Results Parenchymal abnormality was found in 50% (24/48) of patients and included air trapping (37/48, 77%), ground-glass opacities (19/48, 40%), reticulation (18/48, 38%), parenchymal bands (15/48, 31%), traction bronchiectasis (9/48, 19%), mosaic attenuation pattern (9/48, 19%), bronchial wall thickening (6/48, 13%), and consolidation (2/48, 4%). The absence of air trapping was observed in 11/48 (23%), mild air trapping in 20/48 (42%), moderate in 13/48 (27%), and severe in 4/48 (8%). Independent predictors of air trapping were, in decreasing order of importance, gender (p = 0.0085), and age (p = 0.0182). Conclusions Our results, in a limited number of patients, suggest that follow-up with paired inspiratory/expiratory CT in long-COVID patients with persistent respiratory symptoms commonly displays air trapping.
72	L69		Asma Mohammadi, Irina Balan, Shikha Yadav, Wanessa F. Matos, Amrin Kharawala, Mrunanjali Gaddam, Noemi Sarabia, Sri Charitha Koneru, Siva K. Suddapalli, Sima Marzban	Post-COVID-19 Pulmonary Fibrosis	https://doi.org/10.7759/cureus.22770	Published	March 02, 2022	Review	https://www.cureus.com/articles/87859-post-covid-19-pulmonary-fibrosis	Despite having a wide range of clinical features, acute respiratory distress syndrome (ARDS) has emerged as the primary cause of mortality in these patients. Risk factors and comorbidities like advanced age with limited lung function, pre-existing diabetes, hypertension, cardiovascular diseases, and obesity have increased the risk for severe COVID-19 infection. Rise in inflammatory markers like transforming growth factor β (TGF-β), interleukin-6 (IL-6), and expression of matrix metalloproteinase 1 and 7 (MMP-1, MMP-7), along with collagen deposition at the site of lung injury, results in extensive lung scarring and fibrosis. Anti-fibrotic drugs, such as Pirfenidone and Nintedanib, have emerged as potential treatment options for post-COVID-19 pulmonary fibrosis. A lung transplant might be the only life-saving treatment. Despite the current advances in the management of COVID-19, there is still a considerable knowledge gap in the management of long-term sequelae in such patients, especially concerning pulmonary fibrosis. Follow up on the current clinical trials and research to test the efficacy of various anti-inflammatory drugs is needed to prevent long-term sequelae early mortality in these patients.
73	L70		I Stewart, J Jacob, PM George, PL Molyneaux, JC Porter, RJ Allen, JK Baillie, SL Barratt, P Beirne, SM Bianchi, JF Blaikley, J Chalmers, RC Chambers, N Chadhuri, C Coleman, G Collier, EK Denneny, A Docherty, O Elneima, RA Evans, L Fabbri, MA Gibbons, FV Gleeson, B Gooptu, NJ Greening, B Guillen Guio, IP Hall, NA Hanley, V Harris, EM Harrison, M Heightman, TE Hillman, A Horsley, L Houchen-Wolloff, I Jarrold, SR Johnson, MG Jones, F Khan, R Lawson, OC Leavy, N Lone, M Marks, H McAuley, P Mehta, E Omer, D Parekh, K Piper Hanley, M Platé, J Pearl, K Poinasamy, JK Quint, B Raman, M Richardson, P Rivera-Ortega, LC Saunders, R Saunders, MG Semple, M Sereno, A Shikotra, AJ Simpson, A Singapuri, DJF Smith, M Spears, LG Spencer, S Stanel, D Thickett, AAR Thompson, M Thorpe, R Thwaites, SLF Walsh, S Walker, ND Weatherley, M Weeks, JM Wild, DG Wootton, CE Brightling, LP Ho, LV Wain, RG Jenkins	Interstitial lung damage following COVID-19 hospitalisation: an interim analysis of the UKILD Post-COVID study	https://doi.org/10.1101/2022.03.10.22272081	pre-print	March 16, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.03.10.22272081v2.full-text	Introduction Shared characteristics between COVID-19 and pulmonary fibrosis, including symptoms, genetic architecture, and circulating biomarkers, suggests interstitial lung disease (ILD) development may be associated with SARS-CoV-2 infection. Methods - The UKILD Post-COVID study planned interim analysis was designed to stratify risk groups and estimate the prevalence of Post-COVID Interstitial Lung Damage (ILDam) using the Post-HOSPitalisation COVID-19 (PHOSP-COVID) Study. Demographics, radiological patterns and missing data were assessed descriptively. Bayes binomial regression was used to estimate the risk ratio of persistent lung damage >10% involvement in linked, clinically indicated CT scans. Indexing thresholds of percent predicted DLco, chest X-ray findings and severity of admission were used to generate risk strata. Number of cases within strata were used to estimate the amount of suspected Post-COVID ILDam. Results - A total 3702 people were included in the UKILD interim cohort, 2406 completed an early follow-up research visit within 240 days of discharge and 1296 had follow-up through routine clinical review. We linked the cohort to 87 clinically indicated CTs with visually scored radiological patterns (median 119 days from discharge; interquartile range 83 to 155, max 240), of which 74 people had ILDam. ILDam was associated with abnormal chest X-ray (RR 1.21 95%CrI 1.05; 1.40), percent predicted DLco<80% (RR 1.25 95%CrI 1.00; 1.56) and severe admission (RR 1.27 95%CrI 1.07; 1.55). A risk index based on these features suggested 6.9% of the interim cohort had moderate to very-high risk of Post-COVID ILDam. Comparable radiological patterns were observed in repeat scans >90 days in a subset of participants. Conclusion - These interim data highlight that ILDam was not uncommon in clinically indicated thoracic CT up to 8 months following SARS-CoV-2 hospitalisation. Whether the ILDam will progress to ILD is currently unknown, however health services should radiologically and physiologically monitor individuals who have Post-COVID ILDam risk factors.
74	L71		C.Bensaid1H.Guerrouj2I.Ghfir2M.Çaoui2N.Ben Rais Aouad2	Les profils scintigraphiques de la perfusion pulmonaire des patients post COVID-19	https://doi.org/10.1016/j.mednuc.2022.01.075	Published	11 March 2022	Study	https://www.sciencedirect.com/science/article/pii/S0928125822000754	L’incidence des complications thromboemboliques dans l’infection COVID-19 est bien connue, même chez les patients recevant une anticoagulation prophylactique. La scintigraphie pulmonaire est un examen fonctionnel permettant d’étudier les processus physiologiques de la perfusion et d’éliminer une embolie. Matériels et méthodes Nous avons analysé rétrospectivement la scintigraphie pulmonaire de perfusion de 60 patients post-COVID-19, cette exploration consiste à l’injection intraveineuse de macro-agrégats d’albumine marqués au technétium (MAA-99mTc). Notre étude porte sur la présence ou non de défects de perfusion évocateurs de processus embolique ainsi que leurs différents aspects au niveau des deux champs pulmonaires. Résultats En plus de l’étude épidémiologique, des signes cliniques et paracliniques, nos résultats scintigraphiques sont exprimés en probabilité (de faible à forte) à défaut de couplage de la scintigraphie perfusion/ventilation et en confrontation avec les images scanographiques. Conclusion La scintigraphie pulmonaire de perfusion reste un examen incontournable dans le diagnostic de l’embolie, surtout si l’angioscanner est négatif. En cette pandémie, elle occupe une place importante dans le suivi post-COVID.
75	L72		Klaus J. Wirth 1,2 andCarmen Scheibenbogen	Dyspnea in Post-COVID Syndrome following Mild Acute COVID-19 Infections: Potential Causes and Consequences for a Therapeutic Approach	https://doi.org/10.3390/medicina58030419	Published	12 March 2022	Review	https://www.mdpi.com/1648-9144/58/3/419/htm	Dyspnea, shortness of breath, and chest pain are frequent symptoms of post-COVID syndrome (PCS). These symptoms are unrelated to organ damage in most patients after mild acute COVID infection. Hyperventilation has been identified as a cause of exercise-induced dyspnea in PCS. Since there is a broad overlap in symptomatology with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), causes for dyspnea and potential consequences can be deduced by a stringent application of assumptions made for ME/CFS in our recent review papers. One of the first stimuli of respiration in exercise is caused by metabolic feedback via skeletal muscle afferents. Hyperventilation in PCS, which occurs early on during exercise, can arise from a combined disturbance of a poor skeletal muscle energetic situation and autonomic dysfunction (overshooting respiratory response), both found in ME/CFS. The exaggerated respiratory response aggravating dyspnea does not only limit the ability to exercise but further impairs the muscular energetic situation: one of the buffering mechanisms to respiratory alkalosis is a proton shift from intracellular to extracellular space via the sodium–proton-exchanger subtype 1 (NHE1), thereby loading cells with sodium. This adds to two other sodium loading mechanisms already operative, namely glycolytic metabolism (intracellular acidosis) and impaired Na+/K+ATPase activity. High intracellular sodium has unfavorable effects on mitochondrial calcium and metabolism via sodium–calcium-exchangers (NCX). Mitochondrial calcium overload by high intracellular sodium reversing the transport mode of NCX to import calcium is a key driver for fatigue and chronification. Prevention of hyperventilation has a therapeutic potential by keeping intracellular sodium below the threshold where calcium overload occurs.
76	L73		P D Mitchell, J Olaniyi, C Buckley, S C Donnelly	Long COVID syndrome and the lung: how long will it last?	https://doi.org/10.1093/qjmed/hcac070	Published	22 March 2022	SHORT COMMENTARY	https://academic.oup.com/qjmed/advance-article-abstract/doi/10.1093/qjmed/hcac070/6551992	The prevalence and duration of the long-term respiratory complications of COVID-19 infection remains to be elucidated. This short commentary reports on recently published studies in patients post-acute COVID-19 infection in terms of symptom prevalence, physiological and radiological sequela and where only symptoms are present despite investigation. Pulmonary function testing, 6-min walk tests, computed tomography chest and more advanced imaging modalities have been incorporated to reveal the underlying pathophysiology that cause such disabling symptoms in patient with post-acute COVID-9 syndrome (PACS). PACS has a serious impact on people’s ability to return to work, affecting the physical, mental, social sphere and with significant healthcare and general economic consequences for them, their families and society.
77	L74		GuillermoCueto-Robledo123ErnestoRoldan-Valadez45Luis-EugenioGraniel-Palafox6MarisolGarcia-Cesar1Maria-BereniceTorres-Rojas1RocioEnriquez-Garcia6Hector-DanielCueto-Romero2NathalyRivera-Sotelo2Angel-AugustoPerez-Calatayud7	Chronic thromboembolic pulmonary hypertension (CTEPH): a review of another sequel of severe post-Covid-19 pneumonia.	https://doi.org/10.1016/j.cpcardiol.2022.101187	Published	25 March 2022	Review	https://www.sciencedirect.com/science/article/pii/S0146280622000846	The spectrum of pulmonary parenchymal and vascular pathologies related to the COVID-19 have emerged. There is evidence of a specific susceptibility related to thrombotic microangiopathy in situ and a complex immune-inflammatory cascade, especially in the pulmonary vascular bed. The potential to lead to transient or self-correcting sequelae of pulmonary vascular injury will only become apparent with longer-term follow-up. In this review, we aimed to present the findings in a group of patients with severe pneumonia due to covid-19 complicated by acute pe documented by chest angiography, who during a follow-up of more than three months with oral anticoagulant met clinical, hemodynamic, and imaging criteria of chronic thromboembolic pulmonary hypertension. We present a brief review of the epidemiology, pathophysiology, clinical findings, comorbidities, treatment, and imaging findings of chronic thromboembolic pulmonary hypertension as a sequel of severe post-covid-19 pneumonia; and compared and discussed these findings with similar reports from the medical literature.
78	L75		Andreia L. Pinto, Ranjit K. Rai, Jonathan C. Brown, Paul Griffin, James R. Edgar, Anand Shah, Aran Singanayagam, Claire Hogg, Wendy S. Barclay, Clare E. Futter & Thomas Burgoyne	ltrastructural insight into SARS-CoV-2 entry and budding in human airway epithelium	https://doi.org/10.1038/s41467-022-29255-y	Published	25 March 2022	Study	https://www.nature.com/articles/s41467-022-29255-y	Ultrastructural studies of SARS-CoV-2 infected cells are crucial to better understand the mechanisms of viral entry and budding within host cells. Here, we examined human airway epithelium infected with three different isolates of SARS-CoV-2 including the B.1.1.7 variant by transmission electron microscopy and tomography. For all isolates, the virus infected ciliated but not goblet epithelial cells. Key SARS-CoV-2 entry molecules, ACE2 and TMPRSS2, were found to be localised to the plasma membrane including microvilli but excluded from cilia. Consistently, extracellular virions were seen associated with microvilli and the apical plasma membrane but rarely with ciliary membranes. Profiles indicative of viral fusion where tomography showed that the viral membrane was continuous with the apical plasma membrane and the nucleocapsids diluted, compared with unfused virus, demonstrate that the plasma membrane is one site of entry where direct fusion releasing the nucleoprotein-encapsidated genome occurs. Intact intracellular virions were found within ciliated cells in compartments with a single membrane bearing S glycoprotein. Tomography showed concentration of nucleocapsids round the periphery of profiles strongly suggestive of viral budding into these compartments and this may explain how virions gain their S glycoprotein containing envelope.
79	L76		Swarnakar, Rajesh1,; Garje, Yogesh2; Markandeywar, Neeraj3; Mehta, Suyog3	Exploring the common pathophysiological links between IPF, SSc-ILD and post-COVID fibrosis	https://doi.org/10.4103/lungindia.lungindia_89_22	Published	Apr 20, 2022	Article	https://journals.lww.com/lungindia/Fulltext/2022/05000/Exploring_the_common_pathophysiological_links.11.aspx	In coronavirus disease 2019 (COVID-19) patients, dysregulated release of matrix metalloproteinases occurs during the inflammatory phase of acute respiratory distress syndrome (ARDS), resulting in epithelial and endothelial injury with excessive fibroproliferation. COVID-19 resembles idiopathic pulmonary fibrosis (IPF) in several aspects. The fibrotic response in IPF is driven primarily by an abnormally activated alveolar epithelial cells (AECs) which release cytokines to activate fibroblasts. Endoplasmic reticulum (ER) stress is postulated to be one of the early triggers in both diseases. Systemic sclerosis (SSc) is a heterogeneous autoimmune rare connective tissue characterised by fibrosis of the skin and internal organs. Interstitial lung disease (ILD) is a common complication and the leading cause of SSc-related death. Several corollaries have been discussed in this paper for new drug development based on the pathogenic events in these three disorders associated with pulmonary fibrosis. A careful consideration of the similarities and differences in the pathogenic events associated with the development of lung fibrosis in post-COVID patients, IPF patients and patients with SSc-ILD may pave the way for precision medicine. Several questions need to be answered through research, which include the potential role of antifibrotics in managing IPF, SSc-ILD and post-COVID fibrosis. Many trials that are underway will ultimately shed light on their potency and place in therapy.
80	L77		Charles N. S. Allen 1ORCID,Maryline Santerre 1ORCID,Sterling P. Arjona 1,Lea J. Ghaleb 1,Muna Herzi 1,Megan D. Llewellyn 1,Natalia Shcherbik 2 andBassel E. Sawaya 1,3,4,5,*ORCID	SARS-CoV-2 Causes Lung Inflammation through Metabolic Reprogramming and RAGE	https://doi.org/10.3390/v14050983	Published	6 May 2022	Study	https://www.mdpi.com/1999-4915/14/5/983/htm	Clinical studies indicate that patients infected with SARS-CoV-2 develop hyperinflammation, which correlates with increased mortality. The SARS-CoV-2/COVID-19-dependent inflammation is thought to occur via increased cytokine production and hyperactivity of RAGE in several cell types, a phenomenon observed for other disorders and diseases. Metabolic reprogramming has been shown to contribute to inflammation and is considered a hallmark of cancer, neurodegenerative diseases, and viral infections. Malfunctioning glycolysis, which normally aims to convert glucose into pyruvate, leads to the accumulation of advanced glycation end products (AGEs). Being aberrantly generated, AGEs then bind to their receptor, RAGE, and activate several pro-inflammatory genes, such as IL-1b and IL-6, thus, increasing hypoxia and inducing senescence. Using the lung epithelial cell (BEAS-2B) line, we demonstrated that SARS-CoV-2 proteins reprogram the cellular metabolism and increase pyruvate kinase muscle isoform 2 (PKM2). This deregulation promotes the accumulation of AGEs and senescence induction. We showed the ability of the PKM2 stabilizer, Tepp-46, to reverse the observed glycolysis changes/alterations and restore this essential metabolic process.
81	L78		Josalyn L. Cho1,, Raul Villacreses1,, Prashant Nagpal2, Junfeng Guo2,3, Alejandro A. Pezzulo1, Andrew L. Thurman1, Nabeel Y. Hamzeh1, Robert J. Blount1, Spyridon Fortis1,4, Eric A. Hoffman1,2,3, Joseph Zabner1, Alejandro P. Comellas1	Quantitative Chest CT Assessment of Small Airways Disease in Post-Acute SARS-CoV-2 Infection	https://doi.org/10.1148/radiol.212170	Published	Mar 15 2022	Study	https://pubs.rsna.org/doi/10.1148/radiol.212170	Background The long-term effects of SARS-CoV-2 infection on pulmonary structure and function remain incompletely characterized. Purpose To test whether SARS-CoV-2 infection leads to small airways disease in patients with persistent symptoms. Materials and Methods In this single center study at a university teaching hospital, adults with confirmed COVID-19 who remained symptomatic >30 days following diagnosis were prospectively enrolled between June and December 2020 and compared to healthy participants (controls) prospectively enrolled between March and August 2018. Participants with post-acute sequelae of COVID-19 (PASC) were classified as ambulatory, hospitalized, or requiring the intensive care unit (ICU) based on the highest level of care received during acute infection. Symptoms, pulmonary function tests, and chest CT images were collected, and quantitative CT analysis was performed using supervised machine-learning to measure regional ground glass opacities (GGO) and inspiratory and expiratory image-matching to measure regional air trapping. Univariable analyses and multivariable linear regression were used to compare groups. Results 100 participants with PASC (median age, 48 years; 66 women) were evaluated and compared with 106 matched healthy controls. Sixty-seven percent (67/100) of the participants with PASC were classified as ambulatory, 17% (17/100) wer e hospitalized and 16% (16/100) required care in the ICU. Among the hospitalized and ICU groups, the mean percent of total lung classified as GGO was 13.2% and 28.7%, respectively, and was higher than in the ambulatory group (3.7%, p<.001 for both comparisons). The mean percentage of total lung affected by air trapping was 25.4%, 34.6%, and 27.3% in the ambulatory, hospitalized, and ICU groups and 7.2% in healthy controls (p<.001). Air trapping correlated with the residual volume to total lung capacity rati o (RV/TLC; r=0.6, p<.001). Conclusions In survivors of COVID-19, small airways disease occurred independently of initial infection severity. The long-term consequences are unknown.
82	L79	about L78	McGraw, Mark	A Connection Between Long COVID & Small Airways Disease	https://doi.org/10.1097/01.COT.0000831992.95100.43	Published	May 20, 2022	Article	https://journals.lww.com/oncology-times/Fulltext/2022/05200/A_Connection_Between_Long_COVID___Small_Airways.18.aspx	The results the study produced are the product of implementing an expiratory CT. “In the absence of this breathing maneuver, we would have missed this finding,” Comellas noted. “At this time, we are unclear if the small airway disease is due to inflammation versus fibrosis of the airway. The former could be reversible, while the latter is not.” A critical message to emerge from the study is that health care providers “should obtain expiratory CTs in patients who are still symptomatic months later, after initial SARS CoV-2 infection. A normal inspiratory CT, normal lung function, or initial severity of illness are not predictive of whether patients could be suffering from small airways diseases manifested as air trapping,” he said. “In addition, this finding can help in deciding some therapies and referral to pulmonary rehabilitation.”
83	L80		James T. Grist1,,2,,3,,4, Guilhem J. Collier5, Huw Walters1, Minsuok Kim6, Mitchell Chen1, Gabriele Abu Eid1, Aviana Laws1, Violet Matthews1, Kenneth Jacob1, Susan Cross1, Alexandra Eves1, Marianne Durant1, Anthony Mcintyre1, Roger Thompson7, Rolf F. Schulte8, Betty Raman3, Peter A. Robbins2, Jim M. Wild5, Emily Fraser9, Fergus Gleeson	Lung Abnormalities Depicted with Hyperpolarized Xenon MRI in Patients with Long COVID	https://doi.org/10.1148/radiol.220069	Published	May 24 2022	Study	https://pubs.rsna.org/doi/10.1148/radiol.220069	Background Post-Covid-19 condition describes symptoms following COVID-19 infection after four weeks. Symptoms are wide-ranging but breathlessness is common. Purpose The purpose of this study was to determine whether the previously described lung abnormalities on Hp-XeMRI in post-hospitalised COVID-19 participants are also present in non-hospitalised participants with Post-Covid-19 condition. Methods In this prospective study, non-hospitalised Post-Covid-19 condition (NHLC) and post-hospitalised COVID-19 (PHC) participants were enrolled from 06/2020 to 08/2021. Participants had chest CT, hyperpolarized pulmonary 129Xenon MRI (Hp-XeMRI), pulmonary function tests, 1-minute sit-to-stand test and breathlessness questionnaires. Control subjects underwent HP-XeMRI only. CT scans were analysed for post COVID interstitial lung disease severity using a previously published scoring system, and Full-scale Airway Network (FAN) modelling. Analysis used group and pair-wise comparisons between participants and controls, and correlations between participant clinical and imaging data. Results A total of 11 NHLC (4:7 Male: Female, 44 ± 11 years, [37-50], (mean ± SD, [95% CI]) and 12 PHC (10:2, Male: Female, 58 ± 10 years, [52-64]) participants were included, with a significant difference in age between groups, p = 0.05. NHLC participants were 287 ± 79, [240-334] and PHC 143 ± 72, [105-190] days from infection, respectively. NHLC and PHC participants had normal or near normal CT scans (0.3/25 ± 0.6, [0-0.63] and 7/25 ± 5, [4-10], respectively). Gas transfer (DLCO (%)) was different between NHLC and PHC participants (76 ± 8%, [73-83] vs 86 ± 8%, [80-91] respectively, p = 0.04) but there was no evidence of other differences in lung function. Red Blood Cell:Tissue Plasma (RBC:TP) mean was different between volunteers vs PHC (0.45 ± 0.07, [0.43-0.47] vs (0.31 ± 0.10, [0.24-0.37], respectively, p = 0.02) and volunteers vs NHLC (0.37 ± 0.10, [0.31-0.44], p = 0.03) participants, but not between NHLC and PHC participants (p = 0.26). FAN results did not correlate with DLCO or Hp- XeMRI. Conclusion NHLC and PHC subjects showed Hp-XeMRI RBC:TP abnormalities, with NHLC participants demonstrating lower DLCO than PHC participants despite having normal CT scans.
84	L81	About L80	Grace Parraga , Alexander M. Matheson	Step on the 129Xe Gas: The MRI Race to Uncover Drivers of Post-COVID-19 Symptoms	https://doi.org/10.1148/radiol.221098	Published	May 24 2022	Editorial	https://pubs.rsna.org/doi/10.1148/radiol.221098	Previous 129Xe MRI studies focused on ever-hospitalized post-COVID-19 participants which limited our understanding of the post-COVID condition to those with the most severe disease. Alarmingly, here Grist and colleagues reported that both PHC and NHLC participants had significantly lower MRI RBC:barrier ratio compared to healthy volunteers. This important finding tells us that even mild disease can result in persistent symptoms and gas-exchange differences. An exact timepoint at which COVID infection may resolved is still a matter of debate, however here data in never-hospitalized participants was acquired at least six months following infection. It is therefore unlikely that these changes were due to residual infection, and more likely they reflect temporally persistent gas-exchange abnormalities that stem from the pulmonary vasculature or alveolar membrane. Taken together, these results emphasize the power and sensitivity of pulmonary functional imaging and the fact that gas-exchange abnormalities that stem either from the alveolar membrane or pulmonary vasculature may be important pathophysiological drivers of symptoms in post-COVID-19 patients. Moreover, Grist and colleagues reported MRI gas-exchange findings that were beyond the sensitivity of pulmonary function tests including DLCO and were not flagged as obvious abnormalities in chest CT images either. The COVID-19 pandemic has provided unprecedented challenges and important opportunities to better understand the natural history of viral lung infection in millions of patients. These hyperpolarized 129Xe MRI findings reveal new valuable clues about lung abnormalities that endure, months post-infection, perhaps putting post-COVID patients back in the driver's seat of their recovery.
85	L82		Abdelfattah Touman, Mohammed Kahyat, Adeeb Bulkhi, Mutaz Khairo, Wael Alyamani, Ahmad M. Aldobyany, Nabil Ghaleb, Hadeel Ashi, Mohammed Alsobaie, Eid Alqurashi	Post COVID-19 Chronic Parenchymal Lung Changes	https://doi.org/10.7759/cureus.25197	Published	May 21, 2022	Study	https://www.cureus.com/articles/97696-post-covid-19-chronic-parenchymal-lung-changes	Introduction: Persistent parenchymal lung changes are an important long-term sequela of COVID-19. There are limited data on this COVID-19 infection sequela characteristics and trajectories. This study aims to evaluate persistent COVID-19-related parenchymal lung changes 10 weeks after acute viral pneumonia and to identify associated risk factors. Methods: This is a retrospective case-control observational study involving 38 COVID-19 confirmed cases using nasopharyngeal swab reverse transcriptase-polymerase chain reaction (RT-PCR) at King Abdullah Medical City (KAMC) Hospital, Makkah. Patients were recruited from the post-COVID-19 interstitial lung disease (ILD) clinic. Referral to this clinic was based on the pulmonology consultant’s assessment of hospitalized patients suspected of developing COVID-19-related ILD changes during hospitalization. Results: Thirty-eight patients with parenchymal lung changes were evaluated at the ILD clinic. Nineteen patients who had persistent parenchymal changes 10 weeks after the acute illness (group 1) were compared with 19 control patients who had accelerated clinical and/or radiological improvement (group 2). Group 1 was found to have the more severe clinical and radiological disease, with a higher peak value of inflammatory biomarkers. Two risk factors were identified, neutrophil-lymphocyte ratio (NLR) > 3.13 at admission increases the odds ratio (OR) of chronic parenchymal changes by 6.42 and 5.92 in the univariate and multivariate analyses, respectively. Invasive mechanical ventilation had a more profound effect with ORs of 13.09 and 44.5 in the univariate and multivariate analyses, respectively. Conclusion: Herein, we found that only receiving invasive mechanical ventilation and having NLR >3.13 at admission were strong risk factors for persistent parenchymal lung changes. Neither the clinical severity of the acute illness nor the radiological one is found to predict this outcome. None of the medications received during the acute illness were found to alter the risk for this post-COVID-19 infection sequelae.
86	L83		Johannes Kersten, Alexander Wolf, Luis Hoyo, Elina Hüll, Marijana Tadic, Stefanie Andreß, Sascha d’Almeida, Dominik Scharnbeck, Eva Roder, Petra Beschoner, Wolfgang Rottbauer & Dominik Buckert	Symptom burden correlates to impairment of diffusion capacity and exercise intolerance in long COVID patients	https://doi.org/10.1038/s41598-022-12839-5	Published	25 May 2022	Study	https://www.nature.com/articles/s41598-022-12839-5	After acute infection with the SARS-CoV-2 virus, a considerable number of patients remains symptomatic with pathological changes in various organ systems. This study aimed to relate the physical and mental burden of symptoms of long COVID patients to the findings of a somatic evaluation. In patients with persistent long COVID symptoms three months after acute infection we assessed physical and mental health status using the SF-36 questionnaire. The cohort was dichotomised by the results (upper two quartiles vs. lower to quartiles) and compared with regard to transthoracic echocardiography, body plethysmography (including diffusion capacity), capillary blood gas analysis and 6-min walk test (6-MWT). From February 22 to September 13, 2021, 463 patients were prospectively examined, of which 367 completed the SF-36 questionnaire. A positive correlation between initial disease severity (need for hospitalization, intensive care medicine) and resulting symptom burden at follow-up could be demonstrated. Patients with impaired subjective physical and mental status were significantly more likely to be women. There was a significant correlation between symptom severity and reduced exercise tolerance in the 6-MWT (495.6 ± 83.7 m vs 549.7 ± 71.6 m, p < 0.001) and diffusion capacity for carbon monoxide (85.6 ± 14.3% of target vs 94.5 ± 14.4, p < 0.001). In long COVID patients, initial disease severity is correlated with symptom burden after at least 3 months of follow-up. Highly symptomatic long COVID patients show impaired diffusion capacity and 6-MWT despite average or mildly affected mechanical lung parameters. It must be further differentiated whether this corresponds to a transient functional impairment or whether it is a matter of defined organ damage.
87	L84		Valentina Ruggiero 1,2,Rita P. Aquino 1,Pasquale Del Gaudio 1ORCID,Pietro Campiglia 1ORCID andPaola Russo 1,*ORCID	Post-COVID Syndrome: The Research Progress in the Treatment of Pulmonary sequelae after COVID-19 Infection	https://doi.org/10.3390/pharmaceutics14061135	Published	26 May 2022	Review	https://www.mdpi.com/1999-4923/14/6/1135/htm	Post-COVID syndrome or long COVID is defined as the persistence of symptoms after confirmed SARS-CoV-2 infection, the pathogen responsible for coronavirus disease. The content herein presented reviews the reported long-term consequences and aftereffects of COVID-19 infection and the potential strategies to adopt for their management. Recent studies have shown that severe forms of COVID-19 can progress into acute respiratory distress syndrome (ARDS), a predisposing factor of pulmonary fibrosis that can irreversibly compromise respiratory function. Considering that the most serious complications are observed in the airways, the inhalation delivery of drugs directly to the lungs should be preferred, since it allows to lower the dose and systemic side effects. Although further studies are needed to optimize these techniques, recent studies have also shown the importance of in vitro models to recreate the SARS-CoV-2 infection and study its sequelae. The information reported suggests the necessity to develop new inhalation therapies in order to improve the quality of life of patients who suffer from this condition.
88	L85		Katherine M. Littlefield,Renée O. Watson,Jennifer M. Schneider,Charles P. Neff,Eiko Yamada,Min Zhang,Thomas B. Campbell,Michael T. Falta,Sarah E. Jolley,Andrew P. Fontenot,Brent E. Palmer	SARS-CoV-2-specific T cells associate with inflammation and reduced lung function in pulmonary post-acute sequalae of SARS-CoV-2	https://doi.org/10.1371/journal.ppat.1010359	Published	May 26, 2022	Study	https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1010359	As of January 2022, at least 60 million individuals are estimated to develop post-acute sequelae of SARS-CoV-2 (PASC) after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While elevated levels of SARS-CoV-2-specific T cells have been observed in non-specific PASC, little is known about their impact on pulmonary function which is compromised in the majority of these individuals. This study compares frequencies of SARS-CoV-2-specific T cells and inflammatory markers with lung function in participants with pulmonary PASC and resolved COVID-19 (RC). Compared to RC, participants with respiratory PASC had between 6- and 105-fold higher frequencies of IFN-γ- and TNF-α-producing SARS-CoV-2-specific CD4+ and CD8+ T cells in peripheral blood, and elevated levels of plasma CRP and IL-6. Importantly, in PASC participants the frequency of TNF-α-producing SARS-CoV-2-specific CD4+ and CD8+ T cells, which exhibited the highest levels of Ki67 indicating they were activity dividing, correlated positively with plasma IL-6 and negatively with measures of lung function, including forced expiratory volume in one second (FEV1), while increased frequencies of IFN-γ-producing SARS-CoV-2-specific T cells associated with prolonged dyspnea. Statistical analyses stratified by age, number of comorbidities and hospitalization status demonstrated that none of these factors affect differences in the frequency of SARS-CoV-2 T cells and plasma IL-6 levels measured between PASC and RC cohorts. Taken together, these findings demonstrate elevated frequencies of SARS-CoV-2-specific T cells in individuals with pulmonary PASC are associated with increased systemic inflammation and decreased lung function, suggesting that SARS-CoV-2-specific T cells contribute to lingering pulmonary symptoms. These findings also provide mechanistic insight on the pathophysiology of PASC that can inform development of potential treatments to reduce symptom burden.
89	L86		AlessiaVerduri1JonathanHewitt2BenCarter3RobertoTonelli4EnricoClini1BiancaBeghè1	Prevalence of asthma and COPD in a cohort of patients at the follow up after COVID-19 pneumonia	https://doi.org/10.1016/j.pulmoe.2022.05.005	Published	10 June 2022	Study	https://www.sciencedirect.com/science/article/pii/S2531043722001271	According to the study purpose, we were able to show interesting findings. First, data collection helped quantify the proportion of patients with diagnosis of asthma and COPD in a large cohort of people at the follow up after COVID-19 pneumonia. The prevalence of asthmatic patients is in line with that observed in the general population in Italy,10 but it seems larger than previously reported data in a large cohort of COVID-19 patients.11,12 On the other hand, COPD patients in our study cohort are less prevalent than in the general population, 13 which may support a different epidemiology within COVID-19 patients.3 Notwithstanding, the follow-up service provided a new diagnosis of chronic respiratory disease, particularly COPD. This provided patients with an opportunity for an appropriate disease identification and care plan. Second, a clinically meaningful post-COVID mMRC dyspnea score observed in 41.5% of the COPD patients, who were in mild GOLD grade of severity, confirms the findings of Huang et al in a large population of patients discharged in Wuhan and assessed six months later.14 This emphasises that older age is not the only responsible factor for long-term residual dyspnea in COPD survivors. Third, the reduction in DLCO (mean 73.6% pred with <80%pred in 57.3% of cases) as a marker of residual lung damage following interstitial pneumonia was similar to that observed in unselected patients treated with respiratory support therapies (HFNC, NIV, intubation),14, 15, 16 even though more frequent in COPD (75.6%) than in patients with asthma in our cohort. Finally, the great proportion of people with asthma and obesity (43.9%), confirmed that this comorbidity makes asthma difficult to treat17 and may also impact negatively on the patient's perception of good health in individuals recovering from COVID-19. Considering major limitations (i.e. the single-center analysis and the lack of pre-to-post comparison of pulmonary function test in patients with existing diagnosis of asthma and COPD), the study results are informative. Indeed, the patients with asthma and COPD is a representative real-word disease-group, and the follow up assessment can be useful for unknown diagnoses of chronic respiratory disease. Therefore, the findings highlight the importance of a tight respiratory follow-up assessment in individuals recovering from COVID-19 pneumonia who should be investigated for long-term symptoms including dyspnea, especially those underdiagnosed for having asthma or COPD.
90	L87		Marco Chilosi 1,Claudio Doglioni 2ORCID,Claudia Ravaglia 3,*,Guido Martignoni 1,4,Gian Luca Salvagno 5,6,Giovanni Pizzolo 7,Vincenzo Bronte 8 andVenerino Poletti 3,9	Unbalanced IDO1/IDO2 Endothelial Expression and Skewed Keynurenine Pathway in the Pathogenesis of COVID-19 and Post-COVID-19 Pneumonia	https://doi.org/10.3390/biomedicines10061332	Published	6 June 2022	Review	https://www.mdpi.com/2227-9059/10/6/1332/htm	Despite intense investigation, the pathogenesis of COVID-19 and the newly defined long COVID-19 syndrome are not fully understood. Increasing evidence has been provided of metabolic alterations characterizing this group of disorders, with particular relevance of an activated tryptophan/kynurenine pathway as described in this review. Recent histological studies have documented that, in COVID-19 patients, indoleamine 2,3-dioxygenase (IDO) enzymes are differentially expressed in the pulmonary blood vessels, i.e., IDO1 prevails in early/mild pneumonia and in lung tissues from patients suffering from long COVID-19, whereas IDO2 is predominant in severe/fatal cases. We hypothesize that IDO1 is necessary for a correct control of the vascular tone of pulmonary vessels, and its deficiency in COVID-19 might be related to the syndrome’s evolution toward vascular dysfunction. The complexity of this scenario is discussed in light of possible therapeutic manipulations of the tryptophan/kynurenine pathway in COVID-19 and post-acute COVID-19 syndromes. The complex involvement of the TKP activation in the diverse presentations of COVID-19 and PACS poses relevant issues when the possible manipulation of this pathway is considered as a therapeutic option [117]. The complex roles (protective versus harmful) of endothelial TKP activation in different physiological systems and tissues need to be carefully considered in therapeutic planning in different clinical contexts. In COVID-19, the TKP activation may be considered harmful in increasing the systemic concentration of kynurenines and toxic Trp-metabolites, potentially interfering with immune and neurological functions, as previously described. Nevertheless, the endothelial IDO1 expression likely exerts significant protection against vascular dysfunction in the lung, and under this context the inhibition of IDO1 does not appear to be safe, which means that alternative interventions are needed to correct metabolic abnormalities. The correct balance of Trp-metabolites is relevant for maintaining healthful functions, and specific approaches should be selected for treating different COVID-19 clinical presentations. This can be particularly true in PACS, where mild “supportive” therapeutic interventions may ameliorate symptoms and shorten the disease course. Trp supplementation, either dietary or non-nutritional, has been experimentally investigated and proposed to ameliorate neurological disturbances and social behavior in humans by increasing 5-HT production, but its clinical effect is still controversial and prone to genetic variations [257,258,259,260,261,262,263,264,265]. In addition, potential side effects of excessive Trp intake should be evaluated in different clinical settings [266]. Deranged activation of the TKP is common in COVID-19, and Trp supplementation may potentially increase the systemic concentration of harmful Trp metabolites [267]. Melatonin supplementation. Divergence from the serotonin pathway of Trp metabolism induces a defective production of melatonin in COVID-19 patients, and this decrease has prognostic significance [268]. This deficiency may be either indirectly related to the over-activation of the TKP (eventually leading to lower available 5-HT), to the well-documented anti-oxidant and anti-inflammatory roles of melatonin, or both [134,269,270,271,272]. A possible role in protecting pulmonary endothelial cells can be also hypothesized, as observed in pre-eclampsia [273]. Several authors have proposed melatonin as a useful therapeutic tool in contrasting neurological complications and super-infections for both COVID-19 and PACS patients [274,275,276,277,278], and a significant vantage in mortality and recovery rate has been observed in severe cases [279,280,281]. Validation of the therapeutic role of melatonin and its metabolites in COVID-19 and PACS is needed, and clinical trials and the use of reliable animal models are warranted [282,283,284,285,286,287]. IDO inhibitors. The relevant pathogenic and prognostic roles of the different Trp-metabolites in COVID-19 suggest the possible use of specific inhibitors to modulate the enzymes that regulate the TKP [117,288,289]. IDOs and TDO are involved in tumor immunosurveillance and the potential use of inhibitors of these enzymes to restore antitumor immunity is a matter of intense clinical investigation [96,290,291]. Different specific inhibitors are in fact available, and clinical trials are ongoing on a variety of human neoplastic and non-neoplastic diseases [292,293,294,295]. If the pathogenic shift from early/mild to severe COVID-19 pneumonias is in part determined by the modulation of IDO1 and IDO2 expression in the pulmonary microenvironment as here hypothesized, the availability and selective use of specific IDO1 or IDO2 inhibitors might be crucial. A range of selective and potent TDO, IDO1, and IDO2 inhibitors are currently under investigation in cancer research and information from this field may be translationally utilized for new personalized therapies for patients suffering from COVID-19 and PACS [52,86,296,297,298,299]. The inhibition of AHR is feasible, and this approach might be safer in severe cases [300].
91	L88		Mickael Rejaudry Lacavalerie, Sandrine Pierre-Francois, Moustapha Agossou, Jocelyn Inamo, André Cabie, José Luis Barnay & Rémi Neviere	Obese patients with long COVID-19 display abnormal hyperventilatory response and impaired gas exchange at peak exercise	https://doi.org/10.2217/fca-2022-0017	Published	6 Jun 2022	Study	https://www.futuremedicine.com/doi/full/10.2217/fca-2022-0017	Aim: To analyze the impact of obesity on cardiopulmonary response to exercise in people with chronic post-coronavirus disease 2019 (COVID-19) syndrome. Patients & methods: Consecutive subjects with chronic post-COVID syndrome 6 months after nonsevere acute infection were included. All patients received a complete clinical evaluation, lung function tests and cardiopulmonary exercise testing. A total of 51 consecutive patients diagnosed with chronic post-COVID-19 were enrolled in this study. Results: More than half of patients with chronic post-COVID-19 had a significant alteration in aerobic exercise capacity (VO2peak) 6 months after hospital discharge. Obese long-COVID-19 patients also displayed a marked reduction of oxygen pulse (O2pulse). Conclusion: Obese patients were more prone to have pathological pulmonary limitation and pulmonary gas exchange impairment to exercise compared with nonobese COVID-19 patients.
92	L89		Maria T. Tsakok1,,+ , Robert A. Watson1,2,3,, Shyamal J. Saujani1, Mark Kong1, Cheng Xie1, Heiko Peschl1, Louise Wing1, Fiona K. MacLeod1, Brian Shine1, Nick P. Talbot1,5, Rachel E. Benamore1, David W. Eyre1,4,**, Fergus Gleeson1	Chest CT and Hospital Outcomes in Patients with Omicron Compared with Delta Variant SARS-CoV-2 Infection	https://doi.org/10.1148/radiol.220533	Published	Jun 21 2022	Study	https://pubs.rsna.org/doi/full/10.1148/radiol.220533	Background The SARS-Cov-2 Omicron variant demonstrates rapid spread but with reduced disease severity. Studies evaluating the lung imaging findings of Omicron infection versus non-Omicron variants remain lacking. Purpose To compare Omicron and Delta variants of SARS-CoV-2 by their chest CT radiological pattern, biochemical parameters, clinical severity and hospital outcomes after adjusting for vaccination status. Materials and Methods Retrospective study of hospitalized adult patients rt-PCR positive for SARS-CoV-2 with CT pulmonary angiography performed within 7 days of admission between December 1, 2021 and January 14, 2022. Blinded radiological analysis with multiple readers including RSNA CT classification, chest CT severity score (CT-SS, range 0 least severe to 25 most severe) and CT imaging features including bronchial wall thickening. Results 106 patients (Delta n=66, Omicron n=40) were evaluated (mean age, 58 years ± 18, 58 men). In the Omicron group, 37% (15/40) of CT pulmonary angiograms were categorized as normal compared with 15% (10/66) in the Delta group (p=.016). Using a generalized linear model to control for confounding variables, including vaccination status, Omicron variant infection was associated with a CT-SS that was lower by 7.2 points compared to infection with Delta variant (β=-7.2, 95%CI: -9.9, -4.5; p <.001). Bronchial wall thickening was more common with Omicron than with the Delta variant (odds ratio [OR] 2.4, 95%CI: 1.01, 5.92, p=.04). Vaccination with a booster shot was associated with a protective effect on chest infection compared with the unvaccinated (CT-SS median 5 (IQR 0-11), CT-SS median 11 (IQR 7.5-14), respectively; p = .03). The Delta variant was associated with a higher odds ratio of severe disease (OR 4.6, 95%CI: 1.2, 26, p=.01) and critical care admission (OR 7.0, 95%CI: 1.5, 66, p=.004) than the Omicron variant. Conclusion The SARS-COV-2 Omicron variant was associated with fewer and less severe changes on chest CT compared with the Delta variant. Patients with Omicron had greater frequency of bronchial wall thickening but lower clinical severity and improved hospital outcomes than those with Delta. Summary SARS-CoV-2 Omicron variant chest infections are radiologically and clinically less severe than Delta variant infections and are associated with improved hospital outcomes. Key Results ■ In 106 hospitalized adult patients with Omicron (n=40) and Delta variants (n=66) of SARSCoV-2, patients with Omicron had lower median chest CT severity scores (CT-SS) (median, 3.5) compared with Delta (median, 11.8) (p<.001). ■ Patients who had received a vaccine booster dose had lower median CT-SS (median, 5) than the unvaccinated patients (median, 11) (p=.03). ■ Bronchial wall thickening was more common with Omicron than Delta SARS-CoV-2 (odds ratio [OR] 2.4, p=.04).
93	L90		Aurelien Justet, Amy Y. Zhao & Naftali Kaminski	From COVID to fibrosis: lessons from single-cell analyses of the human lung	https://doi.org/10.1186/s40246-022-00393-0	Published	13 June 2022	Review	https://humgenomics.biomedcentral.com/articles/10.1186/s40246-022-00393-0	The increased resolution of single-cell RNA-sequencing technologies has led to major breakthroughs and improved our understanding of the normal and pathologic conditions of multiple tissues and organs. In the study of parenchymal lung disease, single-cell RNA-sequencing has better delineated known cell populations and identified novel cells and changes in cellular phenotypes and gene expression patterns associated with disease. In this review, we aim to highlight the advances and insights that have been made possible by applying these technologies to two seemingly very different lung diseases: fibrotic interstitial lung diseases, a group of relentlessly progressive lung diseases leading to pulmonary fibrosis, and COVID-19 pneumonia, an acute viral disease with life-threatening complications, including pulmonary fibrosis. We discuss changes in cell populations and gene expression, highlighting potential common features, such as alveolar cell epithelial injury and aberrant repair and monocyte-derived macrophage populations, as well as relevance and implications to mechanisms of disease and future directions.
94	L91		Thomas Sonnweber 1,ORCID,Philipp Grubwieser 1ORCID,Sabina Sahanic 1,Anna Katharina Böhm 1,Alex Pizzini 1,Anna Luger 2ORCID,Christoph Schwabl 2ORCID,Sabine Koppelstätter 1,Katharina Kurz 1,Bernhard Puchner 1,Barbara Sperner-Unterweger 3ORCID,Katharina Hüfner 3ORCID,Ewald Wöll 4,Manfred Nairz 1,Gerlig Widmann 2,Ivan Tancevski 1,Judith Löffler-Ragg 1 andGünter Weiss 1,5,ORCID	The Impact of Iron Dyshomeostasis and Anaemia on Long-Term Pulmonary Recovery and Persisting Symptom Burden after COVID-19: A Prospective Observational Cohort Study	https://doi.org/10.3390/metabo12060546	Published	14 June 2022	Study	https://www.mdpi.com/2218-1989/12/6/546/htm	Coronavirus disease 2019 (COVID-19) is frequently associated with iron dyshomeostasis. The latter is related to acute disease severity and COVID-19 convalescence. We herein describe iron dyshomeostasis at COVID-19 follow-up and its association with long-term pulmonary and symptomatic recovery. The prospective, multicentre, observational cohort study “Development of Interstitial Lung Disease (ILD) in Patients With Severe SARS-CoV-2 Infection (CovILD)” encompasses serial extensive clinical, laboratory, functional and imaging evaluations at 60, 100, 180 and 360 days after COVID-19 onset. We included 108 individuals with mild-to-critical acute COVID-19, whereas 75% presented with severe acute disease. At 60 days post-COVID-19 follow-up, hyperferritinaemia (35% of patients), iron deficiency (24% of the cohort) and anaemia (9% of the patients) were frequently found. Anaemia of inflammation (AI) was the predominant feature at early post-acute follow-up, whereas the anaemia phenotype shifted towards iron deficiency anaemia (IDA) and combinations of IDA and AI until the 360 days follow-up. The prevalence of anaemia significantly decreased over time, but iron dyshomeostasis remained a frequent finding throughout the study. Neither iron dyshomeostasis nor anaemia were related to persisting structural lung impairment, but both were associated with impaired stress resilience at long-term COVID-19 follow-up. To conclude, iron dyshomeostasis and anaemia are frequent findings after COVID-19 and may contribute to its long-term symptomatic outcome.
95	L92		Chiara Gattoni,Emanuele Conti,Andrea Casolo,Stefano Nuccio,Carmine Baglieri,Carlo Capelli,Michele Girardi	COVID-19 disease in professional football players: symptoms and impact on pulmonary function and metabolic power during matches	https://doi.org/10.14814/phy2.15337	Published	14 June 2022	Study	https://physoc.onlinelibrary.wiley.com/doi/10.14814/phy2.15337	This study aimed at: (1) Reporting COVID-19 symptoms and duration in professional football players; (2) comparing players’ pulmonary function before and after COVID-19; (3) comparing players’ metabolic power (Pmet) before and after COVID-19. Thirteen male players (Age: 23.9 ± 4.0 years, V̇O2peak: 49.7 ± 4.0 mL/kg/min) underwent a medical screening and performed a running incremental step test and a spirometry test after COVID-19. Spirometric data were compared with the ones collected at the beginning of the same season. Players’ mean Pmet of the 10 matches played before COVID-19 was compared with mean Pmet of the 10 matches played after COVID-19. Players completed a questionnaire on COVID-19 symptoms and duration 6 months following the disease. COVID-19 positivity lasted on average 15 ± 5 days. “General fatigue” and “muscle fatigue” symptoms were reported by all players during COVID-19 and persisted for 77% (general fatigue) and 54% (muscle fatigue) of the players for 37 ± 28 and 38 ± 29 days after the disease, respectively. No significant changes in spirometric measurements were found after COVID-19, even though some impairments at the individual level were observed. Conversely, a linear mixed-effects model analysis showed a significant reduction of Pmet (−4.1 ± 3.5%) following COVID-19 (t = −2.686, p < 0.05). “General fatigue” and “muscle fatigue” symptoms may persist for several weeks following COVID-19 in professional football players and should be considered for a safer return to sport. Players’ capacity to compete at high intensities might be compromised after COVID-19.
96	L93		Mary M. Salvatore Kathleen M. Capaccione Anjali Saqi Jonathan B. Overdevest Rebecca Patrizio David A. Gudis	Characteristic patterns of SARS-CoV-2 on chest CT suggests a hematologic pathway for viral entry into the lung	https://doi.org/10.1016/j.clinimag.2022.06.011	Published	June 25, 2022	Editorial	https://www.clinicalimaging.org/article/S0899-7071(22)00167-X/fulltext	Highlights •Imaging supports that the pulmonary capillaries may be important for transmission of the virus and/or inflammatory mediators to the lung epithelium. •SARS-CoV-2 is about 0.1 microns, however, respiratory droplets are generally 5 microns. The nose would be highly effective at retaining respiratory droplets containing the virus. •spread of virus from endothelium to epithelium explains the vulnerability of those with endothelial instability to worse outcomes and supports stabilizing the vascular endothelium. Abstract Many SARS-CoV-2 studies have supported the theory that the Type II alveolar epithelial cells (AEC-2) are the primary portal of entry of the virus into the lung following its brief nasal occupation. However, the theory of inhalational transmission of the virus from the ciliated and goblet nasal cells to the lung parenchyma is not supported by the imaging findings on chest computerized tomography (CT), leading the authors to consider an alternative pathway from the nose to the lung parenchyma that could explain the peripheral, basilar predominant pattern of early disease. Imaging supports that the pulmonary capillaries may be an important vehicle for transmission of the virus and/or associated inflammatory mediators to the lung epithelium.
97	L94		Harkiran K Kooner1,2, Marrissa J McIntosh1,2, Alexander M Matheson1,2, Carmen Venegas3,4, Nisarg Radadia4, Terence Ho3,4, Ehsan Ahmed Haider5, Norman B Konyer6, Giles E Santyr7,8, Mitchell S Albert9,10, http://orcid.org/0000-0002-0920-2528Alexei Ouriadov11, Mohamed Abdelrazek12, Miranda Kirby13, Inderdeep Dhaliwal14, http://orcid.org/0000-0003-1560-7967J Michael Nicholson14, Parameswaran Nair3,4, Sarah Svenningsen3,4 and http://orcid.org/0000-0002-5619-4145Grace Parraga	129Xe MRI ventilation defects in ever-hospitalised and never-hospitalised people with post-acute COVID-19 syndrome	http://dx.doi.org/10.1136/bmjresp-2022-001235	Published	May 18, 2022	Study	https://bmjopenrespres.bmj.com/content/9/1/e001235	Background Patients often report persistent symptoms beyond the acute infectious phase of COVID-19. Hyperpolarised 129Xe MRI provides a way to directly measure airway functional abnormalities; the clinical relevance of 129Xe MRI ventilation defects in ever-hospitalised and never-hospitalised patients who had COVID-19 has not been ascertained. It remains unclear if persistent symptoms beyond the infectious phase are related to small airways disease and ventilation heterogeneity. Hence, we measured 129Xe MRI ventilation defects, pulmonary function and symptoms in ever-hospitalised and never-hospitalised patients who had COVID-19 with persistent symptoms consistent with post-acute COVID-19 syndrome (PACS). Methods Consenting participants with a confirmed diagnosis of PACS completed 129Xe MRI, CT, spirometry, multi-breath inert-gas washout, 6-minute walk test, St. George’s Respiratory Questionnaire (SGRQ), modified Medical Research Council (mMRC) dyspnoea scale, modified Borg scale and International Physical Activity Questionnaire. Consenting ever-COVID volunteers completed 129Xe MRI and pulmonary function tests only. Results Seventy-six post-COVID and nine never-COVID participants were evaluated. Ventilation defect per cent (VDP) was abnormal and significantly greater in ever-COVID as compared with never-COVID participants (p<0.001) and significantly greater in ever-hospitalised compared with never-hospitalised participants who had COVID-19 (p=0.048), in whom diffusing capacity of the lung for carbon-monoxide (p=0.009) and 6-minute walk distance (6MWD) (p=0.005) were also significantly different. 129Xe MRI VDP was also related to the 6MWD (p=0.02) and post-exertional SpO2 (p=0.002). Participants with abnormal VDP (≥4.3%) had significantly worse 6MWD (p=0.003) and post-exertional SpO2 (p=0.03). Conclusion 129Xe MRI VDP was significantly worse in ever-hospitalised as compared with never-hospitalised participants and was related to 6MWD and exertional SpO2 but not SGRQ or mMRC scores.
98	L95		Hannah Hylton, Alex Long, Charlotte Francis, Rebecca R Taylor, William M Ricketts, Richa Singh and Paul E Pfeffer	Real-world use of the Breathing Pattern Assessment Tool in assessment of breathlessness post-COVID-19	https://doi.org/10.7861/clinmed.2021-0759	Published	June 27, 2022	Study	https://www.rcpjournals.org/content/clinmedicine/early/2022/06/22/clinmed.2021-0759	Introduction Breathing pattern disorders (BPDs) are a common cause of chronic breathlessness, including after acute respiratory illnesses such as COVID pneumonia. BPD is however underdiagnosed, partly as a result of difficulty in clinically assessing breathing pattern. The Breathing Pattern Assessment Tool (BPAT) has been validated for use in diagnosing BPD in patients with asthma but to date has not been validated in other diseases. Methods Patients undergoing face-to-face review in a post-COVID clinic were assessed by a respiratory physician and specialist respiratory physiotherapist. Assessment included a Dyspnoea-12 (D12) questionnaire to assess breathlessness, physiotherapist assessment of breathing pattern including manual assessment of respiratory motion, and BPAT assessment. The sensitivity and specificity of BPAT for diagnosis of BPD in post-COVID patients was assessed. Results BPAT had a sensitivity of 89.5% and specificity of 78.3% for diagnosing BPD in post-COVID breathlessness. Patients with a BPAT score above the diagnostic cut-off had higher levels of breathlessness than those with lower BPAT scores (D12 score mean average 19.4 vs 13.2). Conclusion BPAT has high sensitivity and moderate specificity for BPD in patients with long COVID. This would support its use as a screening test in clinic, and as a diagnostic tool for large cohort studies.
99	L96		Alexander M. Matheson1,2, Marrissa J. McIntosh1,2, Harkiran K. Kooner1,2, Justin Lee3, Vedanth Desaigoudar1,2, Elianna Bier4, Bastiaan Driehuys4, Sarah Svenningsen5, Giles E. Santyr6,7, Miranda Kirby8, Mitchell S. Albert9,10,11, Yurii Shepelytskyi9,10, Vira Grynko9,10, Alexei Ouriadov12, Mohamed Abdelrazek13, Inderdeep Dhaliwal14, J. Michael Nicholson14, Grace Parraga1,2,3,13,14 See fewer authors	Persistent 129Xe MRI Pulmonary and CT Vascular Abnormalities in Symptomatic Individuals with Post-Acute COVID-19 Syndrome	https://doi.org/10.1148/radiol.220492	Published	Jun 28 2022	Study	https://pubs.rsna.org/doi/full/10.1148/radiol.220492	Background In patients with post-acute COVID-19-syndrome (PACS), abnormal gas-transfer and pulmonary vascular density have been reported, but such findings have not been related to each other, or to symptoms and exercise limitation. The pathophysiological drivers of PACS in ever- and never-hospitalized patients are not well-understood. Purpose To determine the relationship of persistent symptoms and exercise limitation with 129Xe MRI and CT pulmonary vascular measurements in individuals with PACS. Materials and Methods In this prospective study, patients with PACS aged 18-80 years with a positive PCR COVID test were recruited from a quaternary-care COVID-19 clinic between April and October 2021. Participants with PACS underwent spirometry, diffusing-capacity-of-the-lung- for-carbon-monoxide (DLCO), 129Xe MRI, and chest CT. Healthy controls had no prior history of COVID-19 underwent spirometry, DLCO, and 129Xe MRI. The 129Xe MRI red-blood-cell (RBC) to alveolar-barrier signal ratio, RBC area-under-the-curve (AUC), CT volume-of-pulmonary-vessels with cross-sectional-area <5mm2 (BV5), and total-blood-volume (TBV) were quantified. St. George's Respiratory Questionnaire (SGRQ), International Physical Activity Questionnaire (IPAQ) and modified Borg Dyspnea Scale (mBDS) measured quality-of-life, exercise limitation and dyspnea. Differences between groups were compared using Welch's T-tests or Welch's ANOVA. Relationships were evaluated using Pearson (r) and Spearman (ρ) correlations. Results Forty participants were evaluated including six controls (mean age, 35±15 years[standard deviation], 3 women) and 34 participants with PACS (mean age, 53±13 years[SD], 18 women), of which 22 were never-hospitalized. The 129Xe MRI RBC:barrier ratio was lower in ever- hospitalized participants (P=.04) compared to controls. BV5 correlated with RBC AUC (ρ=.44,P=.03). The 129Xe MRI RBC:barrier ratio was related to DLCO (r=.57,P=.002) and FEV1 (ρ=.35,P=.03); RBC AUC was related to dyspnea (ρ=-.35,P=.04) and IPAQ score (ρ=.45,P=.02). Conclusion 129Xe MRI measurements were lower in ever- hospitalized participants with post- acute COVID-19-syndrome, 34±25 weeks post-infection compared to controls. 129Xe MRI measures were associated with CT pulmonary vascular density, DLCO, exercise capacity, and dyspnea.
100	L97		Pınar YıldızGülhanAssoc. Prof1Peri MeramArbakProf. Dr.1Ali NihatAnnakkayaProf. Dr1Ege GüleçBalbayProf. Dr.1Öner AbidinBalbayProf. Dr.1	An assessment of post-COVID-19 infection pulmonary functions in healthcare professionals	https://doi.org/10.1016/j.ajic.2022.07.003	Published	20 July 2022	Study	https://www.sciencedirect.com/science/article/pii/S019665532200534X	Highlights •The medium- and long-term effects of COVID-19 infection on pulmonary function are still unknown. •The COVID-19 pandemic adversely affected healthcare professionals, inflicting a heavy burden on the healthcare systems of countries. •Healthcare professionals with persistent complaints who contracted COVID-19 and returned to work using pulmonary function tests, the 6-minute walk test (6MWT), and the diffusing capacity of the lungs for carbon monoxide (DLCO) test. Abstract Introduction and Purpose The medium- and long-term effects of COVID-19 infection on pulmonary function are still unknown. The present study aimed to investigate the pulmonary functions in healthcare professionals who had persistent complaints after contracting COVID-19 and returning to work. Methods The study included COVID-19-infected healthcare professionals from the Düzce University Medical Faculty Hospital who volunteered to participate. Medical histories, medical records, pulmonary function tests, the diffusing capacity of the lungs for carbon monoxide (DLCO) test, and the 6-minute walk test (6MWT) were used to collect data from all participants. Results The study included 53 healthcare professionals, with an average age of 38 ± 10 years (min: 24 years and max: 71 years), including 29 female (54.7%) and 24 male (45.3%) participants. Of the participants, 22.6% were smokers, 35.8% (19 individuals) had comorbidities, and 17% (9 individuals) were hospitalized. The mean length of stay was 9 ± 4 days (mean ± standard deviation). The most prevalent symptoms were weakness (88.7%), muscle aches (67.9%), inability to smell/taste (60.4%), headache (54.7%), fever (45.3%), cough (41.5%), and shortness of breath (37.7%). The mean time to return to work after a positive polymerase chain reaction (PCR) test for COVID-19 was 18 ± 13 days. The average time among post-disease pulmonary function, 6MW, and DLCO tests was 89 ± 36 days (min: 15 and max: 205). The DLCO level decreased in 39.6% (21) of the participants. Female participants had a significantly higher rate of decreased DLCO levels than male participants (25% vs. 55.2%, p = 0.026). DLCO levels were significantly higher in participants with long-term persistent complaints (p = 0.043). The later the time to return to work, the lower the DLCO value (r = −0.290 and p = 0.035). The 6MWT distance was positively correlated with hemoglobin and lymphocyte levels at the time of the disease onset and negatively correlated with D-dimer levels. The most prevalent symptoms during the control visits were shortness of breath/effort dyspnea (24.6%), weakness (9.5%), and muscle aches (7.6%). Conclusion Significant persistent complaints (47.2%) and low DLCO levels (39.6%) were observed in healthcare professionals during control visits at a mean time of 3 months after the COVID-19 infection. Symptoms and spirometry measurements, including DLCO, may be helpful in the follow-up of healthcare professionals who contracted COVID-19. Further comprehensive studies with long-term follow-up periods are required.
101	L98		Koulla Parpa & Marcos Michaelides	Aerobic capacity of professional soccer players before and after COVID-19 infection	https://doi.org/10.1038/s41598-022-16031-7	Published	13 July 2022	Study	https://www.nature.com/articles/s41598-022-16031-7	This investigation aimed to assess the aerobic capacity of professional soccer players pre-and post-COVID-19 infection. Twenty-one division-1 elite soccer players (age 24.24 ± 5.75 years, height 178.21 ± 5.44 cm, weight 74.12 ± 5.21 kg) participated in this study. This observational study compared the same players' aerobic capacity pre-, and 60-days post COVID-19 recovery. The statistical analysis demonstrated that the infected players had significantly lower VO2max values [t(20) = 5.17, p < 0.01, d = 0.613 (medium effect)], and significantly lower VO2 values at respiratory compensation point (RC) [t(20) = 2.97, p < 0.05, d = 0.39 (small effect)] after recovery. Furthermore, results indicated a significantly lower running time (RT) on the treadmill [t(20) = 4.84, p < 0.01, d = 0.46 (small effect)] when compared to the results that were obtained before they got infected. In addition, velocity at VO2max (VVO2max) was significantly lower [t(20) = 2.34, p < 0.05, d = 0.41 (small effect)] and the heart rate values at ventilatory threshold (VT) [t(20) = −2.79, p < 0.01, d = 0.55 (medium effect)] and RC [t(20) = −3.72, p < 0.01, d = 0.52 (medium effect)] were significantly higher post-recovery. The aforementioned findings indicate that post COVID-19 soccer players may not reach full recovery at two months. Therefore, our results highlight that further adaptations and improvements are needed with regard to aerobic capacity before soccer players return to professional games.
102	L99		Kenneth H Dinnon 3rd # 1, Sarah R Leist # 2, Kenichi Okuda # 3, Hong Dang # 3, Ethan J Fritch # 1, Kendra L Gully 2, Gabriela De la Cruz 4, Mia D Evangelista 4, Takanori Asakura 3, Rodney C Gilmore 3, Padraig Hawkins 3, Satoko Nakano 3, Ande West 2, Alexandra Schäfer 2, Lisa E Gralinski 2, Jamie L Everman 5, Satria P Sajuthi 5, Mark R Zweigart 2, Stephanie Dong 2, Jennifer McBride 2, Michelle R Cooley 2, Jesse B Hines 6, Miriya K Love 3, Steve D Groshong 7, Alison VanSchoiack 8, Stefan J Phelan 8, Yan Liang 8, Tyler Hether 8, Michael Leon 8, Ross E Zumwalt 9, Lisa M Barton 10, Eric J Duval 10, Sanjay Mukhopadhyay 11, Edana Stroberg 10, Alain Borczuk 12, Leigh B Thorne 13, Muthu K Sakthivel 14, Yueh Z Lee 14 15, James S Hagood 3 16, Jason R Mock 3 17, Max A Seibold 5 18 19, Wanda K O'Neal # 3, Stephanie A Montgomery # 4 13, Richard C Boucher # 3, Ralph S Baric # 1 2 20	SARS-CoV-2 infection produces chronic pulmonary epithelial and immune cell dysfunction with fibrosis in mice	https://doi.org/10.1126/scitranslmed.abo5070	Published	7 Jul 2022	Study	https://www.science.org/doi/10.1126/scitranslmed.abo5070	A subset of individuals who recover from coronavirus disease 2019 (COVID-19) develop post-acute sequelae of SARS-CoV-2 (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal tissue samples. The mouse-adapted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain MA10 produces an acute respiratory distress syndrome (ARDS) in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute to clinical recovery phases. At 15 to 120 days post-virus clearance, pulmonary histologic findings included subpleural lesions composed of collagen, proliferative fibroblasts, and chronic inflammation, including tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal up-regulation of pro-fibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early anti-fibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC.
103	L100		Peter Ladlow, Oliver O’Sullivan, Alexander N. Bennett, Robert Barker-Davies, Andrew Houston, Rebecca Chamley, Samantha May, Daniel Mills, Dominic Dewson, Kasha Rogers-Smith, Christopher Ward, John Taylor, Joseph Mulae, Jon Naylor, Edward D. Nicol, and David A. Holdsworth	The effect of medium-term recovery status after COVID-19 illness on cardiopulmonary exercise capacity in a physically active adult population	https://doi.org/10.1152/japplphysiol.00138.2022	Published	09 Jun 2022	Study	https://journals.physiology.org/doi/full/10.1152/japplphysiol.00138.2022	A failure to fully recover following coronavirus disease 2019 (COVID-19) may have a profound impact on high-functioning populations ranging from frontline emergency services to professional or amateur/recreational athletes. The aim of the study is to describe the medium-term cardiopulmonary exercise profiles of individuals with “persistent symptoms” and individuals who feel “recovered” after hospitalization or mild-moderate community infection following COVID-19 to an age, sex, and job-role matched control group. A total of 113 participants underwent cardiopulmonary functional tests at a mean of 159 ± 7 days (∼5 mo) following acute illness; 27 hospitalized with persistent symptoms (hospitalized-symptomatic), 8 hospitalized and now recovered (hospitalized-recovered); 34 community managed with persistent symptoms (community-symptomatic); 18 community managed and now recovered (community-recovered); and 26 controls. Hospitalized groups had the least favorable body composition (body mass, body mass index, and waist circumference) compared with controls. Hospitalized-symptomatic and community-symptomatic individuals had a lower oxygen uptake (V̇o2) at peak exercise (hospitalized-symptomatic, 29.9 ± 5.0 mL/kg/min; community-symptomatic, 34.4 ± 7.2 mL/kg/min; vs. control 43.9 ± 3.1 mL/kg/min, both P < 0.001). Hospitalized-symptomatic individuals had a steeper V̇e/V̇co2 slope (lower ventilatory efficiency) (30.5 ± 5.3 vs. 25.5 ± 2.6, P = 0.003) versus. controls. Hospitalized-recovered had a significantly lower oxygen uptake at peak (32.6 ± 6.6 mL/kg/min vs. 43.9 ± 13.1 mL/kg/min, P = 0.015) compared with controls. No significant differences were reported between community-recovered individuals and controls in any cardiopulmonary parameter. In conclusion, medium-term findings suggest that community-recovered individuals did not differ in cardiopulmonary fitness from physically active healthy controls. This suggests their readiness to return to higher levels of physical activity. However, the hospitalized-recovered group and both groups with persistent symptoms had enduring functional limitations, warranting further monitoring, rehabilitation, and recovery.
104	L101		Jimmy Yu,Tobias Granberg,Roya Shams,Sven Petersson,Magnus Sköld,Sven Nyrén,Johan Lundberg	Lung perfusion disturbances in non-hospitalized post-COVID with dyspnea – An MRI feasibility study	https://doi.org/10.1111/joim.13558	Published	10 August 2022	Study	https://onlinelibrary.wiley.com/doi/abs/10.1111/joim.13558	Background Dyspnea is common after COVID-19. Though the underlying mechanisms are largely unknown, lung perfusion abnormalities could contribute to lingering dyspnea. Objectives To detect pulmonary perfusion disturbances in non-hospitalized individuals with post-COVID condition and persistent dyspnea 4–13 months after the disease onset. Methods Individuals with dyspnea and matched healthy controls were recruited for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), a six-minute walk test, and an assessment of dyspnea. The DCE-MRI was quantified using two parametric values: mean time-to-peak (TTP) and TTP ratio, reflecting the total lung perfusion resistance and the fraction of lung with delayed perfusion, respectively. Results Twenty-eight persons with persistent dyspnea (mean age 46.5±8.0 years, 75% women) and 22 controls (mean age 44.1±10.8 years, 73% women) were included. There was no systematic sex difference in dyspnea. The post-COVID group had no focal perfusion deficits but had higher mean pulmonary TTP (0.43±0.04 vs. 0.41±0.03, P = 0.011) and TTP ratio (0.096±0.052 vs. 0.068±0.027, P = 0.032). Post-COVID males had the highest mean TTP 0.47±0.02 and TTP ratio of 0.160±0.039; compared to male controls and post-COVID females (P = 0.001 and P<0.001 respectively). Correlations between dyspnea and perfusion parameters were demonstrated in males (r = 0.83, P<0.001 for mean TTP; r = 0.76, P = 0.003 for TTP ratio), but not in females. Conclusions DCE-MRI demonstrated late contrast bolus arrival in males with post-COVID dyspnea, suggestive of primary vascular lesions or secondary effects of hypoxic vasoconstriction. Since this effect was not regularly observed in female patients, our findings suggest sex differences in the mechanisms underlying post-COVID dyspnea, which warrants further investigation in dedicated trials.
105	L102		Monika Fagevik Olsén,Louise Lannefors,Malin Nygren-BonnierORCID Icon &Ewa-Lena Johansson	Long COVID – respiratory symptoms in non-hospitalised subjects – a cross-sectional study	https://doi.org/10.1080/21679169.2022.2101692	Published	01 Aug 2022	Study	https://www.tandfonline.com/doi/full/10.1080/21679169.2022.2101692	Background The aim of this study was to describe and analyse the variety of respiratory appearances in Long COVID subjects who were not hospitalised during the acute phase of the infection. Methods A consecutive series of 60 subjects participated x¯10.8 months (SD 4.5) after the acute phase of the infection. Respiratory function was tested concerning lung volumes, expiratory flow, muscle strength, physical capacity including concurrent oxygen saturation, chest expansion, lung sounds, pain and breathing pattern. Differences between those with or without positive test and duration of symptoms more or less than 6 months were analysed with T-test, Chi-square test and Fisher’s exact test. Results Decreased forced vital capacity was found in 6/60 (10%), and forced expiratory volume in 1 s and 7/60 (12%), low maximal inspiratory pressure in 38/58 (54%) and low maximal expiratory pressure in 10/58 (17%). Decreased physical capacity was registered in 36/52 (69%), and thoracic expansion in 26/46 (56%). Pathologic lung sounds had 15/58 (26%) and six patients desaturated during the test of physical capacity. A majority (36/58, 67%) presented pain in the ribcage. All but three patients (95%) showed a dysfunctional breathing pattern in sitting and standing. Only poor and fair correlations were found between age, duration and level of physical capacity compared to spirometry, respiratory muscle strength and thoracic expansion. Conclusion Abnormal breathing pattern and respiratory movements as well as pain, and reduced lung volumes, flow, respiratory muscle strength, physical capacity and thoracic expansion may be involved in Long COVID. The breathing symptoms should therefore be looked for in a wider picture beyond spirometry and oximetry.
106	L103	CPET	Esther L van Voorthuizen, MD, Hanneke A C van Helvoort, PhD, Jeanette B Peters, PhD, Michel M van den Heuvel, MD, PhD, Bram van den Borst, MD, PhD	Persistent Exertional Dyspnea and Perceived Exercise Intolerance After Mild COVID-19: A Critical Role for Breathing Dysregulation?	https://doi.org/10.1093/ptj/pzac105	Published	28 July 2022	Study	https://academic.oup.com/ptj/advance-article/doi/10.1093/ptj/pzac105/6651031	Objective After mild COVID-19, a subgroup of patients reported post–acute-phase sequelae of COVID-19 (PASC), in which exertional dyspnea and perceived exercise intolerance were common. Underlying pathophysiological mechanisms remain incompletely understood. The purpose of this study was to examine outcomes from cardiopulmonary exercise testing (CPET) in these patients. Methods In this observational study, participants were patients who were referred for the analysis of PASC after mild COVID-19 and in whom CPET was performed after standard clinical workup turned out unremarkable. Cardiocirculatory, ventilatory, and metabolic responses to and breathing patterns during exercise at physiological limits were analyzed. Results Twenty-one patients (76% women; mean age = 40 years) who reported severe disability in physical functioning underwent CPET at 32 weeks (interquartile range [IQR] = 22–52) after COVID-19. Mean peak O2 uptake was 99% of predicted with normal anaerobic thresholds. No cardiovascular or gas exchange abnormalities were detected. Twenty of the 21 patients (95%) demonstrated breathing dysregulation (ventilatory inefficiency [29%], abnormal course of breathing frequency and tidal volume [57%], absent increase of end-tidal PCO2 [57%], and abnormal resting blood gases [67%]). Conclusion Breathing dysregulation may explain exertional dyspnea and perceived exercise intolerance in patients with PASC after mild COVID-19 and can be present in the absence of deconditioning. This finding warrants further study on the levels of neural control of breathing and muscle function, and simultaneously provides a potential treatment opportunity.
107	L104		Tove LekvaORCID Icon,Thor Ueland,Bente HalvorsenORCID Icon,Sarah Louise Murphy,Anne Ma Dyrhol-Riise,Anders Tveita,Ane-Kristine Finbråten,Alexander Mathiessen,Karl Erik Müller,Trond Mogens Aaløkken,Ole Henning Skjønsberg,Tøri Vigeland Lerum,Pål Aukrust &Tuva Børresdatter Dahl	Markers of cellular senescence is associated with persistent pulmonary pathology after COVID-19 infection	https://doi.org/10.1080/23744235.2022.2113135	Published	19 Aug 2022	Study	https://www.tandfonline.com/doi/full/10.1080/23744235.2022.2113135	Background The lungs are the organ most likely to sustain serious injury from coronavirus disease 2019 (COVID-19). However, the mechanisms for long-term complications are not clear. Patients with severe COVID-19 have shorter telomere lengths and higher levels of cellular senescence, and we hypothesized that circulating levels of the telomere-associated senescence markers chitotriosidase, β-galactosidase, cathelicidin antimicrobial peptide and stathmin 1 (STMN1) were elevated in hospitalized COVID-19 patients compared to controls and could be associated with pulmonary sequelae following hospitalization. Methods Ninety-seven hospitalized patients with COVID-19 who underwent assessment for pulmonary sequelae at three-month follow-up were included in the study. β-Galactosidase and chitotriosidase were analysed by fluorescence; stathmin 1 and cathelicidin antimicrobial peptide were analysed by enzyme immuno-assay in plasma samples from the acute phase and after three-months. In addition, the classical senescence markers cyclin-dependent kinase inhibitor 1A and 2A were analysed by enzyme immuno-assay in peripheral blood mononuclear cell lysate after three months. Results We found elevated plasma levels of the senescence markers chitotriosidase and stathmin 1 in patients three months after hospitalization with COVID-19, and these markers in addition to protein levels of cyclin-dependent kinase inhibitor 2A in cell lysate, were associated with pulmonary pathology. The elevated levels of these markers seem to reflect both age-dependent (chitotriosidase) and age-independent (stathmin 1, cyclin-dependent kinase inhibitor 2A) processes. Conclusions We suggest that accelerated ageing or senescence could be important for long-term pulmonary complications of COVID-19, and our findings may be relevant for future research exploring the pathophysiology and management of these patients.
108	L105		Tanyalak Parimon, M.D, Milena Espindola, Ph.D, Alberto Marchevsky, M.D, Reinaldo Rampolla, M.D, Peter Chen, M.D, Cory M Hogaboam, Ph.D	Potential Mechanisms for Lung Fibrosis Associated with COVID-19 Infection	https://doi.org/10.1093/qjmed/hcac206	Published	26 August 2022	Article	https://academic.oup.com/qjmed/advance-article/doi/10.1093/qjmed/hcac206/6677237	Pulmonary fibrosis is a sequalae of SARS-CoV-2 infection that currently lacks effective preventative or therapeutic measures. Post-viral lung fibrosis due to SARS-CoV-2 has been shown to be progressive on selected patients using imaging studies. Persistent infiltration of macrophages and monocytes, a main feature of SARS-CoV-2 pulmonary fibrosis, and long-lived circulating inflammatory monocytes might be driving factors promoting the profibrotic milieu in the lung. The upstream signal (s) that regulates the presence of these immune cells (despite complete viral clearance) remains to be explored. Current data indicate that much of the stimulating signals are localized in the lungs. However, an ongoing low-grade systemic inflammation in long COVID-19 symptoms suggests that certain non-pulmonary regulators such as epigenetic changes in hematopoietic stem cells might be critical to the chronic inflammatory response. Since nearly one-third of the world population have been infected, a timely understanding of the underlying pathogenesis leading to tissue remodeling is required. Herein, we review the potential pathogenic mechanisms driving lung fibrosis following SARS-CoV-2 infection based upon available studies and our preliminary findings.
109	L106		Jeffrey P. Kanne , Brent P. Little, Jefree J. Schulte, Adina Haramati, Linda B. Haramati	Long-Term Lung Abnormalities Associated with COVID-19 Pneumonia	https://doi.org/10.1148/radiol.221806	Published	Aug 30 2022	Review	https://pubs.rsna.org/doi/full/10.1148/radiol.221806	In the third year of the SARS-CoV-2 pandemic, much has been learned about the long- term effect of COVID-19 pneumonia on the lungs. Approximately one-third of patients with moderate-to-severe pneumonia, especially those requiring intensive care therapy or mechanical ventilation, have residual abnormalities on chest CT one year after presentation. Abnormalities range from parenchymal bands to bronchial dilation to frank fibrosis. Less is known about the long-term pulmonary vascular sequelae, but there appears to be a persistent, increased risk of venothromboembolic events in a small cohort of patients. Finally, the associated histologic abnormalities resulting from SARS- CoV-2 infection are similar to those of patients with other causes of acute lung injury. Summary Some patients with moderate to severe COVID-19 have chest CT abnormalities that persist at least 1 year after infection and may be associated with symptoms. These CT abnormalities show similarities to those described in the 2002–2003 SARS epidemic. Essentials ■ Approximately one-third of patients hospitalized with COVID-19 pneumonia have abnormalities at chest CT 12 months after infection. ■ CT abnormalities range from residual parenchymal bands to fibrosis as well as air trapping and bronchiectasis. ■ A very small number of patients have a persistently elevated risk of venothromboembolic disease after acute infection. ■ The late histopathologic findings of COVID-19 are similar to those of other causes of acute lung injury with a mix of organizing and chronic fibrosing histologic patterns. Additionally, these findings are comparable to those reported with the SARS epidemic.
110	L107		Jong Hyuk Lee, Jae-Joon Yim & Jimyung Park	Pulmonary function and chest computed tomography abnormalities 6–12 months after recovery from COVID-19: a systematic review and meta-analysis	https://doi.org/10.1186/s12931-022-02163-x	Published	06 September 2022	Systematic Review and Meta-analysis	https://link.springer.com/article/10.1186/s12931-022-02163-x	Background Some coronavirus disease 2019 (COVID-19) survivors experience prolonged and varying symptoms, a condition termed post-acute COVID-19 syndrome (PACS). However, the prevalence of chronic pulmonary sequelae of PACS during long-term follow-up remains unclear. Several studies have examined this issue and reported heterogeneous results. Methods We conducted a systematic review and meta-analysis using a random-effects model to estimate the pooled prevalence of the pulmonary sequelae of COVID-19, as demonstrated by pulmonary function testing (PFT) and chest computed tomography (CT) performed at least 6 months after initial infection. PubMed, Embase, and Cochrane Library databases were searched from January 1, 2020 to December 31, 2021 to identify related studies. We investigated whether the prevalence of pulmonary sequelae decreased over time and attempted to identify the factors associated with their development by performing multiple subgroup and meta-regression analyses. Results Of the 18,062 studies identified, 30 met our eligibility criteria. Among these studies, 25 and 22 had follow-up PFT and chest CT data, respectively. The follow-up durations were approximately 6 and 12 months in 18 and 12 studies, respectively. Impaired diffusion capacity was the most common abnormality on PFT (pooled prevalence 35%, 95% confidence interval [CI] 30–41%) with a prevalence of 39% (95% CI 34–45%) and 31% (95% CI 21–40%) in the 6-month and 12-month follow-up studies, respectively (P = 0.115). Restrictive pulmonary dysfunction evident as reduced forced vital capacity was less frequent (pooled prevalence 8%, 95% CI 6–11%); however, its prevalence was lower in the 12-month follow-up studies than in the 6-month follow-up studies (5% [95% CI 3–7%] vs. 13% [95% CI 8–19%], P = 0.006). On follow-up chest CT, the pooled prevalence of persistent ground-glass opacities and pulmonary fibrosis was 34% (95% CI 24–44%) and 32% (95% CI 23–40%), respectively, and the prevalence did not decrease over time. As every meta-analysis showed significant between-study heterogeneity, subgroup and meta-regression analyses were performed to identify potential effect modifiers; the severity of index infection was associated with the prevalence of impaired diffusion capacity and pulmonary fibrosis. Conclusions A substantial number of COVID-19 survivors displayed pulmonary sequelae as part of PACS. Except for restrictive pulmonary dysfunction, the prevalence of these sequelae did not decrease until 1 year after initial infection. Considering the association between the severity of acute COVID-19 and risk of pulmonary sequelae, patients who recover from severe COVID-19 require close respiratory follow-up.
111	L108		Puja Mehta, Ivan O. Rosas & Mervyn Singer	Understanding post-COVID-19 interstitial lung disease (ILD): a new fibroinflammatory disease entity	https://doi.org/10.1007/s00134-022-06877-w	Published	08 September 2022	Article	https://link.springer.com/article/10.1007/s00134-022-06877-w	Immunomodulation and immunity from vaccination and natural infection have reduced mortality from coronavirus disease 2019 (COVID-19). However, there are ongoing concerns regarding emerging variants and residual pulmonary sequelae in survivors, given that the lungs are the principal site for the triumvirate of infection, inflammation and injury. The initial waves of acute, severe COVID-19 were profoundly inflammatory, usually manifest as organising pneumonia ± acute respiratory distress syndrome (ARDS). The extent of the fibrogenic potential of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the modifiability of the pathogenic processes and disease course are unclear. Interestingly patients can develop ‘post-COVID interstitial lung disease’ (PC-ILD) irrespective of having ARDS during the acute phase. Here, we describe our evolving understanding of PC-ILD and the critical need to identify risk factors, including within the critical care setting. We also discuss immunopathomechanisms that may facilitate early intervention to prevent, slow or arrest progression of lung damage e.g. with immunomodulatory and/or anti-fibrotic agents. Future directions The prevalence, severity and impact on healthcare systems of PC-ILD are currently unknown. The influence of viral load, new variants (with varying lung tropism), vaccination, ventilatory strategies, systemic hyperinflammation and immunomodulation [15] (e.g. corticosteroids or cytokine blockade (e.g. interleukin-6 antagonism) in the acute phase of PC-ILD are unknown. The role of immunomodulatory or anti-fibrotic therapies in PC-ILD is currently unresolved. It is tempting to speculate that immunomodulation (used for autoimmune ILD) may have a role in accelerating reversal of “inflammatory” changes, and anti-fibrotics (e.g. nintedanib used in progressive-fibrosing ILD) may attenuate “fibrotic-like” changes. However thus far PC-ILD appears to be non-progressive and clinical trial outcome data are eagerly awaited (Fig. 1). Systematic, longitudinal data capture and deep phenotyping of patients with both persisting and resolving respiratory symptoms post-COVID are critical to unpick the aetiopathogenesis of PC-ILD. This should include clinical, physiological and radiological correlates with paired bio-sampling of both the lung microenvironment (e.g. BAL) and peripheral blood compartments to enable comparison to established f-ILDs. Serial CTs (ideally with in- or pre-hospital baselines) quantifying the extent and character of parenchymal change are needed to understand the relationship, reciprocity and evolution of radiological regions of inflammation and fibrosis. Understanding PC-ILD has global public health implications, but is also a unique opportunity to better understand molecular and cellular mechanisms of initiation, propagation and resolution of lung fibrosis. This may uncover novel therapeutic targets of wider relevance for multi-organ fibrotic diseases.
112	L109		Tony H Ruppert, Zahra Alkhamees, Lydia Hulshizer and Luminita Tudor	Dyspnea Correlations in Patients With Post-Acute Sequelae of COVID-19 Infection		Published	October 3, 2022	Study	https://rc.rcjournal.com/content/67/Suppl_10/3773902.short	Background: COVID-19 is a respiratory disease that has caused a modern global pandemic. A subset of patients continues to complain of dyspnea several weeks and months after the initial acute COVID-19 infection. This project was a retrospective analysis of patients diagnosed with Post-Acute Sequelae of COVID-19 infection (PASC) within an Outpatient COVID Care Center in Central PA. This study focused on identifying any correlations between the breathlessness of long COVID-19 patients and multiple other factors. Methods: After IRB approval, a retrospective study using electronic data from Wellspan Health (York PA) Outpatient COVID Care Center was conducted. 97 patients with pulmonary function testing recorded in the electronic medical record from June 2021 to March 2022 were included in the study. The retrospective study analyzed factors including age, prior to COVID smoking history, rest and/or exercise hypoxemia, history of prior pulmonary diseases, post-bronchodilator spirometry, total lung capacity, diffusing capacity, intubation history due to acute COVID-19, current symptoms of depression as shown by patient health care questionnaire (PHQ6), current symptoms of anxiety as shown by the general anxiety disorder score (GAD7), and cognitive function as shown by Montreal cognitive assessment (MoCA0). Results: 78/97 patients identified dyspnea as a complaint 4-6 weeks after acute COVID-19 infection. Statistical analysis with Chi-square, independent T-test and Mann-Whitney U test demonstrated a P-value greater than 0.05 in all analyses indicating no statistical predictor of post-COVID-19 shortness of breath among the tested considerations. Although they were not statistically significant in this study, factors such as abnormal DLCO, TLC, and elevated scores of PHQ6, and GAD7 showed an interesting trend towards a correlation with post-COVID-19 shortness of breath Conclusions: COVID-19 continues to affect patients, even after the initial infection. This study on long COVID-19 patients showed no statistically significant factors that predicted or correlated with ongoing dyspnea. Limitations to our study include small sample size and only the use of single-center patients. Further research should be conducted with larger sample size and continued factors such as DLCO, TLC, anxiety, depression, and other factors that could predict or influence dyspnea in long COVID-19 patients.
113	L110		A M Bielecka-Dabrowa, A Sakowicz, M Banach, M Maciejewski, K Gryglewska	Diagnostic usefulness of spiroergometry and risk factors of long -COVID in patients with normal left ventricular ejection fraction	https://doi.org/10.1093/eurheartj/ehac544.2464	Published	03 October 2022	Study	https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.2464/6745489	Background Recent evidence has shown that patients with acute SARS-CoV-2 infection might present symptoms of infection a long time after a recovery. Purpose To investigate the risk factors and assess the utility of spiroergometry parameters in differential diagnosing patients presenting the symptoms (dyspnea, fatique, pain in chest, muscle pain, cognitive impairment, taste and smell disturbances) persisting for a few months after recovery from COVID 19 (symptoms of long COVID). Methods and results The 146 patients (pts) with normal left ventricular ejection fraction and without respiratory diseases, hospitalised in Cardiology Department recovering from COVID-19 at three to six months after confirmed diagnosis were included. The clinical examination, laboratory results, echocardiography using Vivid E95–GE Healthcare, non-invasive body mass analysis using Body Composition Analyzer (Tanita Pro), spiroergometry using The MetaSoft® Studio application were analyzed. The subjects were divided into the two following groups: group demonstrating long COVID symptoms (i.e. suffering from one of the following dyspnea, fatique, pain in chest, muscle pain, cognitive impairment, taste or smell disturbances) [N=44 pts] and the group without long COVID symptoms [N=102 pts]. Pts with long COVID symptoms presented significantly higher age (58 versus [vs] 44 years; p<0.0001), higher metabolic age (53 vs 45 years; p=0.01), higher left atrial diameter (37 vs 35 mm; p=0.04), higher left ventricular mass index (LVMI) (83 vs 74 g/m2, p=0.03), higher E/E' (7.3 vs 6; p<0.001) compared to control group. In CPET long COVID pts presented lower forced vital capacity (FVC) (3.6 vs 4.3 L; p=0.009), lower maximal oxygen consumption measured during incremental exercise indexed per kilogram (VO2max) (21 vs 23 ml/min/kg; p=0.04), lower respiratory exchange ratio (RER) (1.0 vs 1.1; p=0.04); lower forced expiratory volume in one second (FEV1) (2.9 vs 3.25 L; p=0,03); higher ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC) (106 vs 100%; p=0.0002) – Figure 1, there were no significant changes in electrocardiogram between groups. The laboratory results pointed that pts with long COVID symptoms had also lower rate of red blood cells (RBC) (4,4 vs 4,6 mln; p=0.01); higher level of glucose (92 vs 90 mg%; p=0.02); lower glomerular filtration rate (GFR) estimate by Modification of Diet in Renal Disease (MDRD) (88 vs 95; p=0.02); higher level of hypersensitive cardiac Troponin T (hsTnT) (6.1 vs 3.9 ng/L; p=0.03). The parameters significant in univariate analyses were included to the multivariate model. The results of multiple logistic regression were as follows: age (OR 4.6, 95% CI: 1.7–11.5; p=0.001) and LVMI (OR 2.5, 95% CI: 1.0–6.6; p=0.04). Conclusions Persistent symptoms in long COVID can mimic those of cardiovascular disease. Spiroergometric parameters are useful in making a proper diagnosis.
114	L111		Aysegul GencerORCID Icon,Buket Caliskaner Ozturk,Sermin BorekciORCID Icon &Bilun Gemicioglu	Bronchodilator Reversibility Testing in Long-Term Cough and Dyspnea after Covid-19 Viral Infection: A Trigger for Asthma?	https://doi.org/10.1080/02770903.2022.2139719	Published	24 Oct 2022	Study	https://www.tandfonline.com/doi/abs/10.1080/02770903.2022.2139719	Background This study aims to investigate the presence of underlying chronic airway disease in individuals with chronic cough and dyspnea lasting longer than eight weeks and who had previously Coronavirus disease 2019(COVID-19) and had no known lung disease. Methods A total of 151 patients admitted to the respiratory diseases outpatient room with the complaint of cough and/or dyspnea that persisted for at least eight weeks following COVID-19 infection were accrued to the study. Demographic characteristics, smoking history, the severity of lung involvement on chest computed tomography in the acute phase of Covid-19 infection, and bronchodilator reversibility test results were recorded. Smoking history and forced expiratory volume in the first second (FEV1) were compared. Results FEV1 increase ≥200 ml was observed in 40(26.5%) patients. In 24(15.9%) patients, an increase in FEV1 was found to be 200 ml and above, and the percentage of FEV1 was 12% or more. While 14(9.3%) patients were diagnosed with asthma, 13(8,6%) patients were diagnosed with nonreversible airflow obstruction (NRAO), and 1(0.7%) patient was diagnosed with chronic obstructive pulmonary disease (COPD). Conclusion COVID-19 infection may play a vital role in initiating asthma pathogenesis. It should be kept in mind that viral infection-related asthma may be the underlying cause of prolonged cough and dyspnea after COVID-19 infection.
115	L112		T VasileiosStavrouabAstaraKyriakiacD GeorgeVavougiosadG IoannisFatouroseS GeorgeMetsiosfKonstantinosKalabakasbDimitriosKaragiannisbZoeDaniilaI KonstantinosGourgoulianisaGeorgeΒasdekisb	Athletes with mild post-COVID-19 symptoms experience increased respiratory and metabolic demands: Α cross-sectional study	https://doi.org/10.1016/j.smhs.2022.10.004	Published	23 October 2022	Study	https://www.sciencedirect.com/science/article/pii/S2666337622000634	Coronavirus Disease 2019 (COVID-19) has significantly affected different physiological systems, with a potentially profound effect on athletic performance. However, to date, such effect has not been neither addressed, nor investigated. Therefore, the aim of this study was to investigate fitness indicators, along with the respiratory and metabolic profile, in post-COVID-19 athletes. Forty male soccer players, were divided into two groups: non-hospitalized COVID-19 (n = 20, Age: 25.2 ± 4.1 years, Body Surface Area (BSA): 1.9 ± 0.2 m2, body fat: 11.8 ± 3.4%) versus (vs) healthy (n = 20, Age: 25.1 ± 4.4 years, BSA: 2.0 ± 0.3 m2, body fat: 10.8 ± 4.5%). For each athlete, prior to cardiopulmonary exercise testing (CPET), body composition, spirometry and lactate blood levels, were recorded. Differences between groups were assessed with the independent samples t-test (<0.05). Several differences were detected between the two groups: ventilation (VE: Resting: 14.7 ± 3.1 vs. 11.5 ± 2.6, p = 0.001; Maximal Effort: 137.1 ± 15.5 vs. 109.1 ± 18.4 L/min, p < 0.001), ratio VE/maximal voluntary ventilation (Resting: 7.9 ± 1.8 vs. 5.7 ± 1.7%, p < 0.001; Maximal Effort: 73.7 ± 10.8 vs. 63.1 ± 9.0, p = 0.002), ratio VE/BSA (Resting: 7.9 ± 2.0 vs. 5.9 ± 1.4%, p = 0.001; Maximal Effort: 73.7 ± 11.1 vs. 66.2 ± 9.2%, p = 0.026), heart rate (Maximal Effort: 191.6 ± 7.8 vs. 196.6 ± 8.6 bpm, p = 0.041), and lactate acid (Resting: 1.8 ± 0.8 vs. 0.9 ± 0.1 mmol/L, p < 0.001; Maximal Effort: 11.0 ± 1.6 vs. 9.8 ± 1.2 mmol/L, p = 0.009), during CPET. No significant differences were identified regarding maximal oxygen uptake (55.7 ± 4.4 vs. 55.4 ± 4.6 ml/min/kg, p = 0.831). Our findings demonstrate a pattern of compromised respiratory function in post-COVID-19 athletes characterized by increased respiratory work at both rest and maximum effort as well as hyperventilation during exercise, which may explain the reported increased metabolic needs.
116	L113		Nagel C.Access ORCID a,b,c,d · Olschewski H.e · Sorichter S.f · Uezgoer G.d · Diehm C.g · Huppert P.h · Iber T.i · Herth F.c,j · Harutyunova S.b,c · Marra A.M.b,k · Benjamin N.b,c · Salkić A.b,c · Grünig E.b,c · Egenlauf B.b,c,j	Impairment of Inspiratory Muscle Function after COVID-19	https://doi.org/10.1159/000527361	Published	Oct 28, 2022	Study	https://www.karger.com/Article/Abstract/527361	Background: Persistent symptoms after acute coronavirus-disease-2019 (COVID-19) are common, and there is no significant correlation with the severity of the acute disease. In long-COVID (persistent symptoms >4 weeks after acute COVID-19), respiratory symptoms are frequent, but lung function testing shows only mild changes that do not explain the symptoms. Although COVID-19 may lead to an impairment of the peripheral nervous system and skeletal muscles, respiratory muscle function has not been examined in this setting. Methods: In this study, we assessed the severity of dyspnea (NYHA-function class) in long-COVID patients and analyzed its association with body mass index (BMI), FEV1, forced vital capacity, other parameters of body plethysmography, diffusing capacity for carbon monoxide (DLCO), arterial blood gases, and inspiratory muscle function, assessed by airway occlusion pressure (P0.1) and maximal inspiratory pressure (PImax) in two respiratory clinics in Germany between Oct 2020 and Aug 2021. Results: A total of 116 patients were included in the study. The mean age was 50.2 ± 14.5 years; BMI, 26.7 ± 5.87 kg/m2; NYHA class I, 19%; II, 27%; III, 41%; and IV, 14%. While lung function values and computed tomography or conventional X-ray of the chest were in the normal range, inspiratory muscle function was markedly impaired. P01 was elevated to 154 ± 83%predicted and PImax was reduced to 41 ± 25%predicted. PImax reduction was strongly associated with the severity of dyspnea but independent of BMI, time after acute COVID-19 and most of the other parameters. Conclusions: This study shows that in long-COVID patients, respiratory symptoms may be mainly caused by reduced inspiratory muscle strength. Assessment of PImax and P0.1 might better explain dyspnea than classical lung function tests and DLCO. A prospective study is needed to confirm these results.
117	L114		Pasquale Maria Parrella, Marco Rumolo, Roberto Bianco, Giada Annarumma, Eugenio di Vaia, and Guido Iaccarino	Alterations of basal spirometry in long COVID patients. Effects of physical activity	https://doi.org/10.1016%2Fj.vph.2022.107065	Published	2022 Oct 14	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9560753/	The long-term sequelae of the COVID-19 (Long Covid, LC), includes of fatigue, exercise intolerance, dyspnea and palpitations 30 days after negative swab. Little is known about the determinants of LC. We verified the impact of physical activity (PA), focusing on lung function, evaluated with traditional spirometry. Out of 73 COVID-19 healed patients referred to the Sports Medicine Clinic of the Federico II University Hospital from December 2020 to May 2021 for sports fitness certification, we selected 19 patients aged between 40 and 65 years, mean age 52.9 ± 6.9 years, 6/13 females/males, BMI 29.3 ± 5.7. Inclusion criteria were COVID severity >1, compliance to spirometry testing, absence of other conditions and medications that could interfere with spirometry. Patients were divided into sportsmen (S, n = 7, practicing PA > 2 h/w) and non- sportsmen (NS, n = 12, practicing PA < 2 h/w,) and subjected to traditional spirometry (Spirostick blue, Gerotherm), for the evaluation of forced vital capacity (FVC), tidal volume (CV), maximum expiratory volume in the first second (FEV1), and FEV1/FVC calculated with reference to the expected theoretical values. Considering the population as whole, we observed the increase in FEV1/FVC comparedto the theoretical value (87.9 ± 1.5 vs. 79.9 ± 0.6%, p < 0.001). This difference was confirmed in both subgroups (S:89.1 ± 2.2 vs. 79.4 ± 1.0%, p < 0.001; NS:87.2 ± 2.0 vs. 80.2 ± 0.8%, p < 0.001). In NS patients the increase is due to the reduction in FVC (3.7 ± 0.2 vs. 4.0 ± 0.2 L, p < 0.05) but not in S patients (4.2 ± 0.4 vs. 4.2 ± 0.3 L, ns). Also, CV reduction is observed in NS patients (3.6 ± 0.2 vs. 4.0 ± 0.2 L, p < 0.05), but not in S patients (4.5 ± 0.3 vs. 4.3 ± 0.3 L, ns). LC is characterized by remodeling of lung function 1 month after negative swab. In NS patients, this is accompanied by structural changes, prevented in S patients. Our data support the importance of PA in the prevention and treatment of LC outcomes.
118	L115		Iqbal, Nousheen, Iffat Khanum, Muhammad Ali Ibrahim Kazi, Syeda Urooj Riaz, Uzzam Ahmed Khawaja, Safia Awan, Muhammad Irfan, Ali Bin Sarwar Zubairi, and Javaid Ahmed Khan	Post COVID-19 sequelae of the respiratory system. A single center experience reporting the compromise of the airway, alveolar and vascular components	https://doi.org/10.4081/monaldi.2022.2412	Published	October 11, 2022	Study	https://www.monaldi-archives.org/index.php/macd/article/view/2412	The long-term sequelae of COVID-19 have now become more common and appreciable. The SARS-CoV-2 virus can cause a variety of infectious and non-infectious pulmonary complications. The purpose of this study is to raise awareness about post-COVID-19 pulmonary sequelae, both infectious and non-infectious, in this geographical area. A retrospective study was conducted from July 1st 2020 to December 20th 2020. A total of 1200 patients were evaluated, with 83 suffering from post-COVID-19 pulmonary complications. The patients' mean age was 62 years (IQR 55-69), with 63 (75.9%) being male. The most common co-morbid illnesses were hypertension (49, 59%) and diabetes (45, 54.2%). The majority of them (37, 44.6%) had severe COVID-19, followed by critical COVID-19 (33, 39.8%). There was no statistically significant difference in recurrence of respiratory symptoms or duration of current illness between non-severe, severe, and critical COVID-19 patients. Non-infectious complications were observed in the majority of patients (n=76, 91.5%), including organizing pneumonia/ground glass opacities in 71 (88%) patients, fibrosis in 44 (55%), pulmonary embolism in 10 (12.5%), pneumomediastinum in 6 (7.4%) and pneumothorax in 7 (8.6%). Infective complications (25, 30.1%) included aspergillus infection in 10 (12.0%) and bacterial infection in 5 (8.47%), with more gram-negative infections and one patient developing Mycobacterium tuberculosis. Post COVID-19 mortality was 11 (13.3%). The long-term pulmonary sequelae of COVID-19 are not rare. Cryptogenic organizing pneumonia, ground glass opacities, and fibrosis were common post-COVID-19 sequelae in our patients. This necessitates frequent close monitoring of these patients in order to initiate early appropriate management and prevent further morbidity and eventual mortality.
119	L116		Udwadia, Zarir F.1; Pawar, Unmesha Prakash2; Nanda, Viral Jayshinh2	Severe interstitial lung disease persisting 2 years post-COVID-19 despite anti-fibrotic therapy	https://doi.org/10.4103/lungindia.lungindia_355_22	Published	Oct 25, 2022	Case Report	https://journals.lww.com/lungindia/Fulltext/2022/11000/Severe_interstitial_lung_disease_persisting_2.17.aspx	This case is presented to highlight the fact that not all patients with COVID pneumonia resolve over time and persistent fibrosis and established severe ILD may be a long-term sequel in some patients. It emphasizes that careful serial follow-up of all such patients is needed till they reach stable lung function. It also suggests that antifibrotics may not have a specific role and till the results of large trials emerge their routine use in the anticipation that they will prevent fibrosis may need to be reconsidered. A recent study shed mechanistic insight and suggests pulmonary PASC is driven by inflammatory cytokines produced by activated SARS CoV-2 specific T cells. These patients also demonstrated 6–105 fold increased frequency of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) producing SARS CoV-2 specific cluster of differentiation-4 (CD4) and CD8 T cells which also co-related with the decline in PFT.[1]
120	L117		ÖzgürBostancıaEmreKaradumanaYunusÇolakbcAli KerimYılmazaMenderesKabadayıaSaitBilgiç	Respiratory muscle strength and pulmonary function in unvaccinated athletes before and after COVID-19 infection: A prospective cohort study	https://doi.org/10.1016/j.resp.2022.103983	Published	11 November 2022	Study	https://www.sciencedirect.com/science/article/pii/S1569904822001422	Highlights •Athletes with COVID-19 infection report fatigue, muscle/joint pain, and headache as the most frequent symptoms, whereas dyspnoea and cough are less reported. •COVID-19 decreases respiratory muscle strength and pulmonary function in unvaccinated athletes despite reporting few respiratory symptoms. •Athletes may need a longer recovery time before being able to return to training and competition. Abstract Purpose We investigated abnormalities and recovery in respiratory function after COVID-19 infection in an unvaccinated elite athlete population. Methods Measurements included maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and peak expiratory flow (PEF). Results The most frequent reported symptoms were fatigue with 80% and muscle/joint pain and headache with 50%, whereas only 10% reported dyspnoea and 30% cough. During follow-up, MIP was up to 13% and MEP up to 8% lower following COVID-19 infection. Likewise, FEV1 was up to 2% and FVC up to 5% lower. While MEP and FEV1 rapidly normalised, MIP and FVC still remained abnormal after 52 days of COVID-19 infection, thereby leading to a restrictive ventilatory pattern. PEF seemed unaffected during follow-up. Conclusions COVID-19 decreases respiratory function in unvaccinated athletes despite reporting few respiratory symptoms and having mild disease. An initiative aimed at reducing the long-term adverse effects following COVID-19 infection seems warranted, which perhaps may be avoided through vaccination.
121	L118		André F. Rendeiro, View ORCID ProfileHiranmayi Ravichandran, View ORCID ProfileJunbum Kim, View ORCID ProfileAlain C. Borczuk, View ORCID ProfileOlivier Elemento, View ORCID ProfileRobert E. Schwartz	Persistent alveolar type 2 dysfunction and lung structural derangement in post-acute COVID-19	https://doi.org/10.1101/2022.11.28.22282811	pre-print	November 29, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.11.28.22282811v1.full-text	SARS-CoV-2 infection can manifest as a wide range of respiratory and systemic symptoms well after the acute phase of infection in over 50% of patients. Key questions remain on the long-term effects of infection on tissue pathology in recovered COVID-19 patients. To address these questions we performed multiplexed imaging of post-mortem lung tissue from 12 individuals who died post-acute COVID-19 (PC) and compare them to lung tissue from patients who died during the acute phase of COVID-19, or patients who died with idiopathic pulmonary fibrosis (IPF), and otherwise healthy lung tissue. We find evidence of viral presence in the lung up to 359 days after the acute phase of disease, including in patients with negative nasopharyngeal swab tests. The lung of PC patients are characterized by the accumulation of senescent alveolar type 2 cells, fibrosis with hypervascularization of peribronchial areas and alveolar septa, as the most pronounced pathophysiological features. At the cellular level, lung disease of PC patients, while distinct, shares pathological features with the chronic pulmonary disease of IPF. which may help rationalize interventions for PC patients. Altogether, this study provides an important foundation for the understanding of the long-term effects of SARS-CoV-2 pulmonary infection at the microanatomical, cellular, and molecular level.
122	L119		Stettner, Mark; Fleischer, Michael; Skoda, Eva-Maria; Teufel, Martin; Kleinschnitz, Christoph	Response Letter to Vink et al. ‘Neurological Study Does Not Provide Any Evidence that Long COVID is Psychosomatic’	https://doi.org/10.1016/j.mri.2022.12.002	Published	2023-02-01	Study	https://www.sciencedirect.com/science/article/pii/S0730725X22002120	Patients recovered from COVID-19 may develop long-COVID symptoms in the lung. For this patient population (post-COVID patients), they may benefit from longitudinal, radiation-free lung MRI exams for monitoring lung lesion development and progression. The purpose of this study was to investigate the performance of a spiral ultrashort echo time MRI sequence (Spiral-VIBE-UTE) in a cohort of post-COVID patients in comparison with CT and to compare image quality obtained using different spiral MRI acquisition protocols. Lung MRI was performed in 36 post-COVID patients with different acquisition protocols, including different spiral sampling reordering schemes (line in partition or partition in line) and different breath-hold positions (inspiration or expiration). Three experienced chest radiologists independently scored all the MR images for different pulmonary structures. Lung MR images from spiral acquisition protocol that received the highest image quality scores were also compared against corresponding CT images in 27 patients for evaluating diagnostic image quality and lesion identification. Spiral-VIBE-UTE MRI acquired with the line in partition reordering scheme in an inspiratory breath-holding position achieved the highest image quality scores (score range = 2.17–3.69) compared to others (score range = 1.7–3.29). Compared to corresponding chest CT images, three readers found that 81.5% (22 out of 27), 81.5% (22 out of 27) and 37% (10 out of 27) of the MR images were useful, respectively. Meanwhile, they all agreed that MRI could identify significant lesions in the lungs. The Spiral-VIBE-UTE sequence allows for fast imaging of the lung in a single breath hold. It could be a valuable tool for lung imaging without radiation and could provide great value for managing different lung diseases including assessment of post-COVID lesions.
123	L120		Laorden, Daniel; Domínguez-Ortega, Javier; Carpio, Carlos; Barranco, Pilar; Villamañán, Elena; Romero, David; Quirce, Santiago; Álvarez-Sala, Rodolfo; Camperos, Ricardo; Agrela, Isamar De; Fernández-Concha, Inés; Freund, Paul Kent Ernesto; Pavón, Jaime; Pose, Katherine	Long COVID outcomes in an asthmatic cohort and its implications for asthma control	https://doi.org/10.1016/j.rmed.2022.107092	Published	2022-12-16	Study	https://www.resmedjournal.com/article/S0954-6111(22)00357-2/fulltext	Highlights • COVID-19 infection had not an influence on asthma outcomes. • There is a potential protection of T2-asthma against acute COVID infection. • The severity of asthma was associated with worse long-term outcomes of COVID-19. The findings observed in this study help us better understand post-acute COVID-19 complications in patients with asthma. Patients with T2-asthma had less chest pain after 12 months post-COVID (OR = 0.319) (table-3). These results are consistent with previous studies, suggesting the potential protection of T2-asthma against acute COVID infection [8, 9, 10, 11]. Viral infections clearly affect asthma outcomes [[3],[8],[11]]. Interestingly, and consistent with previous papers, we have not found that COVID-19 infection had an influence on asthma outcomes at the time of observation in our investigation. Exacerbations, asthma control (measured by ACT), and lung function parameters appeared to be unaffected by COVID-19, at least in most patients (table-3). Unfortunately, we could not perform spirometry on all the study patients because of the pandemic situation. Given that the severity of acute COVID-19 was associated with the development of worse long-term outcomes of COVID-19, it is noteworthy that we found an increased risk of pneumonia in men (OR = 2.828), smokers (OR = 2.568) and subjects previously treated with ICS + LABA (OR = 3.119), it was confirmed by multivariant regression model) (table-2). In line with these findings, we have also observed a higher risk of hospitalization among patients with the same clinical characteristics: men (OR = 2), smokers (OR = 4.803) and treated with ICS + LABA (OR = 2.793). We found less risk in patients previously treated with ICS alone (OR = 0.272) than with an ICS + LABA combination (OR = 2.793), probably explained by severity of asthma in the acute phase of COVID-19, since more severe asthma has been associated with a worse prognosis [[11]]. In contrast, and, as expected, T2-asthma patients had a lower risk of acute SARS-CoV-2 pneumonia (OR = 0.320), which probably influenced the clinical presentation of prolonged COVID. The major drawback of this study is its retrospective design, in several waves of evolution of the pandemic. These circumstances make up the major limitation of the study, which is the absence of a prospective design that allows greater validation of these results. We also believe that some trends seen in our results might have been confirmed by a larger sample, which could have helped to better explore the impact of COVID-19 on asthma outcomes. However, it seems difficult to design this type of study because of the evolution of the pandemic after vaccination. Among the strengths of this study, it includes many non-vaccinated patients with asthma and COVID infection. To our knowledge, this is the first study with a longitudinal evaluation after at least 6 months from the acute infection, including data from interviews and current physical examinations that others studies do not include [[10]]. In conclusion, patients with severe asthma are at an increased risk of developing long COVID, while eosinophilic and T2-asthma could protect against complications of prolonged COVID.
124	L121		Jha, Manika; Gupta, Richa; Saxena, Rajiv	A Precise Method to Detect Post-COVID-19 Pulmonary Fibrosis Through Extreme Gradient Boosting	https://doi.org/10.1007/s42979-022-01526-x	Published	2022-12-13	Study	https://doi.org/10.1007/s42979-022-01526-x	The association of pulmonary fibrosis with COVID-19 patients has now been adequately acknowledged and caused a significant number of mortalities around the world. As automatic disease detection has now become a crucial assistant to clinicians to obtain fast and precise results, this study proposes an architecture based on an ensemble machine learning approach to detect COVID-19-associated pulmonary fibrosis. The paper discusses Extreme Gradient Boosting (XGBoost) and its tuned hyper-parameters to optimize the performance for the prediction of severe COVID-19 patients who developed pulmonary fibrosis after 90 days of hospital discharge. A dataset comprising Electronic Health Record (EHR) and corresponding High-resolution computed tomography (HRCT) images of chest of 1175 COVID-19 patients has been considered, which involves 725 pulmonary fibrosis cases and 450 normal lung cases. The experimental results achieved an accuracy of 98%, precision of 99% and sensitivity of 99%. The proposed model is the first in literature to help clinicians in keeping a record of severe COVID-19 cases for analyzing the risk of pulmonary fibrosis through EHRs and HRCT scans, leading to less chance of life-threatening conditions.
125	L122		Tyagi, Suresh C.; Pushpakumar, Sathnur; Sen, Utpal; Mokshagundam, Sri Prakash L.; Kalra, Dinesh K.; Saad, Mohamed A.; Singh, Mahavir	COVID-19 Mimics Pulmonary Dysfunction in Muscular Dystrophy as a Post-Acute Syndrome in Patients	https://doi.org/10.3390/ijms24010287	Published	2023-01	Review	https://www.mdpi.com/1422-0067/24/1/287	Although progressive wasting and weakness of respiratory muscles are the prominent hallmarks of Duchenne muscular dystrophy (DMD) and long-COVID (also referred as the post-acute sequelae of COVID-19 syndrome); however, the underlying mechanism(s) leading to respiratory failure in both conditions remain unclear. We put together the latest relevant literature to further understand the plausible mechanism(s) behind diaphragm malfunctioning in COVID-19 and DMD conditions. Previously, we have shown the role of matrix metalloproteinase-9 (MMP9) in skeletal muscle fibrosis via a substantial increase in the levels of tumor necrosis factor-α (TNF-α) employing a DMD mouse model that was crossed-bred with MMP9-knockout (MMP9-KO or MMP9-/-) strain. Interestingly, recent observations from clinical studies show a robust increase in neopterin (NPT) levels during COVID-19 which is often observed in patients having DMD. What seems to be common in both (DMD and COVID-19) is the involvement of neopterin (NPT). We know that NPT is generated by activated white blood cells (WBCs) especially the M1 macrophages in response to inducible nitric oxide synthase (iNOS), tetrahydrobiopterin (BH4), and tetrahydrofolate (FH4) pathways, i.e., folate one-carbon metabolism (FOCM) in conjunction with epigenetics underpinning as an immune surveillance protection. Studies from our laboratory, and others researching DMD and the genetically engineered humanized (hACE2) mice that were administered with the spike protein (SP) of SARS-CoV-2 revealed an increase in the levels of NPT, TNF-α, HDAC, IL-1β, CD147, and MMP9 in the lung tissue of the animals that were subsequently accompanied by fibrosis of the diaphragm depicting a decreased oscillation phenotype. Therefore, it is of interest to understand how regulatory processes such as epigenetics involvement affect DNMT, HDAC, MTHFS, and iNOS that help generate NPT in the long-COVID patients.
126	L123		Peroy-Badal, Renata; Sevillano-Castaño, Ana; Núñez-Cortés, Rodrigo; García-Fernández, Pablo; Torres-Castro, Rodrigo; Vilaró, Jordi; Blanco, Isabel; Gimeno-Santos, Elena	The Chester Step Test Is a Reproducible Tool to Assess Exercise Capacity and Exertional Desaturation in Post-COVID-19 Patients	https://doi.org/10.3390/healthcare11010051	Published	2023-01	Study	https://www.mdpi.com/2227-9032/11/1/51	Many people recovering from an acute episode of coronavirus disease (COVID-19) experience prolonged symptoms. Exercise testing is a feasible and cost-effective option for assessing exercise tolerance, fatigue, and dyspnea related to effort. Being that the Chester step test (CST) is a progressive, submaximal test for predicting aerobic capacity, it could be a good option to explore. This study aimed to determine the reproducibility of CST for assessing exertional desaturation and exercise capacity in patients post-COVID-19 disease. A cross-sectional study was conducted on post-COVID-19 patients. Two attempts of the CST were performed. The intraclass correlation coefficient (ICC) was used to assess agreement between the two tests. Forty-two symptomatic post-COVID-19 patients were included, the mean age was 53.8 ± 10.3 years, and 52% were female. There was no significant difference between both tests (p = 0.896). Twenty-four percent of participants (10 cases) had a clinically significant decrease in SpO2 at the first assessment, compared to 30.1% (13 cases) at the second, with no significant difference. An ICC of 0.993 (95% CI: 0.987 to 0.996) was obtained for the total number of steps in the CST.
127	L124		Altersberger, Martin; Grafeneder, Anna; Cho, Yerin; Winkler, Roland; Zwick, Ralf Harun; Mathis, Gebhard; Genger, Martin	One-Year Follow-Up Lung Ultrasound of Post-COVID Syndrome—A Pilot Study	https://doi.org/10.3390/diagnostics13010070	Published	2023-01	Study	https://www.mdpi.com/2075-4418/13/1/70	(1) Background: Millions of people worldwide were infected with COVID-19. After the acute phase of the disease, many suffer from prolonged symptoms, the post-COVID syndrome, especially the phenotype with lung residuals. Many open questions regarding lung ultrasound (LUS) have to be answered. One essential question is the means for optimal following-up of patients with post-COVID-19 residuals with LUS; (2) Methods: A retrospective data analysis of patients after acute COVID-19 infection diagnosed with post-COVID syndrome in the state hospital of Steyr and the rehabilitation center of Hochegg was performed. LUS examinations following a 12-zone scanning protocol were performed, and the LUS score quantified comet tail artifacts. A total of 16 patients were evaluated twice with LUS from May 2020 until June 2021. (3) Results: All patients’ reverberation artifacts were reduced over time. The initial LUS score of 17.75 (SD 4.84) points was decreased over the duration of the second rehabilitation to 8,2 (SD 5.94). The difference in the Wilcoxon test was significant (p < 0.001); (4) Conclusions: Lung ultrasound was a valuable tool in the follow-up of post-COVID-syndrome with lung residuals in the first wave of COVID-19. A reduction in reverberation artifacts was demonstrated. Further studies about the clinical significance have to follow.
128	L125		Siekacz, Kamil; Kumor-Kisielewska, Anna; Miłkowska-Dymanowska, Joanna; Pietrusińska, Małgorzata; Bartczak, Krystian; Majewski, Sebastian; Stańczyk, Adam; Piotrowski, Wojciech J.; Białas, Adam J.	Soluble ITGaM and ITGb2 Integrin Subunits Are Involved in Long-Term Pulmonary Complications after COVID-19 Infection	https://doi.org/10.3390/jcm12010342	Published	1/1/2023	Study	https://www.mdpi.com/2077-0383/12/1/342	(1) Introduction: The role of soluble integrins in post-COVID-19 complications is unclear, especially in long-term pulmonary lesions. The purpose of this study was to investigate the association between soluble ITGa2, ITGaM and ITGb2 integrin subunits and long COVID-19 pulmonary complications. (2) Methodology: Post-COVID-19 patients were enrolled. According to the evidence of persistent interstitial lung lesions on CT, patients were divided into a long-term pulmonary complications group (P(+)) and a control group without long-term pulmonary complications (P(−)). We randomly selected 80 patients for further investigation (40 subjects for each group). Levels of ITGa2, ITGaM and ITGb2 integrin subunits were determined by ELISA assay. (3) Results: The serum concentration of sITGaM and sITGb2 were significantly higher in the P(+) group (sITGaM 18.63 ng/mL [IQR 14.17–28.83] vs. 14.75 ng/mL [IQR 10.91–20] p = 0.01 and sITGb2 10.55 ng/mL [IQR 6.53–15.83] vs. 6.34 ng/mL [IQR 4.98-9.68] p = 0.002). We observed a statistically significant correlation between sITGaM and sITGb2 elevation in the P(+) group (R = 0.42; p = 0.01). Patients from the P(+) group had a lower (1.82 +/−0.84 G/L) lymphocyte level than the P(−)group (2.28 +/−0.79 G/L), p = 0.03. Furthermore, we observed an inverse correlation in the P(−) group between blood lymphocyte count and sITGb2 integrin subunit levels (R = −0.49 p = 0.01). (4) Conclusions: Elevated concentrations of sITGaM and sITGb2 were associated with long-term pulmonary complications in post-COVID-19 patients. Both sITGaM and sITGb2 may be promising biomarkers for predicting pulmonary complications and could be a potential target for therapeutic intervention in post-COVID-19 patients.
129	L126		Matheson, Alexander M.; McIntosh, Marrissa J.; Kooner, Harkiran K.; Abdelrazek, Mohamed; Albert, Mitchell S.; Dhaliwal, Inderdeep; Nicholson, J. Michael; Ouriadov, Alexei; Svenningsen, Sarah; Parraga, Grace	Longitudinal follow-up of postacute COVID-19 syndrome: DLCO, quality-of-life and MRI pulmonary gas-exchange abnormalities	https://doi.org/10.1136/thorax-2022-219378	Published	1/3/2023	Study	https://thorax.bmj.com/content/early/2023/01/03/thorax-2022-219378	129Xe MRI red blood cell to alveolar tissue plasma ratio (RBC:TP) abnormalities have been observed in ever-hospitalised and never-hospitalised people with postacute COVID-19 syndrome (PACS). But, it is not known if such abnormalities resolve when symptoms and quality-of-life scores improve. We evaluated 21 participants with PACS, 7±4 months (baseline) and 14±4 months (follow-up) postinfection. Significantly improved diffusing capacity of the lung for carbon monoxide (DLCO, Δ=14%pred ;95%CI 7 to 21, p<0.001), postexertional dyspnoea (Δ=−0.7; 95%CI=−0.2 to –1.2, p=0.019), St George’s Respiratory Questionnaire-score (SGRQ Δ=−6; 95% CI=−1 to –11, p=0.044) but not RBC:TP (Δ=0.03; 95% CI=0.01 to 0.05, p=0.051) were observed at 14 months. DLCO correlated with RBC:TP (r=0.60, 95% CI=0.22 to 0.82, p=0.004) at 7 months. While DLCO and SGRQ measurements improved, these values did not normalise 14 months post-infection. ClinicalTrials.gov NCT04584671.
130	L127		Rusu, D.	Lésions pulmonaires cavitaires post-COVID-19	https://doi.org/10.1016/j.rmra.2022.11.116	Published	2023-01-01	Study	https://www.sciencedirect.com/science/article/pii/S1877120322002865	Introduction Les lésions pulmonaires cavitaires sont des complications rares et généralement tardives de l’infection SARS-CoV-2. La fréquence de la cavitation pulmonaire au cours de la COVID-19 reste incertaine : l’incidence a été estimée à 1,7 % parmi tous les patients traités pour la COVID-19 à l’hôpital, 3,3 % parmi les patients ayant développé pneumonie COVID-19 et jusqu’à 11 % chez les patients hospitalisés en unité de soins intensif [1], [2]. Méthodes Une série de 14 patients avec des cavitations pulmonaires post-COVID-19 a été analysée. Tous les patients ont été évalués par scanner thoracique, examen microbiologique pour confirmer une co-infection bactérienne ou fongique, ou mycobactérienne, par bronchoscopie avec BAL, examen sérologique pour Aspergillus, marqueurs immuns (ANA, ANCA), test VIH, analyses de laboratoire de routine. Résultats L’âge des patients variait entre 32 et 69 ans. Les lésions pulmonaires cavitaires étaient des complications tardives, la plupart des patients se présentant 2 mois après la COVID-19. Les principaux symptômes associés étaient dyspnée, douleurs thoraciques, toux, hémoptysie, fièvre. La cavitation pulmonaire peut survenir après la maladie COVID-19, même en cas de COVID-19 léger. Parmi les patients évalués, 6 avaient des formes sévères de COVID-19, 5 patients des formes modérées et 3 patients des formes légères. La présentation d’imagerie des cavités était diverse, mais surtout ce sont de cavités avec des parois épaisses, contenant des détritus. Chez les patients évalués, les causes des cavités pulmonaires étaient les surinfections bactériennes (Staphylococcus aureus, Pseudomonas aeruginosae) et fongiques (Aspergillus), les infections mycobactériennes (tuberculose, mycobactéries non tuberculeuses), thromboembolie pulmonaire avec infarctus, les bronchectasies, le néoplasme. Onze patients ont reçu une antibiothérapie et un traitement à la dexaméthasone pendant la COVID-19. Un mécanisme iatrogénique avec l’introduction de traitements corticoïdes pourrait favoriser les surinfections bactériennes ou fongiques et la formation d’abcès pulmonaires. Conclusion La présence de cavitation est considérée comme une manifestation atypique du COVID-19, suggérant un diagnostic alternatif. Lésions cavitaires chez les patients atteints de COVID-19 nécessite un diagnostic différentiel pour des infections superposées, des néoplasmes, des mycobactérioses, d’embolie pulmonaire, de tuberculose, des maladies fongiques, d’infarctus pulmonaire ou de maladie vasculaire thrombembolique associée à COVID-19.
131	L128		Kouri, Andrew; Gupta, Samir	Respiratory manifestations of long COVID	https://doi.org/10.1080/24745332.2022.2156407	Published	2023-01-13	Review	https://doi.org/10.1080/24745332.2022.2156407	As we near the third year of the COVID-19 pandemic, greater attention is now being paid to the potential long-term consequences of SARS-CoV-2 in the hundreds of millions of people infected globally. A syndrome termed “long COVID” has emerged, which predominantly manifests as persistent fatigue, dyspnea, chest pain, and cognitive dysfunction following acute infection. The incidence of long COVID is in the range of 15% based on current best evidence, and symptoms are likely a result of several different pathophysiological mechanisms including multi-organ injury from acute infection, systemic viral persistence, immune dysregulation, and/or autoimmunity. Pulmonary symptoms represent a significant component of long COVID, and there is a growing body of research describing the epidemiology, risk factors, physiology, and radiology of the respiratory manifestations of long COVID. In this clinical review, we examine the most recent evidence relating to “respiratory long COVID,” discuss how innovative technologies such as Xenon-129 gas transfer magnetic resonance imaging (MRI) and respiratory oscillometry are helping to elucidate its unique pathophysiology, and consider the role of preventative strategies and possible treatments such as adapted pulmonary rehabilitation. The burden of respiratory long COVID is likely to continue to grow, and all healthcare professionals who care for patients with respiratory disease must prepare for this emerging chronic condition. This will require increased resources from healthcare decision makers, inventive approaches to healthcare delivery, further research, and the same spirit of collaboration that has enabled the many success stories to date in the global effort against COVID-19.
132	L129		Krueger, Tina; van den Heuvel, Janelle; van Kampen-van den Boogaart, Vivian; van Zeeland, Roel; Mehagnoul-Schipper, D. Jannet; Barten, Dennis G.; Knarren, Lieve; Maas, Arno F. G.; Wyers, Caroline E.; Gach, Debbie; Schols, Annemie M. W. J.; Beijers, Rosanne J. H. C. G.; van den Bergh, Joop P.; van Osch, Frits H. M.	Pulmonary function three to five months after hospital discharge for COVID-19: a single centre cohort study	https://doi.org/10.1038/s41598-023-27879-8	Published	2023-01-13	Study	https://www.nature.com/articles/s41598-023-27879-8	Some COVID-19 survivors suffer from persistent pulmonary function impairment, but the extent and associated factors are unclear. This study aimed to characterize pulmonary function impairment three to five months after hospital discharge and the association with disease severity. Survivors of COVID-19 after hospitalization to the VieCuri Medical Centre between February and December 2020 were invited for follow-up, three to five months after discharge. Dynamic and static lung volumes, respiratory muscle strength and diffusion capacity were measured. The cohort comprised 257 patients after a moderate (n = 33), severe (n = 151) or critical (n = 73) COVID-19 infection with a median follow-up of 112 days (interquartile range 96–134 days). The main sequelae included reduced diffusion capacity (36%) and reduced maximal expiratory pressure (24%). Critically ill patients were more likely to have reduced diffusion capacity than moderate (OR 8.00, 95% CI 2.46–26.01) and severe cases (OR 3.74, 95% CI 1.88–7.44) and lower forced vital capacity (OR 3.29, 95% CI 1.20–9.06) compared to severe cases. Many COVID-19 survivors, especially after a critical disease course, showed pulmonary function sequelae, mainly DLCO impairments, three to five months after discharge. Monitoring is needed to investigate the persistence of these symptoms and the longer-term implications of the COVID-19 burden.
133	L130		Franco-Moreno, A.; Brown-Lavalle, D.; Campos-Arenas, M.; Rodríguez-Ramírez, N.; Muñoz-Roldán, C.; Rubio-Aguilera, A. I.; Muñoz-Rivas, N.; de Girón, J. Bascuñana-Morejón; Fernández-Vidal, E.; Palma-Huerta, E.; Estévez-Alonso, S.; Rodríguez-Gómez, B.; Manzano-Valera, S.; Pedrero-Tomé, R.; Casado-Suela, M.; Bibiano-Guillén, C.; Mir-Montero, M.; Torres-Macho, J.; Bustamante-Fermosel, A.; Moya-Mateo, E.; Mestre-Gómez, B.; Lorente-Ramos, R. M.; Rogado, J.; Obispo, B.; Salazar-Chiriboga, D.; Sáez-Vaquero, T.; Abad-Motos, A.; Cortina-Camarero, C.; Such-Díaz, A.; Ruiz-Velasco, E.; Sierra-Hidalgo, F.; de Carranza-López, M.; Herrera-Morueco, M. A.; Akasbi-Montalvo, M.; Medrano-Izquierdo, P.; Mariscal-Gómez, E.; Marín-Mori, K.; Figueras-González, C.; López-Lallave, S.; Díaz-Díaz, D.; Mauleón-Fernández, C.; Martín-Navarro, J.; Torres-Rubio, P.; Matesanz, C.; Moro-Álvarez, M. J.; Hernández-Rivas, J. A.; the Infanta Leonor Thrombosis Research Group	Acute phase characteristics and long-term complications of pulmonary embolism in COVID-19 compared to non-COVID-19 cohort: a large single-centre study	https://doi.org/10.1186/s12890-023-02323-9	Published	2023-01-18	Study	https://doi.org/10.1186/s12890-023-02323-9	Background To compare the severity of pulmonary embolism (PE) and the long-term complications between patients with and without COVID-19, and to investigate whether the tools for risk stratification of death are valid in this population. Methods We retrospectively included hospitalized patients with PE from 1 January 2016 to 31 December 2022. Comparisons for acute episode characteristics, risk stratification of the PE, outcomes, and long-term complications were made between COVID and non-COVID patients. Results We analyzed 116 (27.5%) COVID patients and 305 (72.4%) non-COVID patients. In patients with COVID-19, the traditional risk factors for PE were absent, and the incidence of deep vein thrombosis was lower. COVID patients showed significantly higher lymphocyte count, lactate dehydrogenase, lactic acid, and D-dimer levels. COVID patients had PE of smaller size (12.3% vs. 25.5% main pulmonary artery, 29.8% vs. 37.1% lobar, 44.7% vs. 29.5% segmental and 13.2% vs. 7.9% subsegmental, respectively; p < 0.001), less right ventricular dysfunction (7.7% vs. 17.7%; p = 0.007) and higher sPESI score (1.66 vs. 1.11; p < 0.001). The need for mechanical ventilation was significantly higher in COVID patients (8.6% vs. 1.3%; p < 0.001); However, the in-hospital death was less (5.2% vs. 10.8%; p = 0.074). The incidence of long-term complications was lower in COVID cohort (p < 0.001). PE severity assessed by high sPESI and intermediate and high-risk categories were independently associated with in-hospital mortality in COVID patients. Conclusion The risk of in-hospital mortality and the incidence of long-term complications were lower in COVID-19. The usual tools for risk stratification of PE are valid in COVID patients.
134	L131		Carvalho, Carlos Roberto Ribeiro; Lamas, Celina Almeida; Chate, Rodrigo Caruso; Salge, João Marcos; Sawamura, Marcio Valente Yamada; Albuquerque, André L. P. de; Junior, Carlos Toufen; Lima, Daniel Mario; Garcia, Michelle Louvaes; Scudeller, Paula Gobi; Nomura, Cesar Higa; Gutierrez, Marco Antonio; Baldi, Bruno Guedes; Group, HCFMUSP Covid-19 Study	Long-term respiratory follow-up of ICU hospitalized COVID-19 patients: Prospective cohort study	https://doi.org/10.1371/journal.pone.0280567	Published	2023-01-20	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0280567	Background Coronavirus disease (COVID-19) survivors exhibit multisystemic alterations after hospitalization. Little is known about long-term imaging and pulmonary function of hospitalized patients intensive care unit (ICU) who survive COVID-19. We aimed to investigate long-term consequences of COVID-19 on the respiratory system of patients discharged from hospital ICU and identify risk factors associated with chest computed tomography (CT) lesion severity. Methods A prospective cohort study of COVID-19 patients admitted to a tertiary hospital ICU in Brazil (March-August/2020), and followed-up six-twelve months after hospital admission. Initial assessment included: modified Medical Research Council dyspnea scale, SpO2 evaluation, forced vital capacity, and chest X-Ray. Patients with alterations in at least one of these examinations were eligible for CT and pulmonary function tests (PFTs) approximately 16 months after hospital admission. Primary outcome: CT lesion severity (fibrotic-like or non-fibrotic-like). Baseline clinical variables were used to build a machine learning model (ML) to predict the severity of CT lesion. Results In total, 326 patients (72%) were eligible for CT and PFTs. COVID-19 CT lesions were identified in 81.8% of patients, and half of them showed mild restrictive lung impairment and impaired lung diffusion capacity. Patients with COVID-19 CT findings were stratified into two categories of lesion severity: non-fibrotic-like (50.8%-ground-glass opacities/reticulations) and fibrotic-like (49.2%-traction bronchiectasis/architectural distortion). No association between CT feature severity and altered lung diffusion or functional restrictive/obstructive patterns was found. The ML detected that male sex, ICU and invasive mechanic ventilation (IMV) period, tracheostomy and vasoactive drug need during hospitalization were predictors of CT lesion severity(sensitivity,0.78±0.02;specificity,0.79±0.01;F1-score,0.78±0.02;positive predictive rate,0.78±0.02; accuracy,0.78±0.02; and area under the curve,0.83±0.01). Conclusion ICU hospitalization due to COVID-19 led to respiratory system alterations six-twelve months after hospital admission. Male sex and critical disease acute phase, characterized by a longer ICU and IMV period, and need for tracheostomy and vasoactive drugs, were risk factors for severe CT lesions six-twelve months after hospital admission.
135	L132		Zheng, Zhen; Peng, Fei; Zhou, Yong	Pulmonary fibrosis: A short- or long-term sequelae of severe COVID-19?	https://doi.org/10.1016/j.pccm.2022.12.002	Published	2023-01-23	Review	https://www.sciencedirect.com/science/article/pii/S277255882300004X	The pandemic of coronavirus disease 2019 (COVID‑19), caused by a novel severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), has caused an enormous impact on the global healthcare. SARS-CoV-2 infection primarily targets the respiratory system. Although most individuals testing positive for SARS-CoV-2 present mild or no upper respiratory tract symptoms, patients with severe COVID-19 can rapidly progress to acute respiratory distress syndrome (ARDS). ARDS-related pulmonary fibrosis is a recognized sequelae of COVID-19. Whether post-COVID-19 lung fibrosis is resolvable, persistent, or even becomes progressive as seen in human idiopathic pulmonary fibrosis (IPF) is currently not known and remains a matter of debate. With the emergence of effective vaccines and treatments against COVID-19, it is now important to build our understanding of the long-term sequela of SARS-CoV-2 infection, to identify COVID-19 survivors who are at risk of developing chronic pulmonary fibrosis, and to develop effective anti-fibrotic therapies. The current review aims to summarize the pathogenesis of COVID-19 in the respiratory system and highlights ARDS-related lung fibrosis in severe COVID-19 and the potential mechanisms. It envisions the long-term fibrotic lung complication in COVID-19 survivors, in particular in the aged population. The early identification of patients at risk of developing chronic lung fibrosis and the development of anti-fibrotic therapies are discussed.
136	L133		Carvalho, Carlos Roberto Ribeiro; Lamas, Celina Almeida; Chate, Rodrigo Caruso; Salge, João Marcos; Sawamura, Marcio Valente Yamada; Albuquerque, André L. P. de; Junior, Carlos Toufen; Lima, Daniel Mario; Garcia, Michelle Louvaes; Scudeller, Paula Gobi; Nomura, Cesar Higa; Gutierrez, Marco Antonio; Baldi, Bruno Guedes; Group, HCFMUSP Covid-19 Study	Long-term respiratory follow-up of ICU hospitalized COVID-19 patients: Prospective cohort study	https://doi.org/10.1371/journal.pone.0280567	Published	2023-01-20	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0280567	Background Coronavirus disease (COVID-19) survivors exhibit multisystemic alterations after hospitalization. Little is known about long-term imaging and pulmonary function of hospitalized patients intensive care unit (ICU) who survive COVID-19. We aimed to investigate long-term consequences of COVID-19 on the respiratory system of patients discharged from hospital ICU and identify risk factors associated with chest computed tomography (CT) lesion severity. Methods A prospective cohort study of COVID-19 patients admitted to a tertiary hospital ICU in Brazil (March-August/2020), and followed-up six-twelve months after hospital admission. Initial assessment included: modified Medical Research Council dyspnea scale, SpO2 evaluation, forced vital capacity, and chest X-Ray. Patients with alterations in at least one of these examinations were eligible for CT and pulmonary function tests (PFTs) approximately 16 months after hospital admission. Primary outcome: CT lesion severity (fibrotic-like or non-fibrotic-like). Baseline clinical variables were used to build a machine learning model (ML) to predict the severity of CT lesion. Results In total, 326 patients (72%) were eligible for CT and PFTs. COVID-19 CT lesions were identified in 81.8% of patients, and half of them showed mild restrictive lung impairment and impaired lung diffusion capacity. Patients with COVID-19 CT findings were stratified into two categories of lesion severity: non-fibrotic-like (50.8%-ground-glass opacities/reticulations) and fibrotic-like (49.2%-traction bronchiectasis/architectural distortion). No association between CT feature severity and altered lung diffusion or functional restrictive/obstructive patterns was found. The ML detected that male sex, ICU and invasive mechanic ventilation (IMV) period, tracheostomy and vasoactive drug need during hospitalization were predictors of CT lesion severity(sensitivity,0.78±0.02;specificity,0.79±0.01;F1-score,0.78±0.02;positive predictive rate,0.78±0.02; accuracy,0.78±0.02; and area under the curve,0.83±0.01). Conclusion ICU hospitalization due to COVID-19 led to respiratory system alterations six-twelve months after hospital admission. Male sex and critical disease acute phase, characterized by a longer ICU and IMV period, and need for tracheostomy and vasoactive drugs, were risk factors for severe CT lesions six-twelve months after hospital admission.
137	L134		Núñez-Fernández, Marta; Ramos-Hernández, Cristina; García-Río, Francisco; Pérez-González, Alexandre; Tilve-Gómez, Amara; Rodríguez-Fernández, Paula; Nodar-Germiñas, Andrés; Fernández-García, Alberto; Ruano-Raviña, Alberto; Fernández-Villar, Alberto	Evolution and long‑term respiratory sequelae after severe COVID-19 pneumonia: nitric oxide diffusion measurement value	https://doi.org/10.1186/s12931-023-02344-2	Published	2023-02-13	Study	https://doi.org/10.1186/s12931-023-02344-2	Introduction There are no published studies assessing the evolution of combined determination of the lung diffusing capacity for both nitric oxide and carbon monoxide (DLNO and DLCO) 12 months after the discharge of patients with COVID-19 pneumonia. Methods Prospective cohort study which included patients who were assessed both 3 and 12 months after an episode of SARS-CoV-2 pneumonia. Their clinical status, health condition, lung function testings (LFTs) results (spirometry, DLNO-DLCO analysis, and six-minute walk test), and chest X-ray/computed tomography scan images were compared. Results 194 patients, age 62 years (P25–75, 51.5–71), 59% men, completed the study. 17% required admission to the intensive care unit. An improvement in the patients’ exercise tolerance, the extent of the areas of ground-glass opacity, and the LFTs between 3 and 12 months following their hospital discharge were found, but without a decrease in their degree of dyspnea or their self-perceived health condition. DLNO was the most significantly altered parameter at 12 months (19.3%). The improvement in DLNO-DLCO mainly occurred at the expense of the recovery of alveolar units and their vascular component, with the membrane factor only improving in patients with more severe infections. Conclusions The combined measurement of DLNO-DLCO is the most sensitive LFT for the detection of the long-term sequelae of COVID-19 pneumonia and it explain better their pathophysiology.
138	L135		Kooner, Harkiran K; McIntosh, Marrissa J; Matheson, Alexander M; Abdelrazek, Mohammed; Albert, Mitchell S; Dhaliwal, Inderdeep; Kirby, Miranda; Ouriadov, Alexei; Santyr, Giles E; Venegas, Carmen; Radadia, Nisarg; Svenningsen, Sarah; Nicholson, J Michael; Parraga, Grace	Post-Acute COVID-19 Syndrome: 129Xe MRI Ventilation Defects and Respiratory Outcomes One Year Later	https://doi.org/10.1148/radiol.222557	Published	2023-02-07	Study	https://pubs.rsna.org/doi/10.1148/radiol.222557	Background In people with post-acute COVID-19 syndrome (PACS) and normal pulmonary function, 129Xe MRI ventilation defects, abnormal quality-of-life scores, and exercise limitation were reported 3-months after infection; the longitudinal trajectory remains unclear. Purpose To measure and compare pulmonary function, exercise capacity, quality-of-life, and 129Xe MRI ventilation defect percent (VDP) in people with PACS evaluated 3- and 15-months post-infection. Materials and Methods In this prospective study, participants with PACS aged 18-80 years were enrolled between July 2020 and August 2021 from two quaternary care centers. They were evaluated 3-months and 15-months post-infection for: 129Xe MRI VDP, diffusing capacity of the lung for carbon monoxide (DLCO), spirometry, oscillometry, six-minute walk distance (6MWD), and St. George's Respiratory Questionnaire (SGRQ). Differences between time-points were evaluated using paired t-tests. Multivariable models were generated to explain exercise capacity and quality-of-life improvements. Odds ratios (OR) were used to evaluate potential treatment influences. Results Fifty-three participants (mean age, 55 years ±18[SD]; 26 male; 27 female) attended both 3- and 15-month visits and were included in analysis. 129Xe MRI VDP (5.4%, 4.2%; P=.003), forced expiratory volume in 1-second (85%pred, 90%pred; P=.001), DLCO (89%pred, 99%pred; P=.002) and SGRQ (35, 25; P<.001) improved between the 3- and 15-month visit. VDP measured at 3- months post-COVID predicted the change in 6MWD (β=-.643, P=.001) while treatment with respiratory medication at 3-months predicted improved 15-month quality-of-life score (OR=4.0; 95%CI:1.2,13.8, P=.03). Conclusion Pulmonary function, gas-exchange, exercise capacity, quality-of-life, and 129Xe MRI ventilation defect percent (VDP) improved in participants with post-acute COVID-19 syndrome evaluated at 15-months as compared to 3-months post-infection. VDP measured at 3-months post-infection correlated with improved exercise capacity, whilst treatment with respiratory medication was associated with improved quality-of-life score at 15-months post-infection. Clinical Trial Registration: www.clinicaltrials.gov NCT05014516 See also the editorial by Vogel-Claussen in this issue.
139	L136		Lalwani, Muskan; Taksande, Avinash B.; Mukku3652008@gmail.com, Muskan; Taksande, Avinash B.	Pulmonary Function Test as a Diagnostic Tool for Post-COVID-19 Effects	https://doi.org/10.7759/cureus.34751	Published	2023-02-07	Review	https://www.cureus.com/articles/116773-pulmonary-function-test-as-a-diagnostic-tool-for-post-covid-19-effects	COVID-19-infected survivors are reporting persistent anomalies upon hospital discharge. After one year, a sizable percentage of COVID-19 survivors still have persistent symptoms affecting different bodily systems. Evidence suggests that the lungs are the most affected organs by COVID-19. It may also cause corollary and other medical issues. The literature on preceding COVID-19 infections reviews that patients may also experience chronic impairment in breathing characteristics after discharge. The outcome of COVID-19 may remain for weeks to months after the initial recovery. Our goal is to determine the superiority of the restrictive pattern, obstructive pattern, and adjusted diffusion in patients post-COVID-19 contamination and to explain the distinctive opinions of breathing characteristics used with those patients. Therefore, lung function tests were measured post-discharge for three to 12 months. According to estimates, 80% of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-infected patients experienced one or more chronic symptoms. Multidisciplinary teams are required to develop preventive measures, rehabilitation methods, and scientific control plans with a completely patient-centered attitude for long-term COVID-19 care. Clarifying the pathophysiologic mechanisms, creating and testing specific interventions, and treating patients with long-term COVID-19 are urgently needed. The goal of this review is to locate research evaluating COVID-19's long-term effects. A person who has suffered from COVID-19 in the past showed changes in their pulmonary function test. So, we have to notice the changes and recovery from post-COVID-19 effects. COVID-19 survivors were observed in an eventual observational study and continuously examined three, six, and 12 months after having COVID-19 infections. We evaluated the clinical features and concentrations of circulating pulmonary epithelial and endothelial markers in COVID-19 survivors with normal or lower diffusion capacity for carbon monoxide (DLCO) six months after discharge to analyze risk factors and underlying pathophysiology.
140	L137		Bazdar, Somayeh; Kwee, Anastasia K. A. L.; Houweling, Laura; de Wit-van Wijck, Yolanda; Mohamed Hoesein, Firdaus A. A.; Downward, George S.; Nossent, Esther J.; Maitland-van der Zee, Anke H.	A Systematic Review of Chest Imaging Findings in Long COVID Patients	https://doi.org/10.3390/jpm13020282	Published	2023-02-01	Review	https://www.mdpi.com/2075-4426/13/2/282	Long COVID is the persistence of one or more COVID-19 symptoms after the initial viral infection, and there is evidence supporting its association with lung damage. In this systematic review, we provide an overview of lung imaging and its findings in long COVID patients. A PubMed search was performed on 29 September 2021, for English language studies in which lung imaging was performed in adults suffering from long COVID. Two independent researchers extracted the data. Our search identified 3130 articles, of which 31, representing the imaging findings of 342 long COVID patients, were retained. The most common imaging modality used was computed tomography (CT) (N = 249). A total of 29 different imaging findings were reported, which were broadly categorized into interstitial (fibrotic), pleural, airway, and other parenchymal abnormalities. A direct comparison between cases, in terms of residual lesions, was available for 148 patients, of whom 66 (44.6%) had normal CT findings. Although respiratory symptoms belong to the most common symptoms in long COVID patients, this is not necessarily linked to radiologically detectable lung damage. Therefore, more research is needed on the role of the various types of lung (and other organ) damage which may or may not occur in long COVID.
141	L138		Björsell, Tove; Sundh, Josefin; Lange, Anna; Ahlm, Clas; Forsell, Mattias N.E.; Tevell, Staffan; Blomberg, Anders; Edin, Alicia; Normark, Johan; Cajander, Sara	Risk factors for impaired respiratory function post COVID-19: A prospective cohort study of nonhospitalized and hospitalized patients	https://doi.org/10.1111/joim.13614	Published	2023-02-23	Study	https://onlinelibrary.wiley.com/doi/abs/10.1111/joim.13614	Background Severe COVID-19 increases the risk for long-term respiratory impairment, but data after mild COVID-19 are scarce. Our aims were to determine risk factors for reduced respiratory function 3–6 months after COVID-19 infection and to investigate if reduced respiratory function would relate to impairment of exercise performance and breathlessness. Methods Patients with COVID-19 were enrolled at the University Hospitals of Umeå and Örebro, and Karlstad Central Hospital, Sweden. Disease severity was defined as mild (nonhospitalized), moderate (hospitalized with or without oxygen treatment), and severe (intensive care). Spirometry, including diffusion capacity (DLCO), was performed 3–6 months after hospital discharge or study enrollment (for nonhospitalized patients). Breathlessness (defined as ≥1 according to the modified Medical Research Council scale) and functional exercise capacity (1-min sit-to-stand test; 1-MSTST) were assessed. Results Between April 2020 and May 2021, 337 patients were enrolled in the study. Forced vital capacity and DLCO were significantly lower in patients with severe COVID-19. Among hospitalized patients, 20% had reduced DLCO, versus 4% in nonhospitalized. Breathlessness was found in 40.6% of the participants and was associated with impaired DLCO. A pathological desaturation or heart rate response was observed in 17% of participants during the 1-MSTST. However, this response was not associated with reduced DLCO. Conclusion Reduced DLCO was the major respiratory impairment 3–6 months following COVID-19, with hospitalization as the most important risk factor. The lack of association between impaired DLCO and pathological physiological responses to exertion suggests that these physiological responses are not primarily related to decreased lung function.
142	L139		Cui, Lu; Fang, Zhuoqing; De Souza, Cristabelle Madona; Lerbs, Tristan; Guan, Yuan; Li, Irene; Charu, Vivek; Chen, Shih-Yu; Weissman, Irving; Wernig, Gerlinde	Innate immune cell activation causes lung fibrosis in a humanized model of long COVID	https://doi.org/10.1073/pnas.2217199120	Published	2023-03-07	Study	https://www.pnas.org/doi/full/10.1073/pnas.2217199120	Significance Post COVID-19 induced pulmonary fibrosis is the most severe of a number of clinical symptoms associated with “long COVID”, a condition which is currently incompletely understood but affects millions given the ongoing COVID-19 pandemic. Using systems biology and mechanistic studies in a humanized mouse model of COVID lung fibrosis, we identify the essential genetic and immunologic perturbations occurring in patients with long COVID lung fibrosis and reveal promising therapeutic targets. Abstract COVID-19 remains a global pandemic of an unprecedented magnitude with millions of people now developing “COVID lung fibrosis.” Single-cell transcriptomics of lungs of patients with long COVID revealed a unique immune signature demonstrating the upregulation of key proinflammatory and innate immune effector genes CD47, IL-6, and JUN. We modeled the transition to lung fibrosis after COVID and profiled the immune response with single-cell mass cytometry in JUN mice. These studies revealed that COVID mediated chronic immune activation reminiscent to long COVID in humans. It was characterized by increased CD47, IL-6, and phospho-JUN (pJUN) expression which correlated with disease severity and pathogenic fibroblast populations. When we subsequently treated a humanized COVID lung fibrosis model by combined blockade of inflammation and fibrosis, we not only ameliorated fibrosis but also restored innate immune equilibrium indicating possible implications for clinical management of COVID lung fibrosis in patients. publisher: Proceedings of the National Academy of Sciences
143	L140		Mulet, Alba; Tarrasó, Julia; Rodríguez-Borja, Enrique; Carbonell-Asins, Juan A; Lope-Martínez, Amaia; Martí-Martinez, Arancha; Murria, Rosa; Safont, Belén; Fernandez-Fabrellas, Estrella; Ros, José A; Rodriguez-Portal, Juan A; Andreu, Ada L; Soriano, Joan B.; Signes-Costa, Jaime	Fibrosis Biomarkers in a Cohort of COVID-19 Patients One Year after Hospital Discharge	https://doi.org/10.1165/rcmb.2022-0474OC	Published	2023-02-27	Study	https://www.atsjournals.org/doi/abs/10.1165/rcmb.2022-0474OC	Beyond the acute infection of coronavirus disease (COVID-19), concern has arisen about long-term effects of SARS-CoV-2 infection. The aim of our study was to analyze if there is any biomarker of fibrogenesis in COVID-19 pneumonia patients capable of predicting post-COVID pulmonary sequelae. We conducted a multicenter, prospective, observational cohort study of patients admitted to hospital with bilateral COVID-19 pneumonia. We classified patients in two groups according to severity, and blood samples to measure MMP1, MMP7, periostin and VEGF, respiratory function tests and HRCT imaging were obtained at 2 and 12 months after hospital discharge. A total of 135 patients were evaluated at 12 months. Median age was 61 (IQR: 19) years and 58.5% were men. We found between-group differences in age, radiological involvement, length of hospital stay and inflammatory laboratory parameters. Differences were found between 2 and 12 months in all functional tests, including improvements in FVC% (98.0 vs. 103.9; p=0.001) and DLCO<80% (60.9% vs. 39.7%; p=0.001). At 12 months, 63% of patients had complete HRTC resolution, but fibrotic changes persisted in 29.4%. Biomarker analysis demonstrated differences at 2 months in periostin (ng/mL) (0.8893 vs. 1.437; p<0.001) and MMP-7 (ng/mL) (8.7249 vs. 15.2181; p<0.001). No differences were found at 12 months. In multivariable analysis, only 2-month periostin was associated with 12-month fibrotic changes (OR: 1.0013 95% CI: 1.0006–1.00231; p=0.003) and 12-month DLCO impairment (OR: 1.0006 95% CI: 1.0000–1.0013; p=0.047). Our data suggest that early periostin post-discharge could predict the presence of fibrotic pulmonary changes.
144	L141		Kewalramani, Namrata; Heenan, Kerri-Marie; McKeegan, Denise; Chaudhuri, Nazia	Post-COVID Interstitial Lung Disease—The Tip of the Iceberg	https://doi.org/10.1016/j.iac.2023.01.004	Published	2023-03-03	Review	https://www.immunology.theclinics.com/article/S0889-8561(23)00004-8/fulltext	Key points •Some patients have persistent symptoms, lung function impairment, and radiological abnormalities post-severe acute respiratory syndrome coronavirus 2 infection. •Post-COVID-fibrotic changes have shown resolution at 12 months, however, in a cohort of patients, the changes persist. •The long-term impact of post-COVID fibrosis remains unknown and ongoing studies are aimed at assessing the frequency and consequences of this new disease entity. •Post-COVID interstitial lung disease may represent a significant burden on the health care systems. Introduction On the March 11, 2020, the World Health Organization (WHO) declared the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a global pandemic, commonly referred to as coronavirus 2019 (COVID-19).1 The first documented case was recognized in Wuhan, China, in December 2019.2 As of November 2022, there have been over 550 million cases worldwide and over 6 million deaths associated with COVID-19.3 The spectrum of presentations and symptoms of COVID-19 can vary widely from asymptomatic carriers to life-threatening respiratory and multi-organ failure. The risk factors for the severity of COVID-19 are thought to correlate with increasing age, body mass index (BMI), and comorbidities such as diabetes, obesity, cardiovascular disease, hypertension, and chronic kidney disease.4, 5, 6, 7 The widespread collaborative efforts of governments, public health, pharmaceutical industry, and researchers have led to a wealth of expertise in tackling the pandemic over a relatively short time. We have effective therapies that can reduce the symptom burden and risk of hospitalization and in-hospital mortality with COVID-19. Antivirals, monoclonal antibodies, and immunomodulatory drugs have emerged through robust trials as treatments for SARS-CoV-2 infection.8,9 Several therapies have been shown to reduce the risk of hospitalization in patients with mild to moderate disease. Treatment of symptomatic COVID-19 with Paxlovid, a SARS-CoV-2 protease inhibitor consisting of nirmatrelvir and ritonavir, has led to a reduction of severe COVID-19 by 89%, without evident safety concerns.10 In non-hospitalized patients with mild to moderate COVID-19 disease, Molnupiravir reduces the risk of hospitalization or death by approximately 50%.11, 12, 13 Coupled with the rollout of mass vaccination programs worldwide, we have seen the mortality from COVID-19 declining despite continued high rates of infection.14,15 Although we are grappling with the changing nature of the virus and attempting to rebuild our lives and economies, we are now faced with an emerging yet unquantifiable health epidemic –post-COVID-19 condition (long COVID). This review will discuss the emerging evidence for the development of post-COVID interstitial lung disease (PC-ILD) focusing on the pathophysiological mechanisms, incidence, diagnosis, and impact of this potentially new and emerging respiratory disease. publisher: Elsevier
145	L142		Barash, Mark; Ramalingam, Vijaya	Post-COVID Interstitial Lung Disease and Other Lung Sequelae	https://doi.org/10.1016/j.ccm.2022.11.019	Published	2023-03-03	Review	https://www.chestmed.theclinics.com/article/S0272-5231(22)00135-6/fulltext	Key points •Post-acute sequelae of SARS-COV-2 or post-COVID conditions are a poorly defined syndrome, possibly with long-lasting effects. •Respiratory failure is one of the most serious complications of COVID-19 infection and contributes to major morbidity and mortality. •Several studies have demonstrated abnormal lung function tests and radiological findings in patients who recovered from COVID-19 infection. •Evidence on post-COVID pulmonary fibrosis is evolving. Introduction Respiratory failure is one of the most serious complications of COVID-19 infection and contributes to significant morbidity and mortality. Illness severity ranges from mild/asymptomatic disease to critical illness requiring mechanical ventilation. There has been increasing concern about pulmonary sequelae, including symptoms, pulmonary function testing (PFT) abnormalities, and pulmonary fibrosis.1 Our knowledge about the natural history of recovery after COVID-19 infection is limited. This article focuses on two concepts. First, the authors seek to describe available knowledge of post-COVID lung disease including pulmonary physiologic changes, imaging characteristics, fibrotic lung disease, and other complications. Next, the authors discuss the post-acute sequelae of SARS-CoV-2 (PASC): a poorly understood syndrome comprising a conglomerate of “head-to-toe” symptoms that afflicts a subset of patients recovering from COVID-19. publisher: Elsevier
146	L143		Grewal, Japnam S.; Carlsten, Christopher; Johnston, James C.; Shah, Aditi S.; Wong, Alyson W.; Ryerson, Christopher J.	Post-COVID dyspnea: prevalence, predictors, and outcomes in a longitudinal, prospective cohort	https://doi.org/10.1186/s12890-023-02376-w	Published	2023-03-13	Study	https://doi.org/10.1186/s12890-023-02376-w	Background The pathophysiology, evolution, and associated outcomes of post-COVID dyspnea remain unknown. The aim of this study was to determine the prevalence, severity, and predictors of dyspnea 12 months following hospitalization for COVID-19, and to describe the respiratory, cardiac, and patient-reported outcomes in patients with post-COVID dyspnea. Methods We enrolled a prospective cohort of all adult patients admitted to 2 academic hospitals in Vancouver, Canada with PCR-confirmed SARS-CoV-2 during the first wave of COVID between March and June 2020. Dyspnea was measured 3, 6, and 12 months after initial symptom onset using the University of California San Diego Shortness of Breath Questionnaire. Results A total of 76 patients were included. Clinically meaningful dyspnea (baseline score > 10 points) was present in 49% of patients at 3 months and 46% at 12 months following COVID-19. Between 3 and 12 months post-COVID-19, 24% patients had a clinically meaningful worsening in their dyspnea, 49% had no meaningful change, and 28% had a clinically meaningful improvement in their dyspnea. There was worse sleep, mood, quality of life, and frailty in patients with clinically meaningful dyspnea at 12 months post-COVID infection compared to patients without dyspnea. There was no difference in PFT findings, troponin, or BNP comparing patients with and without clinically meaningful dyspnea at 12 months. Severity of dyspnea and depressive symptoms at 3 months predicted severity of dyspnea at 12 months. Conclusions Post-COVID dyspnea is common, persistent, and negatively impacts quality of life. Mood abnormalities may play a causative role in post-COVID dyspnea in addition to potential cardiorespiratory abnormalities. Dyspnea and depression at initial follow-up predict longer-term post-COVID dyspnea, emphasizing that standardized dyspnea and mood assessment following COVID-19 may identify patients at high risk of post-COVID dyspnea and facilitating early and effective management.
147	L144		Rai, Deependra K.; Sharma, Priya; Karmakar, Saurabh; Thakur, Somesh; Ameet, H.; Yadav, Rajesh; Gupta, Vatsal B.	Approach to post COVID-19 persistent cough: A narrative review	https://doi.org/10.4103/lungindia.lungindia_250_22	Published	2023-04-01	Review	https://journals.lww.com/lungindia/Fulltext/2023/03000/Approach_to_post_COVID_19_persistent_cough__A.10.aspx	A large proportion of patients who completely recovered from acute coronavirus disease 2019 (COVID-19) infection later continued to experience symptoms even after recovery, irrespective of the severity of the disease. Various terms with varying duration were used for those who had persistent symptoms, of which cough was the most common. We systematically searched the published literature concerning post-COVID-19 cough, its prevalence, and the potential ways to reduce it in clinical practice. The aim of this review was to provide an overview of existing literature concerning post-COVID-19 cough. Literature shows that augmented cough reflex sensitivity is responsible for persistent cough after acute viral upper respiratory infection (URI). Overall, the heightened cough reflex associated with SARSCoV2 induces neurotropism, neuroinflammation, and neuroimmunomodulation via the vagal sensory nerves. Therapies for post-COVID-19 cough aim at the suppression of cough reflex. For a patient who does not respond to early symptomatic treatment, Inhaled corticosteroids can be given a trial to suppress airway inflammation. More trials of novel cough therapies in patients with post-COVID-19 cough using various outcome measures need to be studied in future research. Several agents are currently available for symptomatic relief. However, non-response or refractory cough continues to preclude adequate symptom relief.
148	L145		Hamdy, Rehab M.; Abdelaziz, Ola Hassan; Shamsseldain, Hager Elsayed; Eltrawy, Heba H.	Functional outcomes in post Covid-19 patients with persistent dyspnea: multidisciplinary approach	https://doi.org/10.1007/s10554-023-02819-9	Published	2023-03-06	Study	https://doi.org/10.1007/s10554-023-02819-9	Background: Post-acute sequelae of SARS-CoV-2 (PASC) have emerged as a major health issue in patients who have previously been infected with Covid-19 virus. Purpose: we aimed at the assessment of functional outcomes in post Covid-19 patients with persistent dyspnea using a multidisciplinary approach including clinical assessment, laboratory investigations, exercise ECG, and different echo-Doppler modalities, including left atrial functions. Methods: The current observational randomized controlled study conducted on 60- patients one month after recovery from Covid-19 infection presented with persistent dyspnea compared to 30 healthy volunteers. All participants were subjected to evaluation of dyspnea by different scores, laboratory investigations, stress ECG, and echo-Doppler examination to measure LV dimensions, volumes, systolic and diastolic functions by M-mode, 2D, and tissue Doppler imaging in addition to 2-D speckle tacking LA strain. Results: Post Covid-19 patients had persistent elevation of inflammatory markers, low functional capacity (evidenced by a higher NYHA class, m MRC score, PCFS scale) and decreased METs by stress ECG compared to control group. Post Covid-19 patients showed LV diastolic dysfunction and impairment of 2D-STE LA functions compared to control group. We found negative correlations between LA strain with NYHA class, mMRC scale, LAVI, ESR and CRP; meanwhile, there were significant positive correlations between LA strain with exercise duration and METs. Conclusion: post Covid patients presented with persistent dyspnea demonstrated low functional capacity evidenced by different scores and stress ECG. Moreover, patients with post Covid syndrome showed elevated inflammatory biomarkers, LV diastolic dysfunction in addition to impaired LA strain functions. Impairment of LA strain was closely correlated to different functional scores, inflammatory biomarkers, exercise duration, and METs suggesting that these could to be the possible etiologies for the persistence of post Covid symptoms.
149	L146		Fesu, Dorottya; Polivka, Lorinc; Barczi, Eniko; Foldesi, Marcell; Horvath, Gabor; Hidvegi, Edit; Bohacs, Aniko; Muller, Veronika	Post-COVID interstitial lung disease in symptomatic patients after COVID-19 disease	https://doi.org/10.1007/s10787-023-01191-3	Published	2023-03-24	Study	https://doi.org/10.1007/s10787-023-01191-3	COVID-19 is often associated with long-lasting pulmonary symptoms. Data are scarce about interstitial lung disease (ILD) in patients following COVID-19 hospitalization with persistent symptoms. We retrospectively reviewed all cases sent to pulmonary post-COVID evaluation due to persistent symptoms between February 2021 and February 2022 (N = 318). All patients with suspected ILD (N = 44) were reviewed at the multidisciplinary discussion. Patient characteristics, symptoms, time since hospitalization, detailed lung function measurements and 6-min walk test (6MWT) were evaluated. The post-COVID ILD suspected group included more men (68.2 vs. 31.8%) with significantly older age compared to the control group (64.0 ± 12.3 vs. 51.3 ± 14.9 years). Most patient needed hospital care for COVID-19 pneumonia (68.6% of all patients and 84.1% of ILD suspected group) and average time since hospitalization was 2.4 ± 2.3 months. Persisting symptoms included fatigue (34%), dyspnoea (25.2%), cough (22.6%), and sleep disorders (insomnia 13.2%; sleepiness 8.2%). Post-COVID ILD presented more often with new symptoms of cough and sleepiness. Functional impairment, especially decreased walking distance and desaturation during 6-min walk test (6MWT) were detected in the ILD-suspected group. Respiratory function test in the post-COVID ILD group showed slight restrictive ventilatory pattern (FVC: 76.7 ± 18.1%, FEV1: 83.5 ± 19.1%, TLC: 85.6 ± 28.1%) and desaturation during 6MWT were detected in 41% of patients. LDCT changes were mainly ground glass opacities (GGO) and/or reticular abnormalities in most cases affecting < 10% of the lungs. Our data indicate that suspected post-COVID ILD is affecting 13.8% of symptomatic patients. High resolution chest CT changes were mainly low extent GGO/reticulation, while long-term lung structural changes need further evaluation.
150	L147		Patrucco, Filippo; Solidoro, Paolo; Gavelli, Francesco; Apostolo, Daria; Bellan, Mattia	Idiopathic Pulmonary Fibrosis and Post-COVID-19 Lung Fibrosis: Links and Risks	https://doi.org/10.3390/microorganisms11040895	Published	2023-04-01	Review	https://www.mdpi.com/2076-2607/11/4/895	Idiopathic pulmonary fibrosis (IPF) is considered the paradigmatic example of chronic progressive fibrosing disease; IPF does not result from a primary immunopathogenic mechanism, but immune cells play a complex role in orchestrating the fibrosing response. These cells are activated by pathogen-associated or danger-associated molecular patterns generating pro-fibrotic pathways or downregulating anti-fibrotic agents. Post-COVID pulmonary fibrosis (PCPF) is an emerging clinical entity, following SARS-CoV-2 infection; it shares many clinical, pathological, and immune features with IPF. Similarities between IPF and PCPF can be found in intra- and extracellular physiopathological pro-fibrotic processes, genetic signatures, as well as in the response to antifibrotic treatments. Moreover, SARS-CoV-2 infection can be a cause of acute exacerbation of IPF (AE-IPF), which can negatively impact on IPF patients’ prognosis. In this narrative review, we explore the pathophysiological aspects of IPF, with particular attention given to the intracellular signaling involved in the generation of fibrosis in IPF and during the SARS-CoV-2 infection, and the similarities between IPF and PCPF. Finally, we focus on COVID-19 and IPF in clinical practice.
151	L148		del Corral, Tamara; Fabero-Garrido, Raúl; Plaza-Manzano, Gustavo; Fernández-de-las-Peñas, César; Navarro-Santana, Marcos José; López-de-Uralde-Villanueva, Ibai	Minimal Clinically Important Differences in Inspiratory Muscle Function Variables after a Respiratory Muscle Training Programme in Individuals with Long-Term Post-COVID-19 Symptoms	https://doi.org/10.3390/jcm12072720	Published	2023-01-01	Study	https://www.mdpi.com/2077-0383/12/7/2720	Objective: To establish the minimal clinically important difference (MCID) for inspiratory muscle strength (MIP) and endurance (IME) in individuals with long-term post-COVID-19 symptoms, as well as to ascertain which of the variables has a greater discriminatory capacity and to compare changes between individuals classified by the MCID. Design: Secondary analysis of randomised controlled trial of data from 42 individuals who performed an 8-week intervention of respiratory muscle training programme. Results: A change of at least 18 cmH2O and 22.1% of that predicted for MIP and 328.5s for IME represented the MCID. All variables showed acceptable discrimination between individuals who classified as “improved” and those classified as “stable/not improved” (area under the curve ≥0.73). MIP was the variable with the best discriminative ability when expressed as a percentage of prediction (Youden index, 0.67; sensitivity, 76.9%; specificity, 89.7%). Participants classified as “improved” had significantly greater improvements in quality of life and lung function compared with the participants classified as “stable/not improved”. Conclusion: In individuals with long-term post-COVID-19 symptoms, the inspiratory muscle function variables had an acceptable discriminative ability to assess the efficacy of a respiratory muscle training programme. MIP was the variable with the best discriminative ability, showing better overall performance when expressed as a percentage of prediction.
152	L149		Kooner, Harkiran K.; McIntosh, Marrissa J.; Matheson, Alexander M.; Svenningsen, Sarah; Parraga, Grace	More Data about 129Xe MRI Ventilation Defects in Long COVID-19	https://doi.org/10.1148/radiol.230479	Published	2023-04-18	Study	https://pubs.rsna.org/doi/full/10.1148/radiol.230479	We appreciated the editorial (1) about our study (2), published in Radiology on February 7, 2023. We thank Dr Vogel-Claussen for his insightful analysis and commentary. He correctly pointed out that abnormal xenon 129 (129Xe) MRI ventilation defect percent (VDP) at 15 months after infection (n = 53; 4.2% ± 6.8 [SD]) may derive from patients with post-acute COVID-19 syndrome who self-identified with prior respiratory disease (n = 22; 7.4% ± 9.1). Based on his excellent comments, we thought it would be important to dig deeper into the data, so we performed additional analyses on the subgroups with and without prior respiratory disease. In the subgroup with no self-reported previous lung disease, airways-disease medication at 3 months after COVID-19 infection was associated with a significant and clinically meaningful improvement in the St George Respiratory Questionnaire (SGRQ) score (odds ratio [OR], 3.7; 95% CI: 1.02, 13.14; P = .046) at 15 months compared with 3 months after infection. This was consistent with results in the entire group (OR, 4.0; 95% CI: 1.2, 13.8; P = .03) (2) and the smaller group of participants with prior respiratory illness (OR, 4.5; 95% CI: 0.97, 20.83; P = .05). Therefore, it appears that both subgroups showed an SGRQ improvement, which correlated with airways-disease treatment at 3 months. This finding supports the notion that there is an airways-disease component of post-acute COVID-19 syndrome (3), even in patients with no previous diagnosis of asthma or chronic obstructive pulmonary disease. In the subgroup without respiratory disease, there was significantly improved forced expiratory volume in 1 second (FEV1; from 89% predicted to 97% predicted; P = .009), ratio of FEV1 to forced vital capacity (from 79% to 84%; P = .008), diffusing capacity of the lungs for carbon monoxide (from 88% predicted to 105% predicted; P = .009), SGRQ score (from 35 to 21; P = .003), and MRI VDP (from 3.2% to 1.5%; P < .001) at 15 months after COVID compared with at 3 months (2). Although trending in a similar versus “the right” direction, there were no significant improvements in participants with self-reported prior respiratory disease (FEV1, from 76% predicted to 82% predicted [P = .6]; diffusing capacity of the lungs for carbon monoxide, from 83% predicted to 92% predicted [P > .99]; SGRQ score, from 37 to 30 [P = .2]; and VDP, from 9.4% to 7.4% [P = .2]). As Dr Vogel-Claussen (1) appropriately articulated, patients with post-acute COVID-19 syndrome without previous lung disease may be normalizing and improving over time, whereas those with respiratory disease (mainly asthma in this group) may well be improving, but perhaps to a different baseline. publisher: Radiological Society of North America
153	L150		Norweg, Anna; Yao, Lanqiu; Barbuto, Scott; Nordvig, Anna S.; Tarpey, Thaddeus; Collins, Eileen; Whiteson, Jonathan; Sweeney, Greg; Haas, Francois; Leddy, John	Exercise intolerance associated with impaired oxygen extraction in patients with long COVID	https://doi.org/10.1016/j.resp.2023.104062	Published	2023-07-01	Study	https://www.sciencedirect.com/science/article/pii/S1569904823000502	Highlights •Reduced O2 pulse peak % predicted (impaired oxygen extraction) may be a mechanism of chronic fatigue and exercise intolerance in long COVID. •Our study identified chronotropic intolerance as a potential biomarker in long COVID. •Impaired O2 extraction may have contributed to both mental and peripheral muscle fatigue and early exercise termination in long COVID. •We recommend low-intensity, sub-symptom aerobic exercise to treat long COVID. Abstract Objective Chronic mental and physical fatigue and post-exertional malaise are the more debilitating symptoms of long COVID-19. The study objective was to explore factors contributing to exercise intolerance in long COVID-19 to guide development of new therapies. Exercise capacity data of patients referred for a cardiopulmonary exercise test (CPET) and included in a COVID-19 Survivorship Registry at one urban health center were retrospectively analyzed. Results: Most subjects did not meet normative criteria for a maximal test, consistent with suboptimal effort and early exercise termination. Mean O2 pulse peak % predicted (of 79 ± 12.9) was reduced, supporting impaired energy metabolism as a mechanism of exercise intolerance in long COVID, n = 59. We further identified blunted rise in heart rate peak during maximal CPET. Our preliminary analyses support therapies that optimize bioenergetics and improve oxygen utilization for treating long COVID-19.
154	L151		Cui, Lu; Fang, Zhuoqing; De Souza, Cristabelle Madona; Lerbs, Tristan; Guan, Yuan; Li, Irene; Charu, Vivek; Chen, Shih-Yu; Weissman, Irving; Wernig, Gerlinde	Innate immune cell activation causes lung fibrosis in a humanized model of long COVID	https://doi.org/10.1073/pnas.2217199120	Published	2023-03-07	Study	https://www.pnas.org/doi/10.1073/pnas.2217199120	Significance Post COVID-19 induced pulmonary fibrosis is the most severe of a number of clinical symptoms associated with “long COVID”, a condition which is currently incompletely understood but affects millions given the ongoing COVID-19 pandemic. Using systems biology and mechanistic studies in a humanized mouse model of COVID lung fibrosis, we identify the essential genetic and immunologic perturbations occurring in patients with long COVID lung fibrosis and reveal promising therapeutic targets. Abstract COVID-19 remains a global pandemic of an unprecedented magnitude with millions of people now developing “COVID lung fibrosis.” Single-cell transcriptomics of lungs of patients with long COVID revealed a unique immune signature demonstrating the upregulation of key proinflammatory and innate immune effector genes CD47, IL-6, and JUN. We modeled the transition to lung fibrosis after COVID and profiled the immune response with single-cell mass cytometry in JUN mice. These studies revealed that COVID mediated chronic immune activation reminiscent to long COVID in humans. It was characterized by increased CD47, IL-6, and phospho-JUN (pJUN) expression which correlated with disease severity and pathogenic fibroblast populations. When we subsequently treated a humanized COVID lung fibrosis model by combined blockade of inflammation and fibrosis, we not only ameliorated fibrosis but also restored innate immune equilibrium indicating possible implications for clinical management of COVID lung fibrosis in patients. publisher: Proceedings of the National Academy of Sciences
155	L152		Becker, Richard C.	Evaluating chest pain in patients with post COVID conditions permission to think outside of the box	https://doi.org/10.1007/s11239-023-02808-8	Published	2023-05-01	Article	https://doi.org/10.1007/s11239-023-02808-8	Chest pain is among the most common symptoms of post-COVID-19 Conditions (PCC) that prompts medical attention. Because the SARS-CoV-2 virus has proclivity for many organs and organ systems in the chest, ranging from the heart, lungs, great vessels, lymphatics, and peripheral nerves, clinicians evaluating patients with chest pain must consider a broad differential diagnosis and take a comprehensive approach to management.
156	L153		Fedorowski, Artur; Olsén, Monika Fagevik; Nikesjö, Frida; Janson, Christer; Bruchfeld, Judith; Lerm, Maria; Hedman, Kristofer	Cardiorespiratory dysautonomia in post-COVID-19 condition: Manifestations, mechanisms and management	https://doi.org/10.1111/joim.13652	Published	2023-05-01	Review	https://doi.org/10.1111/joim.13652	A significant proportion of COVID-19 patients experience debilitating symptoms for months after the acute infection. According to recent estimates, approximately one out of ten COVID-19 convalescents reports persistent health issues more than three months after initial recovery. This "post-COVID-19 condition" may include a large variety of symptoms from almost all domains and organs, and for some patients it may mean prolonged sick-leave, homestay, and strongly limited activities of daily life. In this narrative review, we focus on the symptoms and signs of post-COVID-19 condition in adults-particularly those associated with cardiovascular and respiratory systems, such as postural orthostatic tachycardia syndrome (POTS) or airway disorders-and explore the evidence for chronic autonomic dysfunction as a potential underlying mechanism. The most plausible hypotheses regarding cellular and molecular mechanisms behind the wide spectrum of observed symptoms-such as lingering viruses, persistent inflammation, impairment in oxygen sensing systems and circulating antibodies directed to blood pressure regulatory components-are discussed. In addition, an overview of currently available pharmacological and non-pharmacological treatment options is presented. This article is protected by copyright. All rights reserved.
157	L154		Ides, K.; De Meyer, Y.; Dierckx, W.; Lauwers, E.; De Backer, W.	Hyperventilation in Long COVID Patients Is Part of the Clinical Picture		Published	2023-05-01	Study	https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A2156
158	L155		Baalbaki, N.; Cornelissen, M.; Drunen, C.; Houweling, L.; Noij, L.; Golebski, K.; Maitland-van der Zee, A.-H.	Long COVID Patients Show Abnormalities and Activated -inflammatory States of Airway Cells		Published	2023-05-01	Study	https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A1245
159	L156		Back, G.d.; Camargo, P.f.; Silva, R.n.; Oliveira, M.r.; Goulart, C.d.l.; Caruso, F.r.; Silva, A.b.	Long COVID-19 Severity and Its Impacts on Pulmonary Function A 1 Year Follow-Up Study		Published	2023-05-01	Study	https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A6799
160	L157		Morgan, Sandra; Visovsky, Constance; Thomas, Bini; Klein, Aimee B.; Ji, Ming; Schwab, Lauren; Coury, Jillian	Home-Based Pilot Pulmonary Program for Dyspneic Patients Post-COVID-19	https://doi.org/10.1177/10547738231170496	Published	2023-06-01	Study	https://doi.org/10.1177/10547738231170496	It is estimated that at least 10% of people who have had COVID-19 will experience ongoing symptoms such as shortness of breath, fatigue, and cognitive disturbances. Pulmonary exercise has demonstrated improved dyspnea outcomes in other respiratory conditions. Thus, the purpose of this study was to assess the efficacy of a home-based pulmonary rehabilitation program in post-COVID-19 survivors who continue to experience dyspnea. This was a longitudinal, single group pilot study in which 19 patients received a home-based expiratory muscle strength training program over 12 weeks. Outcomes measured at baseline, 6 weeks, and 12 weeks included pulmonary symptoms, functional performance, thoracic expansion, forced expiratory volume, and expiratory resistance measures. Significant improvements were found in pulmonary symptoms (p < .001), functional performance (p = .014), and progressive expiratory resistance capabilities (p < .001). A home-based pulmonary program may be an inexpensive strategy for post-COVID-19 survivors who continue to experience dyspnea.
161	L158		Sandra Morgan, RN, MSN, Constance Visovsky, RN, PhD, FAAN, Bini Thomas, PT, DPT, MSA, EdD, Aimee B. Klein, PT, DPT, DSc, Ming Ji, PhD, Lauren Schwab, RN, MSN, FNP, Jillian Coury, MPH, CRA	Home Health Care or Hospitalization for Adults With Chronic Respiratory Diseases and Post-COVID Syndrome: A Systematic Review \| C37. ONGOING IMPACT OF THE COVID-19 PANDEMIC	https://doi.org/10.1164/ajrccm-conference.2023.207.1	Published	2023-05-01	Study	https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A4890
162	L159		Kleemann, Detlef; Menschikowski, Jörg; Wellhausen, Elisabeth; Prechtl, Anselm; Fritz, Alexander; Jablowski, Silke; Frommhold, Jördis	Prevalence of chronic rhinosinusitis in patients with a Long Covid course	https://doi.org/10.1055/s-0043-1767141	Published	2023-05-01	Study	http://www.thieme-connect.de/DOI/DOI?10.1055/s-0043-1767141	Introduction Assuming that disorders of the sense of smell are an important symptom of chronic rhinosinusitis (CRS), CRS is an exclusion criterion in various studies on olfactory and gustatory disorders associated with Covid-19 and in particular the long-term courses. A few reports in the literature on the prevalence of CRS in covid-19 sufferers showed controversial results. Material and method We report on the collection of anamnestic data and symptom questionnaires from a total of 354 patients from two ENT practices and one rehabilitation clinic. All respondents were confirmed to have a SARS-COV-2 infection. Of this study group, 127 patients (97 of them from the rehabilitation clinic) had a Long Covid course. In addition to the prevalence of chronic sinus problems in the history of the patients group, the focus of this evaluation was the recording of symptoms at the beginning of the illnesses (semiquantitative) and in the post covid phase. Results 43.3% of the surveyed patients with a Long Covid course reported chronic sinus problems in their medical history. The difference to the whole study group was significant. Olfactory and gustatory disturbances, but also headache, dizziness and fever in the early phase of SARS-COV-2 disease were reported as more pronounced by patients with chronic sinus problems than by patients without such a history. The pronounced olfactory and gustatory dysfunction proved to be an early cardinal symptom for a later long covid progression. A significant risk for severe acute courses of SARS-Cov-2 infection in the sense of necessary hospital treatment could not be secured for this group of patients in our study. ISSN: 0935-8943, 1438-8685 issue: S 2 journalAbbreviation: Laryngorhinootologie
163	L160		Duong-Quy, Sy; Vo-Pham-Minh, Thu; Tran-Xuan, Quynh; Huynh-Anh, Tuan; Vo-Van, Tinh; Vu-Tran-Thien, Quan; Nguyen-Nhu, Vinh	Post-COVID-19 Pulmonary Fibrosis: Facts—Challenges and Futures: A Narrative Review	https://doi.org/10.1007/s41030-023-00226-y	Published	2023-05-20	Review	https://doi.org/10.1007/s41030-023-00226-y	Patients with coronavirus disease 2019 (COVID-19) usually suffer from post-acute sequelae of coronavirus disease 2019 (PASC). Pulmonary fibrosis (PF) has the most significant long-term impact on patients’ respiratory health, called post-COVID-19 pulmonary fibrosis (PC19-PF). PC19- PF can be caused by acute respiratory distress syndrome (ARDS) or pneumonia due to COVID-19. The risk factors of PC19-PF, such as older age, chronic comorbidities, the use of mechanical ventilation during the acute phase, and female sex, should be considered. Individuals with COVID-19 pneumonia symptoms lasting at least 12 weeks following diagnosis, including cough, dyspnea, exertional dyspnea, and poor saturation, accounted for nearly all disease occurrences. PC19-PF is characterized by persistent fibrotic tomographic sequelae associated with functional impairment throughout follow-up. Thus, clinical examination, radiology, pulmonary function tests, and pathological findings should be done to diagnose PC19-PF patients. PFT indicated persistent limitations in diffusion capacity and restrictive physiology, despite the absence of previous testing and inconsistency in the timeliness of assessments following acute illness. It has been hypothesized that PC19-PF patients may benefit from idiopathic pulmonary fibrosis treatment to prevent continued infection-related disorders, enhance the healing phase, and manage fibroproliferative processes. Immunomodulatory agents might reduce inflammation and the length of mechanical ventilation during the acute phase of COVID-19 infection, and the risk of the PC19-PF stage. Pulmonary rehabilitation, incorporating exercise training, physical education, and behavioral modifications, can improve the physical and psychological conditions of patients with PC19-PF.
164	L161		Singh, Sally J.; Baldwin, Molly M.; Daynes, Enya; Evans, Rachael A.; Greening, Neil J.; Jenkins, R. Gisli; Lone, Nazir I.; McAuley, Hamish; Mehta, Puja; Newman, Joseph; Novotny, Petr; Smith, David J. F.; Stanel, Stefan; Toshner, Mark; Brightling, Christopher E.	Respiratory sequelae of COVID-19: pulmonary and extrapulmonary origins, and approaches to clinical care and rehabilitation	https://doi.org/10.1016/S2213-2600(23)00159-5	Published	2023-05-19	Article	https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00159-5/fulltext	Although the exact prevalence of post-COVID-19 condition (also known as long COVID) is unknown, more than a third of patients with COVID-19 develop symptoms that persist for more than 3 months after SARS-CoV-2 infection. These sequelae are highly heterogeneous in nature and adversely affect multiple biological systems, although breathlessness is a frequently cited symptom. Specific pulmonary sequelae, including pulmonary fibrosis and thromboembolic disease, need careful assessment and might require particular investigations and treatments. COVID-19 outcomes in people with pre-existing respiratory conditions vary according to the nature and severity of the respiratory disease and how well it is controlled. Extrapulmonary complications such as reduced exercise tolerance and frailty might contribute to breathlessness in post-COVID-19 condition. Non-pharmacological therapeutic options, including adapted pulmonary rehabilitation programmes and physiotherapy techniques for breathing management, might help to attenuate breathlessness in people with post-COVID-19 condition. Further research is needed to understand the origins and course of respiratory symptoms and to develop effective therapeutic and rehabilitative strategies. publisher: Elsevier PMID: 37216955
165	L162		Faria, Nuno; Oliveira, Tiago; Pinto, Paula; Almeida, Vânia; Carvalho, Raquel; Fernandes, Maria José; Sucena, Maria; Gomes, Joana	Role of the one-minute sit-to-stand test in the diagnosis of post COVID-19 condition: a prospective cohort study	https://doi.org/10.36416/1806-3756/e20230027	Published	2023-05-26	Study	https://www.scielo.br/j/jbpneu/a/dHckCvsqzfxjFbwmmcL3h8q/	ABSTRACT Objective: To analyze the relationship between one-minute sit-to-stand test (1MSTST) parameters and a diagnosis of post COVID-19 condition in a cohort of patients who previously had COVID-19. Methods: This was a prospective cohort study of patients with post COVID-19 condition referred for body plethysmography at a tertiary university hospital. Post COVID-19 condition was defined in accordance with the current WHO criteria. Results: Fifty-three patients were analyzed. Of those, 25 (47.2%) met the clinical criteria for post COVID-19 condition. HR was lower in the patients with post COVID-19 condition than in those without it at 30 s after initiation of the 1MSTST (86.2 ± 14.3 bpm vs. 101.2 ± 14.7 bpm; p < 0.001) and at the end of the test (94.4 ± 18.2 bpm vs. 117.3 ± 15.3 bpm; p < 0.001). The ratio between HR at the end of the 1MSTST and age-predicted maximal HR (HRend/HRmax) was lower in the group of patients with post COVID-19 condition (p < 0.001). An HRend/HRmax of < 62.65% showed a sensitivity of 78.6% and a specificity of 82.0% for post COVID-19 condition. Mean SpO2 at the end of the 1MSTST was lower in the patients with post COVID-19 condition than in those without it (94.9 ± 3.6% vs. 96.8 ± 2.4%; p = 0.030). The former group of patients did fewer repetitions on the 1MSTST than did the latter (p = 0.020). Conclusions: Lower SpO2 and HR at the end of the 1MSTST, as well as lower HR at 30 s after initiation of the test, were associated with post COVID-19 condition. In the appropriate clinical setting, an HRend/HRmax of < 62.65% should raise awareness for the possibility of post COVID-19 condition.
166	L163		Zaremba, Solomiia; Miller, Alex; Ovrom, Erik; Senefeld, Jonathon; Wiggins, Chad; Dominelli, Paolo; Joyner, Michael; Welch, Brian; Ramsook, Andrew	Airway luminal area in long COVID patients compared to acute COVID-19 patients	https://doi.org/10.1152/physiol.2023.38.S1.5731335	Published	2023-05-01	Study	https://journals.physiology.org/doi/abs/10.1152/physiol.2023.38.S1.5731335	Background: Patients with respiratory manifestations of acute COVID-19 infection have enlarged luminal areas of central conducting airways demonstrated on computed tomography imaging and abnormal pulmonary function. In some cases, COVID-19 symptoms may persist for more than 4 weeks, referred to as long COVID, and the effect on airway luminal area remains unknown. Herein, we report airway luminal cross-sections areas among a long COVID group, compared to individuals with an acute COVID-19. We aim to investigate if large conducting airways sizes are different between acute COVID-19 and long COVID patients. Methods: A cohort of 181 people with long COVID were screened, of which 20 people (9 men, 11 women; 55.9 ± 14.1 years) were included in analyses. Twenty age, height, and sex matched patients with an acute (< 4 weeks of persistent symptoms from diagnosis) COVID-19 infection (55.7 ± 15.2 years) served as a comparison group. We used a three-dimensional reconstruction of computed tomography imaging to measure luminal areas of the trachea, right and left main bronchi, bronchus intermediate, right and left upper lobe, and left lower lobe bronchi at proximal, middle, and distal cross-sectional points in both groups. Airway luminal area was taken as the average of the three points. We compared average lumen area of long COVID patients with acute COVID-19 individuals, using an independent samples t-test. Results: We found no significant difference comparing measurements of the following airway luminal cross-sectional areas: trachea (277.7 ± 100.4 vs. 268.0 ± 70.5 mm2 p=0.73), right main bronchus (191.0 ± 66.1 vs. 190.1 ± 49.0 mm2, p=0.96), bronchus intermediate (112.3 ± 33.4 vs. 109.3 ± 27.9 mm2, p=0.76), right upper lobe bronchus (74.4 ± 21.0 vs. 73.7 ± 25.5 mm2, p=0.92), left main bronchus (129.1 ± 50.1 vs. 136.9 ± 38.0 mm2, p=0.58), left lower lobe bronchus (57.8 ± 18.2 vs. 59.0 ± 13.4 mm2, p=0.82), and left upper lobe bronchus (80.1 ± 19.5 vs. 77.9 ± 22.9 mm2, p=0.75) in the long COVID and acute COVID-19 groups respectively. Conclusion: In patients with long COVID, compared to those with an acute COVID-19 infection, we did not see differences in central airway luminal areas. Further analysis of a larger cohort is needed to determine whether enlarged airway luminal areas, associated with acute COVID-19, persist in long COVID. This research will expand knowledge on functional consequences for patients with long COVID. Funding: F32HL154320 to JWS; 5R35HL139854 to MJJ. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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1	Ref	PPLC	Authors	Title	DOI	Peer reviewed	Date	type	Link	Keys	Clés

2	N01		Heneka	Immediate and long-term consequences of COVID-19 infections for the development of neurological disease	https://doi.org/10.1186/s13195-020-00640-3	published	4-Jun-20		https://alzres.biomedcentral.com/articles/10.1186/s13195-020-00640-3	Prospective studies are needed to investigate potential correlations between acute and sub-acute COVID-19 infections and long-term neurological sequalae in this patient cohort.	_
3	N02		Yiping Lu, MD Xuanxuan Li, MD, Daoying Geng, MD, Nan Mei, MD, Pu-Yeh Wu, PhD, Chu-Chung Huang, PhD et al.	Cerebral Micro-Structural Changes in COVID-19 Patients – An MRI-based 3-month Follow-up Study	https://doi.org/10.1016/j.eclinm.2020.100484	Published	August 3, 2020	RESEARCH PAPER	https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(20)30228-5/fulltext	The Lancet, August, the 4th : "The study reveals a possible disruption to micro-structural and functional brain integrity in the recovery stages of COVID-19, suggesting long-term consequences of SARSCoV2." "The abnormalities in these brain areas might cause long-term burden to COVID-19 patients after recovery, which was thus worth public attention" British Thoracic Society recommends chest x-ray three months after discharge for all patients admitted to hospital with covid-19	The Lancet, 4 août : "L'étude révèle une possible perturbation de l'intégrité micro-structurelle et fonctionnelle du cerveau dans les stades de récupération du COVID-19, suggérant des conséquences à long terme du SRASCoV2." "Les anomalies dans ces zones cérébrales pourraient entraîner un fardeau à long terme pour les patients atteints de COVID-19 après la guérison, ce qui mérite donc l'attention du public." "La British Thoracic Society recommande une radiographie thoracique trois mois après la sortie pour tous les patients admis à l'hôpital avec covid-19"
4	N03		Beth Rabinovitz,Abhishek Jaywant &Chaya B. Fridman	Neuropsychological functioning in severe acute respiratory disorders caused by the coronavirus: Implications for the current COVID-19 pandemic	https://doi.org/10.1080/13854046.2020.1803408	Published	September 9, 2020	Article	https://www.tandfonline.com/doi/full/10.1080/13854046.2020.1803408	Neurological impacts	Impacts neurologiques
5	N04		Eric Song, Ce Zhang, Benjamin Israelow, Alice Lu-Culligan	Neuroinvasion of SARS-CoV-2 in human and mouse brain	https://doi.org/10.1101/2020.06.25.169946	pre-print	September 8, 2020	New Results	https://www.biorxiv.org/content/10.1101/2020.06.25.169946v2	Research on the entry of the virus into the brain	Recherche sur l'entrée du virus dans le cerveau
6	N05		Martin Sylvester Otte ,Hans Nikolaus Caspar Eckel,Leonard Poluschkin,Jens Peter Klussmann	Olfactory dysfunction in patients after recovering from COVID-19	https://doi.org/10.1080/00016489.2020.1811999	published	August 27, 2020	Research Article	https://www.tandfonline.com/doi/full/10.1080/00016489.2020.1811999	A German study on 91 symptomatic PCR+ patients reports, after 8 weeks, that 45% of them still have a relative loss of smell (hyposmia). Half of the patients with an olfactory loss as a symptom of COVID-19 still have olfactory impairments after two months, although not all of these patients subjectively notice a restriction.	Une étude allemande sur 91 patients PCR+ symptomatiques rapporte, après 8 semaines, que 45% d'entre ont toujours une perte relative d'odorat (hyposmie).
7	N06		Jason C. Lee, MD, PhD, Rohit Nallani, MD, Lauren Cass, MD, MPH, ...	A Systematic Review of the Neuropathologic Findings of Post-Viral Olfactory Dysfunction: Implications and Novel Insight for the COVID-19 Pandemic	https://doi.org/10.1177%2F1945892420957853	published	September 11, 2020	Systematic Review	https://journals.sagepub.com/doi/full/10.1177/1945892420957853	On post-viral olfactory pathologies	Sur les pathologies olfactives post-virales
8	N07		Christos Pantelis, Mahesh Jayaram, Anthony J Hannan, ...	Neurological, neuropsychiatric and neurodevelopmental complications of COVID-19	https://doi.org/10.1177%2F0004867420961472	Published	October 1, 2020	Research Article	https://journals.sagepub.com/doi/full/10.1177/0004867420961472	Neurological, psychiatric, and prenatal complications of covid. "Maternal viral (and other) infections during pregnancy can affect the offspring, with greater incidence of neurodevelopmental disorders, such as autism, schizophrenia and epilepsy."	Complications neurologiques, psychiatriques, et prénatales de la covid. "Maternal viral (and other) infections during pregnancy can affect the offspring, with greater incidence of neurodevelopmental disorders, such as autism, schizophrenia and epilepsy."
9	N08		S. Andrew Josephson, MD1,2; Hooman Kamel, MD3,4	Neurology and COVID-19	https://doi.org/10.1001/jama.2020.14254	Published	September 22/29, 2020	Viewpoint	https://jamanetwork.com/journals/jama/fullarticle/2770855		_
10	N09		Daniela Costa Martins 1, Sofia Branco Ribeiro, Isabel Jesus Pereira, Susana Mestre, Jonathan Rios	Unilateral Hypoglossal Nerve Palsy as a COVID-19 Sequel	https://doi.org/10.1097/phm.0000000000001607	Published	Oct 2020	Case	https://pubmed.ncbi.nlm.nih.gov/33002915/	In Portugal, a case of unilateral hypoglossal (tongue) nerve palsy reported in a patient with a severe form of covid.	Au Portugal, un cas de paralysie unilatérale du nerf hypoglosse (langue) rapporté chez un patient atteint d'une forme sévère de covid.
11	N10		Foteini Stefania Koumpa1,2, Cillian T Forde2 and Joseph G Manjaly2	Sudden irreversible hearing loss post COVID-19	http://dx.doi.org/10.1136/bcr-2020-238419	Published	October 2020	Case report	https://casereports.bmj.com/content/13/11/e238419	Extremely rare case of a priori definitive deafness caused by covid in a 45-year-old British patient, reported in BMJ Case Reports. Hearing loss and tinnitus are temporary sequelae already reported for influenza.	Cas rarissime d'une surdité définitive a priori causée par la covid chez un patient britannique de 45 ans, rapporté dans le BMJ Case Reports. Perte auditive et acouphènes sont des séquelles temporaires déjà rapportées pour la grippe.
12	N11		Butler	Neuropsychiatric complications of covid-19	https://doi.org/10.1136/bmj.m3871	published	13-Oct-20		https://www.bmj.com/content/371/bmj.m3871	o date, most research on long covid has been led by patients, and it suggests this is a common and disabling disorder.21 Further research informing clinical guidelines and our understanding of the mechanisms underlying this disorder is urgently required.22	_
13	N12		Adam Hampshire, William Trender, Samuel R Chamberlain, Amy Jolly, Jon E. Grant	Cognitive deficits in people who have recovered from COVID-19 relative to controls: An N=84,285 online study	https://doi.org/10.1101/2020.10.20.20215863	pre-print	October 21, 2020	Study	https://www.medrxiv.org/content/10.1101/2020.10.20.20215863v1	A large-scale study, not yet reviewed or published, would tend to show a worrying cognitive underperformance of people who had covid, significantly pronounced in hospitalized people.	Une étude de grande ampleur, non encore relue ni publiée, tendrait à montrer une sous-performance cognitive inquiétante des personnes ayant eu la covid, significativement prononcée chez les personnes hospitalisées.
14	N13	Yes	Arun Raj Antony Zulfi Haneef	Systematic review of EEG findings in 617 patients diagnosed with COVID-19	https://doi.org/10.1016/j.seizure.2020.10.014	Published	October 18, 2020	Systematic review	https://www.seizure-journal.com/article/S1059-1311(20)30332-0/abstract	According to a study, covid could be at the origin of attacks in particular in the frontal lobe (more observed in severe covid), some of which could be irreversible (speech, confusion ...). Median in the study: 61 years. The mechanism could be direct (viral) or indirect (decrease in oxygenation caused by covid). The publication is a systematic american study of electroencephalography performed on covid patients, (part of this study at N-Y): The anomalies are notably non-convulsive epileptic states (the prevalence of these epileptic attacks is according to the NY study of 30% in patients who have had a severe form of covid).	Selon une étude, la covid pourrait être à l'origine d'atteintes notamment dans le lobe frontal (davantage observées sur covid sévère), dont certaines risqueraient d'être irréversibles (élocution, confusion...). Médiane dans l'étude: 61 ans. Le mécanisme pourrait être direct (viral) ou indirect (baisse d'oxygénation causée par la covid). La publication est une étude systématique américaine d'électroencéphalographies effectuées sur des malades covid, une partie issus de cette étude à N-Y: Les anomalies sont notamment des états épileptiques non convulsifs (la prévalence de ces atteintes épilep. est selon l'étude de NY de 30% chez les malades ayant eu une forme grave de la covid).
15	N14		Jacob Pellinen Elizabeth Carroll Daniel Friedman Michael Boffa Patricia Dugan David E. Manisha Holmes	Continuous EEG findings in patients with COVID‐19 infection admitted to a New York academic hospital system	https://doi.org/10.1111/epi.16667	Published	02 September 2020	FULL‐LENGTH ORIGINAL RESEARCH	https://onlinelibrary.wiley.com/doi/10.1111/epi.16667	Study in N-Y	étude à N-Y
16	N15		Siukan Law email 1; Albert Wingnang Leung2; Chuanshan Xu3	Do COVID-19 infection among patients increase the risk of Alzheimer’s disease?	https://dx.doi.org/10.21608/mid.2020.46935.1073	Published	Nov 2020	Letter to the Editor	https://mid.journals.ekb.eg/article_120300.html	An article in Microbes and Infectious Deseases indicates that there is no evidence that covid increases the risk of Alzheimer's disease, and that the virus itself is unlikely to enter the central nervous system.	Un article dans Microbes and Infectious Deseases indique qu'aucun élément ne permet de dire que la covid augmente le risque de maladie d'Alzheimer, et qu'il est improbable que le virus lui-même puisse entrer dans le système nerveux central.
17	N16		Pasquale Viola, Massimo Ralli, Davide Pisani, Donatella Malanga, Domenico Sculco, Luigi Messina, Carla	Tinnitus and equilibrium disorders in COVID-19 patients: preliminary results	https://doi.org/10.1007/s00405-020-06440-7	Published	23 October 2020	Study	https://link.springer.com/article/10.1007/s00405-020-06440-7	Tinnitus and balance problems appear with a notable incidence in patients with covid, according to this Italian study.	Acouphènes et problèmes d'équilibre apparaissent avec une incidence notable chez les malades de la covid, selon cette étude italienne.
18	N17		Beauchamp, Leah C.a; b \| Finkelstein, David I.a \| Bush, Ashley I.a; c \| Evans, Andrew H.d \| Barnham, Kevin J.a; b; c;	Parkinsonism as a Third Wave of the COVID-19 Pandemic?	https://doi.org/10.3233/JPD-202211	Published	27 October 2020	Research Article	https://content.iospress.com/articles/journal-of-parkinsons-disease/jpd202211	An Australian research article wonders if the neurotropic aspect of SARS-CoV-2 could be at the origin of a wave of Parkinson's diseases, and warns of the possible disastrous consequences of betting on natural herd immunity. The article notes the still unknown origin of the lethargic encephalitis pandemic that affected 5 million people between 1916 and 1926, causing an outbreak of parkinsonism. Studies had advanced the viral hypothesis (Spanish flu).	Un article de recherche australien se demande si l'aspect neurotrope du SARS-CoV-2 pourrait être à l'origine d'une vague de maladies de Parkinson, et met en garde contre les possibles conséquences désastreuses du pari d'une immunité collective naturelle./. L'article note l'origine toujours inconnue de la pandémie d'encéphalite léthargique qui toucha 5 millions de personnes entre 1916 et 1926, causant une flambée de troubles parkinsoniens. Des études avaient avancé l'hypothèse virale (grippe espagnole).
19	N18	Yes	Elodie Meppiel, M.D. Nathan Peiffer-Smadja, M.D. Alexandra Maury Pierre Tattevin, M.D. Ph.D.	Neurological manifestations associated with COVID-19: a multicentric registry	https://doi.org/10.1016/j.cmi.2020.11.005	Published	November 12, 2020	multicentric registry	https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(20)30698-4/abstract	A French study lists the possible neurological damage from covid. Out of 222 hospitalized patients (median age 63 years) with neurological symptoms, 30% presented with encephalopathy, 25% with ischemic stroke, 9% with encephalitis. One of the authors, @nathanpsmad, presents the results of the study (Meppiel & al, @elomepiel) in this thread https://twitter.com/nathanpsmad/status/1326992035098877958. An important part of the symptoms would be linked more to post-infectious inflammatory mechanisms, even if the direct role of SARS-CoV-2 virions is not ruled out.	Une étude française liste les atteintes neurologiques possibles de la covid. Sur 222 patients hospitalisés (âge médian 63 ans) avec symptômes neurolog., 30% présentent une encéphalopathie, 25% un AVC ischémique, 9% une encéphalite. L'un des auteurs, @nathanpsmad, présente les résultats de l'étude (Meppiel & al, @elomepiel) dans ce thread. https://twitter.com/nathanpsmad/status/1326992035098877958 Une part importante des symptômes serait davantage liée à des mécanismes inflammatoires post-infectieux, même si le rôle direct de virions de SARS-CoV-2 n'est pas écarté.
20	N19		Guilherme Dias De Melo, Françoise Lazarini, Sylvain Levallois, Charlotte Hautefort,	COVID-19-associated olfactory dysfunction reveals SARS-CoV-2 neuroinvasion and persistence in the olfactory system	https://doi.org/10.1126/scitranslmed.abf8396	Published	November 18, 2020	New Results	https://www.science.org/doi/10.1126/scitranslmed.abf8396	First pre-print: https://www.biorxiv.org/content/10.1101/2020.11.18.388819v1.full Finally, olfactory mucosa sampling in COVID-19 patients presenting with persistent loss of smell reveals the presence of virus transcripts and of SARS-CoV-2-infected cells, together with protracted inflammation	Étude finalement bien publiée - Elle n'est pas encore révisée par les pairs ni publiée, mais cette étude 🇨🇵 d'une équipe de l'Institut Pasteur sur l'homme et l'animal montre des charges virales SARS-CoV-2 dans l'épithélium olfactif à même d'expliquer l'anosmie prolongée.
21	N20		SanazKatalaAliGholamrezanezhadbc	COVID-19–related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters Neuroimaging findings in COVID-19: A narrative review	https://doi.org/10.1016/j.neulet.2020.135529	Published	25 November 2020	review	https://www.sciencedirect.com/science/article/pii/S0304394020307990	Brain imaging should be considered in the diagnostic work up of those COVID-19 patients who present with neurological symptoms. In this regard, radiologists and clinicians should be familiar with the spectrum of neuroimaging findings in COVID-19 to detect and understand the disease process, and to evaluate its progression during the course of treatment. Yet, further studies are still warranted regarding the long-term neurological sequel and prognostic implications in COVID-19.	Une rapide revue de la littérature fait le point sur les symptômes neurologiques de la covid, insiste sur l'apport de l'imagerie cérébrale, et appelle à des études plus poussées sur les séquelles neurologiques à long terme.
22	N21	Yes	LIVIA NG	COVID-19 Damages the CNS		opinion	July 10, 2020	opinion	https://neucruit.com/journal/covid19-cns		Neucruit, plateforme 🇬🇧 pour essais cliniques résume : "la covid abîme le système nerveux central" : "le virus peut infecter le liquide cérébro-spinal, causer des œdèmes cérébraux, des vasodilatations méningées et des neurodégénérescences partielles".
23	N22		AvindraNathBryanSmith	Neurological issues during COVID-19: An Overview	https://doi.org/10.1016/j.neulet.2020.135533	Published	25 November 2020	Article	https://www.sciencedirect.com/science/article/pii/S030439402030803X		Séquelles neurologiques de la covid : les auteurs voient cette catégorie de symptômes persistants (qui peut toucher selon eux 10 à 35% des malades) comme la plus lourde sur le long terme, et affirment que les conséquences socio-éco. sont insondables.
24	N23	ES	Jenny Meinhardt, Josefine Radke, […]Frank L. Heppner	Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19	https://doi.org/10.1038/s41593-020-00758-5	Published	30 November 2020	Article	https://www.nature.com/articles/s41593-020-00758-5		Cette étude dans Nature décrit comment le SARS-CoV-2 peut entrer dans le système nerveux central en traversant la muqueuse olfactive, exploitant la proximité immédiate des tissus muqueux olfactifs, endothéliaux et nerveux.
25	N24	Yes	Abdul Mannan Baig	Deleterious Outcomes in Long-Hauler COVID-19: The Effects of SARS-CoV‑2 on the CNS in Chronic COVID Syndrome	https://doi.org/10.1021/acschemneuro.0c00725	Published	November 13, 2020	Viewpoint	https://dx.doi.org/10.1021/acschemneuro.0c00725		Un point de vue sur les impacts neurologiques lors des covids longs ("neuro-covid chronique"). L'auteur évoque des hypothèses de thérapies, notamment anti-inflammatoires, pour lesquelles il préconise des tests cliniques.
26	N25		Fatemeh Sadat Mirfazeli, Atiye Sarabi-Jamab, Amin Jahanbakhshi, Alireza Kordi, Parisa Javadnia Seyed Hamid Reza Faiz	Neuropsychiatric manifestations of COVID-19 can be clustered in three distinct symptom categories	https://doi.org/10.1038/s41598-020-78050-6	Published	01 December 2020	Article	https://www.nature.com/articles/s41598-020-78050-6		Une étude distingue 3 types de troubles neuro. covid : - anosmie/hypogeusie - étourdissemts, maux de tête, réduction de la force des membres - photophobie, état mental modifié, hallucinations, pb vision/élocution, convulsions, AVC, troubles de l'équilibre.
27	N26		Michael Eliezer, Anne-Laurel Hamel, Emmanuel Houdart, Philippe Herman, Juliette Housset, Clement Jourdaine, Corinne Eloit, Benjamin Verillaud, Charlotte Hautefort	Loss of smell in patients with COVID-19 MRI data reveal a transient edema of the olfactory clefts	https://doi.org/10.1212/WNL.0000000000010806	Published	December 08, 2020	Article	https://n.neurology.org/content/95/23/e3145		Des radiologues et ORL français rapportent dans un article publié en ligne le 11 septembre dans la revue Neurology les résultats d’une étude évaluant l’aspect à l’imagerie par résonance magnétique (IRM) de la partie supérieure des fosses nasales de patients anosmiques au début de leur maladie Covid-19. Elle met clairement en évidence que la perte d’odorat (anosmie) dont se plaignent de nombreux patients Covid-19 est fréquemment associée à un gonflement transitoire au niveau de la partie supérieure des fosses nasales, ce que les spécialistes ORL appellent un œdème des fentes olfactives. Suite sur https://www.lemonde.fr/blog/realitesbiomedicales/tag/fente-olfactive/
28	N27	Yes	Rachel Wells, Varun Malik, Anthony G. Brooks, Dominik Linz, Adrian D. Elliott, Prashanthan Sanders, Amanda Page, Mathias Baumert, and Dennis H. Lau	Cerebral Blood Flow and Cognitive Performance in Postural Tachycardia Syndrome: Insights from Sustained Cognitive Stress Test	https://doi.org/10.1161/JAHA.120.017861	Published	5 Dec 2020	RESEARCH ARTICLE	https://www.ahajournals.org/doi/10.1161/JAHA.120.017861	A very important study that demonstrates abnormal cerebral blood flow in patients with POTS during a cognitive test suggesting that "brain fog" has a pathophysiologic basis.	Une base physiopathologique du «brouillard cérébral» («brain fog», l'un des symptômes du covid long) suspectée par l'observation de flux sanguins cérébraux anormaux chez des patients atteints de syndrome de tachycardie orthostatique posturale (POTS).
29	N28		Michael Lange Riyi Shi	Possible Neuroinflammatory Mechanisms Which May Lead to Long-Term Neurological Disorders in COVID-19 Patients	https://doi.org/10.18060/24687	Viewpoint	2020-12-15	Abstract only	https://journals.iupui.edu/index.php/IMPRS/article/view/24687		_
30	N29	Yes	Myoung-Hwa Lee, Ph.D, Daniel P. Perl, M.D., Govind Nair, Ph.D., Wenxue Li, Ph.D., Dragan Maric, Ph.D., Avindra Nath	Microvascular Injury in the Brains of Patients with Covid-19	https://doi.org/10.1056/NEJMc2033369	Published	December 30, 2020	Correspondance	https://www.nejm.org/doi/full/10.1056/NEJMc2033369		Lors d'IRM post-mortem de résolution 25μm-100μm sur des victimes de la covid, sont fréquemment relevées des micro-lésions vasculaires dans le cerveau et le bulbe olfactif, sans atteinte virale directe de neurones.
31	N29	Yes	Lee MH, Perl DP, Nair G, Li W, Maric D, Murray H, Dodd SJ, Koretsky AP, Watts JA, Cheung V, Masliah E, Horkayne-Szakaly I, Jones R, Stram MN, Moncur J, Hefti M, Folkerth RD, Nath A.	NIH study uncovers blood vessel damage and inflammation in COVID-19 patients’ brains but no infection Results from a study of 19 deceased patients suggests brain damage is a byproduct of a patient’s illness.	https://doi.org/10.1056/NEJMc2033369	Published	December 30, 2020	Article	https://www.nih.gov/news-events/news-releases/nih-study-uncovers-blood-vessel-damage-inflammation-covid-19-patients-brains-no-infection	Les données de l'étude menée par le NIH ont surpris l'équipe. "Originally, we expected to see damage that is caused by a lack of oxygen. Instead, we saw multifocal areas of damage that is usually associated with strokes and neuroinflammatory diseases""Our results suggest that this may be caused by the body's inflammatory response to the virus" "We plan to study how COVID-19 harms the brain's blood vessels and whether that produces some of the short- and long-term symptoms we see in patients."	Les données de l'étude menée par le NIH ont surpris l'équipe. "Originally, we expected to see damage that is caused by a lack of oxygen. Instead, we saw multifocal areas of damage that is usually associated with strokes and neuroinflammatory diseases""Our results suggest that this may be caused by the body's inflammatory response to the virus" "We plan to study how COVID-19 harms the brain's blood vessels and whether that produces some of the short- and long-term symptoms we see in patients."
32	N30	Yes	Peter Wostyn	COVID-19 and chronic fatigue syndrome: Is the worst yet to come?	https://doi.org/10.1016/j.mehy.2020.110469	Published	2 January 2021	Hypothesis	https://pubmed.ncbi.nlm.nih.gov/33401106/		Selon le chercheur en psychiatrie Peter Wostyn, le syndrome de fatigue chronique associé au covid long pourrait résulter de dommages aux neurones sensoriels olfactifs, entraînant une réduction de l'écoulement du liquide céphalo-rachidien à travers la lame criblée. Cela conduirait à une congestion du système glymphatique avec une accumulation de toxicité ultérieure dans le système nerveux central. Le chercheur envisage une amélioration des symptômes en drainant le liquide céphalo-rachidien pour rétablir le transport glymphatique et l'élimination des déchets du cerveau.
33	N31		Andrea Pilotto, MD, Stefano Masciocchi, MD, Irene Volonghi, MD, Valeria De Giuli, MD, Francesca Caprioli, MD, Sara Mariotto, MD, Sergio Ferrari, MD, Silvia Bozzetti, MD, Alberto Imarisio, MD, Barbara Risi	Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Encephalitis Is a Cytokine Release Syndrome: Evidences From Cerebrospinal Fluid Analyses	https://doi.org/10.1093/cid/ciaa1933	Published	04 January 2021	Major article	https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1933/6062486?	SARS-CoV-2-related encephalitis were associated with prominent glial activation and neuroinflammatory markers, whereas neuronal markers were increased in severe cases only. The pattern of CSF alterations suggested a cytokine-release syndrome as the main inflammatory mechanism of SARS-CoV-2 related encephalitis.	Les encéphalites déclenchées par la covid trouveraient leur origine, selon cette étude, dans la libération de cytokines qui devient le principal effet inflammatoire.
34	N32	Yes	Eric Song, Ce Zhang, Benjamin Israelow, Alice Lu-Culligan, Anita Huttner, Danielle Seilhean, Nicolas Renier, Kaya Bilguvar, Akiko Iwasaki	Neuroinvasion of SARS CoV 2 in human and mouse	https://doi.org/10.1084/jem.20202135	Published	January 12 2021	Article	https://rupress.org/jem/article/218/3/e20202135/211674/Neuroinvasion-of-SARS-CoV-2-in-human-and-mouse	Tweet by @EricTopol : "There's been controversy as to whether #SARSCoV2 directly attacks brain cells. This new @JExpMed paper supports that it occurs via brain organoids, mouse models, and patient autopsy. And lack of IFN response."	Il y a un débat pour savoir si le SARS-CoV2 peut directement attaquer les cellules cérébrales. En utilisant des organoïdes cérébraux, un modèle animal (souris) et via des autopsies de victimes de la covid, une étude appuie cette possibilité.
35	N33	Yes	Tissa Wijeratne Sheila Crewther	COVID-19 and long-term neurological problems: Challenges ahead with Post-COVID-19 Neurological Syndrome	https://doi.org/10.31128/AJGP-COVID-43	Published	12 January 2021	Article	https://www1.racgp.org.au/ajgp/coronavirus/covid-19-and-long-term-neurological-problems	"The COVID-19-associated neurological disorders reported to date fit into five main categories: encephalopathies, inflammatory central nervous system (CNS) syndromes, ischaemic strokes, peripheral neurological disorders and miscellaneous other CNS disorders. The number of articles reporting longer-term post-COVID-19 neurological effects and symptoms makes an undeniable case for medicine to recognise the Post-COVID-19 Neurological Syndrome (PCNS)". "The pandemic statistics highlight the need for ongoing, careful follow-up of all patients with COVID-19, even those formerly regarded as asymptomatic, with regular screening for likely long-term persistent neurological involvements."	Un article australien classifie les troubles neurologiques associés à la covid : "ils entrent dans 5 catégories : encéphalopathies, syndromes inflammatoires du système nerveux central (SNC), accidents vasculaires cérébraux ischémiques,troubles neurologiques périphériques et divers autres troubles du SNC." "Ces symptômes nous obligent à reconnaître un «syndrome neurologique post-covid» (Post-COVID-19 Neurological Syndrome - PCNS)". "Il y a nécessité d'un suivi continu de tous les patients atteints de la covid, y compris ceux qui étaient considérés auparavant comme asymptomatiques, avec un dépistage régulier des probables implications neurologiques persistantes à long terme".
36	N34		Françoise Chapon	Syndrome de Guillain-Barré et infection au SARS-CoV-2 Guillain-Barré syndrome associated with SARS-CoV-2	https://doi.org/10.1051/medsci/2020210	Published	11 January 2021	Case study	https://www.medecinesciences.org/en/articles/medsci/full_html/2020/12/medsci200210s/medsci200210s.html		Une étude de cas sur des syndromes de Guillain-Barré consécutifs à une infection au SARS-CoV-2.
37	N35		Pratima Kumari, Hussin A. Rothan, Janhavi P. Natekar, Shannon Stone, Heather Pathak, Philip G. Strate, Komal Arora, Margo A. Brinton and Mukesh Kumar	Neuroinvasion and Encephalitis Following Intranasal Inoculation of SARS-CoV-2 in K18-hACE2 Mice	https://doi.org/10.3390/v13010132	Published	19 January 2021	Study on animal model	https://www.mdpi.com/1999-4915/13/1/132/htm	A study on six week old transgenic mice (for susceptibility to SARS-CoV-2," "K18-hACE2-transgenic" "), infected with the covid virus intranasally, revealed neurological symptoms and infection central nervous system. The study notes that unlike the lungs where virions disappear by immune action, the brain is subject to strong kinetics of late infection, which triggers an inflammatory response. Tissue analyzes reveal the presence perivascular hemorrhages, leukocyte infiltrations and the death of some neuronal cells. Antigens of the virus are detected throughout the murine brain, including the cortex, cerebellum and hippocampus. The authors believe that the brain is a site major SARS-CoV-2 infection following intranasal infection: first through the olfactory bulb, then by propagation in the brain by following the axons of neurons in the brain that connect to it. According to Mukesh Kumar, one of the co-authors of the study, is where the virus can take refuge because there is not the same level of immune response as in other organs. This tropism is correlated according to him to systemic symptoms, in particular cardiac, to anosmia, and to other neurological disorders which are characteristic of the long covid. "	Une étude sur des souris de six semaines transgéniques (pour une susceptibilité au SARS-CoV-2, "K18-hACE2-transgenic"), infectées au virus de la covid par voie intranasale, relève des symptômes neurologiques et l'infection du système nerveux central. L'étude note que contrairement aux poumons où les virions disparaissent par l'action immunitaire, le cerveau est sujet à une cinétique forte d'infection plus tardive, qui déclenche une réponse inflammatoire. Des analyses tissulaires, ressort la présence d'hémorragies périvasculaires, des infiltrations de leucocytes et la mort de certaines cellules neuronales. Les antigènes du virus sont détectés dans tout le cerveau murin, y compris le cortex, le cervelet et l'hippocampe. Les auteurs estiment que le cerveau est un site majeur d'infection au SARS-CoV-2 suite à une infection par voie intranasale : d'abord le bulbe olfactif, puis par propagation dans le cerveau en suivant les axones des neurones du cerveau qui s'y connectent. Selon Mukesh Kumar, l'un des co-auteurs de l'étude, c'est là où le virus peut se réfugier parce qu'il n'y a pas le même niveau de réponse immunitaire que dans d'autres organes. Ce tropisme est corrélé selon lui aux symptômes systémiques, notamment cardiaques, à l'anosmie, et à d'autres troubles neurologiques qui sont caractéristiques du covid long.
38	N36		E Guedj, M Million, P Dudouet, H Tissot-Dupont, F Bregeon, S Cammilleri & D Raoult	18F-FDG brain PET hypometabolism in post-SARS-CoV-2 infection: substrate for persistent/delayed disorders?	https://doi.org/10.1007/s00259-020-04973-x	Published	30 July 2020	Short Communication	https://link.springer.com/article/10.1007%2Fs00259-020-04973-x		_
39	N37	Yes	E. Guedj, J. Y. Campion, P. Dudouet, E. Kaphan, F. Bregeon, H. Tissot-Dupont, S. Guis, F. Barthelemy, P. Habert, M. Ceccaldi, M. Million, D. Raoult, S. Cammilleri & C. Eldin	18F-FDG brain PET hypometabolism in patients with long COVID	https://doi.org/10.1007/s00259-021-05215-4	Published	26 January 2021	Study	https://link.springer.com/article/10.1007/s00259-021-05215-4	In comparison to healthy subjects, patients with long COVID exhibited bilateral hypometabolism in the bilateral rectal/orbital gyrus, including the olfactory gyrus; the right temporal lobe, including the amygdala and the hippocampus, extending to the right thalamus; the bilateral pons/medulla brainstem; the bilateral cerebellum	Une étude suggère qu'un hypométabolisme (activité plus basse qu'attendue) dans les zones du cerveau proches du bulbe olfactif, relevé par TEP-scanner cérébral, pourrait être un biomarqueur des malades du covid long. L'étude note que le neurotropisme de certains coronavirus (SRAS, MERS) avait déjà été évoqué (https://sciencedirect.com/science/article/abs/pii/S0889159120303573). Elle relève cependant un hypométabolisme moindre chez 3 patients qui avaient utilisé en traitement initial un spray nasal décongestionnant, et plus important chez les patients ayant une utilisation récente d'inhibiteurs ACE (médicaments contre l'hypertension). L'étude est réalisée sur une cohorte de 35 patients, infectés au SARS-CoV-2 et présentant des séquelles usuelles du covid long. Au sujet de l'étude Guedj & al., l'auteur décrit, dans des commentaires vidéo des résultats, des symptômes neurologiques inversement corrélés avec l'âge, et une corrélation avec le temps écoulé après l'infection, pouvant résulter d'un biais de sélection. Le Dr Guedj (hôpital La Timone) note qu'"on ne peut pas raccrocher l'atteinte du tronc cérébral, très atypique, à un éventuel syndrome de stress post-traumatique". [2/2] https://youtu.be/E5yQEhB-qRA	N001
40	N38		Chiara Pizzanelli, Chiara Milano, Silvia Canovetti, Mirco Cosottini, Gabriele Siciliano	Autoimmune limbic encephalitis related to SARS-CoV-2 infection: Case-report and review of the literature	https://doi.org/10.1016/j.bbih.2021.100210	Published	24 January 2021	Short Communication	https://www.sciencedirect.com/science/article/pii/S2666354621000132		Une étude évoque un cas d'encéphalite limbique autoimmune attribuée à une infection de covid, et répertorie 5 autres cas de cette association dans les publications médicales.
41	N39		Biyan Nathanael Harapan & Hyeon Joo Yoo	Neurological symptoms, manifestations, and complications associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 19 (COVID-19)	https://doi.org/10.1007/s00415-021-10406-y	Published	23 January 2021	Review	https://link.springer.com/article/10.1007/s00415-021-10406-y		Dans Journal of Neurology, une riche revue d'études des connaissances acquises sur les séquelles neurologiques de la covid, avec les mécanismes suspectés, impliquant les systèmes nerveux central et périphérique, ainsi que le musculosquelettique.	N003
42	N40		Tamar Wildwing, Nicole Holt	The neurological symptoms of COVID-19: a systematic overview of systematic reviews, comparison with other neurological conditions and implications for healthcare services	https://doi.org/10.1177%2F2040622320976979	Published	January 28, 2021	Review Article	https://journals.sagepub.com/doi/full/10.1177/2040622320976979		Un aperçu des revues d'études sur les symptômes neurologiques de la covid note que ceux-ci présentent des similarités avec d'autres conditions neurologiques telles que le syndrome de fatigue chronique (SFC) et les troubles neurologiques fonctionnels (TNF).
43	N41		E. Leslie Cameron, Per Møller, Keith S. Karn	Effects of COVID-19 on Sense of Smell: Human Factors/Ergonomics Considerations	https://doi.org/10.1177%2F0018720821990162	Published	February 1, 2021	Research Article	https://journals.sagepub.com/doi/full/10.1177/0018720821990162	COVID-19 is known to reduce the olfactory sense (smell) in people who contract the disease. The duration of the loss is not well characterized at this time, but some may experience permanent dysfunction in the sense of smell. Human factors/ergonomics professionals should be aware of the increased number of people with olfactory dysfunction and consider ways to accommodate them. While the sense of smell is not commonly thought of as a primary means of human-system communication, we rely on smell in many important ways that relate to both quality of life and safety. Olfaction has received relatively little attention from human factors/ergonomics professionals. Product research and development teams have just begun to tap into the sense of smell to augment human system communication.	Un article de recherche s'intéresse à la perte d'odorat dans la covid. Rapportée par 35% des patients, elle est en réalité mesurable dans 98% des cas. L'étude souligne que l'anosmie a d'importantes répercussions dans la vie quotidienne.
44	N42	Yes	Shin Jie Yong	Persistent Brainstem Dysfunction in Long-COVID: A Hypothesis	https://doi.org/10.1021/acschemneuro.0c00793	Published	February 4, 2021	Article	https://pubs.acs.org/doi/10.1021/acschemneuro.0c00793	While the possible causes of long-COVID include long-term tissue damage, viral persistence, and chronic inflammation, the review proposes, perhaps for the first time, that persistent brainstem dysfunction may also be involved. This hypothesis can be split into two parts. The first is the brainstem tropism and damage in COVID-19. As the brainstem has a relatively high expression of ACE2 receptor compared with other brain regions, SARS-CoV-2 may exhibit tropism therein. Evidence also exists that neuropilin-1, a co-receptor of SARS-CoV-2, may be expressed in the brainstem. Indeed, autopsy studies have found SARS-CoV-2 RNA and proteins in the brainstem. The brainstem is also highly prone to damage from pathological immune or vascular activation, which has also been observed in autopsy of COVID-19 cases. The second part concerns functions of the brainstem that overlap with symptoms of long-COVID. The brainstem contains numerous distinct nuclei and subparts that regulate the respiratory, cardiovascular, gastrointestinal, and neurological processes, which can be linked to long-COVID. As neurons do not readily regenerate, brainstem dysfunction may be long-lasting and, thus, is long-COVID. Indeed, brainstem dysfunction has been implicated in other similar disorders, such as chronic pain and migraine and myalgic encephalomyelitis or chronic fatigue syndrome.	Le neurobiologiste Shin Jie Yong (@Shin63714105) détaille une hypothèse sur le covid long. Selon lui, un dysfonctionnement persistant du tronc cérébral, qui régule des processus respiratoire, cardiovasculaire, gastro-intestinal et neurologique, pourrait expliquer une partie des symptômes fonctionnels. Cette atteinte serait alors liée à l'expression de récepteurs ACE2 et neuropiline 1 dans le tronc cérébral, ou à la vulnérabilité de celui-ci aux pathologies immunitaires ou vasculaires. À lire : l'intégralité de l'article de @Shin63714105 sur l'hypothèse d'un dysfonctionnement persistent du tronc cérébral pour expliquer les symptômes neurologiques du covid long. https://drive.google.com/file/d/1p0vtb0pDJx-dvNHGOVbwW4a1u6-1J-cI/view?usp=drivesdk L'auteur avance que ce dysfonctionnement pourrait expliquer la dysautonomie et autres troubles cardiaques, respiratoires, intestinaux, ou systémiques. La faible faculté des neurones du tronc cérébral à se régénérer pourrait laisser présager des symptômes au très long cours.	N001
45	N43	ES	Jakob Matschke, Marc Lütgehetmann, Christian Hagel, Ann Sophie Schröder, Carolin Edler, Herbert Mushumba, Stefan Bonn, Marco Prinz, Christian Gerloff, Markus Glatzel	Neuropathology of patients with COVID-19 in Germany: a post-mortem case series	https://doi.org/10.1016/S1474-4422(20)30308-2	Published	November 2020	Cases Series	https://www.sciencedirect.com/science/article/abs/pii/S1474442220303082		Cette étude, par autopsies, indique une détection de protéines virales du SARS-CoV-2 dans le tronc cérébral chez certaines victimes de la covid.	N001R
46	N44		Jan Remsik 9 Jessica A. Wilcox 9 N. Esther Babady Edward K. Avila Bianca Santomasso Adrienne Boire	Inflammatory Leptomeningeal Cytokines Mediate COVID-19 Neurologic Symptoms in Cancer Patients	https://doi.org/10.1016/j.ccell.2021.01.007	Published	January 16, 2021	Prospective study	https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00051-9	- Inflammatory cytokines are detected in the CSF weeks after SARS-CoV-2 infection - Levels of IFN-β and IL-8 are specifically enriched in the CSF compared with plasma - CSF markers of senescence and neurodegeneration are consistent with neuronal injury - Intracranial levels of MMP-10 correlate with the degree of neurologic disability Here, we present the clinical neurologic characterization of cancer patients with neurologic toxicity after SARS-CoV-2 infection correlated with biochemical analysis of CSF. As comparators, we analyzed CSF collected from cancer patients with an array of neuroinflammatory conditions, including autoimmune encephalitis and chimeric-antigen-receptor T cell (CAR T)-associated neurotoxicity. We correlated CSF composition with degree of neurologic dysfunction. In doing so, we have found evidence for a sustained neuroinflammation and subsequent neuronal damage as a key pathway in the pathogenesis of COVID-19-associated encephalopathy.	Une étude sur des patients cancéreux atteints de la covid et présentant des troubles neurologiques oriente vers un mécanisme de neuroinflammation prolongée et des lésions neuronales consécutives à l'infection. Ce mécanisme est décrit comme élément clé dans la pathogenèse de l'encéphalopathie associée à la covid. Les auteurs notent également que les taux de MMP-10 dans le liquide cérébrospinal sont corrélés avec l'importance des manifestations neurologiques.	N001R
47	N45		Ruqaiyyah Siddiqui,Mohammad Ridwane Mungroo &Naveed Ahmed Khan	SARS-CoV-2 invasion of the central nervous: a brief review	https://doi.org/10.1080/21548331.2021.1887677	Published	08 Feb 2021	Review Article	https://www.tandfonline.com/doi/full/10.1080/21548331.2021.1887677		Une brève revue d'études entreprend de faire le point sur les mécanismes qui permettent au SARS-CoV2 d'entrer dans le système nerveux central.
48	N46		David W. Nauen, MD, PhD1; Jody E. Hooper, MD1; C. Matthew Stewart, MD, PhD2; Isaac H. Solomon	Assessing Brain Capillaries in Coronavirus Disease 2019	https://doi.org/10.1001/jamaneurol.2021.0225	Published	February 12, 2021	Research Letter	https://jamanetwork.com/journals/jamaneurology/fullarticle/2776455	Hannah Davis @ahandvanish (Twitter) : A new possible theory of COVID/#LongCOVID brain fog from Johns Hopkins - large megakaryocyte (bone marrow) cells found in the brain. These could block blood flow through individual capillaries, "resulting in an atypical form of neurologic impairment." 1/ Layman's translation from https://www.medscape.com/viewarticle/945774 "I was taken aback; I couldn't figure out what they were. Then I realized these cells were megakaryocytes from the bone marrow. I have never seen these cells in the brain before." 2/"This might alter the hemodynamics & put pressure on other vessels." None of the samples he examined came from patients with COVID-19 who had had a stroke. Other than the megakaryocytes, the brain looked normal. He examined 15 brains...megakaryocytes were found in 5 cases. 3/"Megakaryocytes are bone marrow cells, not immune cells. Their job is to produce platelets to help the blood clot. They are not normally found outside bone marrow, but they have been reported in other organs in COVID-19 patients." 4/"The big puzzle with finding them in the brain is how they get through the very fine network of blood vessels in the lungs. The geometry just doesn't work. We don't know which part of the COVID inflammatory response makes this happen," said Nauen. 5/Another mention of endothelial dysfunction: The authors suggest one possibility is that altered endothelial or other signaling is recruiting megakaryocytes into the circulation." 6/	Une étude effectuée à partir d'autopsies de victimes de covid retrouve des cellules identifiées comme des mégakaryocytes (cellules de moelle osseuse fabriquant les plaquettes) dans certains échantillons du cerveau, emplacement inédit pour ces cellules. Ceux-ci pourraient bloquer la circulation sanguine à travers les capillaires, entraîner une forme atypique de déficience neurologique, et jouer un rôle dans les troubles de coagulation souvent observés dans la covid.	N002N
49	N47		Anand Ramani, Pranty AbidaIslam1Jay Gopalakrishnan	Neurotropic effects of SARS-CoV-2 modeled by the human brain organoids	https://doi.org/10.1016/j.stemcr.2021.02.007	Published	12 February 2021	Perspective	https://www.sciencedirect.com/science/article/pii/S2213671121000874	Here, we summarize the neurotoxic effects of SARS-CoV-2 using brain organoids and comprehensively discuss how brain organoids could further improve our understanding when they are fine-tuned.	Un article fait le point sur l'utilisation d'organoïdes de cerveaux humains pour comprendre le neurotropisme du virus SARS-CoV-2 à travers différentes études.
50	N48		Roberta Ferrucci, Michelangelo Dini, Elisabetta Groppo, Chiara Rosci, Maria Rita Reitano, Francesca Bai, Barbara Poletti, Agostino Brugnera, Vincenzo Silani, Antonella D’Arminio Monforte and Alberto Priori	Long-Lasting Cognitive Abnormalities after COVID-19	https://doi.org/10.3390/brainsci11020235	Published	13 February 2021	Study	https://www.mdpi.com/2076-3425/11/2/235	We recruited 38 (aged 22–74 years; 27 males) patients hospitalized for complications of SARS-CoV-2 infection in nonintensive COVID units. Participants underwent neuropsychological testing about 5 months after hospital discharge. Of all patients, 42.1% had processing speed deficits, while 26.3% showed delayed verbal recall deficits. Twenty-one percent presented with deficits in both processing speed and verbal memory. Bivariate analysis revealed a positive correlation between the lowest arterial oxygen partial pressure (PaO2) to fractional inspired oxygen (FiO2) (P/F) ratio during hospitalization and verbal memory consolidation performance (SRT-LTS score, r = 0.404, p = 0.027), as well as a positive correlation between SpO2 levels upon hospital arrival and delayed verbal recall performance (SRT-D score, rs = 0.373, p = 0.042). Acute respiratory distress syndrome (ARDS) during hospitalization was associated with worse verbal memory performance (ARDS vs. no ARDS: SRT-LTS mean score = 30.63 ± 13.33 vs. 44.50 ± 13.16, p = 0.007; SRT-D mean score = 5.95 ± 2.56 vs. 8.10 ± 2.62, p = 0.029). Cognitive abnormalities can frequently be found in COVID-19 patients 5 months after hospital discharge. Increased fatigability, deficits of concentration and memory, and overall decreased cognitive speed months after hospital discharge can interfere with work and daily activities.	Dans une étude sur une petite cohorte de malades de la covid hospitalisés mais sans passage en réanimation, des chercheurs retrouvent après 5 mois, chez 42%, des lenteurs cognitives anormales et chez 26% des déficits de remémoration verbale.	N003
51	N49		Edwin Estefan Reza-Zaldívar, Mercedes Azucena Hernández-Sapiéns, Benito Minjarez, Ulises Gómez-Pinedo, Ana Laura Márquez-Aguirre, Juan Carlos Mateos-Díaz, Jorge Matias-Guiu, and Alejandro Arturo Canales-Aguirre	Infection Mechanism of SARS-COV-2 and Its Implication on the Nervous System	https://doi.org/10.3389%2Ffimmu.2020.621735	Published	2021 Jan 29	Review	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878381/	it has been demonstrated that SARS-CoV-2 affects the CNS. As overwhelming proof, there is the isolation of SARS-CoV-2 from cerebrospinal fluid, the colocalization within the olfactory system, the ultrastructural evidence of frontal lobe budding SARS-CoV-2, and the list of neurologic manifestations in the COVID-19 patients. Unfortunately, it is unclear if the neurological symptoms of COVID-19 result from cytokine storm-induced neuroinflammation or some brain areas’ infection. Nevertheless, the CNS and immune system involvement might have remarkably neurologic long-term consequences, including the development of neuropsychiatric disorders.	Une revue d'études entreprend d'établir les voies possibles de la neuroinvasion du SARS-CoV-2, notamment la voie synaptique depuis le bulbe olfactif ainsi que celles des terminaisons nerveuses périphériques, et l'impact sur le système nerveux central. Les auteurs notent qu'il est établi que la covid peut endommager le système nerveux central, et qu'il reste la question de savoir s'il s'agit d'une neuroinflammaiton ou d'une infection directe du tissu cérébral.	N002N
52	N50		Bing Sun, Norina Tang, Michael J. Peluso, Nikita S. Iyer, Leonel Torres, Joanna L. Donatelli, Sadie E. Munter, Christopher C. Nixon, Rachel L. Rutishauser, Isabel Rodriguez-Barraquer, Bryan Greenhouse, John D. Kelly, Jeffrey N. Martin, Steven G. Deeks, Timothy J. Henrich and Lynn Pulliam	Characterization and Biomarker Analyses of Post-COVID-19 Complications and Neurological Manifestations	https://doi.org/10.3390/cells10020386	Published	13 February 2021	Study	https://www.mdpi.com/2073-4409/10/2/386	Plasma from 24 individuals recovering from COVID-19 at 1 to 3 months after initial infection were collected for cytokine and antibody levels and neuronal-enriched extracellular vesicle (nEV) protein cargo analyses. Plasma cytokine IL-4 was increased in all COVID-19 participants. Volunteers with self-reported neurological problems (nCoV, n = 8) had a positive correlation of IL6 with age or severity of the sequalae, at least one co-morbidity and increased SARS-CoV-2 antibody compared to those COVID-19 individuals without neurological issues (CoV, n = 16). Protein markers of neuronal dysfunction including amyloid beta, neurofilament light, neurogranin, total tau, and p-T181-tau were all significantly increased in the nEVs of all participants recovering from COVID-19 compared to historic controls. This study suggests ongoing peripheral and neuroinflammation after COVID-19 infection that may influence neurological sequelae by altering nEV proteins. Individuals recovering from COVID-19 may have occult neural damage while those with demonstrative neurological symptoms additionally had more severe infection.	Une étude s'intéresse aux biomarqueurs neurologiques liés à une infection de covid. Elle suggère une neuroinflammation périphérique continue avec des séquelles neurologiques par la dégradation des vésicules extracellulaires enrichies en neurones.	N004R
53	N51		Maria Rosaria Rizzo*, Giuseppe Paolisso	SARS-CoV-2 Emergency and Long-Term Cognitive Impairment in Older People	https://doi.org/10.14336/AD.2021.0109	Published	27 January 2021	Article	http://www.aginganddisease.org/EN/10.14336/AD.2021.0109	"data on potential long-term damages generally and on long-term cognitive functions impairment of older COVID-19 survivors have yet to be investigated." "we wanted to explore the brain mechanisms of SARS-CoV-2, in order to provide more in-depth analysis and to draw attention to a topic relevant to basic scientific research and, more generally, to the elderly population.Looking forward, we argue that an early clinical and instrumental cognitive assessment can help prevent and slow down this possible complication or at least improve the quality of life for older people Covid-19 survivor."	Un article d'analyse explore les différents mécanismes de dommages cérébraux de la covid, notamment chez les personnes âgées. Il insiste sur l'invalidité chronique qui peut résulter de ces dommages cérébraux.	N003R
54	N52		Amr El-Sayed, Lotfi Aleya & Mohamed Kamel	COVID-19: a new emerging respiratory disease from the neurological perspective	https://doi.org/10.1007/s11356-021-12969-9	Published	15 February 2021	Review	https://link.springer.com/article/10.1007/s11356-021-12969-9	"The involvement of the central nervous system is now suspected to be among the main causes of death."	L'implication des dommages au système nerveux central est désormais suspectée être l'une des principales causes de décès de covid, selon cette revue d'études.
55	N53		Amruta Narayanappa Wesley H.Chastain Meshi Paza Rebecca J.Solch Isabel C. Murray-Brown Jaime B.Befelera Timothy E.Gressetta Michele T. Longo Elizabeth B. Engler-Chiurazzi Gregory Bix	SARS-CoV-2 mediated neuroinflammation and the impact of COVID-19 in neurological disorders	https://doi.org/10.1016/j.cytogfr.2021.02.002	Published	19 February 2021		https://www.sciencedirect.com/science/article/pii/S1359610121000186	Review : Highlights •SARS-CoV-2, a novel coronavirus that severely affects the respiratory system, is the cause of the COVID-19 pandemic. •Illustrates immune cell infiltration, cytokine storm, and inflammation. •Discusses SARS-CoV-2 mediates neuroinflammation and the impact of COVID-19 in neurological disorders. •ATN-161 inhibits SARS-CoV-2 spike protein binding to both integrin α5β1 and α5β1/hACE2. •Summarizes available treatments and vaccines to treat COVID-19 patients.	Une revue d'études très générale aborde la question de la neuro-inflammation induite possible lors d'une infection au SARS-CoV-2.
56	N54		Mazza Mario Gennaro a b Palladini Maria grazia aRebecca De Lorenzo b c Magnaghi Cristiano c Poletti Sara a b Furlan Roberto b d Ciceri Fabio b c 1 Rovere-Querini Patrizia b c Benedetti Francesco a b	Persistent psychopathology and neurocognitive impairment in COVID-19 survivors: effect of inflammatory biomarkers at three-month follow-up	https://doi.org/10.1016/j.bbi.2021.02.021	Published	24 February 2021	Study	https://www.sciencedirect.com/science/article/pii/S0889159121000866	Highlights •COVID-19 is associated with acute and short-term psychiatric implications. •We found depressive symptomatology and neurocognitive impairment at three months. •Systemic inflammation predicted depressive symptomatology and cognitive impairment. •Attention and information processing were strictly related to depression. •COVID-19 related inflammation leads to depression and cognitive dysfunction.	Les résultats d'une étude à 3 mois de l'hospitalisation font suggérer aux auteurs que la covid pourrait causer une inflammation systémique prolongée qui prédispose les patients à une dépression persistante et à un dysfonctionnement neurocognitif associé.
57	N55		Yuanyuan Qin,1 Jinfeng Wu,2 Tao Chen,3 Jia Li,1 Guiling Zhang,1 Di Wu,1 Yiran Zhou,1 Ning Zheng,4 Aoling Cai,2 Qin Ning,5 Anne Manyande,6 Fuqiang Xu,4 Jie Wang,7 and Wenzhen Zhu	Long-term micro-structure and cerebral blood flow changes in patients recovered from COVID-19 without neurological manifestations	https://doi.org/10.1172/JCI147329	Published	February 25, 2021	Study	https://www.jci.org/articles/view/147329	Here, two subtypes (mild type-MG and severe type-SG) with no specific neurological manifestations at the acute stage and no obvious lesions on the conventional MRI three months after discharge were recruited. Changes in gray matter morphometry, cerebral blood flow (CBF) and white matter (WM) microstructure were investigated using MRI. The relationship between brain imaging measurements and inflammation markers were further analyzed. Compared with healthy controls, the decrease in cortical thickness/CBF, and the changes in WM microstructure were observed to be more severe in the SG than MG, especially in the frontal and limbic systems. Furthermore, changes in brain microstructure, CBF and tracts parameters were significantly correlated with inflammatory markers. The indirect injury related to inflammatory storm may damage the brain, that led to these interesting observations. There are also other likely potential causes, such as hypoxemia and dysfunction of vascular endothelium, et al.	Comparé à un groupe contrôle sain, une étude note que la circulation cérébrovasculaire et l'épaisseur corticale a tendance à avoir diminué à 3 mois chez les personnes atteintes de la covid, en particulier dans les systèmes frontal et limbique. Ces constatations se retrouvent corrélées à des marqueurs inflammatoires et à la sévérité de la phase de covid aiguë.	N003A
58	N56		Michael Fleischer, Martin Köhrmann, Sebastian Dolff, Fabian Szepanowski, Karsten Schmidt, Frank Herbstreit, Cansu Güngör, Benjamin Stolte, Katharina Marie Steiner, Christine Stadtler, Joachim Riße, Melanie Fiedler, Gerd Meyer zu Hörste, Anne-K. Mausberg, Clemens Kill, Michael Forsting, Ulrich Sure, Ulf Dittmer, Oliver Witzke, Thorsten Brenner, Christoph Kleinschnitz*, Mark Stettner	Observational cohort study of neurological involvement among patients with SARS-CoV-2 infection	https://doi.org/10.1177%2F1756286421993701	Published	February 26, 2021	Research Article	https://journals.sagepub.com/doi/full/10.1177/1756286421993701	"Cerebrovascular events were the most frequent severe NIV and severe NIV was associated with high mortality. Incidence of NIV increased with respiratory symptoms and NIV and pre-existing neurological morbidities were independent risk factors for fatality. Inflammatory involvement due to BBB disruption and cytokine release drives NIV, rather than direct viral invasion."	Une étude rapporte que dans 75% des décès de covid, les patients présentaient des dysfonctions neurologiques aggravées par la covid ou consécutives à celle-ci. Les analyses du liquide cérébrospinal et du sang suggèrent que la perturbation de la barrière hémato-encéphalique, la libération de cytokines ainsi que des mécanismes auto-immuns sont impliqués dans le développement des troubles neurologiques de la covid. Ces mécanismes tendraient à écarter l'invasion virale directe au niveau cérébral.
59	N57		Martina Sollini 1 2, Silvia Morbelli 3 4, Michele Ciccarelli 1, Maurizio Cecconi 1 2, Alessio Aghemo 1 2, Paola Morelli 1 2, Silvia Chiola 1 2, Fabrizia Gelardi 5 6, Arturo Chiti	Long COVID hallmarks on [18F]FDG-PET/CT: a case-control study	https://doi.org/10.1007/s00259-021-05294-3	Published	2021 Mar 7	Study	https://link.springer.com/article/10.1007/s00259-021-05294-3	Results: In 4/13 long COVID patients, CT images showed lung abnormalities presenting mild [18F]FDG uptake. Many healthy organs/parenchyma SUVs and SUV ratios significantly differed between the two groups (p ≤ 0.05). Long COVID patients exhibited brain hypometabolism in the right parahippocampal gyrus and thalamus (uncorrected p < 0.001 at voxel level). Specific area(s) of hypometabolism characterised patients with persistent anosmia/ageusia, fatigue, and vascular uptake (uncorrected p < 0.005 at voxel level). Conclusion: [18F]FDG PET/CT acknowledged the multi-organ nature of long COVID, supporting the hypothesis of underlying systemic inflammation. Whole-body images showed increased [18F]FDG uptake in several "target" and "non-target" tissues. We found a typical pattern of brain hypometabolism associated with persistent complaints at the PET time, suggesting a different temporal sequence for brain and whole-body inflammatory changes. This evidence underlined the potential value of whole-body [18F]FDG PET in disclosing the pathophysiology of long COVID.	En effectuant un PET-SCAN "corps entier" sur une cohorte de 13 patients qui souffrent de symptômes persistants après une infection de covid, et en comparant avec un groupe contrôle, une équipe italienne confirme les résultats d'une étude française. Un hypométabolisme est noté dans certaines régions cérébrales, notamment le gyrus parahippocampique et le thalamus droits. Des anomalies d'hypermétabolisme sont également retrouvées sur certains organes et tissus, et traduisent un syndrome inflammatoire multi-systémique. Une absorption anormale au niveau du foie, et parfois, de façon plus inquiétante pour les auteurs, de la moelle osseuse, est relevée dans cette cohorte covid long, âgée de 46 à 79 ans, la moitié sans hospitalisation. Les observations de cette étude font dire aux auteurs que les PET-SCAN "corps entier" pourraient devenir un examen de référence dans l'étude des atteintes organiques et systémiques chez les malades covid longs.	N003A
60	N58		Michelle A. Erickson 1,2,* ,Elizabeth M. Rhea 1,2 ,Rachel C. Knopp 1,2 andWilliam A. Banks 1,2,*	Interactions of SARS-CoV-2 with the Blood–Brain Barrier	https://doi.org/10.1007/s00259-021-05294-3	Published	6 March 2021	Review	https://www.mdpi.com/1422-0067/22/5/2681	Emerging data indicate that neurological complications occur as a consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The blood–brain barrier (BBB) is a critical interface that regulates entry of circulating molecules into the CNS, and is regulated by signals that arise from the brain and blood compartments. In this review, we discuss mechanisms by which SARS-CoV-2 interactions with the BBB may contribute to neurological dysfunction associated with coronavirus disease of 2019 (COVID-19), which is caused by SARS-CoV-2. We consider aspects of peripheral disease, such as hypoxia and systemic inflammatory response syndrome/cytokine storm, as well as CNS infection and mechanisms of viral entry into the brain. We also discuss the contribution of risk factors for developing severe COVID-19 to BBB dysfunction that could increase viral entry or otherwise damage the brain.	Une analyse très technique sur la façon dont le virus SARS-CoV-2 pourrait franchir la barrière hémato-encéphalique (vaisseaux sanguins / système cérébral). Une recherche est faite sur les facteurs de risque favorisant cette entrée.	N004
61	N59		Zheng Li, Xingye Li, Jianxiong Shen, Matthew T.V. Chan & William Ka Kei Wu	Miller Fisher syndrome associated with COVID-19: an up-to-date systematic review	https://doi.org/10.1007/s11356-021-13233-w	Published	06 March 2021	Review Article	https://link.springer.com/article/10.1007/s11356-021-13233-w	Recently, during the pandemic infection of the novel SARS-CoV-2, some cases of Miller Fisher syndrome (MFS) have been reported. We want to summarize the main features of patients with MFS and COVID-19. A PubMed search was performed on 8 October to identify references reporting cases with MFS associated with COVID-19 from the first report of COVID-19 to 8 October 2020 using the following keywords: “Miller Fisher syndrome” AND “COVID-19” OR “SARS-CoV-2”. A systematic review from the first report of coronavirus disease 2019 (COVID-19) to 8 October 2020 revealed 7 cases with Miller Fisher syndrome (MFS) associated with COVID-19. The 7 cases came from 5 countries but most of these patients were from Europe (85.7%), especially Spain. There are 5 cases of MFS diagnosed after the laboratory confirmation of SARS-CoV-2 infection. The mean onset time of MFS-associated neurological symptoms was 14.75 days after the diagnosis of COVID-19. However, the two remaining cases presented initially with MFS-associated neurological symptoms followed by the diagnosis of COVID-19. The most common symptoms of COVID-19-associated MFS were perioral paresthesias (57.1%), ataxia (57.1%), blurred vision (42.9), ophthalmoplegia (42.9), and generalized areflexia (42.9). However, more cohort and case-control studies are required to establish the epidemiological linkage.	Une étude systématique de publications sur les interactions entre la covid et le syndrome (rare) de Miller-Fisher (une maladie auto-immune neurologique).
62	N60		Thông Hua-Huy , Christine Lorut , Frédérique Aubourg , Caroline Morbieu , Jonathan Marey , Joëlle Texereau , Isabelle Fajac , Luc Mouthon , Nicolas Roche , and Anh Tuan Dinh-Xuan	Persistent Nasal Inflammation Five Months After Acute Anosmia in Patients with COVID-19	https://doi.org/10.1164/rccm.202011-4258LE	Published	March 04, 2021	Study	https://www.atsjournals.org/doi/10.1164/rccm.202011-4258LE	there is clear evidence of persistent inflammation 5 months after onset of symptoms in COVID patients who have recovered from their OD. Whether this will lead to chronic rhino-sinus diseases is yet to be investigated.	Le point sur les inflammations nasales persistantes, consécutives à la covid, menant à un dysfonctionnement olfactif (anosmie), qui peuvent se prolonger de nombreux mois après l'infection.
63	N61		Ali Al-Ramadan 1,2 ,Omar Rabab’h 1,2 ,Jawad Shah 1,2,3,4,5 andAbeer Gharaibeh	Acute and Post-Acute Neurological Complications of COVID-19	https://doi.org/10.3390/neurolint13010010	Published	9 March 2021	Review	https://www.mdpi.com/2035-8377/13/1/10	we have summarized the most common neurological complications and reported neurological case studies associated with COVID-19, and neurological side effects associated with COVID-19 treatments. Additionally, the post-acute COVID-19 syndrome and long-term neurological complications were discussed. We also explained the proposed mechanisms that are involved in the pathogenesis of these neurological complications.	Une revue d'études fait le point sur les complications neurologiques de la covid. L'analyse rappelle également les différents scénarios qui pourraient expliquer ces séquelles et la façon dont le système nerveux central est affecté.	N004
64	N62		Shibani S.MukerjiaIsaac H.Solomon	What can we learn from brain autopsies in COVID-19?	https://doi.org/10.1016/j.neulet.2020.135528	Published	November 25, 2020	Minireview	https://www.sciencedirect.com/science/article/pii/S0304394020307989	•Chronic neurological disease and acute abnormalities are present in COVID-19 brain autopsies. •Acute hypoxic-injury, hemorrhage, and minimal inflammation are frequently observed. •Low levels of viral SARS-CoV-2 RNA are present; cellular source remains unknown. There remains no clear understanding of the mechanisms that underlie neurological symptoms in COVID-19 and whether SARS-CoV-2 has the potential for neuroinvasion in humans. In this minireview, we discuss what is known from human autopsies in fatal COVID-19, including highlighting studies that investigate for the presence of SARS-CoV-2 in brain and olfactory tissue, and summarize the neuropathological consequences of infection.	Une courte revue d'études s'intéresse aux symptômes neurologiques de la covid.	N006
65	N63		Dipak Kumar, Sadaf Jahan, Andleeb Khan, Arif Jamal Siddiqui, Neeru Singh Redhu, Wahajuddin, Johra Khan, Saeed Banwas, Bader Alshehri & Mohammed Alaidarous	Neurological Manifestation of SARS-CoV-2 Induced Inflammation and Possible Therapeutic Strategies Against COVID-19	https://doi.org/10.1007/s12035-021-02318-9	Published	14 March 2021	Review	https://link.springer.com/article/10.1007/s12035-021-02318-9	This review discusses the concerns regarding the neuronal complications of COVID-19 and the possible mechanisms of amelioration.	_
66	N64		Lisa Bauer, Bas Lendemeijer, Lonneke Leijten, Carmen W. E. Embregts, Barry Rockx, Steven A. Kushner, Femke M.S. de Vrij, Debby van Riel	Replication kinetic, cell tropism and associated immune responses in SARS-CoV-2 and H5N1 virus infected human iPSC derived neural models	https://doi.org/10.1101/2021.03.15.435472	pre-print	March 16, 2021	New Results	https://www.biorxiv.org/content/10.1101/2021.03.15.435472v1	Our findings support the hypothesis that neurological complications might result from local immune responses triggered by virus invasion, rather than abundant SARS-CoV-2 replication in the CNS.	_
67	N65		Amit Mahajan1 and Graeme F. Mason	A sobering addition to the literature on COVID-19 and the brain	https://doi.org/10.1172/JCI148376	Published	March 16, 2021	Commentary	https://www.jci.org/articles/view/148376	Several COVID-19 studies have focused on neuropathology. In this issue of the JCI, Qin, Wu, and Chen, et al. focused specifically on people whose acute infection lacked obvious neurological involvement. Severely infected patients showed abnormal grey matter volumes, white matter diffusion, and cerebral blood flow compared with healthy controls and those with mild infection. The data remain associative rather than mechanistic, but correlations with systemic immune markers suggest effects of inflammation, hypercoagulation, or other aspects of disease severity. Mechanistic research is warranted. Given the lack of obvious neurological symptoms, neurocognitive assessments were not performed, but the findings suggest that such assessments may be warranted in severely affected patients, even without obvious symptoms. Further, studying CNS involvement of other disorders with overlapping pathophysiologies, such as inflammation, coagulation, hypoxia, or direct viral infection may reveal the causes for COVID-19 related neuropathology.	_
68	N66		BrycePolascikB.S.JeffreyBrowndykePh.D.SimonDavisPh.D.AndyLiu	Cognitive consequences of COVID-19 in older adults with cognitive impairment	https://doi.org/10.1016/j.jagp.2021.01.066	Published	16 March 2021	Cases Report	https://www.sciencedirect.com/science/article/pii/S1064748121000920	This case series describes the exacerbation of pre-existing psychiatric and cognitive conditions after COVID-19 recovery in 3 older adults with formal neuropsychological evaluation data.	_
69	N67		Edith L Graham Jeffrey R Clark Zachary S Orban Patrick H Lim April L Szymanski Carolyn Taylor Rebecca M DiBiase Dan Tong Jia Roumen Balabanov Sam U Ho Ayush Batra Eric M Liotta Igor J Koralnik	Persistent neurologic symptoms and cognitive dysfunction in non‐hospitalized Covid‐19 “long haulers”	https://doi.org/10.1002/acn3.51350	Published	23 March 2021	Study	https://onlinelibrary.wiley.com/doi/10.1002/acn3.51350	This is a prospective study of the first 100 consecutive patients (50 SARS‐CoV‐2 laboratory‐positive and 50 laboratory‐negative individuals) presenting to our Neuro‐Covid‐19 clinic between May and November 2020. Due to early pandemic testing limitations, patients were included if they met Infectious Diseases Society of America symptoms of Covid‐19, were never hospitalized for pneumonia or hypoxemia and had neurologic symptoms lasting over 6 weeks. Whereas hypoxemia, systemic inflammation, coagulopathy, and neuroinvasion have been implicated in hospitalized Covid‐19 patients who develop encephalopathy,3 it appears more likely that post‐infectious, autoimmune mechanisms may be at play in “long Covid.” The long‐term impact of “long Covid” on quality of life and potential return to normalcy, through lost productivity and lingering cognitive dysfunction, may be substantial as the pandemic continues to escalate.	_
70	N68		Ritwick Mondal ShramanaDebb Gourav Shom e c Upasan a Ganguly a Durjoy Lahiri a d Julián Benito-Leon	COVID-19 and emerging spinal cord complications: A systematic review	https://doi.org/10.1016/j.msard.2021.102917	Published	21 March 2021	Original article	https://www.sciencedirect.com/science/article/pii/S221103482100184X	Highlights •Spinal cord demyelination in COVID-19 might be an under-recognized neurological complication. •Concerning the prognosis, most of the patients improved and the mortality rate was low. •Spinal cord demyelination should be added to the plethora of immune mediated neurologic complications associated with COVID-19	Une revue d'études fait le point sur les maladies démyélinisantes déclenchées par une covid. Les auteurs concluent que la démyélinisation de la moelle épinière doit être ajoutée à la pléthore de complications neurologiques à médiation immunitaire associées à la maladie.	N006
71	N69		Maura Boldrini, MD, PhD1,2; Peter D. Canoll, MD, PhD3; Robyn S. Klein	How COVID-19 Affects the Brain	https://doi.org/10.1001/jamapsychiatry.2021.0500	Published	March 26, 2021	Article	http://jamanetwork.com/article.aspx?doi=10.1001/jamapsychiatry.2021.0500	Entering through angiotensin-converting enzyme 2 receptors,2 SARS-CoV-2 can damage endothelial cells leading to inflammation, thrombi, and brain damage. Moreover, systemic inflammation leads to decreased monoamines and trophic factors and activation of microglia, resulting in increased glutamate and N-methyl-d-aspartate (NMDA)3 and excitotoxicity (Figure). These insults induce new-onset or re-exacerbation of preexisting neuro-psychiatric symptoms.	Un article dans JAMA Psychiatry dresse un point concis et étayé sur la façon dont le SARS-CoV-2 peut endommager le cerveau, vraisemblablement par des processus indirects d'inflammation et de détérioration de la barrière hémato-encéphalique. "Les symptômes neuro-psychiatriques de la covid pourraient résulter de micro-AVC et de lésions neuronales, ces symptômes diffèrent par conséquent en fonction de la région cérébrale impliquée." L'analyse explore les traitements possibles : les antagonistes des cytokines (étanercept, infliximab), des récepteurs NMDA (kétamine), de TNF-α, ainsi que les voies anti-inflammatoires (aspirine, célécoxib) et les modulateurs des voies de la kynurénine (minocycline).	N006
72	N70		Lis Høy Marbjerg, Christina Jacobsen, Jannik Fonager, Claus Bøgelund, Morten Rasmussen, Anders Fomsgaard, Jytte Banner, Veronika Vorobieva Solholm Jensen	Possible Involvement of Central Nervous System in COVID-19 and Sequence Variability of SARS-CoV-2 Revealed in Autopsy Tissue Samples: A Case Report	https://doi.org/10.1177%2F2632010X211006096	Published	March 27, 2021	Case Report	https://journals.sagepub.com/doi/full/10.1177/2632010X211006096	A forensic autopsy was performed. This revealed severely condensed, almost airless, firm lungs, and the cause of death was severe acute respiratory distress syndrome-associated with COVID-19 (SARS-CoV-2). In addition, SARS-CoV-2 was detected with reverse transcription polymerase chain reaction (RT-PCR) in cerebrospinal fluid, lung tissue, and tracheal sample and specific antibodies for SARS-CoV-2 were detected in cerebrospinal fluid and serum. Subsequent sequencing of the SARS-CoV-2 virus showed variation in nucleotides at 3 sites between SARS-CoV-2 isolates recovered from the tracheal sample, cerebrospinal fluid, and tissues from both lungs, and phylogenetic analysis revealed that the spinal fluid sample differed the most from the other 3 samples.	Lors d'une autopsie d'une victime de la covid, la présence de virions a été confirmée dans le liquide cérébro-spinal, et un séquençage a montré que les particules virales portaient des mutations par rapport à celles des poumons et de la trachée. Pour les auteurs, cette étude appuie l'idée que le SARS-CoV-2 peut être neuroinvasif et provoquer une infection du système nerveux central.	N006
73	N71		Philippe Tellier	SARS-CoV-2, un neurotropisme sous-estimé, peut-être		Published	Mars 2021	Article	https://www.researchgate.net/publication/340772093_SARS-CoV-2_un_neurotropisme_sous-estime_peut-etre		Selon le docteur Philippe Tellier, il faut s'intéresser à l'hypothèse que l’atteinte du tronc cérébral par le SARS-CoV-2 pourrait contribuer à l’insuffisance respiratoire aiguë de certains patients atteints de la covid.
74	N72		I. Conejero,corresponding author1,2 B. Nobile,1,2 E. Olié,1,2,3 and Ph. Courtet1,2,3	How Does COVID-19 Affect the Neurobiology of Suicide?	https://dx.doi.org/10.1007%2Fs11920-021-01227-x	Published	2021 Mar 3	Review	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927764/	We hypothesize that SARS-CoV-2 interacts with multiple biological processes that underlie suicidal behavior, such as the renin-angiotensin system, nicotinic receptors, and central and systemic inflammation. Social distancing measures may also worsen subjective or objective social disconnection, thus increasing the risk of suicide. Interestingly, the drugs used to prevent suicide could be promising options to counteract brain damage caused by this coronavirus.	Une étude suggère que l'attaque du SARS-CoV-2 sur l'organisme, et notamment sur le système nerveux central, pourrait contribuer à des mécanismes d'inflammation chronique de faible intensité qui augmentent le risque de suicide chez les malades.
75	N73		Samir Djemli*, Abdelkrim Tahraoui, Mabrouk Boussena, Faiza Rouag, Ines Refes, Samia Messikh, Ibtissem Chouba, Mohamed Kouadria and Rouya Memouni	The Neuroinvasive Potential of SARS-CoV-2 on the Central Nervous System (lesions in the brain)		Published	08 Apr 2021	Editorial Article	https://www.researchgate.net/publication/350500546_The_Neuroinvasive_Potential_of_SARS-CoV-2_on_the_Central_Nervous_System_lesions_in_the_brain	The coronavirus that causes Covid-19 could infect the central nervous system like other coronaviruses. Is this related to the cases of anosmia reported by doctors among infected people? The more than 340,000 people suffering from Covid-19 complain of a triad of symptoms typical of infection: fever, cough, and difficulty breathing. But some also complain of rarer ailments like headaches, nausea and vomiting. These symptoms are usually associated with a neurological condition. Are they witnessing the invasion by the coronavirus responsible for Covid-19 of the central nervous system?	Un éditorial dans Medical & Clinical Research interroge les différentes possibilités expliquant les symptômes neurologiques de la covid. S'il est confirmé que la défense du corps contre le virus cause un phénomène inflammatoire dans le cerveau, l'intrusion du virus lui-même n'est pas à ce jour confirmée.	N007
76	N74		Maxime Taquet, PhD Prof John R Geddes, MD Prof Masud Husain, FRCP Sierra Luciano, BA Prof Paul J Harrison	6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records	https://doi.org/10.1016/S2215-0366(21)00084-5	Published	April 06, 2021	Retrospective Study	https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(21)00084-5/fulltext	Among 236 379 patients diagnosed with COVID-19, the estimated incidence of a neurological or psychiatric diagnosis in the following 6 months was 33·62% (95% CI 33·17–34·07), with 12·84% (12·36–13·33) receiving their first such diagnosis. For patients who had been admitted to an ITU, the estimated incidence of a diagnosis was 46·42% (44·78–48·09) and for a first diagnosis was 25·79% (23·50–28·25). Regarding individual diagnoses of the study outcomes, the whole COVID-19 cohort had estimated incidences of 0·56% (0·50–0·63) for intracranial haemorrhage, 2·10% (1·97–2·23) for ischaemic stroke, 0·11% (0·08–0·14) for parkinsonism, 0·67% (0·59–0·75) for dementia, 17·39% (17·04–17·74) for anxiety disorder, and 1·40% (1·30–1·51) for psychotic disorder, among others. In the group with ITU admission, estimated incidences were 2·66% (2·24–3·16) for intracranial haemorrhage, 6·92% (6·17–7·76) for ischaemic stroke, 0·26% (0·15–0·45) for parkinsonism, 1·74% (1·31–2·30) for dementia, 19·15% (17·90–20·48) for anxiety disorder, and 2·77% (2·31–3·33) for psychotic disorder. The severity of COVID-19 had a clear effect on subsequent neurological diagnoses. Compared with neurological disorders, common psychiatric disorders (mood and anxiety disorders) showed a weaker relationship with the markers of COVID-19 severity in terms of incidence (table 2) or HRs (table 5). This might indicate that their occurrence reflects, at least partly, the psychological and other implications of a COVID-19 diagnosis rather than being a direct manifestation of the illness.	La plus large étude rétrospective sur les manifestations neurologiques et psychiatriques de la covid entreprend de quantifier la prévalence des symptômes 6 mois après une infection. Les auteurs remarquent que la sévérité de la covid a un effet conséquent sur le diagnostic neurologique ultérieur. Les 4/5e de la cohorte n'ont pas été hospitalisés. Un tiers des patients présente un diagnostic neurologique ou psychiatrique à 6 mois, et 13% pour qui cela constitue le premier diagnostic de ce type. L'étude compte 0,6% qui ont eu une hémorragie intracrânienne, 2,1% un AVC ischémique, 0,7% souffrent de démence, 17,4% de troubles anxieux, 1,4% de troubles psychotiques. Les auteurs remarquent que les troubles psychiatriques habituels (troubles d'anxiété et d'humeur), comparés aux troubles neurologiques, sont moins corrélés avec la sévérité de la phase aiguë. Il est fait la supposition que leur occurence reflète, au moins partiellement, l'impact psychologique d'un diagnostic de covid, davantage qu'une manifestation directe de la maladie. La survenue d'une encéphalopathie, au delà d'un marqueur de sévérité, apparaît comme un possible signal de futurs symptômes neuropsychiatriques et neurodégénératifs. Enfin, des craintes sont émises sur une augmentation de troubles parkinsoniens consécutifs à ces atteintes.	N007
77	N75	R	Jonas A Hosp, Andrea Dressing, Ganna Blazhenets, Tobias Bormann, Alexander Rau, Marius Schwabenland, Johannes Thurow, Dirk Wagner, Cornelius Waller, Wolf D Niesen, Lars Frings, Horst Urbach, Marco Prinz, Cornelius Weiller, Nils Schroeter, Philipp T Meyer	Cognitive impairment and altered cerebral glucose metabolism in the subacute stage of COVID-19	https://doi.org/10.1093/brain/awab009	Published	05 April 2021		https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awab009/6209743	In this prospective cohort study, we assessed neurological and cognitive symptoms in hospitalized coronavirus disease-19 (COVID-19) patients and aimed to determine their neuronal correlates. Patients with reverse transcription-PCR-confirmed COVID-19 infection who required inpatient treatment primarily because of non-neurological complications were screened between 20 April 2020 and 12 May 2020. Patients (age > 18 years) were included in our cohort when presenting with at least one new neurological symptom (defined as impaired gustation and/or olfaction, performance < 26 points on a Montreal Cognitive Assessment and/or pathological findings on clinical neurological examination). Patients with ≥2 new symptoms were eligible for further diagnostics using comprehensive neuropsychological tests, cerebral MRI and 18fluorodeoxyglucose (FDG) PET as soon as infectivity was no longer present. Exclusion criteria were: premorbid diagnosis of cognitive impairment, neurodegenerative diseases or intensive care unit treatment. Of 41 COVID-19 inpatients screened, 29 patients (65.2 ± 14.4 years; 38% female) in the subacute stage of disease were included in the register. Most frequently, gustation and olfaction were disturbed in 29/29 and 25/29 patients, respectively. Montreal Cognitive Assessment performance was impaired in 18/26 patients (mean score 21.8/30) with emphasis on frontoparietal cognitive functions. This was confirmed by detailed neuropsychological testing in 15 patients. 18FDG PET revealed pathological results in 10/15 patients with predominant frontoparietal hypometabolism. This pattern was confirmed by comparison with a control sample using voxel-wise principal components analysis, which showed a high correlation (R2 = 0.62) with the Montreal Cognitive Assessment performance. Post-mortem examination of one patient revealed white matter microglia activation but no signs of neuroinflammation. Neocortical dysfunction accompanied by cognitive decline was detected in a relevant fraction of patients with subacute COVID-19 initially requiring inpatient treatment. This is of major rehabilitative and socioeconomic relevance.	Une nouvelle étude constate des hypométabolismes cérébraux par PET-SCAN chez des malades de la covid un mois après la phase aiguë. Les résultats témoignent d'infarctus subaigus microemboliques et de la présence de marqueurs de lésion axonale. Selon les auteurs, l'hypométabolisme pourrait être une séquelle d'un processus distant dû à une pathologie du tronc cérébral ou de la substance blanche, plutôt qu'à des dommages corticaux directs (par exemple, découplage ou dysfonctionnement de régions stratégiques comme les noyaux aminergiques du tronc cérébral). Cette hypothèse suggérerait que la détérioration neurologique peut être réversible.	N007
78	N76		Markus Ameres, Susanne Brandstetter, Antoaneta A. Toncheva, Michael Kabesch, David Leppert, Jens Kuhle & Sven Wellmann	Association of neuronal injury blood marker neurofilament light chain with mild-to-moderate COVID-19	https://doi.org/10.1007/s00415-020-10050-y	Published	09 July 2020	Letter to the Editors	https://link.springer.com/article/10.1007/s00415-020-10050-y	a neuronal biomarker would be extremely useful to elucidate neuro-axonal injury during an infection with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and in the post-infection follow-up period. Serum neurofilament light chain (sNfL) has recently been considered as a specific biomarker to quantitate neuro-axonal damage in several disorders of the peripheral and central nervous system [5]. Hence, sNfL might also serve as a sensitive screening and follow-up marker for neuronal injury in COVID-19 patients.	Dans une correspondance publiée dans Journal of Neurology, des chercheurs estiment que la chaîne légère du neurofilament sérique (sNfL, déjà utilisée dans plusieurs troubles du système nerveux périphérique et central) devrait être un marqueur sensible de dépistage et de suivi des lésions neuronales chez les patients atteints de la covid.	N009
79	N77		Gabriele Melegari 1,*,Veronica Rivi 2 ,Gabriele Zelent 3,Vincenzo Nasillo 4 ,Elena De Santis 4,Alessandra Melegari 4,Claudia Bevilacqua 5,Michele Zoli 2,Stefano Meletti 6 andAlberto Barbier	Mild to Severe Neurological Manifestations of COVID-19: Cases Reports	https://doi.org/10.3390/ijerph18073673	Published	1 April 2021	Cases Reports	https://www.mdpi.com/1660-4601/18/7/3673	Here, we present two different case-reports of COVID-19 patients, describing neurological complications, diagnostic imaging such as olfactory bulb damage (a mild and unclear underestimated complication) and a severe and sudden thrombotic stroke complicated with hemorrhage with a low-level cytokine storm and respiratory symptom resolution. We discuss the possible mechanisms of virus entrance, together with the causes of COVID-19-related encephalitis, olfactory bulb damage, ischemic stroke, and intracranial hemorrhage.	_
80	N78		Matteo Foschi, Lucio D'Anna, Ahmed Abdelhak, Benjamin Mayer, Hayrettin Tumani, Markus Otto, Samir Abu-Rumeileh	Ongoing challenges in unravelling the association between COVID-19 and Guillain-Barré syndrome	https://doi.org/10.1093/brain/awab069	Published	03 April 2021	Letter to the Editor	https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awab069/6209733	To conclude, we believe that the definitive proof of a possible causal association between COVID-19 and GBS could derive from two different efforts: (i) the conduction of rigorous case-control studies; and (ii) the systematic testing of all patients with GBS for anti-SARS-CoV-2 antibodies. This would allow us to avoid possible underestimation of COVID-19-related GBS by including patients tested negative with PCR whilst positive for untested anti-SARS-CoV-2 antibodies (a bias which reasonably cannot be excluded in the cohort by Keddie et al.1).	_
81	N79		William Camargo-Martínez Ivan Lozada-Martínez Angie Escobar-Collazos Aura Navarro-Coronado Luis Moscote-Salazar Alfonso Pacheco-Hernández Tariq Janjua Pilar Bosque-Varela	Post-COVID 19 Neurological Syndrome: Implications for sequelae’s treatment	https://doi.org/10.1016/j.jocn.2021.04.001	Published	April 08, 2021	REVIEW ARTICLE	https://www.jocn-journal.com/article/S0967-5868(21)00163-6/fulltext	Neurological complications caused by COVID-19 are frequent and represent a risk that compromises the functional capacity and the life of patients. The suspicion of these conditions, the strict control of metabolic alterations and cardiovascular risk factors, the effective and safe treatment of these entities, are a current challenge throughout the pandemic. The rehabilitation process in these patients is a challenge. This is due to the limitations generated by multi-organ damage, as well as risk of brain death. The prognosis of recovery from post-COVID neurological syndrome must be evaluated in a personalized way, depending on target organ damage, especially lungs and heart, which intervene in the process of physical activity and maintenance of daily life activities.	Une revue d'études souligne le défi que représente la rééducation des malades de la covid présentant des séquelles neurologiques, et s'inquiète des difficultés pour la mise en œuvre de ces programmes dans les pays pauvres.	N009
82	N80		Finsterer, Josef	Presentation of Neuro-COVID is Broad and Pathogenesis Diverse		Published	2021-04-08	Letter to the editor	https://escholarship.org/uc/item/01z8q12d	There was no discussion about the putative delineation between neurological disorders due to direct attack of the virus (primary manifestations), secondary CNS/PNS disorders due to the immune response (secondary manifestations), and those occurring as a side effect of the treatment or involvement of other organs than the CNS (tertiary manifestations). Whether such a distinction is truly permissible is under debate. Limited data from animal and basic science research are currently available. Disregarding this debate, there are indications that the virus enters the CNS via the blood brain barrier (BBB) or via retrograde invasion along peripheral nerves, as mentioned in the review.1,15 There are even indications that the virus disrupts the BBB.16 Interestingly, in most of the CNS disorders claimed to have been triggered by direct contact of the virus Klinik Landstrasse, Messerli Institute, Department of Neurology, Vienna, Austriawith CNS structures, investigations of the cerebro-spinal fluid (CSF) did not confirm the presence of the virus in the CSF. Absence of the virus in the CSF has been explained by rapid entering of the virus intra-cellularly, thus being present in the CSF only temporarily for a short time. Accordingly, virus-RNA has been found inside neurons and glial cells. The spectrum of neurological disease triggered by SARS-CoV-2 is broader than anticipated. Neurological disease possibly results from a direct virus attack, from the immune response, or from side effects of the treatment of pulmonary manifestations.	Une lettre publiée dans Western Journal of Emergency Medicine insiste sur le spectre plus large qu'attendu des maladies neurologiques déclenchées par le SRAS-CoV-2. Les affections touchant les systèmes nerveux central et périphérique peuvent résulter d'une attaque virale directe, de la réponse immunitaire, et parfois même des effets secondaires des traitements administrés (hydroxychloroquine, stéroïdes, tocilizumab, azithromycine).	N010
83	N81		Josef Finsterer & Fulvio A Scorza	Clinical and Pathophysiologic Spectrum of Neuro-COVID	https://doi.org/10.1007/s12035-021-02383-0	Published	08 April 2021	Mini-Review	https://link.springer.com/article/10.1007/s12035-021-02383-0	The spectrum of central nervous system disease in COVID-19 patients is much broader than so far anticipated. Peripheral nerves and the skeletal muscle are less predominantly affected. In the vast majority of the cases, there is no direct attack of the virus towards vulnerable structures, which explains why various manifestations of the nervous system manifest favourably to immune suppression or immune modulation. Overall, the pathophysiology and clinical presentation of CNS/PNS involvement in COVID-19 is wider than believed. All patients with COVID-19 should be investigated by the neurologist for primary or secondary involvement of the CNS/PNS in the infection. neuro-COVID responds favourably to immune suppressants or immune modulation.	Un article académique note la grande diversité des possibles atteintes au système nerveux central occasionnées par la covid. Les auteurs remarquent que ces atteintes répondent favorablement aux immunosuppresseurs ou à la modulation immunitaire.	N009
84	N82		Hicham El Otmani	Controverse : le Neuro-Covid-19 existe-t-il ?	https://doi.org/10.1016/j.neurol.2021.02.059	Published	11 April 2021	Opinion	https://www.sciencedirect.com/science/article/pii/S0035378721001016	Cette maladie, dont les manifestations respiratoires et systémiques sont prévalantes, serait responsable de plusieurs manifestations neurologiques. Toutefois, l’analyse critique des données actuellement disponibles montre que les atteintes neurologiques restent mal caractérisées voire difficile à affirmer. En effet, des manifestations comme les céphalées, les vertiges et les myalgies sont celles d’une « forte » grippe et n’ont aucune spécificité, l’anosmie qui est un symptôme très fréquent semble plus liée à une atteinte muqueuse olfactive, le neurotropisme du SARS-Cov-2 semble (à la différence d’autres virus comme celui de la rage ou de l’herpès), très marginal au vu des données biologiques et histologiques actuellement disponibles, les manifestations neurologiques immune-médiées comme le syndrome de Guillain-Barré et les EMAD… sont très rares (au nombre de quelques dizaines) au regard de la grande fréquence de la maladie, pouvant suggérer des coïncidences. Ailleurs, les manifestations neurologiques les plus fréquentes comme le delirium (plus fréquent chez les personnes âgées et en présence d’une atteinte cognitive sous jacente), la maladie cérébrovasculaire (généralement chez des personnes ayant des facteurs de risque vasculaire) sont habituellement retrouvées chez des patients admis en Neuro-réanimation, pour une atteinte respiratoire importante ou une défaillance multi-organes. Il semble que l’essentiel de la Neurologie de la Covid-19 ne soit finalement que le témoin d’une maladie systémique grave…	_
85	N83		Dominique Caparros	Amélioration neurologique inattendue après infection Covid : rôle des anticorps anti-covid sur la microglie de cerveaux endommagés ?	https://doi.org/10.1016/j.neurol.2021.02.015	Published	11 April 2021	Opinion	https://www.sciencedirect.com/science/article/pii/S0035378721000576	L’amélioration neurologique pour ces 4 patients objectivée 2 à 4 semaines après le début de l’infection COVID persiste sur le long terme. L’hypothèse de l’activation des cellules microgliales par les anticorps anti COVID est évoquée. L’effet de la vaccination anti COVID sur le SNC chez les patients cérébro-lésés devra donc êtré analysée.	_
86	N84		Yannick FogangFogoum1Ahmed VessahNjoya2MichelNoubom3JosephKamtchum-Tatuene4Callixte KuateTegueu	Manifestations neurologiques de la COVID-19 à l’hôpital régional de Bafoussam, Cameroun	https://doi.org/10.1016/j.neurol.2021.02.242	Published	11 April 2021	Study	https://www.sciencedirect.com/science/article/pii/S0035378721002848	Il s’agissait d’une étude transversale rétrospective menée de mars à septembre 2020 à l’hôpital régional de Bafoussam, dans l’Ouest Cameroun. Étaient inclus les patients symptomatiques avec un test RT-PCR positif au SARS-CoV-2. Les données sociodémographiques et cliniques notamment les manifestations neurologiques en relation temporelle avec le diagnostic étaient extraites des dossiers des patients à leur sortie. Résultats Nous avons inclus 177 patients. L’âge moyen était de 54,60 ± 17,8 ans. Les manifestations neurologiques étaient retrouvées chez 113 (63,84 %) patients. Les plus fréquentes étaient : les céphalées (58,41 %), les myalgies (50,44 %), l’anosmie (18,58 %), les troubles de la conscience (16,8 %), le délirium (15,04 %), une hémiplégie (4,42 %), l’agueusie (4,42 %). Une hypersialorrhée (2 cas) et un tremblement intentionnel (1 cas). Les diagnostics posés étaient la méningo-encéphalite (11,50 %), l’encéphalopathie (20,35 %) et l’AVC ischémique (4,42 %).	_
87	N85		Svetlana Blitshteyn	Is postural orthostatic tachycardia syndrome (POTS) a central nervous system disorder?	https://doi.org/10.1007/s00415-021-10502-z	Published	07 March 2021	Review	https://link.springer.com/article/10.1007/s00415-021-10502-z	This review outlines existing evidence of POTS as a CNS disorder and proposes a hypothetical model combining key mechanisms in the pathophysiology of POTS. Redefining POTS as a CNS disorder can lead to new possibilities in pharmacotherapy and non-pharmacologic therapeutic interventions in patents affected by this disabling syndrome.	Une chercheuse américaine pense que le syndrome de tachycardie orthostatique posturale (POTS en anglais), un dysfonctionnement du système nerveux autonome, devrait également être considéré comme un trouble du système nerveux central. Cette nouvelle perspective permet selon l'auteure d'envisager d'autres traitements comme les thérapies immunomodulatrices (immunoglobuline intraveineuse, immunoglobuline sous-cutanée ou plasmaphérèse) pour ce symptôme fréquent chez les malades du covid long. Ces thérapies sont utilisées pour les POTS réfractaires au traitement avec des marqueurs auto-immuns positifs, et pourraient être bénéfiques en réduisant la neuroinflammation dans le système nerveux central.	N009
88	N86		Elbakal Ayoub Bourazza Ahmed	Manifestations neurologiques au cours de l’infection au virus COVID-19 : étude prospective à propos de 713 patients	https://doi.org/10.1016/j.neurol.2021.02.236	Published	11 April 2021	Study	https://www.sciencedirect.com/science/article/pii/S0035378721002782	Au total, 713 patients ont été suivis, l’âge moyen était de 31,95 ans avec un faible taux de comorbidités (2,1 %). Les manifestations neurologiques étaient présentes chez 12,8 % des patients (n = 91) notamment les céphalées 5,8 % (n = 41), l’anosmie 5,6 % (n = 40), myalgies 1,4 % (n = 10). Discussion Selon les études les manifestations neurologiques associées à la COVID-19 sont présentes chez 25 % des patients tout au plus, et sont généralement bénignes.	_
89	N87		Woo-Jung Song, MD Christopher K M Hui, MD James H Hull, PhD Prof Surinder S Birring, MD Prof Lorcan McGarvey Prof Stuart B Mazzone, PhD Prof Kian Fan Chung	Confronting COVID-19-associated cough and the post-COVID syndrome: role of viral neurotropism, neuroinflammation, and neuroimmune responses	https://doi.org/10.1016/S2213-2600(21)00125-9	Published	April 12, 2021	Personal View	https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00125-9/fulltext	Cough is one of the most common presenting symptoms of COVID-19, along with fever and loss of taste and smell. Cough can persist for weeks or months after SARS-CoV-2 infection, often accompanied by chronic fatigue, cognitive impairment, dyspnoea, or pain—a collection of long-term effects referred to as the post-COVID syndrome or long COVID. We hypothesise that the pathways of neurotropism, neuroinflammation, and neuroimmunomodulation through the vagal sensory nerves, which are implicated in SARS-CoV-2 infection, lead to a cough hypersensitivity state. The post-COVID syndrome might also result from neuroinflammatory events in the brain. We highlight gaps in understanding of the mechanisms of acute and chronic COVID-19-associated cough and post-COVID syndrome, consider potential ways to reduce the effect of COVID-19 by controlling cough, and suggest future directions for research and clinical practice. Although neuromodulators such as gabapentin or opioids might be considered for acute and chronic COVID-19 cough, we discuss the possible mechanisms of COVID-19-associated cough and the promise of new anti-inflammatories or neuromodulators that might successfully target both the cough of COVID-19 and the post-COVID syndrome.	Dans The Lancet, des chercheurs font l'hypothèse que les voies du neurotropisme, de la neuroinflammation et de la neuro-immunomodulation à travers les nerfs sensoriels vagaux, qui sont impliqués dans l'infection par le SRAS-CoV-2, conduisent à un état d'hypersensibilité à la toux. Pour les auteurs, la compréhension de cette toux persistante est un enjeu pour choisir de nouveaux anti-inflammatoires ou neuromodulateurs qui pourraient cibler avec succès à la fois la toux de la covid et le syndrome post-covid.	N010
90	N88	Yes	Igor C Fontana 1, Débora Guerini Souza 1, Luc Pellerin 2, Diogo O Souza 1 3, Eduardo R Zimmer	About the source and consequences of 18 F-FDG brain PET hypometabolism in short and long COVID-19	https://doi.org/10.1007/s00259-021-05342-y	Published	2021 Apr 4	Letter to the Editor	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019399/	Indeed, it seems that astrocytes substantially contribute to 18F-FDG PET signal [8–10]. Moreover, it is known that astrocytes play pivotal roles in the brain defence against peripheral inflammatory changes [11]. Guedj and colleagues [1] mentioned that acute systemic inflammation and SARS-CoV-2 neurotropism could be related to brain inflammatory alterations. Complementary, other groups identified signs of reactive astrogliosis in post-mortem tissue of COVID-19 patients [12], in cellular models and in brain organoids [13]. In keeping with this, one could not neglect astrocyte dysfunction as the possible cellular origin of brain 18F-FDG PET hypometabolism in COVID-19. In vivo brain imaging of COVID-19 individuals using specific PET radiotracers targeting reactive astrocytes (e.g. 11C-DED and 11C-BU99008) could help settling this matter. While the cellular origins of brain 18F-FDG PET hypometabolism in COVID-19 remain to be defined, it seems clear that we are dealing with persistent synaptic dysfunction. Guedj et al. [1] demonstrated that multiple brain regions are hypometabolic in long COVID. In addition, it seems that there is a link between clinical manifestations and regional glucose hypometabolism. For instance, decreased glucose consumption in the cerebellum was linked to hyposmia/anosmia and cognitive impairment. Another recent study followed up the 18F-FDG brain profile of seven patients in the early phase of infection, 1 month and 6 months after COVID-19 onset. Interestingly, the abnormal cognitive function associated with pre-frontal cortex hypometabolism persisted in all patients for ~6 months [14]. Remarkably, 18F-FDG brain hypometabolism in the pre-frontal cortex is present in multiple neurodegenerative disorders [15] and neuropsychiatric conditions [16], sometimes even preceding the first symptoms. Thus, the cellular origins of COVID-19 18F-FDG PET hypometabolism in short- and long-term scenario remain to be explored, with mounting evidence suggesting an astroglial contribution. Furthermore, persistent 18F-FDG PET hypometabolism in long COVID patients should be carefully monitored in terms of potential sequelae, such as the development of brain disorders.	Un article d'analyse revient sur les hypométabolismes dans le système nerveux central fréquemment relevés chez les malades du covid long. Une 1e hypothèse émise est une dysfonction des astrocytes (cellules gliales du cerveau), qui pourrait selon les auteurs être étudiée par des PET-SCAN utilisant d'autres radiotraceurs comme le ¹¹C-DED et le ¹¹C-BU99008. De plus, les auteurs rappellent que l'hypométabolisme dans le cervelet est ici bien lié à des anosmies et des troubles cognitifs.Ils notent qu'il semble clair qu'il est question d'un dysfonctionnement synaptique persistant. Cette persistance au delà de plusieurs mois est interrogée au regard des maladies neurodégénératives qui font apparaître très tôt des hypométabolismes.	N009
91	N89	R	Aurélie Kas,corresponding author1 Marine Soret,1 Nadya Pyatigoskaya,2 Marie-Odile Habert,1 Adèle Hesters,3 Loic Le Guennec,3 Olivier Paccoud,4 Stéphanie Bombois,#5 Cécile Delorme,#3 and on the behalf of CoCo-Neurosciences study group and COVID SMIT PSL study group	The cerebral network of COVID-19-related encephalopathy: a longitudinal voxel-based 18F-FDG-PET study	https://dx.doi.org/10.1007%2Fs00259-020-05178-y	Published	2021 Jan 15	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810428/	All patients had a consistent pattern of hypometabolism in a widespread cerebral network including the frontal cortex, anterior cingulate, insula and caudate nucleus. Six months after COVID-19 onset, the majority of patients clinically had improved but cognitive and emotional disorders of varying severity remained with attention/executive disabilities and anxio-depressive symptoms, and lasting prefrontal, insular and subcortical 18F-FDG-PET/CT abnormalities.	En suivant 7 patients touchés par une encéphalopathie déclenchée par une infection au SARS-CoV-2, des équipes françaises de l'hôpital de la Pitié Salpêtrière ont noté leurs constatations par imagerie cérébrale. Des PET-SCAN cérébraux jusqu'à 6 mois ont montré l'évolution, généralement favorable, des hypométabolismes et hypermétabolismes dans différentes régions du système nerveux central. Les analyses étaient menées dans le cadre des groupes d'études CoCo-Neurosciences et COVID SMIT PSL.	N010
92	N90		Melanie Dani, consultant geriatrician,A Andreas Dirksen, specialist nurse in syncope,B Patricia Taraborrelli, specialist nurse in syncope,B Miriam Torocastro, syncope research nurse,C Dimitrios Panagopoulos, clinical research fellow in cardiology,D Richard Sutton, professor of clinical cardiology,E and Phang Boon Lim, consultant cardiologistF	Autonomic dysfunction in ‘long COVID’: rationale, physiology and management strategies	https://dx.doi.org/10.7861%2Fclinmed.2020-0896	Published	2021 Jan	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850225/	We describe a series of individuals with symptoms of ‘long COVID’, and we posit that this condition may be related to a virus- or immune-mediated disruption of the autonomic nervous system resulting in orthostatic intolerance syndromes. We suggest that all physicians should be equipped to recognise such cases, appreciate the symptom burden and provide supportive management. We present our rationale for an underlying impaired autonomic physiology post-COVID-19 and suggest means of management. Individual analyses confirmed a severe, bilateral prefrontal hypometabolism in 7/7 patients, including the rectus gyrus (p < 0.05 FWE corrected, Fig. Fig.2,2, Table Table4).4). In every patient, hypometabolism expanded bilaterally to the anterior cingulate and insula (p < 0.05 FWE corrected, Table Table4).4). A mild to moderate parietotemporal associative hypometabolism was observed in 4/7 patients, whereas two others had a severe, spread parietotemporooccipital hypometabolism (#6, 7). Hypermetabolism was found in the visual cortex in patient #1 due to visual stimulation after 18F-FDG injection and in the left frontal cortex in patient #4 due to focal seizure. Notably, bilateral mesiotemporal hypermetabolism was found in one patient (#6) without T2-MRI hyperintensity, whereas hypometabolism was observed in patient #3 with known hippocampal sclerosis and in patient #5 having hippocampal atrophy. Metabolism was decreased in the caudate nucleus in five patients (#2–5, 7) and thalamus in two (#2, 3) (p < 0.05 corrected). Metabolism was decreased in the bilateral cerebellar hemispheres in all patients except one (#4) but increased in the vermis in 5/7 patients (p < 0.05).	Dans une étude qui décrit les dérèglements du système autonome consécutifs à la covid, et notamment le syndrome de tachycardie orthostatique posturale, les auteurs proposent une méthodologie de diagnostic et des pistes de traitements.	N010
93	N91		Theoharis C. Theoharides Christos Cholevas Konstantinos Polyzoidis Antonios Politis	Long‐COVID syndrome‐associated brain fog and chemofog: Luteolin to the rescue	https://doi.org/10.1002/biof.1726	Published	12 April 2021	Review	https://iubmb.onlinelibrary.wiley.com/doi/10.1002/biof.1726	Long‐COVID syndrome symptoms, especially brain fog, are similar to those experienced by patients undertaking or following chemotherapy for cancer (chemofog or chemobrain), as well in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or mast cell activation syndrome (MCAS). The pathogenesis of brain fog in these illnesses is presently unknown but may involve neuroinflammation via mast cells stimulated by pathogenic and stress stimuli to release mediators that activate microglia and lead to inflammation in the hypothalamus. These processes could be mitigated by phytosomal formulation (in olive pomace oil) of the natural flavonoid luteolin.	Une revue d'études compare le brouillard cérébral (symptôme fréquent dans le covid long) à celui qui suit des chimiothérapie anti-cancer, à celui des encéphalomyélites myalgiques, et à celui des troubles des troubles des mastocytes. L'article indique que la pathogenèse de cet état est encore inconnue, mais pourrait impliquer une neuroinflammation via des mastocytes stimulés par des stimuli pathogènes et du stress, libérant des médiateurs qui activent la microglie et conduisent à une inflammation de l'hypothalamus. L'auteur principal, par ailleurs directeur scientifique de la société Algonot qui produit des compléments alimentaires à base de flavonoïdes, évoque une possibilité de traitement par une formulation phytosomale (dans l'huile de grignons d'olive) de la lutéoline flavonoïde naturelle ou de la quercétine.	N010
94	N92		KuaikuaiDuanabEnricoPremicdAndreaPilottodVivianaCristillodAlbertoBenussidIleniaLibridMarcelloGiuntadH. JeremyBockholtbJingyuLiubeRiccardoCamporafAlessandroPezzinidRobertoGasparottifMauroMagonicAlessandroPadovanidVinceCalhoun	Alterations of frontal-temporal gray matter volume associate with clinical measures of older adults with COVID-19	https://doi.org/10.1016/j.ynstr.2021.100326	Published	13 April 2021		https://www.sciencedirect.com/science/article/pii/S2352289521000345	Highlights •We identified gray matter alterations underlying COVID-19 using source-based morphometry. •. Lower gray matter volume (GMV) in frontal regions linked to more severe disability. •Patients receiving oxygen therapy had lower GMV in widespread frontal regions. •Patients with fever presented reduced GMV in temporal and fusiform gyri.	_
95	N93		Sara LaHue, Nina Escueta, Elan Guterman, Vanja Douglas, John Newman	Delirium in Hospitalized Adults with Confirmed SARS-CoV-2 Infection (1973)		Published	April 13, 2021		https://n.neurology.org/content/96/15_Supplement/1973	We included 99 patients diagnosed with COVID-19, of whom 46 patients were only on a medical-surgical ward. Forty-three percent of patients were delirious. Delirious patients were older than non-delirious patients: median(IQR) 62(47–81) vs. 48(38–63) years old (Z=−3.3, p=0.001). Seventy percent of delirious patients were cared for in the ICU at any point during hospitalization, compared with 25% of non-delirious patients (p <0.001). Compared with non-delirious patients, delirious patients had a longer median length of stay in days [8(4–13) vs 14(11–27); Z=−4.2, p<0.001], more likely to have a safety attendant (28% vs 7%, p=0.01), restraints (58% vs 5%, p<0.001), and less likely to be discharged home (39% vs 84%, p<0.001).	_
96	N94		Sachi Gianchandani, Sarah Addison, Yousef Hannawi, Archana Hinduja	Prevalence of Delirium and its Risk Factors in Hospitalized Patients with SARS-CoV-2 Infection (1577)		Published	April 13, 2021		https://n.neurology.org/content/96/15_Supplement/1577	Data of 145 patients with confirmed SARS-CoV-2 infection were available (age 61.4±18.1 years, 41% female, and 29% African American). Delirium occurred in 33.8% of the patients. Patients with delirium were older, and had higher rates of hypertension, hyperlipidemia, diabetes mellitus, dementia, and psychiatric illness compared to those without delirium (P< 0.05). Furthermore, patients with delirium more frequently received supplemental oxygen, had lower PaO2/FiO2 ratio on admission, and higher levels of LDH, CRP and IL-6 compared to those without delirium (P<0.05). In logistic regression models, among the patients’ baseline characteristics, dementia was associated with greater odds of developing delirium (OR 4.25, 95% CI: 1.17–15.37, P=0.027). Additionally, among in-hospital complications, only cardiac complications and sepsis were independently associated with delirium in the logistic regression analysis (OR 9.02, 95% CI: 1.63–50.03, P=0.012, and OR 5.1 95%, CI: 1.88–13.84, P=0.001, respectively).	_
97	N95		Sachi Gianchandani, Sarah Addison, Yousef Hannawi, Archana Hinduja	Impact of Delirium on Outcomes in Hospitalized Patients with SARS-CoV-2 Infection (4871)		Published	April 13, 2021		https://n.neurology.org/content/96/15_Supplement/4871	Data of 145 patients with confirmed SARS-CoV-2 infection were available (age 61.4±18.1 years, 41% female, and 29% African American). Delirium occurred in 33.8% of patients. Patients with delirium had increased length of hospital stay, intensive care unit (ICU) stay, longer duration of mechanical ventilation and higher likelihood of discharge to hospice or death (P<0.05). In Linear regression analyses, longer hospital stay was significantly associated with delirium (B=0.377, 95% CI: 0.723–1.25), renal complications (B=0.203, 95% CI: 0.051–0.355), acute respiratory distress syndrome (ARDS) (B=0.152, 95% CI: 0.0069–0.308) and hyperlipidemia (B=−0.17, 95% CI: −0.327–0.009). Longer ICU stay was also significantly associated with delirium (B=0.39, 95% CI: 0.11–0.67). In ordered logistic regression, older age, ARDS, presence of renal complications, and delirium were independently associated with unfavorable discharge disposition to hospice or nursing home (B=0.046, 95% CI: 0.123–0.079; B=1.48, 95% CI: 0.538–2.441; B=0.902, 95% CI: 0.016–1.789; B=1.207, 95% CI: 0.227–2.188, respectively).	_
98	N96		Niyatee Samudra, Shawniqua Williams Roberson	Electroencephalographic findings in hospitalized patients with SARS-COV-2 (COVID-19) encephalopathy (1672)		Published	April 13, 2021		https://n.neurology.org/content/96/15_Supplement/1672.abstract	The most common indication for EEG monitoring was altered mental status (15/16 patients). Mean age was 59.5, and all patients had non-neurologic medical comorbidities. 7/16 patients were deceased. All EEGs demonstrated continuous generalized slow activity, consistent with encephalopathy, and EEG findings did not appear to relate to mortality outcome. Focal non-epileptiform abnormalities (slow activity or attenuation of faster frequencies) were present in 6/16 patients. Definitive sharp waves were seen in 2/16 patients, both of whom had a history of epilepsy. Whole-brain basic spectral composition (delta, theta, alpha, beta and average band power) did not demonstrate a difference between survivors and non-survivors in this cohort. A history of seizures or epilepsy was more common in deceased patients (42.8% vs 22.2%). Conclusions: EEG findings in patients with COVID-19 encephalopathy were nonspecific. An EEG signature related to mortality was not identified, but a history of seizures or epilepsy was associated with a worse prognosis.	_
99	N97		Keith J.Kincaida1 Justin ChiKunga1 Alexander J.Senetara 1 David Mendoz aa Daniel A.Bonnina Windy L.Purtlebaugha Rainier idhu Kariyawasama Maria Bruzzone aAlexis N.Simpkinsa	Post-COVID seizure: A new feature of “long-COVID”	https://doi.org/10.1016/j.ensci.2021.100340	Published	18 April 2021	Case Report	https://www.sciencedirect.com/science/article/pii/S2405650221000320	Highlights •Patients with COVID-19 can develop multiple neurologic disorders. •Seizure can be a manifestation of the “Long-COVID” syndrome. •Longitudinal studies of neurologic disease in COVID-19 survivors are needed.	_
100	N98		Abu Baker Sheikha Prabal Kumar Chourasi a b Nismat Javed c Mehul Kumar Chourasi a d Sajid S.Suriyae Shubhra Upadhyaya FatimaIjaza Suman Pala Narges Moghimie Rahul Shekhara	Association of Guillain-Barre syndrome with COVID-19 infection: An updated systematic review		Published	18 April 2021	Review Article	https://www.sciencedirect.com/science/article/pii/S0165572821001041	Highlights •AIDP is the common form that can occur concomitant with COVID-19 infection. •Clinical features of GBS with COVID-19 were similar to classical GBS. •Up to date systematic review of 94 cases of GBS with COVID-19 infection.	_
101	N99		Michael Connerney, Rohit Gummi, Catherine Yim, Christopher DeGiorgio	Seizure and Dural Sinus Thrombosis in setting of COVID-19 with 3 and 6 Month Outcomes after Long-Term Anticoagulation (5145)		Published	April 13, 2021	Case Report	https://n.neurology.org/content/96/15_Supplement/5145.abstract	To report how a case of coronavirus-19 (COVID-19) can lead to seizure and dural sinus thrombosis with subsequent clinical outcome after several months of long-term anticoagulation.	_
102	N100		Marjolaine Uginet MD Gautier Breville MD Frédéric Assal MD Karl‐Olof Lövblad MD Maria Isabel Vargas MD Jérôme Pugin MD Jacques Serratrice MD Francois R. Herrmann MD, MPH Patrice H. Lalive MD Gilles Allali	COVID‐19 encephalopathy: Clinical and neurobiological features	https://doi.org/10.1002/jmv.26973	Published	30 March 2021	RESEARCH ARTICLE	https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.26973	On May 10, 2020, 707 patients infected by SARS‐CoV‐2 were hospitalized at the Geneva University Hospitals; 31 (4.4%) consecutive patients with an acute encephalopathy (64.6 ± 12.1 years; 6.5% female) were included in this series, after exclusion of comorbid neurological conditions, such as stroke or meningitis. The severity of the COVID‐19 encephalopathy was divided into severe and mild based on the Richmond Agitation Sedation Scale (RASS): severe cases (n = 14, 45.2%) were defined on a RASS < −3 at worst presentation. The severe form of this so‐called COVID‐19 encephalopathy presented more often a headache. The severity of the pneumonia was not associated with the severity of the COVID‐19 encephalopathy: 28 of 31 (90%) patients did develop an acute respiratory distress syndrome, without any difference between groups (p = .665). Magnetic resonance imaging abnormalities were found in 92.0% (23 of 25 patients) with an intracranial vessel gadolinium enhancement in 85.0% (17 of 20 patients), while an increased cerebrospinal fluid/serum quotient of albumin suggestive of blood‐brain barrier disruption was reported in 85.7% (6 of 7 patients). Reverse transcription‐polymerase chain reaction for SARS‐CoV‐2 was negative for all patients in the cerebrospinal fluid. Although different pathophysiological mechanisms may contribute to this acute encephalopathy, our findings suggest the hypothesis of disturbed brain homeostasis and vascular dysfunction consistent with a SARS‐CoV‐2‐induced endotheliitis.	_
103	N101		AmeenBiadseeacOrDagancZeevOrmianerbFirasKassemacShchadaMasarwabAmeerBiadsee	Eight-month follow-up of olfactory and gustatory dysfunctions in recovered COVID-19 patients	https://doi.org/10.1016/j.amjoto.2021.103065	Published	20 April 2021	Study	https://www.sciencedirect.com/science/article/pii/S0196070921001666	Highlights •52% of patients had full recovery of olfactory sense after 8 months. •38.5% reported only a partial recovery of olfactory sense. •61.5% of patients had full recovery of gustatory function after 8 months. •38.5% reported only a partial recovery of gustatory sense. •Gender did not affect the recovery of olfactory/gustatory functions.	En utilisant des tests gradués olfactifs, une étude note que plus d'un tiers l'une cohorte de malades de la covid n'ont retrouvé que partiellement leur odorat à 8 mois.	N010
104	N102		Eric Song, Christopher M. Bartley, Ryan D. Chow, Thomas T. Ngo, Ruoyi Jiang, Colin R. Zamecnik, Ravi Dandekar, Rita P. Loudermilk, Yile Dai, Feimei Liu, Sara Sunshine, Jamin Liu, Wesley Wu, Isobel A. Hawes, Bonny D. Alvarenga, Trung Huynh, Lindsay McAlpine, Nur-Taz Rahman, Bertie Geng, Jennifer Chiarella, Benjamin Goldman-Israelow, Chantal B.F. Vogels, Nathan D. Grubaugh, Arnau Casanovas-Massana, Brett S. Phinney, Michelle Salemi, Jessa R. Alexander, Juan A. Gallego, Todd Lencz, Hannah Walsh, Anne E. Wapniarski, Subhasis Mohanty, Carolina Lucas, Jon Klein, Tianyang Mao, Jieun Oh, Aaron Ring, Serena Spudich, Albert I. Ko, Steven H. Kleinstein, John Pak, Joseph L. DeRisi, Akiko Iwasaki, Samuel J. Pleasure, Michael R. Wilson, Shelli F. Farhadian	Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms	https://doi.org/10.1016/j.xcrm.2021.100288	Published	April 27, 2021	Study	https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00116-6	Highlights •Immune cell scRNA-seq showed divergent T cell activation in the CNS during COVID-19 •COVID-19 patients had a compartmentalized cytokine response in the CNS •All COVID-19 patients had anti-SARS-CoV-2 antibodies in their CSF, •Five out of seven COVID-19 patients had anti-neural autoantibodies in their CSF "This humoral response included indirect evidence for neuroinvasion of SARS-CoV-2 through the presence of anti-viral antibodies in the CNS during acute SARS-CoV-2 infection" "These data therefore suggest that [this] presence may similarly reflect viral infection of the CNS"	Une étude éditée dans Cell, la plus prestigieuse publication en biologie, remarque que les malades de la covid ont une réponse inflammatoire cytokinique dans le système nerveux central spécifique et compartimentalisée, indépendante des atteintes pulmonaires. Les anticorps au SARS-CoV-2 semblent systématiquement présents dans le liquide cérébrospinal (LCS). Et celui-ci présente une activation spécifique des lymphocytes T et, chez une partie des malades, des auto-anticorps neuraux. Ces anticorps ont des cibles (épitopes) différentes des anticorps sériques de la covid. Les auteurs relient ces constatations aux dommages neurologiques de la covid, qui seraient alors en lien avec ces auto-anticorps. Un complément d'approche sur un modèle murin appuie l'hypothèse selon laquelle la présence d'anticorps dans le LCS ne reflète pas uniquement le transfert passif des anticorps de la circulation systémique, suggérant une possible infection cérébrale, dont les autoanticorps du LCR pourraient être les déclencheurs.Le LCS est le seul substitut de tissu aisément échantillonné chez les humains vivants. Cette étude remet sur le devant de la scène la possibilité que les dommages neurologiques soient en partie liés à une neuroinvasion virale, plutôt que seulement des processus indirects."This humoral response included indirect evidence for neuroinvasion of SARS-CoV-2 through the presence of anti-viral antibodies in the CNS during acute SARS-CoV-2 infection"/"These data therefore suggest that [this] presence may similarly reflect viral infection of the CNS"	N009
105	N103		Mary Kelley, Katrina Samson	Bipallidal lesions in COVID 19 patients: Case series and review of literature. (1583)		Published	April 13, 2021	Case Report	https://n.neurology.org/content/96/15_Supplement/1583	Bipallidal lesions are specific to a handful of conditions and their presence in patients with COVID 19 provides us with insight into how the virus can effect the brain. These findings may reflect liver damage in individuals and/or may be the result of chronic hypoxia, blood glucose variability or vasculitis. Damage to these areas of the brain may be irreversible and create long term disability due to neurological dysfunction of the individuals infected and therefore it is important to identify them early.	_
106	N104		Li Jiao, Yun Yang, Wenhai Yu, Yuan Zhao, Haiting Long, Jiahong Gao, Kaiyun Ding, Chunxia Ma, Jingmei Li, Siwen Zhao, Haixuan Wang, Haiyan Li, Mengli Yang, Jingwen Xu, Junbin Wang, Jing Yang, Dexuan Kuang, Fangyu Luo, Xingli Qian, Longjiang Xu, Bin Yin, Wei Liu, Hongqi Liu, Shuaiyao Lu & Xiaozhong Peng	The olfactory route is a potential way for SARS-CoV-2 to invade the central nervous system of rhesus monkeys	https://doi.org/10.1038/s41392-021-00591-7	Published	24 April 2021	Study	https://www.nature.com/articles/s41392-021-00591-7	In this study, we explored the mechanisms of SARS-CoV-2 neurotropism via our established non-human primate model of COVID-19. In rhesus monkey, SARS-CoV-2 invades the CNS primarily via the olfactory bulb. Thereafter, viruses rapidly spread to functional areas of the central nervous system, such as hippocampus, thalamus, and medulla oblongata. The infection of SARS-CoV-2 induces the inflammation possibly by targeting neurons, microglia, and astrocytes in the CNS. Consistently, SARS-CoV-2 infects neuro-derived SK-N-SH, glial-derived U251, and brain microvascular endothelial cells in vitro. To our knowledge, this is the first experimental evidence of SARS-CoV-2 neuroinvasion in the NHP model, which provides important insights into the CNS-related pathogenesis of SARS-CoV-2.	Chez le singe, le SARS-CoV-2 peut infecter le cerveau puis de proche en proche d'autres parties du système nerveux central en entrant par le bulbe olfactif (étude dans Nature). Cette neuroinvasion provoque des inflammations cytokiniques visant les neurones, les astrocytes et la microglie. Elle n'apparaît pas corrélée à une invasion virale pulmonaire. Les auteurs remarquent que l'importance de la neuroinvasion pourrait être différence chez la souris, le primate ou l'homme. Chez le singe, la réplication virale n'est cependant pas efficace, ce qui suggère que les dommages pathologiques sur le SNC sont causés par des facteurs indirects tels que les «tempêtes de cytokines». L'étude n'exclut pas que la neuro-inflammation puisse être aussi provoquée via la barrière hémato-encéphalique. La troisième voie d'entrée du virus vers le SNC pourrait être la voie gastro-intestinale (système nerveux entérique).	N009
107	N105		Artemios Artemiadis,Andreas Liampas,Loizos Hadjigeorgiou &Panagiotis Zis	Myelopathy associated with SARS-COV-2 infection. A systematic review	https://doi.org/10.1080/01616412.2021.1915078	Published	17 Apr 2021	Research Article	https://www.tandfonline.com/doi/abs/10.1080/01616412.2021.1915078	More than one-third of COVID-19 patients report neurological symptoms and cases of neurological diseases are increasingly accumulating. The aim of this systematic review was to characterize all – to date – reported cases with COVID-19 related myelopathy. Methods׃Eighteen papers were included in this review. Patients of all ages could be affected, although there is a predilection for middle-aged people. Results׃There were no significant co-morbidities or immunodeficiencies in the affected patients. COVID-19 related myelopathy started roughly within the first month after COVID-19 onset, either concomitantly with COVID-19 symptoms or within 10 days after their remission. The vast majority of cases fulfilled our criteria for postinfectious transverse myelitis. However, some cases were considered to have had parainfectious or infectious myelitis or, in one case, vascular myelopathy. Motor, sensory and bowel and/or bladder symptoms predominated the clinical presentation of myelopathies, explained mainly by centrally localized and longitudinally extensive lesions within the cervical and/or thoracic segments of the spinal cord. Occasionally lesions were complicated by necrosis and hemorrhages. Treatment with corticosteroids, intravenous immunoglobulin or plasma exchange was offered mostly a mild to marked improvement within a period of some weeks. Conclusions׃ Considering the imminent arrival of new vaccines against COVID-19 pandemic, and their potential risk for postvaccination transverse myelitis, this characterization of COVID-19 related myelopathy is of utmost importance.	_
108	N106	ES	Guilherme Dias de Melo1,, Françoise Lazarini2,, Sylvain Levallois3,, Charlotte Hautefort4,, Vincent Michel2,5, Florence Larrous1, Benjamin Verillaud4, Caroline Aparicio6, Sebastien Wagner2, Gilles Gheusi2,7, Lauriane Kergoat1, Etienne Kornobis8,9, Flora Donati10,11, Thomas Cokelaer8,9, Rémi Hervochon12, Yoann Madec13, Emmanuel Roze14, Dominique Salmon15, Hervé Bourhy1,, Marc Lecuit3,16, and Pierre-Marie Lledo2,	COVID-19-related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters	https://doi.org/10.1126/scitranslmed.abf8396	Published	03 May 2021	Research Article	https://stm.sciencemag.org/content/early/2021/04/30/scitranslmed.abf8396	Whereas recent investigations have revealed viral, inflammatory and vascular factors involved in SARS-CoV-2 lung pathogenesis, the pathophysiology of neurological disorders in COVID-19 remains poorly understood. Olfactory and taste dysfunction are common in COVID-19, especially in mildly symptomatic patients. Here, we conducted a virologic, molecular, and cellular study of the olfactory neuroepithelium of seven patients with COVID-19 presenting with acute loss of smell. We report evidence that the olfactory neuroepithelium may be a major site of SARS-CoV2 infection with multiple cell types, including olfactory sensory neurons, support cells, and immune cells, becoming infected. SARS-CoV-2 replication in the olfactory neuroepithelium was associated with local inflammation. Furthermore, we showed that SARS-CoV-2 induced acute anosmia and ageusia in golden Syrian hamsters, lasting as long as the virus remained in the olfactory epithelium and the olfactory bulb. Finally, olfactory mucosa sampling from patients showing long-term persistence of COVID-19-associated anosmia revealed the presence of virus transcripts and of SARS-CoV-2-infected cells, together with protracted inflammation. SARS-CoV-2 persistence and associated inflammation in the olfactory neuroepithelium may account for prolonged or relapsing symptoms of COVID-19, such as loss of smell, which should be considered for optimal medical management of this disease.	Une étude sur des hamsters montre sur cet animal une anosmie (perte d'odorat) qui perdure aussi longtemps que le virus reste dans le bulbe et l'épithélium olfactifs. L'analyse sur 7 patients révèle également la présence de cellules infectées par le SRAS-CoV-2 ainsi qu'une inflammation prolongée.	N010
109	N107		Siu Wa Tang, Daiga Helmeste and Brian Leonard	Inflammatory Neuropsychiatric Disorders and COVID-19 Neuroinflammation	https://doi.org/10.1017/neu.2021.13	Published	30 April 2021	Review	https://www.cambridge.org/core/journals/acta-neuropsychiatrica/article/abs/inflammatory-neuropsychiatric-disorders-and-covid19-neuroinflammation/DE79FA11E7111CDFC6478C9DD3925926#	Neuropsychiatric sequalae to COVID-19 infection are beginning to emerge, like previous Spanish influenza and SARS episodes. Streptococcal infection in pediatric patients causing OCD (PANDAS) is another recent example of an infection-based psychiatric disorder. Inflammation associated with neuropsychiatric disorders has been previously reported but there is no standard clinical management approach established. Part of the reason is that it is unclear what factors determine the specific neuronal vulnerability and the efficacy of anti-inflammatory treatment in neuroinflammation. The emerging COVID-19 data suggested that in the acute stage, wide-spread neuronal damage appears to be the result of abnormal and overactive immune responses and cytokine storm is associated with poor prognosis. It is still too early to know if there are long term specific neuronal or brain regional damages associated with COVID-19, resulting in distinct neuropsychiatric disorders. In several major psychiatric disorders where neuroinflammation is present, patients with abnormal inflammatory markers may also experience less than favorable response or treatment resistance when standard treatment is used alone. Evidence regarding the benefits of co-administered anti-inflammatory agents such as COX-2 inhibitor is encouraging in selected patients though may not benefit others. Disease modifying therapies are increasingly being applied to neuropsychiatric diseases characterized by abnormal or hyperreactive immune responses. Adjunct anti-inflammatory treatment may benefit selected patients and is definitely an important component of clinical management in the presence of neuroinflammation.	Une revue d'études dresse un résumé très complet sur la neuro-inflammation que peut causer la covid, en comparaison avec d'autres maladies infectieuses, les pistes thérapeutiques possibles, les techniques d'imagerie pertinentes, et la question des effets à long terme en tant que troubles neuro-psychiatriques inflammatoires.	N010
110	N108		A. L. Ren, R. J. Digby & E. J. Needham	Neurological update: COVID-19	https://doi.org/10.1007/s00415-021-10581-y	Published	30 April 2021	Review	https://link.springer.com/article/10.1007/s00415-021-10581-y	Coronavirus Disease 2019 is predominantly a disorder of the respiratory system, but neurological complications have been recognised since early in the pandemic. The major pathophysiological processes leading to neurological damage in COVID-19 are cerebrovascular disease, immunologically mediated neurological disorders and the detrimental effects of critical illness on the nervous system. It is still unclear whether direct invasion of the nervous system by the Severe Acute Respiratory Syndrome Coronavirus 2 occurs; given the vast numbers of people infected at this point, this uncertainty suggests that nervous system infection is unlikely to represent a significant issue if it occurs at all. In this review, we explore what has been learnt about the neurological complications of COVID-19 over the course of the pandemic, and by which mechanisms these complications most commonly occur.	Cette revue d'études discute des 4 causes principales de dommages neurologiques attribués à la covid : - l'invasion directe du système nerveux central par le SRAS-CoV-2 - les troubles neurologiques à médiation immunologique - la maladie neurovasculaire et thromboembolique - les séquelles neurologiques d'une phase aiguë grave de la maladie	N010
111	N109		Alexios-Fotios A. Mentis	What neurological and psychiatric effects does COVID-19 have on its survivors?	https://doi.org/10.1186/s12916-021-01986-7	Published	29 April 2021	Review	https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-021-01986-7	Furthermore, when compared to neurological disorders, the hazard ratios for psychiatric disorders, such as anxiety and mood disorders, showed a less strong association with encephalopathy and hospitalization. This observation suggests that mental health deterioration due to social distancing and pandemic-related anxiety may have partly contributed to psychiatric illness; thus, it is unlikely they represent a direct manifestation of the COVID-19 illness. Moreover, the underlying mechanisms for such associations include direct effects of viral tropism on the central nervous system, angiotensin-converting enzyme-2 receptor-related neuronal damage, cytokine overproduction and toxicity-related neuronal injury, and immune response-related neuronal injury [1, 5]. The study by Taquet et al. indicates severe neurological and psychiatric illness following infection with COVID-19. The knowledge reaped from this study can assist in health services planning and in identifying future research goals. Globally, the cohort approach reported offers useful, timely, and critically required information for other researchers and funding providers to guide the future steps in the COVID-19 research related to clinical neurosciences and mental health strategy.	_
112	N110		Flavia Mattioli, Chiara Stampatori, […]Giuseppe De Palma	Neurological and cognitive sequelae of Covid-19: a four month follow-up		Published	01 May 2021	Study	https://link.springer.com/article/10.1007/s00415-021-10579-6	The aim of this study is to investigate if objective neurological or cognitive impairment is detect-able four months after SARS-CoV-2 infection, in a group of patients who had mild–moderate COVID-19. A cohort of 120 health care workers previously afected by COVID-19 was examined 4 months after the diagnosis by means of neurological and extensive cognitive evaluation and compared to a group of 30 health care workers who did not have COVID-19 and were similar for age and co morbidities. At 4 month follow-up, 118/120 COVID-19 cases had normal neurological examination, two patients had neurological defcits. COVID-19 patients did not show general cognitive impairment at MMSE. In COVID-19 cases the number of impaired neuropsychological tests was not signifcantly diferent from non COVID-19 cases (mean 1.69 and 1 respectively, Mann–Whitney p=n.s.), as well as all the mean tests’ scores. Anxiety, stress and depression scores resulted to be signifcantly higher in COVID-19 than in non COVID-19 cases. The results do not support the presence of neurological defcits or cognitive impairment in this selected population of mild–moderate COVID-19 patients four months after the diagnosis. Severe emotional disorders in patients who had COVID-19 in the past are confrmed.	Une étude a mesuré les scores cognitifs sur une cohorte de 120 patients d'un personnel hospitalier PCR+ avec seulement des cas légers à modérés de la covid pendant la phase aiguë (2 seulement ayant eu besoin d'une oxygénothérapie). Il n'apparaît pas d'écarts significatifs avec un groupe contrôle (très légèrement moins bon sans écart stat. significatif). Les tests comprenaient des évaluations de fluidité verbale, mémoire, attention, réactivité, et notamment un MMSE (mini-mental state examination).	N010
113	N111		George B. Stefano, Pascal Büttiker, Simon Weissenberger, Anders Martin, Radek Ptacek, Richard M. Kream	Editorial: The Pathogenesis of Long-Term Neuropsychiatric COVID-19 and the Role of Microglia, Mitochondria, and Persistent Neuroinflammation: A Hypothesis	https://doi.org/10.12659/MSM.933015	Published	10 May 2021	Article	https://www.medscimonit.com/download/index/idArt/933015	Persistent comorbidities occur in patients who initially recover from acute coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ‘Long COVID’ involves the central nervous system (CNS), resulting in neuropsychiatric symptoms and signs, including cognitive impairment or ‘brain fog’ and chronic fatigue syndrome. There are similarities in these persistent complications between SARS-CoV-2 and the Ebola, Zika, and influenza A viruses. Normal CNS neuronal mitochondrial function requires high oxygen levels for oxidative phosphorylation and ATP production. Recent studies have shown that the SARS-CoV-2 virus can hijack mitochondrial function. Persistent changes in cognitive functioning have also been reported with other viral infections. SARS-CoV-2 infection may result in long-term effects on immune processes within the CNS by causing microglial dysfunction. This short opinion aims to discuss the hypothesis that the pathogenesis of long-term neuropsychiatric COVID-19 involves microglia, mitochondria, and persistent neuroinflammation.	Des chercheurs élaborent une hypothèse sur les séquelles neurologiques de la covid. Selon eux, un état chronique de pro-inflammation dans les structures du système nerveux central pourrait être perpétué par une activation chronique des lymphocytes T et B due aux épitopes viraux, ciblant au final la microglie cérébrale. Les auteurs proposent des analyses bioinformatiques adaptées sur les peptides concernés pour valider cette hypothèse.	N010
114	N112		Courtney L.McMahon124HilaryStaples34MichalGazi3RicardoCarrion3JennyHsieh	SARS-CoV-2 targets glial cells in human cortical organoids	https://doi.org/10.1016/j.stemcr.2021.01.016	Published	11 May 2021	Study	https://www.sciencedirect.com/science/article/pii/S2213671121000461	Highlights •SARS-CoV-2 infects human cortical organoids at low viral loads within 6 h •Replication of SARS-CoV-2 does not occur within 4 days post infection •SARS-CoV-2 preferentially targets glia and choroid plexus cells in vitro •Cleaved caspase-3 co-localizes with SARS-CoV-2 in cells at 14 days post infection	Dans une étude publiée dans Stem Cell Reports, des chercheurs notent grâce à des organoïdes humains cérébraux que le virus SARS-CoV-2 semblent cibler non pas les neurones mais les cellules gliales et les cellules du plexus choroïde.	N010
115	N113		Eric GUEDJ Françoise LAZARINI Silvia MORBELLI Mathieu CECCALDI Charlotte HAUTEFORT Aurélie KAS Thomas RADULESCO Dominique SALMON-CERON Carole ELDIN	Long COVID and the brain network of Proust's madeleine: targeting the olfactory pathway	https://doi.org/10.1016/j.cmi.2021.05.015	Published	May 17, 2021	Article	https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(21)00238-X/fulltext	Interestingly, the identified pathway seems to describe the limbic network of Proust's famous madeleine: the smell is quickly followed by the taste, recognition (and, more broadly, the memory), and associated emotions. This limbic system is known to be closely linked on brainstem nuclei to the autonomic nervous system, that is also involved during emotional memory processing, and whose dysregulation can lead to cardiovascular, muscular, gastrointestinal and respiratory symptoms (e.g., diarrhoea, dizziness, hypertension, palpitations, or tremor) The fronto-basal cortex is involved in attention and short-term memory linked to the olfactory sense. After being processed and refined in the olfactory bulb and piriform cortex, the olfactory sensory input is processed in the amygdala and hippocampus (two key brain areas involved in emotion and memory), thus making olfaction a privileged sense for accessing memories. Perturbations of the olfactory circuit and functioning can thus result in emotional and cognitive dysfunctions, as described in animal models such as olfactory bulbectomy, a relevant model of depression. Accordingly, loss of olfaction is associated with depressed mood and anxiety in long COVID more strongly than life-threatening symptoms such as shortness of breath do The profile of hypometabolism identified in patients with long COVID does not seem to correspond to those in depression, post-traumatic stress disorder, or even fibromyalgia. If limbic alterations have also been described in these conditions, the association with concomitant hypometabolism of the brainstem and cerebellum is more atypical Nevertheless, we believe that the functional aspect of this remote effect is important since most patients recover after a few months in the absence of obvious brain lesions on brain MRI. This functional recovery could thus be accelerated by different strategies of rehabilitationIf the hypothesis is borne out, the development of new therapeutic strategies must target the olfactory clefts in the most severely impaired patients who will have little or no recovery after rehabilitation, for example, by using intranasally administered anti-inflammatory or antiviral drugs to act [7], beyond functional effects, on the pathological impairment of Proust’s madeleine brain network.	Dans une hypothèse qu'elle dresse sur la neuro-inflammation qui peut être déclenchée par le virus SARS-CoV-2, une équipe française note que le profil d'hypométabolisme cérébral identifié chez les patients atteints de covid long ne semble pas correspondre à ceux en dépression, en état de stress post-traumatique, ou en fibromyalgie. Les auteurs remarquent que, même si des altérations limbiques ont également été décrites dans ces conditions, l'association avec un hypométabolisme concomitant du tronc cérébral et du cervelet est plus atypique. L'équipe table notamment sur une hypothèse liée aux zones afférentes à la mémoire des odeurs ("le chemin de la madeleine de Proust"). En l'absence de lésions distantes connues, l'altération du bulbe olfactif pourrait être selon eux à l'origine d'effets localisés plus en arrière sur la fonction cérébrale d'autres régions limbiques (dont l'amygdale et l'hippocampe), ainsi que le tronc cérébral et le cervelet, par diaschisis (diminution de l'activité fonctionnelle des régions cérébrales des zones cérébrales endommagées connectées) en raison de désafférentation (perte d'entrée).	N009
116	N114		Ingrid H.C.H.M. Philippens, Kinga P. Böszörményi, Jacqueline A. Wubben, Zahra C. Fagrouch, Nikki van Driel, Amber Q. Mayenburg, Diana Lozovagia, Eva Roos, Bernadette Schurink, Marianna Bugiani, Ronald E. Bontrop, Jinte Middeldorp, Willy M. Bogers, Lioe-Fee de Geus-Oei, Jan A.M. Langermans, Marieke A. Stammes, Babs E. Verstrepen, Ernst J. Verschoor	SARS-CoV-2 causes brain inflammation and induces Lewy body formation in macaques	https://doi.org/10.1101/2021.02.23.432474	pre-print	May 05, 2021	Study	https://www.biorxiv.org/content/10.1101/2021.02.23.432474v2.full	Here we show that SARS-CoV-2 infection causes brain inflammation in the macaque model. An increased metabolic activity in the pituitary gland of two macaques was observed by longitudinal positron emission tomography-computed tomography (PET-CT). Post-mortem analysis demonstrated infiltration of T-cells and activated microglia in the brain, and viral RNA was detected in brain tissues from one animal. We observed Lewy bodies in brains of all rhesus macaques. These data emphasize the virus’ capability to induce neuropathology in this nonhuman primate model for SARS-CoV-2 infection. As in humans, Lewy body formation is an indication for the development of Parkinson’s disease, this data represents a warning for potential long-term neurological effects after SARS-CoV-2 infection.	Selon un pre-print (étude ni relue ni publiée), les infections à la covid chez les macaques peuvent causer des inflammations neurologiques et les analyses post-mortem revèlent la présence de corps de Lewy (indicateur de neurodégénérescence de type parkinsonien).	N011
117	N115	R	Lucas Scardua Silva, Rafael Batista Joao, Mateus Henrique Nogueira, Italo Karmann Aventurato, Brunno Machado de Campos, Mariana Rabelo de Brito, Marina Koutsodontis Machado Alvim, Guilherme Vieira Nunes Ludwig, André Schwambach Vieira, Leonilda Maria Barbosa Santos, Alessandro dos Santos Farias, Fernando Cendes, Clarissa Lin Yasuda	Functional and microstructural brain abnormalities, fatigue, and cognitive dysfunction after mild COVID-19	https://doi.org/10.1101/2021.03.20.21253414	pre-print	March 24, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.03.20.21253414v1.full	We conducted a cross-sectional study of 87 non-hospitalized recovered individuals 54 days after the laboratory confirmation of COVID-19. We performed structured interviews, neurological examination, 3T-MRI scans with diffusion tensor images (DTI) and functional resting-state images (fMRI). Also, we investigated fatigue, anxiety, depression, somnolence, language, memory, and cognitive flexibility, using validated instruments. Individuals self-reported a high frequency of headache (40%) and memory difficulties (33%). The quantitative analyses confirmed symptoms of fatigue (68%), excessive somnolence (35%), anxiety (29%), impaired cognitive flexibility (40%) and language impairment (33%). There were widespread cerebral white matter alterations (mainly characterized by increased fractional anisotropy), which correlated with abnormal attention and cognitive flexibility. The resting-state fMRI networks analysis showed severely disrupted brain hyperconnectivity and loss of resting-state networks specificity.	Une étude non relue et non encore publiée (pre-print) utilise l'imagerie du tenseur de diffusion sur des patients souffrant de séquelles neurologiques de la covid deux mois après l'infection. Des altérations de la substance blanche cérébrale semblent répandues et corrélées avec une attention anormale et une flexibilité cognitive. La connectivité cérébrale peut être fortement perturbée, avec des régions excessivement et chaotiquement connectées, associées à une perte significative de spécificité.
118	N116	R	M. Almeria J.C. Cejudo J.Sotoca J.Deus J .Krupinski	Cognitive profile following COVID-19 infection: Clinical predictors leading to neuropsychological impairment	https://doi.org/10.1016/j.bbih.2020.100163	Published	22 October 2020	Study	https://www.sciencedirect.com/science/article/pii/S2666354620301289	Highlights •Neuropsychological deficits related to COVID-19 infection were seen in attention, memory and executive function domains. •Presenting neurological symptoms during COVID-19 infection were risk factors for cognitive deficit. •Oxygen therapy, headache and diarrhea were symptoms associated to poor performance in neuropsychological tests. •Cognitive complains in patients with COVID-19 were associated with anxiety and depressive symptoms.	Une étude indique que le symptôme de diarrhée et la nécessité d'oxygénothérapie chez les malades de la covid sont des facteurs de risque pour de possibles séquelles de déficience neurocognitive.	N010
119	N117	R	P. Voruz, G. Allali, L. Benzakour, A. Nuber-Champier, M. Thomasson, I. Jacot, J. Pierce, P. Lalive, K-O. Lövblad, O. Braillard, M. Coen, J. Serratrice, J. Pugin, R. Ptak, I. Guessous, B.N. Landis, F. Assal, J.A. Péron	Long COVID neuropsychological deficits after severe, moderate or mild infection	https://doi.org/10.1101/2021.02.24.21252329	pre-print	February 26, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.02.24.21252329v1	Methods Standardized neuropsychological, psychiatric, neurological and olfactory tests were administered to 45 patients (categorized according to the severity of their respiratory symptoms during the acute phase) 236.51 ± 22.54 days post-discharge following SARS-CoV-2 infection. Results Deficits were found in all the domains of cognition and the prevalence of psychiatric symptoms was also high in the three groups. The severe performed more poorly on long-term episodic memory and exhibited greater anosognosia. The moderate had poorer emotion recognition, which was positively correlated with persistent olfactory dysfunction. The mild were more stressed, anxious and depressed. Conclusion The data support the hypothesis that the virus targets the central nervous system (and notably the limbic system), and support the notion of different neuropsychological phenotypes. "Our third level of analysis enabled us to go further in characterizing the hypothesized clinical phenotypes. Quantified results pointed to the presence of at least three profiles (patient clusters), corroborating the clinical impressions we had when interviewing and assessing the patients for this study. Patients with the first (neurological) profile were typically aged about 55 years, mostly men, of average educational level, and a small proportion of them had a history of diabetes, cardiovascular disease, or sleep apnea syndrome. At the cognitive level, these patients displayed long-term memory, executive and language disorders. They had more severe anosognosia for their memory difficulties. Nearly all of them reported sleep disorders and emotional apathy. Patients with the second (psychiatric) profile were aged about 45-50 years, and there were equal numbers of men and women. No significant medical antecedents were noted, and the majority of them had had mild or moderate respiratory disease. At the cognitive level, they displayed executive and attentional dysfunctions, which could influence other cognitive domains (e.g., memory recall strategies). At the psychiatric level, they had high scores for depressive symptoms, anxiety, insomnia and stress, and more sporadically exhibited PTSD and dissociative disorders. Our results also indicated the presence of a third (mixed) profile combining the symptoms and clinical characteristics of the two previously described profiles." "This study unambiguously demonstrates the presence of long-term neuropsychological sequelae following SARS-CoV-2 infection, regardless of the severity of the respiratory disease in the acute phase. Some of the cognitive deficits could be explained by psychiatric variables, emphasizing the importance of considering a broad range of psychiatric symptoms. However, not all neuropsychological sequelae could be explained by these variables. The presence of correlations between olfaction, emotion recognition and episodic memory, which share common functional and anatomical substrates, reinforces the hypothesis that the virus targets the CNS (and notably the limbic system). Finally, the data support the notion of different clinical phenotypes, paving the way for clinical guidelines and recommendations for the management of long-term neurological impairment following SARS-CoV-2 infection."	Une étude en pre-print (non relue et non publiée) a suivi sur 6-9 mois des patients atteints d'une covid légère, modérée et sévère avec des tests neurologiques et psychiatriques standardisés. Les auteurs notent que certaines séquelles neurologiques sont liées sans ambiguïté à l'infection au SARS-CoV-2. Enfin, l'étude distingue trois profils de patients, selon des phénotypes neuropsychiatriques, mais rappelle que des biais de sélection peuvent affecter les résultats. Les patients présentant le premier profil (neurologique) étaient généralement âgés d'environ 55 ans, principalement des hommes, d'un niveau d'éducation moyen, et une petite proportion d'entre eux avaient des antécédents de diabète, de maladie cardiovasculaire ou de syndrome d'apnée du sommeil. Au niveau cognitif, ces patients présentaient des troubles de la mémoire, de l'exécutif et du langage à long terme. Ils avaient une anosognosie plus sévère en raison de leurs difficultés de mémoire. Presque tous ont signalé des troubles du sommeil et une apathie émotionnelle. Les patients avec le deuxième profil (psychiatrique) étaient âgés d'environ 45 à 50 ans, et il y avait un nombre égal d'hommes et de femmes. Aucun antécédent médical significatif n'a été noté et la majorité d'entre eux avaient une maladie respiratoire légère ou modérée. Au niveau cognitif, ils présentaient des dysfonctionnements exécutifs et attentionnels, qui pouvaient influencer d'autres domaines cognitifs (par exemple, les stratégies de rappel de mémoire). Au niveau psychiatrique, ils avaient des scores élevés pour les symptômes dépressifs, l'anxiété, l'insomnie et le stress, et présentaient plus sporadiquement le SSPT et les troubles dissociatifs. Nos résultats indiquent également la présence d'un troisième profil (mixte) combinant les symptômes et les caractéristiques cliniques des deux profils précédemment décrits. Cette étude démontre sans ambiguïté la présence de séquelles neuropsychologiques à long terme suite à une infection par le SRAS-CoV-2, quelle que soit la gravité de la maladie respiratoire en phase aiguë. Certains des déficits cognitifs pourraient être expliqués par des variables psychiatriques, soulignant l'importance de considérer un large éventail de symptômes psychiatriques. Cependant, toutes les séquelles neuropsychologiques ne peuvent être expliquées par ces variables. La présence de corrélations entre l'olfaction, la reconnaissance des émotions et la mémoire épisodique, qui partagent des substrats fonctionnels et anatomiques communs, renforce l'hypothèse que le virus cible le SNC (et notamment le système limbique). Enfin, les données soutiennent la notion de différents phénotypes cliniques, ouvrant la voie à des lignes directrices cliniques et des recommandations pour la gestion des troubles neurologiques à long terme suite à une infection par le SRAS-CoV-2.
120	N118		RitwikGhoshaDipayanRoybArpanMandalaShyamal KantiPalaBikashChandra SwaikaaDinabandhuNagaaAlakPanditcBiman KantiRaycJuliánBenito-León	Cerebral venous thrombosis in COVID-19	https://doi.org/10.1016/j.dsx.2021.04.026	Published	18 May 2021	Review	https://www.sciencedirect.com/science/article/pii/S1871402121001387	Highlights •CVT should be listed among the neurological manifestations of COVID-19. •The hypercoagulable state is thought to be the main mechanism in COVID-19 related CVT. •Headache, seizures, and stroke-like/encephalopathy symptoms in the setting of COVID-19 should prompt to rule out CVT.	_
121	N119		Jonathan P Rogers, MRCPsych † Edward Chesney, MRCPsych † Dominic Oliver, MSc Thomas A Pollak, PhD Prof Philip McGuire, FMedSci Paolo Fusar-Poli, PhD Michael S Zandi, PhD Prof Glyn Lewis, PhD Prof Anthony S David, FMedSci	Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic	https://doi.org/10.1016/S2215-0366(20)30203-0	Published	May 18, 2020	Meta-analysis	https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(20)30203-0/fulltext	If infection with SARS-CoV-2 follows a similar course to that with SARS-CoV or MERS-CoV, most patients should recover without experiencing mental illness. SARS-CoV-2 might cause delirium in a significant proportion of patients in the acute stage. Clinicians should be aware of the possibility of depression, anxiety, fatigue, post-traumatic stress disorder, and rarer neuropsychiatric syndromes in the longer term.	Une méta-analyse sur les séquelles neurologiques et psychiatriques comparées du SRAS, du MERS, au regard du SARS-CoV-2.
122	N120		Arvid Edén, Nelly Kanberg, Johanna Gostner, Dietmar Fuchs, Lars Hagberg, Lars-Magnus Andersson, Magnus Lindh, Richard W. Price, Henrik Zetterberg, Magnus Gisslén	CSF Biomarkers in Patients With COVID-19 and Neurologic Symptoms A Case Series	https://doi.org/10.1212/WNL.0000000000010977	Published	January 12, 2021	Case Series	https://n.neurology.org/content/96/2/e294	Our results in patients with COVID-19 and neurologic symptoms suggest an unusual pattern of marked CSF inflammation in which soluble markers were increased but white cell response and other immunologic features typical of CNS viral infections were absent. While our initial hypothesis centered on CNS SARS-CoV-2 invasion, we could not convincingly detect SARS-CoV-2 as the underlying driver of CNS inflammation. These features distinguish COVID-19 CSF from other viral CNS infections and raise fundamental questions about the CNS pathobiology of SARS-CoV-2 infection.	Une étude de cas dans la revue Neurology remarque chez les malades de la covid souffrant de troubles neurologiques un schéma inhabituel d'inflammation marquée du liquide cérébro-spinal, mais sans caractéristiques typiques des infections virales.	N011
123	N121		Jennifer A. Frontera, Sakinah Sabadia, Rebecca Lalchan, Taolin Fang, Brent Flusty, Patricio Millar-Vernetti, Thomas Wisniewski, Andrea B. Troxel, Laura Balcer, Steven Galetta	A Prospective Study of Neurologic Disorders in Hospitalized Patients With COVID-19 in New York City	https://doi.org/10.1212/WNL.0000000000010979	Published	January 26, 2021	Study	https://n.neurology.org/content/96/4/e575	Neurologic disorders were detected in 13.5% of patients with COVID-19 and were associated with increased risk of in-hospital mortality and decreased likelihood of discharge home. Many observed neurologic disorders may be sequelae of severe systemic illness.	_
124	N122		Abhishek Jaywant, W. Michael Vanderlind, George S. Alexopoulos, Chaya B. Fridman, Roy H. Perlis & Faith M. Gunning	Frequency and profile of objective cognitive deficits in hospitalized patients recovering from COVID-19	https://doi.org/10.1038/s41386-021-00978-8	Published	15 February 2021	Study	https://www.nature.com/articles/s41386-021-00978-8	We evaluated the frequency, severity, and profile of cognitive dysfunction in patients recovering from prolonged COVID-19 hospitalization who required acute inpatient rehabilitation prior to discharge. We analyzed cross-sectional scores from the Brief Memory and Executive Test (BMET) in a cohort of N = 57 COVID-19 patients undergoing inpatient rehabilitation, calculating the frequency of impairment based on neuropsychologist diagnosis and by age-normed BMET subtests. In total, 43 patients (75%) were male, 35 (61%) were non-white, and mean age was 64.5 (SD = 13.9) years. In total, 48 (84%) were previously living at home independently. Two patients had documented preexisting cognitive dysfunction; none had known dementia. Patients were evaluated at a mean of 43.2 (SD = 19.2) days after initial admission. In total, 50 patients (88%) had documented hypoxemic respiratory failure and 44 (77%) required intubation. Forty-six patients (81%) had cognitive impairment, ranging from mild to severe. Deficits were common in working memory (26/47 [55%] of patients), set-shifting (21/44 [47%]), divided attention (18/39 [46%]), and processing speed (14/35 [40%]).	_
125	N123		Stéphane Kremer, François Lersy, Mathieu Anheim, Hamid Merdji, Maleka Schenck, Hélène Oesterlé, Federico Bolognini, Olivier Collange, Paul Michel Mertes, Francis Schneider, Samira Fafi-Kremer, Mickael Ohana, Ferhat Meziani, Nicolas Meyer, Julie Helms, François Cotton	Neurologic and neuroimaging findings in patients with COVID-19 A retrospective multicenter study	https://doi.org/10.1212/WNL.0000000000010112	Published	September 29, 2020	Study	https://n.neurology.org/content/95/13/e1868	Patients with COVID-19 may develop a wide range of neurologic symptoms, which can be associated with severe and fatal complications such as ischemic stroke or encephalitis. In terms of meningoencephalitis involvement, even if a direct effect of the virus cannot be excluded, the pathophysiology seems to involve an immune or inflammatory process given the presence of signs of inflammation in both CSF and neuroimaging but the lack of virus in CSF.	_
126	N124		R. Méndez, V. Balanzá-Martínez, S.C. Luperdi, I. Estrada, A. Latorre, P. González-Jiménez, L. Feced, L. Bouzas, K. Yépez, A. Ferrando, D. Hervás, E. Zaldívar, S. Reyes, M. Berk, R. Menéndez	Short-term neuropsychiatric outcomes and quality of life in COVID-19 survivors	https://doi.org/10.1111/joim.13262	Published	03 February 2021	Study	https://onlinelibrary.wiley.com/doi/10.1111/joim.13262	Results Of the 229 screened patients, 179 were included in the final analysis. Amongst survivors, the prevalence of moderately impaired immediate verbal memory and learning was 38%, delayed verbal memory (11.8%), verbal fluency (34.6%) and working memory (executive function) (6.1%), respectively. Moreover, 58.7% of patients had neurocognitive impairment in at least one function. Rates of positive screening for anxiety, depression and post-traumatic stress disorder were 29.6%, 26.8% and 25.1%, respectively. In addition, 39.1% of the patients had psychiatric morbidity. Low QoL for physical and mental components was detected in 44.1% and 39.1% of patients respectively. Delirium and psychiatric morbidity were associated with neurocognitive impairment, and female gender was related with psychiatric morbidity. Conclusion Hospitalized COVID-19 survivors showed a considerable prevalence of neurocognitive impairment, psychiatric morbidity and poor QoL in the short term. It is uncertain if these impacts persist over the long term.	_
127	N125		Domenico Nuzzo , Gaetano Cambula 3 ,Ignazio Bacile, Manfredi Rizzo 4, Massimo Galia , Paola Mangiapane 6, Pasquale Picone 1,2, Daniela Giacomazza 7 and Luca Scalisi	Long-Term Brain Disorders in Post Covid-19 Neurological Syndrome (PCNS) Patient	https://doi.org/10.3390/brainsci11040454	Published	2 April 2021	Case Report	https://www.mdpi.com/2076-3425/11/4/454/htm	The aim of this article is to describe the prolonged neurological clinical consequences related to COVID-19. We believe it is clinically clear that we can define a post-acute COVID-19 neurological syndrome. Therefore, in patients after a severe clinical condition of COVID-19, a deepening of persistent neurological signs is necessary.	_
128	N126		Maithili Sashindranath, Harshal H. Nandurkar	Endothelial Dysfunction in the Brain Setting the Stage for Stroke and Other Cerebrovascular Complications of COVID-19	https://doi.org/10.1161/STROKEAHA.120.032711	Published	2 Apr 2021	Study	https://www.ahajournals.org/doi/10.1161/STROKEAHA.120.032711	Together with findings of fibrin-rich microthrombi, widespread extracellular fibrin deposition in affected various organs and hypercytokinemia, this suggests that COVID-19 is more than a pulmonary viral infection. Evidently, COVID-19 is a thrombo-inflammatory disease. Endothelial cells that constitute the lining of blood vessels are the primary targets of a thrombo-inflammatory response, and severe acute respiratory syndrome coronavirus 2 also directly infects endothelial cells through the ACE2 (angiotensin-converting enzyme 2) receptor. Being highly heterogeneous in their structure and function, differences in the endothelial cells may govern the susceptibility of organs to COVID-19. Here, we have explored how the unique characteristics of the cerebral endothelium may be the underlying reason for the increased rates of cerebrovascular pathology associated with COVID-19.	Des chercheurs dans une étude australienne évoquent le rôle particulier de l'endothélium vasculaire et les dommages qu'il subit. Ces derniers sont, selon les auteurs, impliqués dans les symptômes neurologiques.	N011
129	N127		Matteo Bocci, Clara Oudenaarden, Xavier Sàenz-Sardà, Joel Simrén, Arvid Edén, Jonas Sjölund, Christina Möller, Magnus Gisslén, Henrik Zetterberg, Elisabet Englund, Kristian Pietras	Infection of brain pericytes underlying neuropathology of COVID-19 patients	https://doi.org/10.1101/2021.05.24.445532	pre-print	May 25, 2021	Study	https://www.biorxiv.org/content/10.1101/2021.05.24.445532v1	Here, we used state-of-the-art multiplexed immunostaining of human brains (n = 6 COVID-19, median age = 69,5 years; and n = 7 control, median age = 68 years), and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in peri-vascular cells. Viral particles were identified in the vascular wall and paralleled by peri-vascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood-brain barrier. Notably, cerebrospinal fluid from an additional 16 individuals (n = 8 COVID-19, median age = 67 years; and n = 8 control, median age = 69,5 years) exhibited significantly lower levels of the pericyte marker PDGFRβ in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to peri-vascular inflammation and a locally compromised blood-brain barrier.	Un travail en pre-print (étude non encore relue ni publiée) estime que l'infection par le SARS-CoV-2 des péricytes (cellules qui entourent les capillaires) permet l'entrée du virus dans le système nerveux central, et explique la symptomatologie neurologique. Selon les auteurs, les symptômes neurologiques sont notamment dus à l'inflammation périvasculaire et aux dommages sur la barrière hémato-encéphalique.
130	N128		Benjamin, Butler, Matthew, Song, Jia, Hafeez, Danish, Morrin, Hamilton, Rengasamy, Emma Rachel, Thomas, Lucretia, Ralovska, Silviya, Smakowski, Abigail, Sundaram, Ritika Dilip, Hunt, Camille Kaitlyn, Lim, Mao Fong, Aniwattanapong, Daruj, Singh, Vanshika, Hussain, Zain, Chakraborty, Stuti, Burchill, Ella, Jansen, Katrin, Holling, Heinz, Walton, Dean, Pollak, Thomas A, Ellul, Mark, Koychev, Ivan, Solomon, Tom, Michael, Benedict Daniel, Nicholson, Timothy R, Rooney, Alasdair G	Neurology and neuropsychiatry of COVID-19: a systematic review and meta-analysis of the early literature reveals frequent CNS manifestations and key emerging narratives	https://doi.org/10.1136/jnnp-2021-326405	Published	June 3, 2021	Systematic review and meta-analysis	https://jnnp.bmj.com/content/early/2021/06/03/jnnp-2021-326405	In our review, we summarise point prevalence of 20 neurological and neuropsychiatric complications of COVID-19. The most frequently studied symptoms were heavily weighted towards non-specific features of systemic illness, such as headache, myalgia, fatigue, anosmia and dysgeusia, which are unlikely to be ‘primary’ neurological symptoms. It was predominantly these more non-specific symptoms that were found to have the highest prevalences, ranging from 20.7% (16.1% to 26.1%) to 43.1% (35.2% to 51.3%) (headache and anosmia, respectively). Of note, more specific neurological and neuropsychiatric symptoms such as altered mental status, depression, anxiety, sleep disorder, stroke and seizures were less frequently studied. However, the core psychiatric disorders of depression (23.0% (11.8% to 40.2%)) and anxiety (15.9% (5.6% to 37.7%)) appeared to be highly prevalent. The reported prevalence of major neurological disorders such as ischaemic stroke (1.9% (1.3% to 2.8%)), haemorrhagic stroke (0.4% (0.3% to 0.7%)) and seizure (0.06% (0.06% to 0.07%)) were substantially lower.	Dans le BMJ, une revue systématique d'études et une très large méta-analyse sur les manifestations neurologiques et psychiatriques de la covid. les auteurs notent qu'il pourrait y avoir une sous-estimation de la prévalence de ces symptômes. L'étude conclut que le covid long est susceptible d'être une entité hétérogène avec une étiologie multifactorielle, comprenant la persistance virale, des dérèglements inflammatoires, un déconditionnement physique et des facteurs psychologiques.	N011
131	N129		Thomas Müller	Long COVID - Langzeitfolgen durch chronische Neuroinflammation?	https://doi.org/10.1007/s15202-021-4692-8	Published	10 June 2021	Review	https://link.springer.com/article/10.1007/s15202-021-4692-8	Es trifft nicht nur die Alten und Schwerkranken: Die meisten Patienten mit Long COVID sind relativ jung und haben die Infektion zuhause durchgemacht. Experten vermuten eine chronische Neuroinflammation als Ursache.
132	N130		Maria A. Garcia Paula V. Barreras Allie Lewis Gabriel Pinilla Lori J. Sokoll Thomas Kickler Heba Mostafa Mario Caturegli Abhay Moghekar Kathryn C. Fitzgerald Hopkins Neuro-COVID-19 Group Carlos A. Pardo	Cerebrospinal fluid in COVID-19 neurological complications: Neuroaxonal damage, anti-SARS-Cov2 antibodies but no evidence of cytokine storm	https://doi.org/10.1016/j.jns.2021.117517	Published	May 31, 2021	Study	https://www.jns-journal.com/article/S0022-510X(21)00211-2/fulltext	Highlights •A case-control study of CSF showed a paucity of neuroinflammation changes in CSF of COVID-19 neurological complications. •No evidence of “cytokine storm” was observed in COVID-19 complications such as stroke and encephalopathy •Subsets of CSF cytokine increases are not exclusive of COVID-19 strokes as they are present in non-COVID-19 stroke controls. •No evidence of SARS-CoV2 viral RNA was observed in the CSF. •A high frequency of anti-SARS-CoV2 spike protein IgG antibodies (77% of cases) was observed in CSF from COVID-19 neurological complications •Increase of CSF neurofilament light chain and C-reactive protein was prominent in critical and severe COVID-19 cases CSF from COVID-19 subjects showed absence of pleocytosis or specific increases in pro-inflammatory markers (IL-6, ferritin, or D-dimer). Although pro-inflammatory cytokines (IL-6, TNFα, IL-12p70) and IL-10 were increased in CSF of stroke COVID-19 subjects, a similar increase was observed in non-COVID-19 stroke subjects. Anti-SARS-CoV2 antibodies in CSF of COVID-19 subjects (77%) were observed despite no evidence of SARS-CoV2 viral RNA. CSF-NF-L was elevated in subjects with stroke and critical COVID-19 as compared to controls and other COVID-19 severity categories. CSF-hsCRP was present in all subjects with critical stages of COVID-19 (7/18) but only in 1/82 controls.
133	N131		Don A. Davies, Aida Adlimoghaddam & Benedict C. Albensi	The Effect of COVID-19 on NF-κB and Neurological Manifestations of Disease	https://doi.org/10.1007/s12035-021-02438-2	Published	01 June 2021	Article	https://link.springer.com/article/10.1007/s12035-021-02438-2	Neurological symptoms in COVID-19 patients may arise due to a cytokine storm and a heighten state of inflammation. The nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) is a central pathway involved with inflammation and is shown to be elevated in a dose-dependent matter in response to coronaviruses. NF-κB has a role in cytokine storm syndrome, which is associated with greater severity in COVID-19-related symptoms. Therefore, therapeutics that reduce the NF-κB pathway should be considered in the treatment of COVID-19. Neuro-COVID-19 units have been established across the world to examine the neurological symptoms associated with COVID-19. Neuro-COVID-19 is increasingly becoming an accepted term among scientists and clinicians, and interdisciplinary teams should be created to implement strategies for treating the wide range of neurological symptoms observed in COVID-19 patients.	Une étude suggère que des thérapies visant à réduire la voie de la protéine NF-κB devraient être envisagées dans le traitement de la covid, pour limiter les séquelles neurologiques ("le neuro-covid").	N011
134	N132		Nils Kappelmann,a,b,⁎ Robert Dantzer,c and Golam M. Khandakerd,e,f,g	Interleukin-6 as potential mediator of long-term neuropsychiatric symptoms of COVID-19	https://dx.doi.org/10.1016%2Fj.psyneuen.2021.105295	Published	2021 Jun 3	Article	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172271/	The majority of COVID-19 survivors experience long-term neuropsychiatric symptoms such as fatigue, sleeping difficulties, depression and anxiety. We propose that neuroimmune cross-talk via inflammatory cytokines such as interleukin-6 (IL-6) could underpin these long-term COVID-19 symptoms. This hypothesis is supported by several lines of research, including population-based cohort and genetic Mendelian Randomisation studies suggesting that inflammation is associated with fatigue and sleeping difficulties, and that IL-6 could represent a possible causal driver for these symptoms. Immune activation following COVID-19 can disrupt T helper 17 (TH17) and regulatory T (Treg) cell responses, affect central learning and emotional processes, and lead to a vicious cycle of inflammation and mitochondrial dysfunction that amplifies the inflammatory process and results in immuno-metabolic constraints on neuronal energy metabolism, with fatigue being the ultimate result. Increased cytokine activity drives this process and could be targeted to interrupt it. Therefore, whether persistent IL-6 dysregulation contributes to COVID-19-related long-term fatigue, sleeping difficulties, depression, and anxiety, and whether targeting IL-6 pathways could be helpful for treatment and prevention of long COVID are important questions that require investigation. This line of research could inform new approaches for treatment and prevention of long-term neuropsychiatric symptoms of COVID-19. Effective treatment and prevention of this condition could also help to stem the anticipated rise in depression and other mental illnesses ensuing this pandemic.	Des chercheurs font la supposition que les échanges neuro-immuns d'interleukine-6 (IL-6) qui marquent l'inflammation cytokinique participent aux symptômes neuropsychiatriques prolongés. Viser cette voie des IL-6 serait un possible traitement du covid long.	N011
135	N133		Medha Karnik, Narasimha M. Beeraka, Chinnappa A. Uthaiah, Suma M. Nataraj, Anjali Devi S. Bettadapura, Gjumrakch Aliev & SubbaRao V. Madhunapantula	A Review on SARS-CoV-2-Induced Neuroinflammation, Neurodevelopmental Complications, and Recent Updates on the Vaccine Development	https://doi.org/10.1007/s12035-021-02399-6	Published	05 June 2021	Review	https://link.springer.com/article/10.1007/s12035-021-02399-6	In this review, we have attempted to highlight the landmark discoveries that lead to the development of various vaccines that are currently under different stages of clinical progression. Besides, a brief account of various drug candidates that are being tested to mitigate the burden of COVID-19 was also covered. Further, in a dedicated section, the impact of SARS-CoV-2 infection on neuronal inflammation and neuronal disorders was discussed. In summary, it is expected that the content covered in this article help to understand the pathophysiology of COVID-19 and the impact on neuronal complications induced by SARS-CoV-2 infection while providing an update on the vaccine development.
136	N134		Amarnath Sen	Does serotonin deficiency lead to anosmia, ageusia, dysfunctional chemesthesis and increaed severity of illness in COVID-19?	https://dx.doi.org/10.1016%2Fj.mehy.2021.110627	Published	2021 Jun 6	Article	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180092/	Different mechanisms forwarded to understand anosmia and ageusia in coronavirus patients are not adequate to explain reversible anosmia and ageusia, which are resolved quickly. In addition, the reason behind the impaired chemesthetic sensations in some coronavirus patients remains unknown. In the present paper it is proposed that SARS-CoV-2 patients suffer from depletion of tryptophan, as ACE2, a key element in the process of absorption of tryptophan from the food, is significantly reduced in the patients as coronavirus uses ACE2 as the receptor to enter the host cells. The tryptophan depletion leads to a deficit of serotonin (5-HT) in SARS-COV-2 patients because tryptophan is the precursor in the synthesis of 5-HT. Such 5-HT deficiency can explain anosmia, ageusia and dysfunctional chemesthesis in COVID-19, given the fact that 5-HT is an important neuromodulator in the olfactory neurons, taste receptor cells and transient receptor potential channels (TRP channels) involved in chemesthesis. In addition, 5-HT deficiency worsens silent hypoxemia and depresses hypoxic pulmonary vasoconstriction leading to increased severity of the disease. Also, the levels of anti-inflammatory melatonin (synthesized from 5-HT) and nicotinamide adenine dinucleotide (NAD+, produced from niacin whose precursor is the tryptophan) might decrease in coronavirus patients resulting in the aggravation of the disease. Interestingly, selective serotonin reuptake inhibitors (SSRIs) may not be of much help in correcting the 5-HT deficiency in COVID-19 patients, as their efficacy goes down significantly when there is depletion of tryptophan in the system. Hence, tryptophan supplementation may herald a radical change in the treatment of COVID-19 and accordingly, clinical trials (therapeutic / prophylactic) should be conducted on coronavirus patients to find out how tryptophan supplementation (oral or parenteral, the latter in severe cases where there is hardly any absorption of tryptophan from the food) helps in curing, relieving or preventing the olfactory, gustatory and chemesthetic dysfunctions and in lessening the severity of the disease.	Une étude émet l'hypothèse que l'anosmie et la réactivité chimique des membranes, observés comme symptômes prolongés de la covid, trouvent leur origine dans un déficit en sérotonine qui serait déclenché par l'appauvrissement en tryptophane, un acide aminé.	N014E
137	N135		Virginia F. J. Newcombe, Neha S. Dangayach & Romain Sonneville	Neurological complications of COVID-19	https://doi.org/10.1007/s00134-021-06439-6	Published	07 June 2021	Article	https://link.springer.com/article/10.1007/s00134-021-06439-6	We discuss the neurological complications associated with COVID-19 (NeuroCOVID) for general intensivists with an emphasis on key symptoms and signs to look for which may change management and/or provide a potential avenue for targeted therapies to improve outcomes.
138	N136		Bassetti Claudio L. A., Jung Simon, Helbok Raimund	«Le spectre neurologique du COVID-19»	https://doi.org/10.4414/fms.2021.08813	Published	09.06.2021	Review	https://medicalforum.ch/fr/detail/doi/fms.2021.08813	Afin d’obtenir un aperçu objectif des manifestations neurologiques durant la maladie aiguë et de pouvoir évaluer les conséquences à long terme potentielles du COVID-19, à la fois l’Organisation mondiale de la santé (OMS) et, plus tôt déjà, diverses sociétés de neurologie («World Federation of Neurology», EAN, «Österreichische Gesellschaft für Neurologie», «Deutsche Gesellschaft für Neurologie», «Deutsche Gesellschaft für Neurointensiv- und Notfallmedizin», «Neurocritical Care Society») ont appelé à recenser le mieux possible les patients dans un registre prospectif [7, 39]. L’objectif de ces initiatives est de parvenir à une définition exacte des manifestations neurologiques. Il convient de mentionner le registre ENERGY de l’EAN, qui se focalise sur les manifestations neurologiques durant la maladie aiguë avec un suivi allant jusqu’à un an (covidregistry@ean.org). Plus de 1100 cas de patients issus de 30 pays situés sur trois continents ont déjà été entrés dans le registre. L’EAN a en outre établi une coopération avec la «Neurocritical Care Society» («Global Consortium Study of Neurological Dysfunction in COVID-19» [GCS-NeuroCOVID]) et dispose ainsi de la plus longue portée à ce jour pour évaluer les complications neurologiques [39]. L’intérêt de la communauté neurologique a ainsi certainement été éveillé [40]. De cette façon, il sera possible de remédier aux incertitudes qui persistent encore: Lesquels des symptômes et maladies neurologiques rapportés jusqu’à présent correspondent à une atteinte spécifique du système nerveux? Quels symptômes ou maladies correspondent à un effet non spécifique du COVID-19 sur le système nerveux? Et quels symptômes correspondent à une manifestation concomitante fortuite?	Un article en français dresse un état des connaissances sur les atteintes neurologiques liées à la covid. Il évoque la pathogenèse, les manifestations, et souligne le peu de traitements spécifiques proposés concernant ces symptômes.	N011
139	N137		Lian Yang, Mei Zhou, Lingli Li, Ping Luo, Wenliang Fan, Juanjuan Xu, Qing Chen, Feng Pan, Ping Lei, Chuansheng Zheng & Yang Jin	Characteristics of mental health implications and plasma metabolomics in patients recently recovered from COVID-19	https://doi.org/10.1038/s41398-021-01426-3	Published	21 May 2021	Study	https://www.nature.com/articles/s41398-021-01426-3	Our results also demonstrated significantly different plasma metabolic profiling in recovered COVID-19 patients even at 3 months after their hospital discharge, which was mainly related to purine pathways, amino acids, lipids, and amine metabolism. Certain regions with cerebral WM alterations in the recovered patients showed significant correlations with different metabolites and the mental health scores. We observed multiple alterations in both WM integrity and plasma metabolomics that may explain the deteriorated mental health of recovered COVID-19 patients. These findings may provide potential biomarkers for the mental health evaluation for the recovered COVID-19 patients and potential targets for novel therapeutics.	Une analyse très poussée sur 28 patients hospitalisés et guéris de la covid, utilisant de l'imagerie IRM du tenseur de diffusion, relève des modifications de la substance blanche cérébrale parfois plusieurs mois avec l'hospitalisation. Les relevés montrent des anisotropies fractionnelles réduites et des diffusions pondérées ou radiales augmentées dans certains zones. Les altérations observées sont souvent corrélées aux modifications métaboliques et aux détails des examens standardisés neuropsychiatriques.	N011
140	N138		Gwenaëlle Douaud, Soojin Lee, Fidel Alfaro-Almagro, Christoph Arthofer, Chaoyue Wang, Frederik Lange, Jesper L.R. Andersson, Ludovica Griffanti, Eugene Duff, Saad Jbabdi, Bernd Taschler, Anderson Winkler, Thomas E. Nichols, Rory Collins, Paul M. Matthews, Naomi Allen, Karla L. Miller, Stephen M. Smith	Brain imaging before and after COVID-19 in UK Biobank	https://doi.org/10.1101/2021.06.11.21258690	pre-print	June 15, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.06.11.21258690v1.full-text	There is strong evidence for brain-related pathologies in COVID-19, some of which could be a consequence of viral neurotropism. The vast majority of brain imaging studies so far have focused on qualitative, gross pathology of moderate to severe cases, often carried out on hospitalised patients. It remains unknown however whether the impact of COVID-19 can be detected in milder cases, in a quantitative and automated manner, and whether this can reveal a possible mechanism for the spread of the disease. UK Biobank scanned over 40,000 participants before the start of the COVID-19 pandemic, making it possible to invite back in 2021 hundreds of previously-imaged participants for a second imaging visit. Here, we studied the effects of the disease in the brain using multimodal data from 782 participants from the UK Biobank COVID-19 re-imaging study, with 394 participants having tested positive for SARS-CoV-2 infection between their two scans. We used structural and functional brain scans from before and after infection, to compare longitudinal brain changes between these 394 COVID-19 patients and 388 controls who were matched for age, sex, ethnicity and interval between scans. We identified significant effects of COVID-19 in the brain with a loss of grey matter in the left parahippocampal gyrus, the left lateral orbitofrontal cortex and the left insula. When looking over the entire cortical surface, these results extended to the anterior cingulate cortex, supramarginal gyrus and temporal pole. We further compared COVID-19 patients who had been hospitalised (n=15) with those who had not (n=379), and while results were not significant, we found comparatively similar findings to the COVID-19 vs control group comparison, with, in addition, a greater loss of grey matter in the cingulate cortex, central nucleus of the amygdala and hippocampal cornu ammonis (all \|Z\|>3). Our findings thus consistently relate to loss of grey matter in limbic cortical areas directly linked to the primary olfactory and gustatory system. Unlike in post hoc disease studies, the availability of pre-infection imaging data helps avoid the danger of pre-existing risk factors or clinical conditions being mis-interpreted as disease effects. Since a possible entry point of the virus to the central nervous system might be via the olfactory mucosa and the olfactory bulb, these brain imaging results might be the in vivo hallmark of the spread of the disease (or the virus itself) via olfactory and gustatory pathways.	Careful: The plots for Figure "Left orbitofrontal cortex (thickness)" are the same that one's for "Left superior insula (thickness)". This red flag has to be checked. This point has been corrected.
141	N139		Hannah A.B.Whitmore1†Leo A.Kim	Understanding the Role of Blood Vessels in the Neurological Manifestations of COVID-19	https://doi.org/10.1016/j.ajpath.2021.04.017	Published	11 June 2021	Review	https://www.sciencedirect.com/science/article/pii/S0002944021002601	Originally identified as a respiratory disease, similar to previously discovered SARS and MERS type viruses, concern has since been raised about the effects of SARS-CoV-2 infection on the vasculature. This viral-vascular involvement is of particular concern with regards to the small vessels present in the brain, with mounting evidence demonstrating that SARS-CoV-2 is capable of crossing the blood-brain-barrier.	_
142	N140		Raphael Bernard-Valnet, Sylvain Perriot, Mathieu Canales, Beatrice Pizzarotti, Leonardo Caranzano, Mayté Castro-Jiménez, Jean-Benoit Epiney, Sergiu Vijiala, Paolo Salvioni-Chiabotti, Angelica Anichini, Alexander Salerno, Katia Jaton, Julien Vaucher, Matthieu Perreau, Gilbert Greub, Giuseppe Pantaleo, Renaud A. Du Pasquier	Encephalopathies Associated With Severe COVID-19 Present Neurovascular Unit Alterations Without Evidence for Strong Neuroinflammation	https://doi.org/10.1212/NXI.0000000000001029	Published	June 16, 2021	Study	https://nn.neurology.org/content/8/5/e1029	We detected anti–SARS-CoV-2 immunoglobulin G in patients with severe COVID-19 with signs of intrathecal synthesis for some of them. Of the 4 categories of tested patients, the CSF of IND exhibited the highest level of cytokines, chemokines, and growth factors. By contrast, patients with COVID-19 did not present overall upregulation of inflammatory mediators in the CSF. However, patients with severe COVID-19 (intensive care unit patients) exhibited higher concentrations of CCL2, CXCL8, and vascular endothelium growth factor A (VEGF-A) in the CSF than patients with a milder form of COVID-19. In addition, we could show that intrathecal CXCL8 synthesis was linked to an elevated albumin ratio and correlated with the increase of peripheral inflammation (serum hepatocyte growth factor [HGF] and CXCL10). Conclusions Our results do not indicate active replication of SARS-CoV-2 in the CSF or signs of massive inflammation in the CSF compartment but highlight a specific impairment of the neurovascular unit linked to intrathecal production of CXCL8.	Un article s'interroge sur le rôle éventuel d'un déficit de sérotonine dans la sévérité de la covid et certains symptômes neurologiques.	N011
143	N141		Yidan Xu, Yu Zhuang, Lumei Kang	A Review of Neurological Involvement in Patients with SARS-CoV-2 Infection	https://doi.org/10.12659/MSM.932962	Published	2021-06-19	Review	https://www.medscimonit.com/abstract/index/idArt/932962	This review aims to provide an update on what is currently known about neurological involvement in patients with COVID-19 due to SARS-CoV-2 infection. In this review, we demonstrate invasion routes of SARS-CoV-2, provide evidence to support the neurotropism hypothesis of the virus, and investigate the pathological mechanisms that underlie neurological complications associated with SARS-CoV-2.	_
144	N142		Jeffrey E. Gold 1,*,Ramazan A. Okyay 2,Warren E. Licht 3 andDavid J. Hurley	Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation	https://doi.org/10.3390/pathogens10060763	Published	17 June 2021	Study	https://www.mdpi.com/2076-0817/10/6/763/htm	Our aim was to first determine long COVID prevalence in 185 randomly surveyed COVID-19 patients and, subsequently, to determine if there was an association between occurrence of long COVID symptoms and reactivation of Epstein–Barr virus (EBV) in 68 COVID-19 patients recruited from those surveyed. We found the prevalence of long COVID symptoms to be 30.3% (56/185), which included 4 initially asymptomatic COVID-19 patients who later developed long COVID symptoms. Next, we found that 66.7% (20/30) of long COVID subjects versus 10% (2/20) of control subjects in our primary study group were positive for EBV reactivation based on positive titers for EBV early antigen-diffuse (EA-D) IgG or EBV viral capsid antigen (VCA) IgM. The difference was significant (p < 0.001, Fisher’s exact test). A similar ratio was observed in a secondary group of 18 subjects 21–90 days after testing positive for COVID-19, indicating reactivation may occur soon after or concurrently with COVID-19 infection. These findings suggest that many long COVID symptoms may not be a direct result of the SARS-CoV-2 virus but may be the result of COVID-19 inflammation-induced EBV reactivation.	Est-ce que le neuro-covid pourrait s'expliquer par une réactivation d'une précédente infection au virus d'Epstein-Barr (EBV) ? C'est l'hypothèse que soulève une étude qui remarque que les 2/3 (20 patients sur 30) des malades du covid long testés présentaient une sérologie positive aux antigènes de l'EBV, contre 10% pour le groupe contrôle (2 patients sur 20), soit une corrélation statistiquement significative.	N011
145	N143		Jacques Hugon, Eva-Flore Msika, Mathieu Queneau, Karim Farid & Claire Paquet	Long COVID: cognitive complaints (brain fog) and dysfunction of the cingulate cortex	https://doi.org/10.1007/s00415-021-10655-x	Published	18 June 2021	Study	https://link.springer.com/article/10.1007/s00415-021-10655-x	This long COVID status can include “brain fog” and cognitive deficits that can disturb activities of daily living and can delay complete recovery. Here, we report two cases of neurological long COVID with abnormal FDG PET findings marked by hypometabolic regions of the cingulate cortex.	Des chercheurs font l'hypothèse que le symptôme de brouillard cérébral de deux patients suivis pour un covid long pourrait être lié à un hypométabolisme dans la zone du gyrus cingulaire du cortex cérébral, révélé au PET-SCAN.	N011
146	N144		Andrew C. Yang, Fabian Kern, Patricia M. Losada, Maayan R. Agam, Christina A. Maat, Georges P. Schmartz, Tobias Fehlmann, Julian A. Stein, Nicholas Schaum, Davis P. Lee, Kruti Calcuttawala, Ryan T. Vest, Daniela Berdnik, Nannan Lu, Oliver Hahn, David Gate, M. Windy McNerney, Divya Channappa, Inma Cobos, Nicole Ludwig, Walter J. Schulz-Schaeffer, Andreas Keller & Tony Wyss-Coray	Dysregulation of brain and choroid plexus cell types in severe COVID-19	https://doi.org/10.1038/s41586-021-03710-0	Published	21 June 2021	Study	https://www.nature.com/articles/s41586-021-03710-0	Here, we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control (including 1 terminal influenza) and 8 COVID-19 patients. While a systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations which predict that choroid plexus barrier cells sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover COVID-19 disease-associated microglia and astrocyte subpopulations that share features with pathological cell states reported in human neurodegenerative disease4–6. Synaptic signaling of upper-layer excitatory neurons—evolutionarily expanded in humans7 and linked to cognitive function8—are preferentially affected in COVID-19. Across cell types, COVID-19 perturbations overlap with those in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia, and depression. Our findings and public dataset provide a molecular framework to understand COVID-19 related neurological disease observed now and which may emerge later.
147	N145		Olivia Swain, Sofia K. Romano, Ritika Miryala, Jocelyn Tsai, Vinnie Parikh and George K. E. Umanah	SARS-CoV-2 Neuronal Invasion and Complications: Potential Mechanisms and Therapeutic Approaches	https://doi.org/10.1523/JNEUROSCI.3188-20.2021	Published	23 June 2021	Review	https://www.jneurosci.org/content/41/25/5338	Autopsies of patients confirm the presence of the coronaviruses in the CNS, especially in the brain. The invasion and transmission of SARS-CoV-2 in the CNS is not clearly defined, but, because the endocytic pathway has become an important target for the development of therapeutic strategies for COVID-19, it is necessary to understand endocytic processes in the CNS. In addition, mitochondria and mechanistic target of rapamycin (mTOR) signaling pathways play a critical role in the antiviral immune response, and may also be critical for endocytic activity. Furthermore, dysfunctions of mitochondria and mTOR signaling pathways have been associated with some high-risk conditions such as diabetes and immunodeficiency for developing severe complications observed in COVID-19 patients. However, the role of these pathways in SARS-CoV-2 infection and spread are largely unknown. In this review, we discuss the potential mechanisms of SARS-CoV-2 entry into the CNS and how mitochondria and mTOR pathways might regulate endocytic vesicle–mitochondria interactions and dynamics during SARS-CoV-2 infection. The mechanisms that plausibly account for severe neurologic complications with COVID-19 and potential treatments with Food and Drug Administration-approved drugs targeting mitochondria and the mTOR pathways are also addressed.
148	N146		Rodolfo Furlan Damiano, Bruno F. Guedes, Cristiana Castanho de Rocca, Antonio de Pádua Serafim, Luiz Henrique Martins Castro, Carolina Demarchi Munhoz, Ricardo Nitrini, Geraldo Busatto Filho, Eurípedes Constantino Miguel, Giancarlo Lucchetti & Orestes Forlenza	Cognitive decline following acute viral infections: literature review and projections for post-COVID-19	https://doi.org/10.1007/s00406-021-01286-4	Published	25 June 2021	Review	https://link.springer.com/article/10.1007/s00406-021-01286-4	This article aims to review the state of the art regarding the knowledge about the impact of acute viral infections on human cognition, laying a foundation to explore the possible cognitive decline followed coronavirus disease 2019 (COVID-19). To reach this goal, we conducted a narrative review systematizing six acute viral infections as well as the current knowledge about COVID-19 and its impact on human cognition. Recent findings suggest probable short- and long-term COVID-19 impacts in cognition, even in asymptomatic individuals, which could be accounted for by direct and indirect pathways to brain dysfunction. Understanding this scenario might help clinicians and health leaders to deal better with a wave of neuropsychiatric issues that may arise following COVID-19 pandemic as well as with other acute viral infections, to alleviate the cognitive sequelae of these infections around the world.
149	N147		Ravindra K Garg 1	Spectrum of Neurological Manifestations in Covid-19: A Review	https://doi.org/10.4103/0028-3886.289000	Published	6-Jul-2020	Review	https://www.neurologyindia.com/article.asp?issn=0028-3886;year=2020;volume=68;issue=3;spage=560;epage=572;aulast=Garg	The SARS-CoV-2 virus causes the disease COVID-19 and has the potential to invade the brain. The SARS-CoV-2 virus enters the brain either via a hematogenous route or olfactory system. Angiotensin-converting enzyme two receptors, present on endothelial cells of cerebral vessels, are a possible viral entry point. The most severe neurological manifestations, altered sensorium (agitation, delirium, and coma), are because of hypoxic and metabolic abnormalities. Characteristic cytokine storm incites severe metabolic changes and multiple organ failure. Profound coagulopathies may manifest with ischemic or hemorrhagic stroke. Rarely, SARS-CoV-2 virus encephalitis or pictures like acute disseminated encephalomyelitis or acute necrotizing encephalopathy have been reported. Nonspecific headache is a commonly experienced neurological symptom. A new type of headache “personal protection equipment-related headache” has been described. Complete or partial anosmia and ageusia are common peripheral nervous system manifestations. Recently, many cases of Guillain-Barré syndrome in COVID-19 patients have been observed, and a postinfectious immune-mediated inflammatory process was held responsible for this. Guillain-Barré syndrome does respond to intravenous immunoglobulin. Myalgia/fatigue is also common, and elevated creatine kinase levels indicate muscle injury. Most of the reports about neurological complications are currently from China. COVID-19 pandemic is spreading to other parts of the world; the spectrum of neurological complications is likely to widen further.
150	N148		Narges Moghimi, Mario Di Napoli, José Biller, James E. Siegler, Rahul Shekhar, Louise D. McCullough, Michelle S. Harkins, Emily Hong, Danielle A. Alaouieh, Gelsomina Mansueto & Afshin A. Divani	The Neurological Manifestations of Post-Acute Sequelae of SARS-CoV-2 Infection	https://doi.org/10.1007/s11910-021-01130-1	Published	28 June 2021	Review	https://link.springer.com/article/10.1007/s11910-021-01130-1	This review aims to summarize the incidence, risk factors, possible pathophysiology, and proposed management of neurological manifestations of post-acute sequelae of SARS-CoV-2 infection (PASC) or neuro-PASC based on the published literature.
151	N149		Pablo Najta Helen L.Richards b Dónal G. Fortunea	Brain imaging in patients with COVID-19: A systematic review	https://doi.org/10.1016/j.bbih.2021.100290	Published	2 July 2021	Review	https://www.sciencedirect.com/science/article/pii/S2666354621000934	Highlights •A spectrum of brain changes particularly at advanced stage relates to SARS-CoV-2 •Across severity phases SARS-CoV-2 affects olfactory structures •Emerging abnormalities in COVID-19 is associated with the olfactory brain network Twenty-seven studies were included in the review, including 5 case series, 8 cohort studies and 14 case control studies. The findings revealed predominant involvement of the olfactory system with disruptions across four olfactory structures. Abnormalities also extended to the corpus callosum, cingulate cortex, and insula, jointly implicating the olfactory brain network.
152	N150		Mayuri Gupta and Donald F. Weaver	COVID-19 as a Trigger of Brain Autoimmunity	https://doi.org/10.1021/acschemneuro.1c00403	Published	July 2, 2021	Article	https://pubs.acs.org/doi/full/10.1021/acschemneuro.1c00403	Entry of SARS-CoV-2 into the central nervous system (CNS) activates microglia, triggering chronic neuroinflammation and possibly neurodegeneration. The complex transcriptome of SARS-CoV-2 shares molecular similarities with diverse human CNS protein epitopes, leading to a cytokine storm and various autoantibodies, potentially culminating in an autoimmune state. A COVID-19 initiated CNS autoimmune cascade may occur via multiple pathways including molecular mimicry, bystander activation, epitope spreading, production of autoantibodies, and immortalization of effector B-cells.
153	N151		Nicholas W.LarsenaLauren E.StilesbMitchell G.Miglisa	Preparing for the long-haul: Autonomic complications of COVID-19	https://doi.org/10.1016/j.autneu.2021.102841	Published	3 July 2021	Review	https://www.sciencedirect.com/science/article/pii/S1566070221000710	Many symptoms of post-acute COVID syndrome appear autonomic in nature, suggesting that autonomic impairment may play a central role in the underlying pathophysiology. In this review, we discuss the autonomic symptoms and manifestations of post-acute COVID syndrome, potential mechanisms involved, and future directions for a better understanding of this novel condition.
154	N152		Qing Ye, Jia Zhou, Qi He, Rui-Ting Li, Guan Yang, Yao Zhang, Shu-Jia Wu, Qi Chen, Jia-Hui Shi, Rong-Rong Zhang, Hui-Ming Zhu, Hong-Ying Qiu, Tao Zhang, Yong-Qiang Deng, Xiao-Feng Li, Jian-Feng Liu, Ping Xu, Xiao Yang & Cheng-Feng Qin	SARS-CoV-2 infection in the mouse olfactory system	https://doi.org/10.1038/s41421-021-00290-1	Published	06 July 2021	Study	https://www.nature.com/articles/s41421-021-00290-1	Herein, we demonstrate that intranasal inoculation with SARS-CoV-2 induces robust viral replication in the olfactory epithelium (OE), not the olfactory bulb (OB), resulting in transient olfactory dysfunction in humanized ACE2 (hACE2) mice. The sustentacular cells and Bowman’s gland cells in the OE were identified as the major target cells of SARS-CoV-2 before invasion into olfactory sensory neurons (OSNs). Remarkably, SARS-CoV-2 infection triggers massive cell death and immune cell infiltration and directly impairs the uniformity of the OE structure. Combined transcriptomic and quantitative proteomic analyses revealed the induction of antiviral and inflammatory responses, as well as the downregulation of olfactory receptor (OR) genes in the OE from the infected animals. Overall, our mouse model recapitulates olfactory dysfunction in COVID-19 patients and provides critical clues for understanding the physiological basis for extrapulmonary manifestations of COVID-19.	Sur des souris humanisées (avec réc. hACE2), une équipe montre une forte réplication virale dans l'épithélium olfactif à la suite d'une inoculation intranasale de covid. L'uniformité de l'épithélium et les neurones des récepteurs olfactifs sont touchés.	N014E
155	N153		Michael Marshall	COVID and the brain: researchers zero in on how damage occurs	https://doi.org/10.1038/d41586-021-01693-6	Published	07 July 2021	Article	https://www.nature.com/articles/d41586-021-01693-6	How COVID-19 damages the brain is becoming clearer. New evidence suggests that the coronavirus’s assault on the brain could be multipronged: it might attack certain brain cells directly, reduce blood flow to brain tissue or trigger production of immune molecules that can harm brain cells. These pathways — astrocytes, pericytes and autoantibodies — are not mutually exclusive, and are probably not the only ones: it is likely that people with COVID-19 experience neurological symptoms for a range of reasons. Prüss says a key question is what proportion of cases is caused by each of the pathways. “That will determine treatment,” he says.	Même si le virus du SARS-CoV-2 se réplique peu dans le système nerveux central, il peut néanmoins infecter les astrocytes, cellules qui ont un rôle crucial dans le fonctionnement du cerveau, et provoque des troubles neurologiques par différents mécanismes.	N014E
156	N154		Lu Wang, David Sievert, Alex E. Clark, Sangmoon Lee, Hannah Federman, Benjamin D. Gastfriend, Eric V. Shusta, Sean P. Palecek, Aaron F. Carlin & Joseph G. Gleeson	A human three-dimensional neural-perivascular ‘assembloid’ promotes astrocytic development and enables modeling of SARS-CoV-2 neuropathology	https://doi.org/10.1038/s41591-021-01443-1	Published	09 July 2021	Study	https://www.nature.com/articles/s41591-021-01443-1	Here we show that pericyte-like cells (PLCs), when integrated into a cortical organoid, are capable of infection with authentic SARS-CoV-2. Before infection, PLCs elicited astrocytic maturation and production of basement membrane components, features attributed to pericyte functions in vivo. While traditional cortical organoids showed little evidence of infection, PLCs within cortical organoids served as viral ‘replication hubs’, with virus spreading to astrocytes and mediating inflammatory type I interferon transcriptional responses. Therefore, PLC-containing cortical organoids (PCCOs) represent a new ‘assembloid’ model that supports astrocytic maturation as well as SARS-CoV-2 entry and replication in neural tissue; thus, PCCOs serve as an experimental model for neural infection.	Une étude dans Nature sur des organoïdes cérébraux montre les capacités neuropathologiques du SARS-CoV-2, sa capacité à se répliquer dans les astrocytes, ainsi que des réponses inflammatoires transcriptionnelles par l'interféron de type I.	N014E
157	N155		FatimaKhatoonKartikayPrasadVijayKumar	COVID-19 associated nervous system manifestations	https://doi.org/10.1016/j.sleep.2021.07.005	Published	9 July 2021	Review	https://www.sciencedirect.com/science/article/pii/S1389945721003877	Highlights •Neurological complications observed in COVID-19. •COVID-19 associated central nervous system manifestations. •COVID-19 associated peripheral nervous system manifestations. •COVID-19 and neurodegenerative diseases. •COVID-19 and sleep dysfunction. •SARS-CoV-2-2 prey human genes are involved in sleep apnea. SARS-CoV-2 enters the brain through the olfactory bulb, retrograde axonal transport from peripheral nerve endings, or via hematogenous or lymphatic routes. Notably, COVID-19 infection can cause or even present with different neurological features including encephalopathy, impaired consciousness, confusion, agitation, seizure, ataxia, headache, anosmia, ageusia, neuropathies, and neurodegenerative diseases. In this paper, we provide a brief review of observed neurological manifestations associated with COVID-19.	_
158	N156		AntonJohanssonaMohamed S.MohamedaThiago C.MoulinaHelgi B.Schiöth	Neurological manifestations of COVID-19: A comprehensive literature review and discussion of mechanisms	https://doi.org/10.1016/j.jneuroim.2021.577658	Published	10 July 2021	Review	https://www.sciencedirect.com/science/article/pii/S0165572821001855	Here, we review the literature describing SARS-CoV-2-induced neurological manifestations and provide a comprehensive discussion of proposed mechanisms underlying the neurological pathophysiology. First, we analyse the neuroinvasiveness potential of the coronavirus family based on previous SARS-CoV-1 studies. Then, we describe the current evidence on COVID-19-induced nervous tissue damage, including processes behind brain vasculopathy and cytokine storm. We also discuss in detail anosmia and Guillain-Barré syndrome. Finally, we provide a summarised timeline of the main findings in the field. Future perspectives are presented, and suggestions of further investigations to clarify how SARS-COV-2 can affect the CNS.	_
159	N157		Jai Mathur1, Alan Carson	#3125 Novel framework for neurocognitive COVID-19 assessment	http://dx.doi.org/10.1136/jnnp-2021-BNPA.32	Published	11 March 2021	Review	https://jnnp.bmj.com/content/92/8/A14.abstract	Conclusion Cognitive symptoms are common after confirmed and assumed COVID exposure. We propose a framework for neuropsychiatric assessment and the use of adjuvant imaging and potential biomarkers. Neuropsychiatric history- Part 1 symptoms at onset- in particular disruptions of consciousness and altered mental state. Acute memory impairment, anterograde/retrograde and with/without a temporal gradient. neurocognitive function. ITU admission and oxygen requirements. Part 2 Current cognitive and mental state- in addition to standard history seek evidence of internal inconsistency of memory symptoms and attentional dysregulation. Has social cognition and meta-cognition been affected. Note attribution bias i.e. no Im not depressed, I cant enjoy anything because of my symptoms Background history- subtle suggestion of neurodegeneration and depression, anxiety and functional symptoms should be explored. MRI findings- signal changes in the medial temporal lobe, nonconfluent multifocal white matter hyperintense lesions, and isolated white matter microhemorrhages. Novel biomarkers IL-6, MCP-1, and IP-10.	_
160	N158		Iqra Athar	“Cerebral venous sinus thrombosis sequel of COVID Encephalitis; a rare presentation”	https://doi.org/10.1016/j.hest.2021.07.003	Published	16 July 2021	Case Report	https://www.sciencedirect.com/science/article/pii/S2589238X2100036X	However, its popularity as neuropathogen has increased dramatically. Patient presents a wide range of symptoms. We report a case of Covid-19 encephalitis which was incidentally found to have cerebral venous sinus thrombosis, presented with acute delirium and then developed new onset seizures.	_
161	N159		Adam Hampshire William Trender Samuel R Chamberlain Amy E. Jolly Jon E. Grant Fiona Patrick Ndaba Mazibuko Steve CR Williams Joseph M Barnby Peter Hellyer Mitul A Mehta	Cognitive deficits in people who have recovered from COVID-19	https://doi.org/10.1016/j.eclinm.2021.101044	Published	July 22, 2021	RESEARCH PAPER	https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00324-2/fulltext	Findings People who had recovered from COVID-19, including those no longer reporting symptoms, exhibited significant cognitive deficits versus controls when controlling for age, gender, education level, income, racial-ethnic group, pre-existing medical disorders, tiredness, depression and anxiety. The deficits were of substantial effect size for people who had been hospitalised (N = 192), but also for non-hospitalised cases who had biological confirmation of COVID-19 infection (N = 326). Analysing markers of premorbid intelligence did not support these differences being present prior to infection. Finer grained analysis of performance across sub-tests supported the hypothesis that COVID-19 has a multi-domain impact on human cognition. Interpretation Interpretation. These results accord with reports of ‘Long Covid’ cognitive symptoms that persist into the early-chronic phase. They should act as a clarion call for further research with longitudinal and neuroimaging cohorts to plot recovery trajectories and identify the biological basis of cognitive deficits in SARS-COV-2 survivors.	Selon une étude publiée dans The Lancet, les malades qui se sont remis d'une covid, y compris ceux qui ne rapportent plus de symptômes, présentent des déficits cognitifs, dont l'importance est liée à la gravité de la phase aiguë. Selon l'étude, la différence est faible, mais statistiquement significative, pour les malades avec des symptômes résolus non respiratoires. On retrouve chez les patients qui ont été hospitalisés et ventilés une perte cognitive (0,47 SD) plus importante que chez les patients victimes d'attaque cérébrale (0,24 SD) ou ceux ayant des handicaps d'apprentissage (0,38 SD). Cette perte peut être comparée à 7 pts de QI. L'analyse et le groupe contrôle ont été faits pour prendre en compte les facteurs confondants d'âge, de sexe, de niveau d'éducation, niveau d'éducation, revenu, d'ethnicité, de troubles préexistants, de fatigue, de dépression et d'anxiété.	N012
162	N160		Yu-Hui Liu, Ye-Ran Wang, Qing-Hua Wang, Yang Chen, Xian Chen, Ying Li, Yuan Cen, Cheng Xu, Tian Hu, Xu-Dong Liu, Ling-Li Yang, Si-Jing Li, Xue-Fei Liu, Chun-Mei Liu, Jie Zhu, Wei Li, Li-Li Zhang, Juan Liu & Yan-Jiang Wang	Post-infection cognitive impairments in a cohort of elderly patients with COVID-19	https://doi.org/10.1186/s13024-021-00469-w	Published	19 July 2021	Study	https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-021-00469-w	Compared with controls, COVID-19 patients had lower TICS-40 scores and higher IQCODE scores [TICS-40 median (IQR): 29 (25 to 32) vs. 30 (26 to 33), p < 0.001; IQCODE median (IQR): 3.19 (3.00 to 3.63) vs. 3.06 (3.00 to 3.38), p < 0.001]. Severe COVID-19 patients had lower TICS-40 scores and higher IQCODE scores than non-severe COVID-19 patients [TICS-40 median (IQR): 24 (18 to 28) vs. 30 (26 to 33), p < 0.001; IQCODE median (IQR): 3.63 (3.13 to 4.31) vs. 3.13 (3.00 to 3.56), p < 0.001] and controls [TICS-40 median (IQR): 24 (18 to 28) vs. 30 (26 to 33), p < 0.001; IQCODE median (IQR) 3.63 (3.13 to 4.31) vs. 3.06 (3.00 to 3.38), p < 0.001]. Severe COVID-19 patients had a higher proportion of cases with current cognitive impairment and longitudinal cognitive decline than non-severe COVID-19 patients [dementia: 25 (10.50 %) vs. 9 (0.69 %), p < 0.001; Mild cognitive impairment (MCI): 60 (25.21 %) vs. 63 (4.84 %), p < 0.001] and controls [dementia: 25 (10.50 %) vs. 0 (0 %), p < 0.001; MCI: 60 (25.21 %) vs. 20 (4.29 %), p < 0.001)]. COVID-19 severity, delirium and COPD were risk factors of current cognitive impairment. Low education level, severe COVID-19, delirium, hypertension and COPD were risk factors of longitudinal cognitive decline.	_
163	N161		Wen-Rong Zhan, Jing Huang, Peng-Ming Zeng, Wei-Ya Tian, Zhen-Ge Luo	Emerging neurotropic features of SARS-CoV-2	https://doi.org/10.1093/jmcb/mjab044	Published	21 July 2021	Review	https://academic.oup.com/jmcb/advance-article/doi/10.1093/jmcb/mjab044/6325086	Although several cell types in the brain express angiotensin converting enzyme-2 (ACE2), the main SARS-CoV-2 receptor, and other related proteins, it remains unclear whether the observed neurological manifestations are attributed to virus invasion into the brain or just comorbidities caused by dysregulation of systemic factors. Here, we briefly review the neurological manifestations of SARS-CoV-2, summarize recent evidence for the potential neurotropism of SARS-CoV-2, and discuss the potential mechanisms of COVID-19-associated neurological diseases.	_
164	N162		Neelakshi Pal and Kuntal Gupta*	NEUROLOGICAL MANIFESTATION OF COVID-19: A SHORT REVIEW	https://doi.org/10.20959/wjpr20218-20957	Published	26 June 2021	Review	https://wjpr.s3.ap-south-1.amazonaws.com/article_issue/1625102026.pdf	This review which attempts at understanding the causes, mechanisms and symptoms of various neurological diseases manifested post-COVID infection is one such aspect. SARSCoV-2 virus invades the human systems through receptors namely ACE-2 and TMPSS2, through haematological, neurological or the inflammatory route. The epithelial cells for olfaction and sensory ciliated neurons are affected, impairing smell perception. The viral replication within the taste buds and peripheral chemoreceptors damages the cranial nerves responsible for gustation. Encephalopathy occurs in various forms including lesion of the right temporal lobe, delirium, corpus callosum injury, oedema, nystagmus and cerebritis. The clumping of blood within the vessels is common. Since endothelium is spread all over the body, no organs, except a few, are spared from viral infection. GBS characterized by weakness of lower limbs, paralysis, myelitis and MillerFisher syndrome are prominent. Blurred vision, pupillary defects, retinal vasculitis occur during optic neuritis damaging optic nerves of the orbital cortex. Hearing loss, clot-formation in cochlea and auditory pathway occur during sensorineural impairment. Nociceptors get hyper-stimulated causing pain. The cytokine storm releasing inflammatory mediators is another manifestation.	_
165	N163		Michael S Xydakis, MD Mark W Albers, MD Eric H Holbrook, MD Dina M Lyon, MS Robert Y Shih, MD Prof Johannes A Frasnelli, MD Prof Axel Pagenstecher, MD Alexandra Kupke, DVM Prof Lynn W Enquist, PhD † Prof Stanley Perlman	Post-viral effects of COVID-19 in the olfactory system and their implications	https://doi.org/10.1016/S1474-4422(21)00182-4	Published	July 30, 2021	RAPID REVIEW	https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(21)00182-4/fulltext	The prevalence of CNS and olfactory bulb pathosis in patients with COVID-19 is not known. We postulate that, in people who have recovered from COVID-19, a chronic, recrudescent, or permanent olfactory deficit could be prognostic for an increased likelihood of neurological sequelae or neurodegenerative disorders in the long term. An inflammatory stimulus from the nasal olfactory epithelium to the olfactory bulbs and connected brain regions might accelerate pathological processes and symptomatic progression of neurodegenerative disease. Persistent olfactory impairment with or without perceptual distortions (ie, parosmias or phantosmias) after SARS-CoV-2 infection could, therefore, serve as a marker to identify people with an increased long-term risk of neurological disease.	Les troubles olfactifs (anosmie) de la covid sont vus comme des premiers signes de dommages neurologiques. Lorsque ces troubles sont prolongés, ils pourraient être le signe d'un risque de maladie neurologique ultérieure.	N014E
166	N164		B.Rodríguez-AlfonsoaS.Ruiz SolísbL.Silva-HernándezcI.Pintos PascualdS.Aguado IbáñezeC.Salas Antónf	18F-FDG-PET/CT in SARS-CoV-2 infection and its sequelae18F-FDG-PET/TC ante la infeccion por sars-cov-2 y sus secuelas	https://doi.org/10.1016/j.remnie.2021.07.005	Published	28 July 2021	Review	https://www.sciencedirect.com/science/article/abs/pii/S2253808921001269	To date, knowledge about the usefulness of 18F-FDG-PET/CT in the acute phase has been limited to the incidental detection of SARS-CoV-2 unsuspected pneumonia. Recent studies have been appearing collecting the findings of 18F-FDG-PET/CT in long COVID-19 or persistent COVID-19 state as well as the alterations caused after mass vaccination of the population in the metabolic studies. This work aims to review the existing literature focusing on these three issues and to briefly present our own preliminary experience.
167	N165		Esther S. Oh, MD, PhD1,2,3,4; Tracy D. Vannorsdall, PhD2,5; Ann M. Parker, MD, PhD6,7	Post-acute Sequelae of SARS-CoV-2 Infection and Subjective Memory Problems	http://jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2021.19335	Published	July 29, 2021	Invited Commentary	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2782534	Limitations of the study by Søraas et al2 include the low overall response rate (24%) and potential bias in both participation and responses to survey questions introduced by knowing their SARS-CoV-2 test results. Additionally, there are no data on race or ethnicity, and the results are from a single country in Scandinavia. To advance the current knowledge of cognitive impairment among COVID-19 survivors, longer prospective cohort studies that include individuals from different races and ethnicities are needed to determine symptom persistence, and more importantly, the potential association between subjective cognitive impairment and rate of objective cognitive impairment compared with age-, sex-, and education-adjusted norms. Moreover, the functional consequences of persistent cognitive dysfunction among individuals who may have been at the height of their work productivity before SARS-CoV-2 infection is an important area in need of further investigation. Finally, ongoing efforts to understand the underlying biological mechanism of the effect of SARS-CoV-2 on the brain will be important in identifying those at high risk of developing subsequent cognitive impairment.	_
168	N166		Nelly Kanberg 1 Joel Simrén 1 Arvid Edén Lars-Magnus Andersson Staffan Nilsson Nicholas J. Ashton Pär-Daniel Sundvall Bengt Nellgård Kaj Blennow Henrik Zetterberg Magnus Gisslén	Neurochemical signs of astrocytic and neuronal injury in acute COVID-19 normalizes during long-term follow-up	https://doi.org/10.1016/j.ebiom.2021.103512	Published	July 29, 2021	RESEARCH PAPER	https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(21)00305-4/fulltext	One hundred patients with mild (n = 24), moderate (n = 28), and severe (n = 48) COVID-19 were followed for a median (IQR) of 225 (187–262) days. In the acute phase, patients with severe COVID-19 had higher concentrations of NfL than all other groups (all p < 0·001), and higher GFAp than controls (p < 0·001). GFAp was also significantly increased in moderate disease (p < 0·05) compared with controls. NfL (r = 0·53, p < 0·001) and GFAp (r = 0·39, p < 0·001) correlated with GDF-15 during the acute phase. After six months, NfL and GFAp concentrations had normalized, with no persisting group differences. Despite this, 50 patients reported persistent neurological symptoms, most commonly fatigue (n = 40), “brain-fog” (n = 29), and changes in cognition (n = 25). We found no correlation between persistent neurological symptoms and CNS injury biomarkers in the acute phase. Interpretation The normalization of CNS injury biomarkers in all individuals, regardless of previous disease severity or persisting neurological symptoms, indicates that post COVID-19 neurological sequelae are not accompanied by ongoing CNS injury.
169	N167		Arne Søraas, PhD1; Ragnhild Bø, PhD2; Karl Trygve Kalleberg, PhD3; Nathalie C. Støer, PhD4; Merete Ellingjord-Dale, PhD1; Nils Inge Landrø, PhD5	Self-reported Memory Problems 8 Months After COVID-19 Infection	http://jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2021.18717	Published	July 29, 2021	Research Letter	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2782531	At follow-up, a mean (SD) of 257 (32) days after baseline, 9705 of 13 001 participants (75%) responded, and 72 of 651 of the participants (11%) in the SARS-CoV-2–positive group reported memory problems. In contrast, 254 of 5712 participants (4%) in the SARS-CoV-2–negative group or 80 of 3342 participants (2%) in the untested randomly selected reported memory problems (Figure). In the multiple logistic regression model, SARS-CoV-2 positivity at baseline was strongly associated with reporting memory problems at 8 months follow-up (odds ratio [OR], 4.66; 95% CI, 3.25-6.66) compared to the untested randomly selected group. At follow-up, 267 of 649 participants (41%) in the SARS-CoV-2–positive group reported a significant worsening of health compared with 1 year prior, and 81 of 651 participants (12%) in the SARS-CoV-2–positive group also reported problems concentrating. Additionally, 59 of 267 participants (82%) in the SARS-CoV-2–positive group who reported memory problems also reported a worsening of health. Feeling depressed, having less energy, or pain were reported relatively equally by the different groups. The lack of objective memory tests limits strong conclusions. However, subjective memory concerns have been shown to reflect objective problems and observable changes in everyday function even when controlling for associated factors, such as depression.5 Self-reported memory problems are also a risk factor for later mild cognitive impairment or dementia.6 Nevertheless, a more detailed examination of what type of memory problems are specific for PASC, like working memory vs long-term memory, is warranted in future studies.	Huit mois après l'infection, sur une large cohorte norvégienne de patients testés positifs au SARS-CoV-2, 11% rapportent encore des troubles mnésiques, 12% des difficultés de concentration, et une part importante considère que son état s'est dégradé.	N014E
170	N168		AaronJesuthasanaFlaviaMasseybHadiManjicMichael S.ZandicSarahWiethoff	Emerging potential mechanisms and predispositions to the neurological manifestations of COVID-19	https://doi.org/10.1016/j.jns.2021.117608	Published	4 August 2021	Review	https://www.jns-journal.com/article/S0022-510X(21)00302-6/fulltext	Highlights •The pathophysiology of NeuroCOVID is complex, likely entailing a combination of separate and overlapping mechanisms. •There is increasing evidence for genetic predispositions to NeuroCOVID. •The longer-term symptoms of COVID-19 are being increasingly described and represent an impending burden on healthcare services. •It is pivotal for future studies to further explore demographic and genetic risk factors for developing long COVID, particularly with regard to chronic neurological symptoms, which remain poorly understood. The present review subsequently attempts to address the evolving molecular, cellular and systemic mechanisms of NeuroCOVID, which we have classified as the acute and long-term neurological effects of COVID-19. We place particular emphasis on cerebrovascular, demyelinating and encephalitic presentations, which have been reported. Several mechanisms are presented, especially the involvement of a “cytokine storm”. We explore the genetic and demographic factors that may predispose individuals to NeuroCOVID. The increasingly evident long-term neurological effects are also presented, including the impact of the virus on cognition, autonomic function and mental wellbeing, which represent an impending burden on already stretched healthcare services. We subsequently reinforce the need for cautious surveillance, especially for those with predisposing factors, with effective clinical phenotyping, appropriate investigation and, if possible, prompt treatment. This will be imperative to prevent downstream neurological sequelae, including those related to the long COVID phenotypes that are being increasingly recognised.	Une revue d'études du 𝗻𝗲𝘂𝗿𝗼𝗰𝗼𝘃𝗶𝗱, la pathologie neurologique associée à la covid, entreprend d'en décrire la physiopathologie et les possibles facteurs génétiques prédisposants, tels les variants rs73635825 et rs143936283 de la protéine ACE2. L'article évoque la neuro-inflammation chez l'adulte, celle retrouvée selon un spectre similaire chez l'enfant, et s'interroge sur les séquelles à long terme.	N014E
171	N169		Marco Ruggiero	Application of Ultrasonography to Neuro-COVID-19	https://doi.org/10.21203/rs.3.rs-776630/v1	Pre-print	02 Aug, 2021	Study	https://www.researchsquare.com/article/rs-776630/v1	Here, it is demonstrated that application of ultrasonography to Neuro-COVID-19 requires a specific adaptation that takes into account brain movements synchronous with breathing as well as the sensitivity of SARS-CoV-2 to ultrasounds.	_
172	N170		E. Guedj CampionJ.DudouetP.KaphanE.BregeonF.CeccaldiM.MillionD.RaoultS.CammilleriC.Eldin	Hypométabolisme TEP cérébral chez les patients atteints de COVID long	https://doi.org/10.1016/j.mednuc.2021.06.023	Published	2 August 2021	Study	https://www.sciencedirect.com/science/article/pii/S0928125821000735	Par rapport aux sujets sains, les patients avec COVID long présentaient un hypométabolisme bilatéral fronto-basal incluant le bulbe olfactif, le lobe temporal droit comprenant l’amygdale et l’hippocampe s’étendant jusqu’au thalamus droit, le tronc cérébral bulbo-protubérantiel et le cervelet bilatéral (p-voxel < 0,001, p-cluster < 0,05 FWE corrigé). Ces clusters métaboliques étaient discriminants pour distinguer les patients des sujets sains (classification correcte à 100 %). Ils étaient associés à des plaintes fonctionnelles plus nombreuses et à la survenue des symptômes (anosmie, troubles cognitifs, douleurs, insomnie) (p < 0,05). Le métabolisme du cluster frontal, qui comprenait le bulbe olfactif, était encore plus diminué chez les 7 patients traités par des médicaments ciblant ACE dans un contexte d’HTA (p = 0,032) et moins diminué chez les 3 patients ayant effectué des irrigations nasales au stade inital (p < 0,001). Cette étude démontre un profil d’hypométabolisme cérébral TEP chez des patients COVID long avec une infection SARS-CoV-2 démontrée biologiquement et des plaintes fonctionnelles persistantes plus de 3 semaines. Cet hypométabolisme implique le gyrus olfactif et les régions limbiques/paralimbiques connectées, étendues au tronc cérébral et au cervelet. Ces hypométabolismes sont associés aux symptômes, avec une valeur de biomarqueur pour identifier et potentiellement suivre ces patients. Conclusions L’hypométabolisme du cluster frontal, qui comprenait le bulbe olfactif, semblait être lié aux médicaments ciblant ACE, avec également un meilleur métabolisme de cette région olfactive chez les patients ayant pratiqué des irrigations nasales décongestionnantes, suggérant un rôle possible des récepteurs ACE en tant que passerelle olfactive de ce neurotropisme.	Communication orale d'une étude déjà publiée (cf supra).
173	N171		Eric Guedj,1 Silvia Morbelli,2,3 Elsa Kaphan,4 Jacques-Yves Campion,1 Pierre Dudouet,5 Mathieu Ceccaldi,6 Serge Cammilleri,1 Flavio Nobili2,7 and Carole Eldin	From early limbic inflammation to long COVID sequelae	https://doi.org/10.1093/brain/awab215	Published	17 June 2021	Article	https://academic.oup.com/brain/advance-article-abstract/doi/10.1093/brain/awab215/6303604	Given the demonstration of viral persistence and inflammation in human olfactory epithelium, with diffusion to brain cortex, brainstem and cerebellum after intranasal inoculation in hamsters, 4 we interpreted the results in long COVID as hypometabolic dysfunction of a brain network connected to the olfactory pathway, through a propagation mechanism previously proposed for other coronaviruses, across the lamina cribrosa, from nose to olfactory bulb,5 where ACE2 receptors are strongly expressed. Of note, both RNA and protein of the virus have been found in neurons of COVID-19 patients, with T cell inflammatory infiltration and microglial activation in macaques after apparent remission (for a review, see Guedj et al.6). Hypometabolism of deeper connected regions in the limbic system, brainstem and cerebellum could at least partially correspond to a diaschisis phenomenon in relation to olfactory pathway deafferentation. An alternative explanation would be the diffusion of inflammation/infection to these more posterior regions through a trans-synaptic mechanism previously reported for other coronaviruses,4 possibly in patients with more severe presentation or those with little recovery after rehabilitation. Further multi-modal imaging studies will be needed to determine the possible contributions of each hypothesis. 18F-FDG PET might also be used to identify hypermetabolism within this network at earlier stages, since this feature has already been reported during the acute phase of COVID-19 (either in the presence or absence of encephalitis), especially by Kas et al.,7 and may more directly reflect inflammation/infection.	Qu'est-ce qui peut faire basculer une infection subaiguë de covid vers les séquelles neurologiques retrouvées dans le covid long ? Dans un article publié dans Brain, des chercheurs remarquent que les zones d'hypométabolisme cérébral, observées chez l'essentiel des patients de covid long, sont des zones en hypermétabolisme au stade initial d'une infection subaiguë de covid. Les auteurs interprètent ce résultat comme la marque d'une inflammation cérébrale précoce avec pour conséquence des désordres fonctionnels plus tardif au stade de covid long. Ils notent que cette transition de l’hyper- vers l’hypométabolisme, sur des régions cérébrales spécifiques, est analogue à celle retrouvée dans d'autres modèles inflammatoires et dysimmunitaires comme l’encéphalite. Une explication avancée est une propagation (précédemment proposée pour d'autres coronavirus), à travers la lame criblée de l'ethmoïde, du nez au bulbe olfactif, où les récepteurs ACE2 sont fortement exprimés. Un rapprochement est fait avec des précédent relevés d'ARN et de protéines du virus dans les neurones chez des patients covid, ainsi qu'une infiltration inflammatoire des lymphocytes T et une activation microgliale chez le singe après une rémission apparente. L'hypométabolisme de régions connectées plus profondément dans le système limbique, le tronc cérébral et le cervelet, pourrait correspondre, au moins partiellement, à un phénomène de diaschisis en relation avec la désafférentation des voies olfactives. Une explication alternative est une diffusion de l'inflammation/infection à des régions davantage postérieures, par un mécanisme trans-synaptique précédemment signalés pour d'autres coronavirus, notamment chez les patients plus sévèrement affectés en phase aiguë.	N014E
174	N172		Riccardo Manca 1, Matteo De Marco 1, Paul G Ince 1, Annalena Venneri	Heterogeneity in Regional Damage Detected by Neuroimaging and Neuropathological Studies in Older Adults With COVID-19: A Cognitive-Neuroscience Systematic Review to Inform the Long-Term Impact of the Virus on Neurocognitive Trajectories	https://doi.org/10.3389/fnagi.2021.646908	Published	2021 Jun 3	Article	https://pubmed.ncbi.nlm.nih.gov/34149394/	Results: Ninety studies, mainly single cases and case series, were included. Several neuroimaging and neuropathological findings in older patients with COVID-19 emerged from these studies, with cerebrovascular damage having a prominent role. Abnormalities (hyperintensities, hypoperfusion, inflammation, and cellular damage) were reported in most brain areas. The most consistent cross-aetiology findings were in white matter, brainstem and fronto-temporal areas. Viral DNA was detected mainly in olfactory, orbitofrontal and brainstem areas. Conclusion: Studies on COVID-19 related neural damage are rich and diverse, but limited to description of hospitalised patients with fatal outcome (i.e., in neuropathological studies) or severe symptoms (i.e., in neuroimaging studies). The damage seen in this population indicates acute and largely irreversible dysfunction to neural regions involved in major functional networks that support normal cognitive and behavioural functioning. It is still unknown whether the long-term impact of the virus will be limited to chronic evolution of acute events, whether sub-clinical pathological processes will be exacerbated or whether novel mechanisms will emerge. Based on current literature, future theoretical frameworks describing the long-term impact of COVID-19 infection on mental abilities will have to factor in major trends of aetiological and topographic heterogeneity.
175			Stephan Grimaldi, Stanislas Lagarde, Jean-Robert Harlé, Jean-Robert Harlé, Joseph Boucraut, Eric Guedj	Autoimmune encephalitis concomitant with SARS-CoV-2 infec- tion: Insight from 18F-FDG PET imaging and neuronal autoanti- bodies	https://doi.org/10.2967/jnumed.120.249292	Published	July 24, 2020	Case Report	https://hal.archives-ouvertes.fr/hal-02933208	We report the case of a 72-years-old man with concomitant autoimmune encephalitis and SARS-CoV-2 infection. Methods: Review of clinical examination, CT, PET, MRI imaging, and autoantibodies testing. Results: The patient presented subacute cerebellar syndrome and myoclonus several days after general infectious symptoms. The oropharyngeal swab test was positive for SARS-CoV-2. Brain MRI was normal. CSF testing showed normal cell counts, negative RT-qPCR and no oligoclonal banding. Brain 18F-FDG-PET showed diffuse cortical hypometabolism, associated with putaminal and cerebellum hypermetabolism, compatible with encephalitis, and especially cerebellitis. The immunological study revealed high titers of IgG autoantibodies in serum and CSF directed against the nuclei of Purkinje cells, striatal and hippocampal neurons. Search for neoplasia including whole-body 18F-FDG-PET and CT scans was negative. Treatment with steroids allowed a rapid improvement of symptoms. Conclusion: This clinical case brings arguments on the possible relationship between SARS-CoV-2 infection and autoimmune encephalitis, and on the interest of 18F-FDG-PET in such context.	_
176	N173		Garrett M. Timmons, Torge Rempe, Elizabeth A. Bevins, Vanessa Goodwill, Annalise Miner, Arthur Kavanaugh, Michele Ritter, Jennifer S. Graves	CNS Lymphocytic Vasculitis in a Young Woman With COVID-19 Infection	https://doi.org/10.1212/NXI.0000000000001048	Published	July 28, 2021	Case Report	https://nn.neurology.org/content/8/5/e1048	Here, we report additional evidence for COVID-19–related CNS vasculitis, confirmed by biopsy, in a young healthy patient with otherwise mild COVID-19 infection.	_
177	N174		Luana M. Manosso 1,Camila O. Arent 1,Laura A. Borba 1 ,Luciane B. Ceretta 2,João Quevedo 1,3,4,5 andGislaine Z. Réus	Microbiota-Gut-Brain Communication in the SARS-CoV-2 Infection	https://doi.org/10.3390/cells10081993	Published	6 August 2021	Review	https://www.mdpi.com/2073-4409/10/8/1993/htm	An exacerbated inflammatory state can lead to the blood–brain barrier (BBB) damage as well as to intestinal dysbiosis. These changes, in turn, are associated with microglial activation and reactivity of astrocytes that can promote the degeneration of neurons and be associated with the development of psychiatric disorders and neurodegenerative diseases. Studies also have been shown that SARS-CoV-2 alters the composition and functional activity of the gut microbiota. The microbiota-gut-brain axis provides a bidirectional homeostatic communication pathway. Thus, this review focuses on studies that show the relationship between inflammation and the gut microbiota–brain axis in SARS-CoV-2 infection.
178						From this point on, the survey of studies is no longer as exhaustive as possible. Only those studies which seem to us to bring significant new elements will be listed.
179	N175		Melvin R. Hayden	Hypothesis: Neuroglia Activation Due to Increased Peripheral and CNS Proinflammatory Cytokines/Chemokines with Neuroinflammation May Result in Long COVID	https://doi.org/10.3390/neuroglia2010004	Published	30 August 2021	Review	https://www.mdpi.com/2571-6980/2/1/4/htm	This review aims to summarize many of the cumulated findings associated with LC/PASC and provides supportive and representative illustrations and transmission electron micrographic remodeling changes within brain tissues associated with a stress type of injury as occurs in the classic db/db and novel BTBR ob/ob obesity and diabetes mellitus mice models. These models are utilized to merely provide a response to metabolic stress injury wound healing mechanisms that are also present in humans. This review posits that neuroglial activation and chronic neuroinflammation may be a common denominator for the development of the complex LC/PASC syndrome following acute COVID-19 due to SARS-CoV-2.
180	N176		Yiping Lu, MD 1 Xuanxuan Li, MD 1 Daoying Geng, MD 1 Nan Mei, MD 1 Pu-Yeh Wu, PhD Chu-Chung Huang, PhD Tianye Jia, PhD Yajing Zhao, MD Dongdong Wang, MD Anling Xiao, MD Bo Yin	Cerebral Micro-Structural Changes in COVID-19 Patients – An MRI-based 3-month Follow-up Study	https://doi.org/10.1016/j.eclinm.2020.100484	Published	August 03, 2020	Study	https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(20)30228-5/fulltext	In this prospective study, diffusion tensor imaging (DTI) and 3D high-resolution T1WI sequences were acquired in 60 recovered COVID-19 patients (56.67% male; age: 44.10 ± 16.00) and 39 age- and sex-matched non-COVID-19 controls (56.41% male; age: 45.88 ± 13.90). Registered fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were quantified for DTI, and an index score system was introduced. Regional volumes derived from Voxel-based Morphometry (VBM) and DTI metrics were compared using analysis of covariance (ANCOVA). Two sample t-test and Spearman correlation were conducted to assess the relationships among imaging indices, index scores and clinical information. • View related content for this article Findings In this follow-up stage, neurological symptoms were presented in 55% COVID-19 patients. COVID-19 patients had statistically significantly higher bilateral gray matter volumes (GMV) in olfactory cortices, hippocampi, insulas, left Rolandic operculum, left Heschl's gyrus and right cingulate gyrus and a general decline of MD, AD, RD accompanied with an increase of FA in white matter, especially AD in the right CR, EC and SFF, and MD in SFF compared with non-COVID-19 volunteers (corrected p value <0.05). Global GMV, GMVs in left Rolandic operculum, right cingulate, bilateral hippocampi, left Heschl's gyrus, and Global MD of WM were found to correlate with memory loss (p value <0.05). GMVs in the right cingulate gyrus and left hippocampus were related to smell loss (p value <0.05). MD-GM score, global GMV, and GMV in right cingulate gyrus were correlated with LDH level (p value <0.05). Interpretation Study findings revealed possible disruption to micro-structural and functional brain integrity in the recovery stages of COVID-19, suggesting the long-term consequences of SARS-CoV-2.
181	N177		J. J. Merino, A. Macho-González, J. Benedi & M. P. González	Neurological manifestations of COVID-19 in patients: from path physiology to therapy	https://doi.org/10.1007/s10072-021-05505-7	Published	21 August 2021	Review	https://link.springer.com/article/10.1007/s10072-021-05505-7	In this review, we update the neurological mechanisms by which coronavirus-19 causes neurological manifestation in patients such as encephalomyelitis, Guillain-Barré syndrome, lacunars infarcts, neuropsychiatry disorders such as anxiety and depression, and vascular alterations. This review explains (a) the possible pathways by which coronavirus-19 can induce the different neurological manifestations, (b) the strategies used by the virus to cross the barrier system, (c) how the immune system responds to the infection, and (d) the treatment than can be administered to the COVID-19 patients.
182	N178		Bindu D. Paul, Marian D. Lemle, Anthony L. Komaroff, and Solomon H. Snyder	Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome	https://doi.org/10.1073/pnas.2024358118	Published	August 16, 2021	PERSPECTIVE	https://www.pnas.org/content/118/34/e2024358118	Although most patients recover from acute COVID-19, some experience postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC). One subgroup of PASC is a syndrome called “long COVID-19,” reminiscent of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a debilitating condition, often triggered by viral and bacterial infections, leading to years-long debilitating symptoms including profound fatigue, postexertional malaise, unrefreshing sleep, cognitive deficits, and orthostatic intolerance. Some are skeptical that either ME/CFS or long COVID-19 involves underlying biological abnormalities. However, in this review, we summarize the evidence that people with acute COVID-19 and with ME/CFS have biological abnormalities including redox imbalance, systemic inflammation and neuroinflammation, an impaired ability to generate adenosine triphosphate, and a general hypometabolic state. These phenomena have not yet been well studied in people with long COVID-19, and each of them has been reported in other diseases as well, particularly neurological diseases. We also examine the bidirectional relationship between redox imbalance, inflammation, energy metabolic deficits, and a hypometabolic state. We speculate as to what may be causing these abnormalities. Thus, understanding the molecular underpinnings of both PASC and ME/CFS may lead to the development of novel therapeutics.	Dans une revue d'études, un groupe de chercheurs décrit les éléments communs au covid long et à l'encéphalomyélite myalgique. Ils listent notamment un déséquilibre antioxydants/pro-oxydants, une inflammation systémique et une neuro-inflammation, une capacité altérée à générer de l'adénosine triphosphate et un état hypométabolique général.	N014E
183	N179		Richard C. Becker	Autonomic dysfunction in SARS-COV-2 infection acute and long-term implications COVID-19 editor’s page series	https://doi.org/10.1007/s11239-021-02549-6	Published	17 August 2021	Review	https://link.springer.com/article/10.1007/s11239-021-02549-6	The autonomic nervous system (ANS) is a complex network of nerves originating in the brain, brain stem, spinal cord, heart and extracardiac organs that regulates neural and physiological responses to internal and external environments and conditions. A common observation among patients with the 2019 Coronavirus (CoV) (SARS-severe acute respiratory syndrome CoV-2) (SARS-CoV-2) or COVID-19 [CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019)] in the acute and chronic phases of the disease is tachycardia, labile blood pressure, muscular fatigue and shortness of breath. Because abnormalities in the ANS can contribute to each of these symptoms, herein a review of autonomic dysfunction in SARS-COV-2 infection is provided to guide diagnostic testing, patient care and research initiatives.
184	N180		Silvia Bozzetti, Sergio Ferrari, Serena Zanzoni, Daniela Alberti, Michele Braggio, Sara Carta, Francesco Piraino, Daniele Gabbiani, Domenico Girelli, Riccardo Nocini, Salvatore Monaco, Ernesto Crisafulli & Sara Mariotto	Neurological symptoms and axonal damage in COVID-19 survivors: are there sequelae?	https://doi.org/10.1007/s12026-021-09220-5	Published	07 August 2021	Study	https://link.springer.com/article/10.1007/s12026-021-09220-5	The persistence of neurological symptoms after SARS-CoV-2 infection, as well as the presence of late axonal damage, is still unknown. We performed extensive systemic and neurological follow-up evaluations in 107 out of 193 consecutive patients admitted to the COVID-19 medical unit, University Hospital of Verona, Italy between March and June 2020. We analysed serum neurofilament light chain (NfL) levels in all cases including a subgroup (n = 29) of patients with available onset samples. Comparisons between clinical and biomarker data were then performed. Neurological symptoms were still present in a significant number (n = 49) of patients over the follow-up. The most common reported symptoms were hyposmia (n = 11), fatigue (n = 28), myalgia (n = 14), and impaired memory (n = 11) and were more common in cases with severe acute COVID-19. Follow-up serum NfL values (15.2 pg/mL, range 2.4–62.4) were within normal range in all except 5 patients and did not differentiate patients with vs without persistent neurological symptoms. In patients with available onset and follow-up samples, a significant (p < 0.001) decrease of NfL levels was observed and was more evident in patients with a severe acute disease. Despite the common persistence of neurological symptoms, COVID-19 survivors do not show active axonal damage, which seems a peculiar feature of acute SARS-CoV-2 infection.
185	N181		Edoardo Caronna MD, Alicia Alpuente MD, Marta Torres-Ferrus MD, PhD, Patricia Pozo-Rosich MD, PhD	Toward a better understanding of persistent headache after mild COVID-19: Three migraine-like yet distinct scenarios	https://doi.org/10.1111/head.14197	Published	07 August 2021	Cases Report	https://headachejournal.onlinelibrary.wiley.com/doi/full/10.1111/head.14197	One year after the outbreak of coronavirus disease 2019 (COVID-19), referrals for persistent headache, often defined as “post-COVID headache,” have become increasingly common in outpatient headache clinics. However, it is important to take into consideration that this term may include a spectrum of clinically different headache types. We describe three cases of migraine-like headaches in individuals with a history of mild COVID-19 infection to demonstrate some of the different phenotypes of persistent headaches seen. These cases highlight the importance of a careful evaluation when assessing the complexities of “post-COVID headache” as well as the need to further investigate the different, underlying, pathophysiological mechanisms.
186	N182		Ling Zhang, Li Zhou, Linlin Bao, Jiangning Liu, Hua Zhu, Qi Lv, Ruixue Liu, Wei Chen, Wei Tong, Qiang Wei, Yanfeng Xu, Wei Deng, Hong Gao, Jing Xue, Zhiqi Song, Pin Yu, Yunlin Han, Yu Zhang, Xiuping Sun, Xuan Yu & Chuan Qin	SARS-CoV-2 crosses the blood–brain barrier accompanied with basement membrane disruption without tight junctions alteration	https://doi.org/10.1038/s41392-021-00719-9	Published	06 September 2021	Study	https://www.nature.com/articles/s41392-021-00719-9	SARS-CoV-2 has been reported to show a capacity for invading the brains of humans and model animals. However, it remains unclear whether and how SARS-CoV-2 crosses the blood–brain barrier (BBB). Herein, SARS-CoV-2 RNA was occasionally detected in the vascular wall and perivascular space, as well as in brain microvascular endothelial cells (BMECs) in the infected K18-hACE2 transgenic mice. Moreover, the permeability of the infected vessel was increased. Furthermore, disintegrity of BBB was discovered in the infected hamsters by administration of Evans blue. Interestingly, the expression of claudin5, ZO-1, occludin and the ultrastructure of tight junctions (TJs) showed unchanged, whereas, the basement membrane was disrupted in the infected animals. Using an in vitro BBB model that comprises primary BMECs with astrocytes, SARS-CoV-2 was found to infect and cross through the BMECs. Consistent with in vivo experiments, the expression of MMP9 was increased and collagen IV was decreased while the markers for TJs were not altered in the SARS-CoV-2-infected BMECs. Besides, inflammatory responses including vasculitis, glial activation, and upregulated inflammatory factors occurred after SARS-CoV-2 infection. Overall, our results provide evidence supporting that SARS-CoV-2 can cross the BBB in a transcellular pathway accompanied with basement membrane disrupted without obvious alteration of TJs.
187	N183		Lu Wang, David Sievert, Alex E. Clark, Sangmoon Lee, Hannah Federman, Benjamin D. Gastfriend, Eric V. Shusta, Sean P. Palecek, Aaron F. Carlin & Joseph G. Gleeson	A human three-dimensional neural-perivascular ‘assembloid’ promotes astrocytic development and enables modeling of SARS-CoV-2 neuropathology	https://doi.org/10.1038/s41591-021-01443-1	Published	09 July 2021	Study	https://www.nature.com/articles/s41591-021-01443-1	Pericytes are perivascular cells within the brain that are proposed as SARS-CoV-2 infection points. Here we show that pericyte-like cells (PLCs), when integrated into a cortical organoid, are capable of infection with authentic SARS-CoV-2. Before infection, PLCs elicited astrocytic maturation and production of basement membrane components, features attributed to pericyte functions in vivo. While traditional cortical organoids showed little evidence of infection, PLCs within cortical organoids served as viral ‘replication hubs’, with virus spreading to astrocytes and mediating inflammatory type I interferon transcriptional responses. Therefore, PLC-containing cortical organoids (PCCOs) represent a new ‘assembloid’ model that supports astrocytic maturation as well as SARS-CoV-2 entry and replication in neural tissue; thus, PCCOs serve as an experimental model for neural infection.
188	N184		Eric Guedj,Jacques-Yves Campion,Tatiana Horowitz,Fanny Barthelemy,Serge Cammilleri,Mathieu Ceccaldi,	The impact of COVID-19 lockdown on brain metabolism	https://doi.org/10.1002/hbm.25673	Published	12 October 2021	Study	https://onlinelibrary.wiley.com/doi/full/10.1002/hbm.25673	This study aims to evaluate the impact of French national lockdown of 55 days on brain metabolism of patients with neurological disorders. Whole-brain voxel-based PET analysis was used to correlate 18F-FDG metabolism to the number of days after March 17, 2020 (in 95 patients; mean age: 54.3 years ± 15.7; 59 men), in comparison to the same period in 2019 before the SARS-CoV-2 outbreak (in 212 patients; mean age: 59.5 years ± 15.8; 114 men), and to the first 55 days of deconfinement (in 188 patients; mean age: 57.5 years ± 16.5; 93 men). Lockdown duration was negatively correlated to the metabolism of the sensory-motor cortex with a prevailing effect on the left dominant pyramidal tract and on younger patients, also including the left amygdala, with only partial reversibility after 55 days of deconfinement. Weak overlap was found with the reported pattern of hypometabolism in long COVID (<9%). Restriction of physical activities, and possible related deconditioning, and social isolation may lead to functional disturbances of sensorimotor and emotional brain networks. Of note, this metabolic pattern seems distinct to those reported in long COVID. Further longitudinal studies with longer follow-up are needed to evaluate clinical consequences and relationships on cognitive and mental health against functional deactivation hypothesis, and to extend these findings to healthy subjects in the context of lockdown.	Une équipe de chercheurs s'est penchée sur les effets du confinement du printemps 2020 sur le métabolisme cérébral, depuis une cohorte de patients présentant des troubles neurologiques (non touchés par la covid a priori). L'objectif était de mesurer par PET-SCAN les effets délétères de la réduction d'activité physique, du déconditionnement, de l'isolement social pendant le confinement, par leurs impacts sur les réseaux cérébraux sensorimoteur et émotionnel. L'étude est faite sur 95 patients d'âge moyen de 54 ans, comparée à une cohorte témoin, et à une cohorte post-confinement. Les résultats montrent chez ces patients des altérations métaboliques du faisceau pyramidal dominant gauche et de l'amygdale cérébrale gauche, qui se résorbent partiellement dans les semaines qui suivent le déconfinement. Les auteurs insistent sur le fait que ce schéma métabolique apparaît distinct de ceux rapportés dans les covid longs, lesquels impliquent principalement les zones limbiques droites, en particulier les zones olfactives avec des hypométabolismes sévères. L'étude présente ces résultats comme des éléments confirmant l'impact négatif du confinement sur la santé mentale et cognitive, mais non superposables aux troubles neurologiques du covid long.	N014
189	N185	VP	G.FondabM.MassoncdC.LançonaeR.RichieridefE.Guedj	The neuroinflammatory pathways of post-SARS-CoV-2 psychiatric disorders	https://doi.org/10.1016/j.encep.2021.08.001	Published	30 August 2021	Editorial	https://www.sciencedirect.com/science/article/pii/S0013700621001706	In this line, a recent review of 90 studies including neuroimaging and post-mortem analysis identified temporo-frontal areas as the most consistent cross-etiology impairment, with also microglial activation, and viral DNA detection in olfactory and orbitofrontal areas [10]. These regions have the highest concentrations of angiotensin-converting enzyme 2 (ACE2) receptor on cell surface, the receptor binding to the 1 subunit of the S protein, one of the four structural proteins of the SARS-CoV-2 virion [11]. The involvement of these limbic brain structures is well-known in emotion regulation and psychiatric disorders [12]. While individuals with severe psychiatric disorders have increased risk of mortality or ICU admission [13], [14], [15], we should not exclude that the infection itself may also more directly contribute to the degradation of mental health in infected people. This should be considered in the benefit/risk balance of non-pharmaceutical interventions taken to limit SARS-COV-2 spread, against psychological consequences of these containment measures.	_
190	N186		Daša Viszlayová, Martin Sojka, Silvia Dobrodenková, Szabolcs Szabó, Ondrej Bilec, Mária Turzová, Juraj Ďurina, Barbara Baloghová, Zoltán Borbély, Martin Kršák	SARS-CoV-2 RNA in the Cerebrospinal Fluid of a Patient with Long COVID	https://doi.org/10.1177%2F20499361211048572	Published	October 7, 2021	Case Report	https://journals.sagepub.com/doi/10.1177/20499361211048572	We describe a long COVID patient with SARS-CoV-2 RNA in the cerebrospinal fluid, which seems important, specifically due to recent reports of gray matter volume loss in COVID-19 patients. Further studies of SARS-CoV2 RNA, markers of inflammation, and neuronal damage in the CSF of patients with long COVID would be useful and should address whether the CNS can serve as a reservoir of SARS-CoV-2, clarify the pathway by which COVID-19 contributes to CNS dysfunction, and how best to therapeutically address it.	_
191	N187		Erin Clough, Khoo Ting Chean, Joseph Inigo, Kate E. Tubbesing, Dhyan Chandra, Lee Chaves, Jessica L. Reynolds, Ravikumar Aalinkeel, Stanley A. Schwartz, Alexander Khmaladze & Supriya D. Mahajan	Mitochondrial Dynamics in SARS-COV2 Spike Protein Treated Human Microglia: Implications for Neuro-COVID	https://doi.org/10.1007/s11481-021-10015-6	Published	02 October 2021	Study	https://link.springer.com/article/10.1007/s11481-021-10015-6	We hypothesize that SAR-COV2 induces mitochondrial dysfunction and activation of the mitochondrial-dependent intrinsic apoptotic pathway, resulting in microglial and neuronal apoptosis. The goal of our study was to determine the effect of SARS-COV2 on mitochondrial biogenesis and to monitor cell apoptosis in human microglia non-invasively in real time using Raman spectroscopy, providing a unique spatio-temporal information on mitochondrial function in live cells. We treated human microglia with SARS-COV2 spike protein and examined the levels of cytokines and reactive oxygen species (ROS) production, determined the effect of SARS-COV2 on mitochondrial biogenesis and examined the changes in molecular composition of phospholipids. Our results show that SARS- COV2 spike protein increases the levels of pro-inflammatory cytokines and ROS production, increases apoptosis and increases the oxygen consumption rate (OCR) in microglial cells. Increases in OCR are indicative of increased ROS production and oxidative stress suggesting that SARS-COV2 induced cell death. Raman spectroscopy yielded significant differences in phospholipids such as Phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE) and phosphatidylcholine (PC), which account for ~ 80% of mitochondrial membrane lipids between SARS-COV2 treated and untreated microglial cells. These data provide important mechanistic insights into SARS-COV2 induced mitochondrial dysfunction which underlies neuropathology associated with Neuro-COVID.
192	N188		Paola Ortelli, Davide Ferrazzoli, Luca Sebastianelli, Roberto Maestri, Sabrina Dezi, Danny Spampinato, Leopold Saltuari, Alessia Alibardi, Markus Kofler, Angelo Quartarone, Giacomo Koch, Antonio Oliviero, Viviana Versace	Fatigue and “brain fog” in the aftermath of mild COVID-19: A neuropsychological and TMS study	https://doi.org/10.1016/j.jns.2021.119854	Published	October 01, 2021	Abstract only	https://www.jns-journal.com/article/S0022-510X(21)02550-8/fulltext#relatedArticles	Sixty-seven patients complaining of fatigue and/or “brain fog” and 22 healthy subjects (HS) were enrolled. Fatigue, perceived exertion (evaluated after motor task) and “brain fog” were evaluated. Global cognition and executive functions were assessed with Montreal Cognitive Assessment (MoCA) and Frontal Assessment Battery (FAB). Attention was measured with Sustained Attention, Stroop and Navon computerized-tasks. Transcranial magnetic stimulation (TMS) of the primary motor cortex (M1) evaluated resting motor threshold (RMT), motor evoked potential (MEP) amplitude, and cortical silent period (SP). Intracortical activity was evaluated with paired-pulse TMS protocols including short-interval intracortical inhibition (SICI), reflecting GABAA-mediated inhibition, long-interval intracortical inhibition (LICI), a marker of GABAB receptor activity, and short-latency afferent inhibition (SAI) that indexes central cholinergic transmission. Results Patients reported high level of perceived fatigue, exertion and “brain fog”. MOCA and FAB highlighted poorer performances in patients than HS. At computerized tasks, both, sustained and executive attention were impaired. Patients presented higher RMTs, lower MEPs amplitude and longer SPs, as compared to HS, concurring with a reduced M1 excitability. LICI and SAI were impaired, indicating altered GABAB- and cholinergic neurotransmission. Conclusions Overall, our results demonstrate, in long COVID-19, an important link between fatigue, “brain fog” and central nervous system dysfunctions, characterized by frontal lobe cognitive impairments and altered neurotransmission.
193	N189		Ryan C. N. D'Arcy1,2,3*, Jagdeep K. Sandhu4,5, Shawn Marshall6 and Markus Besemann	Mitigating Long-Term COVID-19 Consequences on Brain Health	https://doi.org/10.3389/fneur.2021.630986	Published	27 September 2021	PERSPECTIVE article	https://www.frontiersin.org/articles/10.3389/fneur.2021.630986/full
194	N190	ES	Jan Wenzel, Josephine Lampe, Helge Müller-Fielitz, Raphael Schuster, Marietta Zille, Kristin Müller, Markus Krohn, Jakob Körbelin, Linlin Zhang, Ümit Özorhan, Christine Stadelmann, François Trottein, Ruben Nogueiras, Rolf Hilgenfeld, Markus Glatzel, Vincent Prevot & Markus Schwaninger	The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells	https://doi.org/10.1038/s41593-021-00926-1	Published	21 October 2021	Study	https://www.nature.com/articles/s41593-021-00926-1	Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood–brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the Mpro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.	Une étude publiée dans Nature renforce la piste des dommages de la covid sur les petits vaisseaux cérébraux, pouvant expliquer les troubles neurologiques du covid long. Selon les auteurs, sont mises en évidence des preuves que les cellules endothéliales du cerveau sont infectées et qu'une protéine du SRAS-CoV-2 peut couper des liaisons de la protéine NEMO, ce qui induit la mort de cellules endothéliales et altère la barrière hémato-encéphalique. L'étude note que l'action d'un inhibiteur de la protéine RIPK (dont certains sont en essai clinique, cf https://nature.com/articles/s41573-020-0071-y -https://sciencedirect.com/science/article/abs/pii/S016561472030002X, comme le sorafénib, le ponatinib ou le pazopanib) pourrait aider à traiter la neuropathologie de la covid.	N014E
195	N191		Jacqueline H. Becker, PhD1; Jenny J. Lin, MD, MPH1; Molly Doernberg, MPH1; Kimberly Stone, MPH1; Allison Navis, MD2; Joanne R. Festa, PhD2; Juan P. Wisnivesky, MD, DrPH1,3	Assessment of Cognitive Function in Patients After COVID-19 Infection	http://jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2021.30645	Published	October 22, 2021	Study	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2785388	In adjusted analyses, hospitalized patients were more likely to have impairments in attention (odds ratio [OR]: 2.8; 95% CI: 1.3-5.9), executive functioning (OR: 1.8; 95% CI: 1.0-3.4), category fluency (OR: 3.0; 95% CI: 1.7-5.2), memory encoding (OR: 2.3; 95% CI: 1.3-4.1), and memory recall (OR: 2.2; 95% CI: 1.3-3.8) than those in the outpatient group. Patients treated in the ED were more likely to have impaired category fluency (OR: 1.8; 95% CI: 1.1-3.1) and memory encoding (OR: 1.7; 95% CI: 1.0-3.0) than those treated in the outpatient setting. No significant differences in impairments in other domains were observed between groups.
196	N192		Abhishek Goyal, Khushboo Saxena, Avishek Kar, Parneet Kaur Bhagtana, Chinta Siva Koti Rupa Sridevi, Swanzil Chaudhary & Rashida Ali	Sleep EEG Signatures in COVID-19 Survivors	https://doi.org/10.1007/s41782-021-00174-0	Published	12 October 2021	Study	https://link.springer.com/article/10.1007/s41782-021-00174-0	Finally 81 patients (55 males, 26 females) underwent Level I PSG. Total sleep time was 345.1 ± 85.1 min. Sleep efficiency was 76.0 ± 14.2%. Mean time (%) during N1, N2, N3 and Rapid Eye movement (REM) was 16.4%, 59.2%, 7.9% and 18.4% percentage, respectively. Mean AHI was 28.7 ± 22.8 per hour and arousal index was 23.9 ± 13.3. Alpha intrusion was the most common EEG finding (78%), followed by cyclical alternating pattern (59%). REM density was significantly increased in 38% of patients. REM alpha bursts and increased spindles were also seen in 27% and 16%. Conclusion Abnormal EEG waves are very commonly seen in COVID-19 survivors. Presence of these abnormal PSG-EEG waves hints that COVID-19 might have similar effects as depression, insomnia on these subjects, at least in short run. Whether these changes are temporary or permanent needs to be evaluated by performing serial polysomnographies in patients with COVID-19 ARDS.
197	N193	Contested	Andrea Dressing, Tobias Bormann, Ganna Blazhenets, Nils Schroeter, Lea I Walter, Johannes Thurow, Dietrich August, Hanna Hilger, Katarina Stete, Kathrin Gerstacker, Susan Arndt, Alexander Rau, Horst Urbach, Siegbert Rieg, Dirk Wagner, Cornelius Weiller, Philipp T Meyer and Jonas A Hosp	Neuropsychological profiles and cerebral glucose metabolism in neurocognitive Long COVID-syndrome	https://doi.org/10.2967/jnumed.121.262677	Published	October 14, 2021	Study	https://jnm.snmjournals.org/content/early/2021/10/14/jnumed.121.262677	Results: Patients self-reported impaired attention, memory, and multitasking abilities (31/31), word-finding difficulties (27/31), and fatigue (24/31). Twelve of 31 patients could not return to the previous level of independence/employment. For all cognitive domains, average group results of the neuropsychological test-battery showed no impairment, but deficits (z-score<-1.5) were present on single-patient level mainly in the domain of visual memory (in 7/31; other domains ≤2/31). Mean MoCA performance (27/30 points) was above the cutoff-value for detection of cognitive impairment (< 26 points), although 9/31 patients performed slightly below this level (23-25 points). In the subgroup of patients who underwent 18F-FDG PET, we found no significant changes of regional cerebral glucose metabolism. Conclusion: Long COVID patients self-report uniform symptoms hampering their ability to work in a relevant fraction. However, cognitive testing showed minor impairments only on single-patient level approximately six months after the infection, whereas functional imaging revealed no distinct pathological changes. This clearly deviates from previous findings in subacute COVID-19 patients, suggesting that underlying neuronal causes are different and possibly related to the high prevalence of fatigue.	L’approche méthodologique de cette équipe a été critiquée dans une lettre publiée dans Brain (Guedj et al., doi: 10.1093/brain/awab215) associant neurologues et médecins nucléaires de Marseille et Gênes (Italie), en particulier le Pr. Eric Guedj (1er auteur des guidelines européennes en imagerie TEP, doi: 10.1007/s00259-021-05603-w), le Pr. Silvia Morbelli (dernière auteure de ces mêmes guidelines, et responsable de cette activité au sein de l’association européenne de médecine nucléaire: https://www.eanm.org/about/organs/committees/neuroimaging-2/), et par le Pr. Flavio Nobili (neurologue, 1er auteur des recommandations conjointes des sociétés européennes de neurologie et de médecine nucléaire pour l’utilisation clinique de l’imagerie TEP, doi: 10.1111/ene.13728). La critique porte sur les points suivants : la non-disponibilité publique des images analysées, la non-publication dans leurs articles des images individuelles natives avant traitement statistique (nous notons que les publications du groupe de Marseille répondent à ces 2 standards, elles ne font pas l’objet de critiques sur les plateformes de post-review, et que la seule lettre publiée en commentaire de ces travaux par des équipes françaises et brésiliennes est particulièrement positive, doi: 10.1007/s00259-021-05342-y), et enfin plus spécifiquement parce que ces auteurs proposent de normaliser la quantification des images sur l’activité métabolique de la substance blanche alors que celle-ci est décrite comme pathologique de façon consensuelle dans la littérature scientifique (doi: 10.1093/brain/awab215).
198	N194		Min Lang, Yuh-Shin Chang, William A. Mehan Jr, Sandra P. Rincon & Karen Buch	Long-term neuroimaging follow-up of COVID-19-related leukoencephalopathy	https://doi.org/10.1007/s00234-021-02829-1	Published	18 October 2021	Short Report	https://link.springer.com/article/10.1007/s00234-021-02829-1	More than a year after the start of the COVID-19 pandemic, long-term neurological manifestations of COVID-19 are increasingly being reported. The long-term sequelae of COVID-19-related leukoencephalopathy, however, remain unclear. Here, we present long-term neuroimaging follow-up in two cases of COVID-19-related leukoencephalopathy. The two cases demonstrate the utility of brain MRI for evaluating neurologic symptoms in critically ill patients with COVID-19, for diagnosis of underlying neural injury and prognostication of future recovery. The presence of leukoencephalopathy may result in chronic neurologic manifestations and may represent a poor prognosticator of neurologic recovery. The presence of leukoencephalomalacia on follow-up neuroimaging is potentially an indicator of irreversible white matter damage, which may be associated with more severe chronic deficits.
199	N195		Stefano Terruzzi, Maurizia Chiusole, Donatella Ottaviani, Umberto Rozzanigo & Costanza Papagno	A case of anterograde amnesia in an MS-like demyelination after COVID-19	https://doi.org/10.1007/s10072-021-05665-6	Published	18 October 2021	Case Report	https://link.springer.com/article/10.1007/s10072-021-05665-6	Finally, the case of MK also shows that it is likely that the SARS-CoV-2 infection has produced an inflammatory response with a CNS demyelination. Stress is a trigger for autoimmunity, including MS, and major stressful life events have been associated with an increased risk of developing MS [4]. In the very recent literature, three cases of MS-like demyelination with an atypical presentation associated with COVID-19 have been reported ([5] for review): indeed, in one case MRI lesions were round in shape and larger than typical MS plaques; in another case, lesions were located mainly in the deep white matter and subcortical areas; finally, in the remaining case, despite the presentation with optic neuritis, the associated field defect rendered the presentation atypical. To our knowledge, MK represents the first case of an MS-like demyelination with typical plaques developed after COVID-19 neutralization where an anterograde amnesia is described.	_
200	N196		Christopher M. Bartley, MD, PhD1,2,3; Claire Johns, MD4; Thomas T. Ngo, BS2,3; Ravi Dandekar, MS2,5; Rita L. Loudermilk, BS2,5; Bonny D. Alvarenga, BA2,5; Isobel A. Hawes, BA2,5,6; Colin R. Zamecnik, PhD2,5; Kelsey C. Zorn, MHS7; Jessa R. Alexander, BA2,5; Anne E. Wapniarski, BA2,5; Joseph L. DeRisi, PhD7,8; Carla Francisco, MD2,5; Kendall B. Nash, MD2,4,5; Sharon O. Wietstock, MD2,5; Samuel J. Pleasure, MD, PhD2,5; Michael R. Wilson, MD2,5	Anti–SARS-CoV-2 and Autoantibody Profiles in the Cerebrospinal Fluid of 3 Teenaged Patients With COVID-19 and Subacute Neuropsychiatric Symptoms	https://doi.org/10.1001/jamaneurol.2021.3821	Published	October 25, 2021	Brief Report	https://jamanetwork.com/journals/jamaneurology/fullarticle/2785032	Are anti–SARS-CoV-2 or antineural antibodies present in the cerebrospinal fluid of pediatric patients with COVID-19 and neuropsychiatric symptoms? Findings In this case series of 3 pediatric patients with subacute neuropsychiatric impairment, 2 had intrathecal anti–SARS-CoV-2 antibodies as well as intrathecal antineural antibodies. Anti–transcription factor 4 (TCF4) autoantibodies in one patient who responded to immunotherapy were validated. Meaning A subset of pediatric patients with COVID-19 and subacute neuropsychiatric symptoms have intrathecal antineural autoantibodies, suggesting central nervous system autoimmunity in pediatric patients with COVID-19 and recent neuropsychiatric symptoms.
201	N197		Robyn Klein, Allison Soung, Cheick Sissoko, Anna Nordvig, Peter Canoll, Madeline Mariani, Xiaoping Jiang, Traci Bricker, James Goldman, Gorazd Rosoklija, Victoria Arango, Mark Underwood, J. John Mann, Adrianus Boon, Andrew Dowrk, Maura Boldrini	COVID-19 induces neuroinflammation and loss of hippocampal neurogenesis	https://doi.org/10.21203/rs.3.rs-1031824/v1	pre-print	29 Oct, 2021	Study	https://www.researchsquare.com/article/rs-1031824/v1	Infection with the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is associated with onset of neurological and psychiatric symptoms during and after the acute phase of illness1-4. Acute SARS-CoV-2 disease (COVID-19) presents with deficits of memory, attention, movement coordination, and mood. The mechanisms of these central nervous system symptoms remain largely unknown. In an established hamster model of intranasal infection with SARS-CoV-25, and patients deceased from COVID-19, we report a lack of viral neuroinvasion despite aberrant BBB permeability, microglial activation, and brain expression of interleukin (IL)-1β and IL-6, especially within the hippocampus and the inferior olivary nucleus of the medulla, when compared with non-COVID control hamsters and humans who died from other infections, cardiovascular disease, uremia or trauma. In the hippocampus dentate gyrus of both COVID-19 hamsters and humans, fewer cells expressed doublecortin, a marker of neuroblasts and immature neurons. Despite absence of viral neurotropism, we find SARS-CoV-2-induced inflammation, and hypoxia in humans, affect brain regions essential for fine motor function, learning, memory, and emotional responses, and result in loss of adult hippocampal neurogenesis. Neuroinflammation could affect cognition and behaviour via disruption of brain vasculature integrity, neurotransmission, and neurogenesis, acute effects that may persist in COVID-19 survivors with long-COVID symptoms.
202	N198		AnnaHeidbrederaThomasSonnweberbAmbraStefaniaAbubakerIbrahimaMatteoCesariaMelanieBergmannaElisabethBrandaueraIvanTancevskibJudithLöffler-RaggbBirgitHögla	Video-polysomnographic findings after acute COVID-19: REM sleep without atonia as sign of CNS pathology?	https://doi.org/10.1016/j.sleep.2021.01.051	Published	2 February 2021	Study	https://www.sciencedirect.com/science/article/pii/S138994572100068X	Highlights 1.Sleep disturbances are frequent after acute COVID-19. 2.Isolated REM-sleep without atonia was present in 36% of the patients after COVID-19. 3.Follow-up investigations are needed to elucidate if RWA in the context of COVID-19 is a sign of neurodegeneration. Eleven patients [nine men, age 52.5 (SD = 11.7) years; BMI 29 (SD = 5.2) kg/m2] were included. At 60 days follow-up after diagnosis, persisting breathing complaints were present in 7/11 (64%) patients. After v-PSG four patients (36%) were diagnosed with obstructive sleep apnea (OSA). Respiratory frequency during sleep was normal and no tachypnea, thoracoabdominal asynchrony, or periodic deep sighing were detected. Four patients (36%) showed REM sleep without atonia (RWA), and two additional patients showed an RWA index within the highest range of normality.
203	N199		Brandon J. DeOre, Kiet A. Tran, Allison M. Andrews, Servio H. Ramirez & Peter A. Galie	SARS-CoV-2 Spike Protein Disrupts Blood–Brain Barrier Integrity via RhoA Activation	https://doi.org/10.1007/s11481-021-10029-0	Published	23 October 2021	Brief Report	https://link.springer.com/article/10.1007/s11481-021-10029-0	The SARS-CoV-2 spike protein has been shown to disrupt blood–brain barrier (BBB) function, but its pathogenic mechanism of action is unknown. Whether angiotensin converting enzyme 2 (ACE2), the viral binding site for SARS-CoV-2, contributes to the spike protein-induced barrier disruption also remains unclear. Here, a 3D-BBB microfluidic model was used to interrogate mechanisms by which the spike protein may facilitate barrier dysfunction. The spike protein upregulated the expression of ACE2 in response to laminar shear stress. Moreover, interrogating the role of ACE2 showed that knock-down affected endothelial barrier properties. These results identify a possible role of ACE2 in barrier homeostasis. Analysis of RhoA, a key molecule in regulating endothelial cytoskeleton and tight junction complex dynamics, reveals that the spike protein triggers RhoA activation. Inhibition of RhoA with C3 transferase rescues its effect on tight junction disassembly. Overall, these results indicate a possible means by which the engagement of SARS-CoV-2 with ACE2 facilitates disruption of the BBB via RhoA activation. Understanding how SARS-CoV-2 dysregulates the BBB may lead to strategies to prevent the neurological deficits seen in COVID-19 patients.	todo
204	N200		Mona Khan Seung-Jun Yoo Marnick Clijsters Wout Backaert Arno Vanstapel Kato Speleman Charlotte Lietaer Sumin Choi Tyler D. Hether Lukas Marcelis Andrew Nam Liuliu Pan Jason W. Reeves Pauline Van Bulck Hai Zhou Marc Bourgeois Yves Debaveye Paul De Munter Jan Gunst Mark Jorissen Katrien Lagrou Natalie Lorent Arne Neyrinck Marijke Peetermans Dietmar Rudolf Thal Christophe Vandenbriele Joost Wauters Peter Mombaerts Laura Van Gerven	Visualizing in deceased COVID-19 patients how SARS-CoV-2 attacks the respiratory and olfactory mucosae but spares the olfactory bulb	https://doi.org/10.1016/j.cell.2021.10.027	Published	November 02, 2021	Study	https://www.cell.com/cell/fulltext/S0092-8674(21)01282-4	Highlights - Postmortem bedside surgical procedure was developed for COVID-19 and control patients - Ciliated cells are the main target cell type for SARS-CoV-2 in respiratory mucosa - Sustentacular cells (non-neuronal) are the main target cell type in olfactory mucosa - No evidence for infection of olfactory sensory neurons or olfactory bulb parenchyma
205	N201		Finja Schweitzer PhD,Yasemin Goereci MD,Christiana Franke MD,Steffi Silling PhD,Fabian Bösl MD,Franziska Maier PhD,Eva Heger PhD,Birgit Deiman PhD,Harald Prüss MD,Oezguer A. Onur MD,Florian Klein MD,Gereon Fink MD,Veronica Di Cristanziano MD,Clemens Warnke MD	CSF analysis in post-COVID-19 is not suggestive of persistent CNS infection	https://doi.org/10.1002/ana.26262	Published	01 November 2021	Brief Communication	https://onlinelibrary.wiley.com/doi/10.1002/ana.26262	Results Cerebrospinal fluid was assessed between day 1-30 (n=12), between day 31-90 (n=8), or later than 90 days (post-COVID-19, n=20) of COVID-19 diagnosis. SARS-CoV-2 RNA was absent in all patients, and in none of the 20 patients with post-COVID-19 syndrome intrathecally produced anti-SARS-CoV-2 antibodies were detected. Interpretation The absence of evidence of SARS-CoV-2 in cerebrospinal fluid argues against a persistent central nervous system infection as a cause of neurological or neuropsychiatric post-COVID-19 syndrome.
206	N202		O. A. Gromova, I. Yu. Torshin, V. A. Semenov, M. V. Putilina & A. G. Chuchalin	Direct and Indirect Neurological Signs of COVID-19	https://doi.org/10.1007/s11055-021-01144-9	Published	04 November 2021	Review	https://link.springer.com/article/10.1007%2Fs11055-021-01144-9	Results. A set of interactions between infection with SARS-CoV-2, metabolic impairments affecting neurotransmitters (acetylcholine, dopamine, serotonin, and GABA), enkephalins, and neurotrophins, micronutrients, chronic and acute inflammation, encephalopathy, cerebral ischemia, and neurodegeneration (including demyelination) was described. The most typical neurological manifestations of COVID-19 were anosmia/ageusia due to ischemia, neurodegeneration, and/or systematic increases in proinflammatory cytokine levels. COVID-19 provoked ischemic stroke, Guillain–Barré syndrome, polyneuropathy, encephalitis, meningitis, and parkinsonism. Coronavirus infection increased the severity of multiple sclerosis and myopathies. The possible roles of the human virome in the pathophysiology of COVID-19 are considered. A clinical case of a patient with neurological complications of COVID-19 is described. Conclusions. In the long-term perspective, COVID-19 promotes increases in neurodegenerative changes, which requires special neurological rehabilitation programs. Use of cholinergic drugs and antihypoxic agents compatible with COVID-19 therapy is advised.
207	N203		Bernhard Prem, David T. Liu, Gerold Besser, Gunjan Sharma, Laura E. Dultinger, Sissy V. Hofer, Martina M. Matiasczyk, Bertold Renner & Christian A. Mueller	Long-lasting olfactory dysfunction in COVID-19 patients	https://doi.org/10.1007/s00405-021-07153-1	Published	10 November 2021	Study	https://link.springer.com/article/10.1007/s00405-021-07153-1	Results After a mean 216 days (SD 73; range 111–457) between OD onset and follow-up testing, the mean Sniffin’ Sticks (TDI) score was 27.1 points (SD 5.8; range 4.25–38.5): 4.0% were anosmic, 72.5% hyposmic, and 23.5% normosmic. At follow-up testing, 73.5% of patients reported improvement, 5.9% deterioration, and 20.6% no change in OD. Moreover, full recovery of self-perceived smell, flavor, and taste was not observed. According to questionnaires, the individual importance of smell did not change, but participants showed improvement in OD-related quality of life (p < 0.001) and had increased parosmia scores (p = 0.014) at follow-up. Conclusion Our results show that long-lasting OD after SARS-CoV-2 infection is a common symptom. The majority of patients had OD in the range of hyposmia, which was confirmed by comprehensive smell tests.	todo
208	N204		Amish M. Khan, BS1; Dorina Kallogjeri, MD, MPH1,2; Jay F. Piccirillo	Growing Public Health Concern of COVID-19 Chronic Olfactory Dysfunction	http://jamanetwork.com/article.aspx?doi=10.1001/jamaoto.2021.3379	Published	November 18, 2021	Research Letter	https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2786433	Based on intermediate estimates, the number of US individuals expected to develop COD by August 2021 was 712 268. Based on low estimates for each event, the number of US individuals who are expected to develop COD is 170 238, and based on the highest estimate, the number is 1 600 241. Disorders estimated that, among US adults 40 years or older, measurable OD was found in up to 13.3 million adults.6 Notably, the age-specific prevalence of OD is 4.2% for individuals between age 40 to 49 years and 39.4% for individuals 80 years and older. The addition of 0.7 to 1.6 million new cases of COD represents a 5.3% to 12% relative increase. COVID-19 affects a younger demographic group than other causes of OD. Thus, the lifelong burden of OD will be much greater for the COVID-19 cohort than for patients in the older age groups. The true number of COD may be far higher than the results in this article indicate.
209	N205		Abdul Mannan Baig	Counting the neurological cost of COVID-19	https://doi.org/10.1038/s41582-021-00593-7	Published	18 November 2021	Article	https://www.nature.com/articles/s41582-021-00593-7	Unlike the oral cavity, the olfactory mucosa in the nose lacks lymphoid aggregates, and this feature could be exploited by SARS-CoV-2 to gain access to the CNS across the cribriform plate. En route to the CNS, SARS-CoV-2 seems to leave signatures in the form of traces of viral RNA and budding of virions from the cells in the olfactory epithelium, olfactory bulb and frontal lobe of the brain4,5,7. In addition, factors such as hypoxia, cerebral ischaemia and the cytokine storm might act together with the neurotrophic effects of SARS-CoV-2 to produce the neurological damage that is reported in COVID-19. With the ongoing COVID-19 pandemic, clusters of patients have emerged with symptoms that continue beyond the acute phase of the disease — a condition commonly known as ‘long COVID’8. A substantial proportion of these so-called ‘long-haulers’ have neurological manifestations, and there is an urgent need to address their health issues. A global consensus is needed on diagnostic approaches, management modalities and follow-up to ensure the well-being of long-haulers in general, and to address the neurological features of COVID-19 in particular9. Topical therapy with antiviral drugs and antibodies, administered via nebulizers and nasal sprays at the portal of entry of SARS-CoV-2, is expected to reduce viral loads and minimize the incidence of neurological complications10. In conclusion, the accumulating evidence on neurological sequelae in patients with COVID-19 is a cause for concern. Without proper care and treatment, patients with these neurological manifestations might be permanently debilitated. Moreover, the continuation of neurological symptoms in long COVID could overwhelm already fractured health-care systems. Consequently, we urgently need to understand and respond to the covert yet potentially incapacitating neurological consequences of COVID-19 in the acute and chronic phases of the disease.	todo
210	N206		Luigi Angelo Vaira, MD, Giovanni Salzano, MD, Serge Le Bon, MD, Angelantonio Maglio, MD, Marzia Petrocelli, MD, Younes Steffens, MD, Enrica Ligas, MSN, Fabio Maglitto, MD, Jerome R. Lechien, MD, PhD, Sven Saussez, MD, PhD, Alessandro Vatrella, MD, Francesco Antonio Salzano, MD, Paolo Boscolo-Rizzo, MD, Claire Hopkins, FRSC (ORLHNS), DM (Oxon), Giacomo De Riu	Prevalence of Persistent Olfactory Disorders in Patients With COVID-19: A Psychophysical Case-Control Study With 1-Year Follow-up	https://doi.org/10.1177%2F01945998211061511	Published	November 23, 2021	Study	https://journals.sagepub.com/doi/abs/10.1177/01945998211061511	The purpose of this multicenter case-control study was to evaluate a group of patients at least 1 year after coronavirus disease 2019 (COVID-19) with Sniffin’ Sticks tests and to compare the results with a control population to quantify the potential bias introduced by the underlying prevalence of olfactory dysfunction (OD) in the general population. The study included 170 cases and 170 controls. In the COVID-19 group, 26.5% of cases had OD (anosmia in 4.7%, hyposmia in 21.8%) versus 3.5% in the control group (6 cases of hyposmia). The TDI score (threshold, discrimination, and identification) in the COVID-19 group was significantly lower than in the control group (32.5 [interquartile range, 29-36.5] vs 36.75 [34-39.5], P < .001). The prevalence of OD was significantly higher in the COVID-19 group, confirming that this result is not due to the underlying prevalence of OD in the general population.	_
211	N207		SadafIftikharFCPSa1Aqeeb UrRehmanb1Muhammad ZainAmeerbAhmadNawazbMuhammadAemaz Ur RehmanMBBSaHareemFarooqMBBSaAbyazAsmarMBBSaMuhammadEbaad Ur Rehmanc	The association of posterior reversible encephalopathy syndrome with COVID-19: A systematic review	https://doi.org/10.1016/j.amsu.2021.103080	Published	20 November 2021	Review	https://www.sciencedirect.com/science/article/pii/S204908012101030X	Highlights •Posterior Reversible Encephalopathy Syndrome (PRES) is a neurological complication of COVID-19. •SARS-CoV-2 disrupts the integrity of cerebral blood vessels through cytokine storm, thus driving the edema of PRES. •COVID-19 is probably additive with hypertension, diabetes and tocilizumab in causing PRES. •Timely diagnosis and treatment are necessary to avoid complications such as cerebral hemorrhage, epilepsy and vision loss. •A favorable outcome is observed in most cases. After rigorous screening as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a total of 34 articles describing 56 cases were selected as a part of this review. The mean age of the patients was 56.6 ± 15.3 years. The most common clinical presentation of PRES was altered mental status (58.9%) followed by seizures (46.4%) and visual disturbances (23.2%) while hypertension and diabetes mellitus were the most commonly reported comorbidities. 91.1% of the cases reported Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) findings suggestive of PRES in the brain. Symptomatic management was employed in most of the cases to control seizures and blood pressure, and 44 patients (78.5%) fully or partially recovered. The most likely underlying mechanism involves COVID-19 mediated cytokine storm syndrome that leads to endothelial damage and increased permeability of the cerebral vessels, thus causing the characteristic edema of PRES. High neuronal and glial cell expression of Angiotensin Converting Enzyme-2 (ACE-2) receptors also suggests the possibility of direct viral damage. Since timely diagnosis and treatment reports a good prognosis, it is vital for physicians and neurologists to be well-versed with this association.	_
212	N208		Dandan Wan, Tingfu Du, Weiqi Hong, Li Chen, Haiying Que, Shuaiyao Lu & Xiaozhong Peng	Neurological complications and infection mechanism of SARS-COV-2	https://doi.org/10.1038/s41392-021-00818-7	Published	23 November 2021	Review	https://www.nature.com/articles/s41392-021-00818-7	In this review, we primarily describe the clinical neurological complications associated with SARS-CoV-2 and discuss the potential mechanisms through which SARS-CoV-2 invades the brain based on the current evidence. Finally, we summarize the experimental models were used to study SARS-CoV-2 neuroinvasion. These data form the basis for studies on the significance of SARS-CoV-2 infection in the brain.	todo
213	N209		Klaus J. Wirth, Carmen Scheibenbogen & Friedemann Paul	An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome	https://doi.org/10.1186/s12967-021-03143-3	Published	22 November 2021	Review	https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-021-03143-3	In this paper we deduce the pathomechanisms resulting in central nervous pathology and the myriad of neurocognitive symptoms. We outline tentative mechanisms of impaired cerebral blood flow, increase in intracranial pressure and central adrenergic hyperactivity and how they can well explain the key symptoms of cognitive impairment, brain fog, headache, hypersensitivity, sleep disturbances and dysautonomia.
214	N210		Thorsten Rudroff 1,2,* ,Craig D. Workman 1 andLaura L. Boles Ponto 3	18F-FDG-PET Imaging for Post-COVID-19 Brain and Skeletal Muscle Alterations	https://doi.org/10.3390/v13112283	Published	15 November 2021	Review	https://www.mdpi.com/1999-4915/13/11/2283/htm	Scientific evidence concerning the subacute and long-term effects of coronavirus disease 2019 (COVID-19) is on the rise. It has been established that infection by serious acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a systemic process that involves multiple organs. The complications and long-term consequences of COVID-19 are diverse and patients need a multidisciplinary treatment approach in the acute and post-acute stages of the disease. A significant proportion of COVID-19 patients experience neurological manifestations, some enduring for several months post-recovery. However, brain and skeletal muscle changes resultant from SARS CoV-2 infection remain largely unknown. Here, we provide a brief overview of the current knowledge, and usefulness, of [18F]fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) to investigate brain and skeletal muscles changes in Post-COVID-19 patients with persistent symptoms. Furthermore, a brief discussion of future 18F-FDG-PET/CT applications that might advance the current knowledge of the pathogenesis of post-COVID-19 is also provided.
215	N211		SadafIftikharFCPSa1Aqeeb UrRehmanb1Muhammad ZainAmeerbAhmadNawazbMuhammadAemaz Ur RehmanMBBSaHareemFarooqMBBSaAbyazAsmarMBBSaMuhammadEbaad Ur Rehmanc	The association of posterior reversible encephalopathy syndrome with COVID-19: A systematic review	https://doi.org/10.1016/j.amsu.2021.103080	Published	20 November 2021	Review	https://www.sciencedirect.com/science/article/pii/S204908012101030X	Highlights •Posterior Reversible Encephalopathy Syndrome (PRES) is a neurological complication of COVID-19. •SARS-CoV-2 disrupts the integrity of cerebral blood vessels through cytokine storm, thus driving the edema of PRES. •COVID-19 is probably additive with hypertension, diabetes and tocilizumab in causing PRES. •Timely diagnosis and treatment are necessary to avoid complications such as cerebral hemorrhage, epilepsy and vision loss. •A favorable outcome is observed in most cases. The most common clinical presentation of PRES was altered mental status (58.9%) followed by seizures (46.4%) and visual disturbances (23.2%) while hypertension and diabetes mellitus were the most commonly reported comorbidities. 91.1% of the cases reported Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) findings suggestive of PRES in the brain. Symptomatic management was employed in most of the cases to control seizures and blood pressure, and 44 patients (78.5%) fully or partially recovered. The most likely underlying mechanism involves COVID-19 mediated cytokine storm syndrome that leads to endothelial damage and increased permeability of the cerebral vessels, thus causing the characteristic edema of PRES. High neuronal and glial cell expression of Angiotensin Converting Enzyme-2 (ACE-2) receptors also suggests the possibility of direct viral damage. Since timely diagnosis and treatment reports a good prognosis, it is vital for physicians and neurologists to be well-versed with this association.	_
216	N212		Athanasia Pataka 1,* ,Seraphim Kotoulas 1 ,Elpitha Sakka 2,Paraskevi Katsaounou 3 andSofia Pappa 4,5	Sleep Dysfunction in COVID-19 Patients: Prevalence, Risk Factors, Mechanisms, and Management	https://doi.org/10.3390/jpm11111203	Published	14 November 2021	Review	https://www.mdpi.com/2075-4426/11/11/1203/htm	Evidence to date suggests that a considerable proportion of COVID-19 patients experience significant sleep disturbances (estimated to afflict up to 50–75%) as well as psychological distress such as depression, anxiety, and traumatic stress. Duration of hospitalization, pre-existing mental health concerns, lower absolute lymphocyte count, and increased neutrophil-to-lymphocyte ratio have been all associated with a greater risk of sleep dysfunction in infected and hospitalized patients. Furthermore, in this review, we discuss the link between sleep deprivation, susceptibility to viral infections, and psychosocial wellbeing in relevance to COVID-19 and summarize the existing evidence regarding the presence and role of sleep apnea in infected individuals. Finally, we highlight the importance of suitable interventions in order to prevent and manage sleep dysfunction and avoid long-term physical and psychological implications. Future research should aim to provide high-quality information including in high risk, underserved, or difficult to reach populations and on the long-term consequences and effectiveness of applied interventions.	_
217	N213		RayanKhaddaj-MallatacNatijaAldibabcMaximeBernardacAnne-SophiePaquetteacAymericFerreirabdSarahLecordieracArmenSaghatelyanbcLouisFlamandaeAymanElAliac	SARS-CoV-2 deregulates the vascular and immune functions of brain pericytes via Spike protein	https://doi.org/10.1016/j.nbd.2021.105561	Published	13 November 2021	Study	https://www.sciencedirect.com/science/article/pii/S0969996121003107	Using cell-based assays, we found that ACE2 expression in human brain vascular pericytes was increased upon S protein exposure. Pericytes exposed to S protein underwent profound phenotypic changes associated with an elongated and contracted morphology accompanied with an enhanced expression of contractile and myofibrogenic proteins, such as α-smooth muscle actin (α-SMA), fibronectin, collagen I, and neurogenic locus notch homolog protein-3 (NOTCH3). On the functional level, S protein exposure promoted the acquisition of calcium (Ca2+) signature of contractile ensheathing pericytes characterized by highly regular oscillatory Ca2+ fluctuations. Furthermore, S protein induced lipid peroxidation, oxidative and nitrosative stress in pericytes as well as triggered an immune reaction translated by activation of nuclear factor-kappa-B (NF-κB) signaling pathway, which was potentiated by hypoxia, a condition associated with vascular comorbidities that exacerbate COVID-19 pathogenesis. S protein exposure combined to hypoxia enhanced the production of pro-inflammatory cytokines involved in immune cell activation and trafficking, namely macrophage migration inhibitory factor (MIF). Using transgenic mice expressing the human ACE2 that recognizes S protein, we observed that the intranasal infection with SARS-CoV-2 rapidly induced hypoxic/ischemic-like pericyte reactivity in the brain of transgenic mice, accompanied with an increased vascular expression of ACE2. Moreover, we found that SARS-CoV-2 S protein accumulated in the intranasal cavity reached the brain of mice in which the nasal mucosa is deregulated. Collectively, these findings suggest that SARS-CoV-2 S protein impairs the vascular and immune regulatory functions of brain pericytes, which may account for vascular-mediated brain damage. Our study provides a better understanding for the mechanisms underlying cerebrovascular disorders in COVID-19, paving the way to develop new therapeutic interventions. Highlights •SARS-CoV-2 S protein increases ACE2 expression in brain pericytes. •ACE2+ brain pericytes adopt a contractile and myofibrogenic phenotype upon exposure to SARS-CoV-2 S protein. •Intracellular Ca2+ dynamics are altered in brain pericytes exposed to SARS-CoV-2 S protein. •SARS-CoV-2 S protein induces a potent inflammatory response in brain pericytes. •Hypoxia potentiates SARS-CoV-2 S protein mediated effects on brain pericytes. •SARS-CoV-2 infection induces an ischemic-like pericyte and vascular ACE2 reactivity in mice expressing human ACE2.	todo
218	N214		FlaviaMattiolia1SimonePivabe2ChiaraStampatoria1FrancescaRighettia1IlariaMegaa1ElenaPelib2EmmaSalacCesareTomasic2Anna MariaIndelicatoe3NicolaLatronicobde24GiuseppeDe Palmae34	Neurologic and cognitive sequelae after SARS-CoV2 infection: Different impairment for ICU patients	https://doi.org/10.1016/j.jns.2021.120061	Published	26 November 2021	Study	https://www.sciencedirect.com/science/article/abs/pii/S0022510X21027635	Highlights •Neurological and cognitive sequelae of COVID-19 in the long term are unknown. •Brain fog and memory deficits are frequently but not homogeneously reported by patients. •We compared neurological deficits and cognition in mild versus severe/critical COVID-19 (ICU) cases) after four months. •Neurological deficits and Cognitive Impairment were more frequent and severe in ICU cases. •PNS was prominently involved and executive functions were mostly impaired. Neurological deficits were found in 2/163 (1.2%) of non-ICU and in 7/52 (13.5%) of the ICU cases, all involving the peripheral nervous system. ICU patients performed significantly worse in all the neuropsychological tests and showed a worse age- and education-corrected cognitive impairment: Cognitive Impairment Index (CII) was higher in ICU than in non-ICU patients (median ICU 3 vs 2, p = .001).	_
219	N215		Philip Hunter	Viral diseases and the brain Long COVID puts the spotlight on how viral infections affect the brain	https://doi.org/10.15252/embr.202154342	Published	29 November 2021	Study	https://www.embopress.org/doi/full/10.15252/embr.202154342	This specific research has been boosted though in light of the long-term neurological effects of SARS-CoV-2 under the banner of Long COVID. Indeed, the pandemic is providing generally fresh insights into the link between viral infections, inflammation, and neurogenerative diseases like Alzheimer’s Disease (AD) and the underlying mechanisms and causes of symptoms such as fatigue or cognitive impairment.
220	N216		Amar D. Desai, MPH + Brian C. Boursiquot, MD + Catherine J. Moore, RN Rakesh Gopinathannair, MD Marc P. Waase, MD, PhD Geoffrey A. Rubin, MD Elaine Y. Wan, MD Show less Show footnotes	Autonomic dysfunction post-acute COVID-19 infection	https://doi.org/10.1016/j.hrcr.2021.11.019	Published	November 26, 2021	Study	https://www.heartrhythmcasereports.com/article/S2214-0271(21)00223-2/fulltext	In this small cohort of patients diagnosed with AD post-SARS-CoV-2 infection, a majority were women, and few had preexisting conditions, suggesting the unpredictability of developing AD after COVID-19 infection. Beta-blockers and vaccines both show efficacy in improving symptoms of suspected post-COVID AD. Further follow-up is necessary to assess efficacy of therapeutics, length of treatment, and time to recovery. Larger prospective studies with longer follow-up are needed to test efficacy of treatments for relief of AD symptoms following COVID-19. Lastly, as novel variants continue to arise, the impact of SARS-CoV-2 reinfection of previously infected individuals, including those with autonomic dysfunction following their first bout of the virus, should be performed to specifically evaluate the impact of reinfection on long-term sequelae like autonomic dysfunction. Key-Points: •AD post-SARS-CoV-2 infection affects primarily female patients without a clear history of pre-existing conditions •AD post-SARS-CoV-2 affects patients showed of a wide age distribution •Beta-blockers and vaccines show strong efficacy in improving symptoms of suspected post-COVID AD
221	N217		Amish M. Khan, BS1; Dorina Kallogjeri, MD, MPH1,2; Jay F. Piccirillo, MD1,3	Growing Public Health Concern of COVID-19 Chronic Olfactory Dysfunction	https://doi.org/10.1001/jamaoto.2021.3379	Published	November 18, 2021	Study	https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2786433	This analysis of new daily cases of COVID-19, acute incidence of OD, and rates of recovery suggest that more than 700 000, and possibly as many as 1.6 million, US individuals experience COD because of SARS-CoV-2. To put this number in context, before the COVID-19 pandemic, the National Institute on Deafness and Other Communication Disorders estimated that, among US adults 40 years or older, measurable OD was found in up to 13.3 million adults.6 Notably, the age-specific prevalence of OD is 4.2% for individuals between age 40 to 49 years and 39.4% for individuals 80 years and older. The addition of 0.7 to 1.6 million new cases of COD represents a 5.3% to 12% relative increase. COVID-19 affects a younger demographic group than other causes of OD. Thus, the lifelong burden of OD will be much greater for the COVID-19 cohort than for patients in the older age groups. The true number of COD may be far higher than the results in this article indicate.
222	N218		Jamoulle, Marc mailto [Université de Liège - ULiège > Département des sciences cliniques > Département des sciences cliniques >] Kazeneza-Mugisha, Gisele [] Zayane, Ayoub	Descriptive and narrative study of Long Covid cases in general practice and diagnostic value of brain scintigraphy		Published	10-déc-2021	Study	https://orbi.uliege.be/handle/2268/265876	In thirteen of the twenty one cases presented, brain scans (ECD Tc-99m) were able to demonstrate a severe disorder of cerebral perfusion. Two follow-up brain scans at three months showed significant improvement. In ten cases, laboratory evidence was lacking. Tissue antibody testing (B-cells) is expected. A patient who presents several months after a Covid with medically unexplained symptoms may well be a Long Covid. There is no known specific treatment. Neurocognitive revalidation and physiotherapy may help those patients who need long-term empathic support to cope with their condition.
223	N219		Antoine Verger, Aurélie Kas, Pierre Dudouet, François Goehringer, Dominique Salmon, Eric Guedj	Visual Interpretation of Brain Hypometabolisms Related to Neurological Long COVID: A French Multicentric Experience	https://doi.org/10.21203/rs.3.rs-1159513/v1	pre-print	20 Dec, 2021	SHORT REPORT	https://www.researchsquare.com/article/rs-1159513/v1	This multicenter study aims to provide a qualitative and consensual description of brain 18F-FDG PET images in patients with suspected neurological long COVID, regarding the previously reported pattern involving olfactory bulbs and other limbic/paralimbic regions, as well as the brainstem and cerebellum. Methods: From the beginning of August 2021 to the end of October 2021, brain 18F-FDG PET exams of patients referred for suspected neurological long COVID with positive reverse transcription polymerase chain reaction (RT-PCR) and/or serology for the SARS-CoV-2 infection were retrospectively reviewed in three French Nuclear Medicine departments. Experimented nuclear physicians from each department had to classify according to the same visual interpretation analysis brain 18F-FDG PET scans as being normal, mildly to moderate (incomplete or moderately hypometabolic), or severely affected within the previously reported long COVID hypometabolic pattern. Results: On the 143 brain 18F-FDG PET performed during this period 3 months, 53% of scans were visually interpreted as normal, 31% as mildly to moderate and 16% as severely affected according to the COVID hypometabolic pattern. Importantly, this specific hypometabolic pattern is reported as identical in the three Nuclear Medicine departments. Typical illustrative examples are provided to help nuclear physicians in the interpretation of long COVID pattern. Conclusion: The proposed PET metabolic pattern is easily identified at visual interpretation in clinical routine in part of patients with suspicion of neurological long COVID, requiring special consideration for fronto-basal paramedian regions, the brainstem and cerebellum.	todo
224	N220		Katarzyna Sklinda1,Andrzej Górecki2,Małgorzata Dorobek3,Jerzy Walecki1,Aneta Modrzyńska3,Bartosz Mruk	Ischemic background of brain fog in long haul COVID-19 – a nuclear magnetic resonance spectroscopy-based metabonomic analysis. Preliminary results	https://doi.org/10.5114/pjr.2021.111100	Published	2021/12/13	Original paper	http://www.polradiol.com/Ischemic-background-of-brain-fog-in-long-haul-COVID-19-a-nuclear-magnetic-resonance-spectroscopy-based-metabonomic-analysis-Preliminary-results,126,45699,1,1.html	A significantly higher concentration of Glx has been found in deep cerebral grey matter in patients suffering from brain fog, as shown in Figure 3, comparing to the metabolic status of a healthy volunteer, as shown in Figure 4. We extrapolate the knowledge of biochemical changes seen in stroke and recognize the metabolic features suggestive of cerebral hypoperfusion. As in stroke, the brain becomes low in energy substrates including glucose and oxygen, and resorts to anaerobic respiration. This leads to increased lactic acid, a byproduct of anaerobic glycolysis. Lactic acid has a negative impact on tissue metabolism and can potentially destroy cells [13,14]. In our case the lactic acid concentration was mildly reduced, which may be considered either as an effect of activation of mechanisms aiming on retrieval of intracellular homeostasis or as an error caused by the relatively small number of probes. The further cascade of cerebral injury is initiated when the energy production such as ATP fails, leading to failure of energy-dependent processes [13] and the release of excitatory neurotransmitters such as glutamate. It acts on receptors in neuronal cells and therefore produces an influx of calcium that activates enzymes that digest cellular proteins, lipids, and nuclear materials. Unlike in stroke, in brain fog the deterioration of cerebral function in limited. Macroscopic manifestation on neuronal disintegration of blood brain barrier was not seen in any of the cases. Lactates are not detectable under normal circumstances; however, in pathological conditions such as neoplasm, hypoxia, or ischaemia the Lac (lactates) are often detected. Glutamate (Glu) overlaps with glutamine (Gln), and they are detected as a Glx peak. It can be elevated in MS [15], liver failure, and Raye’s syndrome [16]. In the current study, we analysed consecutive MR brain imaging scans in patients with brain fog proceeding from 2 major regional COVID-19 hospitals and found that these 11 patients had a higher concentration of Glx and mild reduction of Lac in the deep grey matter of both cerebral hemispheres compared to healthy controls not suffering from brain fog. Brain fog remains a common long-term side effect of COVID-19 of unknown mechanism. A wide range of unspecific lingering symptoms and the impossibility to explain who will suffer from it and who will not point out the necessity of research into this matter. Taking into consideration our knowledge regarding cerebral manifestation of other viral infections, we anticipate a variety of possible scenarios. Brain fog is one of the long-covid symptoms occurring in all subpopulations of patients regardless of age, sex, severity of COVID-19, comorbidities, or vaccination status. There may be several explanations as to why MR spectroscopy did not show an increase of Glx/Cr ratio in every patient. First of all, the brain fog may linger for a non-defined period. Therefore, some patients might have undergone MRS in the recovery phase when the level of Glx was normalizing. Secondly, we performed SV MRS only and not MV MRS acquiring the signal from the voxel positioned in the basal ganglia. This may be a drawback if vascular changes would not distribute evenly showing a predilection to specific cerebral regions. Thirdly, MR spectroscopy is a very demanding imaging method, and the lack of consistent results in other patients may be caused by various reasons such as motion artifacts, lack of proper suppression of water signal, or magnetic field heterogeneity. Conclusions Following results along with clinical course of the brain for imply probable ischaemic background of symptoms.	todo
225	N221		Matthew G.FrankaKathy H.NguyenbJayson B.BallaShelbyHopkinsbTelKelleybMichael V.BarattaaMonikaFleshnerbSteven F.Maiera	SARS-CoV-2 spike S1 subunit induces neuroinflammatory, microglial and behavioral sickness responses: Evidence of PAMP-like properties	https://doi.org/10.1016/j.bbi.2021.12.007	Published	13 December 2021	Study	https://www.sciencedirect.com/science/article/pii/S0889159121006383	Highlights •The SARS-CoV-2 spike S1 subunit induces sickness behavior. •S1 induces a subacute (24 h) and chronic (7d) neuroinflammatory response. •S1 directly induces a proinflammatory response in primary microglia. •S1 activates TLR2 and TLR4 signaling in vitro. •S1 might function as a pathogen-associated molecular pattern. Here, we explore the novel hypothesis that a structural protein (S1) derived from SARS-CoV-2 functions as a pathogen-associated molecular pattern (PAMP) to induce neuroinflammatory processes independent of viral infection. Prior evidence suggests that the S1 subunit of the SARS-CoV-2 spike protein is inflammatory in vitro and signals through the pattern recognition receptor TLR4. Therefore, we examined whether the S1 subunit is sufficient to drive 1) a behavioral sickness response, 2) a neuroinflammatory response, 3) direct activation of microglia in vitro, and 4) activation of transgenic human TLR2 and TLR4 HEK293 cells. Adult male Sprague-Dawley rats were injected intra-cisterna magna (ICM) with vehicle or S1. In-cage behavioral monitoring (8 h post-ICM) demonstrated that S1 reduced several behaviors, including total activity, self-grooming, and wall-rearing. S1 also increased social avoidance in the juvenile social exploration test (24 h post-ICM). S1 increased and/or modulated neuroimmune gene expression (Iba1, Cd11b, MhcIIα, Cd200r1, Gfap, Tlr2, Tlr4, Nlrp3, Il1b, Hmgb1) and protein levels (IFNγ, IL-1β, TNF, CXCL1, IL-2, IL-10), which varied across brain regions (hypothalamus, hippocampus, and frontal cortex) and time (24 h and 7d) post-S1 treatment. Direct exposure of microglia to S1 resulted in increased gene expression (Il1b, Il6, Tnf, Nlrp3) and protein levels (IL-1β, IL-6, TNF, CXCL1, IL-10). S1 also activated TLR2 and TLR4 receptor signaling in HEK293 transgenic cells. Taken together, these findings suggest that structural proteins derived from SARS-CoV-2 might function independently as PAMPs to induce neuroinflammatory processes via pattern recognition receptor engagement.	todo
226	N222		F.J.Carod-Artala1J.C.García-Moncób1	Epidemiology, pathophysiology, and classification of the neurological symptoms of post-COVID-19 syndromeEpidemiología, fisiopatología y clasificación de los síntomas neurológicos post-COVID	https://doi.org/10.1016/j.neurop.2021.07.005	Published	14 December 2021	Review	https://www.sciencedirect.com/science/article/pii/S2667049621000612	Results Patients with history of COVID-19 have been found to present persistent neurological symptoms, including cognitive complaints, memory and concentration problems, headache, anosmia, ageusia, vertigo, and insomnia. Post-COVID-19 syndrome is a heterogeneous disease that lacks a universally accepted definition, which may explain the great variability in the estimated prevalence (2.3%–85%) and symptom duration. The criteria differentiating post-COVID-19 syndrome from chronic fatigue syndrome or critical illness syndrome are ambiguous. Risk factors include older age, female sex, certain comorbidities, and greater number of symptoms in the acute phase. The pathophysiology of the syndrome is largely unknown, although it is probably multifactorial, including immunological mechanisms, neural network dysfunction, neurotransmitter alterations, persistent viral damage, and functional impairment. Conclusions Post-COVID-19 syndrome may present after mild or even asymptomatic SARS-CoV-2 infection, causing limitations in activities of daily living and in quality of life. Further research will clarify the origin and most appropriate management of these neurological alterations.	_
227	N223		Oscar H. Del Brutto,Denisse A. Rumbea,Bettsy Y. Recalde,Robertino M. Mera	Cognitive sequelae of long COVID may not be permanent. A prospective study	https://doi.org/10.1111/ene.15215	Published	16 December 2021	Short Communication	https://onlinelibrary.wiley.com/doi/abs/10.1111/ene.15215	Cognitive performance was evaluated by means of the Montreal Cognitive Assessment (MoCA) in COVID-19 survivors and non-infected individuals. All study participants had four cognitive evaluations, two of them before the pandemic and the other two, six and 18 months after the initial SARS-CoV-2 outbreak infection in the village. Linear mixed effects models for longitudinal data were fitted to assess differences in cognitive performance across COVID-19 survivors and non-infected individuals. Results The study included 78 participants, 50 with history of mild COVID-19 and 28 without. There was a significant – likely age-related – decline in MoCA scores between the two pre-pandemic tests (β: -1.53; 95% C.I.: -2.14 to -0.92; p<0.001), which did not differ across individuals who later developed COVID-19 when compared to non-infected individuals. Six months after infection, only COVID-19 survivors had a significant decline in MoCA scores (β: -1.37; 95% C.I.: -2.14 to -0.61; p<0.001), which reversed after one additional year of follow-up (β: 0.66; 95% C.I.: -0.11 to 1.42; p=0.092). No differences were noticed among non-infected individuals when both post-pandemic MoCA scores were compared. Conclusion Study results suggest that long COVID-related cognitive decline may spontaneously improve over time.	_
228	N224		Enric Vidal, Carlos López-Figueroa, Jordi Rodon, Mónica Pérez, Marco Brustolin, Guillermo Cantero, Víctor Guallar, Nuria Izquierdo-Useros, Jorge Carrillo, Julià Blanco, Bonaventura Clotet, Júlia Vergara-Alert, Joaquim Segalés	Chronological brain lesions after SARS-CoV-2 infection in hACE2-transgenic mice	https://doi.org/10.1177%2F03009858211066841	Published	December 27, 2021	Study	https://journals.sagepub.com/doi/10.1177/03009858211066841	Wild-type mice are minimally susceptible to certain SARS-CoV-2 lineages (beta and gamma variants), whereas hACE2-transgenic mice succumb to SARS-CoV-2 and develop a fatal neurological disease. In this article, we aimed to chronologically characterize SARS-CoV-2 neuroinvasion and neuropathology. Necropsies were performed at different time points, and the brain and olfactory mucosa were processed for histopathological analysis. SARS-CoV-2 virological assays including immunohistochemistry were performed along with a panel of antibodies to assess neuroinflammation. At 6 to 7 days post inoculation (dpi), brain lesions were characterized by nonsuppurative meningoencephalitis and diffuse astrogliosis and microgliosis. Vasculitis and thrombosis were also present and associated with occasional microhemorrhages and spongiosis. Moreover, there was vacuolar degeneration of virus-infected neurons. At 2 dpi, SARS-CoV-2 immunolabeling was only found in the olfactory mucosa, but at 4 dpi intraneuronal virus immunolabeling had already reached most of the brain areas. Maximal distribution of the virus was observed throughout the brain at 6 to 7 dpi except for the cerebellum, which was mostly spared. Our results suggest an early entry of the virus through the olfactory mucosa and a rapid interneuronal spread of the virus leading to acute encephalitis and neuronal damage in this mouse model.	todo
229	N225		FeliciaCebanabSusanLingadLeanna M.W.LuiaYenaLeeacHartejGillaKayla M.TeopizaNelson B.RodriguesaMehalaSubramaniapillaiaJoshua D.Di VincenzoadBingCaoeKangguangLinfgRodrigo B.MansurahRoger C.HoijJoshua D.RosenblatadhKamilla W.MiskowiakklMajVinbergmnVladimirMaleticoRoger S.McIntyreabcdh	Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis	https://doi.org/10.1016/j.bbi.2021.12.020	Published	29 December 2021	Study	https://www.sciencedirect.com/science/article/pii/S0889159121006516	Highlights •Fatigue and cognitive impairment are amongst the most common and debilitating symptoms of post-COVID-19 syndrome. •Approximately 1 in 3 individuals experienced fatigue 12 or more weeks following COVID-19 diagnosis. •Approximately 1 in 5 individuals exhibited cognitive impairment 12 or more weeks following COVID-19 diagnosis. •There was an elevation in proinflammatory markers and functional impairment in a subset of post-COVID individuals. Results The literature search yielded 10,979 studies, and 81 studies were selected for inclusion. The fatigue meta-analysis comprised 68 studies, the cognitive impairment meta-analysis comprised 43 studies, and 48 studies were included in the narrative synthesis. Meta-analysis revealed that the proportion of individuals experiencing fatigue 12 or more weeks following COVID-19 diagnosis was 0.32 (95% CI, 0.27, 0.37; p < 0.001; n = 25,268; I2 = 99.1%). The proportion of individuals exhibiting cognitive impairment was 0.22 (95% CI, 0.17, 0.28; p < 0.001; n = 13,232; I2 = 98.0). Moreover, narrative synthesis revealed elevations in proinflammatory markers and considerable functional impairment in a subset of individuals. Conclusions & relevance A significant proportion of individuals experience persistent fatigue and/or cognitive impairment following resolution of acute COVID-19. The frequency and debilitating nature of the foregoing symptoms provides the impetus to characterize the underlying neurobiological substrates and how to best treat these phenomena.
230	N226		Masud Husain	COVID and the brain	https://doi.org/10.1093/brain/awab421	Published	31 December 2021	Editorial	https://academic.oup.com/brain/article/144/12/3545/6491307	In terms of brain syndromes, it is now evident that COVID is associated with a higher risk of encephalopathy, encephalitis, stroke—ischaemic, haemorrhagic and venous—as well as a subsequent diagnosis of dementia,2,3 although the latter might well be due to be an uncovering of pre-existing cognitive decline. It is also becoming clear that these neurological consequences are much more common following SARS-CoV-2 infection than post-vaccination,3-5 which had been an initial concern particularly following descriptions of cerebral venous thrombosis cases earlier in the year. Psychiatric manifestations such as anxiety and depression are even more frequent after SARS-CoV-2 infection,6 and a particular concern that remains to be properly characterized are the symptoms of so-called ‘long COVID’. The authors then conducted a series of investigations that led them to conclude that one of the SARS-CoV-2 proteases cleaves NEMO (nuclear factor-κΒ essential modulator), which plays a key role in cell survival and prevents apoptosis. Ablation of NEMO in brain blood vessel endothelial cells produced microvascular pathology similar to that in the brains of infected individuals. However, this could be prevented by deleting a specific protein kinase involved in regulating cell death, Ripk3. Together, these observations suggest that an important way in which SARS-CoV-2 might trigger brain changes is via an attack on the endothelium, causing microvascular injury which, in turn, might affect blood–brain barrier integrity and microvascular perfusion. The experiments on NEMO also suggest a potential way to stop such injury occurring. These mechanisms might not be brain specific; SARS-CoV-2 might also mediate injury to other organs via endothelial damage. Clearly though we have a long way to go to understand the multitude effects of COVID on the brain, and why some people seem to be more vulnerable than others. Systemic effects including those of cytokines and other inflammatory mediators might also play a crucial role. Nevertheless, the signs are extremely encouraging that so much progress has been made in this area in such a short time.	todo
231	N227		Ilona Merikanto,Yves Dauvilliers,Frances Chung,Brigitte Holzinger,Luigi De Gennaro,Yun Kwok Wing,Maria Korman,Markku Partinen	Disturbances in sleep, circadian rhythms and daytime functioning in relation to coronavirus infection and Long-COVID – A multinational ICOSS study	https://doi.org/10.1111/jsr.13542	Published	28 December 2021	Study	https://onlinelibrary.wiley.com/doi/10.1111/jsr.13542	To the best of our knowledge, there is no other large-scale multinational sleep study targeting the general population regarding the role of sleep and circadian rhythms along with a variety of psychological, biological, social and economic aspects considered in relation to COVID-19 disease infection risk, severity or Long-COVID. Systematic reviews and cohort studies on the frequency and variety of persistent COVID-19 symptoms indicate that sleep problems and disorders, such as sleep difficulties and insomnia, can be high among COVID-19 patients (Lopez-Leon et al., 2021; Nalbandian, Sehgal, & Gupta, 2021). It is, however, unknown whether different sleep, circadian rhythm, daytime functioning and psychological factors have a role in COVID disease risk and prognosis, and the long-term consequences of the infection, or if there are reciprocal relationships between COVID disease prognosis and development of Long-COVID and sleep disorders. It is plausible that the neurotropic nature of the SARS-CoV-2 infection includes similar peripheral nerve pathways to the central nervous system as Middle East respiratory syndrome (MERS-CoV) and SARS-CoV-1 (Zubair et al., 2020), which also affect sleep, dreaming and daytime functioning (Boldrini et al., 2021; Lam, Wing, & Yu, 2009; Rogers et al., 2021; Zubair et al., 2020). Furthermore, the suggested shared pathways between sleep, dreaming, daytime functioning and SARS-CoV-2 infection leading to Long-COVID can have potential neurodegenerative propensity related to, for example, RBD, parkinsonism and dementia (Brundin, Nath, & Beckham, 2020; Taquet et al., 2021). In a recent polysomnography study, REM sleep without atonia was more prevalent among COVID-19 patients than is usual in general population samples (Heidbreder, Sonnweber, & Stefani, 2021). Furthermore, olfactory impairment is common among patients with RBD (Ross et al., 2008) similarly as among COVID-19 patients (Xydakis, Albers, & Holbrook, 2021).
232	N228		Seshagiri Veerapaneni,Mukaila Raji	COVID-19 and cognitive impairment in the elderly: A literature review	https://doi.org/10.1002/alz.055584	Published	31 December 2021	Review	https://alz-journals.onlinelibrary.wiley.com/doi/abs/10.1002/alz.055584	Based on evidence gathered from scientific literature, this review raises a possibility of nervous system involvement in COVID-19 with progression to dementia or worsening of existing Dementia especially in the elderly patients. Longitudinal neurological assessments of patients after recovery will be crucial in understanding the natural History of COVID-19 in the CNS and monitoring for potential neurologic sequalae and long-term effects on causation and worsening of dementia. The literature review also states the need to start investigating the mechanistic link between Alzheimer's disease and COVID-19 for further follow up.
233	N229		C. (Linda) M. C. van Campen 1,* ,Peter C. Rowe 2 andFrans C. Visser 1	Orthostatic Symptoms and Reductions in Cerebral Blood Flow in Long-Haul COVID-19 Patients: Similarities with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome	https://doi.org/10.3390/medicina58010028	Published	24 December 2021	Study	https://www.mdpi.com/1648-9144/58/1/28/htm	To investigate the overlap in these clinical phenotypes, we compared orthostatic symptoms in daily life and during head-up tilt, heart rate and blood pressure responses to tilt, and reductions in cerebral blood flow in response to orthostatic stress in long-haul COVID-19 patients, ME/CFS controls, and healthy controls. Materials and Methods: We compared 10 consecutive long-haul COVID-19 cases with 20 age- and gender-matched ME/CFS controls with postural tachycardia syndrome (POTS) during head-up tilt, 20 age- and gender-matched ME/CFS controls with a normal heart rate and blood pressure response to head-up tilt, and 10 age- and gender-matched healthy controls. Identical symptom questionnaires and tilt test procedures were used for all groups, including measurement of cerebral blood flow and cardiac index during the orthostatic stress. Results: There were no significant differences in ME/CFS symptom prevalence between the long-haul COVID-19 patients and the ME/CFS patients. All long-haul COVID-19 patients developed POTS during tilt. Cerebral blood flow and cardiac index were more significantly reduced in the three patient groups compared with the healthy controls. Cardiac index reduction was not different between the three patient groups. The cerebral blood flow reduction was larger in the long-haul COVID-19 patients compared with the ME/CFS patients with a normal heart rate and blood pressure response. Conclusions: The symptoms of long-haul COVID-19 are similar to those of ME/CFS patients, as is the response to tilt testing. Cerebral blood flow and cardiac index reductions during tilt were more severely impaired than in many patients with ME/CFS. The finding of early-onset orthostatic intolerance symptoms, and the high pre-illness physical activity level of the long-haul COVID-19 patients, makes it unlikely that POTS in this group is due to deconditioning. These data suggest that similar to SARS-CoV-1, SARS-CoV-2 infection acts as a trigger for the development of ME/CFS.
234	N230		Natalia A. Shnayder 1,2,* ,Timur K. Sirbiladze 1,* ,Irina V. Demko 2,Marina M. Petrova 2 andRegina F. Nasyrova 1,3	Limbic Encephalitis Associated with COVID-19	https://doi.org/10.3390/encyclopedia2010003	Published	22 December 2021	Review	https://www.mdpi.com/2673-8392/2/1/3/htm	An interesting fact is that in most patients with SARS-CoV-2, serological tests on autoimmune panels, including autoantibodies against intracellular, synaptic and surface antigens previously described in LE of a different etiology, were negative [21]. According to this fact, some authors consider the development of SARS-CoV-2-associated para-infectious LE caused by secondary hyperinflammatory syndrome with a massive release of proinflammatory cytokines and chemokines in the limbic system of the brain [21,57,58]. Taken together, these facts explain the scientific and clinical interest in studying the role of pro-inflammatory cytokines, including interleukin-1-beta (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), in the development of para-infectious LE associated with SARS-CoV-2, as overexpression of these cytokines has been described in previous studies of drug resistant para-infectious temporal lobe epilepsy [59,60,61,62,63] and also in cognitive disorders including shot-term and long-term memory [64] and Alzheimer’s type dementia [65]. However, the high tropism of SARS-CoV-2 to the structures of the limbic system of the brain, with the possibility of isolated lesions of these areas in children and adults without respiratory symptoms of COVID-19, and the high number of new cases of this infection in population worldwide indicates the importance of this interdisciplinary problem in neurology and psychiatry. In addition, the development of an autoimmune process in the CNS is also possible after the respiratory symptoms was resolved, as the long-term consequence in patients with the pulmonary form of COVID-19. In patients with a high risk of developing para-infectious LE associated with SARS-CoV-2, the diagnostic algorithm in the acute and subacute periods should include analysis of CSF, EEG monitoring and brain MRI. In patients with asymptomatic or mild COVID-19 (without respiratory symptoms) and long-term consequences of COVID-19 (long-COVID-19), the diagnostic algorithm should include neuropsychological testing, brain MRI, EEG and serological testing (evaluating the pro-inflammatory cytokines and antibodies to SARS-CoV-2 IgG). This algorithm can help in the risk assessment and early diagnosis of para-infectious LE associated with SARS-CoV-2; moreover, it gives information for consideration in treatment planning. An important but controversial issue is the acceptability of revaccination against COVID-19 in patients with high risk of developing para-infectious LE or patients with this disease.
235	N231		Yuda Turana 1,*,† ,Michael Nathaniel 1,† ,Robert Shen 1,† ,Soegianto Ali 1 andRajender R. Aparasu 2	Citicoline and COVID-19-Related Cognitive and Other Neurologic Complications	https://doi.org/10.3390/brainsci12010059	Published	31 December 2021	Review	https://www.mdpi.com/2076-3425/12/1/59/htm	With growing concerns about COVID-19’s hyperinflammatory condition and its potentially damaging impact on the neurovascular system, there is a need to consider potential treatment options for managing short- and long-term effects on neurological complications, especially cognitive function. While maintaining adequate structure and function of phospholipid in brain cells, citicoline, identical to the natural metabolite phospholipid phosphatidylcholine precursor, can contribute to a variety of neurological diseases and hypothetically toward post-COVID-19 cognitive effects. In this review, we comprehensively describe in detail the potential citicoline mechanisms as adjunctive therapy and prevention of COVID-19-related cognitive decline and other neurologic complications through citicoline properties of anti-inflammation, anti-viral, neuroprotection, neurorestorative, and acetylcholine neurotransmitter synthesis, and provide a recommendation for future clinical trials.
236	N232		Anthony Fernandez-Castaneda, Peiwen Lu, Anna C Geraghty, Eric Song, Myoung-Hwa Lee, Jamie Wood, Belgin Yalcin, Kathryn R Taylor, Selena Dutton, Lehi Acosta-Alvarez, Lijun Ni, Daniel Contreras-Esquivel, Jeffrey R Gehlhausen, Jon Klein, Carolina Lucas, Tianyang Mao, Julio Silva, Mario Pena-Hernandez, Alexandra Tabachnikova, Takehiro Takahashi, Laura Tabacof, Jenna Tosto-Mancuso, Erica Breyman, Amy Kontorovich, Dayna McCarthy, Martha Quezado, Marco Hefti, Daniel Perl, Rebecca Folkerth, David Putrino, Avindra Nath, Akiko Iwasaki, Michelle Monje	Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain	https://doi.org/10.1101/2022.01.07.475453	pre-print	January 10, 2022	Study	https://www.biorxiv.org/content/10.1101/2022.01.07.475453v1	Neuroinflammation, particularly microglial reactivity and consequent dysregulation of hippocampal neurogenesis and oligodendrocyte lineage cells, is central to CRCI. We hypothesized that similar cellular mechanisms may contribute to the persistent neurological symptoms associated with even mild SARS-CoV-2 respiratory infection. Here, we explored neuroinflammation caused by mild respiratory SARS-CoV-2 infection, without neuroinvasion, and effects on hippocampal neurogenesis and the oligodendroglial lineage. Using a mouse model of mild respiratory SARS-CoV-2 infection induced by intranasal SARS-CoV-2 delivery, we found white matter-selective microglial reactivity, a pattern observed in CRCI. Human brain tissue from 9 individuals with COVID-19 or SARS-CoV-2 infection exhibits the same pattern of prominent white matter-selective microglial reactivity. In mice, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7-weeks post-infection; among the chemokines demonstrating persistent elevation is CCL11, which is associated with impairments in neurogenesis and cognitive function. Humans experiencing long-COVID with cognitive symptoms (48 subjects) similarly demonstrate elevated CCL11 levels compared to those with long-COVID who lack cognitive symptoms (15 subjects). Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss in subcortical white matter were evident at 1 week, and persisted until at least 7 weeks, following mild respiratory SARS-CoV-2 infection in mice. Taken together, the findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and after SARS-CoV-2 infection, and elucidate cellular deficits that may contribute to lasting neurological symptoms following even mild SARS-CoV-2 infection.
237	N233		Mirren Charnley, Saba Islam, Guneet Bindra, Jeremy Engwirda, Julian Ratcliffe, Jiangtao Zhou, Raffaele Mezzenga, Mark Hulett, Kyunghoon Han, Joshua Berryman, Nicholas Reynolds	Neurotoxic Amyloidogenic Peptides in the Proteome of SARS-COV2: Potential Implications for Neurological Symptoms in COVID-19	https://doi.org/10.21203/rs.3.rs-1201481/v1	pre-print	07 Jan, 2022	Study	https://www.researchsquare.com/article/rs-1201481/v1	However, neurological symptoms such as memory loss, sensory confusion, cognitive and psychiatric issues, severe headaches, and even stroke are reported in as many as 30% of cases and can persist even after the infection is over (so-called ‘long COVID’). These neurological symptoms are thought to be caused by brain inflammation, caused by the virus infecting the central nervous system of COVID-19 patients, however we still don’t understand the molecular mechanisms that trigger these symptoms. The neurological effects of COVID-19 share many similarities to neurodegenerative diseases such as Alzheimer’s and Parkinson’s in which the presence of cytotoxic protein-based amyloid aggregates is a common etiological feature. Following the hypothesis that some neurological symptoms of COVID-19 may also follow an amyloid etiology we performed a bioinformatic scan of the SARS-CoV-2 proteome, detecting peptide fragments that were predicted to be highly amyloidogenic. We selected two of these peptides from the open reading frame 6 (ORF6) and open reading frame 10 (ORF10) proteins. The amyloidogenic virus-derived proteins studied in this work did not include spike (S) protein or any other proteins that have been modified to function as antigens in any current vaccines. We discovered that these ORF protein fragments rapidly self-assemble into amyloid aggregates. Furthermore, these amyloid assemblies were shown to be highly toxic to a neuronal cell line. We introduce and support the idea that cytotoxic amyloid aggregates of SARS-CoV-2 proteins are causing some of the neurological symptoms commonly found in COVID-19 and contributing to long COVID.
238	N234		Viviana Cristillo, Andrea Pilotto, Stefano Cotti Piccinelli, Giulio Bonzi, Antonio Canale, Stefano Gipponi, Michela Bezzi, Matilde Leonardi, Alessandro Padovani & the Neuro Covid Next Study group	Premorbid vulnerability and disease severity impact on Long-COVID cognitive impairment	https://doi.org/10.1007/s40520-021-02042-3	Published	11 January 2022	Study	https://link.springer.com/article/10.1007/s40520-021-02042-3	Results Abnormal MoCA scores at 6 months follow-up were associated with higher pre-hospitalization National Health System (NHS) score (Duca et al. in Emerg Med Pract 22:1–2, 2020) (OR 1.27; 95% CI 1.05–1.6; p = 0.029) and more severe pulmonary disease expressed by the Brescia-COVID Respiratory Severity Scale (Duca et al. in Emerg Med Pract 22:1–2, 2020) (BCRSS > 1OR 4.73; 95% CI 1.53–14.63; p = 0.003) during the acute phase of the disease. Discussion This longitudinal study showed that the severity of COVID-19, indicated by BCRSS, and a complex score given by age and premorbid medical conditions, expressed by NHS, play a major role in modulating the long-term cognitive consequences of COVID-19 disease. Conclusions These findings indicate that the association of age and premorbid factors might identify people at risk for long-term neurological consequences of COVID-19 disease, thus deserving longer and proper follow-up.
239	N235		Peerapon Kiatkittikul, Chetsadaporn Promteangtrong, Anchisa Kunawudhi, Dheeratama Siripongsatian, Taweegrit Siripongboonsitti, Piyanuj Ruckpanich, Supachoke Thongdonpua, Attapon Jantarato, Chaiyawat Piboonvorawong, Nirawan Fonghoi & Chanisa Chotipanich	Abnormality Pattern of F-18 FDG PET Whole Body with Functional MRI Brain in Post-Acute COVID-19	https://doi.org/10.1007/s13139-021-00730-6	Published	15 January 2022	Study	https://link.springer.com/article/10.1007%2Fs13139-021-00730-6	We retrospectively recruited 13 patients with post-acute COVID-19. The post-acute COVID-19 symptoms and neuropsychiatric tests were performed before F-18 FDG PET/CT whole body with PET/rsfMRI brain. Qualitative and semiquantitative analyses were also conducted in both whole body and brain images. Results Among the 13 patients, 8 (61.5%) had myositis, followed by 8 (61.5%) with vasculitis (mainly in the thoracic aorta), and 7 (53.8%) with lung abnormalities.. Interestingly, one patient with a very high serum RBD IgG antibody demonstrated diffuse myositis throughout the body which potentially associated with immune-mediated myositis. One patient experienced psoriasis exacerbation with autoimmune-mediated after COVID-19. Most patients had multiple areas of abnormal brain connectivity involving the frontal and parieto-temporo-occipital lobes, as well as the thalamus. Conclusion The whole body F-18 FDG PET can be a potential tool to assess inflammatory process and support the hyperinflammatory etiology, mainly for lesions in skeletal muscle, vascular wall, and lung, as well as, multiple brain abnormalities in post-acute COVID-19. Nonetheless, further studies are recommended to confirm the results.
240	N236		Sijia Zhao, Kengo Shibata, Peter J. Hellyer, William Trender, Sanjay Manohar, Adam Hampshire, Masud Husain	Rapid vigilance and episodic memory decrements in COVID-19 survivors	https://doi.org/10.1093/braincomms/fcab295	Published	19 January 2022	Study	https://academic.oup.com/braincomms/article/4/1/fcab295/6511053	In the months following acute illness, many more suffer from fatigue, low motivation, disturbed mood, poor sleep and cognitive symptoms, colloquially referred to as ‘brain fog’. But what about individuals who had asymptomatic to moderate COVID-19 and reported no concerns after recovering from COVID-19? Here, we examined a wide range of cognitive functions critical for daily life (including sustained attention, memory, motor control, planning, semantic reasoning, mental rotation and spatial–visual attention) in people who had previously suffered from COVID-19 but were not significantly different from a control group on self-reported fatigue, forgetfulness, sleep abnormality, motivation, depression, anxiety and personality profile. Reassuringly, COVID-19 survivors performed well in most abilities tested, including working memory, executive function, planning and mental rotation. However, they displayed significantly worse episodic memory (up to 6 months post-infection) and greater decline in vigilance with time on task (for up to 9 months). Overall, the results show that specific chronic cognitive changes following COVID-19 are evident on objective testing even amongst those who do not report a greater symptom burden. Importantly, in the sample tested here, these were not significantly different from normal after 6–9 months, demonstrating evidence of recovery over time.
241	N237		Leonard B. Weinstock, MD, FACG, Jill B. Brook, MA, Arthur S. Walters, MD, Ashleigh Goris, RN, BSN, MPH, CIC, FAPIC, Lawrence B. Afrin, MD, Gerhard J. Molderings, MD	Restless legs syndrome is associated with long-COVID in women	https://doi.org/10.5664/jcsm.9898	Published	January 25, 2022	Study	https://jcsm.aasm.org/doi/abs/10.5664/jcsm.9898	STUDY OBJECTIVES: Sleep disturbance is common in long-COVID (LC). Restless legs syndrome (RLS) is characterized by sleep disturbance and has been reported after viral infections. Therefore, we evaluated RLS symptoms cross-sectionally in individuals with LC at both current and pre-COVID19 timepoints. METHODS: LC-focused Facebook adults were recruited for an online assessment of symptoms before COVID-19 infection and during their present LC state in a cross-sectional manner. The LC group documented baseline symptoms retrospectively. Questions were included about the presence/severity of RLS symptoms and assessments of fatigue, quality of life, and sleep apnea. A control group was recruited and included individuals ≥18 years of age who never had overt symptoms of COVID-19. Pregnancy was exclusion criteria for both groups. RESULTS: There were 136 LC participants (89.7% females, age 46.9 ±12.9 years) and 136 controls (65.4% females, age 49.2 ±15.5). RLS prevalence in LC-females was 5.7% pre-COVID-19 and 14.8% post-COVID-19 (p<0.01) vs. 6.7% in control-females. Severity of RLS was moderate in both groups. Logistic regression predicting post-COVID-19 RLS among LC-females failed to find significant effects of hospitalization, sleep apnea, neuropathic pain severity or use of antihistamines and antidepressants. CONCLUSIONS: The baseline prevalence of RLS in LC-females was similar to the general population group as well as to patients in epidemiological studies. The prevalence significantly increased in the LC state. Post-infectious immunological mechanisms may be at play in the production for RLS symptoms.
242	N238		AthinaSamara12EricHerlenius12PatrickO’ Brien34AsmaKhalil567	Potential role of neurofilament in COVID-19 and preeclampsia	https://doi.org/10.1016/j.xcrm.2021.100490	Published	18 January 2022	Commentary	https://www.sciencedirect.com/science/article/pii/S2666379121003670	Neurofilament light (NFL) is a promising circulating biomarker in preeclampsia and COVID-19, even without evident neurological complications. Several pathways might contribute to the elevated serum NFL levels seen in both pathologies. Future studies will determine whether NFL is a long COVID marker and delineate NFL’s role in COVID-19-associated preeclampsia.
243	N239		Fatemeh Sadat Mirfazeli, Atiye Sarabi-Jamab, Victor Pereira-Sanchez, Alireza Kordi, Behnam Shariati, Seyed Vahid Shariat, Salar Bahrami, Shabnam Nohesara, Mostafa Almasi-Dooghaee & Seyed Hamid Reza Faiz	Chronic fatigue syndrome and cognitive deficit are associated with acute-phase neuropsychiatric manifestations of COVID-19: A 9-month follow-up study	https://doi.org/10.1007/s10072-021-05786-y	Published	21 January 2022	Study	https://link.springer.com/article/10.1007/s10072-021-05786-y	The prevalence of long-COVID symptoms is rising but it is not still possible to predict which patients will present them, and which types of symptoms they will present. We followed up 95 patients with confirmed COVID-19 for 9 months to identify and characterize long-COVID symptoms. Easy fatigability was the most common symptom (51.04%), followed by anxiety (38.54%), dyspnea (38.54%), and new-onset headache (38.54%). There was no association between COVID-19 severity in the acute phase and the number of long-COVID symptoms (F(1,93) = 0.75, p = 0.45), and cognitive function (MoCA) scores (F(1,90) = 0.073, p = 0.787) at follow-up. Being female (F(1,92) = − 2.27, p = 0.02), having a higher number of symptoms (F(1,93) = 2.76, p = 0.0068), and experiencing constitutional neuropsychiatric symptoms (F(1,93) = 2.529, p = 0.01) in the acute phase were associated with having chronic fatigue syndrome at follow-up. Moreover, constitutional neuropsychiatric symptoms in the acute phase were associated with a lower MoCA score (F(1,93) = 10.84, p = 0.001) at follow-up. Specific clinical presentations such as constitutional neuropsychiatric symptoms in the acute phase might be predictors of debilitating long-COVID symptoms such as chronic fatigue syndrome and cognitive deficits.
244	N240		Stéphane Kremer, Simonetta Gerevini, Ana Ramos, François Lersy, Tarek Yousry, Meike W. Vernooij, Nicoletta Anzalone & Hans Rolf Jäger	Neuroimaging in patients with COVID-19: a neuroradiology expert group consensus	https://doi.org/10.1007/s00330-021-08499-0	Published	19 January 2022	Article	https://link.springer.com/article/10.1007/s00330-021-08499-0	Neurological and neuroradiological manifestations in patients with COVID-19 have been extensively reported. Available imaging data are, however, very heterogeneous. Hence, there is a growing need to standardise clinical indications for neuroimaging, MRI acquisition protocols, and necessity of follow-up examinations. A NeuroCovid working group with experts in the field of neuroimaging in COVID-19 has been constituted under the aegis of the Subspecialty Committee on Diagnostic Neuroradiology of the European Society of Neuroradiology (ESNR). The initial objectives of this NeuroCovid working group are to address the standardisation of the imaging in patients with neurological manifestations of COVID-19 and to give advice based on expert opinion with the aim of improving the quality of patient care and ensure high quality of any future clinical studies. Key Points • In patients with COVID-19 and neurological manifestations, neuroimaging should be performed in order to detect underlying causal pathology. • The basic MRI recommended protocol includes T2-weighted, FLAIR (preferably 3D), and diffusion-weighted images, as well as haemorrhage-sensitive sequence (preferably SWI), and at least for the initial investigation pre and post-contrast T1 weighted-images. • 3D FLAIR should be acquired after gadolinium administration in order to optimise the detection of leptomeningeal contrast enhancement.
245	N241		Shivam Bhola, Jhillika Trisal, Vikram Thakur, Parneet Kaur, Saurabh Kulshrestha, Shashi Kant Bhatia & Pradeep Kumar	Neurological toll of COVID-19	https://doi.org/10.1007/s10072-022-05875-6	Published	16 January 2022	Review	https://link.springer.com/article/10.1007/s10072-022-05875-6	The review is focused on the manifestation of various neurological disorders linked with both the central nervous system and peripheral nervous system. Disorders such as cytokine release syndrome, encephalitis, acute stroke, and Bell’s palsy are given specific attention and psychological manifestations are also investigated. For a clear conclusion, cognitive impairment, drug addiction disorders, mood and anxiety disorders, and post-traumatic stress disorder are all fully examined. The association of the SARS-CoV-2 with neurological disorders and pathway is yet to be clear. For better understanding, the explanation of the possible mechanism of viral infection influencing the nervous system is also attempted in the review. While several vaccines and drugs are already involved in treating the SARS-CoV-2 condition, the disease is still considered fatal and more likely to leave permanent neurological damage, which leads to an essential requirement for more research to explore the neurological toll of the COVID-19 disease.
246	N242		LaShyra T. Nolen, Shibani S. Mukerji & Nicte I. Mejia	Post-acute neurological consequences of COVID-19: an unequal burden	https://doi.org/10.1038/s41591-021-01647-5	Published	17 January 2022	Comment	https://www.nature.com/articles/s41591-021-01647-5	Our world has witnessed over 275 million confirmed cases of COVID-19 and over 5 million related deaths1. Marginalized communities everywhere continue to be disproportionately affected as the pandemic amplifies longstanding health and healthcare disparities. As an example, in the United States, members of the Black, Indigenous and Latino communities remain two to three times more likely to be infected with SARS-CoV-2, to be hospitalized with COVID-19 and to die from this disease2. Dismantling structural racism is necessary to improve neurological health, as greater attention is focused on understanding and addressing the post-acute neurological consequences of COVID-19, or the neurological manifestations of what is sometimes called long COVID.
247	N243		Alexandra C. Apple,Alexis Oddi,Michael J. Peluso,Breton M. Asken,Timothy J. Henrich,J. Daniel Kelly,Samuel J. Pleasure,Steven G. Deeks,Isabel Elaine Allen,Jeffrey N. Martin,Lishomwa C. Ndhlovu,Bruce L. Miller,Melanie L. Stephens,Joanna Hellmuth … See fewer authors	Risk factors and abnormal cerebrospinal fluid associate with cognitive symptoms after mild COVID-19	https://doi.org/10.1002/acn3.51498	Published	19 January 2022	Study	https://onlinelibrary.wiley.com/doi/full/10.1002/acn3.51498	Cognitive post-acute sequelae of SARS-CoV-2 (PASC) can occur after mild COVID-19. Detailed clinical characterizations may inform pathogenesis. We evaluated 22 adults reporting cognitive PASC and 10 not reporting cognitive symptoms after mild SARS-CoV-2 infection through structured interviews, neuropsychological testing, and optional cerebrospinal fluid (CSF) evaluations (53%). Delayed onset of cognitive PASC occurred in 43% and associated with younger age. Cognitive PASC participants had a higher number of pre-existing cognitive risk factors (2.5 vs. 0; p = 0.03) and higher proportion with abnormal CSF findings (77% vs. 0%; p = 0.01) versus controls. Cognitive risk factors and immunologic mechanisms may contribute to cognitive PASC pathogenesis.
248	N244		Saab C, Valsamis H, Baki S, Leung J, Ghosn S, Lapin B, Chari G, Rasheed I, Park J, Punia V, Nair D, Kaniecki AM, Edhi M	SARS-CoV-2 Slows Brain Rhythms with more Severe Effects in Younger Individuals	https://doi.org/10.21203/rs.3.rs-1197196/v1	pre-print	12 Jan 2022	Study	https://europepmc.org/article/ppr/ppr441883	In a previous study, we developed a computational pipeline for the automated, rapid, high-throughput and objective analysis of brain encephalography (EEG) rhythms. In this retrospective study, we used this pipeline to define the quantitative EEG changes in patients with a PCR-positive diagnosis of C19 (n=31) in the intensive care unit (ICU) of Cleveland Clinic, compared to a group of age-matched PCR-negative (n=38) control patients in the same ICU setting. Qualitative assessment of EEG by two independent teams of electroencephalographers confirmed prior reports with regards to the high prevalence of diffuse encephalopathy in C19 patients, although the diagnosis of encephalopathy was inconsistent between teams. Quantitative analysis of EEG showed distinct slowing of brain rhythms in C19 patients compared to control (enhanced delta power and attenuated alpha-beta power). Surprisingly, these C19-related changes in EEG power were more prominent in patients below age 70. Moreover, machine learning algorithms showed consistently higher accuracy in the binary classification of patients as C19 versus control using EEG power for subjects below age 70 compared to older ones, providing further evidence for the more severe impact of SARS-CoV-2 on brain rhythms in younger individuals irrespective of PCR diagnosis or symptomatology, and raising concerns over potential long-term effects of C19 on brain physiology in the adult population and the utility of EEG monitoring in C19 patients.
249	N245		Akshamal M. Gamage, Kai Sen Tan, Wharton O. Y. Chan, Zhe Zhang Ryan Lew, Jing Liu, Chee Wah Tan, Deepa Rajagopalan, , Quy Xiao Xuan Lin, Le Min Tan, Prasanna Nori Venkatesh, Yew Kwang Ong, Mark Thong, Raymond Tzer Pin Lin, Shyam Prabhakar, De Yun Wang entwdy@nus.edu.sg, Lin-Fa Wang	Human Nasal Epithelial Cells Sustain Persistent SARS-CoV-2 Infection In Vitro, despite Eliciting a Prolonged Antiviral Response	https://doi.org/10.1128/mbio.03436-21	Published	18 January 2022	Study	https://journals.asm.org/doi/10.1128/mbio.03436-21	In this study, the long-term dynamics of SARS-CoV-2 infection were investigated using a human well-differentiated nasal epithelial cell (NEC) model of infection. NECs were observed to release SARS-CoV-2 virus onto the apical surface for up to 28 days postinfection (dpi), further corroborated by viral antigen staining. Single-cell transcriptome sequencing (sc-seq) was utilized to explore the host response from infected NECs after short-term (3-dpi) and long-term (28-dpi) infection. We identified a unique population of cells harboring high viral loads present at both 3 and 28 dpi, characterized by expression of cell stress-related genes DDIT3 and ATF3 and enriched for genes involved in tumor necrosis factor alpha (TNF-α) signaling and apoptosis. Remarkably, this sc-seq analysis revealed an antiviral gene signature within all NEC cell types even at 28 dpi. We demonstrate increased replication of basal cells, absence of widespread cell death within the epithelial monolayer, and the ability of SARS-CoV-2 to replicate despite a continuous interferon response as factors likely contributing to SARS-CoV-2 persistence. This study provides a model system for development of therapeutics aimed at improving viral clearance in immunocompromised patients and implies a crucial role for immune cells in mediating viral clearance from infected epithelia. IMPORTANCE Increasing medical attention has been drawn to the persistence of symptoms (long-COVID syndrome) or live virus shedding from subsets of COVID-19 patients weeks to months after the initial onset of symptoms. In vitro approaches to model viral or symptom persistence are needed to fully dissect the complex and likely varied mechanisms underlying these clinical observations. We show that in vitro differentiated human NECs are persistently infected with SARS-CoV-2 for up to 28 dpi. This viral replication occurred despite the presence of an antiviral gene signature across all NEC cell types even at 28 dpi. This indicates that epithelial cell intrinsic antiviral responses are insufficient for the clearance of SARS-CoV-2, implying an essential role for tissue-resident and infiltrating immune cells for eventual viral clearance from infected airway tissue in COVID-19 patients.
250	N246		Yuda Turana 1,*,† ,Michael Nathaniel 1,† ,Robert Shen 1,† ,Soegianto Ali 1 andRajender R. Aparasu 2	Citicoline and COVID-19-Related Cognitive and Other Neurologic Complications	https://doi.org/10.3390/brainsci12010059	Published	31 December 2021	Study	https://www.mdpi.com/2076-3425/12/1/59/htm	With growing concerns about COVID-19’s hyperinflammatory condition and its potentially damaging impact on the neurovascular system, there is a need to consider potential treatment options for managing short- and long-term effects on neurological complications, especially cognitive function. While maintaining adequate structure and function of phospholipid in brain cells, citicoline, identical to the natural metabolite phospholipid phosphatidylcholine precursor, can contribute to a variety of neurological diseases and hypothetically toward post-COVID-19 cognitive effects. In this review, we comprehensively describe in detail the potential citicoline mechanisms as adjunctive therapy and prevention of COVID-19-related cognitive decline and other neurologic complications through citicoline properties of anti-inflammation, anti-viral, neuroprotection, neurorestorative, and acetylcholine neurotransmitter synthesis, and provide a recommendation for future clinical trials.
251	N247		Natalia A. Shnayder 1,2,* ,Timur K. Sirbiladze 1,* ,Irina V. Demko 2,Marina M. Petrova 2 andRegina F. Nasyrova 1,3	Limbic Encephalitis Associated with COVID-19	https://doi.org/10.3390/encyclopedia2010003	Published	22 December 2021	Review	https://www.mdpi.com/2673-8392/2/1/3/htm	Concluding, we should mention that the number of publications dedicated to para-infectious LE associated with SARS-CoV-2 is currently limited. However, the high tropism of SARS-CoV-2 to the structures of the limbic system of the brain, with the possibility of isolated lesions of these areas in children and adults without respiratory symptoms of COVID-19, and the high number of new cases of this infection in population worldwide indicates the importance of this interdisciplinary problem in neurology and psychiatry. In addition, the development of an autoimmune process in the CNS is also possible after the respiratory symptoms was resolved, as the long-term consequence in patients with the pulmonary form of COVID-19. In patients with a high risk of developing para-infectious LE associated with SARS-CoV-2, the diagnostic algorithm in the acute and subacute periods should include analysis of CSF, EEG monitoring and brain MRI. In patients with asymptomatic or mild COVID-19 (without respiratory symptoms) and long-term consequences of COVID-19 (long-COVID-19), the diagnostic algorithm should include neuropsychological testing, brain MRI, EEG and serological testing (evaluating the pro-inflammatory cytokines and antibodies to SARS-CoV-2 IgG). This algorithm can help in the risk assessment and early diagnosis of para-infectious LE associated with SARS-CoV-2; moreover, it gives information for consideration in treatment planning. An important but controversial issue is the acceptability of revaccination against COVID-19 in patients with high risk of developing para-infectious LE or patients with this disease.
252	N248		Arianna Di Stadio 1,*,†,Michael J. Brenner 2 ,Pietro De Luca 3 ,Maria Albanese 4 ,Luca D’Ascanio 5 ,Massimo Ralli 6 ,Dalila Roccamatisi 7,Cristina Cingolani 5,Federica Vitelli 5,Angelo Camaioni 8,Stefano Di Girolamo 9 andEvanthia Bernitsas 10,†	Olfactory Dysfunction, Headache, and Mental Clouding in Adults with Long-COVID-19: What Is the Link between Cognition and Olfaction? A Cross-Sectional Study	https://doi.org/10.3390/brainsci12020154	Published	24 January 2022	Study	https://www.mdpi.com/2076-3425/12/2/154/htm	We investigated mental clouding, headache, and cognitive function in adult patients with persistent COVID-19 olfactory dysfunction. This multi-center cross-sectional study enrolled 152 adults with self-reported olfactory dysfunction from 3 tertiary centers specialized in COVID-19 olfactory disorders. Inclusion criteria were smell alterations after COVID-19 persisting over 6 months from infection, age >18 and < 65. Exclusion criteria included smell alterations, headache, or memory problems prior to COVID-19 infection. The patients were evaluated by olfactometry, nasal endoscopy, headache scale, cognitive assessment, Mini Mental State Examination (MMSE), and self-reported measures. Smell dysfunction was stratified and classified based on olfactory deficit severity and presence of olfactory distortion (parosmia, cacosmia). Data on smell disorder, mental clouding, MMSE, and headache were analyzed to assess correlations. Among the 152 patients studied, 50 (32.8%) presented with anosmia, 25 (16.4%) with hyposmia, 10 (6.6%) with parosmia/cacosmia, and 58 patients (38.2%) with a combination of hyposmia and parosmia; seven (4.6%) patients suffered from headache exclusively, and two (1.4%) had headache and mental clouding as their primary symptom. Headache was reported by 76 (50%) patients, and mental clouding by 71 (46.7%). The patients reporting headache, mental clouding, or both, had significantly increased risk of suffering from anosmia and/or hyposmia when compared with their counterparts without these neurological symptoms. No patients had reduced MMSE scores. In our cohort of adult patients with post-COVID-19, smell alterations persisting over 6 months, cognitive impairment and headache were associated with more severe olfactory loss, consistent with neuroinflammatory mechanisms mediating a variety of Long-COVID symptoms.
253	N249		MariannaZazhytska1∗AlbanaKodra12∗Daisy A.Hoagland3JustinFrere314John F.Fullard456HaniShayya12Natalie G.McArthur8RasmusMoeller3SkylerUhl3Arina D.Omer7Max E.Gottesman13StuartFirestein8QizhiGong9Peter D.Canoll10James E.Goldman10PanosRoussos45611Benjamin R.tenOever314#Jonathan B.Overdevest12#StavrosLomvardas113#&	Non-cell autonomous disruption of nuclear architecture as a potential cause of COVID-19 induced anosmia	https://doi.org/10.1016/j.cell.2022.01.024	Published	2 February 2022	Study	https://www.sciencedirect.com/science/article/pii/S0092867422001350	Highlights •Downregulation of odor detection pathways may explain COVID-19 induced anosmia. •SARS-CoV-2 mediated disruption of nuclear architecture may impair odor detection. •SARS-CoV-2 mediated nuclear reorganization is non-cell autonomous. SARS-CoV-2 infects less than 1% of cells in the human body, yet it can cause severe damage in a variety of organs. Thus, deciphering the non-cell autonomous effects of SARS-CoV-2 infection is imperative for understanding the cellular and molecular disruption it elicits. Neurological and cognitive defects are among the least understood symptoms of COVID-19 patients, with olfactory dysfunction being their most common sensory deficit. Here, we show that both in humans and hamsters SARS-CoV-2 infection causes widespread downregulation of olfactory receptors (OR) and of their signaling components. This non-cell autonomous effect is preceded by a dramatic reorganization of the neuronal nuclear architecture, which results in dissipation of genomic compartments harboring OR genes. Our data provide a potential mechanism by which SARS-CoV-2 infection alters the cellular morphology and the transcriptome of cells it cannot infect, offering insight to its systemic effects in olfaction and beyond.	Dans une étude publiée dans Cell, des chercheurs expliquent, par des modèles sur l'humain et sur le hamster, que l'infection par le SRAS-CoV-2 peut entraîner une régulation négative généralisée des récepteurs olfactifs et de leurs composants de signalisation. Ils notent que cet effet non cellulaire autonome est précédé d'une réorganisation spectaculaire de l'architecture nucléaire neuronale, entraînant la dissipation des compartiments génomiques abritant les gènes des récepteurs olfactifs. Cette présentation fournit un mécanisme potentiel par lequel l'infection du virus modifie la morphologie cellulaire et le transcriptome des cellules qu'elle ne peut pas infecter, à même d'expliquer les troubles persistants olfactifs. Selon cette équipe américaine, ces déficits à long terme de l'architecture nucléaire pourraient être applicables à d'autres d'autres populations neuronales (et donc à même d'expliquer d'autres symptômes neurologiques du covid long), puisque les neurones adultes du système nerveux central assemblent également des compartiments génomiques cis et trans à longue portée entre les gènes des récepteurs olfactifs et d'autres familles de gènes neuronaux.
254	N250	Care	Kamini Krishnan, YuFang Lin, Kia-Rai M. Prewitt & Dawn A. Potter	Multidisciplinary Approach to Brain Fog and Related Persisting Symptoms Post COVID-19	https://doi.org/10.1007/s42843-022-00056-7	Published	02 February 2022	Article	https://link.springer.com/article/10.1007/s42843-022-00056-7	A third of patients who developed COVID-19 experience a persisting, diverse array of symptoms including respiratory, neurological, and psychiatric complaints referred to as post-acute sequelae of COVID-19 (PASC). Symptoms can last for months after the original infection and appear unrelated to the severity of the initial illness, which suggests that even patients who did not require extensive interventions at the acute stage may experience new and/or long-term symptoms. Brain fog is a colloquial term for a common complaint among patients with PASC and generally implies cognitive impairment in domains of attention and processing speed. There are multiple hypotheses for etiologies and explanations of mechanisms contributing to brain fog in PASC. In this paper, we describe some of the mechanisms associated with brain fog post COVID-19 and provide readers with treatment recommendations that encompass cognition, mood disorders, sleep disorders, and neuroinflammation.
255	N251		Kamen A Tsvetanov, Lennart R B Spindler, View ProfileEmmanuel A Stamatakis, Virginia FJ Newcombe, Victoria C Lupson, Doris A Chatfield, Anne E Manktelow, Joanne G Outtrim, Anne Elmer, Nathalie Kingston, John R Bradley, View ProfileEdward T Bullmore, View ProfileJames B Rowe, David K Menon	Hospitalisation for COVID-19 predicts long lasting cerebrovascular impairment: A prospective observational cohort study	https://doi.org/10.1101/2022.02.01.22270235	Published	February 02, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.02.01.22270235v1.full-text	Human coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has multiple neurological consequences, but its long-term effect on brain health is still uncertain. The cerebrovascular consequences of COVID-19 may also affect brain health. Here we assess cerebrovascular health in 45 hospitalised patients using the resting state fluctuation amplitudes (RSFA) from functional magnetic resonance imaging, in relation to disease severity and in contrast with 42 controls. Widespread changes in frontoparietal RSFA were related to the severity of the acute COVID-19 episode, as indexed by COVID-19 WHO Progression Scale, inflammatory and coagulatory biomarkers. This relationship was not explained by chronic cardiorespiratory dysfunction, age, or sex. Exploratory analysis suggests that the level of cerebrovascular dysfunction is associated with cognitive, mental, and physical health at follow-up. The principal findings were consistent across univariate and multivariate approaches. The results indicate chronic cerebrovascular impairment following severe acute COVID-19, with the potential for long-term consequences on cognitive function and mental wellbeing.
256	N252		George B Stefano 1, Pascal Büttiker 1, Simon Weissenberger 1, Radek Ptacek 1, Fuzhou Wang 2, Tobias Esch 3, Thomas V Bilfinger 4, Richard M Kream 1	Biomedical Perspectives of Acute and Chronic Neurological and Neuropsychiatric Sequelae of COVID-19	https://doi.org/10.2174/1570159x20666211223130228	Published	2021 Dec 23	Review	https://pubmed.ncbi.nlm.nih.gov/34951387/	The incidence of infections from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent for coronavirus disease 2019 (COVID-19), has dramatically escalated following the initial outbreak in China in late 2019, resulting in a global pandemic with millions of deaths. Although the majority of infected patients survive, and the rapid advent and deployment of vaccines have afforded increased immunity against SARS-CoV-2, long term sequelae of SARS-CoV-2 infection have become increasingly recognized. These include, but are not limited to, chronic pulmonary disease, cardiovascular disorders, and proinflammatory-associated neurological dysfunction that may lead to psychological and neurocognitive impairment. A major component of cognitive dysfunction is operationally categorized as "brain fog" which comprises difficulty with concentration, forgetfulness, confusion, depression, and fatigue. Multiple parameters associated with long-term neuropsychiatric sequelae of SARS-CoV-2 infection have been detailed in clinical studies. Empirically elucidated mechanisms associated with the neuropsychiatric manifestations of COVID-19 are by nature complex, but broad based working models have focused on mitochondrial dysregulation leading to systemic reductions of metabolic activity and cellular bioenergetics within CNS structures. Multiple factors underlying the expression of brain fog may facilitate future pathogenic insults leading to repetitive cycles of viral and bacterial propagation. Interestingly, diverse neurocognitive sequelae associated with COVID-19 are not dissimilar from those observed in other historical pandemics, thereby providing a broad and integrative perspective on potential common mechanisms of CNS dysfunction subsequent to viral infection. Poor mental health status may be reciprocally linked to compromised immune processes and enhanced susceptibility to infection by diverse pathogens. By extrapolation, we contend that COVID-19 may potentiate the severity of neurological/neurocognitive deficits in patients afflicted by well-studied neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Accordingly, the prevention, diagnosis, and management of sustained neuropsychiatric manifestations of COVID-19 are pivotal health care directives and provide a compelling rationale for careful monitoring of infected patients, as early mitigation efforts may reduce short- and long-term complications.
257	N253		Kamini Krishnan, Ashley K Miller, Katherine Reiter, Aaron Bonner-Jackson	Neurocognitive Profiles in Patients With Persisting Cognitive Symptoms Associated With COVID-19	https://doi.org/10.1093/arclin/acac004	Published	05 February 2022	Study	https://academic.oup.com/acn/advance-article/doi/10.1093/arclin/acac004/6522998?login=true	A subset of individuals with coronavirus disease 2019 (COVID-19) appears to develop persisting cognitive and medical symptoms. Research in the acute stages of illness, generally utilizing cognitive screening measures or case reports, suggests presence of deficits in attention and executive function. This observational study investigated cognitive functioning among individuals with persistent cognitive complaints about 5.5 months after COVID-19 infection. Methods Patients with polymerase chain reaction confirmed COVID-19 and persistent cognitive complaints underwent comprehensive in-person neuropsychological evaluations. Patients with prior neurological disorders were excluded. When diagnosed, 40% required hospitalization, 15% were in an intensive care unit, 10% needed mechanical ventilation, and 10% experienced delirium. Results This sample was predominately women (90%), White non-Hispanic (70%), with average education of 15 years. Mild cognitive deficits were seen on tests involving attention and processing speed or executive function. Seventy percent of patients were diagnosed with a mood disorder prior to COVID-19 infection. At the time of testing, 35%–40% endorsed moderate to severe mood symptoms and 85% noted significant fatigue as measured by the Fatigue Severity Scale. Conclusions The pattern of cognitive deficits, although mild, is consistent with prior research at the acute stage of the illness. These findings suggest that psychological factors and other persisting symptoms (e.g., sleep, fatigue) may play a significant role in subjective cognitive complaints in patients with persisting complaints post COVID-19 who did not require intensive treatment. These patients would likely benefit from resources to manage persisting or new mood symptoms and compensatory strategies for the cognitive inefficiencies they experience.
258	N254		JessicaHamzelou	What covid-19 does to the brain	https://doi.org/10.1016/S0262-4079(22)00130-0	Published	31 January 2022	Review	https://www.sciencedirect.com/science/article/pii/S0262407922001300?via%3Dihub	OVER the past two years, we have learned that covid-19 can have profound consequences for the brain – in the short and long term. Now, researchers are starting to get a clearer picture of how the coronavirus may cause symptoms that include brain fog, depression, confusion and even stroke. The latest insights suggest that the virus seldom infects brain cells directly, but instead causes harm through blood clots or by spurring a destructive immune response. Encouragingly, many of the effects caused by harmful immune changes are likely to be reversible.
259	N255		Paola Ortelli,Davide Ferrazzoli,Luca Sebastianelli,Roberto Maestri,Sabrina Dezi,Danny Spampinato,Leopold Saltuari,Alessia Alibardi,Michael Engl,Markus Kofler,Angelo Quartarone,Giacomo Koch,Antonio Oliviero,Viviana Versace	Altered motor cortex physiology and dysexecutive syndrome in patients with fatigue and cognitive difficulties after mild COVID-19	https://doi.org/10.1111/ene.15278	Published	09 February 2022	Study	https://onlinelibrary.wiley.com/doi/abs/10.1111/ene.15278	Methods We enrolled 67 patients complaining of fatigue and/or cognitive difficulties after resolution of mild SARS-CoV-2 infection and 22 healthy controls (HC). Persistent clinical symptoms were investigated by means of a 16-item questionnaire. Fatigue, exertion, cognitive difficulties, mood and “well-being” were evaluated through self-administered tools. Utilizing transcranial magnetic stimulation of the primary motor cortex (M1) we evaluated resting motor threshold (RMT), motor evoked potential (MEP) amplitude, cortical silent period (SP) duration, short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), long-interval intracortical inhibition (LICI), and short-latency afferent inhibition (SAI). Global cognition and executive functions were assessed with screening tests. Attention was measured with computerized tasks. Results Post COVID-19 patients reported a mean of 4.9 persistent symptoms, high levels of fatigue, exertion, cognitive difficulties, low levels of well-being and depressive symptoms. Compared to HC, patients presented higher RMTs, lower MEP amplitudes and longer SPs, concurring with reduced M1 excitability. LICI and SAI were also impaired, indicating altered GABAB- and cholinergic neurotransmission. SICI and ICF were not affected. Patients also showed poorer global cognition and executive functions as compared to HC and a clear impairment in sustained and executive attention. Conclusions Patients with fatigue and cognitive difficulties following mild COVID-19 present altered excitability and neurotransmission within M1 and deficits in executive functions and attention.
260	N256		Richard J Smeyne, View ProfileJeffrey Eells, View ProfileDebotri Chatterjee, View ProfileMatthew Byrne, View ProfileShaw M. Akula, View ProfileSrinivas Sriramula, View ProfileDorcas P. O’Rourke, View ProfilePeter Schmidt	COVID-19 infection enhances susceptibility to oxidative-stress induced parkinsonism	https://doi.org/10.1101/2022.02.02.478719	pre-print	February 03, 2022	Study	https://www.biorxiv.org/content/10.1101/2022.02.02.478719v1.full	Background Viral induction of neurological syndromes has been a concern since parkinsonian-like features were observed in patients diagnosed with encephalitis lethargica subsequent to the 1918 influenza pandemic. Given the similarities in the systemic responses following SARS-CoV-2 infection with those observed after pandemic influenza, there is a question if a similar syndrome of post-encephalic parkinsonism could follow COVID-19 infection. Objectives To determine if prior infection with SARS-CoV-2 increased sensitivity to a mitochondrial toxin known to induce parkinsonism. Methods hACE2 mice were infected with SARS-CoV-2 to induce mild to moderate disease. After 31 days recovery, mice were administered a non-lesion inducing dose of the parkinsonian toxin MPTP. Subsequent neuroinflammation and SNpc dopaminergic neuron loss was determined and compared to SARS-CoV-2 or MPTP alone. Results hACE2 mice infected with SARS-CoV-2 or MPTP showed no SNpc DA neuron loss following MPTP. In mice infected and recovered from SARS-CoV-2 infection, MPTP induced a 23% or 19% greater loss of SNpc dopaminergic neurons than SARS-CoV-2 or MPTP, respectively (p□<□0.05). Examination of microglial activation showed a significant increase in the number of activated microglia in the SARS-CoV-2 + MPTP group compared to SARS-CoV-2 or MPTP alone. Conclusions Our observations have important implications for long-term public health, given the number of people that have survived SARS-CoV-2 infection as well as for future public policy regarding infection mitigation. However, it will be critical to determine if other agents known to increase risk of PD also have synergistic effects with SARS-CoV-2 and if are abrogated by vaccination.
261	N257		Nizama Salihefendic, 1 Muharem Zildzic, 2 and Haris Huseinagic 3	Ischemic Vasculitis as a Cause of Brain Disorder’s in Patients with Long Covid: Case Report	https://dx.doi.org/10.5455%2Fmedarh.2021.75.471-474	Published	2021 Dec	Case Report	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8810149/	Objective: The aim of this article is to describe 2 young adults who developed neuropsychiatric symptoms in the course of Long COVID-19 syndrome. Ischemic vasculitis was proved using CT imaging. Case report: We collected data of two younger females who had previously recovered from the acute form of COVID-19 without respiratory complications. They developed in the next 1-2 months a clinical picture of a brain disorder. In both cases, CT and angiography scans of the brain showed signs of ischemic vasculitis. Neurological therapy has led to an improvement of the neuropsychiatric symptoms. Conclusion: Neuropsychiatric disorders in Long Covid syndrome are common and diverse. Two cases of young adults who developed signs of neurological disorder in the post COVID-19 period were presented, and CT scans of the brain showed signs of ischemic vasculitis.
262	N258	ES	Steve Reiken,Leah Sittenfeld,Haikel Dridi,Yang Liu,Xiaoping Liu,Andrew R. Marks	Alzheimer's-like signaling in brains of COVID-19 patients	https://doi.org/10.1002/alz.12558	Published	03 February 2022	Study	https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12558	Methods Brain lysates from control and COVID-19 patients were analyzed for oxidative stress and inflammatory signaling pathway markers, and measurements of Alzheimer’s disease (AD)-linked signaling biochemistry. Post-translational modifications of the ryanodine receptor/calcium (Ca2+) release channels (RyR) on the endoplasmic reticuli (ER), known to be linked to AD, were also measured by co-immunoprecipitation/immunoblotting of the brain lysates. Results We provide evidence linking SARS-CoV-2 infection to activation of TGF-β signaling and oxidative overload. The neuropathological pathways causing tau hyperphosphorylation typically associated with AD were also shown to be activated in COVID-19 patients. RyR2 in COVID-19 brains demonstrated a “leaky” phenotype, which can promote cognitive and behavioral defects. Discussion COVID-19 neuropathology includes AD-like features and leaky RyR2 channels could be a therapeutic target for amelioration of some cognitive defects associated with SARS-CoV-2 infection and long COVID. RESEARCH-IN-CONTEXT Systematic review: The authors reviewed the literature using PubMed. While the mechanisms that lead to cognitive impairment associated with COVID-19 are not well understood, there have been recent reports studying SARS-CoV-2 infection and brain biochemistry and neuropathology. These relevant citations are appropriately cited. Interpretation: Our findings link the inflammatory response to SARS-CoV-2 infection with the neuropathological pathways causing tau hyperphosphorylation typically associated with Alzheimer's disease (AD). Furthermore, our data indicate a role for leaky ryanodine receptor 2 (RyR2) in the pathophysiology of SARS-CoV-2 infection. Future directions: The article proposes that the alteration of cellular calcium dynamics due to leaky RyR2 in COVID-19 brains is associated with the activation of neuropathological pathways that are also found in the brains of AD patients. Both the cortex and cerebellum of SARS-CoV-2–infected patients exhibited a reduced expression of the Ca2+ buffering protein calbindin. Decreased calbindin could render these tissues more vulnerable to cytosolic Ca2+ overload. Ex vivo treatment of the COVID-19 brain using a Rycal drug (ARM210) that targets RyR2 channels prevented intracellular Ca2+ leak in patient samples. Future experiments will explore calcium channels as a potential therapeutic target for the neurological complications associated with COVID-19.	todo
263	N259		Anne M.E. Baker, View ProfileNatalie J. Maffitt, Alessandro Del Vecchio, Katherine M. McKeating, View ProfileMark R. Baker, View ProfileStuart N. Baker, View ProfileDemetris S. Soteropoulos	Neural Dysregulation in Post-Covid Fatigue	https://doi.org/10.1101/2022.02.18.22271040	pre-print	February 21, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.02.18.22271040v1.full-text	Fatigue is a common complaint with substantial impact on daily life, but the neural mechanisms behind post-COVID fatigue remain unclear. We recruited volunteers with self-reported fatigue after a mild COVID infection and carried out a battery of behavioural and neurophysiological tests assessing the central, peripheral and autonomic nervous systems. In comparison to age and gender matched volunteers without fatigue, we show underactivity in specific cortical circuits, dysregulation of autonomic function, and myopathic change in skeletal muscles. Cluster analysis revealed no sub-groupings, suggesting post-COVID fatigue is a single entity with individual variation, rather than a small number of distinct syndromes. These abnormalities on objective tests may indicate novel avenues for principled therapeutic intervention, and could act as fast and reliable biomarkers for diagnosing and monitoring the progression of fatigue over time. Most people infected with SARS-CoV-2 do not require hospitalisation. However, even after a mild infection, a minority develop symptoms that linger for weeks or months (long COVID). Persistent fatigue, where everyday actions become laborious, is one of the more commonly reported after-effects1 and can have a substantial impact on the quality of life and productivity of sufferers2-4. At the time of publication ∼2% of the UK population are experiencing long COVID; >50% report fatigue as their primary symptom5. Fatigue appears to be a multi-system pathology, with immunological, metabolic and hormonal anomalies. These presumably generate changes in neurological function6 which lead to feelings of weakness and actions being more effortful. Changes could occur at many loci – for example, reduced activation of central motor circuits or impaired muscle function could lead to weakness; upregulated sensory feedback could increase sense of effort. To date no studies have investigated deficits in specific neural circuits with post-covid fatigue (pCF).
264	N260		Maria-Ioanna Stefanou, Lina Palaiodimou, Eleni Bakola, Nikolaos Smyrnis, Marianna Papadopoulou, George P. Paraskevas, Emmanouil Rizos, Eleni Boutati, Nikolaos Grigoriadis, Christos Krogias, Sotirios Giannopoulos, Sotirios Tsiodras, Mina Gaga, Georgios Tsivgoulis	Neurological manifestations of long-COVID syndrome: a narrative review	https://doi.org/10.1177%2F20406223221076890	Published	February 17, 2022	Review	https://journals.sagepub.com/doi/full/10.1177/20406223221076890	Accumulating evidence points toward a very high prevalence of prolonged neurological symptoms among coronavirus disease 2019 (COVID-19) survivors. To date, there are no solidified criteria for ‘long-COVID’ diagnosis. Nevertheless, ‘long-COVID’ is conceptualized as a multi-organ disorder with a wide spectrum of clinical manifestations that may be indicative of underlying pulmonary, cardiovascular, endocrine, hematologic, renal, gastrointestinal, dermatologic, immunological, psychiatric, or neurological disease. Involvement of the central or peripheral nervous system is noted in more than one-third of patients with antecedent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, while an approximately threefold higher incidence of neurological symptoms is recorded in observational studies including patient-reported data. The most frequent neurological manifestations of ‘long-COVID’ encompass fatigue; ‘brain fog’; headache; cognitive impairment; sleep, mood, smell, or taste disorders; myalgias; sensorimotor deficits; and dysautonomia. Although very limited evidence exists to date on the pathophysiological mechanisms implicated in the manifestation of ‘long-COVID’, neuroinflammatory and oxidative stress processes are thought to prevail in propagating neurological ‘long-COVID’ sequelae. In this narrative review, we sought to present a comprehensive overview of our current understanding of clinical features, risk factors, and pathophysiological processes of neurological ‘long-COVID’ sequelae. Moreover, we propose diagnostic and therapeutic algorithms that may aid in the prompt recognition and management of underlying causes of neurological symptoms that persist beyond the resolution of acute COVID-19. Furthermore, as causal treatments for ‘long-COVID’ are currently unavailable, we propose therapeutic approaches for symptom-oriented management of neurological ‘long-COVID’ symptoms. In addition, we emphasize that collaborative research initiatives are urgently needed to expedite the development of preventive and therapeutic strategies for neurological ‘long-COVID’ sequelae.
265	N261		César Fernández-de-las-Peñas PhD, José D. Martín-Guerrero PhD, Esperanza Navarro-Pardo PhD, Ignacio Cancela-Cilleruelo PT, MSc, Paloma Moro-López-Menchero PT, MSc & Oscar J. Pellicer-Valero MSc	Exploring Trajectory Curves from Loss of Smell and Taste in Previously Hospitalized COVID-19 Survivors: the LONG-COVID-EXP-CM Multicenter Study	https://doi.org/10.1007/s11606-022-07459-8	Published	22 February 2022	Study	https://link.springer.com/article/10.1007/s11606-022-07459-8	elf-reported loss of smell (anosmia) and taste (ageusia) have a prevalence of 19% and 23% in COVID-19 patients at the acute phase1 and a prevalence of 15% in a post-COVID phase2, 3. Altered taste and smell may lead to disruption to basic daily living activities; nevertheless, almost 80% of patients may expect spontaneous recovery after 6 months4. Most studies investigating loss of smell/taste have used cross-sectional designs assessing their presence just once. Understanding longitudinal patterns of loss of smell/taste could have significant implications for determining comprehensive plans for prevention and management of these post-COVID complications.5 This study explores the recovery trajectory of loss of smell/taste symptom in previously hospitalized COVID-19 survivors by using mosaic and exponential model bar plots for showing the long-term evolution of these symptoms.
266	N262		Giovani Zocche Junior, Lia Fonseca Siqueira, Leonardo Bongiovani Loro, Felipe Valles Fortes, Gabriele Zanirati, Daniel Marinowic, Jaderson Costa da Costa	Neurologic and neuropsychiatric symptoms in long-COVID 19 syndrome: a systematic review	10.21203/rs.3.rs-1359143/v1	pre-print	15 Feb, 2022	Review	researchsquare.com/article/rs-1359143/v1	This broad concept of COVID-19 long defined as symptoms occurring after infection is very relevant for health care taken together with patient complaints related to new emerging variants and prior infections. Therefore, establishing the relationship between neurological symptoms and COVID-19 is very important. For this review, we considered only neurologic or neuropsychiatric findings after a positive SARS-CoV-2 serological test and COVID-19 long symptoms after a negative PCR test, which resulted in 42 studies after exclusions. Our results demonstrated that the most relevant and frequent neurological complaints reported was fatigue, followed by attention or memory difficulties, including brain fog and smell and taste disturbances. This systematic literature review of long COVID-19 aims to enhance the current knowledge regarding symptoms after infection and to discuss long-term COVID-19 concept, given the possibility of new or persistent symptoms.
267	N263		Maria-Ioanna Stefanou, Lina Palaiodimou, Eleni Bakola, Nikolaos Smyrnis, Marianna Papadopoulou, George P. Paraskevas, Emmanouil Rizos, Eleni Boutati, Nikolaos Grigoriadis, Christos Krogias, Sotirios Giannopoulos, Sotirios Tsiodras, Mina Gaga, Georgios TsivgoulisFirst Published February 17, 2022 Review	Neurological manifestations of long-COVID syndrome: a narrative review	https://doi.org/10.1177%2F20406223221076890	Published	17 Feb, 2022	Review	https://journals.sagepub.com/doi/full/10.1177/20406223221076890	To date, there are no solidified criteria for ‘long-COVID’ diagnosis. Nevertheless, ‘long-COVID’ is conceptualized as a multi-organ disorder with a wide spectrum of clinical manifestations that may be indicative of underlying pulmonary, cardiovascular, endocrine, hematologic, renal, gastrointestinal, dermatologic, immunological, psychiatric, or neurological disease. Involvement of the central or peripheral nervous system is noted in more than one-third of patients with antecedent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, while an approximately threefold higher incidence of neurological symptoms is recorded in observational studies including patient-reported data. The most frequent neurological manifestations of ‘long-COVID’ encompass fatigue; ‘brain fog’; headache; cognitive impairment; sleep, mood, smell, or taste disorders; myalgias; sensorimotor deficits; and dysautonomia. Although very limited evidence exists to date on the pathophysiological mechanisms implicated in the manifestation of ‘long-COVID’, neuroinflammatory and oxidative stress processes are thought to prevail in propagating neurological ‘long-COVID’ sequelae. In this narrative review, we sought to present a comprehensive overview of our current understanding of clinical features, risk factors, and pathophysiological processes of neurological ‘long-COVID’ sequelae. Moreover, we propose diagnostic and therapeutic algorithms that may aid in the prompt recognition and management of underlying causes of neurological symptoms that persist beyond the resolution of acute COVID-19. Furthermore, as causal treatments for ‘long-COVID’ are currently unavailable, we propose therapeutic approaches for symptom-oriented management of neurological ‘long-COVID’ symptoms. In addition, we emphasize that collaborative research initiatives are urgently needed to expedite the development of preventive and therapeutic strategies for neurological ‘long-COVID’ sequelae.
268	N264		Philipp T Meyer 1, Sabine Hellwig 1, Ganna Blazhenets 1, Jonas A Hosp	Molecular imaging findings on acute and long-term effects of COVID-19 on the brain: A systematic review	https://doi.org/10.2967/jnumed.121.263085	Published	2022 Feb 17	Review	https://pubmed.ncbi.nlm.nih.gov/35177424/	Molecular imaging techniques like positron emission tomography (PET) and single-photon emission computed tomography (SPECT) have been used to shed light on how the Corona Virus Disease 2019 (COVID-19) affects the human brain. We provide a systematic review that summarizes the current literature according to five predominant topics: 1. Few case reports suggest reversible cortical and subcortical metabolic alterations in rare cases with concomitant, para- or post-infectious encephalitis. 2. Imaging findings in single patients with first manifestations of parkinsonism in the context of COVID-19 resemble those in neurodegenerative parkinsonism (loss of nigrostriatal integrity), but scarceness of data and a lack of follow-up preclude further etiological conclusions (e.g., unmasking/hastening of neurodegeneration vs. (para-) infectious parkinsonism). 3. Several case reports and few systematic studies addressed focal symptoms and lesions, most notably hyposmia. Results are variable, although some studies found regional hypometabolism of regions related to olfaction (e.g., orbitofrontal and mesiotemporal). 4. A case series and systematic studies in inpatients with COVID-19-related encephalopathy (acute to subacute stage) consistently found a frontoparietal-dominant neocortical dysfunction (on imaging and clinically) that proved to be grossly reversible in the majority of cases until 6 months. 5. Studies in "Post-COVID-19 syndrome" provided controversial results. In patients with a high level of self-reported complaints (e.g., fatigue, memory impairment, hyposmia, dyspnea) some authors found extensive areas of limbic and subcortical hypometabolism, while others found no metabolic alterations on PET and only minor cognitive impairments (if any) on neuropsychological assessment. Furthermore, we provide a critical appraisal of studies in regard of frequent methodological issues and current pathophysiological concepts. Finally, we devised possible applications of PET and SPECT in the clinical work-up of diagnostic questions related to COVID-19.
269	N265		Tian Tian,1 Jinfeng Wu,2 Tao Chen,3 Jia Li,1 Su Yan,1 Yiran Zhou,1 Xiaolong Peng,1 Yuanhao Li,1 Ning Zheng,2 Aoling Cai,2 Qin Ning,3 Hongbing Xiang,4 Fuqiang Xu,2,5 Yuanyuan Qin,1 Wenzhen Zhu,1 and Jie Wang2,5	Long-term follow-up of dynamic brain changes in patients recovered from COVID-19 without neurological manifestations	https://doi.org/10.1172/jci.insight.155827	Published	February 22, 2022	Study	https://insight.jci.org/articles/view/155827	METHODS. Dynamic brain changes are crucial for a better understanding and early prevention of “long COVID.” Here, we explored the cross-sectional and longitudinal consequences of COVID-19 on the brain in 34 discharged patients without neurological manifestations. Gray matter morphology, cerebral blood flow (CBF), and volumes of white matter tracts were investigated using advanced magnetic resonance imaging techniques to explore dynamic brain changes from 3 to 10 months after discharge. RESULTS. Overall, the differences of cortical thickness were dynamic and finally returned to the baseline. For cortical CBF, hypoperfusion in severe cases observed at 3 months tended to recover at 10 months. Subcortical nuclei and white matter differences between groups and within subjects showed various trends, including recoverable and long-term unrecovered differences. After a 10-month recovery period, a reduced volume of nuclei in severe cases was still more extensive and profound than that in mild cases. CONCLUSION. Our study provides objective neuroimaging evidence for the coexistence of recoverable and long-term unrecovered changes in 10-month effects of COVID-19 on the brain. The remaining potential abnormalities still deserve public attention, which is critically important for a better understanding of “long COVID” and early clinical guidance toward complete recovery.
270	N266		Marc Jamoulle	Vascular encephalopathy demonstrated by brain single-photon emission computed tomography (SPECT-CT scan) in Long Covid patients	https://hdl.handle.net/2268/288290	Published	2022 March	Study	https://orbi.uliege.be/bitstream/2268/288290/1/Long_Covid_Letter_JABFM_Jamoulle_20220226.pdf	Brain single-photon emission computed tomography (SPECT-CT scanning) has been used in fourteen Long Covid patients seen in family practice with severe neurocognitive problems. Vascular encephalopathy has been demonstrated in each patient and supports the hypothesis of a persistent coagulation disorder in Long Covid. The fourteen patients for whom a brain SPECT CT scan was requested had signs of brain impairment including three or more of the following symptoms; huge tiredness, exercise intolerance, cognitive problems such as brain fog, memory loss, anomia, headache, dysphasia, anosmia, dysgeusia, dysesthesia. Their DUSOI/WONCA severity index was high or maximum and their WONCA COOP charts score was over 20, meaning severe functional loss. Unexpectedly, brain SPECT showed severe alterations in cerebral blood flow in all patients, both cortical and central. All the lesions observed by brain SPECT CT scan are similar in all cases to those shown in Fig 1. This supports the hypothesis of a vascular perfusion disorder and localized brain ischemia secondary to a unexplained process like a coagulation disorder and/or the presence of auto-antibodies4 and could guide a therapeutic approach. It should be noted that fatigue and exhaustion during exercise can result from a difficult extraction of oxygen from the lungs, probably due also to vascular flow impairment.
271	N267		OmidMirmosayyeb12Elham MoasesGhaffary2SaraBagherieh2MahdiBarzegar12Mohammad SadeghDehghan2VahidShaygannejad12	Post COVID-19 Infection Neuromyelitis Optica Spectrum Disorder (NMOSD): A Case Report-Based Systematic Review	https://doi.org/10.1016/j.msard.2022.103697	Published	19 February 2022	Review	https://www.sciencedirect.com/science/article/pii/S2211034822002127	Highlights •NMOSD is a rare CNS inflammatory condition associated with optic neuritis, longitudinally extensive transverse myelitis (LETM), and involving aquaporin-4 (AQP4) in the astrocytic water channel. •Parainfectious pathogenesis as an environmental risk factor could play a key role in triggering NMOSD. •Our systematic review presented the case reports of patients with NMOSD following COVID-19. Abstract Background: One of the rare neuroinflammatory disorders is Neuromyelitis optica spectrum disorder (NMOSD) which involves the central nervous system (CNS), and develops by various etiologies. It is evident that viral infections could cause neurological disorders. In this regard, novel coronavirus (COVID-19) triggers NMOSD, based on reports. We performed this systematic review to evaluate NMOSD patients following COVID-19 infection. Methods: We collected 345 studies from PubMed (Medline), Embase, Scopus, and Web of Science databases from inception to 20 October 2021, and our inclusion criteria were English case reports/case series. Other types of Coronaviridae virus studies, review articles, articles written in any language other than English were excluded as well. Results: 11 case reports were selected from 345 studies and data was extracted according to inclusion criteria. In all cases, NMOSD was reported following COVID-19 infection, and various symptoms such as blurring or loss of vision, weakness, and numbness were common, and the COVID-19 infection was confirmed by different tests such as PCR test, immunoglobulin assay and chest imaging. Conclusion: Review regarding case reports showed that NMOSD is conceivable following COVID-19.
272	N268	Publication of N138 ES	Gwenaëlle Douaud, Soojin Lee, Fidel Alfaro-Almagro, Christoph Arthofer, Chaoyue Wang, Paul McCarthy, Frederik Lange, Jesper L. R. Andersson, Ludovica Griffanti, Eugene Duff, Saad Jbabdi, Bernd Taschler, Peter Keating, Anderson M. Winkler, Rory Collins, Paul M. Matthews, Naomi Allen, Karla L. Miller, Thomas E. Nichols & Stephen M. Smith	SARS-CoV-2 is associated with changes in brain structure in UK Biobank	https://doi.org/10.1038/s41586-022-04569-5	Published	07 March 2022	Study	https://www.nature.com/articles/s41586-022-04569-5	There is strong evidence for brain-related abnormalities in COVID-191–13. It remains unknown however whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. Here, we investigated brain changes in 785 UK Biobank participants (aged 51–81) imaged twice, including 401 cases who tested positive for infection with SARS-CoV-2 between their two scans, with 141 days on average separating their diagnosis and second scan, and 384 controls. The availability of pre-infection imaging data reduces the likelihood of pre-existing risk factors being misinterpreted as disease effects. We identified significant longitudinal effects when comparing the two groups, including: (i) greater reduction in grey matter thickness and tissue-contrast in the orbitofrontal cortex and parahippocampal gyrus, (ii) greater changes in markers of tissue damage in regions functionally-connected to the primary olfactory cortex, and (iii) greater reduction in global brain size. The infected participants also showed on average larger cognitive decline between the two timepoints. Importantly, these imaging and cognitive longitudinal effects were still seen after excluding the 15 cases who had been hospitalised. These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease via olfactory pathways, of neuroinflammatory events, or of the loss of sensory input due to anosmia. Whether this deleterious impact can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow up.
273	N269	ES	Randy L. Gollub	Brain changes after COVID revealed by imaging Imaging before and after infection by the SARS-CoV-2 virus reveals substantial changes in the brain after infection. The work sets an example for the high standards required in large longitudinal neuroimaging studies.	https://doi.org/10.1038/d41586-022-00503-x	Published	08 March 2022	Article	https://www.nature.com/articles/d41586-022-00503-x	Myriad neuropsychiatric symptoms have been attributed to infection with the SARS-CoV-2 virus1,2, from lost sense of smell and taste to headaches, memory problems and more. Knowing precisely how the brain is changed by infection would help us to understand these debilitating symptoms. Large-scale brain-imaging studies can provide quantitative measures of subtle changes — but conducting these studies presents a formidable challenge. Writing in Nature, Douaud et al.3 describe 785 sets of brain scans that mark the first step in tackling this challenge head-on.
274	N270		Jemmyson Romáriode JesusabRodrigo MorettoGalazzicCícero AlvesLopes JúniordMarco Aurélio ZezziArrudaef	Trace element homeostasis in the neurological system after SARS-CoV-2 infection: Insight into potential biochemical mechanisms	https://doi.org/10.1016/j.jtemb.2022.126964	Published	28 February 2022	Review	https://www.sciencedirect.com/science/article/pii/S0946672X2200044X	Highlights •Understanding the role of trace elements in the neurovirulence of SARS-CoV-2. •Insight into potential biochemical mechanisms. •Trends in treatments against SARS-CoV-2 infection. Results The imbalance of important trace elements can accelerate SARS-CoV-2 neurovirulence and increase the neurotoxicity since many neurological processes can be associated with the homeostasis of metal and metalloproteins. Some studies involving animals and humans have suggested the synapse as a vulnerable region of the brain to neurological disorders after viral infection. Considering the combined evidence, some mechanisms have been suggested to understand the relationship between neurological disorders and imbalance of trace elements in the brain after viral infection. Conclusion Trace elements play important roles in viral infections, such as helping to activate immune cells, produce antibodies, and inhibit virus replication. However, the relationship between trace elements and virus infections is complex since the specific functions of several elements remain largely undefined. Therefore, there is still a lot to be explored to understand the biochemical mechanisms involved between trace elements and viral infections, especially in the brain.
275	N271		JonathanTaieb1VictorPitron1MaximeElbaz2AlexandreRouen3CarolineGauriau3DominiqueSalmon4DamienLeger1	Évaluation polysomnographique des troubles du sommeil chez des patients COVID-long	https://doi.org/10.1016/j.msom.2022.01.125	Published	23 February 2022	Study	https://www.sciencedirect.com/science/article/pii/S176944932200125X	De nombreux patients COVID-long décrivent des troubles du sommeil, sur la base d’études cliniques sans polysomnographie (PSG). Notre objectif a été d’évaluer ces troubles du sommeil par un enregistrement PSG. Méthodes Vingt-deux patients COVID-long ont été adressés pour réalisation d’une PSG au centre du sommeil et de la vigilance de l’Hôtel-Dieu. Critères inclusion : critères HAS du COVID-long et critères ICSD3 de l’insomnie chronique. Critères d’exclusion : trouble du sommeil antérieur au COVID. Résultats Vingt-deux patients (13 femmes, 9 hommes), âgés de 45,9 ± 12,8 ; IMC, 24,26 ± 4,61. Vingt et un patients/22 présentent les critères PSG d’insomnie. Un seul patient présente un SAS avec un IAH > 15. Cinquante pour cent ont un TST < 6 heures temps de sommeil total (TST) 352,8 ± 78,2 min ; latence d’endormissement 28,5 ± 23,7 minutes (norme : < 30 min) ; temps d’éveil intra-sommeil 77,7 min 45,3 ± 45,3 (norme : < 30 min). Conclusion À notre connaissance il s’agit de la première étude polysomnographique de patients COVID-long souffrant de troubles du sommeil. Nos résultats confirment la haute prévalence de troubles objectifs PSG chez ces patients.
276	N272		Andrea Ciofalo 1,Carlo Cavaliere 1,* ,Simonetta Masieri 2,Alessandra Di Chicco 1,Irene Fatuzzo 1 ,Federica Lo Re 1 ,Silvia Baroncelli 3 ,Elona Begvarfaj 1,Andrea Adduci 1,Ivano Mezzaroma 4 ,Claudio Maria Mastroianni 5 ,Marco de Vincentiis 1,Antonio Greco 1,Loris Zamai 6,7 andMarco Artico 1	Long-Term Subjective and Objective Assessment of Smell and Taste in COVID-19	https://doi.org/10.3390/cells11050788	Published	24 February 2022	Study	https://www.mdpi.com/2073-4409/11/5/788/htm	Among the first clinical symptoms of the SARS-CoV-2 infection is olfactory–gustatory deficit; this continues for weeks and, in some cases, can be persistent. We prospectively evaluated 162 patients affected by COVID-19 using a visual analogue scale (VAS) for nasal and olfactory–gustatory symptoms. Patients were checked after 7, 14, 21, 28, 90, and 180 days. A total of 118 patients (72.8%) reported an olfactory VAS < 7 at baseline (group B), and 44 (27.2%) reported anosmia (VAS ≥ 7) (group A) and underwent the Brief Smell Identification Test (B-SIT) and Burghart Taste Strips (BTS) to quantify the deficit objectively and repeated the tests to confirm the sense recovery. Group A patients showed B-SIT anosmia and hyposmia in 44.2% and 55.8% of cases, respectively. A total of 88.6% of group A patients reported ageusia with VAS ≥ 7, and BTS confirmed 81.8% of ageusia and 18.2% of hypogeusia. VAS smell recovery was recorded starting from 14 days, with normalization at 28 days. The 28-day B-SIT score showed normosmia in 90.6% of group A patients. The mean time for full recovery (VAS = 0) was shorter in group B (22.9 days) than in group A (31.9 days). Chemosensory deficit is frequently the first symptom in patients with COVID-19, and, in most cases, recovery occurs after four weeks.
277	N273		Srikent Siruvella1 ; Kaushik Sreeram2 ; Vithi Hitendra Patel3	Anticipated Long-Term Cognitive Impairment Following Covid-19 Recovery in Elderly Patients		Published	Feb 18, 2022	Review	https://meddocsonline.org/journal-of-clinical-images/anticipated-long-term-cognitive-impairment-following-covid-19-recovery-in-elderly-patients.pdf	The coronavirus disease 2019 (COVID-19) pandemic was declared by the World Health Organization on 11th March 2020. The novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causing the disease was mainly associated with pulmonary manifestations. But according to the neuroinvasive properties of prior coronaviruses and the similarity of neuropsychological conditions, it appears that patients can develop injurious long-term cognitive events post-COVID-19 infection. Although geriatric patients with underlying comorbidities are highly susceptible to severe disease, most of them survive and recover from COVID-19. The survivors experienced long-lasting cognitive dysfunction that occurred after suffering from COVID-19 neuro infections. A comprehensive review of literature on peerreviewed journals was conducted using a variety of keywords, including COVID-19, late consequences of COVID-19, cognitive impairment, neuroinvasion, and neurodegeneration. This review aimed at exploring the anticipated longterm cognitive impairment in geriatric patients following COVID-19 infection recovery, the neuroinvasive properties of prior Human Coronaviruses (HCoVs), and extensively researched disorders that share similar neurological mechanisms. Deeper insight into the full spectrum of these neurological disorders can result in improved clinical outcomes and better treatment algorithms. Consequently, this review summarizes only what is currently known about SARS-CoV2-mediated neurological injury and establishes a framework for future and larger clinical studies to shed new light on the long-term cognitive impairment after overcoming the primary COVID-19 infection.
278	N274		Philippe Voruz, Alexandre Cionca, Isabele Jacot de Alcântara, Anthony Nuber-Champier, Gilles Allali, Lamyae Benzakour, Marine Thomasson, Patrice H. Lalive, Karl-Olof Lövblad, Olivia Braillard, Mayssam Nehme, Matteo Coen, Jacques Serratrice, Jérôme Pugin, Idris Guessous, Basile N. Landis, Dan Adler, Alessandra Griffa, Dimitri Van De Ville, Frédéric Assal, Julie A. Péron	Functional connectivity underlying cognitive and psychiatric symptoms in post-COVID-19 syndrome: is anosognosia a key determinant?	https://doi.org/10.1093/braincomms/fcac057	Published	09 March 2022	qstudy	https://academic.oup.com/braincomms/advance-article/doi/10.1093/braincomms/fcac057/6545202?login=false	Lack of awareness of cognitive impairment (i.e., anosognosia) could be a key factor for distinguishing between neuropsychological post-COVID-19 condition phenotypes. In this context, the twofold aim of the present study was to i) establish the prevalence of anosognosia for memory impairment, according to the severity of the infection in the acute phase, and ii) determine whether anosognosic patients with post-COVID syndrome have a different cognitive and psychiatric profile from nosognosic patients, with associated differences in brain functional connectivity. A battery of neuropsychological, psychiatric, olfactory, dyspnea, fatigue and quality-of-life tests was administered 227.07 ± 42.69 days post-SARS-CoV-2 infection to 102 patients (mean age: 56.35 years, 65 men, no history of neurological, psychiatric, neuro-oncological or neurodevelopmental disorder prior to infection) who had experienced either a mild (not hospitalized; n = 45), moderate (conventional hospitalization; n = 34) or severe (hospitalization with intensive care unit stay and mechanical ventilation; n = 23) presentation in the acute phase. Patients were first divided into two groups according to the presence or absence of anosognosia for memory deficits (26 anosognosic patients and 76 nosognosic patients). Of these, 49 patients underwent an MRI. Structural images were visually analyzed, and statistical intergroup analyses were then performed on behavioral and functional connectivity measures. Only 15.6% of patients who presented mild disease displayed anosognosia for memory dysfunction, compared with 32.4% of patients with moderate presentation and 34.8% of patients with severe disease. Compared with nosognosic patients, those with anosognosia for memory dysfunction performed significantly more poorly on objective cognitive and olfactory measures. By contrast, they gave significantly more positive subjective assessments of their quality of life, psychiatric status, and fatigue. Interestingly, the proportion of patients exhibiting a lack of consciousness of olfactory deficits was significantly higher in the anosognosic group. Functional connectivity analyses revealed significant decrease in connectivity, in the anosognosic group as compared to the nosognosic group, within and between the following networks: the left default mode, the bilateral somatosensory motor, the right executive control, the right salient ventral attention and the bilateral dorsal attention networks, as well as the right Lobules IV and V of the cerebellum. Lack of awareness of cognitive disorders and, to a broader extent, impairment of the self-monitoring brain system, may be a key factor for distinguishing between the clinical phenotypes of post-COVID syndrome with neuropsychological deficits.
279	N275		Natalia M.Lyra e Silvaab1Fernanda G.Q.Barros-Aragãocd1Fernanda G.De FeliceabcdSergio T.Ferreiracde	Inflammation at the crossroads of COVID-19, cognitive deficits and depression	https://doi.org/10.1016/j.neuropharm.2022.109023	Published	4 March 2022	Review	https://www.sciencedirect.com/science/article/pii/S002839082200082X	Highlights •COVID-19 is frequently associated with acute or persistent neurological impacts. •COVID-19 survivors may be at increased risk for cognitive and mood disorders. •Dementia and neuropsychiatric disorders appear to be risk factors for COVID-19 complications. •Inflammation links COVID-19, Alzheimer's disease and depression. Acute neurological alterations have been associated with SARS-CoV-2 infection. Additionally, it is becoming clear that coronavirus disease 2019 (COVID-19) survivors may experience long-term neurological abnormalities, including cognitive deficits and mood alterations. The mechanisms underlying acute and long-term impacts of COVID-19 in the brain are being actively investigated. Due to the heterogeneous manifestations of neurological outcomes, it is possible that different mechanisms operate following SARS-CoV-2 infection, which may include direct brain infection by SARS-CoV-2, mechanisms resulting from hyperinflammatory systemic disease, or a combination of both. Inflammation is a core feature of COVID-19, and both central and systemic inflammation are known to lead to acute and persistent neurological alterations in other diseases. Here, we review evidence indicating that COVID-19 is associated with neuroinflammation, along with blood-brain barrier dysfunction. Similar neuroinflammatory signatures have been associated with Alzheimer's disease and major depressive disorder. Current evidence demonstrates that patients with pre-existing cognitive and neuropsychiatric deficits show worse outcomes upon infection by SARS-CoV-2 and, conversely, COVID-19 survivors may be at increased risk of developing dementia and mood disorders. Considering the high prevalence of COVID-19 patients that recovered from infection in the world and the alarming projections for the prevalence of dementia and depression, investigation of possible molecular similarities between those diseases may shed light on mechanisms leading to long-term neurological abnormalities in COVID-19 survivors.
280	N276		Abdulrahman K. Ahmed, Reem Sayad, Islam A. Mahmoud, Aya M. Abd EL-Monem, Salma H. Badry, Islam H. Ibrahim, Mahmoud HR Hafez, Mohamed A. El-Mokhtar & Ibrahim M. Sayed	“Anosmia” the mysterious collateral damage of COVID-19	https://doi.org/10.1007/s13365-022-01060-9	Published	05 March 2022	Review	https://link.springer.com/article/10.1007/s13365-022-01060-9	From the beginning of the COVID-19 pandemic, several otolaryngologists described many cases of a sudden loss of smell (anosmia) associated with the disease with or without additional symptoms. Anosmia is often the first and sometimes the only sign in the asymptomatic carriers of COVID-19. Still, this disorder is underestimated, and it is not life-threatening. However, it significantly decreases the quality of life. This olfactory dysfunction continues in several cases even after the nasopharyngeal swab was negative. The occurrence of anosmia can be used as a screening tool for COVID-19 patients and can be used to identify these patients to accomplish the isolation and tracking procedures. In this review, we highlighted the possible mechanisms of anosmia in COVID-19 patients, major pathologies and features of anosmia, implications of anosmia in early diagnosis of COVID-19, evaluation of the smell function during COVID-19, and management and treatment options of COVID-19 anosmia.
281	N277		Pasquale Moretta 1,,† ,Pasquale Ambrosino 2,,† ,Anna Lanzillo 1,Laura Marcuccio 1,Salvatore Fuschillo 3,Antimo Papa 2,Gabriella Santangelo 4,Luigi Trojano 4,‡ andMauro Maniscalco 3,‡	Cognitive Impairment in Convalescent COVID-19 Patients Undergoing Multidisciplinary Rehabilitation: The Association with the Clinical and Functional Status	https://doi.org/10.3390/healthcare10030480	Published	4 March 2022	Study	https://www.mdpi.com/2227-9032/10/3/480/htm	We investigated the possible association between cognitive impairment and the main clinical and functional status variables in a cohort of convalescent COVID-19 patients without premorbid diseases potentially affecting cognition. Methods. We consecutively screened for inclusion of convalescent COVID-19 patients referring to a post-acute care facility for pulmonary rehabilitation. All the enrolled patients were assessed for cognitive functions. We also investigated features of psychological distress (anxiety, depression, symptoms of posttraumatic stress disorder and quality of life) and cardiac and pulmonary functional status. Results. The 63 enrolled patients (mean age 59.82 ± 10.78, male gender = 47) showed a high frequency of depressive symptoms (76.2%) and anxiety (55.5%), and a high prevalence of symptoms of posttraumatic stress disorder (PTSD, 44.4%). About half of the total sample showed reduced cognitive efficiency (RCE, 44.4%) in the domains of spatial and verbal long-term memory and executive functions. Patients with RCE more frequently showed alteration of blood pressure (BP) circadian rhythm (p = 0.01), higher levels of D-Dimer (p = 0.03), had experienced a severe illness (p = 0.02), had longer disease duration (p = 0.04), more clinically relevant symptoms of PTSD (p = 0.02), more frequent cognitive complaints (p = 0.002), higher anxiety scores (p = 0.01) and lower quality of life (p = 0.02) than patients with normal cognitive efficiency. Conclusions. Our findings indicated a possible association between the RCE after COVID-19 and some cardiological variables, including some indirect measures of a residual autonomic disorder, such as the presence of an altered BP circadian rhythm. Future research studies with large samples are needed to provide valid conclusions.
282	N278		Marc Jamoulle, Gisèle Kazeneza-Mugisha, Ayoub Zayane	Descriptive and Narrative Study of Long Covid Cases in General Practice and Diagnostic Value of Single Photon Emission Computed Tomography (SPECT scan)	https://www.medrxiv.org/content/10.1101/2022.03.01.22270897v1.full-text	pre-print	March 02, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.03.01.22270897v1.full-text	Diagnosis is based on careful listening to the patient’s history. Previously unknown irrepressible fatigue, brain fog, working memory disorders with possible anomia, anosmia, dysgeusia or other muli-systemic symptoms occurring after an acute Covid are varying characteristics of Long Covid. Biological evidence of Covid is missing in fourteen patients as PCRs may have been not done or came back negative in the acute phase of the disease. Anti-SARS-CoV-2 antibodies are not always present or are indistinguishable from post-vaccine antibodies. In fourteen severe cases presented, Single Photon Emission Computed Tomography (SPECT scan) after intravenous administration of Technetium-99m (Tc-99m HM-PAO) were able to demonstrate a disorder of cerebral perfusion. Two follow -up brain SPECT at three months showed significant improvement. Further genetic and immunologic study is ongoing for all patient with the help of the international consortium COVID Human Genetic Effort. A patient who presents after a Covid with medically unexplained symptoms may well be a Long Covid. Despite some interesting hypothesis, there is no known specific treatment. Neurocognitive revalidation and physiotherapy may help those patients who need long -term empathic support to cope with their condition. Key messages □ Long Covid is a recent onset, multi-systemic, long-term condition that can be very debilitating. □ The main symptoms are severe fatigue, exertional exhaustion, and cognitive and memory problems, among others. □ Patients who suffer from it may not realize it, may not talk about it, or may attribute their problem to other causes. □ Single Photon Emission Computed Tomography (SPECT CT) contributes to the hypothesis of a vascular perfusion disorder induced by SARS -coV-2 and should be validated as a diagnostic tool in neurological Long Covid. □ Tissue immunity should be available to prove Long Covid in case of humoral seronegativity □ There is no identified treatment that can be recommended yet. Careful listening, empathic support and cognitive and physical rehabilitation are suggested and should be organised or supported by the Belgian state.
283	N279		Anthony Nuber-Champier, Philippe Voruz, Isabele Jacot de Alcântara, Gautier Breville, Gilles Allali, Patrice. H Lalive, Frédéric Assal, Julie Anne Péron	Monocytosis in the Acute Phase of SARS-CoV-2 Infection Predicts the Presence of Anosognosia for Cognitive Deficits in the Chronic Phase	https://doi.org/10.21203/rs.3.rs-1361211/v1	pre-print	02 Mar, 2022	Study	https://www.researchsquare.com/article/rs-1361211/v1	Altered awareness of neuropsychological disorders (i.e., anosognosia) is a striking symptom of post-COVID-19 syndrome. Some leukocytes markers in the acute phase might predict the presence of anosognosia in the chronic phase, but they have not been identified yet. This study aims to determine whether patients with anosognosia for their memory deficits in the chronic phase present specific leukocytes distribution in the acute phase, and if so, whether these leukocytes parameters could predict this anosognosia. First, we compare the acute immunological data of the leukocytes distribution of 20 patients infected with SARS-Cov-2 who displayed anosognosia 69 months after SARS-Cov-2 infection (230.25 ± 46.65 days) versus 41 patients infected with SARS-Cov-2 without developing anosognosia. Second, we performed a ROC analysis to evaluate the predictive value of the leukocytes markers that emerged from this comparison. Blood circulating monocytes (%) at the acute phase of SARS-CoV2 infection is associated with long term post-COVID-19 anosognosia. Finally, serology on admission showing a percentage rate of monocytes of 7.35% of the total number of leukocytes, seems to predict the presence of chronic anosognosia for 6–9 months after infection.
284	N280	ES	Lisa Bauer 4 Brigitta M. Laksono 4 Femke M.S. de Vrij Steven A. Kushner Oliver Harschnitz Debby van Riel	The neuroinvasiveness, neurotropism, and neurovirulence of SARS-CoV-2	https://doi.org/10.1016/j.tins.2022.02.006	Published	March 02, 2022	Review	https://www.cell.com/trends/neurosciences/fulltext/S0166-2236(22)00050-9	Highlights Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection has been shown to be associated with a range of neurological complications during the acute and postacute phases. The pathogenesis of SARS-CoV-2-associated CNS disease is complex and diverse, and cannot be explained by one sole mechanism. To understand the pathogenesis of SARS-CoV-2-associated CNS disease, it is important to gain deeper insights into the neuroinvasiveness, neurotropism, and neurovirulence of SARS-CoV-2. It is also imperative to consider the kinetics, since a viral infection is not a static event. Relevant in vivo models can be used to study the neuroinvasiveness, neurotropism, and neurovirulence of SARS-CoV-2, and in vitro human pluripotent stem cell (hPSC) models can be used to study the neurotropism of the virus and the associated cellular responses. These models may be further leveraged to study differences among SARS-CoV-2 variants and for the design of therapeutic approaches. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection is associated with a diverse spectrum of neurological complications during the acute and postacute stages. The pathogenesis of these complications is complex and dependent on many factors. For accurate and consistent interpretation of experimental data in this fast-growing field of research, it is essential to use terminology consistently. In this article, we outline the distinctions between neuroinvasiveness, neurotropism, and neurovirulence. Additionally, we discuss current knowledge of these distinct features underlying the pathogenesis of SARS-CoV-2-associated neurological complications. Lastly, we briefly discuss the advantages and limitations of different experimental models, and how these approaches can further be leveraged to advance the field.
285	N281		Yu-Hui Liu, MD, PhD1; Yang Chen, MD1; Qing-Hua Wang, MD, PhD1; Ling-Ru Wang, BN1; Li Jiang, BN1; Ying Yang, BN1; Xian Chen, BN2; Ying Li, BN3; Yuan Cen, BN4; Cheng Xu, MD, PhD5; Jie Zhu, MD, PhD1; Wei Li, MD, PhD1; Ye-Ran Wang, MD1; Li-Li Zhang, MD, PhD1; Juan Liu, MD, PhD1; Zhi-Qiang Xu, MD, PhD1; Yan-Jiang Wang, MD, PhD1	One-Year Trajectory of Cognitive Changes in Older Survivors of COVID-19 in Wuhan, China A Longitudinal Cohort Study	https://doi.org/10.1001/jamaneurol.2022.0461	Published	March 8, 2022	Study	https://jamanetwork.com/journals/jamaneurology/fullarticle/2789919	Key Points - Question What is the dynamic trajectory of cognitive changes in the elderly population surviving COVID-19? - Findings In this cohort study of 1438 COVID-19 survivors 60 years and older who were discharged from COVID-19–designated hospitals in Wuhan, China, the incidence of cognitive impairment was higher in COVID-19 survivors, especially those with severe cases, compared with uninfected participants during a 1-year follow-up period. - Meaning The findings suggest that long-term cognitive decline is common after SARS-CoV-2 infection, indicating the necessity of evaluating the impact of the COVID-19 pandemic on the future dementia burden worldwide. Results Among the 3233 COVID-19 survivors and 1317 uninfected spouses screened, 1438 participants who were treated for COVID-19 (691 male [48.05%] and 747 female [51.95%]; median [IQR] age, 69 [66-74] years) and 438 uninfected control individuals (222 male [50.68%] and 216 female [49.32%]; median [IQR] age, 67 [66-74] years) completed the 12-month follow-up. The incidence of cognitive impairment in survivors 12 months after discharge was 12.45%. Individuals with severe cases had lower Telephone Interview of Cognitive Status-40 scores than those with nonsevere cases and control individuals at 12 months (median [IQR]: severe, 22.50 [16.00-28.00]; nonsevere, 30.00 [26.00-33.00]; control, 31.00 [26.00-33.00]). Severe COVID-19 was associated with a higher risk of early-onset cognitive decline (odds ratio [OR], 4.87; 95% CI, 3.30-7.20), late-onset cognitive decline (OR, 7.58; 95% CI, 3.58-16.03), and progressive cognitive decline (OR, 19.00; 95% CI, 9.14-39.51), while nonsevere COVID-19 was associated with a higher risk of early-onset cognitive decline (OR, 1.71; 95% CI, 1.30-2.27) when adjusting for age, sex, education level, body mass index, and comorbidities. Conclusions and Relevance In this cohort study, COVID-19 survival was associated with an increase in risk of longitudinal cognitive decline, highlighting the importance of immediate measures to deal with this challenge.
286	N282		Barbara A. Hanson, View ProfileLavanya Visvabharathy, Sareen T. Ali, Anthony K. Kang, Tulsi R. Patel, Jeffrey R. Clark, Patrick H. Lim, View ProfileZachary S. Orban, Soyoon S. Hwang, Dawn Mattoon, View ProfileAyush Batra, View ProfileEric M. Liotta, View ProfileIgor J. Koralnik	Plasma Biomarkers of Neuropathogenesis in Hospitalized Patients With COVID-19 and Those With Postacute Sequelae of SARS-CoV-2 Infection	https://doi.org/10.1212/NXI.0000000000001151	Published	March 7, 2022	Study	https://nn.neurology.org/content/9/3/e1151.abstract	The pathogenic mechanisms of COVID-19 encephalopathy and neuro-PASC are unknown. We sought to establish biochemical evidence of CNS injury in those patients and their association with neuropsychiatric manifestations and SARS-CoV-2 antigenemia. Results We enrolled a total of 64 study participants, including 9 hospitalized patients with COVID-19 encephalopathy (CE), 9 posthospitalization neuro-PASC (PNP) patients, 38 nonhospitalized neuro-PASC (NNP) patients, and 8 HC subjects. Patients with CE were older, had higher pNfL and pGFAP concentrations, and more frequent pN Ag detection than all neuro-PASC groups. PNP and NNP patients exhibited similar PASC symptoms, decreased quality-of-life measures, and cognitive dysfunction, and 1 of the 38 (2.6%) NNP patients had pN Ag detectable 3 weeks postsymptoms onset. Patients with neuro-PASC presenting with anxiety/depression had higher neuroglial scores, which were correlated with increased anxiety on quality-of-life measures. Discussion pNfL, pGFAP, and pN Ag measurements indicate neuronal dysfunction and systemic involvement in hospitalized COVID-19 patients with encephalopathy. Detection of SARS-CoV-2 N Ag in blood 3 weeks after symptoms onset in a nonhospitalized patient suggests that prolonged antigenic stimulation, or possibly latent infection, may occur. Anxiety was associated with evidence of astroglial activation in patients with neuro-PASC. These data shed new light on SARS-Cov-2 neuropathogenesis and demonstrate the value of plasma biomarkers across the COVID-19 disease spectrum.
287	N283		A.Costanzaab1A.AmeriocdA.AgugliacdG.SerafinicdM.AmorecdR.HasleraeJ.AmbrosettifG.BondolfiabgG.SampognahI.BerardelliiA.FiorillohM.PompiliiK.D.Nguyenjk	Hyper/neuroinflammation in COVID-19 and suicide etiopathogenesis: Hypothesis for a nefarious collision?	https://doi.org/10.1016/j.neubiorev.2022.104606	Published	14 March 2022	Review	https://www.sciencedirect.com/science/article/pii/S0149763422000951	Highlights •Hyperinflammation is a hallmark of COVID-19 disease. •Neuroinflammation is also involved in suicide pathogenesis. •It is possible that the two inflammation cascades share colliding points. •Hyper/neuroinflammation could be synergic in chronic neuropsychiatric sequelae, including suicide. •This is relevant to COVID-19 survivors as long-term impact of the disease is unknown. Accumulating scientific and clinical evidence highlighted pathological hyperinflammation as a cardinal feature of SARS-CoV-2 infection and acute COVID-19 disease. With the emergence of long COVID-19 syndrome, several chronic health consequences, including neuropsychiatric sequelae, have gained attention from the public and medical communities. Since inflammatory mediators have also been accredited as putative biomarkers of suicidal ideations and behaviors, hyper- and neuroinflammation might share some colliding points, overlapping and being interconnected in the context of COVID-19. This review aims to provide a summary of current knowledge on the molecular and cellular mechanisms of COVID-19-associated hyper/neuroinflammation with focus on their relevance to the inflammatory hypothesis of suicide development. Subsequently, strategies to alleviate COVID-19 hyper/neuroinflammation by immunomodulatory agents (many of which at experimental stages) as well as psychopharmacologic/psychotherapeutic approaches are also mentioned. While suicide risk in COVID-19 survivors - until now little known - needs further analysis through longitudinal studies, current observations and mechanistic postulates warrant additional attention to this possibly emerging mental health concern.
288	N284		A.Costanzaab1A.AmeriocdA.AgugliacdG.SerafinicdM.AmorecdR.HasleraeJ.AmbrosettifG.BondolfiabgG.SampognahI.BerardelliiA.FiorillohM.PompiliiK.D.Nguyenjk	Hyper/neuroinflammation in COVID-19 and suicide etiopathogenesis: Hypothesis for a nefarious collision?	https://doi.org/10.1016/j.neubiorev.2022.104606	Published	12 March 2022	Review	https://www.sciencedirect.com/science/article/pii/S0149763422000951	Highlights •Hyperinflammation is a hallmark of COVID-19 disease. •Neuroinflammation is also involved in suicide pathogenesis. •It is possible that the two inflammation cascades share colliding points. •Hyper/neuroinflammation could be synergic in chronic neuropsychiatric sequelae, including suicide. •This is relevant to COVID-19 survivors as long-term impact of the disease is unknown. Abstract Accumulating scientific and clinical evidence highlighted pathological hyperinflammation as a cardinal feature of SARS-CoV-2 infection and acute COVID-19 disease. With the emergence of long COVID-19 syndrome, several chronic health consequences, including neuropsychiatric sequelae, have gained attention from the public and medical communities. Since inflammatory mediators have also been accredited as putative biomarkers of suicidal ideations and behaviors, hyper- and neuroinflammation might share some colliding points, overlapping and being interconnected in the context of COVID-19. This review aims to provide a summary of current knowledge on the molecular and cellular mechanisms of COVID-19-associated hyper/neuroinflammation with focus on their relevance to the inflammatory hypothesis of suicide development. Subsequently, strategies to alleviate COVID-19 hyper/neuroinflammation by immunomodulatory agents (many of which at experimental stages) as well as psychopharmacologic/psychotherapeutic approaches are also mentioned. While suicide risk in COVID-19 survivors - until now little known - needs further analysis through longitudinal studies, current observations and mechanistic postulates warrant additional attention to this possibly emerging mental health concern.
289	N285		E.Guedj1J.YCampion2T.Horowitz1F.Barthelemy1S.Cammilleri1M.Ceccaldi3	L’impact du confinement COVID-19 sur le métabolisme cérébral	https://doi.org/10.1016/j.mednuc.2022.01.011	Published	11 March 2022	Study	https://www.sciencedirect.com/science/article/pii/S0928125822000110	Résultats La durée du confinement était négativement corrélée au métabolisme du cortex sensori-moteur avec un effet prédominant sur le réseau pyramidal de l’hémisphère majeur et chez les patients les plus jeunes, incluant également l’amygdale gauche, avec une réversibilité seulement partielle après 55 jours de déconfinement. Un faible recouvrement était retrouvé avec le profil d’hypométabolisme décrit dans le COVID long (<9 %). Conclusion La restriction des activités physiques, avec son déconditionnement associé, et l’isolement social pourraient entraîner des perturbations fonctionnelles des réseaux cérébraux sensorimoteurs et émotionnels. Ce profil métabolique semble distinct de celui rapporté dans le COVID long. D’autres études longitudinales sont nécessaires, avec un suivi plus long, pour évaluer les conséquences cliniques et, en particulier, l’impact sur la santé cognitive et mentale, et pour étendre ces résultats aux sujets sains dans ce contexte de confinement.
290	N286		Philippe Voruz, Alexandre Cionca, Isabele Jacot de Alcântara, Anthony Nuber-Champier, Gilles Allali, Lamyae Benzakour, Marine Thomasson, Patrice H. Lalive, Karl-Olof Lövblad, Olivia Braillard, Mayssam Nehme, Matteo Coen, Jacques Serratrice, Jérôme Pugin, Idris Guessous, Basile N. Landis, Dan Adler, Alessandra Griffa, Dimitri Van De Ville, Frédéric Assal, Julie A. Péron	Functional connectivity underlying cognitive and psychiatric symptoms in post-COVID-19 syndrome: is anosognosia a key determinant?	https://doi.org/10.1093/braincomms/fcac057	Published	09 March 2022	Study	https://academic.oup.com/braincomms/advance-article/doi/10.1093/braincomms/fcac057/6545202?login=true	Lack of awareness of cognitive impairment (i.e., anosognosia) could be a key factor for distinguishing between neuropsychological post-COVID-19 condition phenotypes. In this context, the twofold aim of the present study was to i) establish the prevalence of anosognosia for memory impairment, according to the severity of the infection in the acute phase, and ii) determine whether anosognosic patients with post-COVID syndrome have a different cognitive and psychiatric profile from nosognosic patients, with associated differences in brain functional connectivity. A battery of neuropsychological, psychiatric, olfactory, dyspnea, fatigue and quality-of-life tests was administered 227.07 ± 42.69 days post-SARS-CoV-2 infection to 102 patients (mean age: 56.35 years, 65 men, no history of neurological, psychiatric, neuro-oncological or neurodevelopmental disorder prior to infection) who had experienced either a mild (not hospitalized; n = 45), moderate (conventional hospitalization; n = 34) or severe (hospitalization with intensive care unit stay and mechanical ventilation; n = 23) presentation in the acute phase. Patients were first divided into two groups according to the presence or absence of anosognosia for memory deficits (26 anosognosic patients and 76 nosognosic patients). Of these, 49 patients underwent an MRI. Structural images were visually analyzed, and statistical intergroup analyses were then performed on behavioral and functional connectivity measures. Only 15.6% of patients who presented mild disease displayed anosognosia for memory dysfunction, compared with 32.4% of patients with moderate presentation and 34.8% of patients with severe disease. Compared with nosognosic patients, those with anosognosia for memory dysfunction performed significantly more poorly on objective cognitive and olfactory measures. By contrast, they gave significantly more positive subjective assessments of their quality of life, psychiatric status, and fatigue. Interestingly, the proportion of patients exhibiting a lack of consciousness of olfactory deficits was significantly higher in the anosognosic group. Functional connectivity analyses revealed significant decrease in connectivity, in the anosognosic group as compared to the nosognosic group, within and between the following networks: the left default mode, the bilateral somatosensory motor, the right executive control, the right salient ventral attention and the bilateral dorsal attention networks, as well as the right Lobules IV and V of the cerebellum. Lack of awareness of cognitive disorders and, to a broader extent, impairment of the self-monitoring brain system, may be a key factor for distinguishing between the clinical phenotypes of post-COVID syndrome with neuropsychological deficits.
291	N287		Light S.N.	The Combined Use of Neuropsychiatric and Neuropsychological Assessment Tools to Make a Differential Dementia Diagnosis in the Presence of “Long-Haul” COVID-19	https://doi.org/10.1159/000522020	Published	March 15, 2022	Case Report	https://www.karger.com/Article/FullText/522020	The longer term neurocognitive/neuropsychiatric consequences of moderate/severe COVID-19 infection have not been explored. The case herein illustrates a complex web of differential diagnosis. The onset, clinical trajectory, treatment course/response, serial neuroimaging findings, and neuropsychological test data were taken into account when assessing a patient presenting 8 months post-COVID-19 (with premorbid attention-deficit hyperactivity disorder, diabetes mellitus, mood difficulties, and a positive family history of vascular dementia). Her acute COVID-19 infection was complicated by altered mental status associated with encephalopathy and bacterial pneumonia. After recovery from COVID-19, the patient continues to experience persisting cognitive and emotive difficulties despite an ongoing psychopharmacotherapy regimen (16 + years), psychotherapy (15 + sessions), and speech-language pathology SLP; 2 × week/for 12 weeks). The purpose of her most recent and comprehensive neuropsychological evaluation was to determine the presence/absence of neurocognitive disorder. The patient is a 62-year-old Caucasian woman. Cognitive screening was completed 3 months post-acute COVID-19 as part of an SLP evaluation, and a full neuropsychological evaluation was conducted 8 months post-COVID-19 recovery on an outpatient basis (in person). The patient had serial neuroimaging. Initial neurological evaluation during acute COVID-19 included unremarkable brain computed tomography (CT)/magnetic resonance imaging. However, follow-up CT (without contrast) revealed, in part, “asymmetric perisylvian atrophy on the left.” Full neuropsychological evaluation at 8 months post-COVID-19 recovery revealed a dysexecutive syndrome characterized by language dysfunction and affective theory-of-mind deficit, consistent with dementia. There is need for careful use of differential diagnosis in COVID-19 patients with multiple risk factors that make them more susceptible to long-term neurological complications post-COVID-19. Differential diagnosis should involve multidisciplinary assessment (e.g., neuropsychology, SLP, neurology, and psychiatry).
292	N288		Cédric Hirzel, , Denis Grandgirard, Bernard Surial, Manon F. Wider, David Leppert, Jens Kuhle, Laura N. Walti, Joerg C. Schefold, Thibaud Spinetti, Franziska Suter-Riniker, Ronald Dijkman, Stephen L. Leib	Neuro-axonal injury in COVID-19: the role of systemic inflammation and SARS-CoV-2 specific immune response	https://doi.org/10.1177%2F17562864221080528	Published	March 12, 2022	Study	https://journals.sagepub.com/doi/10.1177/17562864221080528	In coronavirus disease-2019 (COVID-19) patients, there is increasing evidence of neuronal injury by the means of elevated serum neurofilament light chain (sNfL) levels. However, the role of systemic inflammation and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–specific immune response with regard to neuronal injury has not yet been investigated. Methods: In a prospective cohort study, we recruited patients with mild–moderate (n = 39) and severe (n = 14) COVID-19 and measured sNfL levels, cytokine concentrations, SARS-CoV-2-specific antibodies including neutralizing antibody titers, and cell-mediated immune responses at enrollment and at 28(±7) days. We explored the association of neuro-axonal injury as by the means of sNfL measurements with disease severity, cytokine levels, and virus-specific immune responses. Results: sNfL levels, as an indicator for neuronal injury, were higher at enrollment and increased during follow-up in severely ill patients, whereas during mild–moderate COVID-19, sNfL levels remained unchanged. Severe COVID-19 was associated with increased concentrations of cytokines assessed [interleukin (IL)-6, IL-8, interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α)], higher anti-spike IgG and anti-nucleocapsid IgG concentrations, and increased neutralizing antibody titers compared with mild–moderate disease. Patients with more severe disease had higher counts of defined SARS-CoV-2-specific T cells. Increases in sNfL concentrations from baseline to day 28(±7) positively correlated with anti-spike protein IgG antibody levels and with titers of neutralizing antibodies. Conclusion: Severe COVID-19 is associated with increased serum concentration of cytokines and subsequent neuronal injury as reflected by increased levels of sNfL. Patients with more severe disease developed higher neutralizing antibody titers and higher counts of SARS-CoV-2-specific T cells during the course of COVID-19 disease. Mounting a pronounced virus-specific humoral and cell-mediated immune response upon SARS-CoV-2 infection did not protect from neuro-axonal damage as by the means of sNfL levels.
293	N289		Jacques Hugon,Mathieu Queneau,Marta Sanchez Ortiz,Eva Flore Msika,Karim Farid,Claire Paquet	Cognitive decline and brainstem hypometabolism in long COVID: A case series	https://doi.org/10.1002/brb3.2513	Published	15 March 2022	Study	https://onlinelibrary.wiley.com/doi/10.1002/brb3.2513	Objective To assess FDG cerebral PET in patients suffering from cognitive impairment linked to Long COVID. The COVID pandemic has affected dozens of millions of people around the world and has resulted in the deaths of more than 3 million people. Following the acute forms, it has been reported sometimes long forms of COVID, with involvements of several organs including the brain. Neurological complications can include cognitive disturbances (brain fog) that are very common and can seriously disturb the life of patients. Methods Fluorodeoxyglucose PETs were performed in 3 patients with cognitive decline following COVID infection. Results We report here 3 cases of brain fog with major hypometabolic areas of the pons revealed by the cerebral FDG PET. Conclusion The dysfunction of the locus coeruleus in these patients could partly explain the cognitive disorders observed. Further studies involving larger cohorts of patients suffering from cognitive dysfunction will be needed to determine if the brainstem is frequently affected in these patients.
294	N290		Che Mohd Nasril Che Mohd Nassir 1,* ,Mohd K. I. Zolkefley 2 ,Muhammad Danial Ramli 3 ,Haziq Hazman Norman 4,Hafizah Abdul Hamid 5 andMuzaimi Mustapha	Neuroinflammation and COVID-19 Ischemic Stroke Recovery—Evolving Evidence for the Mediating Roles of the ACE2/Angiotensin-(1–7)/Mas Receptor Axis and NLRP3 Inflammasome	https://doi.org/10.3390/ijms23063085	Published	13 March 2022	Review	https://www.mdpi.com/1422-0067/23/6/3085/htm	Cerebrovascular events, notably acute ischemic strokes (AIS), have been reported in the setting of novel coronavirus disease (COVID-19) infection. Commonly regarded as cryptogenic, to date, the etiology is thought to be multifactorial and remains obscure; it is linked either to a direct viral invasion or to an indirect virus-induced prothrombotic state, with or without the presence of conventional cerebrovascular risk factors. In addition, patients are at a greater risk of developing long-term negative sequelae, i.e., long-COVID-related neurological problems, when compared to non-COVID-19 stroke patients. Central to the underlying neurobiology of stroke recovery in the context of COVID-19 infection is reduced angiotensin-converting enzyme 2 (ACE2) expression, which is known to lead to thrombo-inflammation and ACE2/angiotensin-(1–7)/mitochondrial assembly receptor (MasR) (ACE2/Ang-(1-7)/MasR) axis inhibition. Moreover, after AIS, the activated nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome may heighten the production of numerous proinflammatory cytokines, mediating neuro-glial cell dysfunction, ultimately leading to nerve-cell death. Therefore, potential neuroprotective therapies targeting the molecular mechanisms of the aforementioned mediators may help to inform rehabilitation strategies to improve brain reorganization (i.e., neuro-gliogenesis and synaptogenesis) and secondary prevention among AIS patients with or without COVID-19. Therefore, this narrative review aims to evaluate the mediating role of the ACE2/Ang- (1-7)/MasR axis and NLRP3 inflammasome in COVID-19-mediated AIS, as well as the prospects of these neuroinflammation mediators for brain repair and in secondary prevention strategies against AIS in stroke rehabilitation.
295	N291		Peter A.HallabGangMengbAnnaHudsonaMohammad N.SakibaSara C.HitchmancJamesMacKillopdWarren K.BickeleGeoffrey T.Fongabf	Cognitive function following SARS-CoV-2 infection in a population-representative Canadian sample	https://doi.org/10.1016/j.bbih.2022.100454	Published	25 March 2022	Study	https://www.sciencedirect.com/science/article/pii/S2666354622000448	Background SARS-CoV-2 infection is believed to adversely affect the brain, but the degree of impact on socially relevant cognitive functioning and decision-making is not well-studied, particularly among those less vulnerable to age-related mortality. The current study sought to determine whether infection status and COVID-19 symptom severity are associated with cognitive dysfunction among young and middled-aged adults in the general population, using self-reported lapses in executive control and a standardized decision-making task. Method The survey sample comprised 1958 adults with a mean age of 37 years (SD = 10.4); 60.8% were female. Participants reported SARS-CoV-2 infection history and, among those reporting a prior infection, COVID-19 symptom severity. Primary outcomes were self-reported symptoms of cognitive dysfunction assessed via an abbreviated form of the Barkley Deficits in Executive Functioning Scale (BDEFS) and performance on a validated delay-discounting task. Results Young and middle-aged adults with a positive SARS-CoV-2 infection history reported a significantly higher number of cognitive dysfunction symptoms (Madj = 1.89, SE = 0.08, CI: 1.74, 2.04; n = 175) than their non-infected counterparts (Madj = 1.63, SE = 0.08, CI: 1.47,1.80; n = 1599; β = 0.26, p = .001). Among those infected, there was a dose-response relationship between COVID-19 symptom severity and level of cognitive dysfunction reported, with moderate (β = 0.23, CI: 0.003–0.46) and very/extremely severe (β = 0.69, CI: 0.22–1.16) COVID-19 symptoms being associated with significantly greater cognitive dysfunction. These effects remained reliable and of similar magnitude after controlling for demographics, vaccination status, mitigation behavior frequency, and geographic region, and after removal of those who had been intubated during hospitalization. Very similar—and comparatively larger—effects were found for the delay-discounting task, and when using only PCR confirmed SARS-CoV-2 cases. Conclusions Positive SARS-CoV-2 infection history and moderate or higher COVID-19 symptom severity are associated with significant symptoms of cognitive dysfunction and amplified delay discounting among young and middle-aged adults with no history of medically induced coma.
296	N292		JacquesReis1AlainBuguet2Gustavo C.Román3Peter S.Spencer4	The Covid-19 pandemic, an Environmental Neurology perspective	https://doi.org/10.1016/j.neurol.2022.02.455	Published	22 March 2022	Review	https://www.sciencedirect.com/science/article/pii/S0035378722005495	Neurologists have a particular interest in SARS-CoV-2 because the nervous system is a major participant in Covid-19, both in its acute phase and in its persistent post-Covid phase. The global spread of SARS-CoV-2 infection has revealed most of the challenges and risk factors that humanity will face in the future. We review from an Environmental Neurology perspective some characteristics that have underpinned the pandemic. We consider the agent, SARS-CoV-2, the spread of SARS-CoV-2 influenced by environmental factors, its impact on the brain and some containment measures on brain health. Several questions remain, including the differential clinical impact of variants, the impact of SARS-CoV-2 on sleep and wakefulness, and the neurological components of Long-Covid syndrome. We touch on the role of national leaders and public health policies that have underpinned management of the Covid-19 pandemic. Increased awareness, anticipation and preparedness are needed to address comparable future challenges.
297	N293		Stephen J.FerrandoM.D.abRheaDornbushPh.D., M.P.H.abSeanLynchM.D.abSivanShaharB.A.bLidiaKlepaczM.D.abCarol L.KarmenM.D.bcDonaldChenM.D.bcStephen A.LoboM.D.bcDaniaLermanM.S.W.	Neuropsychological, Medical, and Psychiatric Findings After Recovery From Acute COVID-19: A Cross-sectional Study	https://doi.org/10.1016/j.jaclp.2022.01.003	Published	25 January 2022	Study	https://www.sciencedirect.com/science/article/pii/S2667296022000039	Background Persistent cognitive, medical and psychiatric complaints have been extensively described after recovery from acute SARS-CoV-2 infection. Objective To describe neuropsychological, medical, psychiatric, and functional correlates of cognitive complaints experienced after recovery from acute COVID-19 infection. Methods Sixty participants underwent neuropsychological, psychiatric, medical, functional, and quality-of-life assessments 6–8 months after acute COVID-19. Those seeking care for cognitive complaints in a post-COVID-19 clinical program for post-acute symptoms of COVID-19 (clinical group, N = 32) were compared with those recruited from the community who were not seeking care (nonclinical, N = 28). A subset of participants underwent serological testing for proinflammatory cytokines C-reactive protein, interleukin-6, and tumor necrosis factor-α to explore correlations with neuropsychological, psychiatric, and medical variables. Results For the entire sample, 16 (27%) had extremely low test scores (less than second percentile on at least 1 neuropsychological test). The clinical group with cognitive complaints scored lower than age-adjusted population norms in tests of attention, processing speed, memory, and executive function and scored significantly more in the extremely low range than the nonclinical group (38% vs. 14%, P < 0.04). The clinical group also reported higher levels of depression, anxiety, fatigue, posttraumatic stress disorder, and functional difficulties and lower quality of life. In logistic regression analysis, scoring in the extremely low range was predicted by acute COVID-19 symptoms, current depression score, number of medical comorbidities, and subjective cognitive complaints in the areas of memory, language, and executive functions. Interleukin-6 correlated with acute COVID symptoms, number of medical comorbidities, fatigue, and inversely with measures of executive function. C-reactive protein correlated with current COVID symptoms and depression score but inversely with quality of life. Conclusion Results suggest the existence of extremely low neuropsychological test performance experienced by some individuals months after acute COVID-19 infection, affecting multiple neurocognitive domains. This extremely low neuropsychological test performance is associated with worse acute COVID-19 symptoms, depression, medical comorbidities, functional complaints, and subjective cognitive complaints. Exploratory correlations with proinflammatory cytokines support further research into inflammatory mechanisms and viable treatments.
298	N294	Publication of N219 ES	Antoine Verger, Aurélie Kas, Pierre Dudouet, François Goehringer, Dominique Salmon, Eric Guedj	Visual Interpretation of Brain Hypometabolisms Related to Neurological Long COVID: A French Multicentric Experience	https://doi.org/10.1007/s00259-022-05753-5	Published	23 Mar, 2022	Short communication	https://link.springer.com/article/10.1007/s00259-022-05753-5	This multicenter study aims to provide a qualitative and consensual description of brain 18F-FDG PET images in patients with suspected neurological long COVID, regarding the previously reported pattern involving olfactory bulbs and other limbic/paralimbic regions, as well as the brainstem and cerebellum. Methods: From the beginning of August 2021 to the end of October 2021, brain 18F-FDG PET exams of patients referred for suspected neurological long COVID with positive reverse transcription polymerase chain reaction (RT-PCR) and/or serology for the SARS-CoV-2 infection were retrospectively reviewed in three French Nuclear Medicine departments. Experimented nuclear physicians from each department had to classify according to the same visual interpretation analysis brain 18F-FDG PET scans as being normal, mildly to moderate (incomplete or moderately hypometabolic), or severely affected within the previously reported long COVID hypometabolic pattern. Results: On the 143 brain 18F-FDG PET performed during this period 3 months, 53% of scans were visually interpreted as normal, 31% as mildly to moderate and 16% as severely affected according to the COVID hypometabolic pattern. Importantly, this specific hypometabolic pattern is reported as identical in the three Nuclear Medicine departments. Typical illustrative examples are provided to help nuclear physicians in the interpretation of long COVID pattern. Conclusion: The proposed PET metabolic pattern is easily identified at visual interpretation in clinical routine in part of patients with suspicion of neurological long COVID, requiring special consideration for fronto-basal paramedian regions, the brainstem and cerebellum.
299	N295		Abdulhafeez M. Khair, Rahul Nikam, Sumair Husain, Melanie Ortiz, Gurcharanjeet Kaur	Para and Post-COVID-19 CNS Acute Demyelinating Disorders in Children: A Case Series on Expanding the Spectrum of Clinical and Radiological Characteristics	https://doi.org/10.7759/cureus.23405	Published	March 22, 2022	Case Reports	https://www.cureus.com/articles/89080-para-and-post-covid-19-cns-acute-demyelinating-disorders-in-children-a-case-series-on-expanding-the-spectrum-of-clinical-and-radiological-characteristics	Viral infections can serve as a trigger for variable autoimmune, antibody-mediated demyelinating disorders. There is accumulating evidence that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, causing coronavirus disease 2019 (COVID-19) infection and responsible for the current worldwide pandemic, can lead to a cascade of immune-mediated brain and spinal cord demyelinating injuries. However, such observation in the pediatric age group was only reported in very few patients. Thus, the heterogeneous spectrum of this phenomenon in children is still unfolding. We are reporting a case series of five pediatric patients with a variety of acute central nervous system (CNS) demyelinating disorders in the context of acute or recent COVID-19 infection. A 16-year-old female with anti-myelin oligodendrocyte glycoprotein (MOG) disorder, an eight-year-old male with acute disseminated encephalomyelitis (ADEM), a 13-year-old female with neuromyelitis optica spectrum disorder (NMOSD), and two 14 and 13-year-old females with new-onset multiple sclerosis (MS) are reported, all of whom presented acutely following COVID-19 infection. We propose that para and post-infectious CNS demyelinating disorders can potentially follow acute COVID-19 infection in children. Considering SARS-CoV-2 testing as a part of diagnostic workup is possibly useful. Awareness of the presence of this phenomenon can help in the recognition and management of those patients.
300	N296	ES	Lucia Crivelli,Katie Palmer,Ismael Calandri,Alla Guekht,Ettore Beghi,William Carroll,Jennifer Frontera,David García-Azorín,Erica Westenberg,Andrea Sylvia Winkler,Francesca Mangialasche,Ricardo F. Allegri,Miia Kivipelto	Changes in cognitive functioning after COVID-19: A systematic review and meta-analysis	https://doi.org/10.1002/alz.12644	Published	17 March 2022	Review	https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.12644	We conducted a systematic review and meta-analysis of the cognitive effects of coronavirus disease 2019 (COVID-19) in adults with no prior history of cognitive impairment. Methods Searches in Medline/Web of Science/Embase from January 1, 2020, to December 13, 2021, were performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A meta-analysis of the Montreal Cognitive Assessment (MoCA) total score comparing recovered COVID-19 and healthy controls was performed. Results Oof 6202 articles, 27 studies with 2049 individuals were included (mean age = 56.05 years, evaluation time ranged from the acute phase to 7 months post-infection). Impairment in executive functions, attention, and memory were found in post-COVID-19 patients. The meta-analysis was performed with a subgroup of 290 individuals and showed a difference in MoCA score between post-COVID-19 patients versus controls (mean difference = −0.94, 95% confidence interval [CI] −1.59, −0.29; P = .0049). Discussion Patients recovered from COVID-19 have lower general cognition compared to healthy controls up to 7 months post-infection.
301	N297		Manuel Herrero-Montes,1,2 César Fernández-de-las-Peñas ,3 Diego Ferrer-Pargada,4 Sandra Tello-Mena,4 Ignacio Cancela-Cilleruelo,3 Jorge Rodríguez-Jiménez,3 Domingo Palacios-Ceña,3 and Paula Parás-Bravo1,2	Prevalence of Neuropathic Component in Post-COVID Pain Symptoms in Previously Hospitalized COVID-19 Survivors	https://doi.org/10.1155/2022/3532917	Published	16 Mar 2022	Study	https://www.hindawi.com/journals/ijclp/2022/3532917/	To investigate the prevalence of neuropathic pain symptoms and to analyze the correlation between neuropathic symptoms with pain-related, psychological, and cognitive variables in COVID-19 survivors exhibiting “de novo” post-COVID pain. Methods. Seventy-seven (n = 77) previously hospitalized COVID-19 survivors presenting with post-COVID pain completed demographic (such as age, height, and weight), pain-related (the duration and intensity of pain), psychological (depressive/anxiety levels), and cognitive (catastrophizing and kinesiophobia) variables. The Self-Report Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) questionnaire was also assessed. After conducting multivariable correlation analyses, a stepwise multiple linear regression model was performed to identify S-LANSS predictors. Results. Participants were assessed a mean of 6.0 (SD 0.8) months after hospital discharge. Nineteen (24.6%) exhibited neuropathic pain symptoms (S-LANSS score≥12 points). The S-LANSS score was positively associated with the duration of post-COVID pain (r: 0.262), anxiety levels (r: 0.275), and kinesiophobia level (r: 0.291) (all, < 0.05). The stepwise regression analysis revealed that 12.8% of the S-LANSS variance was just explained by kinesiophobia. Conclusion. This study found that almost 25% of previously hospitalized COVID-19 survivors with “de novo” post-COVID pain reported a neuropathic pain component. The presence of neuropathic pain symptomatology was associated with more anxiety and kinesiophobia, but only kinesiophobia level was significantly associated explaining 12.8% of the variance of the S-LANSS score.
302	N298		Abdullah Egiz 1 2 , Sarvin Farajzadeh-Asl 1 2 , Bassel Alaa Abouzeid 1 2 , Radhi Al-Shaharli 1 2 , Rand Al-Assadi 1 2	The Potential Cerebrovascular Sequelae of Coronavirus Disease 19 in Alzheimer’s Disease: Coincidental or Causative?	https://doi.org/10.5152/eurasianjmed.2022.21146	Published	01 February 2022	Article	https://www.eajm.org/en/the-potential-cerebrovascular-sequelae-of-coronavirus-disease-19-in-alzheimer-s-disease-coincidental-or-causative-133366	Since coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization on March 11, 2020, the impact of this global health crisis has resulted in numerous disruptions to clinical research.1 Coronavirus disease 2019 seems to be leaving a long-lasting effect, reducing the quality of life of many individuals.1 The current research suggests that the long-term sequelae of COVID-19 are likely to disproportionately affect high-risk individuals including Alzheimer’s disease (AD) patients.1 The neuropsychiatric sequelae of COVID-19 have gained attention given its projected weight in the global burden of disability.1 However, it seems that a deeper look into the effect of COVID-19 on AD has overlooked the potential cerebrovascular alterations. Therefore, we would like to highlight the potential cerebrovascular sequelae associated with COVID-19 infections in patients with AD as shown in Figure 1. Alzheimer’s disease and dementia are an increasing global health challenge, affecting nearly 40-50 million people.2 Alzheimer’s disease is a neurodegenerative disease caused by the formation of β-amyloid plaques and neurofibrillary tangles in the cortex, manifesting clinically as a cognitive impairment that progressively declines with age.2 Given the prevalence of the disease, many individuals are at risk of acquiring COVID-19 infections and possibly experiencing neurological sequelae.1 A systematic review by Fraiman et al3 concluded that cerebrovascular events are common findings in COVID-19 infections as authors’ analyses reported 275 patients experienced cerebrovascular accidents (CVAs), ischemic stroke, intracranial hemorrhage, and cerebral venous sinus thrombosis.3,4
303	N299		Ibolya Rutkai, Meredith G. Mayer, Linh M. Hellmers, Bo Ning, Zhen Huang, Christopher J. Monjure, Carol Coyne, Rachel Silvestri, Nadia Golden, Krystle Hensley, Kristin Chandler, Gabrielle Lehmicke, Gregory J. Bix, Nicholas J. Maness, Kasi Russell-Lodrigue, Tony Y. Hu, Chad J. Roy, Robert V. Blair, Rudolf Bohm, Lara A. Doyle-Meyers, Jay Rappaport & Tracy Fischer	Neuropathology and virus in brain of SARS-CoV-2 infected non-human primates	https://doi.org/10.1038/s41467-022-29440-z	Published	01 April 2022		https://www.nature.com/articles/s41467-022-29440-z	Neurological manifestations are a significant complication of coronavirus disease (COVID-19), but underlying mechanisms aren’t well understood. The development of animal models that recapitulate the neuropathological findings of autopsied brain tissue from patients who died from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are critical for elucidating the neuropathogenesis of infection and disease. Here, we show neuroinflammation, microhemorrhages, brain hypoxia, and neuropathology that is consistent with hypoxic-ischemic injury in SARS-CoV-2 infected non-human primates (NHPs), including evidence of neuron degeneration and apoptosis. Importantly, this is seen among infected animals that do not develop severe respiratory disease, which may provide insight into neurological symptoms associated with “long COVID”. Sparse virus is detected in brain endothelial cells but does not associate with the severity of central nervous system (CNS) injury. We anticipate our findings will advance our current understanding of the neuropathogenesis of SARS-CoV-2 infection and demonstrate SARS-CoV-2 infected NHPs are a highly relevant animal model for investigating COVID-19 neuropathogenesis among human subjects.
304	N300		Justin J. Frere, Randal A. Serafini, Kerri D. Pryce, Marianna Zazhytska, Kohei Oishi, Ilona Golynker, Maryline Panis, Jeffrey Zimering, Shu Horiuchi, Daisy A. Hoagland, Rasmus Møller, Anne Ruiz, Jonathan B. Overdevest, Albana Kodra, Peter D. Canoll, James E. Goldman, Alain C. Borczuk, Vasuretha Chandar, Yaron Bram, Robert Schwartz, Stavros Lomvardas, Venetia Zachariou, Benjamin R. tenOever	SARS-CoV-2 infection results in lasting and systemic perturbations post recovery	https://doi.org/10.1101/2022.01.18.476786	pre-print	January 20, 2022	Study	https://www.biorxiv.org/content/10.1101/2022.01.18.476786v1.full	SARS-CoV-2 has been found capable of inducing prolonged pathologies collectively referred to as Long-COVID. To better understand this biology, we compared the short- and long-term systemic responses in the golden hamster following either SARS-CoV-2 or influenza A virus (IAV) infection. While SARS-CoV-2 exceeded IAV in its capacity to cause injury to the lung and kidney, the most significant changes were observed in the olfactory bulb (OB) and olfactory epithelium (OE) where inflammation was visible beyond one month post SARS-CoV-2 infection. Despite a lack of detectable virus, OB/OE demonstrated microglial and T cell activation, proinflammatory cytokine production, and interferon responses that correlated with behavioral changes. These findings could be corroborated through sequencing of individuals who recovered from COVID-19, as sustained inflammation in OB/OE tissue remained evident months beyond disease resolution. These data highlight a molecular mechanism for persistent COVID-19 symptomology and characterize a small animal model to develop future therapeutics.
305	N301		Thibaut Dondaine, Florine Ruthmann, Fanny Vuotto, Louise Carton, Patrick Gelé, Karine Faure, Dominique Deplanque & Régis Bordet	Long-term cognitive impairments following COVID-19: a possible impact of hypoxia	https://doi.org/10.1007/s00415-022-11077-z	Published	24 March 2022	Study	https://link.springer.com/article/10.1007/s00415-022-11077-z	Background Cognitive and emotional disorders frequently persist after recovery from the acute symptoms of COVID-19; possible explanations include pneumonia-induced hypoxia, infection of the central nervous system, and microstrokes. The objective of the present study was to characterize the impact of hypoxia on the cognitive and psychological profile following COVID-19. Methods Sixty-two patients with COVID-19 were enrolled in a cross-sectional study and divided into two groups based on disease severity: outpatients with no pulmonary complications vs. inpatients with hypoxemic pneumonia having received oxygen therapy. All the participants underwent a comprehensive neuropsychological evaluation that included depression, anxiety, fatigue, sleepiness, attentional, memory and executive processes, and social cognition. For the inpatients, we also collected laboratory data (blood gas, blood glucose, fibrin, fibrinogen, D-dimer, and C-reactive protein). Results Cognitive disorders was found in patients with COVID-19: at least 18% had an impairment of memory and 11% had attentional dysfunctions. A high level of fatigue (90% of the patients), anxiety (52%), and depression (50%) was also observed. The impairments in attentional (p < 0.001 for omission and commission in CPT 3) and memory (p < 0.003 for Index Cue Efficiency from free and cue selected reminding test) functions were greater in COVID-19 inpatients that in COVID-19 outpatients. In contrast, levels of fatigue, depression, and anxiety were similarly high in both groups. Conclusions These findings might help to improve the management of COVID-19 patients as a function of the disease severity in particular for patients with hypoxia.
306	N302		FaizaAziouaz1SamahYousfi1YassineMebrouk1ChristineKora2SoumayaElarabi2SihamNasri2ImaneKamaoui2ImaneSkiker2	Aspects radiologiques du neuro-COVID: véritable lien de causalité ou simple coïncidence	https://doi.org/10.1016/j.neurad.2022.01.036	Published	25 March 2022	Study	https://www.sciencedirect.com/science/article/pii/S0150986122000360	Introduction Le neuro-Covid désigne l'ensemble des atteintes du système nerveux associées à l'infection par Sars-CoV-2, et regroupe des entités variées. Elles touchent 8 à 13 % des patients hospitalisés pour infection Covid. Il s'agit soit d'une atteinte directe Objectif L'objectif de notre étude est d'analyser le profil clinico-radiologique des patients étiqueter neuroCovid et de détailler les différents critères permettant de rattacher l'atteinte neurologique à l'infection par le Sars-Cov2. Patients et méthodes Il s'agit d'une étude rétrospective sur dossiers médicaux de 52 patients, colligés au sein du service de neurologie du CHU Mohammed VI d'Oujda, durant une période allant de Mars 2020 à Novembre 2021. Tous les patients ont bénéficié d'un examen clinique rigoureux, d'une IRM médullaire et / ou encéphalique, d'un bilan biologique exhaustif et d'un suivi régulier. Résultats L’âge moyen de nos patients était de 42 ans, avec des extrêmes d’âge, allant de 16 à 71 ans. Le sex-ratio (H/F) était de 0,7. Le raisonnement étiologique s'est basé sur le contexte clinique, l'IRM du névraxe, le bilan biologique et l’évolution sous traitement. Plusieurs aspects radiologiques ont été retrouvés : les accidents ischémiques cérébraux (38%), les encéphalopathies nécrotico-hémorragiques (35%), les atteintes neuro-inflammatoires (21%), telles que des encéphalites ou des myélites, mais également les myéloradiculites (5%). Discussion l'IRM est l'examen de première intention dans l'exploration d'une atteinte neurologique centrale du Sars-Cov-2. Elle permet de mettre en évidence d'une part la lésion responsable du tableau clinique et d'autre part d’éliminer plusieurs hypothèses diagnostiques. La discussion diagnostique se base sur l'exclusion des étiologies pouvant être à l'origine de l'affection neurologique, en se basant sur les données récentes de la littérature, et sur l’évolution sous traitement. Conclusion Le diagnostic étiologique des neuro-Covid reste difficile. La démarche diagnostique doit être rigoureuse pour ne pas lier tout symptôme à l'infection Covid.
307	N303		JulienCoelhoabcJean-ArthurMicoulaud-FranchiabcAnne-SophieWietdDucNguyendJacquesTaillardabPierrePhilipabc	Circadian misalignment is associated with Covid-19 infection	https://doi.org/10.1016/j.sleep.2022.03.015	Published	26 March 2022	Study	https://www.sciencedirect.com/science/article/pii/S1389945722000910	Highlights •Circadian misalignment is frequent (20.8%) in the general population. •Circadian misalignment is associated with Covid-19 infection (OR=2.07 [1.12-3.80]). •Mean sleep duration was not associated with Covid-19 infection. •Appropriate schedules could help to reduce the risk of Covid-19 infection. Background Circadian system contributes to the regulation of inflammatory processes, but the role of circadian misalignment as a risk factor for contracting Covid-19 has up to now been poorly studied. The aim of this study was to explore the relationship between circadian misalignment (chronic disturbance of the circadian system) and the risk of Covid-19 infection in a population of subjects suspected of contact or infection with SARS-CoV-2. Methods Cross-sectional single-center study conducted during a period without lockdown in winter 2021. Recruitment took place in a Covid-19 outpatient testing center. Subjects between 18 and 45 years old were included whether they were symptomatic or not, healthcare workers or not, in contact with a Covid-19 case or not. To determine social jetlag, a proxy of circadian misalignment, they were asked about their usual sleep-wake behaviors. Usual sleep duration and sleep-wake timing were explored on workdays and free days. Social jetlag was defined as at least 2 hours shift of circadian alignment (defined as the difference between mid-sleep on workdays and mid-sleep on free days, mid-sleep as the median between bedtime and rise time). Results One thousand fourteen subjects were included (sampling rate: 10.8%, 39% men, mean age 28± 8) with 56 subjects positive for Covid-19 (positivity rate: 5.5%). Usual mean sleep duration was equivalent in both groups (7h47 versus 7h49, p=0.733). Social jetlag greater than 2 hours comprised 33.3% of subjects in the Covid-19 group versus 20.6% in the control group (p=0.026). After adjustment on age, gender, BMI and work schedules, subjects presenting with social jetlag greater than 2 hours had a 2.07-fold higher likelihood to test positive than subjects who had identical sleep-wake timing on workdays and free days (OR=2.07, 95%CI= [1.12-3.80], p=0.024). Conclusion Circadian misalignment not only is present in subjects infected by Covid-19 but could also be responsible for a higher likelihood of being infected. The chronobiological impact on the immune system or a higher likelihood of being exposed to social contacts during nocturnal activities could explain our findings, which need to be confirmed in a future large cohort study. Regular sleep-wake timing could ultimately become a target for preventing Covid-19 infection.
308	N304		Masha G.SavelieffaEva L.FeldmanabcAmro M.Stinobc	Neurological sequela and disruption of neuron-glia homeostasis in SARS-CoV-2 infection	https://doi.org/10.1016/j.nbd.2022.105715	Published	29 March 2022	Review	https://www.sciencedirect.com/science/article/pii/S0969996122001073	The coronavirus disease 2019 (COVID-19) pandemic is responsible for 267 million infections and over 5 million deaths globally. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a single-stranded RNA beta-coronavirus, which causes a systemic inflammatory response, multi-organ damage, and respiratory failure requiring intubation in serious cases. SARS-CoV-2 can also trigger neurological conditions and syndromes, which can be long-lasting and potentially irreversible. Since COVID-19 infections continue to mount, the burden of SARS-CoV-2-induced neurologic sequalae will rise in parallel. Therefore, understanding the spectrum of neurological clinical presentations in SARS-CoV-2 is needed to manage COVID-19 patients, facilitate diagnosis, and expedite earlier treatment to improve outcomes. Furthermore, a deeper knowledge of the neurological SARS-CoV-2 pathomechanisms could uncover potential therapeutic targets to prevent or mitigate neurologic damage secondary to COVID-19 infection. Evidence indicates a multifaceted pathology involving viral neurotropism and direct neuroinvasion along with cytokine storm and neuroinflammation leading to nerve injury. Importantly, pathological processes in neural tissue are non-cell autonomous and occur through a concerted breakdown in neuron-glia homeostasis, spanning neuron axonal damage, astrogliosis, microgliosis, and impaired neuron-glia communication. A clearer mechanistic and molecular picture of neurological pathology in SARS-CoV-2 may lead to effective therapies that prevent or mitigate neural damage in patients contracting and developing severe COVID-19 infection.
309	N305		Shwan A.AhmadaShvan H.MohammedbBerwn A.AbdullaabBestoon KhSalihaMarwan N.HassanabAbdulwahid M.SalihacFahmi H.KakamadabcHiwa O.AbdullahabHemn AliHassanabSnurOthmanbShadi HamidSidiqb	Post COVID – 19 neurological disorders; a single center experience; a case series	https://doi.org/10.1016/j.amsu.2022.103508	Published	27 March 2022	Case Reports	https://www.sciencedirect.com/science/article/pii/S2049080122002680	Highlights •COVID-19 survivors might be at risk of developing neurological disorders. •The exact prevalence and risk groups are yet to be established. •This study aims to estimate the post-COVID-19 neurological sequelae. Introduction Coronavirus disease 2019 (COVID-19) pandemic, is a newly conducted respiratory disease caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). The current study aims to estimate the neurological diseases which develop after COVID-19 infection. Method This is a single center retrospective case series conducted in seven months. the patients were collected in an out-patient clinic. Diagnosis of COVID-19 and the way of diagnosis is confirmed through either polymerase chain reaction (PCR) test for COVID-19 and/or typical findings on chest computed tomography scan (CT scan). Patients developed neurological symptoms after being infected with COVID-19. Symptoms have to be developed within less than 6 months of recovery, or developed during illness and persisted after recovery. Result A total number of 59 patients infected with SARS-CoV2 were included. The majority of the patients had mild symptoms 32 (54%), 12 (20%) patients developed severe symptoms. Headache was the most common presenting symptom 27(46%) followed by fatigue in 8 (13.5%). The majority of the patients 55 (91.6%) presented with no focal signs. MRI was done for 27 (46%) patients without abnormal finding in 22 cases. Nearly 22 (37.3%) cases were diagnosed as recurrent episodes of migraine or new onset of migraine. All patients were managed according to the underlying pathology, only (28, 47.5%) patients were known to be completely recovered. Conclusion SARS-CoV2 can invade and cause inflammation in the central and peripheral nervous systems. It is responsible for many neurological problems. More studies are necessary to analyze the long term effect of the virus on the nervous system.
310	N306		FrançoisLERSY1CarolineBund2Izzie JacquesNamer2StéphaneKremer1	Evolution des données de neuro-imagerie chez les patients COVID-19 sévères avec atteinte neurologique initiale	https://doi.org/10.1016/j.neurad.2022.01.026	Published	25 March 2022	Study	https://www.sciencedirect.com/science/article/pii/S0150986122000268	Introduction Les complications cérébrales aiguës en lien avec la COVID-19 ont été largement documentées par IRM cérébrales. Le but de cette étude était de présenter l’évolution des données de neuro-imagerie (IRM et PET-TDM au 18F-FDG) chez les patients guéris de la COVID-19. Matériels et méthodes Durant la première vague de la pandémie de COVID-19 entre le 1er mars et le 31 mai 2021, 112 consécutifs patients COVID-19 ayant des manifestations neurologiques ont réalisées une IRM cérébrale aux Hôpitaux Universitaires de Strasbourg. Après guérison, durant le suivi, parmi ces 112 patients, 31 ont réalisé des examens d'imagerie complémentaires (au moins une IRM cérébrale). L'ensemble de ces 31 patients était initialement hospitalisé en réanimation pour une maladie sévère. Résultats 23 hommes (74%) et 8 (26%) femmes ont été inclus avec une moyenne d’âge de 61 ans (18-79 ans). Les diagnostics retenus sur la première IRM cérébrale regroupaient: i) Prise de contraste leptoméningées; ii) Microsaignements diffus (« Critical illness-associated cerebral microbleeds »); iii) AVC ischémique; iv) Suspicion de vascularite cérébrale; v) Lésions démyélinisantes inflammatoires aiguës. Durant le suivi, l’évolution des prises de contraste leptoméningées était dissociée et les microsaignements étaient stables. Les anomalies artérielles pariétales ont régressé chez l'ensemble des sujets ayant une suspicion de vascularite cérébrale. 4 (13%) patients ont présenté de nouvelles complications durant le suivi: AVC ischémique, névrite, nette augmentation de la charge lésionnelle vasculaire chez un patient avec une suspicion initiale de vascularite cérébrale, apparition d'un rehaussement pariétal artériel évocateur d'une vascularite cérébrale. La majorité de nos patients ont démontré une normalisation, au moins partielle, de la perfusion cérébrale. Concernant la volumétrie cérébrale, nous avons observé une perte de volume de 3.2% pour la substance grise sur une période moyenne de 5 mois. Concernant les données de médecine nucléaire, les principaux résultats observés étaient des hypométabolismes temporo-insulaire et des hypermétabolismes des colliculi. Conclusion Lors du suivi, une minorité de nos patients inclus ont démontré de nouvelles complications en imagerie.
311	N307		Jane K. Parker 1,* ,Lisa Methven 1 ,Robert Pellegrino 2 ,Barry C. Smith 3 ,Simon Gane 4 andChristine E. Kelly 1,5	Emerging Pattern of Post-COVID-19 Parosmia and Its Effect on Food Perception	https://doi.org/10.3390/foods11070967	Published	27 March 2022	Study	https://www.mdpi.com/2304-8158/11/7/967/htm	Olfactory dysfunction is amongst the many symptoms of Long COVID. Whilst most people that experience smell loss post COVID-19 recover their sense of smell and taste within a few weeks, about 10% of cases experience long-term problems, and their smell recovery journey often begins a few months later when everyday items start to smell distorted. This is known as parosmia. The aim of this study was to identify the key food triggers of parosmic distortions and investigate the relationship between distortion and disgust in order to establish the impact of parosmia on diet and quality of life. In this cross-sectional study (n = 727), respondents experiencing smell distortions completed a questionnaire covering aspects of smell loss, parosmia and the associated change in valence of everyday items. There was a significant correlation between strength and disgust (p < 0.0001), and when the selected items were reported as distorted, they were described as either unpleasant or gag-inducing 84% of the time. This change in valence associated with loss of expected pleasure and the presence of strange tastes and burning sensations must certainly lead to changes in eating behaviours and serious longer-term consequences for mental health and quality of life.
312	N308		Andrea Frosolini 1,2,*,† ,Daniela Parrino 3,† ,Cristoforo Fabbris 4,Francesco Fantin 1,2,Ingrid Inches 5,Sara Invitto 6 ,Giacomo Spinato 1,4 andCosimo De Filippis 1	Magnetic Resonance Imaging Confirmed Olfactory Bulb Reduction in Long COVID-19: Literature Review and Case Series	https://doi.org/10.3390/brainsci12040430	Published	24 March 2022	Case Series	https://www.mdpi.com/2076-3425/12/4/430/htm	An altered sense of smell and taste was recognized as one of the most characteristic symptoms of coronavirus infection disease (COVID-19). Despite most patients experiencing a complete functional resolution, there is a 21.3% prevalence of persistent alteration at 12 months after infection. To date, magnetic resonance imaging (MRI) findings in these patients have been variable and not clearly defined. We aimed to clarify radiological alterations of olfactory pathways in patients with long COVID-19 characterized by olfactory dysfunction. A comprehensive review of the English literature was performed by analyzing relevant papers about this topic. A case series was presented: all patients underwent complete otorhinolaryngology evaluation including the Sniffin’ Sticks battery test. A previous diagnosis of SARS-CoV-2 infection was confirmed by positive swabs. The MRIs were acquired using a 3.0T MR scanner with a standardized protocol for olfactory tract analysis. Images were first analysed by a dedicated neuroradiologist and subsequently reviewed and compared with the previous available MRIs. The review of the literature retrieved 25 studies; most cases of olfactory dysfunction more than 3 months after SARS-CoV-2 infection showed olfactory bulb (OB) reduction. Patients in the personal case series had asymmetry and a reduction in the volume of the OB. This evidence was strengthened by the comparison with a previous MRI, where the OBs were normal. The results preliminarily confirmed OB reduction in cases of long COVID-19 with an altered sense of smell. Further studies are needed to clarify the epidemiology, pathophysiology and prognosis.
313	N309	ES	Jennifer Abbasi	Even Mild COVID-19 May Change the Brain	https://doi.org/10.1001/jama.2022.4507	Published	March 23, 2022	Article	https://jamanetwork.com/journals/jama/fullarticle/2790595	What We’ve Learned The brain scans and cognitive scores of participants who had been infected with SARS-CoV-2 showed changes between the 2 time points that differed from those seen in the control group, with greater differences among older participants. Although not everyone who became infected with SARS-CoV-2 had these differences, the prior-infection group on average had: greater loss of gray matter thickness in the orbitofrontal cortex and parahippocampal gyrus, areas associated with the sense of smell greater tissue damage in areas connected with the primary olfactory cortex, also linked with smell greater decrease in whole-brain volume and increase in cerebrospinal fluid volume greater decline in the ability to perform complex tasks, which on brain scans was associated with atrophy in crus II, an area of the cerebellum associated with cognition Compared with the control group, volunteers with a prior SARS-CoV-2 infection had an additional 0.2% to 2% gray matter loss or tissue damage on average between their 2 sets of scans. For context, adults lose about 0.2% to 0.3% of gray matter in memory-related brain regions per year, according to Gwenaëlle Douaud, PhD, the study’s lead author and an associate professor at the NDCN. The findings remained statistically significant when the patients hospitalized with COVID-19 were removed from the analysis. Too few influenza cases occurred to draw comparisons, but brain differences among 11 volunteers who developed non–COVID-19 pneumonia between imaging sessions did not substantially overlap with brain regions implicated in the COVID-19 analysis. This could indicate that the study’s findings are specific to SARS-CoV-2 infection, not respiratory infection in general. Possible Explanations In their article, Douaud’s team offered several potential mechanisms by which SARS-CoV-2 infection might directly or indirectly alter brain structure, including reduced sensory input related to loss of smell neuroinflammation or immune reactions direct viral infection of brain cells
314	N310	ES	SERENA SPUDICH AND AVINDRA NATH	Nervous system consequences of COVID-19	https://doi.org/10.1126/science.abm2052	Published	20 Jan 2022	Article	https://www.science.org/doi/10.1126/science.abm2052	Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is considered a respiratory pathogen, myriad neurologic complications—including confusion, stroke, and neuromuscular disorders—manifest during acute COVID-19. Furthermore, maladies such as impaired concentration, headache, sensory disturbances, depression, and even psychosis may persist for months after infection, as part of a constellation of symptoms now called Long Covid. Even young people with mild initial disease can develop acute COVID-19 and Long Covid neuropsychiatric syndromes. The pathophysiological mechanisms are not well understood, although evidence primarily implicates immune dysfunction, including nonspecific neuroinflammation and antineural autoimmune dysregulation. It is uncertain whether unforeseen neurological consequences may develop years after initial infection. With millions of individuals affected, nervous system complications pose public health challenges for rehabilitation and recovery and for disruptions in the workforce due to loss of functional capacity. There is an urgent need to understand the pathophysiology of these disorders and develop disease-modifying therapies.
315	N311		Aureodo Carmo FilhoaEelcovan DuinkerkenabcJulio CesarTolentinoaSergio LuisSchmidta	Attention profile of physically recovered COVID-19 inpatients on the day of discharge	https://doi.org/10.1016/j.jpsychires.2022.03.047	Published	5 April 2022	Study	https://www.sciencedirect.com/science/article/pii/S0022395622001765	Few studies have reported specific attention deficits in post-COVID-19 patients. Attention consists of different subdomains. Disruptions to specific attention subdomains might impair a wide range of everyday tasks, including road safety. As there are millions of COVID-19 patients with different socio-economic backgrounds, screening of attentional performance less dependent on education is needed. Here, we verified if physically recovered COVID-19 inpatients showed specific attention decrements at discharge. The Continuous Visual Attention Test (CVAT) is a Go/No-go task which is independent of participants’ schooling. It detects visuomotor reaction time (RT = intrinsic alertness), variability of reaction time (VRT = sustained attention), omission (focused-attention), and commission errors (response-inhibition). Thirty physically functional COVID-19 inpatients at discharge and 30 non-infected controls underwent the CVAT. A MANCOVA was performed to examine differences between controls and patients, followed by post-hoc ANCOVAs. Then, we identified the percentile score for each patient within the distribution of the CVAT performance of 211 subjects mentally capable of driving (reference group). COVID-19 patients at discharge showed greater RT and VRT, and more omission errors than controls. Twenty-two patients (73%) had performance below the 5th percentile of the reference group in one or more subdomains. As slow visuomotor RT, deficits in focusing and difficulties in keeping visual attention are associated with traffic accidents, we concluded that most COVID-19 patients at discharge had deficits that may increase the risk of road injuries. As these deficits will probably affect other daily activities, a routine assessment with the CVAT could provide useful information on whom to send to post-COVID centers.
316	N312		Helena Ariño, Rosie Heartshorne, Benedict D. Michael, Timothy R. Nicholson, Angela Vincent, Thomas A. Pollak & Alberto Vogrig	Neuroimmune disorders in COVID-19	https://doi.org/10.1007/s00415-022-11050-w	Published	30 March 2022	Review	https://link.springer.com/article/10.1007/s00415-022-11050-w	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the aetiologic agent of the coronavirus disease 2019 (COVID-19), is now rapidly disseminating throughout the world with 147,443,848 cases reported so far. Around 30–80% of cases (depending on COVID-19 severity) are reported to have neurological manifestations including anosmia, stroke, and encephalopathy. In addition, some patients have recognised autoimmune neurological disorders, including both central (limbic and brainstem encephalitis, acute disseminated encephalomyelitis [ADEM], and myelitis) and peripheral diseases (Guillain–Barré and Miller Fisher syndrome). We systematically describe data from 133 reported series on the Neurology and Neuropsychiatry of COVID-19 blog (https://blogs.bmj.com/jnnp/2020/05/01/the-neurology-and-neuropsychiatry-of-covid-19/) providing a comprehensive overview concerning the diagnosis, and treatment of patients with neurological immune-mediated complications of SARS-CoV-2. In most cases the latency to neurological disorder was highly variable and the immunological or other mechanisms involved were unclear. Despite specific neuronal or ganglioside antibodies only being identified in 10, many had apparent responses to immunotherapies. Although the proportion of patients experiencing immune-mediated neurological disorders is small, the total number is likely to be underestimated. The early recognition and improvement seen with use of immunomodulatory treatment, even in those without identified autoantibodies, makes delayed or missed diagnoses risk the potential for long-term disability, including the emerging challenge of post-acute COVID-19 sequelae (PACS). Finally, potential issues regarding the use of immunotherapies in patients with pre-existent neuro-immunological disorders are also discussed.
317	N313		Abdul Mannan Baig*	Correlating Biochemical and Structural Changes in the Brain with Clinical Features in COVID-19	https://doi.org/10.1021/acschemneuro.2c00164	Published	April 2, 2022	Article	https://pubs.acs.org/doi/full/10.1021/acschemneuro.2c00164	With emerging reports of the deleterious effects of SARS-CoV-2 reflecting as neurological deficits in COVID-19, the biochemical and morphological changes it casts on the brain are also being investigated. This is an important niche of research as it is expected to predict and relate the neurological clinical features in the acute phase and chronic syndromic forms of COVID-19. Here debated are the biochemical and structural changes that can be related to the neurological manifestations in COVID-19.
318	N314		Paul Lingor, Antonia F. Demleitner, Andreas W. Wolff & Emily Feneberg	SARS-CoV-2 and neurodegenerative diseases: what we know and what we don’t	https://doi.org/10.1007/s00702-022-02500-w	Published	17 April 2022	Review	https://link.springer.com/article/10.1007/s00702-022-02500-w	Infection of the CNS with the SARS-CoV-2 can occur via different routes and results in para- or post-infectious manifestations with a variety of neurological symptoms. In patients with neurodegenerative diseases, SARS-CoV-2 is often associated with a higher fatality rate, which is a relevant problem in increasingly older populations. Apart from the direct consequences of an infection in patients with neurodegenerative diseases, indirect consequences of the pandemic such as limited access to care facilities and treatment have negative effects on the course of these chronic disorders. The occurrence of long-lasting neurological symptoms after infection with SARS-CoV-2 indicates a prolonged impact on the CNS. However, while it is known that SARS-CoV-2 affects neuronal populations that are relevant in the pathogenesis of neurodegenerative diseases, it is yet unclear whether an infection with SARS-CoV-2 is sufficient to trigger neurodegeneration. Reflecting on the impact of SARS-CoV-2 on neurodegeneration, we provide a concise overview on the current knowledge of SARS-CoV-2-induced pathology in the CNS and discuss yet open questions in the field.
319	N315		Sajal Shukla	The Role of the Blood-Brain Barrier in Stopping the Spread of SARS-CoV-2 to the Brain and Brain Tumors	-	Published	20-4-2022	Article	https://digitalcommons.imsa.edu/sir_presentations/2022/session2/60/	The initial site for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is the upper respiratory system. In many patients, however, the virus finds a way to reach the lungs, which can result in serious infection. Coronavirus can also spread to various parts of the body causing multiorgan failure. Although over 80% of patients with severe COVID-19 demonstrate neurological symptoms, very little direct evidence exists to support the claim that the virus can cross the blood-brain barrier and actively infect the brain. Interestingly, we discovered lung cancer tissue spread to the brain of a COVID-19 patient to be positive for SARS-CoV-2 along with brain tissue adjacent to the metastatic tumor. These findings raise the possibility that metastatic tumors may bring the virus from alternative parts of the body to the brain or may break down the blood-brain barrier to allow for the virus to spread to the brain. In this project, based on extensive literature review, we discuss the role of the blood-brain barrier in limiting the spread of SARS-CoV-2 to the brain and possible mechanisms, which may allow SARS-CoV-2 to reach and infect the brain and brain tumors. We also provide detailed information about the pattern of SARS-CoV-2 detection in metastatic brain tumor and adjacent brain tissue. These findings are important for the understanding of mechanisms by which SARS-CoV-2 can cause brain disease.
320	N316		Marcell P. Szabo, Michiyo Iba, Avindra Nath, Eliezer Masliah & Changyoun Kim	Does SARS-CoV-2 affect neurodegenerative disorders? TLR2, a potential receptor for SARS-CoV-2 in the CNS	https://doi.org/10.1038/s12276-022-00755-7	Published	08 April 2022	Review	https://www.nature.com/articles/s12276-022-00755-7	The coronavirus (COVID-19) pandemic, caused by severe acute respiratory system coronavirus 2 (SARS-CoV-2), has created significant challenges for scientists seeking to understand the pathogenic mechanisms of SARS-CoV-2 infection and to identify the best therapies for infected patients. Although ACE2 is a known receptor for the virus and has been shown to mediate viral entry into the lungs, accumulating reports highlight the presence of neurological symptoms resulting from infection. As ACE2 expression is low in the central nervous system (CNS), these neurological symptoms are unlikely to be caused by ACE2-virus binding. In this review, we will discuss a proposed interaction between SARS-CoV-2 and Toll-like receptor 2 (TLR2) in the CNS. TLR2 is an innate immune receptor that recognizes exogenous microbial components but has also been shown to interact with multiple viral components, including the envelope (E) protein of SARS-CoV-2. In addition, TLR2 plays an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Based on these observations, we hypothesize that TLR2 may play a critical role in the response to SARS-CoV-2 infiltration in the CNS, thereby resulting in the induction or acceleration of AD and PD pathologies in patients.
321	N317		Yahyah Aman	COVID-19-associated cognitive decline	https://doi.org/10.1038/s43587-022-00216-w	Published	04 April 2022	Article	https://www.nature.com/articles/s43587-022-00216-w	There have been reports of negative cognitive outcomes during and after SARS-CoV-2 infection, but the long-term effect of COVID-19 on cognitive function remains unclear. In a study published in JAMA Neurology, Liu and colleagues conducted a 1-year longitudinal assessment of the trajectory of cognitive change in survivors of COVID-19 over the age of 60 (n = 1,438), and age- and sex-matched uninfected control individuals (n = 438), in Wuhan, China. Cognitive assessments were conducted at 6 months and 12 months after discharge from COVID-19-designated hospitals, via questionnaires and telephone interviews. The authors report that survivors of COVID-19 had lower cognitive scores at both time points, and that the incidence of mild cognitive impairment or dementia was higher compared to uninfected individuals. The effects were stronger for those who experienced a severe form of the disease. The incidences of dementia and mild cognitive impairment were 15.00% and 26.15%, respectively, in individuals with severe COVID-19, compared to 0.68% and 5.05%, respectively, in the uninfected control cohort. These findings suggest that, over the long term, severe COVID-19 may lead to an increase in cognitive decline and dementia in older adults, and point to the need to evaluate the effect of the COVID-19 pandemic on future dementia burden worldwide.
322	N318	ES	José WagnerLeonel Tavares-JúnioraAna CéliaCaetano de SouzabJosé WictoPereira BorgescDanilo NunesOliveiraaJosé IbiapinaSiqueira-NetoaManoel AlvesSobreira-NetoaPedroBraga-Netoad	Covid-19 Associated Cognitive Impairment: A Systematic Review	https://doi.org/10.1016/j.cortex.2022.04.006	Published	18 April 2022	Review	https://www.sciencedirect.com/science/article/pii/S0010945222001150	Introduction COVID-19 has a wide range of clinical manifestations. Neurological manifestations in COVID-19 patients were demonstrated during the pandemic, including cognitive impairment. This study aimed to determine any relationship between COVID-19 and cognitive complaints, such as dementia, mild cognitive impairment (MCI), or subjective cognitive decline (SCD). Methods We performed a systematic review of MEDLINE via Ebsco, Cochrane EMBASE, SCOPUS, and LILACS electronic databases of observational studies with COVID-19 patients confirmed by serology or PCR who developed new cognitive impairment or deteriorated from previous cognitive impairment after infection. This review protocol was recorded on PROSPERO with registration number CRD 42021241590. Results A total of 3.520 articles were retrieved and read. Twenty-two studies were selected for our review. A wide range of cognitive assessment tools (n=25) was used. The most described affected domains in these studies were executive functions, attention, and episodic memory. Thirteen studies showed a pattern of cognitive impairment in processing speed, inattention, or executive dysfunction assessed through working memory. Conclusion This review highlights the high frequency of cognitive impairment after COVID-19 infection. However, we were unable to differentiate whether the cognitive impairment found corresponded to mild cognitive impairment or dementia through data from selected studies, and this issue serves as one objective of future studies to be addressed on this topic.
323	N319		ChristopherKäuferaCara S.SchreiberaeAnna-SophiaHartkeaeIvoDendenaStephanieStanelle-BertrambSebastianBeckbNancy MounogouKouassibGeorgBeythiendKathrinBeckerdTomSchreinerdBerfinSchaumburgbAndreasBeinekedeWolfgangBaumgärtnerdeGülsahGabrielbcFranziskaRichterae	Microgliosis and neuronal proteinopathy in brain persist beyond viral clearance in SARS-CoV-2 hamster model	https://doi.org/10.1016/j.ebiom.2022.103999	Published	16 April 2022	Study	https://www.sciencedirect.com/science/article/pii/S2352396422001839	Background Neurological symptoms such as cognitive decline and depression contribute substantially to post-COVID-19 syndrome, defined as lasting symptoms several weeks after initial SARS-CoV-2 infection. The pathogenesis is still elusive, which hampers appropriate treatment. Neuroinflammatory responses and neurodegenerative processes may occur in absence of overt neuroinvasion. Methods Here we determined whether intranasal SARS-CoV-2 infection in male and female syrian golden hamsters results in persistent brain pathology. Brains 3 (symptomatic) or 14 days (viral clearance) post infection versus mock (n = 10 each) were immunohistochemically analyzed for viral protein, neuroinflammatory response and accumulation of tau, hyperphosphorylated tau and alpha-synuclein protein. Findings Viral protein in the nasal cavity led to pronounced microglia activation in the olfactory bulb beyond viral clearance. Cortical but not hippocampal neurons accumulated hyperphosphorylated tau and alpha-synuclein, in the absence of overt inflammation and neurodegeneration. Importantly, not all brain regions were affected, which is in line with selective vulnerability. Interpretation Thus, despite the absence of virus in brain, neurons develop signatures of proteinopathies that may contribute to progressive neuronal dysfunction. Further in depth analysis of this important mechanism is required.
324	N320		HilalKeklicekaHalitSelçukabİlkeKurtcSezerUlukayadGülnurÖztürka	Individuals with a COVID-19 history exhibit asymmetric gait patterns despite full recovery	https://doi.org/10.1016/j.jbiomech.2022.111098	Published	20 April 2022	Study	https://www.sciencedirect.com/science/article/pii/S0021929022001518	COVID-19 is a multisystem infectious disease affecting the body systems. Its neurologic complications include -but are not limited to headache, loss of smell, encephalitis, and cerebrovascular accidents. Even though gait analysis is an objective measure of the neuro-motor system and may provide significant information about the pathophysiology of specific diseases, no studies have investigated the gait characteristics in adults after full recovery from COVID-19. This was a cross-sectional, controlled study that included 12 individuals (mean age, 23.0 ± 4.1 years) with mild-to-moderate COVID-19 history (COVD) and 20 sedentary controls (CONT; mean age, 24.0 ± 3.6 years). Gait was evaluated using inertial sensors on a motorized treadmill. Spatial-temporal gait parameters and gait symmetry were calculated by using at least 512 consecutive steps for each participant. The effect-size analyses were utilized to interpret the impact of the results. Spatial-temporal gait characteristics were comparable between the two groups. The COVD group showed more asymmetrical gait patterns than the CONT group in the double support duration symmetry (p = 0.042), single support duration symmetry (p = 0.006), loading response duration symmetry (p = 0.042), and pre-swing duration symmetry (p = 0.018). The effect size analyses of the differences showed large effects (d = 0.68–0.831). Individuals with a history of mild-to-moderate COVID-19 showed more asymmetrical gait patterns than individuals without a disease history. Regardless of its severity, the multifaceted long-term effects of COVID-19 need to be examined and the scope of clinical follow-up should be detailed.
325	N321		DivyanshiSinghaEktaSinghb	An overview of the neurological aspects in COVID-19 infection	https://doi.org/10.1016/j.jchemneu.2022.102101	Published	14 April 2022	Review	https://www.sciencedirect.com/science/article/pii/S089106182200031X	HIGHLIGHTS •The information provided focuses on COVID-19 adversities extended to the central as well as the peripheral nervous system. •The article helps to understand neurological and neuropsychiatric complications. •This approach can help to develop a recuperative response. The Crown-shaped, severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) triggered the globally fatal illness of Coronavirus disease-2019 (COVID-19). This infection is known to be initially reported in bats and has been causing major respiratory challenges. The primary symptoms of COVID-19 include fever, fatigue and dry cough. As progressed the complications may lead to acute respiratory distress syndrome (ADRS), arrhythmia and shock. This review illustrates the neurological and neuropsychiatric impairments due to COVID-19 infection. The SARS-CoV-2 virus enters via the hematogenous or neural route, spreads to the Central Nervous System (CNS), causing a blood-brain barrier (BBB) dysfunction. Recent scientific articles have reported that SARS-CoV-2 causes several neurological issues such as encephalitis, seizures, acute stroke, delirium, meningoencephalitis and Guillain-Barré Syndrome (GBS). As a long-term effect of this disease certain neuropsychiatric conditions are witnessed such as depression and anxiety. Invasion into followed by degeneration takes place causing an uncontrolled immune response. Transcription factors like NF-κB (nuclear factor kappa light chain enhancer of activated B cells), which modulate genes responsible for inflammatory response gets over expressed. Nrf2 (nuclear factor erythroid 2- related factor 2) counterpoises the inflammation by antioxidant response towards COVID-19 infection. Like every other infection, the severity of this infection leads to deterioration of major organ systems and even leads to death. By the columns of this review, we elaborate on the neurological aspects of this life-threatening infection.
326	N322		AliDehghaniaElhamZokaeibSeyyed MohammadKahaniaElahehAlavinejadcMohammadDehghanidGholam HosseinMeftahieMohammad RezaAfarineshf1	The potential impact of Covid-19 on CNS and psychiatric sequels	https://doi.org/10.1016/j.ajp.2022.103097	Published	8 April 2022	Short communication	https://www.sciencedirect.com/science/article/pii/S1876201822000958	Highlights •Survey answers the question of whether COVID-19 can impact psychiatric disorders, including psychosis and PTSD. •Neuroinvasion of SARS-CoV2 may partially explain why some patients develop mental illnesses. •We also looked at the potential capabilities of COVID-19 that might influence CNS. Due to its high prevalence and fatality, the current Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2) virus, which first emerged in China in 2019, quickly spread around the world and immediately became a serious global health concern. Although respiratory issues were initially the most prominent symptom of coronavirus disease 2019 (COVID-19), it became obvious rapidly that COVID-19, like many other coronavirus family members, could affect the central nervous system (CNS). During the pandemic, CNS involvement expressed itself in a variety of forms, including insomnia, anosmia, headaches, encephalopathies, encephalitis, cerebrovascular accidents, cognitive and memory impairment, and increased psychiatric disorders. Almost everyone who has been infected has at least one of these neurological symptoms, demonstrating that the virus has a high ability to impact the CNS. As the coronavirus pandemic passes its second year, the manifestations it can cause in the long run, such as its psychological sequels, have not yet been thoroughly studied. Given the high importance of this issue in today’s society and due to the lack of reliable knowledge about the COVID-19 landscape on psychiatric disorders, we intend to investigate coronavirus’s possible effect on mental illnesses based on available literature. Because the majority of the psychological effects of the coronavirus can continue for a long period after the pandemic ends, our research can give insight into potential psychiatric sequels associated with COVID-19.
327	N323	ES	Ingrid H. C. H. M. Philippens 1,†,‡ORCID,Kinga P. Böszörményi 1,‡ORCID,Jacqueline A. M. Wubben 1,Zahra C. Fagrouch 1,Nikki van Driel 1,†ORCID,Amber Q. Mayenburg 1ORCID,Diana Lozovagia 1ORCID,Eva Roos 2,Bernadette Schurink 2ORCID,Marianna Bugiani 2,Ronald E. Bontrop 1,3,Jinte Middeldorp 1ORCID,Willy M. Bogers 1ORCID,Lioe-Fee de Geus-Oei 4,5ORCID,Jan A. M. Langermans 1,6ORCID,Ernst J. Verschoor 1,*,§ORCID,Marieke A. Stammes 1,§ORCID andBabs E. Verstrepen 1,†,§ORCID	Brain Inflammation and Intracellular α-Synuclein Aggregates in Macaques after SARS-CoV-2 Infection	https://doi.org/10.3390/v14040776	Published	8 April 2022	Study	https://www.mdpi.com/1999-4915/14/4/776/htm	SARS-CoV-2 causes acute respiratory disease, but many patients also experience neurological complications. Neuropathological changes with pronounced neuroinflammation have been described in individuals after lethal COVID-19, as well as in the CSF of hospitalized patients with neurological complications. To assess whether neuropathological changes can occur after a SARS-CoV-2 infection, leading to mild-to-moderate disease, we investigated the brains of four rhesus and four cynomolgus macaques after pulmonary disease and without overt clinical symptoms. Postmortem analysis demonstrated the infiltration of T-cells and activated microglia in the parenchyma of all infected animals, even in the absence of viral antigen or RNA. Moreover, intracellular α-synuclein aggregates were found in the brains of both macaque species. The heterogeneity of these manifestations in the brains indicates the virus’ neuropathological potential and should be considered a warning for long-term health risks, following SARS-CoV-2 infection.
328	N324		Ahmed M. Eldokla,Aliae A. Mohamed-Hussein,Ahmed M. Fouad,Mariam G. Abdelnaser,Sara T. Ali,Nahed A. Makhlouf,Islam G. Sayed,Hoda A. Makhlouf,Jaffer Shah,Hani Aiash	Prevalence and patterns of symptoms of dysautonomia in patients with long-COVID syndrome: A cross-sectional study	https://doi.org/10.1002/acn3.51557	Published	08 April 2022	Study	https://onlinelibrary.wiley.com/doi/10.1002/acn3.51557	Background The association between autonomic dysfunction and long-COVID syndrome is established. However, the prevalence and patterns of symptoms of dysautonomia in long-COVID syndrome in a large population are lacking. Objective To evaluate the prevalence and patterns of symptoms of dysautonomia in patients with long-COVID syndrome. Methods We administered the Composite Autonomic Symptom Score 31 (COMPASS-31) questionnaire to a sample of post-COVID-19 patients who were referred to post-COVID clinic in Assiut University Hospitals, Egypt for symptoms concerning for long-COVID syndrome. Participants were asked to complete the COMPASS-31 questionnaire referring to the period of more than 4 weeks after acute COVID-19. Results We included 320 patients (35.92 ± 11.92 years, 73% females). The median COMPASS-31 score was 26.29 (0–76.73). The most affected domains of dysautonomia were gastrointestinal, secretomotor, and orthostatic intolerance with 91.6%, 76.4%, and 73.6%, respectively. There was a positive correlation between COMPASS-31 score and long-COVID duration (p < 0.001) and a positive correlation between orthostatic intolerance domain score and post-COVID duration (p < 0.001). There was a positive correlation between orthostatic intolerance domain score and age of participants (p = 0.004). Two hundred forty-seven patients (76.7%) had a high score of COMPASS-31 >16.4. Patients with COMPASS-31 >16.4 had a longer duration of long-COVID syndrome than those with score <16.4 (46.2 vs. 26.8 weeks, p < 0.001). Conclusions Symptoms of dysautonomia are common in long-COVID syndrome. The most common COMPASS-31 affected domains of dysautonomia are gastrointestinal, secretomotor, and orthostatic intolerance. There is a positive correlation between orthostatic intolerance domain score and patients' age.
329	N325		Ili Margalit, Dana Yelin, Moshe Sagi, Maya Merav Rahat, Liron Sheena, Nadav Mizrahi, Yael Gordin, Hadar Agmon, Nitzan Karny Epstein, Alaa Atamna, Ori Tishler, Vered Daitch, Tanya Babich, Donna Abecasis, Yoni Yarom, Shirit Kazum, Dorit Shitenberg, Erik Baltaxe, Odelia Elkana, Irit Shapira-Lichter, Leonard Leibovici, Dafna Yahav	Risk factors and multidimensional assessment of long COVID fatigue: a nested case-control study	https://doi.org/10.1093/cid/ciac283	Published	11 April 2022	Study	https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciac283/6566295	Background Fatigue is the most prevalent and debilitating long COVID symptom, however risk factors and pathophysiology of this condition remain unknown. We assessed risk factors for long COVID fatigue and explored its possible pathophysiology. Methods Nested case-control study in a COVID recovery clinic. Individuals with (cases) and without (controls) significant fatigue were included. We performed a multidimensional assessment evaluating various parameters, including pulmonary function tests and cardiopulmonary exercise testing, and implemented multivariable logistic regression to assess risk factors for significant long COVID fatigue. Results Total of 141 individuals were included. Mean age was 47 (SD 13) years; 115 (82%) were recovering from mild COVID-19. Mean time for evaluation was 8 months following COVID-19. Sixty-six (47%) individuals were classified with significant long COVID fatigue. They had significantly higher number of children, lower proportion of hypothyroidism, higher proportion of sore throat during acute illness and long COVID symptoms, and of physical limitation in daily activities. Individuals with fatigue had poorer sleep quality and higher degree of depression. They had significantly lower heart rate [153.52 (22.64) vs 163.52 (18.53), p=0.038] and oxygen consumption per Kg [27.69 (7.52) vs 30.71 (7.52), p=0.036] at peak exercise. The two independent risk factors for fatigue identified in multivariable analysis were peak exercise heart rate (odds ratio [OR] 0.79 per 10 beats/minute, 95% confidence interval [CI] 0.65-0.96, p=0.019); and long COVID memory impairment (OR 3.76, 95% CI 1.57-9.01, p=0.003). Conclusions Long COVID fatigue may be related to autonomic dysfunction, impaired cognition and decreased mood. This may suggest a limbic-vagal pathophysiology.
330	N326	ES	Carlotta Pipolo ,Daniele Bottai ,Emanuela Fuccillo,Eleonora Aronica,Fabio Bruschi,Antonio Mario Bulfamante,Luca Castellani,Maria Paola Canevini,Davide Chiumello,Sergio Ferrari,Carla Martinelli,Stefano Muttini,Alberto Priori,Alberto Maria Saibene,Chiara Spoldi,Delfina Tosi,Gianluigi Zanusso,Gaetano Pietro Bulfamante,Giovanni Felisati	Evidence of SARS-CoV-2 in nasal brushings and olfactory mucosa biopsies of COVID-19 patients	https://doi.org/10.1371/journal.pone.0266740	Published	April 12, 2022	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0266740	The aim of the present study is to detect the presence of SARS-CoV-2 of patients affected by COVID-19 in olfactory mucosa (OM), sampled with nasal brushing (NB) and biopsy, and to assess whether a non-invasive procedure, such as NB, might be used as a large-scale procedure for demonstrating SARS-CoV-2 presence in olfactory neuroepithelium. Nasal brushings obtained from all the COVID-19 patients resulted positive to SARS-CoV-2 immunocytochemistry while controls were negative. Double immunofluorescence showed that SARS-CoV-2 positive cells included supporting cells as well as olfactory neurons and basal cells. OM biopsies showed an uneven distribution of SARS-CoV-2 positivity along the olfactory neuroepithelium, while OM from controls were negative. SARS-CoV-2 was distinctively found in sustentacular cells, olfactory neurons, and basal cells, supporting what was observed in NB. Ultrastructural analysis of OM biopsies showed SARS-CoV-2 viral particles in the cytoplasm of sustentacular cells. This study shows the presence of SARS-CoV-2 at the level of the olfactory neuroepithelium in patients affected by COVID-19. For the first time, we used NB as a rapid non-invasive tool for assessing a potential neuroinvasion by SARS-CoV-2 infection.
331	N327		Stephanie L Grach ,1 Ravindra Ganesh ,2 Steven A Messina,3 Ryan T Hurt	Post-COVID-19 syndrome: persistent neuroimaging changes and symptoms 9 months after initial infection	https://doi.org/10.1136/bcr-2021-248448	Published	8 April 2022	Case Report	https://casereports.bmj.com/content/bmjcr/15/4/e248448.full.pdf	A previously healthy and active middle-aged woman acquired COVID-19 as an occupational exposure with subsequent persistent post-COVID-19 symptoms including headache, dyspnoea on exertion, chest pressure, tachycardia, anosmia, parosmia, persistent myalgia, vertigo, cognitive decline and fatigue. She presented to a tertiary medical centre for further evaluation after 9 months of persistent symptoms and had a largely unremarkable workup with the exception of a persistently elevated monocyte chemoattractant protein 1, blunted cardiovagal response and non-specific scattered areas of low-level hypometabolism at the bilateral frontal, left precuneus, occipital and parietal regions on PET scan.
332	N328		Mohamed S. Mohamed,Anton Johansson,Jörgen Jonsson † andHelgi B. Schiöth *,†	Dissecting the Molecular Mechanisms Surrounding Post-COVID-19 Syndrome and Neurological Features	https://doi.org/10.3390/ijms23084275	Published	12 April 2022	Review	https://www.mdpi.com/1422-0067/23/8/4275/htm	Many of the survivors of the novel coronavirus disease (COVID-19) are suffering from persistent symptoms, causing significant morbidity and decreasing their quality of life, termed “post-COVID-19 syndrome” or “long COVID”. Understanding the mechanisms surrounding PCS is vital to developing the diagnosis, biomarkers, and possible treatments. Here, we describe the prevalence and manifestations of PCS, and similarities with previous SARS epidemics. Furthermore, we look at the molecular mechanisms behind the neurological features of PCS, where we highlight important neural mechanisms that may potentially be involved and pharmacologically targeted, such as glutamate reuptake in astrocytes, the role of NMDA receptors and transporters (EAAT2), ROS signaling, astrogliosis triggered by NF-κB signaling, KNDy neurons, and hypothalamic networks involving Kiss1 (a ligand for the G-protein-coupled receptor 54 (GPR54)), among others. We highlight the possible role of reactive gliosis following SARS-CoV-2 CNS injury, as well as the potential role of the hypothalamus network in PCS manifestations.
333	N329		Mulazim Hussain Bukhari1*, Shumaila Liaqat2 , Nadia Naseem	Glymphatics and brain fog - the post-COVID-19 phenomenon	https://doi.org/10.51441.BioMedica.5-648	Published	03 March 2022	Mini-review	https://biomedicapk.com/files/pdf/biomedica-648.pdf	Since the COVID-19 pandemic and now since the vaccination, many new signs and symptoms are being observed. Although most people with COVID-19 get better within weeks of illness, there is a wide range of new, relapsing, or ongoing health problems that many people may experience for weeks or more after being infected with the virus that causes COVID-19. Even people who did not have symptoms when they were infected can have post-COVID conditions. The most commonly reported of these symptoms are related to the neurological system, including brain fog, fatigue, anxiety, anosmia, and depression. The role of glymphatics in post-COVID brain fog is a widely studied phenomenon. This review will also explore the possible etio-pathogenesis of brain fog in post-COVID-19 patients.
334	N330		Jeremy M. Morowitz 1,†,Kaylyn B. Pogson 2,†,Daniel A. Roque 3 andFrank C. Church 4,*ORCID	Role of SARS-CoV-2 in Modifying Neurodegenerative Processes in Parkinson’s Disease: A Narrative Review	https://doi.org/10.3390/brainsci12050536	Published	22 April 2022	Review	https://www.mdpi.com/2076-3425/12/5/536/htm	The COVID-19 pandemic, caused by SARS-CoV-2, continues to impact global health regarding both morbidity and mortality. Although SARS-CoV-2 primarily causes acute respiratory distress syndrome (ARDS), the virus interacts with and influences other organs and tissues, including blood vessel endothelium, heart, gastrointestinal tract, and brain. We are learning much about the pathophysiology of SARS-CoV-2 infection; however, we are just beginning to study and understand the long-term and chronic health consequences. Since the pandemic’s beginning in late 2019, older adults, those with pre-existing illnesses, or both, have an increased risk of contracting COVID-19 and developing severe COVID-19. Furthermore, older adults are also more likely to develop the neurodegenerative disorder Parkinson’s disease (PD), with advanced age as the most significant risk factor. Thus, does SARS-CoV-2 potentially influence, promote, or accelerate the development of PD in older adults? Our initial focus was aimed at understanding SARS-CoV-2 pathophysiology and the connection to neurodegenerative disorders. We then completed a literature review to assess the relationship between PD and COVID-19. We described potential molecular and cellular pathways that indicate dopaminergic neurons are susceptible, both directly and indirectly, to SARS-CoV-2 infection. We concluded that under certain pathological circumstances, in vulnerable persons-with-Parkinson’s disease (PwP), SARS-CoV-2 acts as a neurodegenerative enhancer to potentially support the development or progression of PD and its related motor and non-motor symptoms.
335	N331		Dakheelallah M. Almutairi,Abdulaziz H. AlmalkiORCID Icon,Ahmad A. MirzaORCID Icon,Mohammed J. Khalifah,Ammar A. Aljefri,Khalid A. Alsalmi,Majid S. Al-Thaqafy &Mohammed A. Algarni show less	Patterns of self-reported recovery from chemosensory dysfunction following SARS-CoV-2 infection: insights after 1 year of the pandemic	https://doi.org/10.1080/00016489.2022.2062047	Published	24 Apr 2022	Study	https://www.tandfonline.com/doi/abs/10.1080/00016489.2022.2062047	Background The coronavirus disease (COVID-19), due to the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), causes chemosensory dysfunction. Aims/objectives To determine the characteristics of chemosensory dysfunction and to identify factors associated with chemosensory complete recovery and time to recovery. Materials and methods This cross-sectional study included all patients presenting with chemosensory dysfunction and confirmed SARS-CoV-2 infection from May to August 2020 who underwent telemedicine follow-up after 1 year to assess their chemosensory recovery. Results A total of 372 patients were included, of which 53.8% were male. The mean age ± SD was 37.45 ± 13.44. The majority experienced combined (olfactory and gustatory) dysfunction (85.7%), and 315 patients (84.7%) had complete loss of chemosensory function. The independent predictors associated with a low likelihood of complete recovery were parosmia (aOR 0.16, p < .001), upper respiratory tract symptoms (aOR 0.28, p = .001), and dyspnoea (aOR 0.21, p < .001), whereas the factors associated with a long recovery period were parosmia (aOR 12.04, p = .002), headache (aOR 7.19, p = .007), and hypertension (aOR 7.76, p = .039). Conclusions A full recovery outcome was predominant. The presence of parosmia was linked to both an incomplete recovery and a long time to recovery. Significance Parosmia and respiratory symptoms are implicated in the incomplete recuperation of chemosensory function.
336	N332		Karan S.Hingorani1ShivkumarBhadola1Anna M.Cervantes-Arslanian123	COVID-19 and the Brain	https://doi.org/10.1016/j.tcm.2022.04.004	Published	21 April 2022	Review	https://www.sciencedirect.com/science/article/pii/S1050173822000640	Entering the third year into the pandemic, overwhelming evidence demonstrates that Coronavirus disease 2019 (COVID-19) infection is a systemic illness, often with involvement of the central nervous system. Multiple mechanisms may underlie the development of neurologic manifestations of illness, including hypoxia, systemic illness, hypercoagulability, endothelial dysfunction, general critical illness, inflammatory response, and neurotropism of the severe acute respiratory syndrome coronavirus 2 (SARS-Co-V2) virus. COVID-19 infection is associated with neurologic involvement in all stages; acute infection, subacute/post-infection, and growing evidence also suggests during a chronic phase, the post-acute sequalae of COVID-19 (PASC). With over 20,000 published articles on COVID and the brain at the time of writing, it is virtually impossible to present an unbiased comprehensive review of how SARS-Co-V2 impacts the nervous system. In this review, we will present an overview of common neurologic manifestations, in particular focusing on the cerebrovascular complications, and proposed pathophysiology.
337	N333		Stéphane Kremer & H. Rolf Jäger	Brain changes after COVID-19 — how concerned should we be?	https://doi.org/10.1038/s41582-022-00661-6	Published	21 April 2022	Article	https://www.nature.com/articles/s41582-022-00661-6	Analysis of brain images taken before and after infection with SARS-CoV-2 suggests that even mild COVID-19 is associated with brain structure alterations and cognitive impairment. However, the clinical implications for individuals are unclear and further studies are needed to assess the generalizability of the findings and whether the effects are long-lasting. In summary, this important, large cohort study by Douaud et al.1 provides evidence of potentially deleterious effects of mild SARS-CoV-2 infection on brain tissue at the group level. However, the limitations of the study make the full clinical implications of these findings unclear. Further analysis of these data, including correlation with vaccination status, olfactory symptoms, and future development of long COVID symptoms, could provide more insight into the vulnerability of particular subgroups. Importantly, additional follow-up imaging is needed to assess the longevity and reversibility of the observed changes.
338	N334		Ted L. Rothstein	Cortical Grey Matter Volume Loss links to Neurological Sequelae in post COVID-19 “Long Haulers”	https://doi.org/10.21203/rs.3.rs-1582065/v1	pre-print	26 Apr, 2022	Study	https://www.researchsquare.com/article/rs-1582065/v1	Objective COVID-19 (SARS-CoV-2) has been associated with neurological sequelae even in those patients with mild respiratory symptoms. Patients experiencing cognitive symptoms such as “brain fog” and other neurologic sequelae for more than 4 weeks define “long haulers”. There is limited information regarding damage to grey matter structures occurring in COVID-19 “long haulers”. Detecting possible anatomic changes related to COVID-19 is important as conventional Brain MRI often fails to identify disease correlates. 3-dimensional voxel-based morphometry (3D VBM) accurately analyzes, segments and quantifies brain volumes which allows for comparisons between infected COVID-19 “long haulers” and normative data from age and sex-matched healthy controls to obtain values based on their percentage of intracranial volume. Methods This study involved 19 consecutive post COVID-19 surviving “long haulers” who experienced neurologic symptoms. Each patient had Brain MRI with 3D VBM at median time of 72 days following laboratory confirmation. All patients had relatively mild respiratory symptoms which did not require oxygen supplementation, hospitalization, or assisted ventilation. 3D VBM was obtained for whole brain, forebrain parenchyma, cortical grey matter, hippocampus, and thalamus. Results The key finding is a statistically significant loss of cortical grey matter (CGM) volume in each COVID-19 “long hauler”. The loss of CGM volume likely contributes to long term neurological sequelae resulting from COVID-19 infection. Conclusion This study provides evidence for selective loss of volume in CGM as documented by 3D VBM in 19 COVID-19 “long haulers”. Damage to the CGM provides linkage to neurologic symptoms which can affect their quality of life.
339	N335		Mulazim Hussain Bukhari1*, Shumaila Liaqat2 , Nadia Naseem	Glymphatics and brain fog - the post-COVID-19 phenomenon	https://doi.org/10.51441/BioMedica/5-648	Published	03 March 2022	Article	https://biomedicapk.com/files/pdf/biomedica-648.pdf	Since the COVID-19 pandemic and now since the vaccination has emerged as a success, many new signs and symptoms are being observed. Although most people with COVID-19 get better within weeks of illness, there is a wide range of new, relapsing, or ongoing health problems that many people may experience for weeks or more after being infected with the virus that causes COVID-19. Even people who did not have symptoms when they were infected can have post-COVID conditions. The most commonly reported of these symptoms are related to the neurological system, including brain fog, fatigue, anxiety, anosmia, and depression. The role of glymphatics in post-COVID brain fog is a widely studied phenomenon. This review will also explore the possible etio-pathogenesis of brain fog in post-COVID-19 patients. The underlying pathogenesis, after the infection with the virus ends in the brain tissue, may be as follows: 1. It may be immune system hyperactivity, microglial activation with formation of microglial nodules, and destruction of neurons.7 2. It may be due to slow clearance of the virus after infecting the monocytes, which delays the recovery of the patients from post-COVID-19 syndrome.8 3. Angiotensin-converting enzyme 1 and 2 imbalances leading to grave consequences.9 4. Disruption of glymphatics and failure in cleansing system of wastes and proinflammatory cytokines.1 5. Damage of blood-brain barrier due to cytokine storm.10 6. Damage by mimicry or tissue-mimicking effect of autoantibodies.11 7. This may be due to other viruses sitting around and reactivating, e.g., Epstein-Barr virus which, in turn, can cause fatigue.12 The problem in long haulers is the disruption of this lymphatic system, and the inflammatory end products are not washed out and start accumulating and compressing, thus resulting in a brain fog. Majority of this drainage is near the olfactory nerves with a resultant inflammation of the olfactory nerve in COVID-19 infection, leading to altered or loss of sense of smell.18 The ongoing volume overload and inflammation blocks the lymphatics, thus hampering the drainage of fluid to the venous sinuses. As a result, the fluid and the debris start accumulating in the brain. These end products, which affect the hypothalamus, cause fever, metal confusion, loss of sensation, and disturbance of the emotional system (three main jobs of this area are control of temperature, sensation, and emotion). So, the patients develop fatigue, myalgia, and fever.1,17
340	N336		Adam Hampshire Doris A. Chatfield Anne Manktelow MPhil Amy Jolly William Trender Peter J. Hellyer Martina Del Giovane Virginia F.J. Newcombe Joanne G. Outtrim Ben Warne Junaid Bhatti Linda Pointon Anne Elmer Nyarie Sithole John Bradley Nathalie Kingston Stephen J. Sawcer Edward T. Bullmore James B. Rowe David K. Menon	Multivariate profile and acute-phase correlates of cognitive deficits in a COVID-19 hospitalised cohort	https://doi.org/10.1016/j.eclinm.2022.101417	Published	April 28, 2022	Study	https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(22)00147-X/fulltext	Background Preliminary evidence has highlighted a possible association between severe COVID-19 and persistent cognitive deficits. Further research is required to confirm this association, determine whether cognitive deficits relate to clinical features from the acute phase or to mental health status at the point of assessment, and quantify rate of recovery. Methods 46 individuals who received critical care for COVID-19 at Addenbrooke's hospital between 10th March 2020 and 31st July 2020 (16 mechanically ventilated) underwent detailed computerised cognitive assessment alongside scales measuring anxiety, depression and post-traumatic stress disorder under supervised conditions at a mean follow up of 6.0 (± 2.1) months following acute illness. Patient and matched control (N = 460) performances were transformed into standard deviation from expected scores, accounting for age and demographic factors using N = 66,008 normative datasets. Global accuracy and response time composites were calculated (G_SScore & G_RT). Linear modelling predicted composite score deficits from acute severity, mental-health status at assessment, and time from hospital admission. The pattern of deficits across tasks was qualitatively compared with normal age-related decline, and early-stage dementia. Findings COVID-19 survivors were less accurate (G_SScore=-0.53SDs) and slower (G_RT=+0.89SDs) in their responses than expected compared to their matched controls. Acute illness, but not chronic mental health, significantly predicted cognitive deviation from expected scores (G_SScore (p=0.0037) and G_RT (p = 0.0366)). The most prominent task associations with COVID-19 were for higher cognition and processing speed, which was qualitatively distinct from the profiles of normal ageing and dementia and similar in magnitude to the effects of ageing between 50 and 70 years of age. A trend towards reduced deficits with time from illness (r∼=0.15) did not reach statistical significance. Interpretation Cognitive deficits after severe COVID-19 relate most strongly to acute illness severity, persist long into the chronic phase, and recover slowly if at all, with a characteristic profile highlighting higher cognitive functions and processing speed.
341	N337		AdamHampshireaDoris A.ChatfieldbAnne ManktelowMPhilbAmyJollyaWilliamTrenderaPeter J.HellyeraMartina DelGiovaneaVirginia F.J.NewcombebJoanne G.OuttrimbBenWarnebJunaidBhattidLindaPointondAnneElmereNyarieSitholebfJohnBradleybghNathalieKingstonlStephen J.SawceriEdward T.Bullmorecdj…David K.Menonbck1	Multivariate profile and acute-phase correlates of cognitive deficits in a COVID-19 hospitalised cohort	https://doi.org/10.1016/j.eclinm.2022.101417	Published	28 April 2022	Study	https://www.sciencedirect.com/science/article/pii/S258953702200147X	Background Preliminary evidence has highlighted a possible association between severe COVID-19 and persistent cognitive deficits. Further research is required to confirm this association, determine whether cognitive deficits relate to clinical features from the acute phase or to mental health status at the point of assessment, and quantify rate of recovery. Methods 46 individuals who received critical care for COVID-19 at Addenbrooke's hospital between 10th March 2020 and 31st July 2020 (16 mechanically ventilated) underwent detailed computerised cognitive assessment alongside scales measuring anxiety, depression and post-traumatic stress disorder under supervised conditions at a mean follow up of 6.0 (± 2.1) months following acute illness. Patient and matched control (N = 460) performances were transformed into standard deviation from expected scores, accounting for age and demographic factors using N = 66,008 normative datasets. Global accuracy and response time composites were calculated (G_SScore & G_RT). Linear modelling predicted composite score deficits from acute severity, mental-health status at assessment, and time from hospital admission. The pattern of deficits across tasks was qualitatively compared with normal age-related decline, and early-stage dementia. Findings COVID-19 survivors were less accurate (G_SScore=-0.53SDs) and slower (G_RT=+0.89SDs) in their responses than expected compared to their matched controls. Acute illness, but not chronic mental health, significantly predicted cognitive deviation from expected scores (G_SScore (p=0.0037) and G_RT (p = 0.0366)). The most prominent task associations with COVID-19 were for higher cognition and processing speed, which was qualitatively distinct from the profiles of normal ageing and dementia and similar in magnitude to the effects of ageing between 50 and 70 years of age. A trend towards reduced deficits with time from illness (r∼=0.15) did not reach statistical significance. Interpretation Cognitive deficits after severe COVID-19 relate most strongly to acute illness severity, persist long into the chronic phase, and recover slowly if at all, with a characteristic profile highlighting higher cognitive functions and processing speed.
342	N338		AmulyaAgrawalaAniketChauhanaManu KumarShettybGirish M.PcMohit D.GuptacAnubhaGuptaa	ECG-iCOVIDNet: Interpretable AI model to identify changes in the ECG signals of post-COVID subjects	https://doi.org/10.1016/j.compbiomed.2022.105540	Published	30 April 2022	Study	https://www.sciencedirect.com/science/article/pii/S0010482522003328	Highlights •Propose shallow CNNs for the classification of healthy and post-COVID using ECG data. •Proposed ECG-iCOVIDNet works only on the raw ECG data. •ECG-HiCOVIDNet does late fusion of HRV & CNN features extracted from the raw ECG. •Elaborate evaluation has been done against state-of-the-art methods. •ShAP is used to evaluate interpretability at the patient and population level. Objective Studies showed that many COVID-19 survivors develop sub-clinical to clinical heart damage, even if subjects did not have underlying heart disease before COVID. Since Electrocardiogram (ECG) is a reliable technique for cardiovascular disease diagnosis, this study analyzes the 12-lead ECG recordings of healthy and post-COVID (COVID-recovered) subjects to ascertain ECG changes after suffering from COVID-19. Method We propose a shallow 1-D convolutional neural network (CNN) deep learning architecture, namely ECG-iCOVIDNet, to distinguish ECG data of post-COVID subjects and healthy subjects. Further, we employed ShAP technique to interpret ECG segments that are highlighted by the CNN model for the classification of ECG recordings into healthy and post-COVID subjects. Results ECG data of 427 healthy and 105 post-COVID subjects were analyzed. Results show that the proposed ECG-iCOVIDNet model could classify the ECG recordings of healthy and post-COVID subjects better than the state-of-the-art deep learning models. The proposed model yields an F1-score of 100%. Conclusion So far, we have not come across any other study with an in-depth ECG signal analysis of the COVID-recovered subjects. In this study, it is shown that the shallow ECG-iCOVIDNet CNN model performed good for distinguishing ECG signals of COVID-recovered subjects from those of healthy subjects. In line with the literature, this study confirms changes in the ECG signals of COVID-recovered patients that could be captured by the proposed CNN model. Successful deployment of such systems can help the doctors identify the changes in the ECG of the post-COVID subjects on time that can save many lives.
343	N339		Sin ManLam12XunHuang13GuanghouShui13	Neurological aspects of SARS-CoV-2 infection – Lipoproteins and exosomes as Trojan horses	https://doi.org/10.1016/j.tem.2022.04.011	Published	2 May 2022	Review	https://www.sciencedirect.com/science/article/pii/S1043276022000844	Highlights •Increasing evidence point to the neurological consequences of SARS-CoV-2 infection. •SARS-CoV-2 may gain access into the brain by leveraging upon endogenous lipid couriers including HDLs and exosomes. •Lipid rafts mediate SARS-CoV-2 neurotropism by partaking in the production and BBB transmigration of both HDLs and exosomes. •Repurposing existing drugs targeting lipid metabolism provides an expedited track to alleviate the disease burden of COVID-19. SARS-CoV-2 primarily targets lipid-producing cells for viral tropism. In this review, we connect systemic lipid couriers, particularly high-density lipoproteins (HDLs) and exosomes, with the neurological facets of SARS-CoV-2 infection. We discuss how SARS-CoV-2 preferentially targets lipid-secreting cells and usurp host cell lipid metabolism for efficient replication and systemic spreading. Besides providing natural veils for viral materials against host immunity, the inherent properties of some of these endogenous lipid particles to traverse the blood-brain barrier (BBB) also offer alternative routes for SARS-CoV-2 neurotropism. Importantly, viral-driven neurological aberrations mediated by HDLs and exosomes are fueled by lipid rafts, which are implicated in the production and transmigration of these lipid particles across the BBB. Finally, we discuss how repurposing existing drugs targeting lipid rafts and cholesterol homeostasis may be beneficial toward alleviating the global COVID-19 disease burden.
344	N340		Marco Calabria, Carmen García-Sánchez, Nicholas Grunden, Catalina Pons, Juan Antonio Arroyo, Beatriz Gómez-Anson, Marina del Carmen Estévez García, Roberto Belvís, Noemí Morollón, Javier Vera Igual, Isabel Mur, Virginia Pomar & Pere Domingo	Post-COVID-19 fatigue: the contribution of cognitive and neuropsychiatric symptoms	https://doi.org/10.1007/s00415-022-11141-8	Published	30 April 2022	Study	https://link.springer.com/article/10.1007/s00415-022-11141-8	Fatigue in its many forms of physical, mental, and psychosocial exhaustion is a common symptom of post-COVID-19 condition, also known as “Long COVID.” Persistent fatigue in COVID-19 patients is frequently accompanied by cognitive dysfunction and neuropsychiatric symptoms; however, less is known about the relationships between these components of post-COVID-19 condition and fatigue itself. Consequently, the present study sought to (1) distinguish the types of fatigue experienced by participants, and (2) investigate whether cognitive deficits across various domains and neuropsychiatric conditions predicted these different types of fatigue. The study included 136 COVID-19 patients referred for neuropsychological evaluation due to cognitive complaints 8 months on average after SARS-CoV-2 infection. Measures included self-reported fatigue (physical, cognitive, and psychosocial), neuropsychiatric questionnaires (assessing symptoms of depression, anxiety, apathy, and executive functioning), a comprehensive neuropsychological assessment, and self-reported quality of life and everyday functioning. Results showed that reports of clinical significant fatigue were pervasive in our sample (82.3% of participants), with physical fatigue rated highest on average relative to the subscale maximum. Elevated levels of apathy, anxiety, and executive dysfunction in neuropsychiatric measures along with executive and attentional difficulties on cognitive tests were found to be consistently important predictors among different types of fatigue. This implicates both cognitive and neuropsychiatric symptoms as predictors of fatigue in post-COVID-19 condition, and stresses the importance of a holistic approach in assessing and considering potential treatment for COVID-19 patients experiencing fatigue.
345	N341		Barbara Tomasino, Gaia Pellitteri, Francesco Bax, Alessandro Marini, Andrea Surcinelli, Gian Luigi Gigli & Mariarosaria Valente	Multisensory mental representation in covid-19 patients and the possibility of long-lasting gustatory and olfactory dysfunction in the CNS	https://doi.org/10.1038/s41598-022-11119-6	Published	05 May 2022	Study	https://www.nature.com/articles/s41598-022-11119-6	Gustatory (GD) and olfactory (OD) dysfunctions are the most frequent neurological manifestations of COVID-19. We used mental imagery as an experimental psychological paradigm to access olfactory and gustatory brain representations in 80 Italian COVID-19 adult patients (68.75% reported both OD and GD). COVID-19 patients with OD + GD have a significantly and selectively decreased vividness of odor and taste imagery, indicating that COVID-19 has an effect on their chemosensory mental representations. OD + GD length and type influenced the status of mental chemosensory representations. OD + GD were become all COVID-19 negative at the time of testing. Data suggest that patients are not explicitly aware of long-term altered chemosensory processing. However, differences emerge when their chemosensory function is implicitly assessed using self-ratings. Among patients developing OD + GD, self-ratings of chemosensory function (taste, flavor) were significantly lower as compared to those who did not. At the level of mental representation, such differences can be further detected, in terms of a reduced ability to mentally activate an odor or taste mental image. Our study shows that COVID-19 infection not only frequently causes hyposmia and dysgeusia, but that may also alter the mental representations responsible for olfactory and gustatory perception.
346	N342		Aurelian Anghelescu 1,2ORCID,Gelu Onose 2,3,ORCID,Cristina Popescu 2,Mihai Băilă 2,3,Simona Isabelle Stoica 1,2,Ruxandra Postoiu 2,Elena Brumă 2,Irina Raluca Petcu 4,Vlad Ciobanu 5 andConstantin Munteanu 3,6,ORCID	Parkinson’s Disease and SARS-CoV-2 Infection: Particularities of Molecular and Cellular Mechanisms Regarding Pathogenesis and Treatment	https://doi.org/10.3390/biomedicines10051000	Published	26 April 2022	Review	https://www.mdpi.com/2227-9059/10/5/1000/htm	Accumulating data suggest that chronic neuroinflammation-mediated neurodegeneration is a significant contributing factor for progressive neuronal and glial cell death in age-related neurodegenerative pathology. Furthermore, it could be encountered as long-term consequences in some viral infections, including post-COVID-19 Parkinsonism-related chronic sequelae. The current systematic review is focused on a recent question aroused during the pandemic’s successive waves: are there post-SARS-CoV-2 immune-mediated reactions responsible for promoting neurodegeneration? Does the host’s dysregulated immune counter-offensive contribute to the pathogenesis of neurodegenerative diseases, emerging as Parkinson’s disease, in a complex interrelation between genetic and epigenetic risk factors? A synthetic and systematic literature review was accomplished based on the ”Preferred Reporting Items for Systematic Principles Reviews and Meta-Analyses” (PRISMA) methodology, including registration on the specific online platform: International prospective register of systematic reviews—PROSPERO, no. 312183. Initially, 1894 articles were detected. After fulfilling the five steps of the selection methodology, 104 papers were selected for this synthetic review. Documentation was enhanced with a supplementary 47 bibliographic resources identified in the literature within a non-standardized search connected to the subject. As a final step of the PRISMA method, we have fulfilled a Population-Intervention-Comparison-Outcome-Time (PICOT)/Population-Intervention-Comparison-Outcome-Study type (PICOS)—based metanalysis of clinical trials identified as connected to our search, targeting the outcomes of rehabilitative kinesitherapeutic interventions compared to clinical approaches lacking such kind of treatment. Accordingly, we identified 10 clinical trials related to our article. The multi/interdisciplinary conventional therapy of Parkinson’s disease and non-conventional multitarget approach to an integrative treatment was briefly analyzed. This article synthesizes the current findings on the pathogenic interference between the dysregulated complex mechanisms involved in aging, neuroinflammation, and neurodegeneration, focusing on Parkinson’s disease and the acute and chronic repercussions of COVID-19. Time will tell whether COVID-19 neuroinflammatory events could trigger long-term neurodegenerative effects and contribute to the worsening and/or explosion of new cases of PD. The extent of the interrelated neuropathogenic phenomenon remains obscure, so further clinical observations and prospective longitudinal cohort studies are needed.
347	N343		Adam Hampshire, Doris A. Chatfield, Anne Manktelow MPhil, Amy Jolly, William Trender, Peter J. Hellyer, Martina Del Giovane, Virginia F.J. Newcombe, Joanne G. Outtrim, Ben Warne, Junaid Bhatti, Linda Pointon, Anne Elmer, Nyarie Sithole, John Bradley, Nathalie Kingston, Stephen J. Sawcer, Edward T. Bullmore, James B. Rowe, David K. Menon 1, the Cambridge NeuroCOVID Group, the NIHR C	Multivariate profile and acute-phase correlates of cognitive deficits in a COVID-19 hospitalised cohort	https://doi.org/10.1016/j.eclinm.2022.101417	Published	April 28, 2022	Study	https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(22)00147-X/fulltext	Background Preliminary evidence has highlighted a possible association between severe COVID-19 and persistent cognitive deficits. Further research is required to confirm this association, determine whether cognitive deficits relate to clinical features from the acute phase or to mental health status at the point of assessment, and quantify rate of recovery. Methods 46 individuals who received critical care for COVID-19 at Addenbrooke's hospital between 10th March 2020 and 31st July 2020 (16 mechanically ventilated) underwent detailed computerised cognitive assessment alongside scales measuring anxiety, depression and post-traumatic stress disorder under supervised conditions at a mean follow up of 6.0 (± 2.1) months following acute illness. Patient and matched control (N = 460) performances were transformed into standard deviation from expected scores, accounting for age and demographic factors using N = 66,008 normative datasets. Global accuracy and response time composites were calculated (G_SScore & G_RT). Linear modelling predicted composite score deficits from acute severity, mental-health status at assessment, and time from hospital admission. The pattern of deficits across tasks was qualitatively compared with normal age-related decline, and early-stage dementia. Findings COVID-19 survivors were less accurate (G_SScore=-0.53SDs) and slower (G_RT=+0.89SDs) in their responses than expected compared to their matched controls. Acute illness, but not chronic mental health, significantly predicted cognitive deviation from expected scores (G_SScore (p=0.0037) and G_RT (p = 0.0366)). The most prominent task associations with COVID-19 were for higher cognition and processing speed, which was qualitatively distinct from the profiles of normal ageing and dementia and similar in magnitude to the effects of ageing between 50 and 70 years of age. A trend towards reduced deficits with time from illness (r∼=0.15) did not reach statistical significance. Interpretation Cognitive deficits after severe COVID-19 relate most strongly to acute illness severity, persist long into the chronic phase, and recover slowly if at all, with a characteristic profile highlighting higher cognitive functions and processing speed.
348	N344		Christopher Cantrell, Robert Wilson	COVID-Long Haulers Can Develop POTS (Postural Orthostatic Tachycardia Syndrome) with Small Fiber Neuropathy and Abnormal Autonomic Testing (P17-1.005)		Published	May 3, 2022	Study	https://n.neurology.org/content/98/18_Supplement/3392	Objective: A substantial number of COVID long-haulers have developed POTS, which warrants further investigation. This study is intended as a first look at a new and growing patient population that is bringing greater attention to the prevalent autonomic disease of POTS. Background: POTS (Postural Orthostatic Tachycardia Syndrome) is a disorder of autonomic dysregulation involving overactive compensation for postural blood pressure changes. This debilitating syndrome can be associated with small fiber neuropathy and a broad spectrum of autonomic symptoms including palpitations, changes in sweating, and gastrointestinal problems like constipation. Respiratory and gastrointestinal viruses have been known to cause onset of POTS pathophysiology. In approximately 10% of COVID cases, patients experience long-term health effects after the conclusion of their COVID infection. These patients are called COVID “long-haulers.” Design/Methods: We conducted a chart review of 25 Cleveland Clinic post-COVID POTS patients who are mostly female (84%) to learn about this patient population’s distribution of top symptoms, comorbidities, autonomic testing, and autonomic questionnaire scores. Top three symptoms were determined based on the physician’s note from the patients’ initial visit to the Cleveland Clinic Neurology Department. Results: Our chart review revealed a high occurrence of excitatory comorbidities such as chronic migraine (44%) and irritable bowel syndrome (24%). In addition, when assessing patients’ top three POTS symptoms, we found that palpitations, fatigue, and dyspnea were affecting patients most. As with POTS in general, autonomic testing outside of tilt table testing (85.7%) shows variable results with QSART (50%), skin punch biopsy (37.5%), deep breathing (14.3%), and Valsalva testing (0%) all showing positivity rates of 50% or less for our patient sample. Conclusions: Post-COVID POTS could be an excitatory process with hyperadrenergic signaling based on the symptoms and comorbidities. We hope that this chart review will be the launching point for future studies aimed at achieving greater understanding of the post-COVID POTS phenomenon.
349	N345		Emma Reford, Nicki Mohammadi, Natalia Romano Spica, Jenna Tosto, LAURA ROSENBAUM TABACOF, David Putrino, Christopher Kellner	Post Covid-19 Neurological Impairment Effects on Activities of Daily Living: Patient Perspectives from a Remote Patient Monitoring Program (P4-9.002)		Published	May 3, 2022	Study	https://n.neurology.org/content/98/18_Supplement/1322	Objective: Here, we emphasize the debilitating effects on daily life of post covid cognitive impairment, from the patient perspective. In this, we will gain deeper insight into the post-acute illness phase of COVID-19 to formulate more compassionate, supportive, and efficacious treatment protocols. Background: Post Covid-19 acute infection neurological impairment has been shown to be a long term effect of the disease. 18 months after the onset of the COVID-19 pandemic, with over 230 million cases worldwide, it has never been more critical to understand such long term effects. Design/Methods: 46 Patients in a COVID-19 Remote Patient Monitoring Program (Precision Recovery: Mount Sinai Health System) were interviewed regarding their experience with COVID-19. Patients were asked about their experiences navigating COVID-19 diagnoses, the health care system, and their recovery process. Patients were not pointedly asked about cognitive impairment post covid and all mentions were unprompted. References to post-cognitive impairment were analyzed for statistical and qualitative significance. Results: 20/46 (43%) of patients reported cognitive impairment after the acute phase of their covid illness. 8/20 of these individuals (40%) were self identified long-haul covid patients. Patients identified three patterns of impairment: (1) memory; (2) attention; and (3) mental stamina. These new cognitive deficits impacted daily life in four key ways: (1) failure to adhere to daily responsibilities; (2) necessitated decrease in employment responsibilities; (3) insecurity in social interactions; and (4) development of coping strategies. Conclusions: Post covid cognitive impairment significantly impacted both acute and long-haul covid patients. It is therefore critical to acknowledge this potential long-term effect as an outcome for anyone who experiences Covid-19 for improved understanding of patient illness experience and development of covid-19 treatment post-acute infection.
350	N346		Lindsay McAlpine, Adeel Zubair, Serena Spudich	Case Series: Post-COVID Small Fiber Neuropathy (P9-9.002)		Published	May 3, 2022	Case Series	https://n.neurology.org/content/98/18_Supplement/348.abstract	Objective: To report a case series documenting biopsy-proven small fiber neuropathy (SFN) after COVID-19. Background: Patients recovering from COVID-19 who present with sensory as well as autonomic symptoms, including positional orthostatic tachycardia syndrome (POTS), frequently have negative electrodiagnostic testing. Skin biopsy may be required to reveal SFN. Design/Methods: This is a retrospective case series of patients seen in the Yale Neurology COVID-19 Clinic with positive SARS-CoV-2 PCR or antibody or a clinically consistent illness. After laboratory testing and a negative nerve conduction study, all patients underwent skin biopsy to test for intraepidermal SFN. Case 1: A 40F with pre-diabetes (HbA1c 6.2%) developed burning, numbness, and tingling in the hands and legs and POTS 6 weeks after acute COVID-19. Skin biopsy demonstrated non-length dependent SFN. Complete remission of neuropathy symptoms occurred within days of intravenous immunoglobulin (IVIG) therapy, which has been continued longitudinally. Case 2: A 65F with non-insulin dependent diabetes (HbA1c 8.0%) developed excruciating burning pain in her feet and orthostasis within weeks of acute COVID-19. Skin biopsy demonstrated non-length dependent SFN. She experienced partial relief of symptoms after IVIG and gabapentin. Case 3: A 43F with pre-diabetes (HbA1c 6.0%) developed orthostasis, numbness, paresthesias, and a “sunburned” feeling in her face, back, hands, and feet 2 weeks after acute COVID-19. Skin biopsy demonstrated length-dependent SFN. Symptoms improved over several months of pregabalin treatment, but have not resolved. The patient deferred immunotherapy. Case 4: A 40M developed POTS, numbness, and paresthesias in his face and left leg up to the knee within weeks of a clinical COVID-19 illness. Skin biopsy demonstrated non-length dependent SFN. IVIG therapy has resulted in significant improvement in symptoms. Conclusions: Sensory symptoms and POTS occur post-COVID, and SFN should be considered in the differential. Given the time of onset and response to immunotherapy, post-COVID SFN may have an underlying autoimmune etiology.
351	N347		Pietro De Luca Arianna Di Stadio Vito Colacurcio Pasquale Marra Alfonso Scarpa Filippo Ricciardiello Claudia Cassandro Angelo Camaioni Ettore Cassandro	Long COVID, audiovestibular symptoms and persistent chemosensory dysfunction: a systematic review of the current evidence	https://doi.org/10.14639/0392-100X-suppl.1-42-2022-10	Published	2022-04-26	Review	https://www.actaitalica.it/article/view/1886	Objective. The persistence of auditory, vestibular, olfactory, and gustatory dysfunction for an extended time after COVID-19 has been documented, which represents an emerging challenge of which ENT specialists must be aware. This systematic review aims to evaluate the prevalence of persistent audiovestibolar and olfactory/gustatory symptoms in patients with “long-COVID”. Methods. The literature was systematically reviewed according to PRISMA guidelines; PubMed, Scopus and Google Scholar were screened by searching articles on audiovestibular symptoms and olfactory/gustatory dysfunction after SARS-CoV-2 infection. The keywords used were hearing loss, tinnitus, vertigo, smell disorders, parosmia, anosmia, hyposmia, dysgeusia combined with COVID-19 or SARS-CoV-2. Results. 1100 articles were identified. After removal of duplicates (382), 702 articles were excluded, and 16 were included in the systematic review. All articles included identified an association between SARS-CoV-2 infection and persistent hearing or chemosensory impairment. The studies were published over a period of 2 years, between 2019 and 2021. Conclusions. The likelihood of patients with persistent audiovestibular symptoms related to COVID-19 was different among the articles; however, olfactory and gustatory disturbances were more consistently reported. Studies with longer follow-up are required to fully evaluate the long-term impact of these conditions.
352	N348		Herbert Renz-Polster1*, Marie-Eve Tremblay2,3,4,5,6,7, Dorothee Bienzle8 and Joachim E. Fischer1	The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure	https://doi.org/10.3389/fncel.2022.888232	Published	09 May 2022	Review	https://www.frontiersin.org/articles/10.3389/fncel.2022.888232/full	Although myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has a specific and distinctive profile of clinical features, the disease remains an enigma because causal explanation of the pathobiological matrix is lacking. Several potential disease mechanisms have been identified, including immune abnormalities, inflammatory activation, mitochondrial alterations, endothelial and muscular disturbances, cardiovascular anomalies, and dysfunction of the peripheral and central nervous systems. Yet, it remains unclear whether and how these pathways may be related and orchestrated. Here we explore the hypothesis that a common denominator of the pathobiological processes in ME/CFS may be central nervous system dysfunction due to impaired or pathologically reactive neuroglia (astrocytes, microglia and oligodendrocytes). We will test this hypothesis by reviewing, in reference to the current literature, the two most salient and widely accepted features of ME/CFS, and by investigating how these might be linked to dysfunctional neuroglia. From this review we conclude that the multifaceted pathobiology of ME/CFS may be attributable in a unifying manner to neuroglial dysfunction. Because the two key features – post exertional malaise and decreased cerebral blood flow – are also recognized in a subset of patients with post-acute sequelae COVID, we suggest that our findings may also be pertinent to this entity.
353	N349		Matan Sorek Eran Meshorer	Can’t smell the virus: SARS-CoV-2, chromatin organization, and anosmia	https://doi.org/10.1016/j.devcel.2022.04.015	Published	May 09, 2022	SPOTLIGHT	https://www.cell.com/developmental-cell/fulltext/S1534-5807(22)00272-6	Anosmia, or loss of smell, is strongly associated with SARS-CoV-2 infection in humans, but the underlying mechanism remains obscure. In a recent Cell study, Zazhytska et al., 2022 report non-cell-autonomous disruption of long-range genomic interactions of olfactory receptor genes in response to SARS-CoV-2 infection, and these interactions remain disrupted long after virus clearance. Transient anosmia, an inability to smell, is a common symptom associated with many upper respiratory viral infections, including SARS-CoV-2. Typically, upon infection, nasal congestion blocks the odorants in sensory neurons, causing loss of smell. Anosmia in SARS-CoV-2 infection, however, occurs independently from nasal symptoms, and it may last long after the infection is resolved. In addition, the SARS-CoV-2 host cell entry proteins are not expressed by olfactory sensory neurons (OSNs) (Bilinska et al., 2020), and this makes viral infection of these neurons exceedingly rare. These pathological and molecular features raise the possibility that non-cell-autonomous mechanisms may underlie the anosmia that is frequently induced by SARS-CoV-2 infection. In a recent study published in Cell, Zazhytska et al., 2022 explored the non-cell-autonomous molecular changes that occur in response to SARS-CoV-2 infection. As a model, they used golden hamsters (M. auratus), which have a host cell receptor, ACE2, through which SARS-CoV-2 enters cells (Bilinska et al., 2020) and which is highly similar to the human ortholog. They therefore closely resemble humans in SARS-CoV-2-related pathogenicity and immunogenicity (Cleary et al., 2020; Sia et al., 2020). To explore the changes in cellular composition and gene expression following SARS-CoV-2 infection, the authors collected olfactory epithelium (OE) from sham-infected or SARS-CoV-2-infected golden hamsters 1, 3, and 10 days post-infection, and performed single-cell RNA-sequencing (scRNA-seq). They identified 13 different cell types and found, as expected, that sustentacular (SUS) cells, which express the ACE2 receptor, comprise the large majority of the infected cells. Although microglia and assorted immune cells also demonstrated substantial viral uptake, only a small fraction of the OSNs were infected. The cellular effects of direct viral infection were evinced by the fraction of SUS cells decreasing substantially (from ∼20% to ∼6%), whereas viability of OSNs remained unaffected. By day 10, the original cellular composition was restored, and the virus was no longer detected in any of the OE cells. Zazhytska et al., 2022 then analyzed transcriptional changes in OE cells and, remarkably, found a significant reduction in genes related to olfaction, including transcription factors which regulate olfactory receptors (OR) and OR signaling genes. A notable example is adenylyl cyclase 3 (Adcy3), whose loss leads to anosmia in mice (Wong et al., 2000). But why are OR genes dysregulated following SARS-CoV-2 infection? During OSN maturation, the lamin B receptor protein (LBR) is downregulated, and suppressive heterochromatin is rearranged to form nuclear hubs, thus generating “fried-egg”-like inverted nuclei which contain both heterochromatin cores and multi-enhancer hubs (Pourmorady and Lomvardas, 2022). Active OR alleles are arranged in proximity to their corresponding enhancers to enable active mono-allelic transcription. Using Hi-C experiments in sham- and SARS-CoV-2-infected hamsters, the authors found disruption of long-range genomic interactions of OR genes happening already 1 day post-infection (Figure 1). By day 3, they detected more widespread and global chromatin rearrangements. Remarkably, OR gene rearrangements persisted at day 10 post-infection, when the virus is already completely cleared, and this potentially explains the persistent changes in expression of OR-related genes and the long-lasting anosmia that is associated with SARS-CoV-2 infection. The low susceptibility of OSNs to viral entry, together with evident OR chromatin and transcriptional changes, suggests that anosmia is not the result of a direct viral mechanism. To test whether these effects were indeed non-cell-autonomous, the authors performed an elegant experiment. They collected serum from SARS-CoV-2-infected hamsters, whereupon UV irradiation was used to inactivate the virus prior to administration of the irradiated serum directly into the nasal cavity of virus-naïve hamsters. The irradiated serum not only caused a comparable disruption in nuclear architecture to that of SARS-CoV-2-infected hamsters, but, when examined merely 12.5 h after the nasal administration, when the effect of the released cytokines is at its peak, it resulted in faster kinetics than SARS-CoV-2 infection. Subtle reduction in OR gene expression was already detectable at this early timepoint. Taken together, these experiments demonstrate global changes in nuclear architecture related to OR genes in OSNs, caused by components, cellular or viral, that are released from other infected cells, presumably the infected SUS cells, and that operate in trans. The authors’ next goal was to assess the relevance of these findings in humans. Working with postmortem human tissues, the authors compared changes in gene expression between SARS-CoV-2-infected individuals and controls. They found a selective reduction in the expression of OR-related genes in human autopsies, including Adcy3 and other key olfactory transcripts. Furthermore, comparing Hi-C interaction maps between OSNs from SARS-CoV-2-infected human autopsy specimens and OSNs from control autopsies, the authors found large-scale loss of long-distance interactions, many of which were specific to OR-related genes. Overall, these results support the model that non-autonomous disruption of long-range genomic interactions of OR-related genes underlies SARS-CoV-2-induced loss of smell. Such disruptions in nuclear architecture may not be readily re-established in post-mitotic cells such as OSNs, and thus they may also explain the persistence of the anosmia phenotypes for weeks and months after infection, as well as other related phenotypes such as parosmia, a distortion in the sense of smell. This study raises several interesting questions. Although it is clear from the experiments that the mechanism for the loss of smell is non-cell-autonomous and does not require live virus, the specific molecules that are responsible are yet to be identified. Possibilities include non-viable viral particles, molecules secreted from infected cells such as cytokines, and circulating fragments of SUS cells, as dying cells are constantly being shed into the bloodstream. It is also unclear how such a molecule would elicit the profound changes in nuclear architecture in OSNs. Transcriptional studies of SARS-CoV-2 have revealed that the expression of many epigenetic factors correlate with an interferon response and with general activation of transposable elements (Sorek et al., 2022). Therefore, if, as the authors hypothesize, cytokines are responsible for the non-cell-autonomous anosmia, interferon activation in the OSNs may cause changes in expression of these factors, which can lead to the observed chromatin-related phenotype. Another outstanding question is, how specific is the response? Can other neurons or non-dividing cells in general be similarly affected? Can other viruses elicit similar pathologies? Are cells with unique nuclear architectures more susceptible than other cells? Such emerging questions will no doubt be the focus of follow-up investigations.
354	N350		Ameli Gerhard, Harald Prüß & Christiana Franke	Manifestationen im Zentralnervensystem nach COVID-19	https://doi.org/10.1007/s00115-022-01294-2	Published	12 May 2022	Review	https://link.springer.com/article/10.1007/s00115-022-01294-2	Numerous diseases of the central nervous system (CNS), especially in the postacute phase after an infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been described. These include neuroimmunologically mediated diseases, such as encephalopathy, encephalitis, myelitis, acute disseminated encephalomyelitis (ADEM), acute necrotizing hemorrhagic leukoencephalitis (ANHLE) and neuromyelitis optica spectrum disorder (NMOSD) as well as others, such as posterior reversible encephalopathy syndrome (PRES), opsoclonus myoclonus ataxia (OMA) and cerebrovascular diseases. A parainfectious or postinfectious association is discussed but the pathophysiological mechanisms are so far unknown. Underlying mechanisms could be a virus-triggered overactivation of the immune system with hyperinflammation and cytokine storm but possibly also the development of specific autoantibodies against CNS tissue. Direct damage due to the invasion of SARS-CoV‑2 into the brain or spinal cord does not seem to play a relevant role. An exact clinical phenotyping and initiation of additional diagnostics are recommended, also to rule out other causes. To date no medicinal treatment options for CNS manifestations of long COVID exist; however, first results regarding inflammation and autoimmunity are promising and could lead to new treatment approaches.
355	N351		Mitchell G. Miglis, Jordan Seliger, Ruba Shaik & Christopher H. Gibbons	A case series of cutaneous phosphorylated α-synuclein in Long-COVID POTS	https://doi.org/10.1007/s10286-022-00867-0	Published	16 May 2022	Letter to the Editor	https://link.springer.com/article/10.1007/s10286-022-00867-0	As case numbers of coronavirus disease 19 (COVID-19) increase, chronic symptoms, including those of autonomic dysfunction, are being reported with increasing frequency [1], leading to the diagnosis of post-acute sequelae of COVID-19 (PASC), or Long-COVID. In addition, small fiber neuropathy (SFN) has been reported after viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [2]. These associations have prompted our group to systematically perform autonomic testing and skin biopsies in a cohort of patients who have developed postural tachycardia syndrome (POTS) as a consequence of PASC (Long-COVID POTS). As part of this evaluation, all skin biopsy samples undergo immunohistochemical analysis of both intraepidermal nerve fiber density (IENFD) and phosphorylated α-synuclein (p-syn) [3], the pathological form of α-synuclein associated with the neurodegenerative diseases of Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and pure autonomic failure (PAF), as well as isolated REM sleep behavior disorder (iRBD), a prodromal manifestation of synucleinopathy for the majority of patients. We report the presence of p-syn in five young patients with Long-COVID POTS (LC-POTS) but without prodromal features of neurodegenerative disease. Without a comparative biopsy prior to SARS-CoV-2 infection, it is unclear if the presence of p-syn is an incidental and unrelated finding, if the infection triggered accelerated aggregation of p-syn, or if the presence of p-syn predated the infection and predisposed our patients to the development of Long-COVID and/or POTS. One potential theory is that the pre-existing presence of phosphorylated α-synuclein could predispose individuals to more prolonged complications after COVID-19 infection. This would suggest that individuals with PD or other synucleinopathies might be at greater risk of complications [9]. Comparisons with other neurodegenerative diseases with similar morbidity would be required to determine the clinical relevance of this possibility.
356	N352	PESE	Hamidreza Zalpoor, Hooriyeh Shapourian, Abdullatif Akbari, Shaghayegh Shahveh & Leila Haghshenas	Increased neuropilin-1 expression by COVID-19: a possible cause of long-term neurological complications and progression of primary brain tumors	https://doi.org/10.1007/s13577-022-00716-2	Published	09 May 2022	Letter to the Editor	https://link.springer.com/article/10.1007/s13577-022-00716-2	Here, we hypothesized that SARS-CoV-2 infection could lead to long-term neurological complications and progression in primary brain tumors by upregulating the expression of Neuropilin-1 (NRP-1), especially in those who have contracted SARS-CoV-2 several times. NRP-1 acts as a viral entry receptor besides angiotensin-converting enzyme 2 (ACE2), Ephrin (Eph) receptor, and CD147 that can contribute to SARS-CoV-2 viral entry to host cells in CNS, as well as stimulating intracellular signaling pathways which may be associated with pathological complications related to CNS and glioblastoma [2, 3, 5,6,7]. Previous studies have discussed the neurologic impacts of long-COVID, and the implications of this potential neurotropism. It includes how viruses use complete cytokine profiles and cause pain through direct and indirect interactions with nociceptors' plasticity [5]. Recent reports also revealed different nervous system complications observed during the acute and post-infection phases of COVID-19. However, knowledge of the post-acute neurological magnitudes of COVID-19, including memory or cognitive disturbances, insomnia, post-exertional malaise or fatigue, loss of smell or taste, headache, and other sleep disturbances, remained limited. Furthermore, the neurological problems that persisted 3–9 months from their date of infection with SARS-CoV-2 included vertigo, depression, memory, taste or smell disturbances, and cognitive disturbances reported as negatively affecting the neurological health of individuals [1]. In a recent study by Gwenaëlle Douaud et al. [1], the results have shown that COVID-19 can change the brain structure. Their investigation found significant long-term effects in these cases: (a) reduction in gray matter thickness and tissue contrast in the para-hippocampal gyrus and orbitofrontal cortex, (b) changes in tissue damage markers in regions functionally connected to the primary olfactory cortex, and (c) total brain size reduction. Studies conducted previously revealed that the occurrence of neurological symptoms associated with COVID-19, such as acute ischemic stroke (AIS), acute necrotizing encephalitis, encephalopathy, peripheral neuropathy, headaches, seizures, cerebral micro-bleeds, demyelinating diseases, meningitis, Guillain–Barré syndrome, skeletal muscular symptoms, neurodegenerative diseases, as well as multiple cancers like glioblastoma is rapidly increasing [2, 8,9,10]. According to a study by de Joode et al., overall mortality rates for cancer patients with COVID-19 in some studies are between 32.3 and 35.4% [11], and the pooled case mortality rate among patients with cancer and COVID-19 was 25.6% [12]. Also, it has been reported that patients with primary brain tumors [e.g., glioblastoma, astrocytoma, oligodendroglioma, ependymoma, primary central nervous system lymphoma (PCNSL)] are more prone to experience a severe form of COVID-19 and/or a higher rate of mortality [11]. Infection of the CNS with SARS-CoV-2 could result in neurodegenerative diseases due to entry receptors for the virus in this region. NRP-1 is one of the two homologous neuropilins that plays critical roles in physiological and pathological conditions. An essential function of NRP-1 is to act as a receptor for signaling ligands, such as vascular endothelial growth factor (VEGF) (especially VEGF-A), integrins, semaphorins, transforming growth factor-beta (TGF-β), and plexins. It plays an essential role in many processes, including tumor progression, angiogenesis, viral entry, axonal guidance in the CNS and peripheral nervous system (PNS), and immune function [2]. In a study by Cantuti-Castelvetri et al., SARS-CoV-2 was shown to bind with NRP-1 by S protein and ultimately enter neurons and then increase NRP-1 expression and two crucial factors proteases Furin and Transmembrane serine protease 11A (TMPRSS11A) in SARS-CoV-2-infected cells [13]. Since olfactory epithelial cells express high levels of NRP-1 in COVID-19 patients, and VEGF-A is a ligand for NRP-1 [14], this suggests that one cause of patients' cognitive and neurological impairment may be the vulnerability of these brain regions to SARS-CoV-2. In addition, increased expression of NRP-1 may promote viral entry, stimulate intracellular signaling pathways in CNS cells, and contribute to the development and progression of neurodegenerative diseases and primary brain tumors in susceptible individuals. A part of NRPs involved in binding vascular endothelial growth factor A (VEGF-A) is their extracellular b1b2 domain. This receptor plays a major role in angiogenesis as co-receptors for VEGFR-1 and -2 [15]. As VEGF-A binds to NRP-1, it increases the interaction between NRP-1 and GIPC1 (a scaffold protein) and facilitates the assembly of the GAIP/RGS19-interacting protein (GIPC1) + Syx signaling molecular complex, resulting in RhoA GTP binding. RhoA is activated and this activated form leads to the tumor suppressor p27 protein degradation. Therefore, this leads to the proliferation of tumor cells [16]. In addition, angiogenesis, proliferation, and migration mediated by NRP-1/GIPC1 are likely to be regulated by PI3K/Akt/NF-κB pathway activation [15]. In conclusion, we hypothesized that upregulated expression of NRP-1 by COVID-19 may be a significant cause of long-term CNS-related pathological complications and possibly lead to progression of primary brain tumors, especially in cases infected by SARS-CoV-2 several times. Therefore, we suggest that pharmacological targeting of NRP-1 in such susceptible patients could be beneficial and a promising therapeutic approach to combat long-term neurological complications and reduce the risk of primary brain tumors' progression.
357	N353		César Fernández-de-las-Peñas, José D. Martín-Guerrero, Ignacio Cancela-Cilleruelo, Jorge Rodríguez-Jiménez, Paloma Moro-López-Menchero & Oscar J. Pellicer-Valero	Exploring trajectory recovery curves of post-COVID cognitive symptoms in previously hospitalized COVID-19 survivors: the LONG-COVID-EXP-CM multicenter study	https://doi.org/10.1007/s00415-022-11176-x	Published	10 May 2022	Letter to the Editors	https://link.springer.com/article/10.1007/s00415-022-11176-x	The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, responsible of causing coronavirus disease 2019 (COVID-19), primary affects the respiratory system; however, neurological symptoms (e.g., ageusia, anosmia, headache) and also other severe complication are commonly experienced at the acute phase [1, 2]. Neurological symptoms presented at the acute COVID-19 phase such as headache [3] or anosmia [4] are likely present at a post-COVID phase; however, other neurological symptoms, e.g., cognitive disorders, are “de novo” developed in up to 22% of COVID-19 survivors [5]. A recent meta-analysis reported prevalence rates of 32%, 27% and 22% for post-COVID brain fog, memory loss, and attention/concentration problems the six months after respectively [6]. However, the presence of post-COVID cognitive symptoms are questioned by others [7]. Interestingly, the recent definition of post-COVID includes cognitive dysfunction as one of the most common symptoms, after fatigue or dyspnoea [8]. The presence of post-COVID symptoms is overall associated with worse quality of life [9]. In fact, the presence of post-COVID cognitive symptoms represents a challenge for affected individuals since these symptoms affect daily life [10]. Although the presence of post-COVID cognitive symptoms is associated with nervous system changes [11], it seems that these symptoms generally improve over time [12]. However, most studies investigating these symptoms have used cross-sectional designs. Therefore, understanding the longitudinal pattern of post-COVID cognitive symptoms may have significant implications in diagnosis, triaging, and management of post-COVID individuals. This letter to the editor presents the trajectory recovery curves of post-COVID cognitive symptoms using an exponentially fitted bar plot model of the longitudinal evolution of the symptoms in previously hospitalized COVID-19 survivors. We also illustrate the relationships of the cognitive symptoms by means of mosaic plots.
358	N354		Marianna Papadopoulou, Eleni Bakola, Apostolos Papapostolou, Maria-Ioanna Stefanou, Mina Gaga, Vasiliki Zouvelou, Ioannis Michopoulos & Georgios Tsivgoulis	Autonomic dysfunction in long-COVID syndrome: a neurophysiological and neurosonology study	https://doi.org/10.1007/s00415-022-11172-1	Published	10 May 2022	Letter to the Editors	https://link.springer.com/article/10.1007/s00415-022-11172-1	This study provides evidence that autonomic dysfunction may contribute to LCS symptoms that persist for several months beyond the resolution of acute COVID-19. It was demonstrated that LCS patients show vagus atrophy accounting for parasympathetic implication and prolonged SSR latencies, accounting for sympathetic implication. Dysautonomia in acute COVID-19 has been involved in the development of acute respiratory distress syndrome and is attributed to either direct neuronal injury, or to immune-induced mechanisms [5]. In LCS, postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia have been reported and are similar to previous post-viral dysautonomia syndromes [6].
359	N355		Amber N. Edinoff 1,*ORCID,Maithreyi Chappidi 2,E. Saunders Alpaugh 3,Bailey C. Turbeville 4,Evan P. Falgoust 4,Elyse M. Cornett 5ORCID,Kevin S. Murnane 1,6,7,Adam M. Kaye 8ORCID andAlan D. Kaye 5	Neurological and Psychiatric Symptoms of COVID-19: A Narrative Review	https://doi.org/10.3390/psychiatryint3020013	Published	7 May 2022	Review	https://www.mdpi.com/2673-5318/3/2/13/htm	Recently dubbed Long COVID or Long-Haul COVID, those recovering from the initial COVID-19 infection may maintain clinical signs for longer than two or more weeks following the initial onset of the infection. The virus can gain entry into the CNS through axonal transport mediated through the olfactory nerve or hematogenous spread and can also cross the blood–brain barrier to access the temporal lobe and the brainstem. The neurologic and neuropsychiatric symptoms associated with COVID-19 patients are becoming a highly studied area due to the increased frequency of reported cases. Multiple hospital case series and observational studies have found a headache to be a common symptom among patients who are symptomatic with the SARS-CoV-2 virus. The headache described by many of these patients is similar to new daily persistent headache (NDPH). NDPH potentially develops in response to pro-inflammatory cytokines during a persistent systemic or CNS inflammation, mostly due to the initial infection. The treatments investigated were high-dose steroids, tetracycline derivatives, onabotulinum toxin type A, and long-term multidrug regimens. Among the identified symptoms of post-COVID-19 viral illness, fatigue appears to be the most ubiquitous. High-dose vitamin C is currently a suggested therapy proposed for its antioxidant, anti-inflammatory, and immunomodulatory properties. The mental health consequences of this diagnosis are being identified among large portions of COVID-19 survivors. Among these consequences, cases of major depressive disorder (MDD) and anxiety are being reported and closely examined. The aim of this narrative review is to highlight the neurological and psychiatric symptoms that have been associated with Long-Haul COVID and their possible treatments.
360	N356		Frauke Seehusen 1,Jordan J. Clark 2ORCID,Parul Sharma 2,Eleanor G. Bentley 2,Adam Kirby 2,Krishanthi Subramaniam 2,Sabina Wunderlin-Giuliani 1,Grant L. Hughes 3ORCID,Edward I. Patterson 3ORCID,Benedict D. Michael 4,5ORCID,Andrew Owen 6ORCID,Julian A. Hiscox 2,James P. Stewart 2ORCID andAnja Kipar 1,2,*	Neuroinvasion and Neurotropism by SARS-CoV-2 Variants in the K18-hACE2 Mouse	https://doi.org/10.3390/v14051020	Published	11 May 2022	Study	https://www.mdpi.com/1999-4915/14/5/1020/htm	Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) not only affects the respiratory tract but also causes neurological symptoms such as loss of smell and taste, headache, fatigue or severe cerebrovascular complications. Using transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2), we investigated the spatiotemporal distribution and pathomorphological features in the CNS following intranasal infection with SARS-CoV-2 variants, as well as after prior influenza A virus infection. Apart from Omicron, we found all variants to frequently spread to and within the CNS. Infection was restricted to neurons and appeared to spread from the olfactory bulb mainly in basally oriented regions in the brain and into the spinal cord, independent of ACE2 expression and without evidence of neuronal cell death, axonal damage or demyelination. However, microglial activation, microgliosis and a mild macrophage and T cell dominated inflammatory response was consistently observed, accompanied by apoptotic death of endothelial, microglial and immune cells, without their apparent infection. Microgliosis and immune cell apoptosis indicate a potential role of microglia for pathogenesis and viral effect in COVID-19 and the possible impairment of neurological functions, especially in long COVID. These data may also be informative for the selection of therapeutic candidates and broadly support the investigation of agents with adequate penetration into relevant regions of the CNS.
361	N357		Marko Ercegovac 1,2,†,Milika Asanin 1,3,†,Ana Savic-Radojevic 1,4ORCID,Jovan Ranin 1,5,Marija Matic 1,4,Tatjana Djukic 1,4,Vesna Coric 1,4ORCID,Djurdja Jerotic 1,4,Nevena Todorovic 5,Ivana Milosevic 1,5ORCID,Goran Stevanovic 1,5,Tatjana Simic 1,4,6ORCID,Zoran Bukumiric 1,7,* andMarija Pljesa-Ercegovac 1,4,*ORCID	Antioxidant Genetic Profile Modifies Probability of Developing Neurological Sequelae in Long-COVID	https://doi.org/10.3390/antiox11050954	Published	12 May 2022	Study	https://www.mdpi.com/2076-3921/11/5/954/htm	Understanding the sequelae of COVID-19 is of utmost importance. Neuroinflammation and disturbed redox homeostasis are suggested as prevailing underlying mechanisms in neurological sequelae propagation in long-COVID. We aimed to investigate whether variations in antioxidant genetic profile might be associated with neurological sequelae in long-COVID. Neurological examination and antioxidant genetic profile (SOD2, GPXs and GSTs) determination, as well as, genotype analysis of Nrf2 and ACE2, were conducted on 167 COVID-19 patients. Polymorphisms were determined by the appropriate PCR methods. Only polymorphisms in GSTP1AB and GSTO1 were independently associated with long-COVID manifestations. Indeed, individuals carrying GSTP1 Val or GSTO1 Asp allele exhibited lower odds of long-COVID myalgia development, both independently and in combination. Furthermore, the combined presence of GSTP1 Ile and GSTO1 Ala alleles exhibited cumulative risk regarding long-COVID myalgia in carriers of the combined GPX1 LeuLeu/GPX3 CC genotype. Moreover, individuals carrying combined GSTM1-null/GPX1LeuLeu genotype were more prone to developing long-COVID “brain fog”, while this probability further enlarged if the Nrf2 A allele was also present. The fact that certain genetic variants of antioxidant enzymes, independently or in combination, affect the probability of long-COVID manifestations, further emphasizes the involvement of genetic susceptibility when SARS-CoV-2 infection is initiated in the host cells, and also months after.
362	N358		Aurelian Anghelescu 1,2ORCID,Gelu Onose 2,3,ORCID,Cristina Popescu 2,Mihai Băilă 2,3,Simona Isabelle Stoica 1,2,Ruxandra Postoiu 2,Elena Brumă 2,Irina Raluca Petcu 4,Vlad Ciobanu 5 andConstantin Munteanu 3,6,ORCID	Parkinson’s Disease and SARS-CoV-2 Infection: Particularities of Molecular and Cellular Mechanisms Regarding Pathogenesis and Treatment	https://doi.org/10.3390/biomedicines10051000	Published	26 April 2022	Systematic Review	https://www.mdpi.com/2227-9059/10/5/1000/htm	Accumulating data suggest that chronic neuroinflammation-mediated neurodegeneration is a significant contributing factor for progressive neuronal and glial cell death in age-related neurodegenerative pathology. Furthermore, it could be encountered as long-term consequences in some viral infections, including post-COVID-19 Parkinsonism-related chronic sequelae. The current systematic review is focused on a recent question aroused during the pandemic’s successive waves: are there post-SARS-CoV-2 immune-mediated reactions responsible for promoting neurodegeneration? Does the host’s dysregulated immune counter-offensive contribute to the pathogenesis of neurodegenerative diseases, emerging as Parkinson’s disease, in a complex interrelation between genetic and epigenetic risk factors? A synthetic and systematic literature review was accomplished based on the ”Preferred Reporting Items for Systematic Principles Reviews and Meta-Analyses” (PRISMA) methodology, including registration on the specific online platform: International prospective register of systematic reviews—PROSPERO, no. 312183. Initially, 1894 articles were detected. After fulfilling the five steps of the selection methodology, 104 papers were selected for this synthetic review. Documentation was enhanced with a supplementary 47 bibliographic resources identified in the literature within a non-standardized search connected to the subject. As a final step of the PRISMA method, we have fulfilled a Population-Intervention-Comparison-Outcome-Time (PICOT)/Population-Intervention-Comparison-Outcome-Study type (PICOS)—based metanalysis of clinical trials identified as connected to our search, targeting the outcomes of rehabilitative kinesitherapeutic interventions compared to clinical approaches lacking such kind of treatment. Accordingly, we identified 10 clinical trials related to our article. The multi/interdisciplinary conventional therapy of Parkinson’s disease and non-conventional multitarget approach to an integrative treatment was briefly analyzed. This article synthesizes the current findings on the pathogenic interference between the dysregulated complex mechanisms involved in aging, neuroinflammation, and neurodegeneration, focusing on Parkinson’s disease and the acute and chronic repercussions of COVID-19. Time will tell whether COVID-19 neuroinflammatory events could trigger long-term neurodegenerative effects and contribute to the worsening and/or explosion of new cases of PD. The extent of the interrelated neuropathogenic phenomenon remains obscure, so further clinical observations and prospective longitudinal cohort studies are needed.
363	N359		Arvid Edén, MD, PhD1,2; Anna Grahn, MD, PhD1,2; Daniel Bremell, MD, PhD1,2; Anahit Aghvanyan, MD3; Pradeepthi Bathala, MS3; Dietmar Fuchs, PhD4; Johanna Gostner, PhD5; Lars Hagberg, MD, PhD1,2; Nelly Kanberg, MD1,2; Sunsanee Kanjananimmanont, MS3; Magnus Lindh, MD, PhD1; Salvia Misaghian, MS3; Staffan Nilsson, PhD6; Michael Schöll, PhD7,8,9; George Sigal, PhD3; Erika Stentoft, MD1,2; Marie Studahl, MD, PhD1,2; Aylin Yilmaz, MD, PhD1,2; Mingyue Wang, MD3; Martin Stengelin, PhD3; Henrik Zetterberg, MD, PhD7,9,10,11,12; Magnus Gisslén	Viral Antigen and Inflammatory Biomarkers in Cerebrospinal Fluid in Patients With COVID-19 Infection and Neurologic Symptoms Compared With Control Participants Without Infection or Neurologic Symptoms	http://jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2022.13253	Published	May 23, 2022	Study	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2792536	Question: Are cerebrospinal fluid (CSF) SARS-CoV-2 antigens associated with central nervous system inflammation in patients with COVID-19? Findings: Of 44 patients with COVID-19 (23 neurosymptomatic) included in this hospital-based cross-sectional study, CSF nucleocapsid antigen was detectable in 89% of patients with available data and was significantly correlated with immune activation markers (neopterin and interferon γ). Moreover, neurosymptomatic patients had a more pronounced inflammatory CSF profile compared with neuroasymptomatic patients that could not be attributed to differences in COVID-19 severity. Meaning: These results suggest that viral components may contribute to central nervous system immune responses without direct viral invasion and highlight the clinical importance of neurologic symptoms. Importance: Neurologic symptoms are common in COVID-19, but the central nervous system (CNS) pathogenesis is unclear, and viral RNA is rarely detected in cerebrospinal fluid (CSF). Objective: To measure viral antigen and inflammatory biomarkers in CSF in relation to neurologic symptoms and disease severity. Design, Setting, and Participants: This cross-sectional study was performed from March 1, 2020, to June 30, 2021, in patients 18 years or older who were admitted to Sahlgrenska University Hospital, Gothenburg, Sweden, with COVID-19. All patients had CSF samples taken because of neurologic symptoms or within a study protocol. Healthy volunteer and prepandemic control groups were included. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: Outcomes included CSF SARS-CoV-2 nucleocapsid antigen (N-Ag) using an ultrasensitive antigen capture immunoassay platform and CSF biomarkers of immune activation (neopterin, β2-microglobulin, and cytokines) and neuronal injury (neurofilament light protein [NfL]). Results: Forty-four patients (median [IQR] age, 57 [48-69] years; 30 [68%] male; 26 with moderate COVID-19 and 18 with severe COVID-19 based on the World Health Organization Clinical Progression Scale), 10 healthy controls (median [IQR] age, 58 [54-60] years; 5 [50%] male), and 41 patient controls (COVID negative without evidence of CNS infection) (median [IQR] age, 59 [49-70] years; 19 [46%] male) were included in the study. Twenty-one patients were neuroasymptomatic and 23 were neurosymptomatic (21 with encephalopathy). In 31 of 35 patients for whom data were available (89%), CSF N-Ag was detected; viral RNA test results were negative in all. Nucleocapsid antigen was significantly correlated with CSF neopterin (r = 0.38; P = .03) and interferon γ (r = 0.42; P = .01). No differences in CSF N-Ag concentrations were found between patient groups. Patients had markedly increased CSF neopterin, β2-microglobulin, interleukin (IL) 2, IL-6, IL-10, and tumor necrosis factor α compared with controls. Neurosymptomatic patients had significantly higher median (IQR) CSF interferon γ (86 [47-172] vs 21 [17-81] fg/mL; P = .03) and had a significantly higher inflammatory biomarker profile using principal component analysis compared with neuroasymptomatic patients (0.54; 95% CI, 0.03-1.05; P = .04). Age-adjusted median (IQR) CSF NfL concentrations were higher in patients compared with controls (960 [673-1307] vs 618 [489-786] ng/L; P = .002). No differences were seen in any CSF biomarkers in moderate compared with severe disease. Conclusions and Relevance: In this study of Swedish adults with COVID-19 infection and neurologic symptoms, compared with control participants, viral antigen was detectable in CSF and correlated with CNS immune activation. Patients with COVID-19 had signs of neuroaxonal injury, and neurosymptomatic patients had a more marked inflammatory profile that could not be attributed to differences in COVID-19 severity. These results highlight the clinical relevance of neurologic symptoms and suggest that viral components can contribute to CNS immune responses without direct viral invasion.
364	N360		Irene Scala, Simone Bellavia, Marco Luigetti, Valerio Brunetti, Aldobrando Broccolini, Maurizio Gabrielli, Lorenzo Zileri Dal Verme, Paolo Calabresi, Giacomo Della Marca & Giovanni Frisullo	Autonomic dysfunction in non-critically ill COVID-19 patients during the acute phase of disease: an observational, cross-sectional study	https://doi.org/10.1007/s10072-022-06136-2	Published	24 May 2022	Study	https://link.springer.com/article/10.1007/s10072-022-06136-2	Introduction Evidence is emerging about an extra-pulmonary involvement of SARS-CoV-2, including the nervous system. Autonomic dysfunction in patients recovering from acute coronavirus disease 2019 (COVID-19) has been recently described. Dysautonomic symptoms have been reported in the acute phase of the disease, but clear evidence is lacking, especially in the non-critical forms of the infection. Objective The aim of this study is to assess the prevalence of dysautonomia in acute, non-critically ill COVID-19 patients. Methods In this observational, cross-sectional study, we compared 38 non-critically ill patients with acute COVID-19 (COVID + group) to 38 healthy volunteers (COVID − group) in order to assess the prevalence of signs and symptoms of dysautonomia through the administration of the composite autonomic symptom score 31 (COMPASS-31) and an active standing test. Comparisons between groups were performed by means of both univariate and multivariate analyses. Results The prevalence of orthostatic hypotension was significantly higher in the COVID + group. Higher total scores of COMPASS-31 were observed in the COVID + group than controls. Significant differences between groups emerged in the secretomotor, orthostatic intolerance, and gastrointestinal COMPASS-31 domains. All these results maintained the statistical significance after the adjustment for concomitant drugs with a known effect on the autonomic nervous system assumed by the study participants, except for the differences in the gastrointestinal domain of COMPASS-31. Conclusion Our results suggest that an autonomic dysfunction could be an early manifestation of COVID-19, even in the contest of mild forms of the infection.
365	N361		Mia I. Loft, Eva M. Foged, Mai Koreska	An Unexpected Journey: The Lived Experiences of Patients with Long-Term Cognitive Sequelae After Recovering from COVID-19	https://doi.org/10.1177%2F10497323221099467	Published	May 21, 2022	Study	https://journals.sagepub.com/doi/abs/10.1177/10497323221099467	This current study explored the lived experiences of patients with long-term cognitive sequelae after recovering from COVID-19. A qualitative design with in-depth interviews and an analysis inspired by Ricoeur’s interpretation theory was utilised. Contracting COVID-19 and suffering long-term sequelae presented as a life-altering event with significant consequences for one’s social, psychological and vocational being in the world in the months following the infection. Patients living with long-term cognitive sequelae after COVID-19 were in an unknown life situation characterised by feelings of anxiety, uncertainty and concerns about the future, significantly disrupting their life trajectory and forcing them to change their ways of life. While awaiting studies on treatment, symptom management and recovery after persistent sequelae of COVID-19, clinicians and researchers may find inspiration in experiences of other health conditions with similar phenomenology, such as ME/chronic fatigue syndrome and chronic headaches.
366	N362		Sareen T. Ali† , Anthony K. Kang† , Tulsi R. Patel , Jeffrey R. Clark , Gina S. Perez-Giraldo, Zachary S. Orban, Patrick H. Lim, Millenia Jimenez, Edith L. Graham , Ayush Batra , Eric M. Liotta & Igor J. Koralnik	Evolution of neurologic symptoms in non-hospitalized COVID-19 “long haulers”	https://doi.org/10.1002/acn3.51570	Published	25 April 2022	Study	https://onlinelibrary.wiley.com/doi/pdf/10.1002/acn3.51570	Objective: We characterized the evolution of neurologic symptoms and selfperceived recovery of non-hospitalized COVID-19 “long haulers” 6–9 months after their initial Neuro-COVID-19 clinic evaluation. Methods: In this followup study on the first 100 patients, 50 SARS-CoV-2 laboratory-positive (SARS-CoV-2+), and 50 laboratory-negative (SARS-CoV-2�), evaluated at our Neuro-COVID-19 clinic between May and November 2020, patients completed phone questionnaires on their neurologic symptoms, subjective impression of recovery and quality of life. Results: Of 52 patients who completed the study (27 SARS-CoV-2+, 25 SARS-CoV-2�) a median 14.8 (range 11–18) months after symptom onset, mean age was 42.8 years, 73% were female, and 77% were vaccinated for SARS-CoV-2. Overall, there was no significant change in the frequency of most neurologic symptoms between first and follow-up evaluations, including “brain fog” (81 vs. 71%), numbness/tingling (69 vs. 65%), headache (67 vs. 54%), dizziness (50 vs. 54%), blurred vision (34 vs. 44%), tinnitus (33 vs. 42%), and fatigue (87 vs. 81%). However, dysgeusia and anosmia decreased overall (63 vs. 27%, 58 vs. 21%, both p < 0.001). Conversely, heart rate and blood pressure variation (35 vs. 56%, p = 0.01) and gastrointestinal symptoms (27 vs. 48%, p = 0.04) increased at follow-up. Patients reported improvements in their recovery, cognitive function, and fatigue, but quality of life measures remained lower than the US normative population (p < 0.001). SARS-CoV-2 vaccination did not have a positive or detrimental impact on cognitive function or fatigue. Interpretation: Non-hospitalized COVID-19 “long haulers” continue to experience neurologic symptoms, fatigue, and compromised quality of life 14.8 months after initial infection.
367	N363		Josephine Heine1, Katia Schwichtenberg1, Sophia Rekers1, Fabian Bösl1, Christiana Franke1, Kathrin Reetz2,3 & Carsten Finke1,4	White matter changes and cognitive impairment in Long-COVID patients with fatigue		Published	May 2022	Study	https://cognitive-neurology.com/wp-content/uploads/2022/05/Abstract_OHBM_2.pdf	The CAMINO study protocol included a structured neuropsychological assessment of memory, attention, executive functions, and spatial navigation, and a 3T MRI acquisition. The diffusion-weighted scan (multiband EPI, 1.5x1.5x1.5mm, 98 diffusion directions, 1.5mm slice thickness, bvalue=3000s/mm²) was analysed using the FSL FDT Diffusion Toolbox [2]. Preprocessing included correcting for eddy currents, brain extraction, and fitting of diffusion tensor models. Diffusion maps were processed using tract-based spatial statistics (TBSS)[3] and Randomise with FDR correction [4]. Additionally, we segmented high-resolution T1-weighted scans (MPRAGE, 1x1x1mm³) using FSL FIRST [5] to obtain volume estimates and extract microstructural integrity scores for subcortical structures. The study was approved by the ethics committee of Charité–Universitätsmedizin Berlin. Results At a median of 8.4 (3.2-19.8) months after acute SARS-CoV-2 infection, we observed neuropsychological impairments of higher attentional functions (80%, 40/50 of the patients affected)), processing speed (64%, 32/50), executive functions (46%, 23/50), working memory (36%, 18/50), and verbal episodic memory (30%, 15/50). Severe motor (86%, 43/50) and cognitive fatigue (82%, 41/50) were the most prevalent neuropsychiatric features (FSMC: 74.5±11.2). Moreover, we observed increased levels of depressive (BDI-II: 16.6±6.1) and anxiety symptoms (BAI: 14.7±6.9). Diffusion imaging revealed significantly reduced axial diffusivity (AD) of the left amygdala (7.3310-4 (±0.5910-4, patients) vs. 7.6710-4 (±0.5910-4, controls), F(1,93)=4.37, p=.039) and right putamen (6.2210-4 (±0.3610-4) vs. 6.5310-4 (±0.3310-4), F(1,93)=6.76, p=.011). There was no evidence for damage to major white matter tracts on whole brain imaging, including the corpus callosum and association fibres such as the superior longitudinal fasciculus, uncinate, fornix, and cingulum. Clinical scores were significantly associated with white matter and subcortical integrity in patients. Higher anxiety scores correlated with aberrant radial diffusivity (RD) of the amygdala (left: r=-.38, p=.008; right: r=-.43, p=.002) and hippocampus (left: r=-.36, p=.011; right: r=-.40, p=.004). Additionally, increased fatigue was related to altered RD of the caudate nucleus (left: r=-.44, p=.002; right: r=-.04; p=.042 (n.s. after Benjamini-Hochberg correction)) and amygdala (left: r=-.56, p<.001; right: r=-.50, p<.001). Lower attention and executive functioning were associated with integrity of the right uncinate fasciculus (Trail Making Test B, FA: r=-.45, p=.001; Stroop test errors, RD: r=-.40, p=.005). Lastly, impaired spatial navigation performance was accompanied by lower hippocampal volumes (left: r=.49, p<.001; right: r=.38, p=.008) and decreased integrity of hippocampal white matter tracts, including fornix (FA: r=.37, p=.009) and cingulum (MD, left: r=-.42, p=.002; right: r=-.41, p=.003). Conclusions Impairment of higher attentional and executive functions, affective symptoms, and severe fatigue are frequent presentations of Long-COVID patients with neurological complaints. Our analyses show that, in the absence of global white matter damage, compromised microstructural integrity of subcortical hubs contributes to cognitive and neuropsychiatric symptoms in these patients. Future research will determine whether these neuronal correlates represent transient or persistent changes and shed light on their neuroimmunological mechanisms.
368	N364		Julie Fiorentino 1,2,*ORCID,Magali Payne 1,2,Elisa Cancian 3,Alexandra Plonka 1,2,4,Louise-Émilie Dumas 2,5,David Chirio 6,Élisa Demonchy 6,Karine Risso 6,Florence Askenazy-Gittard 2,5,Nicolas Guevara 4ORCID,Laurent Castillo 4,Philippe Robert 1,2,Valeria Manera 1,2,Clair Vandersteen 2,3ORCID andAuriane Gros 1	Correlations between Persistent Olfactory and Semantic Memory Disorders after SARS-CoV-2 Infection	https://doi.org/10.3390/brainsci12060714	Published	31 May 2022	Study	https://www.mdpi.com/2076-3425/12/6/714/htm	Background: One of the main symptoms of COVID-19 is hyposmia or even anosmia. Olfactory identification is most often affected. In addition, some cognitive disorders tend to appear following the infection, particularly regarding executive functions, attention, and memory. Olfaction, and especially olfactory identification, is related to semantic memory which manages general knowledge about the world. The main objective of this study was to determine whether semantic memory is impaired in case of persistent post COVID-19 olfactory disorders. Methods: 84 patients (average age of 42.8 ± 13.6 years) with post COVID-19 olfactory loss were included after consulting to the ENT department. The clinical evaluation was carried out with the Pyramid and Palm Tree Test, the word-retrieval task from the Grémots, the Sniffin’ Sticks Test and the Computerised Olfactory Test for the Diagnosis of Alzheimer’s Disease. Results: Semantic memory was impaired in 20% (n = 17) of patients, especially in the 19–39 age-group. The olfactory threshold was only significantly correlated with the semantic memory scores. Conclusions: Similar to all cognitive disorders, semantic disorders can have a negative impact on quality of life if left untreated. It is essential to carry out specific assessments of post COVID-19 patients to accurately determine their disorders and to put in place the best possible rehabilitation, such as speech and language therapy, to avoid quality-of-life impairment.
369	N365		Michael J. Peluso MD,Steven G. Deeks MD,Maja Mustapic PhD,Dimitrios Kapogiannis MD,Timothy J. Henrich MD,Scott Lu MBBS,Sarah A. Goldberg BA,Rebecca Hoh MS,Jessica Y. Chen,Enrique O. Martinez BA,J. Daniel Kelly MD, PhD,Jeffrey N. Martin MD,Edward J. Goetzl MD	SARS-CoV-2 and Mitochondrial Proteins in Neural-Derived Exosomes of COVID-19	https://doi.org/10.1002/ana.26350	Published	13 March 2022	Study	https://onlinelibrary.wiley.com/doi/10.1002/ana.26350	Objective As SARS-CoV-2 is known to invade neural cell mitochondria, a plasma system for quantifying central nervous system proteins in living humans was used to investigate neuropathogenic mechanisms of long-COVID-19. Methods SARS-CoV-2 proteins and mitochondrial proteins (MPs) in enriched plasma neuron-derived extracellular vesicles (NDEVs) and astrocyte-derived EVs (ADEVs) were quantified in resolved acute COVID-19 without post-acute sequelae of SARS-CoV-2 (PASC), PASC without neuropsychiatric manifestations (NP), PASC with NP and healthy controls. Results NDEV and ADEV mean levels of SARS-CoV-2 S1 and nucleocapsid (N) proteins were higher in all PASC sub-groups than controls, but only N levels were higher in PASC with than without NP. Exosome marker CD81-normalized NDEV mean levels of subunit 6 of MP respiratory chain complex I and subunit 10 of complex III, and neuroprotective MPs Humanin and mitochondrial open-reading frame of the 12S rRNA-c (MOTS-c) all were decreased significantly in PASC with NP but not in PASC without NP relative to controls. NDEV levels of MPs voltage-dependent anion-selective channel protein 1 (VDAC1) and N-methyl-D-aspartate receptor 1 (NMDAR1) were decreased in PASC without and with NP, whereas those of calcium channel MPs mitochondrial calcium uniporter (MCU), sodium/calcium exchanger (NCLX) and leucine zipper EF-hand containing transmembrane 1 protein (LETM1) were decreased only in PASC with NP. ADEV levels of MCU and NCLX only were increased in PASC without and with NP. Interpretation Abnormal NDEV and ADEV levels of SARS-CoV-2 N and S1 protein and MPs correlate with NP and may be biomarkers for long-COVID prognostics and therapeutic trials.
370	N366		Denise Visser, Sandeep S.V. Golla, Sander C.J. Verfaillie, Emma M. Coomans, Roos M. Rikken, Elsmarieke M. van de Giessen, Marijke E. den Hollander, Anouk Verveen, Maqsood Yaqub, Frederik Barkhof, Janneke Horn, Bart Koopman, Patrick Schober, Dook W. Koch, Robert C. Schuit, Albert D. Windhorst, Michael Kassiou, Ronald Boellaard, Michele van Vugt, Hans Knoop, Nelleke Tolboom, Bart N.M. van Berckel	Long COVID is associated with extensive in-vivo neuroinflammation on [18F]DPA-714 PET	https://doi.org/10.1101/2022.06.02.22275916	pre-print	June 04, 2022	Case Reports	https://www.medrxiv.org/content/10.1101/2022.06.02.22275916v1	A significant number of COVID-19 patients develop 'long COVID', a condition defined by long-lasting debilitating, often neurological, symptoms. The pathophysiology of long COVID is unknown. Here we present in-vivo evidence of widespread neuroinflammation in long COVID, using a quantitative assessment, [18F]DPA-714 PET, in two long COVID patients. We reanalyzed historical data from three matched healthy control subjects, for comparison purposes. Both patients with long COVID had widespread increases in [18F]DPA-714 binding throughout the brain. Quantitative measures of binding (BPND values) were increased on average by 121% and 76%, respectively. This implicates profound neuroinflammation in the pathophysiology of long COVID.
371	N367		Rafi Hadad, Johad Khoury, Chen Stanger, Tali Fisher, Sonia Schneer, Rachel Ben-Hayun, Katherine Possin, Victor Valcour, Judith Aharon-Peretz & Yochai Adir	Cognitive dysfunction following COVID-19 infection	https://doi.org/10.1007/s13365-022-01079-y	Published	26 May 2022	Study	https://link.springer.com/article/10.1007/s13365-022-01079-y	The long-term sequelae of COVID-19 and neurologic syndromes post COVID remain poorly understood. The present study aims to characterize cognitive performance in patients experiencing cognitive symptoms post-COVID infection. Patients evaluated at a post COVID clinic in Northern Israel who endorsed cognitive symptoms were referred for neurologic consultation. The neurologic work-up included detailed medical history, symptom inventory, neurological examination, the Montreal Cognitive Assessment (MoCA), laboratory tests and brain CT or MRI. Between December 2020 and June 2021, 46 patients were referred for neurological consultation (65% female), mean age 49.5 (19–72 years). On the MoCA test, executive functions, particularly phonemic fluency, and attention, were impaired. In contrast, the total MoCA score, and memory and orientation subscores did not differ from expected ranges. Disease severity, premorbid condition, pulmonary function tests and hypoxia did not contribute to cognitive performance. Cognitive decline may affect otherwise healthy patients post-COVID, independent of disease severity. Our examination identified abnormalities in executive function, attention, and phonemic fluency. These findings occurred despite normal laboratory tests and imaging findings.
372	N368		Rodolfo Furlan Damiano, Deusdedit Brandão Neto, João Vitor Ribeiro Oliveira, Jonatas Magalhães Santos, Julia Vallin Rodrigues Alves, Bruno F. Guedes, Ricardo Nitrini, Adriana Ladeira de Araújo, Melaine Oliveira, André R. Brunoni, Richard Louis Voegels, Ricardo Ferreira Bento, Geraldo Busatto, Euripedes Constantino Miguel, Orestes V. Forlenza, Fabio de Rezende Pinna & HCFMUSP COVID-19 study group	Association between chemosensory impairment with neuropsychiatric morbidity in post-acute COVID-19 syndrome: results from a multidisciplinary cohort study	https://doi.org/10.1007/s00406-022-01427-3	Published	28 May 2022	Study	https://link.springer.com/article/10.1007/s00406-022-01427-3	Preliminary methodologically limited studies suggested that taste and smell known as chemosensory impairments and neuropsychiatric symptoms are associated in post-COVID-19. The objective of this study is to evaluate whether chemosensory dysfunction and neuropsychiatric impairments in a well-characterized post-COVID-19 sample. This is a cohort study assessing adult patients hospitalized due to moderate or severe forms of COVID-19 between March and August 2020. Baseline information includes several clinical and hospitalization data. Further evaluations were made using several different reliable instruments designed to assess taste and smell functions, parosmia, and neuropsychiatric disorders (using standardized psychiatric and cognitive measures). Out of 1800 eligible individuals, 701 volunteers were assessed on this study. After multivariate analysis, patients reporting parosmia had a worse perception of memory performance (p < 0.001). Moderate/severe hypogeusia was significantly associated with a worse performance on the word list memory task (p = 0.012); Concomitant moderate/severe olfactory and gustatory loss during the acute phase of COVID-19 was also significantly associated with episodic memory impairment (p = 0.006). We found a positive association between reported chemosensory (taste and olfaction) abnormalities and cognition dysfunction in post-COVID-19 patients. These findings may help us identify potential mechanisms linking these two neurobiological functions, and also support the speculation on a possible route through which SARS-CoV-2 may reach the central nervous system.
373	N369		P. Young	Schlafstörungen und Erschöpfungssyndrom bei Long-COVID-Syndrom: Fallbasierte Erfahrungen aus der neurologischen/schlafmedizinischen Rehabilitation Sleep disorders and fatigue syndrome in long COVID syndrome: case-based experiences from neurological/sleep medicine rehabilitation	https://doi.org/10.1007/s11818-022-00353-9	Published	30 May 2022	Case Series	https://link.springer.com/article/10.1007/s11818-022-00353-9	Schlafstörungen und ein klinisch signifikantes Erschöpfungssyndrom werden für das Long-COVID-Syndrom regelhaft beschrieben. Die pathophysiologischen Zusammenhänge sind weitergehend unbekannt. Die klinische Präsentation ist unterschiedlich und muss individuell betrachtet werden. Anhand von vier Fallbeispielen wird dargestellt, welche Symptome ein Long-COVID-Syndrom ausmachen und welche Therapieoptionen zur Verfügung stehen. Eine multimodale individualisierte Rehabilitation scheint geeignet, Betroffene wieder an die prämorbide Leistungsfähigkeit heranzuführen und eine erhebliche Reduktion von insomnischen Beschwerden zu erreichen. Abstract Sleep disturbances and clinically significant fatigue syndrome are regularly described for long COVID syndrome. The pathophysiological correlations remain unknown. The clinical presentation is variable and must be considered individually. Four case studies will be used to illustrate the symptoms that constitute long COVID syndrome and the treatment options available. Multimodal individualized rehabilitation seems to be suitable to return those affected to their premorbid performance and to achieve a considerable reduction in insomniac complaints.
374	N370		A.MenardM.ChineL.MeddebS.CamilleriE.Guedj	Imagerie TEP au 18FDG et Covid-Long : retour d'expérience en pratique clinique	https://doi.org/10.1016/j.mmifmc.2022.03.031	Published	31 May 2022	Article	https://www.sciencedirect.com/science/article/pii/S2772743222000496	Introduction L'hypothèse d'une atteinte cérébrale associée au COVID long neurologique a été posée dès le mois de mai 2020, sur la base des premières descriptions de cas d'anosmie après infection à la COVID-19 et de travaux précédents sur les autres SARS montrant un possible passage du virus de la sphère ORL vers le cerveau, avec une progression trans-synaptique ultérieure vers les régions cérébrales connectées aux bulbes olfactifs, et en particulier les régions limbiques, le tronc cérébral et le cervelet. Ce profil d'atteinte spécifique a été authentifie chez des patients présentant un COVID long neurologique en évaluant l'hypométabolisme de ces régions en imagerie TEP au 18FDG par plusieurs équipes dans le monde. Matériels et méthodes Depuis mai 2020 dans notre centre un suivi standardisé (tous les 3 mois) et pluri disciplinaire est proposé aux patients ayant fait une forme sévère (post hospitalisation) ou ambulatoire mais avec symptômes persistants. Ils sont inclus dans une cohorte de suivi longitudinale avec un recueil à chaque visite des auto questionnaires (qualité de vie :SF36, fatigue :Pichot,dyspnée :MRC,Borg, cognitifs :MoCa, Stress :SSPT) un examen clinique exhaustif, des avis spécialisés avec bilan sanguin et imagerie par TEP selon l'évolution. Nous analysons ici les données des TEP dans notre cohorte à 18 mois. Résultats 201 patients ont été inclus, 190 analysés dont 55% de femmes, d'âge médian de 55 ans, actif dans 60% des cas (24% domaine santé), 58% avec une comorbidité à risque de forme sévère. L'épisode aigue en ambulatoire pour 85 (42.2%) patients, en hospitalisation conventionnelle pour 76 (37.8%) ou en soins intensif/réanimation pour 40 (20%). Une corticothérapie et une oxygénothérapie ont été prescrite pour respectivement 78 (38.8%) et 114 (56.7%). 49 (24.4%) patients ont décompensé ou découvert (7%) une maladie chronique. En moyenne les patients ont eu 2,6 visites et 48% d'entre eux ont un suivi de plus de 12 mois. A S12 du suivi, 122 patients ont le statut de COVID Long (CL+) avec un nb moyen de symp = 3,6+/-2,2 (1-10) et 68 sont guéris (CL-). 81% des patients CL+ ont bénéficié d'une évaluation par TEP entre 6 et 12 mois post COVID et 70% des TEP cérébraux étaient anormaux (hypo métabolisme compatible avec un profil de COVID-long) contre 14% des TEP corps (hyper métabolisme médullaire, articulaire, splénique). Les patients améliorés avant 3 mois durant le suivi (CL-,n=68) ont bénéficié pour 14 d'entre eux (20%) d'un TEP cerebral qui était anormal dans 7 % des cas. L'analyse multi variée retrouve un lien statistique (<0,05) avec un profil clinique particulier du CL+ sexe féminin, un âge <65 ans une fatigue sévère (Pichot >20) une dyspnee (Borg<3 et MRc<1) et les troubles cognitifs. Conclusion L'expérience clinique rapportée au travers de l'analyse de notre cohorte de Covid Long objective un hypo métabolisme cérébrale dans des régions en lien avec la symptomatologie dans 70 % des TEP réalisés. L'hypothèse d'une atteinte cérébrale neuro-inflammatoire par activation microgliale a été posée par plusieurs équipes internationales apres la démonstration d'une inflammation virale de l'épithélium olfactif après infection COVID-19 et d'une activation microgliale sur les séries autopsiques de sujets décédés du COVID-19. L'intérêt du TEP cérébral comme marqueur pronostic d'une évolution chronique et complexe du Covid-Long devra être évalué dans de futures études.
375	N371		Pablo Andrei Appelt, Angélica Taciana Sisconetto, Kelly Savana Minaré Baldo Sucupira, Eduardo de Moura Neto, Tatiane de Jesus Chagas, Rodrigo Bazan, Ariana Moura Cabral, Adriano de Oliveira Andrade, Luciane Aparecida Pascucci Sande de Souza, Gustavo José Luvizutto	Changes in Electrical Brain Activity and Cognitive Functions Following Mild to Moderate COVID-19: A one-Year Prospective Study After Acute Infection	https://doi.org/10.1177%2F15500594221103834	Published	May 29, 2022	Study	https://journals.sagepub.com/doi/abs/10.1177/15500594221103834	The coronavirus disease 2019 (COVID-19) can disrupt various brain functions. Over a one-year period, we aimed to assess brain activity and cognitive function in 53 COVID-19 patients and 30 individuals without COVID-19 (or asymptomatic). The Montreal Cognitive Assessment, Trail Making Test Parts A and B (TMT-A and B), and Digit Span Test were used to assess cognitive function. Cognitive variables and electroencephalography (EEG) data (activity, mobility, and complexity) were compared between the groups at rest and during cognitive demand (F3-F7, Fz-F3, Fz-F4, and F4-F8). There was a reduction in F3-F7 activity during the TMT-B in the COVID-19 group at 6-12 months compared to the controls (p = 0.01) at baseline (p = 0.03), a reduction in signal complexity at F3-F7 at rest in the COVID-19 group at baseline and 6-12 months compared to the controls (p < 0.001), and a reduction in Fz-F4 activity at rest from 6-12 months in the post-COVID group compared to baseline (p = 0.02) and 3-6 months (p = 0.04). At 6-12 months, there was a time increase in TMT-A in the COVID-19 group compared to that in the controls (p = 0.04). Some correlations were found between EEG data and cognitive test in both groups. In conclusion, there was a reduction in brain activity at rest in the Fz-F4 areas and during high cognitive demands in the F3-F7 areas. A reduction in signal complexity in F3-F7 at rest was found in the COVID-19 group at 6-12 months after acute infection. Furthermore, individuals with COVID-19 experience long-term changes in cognitive function.
376	N372		Jonas Jardim de Paula, Rachel E. R. P. Paiva, Nathália Gualberto Souza-Silva, Daniela Valadão Rosa, Fabio Luis de Souza Duran, Roney Santos Coimbra, Danielle de Souza Costa, Pedro Robles Dutenhefner, Henrique Soares Dutra Oliveira, Sarah Teixeira Camargos, Herika Martins Mendes Vasconcelos, Nara de Oliveira Carvalho, Juliana Batista da Silva, Marina Bicalho Silveira, Carlos Malamut, Derick Matheus Oliveira, Luiz Carlos Molinari, Danilo Bretas de Oliveira, José Nélio Januário, Luciana Costa Silva, Luiz Armando De Marco, Dulciene Maria de Magalhaes Queiroz, Wagner Meira, Geraldo Busatto, Débora Marques Miranda & Marco Aurélio Romano-Silva	Selective visuoconstructional impairment following mild COVID-19 with inflammatory and neuroimaging correlation findings	https://doi.org/10.1038/s41380-022-01632-5	Published	14 June 2022	Study	https://www.nature.com/articles/s41380-022-01632-5	People recovered from COVID-19 may still present complications including respiratory and neurological sequelae. In other viral infections, cognitive impairment occurs due to brain damage or dysfunction caused by vascular lesions and inflammatory processes. Persistent cognitive impairment compromises daily activities and psychosocial adaptation. Some level of neurological and psychiatric consequences were expected and described in severe cases of COVID-19. However, it is debatable whether neuropsychiatric complications are related to COVID-19 or to unfoldings from a severe infection. Nevertheless, the majority of cases recorded worldwide were mild to moderate self-limited illness in non-hospitalized people. Thus, it is important to understand what are the implications of mild COVID-19, which is the largest and understudied pool of COVID-19 cases. We aimed to investigate adults at least four months after recovering from mild COVID-19, which were assessed by neuropsychological, ocular and neurological tests, immune markers assay, and by structural MRI and 18FDG-PET neuroimaging to shed light on putative brain changes and clinical correlations. In approximately one-quarter of mild-COVID-19 individuals, we detected a specific visuoconstructive deficit, which was associated with changes in molecular and structural brain imaging, and correlated with upregulation of peripheral immune markers. Our findings provide evidence of neuroinflammatory burden causing cognitive deficit, in an already large and growing fraction of the world population. While living with a multitude of mild COVID-19 cases, action is required for a more comprehensive assessment and follow-up of the cognitive impairment, allowing to better understand symptom persistence and the necessity of rehabilitation of the affected individuals.
377	N373	COA	Anthony Fernández-Castañeda ∗Peiwen Lu ∗ Anna C. Geraghty ∗Eric Song ∗Myoung-Hwa Lee Jamie Wood Michael R. O’Dea Selena Dutton Kiarash Shamardani Kamsi Nwangwu Rebecca Mancusi Belgin Yalçın Kathryn R. Taylor Lehi Acosta-Alvarez Karen Malacon Michael B. Keough Lijun Ni Pamelyn J. Woo Daniel Contreras-Esquivel Angus Martin Shaw Toland Jeff R. Gehlhausen Jon Klein Takehiro Takahashi Julio Silva Benjamin Israelow Carolina Lucas Tianyang Mao Mario A. Peña-Hernández Alexandra Tabachnikova Robert J. Homer Laura Tabacof Jenna Tosto-Mancuso Erica Breyman Amy Kontorovich Dayna McCarthy Martha Quezado Hannes Vogel Marco M. Hefti Daniel P. Perl Shane Liddelow Rebecca Folkerth David Putrino Avindra Nath Akiko Iwasaki Michelle Monje	Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation	https://doi.org/10.1016/j.cell.2022.06.008	Published	June 12, 2022	Study	https://www.cell.com/cell/fulltext/S0092-8674(22)00713-9	COVID survivors frequently experience lingering neurological symptoms that resemble cancer therapy-related cognitive impairment, a syndrome for which white-matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared to SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis and elevated CCL11 at early timepoints, but after influenza only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.
378	N374		MargheritaBertuccelliab1LucianaCiringionea1MariaRubegaaPatriziaBisiacchibcStefanoMasieroabAlessandraDel Feliceab	Cognitive impairment in people with previous COVID-19 infection: a scoping review	https://doi.org/10.1016/j.cortex.2022.06.002	Published	11 June 2022	Review	https://www.sciencedirect.com/science/article/pii/S0010945222001691	Highlights •Long-term cognitive COVID-19 sequelae are a growing public-health issue. •Memory, attention, and executive functions appeared to be the most affected domains. •Anxiety, depression, and PTSD are observed just in the non-ICU hospitalized group. •Larger cohorts and comprehensive neuropsychological batteries are required. Severe acute respiratory syndrome coronavirus 2 is a worldwide public health issue. Almost 2 years into the pandemic, the persistence of symptoms after the acute phase is a well-recognized phenomenon. We conducted a scoping review to map cognitive domain impairments, their frequency, and associated psycho-affective disorders in people with a previous COVID-19 infection. We searched PubMed/MEDLINE, Scopus, and PsycInfo to identify relevant reports published between December 1, 2019 and February 21, 2022. We followed the Preferred-Reporting-Items-for-Systematic-Reviews-and-Meta-Analyses extension for scoping review guidelines. Three independent reviewers selected and charted 25 records out of 922. Memory, attention, and executive functions appeared to be the most affected domains. Delayed recall and learning were the most impaired domains of memory. Among the executive functions, abstraction, inhibition, set shifting, and sustained and selective attention were most commonly impaired. Language and visuo-spatial abilities were rarely affected, although this finding might be biased by the scarcity of reports. Neurological and respiratory conditions were often reported in association with cognitive deficits. Results on psycho-affective conditions were inconclusive due to the low frequency of reported data. Admission to an intensive care unit is not related to cognitive deficits. This review highlighted a potential effect of a previous post-COVID-19 infection on a pattern of memory, attention, and executive functions impairments. These findings need to be confirmed on larger cohorts with comprehensive neuropsychological batteries and correlated to neurophysiological and neurobiological substrates.
379	N375		Mirren Charnley, Saba Islam, Guneet K. Bindra, Jeremy Engwirda, Julian Ratcliffe, Jiangtao Zhou, Raffaele Mezzenga, Mark D. Hulett, Kyunghoon Han, Joshua T. Berryman & Nicholas P. Reynolds	Neurotoxic amyloidogenic peptides in the proteome of SARS-COV2: potential implications for neurological symptoms in COVID-19	https://doi.org/10.1038/s41467-022-30932-1	Published	13 June 2022	Study	https://www.nature.com/articles/s41467-022-30932-1	COVID-19 is primarily known as a respiratory disease caused by SARS-CoV-2. However, neurological symptoms such as memory loss, sensory confusion, severe headaches, and even stroke are reported in up to 30% of cases and can persist even after the infection is over (long COVID). These neurological symptoms are thought to be produced by the virus infecting the central nervous system, however we don’t understand the molecular mechanisms triggering them. The neurological effects of COVID-19 share similarities to neurodegenerative diseases in which the presence of cytotoxic aggregated amyloid protein or peptides is a common feature. Following the hypothesis that some neurological symptoms of COVID-19 may also follow an amyloid etiology we identified two peptides from the SARS-CoV-2 proteome that self-assemble into amyloid assemblies. Furthermore, these amyloids were shown to be highly toxic to neuronal cells. We suggest that cytotoxic aggregates of SARS-CoV-2 proteins may trigger neurological symptoms in COVID-19.
380	N376		MargheritaBertuccelliab1LucianaCiringionea1MariaRubegaaPatriziaBisiacchibcStefanoMasieroabAlessandraDel Feliceab	Cognitive impairment in people with previous COVID-19 infection: a scoping review	https://doi.org/10.1016/j.cortex.2022.06.002	Published	11 June 2022	Review	https://www.sciencedirect.com/science/article/pii/S0010945222001691	Highlights •Long-term cognitive COVID-19 sequelae are a growing public-health issue. •Memory, attention, and executive functions appeared to be the most affected domains. •Anxiety, depression, and PTSD are observed just in the non-ICU hospitalized group. •Larger cohorts and comprehensive neuropsychological batteries are required. Severe acute respiratory syndrome coronavirus 2 is a worldwide public health issue. Almost 2 years into the pandemic, the persistence of symptoms after the acute phase is a well-recognized phenomenon. We conducted a scoping review to map cognitive domain impairments, their frequency, and associated psycho-affective disorders in people with a previous COVID-19 infection. We searched PubMed/MEDLINE, Scopus, and PsycInfo to identify relevant reports published between December 1, 2019 and February 21, 2022. We followed the Preferred-Reporting-Items-for-Systematic-Reviews-and-Meta-Analyses extension for scoping review guidelines. Three independent reviewers selected and charted 25 records out of 922. Memory, attention, and executive functions appeared to be the most affected domains. Delayed recall and learning were the most impaired domains of memory. Among the executive functions, abstraction, inhibition, set shifting, and sustained and selective attention were most commonly impaired. Language and visuo-spatial abilities were rarely affected, although this finding might be biased by the scarcity of reports. Neurological and respiratory conditions were often reported in association with cognitive deficits. Results on psycho-affective conditions were inconclusive due to the low frequency of reported data. Admission to an intensive care unit is not related to cognitive deficits. This review highlighted a potential effect of a previous post-COVID-19 infection on a pattern of memory, attention, and executive functions impairments. These findings need to be confirmed on larger cohorts with comprehensive neuropsychological batteries and correlated to neurophysiological and neurobiological substrates.
381	N377		Sarah E.ConwayaBrian C.HealybJonathanZurawskiaChristopherSeversonaTamaraKaplanaLynnStazzoneaKristinGalettaaTanujaChitnisaMaria K.Houtchensa	COVID-19 severity is associated with worsened neurological outcomes in multiple sclerosis and related disorders	https://doi.org/10.1016/j.msard.2022.103946	Published	13 June 2022	Study	https://www.sciencedirect.com/science/article/pii/S2211034822004576	Highlights •We report on 111 patients with MS and related disorders (MSRD) with COVID-19. •36.9% of MSRD patients had neurologic worsening after COVID-19. •Neurologic worsening was associated with hospitalization for COVID-19. •Neurologic worsening was not associated with age, sex, EDSS, race or disease type. Background Neurologic outcomes in patients with multiple sclerosis (MS) and related disorders (MSRD) following COVID-19 is not well understood. The objective of this study was to investigate neurologic outcomes in patients with MSRD post-COVID-19. Methods This was a retrospective medical records review study of adult patients with MSRD and COVID-19 infection at the Brigham MS Center. Neurologic worsening post-COVID-19 was defined as having a relapse, pseudorelapse, new brain MRI activity, worsening of preexisting MSRD symptoms, or development of other long-term neurologic symptoms. Results 111 patients, 85 (76.6%) females, with a mean [SD] age of 49.3 [12.2] years and median [range] EDSS of 2.5 [0, 8.5] were identified. 41 patients (36.9%) had neurologic worsening post-COVID-19. Of those, 19 (46.3%) had pseudorelapses, 2 (4.8%) had relapses, and 24 (58.5%) patients reported worsening of preexisting MSRD symptoms, or other new long-term neurologic symptoms. Neurologic worsening was associated with hospitalized (moderate or severe) COVID-19 (p = 0.001), treatment for COVID-19 (p = 0.006), and incomplete COVID-19 recovery (p = 0.0267) but not with age, sex, MS type, race, disease duration, EDSS, vitamin D use, or disease modifying therapy use. Conclusions COVID-19 severity and lack of complete systemic recovery were associated with new or worsening neurologic symptoms in 36.9% of MSRD patients.
382	N378		César Fernández-de-las-Peñas, Umut Varol, Víctor Gómez-Mayordomo, María L. Cuadrado & Juan Antonio Valera-Calero	The relevance of headache as an onset symptom in COVID-19: a network analysis of data from the LONG-COVID-EXP-CM multicentre study	https://doi.org/10.1007/s13760-022-01998-x	Published	07 June 2022	Letter to the Editor	https://link.springer.com/article/10.1007/s13760-022-01998-x	The application of network analysis in a large population of COVID-19 survivors from five different hospitals supports the relevance of headache as an onset symptom at the acute COVID-19 phase, in agreement with previous studies. The SARS-CoV-2 virus exhibits neurotropic properties leading to an invasion of the central nervous system through potential direct mechanisms (e.g., haematogenous dissemination or neuronal retrograde dissemination) or others. These mechanisms could activate the trigeminal nerve pathways, contributing to the development of headache and anosmia. Monitoring headache at the acute phase may alert clinicians of an early potential invasion of the central nervous system or of a systemic inflammatory response caused by the SARS-CoV-2 virus. The better prognosis of patients reporting headache during the acute COVID-19 phase could be also linked to a stronger immune response against the SARS-CoV-2 virus. Although this is the largest multicentre cohort study focusing on headache as a COVID-19-onset symptom using a network analysis, it should be considered that we only included hospitalised COVID-19 survivors, and we did not characterise the semiological features of headache as an onset symptom. In conclusion, this multicentre study using a network analysis in a large population of COVID-19 survivors supports the relevance of headache as a key onset symptom at the acute COVID-19 phase.
383	N379		Lise Lamoureux 1,†,Babu Sajesh 1,†,Jessy A. Slota 1,2,†ORCID,Sarah J. Medina 1,Matthew Mayor 1,Kathy L. Frost 1,Bryce Warner 3,Kathy Manguiat 1,Heidi Wood 1,Darwyn Kobasa 2,3ORCID andStephanie A. Booth 1,2,*	Non-Productive Infection of Glial Cells with SARS-CoV-2 in Hamster Organotypic Cerebellar Slice Cultures	https://doi.org/10.3390/v14061218	Published	3 June 2022	Study	https://www.mdpi.com/1999-4915/14/6/1218/htm	The numerous neurological syndromes associated with COVID-19 implicate an effect of viral pathogenesis on neuronal function, yet reports of direct SARS-CoV-2 infection in the brain are conflicting. We used a well-established organotypic brain slice culture to determine the permissivity of hamster brain tissues to SARS-CoV-2 infection. We found levels of live virus waned after inoculation and observed no evidence of cell-to-cell spread, indicating that SARS-CoV-2 infection was non-productive. Nonetheless, we identified a small number of infected cells with glial phenotypes; however, no evidence of viral infection or replication was observed in neurons. Our data corroborate several clinical studies that have assessed patients with COVID-19 and their association with neurological involvement. In summary, we find that a small population of glial cells in hamster cerebellar sections were permissive for SARS-CoV-2, although infection was non-productive even in the absence of a BBB. We speculate that in severe disease, a disrupted BBB could lead to localized infection of glia and may explain the findings of a small number of studies in which viral proteins and RNA have been detected in brain tissue of patients and animals. However, the paucity of SARS-CoV-2 infection observed here aligns more closely with other reports that failed to identify evidence of neuroinvasion. Evidence from experimental models remains inconclusive, and careful examination of clinical cases will undoubtedly be required to shed further light on the troubling long-term neurological manifestations associated with COVID-19.
384	N380		Rosalia Dacosta-Aguayo 1,2,3,Noemí Lamonja-Vicente 1,4ORCID,Carla Chacón 1,4,Lucia Amalía Carrasco-Ribelles 1ORCID,Pilar Montero-Alia 1,4,5,6,Anna Costa-Garrido 1,Rosa García-Sierra 1,5,7ORCID,Victor M. López-Lifante 1,4,8ORCID,Eduard Moreno-Gabriel 1,4,5,9ORCID,Marta Massanella 10,11,12ORCID,Josep Puig 2ORCID,Jose A. Muñoz-Moreno 13,14,Lourdes Mateu 10,11,12,13,15ORCID,Anna Prats 13,Carmina Rodríguez 1,4,5,16,Maria Mataró 3ORCID,Julia G. Prado 10,11,17ORCID,Eva Martínez-Cáceres 18,19,20,Concepción Violán 1,4,17,21,* andPere Torán-Monserrat	Neurocognitive Profile of the Post-COVID Condition in Adults in Catalonia—A Mixed Method Prospective Cohort and Nested Case–Control Study: Study Protocol	https://doi.org/10.3390/vaccines10060849	Published	26 May 2022	Study Protocol	https://www.mdpi.com/2076-393X/10/6/849/htm	The diagnosis of the post-COVID condition is usually achieved by excluding other diseases; however, cognitive changes are often found in the post-COVID disorder. Therefore, monitoring and treating the recovery from the post-COVID condition is necessary to establish biomarkers to guide the diagnosis of symptoms, including cognitive impairment. Our study employs a prospected cohort and nested case–control design with mixed methods, including statistical analyses, interviews, and focus groups. Our main aim is to identify biomarkers (functional and structural neural changes, inflammatory and immune status, vascular and vestibular signs and symptoms) easily applied in primary care to detect cognitive changes in post-COVID cases. The results will open up a new line of research to inform diagnostic and therapeutic decisions with special considerations for cognitive impairment in the post-COVID condition.
385	N381	CPET	David A. HoldsworthID 1,2,3*, Rebecca Chamley2,4, Rob Barker-Davies5,6, Oliver O’SullivanID 5, Peter Ladlow5,7, James L. Mitchell5,8, Dominic Dewson5, Daniel Mills5, Samantha L. J. May5, Mark Cranley9, Cheng Xie3, Edward Sellon3,9, Joseph Mulae1, Jon Naylor1, Betty Raman4, Nick P. Talbot3,10, Oliver J. Rider4, Alexander N. Bennett5,11, Edward D. Nicol	Comprehensive clinical assessment identifies specific neurocognitive deficits in working-age patients with long-COVID	https://doi.org/10.1371/journal.pone.0267392	Published	June 10, 2022	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0267392	Introduction There have been more than 425 million COVID-19 infections worldwide. Post-COVID illness has become a common, disabling complication of this infection. Therefore, it presents a significant challenge to global public health and economic activity. Methods Comprehensive clinical assessment (symptoms, WHO performance status, cognitive testing, CPET, lung function, high-resolution CT chest, CT pulmonary angiogram and cardiac MRI) of previously well, working-age adults in full-time employment was conducted to identify physical and neurocognitive deficits in those with severe or prolonged COVID-19 illness. Results 205 consecutive patients, age 39 (IQR30.0–46.7) years, 84% male, were assessed 24 (IQR17.1–34.0) weeks after acute illness. 69% reported ≥3 ongoing symptoms. Shortness of breath (61%), fatigue (54%) and cognitive problems (47%) were the most frequent symptoms, 17% met criteria for anxiety and 24% depression. 67% remained below pre-COVID performance status at 24 weeks. One third of lung function tests were abnormal, (reduced lung volume and transfer factor, and obstructive spirometry). HRCT lung was clinically indicated in <50% of patients, with COVID-associated pathology found in 25% of these. In all but three HRCTs, changes were graded ‘mild’. There was an extremely low incidence of pulmonary thromboembolic disease or significant cardiac pathology. A specific, focal cognitive deficit was identified in those with ongoing symptoms of fatigue, poor concentration, poor memory, low mood, and anxiety. This was notably more common in patients managed in the community during their acute illness. Conclusion Despite low rates of residual cardiopulmonary pathology, in this cohort, with low rates of premorbid illness, there is a high burden of symptoms and failure to regain pre-COVID performance 6-months after acute illness. Cognitive assessment identified a specific deficit of the same magnitude as intoxication at the UK drink driving limit or the deterioration expected with 10 years ageing, which appears to contribute significantly to the symptomatology of long-COVID.
386	N382		Stefano GiuseppeGrisantiaSaraGarbarinobEmanuelaBarisionecTeresitaAloècMarcoGrossocCristinaSchenoneaMatteoPardiniacEricaBiassoniaFedericoZaottinicRiccardoPicassocSilviaMorbellicCristinaCampidbGiampaolaPescecFedericoMassaaNicolaGirtleracDeniseBattaglinieCorradoCabonacMatteoBassetticAntonioUccelliacAngeloSchenoneacMichelePianadbLuanaBenedettic	Neurological long-COVID in the outpatient clinic: Two subtypes, two courses	https://doi.org/10.1016/j.jns.2022.120315	Published	3 June 2022	Study	https://www.sciencedirect.com/science/article/pii/S0022510X22001770	Highlights •Neurological involvement related to COVID-19 can manifest itself both in the acute phase of infection or during long-COVID. •Neurological symptoms due to SARS-CoV-2 infection can involve both the central and the peripheral nervous system. •Neurological symptoms during COVID-19 may be related to virus-induced injury or iatrogenic injury during hospitalization. •Depending on the severity of SARS-CoV-2 infection, different neurological disorders may develop. Introduction Symptoms referable to central and peripheral nervous system involvement are often evident both during the acute phase of COVID-19 infection and during long-COVID. In this study, we evaluated a population of patients with prior COVID-19 infection who showed signs and symptoms consistent with neurological long-COVID. Methods We prospectively collected demographic and acute phase course data from patients with prior COVID-19 infection who showed symptoms related to neurological involvement in the long-COVID phase. Firstly, we performed a multivariate logistic linear regression analysis to investigate the impact of demographic and clinical data, the severity of the acute COVID-19 infection and hospitalization course, on the post-COVID neurological symptoms at three months follow-up. Secondly, we performed an unsupervised clustering analysis to investigate whether there was evidence of different subtypes of neurological long COVID-19. Results One hundred and nine patients referred to the neurological post-COVID outpatient clinic. Clustering analysis on the most common neurological symptoms returned two well-separated and well-balanced clusters: long-COVID type 1 contains the subjects with memory disturbances, psychological impairment, headache, anosmia and ageusia, while long-COVID type 2 contains all the subjects with reported symptoms related to PNS involvement. The analysis of potential risk-factors among the demographic, clinical presentation, COVID 19 severity and hospitalization course variables showed that the number of comorbidities at onset, the BMI, the number of COVID-19 symptoms, the number of non-neurological complications and a more severe course of the acute infection were all, on average, higher for the cluster of subjects with reported symptoms related to PNS involvement. Conclusion We analyzed the characteristics of neurological long-COVID and presented a method to identify well-defined patient groups with distinct symptoms and risk factors. The proposed method could potentially enable treatment deployment by identifying the optimal interventions and services for well-defined patient groups, so alleviating long-COVID and easing recovery.
387	N383		Julie Fiorentino 1,2,*ORCID,Magali Payne 1,2,Elisa Cancian 3,Alexandra Plonka 1,2,4,Louise-Émilie Dumas 2,5,David Chirio 6,Élisa Demonchy 6,Karine Risso 6,Florence Askenazy-Gittard 2,5,Nicolas Guevara 4ORCID,Laurent Castillo 4,Philippe Robert 1,2,Valeria Manera 1,2,Clair Vandersteen 2,3ORCID andAuriane Gros 1,2	Correlations between Persistent Olfactory and Semantic Memory Disorders after SARS-CoV-2 Infection	https://doi.org/10.3390/brainsci12060714	Published	31 May 2022	Study	https://www.mdpi.com/2076-3425/12/6/714/htm	Background: One of the main symptoms of COVID-19 is hyposmia or even anosmia. Olfactory identification is most often affected. In addition, some cognitive disorders tend to appear following the infection, particularly regarding executive functions, attention, and memory. Olfaction, and especially olfactory identification, is related to semantic memory which manages general knowledge about the world. The main objective of this study was to determine whether semantic memory is impaired in case of persistent post COVID-19 olfactory disorders. Methods: 84 patients (average age of 42.8 ± 13.6 years) with post COVID-19 olfactory loss were included after consulting to the ENT department. The clinical evaluation was carried out with the Pyramid and Palm Tree Test, the word-retrieval task from the Grémots, the Sniffin’ Sticks Test and the Computerised Olfactory Test for the Diagnosis of Alzheimer’s Disease. Results: Semantic memory was impaired in 20% (n = 17) of patients, especially in the 19–39 age-group. The olfactory threshold was only significantly correlated with the semantic memory scores. Conclusions: Similar to all cognitive disorders, semantic disorders can have a negative impact on quality of life if left untreated. It is essential to carry out specific assessments of post COVID-19 patients to accurately determine their disorders and to put in place the best possible rehabilitation, such as speech and language therapy, to avoid quality-of-life impairment.
388	N384		Virginia Fancello 1,*,†ORCID,Giuseppe Fancello 2,†,Stavros Hatzopoulos 1ORCID,Chiara Bianchini 1,Francesco Stomeo 1,Stefano Pelucchi 1 andAndrea Ciorba 1ORCID	Sensorineural Hearing Loss Post-COVID-19 Infection: An Update	https://doi.org/10.3390/audiolres12030032	Published	1 June 2022	Review	https://www.mdpi.com/2039-4349/12/3/32/htm	The course of COVID-19 infection may be complicated by a variety of neurological manifestations. Since the inner ear is vulnerable to viruses, sensorineural hearing loss (SNHL) has been reported to occur following the SARS-CoV-2 infection, often resulting in long-term morbidity and worsening the quality of life. The interest in how the virus affects the inner ear has gradually increased since the pandemic’s spread, but little is still known about the SNHL potentially caused by SARS-CoV-2. The aim of this paper is to evaluate the possible association between SNHL and COVID-19 infection, through a systematic literature review. Currently available data suggest that SARS-CoV-2 may hamper cochlear function; however, available reports are still limited. Large cohort and prospective studies are necessary to evaluate the long-term effects of this viral infection in the inner ear.
389	N385		Lucette A. Cysique, View ORCID ProfileDavid Jakabek, Sophia G. Bracken, Yasmin Allen-Davidian, View ORCID ProfileBenjamin Heng, View ORCID ProfileSharron Chow, Mona Dehhaghi, Ananda Staats Pires, View ORCID ProfileDavid R. Darley, View ORCID ProfileAnthony Byrne, View ORCID ProfileChansavath Phetsouphanh, View ORCID ProfileAnthony Kelleher, View ORCID ProfileGregory J. Dore, View ORCID ProfileGail V. Matthews, View ORCID ProfileGilles J Guillemin, View ORCID ProfileBruce J. Brew	Post-acute COVID-19 cognitive impairment and decline uniquely associate with kynurenine pathway activation: a longitudinal observational study	https://doi.org/10.1101/2022.06.07.22276020	pre-print	June 07, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.06.07.22276020v1.full-text	Cognitive impairment and function post-acute mild to moderate COVID-19 are poorly understood. We report findings of 128 prospectively studied SARS-CoV-2 positive patients. Cognition and olfaction were assessed at 2-, 4- and 12-months post-diagnosis. Lung function, physical and mental health were assessed at 2-month post diagnosis. Blood cytokines, neuro-biomarkers, and kynurenine pathway (KP) metabolites were measured at 2-, 4-, 8- and 12- months. Mild to moderate cognitive impairment (demographically corrected) was present in 16%, 23%, and 26%, at 2-, 4- and 12-months post diagnosis, respectively. Overall cognitive performance mildly, but significantly (p<.001) declined. Cognitive impairment was more common in those with anosmia (p=.05), but only at 2 months. KP metabolites quinolinic acid, 3-hydroxyanthranilic acid, and kynurenine were significantly (p<.001) associated with cognitive decline. The KP as a unique biomarker offers a potential therapeutic target for COVID-19-related cognitive impairment. There is evidence that SARS CoV-2 is associated with objectively tested cognitive impairment (CI) post-acute illness1–3 (see Table S1) but the extent, trajectory, and the nature of this new condition is unclear. Acute COVID-19 disease severity with its attendant complications is a major differential factor in the nature and extent of cognitive deficits4. Severe cases (cases that require hospitalization) are at risk for both indirect and direct mechanisms of COVID-19 associated brain damage, particularly from hypoxia5, 6, stroke, as well as the immune and inflammatory response to SARS-CoV-21. Mild to moderate cases of COVID-19 (not requiring hospitalization) are still at risk of brain dysfunction, and cognitive deficits7, 8. Such cases provide a window into the potential mechanisms of brain injury without the confounding role of severe disease and its complications9–11. As most patients with SARS-CoV-2 virus do not require hospitalization, cognitive decline associated with mild to moderate COVID-19 disease would have significant implications for public health given the current global prevalence of the infection. There are several challenges in addressing the pathogenesis of post-acute COVID-19 CI. First, there is the accurate identification and quantitation of medical co-morbidities particularly pre-morbid psychiatric conditions and illness-associated psychological distress12. Second, appropriate correction for normative demographic effects are imperative to accurately and specifically determine if cognitive deficits are present and to quantify their severity13. Many existing cognitive studies of COVID-19 that used objective testing14 (Table S1) have not appropriately controlled for demographics, mental health, and comorbid medical conditions. This lack of adjustment probably explains some of the large variance in the observed prevalence of CI. In addition, the previous literature on cognition in recovering COVID-19 patients has focused on patients who were hospitalized with severe acute COVID-19 disease (Table S1). Such patients can show extensive neuropsychological impairment (up to 87%) including focal insults due to stroke3, although improvement is detected in about half of this population at 12-months3. Furthermore, most cognitive studies are cross-sectional, and often have relatively small sample sizes (Table S1). Finally, studies have tended to consider olfaction and cognition separately and olfaction, in most instances, has been tested subjectively rather than objectively15. To address these limitations, the current study implements a rigorous neuropsychological framework as advocated via the International Neuropsychology COVID-19 taskforce16 where consideration of disease severity, demographics, mental health, objectively tested olfaction, and co-morbidities is conducted a priori. Furthermore, a longitudinal study design is used because COVID-19 can have lasting effects and post-acute CI are, by definition, time-based processes. The definition of cognitive performance over time is optimized by including the initial visit overall cognitive performance, and practice effect17, 18. Lack of correction for these factors in cognitive studies leads to biased estimation of cognitive change17–19. Using this robust neuropsychological basis, our aim was to elucidate the pathogenesis of COVID-19 associated CI by selecting a range of blood cytokines (Interferons (IFNs), major Interleukins, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α), peripheral biomarkers of brain injury and metabolic products. The selection of the biomarkers is founded on previous immunological findings in the same cohort, where persistently elevated IFNs (i.e., elevated expression of type I IFN (IFN-β) and type III IFN (IFN-λ1)) was associated with chest pain, and dyspnea20 up to 8-month post diagnosis. Next, we elected to test the components of the plasma kynurenine pathway (KP)21, 22 which is an IFN23, 24 stimulated myeloid cell mediated tryptophan degradation pathway important in immune tolerance, neurotoxicity, and vascular injury. The KP is dysregulated in COVID-19 infection25 including in mild cases26, although sex may have a moderating effect27. The peripheral biomarkers of brain injury have been selected because of their detectability in peripheral blood, their ability to facilitate understanding of major neurobiological mechanisms (e.g., neuro-axonal with Neurofilament Light Chain (NFL); astrogliosis with Glial fibrillary acidic protein (GFAP); blood brain barrier permeability (BBB), brain injury and astrocytosis with S100β; macrophage and granulocyte proliferation with Granulocyte macrophage colony-stimulating factor (GMCSF)), and because each is abnormally elevated in COVID-19 infection (NFL28; GFAP29; S100β30; GMCSF31). The aims of the current study were to determine the prevalence of CI and the trajectories of overall cognitive performance (both corrected for age, education, and sex) in COVID-19 cases recovering from mostly mild-moderate acute infection across a 12-month period. This is achieved by using the widely recognized Cogstate computerized battery that is ideal for serial repeating testing. Furthermore, we aimed to elucidate the pathogenesis of the observed cognitive changes. Moreover, the clinical significance of CI was assessed against functional status. The pathogenic axes assessed included systemic disease severity (and indirectly hypoxia), lung function, objectively tested olfaction, pre-existing and illness-associated anxiety and depression, medical comorbidities, initial visit CI, blood cytokines, the KP and peripheral biomarkers of brain injury. Time-variant predictors (all biomarkers but IFN-β IFN-λ1, olfaction) were tested for their main and time association with overall cognitive performance. The KP was also tested for its trajectory and its dynamic links to other biomarkers. Despite the exploratory angle of our study, we expected to detect a level of mild cognitive impairment, but without evidence of severe cognitive deficits or rapid deterioration based on previous studies in similar COVID-19 cases. We hypothesized that systemic disease severity, lung function, objectively tested olfaction, pre-existing and illness-associated anxiety and depression, initial visit CI, IFN-β, Quinolinic Acid as well as involvement of peripheral biomarkers of brain injury would show some level of association with cognitive decline.
390	N386		Erika Cecon, Daniela Fernandois, Nicolas Renault, Caio Fernando Ferreira Coelho, Jan Wenzel, Corentin Bedart, Charlotte Izabelle, Sarah Gallet, Sophie Le Poder, Bernard Klonjkowski, Markus Schwaninger, Vincent Prevot, Julie Dam & Ralf Jockers	Melatonin drugs inhibit SARS-CoV-2 entry into the brain and virus-induced damage of cerebral small vessels	https://doi.org/10.1007/s00018-022-04390-3	Published	13 June 2022	Study	https://link.springer.com/article/10.1007/s00018-022-04390-3	COVID-19 is a complex disease with short- and long-term respiratory, inflammatory and neurological symptoms that are triggered by the infection with SARS-CoV-2. Invasion of the brain by SARS-CoV-2 has been observed in humans and is postulated to be involved in post-COVID state. Brain infection is particularly pronounced in the K18-hACE2 mouse model of COVID-19. Prevention of brain infection in the acute phase of the disease might thus be of therapeutic relevance to prevent long-lasting symptoms of COVID-19. We previously showed that melatonin or two prescribed structural analogs, agomelatine and ramelteon delay the onset of severe clinical symptoms and improve survival of SARS-CoV-2-infected K18-hACE2 mice. Here, we show that treatment of K18-hACE2 mice with melatonin and two melatonin-derived marketed drugs, agomelatine and ramelteon, prevents SARS-CoV-2 entry in the brain, thereby reducing virus-induced damage of small cerebral vessels, immune cell infiltration and brain inflammation. Molecular modeling analyses complemented by experimental studies in cells showed that SARS-CoV-2 entry in endothelial cells is prevented by melatonin binding to an allosteric-binding site on human angiotensin-converting enzyme 2 (ACE2), thus interfering with ACE2 function as an entry receptor for SARS-CoV-2. Our findings open new perspectives for the repurposing of melatonergic drugs and its clinically used analogs in the prevention of brain infection by SARS-CoV-2 and COVID-19-related long-term neurological symptoms.	Selon une étude très prometteuse sur l'animal (souris avec certains gènes humanisés), la mélatonine possède un fort potentiel pour bloquer l'entrée du SARS-CoV-2 au niveau du système nerveux central. À des doses de quelques dizaines de mg par kg, la mélatonine abaisse la charge virale dans le cerveau, et prévient l'infection cérébrale dans la phase aiguë de la maladie, réduisant ainsi les dommages induits par le virus aux petits vaisseaux cérébraux, l'infiltration des cellules immunitaires et l'inflammation cérébrale. La même équipe avait déjà établi que la mélatonine retarde sur le modèle animal l'apparition de symptômes cliniques graves et améliorent la survie. Selon les auteurs, cette découverte ouvre de nouvelles perspectives pour la réutilisation des médicaments mélatoninergiques et de ses analogues utilisés en clinique dans la prévention de l'infection cérébrale par le SRAS-CoV-2 et les symptômes neurologiques à long terme liés à la covid.
391	N387		Fabricia L. Fontes-Dantas, Gabriel G. Fernandes, Elisa G. Gutman, Emanuelle V. De Lima, Leticia S. Antonio, Mariana B. Hammerle, Hannah P. Mota-Araujo, Lilian C. Colodeti, Suzana M. B. Araújo, Talita N. da Silva, Larissa A. Duarte, Andreza L. Salvio, Karina L. Pires, Luciane A. A. Leon, Claudia Cristina F. Vasconcelos, Luciana Romão, View ORCID ProfileLuiz Eduardo B. Savio, Jerson L. Silva, Robson da Costa, Julia R. Clarke, Andrea T. Da Poian, View ORCID ProfileSoniza V. Alves-Leon, Giselle F. Passos, Claudia P. Figueiredo	SARS-CoV-2 spike protein induces TLR-4-mediated long-term cognitive dysfunction recapitulating post-COVID syndrome	https://doi.org/10.1101/2022.06.07.495149	pre-print	June 10, 2022	Study	https://www.biorxiv.org/content/10.1101/2022.06.07.495149v2.full	Cognitive dysfunction is often reported in post-COVID patients, but its underlying mechanisms remain unknown. While some evidence indicate that SARS-CoV-2 can reach and directly impact the brain, others suggest viral neuroinvasion as a rare event. Independently of brain viral infection, the ability of SARS-CoV-2 spike (S) protein to cross the BBB and reach memory-related brain regions has already been shown. Here, we demonstrate that brain infusion of S protein in mice induces late cognitive impairment and increases serum levels of neurofilament light chain (NFL), which recapitulates post-COVID features. Neuroinflammation, hippocampal microgliosis and synapse loss are induced by S protein. Increased engulfment of hippocampal presynaptic terminals late after S protein brain infusion were found to temporally correlate with cognitive deficit in mice. Blockage of TLR4 signaling prevented S-associated detrimental effects on synapse and memory loss. In a cohort of 86 patients recovered from mild COVID-19, genotype GG TLR4 -2604G>A (rs10759931) was associated with poor cognitive outcome. Collectively, these findings indicate that S protein directly impacts the brain and suggest that TLR4 is a potential target to prevent post-COVID cognitive dysfunction. One Sentence Summary TLR4 mediates long-term cognitive impairment in mice and its genetic variant increases the risk of poor cognitive outcome in post-COVID patients.
392	N388		MariaRubegaaLucianaCiringioneaMargheritaBertuccelliabMatildeParamentocGiovanniSparacinocAndreaVianellodStefanoMasieroabAntoninoVallesiabEmanuelaFormaggioabAlessandraDel Feliceab	High-density EEG sleep correlates of cognitive and affective impairment at 12-month follow-up after COVID-19	https://doi.org/10.1016/j.clinph.2022.05.017	Published	25 June 2022	Study	https://www.sciencedirect.com/science/article/pii/S1388245722002942	Highlights •Sleep spindles may be a biomarker of psycho-affective symptoms in long COVID-19. •Survivors perceive a decreased quality of life and post-traumatic stress symptoms . •Post-traumatic stress symptoms may crucially contribute to cognitive impairment. Abstract Objective To disentangle the pathophysiology of cognitive/affective impairment in Coronavirus Disease-2019 (COVID-19), we studied long-term cognitive and affective sequelae and sleep high-density electroencephalography (EEG) at 12-month follow-up in people with a previous hospital admission for acute COVID-19. Methods People discharged from an intensive care unit (ICU) and a sub-intensive ward (nonICU) between March and May 2020 were contacted between March and June 2021. Participants underwent cognitive, psychological, and sleep assessment. High-density EEG recording was acquired during a nap. Slow and fast spindles density/amplitude/frequency and source reconstruction in brain gray matter were extracted. The relationship between psychological and cognitive findings was explored with Pearson correlation. Results We enrolled 33 participants ( 17 nonICU) and 12 controls. We observed a lower Physical Quality of Life index, higher post-traumatic stress disorder (PTSD) score, and a worse executive function performance in nonICU participants. Higher PTSD and Beck Depression Inventory scores correlated with lower executive performance. The same group showed a reorganization of spindle cortical generators. Conclusions Our results show executive and psycho-affective deficits and spindle alterations in COVID-19 survivors – especially in nonICU participants – after 12 months from discharge. Significance These findings may be suggestive of a crucial contribution of stress experienced during hospital admission on long-term cognitive functioning.
393	N389		Richard L.Doty	Olfactory Dysfunction in COVID-19: Pathology and Long-Term Implications for Brain Health	https://doi.org/10.1016/j.molmed.2022.06.005	Published	20 June 2022	Review	https://www.sciencedirect.com/science/article/pii/S1471491422001605	Highlights •COVID-19 has brought to public attention the importance of the sense of smell in everyday life, with untold numbers of patients seeking treatment for decreased ability to smell which, in many cases, may be permanent. •The neuroepithelium that harbors the olfactory receptor cells is directly exposed to the outside environment, making it susceptible to damage from toxic agents and a host of viruses, most notably SARS-CoV-2, the cause of COVID-19. •SARS-CoV-2 invades nearly all types of cells within the olfactory neuroepithelium, but does not appear to significantly invade olfactory receptor cells, which lack the primary entry receptor, angiotensin-converting enzyme II (ACE2). However, other entry receptors may also be involved. •The degree to which SARS-CoV-2 impacts central olfactory processing centers or leads to later neurological disorders has yet to be determined. ABSTRACT Decreased smell function is related to brain health, future mortality, and quality of life. Most people inflicted with the SARS-CoV-2 virus evidence some measurable smell dysfunction during its acute phase, although many are unaware of the loss. Long-term deficits occur in up to 30% of COVID-19 cases, although total anosmia is relatively rare. This review explores what is presently known about the nature and pathophysiology of olfactory dysfunction due to the SARS-CoV-2 virus, including reversible inflammation within the olfactory cleft, downregulation of olfactory receptor proteins, and long-lasting peripheral and central damage to olfactory structures. It also addresses the question as to whether long-term smell loss might increase the likelihood of future development of cognitive and neurological deficits.
394	N390		TomAschman1RonjaMothes1Frank L.Heppner123+HelenaRadbruch1+	What SARS-CoV-2 does to our brains	https://doi.org/10.1016/j.immuni.2022.06.013	Published	20 June 2022	Perspective	https://www.sciencedirect.com/science/article/pii/S1074761322002862	Neurological symptoms in SARS-CoV-2-infected patients have been reported, but their cause remains unclear. In theory, the neurological symptoms observed after SARS-CoV-2 infection could be (i) directly caused by the virus infecting brain cells, (ii) indirectly by our body’s local or systemic immune response towards the virus, (iii) by co-incidental phenomena or (iv) a combination of these factors. As indisputable evidence of intact and replicating SARS-CoV-2 particles in the central nervous system (CNS) is currently lacking, we suggest focusing on the host’s immune reaction when trying to understand the neurocognitive symptoms associated with SARS-CoV-2 infection. In this Perspective, we discuss the possible immune-mediated mechanisms causing functional or structural CNS alterations during acute infection as well as in the post-infectious context. We also review the available literature on CNS affection in the context of COVID-19 infection, as well as observations from animal studies on the molecular pathways involved in sickness behavior.
395	N391	About N373	JenniferKao12Paul W.Frankland12345	COVID fog demystified	https://doi.org/10.1016/j.cell.2022.06.020	Published	15 June 2022	Article	https://www.sciencedirect.com/science/article/pii/S0092867422007255	Acute mild respiratory COVID-19 infection can lead to a more chronic cognitive syndrome known as "COVID fog". New findings from Fernandez-Castaneda et al reveal how glial dysregulation and consequent neural circuit dysfunction may contribute to cognitive impairments in long COVID.
396	N392		Glenn Jennings 1,*ORCID,Ann Monaghan 1,Feng Xue 1,Eoin Duggan 1,2 andRomán Romero-Ortuño 1,2,3ORCID	Comprehensive Clinical Characterisation of Brain Fog in Adults Reporting Long COVID Symptoms	https://doi.org/10.3390/jcm11123440	Published	15 June 2022	Study	https://www.mdpi.com/2077-0383/11/12/3440/htm	Introduction: A subset of individuals experiencing long COVID symptoms are affected by ‘brain fog’, a lay term that often refers to general cognitive dysfunction but one that is still poorly characterised. In this study, a comprehensive clinical characterisation of self-reported brain fog was conducted vis-à-vis other long COVID symptoms and parameters of mental, cognitive, and physical health. (2) Methodology: Adult participants reporting long COVID symptoms were recruited from hospital clinics and as self-referrals. Participants completed a battery of questionnaires and clinical assessments, including COVID-19 history, symptomatology, self-reported scales (Chalder Fatigue Scale [CFQ], Center for Epidemiological Studies Depression Scale, and Impact of Events Scale–Revised), computer-based cognitive assessments (simple response time and choice reaction time tasks), physical performance tests (gait velocity and muscle strength assessments), and an orthostatic active stand test. A systematic comparison between participants with and without self-reported brain fog was conducted, and a backwards binary logistic regression model was computed to identify the strongest independent associations with brain fog. This was complemented by an automatic cluster analysis to rank the importance of associations. Finally, a structural equation model was postulated with a causal model of key symptomatic indicators and functional consequences of brain fog as a latent variable. (3) Results: Of 108 participants assessed, brain fog was a self-reported symptom in 71 (65.7%) participants. Those with brain fog were at a longer point in time since COVID-19 onset and reported longer duration of low activity during the acute illness. When assessed, those with brain fog had higher frequencies of subjective memory impairment, word-finding difficulties, dizziness, myalgia, arthralgia, hyperhidrosis, cough, voice weakness, throat pain, visual and hearing problems, dysosmia, paraesthesia, chest pain, skin rashes, and hair loss; mean scores in fatigue, depression, and post-traumatic stress scales were higher; performance in both computer-based cognitive tasks was poorer; and measured gait speed and grip strength were lower. The logistic regression suggested that the best independent associations with brain fog were memory impairment, CFQ, and myalgia. The cluster analysis suggested that the most important associations with brain fog were CFQ, dizziness, myalgia, reduced gait speed, word-finding difficulties, reduced grip strength, and memory impairment. The SEM was consistent with key indicators of brain fog being CFQ, dizziness, myalgia, word-finding difficulties, and memory impairment; and reduced grip strength, gait speed, and cognitive response times its functional consequences. (4) Conclusions: The findings indicate that self-reported brain fog in long COVID is a recognisable symptom cluster primarily characterised by fatigue, dizziness, myalgia, word-finding difficulties, and memory impairment and has adverse psychological and psychomotor correlates. In long COVID, brain fog should be regarded as a wide-ranging symptom and addressed holistically with medical, psychological, and rehabilitative supports as guided by individual needs.
397	N393		Anna Milan, Philippe Salles, Carolina Pelayo, Reinaldo Uribe-San-Martin	Acute to Chronic Electro-Clinical Manifestations of Neuro-COVID and the Long-Haul Consequences in People With Epilepsy: A Review	https://doi.org/10.7759/cureus.26020	Published	June 16, 2022	Review	https://www.cureus.com/articles/98115-acute-to-chronic-electro-clinical-manifestations-of-neuro-covid-and-the-long-haul-consequences-in-people-with-epilepsy-a-review	Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection can involve the central nervous system (CNS). Acute symptomatic seizures or epileptiform discharges have not been commonly reported in patients with altered mental status related to coronavirus disease 2019 (COVID-19) infection. However, long-term neurological symptoms have been reported after COVID-19 infection (i.e., brain fog, cognitive complaints, and confusion), suggesting chronic encephalopathy. People with epilepsy (PWE) have been specifically affected by the COVID-19 pandemic, with changes in their seizure frequency, quality of life, health care accessibility, and medication interactions. This narrative review highlights possible pathophysiological mechanisms of COVID-19 on the brain, related to short- and long-term epileptiform activity and the impact of this infection on PWE.
398	N394		Yan Zhang,Xue Chen,Lin Jia,Yulin Zhang	Potential mechanism of SARS-CoV-2-associated central and peripheral nervous system impairment	https://doi.org/10.1111/ane.13657	Published	14 June 2022	Review	https://onlinelibrary.wiley.com/doi/full/10.1111/ane.13657	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is more than merely a respiratory disease, as it also presents with various neurological symptoms. SARS-CoV-2 may infect the central nervous system (CNS) and thus is neurotropic. However, the pathophysiological mechanism of coronavirus disease 2019 (COVID-19)-associated neuropathy remains unclear. Many studies have reported that SARS-CoV-2 enters the CNS through the hematogenous and neuronal routes, as well as through the main host neurological immune responses and cells involved in these responses. The neurological immune responses to COVID-19 and potential mechanisms of the extensive neuroinflammation induced by SARS-CoV-2 have been investigated. Although CNS infection with SARS-CoV-2 was shown to lead to neuronal impairment, certain aspects of this mechanism remain controversial and require further analysis. In this review, we discussed the pathway and mechanisms of SARS-CoV-2 invasion in the CNS, and associated clinical manifestations, such as anosmia, headache, and hyposmia. Moreover, the mechanism of neurological damage caused by SARS-CoV-2 may provide potential treatment methods for patients presenting with SARS-CoV-2-associated neuropathy.
399	N395		Jacqueline E. Shanley,Andrew F. Valenciano,Garrett Timmons,Annalise E. Miner,Visesha Kakarla,Torge Rempe,Jennifer H. Yang,Amanda Gooding,Marc A. Norman,Sarah J. Banks,Michelle L. Ritter,Ronald J. Ellis,Lucy Horton,Jennifer S. Graves … See fewer authors	Longitudinal evaluation of neurologic-post acute sequelae SARS-CoV-2 infection symptoms	https://doi.org/10.1002/acn3.51578	Published	15 June 2022	Study	https://onlinelibrary.wiley.com/doi/full/10.1002/acn3.51578	Objective To assess the initial features and evolution of neurologic Postacute Sequelae of SARS-CoV-2 infection (neuro-PASC) in patients with and without prior neurologic disease. Methods Participants with neurologic symptoms following acute SARS-CoV-2 infection were recruited from October 9, 2020 to October 11, 2021. Clinical data included a SARS-CoV-2 infection history, neurologic review of systems, neurologic exam, Montreal cognitive assessment (MoCA), and symptom-based self-reported surveys at baseline (conducted after acute infection) and 6-month follow-up assessments. Results Fifty-six participants (69% female, mean age 50 years, 29% with prior neurologic disease such as multiple sclerosis) were enrolled, of which 27 had completed the 6-month follow-up visit in this ongoing study. SARS-CoV-2 infection severity was largely described as mild (39.3%) or moderate (42.9%). At baseline, following acute infection, the most common neurologic symptoms were fatigue (89.3%) and headaches (80.4%). At the 6-month follow-up, memory impairment (68.8%) and decreased concentration (61.5%) were the most prevalent, though on average all symptoms showed a reduction in reported severity score at the follow-up. Complete symptom resolution was reported in 33.3% of participants by 6 months. From baseline to 6 months, average MoCA scores improved overall though 26.3% of participants’ scores decreased. A syndrome consisting of tremor, ataxia, and cognitive dysfunction (PASC-TAC) was observed in 7.1% of patients. Interpretation Early in the neuro-PASC syndrome, fatigue and headache are the most commonly reported symptoms. At 6 months, memory impairment and decreased concentration were most prominent. Only one-third of participants had completed resolution of neuro-PASC at 6 months, although persistent symptoms trended toward improvement at follow-up.
400	N396		Andrei L. Iosifescu,Wouter S. Hoogenboom,Alexandra J. Buczek,Roman Fleysher,Tim Q. Duong	New-onset and persistent neurological and psychiatric sequelae of COVID-19 compared to influenza: A retrospective cohort study in a large New York City healthcare network	https://doi.org/10.1002/mpr.1914	Published	15 June 2022	Study	https://onlinelibrary.wiley.com/doi/full/10.1002/mpr.1914	Objectives Neurological and neuropsychiatric manifestations of post-acute SARS-CoV-2 infection (neuro-PASC) are common among COVID-19 survivors, but it is unknown how neuro-PASC differs from influenza-related neuro-sequelae. This study investigated the clinical characteristics of COVID-19 patients with and without new-onset neuro-PASC, and of flu patients with similar symptoms. Methods We retrospectively screened 18,811 COVID-19 patients and 5772 flu patients between January 2020 and June 2021 for the presence of new-onset neuro-sequelae that persisted at least 2 weeks past the date of COVID-19 or flu diagnosis. Results We observed 388 COVID-19 patients with neuro-PASC versus 149 flu patients with neuro-sequelae. Common neuro-PASC symptoms were anxiety (30%), depression (27%), dizziness (22%), altered mental status (17%), chronic headaches (17%), and nausea (11%). The average time to neuro-PASC onset was 138 days, with hospitalized patients reporting earlier onset than non-hospitalized patients. Neuro-PASC was associated with female sex and older age (p < 0.05), but not race, ethnicity, most comorbidities, or COVID-19 disease severity (p > 0.05). Compared to flu patients, COVID-19 patients were older, exhibited higher incidence of altered mental status, developed symptoms more quickly, and were prescribed psychiatric drugs more often (p < 0.05). Conclusions This study provides additional insights into neuro-PASC risk factors and differentiates between post-COVID-19 and post-flu neuro-sequelae.
401	N397		Rizaldy TaslimPinzonabVincent OngkoWijayaaAbraham AlJodyaPatrick NallaNunsioaRanbebasa BijakBuanaa	Persistent Neurological Manifestations in Long COVID-19 syndrome: A Systematic Review and Meta-Analysis	https://doi.org/10.1016/j.jiph.2022.06.013	Published	23 June 2022	Systematic Review and Meta-Analysis	https://www.sciencedirect.com/science/article/pii/S1876034122001575	Background Several studies have reported prolonged symptoms especially neurological symptoms following acute infection in patients with COVID-19, known as long COVID-19. There are only few studies investigating this population and relatively less known, including nervous system involvement. A systematic review and meta-analysis of these studies are required to understanding the prevalence of persistent neurological manifestations after COVID-19. Objective To conduct a systematic review and meta-analysis on the persistent neurological manifestations in COVID-19 survivors. Methods Authors conducted a literature search through PubMed and MedRxiv from January 1st, 2020 to October 2021 according to PRISMA guideline. Furthermore, the authors added additional sources by reviewing related references. Studies presenting the neurologic features of long COVID-19 patients in their data were included. Case reports and case series also included in this review. The quality of the studies was assessed based on the Oxford Centre for Evidence-Based Medicine guidelines. Selected studies were included in the meta-analysis of proportion and heterogeneity test. Findings From 128 identified studies, 36 were eligible, with 9944 participants included. Most of the included studies had mean duration of follow-up after COVID-19 onset of less than 6 months. Fatigue was the most common (52.8%, 95%CI 19.9 – 84.4) symptoms of long COVID, followed by cognitive disorder (35.4%, 95%CI 2.1 – 81.7); paresthesia (33.3%, 95%CI 2.7 – 76.6); sleep disorder (32.9%, 95%CI 6.5 – 67.4); musculoskeletal pain (27.8%, 95%CI 12.7 – 46); and dizziness (26.4%, 95%CI 4.6 – 57.9). Conclusion Neurological manifestations are prevalent and persisting in patients with long COVID. The duration of the symptoms are vary among literatures. However, the frequency are mostly observed during the first six months after the illness onset.
402	N398		GiuliaCattarinussiab1AlessandroMiolaab1NicolòTrevisanabSilviaValeggiacElenaTramarincCarlaMucignatdFrancescoMorracMatteoMinervacGiovanniLibrizzicAnnaBordineFrancescoCausinfGiancarloOttavianoeAngeloAntoninibgFabioSambataroabRenzoManaraf	Altered brain regional homogeneity is associated with depressive symptoms in COVID-19	https://doi.org/10.1016/j.jad.2022.06.061	Published	25 June 2022	Study	https://www.sciencedirect.com/science/article/pii/S0165032722007224	Highlights •COVID-19 is associated to depression, anxiety and fatigue. •COVID-19 presents functional connectivity alterations in parieto-temporal regions. •There alterations are associated with the severity of depressive symptoms. Abstract Background COVID-19 is an infectious disease that has spread worldwide in 2020, causing a severe pandemic. In addition to respiratory symptoms, neuropsychiatric manifestations are commonly observed, including chronic fatigue, depression, and anxiety. The neural correlates of neuropsychiatric symptoms in COVID-19 are still largely unknown. Methods A total of 79 patients with COVID-19 (COV) and 17 healthy controls (HC) underwent 3 T functional magnetic resonance imaging at rest, as well as structural imaging. Regional homogeneity (ReHo) was calculated. We also measured depressive symptoms with the Patient Health Questionnaire (PHQ-9), anxiety using the General Anxiety Disorder 7-item scale, and fatigue with the Multidimension Fatigue Inventory. Results In comparison with HC, COV showed significantly higher depressive scores. Moreover, COV presented reduced ReHo in the left angular gyrus, the right superior/middle temporal gyrus and the left inferior temporal gyrus, and higher ReHo in the right hippocampus. No differences in gray matter were detected in these areas. Furthermore, we observed a negative correlation between ReHo in the left angular gyrus and PHQ-9 scores and a trend toward a positive correlation between ReHo in the right hippocampus and PHQ-9 scores. Limitations Heterogeneity in the clinical presentation in COV, the different timing from the first positive molecular swab test to the MRI, and the cross-sectional design of the study limit the generalizability of our findings. Conclusions Our results suggest that COVID-19 infection may contribute to depressive symptoms via a modulation of local functional connectivity in cortico-limbic circuits.
403	N399		Fabio Ferreli, Francesca Gaino, Elena Russo, Matteo Di Bari, Vanessa Rossi, Armando De Virgilio, Luca Malvezzi, Giovanni Colombo, Giovanni Cristalli, Giuseppe Spriano & Giuseppe Mercante	Long-standing gustatory and olfactory dysfunction in COVID-19 patients: a prospective study	https://doi.org/10.1007/s00405-022-07428-1	Published	29 June 2022	Study	https://link.springer.com/article/10.1007/s00405-022-07428-1	Abstract Purpose Our study aimed to describe recovery of gustatory dysfunction (GD) and olfactory dysfunction (OD) in COVID-19 patients, and to analyze variables associated with early or late recovery. Methods Telephone surveys were administered during an 18-month follow-up after COVID-19 diagnosis. One hundred and thirty-two included patients rated olfactory and gustatory function at each follow-up. Results One hundred and twenty-nine patients reported GD, of whom 91 (70.5%) reported severe GD, and 99 patients reported OD, of whom 84 (84.9%) reported severe OD. Seventy-two/129 (55.8%) and 52/99 (52.5%) patients reported an improvement in GD and in OD during the first 7 days from the onset, respectively. At 3-month follow-up, 110/120 patients (85.3%) recovered from GD, while 80/99 patients (80.8%) recovered from OD. At 18-month follow-up, a total of 120/129 patients (93.0%) recovered from GD and 86/99 patients (86.9%) recovered from OD; while 10 patients (7.0%) still reported GD and 13 patients (13.1%) still reported OD. Severe GD/OD at presentation were associated with late complete recovery of taste/smell (p = 0.019 and p = 0.034, respectively). Improvement over the first 7 days from onset was significantly associated with faster recovery (p < 0.001). Conclusions More than 80% of patients reported complete recovery of olfactory/gustatory function in the first 3 months after symptom onset. At 18-month follow-up, patients reporting complete recovery of gustatory and olfactory function were 93% and 87%, respectively. Severity of chemosensory dysfunction at the onset was negatively correlated to recovery, and improvement of taste and/or smell function within the first 7 days from symptom onset was significantly associated with early resolution.
404	N400	PESE	Kazuki Tokumasu 1ORCID,Hiroyuki Honda 1,Naruhiko Sunada 1,Yasue Sakurada 1,Yui Matsuda 1,Koichiro Yamamoto 1ORCID,Yasuhiro Nakano 1ORCID,Toru Hasegawa 1,Yukichika Yamamoto 1,Yuki Otsuka 1ORCID,Hideharu Hagiya 1ORCID,Hitomi Kataoka 1,Keigo Ueda 1,2 andFumio Otsuka 1,2,*ORCID	Clinical Characteristics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Diagnosed in Patients with Long COVID	https://doi.org/10.3390/medicina58070850	Published	25 June 2022	Study	https://www.mdpi.com/1648-9144/58/7/850/htm	Background and Objectives: COVID-19 can be serious not only in the acute phase but also after the acute phase and some patients develop ME/CFS. There have been few studies on patients with long COVID in whom ME/CFS was diagnosed by physicians based on standardized criteria after examinations and exclusion diagnosis and not based on only subjective symptoms. The purpose of this study was to elucidate the detailed characteristics of ME/CFS in patients with long COVID. Materials and Methods: A retrospective descriptive study was performed for patients who visited a COVID-19 aftercare clinic established in Okayama University Hospital during the period was from February 2021 to April 2022. Results: Clinical data were obtained from medical records for 281 patients, and 279 patients who met the definition of long COVID were included. The overall prevalence rate of ME/CFS diagnosed by three sets of ME/CFS criteria (Fukuda, Canadian and IOM criteria) was 16.8% (48.9% in male and 51.1% in females). The most frequent symptoms in ME/CFS patients were general fatigue and post-exertional malaise (89.4% of the patients), headache (34.0%), insomnia (23.4%), dysosmia (21.3%) and dysgeusia (19.1%). Dizziness, chest pain, insomnia and headache were characteristic symptoms related to ME/CFS. The male to female ratio in ME/CFS patients was equal in the present study, although ME/CFS was generally more common in women in previous studies. Given that patients with ME/CFS had more severe conditions in the acute phase of COVID-19, the severity of the acute infectious state might be involved in the pathophysiology of ME/CFS. Conclusions: The prevalence rate of ME/CFS and the characteristic sequelae in the long COVID condition were revealed in this study.
405	N401		Jonas Jardim de Paula, Rachel E. R. P. Paiva, Nathália Gualberto Souza-Silva, Daniela Valadão Rosa, Fabio Luis de Souza Duran, Roney Santos Coimbra, Danielle de Souza Costa, Pedro Robles Dutenhefner, Henrique Soares Dutra Oliveira, Sarah Teixeira Camargos, Herika Martins Mendes Vasconcelos, Nara de Oliveira Carvalho, Juliana Batista da Silva, Marina Bicalho Silveira, Carlos Malamut, Derick Matheus Oliveira, Luiz Carlos Molinari, Danilo Bretas de Oliveira, José Nélio Januário, Luciana Costa Silva, Luiz Armando De Marco, Dulciene Maria de Magalhaes Queiroz, Wagner Meira, Geraldo Busatto, Débora Marques Miranda & Marco Aurélio Romano-Silva	Selective visuoconstructional impairment following mild COVID-19 with inflammatory and neuroimaging correlation findings	https://doi.org/10.1038/s41380-022-01632-5	Published	14 June 2022	Study	https://www.nature.com/articles/s41380-022-01632-5	People recovered from COVID-19 may still present complications including respiratory and neurological sequelae. In other viral infections, cognitive impairment occurs due to brain damage or dysfunction caused by vascular lesions and inflammatory processes. Persistent cognitive impairment compromises daily activities and psychosocial adaptation. Some level of neurological and psychiatric consequences were expected and described in severe cases of COVID-19. However, it is debatable whether neuropsychiatric complications are related to COVID-19 or to unfoldings from a severe infection. Nevertheless, the majority of cases recorded worldwide were mild to moderate self-limited illness in non-hospitalized people. Thus, it is important to understand what are the implications of mild COVID-19, which is the largest and understudied pool of COVID-19 cases. We aimed to investigate adults at least four months after recovering from mild COVID-19, which were assessed by neuropsychological, ocular and neurological tests, immune markers assay, and by structural MRI and 18FDG-PET neuroimaging to shed light on putative brain changes and clinical correlations. In approximately one-quarter of mild-COVID-19 individuals, we detected a specific visuoconstructive deficit, which was associated with changes in molecular and structural brain imaging, and correlated with upregulation of peripheral immune markers. Our findings provide evidence of neuroinflammatory burden causing cognitive deficit, in an already large and growing fraction of the world population. While living with a multitude of mild COVID-19 cases, action is required for a more comprehensive assessment and follow-up of the cognitive impairment, allowing to better understand symptom persistence and the necessity of rehabilitation of the affected individuals.
406	N402		Charlotte Arlt	Shared COVID- and chemo-fog	https://doi.org/10.1038/s41593-022-01120-7	Published	05 July 2022	Article	https://www.nature.com/articles/s41593-022-01120-7	Even after seemingly mild infection with SARS-CoV-2, many suffer from persistent cognitive impairment, or ‘COVID brain fog’, that resembles the ‘chemo-fog’ associated with cancer therapy. Chemo-fog is known to be mediated by microglial reactivity and subsequent neural dysregulation, and a study published in Cell investigated whether COVID recruits similar pathophysiological processes. In a mouse model of mild respiratory SARS-CoV-2 infection, the authors observed elevated cytokines and chemokines in serum and cerebrospinal fluid, increased microglial reactivity specifically in white matter, a loss of oligodendrocytes and myelin, and decreased hippocampal neurogenesis. These changes persisted for many weeks after the respiratory infection had cleared, and had human counterparts: brain tissue from patients with COVID-19 also showed white-matter-specific microglial reactivity and, intriguingly, cytokine CCL11 levels were higher in the plasma of patients with long-COVID who had ‘brain-fog’ than in plasma from patients without cognitive symptoms. Systemic CCL11 injection in mice induced white-matter microglial reactivity in hippocampus, along with impaired neurogenesis. Mild respiratory influenza in mice caused similar neuroinflammation and hippocampal pathology, but only transient subcortical white-matter changes. This work starts to unravel the mechanisms that underlie persistent COVID-related cognitive impairments, opening the door for future studies on how these mechanisms may depend on COVID-19 variant, vaccination status and age.
407	N403		Kirsty Minton	When ‘mild’ COVID-19 is not so mild	https://doi.org/10.1038/s41577-022-00755-8	Published	29 June 2022	Article	https://www.nature.com/articles/s41577-022-00755-8	Neurological symptoms are common even after ‘mild’ COVID-19. Using a mouse model of SARS-CoV-2 infection limited to the respiratory tract, this study shows that even after viral clearance, there is prolonged microglial reactivity in subcortical and hippocampal white matter and increased levels of CCL11 in the cerebrospinal fluid. Loss of myelin-forming oligodendrocytes and reduced hippocampal neurogenesis were also observed. CCL11 administration in mice causes hippocampal microglial reactivity and impaired hippocampal neurogenesis. Increased plasma levels of CCL11 were also observed in patients with Long COVID with cognitive symptoms, and white matter microglial reactivity was observed in patients who died while infected with SARS-CoV-2 without severe COVID-19. Influenza A virus infection also resulted in neuroinflammation but without the prolonged effects on subcortical white matter.
408	N404		Y.-W. Fu, H.-S. Xu, S.-J. Liu	COVID-19 and neurodegenerative diseases	https://doi.org/10.26355/eurrev_202206_29093	Published	28/06/2022	Review	https://www.europeanreview.org/article/29093	OBJECTIVE: The pandemic of Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues, and SARS-CoV-2 variants continue to emerge. In addition to typical fever and respiratory symptoms, many patients with COVID-19 experience a variety of neurological complications. In this review, we analyzed and reviewed the current status and possible mechanisms between COVID-19 and several typical neurodegenerative diseases, particularly Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, hoping to propose the potential direction of further research and concern. MATERIALS AND METHODS: Electronic literature search of the databases (Medline/PubMed, Web of Science, and Google Scholar). The keywords used were COVID-19, SARS-CoV-2, neurodegenerative disease, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. The retrieved relevant articles were reviewed and critically analyzed. RESULTS: SARS-CoV-2 is a highly neuroinvasive neurotropic virus that invades cells through angiotensin-converting enzyme 2 (ACE2) receptor-driven pathway. SARS-CoV-2 neuroinvasion, neuroinflammation, and blood-brain barrier (BBB) dysfunction may contribute to the pathogenesis of neurodegenerative diseases. CONCLUSIONS: Some patients with neurodegenerative diseases have already shown more susceptibility to SARS-CoV-2 infection and significantly higher mortality due to the elderly population with underlying diseases. Moreover, SARS-CoV-2 could cause damage to the central nervous system (CNS) that may substantially increase the incidence of neurodegenerative diseases and accelerate the progression of them
409	N405		Nick R. Natale,John R. Lukens,William A. Petri Jr	The nervous system during COVID-19: Caught in the crossfire	https://doi.org/10.1111/imr.13114	Published	30 June 2022	Review	https://onlinelibrary.wiley.com/doi/10.1111/imr.13114	SARS-CoV-2, the virus that causes coronavirus disease (COVID)-19, has become a persistent global health threat. Individuals who are symptomatic for COVID-19 frequently exhibit respiratory illness, which is often accompanied by neurological symptoms of anosmia and fatigue. Mounting clinical data also indicate that many COVID-19 patients display long-term neurological disorders postinfection such as cognitive decline, which emphasizes the need to further elucidate the effects of COVID-19 on the central nervous system. In this review article, we summarize an emerging body of literature describing the impact of SARS-CoV-2 infection on central nervous system (CNS) health and highlight important areas of future investigation.
410	N406		Mario Mekhael 1 Chan Ho Lim 1 Abdel Hadi El Hajjar 1 Charbel Noujaim 1 Christopher Pottle 1 Noor Makan 1 Lilas Dagher 2 Yichi Zhang 1 Nour Chouman 1 Dan L Li 1 Tarek Ayoub 1 Nassir Marrouche 1 Author	Studying the Effect of Long COVID-19 Infection on Sleep Quality Using Wearable Health Devices: Observational Study	https://doi.org/10.2196/38000	Published	July 2022	Study	https://www.jmir.org/2022/7/e38000/	Background: Patients with COVID-19 have increased sleep disturbances and decreased sleep quality during and after the infection. The current published literature focuses mainly on qualitative analyses based on surveys and subjective measurements rather than quantitative data. Objective: In this paper, we assessed the long-term effects of COVID-19 through sleep patterns from continuous signals collected via wearable wristbands. Methods: Patients with a history of COVID-19 were compared to a control arm of individuals who never had COVID-19. Baseline demographics were collected for each subject. Linear correlations among the mean duration of each sleep phase and the mean daily biometrics were performed. The average duration for each subject’s total sleep time and sleep phases per night was calculated and compared between the 2 groups. Results: This study includes 122 patients with COVID-19 and 588 controls (N=710). Total sleep time was positively correlated with respiratory rate (RR) and oxygen saturation (SpO2). Increased awake sleep phase was correlated with increased heart rate, decreased RR, heart rate variability (HRV), and SpO2. Increased light sleep time was correlated with increased RR and SpO2 in the group with COVID-19. Deep sleep duration was correlated with decreased heart rate as well as increased RR and SpO2. When comparing different sleep phases, patients with long COVID-19 had decreased light sleep (244, SD 67 vs 258, SD 67; P=.003) and decreased deep sleep time (123, SD 66 vs 128, SD 58; P=.02). Conclusions: Regardless of the demographic background and symptom levels, patients with a history of COVID-19 infection demonstrated altered sleep architecture when compared to matched controls. The sleep of patients with COVID-19 was characterized by decreased total sleep and deep sleep.
411	N407		Daniela Latorre	Autoimmunity and SARS-CoV-2 infection: Unraveling the link in neurological disorders	https://doi.org/10.1002/eji.202149475	Published	14 July 2022	Review	https://onlinelibrary.wiley.com/doi/10.1002/eji.202149475	According to the World Health Organization, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has already infected more than 400 million people and caused over 5 million deaths globally. The infection is associated with a wide spectrum of clinical manifestations, ranging from no signs of illness to severe pathological complications that go beyond the typical respiratory symptoms. On this note, new-onset neurological and neuropsychiatric syndromes have been increasingly reported in a large fraction of COVID-19 patients, thus potentially representing a significant public health threat. Although the underlying pathophysiological mechanisms remain elusive, a growing body of evidence suggests that SARS-CoV-2 infection may trigger an autoimmune response, which could potentially contribute to the establishment and/or exacerbation of neurological disorders in COVID-19 patients. Shedding light on this aspect is urgently needed for the development of effective therapeutic intervention. This review highlights the current knowledge of the immune responses occurring in Neuro-COVID patients and discusses potential immune-mediated mechanisms by which SARS-CoV-2 infection may trigger neurological complications.
412	N408	COA	Antoine Verger, Henryk Barthel, Nelleke Tolboom, Francesco Fraioli, Diego Cecchin, Nathalie L. Albert, Bart van Berckel, Ronald Boellaard, Matthias Brendel, Ozgul Ekmekcioglu, Franck Semah, Tatjana Traub-Weidinger, Donatienne van de Weehaeghe, Silvia Morbelli & Eric Guedj	2-[18F]-FDG PET for imaging brain involvement in patients with long COVID: perspective of the EANM Neuroimaging Committee	https://doi.org/10.1007/s00259-022-05913-7	Published	16 July 2022	Editorial	https://link.springer.com/article/10.1007/s00259-022-05913-7	While long COVID is viewed as a multisystemic disease due to the ubiquitous distribution of ACE2 receptors as a virus entry pathway into cells, cerebral impairment has received special attention because of symptoms of possible brain origin: loss of smell and taste, cognitive complaints of brain “fog,” impairment in attentional and memory functions, sleep disturbances, pain, emotion disorders [5], and other symptoms that might be related to dysautonomia, such as breathlessness, tachycardia, and orthostatic intolerance, including orthostatic hypotension [6]. These heterogeneous long COVID symptoms, which also potentially fluctuate over time, are firstly not exclusively specific to genuine brain involvement, and may also correspond in some cases to another disease potentially unmasked by the infection. For example, extracerebral explanations might be assigned to a loss of smell in individuals with a nasal obstruction, to dyspnoea in individuals with lung sequelae, and even in individuals with cognitive complaints presenting severe asthenia. On the other hand, several hypotheses have been proposed to anticipate potential cerebral damage related to the infection [5, 6]. Indeed, acute neurological complications associated with COVID-19 [7, 8], such as stroke or encephalopathy/encephalitis, suggest a possible direct or indirect effect of SARS-CoV-2 on the brain. Moreover, other SARS viruses were similarly associated with neuropsychiatric presentations [9]. Consistent with these findings, a recent meta-analysis showed that the post-illness stage of previous infections with SARS viruses was characterized by memory impairment in 19% of patients, irritability in 13%, insomnia and anxiety in 12%, and a depressed mood in 10% of patients [9]. These associations with neuropsychiatric symptoms were even observed in patients infected with other respiratory viruses, such as the “Spanish” pandemic flu virus in adults and children [10]. Some authors consequently argued for possible direct viral brain invasion [11], while others proposed that cerebral damage might be related to an extensive inflammatory/immune response related to the infection [12]. The two hypotheses may also be linked and could suggest a possible brain pathway. A trans-ethmoidal propagation from the olfactory bulbs through the lamina cribrosa to connected cerebral regions, namely, from the nose to the brain, has been proposed, while alternative or complementary pathways might involve pulmonary innervation or the vascular compartment [13]. Notably, an impairment of olfactory brain areas and their projections to the limbic/paralimbic system, brainstem nuclei, and cerebellum might explain several symptoms of long COVID in sensorial, cognitive, motor, and autonomic dimensions, as well as potentially those in the emotion spectrum. Patients indeed also present psychological and psychiatric symptoms, which are potentially related to the stress associated with the pandemic context, carelessness, chronic evolution, and disability, but which might also be related to brain damages in emotion networks [14]. Overall, neurological and psychiatric symptoms presented by patients with long COVID could at least partially be related to the impairment of the same brain network [15]: the olfactory symptoms with the impairment of the olfactory bulbs; the memory/attention deficits with those of the hippocampus and cingulum; the psychological and psychiatric disorders such as irritability, depression, or anxiety with changes in amygdalae; tachycardia, orthostatic intolerance, or breathlessness as a dysfunction of the autonomic nervous system on brainstem nuclei (dysautonomia); and motor symptoms with the impairment of the cerebellum. Consistent with this hypothesis, the olfactory bulbs have indeed been proposed as a possible pathway in this implicated brain network, as all involved regions are anatomically linked to these olfactory structures [16]. Given the subtle clinical presentations and the heterogeneity of individual profiles, a diagnostic flow chart for a positive diagnosis of long COVID is currently difficult to define. In the future, this diagnosis might be based on a composite definition of clinical, biological, and imaging signatures. At present, biomarkers should first be considered to exclude other underlying aetiologies with respect to the current WHO definition. These biomarkers could also specify the extent of the disease, especially the possible impairment of the brain, which may correspond to both a specific prognosis and management. Nuclear medicine using brain 2-[18F]-FDG (FDG) PET imaging potentially fills these medical needs; however, the observation of cortical metabolic abnormalities and their interpretation at the single-patient level should also be carefully considered based on the patient’s clinical history and potential confounders. The EANM Neuroimaging Committee hereby aims to summarize and discuss potential applications, pitfalls, and prospects of the use of FDG PET to image brain involvement in patients with long COVID. Using brain FDG PET, a hypometabolic profile has been observed in a relevant portion of patients with long COVID, suggesting network-based involvement. Brain FDG PET might therefore be a promising approach to objectify brain involvement in individuals with long COVID, which should correspond to distinct prognoses and management strategies. In addition, brain FDG PET potentially provides a differential diagnosis for clinical symptoms related to neurodegenerative diseases, encephalitis/encephalopathy, or psychiatric disorders. In our opinion, and as previously proposed by Meyer et al. [21], this examination should be considered in these two frameworks only after a dedicated clinical evaluation and after a significant delay (3 to 6 months) from the initial infection, or in case of worsening [19]. Clinicians should remember that cerebral symptoms of long COVID are not limited to cognitive complaints, and consequently, a broader evaluation should be considered beyond the neuropsychometric assessment for these PET indications, especially considering dysautonomia. A multicentre international collaboration among clinicians and patients is expected to improve the brain FDG PET imaging evaluation of long COVID.
413	N409		Agnieszka Guzik, Andżelina Wolan-Nieroda, Maciej Kochman, Lidia Perenc & Mariusz Drużbicki	Impact of mild COVID-19 on balance function in young adults, a prospective observational study	https://doi.org/10.1038/s41598-022-16397-8	Published	16 July 2022	Study	https://www.nature.com/articles/s41598-022-16397-8	Balance is of essential importance in human life. The aim of the study is to examine the incidence of balance impairments in young adults who have recovered from mild COVID-19. The study involved 100 subjects, divided into two groups: the study group (50 individuals) comprised subjects who had recovered from mild COVID-19, and the control group (50 individuals) consisted of healthy subjects matched for gender and age. Balance was assessed using a force platform and clinical tests such as: timed up and go test, 15-s step test, sit-to-stand test and 6-min walk test. The assessment on the platform showed greater balance impairments in the trials with eyes closed; more specifically, compared to the controls, in trials with double-leg support the subjects from the study group acquired significantly higher scores in X average (lateral coordinates) (p < 0.05), Path length, V average (average Centre of Foot Pressure Velocity) (p < 0.05) and Area circular (p < 0.01), with even more significant results in trials with single-leg support in X average (p < 0.001), Y average (anterior–posterior coordinates) (p < 0.001) and Path length (p = 0.004). Higher scores in the timed up and go test were found in the study group (p = 0.013). The control group had higher scores in the remaining tests. The current findings show that mild COVID-19 may lead to balance impairments in young adults. Statistically significant differences in balance were found between the subjects in the study group and the healthy controls. Further studies in this area should take into account more age groups, and patients recovered from severe COVID-19, and should investigate long-term consequences of COVID-19 reflected by balance problems.
414	N410		Konstantinos Dimitriadis, Jan Meis, Hermann Neugebauer, Kristian Barlinn, Bernhard Neumann, Georg Gahn, Piergiorgio Lochner, Benjamin Knier, Sarah Lindemann, Kurt Wolfram Sühs, Kristina Szabo, Thomas Pfefferkorn, Ingo Schirotzek, Tobias Freilinger, Bassa Burc, Albrecht Günther, Matthias Wittstock, Patrick Schramm, Gernot Reimann, Jana Godau, Gabor Nagy, Fatima B. Koenig, Fabian Essig, Hartwig Klinker, Christian Hartmann, Moritz L. Schmidbauer, Tim Steinberg, Lora Lefterova, Christina Klose & Julian Bösel for the IGNITE study group	Neurologic manifestations of COVID-19 in critically ill patients: results of the prospective multicenter registry PANDEMIC	https://doi.org/10.1186/s13054-022-04080-3	Published	16 July 2022	Study	https://ccforum.biomedcentral.com/articles/10.1186/s13054-022-04080-3	Background Neurologic manifestations are increasingly reported in patients with coronavirus disease 2019 (COVID-19). Yet, data on prevalence, predictors and relevance for outcome of neurological manifestations in patients requiring intensive care are scarce. We aimed to characterize prevalence, risk factors and impact on outcome of neurologic manifestations in critically ill COVID-19 patients. Methods In the prospective, multicenter, observational registry study PANDEMIC (Pooled Analysis of Neurologic DisordErs Manifesting in Intensive care of COVID-19), we enrolled COVID-19 patients with neurologic manifestations admitted to 19 German intensive care units (ICU) between April 2020 and September 2021. We performed descriptive and explorative statistical analyses. Multivariable models were used to investigate factors associated with disorder categories and their underlying diagnoses as well as to identify predictors of outcome. Results Of the 392 patients included in the analysis, 70.7% (277/392) were male and the mean age was 65.3 (SD ± 3.1) years. During the study period, a total of 2681 patients with COVID-19 were treated at the ICUs of 15 participating centers. New neurologic disorders were identified in 350 patients, reported by these centers, suggesting a prevalence of COVID-19-associated neurologic disorders of 12.7% among COVID-19 ICU patients. Encephalopathy (46.2%; 181/392), cerebrovascular (41.0%; 161/392) and neuromuscular disorders (20.4%; 80/392) were the most frequent categories identified. Out of 35 cerebrospinal fluid analyses with reverse transcriptase PCR for SARS-COV-2, only 3 were positive. In-hospital mortality was 36.0% (140/389), and functional outcome (mRS 3 to 5) of surviving patients was poor at hospital discharge in 70.9% (161/227). Intracerebral hemorrhage (OR 6.2, 95% CI 2.5–14.9, p < 0.001) and acute ischemic stroke (OR 3.9, 95% CI 1.9–8.2, p < 0.001) were the strongest predictors of poor outcome among the included patients. Conclusions Based on this well-characterized COVID-19 ICU cohort, that comprised 12.7% of all severe ill COVID-19 patients, neurologic manifestations increase mortality and morbidity. Since no reliable evidence of direct viral affection of the nervous system by COVID-19 could be found, these neurologic manifestations may for a great part be indirect para- or postinfectious sequelae of the infection or severe critical illness. Neurologic ICU complications should be actively searched for and treated.
415	N411	COA	JoyMitraaManoharKodavatiaVincent E.ProvasekagK.S.RaobSankarMitraaDale J.HamiltoncdPhilip J.HorneradFarhaan S.VahidyeGavin W.BritzadThomas A.KentfMuralidhar L.Hegdead	SARS-CoV-2 and the central nervous system: Emerging insights into hemorrhage-associated neurological consequences and therapeutic considerations	https://doi.org/10.1016/j.arr.2022.101687	Published	27 July 2022	Review	https://www.sciencedirect.com/science/article/pii/S1568163722001295	Highlights •Although primarily a respiratory virus, Coronavirus also infects human brain in multi-modal pathways. •Ageing is a critical determinant in the COVID-19 onset, progression, and outcome, particularly for neurological impact. •Microbleeds and microstructural-vascular changes are prevalent in COVID-19 infection of brain. •Hemorrhage-mediated neurotoxicity and ageing may synergistically predispose to neurodegeneration/dementia in Covid-19 survivors. •A potential mitigation strategy for COVID-19-associated microhemorrhagic lesions and related neurological disorders. Abstract Coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to impact our lives by causing widespread illness and death and poses a threat due to the possibility of emerging strains. SARS-CoV-2 targets angiotensin-converting enzyme 2 (ACE2) before entering vital organs of the body, including the brain. Studies have shown systemic inflammation, cellular senescence, and viral toxicity-mediated multi-organ failure occur during infectious periods. However, prognostic investigations suggest that both acute and long-term neurological complications, including predisposition to irreversible neurodegenerative diseases, can be a serious concern for COVID-19 survivors, especially the elderly population. As emerging studies reveal sites of SARS-CoV-2 infection in different parts of the brain, potential causes of chronic lesions including cerebral and deep-brain microbleeds and the likelihood of developing stroke-like pathologies increases, with critical long-term consequences, particularly for individuals with neuropathological and/or age-associated comorbid conditions. Our recent studies linking the blood degradation products to genome instability, leading to cellular senescence and ferroptosis, raise the possibility of similar neurovascular events as a result of SARS-CoV-2 infection. In this review, we discuss the neuropathological consequences of SARS-CoV-2 infection in COVID survivors, focusing on possible hemorrhagic damage in brain cells, its association to aging, and the future directions in developing mechanism-guided therapeutic strategies.
416	N412		Kumar, Niraj; Goyal, Abhishek1; Hussain, Arshad2; Saini, Lokesh Kumar3; Chawla, Omna4; Arora, Pankaj5; Daga, Ritu6; Tikka, Sai Krishna7; Goyal, Sandeep Kumar8; Kanchan, Shweta9; Desai, Soaham10; Ahmed, Sohaib11; Das, Sourav12; Dubey, Vaibhav13; Gupta, Ravi14,	SARS-CoV-2 infection is associated with increased odds of insomnia, RLS and dream enactment behavior	https://doi.org/10.4103/indianjpsychiatry.indianjpsychiatry_586_21	Published	Jul 1, 2022	Study	https://journals.lww.com/indianjpsychiatry/Fulltext/2022/64080/SARS_CoV_2_infection_is_associated_with_increased.6.aspx	Background: Literature suggests that the COVID-19 pandemic has resulted in poor sleep quality, especially among the infected population. However, literature regarding the effect of COVID-19 pandemic and SARS-CoV-2 infection on occurrence of insomnia, restless legs syndrome and dream enactment behavior is either scarce or unavailable. Methods: This study was planned to assess the effect of SARS-CoV-2 infection on the occurrence of insomnia, restless legs syndrome (RLS) and dream enactment behavior (DEB). For this cross-sectional study, a questionnaire comprising of items related to demographic details, past medical history, and information related to SARS-CoV-2 infection was distributed through social media. Insomnia was diagnosed using clinical criteria. RLS, DEB, sleep quality, depression and anxiety were assessed using a validated questionnaire. Information regarding the use of hypnotic medications was also gathered. Results: Of the 1596 respondents, 37.2% reported disturbed sleep while insomnia was reported by 22.6% respondents. 27.3% of respondents reported RLS and 17.4% suffered DEB. The odds of insomnia were greater among males (OR = 1.27; 95% CI: 1.03–1.58; P < 0.02) and among those who had SARS-CoV-2 infection (OR = 1.76; 95% CI = 1.42–2.19; P < 0.001). Similarly, SARS-CoV-2 infection was also associated with increased odds of RLS (OR = 2.48; 95% CI = 1.98–3.11; P < 0.001) and DEB (OR = 1.58; 95%CI = 1.21–2.06; P < 0.001). Insomnia, RLS and DEB were more frequent among respondents who required oxygen therapy, those who experienced loss of taste and/or smell, depression and anxiety. Prevalence of insomnia, DEB and RLS was higher than said prevalence among respondents with no history of SARS-CoV-2 infection, but lower than that of those with positive history of SARS-CoV-2 infection. 5.3% of respondents reported taking hypnotic medications before infection, 7% during infection and 5.3% after infection. Conclusion: SARS-CoV-2-infection-related factors in association with environmental factors have increased the prevalence of insomnia, DEB and RLS among subjects having infection. SARS-CoV-2-associated immunological changes, hypoxia and neurotropism may play a role in occurrence of insomnia, DEB and RLS.
417	N413		Josef Finsterer	Letter to the Editor regarding “COVID-19-Related Burden and Risk Perception in Individuals with Chronic Inflammatory Demyelinating Polyneuropathy and Multifocal Motor Neuropathy: A Cross-Sectional Study”	https://doi.org/10.1007/s40120-022-00386-0	Published	16 July 2022	Letter to the Editor	https://link.springer.com/article/10.1007/s40120-022-00386-0	Overall, the interesting study has some limitations that call the results and their interpretation into question. Clarifying these weaknesses would strengthen the conclusions and could improve the study. To assess the impact of diagnosis and treatment on attitudes toward COVID-19, study groups of interest should be homogenized not only in terms of demographics but also in terms of diagnosis, treatment, and comorbidities. Due to the inherent disadvantages, on-site surveys should be preferred to on-line surveys. However, attempting to use an online survey also has advantages, and is timely because investigators can access a wide range of patients, including those who are unable to go to the clinic. Examining questions about psychiatric aspects of patients suffering from immune-mediated disorders in the COVID-19 era is also important. Therefore, discussion of these concerns will deepen understanding of the limitations and benefits of online surveys and the current situation of patients with immune-mediated diseases.
418	N414		Alex K.ChenaXiaolingWangbLynnette P.McCluskeycJohn C.MorgandJeffrey A.SwitzereRohiniMehtafMarthaTingenbShaoyongSubRyan AlanHarrisbDavid C.HesseElizabeth K.Rutkowskie	Neuropsychiatric sequelae of long COVID-19: Pilot results from the COVID-19 neurological and molecular prospective cohort study in Georgia, USA	https://doi.org/10.1016/j.bbih.2022.100491	Published	30 July 2022	Study	https://www.sciencedirect.com/science/article/pii/S2666354622000813	Highlights •Neuropsychiatric symptoms are often reported following COVID-19 infection. •Self-reported symptoms may not be associated with objective dysfunction. •Self-reported symptoms may be associated with depression and anxiety. •Cognitive testing may overestimate clinical impairment in disadvantaged populations. Abstract Background As the coronavirus disease 2019 (COVID-19) pandemic continues, there has been a growing interest in the chronic sequelae of COVID-19. Neuropsychiatric symptoms are observed in the acute phase of infection, but there is a need for accurate characterization of how these symptoms evolve over time. Additionally, African American populations have been disproportionately affected by the COVID-19 pandemic. The COVID-19 Neurological and Molecular Prospective Cohort Study in Georgia (CONGA) was established to investigate the severity and chronicity of these neurologic findings over the five-year period following infection. Methods The CONGA study aims to recruit COVID-19 positive adult patients in Georgia, United States from both the inpatient and outpatient setting, with 50% being African American. This paper reports our preliminary results from the baseline visits of the first 200 patients recruited who were on average 125 days since having a positive COVID-19 test. The demographics, self-reported symptoms, comorbidities, and quantitative measures of depression, anxiety, smell, taste, and cognition were analyzed. Cognitive measures were compared to demographically matched controls. Blood and mononuclear cells were drawn and stored for future analysis. Results Fatigue was the most reported symptom in the study cohort (68.5%). Thirty percent of participants demonstrated hyposmia and 30% of participants demonstrated hypogeusia. Self-reported neurologic dysfunction did not correlate with dysfunction on quantitative neurologic testing. Additionally, self-reported symptoms and comorbidities were associated with depression and anxiety. The study cohort performed worse on cognitive measures compared to demographically matched controls, and African American patients scored lower compared to non-Hispanic White patients on all quantitative cognitive testing. Conclusion Our results support the growing evidence that there are chronic neuropsychiatric symptoms following COVID-19 infection. Our results suggest that self-reported neurologic symptoms do not appear to correlate with associated quantitative dysfunction, emphasizing the importance of quantitative measurements in the complete assessment of deficits. Self-reported symptoms are associated with depression and anxiety. COVID-19 infection appears to be associated with worse performance on cognitive measures, though the disparity in score between African American patients and non-Hispanic White patients is likely largely due to psychosocial, physical health, and socioeconomic factors.
419	N415		Christiana Franke, Peter Berlit & Harald Prüss	Neurological manifestations of post-COVID-19 syndrome S1-guideline of the German society of neurology	https://doi.org/10.1186/s42466-022-00191-y	Published	18 July 2022	Guidelines	https://link.springer.com/article/10.1186/s42466-022-00191-y	Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to COVID-19 (COrona VIrus Disease-2019). SARS-CoV-2 acute infection may be associated with an increased incidence of neurological manifestations such as encephalopathy and encephalomyelitis, ischemic stroke and intracerebral hemorrhage, anosmia and neuromuscular diseases. Neurological manifestations are commonly reported during the post-acute phase and are also present in Long-COVID (LCS) and post-COVID-19 syndrome (PCS). In October 2020, the German Society of Neurology (DGN, Deutsche Gesellschaft für Neurologie) published the first guideline on the neurological manifestations of COVID-19. In December 2021 this S1 guideline was revised and guidance for the care of patients with post-COVID-19 syndrome regarding neurological manifestations was added. This is an abbreviated version of the post-COVID-19 syndrome chapter of the guideline issued by the German Neurological society and published in the Guideline repository of the AWMF (Working Group of Scientific Medical Societies; Arbeitsgemeinschaft wissenschaftlicher Medizinischer Fachgesellschaften). Neurological manifestations are common in patients with LCS and PCS; commonly reported are cognitive deficits, fatigue, headache, myalgia and neuropathy. A comprehensive—ideally interdisciplinary—diagnostic assessment should be initiated in patients who complain about residual or new symptoms more than 3 months after the acute infection. If immune involvement is detected, immunomodulatory therapy may be considered as an individual treatment attempt. A causal therapy does not yet exist; the symptomatic therapy is carried out according to the guidelines of the DGN. Structured neurorehabilitation programs are urgently needed. In parallel, patients should be offered concomitant psychosomatic co-treatment. Avoiding SARS-CoV-2 infection is the key most important preventive factor, and therefore vaccination against SARS-CoV-2 with one of the available vaccines is highly recommended. An interdisciplinary treatment including internal, psychosomatic, and psychiatric expertise is crucial in diagnostic and treatment of PCS patients.
420	N416		S. Iacovides,1 E. Alzueta,2 P.B. Perrin,3 D. Yüksel,2 D. Ramos-Usuga,4,5 O. Kiss,2 M. de Zambotti,2 M. Cortes,6 L. Olabarrieta-Landa,7 J.C. Arango-Lasprilla,5,8,9 and F.C. Baker2	Effects of Long COVID on Sleep Health	https://doi.org/10.1016%2Fj.sleep.2022.05.216	Published	2022 Jul 21	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9300253/	Introduction: COVID-19 has infected millions of people worldwide with growing evidence showing that those individuals may continue to show persistent post-COVID symptoms (long COVID). The aim of this study was to investigate sleep health in an international sample of individuals who reported previously testing positive for COVID-19. Materials and Methods: 1001 individuals who reported a positive diagnosis of COVID-19, across different geographical regions, including North and South America, Sub-Saharan Africa, and Europe, completed an online survey between March 4–June 15, 2021. Self-reported sleep health was assessed using the RU-SATED scale, as recalled before a COVID-19 diagnosis and as reported currently. Results: Individuals reported a poorer overall current sleep health, with poorer ratings across the six dimensions of sleep health (sleep regularity, satisfaction, alertness, timing, efficiency, and duration) compared to their ratings as recalled before COVID-19 infection. Greater severity of symptoms during COVID-19 infection was the strongest predictor of poor current sleep health (p < .001), independent of demographics, presence of a pre-existing condition, and time since infection. Poor current sleep health was associated with poorer current quality of life (p<.001). Conclusions: Poor sleep health is evident in individuals with a history of COVID-19, particularly those with more severe symptoms at the time of their COVID-19 infection, and is associated with a poorer quality of life. Clinicians and researchers should assess sleep health in COVID-19 survivors and investigate long-term associations with their mental and physical health, as well as potential benefits of improving sleep in this population.
421	N417		Nico Sollmann, Ambros J. Beer & Frank Kirchhoff	SARS-CoV-2 infection and the brain: direct evidence for brain changes in milder cases	https://doi.org/10.1038/s41392-022-01072-1	Published	11 July 2022	Article	https://www.nature.com/articles/s41392-022-01072-1	A recent study published in Nature by Douaud and colleagues1 shows that SARS-CoV-2 infection is associated with longitudinal effects, particularly on brain structures linked to the olfactory cortex, modestly accelerated reduction in global brain volume, and enhanced cognitive decline. Thus, even mild COVID-19 can be associated with long-lasting deleterious effects on brain structure and function. The study provides unique insights into COVID-19-associated changes in brain structure. The authors took great care in appropriately matching the case and control groups, making it unlikely that observed differences are due to confounding factors, although this possibility can never be entirely excluded. The mechanisms underlying these infection-associated changes, however, remain to be clarified. Viral neurotropism and direct infection of cells of the olfactory system, neuroinflammation and lack of sensory input have been suggested as reasons for the degenerative events in olfactory-related brain structures and neurological complications.4 These mechanisms are not mutually exclusive and may synergize in causing neurodegenerative disorders as consequence of COVID-19. The study participants became infected between March 2020 and April 2021, before the emergence of the Omicron variant of concern (VOC) that currently dominates the COVID-19 pandemic. During that time period, the Alpha and Beta VOCs dominated in the UK and all results were obtained from individuals between 51 and 81 years of age. It will be of great interest to clarify whether Omicron, that seems to be less pathogenic than other SARS-CoV-2 variants, also causes long-term brain damage. The vaccination status of the participants was not available in the study1 and it will be important to clarify whether long-term changes in brain structure also occur in vaccinated and/or younger individuals. Other important questions are whether these structural changes are reversible or permanent and may even enhance the frequency for neurodegenerative diseases that are usually age-related, such as Alzheimer’s, Parkinson’s or Huntington’s disease. Previous findings suggest that cognitive disorders improve over time after severe COVID-19;5 yet it remains to be determined whether the described brain changes will translate into symptoms later in life such as dementia. Douaud and colleagues report that none of top 10 IDPs correlated significantly with the time interval between SARS-CoV-2 infection and the 2nd MRI acquisition, suggesting that the observed abnormalities might be very long-lasting. Currently, many restrictions and protective measures are relaxed because Omicron is highly transmissible but usually causes mild to moderate acute disease. This raises hope that SARS-CoV-2 may evolve towards reduced pathogenicity and become similar to circulating coronaviruses causing mild respiratory infections. More work needs to be done to clarify whether the current Omicron and future variants of SARS-CoV-2 may also cause lasting brain abnormalities and whether these can be prevented by vaccination or therapy. However, the finding by Douaud and colleagues1 that SARS-CoV-2 causes structural changes in the brain that may be permanent and could relate to neurological decline is of concern and illustrates that the pathogenesis of this virus is markedly different from that of circulating human coronaviruses. Further studies, to elucidate the mechanisms underlying COVID-19-associated neurological abnormalities and how to prevent or reverse them are urgently needed.
422	N418		Srinivas Sriramula1 Rohan Parekh1 Drew Theobald1 Shaw Akula1 Dorcas O’Rourke1 Jeffrey Eells	Long COVID in K18-hACE2 mice causes persistent brain inflammation and cognitive impairment	https://doi.org/10.21203/rs.3.rs-1818930/v1	pre-print	06 Jul, 2022	Study	https://www.researchsquare.com/article/rs-1818930/v1	Evidence suggests that patients with long COVID experience cognitive abnormalities. However, these clinical data are mostly associational studies complicated by confounding variables, thus the mechanisms responsible for persistent neurological symptoms are unknown. Here we establish an animal model of long COVID by eliciting mild disease in K18-hACE2 mice. Following recovery from infection with a low dose of SARS-CoV-2, K18-hACE2 mice show the characteristic lung fibrosis associated with SARS-CoV-2 infection, which correlates with increased expression of the pro-inflammatory kinin B1 receptor (B1R). These mice also have elevated expression of B1Rs and inflammatory markers in the brain and exhibit cognitive impairments such as elevated anxiety and attenuated exploratory behavior. Our data demonstrate that K18-hACE2 mice exhibit persistent effects of SARS-CoV-2 infection on brain tissue, revealing the potential of this model for investigating long COVID. The results further imply that elevated B1R expression may drive the long-lasting inflammatory response associated with SARS-CoV-2 infection.
423	N419		Laura Pelizzari, Marta Cazzoli, Susanna Lipari, Maria Marcella Laganà, Monia Cabinio, Sara Isernia, Alice Pirastru, Mario Clerici, Francesca Baglio	Mid-term MRI evaluation reveals microstructural white matter alterations in COVID-19 fully recovered subjects with anosmia presentation	https://doi.org/10.1177%2F17562864221111995	Published	July 23, 2022	Study	https://journals.sagepub.com/doi/full/10.1177/17562864221111995	Background: Little is still known about the mid/long-term effects of coronavirus disease 2019 (COVID-19) on the brain, especially in subjects who have never been hospitalized due to the infection. In this neuroimaging exploratory study, we analyzed the medium-term effect of COVID-19 on the brain of people who recovered from COVID-19, experienced anosmia during the acute phase of the disease, and have never been hospitalized due to SARS-Co-V-2 infection. Methods: Forty-three individuals who had (COV+, n = 22) or had not (COV−, n = 21) been infected with SARS-Co-V-2 were included in the study; the two groups were age- and sex-matched and were investigated using 3T magnetic resonance imaging (MRI). Gray matter (GM) volume, white matter (WM) hyperintensity volume, WM microstrutural integrity (i.e. fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity [AD], radial diffusivity [RD]) and cerebral blood flow (CBF) differences between the two groups were tested with either analysis of covariance or voxel-wise analyses. Results were family wise error (FWE) corrected. Results: No significant differences between COV+ and COV− groups were observed in terms of GM volume, WM hyperintensity volume, and CBF. Conversely, local WM microstructural alterations were detected in COV+ when compared with COV− with tract-based spatial statistics. Specifically, COV+ showed lower FA (pFWE-peak = 0.035) and higher RD (pFWE-peak = 0.038) than COV− in several WM regions. Conclusion: COVID-19 may produce mid/long-term microstructural effect on the brain, even in case of mild-to-moderate disease not requiring hospitalization. Further investigation and additional follow-ups are warranted to assess if the alterations reported in this study totally recover over time. As brain alterations could increase the risk of cognitive decline, greater knowledge of their trajectories is crucial to aid neurorehabilitation treatments.
424	N420		Amir-Hossein Bayat, Helia Azimi, Meysam Hassani Moghaddam, Vahid Ebrahimi, Mobina Fathi, Kimia Vakili, Gholam-Reza Mahmoudiasl, Mahdi Forouzesh, Mahdi Eskandarian Boroujeni, Zahra Nariman, Hojjat-Allah Abbaszadeh, Arefeh Aryan, Abbas Aliaghaei & Mohammad-Amin Abdollahifar	COVID-19 causes neuronal degeneration and reduces neurogenesis in human hippocampus	https://doi.org/10.1007/s10495-022-01754-9	Published	25 July 2022	Study	https://link.springer.com/article/10.1007/s10495-022-01754-9	Recent investigations of COVID-19 have largely focused on the effects of this novel virus on the vital organs in order to efficiently assist individuals who have recovered from the disease. In the present study we used hippocampal tissue samples extracted from people who died after COVID-19. Utilizing histological techniques to analyze glial and neuronal cells we illuminated a massive degeneration of neuronal cells and changes in glial cells morphology in hippocampal samples. The results showed that in hippocampus of the studied brains there were morphological changes in pyramidal cells, an increase in apoptosis, a drop in neurogenesis, and change in spatial distribution of neurons in the pyramidal and granular layer. It was also demonstrated that COVID-19 alter the morphological characteristics and distribution of astrocyte and microglia cells. While the exact mechanism(s) by which the virus causes neuronal loss and morphology in the central nervous system (CNS) remains to be determined, it is necessary to monitor the effect of SARS-CoV-2 infection on CNS compartments like the hippocampus in future investigations. As a result of what happened in the hippocampus secondary to COVID-19, memory impairment may be a long-term neurological complication which can be a predisposing factor for neurodegenerative disorders through neuroinflammation and oxidative stress mechanisms.
425	N421		Maryame Mohammadian & Ravieh Golchoobian	Potential autonomic nervous system dysfunction in COVID-19 patients detected by heart rate variability is a sign of SARS-CoV-2 neurotropic features	https://doi.org/10.1007/s11033-022-07486-y	Published	09 July 2022	Article	https://link.springer.com/article/10.1007/s11033-022-07486-y	Increasing evidence strongly support that the newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to the development of COVID-19-associated central nervous system (CNS) manifestations. The presence of SARS-CoV-2 viral protein in the brainstem, which includes cardiovascular control centers, has been documented previously. Given the changes in autonomic nervous system function evaluated by heart rate variability (HRV) metrics, which are observed even prior to clinical signs, the potential effect of SARS-CoV-2 on the autonomic nervous system (ANS) center is likely. The integral parts of the brain renin-angiotensin system, as ACE2 enzyme, are highly expressed in the brainstem, which may also be involved in baroreflex sensitivity, playing an important role in HRV. SARS-CoV-2 may bind to ACE2 in order to enter the host brainstem cell and change baroreflex sensitivity due to the altered ratio of the concentration of angiotensin II (Ag II) to angiotensin (1–7). In this article, we discussed the information on the possibility that the SARS-CoV-2 viral particle by disrupting the homeostasis of the brain renin-angiotensin system even without brainstem neuropathological changes, may affect the function of the ANS center in the brainstem. SARS-CoV-2 could influence ANS function before affecting the immune system. It is possible that the altered HRV parameters imply the potential neurotropic characteristics of SARS-CoV-2. Therefore, this potential feature should be taken into account in diagnostic and therapeutic approaches for COVID-19 patients.
426	N422		Madeline G. Andrews , Tanzila Mukhtar, Ugomma C. Eze , +24 , Camille R. Simoneau, Jayden Ross, Neelroop Parikshak, Shaohui Wang, Li Zhou , Mark Koontz, Dmitry Velmeshev, Clara-Vita Siebert, Kaila M. Gemenes , Takako Tabata, Yonatan Perez, Li Wang, Mohammed A. Mostajo-Radji, Martina de Majo , Kevin C. Donohue , David Shin, Jahan Salma , Alex A. Pollen , Tomasz J. Nowakowski, Erik Ullian, G. Renuka Kumar , Ethan A. Winkler, Elizabeth E. Crouch , Melanie Ott, and Arnold R. Kriegstein	Tropism of SARS-CoV-2 for human cortical astrocytes	https://doi.org/10.1073/pnas.2122236119	Published	July 12, 2022	Study	https://www.pnas.org/doi/full/10.1073/pnas.2122236119	Significance Neurological and neuropsychiatric symptoms occur in as many as one-third of patients with or recovering from COVID-19. To address severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neural tropism, we evaluated the vulnerability of primary developing and adult cortical tissue and stem-cell-derived cortical organoids to SARS-CoV-2 infection. We observe robust infection and viral replication in human cortical astrocytes; they become reactive, have increased growth factor signaling, and activate cellular stress. Despite infection in astroglial cells, there is minimal infection of other neural cell types, including neurons. Surprisingly, we discover that astrocyte infection is unlikely to be mediated by the predominant coronavirus receptor, ACE2, and instead observe alternative glycoproteins, CD147 and DPP4, expressed on astrocytes; they are necessary and sufficient for SARS-CoV-2 infection. Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) readily infects a variety of cell types impacting the function of vital organ systems, with particularly severe impact on respiratory function. Neurological symptoms, which range in severity, accompany as many as one-third of COVID-19 cases, indicating a potential vulnerability of neural cell types. To assess whether human cortical cells can be directly infected by SARS-CoV-2, we utilized stem-cell-derived cortical organoids as well as primary human cortical tissue, both from developmental and adult stages. We find significant and predominant infection in cortical astrocytes in both primary tissue and organoid cultures, with minimal infection of other cortical populations. Infected and bystander astrocytes have a corresponding increase in inflammatory gene expression, reactivity characteristics, increased cytokine and growth factor signaling, and cellular stress. Although human cortical cells, particularly astrocytes, have no observable ACE2 expression, we find high levels of coronavirus coreceptors in infected astrocytes, including CD147 and DPP4. Decreasing coreceptor abundance and activity reduces overall infection rate, and increasing expression is sufficient to promote infection. Thus, we find tropism of SARS-CoV-2 for human astrocytes resulting in inflammatory gliosis-type injury that is dependent on coronavirus coreceptors.
427	N423		Bruno Biagianti1,2*, Asia Di Liberto1, Aiello Nicolò Edoardo3,4, Ilaria Lisi5, Letizia Nobilia6, Giulia Delor de Ferrabonc1, Elisa R. Zanier5, Nino Stocchetti2,7 and Paolo Brambilla1,2	Cognitive Assessment in SARS-CoV-2 Patients: A Systematic Review	https://doi.org/10.3389/fnagi.2022.909661	Published	01 July 2022	Review	https://www.frontiersin.org/articles/10.3389/fnagi.2022.909661/full	Background: Patients with post-infective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) often show both short- and long-term cognitive deficits within the dysexecutive/inattentive spectrum. However, little is known about which cognitive alterations are commonly found in patients recovered from SARS-CoV-2, and which psychometric tools clinicians should consider when assessing cognition in this population. The present work reviewed published studies to provide a critical narrative of neuropsychological (NPs) deficits commonly observed after SARS-CoV-2 infection and the tests most suited for detecting such cognitive sequelae depending on illness severity. Methods: This review followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and was pre-registered on Prospective Register of Systematic Reviews (PROSPERO) (CRD42021253079). Observational studies quantitatively assessing cognition in patients with post-infective SARS-CoV-2 were considered. From 711 retrieved articles, 19 studies conducted on patients with SARS-CoV-2 without medical comorbidities were included and stratified by disease severity. Results: The majority of studies (N = 13) adopted first-level tests. The most frequently administered screeners were the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE)—with the former more likely to detect mild, and the latter moderate/severe deficits. Among second-level tests, those assessing attention and executive functions (EFs) were highly represented. Remotely-delivered tests yielded lower percentages of cognitive impairment. Overall, cognitive domains often found to be impaired were EFs, attention, and memory. Conclusion: Cognitive sequelae in patients with post-infective SARS-CoV-2 can be detected with NPs testing. Depending on the psychometric test features, the likelihood of observing cognitive deficits can vary. Further studies on larger sample sizes are needed to investigate the clinical usefulness of second-level tools. The primary goal of preventative health services should be the early detection and intervention of emerging cognitive deficits. Key Points - Cognitive sequelae are prevalent in patients with SARS-CoV-2, while the likelihood of observing such sequelae varies depending on the test used. - Among patients with SARS-CoV-2, MoCA is more likely to detect mild cognitive deficits, whereas MMSE moderate/severe deficits. - Studies using domain-specific tests are needed, to investigate whether some specific cognitive functions are more impaired than others. - A standardized protocol for cognitive assessment in patients with SARS-CoV-2 should be made available to clinicians.
428	N424		Jung Woo Park1,2, Corresponding address, Xiaoyan Wang1,2, Ren-He Xu1,2	Revealing the mystery of persistent smell loss in Long COVID patients	https://doi.org/10.7150/ijbs.73485	Published	2022 Jul 15	Review	https://www.ijbs.com/v18p4795.htm	COVID-19 is hopefully approaching its end in many countries as herd immunity develops and weaker strains of SARS-CoV-2 dominate. However, a new concern occurs over the long-term effects of COVID-19, collectively called “Long COVID”, as some symptoms of the nervous system last even after patients recover from COVID-19. This review focuses on studies of anosmia, i.e., impairment of smell, which is the most common sensory defect during the disease course and is caused by olfactory dysfunctions. It remains mysterious how the olfactory functions are affected since the virus can't invade olfactory receptor neurons. We describe several leading hypotheses about the mystery in hope to provide insights into the pathophysiology and treatment strategies for anosmia.
429	N425	COA	Fernanda Crunfli 1, Victor C Carregari 1, Flavio P Veras 2, Lucas S Silva 1, Mateus Henrique Nogueira 1, André Saraiva Leão Marcelo Antunes 1, Pedro Henrique Vendramini 1, Aline Gazzola Fragnani Valença 1, Caroline Brandão-Teles 1, Giuliana da Silva Zuccoli 1, Guilherme Reis-de-Oliveira 1, Lícia C Silva-Costa 1, Verônica Monteiro Saia-Cereda 1, Bradley J Smith 1, Ana Campos Codo 1, Gabriela F de Souza 1, Stéfanie P Muraro 1, Pierina Lorencini Parise 1, Paulo Hilario Nascimento Saldiva 3, Alessandro S Farias 1, Fernando Cendes 1, Pedro Manoel M Moraes-Vieira 1, Alexandre T Fabro 2, Adriano Sebollela 2, José L Proença-Modena 1, Clarissa L Yasuda 1, Marcelo A Mori 1, Thiago M Cunha 2, Daniel Martins-de-Souza	Morphological, cellular, and molecular basis of brain infection in COVID-19 patients	https://doi.org/10.1073/pnas.2200960119	Published	August 11, 2022	Study	https://www.pnas.org/doi/full/10.1073/pnas.2200960119	Significance Neurological symptoms are among the most prevalent of the extrapulmonary complications of COVID-19, affecting more than 30% of patients. In this study, we provide evidence that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is found in the human brain, where it infects astrocytes and to a lesser extent, neurons. We also show that astrocytes are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike–NRP1 interaction and respond to the infection by remodeling energy metabolism, which in turn, alters the levels of metabolites used to fuel neurons and support neurotransmitter synthesis. The altered secretory phenotype of infected astrocytes then impairs neuronal viability. These features could explain the damage and structural changes observed in the brains of COVID-19 patients. Abstract Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of “long COVID-19” syndrome) has been frequently observed after mild infection. We show the spectrum of cerebral impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal transethmoidal access) from individuals who died of COVID-19. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell–derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike–NRP1 interaction. SARS-CoV-2–infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.
430	N426		ValentinaLetaab†IroBouraabc†Daniel J.van WamelenabdMayelaRodriguez-ViolanteeAngeloAntoninifKallol RayChaudhuriab	Covid-19 and Parkinson's disease: Acute clinical implications, long-COVID and post-COVID-19 parkinsonism	https://doi.org/10.1016/bs.irn.2022.04.004	Published	8 August 2022	Study	https://www.sciencedirect.com/science/article/pii/S0074774222000332	The Coronavirus Disease 2019 (Covid-19), caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has led to unprecedented challenges for the delivery of healthcare and has had a clear impact on people with chronic neurological conditions such as Parkinson's disease (PD). Acute worsening of motor and non-motor symptoms and long-term sequalae have been described during and after SARS-CoV-2 infections in people with Parkinson's (PwP), which are likely to be multifactorial in their origin. On the one hand, it is likely that worsening of symptoms has been related to the viral infection itself, whereas social restrictions imposed over the course of the Covid-19 pandemic might also have had such an effect. Twenty cases of post-Covid-19 para-infectious or post-infectious parkinsonism have been described so far where a variety of pathophysiological mechanisms seem to be involved; however, a Covid-19-induced wave of post-viral parkinsonism seems rather unlikely at the moment. Here, we describe the interaction between SARS-CoV-2 and PD in the short- and long-term and summarize the clinical features of post-Covid-19 cases of parkinsonism observed so far.
431	N427		Luciew, Joshua D. MPAS, PA-C; Erickson, Rodney A. MD; Kaufman, Tara K. MD	Post-COVID-19 neurologic syndrome Another legacy of the pandemic	https://doi.org/10.1097/01.JAA.0000854524.40560.f3	Published	August 9, 2022	Article	https://journals.lww.com/jaapa/Fulltext/9900/Post_COVID_19_neurologic_syndrome__Another_legacy.18.aspx	COVID-19 quickly escalated to a global pandemic in 2020. As research on the topic continues, the medical community has found that this acute illness can cause a new chronic illness: postacute sequelae of SARS-CoV-2 (PASC). Some patients with PASC develop predominately neurologic sequelae (post-COVID-19 neurologic syndrome or PCNS). This article describes PASC and PCNS, their proposed pathogenicity and possible neurovirulence mechanisms, symptoms, and treatment recommendations.
432	N428		Syed SamiAliaAfshanMumtazbMohammad AadilQamaraSameer SaleemTebhacAzmaParhindMehwishButtcMohammad YasirEssar	New-onset Parkinsonism as a Covid-19 infection sequela: A systematic review and meta-analysis	https://doi.org/10.1016/j.amsu.2022.104281	Published	8 August 2022	Systematic Review / Meta-analysis	https://www.sciencedirect.com/science/article/pii/S204908012201041X	Highlights •There have been well-documented reports about the occurrence of parkinsonism after viral infections. •10 studies including 13 patients reported the development of parkinsonism in individuals who recovered from COVID-19 infection. •The commonest symptom of parkinsonism reported in these individuals was cogwheel rigidity 84.6%. •53.8% of individuals fully recovered and had their symptoms resolved after treatment. Background There remains a scarcity of literature regarding COVID-19 and its neurological sequelae. This study highlights Parkinsonism as a post-COVID-19 sequela and helps us understand a possible link between the two. Methods A literature search covering relevant databases was conducted for studies reporting the development of Parkinsonism in patients recovering from COVID-19 infection. A quality assessment tool developed by The Joanna Briggs Institute Critical Appraisal tools for the assessment of case reports was utilized. Fisher's exact test was used to explore the factors associated with COVID-19 and Parkinsonism as its complication. Results Ten studies were included in our study. The median age of patients was 60.0, with an interquartile range of 42.5–72.0. There were 8 males (61.5%) patients, and 53.8% of cases were reported to have at least one comorbidity. Cogwheel rigidity was the most common symptom of Parkinsonism in 11 patients. While the most standard treatment modality used was Levodopa in 76.9% of cases. Using the Fisher's Exact test, it was identified that 10 patients (76.9%) with bradykinesia made a full recovery. Conclusion Despite presumed “recovery” from COVID-19, patients still face a wide range of neurological complications. One of these complications presenting as Parkinsonism requires health care professionals to be on the lookout for the long-term effects of COVID-19. Hence, our study provides information on the possible likely hood of a link between COVID-19 and the development of Parkinsonism as post-COVID neurological sequelae.
433	N429		P. Voruz1,2,3, I. Jacot de Alcântara1,2, A. Nuber-Champier1, A. Cionca1, G. Allali2,3,4, L. Benzakour3,5, P.H. Lalive2,3, K.-O. Lövblad3,6, O. Braillard7, M. Nehme7, M. Coen8, J. Serratrice8, J.-L. Reny8, J. Pugin3,9, I. Guessous3,7, R. Ptak3,10, B.N. Landis3,11, F. Assal2,3,†, J.A. Péron	Frequency of Abnormally Low Neuropsychological Scores in Post-COVID-19 Syndrome: the Geneva COVID-COG Cohort	https://academic.oup.com/acn/advance-article/doi/10.1093/arclin/acac068/6658442	Published	20 July 2022	Study	https://www.researchgate.net/profile/Philippe-Voruz/publication/362581698_Frequency_of_Abnormally_Low_Neuropsychological_Scores_in_Post-COVID-19_Syndrome_the_Geneva_COVID-COG_Cohort/links/62f2cb0a88b83e7320becc4a/Frequency-of-Abnormally-Low-Neuropsychological-Scores-in-Post-COVID-19-Syndrome-the-Geneva-COVID-COG-Cohort.pdf	Objective: Several studies have reported poor long-term neuropsychological performances in patients following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but none has yet considered the effect of administering multiple intercorrelated neuropsychological tests and assessed the frequency of cognitive deficits in a normative population. Our aim was therefore to assess the presence of cumulative neuropsychological deficits in an actual post-coronavirus disease of 2019 (COVID-19) comparison group versus one simulated using Monte-Carlo methods. Method: Validated neuropsychological Monte-Carlo simulation methods were applied to scores from a battery of neuropsychological tests (memory, executive, attentional, perceptual, logical reasoning, language, and ideomotor praxis) administered to 121 patients who had had mild, moderate, or severe COVID-19 (mean age: 56.70 years; 32% women), 222 ± 43 days post-infection. The cumulative percentages of the three severity subgroups were compared with the results of a false discovery rate-corrected probability analysis based on normative data. Results: The cumulative percentages of deficits in memory and executive functions among the severe and moderate patients were significantly higher than those estimated for the normative population. Moderate patients also had significantly more deficits in perception and logical reasoning. In contrast, the mild group did not have significantly more cumulative deficits. Conclusions: Moderate and severe forms of COVID-19 cause greater long-term neuropsychological deficits than those that would be found in a normative population, reinforcing the hypothesis of long-term effects of SARS-CoV-2 on cognitive function, independent of the severity of the initial infection.
434	N430	COA	Maxime Taquet, PhD Rebecca Sillett, BA Lena Zhu, BS Jacob Mendel, MMath Isabella Camplisson, BS Quentin Dercon, MSc Paul J Harrison, FRCPsych	Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1 284 437 patients	https://doi.org/10.1016/S2215-0366(22)00260-7	Published	August 17, 2022	Study	https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(22)00260-7/fulltext	Background COVID-19 is associated with increased risks of neurological and psychiatric sequelae in the weeks and months thereafter. How long these risks remain, whether they affect children and adults similarly, and whether SARS-CoV-2 variants differ in their risk profiles remains unclear. Methods In this analysis of 2-year retrospective cohort studies, we extracted data from the TriNetX electronic health records network, an international network of de-identified data from health-care records of approximately 89 million patients collected from hospital, primary care, and specialist providers (mostly from the USA, but also from Australia, the UK, Spain, Bulgaria, India, Malaysia, and Taiwan). A cohort of patients of any age with COVID-19 diagnosed between Jan 20, 2020, and April 13, 2022, was identified and propensity-score matched (1:1) to a contemporaneous cohort of patients with any other respiratory infection. Matching was done on the basis of demographic factors, risk factors for COVID-19 and severe COVID-19 illness, and vaccination status. Analyses were stratified by age group (age <18 years [children], 18–64 years [adults], and ≥65 years [older adults]) and date of diagnosis. We assessed the risks of 14 neurological and psychiatric diagnoses after SARS-CoV-2 infection and compared these risks with the matched comparator cohort. The 2-year risk trajectories were represented by time-varying hazard ratios (HRs) and summarised using the 6-month constant HRs (representing the risks in the earlier phase of follow-up, which have not yet been well characterised in children), the risk horizon for each outcome (ie, the time at which the HR returns to 1), and the time to equal incidence in the two cohorts. We also estimated how many people died after a neurological or psychiatric diagnosis during follow-up in each age group. Finally, we compared matched cohorts of patients diagnosed with COVID-19 directly before and after the emergence of the alpha (B.1.1.7), delta (B.1.617.2), and omicron (B.1.1.529) variants. Findings We identified 1 487 712 patients with a recorded diagnosis of COVID-19 during the study period, of whom 1 284 437 (185 748 children, 856 588 adults, and 242 101 older adults; overall mean age 42·5 years [SD 21·9]; 741 806 [57·8%] were female and 542 192 [42·2%] were male) were adequately matched with an equal number of patients with another respiratory infection. The risk trajectories of outcomes after SARS-CoV-2 infection in the whole cohort differed substantially. While most outcomes had HRs significantly greater than 1 after 6 months (with the exception of encephalitis; Guillain-Barré syndrome; nerve, nerve root, and plexus disorder; and parkinsonism), their risk horizons and time to equal incidence varied greatly. Risks of the common psychiatric disorders returned to baseline after 1–2 months (mood disorders at 43 days, anxiety disorders at 58 days) and subsequently reached an equal overall incidence to the matched comparison group (mood disorders at 457 days, anxiety disorders at 417 days). By contrast, risks of cognitive deficit (known as brain fog), dementia, psychotic disorders, and epilepsy or seizures were still increased at the end of the 2-year follow-up period. Post-COVID-19 risk trajectories differed in children compared with adults: in the 6 months after SARS-CoV-2 infection, children were not at an increased risk of mood (HR 1·02 [95% CI 0·94–1·10) or anxiety (1·00 [0·94–1·06]) disorders, but did have an increased risk of cognitive deficit, insomnia, intracranial haemorrhage, ischaemic stroke, nerve, nerve root, and plexus disorders, psychotic disorders, and epilepsy or seizures (HRs ranging from 1·20 [1·09–1·33] to 2·16 [1·46–3·19]). Unlike adults, cognitive deficit in children had a finite risk horizon (75 days) and a finite time to equal incidence (491 days). A sizeable proportion of older adults who received a neurological or psychiatric diagnosis, in either cohort, subsequently died, especially those diagnosed with dementia or epilepsy or seizures. Risk profiles were similar just before versus just after the emergence of the alpha variant (n=47 675 in each cohort). Just after (vs just before) the emergence of the delta variant (n=44 835 in each cohort), increased risks of ischaemic stroke, epilepsy or seizures, cognitive deficit, insomnia, and anxiety disorders were observed, compounded by an increased death rate. With omicron (n=39 845 in each cohort), there was a lower death rate than just before emergence of the variant, but the risks of neurological and psychiatric outcomes remained similar. Interpretation This analysis of 2-year retrospective cohort studies of individuals diagnosed with COVID-19 showed that the increased incidence of mood and anxiety disorders was transient, with no overall excess of these diagnoses compared with other respiratory infections. In contrast, the increased risk of psychotic disorder, cognitive deficit, dementia, and epilepsy or seizures persisted throughout. The differing trajectories suggest a different pathogenesis for these outcomes. Children have a more benign overall profile of psychiatric risk than do adults and older adults, but their sustained higher risk of some diagnoses is of concern. The fact that neurological and psychiatric outcomes were similar during the delta and omicron waves indicates that the burden on the health-care system might continue even with variants that are less severe in other respects. Our findings are relevant to understanding individual-level and population-level risks of neurological and psychiatric disorders after SARS-CoV-2 infection and can help inform our responses to them.
435	N431		Meghann Ryan, Huajun Liang, Eleanor Wilson, Andrea Levine, Shyamasundaran Kottilil, Thomas Ernst and Linda Chang	Quantifying the neuropsychiatric symptoms in post-acute sequelae of COVID-19 (PASC) using the NIH Toolbox ® and PROMIS	https://doi.org/10.1515/nipt-2022-0010	Published	August 15, 2022	Study	https://www.degruyter.com/document/doi/10.1515/nipt-2022-0010/html	Objective To quantify neuropsychiatric symptoms reported by individuals with Post-Acute Sequelae of COVID-19 (PASC) using the NIH Toolbox for Assessment of Neurological and Behavioral Function (NIHTB) and Patient-Reported Outcomes Measurement Information System (PROMIS). Methods 30 PASC (20 women, 21–63 years) and 27 control (16 women, 25–68 years) participants completed three NIHTB batteries and selected PROMIS tests. Group differences on fully corrected T-scores were evaluated using analysis of covariance and Cohen’s d effect sizes. A linear regression model predicted the effects from time since diagnosis. Results PASC had poorer emotional health and motor function than controls, including poorer locomotion, endurance and dexterity, but normal cognitive function, ∼7 months post-infection. PASC participants had a steeper age-related decline on the 2-Minute Walk Endurance Test than controls. T-scores on four cognitive and three motor tests improved with longer time since diagnosis. Conclusion NIHTB and PROMIS captured the poorer emotional health and motor function in PASC, including the novel findings of deficits in locomotion and dexterity. The normal cognitive performance suggests subclinical effects that may be compensated by neural and cognitive reserves, and manifested subjectively by the negative psychological effects and fatigue. The persistent emotional and psychiatric symptoms necessitate mental health treatment be prioritized.
436	N432		Michał Chudzik 1ORCID,Mateusz Babicki 2ORCID,Agnieszka Mastalerz-Migas 2ORCID andJoanna Kapusta 3,*ORCID	Persisting Smell and Taste Disorders in Patients Who Recovered from SARS-CoV-2 Virus Infection—Data from the Polish PoLoCOV-CVD Study	https://doi.org/10.3390/v14081763	Published	12 August 2022	Study	https://www.mdpi.com/1999-4915/14/8/1763/htm	In the majority of cases, patients infected with the SARS-CoV-2 virus experience a complete resolution of symptoms within six weeks of acquiring the infection, but an increasing number of patients report persistent symptoms. This study aimed to analyse the prevalence of self-reported smell and/or taste disorders (STDs) in a group of convalescent patients after infection with the SARS-CoV-2 virus and to identify risk factors for the disease. The study included 2218 COVID-19 convalescents after both inpatient and outpatient treatment. The sample group was analysed with regard to chronic diseases, place of isolation and clinical symptoms occurring during COVID-19 along with their duration. The assessment also included the most common symptoms of COVID-19 and the severity of the disease course. A total of 98 patients reported persistent smell and taste disorders up to three months after the end of isolation (67.4% of men and 32.6% of women). The mean age of the participants was 53.8 ± 13.5 years (49.19 ± 14.68 in patients with an STD vs. 54.01 ± 13.44 in patients without an STD). The patients treated for COVID-19 at home (p < 0.001) constituted almost the entire group of patients with persistent smell and taste disorders (97%). Among the patients with persistent smell and taste disorders, 57.1% suffered from at least one chronic condition (vs. 71.4% of patients without an STD). In patients with an STD, the number of symptoms per patient was higher than in the other group at 8.87 ± 3.65 (p = 0.018), while the most common clinical symptoms during the acute phase of COVID-19 were smell and taste disorders (84%) (p < 0.001), significant weakness (70%), headache (60%), cough (55%), arthralgia (51%) (p = 0.034) and back muscle pain (51%). Based on the results obtained, the following conclusions were drawn: the risk of developing persistent smell and taste disorders after COVID-19 is greater in younger people with less comorbidities and a higher number of symptoms during the acute phase of COVID-19. The risk is associated with clinical symptoms occurring during the acute phase of COVID-19, i.e., smell and taste disorders and arthralgia. In addition, this risk is higher in patients receiving outpatient treatment for COVID-19.
437	N433		Michael P.McWilliamsaDaniel H.CoelhoabEvan R.ReiteraRichard M.Costanzo	Recovery from Covid-19 smell loss: Two-years of follow up	https://doi.org/10.1016/j.amjoto.2022.103607	Published	18 August 2022	Study	https://www.sciencedirect.com/science/article/pii/S0196070922002344	Objective - To report long-term patterns of recovery and non-recovery in a large nationwide cohort of subjects with COVID-19 associated smell loss. Study design - Prospectively, longitudinal questionnaires. Setting - Web-based national survey. Methods - A longitudinal survey of adults with COVID-19 and/or sudden change in smell or taste since January 1, 2020 was launched April 10, 2020. Participants were queried again in late May 2022 regarding recovery. Data from respondents with >2 years since loss were analyzed and compared to recovery status of those more recently effected. Results 1103 responded to the survey of whom 946 met inclusion criteria. Among the 267 respondents for whom at least 2 years of follow up was available, 38.2 % reported full recovery, 54.3 % partial, and 7.5 % no recovery. For the entire cohort (all with ≥3 months since smell loss), 38.7 % reported complete recovery, 51.0 % reported partial recovery (ranging from mild complaints to severe phantosmia or dysosmia), and 10.3 % reported no improvement at all. Complete recovery of smell function was significantly higher in those under 40 years old (45.6 % compared to 32.9 % in those over 40). Conclusion Although the vast majority of subjects who do recover do so within the first 3 months, long-term spontaneous recovery can occur. Rates of recovery do not seem to differ depending on when during the pandemic the loss first occurred.
438	N434		Claudio Tana, Enrico Bentivegna, Soo-Jin Cho, Andrea M. Harriott, David García-Azorín, Alejandro Labastida-Ramirez, Raffaele Ornello, Bianca Raffaelli, Eloísa Rubio Beltrán, Ruth Ruscheweyh & Paolo Martelletti	Long COVID headache	https://doi.org/10.1186/s10194-022-01450-8	Published	01 August 2022	Review	https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-022-01450-8	Headache is among the most frequent symptoms persisting or newly developing after coronavirus disease 2019 (COVID-19) as part of the so-called long COVID syndrome. The knowledge on long COVID headache is still limited, however growing evidence is defining the features of this novel condition, in particular regarding clinical characteristics, some pathophysiological mechanisms and first treatment recommendations. Long COVID headache can present in the form of worsening of a preexisting primary headache, or, more specifically, in the form of a new (intermittent or daily) headache starting during the acute infection or after a delay. It often presents together with other long COVID symptoms, most frequently with hyposmia. It can manifest with a migrainous or, more frequently, with a tension-type-like phenotype. Persistent activation of the immune system and trigeminovascular activation are thought to play a role. As there are virtually no treatment studies, treatment currently is largely guided by the existing guidelines for primary headaches with the corresponding phenotype. The present report, a collaborative work of the international group of the Junior Editorial Board of The Journal of Headache and Pain aims to summarize the most recent evidence about long COVID headache and suggests approaches to the diagnosis and treatment of this disorder.
439	N435	COA	Michail Spanos Sigal Shachar 3 Thadryan Sweeney 3 H. Immo Lehmann 3 Priyanka Gokulnath Guoping Li George B. Sigal Rajini Nagaraj Pradeepthi Bathala Farhan Rana Ravi V. Shah David A. Routenberg Saumya Das	Elevation of neural injury markers in patients with neurologic sequelae after hospitalization for SARS-CoV-2 infection	https://doi.org/10.1016/j.isci.2022.104833	Published	August 01, 2022	Study	https://www.cell.com/iscience/fulltext/S2589-0042(22)01105-1	Highlights •40% of hospitalized patients with COVID-19 developed neurological sequelae after recovery •Age, disease severity, and COVID-19 infection were associated with neurological sequelae •GFAP and NF-L were significantly elevated in SARS-CoV-2 infection compared to controls •GFAP and NF-L were elevated in patients with long-term neurological symptoms Summary Patients with SARS-CoV-2 infection (COVID-19) risk developing long-term neurologic symptoms after infection. Here, we identify biomarkers associated with neurologic sequelae one year after hospitalization for SARS-CoV-2 infection. SARS-CoV-2-positive patients were followed using post-SARS-CoV-2 online questionnaires and virtual visits. Hospitalized adults from the pre-SARS-CoV-2 era served as historical controls. 40% of hospitalized patients develop neurological sequelae in the year after recovery from acute COVID-19 infection. Age, disease severity, and COVID-19 infection itself was associated with additional risk for neurological sequelae in our cohorts. Glial fibrillary astrocytic protein (GFAP) and neurofilament light chain (NF-L) were significantly elevated in SARS-CoV-2 infection. After adjusting for age, sex, and disease severity, GFAP and NF-L remained significantly associated with longer term neurological symptoms in patients with SARS-CoV-2 infection. GFAP and NF-L warrant exploration as biomarkers for long-term neurologic complications after SARS-CoV-2 infection.
440	N436		Tan B K J, Han R, Zhao J J, Tan N K W, Quah E S H, Tan C J et al.	Prognosis and persistence of smell and taste dysfunction in patients with covid-19: meta-analysis with parametric cure modelling of recovery curves	https://doi.org/10.1136/bmj-2021-069503	Published	27 July 2022	Systematic review and meta-analysis	https://www.bmj.com/content/378/bmj-2021-069503	Objective To clarify in patients with covid-19 the recovery rate of smell and taste, proportion with persistent dysfunction of smell and taste, and prognostic factors associated with recovery of smell and taste. Design - Systematic review and meta-analysis. Data sources - PubMed, Embase, Scopus, Cochrane Library, and medRxiv from inception to 3 October 2021. Review methods - Two blinded reviewers selected observational studies of adults (≥18 years) with covid-19 related dysfunction of smell or taste. Descriptive prognosis studies with time-to-event curves and prognostic association studies of any prognostic factor were included. Data extraction and synthesis - Two reviewers extracted data, evaluated study bias using QUIPS, and appraised evidence quality using GRADE, following PRISMA and MOOSE reporting guidelines. Using iterative numerical algorithms, time-to-event individual patient data (IPD) were reconstructed and pooled to retrieve distribution-free summary survival curves, with recovery rates reported at 30 day intervals for participants who remained alive. To estimate the proportion with persistent smell and taste dysfunction, cure fractions from Weibull non-mixture cure models of plateaued survival curves were logit transformed and pooled in a two stage meta-analysis. Conventional aggregate data meta-analysis was performed to explore unadjusted associations of prognostic factors with recovery. Main outcome measures - The primary outcomes were the proportions of patients remaining with smell or taste dysfunction. Secondary outcomes were the odds ratios of prognostic variables associated with recovery of smell and taste. Results - 18 studies (3699 patients) from 4180 records were included in reconstructed IPD meta-analyses. Risk of bias was low to moderate; conclusions remained unaltered after exclusion of four high risk studies. Evidence quality was moderate to high. Based on parametric cure modelling, persistent self-reported smell and taste dysfunction could develop in an estimated 5.6% (95% confidence interval 2.7% to 11.0%, I2=70%, τ2=0.756, 95% prediction interval 0.7% to 33.5%) and 4.4% (1.2% to 14.6%, I2=67%, τ2=0.684, 95% prediction interval 0.0% to 49.0%) of patients, respectively. Sensitivity analyses suggest these could be underestimates. At 30, 60, 90, and 180 days, respectively, 74.1% (95% confidence interval 64.0% to 81.3%), 85.8% (77.6% to 90.9%), 90.0% (83.3% to 94.0%), and 95.7% (89.5% to 98.3%) of patients recovered their sense of smell (I2=0.0-77.2%, τ2=0.006-0.050) and 78.8% (70.5% to 84.7%), 87.7% (82.0% to 91.6%), 90.3% (83.5% to 94.3%), and 98.0% (92.2% to 95.5%) recovered their sense of taste (range of I2=0.0-72.1%, τ2=0.000-0.015). Women were less likely to recover their sense of smell (odds ratio 0.52, 95% confidence interval 0.37 to 0.72, seven studies, I2=20%, τ2=0.0224) and taste (0.31, 0.13 to 0.72, seven studies, I2=78%, τ2=0.5121) than men, and patients with greater initial severity of dysfunction (0.48, 0.31 to 0.73, five studies, I2=10%, τ2<0.001) or nasal congestion (0.42, 0.18 to 0.97, three studies, I2=0%, τ2<0.001) were less likely to recover their sense of smell. Conclusions - A substantial proportion of patients with covid-19 might develop long lasting change in their sense of smell or taste. This could contribute to the growing burden of long covid.
441	N437		Leslie M. Kay	COVID-19 and olfactory dysfunction: a looming wave of dementia?	https://doi.org/10.1152/jn.00255.2022	Published	15 Aug 2022	Review	https://journals.physiology.org/doi/full/10.1152/jn.00255.2022	Olfactory dysfunction is a hallmark symptom of COVID-19 disease resulting from the SARS-CoV-2 virus. The cause of the sudden and usually temporary anosmia that most people suffer from COVID-19 is likely entirely peripheral—inflammation and other damage caused by the virus in the sensory epithelium inside the upper recesses of the nasal cavity can damage or prevent chemicals from properly activating the olfactory sensory neurons. However, persistent olfactory dysfunction from COVID-19, in the form of hyposmia and parosmia (decreased or altered smell) may affect as many as 15 million people worldwide. This epidemic of olfactory dysfunction is thus a continuing public health concern. Mounting evidence suggests that the SARS-CoV-2 virus itself or inflammation from the immune response in the nasal sensory epithelium may invade the olfactory bulb, likely via non-neuronal transmission. COVID-19-related long-term olfactory dysfunction and early damage to olfactory and limbic brain regions suggest a pattern of degeneration similar to that seen in early stages of Alzheimer’s disease, Parkinson’s disease, and Lewy body dementia. Thus, long-term olfactory dysfunction coupled with cognitive and emotional disturbance from COVID-19 may be the first signs of delayed onset dementia from neurodegeneration. Few treatments are known to be effective to prevent further degeneration, but the first line of defense against degeneration may be olfactory and environmental enrichment. There is a pressing need for more research on treatments for olfactory dysfunction and longitudinal studies including cognitive and olfactory function from patients who have recovered from even mild COVID-19.
442	N438		Boscolo-Rizzo P, Polesel J, Vaira L A	Smell and taste dysfunction after covid-19	https://doi.org/10.1136/bmj.o1653	Published	27 July 2022	Article	https://www.bmj.com/content/378/bmj.o1653.full	The sense of smell is an ancient and vital perception in mammals, with the olfactory receptor gene family making up 1% of the mammalian genome, and the human olfactory system being able to discriminate among thousands of airborne chemicals at concentrations below the detection limits of the most complex analytical systems.1 However, people only realise the importance of smell when it is lost. The covid-19 pandemic has put both smell and taste disturbances in the spotlight because of the functional impact and severe distress caused by the loss of these senses, their fundamental diagnostic value,2 and, more recently, the high rate of long term dysfunction. The linked meta-analysis by Tan and colleagues (doi:10.1136/bmj-2021-069503) gives a clear picture of the challenge humans face.4 About 5% of people who report initial changes to their sense of smell or taste after covid-19 still report smell and taste dysfunction six months later and, given that an estimated 550 million cases of covid-19 have been reported worldwide as of July 2022, large numbers of patients will be seeking care for these disabling morbidities. Health systems should therefore be ready to provide support to these patients who often report feeling isolated when their symptoms are overlooked by clinicians. More than other senses, smell and taste include emotional and affective elements of experience. These senses cannot be communicated through social networks—as with ideas, imaging, and music, sharing them requires coexistence. Loss of smell and taste adversely affects quality of life by depriving those affected of several everyday pleasures and social bonds.6 People can also experience anorexia, food aversions, malnutrition, anxiety, and depression.7 All these disturbances can be greatly amplified by the onset of qualitative alterations, in particular by parosmia. Parosmia, a fluctuant distorted smell perception, is a common sequela of the olfactory dysfunction associated with covid-19, arising on average three months after SARS-CoV-2 infection.8 For the overwhelming majority, parosmia transforms a pleasant odour into an unpleasant one, and daily activities such as smelling coffee and sensing the flavour of food can become disgusting and emotionally distressing. In addition to the use of nasal steroids, which aim to resolve SARS-CoV-2 induced inflammation, other treatments that have shown some, albeit marginal, benefit in small clinical trials include intranasal vitamin A and supplements of alpha lipoic acid and omega 3 fatty acids.15 As olfactory neuroepithelium is located in the hidden posterior roof of the nasal cavity, specific delivery systems able to distribute drugs to the olfactory region could improve the efficacy of intranasal treatment options. The large number of people with long lasting chemosensory dysfunction after covid-19 offers a unique opportunity to test new treatments in large multicentre trials. Health leaders, policy makers, and research funders should realise the extraordinary importance of good chemosensory function for the wellbeing of humans, allocate adequate resources to support chemosensory research, and sustain medical specialists faced with an exceptional number of patients with smell and taste dysfunction.
443	N439		Paola Ortelli, Francesco Benso, Davide Ferrazzoli, Ilaria Scarano, Leopold Saltuari, Luca Sebastianelli, Viviana Versace & Roberto Maestri	Global slowness and increased intra-individual variability are key features of attentional deficits and cognitive fluctuations in post COVID-19 patients	https://doi.org/10.1038/s41598-022-17463-x	Published	30 July 2022	Study	https://www.nature.com/articles/s41598-022-17463-x	Fatigue, attentional deficits and cognitive fluctuations are the most characterizing symptoms of neurological involvement in Post COVID-19 syndrome (PCS). As the intraindividual variability (IIV) in cognitive performances has been recognized as a hallmark of brain-related disorders associated with cognitive deficits, it could be an interesting measure to elucidate the mechanisms subtending both the attentive impairment and the cognitive fluctuations in these patients. By referring to IIV analysis of Reaction Times (RTs), the present study aims to define the attentive impairment and its relation to fluctuations and fatigue, in patients suffering from Post COVID-19 neurological symptoms. 74 patients were enrolled. They underwent an extensive clinical and neuropsychological assessments, as well as computerized Sustained Attention and Stroop tasks. For studying IIV, RTs distributions of performances in computerized tasks were fitted with ex-Gaussian distribution, for obtaining the τ values. Finally, the Resting Motor Threshold (RMT) was also collected to estimate cortical excitability. 29 healthy volunteers served as controls. Patients showed poorer scores in Montreal Cognitive Assessment and higher RMT, in comparison with controls. In Sustained Attention Task, Mean, µ, σ and τ values were significantly higher in PCS patients (p value = < 0.0001; 0.001; 0.018 and < 0.0001, respectively). Repeated measures ANOVA comparing the RTs mean in Stroop task within-subject and between-subjects revealed significant condition and group effect (p < 0.0001 both) and significant interaction (p = 0.005), indicating worst performances in patients. The mean of the derived interference value was significantly higher in PCS patients than in controls (p = 0.036). Patients suffering from PCS show deficits in attention, both in the sustained and executive components. Both high RTs means and high IIV subtend these deficits and could explain the often-complained cognitive fluctuations in this population.
444	N440		Naim Mahroum 1,*ORCID andYehuda Shoenfeld 2	Autoimmune Autonomic Dysfunction Syndromes: Potential Involvement and Pathophysiology Related to Complex Regional Pain Syndrome, Fibromyalgia, Chronic Fatigue Syndrome, Silicone Breast Implant–Related Symptoms and Post-COVID Syndrome	https://doi.org/10.3390/pathophysiology29030033	Published	28 July 2022	Review	https://www.mdpi.com/1873-149X/29/3/33/htm	The pathophysiological mechanisms involved in chronic disorders such as complex regional pain syndrome, fibromyalgia, chronic fatigue syndrome, silicone breast implant–related symptoms, and post-COVID syndrome have not been clearly defined. The course of the pain in some of the syndromes, the absence of evident tissue damage, and the predominance of alterations in the autonomic nervous system are shared similarities between them. The production of autoantibodies following a trigger in the syndromes was previously described, for instance, trauma in complex regional pain syndrome, infectious agents in fibromyalgia, chronic fatigue syndrome, and post-COVID syndrome, and the immune stimulation by silicone in women with breast implants. In fact, the autoantibodies produced were shown to be directed against the autonomic nervous system receptors, leading to the amplification of the perception of pain alongside various clinical symptoms seen during the clinical course of the syndromes. Therefore, we viewed autoantibodies targeting the autonomic nervous system resulting in autonomic dysfunction as likely the most comprehensive explanation of the pathophysiology of the disorders mentioned. Based on this, we aimed to introduce a new concept uniting complex regional pain syndrome, fibromyalgia, chronic fatigue syndrome, silicone breast implant–related symptoms, and post-COVID syndrome, namely “autoimmune autonomic dysfunction syndromes”. Due to its etiological, pathophysiological, and clinical implications, the suggested term would be more precise in classifying the syndromes under one title. The new title would doubtlessly facilitate both laboratory and clinical studies aimed to improve diagnosis and make treatment options more directed and precise.
445	N441		NedaOmidianaPanteaMohammadibMonaSadeghalvadbHamid-RezaMohammadi-Motlaghb1	Cerebral microvascular complications associated with SARS-CoV-2 infection: How did it occur and how should it be treated?	https://doi.org/10.1016/j.biopha.2022.113534	Published	17 August 2022	Review	https://www.sciencedirect.com/science/article/pii/S0753332222009234	Highlights •Endothelial dysfunction in Blood-Brain Barrier injures cerebrovascular in COVID-19. •Hypercoagulation due to cerebral endothelial damage can cause stroke in COVID-19. •Ischemic stroke due to SARS-CoV-2 infection is mostly present in younger patients. •Anticoagulant therapy may improve cerebrovascular diseases in COVID-19 patients. •Vaccine-induced immune thrombotic thrombocytopenia may rarely occur in some cases. Abstract Cerebral microvascular disease has been reported as a central feature of the neurological disorders in patients with SARS-CoV-2 infection that may be associated with an increased risk of ischemic stroke. The main pathomechanism in the development of cerebrovascular injury due to SARS-CoV-2 infection can be a consequence of endothelial cell dysfunction as a structural part of the blood-brain barrier (BBB), which may be accompanied by increased inflammatory response and thrombocytopenia along with blood coagulation disorders. In this review, we described the properties of the BBB, the neurotropism behavior of SARS-CoV-2, and the possible mechanisms of damage to the CNS microvascular upon SARS-CoV-2 infection.
446	N442		Kristine Lokken, Melissa J Greenfield, Jamie Hansel Robinson, Udit Vipul Shah, Ronald M Lazar, Richard Kennedy, Roy C Martin, Kristen Triebel Gerstenecker, Adam Gerstenecker, Pariya Fazeli Wheeler, Shruti P Agnihotri, David E Vance	A-159 Neurocognitive Performance in Post-Acute Sequelae of COVID-19 (PASC)	https://doi.org/10.1093/arclin/acac060.159	Published	17 August 2022	Study	https://academic.oup.com/acn/article/37/6/1313/6669101	Objective: Describe cognitive function in patients seeking treatment for Post-Acute Sequelae of COVID-19 (PASC). Method: Ninety-two patients underwent neuropsychological evaluation secondary to reported “brain fog” following COVID-19 infection. Patients were referred from the University of Alabama at Birmingham (UAB) Post-COVID Treatment Program. Patients were on average 49 years of age (range: 18-74), female (77%), and White/Caucasian (73%)/Black/AA (25%), with 15.49 years of education (SD = 2.43). Results: Overall, many patients demonstrated mild impairment on a brief global cognitive screener (MoCA; M = 24.78, SD = 3.46). On specific tasks of cognitive abilities, processing speed was variable; ranging from low average (Oral TMT Part A; M = 88.31, SD = 28.78) to below average (Oral SDMT; M = 72.80, SD = 20.37). Memory for immediate recall was low average (CVLT3-Brief Form (BF) Trials 1-4, M = 88.01, SD = 17.11), while delayed recall was average (CVLT3-BF, M = 94.17, SD = 19.11). Performances on measures of attention/working memory (WAIS-IV Digit Span; M = 96.75, SD = 12.54), executive functioning (Oral TMT Part B; M = 92.71, SD = 28.48), language (COWAT; M = 92.03, SD = 14.19) and visuospatial abilities (RBANS Figure Copy M = 104.04, SD = 16.08) were intact. Performance on embedded validity measures was also intact (RDS [95% valid]; CVLT-3 FC [93% valid]). Conclusion: Overall, patients with “brain fog” following COVID-19 infection experience difficulties in specific domains of cognitive functioning. Further investigation of neuropsychological profiles associated with PASC is warranted to inform diagnosis, neurocognitive trajectory, and treatment planning.
447	N443		Merve Hazal Ser, Fatma Zehra Çalıkuşu, Uygur Tanrıverdi, Hikmet Abbaszade, Sena Hakyemez, İlker İnanç Balkan, Rıdvan Karaali & Ayşegül Gündüz	Autonomic and neuropathic complaints of long-COVID objectified: an investigation from electrophysiological perspective	https://doi.org/10.1007/s10072-022-06350-y	Published	22 August 2022	Study	https://link.springer.com/article/10.1007/s10072-022-06350-y	Purpose Here , we aimed to assess the frequency and phenomenology of autonomic and neuropathic complaints of long-COVID and to evaluate them by means of electrophysiology. Methods Step 1. Patients with prior COVID-19 infection were screened by COMPASS-31 and mTORONTO to create the target population for further evaluation. Step 2. Patients with high scores were invited for a detailed history of their complaints and electrophysiological analysis, which included nerve conduction studies, cutaneous silent period (CSP), and sympathetic skin response (SSR). We also constituted a control group composed of healthy subjects of similar age and sex for electrophysiological analysis. Results There were 106 patients, who matched the study criteria. Among them, thirty-eight patients (%35.8) had neuropathic or autonomic complaints or both. Fatigue and headache were significantly more frequent in patients with autonomic and neuropathic complaints. Detailed examination and electrophysiological evaluation were performed in 14 of 38 patients. Neuropathic complaints were patchy and proximally located in the majority. The entire CSP suppression index was higher in the patients (p = 0.002). There was no difference in palmar and plantar SSR between patients and healthy subjects. mTORONTO scores were negatively correlated with palmar and plantar SSR amplitudes, and the correlation was moderate. Conclusion Neuropathic or autonomic complaints were seen in more than one-third of patients with long-COVID. Neuropathic complaints were generally patchy, proximally predominant, asymmetric, or diffuse. The CSP suppression index was abnormal whereas SSRs were normal.
448	N444		Knut Stavem ,Gunnar Einvik,Birgitte Tholin,Waleed Ghanima,Erik Hessen,Christofer Lundqvist	Cognitive function in non-hospitalized patients 8–13 months after acute COVID-19 infection: A cohort study in Norway	https://doi.org/10.1371/journal.pone.0273352	Published	August 22, 2022	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0273352	Studies have reported reduced cognitive function following COVID-19 illness, mostly from hospital settings with short follow-up times. This study recruited non-hospitalized COVID-19 patients from a general population to study prevalence of late cognitive impairment and associations with initial symptoms. We invited patients with PCR-confirmed COVID-19. A postal questionnaire addressed basic demographics, initial COVID-19 symptoms and co-morbidity about 4 months after diagnosis. About 7 months later, we conducted cognitive tests using the Cambridge Neuropsychological Test Automated Battery, comprising four tests for short-term memory, attention and executive function. We present descriptive statistics using z-scores relative to UK population norms and defined impairment as z-score <-1.5. We used multivariable logistic regression with impairment as outcome. Continuous domain scores were analysed by multiple linear regression. Of the initial 458 participants; 305 were invited, and 234 (77%) completed cognitive testing. At median 11 (range 8–13) months after PCR positivity, cognitive scores for short term memory, visuospatial processing, learning and attention were lower than norms (p≤0.001). In each domain, 4–14% were cognitively impaired; 68/232 (29%) were impaired in ≥ 1 of 4 tests. There was no association between initial symptom severity and impairment. Multivariable linear regression showed association between spatial working memory and initial symptom load (6–9 symptoms vs. 0–5, coef. 4.26, 95% CI: 0.65; 7.86). No other dimension scores were associated with symptom load. At median 11 months after out-of-hospital SARS-Cov-2 infection, minor cognitive impairment was seen with little association between COVID-19 symptom severity and outcome.
449	N445	COA	Amy Newhouse, MD,1,3,∗ Michael D. Kritzer, MD, PhD,1 Hamdi Eryilmaz, PhD,1 Nathan Praschan, MD, MPH,1 Joan A. Camprodon, MD, MPH, PhD,1,2 Gregory Fricchione, MD,1 and Zeina Chemali, MD, MPH1,2	Neurocircuitry hypothesis and clinical experience treating neuropsychiatric symptoms of post-acute sequelae of SARS-CoV-2 (PASC)	https://doi.org/10.1016%2Fj.jaclp.2022.08.007	Published	2022 Aug 25	Review	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9404079/	Persistent symptoms following COVID-19 infection have been termed post-acute sequelae of SARS-CoV-2 infection (PASC). Many of these symptoms are neuropsychiatric, such as inattention, impaired memory, and executive dysfunction; these are often colloquially termed “brain fog”. These symptoms are common and often persist long after the acute phase. The pattern of these deficits combined with laboratory, neuroimaging, electroencephalographic and neuropsychological data suggest that these symptoms may be driven by direct and indirect damage to the frontal-subcortical neural networks. Here, we review this evidence, share our clinical experience at an academic medical center, and discuss potential treatment implications. While the exact etiology remains unknown, a neurocircuit-informed understanding of PASC can help guide pharmacology, neuromodulation, physical and psychological therapeutic approaches.
450	N446		Michael Fleischer, Fabian Szepanowski, Muriel Tovar, Klaas Herchert, Hannah Dinse, Adam Schweda, Anne K. Mausberg, Dagny Holle-Lee, Martin Köhrmann, Julia Stögbauer, Daniel Jokisch, Martha Jokisch, Cornelius Deuschl, Eva-Maria Skoda, Martin Teufel, Mark Stettner & Christoph Kleinschnitz	Post-COVID-19 Syndrome is Rarely Associated with Damage of the Nervous System: Findings from a Prospective Observational Cohort Study in 171 Patients	https://doi.org/10.1007/s40120-022-00395-z	Published	26 August 2022	Study	https://link.springer.com/article/10.1007/s40120-022-00395-z	Introduction The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can affect multiple organs. Reports of persistent or newly emergent symptoms, including those related to the nervous system, have increased over the course of the pandemic, leading to the introduction of post-COVID-19 syndrome. However, this novel syndrome is still ill-defined and structured objectification of complaints is scarce. Therefore, we performed a prospective observational cohort study to better define and validate subjective neurological disturbances in patients with post-COVID-19 syndrome. Methods A total of 171 patients fulfilling the post-COVID-19 WHO Delphi consensus criteria underwent a comprehensive neurological diagnostic work-up including neurovascular, electrophysiological, and blood analysis. In addition, magnetic resonance imaging (MRI) and lumbar puncture were conducted in subgroups of patients. Furthermore, patients underwent neuropsychological, psychosomatic, and fatigue assessment. Results Patients were predominantly female, middle-aged, and had incurred mostly mild-to-moderate acute COVID-19. The most frequent post-COVID-19 complaints included fatigue, difficulties in concentration, and memory deficits. In most patients (85.8%), in-depth neurological assessment yielded no pathological findings. In 97.7% of the cases, either no diagnosis other than post COVID-19 syndrome, or no diagnosis likely related to preceding acute COVID-19 could be established. Sensory or motor complaints were more often associated with a neurological diagnosis other than post-COVID-19 syndrome. Previous psychiatric conditions were identified as a risk factor for developing post-COVID-19 syndrome. We found high somatization scores in our patient group that correlated with cognitive deficits and the extent of fatigue. Conclusions Albeit frequently reported by patients, objectifiable affection of the nervous system is rare in post-COVID-19 syndrome. Instead, elevated levels of somatization point towards a pathogenesis potentially involving psychosomatic factors. However, thorough neurological assessment is important in this patient group in order to not miss neurological diseases other than post-COVID-19. Key Summary Points Why carry out this study? To validate subjective neurological complaints in patients with post-COVID-19 by applying a comprehensive neuro-psychiatric diagnostic workup. What was learned from the study? The nervous system is rarely affected in patients with post-COVID-19 syndrome. Psychosomatic factors probably contribute to the pathogenesis of post-COVID-19 syndrome. Patients presenting with post-COVID-19 should be thoroughly assessed in order to not miss other diagnoses.
451	N447		Ayşe YağmurKanraaMeltem GüzinAltınelbFundaAlparslanc	EVALUATION OF RETINAL AND CHOROIDAL PARAMETERS AS NEURODEGENERATION BIOMARKERS IN PATIENTS WITH POST-COVID-19 SYNDROME: Evaluation of retinal and choroidal parameters as neurodegeneration biomarkers in patients with persistent post-COVID symptoms	https://doi.org/10.1016/j.pdpdt.2022.103108	Published	6 September 2022	Study	https://www.sciencedirect.com/science/article/abs/pii/S1572100022003945	Highlights •An overall thinning of the GCL, IPL, and IRL layers can be detected as the direct or indirect effect of SARS-CoV-2, a neurotropic virus, on these layers, rather than a long-term neurodegenerative effect in the post-COVID-19 period. •Statistically significant change in CMT, pRNFL, and CVI parameters are not observed in the post-COVID-19 period. •SARS-CoV-2, as a neurotropic virus, may trigger such neurodegenerative diseases in susceptible individuals in the long term. •The most common neurologic symptom is the headache in the post-COVID-19 period. Abstract Background To investigate the neurodegenerative effects of post-COVID-19 syndrome. Methods This comparative, cross-sectional study included patients who had post-COVID-19 prolonged neurologic symptoms. The control group was selected from volunteer participants with similar age, sex, and spherical equivalent characteristics. After detailed ophthalmic examinations, spectral-domain optic coherence tomography (SD-OCT) analysis of the macula and peripapillary retinal nerve fiber layer (m-RNFL, p-RNFL respectively) were obtained. We also evaluated the choroidal parameters with the ImageJ software. Post-COVID-19 symptoms and disease severity of the patients were also questioned. Results Thirty-four eyes of 20 patients, and 39 eyes of 23 healthy individuals were included in the study. Thinning was found in the inner superior quadrant of mRNFL (p<0.05). More prominent and common thinning of retinal layers was observed in the ganglion cell layer (GCL) and inner plexiform layer (IPL) segments in the patient group. There was no difference between the groups in the calculated choroidal parameters (p>0.05). In the regression models created, lung involvement was the most prominent parameter associated with thinning of the OCT layers. The other factors were male sex, and the presence of loss of taste and smell also led to deterioration in some parameters. Conclusions We detected an overall thinning of the GCL and IPL layers with no significant change in CMT, pRNFL, and CVI in the post-COVID-19 period, indicating the direct or indirect effect of SARS-CoV-2 on these layers, rather than a long-term neurodegenerative effect.
452	N448		Kristin L. Bigos Andrea M. Goldensohn	COVID-19 Infection and Risk for Neuropsychiatric Symptoms	https://doi.org/10.1016/j.biopsych.2022.06.032	Published	01 Oct 2022	Commentary	https://www.biologicalpsychiatryjournal.com/article/S0006-3223(22)01402-0/fulltext	In the current issue of Biological Psychiatry, Gillespie et al. (1) show a notable association between the use of statins and cognitive markers that indicate a decreased psychological vulnerability to depression, including affective bias and reward processing. In this study, use of statins was associated with reduced recognition of angry and fearful faces, and reduced learning about stimuli associated with loss. Further, these indicators of reduced negative bias were not found in patients taking antihypertensive medications, without statins. Future prospective, controlled, randomized, clinical studies should be conducted to determine the potential use of statins as prophylactic treatment for depression. Statins are among the most commonly prescribed classes of medications, and their use has been associated with a lower risk of all-cause mortality, with an even greater effect in patients with dementia (2). These new data suggest a potential role for statins in the prevention and treatment of depression, especially in older adults, which may contribute to their effects on lifespan by promoting psychological resilience. Safe and effective use of medications for the prevention and/or treatment of mood symptoms is even more important during the COVID-19 pandemic. In addition to the acute effects of the virus, some patients experience longer-term symptoms after COVID-19 infection, termed post-acute sequelae of SARS-CoV-2 infection (PASC), and also known as long COVID. Neuropsychological symptoms of PASC include depression, anxiety, cognitive impairment, sleep dysfunction, chronic fatigue, headache, and sensorimotor symptoms. Most studies of neuropsychiatric symptoms related to PASC have been conducted in adults, but there are case reports of children with similar neuropsychiatric manifestations. One study found that 15% of adult patients reported posttraumatic stress symptoms 1 month postdischarge from their COVID-19 hospitalization (5). Another study followed up with patients 3 months postdischarge and found that 15% of patients met the criteria for a diagnosis of depression based on their responses on the Patient Health Questionnaire-9, and 6% of patients experienced suicidality (6). In this study, the greatest predictors of the development of depression were history of a prior psychiatric disorder, female sex, and chronic pulmonary conditions (6), suggesting that those individuals should be most closely monitored for psychiatric symptoms after hospitalization for COVID-19. A separate study recruited patients with no prior psychiatric history and found that subjects who were previously diagnosed with COVID-19 had significantly higher scores of depression (Beck Depression Inventory-II), anxiety (Mood and Anxiety Symptom Questionnaire), and anhedonia (Snaith-Hamilton Pleasure Scale) than those who did not have a COVID-19 infection (7). The scores were highest during the acute phase (14–30 days postdiagnosis) and PASC phase (1–4 months postdiagnosis) compared with more than 4 months postdiagnosis (7). In addition, the subjects with a prior COVID-19 infection had a selective impairment in executive functioning, while alerting and orienting abilities remained intact (7). These case-control studies have become harder to conduct because vaccines have become less effective at preventing infection, and therefore a greater percentage of the population has become infected. However, future research could correlate infection duration and severity with acute and longer-term neuropsychiatric symptoms and structural and functional brain changes, such as task-based functional magnetic resonance imaging (MRI). There is emerging evidence of structural, functional, and biochemical changes in the human brain after COVID-19 infection. A longitudinal study using structural MRI data from the UK Biobank (n = 755, ages 51–81 years) included 401 subjects who tested positive for infection with SARS-CoV-2 between their two MRI scans and 384 control subjects (8). Subjects who had a prior infection showed a greater cognitive decline between their first and second scans, with an average of 4.5 months between reported diagnosis and the second scan. They found structural brain changes in patients after even mild COVID-19 infection, including a greater reduction in global brain size, a greater reduction in gray matter in the orbitofrontal cortex and parahippocampal gyrus, and greater changes in markers of tissue damage in regions connected to the primary olfactory cortex (8). Concerningly, there are also reports of MRI evidence of brain inflammation in children with mild or even asymptomatic COVID-19 infection. A postmortem study found tau hyperphosphorylation in brain lysate from deceased COVID-19 patients (9), which is pathology found in patients with Alzheimer’s disease and associated with neurodegeneration and Alzheimer’s disease progression. The same postmortem study found increased glutamate carboxypeptidase II (GCPII) (9), which is known to be increased with inflammation, aging, and several neuropsychiatric disorders. GCPII is the primary regulator of N-acetylaspartyl glutamate (NAAG), the endogenous ligand for the metabotropic glutamate receptor 3, and increases in GCPII are associated with lower NAAG and cognitive deficits (10). The increased incidence of neuropsychiatric and cognitive symptoms after COVID-19 infection may be related to these signs of brain inflammation and structural damage to key brain regions and circuitries. Consequently, there is an urgent need to identify and/or develop tools for the prevention or treatment of the neuropsychiatric and cognitive symptoms associated with COVID-19 infection. Repurposing medications could provide much-needed treatment options to promote psychological resilience. Neuropsychiatric symptoms are most likely to emerge or worsen in older adults with and without dementia and appear to be the consequence of both COVID-19 infection and prolonged social isolation. Preventive treatment options may be most important for young children, whose brains are still developing and changing at the highest rate and therefore are most vulnerable to viral and immunological insults. Further research is also required to understand the indirect effect of the pandemic on mental health in order to improve prevention, treatment, and planning for increased availability of mental health care services during COVID-19, as well as potential future pandemics.
453	N449		BiancaBesteheraMarleneMachnikaMarieTrollaAntoniaToepfferaAniZerekidzeaToniaRocktäschelaCarinaHellerabcZoraKikinisbStefanBrodoehldKathrinFinkedPhilipp A.ReukeneNilsOpelaAndreasStallmacheChristianGaserad1MartinWaltera1	Larger gray matter volumes in neuropsychiatric long-COVID syndrome	https://doi.org/10.1016/j.psychres.2022.114836	Published	6 September 2022	Study	https://www.sciencedirect.com/science/article/pii/S0165178122004292	Highlights •Neuropsychiatric symptoms are common among long-COVID patients. •Cortical and subcortical gray matter volumes are increased in these patients. •Gray matter alterations occur in limbic and secondary olfactory system. •Gray matter volumes are inversely associated with time since onset of COVID-19. Abstract Neuropsychiatric symptoms are the most common sequelae of long-COVID. As accumulating evidence suggests an impact of survived SARS-CoV-2-infection on brain physiology, it is necessary to further investigate brain structural changes in relation to course and neuropsychiatric symptom burden in long-COVID. To this end, the present study investigated 3T-MRI scans from long-COVID patients suffering from neuropsychiatric symptoms (n = 30), and healthy controls (n = 20). Whole-brain comparison of gray matter volume (GMV) was conducted by voxel-based morphometry. To determine whether changes in GMV are predicted by neuropsychiatric symptom burden and/or initial severity of symptoms of COVID-19 and time since onset of COVID-19 stepwise linear regression analysis was performed. Significantly enlarged GMV in long-COVID patients was present in several clusters (spanning fronto-temporal areas, insula, hippocampus, amygdala, basal ganglia, and thalamus in both hemispheres) when compared to controls. Time since onset of COVID-19 was a significant regressor in four of these clusters with an inverse relationship. No associations with clinical symptom burden were found. GMV alterations in limbic and secondary olfactory areas are present in long-COVID patients and might be dynamic over time. Larger samples and longitudinal data in long-COVID patients are required to further clarify the mediating mechanisms between COVID-19, GMV and neuropsychiatric symptoms.
454	N450		Christina D. Kay 1,†,Ana Sofia Costa 2,3,†ORCID,Tracy D. Vannorsdall 4,5,Paula Aduen 6,Clara Vila-Castelar 6ORCID,Sarah M. Burstein 1,Lauren Pollak 1,Daniel K. Leibel 4,Janet C. Sherman 1,Julia Bungenberg 2,Kathrin Reetz 2,3ORCID andYakeel T. Quiroz 6,*	Neuropsychological Outcomes of COVID-19: A Multicenter, Cross-Cultural Study of Patients Referred for Outpatient Assessment	https://doi.org/10.3390/covid2090092	Published	2 September 2022	Study	https://www.mdpi.com/2673-8112/2/9/92/htm	Objective: Cognitive dysfunction is one of the most frequently reported symptoms in post-acute sequelae of COVID-19 (PASC) and has become a common reason for neuropsychological referral. While data are emerging, we aimed to address possible cross-cultural patterns of neuropsychological outcomes that remain underexplored. Methods: In this cross-sectional, retrospective study, we characterize the cognitive performance, demographic makeup, and clinical characteristics of 84 PASC patients (Mage = 57 years) referred for neuropsychological evaluation to three USA sites and one in Germany. Neuropsychological data (mean demographically adjusted z-scores and frequencies of impairment) were examined across six cognitive domains. Independent t-tests compared performances of previously hospitalized and non-hospitalized patients. Results: Patients were assessed on average seven months post-COVID-19 infection. The majority were women and non-hospitalized. Mean cognitive performance was within the normative range, but high variability existed within and between sites. Deficits were generally mild and most frequent in processing speed (range across sites: 9–57% of patients), executive functioning (range across sites: 4–43% of patients) and attention/working memory (range across sites: 0–43% of patients). Hospitalized patients showed greater cognitive impairment than those not requiring hospitalization. Mood symptoms and fatigue/sleep disturbance were more frequent than objective cognitive impairments. At the time of assessment, most patients were unable to return to work. Conclusions: Cognitive performance in clinically referred PASC patients was, overall, within the normative range. Mild deficits were most frequent in time-based attentional/executive tasks. Other factors, such as affective symptoms and fatigue, were frequent and may significantly impact functioning, perhaps more than cognition. Further work with larger samples and longitudinal measures is needed to clarify the impact of COVID-19 on cognitive function and psychiatric distress.
455	N451		Pasquale Picone, Tiziana Sanfilippo, Rossella Guggino, Luca Scalisi, Roberto Monastero, Roberta Baschi, Valeria Mandalà, Livio San Biagio, Manfredi Rizzo, Daniela Giacomazza, Clelia Dispenza & Domenico Nuzzo	Neurological Consequences, Mental Health, Physical Care, and Appropriate Nutrition in Long-COVID-19	https://doi.org/10.1007/s10571-022-01281-w	Published	14 September 2022	Review	https://link.springer.com/article/10.1007/s10571-022-01281-w	SARS-CoV-2 pandemic has caused a collapse of the world health systems. Now, vaccines and more effective therapies have reversed this crisis but the scenario is further aggravated by the appearance of a new pathology, occurring as SARS-CoV-2 infection consequence: the long-COVID-19. This term is commonly used to describe signs and symptoms that continue or develop after acute infection of COVID-19 up to several months. In this review, the consequences of the disease on mental health and the neurological implications due to the long-COVID are described. Furthermore, the appropriate nutritional approach and some recommendations to relieve the symptoms of the pathology are presented. Data collected indicated that in the next future the disease will affect an increasing number of individuals and that interdisciplinary action is needed to counteract it.
456	N452		Tania LlanaORCID Icon,Candela ZorzoORCID Icon,Magdalena Mendez-LopezORCID Icon &Marta MendezORCID Icon	Memory alterations after COVID-19 infection: a systematic review	https://doi.org/10.1080/23279095.2022.2123739	Published	15 Sep 2022	Review	https://www.tandfonline.com/doi/abs/10.1080/23279095.2022.2123739	SARS-CoV-2 infection has a wide range of both acute and long-term symptoms. Memory alterations have been frequently reported in studies that explore cognition. The main objective of the systematic review is to update and further analyze the existing evidence of objective memory impairments in long-COVID-19 considering sample and study design characteristics, as well as to explore associations between memory performance and their epidemiological, clinical, and pathological features. A total of 13 studies were identified by searching in PubMed, Web of Science, and PsycInfo databases up to May 6, 2022. Most studies evaluated verbal component of memory in the short-term and long-term recall up to 30 min and mainly performed a single assessment completed at 4–6 months after the infection. The samples mainly consisted of middle-aged adults that required hospitalization. Samples were not stratified by sex, age, and severity. Poor verbal learning was reported in most cases (6–58%), followed by deficits in long-term (4–58%) and short-term (4–37%) verbal memory. Visuospatial component of memory was studied less than verbal component, showing impairment of long-term retention of visual items (10–49%). COVID-19 severity in the acute stage was not systematically associated with poor memory performance. Verbal memory deficits were associated with anxiety and depression. The existing literature on objective memory assessment in long-COVID suggests further research is warranted to confirm memory dysfunction in association with epidemiological, pathological, and clinical factors, using both verbal and visuospatial tests, and exploring in deep long-term memory deficits.
457	N453		César Fernández-de-las-Peñas Dr. Med, PhD,Maria L. Cuadrado MD, PhD,Victor Gómez-Mayordomo MD,Juan Torres-Macho MD,Oscar J. Pellicer-Valero PhD,José D. Martín-Guerrero PhD,Lars Arendt-Nielsen Dr. Med, PhD	Headache as a COVID-19 onset symptom and post-COVID-19 symptom in hospitalized COVID-19 survivors infected with the Wuhan, Alpha, or Delta SARS-CoV-2 variants	https://doi.org/10.1111/head.14398	Published	16 September 2022	Study	https://headachejournal.onlinelibrary.wiley.com/doi/10.1111/head.14398	Objective This study looked at differences in the presence of headache as an onset symptom of coronavirus disease 2019 (COVID-19) and as a post-COVID-19 symptom in individuals previously hospitalized owing to infection with the Wuhan, Alpha, or Delta variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Background Headache can be present in up to 50% of individuals during the acute phase of SARS-CoV-2 infection and in 10% of subjects during the post-COVID-19 phase. There are no data on differences in the occurrence of headache in the acute- and post-COVID-19 phase according to the SARS-CoV-2 variants. Methods A cross-sectional cohort study was conducted. Unvaccinated subjects previously hospitalized for COVID-19 caused by the Wuhan (n = 201), Alpha (n = 211), or Delta (n = 202) SARS-CoV-2 variants were scheduled for a telephone interview 6 months after hospital discharge. Hospitalization data were collected from hospital medical records. Results The presence of headache as a COVID-19 onset symptom at hospitalization was higher in subjects with the Delta variant (66/202, 32.7%) than in those infected with the Wuhan (42/201, 20.9%; odds ratio [OR] 1.83, 95% confidence interval [CI] 1.17–2.88) or Alpha (25/211, 11.8%; OR 3.61, 95% CI, 2.16–6.01) variants. The prevalence of post-COVID-19 headache 6 months after hospital discharge was higher in individuals infected with the Delta variant (26/202, 12.9%) than in those infected with the Wuhan (11/201, 5.5%; OR 2.52, 95% CI 1.22–5.31) or Alpha (eight of 211, 3.8%; OR 3.74, 95% CI 1.65–8.49) variants. The presence of headache as a COVID-19 onset symptom was associated with post-COVID-19 headache in subjects infected with the Wuhan (OR 7.75, 95% CI 2.15–27.93) and Delta variants (OR 2.78, 95% CI 1.20–6.42) but not with the Alpha variant (OR 2.60, 95% CI 0.49–13.69). Conclusion Headache was a common symptom in both the acute- and post-COVID-19 phase in subjects infected with the Wuhan, Alpha, and Delta variants but mostly in those infected with the Delta variant.
458	N454		Tim J.Hartungab1ChristianNeumannc1ThomasBahmerdeIrinaChaplinskaya-SobolfMatthiasEndresaghijJohannaGeritzcKarl GeorgHaeuslerkPeter U.HeuschmannlmHannaHildesheimcAndreasHinzbSinaHopffnAnnaHornlMichaelKrawczakoLilianKristpJenniferKudelkacWolfgangLiebqCorinaMaetzlercAnjaMehnert-TheuerkaufbFelipe A.MontellanolkrCarolineMorbachsSeinSchmidttStefanSchreiberuFloSteigerwaldaStefanStörkvwWalterMaetzlerc1CarstenFinkea1	Fatigue and cognitive impairment after COVID-19: A prospective multicentre study	https://doi.org/10.1016/j.eclinm.2022.101651	Published	17 September 2022	Study	https://www.sciencedirect.com/science/article/pii/S2589537022003819	Background Reliable estimates of frequency, severity and associated factors of both fatigue and cognitive impairment after COVID-19 are needed. Also, it is not clear whether the two are distinct sequelae of COVID-19 or part of the same syndrome. Methods In this prospective multicentre study, frequency of post-COVID fatigue and cognitive impairment were assessed in n = 969 patients (535 [55%] female) ≥6 months after SARS-CoV-2 infection with the FACIT-Fatigue scale (cut-off ≤30) and Montreal Cognitive Assessment (≤25 mild, ≤17 moderate impairment) between November 15, 2020 and September 29, 2021 at University Medical Center Schleswig-Holstein, Campus Kiel and University Hospital Würzburg in Germany. 969 matched non-COVID controls were drawn from a pre-pandemic, randomised, Germany-wide population survey which also included the FACIT-Fatigue scale. Associated sociodemographic, comorbid, clinical, psychosocial factors and laboratory markers were identified with univariate and multivariable linear regression models. Findings On average 9 months after infection, 19% of patients had clinically relevant fatigue, compared to 8% of matched non-COVID controls (p < 0.001). Factors associated with fatigue were female gender, younger age, history of depression and the number of acute COVID symptoms. Among acute COVID symptoms, altered consciousness, dizziness and myalgia were most strongly associated with long-term fatigue. Moreover, 26% of patients had mild and 1% had moderate cognitive impairment. Factors associated with cognitive impairment were older age, male gender, shorter education and a history of neuropsychiatric disease. There was no significant correlation between fatigue and cognitive impairment and only 5% of patients suffered from both conditions. Interpretation Fatigue and cognitive impairment are two common, but distinct sequelae of COVID-19 with potentially separate pathophysiological pathways.
459	N455		Md Sakibuzzaman, Anid Hassan, Samira Hayee, Fariah Asha Haque, Sumaita Sadida Bushra, Maisha Maliha, Maksuda Khan Tania, Anahita Sadat, Fahima Akter, Tanusree Mazumder, Joyeta Razzaque, Progga Kapuria, Ishra Jalal, Prince Shah-Riar	Exacerbation of Pre-existing Neurological Symptoms With COVID-19 in Patients With Chronic Neurological Diseases: An Updated Systematic Review	https://doi.org/10.7759/cureus.29297	Published	September 18, 2022	Review	https://www.cureus.com/articles/113896-exacerbation-of-pre-existing-neurological-symptoms-with-covid-19-in-patients-with-chronic-neurological-diseases-an-updated-systematic-review	The neurotropism of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can potentially explain the worsening of symptoms in patients with a history of neurological conditions such as stroke, Parkinson's disease, Alzheimer's, and epilepsy. Several studies have reported that these pre-existing conditions may worsen with a higher frequency of flare-ups, thus resulting in a more significant risk of patient mortality. In this review, we sought to provide an overview of the relationship between pre-existing neurological disorders and COVID-19, focusing on whether the initial infection directly influenced the severity of symptoms. We systematically searched the electronic database PubMed (MEDLINE) and used specific keywords related to our aims from January 2020 to July 2022. All articles published on COVID-19 with keywords pertaining to pre-existing neurological diseases were retrieved and subsequently analyzed. After independent review, the data from 107 articles were selected and evaluated. After analyzing the data from selected articles reviewing the effect of COVID-19 on neurological conditions, we have documented the relationship between said pre-existing neurological diseases, showing an increased risk of hospitalization, admission length, worsening of symptoms, and even mortality in COVID-19 patients.
460	N456		Abdul Mannan Baig*	Differential diagnosis and pathogenesis of the neurological signs and symptoms in COVID-19 and long-COVID syndrome	https://doi.org/10.1111/cns.13957	Published	19 September 2022	EDITORIAL COMMENTARY	https://onlinelibrary.wiley.com/doi/10.1111/cns.13957	Neurological features have now been reported very frequently in the ongoing COVID-19 pandemic caused by SARS-CoV-2. The neurological deficits associated features are observed in both acute and chronic stages of COVID-19 and they appear to overlap with wide-ranging symptoms that can be attributed to being of non-neural origins, thus obscuring the definitive diagnosis of neuro-COVID. The pathogenetic factors acting in concert to cause neuronal injury are now emerging, with SARS-CoV-2 directly affecting the brain coupled with the neuroinflammatory factors have been implicated in the causation of disabilities in acute COVID-19 and patients with Long-COVID syndrome. As the differentiation between a neural origin and other organ-based causation of a particular neurological feature is of prognostic significance, it implores a course of action to this covert, yet important neurological challenge.
461	N457		Dean Walton, Roberto Acampora, Greta Karen Wood, Elias Premi, Ingrid Andreea Ilie, Francesco Lanfranchi & Benedict Daniel Michael	Neurological Complications of COVID-19	https://doi.org/10.1007/978-3-031-08045-6_18	Published	09 September 2022	Review	https://link.springer.com/chapter/10.1007/978-3-031-08045-6_18	The neurological complications of COVID-19 are an expansive and heterogeneous topic. This chapter discusses the neuropathophysiology of COVID-19 and the potential mechanisms through which the disease leads to neurological manifestations while also exploring historical viruses that have also led to neurological sequelae. These complications are then characterized and classified into several groups with support from contemporaneous evidence. In addition to this we examine common neurological imaging and their findings and finally discuss the greatest needs moving forward with regard to evidence and research through collaborative efforts.
462	N458		Alna Carolina Mendes Paranhos, MSc1,2; Ápio Ricardo Nazareth Dias, PhD2; Livia Caroline Machado da Silva2; Gisele Vieira Hennemann Koury, PhD2; Emanuel de Jesus Sousa, PhD2; Antônio José Cerasi Jr, MSc3,4; Givago Silva Souza, PhD1,3; Juarez Antônio Simões Quaresma, PhD1,2; Luiz Fábio Magno Falcão, PhD2,5	Sociodemographic Characteristics and Comorbidities of Patients With Long COVID and Persistent Olfactory Dysfunction	https://doi.org/10.1001/jamanetworkopen.2022.30637	Published	September 8, 2022	Study	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2795995	Key Points Question What are the sociodemographic and clinical characteristics of patients with long COVID and persistent olfactory dysfunction? Findings In this cross-sectional study of 219 patients with long COVID and neurologic symptoms, 64% had olfactory dysfunction, with the highest prevalence among women, adults, and outpatients. Patients with olfactory dysfunction may develop severe olfactory loss (hyposmia or anosmia) that may persist for more than 1 year after the onset of symptoms. Meaning This study suggests that olfactory dysfunction in patients with long COVID may become permanent. Abstract Importance Determining the characteristics, type, and severity of olfactory dysfunction in patients with long COVID is important for the prognosis and potential treatment of the affected population. Objective To describe the sociodemographic and clinical features of patients with long COVID who develop persistent olfactory dysfunction. Design, Setting, and Participants This cross-sectional study, conducted at a rehabilitation center at a public university in the Amazon region of Brazil between September 9, 2020, and October 20, 2021, comprised 219 patients with long COVID and self-reported neurologic symptoms. Of these 219 patients, 139 received a diagnosis of chronic olfactory dysfunction, as confirmed by the Connecticut Chemosensory Clinical Research Center (CCCRC) test. Exposure Clinical diagnosis of long COVID. Main Outcomes and Measures Electronic case report forms were prepared for the collection of sociodemographic and clinical data. Patients’ sense of smell was evaluated via a CCCRC test, and the association of olfactory dysfunction with aspects of daily life was recorded using a questionnaire. Results Of the 219 patients included in the study, 164 (74.9%) were women, 194 (88.6%) were between 18 and 59 years of age (mean [SD] age, 43.2 [12.9] years), 206 (94.1%) had more than 9 years of education, and 115 (52.5%) had a monthly income of up to US $192.00. In the study group, 139 patients (63.5%) had some degree of olfactory dysfunction, whereas 80 patients (36.5%) had normosmia. Patients with olfactory dysfunction had a significantly longer duration of long COVID symptoms than those in the normosmia group (mean [SD], 242.7 [101.9] vs 221.0 [97.5] days; P = .01). Among patients with anosmia, there was a significant association between olfactory dysfunction and daily activities, especially in terms of impairment in hazard detection (21 of 31 patients [67.7%]), personal hygiene (21 of 31 patients [67.7%]), and food intake (21 of 31 patients [67.7%]). Univariable logistic regression analyses found that ageusia symptoms were associated with the occurrence of olfactory dysfunction (odds ratio [OR], 11.14 [95% CI, 4.76-26.07]; P < .001), whereas headache (OR, 0.41 [95% CI, 0.22-0.76]; P < .001) and sleep disorders (OR, 0.48 [95% CI, 0.26-0.92]; P = .02) showed an inverse association with the occurrence of olfactory dysfunction. Conclusions and Relevance Olfactory dysfunction is one of the most important long-term neurologic symptoms of COVID-19, with the highest prevalence seen among women, adults, and outpatients. Patients with olfactory dysfunction may experience persistent severe hyposmia or anosmia more than 1 year from the onset of symptoms, suggesting the possibility of the condition becoming a permanent sequela.
463	N459		AnnaBaumeisteraAnja S.GöritzdCharlesBenoybcLenaJelinekaSteffenMoritza	Long-COVID or long before? Neurocognitive deficits in people with COVID-19	https://doi.org/10.1016/j.psychres.2022.114822	Published	8 September 2022	Study	https://www.sciencedirect.com/science/article/pii/S0165178122004152	Highlights •The COVID group of the follow-up survey reported increased subjective neurocognitive complaints. •These complaints were not consistent with objective test performance. •The COVID group showed a greater depressive symptom burden compared with the non-COVID group. •Complaints need to be put into perspective when considering pre-pandemic data, as they were present prior to infection. Abstract In connection with COVID-19 disease, evidence of persisting psychiatric and neurocognitive effects is accumulating. To examine long COVID symptoms, baseline data from 2015 (i.e., before the pandemic) and follow-up data from 2021 from 428 participants were compared. Participants with COVID-19 reported more subjective neurocognitive complaints in the follow-up, but this did not correspond to the test performance. Also, greater depressive symptoms compared with the no-COVID group were reported. However, these complaints must be put into perspective when considering the baseline data, since complaints were present before the COVID infection. Thus, premorbid performance as well as psychological factors should be considered when discussing long COVID.
464	N460		AshwinKumariaaAbiodunNoahbMatthew A.Kirkmana	Does covid-19 impair endogenous neurogenesis?	https://doi.org/10.1016/j.jocn.2022.09.006	Published	13 September 2022	Opinion	https://www.sciencedirect.com/science/article/pii/S0967586822003575	Highlights •COVID-19 associated impairment in neural stem cell activity may contribute to cognitive impairment and hyposmia. •Neural stem cell dysfunction may be a neuropathological link between neurodegeneration and hyposmia. •Therapeutic upregulation of neural stem cell activity may improve symptoms of long COVID. •SARS-CoV-2 may have a role in oncolytic virotherapy by targeting brain tumour stem cells. Abstract Endogenous neural stem cells are thought to continue to generate new neurons throughout life in the human brain. Endogenous neurogenesis has been proposed to contribute to physiological roles in maintaining and regenerating olfaction, as well as promoting normal cognition, learning and memory. Specific impairments in these processes in COVID-19 – impaired olfaction and cognition – may implicate the SARS-CoV-2 virus in attenuating neurogenesis. Furthermore, neurogenesis has been linked with neuroregeneration; and impaired neuroregeneration has previously been linked with neurodegenerative diseases. Emerging evidence supports an association between COVID-19 infection and accelerated neurodegeneration. Also, structural changes indicating global reduction in brain size and specific reduction in the size of limbic structures – including orbitofrontal cortex, olfactory cortex and parahippocampal gyrus – as a result of SARS-CoV-2 infection have been demonstrated. This paper proposes the hypothesis that SARS-CoV-2 infection may impair endogenous neural stem cell activity. An attenuation of neurogenesis may contribute to reduction in brain size and/or neurodegenerative processes following SARS-CoV-2 infection. Furthermore, as neural stem cells are thought to be the cell of origin in glioma, better understanding of SARS-CoV-2 interaction with tumorigenic stem cells is indicated, with a view to informing therapeutic modulation. The subacute and chronic implications of attenuated endogenous neurogenesis are explored in the context of long COVID. Modulating endogenous neurogenesis may be a novel therapeutic strategy to address specific neurological manifestations of COVID-19 and potential applicability in tumour virotherapy.
465	N461		Erin K. Bailey, Joel E. Kamper & Becky Gius	Anticipated Long-Term Neurobehavioral Outcomes Following COVID-19	https://doi.org/10.1007/978-3-031-08045-6_30	Published	09 September 2022	Article	https://link.springer.com/chapter/10.1007/978-3-031-08045-6_30	First identified in December 2021, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)—the virus causing COVID-19, is responsible for significant morbidity and mortality rates. Given the worldwide impact of COVID-19, there is much interest in the anticipated long-term effects for those with history of SARS-CoV-2 infection. While initially presumed as a respiratory infection, there is now evidence of a broader array of pathophysiological mechanisms which result in a wide spectrum of reported acute and chronic symptoms in patients with confirmed COVID-19. These include including memory and other neurocognitive changes as well as psychiatric and behavioral symptoms. These nonspecific, but often debilitating, sequalaeare complex and difficult to disentangle from more common causes of neurobehavioral change. The goal of this chapter is to discuss anticipated chronic neurocognitive and psychiatric outcomes of COVID-19 survivors based on emerging peer-reviewed literature, data from prior pandemics, and outcome studies from well-characterized, clinically similar syndromes. This unpacking of long-term complications from COVID-19 will seek to set expectations and provide guidance for clinicians who will undoubtably encounter increased volumes of patients with residual post-COVID-19 neurobehavioral changes.
466	N462		Walter J. Lukiw 1,2,3,4,*,Vivian R. Jaber 1,Aileen I. Pogue 2 andYuhai Zhao 1,5	SARS-CoV-2 Invasion and Pathological Links to Prion Disease	https://doi.org/10.3390/biom12091253	Published	7 September 2022	Commentary	https://www.mdpi.com/2218-273X/12/9/1253/htm	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 disease, is a highly infectious and transmissible viral pathogen that continues to impact human health globally. Nearly ~600 million people have been infected with SARS-CoV-2, and about half exhibit some degree of continuing health complication, generically referred to as long COVID. Lingering and often serious neurological problems for patients in the post-COVID-19 recovery period include brain fog, behavioral changes, confusion, delirium, deficits in intellect, cognition and memory issues, loss of balance and coordination, problems with vision, visual processing and hallucinations, encephalopathy, encephalitis, neurovascular or cerebrovascular insufficiency, and/or impaired consciousness. Depending upon the patient’s age at the onset of COVID-19 and other factors, up to ~35% of all elderly COVID-19 patients develop a mild-to-severe encephalopathy due to complications arising from a SARS-CoV-2-induced cytokine storm and a surge in cytokine-mediated pro-inflammatory and immune signaling. In fact, this cytokine storm syndrome: (i) appears to predispose aged COVID-19 patients to the development of other neurological complications, especially those who have experienced a more serious grade of COVID-19 infection; (ii) lies along highly interactive and pathological pathways involving SARS-CoV-2 infection that promotes the parallel development and/or intensification of progressive and often lethal neurological conditions, and (iii) is strongly associated with the symptomology, onset, and development of human prion disease (PrD) and other insidious and incurable neurological syndromes. This commentary paper will evaluate some recent peer-reviewed studies in this intriguing area of human SARS-CoV-2-associated neuropathology and will assess how chronic, viral-mediated changes to the brain and CNS contribute to cognitive decline in PrD and other progressive, age-related neurodegenerative disorders.
467	N463		Emma Kavanagh	Long Covid brain fog: a neuroinflammation phenomenon?	https://doi.org/10.1093/oxfimm/iqac007	Published	27 September 2022	Article	https://academic.oup.com/ooim/advance-article/doi/10.1093/oxfimm/iqac007/6722625	Long Covid is an ongoing problem for large numbers of survivors of SARS-CoV-2 infection. One of its more significant, and as yet under explored symptoms is brain fog. Here we discuss the role of brain fog in Long Covid symptomatology, and consider the impact of this reduction in cognitive function in terms of a Long Covid patient narrative. We then consider the mechanisms likely to contribute to these effects, discussing neuroinflammation and the effects that the activation of microglia can have on cognitive processes, such as learning, memory and emotional regulation.1 Inflammatory cytokines have been found to play a significant role in reductions in LTP and LTD2, a reduction in neurogenesis3, and in dendritic sprouting4. We consider the role of these systems in the cognitive challenges posed by brain fog, and its effects on learning, memory, emotional regulation and the gender disparity noted in the diagnosis of Long Covid. It is hoped that this article will allow for greater examination of the effects of inflammatory factors on brain function, most particularly in terms of their role in chronic conditions.
468	N464		Peter Novak, Matthew P. Giannetti, Emily Weller, Matthew J. Hamilton, Shibani S. Mukerji, Haitham S. Alabsi, David Systrom, Sadie P. Marciano, Donna Felsenstein, William J. Mullally, David M. Pilgrim & Mariana Castells	Network autonomic analysis of post-acute sequelae of COVID-19 and postural tachycardia syndrome	https://doi.org/10.1007/s10072-022-06423-y	Published	28 September 2022	Study	https://link.springer.com/article/10.1007/s10072-022-06423-y	Background The autonomic nervous system (ANS) is a complex network where sympathetic and parasympathetic domains interact inside and outside of the network. Correlation-based network analysis (NA) is a novel approach enabling the quantification of these interactions. The aim of this study is to assess the applicability of NA to assess relationships between autonomic, sensory, respiratory, cerebrovascular, and inflammatory markers on post-acute sequela of COVID-19 (PASC) and postural tachycardia syndrome (POTS). Methods In this retrospective study, datasets from PASC (n = 15), POTS (n = 15), and matched controls (n = 11) were analyzed. Networks were constructed from surveys (autonomic and sensory), autonomic tests (deep breathing, Valsalva maneuver, tilt, and sudomotor test) results using heart rate, blood pressure, cerebral blood flow velocity (CBFv), capnography, skin biopsies for assessment of small fiber neuropathy (SFN), and various inflammatory markers. Networks were characterized by clusters and centrality metrics. Results Standard analysis showed widespread abnormalities including reduced orthostatic CBFv in 100%/88% (PASC/POTS), SFN 77%/88%, mild-to-moderate dysautonomia 100%/100%, hypocapnia 87%/100%, and elevated inflammatory markers. NA showed different signatures for both disorders with centrality metrics of vascular and inflammatory variables playing prominent roles in differentiating PASC from POTS. Conclusions NA is suitable for a relationship analysis between autonomic and nonautonomic components. Our preliminary analyses indicate that NA can expand the value of autonomic testing and provide new insight into the functioning of the ANS and related systems in complex disease processes such as PASC and POTS.
469	N465		Urvish K. Patel, Neev Mehta, Amrapali Patel, Neel Patel, Juan Fernando Ortiz, Mahika Khurana, Eseosa Urhoghide, Akshada Parulekar, Arpita Bhriguvanshi, Nidhi Patel, Anuja Mahesh Mistry, Rutul Patel, Kogulavadanan Arumaithurai, Shamik Shah	Long-Term Neurological Sequelae Among Severe COVID-19 Patients: A Systematic Review and Meta-Analysis	https://doi.org/10.7759/cureus.29694	Published	September 28, 2022	Systematic Review and Meta-Analysis	https://www.cureus.com/articles/110766-long-term-neurological-sequelae-among-severe-covid-19-patients-a-systematic-review-and-meta-analysis	Few studies have thoroughly evaluated the neuro-invasive effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which may contribute to a wide range of sequelae from mild long-term effects like headaches and fatigue to severe events like stroke and arrhythmias. Our study aimed to evaluate the long-term neurological effects of coronavirus disease 2019 (COVID-19) among patients discharged from the hospital. In this systematic review and meta-analysis, we assessed the long-term neurocognitive effects of COVID-19. Post-COVID-19 neurological sequelae were defined as persistent symptoms of headache, fatigue, myalgia, anosmia, dysgeusia, sleep disturbance, issues with concentration, post-traumatic stress disorder (PTSD), suicidality, and depression long after the acute phase of COVID-19. Data from observational studies describing post-COVID-19 neurocognitive sequelae and severity of COVID-19 from September 1, 2019, to the present were extracted following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol with a consensus of three independent reviewers. A systematic review was performed for qualitative evaluation and a meta-analysis was performed for quantitative analysis by calculating log odds of COVID-19 neurocognitive sequelae. The odds ratio (OR) and 95% confidence interval (CI) were obtained and forest plots were created using random effects models. We found seven studies, out of which three were used for quantitative synthesis of evidence. Of the 3,304 post-COVID-19 patients identified, 50.27% were male with a mean age of 56 years; 20.20% had post-COVID-19 symptoms more than two weeks after the acute phase of infection. Among persistence symptoms, neurocognitive symptoms like headache (27.8%), fatigue (26.7%), myalgia (23.14%), anosmia (22.8%), dysgeusia (12.1%), sleep disturbance (63.1%), confusion (32.6%), difficulty to concentrate (22%), and psychiatric symptoms like PTSD (31%), feeling depressed (20%), and suicidality (2%) had a higher prevalence. In meta-analysis, COVID-19 patients with severe symptoms had higher odds of headache (pooled OR: 4.53; 95% CI: 2.37-8.65; p<0.00001; I2: 0%) and myalgia (pooled OR: 3.36; 95% CI: 2.71-4.17; p<0.00001; I2: 0%). Anosmia, fatigue, and dysgeusia had higher but non-significant odds following COVID-19. Although we had sufficient data for headache and fatigue to identify higher rates and associations following COVID-19, we could not establish relationships with other post-COVID-19 neurocognitive séqueles. Long-term follow-up may mitigate the neurocognitive effects among COVID-19 patients as these symptoms are also associated with a poor quality of life.
470	N466		Waldemar Brola & Maciej Wilski	Neurological consequences of COVID-19	https://doi.org/10.1007/s43440-022-00424-6	Published	30 September 2022	Review	https://link.springer.com/article/10.1007/s43440-022-00424-6	In December 2019, cases of pneumonia caused by infection with the previously unknown severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), leading to coronavirus disease 2019 (COVID-19), were identified. Typical manifestations of COVID-19 are fever, cough, fatigue and dyspnoea. Initially, it was thought that the mechanism of action of SARS-CoV-2 was only associated with respiratory tract invasion, but it was later revealed that the infection might involve many other organs and systems, including the central and peripheral nervous systems. Neurological complications associated with SARS-CoV-2 infection include encephalopathy, encephalitis, meningitis, acute disseminated encephalomyelitis (ADEM), ischaemic and haemorrhagic stroke and cerebral venous sinus thrombosis. In cases of peripheral nervous system involvement, smell and taste disorders, myopathy or the signs and symptoms of Guillain‒Barré syndrome are observed. The most common early neurological complications, particularly during the first year of the epidemic, were anosmia and taste disorders, which, according to some studies, occurred in over 80 percent of patients with COVID-19. The proportion of patients with serious neurological manifestations was small compared to the global number of patients, but the numbers of SARS-CoV-2 infections and critical patients increased substantially. The experience from 2 years of the pandemic has shown that approximately 13% of infected patients suffer from severe neurological complications. The relationship between SARS-CoV-2 and the nervous system is not only a cause of neurological complications in previously healthy individuals but also directly and indirectly affects the courses of many nervous system diseases.
471	N467		Max Oliver Mackay Walker Department of Biochemistry, School of Biomedical Science, University of Otago, Dunedin, New Zealand Katherine H Hall Department of General Practice and Rural Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand Katie Peppercorn Department of Biochemistry, School of Biomedical Science, University of Otago, Dunedin, New Zealand Warren Perry Tate	The significance of oxidative stress in the pathophysiology of Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)	https://doi.org/10.18103/mra.v10i9.3050	Published	Sep 20, 2022	Article	https://esmed.org/MRA/mra/article/view/3050	Long COVID is now well accepted as an ongoing post-viral syndrome resulting from infection of a single virus, the pandemic SARS-CoV-2. It mirrors the post-viral fatigue syndrome, Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, a global debilitating illness arising mainly from sporadic geographically-specific viral outbreaks, and from community endemic infections, but also from other stressors. Core symptoms of both syndromes are post-exertional malaise (a worsening of symptoms following mental or physical activity), pervasive fatigue, cognitive dysfunction (brain fog), and sleep disturbance. Long COVID patients frequently also suffer from shortness of breath, relating to the lung involvement of the SARS-CoV-2 virus. There is no universally accepted pathophysiology, or recognized biomarkers yet for Long COVID or indeed for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Clinical case definitions with very similar characteristics for each have been defined. Chronic inflammation, immune dysfunction, and disrupted energy production in the peripheral system has been confirmed in Long COVID and has been well documented in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Neuroinflammation occurs in the brain in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome as shown from a small number of positron emission tomography and magnetic resonance spectroscopy studies, and has now been demonstrated for Long COVID. Oxidative stress, an increase in reactive oxygen and reactive nitrogen species, and free radicals, has long been suggested as a potential cause for many of the symptoms seen in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, resulting from both activation of the brain’s immune system and dysregulation of mitochondrial function throughout the body. The brain as a high producer of energy may be particularly susceptible to oxidative stress. It has been shown in peripheral immune cells that the balanced production of proteins involved in regulation of the reactive oxygen species in mitochondria is disturbed in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Fluctuations in the chronic low level neuroinflammation during the ongoing course of Long COVID as well as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome have been proposed to cause the characteristic severe relapses in patients. This review explores oxidative stress as a likely significant contributor to the pathophysiology of Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, and the mechanisms by which oxidative stress could cause the symptoms seen in both syndromes. Treatments that could mitigate oxidative stress and thereby lessen the debilitating symptoms to improve the life of patients are discussed.
472	N468		Abdul Mannan Baig*, Nigel H. Greig, Joachim Gerlach, Prakash Salunke, Mark Fabrowski, Valentina Viduto, and Tazeen Ali	Underlying Causes and Treatment Modalities for Neurological Deficits in COVID-19 and Long-COVID	https://doi.org/10.1021/acschemneuro.2c00482	Published	October 3, 2022	Article	https://pubs.acs.org/doi/abs/10.1021/acschemneuro.2c00482	With reports of diverse neurological deficits in the acute phase of COVID-19, there is a surge in neurological findings in Long-COVID─a protracted phase of SARS-CoV-2 infection. Very little is known regarding the pathogenic mechanisms of Neuro-COVID in the above two settings in the current pandemic. Herein, we hint toward the possible molecular mechanism that can contribute to the signs and symptoms of patients with neurological deficits and possible treatment and prevention modalities in the acute and chronic phases of COVID-19.
473	N469		Maria CristineCamposTatyanaNeryAna CarolinaStarkeAna Cristinade Bem AlvesAna ElisaSpeckAderbalS Aguiar	Post-viral fatigue in COVID-19: A review of symptom assessment methods, mental, cognitive, and physical impairment	https://doi.org/10.1016/j.neubiorev.2022.104902	Published	3 October 2022	Review	https://www.sciencedirect.com/science/article/pii/S0149763422003918	Highlights •Fatigue is the main sequela of long COVID-19 and needs follow-up. •There are physical and mental manifestations of fatigue in long COVID-19. •This review presents the most used instruments in assessing fatigue in long COVID-19. •Muscle strength, walking, and functional tests assess physical fatigue in long COVID-19. •Executive function psychological tests assess mental fatigue in long COVID-19. Abstract Coronavirus 2 is responsible for Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2), and the main sequela is persistent fatigue. Post-viral fatigue is common and affects patients with mild, asymptomatic coronavirus disease-2019 (COVID-19). However, the exact mechanisms involved in developing post-COVID-19 fatigue remain unclear. Furthermore, physical and cognitive impairments in these individuals have been widely described. Therefore, this review aims to summarize and propose tools from a multifaceted perspective to assess COVID-19 infection. Herein, we point out the instruments that can be used to assess fatigue in long-term COVID-19: fatigue in a subjective manner or fatigability in an objective manner. For physical and mental fatigue, structured questionnaires were used to assess perceived symptoms, and physical and cognitive performance assessment tests were used to measure fatigability using reduced performance.
474	N470		Nikita Chhabra, Marie F. Grill & Rashmi B. Halker Singh	Post-COVID Headache: A Literature Review	https://doi.org/10.1007/s11916-022-01086-y	Published	05 October 2022	Review	https://link.springer.com/article/10.1007/s11916-022-01086-y	Purpose of Review Post-COVID headache may be unique in presentation and mechanism, often presenting as a new phenotype in patients with a history of a primary headache disorder or resulting in a new headache syndrome in those without history of headache. This review presents a description of the literature published focused on post-COVID headache. Additionally, we discuss potential mechanisms and considerations for treatment of post-COVID headache. Recent Findings Headache is one of the most common symptoms of COVID. Common characteristics are revealed when reviewing the phenotypes of headaches that have been described in patients with COVID-19, with most headache phenotypes resembling migraine and new persistent daily headache. Post-COVID headaches are often described as moderate to severe, persistent, and treatment refractory. Summary This review highlights the diversity of presentation of headaches that present as a complication of COVID-19. Treatment of post-COVID headache is challenging, especially in the setting of a pandemic where resources are limited. Clinical Case A 42-year-old woman with a history of episodic migraine without aura presents over video visit with a new headache type. Her typical headaches are predominantly left sided, throbbing in nature, and associated with photophobia and phonophobia. They are fully relieved by oral sumatriptan 2 h after treatment. She describes this new headache as a constant, pulsating, holocephalic pain with no other migrainous features that have been ongoing for 6 weeks. She notes that the headache has been persistent since that time. She has tried over-the-counter acetaminophen and ibuprofen and her typical migraine abortive therapy without relief. She is debilitated and wonders if there is anything that will take the pain away. She shares that she tested positive for COVID-19 about 2 days prior to headache onset and has associated rhinorrhea, anosmia, and ageusia.
475	N471	COA	Samudyata, Ana O. Oliveira, Susmita Malwade, Nuno Rufino de Sousa, Sravan K. Goparaju, Jessica Gracias, Funda Orhan, Laura Steponaviciute, Martin Schalling, Steven D. Sheridan, Roy H. Perlis, Antonio G. Rothfuchs & Carl M. Sellgren	SARS-CoV-2 promotes microglial synapse elimination in human brain organoids	https://doi.org/10.1038/s41380-022-01786-2	Published	05 October 2022	Study	https://www.nature.com/articles/s41380-022-01786-2	Neuropsychiatric manifestations are common in both the acute and post-acute phase of SARS-CoV-2 infection, but the mechanisms of these effects are unknown. In a newly established brain organoid model with innately developing microglia, we demonstrate that SARS-CoV-2 infection initiate neuronal cell death and cause a loss of post-synaptic termini. Despite limited neurotropism and a decelerating viral replication, we observe a threefold increase in microglial engulfment of postsynaptic termini after SARS-CoV-2 exposure. We define the microglial responses to SARS-CoV-2 infection by single cell transcriptomic profiling and observe an upregulation of interferon-responsive genes as well as genes promoting migration and synapse engulfment. To a large extent, SARS-CoV-2 exposed microglia adopt a transcriptomic profile overlapping with neurodegenerative disorders that display an early synapse loss as well as an increased incident risk after a SARS-CoV-2 infection. Our results reveal that brain organoids infected with SARS-CoV-2 display disruption in circuit integrity via microglia-mediated synapse elimination and identifies a potential novel mechanism contributing to cognitive impairments in patients recovering from COVID-19.
476	N472		MichelleMonje12AkikoIwasaki34	The Neurobiology of Long COVID	https://doi.org/10.1016/j.neuron.2022.10.006	Published	7 October 2022	Article	https://www.sciencedirect.com/science/article/pii/S0896627322009102	Persistent neurological and neuropsychiatric symptoms affect a substantial fraction of people after COVID-19 and represent a major component of the post-acute COVID syndrome, also known as long COVID. Here, we review what is understood about the pathobiology of post-acute COVID-19 impacts on the CNS and discuss possible neurobiological underpinnings of the cognitive symptoms affecting COVID-19 survivors. We propose the chief mechanisms that may contribute to this emerging neurological health crisis.
477	N473	COA	Evan Xu, Yan Xie & Ziyad Al-Aly	Long-term neurologic outcomes of COVID-19	https://doi.org/10.1038/s41591-022-02001-z	Published	22 September 2022	Study	https://www.nature.com/articles/s41591-022-02001-z	The neurologic manifestations of acute COVID-19 are well characterized, but a comprehensive evaluation of postacute neurologic sequelae at 1 year has not been undertaken. Here we use the national healthcare databases of the US Department of Veterans Affairs to build a cohort of 154,068 individuals with COVID-19, 5,638,795 contemporary controls and 5,859,621 historical controls; we use inverse probability weighting to balance the cohorts, and estimate risks and burdens of incident neurologic disorders at 12 months following acute SARS-CoV-2 infection. Our results show that in the postacute phase of COVID-19, there was increased risk of an array of incident neurologic sequelae including ischemic and hemorrhagic stroke, cognition and memory disorders, peripheral nervous system disorders, episodic disorders (for example, migraine and seizures), extrapyramidal and movement disorders, mental health disorders, musculoskeletal disorders, sensory disorders, Guillain–Barré syndrome, and encephalitis or encephalopathy. We estimated that the hazard ratio of any neurologic sequela was 1.42 (95% confidence intervals 1.38, 1.47) and burden 70.69 (95% confidence intervals 63.54, 78.01) per 1,000 persons at 12 months. The risks and burdens were elevated even in people who did not require hospitalization during acute COVID-19. Limitations include a cohort comprising mostly White males. Taken together, our results provide evidence of increased risk of long-term neurologic disorders in people who had COVID-19.
478	N474		Rahmouni Nesrine, Rosa-Neto Pedro & Brunet Alain	To the editor: Response to post-infection cognitive impairments in a cohort of elderly patients with COVID-19, by Wang, Y.J. et al. (2021)	https://doi.org/10.1186/s13024-022-00567-3	Published	25 September 2022	Letter to the Editor	https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-022-00567-3	Using spouses as a control group sounds like a good idea at first sight. However, the fact that spouses had to be in better health conditions for them not to catch COVID-19 when their partner did constitute an important bias. Over a third of the COVID-19 patients in this study had their spouses in the control group. The authors acknowledged this issue as one of their limitations and suggested that non-covid pneumonia patients would have been a better option to assess the COVID-19 specificity of the associations. We agree in principle but think that this wouldn’t be sufficient: Cheng et al. [2] reported a longer Intensive Care Unit (ICU) or hospital stay contributes significantly to the development of dementia in patients. Additionally, Katon et al. [3] reported similar results, showing that older adults who experienced acute and critical illness hospitalization had greater chances of cognitive decline compared with patients that were not hospitalized. In the present paper, the authors report that ICU admission is significantly associated with cognitive impairment and cognitive decline, and severe COVID-19 cases had higher frequency of ICU admission than non-severe COVID-19 cases and controls. For the authors to consider that the cognitive impairment and decline of patients in this study are due to their COVID-19 infection is far-fetched as it can be explained by their ICU admission [4]. A more adequate control group for this study would have been a non-COVID-19 ICU patient.
479	N475		RyanGreen125#KarthickMayilsamy15#Andrew R.McGill125TaylorMartinez15BalaChandran1Laura J.Blair135Paula C.Bickford45Shyam S.Mohapatra25SubhraMohapatra15	SARS-CoV-2 Infection Increases the Gene Expression Profile for Alzheimer’s Disease Risk	https://doi.org/10.1016/j.omtm.2022.09.007	Published	24 September 2022	Study	https://www.sciencedirect.com/science/article/pii/S2329050122001322	The COVID-19 pandemic has caused over 600,000,000 infections globally thus far. Up to 30 % of individuals with mild to severe disease develop long-COVID, exhibiting diverse neurologic symptoms including dementias. However, there is a paucity of knowledge of molecular brain markers, and whether these can precipitate the onset of Alzheimer’s disease (AD). Herein, we report the brain gene expression profiles of severe COVID-19 patients showing increased expression of innate immune response genes and genes implicated in AD pathogenesis. The use of a mouse-adapted strain of SARS CoV-2 (MA10) in an aged mouse model shows evidence of viral neurotropism, prolonged viral infection, increased expression of tau aggregator FKBP51, interferon-inducible gene Ifi204, and complement genes C4 and C5AR1. Brain histopathology showed AD signatures including increased tau-phosphorylation, tau-oligomerization, and α-synuclein expression in aged MA10 infected mice. The results of gene expression profiling of SARS CoV-2 infected and AD brains and studies in the MA10 aged mouse model taken together, for the first time provide evidence suggesting that SARS CoV-2 infection alters expression of genes in the brain associated with the development of AD. Future studies of common molecular markers in SARS CoV-2 infection and AD could be useful for developing novel therapies targeting AD.
480	N476	COA	Jolanta B.ZawilskaKatarzynaKuczyńska	Psychiatric and neurological complications of long COVID	https://doi.org/10.1016/j.jpsychires.2022.10.045	Published	20 October 2022	Review	https://www.sciencedirect.com/science/article/pii/S0022395622005982	Highlights •Apart from respiratory tract, COVID-19 affects nervous system. •Psychiatric and neurological symptoms of COVID-19 may persist for over 24 weeks. •Long COVID mostly affects adults but it may be observed in children and adolescents. •Chronic fatigue, depression, anxiety and cognitive deficits are the most common symptoms of long COVID. •Patients with long COVID may demonstrate brain hypometabolism. COVID-19 was primarily considered a pulmonary disease with extrapulmonary manifestations. As the pandemic spread, there has been growing evidence that the disease affects various organs/systems, including the central and peripheral nervous systems. Accumulation of clinical data demonstrates that in a large population of survivors impairments in the function of one or more organs may persist for a long time, a phenomenon commonly known as post COVID or long COVID. Fatigue and cognitive dysfunction, such as concentration problems, short-term memory deficits, general memory loss, a specific decline in attention, language and praxis abilities, encoding and verbal fluency, impairment of executive functions, and psychomotor coordination, are amongst the most common and debilitating features of neuropsychatric symptoms of post COVID syndrome. Several patients also suffer from compromised sleep, depression, anxiety and post-traumatic stress disorder. Patients with long COVID may demonstrate brain hypometabolism, hypoperfusion of the cerebral cortex and changes in the brain structure and functional connectivity. Children and adolescents represent a minority of COVID-19 cases, so not surprisingly data on the long-term sequelae after SARS-CoV-2 infections in these age groups are scarce. Although the pathogenesis, clinical characteristics, epidemiology, and risk factors of the acute phase of COVID-19 have been largely explained, these areas are yet to be explored in long COVID. This review aims to provide an update on what is currently known about long COVID effects on mental health.
481	N477		Dr Alexander Grundmann MD,Dr Chieh-Hsi Wu PhD,Dr Marc Hardwick MD,Prof J Kenneth Baillie MD PhD,Prof Peter JM Openshaw MD PhD,Prof Malcolm G Semple MD PhD,Prof Dankmar Böhning PhD,Prof Sarah Pett MD PhD,Dr Benedict D Michael MD PhD,Dr Rhys H Thomas MD PhD,Prof Ian Galea MD PhD,	Fewer COVID-19 neurological complications with dexamethasone and remdesivir	https://doi.org/10.1002/ana.26536	Published	19 October 2022	Study	https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.26536	Objective To assess the impact of treatment with dexamethasone, remdesivir or both on neurological complications in acute COVID-19. Methods We used observational data from the International Severe Acute and emerging Respiratory Infection Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK). Hospital inpatients aged ≥18 years with laboratory-confirmed SARS-CoV-2 infection admitted between 31 January 2020 and 29 June 2021 were included. Treatment allocation was non-blinded and performed by reporting clinicians. A propensity scoring methodology was used to minimize confounding. Treatment with remdesivir, dexamethasone or both was assessed against standard of care. The primary outcome was a neurological complication occurring at the point of death, discharge, or resolution of the COVID-19 clinical episode. Results Out of 89,297 hospital inpatients, 64,088 had severe COVID-19 and 25,209 had non-hypoxic COVID-19. Neurological complications developed in 4.8% and 4.5% respectively. In both groups, neurological complications associated with increased mortality, ICU admission, worse self-care on discharge and time to recovery. In severe COVID-19, treatment with dexamethasone (n=21,129), remdesivir (n=1,428) and both combined (n=10,846) associated with a lower frequency of neurological complications: OR=0.76 (95% CI=0.69-0.83), OR 0.69 (95% CI=0.51-0.90) and OR=0.54, (95% CI=0.47-0.61) respectively. In non-hypoxic COVID-19, dexamethasone (n=2,580) associated with less neurological complications (OR=0.78, 95% CI 0.62-0.97), while the dexamethasone/remdesivir combination (n=460) showed a similar trend (OR=0.63, 95% CI=0.31-1.15). Interpretation Treatment with dexamethasone, remdesivir or both in patients hospitalised with COVID-19 associated with a lower frequency of neurological complications in an additive manner, such that the greatest benefit was observed in patients who received both drugs together.
482	N478		María Díez-Cirarda, Miguel Yus, Natividad Gómez-Ruiz, Carmen Polidura, Lidia Gil-Martínez, Cristina Delgado-Alonso, Manuela Jorquera, Ulises Gómez-Pinedo, Jorge Matias-Guiu, Juan Arrazola, Jordi A Matias-Guiu	Multimodal neuroimaging in post-COVID syndrome and correlation with cognition	https://doi.org/10.1093/brain/awac384	Published	26 October 2022	Study	https://academic.oup.com/brain/advance-article-abstract/doi/10.1093/brain/awac384/6775147	Brain changes have been reported in the first weeks after SARS-CoV-2 infection. However, limited literature exists about brain alterations in post-COVID syndrome, a condition increasingly associated with cognitive impairment. The present study aimed to evaluate brain functional and structural alterations in patients with post-COVID syndrome, and assess whether these brain alterations were related to cognitive dysfunction. Eighty-six patients with post-COVID syndrome and 36 healthy controls were recruited and underwent neuroimaging acquisition and a comprehensive neuropsychological assessment. Cognitive and neuroimaging examinations were performed 11 months after the first symptoms of SARS-CoV-2. Whole-brain functional connectivity analysis was performed. Voxel-based morphometry was performed to evaluate grey matter volume, and diffusion tensor imaging was carried out to analyse white matter alterations. Correlations between cognition and brain changes were conducted and Bonferroni corrected. Post-COVID syndrome patients presented with functional connectivity changes, characterized by hypoconnectivity between left and right parahippocampal areas, and between bilateral orbitofrontal and cerebellar areas compared to controls. These alterations were accompanied by reduced grey matter volume in cortical, limbic and cerebellar areas, and alterations in white matter axial and mean diffusivity. Grey matter volume loss showed significant associations with cognitive dysfunction. These cognitive and brain alterations were more pronounced in hospitalized patients compared to non-hospitalized patients. No associations with vaccination status were found. The present study shows persistent structural and functional brain abnormalities 11 months after the acute infection. These changes are associated with cognitive dysfunction and contribute to a better understanding of the pathophysiology of the post-COVID syndrome.
483	N479		Dovile Stankevice MD,Alexander Wieck Fjaeldstad MD, PhD,Jane Agergaard MD, PhD,Therese Ovesen MD, DMSc	Long-Term COVID-19 Smell and Taste Disorders Differ Significantly from Other Post-Infectious Cases	https://doi.org/10.1002/lary.30453	Published	28 October 2022	Study	https://onlinelibrary.wiley.com/doi/10.1002/lary.30453	Introduction COVID-19 is causing a wide range of clinical manifestations. Severe complications and long-lasting sequelae have been identified. Thus, olfactory disorders are reported in up to 86% of cases in mild and moderate COVID-19 infections. We present the first study comparing simple and complex post-COVID-19 cases with matched non-COVID-19 post-infectious smell and taste disorders. Methods A total of 328 patients were recruited from the University Clinic for Flavour, Balance and Sleep, Ear-nose-throat Department, Goedstrup Hospital, Denmark. A non-COVID -19 post-infectious population of 148 individuals was identified from the Redcap database, and was matched by duration of smell and taste disorders. Post-COVID-19 patients were divided into 99 patients with simple smell and taste disorders (only suffering from smell and taste disorders after COVID-19); and (81 patients with complex smell and taste disorder plus several other post-COVID-19 complaints). Besides patient-reported outcome measures (PROM) questionnaires and quality of life score (QoL), ear-nose-throat examination, Mini-Mental State Examination (MMSE), orthonasal smell test (Sniffing's sticks), retronasal quick test, and taste screening were performed. Results Cases with post-COVID-19-related smell and taste disorders deviated from non-COVID-19 post-infectious cases; the patients were younger, had a lower occurrence of anosmia/ageusia, and had higher overall smell test scores. In contrast, patients with post-COVID-19-related smell and taste disorders more frequently complained of distorted senses. Parosmia and phantosmia were more prevalent among patients with simple post-COVID-19 complaints than among complex cases and their QoL were more negatively affected. Conclusion Smell and taste function differ significantly between post-COVID-19 and other non-COVID-19 post-viral cases.
484	N480		Marissa Alvarez†, Erick Trent†, Bruno De Souza Goncalves, Duane G. Pereira, Raghav Puri, Nicolas Anthony Frazier, Komal Sodhi and Sneha S. Pillai*	Cognitive dysfunction associated with COVID-19: Prognostic role of circulating biomarkers and microRNAs	https://doi.org/10.3389/fnagi.2022.1020092	Published	04 October 2022	Review	https://www.frontiersin.org/articles/10.3389/fnagi.2022.1020092/full	COVID-19 is renowned as a multi-organ disease having subacute and long-term effects with a broad spectrum of clinical manifestations. The evolving scientific and clinical evidence demonstrates that the frequency of cognitive impairment after COVID-19 is high and it is crucial to explore more clinical research and implement proper diagnostic and treatment strategies. Several central nervous system complications have been reported as comorbidities of COVID-19. The changes in cognitive function associated with neurodegenerative diseases develop slowly over time and are only diagnosed at an already advanced stage of molecular pathology. Hence, understanding the common links between COVID-19 and neurodegenerative diseases will broaden our knowledge and help in strategizing prognostic and therapeutic approaches. The present review focuses on the diverse neurodegenerative changes associated with COVID-19 and will highlight the importance of major circulating biomarkers and microRNAs (miRNAs) associated with the disease progression and severity. The literature analysis showed that major proteins associated with central nervous system function, such as Glial fibrillary acidic protein, neurofilament light chain, p-tau 181, Ubiquitin C-terminal hydrolase L1, S100 calcium-binding protein B, Neuron-specific enolase and various inflammatory cytokines, were significantly altered in COVID-19 patients. Furthermore, among various miRNAs that are having pivotal roles in various neurodegenerative diseases, miR-146a, miR-155, Let-7b, miR-31, miR-16 and miR-21 have shown significant dysregulation in COVID-19 patients. Thus the review consolidates the important findings from the numerous studies to unravel the underlying mechanism of neurological sequelae in COVID-19 and the possible association of circulatory biomarkers, which may serve as prognostic predictors and therapeutic targets in future research.
485	N481		M. AymanHaykalDaniel L.Menkes	The Clinical Neurophysiology of COVID-19- Direct Infection, Long-Term Sequelae and Para-Immunization responses: A literature review	https://doi.org/10.1016/j.cnp.2022.09.005	Published	17 October 2022	Review	https://www.sciencedirect.com/science/article/pii/S2467981X22000397	Highlights •Several neurophysiological techniques are useful in evaluating neurological symptoms related to SARS-CoV-2 infection but cannot affirm a causative association. •There is no specific electrodiagnostic signature that is pathognomonic for SARS-CoV-2 infection, possible vaccination side effects against SARS-CoV-2 or “long COVID”. •However, clinical neurophysiology modalities have a role in the evaluation of “long COVID” as they may provide objective validation of the patient's reported symptoms. Abstract The COVID-19 pandemic resulting from the SARS-CoV-2 virus is in its third year. There is continuously evolving information regarding its pathophysiology and its effects on the nervous system. Clinical neurophysiology techniques are commonly employed to assess for neuroanatomical localization and/or defining the spectrum of neurological illness. There is an evolving body of literature delineating the effects of the SARS-CoV-2 virus on the nervous system as well as para-immunization responses to vaccination against this virus. This review focuses on the use of neurophysiological diagnostic modalities in the evaluation of potential acute and long-term neurological complications in patients that experience direct infection with SARS-CoV-2 and analyzes those reports of para-immunization responses to vaccination against the SARS-CoV-2 virus. The neurophysiological modalities to be discussed include electroencephalography (EEG), evoked potentials (EPs), nerve conduction studies and electromyography (EMG/NCV), autonomic function tests, transcranial magnetic stimulation (TMS) and Transcranial Doppler ultrasound (TCD).
486	N482		César Fernández-de-las-Peñas 1,2,*ORCID,Jo Nijs 3,4,5ORCID,Randy Neblett 6ORCID,Andrea Polli 3,7,8ORCID,Maarten Moens 3,9,10,11,12ORCID,Lisa Goudman 3,7,9,10,11ORCID,Madhura Shekhar Patil 8,Roger D. Knaggs 13,Gisele Pickering 14,15 andLars Arendt-Nielsen 2,16	Phenotyping Post-COVID Pain as a Nociceptive, Neuropathic, or Nociplastic Pain Condition	https://doi.org/10.3390/biomedicines10102562	Published	13 October 2022	Review	https://www.mdpi.com/2227-9059/10/10/2562/htm	Pain after an acute Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) condition (post-COVID pain) is becoming a new healthcare emergency. Precision medicine refers to an evidence-based method of grouping patients based on their diagnostic/symptom presentation and then tailoring specific treatments accordingly. Evidence suggests that post-COVID pain can be categorized as nociceptive (i.e., pain attributable to the activation of the peripheral receptive terminals of primary afferent neurons in response to noxious chemical, mechanical, or thermal stimuli), neuropathic (i.e., pain associated with a lesion or disease of the somatosensory nervous system and limited to a “neuroanatomically plausible” distribution of the system), nociplastic (i.e., pain arising from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain), or mixed type (when two pain phenotypes co-exist). Each of these pain phenotypes may require a different treatment approach to maximize treatment effectiveness. Accordingly, the ability to classify post-COVID pain patients into one of these phenotypes would likely be critical for producing successful treatment outcomes. The 2021 International Association for the Study of Pain (IASP) clinical criteria and grading system provide a framework for classifying pain within a precision pain medicine approach. Here we present data supporting the possibility of grouping patients with post-COVID pain into pain phenotypes, using the 2021 IASP classification criteria, with a specific focus on nociplastic pain, which is probably the primary mechanism involved in post-COVID pain. Nociplastic pain, which is usually associated with comorbid symptomology (e.g., poor sleep quality, fatigue, cognitive–emotional disturbances, etc.) and is considered to be more difficult to treat than other pain types, may require a more nuanced multimodal treatment approach to achieve better treatment outcomes.
487	N483		Marino Marcic 1,*ORCID,Ljiljana Marcic 2,3,Sanja Lovric Kojundzic 4ORCID,Maja Marinovic Guic 3,4,Barbara Marcic 5 andKresimir Caljkusic 1	Chronic Endothelial Dysfunction after COVID-19 Infection Shown by Transcranial Color-Coded Doppler: A Cross-Sectional Study	https://doi.org/10.3390/biomedicines10102550	Published	13 October 2022	Study	https://www.mdpi.com/2227-9059/10/10/2550/htm	In addition to respiratory symptoms, COVID-19 often causes damage to many other organs, especially in severe forms of the disease. Long-term consequences after COVID-19 are common and often have neurological symptoms. Cerebral vasoreactivity may be impaired after acute COVID-19 and in our study, we wanted to show how constant and reversible are the changes in brain vasoreactivity after infection. This cross-sectional observational study included 49 patients diagnosed with COVID-19 and mild neurological symptoms 300 days after the onset of the disease. We used a transcranial color-coded Doppler (TCCD) and a breath-holding test (BHT) to examine cerebral vasoreactivity and brain endothelial function. We analyzed the parameters of the flow rate through the middle cerebral artery (MCA): peak systolic velocity (PSV), end-diastolic velocity (EDV), mean velocity (MV), resistance index (RI) and pulsatility index (PI), and we calculated the breath-holding index (BHI). Subjects after COVID-19 infection had lower measured velocity parameters through MCA at rest period and after BHT, lower relative increases of flow velocities after BHT, and lower BHI. We showed that subjects, 300 days after COVID-19, still have impaired cerebral vasoreactivity measured by TCCD and they have chronic endothelial dysfunction.
488	N484		Concetta Mezzatesta 1,*ORCID,Sara Bazzano 2,Rosa Gesualdo 2,Simone Marchese 1,Maria Luisa Savona 1,Mario Tambone Reyes 3 andVincenzo Provenzano 2	Neurocognitive Disorders in Post and Long Covid Patients: Preliminary Data, Gender Differences and New Diabetes Diagnosis	https://doi.org/10.3390/diabetology3040039	Published	6 October 2022	Study	https://www.mdpi.com/2673-4540/3/4/39/htm	The research is based on a clinical observation of the neurological and neuro-cognitive status of 300 patients, belonging to the Partinico Hospital and the Post-Long Covid clinic, which had contracted the SARS-CoV-2 virus in the period between April 2021 and May 2022. In this paper, we present the analysis of the first 100 patients subjected to a neurocognitive screening protocol. The procedure consists of tests that examine the mechanism of different brain domains to check for the presence of cognitive deficits that arose after the negativization of the viral infection. Through a neurocognitive protocol, the research aims to investigate different brain areas and mental functioning. This allowed us to raise the possibility that the presence of cognitive alterations may be related to the evidence of point-like brain alterations (from the cortex to the trunk) visible through neuroimaging techniques. In the article, we highlight the hypothesis that SARS-covid 2, as stated in recently published studies, can produce an alteration of executive functions such as to configure a real dysexecutive syndrome. This research evaluates the symptomatic gender variability within the sample, the presence of important differences in the affective state, and provides a first observation of the impact of SARS-CoV-2 in diabetic pathology as well.
489	N485		Genaro Gabriel Ortiz 1ORCID,Irma E. Velázquez-Brizuela 1,Genaro E. Ortiz-Velázquez 2,María J. Ocampo-Alfaro 3,Joel Salazar-Flores 4,Daniela L. C. Delgado-Lara 1,5,ORCID andErandis D. Torres-Sanchez 4,ORCID	Alzheimer’s Disease and SARS-CoV-2: Pathophysiological Analysis and Social Context	https://doi.org/10.3390/brainsci12101405	Published	18 October 2022	Review	https://www.mdpi.com/2076-3425/12/10/1405/htm	The COVID-19 pandemic has proven to be a challenge for healthcare systems, especially in terms of the care of patients with Alzheimer’s disease (AD). Age is one of the major risk factors for severe forms of COVID-19, most probably due to the presence of comorbidities and inflammations. It is known that SARS-CoV-2 invades nerve endings and olfactory nerves through the binding of the spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor. This interaction triggers an inflammatory cascade that results in cognitive impairment. In turn, the isoform of apolipoprotein-E4 (APOE-4ε) in AD is a risk factor for increased neuroinflammation through microglia activation, increased oxidative stress, and neurodegeneration. AD and SARS-CoV-2 are associated with increases in levels of inflammatory markers, as well as increases in levels of APOE-4ε, ACE2 and oxidative stress. Thus, there is a synergistic relationship between AD and SARS-CoV-2. In addition, the social isolation and other health measures resulting from the pandemic have led to a higher level of anxiety and depression among AD patients, a situation which may lead to a decline in cognitive function. Therefore, there is a need to develop strategies for keeping the patient calm but active.
490	N486		Laura de Boni, Alexandru Odainic, Natalie Gancarczyk, Luisa Kaluza, Christian P. Strassburg, Xenia A. K. Kersting, Joseph M. Johnson, Ullrich Wüllner, Susanne V. Schmidt, Jacob Nattermann & Gabor C. Petzold	No serological evidence for neuronal damage or reactive gliosis in neuro-COVID-19 patients with long-term persistent headache	https://doi.org/10.1186/s42466-022-00217-5	Published	31 October 2022	Study	https://neurolrespract.biomedcentral.com/articles/10.1186/s42466-022-00217-5	Recent studies have indicated that long-term neurological sequelae after COVID-19 are not accompanied by an increase of canonical biomarkers of central nervous system injury in blood, but subgroup stratifications are lacking. This is a particular concern in chronic headache, which can be a leading symptom of Post-COVID diseases associated with neuronal damage such as vasculitis or autoimmune encephalitis. We here compared patients with mild Post-COVID-19 syndrome and persistent headache (persistent Post-COVID-19 headache) lasting longer than 12 weeks after the initial serological diagnosis, to patients with mild and severe COVID-19 and COVID-19-negative controls. Levels of neurofilament light chain and glial fibrillary astrocytic protein, i.e. markers of neuronal damage and reactive astrogliosis, were lower in blood from patients with persistent Post-COVID-19 headache compared to patients with severe COVID-19. Hence, our pilot serological study indicates that long-term Post-COVID-19 headache may not be a sign of underlying neuronal damage or neuroinflammation.
491	N487		Eduardo A. Albornoz, Alberto A. Amarilla, Naphak Modhiran, Sandra Parker, Xaria X. Li, Danushka K. Wijesundara, Julio Aguado, Adriana Pliego Zamora, Christopher L. D. McMillan, Benjamin Liang, Nias Y. G. Peng, Julian D. J. Sng, Fatema Tuj Saima, Jenny N. Fung, John D. Lee, Devina Paramitha, Rhys Parry, Michael S. Avumegah, Ariel Isaacs, Martin W. Lo, Zaray Miranda-Chacon, Daniella Bradshaw, Constanza Salinas-Rebolledo, Niwanthi W. Rajapakse, Ernst J. Wolvetang, Trent P. Munro, Alejandro Rojas-Fernandez, Paul R. Young, Katryn J. Stacey, Alexander A. Khromykh, Keith J. Chappell, Daniel Watterson & Trent M. Woodruff Show fewer authors	SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein	https://doi.org/10.1038/s41380-022-01831-0	Published	01 November 2022	Study	https://www.nature.com/articles/s41380-022-01831-0	Coronavirus disease-2019 (COVID-19) is primarily a respiratory disease, however, an increasing number of reports indicate that SARS-CoV-2 infection can also cause severe neurological manifestations, including precipitating cases of probable Parkinson’s disease. As microglial NLRP3 inflammasome activation is a major driver of neurodegeneration, here we interrogated whether SARS-CoV-2 can promote microglial NLRP3 inflammasome activation. Using SARS-CoV-2 infection of transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) as a COVID-19 pre-clinical model, we established the presence of virus in the brain together with microglial activation and NLRP3 inflammasome upregulation in comparison to uninfected mice. Next, utilising a model of human monocyte-derived microglia, we identified that SARS-CoV-2 isolates can bind and enter human microglia in the absence of viral replication. This interaction of virus and microglia directly induced robust inflammasome activation, even in the absence of another priming signal. Mechanistically, we demonstrated that purified SARS-CoV-2 spike glycoprotein activated the NLRP3 inflammasome in LPS-primed microglia, in a ACE2-dependent manner. Spike protein also could prime the inflammasome in microglia through NF-κB signalling, allowing for activation through either ATP, nigericin or α-synuclein. Notably, SARS-CoV-2 and spike protein-mediated microglial inflammasome activation was significantly enhanced in the presence of α-synuclein fibrils and was entirely ablated by NLRP3-inhibition. Finally, we demonstrate SARS-CoV-2 infected hACE2 mice treated orally post-infection with the NLRP3 inhibitory drug MCC950, have significantly reduced microglial inflammasome activation, and increased survival in comparison with untreated SARS-CoV-2 infected mice. These results support a possible mechanism of microglial innate immune activation by SARS-CoV-2, which could explain the increased vulnerability to developing neurological symptoms akin to Parkinson’s disease in COVID-19 infected individuals, and a potential therapeutic avenue for intervention.
492	N488		François Goehringer, Alexandra Bruyere, Matthieu Doyen, Sibylle Bevilacqua, Alexandre Charmillon, Sebastien Heyer & Antoine Verger	Brain 18F-FDG PET imaging in outpatients with post-COVID-19 conditions: findings and associations with clinical characteristics	https://doi.org/10.1007/s00259-022-06013-2	Published	02 November 2022	Study	https://link.springer.com/article/10.1007/s00259-022-06013-2	Background Brain 18F-FDG PET imaging has the potential to provide an objective assessment of brain involvement in post-COVID-19 conditions but previous studies of heterogeneous patient series yield inconsistent results. The current study aimed to investigate brain 18F-FDG PET findings in a homogeneous series of outpatients with post-COVID-19 conditions and to identify associations with clinical patient characteristics. Methods We retrospectively included 28 consecutive outpatients who presented with post-COVID-19 conditions between September 2020 and May 2022 and who satisfied the WHO definition, and had a brain 18F-FDG PET for suspected brain involvement but had not been hospitalized for COVID-19. A voxel-based group comparison with 28 age- and sex-matched healthy controls was performed (p-voxel at 0.005 uncorrected, p-cluster at 0.05 FWE corrected) and identified clusters were correlated with clinical characteristics. Results Outpatients with post-COVID-19 conditions exhibited diffuse hypometabolism predominantly involving right frontal and temporal lobes including the orbito-frontal cortex and internal temporal areas. Metabolism in these clusters was inversely correlated with the number of symptoms during the initial infection (r = − 0.44, p = 0.02) and with the duration of symptoms (r = − 0.39, p = 0.04). Asthenia and cardiovascular, digestive, and neurological disorders during the acute phase and asthenia and language disorders during the chronic phase (p ≤ 0.04) were associated with these hypometabolic clusters. Conclusion Outpatients with post-COVID-19 conditions exhibited extensive hypometabolic right fronto-temporal clusters. Patients with more numerous symptoms during the initial phase and with a longer duration of symptoms were at higher risk of persistent brain involvement.
493	N489		Elena Rossi 1,Luciano Mutti 2,3,4ORCID,Andrea Morrione 2,ORCID andAntonio Giordano 1,2,ORCID	Neuro–Immune Interactions in Severe COVID-19 Infection	https://doi.org/10.3390/pathogens11111256	Published	29 October 2022	Review	https://www.mdpi.com/2076-0817/11/11/1256/htm	SARS-CoV-2 is a new coronavirus that has affected the world since 2019. Interstitial pneumonia is the most common clinical presentation, but additional symptoms have been reported, including neurological manifestations. Severe forms of infection, especially in elderly patients, present as an excessive inflammatory response called “cytokine storm”, which can lead to acute respiratory distress syndrome (ARDS), multiorgan failure and death. Little is known about the relationship between symptoms and clinical outcomes or the characteristics of virus–host interactions. The aim of this narrative review is to highlight possible links between neurological involvement and respiratory damage mediated by pathological inflammatory pathways in SARS-CoV-2 infection. We will focus on neuro–immune interactions and age-related immunity decline and discuss some pathological mechanisms that contribute to negative outcomes in COVID-19 patients. Furthermore, we will describe available therapeutic strategies and their effects on COVID-19 neurological symptoms.
494	N490		Harumi Jyonouchi 1,*,Lee Geng 1,Daniel A. Rossignol 2 andRichard E. Frye 3ORCID	Long COVID Syndrome Presenting as Neuropsychiatric Exacerbations in Autism Spectrum Disorder: Insights for Treatment	https://doi.org/10.3390/jpm12111815	Published	2 November 2022	Case Report	https://www.mdpi.com/2075-4426/12/11/1815/htm	COVID-19 causes not only severe respiratory symptoms, but also long-term sequelae, even if the acute-phase symptoms are minor. Neurological and neuropsychiatric symptoms are emerging as major long-term sequalae. In patients with pre-existing behavioral symptoms, such as individuals with autism spectrum disorders (ASD), the emergence of neuropsychiatric symptoms due to long COVID can be difficult to diagnose and manage. Herein, we present three ASD cases who presented with markedly worsening neuropsychiatric symptoms following COVID-19 exposure and subsequent difficulty in managing the post-COVID neuropsychiatric symptoms. Case 1 contracted SARS-CoV-2 during the early stages of the pandemic and treatment targeting COVID-19-induced immune activation was delayed. Case 2 was asymptomatic in the acute stage of a confirmed COVID-19 exposure, but still developed significant neuropsychiatric symptoms. Case 3 demonstrated a difficult course, partly due to pre-existing immune dysregulation and prior use of multiple immunomodulating agents. In cases 1 and 3 for whom serial blood samples were obtained, notable changes in the production of inflammatory and counter-regulatory cytokines by peripheral blood monocytes were observed. The presented cases illustrate the profound effects of COVID-19 on neuropsychiatric symptoms in ASD subjects and the difficulty of managing long-COVID symptoms.
495	N491	About N373	Varun Venkataramani, M.D., Ph.D., and Frank Winkler, M.D., Ph.D.	Microglia in Cancer Therapy-Related Cognitive Impairment	https://doi.org/10.1016/j.tins.2021.02.003	Published	March 02, 2021	Review	https://www.cell.com/trends/neurosciences/fulltext/S0166-2236(21)00035-7	Highlights Cancer survivors frequently exhibit persistent disruptions in cognitive function, including deficits in memory, attention, speed of information processing, and mental health. Studies in both human cancer survivors and preclinical rodent models of chemotherapy and radiation exposure indicate dysregulation of neural plasticity mechanisms underlying cancer therapy-related cognitive impairment. Both cranial irradiation and systemic chemotherapy treatment have been shown to induce a reactive state in microglia. Activated microglia are associated with deficits in neural precursor cell population maintenance and neurogenesis, in synaptic structure and function, and in myelin plasticity. Millions of cancer survivors experience a persistent neurological syndrome that includes deficits in memory, attention, information processing, and mental health. Cancer therapy-related cognitive impairment can cause mild to severe disruptions to quality of life for these cancer survivors. Understanding the cellular and molecular underpinnings of this disorder will facilitate new therapeutic strategies aimed at ameliorating these long-lasting impairments. Accumulating evidence suggests that a range of cancer therapies induce persistent activation of the brain’s resident immune cells, microglia. Cancer therapy-induced microglial activation disrupts numerous mechanisms of neuroplasticity, and emerging findings suggest that this impairment in plasticity is central to cancer therapy-related cognitive impairment. This review explores reactive microglial dysregulation of neural circuit structure and function following cancer therapy.
496	N492		Kathryn L Eschbacher, MD, Rachel A Larsen, MS, Ann M Moyer, MD, PhD, Ramanath Majumdar, PhD, MS, Robert Ross Reichard, MD	Neuropathological findings in COVID-19: an autopsy cohort	https://doi.org/10.1093/jnen/nlac101	Published	10 November 2022	Study	https://academic.oup.com/jnen/advance-article/doi/10.1093/jnen/nlac101/6820985	The literature regarding the neuropathological findings in cases of SARS-CoV-2 infection, which causes coronavirus disease 2019 (COVID-19), is expanding. We identified 72 patients who died of COVID-19 (n = 48) or had recovered shortly before death (n = 24) and had autopsies performed at our institution (49 males, 23 females; median age at death 76.4 years, range: 0.0–95.0 years). Droplet digital polymerase chain reaction (ddPCR) for the detection of SARS-CoV-2 was performed (n = 58) in multiple brain regions. In cases the assay was successfully completed (n = 50), 98.0% were negative (n = 49) and 2% were indeterminate (n = 1). Most histologic findings were typical of the patient age demographic, such as neurodegenerative disease and arteriolosclerosis. A subset of cases demonstrated findings which may be associated with sequelae of critical illness. We identified 3 cases with destructive perivascular lesions with axonal injury, one of which also harbored perivascular demyelinating lesions. These rare cases may represent a parainfectious process versus sequelae of vascular injury. The lack of detectable SARS-CoV-2 by ddPCR or significant histologic evidence of direct infection suggests that active encephalitis is not a feature of COVID-19.
497	N493		Biçem Demir, Elmas Beyazyüz, Murat Beyazyüz, Aliye Çelikkol & Yakup Albayrak	Long-lasting cognitive effects of COVID-19: is there a role of BDNF?	https://doi.org/10.1007/s00406-022-01514-5	Published	10 November 2022	Study	https://link.springer.com/article/10.1007/s00406-022-01514-5	Coronavirus disease 2019 (COVID-19) affects numerous systems of the body during the illness, and there have been long-lasting effects. BDNF plays an important role in synaptic plasticity and synaptic communication. According to the inclusion and exclusion criteria, 54 patients who had COVID-19 infection participated in this study. Thirty-six age-, sex-, body mass index (BMI)-, education level- and smoking status-matched healthy controls were included in the present study. All participants were individually administered the Stroop test and Visual Aural Digit Span Test Form B (VADS-B). Serum BDNF levels were measured by ELISA. Stroop test word reading spontaneous correction number and reading time, word color saying wrong number, spontaneous correction number and reading time, box color speaking spontaneous correction number and reading time, Stroop interference and speed factor duration were significantly higher in the COVID-19 group than in the control group. All scores of the VADS-B test were found to be significantly lower in the COVID-19 group. The mean serum BDNF levels were found to be 10.9 ± 6.9 ng/ml in the COVID-19 group and 12.8 ± 6.4 ng/ml in the healthy control group. Two-way ANOVA showed that the serum mean BDNF level was significantly lower in the COVID-19 group than in the control group. Gender had a significant effect on BDNF levels (F = 12.21; p = 0.008). The present study is the first to demonstrate the association between the role of serum BDNF and cognitive decline in patients with COVID-19 infection. Additionally, there is a significant role of male gender in terms of lower BDNF level and cognitive decline.
498	N494		G. Di Stefano,P. Falco,E. Galosi,G. Di Pietro,C. Leone,A. Truini	A systematic review and metanalysis of neuropathic pain associated with coronavirus disease 2019	https://doi.org/10.1002/ejp.2055	Published	11 November 2022	Review	https://onlinelibrary.wiley.com/doi/abs/10.1002/ejp.2055	Background and objective Neuropathic pain is an occasionally reported complication of coronavirus disease 2019 (COVID-19) that has received increased attention in scientific literature. In this systematic review and metanalysis, we aimed to provide information on the frequency of neuropathic pain associated with COVID-19. Databases and data treatment We systematically reviewed and analysed literature regarding neuropathic pain associated with COVID-19. Literature searches were conducted in PubMed, EMBASE, and Cochrane Library databases. We considered prospective and retrospective studies published up until September 2022 (limitations included English language, full-text publications, and studies including at least 10 patients). A random effects metanalysis was performed and heterogeneity and publication bias were assessed. Results We identified 149 studies. We included 17 studies in the systematic review, and six studies reporting the frequency of neuropathic pain in the acute/subacute phase of COVID-19 in the metanalysis. The estimated frequency of neuropathic pain ranged between 0.4 and 25%. Forest plot analysis showed that the random effect overall frequency was 10% (95% confidence interval: 5-15%), with a high level of heterogeneity (Chi2 = 104; Tau2 = 0.004; df = 5; I2 = 95%; test for overall effect: Z = 3.584; P < 0.0005). The overall risk of bias was moderate in all studies selected, particularly due to the poor description of neuropathic pain diagnostic criteria. Conclusions The pooled estimated frequency of neuropathic pain associated with COVID-19 should be considered with caution due to the high heterogeneity across studies and the poor description of the neuropathic pain diagnostic criteria applied.
499	N495		RafalButowt1KatarzynaBilinska2Christopher S.von Bartheld34	Olfactory dysfunction in COVID-19: new insights into the underlying mechanisms	https://doi.org/10.1016/j.tins.2022.11.003	Published	16 November 2022	Review	https://www.sciencedirect.com/science/article/pii/S016622362200234X	Highlights •The underlying mechanisms of the loss of smell in COVID-19 can be narrowed down to five plausible scenarios in the olfactory epithelium that are not mutually exclusive. •One series of mechanisms focuses on the primary target of SARS-CoV-2 in the olfactory epithelium, the support cells, which provide the mucus to dissolve odorants, and the energy required for olfactory cilia to power olfactory signal transduction, as well as a putative maintenance factor for cilia. •A second set of scenarios emphasizes changes in gene expression in olfactory receptor neurons, which may be linked to the loss of cilia causing the neurons to become immature-like. •Both viral and host factors modulate the prevalence of olfactory dysfunction, with the omicron variant preferring an endosomal route that enters support cells less efficiently, resulting in a relative sparing of olfaction in patients infected with this variant. Abstract The mechanisms of olfactory dysfunction in coronavirus disease 2019 (COVID-19) are still unclear. In this review, we examine potential mechanism that may explain why the sense of smell is lost or altered. Among the current hypotheses, the most plausible is that death of infected support cells in the olfactory epithelium causes – besides altered composition of the mucus – retraction of the cilia on olfactory receptor neurons, possibly because of lack of support-cell derived glucose in the mucus that powers olfactory signal transduction within the cilia. This mechanism is consistent with the rapid loss of smell and the rapid recovery of smell after regeneration of support cells. Host immune responses that cause downregulation of genes involved in olfactory signal transduction occur too late to trigger anosmia, but may contribute to the duration of the olfactory dysfunction.

	A	B	C	D	E	F	G	H	I	J	K	M
1	Ref	PPLC	Authors	Title	DOI	Peer reviewed	Date	type	Link	Keys	Clés

2	P01		Mario Gennaro Mazzaab Rebecca De Lorenzo bc CaterinaConte bc Sara Polettia b Benedetta VaiabIrene Bollettinia	Anxiety and depression in COVID-19 survivors: Role of inflammatory and clinical predictors	https://doi.org/10.1016/j.bbi.2020.07.037	Published	October 1, 2020	Study	https://www.sciencedirect.com/science/article/pii/S0889159120316068	Anxiety - insomnia - depression - post-traumatic stress disorder - OCD: symptoms common in covid survivors one month after hospitalization, according to an Italian survey of 402 patients.	Anxiété - insomnies - dépression - trouble de stress post-traumatique - TOC : des symptômes fréquents chez les survivants de la covid un mois après hospitalisation, selon une étude italienne sur 402 patients.
3	P02		Maxime Taquet, PhD Sierra Luciano, BA Prof John R Geddes, FRCPsych Prof Paul J Harrison, FRCPsych	Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA	https://doi.org/10.1016/S2215-0366(20)30462-4	Published	November 9, 2020	Study	https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(20)30462-4/fulltext	A large Lancet study notes that one in 5 patients with covid suffers from anxiety, depression or insomnia for at least 3 months following infection. The pre-existence of psychiatric disorders is also correlated with the risk of being infected. The study also notes that covid increases the risk of a range of psychiatric disorders, including dementia, including in patients for whom these disorders were not pre-existing.	Une large étude du Lancet note qu'un malade de la covid sur 5 souffre d'anxiété, dépression ou insomnie sur les 3 mois a minima qui suivent sa contamination. La préexistence de troubles psychiatriques est aussi corrélée avec le risque d'être contaminé. L'étude remarque également que la covid majore le risque d'un ensemble de troubles psychiatriques, dont la démence, y compris chez les patients pour qui ces troubles n'étaient pas préexistants.
4	P03		Ipsit V. Vahia, MD1,2; Dilip V. Jeste, MD3; Charles F. Reynolds III, MD4	Older Adults and the Mental Health Effects of COVID-19	https://doi.org/10.1001/jama.2020.21753	Published	November 20, 2020	Viewpoint	https://jamanetwork.com/journals/jama/fullarticle/2773479	An article in JAMA draws a state of knowledge on anxiety disorders, depression and mental health in general in the elderly parts of the population as a consequence of a covid, and emphasizes the importance of nonpharmacological approaches.	Un article dans JAMA dessine un état des connaissances sur les troubles d'anxiété, dépression et santé mentale en général chez les tranches âgées de la population en répercussion d'une covid, et insiste sur l'importance des approches non médicamenteuses.
5	P04		Liam Townsend ,Adam H. Dyer ,Karen Jones,Jean Dunne,Aoife Mooney,Fiona Gaffney,Laura O'Connor,	Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection	https://doi.org/10.1371/journal.pone.0240784	Published	November 9, 2020	RESEARCH ARTICLE	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240784	A study of 128 cases with persistent symptoms, avg. 49.5 ±15 years, 54% of women, indicates that post-viral fatigue does not appear to be associated with the severity of the acute phase, nor with markers of inflammation or immune disorders. Chronic fatigue at 2.5 months is present in 67 patients, or 52%. Of these 67, nine had a history of anxiety or depression, or 13%. Conversely, 9 of the 10 patients who had a history of anxiety/depression experienced persistent fatigue. 55% of patients were hospitalized. Persistent fatigue concerns 67% of women. The study makes a link with the effects of chronic fatigue observed during the SARS and MERS epidemics, and questions the possibility of developing chronic fatigue syndrome (CFS).	Une étude de 128 cas avec des symptômes persistants, d'âge moy. 49,5 ±15 ans, 54% de femmes, indique que la fatigue post-virale n'apparaît pas associée à la sévérité de la phase aiguë, ni aux marqueurs d'inflammation ou de dérèglements immunitaires. La fatigue persistante à 2,5 mois est présente chez 67 patients, soit 52%. Sur ces 67, neuf avait un historique d'anxiété ou de dépression, soit 13%. À l'inverse, 9 patient(e)s sur les 10 qui avaient des antécédents d'anxiété/dépression ont présenté une fatigue persistante. 55% des patients ont été hospitalisés. La fatigue persistante concerne pour 67% des femmes. L'étude fait un lien avec les effets de fatigue chronique relevés lors des épidémies de SARS et MERS, et s'interroge sur la possibilité de développer un syndrome de fatigue chronique. <Stats> La "valeur p" pour le sexe est dans l'étude à 0,2%. Traduction : Si hommes et femmes avaient le même risque de développer une fatigue persistante post-infection covid, il n'y aurait eu que 0,2% de chances d'avoir de telles données (si étude correctement menée). De même, si les antécédents anxiété/dépression n'étaient pas corrélés à un risque plus fort d'être en fatigue persistance post-infection covid, il n'y aurait eu que 2% de chances d'avoir un tel écart dans les données (si l'étude est correctement menée). Et si un taux fort de protéine C réactive (CRP, indicateur d'inflammation) n'était pas corrélé à un risque plus fort d'être en fatigue persistante après infection covid, il n'y aurait eu que 6% de chances d'avoir un tel écart dans les données (si étude correctement menée).
6	P05		Anna Valenzano 1,,Alessia Scarinci 2,,Vincenzo Monda 3 ,	The Social Brain and Emotional Contagion: COVID-19 Effects	https://doi.org/10.3390/medicina56120640	Published	25 November 2020	Review	https://pubmed.ncbi.nlm.nih.gov/33255569/		Une étude italienne analyse la crise sanitaire en tant qu'épidémie émotionnelle, et ses impacts mondiaux sur la santé mentale, par les dépressions et l'anxiété. Elle préconise de s'inspirer des épidémies passées pour la prise en charge thérapeutique.
7	P06		Humanitarian Disaster Institute	COVID-19 MENTAL HEALTH HANDBOOK Evidence-Informed Approaches to Mental Wellbeing During a Pandemic		Published	December 2020	Handbook	https://www.chihealth.com/content/dam/chi-health/website/documents/MentalHealth_Handbook_FINAL.pdf		Un rapport américain de 200 pages, écrits par un panel de médecins, qui traite de la covid et la santé mentale.	N002
8	P07		Syed Z. Iqbal, MD; Benjamin Li, MD; Edore Onigu-Otito, MD; Mohammad Faraz Naqvi, MD; Asim A. Shah, MD	The Long-Term Mental Health Effects of COVID-19	https://doi.org/10.3928/00485713-20201103-01	Published	December 10, 2020	Article	https://www.healio.com/psychiatry/journals/psycann/2020-12-50-12/%7Bbf43fdf5-3a35-4821-8cec-fd332dc442b8%7D/the-long-term-mental-health-effects-of-covid-19		Un article qui décrit les impacts neuropsychiatriques indirectes de la crise sanitaire et des mesures qui y sont liées comme les confinements. Les troubles d'anxiété, les phobies les comportements d'évitement, sont évalués.
9	P08		Ashley Clarke	The Impact of Sustained Psychological Distress and Elevated Anxiety Symptoms on Long-Term Mental and Physical Wellbeing of COVID-19 Healthcare Providers		Published	December 2020	Article	https://www.ceeol.com/search/article-detail?id=913406		Un article académique s'intéresse aux impacts sur la santé mentale et la détérioration des capacités physiques du personnel de santé au front de la crise sanitaire de la covid.
10	P09		Sanjay Kumar1 , Alfred Veldhuis1 , Tina Malhotra2	Neuropsychiatric and Cognitive Sequelae of COVID-19	http://dx.doi.org/10.3389/fpsyg.2021.577529	Published	February 2021	Review	https://www.researchgate.net/publication/349140814_Neuropsychiatric_and_Cognitive_Sequelae_of_COVID-19	In this paper, we will briefly outline how COVID-19 can affect the CNS, review emerging evidence of effects on CNS and explore the possible neuropsychiatric sequelae of the COVID-19 infection.	Une revue d'études britannique répertorie les possibles séquelles neuro-psychiatriques d'une infection de covid. Les auteurs s'interrogent sur les conséquences à long terme pour la rééducation et la réadaptation des malades.	N004R
11	P10		Klaus W.Lange	COVID-19 and global mental health	https://doi.org/10.1016/j.glohj.2021.02.004	Published	13 February 2021	Review Article	https://www.sciencedirect.com/science/article/pii/S241464472100004X	"A focus on the long-term mental health consequences may be at least as important as the measures currently seeking to mitigate the short-term effects of COVID-19 and to save lives."	Cette étude balaie les impacts psychiatriques de la covid via les dommages neurologiques possibles, mais essaie d'évaluer également les impacts psychiatriques indirects de la pandémie.
12	P11		Genoveva Uzunova,Stefano Pallanti &Eric Hollander	Presentation and management of anxiety in individuals with acute symptomatic or asymptomatic COVID-19 infection, and in the post-COVID-19 recovery phase	https://doi.org/10.1080/13651501.2021.1887264	Published	26 Feb 2021	Review Article	https://www.tandfonline.com/doi/full/10.1080/13651501.2021.1887264	Key points Patients with COVID-19 (symptomatic or asymptomatic) exhibit a high frequency of neuropsychiatric complications with highest percentage attributed to anxiety. Multiple biological and psychosocial risk factors for anxiety exist in COVID-19-ill individuals. Biological risk factors include stress, resilience, genetics, gender, age, immune system, direct infection of the central nervous system (CNS) with SARS-CoV-2, comorbid psychiatric and general medical illnesses, ARDS and ICU stay. Anosmia and hypogeusia are COVID-19-specific anxiety risk factors. Knowledge of the anxiety risk factors is essential to focus on timely interventions, because anxiety may be a complication of and exacerbate the COVID-19 course. An inverse correlation exists between resilience and anxiety because of COVID-19, and therefore efforts should be made to increase resilience in COVID-19 patients. In COVID-19, important anxiety mechanism is neuroinflammation resulting from activation of the immune system and an ensuing cytokine storm. The general approach to management of anxiety in COVID-19 should be compassionate, similar to that during trauma or disaster, with efforts focussed on instilling a sense of hope and resilience. In selecting pharmacological treatment of anxiety, the stress response and immune system effects should be key. Medications with cardio-respiratory adverse effects should be avoided in patients with respiratory problems. Anxiety is a disorder that will require for long-term follow up at least one month after COVID-19.	Une revue d'études menée en octobre 2020 dans International Journal of Psychiatry in Clinical Practice considère l'anxiété comme jouant un rôle prépondérant dans l'évolution clinique chez les malades de la covid. L'étude présente l'infection et l'anxiété comme s'influençant mutuellement de façon directe ou indirecte, notamment par des perturbations du système immunitaire. Elle liste aussi des traitements pour soigner ces conséquences, et insiste sur l'objectif de résilience pour la guérison.	N003A
13	P12		Soon Tjin Lim, MRCP, PhD, Benjamin Janaway, MBChB, BMedSci, Harry Costello, MSc MRCPsych, Anand Trip, PhD FRCP,* and Gary Price	Persistent psychotic symptoms following COVID-19 infection	https://doi.org/10.1192%2Fbjo.2020.76	Published	2020 Jul 22	Case Report	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477483/	We report on a female patient who, post-COVID-19 infection, developed an initial delirium followed by persistent and florid psychotic symptoms consisting of persecutory delusion, complex visual and auditory hallucinations and Capgras phenomenon in the absence of hypoxia but elevated tumour necrosis factor (TNF)-α. The psychotic symptoms persisted for about 40 days. Her magnetic resonance imaging brain scan, electroencephalogram, cerebrospinal fluid examination and extensive autoimmune panel did not show any abnormalities. The cause of the psychotic symptoms in this patient were not ascertained but we propose either an inflammatory state, characterised by the patient's elevated TNF-alpha levels as a possible contributing mechanism for her psychosis in line with the proinflammatory changes observed in some cases of psychosis. Or, an alternative, but unproven, hypothesis is one of an antibody-mediated encephalitic event induced by viral infection.	Des cas d'événements psychotiques ont été attribués à la covid. Ils auraient pour origine possible une inflammation caractérisée par des taux élevés de TNF α, ou éventuellement une neuro-invasion qui causerait un événement encéphalitique dont les médiateurs seraient des anticorps.
14	P13		Rachel Noone, Johanna A. Cabassa, Laura Gardner, Bruce Schwartz, and Jonathan E. Alpert Vilma Gabbay	Letter to the Editor: New onset psychosis and mania following COVID-19 infection	https://doi.org/10.1016%2Fj.jpsychires.2020.07.042	Published	2020 Aug 8	Cases Report	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414775/	Here we present two case reports of adult patients with COVID-19 infections who presented with severe psychosis and mania with no prior psychiatric history and in the absence of significant medical or pulmonary symptoms and an unremarkable neurological work-up.	_
15	P14		A.ParraaA.JuanesaC.P.LosadaabcS.Álvarez-SesmeroaV.D.SantanaaI.MartíaJ.UrricelquiaD.Rentero	Psychotic symptoms in COVID-19 patients. A retrospective descriptive study	https://doi.org/10.1016/j.psychres.2020.113254	Published	September 2020	Short communication	https://www.sciencedirect.com/science/article/abs/pii/S0165178120315092	Highlights •Psychotic symptoms have been observed in patients infected by SARS-CoV-2 with no previous psychiatric history. •Psychotic episodes in COVID-19 patients present with confusional symptoms, instaure rapidly and resolve with low doses of antipsychotics. •Psychotic symptoms related to SARS-CoV-2 are more frequent in patients discharged from intensive care units. •Pharmacological treatments utilized against COVID-19 can be related with the new-onset psychotic manifestations.	_
16	P15		Aravinthan Varatharaj, MRCP,a,b Naomi Thomas, MRCPCH,c,d Mark A Ellul, MRCP,e,f,g Nicholas W S Davies, PhD,h Thomas A Pollak, MRCP,i Elizabeth L Tenorio, PhD,k,l Mustafa Sultan,c Ava Easton, PhD,f,m Gerome Breen, Prof, PhD,j Michael Zandi, PhD,n Jonathan P Coles, Prof, PhD, Sarah L Pett, Prof, PhD,o,p Ian Galea, PhD,a,b,* Rhys H Thomas, PhD,c,v,* Benedict D Michael	Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study	https://doi.org/10.1016%2FS2215-0366(20)30287-X	Published	2020 Jun 25	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316461/	Median patient age was 71 years (range 23–94; IQR 58–79). Complete clinical datasets were available for 125 (82%) of 153 patients. 77 (62%) of 125 patients presented with a cerebrovascular event, of whom 57 (74%) had an ischaemic stroke, nine (12%) an intracerebral haemorrhage, and one (1%) CNS vasculitis. 39 (31%) of 125 patients presented with altered mental status, comprising nine (23%) patients with unspecified encephalopathy and seven (18%) patients with encephalitis. The remaining 23 (59%) patients with altered mental status fulfilled the clinical case definitions for psychiatric diagnoses as classified by the notifying psychiatrist or neuropsychiatrist, and 21 (92%) of these were new diagnoses. Ten (43%) of 23 patients with neuropsychiatric disorders had new-onset psychosis, six (26%) had a neurocognitive (dementia-like) syndrome, and four (17%) had an affective disorder. 18 (49%) of 37 patients with altered mental status were younger than 60 years and 19 (51%) were older than 60 years, whereas 13 (18%) of 74 patients with cerebrovascular events were younger than 60 years versus 61 (82%) patients older than 60 years. First nationwide, cross-specialty surveillance study of acute neurological and psychiatric complications of COVID-19. Altered mental status was the second most common presentation, comprising encephalopathy or encephalitis and primary psychiatric diagnoses, often occurring in younger patients.	_
17	P16		Kevin Gournay	Post COVID-19 mental health: please do not forget severe mental health problems	https://doi.org/10.12968/bjmh.2021.0008	Published	13 Mar 2021	Article	https://www.magonlinelibrary.com/doi/full/10.12968/bjmh.2021.0008	Kevin Gournay discusses the impact of COVID-19 and those living with severe mental health problems.	_
18	P17		Zev M. Nakamura, Rebekah P. Nash, Sarah L. Laughon & Donald L. Rosenstein	Neuropsychiatric Complications of COVID-19	https://doi.org/10.1007/s11920-021-01237-9	Published	16 March 2021	Review	https://link.springer.com/article/10.1007/s11920-021-01237-9	Over 30% of patients hospitalized with COVID-19 may exhibit cognitive impairment, depression, and anxiety that persist for months after discharge. These symptoms are even more common in patients who required intensive care for severe effects of the virus. In addition to the pandemic-related psychological stress, multiple biological mechanisms have been proposed to understand the neuropsychiatric symptoms observed with COVID-19. Given limited research regarding effective interventions, we recommend pharmacologic and behavioral strategies with established evidence in other medically-ill populations.	Les conséquences psychiatriques sont fréquentes chez les malades hospitalisés de la covid selon cette étude. Elle peuvent parfois être induites par un traitement inapproprié, comme l'hydroxychloroquine ou les combinaisons lopinavir/ritonavir.	N009
19	P18		María José Valdés-Florido, Álvaro López-Díaz, Fernanda Jazmín Palermo-Zeballos, Nathalia Garrido-Torres, Paula Álvarez-Gil, Iván Martínez-Molina, Victoria Eugenia Martín-Gil, Elena Ruiz-Ruiz, Macarena Mota-Molina, María Paz Algarín-Moriana, Antonio Hipólito Guzmán-del Castillo, Ángela Ruiz-Arcos, Rafael Gómez-Coronado, Sara Galiano-Rus, Alfonso Rosa-Ruiz, Juan Luis Prados-Ojeda, Luis Gutierrez-Rojas, Benedicto Crespo-Facorro & Miguel Ruiz-Veguilla	Clinical characterization of brief psychotic disorders triggered by the COVID-19 pandemic: a multicenter observational study	https://doi.org/10.1007/s00406-021-01256-w	Published	03 April 2021	Study	https://link.springer.com/article/10.1007/s00406-021-01256-w	Psychotic disorders triggered by the COVID-19 pandemic	_
20	P19		V. E. Medvedev	Anxiety and depression in COVID-19: treatment options	https://doi.org/10.14412/2074-2711-2021-2-111-116	Published	27.03.2021	Review	https://nnp.ima-press.net/nnp/article/view/1549	During the examination of post-COVID patients, a direct and indirect negative effect of COVID-19 on the nervous system is found. Among the mediated subjectively significant stress factors of the pandemic, a potential long-term threat to life, prolonged quarantine measures with selfisolation, lack of stable immunity, restriction of access to medical services, etc. are of particular importance. An increased frequency of depression (up to 53.5%), anxiety (up to 50.9%), and mixed anxiety/depressive disorders were reported during the pandemic. Psychopharmacotherapy in patients with COVID-19 should include drugs not only with minimally expressed undesirable effects and adverse drug interactions but also with the presence of additional therapeutic procognitive and somatotropic properties, similar to those identified in the antidepressant fluvoxamine.	_
21	P20		Yuan Yang, PhD,1,2,3,# Wen Li, MD, PhD,1,2,3,# Qinge Zhang, MD, PhD,4,# Ling Zhang, MD, PhD,4,# Teris Cheung, PhD,5 Chee H Ng, MBBS, MD,6, and Yu-Tao Xiang, MD, PhD1,2,3,	Should people with severe mental illness be prioritized for the COVID-19 vaccination?	https://dx.doi.org/10.7150%2Fijbs.57750	Published	2021 Apr 10		https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071759/		_
22	P21		Osman Sinanović	LONG-TERM NEUROPSYCHIATRIC CONSEQUENCES OF SARS-COV INFECTIONS		Published	2021 May	Review	https://pubmed.ncbi.nlm.nih.gov/34010256/	The review of the so far published papers shows that although more and more papers are reporting neuro-logical and psyhiatric manifestations associated with COVID-19, many items remain unclear. The long-term psychological implications of this infectious diseases should not be ignored. In this paper, we aim to present a some of psychological consequences and neurological disorders associat-ed with the SARS-CoV-2 infection, and to emphasize the need a global action that requires close coordination and open-data sharing between hospitals, academic and public health institutions and the fast establishment of harmonised research priorities to face acut and long-term the neurological and psychological consequences.	_
23	P22		Daniella Winter Yoram Braw	COVID-19: Impact of Diagnosis Threat and Suggestibility on Subjective Cognitive Complaints	https://doi.org/10.1016/j.ijchp.2021.100253	Published	24 May 2021		https://www.sciencedirect.com/science/article/pii/S169726002100034X	Background/Objective A subset of recovered COVID-19 patients report persistent neurological symptoms. These include non-specific symptoms (e.g., headaches and fatigue) which were found to be affected by psychological processes in other disorders (e.g., post-concussion syndrome, PCS, after mild traumatic brain injury). The current study assessed the impact of diagnosis threat (i.e., information regarding the long-term neurological impact of COVID-19) and suggestibility on endorsed symptoms of both recovered patients and healthy controls. Method Recovered patients (n = 90) and healthy controls (n = 210) described their cognitive functioning after being randomly assigned to: (a) Experimental group: These participants read an article that explored long-term neurological symptoms among COVID-19 survivors. (b) Control group: These participants read an article providing general information regarding the disease. Results Recovered patients, but not healthy controls, endorsed more symptoms in the experimental condition compared to the control condition. Moreover, suggestibility was correlated with endorsement of symptoms. Conclusions Post COVID-19 neurological symptoms may, at least partially, be affected by non-neurological factors such as diagnosis threat. Information regarding long-term effects of COVID-19 may skew reported symptoms with highly suggestible individuals particularly susceptible to these effects. Further research, however, is needed to validate and elaborate upon these initial findings.	Selon une étude randomisée en aveugle, les symptômes neurologiques prolongés de la covid peuvent partiellement être affectés par des facteurs non neurologiques, comme l'annonce d'un diagnostic inquiétant, notamment chez les personnes très suggestibles.	N011
24	P23		H. Dreßing & A. Meyer-Lindenberg	Künftige Aufgaben der psychiatrischen Begutachtung bei „Long-COVID“	https://doi.org/10.1007/s00115-021-01142-9		07 June 2021		https://link.springer.com/article/10.1007/s00115-021-01142-9	Fazit für die Praxis Mit zunehmender Dauer der COVID-19-Pandemie rücken auch mögliche neuropsychiatrische Langzeitfolgen in den Fokus. Im Rahmen einer Infektion kann das Virus das zentrale Nervensystem befallen und neuropsychiatrische Symptome verursachen. Die Spätfolgen einer durchgemachten COVID-19-Infektion sind zum Teil unspezifisch und im Hinblick auf bleibende Schäden derzeit noch nicht hinreichend zu beurteilen. In der sozialmedizinischen Begutachtungspraxis werden sich in unterschiedlichen Versicherungssystemen sowohl finale als auch kausale gutachtliche Fragestellungen ergeben. Zumindest nach gegenwärtigem Kenntnisstand kann bei der gutachtlichen Einschätzung einer „Long-COVID-Symptomatik“ auf das auch in anderen Kontexten bewährte Vorgehen zurückgegriffen werden.	_
25	P24		B. Ranque	Appeler un chat un chat To call a spade a spade	https://doi.org/10.1016/j.revmed.2021.06.001	Published	18 June 2021	Éditorial	https://www.sciencedirect.com/science/article/abs/pii/S0248866321005208	Pour conclure, il me semble que notre objectif doit être avant tout de rendre au patient son bien-être antérieur et qu’il est bien plus important de faire disparaître les symptômes que d’en avoir une explication physiopathologique parfaitement exacte. Cela nécessite d’évoquer explicitement avec le patient la possibilité de mécanismes cognitifs et comportementaux sous-tendant les symptômes inexpliqués persistant après une COVID-19, c’est-à-dire d’appeler un chat un chat, sans hypocrisie ni mépris des liens complexes qui unissent le corps et l’esprit de tout être humain.	_
26	P25		Yiheng Tu, Yuqi Zhang, Yu Li, Qing Zhao, Yanzhi Bi, Xuejing Lu, Yazhuo Kong, Li Wang, Zhijie Lu & Li Hu	Post-traumatic stress symptoms in COVID-19 survivors: a self-report and brain imaging follow-up study	https://doi.org/10.1038/s41380-021-01223-w	Published	20 July 2021	Study	https://www.nature.com/articles/s41380-021-01223-w	We conducted a two-session study to record PTSS in the COVID-19 survivors discharged from hospitals for a short (i.e., about 3 months, Session 1) to a medium period (i.e., about 6 months, Session 2), as well as brain imaging data in Session 2. The control groups were non-COVID-19 locals. Session 1 was completed for 126 COVID-19 survivors and 126 controls. Session 2 was completed for 47 COVID-19 survivors and 43 controls. The total score of post-traumatic stress disorder (PTSD) checklist for DSM-5 (PCL-5) score was significantly higher in COVID-19 survivors compared with controls in both sessions. The PCL-5 score in COVID-19 survivors was positively correlated with the duration after discharge (r = 0.27, p = 0.003 for Session 1), and increased by 20% from Session 1 to Session 2 for the survivors who participated both sessions. The increase was positively correlated with individual’s test-retest duration (r = 0.46, p = 0.03). Brain structural volume and functional activity in bilateral hippocampus and amygdala were significantly larger in COVID-19 survivors compared with controls. However, the volumes of the left hippocampus and amygdala were negatively correlated with the PCL-5 score for the COVID-19 survivors. Our study suggests that COVID-19 survivors might face possible PTSS deteriorations, and highlights the importance of monitoring mental wellness of COVID-19 survivors.
27	P26		ThorMertz SchouaSamiaJocabGregersWegeneraCecilieBay-Richtera	Psychiatric and neuropsychiatric sequelae of COVID-19 – a systematic review	https://doi.org/10.1016/j.bbi.2021.07.018	Published	30 July 2021	Review	https://www.sciencedirect.com/science/article/pii/S0889159121002816	Highlights •66 studies examined psychiatric or neuropsychiatric sequelae following COVID-19. •Fatigue, anxiety/depression, PTSD, cognitive deficits, and sleep disturbances were most commonly reported. •COVID-19 survivors were at risk of psychiatric sequelae but symptoms generally improve over time.
28	P27		Evan J.KyzarMD PhD1Lawrence J.PurpuraMD23JayeshShah2AnyelinaCantos2Anna S.NordvigMD4Michael T.YinMD2	Anxiety, depression, insomnia, and trauma-related symptoms following COVID-19 infection at long-term follow-up	https://doi.org/10.1016/j.bbih.2021.100315	Published	30 July 2021	Study	https://www.sciencedirect.com/science/article/pii/S2666354621001186	Here, we report findings from a cohort study of 52 participants recruited from the greater New York City area following acute COVID-19 infection. Participants completed the Patient Health Questionnaire-9 (PHQ-9) for depressive symptoms, the Generalized Anxiety Disorder-7 (GAD-7) for anxiety-related symptoms, the Insomnia Severity Scale (ISS) from sleep-related symptoms, and the PTSD Checklist-Civilian version (PCL-C) for trauma-related symptoms both at baseline and at long-term (24 to 60 weeks post-infection) follow-up. We found a high degree of correlation between psychiatric symptom scales within participants. More participants met established cutoffs for clinically significant insomnia and post-traumatic stress at follow-up compared to baseline. Symptom scales for depression, insomnia, and PTSD were increased at long-term follow-up, with only increased PCL-C scores surviving correction for multiple comparisons (Z=2.92, W=434, p=0.004). Our results present evidence from a small cohort that neuropsychiatric symptoms, particularly those related to PTSD, may worsen over time in COVID-19 survivors.
29	P28		Laura Dellazizzo 1,2 ,Nayla Léveillé 1,2,Clara Landry 1,2 andAlexandre Dumais	Systematic Review on the Mental Health and Treatment Impacts of COVID-19 on Neurocognitive Disorders	https://doi.org/10.3390/jpm11080746	Published	29 July 2021	Review	https://www.mdpi.com/2075-4426/11/8/746/htm	First, the pandemic and resulting self-isolation led to many detrimental effects on psychological well-being. Exacerbation and relapses of neurocognitive and behavioral symptoms were observed, as well as emergences of new psychological symptoms (i.e., depression, anxiety). Second, therapeutic and community services for individuals suffering from NCD, such as social support services and outpatient clinics, were disrupted or reduced leading to postponed appointments and evaluations, as well as reduced access to medications. These issues were somewhat palliated with the growth of telemedicine. Conclusions. This systematic review highlights the extent of the effects of the pandemic, and the topics addressed should be taken into consideration by healthcare practitioners, institutions, and policymakers to ensure that proper measures are employed to protect this population from additional harm.
30							From this point on, the survey of studies is no longer as exhaustive as possible. Only those studies which seem to us to bring significant new elements will be listed.
31	P29		Steven J.LamontagneabMakaila F.WintersaDiego A.PizzagallibcMary C.Olmsteadad	Post-acute sequelae of COVID-19: Evidence of mood & cognitive impairment	https://doi.org/10.1016/j.bbih.2021.100347	Published	14 September 2021	Study	https://www.sciencedirect.com/science/article/pii/S2666354621001502	Depressive symptoms were found in the post-acute sequelae of COVID-19 (PASC) sample. •Reward processing and cognitive functioning were impaired in the PASC phase. •PASC was associated with impaired executive function, but not orienting or alerting. •Stress did not moderate PASC effects; between-group pandemic experience was similar. •Protracted inflammatory responses may contribute to post-acute psychiatric sequelae.	_
32	P30		Mario GennaroMazzaabRaffaellaZanardiacMariagraziaPalladinibPatriziaRovere-QueriniadFrancescoBenedettiab	Rapid response to selective serotonin reuptake inhibitors in post-COVID depression	https://doi.org/10.1016/j.euroneuro.2021.09.009	Published	9 October 2021	Review	https://www.sciencedirect.com/science/article/pii/S0924977X21007616	We included 60 patients affected by a major depressive episode and treated with SSRI in the six months following recovery from COVID. The severity of depression was rated at baseline and after four weeks on the Hamilton Depression Rating Scale (HDRS). Response to treatment was considered when the patients achieved a 50% HDRS reduction. To investigate changes of depressive symptomatology over time, repeated measures ANOVAs according to clinical variables were performed. We found that 55 (92%) patients showed a clinical response to antidepressant. Patients showed a significant decrease over time of HDRS score (baseline HDRS = 23.37 ± 3.94, post-treatment HDRS = 6.71±4.41, F = 618.90, p < 0.001), irrespectively of sex, previous psychiatric history, previous history of mood disorder, and SSRI type. This is the first study to explore the SSRI efficacy in post-COVID depression, suggesting rapid antidepressant effects in most patients. SSRIs treatment could contribute to the rapid antidepressant response by directly targeting the neuroinflammation triggered by SARS-CoV-2. We suggest screening psychopathology of COVID-19 survivors to diagnose emergent depression and pharmacologically treat it to reduce the disease burden and related years of life lived with disability.	_
33	P31		Eliza Dąbrowska * ,Beata Galińska-Skok andNapoleon Waszkiewicz	Depressive and Neurocognitive Disorders in the Context of the Inflammatory Background of COVID-19	https://doi.org/10.3390/life11101056	Published	8 October 2021	Review	https://www.mdpi.com/2075-1729/11/10/1056	It is suggested that neuroinflammation and associated central nervous system changes may significantly contribute to the etiopathogenesis of depressive disorders. In addition, symptoms after a COVID-19 infection may persist for up to several weeks after an acute infection as a post-COVID-19 syndrome. Moreover, previous knowledge indicates that among SSRI (selective serotonin reuptake inhibitor) group antidepressants, fluoxetine is a promising drug against COVID-19. In conclusion, further research, observation and broadening of the knowledge of the pathomechanism of a SARS-CoV-2 infection and the impact on potential complications are necessary. It is essential to continue research in order to assess the long-term neuropsychiatric effects in COVID-19 patients and to find new therapeutic strategies.It is suggested that neuroinflammation and associated central nervous system changes may significantly contribute to the etiopathogenesis of depressive disorders. In addition, symptoms after a COVID-19 infection may persist for up to several weeks after an acute infection as a post-COVID-19 syndrome. Moreover, previous knowledge indicates that among SSRI (selective serotonin reuptake inhibitor) group antidepressants, fluoxetine is a promising drug against COVID-19. In conclusion, further research, observation and broadening of the knowledge of the pathomechanism of a SARS-CoV-2 infection and the impact on potential complications are necessary. It is essential to continue research in order to assess the long-term neuropsychiatric effects in COVID-19 patients and to find new therapeutic strategies.	_
34	P32		Mark Shevlin,Emma Nolan,Marcin Owczarek,Orla McBride,Jamie Murphy,Jilly Gibson Miller,Todd K. Hartman,Liat Levita,Liam Mason,Anton P. Martinez,Ryan McKay,Thomas V. A. Stocks,Kate M. Bennett,Philip Hyland,Richard P. Bental	COVID-19-related anxiety predicts somatic symptoms in the UK population	https://doi.org/10.1111/bjhp.12430	Published	27 May 2020	Study	https://bpspsychub.onlinelibrary.wiley.com/doi/full/10.1111/bjhp.12430	During the current COVID-19 pandemic in the United Kingdom, there may be increased levels of generalized anxiety in the general population, but there may also be anxiety specifically associated with COVID-19. This study is the first to show that there is a positive association between both generalized anxiety and COVID-19 specific anxiety and the reporting of somatic symptoms. Indeed, COVID-19 specific anxiety explained unique variance in somatic symptoms after controlling for generalized anxiety and other potential confounding variables.
35	P33		LiuyiRana1WoWanga1MingAibYitingKongbJianmeiChenbLiKuang	Psychological resilience, depression, anxiety, and somatization symptoms in response to COVID-19: A study of the general population in China at the peak of its epidemic	https://doi.org/10.1016/j.socscimed.2020.113261	Published	29 July 2020	Study	https://www.sciencedirect.com/science/article/abs/pii/S0277953620304809	Results The prevalence of depression, anxiety, somatization symptoms was found to be 47.1%, 31.9%, 45.9%, respectively, among all participants. From them, 18.2% showed moderate to severe symptoms of depression, 8.8% showed moderate to severe symptoms of anxiety, and 16.6% showed moderate to severe symptoms of somatization. Psychological resilience was negatively correlated with depression (standardized β = −0.490, P < 0.001), anxiety (standardized β = −0.443, P < 0.001), and somatization symptom scores (standardized β = −0.358, P < 0.001), while controlling for confounding factors. Analysis of the three-factor resilience structure showed that strength and tenacity were correlated with depression (standardized β = −0.256, P < 0.001; standardized β = −0.217, P < 0.001), anxiety (standardized β = −0.268, P < 0.001; standardized β = −0.147, P < 0.001), and somatization symptoms (standardized β = −0.236, P < 0.001; standardized β = −0.126, P < 0.01). Conclusions Our results suggest that there is a high prevalence of psychological distresses among the general population at the peak of the COVID-19 epidemic in China, which is negatively correlated with resilience. Psychological resilience represents an essential target for psychological intervention in a public health emergency. Highlights •Investigated mental health and resilience in response to COVID-19. •The study took place at the peak of the COVID-19 epidemic in China. •In total, 18.2% had depression, 8.8% had anxiety, and 16.6% had somatic symptoms. •Resilience negatively correlated with depression, anxiety, and somatic symptoms. •Resilience represents an essential target for psychological interventions.
36	P34		BarisSancakM.D.UrunOzer AgirbasM.D.CenkKilicM.D.	Long COVID and Its Psychiatric Aspects	https://dx.doi.org/10.1016%2Fj.jaclp.2021.03.003	Published	2021 Mar 29	Letter to the Editor	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005382/	While research on long COVID continues, psychiatrists should be involved in this process. We often see that people with symptoms such as fatigue, insomnia, shortness of breath, or palpitations are referred to psychiatry because no underlying cause can be found. Referral of these patients who experience repetitive physical symptoms to psychiatry often leads them to feel that they are not believed or are inventing symptoms. Interestingly, in the psychiatric outpatient setting, it is not uncommon to discover that the symptoms of patients with similar thoughts are due to overlooked organic causes. In this respect, it is necessary to be curious and open-minded about the chronic effects of a disease such as COVID-19 that can only be fully understood with time. We think that psychiatrists have 2 critical duties here. First, because we are facing a disease whose etiology and long-term symptomatology are not yet fully defined, prematurely diagnosing potential long COVID symptoms as psychiatric disorders may harm the patient by delaying the appropriate treatment. For example, frequent complaints such as shortness of breath, palpitations, and fatigue should not be immediately considered to reflect “anxiety”.2 This attitude may cause an inaccurate diagnosis overlooking the underlying disease, affecting the treatment and the patient's compliance. Therefore a very detailed psychiatric history and examination, inclusive of premorbid characteristics and generating a careful differential diagnosis is essential. Second, it should not be forgotten that psychiatric symptoms may accompany long COVID. Health anxiety and depressive complaints associated with the feeling of hopelessness can be seen. Insomnia and concentration problems are also common psychiatric findings. Long COVID is a condition that may seriously affect the functioning of patients. Diagnosis and treatment of psychiatric symptoms can significantly improve patients' quality of life. Thus, a careful psychiatric examination and effective treatment of psychiatric comorbidities are crucial in patients with COVID-19. There is no information in the literature that psychotropic medicines that are routinely used in the treatment of the previously mentioned psychiatric conditions cause worsening of physical symptoms. Psychotherapy options should be evaluated in cases where there is hesitation about psychopharmacology. In particular, cognitive behavioral therapy is considered to be effective on postviral fatigue and may be useful in long COVID.6
37	P35		Mathilde Horn,a,⁎ Thomas Fovet,a,b Guillaume Vaiva,a,b Fabien D'Hondt,a,b and Ali Amad	Somatic symptom disorders and long COVID: A critical but overlooked topic	https://dx.doi.org/10.1016%2Fj.genhosppsych.2021.06.007	Published	2021 Jun 25	Letter to the Editor	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233051/	As psychiatric symptoms often accompany long COVID, several authors point out the need to discriminate psychiatric from physical symptoms, suggesting that wrongly considering symptoms such as fatigue, insomnia, shortness of breath, as psychiatric symptoms may overlook the underlying disease and delay the appropriate treatment [2]. We agree that people with mental health problems have poorer physical health than the general population and that they face additional obstacles to access appropriate care. Nevertheless, we also think that the reverse is true. The diagnoses of SSD or related disorders are often delayed, after patients have received inappropriate and excessive “diagnosis” testing, dangerous or ineffective therapies, and multiple, often unnecessary, referrals. Considering the risk of SSD following hospitalization related to COVID-19 infection, its potentially detrimental effects on the patient's quality of life, and consequent cost for the health care systems, early detection and optimal management of SSD is essential. For this purpose, Toussaint et al. have recently developed the SSD scale (SSD-12), a self-rating questionnaire composed of 12 items, designed to assess patients' perceptions of their symptom-related thoughts, feelings, and behaviors using questions directly based on the DSM-5 criteria. SSD-12 appears as an easy tool that should assist clinicians in the diagnosis and assessment of SSD [3]. Patients with a diagnosis of SSD should then benefit from multidisciplinary care based on the biopsychosocial model [4]. The main objective of this approach is to help the patients to realize that persistent symptoms arise from the interaction of physiological, cognitive, behavioral, emotional and social factors, which need to be addressed concurrently. Finally, recent literature has highlighted the importance of consultation-liaison psychiatrists (CLPs) in the evaluation of hospitalized patients with COVID-19 [2,5,6]. Indeed, as CLPs use to work with other specialist clinicians, they are particularly well-positioned to manage COVID-19 patients with, or at risk for, SSD who are hospitalized [6]. We believe that a multidisciplinary health care approach of SSD in the context of COVID-19 is an important measure to reduce the psychological impact of the COVID-19 pandemic.
38	P36		S.N. Mosolov	Long-Term Psychiatric Sequelae of SARS-CoV-2 Infection	10.21265/PSYPH.2021.31.25.001	Published	2021	Review	https://www.researchgate.net/profile/Sergey-Mosolov/publication/355118551_Dlitelnye_psihiceskie_narusenia_posle_perenesennoj_ostroj_koronavirusnoj_infekcii_SARS-CoV-2_Long-Term_Psychiatric_Sequelae_of_SARS-CoV-2_Infection/links/615ec49efbd5153f47eac566/Dlitelnye-psihiceskie-narusenia-posle-perenesennoj-ostroj-koronavirusnoj-infekcii-SARS-CoV-2-Long-Term-Psychiatric-Sequelae-of-SARS-CoV-2-Infection.pdf	This psychopathological symptom complex occurs twice as often in patients with COVID-19 as in patients with other acute respiratory viral infections, and is detected in almost one third of all cases and in two thirds of patients with severe coronavirus infection that required hospital admission. Despite the lack of a clear understanding of the pathogenesis, risk factors, prognosis and outcomes of psychopathological symptoms of PCS, it should be regarded as COVID-19 complication that is associated with direct viral damage of the central nervous system (CNS), negative effects of other organ systems damage (primarily cardiovascular and respiratory), and stress response. Considering that the majority of mental health complications, such as asthenia and cognitive deficit, are often accompanied by neurological symptoms, are closely adhered to them and indicate damage of the CNS, it is proposed to define neuropsychiatric PCS as “Brain Long COVID”.
39	P37		Gellan K.AhmedabEman M.KhedraDina A.HamadcTaghreed S.MeshrefcMustafa M.HashemaMai M.Alyd	Long term impact of Covid-19 infection on sleep and mental health: A cross-sectional study	https://doi.org/10.1016/j.psychres.2021.114243	Published	12 October 2021	Study	https://www.sciencedirect.com/science/article/pii/S0165178121005382	Only 8.8% had no psychiatric symptoms while 91.2% had psychiatric symptoms as follow (poor sleep (64.8%), PTSD (28.6%), somatization (41.8%), obsessive-compulsive (OCD) (19.8%), depression (11.5%), anxiety (28%), phobic-anxiety (24.2%), psychoticism (17.6%)). Diabetes, oxygen support or mechanically ventilated were a risk for sleep impairment, while high Neutrophil/lymphocyte ratio(NLR) was the only risk factor for PTSD. Other psychiatric illnesses had several risk factors: being female, diabetes, oxygen support or mechanically ventilated. Abnormal sleep, somatization and anxiety are the most common mental illnesses in Post-Covid19. The critical group is common associated with PTSD, anxiety, and psychosis. Being female, diabetic, having oxygen support or mechanically ventilated, and high NLR level are more vulnerable for mental illness in post COVID19. •The long-term impact of the COVID-19 pandemic on mental health in people is unclear. •Abnormal sleep, somatization, and anxiety are the most common mental illnesses in Post-Covid19. •The critical group is common associated with PTSD, anxiety, and psychosis. •Being female, diabetic, having oxygen support or mechanically ventilated, and high NLR level are more vulnerable for mental illness in post COVID19.	_
40	P38		Rafael A. Rivas-Vazquez, PsyDa,*; Mark A. Blais, PsyDb; and Enrique Carrazana, MDc	Does Anxiety Sensitivity Complicate Recovery From COVID-19 Infection?	https://doi.org/10.4088/PCC.21br03145	Published	November 18, 2021	Case Reports	https://www.psychiatrist.com/pcc/covid-19/anxiety-sensitivity-recovery-covid-19-infection/	We recently assessed 3 individuals recovering from mild COVID-19, none requiring hospitalization or respiratory support, but who were now presenting with panic attacks. Their ages ranged from 29 to 42 years, and all were in good premorbid health. None had cardiovascular or pulmonary disease or other medical comorbidities. Two had no past psychiatric history; one reported a remote history of treatment for anxiety. As a group, they described fatigue, mental dullness, shortness of breath (particularly upon exertion), and difficulty returning to exercise or their normal activity levels. In obtaining detailed history, these patients appeared to demonstrate anxiety sensitivity. Our patients all described heightened vigilance to the somatic sensations that are typically being reported by long haulers (particularly, shortness of breath, chest tightness, fatigue upon exertion) and fear that these sensations meant compromised health status and inability to resume or maintain their premorbid psychosocial functioning. We were struck by how these cognitions triggered rapid escalation of nervousness, anxiety, and panic symptoms. All 3 patients reported reluctance to engage in activities that may elicit physical or somatic symptoms that could mimic or induce panic-like sensations. In addition to appropriate pharmacologic treatment, recommendations included educational and cognitive-behavioral interventions targeting this hypervigilance and misinterpretation of somatic symptoms. We recommend that practitioners be attentive to the possibility of anxiety sensitivity when assessing patients presenting post–COVID-19 infection, as this may complicate recovery and return to premorbid functioning.	_
41	P39		Mario GennaroMazzaabMariagraziaPalladiniaRebeccaDe LorenzobcBeatriceBraviaSaraPolettiabRobertoFurlanbdFabioCiceribc	One-year mental health outcomes in a cohort of COVID-19 survivors	https://doi.org/10.1016/j.jpsychires.2021.11.031	Published	22 November 2021*	Study	https://www.sciencedirect.com/science/article/pii/S0022395621006804	We evaluated 402, 216, and 192 COVID-19 survivors respectively at one, six, and 12 months. A subgroup of 95 patients was evaluated longitudinally both at one, six, and 12 months. Validated self-report questionnaires were administered to assess depression, fatigue, anxiety, and post-traumatic distress. Socio-demographics and setting of care information were gathered for each participant. At six and twelve months, respectively 94 (44%) and 86 (45%) patients self-rated in the clinical range in at least one psychopathological dimension. Pathological fatigue at twelve months was detected in 63 patients (33%). Considering the longitudinal cohort an interaction effect of sex and time was observed for depression (F = 8.63, p < 0.001) and anxiety (F = 5.42, p = 0.005) with males showing a significant increasing trend of symptoms, whereas an opposite course was observed in females.	_
42	P40		Nicole WallbridgeBourmistrova1$TomasSolomon1$PhilipBraude2RebeccaStrawbridge34#BenCarter	Long-term effects of COVID-19 on mental health: A systematic review	https://doi.org/10.1016/j.jad.2021.11.031	Published	16 November 2021	Review	https://www.sciencedirect.com/science/article/pii/S0165032721012532	Highlights •This is the first systematic review to assess longer term psychiatric disorders symptom for COVID-19 survivors. •33 studies were included involving 6,743 participants, with outcomes assessed between one to three months after diagnosis •From the included studies there was no evidence that survivors experienced worse anxiety, or depression than would be expected to the general population levels
43	P41		VeraNezgovorovaaCasara JeanFerrettiaStefanoPallantiabEricHollandera	Modulating neuroinflammation in COVID-19 patients with obsessive-compulsive disorder	https://doi.org/10.1016/j.jpsychires.2021.11.025	Published	17 November 2021	Review	https://www.sciencedirect.com/science/article/pii/S0022395621006749	Exacerbation of symptoms of obsessive-compulsive disorder (OCD) during COVID-19 or new onset of the OCD symptoms resulting from COVID-19 infection is an understudied area of research. It is possible that increased proinflammatory immune status is associated with the onset of obsessive-compulsive symptoms in patients with COVID-19 and that targeted anti-inflammatory treatments for COVID-19 infection can mitigate the new onset of Obsessive-Compulsive (OC) spectrum symptoms. In this review, we cover OCD pathogenesis as related to COVID-19, summarize the impact of cytokines on behavior, and suggest that anti-cytokine treatments can help mitigate post-COVID-19 and new onset of the OC symptoms.	_
44	P42		A.Kachaner1L.Cedric2D.Julie3D.Salmon4B.Ranque5T.De Broucker6M.Elodie3	Diagnostic de trouble fonctionnel somatique chez des patients atteints de symptômes neurologiques inexpliqués post-COVID-19 : l’étude SOMATiC (Somatic Symptom Disorder Triggered by COVID-19)	https://doi.org/10.1016/j.revmed.2021.10.293	Published	24 November 2021	Study	https://www.sciencedirect.com/science/article/pii/S0248866321010171	La plupart des patients ayant des symptômes neurologiques persistants médicalement inexpliqués après un COVID-19 non sévère remplissent les critères diagnostiques d’un trouble fonctionnel somatique selon le DSM-5. Une prise en charge spécifique du trouble fonctionnel dans le COVID long pourrait ainsi permettre d’envisager une amélioration clinique de ces patients.	_
45	P43		Angel Yun-Kuan Thye 1,Jodi Woan-Fei Law 1 ,Loh Teng-Hern Tan 1,2 ,Priyia Pusparajah 1,Hooi-Leng Ser 1 ,Sivakumar Thurairajasingam 2,,Vengadesh Letchumanan 1, andLearn-Han Lee 1,*	Psychological Symptoms in COVID-19 Patients: Insights into Pathophysiology and Risk Factors of Long COVID-19	https://doi.org/10.3390/biology11010061	Published	2 January 2022	Review	https://www.mdpi.com/2079-7737/11/1/61/htm	The neuro-invasive potential of certain coronaviruses has been observed in the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). Based on past outbreaks, including SARS, MERS, and current reports of neuropsychiatric complications following COVID-19, many survivors may be at risk of a number of neuropsychiatric sequelae. Mounting evidence has shown the presence of mental health implications in COVID-19 survivors. This review shows that psychological symptoms including anxiety, depression, and post-traumatic stress disorder (PTSD) have an association with post-COVID-19 infection. The exact cause of these psychiatric sequelae is yet to be determined, but it seems to involve environmental, psychological, and biological factors. Although there are variations in terms of risk factors and the prevalence rate of these psychological symptoms, risk factors including the female gender and having a history of psychiatric disorders appears to be consistent a across few studies, and there are studies showing a higher prevalence rate among post-COVID-19 survivors than among the general population. A therapeutic intervention commonly used to alleviate these psychological symptoms are psychotropic medications, but probiotics could be a safe adjunctive treatment to improve these symptoms. There is growing evidence of studies associating COVID-19 survivors with increased mental health consequences. Mental health implications related to a COVID-19 infection include both acute and long-term consequences. Here we discuss COVID-19-associated psychiatric sequelae, particularly anxiety, depression, and post-traumatic stress disorder (PTSD), drawing parallels to past coronavirus outbreaks. A literature search was completed across three databases, using keywords to search for relevant articles. The cause may directly correlate to the infection through both direct and indirect mechanisms, but the underlying etiology appears more complex and multifactorial, involving environmental, psychological, and biological factors. Although most risk factors and prevalence rates vary across various studies, being of the female gender and having a history of psychiatric disorders seem consistent. Several studies will be presented, demonstrating COVID-19 survivors presenting higher rates of mental health consequences than the general population. The possible mechanisms by which the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the brain, affecting the central nervous system (CNS) and causing these psychiatric sequelae, will be discussed, particularly concerning the SARS-CoV-2 entry via the angiotensin-converting enzyme 2 (ACE-2) receptors and the implications of the immune inflammatory signaling on neuropsychiatric disorders. Some possible therapeutic options will also be considered.
46	P44		Rodolfo FurlanDamianoaMaria Julia GuimarãesCarusoaAlissom VittiCincotoaCristiana Castanhode Almeida RoccaaAntoniode Pádua SerafimaPedroBacchiaBruno F.GuedesbAndré R.BrunonicdefPedro MarioPangRicardoNitrinibScottBeachhiGregoryFricchionehiGeraldoBusattoaEuripedes ConstantinoMiguelaOrestes V.ForlenzaaHCFMUSP COVID-19 Study Group1	Post-COVID-19 psychiatric and cognitive morbidity: Preliminary findings from a Brazilian cohort study	https://doi.org/10.1016/j.genhosppsych.2022.01.002	Published	6 January 2022	Study	https://www.sciencedirect.com/science/article/pii/S0163834322000020	Highlights •This is the first study to capture psychiatric diagnosis in a large cohort of post-COVID-patients using structured clinical interview. •We found a high prevalence of psychiatric diagnosis, such as generalized anxiety disorder, depression, and post-traumatic stress disorder as well cognitive issues 6 months post-COVID-19. •Our findings do not point out to a relationship between disease severity at baseline and the degree of mental and cognitive impairment. Diagnoses of ‘depression’, ‘generalized anxiety disorder’ and ‘post-traumatic stress disorder’ were established respectively in 8%, 15.5% and 13.6% of the sample. After pandemic onset (i.e., within the previous year), the prevalence of ‘depression’ and ‘generalized anxiety disorder’ were 2.56% and 8.14%, respectively. Memory decline was subjectively reported by 51.1% of the patients. Psychiatric or cognitive outcomes were not associated with any clinical variables related to the severity of acute-phase disease, nor by disease-related psychosocial stressors. Conclusions This is the first study to access rates of psychiatric and cognitive morbidity in the long-term outcome after moderate or severe forms of COVID-19 using standardized measures. As a key finding, there was no significant association between clinical severity in the acute-phase of SARS-CoV-2 infection and the neuropsychiatric impairment 6 to 9 months thereafter.
47	P45		César Fernández-de-las-Peñas Open the record for César Fernández-de-las-Peñas , José D. Martín-Guerrero , Ignacio Cancela-Cilleruelo , Paloma Moro-López-Menchero , Jorge Rodríguez-Jiménez and Oscar J. Pellicer-Valero	Trajectory curves of post-COVID anxiety/depressive symptoms and sleep quality in previously hospitalized COVID-19 survivors: the LONG-COVID-EXP-CM multicenter study	https://doi.org/10.1017/S003329172200006X	Published	10 January 2022	Study	https://www.cambridge.org/core/journals/psychological-medicine/article/trajectory-curves-of-postcovid-anxietydepressive-symptoms-and-sleep-quality-in-previously-hospitalized-covid19-survivors-the-longcovidexpcm-multicenter-study/A036B60A0F9CE23EE03E1577E64D30B8	No previous study has investigated the trajectory curve of anxiety/depressive symptoms as post-COVID sequelae. We present here a study investigating the trajectory curves of post-COVID anxiety/depressive symptoms as well as sleep quality, fitted with an exponential trajectory model, in previously hospitalized COVID-19 survivors.
48	P46		Ricardo Titze-de-Almeida, Thaylise Ramalho da Cunha, Letícia Dias dos Santos Silva, Clarisse Santos Ferreira, Caroline Pena Silva, Adriana Pinheiro Ribeiro, Agenor de Castro Moreira Santos Júnior, Pedro Renato de Paula Brandão, Andrezza Paula Brito Silva, Márcia Cristina Oliveira da Rocha, Mary-Ann Elvina Xavier, Simoneide Souza Titze-de-Almeida, Helena Eri Shimizu & Raimundo Nonato Delgado-Rodrigues	Persistent, new-onset symptoms and mental health complaints in Long COVID in a Brazilian cohort of non-hospitalized patients	https://doi.org/10.1186/s12879-022-07065-3	Published	08 February 2022	Study	https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-022-07065-3	Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections lead to acute- and chronic Long COVID (LC) symptoms. However, few studies have addressed LC sequelae on brain functions. This study was aimed to examine if acute symptoms of coronavirus disease 2019 (COVID-19) would persist during LC, and if memory problems would be correlated with sleep, depressive mood, or anxious complaints. Methods Our work followed a cohort of 236 patients from two public hospitals of the Federal District in mid-western Brazil. Patients’ interviews checked for clinical symptoms during acute and LC (5–8 months after real-time reverse transcription polymerase chain reaction, RT-qPCR). Results Most cases were non-hospitalized individuals (86.3%) with a median age of 41.2 years. While myalgia (50%), hyposmia (48.3%), and dysgeusia (45.8%) were prevalent symptoms in acute phase, fatigue (21.6%) followed by headache (19.1%) and myalgia (16.1%) commonly occurred during LC. In LC, 39.8% of individuals reported memory complaints, 36.9% felt anxious, 44.9% felt depressed, and 45.8% had sleep problems. Furthermore, memory complaints were associated with sleep problems (adjusted OR 3.206; 95% CI 1.723–6.030) and depressive feelings (adjusted OR 3.981; 95% CI 2.068–7.815). Conclusions The SARS-CoV-2 infection leads to persistent symptoms during LC, in which memory problems may be associated with sleep and depressive complaints.
49	P47		Milena NogueiraAzevedoab#Elisângela da SilvaRodriguesdh#Emília Augusta Franz VieiraPassosaeMárcio Andrade BarretoFilhoacAna Paula AndradeBarretoacMarcelo Chalhoub CoelhoLimaafMauricio LimaBarretodLuis Fernando SilvaCastro-de-Araujodg	Multimorbidity associated with anxiety symptomatology in post-COVID patients	https://doi.org/10.1016/j.psychres.2022.114427	Published	3 February 2022	Study	https://www.sciencedirect.com/science/article/pii/S0165178122000415	Highlights •Few studies have described post-covid conditions in a population, mainly de low/middle-income country. •Multimorbidity was significantly associated with anxiety symptomatology. •Being male and aging reduced the anxiety and depression score. Abstract The COVID-19 pandemic hit individuals with chronic conditions the hardest. It is known that anxiety symptoms are frequent in post-COVID conditions. We want to examine whether multimorbidity is associated with anxiety in post-COVID patients. We reported descriptive statistics from 389 post-COVID patients and perform a linear regression with anxiety symptoms measured using the Hospital Anxiety and Depression (HAD) scale. For each extra chronic condition, there was a mean increase of 0.11 in the HAD-anxiety score. However, there was a reduction for age and being male. These findings can potentially help policy-makers better organize post-COVID health services and improve patients care.
50	P48		Lamyae Benzakour Frédéric Assal Julie Anne Péron	Covid long neuropsychologique : origine neurologique ou psychiatrique ?		Published	28 avril 2021	Article	https://www.revmed.ch/revue-medicale-suisse/2021/revue-medicale-suisse-736/covid-long-neuropsychologique-origine-neurologique-ou-psychiatrique	Résumé Parmi les symptômes de Covid long, les séquelles neuropsychologiques sont fréquentes dans les suites d’une infection par le SARS-CoV-2, et ce quel que soit le degré de sévérité de l’atteinte respiratoire en phase aiguë. Ces déficits semblent résulter d’une atteinte neurologique, mais aussi de l’installation de troubles psychiatriques. En plus de l’inflammation, qui joue un rôle majeur dans la genèse des séquelles neuropsychologiques, les hypothèses de lésions endothéliales systémiques, de l’existence d’un neurotropisme du SARS-CoV-2, de même que de celles de l’effet du stress et de la mise en jeu de l’axe hypothalamo-hypophysaire-surrénalien, sont proposées. Les complications psychiatriques de l’infection par le SARS-CoV-2 semblent, quant à elles, n’expliquer qu’une partie des séquelles neuropsychologiques. Implications pratiques • Les séquelles neuropsychologiques dans les suites de l’infection par le SARS-CoV-2 sont fréquentes • Le risque de séquelles neuropsychologiques ne dépend pas du niveau de sévérité de l’atteinte respiratoire de l’infection par le SARS-CoV-2 en phase aiguë • Les troubles psychiatriques expliquent une partie des séquelles neuropsychologiques et doivent être recherchés mais des causes neurologiques peuvent également être incriminées • La recherche sur le Covid long doit ouvrir des pistes thérapeutiques, en permettant de mieux caractériser les mécanismes sous-tendant les séquelles neuropsychologiques afin d’optimiser la prise en charge
51	P49		Cristina Delgado-Alonso 1,María Valles-Salgado 1,Alfonso Delgado-Álvarez 1,Natividad Gómez-Ruiz 2 ,Miguel Yus 2 ,Carmen Polidura 2,Carlos Pérez-Izquierdo 3,Alberto Marcos 1,María José Gil 1 ,Jorge Matías-Guiu 1 andJordi A. Matias-Guiu 1,*	Examining Association of Personality Characteristics and Neuropsychiatric Symptoms in Post-COVID Syndrome	https://doi.org/10.3390/brainsci12020265	Published	14 February 2022	Article	https://www.mdpi.com/2076-3425/12/2/265/htm	Highlights •Few studies have described post-covid conditions in a population, mainly de low/middle-income country. •Multimorbidity was significantly associated with anxiety symptomatology. •Being male and aging reduced the anxiety and depression score. Abstract The COVID-19 pandemic hit individuals with chronic conditions the hardest. It is known that anxiety symptoms are frequent in post-COVID conditions. We want to examine whether multimorbidity is associated with anxiety in post-COVID patients. We reported descriptive statistics from 389 post-COVID patients and perform a linear regression with anxiety symptoms measured using the Hospital Anxiety and Depression (HAD) scale. For each extra chronic condition, there was a mean increase of 0.11 in the HAD-anxiety score. However, there was a reduction for age and being male. These findings can potentially help policy-makers better organize post-COVID health services and improve patients care.
52	P50		Alicia W. Villanueva Van Den Hurk, Cady Ujvari, View ProfileNoah Greenspan, View ProfileDolores Malaspina, Xavier F. Jimenez, View ProfileJulie Walsh-Messinger	Childhood Trauma Exposure Increases Long COVID Risk	https://doi.org/10.1101/2022.02.18.22271191	pre-print	February 22, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.02.18.22271191v1.full-text	Methods Participants (N=338) completed online measures of premorbid health, COVID-19 positivity, symptoms, recovery, depression, anxiety, and post-traumatic stress disorder (PTSD). Questionnaires about childhood and recent traumatic experiences were completed by half of the sample (N=162). Results Fifty-three percent of participants developed long COVID, of whom over 60% endorsed exercise intolerance and protracted myalgias, headaches, brain fog, and shortness of breath. Participants who experienced at least one childhood traumatic event were 3-fold more likely to develop the syndrome (OR=3.11, 95% CI, 1.49 to 6.48), while risk was nearly 6-fold increased for two or more events (OR=5.67, CI, 2.44 to 13.13). Regression models showed childhood trauma (OR=5.32, CI, 1.44 to 19.68), older age (OR=1.11, CI, 1.06 to 1.16), female sex (OR=4.02, CI, 1.34 to 12.12), along with chest pain (OR=8.77, CI, 2.80 to 27.43), brain fog (OR=3.33, CI, 1.16 to 9.57) and phantosmia (OR=5.90, CI, 1.40 to 24.86) during acute illness accurately classified long COVID status in 87% of participants. Interpretations Early adversity is a risk-factor for long COVID, likely due to altered immune response, central sensitization, and peripheral dysfunction. Childhood trauma, a crucial social determinant of health, should be routinely assessed in COVID-19 survivors and may aid in determining prognosis.	todo
53	P51		Ziyad Al-Aly	Mental health in people with covid-19	https://doi.org/10.1136/bmj.o415	Published	17 February 2022	Opinion	https://www.bmj.com/content/376/bmj.o415	In April 2021, we published a large-scale systematic characterisation of the clinical manifestations of long covid—the post-acute sequelae that result from an infection with SARS-CoV-2.1 We followed people for six months and showed that covid-19 can lead to post-acute sequelae in nearly every organ system, including increased risk of mental health disorders. The research prompted calls from patients and healthcare practitioners to do a detailed analysis with longer follow-up to better understand the risks of the mental health outcomes experienced by people with covid-19. In our recent study, published in The BMJ, we perform a comprehensive in-depth evaluation of the risks of mental health disorders in people with covid-19 at one year.2 The results show that even when compared to contemporaneous controls of people who did not have covid-19, but were exposed to the same adverse forces of the pandemic—including economic, social, and other stressors—those with covid-19 exhibited increased risk of mental health outcomes. This was consistent in analyses versus a historical control group from a pre-pandemic era. Our research catalogues the breadth of post-acute mental health outcomes experienced by people with covid-19 including depression, anxiety, and stress and adjustment disorders. There was also evidence of increased risk of substance use disorders, neurocognitive decline, and sleep problems. These risks were evident even among those people whose disease was mild and did not require hospital admission for covid-19. Altogether, the findings suggest that people with covid-19 are experiencing increased rates of mental health outcomes, which could have far-reaching consequences. The increased risk of opioid use is of particular concern, especially considering the high rates of opioid use disorders pre-pandemic. The increased risks of mental health outcomes in people with covid-19 demands greater attention now to mitigate much more serious downstream consequences in the future. Some may use our findings to gaslight or dismiss long covid as a psychosomatic condition or explain the myriad manifestations of long covid as the result of mental illness. This dismissal is contrary to scientific evidence and is harmful to patients and communities. Mental health disorders represent one part of the multifaceted nature of long covid which can affect nearly every organ system (including the brain, heart, and kidneys). Our results should be used to promote awareness of this risk among people with covid-19 and to guide efforts for the early identification and treatment of affected individuals. The body of evidence on long covid—from our work and others—suggests the need to reframe our thinking about SARS-CoV-2. It is not only a respiratory virus; it is a systemic virus that may provoke damage and clinical consequences in nearly every organ system—including mental health disorders and neurocognitive decline. Long covid demands greater attention now to better understand it, prevent it, and treat affected individuals. International bodies, governments, and other stakeholders must pay attention. Failure to attend to the risks of long covid risks amplifying the profound losses we have experienced in this global pandemic.
54	P52		Scott Weich	Mental health after covid-19	https://doi.org/10.1136/bmj.o326	Published	16 February 2022	Editorial	https://www.bmj.com/content/376/bmj.o326	What do these studies tell us? Both report significant and consistent but modest associations between SARS-CoV-2 infection and increased rates of psychiatric disorders. Although between group differences persist for at least 12 months,7 the absolute risk of experiencing a psychiatric disorder decreases sharply after the first month.9 Both studies were susceptible to residual confounding and potential misclassification of recurrent versus first onset infections, limiting causal inference and interpretation. Importantly, mental healthcare might have been more accessible to those known to have had covid-19 than contemporaries without this condition or among historical cohorts, further biasing estimates away from the null.10 What have we learnt? Time, money, and scarce research expertise have been devoted to showing, again and on a societal scale, that threat makes people anxious but diminishes for most people when the danger passes.1 Further confirmation has shown that those who are most disadvantaged experience the worst (mental) health outcomes, particularly after the harms caused by a decade of austerity in the UK and many other countries.1112 Health inequalities have widened, particularly for people with serious mental illness who have experienced even more exclusion and premature mortality during the pandemic.1213 The worst of the pandemic might be behind us in terms of mortality and social restrictions. Taking stock, it could be argued that much of the research concerned with the mental health impacts of covid-19 represents more hindsight than insight. Looking back at what happened is arguably less important than reflecting on what we have learnt, what we need to do next, and what we still do not know. Our attachment to syndromal phenotypes14 means that we have learnt remarkably little about the causes of mental ill health—in this case psychopathology associated with a viral pandemic. We continue to generate more heat than light as we reflect on the usual biopsychosocial suspects10 without cutting through to conclusive insights or effective interventions. We do not yet know the true incidence and consequences of long covid,15 and we are still witnessing the unfolding toll of the pandemic on healthcare staff.16 Also, we do not have an effective response to the devastating disruption to health, social care, and voluntary sector services on the lives of people with serious mental illness.17 And while epidemiological research has flourished—at least in terms of scientific publications—we are guilty of failing to prioritise evaluations of mental healthcare interventions, including clinical trials, just when these are most needed.
55	P53		Yan Xie, Evan Xu, Ziyad Al-Aly	Risks of mental health outcomes in people with covid-19: cohort study	https://doi.org/10.1136/bmj-2021-068993	Published	16 February 2022	Study	https://www.bmj.com/content/376/bmj-2021-068993	Results The covid-19 group showed an increased risk of incident anxiety disorders (hazard ratio 1.35 (95% confidence interval 1.30 to 1.39); risk difference 11.06 (95% confidence interval 9.64 to 12.53) per 1000 people at one year), depressive disorders (1.39 (1.34 to 1.43); 15.12 (13.38 to 16.91) per 1000 people at one year), stress and adjustment disorders (1.38 (1.34 to 1.43); 13.29 (11.71 to 14.92) per 1000 people at one year), and use of antidepressants (1.55 (1.50 to 1.60); 21.59 (19.63 to 23.60) per 1000 people at one year) and benzodiazepines (1.65 (1.58 to 1.72); 10.46 (9.37 to 11.61) per 1000 people at one year). The risk of incident opioid prescriptions also increased (1.76 (1.71 to 1.81); 35.90 (33.61 to 38.25) per 1000 people at one year), opioid use disorders (1.34 (1.21 to 1.48); 0.96 (0.59 to 1.37) per 1000 people at one year), and other (non-opioid) substance use disorders (1.20 (1.15 to 1.26); 4.34 (3.22 to 5.51) per 1000 people at one year). The covid-19 group also showed an increased risk of incident neurocognitive decline (1.80 (1.72 to 1.89); 10.75 (9.65 to 11.91) per 1000 people at one year) and sleep disorders (1.41 (1.38 to 1.45); 23.80 (21.65 to 26.00) per 1000 people at one year). The risk of any incident mental health diagnosis or prescription was increased (1.60 (1.55 to 1.66); 64.38 (58.90 to 70.01) per 1000 people at one year). The risks of examined outcomes were increased even among people who were not admitted to hospital and were highest among those who were admitted to hospital during the acute phase of covid-19. Results were consistent with those in the historical control group. The risk of incident mental health disorders was consistently higher in the covid-19 group in comparisons of people with covid-19 not admitted to hospital versus those not admitted to hospital for seasonal influenza, admitted to hospital with covid-19 versus admitted to hospital with seasonal influenza, and admitted to hospital with covid-19 versus admitted to hospital for any other cause. Conclusions The findings suggest that people who survive the acute phase of covid-19 are at increased risk of an array of incident mental health disorders. Tackling mental health disorders among survivors of covid-19 should be a priority.
56	P54		Sarah Houben-Wilke 1 Author Image ; Yvonne MJ Goërtz 1, 2, 3 Author Image ; Jeannet M Delbressine 1 Author Image ; Anouk W Vaes 1 Author Image ; Roy Meys 1, 2, 3 Author Image ; Felipe VC Machado 1, 2, 3 Author Image ; Maarten van Herck 1, 2, 3, 4 Author Image ; Chris Burtin 4 Author Image ; Rein Posthuma 1, 2, 3 Author Image ; Frits ME Franssen 1, 2, 3 Author Image ; Herman Vijlbrief 5 Author Image ; Yvonne Spies 5 Author Image ; Alex J van 't Hul 6 Author Image ; Martijn A Spruit 1, 2, 3 Author Image ; Daisy JA Janssen 1, 7 Author Image	The Impact of Long COVID-19 on Mental Health: Observational 6-Month Follow-Up Study	https://doi.org/10.2196/33704	Published	24.2.2022	Study	https://mental.jmir.org/2022/2/e33704/	Objective: In this longitudinal, observational study, we aimed to reveal symptoms of posttraumatic stress disorder (PTSD) and symptoms of anxiety and depression up to 6 months after the onset of COVID-19–related symptoms in patients with confirmed COVID-19 and persistent complaints. To demonstrate the impact in nonhospitalized patients, we further aimed to compare these outcomes between nonhospitalized and hospitalized patients. Methods: Demographics, symptoms of PTSD (Trauma Screening Questionnaire [TSQ] ≥6 points) and symptoms of anxiety and depression (Hospital Anxiety and Depression Scale [HADS] ≥8 points) were assessed at 3 and 6 months after the onset of COVID-19–related symptoms in members of online long COVID-19 peer support groups. Results: Data from 239 patients with confirmed COVID-19 (198/239, 82.8% female; median age: 50 [IQR 39-56] years) were analyzed. At the 3-month follow-up, 37.2% (89/239) of the patients had symptoms of PTSD, 35.6% (85/239) had symptoms of anxiety, and 46.9% (112/239) had symptoms of depression, which remained high at the 6-month follow-up (64/239, 26.8%, P=.001; 83/239, 34.7%, P=.90; 97/239, 40.6%, P=.08, respectively; versus the 3-month follow-up). TSQ scores and HADS anxiety and depression scores were strongly correlated at the 3- and 6-month follow-ups (r=0.63-0.71, P<.001). Symptoms of PTSD, anxiety, and depression were comparable between hospitalized (n=62) and nonhospitalized (n=177) patients. Conclusions: A substantial percentage of patients with confirmed COVID-19 and persistent complaints reported symptoms of PTSD, anxiety, or depression 3 and 6 months after the onset of COVID-19–related symptoms. The prevalence rates of symptoms of PTSD, anxiety, and depression were comparable between hospitalized and nonhospitalized patients and merely improved over time. Health care professionals need to be aware of these psychological complications and intervene on time in post-COVID-19 patients with persistent complaints.
57	P55		Nadia A.Liyanage-DonabMelodie R.WinawercMarla J.HambergercSachinAgarwalcAlison R.TrainoraKristal A.QuispeaIan M.Kronishab	Association of depression and COVID-induced PTSD with cognitive symptoms after COVID-19 illness	https://doi.org/10.1016/j.genhosppsych.2022.02.006	Published	2 March 2022	Study	https://www.sciencedirect.com/science/article/pii/S016383432200024X	Results Among 153 participants, 44.4% reported at least one cognitive symptom, 18.3% were depressed, and 23.5% had COVID-induced PTSD. Adjusting for covariates, depression (OR 5.15, 95% CI 1.30–20.35, p = 0.02) and COVID-induced PTSD (OR 3.67, 95% CI 1.13–11.89, p = 0.03) were significantly associated with cognitive symptoms; self-reported history of mental illness was also associated (OR 4.90, 95% CI 1.24–19.41, p = 0.02). Conclusions Depression, COVID-induced PTSD, and prior mental illness were strongly associated with cognitive symptoms three months after acute COVID-19 illness.
58	P56		Jean-LucMommaertsMD, MSc, PhD	Where is the mind in COVID-19 causality?	https://doi.org/10.1016/j.bbih.2022.100434	Published	9 March 2022	Article	https://www.sciencedirect.com/science/article/pii/S2666354622000242	Two years into the pandemic, hardly any studies have been done regarding the influence of the mind on COVID-19. However, there is much circumstantial evidence. The mind influences the body in ways relevant to COVID-19. Unfortunately, of the scientifically proven mental factors influencing immunology, many have been intensified by lockdowns. Relevant research might help us see COVID-19 not as a disease straightforwardly caused by a virus but by a whirlpool of factors in which the virus and mind play essential roles. Social nocebo (mass psychogenic illness) may be a significant mind-related factor in the whirlpool through heightening the suggestive idea that worse will come. This insight might bring a more profound view of the human social condition, transcending the present disaster. Meanwhile, the whirlpool metaphor may help acute COVID-19 patients and long-haulers, letting them understand that their mind is one element in the whole, no more and no less.
59	P57		Virginie FreytagNathalie SchicktanzDavid CoynelThomas SchlittEhssan AminiAndreas PapassotiropoulosDominique de Quervain	The Swiss Corona Stress Study: Long Covid symptoms in relation to stress and depressive symptoms	https://doi.org/10.31219/osf.io/2x4pg	pre-print	March 22, 2022	Study	https://osf.io/2x4pg/	Background: An infection with SARS-CoV-2 can lead to long-term health problems known as Long Covid or Post Covid-19 condition. Whereas Long Covid symptoms may induce stress and depressive symptoms, it is also possible that stress and depressive symptoms can contribute to some of the symptoms. Importantly, stress levels and depressive symptoms have been found to be increased during the pandemic and may be also increased after infection. When investigating the prevalence of Long Covid symptoms it seems therefore important to use well-matched controls and to take stress levels and depressive symptoms into account. Methods: We conducted a survey study in over 11’000 subjects in the framework of the Swiss Corona Stress Study (4th survey, November 2021) and assessed stress levels and depressive symptoms (PHQ-9) along with physical and neurological symptoms of the past two weeks. From the 1’428 participants reporting at least one SARS-CoV-2 positive PCR test (98% non-hospitalized), we created 3 non-overlapping groups based on the date of the last reported positive test: at least 9 months before the study (n=774); between 9 and 3 months before the study (n=238); within 3 months before the study (n=416). For each group, we selected an equally sized subset of matched participants from the study pool of 9’651 subjects who didn’t report any SARS-CoV-2 positive test. Results: We found that the prevalence of several physical/neurological symptoms was significantly higher in SARS-CoV-2 positives as compared to the negative controls at all 3 time points. For participants who report having been tested positive at least 9 months ago, the top 3 symptoms as compared to negative controls were loss of smell/taste (prevalence positives: 20%, prevalence negatives: 1%, p=4.0E-20), rapid physical exhaustion (prevalence positives: 29%, prevalence negatives: 15%, p=2.3E-10) and fever (prevalence positives: 10%, prevalence negatives: 3%, p=1.9E-8). Stress levels and depressive symptoms were significantly associated with increased prevalence for most of the symptoms in both SARS-CoV-2 positives and negative controls. However, a history of SARS-CoV-2 infection was not significantly associated with heightened levels of stress or depressive symptoms at any of the investigated time intervals, and a higher prevalence of symptoms in these participants was also observed under adjustment for psychological state measures. Conclusion: The present results indicate that SARS-CoV-2 positivity is associated with higher prevalence of physical or neurological symptoms independently from stress levels or depressive symptoms.
60	P58		Sy Atezaz Saeed MD, MS, Irene S. Pastis MD & Melody Grace Santos MD	COVID-19 and its impact on the brain and Mind- A conceptual model and supporting evidence	https://doi.org/10.1007/s11126-022-09980-9	Published	18 March 2022	Review	https://link.springer.com/article/10.1007/s11126-022-09980-9	Although the reported symptoms of COVID-19 are primarily respiratory with acute respiratory distress syndrome, SARS-CoV-2 has also been shown to affect other organs, including brain, and there are growing reports of neuropsychiatric symptoms due to COVID-19. There are two suggested pathways for how COVID-19 can affect the brain and mind: the direct impact on the brain and impact mediated via stress. Direct impact on the brain is manifested as encephalitis/encephalopathy with altered mental status (AMS) and delirium. In this paper, we summarize evidence from studies of previous outbreaks and current data from the COVID-19 pandemic that describe how COVID-19 is associated with an increased prevalence of anxiety, stress, poor sleep quality, obsessive-compulsive symptoms, and depression among the general population during the pandemic. In addition, we summarize the current evidence that supports how COVID-19 can also impact the CNS directly and result in delirium, cerebrovascular events, encephalitis, unspecified encephalopathy, AMS, or peripheral neurologic disorders.
61	P59		Alexandra Burton 1, Henry Aughterson 1, Daisy Fancourt 1, Keir E J Philip 2	Factors shaping the mental health and well-being of people experiencing persistent COVID-19 symptoms or 'long COVID': qualitative study	https://doi.org/10.1192/bjo.2022.38	Published	2022 Mar 21	Study	https://pubmed.ncbi.nlm.nih.gov/35307048/	Background: Around one in ten people who contract COVID-19 report persistent symptoms or 'long COVID'. Impaired mental health and well-being is commonly reported, including anxiety, depression and reduced quality of life. However, there is limited in-depth research exploring why mental health and well-being are affected in people experiencing long COVID. Aims: To explore factors affecting mental health and well-being from the perspective of people with long COVID. Method: Semi-structured qualitative interviews were audio-recorded and transcribed. Data were analysed using reflexive thematic analysis. Twenty-one people with long COVID participated in the study. Participants were eligible if they self-reported a positive swab test/antibody test or one or more commonly reported COVID-19 symptoms at illness onset. and experiences of one or more long COVID symptoms ≥3 weeks following illness onset. Results: Five themes were identified across participant accounts regarding factors affecting mental health and well-being, including symptoms causing severe disruption to daily life, lack of service and treatment options, uncertainty of illness trajectories, experiences of care and understanding from others and changes to identity. Conclusions: People with long COVID experience a range of factors that negatively affect their mental health and well-being. Providing patient-centred health services that integrate rapidly evolving research in this area is important, as are peer support groups and supported approaches to self-management.
62	P60		Zheng-An Lu 1,†,Le Shi 1,†,Jian-Yu Que 1,Yong-Bo Zheng 1,2,Qian-Wen Wang 1,Wei-Jian Liu 1,Yue-Tong Huang 1,Xiao-Xing Liu 1,Kai Yuan 1,Wei Yan 1,Jie Shi 3,Yan-Ping Bao 3,* andLin Lu 1,2,3,*	Accessibility to Digital Mental Health Services among the General Public throughout COVID-19: Trajectories, Influencing Factors and Association with Long-Term Mental Health Symptoms	https://doi.org/10.3390/ijerph19063593	Published	17 March 2022	Study	https://www.mdpi.com/1660-4601/19/6/3593/htm	Digital mental health services (DMHSs) have great potential for mitigating the mental health burden related to COVID-19, but public accessibility (ease of acquiring services when needed) to DMHSs during the pandemic is largely unknown. Accessibility to DMHSs was tracked longitudinally among a nationwide sample of 18,804 adults in China from before to one year after COVID-19 outbreak. Unconditional and conditional latent growth curve models and latent growth mixture models were fitted to explore the overall growth trend, influencing factors, and latent trajectory classes of accessibility to DMHSs throughout COVID-19. Generalized estimating equation models and generalized linear mixed models were employed to explore the association between accessibility to DMHSs and long-term mental health symptoms. We found that people generally reported increased difficulty in accessing DMHSs from before to one year after COVID-19 outbreak. Males, youngsters, individuals with low socioeconomic status, and individuals greatly affected by COVID-19 reported greater difficulty in accessing DMHSs. Four DMHS accessibility trajectory classes were identified: “lowest–great increase” (6.3%), “moderate low–slight increase” (44.4%), “moderate high–slight decrease” (18.1%) and “highest–great decrease” (31.2%). Trajectory classes reporting greater difficulty in accessing DMHSs were at higher risk for long-term mental symptoms. In conclusion, an overall increase in difficulty in accessing DMHSs is observed throughout COVID-19, and heterogeneity exists in DMHS accessibility trajectories. Our results suggest that easy access to DMHSs should be consistently facilitated. Moreover, access gaps should be reduced across demographic groups, and target populations for service allocation should alter as the pandemic evolves.
63	P61		Tony Kirby	Paul Harrison—investigating the psychiatric sequelae of COVID-19	https://doi.org/10.1016/S2215-0366(22)00116-X	Published	April 2022	Article	https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(22)00116-X/fulltext	The first analysis (published in The Lancet Psychiatry) of more than 60 000 survivors of COVID-19, mostly in the USA, showed that a diagnosis of COVID-19 was associated with an increased incidence of a first or a recurrent psychiatric diagnosis in the following 14 to 90 days compared with six other health events, including influenza, respiratory tract infections, and bone fractures. The greatest increased incidence was found for anxiety disorders. The study also showed that having an existing psychiatric diagnosis was linked to an increased risk of COVID-19. The second study (also published in The Lancet Psychiatry) of more than 230 000 survivors of COVID-19 provided further evidence for substantial psychiatric, and neurological, morbidity in the 6 months after COVID-19 infection. “One in three patients was diagnosed with a psychiatric or neurological condition, and one in eight received their first such diagnosis of this kind”, explains Harrison. “The risks were greatest in, but not limited to, patients who had experienced severe COVID-19.” The third study, published in PLOS Medicine, studied more than 270 000 patients and found that over one in three had one or more features of long-COVID (such as fatigue, pain, or brain fog) recorded between 3 and 6 months after a diagnosis of COVID-19. This was significantly higher than after influenza. The risk of long-COVID features was higher in patients who had more severe COVID-19 illness, and slightly higher among females. White and non-White patients were equally affected. “We plan to extend our work to look at longer-term follow up, as well as to see whether the effects of the virus are evolving over time, in relation to change in dominance of differing variants”, explains Harrison. Other studies that his team has carried out include one showing a marked increase in eating disorders since the pandemic began. He has also just begun a detailed study into brain fog, which will conduct a battery of tests on volunteers with the condition to try to identify the causes and potential treatments. “Early clues are that this could be related to persistent inflammation, or small blood clots in the blood vessels of the brain”, he says.
64	P62		Lily A.BrownaEmilyBallentineaYiqinZhuaEmily L.McGinleybLilianaPezzincBenjaminAbramoffd	The unique contribution of depression to cognitive impairment in Post-Acute Sequelae of SARS-CoV-2 infection	https://doi.org/10.1016/j.bbih.2022.100460	Published	12 April 2022	Study	https://www.sciencedirect.com/science/article/pii/S2666354622000503	Highlights •Depression was positively associated with cognitive impairment post-COVID-19 infection. •Depression was associated with lower performance on verbal fluency, attention, and delayed recall. •Perceived sleep concerns predicted self-reported memory disturbances. •Neither PTSD nor anxiety predicted cognitive impairment memory. Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with significant cognitive impairment and increased risk for mental health comorbidities. This study aimed to identify specific associations between cognitive impairment, self-reported disruptions in memory, and psychiatric symptoms including depression, anxiety, posttraumatic stress disorder (PTSD), and perceived sleep concerns. Methods Data collected from all consecutive patients with Post-Acute Sequelae of SARS-CoV-2 infection (PASC) who presented to a dedicated Post-COVID Clinic were used to evaluate whether certain psychiatric symptoms were more strongly associated with cognitive impairment and self-reported memory disturbances. Results Univariate and multivariable analyses revealed that depression symptom severity was significantly associated with the severity of cognitive impairment among patients with PASC. This association was driven primarily by lower performance on verbal fluency, attention, and delayed recall tasks among patients with higher depression symptoms severity. Perceived sleep concerns were an important predictor of self-reported memory disturbances. Conversely, neither PTSD symptom severity nor anxiety symptom severity were significant predictors of cognitive impairment or self-reported memory disturbances. Conclusions These findings have important clinical implications for justifying the need for screening patients with PASC for both depression and cognitive impairment.
65	P63		Michele Fabrazzo1*, Antonio Russo2, Mario Luciano1, Alessio Camerlengo1, Pierluigi Catapano1, Bianca Amoroso1, Francesco Catapano1 and Nicola Coppola2	Delirium and Psychiatric Sequelae Associated to SARS-CoV-2 in Asymptomatic Patients With Psychiatric History and Mild Cognitive Impairment as Risk Factors: Three Case Reports	https://doi.org/10.3389/fpsyt.2022.868286	Published	07 April 2022	Study	https://www.frontiersin.org/articles/10.3389/fpsyt.2022.868286/full	Human coronaviruses have neuroinvasive and neurotropic abilities that might explain psychiatric outcomes in affected patients. We hypothesized that delirium might be the sole clinical manifestation or even the prodrome of a psychiatric episode consistent with the mental history of a few infected patients with a preexisting diagnosed cognitive impairment. We examined three patients with preexisting mild cognitive impairment and delirium at admission for suspected SARS-CoV-2 infection. We diagnosed delirium using DSM-5 and Confusion Assessment Method (CAM) and measured consciousness level by the Glasgow Coma Scale. All the patients had no history of fever, respiratory complications, anosmia or ageusia, meningitis, and negative cerebrospinal fluid analysis for SARS-CoV-2. Our first patient had no psychiatric history, the second reported only a depressive episode, and the third had a history of bipolar disorder dated back to 40 years before. In the first patient, delirium resolved 2 days following the admission. The other two patients recovered in 4 and 14 days, and delirium appeared as the prodrome of a new psychiatric episode resembling past events. Clinicians should monitor the possibility that SARS-CoV-2 presence in the brain might clinically manifest in the form of delirium and acute psychiatric sequelae, even without other systemic symptoms. Psychiatric history and preexisting mild cognitive impairment are to be considered as predisposing factors for COVID-19 sequelae in delirium patients.
66	P64		Sara Nowakowski 1,2,3,*ORCID,Manasa Kokonda 1,2,Rizwana Sultana 4,Brittany B. Duong 4,Sarah E. Nagy 4,Mohammed F. Zaidan 4,Mirza M. Baig 4,Bryan V. Grigg 5,Justin Seashore 4 andRachel R. Deer 6,7ORCID	Association between Sleep Quality and Mental Health among Patients at a Post-COVID-19 Recovery Clinic	https://doi.org/10.3390/brainsci12050586	Published	30 April 2022	Study	https://www.mdpi.com/2076-3425/12/5/586/htm	A growing body of research documents the persistence of physical and neuropsychiatric symptoms following the resolution of acute COVID-19 infection. To the best of our knowledge, no published study has examined the interaction between insomnia and mental health. Accordingly, we proposed to examine new diagnoses of insomnia, and referrals to pulmonary and sleep medicine clinics for treatment of sleep disorders, in patients presenting to one post-acute COVID-19 recovery clinic. Additionally, we aimed to examine the relationship between poor sleep quality, depression, anxiety, and post-traumatic stress. Patients presented to the clinic on average 2 months following COVID-19 infection; 51.9% (n = 41) were hospitalized, 11.4% (n = 9) were in the intensive care unit, 2.5% (n = 2) were on a mechanical ventilator, and 38.0% (n = 30) were discharged on oxygen. The most commonly reported symptom was fatigue (88%, n = 70), with worse sleep following a COVID-19 infection reported in 50.6% (n = 40). The mean PSQI score was 9.7 (82.3%, n = 65 with poor sleep quality). The mean GAD-7 score was 8.3 (22.8%, n = 14 with severe depression). The mean PHQ-9 was 10.1 (17.8%, n = 18 with severe anxiety). The mean IES-6 was 2.1 (54.4%, n = 43 with post-traumatic stress). Poor sleep quality was significantly associated with increased severity of depression, anxiety, and post-traumatic stress. Future work should follow patients longitudinally to examine if sleep, fatigue, and mental health symptoms improve over time.
67	P65		Daniel Richter, Hannah Schulze, Jeyanthan Charles James, Nadine Siems, Nadine Trampe, Ralf Gold, Christos Krogias & Simon Faissner	Hypoechogenicity of brainstem raphe in long-COVID syndrome–less common but independently associated with depressive symptoms: a cross-sectional study	https://doi.org/10.1007/s00415-022-11154-3	Published	12 May 2022	Study	https://link.springer.com/article/10.1007/s00415-022-11154-3	Objective Long coronavirus disease (Long-COVID) syndrome is a hitherto poorly understood phenomenon with a broad spectrum of symptoms, including depression and anxiety. Depressive symptoms have been associated with brainstem raphe (BR) alterations in transcranial sonography (TCS) that might reflect dysfunction of the serotonergic system. The primary aim was to investigate the connection of BR alterations with depressive and anxiety symptoms in patients with Long-COVID syndrome. Methods In a cross-sectional study design, we included outpatients fulfilling the criteria of Long-COVID syndrome. All patients were examined by TCS in the axial plane with focus on BR signal alterations. The Hospital Anxiety and Depression Scale (HADS) was used to test for symptoms of anxiety and depression. Results We included n = 70 patients with Long-COVID syndrome, of which 28.6% (n = 20) exhibited a reduced echogenicity of BR in the TCS examination. Patients with hypoechogenic BR had higher subscores for anxiety and depression compared to normoechogenic patients (HADS depression: median 8 versus 5.5, p = 0.006; HADS anxiety: median 9 versus 6.5, p = 0.006). After adjustment for reasonable confounders, only the odds ratio (OR) for relevant depressive symptoms was higher among Long-COVID patients with hypoechogenic raphe (adjusted OR 3.884, 95% CI 1.244–12.123). Discussion Hypoechogenic BR alterations are independently associated with depressive symptoms in Long-COVID patients but are not highly frequent. Future studies should investigate whether the hypoechogenicity of the BR is a direct consequence or whether it reflects a priori a higher susceptibility to depressive symptoms after COVID-19, thus enabling to identify COVID-19 patients at higher risk of developing Long-COVID depressive symptoms.
68	P66		Candi M. C. Leung, Margaret K. Ho, Alina A. Bharwani, Hugo Cogo-Moreira, Yishan Wang, Mathew S. C. Chow, Xiaoyan Fan, Sandro Galea, Gabriel M. Leung & Michael Y. Ni	Mental disorders following COVID-19 and other epidemics: a systematic review and meta-analysis	https://doi.org/10.1038/s41398-022-01946-6	Published	17 May 2022	Systematic Review	https://www.nature.com/articles/s41398-022-01946-6	COVID-19 has imposed a very substantial direct threat to the physical health of those infected, although the corollary impact on mental health may be even more burdensome. Here we focus on assessing the mental health impact of COVID-19 and of other epidemics in the community. We searched five electronic databases until December 9, 2020, for all peer-reviewed original studies reporting any prevalence or correlates of mental disorders in the general population following novel epidemics in English, Chinese or Portuguese. We synthesised prevalence estimates from probability samples during COVID-19 and past epidemics. The meta-analytical effect size was the prevalence of relevant outcomes, estimated via random-effects model. I2 statistics, Doi plots and the LFK index were used to examine heterogeneity and publication bias. This study is pre-registered with PROSPERO, CRD42020179105. We identified 255 eligible studies from 50 countries on: COVID-19 (n = 247 studies), severe acute respiratory syndrome (SARS; n = 5), Ebola virus disease (n = 2), and 1918 influenza (n = 1). During COVID-19, we estimated the point prevalence for probable anxiety (20.7%, 95% CI 12.9–29.7), probable depression (18.1%, 13.0–23.9), and psychological distress (13.0%, 0–34.1). Correlates for poorer mental health include female sex, lower income, pre-existing medical conditions, perceived risk of infection, exhibiting COVID-19-like symptoms, social media use, financial stress, and loneliness. Public trust in authorities, availability of accurate information, adoption of preventive measures and social support were associated with less morbidity. The mental health consequences of COVID-19 and other epidemics could be comparable to major disasters and armed conflicts. The considerable heterogeneity in our analysis indicates that more random samples are needed. Health-care professionals should be vigilant of the psychological toll of epidemics, including among those who have not been infected.
69	P67		Zsófia Ocsovszky1, József Otohal1, Blanka Berényi2, Vencel Juhász1, Réka Skoda1, Laura Bokor1, Zsófia Dohy1, Liliána Szabó1, György Nagy3,4, Dávid Becker1, Béla Merkely1,5, and Hajnalka Vágóvagoha@gmail.com1,5	The associations of long-COVID symptoms, clinical characteristics and affective psychological constructs in a non-hospitalized cohort	https://doi.org/10.1556/2060.2022.00030	Published	16 May 2022	Study	https://akjournals.com/view/journals/2060/aop/article-10.1556-2060.2022.00030/article-10.1556-2060.2022.00030.xml	Objective The effects of COVID-19, especially long-COVID, on the psychological health is incompletely understood. We aimed to evaluate the mid-term associations of the long-COVID symptoms and affective factors in a cohort of non-hospitalized patients. Method A total of 166 patients were enrolled in this study, including 119 sedentary/non-athlete and 47 athlete subjects at the Post-COVID Outpatient Clinic of Semmelweis University. Clinical data regarding acute and long-term symptoms were obtained and detailed laboratory testing was carried out. Demographic data and psychological tests were collected. Results We found a positive association between the level of depressive symptoms and anxiety and long-COVID symptom count, while life satisfaction and social support correlated negatively with the long-COVID symptom count. Higher haemoglobin levels and lower LDL-cholesterol were also shown to be moderating factors. A regression model showed that symptoms during acute infection, depression, age, and life satisfaction are predictors of the long-COVID symptom count. The presence of pre-existing affective or anxiety problems was also associated with higher reported long-COVID symptom count. Furthermore, we found significant association between pre-existing mental health problems and the investigated psychological constructs. Conclusion It appears that long COVID-19 is associated with acute symptoms and mental factors. Depression and anxiety have been shown to have a negative effect on symptom perception, and also contribute to a higher number of symptoms in a non-hospitalized sample. Our study suggests bi-directional interconnection between clinical and psychological factors.
70	P68		Dirk Schmoll	Long-COVID: Worauf kann sich der psychiatrische Gutachter stützen? Long COVID: what can the psychiatric expert use for support?	https://doi.org/10.1007/s00115-022-01317-y	Published	24 May 2022	Opinion	https://link.springer.com/article/10.1007/s00115-022-01317-y	Vor dem Hintergrund, dass als pathophysiologisches Korrelat eine Viruspersistenz, ein autoinflammatorischer/autoimmunologischer Prozess und eine Hyperkoagulabilität mit Endotheldysfunktion im Gehirn diskutiert werden, stellt sich die Frage, ob sich nicht doch somatische Befunde erheben lassen, die die Sicherheit einer Kausalitätsbeurteilung erhöhen können? Dabei wäre daran zu denken, einen Antikörpernachweis im Serum und Liquor und vielleicht sogar einen Antigennachweis zu fordern, ggf. auch ein cMRT. Ist dies nicht sogar geboten angesichts einer kürzlich in JAMA Internal Medicine publizierten Studie, in der sich zeigte, dass Menschen ohne Antikörper mehr Krankheitssymptome angaben als diejenigen mit einer nachweisbaren COVID-Erkrankung [1]? Ist das nicht ein Hinweis darauf, dass die Erwartungshaltung neben anderen psychogenen Faktoren die Ausprägung kognitiver oder somatoformer Störungen wesentlich prägt?
71	P69		Sabine Hellwig & Katharina Domschke	Post-COVID-Syndrom – Fokus Fatigue Post-COVID syndrome—Focus fatigue	https://doi.org/10.1007/s00115-022-01306-1	Published	23 May 2022	Article	https://link.springer.com/article/10.1007/s00115-022-01306-1	The World Health Organization (WHO) defines post-coronavirus disease 2019 (COVID-19) as a condition which occurs in individuals with a history of probable or confirmed severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection 3 months after the onset of COVID-19 symptoms, lasts for at least 2 months and cannot be explained by an alternative diagnosis. Core symptoms of post-COVID syndrome are fatigue, dyspnea and cognitive dysfunction, which have an impact on everyday functional level. Neuropsychiatric late sequelae are common in COVID-19 patients, with incidence rates over 30%. Beside the abovementioned core symptoms, sleep disorders, depression and anxiety show increased incidences. According to current opinion, associated neuropsychiatric symptoms are subsumed under the term post-COVID syndrome but are also interpreted as comorbidities, which can promote the manifestation of a post-COVID syndrome. The key symptom fatigue shows symptom overlapping and comorbidity with psychiatric disorders. Imaging studies indicate an organic correlate of fatigue in post-COVID patients. Furthermore, psychosocial aspects and psychiatric comorbidities, such as depression and anxiety disorders as modulating and therefore potentially treatable factors were identified. Treatment of fatigue consists of pharmacological management with stimulants and antidepressants as well as nonpharmacological strategies, most notably cognitive behavioral therapy and exercise-focused interventions. The evidence for this comes from meta-analyses of tumor-associated or post-viral fatigue.
72	P70		Carmen Cecilia Caballero-Domínguez,John Carlos Pedrozo-PupoORCID Icon &Adalberto Campo-AriasORCID Icon	Depression among COVID-19 survivors in Colombia	https://doi.org/10.1080/13548506.2022.2085879	Published	06 Jun 2022	Study	https://www.tandfonline.com/doi/abs/10.1080/13548506.2022.2085879	The COVID-19 survivors are at high risk of meeting the criteria for depression. However, few studies have explored its prevalence and associated factors. The study aimed to know the frequency and variables associated with depression among COVID-19 survivors in Santa Marta, Colombia. A sample of COVID-19 survivors was included. Depression was quantified with the Patient Health Questionnaire (PHQ-9, α = 0.85). Three hundred and thirty survivors participated in the research. They were aged between 18 and 89 years, 61.5% were women, and 49.7% of participants scored above the cut-off point for depression. Depression was associated with female gender, younger age, COVID moderate or severe, and having presented symptoms for more than three weeks. In conclusion, depression occurs in half of the COVID-19 survivors and is higher in younger, women and who report more severe symptoms. Longitudinal studies can provide further information on the long-term impact on the mental health of COVID-19 survivors.
73	P71		Mario Gennaro Mazza, Mariagrazia Palladini, Sara Poletti & Francesco Benedetti	Post-COVID-19 Depressive Symptoms: Epidemiology, Pathophysiology, and Pharmacological Treatment	https://doi.org/10.1007/s40263-022-00931-3	Published	21 June 2022	Review	https://link.springer.com/article/10.1007/s40263-022-00931-3	The Coronavirus Disease 2019 (COVID-19) pandemic is still spreading worldwide over 2 years since its outbreak. The psychopathological implications in COVID-19 survivors such as depression, anxiety, and cognitive impairments are now recognized as primary symptoms of the “post-acute COVID-19 syndrome.” Depressive psychopathology was reported in around 35% of patients at short, medium, and long-term follow-up after the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection. Post-COVID-19 depressive symptoms are known to increase fatigue and affect neurocognitive functioning, sleep, quality of life, and global functioning in COVID-19 survivors. The psychopathological mechanisms underlying post-COVID-19 depressive symptoms are mainly related to the inflammation triggered by the peripheral immune-inflammatory response to the viral infection and to the persistent psychological burden during and after infection. The large number of SARS-CoV-2-infected patients and the high prevalence of post-COVID-19 depressive symptoms may significantly increase the pool of people suffering from depressive disorders. Therefore, it is essential to screen, diagnose, treat, and monitor COVID-19 survivors’ psychopathology to counteract the depression disease burden and related years of life lived with disability. This paper reviews the current literature in order to synthesize the available evidence regarding epidemiology, clinical features, neurobiological underpinning, and pharmacological treatment of post-COVID-19 depressive symptoms. Key Points Post-COVID-19 depressive symptoms have been reported in around 35% of patients at short, medium, and long-term follow-up after infection. The psychopathological mechanisms of post-COVID-19 depressive symptoms are mainly related to the peripheral immune-inflammatory response triggered by the viral infection. Conventional antidepressants have proved to be effective in treating post-COVID-19 depression.
74	P72		E.Meppiel	Le « COVID-Long », entre somatique et psychisme : pour une approche intégrativeCovid “long-gauler”: Between somatic and psyche: For an integrative approach	https://doi.org/10.1016/j.praneu.2022.04.010	Published	19 June 2022	Editorial	https://www.sciencedirect.com/science/article/pii/S187877622200036X	La place du neurologue dans la prise en charge des patients COVID-Long est le plus souvent ponctuelle, dans le but d’assurer au correspondant adressant le patient l’absence de pathologie neurologique évolutive. Il est cependant utile de bien garder en tête ce contexte global et complexe, en évaluant objectivement et individuellement les symptômes neurologiques dont font état les patients, et en pondérant l’indication des examens complémentaires à effectuer. Une IRM cérébrale et une évaluation cognitive seront souvent nécessaires, alors que le PET-scan cérébral reste à ce jour du domaine de la recherche, en dehors d’une indication spécifique non liée au COVID-19. Il est également utile de préciser qu’à ce jour, l’état des connaissances sur le SARS-CoV-2 nous indique qu’il n’y a pas de pathogénicité directe sur le parenchyme cérébral [4], et que les voies olfactives ne sont pas une voie d’entrée du virus vers le système nerveux central [5] contrairement aux hypothèses qui ont pu être émises ces deux dernières années.
75	P73		Sergio Machado1,2,4 Eric Murillo-Rodriguez3,4 Claudio Imperatori4,5 Alberto Souza de Sá Filho6	Neuropsychiatric Consequences of COVID-19: What Do We Know So Far?	https://doi.org/2022;23(4):155-156	Published	June 2022	Review	https://alpha-psychiatry.com/Content/files/sayilar/177/AP_July_2022-155-156.pdf	Studies indicate that COVID-19 causes long-term mental health sequelae in individuals who have recovered from the disease1 . For this reason, a global movement towards recognition and planning of how to deal with mental health problems for all those impacted by the global pandemic is being carried out, whether patients or healthcare professionals. In addition, a better understanding of the role of the virus in the pathophysiology of mental health disorders and long-term mental health sequelae is needed. According to the existing literature, the neuropsychiatric consequences of COVID-19 appear to be due to several factors, such as the direct effect of the infection, the body's responses against the infection, or the psychological sequelae of social isolation, unemployment, and fear for health and well-being. Subsistence3 . Pandi-Perumal et al.4 showed evidence that COVID-19 virus affects the central nervous system (CNS), and that people who recover from COVID-19 develop neurological symptoms such as headache, paresthesia, and changes in levels of consciousness, cerebral edema and neurodegeneration, as well as several acute and long-term neuropsychiatric symptoms. Another important point discussed by authors is that brain pathologies associated with COVID-19 can also impact long-term cognitive status after COVID-19 recovery. According to the studies, the greater the severity of COVID-19, the greater the likelihood of CNS complications, such as symptoms similar to chronic fatigue, neurocognitive deficits, which persist even after recovery from COVID-192 . An increase in symptoms of depression, anxiety and trauma-related stress has also been observed due to the economic crisis and isolation from friends and family. But we cannot forget that the pandemic has had consequences not only for adults, but also for children who have started to study remotely and stay away from friends, as well as changing their routines lead to adaptation disorders, acute stress and other conditions. Corroborating Pandi-Perumal et al.4, Nakamura et al.5 showed that more than 30% of hospitalized patients with COVID-19 had symptoms of cognitive impairment, depression and anxiety that lasted for months after recovery from COVID-19, more common and more severe in patients who required intensive care for severe effects of COVID-19. It was also discussed that in addition to the psychological stress related to the pandemic, several biological mechanisms were thought to be responsible for post-COVID-19 neuropsychiatric symptoms. Therefore, there is no consensus on whether the manifestations of psychiatric disorders result ffrom social causes or whether CNS complications may be responsible, but literature indicates a particularly high prevalence of insomnia, fatigue, cognitive impairment, and anxiety disorders in the first 6 months post-COVID-19.
76	P74		Jennifer A. Frontera, MD1; Naomi M. Simon, MD, MSc2	Bridging Knowledge Gaps in the Diagnosis and Management of Neuropsychiatric Sequelae of COVID-19	https://doi.org/10.1001/jamapsychiatry.2022.1616	Published	June 29, 2022	Special Communication	https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2793903	Importance Neuropsychiatric symptoms have been reported as a prominent feature of postacute sequelae of COVID-19 (PASC), with common symptoms that include cognitive impairment, sleep difficulties, depression, posttraumatic stress, and substance use disorders. A primary challenge of parsing PASC epidemiology and pathophysiology is the lack of a standard definition of the syndrome, and little is known regarding mechanisms of neuropsychiatric PASC. Observations Rates of symptom prevalence vary, but at least 1 PASC neuropsychiatric symptom has been reported in as many as 90% of patients 6 months after COVID-19 hospitalization and in approximately 25% of nonhospitalized adults with COVID-19. Mechanisms of neuropsychiatric sequelae of COVID-19 are still being elucidated. They may include static brain injury accrued during acute COVID-19, neurodegeneration triggered by secondary effects of acute COVID-19, autoimmune mechanisms with chronic inflammation, viral persistence in tissue reservoirs, or reactivation of other latent viruses. Despite rapidly emerging data, many gaps in knowledge persist related to the variable definitions of PASC, lack of standardized phenotyping or biomarkers, variability in virus genotypes, ascertainment biases, and limited accounting for social determinants of health and pandemic-related stressors. Conclusions and Relevance Growing data support a high prevalence of PASC neuropsychiatric symptoms, but the current literature is heterogeneous with variable assessments of critical epidemiological factors. By enrolling large patient samples and conducting state-of-the-art assessments, the Researching COVID to Enhance Recovery (RECOVER), a multicenter research initiative funded by the National Institutes of Health, will help clarify PASC epidemiology, pathophysiology, and mechanisms of injury, as well as identify targets for therapeutic intervention.
77	P75		Rozenkrantz, Liron Kube, Tobias Bernstein, Michael H. Gabrieli, John D. E.	How beliefs about coronavirus disease (COVID) influence COVID-like symptoms? – A longitudinal study.	https://psycnet.apa.org/doi/10.1037/hea0001219	Published	Aug 1, 2022	Study	https://psycnet.apa.org/record/2022-83016-001	Objective: Evidence from psychosomatic and nocebo research has indicated that believing one will develop symptoms makes the experience of such symptoms more likely. We applied this idea in the context of coronavirus disease 2019 (COVID-19). Specifically, we assessed whether beliefs regarding COVID-19 predict COVID-like symptoms 3–4 weeks later, and what specific belief has the greatest influence on symptom experience. Method: We conducted two studies with over 300 participants, approached at two successive timepoints, 3–4 weeks apart. Participants reported their experienced symptoms, COVID-19-related beliefs, demographics, and state anxiety. To target COVID-like symptoms, participants who reported having contracted COVID-19 or attributed their symptoms to another known cause were excluded. Regression analyses were conducted to test the predictive value of beliefs regarding COVID-19 on experienced symptoms. Results: A particular belief regarding one’s estimated symptom severity if infected with coronavirus predicted the experience of symptoms 3–4 weeks later (β = .17, p = .011). This result persisted after controlling for potential confounds, including state anxiety (β = .22, p = .002). Findings were preregistered and replicated in a separate cohort. A novel scale for perception of the body’s ability to fight diseases contributed to mediating the effect of estimated symptom severity on later experienced symptoms. Conclusions: A particular belief about estimated symptom severity if infected with COVID predicted the experience of COVID-like physical symptoms several weeks later. These findings contribute to the understanding of the development of unexplained physical symptoms. Furthermore, identification of a particular belief that increases the likelihood of symptoms informs intervention that may mitigate its effects
78	P76		Lakshmi Chennapragada,a,⁎ Sarah R. Sullivan,a,b,c Kyra K. Hamerling-Potts,a Hannah Tran,a Jake Szeszko,a Joseph Wrobleski,a Emily L. Mitchell,a Samantha Walsh,d and Marianne Goodmana,b	International PRISMA Scoping Review to Understand Mental Health Interventions for Depression in COVID-19 Patients	https://doi.org/10.1016%2Fj.psychres.2022.114748	Published	2022 Jul 25	Review	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9313534/	Preliminary research indicates that the COVID-19 illness affects the mental well-being of patients. This scoping review, thus, aims to examine the current state of research into mental health treatments for depression symptoms in COVID-19 patients. Select databases were searched on 7/1/2021. Full-text articles involved 1) mental health treatment 2) suicide and/or depression outcomes, 3) a quasi-experimental research trial, and 4) a primary analysis. 11 articles were included in this review. The studies spanned 5 countries, and demonstrated immediate positive effects of mental health treatments and tele-health as a treatment modality for depression in COVID-19 patients. 6 studies were randomized controlled trials. Various treatments were administered, including cognitive behavior therapy, mindfulness, and muscle relaxation. Most interventions were conducted in in-patient units and focused on acute symptoms. There were limitations in the design and description of methodology in many studies, which affects the generalizability and replicability of positive findings. Only two studies included a post-intervention follow-up and one study assessed suicide risk. Thus, this review found there is a pressing need for more research in the area, with greater rigor in study methodology, and for treatments targeting long-term symptoms and suicidality, and outpatient services.
79	P77		Matthieu Gasnier1,2, Walid Choucha1,2, Francois Radiguer3, Theo Faulet1,2, Kenneth Chappell1,2, Aurore Bougarel1, Christian Kondarjian1, Paul Thorey1, Antoine Baldacci1, Maryne Ballerini1, Abd El Kader Ait Tayeb1,2, Hugo Herrero1,2, Isabelle Hardy-Leger4, Olivier Meyrignac5, Luc Morin6, Anne-Lise Lecoq7, Tài Pham8, Nicolas Noel4, Fabrice Jollant1,2, David Montani9, Xavier Monnet9, Laurent Becquemont2,7, Emmanuelle Corruble	Comorbidity of long COVID and psychiatric disorders after a hospitalisation for COVID-19: a cross-sectional study	http://dx.doi.org/10.1136/jnnp-2021-328516	Published	August 11, 2022	Study	https://jnnp.bmj.com/content/early/2022/08/10/jnnp-2021-328516.abstract	Objectives - Long COVID is a major public health issue. Whether long COVID is comorbid with psychiatric disorders remains unclear. Here, we investigate the association between long COVID, psychiatric symptoms and psychiatric disorders. Design - Cross-sectional. Settings - Bicêtre Hospital, France, secondary care. Participants One hundred seventy-seven patients admitted in intensive care unit during acute phase and/or reporting long COVID complaints were assessed 4 months after hospitalisation for an acute COVID. Main outcome measures - Eight long COVID complaints were investigated: fatigue, respiratory and cognitive complaints, muscle weakness, pain, headache, paraesthesia and anosmia. The number of complaints, the presence/absence of each COVID-19 complaint as well as lung CT scan abnormalities and objective cognitive impairment) were considered. Self-reported psychiatric symptoms were assessed with questionnaires. Experienced psychiatrists assessed Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition-based diagnoses of psychiatric disorders. Results - One hundred and fifteen (65%) patients had at least one long COVID complaint. The number of long COVID complaints was associated with psychiatric symptoms. The number of long COVID complaints was higher in patients with psychiatric disorders (mean (m) (SD)=2.47 (1.30), p<0.05), new-onset psychiatric disorders (m (SD)=2.41 (1.32), p<0.05) and significant suicide risk (m (SD)=2.67 (1.32), p<0.05) than in patients without any psychiatric disorder (m (SD)=1.43 (1.48)). Respiratory complaints were associated with a higher risk of psychiatric disorder and new-onset psychiatric disorder, and cognitive complaints were associated with a higher risk of psychiatric disorder. Conclusions - Long COVID is associated with psychiatric disorders, new-onset psychiatric disorders and suicide risk. Psychiatric disorders and suicide risk should be systematically assessed in patients with long COVID.
80	P78		JasminaMalletabcCélieMassinidJulienDubreucqeRomainPadovanifGuillaumeFondcgSélim BenjaminGuessoumh	Santé mentale et Covid : toutes et tous concernés. Une revue narrativeMental health during the Covid pandemic, a narrative review	https://doi.org/10.1016/j.amp.2022.07.019	Published	6 August 2022	Review	https://www.sciencedirect.com/science/article/pii/S0003448722002219	Résumé - La pandémie de COVID-19 (due au coronavirus SARS-CoV-2) a apporté des défis sans précédent en termes de santé publique, système de soins et vie quotidienne (incluant le travail et l’éducation), particulièrement lors de la première vague pandémique au début de l’année 2020. Afin de limiter la propagation du virus, de nombreux pays ont imposé des mesures restrictives pour favoriser la distanciation sociale, allant des couvre-feux et fermetures d’écoles à un confinement généralisé. Début 2022, on recense 135 000 décès dus au virus SARS-CoV-2 en France et près de 6 millions dans le monde. Au-delà de l’impact possible du SARS-CoV-2 sur le cerveau, la pandémie a été à l’origine de difficultés humaines complexes, avec un retentissement possible sur la santé mentale des populations. Dans cette revue narrative, nous résumons les données actuelles concernant l’impact de la pandémie sur la santé mentale en s’intéressant aux troubles psychiatriques en population générale et parmi les groupes vulnérables. L’objectif est de promouvoir une prévention ciblée sur ces populations. Notre revue a identifié plusieurs sous-groupes de sujets plus à risque de troubles psychiques dans le contexte de la pandémie de COVID-19 : les endeuillés par la COVID-19, les adolescents, les étudiants, les personnes atteintes par le virus (avec une atteinte potentiellement directe sur le cerveau) et enfin, le personnel de santé. Les disparités de genre ont également été accentuées, en défaveur des femmes. Des mesures de dépistage et de prévention doivent être prises pour limiter l’impact de cette pandémie sur la santé mentale. D’une façon plus générale, l’approche « une santé/one health » qui place la santé humaine (et donc mentale) à l’interface de la santé environnementale et animale semble indispensable pour éviter la survenue de ce type de pandémie et ses conséquences à l’avenir. Abstract - The COVID-19 pandemic (caused by the Sars-CoV-2 coronavirus) led to unprecedented challenges to public health, the healthcare system, and our daily lives (including work and education), particularly during the first wave in early 2020. In order to control infection of the virus, many countries have imposed restrictive measures to promote social distancing, ranging from curfews and school closures to widespread lockdown. At the beginning of 2022, there were 135,000 deaths from Sars-CoV-2 in France (nearly 6 million worldwide). Beyond the possible impact of Sars-CoV-2 on the brain, the pandemic has created complex human situations, with a possible impact on the mental health of populations. In this narrative review, we summarize current data on the impact of the pandemic on mental health in the general population and identify the most vulnerable groups. The goal is to provide more targeted prevention for these populations. Our review has identified several subgroups of subjects at higher risk of disorder in the context of the COVID-19 pandemic: those bereaved by COVID-19, adolescents, students, people with COVID (with potentially direct brain damages), and finally, health care workers. Gender disparities were accentuated, leading to more mental disorders in women. Longitudinal follow-up studies are needed to better identify the effects of the pandemic on the mental health of different populations, and also to define personalized prevention strategies. Screening and prevention measures must be taken to limit the impact of this pandemic on mental health. More generally, the “one health” approach, which places human health at the interface of environmental and animal health, seems essential to avoid the occurrence of this type of pandemic and its consequences in the future.
81	P79		W. BierbauerORCID Icon,J. LüscherORCID Icon &U. ScholzORCID Icon \|Daryl O’Connor (Reviewing editor:)	Illness perceptions in long-COVID: A cross-sectional analysis in adults	https://doi.org/10.1080/23311908.2022.2105007	Published	27 Jul 2022	Study	https://www.tandfonline.com/doi/full/10.1080/23311908.2022.2105007	Symptoms may persist after an acute COVID-19 infection, a phenomenon termed long-COVID. Increasing attention is now directed toward these long-term effects, as many seem to be affected. So far, long-COVID was primarily discussed from a medical perspective, leaving psychological factors on health-related outcomes understudied. Thus, the present study contributes to the current literature by examining Leventhal’s common-sense model of self-regulation, investigating patients’ cognitive and emotional illness perceptions and their association with different health-related outcomes in the context of long-COVID. We examined 246 long-COVID patients (89.0% female, Mage = 45.29 ± 12.12 years), assessing illness perceptions, fatigue, depressive symptoms, anxiety, and quality of life in a cross-sectional survey study. Linear regression analyses were applied to model the unique effects of the illness perception dimension on health-related outcomes. More than half of the sample had elevated levels of depressive symptoms, anxiety, and fatigue. Illness perception dimensions explained between 28% and 37% of the variance across the analyzed health-related outcomes. More symptoms, higher perceived consequences, and higher emotional representation were related to worse health-related outcomes. In general, long-COVID was poorly understood (i.e., low coherence) and perceived as difficult to control (i.e., personal & treatment control). Health professionals involved in counseling should pay close attention to both cognitive and emotional illness perceptions to address possible ways of coping with long-COVID.
82	P80		Sverre UrnesJohnson12Ole MyklebustAmundsen4Miriam SinkerudJohnson3AsleHoffart12ØyvindHalsøy1NoraSkjerdingstad1SaraEbling4Omid V.Ebrahimi12	Psychiatric Symptoms in COVID-19-positive Individuals in the General Population: Trajectories of Depression, Anxiety, and Insomnia	https://doi.org/10.1016/j.psychres.2022.114806	Published	21 August 2022	Study	https://www.sciencedirect.com/science/article/pii/S0165178122003997	Highlights •Those tested positive for COVID-19 experience higher levels of depression after restrictions are lifted. •Psychiatric symptoms of SARS-CoV-2-positive individuals decreased over time •Age and amount of physical activity did not predict the trajectories of anxiety and depression •There were no significant differences in trajectory when compared to matched controls. Abstract The present study investigates differences in the trajectories of anxiety, depression, and sleep problems among infected versus non-infected case-controlled individuals. Patients who tested positive for COVID-19 were selected from a representative sample in Norway (N > 10,000). In total, 126 of these individuals were infected during the project period, and this group was analyzed at T5 (May 2021). Of these positive cases, those who had completed both PHQ-9 and GAD-7 at all three measurement points were selected for longitudinal analysis using multilevel modeling. There was a significant difference at T5 between those who had tested positive for COVID-19 and matched controls. Anxiety and depression were reduced among those who tested positive, but there were no differences in trajectory when compared to matched controls. Limitations include the use of self-report measures and the assessment of symptoms at a time when strict virus mitigation protocols were in place. The present findings indicate that individuals who test positive for COVID-19 exhibit higher levels of depressive symptoms after restrictions are lifted. However, comparison of anxiety and depression symptom trajectories with matched controls reveals that both groups exhibited stable or slightly decreased symptoms.
83	P81		Emily A.TroyeraJordan N.KohnaSuziHongab	Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms	https://doi.org/10.1016/j.bbi.2020.04.027	Published	13 April 2020	Review	https://www.sciencedirect.com/science/article/pii/S088915912030489X	Highlights •The COVID-19 pandemic is a significant source of psychological distress globally. •The novel coronavirus and host immunologic response may also directly affect brain and behavior. •Acute and delayed neuropsychiatric sequelae have been associated with past viral pandemics. •Prospective monitoring of COVID-19 patients is needed to determine neuropsychiatric outcomes. •A psychoneuroimmunology perspective will aid in promoting post-pandemic public mental health. The coronavirus disease 19 (COVID-19) pandemic is a significant psychological stressor in addition to its tremendous impact on every facet of individuals’ lives and organizations in virtually all social and economic sectors worldwide. Fear of illness and uncertainty about the future precipitate anxiety- and stress-related disorders, and several groups have rightfully called for the creation and dissemination of robust mental health screening and treatment programs for the general public and front-line healthcare workers. However, in addition to pandemic-associated psychological distress, the direct effects of the virus itself (several acute respiratory syndrome coronavirus; SARS-CoV-2), and the subsequent host immunologic response, on the human central nervous system (CNS) and related outcomes are unknown. We discuss currently available evidence of COVID-19 related neuropsychiatric sequelae while drawing parallels to past viral pandemic-related outcomes. Past pandemics have demonstrated that diverse types of neuropsychiatric symptoms, such as encephalopathy, mood changes, psychosis, neuromuscular dysfunction, or demyelinating processes, may accompany acute viral infection, or may follow infection by weeks, months, or longer in recovered patients. The potential mechanisms are also discussed, including viral and immunological underpinnings. Therefore, prospective neuropsychiatric monitoring of individuals exposed to SARS-CoV-2 at various points in the life course, as well as their neuroimmune status, are needed to fully understand the long-term impact of COVID-19, and to establish a framework for integrating psychoneuroimmunology into epidemiologic studies of pandemics.
84	P82		Maria SimonettaSpadaaAve MariaBiffiaLucaBelottiaLauraCremaschibClaudiaPalumbocClaraLocatellicBruno MarioCesanadEmiBondic	Psychological impact of COVID-19 after hospital discharge: A follow-up study on Italian recovered patients	https://doi.org/10.1016/j.jad.2022.08.086	Published	24 August 2022	Study	https://www.sciencedirect.com/science/article/pii/S0165032722009417	Highlights •Few data are available regarding the consequences of COVID-19 on survivors’ mental health over the long-term. •Authors investigated the psychological impact in 1457 recovered patients during the post-acute phase. •Almost one third of the sample reported post-traumatic symptoms at follow-up; anxiety was more represented than depression. •Hospitalization, regardless of the care setting, and promptness in follow-up evaluation play a protective role on recovery. Background Since COVID-19 outbreak, clinical experience on its management during the acute phase has rapidly grown, including potential effects on the psychopathological dimension. However, still few data are available regarding the impact on survivors' mental health over the long-term. Methods A sample of 1457 COVID-19 patients underwent a multidisciplinary follow-up protocol, approximately 3 months after hospital discharge, including a psychological evaluation. The primary outcomes were anxiety, depression, resilience, post-traumatic symptoms, and health-related quality of life. Furthermore, we examined the potential role of hospitalization and delay in the follow-up assessment on the increased burden of illness. Results Although a general high level of resilience emerged, suggesting most patients relied on their individual and interpersonal resources to face difficulties related to the pandemic, almost one third of the sample reported signs of psychological distress over time, especially post-traumatic symptoms, with anxiety being more represented than depression. Furthermore, hospitalization – regardless of the setting of care – and promptness in follow-up evaluation were found to play a protective role on patients' recovery and mental wellbeing. Limitations Selection bias of patients exclusively admitted to the hospital; absence of a control group; psychological assessment relying on self-reported instruments. Conclusions The current crisis demands resilience and adjustment resources, either in the acute and post-acute phase. Thus, the clinical effort should aim at relieving the traumatic impact of such condition through timely interventions. Further investigation may address potential predictors of developing a traumatic stress response, in order to identify and promptly treat at-risk subpopulations.
85	P83		Claudio L. A. Bassetti, Raimund Helbok Open the ORCID record for Raimund Helbok[Opens in a new window] , Kristina Adorjan Open the ORCID record for Kristina Adorjan[Opens in a new window] and Peter Falkai	European Psychiatric Association–European Academy of Neurology statement on post-COVID syndrome	https://doi.org/10.1192/j.eurpsy.2022.2317	Published	08 September 2022	Statement	https://www.cambridge.org/core/journals/european-psychiatry/article/epaean-statement-on-postcovid-syndrome/54EFFC48E3B0A85654B04C94A08E680F	Proposed mechanisms of persistent and new onset postinfectious disorders include immune dysregulation with persistent low-grade (neuro-)inflammation, immune dysregulation, autoimmunity, and viral persistence in various tissues [Reference Balcom, Nath and Power13]. Each of these hypotheses needs confirmation in larger scale studies and builds upon direct and indirect neuropathogenic effects of SARS-CoV-2 in the acute phase [Reference Spudich and Nath14]. Long-term neurologic manifestations include fatigue, neurocognitive symptoms, sleep–wake disorders, dysautonomia, hyposmia, hypogeusia, and pain syndromes among others [Reference Balcom, Nath and Power13]. Fatigue was shown in a recent meta-analysis including 36 studies and a total of 9,944 participants to be the most common symptom (mean 52.8%; 95% Confidence Interval 19.9–84.4) [Reference Pinzon, Wijaya, Jody, Nunsio and Buana15]. The large 95% confidence intervals highlight the need for a more strict and homogenous definition of the post-COVID syndrome and its symptoms. The authors also suggest a better analysis in future studies of the longitudinal course of symtpoms, which appear to strongly fluctuate within the first year post-SARS-CoV-2 infection and even during the day. Neurocognitive symptoms are commonly associated with impaired performance in neuropsychological testing and are expected sequelae among ICU survivors including those with COVID-19. Of note, early reports of frontotemporal FDG-PET hypometabolism [Reference Helms, Kremer, Merdji, Clere-Jehl, Schenck and Kummerlen16] during acute COVID-19 have now been replicated in the subacute phase and associated with memory deficits and executive dysfunction [Reference Hosp, Dressing, Blazhenets, Bormann, Rau and Schwabenland17]. Despite longitudinal recovery from cognitive deficits [Reference Blazhenets, Schroeter, Bormann, Thurow, Wagner and Frings18], the increased risk for neurological and psychiatric diagnoses in the 6 months after infection deserves attention [Reference Taquet, Dercon, Luciano, Geddes, Husain and Harrison19]. These data derive from a large retrospective cohort of more than 250,000 survivors of COVID-19 reporting even a higher risk compared to propensity score-matched cohorts of influenza patients and those with other respiratory infections [Reference Taquet, Dercon, Luciano, Geddes, Husain and Harrison19]. Interestingly, even patients with mild and moderate COVID-19 report poor concentration, lack of intellectual clarity and mental fatigue which is referred to as “brain fog” and is poorly captured by conventional testing including the MOCA test [Reference Graham, Clark, Orban, Lim, Szymanski and Taylor20]. This and other consequences of COVID-19 lack of specificity and need a more precise definition. In general, neurological manifestations improve over time [Reference Beghi, Helbok, Ozturk, Karadas, Lisnic and Grosu6, Reference Rass, Beer, Schiefecker, Lindner, Kofler and Ianosi21]; however, long-term effects and new onset neurological diseases including autoimmune diseases and neurodegenerative diseases need close surveillance through national and international registries.
86	P84	AXD	Siwen Wang, MD1; Luwei Quan, BA2; Jorge E. Chavarro, ScD1,3,4; Natalie Slopen, ScD5; Laura D. Kubzansky, PhD5; Karestan C. Koenen, PhD3,5,6; Jae Hee Kang, ScD4; Marc G. Weisskopf, PhD2; Westyn Branch-Elliman, MD7,8; Andrea L. Roberts, PhD2	Associations of Depression, Anxiety, Worry, Perceived Stress, and Loneliness Prior to Infection With Risk of Post–COVID-19 Conditions	https://doi.org/10.1001/jamapsychiatry.2022.2640	Published	September 7, 2022	Study	https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2796097	Key Points Question Is psychological distress before SARS-CoV-2 infection associated with risk of COVID-19–related symptoms lasting 4 weeks or longer, known as post–COVID-19 conditions? Findings This cohort study found that among participants who did not report SARS-CoV-2 infection at baseline (April 2020) and reported a positive SARS-CoV-2 test result over 1 year of follow-up (N = 3193), depression, anxiety, perceived stress, loneliness, and worry about COVID-19 were prospectively associated with a 1.3- to 1.5-fold increased risk of self-reported post–COVID-19 conditions, as well as increased risk of daily life impairment related to post–COVID-19 conditions. Meaning In this study, preinfection psychological distress was associated with risk of post–COVID-19 conditions and daily life impairment in those with post–COVID-19 conditions. Abstract Importance Few risk factors for long-lasting (≥4 weeks) COVID-19 symptoms have been identified. Objective To determine whether high levels of psychological distress before SARS-CoV-2 infection, characterized by depression, anxiety, worry, perceived stress, and loneliness, are prospectively associated with increased risk of developing post–COVID-19 conditions (sometimes called long COVID). Design, Setting, and Participants This prospective cohort study used data from 3 large ongoing, predominantly female cohorts: Nurses’ Health Study II, Nurses’ Health Study 3, and the Growing Up Today Study. Between April 2020 and November 2021, participants were followed up with periodic surveys. Participants were included if they reported no current or prior SARS-CoV-2 infection at the April 2020 baseline survey when distress was assessed and returned 1 or more follow-up questionnaires. Exposures Depression, anxiety, worry about COVID-19, perceived stress, and loneliness were measured at study baseline early in the pandemic, before SARS-CoV-2 infection, using validated questionnaires. Main Outcomes and Measures SARS-CoV-2 infection was self-reported during each of 6 monthly and then quarterly follow-up questionnaires. COVID-19–related symptoms lasting 4 weeks or longer and daily life impairment due to these symptoms were self-reported on the final questionnaire, 1 year after baseline. Results Of 54 960 participants, 38.0% (n = 20 902) were active health care workers, and 96.6% (n = 53 107) were female; the mean (SD) age was 57.5 (13.8) years. Six percent (3193 participants) reported a positive SARS-CoV-2 test result during follow-up (1-47 weeks after baseline). Among these, probable depression (risk ratio [RR], 1.32; 95% CI = 1.12-1.55), probable anxiety (RR = 1.42; 95% CI, 1.23-1.65), worry about COVID-19 (RR, 1.37; 95% CI, 1.17-1.61), perceived stress (highest vs lowest quartile: RR, 1.46; 95% CI, 1.18-1.81), and loneliness (RR, 1.32; 95% CI, 1.08-1.61) were each associated with post–COVID-19 conditions (1403 cases) in generalized estimating equation models adjusted for sociodemographic factors, health behaviors, and comorbidities. Participants with 2 or more types of distress prior to infection were at nearly 50% increased risk for post–COVID-19 conditions (RR, 1.49; 95% CI, 1.23-1.80). All types of distress were associated with increased risk of daily life impairment (783 cases) among individuals with post–COVID-19 conditions (RR range, 1.15-1.51). Conclusions and Relevance The findings of this study suggest that preinfection psychological distress may be a risk factor for post–COVID-19 conditions in individuals with SARS-CoV-2 infection. Future work should examine the biobehavioral mechanism linking psychological distress with persistent postinfection symptoms.
87	P85		Asmaa Azizi Doha Achak Elmadani Saad Abderraouf Hilali Ibtissam Youlyouz-Marfak Abdelghafour Marfak	Post-COVID-19 mental health and its associated factors at 3-months after discharge: A case-control study	https://doi.org/10.1016/j.cegh.2022.101141	Published	September 10, 2022	Study	https://www.ceghonline.com/article/S2213-3984(22)00183-X/fulltext	Background Mental health disorders are among the most significant sequelae of the COVID-19 pandemic. Therefore, the aim of this study is to investigate the mental health status and associated risk factors of Moroccan COVID-19 survivors 3 months after hospital discharge. Methods A case-control study was conducted from September 2021 to February 2022 on 824 participants. 213 were COVID-19 survivors and 611 were control group. Data were collected ether through an online anonymous survey. Anxiety and depression disorders were assessed using Hospital Anxiety and Depression Scale (HADS). Results The average age of all participants was 55.17 ± 16.44. Our findings highlighted higher prevalence of mental health disorders including anxiety and depression in COVID-19 survivors at 3 months after hospital discharge (HADS-A = 12.84; HADS-D = 10.91) compared to control group (HADS-A = 9.90; HADS-D = 8.27) (p < 0.001). Older patients, suffering from type 2 diabetes and kidney diseases, admitted to ICU, who stayed a long duration in the hospital, who had severe and longer duration of symptoms and who used Chloroquine, had higher levels of anxiety and depression after discharge. Conclusions The present investigation highlights the need to develop a post-COVID-19 rehabilitation programs that can better manage the post COVID-19 impact and restore a good mental health for COVID-19 survivors. Also, to create preventative strategies to limit mental health disorders in COVID-19 survivors.
88	P86	AXD	John W. Blackett Milton Wainberg Mitchell S.V. Elkind Daniel E. Freedberg	Potential Long Coronavirus Disease 2019 Gastrointestinal Symptoms 6 Months After Coronavirus Infection Are Associated With Mental Health Symptoms	https://doi.org/10.1053/j.gastro.2021.10.040	Published	October 30, 2021	Study	https://www.gastrojournal.org/article/S0016-5085(21)03712-4/fulltext	Over 200 million people globally have been infected with the severe acute respiratory syndrome coronavirus 2, also known as coronavirus disease 2019 (COVID-19).1 Some COVID-19 survivors recover from acute infection yet suffer from persistent symptoms including fatigue, anxiety, and depression.2 New, chronic gastrointestinal (GI) symptoms are also commonly reported after COVID-19.3, 4, 5, 6, 7 There is an established association between mental health symptoms and chronic GI symptoms, especially irritable bowel syndrome (IBS).8,9 However, the association between mental health symptoms and chronic GI symptoms after COVID-19 has not been fully explored. The Columbia University Institutional Review Board approved this study. This survey study, nested within a prospective cohort of COVID-19 survivors with a minimum of 6 months of follow-up, assessed the hypothesis that mental health symptoms both before and after COVID-19 infection would be associated with post–COVID-19 chronic GI symptoms (see Supplementary Methods for full study details). Of 1783 patients surveyed, 749 (42%) responded (67% women; median age, 43 years). The cohort comprised 61% white, 9.6% black, and 20% other races (with 9.6% choosing not to answer) and 28% Hispanic and 70% non-Hispanic (with 2% choosing not to answer). The survey was completed in English by 93% of respondents and in Spanish by 6.8%. Fifteen percent of patients had been hospitalized for COVID-19, with 1.7% requiring mechanical ventilation. Six months after COVID-19 diagnosis, 220 patients (29%) reported GI symptoms self-perceived to be related to COVID-19. These included 72 (9.6%) with diarrhea, 83 (11%) with constipation, 70 (9.4%) with abdominal pain, 53 (7.1%) with nausea/vomiting, and 122 (16%) with heartburn (Table 1). A GI symptom was the most bothersome current symptom in 83 patients (11%). Overall, these results highlight the potential bidirectionality of mental health and chronic GI symptoms after COVID-19, as has previously been observed in non–COVID-19 studies. Anxiety or sadness may exacerbate functional GI symptoms, and functional GI symptoms may lead to anxiety or sadness.10 Alternatively, a common underlying mechanism could explain both GI and mental health symptoms. This study, which involved an assessment made at a single time point, cannot fully determine the temporality between mental health and GI symptoms after COVID-19. This may be a fruitful area for future studies that can use longitudinal assessment strategies to tease apart the causal chain of events and evaluate strategies to improve long-term GI outcomes after COVID-19. Although all patients with chronic GI symptoms should receive screening for comorbid mental health symptoms, this study provides specific evidence that screening COVID-19 survivors will be high yield. The study has some limitations. The response rate was 42%, raising the possibility of response bias, but, reassuringly, the estimate of prevalence for new GI symptoms after COVID-19 (29%) fell squarely in the middle of the range of 16%–40% from a retrospective study.7 Although post–COVID-19 symptoms were assessed prospectively, reporting of mental health symptoms before COVID-19 was assessed retrospectively and may have been under-reported because of recall bias related to the stigma of such symptoms. Because the survey instrument from which these data were generated was focused primarily on new physical symptoms after COVID-19, there was limited detail on the characteristics of current mental health symptoms. Importantly, the association found between mental health symptoms and GI symptoms after COVID-19 is not necessarily causal. It is possible that post–COVID-19 GI symptoms may be partially due to heightened stress and anxiety arising from pandemic-related lifestyle changes rather than the direct consequence of severe acute respiratory syndrome coronavirus 2 infection. In future studies, a control group assessing the incidence of new GI symptoms in patients who tested negative for COVID would help to clarify this question. In summary, we observed very strong associations between mental health symptoms and post–COVID-19 GI symptoms. Nearly one-third of patients (29%) reported at least 1 new GI symptom after COVID-19. These were not trivial, because over 10% of the cohort reported a GI symptom as their most bothersome COVID-19–related condition.	to Zotero
89	P87	AXD	Julia Lier1*, Kristin Stoll1, Hellmuth Obrig2, Paul Baum3, Lea Deterding4, Nora Bernsdorff1, Franz Hermsdorf1, Ines Kunis1, Andrea Bräsecke1, Sabine Herzig2, Matthias L. Schroeter2, Angelika Thöne-Otto2, Steffi G. Riedel-Heller5, Ulrich Laufs3, Hubert Wirtz4, Joseph Classen1 and Dorothee Saur1	Neuropsychiatric phenotype of post COVID-19 syndrome in non-hospitalized patients	https://doi.org/10.3389/fneur.2022.988359	Published	27 September 2022	Study	https://www.frontiersin.org/articles/10.3389/fneur.2022.988359/full	The post COVID-19 syndrome (PCS) is an emerging phenomenon worldwide with enormous socioeconomic impact. While many patients describe neuropsychiatric deficits, the symptoms are yet to be assessed and defined systematically. In this prospective cohort study, we report on the results of a neuropsychiatric consultation implemented in May 2021. A cohort of 105 consecutive patients with merely mild acute course of disease was identified by its high symptom load 6 months post infection using a standardized neurocognitive and psychiatric-psychosomatic assessment. In this cohort, we found a strong correlation between higher scores in questionnaires for fatigue (MFI-20), somatization (PHQ15) and depression (PHQ9) and worse functional outcome as measured by the post COVID functional scale (PCFS). In contrast, neurocognitive scales correlated with age, but not with PCFS. Standard laboratory and cardiopulmonary biomarkers did not differ between the group of patients with predominant neuropsychiatric symptoms and a control group of neuropsychiatrically unaffected PCS patients. Our study delineates a phenotype of PCS dominated by symptoms of fatigue, somatisation and depression. The strong association of psychiatric and psychosomatic symptoms with the PCFS warrants a systematic evaluation of psychosocial side effects of the pandemic itself and psychiatric comorbidities on the long-term outcome of patients with SARS-CoV-2 infection.	to Zotero
90	P88		Brenda W. J. H. Penninx, Michael E. Benros, Robyn S. Klein & Christiaan H. Vinkers	How COVID-19 shaped mental health: from infection to pandemic effects	https://doi.org/10.1038/s41591-022-02028-2	Published	2022 Oct	Review	https://www.nature.com/articles/s41591-022-02028-2	The Coronavirus Disease 2019 (COVID-19) pandemic has threatened global mental health, both indirectly via disruptive societal changes and directly via neuropsychiatric sequelae after SARS-CoV-2 infection. Despite a small increase in self-reported mental health problems, this has (so far) not translated into objectively measurable increased rates of mental disorders, self-harm or suicide rates at the population level. This could suggest effective resilience and adaptation, but there is substantial heterogeneity among subgroups, and time-lag effects may also exist. With regard to COVID-19 itself, both acute and post-acute neuropsychiatric sequelae have become apparent, with high prevalence of fatigue, cognitive impairments and anxiety and depressive symptoms, even months after infection. To understand how COVID-19 continues to shape mental health in the longer term, fine-grained, well-controlled longitudinal data at the (neuro)biological, individual and societal levels remain essential. For future pandemics, policymakers and clinicians should prioritize mental health from the outset to identify and protect those at risk and promote long-term resilience.
91	P89		Marc Scherlinger, Cédric Lemogne, Renaud Felten & Jean Sibilia	Excess of Post-Acute Sequelae of COVID-19 After the First Wave of the Pandemic		Published	26 September 2022	Study	https://link.springer.com/article/10.1007/s40121-022-00698-6	Introduction To compare the time distribution of initial COVID-19 among patients with self-reported post-acute sequelae of COVID-19 (PASC). Methods We compared the distribution of the date of the reported initial COVID-19 among patients with self-reported PASC and the COVID-19 cases in France between the first wave (January 1–May 11, 2020) and the later period (May 12, 2020–June 30, 2021) using the chi-squared test. COVID-19 cases in France were assessed using previous modeling of COVID-19 burden in France for the first time period, and positive RT-PCR testing for the second time period. Results The study included 567 individuals with PASC (median age 44, [IQR 37–50]; 83.4% women). A total of 293 (51.7%) patients reported an initial COVID-19 infection during the first period while 272 (48%) reported it during the later period (missing data, n = 2; 0.3%). Patients with PASC were 82% more likely to report initial COVID-19 during the first pandemic wave than afterward (OR 1.82, 95% CI [1.55–2.15]; p < 0.0001). Conclusions The incidence of self-reported PASC wave was significantly higher when initial COVID-19 happened during the first pandemic wave than afterward, suggesting the importance of non-viral factors in PASC development. Key Summary Points In France, patients with post-acute sequelae of COVID-19 (PASC) were 82% more likely to report an initial infection during the first pandemic wave, and aggregated around the lockdown announcement. Viral factors (i.e. variants) or prior vaccination were unlikely to explain the observed differences in PASC incidence considering the study period. We hypothesize that the stress induced by the first wave of the pandemic may have fostered the onset or chronicization of symptoms in a subset of patients with PASC.
92	P90		SashaRudenstineaTaliaSchulderaKrish J.BhattbKatMcNealaCatherine K.EttmancSandroGaleac	Long-COVID and comorbid depression and anxiety two years into the COVID-19 pandemic	https://doi.org/10.1016/j.psychres.2022.114924	Published	25 October 2022	Study	https://www.sciencedirect.com/science/article/pii/S0165178122005157	Highlights •The present study investigated demographics, stressors, and long-COVID in relation to depression, anxiety, and comorbid depression and anxiety outcomes. •Results showed that gender was a significant correlate for probable depression, stressors were a significant correlate for probable anxiety, and gender, socioeconomic status, stressors, and long-COVID were all significant correlates for comorbid outcomes. •Findings highlight the importance of social location, stress, and long-COVID, in tandem, as correlates of psychological health during the shifting pandemic. Abstract Long-COVID, or the persistence of COVID-19 symptoms for months after initial infection, has been shown to impact the lives of those affected. The current study sought to investigate the relationships between long-COVID, COVID-19 related stress, depression, anxiety, and comorbid depression and anxiety outcomes. Data were collected in Winter 2021-2022 from a population of adults enrolled in at least one course across multiple City University of New York (CUNY) campuses. Frequencies and chi-square tests were computed to assess for demographics and relationships to probable diagnoses of depression and anxiety, and binary logistic regressions were computed to assess for the odds of probable comorbid depression and anxiety based on demographics, stressors, and long-COVID. Women participants reported higher odds of probable depression outcomes, and stressor levels were significant correlates of probable anxiety outcomes. Women participants, 3.2 [1.5-6.9], as compared to men, lower-SES participants, 2.16 [1.1-4.2], as compared to higher-SES participants, participants with higher COVID-19 related stress levels, 4.8 [2.0-12.0], as compared to those with low levels, and participants with long-COVID, 3.7 [1.9-7.0], as compared to those without, all had higher odds of probable comorbid depression and anxiety. Findings highlight the importance of social location, stress, and long-COVID, in tandem, as correlates of psychological health during the shifting pandemic.
93	P91		Xutong Zheng RN, MSN Student,Min Qian RN, MSN,Xinxin Ye PhD,Man Zhang RN, MSN Student,Chenju Zhan RN,Hui Li RN, MSN Student,Tiantian Luo RN, MSN Student	Implications for long COVID: A systematic review and meta-aggregation of experience of patients diagnosed with COVID-19	https://doi.org/10.1111/jocn.16537	Published	17 October 2022	Review	https://onlinelibrary.wiley.com/doi/abs/10.1111/jocn.16537	Aims and Objectives This review aims to synthesize the available evidence of what patients experience when infected with COVID-19, both in hospital and post-discharge settings. Design This review was conducted using the Joanna Briggs Institute (JBI) methodology for qualitative systematic reviews and evidence synthesis. Reporting of results was presented according to the Enhancing Transparency in Reporting the Synthesis of Qualitative Research (ENTREQ) checklist. Background Coronavirus disease 2019 (COVID-19) continues to be a public health crisis worldwide. Many patients diagnosed with COVID-19 have varied levels of persisting mental disorders. Previous studies have reported the degree, prevalence and outcome of psychological problems. Minimal research explored the experience of patients with long COVID. The real-life experience of patients with COVID-19 from diagnosis to post-discharge can deepen the understanding of nurses, physicians and policymakers. Methods All studies describing the experience of patients were included. Two authors independently appraised the methodological quality of the included studies using the JBI Critical Appraisal Checklist for Qualitative Research 2020. Results This systematic review aggregated patients’ experience of being diagnosed with COVID-19 in both hospitalized and post-discharge settings. Finally, 17 studies met inclusion criteria and quality appraisal guidelines. The selected studies in the meta-synthesis resulted in 12 categories, and further were concluded as five synthesized findings: physical symptoms caused by the virus, positive and negative emotional responses to the virus, positive coping strategies as facilitators of epidemic prevention and control, negative coping strategies as obstacles of epidemic prevention and control, and unmet needs for medical resource. Conclusions The psychological burden of patients diagnosed with COVID-19 is heavy and persistent. Social support is essential in the control and prevention of the epidemic. Nurses and other staff should pay more attention to the mental health of the infected patients both in and after hospitalization.
94	P92		Peter W Ward	Long covid update for primary care should acknowledge functional symptoms	https://doi.org/10.1136/bmj.o2501	Published	19 October 2022	Opinion	https://www.bmj.com/content/379/bmj.o2501.full	It must be a fraught task, writing about long covid. The list of symptoms is huge and we don’t really know how it arises. I often feel inadequate faced with patients distressed by their long covid symptoms. I was bothered by the lack of any mention by Greenhalgh and colleagues of a functional element to long covid.1 It seemed a huge omission to me. Many of the complaints we see in primary care are of a functional nature and there is often a large functional component to physical illnesses like chronic obstructive pulmonary disease, asthma, heart disease, and musculoskeletal pains. How can we start to help people who suffer functional symptoms if there is a taboo about mentioning it? People with functional symptoms are suffering in the same way as those with physical symptoms and if we are to destigmatise this area of medicine then authors as important and respected as Greenhalgh and colleagues should acknowledge their existence. It would be extraordinary if many people suffering long covid did not have a functional element to their presentations. Concentrating on physical tests and bodily mechanisms wholly risks missing this component.
95	P93		Amanda Sacks-Zimmerman, Ph.D. Thomas F. Bergquist, Ph.D. Ellen M. Farr, M.D. Melinda A. Cornwell, Ph.D. Dora Kanellopoulos, Ph.D.	Rehabilitation of Neuropsychiatric Symptoms in Patients with Long-COVID: Position Statement	https://doi.org/10.1016/j.apmr.2022.10.001	Published	October 19, 2022	Article	https://www.archives-pmr.org/article/S0003-9993(22)01658-6/fulltext	Long-COVID, a term used to describe ongoing symptoms following SARS-CoV-2 (COVID-19) infection, parallels the course of other post-viral syndromes. Neuropsychiatric symptoms of Long-COVID can be persistent and interfere with quality of life and functioning. Within the biopsychosocial framework of chronic illness, rehabilitation professionals can address the neuropsychiatric sequelae of Long-COVID. However, current practice models are not designed to address concurrent psychiatric and cognitive symptoms in adults living with Long-COVID. Thus, we present a biopsychosocial framework for Long-COVID and provide treatment strategies based on evidence from current literature of post-viral chronic illness. These recommendations will guide rehabilitation professionals in 1) identifying common neuropsychiatric symptoms in Long-COVID that can be targeted for intervention and 2) addressing these symptoms via integrative interventions taking into account the biopsychosocial presentation of Long-COVID symptoms.
96	P94		KeerthanaSankarMDaMichael K.GouldMDbHallie C.PrescottMDc	Psychological Morbidity After COVID-19 Critical Illness	https://doi.org/10.1016/j.chest.2022.09.035	Published	3 October 2022	Review	https://www.sciencedirect.com/science/article/pii/S0012369222039058	Survivors of ICU hospitalizations often experience severe and debilitating symptoms long after critical illness has resolved. Many patients experience notable psychiatric sequelae such as depression, anxiety, and posttraumatic stress disorder (PTSD) that may persist for months to years after discharge. The COVID-19 pandemic has produced large numbers of critical illness survivors, warranting deeper understanding of psychological morbidity after COVID-19 critical illness. Many patients with critical illness caused by COVID-19 experience substantial post-ICU psychological sequelae mediated by specific pathophysiologic, iatrogenic, and situational risk factors. Existing and novel interventions focused on minimizing psychiatric morbidity need to be further investigated to improve critical care survivorship after COVID-19 illness. This review proposes a framework to conceptualize three domains of risk factors (pathophysiologic, iatrogenic, and situational) associated with psychological morbidity caused by COVID-19 critical illness: (1) direct and indirect effects of the COVID-19 virus in the brain; (2) iatrogenic complications of ICU care that may disproportionately affect patients with COVID-19; and (3) social isolation that may worsen psychological morbidity. In addition, we review current interventions to minimize psychological complications after critical illness.
97	P95		Gaia Sampogna *,Matteo Di Vincenzo,Vincenzo Giallonardo,Francesco Perris,Antonio Volpicelli,Valeria Del Vecchio,Mario LucianoORCID andAndrea Fiorillo	The Psychiatric Consequences of Long-COVID: A Scoping Review	https://doi.org/10.3390/jpm12111767	Published	26 October 2022	Review	https://www.mdpi.com/2075-4426/12/11/1767/htm	The COVID-19 pandemic has represented a new form of traumatic event, affecting the general population worldwide and causing severe disruption of daily routine. A new urgent concern is related to the burden associated with COVID-19 symptoms that persist beyond the onset of infection, the so-called long-COVID syndrome. The present paper aims to: (1) describe the most frequent psychiatric symptoms reported by patients affected by long-COVID syndrome; (2) evaluate methodological discrepancies among the available studies; (3) inform clinicians and policy-makers on the possible strategies to be promoted in order to manage the psychiatric consequences of long-COVID syndrome. Twenty-one papers have been included in the present review, mostly with a cross-sectional or cohort design. Significant heterogeneity of long-COVID syndrome definitions was found. The presence of psychiatric symptoms was evaluated with very different assessment tools. The most common psychiatric symptoms of the long-COVID syndrome included fatigue, cognitive disturbances/impairment, depression, and anxiety symptoms. The rate of fatigue varied from 93.2–82.3% to 11.5%, cognitive impairment/cognitive dysfunction from 61.4% to 23.5% and depressive-anxiety symptoms from 23.5%to 9.5%.
98	P96		Lilly Lerer,1 Michael Marcangelo,2 Leora R. Cherney,3 and Elliot J. Roth3	(30) Characterizing Mood Symptoms in Long Covid: A Qualitative Perspective	https://doi.org/10.1016%2Fj.jaclp.2022.10.033	Published	2022 Nov 10	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9646369/	Abstract: Background Mood symptoms are commonly experienced by individuals with Post-Acute Covid-19 Syndrome (PACS, or “Long Covid”), especially anxiety and depression (1). This qualitative study was performed to investigate experiences of PACS, in order to characterize the nature of self-reported mood symptoms associated with PACS. Methods Semi-structured interviews were conducted with 8 English-speaking adults who met WHO Criteria for PACS, recruited from a general rehabilitation clinic and by word-of-mouth in Chicago between November 2021-March 2022 (2). The interview guide consisted of a modified version of the McGill Illness Narratives Interview (MINI) to elicit descriptions of the nature and impact of the symptoms of PACS. Interviews were de-identified, transcribed, coded using grounded theory methodology, and analyzed for themes. Results Individuals evidenced four distinct trajectories of self-reported mood symptoms during PACS, compared to their pre-PACS baselines: persistence or worsening of pre-PACS mood symptoms, development of mood symptoms not present before PACS, relief of pre-PACS mood symptoms during PACS, or no mood symptoms before or during PACS. Five individuals reported histories of depression and anxiety before PACS occurred, including four individuals receiving ongoing psychiatric treatment. Among these, PACS was associated with worsening of symptoms for four individuals, and did not influence the symptoms of one individual. Three individuals reported no history of anxiety or depression before PACS. Among these, one reported the development of significant mood symptoms during PACS, while two did not. Several themes emerged regarding the contextual factors associated with mood symptoms. Participants described depression, anxiety, insomnia, hopelessness, apathy, and irritability as resulting from multiple sources, including the debilitating nature of symptoms, uncertainty about their ability to work, exposure to distressing news stories, lack of support from family members, financial impact, poor treatment from employers, hopelessness about living with symptoms indefinitely, negative impact on self-image, and the harmful impact of symptoms on marriage, dating life, sexual function, and future childbearing ability. Discussion While epidemiological data has established the prevalence of neuropsychiatric symptoms of PACS, debate exists over their mechanistic etiology, which if known could help refine treatment approaches or identify predictive factors. Themes from this dataset support the hypothesis that circumstantial stressors of PACS are associated with self-reported mood symptoms. However, this relationship was not universal, and supports the practice of a highly individualized treatment approach for individuals with PACS. Finally, while circumstances caused by PACS may influence mood symptoms, research must be conducted to understand primary mechanistic explanations for neuropsychiatric symptoms of PACS.
99	P97		Luigi De Gennaro 1,2,*ORCID,Serena Scarpelli 1ORCID andMaurizio Gorgoni 1,2ORCID	The Effect of COVID-19 on Sleep Quality and Mental Health: Adolescents Are More at Risk Than the Elderly	https://doi.org/10.3390/brainsci12111543	Published	14 November 2022	Editorial	https://www.mdpi.com/2076-3425/12/11/1543/htm	After the appearance of a novel coronavirus (2019-nCoV) during 2019, the virus has spread with alarming speed and a pandemic quickly developed. The complex consequences of the pandemic phenomenon, i.e., the consequences of the pandemic per se and the countermeasures adopted to control infections and deaths, were associated with a negative impact on sleep quality [1] and, in general, mental health [2]. With a global prevalence of sleep disturbances of approximately 30–40%, as suggested by meta-analytical studies [3,4], a stable association with psychological distress has been repeatedly reported [5]. In Europe, Italy was the first country to report high rates of infection and deaths, and, as a consequence, the Italian Government declared unprecedented restrictive measures with a total lockdown on 9 March 2020. Not surprisingly, many studies on the effects of the lockdown and/or the pandemic were conducted in Italy (e.g., [6,7,8,9]), reporting an increase in sleep difficulties associated with the pandemic, particularly during the lockdown periods. Along this vein, the Italian study by Amicucci et al. [10] also investigated the impact of the COVID-19 lockdown during Spring 2020 on sleep quality and mental health. The main merit of this study is a specific focus on two at-risk groups: late adolescents (18–20 years) and the elderly (65–75 years). The authors used a web-based survey and validated questionnaires to assess sleep quality, insomnia, stress, depression, and anxiety. The adolescents reported more insomnia symptoms, worse sleep quality, longer sleep latency, higher daytime dysfunction, a more prevalent disruption of sleep habits (bedtime, get-up time, and nap), and a more negative impact on mental health (higher levels of depression and perceived stress than the elderly). Older participants showed shorter sleep durations, lower habitual sleep efficiency, and greater use of sleep medications. These findings in the elderly are mostly common characteristics of sleep in this age range [11], and they can be considered to have been pre-existing prior to the pandemic. On the other hand, the results from the late adolescents point to pervasive consequences for sleep and mental health in this group. The apparent paradox is represented by the elderly population having the highest risk of morbidity and mortality due to the pandemic, whereas adolescents show the strongest impact in terms of sleep quality and mental health. This finding should be considered in light of previous observations that point to greater resilience in older adults during difficult times [12], which is likely associated with better emotional regulation and coping strategies [13,14] developed over one’s lifetime. Although this study does not allow for the disentanglement of the consequences of the pandemic per se and the consequences of home confinement (i.e., the COVID-19 lockdown), the interpretation in terms of a greater suffering due to the restrictive measures experienced by adolescents seems more tenable, since about sixty percent of adolescents reported the restraining measures having a negative impact on sleep as compared to about forty percent of the elderly. However, a note of caution with regard to the interpretation of these findings is needed, since several pieces of information about the composition of the sample (e.g., job, family composition, social environment, physical activity, and lockdown- or pandemic-related changes in daily habits) are not available and may have affected the results. Longitudinal observations and a greater focus on the possible intervening variables are needed. Another point highlighted by the present study appears relevant from a methodological standpoint for future evaluations of subjective sleep quality during the pandemic. Indeed, in spite of a significant difference in insomnia levels between late adolescents and the elderly, the authors did not find differences in the overall subjective sleep quality expressed by the Pittsburg Sleep Quality Index (PSQI) [15] global score. However, this finding is due to a dissociation in the direction of the differences between groups in specific sleep domains that clearly emerged when assessing the PSQI subscales. Consistent with previous observations [16], this result highlights the complex nature of the pandemic’s influence on sleep, and the exclusive assessment of global sleep quality measures may possibly prevent findings from reflecting this multifaced effect. Overall, the results from Amicucci and coworkers [10] confirm the emerging evidence of late adolescents/young adults having a high vulnerability to pandemic-related sleep and mental health problems (e.g., [8,17,18,19]). In this view, it is crucial to monitor this population over time to detect possible long-term consequences of the pandemic on sleep and psychological wellbeing, determine specific protective and risk factors, and develop timely preventive and interventional strategies.
100	P98		Yunyu Xiao, Mohit M. Sharma, Rohith K. Thiruvalluru, Catherine Gimbrone, Myrna M. Weissman, Mark Olfson, Katherine M. Keyes & Jyotishman Pathak	Trends in psychiatric diagnoses by COVID-19 infection and hospitalization among patients with and without recent clinical psychiatric diagnoses in New York city from March 2020 to August 2021	https://doi.org/10.1038/s41398-022-02255-8	Published	21 November 2022	Study	https://www.nature.com/articles/s41398-022-02255-8	Determining emerging trends of clinical psychiatric diagnoses among patients infected with the SARS-CoV-2 virus is important to understand post-acute sequelae of SARS-CoV-2 infection or long COVID. However, published reports accounting for pre-COVID psychiatric diagnoses have usually relied on self-report rather than clinical diagnoses. Using electronic health records (EHRs) among 2,358,318 patients from the New York City (NYC) metropolitan region, this time series study examined changes in clinical psychiatric diagnoses between March 2020 and August 2021 with month as the unit of analysis. We compared trends in patients with and without recent pre-COVID clinical psychiatric diagnoses noted in the EHRs up to 3 years before the first COVID-19 test. Patients with recent clinical psychiatric diagnoses, as compared to those without, had more subsequent anxiety disorders, mood disorders, and psychosis throughout the study period. Substance use disorders were greater between March and August 2020 among patients without any recent clinical psychiatric diagnoses than those with. COVID-19 positive patients (both hospitalized and non-hospitalized) had greater post-COVID psychiatric diagnoses than COVID-19 negative patients. Among patients with recent clinical psychiatric diagnoses, psychiatric diagnoses have decreased since January 2021, regardless of COVID-19 infection/hospitalization. However, among patients without recent clinical psychiatric diagnoses, new anxiety disorders, mood disorders, and psychosis diagnoses increased between February and August 2021 among all patients (COVID-19 positive and negative). The greatest increases were anxiety disorders (378.7%) and mood disorders (269.0%) among COVID-19 positive non-hospitalized patients. New clinical psychosis diagnoses increased by 242.5% among COVID-19 negative patients. This study is the first to delineate the impact of COVID-19 on different clinical psychiatric diagnoses by pre-COVID psychiatric diagnoses and COVID-19 infections and hospitalizations across NYC, one of the hardest-hit US cities in the early pandemic. Our findings suggest the need for tailoring treatment and policies to meet the needs of individuals with pre-COVID psychiatric diagnoses.
101	P99		Kristen Nishimi, Thomas C. Neylan, Daniel Bertenthal, Emily A. Dolsen, Karen H. Seal & Aoife O’Donovan	Post-traumatic stress disorder and risk for hospitalization and death following COVID-19 infection	https://doi.org/10.1038/s41398-022-02156-w	Published	22 November 2022	Study	https://www.nature.com/articles/s41398-022-02156-w	Post-traumatic stress disorder (PTSD) is associated with an increased risk for physical illnesses and early mortality. However, we do not know if it also increases the risk for adverse outcomes of coronavirus disease 2019 (COVID-19). In this retrospective cohort study, we examined associations of PTSD and other psychiatric disorders with risk for hospitalization and death in the 60 days following a COVID-19 infection in 228,367 U.S. Department of Veteran Affairs (VA) patients who tested positive for COVID-19 between February 2020 and August 2021 (age m = 60.6, 89.5% male). Generalized linear models estimated associations of PTSD and other psychiatric disorders with outcomes following a positive SARS-CoV-2 test, adjusting for socio-demographic, medical, and behavioral factors. Among 228,367 VA patients, 25.6% had PTSD, and 28.2% had a psychiatric disorder other than PTSD. In the 60 days following a positive COVID-19 test, 15% of patients were hospitalized, and 6% died. Patients with PTSD had an increased risk for both hospitalization (adjusted relative risk, ARR = 1.18, 95% CI 1.15–1.21) and death (ARR = 1.13, 95% CI 1.08–1.19) relative to those with no psychiatric disorders, adjusting for socio-demographics. Estimates remained significant when models were additionally adjusted for medical comorbidities and smoking. Patients with other psychiatric disorders also had an increased risk of adverse COVID-19 outcomes, with larger effect sizes than PTSD in older (≥65 years) but not younger patients. In this large-scale study of VA patients, individuals with PTSD, and other psychiatric disorders, had heightened vulnerability to severe adverse outcomes of COVID-19; thus, individuals with PTSD should also be considered at higher risk for severe COVID-19 outcomes, and potentially prioritized for vaccination, screening, and early treatment intervention for COVID-19.
102	P100		Delfina Janiri 1,2,3,*,Matteo Tosato 4ORCID,Alessio Simonetti 1,3ORCID,Silvia Montanari 1,Beatrice Terenzi 1,Antonello Catinari 1,Lorenzo De Mori 1,Gaspare Filippo Ferrajoli 1,Georgios D. Kotzalidis 5ORCID,Francesco Landi 4,Roberto Bernabei 4 andGabriele Sani 1,3ORCID	Post-COVID-19 Psychiatric Symptoms in the Elderly: The Role of Gender and Resilience	https://doi.org/10.3390/jpm12122016	Published	6 December 2022	Study	https://www.mdpi.com/2075-4426/12/12/2016	COVID-19 represents an overwhelming stressor to mental health. Elderly individuals are particularly at risk, but it is still unclear whether the risk is equally distributed among men and women. The aim of this study was to define gender differences in persistent psychiatric symptoms after COVID-19 illness and to test their association with resilience factors. Methods: We assessed 348 individuals aged >65 years at a multidisciplinary post-COVID-19 service. Mood and anxiety symptoms were investigated, as well as psychological distress and resilience, as assessed with the Kessler-10 (K10) Scale and the Connor-Davidson Resilience Scale (CD-RISC), respectively. Multivariate and linear regression analyses were used to test the distribution patterns of psychiatric symptoms and resilience factors. Results: In the total sample, 214 (61.5%) were men (a mean age of 73.25 years ±6.04) and 134 (38.5%) were women (a mean age of 72.69 years ±6.43; p = 0.407). Men and women significantly differed in marital status (χ2 = 25.17; p < 0.001, more men were married), living alone (χ2 = 11.62; p < 0.01, fewer men were living alone), hospitalization during COVID-19 illness (χ2 = 12.35; p < 0.001, more men were hospitalized during COVID-19), and subjective health status before COVID-19 infection (χ2 = 4.32; p < 0.001, men reporting better subjective health than women). Women reported more psychiatric symptoms and fewer resilience factors than men. Low resilience levels significantly predicted psychological distress in both men and women. Conclusions: The female elderly population affected by COVID-19 showed a greater vulnerability to psychiatric symptoms. Our data point to the need to strengthen resilience resources, especially in women.
103	P101		Alessio Simonetti 1,2,*,†,Evelina Bernardi 2,†,Delfina Janiri 1,3,Marianna Mazza 2ORCID,Silvia Montanari 2,Antonello Catinari 2,Beatrice Terenzi 2,Matteo Tosato 4,5ORCID,Vincenzo Galluzzo 5ORCID,Francesca Ciciarello 5,Francesco Landi 4,5 andGabriele Sani 2,6ORCID	Suicide Risk in Post-COVID-19 Syndrome	https://doi.org/10.3390/jpm12122019	Published	7 December 2022	Study	https://www.mdpi.com/2075-4426/12/12/2019	Post-acute sequelae of COVID-19 include several neuropsychiatric disorders. Little is known about the relationship between post-COVID-19 syndrome and suicidality. The aim of the study was to investigate the risk of suicide in subjects with persistent post-COVID-19 syndrome. One-thousand five-hundred eighty-eight subjects were assessed in the Post-Acute Care Service at the Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS of Rome. Assessment included: (a) sociodemographic characteristics; (b) symptoms during and after COVID-19; (c) psychopathological evaluation. Participants were divided in those with (SUI) or without (NON SUI) suicide risk according to the Mini International Neuropsychiatric Interview. Additionally, subjects with SUI were split into those with high (HIGH SUI) and low (LOW SUI) suicide risk. Between-group comparisons were made with t-tests for continuous variables and χ2 tests for categorical variables. SUI showed greater percentages of physical complaints during and after COVID-19, greater percentages of psychiatric history and presence of psychiatric history in relatives, greater percentages of subjects previously undergoing psychopharmacotherapy, and greater levels of anxiety, mixed depressive symptoms, general psychopathology than NON SUI. HIGH SUI showed greater number of symptoms during and after COVID-19 and higher levels of mixed depressive symptoms than LOW SUI. Percentages of subjects undergoing psychotherapy was higher in LOW SUI than HIGH SUI. Greater levels of physical complaints and psychopathology during post-COVID-syndrome might enhance the risk of committing suicide. Treatment of physical complaints and psychotherapy might reduce suicide risk.
104	P102		Mohammad Pourfridoni,Hedyeh Askarpour	COVID-19 and the increase in schizophrenia incidence in the future: A hypothesis and a serious warning	https://doi.org/10.1002/hsr2.978	Published	05 December 2022	Article	https://onlinelibrary.wiley.com/doi/10.1002/hsr2.978	Background and Aims The coronavirus disease 2019 (COVID-19), which has caused a global pandemic, is brought on by the Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). Since the COVID-19 pandemic started so recently, dealing with complications that emerge years later and have the potential to cause several crises for humanity is one of the issues we face in the post-COVID-19 age. Therefore, we wish to discuss a theory and potential dangers surrounding the probability of schizophrenia following COVID-19 infection in this study. Methods The literature search for this article has been entirely internet-based. Information was gathered using the Web of Science, PubMed, Scopus, and Google Scholar databases. Results The results showed that multiple immune system changes brought on by COVID-19 have been identified as potential causes of schizophrenia. Conclusion It is predicted that one of the long-term effects of COVID-19 is an increase in the risk of schizophrenia incidence based on the results of this study, which looked at the pathophysiology and etiology of schizophrenia as well as the pathogenic mechanisms of the SARS-CoV-2. Therefore, healthcare staff should be prepared to handle any potential risks in future.
105	P103		Daisy Fancourt Andrew Steptoe and Feifei Bu	Psychological consequences of long COVID: comparing trajectories of depressive and anxiety symptoms before and after contracting SARS-CoV-2 between matched long- and short-COVID groups	https://doi.org/10.1192/bjp.2022.155	Published	02 December 2022	Study	https://www.cambridge.org/core/journals/the-british-journal-of-psychiatry/article/psychological-consequences-of-long-covid-comparing-trajectories-of-depressive-and-anxiety-symptoms-before-and-after-contracting-sarscov2-between-matched-long-and-shortcovid-groups/923140B3F95F1158C0CDC188002531AE	Background There is a growing global awareness of the psychological consequences of long COVID, supported by emerging empirical evidence. However, the emergence and long-term trajectories of psychological symptoms following the infection are still unclear. Aims To examine when psychological symptoms first emerge following infection with SARS-CoV-2 and the long-term trajectories of psychological symptoms comparing long- and short-COVID groups. Method We analysed longitudinal data from the UCL COVID-19 Social Study (March 2020 to November 2021). We included data from adults living in England who reported contracting SARS-CoV-2 by November 2021 (n = 3115). Of these, 15.9% reported having had long COVID (n = 495). They were matched to participants who had short COVID using propensity score matching on a variety of demographic, socioeconomic and health covariates (n = 962 individuals with 13 325 observations) and data were further analysed using growth curve modelling. Results Depressive and anxiety symptoms increased immediately following the onset of infection in both long- and short-COVID groups. But the long-COVID group had substantially greater initial increases in depressive symptoms and heightened levels over 22 months follow-up. Initial increases in anxiety were not significantly different between groups, but only the short-COVID group experienced an improvement in anxiety over follow-up, leading to widening differences between groups. Conclusions The findings support work on the psychobiological pathways involved in the development of psychological symptoms relating to long COVID. The results highlight the need for monitoring of mental health and provision of adequate support to be interwoven with diagnosis and treatment of the physical consequences of long COVID.
106	P104		Fenton, Caroline; Lee, Arnold	Antidepressants with anti-inflammatory properties may be useful in long COVID depression	https://doi.org/10.1007/s40267-022-00975-x	Published	2022-12-12	Study	https://doi.org/10.1007/s40267-022-00975-x	Long COVID, which is characterised by the presence of persistent symptoms following a COVID infection, may also cause long COVID depression (LCD). Although the risk factors for LCD are not directly characterised, prior mental health visits were associated with an increased risk for long COVID, whereas antidepressant use was not. Current evidence suggests that pro-inflammatory factors in the brain are linked to LCD, thus anti-inflammatory agents may be useful in mitigating LCD. Limited evidence suggests that selective serotonin reuptake inhibitors may also be effective in the treatment of LCD.
107	P105		Benzakour, L.; Voruz, P.; Lador, F.; Guerreiro, I.; Kharat, A.; Assal, F.; Péron, J. A.	Posttraumatic Stress Disorder and Hyperventilation in Post-COVID-19 Syndrome: An Underestimated Association	https://doi.org/10.1016/j.jaclp.2022.08.006	Published	2022-11-01	Case Report	https://www.sciencedirect.com/science/article/pii/S2667296022003147	Hyperventilation syndrome (HVS) is a dysfunctional breathing syndrome in which minute ventilation exceeds metabolic demands, resulting in hemodynamic and chemical changes. Recent data suggest that HVS incidence is high in the post-COVID-19 condition,1 and its management may involve consultation-liaison (CL) psychiatry considering the presence of functional symptoms. In our clinical practice, we observed an association between posttraumatic stress disorder (PTSD), which is also prevalent in the post-COVID-19 condition,2 and HVS that could be explained by a traumatic experience during the acute phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. These 2 phenomena have so far only been studied separately in the post-COVID-19 condition despite the evidence of their interaction in other pathologies. In the present letter case, we would like to highlight the possible interaction between HVS and PTSD in post-COVID-19 condition.
108	P106		Pick, Anton	Is Long Covid a Functional Disorder?	https://doi.org/10.1177/11795727221141193	Published	1/1/2023	Article	https://doi.org/10.1177/11795727221141193	publisher: SAGE Publications ‘Functional disorders’ are described as resulting from pathological changes in bodily ‘function’ rather than ‘structure’. This conceptualisation is thought to offer an explanation as to why standard medical investigations are commonly unremarkable. Other conditions that fall under the umbrella of ‘functional disorder’ include Fibromyalgia, ME/CFS, Chronic Pelvic Pain, Functional Dyspepsia, Functional Neurological Disorder and Overactive Bladder Syndrome. Some clinicians, researchers and patient advocacy groups are supportive of the term as it can be used to validate the patient’s experience in lieu of a clear biological explanation. I suggest, however, the label of ‘functional disorder’ might in other ways be unhelpful. In its most clumsy usage, the term ‘functional’ suggests a fundamental difference between those conditions that are easily explained biomedically and those that aren’t. This distinction is not reflective of real life clinical practice. Diseases thought to be well understood biomedically continue to confound. Firstly, the degree of disability of two patients with the same disease, with the same objective ‘severity’ can diverge massively in terms of their level of disability. For example, in chronic obstructive pulmonary disease (COPD) it is common for different patients with similar imaging and lung function testing results to present entirely differently.4 Secondly, the relationship between proposed biomedical mechanisms and disease outcomes is not straightforward. For example, behavioural factors, such as stress and bereavement, independently increase the risk of adverse cardiac outcomes. Put simply, no two disease presentations are alike, regardless of the results of investigations. Categorising diseases as ‘functional’ or not risks limiting our curiosity about such complexity. The term ‘functional’ evolved from now outdated terms such as ‘psychosomatic’ or ‘hysterical’. Unfortunataly, however, the insidious and stigmatising question of whether a condition is ‘in your head’ or not continues to rear its head. Simply replacing ‘psychosomatic’ with ‘functional’ can seem, at its worst, somewhat cloak and dagger. Its use in this way risks furthering an unhelpful and inaccurate distinction between mind and body. Yet another critique of Descartes’ Cartesian dualism is not required – this has been widely written about elsewhere.5 Any disease or injury, be it Long Covid or a broken arm is experienced in the mind. Designating Long Covid a ‘functional disorder’ may perpetuate stigma and impede scientific curiosity.
109	P107		Kataoka, Mayumi; Hazumi, Megumi; Usuda, Kentaro; Okazaki, Emi; Nishi, Daisuke	Association of preexisting psychiatric disorders with post-COVID-19 prevalence: a cross-sectional study	https://doi.org/10.1038/s41598-023-27405-w	Published	1/7/2023	Study	https://www.nature.com/articles/s41598-023-27405-w	Evidence demonstrating the association of preexisting psychiatric disorders with post-COVID-19 is limited. We aim to investigate the association using larger sample sizes and more extended postinfection periods than previous studies. A total of 6015 (response rate = 77.5%) COVID-19 survivors were surveyed using a self-administered questionnaire from July to September 2021. Poisson regression analysis with robust error variance was performed to estimate post-COVID-19 prevalence ratios (PRs) with or without preexisting psychiatric disorders. Participants with preexisting psychiatric disorders numbered 1067 (17.7%), and with post-COVID-19 were 2149 (35.7%). Post-COVID-19 PR with preexisting psychiatric disorders was 1.09 (95% CI 1.02–1.18, p = 0.013). The interaction between preexisting psychiatric disorders and postinfection periods was significant (p for interaction < 0.001). The subgroup analysis showed that those with preexisting psychiatric disorders might be at greater prolonged risk of post-COVID-19 than those without the disorders. These findings suggested that preexisting psychiatric disorders were associated with an increased post-COVID-19 risk, and post-COVID-19 with preexisting psychiatric disorders might prolong even if time passes.
110	P108		Craparo, Giuseppe; La Rosa, Valentina Lucia; Commodari, Elena; Marino, Graziella; Vezzoli, Michela; Faraci, Palmira; Vicario, Carmelo Mario; Cinà, Gabriella Serena; Colombi, Morena; Arcoleo, Giuseppe; Severino, Maria; Costanzo, Giulia; Gori, Alessio; Mangiapane, Ernesto	What Is the Role of Psychological Factors in Long COVID Syndrome? Latent Class Analysis in a Sample of Patients Recovered from COVID-19	https://doi.org/10.3390/ijerph20010494	Published	1/1/2023	Study	https://www.mdpi.com/1660-4601/20/1/494	Background: This study aimed to identify clusters of long COVID-19 symptoms using latent class analysis and investigate the psychological factors involved in the onset of this syndrome. Method: Five hundred and six subjects recovering from COVID-19 completed a series of standardized questionnaires to evaluate the personality traits, alexithymia, and post-traumatic stress. Results: Five classes were identified: Brain fog (31.82%), No symptoms (20.95%), Sensory disorders (18.77%), Breath impairment (17.59%), and Multiple disorders (10.87%). Women reported post-COVID-19 respiratory symptoms and multiple disorders to a greater extent than men. Hospitalized subjects were more likely to report persistent symptoms after COVID-19 than asymptomatic or home-treated subjects. Antagonism, hyperarousal, and difficulty identifying emotions significantly predicted post COVID-19 symptoms. Conclusions: These findings open new questions for research on long COVID-19 and how states of emotional dysregulation can alter the physiological processes of the body and contribute to the onset of organic pathologies.
111	P109		Sakka, Elpitha; Kalniunas, Arturas; Vitkauskaite, Elzbieta; Salman, Wala; Chaudhri, Subhana; Pappa, Sofia	Psychological Effects and Neuropsychiatric Sequelae in COVID-19 Patients	https://doi.org/10.1002/9781119789741.ch25	Published	1/1/2023	Review	https://onlinelibrary.wiley.com/doi/abs/10.1002/9781119789741.ch25	With the continuity of the COVID-19 global health crisis, the need to establish the short- and long-term health implications of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) virus on infected patients is of critical importance. In this chapter, we summarize information concerning the prevalence of associated mental health effects and neuropsychiatric sequelae in addition to predictive and preventative factors in patients with COVID-19. Evidence to date suggests a significant proportion of infected and hospitalized patients experience a variety of adverse psychological effects, reporting symptoms of depression, anxiety, posttraumatic stress disorder, cognitive impairment, and sleep abnormalities. Severity of COVID-19 infection, duration of hospitalization, admission to the intensive care unit, and preexisting mental health issues have all been associated with a greater risk of developing various psychiatric complications in patients. Identification of relevant factors will hopefully lead to the effective diagnosis and management of symptoms of psychological distress that may arise during or after recovery of COVID-19 more effectively. Finally, we discuss appropriate management strategies and interventions to prevent the immediate and enduring psychological complications in patients with COVID-19, including those of the post-COVID-19 syndrome.
112	P110		Todd, Noah; Pater, Jessica; Li, Jason; Bohn, Camden; Henriksen, Brian; Carroll, Jeanne; Chang, Fen-Lei	Associations Between Psychiatric Symptoms and Cognitive Impairment in Post-Acute Sequelae of COVID	https://doi.org/10.18060/26789	Published	1905-07-14	Study	https://journals.iupui.edu/index.php/IMPRS/article/view/26789	Introduction: Post-acute sequelae of COVID (PASC) is an emerging postviral syndrome affecting patients who have recovered from acute COVID infection. Symptoms can affect many different organ systems, including the CNS. Neuropsychiatric complications are common in PASC, affecting roughly 1 in 3 patients who recover from COVID. The present study aims to investigate relationships between depressive, anxious, somatic, and general psychiatric symptom burden and cognitive impairment in PASC. Methods: Patients were recruited from the Parkview Post-COVID Clinic (PPCC) from April 2021 to March 2022. Patients were deemed eligible if data were available for both Brief Symptomatic Inventory (BSI) and BrainCheck scores. Eligible patients were divided into low or normal cognitive function based on BrainCheck guidelines, and differences in psychiatric symptom severity were assessed via Mann-Whitney U testing. Strength and direction of associations were determined using Pearson’s correlation coefficient. A smaller subset of patients was analyzed for differences in PASC symptom severity based on Omicron or Delta infection. Results: Generalized cognitive and mental flexibility complaints were associated with more severe psychiatric symptom burden in all domains measured by BSI (p = 0.003 and p = 0.01, respectively). Impaired attention was not related to any psychiatric symptom domain (p > 0.05). Impaired memory was related to more severe symptom burden in all psychiatric domains except depression (immediate recall p = 0.015; delayed recall p = 0.015). Conclusion: General cognitive and mental flexibility complaints can be used to prompt clinical suspicion of concurrent psychiatric symptoms. Complaints regarding attention are not linked to any psychiatric symptom domain. Complaints regarding memory can also provide impetus for investigating concurrent psychiatric symptoms, excluding depression. These associations can be used to facilitate earlier diagnosis and treatment of cognitive impairment and psychiatric illness in the context of PASC.
113	P111		Effiong, Andem	Postacute Sequelae of COVID-19 and Adverse Psychiatric Outcomes: Protocol for an Etiology and Risk Systematic Review	https://doi.org/10.2196/43880	Published	2023-03-14	Review	https://xmed.jmir.org/2023/1/e43880	Background: The postacute sequelae of COVID-19 (PASC) is a syndrome characterized by persistent COVID-19 symptoms or the onset of new symptoms following recovery from the initial or acute phase of the illness. Such symptoms often occur 4 or more weeks after being diagnosed with COVID-19. Although a lot of work has gone into understanding the long-term mental health effects of PASC, many questions related to the etiology and risk of this condition remain. Objective: This protocol is for a systematic review assessing the association between PASC and adverse psychiatric outcomes and whether people with PASC are at greater risk of developing an adverse psychiatric outcome than those without PASC. Methods: Various medical literature databases (eg, PubMed and EMBASE) will be searched for eligible articles, using predefined search criteria. Gray literature will also be explored. Epidemiological observational studies and secondary analyses of randomized controlled trials that report a quantitative relationship between PASC and at least one adverse psychiatric outcome will be included. The Population, Exposure of interest, Comparator, and Outcome framework will be used as a standardized framework for the inclusion criteria. The Joanna Briggs Institute critical appraisal tools will be used to assess methodological quality and critically appraise the risk of bias in included studies. A random-effects meta-analysis will be conducted if possible. A formal narrative synthesis will be performed if a meta-analysis is impossible due to substantial heterogeneity across studies. The Grading of Recommendations Assessment, Development and Evaluation approach will be used to rate the cumulative certainty of the evidence for all outcomes. Ethical approval is not required. The study results will be published in a peer-reviewed journal. Results: This study documents and addresses etiology, risk factors, and long-term symptoms of COVID-19 among people with PASC. It focuses on a key priority area for new evidence syntheses on the clinical management of COVID-19 and pandemic-related conditions. It will include evidence on nonhospitalized and hospitalized patients with a history of PASC. Conclusions: Substantial heterogeneity across studies may limit the ability to perform a meta-analysis. Findings will inform disease prevention, decision-making, health care policy, and clinical research (Reviewed by the Plan P #PeerRef Community). Trial Registration: PROSPERO CRD42022308737; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=308737
114	P112		Sun, Luna; Shang, Zhilei; Wu, Lili; Pan, Xiao; Sun, LiangLiang; Ouyang, Hui; Huang, Hai; Zhan, Jingye; Jia, Yanpu; Zhou, Yaoguang; Bai, Yonghai; Xie, Weifen; Liu, Weizhi	One-quarter of COVID-19 patients developed PTSD symptoms: A one-year longitudinal study	https://doi.org/10.1016/j.psychres.2023.115161	Published	2023-05-01	Study	https://www.sciencedirect.com/science/article/pii/S0165178123001129	Highlights •The cumulative occurrence of probable PTSD was 26.7% in COVID-19 patients over 12 months after hospital discharge. •PTSD symptoms of non-severe patients recovered better compared with severe patients. •Patients who were females and had sequelae of cough or dyspnea require special attention during long-term convalescence. Abstract This study investigated the longitudinal development of PTSD symptoms and respiratory sequelae among COVID-19 patients one year after hospital discharge. The cumulative occurrence of probable PTSD in COVID-19 survivors (n = 329) was 26.7%, which significantly decreased over the 12-month period (23.1% to 4.3%). Non-severe patients showed marked improvement in all four clusters of PTSD symptoms at 12 months compared to 3 months, while severe patients only showed improvements in re-experiencing and numbing symptoms. Moreover, being female and having respiratory sequelae increased the risk for chronic PTSD. Psychological interventions are required for COVID-19 patients during long-term convalescence.
115	P113		Chow, Clifton M.; Schleyer, Will; DeLisi, Lynn E	The prevalence of psychiatric symptoms and their correlates as part of the long-COVID syndrome	https://doi.org/10.1016/j.psychres.2023.115166	Published	2023-05-01	Review	https://www.sciencedirect.com/science/article/pii/S0165178123001178	The Long COVID syndrome has now been documented clearly in the literature, but whether or not psychiatric symptoms are prominent is unclear. We performed a retrospective chart review of all patients receiving medical care during the pandemic in an outpatient Long-COVID specialty clinic that serves a large racial and ethnic minority population. As many as 44% of patients had symptoms that necessitated referrals to psychiatrists, predominantly depression or anxiety. Spanish speaking patients had greater COVID severity (48%) than did predominantly English speakers (15%). We conclude that the long COVID syndrome is predominantly a cluster of physical symptoms that are sequelae of the viral infection.
116	P114		Benedetti, Francesco	Immunopsychiatry after COVID-19	https://doi.org/10.1016/j.jadr.2023.100521	Published	2023-04-01	Article	https://www.sciencedirect.com/science/article/pii/S2666915323000604	Immunopsychiatry can be defined as the study of immune-inflammatory pathways in order to identify pathogenetic mechanisms, and targets for treatment, in psychiatric conditions: under the premises that interactions between the immune system and the central nervous system are crucial for brain homeostasis and function, and their disruption has major consequences on mental health. With its terrible burden of disease inflicted on mankind, the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection provided a natural experiment, to provocatively test the relationship between inflammation and mood disorders. Consistent systematic reviews and meta-analyses now affirm that COVID-19 survivors show persistent psychopathology and neurocognitive impairment, with clinically significant depressive psychopathology being reported in around 35% of patients. The cluster of Post-Acute Sequelae of COVID-19 (PASC) symptoms typically emerge after the acute phase of illness, when patients are no longer positive to SARS-CoV-2, including dyspnoea, hypoxia, joint and muscle pain, paraesthesia, dysgeusia, anosmia, fatigue; and, unrelated to the above, neuropsychiatric and neurocognitive symptoms with depression, anxiety, insomnia, difficulties in sustained attention and memory, which worsen over the months. Psychopathological features are the same observed in Major Depressive Disorder, distributing along the same gradient of severity, and including a typically melancholic cognitive vulnerability with self-reproach and depressive cognitive style in evaluating events. Neurocognitive impairment could possibly separate from depression in the long term, but not in the first 6 months after infection, and it is largely overlapping with persistent cognitive deficits described in severe mood disorders. Brain correlates are the same observed in Major Depressive Disorder and in Bipolar Disorder, involving spread disruption of white matter microstructure, reduced grey matter volumes in anterior cingulate cortex, and abnormal functional connectivity in the cortico-limbic circuitries: all the above, being proportional to the degree of persistent systemic inflammation, and not to the severity of the acute illness and of the breadth of exposure to stressful events during the pandemic. We suggest that post-COVID depression provides an invaluable model illness for the study of immune-inflammatory mechanisms involved in the pathogenesis of mood disorders, to identify new targets for treatment, with the aim of restoring mental health and brain homeostasis.
117	P115		Zakia, Halwa; Pradana, Kent; Iskandar, Shelly	Risk factors for psychiatric symptoms in patients with long COVID: A systematic review	https://doi.org/10.1371/journal.pone.0284075	Published	2023-04-07	Review	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0284075	Prolonged symptoms of COVID-19 have been found in many patients, often known as Long COVID. Psychiatric symptoms are commonly seen in Long COVID patients and could last for weeks, even months, after recovery. However, the symptoms and risk factors associated with it remain unclear. In the current systematic review, we provide an overview of psychiatric symptoms in Long COVID patients and risk factors associated with the development of those symptoms. Articles were systematically searched on SCOPUS, PubMed, and EMBASE up to October 2021. Studies involving adults and geriatric participants with a confirmed previous COVID-19 diagnosis and reported psychiatric symptoms that persist for more than four weeks after the initial infection were included. The risk of bias was assessed using the Newcastle-Ottawa Scale (NOS) for observational studies. Prevalence rates and risk factors associated with psychiatric symptoms were collected. This present study was registered at PROSPERO (CRD42021240776). In total, 23 studies were included. Several limitations in this review were the heterogeneity of studies’ outcomes and designs, studies limited to articles published in English, and the psychiatric symptoms mainly were assessed using self-report questionnaires. The most prevalent reported psychiatric symptoms, from the most to the least reported, were anxiety, depression, post-traumatic stress disorder (PTSD), poor sleep qualities, somatic symptoms, and cognitive deficits. Being female and having previous psychiatric diagnoses were risk factors for the development of the reported symptoms.
118	P116		Gasnier, Matthieu; David, Denis; Becquemont, Laurent; Corruble, Emmanuelle; Colle, Romain	128. Long Covid and Psychiatric Disorders 4 Months After a Hospitalization for COVID-19: A Cross Sectional Study	https://doi.org/10.1016/j.biopsych.2023.02.368	Published	2023-05-01	Study	https://www.biologicalpsychiatryjournal.com/article/S0006-3223(23)00442-0/fulltext	Background Long COVID is a major public health issue. Whether long COVID is comorbid with psychiatric disorders remains unclear. Here, we investigate the association between long COVID, psychiatric symptoms and psychiatric disorders. Methods One hundred seventy-seven patients admitted in ICU during acute phase and/or reporting long COVID complaints were assessed four months after hospitalization for an acute COVID-19. Eight long COVID complaints were investigated: fatigue, respiratory and cognitive complaints, muscle weakness, pain, headache, paraesthesia, and anosmia. The number of complaints, the presence/absence of each COVID complaint as well as lung CT-scan abnormalities and objective cognitive impairment) were considered. Self-reported psychiatric symptoms were assessed with questionnaires. Experienced psychiatrists assessed DSM-5-based diagnoses of psychiatric disorders. Results One hundred and fifteen (65%) patients had at least one long COVID complaint. The number of long COVID complaints was associated with psychiatric symptoms. The number of long COVID complaints was higher in patients with psychiatric disorders (m(sd)=2.47(1.30), p<0.05), new onset psychiatric disorders (m(sd)=2.41(1.32), p<0.05), and significant suicide risk (m(sd)=2.67(1.32), p<0.05) than in patients without any psychiatric disorder (m(sd)=1.43 (1.48)). ROC analyses showed that the threshold of one long COVID complaint had a good sensitivity (83.3%) to detect psychiatric disorders. Respiratory complaints were associated with a higher risk of psychiatric disorder and new-onset psychiatric disorder, and cognitive complaints were associated with a higher risk of psychiatric disorder. Conclusions Long COVID is associated with psychiatric disorders, new-onset psychiatric disorders, and suicide risk. Psychiatric disorders and suicide risk should be systematically assessed in patients with long COVID. publisher: Elsevier
119	P117		Nishimi, Kristen; Tan, Jeri; Scoglio, Arielle; Choi, Karmel; Kelley, D. Parker; Neylan, Thomas; O'Donovan, Aoife	37. Associations of Psychological Resilience to Trauma With Somatic Symptoms and COVID-19 Infection Over Two Years	https://doi.org/10.1016/j.biopsych.2023.02.277	Published	2023-05-01	Study	https://www.biologicalpsychiatryjournal.com/article/S0006-3223(23)00351-7/fulltext	Background Experiences of trauma may increase risk for physical health consequences, such as somatic symptoms, chronic conditions, and even infections, due in part to post-traumatic psychological sequelae. However, various internal and external factors cause many individuals to show psychological resilience to trauma, or positive psychological adaptation despite exposure. Thus, showing psychological resilience to prior trauma may be associated with better physical health outcomes, particularly in the face of subsequent stressors such as the COVID-19 pandemic. Methods Among 528 US adults in a longitudinal cohort, we examined psychological resilience to trauma early in the pandemic and levels of somatic symptoms and COVID-19 risk over two years of follow-up. Resilience was defined as one's relative level of psychological health (i.e., low distress and positive functioning) to lifetime trauma burden (i.e., count of traumatic events) in August 2020. Outcomes included somatic symptoms, COVID-19 infection, COVID-19 symptom severity, and long COVID risk assessed every six months. Covariate-adjusted regressions examined associations between resilience and outcomes. Results Higher resilience was associated with lower levels of somatic symptoms across follow-up, adjusting for sociodemographics, COVID-19 infection, and long COVID. One standard deviation higher resilience was associated with 31% lower likelihood of COVID-19 infection across time (Relative Risk=0.69, 95%CI 0.49-0.99), adjusting for sociodemographics and COVID-19 vaccination. In contrast, resilience was not associated with COVID-19 symptom severity or long COVID risk. Conclusions Psychological resilience to trauma may protect against somatic symptom experience and COVID-19 infection risk. Supporting recovery from trauma, both reducing distress and bolstering positive capacities, may benefit later mental and physical health. publisher: Elsevier
120	P118		Simonetti, Alessio; Bernardi, Evelina; Margoni, Stella; Catinari, Antonello; Restaino, Antonio; Ieritano, Valentina; Palazzetti, Marta; Mastrantonio, Federico; Janiri, Delfina; Tosato, Matteo; Landi, Francesco; Sani, Gabriele	Mixed Depression in the Post-COVID-19 Syndrome: Correlation between Excitatory Symptoms in Depression and Physical Burden after COVID-19	https://doi.org/10.3390/brainsci13040688	Published	2023-04-01	Study	https://www.mdpi.com/2076-3425/13/4/688	The relationship between depression and post-COVID-19 disease syndrome (post-COVID-19 syndrome) is established. Nevertheless, few studies have investigated the association between post-COVID-19 syndrome and mixed depression, i.e., a specific sub-form of depression characterized by high level of excitatory symptoms. Aims of the present study are: (a) to compare the post-COVID-19 syndrome’s burden in depressed and non-depressed patients, and (b) to investigate the correlation between post-COVID-19 syndrome’s burden and the severity of mixed depression. One thousand and forty six (n = 1460) subjects with post-COVID-19 syndrome were assessed. Subjects were divided into those with (DEP) or without (CONT) depression. Sociodemographically, post-COVID-19 syndrome’s symptoms number and type were compared. In DEP, association between levels of excitatory symptoms and the presence of post-COVID-19 syndrome’s symptoms were additionally assessed. DEP showed greater percentages of family history of psychiatric disorders than CONT. DEP showed higher percentages of post-COVID-19 symptoms than CONT. A greater level of excitatory symptoms were associated to higher frequencies of post-COVID-19 syndrome’ symptoms. Higher levels of post-COVID-19 syndrome’s symptoms in DEP corroborate the evidence of a common pathway between these two syndromes. Presence of excitatory symptoms seem to additionally add a greater illness burden. Such findings might help clinicians choose the appropriate treatment for such states. More specifically, therapies aimed to treat excitatory symptoms, such as antipsychotics and mood stabilizers, might help reduce the illness burden in post-COVID-19 patients with mixed depression.
121	P119		Schultebraucks, Katharina; Blekic, Wivine; Basaraba, Cale; Corbeil, Tom; Khan, Zain; Henry, Brandy F.; Krawczyk, Noa; Rivera, Bianca D.; Allen, Bennett; Arout, Caroline; Pincus, Harold Alan; Martinez, Diana M.; Levin, Frances R.	The impact of preexisting psychiatric disorders and antidepressant use on COVID-19 related outcomes: a multicenter study	https://doi.org/10.1038/s41380-023-02049-4	Published	2023-04-17	Study	https://www.nature.com/articles/s41380-023-02049-4	Pre-existing mental disorders are linked to COVID-19-related outcomes. However, the findings are inconsistent and a thorough analysis of a broader spectrum of outcomes such as COVID-19 infection severity, morbidity, and mortality is required. We investigated whether the presence of psychiatric diagnoses and/or the use of antidepressants influenced the severity of the outcome of COVID-19. This retrospective cohort study evaluated electronic health records from the INSIGHT Clinical Research Network in 116,498 individuals who were diagnosed with COVID-19 between March 1, 2020, and February 23, 2021. We examined hospitalization, intubation/mechanical ventilation, acute kidney failure, severe sepsis, and death as COVID-19-related outcomes. After using propensity score matching to control for demographics and medical comorbidities, we used contingency tables to assess whether patients with (1) a history of psychiatric disorders were at higher risk of more severe COVID-19-related outcomes and (2) if use of antidepressants decreased the risk of more severe COVID-19 infection. Pre-existing psychiatric disorders were associated with an increased risk for hospitalization, and subsequent outcomes such as acute kidney failure and severe sepsis, including an increased risk of death in patients with schizophrenia spectrum disorders or bipolar disorders. The use of antidepressants was associated with significantly reduced risk of sepsis (p = 0.033), death (p = 0.026). Psychiatric disorder diagnosis prior to a COVID-19-related healthcare encounter increased the risk of more severe COVID-19-related outcomes as well as subsequent health complications. However, there are indications that the use of antidepressants might decrease this risk. This may have significant implications for the treatment and prognosis of patients with COVID-19.
122	P120		Rouquette, Alexandra; Descarpentry, Arthur; Dione, Fallou; Falissard, Bruno; Legleye, Stéphane; Vuillermoz, Cécile; Pastorello, Anne; Meyer, Laurence; Warszawski, Josiane; Davisse-Paturet, Camille; Melchior, Maria; EpiCoV Study Group	Comparison of Depression and Anxiety Following Self-reported COVID-19–Like Symptoms vs SARS-CoV-2 Seropositivity in France	https://doi.org/10.1001/jamanetworkopen.2023.12892	Published	2023-05-11	Study	https://doi.org/10.1001/jamanetworkopen.2023.12892	Key Points Question Is SARS-CoV-2 infection associated with subsequent long-term depression or anxiety? Findings In this propensity score–matched, population-based cohort study of 45 260 participants, COVID-19–like symptoms, but not SARS-CoV-2 infection, during the first months of the pandemic were associated with an increased occurrence of subsequent depression and anxiety 8 months or more after the occurrence of COVID-19–like symptoms, even when SARS-CoV-2 serologic test results were negative. Meaning These findings suggest that SARS-CoV-2 infection is not a risk factor for long-term mental health issues; however, further research is needed to identify factors other than SARS-CoV-2 infection implied in the association between COVID-19–like symptoms and poor mental health outcomes. Abstract Importance The long-term consequences of COVID-19 on mental health are a critical issue given the number of people infected with SARS-CoV-2 worldwide since the beginning of the pandemic. Objective To investigate the associations between self-reported COVID-19–like symptoms or SARS-CoV-2 seropositivity and subsequent depression or anxiety. Design, Setting, and Participants This propensity score–matched cohort study began in May 2020, with follow-ups in November 2020 and July 2021. The study used data from a large, randomly selected, national population–based cohort from France, the EpiCoV (Epidémiologie et Conditions de Vie) study. Of 85 074 individuals 15 years or older who completed the questionnaires at the 3 collection times, 28 568 were excluded because they did not return a blood sample for serologic testing, 1994 because of missing data on outcomes or exposures, and 9252 to respect the temporal sequence (exposure must precede the outcome). Exposures Propensity scores based on various socioeconomic, lifestyle, and health variables were computed to match participants who experienced COVID-19–like symptoms between February and November 2020 or showed SARS-CoV-2 seropositivity in November 2020. Main Outcomes and Measures Logistic regression models were used to estimate associations between these occurrences and depression or anxiety assessed in July 2021 using the Patient Health Questionnaire 9-item and Generalized Anxiety Disorder 7-item scales, respectively. Results Among the 45 260 included participants (mean [SD] age, 51.1 [18.9] years; 52.4% women; 8.0% with depression and 5.3% with anxiety in July 2021), COVID-19–like symptoms were associated with subsequent depression (adjusted odds ratio, 1.70; 95% CI, 1.45-1.99) and anxiety (adjusted OR, 1.57; 95% CI, 1.29-1.92), whereas SARS-CoV-2 seropositivity was not. Furthermore, COVID-19–like symptoms, but not anosmia or dysgeusia alone, were associated with subsequent depression and anxiety in both the seropositive and seronegative subgroups. Conclusions and Relevance In this cohort study of more than 45 000 individuals drawn from the French general population, SARS-CoV-2 infection was not found as a risk factor of subsequent depression or anxiety. Moreover, self-reported COVID-19–like symptoms were associated with depression and anxiety assessed at least 8 months later in both seropositive and seronegative subgroups, suggesting that factors other than SARS-CoV-2 infection are implied in this association.
123	P121		Re’em, Yochai; Stelson, Elisabeth A.; Davis, Hannah E.; McCorkell, Lisa; Wei, Hannah; Assaf, Gina; Akrami, Athena	Factors associated with psychiatric outcomes and coping in Long COVID	https://doi.org/10.1038/s44220-023-00064-6	Published	2023-05-01	Study	https://www.nature.com/articles/s44220-023-00064-6	The relationship between Long COVID (LC) and psychiatric outcomes, as well as factors associated with presence and absence of these, has so far been insufficiently studied. Here we evaluated psychiatric symptoms and coping among patients with LC and patients recovered from COVID-19 who participated in a large international survey. Given increased rates of psychiatric illness with chronic medical conditions and known immune-inflammatory contributors to psychiatric disease, we hypothesized that a subset, but not the entirety, of LC respondents may have comorbid psychopathology. A substantial minority of both groups experienced suicidality, depression and anxiety symptoms, with these symptoms being more common in the LC group. LC respondents used more adaptive coping styles. Psychiatric outcomes in LC were associated with younger age, greater reductions in overall health, higher symptom severity, limitations to physical capability, lower income, financial hardship, psychiatric history, employment impact, male sex, men and non-binary gender, and negative experiences with medical professionals, family, friends, partners and employers.
124	P122		Liu, Teresa C.; Yoo, Sun M.; Sim, Myung S.; Motwani, Yash; Viswanathan, Nisha; Wenger, Neil S.	Perceived Cognitive Deficits in Patients With Symptomatic SARS-CoV-2 and Their Association With Post–COVID-19 Condition:	https://doi.org/10.1001/jamanetworkopen.2023.11974	Published	2023-05-05	Study	https://doi.org/10.1001/jamanetworkopen.2023.11974	Neuropsychiatric symptoms are common in acute SARS-CoV-2 infection and in post–COVID-19 condition (PCC; colloquially known as long COVID), but the association between early presenting neuropsychiatric symptoms and PCC is unknown.To describe the characteristics of patients with perceived cognitive deficits within the first 4 weeks of SARS-CoV-2 infection and the association of those deficits with PCC symptoms.This prospective cohort study was conducted from April 2020 to February 2021, with follow-up of 60 to 90 days. The cohort consisted of adults enrolled in the University of California, Los Angeles, SARS-CoV-2 Ambulatory Program who had a laboratory-confirmed symptomatic SARS-CoV-2 infection and were either hospitalized in a University of California, Los Angeles, hospital or one of 20 local health care facilities, or were outpatients referred by a primary care clinician. Data analysis was performed from March 2022 to February 2023.Laboratory-confirmed SARS-CoV-2 infection.Patients responded to surveys that included questions about perceived cognitive deficits modified from the Perceived Deficits Questionnaire, Fifth Edition, (ie, trouble being organized, trouble concentrating, and forgetfulness) and symptoms of PCC at 30, 60, and 90 days after hospital discharge or initial laboratory-confirmed infection of SARS-CoV-2. Perceived cognitive deficits were scored on a scale from 0 to 4. Development of PCC was determined by patient self-report of persistent symptoms 60 or 90 days after initial SARS-CoV-2 infection or hospital discharge.Of 1296 patients enrolled in the program, 766 (59.1%) (mean [SD] age, 60.0 [16.7] years; 399 men [52.1%]; 317 Hispanic/Latinx patients [41.4%]) completed the perceived cognitive deficit items at 30 days after hospital discharge or outpatient diagnosis. Of the 766 patients, 276 (36.1%) perceived a cognitive deficit, with 164 (21.4%) having a mean score of greater than 0 to 1.5 and 112 patients (14.6 %) having a mean score greater than 1.5. Prior cognitive difficulties (odds ratio [OR], 1.46; 95% CI, 1.16-1.83) and diagnosis of depressive disorder (OR, 1.51; 95% CI, 1.23-1.86) were associated with report of a perceived cognitive deficit. Patients reporting perceived cognitive deficits in the first 4 weeks of SARS-CoV-2 infection were more likely to report symptoms of PCC than those without perceived cognitive deficits (118 of 276 patients [42.8%] vs 105 of 490 patients [21.4%]; χ21, 38.9; P < .001). Adjusting for demographic and clinical factors, perceived cognitive deficits in the first 4 weeks of SARS-CoV-2 were associated with PCC symptoms (patients with a cognitive deficit score of >0 to 1.5: OR, 2.42; 95% CI, 1.62-3.60; patients with cognitive deficit score >1.5: OR, 2.97; 95% CI, 1.86-4.75) compared to patients who reported no perceived cognitive deficits.These findings suggest that patient-reported perceived cognitive deficits in the first 4 weeks of SARS-CoV-2 infection are associated with PCC symptoms and that there may be an affective component to PCC in some patients. The underlying reasons for PCC merit additional exploration.
125	P123		Loftis, Jennifer M.; Firsick, Evan; Shirley, Kate; Adkins, James L.; Le-Cook, Anh; Sano, Emily; Hudson, Rebekah; Moorman, Jonathan	Inflammatory and mental health sequelae of COVID-19	https://doi.org/10.1016/j.cpnec.2023.100186	Published	2023-08-01	Study	https://www.sciencedirect.com/science/article/pii/S2666497623000206	Highlights •Severity of anxiety symptoms reduced over time in adults who tested negative for COVID-19. •In adults negative for COVID-19, less anxiety was accompanied by decreases in inflammatory factors. •Adults with neuro-PASC had depression scores in the moderate-severe range. •Adults with more severe COVID-19 reported significantly greater depression. •Adults with more severe COVID-19 had higher plasma levels of monokine induced by interferon gamma. Abstract The COVID-19 pandemic has caused significant negative consequences to mental health. Increased inflammatory factors and neuropsychiatric symptoms, such as cognitive impairment (“brain fog”), depression, and anxiety are associated with long COVID [post-acute sequelae of SARS-CoV-2 infection (PASC), termed neuro-PASC]. The present study sought to examine the role of inflammatory factors as predictors of neuropsychiatric symptom severity in the context of COVID-19. Adults (n = 52) who tested negative or positive for COVID-19 were asked to complete self-report questionnaires and to provide blood samples for multiplex immunoassays. Participants who tested negative for COVID-19 were assessed at baseline and at a follow-up study visit (∼4 weeks later). Individuals without COVID-19 reported significantly lower PHQ-4 scores at the follow-up visit, as compared to baseline (p = 0.03; 95% CI-1.67 to −0.084). Individuals who tested positive for COVID-19 and experienced neuro-PASC had PHQ-4 scores in the moderate range. The majority of people with neuro-PASC reported experiencing brain fog (70% vs. 30%). Those with more severe COVID-19 had significantly higher PHQ-4 scores, as compared to those with mild disease (p = 0.008; 95% CI 1.32 to 7.97). Changes in neuropsychiatric symptom severity were accompanied by alterations in immune factors, particularly monokine induced by gamma interferon (IFN-γ) (MIG, a. k.a. CXCL9). These findings add to the growing evidence supporting the usefulness of circulating MIG levels as a biomarker reflecting IFN-γ production, which is important because individuals with neuro-PASC have elevated IFN-γ responses to internal SARS-CoV-2 proteins.
126	P124		Ranieri, Jessica; Capuani, Anika; Di Giacomo, Dina; Guerra, Federica; Cilli, Eleonora; Martelli, Alessandra	Psychological Distress and Negative Emotions in Post-COVID Infection: A Comparative Study of the COVID and NO-COVID Young Patients	https://doi.org/10.1177/00332941231177244	Published	2023-05-25	Study	https://doi.org/10.1177/00332941231177244	According to the literature, mental health assumed urgent relevance, and several scholars are debating on the enduring of the neurological and psychiatric symptoms in post COVID patients. Our study aimed to investigate the emotional dimensions in young population to the COVID exposition: primary endpoint was to detect the psychological distress up to 3 months in post-COVID-19. A comparative study was conducted among young adults in Italy. We also assessed dysphoria, depression, anxiety, stress symptoms, pessimism, and positive personality traits. The participants were 140 Italian young aged 18–30 years (mean = 22.1, SD ± 2.65; 65.0% female). The sample was distinguished in two groups: COVID and NO-COVID groups. The results revealed that young who have been exposed to COVID-19 infection evidenced emotional vulnerability by higher psychological distress (depression, anxiety, stress), dysphoria signs (irritability, discontent, interpersonal resentment, and feelings of renunciation/surrender) then No COVID-19 infection young. Furthermore, COVID patients showed higher negative emotions about the expected life, uncertain for future, and loss of motivation (characterized no desires) than NO-COVID infection. In conclusion, the vulnerability of young exposed to COVID infection even in mild severity should be considered as emerging unmet need of mental health recovering: urgent health policy actions to boost the psychological, biological and social strategic pillar for young generation.

	A	B	C	D	E	F	G	H	I	J	K	M
1	Ref	PPLC	Authors	Title	DOI	Peer reviewed	Date	type	Link	Keys	Clés

2	R01		Molly Fisher, Joel Neugarten, Eran Bellin, Milagros Yunes, Lindsay Stahl, Tanya S. Johns	AKI in Hospitalized Patients with and without COVID-19: A Comparison Study	https://doi.org/10.1681/ASN.2020040509	Published	September 1, 2020	Clinical Research	https://jasn.asnjournals.org/content/31/9/2145.abstract	The frequency of acute renal failure during or after severe covid suggests a high prevalence of post-covid kidney disease, according to an American study.	La fréquence des insuffisances rénales aiguës pendant ou après un covid sévère laisse craindre une forte prévalence de malades des reins post-covid, selon une étude américaine.
3	R02		Girish N. Nadkarni	Considering COVID-19 kidney injury	https://doi.org/10.1126/scitranslmed.abd4935		August 19, 2020	EDITORS' CHOICE	https://stm.sciencemag.org/content/12/557/eabd4935		Does SARS-CoV-2 infection have long-term effects on the kidney?
4	R03		Erpicum P, Grosch S, Bouquegneau A, Huart J, Résimont G, Bovy C, Habran L	Atteintes rénales de la COVID-19	https://doi.org/10.1016%2Fj.nephro.2021.06.002	Published	29 novembre 2020	Article Revue médicale Liège	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221000/		Dans la revue médicale de Liège, un article sur les atteintes rénales attribuées à la covid : nécrose tubulaire aiguë de sévérité variable, et congestion des capillaires glomérulaires et péri-tubulaires. Plus rarement, une endothélite.
5	R04		S. Boeger, J. Petrovic, E. Busink, C. Apel, F. Kircelli, R. Pohlmeier	PUK14 ACUTE Renal Failure during COVID-19 and Its LONG-TERM IMPACT on Health System	https://doi.org/10.1016/j.jval.2020.08.2057	Published	December 01, 2020		https://www.valueinhealthjournal.com/article/S1098-3015(20)34313-8/fulltext		Une méta-analyse montre que sur 12000 malades critiques de la covid en Europe, 3126 ont nécessité un support de la fonction rénale. 62% d'entre eux en sont morts, et parmi les survivants 19% devront vivre sous dialyse.
6	R05		Shrikant B Deshmukh, Kavita M Upadhyay, Advait Kulkarni, Sudhir Deshpande, Rajshri Purohit, Milind Kulkarni	Renal Artery Thrombosis: A Post COVID-19 Sequel	https://doi.org/10.24321/2349.7181.202009	Published	2020-12-05	Case Report	https://medical.advancedresearchpublications.com/index.php/MedicineJournal/article/view/458		Un cas rapporté de thrombose de l'artère rénale décrit comme lié à une infection à la covid, dans une étude qui rappelle le risque de thromboses vasculaires aussi bien chez les patients symptomatiques qu'asymptomatiques.
7	R06		Paul M. Palevsky	COVID-19 and AKI: Where Do We Stand?	https://doi.org/10.1681/ASN.2020121768	Published	February 2021	Review	https://jasn.asnjournals.org/content/early/2021/02/25/ASN.2020121768	Finally, it is still too early to understand the effect of the large number of patients with COVID-19–associated AKI on the future epidemiology of kidney disease. It is easy to speculate that unresolved and incompletely resolved AKI will increase the burden of CKD and ESKD and that superimposition of AKI on CKD will accelerate progression to kidney failure.	Un article dresse un état des lieux de la littérature sur les insuffisances rénales aiguës liées à la covid.	N004R
8	R07		Yi-FuFenga1Kun-PengWanga1Jing-GangMoaYing-HeXubLie-ZhiWangaChongJinaXiangChencBinYi	The spatiotemporal trend of renal involvement in COVID-19: a pooled analysis of 17,134 patients	https://doi.org/10.1016/j.ijid.2021.03.082	Published	3 April 2021	Study	https://www.sciencedirect.com/science/article/pii/S1201971221003003	Highlights •Renal involvement in COVID-19 becomes an increasingly serious problem over time. •Spatial differences are significant in renal involvement superimposed COVID-19. •Renal involvement may increase the risk of severity and mortality of COVID-19 patients.	_
9	R08		Pierre Delanaye Justine Huart Antoine Bouquegneau François Jouret	Long-term effects of COVID-19 on kidney function	https://doi.org/10.1016/S0140-6736(21)00881-3	Published	May 15, 2021	Correspondance	https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00881-3/fulltext	Chaolin Huang and colleagues1 have highlighted the putative renal consequences of COVID-19 at 6 months from discharge. A decreased estimated glomerular filtration rate (eGFR) was defined as less than 90 mL/min per 1·73 m2 and was observed in 35% of participants during follow-up. The pathological relevance of an eGFR between 60 and 90 mL/min per 1·73 m2 is questionable in the absence of proteinuria.2 Proteinuria has been frequently described in patients with COVID-19. Our follow-up observations suggest a spontaneous remission within a few weeks after discharge.5 The available data of Huang and colleagues do not support their alarming conclusions about the poor renal prognosis at 6 months after COVID-19.	_
10	R09		Lixue Huang Xiaoying Gu Yeming Wang Chaolin Huang Bin Cao	Long-term effects of COVID-19 on kidney function – Authors' reply	https://doi.org/10.1016/S0140-6736(21)00875-8	Published	May 15, 2021	Correspondance	https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00875-8/fulltext	We agree that the criteria of an eGFR less than 90 mL/min per 1·73 m2 cannot define chronic kidney disease, especially for those with an eGFR between 60 and 90 mL/min per 1·73 m2 in the absence of proteinuria; although, we do not want to ignore patients with preclinical manifestation of kidney damage as proteinuria was not measured then. We hope these important questions can be further answered in future studies.	_
11	R10		Rhian MTouyzMBBCh, PhDMarcus OEBoydTomaszGuzikMD, PhDSandoshPadmanabhanMD, PhDLinsayMcCallumMBChBChristianDellesMDPatrick BMarkMBChB, PhDJohn RPetrieMBChB, PhDFranciscoRiosPhDAugusto CMontezanoPhDRobertSykesMBChB, BMedSciColinBerryMBChB, PhD	Cardiovascular and renal risk factors and complications associated with COVID-19	https://doi.org/10.1016/j.cjco.2021.05.020	Published	16 June 2021	Review	https://www.sciencedirect.com/science/article/pii/S2589790X21001554	Here we discuss cardiovascular and kidney disease in the context of COVID-19 and provide recent advances on putative pathophysiological mechanisms linking cardiovascular disease and COVID-19, focusing on the RAS and ACE2 as well as the immune system and inflammation. We provide up-to-date information on the relationship between hypertension, diabetes, and COVID-19 and emphasize the major cardiovascular diseases associated with COVID-19. We also briefly discuss emerging cardiovascular complications associated with long COVID-19, notably postural tachycardia syndrome (POTS).	_
12	R11		Stéphane Burtey a b Marion Sallée a b	Les atteintes rénales de la COVID-19 - Kidney damage in COVID-19	https://doi.org/10.1016/j.nephro.2021.06.002	Published	23 June 2021	Article	https://www.sciencedirect.com/science/article/pii/S1769725521001383	Il existe une atteinte rénale qui se caractérise par trois atteintes principales, une nécrose tubulaire aiguë survenant dans les cas les plus sévères, une tubulopathie proximale, qui est un marqueur pronostique de la maladie, et une hyalinose segmentaire et focale survenant sur un terrain génétiquement prédisposé. La physiopathologie de l’atteinte rénale du SARS-CoV-2 n’est pas encore définie. Le rôle direct du virus est discuté alors que la tempête cytokinique et les complications hypoxiques et thrombotiques semblent plus importantes. Le devenir à long terme des atteintes rénales paraît plutôt bon. Un suivi à long terme permettra de dire si l’atteinte rénale fait partie du COVID long.
13	R12		Gabriel Cavalcante Lima ChagasAmanda Ribeiro RangelLuisa Macambira NoronhaGeraldo Bezerra da Silva Jr.Gdayllon Cavalcante MenesesAlice Maria Costa MartinsElizabeth De Francesco Daher	COVID-19 and Kidney: a narrative review	https://doi.org/10.1590/1806-9304202100S200003	Published	May 2021	Review	https://www.scielo.br/j/rbsmi/a/twcS7TwJggTThZXKYzjdWnH/?lang=en	In this study, we aimed to present a narrative review on kidney involvement in COVID-19. Kidney involvement could be derived from direct cytopathic effects, immunological mechanisms, indirect effects on renal tissue through other mediators, and dysfunction or injury of other organs.
14	R13		Matthieu Legrand, Samira Bell, Lui Forni, Michael Joannidis, Jay L. Koyner, Kathleen Liu & Vincenzo Cantaluppi	Pathophysiology of COVID-19-associated acute kidney injury	https://doi.org/10.1038/s41581-021-00452-0	Published	05 July 2021	Article	https://www.nature.com/articles/s41581-021-00452-0	Key points Over a quarter of patients hospitalized with coronavirus disease 2019 (COVID-19) have been reported to develop acute kidney injury (AKI). Low molecular weight proteinuria, Fanconi syndrome and histological findings point towards tubular injury. Analyses of kidney biopsy samples from patients with COVID-19 and AKI have inconsistently reported viral infection of kidney cells. Collapsing glomerulopathy has been identified in patients with high-risk APOL1 genotypes, mostly in those without severe respiratory symptoms. Regional inflammation, endothelial injury and renal microthrombi have been reported but their implication in the pathogenesis of COVID-associated AKI remains uncertain. Anti-inflammatory drugs (for example, steroids and IL-6 receptor blockers) seem to limit the development of severe AKI in patients with COVID-19.
15	R14		Burtey S1, Sallée M	Kidney damage in COVID-19	https://doi.org/10.1016/j.nephro.2021.06.002	Published	23 Jun 2021	Review	https://europepmc.org/article/med/34266783	There is renal involvement which is characterised by three main types of damage, acute tubular necrosis occurring in the most severe cases, proximal tubulopathy which is a prognostic marker of the disease and segmental and focal hyalinosis occurring in a genetically predisposed terrain. The pathophysiology of SARS-CoV-2 renal involvement is not yet defined. The direct role of the virus is debated, whereas the cytokine storm and the hypoxic and thrombotic complications seem more important. The long-term outcome of the renal damage appears to be quite good. Long-term follow-up will allow us to say whether the renal damage is part of the long COVID.	_
16	R15		Ian A.Strohbehn1SophiaZhao1HarishSeethapathy1MeghanLee1NifashaRusibamayila1Andrew S.Allegretti1Xavier VelaParada1Meghan E.Sise	Acute kidney injury incidence, recovery, and long-term kidney outcomes among hospitalized patients with COVID-19 and influenza	https://doi.org/10.1016/j.ekir.2021.07.008	Published	15 July 2021	Study	https://www.sciencedirect.com/science/article/pii/S2468024921013024	A total of 2425 patients were included; 1091 (45%) had COVID-19 and 1334 (55%) had influenza. Overall AKI rate was 23% and 13% in patients with COVID-19 and influenza, respectively. Compared to influenza, hospitalized patients with COVID-19 had an increased risk of developing AKI (adjusted hazard ratio, aHR 1.58, 95% CI 1.29–1.94). Patients with AKI were more likely to die during hospital when infected with COVID-19 vs. influenza (aHR 3.55, 95% CI 2.11–5.97). Among patients surviving to hospital discharge, the rate of AKI recovery was lower in patients with COVID-19 (aHR 0.47, 95% CI 0.36–0.62); however, among patients followed for ≥ 90 days, new-onset CKD (aHR 1.24, 95% CI 0.86–1.78) and ≥ 25% eGFR decline at last follow-up (aHR 1.36, 95% CI 0.97–1.90) were not significantly different between the cohorts. Conclusion AKI and mortality rates are significantly higher in COVID-19 than influenza; however, kidney recovery among long-term survivors appears to be similar.	La covid provoque 60% de plus d'insuffisances rénales aiguës que la grippe, avec un taux de rémission deux fois inférieur, selon une étude américaine. Au delà de la rémission, les suivis post-accident rénaux entre covid et grippe sont comparables.	N014E
17							From this point on, the survey of studies is no longer as exhaustive as possible. Only those studies which seem to us to bring significant new elements will be listed.
18	R16		Benjamin Bowe, Yan Xie, Evan Xu and Ziyad Al-Aly	Kidney Outcomes in Long COVID	https://doi.org/10.1681/ASN.2021060734	Published	September 1, 2021	Study	https://jasn.asnjournals.org/content/early/2021/08/25/ASN.2021060734	Methods: We built a cohort of 1,726,683 US Veterans identified from March 01, 2020 to March 15, 2021 including 89,216 30-day COVID-19 survivors and 1,637,467 non-infected controls. We examined risks of AKI, eGFR decline, ESKD, and major adverse kidney events (MAKE) defined as eGFR decline ≥50%, ESKD, or all-cause mortality using inverse probability weighted survival regressions, adjusting for predefined demographic and health characteristics, and algorithmically selected high-dimensional covariates including diagnoses, medications, and laboratory tests. Linear mixed models characterized intra-individual eGFR trajectory. Results: Beyond the acute illness, 30-day survivors of COVID-19 exhibited a higher risk of AKI (aHR=1.94 (95%CI: 1.86,2.04)), eGFR decline ≥30% (1.25 (1.14,1.37)), eGFR decline ≥40% (1.44 (1.37,1.51)), eGFR decline ≥50% (1.62 (1.51,1.74)), ESKD (2.96 (2.49-3.51)), and MAKE (1.66 (1.58,1.74)). There was a graded increase in risks of post-acute kidney outcomes according to the severity of the acute infection (whether patients were non-hospitalized, hospitalized, or admitted to intensive care). Compared to non-infected controls, 30-day COVID-19 survivors exhibited excess eGFR decline of -3.26 (-3.58, -2.94), -5.20 (-6.24, -4.16), and -7.69 (-8.27, -7.12) mL/min/1.73m2/year in non-hospitalized, hospitalized, and those admitted to intensive care during the acute phase of COVID-19 infection.
19	R17		S Svetitsky,1,2 R Shuaib,2 S McAdoo,1,2 and D C Thomas1,	Long-term effects of Covid-19 on the kidney	https://dx.doi.org/10.1093%2Fqjmed%2Fhcab061	Published	2021 Sep 17	FReview	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500011/	Acute kidney injury (AKI) is a common complication of Covid-19 and one associated with increased mortality, especially when requiring renal replacement therapy.1,2 AKI affects over 20% of hospitalized patients and over 50% of patients in the ICU.3 Varying rates of recovery of renal function on discharge are described. Unsurprisingly, pre-existing CKD is a risk factor for dialysis dependence on discharge.4 Previous studies have found that AKI, regardless of cause, results in pre-disposition to progressive CKD and the risk increases with the severity of AKI;5 this will likely be the case with Covid-19 infection as well. Understanding the long-term impact of Covid-19 on the kidney is vital for planning and resource allocation for nephrology services.
20	R18		Joshua D.Long1IanStrohbehn1RaniSawtell1RobyBhattacharyya2Meghan E.Sise1	COVID-19 Survival and its Impact on Chronic Kidney Disease	https://doi.org/10.1016/j.trsl.2021.11.003	Published	10 November 2021	Review	https://www.sciencedirect.com/science/article/pii/S1931524421002668	In this review, we highlight the current understanding of the pathophysiology of COVID-19-associated kidney injury and the impact COVID-19 may have on long-term kidney function. COVID-19-induced acute kidney injury may lead to tubular injury, endothelial injury, and glomerular injury. We highlight histopathologic correlates from large kidney biopsy and autopsy series. By conducting a comprehensive review of published literature to date, we summarize the rates of recovery from COVID-19-associated-AKI. Finally, we discuss how certain genetic differences, including APOL1 risk alleles (a risk factor for collapsing glomerulopathy), coupled with systemic healthcare disparities, may lead to a disproportionate burden of post-COVID-19-kidney function decline among racial and ethnic minority groups. We highlight the need for prospective studies to determine the true incidence of chronic kidney disease burden after COVID-19.	_
21	R19		Wissam H. Faour, Ali Choaib, Elio Issa, Francesca El Choueiry, Khodor Shbaklo, Maryline Alhajj, Ramy Touma Sawaya, Zeina Harhous, Eman Alefishat & Moni Nader	Mechanisms of COVID-19-induced kidney injury and current pharmacotherapies	https://doi.org/10.1007/s00011-021-01520-8	Published	21 November 2021	Review	https://link.springer.com/article/10.1007/s00011-021-01520-8	While significant evidence is currently available online and targets various aspects of the disease, both inflammatory and noninflammatory kidney manifestations secondary to COVID-19 infection are still largely underrepresented. In this review, we summarized current knowledge about COVID-19-related kidney manifestations, their pathologic mechanisms as well as various pharmacotherapies used to treat patients with COVID-19. We also shed light on the effect of these medications on kidney functions that can further enhance renal damage secondary to the illness.	_
22	R20		Togay Evrin, Burak Katipoglu	COVID-19 are dangerous to the kidneys in any situation, not only in a pandemic: LONG-COVID-19 and kidney disease	https://doi.org/10.5603/CJ.a2021.0163	pre-print	2021-12-07	Article	https://journals.viamedica.pl/cardiology_journal/article/view/CJ.a2021.0163	Clinicians who must pay close attention to kidney function evaluation will play a critical role, not only in the group of hospitalized patients, but also in the group of seemingly asymptomatic patients, and notably in the group of patients with LONG-COVID-19. Vaccinations also play an important role in reducing the risk of serious illness, hospitalization, and complications such as LONG-COVID-19.	_
23	R21		Jochen Reiser Ryan Spear Shengyuan Luo	SARS-CoV-2 pirates the kidneys: A scar(y) story	https://doi.org/10.1016/j.cmet.2022.02.005	Published	March 01, 2022	Article	https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00049-3	As the coronavirus disease 2019 (COVID-19) global pandemic continues for a third year, more has been unveiled about its culprit, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Aside from triggering a possibly dire innate immune response, it also causes severe respiratory illness and a myriad of acute and chronic multi-organ damage, with the kidneys being one of the most frequently targeted organs outside the lungs. Accumulating evidence suggests the presence of SARS-CoV-2 in some but not all kidneys from COVID-19 cases, yet at higher concentrations compared to other organs (Puelles et al., 2020). Renal manifestations of COVID-19 can range from acute kidney injury (AKI), hematuria, proteinuria, podocytopathy, and tubulointerstitial fibrosis (Diao et al., 2021). Importantly, a substantial number of individuals with COVID-19 experience post-acute sequelae, a syndrome now referred to as “long COVID,” many of whom suffered worse outcomes of AKI such as rapid kidney function decline and chronic kidney disease (CKD) (Bowe et al., 2021). One key to understanding these phenomena is to determine if the virus infects kidney cells directly and, if so, if this leads to short- and/or long-term renal damage. In the latest issue of Cell Stem Cell, Jansen et al. comprehensively investigated whether direct infection of the kidneys by SARS-CoV-2 introduces a pro-fibrotic phenotype (Jansen et al., 2022). The authors compared kidneys of individuals with COVID-19 compared to matched controls. With data derived from 61 human autopsies and single-RNA nucleus sequencing, the study associated increased interstitial fibrosis with the presence of higher activity in proinflammatory and fibrosis-driving pathways (notably, tumor necrosis factor alpha [TNFα], transforming growth factor beta, nuclear factor kB, and JAK-STAT). Taking this to the next level, the study utilized human induced pluripotent stem cell (hiPSC)-derived kidney organoids to fine map cellular locations of SARS-CoV-2 infection and accompanying signaling changes. In addition to verifying upregulated activity of pro-fibrotic pathways found in SARS-CoV-2-infected autopsied kidneys, the team identified evidence of a molecular crosstalk between proximal tubular cells and PDGFRa/b+ mesenchymal cells (a key source of myofibroblasts) that further contributed to fibrosis. The findings by Jansen and colleagues are exciting and supported by both human tissues and hiPSC-derived organoids. They can serve as strong evidence to support the notion that SARS-CoV-2 can directly drive renal fibrosis, a CKD hallmark, suggesting a likely impact on the worse AKI outcomes during COVID-19 that are often observed. These findings also bridged a knowledge gap, linking acute viral illness to kidney disease during long-COVID. hiPSC-derived organoids have the advantage of being able to assess intercellular interactions, which possibly explains the greater extent of cytopathic changes seen in organoids compared to other studies using SARS-CoV-2-infected ex vivo models comprised solely of tubular epithelial cells and that lacked cytopathic changes (Omer et al., 2021). Jansen et al. provided the first hints that SARS-CoV-2 infection in kidney organoids is amenable to a treatment with a protease inhibitor, providing a glimpse into potential future treatments for COVID-19-related kidney injury. The findings also stimulate further clinical and translational investigations for testing SARS-CoV-2 tropism in the kidneys of infected individuals to identify potential virus-free kidneys for transplantation procured from individuals who died of fulminant COVID-19 (Lee et al., 2022). The use of hiPSC-kidney organoids is not without caveats, however. As the authors pointed out, the protocols to differentiate hiPSCs to model the adult kidney in its entirety are still suboptimal. While excluding extra-renal factors, such as intensive care treatment, the model also isolates kidney cells from the involvement of immune cells. For example, the recruitment of CD68+ macrophages, CD56+ natural killer cells, and CD8+ T cells, alongside strong C5b-9 deposition, was found with tubular necrosis in the kidneys of patients with COVID-19 (Diao et al., 2021). Jansen et al. also observed an interaction between podocytes and the mesenchymal endothelial progenitor population. The cytologic consequences were beyond the study’s scope and therefore not described, but one must recognize podocytopathy, glomerular collapsing, and sclerosis as indispensable parts of the COVID-19-related kidney disease spectrum, in which innate immunity likely plays an essential role. The massive release of immune mediators such as soluble urokinase plasminogen activator receptor (suPAR), TNFα, and interferon gamma, i.e., a cytokine storm, signifies severe COVID-19 and confers substantial risk for AKI (Azam et al., 2020; Karki et al., 2021). Biomarkers predictive of outcomes that are elevated early during disease progression, such as suPAR, have been successfully applied in clinical practice to guide immunomodulative treatment and improve prognosis (Kyriazopoulou et al., 2021). Future studies aiming to examine viral triggers, innate immune mediators, and kidney cell reactivity in concert will need to be performed. In the meantime, Jansen et al. allow us to draw the conclusion that the renal presence of SARS-CoV-2 can bring about pro-inflammatory and pro-fibrotic molecular changes that may prime the kidneys for further damage (including hits from circulating mediators such as suPAR and TNFα), ultimately leading to lasting kidney disease in long COVID. The study by Jansen et al. provides additional insights to allow for a comparison of kidneys infected by SARS-CoV-2 and other viral infections, especially human immunodeficiency virus (HIV) infection (Figure 1). Both SARS-CoV-2 and HIV directly infect podocytes and tubular epithelial cells. Collapsing glomerulopathy, tubulointerstitial fibrosis, and mesangial injury can be seen in both COVID-19 and HIV infection and are perhaps dependent on the amount of the innate immune activation that is mounted as an anti-infection response. Lessons learned from our experience with HIV infection may offer insight into the study of COVID-19-related kidney disease. Is there a set of COVID-19 gene products that converges pro-fibrotic and other pathways in diverse kidney cells and structures? African Americans develop COVID-19 associated with stronger AKI more often than other racial and ethnic groups (Hung et al., 2022). Are socioeconomic factors the sole drivers of these disparities, or is there a role for other genetic factors and environmental factors? It is noteworthy that untreated HIV infection caused glomerulopathy in 50% of African Americans with two APOL1 risk alleles. Data from patients with COVID-19 also suggested AKI, proteinuria, and podocytopathy were more prevalent among those with the high-risk APOL1 genotype. Will there be a need for screening and early detection of CKD in long COVID? Which antivirals and what duration of treatment will ensure clearance of SARS-CoV-2 in the kidneys? A stage is now set for these topics to be addressed.
24	R22		Jitske Jansen 22 Katharina C. Reimer 22 James S. Nagai 22 Finny S. Varghese 23 Gijs J. Overheul Marit de Beer Rona Roverts Deniz Daviran Liline A.S. Fermin Brigith Willemsen Marcel Beukenboom Sonja Djudjaj Saskia von Stillfried Larissa E. van Eijk Mirjam Mastik Marian Bulthuis Wilfred den Dunnen Harry van Goor Jan-Luuk Hillebrands Anat Akiva Peter Boor Victor G. Puelles Jürgen Floege Tobias B. Huber Ronald P. van Rij Ivan G. Costa 21 Rebekka K. Schneider 21 Bart Smeets 21 Rafael Kramann 21	SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids	https://doi.org/10.1016/j.stem.2021.12.010	Published	February 03, 2022	Study	https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00520-8	Kidney failure is frequently observed during and after COVID-19, but it remains elusive whether this is a direct effect of the virus. Here, we report that SARS-CoV-2 directly infects kidney cells and is associated with increased tubule-interstitial kidney fibrosis in patient autopsy samples. To study direct effects of the virus on the kidney independent of systemic effects of COVID-19, we infected human-induced pluripotent stem-cell-derived kidney organoids with SARS-CoV-2. Single-cell RNA sequencing indicated injury and dedifferentiation of infected cells with activation of profibrotic signaling pathways. Importantly, SARS-CoV-2 infection also led to increased collagen 1 protein expression in organoids. A SARS-CoV-2 protease inhibitor was able to ameliorate the infection of kidney cells by SARS-CoV-2. Our results suggest that SARS-CoV-2 can directly infect kidney cells and induce cell injury with subsequent fibrosis. These data could explain both acute kidney injury in COVID-19 patients and the development of chronic kidney disease in long COVID.
25	R23		Juan León-Román, Irene Agraz, Ander Vergara, Natalia Ramos, Nestor Toapanta, Clara García-Carro, Alejandra Gabaldón, Roxana Bury, Sheila Bermejo, Oriol Bestard, María José Soler	COVID-19 infection and renal injury: where is the place for acute interstitial nephritis disease?	https://doi.org/10.1093/ckj/sfac079	Published	14 March 2022	Study	https://academic.oup.com/ckj/advance-article/doi/10.1093/ckj/sfac079/6548197	Novel coronavirus disease infection (COVID-19) was declared a global pandemic in March 2020 and since then has become a major public health problem. The prevalence of COVID-19 infection and acute kidney injury (AKI) is variable depending on several factors such as race/ethnicity, and severity of illness. The pathophysiology of renal involvement in COVID-19 infection is not entirely clear but it could be in part explained by the viral tropism in the kidney parenchyma. AKI in COVID-19 infection can be either by direct invasion of the virus, or as a consequence of immunologic response. Diverse studies have focused on the effect of COVID-19 on glomerulonephritis (GN) patients or the “novo” GN; however, the effect of COVID-19 in acute tubulointerstitial nephritis (ATIN) has been scarcely studied. In this article, we present five cases with different spectrums of COVID-19 infection and ATIN that may suggest that recent diagnosis of ATIN is accompanied with a worse clinical prognosis in comparison with long-term diagnosed ATIN.
26	R24		Sidar Copur, Metehan Berkkan, Carlo Basile, Katherine Tuttle & Mehmet Kanbay	Post-acute COVID-19 syndrome and kidney diseases: what do we know?	https://doi.org/10.1007/s40620-022-01296-y	Published	16 March 2022	Review	https://link.springer.com/article/10.1007/s40620-022-01296-y	COVID-19 presents various respiratory, cardiovascular, neuropsychiatric, musculoskeletal and kidney features during the acute phase; nevertheless, renal involvement in the post-infection period has recently been emphasized. The present review aims to evaluate the growing literature on kidney involvement in the SARS-CoV-2 infection along with clinical features reported both in the acute phase of the infection and in the post-acute COVID-19 period by assessing potential pathophysiological frameworks explaining such conditions. Chronic kidney disease and development of acute kidney injury (AKI) in the course of initial hospitalization are associated with high mortality and morbidity rates. Moreover, growing evidence suggests a decline in renal function in the 6-to-12-month follow-up period even in patients without any signs of AKI during the acute phase. Despite such concerns there are no guidelines regulating the follow-up period or therapeutic alternatives for such patient population. In conclusion, the burden of COVID-19 on the kidney is yet to be determined. Future prospective large scale studies are needed with long follow-up periods assessing kidney involvement via multiple parameters such as biopsy studies, urinalysis, measurement of serum creatinine and cystatin C, directly measured glomerular filtration rate, and assessment of tubular function via urinary β2-microglobulin measurements.
27	R25		Hadadi A. · Farrokhpour H. · Rashedi S. · Kafan S. · Sotoudehnia M. · Rahimzadeh H. · Tabatabaei S. · Razeghi E. · Aghsaeifard Z.	Long term impact of the COVID-19 associated AKI: the relationship between kidney recovery and mortality in a 10-month follow-up cohort study	https://doi.org/10.1159/000524451	Published	April 04, 2022	Study	https://www.karger.com/Article/Abstract/524451	Abstract Introduction: Corona Virus-2019 (COVID-19) associated acute kidney injury (AKI) and its short and mid-term effect on kidney has been well established in the previous literature, indicating a high number of AKI in hospitalized patients associated with high rates of mortality, followed by high rates of unresolved kidney injury at the time of discharge. However, the long-term impact of AKI and its resulting lack of recovery at discharge has not been investigated. Herein, we sought to explore the possible relationship between AKI and unresolved kidney injury and post-discharge mortality. Method: In this cohort study, patients hospitalized with COVID-19 who survived to the discharge were followed for a median of 9.6 months. AKI during hospitalization based on the staging according to KDIGO criteria and Kidney injury status at the time of discharge and other comorbidities and mortality during the follow-up period, were recorded. Using Cox proportional hazards regression, the desired association was investigated after adjustment for potential confounders. Result: Among 1017 discharged patients, 298 patients (29.3%) experienced AKI during hospitalization according to KDIGO criteria, of whom 178 patients (59.7%) were diagnosed with unresolved kidney injury at the time of discharge. After adjusting for potential confounders, Cox regression indicated that AKI stage 3 (HR: 4.56, 95% CI: 1.89-10.99, p=0.001) and unresolved kidney injury at the time of discharge (HR: 2.09, 95% CI: 1.18-3.73, p=0.011) were significantly associated with mortality during the post-discharge period. Additionally, Kaplan-Meier curves for overall survival indicated an increased risk of mortality in patients with stage 2, stage 3 AKI, and unresolved kidney injury at the time of discharge. ( P<0.001) Conclusion: Overall, it was shown that patients with COVID-19 who develop AKI, mainly stage 2 and 3, and patients with unresolved kidney injury at the time of discharge, were at increased risk of mortality, even after hospitalization for an extended time
28	R26		M.Zaidan1F.Gaillard2A.Barnoud3Y.Darhi3P.Samb4L.Grimaldi5	Conséquences à long terme de l’insuffisance rénale aiguë au cours de la COVID-19 : données de l’entrepôt de données de santé de l’AP–HP	https://doi.org/10.1016/j.nephro.2022.07.253	Published	5 September 2022	Study	https://www.sciencedirect.com/science/article/pii/S1769725522003820	Introduction L’insuffisance rénale aiguë (IRA) est une complication fréquente et sévère chez les patients hospitalisés pour COVID-19. Les conséquences rénales à long terme restent à déterminer. Description/Méthodes Il s’agit d’une cohorte de patients adultes hospitalisés à l’AP–HP pendant plus de 24 h pour COVID-19 entre le 01/02/2020 et le 31/05/2020, constituée à partir de l’Entrepôt de Données de Santé de l’AP–HP. Les patients au statut rénal (de base et/ou à distance) indéterminé ont été exclus ou n’ont pas été inclus dans l’analyse par régression logistique des facteurs de risque d’insuffisance rénale chronique (IRC) post-COVID-19. Résultats Au total, 8492 patients ont été admis pour COVID-19 à l’AP–HP sur la période d’étude, incluant 5718 patients sans IRC préalable et dont le statut rénal pouvait être étudié. Sur les 2151 (37,6 %) patients ayant développé une IRA, 481 (22,4 %) sont décédés durant leur séjour, 1195 (55,6 %) ont récupéré une fonction rénale normale et 475 (22,1 %) avaient une altération persistante de la fonction rénale à la sortie d’hospitalisation. Par la suite, 46 patients sont décédés et 628 ont été perdus de vue. Sur les 996 patients survivants et pour lesquels le statut rénal à long terme était disponible, 565 ont récupéré une fonction rénale normale et 431 ont développé une IRC. En analyse multivariée, les facteurs associés au risque d’IRC étaient : l’âge, le sexe masculin, l’hypertension, le diabète, les maladies cardiaques, les transplantations d’organes, le taux d’hémoglobine à l’entrée, la sévérité de l’IRA durant l’hospitalisation, l’oxygénothérapie et le passage en réanimation. Conclusion Notre étude montre un risque important d’IRC chez les patients hospitalisés pour COVID-19 et qui développent une IRA, y compris chez ceux ayant récupéré une fonction « normale » à la sortie d’hospitalisation, soulignant l’intérêt d’une évaluation rénale à distance de la COVID-19.
29	R27		Maureen Brogan1 and Michael J. Ross	COVID-19 and Kidney Disease	https://doi.org/10.1146/annurev-med-042420-104753	Published	September 15, 2022	Review	https://www.annualreviews.org/doi/abs/10.1146/annurev-med-042420-104753	COVID-19 can cause acute kidney injury and may cause or exacerbate chronic kidney diseases, including glomerular diseases. SARS-CoV-2 infection of kidney cells has been reported, but it remains unclear if viral infection of kidney cells causes disease. The most important causes of kidney injury in patients with COVID-19 include impaired renal perfusion and immune dysregulation. Chronic kidney disease, especially kidney failure with kidney replacement therapy and kidney transplant, is associated with markedly increased COVID-19 mortality. Persons with severe kidney disease have been excluded from most clinical trials of COVID-19 therapies, so therapeutic approaches must be extrapolated from studies of patients without kidney disease. Some medications used to treat COVID-19 should be avoided or used at reduced dosages in patients with severe kidney disease and in kidney transplant recipients. Additional research is needed to determine the optimal strategies to prevent and treat COVID-19 in patients with kidney disease.
30	R28		Ivan Cancarevic, Mahmoud Nassar, Luis Medina, Angelica Sanchez, Avish Parikh, Asma Hosna, Bhavana Devanabanda, Mallorie Vest, Fatima Ayotunde, Muhammad Ghallab, Ismail Omran	Nephrotic Syndrome in Adult Patients With COVID-19 Infection or Post COVID-19 Vaccine: A Systematic Review	https://doi.org/10.7759/cureus.29613	Published	September 26, 2022	Study	https://www.cureus.com/articles/110827-nephrotic-syndrome-in-adult-patients-with-covid-19-infection-or-post-covid-19-vaccine-a-systematic-review	Nephrotic syndrome is a condition characterized by damage to podocytes that results in significant proteinuria, edema, hyperlipidemia, and hypercoagulability. Infections and malignancies are frequently associated with nephrotic syndrome. The COVID-19 virus has been associated with several atypical presentations of upper respiratory infections and acute kidney injury. Considering that COVID-19 causes systemic inflammatory changes, it seems plausible that it may also lead to nephrotic syndrome. This study aimed to investigate if an association between COVID-19 and the different types of nephrotic syndromes exists. Data were extracted into a spreadsheet. Statistical analysis was performed using Statistical Package for Social Sciences (SPSS, IBM Corp., Armonk, NY, USA). We performed a systematic search of PubMed/Medline and Embase databases using both medical subject headings (MeSH) and regular keywords associated with COVID-19 and nephrotic syndrome, including different types of nephrotic syndromes. The search was performed on 17th December 2021. We included case reports and case series about adult patients who developed findings suggestive of nephrotic syndrome shortly after infection or vaccination. We excluded cases involving children, pregnant women, articles written in languages other than English, and those that were not retrievable. The relevance and quality of identified articles were assessed. We included 32 articles in the study, primarily case reports and case series. In our study, COVID-19 and the COVID-19 vaccine have been associated with the development of nephrotic syndrome, primarily a collapsing form of focal segmental glomerulosclerosis, although other forms have been observed as well. There was little consistency in patient histories, clinical presentations, clinical courses, or treatment regimens, although it appeared that most cases eventually resolved. More cases need to be reported and analyzed before more definitive conclusions can be reached. In conclusion, nephrotic syndrome is a possible complication of both COVID-19 infection and the COVD-19 vaccine and should be considered in patients exhibiting sudden onset edemas or deterioration in kidney function. While the majority of cases respond to standard treatment, clearer guidelines will need to be developed once more data is available.
31	R29		Amorim, Carlos Eduardo Neves MD, PhD1; Gomes, Vinicius Lafico Teixeira2; Cristelli, Marina Pontello MD, PhD2; Viana, Laila Almeida MD2; de Luca Correa, Hugo MD3; Lima, Gierisson Brenno Borges MSc1; de Sousa Silva, Flaviana Santos MSc1; de Castro Lima, Gabriel Santos MSc1; Rosa, Thiago dos Santos PhD3; Nakamura, Monica Rika MSc2; Quintino, Priscilla Monteiro MSc2; Tedesco-Silva, Helio MD, PhD2; Medina-Pestana, José MD, PhD2	High Prevalence of Long-COVID Among Kidney Transplant Recipients: A Longitudinal Cohort Study	https://doi.org/10.1097/TP.0000000000004359	Published	October 13, 2022	Study	https://journals.lww.com/transplantjournal/Fulltext/9900/High_Prevalence_of_Long_COVID_Among_Kidney.193.aspx	Background. Kidney transplant recipients are at a higher risk to develop more severe clinical forms of coronavirus disease 2019 (COVID-19), perhaps increasing the risk of presenting its long-term clinical complications, labeled as Long-COVID. Methods. This single-center, observational, prospective study included adult kidney transplant recipients with COVID-19 confirmed by reverse transcription polymerase chain reaction between March 20, 2020, and May 31, 2021, who were alive and with functioning graft 3 mo after the onset of symptoms. The prevalence of Long-COVID was investigated by a phone survey using a structured questionnaire of organic symptoms. Adjusted multivariable logistic regression models were used to investigate independent risk factors. Results. Of 1741 patients who developed COVID-19, 465 died, and 37 returned to dialysis. Of the 1239 eligible patients, 780 (63%) answered the survey during the window period. The mean age was 48 ± 12 y, 41% were women, and the mean time from transplantation was 8 ± 6 y. During acute illness, 45% needed hospitalization. Long-COVID was identified in 214 (27%) of the subjects, with body aches being the most prevalent symptom (44%). Of 233 who provided working status, 17% did not return to work within 3 mo. No baseline characteristics or infection-related variables predicted Long-COVID; actually, the number of symptoms in the acute illness was the only independent risk factor identified (hazard ratio, 1.12; 95% confidence interval, 1.02-1.22). Conclusion. In this cohort of kidney transplant recipients, Long-COVID was prevalent and associated with a reduced return to work. The burden of acute phase symptoms was the only risk factor associated with Long-COVID.
32	R30		Byorn W.L. Tan aa Bryce W.Q. Tan aa Amelia L.M. Tan Emily R. Schriver Alba Gutiérrez-Sacristán Priyam Das William Yuan Meghan R. Hutch Noelia García Barrio Miguel Pedrera Jimenez Griffin M. Weber Isaac S. Kohane Tianxi Cai Gilbert S. Omenn John H. Holmes Kee Yuan Ngiam	Long-term kidney function recovery and mortality after COVID-19-associated acute kidney injury: An international multi-centre observational cohort study	https://doi.org/10.1016/j.eclinm.2022.101724	Published	November 07, 2022	Study	https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(22)00454-0/fulltext	Background While acute kidney injury (AKI) is a common complication in COVID-19, data on post-AKI kidney function recovery and the clinical factors associated with poor kidney function recovery is lacking. Methods A retrospective multi-centre observational cohort study comprising 12,891 hospitalized patients aged 18 years or older with a diagnosis of SARS-CoV-2 infection confirmed by polymerase chain reaction from 1 January 2020 to 10 September 2020, and with at least one serum creatinine value 1–365 days prior to admission. Mortality and serum creatinine values were obtained up to 10 September 2021. Findings Advanced age (HR 2.77, 95%CI 2.53–3.04, p < 0.0001), severe COVID-19 (HR 2.91, 95%CI 2.03–4.17, p < 0.0001), severe AKI (KDIGO stage 3: HR 4.22, 95%CI 3.55–5.00, p < 0.0001), and ischemic heart disease (HR 1.26, 95%CI 1.14–1.39, p < 0.0001) were associated with worse mortality outcomes. AKI severity (KDIGO stage 3: HR 0.41, 95%CI 0.37–0.46, p < 0.0001) was associated with worse kidney function recovery, whereas remdesivir use (HR 1.34, 95%CI 1.17–1.54, p < 0.0001) was associated with better kidney function recovery. In a subset of patients without chronic kidney disease, advanced age (HR 1.38, 95%CI 1.20–1.58, p < 0.0001), male sex (HR 1.67, 95%CI 1.45–1.93, p < 0.0001), severe AKI (KDIGO stage 3: HR 11.68, 95%CI 9.80–13.91, p < 0.0001), and hypertension (HR 1.22, 95%CI 1.10–1.36, p = 0.0002) were associated with post-AKI kidney function impairment. Furthermore, patients with COVID-19-associated AKI had significant and persistent elevations of baseline serum creatinine 125% or more at 180 days (RR 1.49, 95%CI 1.32–1.67) and 365 days (RR 1.54, 95%CI 1.21–1.96) compared to COVID-19 patients with no AKI. Interpretation COVID-19-associated AKI was associated with higher mortality, and severe COVID-19-associated AKI was associated with worse long-term post-AKI kidney function recovery.
33	R31		Lirong Lin,Junhui Deng,Jie Li,Luquan Zheng,Zhifeng Wu,Wei Tan,Jurong Yang	Pathogenesis and histological changes of nephropathy associated with COVID-19	https://doi.org/10.1002/jmv.28311	Published	15 November 2022	Review	https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.28311	Coronavirus disease 2019 (COVID-19) can cause damage to multiple organ, not only to the lungs, but also to the kidneys. Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) can cause acute and chronic kidney disease through direct viral infection, indirect injury, and vaccination-related injury. Like lung injury, kidney injury is also an important aspect affecting the severity and prognosis of SARS-CoV-2. This article summarizes the pathogenesis, pathological manifestations, and clinical features of SARS-CoV-2 direct or indirect renal injury. Including direct injury, indirect injury, special comorbidities (receiving kidney transplantation and CKD), and vaccine-related renal injury, and exploring the possible therapeutic effect of anti-SARS-CoV-2 therapy on renal injury. The purpose is to provide reference for understanding COVID-19-related renal injury, guiding clinical and pathological diagnosis and treatment, and evaluating prognosis.
34	R32		Schiffl, Helmut; Lang, Susanne M.	Long-term interplay between COVID-19 and chronic kidney disease	https://doi.org/10.1007/s11255-023-03528-x	Published	2023-02-24	Review	https://doi.org/10.1007/s11255-023-03528-x	Purpose The COVID-19 pandemic may have an impact on the long-term kidney function of survivors. The clinical relevance is not clear. Methods This review summarises the currently published data. Results There is a bidirectional relationship between chronic kidney disease and COVID-19 disease. Chronic kidney diseases due to primary kidney disease or chronic conditions affecting kidneys increase the susceptibility to COVID-19 infection, the risks for progression and critical COVID-19 disease (with acute or acute-on-chronic kidney damage), and death. Patients who have survived COVID-19 face an increased risk of worse kidney outcomes in the post-acute phase of the disease. Of clinical significance, COVID-19 may predispose surviving patients to chronic kidney disease, independently of clinically apparent acute kidney injury (AKI). The increased risk of post-acute renal dysfunction of COVID-19 patients can be graded according to the severity of the acute infection (non-hospitalised, hospitalised or ICU patients). The burden of chronic kidney disease developing after COVID-19 is currently unknown. Conclusion Post-acute COVID-19 care should include close attention to kidney function. Future prospective large-scale studies are needed with long and complete follow-up periods, assessing kidney function using novel markers of kidney function/damage, urinalysis and biopsy studies.
35	R33		Kroll, Marie-Kristin; Schloer, Sebastian; Candan, Peynaz; Korthals, Nadia; Wenzel, Christoph; Ihle, Hannah; Gilhaus, Kevin; Liedtke, Kim Rouven; Schöfbänker, Michael; Surmann, Beate; Schröter, Rita; Neugebauer, Ute; Mall, Gita; Oswald, Stefan; Ludwig, Stephan; Rescher, Ursula; Vollenbröker, Beate; Ciarimboli, Giuliano	Importance of ACE2 for SARS-CoV-2 Infection of Kidney Cells	https://doi.org/10.3390/biom13030472	Published	2023-03-01	Study	https://www.mdpi.com/2218-273X/13/3/472	In late 2019, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as the causative agent of coronavirus disease 2019 (COVID-19) emerged in China and spread rapidly around the world, causing an ongoing pandemic of global concern. COVID-19 proceeds with moderate symptoms in most patients, whereas others experience serious respiratory illness that requires intensive care treatment and may end in death. The severity of COVID-19 is linked to several risk factors including male sex, comorbidities, and advanced age. Apart from respiratory complications, further impairments by COVID-19 affecting other tissues of the human body are observed. In this respect, the human kidney is one of the most frequently affected extrapulmonary organs and acute kidney injury (AKI) is known as a direct or indirect complication of SARS-CoV-2 infection. The aim of this work was to investigate the importance of the protein angiotensin-converting enzyme 2 (ACE2) for a possible cell entry of SARS-CoV-2 into human kidney cells. First, the expression of the cellular receptor ACE2 was demonstrated to be decisive for viral SARS-CoV-2 cell entry in human AB8 podocytes, whereas the presence of the transmembrane protease serine 2 (TMPRSS2) was dispensable. Moreover, the ACE2 protein amount was well detectable by mass spectrometry analysis in human kidneys, while TMPRSS2 could be detected only in a few samples. Additionally, a negative correlation of the ACE2 protein abundance to male sex and elderly aged females in human kidney tissues was demonstrated in this work. Last, the possibility of a direct infection of kidney tubular renal structures by SARS-CoV-2 was demonstrated.

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1	Ref	PPLC	Authors	Title	DOI	Peer reviewed	Date	type	Link	Keys	Clés

2	Ch01		Prateek Kumar Panda, MD, DM, Indar Kumar Sharawat, MD, DM, Pragnya Panda, MD, Vivekanand Natarajan,	Neurological Complications of SARS-CoV-2 Infection in Children: A Systematic Review and Meta-Analysis	https://doi.org/10.1093/tropej/fmaa070	Published	10 September 2020	Systematic Review and Meta-Analysis	https://academic.oup.com/tropej/advance-article/doi/10.1093/tropej/fmaa070/5903829	Children affected by neurological complications	Les enfants peu touchés par des complications neurologiques
3	Ch02	MIS-C	Jayakanthan Kabeerdoss, Rakesh Kumar Pilania, Reena Karkhele, T. Sathish Kumar, Debashish Danda &	Severe COVID-19, multisystem inflammatory syndrome in children, and Kawasaki disease: immunological mechanisms, clinical manifestations and management	https://doi.org/10.1007/s00296-020-04749-4	Published	21 November 2020	Review	https://link.springer.com/article/10.1007/s00296-020-04749-4	An Indian study is investigating the triggering mechanisms of multisystem inflammatory syndrome in children (MIS-C) with covid, whose symptoms resemble those of Kawasaki disease.	Une étude indienne s'intéresse aux mécanismes de déclenchement du syndrome inflammatoire multisystémique chez les enfants (multisystem inflammatory syndrome, MIS-C) atteints de la covid, dont les symptômes évoquent ceux de la maladie de Kawasaki.
4	Ch03		Jonas F Ludvigsson	Case report and systematic review suggest that children may experience similar long‐term effects to adults after clinical COVID‐19	https://doi.org/10.1111/apa.15673	Published	17 November 2020	Cases report and review	https://onlinelibrary.wiley.com/doi/10.1111/apa.15673	According to this case study (9 to 15 years old) accompanied by a review of the literature, long covid is possible in children and mainly affects girls. Out of 5 cases reported in Sweden, 4 had no pre-existing co-morbidities. The study has been critisized in the same journal for its méthodology (Ch11).	Selon cette étude de cas (9 à 15 ans) accompagnée d'une revue de la littérature, le covid long est possible chez les enfants et toucherait surtout les filles. Sur 5 cas rapportés en Suède, 4 n'avaient pas de comorbidités préexistantes. L'étude a été critiquée dans la même publication par 2 médecins pour ses lacunes méthodologiques. (Ch11).
5	Ch04	MIS-C	Anjali Ramaswamy, Nina N. Brodsky, Tomokazu S. Sumida, Michela Comi	Post-infectious inflammatory disease in MIS-C features elevated cytotoxicity signatures and autoreactivity that correlates with severity	https://doi.org/10.1101/2020.12.01.20241364	pre-print	4 Dec 2020		https://www.medrxiv.org/content/10.1101/2020.12.01.20241364v1		Un pre-print identifie des autoanticorps dirigés contre les cellules endothéliales du cœur, dans le cadre du syndrome inflammatoire multisystémique chez les enfants post-covid. Également détaillé dans ce thread d'une des auteurs : https://twitter.com/lucasite_lab/status/1334932293366976512?s=19
6	Ch05		MadhuSharmaMDaSamuelGorsteinMDbMargaret L.Aldrich	Reversible Myocardial Injury Associated With SARS-CoV-2 in an Infant	https://doi.org/10.1016/j.jaccas.2020.09.031	Published	12 October 2020	Case Report	https://www.sciencedirect.com/science/article/pii/S2666084920311827		Un cas rapporté de lésion cardiaque (heureusement réversible), accompagnée d'une insuffisance cardiaque en décompensation aiguë, chez un bébé de 2 mois infecté par le SARS-CoV-2.
7	Ch06	MIS-C	Julie Toubiana1,2, Corinne Levy3,4,5,6,7 , Slimane Allali1	Association between SARS-CoV-2 infection and Kawasaki-like multisystem inflammatory syndrome: a retrospective matched case–control study, Paris, France, April to May 2020	https://doi.org/10.2807/1560-7917.es.2020.25.48.2001813	Published	December 3, 2020	Rapid communication	https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.48.2001813		Etude française sur les cas de syndrome inflammatoire multisystémique chez les enfants, de type maladie de Kawasaki, en région parisienne.
8	Ch07		Caroline Diorio, Kevin O. McNerney, Michele Lambert, Michele Paessler, Elizabeth M. Anderson, Sarah E. Henrickson, Julie Chase, Emily J. Liebling,	Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations	https://doi.org/10.1182/bloodadvances.2020003471	Published	December 8, 2020		https://ashpublications.org/bloodadvances/article/4/23/6051/474421/Evidence-of-thrombotic-microangiopathy-in-children	sC5b9 plasma levels are elevated in children with SARS-CoV-2 infection, even if they have minimal symptoms of COVID-19. A high proportion of children with SARS-CoV-2 infection met clinical criteria for TMA (thrombotic microangiopathy). Study of a biomarker of blood clots in small blood vessels in 50 children with mild (n=21) & severe (n=11) #COVID19, and MIS-C (n=18). -> Biomarker elevated in all groups. -> Evidence of kidney injury in 10% of mild cases (36% severe, 28% MIS-C). The children with mild illness included hospital patients in which #SARSCoV2 had been identified in routine testing before admission (unrelated to #COVID19). As such, it is possible they may not be representative of mild cases generally. It is unclear what the long-term implications of this study are. It is possible these findings are fully reversible. However, there is also the possibility that children who had evidence of blood clots in small blood vessels (TMA) may be at increased risk of developing chronic disease, including cardiovascular and kidney disease in later life. More research with larger samples of children, particularly those from the general community rather than hospital settings, is required to understand whether this is common. Follow-up of affected children is needed to determine whether there are any long-term consequences.	_
9	Ch08		Camilla E Lindan, MD, Kshitij Mankad, FRCR, Dipak Ram, FRCPCH, Larry K Kociolek, MD, V Michelle Silvera, MD, Prof Nathalie Boddaert, MD, Prof Stavros Michael Stivaros, PhD *, Susan Palasis, MD	Neuroimaging manifestations in children with SARS-CoV-2 infection: a multinational, multicentre collaborative study	https://doi.org/10.1016/S2352-4642(20)30362-X	Published	December 15, 2020		https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(20)30362-X/fulltext		Cette étude indique que les complications neurologiques de la covid chez l'enfant sont rares, en contraste avec les adultes. L'analyse de 38 cas montre une variété d'atteintes, parfois graves, chez des sujets sans comorbidités.
10	Ch09		Ebtsam Salah Yonis Mahrous	Impact of COVID-19 on Children		Published	02 January 2021	Review	https://journals.ekb.eg/article_134865_0.html		Un article évoque les conséquences directes mais surtout indirectes de la pandémie de covid sur les enfants.
11	Ch10		Dr. Ardhanaari M Dr.Anita Harry	A SYSTAMATIC REVIEW ON EFFECT OF COVID ON CHILDREN		Published	2020	Review	https://ejmcm.com/article_5865.html		Une autre courte revue d'études sur les effets directs et indirects de la pandémie de covid sur les enfants.
12	Ch11		Viktor Peny Anders Valind	Re: Case Reports and systematic review suggest that children may experience similar long‐term effects to adults after clinical COVID‐19	https://doi.org/10.1111/apa.15764	Published	18 January 2021	LETTER	https://onlinelibrary.wiley.com/doi/abs/10.1111/apa.15764		Dans le Acta Pediatrica qui avait publié une étude de 5 cas d'enfant suédois suspectés d'être atteints d'un covid long (J. Ludvigsson & al.), paraît une lettre de deux médecins qui critiquent la méthodologie de l'étude, jugée inadaptée et insuffisante.
13	Ch12		danilo buonsenso, Daniel Munblit, Cristina De Rose, Dario Sinatti, Antonia Ricchiuto, Angelo Carfi, Piero Valentini	Preliminary Evidence on Long COVID in children	https://doi.org/10.1111/apa.15870	Published	April 9, 2021	Study	https://onlinelibrary.wiley.com/doi/10.1111/apa.15870	ex pre-print in anuary https://www.medrxiv.org/content/10.1101/2021.01.23.21250375v1 We assessed persistent symptoms in pediatric patients previously diagnosed with COVID-19. More than a half reported at least one persisting symptom even after 120 days since COVID-19, with 42.6% being impaired by these symptoms during daily activities. Symptoms like fatigue, muscle and joint pain, headache, insomnia, respiratory problems and palpitations were particularly frequent, as also described in adults.	En Italie, une étude indique que sur 129 enfants suivis (<18 ans, diagnostiqués covid par test PCR, les 3/4 ayant une covid symptomatique, mais seulement 5% hospitalisés), une récupération complète au bout de 4 mois n'est observée que pour 47% d'entre eux. Les symptômes reportés sont principalement l'insomnie, la congestion nasale, la fatigue, les maux de tête, le manque de concentration et les douleurs musculaires.	N001
14	Ch13		Timothy G. Singer Karen Evankovich Kristen Fisher Gail Demmler Harrison Sarah R. Risen	Coronavirus infections in the nervous system of children: a scoping review making the case for long-term neurodevelopmental surveillance	https://doi.org/10.1016/j.pediatrneurol.2021.01.007	Published	January 28, 2021	Scoping Review	https://www.pedneur.com/article/S0887-8994(21)00008-4/fulltext		Une revue d'études sur les effets de 6 coronavirus sur les enfants soutient que ces infections peuvent causer des maladies neurologiques graves chez les enfants, ce qui constitue une menace pour le développement neurologique à long terme.	N001
15	Ch14	MIS-C	Mubbasheer Ahmed, Shailesh Advani, Axel Moreira, Sarah Zoretic, John Martinez, Kevin Chorath, Sebastian Acosta, Rija Naqvi, Finn Burmeister-Morton, Fiona Burmeister, Aina Tarriela, Matthew Petershack, Mary Evans, Ansel Hoang, Karthik Rajasekaran, Sunil Ahuja, Alvaro Moreira	Multisystem inflammatory syndrome in children: A systematic review	https://doi.org/10.1016/j.eclinm.2020.100527	Published	September 04, 2020	Systematic Review	https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(20)30271-6/fulltext	While 71·0% of children (n = 470) were admitted to the intensive care unit, only 11 deaths (1·7%) were reported. Average length of hospital stay was 7·9 ± 0·6 days. Fever (100%, n = 662), abdominal pain or diarrhea (73·7%, n = 488), and vomiting (68·3%, n = 452) were the most common clinical presentation. Serum inflammatory, coagulative, and cardiac markers were considerably abnormal. Mechanical ventilation and extracorporeal membrane oxygenation were necessary in 22·2% (n = 147) and 4·4% (n = 29) of patients, respectively. An abnormal echocardiograph was observed in 314 of 581 individuals (54·0%) with depressed ejection fraction (45·1%, n = 262 of 581) comprising the most common aberrancy. Multisystem inflammatory syndrome is a new pediatric disease associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is dangerous and potentially lethal. With prompt recognition and medical attention, most children will survive but the long-term outcomes from this condition are presently unknown.	_
16	Ch15		Donavyn Coffey	Long-COVID in Children: It's a Thing		Published	February 19, 2021	Article	https://www.medscape.com/viewarticle/946161	"The current data are important and make it clear that long-COVID is occurring in children." "we really need to understand what the true penetration of symptoms is," Danziger-Isakov said, and that requires studying more than 129 patients.	Une analyse revient sur l'étude italienne (qui était alors en pre-print paru le 26/01) sur le covid long chez les enfants. Elle note que les résultats de l'étude sont encore débattus par les spécialistes qui appellent à la prudence sur la prévalence, à cause de biais possibles.
17	Ch16	MIS-C	Peart Akindele, clinical and, research pediatric infectious disease fellow1, Megan M Tschudy, assistant professor of pediatrics2, Anna C Sick-Samuels, assistant professor of pediatrics1	Acute covid-19 and multisystem inflammatory syndrome in children	https://doi.org/10.1136/bmj.n385	Published	01 March 2021	Article	https://www.bmj.com/content/372/bmj.n385	Children with acute covid-19 can present with non-specific symptoms. Exclude covid-19 in children with fever and respiratory tract symptoms or loss of taste or smell, especially if there is possible exposure to others with the virus Consider multisystem inflammatory syndrome (MIS-C) in children presenting with fever and abdominal symptoms—particularly if they develop conjunctivitis or rash—and refer to a paediatric emergency department for evaluation MIS-C can have overlapping symptomatology with disease processes that require prompt treatment, such as sepsis, toxic shock syndrome, myocarditis, and meningitis. Therefore, consider initiation of empiric antibiotics and necessary evaluations if the patient develops cardiovascular or respiratory compromise, evidence of acute abdomen, or meningismus	Un article dans BMJ répond à plusieurs questions concernant la covid et le syndrome inflammatoire multisystémique qui peut lui être consécutif chez l'enfant : les risques d'infection à l'école, les tests, la prévention.	N003A
18	Ch17		Helen Thomson	Children with long covid	https://doi.org/10.1016%2FS0262-4079(21)00303-1	Published	2021 Mar 3	Article	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927578/	Children seem to be fairly well-protected from the most severe symptoms of covid-19. According to the European Centre for Disease Prevention and Control, the majority of children don't develop symptoms when infected with the coronavirus, or their symptoms are very mild. However, it is becoming increasingly apparent that a large number of children with symptomatic and asymptomatic covid-19 are experiencing long-term effects, many months after the initial infection.	Un article d'opinion s'intéresse aux données sur les cas de covid long chez les enfants.
19	Ch18		Danilo Buonsenso * , Ferran Espuny Pujol , Daniel Munblit logo , Sammie Mcfarland , Frances Simpson	Clinical Characteristics, Activity Levels and Mental Health Problems in Children with Long COVID: A Survey of 510 Children	https://doi.org/10.20944/preprints202103.0271.v1	pre-print	9 March 2021	Survey	https://www.preprints.org/manuscript/202103.0271/v1	Our study provides further evidence on Long COVID in children. Symptoms like fatigue, headache, muscle and joint pain, rashes and heart palpitations, and mental health issues like lack of concentration and short memory problems, were particularly frequent and confirm previous observations, suggesting that they may characterize this condition. A better comprehension of Long COVID is urgently needed.	Dans une étude non encore relue ni publiée, sur 510 enfants avec un covid long, les symptômes les plus fréquents sont : l'asthénie, les maux de tête, les douleurs abdominales, musculaires et articulaires, le malaise post-effort et les éruptions cutanées.
20	Ch19	MIS-C	Kerri L. LaRovere, MD1; Becky J. Riggs, MD2; Tina Y. Poussaint, MD3; Cameron C. Young4; Margaret M. Newhams, Heidi R. Flori, MD45; Manish M. Patel, MD24,25; Adrienne G. Randolph, MD4,46; for the Overcoming COVID-19 Investigators	Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome	https://doi.org/10.1001/jamaneurol.2021.0504	Published	March 5, 2021	Original Investigation	https://jamanetwork.com/journals/jamaneurology/fullarticle/2777392	Findings In this study of 1695 patients 21 years or younger hospitalized for acute COVID-19 or multisystem inflammatory syndrome, 365 (22%) had neurologic involvement. Forty-three patients (12%) developed COVID-19–related life-threatening neurologic disorders, 11 (26%) died, and 17 (40%) survived with new neurologic sequelae.	Dans une étude américaine (JAMA Neurology) sur 1695 patients de moins de 21 ans qui ont été hospitalisés pour la covid : 365 patients ont eu une atteinte neurologique pendant l'hospitalisation, dont 43 qui ont développé des troubles neurologiques potentiellement mortels liés au COVID-19. Parmi eux, 11 patients sont décédés et 17 ont survécu avec de nouvelles séquelles neurologiques.	N004
21	Ch20	MIS-C	J.-C. Mercier,a,⁎ A. Maroni,b M. Levy,b I. Melki,c,d U. Meinzer,c,e J. Gaschignard,c,f C. Beyler,g et A. Santos	COVID-19 chez l’enfant : syndrome inflammatoire multi-systémique lié à SARS-CoV-2 mimant un syndrome de Kawasaki	https://dx.doi.org/10.1016%2Fj.banm.2020.11.018	Published	2021 Mar 18	Review	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969823/	S’il est manifeste que les enfants sont moins susceptibles que les adultes au SARS-CoV-2 (COVID-19) et qu’ils développent des formes cliniques moins sévères, un petit nombre, peut-être du fait de comorbidités associées (malformations congénitales, obésité, hypertension artérielle) ou d’une dysrégulation cytokinique inflammatoire, peut présenter une dysfonction ventriculaire gauche et/ou un syndrome de Kawasaki régressant rapidement après un traitement par immunoglobulines intraveineuses et/ou une corticothérapie associée.	_
22	Ch21	MIS-C	Takuya Hara, MD1; Kenji Furuno, MD, PhD1; Kenichiro Yamamura, MD, PhD2; Junji Kishimoto, PhD3; Yumi Mizuno, Mayumi Yashiro, BA9; Yoshikazu Nakamura, MD, PhD9; Toshiro Hara, MD, PhD1	Assessment of Pediatric Admissions for Kawasaki Disease or Infectious Disease During the COVID-19 State of Emergency in Japan	https://doi.org/10.1001/jamanetworkopen.2021.4475	Published	April 6, 2021	Study	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2778178	The development of Kawasaki disease (KD) has been suggested to be associated with droplet- or contact-transmitted infection; however, its triggers and transmission modes remain to be determined. Under an epidemic of SARS-CoV-2, the COVID-19 state of emergency in Japan served as a nationwide social experiment to investigate the impact of quarantine or isolation on the incidence of KD. These findings suggest that contact or droplet transmission is not a major route for KD development and that KD may be associated with airborne disease.	_
23	Ch22	MIS-C	AnjaliRamaswamy1Nina N.Brodsky12Tomokazu S.Sumida13MichelaComi13HiromitsuAsashima13Kenneth B.Hoehn4NingshanLi5YunqingLiu5AagamShah67Neal G.Ravindra67JasonBishai67AlamzebKhan2WilliamLau89BrianSellers8NehaBansal89PamelaGuerrerio10AvrahamUnterman11VictoriaHabet2…Carrie L.Lucas	Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children	https://doi.org/10.1016/j.immuni.2021.04.003	Published	13 April 2021	Study	https://www.sciencedirect.com/science/article/pii/S1074761321001655	Highlights •scRNA-seq of PBMCs from MIS-C patients reveals immunopathology signatures •MIS-C patients display elevated alarmins and NK/CD8+ T-cell cytotoxicity effectors •TRBV11-2-expressing CD4+ and CD8+ memory T cells are expanded in severe MIS-C •Increased plasmablasts and endothelium-reactive IgG are features of severe MIS-C	Une étude sur le PIMS-Covid (syndrome inflammatoire multisystémique pédiatrique) identifie les taux d'alarmine, la cytotoxicité, les récepteurs des cellules T et les signatures plasmablastiques comme biomarqueurs permettant de diagnostiquer la gravité de la maladie.	N011
24	Ch23	MIS-C	Theodore Kouo1 and Worarat Chaisawangwong	SARS-CoV-2 as a superantigen in multisystem inflammatory syndrome in children (MIS-C)	https://doi.org/10.1172/JCI149327	Published	April 12, 2021	Commentary	https://www.jci.org/articles/view/149327	Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare but deadly new disease in children that rapidly progresses to hyperinflammation, shock, and can lead to multiple organ failure if unrecognized. It has been found to be temporally associated with the COVID-19 pandemic and is often associated with SARS-CoV-2 exposure in children. In this issue of the JCI, Porritt, Paschold, and Rivas et al. identify restricted T cell receptor (TCR) β-chain variable domain (Vβ) usage in patients with severe MIS-C indicating a potential role for SARS-CoV-2 as a superantigen. These findings suggest that a blood test that determines the presence of specific TCR beta variable gene segments (TRBV) may identify patients at risk for severe MIS-C.	_
25	Ch24	MIS-C	Vanessa Sancho-Shimizu , Petter Brodin, Aurélie Cobat, Catherine M. Biggs, Julie Toubiana, Carrie L. Lucas, Sarah E. Henrickso, Alexandre Belot, MIS-C@CHGE , Stuart G. Tangye, Joshua D. Milner, Michael Lev, Laurent Abel, Dusan Bogunovic, Jean-Laurent Casanova, Shen-Ying Zhang	SARS-CoV-2–related MIS-C: A key to the viral and genetic causes of Kawasaki disease?	https://doi.org/10.1084/jem.20210446	Published	April 27 2021	Article	https://rupress.org/jem/article/218/6/e20210446/212029/SARS-CoV-2-related-MIS-C-A-key-to-the-viral-and	Multisystem inflammatory syndrome in children (MIS-C) emerged in April 2020 in communities with high COVID-19 rates. This new condition is heterogenous but resembles Kawasaki disease (KD), a well-known but poorly understood and clinically heterogenous pediatric inflammatory condition for which weak associations have been found with a myriad of viral illnesses. Epidemiological data clearly indicate that SARS-CoV-2 is the trigger for MIS-C, which typically occurs about 1 mo after infection. These findings support the hypothesis of viral triggers for the various forms of classic KD. We further suggest that rare inborn errors of immunity (IEIs) altering the immune response to SARS-CoV-2 may underlie the pathogenesis of MIS-C in some children. The discovery of monogenic IEIs underlying MIS-C would shed light on its pathogenesis, paving the way for a new genetic approach to classic KD, revisited as a heterogeneous collection of IEIs to viruses.	_
26	Ch25	PESE	Gabriele Di Sante, Danilo Buonsenso, Cristina De Rose, Piero Valentini, Francesco Ria, Maurizio Sanguinetti, Michela Sali	Immune profile of children with post-acute sequelae of SARS-CoV-2 infection (Long Covid)	https://doi.org/10.1101/2021.05.07.21256539	Pre-print	May 10, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.05.07.21256539v1.full-text	In this study, we documented significant immunologic differences between children that completely recovered from acute infection and those with PASC, providing the first objective laboratory sign of the existence of PASC in children. Healed children restored B-cell homeostasis, by reconstituting the naïve/unswitched B-cell compartment. In PASC children, the consistent amounts of plasmablasts, switched and memory B lymphocytes revealed the involvement of those subsets in the immunopathogenesis of chronic symptoms. Moreover, the persisting high levels of IL6 and IL1β suggest that innate immune response played a pivotal role in children with PASC. Considering their role as mediators of inflammatory responses and auto-immune processes, these findings could explain systemic persisting symptoms such as fatigue and post-exertional malaise, headache, muscle and joint pain, and tachycardia. Our findings provide further evidence that a chronic inflammatory process and immune dysfunction may explain why some children develop PASC, highlighting the importance of further studies aimed to better characterize this new condition. A better understating of PASC will also provide indirect benefits for other post-infectious conditions. Limitations of our study are the low number of children included and the lack of ex-vivo immunologic studies performed after in-vitro stimulation with SARS-CoV-2, which we plan as a future study.	Une étude en pre-print (non relue ni publiée) documente les différences immunologiques significatives entre les enfants qui ont complètement récupéré d'une infection aiguë, et ceux avec un covid long, dans le but d'objectiver le covid long pédiatrique. Les quantités de plasmablastes, de lymphocytes B commutés et mémoires pourraient révéler leur implication dans l'immunopathogenèse des symptômes. De plus, les niveaux élevés persistants d'IL6 et d'IL1β suggèrent que la réponse immunitaire innée a joué un rôle central.	N011?
27	Ch26	VP	Araújo, Naiana Mota; Ferreira, Lis Campos MD; Dantas, Débora Paraíso; Silva, Denison Santos MD dos Santos, Cliomar Alves; Cipolotti, Rosana, Martins-Filho, Paulo Ricardo	First Report of SARS-CoV-2 Detection in Cerebrospinal Fluid in a Child With Guillain-Barré Syndrome	https://doi.org/10.1097/INF.0000000000003146	Published	May 7, 2021	Case Report	https://journals.lww.com/pidj/Abstract/9000/First_Report_of_SARS_CoV_2_Detection_in.95815.aspx	Underlying mechanisms on the association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and neurological complications are still poorly understood. Cases of Guillain-Barré Syndrome (GBS) have been linked to the SARS-CoV-2 infection as the result of dysregulated immune response with damage in neuronal tissues. In the current report, we present the first pediatric case of GBS with detection of SARS-CoV-2 in the cerebrospinal fluid (CFS). This unique case of COVID-19-associated GBS with detection of SARS-CoV-2 RNA in the CSF indicates direct viral involvement inducing peripheral nerve inflammation.	_
28	Ch27		Erika Molteni, Carole H. Sudre, Liane S. Canas, Sunil S. Bhopal, Robert C. Hughes, Michela Antonelli, Benjamin Murray, Kerstin Kläser, Eric Kerfoot, Liyuan Chen, Jie Deng, Christina Hu, Somesh Selvachandran, Kenneth Read, Joan Capdevila Pujol, Alexander Hammers, Tim D. Spector, Sebastien Ourselin, Claire J. Steves, Marc Modat, Michael Absoud, Emma L. Duncan	Illness duration and symptom profile in a large cohort of symptomatic UK school-aged children tested for SARS-CoV-2	https://doi.org/10.1101/2021.05.05.21256649	pre-print	May 13, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.05.05.21256649v2	Methods Data from 258,790 children aged 5-17 years were reported by an adult proxy between 24 March 2020 and 22 February 2021. Illness duration and symptom profiles were analysed for all children testing positive for SARS-CoV-2 for whom illness duration could be determined, considered overall and within younger (5-11 years) and older (12-17 years) groups. Data from symptomatic children testing negative for SARS-CoV-2, matched 1:1 for age, gender, and week of testing, were also assessed. Findings 1,734 children (588 younger, 1,146 older children) had a positive SARS-CoV-2 test result and calculable illness duration within the study time frame. The commonest symptoms were headache (62.2%) and fatigue (55.0%). Median illness duration was six days (vs. three days in children testing negative), and was positively associated with age (rs 0.19, p<1.e-4) with median duration of seven days in older vs. five days in younger children. Seventy-seven (4.4%) children had illness duration ≥28 days (LC28), more commonly experienced by older vs. younger children (59 (5.1%) vs. 18 (3.1%), p=0.046). The commonest symptoms experienced by these children were fatigue (84%), headache (80%) and anosmia (80%); however, by day 28 the symptom burden was low (median, two). Only 25 (1.8%) of 1,379 children experienced symptoms for ≥56 days. Few children (15 children, 0.9%) in the negatively-tested cohort experienced prolonged symptom duration; however, these children experienced greater symptom burden (both throughout their illness and at day 28) than children positive for SARS-CoV-2. Interpretation Some children with COVID-19 experience prolonged illness duration. Reassuringly, symptom burden in these children did not increase with time, and most recovered by day 56. Some children who tested negative for SARS-CoV-2 also had persistent and burdensome illness. A holistic approach for all children with persistent illness during the pandemic is appropriate.	Une étude britannique en preprint (ni relue ni publiée) a suivi 1734 enfants (588 de 5-11 ans et 1146 de 12-17 ans) testés positifs à la covid. 77 enfants (4,4 %) ont eu des symptômes dépassant 28 j, et 25 (1,8 %) parmi 1379 enfants ont présenté des symptômes pendant plus de 55 jours. Les symptômes les plus courants étaient la fatigue (84 %), les maux de tête (80 %) et l'anosmie (80 %). La durée médiane des symptômes était de 6 jours.	N011
29	Ch28	MIS-C - VP	Lael M. Yonker,1 Tal Gilboa,2 Alana F. Ogata,2 Yasmeen Senussi,2 Roey Lazarovits,2 Brittany P. Boribong,1 Yannic C. Bartsch,3 Maggie Loiselle,1 Magali Noval Rivas, Moshe Arditi,4 Galit Alter,10 David R. Walt,11 and Alessio Fasano	Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier	https://doi.org/10.1172/JCI149633	Published	May 25, 2021	Study	https://www.jci.org/articles/view/149633	Methods: Here, we analyzed biospecimens from 100 children: 19 children with MIS-C, 26 with acute COVID-19, and 55 controls. Stool was assessed for SARS-CoV-2 by RT-PCR and plasma was assessed for markers of breakdown of mucosal barrier integrity, including zonulin. Ultrasensitive antigen detection was used to probe for SARS-CoV-2 antigenemia in plasma, and immune responses were characterized. As proof of concept, we treated a MIS-C patient with larazotide, a zonulin antagonist, and monitored impact on antigenemia and clinical response. Results: We showed that in MIS-C, prolonged presence of SARS-CoV-2 in the GI tract leads to release of zonulin, a biomarker of intestinal permeability, with subsequent trafficking of SARSCoV-2 antigens into the bloodstream, leading to hyperinflammation. The MIS-C patient treated with larazotide displayed a coinciding decrease in plasma SARS-CoV-2 Spike antigen levels, inflammatory markers, and a resultant clinical improvement above that achieved with currently available treatments. Conclusion: These mechanistic data of MIS-C pathogenesis provide insight into targets for diagnosing, treating, and preventing MIS-C, which are urgently needed for this increasingly common severe COVID-19-related disease in children.	Selon une étude, le syndrome inflammatoire multisystémique chez les enfants (PIMS-Covid) est provoqué par une libération de zonuline (un biomarqueur de la perméabilité intestinale), affectant la barrière muqueuse colique, et conduisant à une hyperinflammation. Le traitement au larazotide permettrait selon l'étude d'obtenir une diminution des taux plasmatiques d'antigènes du virus et une amélioration clinique supérieure aux traitements standards.	N011
30	Ch29	LC	Daniel Munblit 1,2, Frances Simpson 3, Jeremy Mabbitt 4, Audrey Dunn-Galvin 2,5, Calum Semple, John O Warner	Legacy of COVID-19 infection in children: long-COVID will have a lifelong health/economic impact	http://dx.doi.org/10.1136/archdischild-2021-321882	Published	May 27, 2021	Opinion	https://adc.bmj.com/content/early/2021/05/27/archdischild-2021-321882.full	There is an urgent need to study the impacts of the pandemic on all children as well as those who have had acute infection followed by long-COVID. Such research will help to elaborate on clinical features, mechanisms and strategies to mitigate adverse outcomes. The direct effects must be distinguished from those induced by lockdowns, school closures, parental loss of income, quarantine and other illnesses. This will provide the evidence to influence government action and design of appropriate service provision to protect children and young people from the potentially lifelong adverse effects of the pandemic. Thankfully, a large UK investigation of 3000 infected and 3000 uninfected children has now been funded, ‘The CLoCk Study’. The next step will be trials of interventions to mitigate the potentially lifelong adverse effects of this devastating pandemic.	Un article d'opinion dans le BMJ invite à mener des recherches sur les séquelles neuropsychiatriques de la covid chez l'enfant. Il se félicite que "The CLoCk Study", une grande enquête britannique portant sur 3000 enfants infectés et 3000 enfants non infectés, soit désormais financée.	N011
31	Ch30	LC	L. Siracusa, A. Cascio, S. Giordano, A. A. Medaglia, G. A. Restivo, I. Pirrone, G. F. Saia, F. Collura & C. Colomba	Neurological complications in pediatric patients with SARS-CoV-2 infection: a systematic review of the literature	https://doi.org/10.1186/s13052-021-01066-9	Published	02 June 2021	Review	https://link.springer.com/article/10.1186/s13052-021-01066-9	Forty-four articles reporting 59 cases of neurological manifestations in pediatric patients were included in our review. Most (32/59) cases occurred in the course of a multisystem inflammatory syndrome in children (MIS-C). Neurological disorders secondary to cerebrovascular involvement were reported in 10 cases: 4 children with an ischemic stroke, 3 with intracerebral hemorrhage, 1 with a cerebral sinus venous thrombosis, 1 with a subarachnoid hemorrhage, 1 with multiple diffuse microhemorrhages. Reversible splenial lesions were recognized in 9 cases, benign intracranial hypertension in 4 patients, meningoencephalitis in 4 cases, autoimmune encephalitis in 1 girl, cranial nerves impairment in 2 patients and transverse myelitis in 1 case. Five cases had Guillain-Barré syndrome (GBS) and two, including ours, had ADEM. Radiological investigations were performed in almost all cases (45/60): the most recurrent radiological finding was a signal change in the splenium of the corpus callosum. The presence of SARS-CoV-2 viral nucleic acid in the cerebrospinal fluid was proved only in 2 cases. The outcome was favorable in almost all, except in 5 cases.	Un article italien présente une revue d'études des manifestations neurologiques liées à la covid chez l'enfant. 59 cas sont ici répertoriés, 32 d'entre eux étant consécutifs à un PIMS-Covid (syndrome inflammatoire multisystémique).	N011
32	Ch31	LC	Carmelina Calitri1, Francesca Fantone1, Stefania Benetti1, Maria Maddalena Lupica1,Maria Giovanna Ignaccolo1, Elena Banino1, Alice Viano1, Mariella Pace1, Annalisa Castella2,Flavio Gaido3, Franco Garofalo1, and the ASLTO3 Study Group on Paediatric COVID-19	Long-term clinical and serological follow-up of paediatric patients infected by SARS-CoV-2		Published	June 2021	Case Report	https://www.infezmed.it/media/journal/Vol_29_2_2021_6.pdf	We aimed to describe the course of the Coronavirus Disease 2019 (COVID-19) in a population of children enrolled by place of residence, from diagnosis to recovery, with a long-term clinical and serological follow-up. We identified patients aged <14 years old living in the Turin Health District 3 who had SARS-CoV-2 detected in at least one nasopharyngeal swab from 1st March to 1st June 2020. Epidemiological and clinical features of SARSCoV-2 infection were collected by way of a telephone inquiry. Enrolled patients were tested for SARS-CoV-2 serology in order to provide evidence of seroconversion and persistence of specific antibodies some time after the infection. A total of 46 patients with SARSSUMMARY CoV-2 infection/COVID-19 were identified. The main pattern of viral transmission was intra-family. Eleven children were totally asymptomatic. If symptoms appeared, the disease had a mild course. A single case of COVID-19-related respiratory insufficiency was registered. Among children who underwent serological evaluation, 84% had seroconversion. No significant differences in antibody development were found according to the age and the burden of the disease. Children tested farther from the primary infection had lower antibody index titer values than the others. In conclusion, COVID-19 has a good prognosis in paediatric age. Children are able to develop a valid immune response, although their index titers seem to decrease a long time after the disease.	_
33	Ch32	MIS-C	Fatih Haslak, Kenan Barut, Cansu Durak, Ayten Aliyeva, Mehmet Yildiz, Vafa Guliyeva, Sevki Erdem Varol, Sinem Oral Cebeci, Fatih Aygun, Yusuf Ziya Varli, Abdulrahman Ozel, Sertac Hanedan Onan, Ulkem Kocoglu, Meltem Erol, Fatih Karagozlu, Nujin Ulug, Reyhan Dedeoglu, Sezgin Sahin, Amra Adrovic, Funda Oztunc & Ozgur Kasapcopur	Clinical features and outcomes of 76 patients with COVID-19-related multi-system inflammatory syndrome in children	https://doi.org/10.1007/s10067-021-05780-x	Published	05 June 2021	Study	https://link.springer.com/article/10.1007/s10067-021-05780-x	Overall, 76 subjects (24 females) with a mean age of 8.17 ± 4.42 years were enrolled. Twenty-seven (35.5%) patients were admitted to the PICUs. The two most common systemic involvement patterns were cardiac and gastrointestinal. There was only one lethal outcome in a patient with underlying acute lymphoblastic leukemia. Those with higher procalcitonin levels at admission were found to stay longer in the hospital (r = 0.254, p = 0.027). The risk of PICU admission increased with age (aOR: 1.277; 95% CI: 1.089–1.498; p = 0.003) and with decreased initial serum albumin levels (aOR: 0.105; 95% CI: 0.029–0.378; p = 0.001). Conclusion Although there is a wide clinical variability among the patients with MIS-C, we suggest that those with older age and lower initial serum albumin levels merit close monitoring due to their higher risk for PICU admission.	_
34	Ch33		Caroline L. H. Brackel MD, Coen R. Lap BSc, Emilie P. Buddingh MD, PhD, Marlies A. van Houten MD, PhD, PhD, Simone Hashimoto MD, PhD, Suzanne W. J. Terheggen-Lagro MD, PhD	Pediatric long-COVID: An overlooked phenomenon?	https://doi.org/10.1002/ppul.25521	Published	08 June 2021		https://onlinelibrary.wiley.com/doi/10.1002/ppul.25521	With a response rate of 78% of Dutch pediatric departments, we identified 89 children, aged 2–18 years, suspected of long-COVID with various complaints. Of these children, 36% experienced severe limitations in daily function. The most common complaints were fatigue, dyspnea, and concentration difficulties with 87%, 55%, and 45% respectively. Our case series emphasizes the nonspecific and broad clinical manifestations seen in post-COVID complaints.	Une étude danoise a répertorié au niveau national 89 cas de mineurs présentant une suspicion de covid long. Parmi ceux-ci, 36% ont présenté de graves limitations dans leurs fonctions quotidiennes.	N011
35	Ch34	MIS-C	Jackeline J Rodriguez-Smith, MD Emely L Verweyen, PhD Gwendolyn M Clay, PhD Ysabella M Esteban, MD Sarah R de Loizaga, MD Elizabeth Joy Baker Thuy Do, BS Sanjeev Dhakal, MS Sean M Lang, MD Prof Alexei A Grom, MD David Grier, MD Grant S Schulert	Inflammatory biomarkers in COVID-19-associated multisystem inflammatory syndrome in children, Kawasaki disease, and macrophage activation syndrome: a cohort study	https://doi.org/10.1016/S2665-9913(21)00139-9	Published	June 08, 2021	Study	https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(21)00139-9/fulltext	Between April 30, 2019, and Dec 14, 2020, we enrolled 19 patients with MIS-C (median age 9·0 years [IQR 4·5–15·0]; eight [42%] girls and 11 [58%] boys) and nine patients with Kawasaki disease (median age 2·0 years [2·0–4·0]); seven [78%] girls and two [22%] boys). Patients with MIS-C and Kawasaki disease had similar S100 proteins and IL-18 concentrations but patients with MIS-C were distinguished by significantly higher median concentrations of the IFNγ-induced CXCL9 (1730 pg/mL [IQR 604–6300] vs 278 pg/mL [54–477]; p=0·038). Stratifying patients with MIS-C by CXCL9 concentrations (high vs low) revealed differential severity of clinical and laboratory presentation. Compared with patients with MIS-C and low CXCL9 concentrations, more patients with high CXCL9 concentrations had acute kidney injury (six [60%] of ten vs none [0%] of five), altered mental status (four [40%] of ten vs none [0%] of five), shock (nine [90%] of ten vs two [40%] of five), and myocardial dysfunction (five [50%] of ten vs one [20%] of five); these patients also had higher concentrations of systemic inflammatory markers and increased severity of cytopenia and coagulopathy. By contrast, patients with MIS-C and low CXCL9 concentrations resembled patients with Kawasaki disease, including the frequency of coronary involvement. Elevated concentrations of S100A8/A9, S100A12, and IL-18 were also useful in distinguishing systemic JIA from Kawasaki disease with high sensitivity and specificity. Interpretation Our findings show MIS-C is distinguishable from Kawasaki disease primarily by elevated CXCL9 concentrations. The stratification of patients with MIS-C by high or low CXCL9 concentrations provides support for MAS-like pathophysiology in patients with severe MIS-C, suggesting new approaches for diagnosis and management.	_
36	Ch35	MIS-C	Margaret W. Bultas, PhD, RN, CNE, CNL, CPNP-PC, Kelli Fuller	Multisystem Inflammatory Syndrome in Children and COVID-19 Infections	https://doi.org/10.1177%2F1942602X211021136	Published	June 8, 2021	Review	https://journals.sagepub.com/doi/full/10.1177/1942602X211021136	Information regarding the long-term implications of COVID-19 infections in children, as well as MIS-C, is scarce and is emerging on an almost daily basis. The purpose of this article is to provide an overview of the recent literature regarding COVID-19 and MIS-C, a Kawasaki-like inflammatory syndrome that developed in children around the same time the COVID-19 pandemic began. Because the school nurse monitors children across a variety of developmental domains, they are in a unique position to identify changes and notice long-term trends related to the health and development of children who contract both COVID-19 and MIS-C.
37	Ch36	MIS-C	MichaelGottliebMDaRachelBridwellMDbJosephRaveraMDcBritLongMDb	Multisystem inflammatory syndrome in children with COVID-19	https://doi.org/10.1016/j.ajem.2021.05.076	Published	June 2021	Review	https://www.sciencedirect.com/science/article/pii/S0735675721004605	MIS-C is an inflammatory syndrome which can affect nearly any organ system. The most common symptoms are fever and gastrointestinal symptoms, though neurologic and dermatologic findings are also well-described. The diagnosis includes a combination of clinical and laboratory testing. Patients with MIS-C will often have elevated inflammatory markers and may have an abnormal electrocardiogram or echocardiogram. Initial treatment involves resuscitation with careful assessment for cardiac versus vasodilatory shock using point-of-care ultrasound. Treatment should include intravenous immunoglobulin, anticoagulation, and consideration of corticosteroids. Interleukin-1 and/or interleukin-6 blockade may be considered for refractory cases. Aspirin is recommended if there is thrombocytosis or Kawasaki disease-like features on echocardiogram. Patients will generally require admission to an intensive care unit.	Revue d'études sur la physiopathologie, le diagnostic et le traitement du PIMS-Covid (syndrome inflammatoire multisystémique chez les enfants, déclenché par la covid).	N011
38	Ch37		Prof Eduardo A Oliveira, PhD Enrico A Colosimo, PhD Ana Cristina Simões e Silva, PhD Robert H Mak, PhD Daniella B Martelli, PhD Ludmila R Silva, MSc Hercílio Martelli-Júnior, PhD Maria Christina L Oliveira	Clinical characteristics and risk factors for death among hospitalised children and adolescents with COVID-19 in Brazil: an analysis of a nationwide database	https://doi.org/10.1016/S2352-4642(21)00134-6	Published	June 10, 2021	Study	https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00134-6/fulltext	Of the 82 055 patients younger than 20 years reported to SIVEP-Gripe during the study period, 11 613 (14·2%) had available data showing laboratory-confirmed SARS-CoV-2 infection and were included in the sample. Among these patients, 886 (7·6%) died in hospital (at a median 6 days [IQR 3–15] after hospital admission), 10 041 (86·5%) patients were discharged from the hospital, 369 (3·2%) were in hospital at the time of analysis, and 317 (2·7%) were missing information on outcome. The estimated probability of death was 4·8% during the first 10 days after hospital admission, 6·7% during the first 20 days, and 8·1% at the end of follow-up. Probability of discharge was 54·1% during the first 10 days, 78·4% during the first 20 days, and 92·0% at the end of follow-up. Our competing risks multivariate survival analysis showed that risk of death was increased in infants younger than 2 years (hazard ratio 2·36 [95% CI 1·94–2·88]) or adolescents aged 12–19 years (2·23 [1·84–2·71]) relative to children aged 2–11 years; those of Indigenous ethnicity (3·36 [2·15–5·24]) relative to those of White ethnicity; those living in the Northeast region (2·06 [1·68–2·52]) or North region (1·55 [1·22–1·98]) relative to those in the Southeast region; and those with one (2·96 [2·52–3·47]), two (4·96 [3·80–6·48]), or three or more (7·28 [4·56–11·6]) pre-existing medical conditions relative to those with none.	_
39	Ch38		Joseph R. Hageman, MD	Long COVID-19 or Post-Acute Sequelae of SARS-CoV-2 Infection in Children, Adolescents, and Young Adults	https://doi.org/10.3928/19382359-20210519-02	Published	June 01, 2021	Editorial	https://journals.healio.com/doi/full/10.3928/19382359-20210519-02	Now we need to gather more clinical information about “long COVID-19” or post-acute sequelae of SARS-CoV-2 infection (PASC).	_
40	Ch39		Saba Ahmad, MD	Neurological Complications of COVID-19 in Children	https://doi.org/10.3928/19382359-20210517-01	Published	June 01, 2021	Article	https://journals.healio.com/doi/abs/10.3928/19382359-20210517-01	Neurological complications of coronavirus disease 2019 (COVID-19) are highly variable and can be quite severe, but they are rare in children. A careful understanding of the variety of presentations of neurological symptoms related to COVID-19 is critical for the effective management of these patients. Given the smaller numbers of children with these complications, a comprehensive review of neurological presentations in adults with COVID-19 may help facilitate the understanding of those complications that may present in children and how these presentations may be similar.	_
41	Ch40		Faith Miller, Vincent Nguyen, Annalan MD Navaratnam, Madhumita Shrotri, Jana Kovar, Andrew C Hayward, Ellen Fragaszy, Robert W Aldridge, Pia Hardelid	Prevalence of persistent symptoms in children during the COVID-19 pandemic: evidence from a household cohort study in England and Wales	https://doi.org/10.1101/2021.05.28.21257602	pre-print	June 02, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.05.28.21257602v1.full-text	Using data from 4678 children participating in VirusWatch, a household cohort study, we estimated the prevalence of persistent symptoms lasting ≥4 weeks as 1.7%, and 4.6% in children with a history of SARS-CoV-2 infection. Persistent symptom prevalence was higher in girls, teenagers and children with long-term conditions.
42	Ch41	Hirt	Ellinor Sterky,Selma Olsson-Åkefeldt,Olof Hertting,Eric Herlenius,Tobias Alfven,Malin Ryd Rinder,Samuel Rhedin,Helena Hildenwall	Persistent symptoms in Swedish children after hospitalisation due to COVID-19	https://doi.org/10.1111/apa.15999	Published	22 June 2021	BRIEF REPORT	https://onlinelibrary.wiley.com/doi/10.1111/apa.15999
43	Ch42		Defne Saatci, MD1; Tom A. Ranger, PhD1; Cesar Garriga, PhD1; Ash Kieran Clift, MD1,2; Francesco Zaccardi, PhD3; Pui San Tan, PhD1; Martina Patone, PhD1; Carol Coupland, PhD4; Anthony Harnden, MD1; Simon J. Griffin, MD5,6; Kamlesh Khunti, PhD3; Hajira Dambha-Miller, MD7; Julia Hippisley-Cox, MD1	Association Between Race and COVID-19 Outcomes Among 2.6 Million Children in England	https://doi.org/10.1001/jamapediatrics.2021.1685	Published	June 21, 2021	Study	https://jamanetwork.com/journals/jamapediatrics/fullarticle/2780966	Question Is race associated with COVID-19 testing and hospital outcomes in children in England? Findings In this cohort study of 2 576 353 children (0-18 years of age) in England with COVID-19 disease, children who were Black, Asian, or of mixed race had lower proportions of SARS-CoV-2 tests and had higher positive results and COVID-19 hospitalizations compared with White children. These results held after key demographic factors and selected comorbidities were accounted for. Meaning These findings suggest that race may play an important role in childhood COVID-19 outcomes, which reinforces the continued need for a race-tailored focus on health system performance and targeted public health interventions.
44	Ch43		Lindsay A. Thompson, MD, MS1,2; Maria N. Kelly, MD1	Return to Play After COVID-19 Infection in Children	http://jamanetwork.com/article.aspx?doi=10.1001/jamapediatrics.2021.1485	Published	June 28, 2021	Article	https://jamanetwork.com/journals/jamapediatrics/fullarticle/2781110	As the pandemic continues, children may experience long-term effects from COVID-19 infections. Because children may become “long haulers” or develop multisystem inflammatory syndrome in children (MIS-C), close monitoring after a COVID-19 diagnosis is important. In addition, children who are athletes require a separate return-to-play evaluation before they return to competitive sports or physical activities.
45	Ch44		Michelle Elena Schober, Courtney Leigh Robertson, Mark Stephen Wainwright, Juan David Roa & Ericka Linn Fink	COVID-19 and the Pediatric Nervous System: Global Collaboration to Meet a Global Need	https://doi.org/10.1007/s12028-021-01269-2	Published	28 June 2021	Viewpoint	https://link.springer.com/article/10.1007/s12028-021-01269-2	Emerging data suggest a cohort of patients with COVID-19 will have longitudinal illness affecting their cognitive, physical, and emotional health, but little is known about the long-term impact on affected children and their families. Pediatric collaboratives have begun to provide important initial information on neuroimaging manifestations and the incidence of ischemic stroke in children with COVID 19. The Global Consortium Study of Neurologic Dysfunction in COVID-19-Pediatrics, a multinational collaborative, is working to improve understanding of the epidemiology, mechanisms of neurological manifestations, and the long-term implications of COVID-19 in children and their families.
46	Ch45		Maria Rosaria Scala, Pietro Spennato, Domenico Cicala, Veronica Piccolo, Antonio Varone & Giuseppe Cinalli	Malignant cerebral infarction associated with COVID-19 in a child	https://doi.org/10.1007/s00381-021-05273-x	Published	26 June 2021	Case Report	https://link.springer.com/article/10.1007/s00381-021-05273-x	We present a case of a child with serological evidence of SARS-CoV-2 infection whose onset was a massive right cerebral artery ischemia that led to a malignant cerebral infarction. The patient underwent a life-saving decompressive hemicraniectomy, with good functional recovery, except for residual hemiplegia. During rehabilitation, the patient also developed a lower extremity peripheral nerve neuropathy, likely related to a long-Covid syndrome.	_
47	Ch46	MIS-C	Ravindra Pawar 1,* ,Vijay Gavade 2,Nivedita Patil 1,Vijay Mali 1,3 ,Amol Girwalkar 4,5,Vyankatesh Tarkasband 5,Sanjog Loya 2,Amit Chavan 2,Narendra Nanivadekar 6,Rahul Shinde 7,Uday Patil 2 andSatyan Lakshminrusimha 8	Neonatal Multisystem Inflammatory Syndrome (MIS-N) Associated with Prenatal Maternal SARS-CoV-2: A Case Series	https://doi.org/10.3390/children8070572	Published	2 July 2021	Study	https://www.mdpi.com/2227-9067/8/7/572/htm	We reviewed the perinatal history, clinical features, and outcomes of 20 neonates with features consistent with MIS-C related to maternal SARS-CoV-2 in Kolhapur, India, from 1 September 2020 to 30 April 2021. Anti-SARS-CoV-2 IgG and IgM antibodies were tested in all neonates. Fifteen singletons and five twins born to eighteen mothers with a history of COVID-19 disease or exposure during pregnancy presented with features consistent with MIS-C during the first 5 days after birth. Nineteen were positive for anti-SARS-CoV-2 IgG and all were negative for IgM antibodies. All mothers were asymptomatic and therefore not tested by RTPCR-SARS-CoV-2 at delivery. Eighteen neonates (90%) had cardiac involvement with prolonged QTc, 2:1 AV block, cardiogenic shock, or coronary dilatation. Other findings included respiratory failure (40%), fever (10%), feeding intolerance (30%), melena (10%), and renal failure (5%). All infants had elevated inflammatory biomarkers and received steroids and IVIG. Two infants died. We speculate that maternal SARS-CoV-2 and transplacental antibodies cause multisystem inflammatory syndrome in neonates (MIS-N). Immunomodulation may be beneficial in some cases, but further studies are needed.	_
48	Ch47	MIS-C	Öcal Demir, Sevliya; Tosun, Öykü; Öztürk, Kübra; Duyu, Muhterem; Bucak, Abdülmelik; Akkus, Gökhan; Bayraktar, Ali C; Demirel, Hande N; Arslanoglu, Sertaç; Ovali, Fahri.	SARS-CoV-2 associated multisystem inflammatory syndrome in children (MIS-C). A single center's experience		Published	2021 Apr 23	Study	https://pesquisa.bvsalud.org/global-literature-on-novel-coronavirus-2019-ncov/resource/pt/covidwho-1200473	The median age of 20 children with MIS-C was 80.5 months, 11 of them were male. The most common symptoms at admission were fever (100%), abdominal pain (70%), myalgia (50%), and rash (50%). Lymphopenia, elevated inflammatory markers and cardiac enzymes were their main laboratory findings. Cardiac involvement (90%) consisted of myopericarditis, valvulitis, left ventricular dysfunction, and coronary arteritis. Symptoms mimicking acute appendicitis and ileus were due to gastrointestinal involvement (50%). Macular rash on the trunk, erythema on upper eyelids were striking. Empiric antibiotics and intravenous immunoglobulin were used in all patients, glucocorticoids (90%), anti-thrombotic (65%) and vasoactive (45%) agents were used according to severity of disease. Response to IVIG treatment was poor, whereas glucocorticoids have dramatic affect. Seven patients (35%) were monitored in intensive care unit, none of them required intubation, mechanic ventilation or ECMO. The median recovery time, that is, the period when fever subside and inflammatory markers returned to normal was 9.5 days.	_
49	Ch48		Shoshana Leftin Dobkin,Joseph Collaco,Sharon McGrath-Morrow	Protracted Respiratory Findings in Children Post-COVID-19 Infection	https://doi.org/10.22541/au.162513383.35044135/v1	pre-print	July 01, 2021	Study	https://www.authorea.com/users/423023/articles/528597-protracted-respiratory-findings-in-children-post-covid-19-infection	The mean age at presentation to clinic was 13.1 years (range: 4-19 years). Patients had persistent respiratory symptoms ranging from 1.3 to 6.7 months post-acute infection. Persistent dyspnea and/or exertional dyspnea were present in nearly all (96.6%) of the patients at the time of clinic presentation. Other reported chronic symptoms included cough (51.7%) and exercise intolerance (48.3%). Fatigue was reported in 13.7% of subjects. Many subjects were overweight or obese (62.1%) and eleven subjects had a prior history of asthma. Lung function was normal in most patients. The six-minute walk test (6MWT) revealed exercise intolerance and significant tachycardia in two-thirds of children tested. Conclusion: Exertional dyspnea, cough and exercise intolerance were the most common respiratory symptoms in children with post-acute COVID-19 respiratory symptoms seen in an outpatient pulmonary clinic. Lung function, however, was mostly normal, and exertional intolerance was frequently demonstrated using the 6MWT.	_
50	Ch49	MIS-C	Goodwin, Peter M.	New Data on COVID-19 Related Pediatric Inflammatory Syndrome	https://doi.org/10.1097/01.COT.0000765076.71129.43	Published	July 5, 2021	Article	https://journals.lww.com/oncology-times/Fulltext/2021/07050/New_Data_on_COVID_19_Related_Pediatric.17.aspx?context=LatestArticles	“As PIMS-TS is a very rare complication of COVID-19 in children, our study included a small number of children from one hospital. Nevertheless, these findings can hopefully signal cautious optimism that many of the most severe effects of PIMS appear to resolve within 6 months. However, the persisting fatigue, difficulty exercising, and mental health effects we saw in some children, which can interfere with daily lives, must be closely monitored, and patients should continue to be supported by medical teams with a range of specialisms.”
51	Ch50		Georgia B.NikolopoulouaHelena C.Maltezoub	COVID-19 in children: where do we stand?	https://doi.org/10.1016/j.arcmed.2021.07.002	Published	6 July 2021	Review	https://www.sciencedirect.com/science/article/pii/S018844092100148X	Highlights •Children with SARS-CoV-2 infection are mostly asymptomatic or mildly symptomatic. •The true prevalence of SARS-CoV-2 infection in childhood is most likely underestimated, as asymptomatic children are less frequently tested. •School closures have a limited impact on SARS-CoV-2 transmission, much less than other social distancing measures. •Preliminary results from COVID-19 vaccine trials indicate very good efficacy and tolerability in children. •Vaccination of children 12 years or older is recommended to protect them but mostly to contribute to the achievement of herd immunity.
52	Ch51		Dyani Lewis	Long COVID and kids: scientists race to find answers	https://doi.org/10.1038/d41586-021-01935-7	Published	14 July 2021	Article	https://www.nature.com/articles/d41586-021-01935-7	As COVID-19 has ripped through communities, children have often been spared the worst of the disease’s impacts. But the spectre of long COVID developing in children is forcing researchers to reconsider the cost of the pandemic for younger people. The question is particularly relevant as the proportion of infections that are in young people rises in countries where many adults are now vaccinated — and as debates about the benefits of vaccinating children intensify. Most people who survive COVID-19 recover completely. But for some, the poorly understood condition that’s become known as long COVID can last for months — maybe even years. Nobody yet knows. The condition was first described in adults. But several studies have now reported a similar phenomenon, including symptoms such as headache, fatigue and heart palpitations, in children, even though they rarely experience severe initial symptoms of COVID-19.	Un article dans Nature passe en revue les questionnements des chercheurs sur la prévalence du covid long chez les enfants. Les données manquent encore pour savoir quel pourcentage garderont des séquelles au delà de 6 mois, et à quelle sévérité.
53	Ch52		David S. Younger	Post-acute sequelae of SARS-CoV-2 infection (PASC): peripheral, autonomic, and central nervous system features in a child	https://doi.org/10.1007/s10072-021-05345-5	Published	11 July 2021	Case Report	https://link.springer.com/article/10.1007/s10072-021-05345-5	This paper describes the detailed evaluation and treatment of an adolescent with PASC manifesting progressive post-infectious central, peripheral, and autonomic nervous system (CNS, PNS, and ANS).
54	Ch53		Afreen Khan, MD, Aparna Chakravarty, MD, Abhinav Jain, MD, Rekha Harish, MD, Rizwan Naqishbandi, Twisha Ishani	Clinical spectrum of neurological manifestations in pediatric Covid-19 illness: a case series	https://doi.org/10.1093/tropej/fmab059	Published	10 July 2021	Case Series	https://academic.oup.com/tropej/advance-article/doi/10.1093/tropej/fmab059/6319043	We describe a cohort of three patients with variable neurological presentations by SARS COV-2 infection. It includes one case each of Acute Cerebellitis, Acute encephalomyelitis and Arterial Ischemic Stroke. To the best of our knowledge we report the first pediatric case of acute cerebellitis due to SARS CoV-2 infection. All critically ill patients were treated with methylprednisolone pulse therapy and dexamethasone. Patient with acute cerebellitis in addition required Intravenous Immunoglobulin infusion. All the patients responded to the treatment with complete neurological recovery.
55	Ch54	Hirt	Daniela Say Nigel Crawford Sarah McNab Danielle Wurzel Andrew Steer Shidan Tosif	Post-acute COVID-19 outcomes in children with mild and asymptomatic disease	https://doi.org/10.1016/S2352-4642(21)00124-3	Published	April 20, 2021	CORRESPONDENCE	https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00124-3/fulltext	Follow-up data at 3–6 months were available for 151 (88%) of 171 children, of whom 54 (36%) were asymptomatic and 97 (64%) were symptomatic (ie, with mild, moderate, or severe disease) with acute COVID-19. 12 (8%) children had post-acute COVID-19 symptoms, all of whom were symptomatic with acute COVID-19 (table). The most common post-acute COVID-19 symptoms were mild post-viral cough (six [4%] of 151 children), fatigue (three [2%] children) or both post-viral cough and fatigue (one [1%] child). The duration of post-viral cough ranged from 3 weeks to 8 weeks and of post-viral fatigue ranged from 6 weeks to 8 weeks from the time of symptom onset. At the most recent review in March, 2021, all 151 children had returned to their baseline health status and post-acute COVID-19 symptoms had resolved. Follow-up data for 20 children were not available; seven (35%) of these children had asymptomatic COVID-19.
56	Ch55		Dusan Bogunovic 123456 Miriam Merad	Children and SARS-CoV-2	https://doi.org/10.1016/j.chom.2021.06.015	Published	14 July 2021	Article	https://www.sciencedirect.com/science/article/pii/S1931312821002973	Herein, we discuss known clinical and biological features of SARS-CoV-2 in children and reflect on currently identified immune features and discuss what remains unknown.
57	Ch56		Stephen T JRayMPhilabcdxOmarAbdel-MannanBMBChefMarioSaMDhCharlotteFullerMBChBcdiGreta KWoodMResabKarenPysdenMBChBiMichaelYoongPhDjHelenMcCullaghMBChBiDavidScottMSclMartinMcMahon Michael JGriffithsDPhilabxBenedict DMichaelPhDabaaRachelKneen	Neurological manifestations of SARS-CoV-2 infection in hospitalised children and adolescents in the UK: a prospective national cohort study	https://doi.org/10.1016/S2352-4642(21)00193-0	Published	15 July 2021	Study	https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00193-0/fulltext	Between April 2, 2020, and Feb 1, 2021, 52 cases were identified; in England, there were 51 cases among 1334 children and adolescents hospitalised with COVID-19, giving an estimated prevalence of 3·8 (95% CI 2·9–5·0) cases per 100 paediatric patients. 22 (42%) patients were female and 30 (58%) were male; the median age was 9 years (range 1–17). 36 (69%) patients were Black or Asian, 16 (31%) were White. 27 (52%) of 52 patients were classified into the COVID-19 neurology group and 25 (48%) were classified into the PIMS-TS neurology group. In the COVID-19 neurology group, diagnoses included status epilepticus (n=7), encephalitis (n=5), Guillain-Barré syndrome (n=5), acute demyelinating syndrome (n=3), chorea (n=2), psychosis (n=2), isolated encephalopathy (n=2), and transient ischaemic attack (n=1). The PIMS-TS neurology group more often had multiple features, which included encephalopathy (n=22 [88%]), peripheral nervous system involvement (n=10 [40%]), behavioural change (n=9 [36%]), and hallucinations at presentation (n=6 [24%]). Recognised neuroimmune disorders were more common in the COVID-19 neurology group than in the PIMS-TS neurology group (13 [48%] of 27 patients vs 1 [<1%] of 25 patients, p=0·0003). Compared with the COVID-19 neurology group, more patients in the PIMS-TS neurology group were admitted to intensive care (20 [80%] of 25 patients vs six [22%] of 27 patients, p=0·0001) and received immunomodulatory treatment (22 [88%] patients vs 12 [44%] patients, p=0·045). 17 (33%) patients (10 [37%] in the COVID-19 neurology group and 7 [28%] in the PIMS-TS neurology group) were discharged with disability; one (2%) died (who had stroke, in the PIMS-TS neurology group).	_
58	Ch57		Aurelie MORAND, Jacques-Yves CAMPION, Anne LEPINE, Emmanuelle BOSDURE, Léa LUCCIANI, Serge CAMMILLERI, Brigitte CHABROL, Eric Guedj	Similar patterns of 18F-FDG brain PET hypometabolism in paediatric and adult patients with long COVID: a paediatric case series	https://doi.org/10.1007/s00259-021-05528-4	Published	19 Aug, 2021	Case Series	https://link.springer.com/article/10.1007/s00259-021-05528-4	Paediatric patients demonstrated a similair brain hypometabolic pattern as that found in adult long COVID patients, involving bilateral medial temporal lobes, brainstem and cerebellum (p-voxel < 0.001, p-cluster < 0.05 FWE-corrected), and also the right olfactory gyrus after small volume correction (p-voxel = 0.010 FWE-corrected), with partial recovery in two children at follow-up. Conclusion. These results provide arguments in favour of possible long COVID in children, with a similar functional brain involvement to those found in adults.	Une équipe du CHU Timone constate des profils d'hypométabolisme cérébral, similaires à ceux observés chez l'adulte, sur les 7 enfants de la cohorte présentant des symptômes de covid long. Font apparaître notamment des hypométabolismes : l'amygdale cérébrale, le gyrus parahippocampique, le tronc cérébral, le cervelet, ainsi que les gyrus olfactifs.	N012
59	Ch58		BinhNgoab1Stacey A.Lappcd1BenjaminSiegelceVikashPatelcdLailaHussainicdSonaliBoraabBryanPhilbrookcehKristinWeinschenkabLauraWrightfEvan J.AndersoncdgChristina A.Rostadcd1Grace Y.Gombolayeh1	Cerebrospinal fluid cytokine, chemokine, and SARS-CoV-2 antibody profiles in children with neuropsychiatric symptoms associated with COVID-19	https://doi.org/10.1016/j.msard.2021.103169	Published	July 2021	Study	https://www.sciencedirect.com/science/article/pii/S2211034821004363	Highlights •CSF cytokines/chemokines are unknown in pediatric COVID-19. •We discuss neurological and psychiatric symptoms in five children with COVID-19. •CSF chemokines and SARS-CoV-2 antibodies are elevated. •SARS-CoV-2 antibodies strongly correlate with pro-inflammatory CSF cytokines. Results Three of five NP-COVID-19 patients had psychiatric symptoms, and two patients had encephalopathy and seizures. All patients had full or near resolution of neuropsychiatric symptoms by discharge. One patient received intravenous steroids for treatment for psychiatric symptoms; 3/5 other patients received immunotherapy for MIS-C, including IVIG, high-dose steroids, anakinra, and tocilizumab. Pro-inflammatory chemokines, including MIG, MPC, MIP-1β, and TARC were significantly elevated in NP-COVID-19 patients compared to controls. Two of five patients had elevated CSF neurofilament light chain. CSF SARS-CoV-2 antibody titers to the full-length spike, receptor binding domain and N-terminal domain were significantly elevated. SARS-CoV-2 antibody titers strongly correlated with pro-inflammatory chemokines/cytokines, including IL-1β, IL-2, IL-8, TNF-α, and IFN-γ (P≤0.05 for all). Conclusions A spectrum of neuropsychiatric clinical manifestations can occur in children with SARS-CoV-2 infection. CSF pro-inflammatory chemokines and SARS-CoV-2 antibodies may serve as biomarkers of SARS-CoV-2 mediated NP-COVID-19. Additional study is required to understand the pathophysiologic mechanisms of neuroinflammation in children with COVID-19 and MIS-C.
60	Ch59	CPET	Danilo Buonsenso, MD * Daniela Di Giuda, MD * Louise Sigfrid, MD Daniele Antonio Pizzuto, MD Gabriele Di Sante, PhD Cristina De Rose, MD Ilaria Lazzareschi, MD Michela Sali, PhD Fabiana Baldi, MD Daniela Pia Rosaria Chieffo, MD Prof Daniel Munblit, PhD † Piero Valentini	Evidence of lung perfusion defects and ongoing inflammation in an adolescent with post-acute sequelae of SARS-CoV-2 infection	https://doi.org/10.1016/S2352-4642(21)00196-6	Published	July 30, 2021	Case Report	https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00196-6/fulltext	In conclusion, in this report we present the first detailed evaluation of PASC in an adolescent, providing evidence of pulmonary circulation dysfunction with possible lung microvascular or endothelial damage as detected by CPET and chest SPECT/CT. Currently, most attention has been focused on long COVID in adults, with few studies including children, resulting in a lack of case definitions and management guidelines for this population. This report supports the emerging evidence on long COVID in children and highlights that, although children generally present with mild, acute COVID-19, they are at risk of prolonged organ damage, similar to what has been identified in adults. This report highlights the importance of doing a robust assessment of children presenting with PASC. SPECT/CT is useful to detect microvascular damage in patients with more severe and persisting symptoms. We urge clinicians and policy makers to not underestimate the risk of and consequences of long-term COVID-19 sequelae in children.	Dans un compte-rendu de cas publié dans The Lancet, une équipe a poussé les investigations sur une adolescente de 14 ans active, sans comorbidités, qui avait eu une phase bégnine de covid en octobre 2020 (37,3°C, rhinite, anosmie), mais qui développe le mois d'après des symptômes persistants : maux de tête, douleurs de poitrine, asthénie et tachycardie. Aucun examen biologique (électrocardiogramme, marqueurs de lésions cardiaques, coagulation, marqueurs inflammatoires, échocardiographie, spirométrie pulmonaire, scan pulmonaire sans contraste) ne présente alors d'anomalie. En mai 2021, les symptômes sont toujours présents et la patiente est admise à l'hôpital, à Rome. L'IRM cardiaque est normale, ainsi que les tests psychologiques, neurologiques, et un examen sanguin de routine. L'analyse plus poussée révèle cependant, malgré des taux élevés d'anticorps igG/IgA au SARS-CoV-2, des concentrations hautes d'IL-6 (633 pg/mL), IL-1 (8,55 pg/mL) et TNFα (32,7 pg/mL). Les titrages de lymphocytes T et B sont également inhabituels et suggèrent un fond pro-inflammatoire. Un test de capacité cardio-pulmonaire fait apparaître une réduction légère à modérée de la capacité fonctionnelle (le pic de VO2 était de 24,4 ml/kg/min, ce qui correspond à 68 % du VO2 max prédit), secondaire à une efficacité cardiovasculaire réduite, avec des signes indirects initiaux d'augmentation de la résistance vasculaire pulmonaire (pente VE/VCO2 de 36), et une pression partielle réduite du CO2 de fin d'expiration, suggérant une hypertension pulmonaire. Les tests confirment la présence d'une tachycardie sinusale (fréquence cardiaque maximale de 180 battements par minute), mais pas de modifications sur l'ECG ni signes de limitation ventilatoire (saturation en oxyhémoglobine au pic d'effort à 99%). Étudiant la littérature qui évoque chez l'adulte la possibilité de séquelles vasculaires pulmonaires de covid avec charge résiduelle de caillots sanguins, les auteurs de l'étude pratiquent une tomographie/tomoscintigraphie par émission monophotonique (TEMP) avec ventilation-perfusion (SPECT V/Q en anglais, Single photon emission computed tomography), examen standard pour les troubles thromboemboliques chroniques. Les chercheurs font précéder la TEMP par une scintigraphie pulmonaire planaire avec de l'albumine macroagrégée 99mTc. Alors que la scintigraphie planaire n'a pas montré de zones de diminution de la captation radiopharmaceutique dans les deux poumons, un défaut de perfusion significatif a été observé sur les images de la TEMP dans le segment apical du lobe supérieur droit, qui ne correspondait pas à des altérations parenchymateuses sur les coupes au scanner. Pour les auteurs de l'article, ces résultats pourraient suggérer une implication au niveau microvasculaire, très probablement associée à des dommages endothéliaux, comme le supposent d'autres études chez l'adulte. La TEMP détecte des signes précurseurs d'hypertension pulmonaire avec une surcharge minimale du ventricule droit, ce qui pourrait expliquer la tachycardie compensatrice ressentie lors de l'effort sous-maximal. Les chercheurs concluent à un dysfonctionnement de la circulation pulmonaire avec des dommages microvasculaires et endothéliaux périphériques possibles. De plus, les résultats de la tomodensitométrie et des tests de la fonction respiratoire ont exclu une altération associée à la ventilation. Il s'agit sans doute ici de la première preuve rapportée de dysfonctionnement et de dommages objectivés d'un organe chez un adolescent atteint de covid long (ou PASC). La patiente est depuis traitée avec des stéroïdes oraux (méthylprédnisolone 2g/kg une fois par jour pendant 2 semaines, puis diminution au cours des 4 semaines suivantes, avec un inhibiteur de la pompe à protons) et de l'héparine de bas poids moléculaire (énoxaparine 6000 unités deux fois par jour, avec un plan de passage aux anticoagulants oraux et la poursuite du traitement pendant 6 à 9 mois au total).	N012
61	Ch60		Bibhuti B. Das, MD; S. Kristen Sexon Tejtel, MD; Shriprasad Deshpande, MD; Lara S. Shekerdemian, MD, MHA	A Review of the Cardiac and Cardiovascular Effects of COVID-19 in Adults and Children	https://doi.org/10.14503/THIJ-20-7395	Published	August 02 2021	Review	https://meridian.allenpress.com/thij/article/48/3/e207395/468681/A-Review-of-the-Cardiac-and-Cardiovascular-Effects	Myocardial injury is an essential pathogenic feature of COVID-19, but its mechanisms are not clear. Elevated levels of cardiac biomarkers, chiefly cardiac Tn, indicate acute cardiac injury and are associated with poor outcomes. Continuous inflammation may cause new-onset heart failure and other CV complications, as in other types of viral myocarditis. Endomyocardial biopsy samples may help to differentiate primary viral myocarditis from secondary myocardial dysfunction; however, EMB samples may not confirm myocarditis, so uniform CMR criteria for the diagnosis of SARS-CoV-2 myocarditis are needed. Autopsy findings may eventually enable a better understanding of the pathophysiology of COVID-19 disease and its long-term effects on the heart, thus informing future management.
62	Ch61	Cf Ch27	Erika Molteni, PhD † Carole H Sudre, PhD † Liane S Canas, PhD Sunil S Bhopal, PhD Robert C Hughes, MPH Michela Antonelli, PhD Benjamin Murray, MSc Kerstin Kläser, MSc Eric Kerfoot, PhD Liyuan Chen, MSc Jie Deng, PhD Christina Hu, BA Somesh Selvachandran, MEng Kenneth Read, BSc Joan Capdevila Pujol, PhD Prof Alexander Hammers, PhD Prof Tim D Spector, PhD Prof Sebastien Ourselin, PhD Claire J Steves, PhD Marc Modat, PhD Michael Absoud, PhD Prof Emma L Duncan	Illness duration and symptom profile in symptomatic UK school-aged children tested for SARS-CoV-2	https://doi.org/10.1016/S2352-4642(21)00198-X	Published	August 03, 2021	Study	https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00198-X/fulltext	PUBLICATION of #Ch27 The most common symptoms were headache (1079 [62·2%] of 1734 children), and fatigue (954 [55·0%] of 1734 children). Median illness duration was 6 days (IQR 3–11) versus 3 days (2–7) in children testing negative, and was positively associated with age (Spearman's rank-order rs 0·19, p<0·0001). Median illness duration was longer for older children (7 days, IQR 3–12) than younger children (5 days, 2–9). 77 (4·4%) of 1734 children had illness duration of at least 28 days, more commonly in older than younger children (59 [5·1%] of 1146 older children vs 18 [3·1%] of 588 younger children; p=0·046). The commonest symptoms experienced by these children during the first 4 weeks of illness were fatigue (65 [84·4%] of 77), headache (60 [77·9%] of 77), and anosmia (60 [77·9%] of 77); however, after day 28 the symptom burden was low (median 2 symptoms, IQR 1–4) compared with the first week of illness (median 6 symptoms, 4–8). Only 25 (1·8%) of 1379 children experienced symptoms for at least 56 days. Few children (15 children, 0·9%) in the negatively tested cohort had symptoms for at least 28 days; however, these children experienced greater symptom burden throughout their illness (9 symptoms, IQR 7·7–11·0 vs 8, 6–9) and after day 28 (5 symptoms, IQR 1·5–6·5 vs 2, 1–4) than did children who tested positive for SARS-CoV-2.	Une étude britannique relève que les symptômes prolongés de la covid chez l'enfant (5-17 ans) sont d'autant moins fréquents que les enfants sont jeunes. 4,4% des enfants ont des symptômes au delà d'un mois dans la cohorte étudiée, 1 à 2% au delà de 2 mois.	N014E
63	Ch62		Daniel Munblit, MD, PhD1,2; Louise Sigfrid, MD, PhD3; John O. Warner	Setting Priorities to Address Research Gaps in Long-term COVID-19 Outcomes in Children	http://jamanetwork.com/article.aspx?doi=10.1001/jamapediatrics.2021.2281	Published	August 2, 2021	Viewpoint	https://jamanetwork.com/journals/jamapediatrics/fullarticle/2782612	Large, harmonized longitudinal studies assessing aspects of SARS-CoV-2 infection sequelae in children and adolescents are needed. Although few studies have focused on children,5,6 patient support groups have noted that many children experience long-term COVID-19 consequences. To generate high-quality evidence, studies with controls matched for the same social restrictions are urgently required. Robust case-control studies can facilitate identification of the cause of and risk factors for different long COVID syndromes in children, including well-defined characterization of symptoms, signs, psychological features, and protective factors in children in different settings. Estimation of the impact of long COVID vs the impact of wider pandemic restrictions may provide important information for policy makers to guide clinical and public health management.
64						From this point on, the survey of studies is no longer as exhaustive as possible. Only those studies which seem to us to bring significant new elements will be listed.
65	Ch63		Jacqui Wise	Long covid: One in seven children may still have symptoms 15 weeks after infection, data show	https://doi.org/10.1136/bmj.n2157	Published	01 September 2021	News	https://www.bmj.com/content/374/bmj.n2157	A large study of children and young people who caught SARS-CoV-2 has found that as many as one in seven (14%) may still have symptoms 15 weeks later.1 However, this figure is lower than in some studies that have reported a prevalence of long covid as high as 51% in children and young people.
66	Ch64	Hirt	Terence Stephenson, Terence Stephenson, Snehal Pinto Pereira, Roz Shafran, Bianca De Stavola, Natalia Rojas, Kelsey McOwat, Ruth Simmons, Maria Zavala, Lauren O’Mahoney, Trudie Chalder, Esther Crawley, Tamsin Ford, Anthony Harnden, Isobel Heyman, Olivia Swann, Liz Whittaker, CLoCk Consortium CLoCk Consortium, Shamez Ladhani	Long COVID - the physical and mental health of children and non-hospitalised young people 3 months after SARS-CoV-2 infection; a national matched cohort study (The CLoCk) Study.	https://doi.org/10.21203/rs.3.rs-798316/v1	pre-print	10 Aug, 2021	Study	https://www.researchsquare.com/article/rs-798316/v1	Introduction: We describe post-COVID symptomatology in a national sample of 11-17-year-old children and young people (CYP) with PCR-confirmed SARS-CoV-2 infection compared to test-negative controls. Methods and analysis: A cohort study of test-positive (n=3,065) and age-, sex- and geographically-matched test-negative CYP (n=3,739) completed detailed questionnaires 3 months post-test. Results: At PCR-testing, 35.4% of test-positives and 8.3% of test-negatives had any symptoms whilst 30.6% and 6.2%, respectively, had 3+ symptoms. At 3 months post-testing, 66.5% of test-positives and 53.3% of test-negatives had any symptoms, whilst 30.3% and 16.2%, respectively, had 3+ symptoms. Latent class analysis identified two classes, characterised by “few” or “multiple” symptoms. This latter class was more frequent among test-positives, females, older CYP and those with worse pre-test physical and mental health. Discussion: Test-positive CYP had a similar symptom profile to test-negative CYP but with higher prevalence of single and, particularly, multiple symptoms at PCR-testing and 3 months later.
67	Ch65		Liene Smane, Ieva Roge, Zanda Pucuka & Jana Pavare	Clinical features of pediatric post-acute COVID-19: a descriptive retrospective follow-up study	https://doi.org/10.1186/s13052-021-01127-z	Published	26 August 2021	Study	https://ijponline.biomedcentral.com/articles/10.1186/s13052-021-01127-z	To date, information on COVID-19 long-term post-recovery sequelae in children and adolescents remains scarce. A retrospective descriptive cohort study was performed by collecting data on 92 patients (age ≤ 18 years). All were evaluated during a face-to-face visit following a specially designed post-COVID-19 symptom assessment protocol at the following stage: 1–3 months after COVID-19 onset. Among the 92 children, 45 (49%) were completely free of any COVID-19-related symptoms, while 47 (51%) reported persistence of at least one symptom, in particular tiredness, loss of taste and/or smell and headaches. The most common post-acute COVID-19 clinical features were noted in children aged between 10 and 18 years. A detailed multidisciplinary follow-up of patients with COVID-19 seems relevant, whatever the severity of the symptoms.
68	Ch66		Miranda J. Delahoy, PhD1,2; Dawud Ujamaa, MS1,3; Michael Whitaker, MPH1; Alissa O’Halloran, MSPH1; Onika Anglin, MPH1,3; Erin Burns1; Charisse Cummings, MPH1; Rachel Holstein, MPH1; Anita K. Kambhampati, MPH1; Jennifer Milucky, MSPH1; Kadam Patel, MPH1,3; Huong Pham, MPH1; Christopher A. Taylor, PhD1; Aron J. Hall, DVM1; Alicia M. Fry, MD1; Meredith McMorrow, MD1; Carrie Reed, DSc1; Shikha Garg, MD1*; Fiona P. Havers	Hospitalizations Associated with COVID-19 Among Children and Adolescents — COVID-NET, 14 States, March 1, 2020–August 14, 2021	http://dx.doi.org/10.15585/mmwr.mm7036e2	Published	September 3, 2021	Study	https://www.cdc.gov/mmwr/volumes/70/wr/mm7036e2.htm	What is already known about this topic? COVID-19 can cause severe illness in children and adolescents. What is added by this report? Weekly COVID-19–associated hospitalization rates among children and adolescents rose nearly five-fold during late June–mid-August 2021, coinciding with increased circulation of the highly transmissible SARS-CoV-2 Delta variant. The proportions of hospitalized children and adolescents with severe disease were similar before and during the period of Delta predominance. Hospitalization rates were 10 times higher among unvaccinated than among fully vaccinated adolescents. What are the implications for public health practice? Preventive measures to reduce transmission and severe outcomes in children and adolescents are critical, including vaccination, universal masking in schools, and masking by persons aged ≥2 years in other indoor public spaces and child care centers.
69	Ch67	Hirt	Ali A. Asadi-Pooya, Hamid Nemati, Mina Shahisavandi, Ali Akbari, Amir Emami, Mehrzad Lotfi, Mahtab Rostamihosseinkhani, Zohreh Barzegar, Maryam Kabiri, Zahra Zeraatpisheh, Mohsen Farjoud-Kouhanjani, Anahita Jafari, Fateme Sasannia, Shayan Ashrafi, Masoume Nazeri & Sara Nasiri	Long COVID in children and adolescents	https://doi.org/10.1007/s12519-021-00457-6	Published	03 September 2021	Study	https://link.springer.com/article/10.1007/s12519-021-00457-6	All consecutive children and adolescents who were referred to the hospitals anywhere in Fars province, Iran, from 19 February 2020 until 20 November 2020 were included. All patients had a confirmed diagnosis of COVID-19. In a phone call to patients/parents, at least 3 months after their discharge from the hospital, we obtained their current status and information if their parents agreed to participate. Results In total, 58 children and adolescents fulfilled the inclusion criteria. Twenty-six (44·8%) children/adolescents reported symptoms/complaints of long COVID. These symptoms included fatigue in 12 (21%), shortness of breath in 7 (12%), exercise intolerance in 7 (12%), weakness in 6 (10%), and walking intolerance in 5 (9%) individuals. Older age, muscle pain on admission, and intensive care unit admission were significantly associated with long COVID.
70	Ch68		Giuseppe Fabio Parisi 1 ,Lucia Diaferio 2,Giulia Brindisi 3 ,Cristiana Indolfi 4,Giuseppina Rosaria Umano 4 ,Angela Klain 4,Giuseppe Marchese 5,Daniele Giovanni Ghiglioni 6,Anna Maria Zicari 3,Gian Luigi Marseglia 7 andMichele Miraglia del Giudice 4,	Cross-Sectional Survey on Long Term Sequelae of Pediatric COVID-19 among Italian Pediatricians	https://doi.org/10.3390/children8090769	Published	31 August 2021	Study	https://www.mdpi.com/2227-9067/8/9/769/htm	The survey was emailed once in March 2021 to a sample of Italian pediatricians. A total 267 Italian pediatricians participated in our survey. According to most pediatricians (97.3%), the persistence of symptoms is found in less than 20% of children. Specifically, with regard to the symptoms that persist even after swab negativization, fatigue was the most mentioned one (75.6%). Long-COVID would seem to be a phenomenon of limited occurrence in pediatric ages, affecting less than 20% of children. Among all of the symptoms, the one that was most prevalent was fatigue, a pathological entity that is associated with many viral diseases.
71	Ch69		Nurdan Erol Abdullah Alpinar Cigdem Erol, Erdal Sari and Kubra Alkan	Intriguing New Faces Of Covid-19: Persisting Clinical Symptoms And Cardiac Effects in Children	https://doi.org/10.1017/S1047951121003693	Published	19 August 2021	Study	https://www.cambridge.org/core/journals/cardiology-in-the-young/article/intriguing-new-faces-of-covid19-persisting-clinical-symptoms-and-cardiac-effects-in-children/662BF31CEF4C7D4549C2869B08FEAF5C#	In this study, 121 children between the ages of 0-18 with Covid-19 were evaluated based on their history, blood pressure values, and electrocardiography and echocardiography results. These findings were compared with the findings of the control group which consisted of 95 healthy cases who were in the same age range as the study group and did not have Covid-19. The results were evaluated using the statistics program, SPSS 21. Results: There was no significant difference between the study group and the control group in terms of age, weight, and body mass index. The clinical symptoms (chest and back pain, dizziness, headache, palpitation, fatigue, shortness of breath, loss of balance, coughing) of 37.2% of the cases persisted at least 1 month after Covid-19 recovery. Statistically significant differences were found in systolic blood pressure, left ventricular ejection fraction, relative wall thickness, and tricuspid annular plane systolic excursion.
72	Ch70		Nicola Principi & Susanna Esposito	Are we sure that the neurological impact of COVID 19 in childhood has not been underestimated?	https://doi.org/10.1186/s13052-021-01144-y	Published	18 September 2021		https://link.springer.com/article/10.1186/s13052-021-01144-y	Fortunately, in most of the cases, neurological manifestations, mainly represented by headache and anosmia, are mild and transient and do not significantly complicate the COVID-19 course. However, in some cases, very severe clinical problems associated with relevant alterations of neuroimaging, electroencephalography, nerve conduction studies and electromyography findings can develop. Generally, almost all the children with COVID-19 and neurological manifestations till now described have made a complete recovery, although in some cases this has occurred after several weeks of treatment. Moreover, COVID-19 infection during pregnancy has been found associated with an increased risk of obstetric complications that can lead to neurological acute and long-term manifestations in neonates. Conclusions Based on data showing the neurologic impact of COVID-19 in pediatric age, we suggest monitoring neurological development a few months after healing in pediatric patients who have presented MIS-C, seizures or other neurological manifestations and in children of pregnant women with COVID-19 in order to detect overt and subtle deficits.	_
73	Ch71		Zimmermann, Petra MD, PhD*,†,‡,§; Pittet, Laure F. MD-PhD‡,§,¶; Curtis, Nigel	How Common Is Long COVID in Children and Adolescents?	https://doi.org/10.1097/INF.0000000000003328	Published	September 16, 2021	Review	https://journals.lww.com/pidj/Abstract/9000/How_Common_Is_Long_COVID_in_Children_and.95677.aspx	In children, the risk of coronavirus disease (COVID) being severe is low. However, the risk of persistent symptoms following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is uncertain in this age group, and the features of “long COVID” are poorly characterized. We reviewed the 14 studies to date that have reported persistent symptoms following COVID in children and adolescents. Almost all the studies have major limitations, including the lack of a clear case definition, variable follow-up times, inclusion of children without confirmation of SARS-CoV-2 infection, reliance on self- or parent-reported symptoms without clinical assessment, nonresponse and other biases, and the absence of a control group. Of the 5 studies which included children and adolescents without SARS-CoV-2 infection as controls, 2 did not find persistent symptoms to be more prevalent in children and adolescents with evidence of SARS-CoV-2 infection. This highlights that long-term SARS-CoV-2 infection–associated symptoms are difficult to distinguish from pandemic-associated symptoms.	_
74	Ch72		NeslihanZENGİN1Yusuf ZiyaGÜVEN	Retinal Microvascular and Perfusional Disruption in Paediatric COVID-19: A Case-Control Optical Coherence Tomography Angiography Study	https://doi.org/10.1016/j.pdpdt.2021.102577	Published	11 October 2021	Study	https://www.sciencedirect.com/science/article/pii/S1572100021003835	Significant differences were observed between the two groups in terms of inner, outer, and full VD, as well as inner and full PD. No significant differences in centre VD and PD were observed between groups. Although it was not evident in analysis of choroidal values, inflammatory sites were thickened. FAZ area significantly differed between groups (p < 0.05). NB : vessel density (VD), perfusion density (PD), and foveal avascular zone (FAZ)	Une étude rapporte chez des enfants ayant été malades de la covid, puis rétablis, des dommages subcliniques au niveau de la vascularisation rétinienne. L'étude note que la zone avasculaire fovéale peut s'étendre pendant la phase aiguë de la maladie, sous l'effet de microthromboses et d'ischémies temporaires, par rapport à un cas contrôle. Les auteurs estiment que les patients pédiatriques de la covid devraient être suivis par un examen d'angiographie par tomographie par cohérence optique pour détecter d'éventuels changements rétiniens infracliniques, et que des études à long terme sont nécessaires pour valider ces observations.	N014E
75	Ch73		Mary G Hornick, PhD, Margaret E Olson, PhD, Arun L Jadhav, PhD	SARS-CoV-2 Psychiatric Sequelae: A Review of Neuroendocrine Mechanisms and Therapeutic Strategies	https://doi.org/10.1093/ijnp/pyab069	Published	14 October 2021	Study	https://academic.oup.com/ijnp/advance-article/doi/10.1093/ijnp/pyab069/6396958	We then examine the hypothesis that COVID-19-induced psychiatric disorders result from challenges to the neuroendocrine system, in particular the hypothalamic-pituitary-adrenal (HPA) stress axis and monoamine synthesis, physiological mechanisms that are only further enhanced by the pandemic-induced social environment of fear, isolation, and socioeconomic pressure. Finally, we evaluate several FDA-approved therapeutics in the context of COVID-19-induced psychoneuroendocrine disorders.
76	Ch74		Eleni Gavriilaki, Ioannis Eftychidis and Ioannis Papassotiriou	Update on endothelial dysfunction in COVID-19: severe disease, long COVID-19 and pediatric characteristics	https://doi.org/10.1515/labmed-2021-0134	Published	October 15, 2021	Review	https://www.degruyter.com/document/doi/10.1515/labmed-2021-0134/html	Objectives To review current literature on the role of endothelial dysfunction in coronavirus disease-2019 (COVID-19) infection in terms of pathophysiology, laboratory features and markers, clinical phenotype in adults and children, as well as long COVID-19.	_
77	Ch75		Nooralam Rai MD,Joseph A Cornett BS,Philip Zachariah MD MS MA,Lynne Quittell MD,Stephanie Lovinsky-Desir MD MS	Severe respiratory viral infections in children with history of asymptomatic or mild COVID-19	https://doi.org/10.1002/ppul.25752	Published	06 November 2021	Case series	https://onlinelibrary.wiley.com/doi/10.1002/ppul.25752	Participants Children with prior mild or asymptomatic COVID-19 and no known risk factors for severe respiratory disease, who were hospitalized at our center for acute respiratory illness from October 2020 to May 2021, were reviewed. Main outcomes and measures Co-morbidities, history of prior COVID-19 symptoms, respiratory viral panel findings, acuity of illness, degree of respiratory decompensation based on support and interventions required, duration of hospitalization, and overall clinical course were assessed from the medical record. Results This study included 5 patients (median age, 4 years; age range, 0.8-9 years; 4 [80%] male). All had positive COVID-19 serology, 1 (20%) had mild symptoms, while the others had no symptoms of prior Sars-CoV-2 infection. 3 (60%) had asthma, and the remaining had no co-morbidities. All were admitted between April and May 2021. Two were re-admitted for respiratory symptoms in the subsequent three months. Conclusions and Relevance This case series describes a possible association between severe lower respiratory tract infection and prior mild COVID-19 in children. Larger cohort studies describing the respiratory effects of prior COVID-19 in children are needed.
78	Ch76		Nooralam Rai MD,Joseph A Cornett BS,Philip Zachariah MD MS MA,Lynne Quittell MD,Stephanie Lovinsky-Desir MD MS	Severe respiratory viral infections in children with history of asymptomatic or mild COVID-19	https://doi.org/10.1002/ppul.25752	Published	06 November 2021	Case Reports	https://onlinelibrary.wiley.com/doi/abs/10.1002/ppul.25752	Results This study included 5 patients (median age, 4 years; age range, 0.8-9 years; 4 [80%] male). All had positive COVID-19 serology, 1 (20%) had mild symptoms, while the others had no symptoms of prior Sars-CoV-2 infection. 3 (60%) had asthma, and the remaining had no co-morbidities. All were admitted between April and May 2021. Two were re-admitted for respiratory symptoms in the subsequent three months. Conclusions and Relevance This case series describes a possible association between severe lower respiratory tract infection and prior mild COVID-19 in children. Larger cohort studies describing the respiratory effects of prior COVID-19 in children are needed.	_
79	Ch77		Ieva Roge1*†, Liene Smane2†, Anda Kivite-Urtane3†, Zanda Pucuka2, Iveta Racko1, Lizete Klavina1 and Jana Pavare2†	Comparison of Persistent Symptoms After COVID-19 and Other Non-SARS-CoV-2 Infections in Children	https://doi.org/10.3389/fped.2021.752385	Published	29 October 2021	Study	https://www.frontiersin.org/articles/10.3389/fped.2021.752385/full	Results: In total, 236 pediatric COVID-19 patients were enrolled in the study. Additionally, 142 comparison group patients were also enrolled. Median follow-up time from acute symptom onset was 73.5 days (IQR; 43–110 days) in the COVID-19 patient group and 69 days (IQR, 58–84 days) in the comparison group. Most pediatric COVID-19 survivors (70%, N = 152) reported at least one persistent symptom, but more than half of the patients (53%, N = 117) noted two or more long-lasting symptoms. The most commonly reported complaints among COVID-19 patients included persistent fatigue (25.2%), cognitive sequelae, such as irritability (24.3%), and mood changes (23.3%), as well as headaches (16.9%), rhinorrhea (16.1%), coughing (14.4%), and anosmia/dysgeusia (12.3%). In addition, 105 (44.5%) COVID patients had persistent symptoms after the 12-week cut-off point, with irritability (27.6%, N = 29), mood changes (26.7%, N = 28), and fatigue (19.2%, N = 20) being the most commonly reported ones. Differences in symptom spectrum among the various age groups were seen. Logistic regression analysis showed that long-term persistent symptoms as fever, fatigue, rhinorrhea, loss of taste and/or smell, headaches, cognitive sequelae, and nocturnal sweating were significantly associated with the COVID-19 experience when compared with the controls. Conclusions: We found that at the time of interview almost three-quarters of children reported at least one persistent symptom, but the majority of patients (53%) had two or more concurrent symptoms. The comparison group's inclusion in the study allowed us to identify that symptom persistence is more apparent with COVID-19 than any other non-SARS-CoV-2 infection. More research is needed to distinguish the symptoms of long COVID from pandemic-associated complaints. Each persistent symptom is important in terms of child well-being during COVID-19 recovery.
80	Ch78		Amit Nahum amitna@clalit.org.il and Keren Rochwerger-Biham	Unique presentations of the post COVID-19 infection, multisystem inflammatory syndrome in children.	https://doi.org/10.14785/lymphosign-2021-0027	Published	10 November 2021	Case Reports	https://lymphosign.com/doi/abs/10.14785/lymphosign-2021-0027	We present two patients with unusual manifestations of MIS-C, related to post COVID-19 infection, an infant born to a mother who was severely ill at the very end of pregnancy, presenting with prolonged fever, rash, pericardial effusion, and evidence of coronary arteries wall thickening as a result of inflammation, and, a teenage girl with severe cardiac tamponade without the more common cardiac manifestations of myocardial involvement.Discussion: Post COVID-19 MIS-C can present in a wide variety of manifestations.	_
81	Ch79		Thais T. Fink, Heloisa H.S. Marques, Bruno Gualano, Livia Lindoso, Vera Bain, Camilla Astley, Carlos A. Buchpiguel, Ana Claudia L. Xavier, Marilia Seelaender, Clovis Artur Silva,#* Maria Fernanda B. Pereira	Persistent symptoms and decreased health-related quality of life after symptomatic pediatric COVID-19: A prospective study in a Latin American tertiary hospital	https://dx.doi.org/10.6061%2Fclinics%2F2021%2Fe3511	Published	2021 Nov 17	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8595593/	The median duration between COVID-19 diagnosis (n=53) and follow-up was 4.4 months (0.8-10.7). Twenty-three of 53 (43%) patients reported at least one persistent symptom at the longitudinal follow-up visit and 12/53 (23%) had long COVID-19, with at least one symptom lasting for >12 weeks. The most frequently reported symptoms at the longitudinal follow-up visit were headache (19%), severe recurrent headache (9%), tiredness (9%), dyspnea (8%), and concentration difficulty (4%). At the longitudinal follow-up visit, the frequencies of anemia (11% versus 0%, p=0.030), lymphopenia (42% versus 18%, p=0.020), C-reactive protein level of >30 mg/L (35% versus 0%, p=0.0001), and D-dimer level of >1000 ng/mL (43% versus 6%, p=0.0004) significantly reduced compared with baseline values. Chest X-ray abnormalities (11% versus 2%, p=0.178) and cardiac alterations on echocardiogram (33% versus 22%, p=0.462) were similar at both visits. Comparison of characteristic data between patients with COVID-19 at the longitudinal follow-up visit and controls showed similar age (p=0.962), proportion of male sex (p=0.907), ethnicity (p=0.566), family minimum monthly wage (p=0.664), body mass index (p=0.601), and pediatric pre-existing chronic conditions (p=1.000). The Pediatric Quality of Live Inventory 4.0 scores, median physical score (69 [0-100] versus 81 [34-100], p=0.012), and school score (60 [15-100] versus 70 [15-95], p=0.028) were significantly lower in pediatric patients with COVID-19 at the longitudinal follow-up visit than in controls. CONCLUSIONS: Pediatric patients with COVID-19 showed a longitudinal impact on HRQoL parameters, particularly in physical/school domains, reinforcing the need for a prospective multidisciplinary approach for these patients. These data highlight the importance of closer monitoring of children and adolescents by the clinical team after COVID-19.
82	Ch80		Arostegui, Dalia MD; Castro, Kenny MD; Schwarz, Steven MD; Vaidy, Katherine MD; Rabinowitz, Simon MD; Wallach, Thomas MD	Persistent SARS-CoV-2 Nucleocapsid Protein Presence in the Intestinal Epithelium of a Pediatric Patient 3 Months After Acute Infection	https://doi.org/10.1097/PG9.0000000000000152	Published	November 1, 2021	Case Report	https://journals.lww.com/jpgnr/Fulltext/2022/02000/Persistent_SARS_CoV_2_Nucleocapsid_Protein.9.aspx	In addition to the severe impact of acute respiratory disease during the SARS-CoV-2 pandemic, the issue of “Long COVID” illness has impacted large numbers of patients following the initial infection. Wide ranges of Long Covid incidence have been reported, ranging from 30 to 87%. Long COVID has a variety of clinical manifestations, including gastrointestinal symptoms. Here, we report a case of persistent abdominal pain, 3 months following a SARS-CoV-2 diagnosis, associated with chronic colonic inflammation and the presence of mucosal SARS-CoV-2 virions.	_
83	Ch81		S A Behnood 1, R Shafran 2, S D Bennett 2, Axd Zhang 2, L L O'Mahoney 3, T J Stephenson 2, S N Ladhani 4, B L DeStavola 2, R M Viner 2, O V Swann 5	Persistent symptoms following SARS-CoV-2 infection among children and young people: a meta-analysis of controlled and uncontrolled studies	https://doi.org/10.1016/j.jinf.2021.11.011	Published	2021 Nov 20	Meta Analysis	https://pubmed.ncbi.nlm.nih.gov/34813820/	Twenty two of 3357 unique studies were eligible, including 23,141 CYP. Median duration of follow-up was 125 days (IQR 99-231). Pooled risk difference in post-COVID cases compared to controls (5 studies) were significantly higher for cognitive difficulties (3% (95% CI 1, 4)), headache (5% (1, 8)), loss of smell (8%, (2, 15)), sore throat (2% (1, 2)) and sore eyes (2% (1, 3)) but not abdominal pain, cough, fatigue, myalgia, insomnia, diarrhoea, fever, dizziness or dyspnoea. Pooled prevalence of symptoms in post-COVID participants in 17 studies ranged from 15% (diarrhoea) to 47% (fatigue). Age was associated with higher prevalence of all symptoms except cough. Higher study quality was associated with lower prevalence of all symptoms, except loss of smell and cognitive symptoms. Interpretation: The frequency of the majority of reported persistent symptoms was similar in SARS-CoV-2 positive cases and controls. This systematic review and meta-analysis highlights the critical importance of a control group in studi7777es on CYP post SARS-CoV-2 infection.
84	Ch82		Ashkenazi-Hoffnung, Liat MD,†; Shmueli, Einat MD,†; Ehrlich, Shay MD,†; Ziv, Adi MD,†; Bar-On, Ophir MD,†; Birk, Einat MD,†; Lowenthal, Alexander MD,†; Prais, Dario MD,†	Long COVID in Children Observations From a Designated Pediatric Clinic	https://doi.org/10.1097/INF.0000000000003285	Published	December 2021	Study	https://journals.lww.com/pidj/Fulltext/2021/12000/Long_COVID_in_Children__Observations_From_a.32.aspx	In nearly 60%, symptoms were associated with functional impairment at 1–7 months after the onset of infection. A comprehensive structured evaluation revealed mild abnormal findings in approximately half the patients, mainly in the respiratory aspect	_
85	Ch83		Sammie Mcfarland, Sara Citrenbaum, Ondine Sherwood, Vicky van der Togt, Jeremy S Rossman	Long COVID in children	https://doi.org/10.1016/S2352-4642(21)00338-2	Published	January 01, 2022	CORRESPONDENCE	https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00338-2/fulltext	According to the Methods section, the study appears to only assess children with a defined illness duration (onset and recovery). Recovery was defined as a return to asymptomatic condition or the cessation of symptom logging. As such, this would exclude all children with on-going disease and classify children that stop recording as recovered, even if they might still be experiencing symptoms. The authors tested their assumption that cessation of recording indicated recovery by removing those patients from their calculation and found no significant difference in long COVID prevalence or average symptom duration. However, if patients that ceased recording continued to experience symptoms, these longer duration symptoms would not be identified by the study and their effect would not be accounted for in the existing assumption test. Additionally, the study excludes any children that either had a gap in recording or reported being asymptomatic for more than 1 week before symptoms returned. Patients with long COVID experience a wide range of changing symptoms, including asymptomatic periods. Many long COVID symptoms were added to the Zoe app in November, 2020, but were not included in the existing analysis. With only 77 (4·4%) of 1734 patients showing an illness duration of longer than 28 days, even small changes in patient numbers could result in substantial changes in prevalence. Due to the methods used, the study probably underestimates the actual prevalence of the disease in children.	_
86	Ch84		Deepti Gurdasani, Athena Akrami, Valerie C Bradley, Anthony Costello, Trisha Greenhalgh, Seth Flaxman, Martin McKee, Susan Michie, Christina Pagel, Sarah Rasmussen, Gabriel Scally, Christian Yates, Hisham Ziauddeen	Long COVID in children	https://doi.org/10.1016/S2352-4642(21)00342-4	Published	January 01, 2022	CORRESPONDENCE	https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00342-4/fulltext	First, only a limited number of symptoms reported in long COVID were assessed,1 with other symptoms only captured if parents entered them as free text. Given that logging of symptoms regularly is laborious, this is likely to underestimate persisting symptoms for longer periods of time. Some important symptoms, such as brain fog and low mood, were added to the list only later in the study, and not included in the main illness profile analysis, despite brain fog being reported in 11·3% (105 of 932) and low mood being reported in 15·6% (145 of 932) of older children (age 12 –17 years).1 • View related content for this article Second, the study did not adequately account for the well-known relapsing and remitting nature of long COVID.3 Children with any gap in symptoms longer than 1 week were excluded,1 so children whose symptoms temporarily resolved for more than a week and then recurred, were not counted.1 Third, the duration estimates for long COVID are based on parents either reporting their child as asymptomatic with no symptoms for a week, or the last symptomatic report if parents stopped using the app.1 Use of cessation of proxy-logged symptom data to signal resolution is unlikely to be valid. The drop off in reporting for many parents could instead be related to ongoing illness in children and the demands of managing the needs of the child. Incomplete reporting was higher for children with confirmed infection (10·6%) than in children who had tested negative (3·5%).1 A much higher proportion ceased logging symptoms while still having ongoing symptoms (28·6% among those reporting symptoms for ≥28 days compared with 9·7% for those reporting symptoms for <28 days). This assumption of cessation of logging affects both the duration and prevalence estimates of long COVID. Given these data are probably missing not at random, excluding them (as in the authors’ sensitivity analysis) is also biased, underestimating the symptom duration. Collectively, these factors all introduce bias in a single direction, namely, to underestimate the incidence and duration of long COVID. Given all factors, this underestimation might be substantial, which could partly explain why Molteni and colleagues’ estimates are at least 7 times lower than those of a recently published prospective large-scale study that allowed for remitting and relapsing symptoms, with follow-up at 3 months, 4 but similar to other studies that were limited in systematic assessment of common symptoms of long COVID (appendix).	_
87	Ch85		Erika Molteni, Sunil S Bhopal, Robert C Hughes, Michael Absoud, Emma L Duncan	Long COVID in children – Authors' reply	https://doi.org/10.1016/S2352-4642(21)00344-8	Published	January 01, 2022	CORRESPONDENCE	https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00344-8/fulltext	We disagree that proxy-logging via smartphone is laborious, noting here the high assiduousness (mostly daily) and persistence (>90%) of proxy-reporting. We share concern that proxy-logging cessation before a healthy report might affect results, hence our sensitivity analyses, which included counting all children who had symptoms for at least 4 weeks (LC28) even if logging subsequently ceased, and estimates remained within confidence intervals. When discontinuation occurred, it was mostly at a time concomitant with median illness duration. If all 161 early-cessation children ultimately had LC28, our estimates would increase. However, if LC28 rates were proportionate to the more than 90% of children logged until healthy, seven extra LC28 cases would result, giving LC28 rates of 84 (4·8%) of 1734 children, which is still within our confidence intervals. We allowed for up to a week of logging as asymptomatic (or healthy) within a child's total illness duration, a choice which was informed by the following: (1) this threshold was as previously published;7 (2) the median duration of illness in children with COVID-19 is less than 7 days; and (3) as wellness periods lengthen between illness episodes it becomes increasingly difficult to attribute with clinical confidence later episodes of illness to initial infection. Here, standardising post-COVID syndromes definitions in children will help future research. We disagree with Gurdasani and colleagues that our estimates are seven-fold lower than the CLOCK study. The CLOCK study4 reported 66·5% positively tested and 53·4% negatively tested children had at least one symptom for 3 months post-infection, a risk ratio of 1·25, an extremely modest risk. If we use the same criteria, at 4 weeks our risk ratio was 5·1. Importantly, both CLOCK4 and the ONS1 showed high symptom prevalence in children testing negative, presumably capturing both effects of other illnesses and the pandemic. We reiterate our conclusion that “a holistic approach for all children with persistent illness during the pandemic is appropriate”, irrespective of whether the illness is caused by SARS-CoV-2.3	_
88	Ch86	Hirt	María Bergia, Elena Sanchez-Marcos, Blanca Gonzalez-Haba, Ana Isabel Hernaiz, María de Ceano-Vivas, Milagros García López-Hortelano, María Luz García García, Raquel Jimenez-García, Cristina Calvo	Study of Prevalence and Characteristics of Long Covid in Spanish Children	https://doi.org/10.21203/rs.3.rs-1068678/v1	pre-print	14 Dec, 2021	RESEARCH ARTICLE	https://www.researchsquare.com/article/rs-1068678/v1	Results 451 children met criteria and agreed to participate; 370/451 (82%) presented mild outpatient infection, and 23 required admission in PICU (5.1%). The mean age was 5.9 years old (SD 5.3). A control group of 98 children was included. In 66 cases (14.6%) at least one symptom lasted longer than 12 weeks. Insomnia, concentration problems, apathy or sadness and anxiety were the longest (median >90 days). Age above 5 years (48/66; 72.7%, OR: 3, CI 95% (1.8-5)); admission (OR 3.9 CI 95% (2.2-6.8)), the need for PICU (OR 4.3 CI 95% (1.8-10.4)), and to have a relative with prolonged symptoms (OR 2.8 CI 95% (1.5-5.2)) were significantly associated with Long-COVID. When comparing with controls age above 5 years old, myalgia, asthenia, and loss of appetite were significantly associated with Long-COVID.	_
89	Ch87		Andrea Lo Vecchio, MD, PhD1; Silvia Garazzino, MD2; Andrea Smarrazzo, MD3; Elisabetta Venturini, MD4; Marco Poeta, MD1; Paola Berlese, MD5; Marco Denina, MD2; Antonella Meini, MD6; Raffaele Badolato, MD6; Alberto Villani, MD3; Alfredo Guarino, MD1; Guido Castelli Gattinara, MD3;	Factors Associated With Severe Gastrointestinal Diagnoses in Children With SARS-CoV-2 Infection or Multisystem Inflammatory Syndrome	https://doi.org/10.1001/jamanetworkopen.2021.39974	Published	December 20, 2021	Study	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2787258	Findings In this multicenter cohort study of 685 Italian children with COVID-19, 10% showed severe gastrointestinal involvement characterized by diffuse adeno-mesenteritis, appendicitis, abdominal fluid collection, ileal intussusception, or pancreatitis. Children older than 5 years and those presenting with abdominal pain, leukopenia, or receiving a diagnosis of multisystem inflammatory syndrome were more likely to have severe gastrointestinal manifestations. Meaning Severe gastrointestinal involvement is not uncommon in children with COVID-19, and awareness about its frequency and presentation may help practitioners to appropriately manage children at risk of severe outcomes.
90	Ch88		Amal El Ouarradi,1,& Ilham Bensahi,1 Insaf Alaammari,2 Amal Haoudar,3 Nezha Dini,4 et Mohamed Sabry1	Les complications thromboemboliques chez les enfants au cours de COVID-19 Thromboembolic complications in children during COVID-19	https://dx.doi.org/10.11604%2Fpamj.2021.40.137.31979	Published	2021 Nov. 4	Case Report	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8641641/	Les complications thromboemboliques chez les enfants émergent dans l´ère de COVID-19, on rapporte cette lettre pour attirer l´attention sur ces complications, leurs incidences, le diagnostic et la prise en charge et surtout l´intérêt de l´anticoagulation préventive chez cette population fragile. Il existe de nombreuses différences entre les enfants et les adultes en ce qui concerne la prévalence, la gravité et les complications de l´infection COVID-19. Le pourcentage d'enfants touchés par la COVID-19 est beaucoup plus faible que celui des adultes et ils ont tendance à présenter des symptômes plus légers et une morbidité et une mortalité significativement plus faibles [1,2]. Bien que l'on ait beaucoup appris sur les taux et les risques de complications thromboemboliques (TE) chez les adultes, on en sait relativement peu sur ce problème dans la population pédiatrique. L'incidence globale de la COVID-19 et de la thrombose est nettement inférieure chez les enfants, ce qui a ajouté des défis à l'étude de cette condition dans ce groupe d'âge [3].	_
91	Ch89		Kendall Howard 1,2,Taylor Williams 2,Elizabeth Fitch 2,Heather Ots 2,Esther Pototskiy 1 ,Jay Hawkshead 3,Zelda Ghersin 4 andAlberto E. Musto 1	Neurologic Complications in Adult and Pediatric Patients with SARS-CoV-2 Infection	https://doi.org/10.3390/ctn6010001	Published	23 December 2021	Review	https://www.mdpi.com/2514-183X/6/1/1/htm	Although the mechanism is still unclear, SARS-CoV-2 has been associated with the pathogenesis of intravascular coagulation and angiotensin-converting enzyme-I, both exacerbating systemic inflammation and contributing to hypercoagulation or blood–brain barrier leakage, resulting in ischemic or hemorrhagic stroke. On the other hand, the SARS-CoV-2 spike protein in neural tissue and within the cerebrospinal fluid may induce neural dysfunction, resulting in neuroinflammation, which is exacerbated by peripheral and neural hypercytokinemia that can lead to neuronal damage and subsequent neuroinflammation. A deeper understanding of the fundamental biological mechanisms of neurologic manifestations in SARS-CoV-2 infection can pave the way to identifying a single biomarker or network of biomarkers to help target neuroprotective therapy in patients at risk for developing neurological complications.	_
92	Ch90		Howard J. Heching Anmol Goyal, Brian Harvey, Lindsey Malloy-Walton, Christopher Follansbee, Amanda Mcintosh and Daniel Forsha	Electrocardiographic changes in non-hospitalised children with COVID-19	https://doi.org/10.1017/S1047951121005138	Published	06 January 2022	Study	https://www.cambridge.org/core/journals/cardiology-in-the-young/article/abs/electrocardiographic-changes-in-nonhospitalised-children-with-covid19/76AD6BD372C45F70BEB6963BAB07A468	Of the 82 children meeting inclusion criteria (14.4 years, range 1–18 years, 57% male), 17 patients (21%) demonstrated electrocardiographic changes. Ten patients (12%) had electrocardiogram of borderline significance, which included isolated mild PR prolongation or mild repolarisation abnormalities. The other seven patients (9%) had concerning electrocardiographic findings consisting of more significant repolarisation abnormalities. None of the patients with an abnormal electrocardiogram revealed any echocardiographic abnormality. All abnormal electrocardiograms normalised over time except in two cases. Across the entire cohort, greater COVID-19 disease severity and long COVID were not associated with electrocardiographic abnormalities.
93	Ch91		Rupesh Raina,Sidharth Kumar Sethi,Ronith Chakraborty,Siddhartha Singh,Sharon Teo,Amrit Khooblall,Giovanni Montini,Timothy Bunchman,Rezan Topaloglu,Hui Kim Yap	Blood Filters in Children with COVID-19 and AKI: A Review	https://doi.org/10.1111/1744-9987.13793	Published	08 January 2022	Review	https://onlinelibrary.wiley.com/doi/abs/10.1111/1744-9987.13793	Although pediatric patients only comprise 1-2% of diagnosed cases, their incidence of acute kidney injury ranges from 8.2% to 18.2% compared to 49% in adults. Severe infection, initiated by dysregulated host response, can lead to multiorgan failure. In this review, we focus on the use of various blood filters approved for use in pediatric kidney replacement therapy to mitigate adverse effects of severe illness. Therapeutic effects of these blood filters range from cytokine removal (CytoSorb, HA330, HCO/MCO), endotoxin removal (Toraymyxin, CPFA), both cytokine and endotoxin removal (oXiris), and non-specific removal of proteins (PMMA) that have already been established and can be used to mitigate the various effects of the cytokine storm syndrome in COVID-19.
94	Ch92		Luise Borch, Mette Holm, Maria Knudsen, Svend Ellermann-Eriksen & Soeren Hagstroem	Long COVID symptoms and duration in SARS-CoV-2 positive children — a nationwide cohort study	https://doi.org/10.1007/s00431-021-04345-z	Published	09 January 2022	Study	https://link.springer.com/article/10.1007/s00431-021-04345-z	Most children have a mild course of acute COVID-19. Only few mainly non-controlled studies with small sample size have evaluated long-term recovery from SARS-CoV-2 infection in children. The aim of this study was to evaluate symptoms and duration of ‘long COVID’ in children. A nationwide cohort study of 37,522 children aged 0–17 years with RT-PCR verified SARS-CoV-2 infection (response rate 44.9%) and a control group of 78,037 children (response rate 21.3%). An electronic questionnaire was sent to all children from March 24th until May 9th, 2021. Symptoms lasting > 4 weeks were common among both SARS-CoV-2 children and controls. However, SARS-CoV-2 children aged 6–17 years reported symptoms more frequently than the control group (percent difference 0.8%). The most reported symptoms among pre-school children were fatigue Risk Difference (RD) 0.05 (CI 0.04–0.06), loss of smell RD 0.01 (CI 0.01–0.01), loss of taste RD 0.01 (CI 0.01–0.02) and muscle weakness RD 0.01 (CI 0.00–0.01). Among school children the most significant symptoms were loss of smell RD 0.12 (CI 0.12–0.13), loss of taste RD 0.10 (CI 0.09–0.10), fatigue RD 0.05 (CI 0.05–0.06), respiratory problems RD 0.03 (CI 0.03–0.04), dizziness RD 0.02 (CI 0.02–0.03), muscle weakness RD 0.02 (CI 0.01–0.02) and chest pain RD 0.01 (CI 0.01–0.01). Children in the control group experienced significantly more concentration difficulties, headache, muscle and joint pain, cough, nausea, diarrhea and fever than SARS-CoV-2 infected. In most children ‘long COVID’ symptoms resolved within 1–5 months. Conclusions: Long COVID in children is rare and mainly of short duration.	todo
95	Ch93		Nicola Principi & Susanna Esposito	Reasons in favour of universal vaccination campaign against COVID-19 in the pediatric population	https://doi.org/10.1186/s13052-021-01192-4	Published	10 January 2022	Debate	https://ijponline.biomedcentral.com/articles/10.1186/s13052-021-01192-4	The aim of this manuscript is to explain the reasons for overcoming hesitancy towards COVID-19 vaccination in children and adolescents and to highlight the importance of universal COVID-19 vaccination in the pediatric population. Main findings Recent epidemiological data suggest that the risk that a child with COVID-19 is hospitalized or admitted to the pediatric intensive care unit is greater than initially thought. Children may also suffer from long COVID and school closure because of COVID-19 can cause relevant mental health problems in the pediatric population. Placebo-controlled, observer-blinded, clinical trials showed appropriate efficacy, safety and tolerability of authorized mRNA COVID-19 vaccines in children and adolescents 12–17 years old. Vaccination in children younger than 12 years of age will allow further benefits . Conclusions COVID-19 vaccine administration seems mandatory in all the children and adolescents because of COVID-19 related complications as well as the efficacy, safety and tolerability of COVID-19 vaccines in this population. Due to the recent approval of COVID-9 vaccines for children 5–10 years old, it is desirable that vaccine opponents can understand how important is the universal immunization against COVID-19 for the pediatric subjects.
96	Ch94		Stephanie Enner, MD, Yash D. Shah, MD MPH, Aaqil Ali, BS, Jane E. Cerise, PhD, Justin Esposito, Lorry Rubin, MD, Anupama Subramony, MD, MBA, Sanjeev Kothare, MD, FAAN	Patients Diagnosed with Multisystem Inflammatory Syndrome in Children Have Persistent Neurologic, Sleep, and Psychiatric Symptoms After Hospitalization	https://doi.org/10.1177%2F08830738221075924	Published	January 24, 2022	Study	https://journals.sagepub.com/doi/abs/10.1177/08830738221075924	Methods: We conducted a single-center retrospective chart review and cross-sectional survey of patients diagnosed with MIS-C. Patients and parents were surveyed on symptoms before the COVID-19 pandemic, upon admission, and 23 weeks (interquartile range 20-26 weeks) after discharge. Age and gender-matched patients requiring intensive care unit (ICU) care for status asthmaticus were surveyed as a control group. Results: In this cohort of 47 patients, 77% reported neurological, 60% psychiatric, and 77% sleep symptoms during hospitalization. Prior to hospitalization, 15% reported neurological, 0% psychiatric, and 7% sleep symptoms. Eighteen (50%) of the 36 patients who had neurological symptoms during hospitalization continued to have symptoms on follow-up (odds ratio [OR] = ∞, p = .003]). Similarly, 16 (57%) of 28 patients with psychiatric symptoms reported persistence at follow-up (OR = 5.00; p = .02). Fifteen (42%) of the 18 patients reporting sleep disturbance during hospitalization had persistence on follow-up (OR = 1.9; p = .49). The aggregate of neurological, psychiatric, and sleep symptoms during admission and at follow-up was significantly higher for MIS-C patients requiring ICU care when compared to the control group (p = .01). Conclusions: In this cohort of patients with MIS-C, a majority of patients reported new-onset neuropsychiatric and sleep symptoms. Almost half of these patients had persistent symptoms on a follow-up survey.
97	Ch95		Petra Zimmermann, Laure F Pittet	Long covid in children and adolescents	https://doi.org/10.1136/bmj.o143	Published	20 January 2022	Editorial	https://www.bmj.com/content/376/bmj.o143	Risk appears low, but many questions remain Symptoms involving almost every organ system have been reported after SARS-CoV-2 infection.123 Estimates of the prevalence of long covid (also called post-covid-19 condition, post-acute sequelae of covid-19, or chronic covid syndrome) vary considerably, partly because of confusion around the definition. The term long covid encompasses a broad range of symptoms, including objective complications of covid-19 (pulmonary fibrosis, myocardial dysfunction), mental health conditions, and more subjective, non-specific symptoms resembling those seen in post-viral chronic fatigue syndrome (myalgic encephalomyelitis). Most studies to date have substantial limitations, including small cohorts, absence of control groups, non-standardised capture of symptoms, lack of correction for pre-existing medical conditions, participant reported infection, and variation in follow-up, as well as selection, non-response, misclassification, and recall biases.4 In children and adolescents, acute covid-19 is less severe than in adults.56 Concern among many parents has therefore focused more on the potential long term effects of SARS-CoV-2 infection. Unfortunately, fewer data are available on long covid in young people compared with adults.7 The widely quoted one in seven frequency in children is based on a study with a 13% response rate.78 The linked study by Magnusson and colleagues (doi:10.1136/bmj-2021-066809) used nationwide register data from Norway to estimate the impact of covid-19 on long term healthcare use among 1.3 million children and adolescents.9 The authors identified a short term increase in primary (but not specialist) care use after covid-19 in all the studied age groups. This increase was related to respiratory and general or non-specific conditions, mostly in the four weeks after infection. The increase in primary care use persisted for up to six months among children aged 1-5 years. Notably, covid-19 in children had limited overall impact on healthcare services. The linked study by Magnusson and colleagues (doi:10.1136/bmj-2021-066809) used nationwide register data from Norway to estimate the impact of covid-19 on long term healthcare use among 1.3 million children and adolescents.9 The authors identified a short term increase in primary (but not specialist) care use after covid-19 in all the studied age groups. This increase was related to respiratory and general or non-specific conditions, mostly in the four weeks after infection. The increase in primary care use persisted for up to six months among children aged 1-5 years. Notably, covid-19 in children had limited overall impact on healthcare services. The study’s strengths include its population based design, the inclusion of SARS-CoV-2 negative and non-tested control groups, and comparison with pre-pandemic healthcare use. An unavoidable limitation is that asymptomatic children or those with mild symptoms might not have been tested. Also, changes in testing patterns could have occurred in different age groups and over time, and children testing positive for SARS-CoV-2 might also have had greater exposure to other respiratory viruses. Finally, the anxiety surrounding this previously unknown infection in children might have caused primary care providers and parents to schedule unnecessary follow-up visits after a positive test result. Magnusson and colleagues’ study highlights the difficulty of accurately determining risk of long covid in children and adolescents, and the urgent need for further rigorous studies. Reports suggest that more than half of children who did not have covid-19 experienced symptoms such as headaches, fatigue, sleep disturbance, and concentration difficulties during the pandemic.7 Distinguishing long term symptoms caused by SARS-CoV-2 infection from pandemic related symptoms remains a challenge. One large study in the UK found that nearly all symptoms reported by children who tested positive for SARS-CoV-2 were also reported by those who tested negative.7 Moreover, no difference was reported between the two groups in mental health, overall wellbeing, or impairment of activities. Other studies with control groups have also reported minimal differences in persisting symptoms between children with SARS-CoV-2 infection and those without.4 This underlines the importance of appropriate control groups, including children with other infections and those admitted to hospital for other reasons.
98	Ch96	Hirt	Prof Sir Terence Stephenson, DM Snehal M Pinto Pereira, PhD Prof Roz Shafran, PhD Prof Bianca L de Stavola, PhD Natalia Rojas Kelsey McOwat, MSc Ruth Simmons, PhD Maria Zavala, MPH Lauren O'Mahoney, PhD Prof Trudie Chalder, PhD Prof Esther Crawley, PhD Prof Tamsin J Ford, PhD Prof Anthony Harnden, FRCGP Prof Isobel Heyman, PhD Olivia Swann, PhD Elizabeth Whittaker, PhD CLoCk Consortium Prof Shamez N Ladhani, PhD	Physical and mental health 3 months after SARS-CoV-2 infection (long COVID) among adolescents in England (CLoCk): a national matched cohort study	https://doi.org/10.1016/S2352-4642(22)00022-0	Published	February 07, 2022	Study	https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(22)00022-0/fulltext	23 048 adolescents who tested positive and 27 798 adolescents who tested negative between Jan 1, 2021, and March 31, 2021, were contacted, and 6804 adolescents (3065 who tested positive and 3739 who tested negative) completed the questionnaire (response rate 13·4%). At PCR testing, 1084 (35·4%) who tested positive and 309 (8·3%) who tested negative were symptomatic and 936 (30·5%) from the test-positive group and 231 (6·2%) from the test-negative group had three or more symptoms. 3 months after testing, 2038 (66·5%) who tested positive and 1993 (53·3%) who tested negative had any symptoms, and 928 (30·3%) from the test-positive group and 603 (16·2%) from the test-negative group had three or more symptoms. At 3 months after testing, the most common symptoms among the test-positive group were tiredness (1196 [39·0%]), headache (710 [23·2%]), and shortness of breath (717 [23·4%]), and among the test-negative group were tiredness (911 [24·4%]), headache (530 [14·2%]), and other (unspecified; 590 [15·8%]). Latent class analysis identified two classes, characterised by few or multiple symptoms. The estimated probability of being in the multiple symptom class was 29·6% (95% CI 27·4–31·7) for the test-positive group and 19·3% (17·7–21·0) for the test-negative group (risk ratio 1·53; 95% CI 1·35–1·70). The multiple symptoms class was more frequent among those with positive PCR results than negative results, in girls than boys, in adolescents aged 15–17 years than those aged 11–14 years, and in those with lower pretest physical and mental health. Interpretation Adolescents who tested positive for SARS-CoV-2 had similar symptoms to those who tested negative, but had a higher prevalence of single and, particularly, multiple symptoms at the time of PCR testing and 3 months later. Clinicians should consider multiple symptoms that affect functioning and recognise different clusters of symptoms. The multiple and varied symptoms show that a multicomponent intervention will be required, and that mental and physical health symptoms occur concurrently, reflecting their close relationship.	todo
99	Ch97		Ilaria Viganò, Chiara Vannicola, Maria Paola Canevini	Neurology of COVID-19 - Neuro-Covid in Children	https://doi.org/10.54103/milanoup.57	Published	February 2022	Review	https://air.unimi.it/retrieve/handle/2434/897181/1962512/57-Capitolo%20di%20volume-581-1-10-20211117.pdf	Neurological manifestations in children with HCoV are relatively rare, therefore there is little information about neurodevelopmental sequelae. However, cases of neurological disease associated with SARS-CoV-2 infections in children are rapidly emerging, suggesting a possible greater neurological involrement in the pediatric population affected by this virus than in other HCoVs. Only à small fraction of children affected by SARS-CoV-2 showed neurological manifestations such as seizures, encephalitis, stroke or neuropathies!, In most cases, severe neurological manifes- tations in the pediatric population appeared to be associated with the presence of Mültisystem Inflammatory Syndrome (MIS-C). À review conducted by Chen in 2020 considering 187 children from the six latest reports of MIS-C cases showed that 34% suffered from neurological manifestations!##. Of the 187 children studied, 64 had different neurological symptoms, most of which were headaches, positive meningeal signs (meningism), and altered mental status; taken together, most manifestations represent a central, rather than a peripheral involvement. Neurological symptoms are thought to be secondary to a combination of different mechanisms, including the direct viral effect on the nervous system, the para- and post-infectious inflammation, and the neurological complications of the systemic effects of COVID-19.
100	Ch98		Siberry, Vikram G. R. MS,†; Rowe, Peter C. MD,†	Pediatric Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Overlaps and Opportunities	https://doi.org/10.1097/INF.0000000000003477	Published	February 4, 2022	Article	https://journals.lww.com/pidj/Citation/9000/Pediatric_Long_COVID_and_Myalgic.95546.aspx	The absence of an organized and robust clinical infrastructure for managing pediatric and adult ME/CFS has adversely affected the care of those with ME/CFS in the United States and elsewhere. Patients with ME/CFS at all ages have reported difficulty obtaining direct care. Unlike the situation in HIV and pediatric cancer, there is no coordinated network of centers that could participate in ME/CFS clinical trials. A corollary of this underdevelopment has meant that resources for managing the many people who have developed long COVID were scarce from the start of the pandemic. While post-COVID clinics are starting to emerge, it will be an important part of managing this and planning for future pandemics that we ensure these clinical efforts succeed. It would only be just and equitable to ensure that those with nonpandemic ME/CFS have similar access to care.
101	Ch99		Keerthi Thallapureddy, Khyathi Thallapureddy, Erika Zerda, Neeraj Suresh, Deepak Kamat, Karthik Rajasekaran & Alvaro Moreira	Long-Term Complications of COVID-19 Infection in Adolescents and Children	https://doi.org/10.1007/s40124-021-00260-x	Published	01 February 2022	Review	https://link.springer.com/article/10.1007/s40124-021-00260-x	Recent Findings Children were less likely to develop long COVID when compared to adults. Older children (e.g., adolescents) and those who had symptomatic COVID-19 had a higher probability for long COVID. Summary Families and health care providers need to be aware of a new constellation of long COVID symptoms in the pediatric population. More evidence and time are needed to better understand the potential effects of long COVID-19 in children and adolescents. In comparison to adults, children are less likely to have persistent COVID-19 symptoms.
102	Ch100		ProfSelinaKikkenborg BergPhDadProfSusanneDam NielsenDMScbdUlrikkaNygaardPhDcdProfHenningBundgaardDMScadPernillePalmPhDaCamillaRotvigMScaAnneVinggaard ChristensenPhDa	Long COVID symptoms in SARS-CoV-2-positive adolescents and matched controls (LongCOVIDKidsDK): a national, cross-sectional study	https://doi.org/10.1016/S2352-4642(22)00004-9	Published	8 February 2022	Study	https://www.sciencedirect.com/science/article/pii/S2352464222000049	Findings 24 315 adolescents with a positive SARS-CoV-2 test (case group) and 97 257 matched controls were invited to participate. 3013 matched controls were excluded because of suspected SARS-CoV-2 infection. 6630 (27·3%) responded in the case group and 21 640 (22·3%) responded and were eligible to participate in the control group. Across both groups, median age was 17·6 years (IQR 16·4–18·5), 16 277 (57·6%) of 28 270 responders were female, and 11 993 (42·4%) were male. Participants in the case group had greater odds of having at least one long COVID symptom lasting at least 2 months compared with the control group (3159 [61·9%] vs 12 340 [57·0%], odds ratio 1·22 [95% CI 1·15–1·30]; p<0·0001). Participants in the case group reported significantly lower symptom scores (ie, less somatic distress) on the CSSI-24 than in the control group: mean 10·7 (SD 11·4, median 7·0 [IQR 2·0–15·0]) versus 11·9 (10·6, 9·0 [4·0–17·0]; p<0·0001). Participants in the case group had better quality of life scores on the PedsQL than in the control group: physical functioning mean score 88·7 (SD 13·9, median 93·8 [IQR 84·4–100·0]) versus 86·5 (14·3, 90·6 [81·3–96·9]; p<0·0001); emotional functioning 77·1 (20·3, 80·0 [65·0–95·0]) versus 71·7 (21·4, 75·0 [60·0–90·0]; p<0·0001); social functioning 93·1 (12·5, 100·0 [90·0–100·0]) versus 88·4 (16·2, 95·0 [80·0–100·0]; p<0·0001); and school functioning 66·9 (22·5, 65·0 [60·0–85·0]) versus 62·9 (22·1, 65·0 [50·0–80·0]; p<0·0001). More participants in the case group than in the control group reported 16 or more sick days (1205 [18·2%] vs 2518 [11·6%]; p<0·0001) and 16 or more days of school absence (695 [10·5%] vs 1777 [8·2%]; p<0·0001). Interpretation Participants with SARS-CoV-2-positive tests had more long-lasting symptoms and sick leave, whereas participants in the control group had more short-lasting symptoms and worse quality of life. Knowledge of long COVID in adolescents is important to guide clinical recognition and management of this condition.
103	Ch101	Hirt (publication of Ch96 and Ch64)	Prof SirTerenceStephensonDMaSnehal MPinto PereiraPhDbProfRozShafranPhDaProfBianca Lde StavolaPhDaNataliaRojasaKelseyMcOwatMSccRuthSimmonsPhDcMariaZavalaMPHcLaurenO'MahoneyPhDdProfTrudieChalderPhDeProfEstherCrawleyPhDfProfTamsin JFordPhDgProfAnthonyHarndenFRCGPhProfIsobelHeymanPhDaOliviaSwannPhDiElizabethWhittakerPhDj	Physical and mental health 3 months after SARS-CoV-2 infection (long COVID) among adolescents in England (CLoCk): a national matched cohort study	https://doi.org/10.1016/S2352-4642(22)00022-0	Published	8 February 2022	Study	https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(22)00022-0/fulltext	23 048 adolescents who tested positive and 27 798 adolescents who tested negative between Jan 1, 2021, and March 31, 2021, were contacted, and 6804 adolescents (3065 who tested positive and 3739 who tested negative) completed the questionnaire (response rate 13·4%). At PCR testing, 1084 (35·4%) who tested positive and 309 (8·3%) who tested negative were symptomatic and 936 (30·5%) from the test-positive group and 231 (6·2%) from the test-negative group had three or more symptoms. 3 months after testing, 2038 (66·5%) who tested positive and 1993 (53·3%) who tested negative had any symptoms, and 928 (30·3%) from the test-positive group and 603 (16·2%) from the test-negative group had three or more symptoms. At 3 months after testing, the most common symptoms among the test-positive group were tiredness (1196 [39·0%]), headache (710 [23·2%]), and shortness of breath (717 [23·4%]), and among the test-negative group were tiredness (911 [24·4%]), headache (530 [14·2%]), and other (unspecified; 590 [15·8%]). Latent class analysis identified two classes, characterised by few or multiple symptoms. The estimated probability of being in the multiple symptom class was 29·6% (95% CI 27·4–31·7) for the test-positive group and 19·3% (17·7–21·0) for the test-negative group (risk ratio 1·53; 95% CI 1·35–1·70). The multiple symptoms class was more frequent among those with positive PCR results than negative results, in girls than boys, in adolescents aged 15–17 years than those aged 11–14 years, and in those with lower pretest physical and mental health. Interpretation Adolescents who tested positive for SARS-CoV-2 had similar symptoms to those who tested negative, but had a higher prevalence of single and, particularly, multiple symptoms at the time of PCR testing and 3 months later. Clinicians should consider multiple symptoms that affect functioning and recognise different clusters of symptoms. The multiple and varied symptoms show that a multicomponent intervention will be required, and that mental and physical health symptoms occur concurrently, reflecting their close relationship.
104	Ch102	MIS-C	A Spanaki, O Miller, J Wong, K Pushparajah, P Theocharis	Long term non-invasive endothelial function assessment in patients with paediatric inflammatory multisystem syndrome temporarily associated with Covid 19 (PIMS TS)	https://doi.org/10.1093/ehjci/jeab289.314	Published	04 February 2022	Study	https://academic.oup.com/ehjcimaging/article/23/Supplement_1/jeab289.314/6522472?login=true	Introduction Patients with PIMS-TS present with features of vasculitis (bright coronary arteries and diffuse coronary ectasia on transthoracic echocardiography) and prothrombotic features (e.g. elevated D Dimers) indicating involvement of the endothelial layer in the inflammatory process. Impairment in endothelial function may contribute to the acute but also to possible long-term consequences in patients with PIMS-TS. The aim of this pilot study is to assess non-invasively the endothelial (dys)function using reactive hyperemic peripheral arterial tonometry (RH-PAT) 6 months after the acute inflammatory phase. Methods Ten patients with previous diagnosis of PIMS-TS were compared to age-matched controls. The endothelial function was assessed using the EndoPAT device which provides the reactive hyperemic index (RHI) of endothelial function in a 15-min test. Cardiac function indices by means of LV fractional shortening (FS) was also assessed. Results There were no significant differences regarding age (11.2 ± 3.0 vs 13.6 ± 2.4, p = 0.063), height, weight and body surface area, (BSA: 1.49 ± 0.36 vs 1.52 ± 0.25, p = 0.856) in patients with previous diagnosis of PIMS-TS and controls respectively. The two groups also had similar LV systolic function assessed by FS (36.3 ± 9.1% vs 36.7 ± 7.1%, p = 0.922). The RHI in the PIMS TS group was similar to the control group (1.65 ± 0.43 vs 1.81 ± 0.60, p = 0.533 respectively). Conclusions. Patients with PIMS-TS who may present with features of vasculitis during the acute phase, do not show evidence of endothelial dysfunction during the long term follow-up, suggesting resolution. Further studies are required to accurately determine the endothelial (dys)function during the acute phase of the inflammatory syndrome and course.
105	Ch103		Siberry, Vikram G. R. MS,†; Rowe, Peter C. MD,†	Pediatric Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Overlaps and Opportunities	https://doi.org/10.1097/INF.0000000000003477	Published	February 4, 2022	Article	https://journals.lww.com/pidj/Citation/9000/Pediatric_Long_COVID_and_Myalgic.95546.aspx	David Spodick once wrote: “We must view published material critically (if not biblically), for too often the ‘Conclusions’ giveth, but the ‘Materials and Methods’ taketh away.” In the December 2021 issue of the Pediatric Infectious Diseases Journal, Zimmermann et al1 provide a masterful application of Spodick’s exhortation. Their review of the existing evidence regarding long COVID in children enumerates important methodologic challenges in interpreting this literature, including the heterogeneity of available case definitions for long COVID, differences in the time intervals in which symptoms are ascertained, variability regarding which symptoms are included under the rubric of long COVID, and whether laboratory confirmation of the initial COVID infection is required. Additionally, the authors emphasize that without control groups in many of these studies, and in light of the overlap of some long COVID symptoms with symptoms of prolonged social isolation, it is difficult to discern which symptoms are attributable to the general pandemic circumstances rather than the COVID-19 infection itself. Despite such limitations, it is clear that pediatric patients are at risk for prolonged symptoms following acute SARS-CoV-2 infection. Although many persistent symptoms, such as anosmia, dysgeusia and shortness of breath are unique to the post-COVID state, many other symptoms such as fatigue, cognitive dysfunction, lightheadedness and postexertional malaise overlap with symptoms found in myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). In this commentary, we review case definitions for long COVID and ME/CFS, emphasize recent research findings on the biologic basis of ME/CFS, discuss the overlap with long COVID, and consider opportunities posed by the pandemic to improve the understanding of both conditions.
106	Ch104		Michela Gatta, Alessia Raffagnato, Federica Mason, Rachele Fasolato, Annalisa Traverso, Silvia Zanato & Marina Miscioscia	Sociodemographic and clinical characteristics of paediatric patients admitted to a neuropsychiatric care hospital in the COVID-19 era	https://doi.org/10.1186/s13052-022-01213-w	Published	05 February 2022	Study	https://link.springer.com/article/10.1186/s13052-022-01213-w	Results Risk factors associated with mental health disorders were similar between the two years. The hospitalisation modality showed a decrease in scheduled hospitalisations compared to urgent ones, and among the reasons that led patients to hospitalisation there was a conspicuous increase in eating disorders. More suicidal and self-harming behaviours occurred in the COVID-19 group too, compared to the previous year. The methods used to attempt suicide were changed considerably, with a prevalence of that attempted within the home. Changes in pharmacological therapies also occurred, necessary for more than 80% of inpatients during the COVID year, with a greater use of neuroleptics. There were alarming data about hospitalisation relapses, which increased from 12.2% in the pre-COVID year to 35.0% in the COVID year. Conclusion Data shed light on clinical and policy issues in mental health care during the developmental age. Since the COVID-19 health emergency is not yet over, and its effects, especially on mental health, will be long-term, it is necessary to implement services and activities dedicated to both primary and secondary prevention of neuropsychiatric diseases especially during adolescent ages.
107	Ch105		Janet Chou, Paul G. Thomas & Adrienne G. Randolph	Immunology of SARS-CoV-2 infection in children	https://doi.org/10.1038/s41590-021-01123-9	Published	01 February 2022	Review	https://www.nature.com/articles/s41590-021-01123-9	Children and adolescents exhibit a broad range of clinical outcomes from SARS-CoV-2 infection, with the majority having minimal to mild symptoms. Additionally, some succumb to a severe hyperinflammatory post-infectious complication called multisystem inflammatory syndrome in children (MIS-C), predominantly affecting previously healthy individuals. Studies characterizing the immunological differences associated with these clinical outcomes have identified pathways important for host immunity to SARS-CoV-2 and innate modulators of disease severity. In this Review, we delineate the immunological mechanisms underlying the spectrum of pediatric immune response to SARS-CoV-2 infection in comparison with that of adults.
108	Ch106		Rafael Heiss, Alexandra L Wagner, Lina Tan, Sandy Schmidt, Adrian P. Regensburger, Franziska Ewert, Dilbar Mammadova, Adrian Buehler, Jens Vogel-Claussen, Andreas Voskrebenzev, Oliver Rompel, Armin M. Nagel, Simon Levy, Sebastian Bickelhaupt, Matthias S. May, Michael Uder, Markus Metzler, Regina Trollmann, Joachim Woelfle, View ProfileFerdinand Knieling	Persisting pulmonary dysfunction in pediatric post-acute Covid-19	https://doi.org/10.1101/2022.02.21.22270909	pre-print	February 22, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.02.21.22270909v1	In this cross-sectional clinical trial, we used non-invasive, label-free morphologic and free-breathing phase-resolved functional low-field magnetic resonance imaging (LF-MRI) to identify pulmonary changes in children and adolescents from 5 to <18 years after previously PCR-confirmed SARS-CoV-2 infection. While morphological pathologies were less frequent in children, functional LF-MRI visualized widespread ventilation, perfusion and combined ventilation/perfusion defects compared to healthy controls. The loss of functional lung parenchyma was more pronounced in long Covid than recovered patients. While pulmonary dysfunction was persistent even month after primary infection, LF-MRI demonstrated high capability to visualize and detect these changes in children and adolescents.
109	Ch107		Jeané Cloete,Annelet Kruger,Maureen Masha,Nicolette M du Plessis,Dini Mawela,Mphailele Tshukudu,Tabea Manyane,Lekwetji Komane,Marietjie Venter,Waasila Jassat,Ameena Goga,Ute Feucht	Paediatric hospitalisations due to COVID-19 during the first SARS-CoV-2 omicron (B.1.1.529) variant wave in South Africa: a multicentre observational study	https://doi.org/10.1016/S2352-4642(22)00027-X	Published	18 Feb, 2022	Study	https://www.sciencedirect.com/science/article/abs/pii/S235246422200027X	Between Oct 31 and Dec 11, 2021, 6287 children and adolescents in Tshwane District were recorded as having COVID-19. During this period, 2550 people with COVID-19 were hospitalised, of whom 462 (18%) were aged 19 years or younger. The number of paediatric cases was higher than in the three previous SARS-CoV-2 waves, uncharacteristically increasing ahead of adult hospitalisations. 75 viral samples from adults and children in the district were sequenced, of which 74 (99%) were of the omicron variant. Detailed clinical notes were available for 138 (75%) of 183 children aged ≤13 years with COVID-19 who were hospitalised. 87 (63%) of 138 children were aged 0–4 years. In 61 (44%) of 138 cases COVID-19 was the primary diagnosis, among whom symptoms included fever (37 [61%] of 61), cough (35 [57%]), shortness of breath (19 [31%]), seizures (19 [31%]), vomiting (16 [26%]), and diarrhoea (15 [25%]). Median length of hospital stay was 2 days [IQR 1–3]). 122 (88%) of 138 children with available data needed standard ward care and 27 (20%) needed oxygen therapy. Seven (5%) of 138 children were ventilated and four (3%) died during the study period, all related to complex underlying copathologies. All children and 77 (92%) of 84 parents or guardians with available data were unvaccinated to COVID-19.
110	Ch108		Fainardi, V.; Meoli, A.; Chiopris, G.; Motta, M.; Skenderaj, K.; Grandinetti, R.; Bergomi, A.; Antodaro, F.; Zona, S.; Esposito, S.	Long COVID in Children and Adolescents	https://doi.org/10.3390/life12020285	Published	14 Feb, 2022	Review	https://www.mdpi.com/2075-1729/12/2/285	Nevertheless, there are two long-term consequences of SARS-CoV-2 infection in children that raise concern: multisystem inflammatory syndrome in children (MIS-C) and long COVID. While the understanding and the experience regarding the acute phase of SARS-CoV-2 infection have remarkably increased over time, scientific and clinical research is still exploring the long-term effects of COVID-19. In children, data on long COVID are scant. Reports are conflicting regarding its prevalence, duration and impact on daily life. This narrative review explored the latest literature regarding long COVID-19 in the pediatric population. We showed that long COVID in children might be a relevant clinical problem. In most cases, the prognosis is good, but some children may develop long-term symptoms with a significant impact on their daily life. The paucity of studies on long COVID, including a control group of children not infected by SARS-CoV-2, prevents us from drawing firm conclusions. Whether the neuropsychiatric symptoms widely observed in children and adolescents with long COVID are the consequence of SARS-CoV-2 infection or are due to the tremendous stress resulting from the restrictions and the pandemics is still not clear. In both cases, psychological support can play a fundamental role in managing COVID pandemics in children. More knowledge is needed to share a standardized definition of the syndrome and improve its management and treatment.
111	Ch109		Keith Sacco, Riccardo Castagnoli, Svetlana Vakkilainen, Can Liu, Ottavia M. Delmonte, Cihan Oguz, Ian M. Kaplan, Sara Alehashemi, Peter D. Burbelo, Farzana Bhuyan, Adriana A. de Jesus, Douglas B. Kuhns, Michail S. Lionakis, Thomas M. Snyder, Steven M. Holland, Raphaela Goldbach-Mansky, John S. Tsang & Luigi D. Notarangelo	Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19	https://doi.org/10.1038/s41591-022-01724-3	Published	17 February 2022	Study	https://www.nature.com/articles/s41591-022-01724-3	Pediatric Coronavirus Disease 2019 (pCOVID-19) is rarely severe; however, a minority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might develop multisystem inflammatory syndrome in children (MIS-C), with substantial morbidity. In this longitudinal multi-institutional study, we applied multi-omics (analysis of soluble biomarkers, proteomics, single-cell gene expression and immune repertoire analysis) to profile children with COVID-19 (n = 110) and MIS-C (n = 76), along with pediatric healthy controls (pHCs; n = 76). pCOVID-19 was characterized by robust type I interferon (IFN) responses, whereas prominent type II IFN-dependent and NF-κB-dependent signatures, matrisome activation and increased levels of circulating spike protein were detected in MIS-C, with no correlation with SARS-CoV-2 PCR status around the time of admission. Transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation. The association of MIS-C with the combination of HLA A02, B35 and C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load than pCOVID-19 and pHC. These results identify distinct immunopathological signatures in pCOVID-19 and MIS-C that might help better define the pathophysiology of these disorders and guide therapy.
112	Ch110		Tyler A. Fick, Clifford L. Cua & Simon Lee	Imaging Findings in Pediatric COVID-19: A Review of Current Literature	https://doi.org/10.1007/s40119-022-00256-8	Published	02 March 2022	Review	https://link.springer.com/article/10.1007/s40119-022-00256-8	The recent COVID-19 pandemic has afflicted over 200 million individuals to date, with many different organ systems involved. The pediatric involvement has been variable, but of note is the risk of cardiac disease in pediatric COVID-19 patients. We review here the cardiac involvement in pediatric patients with COVID-19. Several studies highlight a possible cardiotropic nature of SARS-CoV-2, and describe the disease severity in myocarditis, both symptomatic and occult, as well as MIS-C. We describe the expected clinical course of these patients and note the lack of long-term follow-up data and the concerning prevalence of continued abnormal findings on follow-up imaging. With this paucity of long-term cardiac data, we recommend consideration of advanced imaging for pediatric patients with cardiac symptoms and/or elevation of cardiac serum biomarkers. Key Summary Points Several studies have described direct SARS-CoV-2 myocardial infection, raising the possibility of direct cardiotropic nature of COVID-19 in some patients. Abnormal CMR findings have been reported in up to 33% of pediatric MIS-C patients. Up to 14% of pediatric patients continue to have abnormal CMR at follow-up. The clinical implications of these residual abnormal features is yet unknown, highlighting the importance of continued long-term follow-up.
113	Ch111		Guy Hazan,Mehr Zahra Shah,Steven Brennan	Markers for Severe Disease and Long-Term Sequelae in Pediatric Patients with SARS-CoV-2 infection	https://doi.org/10.1111/ped.15177	Published	24 February 2022	Review	https://onlinelibrary.wiley.com/doi/abs/10.1111/ped.15177	Results Review of 101 patients with positive SARS-CoV2 testing found 67 presentations consistent with acute symptomatic infection. Age distribution was bimodal, with predominance in infancy and adolescence. Most (75%) had an extra-pulmonary comorbidity, and fewer patients (33%) had pre-existing lung disease. History of pulmonary comorbidity and obesity were significantly associated with markers for severe disease. Long-term chronic complications were associated with history of underlying lung disease and acute severe COVID-19. Conclusions Demographic and clinical markers were associated with severe COVID-19 in children. Moreover, both the presence of pulmonary comorbidity and severe acute COVID-19 are associated with long-term sequelae.
114	Ch112		Susanna Esposito, Nicola Principi, Chiara Azzari, Fabio Cardinale, Giuseppe Di Mauro, Luisa Galli, Guido Castelli Gattinara, Valentina Fainardi, Alfredo Guarino, Laura Lancella, Amelia Licari, Enrica Mancino, Gian Luigi Marseglia, Salvatore Leonardi, Raffaella Nenna, Stefania Zampogna, Stefano Zona, Annamaria Staiano & Fabio Midulla	Italian intersociety consensus on management of long covid in children	https://doi.org/10.1186/s13052-022-01233-6	Published	09 March 2022	Review	https://ijponline.biomedcentral.com/articles/10.1186/s13052-022-01233-6	Background Two sequelae of pediatric COVID-19 have been identified, the multisystem inflammatory syndrome in children (MIS-C) and the long COVID. Long COVID is much less precisely defined and includes all the persistent or new clinical manifestations evidenced in subjects previously infected by SARS-CoV-2 beyond the period of the acute infection and that cannot be explained by an alternative diagnosis. In this Intersociety Consensus, present knowledge on pediatric long COVID as well as how to identify and manage children with long COVID are discussed. Main findings Although the true prevalence of long COVID in pediatrics is not exactly determined, it seems appropriate to recommend evaluating the presence of symptoms suggestive of long COVID near the end of the acute phase of the disease, between 4 and 12 weeks from this. Long COVID in children and adolescents should be suspected in presence of persistent headache and fatigue, sleep disturbance, difficulty in concentrating, abdominal pain, myalgia or arthralgia. Persistent chest pain, stomach pain, diarrhea, heart palpitations, and skin lesions should be considered as possible symptoms of long COVID. It is recommended that the primary care pediatrician visits all subjects with a suspected or a proven diagnosis of SARS-CoV-2 infection after 4 weeks to check for the presence of symptoms of previously unknown disease. In any case, a further check-up by the primary care pediatrician should be scheduled 3 months after the diagnosis of SARS-CoV-2 infection to confirm normality or to address emerging problems. The subjects who present symptoms of any organic problem must undergo a thorough evaluation of the same, with a possible request for clinical, laboratory and / or radiological in-depth analysis in case of need. Children and adolescents with clear symptoms of mental stress will need to be followed up by existing local services for problems of this type. Conclusions Pediatric long COVID is a relevant problem that involve a considerable proportion of children and adolescents. Prognosis of these cases is generally good as in most of them symptoms disappear spontaneously. The few children with significant medical problems should be early identified after the acute phase of the infection and adequately managed to assure complete resolution. A relevant psychological support for all the children during COVID-19 pandemic must be organized by health authorities and government that have to treat this as a public health issue.
115	Ch113		Carl E. Stafstrom	Neurological effects of COVID-19 in infants and children	https://doi.org/10.1111/dmcn.15185	Published	03 March 2022	Review	https://onlinelibrary.wiley.com/doi/full/10.1111/dmcn.15185	Neurological manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children are becoming increasingly apparent as the coronavirus disease (COVID-19) pandemic continues. While children manifest relatively milder features of the disease, accumulating evidence warrants concern that COVID-19 exacts both acute- and long-term effects on the developing central and peripheral nervous systems. This review focuses on the relatively underinvestigated topic of the effects of SARS-CoV-2 on the brain in infancy and childhood, concluding that clinicians should be attentive to both the acute effects and long-term consequences of COVID-19 from a neurological perspective. What this paper adds - Vertical transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from mother to fetus is extremely rare. - Similar but milder neurological dysfunction occurs in infants and children compared with adults. - There is no definitive evidence that SARS-CoV-2 invades the central nervous system. - Long-term neurological and psychiatric effects of coronavirus disease are emerging. - No data are yet available on variant-specific neurological effects of SARS-CoV-2.
116	Ch114	MIS-C	Eviç Zeynep Başar 1,*,Hafize Emine Sönmez 2,Hüseyin Uzuner 3,4,Aynur Karadenizli 4,5,Hüseyin Salih Güngör 1,Gökmen Akgün 6,Ayşe Filiz Yetimakman 7 ,Selim Öncel 8 andKadir Babaoğlu 1	CXCL10/IP10 as a Biomarker Linking Multisystem Inflammatory Syndrome and Left Ventricular Dysfunction in Children with SARS-CoV-2	https://doi.org/10.3390/jcm11051416	Published	4 March 2022	Study	https://www.mdpi.com/2077-0383/11/5/1416/htm	Background: To investigate the diagnostic accuracy of CXCL10/IP10 for left ventricular (LV) dysfunction in multisystemic inflammatory syndrome (MIS-C). Methods: This cross-sectional, longitudinal study included 36 patients with MIS-C. Patients were classified as follows: (1) patients presenting with Kawasaki-like features (group I = 11); (2) patients presenting with LV systolic dysfunction (group II = 9); and (3) other presentations (group III = 3). CXCL10/IP10 levels were measured upon admission and on days 3 and 7 of treatment. Results: Twenty patients were male and 16 were female. The median age of patients at diagnosis was 7.5 (1.5–17) years. All patients had a fever lasting for a median of 4 (2–7) days. Ten patients had LV systolic dysfunction. The duration of hospitalization was longer in group II. Lymphocyte and platelet counts were lower, whereas NT-pro-BNP, troponin-I, D-dimer, and CXCL10/IP10 levels were higher in group II. Baseline levels of CXCL10/IP10 were weakly negatively correlated with ejection fraction (r = −0.387, p = 0.022). Receiver operator characteristic curve analysis yielded a cutoff value of CXCL10/IP10 to discriminate patients with LV dysfunction was 1839 pg/mL with sensitivity 88% and specificity 68% (Area under curve (AUC) = 0.827, 95% CI 0.682–0.972, p = 0.003). Conclusion: Having a good correlation with cardiac function, CXCL10/IP10 is a potential biomarker to predict LV dysfunction in MIS-C patients.
117	Ch115	Hirt	Thomas Radtke, View ProfileAgne Ulyte, View ProfileMilo A Puhan, View ProfileSusi Kriemler	Long-term symptoms after SARS-CoV-2 infection in school children: population-based cohort with 6-months follow-up	https://doi.org/10.1101/2021.05.16.21257255	pre-print	May 21, 2021	Study	https://www.medrxiv.org/content/10.1101/2021.05.16.21257255v2.full-text	Although long COVID in children exists, it is still unclear to what extent children are affected. The Ciao Corona study is a longitudinal cohort investigating SARS-CoV-2 seroprevalence and clustering of cases among around 2500 children and adolescents (hereafter referred to as children) from 55 randomly selected primary and secondary schools in the canton of Zurich in Switzerland. Between June 2020 and April 2021, we completed three testing phases where we collected venous blood for serological analysis and asked about symptoms with online questionnaires. We compared children who tested positive for SARS-CoV-2 antibodies in October/November 2020 with those who tested negative. Children who were seronegative in October/November 2020 and seroconverted or were not retested in March/April 2021 were excluded from the analysis (n=256). In March-May 2021 we assessed the presence of symptoms occurring since October 2020, lasting for at least 4 weeks, and persisting for either >4 weeks or >12 weeks. Overall, 1355 of 2503 children with a serology result in October/November 2020 and follow up questionnaire in March-May 2021 were included. Among seropositive and seronegative 6-to 16-year-old children, 9% versus 10% reported at least one symptom beyond 4 weeks, and 4% versus 2% at least one symptom beyond 12 weeks. None of the seropositive children reported hospitalization after October 2020. This study suggests a low prevalence of symptoms compatible with long COVID in a randomly selected population-based cohort of children followed over 6 months after serological testing.
118	Ch116	PESE	Amanda K. Morrow, Laura A. Malone, Christina Kokorelis, Lindsay S. Petracek, Ella F. Eastin, Katie L. Lobner, Luise Neuendorff & Peter C. Rowe	Long-Term COVID 19 Sequelae in Adolescents: the Overlap with Orthostatic Intolerance and ME/CFS	https://doi.org/10.1007/s40124-022-00261-4	Published	09 March 2022	Review	https://link.springer.com/article/10.1007/s40124-022-00261-4	Purpose of Review To discuss emerging understandings of adolescent long COVID or post-COVID-19 conditions, including proposed clinical definitions, common symptoms, epidemiology, overlaps with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and orthostatic intolerance, and preliminary guidance on management. Recent Findings The recent World Health Organization clinical case definition of post-COVID-19 condition requires a history of probable or confirmed SARS-CoV-2 infection, with symptoms starting within 3 months of the onset of COVID-19. Symptoms must last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms of the post-COVID-19 condition include, but are not limited to, fatigue, shortness of breath, and cognitive dysfunction. These symptoms generally have an impact on everyday functioning. The incidence of prolonged symptoms following SARS-CoV-2 infection has proven challenging to define, but it is now clear that those with relatively mild initial infections, without severe initial respiratory disease or end-organ injury, can still develop chronic impairments, with symptoms that overlap with conditions like ME/CFS (profound fatigue, unrefreshing sleep, post-exertional malaise, cognitive dysfunction, and orthostatic intolerance). Summary We do not yet have a clear understanding of the mechanisms by which individuals develop post-COVID-19 conditions. There may be several distinct types of long COVID that require different treatments. At this point, there is no single pharmacologic agent to effectively treat all symptoms. Because some presentations of post-COVID-19 conditions mimic disorders such as ME/CFS, treatment guidelines for this and related conditions can be helpful for managing post-COVID-19 symptoms.
119	Ch117	ES	Susanna Esposito, Nicola Principi, Chiara Azzari, Fabio Cardinale, Giuseppe Di Mauro, Luisa Galli, Guido Castelli Gattinara, Valentina Fainardi, Alfredo Guarino, Laura Lancella, Amelia Licari, Enrica Mancino, Gian Luigi Marseglia, Salvatore Leonardi, Raffaella Nenna, Stefania Zampogna, Stefano Zona, Annamaria Staiano & Fabio Midulla	Italian intersociety consensus on management of long covid in children	https://doi.org/10.1186/s13052-022-01233-6	Published	09 March 2022	Review	https://ijponline.biomedcentral.com/articles/10.1186/s13052-022-01233-6	Background Two sequelae of pediatric COVID-19 have been identified, the multisystem inflammatory syndrome in children (MIS-C) and the long COVID. Long COVID is much less precisely defined and includes all the persistent or new clinical manifestations evidenced in subjects previously infected by SARS-CoV-2 beyond the period of the acute infection and that cannot be explained by an alternative diagnosis. In this Intersociety Consensus, present knowledge on pediatric long COVID as well as how to identify and manage children with long COVID are discussed. Main findings Although the true prevalence of long COVID in pediatrics is not exactly determined, it seems appropriate to recommend evaluating the presence of symptoms suggestive of long COVID near the end of the acute phase of the disease, between 4 and 12 weeks from this. Long COVID in children and adolescents should be suspected in presence of persistent headache and fatigue, sleep disturbance, difficulty in concentrating, abdominal pain, myalgia or arthralgia. Persistent chest pain, stomach pain, diarrhea, heart palpitations, and skin lesions should be considered as possible symptoms of long COVID. It is recommended that the primary care pediatrician visits all subjects with a suspected or a proven diagnosis of SARS-CoV-2 infection after 4 weeks to check for the presence of symptoms of previously unknown disease. In any case, a further check-up by the primary care pediatrician should be scheduled 3 months after the diagnosis of SARS-CoV-2 infection to confirm normality or to address emerging problems. The subjects who present symptoms of any organic problem must undergo a thorough evaluation of the same, with a possible request for clinical, laboratory and / or radiological in-depth analysis in case of need. Children and adolescents with clear symptoms of mental stress will need to be followed up by existing local services for problems of this type. Conclusions Pediatric long COVID is a relevant problem that involve a considerable proportion of children and adolescents. Prognosis of these cases is generally good as in most of them symptoms disappear spontaneously. The few children with significant medical problems should be early identified after the acute phase of the infection and adequately managed to assure complete resolution. A relevant psychological support for all the children during COVID-19 pandemic must be organized by health authorities and government that have to treat this as a public health issue.
120	Ch118		Hossein Esmaeilzadeh, Anahita Sanaei Dashti, Negar Mortazavi, Hossein Fatemian & Mohebat Vali	Persistent cough and asthma-like symptoms post COVID-19 hospitalization in children	https://doi.org/10.1186/s12879-022-07252-2	Published	12 March 2022	Study	https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-022-07252-2	Objectives Present study aimed to determine the risk of developing Persistent cough and asthma-like symptoms in hospitalized children due to COVID-19. Methods This prospective study was carried out in a tertiary referral center. During the COVID-19 pandemic, 69 hospitalized pediatric patients admitted with COVID-19 were observed from February 2020 to January 2021. Clinical and laboratory data were recorded, and after discharge, patients were followed and visited for cough and asthma evaluation one, 2 and 6 months later. Patients with asthma-like diagnoses in follow up defined as asthma-like groups, and patients without any sign of asthma were categorized as the non-asthma group. Asthma-like co-morbids and risk factors were evaluated and compared between the two groups. Results In follow-up, most of the COVID-19 hospitalized patients (N = 42) (58.5%) were not affected by asthma-like symptoms. 60.9% of the COVID-19 patients were male. The asthma-like group cases had a significantly familial history of asthma (63.0%), past medical history of asthma (33.3%), and Allergic rhinitis (85.2%). Rates of signs and symptoms during hospitalization were significantly higher in patients with COVID-19 and past medical history of asthma. Conclusions We found an asthma-like prevalence of 41.5% in the cohort of COVID-19 hospitalized children. Family history of asthma and previous history of asthma and allergic rhinitis are risk factors for asthma-like after COVID-19 hospitalization. COVID-19 presentations are more severe in the asthma-like group.
121	Ch119		Danilo Buonsenso‡ , Leonardo Di Gennaro‡, Cristina De Rose, Rosa Morello, Federico D'Ilario, Giuseppe Zampino, Michele Piazza, Attilio L Boner, Cecilia Iraci, Sarah O'Connell, Valentina B Cohen, Susanna Esposito, Daniel Munblit, Joseph Reena, Louise Sigfrid§ & Piero Valentini§	Long-term outcomes of pediatric infections: from traditional infectious diseases to long Covid	https://doi.org/10.2217/fmb-2022-0031	Published	10 Mar 2022	Review	https://www.futuremedicine.com/doi/10.2217/fmb-2022-0031	There is limited evidence available on the long-term impact of SARS-CoV-2 infection in children. In this article, the authors analyze the recent evidence on pediatric long Covid and lessons learnt from a pediatric post-Covid unit in Rome, Italy. To gain a better understanding of the concerns raised by parents and physicians in relation to the potential long-term consequences of this novel infection, it is important to recognize that long-term effect of a post-infectious disease is not a new phenomenon.
122	Ch120		Lynne Peeples	Understanding Kids and COVID As researchers learn more about why COVID-19 tends to be much less severe in children, they’re finding strategies that could help protect all age groups.	https://doi.org/10.1073/pnas.2203753119	Published	March 22, 2022	Article	https://www.pnas.org/doi/full/10.1073/pnas.2203753119	Since the start of the pandemic, even as the circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus shifted from Alpha to Beta to Delta variants, it was clear that most infected children got far less sick than infected adults. We counted our blessings. “The one thing that has allowed us to tolerate this pandemic better than we otherwise would have,” former US Food and Drug Administration (FDA) Commissioner Scott Gottlieb said in a December interview with USA Today, “is that kids weren't getting very sick. If kids were excessively vulnerable to this the way older people were, I think it would have changed how society grappled with this.”
123	Ch121	MIS-C	Sibel Lacinel Gurlevik, Yasemin Ozsurekci, Erdal Sağ, P. Derin Oygar, Selman Kesici, Ümmüşen Kaya Akca, Muserref Kasap Cuceoglu, Ozge Basaran, Sultan Göncü, Jale Karakaya, Ali Bülent Cengiz & Seza Özen	The difference of the inflammatory milieu in MIS-C and severe COVID-19	https://doi.org/10.1038/s41390-022-02029-4	Published	29 March 2022	Study	https://www.nature.com/articles/s41390-022-02029-4	Background Coronavirus disease 19 (COVID-19) may have a severe course in children. Multisystem inflammatory syndrome in children (MIS-C) is the post-COVID complication characterized by an exaggerated inflammation, observed in children. However, data on the underlying pathophysiology are sparse. We therefore aimed to assess the cytokine and chemokine profiles of children with MIS-C and compare these to life-threatening severe SARS-CoV-2 and healthy controls (HCs) to shed light on disease pathophysiology. Methods Samples of 31 children with MIS-C, 10 with severe/critical COVID-19 and 11 HCs were included. Cytokine and chemokine profiles were studied and compared in between groups. Results Most cytokines and chemokines related to IL-1 family and IFN-γ pathway (including IL-18 and MIG/CXCL9) and IL-17A were significantly higher in the MIS-C group when compared to the severe/critical COVID-19 group and HCs. IP-10/CXCL10 and IL-10 were higher in both MIS-C patients and severe/critical COVID-19 compared to HCs. Conclusion Our results suggest that IL-1 and IFN-γ pathways play an important role in the pathophysiology of MIS-C. Impact This study defines a pattern of distinctive immune responses in children with MIS-C and in patients with severe/critical COVID-19. As the COVID-19 pandemic continues, biomarkers to identify MIS-C risk are needed to guide our management that study results may shed light on it.
124	Ch122	MIS-C	Domenico Umberto De Rose 1,2 ,Flaminia Pugnaloni 1,Monica Calì 1,Sara Ronci 1,3,Stefano Caoci 1,Chiara Maddaloni 1,Ludovica Martini 1,Alessandra Santisi 1,Andrea Dotta 1 andCinzia Auriti 1,*	Multisystem Inflammatory Syndrome in Neonates Born to Mothers with SARS-CoV-2 Infection (MIS-N) and in Neonates and Infants Younger Than 6 Months with Acquired COVID-19 (MIS-C): A Systematic Review	https://doi.org/10.3390/v14040750	Published	2 April 2022	Review	https://www.mdpi.com/1999-4915/14/4/750/htm	Introduction: There is an increasing literature describing neonates born to mothers with SARS-CoV-2 infection (MIS-N) and infants infected with SARS-CoV-2 who presented with a severe disease (MIS-C). (2) Methods: To investigate clinical features of multisystem inflammatory syndrome in neonates and infants under six months of age, we used a systematic search to retrieve all relevant publications in the field. We screened in PubMed, EMBASE and Scopus for data published until 10 October 2021. (3) Results: Forty-eight articles were considered, including 29 case reports, six case series and 13 cohort studies. Regarding clinical features, only 18.2% of MIS-N neonates presented with fever; differently from older children with MIS-C, in which gastrointestinal symptoms were the most common manifestation, we displayed that cardiovascular dysfunction and respiratory distress are the prevalent findings both in neonates with MIS-N and in neonates/infants with MIS-C. (4) Conclusions: We suggest that all infants with suspected inflammatory disease should undergo echocardiography, due to the possibility of myocardial dysfunction and damage to the coronary arteries observed both in neonates with MIS-N and in neonates/infants with MIS-C. Moreover, we also summarize how they were treated and provide a therapeutic algorithm to suggest best management of these fragile infants.
125	Ch123		Ran D. Goldman	Long COVID in children	https://doi.org/10.46747/cfp.6804263	Published	April 13, 2022	Article	https://www.cfp.ca/content/68/4/263.full	Question - Several physicians in our family medicine clinic noted a recent increase in the number of children with nonspecific symptoms after having had COVID-19. Based on the assumption that these children may have long COVID syndrome, what is the recommended treatment? Answer - Lockdowns and isolation during the COVID-19 pandemic have affected the physical and mental health of children and adolescents. A recognized complication of COVID-19 is a post–COVID-19 syndrome (long COVID) that was initially reported in adults with an estimated prevalence of 10%. More recent reports on long COVID in children suggest a prevalence of 8% to 10%, but small cohorts, a range of symptoms, and challenges in defining the syndrome make accurately estimating the prevalence difficult. Furthermore, providers may find it challenging to differentiate between neuropsychiatric symptoms that are consequences of COVID-19 infection versus those that are a result of stress, anxiety, or changes in behaviour owing to restrictions associated with the pandemic. Until more evidence is available, management includes obtaining a detailed history, performing a comprehensive physical examination, and aiming to relieve symptoms while following up every 2 to 4 months. Since the start of the COVID-19 pandemic, illness among children was considered mild.1,2 Even during the surge in prevalence of the highly transmissible Omicron variant of COVID-19 in late 2021, while many more children became symptomatic, their illness remained mild, and complications resulting in admission to hospital were few and far between.3,4 Nevertheless, lockdowns, supply chain complications, and isolation have had an impact on children. School closures and regional lockdowns were detrimental to children and adolescents’ physical activity owing to more time on screen and longer periods of sleep,5 and increases in housing and food insecurity were well documented, with concerns about the long-term health of children.6 Furthermore, reliable reports in the early stages of the pandemic described an increased prevalence of depression, anxiety, and behaviour problems in children,7 as well as delays in seeking emergency care.8 A recognized complication of COVID-19 has been termed post–COVID-19 syndrome, or long COVID. The United Kingdom’s National Institute for Health and Care Excellence definition of long COVID includes acute COVID-19, defined by signs and symptoms lasting up to 4 weeks; postacute or ongoing symptomatic COVID-19, when symptoms persist from 4 to 12 weeks; and post– COVID-19 syndrome, defined by signs and symptoms that continue for more than 12 weeks after the onset of acute symptoms. Long COVID includes both postacute COVID-19 and post–COVID-19 syndrome.9 Long COVID was initially reported in adults and included cardio-respiratory conditions, symptoms of fatigue, headache, dyspnea, and anosmia, and it was more likely to occur with older age, with higher body mass index, and among women.10 It has been estimated that up to 10% of adults who test positive for COVID-19 may experience long COVID.11 The list of postviral symptomatology among people who contracted COVID-19 is long and includes nonspecific conditions that are highly prevalent, such as sleep changes, difficulty concentrating, and anxiety.
126	Ch124		Bernice D. Mowery	Long COVID and COVID-19 Omicron Variant in Children	-	Published	April 2022	Review	https://www.proquest.com/openview/63455d3a1b93e30d8efa554132f1b6ca/1?pq-origsite=gscholar&cbl=47659	Long COVID, also called post-COVID-19 syndrome or post-acute sequelae of SARS-CoV-2 (PASC), has recently been recognized but not yet defined in children (Zimmermann et al., 2021). The first large study of children with long COVID, which includes a comparison group, is a Denmark nationwide cohort study that included 37,522 children aged 0 to 17 years with RT-PCR verified SARS-CoV-2 infection (response rate 44.9%) and a control group of 78,037 children (response rate 21.3%). None of the children had been vaccinated because data were collected between January 27, 2020, and March 19, 2021 (Borch et al., 2022). Of the children infected with SARS-CoV-2, 7% were asymptomatic during original infections. Symptoms increased with age, 14.8% in age 0 to 5 years versus 28% in age 6 to 17 years (p = 0.000). More children in the SARS-CoV-2 than in the control group had symptoms lasting greater than four weeks (p < 0.0001), and children testing positive for SARS-CoV-2 reported a higher burden of illness, with 36.6% reporting three or more symptoms. Pre-school children in the COVID-19 group experienced statistically more fatigue, loss of smell and taste, and muscle weakness. School-aged children’s most predominant symptoms were loss of smell and taste, fatigue, respiratory problems, dizziness, muscle weakness, and chest pain. Children in the control group experienced significantly more concentration difficulties, headache, muscle and joint pain, cough, nausea, diarrhea, and fever. Long COVID symptoms resolved in one to five months for 54% to 75% of children. The investigators postulate that concentration difficulties (such as headache), muscle and joint pain, and nausea the control group may reflect the negative social consequences of the pandemic on children. The COVID-19 group reported higher scores on the World Health Organization-Five Well-Being Index (WHO-5) than the control group, which supports this hypothesis. Potential study limitations include those typical of observational studies, which do not include objective evaluations and diffusion risk because the control group may have included children with asymptomatic COVID-19. Further study is needed to clarify long COVID-19 and determine the effects of vaccination on long COVID-19 in the pediatric population.
127	Ch125		Nadine Peart Akindele, Lisa Pieterse, San Suwanmanee, Diane E Griffin	B cell responses in hospitalized SARS-CoV-2-infected children with and without Multisystem Inflammatory Syndrome	https://doi.org/10.1093/infdis/jiac119	Published	18 April 2022	Study	https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiac119/6569992?login=true	Multisystem inflammatory syndrome in children (MIS-C) can complicate infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but differences in the immune responses during MIS-C compared to coronavirus disease 2019 (COVID-19) are poorly understood. We longitudinally compared the amounts and avidity of plasma anti-nucleocapsid (N) and spike (S) antibodies, phenotypes of B cells and numbers of virus-specific antibody-secreting cells in circulation of children hospitalized with COVID-19 (N=10) and with MIS-C (N=12). N-specific IgG was higher early after presentation for MIS-C than COVID-19 patients and avidity of N- and S-specific IgG at presentation did not mature further during follow up as it did for COVID-19. Both groups had waning proportions of B cells in circulation and decreasing but sustained production of virus-specific antibody-secreting cells for months. Overall, B cell responses were similar, but those with MIS-C demonstrated a more mature antibody response at presentation, suggesting a postinfectious entity compared to COVID-19.
128	Ch126		F. A. Khaydarova, N. U. Alimova, A. V. Alieva, A. S. Sadykova, M. D. Aripova	Impact of COVID-19 infection on the development of type 1 diabetes mellitus in children and adolescents	https://doi.org/10.14341/DM12785	Published	April 2022	Study	https://www.dia-endojournals.ru/jour/article/view/12785?locale=en_US	Children did not escape the COVID-19 pandemic. Although, in general, the course of viral infection in children is mild, the question of the long-term effects of COVID-19 on a child and adolescent, in particular, on pancreatic beta cells, remains unclear. Аim: Тo study the characteristics of children with diabetes mellitus identified after COVID-19 infection. Materials and methods: This article presents the preliminary results obtained from children and adolescents hospitalized at the RSSPMCE clinic with the newly diagnosed diabetes mellitus after COVID infection, as well as a systematic review of 61 clinical cases (case series study). Results: Of the 120 children hospitalized at the RSSPMCE clinic with newly diagnosed diabetes, 15 were diagnosed with diabetes after COVID-19 infection, all in a state of diabetic ketoacidosis. Only 20% of children knew about the previous COVID-19 infection, the course of the disease was mild, in 80% of children the infection was asymptomatic. At the time of diabetes onset, all children had a high level of HbA1c - above 10%, a low level of vitamin D, high levels of antibodies to SARS-CoV-2 (IgG), and the need for insulin was above the average. Conclusion: The SARS CoV-2 virus could be the direct cause of the development of diabetes mellitus in children, even with the asymptomatic course of the viral infection. However, the question remains about the exact classification of diabetes after COVID-19 in children. It is necessary to inform the population about the first signs and symptoms of diabetes mellitus in order to timely consult a doctor for the diagnosis of diabetes mellitus.
129	Ch127		Frank Zhu & Jocelyn Y. Ang	COVID-19 Infection in Children: Diagnosis and Management	https://doi.org/10.1007/s11908-022-00779-0	Published	11 April 2022	Review	https://link.springer.com/article/10.1007/s11908-022-00779-0	Purpose of Review Due to the rapidly changing landscape of COVID-19, the purpose of this review is to provide a concise and updated summary of pediatric COVID-19 diagnosis and management. Recent Findings The relative proportion of pediatric cases have significantly increased following the emergence of the Omicron variant (from < 2% in the early pandemic to 25% from 1/27 to 2/3/22). While children present with milder symptoms than adults, severe disease can still occur, particularly in children with comorbidities. There is a relative paucity of pediatric data in the management of COVID-19 and the majority of recommendations remain based on adult data. Summary Fever and cough remain the most common clinical presentations, although atypical presentations such as “COVID toes,” anosmia, and croup may be present. Children are at risk for post-infectious complications such as MIS-C and long COVID. Nucleic acid amplification tests through respiratory PCR remain the mainstay of diagnosis. The mainstay of management remains supportive care and prevention through vaccination is highly recommended. In patients at increased risk of progression, interventions such as monoclonal antibody therapy, PO Paxlovid, or IV remdesivir × 3 days should be considered. In patients with severe disease, the use of remdesivir, dexamethasone, and immunomodulatory agents (tocilizumab, baricitinib) is recommended. Children can be at risk for thrombosis from COVID-19 and anticoagulation is recommended in children with markedly elevated D-dimer levels or superimposed clinical risk factors for hospital associated venous thromboembolism.
130	Ch128		Rosa Savino 1,*ORCID,Anna N. Polito 1,Giulia Arcidiacono 1,Mariacristina Poliseno 2ORCID andSergio Lo Caputo 2ORCID	Neuropsychiatric Disorders in Pediatric Long COVID-19: A Case Series	https://doi.org/10.3390/brainsci12050514	Published	19 April 2022	Case Report	https://www.mdpi.com/2076-3425/12/5/514/htm	Few data are available regarding the incidence and the evolution of neuropsychiatric manifestations in children with a history of COVID-19. We herein report five consequent cases of pediatric patients with psychiatric and neurological symptoms of long COVID-19. All patients, mainly males, reported asymptomatic-to-mild COVID-19 and underwent home self-isolation. Abnormal movements, anxiety, and emotional dysregulation were the most recurrent symptoms observed from a few weeks to months after the resolution of the acute infection. A later onset was observed in younger patients. Blood tests and brain imaging resulted in negative results in all subjects; pharmacological and cognitive behavioral therapy was set. A multifactorial etiology could be hypothesized in these cases, as a result of a complex interplay between systemic and brain inflammation and environmental stress in vulnerable individuals. Longer follow-up is required to observe the evolution of neuropsychiatric manifestation in the present cohort and other young patients with previous SARS-CoV-2 infection.
131	Ch129		Michele Piazza 1ORCID,Maria Di Cicco 2ORCID,Luca Pecoraro 1ORCID,Michele Ghezzi 3ORCID,Diego Peroni 2,*ORCID andPasquale Comberiati 2ORCID	Long COVID-19 in Children: From the Pathogenesis to the Biologically Plausible Roots of the Syndrome	https://doi.org/10.3390/biom12040556	Published	8 April 2022	Review	https://www.mdpi.com/2218-273X/12/4/556/htm	Long Coronavirus disease-19 (COVID-19) refers to the persistence of symptoms related to the infection with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). This condition is described as persistent and can manifest in various combinations of signs and symptoms, such as fatigue, headache, dyspnea, depression, cognitive impairment, and altered perception of smells and tastes. Long COVID-19 may be due to long-term damage to different organs—such as lung, brain, kidney, and heart—caused by persisting viral-induced inflammation, immune dysregulation, autoimmunity, diffuse endothelial damage, and micro thrombosis. In this review, we discuss the potential and biologically plausible role of some vitamins, essential elements, and functional foods based on the hypothesis that an individual’s dietary status may play an important adjunctive role in protective immunity against COVID-19 and possibly against its long-term consequences.
132	Ch130		Berfin Uysal, Tuğberk Akça, Okan Akacı, Fahrettin Uysal	The Prevalence of Post-COVID-19 Hypertension in Children	https://doi.org/10.1177%2F00099228221085346	Published	April 24, 2022	Study	https://journals.sagepub.com/doi/abs/10.1177/00099228221085346	Coronavirus disease 2019 (COVID-19) is the greatest pandemic in a century. In this study, children with mild COVID-19 infections were evaluated at least 8 weeks after the polymerase chain reaction (PCR) test positivity, and the frequency of hypertension (HT) in these children was investigated. These results were compared to those of the control group, which consisted of 32 healthy children in the same age range as the trial group but who did not have COVID-19. This prospective multicenter study was conducted including children aged 10 to 18 years. There were 16 patients (16%) who had elevated systolic blood pressure, while 11 patients (11%) had stage-1 HT and 1 patient (1%) had stage-2 HT. It was revealed that children with COVID-19 had significantly higher systolic and diastolic blood pressures than normal healthy children. The findings of this study contribute toward increasing the understanding of the sequelae of mild COVID-19 in pediatric patients.
133	Ch131		Mayank Gupta, MDa,*; Nihit Gupta, MDb; and Michael Esang, MDa	Long COVID in Children and Adolescents	https://doi.org/10.4088/PCC.21r03218	Published	April 26, 2022	Review	https://www.psychiatrist.com/pcc/covid-19/long-covid-children-adolescents/	Objective: To review the empirical evidence regarding neuropsychiatric illness (long coronavirus disease [COVID]) in children and adolescents post–severe acute respiratory coronavirus disease 2 (SARS-CoV-2) infection. Data Sources: A search of PubMed, PsycINFO, Cochrane Library, and Google Scholar was conducted from the date of inception until February 2022 using the keywords corona*, COVID-19, SARS-CoV-2, mental health, depression, anxiety, neurological, psychiatric, long COVID, and post-COVID outcomes. Age filters were used to include children and adolescents aged ≤ 18 years. Study Selection: The search resulted in the identification of 526 articles; 48 articles met the inclusion criteria. Data Extraction: Results are presented using a narrative review format. Data regarding long COVID in children and adolescents post–SARS-CoV-2 infection were extracted to understand epidemiologic trends, preventive measures, and treatment options. Results: Studies during the initial phase of the pandemic reported a mixed range of symptoms from case reports or case series. However, multisystem inflammatory syndrome in children (MIS‐C) was widely reported. During the subsequent phases, the emergence of new variants led to a surge of SARS-CoV-2 infections in pediatric populations. There were highly variable, mixed symptom clusters within 60 days post-infection, which resolved in many patients within 6 months. There were prolonged illnesses and impairments in some children and adolescents with long COVID, and many had similar symptoms even though they tested negative for COVID-19. Conclusions: Long COVID symptoms are both physical and mental in nature among children and adolescents. The impairments have the potential to affect long-term functioning and increase the overall burden on health care delivery. Despite current studies having methodological issues, there is a consensus to provide multidisciplinary and holistic care to those in need. Long COVID in children and adolescents is a distinct clinical condition that presents in relapsing and remitting patterns and is recognized cross-culturally with a mixed range of highly variable symptoms within 60 days of SARS-CoV-2 infection. Many who tested negative for COVID-19 also had long COVID symptoms with impairments similar to those who tested positive. Epidemiology, risk factors, and mechanisms are largely unknown, and although most children and adolescents recover from long COVID within 6 months, many suffer from persistent illness and impairments. Vaccinations may play a role in prevention of long COVID in children and adolescents, and multidisciplinary specialized COVID rehabilitation clinics are a step in the right direction.
134	Ch132		Gökçen Kartal Öztürk, Burçin Beken, Sümeyra Doğan & Himmet Haluk Akar	Pulmonary function tests in the follow-up of children with COVID-19	https://doi.org/10.1007/s00431-022-04493-w	Published	06 May 2022	Study	https://link.springer.com/article/10.1007/s00431-022-04493-w	The SARS-CoV-2 virus has infected more than 235 million people since it was accepted as a pandemic in March 2020. Although a milder disease is seen in the pediatric age group, the extent of lung damage and its long-term effects are still unknown. In this study, persistent respiratory symptoms and pulmonary function tests were investigated in children with COVID-19. Fifty children with a confirmed diagnosis of COVID-19 were included in the study. Patients were evaluated for ongoing respiratory symptoms and pulmonary function tests 3 months after infection. Patients with and without persistent symptoms were compared in terms of demographic, clinical, laboratory, and radiological characteristics and also disease severity. Three months after infection, persistent respiratory symptoms were found to be present in 28% of patients; cough, chest pain and tightness, dyspnea, and exertional dyspnea were the most common symptoms. Three patients had an obstructive deficit, and one had a restrictive deficit. Four patients had impaired diffusing capacity of the lungs for carbon monoxide (DLCO). A significant decrease in FEV1/FVC and an increase in lung clearance index were found in the patients with persistent respiratory symptoms. Persistent respiratory symptoms were present in 50% of patients who had severe disease and 12.5% with non-severe disease. DLCO was also significantly lower in the severe disease group. Conclusions: Our study suggests that the persistence of respiratory symptoms is not related to the severity of acute COVID-19 in children. The inflammatory process due to COVID-19 may continue regardless of its severity, and consequently, peripheral airways may be affected.
135	Ch133	MIS-C	Conor McCafferty, Tengyi Cai, Delphine Borgel, Dominique Lasne, Sylvain Renolleau, Meryl Vedrenne-Cloquet, Damien Bonnet, Jemma Wu, Thiri Zaw, Atul Bhatnagar, Xiaomin Song, Suelyn Van Den Helm, Natasha Letunica, Chantal Attard, Vasiliki Karlaftis, Slavica Praporski, Vera Ignjatovic & Paul Monagle	Pathophysiological pathway differences in children who present with COVID-19 ARDS compared to COVID -19 induced MIS-C	https://doi.org/10.1038/s41467-022-29951-9	Published	02 May 2022	Article	https://www.nature.com/articles/s41467-022-29951-9	COVID-19 has infected more than 275 million worldwide (at the beginning of 2022). Children appear less susceptible to COVID-19 and present with milder symptoms. Cases of children with COVID-19 developing clinical features of Kawasaki-disease have been described. Here we utilise Mass Spectrometry proteomics to determine the plasma proteins expressed in healthy children pre-pandemic, children with multisystem inflammatory syndrome (MIS-C) and children with COVID-19 induced ARDS. Pathway analyses were performed to determine the affected pathways. 76 proteins are differentially expressed across the groups, with 85 and 52 proteins specific to MIS-C and COVID-19 ARDS, respectively. Complement and coagulation activation are implicated in these clinical phenotypes, however there was significant contribution of FcGR and BCR activation in MIS-C and scavenging of haem and retinoid metabolism in COVID-19 ARDS. We show global proteomic differences in MIS-C and COVID-ARDS, although both show complement and coagulation dysregulation. The results contribute to our understanding of MIS-C and COVID-19 ARDS in children.
136	Ch134		Karel Kostev, Lee Smith, Ai Koyanagi, Marcel Konrad & Louis Jacob	Post-COVID-19 conditions in children and adolescents diagnosed with COVID-19	https://doi.org/10.1038/s41390-022-02111-x	Published	14 May 2022	Study	https://www.nature.com/articles/s41390-022-02111-x	Background This study aimed to investigate the prevalence of and the factors associated with post-COVID-2019 condition in COVID-19 children and adolescents in Germany. Methods The present retrospective cohort study used data from the Disease Analyzer database (IQVIA), and included patients aged <18 years who were diagnosed with COVID-19 in one of 524 general and 81 pediatric practices in Germany between October 2020 and August 2021 (index date: first COVID-19 diagnosis). Post-COVID-19 condition was assessed between the index date and November 2021. Covariates included age, sex, type of practice, and chronic conditions documented in at least 1% of the population. Results There were 6568 children and adolescents included in this study (mean [SD] age 10.1 [4.9] years; 49.2% girls). The prevalence of post-COVID-19 condition was 1.7% in the population. Patients aged 13–17 years were more likely to be diagnosed with post-COVID-19 condition compared with those being aged ≤5 years (RR = 3.14). Anxiety disorders (RR = 2.53), somatoform disorders (RR = 2.11), and allergic rhinitis (RR = 2.02) were also significantly associated with post-COVID-19 condition. Conclusion Post-COVID-19 condition was rare in COVID-19 children and adolescents in Germany. Data from other settings are warranted to confirm these findings. Impact The prevalence of post-COVID-19 condition was 1.7% in this population of children and adolescents. Older children and adolescents were more likely to be diagnosed with post-COVID-19 condition than their younger counterparts. Anxiety disorders, somatoform disorders, and allergic rhinitis were significantly associated with post-COVID-19 condition. More data from other settings and countries are warranted to corroborate or refute these findings.
137	Ch135		Carla Petrella 1,†ORCID,Raffaella Nenna 2,†ORCID,Laura Petrarca 2,Francesca Tarani 2,Roberto Paparella 2ORCID,Enrica Mancino 2,Greta Di Mattia 2,Maria Giulia Conti 2,Luigi Matera 2,Enea Bonci 3ORCID,Flavio Maria Ceci 3ORCID,Giampiero Ferraguti 3ORCID,Francesca Gabanella 1,Christian Barbato 1ORCID,Maria Grazia Di Certo 1,Luca Cavalcanti 4ORCID,Antonio Minni 4,Fabio Midulla 2,Luigi Tarani 2,‡ORCID andMarco Fiore 1,*,‡ORCID	Serum NGF and BDNF in Long-COVID-19 Adolescents: A Pilot Study	https://doi.org/10.3390/diagnostics12051162	Published	7 May 2022	Study	https://www.mdpi.com/2075-4418/12/5/1162/htm	COVID-19 (COronaVIrus Disease 19) is an infectious disease also known as an acute respiratory syndrome caused by the SARS-CoV-2. Although in children and adolescents SARS-CoV-2 infection produces mostly mild or moderate symptoms, in a certain percentage of recovered young people a condition of malaise, defined as long-COVID-19, remains. To date, the risk factors for the development of long-COVID-19 are not completely elucidated. Neurotrophins such as NGF (Nerve Growth Factor) and BDNF (Brain-Derived Neurotrophic Factor) are known to regulate not only neuronal growth, survival and plasticity, but also to influence cardiovascular, immune, and endocrine systems in physiological and/or pathological conditions; to date only a few papers have discussed their potential role in COVID-19. In the present pilot study, we aimed to identify NGF and BDNF changes in the serum of a small cohort of male and female adolescents that contracted the infection during the second wave of the pandemic (between September and October 2020), notably in the absence of available vaccines. Blood withdrawal was carried out when the recruited adolescents tested negative for the SARS-CoV-2 (“post-infected COVID-19”), 30 to 35 days after the last molecular test. According to their COVID-19 related outcomes, the recruited individuals were divided into three groups: asymptomatics, acute symptomatics and symptomatics that over time developed long-COVID-19 symptoms (“future long-COVID-19”). As a control group, we analyzed the serum of age-matched healthy controls that did not contract the infection. Inflammatory biomarkers (TNF-α, TGF-β), MCP-1, IL-1α, IL-2, IL-6, IL-10, IL-12) were also analyzed with the free oxygen radicals’ presence as an oxidative stress index. We showed that NGF serum content was lower in post-infected-COVID-19 individuals when compared to healthy controls; BDNF levels were found to be higher compared to healthy individuals only in post-infected-COVID-19 symptomatic and future long-COVID-19 girls, leaving the BDNF levels unchanged in asymptomatic individuals if compared to controls. Oxidative stress and inflammatory biomarkers were unchanged in male and female adolescents, except for TGF-β that, similarly to BDNF, was higher in post-infected-COVID-19 symptomatic and future long-COVID-19 girls. We predicted that NGF and/or BDNF could be used as early biomarkers of COVID-19 morbidity in adolescents.
138	Ch136		Silvia Bloise, Sara Isoldi, Alessia Marcellino, Enrica De Luca, Anna Dilillo, Saverio Mallardo, Vanessa Martucci, Mariateresa Sanseviero, Emanuela Del Giudice, Donatella Iorfida, Rita Leone, Alessia Testa, Beatrice Frasacco, Pietro Gizzone, Claudia Proietti Ciolli, Alessandro Sinceri, Francesca Zuliani, Elena Zanardi, Anna Gambarotto, Anna Lisa Grandinetti, Flavia Ventriglia & Riccardo Lubrano	Clinical picture and long-term symptoms of SARS-CoV-2 infection in an Italian pediatric population	https://doi.org/10.1186/s13052-022-01270-1	Published	21 May 2022	Study	https://ijponline.biomedcentral.com/articles/10.1186/s13052-022-01270-1	Background SARS-CoV-2 infection in the pediatric age group has a milder course than in adults, but in some cases even children may present with severe forms or develop long-term consequences. The aim of this study was to analyze the clinical features, long-term effects, lifestyle changes and psychological effects of SARS-CoV-2 infection in a pediatric sample of the Italian population. Methods We conducted a telephone survey among 3075 children infected with SARS-CoV-2 in the Latina Local Health Authority. Outcomes included: clinical features of infection, long-term symptoms, lifestyle changes and emotional symptoms during the illness. The information obtained was automatically linked to a spreadsheet and analyzed. Results One thousand four hundred thirteen children agreed to participate in the study; the mean age was 112.8 ± 21.9 months. Children were infected mainly inside familial clusters (59.6%; n = 842); 99% (n = 1399) of children were asymptomatic or exhibited mild symptoms. 20% (n = 259) of children experienced long-term symptoms; risk factors were: older age, higher body mass index and longer duration of infection. Throughout the period of infection, children spent most of the time on devices like tv-video, social media and mobile phone for non-educational activities. 58.8% (n = 620) of parents expressed a negative opinion about distance learning. Finally, we observed that 49,6% (n = 532) of children experienced psychological symptoms during quarantine period. Conclusion Despite a lower susceptibility to COVID-19 in children, it is important to keep the focus high in children, both because of the possible long symptoms after infection and the impact on a children’s mental and physical health due to pandemic. We believe that the return to school or other extracurricular activities are important to correct some of the risk factors for the long COVID syndrome, as obesity, and to limit the cultural damage generated by distance learning and psychological effects related to restrictive measures.
139	Ch137		Diana Drogalis-Kim, DO; Collin Kramer, MD; Silvestre Duran	Ongoing Dizziness Following Acute COVID-19 Infection: A Single Center Pediatric Case Series	https://doi.org/10.1542/peds.2022-056860	Published	June 01 2022	Case Series	https://publications.aap.org/pediatrics/article/doi/10.1542/peds.2022-056860/188138/Ongoing-Dizziness-Following-Acute-COVID-19	Dizziness is a common concern discussed at adolescent medical visits. In this series, we describe 9 pediatric patients with Post-Acute Sequelae of SARS-CoV-2 (PASC) who presented with persistent, debilitating dizziness for weeks to months after their acute infection. Among the 9 patients, median age was 14 years (range: 11-17), 6 were female, and 8 had not received any SARS-CoV-2 vaccines. Five patients met diagnostic criteria for postural orthostatic tachycardia syndrome (POTS) by active standing testing and benefited from a combination of non-pharmacologic therapy (NPT) and medication. NPT alone did not improve symptoms in any patients. Patients who did not meet conventional criteria for POTS, but continued to have symptoms despite NPT compliance, also demonstrated subjective improvement in dizziness when medications were initiated. The majority of patients experienced improvement in dizziness and quality of life, including returning to sports teams and a regular school schedule. A review of the PACS literature demonstrates increasing recognition of a subset of patients who develop autonomic dysfunction, including POTS, although the etiology and prognosis are not completely understood. Our case series aims to highlight the phenomenon of dysautonomia after acute SARS-CoV-2 infection and its response to therapy.
140	Ch138	PESE	Nicole Töpfner, Martin Alberer, Tobias Ankermann, Stephan Bender, Reinhard Berner, Jan de Laffolie, Jens Dingemann, Dirk Heinicke, Johannes Peter Haas, Markus Hufnagel, Thomas Hummel, Hans-Iko Huppertz, Markus Knuf, Robin Kobbe, Thomas Lücke, Joachim Riedel, Josef Rosenecker, Joachim Wölfle, Barbara Schneider, Dominik Schneider, Valentin Schriever, Anne Schroeder, Silvia Stojanov, Tobias Tenenbaum, Stefan Trapp, Daniel Vilser, Folke Brinkmann, Uta Behrends	Einheitliche Basisversorgung von Kindern und Jugendlichen mit Long COVID Stellungnahme einer multidisziplinären Arbeitsgruppe der DGKJ-Konvent-Gesellschaften (Stand: Februar 2022) Recommendation for standardized medical care for children and adolescents with long COVID Statement of a multidisciplinary pediatric expert group of the DGKJ convent societies (status: February 2022)	https://doi.org/10.1007/s00112-021-01408-1	Published	25 May 2022	Review	https://link.springer.com/article/10.1007/s00112-021-01408-1	Das vorliegende Konsensuspapier bietet in Ergänzung zur AWMF-S1-Leitlinie eine Übersicht über die verschiedenen klinischen Aspekte von Long COVID im Kindes- und Jugendalter. Es wurde von Vertreter:innen aus 19 Fachgesellschaften des DGKJ-Konvents und kooperierenden Fachgesellschaften erstellt und bietet Expertenempfehlungen für die Praxis auf Grundlage der bisherigen, noch geringen studienbasierten Evidenz zu Long COVID im Kindes- und Jugendalter. Es enthält Screeningfragen zu Long COVID sowie einen Vorschlag zur strukturierten, standardisierten pädiatrischen Anamnese und zur diagnostischen Evaluation bei V. a. Long COVID. Dazu werden ein zeit- und ressourcensparender Erfassungsbogen, der die Komplexität des Krankheitsbildes berücksichtigt, über die Internetseiten der DGKJ und DGPI zur Verfügung gestellt und weitere Fragebögen zur Abklärung von spezifischen neurokognitiven und/oder psychischen Störungen sowie post-exertioneller Malaise (PEM) und myalgischer Enzephalomyelitis/chronischem Fatigue-Syndrom (ME/CFS) benannt. Anhand der jeweiligen anamnestisch und klinisch ermittelten Hauptsymptome werden ein gestuftes, diagnostisches Vorgehen und eine multidisziplinäre Betreuung empfohlen. Abstract This current consensus paper for long COVID complements the existing AWMF S1 guidelines for long COVID with a detailed overview on the various clinical aspects of long COVID in children and adolescents. Members of 19 different pediatric societies of the DGKJ convent and collaborating societies together provide expert-based recommendations for the clinical management of long COVID based on the currently available but limited academic evidence for long COVID in children and adolescents. It contains screening questions for long COVID and suggestions for a structured, standardized pediatric medical history and diagnostic evaluation for patients with suspected long COVID. A time and resource-saving questionnaire, which takes the clinical complexity of long COVID into account, is offered via the DGKJ and DGPI websites as well as additional questionnaires suggested for an advanced screening of specific neurocognitive and/or psychiatric symptoms including post-exertional malaise (PEM) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). According to the individual medical history as well as clinical signs and symptoms a step by step diagnostic procedure and a multidisciplinary therapeutic approach are recommended.
141	Ch139		M.GlaiR.GuedriZ.FitouriS.Ben Becher	Etude comparative des formes d'atteinte COVID-19 pédiatrique	https://doi.org/10.1016/j.mmifmc.2022.03.123	Published	31 May 2022	Study	https://www.sciencedirect.com/science/article/pii/S2772743222001416	L'atteinte COVID-19 pédiatrique est rare et bénigne selon les données mondiales. Deux formes cliniques ont été essentiellement décrites chez l'enfant. Il s'agit de la forme aigüe active et du syndrome inflammatoire multi systémique (MIS-C syndrome). L'objectif de ce travail était de comparer les aspects épidémio-cliniques, diagnostiques, thérapeutiques et évolutifs des deux formes d'atteinte COVID-19 pédiatrique. Matériels et méthodes Il s'agissait d'une étude rétrospective menée sur une année (mars 2020-mars 2021) dans une unité d'isolement COVID-19.L'infection à SARS-CoV-2 a été confirmée par RT-PCR sur prélèvement nasopharyngé. Les cas de MIS-C syndrome répondaient à la définition de l'organisation mondiale de la santé (OMS). Résultats Nous avons colligé 99 patients répartis en 67 formes aigües (67,7 %) et 32 cas de MIS-C syndrome (32,3 %). En comparaison avec l'infection active, les patients du groupe MIS-C étaient plus âgés (7,5 ans contre 3,8 ans ;p<0.05). Ainsi, les signes les plus retrouvés étaient la fièvre [100 % (n=32) contre 79,1 % (n=53) ;p<0.05], les signes cutanéo-muqueux [90,6 % (n=29) contre 7,5 % (n=5) ;p<0,05], les manifestations cardiaques [68,8 % (n=22) contre 3 % (n=2) ;p<0,05] et les signes digestifs [56,3 % (n=18) contre 19,4 % (n=13) ;p<0,05]. Cependant, l'atteinte respiratoire était plus rarement rapportée [6,3 % (n=2) contre 56,7 % (n=38) ;p<0,05]. La myocardite (40,6 % ; n=13) et l'état de choc cardiogénique (18,75 % ; n=6) étaient les complications cardiaques les plus redoutées. Les anomalies biologiques les plus retrouvées au cours du MIS-C étaient le syndrome inflammatoire [87,5 % (n=25) contre 39,5 % (n=17) ;p<0,05], l'anémie [62,5 % (n=20) contre 35,8 % (n=24) ;p<0,05], la lymphopénie [75 % (n=24) contre 32,8 % (n=22) ;p<0.05], l'ascension des D-dimères (65,6 % ; n=21) et l'élévation des troponines (40,6 % ; n=13). Le traitement était symptomatique dans l'infection active. Le recours à l'oxygène était indiqué dans 22 % des cas. Pour la forme inflammatoire systémique, le traitement était basé sur les immunoglobulines dans 100 % des cas et sur la corticothérapie dans 75 % des cas. Trois décès sur des terrains fragilisés ont été déplorés pour la forme aigüe. Aucun décès n'était survenu dans le groupe MIS-C. Conclusion Le MIS-C syndrome est une forme retardée de l'infection COVID-19. Les facteurs susceptibles de déclencher la cascade inflammatoire post exposition au virus restent en cours de recherche.
142	Ch140		Juanjie Tang, Tanya Novak, Julian Hecker, Gabrielle Grubbs, Fatema Tuz Zahra, Lorenza Bellusci, Sara Pourhashemi, Janet Chou, Kristin Moffitt, Natasha B. Halasa, Stephanie P. Schwartz, Tracie C. Walker, Keiko M. Tarquinio, Matt S. Zinter, Mary A. Staat, Shira J. Gertz, Natalie Z. Cvijanovich, Jennifer E. Schuster, Laura L. Loftis, Bria M. Coates, Elizabeth H. Mack, Katherine Irby, Julie C. Fitzgerald, Courtney M. Rowan, Michele Kong, Heidi R. Flori, Aline B. Maddux, Steven L. Shein, Hillary Crandall, Janet R. Hume, Charlotte V. Hobbs, Adriana H. Tremoulet, Chisato Shimizu, Jane C. Burns, Sabrina R. Chen, Hye Kyung Moon, Christoph Lange, Adrienne G. Randolph & Surender Khurana	Cross-reactive immunity against the SARS-CoV-2 Omicron variant is low in pediatric patients with prior COVID-19 or MIS-C	https://doi.org/10.1038/s41467-022-30649-1	Published	27 May 2022	Study	https://www.nature.com/articles/s41467-022-30649-1	Neutralization capacity of antibodies against Omicron after a prior SARS-CoV-2 infection in children and adolescents is not well studied. Therefore, we evaluated virus-neutralizing capacity against SARS-CoV-2 Alpha, Beta, Gamma, Delta and Omicron variants by age-stratified analyses (<5, 5–11, 12–21 years) in 177 pediatric patients hospitalized with severe acute COVID-19, acute MIS-C, and in convalescent samples of outpatients with mild COVID-19 during 2020 and early 2021. Across all patients, less than 10% show neutralizing antibody titers against Omicron. Children <5 years of age hospitalized with severe acute COVID-19 have lower neutralizing antibodies to SARS-CoV-2 variants compared with patients >5 years of age. As expected, convalescent pediatric COVID-19 and MIS-C cohorts demonstrate higher neutralization titers than hospitalized acute COVID-19 patients. Overall, children and adolescents show some loss of cross-neutralization against all variants, with the most pronounced loss against Omicron. In contrast to SARS-CoV-2 infection, children vaccinated twice demonstrated higher titers against Alpha, Beta, Gamma, Delta and Omicron. These findings can influence transmission, re-infection and the clinical disease outcome from emerging SARS-CoV-2 variants and supports the need for vaccination in children.
143	Ch141		Sepideh Benvari, Shima Mahmoudi & Mohsen Mohammadi	Gastrointestinal viral shedding in children with SARS-CoV-2: a systematic review and meta-analysis	https://doi.org/10.1007/s12519-022-00553-1	Published	04 June 2022	Review	https://link.springer.com/article/10.1007/s12519-022-00553-1	Background Coronavirus disease 2019 (COVID-19) has different manifestations in pediatric cases. It is assumed that they might present more gastrointestinal symptoms with a different viral shedding pattern in gastrointestinal samples. In this systematic review and meta-analysis, we aimed to evaluate the viral shedding pattern in gastrointestinal specimens of children with COVID-19. Methods We searched all published studies in English language in PubMed, Web of Science, and Scopus, up to date as of October 2021. Our search included the term "severe acute respiratory syndrome coronavirus 2, COVID-19, SARS-CoV-2, novel coronavirus, or coronavirus; and shed, excrete, secret, or carriage; and stool or rectal; and children or pediatrics". We included studies evaluating SARS-CoV-2 shedding in gastrointestinal specimens, including rectal swabs and stool samples of children with COVID-19 infection. We excluded duplicated data, case reports, and studies without original data. Results Twelve studies met the eligibility criteria for the qualitative synthesis, 10 of which were included in the meta-analysis. The pooled prevalence of gastrointestinal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in children with COVID-19 was 86% (95% confidence interval 73%–96%, I2 = 62.28%). After respiratory specimen had become negative, 72% (43/60) had persistent shedding in gastrointestinal specimens. The gastrointestinal RNA had a positive test result for more than 70 days after symptoms onset. Conclusions Gastrointestinal shedding of SARS-CoV-2 might occur in a substantial portion of children and might persist long after negative respiratory testing. Further research is recommended to find the role of SARS-CoV-2 gastrointestinal shedding in transmission in children.
144	Ch142		Ruting Wang, Zifeng Wu, Chaoli Huang, Kenji Hashimoto, Ling Yang & Chun Yang	Deleterious effects of nervous system in the offspring following maternal SARS-CoV-2 infection during the COVID-19 pandemic	https://doi.org/10.1038/s41398-022-01985-z	Published	06 June 2022	Review	https://www.nature.com/articles/s41398-022-01985-z	During the Coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is universally susceptible to all types of populations. In addition to the elderly and children becoming the groups of great concern, pregnant women carrying new lives need to be even more alert to SARS-CoV-2 infection. Studies have shown that pregnant women infected with SARS-CoV-2 can lead to brain damage and post-birth psychiatric disorders in offspring. It has been widely recognized that SARS-CoV-2 can affect the development of the fetal nervous system directly or indirectly. Pregnant women are recommended to mitigate the effects of COVID-19 on the fetus through vaccination, nutritional supplements, and psychological support. This review summarizes the possible mechanisms of the nervous system effects of SARS-CoV-2 infection on their offspring during the pregnancy and analyzes the available prophylactic and treatment strategies to improve the prognosis of fetal-related neuropsychiatric diseases after birth.
145	Ch143		Cooper, Shiri MD†,⁑; Tobar, Ana MD,⁑; Konen, Osnat MD‡,⁑; Orenshtein, Naama MD§,⁑; Kropach, Nesia MD§,⁑; Landau, Yuval MD PhD¶,⁑; Mozer-Glassberg, Yael MD†,⁑; Bar-Lev, Michal Rosenfeld MD†,⁑; Shaoul, Ron MD*; Shamir, Raanan MD†,⁑; Waisbourd-Zinman, Orith MD†,⁑	Long COVID-19 Liver Manifestation in Children	https://doi.org/10.1097/MPG.0000000000003521	Published	June 10, 2022	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0267392	Objectives: SARS CoV-2, the novel coronavirus responsible for coronavirus disease (COVID-19), has been a major cause of morbidity and mortality worldwide. Gastrointestinal and hepatic manifestations during acute disease have been reported extensively in the literature. Post-COVID-19 cholangiopathy has been increasingly reported in adults. In children, data are sparse. Our aim was to describe pediatric patients who recovered from COVID-19 and later presented with liver injury. Methods: This is a retrospective case-series study of pediatric patients with post-COVID-19 liver manifestations. We collected data on demographics, medical history, clinical presentation, laboratory results, imaging, histology, treatment, and outcome. Results: We report five pediatric patients who recovered from COVID-19 and later presented with liver injury. Two types of clinical presentation were distinguishable. Two infants aged 3 and 5 months, previously healthy, presented with acute liver failure that rapidly progressed to liver transplantation. Their liver explant showed massive necrosis with cholangiolar proliferation and lymphocytic infiltrate. Three children, two aged 8 years and one aged 13 years, presented with hepatitis with cholestasis. Two children had a liver biopsy significant for lymphocytic portal and parenchyma inflammation, along with bile duct proliferations. All three were started on steroid treatment; liver enzymes improved, and they were weaned successfully from treatment. For all five patients, extensive etiology workup for infectious and metabolic etiologies were negative. Conclusions: We report two distinct patterns of potentially long COVID-19 liver manifestations in children with common clinical, radiological, and histopathological characteristics after a thorough workup excluded other known etiologies.
146	Ch144		Andrea G. Edlow, MD, MSc1; Victor M. Castro, MS2,3; Lydia L. Shook, MD1; Anjali J. Kaimal, MD, MAS1; Roy H. Perlis, MD, MSc2	Neurodevelopmental Outcomes at 1 Year in Infants of Mothers Who Tested Positive for SARS-CoV-2 During Pregnancy	http://jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2022.15787	Published	June 9, 2022	Study	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2793178	Key Points Question Is COVID-19 exposure in utero associated with increased risk for neurodevelopmental disorders in the first year of life? Findings In this cohort study of 7772 infants delivered during the COVID-19 pandemic, those born to the 222 mothers with a positive SARS-CoV-2 polymerase chain reaction test during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first 12 months after delivery, even after accounting for preterm delivery. Meaning These preliminary findings suggest that COVID-19 exposure may be associated with neurodevelopmental changes and highlight the need for prospective investigation of outcomes in children exposed to COVID-19 in utero. Abstract Importance Epidemiologic studies suggest maternal immune activation during pregnancy may be associated with neurodevelopmental effects in offspring. Objective To evaluate whether in utero exposure to SARS-CoV-2 is associated with risk for neurodevelopmental disorders in the first 12 months after birth. Design, Setting, and Participants This retrospective cohort study examined live offspring of all mothers who delivered between March and September 2020 at any of 6 Massachusetts hospitals across 2 health systems. Statistical analysis was performed from October to December 2021. Exposures Maternal SARS-CoV-2 infection confirmed by a polymerase chain reaction test during pregnancy. Main Outcomes and Measures Neurodevelopmental disorders determined from International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic codes over the first 12 months of life; sociodemographic and clinical features of mothers and offspring; all drawn from the electronic health record. Results The cohort included 7772 live births (7466 pregnancies, 96% singleton, 222 births to SARS-CoV-2 positive mothers), with mean (SD) maternal age of 32.9 (5.0) years; offspring were 9.9% Asian (772), 8.4% Black (656), and 69.0% White (5363); 15.1% (1134) were of Hispanic ethnicity. Preterm delivery was more likely among exposed mothers: 14.4% (32) vs 8.7% (654) (P = .003). Maternal SARS-CoV-2 positivity during pregnancy was associated with greater rate of neurodevelopmental diagnoses in unadjusted models (odds ratio [OR], 2.17 [95% CI, 1.24-3.79]; P = .006) as well as those adjusted for race, ethnicity, insurance status, offspring sex, maternal age, and preterm status (adjusted OR, 1.86 [95% CI, 1.03-3.36]; P = .04). Third-trimester infection was associated with effects of larger magnitude (adjusted OR, 2.34 [95% CI, 1.23-4.44]; P = .01). Conclusions and Relevance This cohort study of SARS-CoV-2 exposure in utero found preliminary evidence that maternal SARS-CoV-2 may be associated with neurodevelopmental sequelae in some offspring. Prospective studies with longer follow-up duration will be required to exclude confounding and confirm these associations.
147	Ch145		XiangmingMengaKangxuZhuaJingWangbPanLiuc	Can SARS-CoV-2 positive pregnant women affect the hearing of their newborns: A systematic review	https://doi.org/10.1016/j.amjoto.2022.103523	Published	2 June 2022	Review	https://www.sciencedirect.com/science/article/pii/S0196070922001508	The 2019 coronavirus disease (COVID-19) pandemic has caused over 500 million confirmed cases (including pregnant women) worldwide. Recently, hearing status in newborns born to mothers with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has received attention. This systematic review outlines the current knowledge regarding the effects of maternal SARS-CoV-2 infection during pregnancy on newborn hearing. Intrauterine SARS-CoV-2 infection has the potential to affect the auditory system of the newborn due to intrauterine hypoxia and vertical transmission. SARS-CoV-2 might have a greater influence on hearing loss (HL) in newborns during the second and third trimesters of pregnancy. Therefore, all newborns whose mothers had COVID-19 during pregnancy should be evaluated for cochlear function, regardless of whether their mothers were symptomatic at the time of the disease. However, the understanding of this issue is not consistent and remains controversial. Since early identification and intervention of congenital HL are crucial to the language development of newborns, newborns should be provided with audiological evaluation by various approaches, including Tele-audiology, in the COVID-19 era.
148	Ch146		Gianfranco Trapani, Giuseppe Verlato, Enrico Bertino, Giulia Maiocco, Roberta Vesentini, Alessia Spadavecchia, Angelica Dessì & Vassilios Fanos	Long COVID-19 in children: an Italian cohort study	https://doi.org/10.1186/s13052-022-01282-x	Published	03 June 2022	Study	https://link.springer.com/article/10.1186/s13052-022-01282-x	Background Long COVID-19 syndrome is a complex of symptoms that occurs after the acute SARS-CoV-2 infection, in the absence of other possible diagnoses. Studies on Long COVID-19 in pediatric population are scanty and heterogeneous in design, inclusion criteria, outcomes, and follow-up time. The objective of the present study is to assess the prevalence of Long COVID-19 syndrome in a cohort of Italian pediatric primary care patients, observed for a period of time of 8 to 36 weeks from healing. Prevalence was also assessed in a cohort of pediatric patients hospitalized during acute infection. Methods Data concerning 629 primary care patients with previous acute SARS-CoV-2 infection were collected by a questionnaire filled in by Primary Care Pediatrician (PCP). The questionnaire was administrated to patients by 18 PCPs based in 8 different Italian regions from June to August 2021. Data concerning 60 hospitalized patients were also collected by consultation of clinical documents. Results Cumulative incidence of Long COVID-19 resulted to be 24.3% in primary care patients and 58% in hospitalized patients. The most frequently reported symptoms were abnormal fatigue (7%), neurological (6.8%), and respiratory disorders (6%) for the primary care cohort. Hospitalized patients displayed more frequently psychological symptoms (36.7%), cardiac involvement (23.3%), and respiratory disorders (18.3%). No difference was observed in cumulative incidence in males and females in both cohorts. Previous diseases did not influence the probability to develop Long COVID-19. The prevalence of Long COVID-19 was 46.5% in children who were symptomatic during acute infection and 11.5% in asymptomatic ones. Children aged 0 to 5 years had a greater risk to develop respiratory symptoms, while adolescents (aged 11–16 years) had a greater risk to develop neurological and psychological Long COVID-19 symptoms. Conclusions Our study demonstrates that Long COVID-19 is a reality in pediatric age and could involve even patients with mild or no acute symptoms. The results stress the importance of monitoring primary care pediatric patients after acute COVID-19 infection and the relevance of vaccination programs in pediatric population, also in order to avoid the consequences of Long COVID-19 syndrome.
149	Ch147		N.ElengaabdM.-J.WandjicdJ.SibanabcdefM.NacherdeM.Demarbdf	Neonatal outcomes related to maternal SARS-CoV-2 infection in French Guiana: A case-control study	https://doi.org/10.1016/j.jiph.2022.06.003	Published	14 June 2022	Study	https://www.sciencedirect.com/science/article/pii/S1876034122001472	Background This study aims to assess the neonatal outcomes related to maternal SARS-COV-2 infection. Methods In this study, we identified newborns born between May 14 and August 31, 2020, to mothers who were PCR-SRAS-CoV-2 positive at the time of delivery. From the cohort of 974 infants, we performed a nested case-control study. Results During the study period, 133 (13.7%) mothers were positive for SARS‐CoV‐2. Among the 35 pregnant women with COVID-19 symptoms (26.3%), cough was the most common symptom, present in half of the cases. Four of them have progressed to critical pneumonia requiring transfer to intensive care unit. The neonates from mothers with positive SARS-CoV-2-RT-PCR, were routinely tested for COVID-19 within the first 24 h after labor, and 3 other newborns tested in the presence of symptoms. There was no significant difference between the two groups with respect to preterm birth, meconium-stained amniotic fluid distress, and neonatal asphyxia. Most infants were breastfed at birth, regardless of their mothers' COVID-19 status. In COVID-19-positive pregnant women admitted to intensive care unit, the proportion of preterm births (OR=12.5 [1.7–90.5]), fetal death in utero (OR=25.9 [2.2–305]) and admission in neonatal intensive care unit admission (OR=13.4 [3.0–60]), appeared higher than the controls. No maternal deaths were recorded. Conclusions Our data suggest little neonatal morbidity associated with maternal COVID-19, except for those born to mothers admitted to intensive care unit. However, under breastfeeding conditions with rigorous hygiene precautions and parental education, the risk of transmission of SARS-COV-2 virus to the newborn was very low.
150	Ch148		Jennifer A. Burney, PhD1; Samantha C. Roberts, MPH2,3; Laurel L. DeHaan, PhD4; Chisato Shimizu, MD2,3; Emelia V. Bainto, BS2,3; Jane W. Newburger, MD5,6; Samuel Dominguez, MD, PhD7; Pei-Ni Jone, MD7; Preeti Jaggi, MD8; Jacqueline R. Szmuszkovicz, MD9; Anne H. Rowley, MD10; Nichole Samuy, MD11; Paul Scalici, MD11; Adriana H. Tremoulet, MD2,3; Daniel R. Cayan, PhD4; Jane C. Burns, MD2,3; and the KIDCARE Study Investigators	Epidemiological and Clinical Features of Kawasaki Disease During the COVID-19 Pandemic in the United States	https://doi.org/10.1001/jamanetworkopen.2022.17436	Published	June 17, 2022	Study	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2793496	Key Points Question How did the incidence and nature of Kawasaki disease (KD) in the United States change during the COVID-19 pandemic? Findings In this cohort study of 3922 children with KD, cases of KD across the United States fell by 28% and remained low during periods of COVID-19–related masking and school closure. In the San Diego region, there was a disproportionate decline in KD cases in children aged 1 to 5 years, male children, and Asian children, and clinical features including strawberry tongue, enlarged cervical lymph node, and subacute periungual desquamation were rare. Meaning These findings suggest that social behavior is associated with exposure to the agent(s) that trigger KD and are consistent with a respiratory portal of entry for the agent(s). Abstract Importance Public health measures implemented during the COVID-19 pandemic had widespread effects on population behaviors, transmission of infectious diseases, and exposures to environmental pollutants. This provided an opportunity to study how these factors potentially influenced the incidence of Kawasaki disease (KD), a self-limited pediatric vasculitis of unknown etiology. Objectives To examine the change in KD incidence across the United States and evaluate whether public health measures affected the prevalence of KD. Design, Setting, and Participants This multicenter cohort study included consecutive, unselected patients with KD who were diagnosed between January 1, 2018, and December 31, 2020 (multicenter cohort with 28 pediatric centers), and a detailed analysis of patients with KD who were diagnosed between January 1, 2002, and November 15, 2021 (Rady Children’s Hospital San Diego [RCHSD]). Main Outcomes and Measures For the multicenter cohort, the date of fever onset for each patient with KD was collected. For RCHSD, detailed demographic and clinical data as well as publicly available, anonymized mobile phone data and median household income by census block group were collected. The study hypothesis was that public health measures undertaken during the pandemic would reduce exposure to the airborne trigger(s) of KD and that communities with high shelter-in-place compliance would experience the greatest decrease in KD incidence. Results A total of 2461 KD cases were included in the multicenter study (2018: 894; 2019: 905; 2020: 646), and 1461 cases (median [IQR] age, 2.8 years [1.4-4.9 years]; 900 [61.6%] males; 220 [15.1%] Asian, 512 [35.0%] Hispanic, and 338 [23.1%] White children) from RCHSD between 2002 and 2021 were also included. The 28.2% decline in KD cases nationally during 2020 (646 cases) compared with 2018 (894 cases) and 2019 (905 cases) was uneven across the United States. For RCHSD, there was a disproportionate decline in KD cases in 2020 to 2021 compared with the mean (SD) number of cases in earlier years for children aged 1 to 5 years (22 vs 44.9 [9.9]; P = .02), male children (21 vs 47.6 [10.0]; P = .01), and Asian children (4 vs 11.8 [4.4]; P = .046). Mobility data did not suggest that shelter-in-place measures were associated with the number of KD cases. Clinical features including strawberry tongue, enlarged cervical lymph node, and subacute periungual desquamation were decreased during 2020 compared with the baseline period (strawberry tongue: 39% vs 63%; P = .04; enlarged lymph node: 21% vs 32%; P = .09; periungual desquamation: 47% vs 58%; P = .16). School closures, masking mandates, decreased ambient pollution, and decreased circulation of respiratory viruses all overlapped to different extents with the period of decreased KD cases. KD in San Diego rebounded in the spring of 2021, coincident with lifting of mask mandates. Conclusions and Relevance In this study of epidemiological and clinical features of KD during the COVID-19 pandemic in the United States, KD cases fell and remained low during the period of masking and school closure. Mobility data indicated that differential intensity of sheltering in place was not associated with KD incidence. These findings suggest that social behavior is associated with exposure to the agent(s) that trigger KD and are consistent with a respiratory portal of entry for the agent(s).
151	Ch149		Prof Selina Kikkenborg Berg, PhD Pernille Palm, PhD Ulrikka Nygaard, PhD Prof Henning Bundgaard, DMSc Maria Nivi Schmidt Petersen, MSc Siri Rosenkilde, MSc Anne Bonde Thorsted, MSc Prof Annette Kjær Ersbøll, PhD Prof Lau Casper Thygesen, PhD Prof Susanne Dam Nielsen, DMSc Anne Vinggaard Christensen, PhD	Long COVID symptoms in SARS-CoV-2-positive children aged 0–14 years and matched controls in Denmark (LongCOVIDKidsDK): a national, cross-sectional study	https://doi.org/10.1016/S2352-4642(22)00154-7	Published	June 22, 2022	Study	https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(22)00154-7/fulltext	Background After the acute phase of SARS-CoV-2 infection, children can develop long COVID symptoms. We aimed to investigate the prevalence of long-lasting symptoms, the duration and intensity of symptoms, quality of life, number of sick days and absences from daycare or school, and psychological and social outcomes in children aged 0–14 years who had been infected with SARS-CoV-2 relative to controls with no history of SARS-CoV-2 infection. Methods A nationwide cross-sectional study was conducted including children with a confirmed SARS-CoV-2-positive PCR test (cases) and matched controls from Danish national registers. A survey was sent to mothers (proxy reporting) of children aged 0–14 years who had had a positive SARS-CoV-2 test between Jan 1, 2020, and July 12, 2021, and a control group matched (1:4) by age and sex. The survey included the Pediatric Quality of Life Inventory (PedsQL) and the Children's Somatic Symptoms Inventory-24 (CSSI-24) to capture current overall health and wellbeing, and ancillary questions about the 23 most common long COVID symptoms. Descriptive statistics and logistic regression analysis were used. Clinically relevant differences were defined as those with a Hedges' g score greater than 0·2. This study is registered at ClinicalTrials.gov (NCT04786353). Findings Responses to the survey were received from 10 997 (28·8%) of 38 152 cases and 33 016 (22·4%) of 147 212 controls between July 20, 2021, and Sept 15, 2021. Median age was 10·2 years (IQR 6·6–12·8) in cases and 10·6 years (6·9–12·9) in controls. 5267 (48·2%) cases and 15 777 (48·3%) controls were female, and 5658 (51·8%) cases and 16 870 (51·7%) controls were male. Cases had higher odds of reporting at least one symptom lasting more than 2 months than did controls in the 0–3 years age group (478 [40·0%] of 1194 vs 1049 [27·2%] of 3855; OR 1·78 [95% CI 1·55–2·04], p<0·0001), 4–11 years age group (1912 [38·1%] of 5023 vs 6189 [33·7%] of 18 372; 1·23 [1·15–1·31], p<0·0001), and 12–14 years age group (1313 [46·0%] of 2857 vs 4454 [41·3%] of 10 789; 1·21 [1·11–1·32], p<0·0001). Differences in CSSI-24 symptom scores between cases and controls were statistically significant but not clinically relevant. Small clinically relevant differences in PedsQL quality-of-life scores related to emotional functioning were found in favour of cases in the children aged 4–11 years (median score 80·0 [IQR 65·0–95·0]) in cases vs 75·0 [60·0–85·0] in controls; p<0·0001) and 12–14 years (90·0 [70·0–100·0] vs (85·0 [65·0–95·0], p<0·0001). PedsQL social functioning scores were also higher in cases (100·0 [90·0–100·0] than controls (95·0 [80·0–100·0]) in the 12–14 years age group (p<0·0001; Hedges g>0·2). Interpretation Compared with controls, children aged 0–14 years who had a SARS-CoV-2 infection had more prevalent long-lasting symptoms. There was a tendency towards better quality-of-life scores related to emotional and social functioning in cases than in controls in older children. The burden of symptoms among children in the control group requires attention. Long COVID must be recognised and multi-disciplinary long COVID clinics for children might be beneficial.
152	Ch150		Costanza Di Chiara 1,*ORCID,Silvia Carraro 2ORCID,Stefania Zanconato 2,Sandra Cozzani 1,Eugenio Baraldi 3,Carlo Giaquinto 1,Valentina Agnese Ferraro 2,†ORCID andDaniele Donà 1,†	Preliminary Evidence on Pulmonary Function after Asymptomatic and Mild COVID-19 in Children	https://doi.org/10.3390/children9070952	Published	25 June 2022	Study	https://www.mdpi.com/2227-9067/9/7/952/htm	Background: While it has been described that adults can develop long-lasting deterioration in pulmonary function (PF) after coronavirus disease 19 (COVID-19), regardless of disease severity, data on the long-term pneumological impact of SARS-CoV-2 infection in children are lacking. Methods: Performing a single-center, prospective, observational study on children aged 6–18 years with a previous diagnosis of asymptomatic/mild COVID-19, we evaluated the long-term impact of mild severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children. Results: A total of 61 subjects underwent spirometry after a mean time of 10 ± 4 months from asymptomatic or mild infection. None of the children reported any respiratory symptoms, needed any inhaled therapy, or had abnormal lung function. Conclusions: In our study, we observed that children and adolescents did not develop chronic respiratory symptoms and did not present lung function impairment after asymptomatic or mild SARS-CoV-2 infection. In our study, one of the largest Italian pediatric cohorts, we evaluated the long-term impact of mild SARS-CoV-2 infection in children, finding no effect on respiratory symptoms and lung function. Long-term loss of PF, due to an abnormal inflammatory response, was previously observed in children after respiratory viral infections, especially given by RSV and Rhinovirus [8,9,10]. In addition, preliminary results on long-covid in children showed that more than 40% presented at least one symptom >60 days after acute infection, and some of them developed respiratory symptoms after COVID-19 [2]. Therefore, we investigated PF in children after COVID-19, in order to assess whether asymptomatic or mild SARS-CoV-2 infection could sub-clinically impair respiratory parameters. In our population of children with a history of asymptomatic or mildly symptomatic SARS-CoV-2 infection, we found, indeed, no persistent respiratory symptoms (either at rest or on exertion) and normal lung function. Our results are in keeping with two previous pediatric studies [3,4] that found no effect on lung function in the first 6 months after asymptomatic or mild SARS-CoV-2 infection. On the other hand, focusing on a sub-group of children affected by a more severe SARS-CoV-2 infection, Knoke et al. observed a significant reduction in some spirometric parameters (i.e., FVC and MEF75) and impaired DLCO [4]. Our study has several limitations. First, including only children with mild or asymptomatic SARS-CoV-2 infection, we cannot provide any information on the possible detrimental effect of more severe cases (which are indeed very rare during childhood). Secondly, we performed only spirometry and did not examine the pulmonary gas exchange capacity. 5. Conclusions In conclusion, we observed that children and adolescents did not develop chronic respiratory symptoms and did not present lung function impairment after asymptomatic or mild SARS-CoV-2 infection. Further studies are needed to confirm our findings and to investigate the possible long-term effects of COVID-19 on lung function in children with moderate/severe infection.
153	Ch151		Maren Johanne Heilskov Rytter	Difficult questions about long COVID in children	https://doi.org/10.1016/S2352-4642(22)00167-5	Published	June 22, 2022	Comment	https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(22)00167-5/fulltext	Research in COVID-19 is like trying to hit a moving target. The present study is already somewhat historical because the children surveyed were infected with a different strain of SARS-CoV-2 than is currently dominant, and more recent strains appear to cause less severe symptoms. Additionally, since the majority of children in Denmark have immunity from previous infection, they might have milder symptoms if infected with SARS-CoV-2 again, limiting the future generalisability of the findings. The differences found in Kikkenborg Berg and colleagues' study8 are small and probably of limited clinical relevance. Because most symptoms were mild, and the small excess of non-specific symptoms was accompanied by a paradoxical higher quality of life in children who have had COVID-19, the study findings can be considered reassuring. On a population level, the overall impact on children of having had COVID-19 is probably small, and less than the indirect effects of the pandemic. For most children with non-specific symptoms following COVID-19, the symptoms are more likely to be caused by something other than COVID-19 and, if they are related to COVID-19, they are likely to pass with time.
154	Ch152		Dustin D. Flannery, Alvaro Zevallos Barboza, Madeline R. Pfeifer, Mark L. Hudak, Kimberly Barnette, Trace R. Getzlaff, Sascha R. Ellington, Kate R. Woodworth, Miren B. Dhudasia, Sagori Mukhopadhyay, Danielle D. Weinberg, Elizabeth E. Foglia & Karen M. Puopolo	Perinatal COVID-19 maternal and neonatal outcomes at two academic birth hospitals	https://doi.org/10.1038/s41372-022-01446-x	Published	01 July 2022	Study	https://www.nature.com/articles/s41372-022-01446-x	Objective Describe 1-month outcomes among newborns of persons with perinatal COVID-19. Study design Prospective observational study of pregnant persons who tested positive for SARS-CoV-2 between 14 days before and 3 days after delivery and their newborns, from 3/2020 to 3/2021 at two urban high-risk academic hospitals. Phone interviews were conducted to determine 1-month newborn outcomes. Results Among 9748 pregnant persons, 209 (2.1%) tested positive for perinatal SARS-CoV-2. Symptomatically infected persons were more likely to have a preterm delivery due to worsening maternal condition and their newborns were more likely to test positive for SARS-CoV-2 compared with asymptomatic persons. Six of 191 (3.1%) infants tested were positive for SARS-CoV-2; none had attributable illness before discharge. Of 169 eligible families, 132 (78.1%) participated in post-discharge interviews; none reported their newborn tested positive for SARS-CoV-2 by 1 month of age. Conclusion Symptomatic perinatal COVID-19 had a substantial effect on maternal health but no apparent short-term effect on newborns.
155	Ch153		Sandra Lopez-Leon, Talia Wegman-Ostrosky, Norma Cipatli Ayuzo del Valle, Carol Perelman, Rosalinda Sepulveda, Paulina A. Rebolledo, Angelica Cuapio & Sonia Villapol	Long-COVID in children and adolescents: a systematic review and meta-analyses	https://doi.org/10.1038/s41598-022-13495-5	Published	23 June 2022	Systematic review and meta-analysis	https://www.nature.com/articles/s41598-022-13495-5	The objective of this systematic review and meta-analyses is to estimate the prevalence of long-COVID in children and adolescents and to present the full spectrum of symptoms present after acute COVID-19. We have used PubMed and Embase to identify observational studies published before February 10th, 2022 that included a minimum of 30 patients with ages ranging from 0 to 18 years that met the National Institute for Healthcare Excellence (NICE) definition of long-COVID, which consists of both ongoing (4 to 12 weeks) and post-COVID-19 (≥ 12 weeks) symptoms. Random-effects meta-analyses were performed using the MetaXL software to estimate the pooled prevalence with a 95% confidence interval (CI). Heterogeneity was assessed using I2 statistics. The Preferred Reporting Items for Systematic Reviewers and Meta-analysis (PRISMA) reporting guideline was followed (registration PROSPERO CRD42021275408). The literature search yielded 8373 publications, of which 21 studies met the inclusion criteria, and a total of 80,071 children and adolescents were included. The prevalence of long-COVID was 25.24%, and the most prevalent clinical manifestations were mood symptoms (16.50%), fatigue (9.66%), and sleep disorders (8.42%). Children infected by SARS-CoV-2 had a higher risk of persistent dyspnea, anosmia/ageusia, and/or fever compared to controls. Limitations of the studies analyzed include lack of standardized definitions, recall, selection, misclassification, nonresponse and/or loss of follow-up, and a high level of heterogeneity.
156	Ch154		Lokesh Saini ∗ Deepthi Krishna ∗ Sarbesh Tiwari Jagdish Prasad Goyal Prawin Kumar Daisy Khera Bharat Choudhary Siyaram Didel Ravisekhar Gadepalli Kuldeep Singh	Post COVID-19 immune mediated neurological complications in children – A Ambispective study	https://doi.org/10.1016/j.pediatrneurol.2022.06.010	Published	July 05, 2022	Study	https://www.pedneur.com/article/S0887-8994(22)00115-1/fulltext	Background The neurological manifestation following a SARS-CoV2 infection is varied, and till now, only a few studies have reported the same. Our study aimed to identify the varied spectrum of neurological manifestation following SARS-CoV2 infection. Methods We used retrospective data from May 2021 to July 2021 and prospective study data from August to September 2021, including that from children aged between one month and 18 years of age who presented to a tertiary care referral center with the neurological manifestation and had a history of COVID-19 infection or exposure and positive SARS-CoV-2 serology. The neuro-radiological manifestations were further categorized as in a predesigned proforma. Results Case records of the 18 children who fulfilled the criteria were included in the study; among them, seven (38.8%) were male, and 11 (61.1%) were female. Predominant presentation in our study group was status epilepticus (6/18) and Guillain-Barré Syndrome (5/18). Other manifestations included stroke (2/18), demyelinating syndromes (3/18), autoimmune encephalitis (2/18). Most of the children had favorable outcomes except for one mortality in our cohort. Interpretation Delayed complications following SARS-CoV2 infection with varied manifestations are seen in children. A temporal correlation was noted between the COVID-19 infection and the increasing number of neurological cases after the second wave. Steroids could be beneficial while treating such patients, especially in the presence of high inflammatory markers. Testing for SARS-CoV2 serology during the pandemic can give a clue to the underlying etiology. Further multicentric studies are required to understand the varied neurological manifestations following SARS-CoV2 infection in children.
157	Ch155		Rhishikesh Thakre, Sandeep Kadam, Nandkishor Shrikishanji Kabra	Clinical Characteristics and Outcomes of Neonatal SARS-CoV-2 Infection in India: A Systematic Review		Published	June 2022	Review	https://www.perinatology.in/clinical-characteristics-and-outcomes-of-neonatal-sarscov2-infection-in-india-a-systematic-review	Aim: To perform a systematic review to gather information on the clinical characteristics and outcomes of neonates infected with SARS-CoV-2 in India Materials and Methods: A comprehensive search of literature published between January 1, 2020, and June 30, 2021, was performed. Studies that included neonates < 29 days old, born in India, and diagnosed with SARS-CoV-2 infection and provided data regarding the clinical manifestations, and/or laboratory tests, or radiological examinations were considered. All the included studies were evaluated for methodological quality, and the necessary data were collated. Results: A total of 22 observational studies met the inclusion criteria. We identified 335 infected neonates. The diagnosis of SARS-CoV-2 infection was made within 48 hours of birth in 44.1% of the cases. Most of these neonates were born to SARS-CoV-2–positive mothers (97.8%). Among the infected neonates, 21.7% were preterm, and 48.6% were low birth weight. Most of the neonates were asymptomatic (66.8%). The most common clinical features were cough, respiratory distress, and hypoxia (67%), and severe illness occurred in 2.9% of the neonates. The reported mortality was 2%. Conclusions: The available evidence (limited and of low quality) suggests that the risk of SARS-CoV-2 infection in neonates was low in India. The source of infection was the mother. Most of the neonates were asymptomatic, and respiratory symptoms were the most common clinical presentation. Most neonates stabilized upon receiving supportive care, and the overall prognosis was good.
158	Ch156		Cocciolillo, Fabrizio MD; Di Giuda, Daniela MD,†; Morello, Rosa MD‡; De Rose, Cristina MD‡; Valentini, Piero MD‡; Buonsenso, Danilo MD, PhD‡,§	Orbito-Frontal Cortex Hypometabolism in Children With Post-COVID Condition (Long COVID): A Preliminary Experience	https://doi.org/10.1097/INF.0000000000003578	Published	July 13, 2022	Case Reports	https://journals.lww.com/pidj/Abstract/2022/08000/Orbito_Frontal_Cortex_Hypometabolism_in_Children.12.aspx	We describe 3 children with new-onset neurocognitive problems after coronavirus disease 2019 (COVID-19), that showed, at the brain [18F]-fluorodeoxyglucose positron emission tomography/computed tomography, hypometabolism in the left orbito-frontal region. The voxel-wise analysis confirmed a cluster of hypometabolic voxels in this region with a peak at −18/46/−4mm (179 voxels, T-Score 8.1). These findings may explain neurocognitive symptoms that some children develop after COVID-19 and require further investigations.
159	Ch157		Ali A Asadi-Pooya,Meshkat Nemati,Hamid Nemati	‘Long COVID’: Symptom persistence in children hospitalised for COVID-19	https://doi.org/10.1111/jpc.16120	Published	19 July 2022	Study	https://onlinelibrary.wiley.com/doi/full/10.1111/jpc.16120	Aim We aimed to describe the long-term outcome with respect to symptom persistence amongst children hospitalised for COVID-19. Methods This was a follow-up study of 58 children and adolescents hospitalised with COVID-19. For all patients, the data were collected in a phone call to the family in December 2021 (9 months after the initial study and more than 13 months after their admission to hospital). We inquired about their current health status and obtained information, if the responding parent consented orally to participate and answer the questions. Results Fifty-one children and adolescents were studied. Only five patients (10%) had persistent symptoms compatible with long-COVID; the reported symptoms include fatigue in four (8%), weakness in three (6%), exercise intolerance in two (4%) and shortness of breath in two (4%) patients. Four patients (7.8%), who did not have any symptoms of long-COVID in phase 1 of the study, reported new-onset symptoms or complaints that are potentially compatible with the diagnosis of long-COVID (weakness, myalgia, excess sputum, cough, fatigue) in the current phase. Conclusions Symptom persistence of long-COVID is infrequent amongst children hospitalised for COVID-19. Most of the symptoms of long-COVID will resolve with the passage of time and the residual symptoms are often mild and tolerable. The scientific community should carefully and clearly define long-COVID and its natural course in order to facilitate and harmonise future studies. What is already known on this topic In a previous study, we observed that 45% of children and adolescents, who were hospitalized with COVID-19, reported symptoms of long-COVID These symptoms included fatigue, shortness of breath, exercise intolerance, weakness, and walking intolerance. What this paper adds Most symptoms of long-COVID in children and adolescents will resolve with the passage of time. Symptom persistence of long-COVID is not a common condition in children and adolescents. Scientific community should carefully and clearly define long-COVID.
160	Ch158		Iris Shachar-Lavie1 Maayan Shorer2 Hila Segal1 Silvana Fennig1 Liat Ashkenazi-Hoffnung	Mental Health among Children with Long COVID during the COVID- 19 Pandemic	https://doi.org/10.21203/rs.3.rs-1797505/v1	pre-print	22 Jul, 2022	Study	https://www.researchsquare.com/article/rs-1797505/v1	Purpose A growing number of studies report that persons of all ages, infected with SARS-CoV-2, may experience long-term persistent symptoms, known as Long-COVID (LC) or post COVID-19 condition. This is one of the first studies examining the consequences of LC on children’s mental health. Method In this case control study, we compared select mental health aspects of 103 children diagnosed with LC to a control group of 113 children uninfected with SARS-COV-2; all 4–18 years old. Both groups were assessed via parents’ questionnaires. Results In comparison to the control group, children with LC exhibited more memory difficulties. However, no group differences emerged in other functional aspects (connection with friends and engagement in physical activities), problems with concentration, or levels of emotional-behavioral problems (externalizing, internalizing, ADHD, and PTSD symptoms). We also found that children with LC had greater exposure to COVID 19 related stressors. Higher levels of parental worries regarding their children’s functioning and economic difficulties at home significantly predicted higher levels of children’s emotional-behavioral problems and were better predictors than the child’s age, social functioning, or LC diagnosis. Conclusions LC was associated with impairments in some aspects of children’s memory which may relate to academic functioning, but not with higher rates of emotional-behavioral problems, thus warranting interventional programs addressing school functioning and cognitive abilities in this population. Additionally, parents' economic stress and worries regarding their child’s emotional adjustment during the pandemic, are important factors affecting pandemic-related emotional-behavioral problems among children, regardless of COVID-19 infection, that should be addressed.
161	Ch159		Anna L. Funk, PhD, MSc1; Nathan Kuppermann, MD, MPH2,3; Todd A. Florin, MD, MSCE4,5; Daniel J. Tancredi, PhD3; Jianling Xie, MD, MPH1; Kelly Kim, BSc1; Yaron Finkelstein, MD6,7; Mark I. Neuman, MD, MPH8,9; Marina I. Salvadori, MD10; Adriana Yock-Corrales, MD11; MBChB, PhD42,43,44; Daniel C. Payne, PhD45; Richard Malley, MD46; Meredith L. Borland, MD47,48,49; Andrea K. Morrison, MD, MS50; Maala Bhatt, MD51; Pedro B. Rino, MD52; Isabel Beneyto Ferre, MD53; Michelle Eckerle, MD54,55; April J. Kam, MD56; Shu-Ling Chong, MPH57; Laura Palumbo, MD58; Maria Y. Kwok, MD, MPH59; Jonathan C. Cherry, MD60; Naveen Poonai, MD61; Muhammad Wassem, MD62; Norma-Jean Simon, MPH5,63; Stephen B. Freedman, MDCM, MSc64,65,66; for the Pediatric Emergency Research Network–COVID-19 Study Team	Post–COVID-19 Conditions Among Children 90 Days After SARS-CoV-2 Infection	https://doi.org/10.1001/jamanetworkopen.2022.23253	Published	July 22, 2022	Study	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2794484	Key Points Question What proportion of children infected with SARS-CoV-2 who were tested in emergency departments (EDs) reported post–COVID-19 conditions (PCCs) 90 days after their ED visits? Findings In this cohort study of 1884 SARS-CoV-2–positive children with 90-day follow-up, 5.8% of patients, including 9.8% of hospitalized children and 4.6% of discharged children, reported PCCs. Characteristics associated with PCCs included being hospitalized 48 hours or more, having 4 or more symptoms reported at the index ED visit, and being 14 years of age or older. Meaning This study suggests that, given the prevalence of PCCs, appropriate guidance and follow-up are required for children testing positive for SARS-CoV-2. Abstract Importance Little is known about the risk factors for, and the risk of, developing post–COVID-19 conditions (PCCs) among children. Objectives To estimate the proportion of SARS-CoV-2–positive children with PCCs 90 days after a positive test result, to compare this proportion with SARS-CoV-2–negative children, and to assess factors associated with PCCs. Design, Setting, and Participants This prospective cohort study, conducted in 36 emergency departments (EDs) in 8 countries between March 7, 2020, and January 20, 2021, included 1884 SARS-CoV-2–positive children who completed 90-day follow-up; 1686 of these children were frequency matched by hospitalization status, country, and recruitment date with 1701 SARS-CoV-2–negative controls. Exposure SARS-CoV-2 detected via nucleic acid testing. Main Outcomes and Measures Post–COVID-19 conditions, defined as any persistent, new, or recurrent health problems reported in the 90-day follow-up survey. Results Of 8642 enrolled children, 2368 (27.4%) were SARS-CoV-2 positive, among whom 2365 (99.9%) had index ED visit disposition data available; among the 1884 children (79.7%) who completed follow-up, the median age was 3 years (IQR, 0-10 years) and 994 (52.8%) were boys. A total of 110 SARS-CoV-2–positive children (5.8%; 95% CI, 4.8%-7.0%) reported PCCs, including 44 of 447 children (9.8%; 95% CI, 7.4%-13.0%) hospitalized during the acute illness and 66 of 1437 children (4.6%; 95% CI, 3.6%-5.8%) not hospitalized during the acute illness (difference, 5.3%; 95% CI, 2.5%-8.5%). Among SARS-CoV-2–positive children, the most common symptom was fatigue or weakness (21 [1.1%]). Characteristics associated with reporting at least 1 PCC at 90 days included being hospitalized 48 hours or more compared with no hospitalization (adjusted odds ratio [aOR], 2.67 [95% CI, 1.63-4.38]); having 4 or more symptoms reported at the index ED visit compared with 1 to 3 symptoms (4-6 symptoms: aOR, 2.35 [95% CI, 1.28-4.31]; ≥7 symptoms: aOR, 4.59 [95% CI, 2.50-8.44]); and being 14 years of age or older compared with younger than 1 year (aOR, 2.67 [95% CI, 1.43-4.99]). SARS-CoV-2–positive children were more likely to report PCCs at 90 days compared with those who tested negative, both among those who were not hospitalized (55 of 1295 [4.2%; 95% CI, 3.2%-5.5%] vs 35 of 1321 [2.7%; 95% CI, 1.9%-3.7%]; difference, 1.6% [95% CI, 0.2%-3.0%]) and those who were hospitalized (40 of 391 [10.2%; 95% CI, 7.4%-13.7%] vs 19 of 380 [5.0%; 95% CI, 3.0%-7.7%]; difference, 5.2% [95% CI, 1.5%-9.1%]). In addition, SARS-CoV-2 positivity was associated with reporting PCCs 90 days after the index ED visit (aOR, 1.63 [95% CI, 1.14-2.35]), specifically systemic health problems (eg, fatigue, weakness, fever; aOR, 2.44 [95% CI, 1.19-5.00]). Conclusions and Relevance In this cohort study, SARS-CoV-2 infection was associated with reporting PCCs at 90 days in children. Guidance and follow-up are particularly necessary for hospitalized children who have numerous acute symptoms and are older.
162	Ch160		Samuela Tarantino 1,*,Sonia Graziano 1,Chiara Carducci 1,Rosaria Giampaolo 2 andTeresa Grimaldi Capitello 1ORCID	Cognitive Difficulties, Psychological Symptoms, and Long Lasting Somatic Complaints in Adolescents with Previous SARS-CoV-2 Infection: A Telehealth Cross-Sectional Pilot Study	https://doi.org/10.3390/brainsci12080969	Published	23 July 2022	Study	https://www.mdpi.com/2076-3425/12/8/969/htm	Background. Few studies have evaluated cognitive functioning and mental health in children and adolescents who contracted the SARS-CoV-2 infection. We investigated the prevalence and association of neuropsychological difficulties, psychological symptoms, and self-reported long-COVID complaints in a sample of adolescents. Methods. Thirty-one adolescents infected by COVID-19 within 3–6 months prior to the assessment were included. Neuropsychological difficulties, psychological symptoms, and self-reported long-COVID complaints were evaluated using a checklist and a battery of multiple standardized measures, using a telehealth procedure. Symptoms during the infection were also detected. Results. We included 31 adolescents (23 girls, 8 boys; mean age 14.1, SD = 2). We found borderline scores in 32.3% and 45.2% of our sample for phonemic and category fluency, respectively. A high percentage of participants showed symptoms of depression (80.6%) and anxiety (61.3%). Fifty-eight percent reported at least one long-COVID symptom. The most common symptoms were headache and attention problems (58%). Subjects presenting numbness/weakness, fatigue, brain fog, or attention problems had higher scores in depression, anxiety, and post-traumatic stress symptoms (p ≤ 0.05). Conclusion. This is a pilot study limited by the lack of control group. However, we found that cognitive, psychological, and physical symptoms were very common among adolescents recovered from COVID-19.
163	Ch161		Lyudmyla Kompaniyets, PhD1; Lara Bull-Otterson, PhD1; Tegan K. Boehmer, PhD1; Sarah Baca1,2; Pablo Alvarez, MPH1,2; Kai Hong, PhD1; Joy Hsu, MD1; Aaron M. Harris, MD1; Adi V. Gundlapalli, MD, PhD1; Sharon Saydah	Post–COVID-19 Symptoms and Conditions Among Children and Adolescents — United States, March 1, 2020–January 31, 2022		Published	August 5, 2022	Study	https://www.cdc.gov/mmwr/volumes/71/wr/mm7131a3.htm	Summary What is already known about this topic? Children and adolescents might be at risk for certain post-COVID symptoms and conditions. What is added by this report? Compared with patients aged 0–17 years without previous COVID-19, those with previous COVID-19 had higher rates of acute pulmonary embolism (adjusted hazard ratio = 2.01), myocarditis and cardiomyopathy (1.99), venous thromboembolic event (1.87), acute and unspecified renal failure (1.32), and type 1 diabetes (1.23), all of which were rare or uncommon in this study population. What are the implications for public health practice? COVID-19 prevention strategies, including vaccination for all eligible persons aged ≥6 months, are critical to preventing SARS-CoV-2 infection and subsequent illness, and reducing the public health impact of post-COVID symptoms and conditions among persons aged 0–17 years.
164	Ch162		Dicle Sener Okur	Neurological symptoms and signs associated with COVID-19 in pediatric patients: a single-center experience	https://doi.org/10.1097%2FMD.0000000000029920	Published	2022 Aug 5	Study	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9351517/	There is insufficient evidence on SARS-CoV-2 induced neurological effects. Studies on CNS involvement during COVID-19 in children are limited. This study aims to identify and manage the neurological signs and symptoms in COVID-19-infected pediatric patients during follow up and plan future follow-ups. Children diagnosed COVID-19 and hospitalized in the pediatric pandemic services, between March 18, 2020, and June 18, 2021, were included in the study. Children with underlying neurological disease were excluded from the study. Patient data retrieved from hospital files and medical records. Children divided into 2 groups, 1 and 2, based on the presence or absence of neurological findings. A total of 243 children received follow-ups in the pandemic wards, 35 (14.4%) of these patients had neurological findings. Major neurological manifestations were headache (n:17, 7%), seizure (n:4, 1.6%), and anosmia/hyposmia (n:17, 7%). The number of boys (n:13, 37.1%) was smaller than the number of girls (n:22, 62.9%) in Group 1. Group 1 showed higher blood leukocyte, lymphocyte, thrombocyte, AST, LDH, d-dimer values. Anosmia/hyposmia occurred more often in girls, anosmia and headache occurred more often over 9 years of age. Pulmonary and hematologic involvement was more common in children with anosmia and headache. Our study is one of the few studies on neurological involvement in COVID-19 in children. To the best of our knowledge, there is limited data on these subjects in the literature.
165	Ch163		Dinah V. Parums	Editorial: Long-Term Effects of Symptomatic and Asymptomatic SARS-CoV-2 Infection in Children and the Changing Pathogenesis of Common Childhood Viruses Driven by the COVID-19 Pandemic	https://doi.org/10.12659/MSM.937927	Published	01 August 2022	Editorial	https://medscimonit.com/abstract/full/idArt/937927	The range of long-term clinical conditions following SARS-CoV-2 infection in adults is now recognized. However, the prevalence, presentation, and risk factors for long COVID, or post-COVID-19, in children are less well understood because there have been few follow-up studies or long-term clinical trials in children with COVID-19. However, recent studies have shown that children with mild or asymptomatic COVID-19 may develop long-term sequelae that include cough, fatigue, and lethargy. The incidence and severity of common childhood respiratory viruses have changed in the past year, including respiratory syncytial virus (RSV). Hepatitis of unknown cause in children with SARS-CoV-2 infection is increasingly reported. Although both a viral cause and an autoimmune cause have been proposed, adenovirus type 41 infection is of current interest. These findings support immunization programs for SARS-CoV-2 in children, and infection surveillance and monitoring of the changing patterns and severity of other pediatric viral infections, including adenovirus type 41 and RSV, to develop and administer effective vaccines. This Editorial aims to highlight what is currently known of the long-term effects of symptomatic and asymptomatic SARS-CoV-2 infection in children and the changing epidemiology and pathogenesis of previously common childhood viral infections now driven by the COVID-19 pandemic.
166	Ch164		Rowena Ng, Gray Vargas, Dasal Tenzin Jashar, Amanda Morrow, Laura A Malone	Neurocognitive and Psychosocial Characteristics of Pediatric Patients With Post-Acute/Long-COVID: A Retrospective Clinical Case Series	https://doi.org/10.1093/arclin/acac056	Published	29 July 2022	Study	https://academic.oup.com/acn/advance-article/doi/10.1093/arclin/acac056/6651311	Objective Studies suggest a large number of patients have persistent symptoms following COVID-19 infection—a condition termed “long COVID.” Although children and parents often report cognitive difficulties after COVID, very few if any studies have been published including neuropsychological testing. Methods A retrospective chart review was completed for the first 18 patients referred for a neuropsychological evaluation from a multidisciplinary pediatric post-COVID clinic. The neuropsychological screening battery assessed verbal fluency and category switching, attention, working memory, processing speed, and verbal learning and memory. Patients’ caregivers also completed standardized questionnaires regarding day-to-day mood and behavior. Results At intake, the most common neurologic symptoms reported by caregivers were attention problems (83.3%), fatigue/lethargy (77.7%), sleep disturbance (77.7%), dizziness/vertigo (72.2%), and headaches (72.2%). On rating scales, most caregivers endorsed concerns for depressed mood and anxiety (14/15 and 12/15). A large proportion of patients had difficulties with attention (9/18) and depressed mood/anxiety (13/18) before COVID. On cognitive testing, the majority of the patients performed within or above broad average range (≥16th percentile) across most domains. However, a little over half of the patients performed below average on auditory attention measures. Conclusions Within our clinically referred sample, children who reported lingering cognitive symptoms after COVID-19 often had a preexisting history of attention and/or mood and anxiety concerns. Many of these patients performed below average in attention testing, but it remains to be seen whether this was due to direct effects of COVID, physical symptoms, and/or preexisting difficulties with attention or mood/anxiety.
167	Ch165		Suchitra Rao, MBBS, MSCS1; Grace M. Lee, MD, MPH2; Hanieh Razzaghi, MPH3; Vitaly Lorman, PhD3; Asuncion Mejias, MD, PhD4; Nathan M. Pajor, MD5; Deepika Thacker, MD6; Ryan Webb, MS3; Kimberley Dickinson, BS3; L. Charles Bailey, MD, PhD3; Ravi Jhaveri, MD7; Dimitri A. Christakis, MD, MPH8,9; Tellen D. Bennett, MD, MS1; Yong Chen, PhD10; Christopher B. Forrest, MD, PhD3	Clinical Features and Burden of Postacute Sequelae of SARS-CoV-2 Infection in Children and Adolescents	https://doi.org/10.1001/jamapediatrics.2022.2800	Published	August 22, 2022	Study	https://jamanetwork.com/journals/jamapediatrics/fullarticle/2795569	Key Points Question - What are the incidence and clinical features of postacute sequelae of SARS-CoV-2 infection (PASC) in children? Findings - In this cohort study including 659 286 children tested for SARS-CoV-2 by antigen or polymerase chain reaction, the symptom, condition, and medication with the strongest associations with SARS-CoV-2 infection were loss of taste/smell, myocarditis, and cough and cold preparations, respectively. The incidence proportion of non–multisystem inflammatory syndrome in children–related PASC in the viral test–positive group exceeded the incidence proportion in the viral test–negative group by 3.7%, with increased rates associated with acute illness severity, young age, and medical complexity. Meaning - PASC in children appears to be uncommon, with features that differ from adults. Abstract Importance - The postacute sequelae of SARS-CoV-2 infection (PASC) has emerged as a long-term complication in adults, but current understanding of the clinical presentation of PASC in children is limited. Objective - To identify diagnosed symptoms, diagnosed health conditions, and medications associated with PASC in children. Design, Setting and Participants - This retrospective cohort study used electronic health records from 9 US children’s hospitals for individuals younger than 21 years who underwent antigen or reverse transcriptase–polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 between March 1, 2020, and October 31, 2021, and had at least 1 encounter in the 3 years before testing. Exposures - SARS-CoV-2 positivity by viral test (antigen or RT-PCR). Main Outcomes and Measures - Syndromic (symptoms), systemic (conditions), and medication PASC features were identified in the 28 to 179 days following the initial test date. Adjusted hazard ratios (aHRs) were obtained for 151 clinically predicted PASC features by contrasting viral test–positive groups with viral test–negative groups using proportional hazards models, adjusting for site, age, sex, testing location, race and ethnicity, and time period of cohort entrance. The incidence proportion for any syndromic, systemic, or medication PASC feature was estimated in the 2 groups to obtain a burden of PASC estimate. Results - Among 659 286 children in the study sample, 348 091 (52.8%) were male, and the mean (SD) age was 8.1 (5.7) years. A total of 59 893 (9.1%) tested positive by viral test for SARS-CoV-2, and 599 393 (90.9%) tested negative. Most were tested in outpatient testing facility settings (322 813 [50.3%]) or office settings (162 138 [24.6%]). The most common syndromic, systemic, and medication features were loss of taste or smell (aHR, 1.96; 95% CI, 1.16-3.32), myocarditis (aHR, 3.10; 95% CI, 1.94-4.96), and cough and cold preparations (aHR, 1.52; 95% CI, 1.18-1.96), respectively. The incidence of at least 1 systemic, syndromic, or medication feature of PASC was 41.9% (95% CI, 41.4-42.4) among viral test–positive children vs 38.2% (95% CI, 38.1-38.4) among viral test–negative children, with an incidence proportion difference of 3.7% (95% CI, 3.2-4.2). A higher strength of association for PASC was identified in those cared for in the intensive care unit during the acute illness phase, children younger than 5 years, and individuals with complex chronic conditions. Conclusions and Relevance - In this large-scale, exploratory study, the burden of pediatric PASC that presented to health systems was low. Myocarditis was the most commonly diagnosed PASC-associated condition. Acute illness severity, young age, and comorbid complex chronic disease increased the risk of PASC.
168	Ch166		Ki PuiLamaMarcosChiñasabAmélie M.JuléacMariaTayloraMarinaOhashidMehdiBenamaraElenaCrestaniaMary Beth F.SonaJanetChouaCatherineGebhartdTalalChatilaaJaneNewburgereAdrienneRandolphfMariaGutierrez-ArcelusabLauren A.Hendersona	SARS-CoV-2-specific T cell responses in patients with multisystem inflammatory syndrome in children	https://doi.org/10.1016/j.clim.2022.109106	Published	30 August 2022	Study	https://www.sciencedirect.com/science/article/pii/S1521661622001875	Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infections that occurs in the pediatric population. We sought to characterize T cell responses in MIS-C compared to COVID-19 and pediatric hyperinflammatory syndromes. MIS-C was distinct from COVID-19 and hyperinflammatory syndromes due to an expansion of T cells expressing TRBV11–2 that was not associated with HLA genotype. Children diagnosed with MIS-C, but who were negative for SARS-CoV-2 by PCR and serology, did not display Vβ skewing. There was no difference in the proportion of T cells that became activated after stimulation with SARS-CoV-2 peptides in children with MIS-C compared to convalescent COVID-19. The frequency of SARS-CoV-2-specific TCRs and the antigens recognized by these TCRs were comparable in MIS-C and COVID-19. Expansion of Vβ11–2+ T cells was a specific biomarker of MIS-C patients with laboratory confirmed SARS-CoV-2 infections. Children with MIS-C had robust antigen-specific T cell responses to SARS-CoV-2.
169	Ch167		Roberta Pellegrino, Elena Chiappini, Amelia Licari, Luisa Galli & Gian Luigi Marseglia	Prevalence and clinical presentation of long COVID in children: a systematic review	https://doi.org/10.1007/s00431-022-04600-x	Published	15 September 2022	Review	https://link.springer.com/article/10.1007/s00431-022-04600-x	A systematic literature review was conducted up to 15th February 2022 to summarize long COVID evidence and to assess prevalence and clinical presentation in children and adolescents. Articles reporting long COVID prevalence and symptoms based on original data in the paediatric population were included. Case series quality was assessed through the JBI Critical Appraisal Checklist. For observational studies, adherence to STROBE checklist was evaluated. Twenty-two articles were included: 19 observational studies (12 cohort/7 cross-sectional) and 3 case series. Nine studies provided a control group. We found a high variability in terms of prevalence (1.6–70%). The most frequently reported symptoms were fatigue (2–87%), headache (3.5–80%), arthro-myalgias (5.4–66%), chest tightness or pain (1.4–51%), and dyspnoea (2–57.1%). Five studies reported limitations in daily function due to long COVID. Alterations at brain imaging were described in one study, transient electrocardiographic abnormalities were described in a minority of children, while most authors did not evidence long-term pulmonary sequelae. Older age, female sex, and previous long-term pathological conditions were more frequently associated with persistent symptoms. Conclusion: Long COVID evidence in children is limited, heterogeneous, and based on low-quality studies. The lockdown consequences are difficult to distinguish from long COVID symptoms. High-quality studies are required: WHO definition of long COVID should be used, controlled clinical studies should be encouraged, and the impact of new variants on long COVID prevalence should be investigated to ensure an objective analysis of long COVID characteristics in children and a proper allocation of healthcare system resources. What is Known: • Children rarely develop a severe respiratory disease in the acute phase of COVID-19. • A limited number of patients develop a multisystem inflammatory condition that can lead to multiorgan failure and shock. What is New: • Persistent symptoms after SARS-CoV-2 infection are reported in children and limitations in daily function due to long COVID symptoms affect school attendance. • Functional complaints of post-acute COVID are difficult to be distinguished from those due to social restrictions.
170	Ch168		CARL A. PIERCEKEVAN C. HEROLD BETSY C. HEROLD JANET CHOU ADRIENNE RANDOLPHBINITA KANE SAMMIE MCFARLANDDEEPTI GURDASANI CHRISTINA PAGEL PETER HOTEZ SARAH COBEY AND SCOTT E. HENSLEY	COVID-19 and children	https://doi.org/10.1126/science.ade1675	Published	8 Sep 2022	Article	https://www.science.org/doi/full/10.1126/science.ade1675	There has been substantial research on adult COVID-19 and how to treat it. But how do severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections afflict children? The COVID-19 pandemic has yielded many surprises, not least that children generally develop less severe disease than older adults, which is unusual for a respiratory disease. However, some children can develop serious complications from COVID-19, such as multisystem inflammatory syndrome in children (MIS-C) and Long Covid, even after mild or asymptomatic COVID-19. Why this occurs in some and not others is an important question. Moreover, when children do contract COVID-19, understanding their role in transmission, especially in schools and at home, is crucial to ensuring effective mitigation measures. Therefore, in addition to nonpharmaceutical interventions, such as improved ventilation, there is a strong case to vaccinate children so as to reduce possible long-term effects from infection and to decrease transmission. But questions remain about whether vaccination might skew immune responses to variants in the long term. As the experts discuss below, more is being learned about these important issues, but much more research is needed to understand the long-term effects of COVID-19 in children
171	Ch169		Ellen K. Kendall, BA1; Veronica R. Olaker, BS1; David C. Kaelber, MD, PhD2; Rong Xu, PhD1; Pamela B. Davis, MD, PhD3Ellen K. Kendall, BA1; Veronica R. Olaker, BS1; David C. Kaelber, MD, PhD2; Rong Xu, PhD1; Pamela B. Davis, MD, PhD3	Association of SARS-CoV-2 Infection With New-Onset Type 1 Diabetes Among Pediatric Patients From 2020 to 2021	https://doi.org/10.1001/jamanetworkopen.2022.33014	Published	September 23, 2022	Study	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2796649	Introduction Incidence of new-onset type 1 diabetes (T1D) increased during the COVID-19 pandemic,1 and this increase has been associated with SARS-CoV-2 infection.2 The US Centers for Disease Control and Prevention reported that pediatric patients with COVID-19 were more likely to be diagnosed with diabetes after infection, although types 1 and 2 were not separated.3 Therefore, whether COVID-19 was associated with new-onset T1D among youths remains unclear. This cohort study assessed whether there was an increase in new diagnoses of T1D among pediatric patients after COVID-19. Methods Data were obtained using TriNetX Analytics Platform, a web-based database of deidentified electronic health records of more than 90 million patients, from the Global Collaborative Network, which includes 74 large health care organizations across 50 US states and 14 countries with diverse representation of geographic regions, self-reported race, age, income, and insurance types.4 The MetroHealth System institutional review board deemed the study exempt because it was determined to be non–human participant research. The study followed the STROBE reporting guideline. The study population comprised pediatric patients in 2 cohorts: (1) patients aged 18 years or younger with SARS-CoV-2 infection between March 2020 and December 2021 and (2) patients aged 18 years or younger without SARS-CoV-2 infection but with non–SARS-CoV-2 respiratory infection during the same period. SARS-CoV-2 infection was defined as described in prior studies.5 These cohorts were subdivided into groups aged 0 to 9 years and 10 to 18 years. Cohorts were propensity score matched (1:1 using nearest-neighbor greedy matching) for demographics and family history of diabetes (Table). Risk of new diagnosis of T1D within 1, 3, and 6 months after infection were compared between matched cohorts using hazard ratios (HRs) and 95% CIs. Statistical analyses were conducted in the TriNetX Analytics Platform. Further details and analyses from the TriNetX database are given in the eMethods in the Supplement. Results The Table shows population characteristics before and after matching. The study population included 1 091 494 pediatric patients: 314 917 with COVID-19 and 776 577 with non–COVID-19 respiratory infections. The matched cohort included 571 256 pediatric patients: 285 628 with COVID-19 and 285 628 with non–COVID-19 respiratory infections. By 6 months after COVID-19, 123 patients (0.043%) had received a new diagnosis of T1D, but only 72 (0.025%) were diagnosed with T1D within 6 months after non–COVID-19 respiratory infection. At 1, 3, and 6 months after infection, risk of diagnosis of T1D was greater among those infected with SARS-CoV-2 compared with those with non–COVID-19 respiratory infection (1 month: HR, 1.96 [95%CI, 1.26-3.06]; 3 months: HR, 2.10 [95% CI, 1.48-3.00]; 6 months: HR, 1.83 [95% CI, 1.36-2.44]) and in subgroups of patients aged 0 to 9 years, a group unlikely to develop type 2 diabetes, and 10 to 18 years (Figure). Similar increased risks were observed among children infected with SARS-CoV-2 compared with other control cohorts at 6 months (fractures: HR, 2.09 [95% CI, 1.41- 3.10]; well child visits: HR, 2.10 [95% CI, 1.61- 2.73]). Discussion In this study, new T1D diagnoses were more likely to occur among pediatric patients with prior COVID-19 than among those with other respiratory infections (or with other encounters with health systems). Respiratory infections have previously been associated with onset of T1D,6 but this risk was even higher among those with COVID-19 in our study, raising concern for long-term, post–COVID-19 autoimmune complications among youths. Study limitations include potential biases owing to the observational and retrospective design of the electronic health record analysis, including the possibility of misclassification of diabetes as type 1 vs type 2, and the possibility that additional unidentified factors accounted for the association. Results should be confirmed in other populations. The increased risk of new-onset T1D after COVID-19 adds an important consideration for risk-benefit discussions for prevention and treatment of SARS-CoV-2 infection in pediatric populations.
172	Ch170		Marco Roversi, Luana Coltella, Livia Piccioni, Umberto Raucci, Antonio Torelli, Laura Papini, Carla Olita, Antonino Reale, Carlo Federico Perno, Alberto Villani & Cristina Russo	Relationship between viral load and symptoms in children infected with SARS-CoV-2	https://doi.org/10.1038/s41390-022-02293-4	Published	07 September 2022	Study	https://www.nature.com/articles/s41390-022-02293-4	Background The purpose of this study is to evaluate the association between SARS-CoV-2 viral load in respiratory secretions of infected children and signs/symptoms of COVID-19. Methods We reported the clinical characteristics of SARS-CoV-2-infected children during the study period. We compared viral load for several clinical variables, performed a predictive linear regression analysis to identify signs and symptoms significantly associated with viral load, and searched for discriminant viral load thresholds for symptomatic versus asymptomatic infections based on receiver-operating characteristics. Results A total of 570 patients were included. The median age was 4.75 years. Comparison of CT values by dichotomous variable showed higher viral loads in children with fever, respiratory symptoms, and previous exposure to SARS-CoV-2. The linear regression analysis confirmed a significant relationship between the CT value with these variables and with age, other symptoms, and asymptomaticity. In particular, infants with fever and SARS-CoV-2 exposure had higher viral loads. No viral load cut-offs were found to distinguish symptomatic from asymptomatic patients. Conclusion Our study shows that fever, SARS-CoV-2 exposure, and respiratory symptoms are associated with higher viral load in children, especially infants, while age, presence of nonrespiratory symptoms, or absence of any symptoms are associated with lower viral load. Impact Key message: the clinical variables that best predict viral load in infected children are history of previous exposure to a SARS-CoV-2-infected person and presence of fever and respiratory symptoms (higher viral load). Added value to the current literature: this is the first article to prove this point. Impact: SARS-CoV-2 viral load should not be used as a measure of clinical severity of COVID-19 in the pediatric population; however, lower viral load appears to be associated with asymptomatic COVID-19 in older children.
173	Ch171		Millicent Aarah-Bapuah,Stella Sarpomaa Oppong,Anita Ohenewaa Yawson,Gladys Dzansi &Samuel Adjorlolo	Covid-19 and mental health of children and adolescents: A systematic review	https://doi.org/10.1080/23311908.2022.2111849	Published	09 Sep 2022	Systematic review	https://www.tandfonline.com/doi/full/10.1080/23311908.2022.2111849	The outbreak of the COVID-19 pandemic had imposed considerable risk on public health, and had generated unprecedented levels of panic. There are increasing concerns over the possible negative impact of COVID-19 on the mental health of children/adolescents. This review was conducted to describe the impact of COVID-19 on the mental health of children and adolescents. An electronic search was conducted in PubMed, CINAHL, MEDLINE, and the WHO Global Health database on COVID-19. The 2020 updated Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guideline and an adapted Joanna Briggs aetiology review methodology were followed in conducting this review. A total of 21 studies from 8 different countries located on 4 continents (Asia, Europe, North America & South America), reporting on sample size of 56,368 met the inclusion criteria. Using the JBI critical appraisal tool for studies reporting on prevalence data, the quality of most of the studies was assessed to be moderate. Prevalence of depression, anxiety and stress was estimated to range from 7.2% to 78%; of anxiety, from 15% to 78%, depression, from 7.2% to 43.7% and stress, at 17.3%. Correlates for COVID −19 related mental health outcomes were identified as female gender and social isolation among others. The COVID-19 pandemic has negatively affected the mental health of children and adolescents. It is recommended that governments and health agencies prioritize mental health, especially for children and adolescents to prevent long-term effects on them.
174	Ch172		Sung Min Cho, Nicole White, Lavienraj Premraj, Denise Battaglini, Jonathon Fanning, Jacky Suen, Gianluigi Li Bassi, John Fraser, Chiara Robba, Matthew Griffee, Bhagteshwar Singh, Barbara Wanjiru Citarella, Laura Merson, Tom Solomon, David Thomson	Neurological manifestations of COVID-19 in adults and children	https://doi.org/10.1093/brain/awac332	Published	10 September 2022	Study	https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awac332/6695387	Different neurological manifestations of COVID-19 in adults and children and their impact have not been well characterized. We aimed to determine the prevalence of neurological manifestations and in-hospital complications among hospitalized COVID-19 patients and ascertain differences between adults and children. We conducted a prospective multicenter observational study using the International Severe Acute Respiratory and emerging Infection Consortium cohort across 1507 sites worldwide from January/30th/2020 to May/25th/2021. Analyses of neurological manifestations and neurological complications considered unadjusted prevalence estimates for predefined patient subgroups, and adjusted estimates as a function of patient age and time of hospitalization using generalized linear models. Overall, 161,239 patients (158,267 adults; 2,972 children) hospitalized with COVID-19 and assessed for neurological manifestations and complications were included. In adults and children, the most frequent neurological manifestations at admission were fatigue (adults: 37.4%; children: 20.4%), altered consciousness (20.9%; 6.8%), myalgia (16.9%; 7.6%), dysgeusia (7.4%; 1.9%), anosmia (6.0%; 2.2%), and seizure (1.1%; 5.2%). In adults, the most frequent in-hospital neurological complications were stroke (1.5%), seizure (1%), and central nervous system (CNS) infection (0.2%). Each occurred more frequently in ICU than in non-ICU patients. In children, seizure was the only neurological complication to occur more frequently in ICU vs. non-ICU (7.1% vs. 2.3%, P < .001). Stroke prevalence increased with increasing age, while CNS infection and seizure steadily decreased with age. There was a dramatic decrease in stroke over time during the pandemic. Hypertension, chronic neurological disease, and the use of extracorporeal membrane oxygenation were associated with increased risk of stroke. Altered consciousness was associated with CNS infection, seizure, and stroke. All in-hospital neurological complications were associated with increased odds of death. The likelihood of death rose with increasing age, especially after 25 years of age. In conclusion, adults and children have different neurological manifestations and in-hospital complications associated with COVID-19. Stroke risk increased with increasing age, while CNS infection and seizure risk decreased with age.
175	Ch173		Stephenson, Terencea; Shafran, Roza; Ladhani, Shamez N.b	Long COVID in children and adolescents	https://doi.org/10.1097/QCO.0000000000000854	Published	Aug 3, 2022	Review	https://journals.lww.com/co-infectiousdiseases/Fulltext/2022/10000/Long_COVID_in_children_and_adolescents.14.aspx	Purpose of review Although acute COVID-19 has been milder in children and young people compared with adults, there is a concern that they may suffer persistent symptoms. There is a need to define the clinical phenotype, determine those most at risk, the natural course of the condition and evaluate preventive and therapeutic strategies for both mental health and physical symptoms. Recent findings More recent studies with control groups reported a lower prevalence of persistent symptoms in children and young people exposed to SARS-CoV-2. A systematic review and meta-analysis found that the frequency of the majority of reported persistent symptoms is similar in SARS-CoV-2 positive cases and controls. Children and young people infected with SARS-COV-2 had small but significant increases in persisting cognitive difficulties, headache and loss of smell. Factors associated with persisting, impairing symptoms include increased number of symptoms at the time of testing, female sex, older age, worse self-rated physical and mental health, and feelings of loneliness preinfection. Summary This review highlights the importance of a control group in studies following SARS-CoV-2 infection, the need for case definitions and research to understand the outcomes of long COVID in children and young people.
176	Ch174		Domenico Paolo La Regina 1,Daniela Pepino 2,Raffaella Nenna 1ORCID,Elio Iovine 1,Enrica Mancino 1,Gianmarco Andreoli 2,Anna Maria Zicari 1,Alberto Spalice 1,Fabio Midulla	Pediatric COVID-19 Follow-Up with Lung Ultrasound: A Prospective Cohort Study	https://doi.org/10.3390/diagnostics12092202	Published	11 September 2022	Study	https://www.mdpi.com/2075-4418/12/9/2202/htm	During the COVID-19 pandemic, lung ultrasound (LUS) was widely used to assess SARS-CoV-2 infection. To date, there are patients with persistence of symptoms after acute infection. Therefore, it may be useful to have an objective tool to follow these patients. The aim of our study was to evaluate the presence of LUS artifacts after SARS-CoV-2 infection in children and to analyze the associations between time elapsed since infection and symptomatology during acute infection. We conducted an observational study, enrolling 607 children infected with SARS-CoV-2 in the previous twelve months. All patients performed a LUS and medical history of demographic and clinical data. We observed irregular pleural lines in 27.5%, B-lines in 16.9%, and subpleural consolidations in 8.6% of the cases. These artifacts were more frequently observed in the lower lobe projections. We have observed that the frequency of artifacts decreases with increasing time since infection. In symptomatic patients during COVID infection, B-lines (p = 0.02) were more frequently found. In our sample, some children, even after months of acute infection, have ultrasound artifacts and showed an improvement with the passage of time from the acute episode. Our study provides additional evidence about LUS in children with previous COVID-19 as a support to follow these patients in the months following the infection.
177	Ch175	ME	Anna-Lisa Sorg, MSc1,2; Selina Becht, MSc1; Marietta Jank, MD3; Jakob Armann, MD4; Ulrich von Both, MD5; Markus Hufnagel, MD6; Fabian Lander, MD7; Johannes G. Liese, MD8; Tim Niehues, MD9; Eva Verjans, MD10; Martin Wetzke, MD11; Silvia Stojanov, MD12; Uta Behrends, MD12; Christian Drosten, MD13; Horst Schroten, MD3; Rüdiger von Kries, MD1	Association of SARS-CoV-2 Seropositivity With Myalgic Encephalomyelitis and/or Chronic Fatigue Syndrome Among Children and Adolescents in Germany	https://doi.org/10.1001/jamanetworkopen.2022.33454	Published	September 27, 2022	Study	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2796733	Key Points Question Is SARS-CoV-2 seropositivity associated with symptoms of myalgic encephalomyelitis and/or chronic fatigue syndrome (ME/CFS) in children and adolescents? Findings This cross-sectional study of hospital-based SARS-CoV-2 seroprevalence surveys in Germany compared seropositive and seronegative children and adolescents and identified an excess of possible ME/CFS symptoms with serological evidence of preceding SARS-CoV-2 infection. This association almost disappeared with adjustment for confounders and restriction to children and adolescents unaware of preceding infection. Meaning These findings suggest that the risk of ME/CFS after SARS-CoV-2 infection in children and adolescents may be small and that recall bias may contribute to risk estimates. Abstract Importance During the COVID-19 pandemic, a reduction in quality of life and physical and mental health among children and adolescents has been reported that may be associated with SARS-CoV-2 infection and/or containment measures. Objective To assess the association of SARS-CoV-2 seropositivity with symptoms that may be related to myalgic encephalomyelitis and/or chronic fatigue syndrome (ME/CFS) among children and adolescents. Design, Setting, and Participants This substudy of the cross-sectional SARS-CoV-2 seroprevalence surveys in Germany (SARS-CoV-2 KIDS) was performed in 9 pediatric hospitals from May 1 to October 31, 2021. Pediatric patients were recruited during an inpatient or outpatient visit regardless of the purpose of the visit. Parental questionnaires and serum samples were collected during clinically indicated blood draws. The parental questionnaire on demographic and clinical information was extended by items according to the DePaul Symptom Questionnaire, a pediatric screening tool for ME/CFS in epidemiological studies in patients aged 5 to 17 years. Exposures Seropositivity was determined by SARS-CoV-2 IgG antibodies in serum samples using enzyme-linked immunosorbent assays. Main Outcomes and Measures Key symptoms of ME/CFS were evaluated separately or as clustered ME/CFS symptoms according to the DePaul Symptom Questionnaire, including fatigue. Results Among 634 participants (294 male [46.4%] and 340 female [53.6%]; median age, 11.5 [IQR, 8-14] years), 198 (31.2%) reported clustered ME/CFS symptoms, including 40 of 100 SARS-CoV-2–seropositive (40.0%) and 158 of 534 SARS-CoV-2–seronegative (29.6%) children and adolescents. After adjustment for sex, age group, and preexisting disease, the risk ratio for reporting clustered ME/CFS symptoms decreased from 1.35 (95% CI, 1.03-1.78) to 1.18 (95% CI, 0.90-1.53) and for substantial fatigue from 2.45 (95% CI, 1.24-4.84) to 2.08 (95% CI, 1.05-4.13). Confinement to children and adolescents with unknown previous SARS-CoV-2 infection status (n = 610) yielded lower adjusted risks for all symptoms except joint pain ME/CFS–related symptoms. The adjusted risk ratio was 1.08 (95% CI, 0.80-1.46) for reporting clustered ME/CFS symptoms and 1.43 (95% CI, 0.63-3.23) for fatigue. Conclusions and Relevance These findings suggest that the risk of ME/CFS in children and adolescents owing to SARS-CoV-2 infection may be very small. Recall bias may contribute to risk estimates of long COVID-19 symptoms in children. Extensive lockdowns must be considered as an alternative explanation for complex unspecific symptoms during the COVID-19 pandemic.
178	Ch176		Anita Slomski	Long COVID in Children	https://doi.org/10.1001/jama.2022.15439	Published	October 4, 2022	Editorial	https://jamanetwork.com/journals/jama/article-abstract/2796961	Postacute sequelae of SARS-CoV-2 infection (PASC) appears to be uncommon in children and presents with features different from long COVID in adults, according to a cohort study published in JAMA Pediatrics that included 659 286 children. Investigators used electronic health records from 9 US children’s hospitals to collect data on children and adolescents who had an antigen or reverse transcriptase–polymerase chain reaction (RT-PCR) test for SARS-CoV-2. The average age of the children in the study was 8.1 years. In the study sample, 9.1% tested positive for SARS-CoV-2.
179	Ch177		Sara Prosperi, Francesco Chiarelli	COVID-19 and diabetes in children	https://doi.org/10.6065/apem.2244150.075	Published	September 30, 2022	Review	https://e-apem.org/journal/view.php?number=955	This review describes the impact of coronavirus disease 2019 (COVID-19) in children and adolescents, investigating changes in diabetes presentation during the COVID-19 pandemic, possible links between severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection and diabetes, and mechanisms of pancreatic β-cell destruction. Although glycemic control in individuals with already known diabetes mellitus did not worsen during the pandemic, there was a worrying increase in diabetic ketoacidosis in children with new-onset diabetes, probably due to containment measures and delayed access to emergency departments. Moreover, new evidence suggests that SARS-CoV-2 has the capacity to directly and indirectly induce pancreatic β-cell destruction, and the risk of newly diagnosed diabetes after COVID-19 increased in both children and adults. While long-term studies continue to follow children with SARS-CoV-2 infection, this review discusses available findings on the relationship between COVID-19 and diabetes. It is important to emphasize the need to maintain close links between families of children with chronic conditions and their pediatricians, as well as to promote early access to healthcare services, in order to reduce dangerous delays in diabetes diagnosis and prevent diabetic ketoacidosis.
180	Ch178		Corey Diamond, PharmD	Study gives clinicians snapshot into long COVID for children	https://doi.org/10.1016/j.ptdy.2022.10.018	Published	October 01, 2022		https://www.pharmacytoday.org/article/S1042-0991(22)00801-5/fulltext	Their regression model found that children who tested positive for COVID-19 hospitalized for more than 48 hours had an over 2.5-fold stronger association with post–COVID-19 conditions compared to nonhospitalized children. These conditions were also strongly associated with symptom quantity at the index ED visit. Compared to children with 3 or fewer symptoms on ED presentation, children who tested positive for COVID-19 with 7 or more symptoms and 4 or more symptoms had about a 4.5-fold and 2.5-fold stronger association with post–COVID-19 conditions at 90 days, respectively. The final risk factor they reported was age: Children who tested positive for COVID-19 who were 14 years or older had about a 2.5-fold stronger association with post–COVID-19 conditions at 90 days compared to children younger than one year. Strength of the design As a result of limitations in study methodology early in the pandemic, the literature has presented conflicting evidence of whether children were at risk of manifesting long COVID after acute COVID-19 infection. Early reports from 2020 and 2021 estimated that post–COVID-19 conditions occurred in up to 58% of pediatric patients with COVID-19, while other reports describe no disparity. Funk and colleagues’ study now provides important insights into the characterization of COVID-19 in children as it is the first large prospective cohort study to investigate long COVID in children seeking ED care with advanced methodology that significantly mitigates bias. “Our PCC [post-COVID-19 conditions] assessment approach, which clarifies the presence of the reported symptoms prior to the index ED visit, represents a methodological advance compared with prior assessments that focused on the presence or absence of symptoms in the preceding 7 days,” stated the authors. They go on to say that by including children with repeat COVID-19 test results within 14 days of the index ED visit, the researchers were able to eliminate the risk of false-negative tests results. “Thus, our evaluation provides a realistic estimate of PCC prevalence along with a comparator group.”
181	Ch179		Kamran Hessami, MD1; Amir Hossein Norooznezhad, MD2; Sonia Monteiro, MD3; Enrico R. Barrozo, PhD4; Abolfazl Shirdel Abdolmaleki, MD, MPH5; Sara E. Arian, MD6; Nikan Zargarzadeh, MD7; Lara S. Shekerdemian, MD8; Kjersti M. Aagaard, MD, PhD4; Alireza A. Shamshirsaz, MD1	COVID-19 Pandemic and Infant Neurodevelopmental Impairment A Systematic Review and Meta-analysis	https://doi.org/10.1001/jamanetworkopen.2022.38941	Published	October 28, 2022	Systematic Review and Meta-analysis	https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2797911	Key Points Question Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic? Findings This meta-analysis of 8 studies including 21 419 infants found that 7% of infants who had neurodevelopmental screening during the COVID-19 pandemic were at risk of neurodevelopmental impairment, and 12% of those with gestational exposure to SARS-CoV-2 were at risk for neurodevelopmental impairment. Communication impairment was the sole neurodevelopmental domain of significantly increased risk of occurrence during the COVID-19 pandemic. Meaning These findings suggest that overall neurodevelopment was not changed by the COVID-19 pandemic, but birth or being raised during the SARS-CoV-2 pandemic, regardless of gestational exposure, was associated with a significant risk of communication impairment among the infants. Abstract Importance - Primary studies proposed that aberrant maternal antiviral immunity and/or giving birth in quarantine, such as during the ongoing COVID-19 pandemic, may be associated with the risk of neurodevelopmental impairment (NDI) in offspring. Objectives - To evaluate the associations of birth and being raised during the COVID-19 pandemic with risk of NDI among infants and to assess the association of gestational exposure to SARS-CoV-2 with risk of NDI. Data Sources - PubMed, Web of Science, Scopus, Embase, and preprint servers were systematically searched from inception to March 25, 2022. Study Selection - Studies evaluating the neurodevelopment of infants born during the SARS-CoV-2 pandemic were included in this systematic review and meta-analysis. Studies using Ages and Stages Questionnaires, Third Edition (ASQ-3), were used for quantitative meta-analysis. Data Extraction and Synthesis - Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses, a random-effects model meta-analysis was used to pool the proportion and odds ratios (ORs) of overall NDI, as well as each developmental domain on ASQ-3 with the corresponding 95% CI. Main Outcomes and Measures - The primary outcome was the risk of overall NDI among infants screened during the pandemic vs prepandemic. The secondary outcome was the comparison of NDI by ASQ-3 domain among infants born to women with known gestational exposure to SARS-CoV-2 vs no exposure. Results - A total of 8 studies were included, including 21 419 infants (11 438 screened in pandemic and 9981 in prepandemic period). NDI was present in 330 of 8992 infants (7%; 95% CI, 4%-10%) screened during the COVID-19 pandemic from January 2020 to January 2021. Among the pandemic cohort, the prevalence of NDI among infants with gestational exposure to SARS-CoV-2 was 77 of 691 (12%; 95% CI, 6%-18%). Compared with the prepandemic cohort (2015-2019), the pandemic cohort was more likely to have communication impairment (OR, 1.70; 95% CI, 1.37-2.11; P < .001), without significant differences in other ASQ-3 domains (eg, gross motor, fine motor, personal-social, and problem-solving). In contrast, maternal SARS-CoV-2 infection was not associated with significant differences in any neurodevelopment domain in offspring, except for increasing the odds of fine motor impairment (OR, 3.46; 95% CI, 1.43-8.38; P < .001). Conclusions and Relevance In this systematic review and meta-analysis examining the association between COVID-19 pandemic and the risk of NDI, findings suggest that overall neurodevelopment in the first year of life was not changed by either being born or raised during the SARS-CoV-2 pandemic or by gestational exposure to SARS-CoV-2. Interestingly, the first year of life during the COVID-19 pandemic, regardless of maternal infection, was significantly associated with the risk of communication delay among the offspring.
182	Ch180		by Alba Gonzalez-Aumatell 1,2,*,†ORCID,Maria Victoria Bovo 1,†,Clara Carreras-Abad 1ORCID,Sara Cuso-Perez 1,Èlia Domènech Marsal 1,Roser Coll-Fernández 3,Aroia Goicoechea Calvo 3,Maria Giralt-López 4,5ORCID,Antonia Enseñat Cantallops 6,Sara Moron-Lopez 7,8ORCID,Javier Martinez-Picado 7,8,9,10ORCID,Paula Sol Ventura 11ORCID,Carlos Rodrigo 1,2ORCID andMaria Méndez Hernández 1,2ORCID	Social, Academic, and Health Status Impact of Long COVID on Children and Young People: An Observational, Descriptive, and Longitudinal Cohort Study	https://doi.org/10.3390/children9111677	Published	31 October 2022	Study	https://www.mdpi.com/2227-9067/9/11/1677	There is a lack of evidence of the health impacts due to long COVID among children and young people (CYP). The objective of this study is to determine the main clinical characteristics of long COVID in CYP and to investigate the academic, social, and health status impacts of long COVID in this population. An observational, descriptive, and longitudinal study on CYP who presented COVID-19 symptoms for more than twelve weeks after SARS-CoV-2 infection was performed between December 2020 and May 2021. Fifty CYP were included, with a median age of 14.1 years, 33 (66%) were female, and 17 (34%) had a relative diagnosed with long COVID. Since the initial infection and up to the first visit, CYP had persisting symptoms for a median of 4.1 months, and for 18 (36%) CYP these symptoms persisted for more than 6 months. Fatigue (100%), neurocognitive disorders (74%), muscular weakness (74%), and headache (72%) were the most reported symptoms. A total of 9 (18%) CYP could not attend school, 17 (34%) had a reduced schedule, 33 (66%) showed a decreased school performance, and 68% had stopped extracurricular activities. This preliminary study shows the impact that long COVID has on the health, academic, and social life of CYP.
183	Ch181		Leonardo Di Gennaro, Piero Valentini, Silvia Sorrentino, Maria Antonietta Ferretti, Erica De Candia, Maria Basso, Stefano Lancellotti, Raimondo De Cristofaro, Cristina De Rose, Francesco Mariani, Rosa Morello, Ilaria Lazzareschi, Louise Sigfrid, Daniel Munblit & Danilo Buonsenso	Extended coagulation profile of children with Long Covid: a prospective study	https://doi.org/10.1038/s41598-022-23168-y	Published	01 November 2022	Study	https://www.nature.com/articles/s41598-022-23168-y	Emerging data suggests that endotheliopathy changes can be associated with post covid condition (PCC) in adults. Research on the matter in children is lacking. We analyzed an extended coagulation profile including biomarkers of endothelial damage in children with PCC and compared it with a control group of children that fully recovered post- SARS-CoV-2 infection. A case-control study enrolling children below 18 years of age with previous microbiologically confirmed SARS-CoV-2 infection in a pediatric post-covid unit in Italy ≥ 8 weeks after the initial infection. Samples were taken at 8 and 12 weeks after the SARS-CoV-2 diagnosis and analyzed for coagulation profiling (fibrinogen, prothrombin time, international normalized ratio, activated partial thromboplastin time, d-dimers, factor VIII coagulant activity, plasma von Willebrand factor (VWF) antigen and VWF ristocetin cofactor (RC)). We compared coagulation profiles in samples from children identified with PCC (at least one, or three or more symptoms, which could not be explained by an alternative diagnosis, at the 8- and 12-week follow-up assessment using the pediatric Long Covid International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) survey. Seventy-five children were enrolled, 49.3% were females, the median age was 10.2 (IQR 4.9) years. Forty-six (61%) of the children had at least one persisting symptom at the eight weeks post-onset, (PCC8); 39/75 (52%) had persistent symptoms for more than 12 weeks (PCC12) and 15/75(32%) had at least three persisting symptoms (PCC ≥ 3) at 12 weeks. Children with PCC presented more frequently with abnormal D-Dimer levels above the reference range compared to children that had fully recovered at the 8–12 weeks (39.1% vs. 17.2%, p = 0.04), and 12 week follow up or more (41% vs. 17.2%, p = 0.05), and in children with three or more symptoms at 12 weeks follow up compared to those that had recovered (64.3% vs. 22.2%, p = 0.002). For the other coagulation profiles, there were abnormal values detected for VWF, FVIII, RC and Fibrinogen but no significant differences between children with PCC compared to controls. Although the majority of children in our cohort showed coagulation profile within or close to normal ranges, we found that a higher proportion of children with PCC, and specifically those with a more severe spectrum characterized with three or more persisting symptoms, had abnormal D-dimer levels compared to other children that fully recovered from an acute SARS-CoV-2 infection.
184	Ch182		Martin Roessler ,Falko Tesch,Manuel Batram,Josephine Jacob,Friedrich Loser,Oliver Weidinger,Danny Wende,Annika Vivirito,Nicole Toepfner,Franz Ehm,Martin Seifert,Oliver Nagel,Christina König,Roland Jucknewitz,Jakob Peter Armann,Reinhard Berner,Marina Treskova-Schwarzbach,Dagmar Hertle,Stefan Scholz,Stefan Stern,Pedro Ballesteros,Stefan Baßler,Barbara Bertele,Uwe Repschläger,Nico Richter,Cordula Riederer,Franziska Sobik,Anja Schramm,Claudia Schulte,Lothar Wieler,Jochen Walker,Christa Scheidt-Nave,Jochen Schmitt	Post-COVID-19-associated morbidity in children, adolescents, and adults: A matched cohort study including more than 157,000 individuals with COVID-19 in Germany	https://doi.org/10.1371/journal.pmed.1004122	Published	November 10, 2022	Study	https://journals.plos.org/PLoSmedicine/article?id=10.1371/journal.pmed.1004122	Background Long-term health sequelae of the Coronavirus Disease 2019 (COVID-19) are a major public health concern. However, evidence on post-acute COVID-19 syndrome (post-COVID-19) is still limited, particularly for children and adolescents. Utilizing comprehensive healthcare data on approximately 46% of the German population, we investigated post-COVID-19-associated morbidity in children/adolescents and adults. Methods and findings We used routine data from German statutory health insurance organizations covering the period between January 1, 2019 and December 31, 2020. The base population included all individuals insured for at least 1 day in 2020. Based on documented diagnoses, we identified individuals with polymerase chain reaction (PCR)-confirmed COVID-19 through June 30, 2020. A control cohort was assigned using 1:5 exact matching on age and sex, and propensity score matching on preexisting medical conditions. The date of COVID-19 diagnosis was used as index date for both cohorts, which were followed for incident morbidity outcomes documented in the second quarter after index date or later.Overall, 96 prespecified outcomes were aggregated into 13 diagnosis/symptom complexes and 3 domains (physical health, mental health, and physical/mental overlap domain). We used Poisson regression to estimate incidence rate ratios (IRRs) with 95% confidence intervals (95% CIs). The study population included 11,950 children/adolescents (48.1% female, 67.2% aged between 0 and 11 years) and 145,184 adults (60.2% female, 51.1% aged between 18 and 49 years). The mean follow-up time was 236 days (standard deviation (SD) = 44 days, range = 121 to 339 days) in children/adolescents and 254 days (SD = 36 days, range = 93 to 340 days) in adults. COVID-19 and control cohort were well balanced regarding covariates. The specific outcomes with the highest IRR and an incidence rate (IR) of at least 1/100 person-years in the COVID-19 cohort in children and adolescents were malaise/fatigue/exhaustion (IRR: 2.28, 95% CI: 1.71 to 3.06, p < 0.01, IR COVID-19: 12.58, IR Control: 5.51), cough (IRR: 1.74, 95% CI: 1.48 to 2.04, p < 0.01, IR COVID-19: 36.56, IR Control: 21.06), and throat/chest pain (IRR: 1.72, 95% CI: 1.39 to 2.12, p < 0.01, IR COVID-19: 20.01, IR Control: 11.66). In adults, these included disturbances of smell and taste (IRR: 6.69, 95% CI: 5.88 to 7.60, p < 0.01, IR COVID-19: 12.42, IR Control: 1.86), fever (IRR: 3.33, 95% CI: 3.01 to 3.68, p < 0.01, IR COVID-19: 11.53, IR Control: 3.46), and dyspnea (IRR: 2.88, 95% CI: 2.74 to 3.02, p < 0.01, IR COVID-19: 43.91, IR Control: 15.27). For all health outcomes combined, IRs per 1,000 person-years in the COVID-19 cohort were significantly higher than those in the control cohort in both children/adolescents (IRR: 1.30, 95% CI: 1.25 to 1.35, p < 0.01, IR COVID-19: 436.91, IR Control: 335.98) and adults (IRR: 1.33, 95% CI: 1.31 to 1.34, p < 0.01, IR COVID-19: 615.82, IR Control: 464.15). The relative magnitude of increased documented morbidity was similar for the physical, mental, and physical/mental overlap domain. In the COVID-19 cohort, IRs were significantly higher in all 13 diagnosis/symptom complexes in adults and in 10 diagnosis/symptom complexes in children/adolescents. IRR estimates were similar for age groups 0 to 11 and 12 to 17. IRs in children/adolescents were consistently lower than those in adults. Limitations of our study include potentially unmeasured confounding and detection bias. Conclusions In this retrospective matched cohort study, we observed significant new onset morbidity in children, adolescents, and adults across 13 prespecified diagnosis/symptom complexes, following COVID-19 infection. These findings expand the existing available evidence on post-COVID-19 conditions in younger age groups and confirm previous findings in adults.
185	Ch183		RJ Langley, PD Burns, PL Davies, C Presslie	P230 Assessment of Cardio-pulmonary function in children and adolescents with suspected long COVID	http://dx.doi.org/10.1136/thorax-2022-BTSabstracts.362	Published	November 11, 2022	Study	https://thorax.bmj.com/content/77/Suppl_1/A207.abstract	Introduction Persistent respiratory symptoms and exercise intolerance following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents is common.1 Our aim was to review the clinical data on patients who had been referred with suspected long COVID (LC). Unfortunately, there is a lack of an agreed definition for LC. The patient cohort were referred with persistent respiratory symptoms/signs (cough, exertional dyspnoea or wheeze) for at least 3 months following confirmed (PCR or antigen test positive) mild SARS-CoV-2 infection that did not require hospitalisation. Methods This was a retrospective analysis of clinical data obtained during clinical assessment. Patients had undergone pulmonary function tests (PFTs) including; spirometry, Single breath transfer factor (T LCO) and static lung volume measurements (Vyntus Body – VyaireTM Medical) followed by an incremental maximal ramp cardiopulmonary exercise testing (CPET) performed on a cycle ergometer (Jaeger CPX & Vyntus ONE – VyaireTM Medical). Results Seven patients (four male) with suspected LC had undergone PFTs and CPET. Demographics and summary data are presented (table 1). Five had normal PFT results. Of the two that had abnormal PFTs both had co-existing morbidities. One had mild airflow obstruction (previous pneumothorax) and the other had a restrictive defect (Di-George syndrome and obesity). Three patients had a reduced peak Oxygen uptake (VO2peak < 85% predicted). The cardiovascular and gas exchange response to incremental exercise were normal and there was no evidence of ventilatory limitation or dysfunctional breathing in any of the patients. Conclusions Although only a small cohort was examined, this study suggests that SARS-CoV-2 infection does not seem to be causing any longstanding cardiopulmonary function impairment in children and adolescents. Whilst there may be pathophysiological changes following SARS-CoV-2 infection, as previously reported in adults,2 a reduced aerobic capacity is seen in some of these patients and this may due to physical de-conditioning rather than any physiological impairment caused by SARS-CoV-2 infection.
186	Ch184		CamilleBréhin	Diagnostic d’un syndrome inflammatoire multi-systémique pédiatrique associé à la COVID-19Diagnosis of a Pediatric Inflammatory multisystemic Syndrome associated with COVID-19	https://doi.org/10.1016/j.jpp.2022.11.001	Published	15 November 2022	Article	https://www.sciencedirect.com/science/article/pii/S0987798322001360	Résumé Suite à la propagation de la pandémie de coronavirus 2019 (COVID-19), une nouvelle entité pathologique est apparue, définie comme le syndrome inflammatoire multi-systémique pédiatrique associé à la COVID-19 (PIMS-TS), ou le syndrome inflammatoire multisystémique chez l’enfant (MIS-C). Cet article a pour but de détailler la démarche pour établir le diagnostic de syndrome inflammatoire multi-systémique pédiatrique (PIMS). Le PIMS est une affection rare et grave. Cette affection nécessite d’être détectée précocement pour enclencher une prise en charge hospitalière en urgence. Il faut évoquer un PIMS chez un enfant présentant les signes d’appel suivants : fièvre élevée avec altération marquée de l’état général et présentant des signes digestifs. Ce syndrome doit être envisagé chez les enfants présentant des caractéristiques de la maladie de Kawasaki (typique ou atypique) ou du syndrome de choc toxique ou en cas de tableau d'insuffisance cardiaque aigue/myocardite aigue. Comme ce domaine évolue rapidement, des modifications dans les mois à venir sont possibles, au fur et à mesure de l’évolution de la pandémie. Abstract Following the spread of the 2019 coronavirus (COVID-19) pandemic, a new disease entity has emerged, defined as Pediatric Inflammatory Multisystemic Syndrome temporally associated with COVID-19 (PIMS-TS), or Multisystem Inflammatory Syndrome in Children (MIS-C). The purpose of this article is to detail the approach to establishing the diagnosis of pediatric multisystemic inflammatory syndrome (PIMS). PIMS is a rare and serious condition. This condition needs to be detected early to initiate emergency hospital management. PIMS should be considered in a child presenting with the following warning signs: high fever with marked deterioration in general condition and digestive signs. This syndrome should be considered in children with features of Kawasaki disease (typical or atypical) or toxic shock syndrome or in cases of acute heart failure/acute myocarditis. As this area is rapidly evolving, changes in the coming months are possible; as the pandemic progresses.
187	Ch185		Alexandra Brugler Yonts, MD, Justin Burton, MD, and Linda Jones Herbert, PhD	A Review of Current Evaluation and Management Strategies in Pediatric Postacute Sequelae of COVID-19	https://doi.org/10.3928/19382359-20220913-08	Published	November 01, 2022	Review	https://journals.healio.com/doi/abs/10.3928/19382359-20220913-08	Pediatric postacute sequelae of COVID-19 (pPASC), or long COVID, is a complex, heterogeneous, multisystem syndrome that leads to disruption in the lives of children and adolescents for months, and possibly years, after recovery from acute SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection. While the underlying pathophysiologic mechanisms of PASC are still under investigation, clinicians are facing the immediate challenges of treating these patients. In this article, we provide an overview of the current multidisciplinary evaluation of patients with pPASC. We also offer guidance on the medical, psychological, and rehabilitative management strategies based on experience with both pPASC and patients with other postviral syndromes
188	Ch186		Alexandra Brugler Yonts, MD, Justin Burton, MD, and Linda Jones Herbert, PhD	Pediatric Long-COVID: A Review of the Definition, Epidemiology, Presentation, and Pathophysiology	https://doi.org/10.3928/19382359-20220913-06	Published	November 01, 2022	Review	https://journals.healio.com/doi/abs/10.3928/19382359-20220913-06	Although children have been largely spared the most severe consequences of acute infection with SARS-CoV-2 virus, it is estimated that up to one-quarter of the more than 14 million children diagnosed as having coronavirus disease 2019 (COVID-19) have developed persistent symptoms of fatigue, postexertional malaise, neurologic and cognitive symptoms, and other symptoms that interfere with activities of daily living for months after their initial illness. Pediatric postacute sequelae of COVID-19 (pPASC), or long-COVID, is a complex, heterogeneous, postviral condition involving multiple body systems and is likely attributable to several concurrent underlying physiologic processes, including damage from direct viral invasion, endovascular dysfunction and microthrombosis, viral persistence, and the development of autoimmunity. In this review, we explore the current state of the literature regarding definition, epidemiology, clinical presentation, and proposed pathophysiologic mechanisms of pPASC.
189	Ch187		Alpana Waghmare, MD Diego R. Hijano, MD MSc	SARS-CoV-2 infection and COVID-19 in children	https://doi.org/10.1016/j.ccm.2022.11.014	Published	November 21, 2022	Review	https://www.chestmed.theclinics.com/article/S0272-5231(22)00130-7/fulltext	Key points •SARS-CoV-2 prevalence is high in pediatric populations, especially during the Omicron variant and subvariant waves. •Clinical manifestations of COVID-19 are generally less severe than in adults, though severe disease can occur in high-risk individuals. •Multisystem inflammatory syndrome in children is a unique post-COVID phenomenon that occurs rarely, mostly in children approximately one month after acute SARS-CoV-2 infection. •SARS-CoV-2 vaccination remains crucial to prevent severe disease in children. •Treatment considerations generally follow recommendations for adults and older adolescents should be managed similarly to adults. Epidemiology Several databases are available to determine the burden of SARS-CoV-2 infection and COVID-19 in pediatric populations. The COVerAGE database (COVerAGE-DB), an open-access database from over 103 countries, recorded 56.9 million COVID-19 cases children and adolescents under 20 years of age with a prevalence range from 0–37% of the national caseload across countries1. Of these, 63% occurred among adolescents ages 10–19, and 37% among children ages 0–9. The Pediatric COVID-19 case registry, the largest registry in the US, collected information from 12,917 children with COVID-19 during the first year of the pandemic2. Infections were most common among those 12-18 years of age (31%), followed by 5-11 years of age (24%) with no significant difference in gender. Most cases were in White Caucasians followed by in Blacks. One in four cases were in Hispanic/Latinos. Reported COVID-19 cases in children increased significantly in 2022 during the Omicron surge. In the US alone, more than 5 million of a total 13 million cases were diagnosed between January 1st and May 12th, 2022 and the percent of total cases occurring in children increased from 10% to 30%3, 4, 5. As of February 2022, almost 75% of children and adolescents had serologic evidence of previous infection with SARS-CoV-2, with approximately one third becoming newly seropositive since December 2021 with the highest in the age group with lowest vaccination rates (5–11 years, 28%)6. Most children appear to have asymptomatic, mild, or moderate disease and recover within one to two weeks of disease onset7, 8, 9. However, children with COVID-19 may develop severe complications, such as respiratory distress syndrome, myocarditis, acute renal failure, and multisystem organ failure10, 11, 12, 13, 14. Around 0.1-1.5% of pediatric COVID-19 patients require hospitalization, representing close to 5% of all pediatric hospitalizations in the US3. Age, race, and ethnicity have been described as risk factors for hospitalization with the highest rates seen in those <12 months of age, Hispanics, and Non-Hispanic Black children15, 16, 17, 18, 19, 20. The annual COVID-19-associated hospitalization rate by age is shown in Table 1. Among children hospitalized with COVID-19 in the US, between 28% to 40% required ICU, 6% to 18% needed invasive mechanical ventilation, and up to 3% died21,22.
190	Ch188		Réka Garai, Péter Krivácsy, Vivien Herczeg, Fanni Kovács, Bálint Tél, Judit Kelemen, Anna Máthé, Eszter Zsáry, Johanna Takács, Dániel Sándor Veres & Attila J. Szabó	Clinical assessment of children with long COVID syndrome	https://doi.org/10.1038/s41390-022-02378-0	Published	07 December 2022	Study	https://www.nature.com/articles/s41390-022-02378-0	Background There is a need for further understanding pediatric long COVID syndrome (LCS) to be able to create specific case definitions and guidelines for providing good clinical care. Methods Medical records of all LCS patients who presented at our designated LC clinic were collected. We carried out descriptive analyses summarizing the history, clinical presentation, and findings of children, while doing a diagnosis of exclusion with multi-disciplinary medical examinations (physical, laboratory, and radiological examinations, specialist consultations, etc.) without a control group. Results Most children reported at least minor impairment to their quality of life, of which 17 (23%) had moderate or severe difficulties. Findings that could be directly connected to the linked complaint category were observed in an average of 18%, respiratory symptoms with objective alterations being the most frequent (37%). Despite our detecting mostly non-specific conditions, in a smaller number we identified well-described causes such as autoimmune thyroiditis (7%). Conclusions The majority of children stated an impairment in their quality of life, while symptom-related conditions were detected only in a minority. Controlled studies are needed to separate the effect of the pandemic era from the infection itself. Evidence-based pediatric guidelines could aid to rationalize the list of recommended examinations. Impact Long COVID syndrome is a complex entity with a great impact on children’s everyday lives. Still, there is no clear guidance for pediatric clinical management. Systematic, detailed studies with medical assessment findings could aid the process of creating evidence-based guidelines. We present validated systematic information collected during in-person medical assessments with detailed medical findings and quality of life changes. While making a diagnosis of exclusion, we could confirm symptom-related conditions only in a minority of children; however, the majority reported at least minor impairment to their quality of life.
191	Ch189		Roxane Dumont, Viviane Richard, Elsa Lorthe, Andrea Loizeau, Francesco Pennacchio, María-Eugenia Zaballa, Hélène Baysson, Mayssam Nehme, Anne Perrin, Arnaud G. L’Huillier, Laurent Kaiser, Rémy P. Barbe, Klara M. Posfay-Barbe, Silvia Stringhini, SEROCoV-KIDS study group & Idris Guessous	A population-based serological study of post-COVID syndrome prevalence and risk factors in children and adolescents	https://doi.org/10.1038/s41467-022-34616-8	Published	29 November 2022	Study	https://www.nature.com/articles/s41467-022-34616-8	Post-COVID syndrome remains poorly studied in children and adolescents. Here, we aimed to investigate the prevalence and risk factors of pediatric post-COVID in a population-based sample, stratifying by serological status. Children from the SEROCoV-KIDS cohort study (State of Geneva, Switzerland), aged 6 months to 17 years, were tested for anti-SARS-CoV-2 N antibodies (December 2021-February 2022) and parents filled in a questionnaire on persistent symptoms in their children (lasting over 12 weeks) compatible with post-COVID. Of 1034 children tested, 570 (55.1%) were seropositive. The sex- and age-adjusted prevalence of persistent symptoms among seropositive children was 9.1% (95%CI: 6.7;11.8) and 5.0% (95%CI: 3.0;7.1) among seronegatives, with an adjusted prevalence difference (ΔaPrev) of 4.1% (95%CI: 1.1;7.3). Stratifying per age group, only adolescents displayed a substantial risk of having post-COVID symptoms (ΔaPrev = 8.3%, 95%CI: 3.5;13.5). Identified risk factors for post-COVID syndrome were older age, having a lower socioeconomic status and suffering from chronic health conditions, especially asthma. Our findings show that a significant proportion of seropositive children, particularly adolescents, experienced persistent COVID symptoms. While there is a need for further investigations, growing evidence of pediatric post-COVID urges early screening and primary care management.
192	Ch190		Manjula D. Nugawela, Terence Stephenson, Roz Shafran, Bianca L. De Stavola, Shamez N. Ladhani, Ruth Simmons, Kelsey McOwat, Natalia Rojas, Emma Dalrymple, Emily Y. Cheung, Tamsin Ford, Isobel Heyman, Esther Crawley & Snehal M. Pinto Pereira	Predictive model for long COVID in children 3 months after a SARS-CoV-2 PCR test	https://doi.org/10.1186/s12916-022-02664-y	Published	30 November 2022	Study	https://link.springer.com/article/10.1186/s12916-022-02664-y	Background To update and internally validate a model to predict children and young people (CYP) most likely to experience long COVID (i.e. at least one impairing symptom) 3 months after SARS-CoV-2 PCR testing and to determine whether the impact of predictors differed by SARS-CoV-2 status. Methods Data from a nationally matched cohort of SARS-CoV-2 test-positive and test-negative CYP aged 11–17 years was used. The main outcome measure, long COVID, was defined as one or more impairing symptoms 3 months after PCR testing. Potential pre-specified predictors included SARS-CoV-2 status, sex, age, ethnicity, deprivation, quality of life/functioning (five EQ-5D-Y items), physical and mental health and loneliness (prior to testing) and number of symptoms at testing. The model was developed using logistic regression; performance was assessed using calibration and discrimination measures; internal validation was performed via bootstrapping and the final model was adjusted for overfitting. Results A total of 7139 (3246 test-positives, 3893 test-negatives) completing a questionnaire 3 months post-test were included. 25.2% (817/3246) of SARS-CoV-2 PCR-positives and 18.5% (719/3893) of SARS-CoV-2 PCR-negatives had one or more impairing symptoms 3 months post-test. The final model contained SARS-CoV-2 status, number of symptoms at testing, sex, age, ethnicity, physical and mental health, loneliness and four EQ-5D-Y items before testing. Internal validation showed minimal overfitting with excellent calibration and discrimination measures (optimism-adjusted calibration slope: 0.96575; C-statistic: 0.83130). Conclusions We updated a risk prediction equation to identify those most at risk of long COVID 3 months after a SARS-CoV-2 PCR test which could serve as a useful triage and management tool for CYP during the ongoing pandemic. External validation is required before large-scale implementation.
193	Ch191		G. Biesbroek ,B. Kapitein ,I. M. Kuipers ,M. P. Gruppen,D. van Stijn,T. E. Peros,M. van Veenendaal,M. H. A. Jansen,C. W. van der Zee,M. van der Kuip,E. G. J. von Asmuth,M. G. Mooij,M. E. J. den Boer,G. W. Landman,M. A. van Houten,D. Schonenberg-Meinema,A. M. Tutu van Furth,M. Boele van Hensbroek,H. Scherpbier,K. E. van Meijgaarden,T. H. M. Ottenhoff,S. A. Joosten,N. Ketharanathan,M. Blink,C. L. H. Brackel,H. L. Zaaijer,P. Hombrink,J. M. van den Berg,E. P. Buddingh ,T. W. Kuijpers	Inflammatory responses in SARS-CoV-2 associated Multisystem Inflammatory Syndrome and Kawasaki Disease in children: An observational study	https://doi.org/10.1371/journal.pone.0266336	Published	November 30, 2022	Study	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0266336	Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe inflammatory disease in children related to SARS-CoV-2 with multisystem involvement including marked cardiac dysfunction and clinical symptoms that can resemble Kawasaki Disease (KD). We hypothesized that MIS-C and KD might have commonalities as well as unique inflammatory responses and studied these responses in both diseases. In total, fourteen children with MIS-C (n=8) and KD (n=6) were included in the period of March-June 2020. Clinical and routine blood parameters, cardiac follow-up, SARS-CoV-2-specific antibodies and CD4+ T-cell responses, and cytokine-profiles were determined in both groups. In contrast to KD patients, all MIS-C patients had positive Spike protein-specific CD3+CD4+ T-cell responses. MIS-C and KD patients displayed marked hyper-inflammation with high expression of serum cytokines, including the drug-targetable interleukin (IL)-6 and IFN-γ associated chemokines CXCL9, 10 and 11, which decreased at follow-up. No statistical differences were observed between groups. Clinical outcomes were all favourable without cardiac sequelae at 6 months follow-up. In conclusion, MIS-C and KD-patients both displayed cytokine-associated hyper-inflammation with several high levels of drug-targetable cytokines.
194	Ch192		Fauveau, Valentin; Jacobi, Adam; Bernheim, Adam; Chung, Michael; Benkert, Thomas; Fayad, Zahi A.; Feng, Li	Performance of spiral UTE-MRI of the lung in post-COVID patients	https://doi.org/10.1016/j.ijporl.2022.111406	Published	2023-01-01	Study	https://www.sciencedirect.com/science/article/pii/S0165587622003676	Objectives The audio-vestibular equivalent of neurological symptoms secondary to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been discussed; however, it has not been fully clarified. Although it has been reported that the vestibulocochlear system is affected in adult coronavirus disease-2019 (COVID-19) patients, there is no study in the literature in which the pediatric patient group with COVID-19 was evaluated comprehensively with auditory and vestibular tests. In this study, the short-term damage caused by SARS-CoV-2 in the vestibulocochlear system in pediatric patients was examined. Methods This study aimed to evaluate the vestibulocochlear system of pediatric patients (aged 9–15 years) with a recent history of COVID-19. The study included 35 individuals with a recent history of COVID-19 and 35 age-gender-matched healthy individuals (control group). Pure tone audiometry, suppressed otoacoustic emission (OAE), video head impulse test (VHIT), and cervical and ocular vestibular evoked myogenic potentials (c/o-VEMP) tests were administered to all participants following their otoscopic examinations, and the obtained data were compared between the two groups. Results When the data obtained with pure tone audiometry were compared, statistically significant differences were found between the groups at four different frequencies (1000, 2000, 4000, and 8000 Hz) in favor of the control group. There was a statistically significant difference between the groups in the signal-to-noise ratio (SNR) values obtained before noise at 2800 Hz and before and after noise at 4000 Hz. VHIT lateral gain, LARP gain, and RALP gain were statistically significantly lower in the COVID-19 group than in the control group (p < 0.05). VHIT lateral asymmetry parameter was measured higher in the COVID-19 group than in the control group, and this difference was statistically significant (p < 0.05). In the VHIT test, the asymmetry parameter was significantly higher in the COVID-19 group (p < 0.05). In the o-VEMP test, n10 latency, p15 latency, n10-p15 interlatency, n10-p15 interpeak amplitude, and asymmetry parameters were measured, and no statistically significant difference was found between the COVID-19 group and the control group (p > 0.05). Conclusion Evidence was obtained that the cochleovestibular system was damaged in pediatric patients in the early post-COVID-19 period.
195	Ch193		Melgar, Michael	Council of State and Territorial Epidemiologists/CDC Surveillance Case Definition for Multisystem Inflammatory Syndrome in Children Associated with SARS-CoV-2 Infection — United States	https://doi.org/10.15585/mmwr.rr7104a1	Published	2022	Recommendations and Reports	https://www.cdc.gov/mmwr/volumes/71/rr/rr7104a1.htm	Since May 14, 2020, CDC has conducted national surveillance for multisystem inflammatory syndrome in children (MIS-C) associated with infection with SARS-CoV-2, the virus that causes COVID-19, among persons aged <21 years using a CDC case definition based on public health need and data from early reports of patients with this condition. Recent analyses of accumulated data indicated that certain criteria from the 2020 CDC MIS-C case definition performed better than others in distinguishing MIS-C from other illnesses and that certain other criteria likely contributed to misclassification. To incorporate lessons learned from MIS-C surveillance and public health investigations and to improve feasibility of implementation by surveillance staff at state, local, territorial, and tribal health departments, the Council of State and Territorial Epidemiologists (CSTE) and CDC developed a CSTE/CDC position statement (approved by CSTE in 2022) that includes an MIS-C surveillance case definition for voluntary reporting to CDC (effective January 1, 2023). This report summarizes the evidence and rationale supporting the components of the CSTE/CDC MIS-C surveillance case definition and describes the methods used to develop the definition. These methods included convening MIS-C clinical experts (i.e., consultants) regarding identification of MIS-C and its distinction from other pediatric conditions, a review of available literature comparing MIS-C phenotype with that of pediatric COVID-19 and other hyperinflammatory syndromes, and retrospective application of different criteria to data from MIS-C cases previously reported to CDC. The CSTE/CDC surveillance case definition for MIS-C includes four important changes, in comparison with the 2020 CDC MIS-C case definition. These changes are 1) no required duration of subjective or measured fever; 2) requirement of C-reactive protein ≥3.0 mg/dL to indicate systemic inflammation; 3) adjustments to criteria of organ system involvement to include addition of shock as a separate category and elimination of respiratory, neurologic, and renal criteria; and 4) new requirements on timing of positive SARS-CoV-2 laboratory testing relative to the MIS-C illness. Although MIS-C is not a nationally notifiable condition and reporting is voluntary, CSTE and CDC recommend that all states and territories report all cases meeting confirmed, probable, or suspect criteria of the CSTE/CDC MIS-C surveillance case definition beginning January 1, 2023, for cases with MIS-C illness onset on or after that date.
196	Ch194		Khoo, Weng Hua; Jackson, Katherine; Phetsouphanh, Chansavath; Zaunders, John J.; Alquicira-Hernandez, José; Yazar, Seyhan; Ruiz-Diaz, Stephanie; Singh, Mandeep; Dhenni, Rama; Kyaw, Wunna; Tea, Fiona; Merheb, Vera; Lee, Fiona X. Z.; Burrell, Rebecca; Howard-Jones, Annaleise; Koirala, Archana; Zhou, Li; Yuksel, Aysen; Catchpoole, Daniel R.; Lai, Catherine L.; Vitagliano, Tennille L.; Rouet, Romain; Christ, Daniel; Tang, Benjamin; West, Nicholas P.; George, Shane; Gerrard, John; Croucher, Peter I.; Kelleher, Anthony D.; Goodnow, Christopher G.; Sprent, Jonathan D.; Powell, Joseph E.; Brilot, Fabienne; Nanan, Ralph; Hsu, Peter S.; Deenick, Elissa K.; Britton, Philip N.; Phan, Tri Giang	Tracking the clonal dynamics of SARS-CoV-2-specific T cells in children and adults with mild/asymptomatic COVID-19	https://doi.org/10.1016/j.clim.2022.109209	Published	2023-01-01	Study	https://www.sciencedirect.com/science/article/pii/S152166162200290X	Highlights • Children have diverse polyclonal SARS-CoV-2-specific naïve T cells. • Adults have clonally expanded exhausted SARS-CoV-2-specific memory T cells. • Interferon-activated naïve T cells differentiate into memory T cells in adults but not children. • Adults but not children develop robust memory T cell responses to SARS-CoV-2. Abstract Children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop less severe coronavirus disease 2019 (COVID-19) than adults. The mechanisms for the age-specific differences and the implications for infection-induced immunity are beginning to be uncovered. We show by longitudinal multimodal analysis that SARS-CoV-2 leaves a small footprint in the circulating T cell compartment in children with mild/asymptomatic COVID-19 compared to adult household contacts with the same disease severity who had more evidence of systemic T cell interferon activation, cytotoxicity and exhaustion. Children harbored diverse polyclonal SARS-CoV-2-specific naïve T cells whereas adults harbored clonally expanded SARS-CoV-2-specific memory T cells. A novel population of naïve interferon-activated T cells is expanded in acute COVID-19 and is recruited into the memory compartment during convalescence in adults but not children. This was associated with the development of robust CD4+ memory T cell responses in adults but not children. These data suggest that rapid clearance of SARS-CoV-2 in children may compromise their cellular immunity and ability to resist reinfection.
197	Ch195		Lee, Danyel; Le Pen, Jérémie; Yatim, Ahmad; Dong, Beihua; Aquino, Yann; Ogishi, Masato; Pescarmona, Rémi; Talouarn, Estelle; Rinchai, Darawan; Zhang, Peng; Perret, Magali; Liu, Zhiyong; Jordan, Iolanda; Elmas Bozdemir, Sefika; Bayhan, Gulsum Iclal; Beaufils, Camille; Bizien, Lucy; Bisiaux, Aurelie; Lei, Weite; Hasan, Milena; Chen, Jie; Gaughan, Christina; Asthana, Abhishek; Libri, Valentina; Luna, Joseph M.; Jaffré, Fabrice; Hoffmann, H.-Heinrich; Michailidis, Eleftherios; Moreews, Marion; Seeleuthner, Yoann; Bilguvar, Kaya; Mane, Shrikant; Flores, Carlos; Zhang, Yu; Arias, Andrés A.; Bailey, Rasheed; Schlüter, Agatha; Milisavljevic, Baptiste; Bigio, Benedetta; Le Voyer, Tom; Materna, Marie; Gervais, Adrian; Moncada-Velez, Marcela; Pala, Francesca; Lazarov, Tomi; Levy, Romain; Neehus, Anna-Lena; Rosain, Jérémie; Peel, Jessica; Chan, Yi-Hao; Morin, Marie-Paule; Pino-Ramirez, Rosa Maria; Belkaya, Serkan; Lorenzo, Lazaro; Anton, Jordi; Delafontaine, Selket; Toubiana, Julie; Bajolle, Fanny; Fumadó, Victoria; DeDiego, Marta L.; Fidouh, Nadhira; Rozenberg, Flore; Pérez-Tur, Jordi; Chen, Shuibing; Evans, Todd; Geissmann, Frédéric; Lebon, Pierre; Weiss, Susan R.; Bonnet, Damien; Duval, Xavier; CoV-Contact Cohort; COVID, Human Genetic Effort; Pan-Hammarström, Qiang; Planas, Anna M.; Meyts, Isabelle; Haerynck, Filomeen; Pujol, Aurora; Sancho-Shimizu, Vanessa; Dalgard, Clifford; Bustamante, Jacinta; Puel, Anne; Boisson-Dupuis, Stéphanie; Boisson, Bertrand; Maniatis, Tom; Zhang, Qian; Bastard, Paul; Notarangelo, Luigi; Béziat, Vivien; Perez de Diego, Rebeca; Rodriguez-Gallego, Carlos; Su, Helen C.; Lifton, Richard P.; Jouanguy, Emmanuelle; Cobat, Aurélie; Alsina, Laia; Keles, Sevgi; Haddad, Elie; Abel, Laurent; Belot, Alexandre; Quintana-Murci, Lluis; Rice, Charles M.; Silverman, Robert H.; Zhang, Shen-Ying; Casanova, Jean-Laurent	Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children	https://doi.org/10.1126/science.abo3627	Published	2022-12-20	Study	https://www.science.org/doi/full/10.1126/science.abo3627	Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic dsRNA-sensing OAS1 and OAS2 generate 2′-5′-linked oligoadenylates (2-5A) that activate the ssRNA-degrading RNase L. Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNASEL deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or SARS-CoV-2 stimulation. Exogenous 2-5A suppresses cytokine production in OAS1- but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by MAVS deficiency. Recessive OAS–RNase L deficiencies in these patients unleash the production of SARS-CoV-2–triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.
198	Ch196		Sabatino, Jolanda; Di Chiara, Costanza; Di Candia, Angela; Sirico, Domenico; Donà, Daniele; Fumanelli, Jennifer; Basso, Alessia; Pogacnik, Pietro; Cuppini, Elena; Romano, Letizia Rosa; Castaldi, Biagio; Reffo, Elena; Cerutti, Alessia; Biffanti, Roberta; Cozzani, Sandra; Giaquinto, Carlo; Di Salvo, Giovanni	Mid- and Long-Term Atrio-Ventricular Functional Changes in Children after Recovery from COVID-19	https://doi.org/10.3390/jcm12010186	Published	2023-01	Study	https://www.mdpi.com/2077-0383/12/1/186	Background: Although most children may experience mild to moderate symptoms and do not require hospitalization, there are little data on cardiac involvement in COVID-19. However, cardiac involvement is accurately demonstrated in children with MISC. The objective of this study was to evaluate cardiac mechanics in previously healthy children who recovered from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in a long-term follow-up by means of two-dimensional speckle-tracking echocardiography (STE). Methods: We analyzed a cohort of 157 paediatric patients, mean age 7.7 ± 4.5 years (age range 0.3–18 years), who had a laboratory-confirmed diagnosis of SARS-CoV-2 infection and were asymptomatic or mildly symptomatic for COVID-19. Patients underwent a standard transthoracic echocardiogram and STE at an average time of 148 ± 68 days after diagnosis and were divided in three follow-up groups (<180 days, 180–240 days, >240 days). Patients were compared with 107 (41 females—38%) age- and BSA-comparable healthy controls (CTRL). Results: Left ventricular (LV) global longitudinal strain (post-COVID-19: −20.5 ± 2.9%; CTRL: −21.8 ± 1.7%; p < 0.001) was significantly reduced in cases compared with CTRLs. No significant differences were seen among the three follow-up groups (p = NS). Moreover, regional longitudinal strain was significantly reduced in LV apical-wall segments of children with disease onset during the second wave of the COVID-19 pandemic compared to the first wave (second wave: −20.2 ± 2.6%; first wave: −21.2 ± 3.4%; p = 0.048). Finally, peak left atrial systolic strain was within the normal range in the post-COVID-19 group with no significant differences compared to CTRLs. Conclusions: Our study demonstrated for the first time the persistence of LV myocardial deformation abnormalities in previously healthy children with an asymptomatic or mildly symptomatic (WHO stages 0 or 1) COVID-19 course after an average follow-up of 148 ± 68 days. A more significant involvement was found in children affected during the second wave. These findings imply that subclinical LV dysfunction may also be a typical characteristic of COVID-19 infection in children and are concerning given the predictive value of LV longitudinal strain in the general population.
199	Ch197		Vasichkina, Elena; Alekseeva, Daria; Kudryavtsev, Igor; Glushkova, Anzhela; Starshinova, Anastasia Y.; Malkova, Anna; Kudlay, Dmitry; Starshinova, Anna	COVID-19 Heart Lesions in Children: Clinical, Diagnostic and Immunological Changes	https://doi.org/10.3390/ijms24021147	Published	1/1/2023	Review	https://www.mdpi.com/1422-0067/24/2/1147	In the beginning of COVID-19, the proportion of confirmed cases in the pediatric population was relatively small and there was an opinion that children often had a mild or asymptomatic course of infection. Our understanding of the immune response, diagnosis and treatment of COVID-19 is highly oriented towards the adult population. At the same time, despite the fact that COVID-19 in children usually occurs in a mild form, there is an incomplete understanding of the course as an acute infection and its subsequent manifestations such as Long-COVID-19 or Post-COVID-19, PASC in the pediatric population, correlations with comorbidities and immunological changes. In mild COVID-19 in childhood, some authors explain the absence of population decreasing T and B lymphocytes. Regardless of the patient’s condition, they can have the second phase, related to the exacerbation of inflammation in the heart tissue even if the viral infection was completely eliminated—post infectious myocarditis. Mechanism of myocardial dysfunction development in MIS-C are not fully understood. It is known that various immunocompetent cells, including both resident inflammatory cells of peripheral tissues (for example macrophages, dendritic cells, resident memory T-lymphocytes and so on) and also circulating in the peripheral blood immune cells play an important role in the immunopathogenesis of myocarditis. It is expected that hyperproduction of interferons and the enhanced cytokine response of T cells 1 and 2 types contribute to dysfunction of the myocardium. However, the role of Th1 in the pathogenesis of myocarditis remains highly controversial. At the same time, the clinical manifestations and mechanisms of damage, including the heart, both against the background and after COVID-19, in children differ from adults. Further studies are needed to evaluate whether transient or persistent cardiac complications are associated with long-term adverse cardiac events.
200	Ch198		Baptista de Lima, Joana; Salazar, Luís; Fernandes, Alexandre; Teixeira, Carla; Marques, Laura; Afonso, Caldas	Long COVID in Children and Adolescents: A Retrospective Study in a Pediatric Cohort	https://doi.org/10.1097/INF.0000000000003829	Published	1/4/2023	Study	https://journals.lww.com/pidj/Fulltext/9900/Long_COVID_in_Children_and_Adolescents__A.311.aspx	Abstract Studies on long coronavirus disease (COVID) in children are scarce. We aimed to describe persistent symptoms and identify risk factors for its development. In our study population, 17.6% presented with long COVID, with respiratory symptoms more frequent in the first weeks and neuropsychiatric symptoms over time. Chronic conditions and obesity were risk factors, and adolescents were at a greater risk for long COVID. Children infected with Severe acute respiratory syndrome coronavirus 2 are usually asymptomatic or with a mild form of coronavirus disease (COVID).1 While the acute symptoms are well defined, the long-term symptoms are not. Most COVID-19 patients achieve full recovery within 3–4 weeks after infection; however, in some cases, persistent symptoms can be seen weeks or months after recovery.2 According to National Institute for Health and Care Excellence guidelines, symptoms from onset to 4 weeks after diagnosis are considered acute COVID-19.3 The persistence of symptoms from 4 to 12 weeks is defined as ongoing symptomatic COVID-19, whereas symptoms that continue 12 weeks after diagnosis are considered post-COVID-19. Either ongoing symptomatic COVID-19 or post-COVID-19 is considered long COVID.3 In children, information on COVID-19 persistent symptoms remains scarce. Recent studies have shown that common persistent symptoms include fatigue, headache, postviral cough, anosmia, dyspnea and chest pain.4–6 In this study, we aimed to identify the prevalence of COVID-19 persistent symptoms in patients presenting to a tertiary hospital and to investigate possible risk factors for the development of long-term COVID.
201	Ch199		Jason, Leonard A.; Johnson, Madeline; Torres, Chelsea	Pediatric Post-Acute Sequelae of SARS-CoV-2 infection	https://doi.org/10.1080/21641846.2022.2162764	Published	1/1/2023	Study	https://doi.org/10.1080/21641846.2022.2162764	Aim Youth who have not recovered from COVID-19 have been referred to as having Post-Acute Sequelae of SARS-CoV-2 Infection (PASC). The goal of this study was to better understand which symptoms persisted since onset of infection and how these symptoms compare to symptoms experienced by those with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).Method A sample of 19 parents who had a child with PASC were recruited using social media to fill out a questionnaire detailing symptoms at two time points. The first time point included their child’s current symptoms and the second captured symptoms at initial infection. These participants were compared to a sample of 19 youth with ME/CFS.Results Findings indicated significant decreases among several immune, neuroendocrine, pain, post-exertional malaise (PEM), and COVID-19 Centers for Disease Control and Prevention (CDC) domain symptoms from time of acute infection to time of current reporting. Fatigue remained at a high level as did several symptoms within the sleep and PEM domains. Participants with ME/CFS had overall worse symptomatology when compared to participants with PASC, especially in the neurocognitive domain.Conclusion Most symptoms of those with PASC decline over time, but several remain at high levels, including fatigue. These findings are helpful in better understanding common symptom presentation profiles for youth with PASC and can be used to more adequately tailor diagnostic criteria and treatment strategies for youth.
202	Ch200		Buonsenso, Danilo	Further evidence from a large US electronic health record-based study that some children and adolescents can develop postacute sequelae of SARS-CoV-2 infection	https://doi.org/10.1136/ebnurs-2022-103632	Published	1/4/2023	Study	https://ebn.bmj.com/content/early/2023/01/03/ebnurs-2022-103632	publisher: Royal College of Nursing section: Commentary PMID: 36599668 Implications for practice and research This study provides further evidence that a subgroup of children (about 3%) and adolescents develop postacute sequelae (PASC) other than multitystem inflammatory syndrome in children (MIS-C) after SARS-CoV-2 infection. There is urgent need to implement to identify diagnostics, biomarkers and potential therapeutics of PASC. Context There is a growing body of evidence that a subgroup of children and adolescents do not fully recover from acute SARS-CoV-2 infection, but can develop a cohort of persisting signs and symptoms otherwise unexplained by routine diagnostics.1 This condition is known as PASC, or postcovid condition or Long Covid. However, available studies were mostly limited by either lack of control groups, small …
203	Ch201		Petrella, Carla; Nenna, Raffaella; Petrarca, Laura; Tarani, Francesca; Paparella, Roberto; Mancino, Enrica; Di Mattia, Greta; Conti, Maria Giulia; Matera, Luigi; Bonci, Enea; Ceci, Flavio Maria; Ferraguti, Giampiero; Gabanella, Francesca; Barbato, Christian; Di Certo, Maria Grazia; Cavalcanti, Luca; Minni, Antonio; Midulla, Fabio; Tarani, Luigi; Fiore, Marco	Serum NGF and BDNF in Long-COVID-19 Adolescents: A Pilot Study	https://doi.org/10.3390/diagnostics12051162	Published	5/1/2022	Study	https://www.mdpi.com/2075-4418/12/5/1162	COVID-19 (COronaVIrus Disease 19) is an infectious disease also known as an acute respiratory syndrome caused by the SARS-CoV-2. Although in children and adolescents SARS-CoV-2 infection produces mostly mild or moderate symptoms, in a certain percentage of recovered young people a condition of malaise, defined as long-COVID-19, remains. To date, the risk factors for the development of long-COVID-19 are not completely elucidated. Neurotrophins such as NGF (Nerve Growth Factor) and BDNF (Brain-Derived Neurotrophic Factor) are known to regulate not only neuronal growth, survival and plasticity, but also to influence cardiovascular, immune, and endocrine systems in physiological and/or pathological conditions; to date only a few papers have discussed their potential role in COVID-19. In the present pilot study, we aimed to identify NGF and BDNF changes in the serum of a small cohort of male and female adolescents that contracted the infection during the second wave of the pandemic (between September and October 2020), notably in the absence of available vaccines. Blood withdrawal was carried out when the recruited adolescents tested negative for the SARS-CoV-2 (“post-infected COVID-19”), 30 to 35 days after the last molecular test. According to their COVID-19 related outcomes, the recruited individuals were divided into three groups: asymptomatics, acute symptomatics and symptomatics that over time developed long-COVID-19 symptoms (“future long-COVID-19”). As a control group, we analyzed the serum of age-matched healthy controls that did not contract the infection. Inflammatory biomarkers (TNF-α, TGF-β), MCP-1, IL-1α, IL-2, IL-6, IL-10, IL-12) were also analyzed with the free oxygen radicals’ presence as an oxidative stress index. We showed that NGF serum content was lower in post-infected-COVID-19 individuals when compared to healthy controls; BDNF levels were found to be higher compared to healthy individuals only in post-infected-COVID-19 symptomatic and future long-COVID-19 girls, leaving the BDNF levels unchanged in asymptomatic individuals if compared to controls. Oxidative stress and inflammatory biomarkers were unchanged in male and female adolescents, except for TGF-β that, similarly to BDNF, was higher in post-infected-COVID-19 symptomatic and future long-COVID-19 girls. We predicted that NGF and/or BDNF could be used as early biomarkers of COVID-19 morbidity in adolescents.
204	Ch202		Pereira, Snehal M. Pinto; Nugawela, Manjula D.; Rojas, Natalia K.; Shafran, Roz; McOwat, Kelsey; Simmons, Ruth; Ford, Tamsin; Heyman, Isobel; Ladhani, Shamez N.; Cheung, Emily Y.; Fox-Smith, Lana; Dalrymple, Emma; Stephenson, Terence	Post-COVID-19 condition at 6 months and COVID-19 vaccination in non-hospitalised children and young people	https://doi.org/10.1136/archdischild-2022-324656	Published	1/4/2023	Study	https://adc.bmj.com/content/early/2023/01/04/archdischild-2022-324656	Objectives To describe the physical and mental health of children and young people (CYP) 6 months after infection with SARS-CoV-2 and explore whether this varies by COVID-19 vaccination. Design A non-hospitalised, national cohort of people aged 11–17 years old with PCR-confirmed SARS-CoV-2 infection and PCR negatives matched at study invitation, by age, sex, region and date of testing who completed questionnaires 6 months after PCR testing. The questionnaire included 21 symptoms and standardised scales (eg, EQ-5D-Y and Chalder Fatigue Scale). Results 6407 test-positive and 6542 test-negative CYP completed the 6-month questionnaire: 60.9% of test-positive vs 43.2% of test-negative CYP reported at least one symptom 6 months post-test; 27.6% of test-positive vs 15.9% of test-negative CYP reported 3+ symptoms. Common symptoms at 6 months were tiredness and shortness of breath among both test-positive and test-negative CYP; however, the prevalence of both was higher in test-positive (38.4% and 22.8%, respectively) compared with test-negative CYP (26.7% and 10.9%, respectively). 24.5% test-positive vs 17.8% test-negative CYP met the Delphi research definition of long COVID. Mental health, well-being, fatigue and health-related quality of life scores were similar among test-positive and test-negative CYP 6 months post-test. Similarly, symptomatology was similar among COVID-19-vaccinated and COVID-19-unvaccinated test-positive and test-negative CYP. Conclusions Six-months post-PCR testing, CYP who tested positive for SARS-CoV-2 had similar symptoms to those who tested negative, but test-positive CYP had higher symptom prevalence. Mental health, well-being, fatigue and health-related quality of life were similar among test-positive and test-negative CYP, and symptoms at 6 months were similar in COVID-19 vaccinated and unvaccinated. Trial registration number ISRCTN 34804192.
205	Ch203		Marina Avramescu, View ORCID ProfilePierre Isnard, Sarah Temmam, Agnes Chevalier, Paul Bastard, Mikael Attia, Romain Berthaud, Marc Fila, Claire Dossier, Julien Hogan, Tim Ulinski, Damia Leguevaques, Ferielle Louillet, Edouard Martinez Casado, Jean-Michel Halimi, Sylvie Cloarec, Ariane Zaloszyc, Camille Faudeux, Caroline Rousset-Rouviere, Stephanie Clave, Jerome Harambat, Edouard Rollot, Thomas Simon, Megan Nallet-Amate, Bruno Ranchin, Justine Bacchetta, Florence Porcheret, Josselin Bernard, Amelie Ryckewaert, Anne Jamet, Jacques Fourgeaud, Nicolas Da Rocha, Philippe Perot, Nicolas Kuperwasser, Naim Bouazza, Marion Rabant, Jean-Paul Duong Van Huyen, Matthieu P Robert, Julien Zuber, Jean-Laurent Casanova, marc eloit, Isabelle Sermet-Gaudelus, Olivia Boyer	Acute tubulointerstitial nephritis with or without uveitis: a novel form of post-acute COVID-19 syndrome in children	https://doi.org/10.1101/2023.01.23.23284848	pre-print	January 26, 2023	Study	https://www.medrxiv.org/content/10.1101/2023.01.23.23284848v1	Background COVID-19 is a complex multisystem disease, frequently associated with kidney injury. Since the beginning of the COVID-19 pandemic, we observed a striking increase in the incidence of acute tubulointerstitial nephritis (aTIN) without or with uveitis (TINUs) among children. This prompted us to examine whether SARS-CoV-2 might be the underlying trigger. Methods We conducted a French nationwide retrospective cohort study. We included all consecutive children diagnosed with aTIN or TINUs of undetermined cause between April-2020 and March-2021. SARS-CoV-2 antibody responses were tested by a luciferase immunoprecipitation system and compared to age-matched controls. Immunohistochemistry, immunofluorescence and molecular microbiology analyses were performed on kidney biopsies. Results Forty-eight children were included with a median age at diagnosis of 14.7 years (9.4-17.6). aTIN and TINUs incidence rates increased 3-fold and 12-fold, respectively, compared to pre-pandemic years. All patients had impaired kidney function with a median eGFR of 31.9 ml/min/1.73m2 at diagnosis. Kidney biopsies showed lesions of acute tubulointerstitial nephritis and 25% of patients had fibrosis. No patient had concomitant acute COVID-19. All 16 children tested had high anti-N IgG titers and one had anti-S IgGs. Next-generation sequencing failed to detect any infectious agents in kidney biopsies. However, SARS-CoV-2 RNA was detected by PCR in two kidney samples supporting a potential direct link between SARS-CoV-2 and aTIN/TINUs. Conclusions We describe a novel form of post-acute COVID-19 syndrome in children, unique in its exclusive kidney and eye involvement, and its distinctive anti-SARS-CoV-2 N+/S- serological profile. Our results support a causal association linking SARS-CoV-2 infection to this newly-reported burst of renal/eye inflammation.
206	Ch204		Ping-Ing Lee a, Po-Ren Hsueh	Multisystem inflammatory syndrome in children: A dysregulated autoimmune disorder following COVID-19	https://doi.org/10.1016/j.jmii.2023.01.001	Published	2023-01-16	Review	https://www.sciencedirect.com/science/article/pii/S1684118223000014	Multisystem inflammatory syndrome in children (MIS-C) is a dysregulated autoimmune-mediated illness in genetically susceptible patients following COVID-19 with an interval of 2–6 weeks. The median age of patients with MIS-C is 6–11 years. Most common manifestations are involvement of gastrointestinal tract, cardiovascular system, hematological system, and mucocutaneous system. Respiratory tract, neurological system, musculoskeletal system, and kidney are less frequently affected. Mucocutaneous manifestations and coronary artery abnormalities characteristic for Kawasaki disease (KD) may be observed in a significant proportion of MIS-C patients that may make the differential diagnosis be difficult for some patients, especially in the post-pandemic era. The mortality rate is 1–3%. Management and prognosis of MIS-C are similar to that of KD. MIS-C and KD may share a common pathogenic process. Based on the observation of MIS-C-like illness in uninfected neonates, i.e. multisystem inflammatory syndrome in neonates, both MIS-C and KD may be a consequence of dysregulated, over-exaggerated humoral immune responses triggered by a specific infectious agent. publisher: Elsevier
207	Ch205		Garazzino, Silvia; Denina, Marco; Pruccoli, Giulia; Funiciello, Elisa; Ramenghi, Ugo; Fagioli, Franca	Long COVID-19/post-COVID condition in children: do we all speak the same language?	https://doi.org/10.1186/s13052-023-01417-8	Published	2023-01-20	Article	https://doi.org/10.1186/s13052-023-01417-8	Post-COVID condition is a new and highly debated entity that is still to be outlined in its complexity, especially in the pediatric population. In response to the article by Trapani and colleagues, we report the results of a long-term follow-up conducted in the outpatient clinic of the Pediatric Infectious Diseases Unit on children admitted to our hospital with SARS-CoV-2 infection.
208	Ch206		Morello, Rosa; Martino, Laura; Buonsenso, Danilo	Diagnosis and management of post-COVID (Long COVID) in children: a moving target	https://doi.org/10.1097/MOP.0000000000001221	Published	2023-01-24	Review	https://journals.lww.com/co-pediatrics/Fulltext/9900/Diagnosis_and_management_of_post_COVID__Long.63.aspx	Purpose of review This review describes recent findings about post-COVID condition (PCC, or Long COVID) in children, including current knowledge about its epidemiology, clinical presentation, pathogenesis and care. Recent findings There is no internationally agreed definition of PCC, although now most researchers agree that it is a complex clinical symptomatology persisting for at least 3 months after COVID-19, without an alternative diagnosis. There are several uncertainties about paediatric PCC. So far, available literature suggest that 1–3% of recognized children with Severe Acute Respiratory Syndrome COronaVirus 2 (SARS-CoV-2) infection may develop PCC. Its pathogenesis is unknown, although there is increasing evidence about possible abnormalities in the immune responses, cellular metabolism and intestinal microbiota, along with chronic endothelitis. Summary Management of PCC in children is complex and require a multidisciplinary approach, with the goal of offering the best care possible to support diagnostics, research, mental health and access to research projects.
209	Ch207		Garazzino, Silvia; Denina, Marco; Pruccoli, Giulia; Funiciello, Elisa; Ramenghi, Ugo; Fagioli, Franca	Long COVID-19/post-COVID condition in children: do we all speak the same language?	https://doi.org/10.1186/s13052-023-01417-8	Published	2023-01-20	Article	https://doi.org/10.1186/s13052-023-01417-8	Self-completed questionnaires administered to families and not associated with targeted assessments (especially from a neurologic or psychiatric perspective) and not supported by a medical examination risk to overestimate PCC. Indeed, many reported symptoms in older children and adolescents (such as fatigue and psychological symptoms) may be related to the complex social situation that occurred during the Pandemic as a consequence of school closure, suspension of recreational activities and social isolation. In our opinion, children identified by an indirect approach (phone call, parental questionnaires) as suffering from PCC should be clinically assessed by a multidisciplinary team to confirm or rule out the diagnosis and schedule an appropriate follow-up. In a nationwide cohort study, Boch et al. demonstrated that symptoms lasting > 4 weeks reported through an electronic questionnaire were common also in control children, with an estimated PCC prevalence of 0.8% in the SARS-CoV-2 positive group. Authors concluded that concentration difficulties, headache, muscle and joint pain as well as nausea should not be considered symptoms of PCC as they were frequently reported also in the control group. On the contrary, fatigue, loss of smell and taste, dizziness, muscle weakness, chest pain and respiratory problems were more frequently found in SARS-CoV-2 children, especially in those aging 6-17 years and were thus not attributed to psychological sequelae of social restrictions [9]. In our cohort of hospitalized children, with a minimum 6 month-follow-up, PCC was rare, also considering that many patients had pre-existing concomitant diseases. Only symptoms occurring or persisting within 12 weeks from SARS-CoV-2 infection were deemed consistent with sequelae of COVID-19, according to temporal criteria established by WHO in adults [10]. Furthermore, a long recovery is relatively common in other viral diseases, such as EBV, CMV or enteric viruses infections and a short follow-up of SARS-CoV-2 infected children could be misleading.
210	Ch208		Sakurada, Yasue; Otsuka, Yuki; Tokumasu, Kazuki; Sunada, Naruhiko; Honda, Hiroyuki; Nakano, Yasuhiro; Matsuda, Yui; Hasegawa, Toru; Ochi, Kanako; Hagiya, Hideharu; Ueda, Keigo; Kataoka, Hitomi; Otsuka, Fumio	Trends in Long COVID Symptoms in Japanese Teenage Patients	https://doi.org/10.3390/medicina59020261	Published	2023-02-01	Study	https://www.mdpi.com/1648-9144/59/2/261	Background: Since the start of the global pandemic of coronavirus disease 2019 (COVID-19), not only adults but also many children have suffered from it. However, the clinical characteristics of long COVID in children remain unclear. Methods: In this retrospective observational study conducted in a single facility, we reviewed the medical records of all long COVID patients who visited Okayama University Hospital from February 2021 to October 2022, and we compared the clinical characteristics of long COVID in teenagers (11 to 18 years of age) with those in adults. Results: Data for 452 long COVID patients including 54 teenagers (11.9%) were analyzed. Fatigue was the most frequent symptom in teenagers (55.6% of the patients) and also in adults. On the other hand, the percentage of teenagers who complained of headache, which was the second most frequent complaint, was significantly higher than the percentage of adults (35.2% vs. 21.9%, p < 0.05). A comparison of the frequencies of symptoms depending on the viral variant showed that fatigue and headache were predominant symptoms in the Omicron variant phase. Of the 50 teenagers who were enrolled in schools, 28 (56.0%) could not attend school due to long COVID symptoms. The most common symptoms as reasons for absence from school were fatigue (85.7% of the patients), headache (42.9%), and insomnia (32.1%). Conclusions: Attention should be paid to the symptoms of fatigue and headache in teenagers with long COVID.
211	Ch209		WHO	A clinical case definition for post COVID-19 condition in children and adolescents by expert consensus, 16 February 2023		Published	2023-02-16	Study	https://www.who.int/publications-detail-redirect/WHO-2019-nCoV-Post-COVID-19-condition-CA-Clinical-case-definition-2023-1	Overview The WHO definition of post Covid-19 condition for adults was published in October 2021. This enables a shared understanding of this important problem between people affected by post Covid-19 condition, healthcare workers, researchers and other stakeholders. A separate clinical case definition for children and adolescents has been formed, through a process of expert consensus, which recognizes the unique health needs and challenges of this group of people.
212	Ch210		Jamaica Balderas, Lourdes María del Carmen; Navarro Fernández, Amairani; Dragustinovis Garza, Susana Azeneth; Orellana Jerves, María Isabel; Solís Figueroa, Walter Ernesto; Koretzky, Solange Gabriela; Márquez González, Horacio; Klünder Klünder, Miguel; Espinosa, Juan Garduño; Nieto Zermeño, Jaime; Villa Guillén, Mónica; Rosales Uribe, Rómulo Erick; Olivar López, Victor	Long COVID in children and adolescents: COVID-19 follow-up results in third-level pediatric hospital	https://doi.org/10.3389/fped.2023.1016394	Published	2023-01-30	Study	https://www.frontiersin.org/articles/10.3389/fped.2023.1016394	IntroductionIn children, the manifestations of coronavirus disease 2019 (COVID-19) in the acute phase are considered mild compared with those in adults; however, some children experience a severe disease that requires hospitalization. This study was designed to present the operation and follow-up results of the Post-COVID-19 Detection and Monitoring Sequels Clinic of Hospital Infantil de Mexico Federico Gómez in managing children with a history of SARS-CoV-2 infection.MethodsThis was a prospective study conducted from July 2020 to December 2021, which included 215 children aged 0–18 years who tested positive for SARS-CoV-2 on polymerase chain reaction and/or immunoglobulin G test. The follow-up was conducted in the pulmonology medical consultation; ambulatory and hospitalized patients were assessed at 2, 4, 6, and 12 months.ResultsThe median age of the patients was 9.02 years, and neurological, endocrinological, pulmonary, oncological, and cardiological comorbidities were the most commonly observed among the patients. Moreover, 32.6% of the children had persistent symptoms at 2 months, 9.3% at 4 months, and 2.3% at 6 months, including dyspnea, dry cough, fatigue, and runny nose; the main acute complications were severe pneumonia, coagulopathy, nosocomial infections, acute renal injury, cardiac dysfunction, and pulmonary fibrosis. The more representative sequelae were alopecia, radiculopathy, perniosis, psoriasis, anxiety, and depression.ConclusionsThis study showed that children experience persistent symptoms, such as dyspnea, dry cough, fatigue, and runny nose, although to a lesser extent than adults, with significant clinical improvement 6 months after the acute infection. These results indicate the importance of monitoring children with COVID-19 through face-to-face consultations or telemedicine, with the objective of offering multidisciplinary and individualized care to preserve the health and quality of life of these children.
213	Ch211		Faux-Nightingale, Alice; Burton, Claire; Twohig, Helen; Blagojevic-Bucknall, Milica; Carroll, Will; Chew-Graham, Carolyn A.; Dunn, Kate; Gilchrist, Francis; Helliwell, Toby; Lawton, Oliver; Lawton, Sarah; Mallen, Christian; Saunders, Benjamin; Windt, Danielle van der; Welsh, Victoria	Symptom patterns and life with post-acute COVID-19 in children aged 8-17: a mixed methods studyprotocol	https://doi.org/10.3399/BJGPO.2022.0149	Published	2023-02-09	Study	https://bjgpopen.org/content/early/2023/02/08/BJGPO.2022.0149	Background While there is a substantial body of knowledge about acute COVID-19, less is known about long-COVID, where symptoms continue beyond four weeks. Aim This study aims to describe longer-term effects of COVID-19 infection in children and young people (CYP) and identify their needs in relation to long-COVID. Design & setting This study comprises an observational prospective cohort study and a linked qualitative study, identifying participants aged 8–17 years in the West Midlands of England. Method CYP will be invited to complete online questionnairesto monitor incidences and symptoms of Covid-19 over a 12-month period. CYP who have experienced long-term effects of COVID will be invited to interview, and those currently experiencing symptoms will be asked to document their experiences in a diary. Professionals who work with CYP will be invited to explore the impact of long-COVID on the wider experiences of CYP, in a focus group. Descriptive statistics will be used to describe the incidence and rates of resolution of symptoms, and comparisons made between exposed and non-exposed groups. Logistic regression models will be used to estimate associations between candidate predictors and the development of long-COVID, and linear regression will be used to estimate associations between candidate predictors. Qualitative data will be analysed thematically using the constant comparison method. Conclusion This study will describe features and symptoms of long-COVID and explore the impact of long-COVID within the lives of CYP and their families, to provide better understanding of long-COVID and inform clinical practice.
214	Ch212		Hicks, Steven D.	Comparison of Symptom Duration Between Children With SARS-CoV-2 and Peers With Other Viral Illnesses During the COVID-19 Pandemic	https://doi.org/10.1177/00099228231152840	Published	2023-02-07	Study	https://doi.org/10.1177/00099228231152840	Some children and young people (CYP) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) experience persistent symptoms, commonly called ?long COVID.? It remains unclear whether symptoms of SARS-CoV-2 persist longer than those of other respiratory viruses, particularly in young children. This cross-sectional study involved 372 CYP (0-15 years) tested for SARS-CoV-2. Character and duration of symptoms (cough, runny nose, sore throat, rash, diarrhea, vomiting, sore muscles, fatigue, fever, loss of smell) were compared between CYP with a positive test (n = 100) and those with a negative test (n = 272), while controlling for medical/demographic covariates. The average duration of symptoms for CYP with a positive SARS-CoV-2 test (8.5 ± 10 days) did not differ from that of CYP with a negative test (7.2 ± 5 days, P = .71, d = 0.046). A positive SARS-CoV-2 test did not increase the risk (36/372, 10%) of symptoms persisting for ≥3 weeks (odds ratio = 0.96, 95% confidence interval = 0.45-2.0). These results suggest CYP with non-SARS-CoV-2 infections experience a similar duration of symptoms as peers with SARS-CoV-2 infection.
215	Ch213		Tonyali, Aysegul; Karacetin, Gul; Yesilkaya, Celal; Arik, Feyza Nur Tas; Kayan Ocakoglu, Binay	Appearance of extrapyramidal symptoms in adolescent psychiatry patients during COVID-19 infection	https://doi.org/10.1002/jmv.28556	Published	2023-02-04	Study	https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.28556	Since the start of the pandemic, there has been an increase in the incidence of psychiatric morbidity among those infected with coronavirus disease 2019 (COVID-19) and those indirectly affected by COVID-19. There has been a considerable increase in the number of individuals with such psychiatric conditions as depression, acute stress disorders, anxiety, and posttraumatic stress disorder (PTSD). About one-third of patients with COVID-19 are reported to have developed short and long-term neuropsychiatric conditions such as delirium, agitation, altered consciousness, hypoxic encephalopathy encephalitis, dysexecutive syndrome, cerebrovascular complications (e.g., stroke), hypoxic encephalopathy, convulsions, neuromuscular dysfunction, demyelinating processes, or parkinsonism through several pathophysiological mechanisms. Nevertheless, as the pandemic progressed, data on neuropsychiatric manifestations implied that the pathologic capacity of COVID-19 and its association with the onset and/or exacerbation of psychiatric morbidity indicate that COVID-19 is potentially related to neuropsychiatric involvement. Patients with existing mental disorders under psychotropic treatment exposed to the COVID-19 infection have been represented by an increased risk of worsened psychiatric symptoms and expanded drug side effects. The present study aimed to describe five pediatric patients with various psychiatric illness that experienced COVID-19 infection and had potentially associated neuropsychiatric involvement, such as exacerbation of underlying psychiatric symptoms and extrapyramidal side effects. To the best of our knowledge, the present study is the first to describe adolescents with COVID-19 infection that presented with a series of manifestations in the form of an increase in extrapyramidal symptoms (EPS) during exacerbation of underlying psychiatric disease.
216	Ch214		Baptista de Lima, Joana; Salazar, Luís; Fernandes, Alexandre; Teixeira, Carla; Marques, Laura; Afonso, Caldas	Long COVID in Children and Adolescents: A Retrospective Study in a Pediatric Cohort	https://doi.org/10.1097/INF.0000000000003829	Published	2023-01-04	Study	https://journals.lww.com/pidj/Fulltext/9900/Long_COVID_in_Children_and_Adolescents__A.311.aspx	Studies on long coronavirus disease (COVID) in children are scarce. We aimed to describe persistent symptoms and identify risk factors for its development. In our study population, 17.6% presented with long COVID, with respiratory symptoms more frequent in the first weeks and neuropsychiatric symptoms over time. Chronic conditions and obesity were risk factors, and adolescents were at a greater risk for long COVID. Children infected with Severe acute respiratory syndrome coronavirus 2 are usually asymptomatic or with a mild form of coronavirus disease (COVID).1 While the acute symptoms are well defined, the long-term symptoms are not. Most COVID-19 patients achieve full recovery within 3–4 weeks after infection; however, in some cases, persistent symptoms can be seen weeks or months after recovery.2 According to National Institute for Health and Care Excellence guidelines, symptoms from onset to 4 weeks after diagnosis are considered acute COVID-19.3 The persistence of symptoms from 4 to 12 weeks is defined as ongoing symptomatic COVID-19, whereas symptoms that continue 12 weeks after diagnosis are considered post-COVID-19. Either ongoing symptomatic COVID-19 or post-COVID-19 is considered long COVID.3 In children, information on COVID-19 persistent symptoms remains scarce. Recent studies have shown that common persistent symptoms include fatigue, headache, postviral cough, anosmia, dyspnea and chest pain.4–6 In this study, we aimed to identify the prevalence of COVID-19 persistent symptoms in patients presenting to a tertiary hospital and to investigate possible risk factors for the development of long-term COVID.
217	Ch215		Ahn, Bin; Choi, Sung Hwan; Yun, Ki Wook	Non-neuropsychiatric Long COVID Symptoms in Children Visiting a Pediatric Infectious Disease Clinic After an Omicron Surge	https://doi.org/10.1097/INF.0000000000003862	Published	2023-02-24	Study	https://journals.lww.com/pidj/Fulltext/9900/Non_neuropsychiatric_Long_COVID_Symptoms_in.353.aspx	Although much interest has emerged regarding post-COVID conditions, data on children and adolescents are limited. The prevalence of long COVID and common symptoms were analyzed in this case-control study of 274 children. Prolonged non-neuropsychiatric symptoms were more frequent in the case group (17.0% and 4.8%, P = 0.004). Abdominal pain (6.6%) was the most common long COVID symptom. There has been much interest in the aftereffects of coronavirus disease 2019 (COVID-19) because the beginning of the epidemic. However, interest in the long-term outcomes of COVID-19 has emerged, as a large part of the world’s population was infected with the Omicron variant BA2 in early 2022 and fatigue causing prolonged limitation of social activity has been increasingly reported.1 A proportion of persons with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection experience long-term symptoms. Over the course of the pandemic, various terms, including “long COVID,” “long-haul COVID” and “post COVID-19 condition” have been proposed. The World Health Organization (WHO) defines long COVID as symptoms that develop usually 3 months after COVID-19 onset, persist for more than 2 months and cannot be explained by any other etiology.2 However, it has been suggested that these diagnostic criteria cannot be applied uniformly in children and adolescents because this population experiences many viral infections and somatic symptoms. Supporting this limitation, relevant data in children and adolescents are controversial. Moreover, distinguishing neuropsychiatric long COVID symptoms from pandemic-related symptoms is difficult, particularly in adolesents.3 Therefore, in this study, we analyzed the prevalence of non-neuropsychiatric long COVID symptoms among Korean children and adolescents who were laboratory confirmed to have SARS-CoV-2 infections in February–April.
218	Ch216		Goretzki, Sarah C.; Brasseler, Maire; Dogan, Burcin; Hühne, Tom; Bernard, Daniel; Schönecker, Anne; Steindor, Mathis; Gangfuß, Andrea; Della Marina, Adela; Felderhoff-Müser, Ursula; Dohna-Schwake, Christian; Bruns, Nora	High Prevalence of Alternative Diagnoses in Children and Adolescents with Suspected Long COVID—A Single Center Cohort Study	https://doi.org/10.3390/v15020579	Published	2023-02-01	Study	https://www.mdpi.com/1999-4915/15/2/579	Background: Long COVID (LC) is a diagnosis that requires exclusion of alternative somatic and mental diseases. The aim of this study was to examine the prevalence of differential diagnoses in suspected pediatric LC patients and assess whether adult LC symptom clusters are applicable to pediatric patients. Materials and Methods: Pediatric presentations at the Pediatric Infectious Diseases Department of the University Hospital Essen (Germany) were assessed retrospectively. The correlation of initial symptoms and final diagnoses (LC versus other diseases or unclarified) was assessed. The sensitivity, specificity, negative and positive predictive values of adult LC symptom clusters were calculated. Results: Of 110 patients, 32 (29%) suffered from LC, 52 (47%) were diagnosed with alternative somatic/mental diseases, and 26 (23%) remained unclarified. Combined neurological and respiratory clusters displayed a sensitivity of 0.97 (95% CI 0.91–1.00) and a negative predictive value of 0.97 (0.92–1.00) for LC. Discussion/Conclusions: The prevalence of alternative somatic and mental diseases in pediatric patients with suspected LC is high. The range of underlying diseases is wide, including chronic and potentially life-threatening conditions. Neurological and respiratory symptom clusters may help to identify patients that are unlikely to be suffering from LC.
219	Ch217		Avittan, Hadar; Kustovs, Dmitrijs	Cognition and Mental Health in Pediatric Patients Following COVID-19	https://doi.org/10.3390/ijerph20065061	Published	2023-01-01	Review	https://www.mdpi.com/1660-4601/20/6/5061	The global coronavirus pandemic has significantly impacted public health and has been a research subject since its emergence in 2019. The acute phase of the disease leads to pulmonary and non-pulmonary manifestations, which in some individuals may progress to long-lasting symptoms. In this article, we conducted a narrative review of the current literature to summarize current knowledge regarding long COVID syndrome in children, focusing on cognitive symptoms. The review included a search of three databases (PubMed, Embase, and Web of Science) using the key phrases “post COVID-19 cognitive pediatric”, “long COVID pediatric”, “mental health long COVID children”, and “COVID-19 cognitive symptoms”. A total of 102 studies were included. The review revealed that the main long-term cognitive symptoms following COVID-19 were memory and concentration deficits, sleep disturbances, and psychiatric states such as anxiety and stress. In addition to the direct physiological effects of a viral infection, there are psychological, behavioral, and social factors contributing to cognitive impairment, which should be addressed regarding the pediatric population. The high prevalence of neurocognitive symptoms in children following COVID-19 emphasizes the importance of understanding the mechanisms of nervous system involvement.
220	Ch218		Budziło, Oskar; Irga-Jaworska, Ninela; Myszyńska, Marcelina; Malanowska, Magdalena; Niedźwiecki, Maciej	The Impact of Past COVID-19 Infection on Selected Lymphocyte Subsets in Pediatric Patients	https://doi.org/10.3390/vaccines11030659	Published	2023-03-01	Study	https://www.mdpi.com/2076-393X/11/3/659	The impact of past COVID-19 infection on the immune system remains unidentified. So far, several papers have revealed the dependence between the count of lymphocytes and their subsets and the outcome of an acute disease. However, still there is little information about long-term consequences, particularly in the pediatric population. We attempted to verify whether a dysregulation of the immune system may be the reason for observed complications after past COVID-19 infection. Hence, we tried to prove that abnormalities in lymphocyte subpopulations are found in patients a certain time after the COVID-19 infection. In our paper, we enrolled 466 patients after SARS-CoV-2 infection, and evaluated their subsets of lymphocytes within 2–12 months after infection and compared them to the control group assessed several years before the pandemic. It occurred that main differences are observed in CD19+ lymphocytes and the index CD4+/CD8+ lymphocytes. We believe that this is only the introduction to further investigation of the immune system of pediatric patients post-COVID-19 infection.
221	Ch219		Filippatos, Filippos; Tatsi, Elizabeth-Barbara; Michos, Athanasios	Immunology of Multisystem Inflammatory Syndrome after COVID-19 in Children: A Review of the Current Evidence	https://doi.org/10.3390/ijms24065711	Published	2023-01-01	Review	https://www.mdpi.com/1422-0067/24/6/5711	Immune responses following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children are still under investigation. Even though coronavirus disease 2019 (COVID-19) is usually mild in the pediatric population, some children exhibit severe clinical manifestations, require hospitalization, or develop the most severe condition: a multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 infection. The activated innate, humoral and T-cell-mediated immunological pathways that lead certain pediatric populations to present with MIS-C or remain asymptomatic after SARS-CoV-2 infection are yet to be established. This review focuses on the immunological aspects of MIS-C with respect to innate, humoral, and cellular immunity. In addition, presents the role of the SARS-CoV-2 Spike protein as a superantigen in the pathophysiological mechanisms, discusses the great heterogeneity among the immunological studies in the pediatric population, and highlights possible reasons why some children with a certain genetic background present with MIS-C.
222	Ch220		Kumar, Prawin; Jat, Kana Ram	Post-COVID-19 Sequelae in Children	https://doi.org/10.1007/s12098-023-04473-4	Published	2023-03-08	Review	https://doi.org/10.1007/s12098-023-04473-4	Coronavirus disease 19 (COVID-19), caused by the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), has been implicated in having post-COVID-19 sequelae in both adults and children. There is a lack of good data on the prevalence and risk factors for post-COVID-19 sequelae in children. The authors aimed to review the current literature on post-COVID sequelae. The prevalence of post-COVID sequelae in children is highly variable among studies, with an average of 25%. The sequelae may affect many organ systems, though mood symptoms, fatigue, cough, dyspnea, and sleep problems are common. In many studies, it is difficult to establish a causal association due to the lack of a control group. Furthermore, it is difficult to differentiate whether the neuropsychiatric symptoms in children after COVID-19 are due to infection or a result of lockdowns and social restrictions imposed by the pandemic. Children with COVID-19 should be followed by a multidisciplinary team and screened for symptoms, followed by focused laboratory evaluations as needed. There is no specific treatment for the sequelae. Only symptomatic and supportive treatment is required in most cases. More research is necessary to standardize the definitions of sequelae, establish a causal association, assess various treatment options, and the effects of different virus variants, and finally, see the impact of vaccination on the sequelae.
223	Ch221		Burki, Talha	Clinical case definition of post-COVID-19 condition in children: a good start, but improvements are needed	https://doi.org/10.1016/S2213-2600(23)00081-4	Published	2023-03-07	Article	https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00081-4/fulltext	WHO outlined several research priorities for post-COVID-19 condition in children and adolescents. These included confirming whether certain symptoms tend to cluster together and whether a minimum number of symptoms are necessary to make a diagnosis. Ascertaining prevalence might prove impossible. Some children are too young to communicate their symptoms and others will not present to health care. “Future research will have to tease out which of the more non-specific symptoms are linked to COVID-19”, Freedman told The Lancet Respiratory Medicine.“ Research into long COVID is a complicated prospect”, added Martin Hibberd, Professor of Emerging Infectious Diseases at London School of Hygiene & Tropical Medicine (London, UK). “You have to compare cases to controls, and we are talking about a lot of non-specific or mild symptoms that are common in the general population.” Moreover, SARS-CoV-2 is likely to have now infected billions of people around the world. Countries have mostly discontinued testing for the virus and a lot of cases are asymptomatic anyway. Identifying control populations will be tricky. It is possible that widespread exposure to SARS-CoV-2 alongside the rollout of the vaccines will drive down prevalence of post-COVID-19 condition. Alternatively, the emergence of a new variant might cause its prevalence to rise. But proving either eventuality will be difficult without controls. Hibberd stressed that one would expect to see lingering symptoms in a minority of individuals who have contracted a viral infection. “If we can get an idea of the proportion of children and adults who have long COVID, based on the definitions WHO has provided, we can at least identify whether COVID-19 is more or less likely to result in long-term consequences than other respiratory infections”, he said. Freedman would like to see future research directed towards establishing biomarkers for long COVID, with the aim of preventing the condition from happening in the first place. He cautioned that some questions might prove irresolvable. “This is not the first illness for which we have struggled with the diagnostic criteria”, said Freedman. “It has happened with chronic fatigue syndrome, for example. Maybe we will not be able to get all the answers.” publisher: Elsevier PMID: 36898399
224	Ch222		Zheng, Yong-Bo; Zeng, Na; Yuan, Kai; Tian, Shan-Shan; Yang, Ying-Bo; Gao, Nan; Chen, Xuan; Zhang, An-Yi; Kondratiuk, Alexandra L.; Shi, Pei-Pei; Zhang, Fang; Sun, Jie; Yue, Jing-Li; Lin, Xiao; Shi, Le; Lalvani, Ajit; Shi, Jie; Bao, Yan-Ping; Lu, Lin	Prevalence and risk factor for long COVID in children and adolescents: A meta-analysis and systematic review	https://doi.org/10.1016/j.jiph.2023.03.005	Published	2023-05-01	Study	https://www.sciencedirect.com/science/article/pii/S1876034123000710	Background Millions of COVID-19 pediatric survivors are facing the risk of long COVID after recovery from acute COVID-19. The primary objective of this study was to systematically review the available literature and determine the pooled prevalence of, and risk factors for long COVID among the pediatric survivors. Methods Studies that assessed the prevalence of, or risk factors associated with long COVID among pediatric COVID-19 survivors were systematically searched in PubMed, Embase, and Cochrane Library up to December 11th, 2022. Random effects model was performed to estimate the pooled prevalence of long COVID among pediatric COVID-19 patients. Subgroup analyses and meta-regression on the estimated prevalence of long COVID were performed by stratification with follow-up duration, mean age, sex ratio, percentage of multisystem inflammatory syndrome, hospitalization rate at baseline, and percentage of severe illness. Results Based on 40 studies with 12,424 individuals, the pooled prevalence of any long COVID was 23.36 % ([95 % CI 15.27–32.53]). The generalized symptom (19.57 %, [95 % CI 9.85–31.52]) was reported most commonly, followed by respiratory (14.76 %, [95 % CI 7.22–24.27]), neurologic (13.51 %, [95 % CI 6.52–22.40]), and psychiatric (12.30 %, [95% CI 5.38–21.37]). Dyspnea (22.75 %, [95% CI 9.38–39.54]), fatigue (20.22 %, [95% CI 9.19–34.09]), and headache (15.88 %, [95 % CI 6.85–27.57]) were most widely reported specific symptoms. The prevalence of any symptom during 3–6, 6–12, and> 12 months were 26.41 % ([95 % CI 14.33–40.59]), 20.64 % ([95 % CI 17.06–24.46]), and 14.89 % ([95 % CI 6.09–26.51]), respectively. Individuals with aged over ten years, multisystem inflammatory syndrome, or had severe clinical symptoms exhibited higher prevalence of long COVID in multi-systems. Factors such as older age, female, poor physical or mental health, or had severe infection or more symptoms were more likely to have long COVID in pediatric survivors. Conclusions Nearly one quarter of pediatric survivors suffered multisystem long COVID, even at 1 year after infection. Ongoing monitoring, comprehensive prevention and intervention is warranted for pediatric survivors, especially for individuals with high risk factors.
225	Ch223		Brum, Andrea C.; Vain, Nestor E.	Impact of perinatal COVID on fetal and neonatal brain and neurodevelopmental outcomes	https://doi.org/10.1016/j.siny.2023.101427	Published	2023-03-08	Review	https://www.sciencedirect.com/science/article/pii/S1744165X23000033	After three years of the COVID-19 pandemic, we have learned many aspects of the disease and the virus: its molecular structure, how it infects human cells, the clinical picture at different ages, potential therapies, and the effectiveness of prophylaxis. Research is currently focused on the short- and long-term consequences of COVID-19. We review the available information on the neurodevelopmental outcome of infants born during the pandemic from infected and non-infected mothers, as well as the neurological impact of neonatal SARS-CoV-2 infection. We also discuss the mechanisms that could potentially affect the fetal or neonatal brain including direct impact after vertical transmission, maternal immune activation with a proinflammatory cytokine storm, and finally the consequences of complications of pregnancy secondary to maternal infection that could affect the fetus. Several follow-up studies have noted a variety of neurodevelopmental sequelae among infants born during the pandemic. There is controversy as to the exact etiopathogenesis of these neurodevelopmental effects: from the infection itself or as a result of parental emotional stress during that period. We summarize case reports of acute neonatal SARS-CoV-2 infections associated with neurological signs and neuroimaging changes. Many infants born during previous pandemics caused by other respiratory viruses demonstrated serious neurodevelopmental and psychological sequelae that were only recognized after several years of follow-up. It is essential to warn health authorities about the need for very long-term continuous follow up of infants born during the SARS-CoV-2 pandemic for early detection and treatment that could help mitigate the neurodevelopmental consequences of perinatal COVID-19.
226	Ch224		Rotulo, Gioacchino Andrea; Palma, Paolo	Understanding COVID-19 in children: immune determinants and post-infection conditions	https://doi.org/10.1038/s41390-023-02549-7	Published	2023-03-06	Review	https://www.nature.com/articles/s41390-023-02549-7	Abstract Coronavirus disease 2019 in children presents with milder clinical manifestations than in adults. On the other hand, the presence of a wide range of inflammatory manifestations, including multisystem inflammatory syndrome in children (MIS-C), in the period after infection suggests a particular susceptibility of some children toward severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Both protective factors that prevent evolution to severe forms and risk factors for post-infectious conditions are likely to be found in age-related differences in the immune system. The prompt innate response with type I IFN production and the generation of neutralizing antibodies play a crucial role in containing the infection. The greater number of naive and regulatory cells in children helps to avoid the cytokine storm while the causes of the intense inflammatory response in MIS-C need to be elucidated. This review aims to analyze the main results of the recent literature assessing immune response to SARS-CoV-2 over the pediatric age group. We summarized such observations by dividing them into innate and acquired immunity, then reporting how altered immune responses can determine post-infectious conditions. Impact The main immune markers of acute SARS-CoV-2 infection in children are summarized in this review. This paper reports a broad overview of age-related differences in the immune response to SARS-CoV-2 and emerging post-infection conditions. A summary of currently available therapies for the pediatric age group is provided. publisher: Nature Publishing Group
227	Ch225		Edlow, Andrea G.; Castro, Victor M.; Shook, Lydia L.; Haneuse, Sebastien; Kaimal, Anjali J.; Perlis, Roy H.	Sex-Specific Neurodevelopmental Outcomes Among Offspring of Mothers With SARS-CoV-2 Infection During Pregnancy	https://doi.org/10.1001/jamanetworkopen.2023.4415	Published	2023-03-23	Study	https://doi.org/10.1001/jamanetworkopen.2023.4415	Key Points Question Is in utero exposure to maternal SARS-CoV-2 infection associated with greater rates of neurodevelopmental disorder diagnoses in male or female offspring, compared with controls with no such exposure? Findings This cohort study of 18 355 infants delivered after February 2020 found that male but not female offspring born to mothers with a positive SARS-CoV-2 polymerase chain reaction test result during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first 12 months after delivery, even after accounting for preterm delivery. Meaning These findings suggest that male offspring exposed to SARS-CoV-2 in utero may be at increased risk for neurodevelopmental disorders. Abstract Importance Prior studies using large registries have suggested a modest increase in risk for neurodevelopmental diagnoses among children of mothers with immune activation during pregnancy, and such risk may be sex-specific. Objective To determine whether in utero exposure to SARS-CoV-2 is associated with sex-specific risk for neurodevelopmental disorders up to 18 months after birth, compared with unexposed offspring born during or prior to the COVID-19 pandemic period. Design, Setting, and Participants This retrospective cohort study included the live offspring of all mothers who delivered between January 1 and December 31, 2018 (born and followed up before the COVID-19 pandemic), between March 1 and December 31, 2019 (born before and followed up during the COVID-19 pandemic), and between March 1, 2020, and May 31, 2021 (born and followed up during the COVID-19 pandemic). Offspring were born at any of 8 hospitals across 2 health systems in Massachusetts. Exposures Polymerase chain reaction evidence of maternal SARS-CoV-2 infection during pregnancy. Main Outcomes and Measures Electronic health record documentation of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnostic codes corresponding to neurodevelopmental disorders. Results The COVID-19 pandemic cohort included 18 355 live births (9399 boys [51.2%]), including 883 (4.8%) with maternal SARS-CoV-2 positivity during pregnancy. The cohort included 1809 Asian individuals (9.9%), 1635 Black individuals (8.9%), 12 718 White individuals (69.3%), and 1714 individuals (9.3%) who were of other race (American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, more than 1 race); 2617 individuals (14.3%) were of Hispanic ethnicity. Mean maternal age was 33.0 (IQR, 30.0-36.0) years. In adjusted regression models accounting for race, ethnicity, insurance status, hospital type (academic center vs community), maternal age, and preterm status, maternal SARS-CoV-2 positivity was associated with a statistically significant elevation in risk for neurodevelopmental diagnoses at 12 months among male offspring (adjusted OR, 1.94 [95% CI 1.12-3.17]; P = .01) but not female offspring (adjusted OR, 0.89 [95% CI, 0.39-1.76]; P = .77). Similar effects were identified using matched analyses in lieu of regression. At 18 months, more modest effects were observed in male offspring (adjusted OR, 1.42 [95% CI, 0.92-2.11]; P = .10). Conclusions and Relevance In this cohort study of offspring with SARS-CoV-2 exposure in utero, such exposure was associated with greater magnitude of risk for neurodevelopmental diagnoses among male offspring at 12 months following birth. As with prior studies of maternal infection, substantially larger cohorts and longer follow-up will be required to reliably estimate or refute risk.
228	Ch226		Rajamanickam, Anuradha; Nathella, Pavan Kumar; Venkataraman, Aishwarya; Dasan, Bindu; Putlibai, Sulochana; Ahamed, Shaik Fayaz; Selvaraj, Nandhini; Sadasivam, Kalaimaran; Sundaram, Balasubramanian; Nutman, Thomas B.; Babu, Subash	Levels of Complement Components in Children With Acute COVID-19 or Multisystem Inflammatory Syndrome	https://doi.org/10.1001/jamanetworkopen.2023.1713	Published	2023-03-24	Study	https://doi.org/10.1001/jamanetworkopen.2023.1713	Key Points Question Are multisystem inflammatory syndrome in children (MIS-C) and COVID-19 in children associated with alterations in complement expression and function? Findings In this cross-sectional study with 145 participants, MIS-C and COVID-19 were associated with higher levels of complement components, activation products, and regulators. Additionally, complement levels pretreatment were found to be potential biomarkers of disease severity in MIS-C and COVID-19. Meaning The findings of this study suggest that complement activation was associated with the pathogenesis of MIS-C and acute COVID-19 and is a potential biomarker of disease severity. Abstract Importance Multisystem inflammatory syndrome in children (MIS-C) is a severe and unrestrained inflammatory response with multiorgan involvement, which occurs within a few weeks following the resolution of acute SARS-CoV-2 infection. The complement system is a vital part of the innate immune system and plays a role in COVID-19 pathogenesis. Objective To examine and compare the levels of complement components and regulators along with complement activation products in the different clinical spectrum of children with SARS-CoV-2 and a control group. Design, Setting, and Participants This cross-sectional study analyzed children with MIS-C admitted to a single hospital in India from June through September 2020. Eligible participants were children who were hospitalized of either sex, aged 1 to 18 years. Data were analyzed August 2022. Measures Levels of complement components and regulators along with complement activation products in all the groups of children. Mann-Whitney U test and Kruskal-Wallis analysis were used to compare the complement component levels, and Spearman rank correlation analysis was used to describe the association between complement components and laboratory and biochemical parameters. Results A total 145 children were included (median age, 5 years [range, 1 month-17 years); 84 [58%] male): 44 children with MIS-C, 33 with acute COVID-19 (reverse transcriptase–polymerase chain reaction [RT-PCR] positive), 47 with convalescent COVID-19 (immunoglobulin G–positive non-MIS-C) and 21 children for a control group (both serology and RT-PCR negative). Children with MIS-C and COVID-19 had higher levels of C1q (geometric mean [SD]: MIS-C, 61.5 [18.5] ng/mL; acute COVID-19, 56.9 [18.6] ng/mL; controls, 24.1 [3.3] ng/mL), C2 (MIS-C, 605.8 [219.7] ng/mL; acute COVID-19, 606.4 [167.7] ng/mL; controls, 255.9 [73.3] ng/mL), C3 (MIS-C, 318.2 [70.7] ng/mL; acute COVID-19, 237.7 [61.8] ng/mL; controls, 123.4 [15.7] ng/mL), C4b (MIS-C, 712.4 ng/mL; acute COVID-19, 640.7 ng/mL; controls, 351.5 ng/mL), C5 (MIS-C, 1487 ng/mL; acute COVID-19, 1364 ng/mL; controls, 561.9 ng/mL), C5a, (MIS-C, 2614.0 [336.2] ng/mL; acute COVID-19, 1826.0 [541.0] ng/mL; controls, 462.5 [132.4] ng/mL), C3b/iC3b (MIS-C, 3971.0 [635.1] ng/mL; acute COVID-19, 3702.0 [653.9] ng/mL; controls, 2039.0 [344.5] ng/mL), and factor B (MIS-C, 47.6 [7.8] ng/mL; acute COVID-19, 44.6 [6.3] ng/mL; controls, 27.5 [5.0] ng/mL), factor D (MIS-C, 44.0 [17.2] ng/mL; acute COVID-19, 33.8 [18.4] ng/mL; controls, 21.3 [6.1] ng/mL), and factor H (MIS-C, 53.1 [4.0] ng/mL; acute COVID-19, 50.8 [5.7] ng/mL; controls, 43.6 [3.8] ng/mL) in comparison with convalescent and control children. In addition, children with MIS-C had significantly elevated levels of C3 (318.2 [70.7] ng/mL vs 237.7 [61.8] ng/mL), C5a (2614 [336.2] ng/mL vs 1826 [541.0] ng/mL), and mannose-binding lectin (79.4 [12.4] ng/mL vs 69.6 [14.7] ng/mL) in comparison to children with acute COVID-19. Levels of some of these analytes at admission (ie, pretreatment) were more elevated in children with MIS-C who needed pediatric intensive care unit (PICU) support as compared with those who did not require PICU support, and in children with COVID-19 who developed moderate to severe disease compared with those who developed mild disease. Overall, MIS-C and acute COVID-19 were associated with the hyperactivation of complement components and complement regulators. Conclusions and Relevance In this cross-sectional study, the complement system was associated with the pathogenesis of MIS-C and COVID-19 in children; complement inhibition could be further explored as a potential treatment option.
229	Ch227		Mariani, Francesco; Morello, Rosa; Traini, Daniele Omar; La Rocca, Anna; De Rose, Cristina; Valentini, Piero; Buonsenso, Danilo	Risk Factors for Persistent Anosmia and Dysgeusia in Children with SARS-CoV-2 Infection: A Retrospective Study	https://doi.org/10.3390/children10030597	Published	2023-03-01	Study	https://www.mdpi.com/2227-9067/10/3/597	Background: Olfactory and gustative dysfunctions are two of the most common post-acute sequelae of SARS-CoV-2 infection in children, which can have a negative impact on the routines of children and families. As several children have had COVID-19 since the Omicron variant, it is important to investigate if this increase in infections is reflected in higher olfactory/taste disfunctions. The primary aim of this study was to characterize the presence of olfactory/gustative problems in a cohort of children, its evolution, and its association with risk factors such as COVID-19 variant, hospitalization, presence of olfactory/gustative dysfunction during the acute phase, and vaccination. Methods: This was a retrospective analysis of children with microbiologically confirmed SARS-CoV-2 infection evaluated in person at a referral pediatric post-COVID-19 clinic in Rome, Italy. We included children younger than 19 years old, evaluated from the beginning of the pandemic up to October 2022. At specific timepoints, we investigated the presence of olfactory/taste disfunctions and evaluated them according to the SARS-CoV-2 variants circulating at the time of infection. Results: A total of 1250 children (650 females; 52.0%) with a mean age of 6.77 (±4.12) years were included in the study. At 3, 6, 12, and 18 months, 12 (9.6%), 7 (5.6%), 2 (1.6%), and 1 (0.8%) of the children reported anosmia and dysgeusia post-COVID-19 infection, respectively. The presence of anosmia and dysgeusia during the acute phase of infection and being infected with a pre-Omicron variant were found to be significant risk factors for persistent olfactory and gustatory dysfunction during all follow-up periods. Conclusions: anosmia and dysgeusia symptoms tended to decrease gradually over time, but not all children recovered quickly.
230	Ch228		McCrindle, Brian W.; Harahsheh, Ashraf S.; Handoko, Ryan; Raghuveer, Geetha; Portman, Michael A.; Khoury, Michael; Newburger, Jane W.; Lee, Simon; Jain, Supriya S.; Khare, Manaswitha; Dahdah, Nagib; Manlhiot, Cedric	SARS-CoV-2 Variants and Multisystem Inflammatory Syndrome in Children	https://doi.org/10.1056/NEJMc2215074	Published	2023-03-22	Study	https://doi.org/10.1056/NEJMc2215074	A total of 2017 patients were enrolled in the study. The demographic characteristics of the patients (Table S1 in the Supplementary Appendix, available with the full text of the letter at NEJM.org) were similar to those of the broader population of children with MIS-C. Patients during the delta (B.1.617.2) and omicron (B.1.1.529) periods were younger, showed greater phenotypic similarity to patients with Kawasaki’s disease, and had a lower incidence of respiratory dysfunction and coronary-artery dilatation than patients during the ancestral and alpha+ (B.1.1.7 plus other circulating minor variants) periods (Table 1). After the ancestral period, immunomodulatory management evolved to include greater use of glucocorticoids. Concurrently, the risks of serious complications (arrhythmia, cardiac arrest, renal complications, coagulopathy, and thrombosis), admission to an intensive care unit, and death decreased, with the most pronounced decrease occurring during the omicron period. Across all the variant periods, the risk of ventricular dysfunction was highest among the patients hospitalized during the alpha+ period as compared with those during the ancestral period (35% vs. 28%, relative risk, 1.19; 95% confidence interval, 1.04 to 1.35). Although the clinical phenotype became milder over time, severe disease was still prevalent, with 23% of the patients during the omicron period presenting with shock and with 37% being admitted to an intensive care unit. The features of MIS-C at presentation were more often similar to the features of Kawasaki’s disease among patients hospitalized with SARS-CoV-2 infection during the more recent variant periods than among those during the earlier periods; however, without a definitive diagnostic test for either condition, it remains to be determined whether this represents a true change in phenotype or an increase in the number of patients with Kawasaki’s disease who meet the criteria for MIS-C through concurrent but unrelated SARS-CoV-2 infection. Although we acknowledge the limitations of the ecologic study design and the inherent risk of misclassification of variant at the patient level, our data support observations that the severity of MIS-C has decreased with each subsequent SARS-CoV-2 variant. Nevertheless, critical illness in patients hospitalized with MIS-C remains prevalent. publisher: Massachusetts Medical Society _eprint: https://doi.org/10.1056/NEJMc2215074
231	Ch229		Bentes, Aline Almeida; dos Santos Junior, Walter Rebuite; Pessoa, Natalia Lima; Costa, Thais Alkifeles; Oliveira, Gabriela Fernanda Garcia; Diniz, Lilian Martins Oliveira; Torres, Bruna Ribeiro; Teixeira, Daniela Caldas; Mendes, Renata Barandas; Avelar, Ana Beatriz Alvim; Campos, Marco Antônio; Kroon, Erna Geessien; Drumond, Betania Paiva	Neuro-COVID-19 With or Without the Multisystem Inflammatory Syndrome (MIS-C): A Single-Center Study	https://doi.org/10.1007/s12031-023-02109-y	Published	2023-03-28	Study	https://doi.org/10.1007/s12031-023-02109-y	This study evaluates the range of neurological manifestation in children with COVID-19 (neuro-COVID-19) both with and without the multisystem inflammatory syndrome (MIS-C) and the persistence of symptoms after hospital discharge. The study was conducted as a prospective study of children and adolescents under 18 years of age who were admitted to a children’s hospital for infectious diseases from January 2021 to January 2022. The children had no previous neurological or psychiatric disorders. Out of the 3021 patients evaluated, 232 were confirmed to have COVID-19 and 21 of these patients (9%) showed neurological manifestations associated with the virus. Of these 21 patients, 14 developed MIS-C, and 7 had neurological manifestations unrelated to MIS-C. There was no statistical difference regarding the neurological manifestations during hospitalization and outcomes between patients with neuro-COVID-19 who had or did not have MIS-C, except for seizures that occurred more frequently in patients with neuro-COVID-19 without MIS-C (p-value = 0.0263). One patient died, and 5 patients still had neurological or psychiatric manifestations at discharge, which persisted for up to 7 months. The study highlights that SARS-CoV-2 infection can affect the central and peripheral nervous system, particularly in children and adolescents with MIS-C, and that it is crucial to be vigilant for long-term adverse outcomes, as the neurological and psychiatric effects of COVID-19 in children are emerging during an important stage of brain development.
232	Ch230		Selvakumar, Joel; Havdal, Lise Beier; Drevvatne, Martin; Brodwall, Elias Myrstad; Lund Berven, Lise; Stiansen-Sonerud, Tonje; Einvik, Gunnar; Leegaard, Truls Michael; Tjade, Trygve; Michelsen, Annika E.; Mollnes, Tom Eirik; Lund-Johansen, Fridtjof; Holmøy, Trygve; Zetterberg, Henrik; Blennow, Kaj; Sandler, Carolina X.; Cvejic, Erin; Lloyd, Andrew R.; Wyller, Vegard Bruun Bratholm	Prevalence and Characteristics Associated With Post–COVID-19 Condition Among Nonhospitalized Adolescents and Young Adults	https://doi.org/10.1001/jamanetworkopen.2023.5763	Published	2023-03-30	Study	https://doi.org/10.1001/jamanetworkopen.2023.5763	Key Points Question What are the prevalence and associated risk factors of post–COVID-19 condition (PCC) in young people after mild acute infection? Findings This cohort study included 382 SARS-CoV-2–positive individuals and a control group of 85 SARS-CoV-2–negative individuals aged 12 to 25 years who were assessed at the early convalescent stage and at 6-month follow-up. When applying the World Health Organization case definition of PCC, prevalence at 6 months was 49%, but was also comparably high (47%) in the control group. PCC was not associated with biological markers specific to viral infection, but with initial symptom severity and psychosocial factors. Meaning These findings suggest that persistent symptoms in this age group are related to factors other than SARS-CoV-2 infection, and therefore question the usefulness of the WHO case definition of PCC. Abstract Importance The prevalence and baseline risk factors of post–COVID-19 condition (PCC) remain unresolved among the large number of young people who experienced mild COVID-19. Objectives To determine the point prevalence of PCC 6 months after the acute infection, to determine the risk of development of PCC adjusted for possible confounders, and to explore a broad range of potential risk factors. Design, Setting, and Participants This cohort study included nonhospitalized individuals from 2 counties in Norway between ages 12 and 25 years who underwent reverse transcription–polymerase chain reaction (RT-PCR) testing. At the early convalescent stage and at 6-month follow-up, participants underwent a clinical examination; pulmonary, cardiac, and cognitive functional testing; immunological and organ injury biomarker analyses; and completion of a questionnaire. Participants were classified according to the World Health Organization case definition of PCC at follow-up. Association analyses of 78 potential risk factors were performed. Exposures SARS-CoV-2 infection. Main Outcomes and Measures The point prevalence of PCC 6 months after RT-PCR testing in the SARS-CoV-2–positive and SARS-CoV-2–negative groups, and the risk difference with corresponding 95% CIs. Results A total of 404 individuals testing positive for SARS-CoV-2 and 105 individuals testing negative were enrolled (194 male [38.1%]; 102 non-European [20.0%] ethnicity). A total of 22 of the SARS-CoV-2–positive and 4 of the SARS-CoV-2–negative individuals were lost to follow-up, and 16 SARS-CoV-2–negative individuals were excluded due to SARS-CoV-2 infection in the observational period. Hence, 382 SARS-CoV-2–positive participants (mean [SD] age, 18.0 [3.7] years; 152 male [39.8%]) and 85 SARS-CoV-2–negative participants (mean [SD] age, 17.7 [3.2] years; 31 male [36.5%]) could be evaluated. The point prevalence of PCC at 6 months was 48.5% in the SARS-CoV-2–positive group and 47.1% in the control group (risk difference, 1.5%; 95% CI, −10.2% to 13.1%). SARS-CoV-2 positivity was not associated with the development of PCC (relative risk [RR], 1.06; 95% CI, 0.83 to 1.37; final multivariable model utilizing modified Poisson regression). The main risk factor for PCC was symptom severity at baseline (RR, 1.41; 95% CI, 1.27-1.56). Low physical activity (RR, 0.96; 95% CI, 0.92-1.00) and loneliness (RR, 1.01; 95% CI, 1.00-1.02) were also associated, while biological markers were not. Symptom severity correlated with personality traits. Conclusions and Relevance The persistent symptoms and disability that characterize PCC are associated with factors other than SARS-CoV-2 infection, including psychosocial factors. This finding raises questions about the utility of the World Health Organization case definition and has implications for the planning of health care services as well as for further research on PCC.
233	Ch231		Chen, Erin Y.; Burton, Justin M.; Johnston, Alicia; Morrow, Amanda K.; Yonts, Alexandra B.; Malone, Laura A.	Considerations in Children and Adolescents related to COVID-19	https://doi.org/10.1016/j.pmr.2023.03.004	Published	2023-03-30	Review	https://www.pmr.theclinics.com/article/S1047-9651(23)00020-7/fulltext	Key Points: -PCPs should screen for PASC in children with a history of SARS-CoV-2 infection. -PASC is a complex, multisystemic disease that benefits from a multifaceted treatment approach. -Lifestyle interventions, physical rehabilitation, and mental health management are important in improving pediatric PASC patients’ quality of life. publisher: Elsevier
234	Ch232		Ramaswamy, Viraraghavan Vadakkencherry; Abiramalatha, Thangaraj; Pullattayil S, Abdul Kareem; Trevisanuto, Daniele	Multisystem inflammatory disease in neonates (MIS-N) due to maternal COVID-19	https://doi.org/10.1016/j.siny.2023.101431	Published	2023-03-30	Review	https://www.sciencedirect.com/science/article/pii/S1744165X23000070	Multisystem inflammatory disease in neonates (MIS-N) is a disease of immune dysregulation presenting in the newborn period. Thouvgh its etiopathogenesis is proposed to be similar to multisystem inflammatory disease in Children (MIS-C), the exact pathophysiology is largely unknown as of present. The definition of MIS-N is contentious. The evidence for its incidence, the clinical features, profile of raised inflammatory markers, treatment strategies and outcomes stem from case reports, case series and cohort studies with small sample sizes. Though the incidence of MIS-N in severe acute respiratory syndrome caused by the coronavirus CoVID-2 (SARS-CoV-2) infected asymptomatic neonates is low, its incidence in symptomatic neonates is relatively higher. Further, amongst the neonates who are treated as MIS-N, the mortality rate is high. The review also evaluates the various other unresolved aspects of MIS-N from limited published literature and identifies knowledge gaps which could be areas of future research.
235	Ch233		Druzak, Samuel; Iffrig, Elizabeth; Roberts, Blaine R.; Zhang, Tiantian; Fibben, Kirby S.; Sakurai, Yumiko; Verkerke, Hans P.; Rostad, Christina A.; Chahroudi, Ann; Schneider, Frank; Wong, Andrew Kam Ho; Roberts, Anne M.; Chandler, Joshua D.; Kim, Susan O.; Mosunjac, Mario; Mosunjac, Marina; Geller, Rachel; Albizua, Igor; Stowell, Sean R.; Arthur, Connie M.; Anderson, Evan J.; Ivanova, Anna A.; Ahn, Jun; Liu, Xueyun; Maner-Smith, Kristal; Bowen, Thomas; Paiardini, Mirko; Bosinger, Steve E.; Roback, John D.; Kulpa, Deanna A.; Silvestri, Guido; Lam, Wilbur A.; Ortlund, Eric A.; Maier, Cheryl L.	Multiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19	https://doi.org/10.1038/s41467-023-37269-3	Published	2023-04-04	Study	https://www.nature.com/articles/s41467-023-37269-3	The pathogenesis of multi-organ dysfunction associated with severe acute SARS-CoV-2 infection remains poorly understood. Endothelial damage and microvascular thrombosis have been identified as drivers of COVID-19 severity, yet the mechanisms underlying these processes remain elusive. Here we show alterations in fluid shear stress-responsive pathways in critically ill COVID-19 adults as compared to non-COVID critically ill adults using a multiomics approach. Mechanistic in-vitro studies, using microvasculature-on-chip devices, reveal that plasma from critically ill COVID-19 adults induces fibrinogen-dependent red blood cell aggregation that mechanically damages the microvascular glycocalyx. This mechanism appears unique to COVID-19, as plasma from non-COVID sepsis patients demonstrates greater red blood cell membrane stiffness but induces less significant alterations in overall blood rheology. Multiomics analyses in pediatric patients with acute COVID-19 or the post-infectious multi-inflammatory syndrome in children (MIS-C) demonstrate little overlap in plasma cytokine and metabolite changes compared to adult COVID-19 patients. Instead, pediatric acute COVID-19 and MIS-C patients show alterations strongly associated with cytokine upregulation. These findings link high fibrinogen and red blood cell aggregation with endotheliopathy in adult COVID-19 patients and highlight differences in the key mediators of pathogenesis between adult and pediatric populations.
236	Ch234		Abdulaziz Alsufyani, Amal	Post-COVID-19 effect on biochemical parameters in children: Should we take heed?	https://doi.org/10.1016/j.sjbs.2023.103649	Published	2023-05-01	Study	https://www.sciencedirect.com/science/article/pii/S1319562X23000943	The aim of this research is to analyze the potential impact of the COVID-19 infection on the serum biochemical concentration of children 6 months after recovery from the infection. The study included 72 children with a median age of 11 years. The case group consisted of 37 children who had contracted COVID-19 6 months prior to the analysis. They reported no other pre- or post-covid chronic or systemic diseases. The control group consisted of 35 children who had no prior record of COVID-19 infection. The analysis showed a substantial variation (P = 0.026) in the mean urea values (mmol/L) between the case group (4.513 ± 0.839) and the control group (5.425 ± 1.173). However, both groups' urea levels were within the normal range of their age group. No statistical differences were found analyzing the variations between the two groups in the levels of LDH, AST, ALT, BiliT, GGT, AlbBCG2, CRP, CK, AlKP, UA, Phos, Crea2, Gluc, Ca, Na, K, Cl, TP, TC, TG, and HDL (P > 0.05). The DMFT score was substantially greater (P < 0.002) in the infected team (5.38 ± 2.841) in comparison to the non-infected group (2.6 ± 2.257). The study indicates that COVID-19 infection does not leave biochemical alterations among children who did not have pre-existing conditions. The biochemical analysis suggests that children recover better than adults from COVID-19. Furthermore, it calls for investigating non-lethal COVID-19 infection as a tool to discover underlying conditions. The DMFT score shows a correlation between COVID-19 infection and caries. However, the nature of the correlation is yet to be investigated.
237	Ch235		Mungmunpuntipantip, Rujittika; Wiwanitkit, Viroj	Long COVID in Children up to 12 y of Age – A Retrospective Telephonic Survey: Correspondence	https://doi.org/10.1007/s12098-023-04619-4	Published	2023-04-21	Letter to editor	https://doi.org/10.1007/s12098-023-04619-4	To the Editor: We would like to share ideas on the publication “Long COVID in children up to 12 y of age - A retrospective telephonic survey published in IJP [1].” Sah et al. conducted a telephonic survey to investigate the outcome of children hospitalized with COVID-19 infection in a tertiary care hospital in North India in terms of persistent symptoms [1]. In comparison to earlier research, Sah et al. discovered that the incidence of long-COVID was low in this telephone survey [1]. According to Sah et al., long-COVID data can impact vaccine policy for children and transform the perception of COVID-19 in children from a benign condition to one with the potential to create long-term chronic severe health consequences [1]. Long-COVID-19 has an issue that requires immediate action. Other critical difficulties must also be addressed. An important issue is that this study by Sah et al. validated the patients’ prior apparent clinical diagnosis, however, the patient could still have undetected co-morbid illnesses. Also the patients may have been given the second COVID-19 vaccine [2]. Earlier immunizations must be discussed as well. There must be sufficient evidence to reach a conclusion about how the illness affects health issues. One might believe that protracted COVID, also known as extended COVID-19, is not the major source of all symptoms experienced by a patient with the illness.
238	Ch236		Morello, Rosa; Mariani, Francesco; Mastrantoni, Luca; Rose, Cristina De; Zampino, Giuseppe; Munblit, Daniel; Sigfrid, Louise; Valentini, Piero; Buonsenso, Danilo	Risk factors for post-COVID-19 condition (Long Covid) in children: a prospective cohort study	https://doi.org/10.1016/j.eclinm.2023.101961	Published	2023-05-01	Study	https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00138-4/fulltext	Background Adults and children can develop post-Covid-19 condition (PCC) (also referred to as Long Covid). However, existing evidence is scarce, partly due to a lack of a standardised case definition, short follow up duration, and heterogenous study designs, resulting in wide variation of reported outcomes. The primary aim of this study was to characterise risk factors for PCC and longitudinal rates of recovery in a cohort of children and young people using a standardised protocol. Methods We performed a prospective “disease-based” cohort study between 01/02/2020 to 31/10/2022 including children aged 0–18 years old, with a previous diagnosis of Covid-19. Children with microbiologically confirmed SARS-CoV-2 infection, were invited for an in-clinic follow-up assessment at a paediatric post-covid clinic in Rome, Italy, at serial intervals (3-, 6-, 12- and 18-months post-onset). PCC was defined as persistence of otherwise unexplained symptoms for at least three months after initial infection. The statistical association between categorical variables was obtained by Chi-squared tests or Fisher's exact tests. Multivariable logistic regressions are presented using odds ratios (OR) and 95% confidence interval (CI). Survival analysis was conducted using the Kaplan–Meier method. Findings 1243 children were included, median age: 7.5 (4–10.3) years old; 575 (46.3%) were females. Of these, 23% (294/1243) were diagnosed with PCC at three months post-onset. Among the study population, 143 patients remained symptomatic at six months, 38 at 12 months, and 15 at 18 months follow up evaluation. The following risk factors were associated with PCC: >10 years of age (OR 1.23; 95% CI 1.18–1.28), comorbidities (OR 1.68; 95% CI 1.14–2.50), and hospitalisation during the acute phase (OR 4.80; 95%CI 1.91–12.1). Using multivariable logistic regression, compared to the Omicron variant, all other variants were significantly associated with PCC at 3 and 6 months. At least one dose of vaccine was associated with a reduced, but not statistically significant risk of developing PCC. Interpretation In our study, acute-phase hospitalisation, pre-existing comorbidity, being infected with pre-Omicron variants and older age were associated with a higher risk of developing PCC. Most children recovered over time, but one-in-twenty of those with PCC at three months reported persistent symptoms 18 months post-Sars-CoV-2 infection. Omicron infection was associated with shorter recovery times. We did not find a strong protective effect of vaccination on PCC development. Although our cohort cannot be translated to all Italian children with PCC as more nationwide studies are needed, our findings highlight the need of new strategies to prevent and treat pediatric PCC are needed. publisher: Elsevier PMID: 37073325
239	Ch237		Burns, Madeleine D.; Bartsch, Yannic C.; Davis, Jameson P.; Boribong, Brittany P.; Loiselle, Maggie; Kang, Jaewon; Kane, Abigail S.; Edlow, Andrea G.; Fasano, Alessio; Alter, Galit; Yonker, Lael M.	Long-term humoral signatures following acute pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children	https://doi.org/10.1038/s41390-023-02627-w	Published	2023-05-12	Study	https://www.nature.com/articles/s41390-023-02627-w	Background Although most children experience mild symptoms during acute SARS-CoV-2 infection, some develop the severe post-COVID-19 complication, Multisystem Inflammatory Syndrome in Children (MIS-C). While acute presentations of COVID-19 and MIS-C have been well immunophenotyped, little is known about the lasting immune profile in children after acute illness. Methods Children 2 months–20 years of age presenting with either acute COVID-19 (n = 9) or MIS-C (n = 12) were enrolled in a Pediatric COVID-19 Biorepository at a single medical center. We deeply profiled humoral immune responses and circulating cytokines following pediatric COVID-19 and MIS-C. Results Twenty-one children and young adults provided blood samples at both acute presentation and 6-month follow-up (mean: 6.5 months; standard deviation: 1.77 months). Pro-inflammatory cytokine elevations resolved after both acute COVID-19 and MIS-C. Humoral profiles continue to mature after acute COVID-19, displaying decreasing IgM and increasing IgG over time, as well as stronger effector functions, including antibody-dependent monocyte activation. In contrast, MIS-C immune signatures, especially anti-Spike IgG1, diminished over time. Conclusions Here, we show the mature immune signature after pediatric COVID-19 and MIS-C, displaying resolving inflammation with recalibration of the humoral responses. These humoral profiles highlight immune activation and vulnerabilities over time in these pediatric post-infectious cohorts. Impact The pediatric immune profile matures after both COVID-19 and MIS-C, suggesting a diversified anti-SARS-CoV-2 antibody response after resolution of acute illness. While pro-inflammatory cytokine responses resolve in the months following acute infection in both conditions, antibody-activated responses remain relatively heightened in convalescent COVID-19. These data may inform long-term immunoprotection from reinfection in children with past SARS-CoV-2 infections or MIS-C.
240	Ch238		Pinto Pereira, Snehal M.; Mensah, Anna; Nugawela, Manjula D.; Stephenson, Terence; Ladhani, Shamez N.; Dalrymple, Emma; Dudley, Jake; McOwat, Kelsey; Simmons, Ruth; Heyman, Isobel; Segal, Terry; Semple, Malcolm G.; Xu, Laila; Shafran, Roz; Buszewicz, Marta; Chalder, Trudie; Crawley, Esther; De Stavola, Bianca; Ford, Tamsin; Garg, Shruti; Harnden, Anthony; Hargreaves, Dougal; Levin, Michael; Poustie, Vanessa; Semple, Calum; Sharma, Kishan; Swann, Olivia; Whittaker, Elizabeth	Long COVID in Children and Youth After Infection or Reinfection with the Omicron Variant: A Prospective Observational Study	https://doi.org/10.1016/j.jpeds.2023.113463	Published	2023-05-11	Study	https://www.sciencedirect.com/science/article/pii/S0022347623003116	To describe the prevalence of long COVID in children infected for the first time (n=332) or reinfected (n=243) with Omicron variant SARS-CoV-2, compared with test-negative children (n=311). 12-16% infected with Omicron met the research definition of long COVID at 3 and 6 months after infection, with no evidence of difference between cases of first-positive and reinfection (pchi-square=0.17).
241	Ch239		Rybkina, Ksenia; Bell, Joseph N.; Bradley, Marissa C.; Wohlbold, Teddy; Scafuro, Marika; Meng, Wenzhao; Korenberg, Rebecca C.; Davis-Porada, Julia; Anderson, Brett R.; Weller, Rachel J.; Milner, Joshua D.; Moscona, Anne; Porotto, Matteo; Luning Prak, Eline T.; Pethe, Kalpana; Connors, Thomas J.; Farber, Donna L.	SARS-CoV-2 infection and recovery in children: Distinct T cell responses in MIS-C compared to COVID-19	https://doi.org/10.1084/jem.20221518	Published	2023-05-03	Study	https://doi.org/10.1084/jem.20221518	SARS-CoV-2 infection for most children results in mild or minimal symptoms, though in rare cases severe disease can develop, including a multisystem inflammatory syndrome (MIS-C) with myocarditis. Here, we present longitudinal profiling of immune responses during acute disease and following recovery in children who developed MIS-C, relative to children who experienced more typical symptoms of COVID-19. T cells in acute MIS-C exhibited transient signatures of activation, inflammation, and tissue residency which correlated with cardiac disease severity, while T cells in acute COVID-19 upregulated markers of follicular helper T cells for promoting antibody production. The resultant memory immune response in recovery showed increased frequencies of virus-specific memory T cells with pro-inflammatory functions in children with prior MIS-C compared to COVID-19 while both cohorts generated comparable antibody responses. Together our results reveal distinct effector and memory T cell responses in pediatric SARS-CoV-2 infection delineated by clinical syndrome, and a potential role for tissue-derived T cells in the immune pathology of systemic disease.
242	Ch240		Dash, Nabaneeta; Verma, Sanjay	Long COVID in Children up to 12 y of Age – A Retrospective Telephonic Survey: Author’s Reply	https://doi.org/10.1007/s12098-023-04620-x	Published	2023-05-02	Letter to editor	https://doi.org/10.1007/s12098-023-04620-x	To the Editor: We thank Mungmunpuntipantip and Wiwanikit for their comments and reflections on our paper [1, 2]. We understand that they are concerned regarding the lower incidence of long-COVID in our study subjects and the effect of underlying disease on diagnosis of long-COVID. We agree with them that the incidence in our survey was lower as compared to other studies done mostly from developed countries [3]. We have already mentioned in our paper the various factors which might be responsible for the lower incidence like exclusion of older children, difference in methodology of study, cultural factors, and duration of follow-up. This study was only a telephonic survey and was done to sensitize treating physicians that long-COVID can be seen in Indian children too, and population-based surveys would be required to determine actual incidence and prevalence of this entity in our population. We agree with the authors that underlying co-morbidities can influence the symptoms of long- COVID. But in our cohort, the 3 children who had persistent symptoms following diagnosis of acute COVID-19 illness did not have any underlying co-morbidities. Hence we feel that larger prospective surveys are required to provide a more definitive answer to the pertinent questions on incidence and prevalence of long-COVID in pediatric age group, especially in developing country like ours.
243	Ch241		Saniasiaya, Jeyasakthy	Vestibular migraine: a manifestation of long COVID syndrome in children	https://doi.org/10.1136/bcr-2023-255734	Published	2023-05-01	Case Report	https://casereports.bmj.com/content/16/5/e255734	Long COVID-19 syndrome has been reported among children and adolescents following COVID-19 recovery. Among them, notable symptoms include myalgia, insomnia, loss of smell and headache. Yet, novel manifestations are being discovered daily. Herein, we report two cases of vestibular migraine post-COVID-19 involving two children who presented with vestibular migraine symptoms following COVID-19 infection and their management. Children post-COVID-19 should be thoroughly evaluated for vestibular migraine symptoms so they can be managed promptly. This is the first article to report vestibular migraine as a manifestation of long COVID-19 syndrome.
244	Ch242		Hassan, Nurulhuda Mat; Salim, Hani Syahida; Amaran, Safiya; Yunus, Nurul Izza; Yusof, Nurul Azreen; Daud, Norwati; Fry, Deborah	Prevalence of mental health problems among children with long COVID: A systematic review and meta-analysis	https://doi.org/10.1371/journal.pone.0282538	Published	2023-05-17	Systematic review and meta-analysis	https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0282538	Introduction The number of children with mental health problems has more than doubled since the COVID-19 pandemic. However, the effect of long Covid on children’s mental health is still debatable. Recognising long Covid as a risk factor for mental health problems in children will increase awareness and screening for mental health problems following COVID-19 infection, resulting in earlier intervention and lower morbidity. Therefore, this study aimed to determine the proportion of mental health problems post-COVID-19 infection in children and adolescents, and to compare them with the population with no previous COVID-19 infection. Methodology A systematic search was done in seven databases using pre-defined search terms. Cross-sectional, cohort and interventional studies reporting the proportion of mental health problems among children with long COVID in the English language from 2019 to May 2022 were included. Selection of papers, extraction of data and quality assessment were done independently by two reviewers. Studies with satisfactory quality were included in meta-analysis using R and Revman software programmes. Results The initial search retrieved 1848 studies. After screening, 13 studies were included in the quality assessments. Meta-analysis showed children who had previous COVID-19 infection had more than two times higher odds of having anxiety or depression, and 14% higher odds of having appetite problems, compared to children with no previous infection. The pooled prevalence of mental health problems among the population were as follows; anxiety: 9%(95% CI:1, 23), depression: 15%(95% CI:0.4, 47), concentration problems: 6%(95% CI: 3, 11), sleep problems: 9%(95% CI:5, 13), mood swings: 13% (95%CI:5, 23) and appetite loss: 5%(95% CI:1, 13). However, studies were heterogenous and lack data from low- and middle-income countries. Conclusion Anxiety, depression and appetite problems were significantly increased among post-COVID-19 infected children, compared to those without a previous infection, which may be attributed to long COVID. The findings underscore the importance of screening and early intervention of children post-COVID-19 infection at one month and between three to four months.
245	Ch243		AbdelMassih, Antoine; Hanafy, Maram; Elahmady, Maryam; Kozman, Sylvia; Diab, Nourine; Husseiny, Reem; Deyab, Ashrakat; Mady, Aalaa; Yasser, Alia; R.AbdelHalim, Amira; Mohyeldin, Aya; Abdelgadir, Ayat; Abdelaziz, Eslam; Elghamry, Farida; Shehata, Hana; Milad, Karim; Fouda, Lamya; Hesham, Mawada; Adly, Mina; Omar, Yasmin	Non-Multisystem Inflammatory Syndrome in Children—Postacute Sequelae of Paediatric COVID-19: Autoimmune or Autoinflammatory? A Systematic Review of the Reported Cases	https://doi.org/10.3390/rheumato3020011	Published	2023-05-30	Review	https://www.mdpi.com/2674-0621/3/2/11	Three years after its emergence, coronavirus disease 2019 (COVID-19) continues to be a leading cause of worldwide morbidity and mortality. This systematic review comprises relevant case reports that discuss non-multisystem inflammatory syndrome in children (non-MIS-C) and postacute sequalae of COVID-19 (PASC) in the paediatric population, also known as long COVID syndrome. The study aims to highlight the prevalent time interval between COVID-19 and the development of non-MIS-C post-infectious sequalae (PIS). Databases were searched for studies that met our inclusion and exclusion criteria. The final screening revealed an equal sex distribution where the commonest age intervals were school-age and adolescence, with 38% of the patients being older than six years. Interestingly, hospital admission during the course of COVID-19 was not a predictor of the subsequent PASC; forty-nine patients (44.9%) were hospitalized while sixty patients (55.1%) were not hospitalized. Moreover, the most predominant time interval between COVID-19 and the developing PASC was within 14 days from the start of COVID-19 infection (61%). These findings suggest a crucial link between COVID-19 and immune PIS in the paediatric population, especially those older than six years. Accordingly, follow-up and management are encouraged in case of unusual symptoms and signs following COVID-19 infection, regardless of the COVID-19 infection severity.

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1	Ref	PPLC	Authors	Title	DOI	Peer reviewed	Date	type	Link	Keys	Clés

2	MO01		Andrea Dennis, Malgorzata Wamil, Sandeep Kapur, Johann Alberts, Andrew D. Badley	Multi-organ impairment in low-risk individuals with long COVID	https://doi.org/10.1101/2020.10.14.20212555	pre-print	October 16, 2020	Study	https://www.medrxiv.org/content/10.1101/2020.10.14.20212555v1	A preprint study (not yet peer reviewed) recruiting patients with post-covid symptoms shows 2/3 the presence of deficiencies in at least one organ. Heart / lungs: 1/3 Pancreas: 1/6 Kidneys / liver: 1/10 Rate: 1/20 In a young, low-risk population with ongoing symptoms, almost 70% of individuals have impairment in one or more organs four months after initial symptoms of SARS-CoV-2 infection The cohort is 201 patients (70% women), with an average age of 44 years, who were followed for a median of 140 days after the first symptoms. The prevalence of pre-existing morbidity is moderate (obesity: 20%, hypertension: 6%, diabetes: 2%, heart disease: 4%). The most common symptoms are fatigue (98%), muscle pain (88%), shortness of breath (87%), headaches (83%). The impariments concern the heart (32%), the lungs (33%), the kidneys (12%), the liver (10%), the pancreas (17%), the spleen (6%).	Une étude en preprint (non encore relue par les pairs) qui recrutent des patients ayant des symptômes post-covid fait apparaître pour les 2/3 la présence de déficiences sur au moins un organe. Cœur/poumons : 1/3 Pancréas : 1/6 Reins/foie : 1/10 Rate : 1/20 La cohorte est de 201 patients (70% de femmes), de moyenne d'âge 44 ans, qui ont été suivis sur une médiane de 140 jours après les premiers symptômes. La prévalence de morbidité préexistante est modérée (obésité : 20%, hypertension : 6%, diabète : 2%, maladie cardiaque : 4%). Les symptômes les + fréquents sont l'état d'épuisement (98%), douleurs musculaires (88%), essoufflement (87%), migraine (83%). Les déficiences concernent le cœur (32%), les poumons (33%), les reins (12%), le foie (10%), le pancréas (17%), la rate (6%).
3	MO02		Carole H. Sudre, Benjamin Murray, Thomas Varsavsky, Mark S. Graham, Tim Spector, Claire J. Steves	Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App	https://doi.org/10.1038/s41591-021-01292-y	Published	Preprint le 10/21/2020 Dans Nature le 10 March 2021	Article	https://www.nature.com/articles/s41591-021-01292-y anciennement https://www.medrxiv.org/content/10.1101/2020.10.19.20214494v1	@Timspector's study from @KingsCollegeLon, based on feedback from the COVID Symptom Study app, reports symptoms ≥1 months for 13-14% of participants, ≥3 months for 2.3%, with uncertainties : The study, which is in pre-print (not yet reviewed or published in a journal), qualifies these estimates as conservative, recognizing a series of biases that may under- or overestimate these impacts. . 558 (13.3%) had symptoms lasting >28 days, 189 (4.5%) for >8 weeks 39 and 95 (2.3%) for >12 weeks. Long-COVID was characterised by symptoms of fatigue, It is made available under a CC-BY-NC-ND 4.0 International license .(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. medRxiv preprint doi: https://doi.org/10.1101/2020.10.19.20214494; this version posted October 21, 2020. The copyright holder for this preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 40 headache, dyspnoea and anosmia and was more likely with increasing age, BMI and female 41 sex. Experiencing more than five symptoms during the first week of illness was associated 42 with Long-COVID, OR=3.53 [2.76;4.50]	L'étude de @timspector du @KingsCollegeLon, basée sur les retours de l'appli "COVID Symptom Study", rapporte des symptômes ≥1 mois pour 13-14% des participants, ≥3 mois pour 2,3%, avec des incertitudes. L'étude qualifie ces estimations de prudentes, reconnaissant une série de biais pouvant sous- ou sur-estimer ces incidences.
4	MO03		Gareth Iacobucci	Long covid: Damage to multiple organs presents in young, low risk patients	https://doi.org/10.1136/bmj.m4470	Article publié sur un pre-print	November 17, 2020	News	https://www.bmj.com/content/371/bmj.m4470	Young patients, at low risk, who keep symptoms after an acute phase (only 18% with hospitalization), mainly present deficiencies in one or more organs, according to a study reviewed at the BMJ.	Les patients jeunes, à faible risque, qui gardent des symptômes après une phase aiguë, (seulement 18% avec hospitalisation), présentent majoritairement des déficiences à un ou plusieurs organes, selon une étude en relecture au BMJ. (https://www.medrxiv.org/content/10.1101/2020.10.14.20212555v1)
5	MO04		Melvin R. Hayden	An Immediate and Long-Term Complication of COVID-19 May Be Type 2 Diabetes Mellitus: The Central Role of β-Cell Dysfunction, Apoptosis and Exploration of Possible Mechanisms	https://doi.org/10.3390/cells9112475	Published	13 November 2020	Review	https://www.mdpi.com/2073-4409/9/11/2475	A fairly technical study is concerned about the possibility that covid amplifies, or causes, type 2 diabetes in the long term. It describes the processes and phenomena that could come into play.	Une étude assez technique s'inquiète de la possibilité que la covid amplifie, ou provoque, des diabètes de type 2 sur le long terme. Elle décrit les processus et phénomènes qui pourraient entrer en jeu.
6	MO05		Victoria Higgins,Dorsa Sohaei,Eleftherios P. Diamandis &Ioannis Prassas	COVID-19: from3 an acute to chronic disease? Potential long-term health consequences	https://doi.org/10.1080/10408363.2020.1860895	Published	21 Dec 2020	Review	https://www.tandfonline.com/doi/full/10.1080/10408363.2020.1860895		Une revue de la littérature sur les différents aspects d'atteintes aux organes sur le long terme de la covid. •Pulmonary manifestations •Cardiovascular " •Hematologic " •Renal " •Central nervous system " •Post-Intensive care syndrome •Psychosocial "	N001R
7	MO06		Satish Kumar Sharma Iqra Rahat	A pathophysiological review on understanding multiorgan effects of COVID-19		Published	Dec 2020	Review	https://ejmcm.com/article_3640.html		_
8	MO07		Robert J. Rolfe, Colin M. Smith and Cameron R. Wolfe	The Emerging Chronic Sequelae of COVID-19 and Implications for North Carolina	https://doi.org/10.18043/ncm.82.1.75	Published	January 2021	Research Article	https://www.ncmedicaljournal.com/content/82/1/75.full		Avec l'expérience du SRAS et du MERS, une étude en Caroline du Nord s'intéresse aux séquelles à long terme de la covid, répercutées sur plusieurs organes, et notamment les séquelles neuro-psychiatriques et cérébrovasculaires.	N001R
9	MO08		KM Capaccione, MD, PhD # H Yang, MD E West, MD E Desperito, MD C Ruzal-Shapiro, MD MM Salvatore	Pathophysiology and Imaging Findings of COVID-19 Infection: An Organ-System Based Review	https://doi.org/10.1016/j.acra.2021.01.022	Published	February 03, 2021	REVIEW ARTICLE	https://www.academicradiology.org/article/S1076-6332(21)00031-3/fulltext	Though pulmonary findings are the most prevalent presentation, COVID-19 may have multiple manifestations and recognition of the extrapulmonary manifestations is especially important because of the potential serious and long-term effects of COVID-19 on multiple organ systems.	Les caractéristiques radiologiques en imagerie médicale de la covid sur un ensemble d'organes sont détaillées dans cette revue d'études, pointant des séquelles à long terme de l'infection.	N002
10	MO09		Mingchao Zhu, Diliang Chen, Ya Zhu, Xusheng Xiong, Yan Ding, Feibo Guo, Mingan Zhu & Junyang Zhou	Long-term sero-positivity for IgG, sequelae of respiratory symptoms, and abundance of malformed sperms in a patient recovered from severe COVID-19	https://doi.org/10.1007/s10096-021-04178-6	Published	08 February 2021	Brief Report	https://link.springer.com/article/10.1007/s10096-021-04178-6	The patient’s antiviral immunoglobulin G (IgG) continued to be positive for more than 11 months, and his small airway function was abnormal, and he suffered from respiratory problems (cough, chest pain, chest tightness, and shortness of breath), unstructured sleep apnea hypopnea syndrome, and nocturnal sleep hypoxemia. His abnormal sperm rate increased obviously, and sperm activity decreased obviously.	Des altérations des spermatozoïdes dues à la covid sont possibles, comme en témoigne cette étude de cas d'un patient touché par un taux de 96% de déformation des spermatozoïdes et d'une tératospermie.	N003R2
11	MO10		Sandra Willia b Renata Lüthold b Adam Hunt b Nadescha Viviane Hänggi b Donikë Sejdiu b Camila Scaff b Nicole Bender b1 Kaspar Staub Patricia Schlagenhauf	COVID-19 Sequelae in adults aged less than 50 years: A Systematic Review	https://doi.org/10.1016/j.tmaid.2021.101995	Published	22 February 2021	Review	https://www.sciencedirect.com/science/article/pii/S1477893921000363	Sequelae persistence since infection spanned 14 days to three months. Sequelae included persistent fatigue (39–73% of assessed persons), breathlessness (39–74%), decrease in quality of life (44–69%), impaired pulmonary function, abnormal CT findings including pulmonary fibrosis (39–83%), evidence of peri-/perimyo-/myocarditis (3–26%), changes in microstructural and functional brain integrity with persistent neurological symptoms (55%), increased incidence of psychiatric diagnoses (5.8% versus 2.5–3.4% in controls), incomplete recovery of olfactory and gustatory dysfunction (33–36% of evaluated persons).	Une revue d'études systématique des différentes séquelles à 3 mois chez les adultes de moins de 50 ans touchés par la covid, qui note l'importance des séquelles pulmonaires, cardiaques et neurologiques.	N003A
12	MO11		Jia Liu, Yufeng Li, Qian Liu, Qun Yao, Xi Wang, Huanyu Zhang, Rong Chen, Liang Ren, Juan Min, Fei Deng, Bing Yan, Liang Liu, Zhihong Hu, Manli Wang & Yiwu Zhou	SARS-CoV-2 cell tropism and multiorgan infection	https://doi.org/10.1038/s41421-021-00249-2	Published	23 March 2021		https://www.nature.com/articles/s41421-021-00249-2	In conclusion, our results identified SARS-CoV-2 cell tropism in multiple organs (Fig. 1e), indicating that SARS-CoV-2 infects not only the respiratory system (e.g., lungs and trachea) but also the kidneys, small intestines, pancreas, blood vessels, and other tissues. Recently, we disclosed that SARS-CoV-2 also targeted sweat glands and vascular endothelial cells in the skin15. These findings suggest that direct viral infection could, at least partially, contribute to multiorgan injury. Our results also proved a possible correlation between SARS-CoV-2 organotropism and ACE2 distribution, providing supporting evidence for the multiorgan infection of the virus. While our study was limited by its size, its sheds new light into the mechanism of viral infection/transmission and provides valuable information for COVID-19 control.	Un travail dans Nature relève des preuves indiquant que le système gastro-intestinal pourrait servir de voie de transmission du SARS-CoV-2 et avoir un effet d'amplification. L'étude note les cibles potentielles du virus, outre le système respiratoire : reins, intestin grêle, pancréas, vaisseaux sanguins, ainsi que d'autres organes et tissus évoqués plus récemment, comme les glandes sudoripares et les cellules endothéliales vasculaires de la peau.	N011
13	MO12		Daniel Ayoubkhani, principal statistician1, Kamlesh Khunti, professor of primary care diabetes and vascular medicine2, Vahé Nafilyan, principal statistician1, Thomas Maddox, statistician1, Ben Humberstone, deputy director of health analysis and life events division1, Ian Diamond, UK national statistician1, Amitava Banerjee	Post-covid syndrome in individuals admitted to hospital with covid-19: retrospective cohort study	https://doi.org/10.1136/bmj.n693	Published	31 March 2021		https://www.bmj.com/content/372/bmj.n693.full	Over a mean follow-up of 140 days, nearly a third of individuals who were discharged from hospital after acute covid-19 were readmitted (14 060 of 47 780) and more than 1 in 10 (5875) died after discharge, with these events occurring at rates four and eight times greater, respectively, than in the matched control group. Rates of respiratory disease (P<0.001), diabetes (P<0.001), and cardiovascular disease (P<0.001) were also significantly raised in patients with covid-19, with 770 (95% confidence interval 758 to 783), 127 (122 to 132), and 126 (121 to 131) diagnoses per 1000 person years, respectively. Rate ratios were greater for individuals aged less than 70 than for those aged 70 or older, and in ethnic minority groups compared with the white population, with the largest differences seen for respiratory disease (10.5 (95% confidence interval 9.7 to 11.4) for age less than 70 years v 4.6 (4.3 to 4.8) for age ≥70, and 11.4 (9.8 to 13.3) for non-white v 5.2 (5.0 to 5.5) for white individuals). Conclusions Individuals discharged from hospital after covid-19 had increased rates of multiorgan dysfunction compared with the expected risk in the general population. The increase in risk was not confined to the elderly and was not uniform across ethnicities. The diagnosis, treatment, and prevention of post-covid syndrome requires integrated rather than organ or disease specific approaches, and urgent research is needed to establish the risk factors	_
14							From this point on, the survey of studies is no longer as exhaustive as possible. Only those studies which seem to us to bring significant new elements will be listed.
15	MO13		Vinod Nikhra	COVID-19 and Long Covid: Organs Damage and Dysfunctions, and Implications for Clinical Course	http://dx.doi.org/10.29328/ebook1005	Published	October 2021	Article	https://www.researchgate.net/publication/355582623_COVID-19_and_Long_Covid_Organs_Damage_and_Dysfunctions_and_Implications_for_Clinical_Course	Like any other infectious disease, the prognosis of COVID-19 is in􀏐luenced by infecting agent, the SARS-CoV-2 virus load and the extent of organs af􀏐liction and damage. COVID-19 having a propensity for multiorgan involvement carries an adverse prognosis during the clinical course as well as later during the post-recovery period persisting as Long Covid. The direct cytopathic effects of SARS-CoV-2 virus and the erratic and hyper-in􀏐lammatory response lead to tissue injury in various organs coupled with physiological dysfunctions and complications. In fact, the multi-system manifestations of COVID-19 are caused by a combination of speci􀏐ic host defence responses with associated in􀏐lammatory activity and vascular involvement with coagulopathy and a distinct propensity to develop thromboembolic complications. Simultaneously, comorbidities such as diabetes, hypertension and cardiovascular diseases in􀏐luence the disease severity and mortality.
16	MO14		Jude Savarraj, Eun S. Park, Gabriela D. Colpo, Sarah N. Hinds, Diego Morales, Hilda Ahnstedt, Atzhiry S. Paz, Andres Assing, Fudong Liu, Shivanki Juneja, Eunhee Kim, Sung-min Cho, Aaron M. Gusdon, Pramod Dash, Louise D. McCullough & H. Alex Choi	Brain injury, endothelial injury and inflammatory markers are elevated and express sex-specific alterations after COVID-19	https://doi.org/10.1186/s12974-021-02323-8	Published	27 November 2021	Study	https://link.springer.com/article/10.1186/s12974-021-02323-8	The acute elevation of BIMs, CCs, and EIMs and the robust associations among them at COVID-19 hospitalization are suggestive of brain and endothelial injury. Higher BIM and inflammatory markers in men additionally suggest that men are more susceptible to the risk compared to women.
17	MO15	VP	Akmaljon Odilov 1,* ,Alexey Volkov 1,2 ,Adhamjon Abdullaev 3 ,Tatiana Gasanova 4 ,Tatiana Lipina 5 andIgor Babichenko 1	COVID-19: Multiorgan Dissemination of SARS-CoV-2 Is Driven by Pulmonary Factors	https://doi.org/10.3390/v14010039	Published	26 December 2021	Study	https://www.mdpi.com/1999-4915/14/1/39/htm	Multi-organ failure is one of the common causes of fatal outcome in COVID-19 patients. However, the pathogenetic association of the SARS-CoV-2 viral load (VL) level with fatal dysfunctions of the lungs, liver, kidneys, heart, spleen and brain, as well as with the risk of death in COVID-19 patients remains poorly understood. SARS-CoV-2 VL in the lungs, heart, liver, kidneys, brain, spleen and lymph nodes have been measured by RT qPCR using the following formula: NSARS-CoV−2/NABL1 × 100. Dissemination of SARS-CoV-2 in 30.5% of cases was mono-organ, and in 63.9% of cases, it was multi-organ. The average SARS-CoV-2 VL in the exudative phase of diffuse alveolar damage (DAD) was 60 times higher than in the proliferative phase. The SARS-CoV-2 VL in the lungs ranged from 0 to 250,281 copies. The “pulmonary factors” of SARS-CoV-2 multi-organ dissemination are the high level of SARS-CoV-2 VL (≥4909) and the exudative phase of DAD. The frequency of SARS-CoV-2 dissemination to lymph nodes was 86.9%, heart–56.5%, spleen–52.2%, liver–47.8%, kidney–26%, and brain–13%. We found no link between the SARS-CoV-2 VL level in the liver, kidneys, and heart and the serum level of CPK, LDH, ALP, ALT, AST and Cr of COVID-19 patients. Isolated detection of SARS-CoV-2 RNA in the myocardium of COVID-19 patients who died from heart failure is possible. The pathogenesis of COVID-19-associated multi-organ failure requires further research in a larger cohort of patients.
18	MO16		Jovana Milic, Sara Barbieri, Licia Gozzi, Alberto Brigo, Bianca Beghé, Alessia Verduri, Erica Bacca, Vittorio Iadisernia, Gianluca Cuomo, Giovanni Dolci, Dina Yaacoub, Emanuele Aprile, Michella Belli, Maria Venuta, Marianna Meschiari, Giada Sebastiani, Enrico Clini, Cristina Mussini, Amedeo Lonardo, Giovanni Guaraldi, Paolo Raggi	Metabolic associated fatty liver disease is highly prevalent in the post-acute COVID syndrome	https://doi.org/10.1093/ofid/ofac003	Published	10 January 2022	Study	https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofac003/6501509	We included 235 patients followed at a single university outpatient clinic. The diagnosis of PACS was based on ≥1 cluster of symptoms: respiratory, neurocognitive, musculoskeletal, psychological, sensory, dermatological. The outcome was prevalence of MAFLD detected by transient elastography during the first post-discharge follow-up outpatient visit. The prevalence of MAFLD at the time of hospital admission was calculated retrospectively using the hepatic steatosis index. Results Of 235 patients, 162 (69%) were men (median age 61). The prevalence of MAFLD was 55.3% at follow-up and 37.3% on admission (p<0.001). Insulin resistance (OR=1.5, 95%CI: 1.14-1.96), body mass index (OR=1.14, 95%CI: 1.04-1.24), and the metabolic syndrome (OR=2.54, 95%CI: 1.13-5.68), were independent predictors of MAFLD. The number of PACS clusters was inversely associated with MAFLD (OR=0.86, 95%CI: 0.76-0.97). Thirty-one patients (13.2%) had MAFLD with no other associated PACS clusters. All correlations between MAFLD and other PACS clusters were weak. Conclusions MAFLD was highly prevalent after hospital discharge and may represent a specific PACS-cluster phenotype, with potential long-term metabolic and cardiovascular health implications.
19	MO17		Peter Novak MD, PhD,Shibani S. Mukerji MD, PhD,Haitham S. Alabsi DO,David Systrom MD,Sadie P. Marciano PA-C,Donna Felsenstein MD,William J. Mullally MD,David M. Pilgrim MD	Multisystem Involvement in Post-Acute Sequelae of Coronavirus Disease 19	https://doi.org/10.1002/ana.26286	Published	24 December 2021	Study	https://onlinelibrary.wiley.com/doi/10.1002/ana.26286	Summary Post-acute sequelae of coronavirus disease 2019 (COVID-19; PASC) is a complication of COVID-19 disease associated with chronic fatigue, brain fog and orthostatic intolerance. Pathophysiology of PASC is poorly understood. This study evaluated patients with PASC following mild COVID-19 infection using standardized autonomic assessments, including Valsalva maneuver, deep breathing, sudomotor and tilt tests with cerebral blood flow velocity (CBFv) measurements, and skin biopsies for small fiber neuropathy (SFN). This study showed that PASC following mild COVID-19 is associated with multisystem involvement, including cerebrovascular and respiratory dysregulation, small fiber neuropathy, and related dysautonomia and chronic inflammation. Autonomic testing expanded for cerebrovascular measurements and skin biopsies can explain some of the PASC symptoms and could guide treatment. Objective The purpose of this study was to describe cerebrovascular, neuropathic, and autonomic features of post-acute sequelae of coronavirus disease 2019 ((COVID-19) PASC). Methods This retrospective study evaluated consecutive patients with chronic fatigue, brain fog, and orthostatic intolerance consistent with PASC. Controls included patients with postural tachycardia syndrome (POTS) and healthy participants. Analyzed data included surveys and autonomic (Valsalva maneuver, deep breathing, sudomotor, and tilt tests), cerebrovascular (cerebral blood flow velocity [CBFv] monitoring in middle cerebral artery), respiratory (capnography monitoring), and neuropathic (skin biopsies for assessment of small fiber neuropathy) testing and inflammatory/autoimmune markers. Results Nine patients with PASC were evaluated 0.8 ± 0.3 years after a mild COVID-19 infection, and were treated as home observations. Autonomic, pain, brain fog, fatigue, and dyspnea surveys were abnormal in PASC and POTS (n = 10), compared with controls (n = 15). Tilt table test reproduced the majority of PASC symptoms. Orthostatic CBFv declined in PASC (−20.0 ± 13.4%) and POTS (−20.3 ± 15.1%), compared with controls (−3.0 ± 7.5%, p = 0.001) and was independent of end-tidal carbon dioxide in PASC, but caused by hyperventilation in POTS. Reduced orthostatic CBFv in PASC included both subjects without (n = 6) and with (n = 3) orthostatic tachycardia. Dysautonomia was frequent (100% in both PASC and POTS) but was milder in PASC (p = 0.002). PASC and POTS cohorts diverged in frequency of small fiber neuropathy (89% vs 60%) but not in inflammatory markers (67% vs 70%). Supine and orthostatic hypocapnia was observed in PASC. Interpretation PASC following mild COVID-19 infection is associated with multisystem involvement including: (1) cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction; (2) small fiber neuropathy and related dysautonomia; (3) respiratory dysregulation; and (4) chronic inflammation. ANN NEUROL 2022
20	MO18		Shunya Tsuji, Shohei Minami, Rina Hashimoto, Yusuke Konishi, Tatsuya Suzuki, Tamae Kondo, Miwa Sasai, Shiho Torii, Chikako Ono, Shintaro Shichinohe, Shintaro Sato, Masahiro Wakita, Shintaro Okumura, Sosuke Nakano, Tatsuyuki Matsudaira, Tomonori Matsumoto, Shimpei Kawamoto, Masahiro Yamamoto, Tokiko Watanabe, Yoshiharu Matsuura, Kazuo Takayama, Takeshi Kobayashi, Toru Okamoto & Eiji Hara	SARS-CoV-2 infection triggers paracrine senescence and leads to a sustained senescence-associated inflammatory response	https://doi.org/10.1038/s43587-022-00170-7	Published	25 January 2022	Study	https://www.nature.com/articles/s43587-022-00170-7	Reports of post-acute COVID-19 syndrome, in which the inflammatory response persists even after SARS-CoV-2 has disappeared, are increasing1, but the underlying mechanisms of post-acute COVID-19 syndrome remain unknown. Here, we show that SARS-CoV-2-infected cells trigger senescence-like cell-cycle arrest2,3 in neighboring uninfected cells in a paracrine manner via virus-induced cytokine production. In cultured human cells or bronchial organoids, these SASR-CoV-2 infection-induced senescent cells express high levels of a series of inflammatory factors known as senescence-associated secretory phenotypes (SASPs)4 in a sustained manner, even after SARS-CoV-2 is no longer detectable. We also show that the expression of the senescence marker CDKN2A (refs. 5,6) and various SASP factor4 genes is increased in the pulmonary cells of patients with severe post-acute COVID-19 syndrome. Furthermore, we find that mice exposed to a mouse-adapted strain of SARS-CoV-2 exhibit prolonged signs of cellular senescence and SASP in the lung at 14 days after infection when the virus was undetectable, which could be substantially reduced by the administration of senolytic drugs7. The sustained infection-induced paracrine senescence described here may be involved in the long-term inflammation caused by SARS-CoV-2 infection.
21	MO19		Maryam Kaviani1†, www.frontiersin.orgSomayeh Keshtkar1,2†, www.frontiersin.orgSaeede Soleimanian1, www.frontiersin.orgFatemeh Sabet Sarvestani1, www.frontiersin.orgNegar Azarpira1* and www.frontiersin.orgSara Pakbaz3	Susceptibility to Metabolic Diseases in COVID-19: To be or Not to be an Issue	https://doi.org/10.3389/fmolb.2022.803314	Published	03 February 2022	Review	https://www.frontiersin.org/articles/10.3389/fmolb.2022.803314/full	Although COVID-19 primarily affects the lungs, multiple reports exist on the effect of this infection on the kidneys, cardiovascular system, and gastrointestinal tract. Studies have also indicated the increased risk of severe COVID-19 in patients with diabetes. On the other hand, COVID-19 may predispose patients to diabetes, as the most common metabolic disease. Recent studies have shown that Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) binds to Angiotensin-Converting Enzyme 2 (ACE2) receptors, which are expressed in the tissues and organs involved in regulating the metabolic status including pancreas, adipose tissue, gastrointestinal tract, and kidneys. Therefore, SARS-CoV-2 may result in metabolic disturbance. However, there are still many unknowns about SARS-CoV-2, which are required to be explored in basic studies. In this context, special attention to molecular pathways is warranted for understanding the pathogenesis of the disease and achieving therapeutic opportunities. Hence, the present review aims to focus on the molecular mechanisms associated with the susceptibility to metabolic diseases amongst patients recovered from COVID-19.
22	MO20		Tom Norris ORCHID logo ; Cameron Razieh; Thomas Yates; Francesco Zaccardi; Clare L. Gillies; Yogini V. Chudasama ORCHID logo ; Alex Rowlands; Melanie J. Davies; Gerry P. McCann; Amitava Banerjee; Annemarie B. Docherty; Peter J.M. Openshaw; J. Kenneth Baillie; Malcolm G. Semple; Claire A. Lawson; Kamlesh Khunti	Admission Blood Glucose Level and Its Association With Cardiovascular and Renal Complications in Patients Hospitalized With COVID-19	https://doi.org/10.2337/dc21-1709	Published	March 11 2022	Study	https://diabetesjournals.org/care/article/doi/10.2337/dc21-1709/144732	To investigate the association between admission blood glucose levels and risk of in-hospital cardiovascular and renal complications. RESEARCH DESIGN AND METHODS In this multicenter prospective study of 36,269 adults hospitalized with COVID-19 between 6 February 2020 and 16 March 2021 (N = 143,266), logistic regression models were used to explore associations between admission glucose level (mmol/L and mg/dL) and odds of in-hospital complications, including heart failure, arrhythmia, cardiac ischemia, cardiac arrest, coagulation complications, stroke, and renal injury. Nonlinearity was investigated using restricted cubic splines. Interaction models explored whether associations between glucose levels and complications were modified by clinically relevant factors. RESULTS Cardiovascular and renal complications occurred in 10,421 (28.7%) patients; median admission glucose level was 6.7 mmol/L (interquartile range 5.8–8.7) (120.6 mg/dL [104.4–156.6]). While accounting for confounders, for all complications except cardiac ischemia and stroke, there was a nonlinear association between glucose and cardiovascular and renal complications. For example, odds of heart failure, arrhythmia, coagulation complications, and renal injury decreased to a nadir at 6.4 mmol/L (115 mg/dL), 4.9 mmol/L (88.2 mg/dL), 4.7 mmol/L (84.6 mg/dL), and 5.8 mmol/L (104.4 mg/dL), respectively, and increased thereafter until 26.0 mmol/L (468 mg/dL), 50.0 mmol/L (900 mg/dL), 8.5 mmol/L (153 mg/dL), and 32.4 mmol/L (583.2 mg/dL). Compared with 5 mmol/L (90 mg/dL), odds ratios at these glucose levels were 1.28 (95% CI 0.96, 1.69) for heart failure, 2.23 (1.03, 4.81) for arrhythmia, 1.59 (1.36, 1.86) for coagulation complications, and 2.42 (2.01, 2.92) for renal injury. For most complications, a modifying effect of age was observed, with higher odds of complications at higher glucose levels for patients age <69 years. Preexisting diabetes status had a similar modifying effect on odds of complications, but evidence was strongest for renal injury, cardiac ischemia, and any cardiovascular/renal complication. CONCLUSIONS Increased odds of cardiovascular or renal complications were observed for admission glucose levels indicative of both hypo- and hyperglycemia. Admission glucose could be used as a marker for risk stratification of high-risk patients. Further research should evaluate interventions to optimize admission glucose on improving COVID-19 outcomes.
23	MO21		Jan K. Hennigs, Tim Oqueka, Lars Harbaum & Hans Klose	Organbezogene Folgeerscheinungen von COVID‑19 bei Erwachsenen Organ-specific sequelae of COVID-19 in adults	https://doi.org/10.1007/s00103-022-03513-2	Published	16 March 2022	Review	https://link.springer.com/article/10.1007/s00103-022-03513-2	Organ-specific sequelae after COVID-19 occur frequently and are highly diverse in their features. Sequelae and symptoms persisting for more than four weeks after COVID-19 define the condition “long COVID.” Organ-specific sequelae of COVID-19 generally occur more often after severe disease. Yet, duration and intensity of organ-specific sequelae are highly variable. While pulmonary sequelae typically persist after more severe acute disease, COVID-19 sequelae may also develop weeks after infection and can affect any organ. The degree of SARS-CoV‑2 specificity of COVID-19 sequelae, however, remains unclear. Thus, diagnosis and treatment of COVID-19 sequelae represent an interdisciplinary challenge. Diagnostic and therapeutic approaches are guided by type, extent, and cause of the specific sequelae as targeted therapy options for long COVID are lacking. In the present work, we review current knowledge regarding the prevalence/incidence, duration, specificity, type, and extent of organ-specific COVID-19 sequelae and summarize current diagnostic and therapeutic strategies (as of November 2021).
24	MO22		SavasOzturk1KenanTurgutalp2MustafaArici3NumanGorgulu4Halil ZekiTonbul5NecmiEren6VedatGencer7Mehmet DenizAyli8İremPembegul9Murside EsraDolarslan10ZeynepUral11HulyaColak12Tuba ElifOzler13OzgurCan14Mehmet EminDemir15OrcunAltunoren16BulentHuddam17KursadOnec18…KenanAtes29	The Longitudinal Evolution of Post-COVID-19 Outcomes Among Hemodialysis Patients in Turkey	https://doi.org/10.1016/j.ekir.2022.03.017	Published	25 March 2022	Study	https://www.sciencedirect.com/science/article/pii/S2468024922012372	Background Hemodialysis (HD) patients have increased risk for short-term adverse outcomes of COVID-19. However, complications and survival at the post-COVID-19 period have not been published extensively. Methods We conducted a national, multicenter observational study that included adult maintenance HD patients recovered from confirmed COVID-19. A control HD group without COVID-19 was selected from patients in the same center. We investigated the characteristics and outcomes in the follow-up of HD patients and compare them with the non-COVID group. Results A total of 1223 patients (635 patients in COVID-19 group, 588 patients in non-COVID group) from 47 centers were included in the study. The patients' baseline and HD characteristics were almost similar. 28th day mortality and mortality between 28th day-90th day were higher in the COVID-19 group than non-COVID group [19 (3.0%) patients vs. none (0%); 15 (2.4%) patients vs. 4 (0.7%) patients, respectively]. The presence of respiratory symptoms, rehospitalization, need for home oxygen therapy, lower respiratory tract infection, A-V fistula thrombosis were significantly higher in the COVID-19 group in both the first 28 days and between 28-90 days. In the multivariable analysis, age [Odds ratio (OR) (95% confidence interval[CI]): 1.029(1.004-1.056)], group (COVID-19 group vs. non-COVID group) [OR (95%CI): 7.258(2.538-20.751) and vascular access type (tunneled catheter/AV fistula) [OR(95%CI): 2.512 (1.249-5.051)] were found as independent parameters related to 90-day mortality. Conclusion In the post-COVID period, maintenance HD patients who have had COVID-19 have increased rehospitalization, respiratory problems, vascular access problems, and high mortality compared to the non-COVID HD patients.
25	MO23		Adekunle Sanyaolu, Aleksandra Marinkovic, Stephanie Prakash, Anne Zhao, Vyshnavy Balendra, Nafees Haider, Isha Jain, Teodora Simic & Chuku Okorie	Post-acute Sequelae in COVID-19 Survivors: an Overview	https://doi.org/10.1007/s42399-022-01172-7	Published	06 April 2022	Review	https://link.springer.com/article/10.1007/s42399-022-01172-7	In the acute phase of SARS-CoV-2 infection, varying degrees of clinical manifestations have been noticed in patients. Some patients who recovered from the infection developed long-term effects which have become of interest to the scientific and medical communities, as it relates to pathogenesis and the multidisciplinary approach to treatment. Long COVID (long-term or long-haul) is the collective term used to define recovered individuals of SARS-CoV-2 infection who have presented with persistent COVID symptoms, as well as the emergence of disorders and complications. Following the review of literature from major scientific databases, this paper investigated long COVID and the resulting post-sequela effects on survivors, regardless of initial disease severity. The clinical manifestations and multisystem complications of the disease specifically, cardiovascular, neurologic and psychologic, hematologic, pulmonary, dermatologic, and other ailments were discussed. Patients with chronic COVID-19 were found to experience heart thrombosis leading to myocardial infarction, inflammation, lung fibrosis, stroke, venous thromboembolism, arterial thromboembolism, “brain fog”, general mood dysfunctions, dermatological issues, and fatigue. As the disease continues to progress and spread, and with the emergence of new variants the management of these persisting symptoms will pose a challenge for healthcare providers and medical systems in the next period of the pandemic. However, more information is needed about long COVID, particularly concerning certain patient populations, variability in follow-up times, the prevalence of comorbidities, and the evolution of the spread of infection. Thus, continued research needs to be conducted concerning the disease pathology to develop preventative measures and management strategies to treat long COVID.
26	MO24		Andrew J. Morrow, Robert Sykes, Alasdair McIntosh, Anna Kamdar, Catherine Bagot, Hannah K. Bayes, Kevin G. Blyth, Michael Briscoe, Heerajnarain Bulluck, David Carrick, Colin Church, David Corcoran, Iain Findlay, Vivienne B. Gibson, Lynsey Gillespie, Douglas Grieve, Pauline Hall Barrientos, Antonia Ho, Ninian N. Lang, Vera Lennie, David J. Lowe, Peter W. Macfarlane, Patrick B. Mark, Kaitlin J. Mayne, Alex McConnachie, Ross McGeoch, Christopher McGinley, Connor McKee, Sabrina Nordin, Alexander Payne, Alastair J. Rankin, Keith E. Robertson, Giles Roditi, Nicola Ryan, Naveed Sattar, Sarah Allwood-Spiers, David Stobo, Rhian M. Touyz, Gruschen Veldtman, Stuart Watkins, Sarah Weeden, Robin A. Weir, Paul Welsh, Ryan Wereski, CISCO-19 Consortium, Kenneth Mangion & Colin Berry	A multisystem, cardio-renal investigation of post-COVID-19 illness	https://doi.org/10.1038/s41591-022-01837-9	Published	23 May 2022	Study	https://www.nature.com/articles/s41591-022-01837-9	The pathophysiology and trajectory of post-Coronavirus Disease 2019 (COVID-19) syndrome is uncertain. To clarify multisystem involvement, we undertook a prospective cohort study including patients who had been hospitalized with COVID-19 (ClinicalTrials.gov ID NCT04403607). Serial blood biomarkers, digital electrocardiography and patient-reported outcome measures were obtained in-hospital and at 28–60 days post-discharge when multisystem imaging using chest computed tomography with pulmonary and coronary angiography and cardio-renal magnetic resonance imaging was also obtained. Longer-term clinical outcomes were assessed using electronic health records. Compared to controls (n = 29), at 28–60 days post-discharge, people with COVID-19 (n = 159; mean age, 55 years; 43% female) had persisting evidence of cardio-renal involvement and hemostasis pathway activation. The adjudicated likelihood of myocarditis was ‘very likely’ in 21 (13%) patients, ‘probable’ in 65 (41%) patients, ‘unlikely’ in 56 (35%) patients and ‘not present’ in 17 (11%) patients. At 28–60 days post-discharge, COVID-19 was associated with worse health-related quality of life (EQ-5D-5L score 0.77 (0.23) versus 0.87 (0.20)), anxiety and depression (PHQ-4 total score 3.59 (3.71) versus 1.28 (2.67)) and aerobic exercise capacity reflected by predicted maximal oxygen utilization (20.0 (7.6) versus 29.5 (8.0) ml/kg/min) (all P < 0.01). During follow-up (mean, 450 days), 24 (15%) patients and two (7%) controls died or were rehospitalized, and 108 (68%) patients and seven (26%) controls received outpatient secondary care (P = 0.017). The illness trajectory of patients after hospitalization with COVID-19 includes persisting multisystem abnormalities and health impairments that could lead to substantial demand on healthcare services in the future.
27	MO25		Colin Berry 1 and Kenneth Mangion 2	Multisystem involvement is common in post-COVID-19 syndrome	https://doi.org/10.1038/s41591-022-01838-8	Published	23 May 2022	Research Briefing	https://www.nature.com/articles/s41591-022-01838-8	A prospective clinical study evaluating patients 28–60 days after hospitalization for COVID-19 reveals increased cardio-renal inflammation, reduced lung function and poorer self-reported clinical outcomes in patients relative to that in control participants.
28	MO26		NICOLE EICHERT; ALISON TELFORD; ADRIANA ROCA-FERNANDEZ; AZLINDA HAMID; HELENA B. THOMAIDES-BREARS; ANDREA DENNIS; RAJARSHI BANERJEE; SARAH ALI; GAYA THANABALASINGHAM; GRAHAM KEMP; DANIEL CUTHBERTSON; AMITAVA BANERJEE	1166-P: Distinct Phenotypes of Multiorgan Abnormalities in Long COVID and Type 2 Diabetes Identified by Multiparametric Magnetic Resonance Imaging	https://doi.org/10.2337/db22-1166-P	Published	June 01 2022	Study	https://diabetesjournals.org/diabetes/article/71/Supplement_1/1166-P/146323	Introduction: Both long COVID and Type 2 Diabetes (T2D) are multi-system conditions requiring multi-organ assessment to monitor organ health and detect co-morbidities earlier. Here, we defined multi-organ abnormalities in both patient groups with a rapid, non-contrast MRI scan. Methods: We recruited 135 long COVID patients (NCT04369807) and 135 T2D patients (NCT04114682) . MRI data were acquired for organ-specific measures of size, fat deposition and fibroinflammation (CoverScan®, Perspectum Ltd.) . Reference values were based on 92 controls and published literature. Results: There was a high prevalence of organ abnormality in both patient groups (Figure, left) , including increased fat deposition (steatosis) in liver, pancreas, and kidney (Figure, right) . 35% of T2D patients had clustering of abnormalities involving at least 2 organs, compared to 23% in long COVID. Abnormalities affecting the liver and renomegaly were more common in T2D than in long COVID. Considering only obese patients, liver fibroinflammation, hepatomegaly, and renomegaly remained significantly more prevalent in T2D than in long COVID. Conclusion: Multi-organ MRI assessment can enrich the current blunt assessment of multi-system abnormalities in diverse disease states to inform earlier intervention and treatments.
29	MO27		Justin J. Frere, Randal A. Serafini, Kerri D. Pryc, Shu Horiuchi, Daisy A. Hoagland, Rasmus Møller, Anne Ruiz, Albana Kodra, Jonathan B. Overdevest, Peter D. Canoll, Alain C. Borczuk, Vasuretha Chandar, Yaron Bram, Robert Schwartz, Stavros Lomvardas, Venetia Zachariou, Benjamin R. tenOever	SARS-CoV-2 infection in hamsters and humans results in lasting and unique systemic perturbations post recovery	https://doi.org/10.1126/scitranslmed.abq3059	Published	7 Jun 2022	Study	https://www.science.org/doi/10.1126/scitranslmed.abq3059	The host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in prolonged pathologies collectively referred to as post-acute sequalae of COVID-19 (PASC) or long COVID. To better understand the mechanism underlying long COVID biology, we compared the short- and long-term systemic responses in the golden hamster following either SARS-CoV-2 or influenza A virus (IAV) infection. Results demonstrated that SARS-CoV-2 exceeded IAV in its capacity to cause permanent injury to the lung and kidney and uniquely impacted the olfactory bulb (OB) and epithelium (OE). Despite a lack of detectable infectious virus, the OB and OE demonstrated myeloid and T cell activation, proinflammatory cytokine production, and an interferon response that correlated with behavioral changes extending a month post viral clearance. These sustained transcriptional changes could also be corroborated from tissue isolated from individuals who recovered from COVID-19. These data highlight a molecular mechanism for persistent COVID-19 symptomology and provide a small animal model to explore future therapeutics.
30	MO28		JihoonShinabShinichiroToyodaaShigekiNishitaniaToshiharuOnoderaaShiroFukudaaShunbunKitaacAtsunoriFukuharaacIichiroShimomuraa	SARS-CoV-2 infection impairs the insulin/IGF signaling pathway in the lung, liver, adipose tissue, and pancreatic cells via IRF1	https://doi.org/10.1016/j.metabol.2022.155236	Published	8 June 2022	Study	https://www.sciencedirect.com/science/article/pii/S0026049522001147	Highlights •SARS-CoV-2 infection impairs insulin/IGF signaling pathway genes in the host lung, liver, adipose tissue, and pancreatic cells in part by IRF1 activation. •IRF1 gene expression is highly relevant to risk factors for severe COVID-19, such as older age, male sex, obesity, and diabetes. •Critical patients with COVID-19 have higher IRF1 and lower insulin/IGF signaling pathway genes in whole blood. •Hormonal interventions, such as DHT and DEX, may ameliorate the pathological traits in SARS-CoV-2 infectable cells and tissues. Background COVID-19 can cause multiple organ damages as well as metabolic abnormalities such as hyperglycemia, insulin resistance, and new onset of diabetes. The insulin/IGF signaling pathway plays an important role in regulating energy metabolism and cell survival, but little is known about the impact of SARS-CoV-2 infection. The aim of this work was to investigate whether SARS-CoV-2 infection impairs the insulin/IGF signaling pathway in the host cell/tissue, and if so, the potential mechanism and association with COVID-19 pathology. Methods To determine the impact of SARS-CoV-2 on insulin/IGF signaling pathway, we utilized transcriptome datasets of SARS-CoV-2 infected cells and tissues from public repositories for a wide range of high-throughput gene expression data: autopsy lungs from COVID-19 patients compared to the control from non-COVID-19 patients; lungs from a human ACE2 transgenic mouse infected with SARS-CoV-2 compared to the control infected with mock; human pluripotent stem cell (hPSC)-derived liver organoids infected with SARS-CoV-2; adipose tissues from a mouse model of COVID-19 overexpressing human ACE2 via adeno-associated virus serotype 9 (AAV9) compared to the control GFP after SARS-CoV-2 infection; iPS-derived human pancreatic cells infected with SARS-CoV-2 compared to the mock control. Gain and loss of IRF1 function models were established in HEK293T and/or Calu3 cells to evaluate the impact on insulin signaling. To understand the mechanistic regulation and relevance with COVID-19 risk factors, such as older age, male sex, obesity, and diabetes, several transcriptomes of human respiratory, metabolic, and endocrine cells and tissue were analyzed. To estimate the association with COVID-19 severity, whole blood transcriptomes of critical patients with COVID-19 compared to those of hospitalized noncritical patients with COVID-19. Results We found that SARS-CoV-2 infection impaired insulin/IGF signaling pathway genes, such as IRS, PI3K, AKT, mTOR, and MAPK, in the host lung, adipose tissue, and pancreatic cells. The impairments were attributed to interferon regulatory factor 1 (IRF1), and its gene expression was highly relevant to risk factors for severe COVID-19; increased with aging in the lung, specifically in men; augmented by obese and diabetic conditions in adipose tissue and pancreatic islets. IRF1 activation was significantly associated with the impaired insulin signaling in human cells. IRF1 intron variant rs17622656-A, which previously reported to associated with COVID-19 prevalence, increased the IRF1 gene expression in human tissue and frequently found in American and European population. Critical patients with COVID-19 exhibited higher IRF1 and lower insulin/IGF signaling pathway genes in the whole blood compared to hospitalized noncritical patients. Hormonal interventions, such as dihydrotestosterone and dexamethasone, ameliorated the pathological traits in SARS-CoV-2 infectable cells and tissues. Conclusions The present study provides the first scientific evidence that SARS-CoV-2 infection impairs the insulin/IGF signaling pathway in respiratory, metabolic, and endocrine cells and tissues. This feature likely contributes to COVID-19 severity with cell/tissue damage and metabolic abnormalities, which may be exacerbated in older, male, obese, or diabetic patients.
31	MO29	CPET	Matthew S. Durstenfeld, View ORCID ProfileMichael J. Peluso, Punita Kaveti, Christopher Hill, Danny Li, Erica Sander, Shreya Swaminathan, Victor M. Arechiga, Kaiwen Sun, Yifei Ma, Victor Zepeda, Scott Lu, Sarah A Goldberg, Rebecca Hoh, Ahmed Chenna, Brandon C. Yee, John W. Winslow, View ORCID ProfileChristos J. Petropoulos, Sithu Win, J. Daniel Kelly, David V. Glidden, Timothy J. Henrich, View ORCID ProfileJeffrey N. Martin, Yoo Jin Lee, Mandar A. Aras, Carlin S. Long, Donald J. Grandis, View ORCID ProfileSteven G. Deeks, Priscilla Y. Hsue	Inflammation during early post-acute COVID-19 is associated with reduced exercise capacity and Long COVID symptoms after 1 year	https://doi.org/10.1101/2022.05.17.22275235	pre-print	June 01, 2022	Study	https://www.medrxiv.org/content/10.1101/2022.05.17.22275235v2	BACKGROUND Mechanisms underlying persistent cardiopulmonary symptoms following SARS-CoV-2 infection (post-acute sequelae of COVID-19 “PASC” or “Long COVID”) remain unclear. The purpose of this study was to elucidate the pathophysiology of cardiopulmonary PASC using multimodality cardiovascular imaging including cardiopulmonary exercise testing (CPET), cardiac magnetic resonance imaging (CMR) and ambulatory rhythm monitoring. METHODS We performed CMR, CPET, and ambulatory rhythm monitoring among adults > 1 year after PCR-confirmed SARS-CoV-2 infection in the UCSF Long-Term Impact of Infection with Novel Coronavirus cohort (LIINC; NCT04362150) and correlated findings with previously measured biomarkers. We used logistic regression to estimate associations with PASC symptoms (dyspnea, chest pain, palpitations, and fatigue) adjusted for confounders and linear regression to estimate differences between those with and without symptoms adjusted for confounders. RESULTS Out of 120 participants in the cohort, 46 participants (unselected for symptom status) had at least one advanced cardiac test performed at median 17 months following initial SARS-CoV-2 infection. Median age was 52 (IQR 42-61), 18 (39%) were female, and 6 (13%) were hospitalized for severe acute infection. On CMR (n=39), higher extracellular volume was associated with symptoms, but no evidence of late-gadolinium enhancement or differences in T1 or T2 mapping were demonstrated. We did not find arrhythmias on ambulatory monitoring. In contrast, on CPET (n=39), 13/23 (57%) with cardiopulmonary symptoms or fatigue had reduced exercise capacity (peak VO2<85% predicted) compared to 2/16 (13%) without symptoms (p=0.008). The adjusted difference in peak VO2 was 5.9 ml/kg/min lower (−9.6 to −2.3; p=0.002) or −21% predicted (−35 to −7; p=0.006) among those with symptoms. Chronotropic incompetence was the primary abnormality among 9/15 (60%) with reduced peak VO2. Adjusted heart rate reserve <80% was associated with reduced exercise capacity (OR 15.6, 95%CI 1.30-187; p=0.03). Inflammatory markers (hsCRP, IL-6, TNF-α) and SARS-CoV-2 antibody levels measured early in PASC were negatively correlated with peak VO2 more than 1 year later. CONCLUSIONS Cardiopulmonary symptoms and elevated inflammatory markers present early in PASC are associated with objectively reduced exercise capacity measured on cardiopulmonary exercise testing more than 1 year following COVID-19. Chronotropic incompetence may explain reduced exercise capacity among some individuals with PASC.
32	MO30		Mahavir Singh, Sathnur Pushpakumar, Nia Bard, Yuting Zheng, Rubens P. Homme, Sri Prakash L. Mokshagundam & Suresh C. Tyagi	Simulation of COVID-19 symptoms in a genetically engineered mouse model: implications for the long haulers	https://doi.org/10.1007/s11010-022-04487-0	Published	22 June 2022	Study	https://link.springer.com/article/10.1007/s11010-022-04487-0	The ongoing pandemic (also known as coronavirus disease-19; COVID-19) by a constantly emerging viral agent commonly referred as the severe acute respiratory syndrome corona virus 2 or SARS-CoV-2 has revealed unique pathological findings from infected human beings, and the postmortem observations. The list of disease symptoms, and postmortem observations is too long to mention; however, SARS-CoV-2 has brought with it a whole new clinical syndrome in “long haulers” including dyspnea, chest pain, tachycardia, brain fog, exercise intolerance, and extreme fatigue. We opine that further improvement in delivering effective treatment, and preventive strategies would be benefited from validated animal disease models. In this context, we designed a study, and show that a genetically engineered mouse expressing the human angiotensin converting enzyme 2; ACE-2 (the receptor used by SARS-CoV-2 agent to enter host cells) represents an excellent investigative resource in simulating important clinical features of the COVID-19. The ACE-2 mouse model (which is susceptible to SARS-CoV-2) when administered with a recombinant SARS-CoV-2 spike protein (SP) intranasally exhibited a profound cytokine storm capable of altering the physiological parameters including significant changes in cardiac function along with multi-organ damage that was further confirmed via histological findings. More importantly, visceral organs from SP treated mice revealed thrombotic blood clots as seen during postmortem examination. Thus, the ACE-2 engineered mouse appears to be a suitable model for studying intimate viral pathogenesis thus paving the way for identification, and characterization of appropriate prophylactics as well as therapeutics for COVID-19 management.
33	MO31		Kirsty Minton	Mechanistic insights into Long COVID in hamsters	https://doi.org/10.1038/s41577-022-00757-6	Published	29 June 2022	Brief Report	https://www.nature.com/articles/s41577-022-00757-6	Using a golden hamster model, Frere et al. compared the short- and long-term responses to SARS-CoV-2 and influenza A virus (IAV) infection to better understand the mechanisms that account for persistent COVID-19 symptoms. At 3 days post infection (3dpi), both viruses induced a robust type I interferon response that cleared acute infection from the respiratory tract. Both viruses also induced an acute inflammatory response in peripheral tissues such as heart, kidney and lung, but by 31dpi (which would be defined as Long COVID in humans), SARS-CoV-2-infected hamsters had greater evidence of peripheral organ damage than IAV-infected hamsters. Furthermore, SARS-CoV-2-infected hamsters uniquely had prolonged inflammation in the olfaction system and various brain regions including striatum and cerebellum. This inflammation was evident in the absence of infectious virus and was associated with behavioural changes.
34	MO32		Michael J. Paidas, Daniela S. Cosio, Saad Ali, Norma Sue Kenyon & Arumugam R. Jayakumar	Long-Term Sequelae of COVID-19 in Experimental Mice	https://doi.org/10.1007/s12035-022-02932-1	Published	13 July 2022	Study	https://link.springer.com/article/10.1007/s12035-022-02932-1	We recently reported acute COVID-19 symptoms, clinical status, weight loss, multi-organ pathological changes, and animal death in a murine hepatitis virus-1 (MHV-1) coronavirus mouse model of COVID-19, which were similar to that observed in humans with COVID-19. We further examined long-term (12 months post-infection) sequelae of COVID-19 in these mice. Congested blood vessels, perivascular cavitation, pericellular halos, vacuolation of neuropils, pyknotic nuclei, acute eosinophilic necrosis, necrotic neurons with fragmented nuclei, and vacuolation were observed in the brain cortex 12 months post-MHV-1 infection. These changes were associated with increased reactive astrocytes and microglia, hyperphosphorylated TDP-43 and tau, and a decrease in synaptic protein synaptophysin-1, suggesting the possible long-term impact of SARS-CoV-2 infection on defective neuronal integrity. The lungs showed severe inflammation, bronchiolar airway wall thickening due to fibrotic remodeling, bronchioles with increased numbers of goblet cells in the epithelial lining, and bronchiole walls with increased numbers of inflammatory cells. Hearts showed severe interstitial edema, vascular congestion and dilation, nucleated red blood cells (RBCs), RBCs infiltrating between degenerative myocardial fibers, inflammatory cells and apoptotic bodies and acute myocyte necrosis, hypertrophy, and fibrosis. Long-term changes in the liver and kidney were less severe than those observed in the acute phase. Noteworthy, the treatment of infected mice with a small molecule synthetic peptide which prevents the binding of spike protein to its respective receptors significantly attenuated disease progression, as well as the pathological changes observed post-long-term infection. Collectively, these findings suggest that COVID-19 may result in long-term, irreversible changes predominantly in the brain, lung, and heart.
35	MO33		Angela R.ShihMDaJosephMisdrajiMDb	COVID-19: Gastrointestinal and Hepatobiliary Manifestations	https://doi.org/10.1016/j.humpath.2022.07.006	Published	16 July 2022	Review	https://www.sciencedirect.com/science/article/pii/S0046817722001794	SARS-CoV-2 is the viral agent of COVID-19, a pandemic that surfaced in 2019. While predominantly a respiratory ailment, patients with COVID-19 can have gastrointestinal and hepatobiliary manifestations. These manifestations are often mild and transient, but they can be severe and consequential. In the gastrointestinal tract, ischemic enterocolitis is the most common and significant consequence of COVID-19. In the liver, the reported pathologic findings may often be related to consequences of severe systemic viral infection, but reports of hepatitis presumed to be due to SARS-CoV-2 suggest that direct viral infection of the liver may be a rare complication of COVID-19. In both the GI tract and liver, lingering symptoms of GI or hepatic injury after resolution of pulmonary infection may be part of the evolving spectrum of long COVID.
36	MO34		Luigi di Filippo, Stefano Frara, Mauro Doga & Andrea Giustina	The osteo-metabolic phenotype of COVID-19: an update	https://doi.org/10.1007/s12020-022-03135-3	Published	20 July 2022	Review	https://link.springer.com/article/10.1007/s12020-022-03135-3	Context In the multifaceted COVID-19 clinical scenario characterized by a multi-system disorder with negative implications not only on respiratory function but also on cardiac, hematological, neurological and endocrine-metabolic systems, a distinctive osteo-metabolic phenotype with an independent influence on disease severity and recovery of patients affected was early reported. Aim To summarize and update the main evidences regarding the distinct components of this phenotype in acute and Long COVID-19, reinforcing its clinical relevance and discussing the main pathophysiological and clinical-therapeutic implications of the most recent reported findings. Results This emerging phenotype is characterized by a widespread acute hypocalcemia and hypovitaminosis D with an impaired compensatory parathyroid hormone response, and a high prevalence of skeletal complications such as vertebral fractures. The clinical relevance of this osteo-metabolic phenotype on acute COVID-19 is well characterized, and novel seminal evidences are progressively highlighting its importance also in predicting patient’s long-term outcomes and Long COVID-19 occurrence. Conclusions These findings reinforced the central role of a multidisciplinary team, including endocrinologists, in evaluating these patients for a proactive search of each aspect of the osteo-metabolic phenotype components since they may represent suitable therapeutic targets to prevent SARS-CoV-2 infection, poor COVID-19 outcomes, Long COVID-19 occurrence and even possibly better responses to COVID-19 vaccination.
37	MO35		Francesco Bandera	Return to high-hazard occupations after COVID-19 infection: a cardiopulmonary assessment approach	https://doi.org/10.1093/eurjpc/zwac072	Published	11 August 2022	Editorial	https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac072/6659216	This editorial refers to ‘Cardiopulmonary assessment prior to returning to high-hazard occupations post symptomatic COVID-19 infection : a position statement of the Aviation and Occupational Cardiology Task Force of the European Association of Preventive Cardiology’ by R. Rienks et al.https://doi.org/doi:10.1093/eurjpc/zwac041. Since the first outbreak of severe acute respiratory syndrome–related coronavirus 2 in late 2019, and across its progressive spreading to pandemic, medical community has been making constant progresses in prevention, treatment and management of COVID-19 disease. Beyond the efforts to fight the virus spread and to cure the acute infection, the need of bringing back people recovered from COVID-19 to their life has become a priority. Indeed, even if the majority of COVID-19 infections recovers without residual symptoms, a variable percentage of patients experiences the ‘post-COVID-19 syndrome’—a wide spectrum of long-lasting (beyond 12 weeks) clinical manifestations, including cardiopulmonary, renal and neurological problems.1 The prevalence and the severity of post-COVID-19 syndrome are related to the age and the frailty of the subjects, occurring more frequently after severe diseases requiring prolonged hospitalization. Nevertheless, it does not affect only elderly people, being diagnosed in about 40% of subjects between 18 and 49 years.2 Therefore, the need of evaluate active workers before reincorporation, providing a certification or simply reassuring the patient, is a frequent task common to general practitioners and specialists.
38	MO36		Young Hyun Che1, Yong Jun Kim1,2,3	Understanding the cellular pathogenesis of COVID-19 symptoms using organoid technology	https://doi.org/10.51335/organoid.2022.2.e16	Published	June 25, 2022	Review	https://j-organoid.org/journal/view.php?doi=10.51335/organoid.2022.2.e16	Patients with coronavirus disease 2019 (COVID-19), which has recently caused a pandemic, have reported symptoms of coronavirus infection that are not well understood by the medical community in general. After severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, several symptoms, including acute clinical signs and possible sequelae, manifest in multiple organs. It is necessary to precisely identify the cells susceptible to SARS-CoV-2 infection in order to comprehend the mechanism of symptom occurrence, identify molecular targets for therapeutic development, and prevent current or future threats. Following the use of cell lines, animal models, and stem cell-derived symptom-relevant cells, recent research on the pathophysiology of human diseases has utilized organoid models. This article provides a summary of recent research on the tissue- or organ-specific cellular targets of SARS-CoV-2 aiming to understand the pathophysiology of COVID-19.
39	MO37		Nicholas L. DePace & Joe Colombo	Long-COVID Syndrome and the Cardiovascular System: A Review of Neurocardiologic Effects on Multiple Systems	https://doi.org/10.1007/s11886-022-01786-2	Published	30 September 2022	Review	https://link.springer.com/article/10.1007/s11886-022-01786-2	Purpose of Review Long-COVID syndrome is a multi-organ disorder that persists beyond 12 weeks post-acute SARS-CoV-2 infection (COVID-19). Here, we provide a definition for this syndrome and discuss neuro-cardiology involvement due to the effects of (1) angiotensin-converting enzyme 2 receptors (the entry points for the virus), (2) inflammation, and (3) oxidative stress (the resultant effects of the virus). Recent Findings These effects may produce a spectrum of cardio-neuro effects (e.g., myocardial injury, primary arrhythmia, and cardiac symptoms due to autonomic dysfunction) which may affect all systems of the body. We discuss the symptoms and suggest therapies that target the underlying autonomic dysfunction to relieve the symptoms rather than merely treating symptoms. In addition to treating the autonomic dysfunction, the therapy also treats chronic inflammation and oxidative stress. Together with a full noninvasive cardiac workup, a full assessment of the autonomic nervous system, specifying parasympathetic and sympathetic (P&S) activity, both at rest and in response to challenges, is recommended. Cardiac symptoms must be treated directly. Cardiac treatment is often facilitated by treating the P&S dysfunction. Cardiac symptoms of dyspnea, chest pain, and palpitations, for example, need to be assessed objectively to differentiate cardiac from neural (autonomic) etiology. Summary Long-term myocardial injury commonly involves P&S dysfunction. P&S assessment usually connects symptoms of Long-COVID to the documented autonomic dysfunction(s).
40	MO38		Ali A.Rizvia1AmitaKathuriaaWaelAl MahmeedbKhalidAl-RasadicKamilaAl-AlawidMaciejBanachefgYajnavalkaBanerjeehAntonioCerielloiMustafaCesurjFrancescoCosentinokMassimoGalialSu-YenGohmAndrejJaneznSanjayKalraoPeterKemplerpNaderLessanqPauloLotuforNikolaosPapanassRaul D.SantostuAnca P.StoianvPeter P.TothwVijayViswanathanxManfrediRizzoy1	Post-COVID syndrome, inflammation, and diabetes	https://doi.org/10.1016/j.jdiacomp.2022.108336	Published	6 October 2022	Article	https://www.sciencedirect.com/science/article/pii/S1056872722002483	Highlights •SARS CoV 2 infection beyond the acute phase may continue to cause symptoms that together form the so-called “Long COVID” or “Post-COVID Syndrome” •The pathophysiologic mechanisms involve a heightened systemic inflammatory state, cardiometabolic derangements, and glucose intolerance •Significant hyperglycemia leading to new-onset diabetes or worsening of preexisting disease may occur •The prediction, course, and management of COVID-related hyperglycemia remain to be fully elucidated Abstract The raging COVID-19 pandemic is in its third year of global impact. The SARS CoV 2 virus has a high rate of spread, protean manifestations, and a high morbidity and mortality in individuals with predisposing risk factors. The pathophysiologic mechanisms involve a heightened systemic inflammatory state, cardiometabolic derangements, and varying degrees of glucose intolerance. The latter can be evident as significant hyperglycemia leading to new-onset diabetes or worsening of preexisting disease. Unfortunately, the clinical course beyond the acute phase of the illness may persist in the form of a variety of symptoms that together form the so-called “Long COVID” or “Post-COVID Syndrome”. It is thought that a chronic, low-grade inflammatory and immunologic state persists during this phase, which may last for weeks or months. Although numerous insights have been gained into COVID-related hyperglycemia and diabetes, its prediction, course, and management remain to be fully elucidated.
41	MO39		Nina L. Stute,Rachel E. Szeghy,Jonathon L. Stickford,Valesha P. Province,Marc A. Augenreich,Stephen M. Ratchford,Abigail S. L. Stickford	Longitudinal observations of sympathetic neural activity and hemodynamics during 6 months recovery from SARS-CoV-2 infection	https://doi.org/10.14814/phy2.15423	Published	23 September 2022	Study	https://physoc.onlinelibrary.wiley.com/doi/10.14814/phy2.15423	Cross-sectional data indicate that acute SARS-CoV-2 infection increases resting muscle sympathetic nerve activity (MSNA) and alters hemodynamic responses to orthostasis in young adults. However, the longitudinal impact of contracting SARS-CoV-2 on autonomic function remains unclear. The aim of this study was to longitudinally track MSNA, sympathetic transduction to blood pressure (BP), and hemodynamics over 6 months following SARS-CoV-2 infection. Young adults positive with SARS-CoV-2 reported to the laboratory three times over 6 months (V1:41 ± 17, V2:108 ± 21, V3:173 ± 16 days post-infection). MSNA, systolic (SBP) and diastolic (DBP) blood pressure, and heart rate (HR) were measured at rest, during a cold pressor test (CPT), and at 30° head-up tilt (HUT). Basal SBP (p = 0.019) and DBP (p < 0.001) decreased throughout the 6 months, whereas basal MSNA and HR were not different. Basal sympathetic transduction to BP and estimates of baroreflex sensitivity did not change over time. SBP and DBP were lower during CPT (SBP: p = 0.016, DBP: p = 0.007) and HUT at V3 compared with V1 (SBP: p = 0.041, DBP: p = 0.017), with largely no changes in MSNA. There was a trend toward a visit-by-time interaction for burst incidence (p = 0.055) during HUT, wherein at baseline immediately prior to tilting, burst incidence was lower at V3 compared with V1 (p = 0.014), but there were no differences between visits in the 30 HUT position. These results support impairments to cardiovascular health, and potentially autonomic function, which may improve over time. However, the improvements in BP over 6 months recovery from mild SARS-CoV-2 infection are likely not a direct result of changes in sympathetic activity.
42	MO40		Eulogio Pleguezuelos, Amin Del Carmen, Eva Moreno, Pilar Ortega, Alejandro Robles, Mateo Serra-Prat, Marc Miravitlles, Joan Carles Yebenes & Manuel V. Garnacho-Castaño	Impaired pulmonary and muscle function during moderate exercise in female patients recovered from SARS-CoV-2	https://doi.org/10.1038/s41598-022-24941-9	Published	04 December 2022	Study	https://www.nature.com/articles/s41598-022-24941-9	This study aimed to assess pulmonary and muscle dysfunction by analyzing the slow component of oxygen uptake (VO2SC), and mechanical and ventilatory efficiency in adult women recovered from the severe acute respiratory syndrome coronavirus type II (SARS-CoV-2) during a constant load test. 32 women (N = 17 patients with SARS-CoV-2; N = 15 control group) performed two cardiopulmonary exercise tests (CPX) on a cycle ergometer. In the first test, the participants performed incremental CPX until extenuation. In the second test the participants performed a 10-min CPX at a constant load intensity (watts) corresponding to the first ventilatory threshold. There was a 48–72 h rest period between the two tests. There was a significant increase in the VO2SC in the patients recovered from SARS-CoV-2 (160.4 ± 60 mL min−1) in comparison with the healthy participants (59.6 ± 65 mL min−1) (P < 0.001). Mechanical efficiency significantly decreased in patients recovered from SARS-CoV-2 compared to the control group (P = 0.04). Ventilatory inefficiency significantly increased in the patients recovered from SARS-CoV-2 compared with the control group (P < 0.001). Adult women recovered from SARS-CoV-2 infection have important pulmonary and muscular dysfunction and fatigue which contributes to increasing the VO2SC and reducing mechanical and ventilatory efficiency during mild-moderate exercise at a constant load.
43	MO41		Babity, Mate; Zamodics, Mark; Konig, Albert; Kiss, Anna Reka; Horvath, Marton; Gregor, Zsofia; Rakoczi, Reka; Kovacs, Eva; Fabian, Alexandra; Tokodi, Marton; Sydo, Nora; Csulak, Emese; Juhasz, Vencel; Lakatos, Balint Karoly; Vago, Hajnalka; Kovacs, Attila; Merkely, Bela; Kiss, Orsolya	Cardiopulmonary examinations of athletes returning to high-intensity sport activity following SARS-CoV-2 infection	https://doi.org/10.1038/s41598-022-24486-x	Published	2022-12-15	Study	https://www.nature.com/articles/s41598-022-24486-x	After SARS-CoV-2 infection, strict recommendations for return-to-sport were published. However, data are insufficient about the long-term effects on athletic performance. After suffering SARS-CoV-2 infection, and returning to maximal-intensity trainings, control examinations were performed with vita-maxima cardiopulmonary exercise testing (CPET). From various sports, 165 asymptomatic elite athletes (male: 122, age: 20y (IQR: 17-24y), training:16 h/w (IQR: 12–20 h/w), follow-up:93.5 days (IQR: 66.8–130.0 days) were examined. During CPET examinations, athletes achieved 94.7 ± 4.3% of maximal heart rate, 50.9 ± 6.0 mL/kg/min maximal oxygen uptake (V̇O2max), and 143.7 ± 30.4L/min maximal ventilation. Exercise induced arrhythmias (n = 7), significant horizontal/descending ST-depression (n = 3), ischemic heart disease (n = 1), hypertension (n = 7), slightly elevated pulmonary pressure (n = 2), and training-related hs-Troponin-T increase (n = 1) were revealed. Self-controlled CPET comparisons were performed in 62 athletes: due to intensive re-building training, exercise time, V̇O2max and ventilation increased compared to pre-COVID-19 results. However, exercise capacity decreased in 6 athletes. Further 18 athletes with ongoing minor long post-COVID symptoms, pathological ECG (ischemic ST-T changes, and arrhythmias) or laboratory findings (hsTroponin-T elevation) were controlled. Previous SARS-CoV-2-related myocarditis (n = 1), ischaemic heart disease (n = 1), anomalous coronary artery origin (n = 1), significant ventricular (n = 2) or atrial (n = 1) arrhythmias were diagnosed. Three months after SARS-CoV-2 infection, most of the athletes had satisfactory fitness levels. Some cases with SARS-CoV-2 related or not related pathologies requiring further examinations, treatment, or follow-up were revealed.
44	MO42		Khreefa, Zaid; Barbier, Mallory T.; Koksal, Ali Riza; Love, Gordon; Del Valle, Luis	Pathogenesis and Mechanisms of SARS-CoV-2 Infection in the Intestine, Liver, and Pancreas	https://doi.org/10.3390/cells12020262	Published	1/1/2023	Review	https://www.mdpi.com/2073-4409/12/2/262	The novel coronavirus, SARS-CoV-2, rapidly spread worldwide, causing an ongoing global pandemic. While the respiratory system is the most common site of infection, a significant number of reported cases indicate gastrointestinal (GI) involvement. GI symptoms include anorexia, abdominal pain, nausea, vomiting, and diarrhea. Although the mechanisms of GI pathogenesis are still being examined, viral components isolated from stool samples of infected patients suggest a potential fecal–oral transmission route. In addition, viral RNA has been detected in blood samples of infected patients, making hematologic dissemination of the virus a proposed route for GI involvement. Angiotensin-converting enzyme 2 (ACE2) receptors serve as the cellular entry mechanism for the virus, and these receptors are particularly abundant throughout the GI tract, making the intestine, liver, and pancreas potential extrapulmonary sites for infection and reservoirs sites for developing mutations and new variants that contribute to the uncontrolled spread of the disease and resistance to treatments. This transmission mechanism and the dysregulation of the immune system play a significant role in the profound inflammatory and coagulative cascades that contribute to the increased severity and risk of death in several COVID-19 patients. This article reviews various potential mechanisms of gastrointestinal, liver, and pancreatic injury.
45	MO43		Balasubramaniam, Arun; Tedbury, Philip R.; Mwangi, Simon M.; Liu, Yunshan; Li, Ge; Merlin, Didier; Gracz, Adam D.; He, Peijian; Sarafianos, Stefan G.; Srinivasan, Shanthi	SARS-CoV-2 Induces Epithelial-Enteric Neuronal Crosstalk Stimulating VIP Release	https://doi.org/10.3390/biom13020207	Published	2023-02-01	Study	https://www.mdpi.com/2218-273X/13/2/207	Background: Diarrhea is present in up to 30–50% of patients with COVID-19. The mechanism of SARS-CoV-2-induced diarrhea remains unclear. We hypothesized that enterocyte–enteric neuron interactions were important in SARS-CoV-2-induced diarrhea. SARS-CoV-2 induces endoplasmic reticulum (ER) stress in enterocytes causing the release of damage associated molecular patterns (DAMPs). The DAMPs then stimulate the release of enteric neurotransmitters that disrupt gut electrolyte homeostasis. Methods: Primary mouse enteric neurons (EN) were exposed to a conditioned medium from ACE2-expressing Caco-2 colonic epithelial cells infected with SARS-CoV-2 or treated with tunicamycin (ER stress inducer). Vasoactive intestinal peptides (VIP) expression and secretion by EN were assessed by RT-PCR and ELISA, respectively. Membrane expression of NHE3 was determined by surface biotinylation. Results: SARS-CoV-2 infection led to increased expression of BiP/GRP78, a marker and key regulator for ER stress in Caco-2 cells. Infected cells secreted the DAMP protein, heat shock protein 70 (HSP70), into the culture media, as revealed by proteomic and Western analyses. The expression of VIP mRNA in EN was up-regulated after treatment with a conditioned medium of SARS-CoV-2-infected Caco-2 cells. CD91, a receptor for HSP70, is abundantly expressed in the cultured mouse EN. Tunicamycin, an inducer of ER stress, also induced the release of HSP70 and Xbp1s, mimicking SARS-CoV-2 infection. Co-treatment of Caco-2 with tunicamycin (apical) and VIP (basolateral) induced a synergistic decrease in membrane expression of Na+/H+ exchanger (NHE3), an important transporter that mediates intestinal Na+/fluid absorption. Conclusions: Our findings demonstrate that SARS-CoV-2 enterocyte infection leads to ER stress and the release of DAMPs that up-regulates the expression and release of VIP by EN. VIP in turn inhibits fluid absorption through the downregulation of brush-border membrane expression of NHE3 in enterocytes. These data highlight the role of epithelial-enteric neuronal crosstalk in COVID-19-related diarrhea.
46	MO44		Rizvi, Anam; Ziv, Yonatan; Crawford, James M.; Trindade, Arvind J.	Gastrointestinal and Hepatobiliary Symptoms and Disorders with Long (Chronic) COVID Infection	https://doi.org/10.1016/j.gtc.2022.09.002	Published	2023-03-01	Review	https://www.gastro.theclinics.com/article/S0889-8553(22)00066-8/fulltext	Long (chronic) COVID syndrome is an evolving multisystem disease occurring 4 to 12 weeks after acute COVID-19 infection. •Gastrointestinal (GI) and hepatobiliary manifestations of long COVID syndrome are common. •Abdominal pain, nausea and vomiting, diarrhea, constipation, loss of taste, loss of appetite, weight loss, postinfectious irritable bowel syndrome, dyspepsia, and post-COVID cholangiopathy are GI and hepatobiliary sequelae of long COVID syndrome. •Vaccination against COVID-19 is currently the best measure to prevent long COVID sequelae. •Long COVID is likely to pose a significant strain on the health-care system in terms of outpatient care and economic costs in the future. Background The COVID-19 pandemic has affected more than 590 million people with about 6 million deaths worldwide to date.1 For many COVID-19 infection has been a transient and acute illness. However, some have experienced a persistence or new development of symptoms not attributable to alternative causes. This has created a new medical disease/syndrome to characterize a postacute COVID-19 syndrome now known as “long COVID,” which is referred to throughout this review (other designations include post–COVID-19 syndrome, post-COVID conditions, postacute COVID-19, or chronic COVID).2 Evidence is accumulating that long COVID is a multiorgan disease, involving the cardiopulmonary, neurologic, gastrointestinal (GI), nephrological, and other systems.3,4 Substantial debate exists regarding the delineation of long COVID syndrome. The National Institute for Health and Care Excellence defines long COVID as sustained symptoms after acute COVID-19, not attributable to alternative diagnoses, including symptomatic COVID-19 from more than 4 to 12 weeks and post–COVID-19 syndrome more than 12 weeks postinfection.5 The US Centers for Disease Control and Prevention (CDC) demarcates long COVID as prolonged sequelae greater than 4 weeks postinfection.6 Due to varying definitions, the prevalence of long COVID syndrome is reported with a wide range from 10% to 87% of patients who were afflicted with COVID-19 infection.3,7,8 If a 10% prevalence is selected more than 50 million patients would be afflicted with long-COVID.9 The associated risk factors and precipitants of long COVID syndrome remain abstruse. Although poor baseline health and severe acute COVID-19 illness have been associated with the development of long COVID,10 puzzlingly it also frequently occurs in patients with mild-to-moderate disease not requiring critical care or respiratory support.11, 12, 13, 14 It is apparent though that long COVID is likely to herald growing challenges to the health-care system.6,15 Long COVID syndrome has extensive economic influence because residual symptoms can cause a loss of quality of life and earnings and an increase in medical spending. The incidence, costs, and impact of long COVID are continually being revised so the impact is difficult to estimate. Recent estimates suggest that long COVID syndrome could cost up to USD 3.7 trillion, with 59% of the total cost secondary to loss of quality of life. For perspective, the economic cost would rival the cost of the Great Recession.16,17 This cost amounts to USD 11,000 per person, or approximately 17% of the pre-COVID US gross domestic product (GDP).16,17 In this case, the increased health-care utilization alone would cost USD 528 billion in total.16,17 Patient’s self-reported experiences agree with these estimates as surveys from the COVID-19 Longhauler Advocacy Project suggest that more than 42% of patients with long COVID have medical bills more than USD 5000 and 51% are able to work fewer hours due to long COVID.18 This article reviews long-COVID syndrome in relation to the GI and hepatobiliary systems.
47	MO45		Gareau, Mélanie G.; Barrett, Kim E.	Role of the microbiota-gut-brain axis in postacute COVID syndrome	https://doi.org/10.1152/ajpgi.00293.2022	Published	2023-04-01	Review	https://journals.physiology.org/doi/full/10.1152/ajpgi.00293.2022	The COVID-19 pandemic has resulted in the infection of hundreds of millions of individuals over the past 3 years, coupled with millions of deaths. Along with these more acute impacts of infection, a large subset of patients has developed symptoms that collectively comprise “postacute sequelae of COVID-19” (PASC, also known as long COVID), which can persist for months and maybe even years. In this review, we outline the current knowledge on the role of impaired microbiota-gut-brain (MGB) axis signaling in the development of PASC and the potential mechanisms involved, which may lead to a better understanding of disease progression and treatment options in the future.
48	MO46		Vaz, Nuno; Franquet, Elisa; Heidari, Pedram; Chow, David Z.; Jacene, Heather A.; Ng, Thomas S. C.	COVID-19: Findings in nuclear medicine from head to toe	https://doi.org/10.1016/j.clinimag.2023.04.003	Published	2023-07-01	Article	https://www.sciencedirect.com/science/article/pii/S0899707123000797	Highlights •Clinical and imaging manifestations of COVID-19 may occur outside of the respiratory tract and extend beyond the acute phase. •Evidence of inflammation involving any organ system should be carefully sought in patients with known or suspected COVID-19. •The most common nuclear imaging finding of COVID-19 vaccination is hypermetabolic axillary lymphadenopathy. Abstract COVID-19 is a multisystemic disease, and hence its potential manifestations on nuclear medicine imaging can extend beyond the lung. Therefore, it is important for the nuclear medicine physician to recognize these manifestations in the clinic. While FDG-PET/CT is not indicated routinely in COVID-19 evaluation, its unique capability to provide a functional and anatomical assessment of the entire body means that it can be a powerful tool to monitor acute, subacute, and long-term effects of COVID-19. Single-photon scintigraphy is routinely used to assess conditions such as pulmonary embolism, cardiac ischemia, and thyroiditis, and COVID-19 may present in these studies. The most common nuclear imaging finding of COVID-19 vaccination to date is hypermetabolic axillary lymphadenopathy. This may pose important diagnostic and management dilemmas in oncologic patients, particularly those with malignancies where the axilla constitutes a lymphatic drainage area. This article aims to summarize the relevant literature published since the beginning of the pandemic on the intersection between COVID-19 and nuclear medicine.
49	MO47		Joseph, Phillip; Singh, Inderjit; Oliveira, Rudolf; Capone, Christine A.; Mullen, Mary P.; Cook, Dane B.; Stovall, Mary Catherine; Squires, Johanna; Madsen, Kristine; Waxman, Aaron B.; Systrom, David M.	Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-Acute Sequelae of SARS-CoV-2: More in Common Than Not?	https://doi.org/10.1016/j.chest.2023.03.049	Published	2023-04-11	Review	https://journal.chestnet.org/article/S0012-3692(23)00502-0/abstract	<h2>ABSTRACT</h2><h3>Topic Importance</h3><p>Post-Acute Sequelae of SARS-CoV-2 (PASC) is a long-term consequence of acute infection from coronavirus disease 2019 (COVID-19). Clinical overlap between PASC and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been observed, with shared symptoms including intractable fatigue, postexertional malaise, and orthostatic intolerance. The mechanistic underpinnings of such symptoms are poorly understood.</p><h3>Review Findings</h3><p>Early studies suggest deconditioning as the primary explanation for exertional intolerance in PASC. Cardiopulmonary exercise testing (CPET) reveals perturbations related to systemic blood flow and ventilatory control associated with acute exercise intolerance in PASC, which are not typical of simple detraining. Hemodynamic and gas exchange derangements in PASC have substantial overlap with those observed with ME/CFS, suggestive of shared mechanisms.</p><h3>Summary</h3><p>This review aims to illustrate exercise pathophysiologic commonalities between PASC and ME/CFS that will help guide future diagnostics and treatment.</p>
50	MO48		Sousa Rêgo, Luma Ornelas; Alves Braga, Lara Landulfo; Vilas-Boas, Gustavo Sampaio; Oliveira Cardoso, Maiana Santos; Duraes, Andre Rodrigues	Cardiovascular and Neurological Complications of COVID-19: A Narrative Review	https://doi.org/10.3390/jcm12082819	Published	2023-01-01	Review	https://www.mdpi.com/2077-0383/12/8/2819	A novel coronavirus emerged in China in late 2019 as a disease named coronavirus disease 2019. This pathogen was initially identified as causing a respiratory syndrome, but later, it was found that COVID-19 could also affect other body systems, such as the neurological and cardiovascular systems. For didactic purposes, cardiovascular and neurological manifestations of SARS-CoV-2 have been classified in three different groups: acute complications, late complications, and post-vaccine complications. Therefore, the following study has the goal to summarize and disseminate the present knowledge about the cardiovascular and neurological manifestations of COVID-19 based on the latest and most up-to-date data available and, thus, promote more prepared medical care for these conditions as the medical team is updated. Based on what is brought on this revision and its understanding, the medical service becomes more aware of the causal relationship between some conditions and COVID-19 and can better prepare for the most prevalent conditions to associate and, consequently, to treat patients earlier. Therefore, there is a chance of better prognoses in this context and the need to increase the number of studies about complications related to SARS-CoV-2 infection for a better understanding of other associated conditions.
51	MO49		Gomes-Neto, Mansueto; Conceição, Lino Sérgio Rocha; Gois, Caroline Oliveira; Carvalho, Vitor Oliveira	Comment on: “Low Cardiorespiratory Fitness Post‐COVID‐19: A Narrative Review”	https://doi.org/10.1007/s40279-023-01845-w	Published	2023-04-24	Letter to editor	https://doi.org/10.1007/s40279-023-01845-w	While Schwendinger et al. [1] provided an excellent narrative review, no meta-analysis was performed. It is important to pool the data to guide researchers and clinicians about the magnitude of V˙ O2peak difference in post-COVID-19 patients in comparison with healthy controls. In this context, using the studies included by Schwendinger et al. [1], we summarize the quantitative data from studies that compared V˙ O2peak between post-COVID-19 patients and healthy controls. When pooling all studies together that compared post-COVID-19 patients with healthy controls, we observed a significantly higher V˙ O2peak in the healthy control group compared with post-COVID-19 patients (mean difference [MD] 6.3 mLO2·kg−1·min−1, 95% confidence interval [CI] 2.8–9.8, I2 = 86%, 9 studies, N = 566, p = 0.0004) (Fig. 1a). In addition, in a subgroup analysis, considering the disease severity (severe vs non-severe post-COVID-19 patients), non-severe post-COVID-19 patients showed higher V˙ O2peak values than severe post-COVID-19 patients (MD 3.7 mLO2·kg−1·min−1, 95% CI 1.9–5.5, I2 = 34%, 5 studies, N = 226, p = 0.000) (Fig. 1b). Given the results presented by Schwendinger et al. [1] and reinforced by this meta-analysis, the severity of COVID-19 can also be considered a factor associated with impaired cardiorespiratory fitness. Therefore, it is reasonable for health professionals to assess cardiorespiratory fitness in post-COVID-19 patients [3]. Hence, the diagnosis and therapeutic strategies can be adopted, given the association between low cardiorespiratory fitness and lower survival [4]. Thus, it is possible that cardiopulmonary rehabilitation programs, that have exercise as the core component, can contribute to the recovery of these patients and should be part of the care of post-COVID-19 patients. In conclusion, we congratulate Schwendinger et al. [1] for their work on this important topic. Additionally, the meta-analysis of the included studies showed a difference of 6.3 mL O2·kg−1·min−1 in V˙ O2peak between healthy controls and post-COVID-19 patients. Finally, it is important to reinforce the need for further studies to investigate whether early cardiopulmonary rehabilitation can improve cardiorespiratory fitness more efficiently in these populations.
52	MO50		Schwendinger, Fabian; Knaier, Raphael; Radtke, Thomas; Schmidt-Trucksäss, Arno	Response to Comment on: “Low Cardiorespiratory Fitness Post‐COVID‐19: A Narrative Review”	https://doi.org/10.1007/s40279-023-01848-7	Published	2023-04-24	Letter to editor	https://doi.org/10.1007/s40279-023-01848-7	The analyses by Gomes Neto et al. [1] quantifying the level of CRF of patients post-COVID-19 in relation to healthy counterparts are a valuable addition to the findings of our review, although between-study heterogeneity was large (see test for heterogeneity in Figs. 1 and 2). Among other factors, differences in COVID-19 severity, prevalence and type of persisting symptoms, and follow-up period may contribute to the observed heterogeneity. Moreover, results of our sub-group analysis suggest that acute COVID-19 sequelae and symptoms of post-COVID-19 may indeed be the main driver of low CRF post-COVID-19. The presence of especially asymptomatic comorbidities may contribute only minor to lower CRF compared with healthy controls.
53	MO51		Iqbal, Phool; Ata, Fateen; Chaudhry, Hassan; Muthanna, Bassam; Waqas Younas, Hafiz; Munamm, Syed Ata ul; Sharma, Rohit; Fadah, Kahtan; Elazzazy, Shereen; Hamad, Anas; Said Abu Tabar, Osama; Omar, Nabil E.	Post-COVID-19-associated multiorgan complications or “long COVID” with literature review and management strategy discussion: A meta-analysis	https://doi.org/10.1002/hsr2.1211	Published	2023-04-14	Systematic review and meta-analysis	https://onlinelibrary.wiley.com/doi/abs/10.1002/hsr2.1211	Objective To investigate the post-COVID-19 long-term complications or long COVID of various organ systems in patients after 3 months of the infection, specifically before the Omicron variant, with comparative literature analysis. Methods A systemic literature search and meta-analysis were conducted using multiple electronic databases (PubMed, Scopus, Cochrane library) with predefined search terms to identify eligible articles. Eligible studies reported long-term complications of COVID-19 infection before the Omicron variant infection. Case reports, case series, observational studies with cross-sectional or prospective research design, case–control studies, and experimental studies that reported post-COVID-19 complications were included. The complications reported after 3 months after the recovery from COVID-19 infection were included in the study. Results The total number of studies available for analysis was 34. The effect size (ES) for neurological complications was 29% with 95% confidence interval (CI): 19%–39%. ES for psychiatric complications was 24% with 95% CI: 7%–41%. ES was 9% for cardiac outcomes, with a 95% CI of 1%–18%. ES was 22%, 95% CI: 5%–39% for the gastrointestinal outcome. ES for musculoskeletal symptoms was 18% with 95% CI: 9%–28%. ES for pulmonary complications was 28% with 95% CI: 18%–37%. ES for dermatological complications was 25%, with a 95% CI of 23%–26%. ES for endocrine outcomes was 8%, with a 95% CI of 8%–9%. ES size for renal outcomes was 3% with a 95% CI of 1%–7%. At the same time, other miscellaneous uncategorized outcomes had ES of 39% with 95% CI of 21%–57%. Apart from analyzing COVID-19 systemic complications outcomes, the ES for hospitalization and intensive care unit admissions were found to be 4%, 95% CI: 0%–7%, and 11% with 95% CI: 8%–14%. Conclusion By acquiring the data and statistically analyzing the post-COVID-19 complications during the prevalence of most virulent strains, this study has generated a different way of understanding COVID-19 and its complications for better community health.
54	MO52		Kuznik, B. I.; Shapovalov, K. G.; Chalisova, N. I.	Changes in the State of Vital Systems with Long COVID-19	https://doi.org/10.1134/S2079086423020044	Published	2023-04-01	Article	https://doi.org/10.1134/S2079086423020044	Long COVID-19 is a chronic disease that continues to be studied. Data on epidemiology and the main symptoms typical for long COVID-19 are presented. Issues related to the pathogenesis of the disease are discussed. At the same time, special attention is paid to the inflammation process (including of the vascular wall endothelium), the state of the immune system (cytokine storm), the hemostasis system (the mechanism for the development of microangiopathy and thrombosis), and oxidative stress. During the analysis, a special place is given to central nervous system disorders (including organic brain damage) and disorders of cognitive functions. In addition, currently known complications from the cardiovascular system and respiratory organs are described. The treatment and rehabilitation of patients with long COVID-19 is not only a medical, but also a significant social problem.
55	MO53		Durstenfeld, Matthew S; Peluso, Michael J; Kaveti, Punita; Hill, Christopher; Li, Danny; Sander, Erica; Swaminathan, Shreya; Arechiga, Victor M; Lu, Scott; Goldberg, Sarah A; Hoh, Rebecca; Chenna, Ahmed; Yee, Brandon C; Winslow, John W; Petropoulos, Christos J; Kelly, J Daniel; Glidden, David V; Henrich, Timothy J; Martin, Jeffrey N; Lee, Yoo Jin; Aras, Mandar A; Long, Carlin S; Grandis, Donald J; Deeks, Steven G; Hsue, Priscilla Y	Reduced exercise capacity, chronotropic incompetence, and early systemic inflammation in cardiopulmonary phenotype Long COVID	https://doi.org/10.1093/infdis/jiad131	Published	2023-05-11	Study	https://doi.org/10.1093/infdis/jiad131	Mechanisms underlying persistent cardiopulmonary symptoms following SARS-CoV-2 infection (post-acute sequelae of COVID-19 “PASC” or “Long COVID”) remain unclear. This study sought to elucidate mechanisms of cardiopulmonary symptoms and reduced exercise capacity.We conducted cardiopulmonary exercise testing (CPET), cardiac magnetic resonance imaging (CMR) and ambulatory rhythm monitoring among adults > 1 year after confirmed SARS-CoV-2 infection in a post-COVID cohort, compared those with or without symptoms, and correlated findings with previously measured biomarkers.Sixty participants (median age 53, 42% female, 87% non-hospitalized) were studied at median 17.6 months following SARS-CoV-2 infection. On CPET, 18/37 (49%) with symptoms had reduced exercise capacity (<85% predicted) compared to 3/19 (16%) without symptoms (p = 0.02). Adjusted peak VO2 was 5.2 ml/kg/min lower (95%CI 2.1-8.3; p = 0.001) or 16.9% lower percent predicted (95%CI 4.3-29.6; p = 0.02) among those with symptoms. Chronotropic incompetence was common. Inflammatory markers and antibody levels early in PASC were negatively correlated with peak VO2 more than 1 year later. Late-gadolinium enhancement on CMR and arrhythmias were absent.Cardiopulmonary symptoms >1 year following COVID-19 were associated with reduced exercise capacity, which was associated with elevated inflammatory markers early in PASC. Chronotropic incompetence may explain exercise intolerance among some with cardiopulmonary Long COVID.
56	MO54		Contreras, Alejandra Meza; Newman, Darrell B.; Cappelloni, Lucio; Niven, Alexander S.; Mueller, Michael R.; Ganesh, Ravindra; Squires, Ray W.; Bonikowske, Amanda R.; Allison, Thomas G.	Cardiopulmonary testing in long COVID-19 versus non–COVID-19 patients with undifferentiated Dyspnea on exertion	https://doi.org/10.1016/j.pcad.2023.05.005	Published	2023-05-19	Study	https://www.sciencedirect.com/science/article/pii/S0033062023000531	Background Dyspnea and fatigue are characteristics of long SARS-CoV-2 (COVID)-19. Cardiopulmonary exercise testing (CPET) can be used to better evaluate such patients. Research question How significantly and by what mechanisms is exercise capacity impaired in patients with long COVID who are coming to a specialized clinic for evaluation? Study design and methods We performed a cohort study using the Mayo Clinic exercise testing database. Subjects included consecutive long COVID patients without prior history of heart or lung disease sent from the Post-COVID Care Clinic for CPET. They were compared to a historical group of non–COVID patients with undifferentiated dyspnea also without known cardiac or pulmonary disease. Statistical comparisons were performed by t-test or Pearson's chi2 test controlling for age, sex, and beta blocker use where appropriate. Results We found 77 patients with long COVID and 766 control patients. Long COVID patients were younger (47 ± 15 vs 50 ± 10 years, P < .01) and more likely female (70% vs 58%, P < .01). The most prominent difference on CPETs was lower percent predicted peak V̇O2 (73 ± 18 vs 85 ± 23%, p < .0001). Autonomic abnormalities (resting tachycardia, CNS changes, low systolic blood pressure) were seen during CPET more commonly in long COVID patients (34 vs 23%, P < .04), while mild pulmonary abnormalities (mild desaturation, limited breathing reserve, elevated V̇E/V̇CO2) during CPET were similar (19% in both groups) with only 1 long COVID patient showing severe impairment. Interpretation We identified severe exercise limitation among long COVID patients. Young women may be at higher risk for these complications. Though mild pulmonary and autonomic impairment were common in long COVID patients, marked limitations were uncommon. We hope our observations help to untangle the physiologic abnormalities responsible for the symptomatology of long COVID.

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NE PAS MODIFIER CETTE FEUILLE - SA MISE A JOUR EST AUTOMATIQUE

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D01

No

Vittori

COVID-19 Pandemic Acute Respiratory Distress Syndrome Survivors: Pain After the Storm?

https://doi.org/10.1213/ANE.0000000000004914

published

1-Jul-20

https://journals.lww.com/anesthesia-analgesia/fulltext/2020/07000/covid_19_pandemic_acute_respiratory_distress.19.aspx

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4

D02

No

Mahase

Covid-19: What do we know about “long covid”?

https://doi.org/10.1136/bmj.m2815

published

14-Jul-20

https://www.bmj.com/content/370/bmj.m2815.short

“Long covid” is a term being used to describe illness in people who have either recovered from covid-19 but are still report lasting effects of the infection or have had the usual symptoms for far longer than would be expected

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5

D03

No

Avis de l’Académie : Les séquelles de la Covid-19

http://www.academie-medecine.fr/avis-de-lacademie-les-sequelles-de-la-covid-19/

"Shortness of breath, cough, a few weeks or months after infection, pulmonologists call on former patients to have a pulmonary check-up, even if they have the feeling of being totally recovered."

"Essoufflement, toux, quelques semaines ou mois après l'infection, les pneumologues appellent les anciens malades à faire un bilan pulmonaire, même s'ils ont le sentiment d'être totalement rétablis."

6

D04

No

APP - The COVID Symptom Study was created by doctors and scientists working in partnership with ZOE – a health science company.

How long does COVID-19 last?

6-Jun-20

https://covid.joinzoe.com/post/covid-long-term?fbclid=IwAR1RxIcmmdL-EFjh_aI-

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7

D05

No

Torjesen

NICE cautions against using graded exercise therapy for patients recovering from covid-19

https://doi.org/10.1136/bmj.m2912

published

21-Jul-20

https://www.bmj.com/content/370/bmj.m2912

The large number of patients experiencing post-viral fatigue after covid-19 has now shone a spotlight on the controversial technique again.

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8

D06

No

REVUE MÉDICALE SUISSE

COVID-19: Que sait-on aujourd’hui sur ses différentes séquelles ?

https://doi.org/10.53738/REVMED.2020.16.701.1466

opinion

https://www.revmed.ch/RMS/2020/RMS-N-701/COVID-19-Que-sait-on-aujourd-hui-sur-ses-differentes-sequelles

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9

D07

No

Nisreen A Alwan

What exactly is mild covid-19?

published

28-Jul-20

https://blogs.bmj.com/bmj/2020/07/28/nisreen-a-alwan-what-exactly-is-mild-covid-19/

We still know very little about covid-19, but we do know that we cannot fight what we do not measure
I am advocating for precise case definitions for covid-19 morbidity that reflect the degree of severity of infection and allow us to measure moderate and long term health and wellbeing outcomes

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10

D08

No

Alwan

A negative COVID-19 test does not mean recovery

https://doi.org/10.1038/d41586-020-02335-z

published

11-Aug-20

https://www.nature.com/articles/d41586-020-02335-z

Defining and measuring recovery from COVID-19 should be more sophisticated than checking for hospital discharge, or testing negative for active infection or positive for antibodies. Once recovery is defined, we can differentiate COVID that quickly goes away from the prolonged form.
The ‘recovery’ definition must include duration, severity and fluctuation of symptoms, as well as functionality and quality of life

A good starting point are the studies characterizing typical symptoms on a population level.

Measuring recovery is not an easy ask with health and surveillance systems already struggling to cope. It makes sense to set up disease registers, akin to cancer registries, to track people over time and record their condition. This could be done through quick monthly, and subsequently annual, check-ups with health-care providers. If national registers are not quickly forthcoming, local ones could be started.

11

D09

No

Burgers

“Long covid”: the Dutch response

https://doi.org/10.1136/bmj.m3202

published

14-Aug-20

general practitioner

https://www.bmj.com/content/370/bmj.m3202.full

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12

D10

No

WHO Director-General's opening remarks at the media briefing on COVID-19 - 21 August 2020

21-Aug-20

WHO

https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---21-august-2020

Last month my colleague Dr Maria van Kerkhove contacted a group called Long COVID SOS, representing patients with long-term effects from COVID-19 infection.
This afternoon I had the privilege of speaking with them. They told us about their experience, and the ongoing challenges they face. These patients want three things: recognition, rehabilitation and research.
Recognition of their disease, appropriate rehabilitation services, and more research to be done into the long-term effects of this new illness.
Although we have learned so much about this disease, we only have less than 8 months of experience to draw on. We still know relatively little about the long-term effects.
My message to these patients was: we hear you loud and clear, and we are committed to working with countries to ensure you receive the services you need, and to advancing research to serve you better.

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13

D11

No

Allocution liminaire du Directeur général de l’OMS au point de presse sur la COVID-19 – 21 août 2020

21-Aug-20

WHO

https://www.who.int/fr/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---21-august-2020

Le mois dernier, ma collègue, la Dre Maria van Kerkhove, a contacté les membres d’un groupe dont le nom est « Long COVID SOS », qui représente des patients chez qui la COVID-19 a des effets à long terme. Cet après-midi, j’ai eu le plaisir de m’entretenir avec eux. Ils m’ont parlé de leur expérience et des difficultés auxquelles ils sont confrontés. Ces patients réclament 3 choses : reconnaissance, réadaptation et recherche. Reconnaissance de leur maladie, services de réadaptation adaptés et travaux de recherche supplémentaires sur les effets à long terme de cette nouvelle maladie. Bien que nous ayons beaucoup appris sur cette maladie, nous avons moins de 8 mois de recul à peine. Nous en savons encore relativement peu sur ses effets à long terme. Voilà ce que j’ai répondu à ces patients : nous avons bien compris votre message et nous nous engageons à collaborer avec les pays pour que vous puissiez bénéficier des services dont vous avez besoin et pour faire progresser la recherche en votre faveur.

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D12

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Prerna Garg MD Umang Arora MD Arvind Kumar MD Naveet Wig MD

The “post‐COVID” syndrome: How deep is the damage?

https://doi.org/10.1002/jmv.26465

opinion published

27-Aug-20

LETTER TO THE EDITOR

https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.26465

Journal of Medical Virology.
Letter : «The “Post‐COVID” Syndrome: How Deep is the Damage?»
symptoms due to persistent chronic inflammation (convalescent phase), sequelae of organ damage (acute lung and kidney injury resulting in pulmonary fibrosis and chronic kidney disease, respectively), and nonspecific effects from the hospitalization and social isolation (nutritional anemia, muscle wasting)

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D13

Nabavi Nisreen Alwan, Paul Garner, Fiona Godlee,Trisha Greenhalgh, Nick Peters, Valentina Puntmann, Tim Spector

Long covid: How to define it and how to manage it

https://doi.org/10.1136/bmj.m3489

opinion

7-Sep-20

BMJ Webinar

https://www.bmj.com/content/370/bmj.m3489 https://docs.google.com/document/d/1qlz_zdp6ZoKJpM7DEtt028hi0mzTwD11Vln8gjCboEY/edit?usp=sharing

“not recovering [for] several weeks or months following the start of symptoms that were suggestive of covid, whether you were tested or not.”

A very common feature is the relapsing, remitting nature of the illness, where you feel as though you’ve recovered, then it hits you back,”

"#LongCovid Diagnostic, Prise en charge, Pronostic",
un webinar d'1h13 organisé par le BMJ :
[avec Liverpool Sch. of Tropical Medicine
Universities of Southampton, Oxford, Hospital Frankfurt
Imperial & Kings Colleges London]

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D14

Karthikeyan P Iyengar1, Raju Vaishya2

Long-term health consequences of COVID-19 disease

https://doi.org/10.4103/am.am_109_20

Published

9-Sep-20

REVIEW ARTICLE

https://www.apollomedicine.org/article.asp?issn=0976-0016;year=2020;volume=17;issue=5;spage=32;epage=35;aulast=Iyengar

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17

D15

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Benjamin Davido
Sophie Seang
Roland Tubiana
Pierre de Truchis

Post–COVID-19 chronic symptoms: a postinfectious entity?

https://doi.org/10.1016/j.cmi.2020.07.028

Published

22-Jul-20

COMMENTARY

https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(20)30436-5/fulltext

APHP study, dysautonomia. Overall, we believe patients with persistent symptoms (beyond 8 weeks after the onset of COVID-19) should consult their general practitioner for a first evaluation, including biological tests with COVID-19 serology, antinuclear antibodies and transthoracic echocardiography to rule out other diagnosis, especially myopericarditis, with a chest computed tomographic scan to assess precisely whether there is any sequelae of COVID-19 and offer reassurance. In case of persistent symptoms beyond 3 months, it could be relevant to investigate deeply the possible relationship between those chronic inflammatory symptoms and COVID-19, and to work hand in hand with other specialists, including a psychologist, a pneumologist, a neurologist and a specialist in physical medicine and rehabilitation.
SARS-CoV-2 could probably play the same role of an immune trigger, as already known in Guillain-Barré syndrome and other autoimmune diseases. Therefore, patients should be tested for antinuclear antibodies and the tests repeated over time after 6 weeks, especially if they are young women with rheumatologic pain, in order to rule out a possible dormant underlying autoimmune disease.

étude de l'APHP, évocation de la dysautonomie

N0

___Definition of long covid___

Published commentary on 22-Jul-20:
"Post–COVID-19 chronic symptoms: a postinfectious entity?"
étude de l'APHP, évocation de la dysautonomie
Link: https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(20)30436-5/fulltext
Extract: "APHP study, dysautonomia. Overall, we believe patients with persistent symptoms (beyond 8 weeks after the onset of COVID-19) should consult their general practitioner for a first evaluation, including biological tests with COVID-19 serology, antinuclear antibodies and transthoracic echocardiography to rule out other diagnosis, especially myopericarditis, with a chest computed tomographic scan to assess precisely whether there is any sequelae of COVID-19 and offer reassurance. In case of persistent symptoms beyond 3 months, it could be relevant to investigate deeply the possible relationship between those chronic inflammatory symptoms and COVID-19, and to work hand in hand with other specialists, including a psychologist, a pneumologist, a neurologist and a specialist in physical medicine and rehabilitation.
SARS-CoV-2 could probably play the same role of an immune trigger, as already known in Guillain-Barré syndrome and other autoimmune diseases. Therefore, patients should be tested for antinuclear antibodies and the tests repeated over time after 6 weeks, especially if they are young women with rheumatologic pain, in order to rule out a possible dormant underlying autoimmune disease."

18

D16

From doctors as patients: a manifesto for tackling persisting symptoms of covid-19

https://doi.org/10.1136/bmj.m3565

published

15-Sep-20

https://www.bmj.com/content/370/bmj.m3565

Widespread testing was not available in the early days of the pandemic. The timing of tests for active covid-19 infection (such as RT-PCR tests) affects test performance, and even if performed at an optimal time, the test is associated with a considerable risk of false negatives.9 We know antibody tests have mainly been validated in patients in hospital and are poorly sensitive early in the illness.10 There are few data regarding testing later in the disease course, and false negatives seem to be common. Some people do not seroconvert11 despite having previously tested positive. Where current guidance has been issued, such as the statement from the National Institute for Health and Care Excellence5 cautioning against graded exercise therapy in the context of covid-19, it should be communicated quickly to clinicians on the front line.

clinicians should “be open about uncertainty and transparent in the ways in which we acknowledge the limitations of the imperfect data we have no choice but to use.”2 We argue that this means accepting an emerging picture that prolonged symptoms are having a substantial impact on a significant minority of people and acknowledging that death is not the only outcome to measure.

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D17

Wise

Long covid: doctors call for research and surveillance to capture disease

https://doi.org/10.1136/bmj.m3586

published

15-Sep-20

A group of doctors who have been affected by persistent symptoms of covid-19 have written a manifesto based on their personal experiences

https://www.bmj.com/content/370/bmj.m3586

the doctors warned against reliance on “one size fits all” online rehabilitation services as they risk “serious harm to patients if pathology goes undetected.”

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20

D18

Yes

Rita Rubin, MA

As Their Numbers Grow, COVID-19 “Long Haulers” Stump Experts

https://doi.org/10.1001/jama.2020.17709

Published

23-Sep-20

Medical News & Perspectives

https://jamanetwork.com/journals/jama/fullarticle/2771111

An article in JAMA notes that #LongCovid is increasingly being likened to myalgic encephalomyelitis (ME / CFS).
It affects women four times more than men, with an average age of 40 years, and concerns 10% of symptomatic patients.

Un article dans JAMA note que le #LongCovid est de plus en plus assimilé à une encéphalomyélite myalgique (ME/SFC).
Il toucherait 4x plus les femmes que les hommes, de moyenne d'âge 40 ans, et concernerait 10% des malades symptomatiques.

21

D19

The BMJ interview: Anthony Fauci on covid-19

https://doi.org/10.1136/bmj.m3703

published

23-Sep-20

https://www.bmj.com/content/370/bmj.m3703.short

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22

D20

Perego

Why the Patient-Made Term 'Long Covid' is needed

https://doi.org/10.12688/wellcomeopenres.16307.1

under-review

24-Sep-20

https://wellcomeopenresearch.org/articles/5-224

Long Covid’ is a patient-made term that, in the absence of formally agreed definitions, we use here to describe diverse symptoms persisting beyond four weeks after symptom onset suggestive of COVID-19.

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23

D21

Hopkins

Managing long covid: don’t overlook olfactory dysfunction

https://doi.org/10.1136/bmj.m3736

published

25-Sep-20

https://www.bmj.com/content/370/bmj.m3736.full

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24

D020

Godlee

Covid-19: We need to understand the risks to tackle them

https://doi.org/10.1136/bmj.m3790

published

1-Oct-20

https://www.bmj.com/content/371/bmj.m3790

And people do need to get back to work, to stave off the damaging effects on health and wellbeing of unemployment and economic decline

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25

D021

Yes

Alwan

Why we need to keep using the patient made term “Long Covid”

published

1-Oct-20

https://blogs.bmj.com/bmj/2020/10/01/why-we-need-to-keep-using-the-patient-made-term-long-covid/

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26

D022

Yelin

Long-term consequences of COVID-19: research needs

https://doi.org/10.1016/S1473-3099(20)30701-5

published

1-Oct-20

https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30701-5/fulltext#.X6Ihwv6-MLM.twitter

The participation of an international and interdisciplinary group of researchers is essential. Multisite and multinational projects are needed because a description from one group or one site cannot discern between universal features and features of the local health system or the local population.

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27

D023

withdrawn

Martin

Long Covid: quantitative and qualitative analyses of online Long Haulers’ experiences, emotions and practices in the UK

https://doi.org/10.1101/2020.10.01.20201699

under-review

4-Oct-20

social media and discourse analysis of UK

https://www.medrxiv.org/content/10.1101/2020.10.01.20201699v1

a) the time-frames assigned to Covid-19; b) the range of symptoms, which affects testing/diagnoses; c) the emotional/intellectual impact on Long Haulers; d) lack of resources and information.

_

28

D024

Del Rio

Long-term Health Consequences of COVID-19

https://doi.org/10.1001/jama.2020.19719

published

5-Oct-20

https://jamanetwork.com/journals/jama/fullarticle/2771581

postacute COVID-19 is defined as the presence of symptoms extending beyond 3 weeks from the initial onset of symptoms and chronic COVID-19 as extending beyond 12 weeks.

_

29

D025

FelicityCallardaElisaPeregob

How and why patients made Long Covid

https://doi.org/10.1016/j.socscimed.2020.113426

Published

7-Oct-20

Short communication

https://www.sciencedirect.com/science/article/pii/S0277953620306456

An article in @socscimed describes how the #LongCovid community was formed and made it known through hashtags and arrests from the authorities.
"the first illness to be collectively made by patients finding one another through various social media."

Un article dans @socscimed décrit comment la communauté #LongCovid s'est constituée et fait connaître par hashtags et interpellations des autorités.
"the first illness to be collectively made by patients finding one another through various social media."

30

D026

Nature

Long COVID: let patients help define long-lasting COVID symptoms

https://doi.org/10.1038/d41586-020-02796-2

Published

7-Oct-20

EDITORIAL

https://www.nature.com/articles/d41586-020-02796-2

@nature editorial highlighting the call to properly define recovery (to #CountLongCovid) to descibe prolonged #COVID19 symptoms.
They are also calling for the definition of recovery from COVID-19 to be based on criteria that extend beyond just testing negative for COVID. People’s symptoms should be considered, too, such as chest heaviness, breathlessness, muscle pains, palpitations and fatigue, Such terms also carry assumptions about the condition’s underlying physiology that have not yet been properly investigated.
Words such as ‘post’, ‘syndrome’ and ‘chronic’ risk delegitimizing suffering, the authors argue, and that will make it harder for people to access care.

@nature editorial highlighting the call to properly define recovery (to #CountLongCovid) to descibe prolonged #COVID19 symptoms.

31

D027

John E. Morley

COVID-19 — The Long Road to Recovery

Published

5-Oct-20

Editorial

https://link.springer.com/article/10.1007/s12603-020-1473-6

These symptoms of “long Covid” include: fatigue, cough, dyspnea, loss of taste and smell, muscle weakness, muscle and joint pain, headache, confusion, conjunctivitis, chest pain, decreased mobility and falls

Court éditorial sur le #LongCovid et la réadaptation à fournir aux malades, notamment âgés, dans The Journal of Nutrition, Health & Aging, évoquant le programme d'exercices "ViviFrail".

32

D028

Halpin

Long COVID and chronic COVID syndromes

https://doi.org/10.1002/jmv.26587

LETTER TO THE EDITOR Free Access

9-Oct-20

https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.26587

Long COVID or postacute COVID (symptoms beyond 3 weeks) and chronic post‐COVID syndrome (beyond 12 weeks) are multisystem syndromes and need a multifaceted approach to tackle the physical, cognitive, psychological, social, and vocational domains of this health condition.

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33

D029

Kingstone

Finding the 'right' GP: a qualitative study of the experiences of people with long-COVID

https://doi.org/10.3399/bjgpopen20x101143

published

13-Oct-20

24 interviews.

https://pubmed.ncbi.nlm.nih.gov/33051223/

Patients require their GP to believe their symptoms and to demonstrate empathy and understanding

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34

D030

Mahase

Long covid could be four different syndromes, review suggests

https://doi.org/10.1136/bmj.m3981

published

14-Oct-20

according to a review by the National Institute for Health Research (NIHR).

https://www.bmj.com/content/371/bmj.m3981

people experiencing long term effects of covid-19 may have different syndromes such as post-intensive care syndrome, post-viral fatigue syndrome, and long term covid syndrome

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35

D031

NIHR

Living with Covid19

https://doi.org/10.3310/themedreview_41169

Published

15-Oct-20

Themed Review

https://evidence.nihr.ac.uk/themedreview/living-with-covid19/

A dynamic review by the NIHR institute (▶ https://evidence.nihr.ac.uk/themedreview/living-with-covid19/) lists at least 4 causes of #LongCovid:
- 1/ permanent lung or heart sequelae 2/ - myalgic encephalomyelitis / CFS
- 3/ post-resuscitation syndrome 4/ - persistence of symptoms
People experience a wide range of fluctuating and multisystem symptoms that need to be acknowledged. A common theme is that symptoms arise in one physiological system then abate only for symptoms to arise in a different system.
Ongoing Covid19 needs to be considered holistically (both in service provision and in research).
The varying degrees of dependency mean support in the community should be considered alongside hospital one stop clinics.
“COVID-19 is clearly a complex multisystem disease and not just restricted to the cardiopulmonary systems. This is so, both in the acute phase and the post-acute recovery phase. Our service personnel who are undergoing multidisciplinary inpatient rehabilitation, at DMRC Stanford Hall, for their post COVID-19 sequalae commonly complain of fatigue (which can be severe), myalgias, anxiety, low mood, cognitive problems and atypical chest pain.”
Group Captain Alex Bennett, Defence Professor of Rheumatology and Rehabilitation, Stanford Hall

Une étude dynamique de l'institut 🇬🇧 NIHR
répertorie au moins 4 causes de #LongCovid :
- séquelles permanentes poumons ou cœur
- encéphalomyélite myalgique / SFC
- syndrome post-réanimation
- persistance des symptômes

36

D032

COVID-19 guideline scope: management of
the long-term effects of COVID-19

19-Oct-20

NICE

https://www.nice.org.uk/guidance/gid-ng10179/documents/final-scope

Signs and symptoms that develop during or following an infection consistent with
COVID-19, continue for more than 12 weeks and are not explained by an alternative
diagnosis. It usually presents with clusters of symptoms, often overlapping, which
can fluctuate and change over time and can affect any system in the body.
Post-COVID-19 syndrome may be considered before 12 weeks while the possibility
of an alternative underlying disease is also being assessed.

_

37

D033

Mannan Baig

Chronic COVID Syndrome: Need for an appropriate medical terminology for Long‐COVID and COVID Long‐Haulers

https://doi.org/10.1002/jmv.26624

published

23-Oct-20

https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.26624

the term chronic covid syndrome (CCS) would be a more traditional way of symbolizing the so‐called long‐covid and long‐haulers in COVID‐19.

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38

D034

Ryan Syrek

Trending Clinical Topic: COVID Syndromes

opinion

30-Oct-20

DISCLOSURES

https://reference.medscape.com/viewarticle/937400

The syndromes linked to covid make the headlines in Drugs and Diseases, with the arrival of the “long covid” classification, as well as “coronaphobia” which designates the psychological and psychiatric effects of the pandemic on the population.

Les différents syndromes liés à la covid font la une dans Drugs and Diseases, avec l'arrivée de la classification "long covid", ainsi que du terme "coronaphohie" qui désigne les effets psychologiques et psychiatriques de la pandémie sur la population.

39

D035

WHO Director-General's opening remarks at the media briefing on COVID-19 - 30 October 2020

published

30-Oct-20

WHO

https://www.who.int/fr/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---30-october-2020

Over the past few months, I have heard first hand from people who face mid to long-term effects of COVID-19 infection.

What’s really concerning is the vast spectrum of symptoms that fluctuate over time, often overlap and can affect any system in the body.

From fatigue, a cough and shortness of breath, to inflammation and injury of major organs - including the lungs and heart. And even neurological and psychologic effects.

Although we’re still learning about the virus, what’s clear is that this is not just a virus that kills people.

To a significant number of people, this virus poses a range of serious long-term effects.

While people do recover, it can be slow – sometimes weeks or months – and it is not always a linear route to recovery.

Though exact numbers of people experiencing the long-term affects are not yet clearly defined, post COVID-19 symptoms and complications have been reported in both non-hospitalised and hospitalised patients.

There have been cases in women and men, both young and old. And even in children.

WHO will continue to do more research to establish best standards of care to accelerate recovery and prevent such complications.

It is imperative that governments recognise the long-term effects of COVID-19 and also ensure access to health services to all of these patients.

This includes primary health care and when needed specialty care and rehabilitation.

I’d now like to hand over the floor to three patients who are still combatting the long-term effects of COVID-19 so that we can hear their stories.
First, Professor Paul Garner from Liverpool School of Tropical Medicine who has himself been recovering from COVID-19 since March.

_

40

D036

Allocution liminaire du Directeur général de l’OMS lors du point presse sur la COVID-19 – 30 octobre 2020

published

30-Oct-20

WHO

https://www.who.int/fr/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---30-october-2020

Ce qui est vraiment inquiétant, c’est la grande diversité des symptômes qui évoluent dans le temps, se chevauchent souvent et peuvent affecter n’importe quel système corporel.

Ces symptômes vont de la fatigue, la toux et l’essoufflement à une inflammation et des lésions des principaux organes, y compris les poumons et le cœur. Sans oublier les effets neurologiques et psychologiques.

_

41

D037

Alwan

Scientific consensus on the COVID-19 pandemic: we need to act now

https://doi.org/10.1016%2FS0140-6736(20)32153-X

published

31-Oct-20

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557300/

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42

D038

MCorkell

Patient-Led Research for COVID-19: Embedding Patients in the Long COVID Narrative

https://doi.org/10.31219/osf.io/n9e75

under-review

Patient led research

https://osf.io/n9e75

These patients have what is now referred to as Long COVID [22], which we define as being symptomatic from COVID-19 for over three weeks, with many experiencing debilitating symptoms for month

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43

D039

Megan Tatum

I could barely function' – the devastating effects of long COVID

https://doi.org/10.1211/PJ.2020.20208498

opinion

5-Nov-20

Analysis

https://www.pharmaceutical-journal.com/news-and-analysis/features/i-could-barely-function-the-devastating-effects-of-long-covid/20208498.article?firstPass=false

The Pharmaceutical Journal (Drapeau du Royaume-Uni) publishes an article on #longcovid, with the advice of several specialists.

Le Pharmaceutical Journal (🇬🇧) publie un article sur le #covidlong, avec l'avis de plusieurs spécialistes.

44

D040

Yes

CDC

Late Sequelae of COVID-19

Published

13-Nov-20

Article

https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/late-sequelae.html

The CDC takes stock of the knowledge acquired on the sequelae of covid.
Long covid appears to be protean, both in its etiology and in its symptoms. The SARS-CoV-2 virus has a very strong affinity with the ACE2 receptors present on the surface of many types of cells. We can therefore find damage to various organs, such as the heart, kidneys, or, in this study, the lungs. A persistent inflammatory state is also suspected to be the cause of symptoms over the long term, insofar as it had already been noted that a sepsis could cause immune sequelae. A third category of cause of persistent symptoms could be linked to a viral reservoir located in one or more organs, such as infected retinal cells in the case of the Ebola virus. Finally, poor regulation of neutralizing antibodies could explain other symptoms. To this basic etiology, factors may be added:
1/- physical deconditioning 2/ - pre-existing comorbidities 3/ - post-traumatic psychological sequelae or related to changes in the rhythm of life due to the pandemic.
In the United States, large studies are underway on the sequelae of covid, including:
In Maryland: "A longitudinal study of COVID-19 sequelae and immunity" and in San Francisco: "Long-term impact of infection with novel coronavirus (COVID-19) (LIINC)". These studies will extend over several years.

The most commonly reported symptoms include fatigue, dyspnea, cough, arthralgia, and chest pain. Other reported symptoms include cognitive impairment, depression, myalgia, headache, fever, and palpitations. More serious complications appear to be less common but have been reported. These complications include:
Cardiovascular: myocardial inflammation, ventricular dysfunction Respiratory: pulmonary function abnormalities
Renal: acute kidney injury Dermatologic : rash, alopecia
Neurological: olfactory and gustatory dysfunction, sleep dysregulation, altered cognition, memory impairment
Psychiatric: depression, anxiety, changes in mood
Characterization of the etiology and pathophysiology of late sequelae is underway, and may reflect organ damage from the acute infection phase, manifestations of a persistent hyperinflammatory state, ongoing viral activity associated with a host viral reservoir, or an inadequate antibody response.

Les CDC (qui représentent l'agence fédérale de santé publique des É-U) dressent un bilan des connaissances acquises sur les séquelles de la covid. Le virus SARS-CoV-2 a une affinité très forte avec les récepteurs ACE2 présents à la surface de nombreux types de cellules. On peut donc retrouver des atteintes à divers organes, comme le cœur, les reins, ou, dans cette étude, les poumons.
Le covid long apparaît comme protéiforme, aussi bien dans son étiologie que dans ses symptômes. Un état inflammatoire persistant est également soupçonné d'être la cause de symptômes sur le long cours, dans la mesure où il avait déjà été noté qu'un état septique pouvait engendrer des séquelles immunitaires. Une 3e catégorie de cause de symptômes persistants pourrait être liée à un réservoir viral situé dans un ou plusieurs organes, comme les cellules rétiniennes infectées dans le cas du virus Ebola. Enfin, une mauvaise régulation des anticorps neutralisants pourrait expliquer d'autres symptômes. À cette étiologie de base, des facteurs peuvent s'ajouter :
- le déconditionnement physique
- des comorbidités pré-existantes
- des séquelles psychologiques post-traumatiques ou liées aux changements dans le rythme de vie du fait de la pandémie. Aux États-Unis, de larges études sont en cours sur les séquelles de la covid, notamment :
Dans le Maryland : "A longitudinal study of COVID-19 sequelae and immunity" et à San Francisco : "Long-term impact of infection with novel coronavirus (COVID-19) (LIINC)". Ces études vont s'étendre sur plusieurs années.

45

D041

Matthew Zirui Tay, Chek Meng Poh, Laurent Rénia, Paul A. MacAry & Lisa F. P. Ng

The trinity of COVID-19: immunity, inflammation and intervention

https://doi.org/10.1038/s41577-020-0311-8

Published

28-Apr-20

Review Article

https://www.nature.com/articles/s41577-020-0311-8

Un état inflammatoire persistant est également soupçonné d'être la cause de symptômes sur le long cours

46

D042

Now published in Therapeutic Advances in Chronic Disease doi: 10.1177/2040622320976979

Wildwing

The Neurological Symptoms of Long COVID-19: A Comparison with other Neurological Conditions and Implications for Healthcare Services

https://doi.org/10.1101/2020.07.21.20158816

under-review

https://www.medrxiv.org/content/10.1101/2020.07.21.20158816v3

When compared, these Long Covid symptoms are very similar to other neurological conditions such as Chronic Fatigue Syndrome (CFS) and Functional Neurological Disorder (FND).

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47

D043

Lancet

Facing up to long COVID

https://doi.org/10.1016/S0140-6736(20)32662-3

Published

12-Dec-20

Editorial

https://www.thelancet.com/journals/ebiom/article/PIIS0140-6736(20)32662-3/fulltext

long COVID affects even young adults, so effective public health messaging for such individuals about the risks of infection is warranted

Le COVID long affecte même les jeunes adultes, de sorte qu'un message de santé publique efficace pour ces personnes sur les risques d'infection est justifié

48

D044

National Institute for Health and Care Excellence (NICE)

COVID-19 rapid guideline: managing the long-term effects of COVID-19
NICE guideline [NG188]

Published

18-Dec-20

Guideline

https://www.nice.org.uk/guidance/ng188

Le National Institute for Health and Care Excellence (NICE), le Scottish Intercollegiate Guidelines Network (SIGN) et le Royal College of General Practitioners (RCGP) éditent des lignes directrices pour le #covidlong.Le "booklet" :
https://www.sign.ac.uk/patient-and-public-involvement/patient-publications/long-covid
Ce site de NICE sera mis à jour en fonction des découvertes et progrès dans les soins. Un article d'opinion dans The Lancet témoigne de la déception de plusieurs spécialistes à propos de ce guide
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32705-7/fulltext
Il lui est reproché une vision superficielle du sujet, une faible prise en compte des données de l'OMS et un choix contestable de dénominations.

49

D045

S. Deblina Datta, MD1; Amish Talwar, MD, MPH1; James T. Lee, MD, MSc1,2

A Proposed Framework and Timeline of the Spectrum of Disease Due to SARS-CoV-2 Infection
Illness Beyond Acute Infection and Public Health Implications

https://doi.org/10.1001/jama.2020.22717

Published

18-Nov-20

Viewpoint

https://jamanetwork.com/journals/jama/fullarticle/2773338

Une présentation dans JAMA Psychiatry des phases de la covid et notamment des symptômes à distance de l'infection. La présentation date de mi-novembre.

50

D046

Nisreen A Alwan1 2 3, Luke Johnson1

Long COVID: where do we start with the case definitions?

pre-print

1-Dec-20

Viewpoint

https://www.google.com/url?sa=t&source=web&rct=j&url=https://osf.io/hndtm/download/%3Fformat%3Dpdf&ved=2ahUKEwj_x8KkxOztAhVMzBoKHU6VCrwQFjAAegQIAhAB&usg=AOvVaw2RiDiXl4D_iOSKeD2JF5Nj

_

51

D047

Manoj Sivan, Sharon Taylor

NICE guideline on long covid

https://doi.org/10.1136/bmj.m4938

Published

23-Dec-20

Editorial

https://www.bmj.com/content/371/bmj.m4938.full

Un éditorial dans la publication médicale BMJ émet quelques critiques sur le guide du National Institute for Health and Care Excellence concernant les effets à long terme de la covid, et appelle à des directives plus pragmatiques.

52

D048

The Lancet

6 months consequences of covid19

https://doi.org/10.1016/S0140-6736(20)32656-8

Published

1-Jul-21

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32656-8/fulltext

_

53

D049

BMJ

Managing the long term effects of covid-19: summary of NICE, SIGN, and RCGP rapid guideline

https://doi.org/10.1136/bmj.n136

Published

22-Jan-21

Guidelines

https://www.bmj.com/content/372/bmj.n136.full

La revue médicale BMJ publie un résumé des recommandations pour les effets à long terme de la covid qu'avaient élaboré l'institut NICE, les réseaux académiques britanniques SIGN et RCGP (guide critiqué par certains spécialistes dans The Lancet).

54

D050

WHO - OMS

COVID-19 Clinical management: living guidance

Published

25-Jan-21

Living guidance

https://www.who.int/publications/i/item/WHO-2019-nCoV-clinical-2021-1

L'OMS ajoute un chapitre sur le suivi médical des covids longs dans son guide de recommandations cliniques.
-> https://who.int/publications/i/item/WHO-2019-nCoV-clinical-2021-1
PDF (pp 60-61)-> https://apps.who.int/iris/rest/bitstreams/1328457/retrieve
Annexes et études utilisées (pp 10-21) -> https://apps.who.int/iris/bitstream/handle/10665/338871/WHO-2019-nCoV-clinical-web_annex-2021.1-eng.pdf

55

D051

Felicity Callard, Elisa Perego

How and why patients made Long Covid

https://doi.org/10.1016/j.socscimed.2020.113426

Published

1-Jan-21

Short communication

https://www.sciencedirect.com/science/article/pii/S0277953620306456

Un article dans Social Science & Medicine (écrit par @felicitycallard et @elisaperego78) rappelle les étapes de la reconnaissance du covid long.

56

D052

Antonis S Manolis, Theodora A Manolis

Long COVID: An Emerging Puzzle

Published

23-Jan-21

Editorial

http://rhythmos.gr/index.php/Rhythmos/article/view/497

Un éditorial dans une publication médicale grecque fait le point sur les connaissances acquises sur le covid long. Il évoque le "post Covid-19 neurological syndrome" (PCNS) ainsi que les pistes de mécanismes potentiels expliquant le covid long.

57

D053

Jean-Louis Vincent

COVID-19: it is all about sepsis

https://doi.org/10.2217/fmb-2020-0312

Published

25-Jan-21

EDITORIAL

https://www.futuremedicine.com/doi/full/10.2217/fmb-2020-0312

Selon un éditorial dans Future Medecine, la covid, par son caractère systémique et sa gravité essentiellement en rapport avec une réponse inadéquate de l'organisme à l'infection, devrait être qualifiée de septicémie.

58

D054

Daniel M Altmann

Decoding the unknowns in long covid

https://doi.org/10.1136/bmj.n132

Published

4-Feb-21

Opinion

https://www.bmj.com/content/372/bmj.n132

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59

D055

Nina Schor

Working together to understand long-term effects of COVID-19

Published

2-May-21

Opinion

https://schorline.ninds.nih.gov/2021/02/05/long-term-covid-19/amp/

_

60

D056

Vinod Nikhra

Living with 'Long COVID-19': The Long-term Complications and Sequelae

http://dx.doi.org/10.13140/RG.2.2.30322.84167

Pre-print

1-Feb-21

REVIEW ARTICLE

https://www.researchgate.net/publication/349009777

As apparent, the ‘long Covid’ afflictions are more common than realised earlier. The symptoms can escalate in patients with co-morbid conditions. The persistent symptoms among COVID-19 survivors pose new challenges to the healthcare providers and may be suitably managed with a combination of pharmacological and non-pharmacological treatments, and holistic healthcare. In addition, by reducing the inflammation and continuing damage in various organs, the prognosis can be improved.

Une revue d'études en pre-print (en relecture, non publiée) fait un tour d'horizon des éléments connus sur le covid long, les symptômes et les organes affectés, et aborde la gestion sur le long terme et les traitements et soins pour la guérison.

N004

___Definition of long covid___

Pre-Print review article on 1-Feb-21:
"Living with 'Long COVID-19': The Long-term Complications and Sequelae"
Une revue d'études en pre-print (en relecture, non publiée) fait un tour d'horizon des éléments connus sur le covid long, les symptômes et les organes affectés, et aborde la gestion sur le long terme et les traitements et soins pour la guérison.
Link: https://www.researchgate.net/publication/349009777
Extract: "As apparent, the ‘long Covid’ afflictions are more common than realised earlier. The symptoms can escalate in patients with co-morbid conditions. The persistent symptoms among COVID-19 survivors pose new challenges to the healthcare providers and may be suitably managed with a combination of pharmacological and non-pharmacological treatments, and holistic healthcare. In addition, by reducing the inflammation and continuing damage in various organs, the prognosis can be improved."

61

D057

Diego Castanares Zapatero (KCE), Germaine Hanquet (KCE), Koen Van
den Heede (KCE)

EPIDEMIOLOGY OF LONG COVID: A
PRAGMATIC REVIEW OF THE
LITERATURE

Working paper

27-Jan-21

Review

https://kce.fgov.be/sites/default/files/atoms/files/2020-04HSR_LongCOVID_COVID%20Contributions_01022021.pdf

It is estimated that in the first 12 weeks after the onset of the COVID-19 infection between 5% and 36% of patients still have symptoms. In specific patient groups (e.g. patients that have been hospitalised in the acute phase) higher rates were observed. Twelve weeks or more after onset of the disease, still about 2-15% of COVID-19 patients have symptoms.
• The most commonly reported long-term symptoms of long COVID are fatigue (up to
98%), dyspnoea (up to 93%) and headache (up to 91%). Yet it should be noted that a wide range of symptoms affect different body systems (e.g. neurological, cardiovascular, gastrointestinal) and fluctuate over time. For a large group of patients it seems that symptoms improve over time. Nevertheless, in a substantial number of cases symptoms persist. In addition to the symptoms, an impact on activities of daily life and (social) functioning is reported.
• Patients with long COVID are more likely to be older, suffer from pre-existing comorbidities, obesity or psychiatric disorders and have blood type A compared to COVID-19 patients that do not have long-term consequences. In addition, there are indications that a higher number of symptoms in the acute phase of the disease and the presence of specific symptoms such as fatigue, headache, dyspnoea, pain with deep breath, sensitive skin, hoarse voice and myalgia are also risk factors for developing long COVID.

Un document de travail rédigé par le KCE (Centre fédéral d'expertise des soins de santé, en Belgique) étudie l'épidémiologie du covid long : sa fréquence, la prévalence des symptômes, les facteurs de risque.

N003

___Definition of long covid___

Working Paper review on 27-Jan-21:
"EPIDEMIOLOGY OF LONG COVID: A
PRAGMATIC REVIEW OF THE
LITERATURE"
Un document de travail rédigé par le KCE (Centre fédéral d'expertise des soins de santé, en Belgique) étudie l'épidémiologie du covid long : sa fréquence, la prévalence des symptômes, les facteurs de risque.
Link: https://kce.fgov.be/sites/default/files/atoms/files/2020-04HSR_LongCOVID_COVID%20Contributions_01022021.pdf
Extract: "It is estimated that in the first 12 weeks after the onset of the COVID-19 infection between 5% and 36% of patients still have symptoms. In specific patient groups (e.g. patients that have been hospitalised in the acute phase) higher rates were observed. Twelve weeks or more after onset of the disease, still about 2-15% of COVID-19 patients have symptoms.
• The most commonly reported long-term symptoms of long COVID are fatigue (up to
98%), dyspnoea (up to 93%) and headache (up to 91%). Yet it should be noted that a wide range of symptoms affect different body systems (e.g. neurological, cardiovascular, gastrointestinal) and fluctuate over time. For a large group of patients it seems that symptoms improve over time. Nevertheless, in a substantial number of cases symptoms persist. In addition to the symptoms, an impact on activities of daily life and (social) functioning is reported.
• Patients with long COVID are more likely to be older, suffer from pre-existing comorbidities, obesity or psychiatric disorders and have blood type A compared to COVID-19 patients that do not have long-term consequences. In addition, there are indications that a higher number of symptoms in the acute phase of the disease and the presence of specific symptoms such as fatigue, headache, dyspnoea, pain with deep breath, sensitive skin, hoarse voice and myalgia are also risk factors for developing long COVID."

62

D058

HAS

Covid-19 : diagnostiquer et prendre en charge les adultes présentant des symptômes prolongés

Published

COMMUNIQUÉ DE PRESSE

https://www.has-sante.fr/jcms/p_3237458/fr/covid-19-diagnostiquer-et-prendre-en-charge-les-adultes-presentant-des-symptomes-prolonges

Also : https://www.has-sante.fr/jcms/p_3237041/fr/symptomes-prolonges-suite-a-une-covid-19-de-l-adulte-diagnostic-et-prise-en-charge

La Haute autorité de santé (autorité administrative indépendante en France) publie des recommandations et des fiches pratiques à destination des professionnels de santé pour suivre les patients covids longs.

N002

___Definition of long covid___

Published communiqué de presse on :
"Covid-19 : diagnostiquer et prendre en charge les adultes présentant des symptômes prolongés"
La Haute autorité de santé (autorité administrative indépendante en France) publie des recommandations et des fiches pratiques à destination des professionnels de santé pour suivre les patients covids longs.
Link: https://www.has-sante.fr/jcms/p_3237458/fr/covid-19-diagnostiquer-et-prendre-en-charge-les-adultes-presentant-des-symptomes-prolonges
Extract: "Also : https://www.has-sante.fr/jcms/p_3237041/fr/symptomes-prolonges-suite-a-une-covid-19-de-l-adulte-diagnostic-et-prise-en-charge"

63

D059

Sarah Bradbury

Long COVID-19' and the implications for the dental profession

https://doi.org/10.1038/s41404-021-0655-1

Published

8-Feb-21

Opinion

https://www.nature.com/articles/s41404-021-0655-1

Un article d'opinion qui traite de l'émergence mondial des cas de covid longs, et de l'implication des professionnels de chirurgie dentaire comme soignants devant être protégés.

64

D060

Robert M. DiSogra

ONLINE FEATURE | Labeling COVID-19’s Long-Term Effects—What’s the Diagnosis?

Published

1-Feb-21

Article

https://www.audiology.org/audiology-today-januaryfebruary-2021/online-feature-labeling-covid-19%E2%80%99s-long-term-effects%E2%80%94what%E2%80%99s

"This article addresses and defines the language associated with COVID-19 and reports on the attempts being made to establish appropriate medical terminology as it pertains to COVID-19 patients who are still experiencing medical issues for weeks and even months after the diagnosis."

Court article sur la terminologie covid et covid long.

65

D061

Terry Murray

Unpacking “long COVID”

Published

11-Feb-21

Article

https://cmajnews.com/2021/02/11/covid-longhaul-1095923/

Experts at a recent World Health Organization meeting warned that the long-term complications of COVID-19, known as “long COVID” or post COVID-19 condition, may become a crisis within a crisis for health systems already stretched thin by the pandemic.

Article sur l'alerte d'autorités sanitaires qui craignent que le covid long devienne une pandémie dans la pandémie.

66

D062

SONI, SARTHAK NILANG; NIMBALKAR, SOMASHEKHAR MARUTIRAO

Long COVID Syndrome Following Infection with SARS-CoV-2- A Devastating Influence on Health Status in Some Affected Individuals.

Published

1-Feb-21

Article

https://web.a.ebscohost.com/abstract?direct=true&profile=ehost&scope=site&authtype=crawler&jrnl=0973709X&AN=148789277&h=N7m50kypExfC95QuaquuXnT9XA0gM2NtNKxQuRH1x02DKw83vt9qnODj%2bYrW%2bVcWUuoBLeLCDtvCryPl7%2bYtVw%3d%3d&crl=c&resultNs=AdminWebAuth&resultLocal=ErrCrlNotAuth&crlhashurl=login.aspx%3fdirect%3dtrue%26profile%3dehost%26scope%3dsite%26authtype%3dcrawler%26jrnl%3d0973709X%26AN%3d148789277

As more people become fatally ill with COVID19, it is now clear that many patients who developed a mild illness, recovered from a serious illness, or had an asymptomatic infection are also beginning to suffer from a newly described entity called long Covid. Studies show that show COVID-19 influences the cardiovascular framework, yet the general effects stay Obscured. Impaired diffusion capacity, lower respiratory muscle strength, and lung imaging abnormalities are seen in COVID-19 patients in the early recovery stage. As compared to non-severe cases, severe patients had a higher incidence of Diffusion capacity of lung for carbon monoxide (DLCO) impairment and are more prone to total lung capacity decrease and 6-Minute Walk Test (6MWT) decline. The degree and seriousness of long‑term well-being outcomes remain unclear, yet increasing information points in the direction of poorer physiological outcomes. Long‑term sequelae of COVID-19 will have enduring implications on those afflicted's physical, mental, and social health while having a substantial monetary impact on society.

Article non accessible pour le moment.

67

D063

John N Aucott

Long-haul COVID: heed the lessons from other infection-triggered illnesses

https://doi.org/10.1016/S0140-6736(21)00446-3

Published

5-Mar-21

CORRESPONDENCE

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00446-3/fulltext

In listening to patients, the resolution of objective abnormalities is often not the whole story of their illness, and symptoms such as fatigue could instead be the most devastating to patients' quality of life.

"L'expérience auprès des patients permet de comprendre que le traitement des symptômes les plus objectivables n'est souvent pas l'essentiel. Ce sont les symptômes comme l'asthénie qui sont les plus dévastateurs sur leur qualité de vie"

N004

___Definition of long covid___

Published correspondence on 5-Mar-21:
"Long-haul COVID: heed the lessons from other infection-triggered illnesses"
"L'expérience auprès des patients permet de comprendre que le traitement des symptômes les plus objectivables n'est souvent pas l'essentiel. Ce sont les symptômes comme l'asthénie qui sont les plus dévastateurs sur leur qualité de vie"
Link: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00446-3/fulltext
Extract: "In listening to patients, the resolution of objective abnormalities is often not the whole story of their illness, and symptoms such as fatigue could instead be the most devastating to patients' quality of life."

68

D064

Erin Dean

Long-COVID: what it means and how to manage the longer-term effects

Published

14-Jan-21

Article

https://rcni.com/nursing-standard/newsroom/clinical-update/long-covid-what-it-means-and-how-to-manage-longer-term-effects-170741

Many people who have had COVID-19 have reported ongoing symptoms weeks and months after they first fell ill. There is growing evidence that people can experience long-term health effects and about 10% of people with initially mild illness report symptoms lasting more than four weeks.

Article non accessible pour le moment.

69

D065

Hossein Akbarialiabad * , Mohammad Hossein Taghrir , Ashkan Abdollahi , Nasrollah Ghahramani , Manasi Kumar , Shahram paydar , Babak Razani , John Mwangi , Ali A. Asadi-Pooya , Leila Malekmakan , Bahar Bastani

Long COVID, A Comprehensive Systematic Scoping Review

https://doi.org/10.1007/s15010-021-01666-x

pre-print

18-Mar-21

https://www.preprints.org/manuscript/202103.0490/v1

Une étude systématique non publiée pour l'instant fait un état des lieux de la production de travaux sur le covid long. Les question de dénomintion, de diagnostic,

70

D066

Ani Nalbandian, Kartik Sehgal, Aakriti Gupta, Mahesh V. Madhavan, Claire McGroder, Jacob S. Stevens, Joshua R. Cook, Mitchell S. V. Elkind, Jean M. Connors, John P. Bilezikian, Donald W. Landry & Elaine Y. Wan

Post-acute COVID-19 syndrome

https://doi.org/10.1038/s41591-021-01283-z

Published

22-Mar-21

Review Article

https://www.nature.com/articles/s41591-021-01283-z

Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics.

Un article dans Nature fait une revue d'études du covid long et décrit un cadre interdisciplinaire de soins pour les malades.

N010

___Definition of long covid___

Published review article on 22-Mar-21:
"Post-acute COVID-19 syndrome"
Un article dans Nature fait une revue d'études du covid long et décrit un cadre interdisciplinaire de soins pour les malades.
Link: https://www.nature.com/articles/s41591-021-01283-z
Extract: "Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics."

71

D067

Sarah Jane Palmer

Government funding for research into long COVID

https://doi.org/10.12968/bjca.2021.0027

Published

18-Mar-21

https://www.magonlinelibrary.com/doi/abs/10.12968/bjca.2021.0027

_

72

D068

NIHR

Living with Covid19 – Second review

https://doi.org/10.3310/themedreview_45225

Published

16-Mar-21

Review

https://evidence.nihr.ac.uk/themedreview/living-with-covid19-second-review/

A dynamic review of the evidence around ongoing Covid19 (often called Long Covid).
.Executive summary
.NIHR Centre for Engagement and Dissemination
.What are we aiming to achieve with our Living with Covid19 reviews?
.Framing the evidence
.What is ‘Long Covid’?
.How many people who have had Covid 19 will experience ongoing symptoms?
.The causes of Long Covid
.Impact of Long Covid on daily living
.Diagnosing and predicting the course of Long Covid
.Management of Long Covid
.Conclusion

L'institut britannique NIHR publie sa deuxième (très complète) revue d'études sur le covid long.
"Il y a des indices qui suggèrent que le covid long est une maladie toujours active, avec des indices immunologiques de réponses inflammatoires prolongées, d'activité virale persistante et/ou de troubles de coagulation. Pour certains malades du covid long, il pourrait y avoir le potentiel d'une détérioration additionnelle."

N004A

___Definition of long covid___

Published review on 16-Mar-21:
"Living with Covid19 – Second review"
L'institut britannique NIHR publie sa deuxième (très complète) revue d'études sur le covid long.
"Il y a des indices qui suggèrent que le covid long est une maladie toujours active, avec des indices immunologiques de réponses inflammatoires prolongées, d'activité virale persistante et/ou de troubles de coagulation. Pour certains malades du covid long, il pourrait y avoir le potentiel d'une détérioration additionnelle."
Link: https://evidence.nihr.ac.uk/themedreview/living-with-covid19-second-review/
Extract: "A dynamic review of the evidence around ongoing Covid19 (often called Long Covid).
.Executive summary
.NIHR Centre for Engagement and Dissemination
.What are we aiming to achieve with our Living with Covid19 reviews?
.Framing the evidence
.What is ‘Long Covid’?
.How many people who have had Covid 19 will experience ongoing symptoms?
.The causes of Long Covid
.Impact of Long Covid on daily living
.Diagnosing and predicting the course of Long Covid
.Management of Long Covid
.Conclusion"

73

D069

WIKIY

covid long haulers

Opinion

Article

https://www.wikiy.org/en/Covid_long_haulers-6286462884

Résumé de quelques éléments connus sur le covid long. Sans relecture.

74

D070

Claire Davies

Key learning points: NICE COVID-19—long-term effects

Opinion

18-Mar-21

Article

https://www.guidelinesinpractice.co.uk/infection/key-learning-points-nice-covid-19-long-term-effects/455901.article

Dr Claire Davies distils the NICE guideline on managing the long-term effects of COVID-19 into six key learning points for primary care

Un résumé des recommandations du National Institutre for health and Care Excellence (NICE) pour l'approche et le traitement du covid long.

75

D071

Andrea M. Lerner, MD, Daphne A. Robinson, PhD, Linda Yang, Johanna S. Schneider, PhD, Adaora A. Adimora, MD, MPH*, Emily J. Erbelding

Toward Understanding COVID-19 Recovery: National Institutes of Health Workshop on Postacute COVID-19

https://doi.org/10.7326/M21-1043

Published

30-Mar-21

https://www.acpjournals.org/doi/full/10.7326/M21-1043

As the number of reports of postacute COVID-19 continues to increase, fundamental questions must be answered. We urgently need a collaborative research approach that includes harmonized case definitions; delineation of epidemiology, natural history, and pathophysiology; and strategies to address longtime health disparities. This will enable the optimum implementation of evidence-based diagnostic, therapeutic, and preventive strategies essential to help mitigate the pain and suffering of individuals with postacute COVID-19.

Bilan d'un workshop américain sur le covid long, organisé par le National Institute of Allergy and Infectious Diseases (NIAID).

N006

___Definition of long covid___

Published article on 30-Mar-21:
"Toward Understanding COVID-19 Recovery: National Institutes of Health Workshop on Postacute COVID-19"
Bilan d'un workshop américain sur le covid long, organisé par le National Institute of Allergy and Infectious Diseases (NIAID).
Link: https://www.acpjournals.org/doi/full/10.7326/M21-1043
Extract: "As the number of reports of postacute COVID-19 continues to increase, fundamental questions must be answered. We urgently need a collaborative research approach that includes harmonized case definitions; delineation of epidemiology, natural history, and pathophysiology; and strategies to address longtime health disparities. This will enable the optimum implementation of evidence-based diagnostic, therapeutic, and preventive strategies essential to help mitigate the pain and suffering of individuals with postacute COVID-19."

76

D072

Gail Carson

Research priorities for Long Covid: refined through an international multi-stakeholder forum

https://doi.org/10.1186/s12916-021-01947-0

Published

31-Mar-21

Commentary

https://link.springer.com/article/10.1186/s12916-021-01947-0

Research on Long Covid will require a multi-disciplinary and globally coordinated approach that supports harmonised and large-scale case-control and interventional studies that have the power to provide quality evidence to inform policy and patient care across the full range of populations and countries affected.
Governments of the world need to ensure the strengthening of health systems to be able to provide treatment, support and rehabilitation to improve long-term COVID-19 outcomes. To prevent Long Covid becoming the pandemic of 2021, controlling the high rates of infection has to remain a global priority.

Compte-rendu d'un forum sur le covid long organisé par l'International Severe Acute Respiratory and emerging Infection Consortium (ISARIC), un institut britannique.

77

D073

A.V.RaveendranabRajeevJayadevancS.Sashidharan

Long COVID: An overview

https://doi.org/10.1016/j.dsx.2021.04.007

Published

20-Apr-21

Review

https://www.sciencedirect.com/science/article/pii/S1871402121001193

Highlights
•Long COVID denote persistence of symptoms in those recovered from COVID-19.
•Reason for the persistence of symptoms has to be identified.
•Long COVID can be divided into different categories based on symptoms.
•Treatment of long COVID requires a multi-disciplinary approach.

_

78

D074

Vivien Marx

Scientists set out to connect the dots on long COVID

https://doi.org/10.1038/s41592-021-01145-z

Published

28-Apr-21

Article

https://www.nature.com/articles/s41592-021-01145-z

_

79

D075

Altiery De Jesus, Vivian V., Alwan, Nisreen, Callard, Felicity and Berger, Zackary

Listening to Long COVID: Epistemic Injustice and COVID-19 morbidity

http://dx.doi.org/10.31219/osf.io/tfbnd

Pre-print

22-Mar-21

Article

https://eprints.soton.ac.uk/448347/

In Long Covid, symptoms do not resolve within several weeks after acute infection with SARS-CoV-2. Patients with COVID-19 and long COVID face stigma and discrimination. One important type of discrimination is epistemic injustice which includes testimonial and hermeneutical injustices. Testimonial injustices occur when healthcare professional disregard or discount patients’ symptoms. This worsens healthcare outcomes and exacerbates challenges to adequate healthcare access at the individual level. Furthermore, testimonial injustices may lead to hermeneutical injustices – systemic underrepresentation of the experiences of the marginalized and minoritized. Healthcare professionals play an essential role in mitigating injustices and have a duty to reduce harms done to patients with long COVID. It is crucial that the clinician avoid multiplying associated harms by not engaging in epistemic injustices.

We suggest the disability model as an approach to improve clinicians’ response to long covid. Epistemic injustice leads to systemic inequities that affect those with chronic disease in general, particularly in populations suffering from structural inequities. The COVID-19 pandemic provides an opportunity for solidarity with those suffering from other chronic diseases that have been marginalized and stigmatized.

_

80

D076

Dr Tanu Singhal

The Chronic Effects of COVID-19 or “Long COVID”

Published

1-Apr-21

Review

http://articles.theindianpractitioner.com/index.php/tip/article/view/1151

The term “long COVID” is used to refer to patients who have persisting symptoms for 4 weeks or more after onset of COVID-19. The prevalence of these ymptoms is reported to range from 10-80%. The commonest symptoms include fatigue, dyspnoea, chest pain, hair loss, loss of sense of taste and smell, cognitive difficulties, anxiety and depression. Serious complications in this period include thrombo embolic events (stroke, myocardial infarction, limb ischemia and venous
thromboembolism), infections, pulmonary fibrosis and multi system inflammatory syndrome. Patients with post COVID-19 symptoms should be first evaluated in primary care and those with serious issues referred to appropriate specialties. The others should be provided with supportive and symptomatic care including respiratory care, nutrition, immunization, mental health support, management of comorbidities and if indicated anticoagulation and treatment of infections. The routine use of steroids, antifibrotics, anticoagulants, anti depressents and antibiotics in these patients should be avoided.

_

81

D077

Dibanur Rashid Siddiqua*1, Md. Shahadat Hossain2

Potential long term adverse health outcomes of COVID-19

https://doi.org/10.3329/bccj.v9i1.53055

Published

20-Feb-21

Review

https://www.banglajol.info/index.php/BCCJ/article/download/53055/37525

The coronavirus disease 2019(COVID-19) pandemic poses an extraordinary challenges to patients, communities and
overall health care systems. It has resulted in millions of people infected worldwide and has indirectly devastated even
more individuals with prolonged post-infectious symptoms. The burden of survivors having post-COVID symptoms is
likely to be huge. Multidisciplinary post-COVID-19 clinics are now playing a pivotal role addressing both persistent
symptoms and potential long term sequelae. In this review, we tried to summarize the adverse health outcomes based
on current evidences, assess the potential risk of long-term complications and make certain recommendations.

_

82

D078

Simon Décary, PT, PhD1, Isabelle Gaboury, PhD2, Sabrina Poirier3, Christiane Garcia4, Scott Simpson, BA, CWC5, Michelle Bull, PhD6, Darren Brown, MSc, MRes7, Frédérique Daigle

Humility and Acceptance: Working Within Our Limits With Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

https://www.jospt.org/doi/10.2519/jospt.2021.0106

Published

30-Apr-21

Editorial

https://www.jospt.org/doi/full/10.2519/jospt.2021.0106

The term long COVID was coined by patients to describe the long-term consequences of COVID-19. One year into the pandemic, it was clear that all patients—those hospitalized with COVID-19 and those who lived with the disease in the community—were at risk of developing debilitating sequelae that would impact their quality of life. Patients with long COVID asked for rehabilitation. Many of them, including previously healthy and fit clinicians, tried to fight postviral fatigue with exercise-based rehabilitation. We observed a growing number of patients with long COVID who experienced adverse effects from exercise therapy and symptoms strikingly similar to those of myalgic encephalomyelitis (ME). Community-based physical therapists, including those in private practice, unaware of safety issues, are preparing to help an influx of patients with long COVID. In this editorial, we expose growing concerns about long COVID and ME. We issue safety recommendations for rehabilitation and share resources to improve care for those with postviral illnesses.

_

83

D079

Kristine Anne Scordo, PhD, APRN, ACNP-BC, FAANP ; Misty M. Richmond, PhD, APRN, PMHNP-BC ; Nancy Munro

Post-COVID-19 Syndrome: Theoretical Basis, Identification, and Management

https://doi.org/10.4037/aacnacc2021492

Published

4-May-21

Article

https://aacnjournals.org/aacnacconline/article/doi/10.4037/aacnacc2021492/31445

This article addresses the possible etiology of postviral syndromes and describes reported symptoms and suggested management of post-COVID syndrome.

Une très riche revue d'études fait un bilan de la physiopathologie possible du covid long, et des soins envisageables. Le parallèle avec l'encéphalomyélite myalgique (EM), voire l'équivalence dans certains cas, est souligné. L'article rappelle que les changements métaboliques de l'EM pourraient être dus aux auto-anticorps des récepteurs ß2-adrénergiques et des récepteurs de l'acétylcholine M3. Il cite égalementent les traitements étudiés de l'EM, notamment l'élimination par immunoadsorption des autoanticorps ß2, conduisant selon des études (https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193672) à une amélioration de la fatigue des patients. Des similitudes avec l'EM, pour laquelle on suspecte des troubles du drainage lymphatique de la microglie dans le cerveau, sont évoquées. Pour l'EM, le «brouillard cérébral» pourrait être dû à une diminution du flux cérébral sanguin secondaire à une vasoconstriction sympathique excessive en présence de récepteurs ß2 dysfonctionnels. La publication évoque enfin des traitements et recommandations d'examen selon les symptômes.

N009

___Definition of long covid___

Published article on 4-May-21:
"Post-COVID-19 Syndrome: Theoretical Basis, Identification, and Management"
Une très riche revue d'études fait un bilan de la physiopathologie possible du covid long, et des soins envisageables. Le parallèle avec l'encéphalomyélite myalgique (EM), voire l'équivalence dans certains cas, est souligné. L'article rappelle que les changements métaboliques de l'EM pourraient être dus aux auto-anticorps des récepteurs ß2-adrénergiques et des récepteurs de l'acétylcholine M3. Il cite égalementent les traitements étudiés de l'EM, notamment l'élimination par immunoadsorption des autoanticorps ß2, conduisant selon des études (https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193672) à une amélioration de la fatigue des patients. Des similitudes avec l'EM, pour laquelle on suspecte des troubles du drainage lymphatique de la microglie dans le cerveau, sont évoquées. Pour l'EM, le «brouillard cérébral» pourrait être dû à une diminution du flux cérébral sanguin secondaire à une vasoconstriction sympathique excessive en présence de récepteurs ß2 dysfonctionnels. La publication évoque enfin des traitements et recommandations d'examen selon les symptômes.
Link: https://aacnjournals.org/aacnacconline/article/doi/10.4037/aacnacc2021492/31445
Extract: "This article addresses the possible etiology of postviral syndromes and describes reported symptoms and suggested management of post-COVID syndrome."

84

D080

Waqaar Shah
Melissa Heightman
Stella O'Brien

UK guidelines for managing long-term effects of COVID-19

https://doi.org/10.1016/S0140-6736(21)00847-3

Published

8-May-21

Commentary

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00847-3/fulltext

We stressed the need for timely referral and investigation and for the development of individualised treatment plans. We reject Gorna and colleagues'1 suggestion that we overly focus on self-management.

_

85

D081

Piero L Olliaro

An integrated understanding of long-term sequelae after acute COVID-19

https://dx.doi.org/10.1016%2FS2213-2600(21)00206-X

Published

5-May-21

Article

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099314/

The recognition of so-called long COVID has been a great emotional relief for the many who are struggling with the aftereffects of COVID-19. Now we need to dissect this highly heterogenous syndrome; better delineate clusters of symptoms; differentiate it from other conditions and consequences of infections and hospitalisation; understand the pathophysiology, predisposing conditions, and risk factors; and indeed, learn how to better look after people with long-term complications after acute COVID-19. Dealing with such complexity requires a multidisciplinary approach and patients' involvement.

_

86

D082

Sherry Leviner

Recognizing the Clinical Sequelae of COVID-19 in Adults: COVID-19 Long-Haulers

https://doi.org/10.1016/j.nurpra.2021.05.003

Published

7-May-21

Article

https://www.npjournal.org/article/S1555-4155(21)00222-1/fulltext

Highlights
•Long-hauler is a term that refers to the long-term effects of COVID-19
•Long-haul COVID-19 is a diagnosis of exclusion
•Do not ignore the emotional dimension of long-haul COVID
The persistent symptoms associated with COVID-19 are frustrating for patients who just want to be normal, to return to their previous level of function prior to COVID-19. Unfortunately there are no clear answers for them at this time and NPs should share this with them. Alternative explanations for symptoms need to be ruled out prior associating the symptoms with long-haul COVID-19. If a COVID-19 care center is available, patients should be referred. If a COVID-19 care center is not available, specialists need to be consulted. Given the impact on mental health, evaluating the mental health of long-haulers is a priority.

_

87

D083

Piotr Walczak and Miroslaw Janowski

The COVID-19 Menace

https://doi.org/10.1002/gch2.202100004

Published

1-May-21

Review

https://onlinelibrary.wiley.com/doi/pdf/10.1002/gch2.202100004

Clinically, there is enormous variability in the severity of the disease. Severe consequences are seen in a relatively small number of patients, most show moderate symptoms, but asymptomatic cases, especially among young people, drive disease spread. Unfortunately, the number of local infections can quickly build up, causing disease outbreaks suddenly exhausting health services’ capacity. Therefore, COVID-19 is dangerous and unpredictable and has become the most serious threat for generations. Here, the latest research on COVID-19 is summarized, including its spread, testing methods, organ-specific complications, the role of comorbidities, long-term consequences, mortality, as well as a new hope for immunity, drugs, and vaccines.

_

88

D084

Avindra Nath

Long-Haul COVID

https://doi.org/10.1212/WNL.0000000000010640

Published

29-Sep-20

Article

https://n.neurology.org/content/95/13/559

Although there are no peer reviewed papers at the moment on these patients, many news articles have been written about this phenomenon1,–,4 and there are Facebook groups with several thousand patients describing these symptoms. They call the illness, “Long-Haul COVID” or “Long-tail COVID.” Many of these patients are health care workers who had massive exposure to the virus early in the pandemic and describe having symptoms for “100+ days.”

_

89

D085

DIEGO CASTANARES-ZAPATERO, PATRICE CHALON, KOEN VAN DEN HEEDE

COVID 19 – KCE CONTRIBUTIONS
PATHOPHYSIOLOGY OF LONG COVID:
A PRELIMINARY REPORT

Published

18-May-21

Review

https://kce.fgov.be/sites/default/files/atoms/files/2020-04HSR_Long%20COVID_Scientific_Report.pdf

Key points
• The pathophysiology contributing to long COVID symptoms is so far unkown. Since the
spectrum of symptoms is very wide, responsible mechanisms are probably numerous and
intertwined.
• While many articles elaborate on the putative mechanims involved in the
symptomatology, there is little empirical data on the pathophysiology based on
measurements among long COVID patients. In addition, the quality of data is limited due
to heterogenous timings of inclusion, different initial disease severity and a lack of a
comparator group. As such, the reported results need to be interpreted with caution. The
current literature is highly hypothetical, cannot be generalized and is subject to change.
• A distinction has to be made between two categories of mechanisms by which persisting
symptoms come about:
o Organ injury at the early phase of infection;
o Persisting and/or residual symptoms without evidence of readily measurable markers
of organ injury.
• Current literature suggests the following general pathophysiological mechanisms: (1)
virus-driven tissue damage and (2) dysregulated immune and inflammatory reactions in
response to the infection, giving rise to multiple disorders (microcirculation disorders
associated with coagulation and fibrosis pathway activation, auto-immune manifestations
and metabolic disturbances).
• Long COVID has to be differentiated from Post-Intensive-Care-Syndrome (PICS),
comprising long-term physical, psychological and cognitive disabilities that can occur in
patients who have previously been hospitalised in Intensive care unit (ICU).

Le centre fédéral (belge) d'expertise des soins de santé (KCE) édite un rapport sur la physiopathologie du covid long. Il invite à la prudence sur les hypothèses formulées jusqu'à présent, compte tenu du peu de données empiriques sur la physiopathologie basées sur des mesures systématiques.
Le rapport note que la littérature actuelle évoque les mécanismes physiopathologiques généraux suivants :
1 - lésions tissulaires causées par le virus
2 - réactions immunitaires et inflammatoires dérégulées en réponse à l'infection, donnant lieu à de multiples troubles (troubles de la microcirculation associée à l'activation des voies de coagulation et de fibrose, manifestations auto-immunes et troubles métaboliques).

N011

___Definition of long covid___

Published review on 18-May-21:
"COVID 19 – KCE CONTRIBUTIONS
PATHOPHYSIOLOGY OF LONG COVID:
A PRELIMINARY REPORT"
Le centre fédéral (belge) d'expertise des soins de santé (KCE) édite un rapport sur la physiopathologie du covid long. Il invite à la prudence sur les hypothèses formulées jusqu'à présent, compte tenu du peu de données empiriques sur la physiopathologie basées sur des mesures systématiques.
Le rapport note que la littérature actuelle évoque les mécanismes physiopathologiques généraux suivants :
1 - lésions tissulaires causées par le virus
2 - réactions immunitaires et inflammatoires dérégulées en réponse à l'infection, donnant lieu à de multiples troubles (troubles de la microcirculation associée à l'activation des voies de coagulation et de fibrose, manifestations auto-immunes et troubles métaboliques).
Link: https://kce.fgov.be/sites/default/files/atoms/files/2020-04HSR_Long%20COVID_Scientific_Report.pdf
Extract: "Key points
• The pathophysiology contributing to long COVID symptoms is so far unkown. Since the
spectrum of symptoms is very wide, responsible mechanisms are probably numerous and
intertwined.
• While many articles elaborate on the putative mechanims involved in the
symptomatology, there is little empirical data on the pathophysiology based on
measurements among long COVID patients. In addition, the quality of data is limited due
to heterogenous timings of inclusion, different initial disease severity and a lack of a
comparator group. As such, the reported results need to be interpreted with caution. The
current literature is highly hypothetical, cannot be generalized and is subject to change.
• A distinction has to be made between two categories of mechanisms by which persisting
symptoms come about:
o Organ injury at the early phase of infection;
o Persisting and/or residual symptoms without evidence of readily measurable markers
of organ injury.
• Current literature suggests the following general pathophysiological mechanisms: (1)
virus-driven tissue damage and (2) dysregulated immune and inflammatory reactions in
response to the infection, giving rise to multiple disorders (microcirculation disorders
associated with coagulation and fibrosis pathway activation, auto-immune manifestations
and metabolic disturbances).
• Long COVID has to be differentiated from Post-Intensive-Care-Syndrome (PICS),
comprising long-term physical, psychological and cognitive disabilities that can occur in
patients who have previously been hospitalised in Intensive care unit (ICU)."

90

D086

Andrew Briggs & Anna Vassall

Count the cost of disability caused by COVID-19

https://doi.org/10.1038/d41586-021-01392-2

Published

26-May-21

Article

https://www.nature.com/articles/d41586-021-01392-2

We approximate that the health burden due to COVID-induced disability across all age groups could be around 30% overall. We arrived at this crude figure using modest assumptions about the duration and severity of COVID-19-related disease (see Supplementary information). This number also assumes a loss of 0.5 DALYs for an average case of long COVID, regardless of age, and includes DALYs lost as a result of COVID-19 deaths, using standard methods5.

This exercise hints at how much of the long-term health impact we could be missing by counting only deaths.

Selon une analyse dans Nature, le fardeau de santé dû au handicap induit par la covid dans tous les groupes d'âge serait d'environ 30 % sur l'ensemble des pertes de vie en bonne santé du covid.
La part est d'autant plus forte dans les populations plus jeunes des pays riches.

N011

___Definition of long covid___

Published article on 26-May-21:
"Count the cost of disability caused by COVID-19"
Selon une analyse dans Nature, le fardeau de santé dû au handicap induit par la covid dans tous les groupes d'âge serait d'environ 30 % sur l'ensemble des pertes de vie en bonne santé du covid.
La part est d'autant plus forte dans les populations plus jeunes des pays riches.
Link: https://www.nature.com/articles/d41586-021-01392-2
Extract: "We approximate that the health burden due to COVID-induced disability across all age groups could be around 30% overall. We arrived at this crude figure using modest assumptions about the duration and severity of COVID-19-related disease (see Supplementary information). This number also assumes a loss of 0.5 DALYs for an average case of long COVID, regardless of age, and includes DALYs lost as a result of COVID-19 deaths, using standard methods5.

This exercise hints at how much of the long-term health impact we could be missing by counting only deaths."

91

D087

Kevin Roe

The Symptoms and Clinical Manifestations Observed in COVID-19 Patients/Long COVID-19 Symptoms that Parallel Toxoplasma gondii Infections

https://doi.org/10.1007/s11481-021-09997-0

Published

29-May-21

Letter to the Editor

https://link.springer.com/article/10.1007/s11481-021-09997-0

It is significant that virtually all of the diverse and distinctive symptoms of Long COVID-19 can be explained as symptoms of toxoplasmosis in patients having activated or reactivated T. gondii (Vidal 2019). Toxoplasmosis patients suffer a wide variety of symptoms, including dyspnoea, fevers, seizures, headaches, changes in vision, altered mental status, focal neurological deficits, mental confusion, cognitive dysfunction, ataxia, behavioral or psychomotor changes, involuntary movements, pneumonia, and a spectrum of cranial nerve palsies (Vidal 2019).

Several distinctive Long COVID-19 symptoms can be matched if toxoplasmosis induced cranial nerve palsies affect the functions of the 12 cranial nerves, creating symptoms including anosmia from a palsy of the olfactory nerve (I), vertigo (dizziness), tinnitus and otalgia (earache) from a palsy of the vestibulocochlear nerve (VIII), and dysgeusia from palsies of the facial nerve (VII), glossopharyngeal nerve (IX), and vagus nerve (X) (Khaku et al. 2017).

Dans le Journal of Neuroimmune Pharmacology, un chercheur émet l'hypothèse que la covid pourrait réactiver partiellement ou entièrement une infection latente à la toxoplasmose (dont la prévalence atteint 60% dans certaines régions du monde). Cette synergie bidirectionnelle, par des dysfonctionnements cellulaires immunitaires, dont l'épuisement des lymphocytes T, serait une possibilité pour expliquer la mortalité de la covid et le tableau clinique, notamment les atteintes neurologiques, du covid long.

N011

___Definition of long covid___

Published letter to the editor on 29-May-21:
"The Symptoms and Clinical Manifestations Observed in COVID-19 Patients/Long COVID-19 Symptoms that Parallel Toxoplasma gondii Infections"
Dans le Journal of Neuroimmune Pharmacology, un chercheur émet l'hypothèse que la covid pourrait réactiver partiellement ou entièrement une infection latente à la toxoplasmose (dont la prévalence atteint 60% dans certaines régions du monde). Cette synergie bidirectionnelle, par des dysfonctionnements cellulaires immunitaires, dont l'épuisement des lymphocytes T, serait une possibilité pour expliquer la mortalité de la covid et le tableau clinique, notamment les atteintes neurologiques, du covid long.
Link: https://link.springer.com/article/10.1007/s11481-021-09997-0
Extract: "It is significant that virtually all of the diverse and distinctive symptoms of Long COVID-19 can be explained as symptoms of toxoplasmosis in patients having activated or reactivated T. gondii (Vidal 2019). Toxoplasmosis patients suffer a wide variety of symptoms, including dyspnoea, fevers, seizures, headaches, changes in vision, altered mental status, focal neurological deficits, mental confusion, cognitive dysfunction, ataxia, behavioral or psychomotor changes, involuntary movements, pneumonia, and a spectrum of cranial nerve palsies (Vidal 2019).

Several distinctive Long COVID-19 symptoms can be matched if toxoplasmosis induced cranial nerve palsies affect the functions of the 12 cranial nerves, creating symptoms including anosmia from a palsy of the olfactory nerve (I), vertigo (dizziness), tinnitus and otalgia (earache) from a palsy of the vestibulocochlear nerve (VIII), and dysgeusia from palsies of the facial nerve (VII), glossopharyngeal nerve (IX), and vagus nerve (X) (Khaku et al. 2017)."

92

D088

Manuela Funke-Chambour, Laurence Feldmeyer, Robert Hoepner, Uyen Huynh-Do, Britta Maurer, Emrush Rexhaj, and Thomas Geiser

Das Long-COVID-Syndrom – ein neues Krankheitsbild nach COVID-19-Infekt

https://doi.org/10.1024/1661-8157/a003678

Published

21-May-21

Review

https://econtent.hogrefe.com/doi/full/10.1024/1661-8157/a003678

Long-term consequences are increasingly reported in the current literature after COVID-19 infections. Some patients suffer from persistent pulmonary and extrapulmonary symptoms even months after the acute infection. Pulmonary impairment, but also dysregulation and effects on immune system, cardiovascular system, neurological system, skin and kidney are described or anticipated. This mini review gives a short update to the practitioner about the current knowledge about Long COVID.

_

93

D089

Alison Twycross

Living with long Covid: some reflections 14 months down the line

http://dx.doi.org/10.1136/ebnurs-2021-103449

Published

26-May-21

Editorial

https://ebn.bmj.com/content/early/2021/05/25/ebnurs-2021-103449

As I write this editorial, it is almost 14 months since I first developed COVID-19 symptoms and my journey with long COVID-19 continues. In their guideline on long COVID-19 NICE/SIGN define post-COVID-19 syndrome as signs and symptoms that develop during or after a COVID-19 infection, continuing for more than 12 weeks, and not explained by an alternative diagnosis.

_

94

D090

Emma Sheppard

Your Fear of Long Covid

Published

20-May-21

Article

https://blogs.bmj.com/medical-humanities/2021/05/20/your-fear-of-long-covid/

There is a lot in media about Long Covid—and in particular about the big concerns about how living with Long Covid must be awful. This fear of Long Covid is shaped by ableism, but that same ableism—and how we talk about Long Covid—impacts people already living with chronic illnesses that have a lot in common with Long Covid.

_

95

D091

Zheng Yao Low, Ashley Jia Wen Yip, Anshika Sharma & Sunil K. Lal

SARS coronavirus outbreaks past and present—a comparative analysis of SARS-CoV-2 and its predecessors

https://doi.org/10.1007/s11262-021-01846-9

Published

1-Jun-21

https://link.springer.com/article/10.1007/s11262-021-01846-9

The Coronavirus Disease 2019 (COVID-19), a pneumonic disease caused by the SARS Coronavirus 2 (SARS-CoV-2), is the 7th Coronavirus to have successfully infected and caused an outbreak in humans. Genome comparisons have shown that previous isolates, the SARS-related coronavirus (SARSr-CoV), including the SARS-CoV are closely related, yet different in disease manifestation. Several explanations were suggested for the undetermined origin of SARS-CoV-2, in particular, bats, avian and Malayan pangolins as reservoir hosts, owing to the high genetic similarity. The general morphology and structure of all these viral isolates overlap with analogous disease symptoms such as fever, dry cough, fatigue, dyspnoea and headache, very similar to the current SARS-CoV-2. Chest CT scans for SARS-CoV-2, SARS-CoV and MERS-CoV reveal pulmonary lesions, bilateral ground-glass opacities, and segmental consolidation in the lungs, a common pathological trait. With greatly overlapping similarities among the previous coronavirus, the SARS-CoV, it becomes interesting to observe marked differences in disease severity of the SARS-CoV-2 thereby imparting it the ability to rapidly transmit, exhibit greater stability, bypass innate host defences, and increasingly adapt to their new host thereby resulting in the current pandemic. The most recent B.1.1.7, B.1.351 and P.1 variants of SARS-CoV-2, highlight the fact that changes in amino acids in the Spike protein can contribute to enhanced infection and transmission efficiency. This review covers a comparative analysis of previous coronavirus outbreaks and highlights the differences and similarities among different coronaviruses, including the most recent isolates that have evolved to become easily transmissible with higher replication efficiency in humans.

_

96

D092

Daniela Giacomazza , Domenico Nuzzo
Submitted by: Daniela Giacomazza

Post-Acute COVID-19 Neurological Syndrome

Published

https://encyclopedia.pub/10733

The emergency caused by SARS-CoV-2 had, and still has, devastating socio-economic aspects. Assessing the impact of COVID-19 on vulnerable groups of people is crucial for the adaptation of governments’ responses. Growing scientific evidence suggests that it is essential to keep the attention on people after acute SARS-CoV-2 infection; indeed, some clinical manifestations are frequently present even after recovery. There is consensus on the need to define which symptoms persist after the infection and which disabilities may arise after COVID-19. Recent reviews, case reports, and original contributions suggest that various organs may be affected, and neurological symptoms are present in about one third of patients with COVID-19. Neurological complications after severe COVID-19 infection might include delirium, brain inflammation, stroke, and nerve damage. In the recent pandemic, neurologists and neurobiologists have a chance to study key features of infection neurology.

_

97

D093

CésarFernández-de-las-PeñasaLidiane L.FlorencioaVíctorGómez-MayordomobMaría L.CuadradobcDomingoPalacios-CeñaaArkiath VeettilRaveendrand

Proposed integrative model for post-COVID symptoms

https://doi.org/10.1016/j.dsx.2021.05.032

Published

1-Jun-21

Article

https://www.sciencedirect.com/science/article/pii/S1871402121001764

Highlights
•The first differentiation is to determine the presence of new-onset or exacerbated post-COVID symptoms.
•The second differentiation is to determine if the post-COVID symptom is persistent or delayed in relation to the acute phase.
•Individual, biological, hospitalization/treatment and COVID-19 outbreak surrounding factors must be considered.
The first consideration is to define which symptoms are of “new-onset” (symptoms never experienced by a patient before COVID-19 and experienced the first time after) and which symptoms are “exacerbated” (symptoms experienced by a patient prior to COVID-19 but aggravated later) after infection. The second consideration includes defining “persistent” (symptoms experienced at the acute phase and continuing after without remission period) and “delayed-onset” (symptoms not experienced at the acute phase of the infection but appearing after a “latency period”). This model integrates predisposing individual factors, biological factors associated to the severity of disease, hospitalization/treatment factors, and outbreak surrounding factors which may promote post-COVID.
Conclusion: Since current literature on post-COVID is heterogeneous, this integrative model could help to a better characterization of long-COVID.

_

98

D094

Sheetal Gandotra 1, and Derek Russell 1,2

The Long and the Short of It: Is “Long COVID” More Than Slow Resolution of the Acute Disease?

https://doi.org/10.1513/AnnalsATS.202103-255ED

Published

1-Jun-21

Article

https://www.atsjournals.org/doi/full/10.1513/AnnalsATS.202103-255ED

Though the COVID-19 pandemic may show signs of waning, an “epi-pandemic” of persistent symptoms from this novel disease is upon us. It is now clear that this is a concern not only to those who had life-threatening complications early in the course of infection but also to patients who were never hospitalized. Long COVID may be with us for a long time. Despite the danger and saliency of the acute phase of COVID-19, the longer-term aspects of this disease cannot be overlooked.

_

99

D095

Caroline Kamau-Mitchell

Risk that debilitating fatigue after covid-19 might last years: Evidence report for the House of Lords Select Committee on Risk Assessment and Risk Planning

Published

1-May-21

Article

https://www.researchgate.net/publication/351870234_Risk_that_debilitating_fatigue_after_covid-19_might_last_years_Evidence_report_for_the_House_of_Lords_Select_Committee_on_Risk_Assessment_and_Risk_Planning

Key points
• There is the risk of higher unemployment rates among people who had covid-19.
• There is the risk of higher underemployment rates among people who had covid-19 e.g.,
more switching to part-time working or lower skilled jobs because of health problems.
• There is the risk of future staff shortages in occupations with a high prevalence of covid19.
• Based on the evidence, this report encourages the government to measure the percentage
of people who developed CFS/ME after being infected with covid-19.
The government should measure prevalence of post-covid-19 CFS/ME, conduct modelling to
assess high risk occupational groups, intervene to prevent unemployment, underemployment and
workforce shortages, guide healthcare staff, advise employers/workers, and inspire research into
prevention of post-covid-19 CFS/ME.

Un rapport commandé par la Chambre des lords (UK) demande à ce que soit évaluée la proportion des malades du covid long qui développent une encéphalomyélite myalgique.
Le texte, citant une étude sur le SRAS (https://pubmed.ncbi.nlm.nih.gov/20008700/) qui relevait qu'un quart des malades avaient toujours une fatigue chronique 4 ans après l'infection, insiste sur le fait que la pathologie de covid long pourrait s'étaler sur des années, générant un lourd impact sur l'emploi des personnes malades.

N011

___Definition of long covid___

Published article on 1-May-21:
"Risk that debilitating fatigue after covid-19 might last years: Evidence report for the House of Lords Select Committee on Risk Assessment and Risk Planning"
Un rapport commandé par la Chambre des lords (UK) demande à ce que soit évaluée la proportion des malades du covid long qui développent une encéphalomyélite myalgique.
Le texte, citant une étude sur le SRAS (https://pubmed.ncbi.nlm.nih.gov/20008700/) qui relevait qu'un quart des malades avaient toujours une fatigue chronique 4 ans après l'infection, insiste sur le fait que la pathologie de covid long pourrait s'étaler sur des années, générant un lourd impact sur l'emploi des personnes malades.
Link: https://www.researchgate.net/publication/351870234_Risk_that_debilitating_fatigue_after_covid-19_might_last_years_Evidence_report_for_the_House_of_Lords_Select_Committee_on_Risk_Assessment_and_Risk_Planning
Extract: "Key points
• There is the risk of higher unemployment rates among people who had covid-19.
• There is the risk of higher underemployment rates among people who had covid-19 e.g.,
more switching to part-time working or lower skilled jobs because of health problems.
• There is the risk of future staff shortages in occupations with a high prevalence of covid19.
• Based on the evidence, this report encourages the government to measure the percentage
of people who developed CFS/ME after being infected with covid-19.
The government should measure prevalence of post-covid-19 CFS/ME, conduct modelling to
assess high risk occupational groups, intervene to prevent unemployment, underemployment and
workforce shortages, guide healthcare staff, advise employers/workers, and inspire research into
prevention of post-covid-19 CFS/ME."

100

D096

The Lancet Respiratory Medicine

COVID-19 pathophysiology: looking beyond acute disease

https://doi.org/10.1016/S2213-2600(21)00242-3

Published

1-Jun-21

Editorial

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00242-3/fulltext

Little more than a year on, a picture of a new disease entity is coming into focus—with a distinct range of clinical and pathophysiological features—as described by Marcin Osuchowski and colleagues in the first of a Series of four papers in The Lancet Respiratory Medicine.

_

101

D097

Mary Fran Tracy

Understanding the Impact of COVID-19: Now and for the Future

https://doi.org/10.4037/aacnacc2021636

Published

15-Jun-21

Article

https://aacnjournals.org/aacnacconline/article/32/2/157/31466/Understanding-the-Impact-of-COVID-19-Now-and-for

We will be addressing the consequences of the pandemic for years to come, whether for the patients who contracted the disease or the health care workers who cared for them.

_

102

D098

Jon D. Kaiser

Long Haulers Syndrome—An Integrative Approach to Etiology and Treatment

Published

1-Jun-21

Article

http://www.imjournal.com/abstracts/23042.html

Many research centers, including Mount Sinai Health System’s Center for Post-COVID Care in New York City, have recently been set up to investigate and treat the growing number of patients who remain persistently symptomatic after acute COVID-19 infection. Additional research is clearly necessary to properly characterize, diagnose, and treat this highly challenging condition, as well as to develop an evidence-based, systems-oriented approach for caring for postCOVID-19 syndrome patients.

_

103

D099

Michael Marshall

The four most urgent questions about long COVID
Scientists are starting to get insights into the lingering disorder that affects some people infected with SARS-CoV-2 — but many mysteries remain unsolved.

https://doi.org/10.1038/d41586-021-01511-z

Published

9-Jun-21

Article

https://www.nature.com/articles/d41586-021-01511-z

How many people get long COVID and who is most at risk? What is the underlying biology of long COVID? What is the relationship between long COVID and other post-infection syndromes? What can be done to help people with long COVID?

Un article dans Nature résume les 4 questions cruciales que pose le covid long :
- Combien de personnes ont un covid long et qui est le plus à risque ?
- Quelle est la biologie sous-jacente du covid long ?
- Quelle est la relation entre le covid long et les autres syndromes post-infection ?
- Que peut-on faire pour aider les personnes atteintes du covid long ?
L'article évoque les pistes médicamenteuses, notamment un agent anti-fibrosant et anti-inflammatoire (deupirfénidone) développé à Boston,
ou encore au Royaume-Uni, l'apixaban, un anticoagulant, et l'atorvastatine, un anti-inflammatoire.

N011

___Definition of long covid___

Published article on 9-Jun-21:
"The four most urgent questions about long COVID
Scientists are starting to get insights into the lingering disorder that affects some people infected with SARS-CoV-2 — but many mysteries remain unsolved."
Un article dans Nature résume les 4 questions cruciales que pose le covid long :
- Combien de personnes ont un covid long et qui est le plus à risque ?
- Quelle est la biologie sous-jacente du covid long ?
- Quelle est la relation entre le covid long et les autres syndromes post-infection ?
- Que peut-on faire pour aider les personnes atteintes du covid long ?
L'article évoque les pistes médicamenteuses, notamment un agent anti-fibrosant et anti-inflammatoire (deupirfénidone) développé à Boston,
ou encore au Royaume-Uni, l'apixaban, un anticoagulant, et l'atorvastatine, un anti-inflammatoire.
Link: https://www.nature.com/articles/d41586-021-01511-z
Extract: "How many people get long COVID and who is most at risk? What is the underlying biology of long COVID? What is the relationship between long COVID and other post-infection syndromes? What can be done to help people with long COVID?"

104

D100

Dinah V. Parums

Editorial: Long COVID, or Post-COVID Syndrome,
and the Global Impact on Health Care

https://doi.org/10.12659/MSM.933446

Editorial

https://www.medscimonit.com/download/index/idArt/933446

The clinical manifestations of long COVID and its prevalence in all age groups who initially appear to have recovered from acute SARS-CoV-2 infection are now recognized. However, the effects on society, the economy, and healthcare provision have yet to be realized. There is also concern that in older adults, the symptoms of long COVID are under-reported and may be assumed to be due to age-related comorbidities. Now that SARS-CoV-2 infection and its variants are endemic, and vaccination programs may not be completely effective the diagnosis and management of long COVID is expected to become a global public health priority.During 2020, increasing numbers of case reports, case series, and small observational studies reported long-term complications of coronavirus disease 2019 (COVID-19) in patients who had recovered from acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Long COVID has a prevalence of between 10-30% in patients with a recent history of SARS-CoV-2 infection. Pulmonary, hematologic, cardiovascular, neuropsychiatric, renal, endocrine, gastrointestinal and hepatobiliary, and dermatologic involvement, and chronic multisystem inflammatory syndrome in children (MIS-C) highlights the requirement for a multidisciplinary approach to the management of patients with long COVID. This Editorial aims to present the current status of long COVID, or post-COVID syndrome, and its global impact on health and the provision of health care.

_

105

D101

Anthony L.Komaroff1W. IanLipkin2

Insights from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome May Help Unravel the Pathogenesis of Post-Acute COVID-19 Syndrome

https://doi.org/10.1016/j.molmed.2021.06.002

Published

7-Jun-21

Review

https://www.sciencedirect.com/science/article/pii/S1471491421001349

Highlights
•In some people, the aftermath of acute COVID-19 is a lingering illness with fatigue and cognitive defects, known as post-COVID-19 syndrome or “long COVID”.
•Post-COVID-19 syndrome is similar to post-infectious fatigue syndromes triggered by other infectious agents, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a condition that patients often report is preceded by an infectious-like illness.
•ME/CFS is associated with underlying abnormalities of the central and autonomic nervous system, immune dysregulation, disordered energy metabolism and redox imbalance. It is currently unclear if the same abnormalities will be identified in post-COVID-19 syndrome.
•The US and other developed nations have committed considerable support for research on post-COVID illnesses.
Abstract
SARS-CoV-2 can cause chronic and acute disease. Post-Acute Sequelae of SARS-CoV-2 infection (PASC) include injury to the lungs, heart, kidneys and brain, that may produce a variety of symptoms. PASC also includes a post-COVID-19 syndrome (“long COVID”) with features that can follow other acute infectious diseases as well as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Here we summarize what is known about the pathogenesis of ME/CFS and of acute COVID-19, and speculate that the pathogenesis of post-COVID-19 syndrome in some people may be similar to that of ME/CFS. We propose molecular mechanisms that might explain the fatigue and related symptoms in both illnesses, and suggest a research agenda for both ME/CFS and post-COVID-19 syndrome.

Une revue d'études invite à s'inspirer des connaissances sur l'encéphalomyélite myalgique pour comprendre divers aspects des pathologies du covid long.

N011

___Definition of long covid___

Published review on 7-Jun-21:
"Insights from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome May Help Unravel the Pathogenesis of Post-Acute COVID-19 Syndrome"
Une revue d'études invite à s'inspirer des connaissances sur l'encéphalomyélite myalgique pour comprendre divers aspects des pathologies du covid long.
Link: https://www.sciencedirect.com/science/article/pii/S1471491421001349
Extract: "Highlights
•In some people, the aftermath of acute COVID-19 is a lingering illness with fatigue and cognitive defects, known as post-COVID-19 syndrome or “long COVID”.
•Post-COVID-19 syndrome is similar to post-infectious fatigue syndromes triggered by other infectious agents, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a condition that patients often report is preceded by an infectious-like illness.
•ME/CFS is associated with underlying abnormalities of the central and autonomic nervous system, immune dysregulation, disordered energy metabolism and redox imbalance. It is currently unclear if the same abnormalities will be identified in post-COVID-19 syndrome.
•The US and other developed nations have committed considerable support for research on post-COVID illnesses.
Abstract
SARS-CoV-2 can cause chronic and acute disease. Post-Acute Sequelae of SARS-CoV-2 infection (PASC) include injury to the lungs, heart, kidneys and brain, that may produce a variety of symptoms. PASC also includes a post-COVID-19 syndrome (“long COVID”) with features that can follow other acute infectious diseases as well as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Here we summarize what is known about the pathogenesis of ME/CFS and of acute COVID-19, and speculate that the pathogenesis of post-COVID-19 syndrome in some people may be similar to that of ME/CFS. We propose molecular mechanisms that might explain the fatigue and related symptoms in both illnesses, and suggest a research agenda for both ME/CFS and post-COVID-19 syndrome."

106

D102

Dinah V. Parums

Editorial: Long COVID, or Post-COVID Syndrome, and the Global Impact on Health Care

https://doi.org/10.12659/MSM.933446

Published

7-Jun-21

Editorial

https://www.medscimonit.com/abstract/index/idArt/933446?

During 2020, increasing numbers of case reports, case series, and small observational studies reported long-term complications of coronavirus disease 2019 (COVID-19) in patients who had recovered from acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Long COVID has a prevalence of between 10-30% in patients with a recent history of SARS-CoV-2 infection. Pulmonary, hematologic, cardiovascular, neuropsychiatric, renal, endocrine, gastrointestinal and hepatobiliary, and dermatologic involvement, and chronic multisystem inflammatory syndrome in children (MIS-C) highlights the requirement for a multidisciplinary approach to the management of patients with long COVID. This Editorial aims to present the current status of long COVID, or post-COVID syndrome, and its global impact on health and the provision of health care

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P.CathébrasJ.GoutteB.GramontM.Killian

« COVID long » : une opportunité pour approcher la complexité des syndromes fonctionnels post-infectieux“Long-haul COVID”: An opportunity to address the complexity of post-infectious functional syndromes

https://doi.org/10.1016/j.revmed.2021.05.020

Published

9-Jun-21

Article

https://www.sciencedirect.com/science/article/pii/S024886632100518X

This clinically unspecific syndrome must be put in perspective with the post-infectious syndromes known for a long time but ultimately poorly understood and little studied, qualified, for lack of convincing arguments for a unambiguous pathophysiology and better terms, as functional somatic syndromes. The clinical implications for clinical care (“holistic” work-up and care of patients), for research (need for truly “bio-psycho-social” investigations), and the social implications of “long COVID” (social construction of the syndrome through the experiences of patients exposed on social networks, inequalities in the face of the disease and its socioeconomic consequences) are considered. “Long COVID” must be view, because of its expected prevalence, as an opportunity to address the complexity of post-infectious (functional) syndromes, their risk factors, and the biological, psychological and social mechanisms underlying them.

En évoquant d'autres syndromes post-infectieux que le covid long, comme ceux qui peuvent prolonger le SARS, le MERS, Ebola, le chikungunya ou la dengue, les auteurs de cet article essaient d'établir les particularités de ces symptômes. Ils notent également le rôle des associations de malades dans la reconnaissance de la maladie, rappellent les hypothèses physiopathologiques, et enfin dressent des pistes de prise en charge.

N011

___Definition of long covid___

Published article on 9-Jun-21:
"« COVID long » : une opportunité pour approcher la complexité des syndromes fonctionnels post-infectieux“Long-haul COVID”: An opportunity to address the complexity of post-infectious functional syndromes"
En évoquant d'autres syndromes post-infectieux que le covid long, comme ceux qui peuvent prolonger le SARS, le MERS, Ebola, le chikungunya ou la dengue, les auteurs de cet article essaient d'établir les particularités de ces symptômes. Ils notent également le rôle des associations de malades dans la reconnaissance de la maladie, rappellent les hypothèses physiopathologiques, et enfin dressent des pistes de prise en charge.
Link: https://www.sciencedirect.com/science/article/pii/S024886632100518X
Extract: "This clinically unspecific syndrome must be put in perspective with the post-infectious syndromes known for a long time but ultimately poorly understood and little studied, qualified, for lack of convincing arguments for a unambiguous pathophysiology and better terms, as functional somatic syndromes. The clinical implications for clinical care (“holistic” work-up and care of patients), for research (need for truly “bio-psycho-social” investigations), and the social implications of “long COVID” (social construction of the syndrome through the experiences of patients exposed on social networks, inequalities in the face of the disease and its socioeconomic consequences) are considered. “Long COVID” must be view, because of its expected prevalence, as an opportunity to address the complexity of post-infectious (functional) syndromes, their risk factors, and the biological, psychological and social mechanisms underlying them."

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Harald Brüssow, Kenneth Timmis

COVID-19: long covid and its societal consequences

https://doi.org/10.1111/1462-2920.15634

Published

10-Jun-21

Minireview

https://sfamjournals.onlinelibrary.wiley.com/doi/abs/10.1111/1462-2920.15634

we summarize recent findings about COVID-19 sequelae, with a particular focus on long covid. We also discuss some of the long scars that COVID-19 and long covid will collectively leave on society that we term Societal Long Covid.

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Loren Bonner

‘;Long COVID’ needs to be addressed by multiple specialties

https://doi.org/10.1016/j.ptdy.2021.05.011

Published

1-Jun-21

Article

https://www.pharmacytoday.org/article/S1042-0991(21)00383-2/fulltext

‘;Long COVID’ needs to be addressed by multiple specialties

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Garg M, Maralakunte M, Garg S, Dhooria S, Sehgal I, Bhalla AS, Vijayvergiya R, Grover S, Bhatia V, Jagia P, Bhalla A, Suri V, Goyal M, Agarwal R, Puri GD, Sandhu MS

The Conundrum of ‘Long-COVID-19ʹ: A Narrative Review

https://doi.org/10.2147/IJGM.S316708

Published

14-Jun-21

Review

https://www.dovepress.com/the-conundrum-of-long-covid-19-a-narrative-review-peer-reviewed-fulltext-article-IJGM

With the data on Long-COVID-19 still emerging, the present review aims to highlight its epidemiology, protean clinical manifestations, risk predictors, and management strategies. With the re-emergence of new waves of SARS-CoV-2 infection, Long-COVID-19 is expected to produce another public health crisis on the heels of current pandemic. Thus, it becomes imperative to emphasize this condition and disseminate its awareness to medical professionals, patients, the public, and policymakers alike to prepare and augment health care facilities for continued surveillance of these patients.

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P Cathébras 1, J Goutte 2, B Gramont 2, M Killian 2

["Long-haul COVID": An opportunity to address the complexity of post-infectious functional syndromes]

https://doi.org/10.1016/j.revmed.2021.05.020

Published

9-Jun-21

Article

https://pubmed.ncbi.nlm.nih.gov/34127310/

Cf D104

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Karen A. Hacker, MD, MPH1; Peter A. Briss, MD, MPH1; Lisa Richardson, MD, MPH1; Janet Wright, MD1; Ruth Petersen

COVID-19 and Chronic Disease: The Impact Now and in the Future

http://dx.doi.org/10.5888/pcd18.210086

Published

17-Jun-21

Article

https://www.cdc.gov/PCD/issues/2021/21_0086.htm

The impact of SARS-CoV-2, the virus that causes COVID-19, on people with or at risk for chronic disease cannot be overstated. COVID-19 has impeded chronic disease prevention and disrupted disease management. The problems and solutions outlined here are critically important to help those committed to chronic disease prevention and intervention to identify ways forward.

NCCDPHP is adjusting, preparing, and implementing multiple strategies to address the future. Although the work will be challenging, opportunities abound. NCCDPHP is committed to working with the health care community and a variety of partners at federal, state, and local levels to help address the realities of the post-COVID era.

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Zahin Amin-Chowdhury & Shamez N. Ladhani

Causation or confounding: why controls are critical for characterizing long COVID

https://doi.org/10.1038/s41591-021-01402-w

Published

17-Jun-21

Correspondence

https://www.nature.com/articles/s41591-021-01402-w

It is increasingly apparent that the long-term impact of this pandemic will be considerable and will substantially affect quality of life. Current best-guess estimates for long COVID (defined as self-reported persistence of any symptoms for 12 weeks or more after COVID-19) in population-based UK studies range from 2.2% (ref. 8) to 13.7% (ref. 4), and systematic assessment of available data identify female sex, middle age, white ethnicity and specific underlying co-morbidities as potential risk factors7. More robust, well-conducted longitudinal studies are urgently needed for proper characterization of this syndrome to inform clinicians, to develop evidence-based guidelines and to direct healthcare resources to where they are most needed.

En évoquant leur propre étude qui constate à 7 mois 3% de personnes infectées par la covid qui gardent des symptômes continus, et 11% qui gardent des symptômes épisodiques, des auteurs demandent davantage d'études sur la prévalence du covid long.

N011

___Definition of long covid___

Published correspondence on 17-Jun-21:
"Causation or confounding: why controls are critical for characterizing long COVID"
En évoquant leur propre étude qui constate à 7 mois 3% de personnes infectées par la covid qui gardent des symptômes continus, et 11% qui gardent des symptômes épisodiques, des auteurs demandent davantage d'études sur la prévalence du covid long.
Link: https://www.nature.com/articles/s41591-021-01402-w
Extract: "It is increasingly apparent that the long-term impact of this pandemic will be considerable and will substantially affect quality of life. Current best-guess estimates for long COVID (defined as self-reported persistence of any symptoms for 12 weeks or more after COVID-19) in population-based UK studies range from 2.2% (ref. 8) to 13.7% (ref. 4), and systematic assessment of available data identify female sex, middle age, white ethnicity and specific underlying co-morbidities as potential risk factors7. More robust, well-conducted longitudinal studies are urgently needed for proper characterization of this syndrome to inform clinicians, to develop evidence-based guidelines and to direct healthcare resources to where they are most needed."

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Melanie Newman, freelance journalist

Chronic fatigue syndrome and long covid: moving beyond the controversy

https://doi.org/10.1136/bmj.n1559

Published

24-Jun-21

Opinion

https://www.bmj.com/content/373/bmj.n1559.full

A decade after publication it seems unlikely that a consensus will ever be reached. The National Institute for Health and Care Excellence has since reviewed its guidance on ME/CFS, and the draft guidance2 expresses concerns about inappropriate use of exercise and CBT, stating that the evidence is mixed or unclear.
Tensions have now resurfaced with the advent of the pandemic and “long” covid or post-covid symptoms. As many as 376 000 people in the UK report symptoms more than 12 months after the first onset of covid-19,3 often experiencing extreme fatigue along with a wide range of other symptoms.
Clinicians report a complex picture. Patients with long covid are a diverse group, and it’s hard to know what treatment path to put them on. Finding the right balance between gentle activity to avoid deconditioning and not triggering post-exercise malaise is important in each patient. But the advice given, the research conducted, and how it is communicated have become highly sensitive issues.

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Amali U Lokugamage, Frances K Simpson, founding member of Long Covid Kids and LongCovidSOS, Carolyn A Chew-Graham

Patient commentary: How power imbalances in the narratives, research, and publications around long covid can harm patients

https://doi.org/10.1136/bmj.n1579

Published

25-Jun-21

Commentary

https://www.bmj.com/content/373/bmj.n1579.full

We don’t deny that all symptoms will have a psychological impact on the individual, and we would not wish psychological impacts to be stigmatised or ignored, but organic illness must be investigated and should be excluded only after appropriate investigation.1 People with long covid describe feeling “gaslighted” because the opinions of a few have tended to dominate the evolution of treatment, investigation, and a growing knowledge base.1

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Heald, Adrian; Riste, Lisa; Walther, Andreas; Stedman, Mike; Mukherjee, Annice

Reducing fatigue-related symptoms in Long COVID-19: finding an intervention that works

https://doi.org/10.1192/bjo.2021.681

Published

1-Jun-21

Case series

https://www.proquest.com/openview/f6426c9cd91e2c3d56b6386beec5c116/1?pq-origsite=gscholar&cbl=3962591

It was pointed out that an early intervention applying management techniques used in patients with CFS/ME appeared to help reduce the fatigue related symptoms of Long COVID. Here we present an analysis of a consecutive case series of the first twenty patients’ data collected. Our aim was to evaluate the potential of this mode of treatment for Long COVID.
Our findings indicate that this intervention based on massage and mobility exercises significantly reduced fatigue related to Long COVID. It may be that early intervention and supportive treatments at the end of the acute phase of COVID-19 can help overcome acute phase symptoms and prevent them becoming chronic/enduring

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Michael Le Page Helen Thomson Adam Vaughan Clare Wilson

Getting to grips with long covid

https://doi.org/10.1016/S0262-4079(21)01081-2

Published

26-Jun-21

Article

https://www.sciencedirect.com/science/article/pii/S0262407921010812

What is clear is that even after the pandemic is brought under control, millions of people will be left with lingering symptoms that prevent them from working and enjoying life. Here is what we know so far.

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Prof John D. Potter*

Update on Long-COVID

Published

Opinion

https://sciblogs.co.nz/public-health-expert/2021/06/15/update-on-long-covid/

This blog post updates an earlier post on Long-COVID and reports that estimates of prevalence are still wide at about 15 to 65% of those initially infected with the pandemic virus, SARS-CoV-2. As things stand now across the world, we do not yet have systems in place to diagnose and manage the massive burden of the disease that is Long-COVID. An elimination strategy that includes, but is not limited to, widespread vaccination is not only crucial to reduce the acute case load and high mortality associated with infection with SARS-CoV-2 but is also key to minimising the damage that Long-COVID is otherwise certain to create for individuals, whanau, communities, and nations.

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Priya Sharma, Senior Resident,a,∗ Sumit Bharti, Senior Resident,b and Isha Garg, Assistant Professorc

Post COVID fatigue: Can we really ignore it?

https://dx.doi.org/10.1016%2Fj.ijtb.2021.06.012

Published

23-Jun-21

Review

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220285/

It's difficult for physicians to predict when symptoms will improve as it varies differently in different people. Patient's recovery depends on various factors including age, associated comorbidities, severity of COVID-19 infection. Some symptoms, like fatigue, might continue even while others improve or go away. This review addresses the pathogenesis, presentation of post covid fatigue, its severity and its management.

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Fiona Godlee, editor in chief

How can we manage covid fatigue?

https://doi.org/10.1136/bmj.n1610

Published

24-Jun-21

Opinion

https://www.bmj.com/content/373/bmj.n1610.full

What’s the long term outlook after covid? And what’s the prognosis for health systems and staff struggling with covid pressures, waiting lists, and stretched resources?

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U. Tirelli, R. Taibi, S. Chirumbolo

Post COVID syndrome: a new challenge for medicine

https://doi.org/10.26355/eurrev_202106_26154

Published

1-Jun-21

Commentary

https://www.europeanreview.org/article/26154

The scientific community is actually wondering about the etiopathogenesis and clinical development of this “post-COVID” complex symptomatology, very close to symptoms typically observed in chronic fatigue syndrome, so recently named as “post-acute sequelae of COVID-19 (PASC)”. This commentary tries to focus on the most recent news about this issue.

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Dr Vinod Nikhra

Exploring Etiopathophysiological Links for ‘Long Covid’

https:// .org/0000-0003-0859-5232

pre-print

1-Jun-21

Review

https://www.researchgate.net/profile/Vinod-Nikhra/publication/352720529_Exploring_Etiopathophysiological_Links_for_'Long_Covid'/links/60d5320a299bf1ea9ebac094/Exploring-Etiopathophysiological-Links-for-Long-Covid.pdf

Long Covid is a multisystem disorder entailing multiple symptoms related to various organs. There are several theories about the etiology of Long Covid such as continuing presence of the virus and its biologically active fragments, reinfection with the same or a different variant, dysfunctional immune reactions leading to a
chronic inflammatory state, an ill-defined condition exhibiting symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suggestive of a complex, multisystem disorder, post-traumatic stress following severe COVID-19 illness and critical care issues, and aftermath resulting due to disturbed microbiota in gut, lungs, and other organs.
LONG COVID PATHOGENESIS -NEW INSIGHTS: The SARS-CoV-2 infection activates the humoral immunity leading to formation of antigen-antibody complexes and the antigen-antibody reactions, which may propagate to organ damage. Simultaneously, viral superantigens may overstimulate immune responses, inducing negative feedback loops to hamper immune function and allow the virus to persist and replicate. The persistent virus may contribute to long Covid There may develop various autoantibodies causing tissue injury and fibrosis in lungs and other organs. The Altered Microbiome leading to the microbial
dysbiosis has also been implicated in persisting inflammatory processes culminating as Long Covid.

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Dorothy Wall

The Importance of Listening in Treating Invisible Illness and Long-Haul COVID-19

https://doi.org/10.1001/amajethics.2021.590

Published

1-Jul-21

Opinion

https://journalofethics.ama-assn.org/article/importance-listening-treating-invisible-illness-and-long-haul-covid-19/2021-07

Yet those with invisible, controversial illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often have symptoms not explained by standard laboratory values. For instance, one of the cardinal features of ME/CFS is postexertional malaise, the exacerbation of symptoms—fatigue, pain, cognitive dysfunction—following exertion, which contradicts studies showing the health benefits of exercise. In these cases, overly physicalist approaches to caring for patients are not likely to be helpful, and a clinician’s willingness to listen to a patient’s experience of illness becomes essential.

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Steven Phillips, M.D., M.P.H., and Michelle A. Williams, Sc.D.

Confronting Our Next National Health Disaster — Long-Haul Covid

https://doi.org/10.1056/NEJMp2109285

Published

30-Jun-21

Opinion

https://www.nejm.org/doi/full/10.1056/NEJMp2109285

Though most Americans may be able to do so, restoration of normality does not apply to the 10% to 30% of those who are still experiencing debilitating symptoms months after being infected with Covid-19.1 Unfortunately, current numbers and trends indicate that “long-haul Covid” (or “long Covid”) is our next public health disaster in the making. What form will this disaster take, and what can we do about it? To understand the landscape, we can start by charting the scale and scope of the problem and then apply the lessons of past failures in approaching postinfection chronic disease syndromes.

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Jacqui Wise

Covid-19: Long covid cases are underreported in GP records, research suggests

https://doi.org/10.1136/bmj.n1685

Published

2-Jul-21

Opinion

https://www.bmj.com/content/374/bmj.n1685

GPs may be underreporting long covid say researchers who analysed 58 million patients’ primary care records and found a much lower prevalence than previous survey estimates.

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126

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Edward P Hoffer

Long Covid: does it exist? What is it? We can we do for sufferers?

https://doi.org/10.1016/j.amjmed.2021.05.023

Published

5-Jul-21

COMMENTARY

https://www.amjmed.com/article/S0002-9343(21)00399-5/fulltext

It is easy for physicians to attribute symptoms to anxiety, but this is neither helpful to our patients nor necessarily true. “Hard” neurologic illnesses, including ischemic strokes and intracranial hemorrhage have been found to be more common in patients recovered from even mild Covid-1911. Certainly the two leading hypotheses as to the cause of “long-Covid” are psychosomatic and immune-mediated, but persisting small vessel thrombi have also been postulated.
Pending the results of larger controlled studies, what can we offer our patients? While anecdotal at this point, many patients with persisting symptoms after a mild/asymptomatic infection have reported improvement in symptoms after vaccination. Since these patients are still at risk for reinfection, advising vaccination is appropriate whether or not it helps their symptoms. Critically, we should not dismiss their complaints as being “all in their head.” This may be wrong, and even if correct is not helpful. It is appropriate to acknowledge their distress, get those with fatigue and/or dyspnea in a structured exercise program, and work with all on symptomatic relief.

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Vivienne Harte

Reflections on a Support Group for Doctors Recovering from Long Covid

Published

1-Jul-21

Opinion

https://groupanalyticsociety.co.uk/contexts/issue-91/articles/reflections-on-a-support-group-for-doctors-recovering-from-long-covid/

In October 2020 I was invited by Dr Clare Gerada, in her capacity as Chair of the charity Doctors in Distress (DiD), to facilitate an on-line support group for medical doctors experiencing symptoms of Long Covid. The group was free, through the charity, to doctors at any stage of their career working in the UK.

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George F. Gao

Editorial: COVID-19: A Year Long and Beyond?

http://weekly.chinacdc.cn/en/article/doi/10.46234/ccdcw2021.052

Published

19-Feb-21

Article

http://weekly.chinacdc.cn/en/article/doi/10.46234/ccdcw2021.052

Looking into the future, there will still be many uncertainties in 2021. One of them is that the COVID-19 pandemic might become a lasting epidemic or endemic.

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Guy A. Richards0 Adrian Wentzel1 Robert Miller2 Richard Van Zyl Smit3

Post-acute COVID-19 sequelae - 'COVID long hauler'

https://doi.org/10.18772/26180197.2021.v3n2a4

Published

5-Jul-21

Review

https://journals.co.za/doi/abs/10.18772/26180197.2021.v3n2a4

Severe acute respiratory syndrome coronavirus-2 infection manifests with an acute illness of varying severity and unpredictable mortality. Those who survive may develop a more prolonged disease process called post-acute COVID-19 sequelae which causes considerable disability regardless of the severity of the acute disease.
Two phenotypes have been described. First, those with persistent organ dysfunction related to the degree of the inflammatory response and second those with less well defined, but no less troublesome symptoms, that considerably impact the quality of life.
This review discusses both phenotypes and the proposed mechanisms and also explores possible therapies for this condition.

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Charee M.ThompsonaKayla B.RhidenourbKate G.BlackburncAshley K.BarrettbSaraBabu

Using crowdsourced medicine to manage uncertainty on Reddit: The case of COVID-19 long-haulers

https://doi.org/10.1016/j.pec.2021.07.011

Published

13-Jul-21

Study

https://www.sciencedirect.com/science/article/pii/S0738399121004705

Highlights
•Online communities are a site for crowdsourced medicine and collective uncertainty management.
•The social media platform Reddit helps COVID-19 long-haulers manage their uncertainty.
•Long-haulers’ talk reflects information-seeking functions through symptom language.
•Long-haulers’ talk reflects support-seeking functions through support and identity language.
•Health care providers should employ sensitivity when addressing long-haulers’ anxiety and symptoms.

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Simon Denegri and Bella Starling

COVID-19 and patient engagement in health research: What have we learned?

https://doi.org/10.1503/cmaj.210998

Published

12-Jul-21

Commentary

https://www.cmaj.ca/content/193/27/E1048

KEY POINTS
Patient engagement has occupied an increasingly prominent place on the agenda of health care and research systems in recent years.
The COVID-19 global pandemic has highlighted both the fragility of patient engagement in research and innovative developments in this sphere.
Better digital engagement of patient groups has removed some of the long-standing barriers to patient and public engagement such as geography, inaccessible environments and cost, enabling new kinds of collaboration.
The research community including patients must build on the lessons learned during COVID-19 to strengthen the foundation for patient engagement in research and policy.

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132

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Charles Schmidt

COVID-19 long haulers

https://dx.doi.org/10.1038%2Fs41587-021-00984-7

Published

13-Jul-21

Article

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277229/

Without a clear unifying mechanism, long-COVID treatments face an uphill battle. “It’s challenging to treat something if you don’t know what’s causing it,” says Timothy Henrich, a physician and professor at the University of California, San Francisco. Tony Butler, managing director of Roth Capital Partners in New York, says the lack of an obvious target or mechanism in long-COVID leaves investors wary, despite the growing market. Right now, he says “it’s not seen as a growth area.” Cosme Ordonez, managing director and a senior equity research analyst who covers biotech at National Securities Corporation in Boca Raton, Florida, agrees. “To develop a novel candidate, we need something more specific to the condition,” he says. “In the case of acute COVID, we know that we need to block the virus and hyperinflammatory state. But the science behind long-COVID has lots of caveats, and we don’t really know what’s driving the disease. The targets are not well defined and correlated with the syndrome, and that might explain why industry is not jumping all over this because the market is potentially huge.” As mechanistic insights into long-COVID emerge, Ordonez expects industry funding will follow, with more biotech companies jumping in “within the next two to five years,” he says.

Un article fait un état des lieux de la recherche sur le covid long et les difficultés des chercheurs à proposer des traitements quand la cause est encore mal définie.
L'auteur évoque des médicaments déjà prodigués (ivabradine), et d'autres à l'essai :
- Ampligen (rintatolimod)
- LYT-100 (pirfenidone)
- leronlimab
- LMWF5A (aspartyl-alanyl-diketopiperazine)
- SNG001 (interféron bêta inhalé)
qui sont ainsi testés pour différents symptômes du covid long.

N012

___Definition of long covid___

Published article on 13-Jul-21:
"COVID-19 long haulers"
Un article fait un état des lieux de la recherche sur le covid long et les difficultés des chercheurs à proposer des traitements quand la cause est encore mal définie.
L'auteur évoque des médicaments déjà prodigués (ivabradine), et d'autres à l'essai :
- Ampligen (rintatolimod)
- LYT-100 (pirfenidone)
- leronlimab
- LMWF5A (aspartyl-alanyl-diketopiperazine)
- SNG001 (interféron bêta inhalé)
qui sont ainsi testés pour différents symptômes du covid long.
Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277229/
Extract: "Without a clear unifying mechanism, long-COVID treatments face an uphill battle. “It’s challenging to treat something if you don’t know what’s causing it,” says Timothy Henrich, a physician and professor at the University of California, San Francisco. Tony Butler, managing director of Roth Capital Partners in New York, says the lack of an obvious target or mechanism in long-COVID leaves investors wary, despite the growing market. Right now, he says “it’s not seen as a growth area.” Cosme Ordonez, managing director and a senior equity research analyst who covers biotech at National Securities Corporation in Boca Raton, Florida, agrees. “To develop a novel candidate, we need something more specific to the condition,” he says. “In the case of acute COVID, we know that we need to block the virus and hyperinflammatory state. But the science behind long-COVID has lots of caveats, and we don’t really know what’s driving the disease. The targets are not well defined and correlated with the syndrome, and that might explain why industry is not jumping all over this because the market is potentially huge.” As mechanistic insights into long-COVID emerge, Ordonez expects industry funding will follow, with more biotech companies jumping in “within the next two to five years,” he says."

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M. Lagadinou, E. Kostopoulou, A. Karatza, M. Marangos, D. Gkentzi

The prolonged effects of COVID-19.
A new “threat”?

https://doi.org/10.26355/eurrev_202107_26253

Published

1-Jul-21

Article

https://www.europeanreview.org/article/26253

Coronavirus ‘long-haulers” currently represent a significant public health concern. Recent reports suggest that persistent effects of COVID-19, such as fatigue, dyspnea, chest pain, anxiety, depression, arthralgia, may last for months and lead to a decline in quality of life. Risk factors for long COVID are still not very well understood. Survivors suffer from ongoing symptoms. This new entity highlights the need for a multidisciplinary approach that would enable elose monitoring of affected patients and implementation of measures that could reduce the impact of the pandemic on the overall patient wellbeing after the resolution of acute symptoms.

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Xiaoying Gu
Bin Cao

In-hospital complications associated with COVID-19

https://doi.org/10.1016/S0140-6736(21)00983-1

Published

17-Jul-21

COMMENT

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00983-1/fulltext

In The Lancet, Thomas Drake and colleagues5 report their prospective study of in-hospital complications of COVID-19 and the impact on clinical prognosis at discharge, initiated at the early stages of the pandemic. 73 197 adult patients were studied, of whom 44% were female and 73% were White, from 302 UK health-care facilities, with COVID-19 and admitted to hospital between Jan 4 and Aug 4, 2020. The study showed that among those admitted to hospital with COVID-19, a high proportion (49·7%) had at least one complication. The occurrence of complications was not only associated with a higher risk of mortality during hospitalisation, but also reduced the ability of patients to self-care once discharged.
Whether this difference in complications on mortality was statistically significant was not examined by the authors. This finding is independent of the presence and number of comorbidities and indicates that attention should also be paid to younger patients who are less likely to die during the acute phase but more likely to live longer with complications in the days after acute or subacute COVID-19.

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Harry Crook, research assistant1, Sanara Raza, research assistant1, Joseph Nowell, research assistant1, Megan Young, clinical research officer1, Paul Edison

Long covid—mechanisms, risk factors, and management

https://doi.org/10.1136/bmj.n1648

Published

26-Jul-21

Review

https://www.bmj.com/content/374/bmj.n1648

This review summarizes studies of the long term effects of covid-19 in hospitalized and non-hospitalized patients and describes the persistent symptoms they endure. Risk factors for acute covid-19 and long covid and possible therapeutic options are also discussed.

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Ioana Visan

Long COVID

https://doi.org/10.1038/s41591-021-01433-3

Published

27-Jul-21

Article

https://www.nature.com/articles/s41590-021-00992-4

The most frequent lasting symptoms in non-hospitalized patients aged 31–45 and 45–60 were disturbed taste and smell (34 and 28%, respectively), fatigue (31 and 33%), dyspnea (17 and 18%), concentration problems (19 and 21%) and memory problems (16 and 22%). Of non-hospitalized patients over 30, 7% experienced severe fatigue as compared to 24% of hospitalized patients. In non-hospitalized patients, antibody titers at 2 months were associated with the severity of the initial illness, while persistent fatigue was associated with the severity of the initial illness, fever during the initial illness and female gender.

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Nisreen A. Alwan

The road to addressing Long Covid

https://doir.org/10.1126/science.abg7113

Published

30-Jul-21

Article

https://science.sciencemag.org/content/373/6554/491.full

Long Covid is likely the first illness in history that has been defined by patients through social media platforms such as Twitter and Facebook. People with Long Covid formed a movement that demanded recognition of what was happening to them. During the first wave of the pandemic in 2020, online testimonials of prolonged symptoms following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were the only source of reassurance to others with a similar experience, including this author (2). In the absence of any guidance or recognition about the possibility of a persistent illness, peer support is all that people with Long Covid had. Many previously healthy and active people described persistent symptoms of the acute illness that fluctuated, with new symptoms appearing weeks later. In many countries, most nonhospitalized people did not have lab confirmation of SARS-CoV-2 infection owing to lack of access to community testing, so their symptoms remained without a diagnosis.

By summer 2020, thousands were joining social media support groups. A common theme started to emerge: lack of recognition by the medical profession. Patients, including doctors, with Long Covid were consulting their health care providers, and their symptoms were commonly minimized, dismissed, or labeled as anxiety (3). A narrative emerged of people struggling to make sense of their symptoms and forming their own groups to understand and research what was happening to them in an international citizen science movement (4). The testimonials of people living with Long Covid demonstrated themes of stigma and discrimination.

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Sean L Davidson, psychiatry registrar1, David B Menkes

Long covid: reshaping conversations about medically unexplained symptoms

https://doi.org/10.1136/bmj.n1859

Published

28-Jul-21

Article

https://www.bmj.com/content/374/bmj.n1859.full

Patients presenting with symptoms in the presence of normal diagnostic tests account for 26-35% of consultations in primary care.4 The banner of medically unexplained symptoms encompasses heterogeneous issues—simple transient problems, recognised symptom complexes such as chronic fatigue syndrome, and emerging phenomena like long covid. All present challenges to the doctor-patient relationship, confer risks of overdiagnosis and overtreatment, and can provoke frustration and anxiety in junior and experienced clinicians alike.25
These common clinical scenarios emphasise the pressing need for a framework to aid communication with patients who are frustrated by the mismatch of disabling symptoms and normal investigations.

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Joan Stephenson

New Federal Guidance Says COVID-19’s Long-term Effects Can Qualify as a Disability

http://jamanetwork.com/article.aspx?doi=10.1001/jamahealthforum.2021.2820

Published

3-Aug-21

Article

https://jamanetwork.com/journals/jama-health-forum/fullarticle/2782892

People in the US who experience persistent, recurring, or new symptoms after infection with COVID-19—a condition known as long COVID—can qualify as having a disability under federal civil rights laws and receive appropriate accommodations and services, the Biden-Harris administration announced last week.

The US Department of Health and Human Services (HHS) and the Department of Justice jointly released new guidance that classifies long COVID—also known in the research community as postacute sequelae of SARS-CoV-2 infection—as a physical or mental impairment, which means that those affected can qualify for discrimination protections under the Americans with Disabilities Act (ADA).

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Dietrich August, Veronika Götz, Katarina Stete

Persistierende Beschwerden nach akuter COVID-19-Erkrankung: „Long-COVID“?
Persisting symptoms after COVID-19: „Long COVID“?

Published

3-Aug-21

Article

https://www.thieme-connect.com/products/ejournals/abstract/10.1055/a-1447-9253

Some patients complain of persisting symptoms after acute COVID-19. There is no universal definition yet for these post-acute sequelae, also termed Long COVID. Although their prevalence remains to be established, a delayed recovery seems to be more common than after other acute infectious diseases. Common complaints include fatigue with exercise intolerance, dyspnea on exertion, chest pain, and neuropsychiatric symptoms. Female sex, comorbidities, and severity of the acute disease have been identified as risk factors for persisting symptoms. It is, however, important to highlight that they are not limited to patients after severe COVID-19. Whilst their pathogenesis and prognosis is largely unknown, diagnostic evaluation should focus on exclusion of objective organ dysfunctions. Due to the variable presentation, management is interdisciplinary and may include physiotherapy, rehabilitation programmes, and psychological support. This article aims to summarize the current – limited – evidence on persisting symptoms after COVID-19.

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141

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Steven Phillips, M.D., M.P.H., and Michelle A. Williams

Confronting Our Next National Health Disaster — Long-Haul Covid

10.1056/NEJMp2109285

Published

12-Aug-21

Opinion

https://www.nejm.org/doi/full/10.1056/NEJMp2109285

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142

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Akiko Iwasaki

How COVID-19 has transformed my science

https://doi.org/10.1016/j.neuron.2021.07.022

Published

6-Aug-21

Opinion

https://www.sciencedirect.com/science/article/pii/S0896627321005432

In this NeuroView, I recount pivotal moments that have transformed the way I do science.

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From this point on, the survey of studies is no longer as exhaustive as possible. Only those studies which seem to us to bring significant new elements will be listed.

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Paul G. Auwaerter

The Race to Understand Post–COVID-19 Conditions

https://doi.org/10.7326/M21-3072

Published

31-Aug-21

Opinion

https://www.acpjournals.org/doi/full/10.7326/M21-3072

_

145

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Jun Wang,a,b,1 Fanghua Mei,c,1 Lu Bai,a,b Suhua Zhou,c Di Liu,a,b Lulu Yao,a,b Amrita Ahluwalia,d Reza A. Ghiladi,e Lei Su,f Tong Shu,f Miaozi Gong,g Xiaofang Wang,h Lijun Zhu,i Kun Cai,c,∗ and Xueji Zhang

Serum nitrite and nitrate: A potential biomarker for post-covid-19 complications?

https://dx.doi.org/10.1016%2Fj.freeradbiomed.2021.08.237

Published

30-Aug-21

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404395/

Dysregulation of NOx had been reported in SARS-CoV-2 infected populations, but whether patients recovered from COVID-19 disease present with restored NOx is unknown. In this study, serum NO2− and NO3− were quantified and analyzed among 109 recovered adults in comparison to a control group of 166 uninfected adults. Nitrite or nitrate levels were not significantly different among mild-, common-, severe- and critical-type patients. However, these recovered patients had dramatically lower NO2− and NO2−/NO3− than the uninfected group (p < 0.0001), with significantly higher NO3− levels (p = 0.0023) than the uninfected group. Nitrate and nitrite/nitrate were positively and negatively correlated with patient age, respectively, with age 65 being a turning point among recovered patients. These results indicate that low NO2−, low NO2−/NO3− and high NO3− may be a potential biomarker of long-term poor or irreversible outcomes after SARS-CoV-2 infection. It suggests that NO metabolites might serve as a predictor to track the health status of recovered COVID-19 patients, highlighting the need to elucidate the role of NO after SARS-CoV-2 infection.

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Adam W Gaffney, MD MPH

The Long-COVID Conundrum

https://doi.org/10.1016/j.amjmed.2021.07.037

Published

20-Aug-21

Editorial

https://www.amjmed.com/article/S0002-9343(21)00525-8/fulltext

One study1 found that 1 in 3 non-hospitalized adults report 1+ symptom 6 months post-COVID-19. While one study found eventual resolution of symptoms in children,2 another found persistence among 57% of non-hospitalized children and 36% of initially asymptomatic children.3 Such estimates fuel concerns that Long COVID is the “next public health disaster in the making” that could afflict more than one in twenty Americans.4
There are important caveats, however. First, such estimates should be interpreted in the context of what we know about symptom persistence after other common respiratory infections, and in other prevalent conditions.

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Richard Beasley
Nethmi Kearns
Tom Hills

Charting a course for the management of long COVID

https://doi.org/10.1016/S2213-2600(21)00314-3

Published

17-Aug-21

Comment

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00314-3/fulltext

It is difficult to think beyond the immediate crisis, when wave after wave of the COVID-19 pandemic has repeatedly overwhelmed health systems and resulted in high rates of mortality and severe disruption to normal life. However, the recognition of a syndrome of prolonged, multisystem disability in survivors of COVID-191, 2, 3—commonly referred to as long COVID or the post-COVID-19 condition—has made obtaining knowledge of its pathogenesis, prognosis, and management an important competing priority. A comprehensive, coordinated global research strategy for the post-acute sequelae of COVID-19, rather than a piecemeal approach, is clearly required, although difficult to achieve in the midst of a pandemic.
For this reason, the Position Paper from the UK-based International COVID-19 Airways Diseases Group in The Lancet Respiratory Medicine,4 presenting research priorities for the long-term effects of COVID-19 in the context of airways disease, is to be welcomed. The consensus recommendations, which are both broad and insightful, will inform future research efforts.

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Davies Adeloye, PhD *
Omer Elneima, MRCP *
Luke Daines, MBChB *
Krisnah Poinasamy, LLM *
Prof Jennifer K Quint, FRCP
Samantha Walker, PhD
Prof Chris E Brightling, FMedSci
Prof Salman Siddiqui, FRCP
Prof John R Hurst, FRCP
Prof James D Chalmers, PhD
Paul E Pfeffer, PhD
Petr Novotny, MUDr
Thomas M Drake, MBChB
Prof Liam G Heaney, MRCP †
Prof Igor Rudan, PhD †
Prof Aziz Sheikh, MD †
Prof Anthony De Soyza, PhD †
on behalf of theInternational COVID-19 Airways Diseases Group

The long-term sequelae of COVID-19: an international consensus on research priorities for patients with pre-existing and new-onset airways disease

https://doi.org/10.1016/S2213-2600(21)00286-1

Published

17-Aug-21

POSITION PAPER

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00286-1/fulltext

Persistent ill health after acute COVID-19—referred to as long COVID, the post-acute COVID-19 syndrome, or the post-COVID-19 condition—has emerged as a major concern. We undertook an international consensus exercise to identify research priorities with the aim of understanding the long-term effects of acute COVID-19, with a focus on people with pre-existing airways disease and the occurrence of new-onset airways disease and associated symptoms. 202 international experts were invited to submit a minimum of three research ideas. After a two-phase internal review process, a final list of 98 research topics was scored by 48 experts. Patients with pre-existing or post-COVID-19 airways disease contributed to the exercise by weighting selected criteria. The highest-ranked research idea focused on investigation of the relationship between prognostic scores at hospital admission and morbidity at 3 months and 12 months after hospital discharge in patients with and without pre-existing airways disease. High priority was also assigned to comparisons of the prevalence and severity of post-COVID-19 fatigue, sarcopenia, anxiety, depression, and risk of future cardiovascular complications in patients with and without pre-existing airways disease. Our approach has enabled development of a set of priorities that could inform future research studies and funding decisions. This prioritisation process could also be adapted to other, non-respiratory aspects of long COVID.

Un large groupe de chercheurs, accompagné par des malades, mène un exercice de consensus international et identifie, dans The Lancet Respiratory Medicine, des priorités de recherche dans le but de comprendre les effets à long terme de la covid.

N014E

___Definition of long covid___

Published position paper on 17-Aug-21:
"The long-term sequelae of COVID-19: an international consensus on research priorities for patients with pre-existing and new-onset airways disease"
Un large groupe de chercheurs, accompagné par des malades, mène un exercice de consensus international et identifie, dans The Lancet Respiratory Medicine, des priorités de recherche dans le but de comprendre les effets à long terme de la covid.
Link: https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00286-1/fulltext
Extract: "Persistent ill health after acute COVID-19—referred to as long COVID, the post-acute COVID-19 syndrome, or the post-COVID-19 condition—has emerged as a major concern. We undertook an international consensus exercise to identify research priorities with the aim of understanding the long-term effects of acute COVID-19, with a focus on people with pre-existing airways disease and the occurrence of new-onset airways disease and associated symptoms. 202 international experts were invited to submit a minimum of three research ideas. After a two-phase internal review process, a final list of 98 research topics was scored by 48 experts. Patients with pre-existing or post-COVID-19 airways disease contributed to the exercise by weighting selected criteria. The highest-ranked research idea focused on investigation of the relationship between prognostic scores at hospital admission and morbidity at 3 months and 12 months after hospital discharge in patients with and without pre-existing airways disease. High priority was also assigned to comparisons of the prevalence and severity of post-COVID-19 fatigue, sarcopenia, anxiety, depression, and risk of future cardiovascular complications in patients with and without pre-existing airways disease. Our approach has enabled development of a set of priorities that could inform future research studies and funding decisions. This prioritisation process could also be adapted to other, non-respiratory aspects of long COVID."

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Catherine Tourette-Turgis a, ⁎ : Fondatrice et directrice de l'Université des patients-Sorbonne Université, Dominique Salmon b : Médecin, professeur des universités-praticien hospitalier en maladies infectieuses, Pauline Oustric c : Cofondatrice de l'association Covid-long France #ApresJ20, Faustine Hélie c : Cofondatrice de #ApresJ20, Mylène Rahel Damamme c : Cofondatrice de #ApresJ20

Expérience patient, autorité épistémique et enjeux sanitaires : l'exemple du Covid long - Patient experience, epistemic authority and health challenges: the example of long COVID

https://doi.org/10.1016/S0038-0814(21)00217-6

Published

8-Jun-21

Article

https://www.em-consulte.com/article/1461696/alertePM

Depuis février 2020, des centaines de milliers de malades sont confrontés à des symptômes persistants après leur infection

Avec leurs cliniciens, ces patients sont exposés à un haut degré d'incertitude et à l'urgence de la production de cadres conceptuels visant la reconnaissance, la prise en charge et la légitimation de leur expérience de malades confrontés à des symptômes nouveaux et prolongés, comme à des controverses quant à la qualification de ces symptômes

En ce sens, le Covid long illustre la nécessité de combiner les savoirs expérientiels collectifs des malades et les savoirs scientifiques au bénéfice des patients, des cliniciens et de la recherche.

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Lacedonia D. · Scioscia G. · De Pace C.C. · Laricchiuta A. · Tondo P. · Sabato R. · Foschino Barbaro M.P.

How Are We Handling the Post-COVID Patients? The Dance of Uncertainties

https://doi.org/10.1159/000518330

Published

3-Sep-21

Letter to the Editor

https://www.karger.com/Article/FullText/518330

In conclusion, despite the rich literature on this topic, the possibility of having clear recommendations about the management of patients affected by PACS still seems far away, in terms of timing of visits, clinical and functional assessments, and treatment. According to our survey, there is a tacit common line of action diffused among the pulmonologists with only some little differences in the management according to the number of patients following up. Main open issues should be solved with standardized European guidelines in order to obtain a better clinical practice for optimizing the safety of patients and the administration of health-care resources.

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ONS

ONS: Short report on Long COVID, 22 July 2021

Published

30-Jul-21

Article

https://www.gov.uk/government/publications/ons-short-report-on-long-covid-22-july-2021

This report is provided at the request of SAGE and includes information from ongoing studies investigating long COVID including the COVID-19 Longitudinal Health and Wellbeing National Core Study-CONVALESCENCE Study, REACT-2, PHOSP-COVID, ONS’s COVID-19 Infection Survey (CIS) and the COVID Symptom Study App.

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Elizabeth Murphy, Kiera McDowall, Peter McDowall

Should long-term symptoms following COVID-19 infection be considered an occupational disease?

https://doi.org/10.1093/occmed/kqab103

Published

13-Sep-21

Article

https://academic.oup.com/occmed/advance-article/doi/10.1093/occmed/kqab103/6369377?login=true

The question whether ‘long COVID’ is an occupational disease or a problem for the nation at large is clearly important and there are a wide array of questions. From an occupational health perspective, it brings an opportunity to focus on an individual’s daily function, workability and engagement in work in order to promote good health and productivity. When return to work is not feasible, NHS workers already have access to the NHS Injury Allowance and possible application for NHS pensions benefits. Given the scale of the problem and financial complexities, this may ultimately be more a question for the economists than anyone else

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McClymont, G.

The Role of Patients and Patient Activism in the Development of Long COVID Policy

https://doi.org/10.17863/CAM.75505

Published

15-Sep-21

Article

https://www.repository.cam.ac.uk/handle/1810/328051

Long Covid awareness originated from Long Covid patients, known as long haulers, finding each other on social media and support groups. Long hauler patient activism has been the driving force behind Long Covid recognition, research and health policy development. Two support groups have played key roles: The Body Politic COVID-19 Support Group and The Long Covid Patient Support Group. These bodies have raised awareness of Long Covid in the media, and in academic and medical communities. They have also provided support for long haulers. The Body Politic COVID-19 Support Group produced a patient-led research report which catalysed research policy for Long Covid. Peer-reviewed research has revealed a diverse array of severe, multi-organ symptoms of Long Covid and has recommended a multi-disciplinary healthcare approach to Long Covid. This recommendation has been adopted by various governments and medical institutions, which have opened Long Covid clinics. Population morbidity from Long Covid is a rising challenge, requiring research, a multi-disciplinary healthcare approach and socio-economic support.

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154

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Darren A Brown1, Kelly K O’Brien

Conceptualising Long COVID as an episodic health condition

http://dx.doi.org/10.1136/bmjgh-2021-007004

Published

22-Sep-21

Commentary

https://gh.bmj.com/content/6/9/e007004

Long COVID presents with multidimensional clusters of symptoms that can fluctuate, sometimes unpredictably, whereby symptoms adversely affect general well-being and ability to perform day-to-day activities, exercise or work.
We propose that Long COVID should be conceptualised as an episodic illness, characterised by health-related challenges (or disability) that may be multidimensional, episodic and unpredictable in nature.
Dimensions of disability experienced by people living with Long COVID may include physical, cognitive, mental and emotional health, daily activities, social inclusion and uncertainty, with uncertainty and worrying about the future a key dimension of disability.
The role for rehabilitation is important for people living with Long COVID, offering a goal-oriented, person-centred approach to prevent, mitigate and address episodic disability.
Future directions include establishing valid and reliable measures of episodic disability, assessing effectiveness of rehabilitation approaches and interventions and building on existing international collaborations and community-engaged partnerships to advance practice, research and policy.

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J. Lechner-Scott
M. Levy
C. Hawkes
A. Yeh
G. Giovannoni

Long COVID or post COVID-19 syndrome

https://doi.org/10.1016/j.msard.2021.103268

Published

17-Sep-21

EDITORIAL

https://www.msard-journal.com/article/S2211-0348(21)00535-6/fulltext

SARS-COV- 2 is now recognized to be responsible not only for a lung condition but a multi-organ syndrome1. After the initial acute infection, like many other viral disorders, a multitude of long-lasting symptoms have been described.
Neuropsychiatric symptoms that occur during or after infection with SARS-2 are not simply related to emotional stress. This concept is given provisional support by the presence of inflammatory CSF in five cases of childhood Multisystem Inflammatory Syndrome (MIS-C), three of whom presented with neuropsychiatric symptoms one month after acute infection9, suggesting CNS inflammatory consequences may occur in all age groups. SARS-2 is neurotropic and appears to enter the brain through the olfactory neurons10, spreading to the frontal lobes as shown by impaired executive function and frontal abnormalities on MRI, EEG and PET11.
The most supported theory is an autoimmune process with an exaggerated innate immune response and cytokine activation. Most patients with severe COVID-19 exhibit substantially elevated serum levels of pro-inflammatory cytokines including interleukin 6, 1- beta, 2, 8, 17, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, chemokine ligand 2 and 10, and tumour necrosis factor alpha, resulting in the now well- recognised cytokine storm15. The presence of oligoclonal IgG bands and activated microglia resemble the process causing fatigue and cognitive impairment in MS16.

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L.Bertoletti

COVID-19 : embolie pulmonaire ou endothélite pulmonaire ?

https://doi.org/10.1016/j.jdmv.2021.08.129

Published

25-Sep-21

Article

https://www.sciencedirect.com/science/article/pii/S2542451321002339

L’analyse post-mortem des poumons de patients a permis de mettre en évidence une atteinte de la perfusion capillaire pulmonaire, puis par la démonstration d’une infection directe de l’endothélium vasculaire pulmonaire par le virus. Cette atteinte endothéliale a permis d’expliquer ensuite le développement des lésions de thrombose in situ, en combinaison avec l’orage inflammatoire secondaire décrit dans la COVID-19. Le concept de thrombo-inflammation était conforté dans notre compréhension de la maladie.

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157

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Viet-Thi Tran, Carolina Riveros, Bérangère Clepier, Moïse Desvarieux, Camille Collet, Youri Yordanov, Philippe Ravaud

Development and Validation of the Long Coronavirus Disease (COVID) Symptom and Impact Tools: A Set of Patient-Reported Instruments Constructed From Patients’ Lived Experience

https://doi.org/10.1093/cid/ciab352

Published

29-Apr-21

Study

https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab352/6252414

To develop and validate patient-reported instruments, based on patients’ lived experiences, for monitoring the symptoms and impact of long coronavirus disease (covid).
Methods
The long covid Symptom and Impact Tools (ST and IT) were constructed from the answers to a survey with open-ended questions to 492 patients with long COVID.
Conclusions
The long covid ST and IT tools, constructed from patients’ lived experiences, provide the first validated and reliable instruments for monitoring the symptoms and impact of long covid.

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Dr Ashish Chaudhry General Practitioner and Medical Educator. Member of the UK Doctors Long COVID Group.
with contributions from
Clare Rayner Occupational Health Physician Asad Khan Respiratory Physician
Dr Harsha Master

Long Covid
Dr Ashish Chaudhry General Practitioner and Medical Educator. Member of the UK Doctors Long COVID Group.
with contributions from
Clare Rayner Occupational Health Physician Asad Khan Respiratory Physician
Dr Harsha Master GP Lead, Hertfordshire Community NHS Trust COVID-19 Rehabilitation Service
Learning over the last year from those with lingering symptoms

Published

1-Sep-21

Article

https://www.mountsinai.org/files/MSHealth/Assets/HS/Locations/Abilities-Research-Center/BJ-Sept2021-LongCovid.pdf

Consider that the sequelae after acute covid infection can be multisystem, fluctuate and last for prolonged periods. The medical
profession is only just beginning to describe cases, so evidence for any
interventions are still limited and usually based on expert consensus
or anecdote. It is therefore vital that we focus on the possibility of illness
rather than probability in initial stages, and symptoms are screened
for and diagnostic nets cast wide in patients who remain symptomatic.
Long covid will leave an impact on the NHS for years to come, and
there is an opportunity to support your patients through the unknown
with compassion and courage so they may have access to appropriate
health care

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Pierce, Janet D.; Shen, Qiuhua; Cintron, Samantha A.; Hiebert, John B.

Post-COVID-19 Syndrome

Published

12-Oct-21

Review

https://journals.lww.com/nursingresearchonline/Abstract/9000/Post_COVID_19_Syndrome.99627.aspx

Although studies examining the pathophysiology of post-COVID-19 syndrome are still relatively few, there is growing evidence that this is a complex and multifactorial syndrome involving virus-specific pathophysiologic variations that affect many mechanisms but specifically oxidative stress, immune function, and inflammation. Further research is needed to elucidate the pathophysiology, pathogenesis, and longer-term consequences involved in post-COVID-19 syndrome.

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Emily R. Pfaff, Andrew T Girvin, Tellen D. Bennett, Abhishek Bhatia, Ian M. Brooks, Rachel R Deer, Jonathan P Dekermanjian, Sarah Elizabeth Jolley, Michael G. Kahn, Kristin Kostka, Julie A McMurry, Richard Moffitt, Anita Walden, Christopher G Chute, Melissa A Haendel

Who has long-COVID? A big data approach

https://doi.org/10.1101/2021.10.18.21265168

pre-print

22-Oct-21

Study

https://www.medrxiv.org/content/10.1101/2021.10.18.21265168v1.full-text

The combined demographics of the long-COVID clinic patients supplied by the three sites (first two columns of Table 1) show significant differences from the COVID-19 patients at those sites who did not attend the long-COVID clinic (third and fourth columns of Table 1). Notably, non-hospitalized long-COVID clinic patients are disproportionately female. Long-COVID clinic patients who were hospitalized with acute COVID-19 are disproportionately Black when compared with all patients hospitalized with acute COVID-19, and are much more likely to have a pre-COVID-19 comorbidity (diabetes, kidney disease, congestive heart failure, or pulmonary disease).

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Noelle M. Cocoros, DSc, MPH1; Elisabeth Svensson, PhD2,3; Szimonetta Komjáthine Szépligeti, MSc2; Søren Viborg Vestergaard, MD2; Péter Szentkúti, MSc2; Reimar W. Thomsen, MD, PhD2; Per Borghammer, MD, PhD, DMSc4; Henrik Toft Sørensen, MD, PhD, DMSc, DSc2,5; Victor W. Henderson, MD, MS2,6,7

Long-term Risk of Parkinson Disease Following Influenza and Other Infections

https://doi.org/10.1001/jamaneurol.2021.3895

Published

25-Oct-21

Study

https://jamanetwork.com/journals/jamaneurology/article-abstract/2785029

Results Of 61 626 included individuals, 23 826 (38.7%) were female, and 53 202 (86.3%) were older than 60 years. A total of 10 271 individuals with Parkinson disease and 51 355 controls were identified. Influenza diagnosed at any time during a calendar year was associated with Parkinson disease more than 10 years later (OR, 1.73; 95% CI, 1.11-2.71). When influenza exposure was restricted to months of highest influenza activity, an elevated OR with a wider confidence interval was found (OR, 1.52; 95% CI, 0.80-2.89). There was no evidence of an association with any type of infection more than 10 years prior to Parkinson disease (OR, 1.04; 95% CI, 0.98-1.10). Several specific infections yielded increased odds of Parkinson disease within 5 years of infection, but results were null when exposure occurred more than 10 years prior.

Conclusions and Relevance In this case-control study, influenza was associated with diagnoses of Parkinson disease more than 10 years after infection. These observational data suggest a link between influenza and Parkinson disease but do not demonstrate causality. While other infections were associated with Parkinson disease diagnoses soon after infection, null associations after more than 10 years suggest these shorter-term associations are not causal.

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Questionable methodology

Joane Matta, PhD1; Emmanuel Wiernik, PhD1; Olivier Robineau, MD, PhD2,3; Fabrice Carrat, MD, PhD3; Mathilde Touvier, PhD4; Gianluca Severi, PhD5,6; Xavier de Lamballerie, MD, PhD7; Hélène Blanché, PhD8; Jean-François Deleuze, PhD8; Clément Gouraud, MD, MSc9; Nicolas Hoertel, MD, PhD10; Brigitte Ranque, MD, PhD11; Marcel Goldberg, MD, PhD1; Marie Zins, MD, PhD1; Cédric Lemogne, MD, PhD

Association of Self-reported COVID-19 Infection and SARS-CoV-2 Serology Test Results With Persistent Physical Symptoms Among French Adults During the COVID-19 Pandemic

http://jamanetwork.com/article.aspx?doi=10.1001/jamainternmed.2021.6454

Published

8-Nov-21

Original Research

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2785832

Findings In this cross-sectional analysis of 26 823 adults from the population-based French CONSTANCES cohort during the COVID-19 pandemic, self-reported COVID-19 infection was associated with most persistent physical symptoms, whereas laboratory-confirmed COVID-19 infection was associated only with anosmia. Those associations were independent from self-rated health or depressive symptoms.
Meaning Findings suggest that persistent physical symptoms after COVID-19 infection should not be automatically ascribed to SARS-CoV-2; a complete medical evaluation may be needed to prevent erroneously attributing symptoms to the virus.
The results of this cross-sectional analysis of a large, population-based French cohort suggest that physical symptoms persisting 10 to 12 months after the COVID-19 pandemic first wave may be associated more with the belief in having experienced COVID-19 infection than with actually being infected with the SARS-CoV-2 virus. Although our study cannot determine the direction of the association between belief and symptoms, our results suggest that further research regarding persistent physical symptoms after COVID-19 infection should also consider mechanisms that may not be specific to the SARS-CoV-2 virus. From a clinical perspective, patients in this situation should be offered a medical evaluation to prevent their symptoms being erroneously attributed to COVID-19 infection and to identify cognitive and behavioral mechanisms that may be targeted to relieve the symptoms.

Un article dans JAMA Internal Medicine avance que la persistance de symptômes après une infection de SARS-CoV-2 ne devrait pas être automatiquement associée au SARS-CoV-2.
L'étude note que seule l'anosmie est un symptôme prolongé qui semble directement corrélé à une sérologie positive, au contraire de plusieurs autres symptômes habituellement rapportés par les personnes qui pensent avoir été infectées (fatigue, douleurs thoraciques, problèmes digestifs, difficultés à respirer...). Etaient considérés prolongés les symptômes déclarés de plus de 8 semaines. Les symptômes sont auto-déclarés dans l'étude et les tests sérologiques sont considérés positifs pour un ratio de densité optique supérieure ou égale à 1,1. La sérologie a été faite pour la protéine S (S-igG), indistinctement à l'intérieur d'un intervalle de 7 mois.

Dès sa parution, cette étude est sévèrement critiquée par plusieurs experts renommés. Les interprétations qui en découlent sont jugées potentiellement non concluantes et trompeuses/fallacieuses ("misleading").
https://www.sciencemediacentre.org/expert-reaction-to-study-looking-at-the-association-of-self-reported-covid-19-infection-and-sars-cov-2-serology-test-results-with-persistent-physical-symptoms/
Francis Wilson, l'un des experts internationaux les plus réputés en conception et interprétation d'études médicales, estime l'étude française de JAMA faussée/impropre ("flawed") en raisons de lourds biais méthodologiques.
https://methodsmanmd.medium.com/is-long-covid-even-real-704bb74ab619

N016

___Definition of long covid___

Published original research on 8-Nov-21:
"Association of Self-reported COVID-19 Infection and SARS-CoV-2 Serology Test Results With Persistent Physical Symptoms Among French Adults During the COVID-19 Pandemic"
Un article dans JAMA Internal Medicine avance que la persistance de symptômes après une infection de SARS-CoV-2 ne devrait pas être automatiquement associée au SARS-CoV-2.
L'étude note que seule l'anosmie est un symptôme prolongé qui semble directement corrélé à une sérologie positive, au contraire de plusieurs autres symptômes habituellement rapportés par les personnes qui pensent avoir été infectées (fatigue, douleurs thoraciques, problèmes digestifs, difficultés à respirer...). Etaient considérés prolongés les symptômes déclarés de plus de 8 semaines. Les symptômes sont auto-déclarés dans l'étude et les tests sérologiques sont considérés positifs pour un ratio de densité optique supérieure ou égale à 1,1. La sérologie a été faite pour la protéine S (S-igG), indistinctement à l'intérieur d'un intervalle de 7 mois.

Dès sa parution, cette étude est sévèrement critiquée par plusieurs experts renommés. Les interprétations qui en découlent sont jugées potentiellement non concluantes et trompeuses/fallacieuses ("misleading").
https://www.sciencemediacentre.org/expert-reaction-to-study-looking-at-the-association-of-self-reported-covid-19-infection-and-sars-cov-2-serology-test-results-with-persistent-physical-symptoms/
Francis Wilson, l'un des experts internationaux les plus réputés en conception et interprétation d'études médicales, estime l'étude française de JAMA faussée/impropre ("flawed") en raisons de lourds biais méthodologiques.
https://methodsmanmd.medium.com/is-long-covid-even-real-704bb74ab619
Link: https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2785832
Extract: "Findings In this cross-sectional analysis of 26 823 adults from the population-based French CONSTANCES cohort during the COVID-19 pandemic, self-reported COVID-19 infection was associated with most persistent physical symptoms, whereas laboratory-confirmed COVID-19 infection was associated only with anosmia. Those associations were independent from self-rated health or depressive symptoms.
Meaning Findings suggest that persistent physical symptoms after COVID-19 infection should not be automatically ascribed to SARS-CoV-2; a complete medical evaluation may be needed to prevent erroneously attributing symptoms to the virus.
The results of this cross-sectional analysis of a large, population-based French cohort suggest that physical symptoms persisting 10 to 12 months after the COVID-19 pandemic first wave may be associated more with the belief in having experienced COVID-19 infection than with actually being infected with the SARS-CoV-2 virus. Although our study cannot determine the direction of the association between belief and symptoms, our results suggest that further research regarding persistent physical symptoms after COVID-19 infection should also consider mechanisms that may not be specific to the SARS-CoV-2 virus. From a clinical perspective, patients in this situation should be offered a medical evaluation to prevent their symptoms being erroneously attributed to COVID-19 infection and to identify cognitive and behavioral mechanisms that may be targeted to relieve the symptoms."

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Xiong R, Gunter C, Fleming E, Vernon SD, Bateman L, Unutmaz D, Oh J

Multi-‘omics of host-microbiome interactions in short- and long-term Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

https://doi.org/10.1101/2021.10.27.466150

pre-print

28-Oct-21

Study

https://europepmc.org/article/ppr/ppr413593

Overall, ME/CFS was characterized by reduced gut microbiome diversity and richness with high heterogeneity, and depletion of sphingomyelins and short-chain fatty acids in the plasma. We found significant differences when stratifying by cohort; short-term ME/CFS was associated with more microbial dysbiosis, but long-term ME/CFS was associated with markedly more severe phenotypic and metabolic abnormalities. We identified a reduction in the gene-coding capacity (and relative abundance of butyrate producers) of microbial butyrate biosynthesis together with a reduction in the plasma concentration of butyrate, especially in the short-term group. Global co-association and detailed gene pathway correlation analyses linking the microbiome and metabolome identified additional potential biological mechanisms underlying host-microbiome interactions in ME/CFS, including bile acids and benzoate pathways. Finally, we built multiple state-of-the-art classifiers to identify microbes, microbial gene pathways, metabolites, and clinical features that individually or together, were most able to differentiate short or long-term MECFS, or MECFS vs. healthy controls. Taken together, our study presents the highest resolution, multi-cohort and multi-‘omics analysis to date, providing an important resource to facilitate mechanistic hypotheses of host-microbiome interactions in ME/CFS.

Dans une étude en pre-print (non relue ni publiée) sur l'encéphalomyélite myalgique (EM), des chercheurs, en notant des similitudes avec le covid long, entreprennent de construire plusieurs classificateurs de pointe pour identifier les microbes, les voies génétiques microbiennes, les métabolites et les caractéristiques cliniques qui, individuellement ou ensemble, sont les plus à même de différencier les EM courte ou de long terme, ou les patients EM des témoins sains.

N016

___Definition of long covid___

Pre-Print study on 28-Oct-21:
"Multi-‘omics of host-microbiome interactions in short- and long-term Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)"
Dans une étude en pre-print (non relue ni publiée) sur l'encéphalomyélite myalgique (EM), des chercheurs, en notant des similitudes avec le covid long, entreprennent de construire plusieurs classificateurs de pointe pour identifier les microbes, les voies génétiques microbiennes, les métabolites et les caractéristiques cliniques qui, individuellement ou ensemble, sont les plus à même de différencier les EM courte ou de long terme, ou les patients EM des témoins sains.
Link: https://europepmc.org/article/ppr/ppr413593
Extract: "Overall, ME/CFS was characterized by reduced gut microbiome diversity and richness with high heterogeneity, and depletion of sphingomyelins and short-chain fatty acids in the plasma. We found significant differences when stratifying by cohort; short-term ME/CFS was associated with more microbial dysbiosis, but long-term ME/CFS was associated with markedly more severe phenotypic and metabolic abnormalities. We identified a reduction in the gene-coding capacity (and relative abundance of butyrate producers) of microbial butyrate biosynthesis together with a reduction in the plasma concentration of butyrate, especially in the short-term group. Global co-association and detailed gene pathway correlation analyses linking the microbiome and metabolome identified additional potential biological mechanisms underlying host-microbiome interactions in ME/CFS, including bile acids and benzoate pathways. Finally, we built multiple state-of-the-art classifiers to identify microbes, microbial gene pathways, metabolites, and clinical features that individually or together, were most able to differentiate short or long-term MECFS, or MECFS vs. healthy controls. Taken together, our study presents the highest resolution, multi-cohort and multi-‘omics analysis to date, providing an important resource to facilitate mechanistic hypotheses of host-microbiome interactions in ME/CFS."

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Annа Malkova 1,* ,Igor Kudryavtsev 2,Anna Starshinova 3,Dmitry Kudlay 4,5 ,Yulia Zinchenko 6 ,Anzhela Glushkova 7,Piotr Yablonskiy 1,6 andYehuda Shoenfeld

Post COVID-19 Syndrome in Patients with Asymptomatic/Mild Form

https://doi.org/10.3390/pathogens10111408

Published

30-Oct-21

Review

https://www.mdpi.com/2076-0817/10/11/1408/htm

According to the analysis, PCS develops on average in 30–60% of patients, mainly among women. Fatigue, shortness of breath, cough, and anosmia were reported as the most common symptoms. The possible association between the described PCS symptoms and brain damage was revealed. We assume the possibility of an alternative course of COVID-19, which develops in genetically predisposed individuals with a stronger immune response, in which it predominantly affects the cells of the nervous system, possibly with the presence of an autoimmune component, which might have similarity with chronic fatigue syndrome or autoimmune disautonomia. Thus, the gender (female) and the presence of anosmia during an asymptomatic or mild course of the disease can be predictive factors for the development of PCS, which can be caused by autoimmune damage to neurons, glia, and cerebral vessels.

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Tripathi, Awatansh Kumar Rajkumar; Pinto, Lancelot Mark,

Long COVID: “And the fire rages on”

https://doi.org/10.4103/lungindia.lungindia_980_20

Published

Review

https://journals.lww.com/lungindia/Fulltext/2021/11000/Long_COVID___And_the_fire_rages_on_.12.aspx

With the increasing cohort of COVID-19 survivors worldwide, we now realize the proportionate rise in post-COVID-19 syndrome. In this review article, we try to define, summarize, and classify this syndrome systematically. This would help clinicians to identify and manage this condition more efficiently. We propose a tool kit that might be useful in recording follow-up data of COVID-19 survivors.

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Vinod Nikhra

COVID-19 and Long Covid: Organs
Damage and Dysfunctions, and
Implications for Clinical Course

https://dx.doi.org/10.29328/ebook1005

Published

18-Oct-21

Review

https://www.researchgate.net/profile/Vinod-Nikhra/publication/355582623_COVID-19_and_Long_Covid_Organs_Damage_and_Dysfunctions_and_Implications_for_Clinical_Course/links/61776e4b3c987366c3e9b3a5/COVID-19-and-Long-Covid-Organs-Damage-and-Dysfunctions-and-Implications-for-Clinical-Course.pdf

Like any other infectious disease, the prognosis of COVID-19 is inϐluenced by infecting agent, the SARS-CoV-2 virus load and the extent of organs afϐliction and damage. COVID-19 having a propensity for multiorgan involvement carries an adverse prognosis during the clinical course as well as later during the post-recovery period persisting as Long Covid. The direct cytopathic effects of SARS-CoV-2 virus and the erratic and hyper-inϐlammatory response lead to tissue injury in various organs coupled with physiological dysfunctions and complications. In fact, the multi-system manifestations of COVID-19 are caused by a combination of speciϐic host defence responses with associated inϐlammatory activity and vascular involvement with coagulopathy and a distinct propensity to develop thromboembolic complications. Simultaneously, comorbidities such as diabetes, hypertension and cardiovascular diseases inϐluence the disease severity and mortality.

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Law, Julianne

Long COVID: the next Public Health crisis in the United Kingdom (UK) after the COVID-19 pandemic

Published

Article

https://research.bangor.ac.uk/portal/en/researchoutputs/long-covid-the-next-public-health-crisis-in-the-united-kingdom-uk-after-the-covid19-pandemic(f6449a47-153c-48dc-8ad9-52e62a7ed14e).html

Recent research by the government in the UK has found that two million people are affected by long COVID. This article discusses what long COVID is, what the symptoms are, and how it is diagnosed and treated. This article also discusses how the National Health Service (NHS) plans to treat people using ‘long COVID out-patient clinics.’ Long COVID is becoming a significant public health crisis in the UK, and in the rest of the world. Long COVID has affected people in every part of society; it has affected the rich and the poor, although it has affected the poor in greater numbers than the rich. The budgetary implications of attempting to treat two million people for this disease are discussed, as are the implications of not treating people with long COVID.

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Arad Dotan
Yehuda Shoenfeld

Post-COVID syndrome: the aftershock of SARS-CoV-2

https://doi.org/10.1016/j.ijid.2021.11.020

Published

13-Nov-21

Editorial

https://www.ijidonline.com/article/S1201-9712(21)00867-5/fulltext

Accumulation evidence along the pandemic raised an association between the SARS-CoV-2 and autoimmunity (1). SARS-CoV-2 infected patients have a high presence of various autoantibodies (1). Moreover, numerous cases of new-onset of autoimmune-related disorders had been documented following the infection, including both organ-specific and systemic autoimmune diseases (1). Due to the accumulating evidence of persistent post-infectious symptoms reported by numerous recovered patients, the focus of the medical and research communities might need to start shifting focus from the acute phase of COVID-19 to the chronic manifestations of the SARS-CoV-2 infection, referred to as by “post-COVID syndrome”. Post-COVID syndrome presents as non-specific symptoms, most commonly fatigue, headache, dyspnea, anosmia, and memory complaint, which is suspiciously similar to the infection-induced myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (15,18). As current studies suggest an involvement of immune-related dysfunction in the development of post-COVID syndrome, immunosuppressive therapeutic options could be beneficial in parallel to heist SARS-CoV-2 vaccination of the population (15,20,21).

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Alex J Walker, Brian MacKenna, Peter Inglesby, Laurie Tomlinson, Christopher T Rentsch, Helen J Curtis, Caroline E Morton, Jessica Morley, Amir Mehrkar, Seb Bacon, George Hickman, Aaron Fowles, Nasreen Parkes, Ian J Douglas and Stephen JW Evans

Clinical coding of long COVID in English primary care: a federated analysis of 58 million patient records in situ using OpenSAFELY

https://doi.org/10.3399/BJGP.2021.0301

Published

18-Jun-21

Study

https://bjgp.org/content/71/712/e806

Method Working on behalf of NHS England, OpenSAFELY data were used encompassing 96% of the English population between 1 February 2020 and 25 May 2021. The proportion of people with a recorded code for long COVID was measured overall and by demographic factors, electronic health record software system (EMIS or TPP), and week.
Results Long COVID was recorded for 23 273 people. Coding was unevenly distributed among practices, with 26.7% of practices having never used the codes. Regional variation ranged between 20.3 per 100 000 people for East of England (95% confidence interval [CI] = 19.3 to 21.4) and 55.6 per 100 000 people in London (95% CI = 54.1 to 57.1). Coding was higher among females (52.1, 95% CI = 51.3 to 52.9) than males (28.1, 95% CI = 27.5 to 28.7), and higher among practices using EMIS (53.7, 95% CI = 52.9 to 54.4) than those using TPP (20.9, 95% CI = 20.3 to 21.4).

_

170

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Ash Routen, Lauren O’Mahoney, Daniel Ayoubkhani, Amitava Banerjee, Chris Brightling, Melanie Calvert, Nishi Chaturvedi, Ian Diamond, Rosalind Eggo, Paul Elliott, Rachael A. Evans, Shamil Haroon, Emily Herret, Margaret E. O’Hara, Roz Shafran, Julie Stanborough, Terence Stephenson, Jonathan Sterne, Helen Ward & Kamlesh Khunti

Understanding and tracking the impact of long COVID in the United Kingdom

https://doi.org/10.1038/s41591-021-01591-4

Published

22-Nov-21

Correspondence

https://www.nature.com/articles/s41591-021-01591-4

The research community have joined patient researchers in their efforts to improve understanding of long COVID, including its symptoms, health impacts, pathophysiology and treatments. Patient and public involvement is a feature of all the studies described above, with research teams working with patient partners from diverse backgrounds, as well as engaging with national long-COVID support groups. Multidisciplinary research collaboration with patients at the core, as well as co-producing the research as equal partners, is crucial for developing a comprehensive approach to unraveling the complexity and heterogeneity of long COVID. This co-production will be fundamental in the development of targeted therapeutic approaches and to inform health service provision to meet the large unmet need from long COVID.

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KCE. - Castanares-Zapatero Diego, Kohn Laurence, Dauvrin Marie, Detollenaere Jens, Maertens de Noordhout Charline, Primus-de Jong Célia, Cleemput Irina, Van den Heede Koen

Long COVID: Pathophysiology – epidemiology and patient needs

Published

1-Nov-21

Article

https://kce.fgov.be/en/long-covid-pathophysiology-%E2%80%93-epidemiology-and-patient-needs

In this short scientific report we describe the main rationale, research objectives and methods, results and conclusions of the KCE study on long COVID.*

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Helen Fogarty,Ellie Karampini,Andrew S. O'Donnell,Soracha E. Ward,Jamie M. O'Sullivan,James S. O'Donnell

Persistent endotheliopathy in the pathogenesis of long COVID syndrome - Reply to comment from von Meijenfeldt et al.

https://doi.org/10.1111/jth.15578

Published

4-Nov-21

Letter to the editor

https://onlinelibrary.wiley.com/doi/10.1111/jth.15578

The key question posed by our collective data is whether persistent hemostatic dysfunction following COVID-19 is contributing to post-acute sequelae of SARS-CoV-2 infection (PASC or long COVID syndrome).9 In our study, we observed weak associations between 6-min walk test distance and both VWF:Ag and VWF propeptide levels at a median of 68 days after acute COVID-19.4 In contrast, using the subjective Sheehan disability scale to assess functional impairment, von Meijenfeldt et al. found no relationship with any hemostatic biomarkers at either 8 or 12 months after discharge.1 The differences in these results may be attributable to a variety of potential confounders. In particular, both studies included a relatively small number of patients (n = 50 and n = 44, respectively), and long COVID symptomatology was assessed using a combination of objective and subjective protocols performed at varying time points following discharge. Moreover, there were also differences between the study cohorts with respect to initial COVID-19 severity; patient comorbidities including obesity; and differences in patient management during acute COVID-19 (including anticoagulant therapy intensity). Finally, accumulating recent data have highlighted significant phenotypic heterogeneity amongst patients with long COVID syndrome.9, 10 In this context, it is clear that much larger stratified prospective studies that include state-of-the-art imaging will be essential to defining any relationship and/or any potential causality between PASC and persistent hemostatic dysfunction. Given the huge morbidity associated with long COVID, coupled with the limited understanding of the underlying disease pathogenesis, such studies are required as a matter of urgency.

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Gema M. Lledó #
Jacobo Sellares #
Carlos Brotons #
Mireia Sans #
Juana M. Díez Antón
Julià Blanco
Quique Bassat
Adelaida Sarukhan
José M. Miró ##
Silvia de Sanjosé

Post-acute COVID-19 syndrome (PACS): a new tsunami requiring a universal case definition

https://doi.org/10.1016/j.cmi.2021.11.015

Published

23-Nov-21

Article

https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(21)00661-3/fulltext

The SARS-CoV-2 pandemic has led to severe socio-economic and health impacts with few comparable precedents in the contemporary era. In addition to the acute and dramatic outcomes, the longer-term consequences have become a challenge. According to current data, 80% of COVID-19 patients develop a mild or moderate disease (1), 15% a severe disease and 5% a critical disease with different complications such as acute respiratory distress syndrome (ARDS), sepsis and septic shock, thromboembolism and multi-organ failure. When compared to influenza, there are many differences in terms of clinical features, morbidity and mortality (2), and more so when considering the CFR (case fatality rate) of COVID-19 [0.1-25%] (3) with that of the more recent pandemic of influenza A H1N1 of 2009 [0.001-0.011%] (4). Patients with cancer and transplant recipients have an increased risk of worse outcomes, but no evidence on worse prognosis has been demonstrated in patients with primary immunodeficiencies and human immunodeficiency virus (HIV) infection (5, 6). However, patients with systemic autoimmune diseases and high doses of corticosteroids or rituximab seem to be associated with more unfavourable outcomes (7).

The underlying cause of the persistence of symptoms has yet to be established, but many theories have been hypothesised. They mainly address virus-specific pathophysiological changes, aberrant immune responses and inflammatory damage in response to the acute infection (18) and mechanisms of viral persistence (19,20). More recently, the roles of exosomes (21) and the intervention of mast cells ((22) have also come under consideration. These potential underlying etiological causes must be explored if we are to improve our understanding of the mechanisms contributing to the pathophysiology of PACS. The ambiguity regarding PACS risk factors, due to variations in reporting, study design and clinical and demographic characteristics of participants, is currently the main problem. However, female sex, high numbers of symptoms and antibodies to SARS-CoV-2 may play a role in pathogenesis, although some studies have found no significant differences. New lines of research investigate specific biomarkers to establish clusters for both severe COVID-19 and PACS using machine learning techniques to resolve the discrepancies addressed above (23). We must ensure the follow up of these patients, with a view to finding out how long these symptoms persist and whether they develop into chronic disorders. These conditions can lead to hospital readmission, estimated at around 3.6-4.5% in the first 30 days (24,25) and up to 27% after six months (26), resulting in a dramatic impact on communities and healthcare systems.
To date, there is no definitive treatment for managing the prolonged symptoms of PACS, although there are options for specific symptoms. Surprisingly, there are case reports, case series and some recent studies suggest that COVID-19 vaccines may improve or resolve long-term symptoms (27). However, effective antiviral treatment from the early stage of infection may be the best way to minimise the likelihood of developing PACS. Unfortunately, symptoms such as fatigue, are difficult to tackle, but suitable rehabilitation programmes may bring enormous benefit to “long-haulers” for pulmonary, cardiological or neurological sequelae. Furthermore, appropriate psychological support should be considered as an additional treatment.

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Alan Roth, DO, Pan San Chan, MD, Wayne Jonas, MD

Addressing the Long COVID Crisis: Integrative Health and Long COVID

https://doi.org/10.1177%2F21649561211056597

Published

16-Nov-21

Review

https://journals.sagepub.com/doi/10.1177/21649561211056597

Patients experience a wide range of symptoms, including serious organ system effects such as pulmonary fibrosis, myocarditis, new diabetes diagnoses, stroke, and other cerebrovascular events. They also experience ongoing pain, fatigue, and cognitive dysfunction. We suggest here that these patients require an integrative health approach, one that combines traditional medical management, non-pharmacological approaches, and behavior and lifestyle changes. Such an approach has been shown to be beneficial in other chronic illnesses such as fibromyalgia, chronic fatigue syndrome, and post-Lyme disease.

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LiqinWangabDinahFoerabcErinMacPhaulaYing-ChihLoabDavid W.BatesabLiZhouab

PASCLex: A comprehensive post-acute sequelae of COVID-19 (PASC) symptom lexicon derived from electronic health record clinical notes

https://doi.org/10.1016/j.jbi.2021.103951

Published

13-Nov-21

Study

https://www.sciencedirect.com/science/article/pii/S153204642100280X

PASCLex included 355 symptoms consolidated from 1520 UMLS concepts of 16,466 synonyms. NLP achieved an averaged precision of 0.94 and an estimated recall of 0.84. Symptoms with the highest frequency included pain (43.1%), anxiety (25.8%), depression (24.0%), fatigue (23.4%), joint pain (21.0%), shortness of breath (20.8%), headache (20.0%), nausea and/or vomiting (19.9%), myalgia (19.0%), and gastroesophageal reflux (18.6%).
Highlights
•Research focused on post-acute sequelae of COVID-19 (PASC) symptoms.
•A large COVID-19 cohort in electronic health records (EHR) was followed for post-infection sequalae.
•Ontology, EHR data and natural language processing were used for lexicon development.
•Symptom lexicon can support NLP to extract PASC symptoms from clinical notes.

todo

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Phillip H.RothaMariacarlaGadebusch-Bondio

The contested meaning of “long COVID” – Patients, doctors, and the politics of subjective evidence

https://doi.org/10.1016/j.socscimed.2021.114619

Published

30-Nov-21

Article

https://www.sciencedirect.com/science/article/pii/S0277953621009515

Highlights
•Experiential knowledge can fill crucial gaps in the pandemic discourse.
•Long COVID online self-advocacy provides a rich source of subjective evidence.
•Patient subjective evidence is challenging the normative role of clinical evidence.
•Activism made long COVID diagnosis as a requirement for recognition obsolete.
In our article, we reconstruct how the patient-made term “long COVID” was able to become a widely accepted concept in public discourses. While the condition was initially invisible to the public eye, we show how the mobilization of subjective evidence online, i.e., the dissemination of reports on the different experiences of lasting symptoms, was able to transform the condition into a crucial feature of the coronavirus pandemic. We explore how stakeholders used the term “long COVID” in online media and in other channels to create their illness and group identity, but also to demarcate the personal experience and experiential knowledge of long COVID from that of other sources. Our exploratory study addresses two questions. Firstly, how the mobilization of subjective evidence leads to the recognition of long COVID and the development of treatment interventions in medicine; and secondly, what distinguishes these developments from other examples of subjective evidence mobilization. We argue that the long COVID movement was able to fill crucial knowledge gaps in the pandemic discourses, making long COVID a legitimate concern of official measures to counter the pandemic. By first showing how illness experiences were gathered that defied official classifications of COVID-19, we show how patients made the “long COVID” term. Then we compare the clinical and social identity of long COVID to that of chronic fatigue syndrome (ME/CFS), before we examine the social and epistemic processes at work in the digital and medial discourses that have transformed how the pandemic is perceived through the lens of long COVID. Building on this, we finally demonstrate how the alignment of medical professionals as patients with the movement has challenged the normative role of clinical evidence, leading to new forms of medical action to tackle the pandemic.

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Olga A.Sukochevaab1RebekahMaksoudbc1Narasimha M.BeerakadSabbaRao V.MadhunapantuladeMikhailSinelnikovfVladimir N.NikolenkofMargarita E.NeganovagSergey G.KlochkovgMohammadAmjad KamalhiSonyaMarshall-GradisnikbcDonald RStaines

Analysis of post COVID-19 condition and its overlap with myalgic encephalomyelitis/chronic fatigue syndrome

https://doi.org/10.1016/j.jare.2021.11.013

Published

26-Nov-21

Review

https://www.sciencedirect.com/science/article/pii/S2090123221002320

Considering the pandemic is still ongoing, more time is required to confirm post COVID-19 condition diagnosis in the COVID-19 infected cohorts, although many reported post COVID-19 symptoms overlap with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

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Emily R. Pfaff, Andrew T. Girvin, Tellen D. Bennett,, Abhishek Bhatia, Ian M. Brooks, Rachel R. Deer, Jonathan P. Dekermanjian, Sarah Elizabeth Jolley, Michael G. Kahn, Kristin Kostka, Julie A. McMurry, Richard Moffitt, Anita Walden, Christopher G. Chute, Melissa A. Haendel

Who has long-COVID? A big data approach [preprint]

https://doi.org/10.1101/2021.10.18.21265168

pre-print

22-Oct-21

Study

https://escholarship.umassmed.edu/umccts_pubs/253/

Findings Our models identified potential long-COVID patients with high accuracy, achieving areas under the receiver operator characteristic curve of 0.91 (all patients), 0.90 (hospitalized); and 0.85 (non-hospitalized). Important features include rate of healthcare utilization, patient age, dyspnea, and other diagnosis and medication information available within the EHR. Applying the “all patients” model to the larger N3C cohort identified 100,263 potential long-COVID patients.

Interpretation Patients flagged by our models can be interpreted as “patients likely to be referred to or seek care at a long-COVID specialty clinic,” an essential proxy for long-COVID diagnosis in the current absence of a definition. We also achieve the urgent goal of identifying potential long-COVID patients for clinical trials. As more data sources are identified, the models can be retrained and tuned based on study needs.

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Corey H. Basch, Eunsun Park, Betty Kollia & Nasia Quinones

Online News Coverage of COVID-19 Long Haul Symptoms

https://doi.org/10.1007/s10900-021-01053-5

Published

3-Dec-21

Study

https://link.springer.com/article/10.1007/s10900-021-01053-5

The purpose of this study was to describe the content of news coverage of COVID-19 long haul symptoms currently posted on the internet. This study utilized Google News, a news aggregator service, and included the first 100 English language pieces of news. Video content and news article content were coded in depth for information on COVID-19 long haul symptoms. A total of 41% of news reports mentioned the length of time that the COVID-19 related symptoms persist. The length of time was reported to range from 1 month to more than 1 year. The symptom most commonly mentioned was tiredness or fatigue (74%), followed by difficulty breathing or shortness of breath (62 cases; 62%), and difficulty thinking or concentrating (50 cases; 50%). Other symptoms were mentioned less frequently. There were no statistically significant differences in any of the content including having video, written news reports, or both video and written news reports by source of the news reports based on consumer, professional, or television or internet-based news (p = .14). More complete coverage by online news media of the long-term effects of COVID-19 enhances public awareness of the post-acute syndromes, augments health providers’ awareness of the range of chronic COVID-19 effects and the possibility of a second infection, increases the probability of patients’ seeking and obtaining the proper care for their symptoms, and contributes to preventive actions for enhancing public health.

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Janet V Diaz,corresponding author a Margaret Herridge, b Silvia Bertagnolio, c Hannah E Davis, d Tarun Dua, e Charu Kaushic, f John C Marshall, g Maria del Rosario Pérez, a Nathalie Strub-Wourgaft, h and Joan B Soriano a

Towards a universal understanding of post COVID-19 condition

https://dx.doi.org/10.2471%2FBLT.21.286249

Published

5-Oct-21

Article

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640686/

Finally, this work must be multicentre and multidisciplinary, and involve international cooperation. Collecting standardized and harmonized data on post COVID-19 condition will be paramount, as available published studies are small, heterogeneous in nature, too short in their follow-up, and with narrow focus on a few organ systems assessed. To support systematic collection of comparable data across the world, WHO has developed a Global Clinical Platform and standardized case report forms for acute COVID-19 and post COVID-19 condition that are available for all Member States and interested parties.27 Data should be synthesized to extend the available collective experience with this condition and its insights, and should be meta-analysed to enlarge the available experience from a few hundred person-years’ experience to many more orders of magnitude. Data sharing should be undertaken in the broadest sense, to include experience in all affected patients and in subgroups by demographic and clinical variables. Technologies analysing large data sets and tools of artificial intelligence applied directly to text of electronic health records are already available to be used.28 Follow-up from existing trials that randomized patients less than one year ago could be of enormous value, with little investment required to support data collection. The recent National Institutes for Health announcement of specific funds and setting up a biospecimen bank will steer research and researchers on this topic.29 Multinational data sharing should be promoted to ensure broad demographics, variable case mix with diverse genetics and the effects of distinct health-care systems and access to treatments. Making sense of heterogeneous data sources and their appropriate interpretation are both a challenge and part of the final solution to better understand post-COVID-19 condition.

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Philip Hunter

Navigating the social identity of long covid

https://doi.org/10.1136/bmj.n2933

Published

26-Nov-21

Opinion

https://www.bmj.com/content/375/bmj.n2933

Medical research into the pathophysiology of long covid, and how it can be treated is urgently needed, but it is also essential to consider social factors that may be implicated in the recovery of the millions of people with long covid across the world. It is not possible to holistically understand any individual’s experiences, without understanding their connection and place within the broader community around them. Research shows that social connections and belonging are essential determinants of health and wellbeing.

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Susanne Rabady, Johann Altenberger, Markus Brose, Doris-Maria Denk-Linnert, Elisabeth Fertl, Florian Götzinger, Maria de la Cruz Gomez Pellin, Benedikt Hofbaur, Kathryn Hoffmann MPH, MD, Renate Hoffmann-Dorninger MD, Rembert Koczulla, Oliver Lammel, Bernd Lamprecht, Judith Löffler-Ragg, Christian A. Müller, Stefanie Poggenburg, Hans Rittmannsberger, Paul Sator, Volker Strenger, Karin Vonbank, Johannes Wancata, Thomas Weber, Jörg Weber, Günter Weiss, Maria Wendler & Ralf-Harun Zwick

Leitlinie S1: Long COVID: Differenzialdiagnostik und Behandlungsstrategien

https://doi.org/10.1007/s00508-021-01974-0

Published

1-Dec-21

Guideline

https://link.springer.com/article/10.1007%2Fs00508-021-01974-0

This guideline comprises the state of science at the time of the editorial deadline. In view of the high turnover of knowledge the guideline is designed as a living guideline. The main objective was to provide a tool for the use in primary care, being considered well suited as a first point of entry and for the provision of care. The guideline gives recommendations on the differential diagnosis of symptoms following SARS-CoV‑2 infection, on their therapeutic options, as well as for guidance and care of the patients concerned. It also offers advice concerning return to daily life and rehabilitation. Long COVID being a very variable condition, we chose an interdisciplinary approach.

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Elisa Perego

Patient made Long Covid empowers the patient voice

https://doi.org/10.31235/osf.io/796am

pre-print

22-Dec-21

Article

https://osf.io/preprints/socarxiv/796am/

Successful, patient-driven advocacy and research in Long Covid is contributing to change our understanding of SARS-CoV-2 infection, viral-onset diseases, and knowledge building in medicine and beyond. Events and epistemic shifts surrounding the rise of Long Covid represent a massive opportunity for empowering the patient voice. Strategies that have proven key to grassroots Long Covid advocacy in our digital era could be further explored and expanded across different patient communities. It is my hope that patient-centred expertise will be further incorporated into the biomedical community. This would contribute to critical changes in medical awareness of chronic diseases and patient care.

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Aditya Gupta, Vibha Jain & Amritpal Singh

Stacking Ensemble-Based Intelligent Machine Learning Model for Predicting Post-COVID-19 Complications

https://doi.org/10.1007/s00354-021-00144-0

Published

14-Dec-21

Study

https://link.springer.com/article/10.1007/s00354-021-00144-0

In this article, a stacking ensemble learning technique based on deep neural networks is proposed for the early prediction of heart disease in COVID-19 survivors. The proposed model is trained using heart-related data collected from COVID-19 survivors under a tenfold cross-validation framework. The proposed model is tested and the performance is compared with different baseline machine learning algorithms. Various performance evaluation metrics, namely accuracy, specificity, precision, and recall, are used for performance measurement. In addition, two statistical measures are evaluated, namely, the root mean square error (RMSE) and the mean absolute error (MAE). The proposed stacking ensemble strategy achieves an accuracy of 93.23% while predicting heart disease. Moreover, the results of specificity (95.74%), precision (95.24%), and recall (92.05%) show the improved performance of the proposed approach in comparison to baseline learning algorithms.

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Anthony S David

Long covid: research must guide future management

https://doi.org/10.1136/bmj.n3109

Published

17-Dec-21

Opinion

https://www.bmj.com/content/375/bmj.n3109

Emerging evidence suggests that long-covid is as likely to follow mild and even unconfirmed infection as severe illness requiring hospitalisation and respiratory support, although population-based studies on non-hospitalised cases are required to complete the picture.4 New preliminary data suggest that people admitted to hospital with covid-19 who reported long covid symptoms had made only limited improvement after a full year.5 The demographic risk factors for covid-19 illness: age, male sex, ethnic minority status, underlying medication conditions, etc., do not seem to apply to post-covid syndrome.6 This all points to the need to improve our understanding of post-covid syndrome. UKRI-funded research using established clinical databases and longitudinal cohorts should seek to clarify these questions.
Will the new long-covid multidisciplinary teams be the setting of a never-ending journey round in circles or will they have the courage to accept uncertainty? Increasing evidence shows organ damage and pathological changes post covid, and we must be aware of many patients who have severe and debilitating fatigue and have not been believed or offered much help at all. But we must also remain open minded that some multi-symptom presentations may not be due to hitherto unidentified multi-system pathologies (with negative investigations), but a singular mechanism of heightened awareness of bodily sensations and objective malfunctions.

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Rita Smith

Long COVID: The Pandemic Aftermath

Published

Article

https://www.phnurse.org/assets/docs/Smith%20Rita%20Long%20Covid%20Article%20FLNursQ%202021%20APHN%20Post%20121521.pdf

History of Long COVID

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Pasquale Ambrosino 1 ,Anna Lanzillo 2 andMauro Maniscalco 3,*

COVID-19 and Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications

https://doi.org/10.3390/biomedicines10010047

Published

27-Dec-21

Editorial

https://www.mdpi.com/2227-9059/10/1/47/htm

Growing evidence suggests a central role of endothelial dysfunction and systemic inflammation in the pathogenesis of most COVID-19 manifestations [4]. Accordingly, persistent endothelial dysfunction and a prolonged inflammatory response have been documented even after the acute phase [5]. However, the pathophysiological mechanisms determining the acute and post-acute manifestations of COVID-19 are still a matter requiring study, given that a better understanding of these mechanisms would allow for the implementation of more effective personalized approaches.
In this Special Issue, we aimed to collect a number of original research articles and reviews on the pathophysiology and diagnostics of COVID-19 and post-acute COVID-19 syndrome, with a focus on new prognostic and therapeutic applications.

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Anita Slomski

Belief in Having Had COVID-19 Linked With Long COVID Symptoms

https://doi.org/10.1001/jama.2021.23318

Published

4-Jan-22

Article

https://jamanetwork.com/journals/jama/article-abstract/2787741

Researchers analyzed survey data and serology results from 26 823 adults in France. They found no relationship between the participants’ belief about whether they’d had COVID-19 and their antibody test results from blood samples collected between May and November 2020.

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Akshara Ramasamy

How Does Gender Impact Long COVID?

Published

1-Jan-22

Article

http://sites.utexas.edu/melamed-lab/2021/12/20/how-does-gender-impact-long-covid/

Current evidence suggests that COVID-19 may trigger an autoimmune reaction in some people, which might explain why the syndrome tends to be more frequent in women (i.e. as women are more likely to develop autoimmune diseases).5 According to a study by women’s health experts Dr. Sabra Klein and Dr. Katie Flanagan, women tend to have stronger immune systems than men and greater vaccine efficacy as a result.6 While a robust immune response may be helpful in the early stages of a COVID-19 infection, it may also make women more susceptible to long-term autoimmune problems (as autoimmunity is thought to arise due to a mistaken overzealous immune response against the body’s self proteins, leading to damage of different body systems).
Researchers are now looking into the role of estrogen in long COVID development as one possible factor that may explain differences in immunological responses between men and women. A study from King’s College in London reported that post-menopausal women between the ages of 50 and 60 with low levels of estrogen were found to be at the most risk for long-term COVID symptoms.7 This hormone interacts with the immune system in a variety of ways, including regulating the creation of immune cells and their response to infection. Consequently, sex hormones may be one potential link that could explain the significant differences and immune mechanisms involved in long COVID in women and men.

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Eric Lyerly Esq.

Long COVID: Accommodating a slippery fish

https://doi.org/10.1002/cala.40712

Published

10-Jan-22

Article

https://onlinelibrary.wiley.com/doi/10.1002/cala.40712

Post-COVID conditions, long COVID, long-haul COVID, post-acute COVID, chronic COVID — these names each refer to the long-term effects of a COVID-19 infection. The Centers for Disease Control describes long COVID as a “wide range of new, returning, or ongoing health problems” related to COVID-19.

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Kieran L. Quinn ,Chaim M. Bell

Pandemic health consequences: Grasping the long COVID tail

https://doi.org/10.1371/journal.pmed.1003891

Published

25-Jan-22

Article

https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1003891

Early pandemic public messaging strategies focused on flattening the peak of the acute COVID-19 infection curve to preserve healthcare system capacity and its ability to deliver high-quality care. These efforts were generally successful. To preserve ongoing system capacity and provide high-quality patient care, the long COVID tail does not require further flattening, but rather demands new clinical and health policy strategies to address its potential for long-term suffering. Here, we must recognize that the head of the pandemic often demands our immediate attention, but we must not ignore its long and deadly tail.

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Chris Baraniuk

Covid-19: How Europe is approaching long covid

https://doi.org/10.1136/bmj.o158

Published

20-Jan-22

Article

https://www.bmj.com/content/376/bmj.o158.full

In the UK, there are more than 80 NHS run long covid clinics. Long covid services were highlighted as part of £6.6bn in new funding announced in March 2021 for the ongoing NHS response to the pandemic.3 Separately, the Scottish government has announced £10m in funding for local health boards to help patients who have long term symptoms.
In the European Union, specialist long covid clinics are reported to be operating in Belgium, France, Germany, and Spain, among others, but these rarely cater for more than a small part of the population.
In Italy, no government funded clinics for long covid have yet been established, according to Danilo Buonsenso at Gemelli University Hospital in Rome, although some hospitals have day clinics for following up patients who had been admitted to hospital during the acute stage of covid-19. A few of the day clinics include patients who have no history of hospital admission for covid-19, however, “the waiting list is incredibly high,” Buonsenso adds.
In May 2021, the Italian government allocated around €28m for 2021 and €24m for 2022, to the “respiratory care” of covid-19 patients who had been admitted to hospital.4 In July, Italy’s National Institute of Health (ISS) published a report on interim indications on long covid management,5 which refers to the need for specialist “post-covid clinics” as well as facilities linked to general practice and hospitals.
The French National Authority for Health (HAS) published official guidelines for the follow-up of long covid patients in February 2021, stating that most can be followed up through primary care.

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DominiqueSALMON CÉRONabBenjaminDAVIDOcRolandTUBIANAdeFrançoiseLINARDaCatherine TOURETTETURGISfPaulineOUSTRICghAlainSOBELaiAntoineCHERETjk

Les formes prolongées de la COVID-19 ou COVID long : formes cliniques et prise en chargeLong COVID : clinical forms and management

https://doi.org/10.1016/j.mmifmc.2021.12.001

Published

21-Jan-22

Article

https://www.sciencedirect.com/science/article/abs/pii/S2772743221000118

L'origine de ces symptômes n'est pas encore élucidée et certaines hypothèses sont en cours d'exploration, comme par exemple une persistance virale qui a été démontrée dans certains cas, une réponse inflammatoire notamment mastocytaire excessive, ou bien un défaut de l'immunité innée ou adaptative. Des facteurs génétiques et hormonaux sont possiblement associés. La prise en charge des patients doit être initiée dès le premier recours aux soins. Suite à une analyse approfondie des symptômes, des diagnostics seront portés et feront l'objet d'une prise en charge multidisciplinaire où les traitements symptomatiques et la rééducation tiennent une place importante. Si le recours à l'hospitalisation est rare, ces formes prolongées, maintenant appelées « COVID long », vont avoir un impact sociétal majeur nécessitant la mise en place de politiques publiques adaptées.

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Theoharis C. Theoharides

Could SARS-CoV-2 Spike Protein Be Responsible for Long-COVID Syndrome?

https://doi.org/10.1007/s12035-021-02696-0

Published

13-Jan-22

Article

https://link.springer.com/article/10.1007/s12035-021-02696-0

However, increasing evidence indicates that many patients develop a chronic condition characterized by fatigue and neuropsychiatric symptoms, termed long-COVID. Most of the vaccines produced so far for COVID-19 direct mammalian cells via either mRNA or an adenovirus vector to express the spike protein, or administer recombinant spike protein, which is recognized by the immune system leading to the production of neutralizing antibodies. Recent publications provide new findings that may help decipher the pathogenesis of long-COVID. One paper reported perivascular inflammation in brains of deceased patients with COVID-19, while others showed that the spike protein could damage the endothelium in an animal model, that it could disrupt an in vitro model of the blood-brain barrier (BBB), and that it can cross the BBB resulting in perivascular inflammation. Moreover, the spike protein appears to share antigenic epitopes with human molecular chaperons resulting in autoimmunity and can activate toll-like receptors (TLRs), leading to release of inflammatory cytokines. Moreover, some antibodies produced against the spike protein may not be neutralizing, but may change its conformation rendering it more likely to bind to its receptor. As a result, one wonders whether the spike protein entering the brain or being expressed by brain cells could activate microglia, alone or together with inflammatory cytokines, since protective antibodies could not cross the BBB, leading to neuro-inflammation and contributing to long-COVID. Hence, there is urgent need to better understand the neurotoxic effects of the spike protein and to consider possible interventions to mitigate spike protein-related detrimental effects to the brain, possibly via use of small natural molecules, especially the flavonoids luteolin and quercetin.

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Olcay Y. Jones 1,* andSencer Yeralan 2,*

Is Long COVID a State of Systemic Pericyte Disarray?

https://doi.org/10.3390/jcm11030572

Published

24-Jan-22

Article

https://www.mdpi.com/2077-0383/11/3/572/htm

The most challenging aspect of Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) or Long COVID remains for the discordance between the viral damage from acute infection in the recent past and susceptibility of Long COVID without clear evidence of post infectious inflammation or autoimmune reactions. In this communication we propose that disarray of pericytes plays a central role in emerge of Long COVID. We assume pericytes are agents with “Triple-A” qualities, i.e., analyze-adapt and advance, necessary for sustainability of host homeostasis. Based on this view, we further suggest Long COVID may provide a model system to integrate system theory and complex adaptive systems to explore a new class of maladies those are currently not well defined and with no remedies.

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Riccardo Cau
Gavino Faa
Valentina Nardi
Antonella Balestrieri
Josep Puig
Jasjit S Suri
Roberto SanFilippo
Luca Saba

Long-COVID diagnosis: from diagnostic to advanced AI-driven models

https://doi.org/10.1016/j.ejrad.2022.110164

Published

17-Jan-22

Review

https://www.ejradiology.com/article/S0720-048X(22)00014-6/fulltext

Highlights
•Among COVID-19 survivors, a fraction of patients reports persistent symptoms related to multiorgan involvement.
•Time and resources will be needed to help clinicians understand and manage long-term COVID-19 sequelae.
•Artificial intelligence in COVID-19 evaluation is promising for different tasks, including. image analysis, decision-making and prognosis prediction.
Abstract
SARS-COV 2 is recognized to be responsible for a multi-organ syndrome. In most patients, symptoms are mild. However, in certain subjects, COVID-19 tends to progress more severely. Most of the patients infected with SARS-COV2 fully recovered within some weeks. In a considerable number of patients, like many other viral infections, various long-lasting symptoms have been described, now defined as “long COVID-19 syndrome”.
Given the high number of contagious over the world, it is necessary to understand and comprehend this emerging pathology to enable early diagnosis and improve patents outcomes. In this scenario, AI-based models can be applied in long-COVID-19 patients to assist clinicians and at the same time, to reduce the considerable impact on the care and rehabilitation unit. The purpose of this manuscript is to review different aspects of long-COVID-19 syndrome from clinical presentation to diagnosis, highlighting the considerable impact that AI can have.

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Yapeng Su 28 Dan Yuan 28 Daniel G. Chen 28 Rachel H. Ng Kai Wang Jongchan Choi Sarah Li Sunga Hong Rongyu Zhang Jingyi Xie Sergey A. Kornilov Kelsey Scherler Ana Jimena Pavlovitch-Bedzyk Shen Dong Christopher Lausted Inyoul Lee Shannon Fallen hengzhen L. Dai Priyanka Baloni Brett Smith Venkata R. Duvvuri Kristin G. Anderson Jing Li 9 Biobanking Unit, Terri Wrin Christos J. Petropoulos Hunter R. Cole Trevan D. Fischer Wei Wei Dave S.B. Hoon Nathan D. Price Naeha Subramanian Joshua A. Hill Jennifer Hadlock Andrew T. Magis Antoni Ribas Lewis L. Lanier Scott D. Boyd Jeffrey A. Bluestone Helen Chu Leroy Hood Raphael Gottardo Philip D. Greenberg Mark M. Davis Jason D. Goldman James R. Heath

Multiple Early Factors Anticipate Post-Acute COVID-19 Sequelae

https://doi.org/10.1016/j.cell.2022.01.014

Published

24-Jan-22

Study

https://www.cell.com/cell/fulltext/S0092-8674(22)00072-1

Highlights
Longitudinal multiomics associate PASC with autoantibodies, viremia and comorbidities
Reactivation of latent viruses during initial infection may contribute to PASC
Subclinical autoantibodies negatively correlate with anti-SARS-CoV-2 antibodies
Gastrointestinal PASC uniquely present with post-acute expansion of cytotoxic T cells
SUMMARY
Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk-factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data, and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific autoantibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.

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VP

Dominique Grandjean, Dorsaf Slama, Capucine Gallet, Clothilde Julien, Emilie Seyrat, Marc Blondot, Judith Elbaz, Maissa Benazaiez, View ProfileDominique Salmon

Screening for SARS-CoV-2 persistence in Long COVID patients using sniffer dogs and scents from axillary sweats samples

https://doi.org/10.1101/2022.01.11.21268036

pre-print

12-Jan-22

Study

https://www.medrxiv.org/content/10.1101/2022.01.11.21268036v1

Objectives Dogs can be trained to identify several substances not detected by humans, corresponding to specific volatile organic compounds (VOCs). The presence of VOCs, triggered by SARS-CoV-2 infection, was tested in sweat from Long COVID patients.
Patients and methods An axillary sweat sample of Long COVID patients and of COVID-19 negative, asymptomatic individuals was taken at home to avoid any hospital contact. Swabs were randomly placed in olfaction detection cones, and the material sniffed by at least 2 trained dogs.
Results Forty-five Long COVID patients, mean age 45 (6-71), 73.3% female, with prolonged symptoms evolving for a mean of 15.2 months (5-22) were tested. Dogs discriminated in a positive way 23/45 (51.1%). Long COVID patients versus 0/188 (0%) control individuals (p<.0001).
Conclusion This study suggests the persistence of a viral infection in some Long COVID patients and the possibility of providing a simple, highly sensitive, non-invasive test to detect viral presence, during acute and extended phases of COVID-19.

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Jaskiran Kaur Bhogal, Freya Mills, Amelia Dennis, Cristina Spoiala, Joanna Milward, Sidra Saeed, Leah Ffion Jones, Dale Weston, Holly Carter

The Effects of Messaging on Expectations and Understanding of Long COVID: An Online Randomised Trial

https://doi.org/10.1101/2022.01.18.22269467

pre-print

23-Jan-22

Study

https://www.medrxiv.org/content/10.1101/2022.01.18.22269467v1

Interventions Participants were presented with a scenario describing a positive COVID-19 test result and then presented with one of eight scenarios describing a Long COVID diagnosis.
Primary and Secondary Outcome Measures Various outcome measures relating to illness expectations were captured including: symptom severity, symptom duration, quality of life, personal control, treatment control and illness coherence.
Results We ran a series of 2 × 2 × 2 ANOVAs on the outcome variables. We found a main effect of illness description: individuals reported longer symptom duration and less illness coherence when the illness was described as Long COVID (compared to ongoing COVID-19 recovery). There was a main effect of illness uncertainty: when uncertainty was emphasised, participants reported longer expected symptom duration, less treatment control, and less illness coherence than when uncertainty was not emphasised. There was also a main effect of efficacy of support: participants reported higher personal control and higher treatment control when support was enhanced (compared to basic support). We also found an interaction between illness description and efficacy of support: when support was enhanced, participants reported less illness coherence for Long COVID (compared to ongoing COVID-19 recovery).
Conclusions Communications around Long COVID should not emphasise symptom uncertainty and should provide people with information on how they can facilitate their recovery and where they can access additional support. The findings also suggest that use of the term ongoing COVID-19 recovery, where possible, may reduce negative expectations associated with the illness.

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NIPH

COVID-19: Post COVID-19 condition. A rapid review

Published

Review

https://www.fhi.no/en/publ/2022/COVID-19-Post-COVID-19-condition/

In this rapid review, we summarise research on the proportion of patients who get long-term symptoms, which long-term symptoms occur after COVID-19, how long the symptoms persist and which patient groups that have the greatest risk of experiencing long-term symptoms.

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Bevyn Jarrott,Richard Head,Kirsty G. Pringle,Eugenie R. Lumbers,Jennifer H. Martin

“LONG COVID”—A hypothesis for understanding the biological basis and pharmacological treatment strategy

https://doi.org/10.1002/prp2.911

Published

13-Jan-22

Review

https://bpspubs.onlinelibrary.wiley.com/doi/10.1002/prp2.911

Infection of humans with SARS-CoV-2 virus causes a disease known colloquially as “COVID-19” with symptoms ranging from asymptomatic to severe pneumonia. Initial pathology is due to the virus binding to the ACE-2 protein on endothelial cells lining blood vessels and entering these cells in order to replicate. Viral replication causes oxidative stress due to elevated levels of reactive oxygen species. Many (~60%) of the infected people appear to have eliminated the virus from their body after 28 days and resume normal activity. However, a significant proportion (~40%) experience a variety of symptoms (loss of smell and/or taste, fatigue, cough, aching pain, “brain fog,” insomnia, shortness of breath, and tachycardia) after 12 weeks and are diagnosed with a syndrome named “LONG COVID.” Longitudinal clinical studies in a group of subjects who were infected with SARS-CoV-2 have been compared to a non-infected matched group of subjects. A cohort of infected subjects can be identified by a battery of cytokine markers to have persistent, low level grade of inflammation and often self-report two or more troubling symptoms. There is no drug that will relieve their symptoms effectively. It is hypothesized that drugs that activate the intracellular transcription factor, nuclear factor erythroid-derived 2-like 2 (NRF2) may increase the expression of enzymes to synthesize the intracellular antioxidant, glutathione that will quench free radicals causing oxidative stress. The hormone melatonin has been identified as an activator of NRF2 and a relatively safe chemical for most people to ingest chronically. Thus, it is an option for consideration of re-purposing studies in “LONG COVID” subjects experiencing insomnia, depression, fatigue, and “brain fog” but not tachycardia. Appropriately designed clinical trials are required to evaluate melatonin.

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ME

Todd E. Davenport Staci R. Stevens Jared Stevens Christopher R. Snell J. Mark Van Ness

We Already Know Enough to Avoid Making the Same Mistakes Again With Long COVID

https://doi.org//10.2519/jospt.blog.20210310

Published

10-Mar-21

Article

https://www.jospt.org/do/10.2519/jospt.blog.20210310/full/

Based on experience with past coronaviruses, the emerging challenge of prolonged symptoms after infection with the novel coronavirus 2019 (SARS-CoV-2) is unsurprising. Data from a large international web-based patient survey indicate substantial symptom overlap between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) at 6 months following the onset of first symptoms, including three quarters of participants suffering from fatigue and postexertional malaise, and over half with cognitive dysfunction.4 Apparent similarities between the presentations of long COVID and ME/CFS suggest that we may apply what we have learned from ME/CFS to long COVID.

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ME - PESE

Todd E. Davenport Staci R. Stevens Jared Stevens Christopher R. Snell J. Mark Van Ness

Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID: Postexertional Symptom Exacerbation is an Abnormal Response to Exercise/Activity

https://doi.org//10.2519/jospt.blog.20220202

Published

2-Feb-22

Article

https://www.jospt.org/do/10.2519/jospt.blog.20220202

Prolonged symptoms after infection with the novel coronavirus 2019 (SARS-COV-2) are an emerging challenge to individual patients, society, and clinicians. In a previous post on the JOSPT Blog, we identified several lessons from research and clinical practice in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) that are important lessons for long COVID. The purpose of this post is to discuss the phenomenon of postexertional symptom exacerbation (PESE) and its clinical identification to recognize the potential onset of long COVID.
Data from a large international web-based patient survey indicate substantial symptom overlap between postacute SARS-COV-2 infection (long COVID) and ME/CFS at 6 months following the onset of first symptoms. Three quarters of respondents noted disabling fatigue and over half noted cognitive dysfunction.4 A unique finding of this survey was that 75% of respondents noted PESE, which is a worsening of symptoms after activity/exercise.4 PESE is foundational to the diagnosis of ME/CFS and it is common with long COVID.4,5 This observation suggests we can further extend lessons from ME/CFS to develop our understanding of long COVID.

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ME - PESE

Todd E. Davenport Staci R. Stevens Jared Stevens Christopher R. Snell J. Mark Van Ness

Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 2: Physiological Characteristics During Acute Exercise Are Abnormal in People With Postexertional Symptom Exacerbation

https://doi.org//10.2519/jospt.blog.20220209

Published

9-Feb-22

Article

https://www.jospt.org/do/10.2519/jospt.blog.20220209

In a previous post on the JOSPT Blog, we outlined the connection between postacute sequalae to novel coronavirus (long COVID) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) through their common clinical presentation: postexertional symptom exacerbation (PESE). PESE suggests the presence of abnormal physiological responses to exercise/activity. These physiological responses may be measured using cardiopulmonary exercise testing (CPET), which allows for careful characterization of cardiac, pulmonary, and metabolic functioning during exercise. We will review the characteristic findings on CPET in people with PESE.

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Todd E. Davenport Staci R. Stevens Jared Stevens Christopher R. Snell J. Mark Van Ness

Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 3: “Energy System First Aid” for People With Postexertional Symptom Exacerbation

https://doi.org//10.2519/jospt.blog.20220216

Published

16-Feb-22

Article

https://www.jospt.org/do/10.2519/jospt.blog.20220216

In a previous post, we demonstrated that the symptoms and physiology of postexertional symptom exacerbation (PESE) are inconsistent with deconditioning. PESE worsens in response to exercise and demonstrates a variable clinical presentation. We will build a clinical rationale for energy system first aid as a place to start helping people with PESE.
Graded Exercise May Be Harmful to People With PESE
It is not surprising that patients with PESE frequently report worsening symptoms and function with exercise prescribed based on time and activity quotas,1 based on the physiological evidence. The United Kingdom’s Pacing, graded Activity, and Cognitive behaviour therapy, a randomized Evaluation (UK PACE) compared the clinical outcomes of specialist medical care, adaptive pacing, and graded exercise therapy (GET) in 641 people with idiopathic, disabling fatigue.9 In this study, GET was a quota-based progressive exercise program, where subjects incrementally increased exercise regardless of symptoms. PESE was not a specific recruitment criterion for this trial.8,9 The trial did not adhere to the published protocol, without appropriate justification. The raw data was independently reanalyzed according to the original protocol,10 Upon reanalysis, most symptomatic and functional outcome findings from the UK PACE trial did not reach thresholds for clinical relevance. Many ME/CFS experts contend the results of GET are marginal, probably not clinically relevant or beneficial.10
Despite the important concerns of the UK PACE trial, the trial continues to exert outsized influence on clinical guidelines.3 Some countries' systems developed formal treatment pathways based on flawed results. Treatment pathways involving GET may have exposed an untold number of patients with ME/CFS worldwide to a GET program that, at best, is marginally effective, and at worst, may be harmful. Recent clinical guidelines for people with PESE, such as long COVID, no longer involve GET.6,7 These omissions reflect the ongoing re-evaluation of how clinical care should proceed for people with PESE, including people with long COVID. Implicit to this re-evaluation is a further reflection on the generally accepted idea that "movement is medicine" in a way that universally benefits clinical populations.

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Duerlund LS , Shakar S, Nielsen H , Bodilsen J

Positive Predictive Value of the ICD-10 Diagnosis Code for Long-COVID

https://doi.org/10.2147/CLEP.S344515

Published

9-Feb-22

Study

https://www.dovepress.com/positive-predictive-value-of-the-icd-10-diagnosis-code-for-long-covid-peer-reviewed-fulltext-article-CLEP

Purpose: To examine the positive predictive value (PPV) of International Classification version 10 (ICD-10) diagnosis codes for long coronavirus disease 2019 (long-COVID) in a Danish Health registry.
Patients and Methods: This was a medical record review of all patients with a diagnosis code of long-COVID (DB948A) at all hospitals in the North Denmark Region from February 27, 2020 through June 30, 2021. Confirmed long-COVID was categorized as fulfillment of all three criteria: (1) a positive polymerase chain reaction (PCR) test for SARS-CoV-2 on a respiratory sample or a positive serum antibody test, (2) symptoms suggestive of long-COVID with no other diagnosis considered more likely, and (3) symptom duration > 6 weeks.
Results: A total of 306 patients were assigned a hospital diagnosis code for long-COVID corresponding to 1.4% of all SARS-CoV-2 positive individuals during the study period (n=21,727). Next, 40 patients were excluded due to incomplete diagnostic evaluation at time of record review leaving 266 patients for analysis. The patients had a median age of 51 years (interquartile range 43– 60) and 175/266 (66%) were females. Long-COVID was confirmed in 249/266 yielding an overall PPV of 94% (95%CI: 90– 96) and did not differ substantially according to most age groups, sex, previous hospitalization for COVID-19, or by using 12 weeks of symptom duration as cut-off. The PPV was low for children and adolescents (n=5), the very elderly (n=9), and those included by secondary long-COVID diagnoses (n=10).
Conclusion: The overall PPV of diagnosis codes for long-COVID in the North Denmark Region was high and was likely suitable for future registry-based studies of long-COVID. Caution is advised at the extremes of age and secondary diagnosis codes.

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The interacting physiology of COVID-19 and the reninangiotensin-aldosterone system: Key agents for treatment

https://doi.org/10.1002/prp2.917

Published

29-Nov-21

Review

https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1002/prp2.917

SARS-CoV-2 interacting with its receptor, angiotensin-converting enzyme 2 (ACE2), turns the host response to viral infection into a dysregulated uncontrolled inflammatory response. This is because ACE2 limits the production of the peptide angiotensin II (Ang II) and SARS-CoV-2, through the destruction of ACE2, allows the uncontrolled production of Ang II. Recovery from trauma requires activation of both a tissue response to injury and activation of a whole-body response to maintain tissue perfusion. Tissue and circulating renin-angiotensin systems (RASs) play an essential role in the host response to infection and injury because of the actions of Ang II, mediated via its AT1 receptor. Both tissue and circulating arms of the renin angiotensin aldosterone system's (RAAS) response to injury need to be regulated. The effects of Ang II and the steroid hormone, aldosterone, on fluid and electrolyte homeostasis and on the circulation are controlled by elaborate feedback networks that respond to alterations in the composition and volume of fluids within the circulatory system. The role of Ang II in the tissue response to injury is however, controlled mainly by its metabolism and conversion to Ang-(1-7) by the enzyme ACE2. Ang-(1-7) has effects that are contrary to Ang II-AT1R mediated effects. Thus, destruction of ACE2 by SARS-CoV-2 results in loss of control of the pro-inflammatory actions of Ang II and tissue destruction. Therefore, it is the response of the host to SARS-CoV-2 that is responsible for the pathogenesis of COVID-19.

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Nikki Kean

Long-Haul COVID-19: Gut Microbiome May Hold the Key

Published

2-Feb-22

Article

https://www.clinicaladvisor.com/home/topics/gastroenterology-information-center/long-haul-covid-19-linked-altered-microbiome/

A patient’s gut microbiome may be linked to the risk of developing long-haul COVID-19 after initial infection with SARS-CoV-2, according to a study published online in the journal Gut.1
Although most people with COVID-19 recover within weeks of infection, some experience symptoms 4 or more weeks after COVID-19, according to the Centers for Disease Control and Prevention. These long-haul COVID conditions are also known as post-COVID, long COVID, post-acute COVID-19, long-term effects of COVID, or chronic COVID.2
Huang et al have reported that up to 75% of patients hospitalized with COVID-19 described at least 1 symptom 6 months after discharge.3 These included respiratory, neuropsychiatric (headache, dizziness, loss of taste and smell, anxiety, poor concentration, disrupted sleep, low mood, poor memory, blurred vision), gastrointestinal, hair loss, and musculoskeletal symptoms as well as fatigue.

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Pustake, Manas1,; Tambolkar, Isha2; Giri, Purushottam3; Gandhi, Charmi1

SARS, MERS and CoVID-19
An overview and comparison of clinical, laboratory and radiological features

https://doi.org/10.4103/jfmpc.jfmpc_839_21

Published

1-Jan-22

Review

https://journals.lww.com/jfmpc/Fulltext/2022/01000/SARS,_MERS_and_CoVID_19__An_overview_and.3.aspx

In the 21st century, we have seen a total of three outbreaks by members of the coronavirus family. Although the first two outbreaks did not result in a pandemic, the third and the latest outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) culminated in a pandemic. This pandemic has been extremely significant on a social and international level. As these viruses belong to the same family, they are closely related. Despite their numerous similarities, they have slight distinctions that render them distinct from one another. The Severe Acute Respiratory Distress Syndrome and Middle East Respiratory Syndrome (MERS) cases were reported to have a very high case fatality rate of 9.5 and 34.4% respectively. In contrast, the CoVID-19 has a case fatality rate of 2.13%. Also, there are no clear medical countermeasures for these coronaviruses yet. We can cross information gaps, including cultural weapons for fighting and controlling the spread of MERS-CoV and SARS-CoV-2, and plan efficient and comprehensive defensive lines against coronaviruses that might arise or reemerge in the future by gaining a deeper understanding of these coronaviruses and the illnesses caused by them. The review thoroughly summarises the state-of-the-art information and compares the biochemical properties of these deadly coronaviruses with the clinical characteristics, laboratory features and radiological manifestations of illnesses induced by them, with an emphasis on comparing and contrasting their similarities and differences.

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Daniel Munblit, Timothy R. Nicholson, Dale M. Needham, Nina Seylanova, Callum Parr, Jessica Chen, Alisa Kokorina, Louise Sigfrid, Danilo Buonsenso, Shinjini Bhatnagar, Ramachandran Thiruvengadam, Ann M. Parker, Jacobus Preller, Sergey Avdeev, Frederikus A. Klok, Allison Tong, Janet V. Diaz, Wouter De Groote, Nicoline Schiess, Athena Akrami, Frances Simpson, Piero Olliaro, Christian Apfelbacher, Regis Goulart Rosa, Jennifer R. Chevinsky, Sharon Saydah, Jochen Schmitt, Alla Guekht, Sarah L. Gorst, Jon Genuneit, Luis Felipe Reyes, Alan Asmanov, Margaret E. O’Hara, Janet T. Scott, Melina Michelen, Charitini Stavropoulou, John O. Warner, Margaret Herridge & Paula R. Williamson

Studying the post-COVID-19 condition: research challenges, strategies, and importance of Core Outcome Set development

https://doi.org/10.1186/s12916-021-02222-y

Published

4-Feb-22

Opinion

https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-021-02222-y

Background
A substantial portion of people with COVID-19 subsequently experience lasting symptoms including fatigue, shortness of breath, and neurological complaints such as cognitive dysfunction many months after acute infection. Emerging evidence suggests that this condition, commonly referred to as long COVID but also known as post-acute sequelae of SARS-CoV-2 infection (PASC) or post-COVID-19 condition, could become a significant global health burden.
Main text
While the number of studies investigating the post-COVID-19 condition is increasing, there is no agreement on how this new disease should be defined and diagnosed in clinical practice and what relevant outcomes to measure. There is an urgent need to optimise and standardise outcome measures for this important patient group both for clinical services and for research and to allow comparing and pooling of data.
Conclusions
A Core Outcome Set for post-COVID-19 condition should be developed in the shortest time frame possible, for improvement in data quality, harmonisation, and comparability between different geographical locations. We call for a global initiative, involving all relevant partners, including, but not limited to, healthcare professionals, researchers, methodologists, patients, and caregivers. We urge coordinated actions aiming to develop a Core Outcome Set (COS) for post-COVID-19 condition in both the adult and paediatric populations.

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Terence Stephenson1
, Benjamin Allin2
, Manjula D Nugawela1
, Natalia Rojas1
, Emma
Dalrymple1
, Snehal M Pinto Pereira3
, Manas Soni4
, Marian Knight2
, Emily Y Cheung1
,
Isobel Heyman1
, CLoCk Consortium5
, Roz Shafran

Long COVID (Post-COVID-19 condition) in Children: a modified Delphi Process

Published

1-Feb-22

Study

http://press.psprings.co.uk/adc/february/AAMadc323624.pdf

Objective The aim of this study was to derive a research definition for ‘Long COVID (PostCOVID-19 condition)’ in children and young people (CYP) to allow comparisons between research studies.
Design A three-phase online Delphi process was used, followed by a consensus meeting. Participants were presented with 49 statements in each phase and scored them from 1-9 based on how important they were for inclusion in the research definition of Long COVID in CYP. The consensus meeting was held to achieve representation across the stakeholder groups. Statements agreed at the consensus meeting were reviewed by participants in the Patient Public Involvement (PPI) Research Advisory Group. Setting The study was conducted remotely using online surveys and a virtual consensus meeting. Participants 120 people with relevant expertise were divided into three panels according to their area of expertise: Service Delivery, Research (or combination of research and service delivery) and Lived Experience. The PPI Research Advisory group consisted of CYP aged 11-17 years. Main outcome measures Consensus was defined using existing guidelines. If consensus was achieved in two or more panels or was on the border between one and two panels, those statements were discussed and voted on at the consensus meeting.
Results Ten statements were taken forward for discussion in the consensus meeting and five statements met threshold to be included in the research definition of Long COVID among CYP. The research definition aligned to the clinical case definition of the World Health Organisation is proposed as follows: Post-COVID-19 condition occurs in young people with a history of confirmed SARS CoV-2 infection, with at least one persisting physical symptom for a minimum duration of 12 weeks after initial testing that cannot be explained by an AUTHOR ACCEPTED MANUSCRIPT 3 alternative diagnosis. The symptoms have an impact on everyday functioning, may continue or develop after COVID-19 infection, and may fluctuate or relapse over time. The positive COVID test referred to in this definition can be a lateral flow antigen test, a PCR test or an antibody test.
Conclusions This is the first research definition of Long COVID (Post-COVID-19 condition) in CYP and complements the clinical case definition in adults proposed by WHO.
What this study adds
1. The first research definition of Long COVID in CYP that complements the definition
proposed by WHO for adults.
How this study might affect research, practice or policy
1. Ability to reliably compare and evaluate studies on prevalence, course and outcome of
Long COVID in CYP using this definition.

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Rafael A. Rivas-Vazquez, Gustavo Rey, Alan Quintana & Ana A. Rivas-Vazquez

Assessment and Management of Long COVID

https://doi.org/10.1007/s42843-022-00055-8

Published

9-Feb-22

Review

https://link.springer.com/article/10.1007/s42843-022-00055-8

Broad variability during acute COVID-19 infection is seen, ranging from asymptomatic presentation to death. The vast majority of individuals who develop COVID-19 return to their pre-COVID-19 baseline within several weeks. However, a portion of patients will develop a post-COVID-19 syndrome of persistent cognitive, somatic, and behavioral symptoms. This syndrome, designated as post-acute sequelae of SARS-CoV-2 infection, is more commonly known as long COVID. The objectives of this paper are to inform psychologists regarding our current understanding of the underlying pathophysiology of COVID-19, review criteria for range of severity during acute illness, present clinical manifestations of long haul phenomena, and discuss the emerging literature base of evidence-based treatment and management approaches.

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BjørnBlomberg12Rebecca JaneCox13NinaLangeland12

Long-COVID: A growing problem in need of intervention

https://doi.org/10.1016/j.xcrm.2022.100552

Published

14-Feb-22

Commentary

https://www.sciencedirect.com/science/article/pii/S2666379122000581

The number of people who have survived COVID-19 is overwhelming – official figures approach half a billion (https://covid19.who.int). Thus, any long-term consequences in COVID-19 survivors could have a huge impact on public health and on healthcare services in the coming months and years, with potentially 100 million individuals affected.

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Nisreen A. Alwan

Lessons from Long COVID: working with patients to design better research

https://doi.org/10.1038/s41577-022-00692-6

Published

15-Feb-22

Comment

https://www.nature.com/articles/s41577-022-00692-6

The perspectives of people with lived experience of any condition being researched must actively inform the research questions asked and the way in which we go about answering them. The experience of Long Covid gives a contemporary example of how working together with patients is integral to medical research.

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Alexandra Flemming

First glimpses into the mechanisms of Long COVID

https://doi.org/10.1038/s41577-022-00691-7

Published

15-Feb-22

Article

https://www.nature.com/articles/s41577-022-00691-7

Post-acute sequelae of COVID-19 (PASC), sometimes referred to as ‘Long COVID’, are observed in 30–70% of individuals post-SARS-CoV-2 infection. These can include loss of sense of smell, memory loss, fatigue, shortness of breath, gastrointestinal (GI) distress and other symptoms. Autoimmune processes and unresolved viral fragments have been proposed as causative, but experimental validation for these hypotheses is lacking. Now, a longitudinal multi-omic study of >300 patients by Su et al. reveals that some factors present at disease onset, such as pre-existing type 2 diabetes, latent EBV reactivation, circulating SARS-CoV-2 RNA fragments as well as specific autoantibodies, associate with specific PASC. The authors identified four different immune endotypes at 2–3 months post disease onset that differentially associate with PASC. Interestingly, they find that bystander activation of CMV-specific T cells during acute disease is associated with GI PASC. A second study by Vijayakumar et al. shows persistent immunological and proteomic abnormalities in the lungs of patients with ongoing respiratory symptoms after COVID-19, with continuing activation of CD8+ T cells and elevated levels of proteins associated with apoptosis, tissue repair and epithelial injury.

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Aluko A. Hope, MD, MSCE
Teresa H. Evering, MD, MS

Post-Acute Sequelae of SARS CoV-2 infection

https://doi.org/10.1016/j.idc.2022.02.004

Published

14-Feb-22

Review

https://www.id.theclinics.com/article/S0891-5520(22)00025-3/fulltext

Key Points
•Post-Acute-Sequelae of SARS-CoV-2 infection (PASC) or Long COVID is a heterogeneous, multi-system, relapsing and remitting illness that can affect patients infected with SARS-CoV-2 regardless of the severity of the acute infection.
•Estimates of the incidence and prevalence of Long COVID symptoms vary widely across published studies.
•The diagnosis of Long COVID is currently primarily based on history and physical examination and may require a multidisciplinary approach to care.
•The overall approach to the treatment of Long COVID is to focus on symptom management, functional goals and improvements in the quality of life.
The clinical spectrum of SARS-CoV-2 infection ranges from asymptomatic to critical illness, which may include severe sepsis and acute respiratory failure1. When symptomatic, acute COVID-19 illness will typically last days to weeks and most of the symptoms are thought to be mediated by the replication of the virus and the initial immune response to the infection2. As the COVID-19 pandemic continues, it has become increasingly clear that clinical sequelae and symptoms may persist for weeks to months beyond the acute stage of SARS-CoV-2 infection for a significant proportion of patients. This chronic illness has been termed Post-Acute Sequelae of SARS-CoV-2 Infection (PASC), post-COVID syndrome, or Long COVID. A less common post-acute hyperinflammatory illness (multisystem inflammatory syndrome in children (MIS-C) and multisystem inflammatory syndrome in adults (MIS-A) has also been characterized. MIS-C and MIS-A will typically occur two to five weeks after the initial SARS-CoV-2 infection and are thought to be mediated by a dysregulated immune response1. Patients with these syndromes may suffer from cardiovascular, gastrointestinal, neurologic, dermatologic and mucocutaneous manifestations like Kawasaki disease3,4, and is discussed further in Chapter 12. This review will highlight what is known about the epidemiology, clinical features, pathophysiology, and risk factors of Long COVID and summarize current rational approaches for diagnosis, prevention and treatment of this new syndrome based on emerging literature and expert opinion.

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Moniek van Zitteren, Marit C. van Boreen & Jerry Spanjer

Adequate beoordeling van long covid

https://doi.org/10.1007/s12498-022-1475-x

Published

22-Feb-22

Article

https://link.springer.com/article/10.1007/s12498-022-1475-x

It is now known that Covid-19 can lead to long-term complaints with significant limitations. These are not always easy to objectify or factual information is missing. The development of a guideline for complaints that are difficult to objectify for occupational and insurance medical practice is desirable in order to arrive at an adequate assessment of the load capacity of lung covid patients.
For the time being, one will have to fall back on known information about similar medical conditions and the currently applicable protocols. Collaboration between occupational medicine and insurance medicine seems essential in this regard, as does reaching consensus in the assessment of such complaints.

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César Fernández-de-las-Peñas, Juan Torres-Macho, María Velasco-Arribas, Susana Plaza-Canteli, José A. Arias-Navalón, Valentín Hernández-Barrera & Carlos Guijarro

Preexisting hypertension is associated with a greater number of long-term post-COVID symptoms and poor sleep quality: a case–control study

https://doi.org/10.1038/s41371-022-00660-6

Published

16-Feb-22

Study

https://www.nature.com/articles/s41371-022-00660-6

There has been an increasing interest in the presence of symptoms after the acute phase (post-COVID symptoms) of infection, e.g., long COVID. Long COVID is defined as those symptoms appearing during or after SARS-CoV-2 infection during far longer than it would be expected [5]. Current evidence suggests that the presence of post-COVID symptoms ranges from 35 to 60% depending on the symptom and the follow-up period [6]; however, most studies did not consider the role of previous medical co-morbidities. This study analyzed the association of hypertension and long-term post-COVID symptoms in previously hospitalized COVID-19 patients.

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Ian Albert Clark

Chronic cerebral aspects of long COVID, post-stroke syndromes and similar states share their pathogenesis and perispinal etanercept treatment logic

https://doi.org/10.1002/prp2.926

Published

Review

https://pubmed.ncbi.nlm.nih.gov/35174650/

The chronic neurological aspects of traumatic brain injury, post-stroke syndromes, long COVID-19, persistent Lyme disease, and influenza encephalopathy having close pathophysiological parallels that warrant being investigated in an integrated manner. A mechanism, common to all, for this persistence of the range of symptoms common to these conditions is described. While TNF maintains cerebral homeostasis, its excessive production through either pathogen-associated molecular patterns or damage-associated molecular patterns activity associates with the persistence of the symptoms common across both infectious and non-infectious conditions. The case is made that this shared chronicity arises from a positive feedback loop causing the persistence of the activation of microglia by the TNF that these cells generate. Lowering this excess TNF is the logical way to reducing this persistent, TNF-maintained, microglial activation. While too large to negotiate the blood-brain barrier effectively, the specific anti-TNF biological, etanercept, shows promise when administered by the perispinal route, which allows it to bypass this obstruction.

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A.López-SampaloaM.R.Bernal-LópezabR.Gómez-Huelgasab

Persistent COVID-19 syndrome. A narrative review
Síndrome de COVID-19 persistente. Una revisión narrativa

https://doi.org/10.1016/j.rceng.2021.10.001

Published

28-Feb-22

Review

https://www.sciencedirect.com/science/article/pii/S225488742200008X

As the coronavirus-2019 disease (COVID-19) pandemic, caused by the infection with severe acute respiratory syndrome (SARS-CoV-2) coronavirus type 2, has progressed, persistent COVID-19 syndrome is an increasingly recognized problem on which a significant volume of medical literature is developing. Symptoms may be persistent or appear, after an asymptomatic period, weeks or months after the initial infection. The clinical picture is as markedly heterogeneous and multisystemic as in the acute phase, so multidisciplinary management is required. In addition, their appearance is not related to the severity of the initial infection, so they can affect both mild patients, even asymptomatic, and seriously ill patients who have required hospitalization. Although it can affect people of any age, it is more common in middle-aged women. The sequelae can generate a high impact on the quality of life, and in the work and social environment. The objective of this paper is to review persistent COVID-19 syndrome, to know its clinical manifestations and the strategies for the management and follow-up of these patients.

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PESE

CristinaRoldán-JiménezabAntonio ICuesta-Vargas

Proposal for assessment of the predominant symptom and physical function in patients suffering from Long COVID

https://doi.org/10.1016/j.mehy.2022.110811

Published

1-Mar-22

Article

https://www.sciencedirect.com/science/article/pii/S0306987722000512

Long COVID patients present a cluster of symptoms that overlaps with other post-infectious conditions, such as patients diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Besides fatigue, one of the most limiting clinical manifestations in ME/CFS is post-exertional malaise (PEM), which Long COVID patients also report. Therefore, there are concerns about treatment approaches in rehabilitation for long COVID patients. Up to date, Long COVID patients present fatigue and respiratory symptoms predominantly. The hypothesis presented in this paper is that the treatment approach for Long COVID patients may depend on the aetiology of their symptoms, which objective tests can assess. And the primary affected system in a given patient may determine the individual response to physical exhaustion. Then, we propose an assessment to confirm the system impaired under the predominant symptom to guide the rehabilitation intervention. Fatigue-related symptoms, PEM, physical deconditioning and response to exertion should be assessed in Long COVID patients with predominant fatigue. In contrast, the respiratory function by spirometry and the diffusion capacity should be objectively assessed in those patients with predominantly respiratory symptoms. Future research should develop and validate patient-reported outcomes or cardiopulmonary exercise testing to objectively assess the symptoms and functional status in Long COVID patients to reinforce the proposed assessment.

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LewisKazisMarySlavinHannahBaileyEmilyHickeyAileenLedinghamAnanyaVasudevanRonaldTompkins

Appraisal of Long COVID: Lessons to be Learned from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

https://doi.org/10.1016/j.apmr.2022.01.008

Published

2-Mar-22

Review

https://www.sciencedirect.com/science/article/pii/S0003999322000284

Little is known regarding after-effects of Long-COVID-19 (LC), while ME/CFS has been extensively researched. We performed a rigorous scoping review to inform a better definition of symptomatology of LC and cross-cutting similarities with ME/CFS. Our objective was to review the National Institutes of Health (NIH) ME/CFS Common Data Elements (CDEs), identify Patient Reported Outcome Measures (PROMs) and link items to the World Health Organization (WHO) International Classification of Functioning, Disability and Health (ICF) codes to inform efforts to define LC.
Data Synthesis
Six articles specifically compared LC and ME/CFS for symptom overlap. Similarities between ME/CFS and Long COVID symptoms include: fatigue, post exertional malaise (PEM), cognitive symptoms, sleep dysfunction, pain, noise and light hypersensitivity, orthostatic intolerance, cardiac, gastrointestinal and immune pathologies. The 944 items from 38 PROM CDEs were coded based on common ME/CFS and LC symptoms. The percent of items linked to one or more ICF categories (1288 codes) was as follows: Body Function (b codes) 73%: Fatigability, N=252 (20%); Cognitive functions, N=234 (18%); Sleep functions, N=139, 11%; and Pain, N=119, (9%). Activity and Participation (d codes), N=332, (26%). Environment (e codes), N=11, 0.9%.
Conclusions
The ICF provides a common language to assess ME/CFS and LC cross-cutting symptoms and their impact on body function, activity and participation. This review of ME/CFS CDE's can help identify common symptoms, such as PEM, and encourage appropriate symptom management to prevent cycles of overexertion and relapse for those with LC.

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Juan Carlos Villar
Nolbert Gumisiriza
Lucas Guimarães Abreu
Richard J Maude
Robert Colebunders

Defining post-COVID condition

https://doi.org/10.1016/S1473-3099(22)00060-3

Published

1-Mar-22

Article

https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(22)00060-3/fulltext

Joan B Soriano and colleagues1 proposed a clinical case definition for post-COVID-19 condition. We thank this WHO-led working group for their efforts to provide an operational definition for this emerging, challenging condition.
Similar to previous statements by the Centers for Disease Control and Prevention2 and the National Institute for Health and Care Excellence,3 the criterion “SARS-CoV-2 laboratory confirmation” was not included in the definition proposed by this working group. There are some compelling reasons supporting this perspective. A post-COVID-19 condition can affect people who have only minor, non-specific or even no symptoms during the acute phase of the infection. Such cases are not regularly tested for SARS-CoV-2. Additionally, there has been inadequate access to testing in low-income and middle-income countries (LMICs). People also avoid testing for fear of the consequences of a positive result. Furthermore, if done late, tests can become negative, making a retrospective diagnosis unfeasible.
Although a clinical definition without laboratory confirmation increases sensitivity (allowing more affected people to receive care), it comes with a trade-off with specificity. Hence, a stricter definition might be required for research purposes and comparison between different settings.

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ME - PESE

Todd E. Davenport Staci R. Stevens Jared Stevens Christopher R. Snell J. Mark Van Ness

Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 4: Heart Rate Monitoring to Manage Postexertional Symptom Exacerbation

https://doi.org//10.2519/jospt.blog.20220223

Published

23-Feb-22

Article

https://www.jospt.org/do/10.2519/jospt.blog.20220223

Summary
A combination of HRM and symptom journaling will best assist patients and clinicians to track outcomes and adjust the HRM program as needed. The patient and clinician should collaborate to determine the “Key 3” symptoms of PESE that are most functionally limiting to the patient. Symptoms may be assessed using a formalized questionnaire,1,3,9 or they may be qualitatively determined based on discussion with the patient. The presence and severity of Key 3 symptoms can be reassessed over time to determine the effectiveness of the HRM program.
- The physiology underlying postexertional symptom exacerbation (PESE) is abnormal in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and likely long COVID. Activity pacing approaches appear warranted to accommodate the unusual physiological deficits of PESE.
The Rationale for Heart Rate Monitoring
Similar to people living with ME/CFS,7 people living with long COVID have reported finding activity pacing to be helpful. This idea is reflected in current safe rehabilitation guidelines for this condition.8 PESE is challenging to self-manage because of the variability in onset, duration, and nature from person to person.2,6 Social stigma associated with PESE may lead people to overexert to meet the demands of their daily tasks. This stigma may be exacerbated by people telling patients that “it’s all in their head” or they “just need to exercise.” Variability and stigma, in turn, make it difficult to identify important activity triggers in the early stages of learning to manage PESE.
PESE is characterized by aerobic system dysfunction. Pacing based on heart rate can help the patient avoid the dysfunctional aerobic system by keeping their activity intensity at a level anaerobic metabolism will dominate. Heart rate monitoring (HRM) provides an element of predictive potential for the patient to understand when their activities exceed physiological limits and eventually may result in PESE. In this post, we will discuss activity pacing to manage PESE that is based on HRM.

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Joanne Elizabeth Hunt

Making space for disability studies within a structurally competent medical curriculum: Reflections on Long Covid

https://doi.org/10.31235/osf.io/p9qyk

pre-print

28-Feb-22

Article

https://osf.io/preprints/socarxiv/p9qyk/

Whilst critically informed approaches to medical education are increasingly advocated in literature, discussion of the potential role of disability studies in informing pedagogy and practice is largely lacking. The emergence of Long Covid, alongside the possibility of a wave of covid-related disability, underlines an urgent need for medicine to develop more contextualised, nuanced and structurally competent understandings of chronic illness and disability. This article argues that the integration of thinking from disability studies into medical curricula offers a pathway to such understanding, informing a more equitable, holistic and patient-centred approach to practice. Further, a structurally competent, anti-ableist approach positions clinicians and patients as allies, working together within a structural context that constrains both parties. Such positioning may mitigate tensions within the clinical encounter, tensions that are well-documented in the realm of marginalised chronic illness and disability. Whilst the possibilities arising from a partnership between disability studies and medicine are numerous, the foci here are the social relational model of disability and the concept of psycho-emotional disablism, within a broader paradigm of critical disability studies. It is argued that inadequate healthcare provision and policy in the realm of Long Covid can be understood as a form of structural and psycho-emotional disablism, arising from and reinforcing an ableist psychosocial imaginary permeated with neoliberal assumptions, and carrying a risk of furthering both disability and impairment. After considering Long Covid through these particular lenses, the article concludes with a discussion of how a partnership between disability studies and a structurally competent approach to medical education might translate into practice.

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Michael J. Peluso
Steven G. Deeks

Early clues regarding the pathogenesis of long-COVID

https://doi.org/10.1016/j.it.2022.02.008

Published

8-Mar-22

Article

https://www.cell.com/trends/immunology/fulltext/S1471-4906(22)00047-3

Intense investigation into the predictors and determinants of post-acute sequelae of SARS-CoV-2 infection (PASC), including ‘long COVID’, is underway. Recent studies provide clues to the mechanisms that might drive this condition, with the goal of identifying host or virus factors that can be intervened upon to prevent or reverse PASC.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to systemic symptoms, which in most people resolve within a few weeks. A poorly characterized subset of individuals, however, have persistent symptoms that last for many weeks or longer. The syndrome has many names, including ‘post-acute sequelae of SARS-CoV-2 infection’ (PASC) and ‘post-acute coronavirus disease (COVID) syndrome’ (PACS), but is more widely known as ‘long COVID’. Due in part to the formation of a very powerful and effective advocacy community, the US Congress recently allocated over $1 billion dollars for the study of PASC. The National Institutes of Health (NIH) is now implementing a massive program [Researching COVID to Enhance Recovery (RECOVER); www.recovercovid.org]; the UK and other countries already have several ongoing initiatives. The study of PASC has become a major research priority that will presumably lead to discoveries relevant to other post-infectious syndromes, many of which are similar to PASC.
There are dozens of epidemiologic studies, most leveraging electronic medical records, describing the natural history of PASC. In general, these studies have found that sex, severity of initial COVID-19, the presence of certain comorbidities (including obesity, diabetes, and chronic lung disease), and socioeconomic status can affect the risk of an individual with COVID-19 developing PASC. Newer clinical and translational studies are beginning to explore its pathogenesis, providing clues about some of the mechanistic pathways that might contribute to this condition.
We can now expect the emergence of major scientific efforts addressing the pathogenesis of PASC. In one of the first systematic studies, a large collaborative group organized by the Institute for Systems Biology (Seattle, WA, USA) performed a longitudinal multi-omic systems biology analysis of over 200 individuals who were followed for 2–3 months after acute infection [1.]. Several factors were associated with the development of PASC, including pre-existing diabetes mellitus, high-level SARS-CoV-2 viremia, and Epstein-Barr virus (EBV) reactivation during acute infection. The investigators also identified the presence of certain autoantibodies, including those targeting type I interferons (IFNs), that could predict PASC. Their observations suggest plausible mechanisms by which SARS-CoV-2 infection can cause persistent symptoms. For example, a higher degree of SARS-CoV-2 viremia likely reflects higher tissue viral burden and increased likelihood of end-organ damage. Higher viremia might also be associated with immunologic perturbations that could lead to organ dysfunction; some of these might persist beyond early convalescence. The relationships for other factors are less clear, for example, EBV viremia may more plausibly reflect the severity of initial illness rather than represent a causal mechanism of PASC, although the recent observation that EBV reactivation might lead to multiple sclerosis suggests this virus can contribute to autoimmune syndromes [2.]. Furthermore, the identification of a relationship with anti-IFN antibodies, previously shown to be important in acute COVID-19 [3.], suggests another mechanism that may tie together an impaired antiviral response, an enhanced inflammatory response, and generation of downstream autoimmune processes.
In a different analysis of several hundred individuals during acute infection and up to a year later [4.], Cervia and colleagues identified a distinct SARS-CoV-2 specific immunoglobulin signature during acute infection among those who went on to develop PASC. Specifically, they found that reduced IgM and IgG3 titers during acute infection were a risk factor for PASC, which the authors suggest might be related to reduced production of type I IFNs resulting in a failure of isotype switching. Using these laboratory measurements in combination with certain clinical factors (e.g., age, asthma history, number of acute COVID-19 symptoms), the team generated a prediction model to identify those who developed PASC [4.]. In yet another recent study, Liu and colleagues found differences in the gut microbiome associated with neuropsychiatric and pulmonary PASC symptoms [5.]. These studies add to a growing body of literature suggesting that a combination of virus and host factors, including potential viral antigen persistence (preliminary) [6.], residual inflammation [7.,8.], microvascular dysregulation [9.], and autoimmune phenomena [10.] might contribute to PASC (Figure 1).

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Lauren E. Wisk, PhD, Graham Nichol, MD, MPH, Joann G. Elmore

Toward Unbiased Evaluation of Postacute Sequelae of SARS-CoV-2 Infection: Challenges and Solutions for the Long Haul Ahead

https://doi.org/10.7326/M21-4664

Published

8-Mar-22

Opinion

https://www.acpjournals.org/doi/10.7326/M21-4664

Early reporting of postacute SARS-CoV-2 syndrome (PASC), or “long COVID” (1), foretells a difficult challenge developing in parallel to the ongoing pandemic. Some patients with prior acute COVID-19 report multiple new or persistent symptoms affecting nearly every organ system (2). In the United States, PASC has already been approved for inclusion and protections within the Americans with Disabilities Act (3) despite limited study data or medical consensus. Yet, we do not know what constitutes long COVID or how to formally diagnose it (4). An improved understanding of this condition is needed to provide appropriate care for our patients. However, developing high-quality scientific evidence on PASC presents a unique challenge due to the evolving circumstances of SARS-CoV-2 and the pandemic itself. Such work will indeed be a long haul.

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Alain Trautmann

La fatigue chronique, un symptôme trop souvent négligé
I. Une immunité dérégulée à son origine ?
Mechanisms underlying chronic fatigue, a symptom too often overlooked

https://doi.org/10.1051/medsci/2021143

Published

Article

https://www.medecinesciences.org/fr/articles/medsci/full_html/2021/08/msc200438/msc200438.html

Acute fatigue after exertion, like acute inflammation after injury, is useful for our body. On the contrary, both chronic fatigue and chronic inflammation are deleterious, and they are associated in many diseases. In this first part, we will analyze different immune phenomena (bystander activation, memory of the innate immune system, link with the intestinal microbiota) involved in triggering chronic inflammation. This review aims at looking for links between different signs and symptoms associated with chronic fatigue, as well as between different diseases in which severe chronic fatigue can manifest. Possible underlying mechanisms for these phenomena are discussed. This is a proposal made by a researcher, with no clinical experience, to doctors confronted with an entity that is still largely mysterious. The link between chronic inflammation, neuroinflammation and fatigue will be examined in a second part.

La fatigue aiguë après un effort, comme l’inflammation aiguë après une blessure, sont utiles à notre organisme. En revanche, la fatigue chronique, comme l’inflammation chronique, sont délétères, et elles sont associées dans de nombreuses maladies. Nous analyserons dans cette première partie différents phénomènes immunitaires impliqués dans le déclenchement de l’inflammation chronique. Cette revue vise à proposer des liens entre différents signes et symptômes associés à la fatigue chronique, ainsi qu’entre différentes maladies dans lesquelles peut se manifester une fatigue chronique grave. Des mécanismes possibles, sous-jacents à ces processus, et leurs liens, sont également discutés. Il s’agit ici d’une proposition faite par un chercheur, sans expérience clinique, à des médecins confrontés à une entité qui reste encore largement mystérieuse. L’articulation entre inflammation chronique, neuro-inflammation et fatigue, sera examinée dans une deuxième partie.

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Alain Trautmann

Mécanismes sous-jacents à la fatigue chronique, un symptôme trop souvent négligé
II. De l’immunité dérégulée à la neuroinflammation et ses conséquences
Mechanisms underlying chronic fatigue, a symptom too often overlooked II- From deregulated immunity to neuroinflammation and its consequences

https://doi.org/10.1051/medsci/2021170

Published

Article

https://www.medecinesciences.org/fr/articles/medsci/full_html/2021/09/msc200704/msc200704.html

Hypothalamus stimulation by inflammatory and / or stress signals can trigger activation of the HPA (hypothalamic-pituitary-adrenal) axis, which includes the hypothalamus, pituitary and adrenal gland. Acute activation of the HPA axis is fundamental for the fight or flight response. It allows a maximal energy mobilization available for an effort, whilst erasing fatigue. On the contrary, the chronic activation of this axis decreases muscle efficiency and leads to chronic fatigue. In this second part of our review will be discussed several strategic points that need to be considered for attempting to understand and treat together inflammation and chronic fatigue.

L’activation de l’hypothalamus par des signaux inflammatoires et/ou de stress peut déclencher celle de l’axe HPA (hypothalamic-pituitary-adrenal axis), qui intègre l’hypothalamus, l’hypophyse et la glande surrénale. L’activation aiguë de l’axe HPA est fondamentale pour la réponse fight or flight (« combats ou fuis »). Elle permet de mobiliser un maximum d’énergie pour un effort, tout en effaçant la fatigue. En revanche, son activation chronique diminue l’efficacité musculaire et entraîne une fatigue chronique. On discutera dans cette partie de plusieurs points stratégiques à considérer pour tenter de comprendre et de traiter ensemble inflammation et fatigue chroniques.

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López-Sampalo A1, Bernal-López MR2, Gómez-Huelgas R2

Persistent COVID-19 syndrome. A narrative review
Síndrome de COVID-19 persistente. Una revisión narrativa

https://doi.org/10.1016/j.rceng.2021.10.001

Published

28-Feb-22

Review

https://europepmc.org/article/pmc/pmc8882405

As the coronavirus-2019 disease (COVID-19) pandemic, caused by the infection with severe acute respiratory syndrome (SARS-CoV-2) coronavirus type 2, has progressed, persistent COVID-19 syndrome is an increasingly recognized problem on which a significant volume of medical literature is developing. Symptoms may be persistent or appear, after an asymptomatic period, weeks or months after the initial infection. The clinical picture is as markedly heterogeneous and multisystemic as in the acute phase, so multidisciplinary management is required. In addition, their appearance is not related to the severity of the initial infection, so they can affect both mild patients, even asymptomatic, and seriously ill patients who have required hospitalization. Although it can affect people of any age, it is more common in middle-aged women. The sequelae can generate a high impact on the quality of life, and in the work and social environment. The objective of this paper is to review persistent COVID-19 syndrome, to know its clinical manifestations and the strategies for the management and follow-up of these patients.

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Khalid SaadAlharbiaYogendraSinghbWaleedHassan almalkicSushamaRawatdObaidAfzaleAbdulmalik SalehAlfawaz AltamimieImranKazmifFahad A.Al-AbbasifSami I.AlzareaaSachin KumarSinghgShvetankBhatthDinesh KumarChellappaniKamalDuajkGauravGuptalm

Gut Microbiota Disruption in COVID-19 or Post-COVID Illness Association with severity biomarkers: A Possible Role of Pre / Pro-biotics in manipulating microflora

https://doi.org/10.1016/j.cbi.2022.109898

Published

21-Mar-22

Review

https://www.sciencedirect.com/science/article/pii/S000927972200103X

Highlights
•COVID-19 has emerged as the world's most dangerous epidemic.
•COVID-19 has had a minimal therapeutic response.
•This review explained a role of gastrointestinal tract microbiome in the acute COVID-19.
Coronavirus disease (COVID-19), a coronavirus-induced illness attributed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, is thought to have first emerged on November 17, 2019. According to World Health Organization (WHO). COVID-19 has been linked to 379,223,560 documented occurrences and 5,693,245 fatalities globally as of 1st Feb 2022. Influenza A virus that has also been discovered diarrhea and gastrointestinal discomfort was found in the infected person, highlighting the need of monitoring them for gastro intestinal tract (GIT) symptoms regardless of whether the sickness is respiration related. The majority of the microbiome in the intestines is Firmicutes and Bacteroidetes, while Bacteroidetes, Proteobacteria, and Firmicutes are found in the lungs. Although most people overcome SARS-CoV-2 infections, many people continue to have symptoms months after the original sickness, called Long-COVID or Post COVID. The term “post-COVID-19 symptoms” refers to those that occur with or after COVID-19 and last for more than 12 weeks (long-COVID-19). The possible understanding of biological components such as inflammatory, immunological, metabolic activity biomarkers in peripheral blood is needed to evaluate the study. Therefore, this article aims to review the informative data that supports the idea underlying the disruption mechanisms of the microbiome of the gastrointestinal tract in the acute COVID-19 or post-COVID-mediated elevation of severity biomarkers.

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Nidheesh V. R., Aswini Kumar Mohapatra, Unnikrishnan V. K., Jijo Lukose, Vasudevan Baskaran Kartha & Santhosh Chidangil

Post-COVID syndrome screening through breath analysis using electronic nose technology

https://doi.org/10.1007/s00216-022-03990-z

Published

18-Mar-22

Study

https://link.springer.com/article/10.1007/s00216-022-03990-z

There is an urgent need to have reliable technologies to diagnose post-coronavirus disease syndrome (PCS), as the number of people affected by COVID-19 and related complications is increasing worldwide. Considering the amount of risks associated with the two chronic lung diseases, asthma and chronic obstructive pulmonary disease (COPD), there is an immediate requirement for a screening method for PCS, which also produce symptoms similar to these conditions, especially since very often, many COVID-19 cases remain undetected because a good share of such patients is asymptomatic. Breath analysis techniques are getting attention since they are highly non-invasive methods for disease diagnosis, can be implemented easily for point-of-care applications even in primary health care centres. Electronic (E-) nose technology is coming up with better reliability, ease of operation, and affordability to all, and it can generate signatures of volatile organic compounds (VOCs) in exhaled breath as markers of diseases. The present report is an outcome of a pilot study using an E-nose device on breath samples of cohorts of PCS, asthma, and normal (control) subjects. Match/no-match and k-NN analysis tests have been carried out to confirm the diagnosis of PCS. The prediction model has given 100% sensitivity and specificity. Receiver operating characteristics (ROC) has been plotted for the prediction model, and the area under the curve (AUC) is obtained as 1. The E-nose technique is found to be working well for PCS diagnosis. Our study suggests that the breath analysis using E-nose can be used as a point-of-care diagnosis of PCS.

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Santosh K. Chaturvedi

How Long is Your Covid? The Catch of ’22

https://doi.org/10.1007/s40737-022-00277-5

Published

17-Mar-22

Editorial

https://link.springer.com/article/10.1007/s40737-022-00277-5

What is not clear is what should be the duration for considering it as a long covid. For other disorders, it was known that a disorder can be acute which is short-lasting, or chronic which is longer lasting than the acute one. Some disorders are also considered sub-acute. For example, the definition of chronic pain is when pain lasts longer than expected so it can be of a variable duration—a few days, weeks, three months, or six months. So, is long covid considered as long covid, when the duration is more than a week, two weeks, one month, 3 months, or a year or is it when it is longer than expected? In time, these issues need to be addressed for researchers to focus on long covid, based on a consensus on the duration.
Thus, the impact of different variants like delta and omicron was the focus of healthcare and public attention in 2020 and 2021, long covid will be the focus in 2022, and maybe later as well. One can say that covid 19 was the catch of 2020, and delta and omicron variants were the catch of 2021.
The catch of 2022 is long covid!
And how long this long-covid will last, only time will tell!

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Kelly K O'Brien,corresponding author#1,2,3,4 Darren A Brown,#5,6 Colm Bergin,7,8 Kristine M Erlandson,9 Jaime H Vera,10,11 Lisa Avery,12,13 Soo Chan Carusone,14 Angela M Cheung,2,12,15 Susie Goulding,16 Richard Harding,17 Lisa McCorkell,18 Margaret O'Hara,19 Larry Robinson,20 Catherine Thomson,6 Hannah Wei,21 Natalie St Clair-Sullivan,11 Brittany Torres,1 Ciaran Bannan,7,8 Niamh Roche,22 Ruth Stokes,22 Patriic Gayle,23 and Patricia Solomon24

Long COVID and episodic disability: advancing the conceptualisation, measurement and knowledge of episodic disability among people living with Long COVID – protocol for a mixed-methods study

https://dx.doi.org/10.1136%2Fbmjopen-2022-060826

Published

6-Mar-22

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905414/

In phase 1, we will conduct semistructured interviews with adults living with Long COVID to explore experiences of disability (dimensions, uncertainty, trajectories, influencing contextual factors) and establish an episodic disability (ED) framework in the context of Long COVID (n~10 each country). Using the conceptual framework, we will establish the Long COVID Episodic Disability Questionnaire (EDQ). In phase 2, we will examine the validity (construct, structural) and reliability (internal consistency, test–retest) of the EDQ for use in Long COVID. We will electronically administer the EDQ and four health status criterion measures with adults living with Long COVID, and readminister the EDQ 1 week later (n~170 each country). We will use Rasch analysis to refine the EDQ, and confirm structural and cross-cultural validity. We will calculate Cronbach’s alphas (internal consistency reliability), and intraclass correlation coefficients (test–retest reliability), and examine correlations for hypotheses theorising relationships between EDQ and criterion measure scores (construct validity). Using phase 2 data, we will characterise the profile of disability using structural equation modelling techniques to examine relationships between dimensions of disability and the influence of intrinsic and extrinsic contextual factors. This research involves an academic–clinical–community partnership building on foundational work in ED measurement, Long COVID and rehabilitation.

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Rachel Coomey

Long Covid: The Long Road Ahead

Published

1-Mar-22

Article

http://rcpi-live-cdn.s3.amazonaws.com/wp-content/uploads/2022/03/6.-Rachel-Coomey-TCD-Long-Covid-The-Long-Road-Ahead.pdf

The Covid-19 pandemic has dominated news headlines and public discussion for the past two years.
We have been inundated with information about positivity rates and death rates, numbers in intensive
care and economic impact. One aspect that has remained relatively underreported, however, is “Long
Covid”, the persistence of symptoms in the weeks or months after SARS-CoV-2 infection (1). Long
Covid rose to prominence due to social media, and its exact pathophysiology and long-term
implications are yet to be fully understood (2). 2% of the UK population reported themselves to
currently be suffering from Long Covid in January 2022, with 63% of those stating that the condition
was adversely impacting their day-to-day activities (3). One in four UK employers report that Long
Covid is a major cause of employee absence in their companies (4). While, thankfully, death rates due
to Covid are decreasing and fewer people are being admitted to intensive care in recent months, we
are yet to fully come to terms with many after-effects of the pandemic, including Long Covid. Given
that many effects of Long Covid may negatively affect ability to drive safely, I believe this issue is
hugely important, and pertinent to medical fitness to drive.

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MartinKaatzSteffenSpringerRogerSchubertMichaelZieger

Representation of long COVID syndrome in the awareness of the population is revealed by Google Trends analysis

https://doi.org/10.1016/j.bbih.2022.100455

Published

26-Mar-22

Study

https://www.sciencedirect.com/science/article/pii/S266635462200045X

Highlights
•Long COVID plays a non-negligible role in the information needs, as evidenced by the growing search interest during the pandemic.
•Symptoms ageusia and anosmia became relatively well-known and relevant during the pandemic.
•Google Trends is a useful tool, well suited for demonstrating the population's awareness of certain infodemiological topics.
In some COVID-19 patients, symptoms persist for several weeks and sometimes, after the acute disease phase, these patients develop new symptoms, which then represents a transition into the so-called long COVID. The exact demarcation of the terms and generally applicable definitions are still discussed, but the phenomenon is most commonly referred to as long COVID.
In this study, Google Trends data have been used to track levels of public awareness for long COVID and some important symptoms during the course of the COVID-19 pandemic.
The results of this analysis clearly demonstrate the public interest in the new topic of long COVID, as documented by a corresponding search volume. This is related to the disease COVID-19, which is being spread by the corona pandemic. Relevant symptoms for COVID-19 or long COVID, for example ageusia and anosmia, only started to receive more public attention during the pandemic.
Therefore, Google Trends is a useful tool to demonstrate the population's awareness of certain infodemiological topics like long COVID.

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Joanne Hunt, Charlotte Blease, Keith J Geraghty

Long Covid at the crossroads: Comparisons and lessons from the treatment of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

https://doi.org/10.1177%2F13591053221084494

Published

27-Mar-22

Article

https://journals.sagepub.com/doi/10.1177/13591053221084494

Whilst parallels have been drawn between Long Covid and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), there is a well-documented history of negative stereotyping and marginalisation of patients with ME/CFS. A socio-politically oriented comparison of scientific, clinical and societal responses to Long Covid and ME/CFS is thus important to prevent similar harms arising among Long Covid patients. We identify four reasons for injustices in the treatment of ME/CFS patients, and discuss the risk of Long Covid following a similar trajectory. We conclude with policy and practice recommendations to help prevent such injustices arising again, including consideration of critical reflexivity in medical education.

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Petter Brodin, Giorgio Casari, Liam Townsend, Cliona O’Farrelly, Ivan Tancevski, Judith Löffler-Ragg, Trine H. Mogensen, Jean Laurent Casanova & The COVID Human Genetic Effort

Studying severe long COVID to understand post-infectious disorders beyond COVID-19

https://doi.org/10.1038/s41591-022-01766-7

Published

5-Apr-22

Correspondence

https://www.nature.com/articles/s41591-022-01766-7

In our cohort of patients with severe long COVID, we will investigate B cell and T cell responses to SARS-CoV-2 and will assess somatic hypermutation and clonal evolution relative to the patterns seen in people who recovered from COVID-19 without persistent signs and symptoms. This will serve as an indirect test of ongoing antigen exposure in patients with severe long COVID. Also, by assessing functional states of SARS-CoV-2-specific T cells, we will determine if patients with long COVID exhibit evidence of functional impairment that could explain viral persistence.
One study used structural modeling to identify a possible superantigen motif within the SARS-CoV-2 spike protein near the S1–S2 cleavage site6. As indirect support for the possibility of superantigen-mediated stimulation, expansion of TRVB21-3+ cells has been observed in patients with MIS-C2 (Fig. 1b). Many pathogens contain superantigens able to activate T cells in a nonspecific manner, such as staphylococci that cause staphylococcal toxic shock syndrome. Interestingly, this syndrome has been reported to induce persistent symptoms that bear similarity to those seen in severe long COVID10. This overlap of symptoms suggests either a direct effect of the superantigen on tissues or immune dysregulation that gives rise to persistent symptoms after infection.
As for the neurological symptoms common in long COVID and other post-infectious disorders, it is worth considering possible neurotoxin motifs. Such motifs have been described for the SARS-CoV-2 coronavirus6, and these neurotoxins could in theory exert direct effects on both the central nervous system and peripheral nervous system. We plan to perform TCR sequencing in patients with severe long COVID in search of expansion of TRVB21-3+ cells, as in MIS-C, and we will also perform in vitro stimulation assays using soluble S1 protein to assess T cell reactivity and possible functional dysregulation as an element of disease.
Superantigen-mediated T cell activation can trigger broad B cell activation, and production of autoantibodies against a range of tissues has been shown in MIS-C2,5 and in patients with acute COVID-19. Also, chronic activation of the immune system by viral persistence can induce autoimmune responses, and molecular mimicry between components of a pathogen and host tissue can lead to specific post-infectious autoimmunity. Structural similarity between human neuronal antigens and SARS-CoV-2 proteins has been suggested. A particular form of autoimmunity described in long COVID is postural orthostatic tachycardia syndrome, a form of autonomic dysregulation that is possibly induced by functional autoantibodies that target G protein–coupled receptors on neurons (Fig. 1b).
Another type of autoimmunity relevant to SARS-CoV-2 infection is the production of neutralizing autoantibodies to type I interferons, which explains a sizeable fraction of cases of hypoxemic COVID-19 pneumonia1. If such neutralizing autoantibodies are present before SARS-CoV-2 infection, due to prior infections or vaccinations, then a patient is clearly at risk of developing severe acute COVID-19. However, such neutralizing autoantibodies might also appear after SARS-CoV-2 infection, in which case they might instead enable viral persistence, the formation of a viral reservoir and long COVID. To test this hypothesis, we will look for the presence of neutralizing autoantibodies to type I interferons in patients with long COVID.
Collectively, we believe that our genetic and immunological studies of patients with severe long COVID hold potential for better understanding of this complex condition, and by focusing on severe cases that develop after mild COVID-19, we maximize our chances of success. Our results would probably be applicable beyond COVID-19 and will hopefully provide important insights of relevance into other post-infectious disorders such as myalgic encephalomyelitis.

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PeterValentMDaCemAkinMD, PhDbPatriziaBonadonnaMDcKnutBrockowMDdMarekNiedoszytkoMD, PhDeBoguslawNedoszytkoPhDfJoseph H.ButterfieldMDgIvanAlvarez-TwoseMD, PhDhKarlSotlarMDiJulianaSchwaabMDjMohamadJawharMDjAndreasReiterMDjMarianaCastellsMD, PhDkWolfgang R.SperrMDaHanneke C.Kluin-NelemansMD, PhDlOlivierHermineMD, PhDmJasonGotlibMD, MSnRobertaZanottiMDo…KarinHartmannMD

Risk and management of patients with mastocytosis and MCAS in the SARS-CoV-2 (COVID-19) pandemic: Expert opinions

https://doi.org/10.1016/j.jaci.2020.06.009

Published

5-Aug-20

Article

https://www.sciencedirect.com/science/article/pii/S0091674920308393

Risk factors concerning COVID-19–induced morbidity and mortality include advanced age, an impaired immune system, cardiovascular or pulmonary diseases, obesity, diabetes mellitus, and cancer treated with chemotherapy. Here, we discuss the risk and impact of COVID-19 in patients with mastocytosis and mast cell activation syndromes. Because no published data are yet available, expert opinions are, by necessity, based on case experience and reports from patients. Although the overall risk to acquire the severe acute respiratory syndrome coronavirus 2 may not be elevated in mast cell disease, certain conditions may increase the risk of infected patients to develop severe COVID-19. These factors include certain comorbidities, mast cell activation–related events affecting the cardiovascular or bronchopulmonary system, and chemotherapy or immunosuppressive drugs. Therefore, such treatments should be carefully evaluated on a case-by-case basis during a COVID-19 infection. In contrast, other therapies, such as anti–mediator-type drugs, venom immunotherapy, or vitamin D, should be continued. Overall, patients with mast cell disorders should follow the general and local guidelines in the COVID-19 pandemic and advice from their medical provider.

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Frank Powitz

Anhaltende Beschwerden bei bis zu 15% der COVID-19-Patienten
Long-/Post-Covid-Syndrom: Genesen heißt nicht gesund
Long-/Post-Covid-Syndrome: Recovered doesn´t mean healthy

https://doi.org/10.1007/s15006-022-0721-6

Published

1-Apr-22

Article

https://link.springer.com/article/10.1007/s15006-022-0721-6

Noch unklare Ursache
Die genauen Ursachen des Long-/Post-Covid-Syndroms sind bislang nicht bekannt, und es fehlen laut Leitlinie für viele klinische Probleme noch pathophysiologische Evidenzen und klinische Studien. Diskutiert wird als Ursache die mögliche Persistenz von Viren oder Virusbestandteilen über Wochen und Monate. Aber auch postinfektiöse strukturelle Gewebeschäden - inklusive Endothelschäden und einer gestörten Mikrovaskularisierung - sowie eine Hyperkoagulabilität und Thrombosen können möglicherweise eine Rolle spielen. Das gilt ebenso für eine chronische Immundysregulation, für Autoimmunphänomene sowie für eine Dysregulation des Renin-Angiotensin-Aldosteron-Systems oder auch für Nebenwirkungen der COVID-19-Therapie.

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Sven H. Loosen, Björn-Erik Ole Jensen, Christian Tanislav, Tom Luedde, Christoph Roderburg & Karel Kostev

Obesity and lipid metabolism disorders determine the risk for development of long COVID syndrome: a cross-sectional study from 50,402 COVID-19 patients

https://doi.org/10.1007/s15010-022-01784-0

Published

30-Mar-22

Article

https://link.springer.com/article/10.1007/s15010-022-01784-0

Purpose
Metabolic disorders have been identified as major risk factors for severe acute courses of COVID-19. With decreasing numbers of infections in many countries, the long COVID syndrome (LCS) represents the next major challenge in pandemic management, warranting the precise definition of risk factors for LCS development.
Methods
We identified 50,402 COVID-19 patients in the Disease Analyzer database (IQVIA) featuring data from 1056 general practices in Germany. Multivariate logistic regression analysis was used to identify risk factors for the development of LCS.
Results
Of the 50,402 COVID-19 patients included into this analysis, 1,708 (3.4%) were diagnosed with LCS. In a multivariate regression analysis, we identified lipid metabolism disorders (OR 1.46, 95% CI 1.28–1.65, p < 0.001) and obesity (OR 1.25, 95% CI 1.08–1.44, p = 0.003) as strong risk factors for the development of LCS. Besides these metabolic factors, patients’ age between 46 and 60 years (compared to age ≤ 30, (OR 1.81 95% CI 1.54–2.13, p < 0.001), female sex (OR 1.33, 95% CI 1.20–1.47, p < 0.001) as well as pre-existing asthma (OR 1.67, 95% CI 1.39–2.00, p < 0.001) and depression (OR 1.27, 95% CI 1.09–1.47, p = < 0.002) in women, and cancer (OR 1.4, 95% CI 1.09–1.95, p = < 0.012) in men were associated with an increased likelihood of developing LCS.
Conclusion
Lipid metabolism disorders and obesity represent age-independent risk factors for the development of LCS, suggesting that metabolic alterations determine the risk for unfavorable disease courses along all phases of COVID-19.

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Paula Boaventura 1,2,3,*,Sofia Macedo 1,2 ,Filipa Ribeiro 1,2,Sónia Jaconiano 4 andPaula Soares 1,2,3

Post-COVID-19 Condition: Where Are We Now?

https://doi.org/10.3390/life12040517

Published

31-Mar-22

Review

https://www.mdpi.com/2075-1729/12/4/517/htm

COVID-19 is currently considered a systemic infection involving multiple systems and causing chronic complications. Compared to other post-viral fatigue syndromes, these complications are wider and more intense. The most frequent symptoms are profound fatigue, dyspnea, sleep difficulties, anxiety or depression, reduced lung capacity, memory/cognitive impairment, and hyposmia/anosmia. Risk factors for this condition are severity of illness, more than five symptoms in the first week of the disease, female sex, older age, the presence of comorbidities, and a weak anti-SARS-CoV-2 antibody response. Different lines of research have attempted to explain these protracted symptoms; chronic persistent inflammation, autonomic nervous system disruption, hypometabolism, and autoimmunity may play a role. Due to thyroid high ACE expression, the key molecular complex SARS-CoV-2 uses to infect the host cells, thyroid may be a target for the coronavirus infection. Thyroid dysfunction after SARS-CoV-2 infection may be a combination of numerous mechanisms, and its role in long-COVID manifestations is not yet established. The proposed mechanisms are a direct effect of SARS-CoV-2 on target cells, an indirect effect of systemic inflammatory immune response, and a dysfunction of the hypothalamic-pituitary-thyroid (HPT) axis leading to decreased serum TSH. Only a few studies have reported the thyroid gland status in the post-COVID-19 condition. The presence of post-COVID symptoms deserves recognition of COVID-19 as a cause of post-viral fatigue syndrome. It is important to recognize the affected individuals at an early stage so we can offer them the most adequate treatments, helping them thrive through the uncertainty of their condition.

todo

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Ahmed Samir Abdelhafiz ,Asmaa Ali,Ayman Mohamed Maaly,Mohamed Anwar Mahgoub,Hany Hassan Ziady,Eman Anwar Sultan

Predictors of post-COVID symptoms in Egyptian patients: Drugs used in COVID-19 treatment are incriminated

https://doi.org/10.1371/journal.pone.0266175

Published

31-Mar-22

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0266175

Objectives
COVID-19 is a multisystem disease, and some patients suffer from physical or psychological symptoms for weeks or even months after infection, which is described as post-COVID syndrome. The goal of this study is evaluating the prevalence of post-COVID-19 symptoms among Egyptian patients and detecting the factors associated with the presence of these symptoms.
Methods
An on-line cross-sectional survey using Google Forms was used to conduct the present study, which took place between June and August 2021.
Results
Three hundred and ninety-six participants filled in the survey. The mean age of participants was 41.4 years. Most participants had mild to moderate COVID-19 (81.31%). The prevalence of post-COVID-19 symptoms was 87.63%, where the most frequent symptom was fatigue (60.86%). Female sex, the presence of comorbidities, lower degree of education, longer disease duration, as well as severe and critical forms of the disease were significantly associated with the presence of post-COVID symptoms. Using regression analysis, the predictors of post-COVID symptoms were severe and critical forms of the disease and intake of antibiotics and corticosteroids for treatment of COVID-19.
Conclusions
COVID-19 is followed by high prevalence of post-COVID symptoms. To the best of our knowledge, this is the first study to report the relationship between the use of antibiotics and the development of post-COVID symptoms. We recommend further studies to understand this relationship. We also recommend restricting the use of these drugs to indicated cases according to the international guidelines. More studies are needed to gain better understanding of post-COVID symptoms especially in females.

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Linzy Houchen-Wolloff1,2, Krisnah Poinasamy3, Kate Holmes4, Maryrose Tarpey5, Claire Hastie6, Kelly Raihani6, Natalie Rogers6, Nikki Smith6, Dawn Adams7, Paul Burgess7, Omer Elneima1,2, John Geddes14, Simon Heller15, Ling-Pei Ho16,17, Joseph Jacob18,19, Hamish McAuley1,2, Aarti Parmar1,2, Jennifer K Quint20, Betty Raman21, Matthew Rowland22, Amisha Singapuri2, Sally J Singh1,2, David Thomas23, Mark R Toshner24,25, Louise V Wain2,26, Alex Robert Horsley27, Michael Marks28, Christopher E Brightling1,2, Rachael A Evans

Joint patient and clinician priority setting to identify 10 key research questions regarding the long-term sequelae of COVID-19

http://dx.doi.org/10.1136/thoraxjnl-2021-218582

Published

30-Mar-22

Article

https://thorax.bmj.com/content/early/2022/03/29/thoraxjnl-2021-218582.abstract

Given the large numbers of people infected and high rates of ongoing morbidity, research is clearly required to address the needs of adult survivors of COVID-19 living with ongoing symptoms (long COVID). To help direct resource and research efforts, we completed a research prioritisation process incorporating views from adults with ongoing symptoms of COVID-19, carers, clinicians and clinical researchers. The final top 10 research questions were agreed at an independently mediated workshop and included: identifying underlying mechanisms of long COVID, establishing diagnostic tools, understanding trajectory of recovery and evaluating the role of interventions both during the acute and persistent phases of the illness.

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Michelle Medeiros1, Hillary Anne Edwards1, Claudia Rose Baquet1,2

Research in the USA on COVID-19’s long-term effects: measures needed to ensure black, indigenous and Latinx communities are not left behind

http://dx.doi.org/10.1136/medethics-2021-107436

Published

1-Apr-22

Article

https://jme.bmj.com/content/early/2022/03/31/medethics-2021-107436

The SARS-CoV-2 (COVID-19) pandemic continues to expose underlying inequities in healthcare for black, indigenous and Latinx communities in the USA. The gaps in equitable care for communities of colour transcend the diagnosis, treatment and vaccinations related to COVID-19. We are experiencing a continued gap across racial and socioeconomic lines for those who suffer prolonged effects of COVID-19, also known as ‘Long COVID-19’. What we know about the treatment for Long COVID-19 so far is that it is complex, requires a multidisciplinary approach and there is still much research needed to fully understand the effects. In this paper, we discuss pragmatic considerations for including affected communities, relevant stakeholders, and leaders from communities of colour in the planning and implementation of Long COVID-19 research.

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Petter Brodin, Giorgio Casari, Liam Townsend, Cliona O’Farrelly, Ivan Tancevski, Judith Löffler-Ragg, Trine H. Mogensen, Jean Laurent Casanova & The COVID Human Genetic Effort

Studying severe long COVID to understand post-infectious disorders beyond COVID-19

https://doi.org/10.1038/s41591-022-01766-7

Published

5-Apr-22

Study

https://www.nature.com/articles/s41591-022-01766-7

In our cohort of patients with severe long COVID, we will investigate B cell and T cell responses to SARS-CoV-2 and will assess somatic hypermutation and clonal evolution relative to the patterns seen in people who recovered from COVID-19 without persistent signs and symptoms. This will serve as an indirect test of ongoing antigen exposure in patients with severe long COVID. Also, by assessing functional states of SARS-CoV-2-specific T cells, we will determine if patients with long COVID exhibit evidence of functional impairment that could explain viral persistence.
One study used structural modeling to identify a possible superantigen motif within the SARS-CoV-2 spike protein near the S1–S2 cleavage site6. As indirect support for the possibility of superantigen-mediated stimulation, expansion of TRVB21-3+ cells has been observed in patients with MIS-C2 (Fig. 1b). Many pathogens contain superantigens able to activate T cells in a nonspecific manner, such as staphylococci that cause staphylococcal toxic shock syndrome. Interestingly, this syndrome has been reported to induce persistent symptoms that bear similarity to those seen in severe long COVID10. This overlap of symptoms suggests either a direct effect of the superantigen on tissues or immune dysregulation that gives rise to persistent symptoms after infection.
As for the neurological symptoms common in long COVID and other post-infectious disorders, it is worth considering possible neurotoxin motifs. Such motifs have been described for the SARS-CoV-2 coronavirus6, and these neurotoxins could in theory exert direct effects on both the central nervous system and peripheral nervous system. We plan to perform TCR sequencing in patients with severe long COVID in search of expansion of TRVB21-3+ cells, as in MIS-C, and we will also perform in vitro stimulation assays using soluble S1 protein to assess T cell reactivity and possible functional dysregulation as an element of disease.Superantigen-mediated T cell activation can trigger broad B cell activation, and production of autoantibodies against a range of tissues has been shown in MIS-C2,5 and in patients with acute COVID-19. Also, chronic activation of the immune system by viral persistence can induce autoimmune responses, and molecular mimicry between components of a pathogen and host tissue can lead to specific post-infectious autoimmunity. Structural similarity between human neuronal antigens and SARS-CoV-2 proteins has been suggested. A particular form of autoimmunity described in long COVID is postural orthostatic tachycardia syndrome, a form of autonomic dysregulation that is possibly induced by functional autoantibodies that target G protein–coupled receptors on neurons (Fig. 1b).
Another type of autoimmunity relevant to SARS-CoV-2 infection is the production of neutralizing autoantibodies to type I interferons, which explains a sizeable fraction of cases of hypoxemic COVID-19 pneumonia1. If such neutralizing autoantibodies are present before SARS-CoV-2 infection, due to prior infections or vaccinations, then a patient is clearly at risk of developing severe acute COVID-19. However, such neutralizing autoantibodies might also appear after SARS-CoV-2 infection, in which case they might instead enable viral persistence, the formation of a viral reservoir and long COVID. To test this hypothesis, we will look for the presence of neutralizing autoantibodies to type I interferons in patients with long COVID.
Collectively, we believe that our genetic and immunological studies of patients with severe long COVID hold potential for better understanding of this complex condition, and by focusing on severe cases that develop after mild COVID-19, we maximize our chances of success. Our results would probably be applicable beyond COVID-19 and will hopefully provide important insights of relevance into other post-infectious disorders such as myalgic encephalomyelitis.

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Bala Munipalli, Lynsey Seim, Nancy L. Dawson, Dacre Knight & Abd Moain Abu Dabrh

Post-acute sequelae of COVID-19 (PASC): a meta-narrative review of pathophysiology, prevalence, and management

https://doi.org/10.1007/s42399-022-01167-4

Published

4-Apr-22

Review

https://link.springer.com/article/10.1007/s42399-022-01167-4

Coronavirus Disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Over 220 countries and territories have been affected by this virus, and the infection rate has continued to rise. As patients recover from the virus, many are experiencing lingering symptoms. Understanding the impact of demographics and comorbidities on symptom prevalence, manifestations, and severity is not only relevant during acute infection, it is critical to the clinical management of patients with post-acute sequelae of COVID-19, also known as PASC. Herein, we provide a comprehensive review on the most recent research related to PASC. Specifically, we focus on the description of the disorder itself, compared to acute COVID-19, and which types of patients are most affected by long-term sequelae. Further, we share recommendations for management of the most common complications of PASC.
We propose the following simplified symptom course-based categorization:
Subacute or ongoing COVID-19 (PACS, post-acute COVID-19 syndrome) defined as symptoms continuing beyond the 4 weeks of acute infection, up to 12 weeks.
Post-COVID-19 syndrome / conditions (PCS, PCC, long-COVID, long-haulers’ syndrome) chronic ongoing COVID-19 symptoms beyond 12 weeks from acute infection.
Post-acute sequelae of COVID-19 (PASC) symptoms persisting beyond the 4-week period of acute infection. Both PACS (i.e., 4–12 weeks) and PCS (i.e., > 12 weeks) are identified as two different chronological stages of Post-COVID Conditions.
PASC is becoming a recognizable and crucial clinical entity as data continue to inform of its pathogenesis, presentation, and clinical course. Anecdotal reporting has also raised questions about the implications of receiving a COVID-19 vaccine and the improvement in PASC. One out of five patients report improvement, mainly brain fog and anosmia, after SARS-CoV-2 vaccination [116]. Two-thirds of patients with PASC saw no worsening of symptoms after vaccination; fever, chills, and gastro-intestinal symptoms were frequently reported, similar to the general population [116]. This will require further research.
The current understanding suggests PASC is caused by ACE2 receptor-binding, immune-dysregulation, and stimulation of hyper-inflammatory and hyper-coagulation pathways [9]. Preexisting conditions and the relationship to PASC remain largely unclear. Demographic data show higher prevalence and severity in females, with significant impact on under-resourced and disparate communities.
The long-term management of PASC remains largely unknown. The most reported follow-up assessments include quality of life, functional neurocognitive and psychological evaluations, pulmonary function screening, and occupational rehabilitation. The multiorgan and heterogenous manifestation of PASC requires the need for multidisciplinary, coordinated care management that includes peer and community support for patients presenting with PACS.
The strength of this review study is the succinct, up-to-date information it provides, including a table summarizing current management recommendations from literature, focused to general physicians, and primary care providers who are most likely to see PASC patients front-line. The meta-narrative review approach is deemed feasible, robust, and appropriate at this stage to outline existing evidence and gaps in knowledge for future direction.

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Mark A Faghy,Thomas Maden-Wilkinson,Ross Arena,Robert J Copeland,Rebecca Owen,Henry Hodgkins &Ash Willmott

COVID-19 patients require multi-disciplinary rehabilitation approaches to address persisting symptom profiles and restore pre-COVID quality of life

https://doi.org/10.1080/17476348.2022.2063843

Published

18-Apr-22

Study

https://www.tandfonline.com/doi/full/10.1080/17476348.2022.2063843

Background
Long-COVID diagnosis is prominent, and our attention must support those experiencing debilitating and long-standing symptoms. To establish patient pathways, we must consider the societal and economic impacts of sustained COVID-19. Accordingly, we sought to determine the pertinent areas impacting quality of life (QoL) following a COVID-19 infection.
Research methods
Three hundred and eighty-one participants completed a web-based survey (83% female, 17% male) consisting of 70 questions across 7 sections (demographics, COVID-19 symptoms; QoL; sleep quality; breathlessness; physical activity and mental health). Mean age, height, body mass and body mass index (BMI) were 42 ± 12 years, 167.6 ± 10.4 cm, 81.2 ± 22.2 kg, and 29.1 ± 8.4 kg.m2, respectively.
Results
Participant health was reduced because of COVID-19 symptoms (‘Good health’ to ‘Poor health’ [P < 0.001]). Survey respondents who work reported ongoing issues with performing moderate (83%) and vigorous (79%) work-related activities.
Conclusions
COVID-19 patients report reduced capacity to participate in activities associated with daily life, including employment activities. Bespoke COVID-19 support pathways must consider multi-disciplinary approaches that address the holistic needs of patients to restore pre-pandemic quality of life and address experienced health and wellbeing challenges.
Plain Language Summary: The long-term impact of long-COVID has a dramatic impact upon daily activities and lifestyle. The development of bespoke support pathways to support patients must address the physical and psychological considerations to adequately restore pre-COVID quality of life and address broader societal and economic implications, especially for those that are of working age.

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Arthur A. Mirin,Mary E. Dimmock &Leonard A. JasonORCID Icon

Updated ME/CFS prevalence estimates reflecting post-COVID increases and associated economic costs and funding implications

https://doi.org/10.1080/21641846.2022.2062169

Published

11-Apr-22

Article

https://www.tandfonline.com/doi/abs/10.1080/21641846.2022.2062169

In this article, we update our earlier analyses of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) economic impact and its National Institutes of Health (NIH) funding versus disease burden, taking into account the anticipated new cases of ME/CFS resulting from COVID-19. Prior to the COVID pandemic, we estimated a United States ME/CFS prevalence of 1.5 million and an annual economic impact of $36–51 billion. Now, due to COVID and its resulting post-acute sequalae, we estimate total ME/CFS prevalence could rise to between five and nine million. This would incur an annual U.S. economic impact of $149 to $362 billion in medical expenses and lost income, exclusive of other costs, such as disability benefits, social services, and lost wages of caretakers. NIH funding for ME/CFS research would need to expand from the current amount of $15 million per year to approximately $472–$600 million annually, up to a 40-fold increase, to be commensurate with that of similarly burdensome diseases.

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Joan Stephenson, PhD1

Biden Administration Outlines Strategy to Tackle Long COVID

https://doi.org/10.1001/jamahealthforum.2022.1280

Published

12-Apr-22

Article

https://jamanetwork.com/journals/jama-health-forum/fullarticle/2791210

In a presidential memorandum issued last week, the Biden administration ordered the secretary of Health and Human Services (HHS) to create a national action plan to coordinate research on long-term effects of COVID-19, or long COVID, and support for patients experiencing the condition.
The HHS “will be leading a government-wide response to Long COVID focused on three main goals: improving care services and other support for individuals with Long COVID; enhancing education and outreach among the public-private sector and the medical community; and advancing research to support both goals,” HHS Secretary Xavier Becerra said during a White House COVID-19 Response Team briefing.
It is not yet clear how many people are affected by long COVID. According to a March 2022 federal government report, findings from US studies suggest that 10% to 30% of people with COVID-19 will develop symptoms that last longer than 4 weeks, with some resulting in significant disability. Based on these estimates, 7.7 million to 23 million people in the US may have developed long COVID as of February 2022.
In August 2021, HHS and the Department of Justice released new guidance that classifies long COVID as a physical or mental impairment, which means that individuals who are affected can qualify as having a disability under federal civil rights laws and receive appropriate accommodations and services.
The presidential memorandum directs HHS to issue a report in 120 days that will provide information about available services and support across federal agencies to help people experiencing long COVID. In addition, the report “will specifically address the long-term effects of COVID-19 on high-risk communities and efforts to address disparities in access to services and supports,” according to a White House fact sheet about the administration’s plan to address long COVID.

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Lakshmi Krishnan

An Extraordinary Sequel: The ‘Russian’ Influenza and Enduring Sequelae in Victorian Culture

https://doi.org/10.1093/jvcult/vcac012

Published

5-Apr-22

Article

https://academic.oup.com/jvc/advance-article/doi/10.1093/jvcult/vcac012/6563702?login=true

In 1895, the crime-writing duo of L. T. Meade and Clifford Halifax, MD, published ‘A Doctor’s Dilemma’ in The Strand Magazine. In it, the young physician Arthur Feveral describes a recent influenza outbreak which has left an ‘extraordinary sequel . . . My health is gone—my nerve has deserted me’. Influenza plays a central role in this fiction, but Feveral’s story is simply one of many – documentary and fictionalized – that populate the pages of late nineteenth-century British periodicals. The ‘Russian’ influenza pandemic of 1889–1894 was the last great European outbreak of the nineteenth century, leaving in its wake such widely discussed neurological effects (neurasthenia, psychosis, and melancholy) that they earned their own nosography: ‘influenza nervosa’. This paper examines the pandemic’s enduring cultural and biosocial impact through the framework of sequelae – chronic conditions arising in the aftermath of acute illness. Drawing on medical case histories, criminal reports, illness narratives, and works of fiction, it explores how the Victorians taxonomized and theorized such long-term effects of infectious disease. First, sequelae became a category separate from ‘complications’, vital to broader preoccupations with prolonged illness, uncertainty, and moral and bodily weakness and degeneracy, and the Victorians scaffolded around it notions of vigour and debility, difference, predisposition, and heredity. Second, they domesticated and repurposed colonial and tropical theories of hygiene as explanatory frameworks. Through close readings of ‘long influenza’ in the clinic and in fiction, this paper also frames the kinds of narratives which gained especial purchase, and the sufferers deemed both susceptible and sympathetic. Finally, it argues that the acute phase of infectious anxiety gave way to a longue durée of sequelae, and that Victorian responses provide critical insights and warnings for our own era.

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Anushri Umesh, Kumar Pranay, Ramesh Chandra Pandey & Mukesh Kumar Gupta

Evidence mapping and review of long-COVID and its underlying pathophysiological mechanism

https://doi.org/10.1007/s15010-022-01835-6

Published

30-Apr-22

Review

https://link.springer.com/article/10.1007/s15010-022-01835-6

Purpose
Apart from the global disease burden of acute COVID-19 disease, the health complications arising after recovery have been recognized as a long-COVID or post-COVID-19 syndrome. Evidences of long-COVID symptoms involving various organ systems are rapidly growing in literature. The objective was to perform a rapid review and evidence mapping of systemic complications and symptoms of long-COVID and underlying pathophysiological mechanisms.
Methods
Publications reporting clinical trials, observational cohort studies, case–control studies, case-series, meta-analysis, and systematic reviews, focusing on the squeal of the disease, consequences of COVID-19 treatment/hospitalization, long-COVID, chronic COVID syndrome, and post acute COVID-19 were reviewed in detail for the narrative synthesis of frequency, duration, risk factors, and pathophysiology.
Results
The review highlights that pulmonary, neuro-psychological, and cardiovascular complications are major findings in most epidemiological studies. However, dysfunctional gastrointestinal, endocrine, and metabolic health are recent findings for which underlying pathophysiological mechanisms are poorly understood. Analysis of the clinical trial landscape suggests that more than 50% of the industry-sponsored trials are focused on pulmonary symptoms. In contrast to the epidemiological trends and academic trials, cardiovascular complications are not a focus of industry-sponsored trials, suggestive of the gaps in the research efforts.
Conclusion
The gap in epidemiological trends and academic trials, particularly concerning cardiovascular complications not being a focus of industry-sponsored trials is suggestive of the gaps in research efforts and longer follow-up durations would help identify other long-COVID-related health issues such as reproductive health and fertility.

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Poloni, Tino Emanuele,*; Medici, Valentina; Zito, Antonio; Carlos, Arenn Faye

The long-COVID-19 in older adults
facts and conjectures

https://doi.org/10.4103/1673-5374.339483

Published

5-Jan-22

Article

https://journals.lww.com/nrronline/Fulltext/2022/12000/The_long_COVID_19_in_older_adults__facts_and.27.aspx

The coronavirus disease-19 (COVID-19) has greatly affected the overall health of the elderly population through direct biological (infection-related) and indirect psychosocial (quarantine- and isolation-related) effects. Because the severe form of COVID-19 most frequently targets this population, the prevalence of long-term sequelae is expected to rise consequentially in people ≥ 65 years old. The prominent neuropsychiatric consequences of COVID-19 and the cognitive frailty seen in older adults can both have a negative impact on their mental health. To explore the behavioral, neurological, and psychosocial consequences of COVID-19, we conducted separate studies on different populations of older adult people residing in Lombardy – the Italian epicenter of the first pandemic wave in spring 2020. In one study, we found that behavioral changes (i.e., delirium) were a frequent symptom of COVID-19, manifesting at disease onset and preceding the typical symptoms in about 1/3 (36.8%) of cases, particularly in patients with neurocognitive disorders (NCD), such as dementia (major-NCD) or mild cognitive impairment (mild-NCD). Delirium was also associated with short-term mortality and potential long-term cognitive sequelae (Poloni et al., 2020). To uncover the neuropathology underlying behavioral changes and their possible effects over time, we compared 9 brains of elderly patients who had died of COVID-19 (with and without dementia) with 6 brains from age-matched non-COVID controls. The main finding was an excessive innate immune response, represented by microglial hyperactivation. Although we observed severe inflammatory changes especially in the brainstem, we did not find neuropathological evidence suggestive of SARS-CoV-2 replication in the brain (Gagliardi et al., 2021; Poloni et al., 2021). In a study evaluating the psychosocial consequences of the lockdown due to the pandemic (Carlos et al., 2021), we observed that those with mild-moderate dementia were unable to cope and adapt to the life changes caused by the restrictions and consequently suffered from depression and cognitive decline. Before COVID, patients with dementia normally engaged in habitual daily activities. The disruption of said routines, the inability to engage in new activities, and the incapability to use modern technologies all triggered psychological distress and some degree of cognitive and motor regression (Figure 1A). Although lockdown (the sternest form of quarantine in history) protected them from COVID-19, the social seclusion and the inability to access primary care treatment – aggravated by an unprepared and unequipped primary care health sector – caused further complications (Carlos et al., 2021). Moreover, the general effects of the pandemic in terms of loss of “individual freedom”, economic crisis, and mass media conditioning should not be overlooked due to their possible impact on mental health.

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Daniel Munblit
Margaret E O'Hara
Athena Akrami
Elisa Perego
Piero Olliaro
Dale M Needham

Long COVID: aiming for a consensus

https://doi.org/10.1016/S2213-2600(22)00135-7

Published

4-May-22

Article

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00135-7/fulltext

The spectrum of signs and symptoms that can newly occur and persist for months to years after SARS-CoV-2 infection was initially named long COVID. This term was collectively created by the patient community in the spring of 2020,1 and was later followed by other terms, such as post-COVID-19 condition, post-acute sequelae of SARS-CoV-2 infection, and post-COVID syndrome.2 This condition can affect different organs and body systems, with a wide range of signs and symptoms reported. Given the magnitude of the sequelae of SARS-CoV-2 infection, it is essential to agree upon the nomenclature and definition to assess its incidence, subtypes, and severity. This process cannot be left to agencies, health-care providers, or researchers alone, but requires extensive consultation, notably including the people affected.
In early 2021, WHO established technical working groups to provide a clinical case definition for this condition and amplified the calls of patient groups for recognition, research, and rehabilitation. A rapidly increasing number of studies started to investigate the incidence and prevalence, features, and risk factors of the prolonged sequelae of SARS-CoV-2 infection, the underlying mechanisms, and case management approaches.
The spectrum of signs and symptoms that can newly occur and persist for months to years after SARS-CoV-2 infection was initially named long COVID. This term was collectively created by the patient community in the spring of 2020,1 and was later followed by other terms, such as post-COVID-19 condition, post-acute sequelae of SARS-CoV-2 infection, and post-COVID syndrome.2 This condition can affect different organs and body systems, with a wide range of signs and symptoms reported. Given the magnitude of the sequelae of SARS-CoV-2 infection, it is essential to agree upon the nomenclature and definition to assess its incidence, subtypes, and severity. This process cannot be left to agencies, health-care providers, or researchers alone, but requires extensive consultation, notably including the people affected.
In early 2021, WHO established technical working groups to provide a clinical case definition for this condition and amplified the calls of patient groups for recognition, research, and rehabilitation. A rapidly increasing number of studies started to investigate the incidence and prevalence, features, and risk factors of the prolonged sequelae of SARS-CoV-2 infection, the underlying mechanisms, and case management approaches.

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Emily R Pfaff, PhD *
Andrew T Girvin, PhD *
Tellen D Bennett, MD
Abhishek Bhatia, MS
Ian M Brooks, PhD
Rachel R Deer, PhD
Jonathan P Dekermanjian, MS
Sarah Elizabeth Jolley, MD
Michael G Kahn, MD
Kristin Kostka, MPH
Julie A McMurry, MPH
Richard Moffitt, PhD
Anita Walden, MS
Prof Christopher G Chute, MD
Prof Melissa A Haendel, PhD

Identifying who has long COVID in the USA: a machine learning approach using N3C data

https://doi.org/10.1016/S2589-7500(22)00048-6

Published

16-May-22

Study

https://www.thelancet.com/journals/landig/article/PIIS2589-7500(22)00048-6/fulltext

Background
Post-acute sequelae of SARS-CoV-2 infection, known as long COVID, have severely affected recovery from the COVID-19 pandemic for patients and society alike. Long COVID is characterised by evolving, heterogeneous symptoms, making it challenging to derive an unambiguous definition. Studies of electronic health records are a crucial element of the US National Institutes of Health's RECOVER Initiative, which is addressing the urgent need to understand long COVID, identify treatments, and accurately identify who has it—the latter is the aim of this study.
Methods
Using the National COVID Cohort Collaborative's (N3C) electronic health record repository, we developed XGBoost machine learning models to identify potential patients with long COVID. We defined our base population (n=1 793 604) as any non-deceased adult patient (age ≥18 years) with either an International Classification of Diseases-10-Clinical Modification COVID-19 diagnosis code (U07.1) from an inpatient or emergency visit, or a positive SARS-CoV-2 PCR or antigen test, and for whom at least 90 days have passed since COVID-19 index date. We examined demographics, health-care utilisation, diagnoses, and medications for 97 995 adults with COVID-19. We used data on these features and 597 patients from a long COVID clinic to train three machine learning models to identify potential long COVID among all patients with COVID-19, patients hospitalised with COVID-19, and patients who had COVID-19 but were not hospitalised. Feature importance was determined via Shapley values. We further validated the models on data from a fourth site.
Findings
Our models identified, with high accuracy, patients who potentially have long COVID, achieving areas under the receiver operator characteristic curve of 0·92 (all patients), 0·90 (hospitalised), and 0·85 (non-hospitalised). Important features, as defined by Shapley values, include rate of health-care utilisation, patient age, dyspnoea, and other diagnosis and medication information available within the electronic health record.
Interpretation
Patients identified by our models as potentially having long COVID can be interpreted as patients warranting care at a specialty clinic for long COVID, which is an essential proxy for long COVID diagnosis as its definition continues to evolve. We also achieve the urgent goal of identifying potential long COVID in patients for clinical trials. As more data sources are identified, our models can be retrained and tuned based on the needs of individual studies.

Notable differences include the high importance of dexamethasone in the hospitalised model, which decreased the likelihood of an individual patient being labelled as a potential long COVID patient. Dexamethasone is not present in the top 50 features of the non-hospitalised model. Similarly, cough and dyssomnia, which increased the likelihood of an individual beinglabelled as a potential long COVID patient, are important features in the non-hospitalised model, but do not appear in the hospitalised model. COVID-19 vaccination after acute disease, which is consistently an important feature in all three models, decreased the likelihood of patients being labelled as potentially having long COVID. This result is noteworthy and indicates that not only does vaccination against SARS-CoV-2 protect against hospitalisation and death, but that it might also protect against long COVID.

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Yusuke Miyazato Shinya Tsuzuki Shinichiro Morioka Mari Terada Satoshi Kutsuna Sho Saito Yumiko Shimanishi Kozue Takahashi Mio Sanada Masako Akashi Chika Kuge Yasuyo Osanai Keiko Tanaka Michiyo Suzuki Kayoko Hayakawa Norio Ohmagari

Factors associated with development and persistence of post-COVID conditions: A cross-sectional study

https://doi.org/10.1016/j.jiac.2022.04.025

Published

18-May-22

Survey

https://www.jiac-j.com/article/S1341-321X(22)00139-8/fulltext

Introduction
The post-COVID condition has become a social concern. Although the patient characteristics associated with the development of this condition are partially known, those associated with its persistence have not been identified.
Methods
We conducted a cross-sectional questionnaire-based survey among patients who had recovered from COVID-19 and visited the National Center for Global Health and Medicine between February 2021 and March 2021. Demographic and clinical data, and data regarding the presence and duration of post-COVID conditions were obtained. We identified factors associated with the development and persistence of post-COVID conditions using multivariate logistic and linear regression analyses, respectively.
Results
We analyzed 457 of 526 responses (response rate, 86.9%). The median patient age was 47 years. Of these, 378 patients (84.4%) had mild disease in the acute phase. The number of patients with symptoms at 6 and 12 months after onset or diagnosis was 120 (26.3%) and 40 (8.8%), respectively. Women were at risk of developing fatigue (odds ratio [OR]: 2.03, 95% confidence interval [CI]: 1.31–3.14), dysosmia (OR: 1.91, 95%CI: 1.24–2.93), dysgeusia (OR: 1.56, 95%CI: 1.02–2.39), hair loss (OR: 3.00, 95%CI: 1.77–5.09), and persistence of any symptoms (coefficient: 38.0, 95%CI: 13.3–62.8). Younger age and low body mass index were factors for developing dysosmia (OR: 0.96, 95%CI: 0.94–0.98 and OR: 0.94, 95%CI: 0.89–0.99, respectively) and dysgeusia (OR: 0.98, 95%CI: 0.96–1.00 and OR: 0.93, 95%CI: 0.88–0.98, respectively).
Conclusion
We identified factors involved in the development and persistence of post-COVID conditions. Many patients, even those with mild conditions, experience long-term residual symptoms.

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Solomiia Savedchuk, Rasha Raslan, Sarah Nystrom and Matthew A. Sparks

Emerging Viral Infections and the Potential Impact on Hypertension, Cardiovascular Disease, and Kidney Disease

https://doi.org/10.1161/CIRCRESAHA.122.320873

Published

12-May-22

Article

https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.122.320873

Viruses are ubiquitous in the environment and continue to have a profound impact on human health and disease. The COVID-19 pandemic has highlighted this with impressive morbidity and mortality affecting the world’s population. Importantly, the link between viruses and hypertension, cardiovascular disease, and kidney disease has resulted in a renewed focus and attention on this potential relationship. The virus responsible for COVID-19, SARS-CoV-2, has a direct link to one of the major enzymatic regulatory systems connected to blood pressure control and hypertension pathogenesis, the renin-angiotensin system. This is because the entry point for SARS-CoV-2 is the ACE2 (angiotensin-converting enzyme 2) protein. ACE2 is one of the main enzymes responsible for dampening the primary effector peptide Ang II (angiotensin II), metabolizing it to Ang-(1-7). A myriad of clinical questions has since emerged and are covered in this review. Several other viruses have been linked to hypertension, cardiovascular disease, and kidney health. Importantly, patients with high-risk apolipoprotein L1 (APOL1) alleles are at risk for developing the kidney lesion of collapsing glomerulopathy after viral infection. This review will highlight several emerging viruses and their potential unique tropisms for the kidney and cardiovascular system. We focus on SARS-CoV-2 as this body of literature in regards to cardiovascular disease has advanced significantly since the COVID-19 pandemic.

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David M. Cutler, PhD1

The Costs of Long COVID

https://doi.org/10.1001/jamahealthforum.2022.1809

Published

12-May-22

Article

https://jamanetwork.com/journals/jama-health-forum/fullarticle/2792505

In an October 2020 analysis, we estimated9 the then-nascent COVID-19 pandemic might result in $2.6 trillion of cost as a result of long COVID. Unfortunately, our estimate seems very much on target.
The massive cost of long COVID has several policy implications. Investing in treatments for long COVID is obviously a high priority. According to a recent report from the Rockefeller Foundation, progress to date has been “achingly slow” and that needs to change.10 Experimenting with ways to make employment easier for people with long-term complications is also a high priority. People with chronic fatigue may be better able to work at home or with frequent breaks than they can with a time-delimited office day and a long commute. By speeding up the transition to telework, enhanced employment opportunities for those with long COVID may be possible.
In addition, the economic cost of long COVID reinforces the value of comprehensive actions to prevent and treat new infections. Mask mandates are unpopular in many areas and a substantial share of the public resists being vaccinated—though each action should still be encouraged. But additional progress might also be made through expanding rapid COVID-19 test capability, global surveillance to detect new SARS-CoV-2 variants, and immediate action should any such variants be detected. Such measures have associated costs, but no matter how large these costs are, they pale compared with the potential benefits.

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Michael C. Sneller, MD, C. Jason Liang, PhD, Adriana R. Marques, MD, Joyce Y. Chung, MD, Sujata M. Shanbhag, MD, Joseph R. Fontana, MD, Haniya Raza, DO, Onyi Okeke, MD, Robin L. Dewar, PhD, Bryan P. Higgins, RN, Katie Tolstenko, FNP, Richard W. Kwan, MPAS, Kathleen R. Gittens, RN, Catherine A. Seamon, RN, Genevieve McCormack, Jacob S. Shaw, Grace M. Okpali, Melissa Law, RN, Krittin Trihemasava, Brooke D. Kennedy, Victoria Shi, MS, J. Shawn Justement, Clarisa M. Buckner, PhD, Jana Blazkova, PhD, Susan Moir, PhD, Tae-Wook Chun, PhD, and H. Clifford Lane, MD

A Longitudinal Study of COVID-19 Sequelae and Immunity: Baseline Findings

https://www.acpjournals.org/doi/full/10.7326/M21-4905

Published

24-May-22

Study

https://www.acpjournals.org/doi/full/10.7326/M21-4905

Background: A substantial proportion of persons who develop COVID-19 report persistent symptoms after acute illness. Various pathophysiologic mechanisms have been implicated in the pathogenesis of postacute sequelae of SARS-CoV-2 infection (PASC).
Objective: To characterize medical sequelae and persistent symptoms after recovery from COVID-19 in a cohort of disease survivors and controls.
Design: Cohort study. (ClinicalTrials.gov: NCT04411147)
Setting: National Institutes of Health Clinical Center, Bethesda, Maryland.
Participants: Self-referred adults with laboratory-documented SARS-CoV-2 infection who were at least 6 weeks from symptom onset were enrolled regardless of presence of PASC. A control group comprised persons with no history of COVID-19 or serologic evidence of SARS-CoV-2 infection, recruited regardless of their current health status. Both groups were enrolled over the same period and from the same geographic area.
Measurements: All participants had the same evaluations regardless of presence of symptoms, including physical examination, laboratory tests and questionnaires, cognitive function testing, and cardiopulmonary evaluation. A subset also underwent exploratory immunologic and virologic evaluations.
Results: 189 persons with laboratory-documented COVID-19 (12% of whom were hospitalized during acute illness) and 120 antibody-negative control participants were enrolled. At enrollment, symptoms consistent with PASC were reported by 55% of the COVID-19 cohort and 13% of control participants. Increased risk for PASC was noted in women and those with a history of anxiety disorder. Participants with findings meeting the definition of PASC reported lower quality of life on standardized testing. Abnormal findings on physical examination and diagnostic testing were uncommon. Neutralizing antibody levels to spike protein were negative in 27% of the unvaccinated COVID-19 cohort and none of the vaccinated COVID-19 cohort. Exploratory studies found no evidence of persistent viral infection, autoimmunity, or abnormal immune activation in participants with PASC.
Limitations: Most participants with COVID-19 had mild to moderate acute illness that did not require hospitalization. The prevalence of reported PASC was likely overestimated in this cohort because persons with PASC may have been more motivated to enroll. The study did not capture PASC that resolved before enrollment.
Conclusion: A high burden of persistent symptoms was observed in persons after COVID-19. Extensive diagnostic evaluation revealed no specific cause of reported symptoms in most cases. Antibody levels were highly variable after COVID-19.

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About D255

Aluko A. HopeAluko A. Hope

Understanding and Improving Recovery From COVID-19

https://doi.org/10.7326/M22-1492

Published

Editorial

https://www.acpjournals.org/doi/full/10.7326/M22-1492

The study results will be unsurprising to clinicians who have been seeing a high volume of patients with PASC. First, participants with PASC reported more symptoms and worse physical and mental health status than COVID-19 survivors without PASC or control participants. Patients with PASC reported a median of 2 (IQR, 1 to 4) symptoms, with the most common being fatigue, dyspnea, changes in smell, cognitive changes, and sleep changes. Second, the investigators found few differences between COVID-19 survivors and control participants in objective tests, such as physical examination, neurocognitive assessment, and plasma inflammatory biomarkers. Importantly, they found no differences in the levels of immunologic markers that might indicate a potential immunologic mechanism for PASC.
This is a small study of a group of highly motivated participants, and these findings should not lead to changes in clinical care. However, the study's strengths include that the extensive evaluations performed as part of the study protocol mirror the often exhaustive and expensive evaluations that many patients with PASC get when they seek care. After these patients endure these evaluations, they are often told that everything is normal and nothing is wrong, implying that their subjective reports are less credible than the objective findings. Unfortunately, this study did not attempt to measure an important symptom complex that many believe is the hallmark of PASC: postexertional symptom exacerbation, or postexertional malaise (PEM) (4, 9). This refers to worsening of the patient's fatigue, cognitive changes, and other symptoms after physical, cognitive, social, or emotional exertion. Patients report that the worsening is often delayed from the onset of the trigger and out of proportion to the degree of exertion. Practically, acknowledging the importance of PEM means that detailed subjective and objective assessments need to account for the fact that patients' symptoms and performance may change dramatically depending on whether they are in a restful or stressful state. In addition, assessment of PEM needs to consider stressful states in the context of a patient's pre–COVID-19 level of function and fitness across multiple health domains. Future studies need to better capture these issues.
Although the investigators aimed to enroll post–COVID-19 participants with a wide spectrum of initial disease severity and without regard for the presence or absence of PASC, the nature of their recruitment process may have led to overrepresentation of patients with higher levels of physical function who were nevertheless worried about persistent symptoms. Importantly, the control participants were not matched on age or gender, and the investigators conducting the physical examinations were not blinded to study group. Although their definition of PASC has face validity, the investigators did not consider how other more restrictive definitions would have affected their findings. Their approach to identifying comorbid conditions, such as anxiety, in the study sample likely overrepresented this diagnosis in patients with PASC given that central or peripheral autonomic impairment is a common feature of many postviral fatigue syndromes and is often misdiagnosed as an anxiety syndrome. Because most of the study enrollment occurred before the advent of COVID-19 vaccines, these findings may not be generalizable to a population of fully vaccinated adults.
As we emerge from the hell of the COVID-19 pandemic, it is time to insist on painstaking study and care of survivors of COVID-19. Without a fuller understanding of pathophysiology and disease course, we must not allow normal objective tests to negate our patients' subjective experiences. We need to explore whether real-world measurements during both restful and stressful conditions offer insight into the mechanisms of PASC. While we gather evidence, our patients deserve personalized care pathways that acknowledge the many biopsychosocial factors involved in illness recovery.

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D. Castanares-ZapateroORCID Icon,P. Chalon,L. Kohn,M. Dauvrin,J. Detollenaere,C. Maertens de Noordhout,C. Primus-de Jong,I. Cleemput &K. Van den Heede show less

Pathophysiology and mechanism of long COVID: a comprehensive review

https://doi.org/10.1080/07853890.2022.2076901

Published

20-May-22

Review

https://www.tandfonline.com/doi/full/10.1080/07853890.2022.2076901

Background: After almost 2 years of fighting against SARS-CoV-2 pandemic, the number of patients enduring persistent symptoms long after acute infection is a matter of concern. This set of symptoms was referred to as “long COVID”, and it was defined more recently as “Post COVID-19 condition” by the World health Organization (WHO). Although studies have revealed that long COVID can manifest whatever the severity of inaugural illness, the underlying pathophysiology is still enigmatic.
Aim: To conduct a comprehensive review to address the putative pathophysiology underlying the persisting symptoms of long COVID.
Method: We searched 11 bibliographic databases (Cochrane Library, JBI EBP Database, Medline, Embase, PsycInfo, CINHAL, Ovid Nursing Database, Journals@Ovid, SciLit, EuropePMC, and CoronaCentral). We selected studies that put forward hypotheses on the pathophysiology, as well as those that encompassed long COVID patients in their research investigation.
Results: A total of 98 articles were included in the systematic review, 54 of which exclusively addressed hypotheses on pathophysiology, while 44 involved COVID patients. Studies that included patients displayed heterogeneity with respect to the severity of initial illness, timing of analysis, or presence of a control group. Although long COVID likely results from long-term organ damage due to acute-phase infection, specific mechanisms following the initial illness could contribute to the later symptoms possibly affecting many organs. As such, autonomic nervous system damage could account for many symptoms without clear evidence of organ damage. Immune dysregulation, auto-immunity, endothelial dysfunction, occult viral persistence, as well as coagulation activation are the main underlying pathophysiological mechanisms so far.
Conclusion: Evidence on why persistent symptoms occur is still limited, and available studies are heterogeneous. Apart from long-term organ damage, many hints suggest that specific mechanisms following acute illness could be involved in long COVID symptoms.
KEY MESSAGES
Long-COVID is a multisystem disease that develops regardless of the initial disease severity. Its clinical spectrum comprises a wide range of symptoms.
The mechanisms underlying its pathophysiology are still unclear. Although organ damage from the acute infection phase likely accounts for symptoms, specific long-lasting inflammatory mechanisms have been proposed, as well.
Existing studies involving Long-COVID patients are highly heterogeneous, as they include patients with various COVID-19 severity levels and different time frame analysis, as well.

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A.Menard1M.Chine2L.Meddeb1P.Rossi2

Du suivi Post-Covid au Covid-Long : Score pronostic à partir d'une prise en charge holistique

https://doi.org/10.1016/j.mmifmc.2022.03.125

Published

31-May-22

Study

https://www.sciencedirect.com/science/article/pii/S277274322200143X

Introduction
Le COVID long est un problème de santé publique émergent manquant à ce jour d'une définition claire (OMS). Les médecins généralistes, en première ligne, aurait besoin d'un outil holistique, reproductible et facile pour les aider à évaluer le pronostic d'évolution vers un Covid-long chez leur patient ayant contracté une infection par le Sars-Cov-19
Matériels et méthodes
Depuis mai 2020 dans notre centre un suivi standardisé (tous les 3 mois) et pluri disciplinaire est proposé aux patients ayant fait une forme sévère (post hospitalisation) ou ambulatoire mais avec symptômes persistants. Ils sont inclus dans une cohorte de suivi longitudinale avec un recueil à chaque visite des auto questionnaires (qualité de vie : SF36, fatigue : Pichot,dyspnée : MRC,Borg, cognitifs : MoCa, Stress : SSPT) un examen clinique exhaustif, des avis spécialisés avec bilan sanguin et imagerie selon l'évolution. L'objectif de notre étude est de décrire l'ensemble de nos données sur les caractéristiques socio-clinico-biologiques des patients inclus (J0) avec au moins une consultation de suivi Post Covid > à 4 semaines (S4) ayant évolué ou pas vers un Covid-Long ( > 12S) pour construire un score composite du Covid-Long.
Résultats
201 patients ont été inclus, 190 analysés dont 55 % de femmes, d'âge médian de 55 ans, actif dans 60 % des cas (24 % domaine santé), 58 % avec une comorbidité à risque de forme sévère. L'épisode aigue en ambulatoire pour 85 (42.2 %) patients, en hospitalisation conventionnelle pour 76 (37.8 %) ou en soins intensif/réanimation pour 40 (20 %). Une corticothérapie et une oxygénothérapie ont été prescrite pour respectivement 78 (38.8 %) et 114 (56.7 %). 49 (24.4 %) patients ont décompensé ou découvert (7 %) une maladie chronique. En moyenne les patients ont eu 2,6 visites et 48 % d'entre eux ont un suivi de plus de 12 mois. A S12 du suivi, 122 patients ont le statut de COVID Long (CL+) avec un nb moyen de symp = 3,6+/-2,2 (1-10) et 68 sont guéris (CL-). En analyse uni variée les FDR de CL+/CL- sont 1) le sexe féminin (p=0.004), un âge< à 65 ans (p=0.002) et être personnel de santé (p=0.022). 2) à J0 : anosmie/agueusie (p=0.011), myalgies (p=0.041) et épisode initiale ambulatoire (p=0.002). 3) à S4 : une dyspnée [échelle de Borg ≥ 3 (p=0.003)+ mMRC ≥ 1 (p=0.036)] et une Fatigue sévère [Pichot ≥ 20 (p<0.001)]. Dans le modèle de régression logistique multivariée, les FDR de CL+ sont à J0 d'avoir un âge < à 65 ans et fait un COVID aigue peu sévère avec prise en charge en ambulatoire avec respectivement OR 2.4 (IC95 : [1.0 ; 5.4]) et OR 2.3 (IC95 : [2.3 ; 4.6]). 2) à S4 post COVID d'avoir des difficultés cognitives OR 6.046 (IC95 : [1.82 ; 20.1]) et les signes fonctionnels psychiatriques OR 5.9 (IC95 : [1.7 ; 20.4]) ainsi qu'une Fatigue sévère OR 5.4 (IC95 : [1.2 ; 24.1]). En modélisant nos résultats nous avons construit un score composite comme outil pronostique de Covid-Long. Dans la formule chaque item en gras devra etre remplacé par 0 ou1 selon abscence ou presence, femme (1) et age en chiffre.
=1/(1+(EXP((-1)*((-2,745)+(-0,329)*Femme+0,005*AgeQuantitatif +0,589*ambulatoire +(-0,418)*FDR-HCSP+0,9*Symptômes<5+(0,181)*Borg > 3+0,263*mMRC > 1+1,694*Pichot > 20+1,72*anosmie/agueusie+1,799*DifficultésCognitives+1,766*SymptomesPsychiatriques+2,008*DiagnosticDifferentiel)))
Conclusion
Ce score, apres une validation externe, nous permettra d'évaluer le pourcentage de risque d'évoluer vers un COVID long qu'aura chaque patient d'après ses données du J0 et de sa première consultation post covid. Cette étude objective à nouveau la nécessité de chercher à la fois la présence des symptômes mais aussi de les quantifier par des échelles simples et reproductibles.

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Haider, Saman1; Janowski, Adam J.1; Lesnak, Joseph B.1; Hayashi, Kazuhiro1; Dailey, Dana L.2; Chimenti, Ruth1; Frey-Law, Laura A.1; Sluka, Kathleen A.1,*

A comparison of pain, fatigue, and function between post-COVID-19 condition, fibromyalgia, and chronic fatigue syndrome: a survey study

https://doi.org/10.1097/j.pain.0000000000002711

Published

8-Jun-22

Study

https://journals.lww.com/pain/Abstract/9900/A_comparison_of_pain,_fatigue,_and_function.115.aspx

A growing number of individuals report prolonged symptoms following acute COVID-19 infection, known as post-COVID-19 condition (post-COVID-19). While studies have emerged investigating the symptom sequelae of post-COVID-19, there has been limited investigation into the characterization of pain, fatigue, and function in these individuals, despite initial reports of a clinical phenotype similar to fibromyalgia (FMS) and chronic fatigue syndrome/myalgic encephalomyelitis (CFS). This study aimed to characterize multiple symptom domains in individuals reporting post-COVID-19 and compare its clinical phenotype to those with FMS and CFS. A total of 707 individuals with a single or comorbid diagnosis of post-COVID-19, FMS, and/or CFS completed multiple surveys assessing self-reported pain, fatigue, physical and cognitive function, catastrophizing, kinesiophobia, anxiety, depression, dyspnea, and sleep quality. In all three diagnoses, elevated pain, fatigue, anxiety, depression, catastrophizing, and kinesiophobia were reported. Physical and cognitive function were similarly impacted among individuals with post-COVID-19, FMS, and CFS; however, individuals with post-COVID-19 reported lower pain and fatigue than FMS and CFS. The comorbid diagnosis of post-COVID-19 with FMS and/or CFS further exacerbated pain, fatigue, and psychological domains when compared to post-COVID-19 alone. In summary, individuals with post-COVID-19 report a symptom phenotype similar to FMS and CFS, negatively impacting cognitive and physical function, but with less severe pain and fatigue overall. These findings may help direct future investigations of the benefit of a biopsychosocial approach to the clinical management of post-COVID-19.

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Chen Chen, Spencer R. Haupert, Lauren Zimmermann, Xu Shi, Lars G. Fritsche, Bhramar Mukherjee

Global Prevalence of Post-Coronavirus Disease 2019 (COVID-19) Condition or Long COVID: A Meta-Analysis and Systematic Review

https://doi.org/10.1093/infdis/jiac136

Published

16-Apr-22

Review

https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiac136/6569364

Background
This study aims to examine the worldwide prevalence of post-coronavirus disease 2019 (COVID-19) condition, through a systematic review and meta-analysis.
Methods
PubMed, Embase, and iSearch were searched on July 5, 2021 with verification extending to March 13, 2022. Using a random-effects framework with DerSimonian-Laird estimator, we meta-analyzed post-COVID-19 condition prevalence at 28+ days from infection.
Results
Fifty studies were included, and 41 were meta-analyzed. Global estimated pooled prevalence of post-COVID-19 condition was 0.43 (95% confidence interval [CI], .39–.46). Hospitalized and nonhospitalized patients had estimates of 0.54 (95% CI, .44–.63) and 0.34 (95% CI, .25–.46), respectively. Regional prevalence estimates were Asia (0.51; 95% CI, .37–.65), Europe (0.44; 95% CI, .32–.56), and United States of America (0.31; 95% CI, .21–.43). Global prevalence for 30, 60, 90, and 120 days after infection were estimated to be 0.37 (95% CI, .26–.49), 0.25 (95% CI, .15–.38), 0.32 (95% CI, .14–.57), and 0.49 (95% CI, .40–.59), respectively. Fatigue was the most common symptom reported with a prevalence of 0.23 (95% CI, .17–.30), followed by memory problems (0.14; 95% CI, .10–.19).
Conclusions
This study finds post-COVID-19 condition prevalence is substantial; the health effects of COVID-19 seem to be prolonged and can exert stress on the healthcare system.

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Diane E. Griffin

Why does viral RNA sometimes persist after recovery from acute infections?

https://doi.org/10.1371/journal.pbio.3001687

Published

1-Jun-22

Article

https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001687

DNA viruses often persist in the body of their host, becoming latent and recurring many months or years later. By contrast, most RNA viruses cause acute infections that are cleared from the host as they lack the mechanisms to persist. However, it is becoming clear that viral RNA can persist after clinical recovery and elimination of detectable infectious virus. This persistence can either be asymptomatic or associated with late progressive disease or nonspecific lingering symptoms, such as may be the case following infection with Ebola or Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Why does viral RNA sometimes persist after recovery from an acute infection? Where does the RNA come from? And what are the consequences?

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JUSTIN J. FRERE RANDAL A. SERAFINI KERRI D. PRYCE MARIANNA ZAZHYTSKAKOHEI OISHI ILONA GOLYNKER MARYLINE PANISJEFFREY ZIMERING SHU HORIUCHI DAISY A. HOAGLAND RASMUS MØLLER ANNE RUIZ ALBANA KODRA JONATHAN B. OVERDEVEST PETER D. CANOLLALAIN C. BORCZUKVASURETHA CHANDARYARON BRAM ROBERT SCHWARTZ STAVROS LOMVARDAS VENETIA ZACHARIOU AND BENJAMIN R. TENOEVER

SARS-CoV-2 infection in hamsters and humans results in lasting and unique systemic perturbations post recovery

https://doi.org/10.1126/scitranslmed.abq3059

Published

7-Jun-22

Study

https://www.science.org/doi/10.1126/scitranslmed.abq3059

The host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in prolonged pathologies collectively referred to as post-acute sequalae of COVID-19 (PASC) or long COVID. To better understand the mechanism underlying long COVID biology, we compared the short- and long-term systemic responses in the golden hamster following either SARS-CoV-2 or influenza A virus (IAV) infection. Results demonstrated that SARS-CoV-2 exceeded IAV in its capacity to cause permanent injury to the lung and kidney and uniquely impacted the olfactory bulb (OB) and epithelium (OE). Despite a lack of detectable infectious virus, the OB and OE demonstrated myeloid and T cell activation, proinflammatory cytokine production, and an interferon response that correlated with behavioral changes extending a month post viral clearance. These sustained transcriptional changes could also be corroborated from tissue isolated from individuals who recovered from COVID-19. These data highlight a molecular mechanism for persistent COVID-19 symptomology and provide a small animal model to explore future therapeutics.

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MonaSadat Larijania1FatemehAshrafiana1FahimehBagheri AmiribMohammadBanifazlcAnahitaBavandaAfsanehKaramidFatemehAsgari ShokoohaAmitisRamezania

Characterization of long COVID-19 manifestations and its associated factors: A prospective cohort study from Iran

https://doi.org/10.1016/j.micpath.2022.105618

Published

11-Jun-22

Study

https://www.sciencedirect.com/science/article/pii/S0882401022002315

Highlights
•Post-COVID-19 could possibly initiate long after full recovery and different window time.
•Different manifestations of SARS-CoV-2 may not be resolved fully.
•According to our findings, no association found between the patients' clinical history and COVID-19 long term side effects.
•Unpredictable outcomes post-COVID-19 vaccination draw attentions as well as the viral effects.
The prevalence and variety complaints of COVID-19 cases in a long term have been investigated in recent studies. The symptoms over the time are various and unpredictable which may persist several weeks after full recovery. The importance of long-COVID-19 manifestations includes its effect on the recovered cases which requires a rational management based on an accurate guideline to handle post-acute COVID-19 state. The aim of this study was to evaluate the incidence of post-acute COVID-19 syndrome and to identify the associated risk factors as well as to compare new and persistent symptoms at different post-acute phases.
Totally 254 individuals from Pasteur Institute of Iran (or/and their relatives) were investigated who had a previously confirmed COVID-19 PCR test. The long-term manifestations of the virus were categorized through a time window as acute, ongoing, post-COVID and persistent phases and the individuals were assessed by the face-to-face or the phone call interview according to their complaints. The data were then statistically analyzed to determine the frequency of the symptoms and also the associated factors in which a p value < 0.05 was considered significant.
Except a small asymptotic group of five, 249 cases progressed the symptoms to acute phase among which 64.1% reported at least one symptom in post-acute phase. Neurological sequelae were found as the most frequent symptom (91.6%). Furthermore, there was a significant association between the underlying diseases, age and acute phase symptoms to the post-acute phase syndrome susceptibility (p < 0.05).
In conclusion, the increasing number of the reports and studies on long COVID-19 which can hugely affect the life quality should be more investigated and explored in terms of the pathophysiology to achieve appropriate treatments in time. The clusters of symptoms, specially a combination of neurological signs, presenting over months after the recovery impose a huge difficulty to the recovered population.

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Chengliang Yang
Hedi Zhao
Scott J Tebbutt

A glimpse into long COVID and symptoms

https://doi.org/10.1016/S2213-2600(22)00217-X

Published

10-Jun-22

CORRESPONDENCE

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00217-X/fulltext

Long COVID has significant implications for individuals, health-care systems, and society. Those affected might have reduced functional capacity and cognitive and physical limitations, ultimately resulting in reduced autonomy and increased dependency on caregivers and other societal supports. Hence, more comprehensive understanding of long COVID would aid policymakers and health-care systems in developing, implementing, and evaluating future policies and health resource planning reflective of the population's needs. In The Lancet Respiratory Medicine, Lixue Huang and colleagues1 addressed this topic in a longitudinal follow-up of patients after SARS-CoV-2 infection during the early phase of the COVID-19 pandemic (between January, 2020, and May, 2021). To date, this study has the longest duration of follow-up for post-COVID-19 outcomes in patients who survived hospitalisation for COVID-19. Still, many questions remain about the reported symptoms of long COVID, and the people who continue to live with it.
Persistent physical symptoms attributed to COVID-19 might not be specific to SARS-CoV-2 infection.2 Knowledge of previous SARS-CoV-2 infection might increase a person's likelihood of experiencing persistent physical symptoms—either by affecting perception of symptoms that might have predated the infection or by promoting maladaptive health behaviours, such as reducing physical activity or dietary exclusion, in an effort to improve health.2 It is therefore crucial to delineate individual symptom manifestations before and after infection, in addition to the overall dynamics of COVID-19 symptomatology in infected populations during this pandemic.
Huang and colleagues1 stated that their questionnaires included the SARS-CoV-2 vaccination survey, blood specimens for complete blood count, renal function, liver function, lipid test, and routine urine;1 however, the results of these laboratory studies were omitted. Furthermore, whether self-reported symptoms of chest pain and palpitations were corroborated by objective clinical and diagnostic findings was unclear. It might be useful to have a separate analysis of respondents with or without chronic diseases such as chronic kidney disease or chronic obstructive pulmonary disease to delineate whether these affect the degree of symptomatology. The omicron variant of SARS-CoV-2 (B.1.1.529 and its sublineages) has a higher risk of reinfection compared with the other variants.3 Reinfection information of relevance to these patients could help clarify the effect of long COVID among survivors.
COVID-19 survivors at 2 years had more problems with fatigue, muscle weakness, sleep difficulties, dizziness, headache, and myalgia than COVID-19 survivors at 1 year.1 There is increasing evidence for brain-related injuries in patients with COVID-19.4, 5 Even mild COVID-19 is linked to brain damage, which might provide insight into neurological or cognitive symptoms such as difficulty concentrating, trouble sleeping, memory loss, or confusion associated with long COVID.4 This might be one of the particularly relevant issues in long COVID pathogenesis,6 warranting further investigation. Moreover, many of these symptoms might be further exacerbated by physical deconditioning or sedentary behaviours, a history of smoking or alcohol consumption, pregnancy, or an overall shift to work-from-home structures. Furthermore, it would be important to capture not only the symptom presence, but the degree of impairment associated with these symptoms, whether it might be due to loss of work productivity or increased health-care use. It would be important to address not only the symptoms, but also the associations with various contributing factors to better characterise the populations at risk. This information would allow for better generalisation and the proposal of future strategies to mitigate the effects of long COVID.

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Lixue Huang
Xiaoying Gu
Hui Zhang
Bin Cao

A glimpse into long COVID and symptoms – Authors' reply

https://doi.org/10.1016/S2213-2600(22)00212-0

Published

10-Jun-22

CORRESPONDENCE

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00212-0/fulltext

In our study, we described the dynamics of long COVID symptoms in COVID-19 survivors with various disease severities, which was one of our main research objectives.1 In their Correspondence, Chengliang Yang and colleagues noted that delineating individual symptom manifestations at pre-infection and post-infection timepoints is important because some physical symptoms might have been present before SARS-CoV-2 infection. We agree with Yang and colleagues on this matter, and their suggestion that this information could help to find excess symptom burden post-SARS-CoV-2 infection. In our study, to address the problem that some symptoms might have been present before COVID-19, sequelae symptoms were defined as those that were newly occurring and persistent, or worse than the status before getting COVID-19, and could not be explained by an alternative disease.
The sequelae symptoms observed in our study, including the physical symptoms mentioned by Yang and colleagues, might not be specific to SARS-CoV-2 infection, which was acknowledged as a limitation in our published Article.1 It is not only quite challenging to distinguish whether the observed physical symptoms were direct effects of COVID-19 or not, but also the degree of impairment related to these symptoms. To the best of our knowledge, no validated symptom questionnaire was available at the time of our study. There are also several limitations of self-reported symptom surveys, including information bias and difficulty of objective diagnosis of subjective symptoms (eg, chest pain and palpitations). We mentioned the potential information bias of using self-report symptom questionnaires in our Article.1
We did laboratory tests at three follow-up visits, including complete blood count, renal function, liver function, lipid test, and routine urine. The laboratory findings of 1164 COVID-19 survivors who completed 6-month and 12-month follow-up visits were shown in the appendix (table S5) of our previously published Article.2 Most survivors showed normal ranges for the laboratory indicators. Due to data insufficiency before COVID-19, it was difficult to interpret the observed laboratory abnormalities among some participants at follow-up because some results might have been new or persistent; thus, we did not show laboratory findings in our 2-year follow-up study. As for SARS-CoV-2 vaccination, of the 1294 COVID-19 survivors who participated in face-to-face interviews at the 2-year follow-up, 1054 (81·5%) were vaccinated, and 705 (54·5%) received at least two doses. The 2-year follow-up was completed on Jan 10, 2022, which, to our knowledge, predated the emergence of the first case of COVID-19 caused by omicron (B.1.1.529) in Wuhan. We cannot provide reinfection information of omicron with data already obtained, but we hope to answer related questions in a future follow-up study.
Specific abnormalities after mild SARS-CoV-2 infection could be helpful to uncover the pathogenesis of long COVID, including brain damage,3 increased risk of cardiovascular event,4 or diabetes.5 There are several hypotheses related to the pathogenesis of long COVID, including persistent virus or viral antigens and RNA in tissues that drive chronic inflammation, the triggering of autoimmunity after acute viral infection, dysbiosis of the microbiome or virome, and unrepaired tissue damage.6 There is still a long way to go to fully understand the pathogenesis of COVID-19; and once more knowledge is accumulated, this new evidence might also apply to the study of inflammatory processes that are involved in other respiratory infections.

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Diana Araja *ORCID,Uldis Berkis andModra MurovskaORCID

COVID-19 Pandemic-Revealed Consistencies and Inconsistencies in Healthcare: A Medical and Organizational View

https://doi.org/10.3390/healthcare10061018

Published

31-May-22

Study

https://www.mdpi.com/2227-9032/10/6/1018/htm

The circumstances of the Coronavirus disease caused by the SARS-CoV-2 virus (COVID-19) pandemic have had a significant impact on global and national developments, affecting the existence of society in all its expressions, as well as the lives of people themselves. In the context of the pandemic, increased attention has been focused on acute measures, but the ending of the pandemic is expected as a resolution of the related healthcare problems. However, there are several indicators that the COVID-19 pandemic might induce long-term consequences for individual and public health. Some of the consequences are inferred and predictable, but there are also areas of medicine that have been indirectly affected by the pandemic, and these consequences have not yet been sufficiently explored. This study is focused on drawing attention to some of the COVID-19 pandemic consistencies and the pandemic-revealed inconsistencies in healthcare. Content analysis and statistical analysis were applied to achieve the aim of the study. The main findings of the study address chronic disease burden (particularly, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)), healthcare governance and organizational issues, and the synergy between health policy perspectives and innovative solutions in practice. The study provides insight into the particular healthcare issues affected by the COVID-19 pandemic, such as the increase in mortality in some diagnoses besides COVID-19 and the possible emergence of a new type of resistance—vaccine-resistance—contemporaneously supporting the identification of the tendencies and currently unnoticed indirect consistencies and inconsistencies revealed by the pandemic.

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Diana Duong

The evolving picture of long COVID

https://doi.org/10.1503/cmaj.1096004

Published

19-Jun-22

Article

https://www.cmaj.ca/content/194/24/E850

Some big remaining questions
Researchers have to account for a large number of factors as both COVID-19 and the global pandemic response evolves. People exposed to SARS-CoV-2 in the spring of 2020 — before vaccines, variants, and new therapeutics — may not experience the same long-haul symptoms as those exposed during the later Delta and Omicron waves.
There also needs to be more understanding of the mechanism of the disease, which could open a door to potential treatment, says Alain Piché, a microbiologist, infectious disease physician, and director of a post-COVID clinic in Sherbrooke.
“At this point, we really need new drugs or known drugs that will be effective against long COVID, because I’m seeing so many patients that have a huge impairment on their daily lives,” he says.
“They cannot work, they cannot take care of themselves, they need somebody around, they forget things, they cannot concentrate, they cannot live a normal life anymore. Unfortunately, these patients are severely impaired and this is too common. I’ve seen so many of these patients and there are few things that we can do to help them besides trying to ease some of the symptoms.”
Piché hopes that studies like Cheung’s RECLAIM study as well as several others around the world — which hopefully will be available within the next year to 18 months — will provide much-needed answers.

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Daniel Munblit, PhD *
Timothy Nicholson, PhD *
Athena Akrami, PhD
Christian Apfelbacher, PhD
Jessica Chen, BSc
Wouter De Groote, PhD
Janet V Diaz, MD
Sarah L Gorst, PhD
Nicola Harman, PhD
Alisa Kokorina, BSc
Piero Olliaro, PhD
Callum Parr, BSc
Jacobus Preller, MD
Nicoline Schiess, MD
Jochen Schmitt, MD
Nina Seylanova, MD
Frances Simpson, MSc
Allison Tong, PhD
Prof Dale M Needham, MD *
Paula R Williamson, PhD *

A core outcome set for post-COVID-19 condition in adults for use in clinical practice and research: an international Delphi consensus study

https://doi.org/10.1016/S2213-2600(22)00169-2

Published

14-Jun-22

Article

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00169-2/fulltext

Health consequences that persist beyond the acute infection phase of COVID-19, termed post-COVID-19 condition (also commonly known as long COVID), vary widely and represent a growing global health challenge. Research on post-COVID-19 condition is expanding but, at present, no agreement exists on the health outcomes that should be measured in people living with the condition. To address this gap, we conducted an international consensus study, which included a comprehensive literature review and classification of outcomes for post-COVID-19 condition that informed a two-round online modified Delphi process followed by an online consensus meeting to finalise the core outcome set (COS). 1535 participants from 71 countries were involved, with 1148 individuals participating in both Delphi rounds. Eleven outcomes achieved consensus for inclusion in the final COS: fatigue; pain; post-exertion symptoms; work or occupational and study changes; survival; and functioning, symptoms, and conditions for each of cardiovascular, respiratory, nervous system, cognitive, mental health, and physical outcomes. Recovery was included a priori because it was a relevant outcome that was part of a previously published COS on COVID-19. The next step in this COS development exercise will be to establish the instruments that are most appropriate to measure these core outcomes. This international consensus-based COS should provide a framework for standardised assessment of adults with post-COVID-19 condition, aimed at facilitating clinical care and research worldwide.

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Hans Henri P.KlugeaNatasha AzzopardiMuscataContribution from -SatishMishraaSusanneNielsenaFlorianTilleaDinaPfeiferaLongCOVID EuropebManojSivana

Call for action: Health services in the European region must adopt integrated care models to manage Post-Covid-19 Condition

https://doi.org/10.1016/j.lanepe.2022.100435

Published

22-Jun-22

Article

https://www.sciencedirect.com/science/article/pii/S2666776222001296?via%3Dihub

Success in this pandemic is not only developing new diagnostics, treatments and vaccinations to prevent hospitalisations and deaths, but also ensuring provision of accessible, affordable and individualised long-term rehabilitative care, thereby reducing disease burden and restoring best quality of life for the affected population.
In a call for action, the recommendation is to:
•Build capacity for early identification and recognition of symptoms of Post-Covid-19 Condition.
•Strengthen primary health care to manage Post-Covid-19 Condition when medically indicated, and to be the point of referral for more severe cases.
•Acknowledge the need for individualized long-term rehabilitative care for persons with Post-Covid-19 Condition.
•Strengthen the health system to be able to provide an individualised multidisciplinary care pathway in which patient's multi-system symptoms and rehabilitation needs are assessed and managed, informed by real world outcome data and patient experience.

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Toluwalase Awoyemi, Ujunwa Ebili, Abiola Olusanya, Kayode E. Ogunniyi, Adedolapo V. Adejumo

Twitter Sentiment Analysis of Long COVID Syndrome

https://doi.org/10.7759/cureus.25901

Published

13-Jun-22

Study

https://www.cureus.com/articles/99095-twitter-sentiment-analysis-of-long-covid-syndrome

Background
Long COVID syndrome originated as a patient phrased terminology which was initially used to describe a group of vague symptoms that persisted after recovering from COVID-19. However, it has moved from a patient lingo to a recognized pathological entity which refers to a group of symptoms that lasts weeks or months after the COVID-19 illness. The novelty of this condition, the inadequacy of research on long COVID syndrome, and its origin as a patient-coined terminology necessitated exploring the disease's sentiments and conversations by analyzing publicly available tweets.
Method
Tweets were extracted using the Twarc2 tool for tweets in the English language with the keywords (long COVID syndrome, long COVID, post-COVID syndrome, post-acute sequelae of SARS-CoV-2, long-term COVID, long haulers, and chronic COVID syndrome) between March 25, 2022, and April 1, 2022. The analyses included frequency of the keywords, sentiment analysis, and topic modeling to identify and explore discussion topics over time. A natural language approach and the latent Dirichlet allocation algorithm were used to determine the most shared tweet topics, categorize clusters, and identify themes based on keyword analysis.
Results
The search yielded 62,232 tweets. The tweets were reduced to 10,670 tweets after removing the duplicates. The vast majority of the tweets originated from the United States of America (38%), United Kingdom (30%), and Canada (13%), with the most common hashtags being #longcovid (36%) and #covid (6.36%), and the most frequently used word being people (1.05%). The top three emotions detected by our analysis were trust (11.68%), fear (11.26%), and sadness (9.76%). The sentiment analysis results showed that people have comparable levels of positivity (19.90%) and negativity (18.39%) towards long COVID.
Conclusions
Our analysis revealed comparable sentiments about long COVID syndrome, albeit slightly positive. Most tweets connoted trust (positive), fear (negative), and sadness (negative). These emotions were linked with concerns about the infection, pandemic, chronic disability, and governmental policies. We believe this study would be important in guiding information dissemination and governmental policy implementation necessary in tackling long COVID syndrome.

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Christina PagelChristina Pagel

The covid waves continue to come

https://doi.org/10.1136/bmj.o1504

Published

17-Jun-22

Opinion

https://www.bmj.com/content/377/bmj.o1504

Omicron continues to drive waves of covid infections, writes Christina Pagel, but let’s not give up trying to control transmission
We are just over five months into 2022 and have already seen two record highs of coronavirus infection in England, with population prevalence peaking at 7% in early January (omicron BA.1) and 8% in late March (omicron BA.2).1 After eight weeks of declining prevalence, infections have started to increase again with the rise of yet another set of omicron variants. Instead of just one new variant, we currently have four: BA.2.12.1 (dominant in the US), BA.4 and BA.5 (dominant in South Africa), and BA.5.1 (dominant in Portugal). Together, these four variants became dominant in England in early June,2 and it looks as if BA.5 and BA.5.1 will likely win out to become the overall dominant variants.3 So what does this mean for the shorter and longer term?
In the short term, we will see another wave of infections here, likely peaking at the end of June/early July. South Africa’s BA.4/5 wave has now passed, with fewer hospital admissions and deaths than in their BA.1 wave in December. Portugal’s BA.5 wave looks to have just peaked, with a similar magnitude of deaths and hospital admissions to their first omicron BA.1 wave. While omicron BA.2 became dominant in both South Africa and Portugal, it did not result in a second large wave of infections.4 It did, however, in England and we will be the first (but not the last) big country to have a BA.4/5 wave after having had two previous omicron waves (BA.1 and BA.2). This means that we might get some additional protection from the high number of infections we had in March, which will reduce the size of this coming wave. Nonetheless, a significant proportion of the country will get sick, especially as the population’s immunity from boosters is waning.
While omicron might be somewhat less severe than delta, and people have higher immunity through vaccination and previous infection, it is not mild. At a population level, its sheer transmissibility more than compensates for any reduction in experienced disease severity or symptoms for the individual. For instance, in the five months of the omicron era since 1 January 2022, almost 20 000 people have died with covid-19 mentioned on their death certificate.5 Almost exactly the same number of people had it mentioned on their death certificate in the six months that delta was dominant in England in 2021—but we have just started yet another omicron wave and so deaths from this variant will rise still further.

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McSpedon, Corinne

Long COVID: What We Know Now

https://doi.org/10.1097/01.NAJ.0000842232.15530.f1

Published

23-Jun-22

Article

https://journals.lww.com/ajnonline/Fulltext/2022/07000/Long_COVID__What_We_Know_Now.18.aspx

A growing population struggles with ongoing health problems.
An overview of this emerging health issue—and what's being done to study and address it.

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Lisa Langnickel, Johannes Darms, Katharina Heldt, Denise Ducks, Juliane Fluck

Continuous development of the semantic search engine preVIEW: from COVID-19 to long COVID

https://doi.org/10.1093/database/baac048

Published

1-Jul-22

Study

https://academic.oup.com/database/article/doi/10.1093/database/baac048/6625658

preVIEW is a freely available semantic search engine for Coronavirus disease (COVID-19)-related preprint publications. Currently, it contains >43 800 documents indexed with >4000 semantic concepts, annotated automatically. During the last 2 years, the dynamic situation of the corona crisis has demanded dynamic development. Whereas new semantic concepts have been added over time—such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of interest—the service has been also extended with several features improving the usability and user friendliness. Most importantly, the user is now able to give feedback on detected semantic concepts, i.e. a user can mark annotations as true positives or false positives. In addition, we expanded our methods to construct search queries. The presented version of preVIEW also includes links to the peer-reviewed journal articles, if available. With the described system, we participated in the BioCreative VII interactive text-mining track and retrieved promising user-in-the-loop feedback. Additionally, as the occurrence of long-term symptoms after an infection with the virus SARS-CoV-2—called long COVID—is getting more and more attention, we have recently developed and incorporated a long COVID classifier based on state-of-the-art methods and manually curated data by experts. The service is freely accessible under https://preview.zbmed.de

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Olalekan Lee Aiyegbusi
Applied Health Research

A core outcome set for post-COVID-19 condition in adults for use in clinical practice and research: an international Delphi consensus study

https://doi.org/10.1016/S2213-2600(22)00169-2

Published

14-Jun-22

Study

https://research.birmingham.ac.uk/en/publications/a-core-outcome-set-for-post-covid-19-condition-in-adults-for-use-

Health consequences that persist beyond the acute infection phase of COVID-19, termed post-COVID-19 condition (also commonly known as long COVID), vary widely and represent a growing global health challenge. Research on post-COVID-19 condition is expanding but, at present, no agreement exists on the health outcomes that should be measured in people living with the condition. To address this gap, we conducted an international consensus study, which included a comprehensive literature review and classification of outcomes for post-COVID-19 condition that informed a two-round online modified Delphi process followed by an online consensus meeting to finalise the core outcome set (COS). 1535 participants from 71 countries were involved, with 1148 individuals participating in both Delphi rounds. Eleven outcomes achieved consensus for inclusion in the final COS: fatigue; pain; post-exertion symptoms; work or occupational and study changes; survival; and functioning, symptoms, and conditions for each of cardiovascular, respiratory, nervous system, cognitive, mental health, and physical outcomes. Recovery was included a priori because it was a relevant outcome that was part of a previously published COS on COVID-19. The next step in this COS development exercise will be to establish the instruments that are most appropriate to measure these core outcomes. This international consensus-based COS should provide a framework for standardised assessment of adults with post-COVID-19 condition, aimed at facilitating clinical care and research worldwide.

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Shankar, R
Perera, B
Roy, A
Courtenay, K
Laugharne, R
Sivan, M

Post-COVID syndrome and adults with intellectual disability: another vulnerable population forgotten?

http://dx.doi.org/10.1192/bjp.2022.89

Published

29-Jun-22

Editorial

https://pearl.plymouth.ac.uk/handle/10026.1/19356

An area of interest presently is the lingering symptoms after COVID-19, i.e. post-COVID-19 syndrome (PCS). Specifics of diagnosis and management of PCS are emerging. However, vulnerable populations such as those with intellectual disabilities, who were disproportionately affected by the pandemic, risk being ‘left behind’ from these considerations.

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Marie Norredam
Sally Hayward
Anna Deal
Charles Agyemang
Sally Hargreaves

Understanding and addressing long-COVID among migrants and ethnic minorities in Europe

https://doi.org/10.1016/j.lanepe.2022.100427

Published

29-Jun-22

Comment

https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(22)00121-1/fulltext

Several European countries have observed an increasing number of patients with long-term health consequences of COVID-19, popularly termed long-COVID. In the UK alone, recent numbers have shown around 860,000 people with self-reported long-COVID at least 12 weeks after infection, symptoms of which include persistent fatigue, neurological difficulties such as depression, headache, and memory loss as well as cardiopulmonary symptoms including cough, dyspnea and chest pain.1 A wealth of evidence suggests that migrants and ethnic minorities have been disproportionally impacted by COVID-19, in terms of cases, hospitalisations, deaths and mental health outcomes in many European countries.2,3 In addition, emerging data have suggested inequities in the delivery of vaccines to these populations.4 We here describe migrants and ethnic minorities combined because these groups overlap and share common characteristics including socioeconomic and psychosocial vulnerabilities. The term ‘migrants’ is used as an umbrella term encompassing all the different subgroups of people who immigrated including asylum seekers, undocumented immigrants etc. The extent to which migrants and ethnic minorities are impacted by long-COVID is, however, not known, despite an increasing literature identifying a number of relevant risk factors for long-COVID including older age, disease severity, comorbidities and admission to Intensive Care Units.1,5 The few studies on long-COVID that do include data on migrants and ethnic minorities suggest that they are disproportionately impacted by long-COVID, but data are lacking in European countries and beyond.6,7 One UK study found that among 100 patients assessed by telephone interview 4-8 weeks after discharge from admission for a severe COVID-19 infection, those belonging to Black, Asian, and minority ethnic groups were more likely to experience dyspnea than White individuals (42.1% versus 25%) whereas rates of Post Traumatic Stress Disorder (PTSD) were similar.6 A US study based on 711 telephone interviews done among individuals at least 2 months after a positive test result for COVID-19 found that individuals reporting as Black were at higher risk of having ‘any long-COVID symptom’ and specifically dyspnea and arthralgia/myalgia compared to other ethnic groups including those reporting as White.7 These ethnicity datasets are highly heterogeneous and rarely disaggregated by migrant status, making it difficult to assess the impact on more recent arrivals from overseas, who may have a range of unique risk factors for worse health outcomes, including restricted access to health and vaccination systems.8,9

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National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Care Services; Laura Aiuppa Denning and Erin Hammers Forstag, Rapporteurs

Long COVID
Examining Long-Term Health Effects of COVID-19 and Implications for the Social Security Administration: Proceedings of a Workshop

Published

1-Jun-22

Book

https://nap.nationalacademies.org/catalog/26619/long-covid-examining-long-term-health-effects-of-covid-19

Long COVID' refers to the wide range of long-lasting symptoms experienced by some patients after a SARS-CoV-2 infection. The most common symptoms include fatigue, headache, brain fog, shortness of breath, hair loss, and pain. At this time, there are many knowledge gaps related to Long COVID, including the prevalence of the condition, the impact of the symptoms on survivors' ability to function, and the long-term course of the condition. While many individuals with Long COVID recover within one year, others experience little or no decrease in symptom severity over time.

Long COVID symptoms can affect a person's ability to work and otherwise function in daily life, so people with the condition may need to utilize programs such as Social Security Disability Insurance (SSDI) and the Supplemental Security Income Program (SSI). The Social Security Administration (SSA), which administers both of these programs, requested that the National Academies of Sciences, Engineering, and Medicine host a public workshop to discuss research into the long-term health effects of COVID-19, their impacts on individuals and populations, and how the SSDI and SSI programs can support individuals who suffer disability as a result of Long COVID. This publication summarizes the presentation and discussion of the workshop.

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B Patterson
J Ruppenkamp
F Richards
R Debnath
AC El Khoury
JK DeMartino
B Bookhart
C Holy
P Coplan

EE211 Cost of Long COVID Following Severe Disease - a US Healthcare Database Analysis

https://doi.org/10.1016/j.jval.2022.04.460

Published

1-Jul-22

Study

https://www.valueinhealthjournal.com/article/S1098-3015(22)00661-1/fulltext

Objectives
Continued morbidity following Coronavirus disease 2019 (COVID-19), or long COVID (LC), is defined by the World Health Organization (WHO) as conditions lasting > 2 months and identified 3 months after COVID-19 onset. LC might be particularly prevalent in severe COVID-19 patients. The impact of LC on healthcare costs is unknown.
Methods
Patients with severe/critical COVID-19 (first date =index) from April 1, 2020, onwards, with ≥ 6 months of continuous enrollment pre- and post-index, in IBM® MarketScan® Commercial and Medicare Supplemental databases, were identified. Severe disease was defined as admissions with respiratory distress/failure, with or without organ/neurological dysfunction or shock/tachypnea/tachycardia/hypoxemia. Variables for all patients included demographics, comorbidities (Elixhauser index (EI) and all 31 Elixhauser disease domains), and COVID-19 signs/symptoms. Disease duration was defined as follows: from 5 days before positive test to last related visit/prescription. A ≤ 35-day gap between visits/prescription was allowed. LC was defined as disease duration ≥ 5 months. All-cause (with any diagnostic code) and disease-specific costs (with COVID-19 related diagnostic codes) for patients with and without LC (non-LC) were estimated from index to end of disease duration or last available date (for ongoing disease), using generalized linear model with gamma distribution and log link.
Results
13.7% (95%CI: 13.5%-13.9%) with severe/critical COVID-19 had LC. Average available duration of LC for costing analyses was 213.1 days (95%CI: 207.8-218.3). In contrast, non-LC duration of disease averaged 53.6 days (95%CI: 53.1-54.2) Between LC and non-LC patients, all-cause costs significantly increased in commercially-insured and Medicare patients by respectively $58,445 (95%CI: $49,453-$67,437 – from $46,912 (non-LC) to $105,357 (LC)) and $34,940 (95%CI: $28,990-$40,889 – from $29,491 (non-LC) to 64,412 (LC)).
Conclusion
As observed over 213 days, all-cause cost of COVID-19 almost doubled in severe COVID-19 patients with LC vs without LC. These costs are expected to further increase with increased follow-up time.

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Tom Lawton
Nisreen A Alwan

The UK COVID-19 Inquiry must examine the foundations of pandemic decision making

https://doi.org/10.1016/S0140-6736(22)01332-0

Published

18-Jul-22

Article

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01332-0/fulltext

First, long COVID is not centred in the Terms of Reference. The chronic illness burden created by mass SARS-CoV-2 infection is the living legacy of this pandemic and needs to be a priority area for the UK COVID-19 Inquiry. At the start of the pandemic in 2020, data were available about clinical outcomes in severe acute respiratory syndrome3 and early reports from COVID-19 survivors4 pointed to longer-term sequelae with potentially serious effects for individuals and the population. On the basis of data up to August, 2021, at least one in nine of those infected with SARS-COV-2 reported experiencing long COVID at 12 weeks from onset of infection.5 Population estimates from the UK's Office for National Statistics (ONS), as of June 4, 2022, point to an estimated burden of 2 million people living with long COVID for more than 4 weeks (3% of the population), of whom 105 000 are aged 2–16 years and 95 000 are aged 17–24 years.6 A Bank of England publication in May, 2022, stated that the UK workforce has shrunk by 440 000 people (1·3%) since the final quarter of 2019 and is 2·5% below the January, 2020 forecast, and that the share of the population aged 16–64 years who are outside the workforce because of long-term sickness is a record high, with a particularly sharp rise among women.7 This could at least partly be due to long COVID.7
The UK COVID-19 Inquiry has the potential to enhance our understanding of what has so far happened during the pandemic. This should be an opportunity to learn valuable lessons that could have global relevance, and hopefully improve any response to future pandemics. But there is a need for the Inquiry to examine the principles that underpinned the UK's responses if it is to have a meaningful, lasting impact. An opaque culture, which has signs of being driven by political convenience, has pervaded many aspects of the UK's pandemic response. The Inquiry must examine and be able to challenge the underlying culture and assumptions that shaped the UK Government's pandemic policies.

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Karin Magnusson1 Aleksandra Turkiewicz2
Signe Flottorp1 Martin Englund

Development of long-covid, or prevalent complaints in general?

https://doi.org/10.21203/rs.3.rs-1684643/v1

pre-print

18-Jul-22

Study

https://www.researchsquare.com/article/rs-1684643/v1

Objectives: To study the prevalence and patterns of typical post-covid complaints in ~2.3 million persons with and without confirmed COVID-19.
Methods: In a Nation-wide population-based prospective cohort study, we studied all persons aged 18-70 years living in Norway and who tested positive (n=75 979), negative (n=1 167 582) and who were not tested for SARS-CoV-2 (n=1 084 578) from August 1st 2020 to August 1st 2021 (non-hospitalized from -2 to +14 days from test date), who were, or were not vaccinated against COVID-19. Our main outcome measures were the period prevalence of single-occurring or different combinations of complaints based on medical records: 1) Pulmonary (dyspnea and/or cough), 2) Neurological (concentration problems, memory loss), and/or 3) General complaints (fatigue).
Results: In persons testing positive, 64 (95% confidence interval: 54 to 73) and 122 (111 to 113) more persons per 10 000 persons had pulmonary complaints 5-6 months after the test compared to 10 000 persons testing negative or untested, respectively. The corresponding difference in prevalence of general complaints (fatigue) was 181 (168 to 195) and 224 (211 to 238) per 10 000, and of neurological complaints 5 (2 to 8) and 9 (6-13) per 10 000. Overlap between complaints was rare.
Conclusions: Post-covid complaints were only slightly more prevalent in persons with than without confirmed COVID-19. Still, long-covid may pose a substantial burden to healthcare systems in the future given the lasting high incidence of symptomatic COVID-19 in both vaccinated and unvaccinated individuals.

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Dasom I. Ham

Long-Haulers and Labor Market Outcomes

https://doi.org/10.21034/iwp.60

pre-print

1-Jul-22

Study

https://ideas.repec.org/p/fip/fedmoi/94528.html

There have been growing concerns about long-haulers or individuals with long-term COVID-19 health complications (long-haul COVID). While the medical field has been investigating the health complications, there has been limited research on the relationship between long-haul COVID and labor market outcomes. To investigate this relationship, I used the University of Southern California Understanding America Study COVID-19 longitudinal survey to provide a snapshot of mid-2021. I first find about 24.1% of individuals who have had COVID are long-haulers and 25.9% of long-haulers reported that their long-haul COVID affected employment or work hours. I then find that a majority of these affected long-haulers remained employed and in same employment type. But I find that their mean change in work hours and paycheck declined. Afterwards, I tested whether long-haul COVID is associated with negative changes in labor market outcomes. When I combined long-haulers who reported that their health complications did or did not affect work, I failed to find that long-haulers are less likely to be employed relative to individuals without prior COVID infection. But, when I discern long-haulers by whether long-haul COVID affected work, I find that long-haulers who reported long-haul COVID affected work are 10 percentage points less likely to be employed and, on average, work 50% fewer hours than individuals without prior COVID infection. In contrast, I failed to find evidence that affected long-haulers receive a lower paycheck earning relative to individuals without prior COVID infection. Lastly, when comparing these affected long-haulers against similar individuals, I find evidence that they are more impacted in their employed status and work hours. Due to limitations, future data collection and research would provide a more robust picture.

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Nick Mayer; Bernardo Meza-Torres; Cecilia Okusi; Gayathri Delanerolle; Martin Chapman; Wenjuan Wang; Sneha Anand; Michael Feher; Jack Macartney; Rachel Byford; Mark Joy; Piers Gatenby; Vasa Curcin; Trisha Greenhalgh; Brendan Delaney; Simon de Lusignan

Developing a long covid phenotype for post-acute COVID-19 in a national primary care sentinel cohort: an observational retrospective database analysis

https://doi.org/10.2196/36989

Published

21-Jul-22

Study

https://preprints.jmir.org/preprint/36989/accepted

Background:
Following COVID-19 up to 40% of people have ongoing health problems, referred to as “post-acute COVID-19” or long covid (LC). LC varies from a single persisting symptom to a complex multi-system disease. Research has flagged that this condition is under recorded in primary care record; and seeks to better define its clinical characteristics and management. Phenotypes provide a standard method for case definition and identification from routine data and are usually machine processable. A LC phenotype can underpin research into this condition.
Objective:
To develop a phenotype for long COVID-19 to inform the epidemiology and future research into this condition. We will compare clinical symptoms in people with long COVID-19 before and after their index infection. We will also compare people recoded as having acute infection with those with LC who have been hospitalised with those who are not.
Methods:
We used data from the Primary Care Sentinel Cohort (PCSC) of the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database. The PCSC is recruited to be nationally representative of the English population. We developed a long LC phenotype using our established three-step ontological method: (1) Ontological step: Defining the reasoning process underpinning the phenotype; (2) Coding step: Exploring what clinical terms are available; (3) Logical extract model: testing performance. We created version of this phenotype using Protégé in the ontology web language (OWL) for Bioportal and using Phenoflow. We used the phenotype to compare people with long COVID-19 with: (1) Their symptoms in the year prior to acquiring COVID-19; and (2) People with acute COVID-19. We also compared hospitalised people with long COVID-19 with those not hospitalised. We compared socio-demographic details (age, gender, ethnicity, socioeconomic-status, obesity and smoking), comorbidities (cardiometabolic, respiratory and mental health) and Office of National Statistics (ONS) defined long covid symptoms between groups. We used descriptive statistics and logistic regression.
Results:
The long covid phenotype, available in Bioportal and Phenoflow, formats that differentiates people hospitalised with LC from people who are not, and where there no index infection is identified. The PCSC (N=7.4 million) includes 428,479 patients with an acute COVID-19 diagnosis confirmed by a laboratory test and 10,772 patients with clinically diagnosed COVID-19. We have before and after symptoms related to LC for hospitalized and community strata. 7,471 (1.74%;95CI=1.70-1.78) people were coded as having LC, 1,009 (13.5%;95CI=12.7-14.3) had a hospital admission related to acute COVID-19, 6,462 (86.5%;95CI=85.7-87.3) were not admitted to hospital of whom 2,728 had no COVID-19 index date recorded. 15.6% (95CI=14.7-16.5) of people with LC were hospitalised compared to 4.9% (95CI=4.8-5.0, p<0.0001) with uncomplicated COVID-19.
Conclusions:
Our long covid phenotype identifies LC cases and enables us to conduct a comparison between LC and defined comparator groups. Clinical Trial: Not applicable

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Fern Davies, Ilora Finlay, Helen Howson, Nicholas Rich

Recommendations for a voluntary Long COVID Registry

https://doi.org/10.1177%2F01410768221114964

Published

26-Jul-22

Article

https://journals.sagepub.com/doi/full/10.1177/01410768221114964

Long COVID has had a profound impact on the lives and health of many people around the globe.1 Estimates of the number of people affected vary, but on the 6th May 2022, the Office of National Statistics (ONS) identified that there were 1.8 million (2.8%) people living in private households in the UK alone who were experiencing self-reported long COVID symptoms.2 The same data identified that symptoms adversely affect the day-to-day activities of 1.2 million people in the UK.2 However, the long-term consequences of SARS-CoV-2 infection and the subsequent impact on public health are still largely unknown and present a major challenge to health and care systems moving forward. A mechanism to facilitate long-term monitoring of long COVID is therefore essential to support research, service improvement and enhance understanding of the disease as it evolves. In response to this, the aim of this commentary is to outline key recommendations for a voluntary Long COVID Registry in Wales. In this paper, five key recommendations are highlighted that should be considered in the development of a Long COVID Registry. These include: 1) a dual purpose of research and service improvement; 2) experiential co-design with end-users; 3) recruitment of a self-referred population and inclusion of a control group; 4) utilisation of digital infrastructures and 6) a prudent and integrated approach.

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GiovanniGuaraldiabJovanaMilicaMatteoCesaricLeonardLeibovicidFedericaMandreoliePaoloMissierfRenzoRozzinigAnna MariaCattelanhFedericoMottaaCristinaMussiniabAndreaCossarizzai

The interplay of post-acute COVID-19 syndrome and aging: a biological, clinical and public health approach

https://doi.org/10.1016/j.arr.2022.101686

Published

30-Jul-22

Review

https://www.sciencedirect.com/science/article/pii/S1568163722001283

Highlights
•PACS is a condition of growing interest for clinical and public health reasons.
•PACS occurs even in individuals with mild or asymptomatic acute SARS COV-2 infection.
•PACS is likely driven by a vicious cycle of inflammaging and immunosenescence.
•This altered immune-metabolic condition may affect aging trajectories.
•Aging trajectoris may be depicted by the relationship between frailty and resilience.
Abstract
The post-acute COVID-19 syndrome (PACS) is characterized by the persistence of fluctuating symptoms over three months from the onset of the possible or confirmed COVID-19 acute phase. Current data suggests that at least 10% of people with previously documented infection may develop PACS, and up to 50–80% of prevalence is reported among survivors after hospital discharge. This viewpoint will discuss various aspects of PACS, particularly in older adults, with a specific hypothesis to describe PACS as the expression of a modified aging trajectory induced by SARS CoV-2. This hypothesis will be argued from biological, clinical and public health view, addressing three main questions: (i) does SARS-CoV-2-induced alterations in aging trajectories play a role in PACS?; (ii) do people with PACS face immuno-metabolic derangements that lead to increased susceptibility to age-related diseases?; (iii) is it possible to restore the healthy aging trajectory followed by the individual before pre-COVID?. A particular focus will be given to the well-being of people with PACS that could be assessed by the intrinsic capacity model and support the definition of the healthy aging trajectory.

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Burhan Fatih Kocyigit & Ahmet Akyol

The relationship between COVID-19 and fibromyalgia syndrome: prevalence, pandemic effects, symptom mechanisms, and COVID-19 vaccines

https://doi.org/10.1007/s10067-022-06279-9

Published

8-Jul-22

Article

https://link.springer.com/article/10.1007/s10067-022-06279-9

On March 11, 2020, the World Health Organization, realizing the level of spread worldwide and the severity of the condition, accepted coronavirus disease 19 (COVID-19) as a pandemic. Subsequently, quarantine conditions were implemented around the world, and these triggered particular results. Like all other individuals, fibromyalgia syndrome (FMS) patients were affected by these conditions. The stress load in pandemic conditions, difficulties in accessing healthcare services, changes in exercise compliance, variations in physiotherapy programs, and remote work conditions all had an impact on FMS patients. Although general expectations were negative, some FMS patients were able to manage the pandemic conditions and even turn them in their favor. This is thought to be due to this patient group having established strategies to cope with stress in the pre-pandemic period, and they had sufficient ability to adapt to changing situations. FMS-related symptoms occur in a subset of individuals following COVID-19. One of the factors is the increased psychological burden after COVID-19. There is evidence that neuroinflammatory pathways affect neuroplasticity in the central nervous system and trigger the onset of FMS-related symptoms. Among the probable mechanisms are alterations in inflammatory and anti-inflammatory pathways. Changes in the autonomic nervous system with the effect of SARS-CoV-2 may induce the emergence of FMS-related symptoms. FMS and COVID-19 can coexist, and FMS may create a tendency to vaccine hesitancy. Future studies should focus on elucidating FMS-related symptoms occurring post-COVID-19. There is a need to determine distinctions between the FMS clinical status that emerged following COVID-19 and the regular patient group in terms of diagnosis, treatment, and follow-up.
Key Points
• Conflicting results have been observed in studies investigating the impacts of COVID-19 on FMS patients. In addition to studies revealing unfavorable effects, there are also articles reporting a steady course and even positive impacts.
• No significant difference was detected between the groups with and without a diagnosis of FMS in terms of hospitalization and mortality outcomes related to COVID-19.
• Several mechanisms have been proposed to explain the onset of FMS-related symptoms following COVID-19. During periods of lock-down and self-isolation, individuals are influenced biopsychosocially. Activation of some inflammatory pathways, changes in plasticity-central sensitization, and alterations in pain pathways are also plausible explanations.

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Darja ReuschkeORCID Icon &Donald HoustonORCID Icon

The impact of Long COVID on the UK workforce

https://doi.org/10.1080/13504851.2022.2098239

Published

6-Jul-22

Study

https://www.tandfonline.com/doi/full/10.1080/13504851.2022.2098239

COVID-19 is more likely to lead to Long COVID among persons of working age. We outline the first estimates of the impact of Long Covid on employment in the UK. Using estimates of cumulative prevalence of Long COVID, activity-limiting Long COVID in the working-age population and of economic inactivity and job loss resulting from Long COVID, we provide evidence of the profound impact of Long COVID on national labour supply. Since the start of the pandemic, cumulatively 2.9 million people of working age (7% of the total) in the UK have had, or still have, Long COVID. This figure will continue to rise due to very high infection rates in the Omicron wave. Since the beginning of the pandemic, economic inactivity due to long-term sickness has risen by 120,900 among the working-age population, fuelling the UK’s current labour shortage. An estimated 80,000 people have left employment due to Long COVID. We argue that governments need to tackle the twin challenges to public health and labour supply and provide employment protection and financial support for individuals and firms affected by Long COVID.

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Jennifer Abbasi

The US Now Has a Research Plan for Long COVID—Is It Enough?

https://doi.org/10.1001/jama.2022.14536

Published

12-Aug-22

Article

https://jamanetwork.com/journals/jama/article-abstract/2795468

More than 2 years after patients with lingering health problems coined the term Long COVID, the US government has unveiled a research plan to understand, prevent, and treat the broad range of persistent and sometimes debilitating disease symptoms that are now known to affect many people after initial SARS-CoV-2 infection. The National Research Action Plan on Long COVID, released this August 3, has been met with a mixture of enthusiasm and disappointment.
What Is Long COVID?
A new US government research plan presents an interim definition of Long COVID. It broadly defines Long COVID as signs, symptoms, and conditions that continue or develop after initial COVID-19 or SARS-CoV-2 infection. The plan defines the signs, symptoms, and conditions as follows:
Are present 4 weeks or more after the initial phase of infection
May be multisystemic
May present with a relapsing-remitting pattern and progression or worsening over time, with the possibility of severe and life-threatening events even months or years after infection
The plan emphasizes that Long COVID is not 1 single condition. Instead, it represents many potentially overlapping entities that likely have different biological causes and different risk factors and outcomes.
Adapted from the National Research Action Plan on Long COVID. Department of Health and Human Services; August 2022.

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Mohammad Hossein Taghrir*, Hossein Akbarialiabad*, Ashkan Abdollahi, Nasrollah Ghahramani, Bahar Bastani, Shahram Paydar, Babak Razani, John Mwangi, Ali A. Asadi-Pooya, Jamshid Roozbeh, Leila Malekmakan, Manasi Kumar**

Inequity and disparities mar existing global research evidence on Long COVID

https://doi.org/10.1177%2F17579759221113276

Published

12-Aug-22

Article

https://journals.sagepub.com/doi/abs/10.1177/17579759221113276

Since the pandemic began in December 2019, SARS-Cov2 has accentuated the wide gap and disparities in socioeconomic and healthcare access at individual, community, country, and regional levels. More than two years into the current pandemic, up to three-fourths of the patients are reporting continued signs and symptoms beyond the acute phase of COVID-19, and Long COVID portends to be a major challenge in the future ahead. With a comprehensive overview of the literature, we found that most studies concerning long COVID came from high and upper-middle income countries, and people of low-income and lower-and-middle income regions and vulnerable groups with comorbid conditions have been neglected. Apart from the level of income, there is a significant geographical heterogeneity in investigating the Post-Acute Sequelae of COVID-19 (PASC) or what we call now, long COVID. We believe that these recognizing health disparities is crucial from equity perspective and is the first step toward global health promotion.

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Nikhil Mayor 1 Bernardo Meza-Torres 2, 3 Cecilia Okusi 4 Gayathri Delanerolle 4 Martin Chapman 5 Wenjuan Wang 5 Sneha Anand 4 Michael Feher 2 Jack Macartney 2 Rachel Byford 2 Mark Joy 2 Piers Gatenby 1 Vasa Curcin 5 Trisha Greenhalgh 2 Brendan Delaney 4 Simon de Lusignan 2, 6 Author

Developing a Long COVID Phenotype for Postacute COVID-19 in a National Primary Care Sentinel Cohort: Observational Retrospective Database Analysis

https://doi.org/10.2196/36989

Published

Study

https://publichealth.jmir.org/2022/8/e36989

Background:
Following COVID-19, up to 40% of people have ongoing health problems, referred to as postacute COVID-19 or long COVID (LC). LC varies from a single persisting symptom to a complex multisystem disease. Research has flagged that this condition is underrecorded in primary care records, and seeks to better define its clinical characteristics and management. Phenotypes provide a standard method for case definition and identification from routine data and are usually machine-processable. An LC phenotype can underpin research into this condition.
Objective:
This study aims to develop a phenotype for LC to inform the epidemiology and future research into this condition. We compared clinical symptoms in people with LC before and after their index infection, recorded from March 1, 2020, to April 1, 2021. We also compared people recorded as having acute infection with those with LC who were hospitalized and those who were not.
Methods:
We used data from the Primary Care Sentinel Cohort (PCSC) of the Oxford Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database. This network was recruited to be nationally representative of the English population. We developed an LC phenotype using our established 3-step ontological method: (1) ontological step (defining the reasoning process underpinning the phenotype, (2) coding step (exploring what clinical terms are available, and (3) logical extract model (testing performance). We created a version of this phenotype using Protégé in the ontology web language for BioPortal and using PhenoFlow. Next, we used the phenotype to compare people with LC (1) with regard to their symptoms in the year prior to acquiring COVID-19 and (2) with people with acute COVID-19. We also compared hospitalized people with LC with those not hospitalized. We compared sociodemographic details, comorbidities, and Office of National Statistics–defined LC symptoms between groups. We used descriptive statistics and logistic regression.
Results:
The long-COVID phenotype differentiated people hospitalized with LC from people who were not and where no index infection was identified. The PCSC (N=7.4 million) includes 428,479 patients with acute COVID-19 diagnosis confirmed by a laboratory test and 10,772 patients with clinically diagnosed COVID-19. A total of 7471 (1.74%, 95% CI 1.70-1.78) people were coded as having LC, 1009 (13.5%, 95% CI 12.7-14.3) had a hospital admission related to acute COVID-19, and 6462 (86.5%, 95% CI 85.7-87.3) were not hospitalized, of whom 2728 (42.2%) had no COVID-19 index date recorded. In addition, 1009 (13.5%, 95% CI 12.73-14.28) people with LC were hospitalized compared to 17,993 (4.5%, 95% CI 4.48-4.61; P<.001) with uncomplicated COVID-19.
Conclusions:
Our LC phenotype enables the identification of individuals with the condition in routine data sets, facilitating their comparison with unaffected people through retrospective research. This phenotype and study protocol to explore its face validity contributes to a better understanding of LC.

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World Bank

Long COVID
The Extended Effects of the Pandemic on Labor Markets in Latin America and the Caribbean

https://doi.org/10.1596/37682

Published

1-Jul-22

Article

https://elibrary.worldbank.org/doi/epdf/10.1596/37682

More than a year on from the start of the Coronavirus (COVID-19) pandemic and with massive vaccination campaigns underway, over a quarter of the adult population in Latin America and the Caribbean (LAC) who had a job before the pandemic were still not working. Of these, over half left the labor force entirely. Women, young people, older workers, and individuals with low educational attainment levels have been disproportionately affected by this crisis. In many cases, workers have become discouraged or unable to return to work, exiting the labor market altogether. The exit of workers from the labor market was simultaneously accompanied by entry from inactivity into the labor force at unprecedented levels during the pandemic, suggesting that further examination at the country level is required to understand the role of government transfers and care work as determinants of people’s activity choices. Still, as of mid-2021, inactivity rates remained higher than before the pandemic in most countries.

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Lin Zhang1J. Paulo Moreira2,3,Yan Xi

What is Long COVID-19?Clarifying Definitions and Symptoms

https://doi.org/10.56226/ihr.v1i2.28

Published

8-Aug-22

Review

https://internationalhealthcarereview.com/index.php/home/article/view/28/4

Background:What is the definition of Long COVID-19? What are its currently acknowledged symptoms? As this is a new condition suspected to be evolving as a potentially post-Pandemic new disease, it becomes relevant to clarify the current definitions of Long COVID-19. The article puts together the most recent definitions and briefly discusses points of common understanding and points of uncertainty.Objectives:The main aim of the article is to clarify the definitions and symptoms of Long COVID-19 as international evidence defines them. This is relevant to support health professionals and interested parties to access a structured clarification of the disease at this stage of knowledge. Supporting evidence-based intervention is the fundamental objective of the article.Methods:The Rapid Literature Reviewis a form of evidence synthesis that providestimely information for decision making and evidence-based practice compared with standard systematic reviews. The review used the following sources: Web of Science and PubMed,.The Search used the keywords ‘Long Covid-19’, ‘Definitions’ and ‘Symptoms’ and limited to articles published between January 2021 and June 2022.There were two reviewers to selectarticles based on the inclusion/exclusion criteria(keywords defined and time span of publications).Both reviewers appraised criticallyand rigorously within the criteria defined and a summary was produced.Results:Six articles were identified as relevant for the objectives of this article. These were individually evaluated on the contribution to clarifying definitions and symptoms of Long COVID-19. Definitions seem to follow the initial definition made available in a publication from World Health Organization. However, the follow-up articles seem to add additional interpretations and associated symptoms.Main Contribution to Evidence-Based Practice:The article puts together the recent evolution of the definition of Long COVID-19 and associated symptoms to support clinical decision-making and evidence-based practice.

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Rachel L. Levine

Addressing the Long-term Effects of COVID-19

http://jamanetwork.com/article.aspx?doi=10.1001/jama.2022.14089

Published

3-Aug-22

Article

https://jamanetwork.com/journals/jama/article-abstract/2795139

The COVID-19 pandemic is the most significant medical and public health challenge the US has encountered in the last 100 years. As of July 26, 2022, an estimated 90 million cases of COVID-19 have been reported in the US, with an estimated 1 million COVID-19–related deaths. The current number of SARS-CoV-2 infections is difficult to estimate accurately, considering that many individuals with positive self-test results do not seek care or report their infection. At the same time, new coronavirus variants continue to emerge, with Omicron subvariants such as BA.5 and BA.4 now identified as the dominant circulating strains.
From the start of the pandemic, infected individuals exhibited different patterns of recovery. Some patients partnered with other groups of patients with similar or overlapping sets of symptoms and voiced their concerns to health care professionals, allowing recognition of what has been referred to as “Long COVID.”1
In defining Long COVID, 2 perspectives need to be balanced: the need to learn more and avoid premature definitions that inappropriately exclude patients in need of care, and the need to establish interim definitions to enable access to health care and disability services as the science of Long COVID continues to emerge.
Long COVID and associated conditions as well as the longer-term sequelae of the pandemic will continue to affect patients and families. The medical and public health community have made dedicated efforts during the last 2½ years to stopping the spread of this deadly coronavirus and have implemented prevention methods, developed treatments, and released vaccines that have been central to reducing initial COVID-19 infections and preventing Long COVID.
It is important to focus a new lens on the pandemic and direct much-needed attention to Long COVID. Taking care of affected patients presents challenges given the incompleteness of research, the lack of sufficient diagnostics support, and pervasive problems with access to services. The provisions in the presidential memo are important elements for mounting an effective approach for addressing the long-term effects of COVID.

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UKCDR

COVID-19 FUNDED RESEARCH PROJECTS IN FOCUS

Published

1-Jul-22

Article

https://www.ukcdr.org.uk/wp-content/uploads/2022/07/UPDATED-UKCDR-0722-Tracker-Highlights-Long-Covid-250722-1.pdf

As the coronavirus pandemic evolves, there is increased interest in the emerging phenomenon, now commonly referred to as “long COVID”, which encompasses a wide spectrum of persistent and newly emerging multisystemic symptoms following COVID-19 infection. These include cough, fatigue, shortness of breath, alterations in taste and smell, depression and mood disturbances (1). Cardiac, pulmonary and renal sequalae may also follow COVID-19 infections. To date, there is a lack of consensus on a clear definition, diagnosis, clinical characterization and management, rehabilitation and appropriate support for sufferers in addition to difficulties in ascertaining its prevalence (1) (2) (3). Here, we present the scope of funded research activity focused on long COVID, drawing on evidence from the July 2022 update of the Living Mapping Review (LMR) of COVID-19 funded research projects and the UKCDR/GLOPID-R.

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Jannathul Firdous, Nang Thinn Thinn Htike, Alia Afiqah Binti Zainudin, Azizah Haziqah Binti Azizah Ariffin, Mohamad Aidel Mukhriz Bin Mohd Burhan, Nurin Zahirah Binti Zulhisham

Impacts on post-COVID-19 sequelae: A systemic Review

http://dx.doi.org/10.7324/JAPS.2022.121003

Published

31-Jul-22

Review

https://japsonline.com/abstract.php?article_id=3742&sts=2

Concerns on whether or not coronavirus disease 2019 (COVID-19) can cause long-term impact are rising since many aspects of the disease are still under investigation. This systemic review was carried out to recognize the post- COVID-19 sequelae infection in various body systems and to analyze the comorbidities in survivors who suffered long-term impacts. The choice of words used to search is “post-COVID-19,” “COVID-19,” and “SARS-CoV-2 infection.” A total of 1,282 articles were extracted. Reports suggested that a wide range of sequelae were faced by the survivors which affected various systems, mainly the respiratory, gastrointestinal, nervous, cardiovascular, and musculoskeletal systems, while rarely affect other systems such as the endocrine, vascular, renal, and urogenital systems. Comorbidities are involved in determining the harshness of sequelae and the persistence of symptoms of post-severe acute respiratory syndrome coronavirus-2 infection. COVID-19 survivors may present with different symptoms and conditions that vary from mild symptoms to severe and rare conditions. It is crucial to understand the sequelae of post-COVID-19 for prevention and help to establish pandemic control strategies and rehabilitation needs.

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Blake Hereth, postdoctoral fellow1, Paul Tubig, assistant professor2, Ashton Sorrels, graduate student3, Anna Muldoon, graduate student4, Kelly Hills, graduate student1, Nicholas G Evans, associate professor1

Long covid and disability: a brave new world

https://doi.org/10.1136/bmj-2021-069868

Published

1-Aug-22

Article

https://www.bmj.com/content/378/bmj-2021-069868.full

Nicholas Evans and colleagues argue that long covid needs to be better recognised, understood, and supported, and should stimulate a rethink of our approach to disability.
Key messages
- The rise of long covid has created millions of new people with disabilities who will have to navigate the post-pandemic world
- The need for change to support people with disabilities predated the pandemic
- Long covid needs to be legally recognised as disabling through clinical research and practice
- The state must support people with long covid through expanded or reformed infrastructure and policy and by changing social norms
- Such changes will benefit all disabled people and wider society

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Sandro Galea

The Post–COVID-19 Case for Primary Care

https://doi.org/10.1001/jamahealthforum.2022.3096

Published

28-Jul-22

Article

https://jamanetwork.com/journals/jama-health-forum/fullarticle/2794949

As the pandemic moves to a stage that occasions reflection, scholarship is emerging about how we may rethink primary care in the postpandemic moment, with a focus on innovations in service delivery, digital medicine, and payment structures. These efforts to reconsider primary care delivery are indeed important and should be encouraged. A broader public conversation that clarifies and elevates the role of primary care can make an important contribution to a national reconsideration of the centrality of primary care.

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Celina Silvia Stafie 1ORCID,Sorina Mihaela Solomon 2,*,Irina-Georgeta Sufaru 2,*ORCID,Maria Manaila 3,Ingrid Ioana Stafie 3,Gabriela Melinte 3,Bianca Simionescu 4 andLetitia Leustean 5

Pathogenic Connections in Post-COVID Conditions: What Do We Know in the Large Unknown? A Narrative Review

https://doi.org/10.3390/v14081686

Published

30-Jul-22

Review

https://www.mdpi.com/1999-4915/14/8/1686/htm

The coronavirus 2019 (COVID-19) disease has long-term effects, known as post-COVID conditions (PCC) or long-COVID. Post-COVID-19 syndrome is defined by signs and symptoms that occur during or after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection which persist for more than 12 weeks and cannot be supported by an alternative diagnosis. The cardiovascular damage caused by COVID-19 in the severe forms of the disease is induced by severe systemic inflammation, considered to be one of the causes of myocardial lesions, with increased levels of circulating cytokines and toxic response mediators. We have focused on conditions that can induce long-COVID-19, or multisystem inflammatory syndrome in adults or children (MIS-C/MIS-A), with an emphasis on endocrinological and metabolic disorders. Although described less frequently in children than in adults, long-COVID syndrome should not be confused with MIS-C, which is an acute condition characterized by multisystem involvement and paraclinical evidence of inflammation in a pediatric patient who tested positive for SARS-CoV-2. At the same time, we mention that the MIS-A symptoms remit within a few weeks, while the duration of long-COVID is measured in months. Long-COVID syndrome, along with its complications, MIS-A and MIS-C, represents an important challenge in the medical community. Underlying comorbidities can expose both COVID-19 adult and pediatric patients to a higher risk of negative outcomes not only during, but in the aftermath of the SARS-CoV-2 infection as well.

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Eleni Gavriilaki
Styliani Kokoris

COVID-19 sequelae: can long-term effects be predicted?

https://doi.org/10.1016/S1473-3099(22)00529-1

Published

25-Aug-22

Comment

https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(22)00529-1/fulltext

In this context, the study by Jeremy Werner Deuel and colleagues,10 reported in The Lancet Infectious Diseases, explores sequelae after SARS-CoV-2 infection in young adults (median age 21 years [IQR 21–23]). Deuel and colleagues did a longitudinal cohort study of 501 mainly young male adults (464 [93%]) undertaking a comprehensive test battery designed to evaluate physical and psychosocial outcomes after COVID-19. All participants at the time of the study had not received a dose of any COVID-19 vaccine and were members of the Swiss Armed Forces. Increased BMI, dyslipidaemia, and decreased physical endurance 6 months after COVID-19 were suggestive of a higher risk of developing metabolic disorders and possible cardiovascular complications. These findings might support the hypothesis of endothelial dysfunction as a primary driver of COVID-19 sequelae. Obesity, dyslipidaemia, and low physical activity are known risk factors for future cardiovascular complications, characterised by endothelial dysfunction. Cardiovascular risk factors can be modified through lifestyle changes and medications. More importantly, novel vascular and biochemical markers have been discovered over the last decade that can better predict cardiovascular risk.11
In conclusion, although no accurate prediction models exist for who will develop severe COVID-19 or sequelae, risk factors of vascular damage have emerged as important predictors. Large and high-quality studies are needed utilising multidisciplinary teams not only from different medical specialties but also from computational scientists that could suggest novel predictive models for the development of COVID-19 sequelae.

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Sateesh M.SakhamuriaSatishJankiebLexley M.Pinto Pereirac

Calling on Latin America and the Caribbean countries to recognise the disability from long COVID

https://doi.org/10.1016/j.lana.2022.100362

Published

26-Aug-22

Article

https://www.sciencedirect.com/science/article/pii/S2667193X2200179X?via%3Dihub

Long COVID sufferers voiced the term on social media after being stigmatised, denied access to medical/specialist services or diagnosis, and feeling “fobbed off,” hoping their burden of devastating debilitation would stop being dismissed.1 This multi-dimensional disability is characterised by diverse health-related challenges embracing physical, mental, and cognitive issues, affecting daily activities, social, family, and employment relationships. Considering its life-changing impact on disabling resumption of normalcy, mentation, and work capacity, the 2006 United Nations Convention on the Rights of Persons with Disabilities qualifies it as a disability.2 An impending enormous influx of new entrants to the disability community is signalled by adverse health issues for six months or more in half of COVID-19 survivors from a large systemic review of 57 reports.3 The longest longitudinal cohort of COVID-19 patients, studied two years post-hospitalisation in Wuhan, found that 11% who did not return to work had decreased physical function or were unwilling to do so.4 As of early 2022 long COVID has distressed 23 million Americans, driving an approximate million people jobless, causing yet unknown significant public health, social, and economic outcomes.
The Americas have probably been the hardest hit by COVID-19 globally. By the fourth week of May 2022, the Latin America and the Caribbean countries (LAC) were contributing an enormous cumulative COVID-19 global burden with about 13% of reported acute cases and 27% of confirmed deaths, despite having only 8% of the world's population.6 Brazil, Argentina, Columbia, Mexico, and Chile are worst affected, contributing more than 80% of the LACs burden. During the pandemic, LAC suffered the worst economic decline in two hundred years, devastating the region's society, economics, and health systems. Extrapolating Long COVID's estimated global prevalence of 43% (irrespective of hospitalization or disease severity)7 to the LAC signifies a current prevalence of more than 29 million cases of this new emergent pandemic.
Prioritising disability is a global public health and human rights issue. Interestingly, the recent Global Disability Summit discussed interventional measures for long COVID but did not acknowledge it as a disability.8 Besides the exemplary initiative of the United States in recognising long COVID as a disability,9 neither international nor regional responses to disability benefit policies and employee protection after long COVID are forthcoming. The American commitment to long COVID recovery is bolstered by the National Institute of Health (September 2021) $470 million award to the RECOVERY (Researching COVID to Enhance Recovery) collaborative research proposal on mechanisms and management of long COVID10 and the Biden Administration's first-ever interagency national research action plan (April 2022) committing $20 million to investigate optimum health care for long COVID sufferers. Though the United States has a robust and historical relationship with the LAC region straddling economic, defence, cultural, and social spheres, government responses in most LAC countries have not used the model to recognise the disability from long COVID or the needs of sufferers.
Priorities at different strata for LAC to address the suffering, needs, and disability inflicted by long COVID are presented in Table 1. Governments can pioneer policies to encourage mutual employer-employee work output, thereby improving opportunities for long COVID sufferers, avoiding discrimination against the disabled, and motivating occupational rehabilitation, which will promote cost savings and reforms for the disability workforce. National funding for scientific scrutiny into the mysteries of long COVID will boost research and surveillance.

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Elise Paul, Daisy Fancourt

OP30 Do stressors increase the risk of long COVID? A longitudinal study of adversity worries and experiences in the two months prior to COVID-19 infection and the development of long COVID in 1,962 UK adults

http://dx.doi.org/10.1136/jech-2022-SSMabstracts.30

Published

26-Aug-22

Study

https://jech.bmj.com/content/76/Suppl_1/A15.1

Abstract
Background - Long COVID is increasingly recognised as public health burden. Ongoing inflammatory processes have been found to underlie the post-acute sequalae, as in other viral infections. Psychological stress can trigger increases in circulating markers of inflammation, with higher inflammation in turn associated with a greater propensity for developing chronic illness. However, research on risk factors for long COVID has focused almost entirely on demographic and infection-related characteristics, to the exclusion of psychosocial predictors such as stress immediately preceding the index infection. Research on whether stressors predict the development of specific long COVID symptoms is also needed, because some long COVID symptoms may be more debilitating than others and have different risk factors.
Methods - Data from 1,962 UK adults who had previously been infected with COVID-19 and who took part in the UCL COVID-19 Social Study were analysed. The number of adverse experiences (e.g., job loss) and the number of adversity worries measured within the two months prior to COVID-19 infection were used to predict the development of self-reported long COVID and the presence of three specific long COVID symptoms (difficulty with mobility, cognition, and self-care). Logistic regression analyses controlled for a range of COVID-19 infection characteristics, socio-demographics, and health-related factors.
Results - One in five who had been infected with COVID-19 had either been diagnosed with or believed themselves to have had long COVID. Odds of self-reported long COVID increased by 1.31 (95% confidence interval [CI]: 1.04 to 1.64) for each additional worry about adversity in the two months prior to COVID-19 infection. The number of adversity experiences corresponded with increased odds of difficulty with self-care (e.g., dressing, washing all over) by 1.68 (95% CI: 1.08 to 2.61).
Discussion - Results suggest a central role of stress in the time preceding the acute COVID-19 infection for the development of long COVID and point to the importance of prioritising and monitoring COVID-19 patients who have been affected by stress for ongoing care and prevention. A more comprehensive understanding of whether psychosocial circumstances in the time period leading up to infection could aid in identifying early in the disease who is most likely to be negatively impacted due to ongoing symptoms.

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Charmaine van Eeden,Mohammed S. Osman &Jan Willem Cohen Tervaert

Fatigue in ANCA-associated vasculitis (AAV) and systemic sclerosis (SSc): similarities with Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A critical review of the literature

https://doi.org/10.1080/1744666X.2022.2116002

Published

31-Aug-22

Review

https://www.tandfonline.com/doi/abs/10.1080/1744666X.2022.2116002

Introduction
Persistent debilitating fatigue is a frequent complaint in patients with systemic autoimmune rheumatic diseases (SARDs). Fatigue is, however, frequently overlooked in the clinic, and patients who successfully achieve remission of their disease, often still have a lowered quality of life due to its persistence. How similar is this fatigue to Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), what is this fatigue associated with, and what tools/approaches (if any), have resulted in the improvement of fatigue in these patients is poorly defined.
Areas covered
Similarities between the pathophysiology of ME/CFS, systemic sclerosis (SSc) and primary systemic vasculitides (PSV) are discussed, followed by an in-depth review of the prevalence and correlates of fatigue in these diseases. The authors reviewed literature from MEDLINE, APA PsycInfo, Embase, and CINAHL.
Expert opinion
Persistent fatigue is a prominent feature in SARDs and may not be associated with components commonly associated with disease activity and/or progression. Immune and metabolic commonalities exist between ME/CFS, SSc, and PSVs – suggesting that common pathways inherent to the diseases and fatigue may be present. We suggest that patients with features of ME/CFS need to be identified by treating physicians, as they may require alternative approaches to therapy to improve their quality of life.

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LarryAuaCristianCapotescubGilEyalcGabrielleFinestonec

Long covid and medical gaslighting: Dismissal, delayed diagnosis, and deferred treatment

https://doi.org/10.1016/j.ssmqr.2022.100167

Published

7-Sep-22

Article

https://www.sciencedirect.com/science/article/pii/S2667321522001299

Highlights
•Long Covid patients use language of gaslighting to describe physicians interactions.
•Online survey shows experiences of dismissal, delayed diagnosis, and deferred treatment.
•Medical gaslighting likely exacerbated by social inequalities in the United States.
Abstract
While we know a lot more about Long Covid today, patients who were infected with Covid-19 early on in the pandemic and developed Long Covid had to contend with medical professionals who lacked awareness of the potential for extended complications from Covid-19. Long Covid patients have responded by labeling their contentious interactions with medical professionals, organizations, and the broader medical system as “gaslighting.” We argue that the charge of medical gaslighting can be understood as a form of ontological politics. Not only do patients demand that their version of reality be recognized, but they also blame the experts who hold gatekeeping power over their medical care for producing a distorted version of said reality. By analyzing results from an online survey of Long Covid patients active on social media in the United States (n = 334), we find that experiences of contention and their reframing as “gaslighting” were common amongst our respondents. In short answer responses about their experience obtaining medical care for Long Covid, our respondents described encountering medical professionals who dismissed their experience, leading to lengthy diagnostic odysseys and lack of treatment options for Long Covid. Even though we are limited by characteristics of our sample, there is good reason to believe that these experiences and their contentious reframing as medical gaslighting are exacerbated by gender, class, and racial inequalities.

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Simon Haunhorst, Wilhelm Bloch, Heiko Wagner, Claudia Ellert, Karsten Krüger, Daniel C Vilser, Kathrin Finke, Philipp Reuken, Mathias W Pletz, Andreas Stallmach, Christian Puta

Long COVID: a narrative review of the clinical aftermaths of COVID-19 with a focus on the putative pathophysiology and aspects of physical activity

https://doi.org/10.1093/oxfimm/iqac006

Published

16-Sep-22

Review

https://academic.oup.com/ooim/advance-article/doi/10.1093/oxfimm/iqac006/6701971

The pandemic coronavirus disease 2019 (COVID-19) can cause multi-systemic symptoms that can persist beyond the acute symptomatic phase. The post-acute sequelae of COVID-19 (PASC), also referred to as Long COVID, describe the persistence of symptoms and/or long-term complications beyond four weeks from the onset of the acute symptoms and are estimated to affect at least 20% of the individuals infected with SARS-CoV-2 regardless of their acute disease severity. The multi-faceted clinical picture of Long COVID encompasses a plethora of undulating clinical manifestations impacting various body systems such as fatigue, headache, attention disorder, hair loss, and exercise intolerance. The physiological response to exercise testing is characterized by a reduced aerobic capacity, cardiocirculatory limitations, dysfunctional breathing patterns, and an impaired ability to extract and use oxygen. Still, to this day, the causative pathophysiological mechanisms of Long COVID remain to be elucidated, with long-term organ damage, immune system dysregulation, and endotheliopathy being among the hypotheses discussed. Likewise, there is still a paucity of treatment options and evidence-based strategies for the management of the symptoms. In sum, this review explores different aspects of Long COVID and maps the literature on what is known about its clinical manifestations, potential pathophysiological mechanisms, and treatment options.

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Howard Bauchner

It's Time To Create A National Long COVID Compensation Program

https://www.healthaffairs.org/do/10.1377/forefront.20220914.188014

Published

16-Sep-22

Article

https://www.healthaffairs.org/content/forefront/s-time-create-national-long-covid-compensation-program

In the face of this daunting challenge, the US should look to the example of a very successful national program of care. In 1986, after years of debate, Congress created the National Vaccine Injury Compensation Program (NVICP) to ensure a stable supply of vaccines, protect vaccine manufactures from liability claims, and fairly compensate individuals who had very rare medical consequences associated with vaccines.
The new law added a tax to each vaccine administered, pooled the funds, and created a system to compensate individuals injured by a vaccine. It is a no-fault system, involving both HHS and the Department of Justice (DOJ). A claimant, or a representative of the claimant, presents evidence that they have been harmed by a vaccine, medical experts in HHS determine if the claimant meets edibility criteria and the case is referred to the DOJ, and the “vaccine courts” for adjudication.
To help claimants, the program created a vaccine injury table listing which vaccines are associated with which specific injury. Since 1988, more than 5,000 claims, mostly related to the influenza vaccine, have been awarded. This program has protected manufacturers from liability claims and therefore reduced the risk of entering the market, a key step to ensuring a stable vaccine supply and spurring the development and introduction of new vaccines. Virtually every public health group acknowledges this mechanism has allowed for one of the great public health success stories in the US: very high sustained vaccination rates in all children, regardless of socioeconomic status, race, or ethnicity.
With this model in mind, the US should create the NLCCP. Several entities could contribute to such a fund, including pharmaceutical and other companies that have reaped substantial profit since the pandemic began; and health and disability insurers, who would benefit from such a program. Policy makers might also consider adding an additional tax to vaccines to fund the program.
Rather than having disability insurers process claims, many of which will likely be contentious, a group of experts—perhaps lawyers, perhaps clinical authorities, perhaps both—should be charged with determining whether individuals meet pre-specified diagnostic criteria and the corresponding award amounts. (This approach would echo that of the National Vaccine Injury Compensation Program.)
Importantly, those without disability insurance could also file claims, an option that should help minimize disparities in care and compensation. The same group of experts could also determine which treatments for long COVID should be supported by either the program or health insurers. These determinations would be based upon recommendations from professional medical groups and have the added benefit of relieving health insurers of the challenge of making these decisions.

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Robert Leaman1
, Rezarta Islamaj1
, Alexis Allot1
, Qingyu Chen1
, W. John Wilbur1
, and Zhiyong Lu1,2,*

Comprehensive identification of Long Covid articles with human-in-theloop machine learning

Pre-print

1-Sep-22

Study

https://arxiv.org/ftp/arxiv/papers/2209/2209.08124.pdf

Highlights
• We propose a semi-automated classification framework for creating scientific literature
collections with reduced need for human labels.
• Our framework integrates automated classifiers of varying accuracy to provide a reliable
classification for each article and flags articles where human effort is needed.
• We use our framework to identify PubMed articles on Long Covid, also known as post-acute
sequelae of SARS-CoV-2.
• As of November 2021, we identify 5,645 articles relevant to Long Covid – 75.8% of which do not
mention Long Covid by name – and have collected 496 synonymous terms for Long Covid.
A significant percentage of COVID-19 survivors experience ongoing multisystemic symptoms that often affect daily living, a condition known as Long Covid or post-acute-sequelae of SARS-CoV-2 infection. However, identifying Long Covid articles is challenging since articles refer to the condition using a variety of less common terms or refrain from naming it at all. We developed an iterative human-in-the-loop machine learning framework designed to effectively leverage the data available and make the most efficient use of human labels. Specifically, our approach combines data programming with active learning into a robust ensemble model. Evaluating our model on a holdout set demonstrates over three times the sensitivity of other methods. We apply our model to PubMed to create the Long Covid collection, and demonstrate that (1) most Long Covid articles do not refer to Long Covid by any name (2) when the condition is named, the name used most frequently in the biomedical literature is Long Covid, and (3) Long Covid is associated with disorders in a wide variety of body systems. The Long Covid collection is updated weekly and is searchable online at the LitCovid portal:
https://www.ncbi.nlm.nih.gov/research/coronavirus/docsum?filters=e_condition.LongCovid

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Brian Owens

How “long covid” is shedding light on postviral syndromes

https://doi.org/10.1136/bmj.o2188

Published

21-Sep-22

Article

https://www.bmj.com/content/378/bmj.o2188

The global burden of long covid has put a spotlight on the long neglected mystery of postviral syndromes. Brian Owens asks what’s changing.
Unanswered questions
Finding a common cause of the various syndromes would be a breakthrough in postviral syndrome research.
Several hypotheses have been put forward, including persistent but undetected infections, autoimmune responses, dysregulation of the microbiome, and tissue damage.4 But Andrew Lloyd of the University of New South Wales mostly dismisses those ideas. “The lessons we’ve learned from other post-infection syndromes is that it is not a persistent infection, not immunological, not a simple psychological disorder,” he says.
Among researchers who study these illnesses, including long covid, the smart money is now on some kind of disorder of the central nervous system,5 he explains. And since there’s no clear evidence of any major structural problems in the brain, this suggests that the disorder lies at the cellular and protein level.
“There is some circumstantial evidence to support that,” he says. “But nothing concrete yet.”
Treatments
Alba Azola, co-director of the Post-Acute Covid-19 Team at Johns Hopkins University School of Medicine in Baltimore, USA, has been treating patients with lingering covid-19 symptoms since April 2020.
At first, the patients with long covid seemed to have a lot in common with people with postural orthostatic tachycardia syndrome (POTS), a blood circulation disorder characterised by elevated heart rate and other symptoms brought on by standing up, as fatigue and brain fog are also common symptoms of that condition. So Azola, a physical and rehabilitation physician, along with a team of physiotherapists, started treating these patients using the same protocols as for POTS, focusing on things such as diet and exercise.
But after about three months it was clear that this exercise focused treatment regimen was not working. The team realised that long covid was more like ME/CFS, says Azola, and began drawing on ideas from that area instead. This meant focusing on managing and conserving energy levels and understanding which triggers can bring on fatigue, to get off what she calls the “corona-coaster,” where patients start to feel better, become more active, and then crash.
She says that, in the absence of a reliable treatment or cure, patients need to learn to live with the condition by being selective with their energy and what they invest it in, which can be as simple as using a chair in the shower to avoid unnecessary exertion. “I learned all of this from the ME/CFS community,” she says.

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Ethan B. Jansen,Spencer N. Orvold,Cynthia L. Swan,Anthony Yourkowski,Brittany M. Thivierge,Magen E. Francis,Anni Ge,Melissa Rioux,Joseph Darbellay,John G. Howland,Alyson A. Kelvin

After the virus has cleared—Can preclinical models be employed for Long COVID research?

https://doi.org/10.1371/journal.ppat.1010741

Published

7-Sep-22

Review

https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1010741

Abstract
Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) can cause the life-threatening acute respiratory disease called COVID-19 (Coronavirus Disease 2019) as well as debilitating multiorgan dysfunction that persists after the initial viral phase has resolved. Long COVID or Post-Acute Sequelae of COVID-19 (PASC) is manifested by a variety of symptoms, including fatigue, dyspnea, arthralgia, myalgia, heart palpitations, and memory issues sometimes affecting between 30% and 75% of recovering COVID-19 patients. However, little is known about the mechanisms causing Long COVID and there are no widely accepted treatments or therapeutics. After introducing the clinical aspects of acute COVID-19 and Long COVID in humans, we summarize the work in animals (mice, Syrian hamsters, ferrets, and nonhuman primates (NHPs)) to model human COVID-19. The virology, pathology, immune responses, and multiorgan involvement are explored. Additionally, any studies investigating time points longer than 14 days post infection (pi) are highlighted for insight into possible long-term disease characteristics. Finally, we discuss how the models can be leveraged for treatment evaluation, including pharmacological agents that are currently in human clinical trials for treating Long COVID. The establishment of a recognized Long COVID preclinical model representing the human condition would allow the identification of mechanisms causing disease as well as serve as a vehicle for evaluating potential therapeutics.
Author summary
Not everyone who develops COVID-19 (Coronavirus Disease 2019) recovers completely after 5 days, 14 days, or even 12 weeks. People who experience continuing or new symptoms such as fatigue, difficulty breathing, joint pain, heart dysfunction, and memory issues are now recognized as having “Long COVID” or Post-Acute Sequelae of COVID-19 (PASC). Although Long COVID has been estimated to affect 30% to 75% of recovering COVID-19 patients in some studies, the illness is poorly understood, leaving us unable to properly support patients in their recovery. Here, we summarize COVID-19 and Long COVID in people then discuss the potential utility of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) animal models to address problems of Long COVID. We review SARS-CoV-2 infection and disease manifestations in mice, Syrian hamsters, ferrets, and nonhuman primates (NHPs). Specifically, the virology, pathology, immune responses, and multiorgan involvement are summarized. These models are rationally examined for their use in understanding the complexities of the multiorgan involvement during Long COVID and the potential for their use in screening therapeutics such as anti-inflammatory drugs, which are currently used for treating other diseases. The aim of this review is to highlight Long COVID preclinical animal models that could be used for Long COVID research and to screen for pharmacological interventions.

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Puja Mehta, Ivan O. Rosas & Mervyn Singer

Long Covid: where we stand and challenges ahead

https://doi.org/10.1038/s41418-022-01052-6

Published

7-Sep-22

Review

https://www.nature.com/articles/s41418-022-01052-6

Post-acute sequelae of SARS-CoV-2 (PASC), also known as Post-Covid Syndrome, and colloquially as Long Covid, has been defined as a constellation of signs and symptoms which persist for weeks or months after the initial SARS-CoV-2 infection. PASC affects a wide range of diverse organs and systems, with manifestations involving lungs, brain, the cardiovascular system and other organs such as kidney and the neuromuscular system. The pathogenesis of PASC is complex and multifactorial. Evidence suggests that seeding and persistence of SARS-CoV-2 in different organs, reactivation, and response to unrelated viruses such as EBV, autoimmunity, and uncontrolled inflammation are major drivers of PASC. The relative importance of pathogenetic pathways may differ in different tissue and organ contexts. Evidence suggests that vaccination, in addition to protecting against disease, reduces PASC after breakthrough infection although its actual impact remains to be defined. PASC represents a formidable challenge for health care systems and dissecting pathogenetic mechanisms may pave the way to targeted preventive and therapeutic approaches.
Facts
PASC is a frequent legacy of acute SARS-CoV-2 infection, affecting over 10% of patients with different signs and symptoms across a wide range of organs and systems.
The most frequent manifestations of PASC, in addition to compromised lung functions, include: neurocognitive alterations; alterations of cardiovascular functions and increased risk of acute events; fatigue.
The SARS-CoV-2 virus seeds and persists in different organs and tissues.
The pathogenesis of PASC is multifactorial and includes: virus seeding and persistence in different organs; activation and response to unrelated viruses (e.g., EBV); autoimmunity; uncontrolled inflammation.
Biomarkers of clinical PASC include levels of IgG, cytokines, chemokines, PTX3, and interferons.
Vaccination reduces PASC after breakthrough infection.
Open questions
Occurrence, mechanism, and significance of SARS-CoV-2 persistence in different organs.
Mechanisms, targets, and significance of autommune reactions.
Role of other viruses.
Impact of host genetics and microbiome.
Actual impact of vaccination in people who get breakthrough infections and its duration.
Occurrence and severity of PASC after infection with future variants.
Preventive and therapeutic approaches.

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F.AlghamdiaR.OwenbR.E.M.AshtonbA.D.ObotibaaR.M.MeertensaE.HydecM.A.FaghybK.M.KnappaP.RogersdW.D.Straina

Post-acute COVID syndrome (long COVID): What should radiographers know and the potential impact for imaging services

https://doi.org/10.1016/j.radi.2022.08.009

Published

13-Sep-22

Review

https://www.sciencedirect.com/science/article/pii/S1078817422001195

Objectives
The COVID-19 pandemic caused an unprecedented health crisis resulting in over 6 million deaths worldwide, a figure, which continues to grow. In addition to the excess mortality, there are individuals who recovered from the acute stages, but suffered long-term changes in their health post COVID-19, commonly referred to as long COVID. It is estimated there are currently 1.8 million long COVID sufferers by May 2022 in the UK alone. The aim of this narrative literature review is to explore the signs, symptoms and diagnosis of long COVID and the potential impact on imaging services.

Key findings
Long COVID is estimated to occur in 9.5% of those with two doses of vaccination and 14.6% if those with a single dose or no vaccination. Long COVID is defined by ongoing symptoms lasting for 12 or more weeks post acute infection. Symptoms are associated with reductions in the quality of daily life and may involve multisystem manifestations or present as a single symptom.

Conclusion
The full impact of long COVID on imaging services is yet to be realised, but there is likely to be significant increased demand for imaging, particularly in CT for the assessment of lung disease. Educators will need to include aspects related to long COVID pathophysiology and imaging presentations in curricula, underpinned by the rapidly evolving evidence base.

Implications for practice
Symptoms relating to long COVID are likely to become a common reason for imaging, with a particular burden on Computed Tomography services. Planning, education and updating protocols in line with a rapidly emerging evidence base is going to be essential.

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Arthur A. Mirin,Mary E. Dimmock &Leonard A. JasonORCID Icon

A preliminary estimate of the economic impact of long COVID in the United States

https://doi.org/10.1080/21641846.2022.2124064

Published

13-Sep-22

Article

https://www.tandfonline.com/doi/abs/10.1080/21641846.2022.2124064

Post-Acute Sequelae of SARS CoV-2 infection (PASC), more commonly referred to as Long COVID, is one of the most daunting health-care grand challenges facing the United States today. Affecting millions of Americans, Long COVID extracts a huge cost both socially and economically. In this article, we provide a preliminary estimate of the annual income loss and medical costs due to Long COVID in the United States. With many Long COVID patients either meeting the diagnostic criteria for myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) or exhibiting symptoms consistent with ME/CFS, we utilize ME/CFS to help guide our estimates. Based on the nearly 86 million documented US COVID survivors as of June 25, 2022, and considering a range of 5% to 20% of those survivors currently afflicted with Long COVID, we estimate annual medical costs to range from $43 billion to $172 billion, and lost income to range from $101 billion to $430 billion. This corresponds to an annual economic impact (exclusive of costs of disability services, social services, and lost income on the part of caretakers) ranging from roughly $140 billion to $600 billion.

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Kieran L. Quinn, Gabrielle M. Katz, Pavlos Bobos, Beate Sander, Candace D. McNaughton, Angela M. Cheung, Margaret S. Herridge, Clare L. Atzema, Karen B. Born, Christine Chan, Vincent Chien, David M. Kaplan, Jeffrey Kwong, Susan Leung, Linda Mah, Sharmistha Mishra, Andrew M. Morris, Christopher J. Mushquash, Karen Palmer, Alexandra Rendely, Arthur S. Slutsky, Rosa Stalteri, Fahad A. Razak

Understanding the Post COVID-19 Condition (Long COVID) in Adults and the Expected Burden for Ontario

https://doi.org/10.47326/ocsat.2022.03.65.1.0

Published

7-Sep-22

Study

https://covid19-sciencetable.ca/sciencebrief/understanding-the-post-covid-19-condition-long-covid-in-adults-and-the-expected-burden-for-ontario/

Key Message
The post COVID-19 condition is a complex and heterogeneous syndrome that develops in people with prior SARS-CoV-2 infection. More than 100 symptoms have been reported in people with the post COVID-19 condition, and these appear to be associated with reduced quality of life, reduced function, and impairments in people’s ability to work and care for themselves. There remains significant uncertainty in the definition, magnitude of prevalence, causes, risk factors, prevention, and prognosis of the post COVID-19 condition, as well as its impact on people’s quality of life, function, and ability to work. Nonetheless, the reported range of these effects in the published literature suggests that the post COVID-19 condition poses substantial health risks to adults across a diverse range of outcomes that have the potential to impart a considerable burden on individuals and healthcare systems. More contemporary evidence in the era of widespread vaccination and emerging variants resulting in less severe illness than earlier variants suggests that the post COVID-19 condition may now be less frequent following SARS-CoV-2 infection. Still, a proactive and comprehensive strategy to manage the post COVID-19 condition needs to be developed by health systems and policy makers. This strategy should include substantial investments in research and health system resources to mitigate the long-term health, social, and economic impacts of the post COVID-19 condition in Ontario.
Summary
Background
The post COVID-19 condition is a complex and heterogeneous syndrome that can develop in people with prior SARS-CoV-2 infection. The goal of this Science Brief is to identify and support the healthcare care needs of adults living with the post COVID-19 condition and their caregivers, and to inform health system and social resource planning to be able to meet those needs.
Questions
How has the post COVID-19 condition been defined?
What are the potential underlying causes of the post COVID-19 condition?
What is the prevalence of the post COVID-19 condition?
What are the symptoms and sequelae of the post COVID-19 condition?
Who is at risk of developing the post COVID-19 condition, and can this risk be mitigated?
What is the impact of the post COVID-19 condition on functional limitations, health system utilization, and utilization of long-term disability and unemployment benefits?
How are healthcare systems delivering care to people with the post COVID-19 condition?
What barriers exist to providing clinical support to those with the post COVID-19 condition?
What are the current knowledge gaps about the post COVID-19 condition?
Findings
The post COVID-19 condition is variably defined as the persistence of symptoms or sequelae occurring at least 4 or 12 weeks after probable or confirmed SARS-CoV-2 infection. Combined evidence estimates the prevalence of new or persistent symptoms at 4 or more weeks from SARS-CoV-2 infection to be 43% (54% among hospitalized persons, including those admitted to the intensive care unit, and 34% among those who are not hospitalized) and between 10-20% at 12 or more weeks, depending on the definition and data used to inform those estimates. Data from more recent pandemic time periods suggests a much lower overall prevalence. The five most frequently observed individual symptoms were fatigue (23%, 95% confidence interval (CI) 17-30), memory deficits (14%, 95% CI 10-19), shortness of breath (13%, 95% CI 0.11-0.15), sleep problems (11%, 95% CI 5-23), and joint pain (10%, 95% CI 4-22). The systemic nature of the condition is believed to be related to viral persistence, inflammation, autoimmunity, and/or coagulopathy. More than 100 symptoms have been reported in people with the post COVID-19 condition, and these appear to be associated with reduced function, impairments in people’s ability to work and care for themselves, poor quality of life, and high healthcare use. Vaccination against COVID-19 with one or two doses of vaccine prior to SARS-CoV-2 infection was associated with a reduction of approximately 50% in the risk of developing lingering symptoms at either time point. The benefits of vaccination in reducing the development of the post COVID-19 condition were also observed in people who were vaccinated after SARS-CoV-2 infection, as well as potentially in those with established post COVID–19 condition. High-quality care for people with the post COVID-19 condition is limited by a lack of proven therapies, potential inequities in care that are driven by limited access to primary and specialized care, and inconsistent application of insurance policies for reimbursement. There is also variable use of and lack of diagnostic and physician fee codes to track and evaluate care delivery and outcomes at a population level.
Interpretation
The post COVID-19 condition poses substantial health risks across a diverse range of outcomes that may result in a considerable burden for Ontarians, the economy, and the healthcare system. More contemporary evidence in the era of widespread vaccination and emerging variants resulting in less severe illness than earlier variants suggests that the post COVID-19 condition may now be less frequent following SARS-CoV-2 infection. Due to limitations in the quality of available published evidence, however, there remains significant uncertainty in the definition, prevalence, causes, risk factors, prevention, and prognosis of the post COVID-19 condition, as well as its impact on people’s quality of life, function, and ability to work. There is also considerable uncertainty about the magnitude of these potential effects. Nonetheless, a proactive and comprehensive strategy to manage the post COVID-19 condition needs to be developed by health systems and policymakers. This strategy should include substantial investments in research and health system resources to mitigate the long-term health, social, and economic impacts of the post COVID-19 condition in Ontario.

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AXD

Afagh Garjani, View ORCID ProfileRodden M. Middleton, View ORCID ProfileRichard Nicholas, View ORCID ProfileNikos Evangelou

Recovery From COVID-19 in Multiple Sclerosis
A Prospective and Longitudinal Cohort Study of the United Kingdom Multiple Sclerosis Register

https://doi.org/10.1212/NXI.0000000000001118

Published

30-Nov-21

Study

https://nn.neurology.org/content/9/1/e1118

Background and Objectives To understand the course of recovery from coronavirus disease 2019 (COVID-19) among patients with multiple sclerosis (MS) and to determine its predictors, including patients' pre–COVID-19 physical and mental health status.
Methods This prospective and longitudinal cohort study recruited patients with MS who reported COVID-19 from March 17, 2020, to March 19, 2021, as part of the United Kingdom MS Register (UKMSR) COVID-19 study. Participants used online questionnaires to regularly update their COVID-19 symptoms, recovery status, and duration of symptoms for those who fully recovered. Questionnaires were date stamped for estimation of COVID-19 symptom duration for those who had not recovered at their last follow-up. The UKMSR holds demographic and up-to-date clinical data on participants as well as their web-based Expanded Disability Status Scale (web-EDSS) and Hospital Anxiety and Depression Scale (HADS) scores. The association between these factors and recovery from COVID-19 was assessed using multivariable Cox regression analysis.
Results Of the 7,977 patients with MS who participated in the UKMSR COVID-19 study, 599 reported COVID-19 and prospectively updated their recovery status. Twenty-eight hospitalized participants were excluded. At least 165 participants (29.7%) had long-standing COVID-19 symptoms for ≥4 weeks and 69 (12.4%) for ≥12 weeks. Participants with pre–COVID-19 web-EDSS scores ≥7, participants with probable anxiety and/or depression (HADS scores ≥11) before COVID-19 onset, and women were less likely to report recovery from COVID-19.
Discussion Patients with MS are affected by postacute sequelae of COVID-19. Preexisting severe neurologic impairment or mental health problems appear to increase this risk. These findings can have implications in tailoring their post–COVID-19 rehabilitation.

to Zotero

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AXD

Jana L Hirschtick, Andrea R Titus, Elizabeth Slocum, Laura E Power, Robert E Hirschtick, Michael R Elliott, Patricia McKane, Nancy L Fleischer

Population-Based Estimates of Post-acute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection (PASC) Prevalence and Characteristics

https://doi.org/10.1093/cid/ciab408

Published

19-May-21

Study

https://academic.oup.com/cid/article/73/11/2055/6276644

Background
Emerging evidence suggests many people have persistent symptoms after acute coronavirus disease 2019 (COVID-19) illness. Our objective was to estimate the prevalence and correlates of post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC).
Methods
We used a population-based probability survey of adults with COVID-19 in Michigan. Living noninstitutionalized adults aged ≥18 in the Michigan Disease Surveillance System with COVID-19 onset through mid-April 2020 were eligible for selection (N = 28 000). Among 2000 selected, 629 completed the survey between June–December 2020. We estimated PASC prevalence, defined as persistent symptoms ≥30 (30-day COVID-19) or ≥60 (60-day COVID-19) days post–COVID-19 onset, overall and by sociodemographic and clinical factors. We used modified Poisson regression to produce adjusted prevalence ratios (aPRs) for potential risk factors.
Results
The analytic sample (n = 593) was predominantly female (56.1%), aged ≥45 years (68.2%), and non-Hispanic White (46.3%) or Black (34.8%). Thirty- and 60-day COVID-19 were highly prevalent (52.5% and 35.0%), even among nonhospitalized respondents (43.7% and 26.9%) and respondents reporting mild symptoms (29.2% and 24.5%). Respondents reporting very severe (vs mild) symptoms had 2.25 times higher prevalence of 30-day COVID-19 (aPR, 2.25; 95% CI, 1.46–3.46) and 1.71 times higher prevalence of 60-day COVID-19 (aPR, 1.71; 95% CI: 1.02–2.88). Hospitalized (vs nonhospitalized) respondents had ~40% higher prevalence of both 30-day (aPR, 1.37; 95% CI: 1.12–1.69) and 60-day (aPR, 1.40; 95% CI: 1.02–1.93) COVID-19.
Conclusions
PASC is highly prevalent among cases reporting severe initial symptoms and, to a lesser extent, cases reporting mild and moderate symptoms.

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Rachel L. Levine

Addressing the Long-term Effects of COVID-19

https://doi.org/10.1001/jama.2022.14089

Published

3-Aug-22

Viewpoint

https://jamanetwork.com/journals/jama/fullarticle/2795139

Conclusions

Long COVID and associated conditions as well as the longer-term sequelae of the pandemic will continue to affect patients and families. The medical and public health community have made dedicated efforts during the last 2½ years to stopping the spread of this deadly coronavirus and have implemented prevention methods, developed treatments, and released vaccines that have been central to reducing initial COVID-19 infections and preventing Long COVID.

It is important to focus a new lens on the pandemic and direct much-needed attention to Long COVID. Taking care of affected patients presents challenges given the incompleteness of research, the lack of sufficient diagnostics support, and pervasive problems with access to services. The provisions in the presidential memo are important elements for mounting an effective approach for addressing the long-term effects of COVID.

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Nina Smyth ,Nisreen A. Alwan ,Rebecca Band,Ashish Chaudhry,Carolyn A. Chew-Graham,Dipesh Gopal,Monique Jackson,Tom Kingstone,Alexa Wright,Damien Ridge

Exploring the lived experience of Long Covid in black and minority ethnic groups in the UK: Protocol for qualitative interviews and art-based methods

https://doi.org/10.1371/journal.pone.0275166

Published

3-Oct-22

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0275166

Some people experience prolonged symptoms following an acute COVID-19 infection including fatigue, chest pain and breathlessness, headache and cognitive impairment. When symptoms persist for over 12 weeks following the initial infection, and are not explained by an alternative diagnosis, the term post-COVID-19 syndrome is used, or the patient-defined term of Long Covid. Understanding the lived experiences of Long Covid is crucial to supporting its management. However, research on patient experiences of Long Covid is currently not ethnically diverse enough. The study aim is to explore the lived experience of Long Covid, using qualitative interviews and art-based methods, among people from ethnically diverse backgrounds (in the UK), to better understand wider systems of support and healthcare support needs. Co-created artwork will be used to build on the interview findings. A purposive sampling strategy will be used to gain diverse experiences of Long Covid, sampling by demographics, geographic locations and experiences of Long Covid. Individuals (aged >18 years) from Black and ethnic minority backgrounds, who self-report Long Covid symptoms, will be invited to take part in a semi-structured interview. Interviews will be analysed thematically. A sub-sample of participants will be invited to co-create visual artwork to further explore shared narratives of Long Covid, enhance storytelling and increase understanding about the condition. A patient advisory group, representing diversity in ethnicity and experiences of Long Covid, will inform all research stages. Stakeholder workshops with healthcare professionals and persons, systems or networks important to people’s management of Long Covid, will advise on the integration of findings to inform management of Long Covid. The study will use patient narratives from people from diverse ethnic backgrounds, to raise awareness of Long Covid and help inform management of Long Covid and how wider social systems and networks may inform better healthcare service access and experiences.

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Jonathan Koss 1 Author Orcid Image ; Sabine Bohnet-Joschko 1 Author Orcid Image

Social Media Mining of Long-COVID Self-Medication Reported by Reddit Users: Feasibility Study to Support Drug Repurposing

https://doi.org/10.2196/39582

Published

Study

https://formative.jmir.org/2022/10/e39582/

Background:
Since the beginning of the COVID-19 pandemic, over 480 million people have been infected and more than 6 million people have died from COVID-19 worldwide. In some patients with acute COVID-19, symptoms manifest over a longer period, which is also called “long-COVID.” Unmet medical needs related to long-COVID are high, since there are no treatments approved. Patients experiment with various medications and supplements hoping to alleviate their suffering. They often share their experiences on social media.
Objective:
The aim of this study was to explore the feasibility of social media mining methods to extract important compounds from the perspective of patients. The goal is to provide an overview of different medication strategies and important agents mentioned in Reddit users’ self-reports to support hypothesis generation for drug repurposing, by incorporating patients’ experiences.
Methods:
We used named-entity recognition to extract substances representing medications or supplements used to treat long-COVID from almost 70,000 posts on the “/r/covidlonghaulers” subreddit. We analyzed substances by frequency, co-occurrences, and network analysis to identify important substances and substance clusters.
Results:
The named-entity recognition algorithm achieved an F1 score of 0.67. A total of 28,447 substance entities and 5789 word co-occurrence pairs were extracted. “Histamine antagonists,” “famotidine,” “magnesium,” “vitamins,” and “steroids” were the most frequently mentioned substances. Network analysis revealed three clusters of substances, indicating certain medication patterns.
Conclusions:
This feasibility study indicates that network analysis can be used to characterize the medication strategies discussed in social media. Comparison with existing literature shows that this approach identifies substances that are promising candidates for drug repurposing, such as antihistamines, steroids, or antidepressants. In the context of a pandemic, the proposed method could be used to support drug repurposing hypothesis development by prioritizing substances that are important to users.

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ME

Wolfgang Hausotter

Long- und Post-COVID versus Chronic Fatigue Syndrome
Chronische Erschöpfungssyndrome im Vergleich

https://doi.org/10.1007/s15202-022-5508-1

Published

4-Oct-22

Article

https://link.springer.com/article/10.1007/s15202-022-5508-1

Das Chronic Fatigue Syndrome ist seit vielen Jahren bekannt und fasst die immer wieder beschriebene Symptomatik der chronischen Müdigkeit und vorzeitigen Erschöpfbarkeit mit den verschiedenen Begleitbeschwerden zusammen. Eine überzeugende Erklärung für das Syndrom fand sich bislang nicht. Wird CFS nun mit dem erst seit zwei Jahren beobachteten Post-COVID-Syndrom verglichen, ergeben sich eklatante Parallelen. So ist die Symptomatik bei CFS und Post-COVID-19 im Grunde identisch. Wie beim Post-COVID-Syndrom wird auch beim CFS seit Jahrzehnten ein Zusammenhang mit einer Virusinfektion etwa Epstein-Barr- oder Herpesvirus diskutiert, ohne dass dahingehend ein wissenschaftlicher Konsens erzielt werden konnte. Ebenso wurde die Möglichkeit einer psychischen Ursache über eine längere Zeit erwogen, jedoch konnte sie in den meisten Fällen nicht überzeugend belegt werden. Im Vergleich dazu besteht beim Post-COVID-Syndrom ein enger zeitlicher Zusammenhang mit der akuten SARS-CoV-2-Infektionskrankheit und dadurch eine allgemeine wissenschaftliche Übereinstimmung hinsichtlich einer viralen Genese.
Die neu aufgetretene Infektion COVID-19 lässt daher die lange bekannte Krankheitsentität CFS in neuem Licht erscheinen. Obgleich bisher kein allgemein anerkannter Beweis für eine Virusgenese vorliegt, ist es naheliegend, diese frühere Theorie für die Entstehung eines CFS wieder aufzugreifen.
Eine ausschließlich psychische Genese kann dann wohl nicht mehr angenommen werden. Psychische Störungen sind dementsprechend eher als Folgeerscheinungen zu werten - der erlebten Beeinträchtigung, der Hilflosigkeit, der Einschränkung sozialer Kontakte, der negativen Emotionen und Kognitionen durch die ständige Müdigkeit und Erschöpfung im Sinne eines biopsychosozialen Krankheitsmodells.
Fazit für die Praxis
Das seit Jahrzehnten bekannte und umstrittene Chronic Fatigue Syndrome, wofür bis heute, trotz zweifellos im Einzelfall, schwerwiegender subjektiver Beeinträchtigung, keine objektiven Nachweise bestehen, hat seit zwei Jahren im Rahmen der COVID-19-Erkrankung außerordentliche Parallelen im Long- und Post-COVID-Syndrom gefunden. Frühere Diskussionen über eine mögliche Virusgenese sind dadurch wieder aktuell geworden, sodass die Annahme einer rein seelischen Störung nicht mehr überzeugt - obgleich nach wie vor entsprechende allgemein akzeptierte Belege dafür fehlen.

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DavidRussellaNaomi J.SpencebJo-Ana D.ChasecTatumSchwartzaChrista M.TumminellodErinBouldin

Support amid uncertainty: Long COVID illness experiences and the role of online communities

https://doi.org/10.1016/j.ssmqr.2022.100177

Published

4-Oct-22

Interview Study

https://www.sciencedirect.com/science/article/pii/S2667321522001391

Highlights
•Long COVID is experienced as a complex and unpredictable illness.
•Uncertainty surrounding Long COVID was heightened early in the pandemic.
•Many with Long COVID experienced medical gaslighting in healthcare interactions.
•Online communities for Long COVID provided validation of illness and social support.
Abstract
Long COVID is characterized by persistent and debilitating long-term symptoms from COVID-19. Many persons with Long COVID began gathering in online communities during the early phases of the pandemic to share their illness experiences. This qualitative interview study explored the subjective experiences of 20 persons with Long COVID recruited from five online communities. Their understandings of illness and associated implications for social relationships with family and friends, healthcare professionals, and online community members were explored. Three themes were identified from our analysis, including (1) complex and unpredictable illness experienced amid an evolving understanding of the pandemic; (2) frustration, dismissal, and gaslighting in healthcare interactions; and (3) validation and support from online communities. These findings highlight the significant uncertainty that persons with Long COVID navigated, the features of their often dismaying healthcare experiences, and the ways in which online communities aided them in understanding their illness.

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VerónicaTíscar-GonzálezabcdSheilaSánchez-GómezefAnaLafuente MartínezeAnaPeña SerranoeMartaTwose LópezeSofíaDíaz AlonsoeMartaBartolomé-RupérezgJanirePortuondo-JiménezahIñakiZorrilla-Martínezefi

Vivencias e impacto en la calidad de vida de personas con COVID persistenteExperiences and impact on the quality of life of people with long COVID

https://doi.org/10.1016/j.gaceta.2022.102247

Published

1-Oct-22

Study

https://www.sciencedirect.com/science/article/pii/S0213911122001285?via%3Dihub

Objective
To explore the experiences of people with persistent COVID in the Basque Country more than a year after the start of the pandemic, in order to understand the health and social impact it has, as well as to detect possible areas for improvement in the care that these people receive in order to develop health programms to support their recovery.
Method
Qualitative phenomenological study. In-depth interviews will be carried out as a data collection technique until saturation of the discourse. Patients of legal age who present persistent COVID symptomatology with an evolution time of more than 12 weeks were included. Contact with the patients was made through the Basque Long COVID Collective. The interviews were carried out and recorded through the ZOOM application. After the literal transcription of the interviews, the thematic analysis will be carried out, identifying the first units of meaning and assigning codes that will later be grouped into the different categories.
Results
20 patients participated. A total of three main categories emerged from the analysis of the discourses: 1) affecting/impacting patients’ quality of life; 2) identifying improvements in healthcare; and 3) comforting aspects.
Conclusions
This study shows the significant impact on the quality of life suffered by these people. It is necessary to design health policies that favour a personalised, comprehensive and multidisciplinary approach to these patients.

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KaiFischeraJ. JamesReadebW. BenediktSchmal

What cannot be cured must be endured: The long-lasting effect of a COVID-19 infection on workplace productivity

https://doi.org/10.1016/j.labeco.2022.102281

Published

6-Oct-22

Study

https://www.sciencedirect.com/science/article/pii/S0927537122001713

Highlights
•We estimate the causal effect of a COVID-19 infection on individual productivity.
•We identify a population effect as all true infections are identified.
•We find a persistent deterioration for more than half a year after an infection.
•Other respiratory infections do not have the same effect.
•Individual productivity is negatively affected by infections of colleagues.
Abstract
The COVID-19 pandemic has triggered economic shock waves across the globe. Exploiting a natural experiment, this paper estimates how being infected with the virus shapes individual-level productivity after having recovered. Studying the performance of professional athletes in Germany and Italy and applying a staggered difference-in-differences design, we find that individual performance drops by around 6 percent after a previously infected athlete returns to the pitch. This striking deterioration remains persistent over time – amounting to 5% eight months after the infection. The effect increases with age and infection severity, and is spread disproportionally over the course of a match. We detect no productivity effects for other respiratory infections. We take these findings as first evidence that the pandemic might cause long-lasting effects on worker productivity and economic growth.

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Sabina Mirza

Supporting staff with long COVID and making reasonable adjustments

https://doi.org/10.1038/s41404-022-1739-2

Published

10-Oct-22

Article

https://www.nature.com/articles/s41404-022-1739-2

The Equality and Human Rights Commission (EHRC) has clarified that not all people with long COVID will be classed as disabled under the Equality Act 2010.2 Whether a person's long COVID will be considered a disability, will depend on the severity and duration of the symptoms. This issue was recently considered at the preliminary employment tribunal hearing of Burke v Turning Point Scotland.3 The Tribunal found that Mr Burke's 'post viral fatigue syndrome' in which he experienced substantial and long-term side effects arising from him contracting COVID-19 in November 2020, was a disability.
This decision does not automatically mean that every person suffering from long COVID will be classed as a disabled person, and each case will need to be reviewed separately and assessed on its own facts. It is advisable for you to carefully consider whether a staff member who reports suffering from long COVID, meets the definition of disability under the Equality Act 2010. If so your statutory duty to make 'reasonable adjustments' in the workplace will apply to them. So, if you agreed for a staff member with COVID related long term heart problems to undertake some duties at home, then if this medical condition is recognised as a disability, it would be difficult to justify why this working arrangement could not continue for that staff member as a 'reasonable' adjustment.
A staff member with long COVID could be discriminated against if their symptoms are not recognised in line with the definition of disability under the Equality Act. If the employer fails to implement reasonable adjustments, the staff member could pursue a disability discrimination claim. Therefore, it is advisable for you to apply the same considerations to a staff member with long COVID as you would for a staff member with any long-term health condition or disability. There is no cap on the award a judge can give for disability discrimination so it is always better to take a cautious position. Furthermore a discrimination claim, whether successful or not (especially if related to COVID-19) is likely to generate negative publicity for a dental practice. It may also create irreparable damage to your dental practices image and patient base, where some of your patients will have disabilities or suffer from long COVID.
' The onus is on the employer to show any adjustments implemented are reasonable when a disabled person is placed at a substantial disadvantage. Sometimes, it can be difficult to determine what is considered 'reasonable'.'

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CPET

Matthew S. Durstenfeld, MD, MAS1,2; Kaiwen Sun, MD1; Peggy Tahir, MLIS, MA3; Michael J. Peluso, MD, MHS, MPhil, DTMH1,4; Steven G. Deeks, MD1,4; Mandar A. Aras, MD, PhD1,5; Donald J. Grandis, MD1,5; Carlin S. Long, MD1,5; Alexis Beatty, MD1,5,6; Priscilla Y. Hsue, MD1,2

Use of Cardiopulmonary Exercise Testing to Evaluate Long COVID-19 Symptoms in Adults
A Systematic Review and Meta-analysis

https://doi.org/10.1001/jamanetworkopen.2022.36057

Published

12-Oct-22

Systematic Review and Meta-analysis

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2797203

Key Points
Question Is exercise capacity reduced more than 3 months after SARS-CoV-2 infection among those with long COVID-19 (LC) symptoms compared with recovered individuals without symptoms, and what patterns of limitations on cardiopulmonary exercise testing (CPET) are common?
Findings In this systematic review and meta-analysis of 38 studies comprising 2160 participants, exercise capacity was reduced by 4.9 mL/kg/min among individuals with symptoms consistent with LC compared with individuals without symptoms more than 3 months after SARS-CoV-2 infection. Findings among individuals with exertional intolerance suggest that deconditioning, dysfunctional breathing, chronotropic incompetence, and abnormal peripheral oxygen extraction and/or use may contribute to reduced exercise capacity.
Meaning These findings suggest that CPET may provide insight into the mechanisms for reduced exercise capacity among individuals with LC.
Abstract
Importance Reduced exercise capacity is commonly reported among individuals with COVID-19 symptoms more than 3 months after SARS-CoV-2 infection (long COVID-19 [LC]). Cardiopulmonary exercise testing (CPET) is the criterion standard to measure exercise capacity and identify patterns of exertional intolerance.
Objectives To estimate the difference in exercise capacity among individuals with and without LC symptoms and characterize physiological patterns of limitations to elucidate possible mechanisms of LC.
Data Sources A search of PubMed, EMBASE, Web of Science, preprint servers, conference abstracts, and cited references was performed on December 20, 2021, and again on May 24, 2022. A preprint search of medrxiv.org, biorxiv.org, and researchsquare.com was performed on June 9, 2022.
Study Selection Studies of adults with SARS-CoV-2 infection more than 3 months earlier that included CPET-measured peak oxygen consumption (V̇o2) were screened independently by 2 blinded reviewers; 72 (2%) were selected for full-text review, and 35 (1%) met the inclusion criteria. An additional 3 studies were identified from preprint servers.
Data Extraction and Synthesis Data extraction was performed by 2 independent reviewers according to the PRISMA reporting guideline. Data were pooled using random-effects models.
Main Outcomes and Measures Difference in peak V̇o2 (in mL/kg/min) among individuals with and without persistent COVID-19 symptoms more than 3 months after SARS-CoV-2 infection.
Results A total of 38 studies were identified that performed CPET on 2160 individuals 3 to 18 months after SARS-CoV-2 infection, including 1228 with symptoms consistent with LC. Most studies were case series of individuals with LC or cross-sectional assessments within posthospitalization cohorts. Based on a meta-analysis of 9 studies including 464 individuals with LC symptoms and 359 without symptoms, the mean peak V̇o2 was −4.9 (95% CI, −6.4 to −3.4) mL/kg/min among those with symptoms with a low degree of certainty. Deconditioning and peripheral limitations (abnormal oxygen extraction) were common, but dysfunctional breathing and chronotropic incompetence were also described. The existing literature was limited by small sample sizes, selection bias, confounding, and varying symptom definitions and CPET interpretations, resulting in high risk of bias and heterogeneity.
Conclusions and Relevance The findings of this systematic review and meta-analysis study suggest that exercise capacity was reduced more than 3 months after SARS-CoV-2 infection among individuals with symptoms consistent with LC compared with individuals without LC symptoms, with low confidence. Potential mechanisms for exertional intolerance other than deconditioning include altered autonomic function (eg, chronotropic incompetence, dysfunctional breathing), endothelial dysfunction, and muscular or mitochondrial pathology.

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I Nagyova

Long COVID and NCDs: the Elephant in the Room: Iveta Nagyova

https://doi.org/10.1093/eurpub/ckac129.140

Published

25-Oct-22

Article

https://academic.oup.com/eurpub/article/32/Supplement_3/ckac129.140/6766365

Issue/problem
COVID-19 has now emerged as a public health concern that not only disrupted healthcare services of people living with non-communicable diseases (NCDs) but likely also increase the burden of NCDs.
Description of the problem
Before the pandemic, SDG target 3.4, which calls for a reduction in premature mortality from NCDs by one third by 2030, was expected to be achieved by 17.5% of countries, and a further of 23% could achieve the target with a slight acceleration in decline. Currently, most countries are off track due to disruption of healthcare services for people with NCDs, overstretched health systems, and fewer resources than before the pandemic. In addition, only around one in four people who had COVID-19 reported feeling fully recovered within a year of being discharged from hospital. The adverse health effects from long COVID range from ‘invisible symptoms’ such as fatigue and difficulty concentrating, to neurological and neuropsychiatric symptoms, respiratory and cardiovascular problems, and metabolic disease.
Results
The COVID-19 pandemic has shown that siloed programmes are increasingly unfit, and the bidirectional relationships between communicable diseases and NCDs underscore the need to dismantle disease-specific silos, emphasising reforms and investments that improve a wide range of health outcomes. Cost-effective, feasible, and relevant interventions that target both physical and mental health impairments are urgently required.
Lessons
By 2030, ministries of health would need to contribute about 20% of their budgets to high-priority NCD interventions. Protecting current investments and scaling up cost-effective public health interventions is especially crucial in the context of long haul COVID and NCDs. Policy makers and planners will need concrete guidance for making progress on SDG target 3.4, often with overburdened health systems and scarcer resources.

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Organised by: EUPHA-CHR, Chair persons: Sarah Cuschieri (Malta), Julian Mamo (EUPHA-CHR)

3.D. Workshop: An urgent need to fully understand Long Covid-19 and its sequela

https://doi.org/10.1093/eurpub/ckac129.135

Published

25-Oct-22

Article

https://academic.oup.com/eurpub/article/32/Supplement_3/ckac129.135/6765873

Introduction
Covid-19 has been a pandemic for the past two years. From early on, it became obvious that some of the individuals surviving the infection continued to experience symptoms beyond the acute phase of the infection or else developed symptoms after the acute infection. Multiple terminologies describing this phenomenon started to appear with ‘Long Covid’ being a popular nomenclature. It soon became evident that Long Covid can affect almost all the body's systems with a plethora of associated symptoms, while new symptoms keep on emerging across time. These persistent symptoms are noted to act differently among different individuals, irrelevant whether they were previously healthy or previously suffering from any chronic disease/s. Indeed, while some experienced persistent symptoms for a couple of weeks, some had persistent symptoms for months. The variations in the severity of symptoms are another feature that became evident among Long Covid sufferers. The year 2021 saw the approval of different Covid-19 vaccines and the initiation of vaccination rollouts across Europe. As the vaccine population coverage progressed, it was anticipated that the lower viral infectivity rate will also decrease the occurrence of Long Covid-19 among the vaccinated as compared to the unvaccinated. Yet breakthrough Covid-19 infections still occurred along with the development of Long Covid-19 among vaccinated, especially as new variants emerged and immunity waned. Long Covid-19 is still a relatively new condition with unspecified pathophysiology and unknown long-term disability trajectory. Therefore, it is imperative that this condition is put into the spotlight to comprehend this pandora's box while trying to prevent its occurrence and the associated sequela.
Aim
Considering the fluidly of this condition with speculations that Long Covid might be the new chronic disease of this decade, this workshop is set to provide a multidisciplinary platform for emerging evidence on Long Covid originating from across Europe. In fact, the presentations in this workshop will tackle various aspects pertaining to Long Covid. The first presentation will provide evidence on the different risk factors and symptoms of Long Covid. The second presentation will discuss the association of multimorbidity and socio-economic factors as risk factors of Long-Covid. The third presentation will bring forward the perspectives of those suffering from the condition and the need for an integration of health care targeting both Long Covid and chronic diseases. While the fourth presentation will discuss the burden of Long-Covid symptoms and its impact on the quality of life. Finally, the bidirectional relationship between Long Covid-19 and NCDs along with the required public health action will be discussed. This will be followed by a discussion between the presenters and the audience.
Key messages
• Long Covid-19 is a common occurrence among healthy and chronic diseases population alike with a plethora of contributing risk factors.
• An integrated healthcare plan is required to decrease the impact of Long Covid-19 on the population while simultaneously managing other underlying conditions and diseases.

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Joanna Dietzel

Long-COVID, Post-COVID und Chronic Fatigue – Symptom, Syndrom, Diagnose
Long-COVID, post-COVID, and chronic fatigue—symptom, syndrome, diagnosis

https://doi.org/10.1007/s42212-022-00508-7

Published

24-Oct-22

Review

https://link.springer.com/article/10.1007/s42212-022-00508-7

Einleitung
Langsam lässt sich die neue Terminologie besser überblicken, die sich im Laufe der Coronaepidemie entwickelt hat und die postakute Phasen betrifft oder die postinfektiösen, chronifizierten Folgeerkrankungen umschreibt. Zwar gibt es weiterhin begriffliche Überlappungen, wie in der wissenschaftlichen Literatur aus der frühen Phase der Pandemie, aber Unterschiede zwischen den Termini und Gemeinsamkeiten mit bereits bekannten Krankheitsbildern wie der myalgischen Encephalomyelitis/Chronic Fatigue (CFS/ME) werden immer deutlicher.

Sobald das Virus im PCR-Test nicht mehr nachweisbar ist, darf die Arbeitnehmer*in wieder an den Arbeitsplatz zurück, mit dem Genesenenstatus waren in den Hochphasen der Pandemie Privilegien verbunden. Ein wesentlicher Anteil aller Infizierten aber, nämlich etwa 10 %, haben im Anschluss an die Phase, in der der Antigen- oder PCR-Test positiv war, weiterhin Krankheitszeichen, vergleichbar mit der akuten Phase einer Corona oder z. B. einer Grippeinfektion: Muskelschmerzen, Abgeschlagenheit, Konzentrationsstörungen, Atemstörungen [1]. Die Symptome sind oft so ausgeprägt, dass sich eine wochen- bis monatelange Arbeitsunfähigkeit anschließt; es wird in europäischen Gesundheitsministerien von einer Long-COVID-Krise gesprochen. Im Folgenden werden die Termini Long-COVID, Post-COVID und Chronic Fatigue definiert, angelehnt an die Vorschläge der großen Fachgesellschaften und der WHO.

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Mun-Keat Looi, Elisabeth Mahase

Has covid-19 become milder?

https://doi.org/10.1136/bmj.o2516

Published

27-Oct-22

Article

https://www.bmj.com/content/379/bmj.o2516.full

Deaths and hospital admissions are falling, so does this mean that the virus is less severe? The BMJ asks the experts
Is covid-19 really getting milder?
The short answer is no. Covid-19 is still a deadly disease, having killed almost 1.1 million people in 2022 at the time of writing. There remains a high risk of hospital admission and death for anyone without prior immunity. With some populations still largely unexposed to the virus, such as in China, and variation in the types of vaccines used in different places, it would be cavalier to call covid-19 anything but serious.
“It’s really hard to compare the severe disease aspects of [variants] because the immunity of our population is so different,” says Steve Griffin, associate professor at the University of Leeds. “When people call omicron mild, yes, there’s probably a lesser tendency for it to go deep in the lungs. But if you think about the clinical impact of it, because of its massive prevalence, even though it’s got a lower chance of causing the sorts of severe disease we’re talking about with acute covid-19, the actual clinical impact is still very, very marked.”
David Strain, senior clinical lecturer at the University of Exeter Medical School, points out that covid-19 tends to make other diseases worse. “It doesn’t matter what those other diseases are,” he told The BMJ in August 2022. “Patients who’ve got longstanding Crohn’s disease are coming in with exacerbations of their Crohn’s or their coeliac or their arthritis.”
Monica Verduzco Gutierrez, professor and chair of the Department of Rehabilitation Medicine at the Long School of Medicine in San Antonio, Texas, also emphasises that even mild covid-19 could cause long covid, with lingering symptoms and debility.
She adds that we’ve yet to fully understand the impact of reinfections. A study of the health records of six million people held by the US Department of Veteran Affairs, released as a preprint in June,1 suggested that people who had a second or third covid-19 infection had considerably higher rates of heart disease, kidney disorders, and other health problems during the first 30 days of infection, as well as in the months that followed, than people who had been infected only once.

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Chih-ChengLaiaChi-KueiHsubMuh-YongYencPing-IngLeedWen-ChienKoefPo-RenHsuehghij

Long COVID: An inevitable sequela of SARS-CoV-2 infection

https://doi.org/10.1016/j.jmii.2022.10.003

Published

15-Oct-22

Review

https://www.sciencedirect.com/science/article/pii/S1684118222001864

At present, there are more than 560 million confirmed cases of the coronavirus disease 2019 (COVID-19) worldwide. Although more than 98% of patients with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection can survive acute COVID, a significant portion of survivors can develop residual health problems, which is termed as long COVID. Although severe COVID-19 is generally associated with a high risk of long COVID, patients with asymptomatic or mild disease can also show long COVID. The definition of long COVID is inconsistent and its clinical manifestations are protean. In addition to general symptoms, such as fatigue, long COVID can affect many organ systems, including the respiratory, neurological, psychosocial, cardiovascular, gastrointestinal, and metabolic systems. Moreover, patients with long COVID may experience exercise intolerance and impaired daily function and quality of life. Long COVID may be caused by SARS-CoV-2 direct injury or its associated immune/inflammatory response. Assessment of patients with long COVID requires comprehensive evaluation, including history taking, physical examination, laboratory tests, radiography, and functional tests. However, there is no known effective treatment for long COVID. Based on the limited evidence, vaccines may help to prevent the development of long COVID. As long COVID is a new clinical entity that is constantly evolving, there are still many unknowns, and further investigation is warranted to enhance our understanding of this disease.

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Jayesh Cherusseri 1ORCID,Claire Mary Savio 2ORCID,Mohammad Khalid 1,3,*ORCID,Vishal Chaudhary 4,5,*,Arshid Numan 1,3,Sreekanth J. Varma 6ORCID,Amrutha Menon 7 andAjeet Kaushik 8,9

SARS-CoV-2-on-Chip for Long COVID Management

https://doi.org/10.3390/bios12100890

Published

18-Oct-22

Review

https://www.mdpi.com/2079-6374/12/10/890/htm

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a “wicked evil” in this century due to its extended progression and huge human mortalities. Although the diagnosis of SARS-CoV-2 viral infection is made simple and practical by employing reverse transcription polymerase chain reaction (RT-PCR) investigation, the process is costly, complex, time-consuming, and requires experts for testing and the constraints of a laboratory. Therefore, these challenges have raised the paradigm of on-site portable biosensors on a single chip, which reduces human resources and enables remote access to minimize the overwhelming burden on the existing global healthcare sector. This article reviews the recent advancements in biosensors for long coronavirus disease (COVID) management using a multitude of devices, such as point-of-care biosensors and lab-on-chip biosensors. Furthermore, it details the shift in the paradigm of SARS-CoV-2-on-chip biosensors from the laboratory to on-site detection with intelligent and economical operation, representing near-future diagnostic technologies for public health emergency management.

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Stefanos G. Sakellaropoulos, Muhammad Ali, Athanasios Papadis, Muhemin Mohammed, Andreas Mitsis, Zaza Zivzivadze

Is Long COVID Syndrome a Transient Mitochondriopathy Newly Discovered: Implications of CPET

https://doi.org/10.14740/cr1419

Published

13-Oct-22

Article

https://cardiologyres.org/index.php/Cardiologyres/article/view/1419

The new outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has an impact worldwide, primarily as a medical emergency. Even that the total constellation is considered as a pandemic of acute respiratory disease, coronavirus disease 2019 (COVID-19) gives rise to dysfunction in multiple organs (e.g., brain, lungs, heart, muscles) that impairs cardiopulmonary (CP) function. Parallel to the CP consequences of COVID-19 is a significant reduction in physical activity. Cardiopulmonary exercise testing (CPET) is daily used in clinical practice to define prognosis, provide risk stratification and treatment strategy. As such, the significance of CPET is crucial concerning clinical assessments of COVID-19 patients. Furthermore, new studies aim at understanding the effects of SARS-CoV-2 infection in long term. Multiple studies have investigated the cardiopulmonary function and impairment of exercise endurance in such patients, as well as a possible prolonged physical impairment. With this review, we summarize the COVID-19-associated pathophysiology for the Long COVID (LC) syndrome as well as the importance of performing CPET.

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Ana Paula Andrade Barreto ,Marcio Andrade Barreto Filho ,Lucimeire Cardoso Duarte ,Thiago Cerqueira-Silva,Aquiles Camelier,Natalia Machado Tavares,Manoel Barral-Netto,Viviane Boaventura ,Marcelo Chalhoub Coelho Lima ,on behalf of the CPC study group

Metabolic disorders and post-acute hospitalization in black/mixed-race patients with long COVID in Brazil: A cross-sectional analysis

https://doi.org/10.1371/journal.pone.0276771

Published

31-Oct-22

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0276771

Background
Although low-middle income countries have been disproportionately affected by the COVID-19 pandemic, there is scarce information about the impact of long COVID on their population. This study aimed to evaluate long COVID symptomatology, complications (hospital readmission and metabolic disorders), and main clinical features that impact Quality of Life (QoL).
Methods
This cross-sectional study provides a detailed clinical and laboratory picture of individuals who presented residual symptoms after mild to severe acute COVID-19. Between Aug-2020 to Sep-2021, long COVID patients were evaluated in a reference center for long COVID in Bahia State, Brazil. The EQ-5D-5L questionnaire accessed QoL.
Results
A total of 1164 (52 ±13.4 years, 57% female, 88% black/mixed-race) were evaluated 2.3 [IQR = 1.6–3.7] months after mild (n = 351, 30.2%), moderate (338, 29.0%) or severe (475, 40.8%) acute illness. Dyspnea (790, 67.9%), fatigue (738, 63.5%), and chest pain (525, 42.9%) were the most frequent residual symptoms regardless of acute severity, affecting the QoL of 88.9% of patients (n/N—826/925), mainly the domains of anxiety/depression and pain/discomfort. High levels of HbA1c were detected for 175 out of 664 patients (26.6%), 40% of them without a previous diagnosis of diabetes mellitus. Of note, hospital admission one-to-three months after the acute phase of disease was required for 51 (4.4%) patients.
Conclusion
In this majority-black/mixed-race population, long COVID was associated with post-acute hospitalization, newly diagnosed diabetes mellitus, and decreased QoL, particularly in women and regardless of disease severity of acute infection, suggesting important implications for health care system.

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Sedina Lewis, Public Health Specialist
Tha Han, Consultant in Public Health
Anthony Wakhisi, Public Health Intelligence Lead

Health Needs Assessment
Long COVID

Published

1-Aug-22

Guide

https://www.haveringdata.net/wp-content/uploads/2022/10/Havering-Long-COVID-needs-assessment-Final.pdf

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Ziyad Al-Aly, Anupam Agarwal, Nisreen Alwan & Valerie A. Luyckx

Long COVID: long-term health outcomes and implications for policy and research

https://doi.org/10.1038/s41581-022-00652-2

Published

1-Nov-22

Article

https://www.nature.com/articles/s41581-022-00652-2

Long COVID, which refers to post-acute and chronic sequelae of SARS-CoV-2 infection, can affect nearly every organ system and all demographic groups. The high and growing toll of long COVID calls for an urgent need to understand how to prevent and treat it. Governments and health systems must address the care needs of people with long COVID.

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Aurelie Fischer 1 Author Orcid Image ; Abir Elbeji 1 Author Orcid Image ; Gloria Aguayo 1 Author Orcid Image ; Guy Fagherazzi 1 Author Orcid Image

Recommendations for Successful Implementation of the Use of Vocal Biomarkers for Remote Monitoring of COVID-19 and Long COVID in Clinical Practice and Research

https://doi.org/10.2196/40655

Published

Article

https://i-jmr.org/2022/2/e40655/

The COVID-19 pandemic accelerated the use of remote patient monitoring in clinical practice or research for safety and emergency reasons, justifying the need for innovative digital health solutions to monitor key parameters or symptoms related to COVID-19 or Long COVID. The use of voice-based technologies, and in particular vocal biomarkers, is a promising approach, voice being a rich, easy-to-collect medium with numerous potential applications for health care, from diagnosis to monitoring. In this viewpoint, we provide an overview of the potential benefits and limitations of using voice to monitor COVID-19, Long COVID, and related symptoms. We then describe an optimal pipeline to bring a vocal biomarker candidate from research to clinical practice and discuss recommendations to achieve such a clinical implementation successfully.

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A.M.MalkovaY.Shoenfeld

Autoimmune autonomic nervous system imbalance and conditions: Chronic fatigue syndrome, fibromyalgia, silicone breast implants, COVID and post-COVID syndrome, sick building syndrome, post-orthostatic tachycardia syndrome, autoimmune diseases and autoimmune/inflammatory syndrome induced by adjuvants

https://doi.org/10.1016/j.autrev.2022.103230

Published

5-Nov-22

Review

https://www.sciencedirect.com/science/article/abs/pii/S1568997222002002

Chronic fatigue syndrome (CFS), fibromyalgia, silicone breast implants syndrome (SBIs), COVID and post-COVID syndrome (PCS), sick building syndrome (SBS), post-orthostatic tachycardia syndrome (POTS), autoimmune diseases and autoimmune/inflammatory syndrome induced by adjuvants (ASIA) are frequently accompanied by clinical symptoms characteristic for dysautonomia: severe fatigue, dizziness, fogginess, memory loss, dry mouth and eyes, hearing dysfunction, tachycardia etc. The recent discovery of an imbalance of autoantibodies against G protein-coupled receptors (GPCR) in some autoimmune diseases, post-COVID syndrome, SBIs allowed researchers to assume the novel mechanism in these conditions - autoimmune autonomic nervous system imbalance.

In this review, all data published on an imbalance of autoantibodies against GPCR, clinical symptoms and pathogenic mechanisms in CFS, Fibromyalgia, SBIs, COVID and PCS, SBS, POTS, and some autoimmune diseases were analyzed. Possible criteria to diagnose the autoimmune autonomic nervous system imbalance were created.

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M.TalmatkadiP.FoulquiéA.DéguilhemS.RennerL.ChâteauneufA.MebarkiN.TexierS.Schuck

Création d'un algorithme d'identification d'expériences vécues par des patients ou leurs proches à partir de messages issus des réseaux sociaux : un cas d'usage sur le COVID long

https://doi.org/10.1016/j.respe.2022.09.045

Published

4-Nov-22

Study

https://www.sciencedirect.com/science/article/pii/S0398762022008021

Introduction
La pandémie de COVID-19 a entrainé une masse d'informations sur les réseaux sociaux et forums provenant de multiples acteurs : gouvernements, journalistes ou encore citoyens. Parmi ces messages, de nombreux patients se sont saisis de ces outils pour partager leurs symptômes et se regrouper en communauté, comme c'est le cas des patients atteints de COVID long avec le hashtag #aprèsJ20. Un algorithme de traitement automatique du langage naturel capable d'identifier les messages constituant des expériences de santé vécues par des patients ou des proches permettrait d'exploiter ces données de vie réelle dans un objectif de santé publique.
Méthodes
A partir de différentes sources, 12 430 messages issus de forums et réseaux sociaux (Twitter, Facebook) ont été extraits sur différentes pathologies : cancer (sans précision d'une localisation), diabète, maladie de Fabry, COVID-19, sevrage tabagique. Ces messages ont été manuellement analysées et codifiées en trois catégories selon la nature de l'internaute : patient/aidant ou proche/répondant. Sur la base de ce « gold standard », un modèle de « machine learning » a été créé et entrainé, couplé avec des champs lexicaux marqueurs d'expériences vécues (par exemple, la présence d'un récit à la première personne ou du champ lexical de la famille). Deux modèles Xgboost ont été choisis permettant de déterminer en premier lieu si l'internaute est un proche de malade ou non, puis dans un second temps, si c'est un patient ou non. Pour être validé, ce modèle a été appliqué sur des messages spécifiques au COVID long. Une sélection aléatoire de ces messages couplée à une annotation par trois annotateurs a permis de mesurer les performances du modèle.
Résultats
Après application de l'algorithme d'identification d'expériences vécues par des patients ou des proches, 700 messages ont été revus et annotés sur le COVID long. Les catégories patients et aidants ont été regroupées en raison des nombreux cas de formes familiales de COVID long rapportés sur les réseaux sociaux. Les performances du modèle ont permis de mesurer une sensibilité de 96 %, une spécificité de 76 %, une « accuracy » à 87 % et une précision de 84 %.
Conclusion
Un algorithme identifiant les expériences vécues par des patients ou des proches au sein des messages issus des réseaux sociaux facilite leur utilisation comme données de vie réelle. Les bonnes performances de l'algorithme, notamment sur les formes longues de COVID-19, permettent un suivi prospectif de ces patients dans un objectif de santé publique. Une future version du modèle devra intégrer la possibilité d'identifier au sein d'un même message la présence d'expériences à la fois de patients et de proches, notamment en cas de formes familiales (”mon fils et moi avons un covid long ”).

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Fern Davies , Ilora Finlay, Nick Rich, Helen Howsen

Recommendations for a Long COVID Registry: A Prudent and Integrated Approach

http://doi.org/10.5334/ijic.ICIC22256

Published

4-Nov-22

Research

https://www.ijic.org/articles/abstract/10.5334/ijic.ICIC22256/

Introduction: Long COVID has had a profound impact on the lives and health of many people around the globe, with 1.5 million (2.4%) people in the UK alone experiencing self-reported symptoms. Whilst the prevalence and long-term consequences of SARS-CoV-2 infection remain largely unknown, modelling suggests a significant increase of long COVID patients and consequent challenge for the health and care system during the next stage of the pandemic. In response to this, the Bevan Commission were asked to make recommendations on how to set about establishing a voluntary registry for long COVID in Wales, in order to undertake long-term monitoring of the disease.
Aims and Methods: The aim of this research was to understand the UK context for setting up a voluntary long COVID registry and to make recommendations for a long COVID registry in Wales. A multi-stakeholder advisory board of twenty-five members was established, with a diverse range of expertise. Patient representatives were recruited to engage in the process of co-production, as aligned with the prudent healthcare principles . A qualitative and inductive methodology was adopted, supported by a multi-methods approach. This included exploratory desktop research, observations of four advisory board meetings and expert interviews. The multiple methods identified above contributed to the findings of this work and key recommendations.
Key Findings: The main findings indicate that there are no known voluntary long COVID registries that have been launched within the UK. However, the advisory board unanimously agreed the importance of a registry in Wales (or similar mechanism) for long-term monitoring of the disease and to facilitate research and service improvement. Digital infrastructure and linkages were identified as essential in the development of a registry, yet findings suggested a current disconnect and need for enhanced co-ordination and interoperability between resources, databases and organisations.
The need for co-production with end-users of a Long COVID Registry, such as healthcare professionals and patient groups, was an enduring finding during advisory board meetings, as was the need to promote equity of access and inclusion of a self-referred population. Findings from the patient representatives specifically identified a feeling of abandonment and described care as ‘disjointed’, particularly when referred to multiple healthcare professionals, specialities and resources. This promotes the need for a prudent and integrated approach to make effective use of available resources and to derive optimal value from a Long COVID Registry in Wales.
Conclusion: To conclude, this research identifies the importance of an integrated and multidisciplinary approach to improve the monitoring and management of long COVID and in turn address anticipated health system challenges. This approach should be central to inform the development of a Long COVID Registry within Wales. Digital infrastructure and linkages are key solutions to harness the technological capabilities within Wales and optimise the success of a registry.
Implications for applicability/transferability, sustainability, and limitations: This research has informed health policy decisions related to the effective care and research of long COVID in Wales. It also provides valuable recommendations for voluntary disease registries moving forward. However, it should be acknowledged that the research is only representative of one geographical context and healthcare system.

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Ann M. O’Hare, MA, MD1,2,3; Elizabeth K. Vig, MD, MPH2,3; Theodore J. Iwashyna, MD, PhD4; Alexandra Fox, PhD5; Janelle S. Taylor, PhD6; Elizabeth M. Viglianti, MD7; Catherine R. Butler, MD, MA1,2,3; Kelly C. Vranas, MD, MCR8,9; Mark Helfand, MD, MPH8,9; Anaïs Tuepker, PhD, MPH8,9; Shannon M. Nugent, PhD8,9; Kara A. Winchell, MA8; Ryan J. Laundry, BS1; C. Barrett Bowling, MD, MSPH10,11; Denise M. Hynes, RN, PhD8,9,12; Matthew L. Maciejewski, PhD13,14,15; Amy S. B. Bohnert, PhD16,17; Emily R. Locke, MPH1,5; Edward J. Boyko, MD, MPH2,3,5; George N. Ioannou, BMBCh, MS1,2,3,5; for the VA COVID Observational Research Collaboratory (CORC)

Complexity and Challenges of the Clinical Diagnosis and Management of Long COVID

http://jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2022.40332

Published

3-Nov-22

Qualitative analysis

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2798146

Key Points
Question What themes pertaining to long COVID can be identified in qualitative analysis of health records from the Department of Veterans Affairs health system?
Findings This qualitative study including health records from 200 randomly sampled veterans identified 2 dominant themes: (1) clinical uncertainty: it was often unclear whether particular symptoms were due to long COVID, given the medical complexity and functional limitations of many patients and absence of specific markers for this condition, which led to ongoing monitoring, diagnostic testing, and referral; and (2) care fragmentation: post–COVID-19 care processes were often siloed from other care and could be burdensome to patients.
Meaning These findings highlight the complexity of diagnosing and managing long COVID in clinical settings.
Abstract
Importance There is increasing recognition of the long-term health effects of SARS-CoV-2 infection (sometimes called long COVID). However, little is yet known about the clinical diagnosis and management of long COVID within health systems.
Objective To describe dominant themes pertaining to the clinical diagnosis and management of long COVID in the electronic health records (EHRs) of patients with a diagnostic code for this condition (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code U09.9).
Design, Setting, and Participants This qualitative analysis used data from EHRs of a national random sample of 200 patients receiving care in the Department of Veterans Affairs (VA) with documentation of a positive result on a polymerase chain reaction (PCR) test for SARS-CoV-2 between February 27, 2020, and December 31, 2021, and an ICD-10 diagnostic code for long COVID between October 1, 2021, when the code was implemented, and March 1, 2022. Data were analyzed from February 5 to May 31, 2022.
Main Outcomes and Measures A text word search and qualitative analysis of patients’ VA-wide EHRs was performed to identify dominant themes pertaining to the clinical diagnosis and management of long COVID.
Results In this qualitative analysis of documentation in the VA-wide EHR, the mean (SD) age of the 200 sampled patients at the time of their first positive PCR test result for SARS-CoV-2 in VA records was 60 (14.5) years. The sample included 173 (86.5%) men; 45 individuals (22.5%) were identified as Black and 136 individuals (68.0%) were identified as White. In qualitative analysis of documentation pertaining to long COVID in patients’ EHRs 2 dominant themes were identified: (1) clinical uncertainty, in that it was often unclear whether particular symptoms could be attributed to long COVID, given the medical complexity and functional limitations of many patients and absence of specific markers for this condition, which could lead to ongoing monitoring, diagnostic testing, and specialist referral; and (2) care fragmentation, describing how post–COVID-19 care processes were often siloed from and poorly coordinated with other aspects of care and could be burdensome to patients.
Conclusions and Relevance This qualitative study of documentation in the VA EHR highlights the complexity of diagnosing long COVID in clinical settings and the challenges of caring for patients who have or are suspected of having this condition.

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Lin Zhang, Jie Lei, Jintao Zhang, Longlong Yin, Yanjiao Chen, Yan Xi & Joaquim Paulo Moreira

Undiagnosed Long COVID-19 in China Among Non-vaccinated Individuals: Identifying Persistent Symptoms and Impacts on Patients' Health-Related Quality of Life

https://doi.org/10.1007/s44197-022-00079-9

Published

24-Nov-22

Study

https://link.springer.com/article/10.1007/s44197-022-00079-9

Is Long COVID-19 under-diagnosed? The definition of this new condition has received many contributions, and it is still under development as a great variety of symptoms have been associated to it. This study explores the possibility that there are non-diagnosed cases among individuals who have been infected by SARS-CoV-2 and have not been vaccinated. The long-term symptoms identified among a sample 255 individuals have been associated to Long COVID-19 by recent literature. The study relates these symptoms to risk factors and health-related quality of life (HRQoL) negative impacts. The individuals were screened 1 year after discharge to explore its potential relation to Long COVID-19. Patients diagnosed with COVID-19 and discharged from designated hospitals in a Chinese province between January and April 2020 were included in this study. They received computed tomography (CT) scans one month after discharge. One year after discharge, patients were invited to physical examination and interviewed with questionnaire on health-related quality of life (HRQoL) and post-COVID-19 symptoms. Tobit regression and Logistic regression were applied to evaluate the risk factors for health utility value and pain/discomfort and anxiety/depression. One year after discharge, 39.61% patients complained of several of the symptoms associated to Long COVID-19. More than half had abnormal chest CT. Previous studies focused on the post-COVID-19 symptoms and chest CT findings of patients, but few studies have assessed the COVID-19-associated risk factors for health-related quality of life.

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MarijaPantelicDPhilabNidaZiauddeenPhDcdMarkBoyesPhDefMargaret EO'HaraPhDgClaireHastieBScgProfNisreen AAlwanPhDcdh

The prevalence of stigma in a UK community survey of people with lived experience of long COVID

https://doi.org/10.1016/S0140-6736(22)02294-2

Published

24-Nov-22

Study

https://www.sciencedirect.com/science/article/abs/pii/S0140673622022942

Background
Stigma can be experienced as perceived or actual disqualification from social and institutional acceptance on the basis of one or more physical, health-related, behavioural, or other attributes deemed to be undesirable. Long COVID is a predominantly multisystem condition that occurs in people with a history of SARS-CoV-2 infection, often resulting in functional disability, which limits day-to-day activities. We aimed to quantify the burden of stigma experienced in a community-based sample of people with lived experience of long COVID.
Methods
Data from the follow-up of a long COVID longitudinal online survey was used. The survey was coproduced with people living with long COVID. 13 questions on stigma were included to develop a Long COVID Stigma Scale capturing three domains: enacted (overt experiences of discrimination due to long COVID), internalised (internalising negative associations with long COVID and accepting them as self-applicable), and anticipated (expectation of bias or poor treatment by others) stigma. Data were collected through a social media survey with convenience non-probability sampling.
Findings
966 (47·9%) of 2016 participants from the UK completed the follow-up survey and 888 responded to the questions on stigma. The mean age of respondents was 48·3 years (SD 10·7), and 84·6% identified as female. Roughly half (n=460, 50·4%) reported having a formal, clinical, long COVID diagnosis, and of these, 440 responded to the questions on stigma. The prevalence of people experiencing overall stigma at least sometimes was 95·4% (n=847), prevalence of enacted stigma was 62·7% (n=557), internalised stigma was 86·4% (n=767), and anticipated stigma was 90·8% (n=806). Prevalence of stigma was higher in respondents with a formal diagnosis of long COVID (97·5%; n=429) than in those without (93·2%; n=413).
Interpretation
This study highlights widespread and multilayered stigmas experienced by people living with long COVID in the UK, which presents a serious public health concern. The broader literature on stigmatised health conditions consistently suggests that stigma drives people away from health services, contributes to psychological distress, and compromises long-term physical outcomes. The higher proportion experiencing stigma in those with clinical diagnosis of long COVID might be indicative of stigma within the health-care system. Findings from this study should be taken into consideration within clinical practice and health care, social care, employment, and education policies.

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Ilduara Pintos-Pascual1*, Victor Moreno-Torres1,2, Fatima Ibánez-Estéllez1, Pilar Corrales-Rodriguez1,
Ana Treviño2, Manuel Corpas3, Octavio Corral2, Vicente Soriano2, and Carmen de Mendoza1

Is SARS-CoV-2 the only cause of long-COVID?

https://doi.org/10.24875/AIDSRev.22000025

Published

11-Mar-22

Article

https://www.aidsreviews.com/resumen.php?id=1616

Around 10% of adults infected with SARS-CoV-2 that survive a first episode of COVID-19 appear to experience long-term clinical manifestations. The signs and symptoms of this post-acute COVID-19 syndrome (PACS) include fatigue, dyspnea, joint pain, myalgia, chest pain, cough, anosmia, dysgeusia, headache, depression, anxiety, memory loss, concentration difficulties, and insomnia. These sequelae remind the constellation of clinical manifestations previously recognized as myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS). This condition has been described following distinct infectious events, mostly acute viral illnesses. In this way, the pathophysiology of PACS might overlap with mechanisms involved in other post-infectious fatigue syndromes. The risk of PACS is more frequent in women than men. Additional host genetic factors could be involved. There is a dysregulation of multiple body organs and systems, involving the immune system, the coagulation cascade, endocrine organs, autonomic nervous system, microbiota–gut–brain axis, hypothalamic–pituitary–adrenal axis, hypothalamic–pituitary–thyroid axis, etc. Hypothetically, an abnormal response to certain infectious agents could trigger the development of postinfectious fatigue syndromes.

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Mawuena Binka, Braeden Klaver, Georgine Cua, Alyson W Wong, Chad Fibke, Héctor A Velásquez García, Prince Adu, Adeera Levin, Sharmistha Mishra, Beate Sander, Hind Sbihi, Naveed Z Janjua

An Elastic Net Regression Model for Identifying Long COVID Patients Using Health Administrative Data: A Population-Based Study

https://doi.org/10.1093/ofid/ofac640

Published

24-Nov-22

Study

https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofac640/6845426

Background
Long COVID patients experience persistent symptoms after acute SARS-CoV-2 infection. Healthcare utilization data could provide critical information on the disease burden of long COVID for service planning, however, not all patients are diagnosed or assigned long COVID diagnostic codes. We developed an algorithm to identify individuals with long COVID using population-level health administrative data from British Columbia (BC), Canada.
Methods
An elastic net penalized logistic regression model was developed to identify long COVID patients based on demographic characteristics, pre-existing conditions, COVID-19-related data, and all symptoms/conditions recorded 28-183 days after the COVID-19 symptom onset/reported (index) date of known long COVID patients (N = 2,430) and a control group (N = 24,300); selected from all adult COVID-19 cases in BC with an index date on/before October 31, 2021 (N = 168,111). Known long COVID cases were diagnosed in a clinic and/or had the ICD-10-CA code for “Post COVID-19 condition” in their records.
Results
The algorithm retained known symptoms/conditions associated with long COVID, demonstrating high sensitivity (86%), specificity (86%), and area under the receiver operator curve (93%). It identified 25,220 (18%) long COVID patients among the remaining 141,381 adult COVID-19 cases; over ten times the number of known cases. Known and predicted long COVID patients had comparable demographic and health-related characteristics.
Conclusions
Our algorithm identified long COVID patients with a high level of accuracy. This large cohort of long COVID patients will serve as a platform for robust assessments on the clinical course of long COVID, and provide much needed concrete information for decision-making.

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Ronald W.DamantaLiamRourkeaYingCuibGrace Y.LamaMaeve P.SmithaDesi P.FuhraJaqueline K.TayaRhea A.VarugheseaCheryl R.LarattaaAngelaLauaEric Y.WongaMichael K.SticklandaGiovanniFerraraa

Reliability and validity of the post COVID-19 condition stigma questionnaire: A prospective cohort study

https://doi.org/10.1016/j.eclinm.2022.101755

Published

25-Nov-22

Study

https://www.sciencedirect.com/science/article/pii/S2589537022004849

Background
Many of the 10–20% percent of COVID-19 survivors who develop Post COVID-19 Condition (PCC, or Long COVID) describe experiences suggestive of stigmatization, a known social determinant of health. Our objective was to develop an instrument, the Post COVID-19 Condition Stigma Questionnaire (PCCSQ), with which to quantify and characterise PCC-related stigma.
Methods
We conducted a prospective cohort study to assess the reliability and validity of the PCCSQ. Patients referred to our Post COVID-19 Clinic in the Canadian City of Edmonton, Alberta between May 29, 2021 and May 24, 2022 who met inclusion criteria (attending an academic post COVID-19 clinic; age ≥18 years; persistent symptoms and impairment at ≥ 12 weeks since PCR positive acute COVID-19 infection; English-speaking; internet access; consenting) were invited to complete online questionnaires, including the PCCSQ. Analyses were conducted to estimate the instrument's reliability, construct validity, and association with relevant instruments and defined health outcomes.
Findings
Of the 198 patients invited, 145 (73%) met inclusion criteria and completed usable questionnaires. Total Stigma Score (TSS) on the PCCSQ ranged from 40 to 174/200. The mean (SD) was 103.9 (31.3). Cronbach's alpha was 0.97. Test-retest reliability was 0.92. Factor analysis supported a 6-factor latent construct. Subtest reliabilities were >0.75. Individuals reporting increased TSS occurred across all demographic groups. Increased risk categories included women, white ethnicity, and limited educational opportunities. TSS was positively correlated with symptoms, depression, anxiety, loneliness, reduced self-esteem, thoughts of self-harm, post-COVID functional status, frailty, EQ5D5L score, and number of ED visits. It was negatively correlated with perceived social support, 6-min walk distance, and EQ5D5L global rating. Stigma scores were significantly increased among participants reporting employment status as disabled.
Interpretation
Our findings suggested that the PCCSQ is a valid, reliable tool with which to estimate PCC-related stigma. It allows for the identification of patients reporting increased stigma and offers insights into their experiences.

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Rónan Astin,Amitava Banerjee,Mark R. Baker,Melanie Dani,Elizabeth Ford,James H. Hull,Phang Boon Lim,Melitta McNarry,Karl Morten,Oliver O'Sullivan,Etheresia Pretorius,Betty Raman,Demetris S. Soteropoulos,Maxime Taquet,Catherine N. Hall

Long COVID: mechanisms, risk factors and recovery

https://doi.org/10.1113/EP090802

Published

22-Nov-22

Review

https://physoc.onlinelibrary.wiley.com/doi/10.1113/EP090802

New Findings
What is the topic of this review?
The emerging condition of long COVID, its epidemiology, pathophysiological impacts on patients of different backgrounds, physiological mechanisms emerging as explanations of the condition, and treatment strategies being trialled. The review leads from a Physiological Society online conference on this topic.
What advances does it highlight?
Progress in understanding the pathophysiology and cellular mechanisms underlying Long COVID and potential therapeutic and management strategies.
Abstract
Long COVID, the prolonged illness and fatigue suffered by a small proportion of those infected with SARS-CoV-2, is placing an increasing burden on individuals and society. A Physiological Society virtual meeting in February 2022 brought clinicians and researchers together to discuss the current understanding of long COVID mechanisms, risk factors and recovery. This review highlights the themes arising from that meeting. It considers the nature of long COVID, exploring its links with other post-viral illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome, and highlights how long COVID research can help us better support those suffering from all post-viral syndromes. Long COVID research started particularly swiftly in populations routinely monitoring their physical performance – namely the military and elite athletes. The review highlights how the high degree of diagnosis, intervention and monitoring of success in these active populations can suggest management strategies for the wider population. We then consider how a key component of performance monitoring in active populations, cardiopulmonary exercise training, has revealed long COVID-related changes in physiology – including alterations in peripheral muscle function, ventilatory inefficiency and autonomic dysfunction. The nature and impact of dysautonomia are further discussed in relation to postural orthostatic tachycardia syndrome, fatigue and treatment strategies that aim to combat sympathetic overactivation by stimulating the vagus nerve. We then interrogate the mechanisms that underlie long COVID symptoms, with a focus on impaired oxygen delivery due to micro-clotting and disruption of cellular energy metabolism, before considering treatment strategies that indirectly or directly tackle these mechanisms. These include remote inspiratory muscle training and integrated care pathways that combine rehabilitation and drug interventions with research into long COVID healthcare access across different populations. Overall, this review showcases how physiological research reveals the changes that occur in long COVID and how different therapeutic strategies are being developed and tested to combat this condition.

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Maciej Debski,Vasiliki Tsampasian,Shawn Haney,Katy Blakely,Samantha Weston,Eleana Ntatsaki,Mark Lim,Susan Madden,Aris Perperoglou,Vassilios S. Vassiliou

Post-COVID-19 syndrome risk factors and further use of health services in East England

https://doi.org/10.1371/journal.pgph.0001188

Published

30-Nov-22

Study

https://journals.plos.org/globalpublichealth/article?id=10.1371/journal.pgph.0001188

Post-COVID syndrome, defined as symptoms persisting for more than twelve weeks after the diagnosis of COVID-19, has been recognised as a new clinical entity in the context of SARS-CoV-2 infection. This study was conducted to characterise the burden and predictors for post-COVID-19 syndrome in the local population. It was a community-based web-survey study conducted in Norfolk, East England, UK. We sent the survey to patients with confirmed COVID-19 infection by real-time polymerase chain reaction by December 6th, 2020. Questions related to the pre-COVID and post-COVID level of symptoms and further healthcare use. Baseline characteristics were collected from the primary care records. Logistic regression analysis was conducted to establish predictors for post-COVID-19 syndrome and further healthcare utilisation. Of 6,318 patients, survey responses were obtained from 1,487 participants (23.5%). Post-COVID-19 syndrome symptoms were experienced by 774 (52.1%) respondents. Male sex compared to female sex was a factor protective of post-COVID symptoms; relative risk (RR) 0.748, 95% confidence interval (CI), 0.605–0.924. Body mass index was associated with a greater risk of developing post-COVID-19 symptoms (RR 1.031, 95% CI, 1.016–1.047, for 1 kg/m2). A total of 378 (25.4%) people used further health services after their index COVID-19 infection, of whom 277 (73.2%) had post-COVID symptoms. Male sex was negatively associated with the use of further health services (RR 0.618, 95% CI, 0.464–0.818) whereas BMI was positively associated (RR 1.027, 95% CI, 1.009–1.046). Overall, post-COVID-19 symptoms increased the probability of using health services with RR 3.280, 95% CI, 2.540–4.262. This survey of a large number of people previously diagnosed with COVID-19 across East England shows a high prevalence of self-reported post-COVID-19 syndrome. Female sex and BMI were associated with an increased risk of post-COVID-19 syndrome and further utilisation of healthcare.

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Anna Herminghaus
Marcin F. Osuchowski

How sepsis parallels and differs from COVID-19

https://doi.org/10.1016/j.ebiom.2022.104355

Published

2-Dec-22

Article

https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00537-0/fulltext

There is a striking parallel between bacterial sepsis and COVID-19 phenotypes: the long-term sequelae. In both patient groups, the hospital discharge does not equal full recovery, but it is frequently followed by protracted, incapacitating consequences. While in bacterial sepsis, the post-discharge complications are referred to as post-sepsis syndrome and/or Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS), whereas, in SARS-CoV-2 infected patients, they are known as “long-COVID”. Long-COVID is not very different from post-sepsis syndrome. The most common persistent symptoms include fatigue, muscle pain, poor sleep, cardiac and cognitive disturbances (e.g. arrhythmias, short-term memory loss).7 Remarkably, a new, troubling difference exists: unlike in sepsis, long-COVID is frequently diagnosed in mildly SARS-CoV-2 infected patients (i.e. no hospital stay).8 The presence of the “long-phenotype” in both illnesses strongly indicates a severe and protracted deregulation of the immune-inflammatory (with clear immunosuppression features) and organ homeostasis. In the context of the slowly subsiding severe COVID-19 manifestations, we should re-focus on the long-term sequalae to evaluate a potential risk of increase in chronic debilitations in individuals, repeatedly exposed to the virus, as SARS-CoV-2 becomes seasonal/endemic.
A comparison of the pre-clinical research in sepsis and COVID-19 brings several important lessons. A subjective (and largely undeserved) disappointment in pre-clinical bacterial sepsis studies has not been shared by COVID-19 modeling. On the contrary, despite logistic challenges, modeling of SARS-COV-2 infection has demonstrated its robust utility. One of the key advantages of pre-clinical COVID-19 research is the rich palette of species (including non-human primates), while >90% of bacterial sepsis studies are performed in mice and rats. A multi-species approach considerably enhances reproducibility and translatability concurrently reducing idiosyncratic findings. Animal COVID-19 models were well-predictive of both successes (e.g. anti-SARS-CoV-2 monoclonal antibodies, remdesivir, vaccines) and failures (e.g. hydroxychloroquine, lopinavir/ritonavir) of clinically-tested substances.9 Given intuitive drive for benefits, the latter should not be underappreciated; “negative” findings hold a valuable life-/time and cost-saving potential. Notably, anti-TNF treatment in a clinically relevant mouse model of cecal ligation and puncture sepsis predicted failure of that therapy three years before the failed clinical trials.10 A clear pre-clinical parallel for sepsis and COVID-19 models exist: they both can be employed to cover identical research niches: i) mild-to-severe disease phenotypes, ii) defined cohort targeting, iii) selected pathophysiological insights (e.g. compartmentalization of responses). Furthermore, long-term sequalae can be effectively investigated in both bacterial sepsis and COVID-19 models.

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Guo, Yi; Wang, Hao; Xiao, Mingzhong; Guan, Xin; Lei, Yanshou; Diao, Tingyue; Long, Pinpin; Zeng, Rui; Lai, Xuefeng; Cai, Hao; You, Yutong; Wen, Yuying; Li, Wenhui; Wang, Xi; Wang, Yufei; Chen, Qinlin; Yang, Yuchan; Qiu, Yutong; Chen, Jishuai; Zeng, Huidan; Ni, Wei; Zhao, Youyun; Ouyang, Kani; Wang, Jingzhi; Wang, Qi; Liu, Li; Song, Lulu; Wang, Youjie; Guo, Huan; Li, Xiaodong; Wu, Tangchun; Yuan, Yu

Long-term outcomes of COVID-19 convalescents: An 18.5-month longitudinal study in Wuhan

https://doi.org/10.1186/s41256-022-00283-x

Published

Study

https://doi.org/10.1186/s41256-022-00283-x

COVID-19 is a serious threat to human health and development. The acute burden of the pandemic includes more than 18.2 million deaths worldwide, and is unprecedented in modern times. This represents only a fraction of the total burden, as it excludes infection sequelae. An effective global strategic paradigm has been missing throughout the pandemic. The ‘flattening the curve’ approach neglected the importance of infection sequelae, and being centered on healthcare capacity was conceptually contrary to a people-centered health system. In March 2022, the World Health Organization revised its pandemic approach, importantly shifting emphasis away from managing transmission and towards prevention. Despite limitations, this now recognizes the role of infection sequelae, whose impact is becoming clearer in both variety and scale. Drawing on the foundational concepts of Sun Tzu and Carl von Clausewitz, most country approaches do not qualify as strategies, but rather as operational plans. They are also largely ineffective, neglecting infection sequelae, viral evolution dangers and other parameters. The purpose of this article is to summarize the evidence on COVID-19 infection sequelae, and alongside other contextual parameters use this to motivate that infection should be prevented. This is then used to answer the question: What is an effective strategy against COVID-19?

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Demir, Ismail; Aydin, Sukru; Cengiz, Deniz Ugur

The short-term effect of COVID-19 on the cochleovestibular system in pediatric patients

https://doi.org/10.1016/j.ijid.2022.12.008

Published

Study

https://www.ijidonline.com/article/S1201-9712(22)00642-7/fulltext

Publisher: Elsevier
PMID: 36509334
Highlights
•Most participants had an improved physical and psychological health status
•We observed sequelae symptoms in 45.2% of participants at 18.5 months
•We observed abnormal chest CT patterns in about 30% of participants at 18.5 months
•The convalescents still had mild depression or anxiety disorders at the last visit
Long-term outcomes of COVID-19 convalescents: An 18.5-month longitudinal study in Wuhan
Abstract
Objective
To describe the full scope of long-term outcomes and the ongoing pathophysiological alterations among the COVID-19 survivor.
Methods
We established a longitudinal cohort of 208 COVID-19 convalescents and followed them at 3.3 (IQR: 1.3, 4.4, visit 1), 9.2 (IQR: 9.0, 9.6, visit 2), and 18.5 (IQR: 18.2, 19.1, visit 3) months after infection, respectively. Serial changes in multiple physical and psychological outcomes were comprehensively characterized. We additionally explored the potential risk factors of SARS-CoV-2 antibody response and sequelae symptoms.
Results
We observed continuous improvement of sequelae symptoms, lung function, chest CT, 6-minute walk test, and the Borg dyspnoea scale, whereas sequelae symptoms (at least one) and abnormal chest CT patterns still existed in 45.2% and about 30% of the patients at 18.5 months, respectively. Both anxiety and depression disorders were alleviated for the convalescents, although the depression status was sustained for a longer duration.
Conclusions
Most COVID-19 convalescents had an overall improved physical and psychological health status, whereas sequelae symptoms, residual lesions on lung function, exercise impairment, and mental health disorders were still observed in a small proportion of the participants at 18.5 months after infection. Implementing appropriate preventive and management strategies for the ever-growing COVID-19 population is warranted.

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Khalife, Jade

Effective strategies against COVID-19 and the importance of infection sequelae

https://doi.org/10.1093/occmed/kqac119

Published

Study

https://doi.org/10.1093/occmed/kqac119

The COVID-19 pandemic has given rise to an increasing number of patients with ‘long COVID’. Long COVID is the persistence of symptoms for weeks or months after an infection by SARS-CoV-2. It often impacts on the professional life of affected people.The aim of this study is to understand the experiences and needs of people with long COVID in relation to their return to work.A qualitative study, combining individual interviews and online forum discussions, was performed early 2021, as part of a larger mixed method study on the needs of long COVID patients in Belgium.One hundred and thirty-four people participated in the study. Participants described various clinical symptoms precluding their return to work. They also face sceptical reactions from employers and colleagues and a lack of support from the social welfare system to facilitate their return to work. These barriers have various impacts, including psychological ones, likely to compromise the professional future of long COVID patients.While the analysis of patients’ experiences shows variation in long COVID patients’ experiences with return to work, it may help occupational physicians and healthcare practitioners to better take up their crucial role in the return to work of long COVID patients, including raising employers’ and colleagues’ awareness of the specific difficulties related to long COVID.

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Baskett, William I; Qureshi, Adnan I; Shyu, Daniel; Armer, Jane M; Shyu, Chi-Ren

COVID-Specific Long-Term Sequelae in Comparison to Common Viral Respiratory Infections: An Analysis of 17,487 Infected Adult Patients

https://doi.org/10.1093/ofid/ofac683

Published

Study

https://doi.org/10.1093/ofid/ofac683

better understanding of long-term health effects after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become one of the healthcare priorities in the current pandemic. We analyzedlarge and diverse patient cohort to study health effects related to SARS-CoV-2 infection occurring more than one month post-infection.We analyzed 17,487 patients who received diagnoses for SARS-CoV-2 infection in a total of 122 healthcare facilities in the United States prior to April, 14,2022. Patients were propensity score matched with patients diagnosed with the common cold, influenza, or viral pneumonia from March 1, 2020, to April 1, 2021. For each outcome, SARS-CoV-2 was compared to a generic Viral Respiratory Infection (VRI) by predicting diagnoses in the period between 30 and 365 days post-infection. Both COVID-19 and VRI patients were propensity score matched with patients with no record of COVID-19 or VRI and the same methodology was applied. Diagnoses where COVID-19 infection was a significant positive predictor in both COVID-19 vs VRI and COVID-19 vs Control comparisons were considered COVID-19-specific effects.Compared to common VRIs, SARS-CoV-2 was associated with diagnoses palpitations, hair loss, fatigue, chest pain, dyspnea, joint pain, and obesity in the post-infectious period.We identify that some diagnoses commonly described as “long COVID” do not appear significantly more frequent post-COVID-19 infection compared to other common VRIs. We also identify sequelae which are specifically associated with a prior SARS-CoV-2 infection.

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Ishii, Shinya; Sugiyama, Aya; Ito, Noriaki; Miwata, Kei; Kitahara, Yoshihiro; Okimoto, Mafumi; Kurisu, Akemi; Abe, Kanon; Imada, Hirohito; Akita, Tomoyuki; Kubo, Tatsuhiko; Nagasawa, Akira; Nakanishi, Toshio; Takafuta, Toshiro; Kuwabara, Masao; Tanaka, Junko

The role of discrimination in the relation between COVID-19 sequelae, psychological distress, and work impairment in COVID-19 survivors

https://doi.org/10.1038/s41598-022-26332-6

Published

Study

https://www.nature.com/articles/s41598-022-26332-6

Perceived discrimination and work impairment are commonly observed in COVID-19 survivors, but their relationship has not been well understood. We aimed to evaluate the role of discrimination in the development of psychological distress and work impairment in COVID-19 survivors. From April 2020 to November 2021, 309 patients were recruited at two designated COVID-19 hospitals in Japan. Participants completed a standardized questionnaire including COVID-19 sequelae, psychological distress, impairments in work performance and perceived discrimination. The majority of participants (62.5%) experienced one or more COVID-19 sequelae. Psychological distress was observed in 36.9% and work impairment in 37.9%. In multivariate logistic regression analyses, COVID-19 sequelae and discrimination were associated with both psychological distress and work impairment. Mediation analysis demonstrated that the direct effect of sequelae on work impairment was non-significant after accounting for psychological distress, suggesting that the effect of sequelae on work impairment was mainly mediated through psychological distress. These findings were replicated in a subgroup analysis limited to patients with mild COVID-19. We conclude that discrimination plays an important role in the development of psychological distress and work impairment, and that both discrimination and psychological distress should be targets of intervention in COVID-19 survivors.

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Lapteva, E. S.; Ariev, A. L.; Arieva, G. T.; Tsutsunawa, M. R.; Diachkova-Gerceva, D. C.

On the Role of Geriatric Services in the Diagnosis and Monitoring of Outcomes of Post-Covid Syndrome (Review)

https://doi.org/10.1134/S2079057022040105

Published

Review

https://doi.org/10.1134/S2079057022040105

In addition to the rapid spread of the pandemic in waves across the globe today, there is a growing problem called “long-COVID-19,” a term that describes the long-term effects of the novel coronavirus infection COVID-19. How the disease proceeds after “recovery,” including long-term physical and psychological health consequences, and the future of COVID-19 survivors remains largely unclear. This is especially true for older age groups. This article summarizes the experience of foreign studies aimed at determining the duration and clarifying the nature of multi-organ complications after suffering from COVID-19, as well as ways of the long-term rehabilitation of patients in older age groups with post-COVID syndrome.

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Kohn, Laurence; Dauvrin, Marie; Detollenaere, Jens; Primus-de-Jong, Célia; Maertens de Noordhout, Charline; Castanares-Zapatero, Diego; Cleemput, Irina; Van den Heede, Koen

Difficultés rencontrées par les patients COVID long dans le système de santé belge

https://doi.org/10.3917/spub.225.0663

Published

Study

https://www.cairn.info/revue-sante-publique-2022-5-page-663.htm

Introduction : Suite à une infection COVID-19, bon nombre de personnes ont ressenti divers symptômes pendant plusieurs semaines et mois, et ce, même après une phase aiguë légère. Ces personnes atteintes de « COVID long » se sont trouvées confrontées au système de soins de santé, non sans difficultés.But de l’étude : Afin de mieux comprendre leurs expériences, nous avons complété les informations obtenues via une enquête en ligne par une approche qualitative mixte, comprenant 33 entretiens individuels et les discussions de 101 participants à un forum durant le mois de mars 2021.Résultats : Plusieurs lacunes ont été mises en évidence lors des contacts des patients « COVID long » avec le système de santé, comme l’absence d’écoute ou d’empathie de certains professionnels de la santé, d’approche systématique ou proactive lors du bilan diagnostique, ou encore l’absence de coordination interdisciplinaire. Les patients se sentent incompris et se voient obligés de développer leurs propres stratégies afin d’établir un diagnostic ou un traitement. Le malaise des patients les ont amenés à remettre en question la valeur de la médecine et à recourir à des thérapies non conventionnelles afin de soulager leurs symptômes, parfois à un prix élevé.Conclusions : Mieux informer le corps médical quant à la manifestation de la maladie et aux prises en charge possibles, y compris les possibilités de remboursement, permettrait de le sensibiliser et de lui donner les outils pour répondre aux besoins des patients « COVID long ». Évaluer de manière globale le patient via un « bilan interdisciplinaire » est nécessaire.

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Suran, Melissa

HHS Releases New Report on Long COVID Experiences

https://doi.org/10.1001/jama.2022.20052

Published

Article

https://doi.org/10.1001/jama.2022.20052

The US Department of Health and Human Services (HHS) published a report highlighting the experiences of patients with long COVID. Between 5% and 30% of people who had COVID-19 may develop long COVID conditions, and about 1 million individuals aren’t in the workforce “at any given time” because of related symptoms, according to an HHS statement. It also notes that researchers have documented more than 50 long COVID conditions that affect nearly all organ systems.

“Long COVID isn’t one condition,” Deputy Assistant Secretary for Science and Medicine Michael Iademarco, MD, MPH, said in the statement. “The Health+ Long COVID Report allows us to hear directly from patients so we can better understand the complexities of this multisystemic condition and enrich our understanding and response to Long COVID and its associated conditions.”

A literature review, 4 workshops, and interviews with more than 60 people about long COVID served as the report’s foundation. Participants were recruited from a diverse group to include those who had long COVID as well as caregivers and health care professionals. Researchers then synthesized common themes that emerged to paint a picture of shared long COVID experiences.

The report—commissioned by HHS and produced by Coforma, an independent research agency—also explores how and why the effects of long COVID can vary from person to person and ways in which individuals with related conditions can improve their quality of life and care. It points out that related conditions likely disproportionately affect historically underserved communities.

“Long COVID will be around long after the pandemic subsides,” the report concludes. “We can reduce the severity and breadth of that impact, however, if we act collectively and urgently.”

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Moretti, Chiara; Collaro, Concetta; Terzoni, Cristina; Colucci, Gennaro; Copelli, MariaRosa; Sarli, Leopoldo; Artioli, Giovanna

Dealing with uncertainty. A qualitative study on the illness’ experience in patients with Long-COVID in Italy

https://doi.org/10.23750/abm.v93i6.14059

Published

Study

https://mattioli1885journals.com

number: 6
Abstract. Background and goals: An unknown proportion of people who had COVID-19 infection continue to experience symptoms such as fatigue, breathlessness, joint or muscle pain, difficulty sleeping, and brain fog. These symptoms have a significant impact on the quality of life. Long-COVID is a new multisystem disease still under investigation. This research aims to explore the illness experienced by patients suffering from Long-COVID in Italy. Research Design and Methods: Qualitative methodology with semi- structured interviews. Participants were recruited on the Facebook patient group between October 2021 and January 2022. Partici-pants had been experiencing symptoms for at least three months following confirmed COVID-19 infection. Interviews were conducted by video call, recorded and transcribed with consent. The thematic analysis method has been chosen to infer data from textual material. Results: 17 interviews with women with Long-COVID have been analysed. The main themes include: a total change of life due to the symptomatology, loss ofautonomy that affects social, family and professional life; social isolation, a sense of abandonment often in-creased by stigma, the difficulty of being believed and achieving diagnosis; difficulty in managing symptoms and accessing to care services; living with uncertainty caused by the lack of institutional, social, professional, familial and medical support. Conclusions: Intervention programs, both institutional and social-health policies should be developed for patients with Long-COVID. The impact of symptoms could be reduced by develop-ing standards and protocols, and by ensuring access to care and to multi-disciplinary rehabilitation. Further development of knowledge on Long-COVID is essential.

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Guzman-Esquivel, Jose; Mendoza-Hernandez, Martha A.; Guzman-Solorzano, Hannah P.; Sarmiento-Hernandez, Karla A.; Rodriguez-Sanchez, Iram P.; Martinez-Fierro, Margarita L.; Paz-Michel, Brenda A.; Murillo-Zamora, Efren; Rojas-Larios, Fabian; Lugo-Trampe, Angel; Plata-Florenzano, Jorge E.; Delgado-Machuca, Marina; Delgado-Enciso, Ivan

Clinical Characteristics in the Acute Phase of COVID-19 That Predict Long COVID: Tachycardia, Myalgias, Severity, and Use of Antibiotics as Main Risk Factors, While Education and Blood Group B Are Protective

https://doi.org/10.3390/healthcare11020197

Published

1-Jan-23

Study

https://www.mdpi.com/2227-9032/11/2/197

Background: Risk factors for developing long COVID are not clearly established. The present study was designed to determine if any sign, symptom, or treatment of the acute phase, or personal characteristics of the patient, is associated with the development of long COVID. Methods: A cohort study was carried out, randomly selecting symptomatic COVID-19 patients and not vaccinated. The severity of the acute illness was assessed through the number of compatible COVID-19 symptoms, hospitalizations, and the symptom severity score using a 10-point visual analog scale. Results: After multivariate analysis, a severity score ≥8 (RR 2.0, 95%CI 1.1–3.5, p = 0.022), hospitalization (RR 2.1, 95%CI 1.0–4.4, p = 0.039), myalgia (RR 1.9, 95%CI 1.08–3.6, p = 0.027), tachycardia (RR 10.4, 95%CI 2.2–47.7, p = 0.003), and use of antibiotics (RR 2.0, 95%CI 1.1–3.5, p = 0.022), was positively associated with the risk of having long COVID. Higher levels of education (RR 0.6, 95%CI 0.4–0.9, p = 0.029) and type positive B blood group (B + AB, RR 0.44, 95%CI 0.2–0.9, p = 0.044) were protective factors. The most important population attributable fractions (PAFs) for long COVID were myalgia (37%), severity score ≥8 (31%), and use of antibiotics (27%). Conclusions: Further studies in diverse populations over time are needed to expand the knowledge that could lead us to prevent and/or treat long COVID.

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Lippi, Giuseppe; Sanchis‑Gomar, Fabian; Henry, Brandon M.

COVID-19 and its long-term sequelae: what do we know in 2023?

https://doi.org/10.20452/pamw.16402

Published

9-Jan-23

Review

https://www.mp.pl/paim/issue/article/16402

Post‑viral syndrome is a well‑known medical condition characterized by different levels of physical, cogni‑tive, and emotional impairment that may persist with fluctuating severity after recovering from an acute viral infection. Unsurprisingly, COVID‑19 may also be accompanied by medium- and long‑term clinical sequelae after recovering from a SARS‑CoV‑2 infection. Although many clinical definitions have been provided, “long‑ COVID” can be defined as a condition occurring in patients with a history of SARS‑CoV‑2 infection, developing 3 months from the symptoms onset, persisting for at least 2 months, and not explained by alternative diagnoses. According to recent global analyses, the cumulative prevalence of long‑ COVID seems to range between 9% and 63%, and is up to 6‑ fold higher than that of similar postv iral infection conditions. Long‑COVID primarily encompasses the presence of at least 1 symptom, such as fatigue, dyspnea, cognitive impairment / brain fog, postexertional malaise, memory issues, musculoskel‑etal pain / spasms, cough, sleep disturbances, tachycardia / palpitations, altered smell / taste perception, headache, chest pain, and depression. The most important demographic and clinical predictors to date are female sex, older age, cigarette smoking, pre‑existing medical conditions, lack of COVID‑19 vac‑cination, infection with pre‑Omicron SARS‑CoV‑2 variants, number of acute phase symptoms, viral load, severe / critical COVID‑19 illness, as well as invasive mechanical ventilation. Concerning the care for long‑ COVID patients, the greatest challenge is the fact that this syndrome cannot be considered a single clinical entity, and thus it needs an integrated multidisciplinary management, specifically tailored to the type and severity of symptoms.

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Jacobs, Elizabeth T.; Catalfamo, Collin J.; Colombo, Paulina M.; Khan, Sana M.; Austhof, Erika; Cordova-Marks, Felina; Ernst, Kacey C.; Farland, Leslie V.; Pogreba-Brown, Kristen

Pre-existing conditions associated with post-acute sequelae of COVID-19

https://doi.org/10.1016/j.jaut.2022.102991

Published

1-Feb-23

Study

https://www.sciencedirect.com/science/article/pii/S0896841122001998

Highlights
•Post-acute sequelae of COVID-19 (PASC) has been increasingly observed to occur in patients who have been infected with SARS-CoV-2.
•To date, it is not known which comorbidities may increase an individual's risk of developing PASC.
•This study shows that those with autoimmune diseases were more likely to develop PASC than those without these comorbidities.
Abstract
Post-acute sequelae of COVID-19 (PASC) are conditions that occur or remain at least 28 days after SARS-CoV-2 infection. While some risk factors for PASC have been identified, little is known about pre-existing conditions that render one susceptible to developing PASC. Data from participants (n = 1224) in a longitudinal COVID-19 cohort study in Arizona were used to investigate comorbid conditions associated with PASC. After adjustment of the models for age, BMI, gender, race, and smoking, the following pre-existing conditions were statistically significantly associated with the development of PASC: asthma (OR = 1.54; 95% CI = 1.10–2.15); chronic constipation (OR = 4.29; 95% CI = 1.15–16.00); reflux (OR = 1.54; 95% CI = 1.01–2.34); rheumatoid arthritis (OR = 3.69; 95%CI = 1.15–11.82); seasonal allergies (OR = 1.56; 95% CI = 1.22–1.98); and depression/anxiety (OR = 1.72; 95% CI = 1.17–2.52). When grouping conditions together, statistically significant associations with PASC were observed for respiratory (OR = 1.47; 95% CI = 1.06–2.14); gastrointestinal (OR = 1.62; 95% CI = 1.16–2.26), and autoimmune conditions (OR = 4.38; 95% CI = 1.59–12.06). After adjustment for severity of acute SARS-CoV-2 infection and depression/anxiety, seasonal allergies (OR = 1.48; 95% CI 1.15–1.91) and autoimmune disease (OR = 3.78; 95% CI - 1.31-10.91) remained significantly associated with risk for PASC. These findings indicate that numerous pre-existing conditions may be associated with an increased risk for the development of PASC. Patients with these conditions should consider taking extra steps to avoid infection.

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Barker, Kristin Kay; Whooley, Owen; Madden, Erin F.; Ahrend, Emily E.; Greene, R. Neil

The long tail of COVID and the tale of long COVID: Diagnostic construction and the management of ignorance

https://doi.org/10.1111/1467-9566.13599

Published

29-Dec-22

Article

https://onlinelibrary.wiley.com/doi/abs/10.1111/1467-9566.13599

We bring together insights from the sociology of diagnosis and the sociology of ignorance to examine the early diagnostic unfolding of ‘Long COVID’ (LC). Originally described by patient activists, researchers set out to ponder its unwieldy clinical boundaries. Using a scoping review method in tandem with qualitative content analytic techniques, we analyse medicine’s initial struggles to construct a LC diagnosis. Paying attention to the dynamics of ignorance, we highlight three consequential conceptual manoeuvres in the early classifications of LC: causal agnosticism concerning the relationship between COVID-19 and LC, evasion of lumping LC with similar conditions; and the predictable splitting off of medically explainable cases from the LC designation. These manoeuvres are not maleficent, inept or unreasonable. They are practical but impactful responses to the classificatory dilemmas present in the construction of diagnoses amidst ignorance. Although there are unique aspects to LC, we suggest that its early fate is nevertheless emblematic of medicine’s diagnostic standardisation processes more generally. To varying degrees, diagnoses are ignorance management strategies; they create a pathway through the uncertainty at the core of disease realities. However, while diagnoses circumscribe some types of ignorance, they produce others through the creation of blind spots and paths not taken.

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Berg, Selina Kikkenborg; Palm, Pernille

Playing catch with long COVID – Understanding a new disease

https://doi.org/10.1016/j.lanepe.2022.100568

Published

1-Feb-23

Article

https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(22)00264-2/fulltext

publisher: Elsevier
PMID: 36597517
This study from the CLoCk study by Pereira et al. is a large-scale English, matched longitudinal cohort study of children and adolescents 11–17 years of age reporting symptoms and well-being.3 The included children and adolescents were all tested and those with confirmed SARS-CoV-2 infection were compared to those SARS-CoV-2 PCR-negative.
The study shows that across all time points, adverse symptoms were generally more common in test-positive compared to test-negative children and adolescents. Symptoms presentation at time of testing e.g. shortness of breaths was 5.4% higher after 12 months and tiredness was 13.8% higher at 12 months in positive compared to negative. More new-onset long-COVID symptoms were also found at 6 and 12 months in the SARS-CoV-2 positive group. Overall wellbeing is better among SARS-CoV-2 positives which is in line with previous research.5,6 Specific symptoms and quality of life issues presenting at 6 months and 12 months shows varying patterns of differences between groups, suggesting that multiple factors influencing symptoms developing during the follow up time.
The authors should be applauded for carrying out a large, well-planned study that also includes a control group. Further that the participants were asked to report symptoms at multiple times at 0,3,6 and 12 months posttest. A mayor concern is, however, a large drop out. Only 5086 of the 127,896 in the initial invited group responded to the final questionnaire after 12 months. Therefore, the results are indicative rather than conclusive due to lack of generalizability, and selection bias. It is a strength that the children and adolescents were asked to answer themselves not using parent proxy.7
Even when planning a study carefully some problems are interfering with the data. One problem is the changing variants questioning if the results are transferable for the Omicron variant. Another major issue is the offer to vaccinate during the follow up period. The authors make a note in the methods section, that 66% in both groups received vaccination between 6 and 12 months, However, the impact on the results are not discussed. E.g., late onset of headache and dizziness could be related to vaccines.8,9 Measuring symptoms of long COVID over time is very complex as it is impossible to control for interfering symptoms. Also, the long COVID symptoms being so unspecific and similar to symptoms that occur from varies reasons such as other viral infections, stress reactions after long school hours, after sport, and for the girls hormonal symptoms. In this study symptom burden decrease only to increase with new onset symptoms over time. The fluctuational patters is described before in long COVID4,6 however, it cannot be ruled out that new symptoms are connected to e.g. vaccines or other viral infections. So even when designing with a control group, it is difficult to control for extrinsic factors. Also a vulnerability to comorbid disease is suggested and might explain new onset symptoms long after the initial COVID-19 diagnose.10
Previous studies including our study the LongCOVIDKidsDK shows age and gender differences with girls presenting more symptoms after puberty than boys and with more symptoms among adolescents than younger children.6 The authors don't address this important issue and should be encouraged to look more into this.
The overall take home message is that most children seem to recover quickly. However, some experience long lasting symptoms and difference between groups are found up to 12 months after the initial diagnosis. Behind these numbers is probable hidden a smaller group that are affected significantly by long-lasting symptoms. General practitioners and pediatricians should be aware of the potential burden in children. Furthermore, we still lack public accept and see skepticism from some health professionals, despite mounting evidence of long COVID. More clinical research is now needed to investigate the biological mechanisms and develop effective preventional strategies and treatments.

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Ogungbe, Oluwabunmi; Slone, Sarah; Alharthi, Abeer; Tomiwa, Tosin; Kumbe, Baridosia; Bergman, Alanna; McNabb, Katherine; Wright, Rhonda Smith; Farley, Jason E.; Himmelfarb, Cheryl R. Dennison; Cooper, Lisa A.; Post, Wendy S.; Davidson, Patricia M.; Commodore-Mensah, Yvonne

“Living like an empty gas tank with a leak”: Mixed methods study on post-acute sequelae of COVID-19

https://doi.org/10.1371/journal.pone.0279684

Published

30-Dec-22

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0279684

Background The burden and presentation of post-acute sequela of SARS-CoV-2 infection (PASC) are a developing major public health concern. Objectives To characterize the burden of PASC in community-dwelling individuals and understand the experiences of people living with PASC. Methods This mixed-methods study of COVID-19 positive community-dwelling persons involved surveys and in-depth interviews. Main outcome was self-report of possible PASC symptoms 3 weeks or longer after positive COVID-19 test. In-depth interviews were guided by a semi-structured interview guide with open-ended questions and probes based on emerging literature on PASC and the impact of COVID-19. Results With a survey response rate of 70%, 442 participants were included in this analysis, mean (SD) age 45.4 (16.2) years, 71% female, 12% Black/African American. Compared to those with no PASC symptoms, persons who reported PASC symptoms were more likely to be older (mean age: 46.5 vs. 42; p = 0.013), female (74.3% vs. 61.2%; p = 0.010), to have pre-existing conditions (49.6% vs. 34%; p = 0.005), and to have been hospitalized for COVID-19 (14.2% vs. 2.9%; p = 0.002). About 30% of the participants experienced severe fatigue; the proportion of persons reporting severe fatigue was 7-fold greater in those with PASC symptoms (Adjusted Prevalence Ratio [aPR] 6.73, 95%CI: 2.80–16.18). Persons with PASC symptoms were more likely to report poor quality of life (16% vs. 5%, p<0.001) and worse mental health functioning (Mean difference: -1.87 95%CI: -2.38, -1.37, p<0.001). Themes from in-depth interviews revealed PASC was experienced as debilitating. Conclusions In this study, the prevalence of PASC among community-dwelling adults was substantial. Participants reported considerable coping difficulties, restrictions in everyday activities, invisibility of symptoms and experiences, and impediments to getting and receiving PASC care.

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Himmels, Jan Peter

Post COVID-19 condition and new onset diseases after COVID-19

Published

1-Dec-22

Review

https://fhi.brage.unit.no/fhi-xmlui/bitstream/handle/11250/3040161/Himmels-2022-Pos.pdf?sequence=1

Current evidence suggests that patients who have been hospitalised or undergone non-invasive
ventilation due to severe COVID-19 experience similar long-term consequences as patients who
have been exposed to similar treatment due to other RTIs. These findings support the current
rehabilitation practise of providing similar care to patients post-COVID as after other severe
RTIs. Controlled studies also found that most symptoms reported by COVID-19-patients were
also reported in the uninfected general population, albeit to a lesser extent. The symptoms that
are most specific for COVID-19 seems to be altered smell and taste and neurological diagnoses,
although with equally common reporting of dyspnoea and fatigue. Most reported symptoms and
new onset diseases are also seen in the follow-up period of other RTIs. Symptom burden appears
to decrease over time, but we do not know if or when these symptoms might disappear. The data
also reflect that many of the reported symptoms are prevalent in non-infected populations.
Although the evidence base is growing and steadily becomes more trustworthy, some aspects
remain uncertain. Our findings continue to reflect long term symptoms in patients who were
infected early in the pandemic. New virus variants causing milder disease will likely reduce the
overall risk and burden of long-term symptoms. Therapeutic advancements and vaccination
impact outcomes and probably lead to milder courses of disease, contributing to a further
reduction in the prevalence and burden of long-term symptoms. Studies on consequences of
breakthrough infections, and comparative studies on vaccinated versus non vaccinated
populations are already pointing in the directions of fewer long-term symptoms. Persons with
asymptomatic COVID-19, or those not tested are not well researched.

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Davis, Hannah E.; McCorkell, Lisa; Vogel, Julia Moore; Topol, Eric J.

Long COVID: major findings, mechanisms and recommendations

https://doi.org/10.1038/s41579-022-00846-2

Published

13-Jan-23

Review

https://www.nature.com/articles/s41579-022-00846-2

Long COVID is an often debilitating illness that occurs in at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. More than 200 symptoms have been identified with impacts on multiple organ systems. At least 65 million individuals worldwide are estimated to have long COVID, with cases increasing daily. Biomedical research has made substantial progress in identifying various pathophysiological changes and risk factors and in characterizing the illness; further, similarities with other viral-onset illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome have laid the groundwork for research in the field. In this Review, we explore the current literature and highlight key findings, the overlap with other conditions, the variable onset of symptoms, long COVID in children and the impact of vaccinations. Although these key findings are critical to understanding long COVID, current diagnostic and treatment options are insufficient, and clinical trials must be prioritized that address leading hypotheses. Additionally, to strengthen long COVID research, future studies must account for biases and SARS-CoV-2 testing issues, build on viral-onset research, be inclusive of marginalized populations and meaningfully engage patients throughout the research process.

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Leitzke, Marco

Is the post-COVID-19 syndrome a severe impairment of acetylcholine-orchestrated neuromodulation that responds to nicotine administration?

https://doi.org/10.1186/s42234-023-00104-7

Published

18-Jan-23

Article

https://doi.org/10.1186/s42234-023-00104-7

Following a SARS-CoV-2 infection, many individuals suffer from post-COVID-19 syndrome. It makes them unable to proceed with common everyday activities due to weakness, memory lapses, pain, dyspnea and other unspecific physical complaints. Several investigators could demonstrate that the SARS-CoV-2 related spike glycoprotein (SGP) attaches not only to ACE-2 receptors but also shows DNA sections highly affine to nicotinic acetylcholine receptors (nAChRs). The nAChR is the principal structure of cholinergic neuromodulation and is responsible for coordinated neuronal network interaction. Non-intrinsic viral nAChR attachment compromises integrative interneuronal communication substantially. This explains the cognitive, neuromuscular and mood impairment, as well as the vegetative symptoms, characterizing post-COVID-19 syndrome. The agonist ligand nicotine shows an up to 30-fold higher affinity to nACHRs than acetylcholine (ACh). We therefore hypothesize that this molecule could displace the virus from nAChR attachment and pave the way for unimpaired cholinergic signal transmission. Treating several individuals suffering from post-COVID-19 syndrome with a nicotine patch application, we witnessed improvements ranging from immediate and substantial to complete remission in a matter of days.

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Van Wambeke, Erika; Bezler, Cécile; Kasprowicz, Anne-Marie; Charles, Anne-Laure; Andres, Emmanuel; Geny, Bernard

Two-Years Follow-Up of Symptoms and Return to Work in Complex Post-COVID-19 Patients

https://doi.org/10.3390/jcm12030741

Published

1-Jan-23

Study

https://www.mdpi.com/2077-0383/12/3/741

Introduction: Many COVID-19 patients present with severe long-lasting symptoms. They might benefit from a coordination team to manage such complex situations, but late efficacy still needs to be determined. Population and Methods: Out of 105 contacts, 45 patients had two phone consultations separated by personalized support 15 and 22 months, respectively, after COVID infection. Self-reported symptoms, feelings of improvement and ability to return to work allowed us to determine the efficacy of the therapeutic strategy proposed. Results: Unlike what was expected, many post-COVID-19 patients directly contacted the coordination team and had significant pre-existing comorbidities. Despite exercise, respiratory, olfactory rehabilitations, cognition/speech therapy and/or psychological support, the more frequent self-reported symptoms (fatigue, neurocognitive disorders, muscles and joint pain) did not resolve. However, dyspnea, anxiety and chest pain were significantly reduced. Finally, 2/3 of the patients felt some degree of improvement and returned to work either partially or fully, but 1/3 remained complaining of symptoms and out of work as late as 22 months after COVID occurrence. All patients greatly appreciated the second phone consultation. Conclusions: In such complex situations, besides early and adapted rehabilitations and psychological help allowing better symptom management, relatively simple actions such as a phone call might be very useful to reduce patients’ feelings of abandonment.

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Shelton, A Teresa

Epstein-Barr Virus Testing-to-Treatment in Long COVID Patients: A Review and Recommendation

Published

18-Jan-23

Review

https://digitalshowcase.lynchburg.edu/dmscjournal/vol5/iss1/101

Incidence rates are increasing worldwide of symptoms persisting for several months or longer after Coronavirus 19 (COVID-19, SARS-Co-2) acute infection known as the post-acute sequelae of COVID-19 (PASC, long COVID). Research demonstrates Epstein-Barr virus (EBV) latent reactivation in hospitalized patients with COVID-19 carries a higher mortality rate when untreated. A critical link between EBV and long COVID symptoms connects the hyperinflammatory cascade and immune dysfunction common to both viral conditions. A clinical review of emerging literature justifies the rationale for testing and treatment of EBV in cases of PASC. Current World Health Organization (WHO) Post-COVID Care Center (PCCC) clinical guidelines for outpatient treatment of long COVID and Multisystem Inflammatory Syndrome (MIS) involve multiple specialty provider access yet exclude viral co-infection screening and treatment for EBV. No patented therapy for EBV exists, and the literature review reveals profound evidence for a Federal Drug Administration (FDA) approved treatment for EBV infection. To reduce long COVID symptoms, a proposed evaluation and treatment plan for future research of EBV reactivation in PASC patients is merited. Primary care and PCCC clinics need a standardized therapy for EBV and PASC co-infection to improve patient outcomes.

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Quinn, Kieran L.; Razak, Fahad; Cheung, Angela M.

Diagnosing post-COVID-19 condition (long COVID) in adults

https://doi.org/10.1503/cmaj.220818

Published

17-Jan-23

Review

https://www.cmaj.ca/content/195/2/E78

About 1.4 million people in Canada have been affected by long COVID
The 2022 Canadian COVID-19 Antibody and Health Survey reported that nearly 15% of adults in Canada with suspected or confirmed SARS-CoV-2 infection had symptoms beyond 3 months.2 Females (18.0%) were more likely than males (11.6%) to report lingering symptoms.2 A 2022 meta-analysis and systematic review of early pandemic experiences with more severe variants reported an overall global prevalence of 43%, which differed among people who were admitted to hospital (54%) and those who were not (34%).3 Consequently, contemporary prevalence may be far lower owing to high vaccination rates, evolving therapies and less virulent variants, resulting in less severe disease overall.3

Long COVID is systemic in nature
This may be related to the expression of angiotensin-converting-enzyme 2 (ACE2) receptors in different organ systems, through which SARS-CoV-2 enters a cell.4 Several pathophysiological mechanisms may contribute differentially to long COVID, including cellular damage, persistent inflammation or viremia, autoimmunity and a procoagulant state.4

Long COVID can affect most organ systems in the body
The condition has substantial effects on patients’ daily well-being and functioning.3,4 More than 100 symptoms have been reported in people with long COVID, and female sex appears to be an independent risk factor. The most common potentially modifiable symptoms include fatigue (23%–63%), anxiety and depression (23%–46%), dyspnea (11%–43%), sleep disturbances (11%–31%) and palpitations (6%–22%).3,4

Many people with long COVID have lingering symptoms
Although many people recover from long COVID, some continue to have symptoms and are unable to return to full-time work at 1 year after infection.2,5 In a 2022 longitudinal cohort study5 involving 1192 people who were admitted to hospital in Wuhan, China, and who survived COVID-19, 68% had at least 1 symptom at 6 months after infection, which decreased to 55% at 2 years. A total of 21% of people who were previously employed had not returned to work,5 and the same proportion of people in Canada reported that their symptoms often or always limited their daily activities.2

publisher: CMAJ
section: Practice
PMID: 36649955

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D367

Quinn, Kieran L.; Razak, Fahad; Cheung, Angela M.

Assessing common and potentially modifiable symptoms of post-COVID-19 condition (long COVID) in adults

https://doi.org/10.1503/cmaj.220823

Published

17-Jan-23

Review

https://www.cmaj.ca/content/195/2/E76

Fatigue is the most common symptom of long COVID
Fatigue is associated with diminished activity tolerance and postexertional malaise and symptom exacerbation. Providers should assess its frequency, severity, duration, impact, and alleviating and exacerbating factors (physical, cognitive and psychological), as well as sleep hygiene and effect on daily activities. To rule out other causes, a comprehensive history, physical examination and routine bloodwork including hemoglobin and thyroid-stimulating hormone are important.1

People with long COVID frequently experience anxiety or depression
It is important to validate a person’s psychological experience during long COVID and screen for symptoms of anxiety and depression, which are common. Providers should explore isolation, stress and any underlying drivers of psychological symptoms, with a focus on potential impairment in function.1

Assessment of dyspnea on exertion should explore a physical examination and oxygen saturation monitoring during a walk test2
In people with normoxia and mild acute illness, dyspnea may be due to weak respiratory muscles and cardiac or noncardiac diseases. A limited set of routine investigations, in addition to pulmonary function and natriuretic peptide tests, may be useful in differentiating people with post-viral reactive airway disease from weak respiratory muscles and cardiac disease. For more severe dyspnea, residual lung abnormalities (e.g., fibrosis) or cardiac disease may explain the dyspnea requiring specific investigations, such as chest radiograph, echocardiography and a 6-minute walk test.2

Evaluation of sleep disturbances should explore sleep pattern, duration, quality, frequency of awakenings and whether the person feels refreshed after waking
Special attention needs to be paid to the use of alcohol, cannabis, caffeine and sleep medications by people with long COVID. Severe acute illness may warrant a sleep study as the need for supplemental oxygen owing to nocturnal hypoxemia was reported in 6.6% of people who were admitted to hospital 60 days after acute COVID-19, which may persist beyond 90 days.3

Investigation of palpitations should include orthostatic vital signs and a 12-lead electrocardiogram
Cardiac dysautonomia has been associated with long COVID.4 Postural orthostatic tachycardia syndrome can be diagnosed with orthostatic vital signs and a 10-minute stand test.5 Holter monitoring may help distinguish inappropriate sinus tachycardia (the most common arrhythmia associated with long COVID) from other arrhythmias.5
publisher: CMAJ
section: Practice
PMID: 36649958

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Khosla, Seema; Cheung, Joseph; Gurubhagavatula, Indira; Medicine, on behalf of the COVID-19 Task Force of the American Academy of Sleep

Sleep Assessment in Long COVID Clinics: A Necessary Tool for Effective Management

https://doi.org/10.1212/CPJ.0000000000200079

Published

1-Feb-23

Study

https://cp.neurology.org/content/13/1/e200079

As we adapt to SARS-CoV-2, it has become apparent that the acute illness is not the only threat from this virus. Long COVID has emerged as a potentially disabling condition with multiple varied symptoms. We propose that querying patients about their sleep may allow for the assessment of a sleep-related disorder that is amenable to treatment. In addition, hypersomnolence is a prominent feature and may mimic other organic hypersomnias; therefore, inquiring about COVID-19 infection in sleepy patients is suggested.

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Saigle, Victoria

“My family doctor didn’t know how to help me”: a teenager’s perspective on being diagnosed with long COVID

https://doi.org/10.1503/cmaj.221846

Published

17-Jan-23

Article

https://www.cmaj.ca/content/195/2/E84

Around the 3-month mark, my mom found a study that was enrolling long COVID patients. We had a phone call with the study group and did blood work. When we saw the [study] doctor in person, they said I had symptoms that a lot of long COVID patients have. The study was one of the only ones that would accept me — I was 16 at the time. I liked knowing that there was something they could help me with; it wasn’t just like, “Oh, you’re sick.” It was, “We’ll help you through it.” The long COVID team is great. They listen.

For a while, I had been crashing every 4 days. I’d feel good for a few days and then, by around day 4, I’d need to sleep for 18 hours. The long COVID clinic explained that, as I started feeling better, I’d have to take baby steps. If I didn’t, I’d get so fatigued that my body would start to shut down and tell me I needed to stop and rest. They also recommended that I take a higher dose of ferritin because my levels were still low.

Long COVID affected me a lot last year and a bit this year. I stopped doing basically everything — fastpitch, rugby and school. I didn’t see anybody. The only thing that I did was work, but I wasn’t working as much as I used to. Now, I’m still tired but I don’t need to take a nap every few days. However, I’m not at the level that I was before having COVID. — Interviewee preferred to remain anonymous
publisher: CMAJ
section: Humanities
PMID: 36649954

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Saigle, Victoria

A patient’s perspective on long COVID: improvement month to month not week to week

https://doi.org/10.1503/cmaj.221816

Published

17-Jan-23

Article

https://www.cmaj.ca/content/195/2/E83

I got COVID in early January of 2022. It lasted 10 days and then in mid-to-late February, I got additional symptoms. It started with a lack of appetite, dizziness and extreme fatigue, and then psychological symptoms, like anxiety and depression. The nausea, lack of appetite and weight loss were the most concerning. At its worst, walking around the house or to the end of the driveway was difficult. I slept 16–18 hours a day. In mid-to-late March, I saw my primary care doctor and other specialists to try to figure out what was wrong.

Initially, they were thinking something else was going on, maybe an autoimmune disease or cancer. I had lost 30 pounds in 3 to 4 weeks. I saw a gastroenterologist and an internal medicine specialist, had a CT scan of my chest and abdomen, an upper GI scope and a whole bunch of blood work, as well as an abdominal ultrasound and an echocardiogram. After all of the tests were done, long COVID kind of became a diagnosis of exclusion.

In early May 2022, I got an appointment at a long COVID clinic. My wife had heard of the clinic and we emailed them directly. No one that I had seen up to that point was willing to do anything else. I felt like I was stuck.

The long COVID clinic had the benefit of a 3 and a half month history and all the medical tests that showed essentially nothing. They took a thorough history, did some more tests and said it fit with long COVID. One thing they talked about was the importance of pacing and setting a level of activity I could achieve without pushing myself. It was relearning what I could manage and then slowly building up my activity. Other than time and rest, that’s probably the most important concept that I had to get my head around. I see improvement month to month, not week to week, which I’m still coming to terms with.

The nausea and the poor appetite disappeared first, and after 4 or 5 months my weight returned. The fatigue, lightheadedness, dizziness and my exercise tolerance are still works in progress.

I was off work for 4 or 5 months. I work as a large animal vet. It’s a physically demanding job with long hours. At that time, my work involved night work and getting called in at irregular hours. I have not returned to that, but I now work about 60% of a normal week. My employer was super supportive and I couldn’t ask for more. My work, my wife and my family are my rocks that helped me get through this. Before this, I had no significant problems and took no medications. I felt like a healthy 52-year-old man.

It’s been really difficult to be that sick and not have an accepted hypothesis about what’s going on. I understand that sometimes we don’t know, but it’s important to see a path forward. In the summer, I spoke with people who also went through long COVID. Finding a way for patients to talk to others with the disease would be a huge help. The psychological part of long COVID could also be discussed more. I am on medication now, but at times I got the feeling that there was a temptation to explain all of my symptoms as being psychological. The uncertainty, lack of experience with long COVID and the dearth of clinicians to treat me resulted in extreme difficulty accessing any disability insurance. It has been very hard to get the details of my symptoms and their effects into my records in sufficient measure for insurers to feel it is worthy of a claim. — Patient wished to remain anonymous
publisher: CMAJ
section: Humanities
PMID: 36649950

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Huerne, Katherine; Filion, Kristian B.; Grad, Roland; Ernst, Pierre; Gershon, Andrea S.; Eisenberg, Mark J.

Epidemiological and Clinical Perspectives of Long COVID Syndrome

https://doi.org/10.1016/j.ajmo.2023.100033

Published

18-Jan-23

Review

https://www.sciencedirect.com/science/article/pii/S2667036423000031

UNSTRUCTURED ABSTRACT
Long COVID, or post-acute COVID-19 syndrome, is characterized by multi-organ symptoms lasting 2+ months after initial COVID-19 virus infection. This review presents the current state of evidence for long COVID syndrome, including the global public health context, incidence, prevalence, cardiopulmonary sequelae, physical and mental symptoms, recovery time, prognosis, risk factors, rehospitalization rates, and the impact of vaccination on long COVID outcomes. Results are presented by clinically relevant subgroups. Overall, 10-35% of COVID survivors develop long COVID, with common symptoms including fatigue, dyspnea, chest pain, cough, depression, anxiety, post-traumatic stress disorder, memory loss, and difficulty concentrating. Delineating these issues will be crucial to inform appropriate post-pandemic health policy and protect the health of COVID-19 survivors, including potentially vulnerable or underrepresented groups. Directed to policymakers, health practitioners, and the general public, we provide recommendations and suggest avenues for future research with the larger goal of reducing harms associated with long COVID syndrome.

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N3C Consortium; RECOVER Consortium; Reese, Justin T.; Blau, Hannah; Casiraghi, Elena; Bergquist, Timothy; Loomba, Johanna J.; Callahan, Tiffany J.; Laraway, Bryan; Antonescu, Corneliu; Coleman, Ben; Gargano, Michael; Wilkins, Kenneth J.; Cappelletti, Luca; Fontana, Tommaso; Ammar, Nariman; Antony, Blessy; Murali, T. M.; Caufield, J. Harry; Karlebach, Guy; McMurry, Julie A.; Williams, Andrew; Moffitt, Richard; Banerjee, Jineta; Solomonides, Anthony E.; Davis, Hannah; Kostka, Kristin; Valentini, Giorgio; Sahner, David; Chute, Christopher G.; Madlock-Brown, Charisse; Haendel, Melissa A.; Robinson, Peter N.; Spratt, Heidi; Visweswaran, Shyam; Flack, Joseph Eugene; Yoo, Yun Jae; Gabriel, Davera; Alexander, G. Caleb; Mehta, Hemalkumar B.; Liu, Feifan; Miller, Robert T.; Wong, Rachel; Hill, Elaine L.; Thorpe, Lorna E.; Divers, Jasmin

Generalisable long COVID subtypes: Findings from the NIH N3C and RECOVER programmes

https://doi.org/10.1016/j.ebiom.2022.104413

Published

1-Jan-23

Study

http://www.scopus.com/inward/record.url?scp=85144488606&partnerID=8YFLogxK

Background: Stratification of patients with post-acute sequelae of SARS-CoV-2 infection (PASC, or long COVID) would allow precision clinical management strategies. However, long COVID is incompletely understood and characterised by a wide range of manifestations that are difficult to analyse computationally. Additionally, the generalisability of machine learning classification of COVID-19 clinical outcomes has rarely been tested. Methods: We present a method for computationally modelling PASC phenotype data based on electronic healthcare records (EHRs) and for assessing pairwise phenotypic similarity between patients using semantic similarity. Our approach defines a nonlinear similarity function that maps from a feature space of phenotypic abnormalities to a matrix of pairwise patient similarity that can be clustered using unsupervised machine learning. Findings: We found six clusters of PASC patients, each with distinct profiles of phenotypic abnormalities, including clusters with distinct pulmonary, neuropsychiatric, and cardiovascular abnormalities, and a cluster associated with broad, severe manifestations and increased mortality. There was significant association of cluster membership with a range of pre-existing conditions and measures of severity during acute COVID-19. We assigned new patients from other healthcare centres to clusters by maximum semantic similarity to the original patients, and showed that the clusters were generalisable across different hospital systems. The increased mortality rate originally identified in one cluster was consistently observed in patients assigned to that cluster in other hospital systems. Interpretation: Semantic phenotypic clustering provides a foundation for assigning patients to stratified subgroups for natural history or therapy studies on PASC. Funding: NIH (TR002306/OT2HL161847-01/OD011883/HG010860), U.S.D.O.E. (DE-AC02-05CH11231), Donald A. Roux Family Fund at Jackson Laboratory, Marsico Family at CU Anschutz.

377

D373

Dotan, Arad; Shoenfeld, Yehuda

Editorial for “Post COVID-19 Syndrome in Patients with Asymptomatic/Mild Form”

https://doi.org/10.3390/pathogens12020167

Published

1-Feb-23

Editorial

https://www.mdpi.com/2076-0817/12/2/167

Due to the unclear criteria for PCS prevention, diagnosis, management tactics, and contributing factors, Anna Malkova et al. conducted a review analysis of publications about COVID-19 in online databases from December 2019 to September 2021 [7]. This analysis looked at research on post-COVID-19 syndrome in patients with asymptomatic and mild SARS-CoV-2 infections. The inclusion criteria were asymptomatic or mild forms of COVID-19 diagnosed with a PCR test, the development of PCS symptoms a minimum of 1 month after, and the description of the developed PCS symptoms. Unfortunately, only a small number of published papers had described the type of PCS manifestations; thus, this study could not follow the PRISMA guidelines. Nevertheless, 11 studies were reviewed, which included the sum of 13,637 SARS-CoV-2-infected patients. PCS developed among approximately 30–60% of patients with asymptomatic or mild forms of COVID-19, and the most common symptoms were fatigue, shortness of breath, cough, anosmia, and ageusia. In addition, other signs of central nervous system damage were reported, including headaches and brain fog. Furthermore, a meta-analysis that defined PCS as ranging from 14 to 110 days after the viral infection estimated that 80% of the infected patients with SARS-CoV-2 developed one or more long-term symptoms [8].
Notably, females had a higher risk of developing PCS in comparison to males, with an approximately 1.25 ratio (on average, 60% of PCS patients were females). These results highlight the immense importance of further research in sufficient therapeutic agents for PCS manifestations. In addition, current evidence suggests that the severity and mortality of COVID-19 are higher in males than in females, whereas females are at an increased risk of COVID-19 reinfection and the development of PCS [9]. These conflicting risks between the severity and mortality of COVID-19 compared to the development of PCS could be explained by the generally more aggressive immune system of females [10,11].
Differences between the sexes are well studied in numerous infectious diseases, as well as in response to vaccinations [9,12]. Sex-specific expression patterns of proteins that mediate virus binding and entry and divergent reactions of the immune and endocrine systems, particularly the hypothalamic–pituitary–adrenal axis, in response to acute stress might explain the higher severity of COVID-19 in men [9]. Additionally, as enhanced immunoreactivity in females provides better protection against infections, it contributes to enhanced autoreactivity, thereby contributing to the induction of more autoimmune manifestations and diseases than in males, such as SLE, multiple sclerosis, rheumatoid arthritis, and numerous others [11,13,14]. Furthermore, COVID-19 has been shown to be associated with many autoantibodies, as well as autoimmune manifestations [10,15,16,17,18]. Thus, the PCS course of the disease may have at least a partial autoimmune factor; otherwise, it would not be logical that females would be at an elevated risk. Importantly, as the severity of COVID-19 is higher in males than in females, it could be assumed that the difference in the risk of PCS is not primarily due to the severity of the COVID-19 infection.
The possible association between the described PCS symptoms and brain damage that occurs during an SARS-CoV-2 infection suggests that PCS patients commonly have a clinical presentation similar to that of encephalomyelitis/chronic fatigue syndrome (ME/CFS): severe fatigue, sleep disorders, cognitive impairments, and different manifestations of autonomic dysfunction exacerbated in physical exercise [8,10]. Furthermore, close to 20 distinct autoantibodies which target the GPCR of the nervous system and renin-angiotensin system-related molecules were found to be significantly associated with the clinical severity of COVID-19 [10]. Additionally, these autoantibodies were elevated in a subset of ME/CFS patients, specifically, the β2 adrenergic and M3 and M4 cholinergic receptor antibodies, as well as in other similar disorders [19,20,21]. Thus, autoimmune-mediated autonomic nervous system dysfunction, referred to as dysautonomia, may contribute to the disease course of PCS, which is similar to ME/CFS [10,21,22,23]. Notably, supervised and moderate physical exercise was shown to stabilize the autonomic nervous system. Thus, it may also be beneficial for PCS patients. Additionally, therapeutic options such as immunomodulatory and immunosuppressive therapy could benefit some PCS patients, whereas plasmapheresis and IVIG could be considered in severe cases [1,10,22,23]
number: 2
publisher: Multidisciplinary Digital Publishing Institute

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Prasada Kabekkodu, Shama; Chakrabarty, Sanjiban; Jayaram, Pradyumna; Mallya, Sandeep; Thangaraj, Kumarasamy; Singh, Keshav K; Satyamoorthy, Kapaettu

Severe acute respiratory syndrome coronaviruses contributing to mitochondrial dysfunction: Implications for post-COVID complications

https://doi.org/10.1016/j.mito.2023.01.005

Published

1-Mar-23

Review

https://www.sciencedirect.com/science/article/pii/S1567724923000053

Highlights
•Mitochondria are vital cellular organelles linked to the production of ATP, biosynthesis of fatty acids, calcium signaling, regulation of cell cycle, apoptosis, and innate immune response among others.
•Several RNA viruses target mitochondria leading to abnormal anterograde and retrograde grade signaling to facilitate growth and survival.
•Mitochondria plays a role in controlling immunity against SARS-CoV-2, and its infection leads to alteration in both structure and function of the mitochondria.
•SARS-CoV participates in stress response, apoptosis pathways and mitochondrial fusion in host cells.
•Research concentrating on SARS-CoV-2 modulation of essential mitochondrial activities should close the gap in COVID-19 prevention and treatment.
Abstract
Mitochondria play a central role in oxidative phosphorylation (OXPHOS), bioenergetics linked with ATP production, fatty acids biosynthesis, calcium signaling, cell cycle regulation, apoptosis, and innate immune response. Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) infection manipulates the host cellular machinery for its survival and replication in the host cell. The infectiaon causes perturbed the cellular metabolism that favours viral replication leading to mitochondrial dysfunction and chronic inflammation. By localizing to the mitochondria, SARS CoV proteins increase reactive oxygen species (ROS) levels, perturbation of Ca2+ signaling, changes in mtDNA copy number, mitochondrial membrane potential (MMP), mitochondrial mass, and induction of mitophagy. These proteins also influence the fusion and fission kinetics, size, structure, and distribution of mitochondria in the infected host cells. This results in compromised bioenergetics, altered metabolism, and innate immune signaling, and hence can be a key player in determining the outcome of SARS-CoV infection. SARS-CoV infection contributes to stress and activates apoptotic pathways. This review summarizes how mitochondrial function and dynamics are affected by SARS-CoV and how the mitochondria-SARS-CoV interaction benefits viral survival and growth by evading innate host immunity. We also highlight how the SARS-CoV-mediated mitochondrial dysfunction contributes to post-COVID complications. Besides, a discussion on targeting virus-mitochondria interactions as a therapeutic strategy is presented.

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Levine, Kristin S.; Leonard, Hampton L.; Blauwendraat, Cornelis; Iwaki, Hirotaka; Johnson, Nicholas; Bandres-Ciga, Sara; Ferrucci, Luigi; Faghri, Faraz; Singleton, Andrew B.; Nalls, Mike A.

Virus exposure and neurodegenerative disease risk across national biobanks

https://doi.org/10.1016/j.neuron.2022.12.029

Published

19-Jan-23

Study

https://www.cell.com/neuron/abstract/S0896-6273(22)01147-3

Highlights
•Identified 45 pairs of viral exposures associated with increased risk of NDDs
•Replicated 22 of the viral exposures/NDD pairings
•Replicated the previously reported Epstein-Barr and multiple sclerosis association
•Follow-up shows significantly elevated risk of NDD years after viral exposure
Summary
With recent findings connecting the Epstein-Barr virus to an increased risk of multiple sclerosis and growing concerns regarding the neurological impact of the coronavirus pandemic, we examined potential links between viral exposures and neurodegenerative disease risk. Using time series data from FinnGen for discovery and cross-sectional data from the UK Biobank for replication, we identified 45 viral exposures significantly associated with increased risk of neurodegenerative disease and replicated 22 of these associations. The largest effect association was between viral encephalitis exposure and Alzheimer’s disease. Influenza with pneumonia was significantly associated with five of the six neurodegenerative diseases studied. We also replicated the Epstein-Barr/multiple sclerosis association. Some of these exposures were associated with an increased risk of neurodegeneration up to 15 years after infection. As vaccines are currently available for some of the associated viruses, vaccination may be a way to reduce some risk of neurodegenerative disease.
publisher: Elsevier
PMID: 36669485

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Nepotchatykh, Evguenia; Caraus, Iurie; Elremaly, Wesam; Leveau, Corinne; Elbakry, Mohamed; Godbout, Christian; Rostami-Afshari, Bita; Petre, Diana; Khatami, Nasrin; Franco, Anita; Moreau, Alain

Circulating microRNA expression signatures accurately discriminate myalgic encephalomyelitis from fibromyalgia and comorbid conditions

https://doi.org/10.1038/s41598-023-28955-9

Published

2-Feb-23

Study

https://www.nature.com/articles/s41598-023-28955-9

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and fibromyalgia (FM) are two chronic complex diseases with overlapping symptoms affecting multiple systems and organs over time. Due to the absence of validated biomarkers and similarity in symptoms, both disorders are misdiagnosed, and the comorbidity of the two is often unrecognized. Our study aimed to investigate the expression profiles of 11 circulating miRNAs previously associated with ME/CFS pathogenesis in FM patients and individuals with a comorbid diagnosis of FM associated with ME/CFS (ME/CFS + FM), and matched sedentary healthy controls. Whether these 11 circulating miRNAs expression can differentiate between the two disorders was also examined. Our results highlight differential circulating miRNAs expression signatures between ME/CFS, FM and ME/CFS + FM, which also correlate to symptom severity between ME/CFS and ME/CFS + FM groups. We provided a prediction model, by using a machine-learning approach based on 11 circulating miRNAs levels, which can be used to discriminate between patients suffering from ME/CFS, FM and ME/CFS + FM. These 11 miRNAs are proposed as potential biomarkers for discriminating ME/CFS from FM. The results of this study demonstrate that ME/CFS and FM are two distinct illnesses, and we highlight the comorbidity between the two conditions. Proper diagnosis of patients suffering from ME/CFS, FM or ME/CFS + FM is crucial to elucidate the pathophysiology of both diseases, determine preventive measures, and establish more effective treatments.

381

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Samper-Pardo, M.; Oliván-Blázquez, B.; Magallón-Botaya, R.; Méndez-López, F.; Bartolomé-Moreno, C.; León-Herrera, S.

The emotional well-being of Long COVID patients in relation to their symptoms, social support and stigmatization in social and health services: a qualitative study

https://doi.org/10.1186/s12888-022-04497-8

Published

25-Jan-23

Study

https://doi.org/10.1186/s12888-022-04497-8

Background
Long COVID patients have experienced a decline in their quality of life due to, in part but not wholly, its negative emotional impact. Some of the most prevalent mental health symptoms presented by long COVID patients are anxiety, depression, and sleep disorders. As such, the need has arisen to analyze the personal experiences of these patients to understand how they are managing their daily lives while dealing with the condition. The objective of this study is to increase understanding about the emotional well-being of people diagnosed with long COVID.
Methods
A qualitative design was created and carried out using 35 patients, with 17 participants being interviewed individually and 18 of them taking part in two focus groups. The participating patients were recruited in November and December 2021 from Primary Health Care (PHC) centers in the city of Zaragoza (Northern Spain) and from the Association of Long COVID Patients in Aragon. The study topics were emotional well-being, social support networks, and experience of discrimination. All an inductive thematic content analyses were performed iteratively using NVivo software.
Results
The Long COVID patients identified low levels of self-perceived well-being due to their persistent symptoms, as well as limitations in their daily lives that had been persistent for many months. Suicidal thoughts were also mentioned by several patients. They referred to anguish and anxiety about the future as well as a fear of reinfection or relapse and returning to work. Many of the participants reported that they have sought the help of a mental health professional. Most participants identified discriminatory situations in health care.
Conclusions
It is necessary to continue researching the impact that Long COVID has had on mental health, as well as to provide Primary Health Care professionals with evidence that can guide the emotional treatment of these patients

382

D378

Kaufmann, Julia; Gould, Odette; Lloyd, Vett

Seeking Care for Long COVID: A Narrative Analysis of Canadian Experiences

https://doi.org/10.1177/23743735231151770

Published

1-Jan-23

Study

https://doi.org/10.1177/23743735231151770

The goal of this study was to explore the experiences of individuals seeking care for long COVID-19 in the Canadian healthcare system. Recorded virtual interviews were carried out with 8 participants and narrative analysis was used to examine the stories produced and identify the central narratives that defined participants? experiences. Care-seeking experiences were characterized by (1) often debilitating multi-system symptoms for which little information about prognosis was available and no effective treatments were provided, (2) compounded by the frustration of trying to convince family, friends, and health care practitioners of the legitimacy of their illness, (3) access to medical care was severely limited by the global pandemic and associated higher thresholds for care, (4) like others suffering from complex, multi-system conditions, people with long COVID are often struggling with a health-care system ill-suited for dealing with long-term and possibly chronic conditions. To make system-level improvements to better serve those with chronic conditions, it is critical that we understand the care-seeking experiences of chronic illness patients, including the unique experiences of those with long COVID.

383

D379

N3C Consortium; RECOVER Consortium; Reese, Justin T.; Blau, Hannah; Casiraghi, Elena; Bergquist, Timothy; Loomba, Johanna J.; Callahan, Tiffany J.; Laraway, Bryan; Antonescu, Corneliu; Coleman, Ben; Gargano, Michael; Wilkins, Kenneth J.; Cappelletti, Luca; Fontana, Tommaso; Ammar, Nariman; Antony, Blessy; Murali, T. M.; Caufield, J. Harry; Karlebach, Guy; McMurry, Julie A.; Williams, Andrew; Moffitt, Richard; Banerjee, Jineta; Solomonides, Anthony E.; Davis, Hannah; Kostka, Kristin; Valentini, Giorgio; Sahner, David; Chute, Christopher G.; Madlock-Brown, Charisse; Haendel, Melissa A.; Robinson, Peter N.; Spratt, Heidi; Visweswaran, Shyam; Flack, Joseph Eugene; Yoo, Yun Jae; Gabriel, Davera; Alexander, G. Caleb; Mehta, Hemalkumar B.; Liu, Feifan; Miller, Robert T.; Wong, Rachel; Hill, Elaine L.; Thorpe, Lorna E.; Divers, Jasmin

Generalisable long COVID subtypes: Findings from the NIH N3C and RECOVER programmes

https://doi.org/10.1016/j.ebiom.2022.104413

Published

1-Jan-23

Article

http://www.scopus.com/inward/record.url?scp=85144488606&partnerID=8YFLogxK

Background: Stratification of patients with post-acute sequelae of SARS-CoV-2 infection (PASC, or long COVID) would allow precision clinical management strategies. However, long COVID is incompletely understood and characterised by a wide range of manifestations that are difficult to analyse computationally. Additionally, the generalisability of machine learning classification of COVID-19 clinical outcomes has rarely been tested. Methods: We present a method for computationally modelling PASC phenotype data based on electronic healthcare records (EHRs) and for assessing pairwise phenotypic similarity between patients using semantic similarity. Our approach defines a nonlinear similarity function that maps from a feature space of phenotypic abnormalities to a matrix of pairwise patient similarity that can be clustered using unsupervised machine learning. Findings: We found six clusters of PASC patients, each with distinct profiles of phenotypic abnormalities, including clusters with distinct pulmonary, neuropsychiatric, and cardiovascular abnormalities, and a cluster associated with broad, severe manifestations and increased mortality. There was significant association of cluster membership with a range of pre-existing conditions and measures of severity during acute COVID-19. We assigned new patients from other healthcare centres to clusters by maximum semantic similarity to the original patients, and showed that the clusters were generalisable across different hospital systems. The increased mortality rate originally identified in one cluster was consistently observed in patients assigned to that cluster in other hospital systems. Interpretation: Semantic phenotypic clustering provides a foundation for assigning patients to stratified subgroups for natural history or therapy studies on PASC. Funding: NIH (TR002306/OT2HL161847-01/OD011883/HG010860), U.S.D.O.E. (DE-AC02-05CH11231), Donald A. Roux Family Fund at Jackson Laboratory, Marsico Family at CU Anschutz.

384

D380

Dotan, Arad; Shoenfeld, Yehuda

Editorial for “Post COVID-19 Syndrome in Patients with Asymptomatic/Mild Form”

https://doi.org/10.3390/pathogens12020167

Published

1-Feb-23

Editorial

https://www.mdpi.com/2076-0817/12/2/167

The possible association between the described PCS symptoms and brain damage that occurs during an SARS-CoV-2 infection suggests that PCS patients commonly have a clinical presentation similar to that of encephalomyelitis/chronic fatigue syndrome (ME/CFS): severe fatigue, sleep disorders, cognitive impairments, and different manifestations of autonomic dysfunction exacerbated in physical exercise [8,10]. Furthermore, close to 20 distinct autoantibodies which target the GPCR of the nervous system and renin-angiotensin system-related molecules were found to be significantly associated with the clinical severity of COVID-19 [10]. Additionally, these autoantibodies were elevated in a subset of ME/CFS patients, specifically, the β2 adrenergic and M3 and M4 cholinergic receptor antibodies, as well as in other similar disorders [19,20,21]. Thus, autoimmune-mediated autonomic nervous system dysfunction, referred to as dysautonomia, may contribute to the disease course of PCS, which is similar to ME/CFS [10,21,22,23]. Notably, supervised and moderate physical exercise was shown to stabilize the autonomic nervous system. Thus, it may also be beneficial for PCS patients. Additionally, therapeutic options such as immunomodulatory and immunosuppressive therapy could benefit some PCS patients, whereas plasmapheresis and IVIG could be considered in severe cases [1,10,22,23].
number: 2
publisher: Multidisciplinary Digital Publishing Institute

385

D381

Kudoh, Ryohei; Komiya, Kosaku; Shinohara, Aya; Kageyama, Takaaki; Hiramatsu, Kazufumi; Kadota, Jun-ichi

Marital status and post-COVID-19 conditions

https://doi.org/10.1016/j.resinv.2023.01.001

Published

1-Mar-23

Study

https://www.sciencedirect.com/science/article/pii/S2212534523000084

Although studies have investigated the factors associated with psychological post-COVID-19 symptoms, the impact of marital status on symptom development has not been fully determined. This study conducts a questionnaire survey to investigate the association between marital status and the proportion of patients with post-COVID-19 symptoms in 749 cases as valid responses. Depressive state and memory impairment were more frequently seen in the no-spouse group when each symptom was compared according to marital status. Particularly in individuals in the 40s who had minor COVID-19 illness, this trend was noted. Single patients with mild COVID-19 illness may need proactive psychological support.

386

D382

Cooper, Emily; Lound, Adam; Atchison, Christina J.; Whitaker, Matthew; Eccles, Caroline; Cooke, Graham S.; Elliott, Paul; Ward, Helen

Awareness and perceptions of Long COVID among people in the REACT programme: Early insights from a pilot interview study

https://doi.org/10.1371/journal.pone.0280943

Published

26-Jan-23

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0280943

Background Long COVID is a patient-made term describing new or persistent symptoms experienced following SARS-CoV-2 infection. The Real-time Assessment of Community Transmission-Long COVID (REACT-LC) study aims to understand variation in experiences following infection, and to identify biological, social, and environmental factors associated with Long COVID. We undertook a pilot interview study to inform the design, recruitment approach, and topic guide for the REACT-LC qualitative study. We sought to gain initial insights into the experience and attribution of new or persistent symptoms and the awareness or perceived applicability of the term Long COVID. Methods People were invited to REACT-LC assessment centres if they had taken part in REACT, a random community-based prevalence study, and had a documented history of SARS-CoV-2 infection. We invited people from REACT-LC assessment centres who had reported experiencing persistent symptoms for more than 12 weeks to take part in an interview. We conducted face to face and online semi-structured interviews which were transcribed and analysed using Thematic Analysis. Results We interviewed 13 participants (6 female, 7 male, median age 31). Participants reported a wide variation in both new and persistent symptoms which were often fluctuating or unpredictable in nature. Some participants were confident about the link between their persistent symptoms and COVID-19; however, others were unclear about the underlying cause of symptoms or felt that the impact of public health measures (such as lockdowns) played a role. We found differences in awareness and perceived applicability of the term Long COVID. Conclusion This pilot has informed the design, recruitment approach and topic guide for our qualitative study. It offers preliminary insights into the varied experiences of people living with persistent symptoms including differences in symptom attribution and perceived applicability of the term Long COVID. This variation shows the value of recruiting from a nationally representative sample of participants who are experiencing persistent symptoms.

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Hitch, Danielle; Deféin, Elle; Lloyd, Melanie; Rasmussen, Bodil; Haines, Kimberley; Garnys, Eleanor

Beyond the case numbers: Social determinants and contextual factors in patient narratives of recovery from COVID-19

https://doi.org/10.1016/j.anzjph.2022.100002

Published

1-Feb-23

Study

https://www.sciencedirect.com/science/article/pii/S1326020022000024

Objective
This study aimed to describe and contextualise COVID-19 recovery from the perspective of patient-lived experience, to inform the evolving public health response to the pandemic.
Methods
Narrative interviews were completed with 37 adult Australians between six and 10 months following their COVID-19 diagnosis. Verbatim transcripts were analysed thematically and trustworthiness was supported by multiple strategies to ensure rigour.
Results
Three themes were identified: 1) trajectories of recovery, 2) back to ‘some sort of normal’ and 3) the importance of work. Resumed participation in activities of daily life, the influence of social determinants of health and the impact of contextual factors were prominent features in the recovery narratives.
Conclusions
The COVID-19 pandemic presents both challenges and opportunities for public health systems to formulate appropriate responses and make improvements. Behind the case numbers, patient narratives described the uncertainty, diversity and multiple pathways to recovery that need to inform public health policy.
Implications for public health
Looking beyond the case numbers reveals a complex landscape characterised by uncertainty, diversity and multiple pathways to recovery. The pandemic presents challenges and opportunities for public health in Australia and New Zealand, lived experience expertise is crucial to the formulation of an effective response.

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D384

Marks, David F

Treatment Harms to Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

https://doi.org/10.33140/ABBSR.06.01.01

Published

19-Jan-23

Review

https://www.opastpublishers.com/open-access-articles/treatment-harms-to-patients-with-myalgic-encephalomyelitischronic-fatigue-syndrome.pdf

Despite evidence of physiological and cellular abnormalities in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS), the dominant therapeutic approach has been cognitive behaviour therapy (CBT) and graded exercise therapy (GET). Patients report distress and dissatisfaction following healthcare encounters based on GET and CBT. A significant body of research suggests that CBT and GET are harmful for many patients with ME/CFS. These findings raise ethical concerns and suggest that more collaborative working between scientists, therapists and patients would be helpful in making scientific progress in this difficult field.

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D385

Herminghaus, Anna; Osuchowski, Marcin F.

How sepsis parallels and differs from COVID-19

https://doi.org/10.1016/j.ebiom.2022.104355

Published

1-Dec-22

Article

https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00537-0/fulltext

There is a striking parallel between bacterial sepsis and COVID-19 phenotypes: the long-term sequelae. In both patient groups, the hospital discharge does not equal full recovery, but it is frequently followed by protracted, incapacitating consequences. While in bacterial sepsis, the post-discharge complications are referred to as post-sepsis syndrome and/or Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS), whereas, in SARS-CoV-2 infected patients, they are known as “long-COVID”. Long-COVID is not very different from post-sepsis syndrome. The most common persistent symptoms include fatigue, muscle pain, poor sleep, cardiac and cognitive disturbances (e.g. arrhythmias, short-term memory loss).7 Remarkably, a new, troubling difference exists: unlike in sepsis, long-COVID is frequently diagnosed in mildly SARS-CoV-2 infected patients (i.e. no hospital stay).8 The presence of the “long-phenotype” in both illnesses strongly indicates a severe and protracted deregulation of the immune-inflammatory (with clear immunosuppression features) and organ homeostasis. In the context of the slowly subsiding severe COVID-19 manifestations, we should re-focus on the long-term sequalae to evaluate a potential risk of increase in chronic debilitations in individuals, repeatedly exposed to the virus, as SARS-CoV-2 becomes seasonal/endemic.
A comparison of the pre-clinical research in sepsis and COVID-19 brings several important lessons. A subjective (and largely undeserved) disappointment in pre-clinical bacterial sepsis studies has not been shared by COVID-19 modeling. On the contrary, despite logistic challenges, modeling of SARS-COV-2 infection has demonstrated its robust utility. One of the key advantages of pre-clinical COVID-19 research is the rich palette of species (including non-human primates), while >90% of bacterial sepsis studies are performed in mice and rats. A multi-species approach considerably enhances reproducibility and translatability concurrently reducing idiosyncratic findings. Animal COVID-19 models were well-predictive of both successes (e.g. anti-SARS-CoV-2 monoclonal antibodies, remdesivir, vaccines) and failures (e.g. hydroxychloroquine, lopinavir/ritonavir) of clinically-tested substances.9 Given intuitive drive for benefits, the latter should not be underappreciated; “negative” findings hold a valuable life-/time and cost-saving potential. Notably, anti-TNF treatment in a clinically relevant mouse model of cecal ligation and puncture sepsis predicted failure of that therapy three years before the failed clinical trials.10 A clear pre-clinical parallel for sepsis and COVID-19 models exist: they both can be employed to cover identical research niches: i) mild-to-severe disease phenotypes, ii) defined cohort targeting, iii) selected pathophysiological insights (e.g. compartmentalization of responses). Furthermore, long-term sequalae can be effectively investigated in both bacterial sepsis and COVID-19 models.
Given that bacterial sepsis and COVID-19 parallels heavily intertwine with contrasts, it is critical to carefully dissect them into defined, manageable pieces of pathophysiological evidence (eg, by a given system, compartment) before any further therapeutic action is recommended. Equally important is that we avoid a reflexive transplantation of ready-to-use preconceptions (eg, “cytokine storm”) from an existing disease while dealing with any new entity. Well-designed pre-clinical studies can aid in a translationally valid verification of virtually any of the above concepts at the fraction of time/costs required for a clinical trial execution.
publisher: Elsevier
PMID: 36470836

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Xu, Wangzi; Cao, Yu; Wu, Lin

No Causal Effects Detected in COVID-19 and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Two Sample Mendelian Randomization Study

https://doi.org/10.3390/ijerph20032437

Published

1-Jan-23

Study

https://www.mdpi.com/1660-4601/20/3/2437

New clinical observational studies suggest that Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a sequela of COVID-19 infection, but whether there is an exact causal relationship between COVID-19 and ME/CFS remains to be verified. To investigate whether infection with COVID-19 actually causes ME/CFS, this paper obtained pooled data from the Genome Wide Association Study (GWAS) and analyzed the relationship between COVID susceptibility, hospitalization and severity of COVID and ME/CFS, respectively, using two-sample Mendelian randomization (TSMR). TSMR analysis was performed by inverse variance weighting (IVW), weighted median method, MR-Egger regression and weighted mode and simple mode methods, respectively, and then the causal relationship between COVID-19 and ME/CFS was further evaluated by odds ratio (OR). Eventually, we found that COVID-19 severity, hospitalization and susceptibility were all not significantly correlated with ME/CFS (OR:1.000,1.000,1.000; 95% CI:0.999–1.000, 0.999–1.001, 0.998–1.002; p = 0.333, 0.862, 0.998, respectively). We found the results to be reliable after sensitivity analysis. These results suggested that SARS-CoV-2 infection may not significantly contribute to the elevated risk of developing CFS, and therefore ME/CFS may not be a sequela of COVID-19, but may simply present with symptoms similar to those of CFS after COVID-19 infection, and thus should be judged and differentiated by physicians when diagnosing and treating the disease in clinical practice.

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Pink, Isabell; Welte, Tobias

Risiko und Häufigkeit von Long-COVID

https://doi.org/10.1007/s11298-022-3104-5

Published

1-Feb-23

Article

https://doi.org/10.1007/s11298-022-3104-5

Fazit für die Praxis
Wahrscheinlich leiden 10-20% aller SARS-CoV-2-infizierten Patient*innen unter Long-COVID-Beschwerden.
Die Beschwerden sind mannigfaltig und in der Intensität häufig im zeitlichen Verlauf regredient.
Es gibt keine pathognomonischen Befunde oder laborchemischen Parameter für Long-COVID.
Die häufigsten Beschwerden sind Fatigue, Dyspnoe, Anosmie und Ageusie sowie Kopfschmerzen, Gelenkschmerzen, Husten, kognitive Einschränkungen und Schlafstörungen.
Vor allem das weibliche Geschlecht, > 5 Symptome während COVID-19 und ein höherer COVID-19-Schweregrad sind mögliche Prädiktoren für Long-COVID.
Hospitalisierte Patientinnen und Patienten und solche mit massiver Erschöpfung und Belastungsintoleranz sollten einer stationären Rehabilitationsmaßnahme zugeführt werden.
Patientinnen und Patienten mit kardiovaskulären Komplikationen während der Akuterkrankung oder Notwendigkeit einer intensivstationären Behandlung sollten sechs bis zwölf Wochen nach COVID-19 eine kardiologische Diagnostik erhalten, da das Risiko kardiovaskulärer Komplikationen für diese Patientengruppe unabhängig von Long-COVID auch ein Jahr nach der Infektion erhöht ist.

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Yan, Michael Zhipeng; Yang, Ming; Lai, Ching-Lung

Post-COVID-19 Syndrome Comprehensive Assessment: From Clinical Diagnosis to Imaging and Biochemical-Guided Diagnosis and Management

https://doi.org/10.3390/v15020533

Published

1-Feb-23

Review

https://www.mdpi.com/1999-4915/15/2/533

The COVID-19 outbreak was first reported in 2019, causing massive morbidity and mortality. The majority of the COVID-19 patients survived and developed Post-COVID-19 Syndrome (PC19S) of varying severity. Currently, the diagnosis of PC19S is achieved through history and symptomatology that cannot be explained by an alternative diagnosis. However, the heavy reliance on subjective reporting is prone to reporting errors. Besides, there is no unified diagnostic assessment tool to classify the clinical severity of patients. This leads to significant difficulties when managing patients in terms of public resource utilization, clinical progression monitorization and rehabilitation plan formulation. This narrative review aims to review current evidence of diagnosis based on triple assessment: clinical symptomatology, biochemical analysis and imaging evidence. Further assessment tools can be developed based on triple assessment to monitor patient’s clinical progression, prognosis and intervals of monitoring. It also highlights the high-risk features of patients for closer and earlier monitoring. Rehabilitation programs and related clinical trials are evaluated; however, most of them focus on cardiorespiratory fitness and psychiatric presentations such as anxiety and depression. Further research is required to establish an objective and comprehensive assessment tool to facilitate clinical management and rehabilitation plans.

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Perlis, Roy H.; Lunz Trujillo, Kristin; Safarpour, Alauna; Santillana, Mauricio; Ognyanova, Katherine; Druckman, James; Lazer, David

Association of Post–COVID-19 Condition Symptoms and Employment Status

https://doi.org/10.1001/jamanetworkopen.2022.56152

Published

15-Feb-23

Study

https://doi.org/10.1001/jamanetworkopen.2022.56152

Key Points
Question Is post–COVID-19 condition (PCC), also known as long COVID, associated with differences in employment status that might suggest functional impairment?

Findings Among 15 308 individuals with prior COVID-19 infection, those with PCC were less likely to be employed full-time and more likely to be unemployed. These differences persisted after adjustment for demographic differences between those with and without PCC.

Meaning These findings suggest that individuals with PCC are less likely to be working and to be working full time.

Abstract
Importance Little is known about the functional correlates of post–COVID-19 condition (PCC), also known as long COVID, particularly the relevance of neurocognitive symptoms.

Objective To characterize prevalence of unemployment among individuals who did, or did not, develop PCC after acute infection.

Design, Setting, and Participants This survey study used data from 8 waves of a 50-state US nonprobability internet population-based survey of respondents aged 18 to 69 years conducted between February 2021 and July 2022.

Main Outcomes and Measures The primary outcomes were self-reported current employment status and the presence of PCC, defined as report of continued symptoms at least 2 months beyond initial month of symptoms confirmed by a positive COVID-19 test.

Results The cohort included 15 308 survey respondents with test-confirmed COVID-19 at least 2 months prior, of whom 2236 (14.6%) reported PCC symptoms, including 1027 of 2236 (45.9%) reporting either brain fog or impaired memory. The mean (SD) age was 38.8 (13.5) years; 9679 respondents (63.2%) identified as women and 10 720 (70.0%) were White. Overall, 1418 of 15 308 respondents (9.3%) reported being unemployed, including 276 of 2236 (12.3%) of those with PCC and 1142 of 13 071 (8.7%) of those without PCC; 8229 respondents (53.8%) worked full-time, including 1017 (45.5%) of those with PCC and 7212 (55.2%) without PCC. In survey-weighted regression models excluding retired respondents, the presence of PCC was associated with a lower likelihood of working full-time (odds ratio [OR], 0.71 [95% CI, 0.63-0.80]; adjusted OR, 0.84 [95% CI, 0.74-0.96]) and with a higher likelihood of being unemployed (OR, 1.45 [95% CI, 1.22-1.73]; adjusted OR, 1.23 [95% CI, 1.02-1.48]). The presence of any cognitive symptom was associated with lower likelihood of working full time (OR, 0.70 [95% CI, 0.56-0.88]; adjusted OR, 0.75 [95% CI, 0.59-0.84]).

Conclusions and Relevance PCC was associated with a greater likelihood of unemployment and lesser likelihood of working full time in adjusted models. The presence of cognitive symptoms was associated with diminished likelihood of working full time. These results underscore the importance of developing strategies to treat and manage PCC symptoms.

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Davisse-Paturet, Camille; Orri, Massimiliano; Legleye, Stéphane; Florence, Aline-Marie; Hazo, Jean-Baptiste; Warszawski, Josiane; Falissard, Bruno; Geoffroy, Marie-Claude; Melchior, Maria; Rouquette, Alexandra; Group, the EPICOV study

Suicidal ideation following self-reported COVID-19-like symptoms or serology-confirmed SARS-CoV-2 infection in France: A propensity score weighted analysis from a cohort study

https://doi.org/10.1371/journal.pmed.1004171

Published

14-Feb-23

Study

https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004171

Background A higher risk of suicidal ideation associated with self-report of Coronavirus Disease 2019 (COVID-19)-like symptoms or COVID-19 infection has been observed in cross-sectional studies, but evidence from longitudinal studies remains limited. The aims of this study were 2-fold: (1) to explore if self-reported COVID-19-like symptoms in 2020 were associated with suicidal ideation in 2021; (2) to explore if the association also existed when using a biological marker of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in 2020. Methods and findings A total of 52,050 participants from the French EpiCov cohort were included (median follow-up time = 13.7 months). In terms of demographics, 53.84% were women, 60.92% were over 45 years old, 82.01% were born in mainland France from parents born in mainland France, and 59.38% completed high school. COVID-19-like symptoms were defined as participant report of a sudden loss of taste/smell or fever alongside cough, shortness of breath, or chest oppression, between February and November 2020. Symptoms were self-reported at baseline in May 2020 and at the first follow-up in Autumn 2020. Serology-confirmed SARS-CoV-2 infection in 2020 was derived from Spike protein ELISA test screening in dried-blood-spot samples. Samples were collected from October 2020 to March 2021, with 94.4% collected in 2020. Suicidal ideation since December 2020 was self-reported at the second follow-up in Summer 2021. Associations of self-reported COVID-19-like symptoms and serology-confirmed SARS-CoV-2 infection in 2020 with suicidal ideation in 2021 were ascertained using modified Poisson regression models, weighted by inverse probability weights computed from propensity scores. Among the 52,050 participants, 1.68% [1.54% to 1.82%] reported suicidal ideation in 2021, 9.57% [9.24% to 9.90%] had a serology-confirmed SARS-CoV-2 infection in 2020, and 13.23% [12.86% to 13.61%] reported COVID-19-like symptoms in 2020. Self-reported COVID-19-like symptoms in 2020 were associated with higher risks of later suicidal ideation in 2021 (Relative Riskipw [95% CI] = 1.43 [1.20 to 1.69]), while serology-confirmed SARS-CoV-2 infection in 2020 was not (RRipw = 0.89 [0.70 to 1.13]). Limitations of this study include the use of a single question to assess suicidal ideation, the use of self-reported history of mental health disorders, and limited generalizability due to attrition bias. Conclusions Self-reported COVID-19-like symptoms in 2020, but not serology-confirmed SARS-CoV-2 infection in 2020, were associated with a higher risk of subsequent suicidal ideation in 2021. The exact role of SARS-CoV-2 infection with respect to suicide risk has yet to be clarified. Including mental health resources in COVID-19-related settings could encourage symptomatic individuals to care for their mental health and limit suicidal ideation to emerge or worsen.

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Iwasaki, Akiko; Putrino, David

Why we need a deeper understanding of the pathophysiology of long COVID

https://doi.org/10.1016/S1473-3099(23)00053-1

Published

14-Feb-23

Article

https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(23)00053-1/fulltext

The main disease hypotheses for the root causes of long COVID include viral persistence (infectious virus, viral RNA, or viral proteins), autoimmunity triggered by the infection, reactivation of latent viruses, and inflammation-triggered chronic changes leading to tissue dysfunction and damage (figure).

There is growing and compelling evidence that SARS-CoV-2 infects and produces its RNA and proteins in a wide range of cell types in tissues, including the gastrointestinal, respiratory, cardiovascular, lymphoid, endocrine, urogenital, ocular, skin, muscular, and peripheral nervous system and CNS tissues.2 Circulating spike proteins are observed in 60% of patients with long COVID between 2 and 12 months after infection.3 Although the presence of viral RNA and proteins do not necessarily indicate persistent infection, viral RNA can trigger innate immune responses and viral proteins might cause tissue damage and stimulate persistent activation of lymphocytes, which lead to chronic inflammation.
In people with long COVID, assessment of autoantibodies to human exoproteome using rapid extracellular antigen profiling revealed no significant differences from people without long COVID.4 However, autoantibodies to intracellular antigens5 or autoreactive T cells might have a role in long COVID.
There is also emerging evidence for latent herpesviruses reactivation in people with long COVID. Reactivation of latent Epstein-Barr virus, but not the acute mononucleosis infection, is found in people with long COVID,4, 6 and Epstein-Barr virus viraemia at the time of acute COVID is predictive for long COVID.5
Local inflammatory response to SARS-CoV-2 in one organ can cause lasting alterations in distant tissues and organs. In a mouse model, even mild lung-restricted COVID-19 (in which the infectious virus became undetectable within a week) was found to induce prolonged changes in the CNS, including microglial activation, oligodendrocyte loss, and reduced myelination, for up to 7 weeks after infection.7
Beyond these potential root causes, many secondary pathological changes have been observed in people with long COVID, including the formation of micro-clots and platelet activation,8 reduced cortisol,4, 5 and mitochondrial dysfunction.9
Despite the multifactorial pathogenesis, available data show that long COVID is an organic post-acute infection syndrome (PAIS) with clear physiological dysfunction that is often not consistently apparent using standard medical diagnostic tests. This discrepancy highlights the need for a new generation of more sensitive testing procedures for people with PAIS. Although it is not known whether pre-existing psychological diagnoses might influence the risk of long COVID (eg, by affecting the host endocrine and immune systems), it is neither productive nor clinically or scientifically valid to classify long COVID as a psychosomatic condition.
As avoiding COVID-19 becomes increasingly difficult, we argue that deep biological analyses will identify biomarkers for long COVID and possibly identify distinct endotypes driven by different root causes so that the risk of contracting long COVID is better defined. Biomarker identification will not only be crucial for identifying predisposing factors but also allow us to implement safer, evidence-based policies. Similarly, molecular, cellular, and physiological analyses will inform precision interventions that target the root causes of each long COVID endotype. For example, persistent viral infection could be targeted by antivirals; long COVID driven by autoimmune disease could be treated using monoclonal antibodies that target lymphocytes or drugs that block cytokines and cytokine signalling; and, if the reactivation of herpesviruses contributes to disease, targeting such viruses using antivirals or vaccines could be considered. Diagnostic criteria considering the root causes to prevent and treat long COVID will require large longitudinal studies. If therapeutic targeting of root causes is not feasible, the downstream pathological changes of long COVID could still be treated.
publisher: Elsevier

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Suran, Melissa

Long COVID Linked With Unemployment in New Analysis

https://doi.org/10.1001/jama.2023.0157

Published

15-Feb-23

Editorial

https://doi.org/10.1001/jama.2023.0157

Although COVID-19’s designation as a national and public health emergency is nearing its end in the US, post–COVID-19 condition, also known as long COVID, seems to be sticking around. Now, new research adds to evidence that long COVID may be affecting the workforce. A survey-based study of more than 15 000 people with prior COVID-19, published in JAMA Network Open, found that those with self-reported long COVID symptoms were more likely to be unemployed.The employment research builds on an October study focused on the prevalence of long COVID. Both analyses used the same US data set derived from an internet survey called the COVID States Project. Despite its name, the survey casts a wide net of questions related to behavior and beliefs, including many items unrelated to COVID-19. Respondents are also asked about their political stances and social networks, for example. This means the survey doesn’t introduce bias about the illness, Roy Perlis, MD, MSc, lead author of both studies, said in an interview with JAMA.

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Pike, Jamison

Direct Medical Costs Associated With Post–COVID-19 Conditions Among Privately Insured Children and Adults

https://doi.org/10.5888/pcd20.220292

Published

9-Feb-23

Study

https://www.cdc.gov/pcd/issues/2023/22_0292.htm

Introduction

SARS-CoV-2, the virus that causes COVID-19, has caused more than 100.2 million infections and more than 1 million deaths in the US as of November 2022, yet information on the economic burden associated with post–COVID-19 conditions is lacking. We estimated the possible economic burden associated with post–COVID-19 conditions by comparing direct medical costs among patients younger than 65 years with and without COVID-19 in the postacute period.

Methods

Commercially insured children and adults with a COVID-19 diagnosis (cases) during April–August 2020 were matched to those without COVID-19 (controls) on a 1:4 ratio. Direct medical costs represented 1-, 3-, and 6-month total expenditures per person starting 31 days after the diagnosis date. We used a 2-part model to evaluate cost differences among individuals with and without COVID-19, adjusted for patient characteristics.

Results

Costs were higher among cases compared with controls. Direct medical costs among child cases were 1.82, 1.72, and 1.70 times higher than controls over 1, 3, and 6 months, respectively. Direct medical costs among adult cases were 1.69, 1.54, and 1.46 times higher than costs among controls over 1, 3, and 6 months, respectively. Relative differences in costs were highest among adults aged 50 to 64 years. In a subset of people with COVID-19, costs were higher among hospitalized cases compared with nonhospitalized cases.

Conclusion

Our findings suggest a considerable economic burden of COVID-19 even after the resolution of acute illness, highlighting the importance of prevention and mitigation measures to reduce the economic impact of COVID-19 on the US health care system.

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Ferrara, Francesco; Zovi, Andrea; Masi, Marta; Langella, Roberto; Trama, Ugo; Boccellino, Mariarosaria; Vitiello, Antonio

Long COVID could become a widespread post-pandemic disease? A debate on the organs most affected

https://doi.org/10.1007/s00210-023-02417-5

Published

11-Feb-23

Article

https://doi.org/10.1007/s00210-023-02417-5

Long COVID is an emerging problem in the current health care scenario. It is a syndrome with common symptoms of shortness of breath, fatigue, cognitive dysfunction, and other conditions that have a high impact on daily life. They are fluctuating or relapsing states that occur in patients with a history of SARS-CoV-2 infection for at least 2 months. They are usually conditions that at 3 months after onset cannot be explained by an alternative diagnosis. Currently very little is known about this syndrome. A thorough review of the literature highlights that the cause is attributable to deposits of tau protein. Massive phosphorylation of tau protein in response to SARS-CoV-2 infection occurred in brain samples from autopsies of people previously affected with COVID-19. The neurological disorders resulting from this clinical condition are termed tauopathies and can give different pathological symptoms depending on the involved anatomical region of the brain. Peripheral small-fiber neuropathies are also evident among patients with Long COVID leading to fatigue, which is the main symptom of this syndrome. Certainly more research studies could confirm the association between tau protein and Long COVID by defining the main role of tau protein as a biomarker for the diagnosis of this syndrome that is widespread in the post-pandemic period.

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Epsi, Nusrat J.; Powers, John H.; Lindholm, David A.; Mende, Katrin; Malloy, Allison; Ganesan, Anuradha; Huprikar, Nikhil; Lalani, Tahaniyat; Smith, Alfred; Mody, Rupal M.; Jones, Milissa U.; Bazan, Samantha E.; Colombo, Rhonda E.; Colombo, Christopher J.; Ewers, Evan C.; Larson, Derek T.; Berjohn, Catherine M.; Maldonado, Carlos J.; Blair, Paul W.; Chenoweth, Josh; Saunders, David L.; Livezey, Jeffrey; Maves, Ryan C.; Edwards, Margaret Sanchez; Rozman, Julia S.; Simons, Mark P.; Tribble, David R.; Agan, Brian K.; Burgess, Timothy H.; Pollett, Simon D.; Group, for the EPICC COVID-19 Cohort Study

A machine learning approach identifies distinct early-symptom cluster phenotypes which correlate with hospitalization, failure to return to activities, and prolonged COVID-19 symptoms

https://doi.org/10.1371/journal.pone.0281272

Published

9-Feb-23

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0281272

Background Accurate COVID-19 prognosis is a critical aspect of acute and long-term clinical management. We identified discrete clusters of early stage-symptoms which may delineate groups with distinct disease severity phenotypes, including risk of developing long-term symptoms and associated inflammatory profiles. Methods 1,273 SARS-CoV-2 positive U.S. Military Health System beneficiaries with quantitative symptom scores (FLU-PRO Plus) were included in this analysis. We employed machine-learning approaches to identify symptom clusters and compared risk of hospitalization, long-term symptoms, as well as peak CRP and IL-6 concentrations. Results We identified three distinct clusters of participants based on their FLU-PRO Plus symptoms: cluster 1 (“Nasal cluster”) is highly correlated with reporting runny/stuffy nose and sneezing, cluster 2 (“Sensory cluster”) is highly correlated with loss of smell or taste, and cluster 3 (“Respiratory/Systemic cluster”) is highly correlated with the respiratory (cough, trouble breathing, among others) and systemic (body aches, chills, among others) domain symptoms. Participants in the Respiratory/Systemic cluster were twice as likely as those in the Nasal cluster to have been hospitalized, and 1.5 times as likely to report that they had not returned-to-activities, which remained significant after controlling for confounding covariates (P < 0.01). Respiratory/Systemic and Sensory clusters were more likely to have symptoms at six-months post-symptom-onset (P = 0.03). We observed higher peak CRP and IL-6 in the Respiratory/Systemic cluster (P < 0.01). Conclusions We identified early symptom profiles potentially associated with hospitalization, return-to-activities, long-term symptoms, and inflammatory profiles. These findings may assist in patient prognosis, including prediction of long COVID risk.

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Gottschalk, Carl Gunnar; Peterson, Daniel; Armstrong, Jan; Knox, Konstance; Roy, Avik

Potential molecular mechanisms of chronic fatigue in long haul COVID and other viral diseases

https://doi.org/10.1186/s13027-023-00485-z

Published

7-Feb-23

Review

https://doi.org/10.1186/s13027-023-00485-z

Historically, COVID-19 emerges as one of the most devastating diseases of humankind, which creates an unmanageable health crisis worldwide. Until now, this disease costs millions of lives and continues to paralyze human civilization's economy and social growth, leaving an enduring damage that will take an exceptionally long time to repair. While a majority of infected patients survive after mild to moderate reactions after two to six weeks, a growing population of patients suffers for months with severe and prolonged symptoms of fatigue, depression, and anxiety. These patients are no less than 10% of total COVID-19 infected individuals with distinctive chronic clinical symptomatology, collectively termed post-acute sequelae of COVID-19 (PASC) or more commonly long-haul COVID. Interestingly, Long-haul COVID and many debilitating viral diseases display a similar range of clinical symptoms of muscle fatigue, dizziness, depression, and chronic inflammation. In our current hypothesis-driven review article, we attempt to discuss the molecular mechanism of muscle fatigue in long-haul COVID, and other viral diseases as caused by HHV6, Powassan, Epstein–Barr virus (EBV), and HIV. We also discuss the pathological resemblance of virus-triggered muscle fatigue with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

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Zhang, Yongkang; Hu, Hui; Fokaidis, Vasilios; V, Colby Lewis; Xu, Jie; Zang, Chengxi; Xu, Zhenxing; Wang, Fei; Koropsak, Michael; Bian, Jiang; Hall, Jaclyn; Rothman, Russell L.; Shenkman, Elizabeth A.; Wei, Wei-Qi; Weiner, Mark G.; Carton, Thomas W.; Kaushal, Rainu

Identifying environmental risk factors for post-acute sequelae of SARS-CoV-2 infection: An EHR-based cohort study from the recover program

https://doi.org/10.1016/j.envadv.2023.100352

Published

1-Apr-23

Study

https://www.sciencedirect.com/science/article/pii/S2666765723000121

Highlights
•The first study to identify environmental risk factors for Long-COVID.
•Comprehensive COVID-19 patient data linked with environmental characteristics.
•Nearly 200 exposome factors across three domains were examined.
•Air pollutions and neighborhood deprivation are important risk factors.
•Significant heterogeneity of risk factors across geographic regions.
Abstract
Post-acute sequelae of SARS-CoV-2 infection (PASC) affects a wide range of organ systems among a large proportion of patients with SARS-CoV-2 infection. Although studies have identified a broad set of patient-level risk factors for PASC, little is known about the association between “exposome”—the totality of environmental exposures and the risk of PASC. Using electronic health data of patients with COVID-19 from two large clinical research networks in New York City and Florida, we identified environmental risk factors for 23 PASC symptoms and conditions from nearly 200 exposome factors. The three domains of exposome include natural environment, built environment, and social environment. We conducted a two-phase environment-wide association study. In Phase 1, we ran a mixed effects logistic regression with 5-digit ZIP Code tabulation area (ZCTA5) random intercepts for each PASC outcome and each exposome factor, adjusting for a comprehensive set of patient-level confounders. In Phase 2, we ran a mixed effects logistic regression for each PASC outcome including all significant (false positive discovery adjusted p-value < 0.05) exposome characteristics identified from Phase I and adjusting for confounders. We identified air toxicants (e.g., methyl methacrylate), particulate matter (PM2.5) compositions (e.g., ammonium), neighborhood deprivation, and built environment (e.g., food access) that were associated with increased risk of PASC conditions related to nervous, blood, circulatory, endocrine, and other organ systems. Specific environmental risk factors for each PASC condition and symptom were different across the New York City area and Florida. Future research is warranted to extend the analyses to other regions and examine more granular exposome characteristics to inform public health efforts to help patients recover from SARS-CoV-2 infection.

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Wang, Siwen; Li, Yanping; Yue, Yiyang; Yuan, Changzheng; Kang, Jae Hee; Chavarro, Jorge E.; Bhupathiraju, Shilpa N.; Roberts, Andrea L.

Adherence to Healthy Lifestyle Prior to Infection and Risk of Post–COVID-19 Condition

https://doi.org/10.1001/jamainternmed.2022.6555

Published

6-Feb-23

Study

https://doi.org/10.1001/jamainternmed.2022.6555

Question Is a healthy lifestyle (healthy body mass index, never smoking, high-quality diet, moderate alcohol intake, regular exercise, and adequate sleep) prior to SARS-CoV-2 infection protective of post–COVID-19 condition (PCC)?
Findings In this prospective cohort study of 1981 women who reported a positive SARS-CoV-2 test from April 2020 to November 2021, adherence to a healthy lifestyle prior to infection was inversely associated with risk of PCC in a dose-dependent manner. Compared with those who did not have any healthy lifestyle factors, those with 5 or 6 had half the risk of PCC.
Meaning Preinfection healthy lifestyle was associated with a substantially decreased risk of PCC.
Abstract
Importance Few modifiable risk factors for post–COVID-19 condition (PCC) have been identified.
Objective To investigate the association between healthy lifestyle factors prior to SARS-CoV-2 infection and risk of PCC.
Design, Setting, and Participants In this prospective cohort study, 32 249 women in the Nurses’ Health Study II cohort reported preinfection lifestyle habits in 2015 and 2017. Healthy lifestyle factors included healthy body mass index (BMI, 18.5-24.9; calculated as weight in kilograms divided by height in meters squared), never smoking, at least 150 minutes per week of moderate to vigorous physical activity, moderate alcohol intake (5 to 15 g/d), high diet quality (upper 40% of Alternate Healthy Eating Index–2010 score), and adequate sleep (7 to 9 h/d).
Main Outcomes and Measures SARS-CoV-2 infection (confirmed by test) and PCC (at least 4 weeks of symptoms) were self-reported on 7 periodic surveys administered from April 2020 to November 2021. Among participants with SARS-CoV-2 infection, the relative risk (RR) of PCC in association with the number of healthy lifestyle factors (0 to 6) was estimated using Poisson regression and adjusting for demographic factors and comorbidities.
Results A total of 1981 women with a positive SARS-CoV-2 test over 19 months of follow-up were documented. Among those participants, mean age was 64.7 years (SD, 4.6; range, 55-75); 97.4% (n = 1929) were White; and 42.8% (n = 848) were active health care workers. Among these, 871 (44.0%) developed PCC. Healthy lifestyle was associated with lower risk of PCC in a dose-dependent manner. Compared with women without any healthy lifestyle factors, those with 5 to 6 had 49% lower risk (RR, 0.51; 95% CI, 0.33-0.78) of PCC. In a model mutually adjusted for all lifestyle factors, BMI and sleep were independently associated with risk of PCC (BMI, 18.5-24.9 vs others, RR, 0.85; 95% CI, 0.73-1.00, P = .046; sleep, 7-9 h/d vs others, RR, 0.83; 95% CI, 0.72-0.95, P = .008). If these associations were causal, 36.0% of PCC cases would have been prevented if all participants had 5 to 6 healthy lifestyle factors (population attributable risk percentage, 36.0%; 95% CI, 14.1%-52.7%). Results were comparable when PCC was defined as symptoms of at least 2-month duration or having ongoing symptoms at the time of PCC assessment.
Conclusions and Relevance In this prospective cohort study, pre-infection healthy lifestyle was associated with a substantially lower risk of PCC. Future research should investigate whether lifestyle interventions may reduce risk of developing PCC or mitigate symptoms among individuals with PCC or possibly other postinfection syndromes.

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de Andrade, Evandro Carvalho; Pinheiro, Luana Ibiapina C. C.; Pinheiro, Plácido Rogério; Nunes, Luciano Comin; Pinheiro, Mirian Calíope Dantas; Pereira, Maria Lúcia Duarte; de Abreu, Wilson Correia; Filho, Raimir Holanda; Simão Filho, Marum; Pinheiro, Pedro Gabriel C. D.; Nunes, Rafael Espíndola Comin

Hybrid model for early identification post-Covid-19 sequelae

https://doi.org/10.1007/s12652-023-04555-3

Published

6-Feb-23

Study

https://doi.org/10.1007/s12652-023-04555-3

Artificial Intelligence techniques based on Machine Learning algorithms, Neural Networks and Naïve Bayes can optimise the diagnostic process of the SARS-CoV-2 or Covid-19. The most significant help of these techniques is analysing data recorded by health professionals when treating patients with this disease. Health professionals' more specific focus is due to the reduction in the number of observable signs and symptoms, ranging from an acute respiratory condition to severe pneumonia, showing an efficient form of attribute engineering. It is important to note that the clinical diagnosis can vary from asymptomatic to extremely harsh conditions. About 80% of patients with Covid-19 may be asymptomatic or have few symptoms. Approximately 20% of the detected cases require hospital care because they have difficulty breathing, of which about 5% may require ventilatory support in the Intensive Care Unit. Also, the present study proposes a hybrid approach model, structured in the composition of Artificial Intelligence techniques, using Machine Learning algorithms, associated with multicriteria methods of decision support based on the Verbal Decision Analysis methodology, aiming at the discovery of knowledge, as well as exploring the predictive power of specific data in this study, to optimise the diagnostic models of Covid-19. Thus, the model will provide greater accuracy to the diagnosis sought through clinical observation.

404

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Tan, Hao; Liu, Jiayan; Zeng, Fanrui

China needs a scientific long COVID recovery-support platform

https://doi.org/10.1016/S0140-6736(23)00138-1

Published

4-Feb-23

Article

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00138-1/fulltext

Post-COVID-19 condition (also known as long COVID) emerged as a major public health problem in the post-pandemic era.1 Timely and sufficient information guidance and support are crucial for an effective response to long COVID. With China likely to end its zero-COVID strategy in the future,2, 3 it seems inevitable that long COVID will become a major concern for China. According to the longest follow-up study so far, more than 55% of COVID-19 patients in Wuhan (China) still have symptoms 2 years later.4 As the most populous country in the world, China is at acute risk of national crisis on account of long COVID.
However, there is currently no publicly available authoritative platform to explain long COVID symptoms in China, and the public does not have access to reliable scientific information, leading to little awareness and scientific knowledge of long COVID. The absence of authoritative sources of information or official, well-informed platforms to support patients with long COVID could prolong and exacerbate the symptoms of long COVID and contribute to psychological distress due to the absence of timely guidance. In addition, China has insufficient medical resources (the number of physicians in China is only 0·198% of the total population, which is nearly half the proportion in high-income countries, according to World Bank data in 2017). The dearth of medical resources and absence of an official recovery-support platform could lead to patients with long COVID not receiving timely health guidance during recovery, and the Government and related workers being unable to respond effectively to long COVID.

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Loreche, Arianna Maever; Pepito, Veincent Christian F.; Dayrit, Manuel M.

Long Covid: A call for global action

https://doi.org/10.1002/puh2.69

Published

15-Jul-05

Article

https://onlinelibrary.wiley.com/doi/abs/10.1002/puh2.69

The COVID-19 pandemic has resulted in another global health crisis with millions of individuals with Long Covid experiencing disability, worse health-related quality of life, and productivity and income losses. Despite its impact on population health outcomes, health systems, and the economy, there remains a need for a global consensus on its standard definition, diagnostic approaches, and treatment plans to manage symptoms. In many low- and middle-income countries (LMICs), there are limited published estimates on Long Covid, limited studies on its diagnostics and therapeutics, and limited media and news coverage. We advocate for a global action plan and necessary investments on Long Covid research and treatment, meaningful involvement of patients and cooperation between high-income countries and LMICs, stronger and more effective public health communication surrounding the risks of Long Covid, and support toward financial risk protection as advocated by Universal Health Care.

406

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Russell, Clark D.; Lone, Nazir I.; Baillie, J. Kenneth

Comorbidities, multimorbidity and COVID-19

https://doi.org/10.1038/s41591-022-02156-9

Published

1-Feb-23

Review

https://www.nature.com/articles/s41591-022-02156-9

The influence of comorbidities on COVID-19 outcomes has been recognized since the earliest days of the pandemic. But establishing causality and determining underlying mechanisms and clinical implications has been challenging—owing to the multitude of confounding factors and patient variability. Several distinct pathological mechanisms, not active in every patient, determine health outcomes in the three different phases of COVID-19—from the initial viral replication phase to inflammatory lung injury and post-acute sequelae. Specific comorbidities (and overall multimorbidity) can either exacerbate these pathological mechanisms or reduce the patient’s tolerance to organ injury. In this Review, we consider the impact of specific comorbidities, and overall multimorbidity, on the three mechanistically distinct phases of COVID-19, and we discuss the utility of host genetics as a route to causal inference by eliminating many sources of confounding. Continued research into the mechanisms of disease-state interactions will be crucial to inform stratification of therapeutic approaches and improve outcomes for patients.

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National COVID-19 Health and Research Advisory Committee

Advice 29: Update on Long COVID

Published

26-Apr-22

Recommendations and Reports

https://www.nhmrc.gov.au/sites/default/files/2023-02/NCHRAC-Advice-29-Update-on-Long-COVID.pdf

Clinical Care
• Long COVID is a complex condition that can impact multiple organs; people with the
condition can display a variety of signs and symptoms.
• In addition to physical symptoms, there is evidence that the experience of continued
poor health has a clinically observable psychological impact in those with Long COVID.
• Consensus on a case definition for Long COVID is required to ensure consistent and
appropriate diagnosis and treatment for individuals.
• Development of a case definition should occur in collaboration with people with lived
experience of Long COVID to ensure the criteria are meaningful and relevant to the
Australian context.

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Lafkas, Sara McPhee; Christensen, Marin; Madsen, Susan R.

The Impact of COVID-19 on Women and Work: Career Advancement Challenges

https://doi.org/10.3390/merits3010011

Published

1-Mar-23

Study

https://www.mdpi.com/2673-8104/3/1/11

The COVID-19 pandemic upended countless lives all over the world. Considerable research has shown that women’s career progression has been more negatively impacted by the pandemic than men’s, especially in the wake of school closures and increased childcare responsibilities. In order to understand more deeply the impact of the pandemic on women’s careers, a large mixed-method survey was conducted in Utah, a western state in the United States. This article reports on the responses of 2564 respondents to one of three open-ended questions taken from the overall survey, namely: “How has the pandemic impacted your career advancement experiences and opportunities over the short term and longer term?” The article frames the findings of this question by outlining workplace conditions and structures that contributed to women not advancing prior to the pandemic and applies the lenses of identity theory and systems psychodynamic theory to illustrate tendencies for workers and organizations to maintain the gendered dynamics that impede women’s career advancement. Findings included 59.1 percent of respondents who described a negative effect on their career advancement caused by the pandemic. Overarching themes and sub-themes were identified from these negative effects. Overarching themes included: (1) “Everything is on hold”; (2) “Lost or relinquished opportunity”; (3) “Reevaluation of Career”; and (4) “Experiences by Characteristics.” The latter theme highlighted unique experiences women faced versus men and manifested the gendered dynamics identified by identity and psychodynamic theories. Findings highlighted the importance of making workplace changes such as more flexible work and/or hybrid work arrangements, improved leave policies, the provision of childcare and other support services, and government policies that eliminate gendered barriers to women’s career advancement.

409

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Plebani, Mario

COVID-19 and Biomarkers: The Contribution of the Journal

https://doi.org/10.3390/jcm12051853

Published

1-Jan-23

Article

https://www.mdpi.com/2077-0383/12/5/1853

Three years after coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization (WHO), several features of the pathogenesis and innate immune response to SARS-CoV-2 (severe acute respiratory syndrome coronavirus disease 2) have now been clarified. Several studies have highlighted the crucial interplay among inflammation, thrombosis, cardiovascular diseases, multi-visceral manifestations, and SARS-CoV-2 infection, namely, linking the roles of cytokines, neutrophil extracellular traps (NETs), nucleosomes, histones, and the coagulation cascade. Although dramatic improvements have been achieved in better understanding the pathophysiology of the disease, the mechanisms of innate immune response and more appropriate therapeutic treatments, reliable and accurate biomarkers for the early risk stratification and clinical management of COVID-19 patients are still lacking. A series of papers recently published in the Journal have provided new insights into some interesting and potentially useful biomarkers in COVID-19. The first paper is by Simon T-P et al., who evaluated the prognostic value of bioactive adrenomedullin (bio-ADM) in critically ill patients with COVID-19. The rationale of the study, as underlined by the authors, is that “endothelial cell infection, inflammation and activation with the subsequent interruption of endothelial barrier function have been described in COVID-19 patients and adrenomedullin (ADM) has been shown to play a key role in regulating vascular hyper- permeability and endothelial stability/integrity in patients with severe infection” [1].
number: 5
publisher: Multidisciplinary Digital Publishing Institute

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Fialho, Maria Fernanda Pessano; Brum, Evelyne Silva; Oliveira, Sara Marchesan

Could the fibromyalgia syndrome be triggered or enhanced by COVID-19?

https://doi.org/10.1007/s10787-023-01160-w

Published

27-Feb-23

Article

https://doi.org/10.1007/s10787-023-01160-w

Fibromyalgia (FM) is a complex disease with an uncertain aetiology and intricate pathophysiology. Although its genesis is not fully explained, potential environmental factors, such as viral infections might trigger FM or worsen patients' clinical outcomes. The SARS-CoV-2 virus may affect central and peripheral nervous systems, leading to musculoskeletal, neurological, and psychological disturbances. These symptoms might persist at least 12 months beyond the recovery, often referred to as post-COVID syndrome, which resembles FM syndrome. In this sense, we argued the potential consequences of COVID-19 exclusively on FM syndrome. First, we have described post-COVID syndrome and its painful symptoms. Afterwards, we argued whether FM syndrome could be triggered or enhanced by COVID-19 infection or by numerous and persistent stressors imposed daily by the pandemic setting (isolation, uncertainty, depression, mental stress, generalized anxiety, and fear of the virus). In addition, we have demonstrated similarities between pathophysiological mechanisms and cardinal symptoms of FM and COVID-19, speculating that SARS-CoV-2 might represent a critical mediator of FM or an exacerbator of its symptoms once both syndromes share similar mechanisms and complaints. Therefore, pharmacologic and non-pharmacological approaches commonly used to treat FM could serve as strategic therapies to attenuate painful and neurological manifestations of post-COVID syndrome. Although it is still theoretical, clinicians and researchers should be alert of patients who develop symptoms similar to FM or those who had their FM symptoms increased post-COVID to manage them better.

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Deng, Yamin; Han, Shasha; Liu, Jue; Guo, Li; Feng, Luzhao; Liao, Yilan; Peng, Zhixing; Ren, Lili; Yang, Weizhong; Wang, Jianwei

The risks of death and hospitalizations associated with SARS-CoV-2 Omicron declined after lifting testing and quarantining measures

https://doi.org/10.1016/j.jinf.2023.02.033

Published

27-Feb-23

Study

https://www.journalofinfection.com/article/S0163-4453(23)00118-4/fulltext

We reported the estimated infection–fatality ratio (IFR) and infection-hospitalization ratio (IHR) after lifting non-pharmaceutical interventions using a mathematical compartment model that accounted for unascertained infections. China lifted the testing and quarantining measures against SARS-CoV-2 Omicron on 7 December 2022. One online survey study conducted on December 27-30, 2022, in Macao, China, reported 70% of the population infection rates.1 This concurrence of the surge of Omicron infection and the excess winter mortality among old adults has sparked a widespread susception of an increasing medical burden of the disease after the lifting. However, a well-known problem with web surveys is selection bias, which could lead to unreliable survey outcomes.2 It is unclear which statistical techniques 3 were used to address the problem. Moreover, the authors noted that unascertained infections were difficult to count in the survey.
The risks of death and hospitalization provide an alternative way of converting COVID-19 mortality into an estimate of infections and further into the requirement of hospital resources, and a reverse way to convert the requirement of hospital resources into an estimate of infections and further into COVID-19 mortality, which together comprises a self-checking robust way to qualify for the medical burdens of Omicron variants. Thus, a better understanding of the changes in IFR and IHR after lifting testing measures is needed. We highlighted the difference between IFR—a metric quantifying the likelihood of people dying once infected,4 and the case-fatality ratio (CFR) with the infections being replaced by the ascertained infections. Because of the great uncertainty surrounding the number of infections after the lifting, estimates of the IFR and IHR that rely on detected cases are likely to be misleading.
Our age-specific and all-age estimation of the IFR and IHR showed that the risk of death and hospitalizations among people infected with Omicron declined after the lifting, with considerably lower values than reported CFR and CHR. Understanding these changes in IFR and IHR has direct implications for quantifying the need for medical resources, especially when great uncertainty surrounds the number of infections after the lifting. Although our analysis shows relatively stable IFRs and IHRs across different periods, it is key to remark that most Omicron infections recorded in our data occurred in seasons other than winter. We were not able to evaluate the differences in risks across seasons, but our findings present a basis for future comparison. The finding has profound implications for understanding the medical burden of pathology and informing medical resource allocations, which should take into consideration the impact of case ascertaining measures and the limitation in data collection.
publisher: Elsevier
PMID: 36858179

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Abenavoli, Ludovico; Gentile, Ivan

COVID-19: Where We Are and Where We Are Going

https://doi.org/10.3390/diseases11010040

Published

1-Mar-23

Article

https://www.mdpi.com/2079-9721/11/1/40

The impact of COVID-19 on global health has been colossal. By the end of 2021, there were reports of over 672 million cumulative confirmed cases and 6.8 million deaths from COVID-19 [1], and these statistics continue to increase. However, these figures almost certainly constitute an underestimation of the true number of cases and deaths. The pandemic has put health systems under pressure in both developing and high-income countries [2,3]. With this in mind, national health systems are expected to be able to answer to the following questions: how do we manage the current epidemic? How do we realize measures to prevent future epidemics? How do we maximize health gain and health equity in the long term?
Since 2019, the rapid availability of new vaccines and new antiviral treatments has considerably altered the evolution of the pandemic [4]. However, from a medical research perspective, the pandemic represents a transitional moment in human history. In the last three years, extensive scientific research has been conducted on COVID-19, causing a delaying in research breakthroughs for other diseases. Moreover, the pandemic exacerbated the health of those affected by noncommunicable diseases by delaying and disrupting their diagnoses, treatments and follow-up appointments [5].
In addition, the indirect impact of COVID-19 on the changes of livelihoods, education systems and social protection is relevant, and these changes open up several challenges. However, it is important to underline the aims of the COVID-19 pandemic research, which should include effectiveness, efficiency and equity.
From a clinical point of view, we have gained a great deal of experience on this topic. In fact, COVID-19 is now considered not only a respiratory illness, but a complex disorder that affects the cardiovascular, gastrointestinal, and urinary systems [6,7,8]. In addition, several neurological manifestations have been observed in patients with SARS-CoV-2 infection [9]. Some examples include dysgeusia, hyposmia, encephalitis, meningitis, and acute cerebrovascular disease, most likely due to direct infection of the brain, induced hyperinflammatory response, hypercoagulation, and immune-mediated processes [10]. Long COVID-19 represents a new medical challenge. Currently, there is no consensus regarding the management of this complex condition, which causes the onset of several manifestations associated with different tissues. There is no definitive accepted treatment, but therapies focused on specific symptoms are commonly prescribed [11]. For this reason, a multidisciplinary approach to improving the management of patients with long COVID-19 is suggested [12,13].
number: 1
publisher: Multidisciplinary Digital Publishing Institute

413

D409

Scharf, Rüdiger E.; Anaya, Juan-Manuel

Post-COVID Syndrome in Adults—An Overview

https://doi.org/10.3390/v15030675

Published

1-Mar-23

Review

https://www.mdpi.com/1999-4915/15/3/675

This article provides an overview of various aspects related to post-COVID syndrome. Apart from its prevalence, symptoms and sequelae, risk determinants, and psychosocial implications, the pathogenesis of post-COVID condition is discussed in more detail. A focus on thrombo-inflammation in SARS-CoV-2 infection, the role of neutrophil extracellular traps, and the prevalence of venous thromboembolism is made. Moreover, COVID-19 and post-COVID syndrome in immunocompromising conditions, and the impact of vaccination on the prevention and treatment of post-COVID symptoms are reviewed. Autoimmunity is a hallmark of post-COVID syndrome, and, therefore, is another focus of this article. Thus, misdirected cellular and humoral immune responses can enhance the risk of latent autoimmunity in post-COVID syndrome. Facing the high prevalence of COVID-19 cases worldwide, it can be assumed that autoimmune disorders will increase globally over the next few years. Recent advances in identifying genetically determined variants may open the avenue for a better understanding of the susceptibility to and severity of SARS-CoV-2 infection and post-COVID syndrome.

414

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Alwan, Nisreen A.

Healing Long Covid: a marathon not a sprint

https://doi.org/10.1016/S0140-6736(23)00408-7

Published

4-Mar-23

Article

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00408-7/fulltext

I have been immersed in Long Covid both personally and professionally since the summer of 2020. I experienced the condition myself, wrote and spoke about it on various national and international platforms, and did research trying to understand its features and effects. Now there is a handbook about the condition that I was eager to read, even though it is written mainly from the individual patient's point of view rather than the population-level perspective that I often see things through and advocate for as a public health professional.
publisher: Elsevier

415

D411

Scholz, Urte; Bierbauer, Walter; Lüscher, Janina

Social Stigma, Mental Health, Stress, and Health-Related Quality of Life in People with Long COVID

https://doi.org/10.3390/ijerph20053927

Published

1-Jan-23

Study

https://www.mdpi.com/1660-4601/20/5/3927

A considerable amount of people who have been infected with SARS-CoV-2 experience ongoing symptoms, a condition termed long COVID. This study examined nuanced experiences of social stigma in people with long COVID and their associations with perceived stress, depressive symptoms, anxiety, and mental and physical health-related quality of life (hrqol). A total of N = 253 participants with long COVID symptoms (mean age = 45.49, SD = 12.03; n = 224, 88.5% women) completed a cross-sectional online survey on overall social stigma and the subfacets enacted and perceived external stigma, disclosure concerns, and internalized stigma. Data were analysed using multiple regression and controlling for overall burden of consequences of long COVID, overall burden of symptoms of long COVID, and outcome-specific confounders. In line with our preregistered hypotheses, total social stigma was related to more perceived stress, more depressive symptoms, higher anxiety, and lower mental hrqol, but—in contrast to our hypothesis—it was unrelated to physical hrqol after controlling for confounders. The three subscales of social stigma resulted in differential associations with the outcomes. Social stigma experiences go hand in hand with worse mental health in people with long COVID. Future studies should examine potential protective factors to buffer the effects of social stigma on people’s well-being.

416

D412

Blanchflower, David; Bryson, Alex

Long Covid in the United States

pre-print

1-Feb-23

Study

http://www.nber.org/papers/w30988.pdf

Long COVID in the United States Although yet to be clearly identified as a clinical condition, there is immense concern at the health and wellbeing consequences of long COVID. Using data collected from nearly half a million Americans in the period June 2022-December 2022 in the US Census Bureau’s Household Pulse Survey (HPS), we find 14 percent reported suffering long COVID at some point, half of whom reported it at the time of the survey. Its incidence varies markedly across the United States – from 11 percent in Hawaii to 18 percent in West Virginia – and is higher for women than men, among Whites compared with Blacks and Asians, and declines with rising education and income. It peaks in midlife in the same way as negative affect. Ever having had long COVID is strongly associated with negative affect (anxiety, depression, worry and a lack of interest in things). The effect is larger among those who currently report long COVID, especially if they report severe symptoms. In contrast, those who report having had short COVID report higher wellbeing than those who report never having had COVID. Long COVID is also strongly associated with physical mobility problems, and with problems dressing and bathing. It is also associated with mental problems as indicated by recall and understanding difficulties. Again, the associations are strongest among those who currently report long COVID, while those who said they had had short COVID have fewer physical and mental problems than those who report never having had COVID. Vaccination is associated with lower negative affect, including among those who reported having had long COVID.

417

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Thurner, Carolin; Stengel, Andreas

Long-COVID syndrome: physical–mental interplay in the spotlight

https://doi.org/10.1007/s10787-023-01174-4

Published

9-Mar-23

Review

https://doi.org/10.1007/s10787-023-01174-4

Patients suffering from Long-COVID syndrome experience a variety of different symptoms on a physical, but also on a psychological and social level. Previous psychiatric conditions such as depression and anxiety have been identified as separate risk factors for developing Long-COVID syndrome. This suggests a complex interplay of different physical and mental factors rather than a simple cause–effect relationship of a specific biological pathogenic process. The biopsychosocial model provides a foundation for understanding these interactions and integrating them into a broader perspective of the patient suffering from the disease instead of the individual symptoms, pointing towards the need of treatment options on a psychological as well as social level besides biological targets. This leads to our conclusion, that the biopsychosocial model should be the underlying philosophy of understanding, diagnosing and treating patients suffering from Long-COVID syndrome, moving away from the strictly biomedical understanding suspected by many patients, treaters and the media while also reducing the stigma still associated with the suggestion of a physical–mental interplay.

418

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Yang, Chengliang; Tebbutt, Scott J.

Long COVID: the next public health crisis is already on its way

https://doi.org/10.1016/j.lanepe.2023.100612

Published

10-Mar-23

Article

https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(23)00030-3/fulltext

In the current issue of The Lancet Regional Health - Europe, Wahlgren and colleagues report on a longitudinal follow-up of COVID-19 patients who were hospitalized during the first pandemic wave (between March and May 2020) in Sweden,2 one of the longest follow-up studies of hospitalized COVID-19 patients to date. Using a 37-point questionnaire, patients reported that cognition, sensorimotor impairments and fatigue were their most common persistent symptoms; up to 84% of patients still had problems affecting their daily lives 24 months after acute infection. Approximately half of the cohort who were on sick leave associated with LC at 4 months after infection remained on sick leave at 24 months, with health risks such as hospitalization for cardiovascular disease.2 Similarly, a UK study confirmed that COVID-19 infection, including LC, was associated with increased short- and long-term risk of cardiovascular disease and death, particularly in those who had severe COVID.3 Nevertheless, many questions remain regarding the reported symptoms of LC, the effectiveness of COVID-19 vaccines against LC, and the vulnerable population for LC.
To date, more than 200 LC symptoms have been reported. In Wahlgren's study cohort, up to 11% (19/165) of patients' mental health was affected by psychiatric disorders.2 Importantly, indications of cognitive impairment, sensorimotor disorders, and fatigue are generally based on patient self-report, which is less objective than clinician diagnoses and might not be uniform and accurate across the study population. Persistent physical symptoms after the acute COVID-19 phase may not be due to SARS-CoV-2 infection, as some symptoms may have already been present before COVID-19.4 A Spanish group compared the differences in LC symptoms between hospitalized and non-hospitalized patients two years after acute infection. Their cross-sectional study showed that 59.7% of hospitalized patients and 67.5% of non-hospitalized patients had at least one LC symptom two years after infection.5 However, neither the Wahlgren nor Spanish studies included healthy controls, limiting their ability to separate effects independently with COVID-19 from those associated with matched control populations.2,5 Indeed, few studies examining LC have used an uninfected control group, and the clinical presentation of LC patients, including symptoms, physical assessment, mental health and psychotherapy, and diagnostic investigation, remains incompletely characterized in most published studies. From a clinical viewpoint, LC patients require precise medical assessment to prevent pre-existing or unrelated symptoms from being erroneously attributed to COVID-19 infection, and to identify pathophysiologic mechanisms for targeted symptom relief. Currently, objective clinical measures are limited, and biomarkers are urgently needed to close the diagnostic gap for LC.
In Wahlgren's study, 91% of patients received more than two doses of COVID-19 vaccine, but the vaccine type was unknown.2 Whether or not vaccination, particularly with inactivated virus, protects against LC symptoms, remains controversial. A recent national cohort study from Israel evaluated clinical sequelae in vaccinated patients with mild COVID-19 up to one year post-infection, compared to uninfected and unvaccinated SARS-CoV-2-infected patients as controls. This study concluded that vaccinated mild patients with a breakthrough SARS-CoV-2 infection had reduced risk of lingering dyspnea compared to unvaccinated individuals, while risks for other adverse health outcomes were comparable.6 A Hong Kong study found that those who received two doses of BNT162b2 (mRNA vaccine) had higher levels of protection against severe COVID-19 than those who received two doses of CoronaVac (inactive virus vaccine), especially in older age groups.7 Researchers in Malaysia compared the duration of protection using BNT162b2 and CoronaVac vaccines, and found protection diminished more rapidly after two doses of CoronaVac, especially against mild and moderate COVID-19.8 Turkish researchers reported that participants receiving a third dose of BNT162b2 had significantly increased neutralizing antibody titers compared to a third dose of CoronaVac.9 Surprisingly, a recent Chinese study showed that patients with breakthrough infection who had received three doses of inactivated virus COVID-19 vaccine had significantly lower titers of neutralizing antibodies to Omicron BA.2, BA.4 and BA.5 variants compared to patients with breakthrough infection who had received two doses of inactivated virus vaccine.10 These results suggest that repeated inactivated virus vaccination back-boosts prior memory and dampens immune responses to new antigenically-related but different viral strains,10 likely due to stronger immune imprinting against the ancestral strain and suppression of the neutralizing antibody response against new Omicron variants.
A recent study from the United States suggests current COVID-19 vaccines (including WA1/BA.5 bivalent mRNA vaccine) are ineffective against BQ and XBB Omicron due to the superiority of these subvariants in evading antibodies.11 Emerging SARS-CoV-2 variants such as XBB 1.5 and evidence of waning vaccine efficacy due to immune escape pose significant potential barriers to control of the COVID-19 pandemic. According to a World Health Organization (WHO) report, only 30.61% of people worldwide have received booster vaccines.12 Number of people at risk of developing LC might be greater than earlier predictions, especially in unvaccinated populations in lower-income countries, post-COVID-19 patients living in socioeconomically deprived areas, and seriously ill and vulnerable patients.12,13 The increasing prevalence of LC threatens healthcare systems worldwide and seriously affects socioeconomic recovery. Strategies are urgently needed to address this developing public health crisis.
publisher: Elsevier

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Tabassum, Farah; Selke, Moira Sarah A.; MacQuarrie, Maureen; Stein, Eleanor

Lessons for Long COVID from Myalgic Encephalomyelitis (ME) care

Published

28-Mar-23

Article

https://www.cmaj.ca/content/lessons-long-covid-myalgic-encephalomyelitis-me-care, /content/lessons-long-covid-myalgic-encephalomyelitis-me-care

We thank Quinn et al. for their three timely articles on long COVID. Our comments are mostly directed towards the treating article(1) but also aim to bring awareness to the existing body of literature regarding myalgic encephalomyelitis (ME), which is a disease that shares many overlapping symptoms with long COVID and most commonly also arises in a post-infectious setting.

Quinn et al. raise the similarities between long COVID and ME but unfortunately limit the comparison to the section on the mental health consequences of long COVID.(1) Beyond the potential mental health sequelae, parallels between long COVID and ME symptomatology have been written about, starting early on in the pandemic, and it is now apparent that about half of individuals with long COVID meet ME diagnostic criteria.(2) Much of the experience gained from the research and care of people with ME may be both relevant and significant for long COVID.

It is noted in the article by Quinn et al. that cognitive behavioural therapy (CBT) for the treatment of fatigue is controversial.(1) We wish to highlight however, that within the context of ME, the use of CBT as a treatment for fatigue is not recommended.(3,4) The NICE ME/CFS guidelines, referenced in the article(5) which Quinn et al. cite, were updated in October 2021 and note that CBT is only to be offered as general support for those with ME/CFS to “... reduce the distress associated with having a chronic illness,” and/or to manage comorbid mood disorder, but not as a cure.(3) This is in keeping with the approaches used in any chronic disabling condition, in order to address comorbid mental health disorders and provide coping strategies for living with a chronic disease.

Post-exertional malaise (PEM), sometimes referred to as post-exertional symptom exacerbation, is the hallmark feature of ME(4) and can be found in long COVID.(2) Based on experience with ME, the “structured and symptom-guided” return to activity suggested by Quinn et al.(1) needs to be clarified, as the term “structured” can be problematic.

A “structured” rehabilitation program(1) should not be confused with strategies founded in graded exercise therapy (GET). GET, as defined in the 2021 NICE ME/CFS guidelines as utilizing “fixed incremental increases in the time spent being physically active” is not to be undertaken(3). It should be noted that activity of any nature, for some, may exacerbate symptoms and could even result in relapses with long-term consequences.(3,4) The WHO COVID-19 Clinical management: living guidance document contains similar cautions for long COVID.

A “symptom - guided” rehabilitation program is in keeping with concepts of pacing, and should be emphasized. Pacing, which Quinn et al. do reference,(1) is a quintessential management strategy for PEM well founded in the ME field of practice(4) with tools readily available for practitioners and patients, such as through the Bateman Horne Center and Workwell Foundation websites.

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Tate, Warren P.; Walker, Max O. M.; Peppercorn, Katie; Blair, Anna L. H.; Edgar, Christina D.

Towards a Better Understanding of the Complexities of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID

https://doi.org/10.3390/ijms24065124

Published

1-Jan-23

Review

https://www.mdpi.com/1422-0067/24/6/5124

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition arising in susceptible people, predominantly following viral infection, but also other stressful events. The susceptibility factors discussed here are both genetic and environmental although not well understood. While the dysfunctional physiology in ME/CFS is becoming clearer, understanding has been hampered by different combinations of symptoms in each affected person. A common core set of mainly neurological symptoms forms the modern clinical case definition, in the absence of an accessible molecular diagnostic test. This landscape has prompted interest in whether ME/CFS patients can be classified into a particular phenotype/subtype that might assist better management of their illness and suggest preferred therapeutic options. Currently, the same promising drugs, nutraceuticals, or behavioral therapies available can be beneficial, have no effect, or be detrimental to each individual patient. We have shown that individuals with the same disease profile exhibit unique molecular changes and physiological responses to stress, exercise and even vaccination. Key features of ME/CFS discussed here are the possible mechanisms determining the shift of an immune/inflammatory response from transient to chronic in ME/CFS, and how the brain and CNS manifests the neurological symptoms, likely with activation of its specific immune system and resulting neuroinflammation. The many cases of the post viral ME/CFS-like condition, Long COVID, following SARS-CoV-2 infection, and the intense research interest and investment in understanding this condition, provide exciting opportunities for the development of new therapeutics that will benefit ME/CFS patients.

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Yu, Zhebin; Ekström, Sandra; Bellander, Tom; Ljungman, Petter; Pershagen, Göran; Eneroth, Kristina; Kull, Inger; Bergström, Anna; Georgelis, Antonios; Stafoggia, Massimo; Gruzieva, Olena; Melén, Erik; Almqvist, Catarina; Andersson, Niklas; Ballardini, Natalia; Bergström, Anna; Björkander, Sophia; Brodin, Petter; Castel, Anna; Ekström, Sandra; Georgelis, Antonios; Hammarström, Lennart; Pan-Hammarström, Qiang; Hallberg, Jenny; Jansson, Christer; Kere, Maura; Kull, Inger; Lauber, André; Lövquist, Alexandra; Melén, Erik; Mjösberg, Jenny; Mogensen, Ida; Palmberg, Lena; Pershagen, Göran; Roxhed, Niclas; Schwenk, Jochen

Ambient air pollution exposure linked to long COVID among young adults: a nested survey in a population-based cohort in Sweden

https://doi.org/10.1016/j.lanepe.2023.100608

Published

7-Mar-23

Study

https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(23)00026-1/fulltext

Background
Post COVID-19 conditions, also known as long COVID, are of public health concern, but little is known about their underlying risk factors. We aimed to investigate associations of air pollution exposure with long COVID among Swedish young adults.
Methods
We used data from the BAMSE (Children, Allergy, Environment, Stockholm, Epidemiology [in Swedish]) cohort. From October 2021 to February 2022 participants answered a web-questionnaire focusing on persistent symptoms following acute SARS-CoV-2 infection. Long COVID was defined as symptoms after confirmed infection with SARS-CoV-2 lasting for two months or longer. Ambient air pollution levels (particulate matter ≤2.5 μm [PM2.5], ≤10 μm [PM10], black carbon [BC] and nitrogen oxides [NOx]) at individual-level addresses were estimated using dispersion modelling.
Findings
A total of 753 participants with SARS-CoV-2 infection were included of whom 116 (15.4%) reported having long COVID. The most common symptoms were altered smell/taste (n = 80, 10.6%), dyspnea (n = 36, 4.8%) and fatigue (n = 34, 4.5%). Median annual PM2.5 exposure in 2019 (pre-pandemic) was 6.39 (interquartile range [IQR] 6.06–6.71) μg/m3. Adjusted Odds Ratios (95% confidence intervals) of PM2.5 per IQR increase were 1.28 (1.02–1.60) for long COVID, 1.65 (1.09–2.50) for dyspnea symptoms and 1.29 (0.97–1.70) for altered smell/taste. Positive associations were found for the other air pollutants and remained consistent across sensitivity analyses. Associations tended to be stronger among participants with asthma, and those having had COVID during 2020 (versus 2021).
Interpretation
Ambient long-term PM2.5 exposure may affect the risk of long COVID in young adults, supporting efforts for continuously improving air quality.
publisher: Elsevier

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Spence, Naomi J; Russell, David; Bouldin, Erin D; Tumminello, Christa M; Schwartz, Tatum

Getting back to normal? Identity and role disruptions among adults with Long COVID

https://doi.org/10.1111/1467-9566.13628

Published

1-Mar-23

Study

https://doi.org/10.1111/1467-9566.13628

Long COVID is a novel chronic illness with a variety of symptoms that people who have labelled themselves 'long-haulers' experience for an extended duration following a COVID-19 infection. We draw on in-depth interviews conducted in March-April 2021 with 20 working-aged adults in the U.S. who self-identified as long-haulers to understand the consequences for identities. The results demonstrate that Long COVID has important consequences for identities and sense of self. Long-haulers described experiencing three stages of biographical disruptions: realising their illness experience as misaligned with sense of self and embodied, age-based expectations; facing challenges to identities and changes in social roles; and reconciling illness and identity in the context of an uncertain prognosis. It remains unclear how long-haulers will resolve biographical disruptions and identity conflicts, especially as scientific insights about this novel condition emerge. Such outcomes may depend largely on whether Long COVID remains a contested illness or medical knowledge progresses to improve their quality of life. For now, healthcare providers may approach Long COVID holistically to address the identity disruptions that long-haulers face as they manage the consequences of this chronic illness.

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Song, Zirui; Giuriato, Mia

Demographic And Clinical Factors Associated With Long COVID

https://doi.org/10.1377/hlthaff.2022.00991

Published

1-Mar-23

Study

https://www.healthaffairs.org/doi/abs/10.1377/hlthaff.2022.00991

Risk factors for postacute sequelae of SARS-CoV-2 infection (“long COVID”) in community-dwelling populations remain poorly understood. Large-scale data, follow-up, comparison groups, and a consensus definition of long COVID are often lacking. Using data from the OptumLabs Data Warehouse on a nationwide sample of commercial and Medicare Advantage enrollees from the period January 2019 through March 2022, we examined demographic and clinical factors associated with long COVID, using two definitions of people who suffer symptoms long after they were first diagnosed with COVID-19 (“long haulers”). We identified 8,329 long haulers using the narrow definition (diagnosis code), 207,537 long haulers using the broad definition (symptom based), and 600,161 non–long haulers (comparison group). On average, long haulers were older and more likely female, with more comorbidities. Among narrow-definition long haulers, the leading risk factors for long COVID included hypertension, chronic lung disease, obesity, diabetes, and depression. Their time between initial COVID-19 diagnosis and diagnosis of long COVID averaged 250 days, with racial and ethnic differences. Broad-definition long haulers exhibited similar risk factors. Distinguishing long COVID from the progression of underlying conditions can be challenging, but further study may advance the evidence base related to the identification, causes, and consequences of long COVID.

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Matsuda, Yui; Tokumasu, Kazuki; Otsuka, Yuki; Sunada, Naruhiko; Honda, Hiroyuki; Sakurada, Yasue; Nakano, Yasuhiro; Hasegawa, Toru; Obika, Mikako; Ueda, Keigo; Otsuka, Fumio

Symptomatic Characteristics of Hypozincemia Detected in Long COVID Patients

https://doi.org/10.3390/jcm12052062

Published

1-Jan-23

Study

https://www.mdpi.com/2077-0383/12/5/2062

Objectives: The aim of this study was to determine the characteristics of hypozincemia in long COVID patients. Methods: This study was a single-center retrospective observational study for outpatients who visited the long COVID clinic established in a university hospital during the period from 15 February 2021 to 28 February 2022. Characteristics of patients with a serum zinc concentration lower than 70 μg/dL (10.7 μmol/L) were compared with characteristics of patients with normozincemia. Results: In a total of 194 patients with long COVID after excluding 32 patients, hypozincemia was detected in 43 patients (22.2%) including 16 male patients (37.2%) and 27 female patients (62.8%). Among various parameters including the background characteristics of the patients and medical histories, the patients with hypozincemia were significantly older than the patients with normozincemia (median age: 50 vs. 39 years). A significant negative correlation was found between serum zinc concentrations and age in male patients (R = −0.39; p < 0.01) but not in female patients. In addition, there was no significant correlation between serum zinc levels and inflammatory markers. General fatigue was the most frequent symptom in both male patients with hypozincemia (9 out of 16: 56.3%) and female patients with hypozincemia (8 out of 27: 29.6%). Patients with severe hypozincemia (serum zinc level lower than 60 μg/dL) had major complaints of dysosmia and dysgeusia, which were more frequent complaints than general fatigue. Conclusions: The most frequent symptom in long COVID patients with hypozincemia was general fatigue. Serum zinc levels should be measured in long COVID patients with general fatigue, particularly in male patients.

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Tanne, Janice Hopkins

Covid-19: US studies show racial and ethnic disparities in long covid

https://doi.org/10.1136/bmj.p535

Published

6-Mar-23

Article

https://www.bmj.com/content/380/bmj.p535

Black and Hispanic Americans are more likely than white Americans to have symptoms of long covid and some people who had covid early in the epidemic may have long covid but not be diagnosed as such because of coding changes, show studies funded by the National Institutes of Health.123

Long covid was defined by the Centers for Disease Control and Prevention in December 2022, and includes general symptoms as well as respiratory, cardiovascular, neurological, digestive, and other symptoms.4

Mitchell Elkind, professor of neurology and epidemiology at Columbia University Medical Center in New York and chief clinical officer of the American Heart Association, said, “New evidence suggests that there may be important differences in how long covid manifests in different racial and ethnic groups. Further research is needed to understand better the mechanisms for these differences in symptoms and access to care, and also if diagnostic codes assigned by clinicians …

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Quinn, Kieran L.; Razak, Fahad; Cheung, Angela M.

Diagnostiquer le syndrome post-COVID-19 (COVID-19 de longue durée) chez l’adulte

https://doi.org/10.1503/cmaj.220818-f

Published

6-Mar-23

Article

https://www.cmaj.ca/content/195/9/E346

La COVID-19 de longue durée est un syndrome systémique
Cette caractéristique serait associée à l’expression dans différents organes des récepteurs de l’enzyme de conversion de l’angiotensine 2 (ECA2), utilisés par le SRAS-CoV-2 pour pénétrer dans les cellules4. Plusieurs mécanismes pathophysiologiques pourraient contribuer à la COVID-19 de longue durée, notamment les lésions cellulaires, la persistance de l’inflammation ou de la virémie, l’auto-immunité et un état procoagulant4.

La COVID-19 de longue durée peut toucher la plupart des systèmes organiques
Le syndrome bouleverse le fonctionnement et le bien-être des patients au quotidien3,4. Plus de 100 symptômes de la COVID-19 de longue durée ont été déclarés. Par ailleurs, le sexe féminin semble être un facteur de risque indépendant. Les symptômes les plus fréquents qui peuvent être traités comprennent la fatigue (23 %–63 %), l’anxiété et la dépression (23 %–46 %), la dyspnée (11 %–43 %), les troubles du sommeil (11 %–31 %) et les palpitations (6 %–22 %)3,4.

Beaucoup de personnes atteintes de la COVID-19 de longue durée ont des symptômes persistants
De nombreuses personnes guérissent de la COVID-19 de longue durée, mais certaines continuent de souffrir de symptômes au point de ne pas pouvoir reprendre une activité à temps plein au bout de 1 an2,5. Une étude longitudinale de cohorte publiée en 20225 a suivi 1192 personnes hospitalisées à Wuhan (Chine) ayant survécu à la COVID-19: 68 % présentaient au moins 1 symptôme 6 mois après l’infection; cette proportion avait diminué à 55 % après 2 ans. Parmi les participants qui occupaient auparavant un emploi, 21 % n’avaient pas repris le travail5, ce qui correspond à la proportion de personnes au Canada ayant déclaré que leurs symptômes restreignaient souvent ou toujours leurs activités quotidiennes2.
publisher: CMAJ
section: Pratique
PMID: 36878549

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Nobili, Alessandro; D’Avanzo, Barbara; Tettamanti, Mauro; Galbussera, Alessia Antonella; Remuzzi, Giuseppe; Fortino, Ida; Leoni, Olivia; Harari, Sergio; Mannucci, Pier Mannuccio

Post-COVID condition: dispensation of drugs and diagnostic tests as proxies of healthcare impact

https://doi.org/10.1007/s11739-023-03228-5

Published

21-Mar-23

Study

https://doi.org/10.1007/s11739-023-03228-5

With the goal to increase knowledge on the healthcare impact of the post-COVID-19 condition we exploited the administrative claims database of Lombardy, the largest Italian region and the first after China to be heavily hit by the SARS-CoV-2 pandemic in February–May 2020. We chose to employ the dispensation of drugs and diagnostic tests as proxies of the impact of the post-COVID condition in 46,574 cases who recovered from COVID-19 and were negative at PCR testing within June 20, 2020. Data were obtained throughout the 18-month post-negativization period until December 2021 and results on the use of drugs and diagnostic tests were compared with those accrued in the same cases during the pre-COVID period in July–December 2019. After an increase in the first semester after SARS-CoV-2 negativization (July–December 2020), trends in the dispensation of drugs according to the broad ATC classes and of diagnostic tests decreased or remained substantially stable. However, dispensation of drugs for acid related disorders (A02), diabetes (A10), heparins (B01AB), direct oral anticoagulants (B01AP), antipsychotics (N05A), antidepressants (N06A) and for obstructive airways diseases (R03) was still higher than in the pre-COVID period. These findings, based upon drug and diagnostic test dispensation as proxies of the healthcare impact of the post-COVID condition, show that in a substantial proportion of recovered cases the post-COVID condition is active and clinically relevant 18 months after the acute disease. The findings also provide indirect evidence of the body organs and systems more compromised in the post-COVID period.

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Salisbury, Helen

Helen Salisbury: Unexplained symptoms aren’t always long covid

https://doi.org/10.1136/bmj.p654

Published

21-Mar-23

Article

https://www.bmj.com/content/380/bmj.p654

On busy days in general practice I often long for straightforward presentations—the sort where the patient seems to have read a medical textbook, as the history and symptoms fit so neatly with the examination findings. Diagnosis and management are simple, the patient is helped, and I feel useful. An added bonus is that the consultation is likely to be achievable within the allotted time (I might even fit in a cup of tea).

However, especially now that we’ve passed many of general practice’s more predictable elements to other healthcare workers, most of our work isn’t so tidy. Sometimes the symptoms suggest sciatica, but the examination findings are much more in keeping with arthritis (does the patient have both?), or the various elements of a patient’s history don’t seem to fit together to make any physiological or pathological sense.

How we respond to presentations that we don’t immediately understand makes a difference to us and the patient. At my best, I engage with such cases with empathy and enthusiasm, working with the patient to reach a diagnosis. I share my uncertainty and the various possibilities—ranging from the “likely and harmless” to the “unlikely but definitely needs excluding”—and discuss how we might investigate or who we might ask for advice. As long as I attend to the patient’s immediate needs (time off work, analgesia, or other symptom control) I can demonstrate that, although I don’t know the answers, I do take the questions seriously. When I’m stressed and rushed, it takes effort to muster this enthusiasm and suppress that feeling of “heart sink” that comes when I feel as though I have little to offer.

Long covid throws this problem into sharp relief. Two million patients in the UK have persistent symptoms after covid infection, and 1.2 million have had these symptoms for over a year.1 Fatigue, breathlessness, muscle ache, and loss of smell are the most common symptoms, but there’s a very long list of possible effects involving almost every system and part of the body.2 Currently, we have an incomplete understanding of what’s happening and little in the way of effective treatment.

As the vast majority of people in the UK have now had at least one episode of covid infection, a real concern is that patients or their doctors may attribute symptoms too readily to long covid and so miss other conditions.3 In our practice we’ve recently diagnosed two cases of lung cancer, which might have presented sooner if the persistent cough and malaise hadn’t been misinterpreted as the lingering effects of covid infection. When the patient opens with, “I’ve not been right ever since I had covid,” we must take care to exclude other diagnoses before we blame the virus.
publisher: British Medical Journal Publishing Group
section: Opinion
PMID: 36944437

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Szabo, Sandor; Zayachkivska, Oksana; Hussain, Alamdar; Muller, Veronika

What is really ‘Long COVID’?

https://doi.org/10.1007/s10787-023-01194-0

Published

25-Mar-23

Article

https://doi.org/10.1007/s10787-023-01194-0

The previous acute respiratory diseases caused by viruses originating from China or the middle east (e.g., SARS, MERS) remained fast developing short diseases without major sequalae or any long-lasting complications. The new COVID-19, on the other hand, not only that it rapidly spread over the world, but some patients never fully recovered or even if they did, a few weeks later started to complain not only of shortness of breath, if any, but general weakness, muscle pains and ‘brain fog’, i.e., fuzzy memories. Thus, these signs and symptoms were eventually labelled ‘long COVID’, for which the most widely used definition is ‘new signs and symptoms occurring 4–8 weeks after recovering from acute stage of COVID-19’. The other most frequent manifestations associated with long COVID include headache, loss of memory, smell and of hair, nausea, and vomiting. Thus, long COVID is not a simple disease, but complex disorder of several organ systems malfunctioning; hence, it is probably more appropriate to call this a syndrome. The pathogenesis of long COVID syndrome is poorly understood, but initial and persistent vascular endothelial injury that often triggers the formation of microthrombi that if dislodged as emboli, damage several organs, especially in the brain, heart and kidney, by creating microinfarcts. The other major contributory mechanistic factor is the persistent cytokine storm that may last longer in long COVID patients than in others, probably triggered by aggregates of SARS-Co-2 discovered recently in the adrenal cortex, kidney and brain. The prevalence of long COVID is relatively high, e.g., initially varied 3–30%, and recent data indicate that 2.5% of UK population suffers from this syndrome, while in the US 14.7% of acute COVID-19 patients continued to have symptoms longer than 2 months. Thus, the long COVID syndrome deserves to be further investigated, both from clinical and basic research perspectives.

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Morgan, Jules

Long COVID? What is that?

https://doi.org/10.1016/S2213-2600(23)00126-1

Published

24-Mar-23

Article

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00126-1/fulltext

Some people do not believe long COVID (also known as post-COVID-19 condition) is real. In fact, patients have reported that there are even doctors who sit in this camp, who might dismiss their symptoms as psychosomatic, or do not know how to recognise or treat long COVID. It is complicated, even for researchers. People might not have had severe symptoms when infected with SARS-CoV-2 virus, they might be young, without a significant medical history or risk factors. Although studies suggest around 10–20% of individuals who did not have severe acute disease might develop long COVID symptoms, the number of people who are facing long-term effects is hard to quantify. There are common symptoms, such as fatigue, shortness of breath on exertion, and cognitive and executive dysfunction, but the list is extensive and changeable, and many experience problems with multiple organs. People with long COVID are asking “Why me?” and “When will it end?”
publisher: Elsevier
PMID: 36972723

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Sherif, Zaki A; Gomez, Christian R; Connors, Thomas J; Henrich, Timothy J; Reeves, William Brian; RECOVER Mechanistic Pathway Task Force

Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC)

https://doi.org/10.7554/eLife.86002

Published

22-Mar-23

Review

https://doi.org/10.7554/eLife.86002

COVID-19, with persistent and new onset of symptoms such as fatigue, post-exertional malaise, and cognitive dysfunction that last for months and impact everyday functioning, is referred to as Long COVID under the general category of post-acute sequelae of SARS-CoV-2 infection (PASC). PASC is highly heterogenous and may be associated with multisystem tissue damage/dysfunction including acute encephalitis, cardiopulmonary syndromes, fibrosis, hepatobiliary damages, gastrointestinal dysregulation, myocardial infarction, neuromuscular syndromes, neuropsychiatric disorders, pulmonary damage, renal failure, stroke, and vascular endothelial dysregulation. A better understanding of the pathophysiologic mechanisms underlying PASC is essential to guide prevention and treatment. This review addresses potential mechanisms and hypotheses that connect SARS-CoV-2 infection to long-term health consequences. Comparisons between PASC and other virus-initiated chronic syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome will be addressed. Aligning symptoms with other chronic syndromes and identifying potentially regulated common underlining pathways may be necessary for understanding the true nature of PASC. The discussed contributors to PASC symptoms include sequelae from acute SARS-CoV-2 injury to one or more organs, persistent reservoirs of the replicating virus or its remnants in several tissues, re-activation of latent pathogens such as Epstein–Barr and herpes viruses in COVID-19 immune-dysregulated tissue environment, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation dysregulation, dysfunctional brainstem/vagus nerve signaling, dysautonomia or autonomic dysfunction, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. The individualized nature of PASC symptoms suggests that different therapeutic approaches may be required to best manage specific patients.

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Tsampasian, Vasiliki; Elghazaly, Hussein; Chattopadhyay, Rahul; Debski, Maciej; Naing, Thin Kyi Phyu; Garg, Pankaj; Clark, Allan; Ntatsaki, Eleana; Vassiliou, Vassilios S.

Risk Factors Associated With Post−COVID-19 Condition: A Systematic Review and Meta-analysis

https://doi.org/10.1001/jamainternmed.2023.0750

Published

23-Mar-23

Systematic review and meta-analysis

https://doi.org/10.1001/jamainternmed.2023.0750

Key Points
Question Which individuals are at risk of developing post−COVID-19 condition (PCC)?

Findings This systematic review and meta-analysis of 41 studies including 860 783 patients found that female sex, older age, higher body mass index, smoking, preexisting comorbidities, and previous hospitalization or ICU admission were risk factors significantly associated with developing PCC, and that SARS-CoV-2 vaccination with 2 doses was associated with lower risk of PCC.

Meanings The findings of this systematic review and meta-analysis provide a profile of the characteristics associated with increased risk of developing PCC and suggest that vaccination may be protective against PCC.

Abstract
Importance Post−COVID-19 condition (PCC) is a complex heterogeneous disorder that has affected the lives of millions of people globally. Identification of potential risk factors to better understand who is at risk of developing PCC is important because it would allow for early and appropriate clinical support.

Objective To evaluate the demographic characteristics and comorbidities that have been found to be associated with an increased risk of developing PCC.

Data sources Medline and Embase databases were systematically searched from inception to December 5, 2022.

Study Selection The meta-analysis included all published studies that investigated the risk factors and/or predictors of PCC in adult (≥18 years) patients.

Data Extraction and Synthesis Odds ratios (ORs) for each risk factor were pooled from the selected studies. For each potential risk factor, the random-effects model was used to compare the risk of developing PCC between individuals with and without the risk factor. Data analyses were performed from December 5, 2022, to February 10, 2023.

Main Outcomes and Measures The risk factors for PCC included patient age; sex; body mass index, calculated as weight in kilograms divided by height in meters squared; smoking status; comorbidities, including anxiety and/or depression, asthma, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, immunosuppression, and ischemic heart disease; previous hospitalization or ICU (intensive care unit) admission with COVID-19; and previous vaccination against COVID-19.

Results The initial search yielded 5334 records of which 255 articles underwent full-text evaluation, which identified 41 articles and a total of 860 783 patients that were included. The findings of the meta-analysis showed that female sex (OR, 1.56; 95% CI, 1.41-1.73), age (OR, 1.21; 95% CI, 1.11-1.33), high BMI (OR, 1.15; 95% CI, 1.08-1.23), and smoking (OR, 1.10; 95% CI, 1.07-1.13) were associated with an increased risk of developing PCC. In addition, the presence of comorbidities and previous hospitalization or ICU admission were found to be associated with high risk of PCC (OR, 2.48; 95% CI, 1.97-3.13 and OR, 2.37; 95% CI, 2.18-2.56, respectively). Patients who had been vaccinated against COVID-19 with 2 doses had a significantly lower risk of developing PCC compared with patients who were not vaccinated (OR, 0.57; 95% CI, 0.43-0.76).

Conclusions and Relevance This systematic review and meta-analysis demonstrated that certain demographic characteristics (eg, age and sex), comorbidities, and severe COVID-19 were associated with an increased risk of PCC, whereas vaccination had a protective role against developing PCC sequelae. These findings may enable a better understanding of who may develop PCC and provide additional evidence for the benefits of vaccination.

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Jackson, Sally

Online Health Communities in Controversy over ME/CFS and Long Covid

https://doi.org/10.47368/ejhc.2023.203

Published

24-Mar-23

Article

https://ejhc.org/article/view/3559

The condition known variously as myalgic encephalomyelitis, chronic fatigue syndrome, or ME/CFS has been steeped in controversy for 40 years or more. Long Covid, first noticed and named in 2020, has become entangled with the ME/CFS controversy because of striking similarities in the experiences of patients suffering from the two illnesses. Online health communities (OHCs) have played central roles in both controversies, but these are not the kinds of roles that have been so well-documented in prior literature. While prior research has established many ways in which participation in an OHC may benefit or otherwise affect community members themselves, this essay focuses on how OHCs contribute to positional shifts in health controversies that involve other communities as well. Using a framework for understanding health controversies as argumentative polylogues, I show that OHCs arguing with other players have made contributions that are both effective in gaining ground for the OHCs' own goals and in elevating the overall quality of the debate. Further, in some cases these contributions have been so innovative as to suggest surprising future trajectories for OHCs.

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Pan, Daniel; Pareek, Manish

Toward a Universal Definition of Post–COVID-19 Condition—How Do We Proceed?

https://doi.org/10.1001/jamanetworkopen.2023.5779

Published

5-Apr-23

Article

https://doi.org/10.1001/jamanetworkopen.2023.5779

Finally, in our opinion, future observational studies that aim to investigate the prevalence and natural history of PCC must be longitudinal in nature, so that repeated measurements of symptoms and different outcomes are taken over time. Ideally, such studies should also include patients whose symptoms and signs that did not have a disproportionately severe effect on a patient’s quality of life, far beyond what is expected from their initial infection, as a control group so that comparisons can be made to the PCC group, Clearly, PCC is not just signs and symptoms that occur following COVID-19; it is disproportionately prolonged and severe signs and symptoms, indicative of the development of a new condition following an initial infection.

Once the natural history of PCC is better defined, treatment for PCC can then be developed more effectively. PCC is a syndrome, not a single disease. Indeed, PCC is most likely to be a manifestation of multiple diseases mediated by different mechanisms. For example, while fatigue and dyspnea may be highly prevalent in patients with PCC, some patients acquire these symptoms due to the development of interstitial lung disease following severe infection; others will have the same symptoms but no clear organ dysfunction and perhaps even mild initial infection. A therapy that could potentially help to improve the symptoms of patients with COVID-19 interstitial lung disease must only be assessed in a trial that targets that subgroup of patients with PCC; if the therapy was targeted at everyone with PCC, where COVID-19 related interstitial lung disease only constitutes a small proportion, the therapy will show no effect and important resources that were used to perform the trial will be wasted.

Chaichana and colleagues2 found that much more can be done in the design of future studies for patients with PCC. Observational studies aiming to define the natural history of PCC must be longitudinal in design, with accurately defined control groups, that are inclusive of everyone who has, and will be affected by, the syndrome. These studies must have one unified definition and title of the same syndrome, that is agreed on by patients, clinicians, and academics alike, and have the potential to identify different disease phenotypes. Clinical trials of interventions or drug therapy for PCC can then be tailored specifically to the patients with the characteristics that make a disease phenotype, rather than everyone with PCC syndrome. To treat PCC, we must first develop better studies that can identify what PCC actually is. Only then can we have a more personalized and effective approach to the treatment of those affected.

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Saunders, Chloe; Sperling, Søren; Bendstrup, Elisabeth

A new paradigm is needed to explain long COVID

https://doi.org/10.1016/S2213-2600(22)00501-X

Published

1-Feb-23

Article

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00501-X/fulltext

We now have adequate data to describe the core symptoms, course, and prevalence of long COVID. Core symptoms include breathing difficulties, muscle pain, anosmia, tingling extremities, and general tiredness. Many of these symptoms are non-specific, but are seen at higher rates in people with long COVID than would be expected in the general population.1
Despite intense research in the area, no clear pathogenesis has been established that can explain the full range of long COVID symptoms.2 Studies have found that patients' symptoms in many cases persist beyond the point at which pathophysiological observations can adequately explain them.3 Symptoms not adequately explained by traditional medical research paradigms are common across medicine and represent the most common diagnosis in some specialities.4 Persistent symptoms are highly prevalent in the general population5 and even within well-defined disease cohorts there is often little association between objective pathophysiology and symptom burden.6
• View related content for this article

Coherent and relatable explanatory models are key to engaging patients with appropriate treatment, and act as a model to guide research. This need for explanatory models in long COVID invites various responses. The first response is to continue a search for an all-encompassing pathophysiological mechanism. The second response is to pursue a personalised medicine approach through attempts to cluster clinical phenotypes. We propose a third response that allows for a more complex understanding of the reciprocal relationships between triggers, conditioning mechanisms, and symptoms. Long COVID could be explained as an embodied condition with heterogeneous biological, psychological (experiential), and social (or environmental) factors integrated in complex relationships (figure).
These complex relationships in symptom generation and persistence have been most extensively researched by those working in the field of functional disorders.7 Specific linear causal processes within the organs and tissues are not able to explain all physical suffering. For some conditions, it is necessary to approach treatment holistically rather than on an individual pathophysiological basis. Effective treatments and rehabilitation approaches for functional disorders are known,8 and many of them are already employed in long COVID clinics. However, explicit explanatory models that address the need for a multidisciplinary and integrated treatment provision are key to better clinical services. Poorly integrated explanatory models contribute to poor care and stigma for people who are ill in these specific ways.
In summary, we highly welcome research into the cellular and physiological mechanisms behind persistent symptoms, including post-viral fatigue. However, it is increasingly clear that simple, causative relationships between pathophysiology and symptoms inadequately explain many diseases and chronic health conditions, including long COVID. There is an available body of literature on the multiple factors involved in the generation, perception, and persistence of functional symptoms, and models through which to integrate these. We are moving into a new era in long COVID research and treatment that would benefit from an integrated paradigm through which to understand human illness. We suggest it is time to break taboos based on a dualistic understanding of physical versus mental illness and bring in existing knowledge about functional somatic symptoms to provide improved explanations and treatments.
publisher: Elsevier
PMID: 36620963

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Cornish, Flora; Stelson, Elisabeth A.

Concerns regarding a suggested long COVID paradigm

https://doi.org/10.1016/S2213-2600(23)00095-4

Published

1-Apr-23

Article

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00095-4/fulltext

In Chloe Saunders and colleagues’ Comment,1 they recommend a model (which they term new) in which biological, social, experiential, and psychological factors interact to cause long COVID (also known as post-COVID-19 condition). To us—public health scholars with lived experience of post-COVID-19 condition—the model appears indistinguishable from old biopsychosocial models. For decades, such models have been misused to inaccurately characterise similar conditions, such as myalgic encephalomyelitis (also known as chronic fatigue syndrome), as rooted in patients’ own maladaptive psychological processes.2 The authors claim that a merit of their model is its ability to engage patients. We dispute this claim. Insisting on psychological and social origins of the disease is more likely to disengage patients. We thus caution respiratory medical colleagues against adopting language that treats the psychological as causal.
To engage patients, a patient-centred perspective, rather than a physician-centred perspective, calls for listening to patients’ experience. Saunders and colleagues’ model suggests that societal “illness narratives” contribute to patients’ maladjusted thinking (eg, “catastrophising” or “illness perceptions”) and behaviour (“avoidant illness behaviours”), thereby causing their symptoms. However, this does not match patients’ experiences, in which symptoms precede the development of illness narratives. Patients typically report surprise and bafflement at their post-COVID-19 condition symptoms, often believing themselves recovered before having recurrent or new symptoms.3 The very counterintuitive post-exertional malaise (ie, onset of symptoms 24–48 h after overexertion) is very common in post-COVID-19 condition. Patients report wanting and trying to return to daily activities, only to be prevented—contrary to their expectations—by the delayed exacerbation of symptoms.4 In short, the temporal ordering of post-COVID-19 condition events are entirely at odds with the claim that “illness narratives” are causal. This mismatch with patients’ experience is unlikely to engage them.
Further, people with post-COVID-19 condition report that some of their greatest challenges in securing clinical, workplace, and family and friend support lies in the dismissal of their condition, reinforced by assumptions that their symptoms are self-generated.5 Even if this is not the intention, biopsychosocial-type models are easily understood as blaming patients’ faulty thinking.
We support holistic care but suggest that health professionals can address psychological and social aspects of managing post-COVID-19 condition without needing to make unsubstantiated claims about causes. We recommend clinicians critically reflect on how their own causal models—which are themselves “illness narratives”—contribute to public misunderstanding of post-COVID-19 condition. Health professionals’ illness narratives should support rather than blame patients.
publisher: Elsevier
PMID: 36997264

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Schwendinger, Fabian; Knaier, Raphael; Schmidt-Trucksäss, Arno

Concerns regarding a suggested long COVID paradigm

https://doi.org/10.1016/S2213-2600(23)00094-2

Published

1-Apr-23

Article

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00094-2/fulltext

We read with great interest the Comment by Chloe Saunders and colleagues1 that suggested a new paradigm to explain long COVID (also known as post-COVID-19 condition) as an embodied condition with heterogeneous biological, psychological, and social factors that might be interrelated.
We value the proposal of transitioning towards an individualised approach for the treatment of patients with post-COVID-19 condition. Due to the multifaceted nature of the condition,2 the universal treatment principle is clearly obsolete in these patients. Incorporating information on experiential, psychological, and social factors in addition to biological findings could be beneficial in providing integral treatment.1
• View related content for this article

However, we are afraid the Comment by Saunders and colleagues and the advocated paradigm could be misinterpreted by some readers. The common misconception that post-COVID-19 condition is largely psychological or a consequence of deconditioning is still widely circulating in the general population and even among some professionals. We thus highlight several shortcomings regarding the biological factors in Saunder and colleagues’ main figure and add relevant evidence that could aid the adequate interpretation of their article.
Figure thumbnail fx1
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Copyright © 2023 Picture Alliance/Getty Images
Besides those presented in the authors’ main figure, there are indeed important additional factors that have been suggested as contributing to post-COVID-19 condition, including (but not limited to) viral persistence,3 systemic inflammation,3 endothelial dysfunction and vascular damage,3 microclotting,3 mitochondrial dysfunction,4 and altered microbiome.3 These findings have been supported by numerous studies to date; however, these studies must be confirmed through further investigation. All these potential pathophysiological mechanisms should be considered when aiming to explain post-COVID-19 condition in an individual.
The authors also present deconditioning as a biological conditioning mechanism for post-COVID-19 condition. Deconditioning is often incorrectly described as the main mechanism of exercise intolerance—a symptom that is frequently present in these patients.5 A review of 32 studies performing cardiopulmonary exercise testing in patients who had had COVID-19 showed that peripheral, followed by cardiovascular, factors and lung diffusion limitations are central to low cardiorespiratory fitness and exercise intolerance.5 Deconditioning should thus be seen as a consequence of persistent organ limitations that prevent the patients from being physically active.5
We hope this correspondence will support the integral model proposed by Saunders and colleagues1 and contribute to the adequate interpretation of their article.
publisher: Elsevier
PMID: 36997262

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Palen, Jenny van der

Concerns regarding a suggested long COVID paradigm

https://doi.org/10.1016/S2213-2600(23)00088-7

Published

1-Apr-23

Article

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00088-7/fulltext#%20

Upon reading Chloe Saunders and colleagues’ Comment,1 it is striking how this new paradigm is essentially the old paradigm for medically unexplained symptoms and contested illnesses.2 The authors advance an alleged philosophical problem they call “taboos based on a dualistic understanding of physical versus mental illness”. They assert such “Poorly integrated explanatory models contribute to poor care and stigma for people who are ill in these specific ways.”
For the sake of argument, let us consult the lemma dualism: “In the philosophy of mind, dualism is the theory that the mental and the physical—or mind and body or mind and brain—are, in some sense, radically different kinds of things. Because common sense tells us that there are physical bodies, and because there is intellectual pressure towards producing a unified view of the world, one could say that materialist monism is the ‘default option’.”3
• View related content for this article

If monism is the default option, pushback against implicitly systemic “dualistic understanding”1 is a non sequitur. In actuality, what Saunders and colleagues seem to oppose is divergence of care pathways across the salient care needs of patients. Although their explanatory model is agnostic on this point, the authors assert some patients “are ill in these specific ways” that demand integrated care—specifically, “effective treatments and rehabilitation approaches for functional disorders”. In effect, this routes patients who are ill in these specific (ie, non-specific) ways along a specific care pathway to specific clinical services and obscures their care needs.
Hand poked on a row of wooden dominoes, with the words “COVID19” on the first piece and the words “LONG COVID” on subsequent pieces.
View Large Image
Copyright © 2023 Jikaboom/Getty Images
This paradigm promotes “a non-dualistic approach” to justify special pleading for patients who are allegedly ill in these ontologically distinct but vague ways4 (unlike patients well served by “a dualistic understanding”1). When the authors argue an explanatory model of long COVID (also known as post-COVID-19 condition) cannot succeed “on an individual pathophysiological basis alone” but necessitates “social, experiential, and psychological factors”, they ostensibly subscribe to a pluralistic understanding. However, treatment provision is narrowly defined according to their fixed understanding.
An integrated model of post-COVID-19 condition that a priori rejects “simple, causative relationships between pathophysiology and symptoms”, insistent on analysing it as a multifactorial clinical entity with non-linear causal processes, flouts basic principles of parsimony, saliency,5 and incommensurability. Successful integration of epistemically distinct domains, by a single field (of functional disorders), no less, is an extraordinary claim. The authors seem content to endorse an evidence base that has historically failed to deliver on that claim.
publisher: Elsevier
PMID: 36997263

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Saunders, Chloe; Sperling, Søren; Bendstrup, Elisabeth

Concerns regarding a suggested long COVID paradigm – Authors' reply

https://doi.org/10.1016/S2213-2600(23)00087-5

Published

1-Apr-23

Article

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00087-5/fulltext

We thank the authors of these three helpful responses to our previously published Comment.1 We welcome Fabian Schwendinger and colleagues highlighting some important factors related to the ongoing immune response that we did not expand upon and for introducing the microbiome. Knowing which factors are necessary and sufficient to understand and treat long COVID (also known as post-COVID-19 condition) across the spectrum is an important goal of a research programme. An exploratory model is needed as the starting point of such a research programme, but scientific models are updated as research progresses.2 Our simple assertion is that post-COVID-19 condition has features of complex illness, best understood by models that can integrate illness mechanisms across domains. There are, of course, existing paradigms that address the complexity of human illness.3, 4 We suggest a paradigm capable of modelling complexity to how we think about post-COVID-19 condition.
We understand the concerns of Jenny van der Palen about the historical insufficiency of similarly motivated attempts. However, we cautiously suggest that this is a different moment in history. Advancements in the past 20 years in the science of causal inference promise improved computational models of complexity.5 Such approaches are a route towards personalised precision interventions for complex and heterogeneous illnesses. To benefit, post-COVID-19 condition research must equip itself with a model that can integrate the diverse factors that research is revealing to be meaningful in post-COVID-19 condition, and investigate the likely nature of these relationships,6 without creating a model of redundant complexity. Potential illness mechanisms might be held in balance proportionally to their promise to deliver treatment interventions, as well as on the basis other pragmatic criteria.7 We also suggest that it is equally important to understand how illness mechanisms relate to each other as it is to isolate individual causes. Logic suggests it is at the crossroads of systems, where maintaining reciprocal relationships between illness mechanisms have established themselves, that one will find the most effective interventions.8
• View related content for this article

Taking up just on piece of this complex puzzle, we echo Schwendinger and colleagues that cardiorespiratory deconditioning should not be considered the sole cause of exercise intolerance in post-COVID-19 condition.9 Considering the mutually interlocking interactions of illness mechanisms when they occur in the body, it becomes clear that limits of tolerance will not be the same for everyone. Some people will have scarred lungs, whereas others might have developed dysautonomia, mitochondrial changes, or microclots. On top of this, people could have neuroimmune changes strongly altering their responses into one of constant and perpetual illness.10 At the same time, movement-based therapies might be considered as working at the crossroads of multiple pathophysiological processes seen in post-COVID-19 condition.11, 12, 13, 14
In the clinic, different combinations of illness mechanisms (with complex interrelationships) will be relevant for different individuals. As highlighted by Flora Cornish and colleagues in their response, the explanation for symptoms that is co-constructed between a patient and a clinician must relate to the individual's specific symptoms and lived experience, if it is to engage the patient in treatment. We strongly echo Cornish and colleagues that clinicians should not consider only the psychological or social origins of complex illnesses, especially if this is used to dismiss, discharge, or otherwise discriminate against patients. When integrative models of illness are misused to justify blaming patients for their symptoms, this is a misunderstanding of the complex interactions that occur between body, mind, and environment.
The shared wish of most health-care professionals, patients, and researchers is that effective treatment and rehabilitation options are developed and made available to help people with post-COVID-19 condition. However, there is a lot at stake in getting these conversations right. In research, models of illness that integrate complexity can paradoxically provide simpler explanations of findings, if they provide a more accurate mirror to the reality of biological functioning.2 In the clinic, our experience is that when integrative explanations are co-constructed with patients, this can clarify—rather than obscure—care needs and expand therapeutic options.
publisher: Elsevier
PMID: 36997265

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Verduzco-Gutierrez, Monica

Sequelae of COVID-19 and the need for Post-COVID Rehabilitation

https://doi.org/10.1016/j.pmr.2023.03.001

Published

30-Mar-23

Article

https://www.pmr.theclinics.com/article/S1047-9651(23)00017-7/fulltext

The COVID-19 pandemic is defining for our generation. The pandemic has had an unprecedented impact on every aspect of our lives. It has not only affected patients, particularly those from marginalized communities, highlighting healthcare disparities, but has also had long lasting effects on the healthcare workforce for generations to come.
One area that has emerged as a significant concern is the growing number of persons who are acquiring new disabilities and therefore there is a need for care from a multidisciplinary team, inclusive of Physical Medicine and Rehabilitation specialists to address those needs throughout the healthcare continuum.
This edition of PM&R Clinics explores the various ways in which the pandemic has led to the emergence of new disabilities and how these challenges have been addressed by physical medicine and rehabilitation specialists and their colleagues via post-COVID rehabilitation. We address the impacts of SARS-CoV-2 infection on a person’s health in this edition of PM&R Clinics. These impacts range from acute tissue damage and critical illness polyneuromyopathy in hospitalized patients to the development of Long COVID or post-acute sequelae of SARS-CoV-2 (PASC) in individuals with mild disease. The pandemic also disrupted healthcare services and rehabilitation programs, often making it more difficult for patients to access healthcare, and this will be addressed as well. The pandemic also showed us the need for prehabilitation services, and this is also discussed.
A comprehensive understanding of the impact of COVID-19 on individuals who are acquiring new disabilities and have a need for post-COVID rehabilitation is provided by a series of expert authors who have delivered quality care on the front lines, in clinics, and rehabilitation centers. Long COVID, thought to impact 10 to 20 percent of those who had COVID-19, will be the defining illness of our generation. This series offers guidance and recommendations for healthcare professionals to care for persons who may have new challenges and disabilities due to PASC, and ensure they patients have the necessary support and resources to adapt and thrive.
publisher: Elsevier

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Xiao, Weijun; Liu, Xiaoyang; Wang, Hao; Huang, Yiman; Dai, Zhenwei; Si, Mingyu; Fu, Jiaqi; Chen, Xu; Jia, Mengmeng; Leng, Zhiwei; Cui, Dan; Mak, Winnie W. S.; Dong, Liming; Su, Xiaoyou

Mediating role of resilience in the relationship between COVID-19 related stigma and mental health among COVID-19 survivors: a cross-sectional study

https://doi.org/10.1186/s40249-023-01074-3

Published

28-Mar-23

Study

https://doi.org/10.1186/s40249-023-01074-3

Background
The global coronavirus disease 2019 (COVID-19) has caused many negative effects on physical and mental health of patients who have survived COVID-19. Apart from some long-lasting physical sequelae, those COVID-19 survivors are also suffering stigma and discrimination at different levels around the world. The current study aims to assess the role resilience played in stigma and mental disorders among COVID-19 survivors.

Methods
The cross-sectional study was carried out among former COVID-19 patients in Jianghan District (Wuhan, China) from June 10 to July 25, 2021. The demographic questions, the Impact of Events Scale-Revised, the Generalized Anxiety Disorder Questionnaire, the Patient Health Questionnaire, the Resilience Style Questionnaire and the Short Version of COVID-19 Stigma Scale of 12 items were used to collect relevant information of the participants. Descriptive analyses, Pearson correlation analysis and Structural Equation Modeling were used to make data description and analysis.

Results
A total of 1541 out of 1601 COVID-19 survivors (887 females and 654 males) were included in the analysis. Perceived stigma of those COVID-19 survivors correlates significantly with anxiety (r = 0.335, P < 0.001), depression (r = 0.325, P < 0.001) and post-traumatic stress disorder (PTSD) (r = 0.384, P < 0.001). It has a direct effect on COVID-19 survivors’ anxiety (β = 0.326, P < 0.001), depression (β = 0.314, P < 0.001), PTSD (β = 0.385, P < 0.001) and their resilience (β = − 0.114, P < 0.01). Resilience partially mediated the association between perceived stigma and anxiety (β = 0.020, P < 0.01), depression (β = 0.020, P < 0.01), and PTSD (β = 0.014, P < 0.01) among COVID-19 survivors.

Conclusion
Stigma has a significant negative impact on mental health, while resilience plays a mediator role in the relationship between stigma and mental health among COVID-19 survivors. Based on our study, we suggested that when designing psychological interventions for COVID-19 survivors, consideration should be taken into account to reduce stigma and improve resilience.

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Katz, Nicole B.; Hunter, Tracey L.; Flores, Laura E.; Silver, Julie K.

Addressing Rehabilitation Healthcare Disparities During the COVID-19 Pandemic and Beyond

https://doi.org/10.1016/j.pmr.2023.03.005

Published

30-Mar-23

Review

https://www.pmr.theclinics.com/article/S1047-9651(23)00021-9/fulltext

Key Points
•There are disproportionately higher rates of infection, severe illness, and hospitalization from acute COVID-19 infection in people from racial/ethnic minority groups as compared to White/Caucasian individuals, which likely attributes to inequitable post-acute sequelae SARS-CoV-2 and rehabilitation needs.
•Individuals with disabilities have been adversely impacted by the COVID-19 pandemic and require specialized rehabilitation treatment plans.
•Telemedicine should be further explored as a modality to increase accessibility of healthcare to historically and socially marginalized and underrepresented populations (e.g., individuals with disabilities, people who identify with race/ethnic minority groups, and pediatric, elderly, pregnant people).Publisher: Elsevier

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Cimolai, Nevio

The Ambiguity of Using the Long COVID Diagnosis

Published

26-Apr-23

Article

https://www.cmaj.ca/content/ambiguity-using-long-covid-diagnosis, /content/ambiguity-using-long-covid-diagnosis

The Practice synopsis from Quinn et al. illustrates practical ambiguities for clinical diagnoses of Long COVID.[1] The WHO case definition, if taken literally, would encompass very broad and indeed overwhelming working bases for inclusion. Of past, overarching clinical and syndromic definitions often add to more confusion than not.[2] Outside of attributing disease to former laboratory diagnoses of SARS-CoV-2 infection, there is little other tangible diagnostic confirmation that can be credible at this time. There is the likelihood that overinclusion or overgeneralization has potential to muddle study of those that may particularly have bonafide virus-specific long-term illness. It would be more likely that confounders can be partially avoided by study of more well-defined post-infectious clinical entities rather than using overly inclusive WHO or similar definitions.
Furthermore, the authors, although accepting lack of diagnostic standards, continue to project potentially confusing practice points. For example, while citing meta-analysis to project global prevalence, it would be well-known that such meta-analysis would be jeopardized by variable definitions used throughout the world for Long COVID. While expressing doubts of definitive diagnostic criteria, the authors nevertheless venture into mechanisms of pathogenesis (Practice point #3). It is yet another distant projection that any veritable such illness would be affecting most organs (Practice point #4). In Practice point #5, the authors reference Huang et al.[3] The latter details outcomes of patients who were infected during January-May, 2020, and yet it is well-known that laboratory diagnostic methods for confirming infection, which are not concretely detailed in the paper, were largely being honed in January-February of that same year even in China.
Whether direct experience or published science, it is well-established that prolonged or intense illnesses can be associated with extended recoveries after non-COVID-19 viral or non-viral illnesses. In context, use of ‘Long COVID’ terminology fares at first glance to be no better than designation of the same as ‘post-viral syndrome’. There is jeopardy in having patients expect, and physicians believe, that any form of prolonged illness after COVID-19 should necessarily extract preliminary cause-and-effect relationship. Assessment and management should be focused on primary care since most patients with Long COVID diagnoses as is will convalesce over weeks to months and with return to pre-infection functioning without much intervention if any. That should not discourage academic and specialist study that could perhaps confirm more precise and differentiated long-term COVID-related diseases whether attributable directly to virus or associated viral illness pathology. Until further elucidated, the issue of ‘d

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Szabo, Sandor; Gyires, Klara; Zayachkivska, Oksana

Introduction to the ‘long COVID’ special issue

https://doi.org/10.1007/s10787-023-01197-x

Published

1-Apr-23

Article

https://doi.org/10.1007/s10787-023-01197-x

Acute respiratory diseases caused by viruses or bacteria usual get resolved quickly and patients recover fast. Namely, even people who survived MERS or the first SARS, caused by another coronavirus, recovered after intensive treatment, and no subacute or chronic sequalae of the disease were noted. COVID-19, induced by the SARS-CoV-2 virus, behaved very differently, since about 3–30% of acute COVID-19 patients complain about shortness of breath, fatigue, headache, ‘brain fog’, muscle weakness and general fatigue more than 4 weeks after the initial infection. Or, even worse, some patients who have completely recovered show up with these nonspecific, multiorgan signs and symptoms. More alarming is the recent recognition that vaccination against SARS-CoV-2 does not offer protection, i.e., it may reduce the risk of long COVID, but it does not eliminate it. Needless to say, the pathogenesis of long COVID is poorly understood and no specific treatment is available; only symptomatic relief that makes both patients and clinicians very frustrated.

Because of the wide-spread, worldwide occurrence of the long COVID syndrome (LCS), we organized in 2022 a symposium on long COVID, with international participation, at the Hungarian Academy of Sciences. We then asked participants to prepare short original or review articles on their presentations that appear in this special issue of Inflammopharmacology, thanks to its forward looking editor Prof. Kim Rainsford. Namely, despite of our insufficient understanding of the molecular and cellular mechanisms of LCS, we know that it is a multiorgan inflammatory process, perpetuated by cytokine storm and complicated by multiorgan thrombi. due to the damage of vascular endothelial cells. By disseminating information about the manifestation, clinical and public health aspects, as well as the ‘little we know’ about the pathogenesis of LCS, thanks to the generosity of Inflammopharmacology, we hope this publication will not only generate more data collection about the clinical manifestations and epidemiology of long COVID, but also stimulate more clinical and basic research to better understand and treat more successfully this new syndrome of the twenty-first century.

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Aquino, Katherine C.; Jarrow, Jane; Vance, Lisa; Rei-Skoff, Ametrine Elizabeth

Long COVID as a chronic illness: giving credibility to support students

https://doi.org/10.1002/dhe.31478

Published

26-Mar-23

Article

https://onlinelibrary.wiley.com/doi/abs/10.1002/dhe.31478

The SARS-CoV-2 virus continues to account for millions of short- and long-term conditions that can impact an individual's cognition, breathing, and digestion. Specifically, Long COVID creates long-term health problems, diagnosable if COVID-19 symptoms present after an initial infection. Approximately 15% of U.S. adults with a prior positive COVID-19 diagnosis experience Long COVID symptoms. (See Roy H. Perlis, et al, Prevalence and Correlates of Long COVID Symptoms Among US Adults, 5 JAMA NETW OPEN 10 (October 27, 2022).) Long COVID is plaguing individuals’ ability to return to their typical functioning, including their ability to return to work. (See Katie Bach, New Data Shows Long Covid Is Keeping as Many as 4 Million People Out of Work, BROOKINGS INSTITUTE (August 24, 2022) (https://brook.gs/3xktTkC).)

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Zang, Chengxi; Zhang, Yongkang; Xu, Jie; Bian, Jiang; Morozyuk, Dmitry; Schenck, Edward J.; Khullar, Dhruv; Nordvig, Anna S.; Shenkman, Elizabeth A.; Rothman, Russell L.; Block, Jason P.; Lyman, Kristin; Weiner, Mark G.; Carton, Thomas W.; Wang, Fei; Kaushal, Rainu

Data-driven analysis to understand long COVID using electronic health records from the RECOVER initiative

https://doi.org/10.1038/s41467-023-37653-z

Published

7-Apr-23

Study

https://www.nature.com/articles/s41467-023-37653-z

Recent studies have investigated post-acute sequelae of SARS-CoV-2 infection (PASC, or long COVID) using real-world patient data such as electronic health records (EHR). Prior studies have typically been conducted on patient cohorts with specific patient populations which makes their generalizability unclear. This study aims to characterize PASC using the EHR data warehouses from two large Patient-Centered Clinical Research Networks (PCORnet), INSIGHT and OneFlorida+, which include 11 million patients in New York City (NYC) area and 16.8 million patients in Florida respectively. With a high-throughput screening pipeline based on propensity score and inverse probability of treatment weighting, we identified a broad list of diagnoses and medications which exhibited significantly higher incidence risk for patients 30–180 days after the laboratory-confirmed SARS-CoV-2 infection compared to non-infected patients. We identified more PASC diagnoses in NYC than in Florida regarding our screening criteria, and conditions including dementia, hair loss, pressure ulcers, pulmonary fibrosis, dyspnea, pulmonary embolism, chest pain, abnormal heartbeat, malaise, and fatigue, were replicated across both cohorts. Our analyses highlight potentially heterogeneous risks of PASC in different populations.

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Espín, Estefanía; Yang, Chengliang; Shannon, Casey P.; Assadian, Sara; He, Daniel; Tebbutt, Scott J.

Cellular and molecular biomarkers of long COVID: a scoping review

https://doi.org/10.1016/j.ebiom.2023.104552

Published

1-May-23

Review

https://www.sciencedirect.com/science/article/pii/S2352396423001172

Background
Long-COVID (LC) encompasses diverse symptoms lasting months after the initial SARS-CoV-2 infection. Symptoms can be debilitating and affect the quality of life of individuals with LC and their families. Although the symptoms of LC are well described, the aetiology of LC remains unclear, and consequently, patients may be underdiagnosed. Identification of LC specific biomarkers is therefore paramount for the diagnosis and clinical management of the syndrome. This scoping review describes the molecular and cellular biomarkers that have been identified to date with potential use for diagnosis or prediction of LC.
Methods
This review was conducted using the Joanna Briggs Institute (JBI) Methodology for Scoping Reviews. A search was executed in the MEDLINE and EMBASE databases, as well as in the grey literature for original studies, published until October 5th, 2022, reporting biomarkers identified in participants with LC symptoms (from all ages, ethnicities, and sex), with a previous infection of SARS-CoV-2. Non-English studies, cross-sectional studies, studies without a control group, and pre-prints were excluded. Two reviewers independently evaluated the studies, extracted population data and associated biomarkers.
Findings
23 cohort studies were identified, involving 2163 LC patients [median age 51.8 years, predominantly female sex (61.10%), white (75%), and non-vaccinated (99%)]. A total of 239 candidate biomarkers were identified, consisting mainly of immune cells, immunoglobulins, cytokines, and other plasma proteins. 19 of the 239 candidate biomarkers identified were evaluated by the authors, by means of receiver operating characteristic (ROC) curves.
Interpretation
Diverse cellular and molecular biomarkers for LC have been proposed. Validation of candidate biomarkers in independent samples should be prioritized. Modest reported performance (particularly in larger studies) suggests LC may encompass many distinct aetiologies, which should be explored e.g., by stratifying by symptom clusters and/or sex.
Funding
Dr. Tebbutt has received funding from the Canadian Institutes of Health Research (177747) to conduct this work. The funding source was not involved in this scoping review, or in the decision to submit this manuscript for publication.

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Majumder, Rajib; Ghosh, Sanmitra; Singh, Manoj K.; Das, Arpita; Roy Chowdhury, Swagata; Saha, Abinit; Saha, Rudra P.

Revisiting the COVID-19 Pandemic: An Insight into Long-Term Post-COVID Complications and Repurposing of Drugs

https://doi.org/10.3390/covid3040037

Published

1-Apr-23

Review

https://www.mdpi.com/2673-8112/3/4/37

SARS-CoV-2 is a highly contagious and dangerous coronavirus that has been spreading around the world since late December 2019. Severe COVID-19 has been observed to induce severe damage to the alveoli, and the slow loss of lung function led to the deaths of many patients. Scientists from all over the world are now saying that SARS-CoV-2 can spread through the air, which is a very frightening prospect for humans. Many scientists thought that this virus would evolve during the first wave of the pandemic and that the second wave of reinfection with the coronavirus would also be very dangerous. In late 2020 and early 2021, researchers found different genetic versions of the SARS-CoV-2 virus in many places around the world. Patients with different types of viruses had different symptoms. It is now evident from numerous case studies that many COVID-19 patients who are released from nursing homes or hospitals are more prone to developing multi-organ dysfunction than the general population. Understanding the pathophysiology of COVID-19 and its impact on various organ systems is crucial for developing effective treatment strategies and managing long-term health consequences. The case studies highlighted in this review provide valuable insights into the ongoing health concerns of individuals affected by COVID-19.

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Tsuchida, Tomoya; Yoshimura, Naohito; Ishizuka, Kosuke; Katayama, Kohta; Inoue, Yoko; Hirose, Masanori; Nakagama, Yu; Kido, Yasutoshi; Sugimori, Hiroki; Matsuda, Takahide; Ohira, Yoshiyuki

Five cluster classifications of long COVID and their background factors: A cross-sectional study in Japan

https://doi.org/10.1007/s10238-023-01057-6

Published

7-Apr-23

Study

https://doi.org/10.1007/s10238-023-01057-6

Purpose
The long-term symptoms of coronavirus disease 2019 (COVID-19), i.e., long COVID, have drawn research attention. Evaluating its subjective symptoms is difficult, and no established pathophysiology or treatment exists. Although there are several reports of long COVID classifications, there are no reports comparing classifications that include patient characteristics, such as autonomic dysfunction and work status. We aimed to classify patients into clusters based on their subjective symptoms during their first outpatient visit and evaluate their background for these clusters.

Methods
Included patients visited our outpatient clinic between January 18, 2021, and May 30, 2022. They were aged ≥ 15 years and confirmed to have SARS-CoV-2 infection and residual symptoms lasting at least 2 months post-infection. Patients were evaluated using a 3-point scale for 23 symptoms and classified into five clusters (1. fatigue only; 2. fatigue, dyspnea, chest pain, palpitations, and forgetfulness; 3. fatigue, headache, insomnia, anxiety, motivation loss, low mood, and forgetfulness; 4. hair loss; and 5. taste and smell disorders) using CLUSTER. For continuous variables, each cluster was compared using the Kruskal–Wallis test. Multiple comparison tests were performed using the Dunn’s test for significant results. For nominal variables, a Chi-square test was performed; for significant results, a residual analysis was conducted with the adjusted residuals.

Results
Compared to patients in other cluster categories, those in cluster categories 2 and 3 had higher proportions of autonomic nervous system disorders and leaves of absence, respectively.

Conclusions
Long COVID cluster classification provided an overall assessment of COVID-19. Different treatment strategies must be used based on physical and psychiatric symptoms and employment factors.

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Thompson, S.

Employers must provide better support to workers with long covid

https://doi.org/10.1136/bmj.p800

Published

6-Apr-23

Article

https://www.bmj.com/content/381/bmj.p800

People with long covid need to be believed, trusted, and offered flexible workplace adaptations by employers, writes S Thompson
There are shining examples of success among people who’ve returned to work with long covid—where employees have been offered slow, flexible phased returns that take months or years, and where the goal is to balance work, life, and illness. In these cases, employees are at the centre of conversations about returning to work and are asked what they need and can honestly manage—not on their best day, but on their worst. Strong collaboration is needed between employee, occupational health, HR, and the employer to make this happen. Any relapses in an employee’s symptoms should be met with swift action to reduce their hours and responsibilities, in turn reducing the length and impact of the relapse.

Finding yourself unexpectedly limited physically and/or cognitively because of long covid can be devastating. Yet being unable to work—either because you can’t or your employer refuses to make the adjustments that would allow you to—is a further blow, both financially and emotionally. The key to supporting this group of people is shunning stigma and embracing an open culture of understanding and trust.

Many people with long covid are frontline health and other key workers who worked through the worst of the covid-19 pandemic. That they should now be disbelieved or dismissed, instead of supported, is a great injustice. Recognising that each person with long covid is unique, believing them, and personalising adaptations to their symptoms can make it possible, practical, rewarding, and fulfilling for people with long covid to work—it just needs the support of employers to make it happen.
publisher: British Medical Journal Publishing Group
section: Opinion
PMID: 37024137

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Karpman, Michael; Zuckerman, Stephen; Morriss, Sarah

Health Care Access and Affordability Among US Adults Aged 18 to 64 Years With Self-reported Post–COVID-19 Condition

https://doi.org/10.1001/jamanetworkopen.2023.7455

Published

10-Apr-23

Study

https://doi.org/10.1001/jamanetworkopen.2023.7455

Key Points
Question Are adults with post–COVID-19 condition (PCC) more likely than other adults to experience health care access and affordability challenges?

Findings In this survey study of 9484 US adults aged 18 to 64 years, a statistically higher rate of respondents with self-reported PCC did not obtain needed health care in the past year because of cost compared with adults without PCC. Adults with PCC were also more likely to have unmet needs because of difficulties getting timely appointments or health plan authorization, among other challenges with health care institutions or health insurance.

Meaning These findings suggest that improved health care access for adults with PCC may require developing clinical protocols and addressing insurance-related barriers.

Abstract
Importance Many US adults report having post–COVID-19 condition (PCC), but little is known about their access to health care.

Objective To estimate the association of PCC with access and affordability challenges among US adults aged 18 to 64 years.

Design, Setting, and Participants This survey study used data from the Health Reform Monitoring Survey, a probability-based internet survey conducted June 17 to July 5, 2022. Participants included a nationally representative sample of 9484 US adults ages 18 to 64 years drawn from the Ipsos KnowledgePanel.

Main Outcomes and Measures Self-reported PCC was defined as experiencing symptoms more than 4 weeks after first having COVID-19 that were not explained by another condition or factor. Access and affordability outcomes included having a usual place of care; forgoing care in the past 12 months because of costs, difficulty finding clinicians, or difficulty using health insurance; having problems paying family medical bills in the past 12 months; and having past-due medical debt.

Results Of 19 162 panel members recruited for the survey, 9599 individuals completed the survey (completion rate, 50.1%) and 9484 respondents were included in the final analytic sample (4720 females [50.6%, weighted]; mean [SD] age, 41.0 [13.5] years). A total of 3382 respondents (36.4%; 95% CI, 34.7%-38.2%) reported ever being diagnosed with COVID-19, among whom, 833 respondents (22.5%; 95% CI, 20.9%-24.2%) reported currently having PCC. After adjustment for differences in demographic, health, and geographic characteristics, adults with PCC were more likely than 2549 adults with a COVID-19 diagnosis but no report of PCC and 6102 adults never diagnosed with COVID-19 to report unmet health care needs in the past 12 months because of the following challenges: costs (27.0%; 95% CI, 23.2%-30.7% vs 18.3%; 95% CI, 15.9%-20.7% and 17.5%; 95% CI, 15.4%-19.6%) and difficulties finding clinicians accepting new patients (16.4%; 95% CI, 14.3%-18.4% vs 10.1%; 95% CI, 8.8%-11.5% and 10.7%; 95% CI, 9.6%-11.8%), getting a timely appointment (22.0%; 95% CI, 19.3%-24.8% vs 14.4%; 95% CI, 13.2%-15.7% and 13.9%; 95% CI, 12.9%-14.8%), and getting health plan care authorization (16.6%; 95% CI, 14.6%-18.6% vs 10.8%; 95% CI, 9.6%-12.1% and 10.3%; 95% CI, 9.4%-11.2%) (P < .001 for all comparisons).

Conclusions and Relevance This study found that adults aged 18 to 64 years with PCC were more likely than other adults to have difficulty getting and paying for health care. These findings suggest that policies aimed at improving access and affordability may focus on accelerating development of treatments and clinical guidelines, training clinicians, and addressing insurance-related administrative and cost barriers.

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Ramasamy, Akshara; Wang, Chumeng; Brode, W. Michael; Verduzco-Gutierrez, Monica; Melamed, Esther

Immunologic and Autoimmune Related Sequelae of SARS-CoV-2 infection: Clinical Symptoms and Mechanisms of Disease

https://doi.org/10.1016/j.pmr.2023.04.004

Published

11-Apr-23

Review

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10086105/

The continued Coronavirus Disease 2019 (COVID-19) pandemic has resulted in over 600 million infections worldwide, with 10-30% of patients experiencing post-acute sequelae of SARS-CoV-2 (PASC). Despite initial signs of COVID-19 as a primarily respiratory disease, it has become clear that there is multi-organ dysfunction that can occur both in the acute stage of SARS-CoV-2 infection and PASC. Mechanistically, it is known that SARS-CoV-2 enters cells through an interaction between angiotensin-converting enzyme 2 receptor and SARS-CoV-2 Spike protein and leads to an acute illness that can last between one to four weeks. Less is known about the exact mechanism of PASC, although several proposed possibilities include direct SARS-CoV-2 tissue invasion, persistent inflammation and rise of autoimmunity, as well as potential persistence of SARS-CoV-2 virus or immunogenicity from residual SARS-CoV-2 RNA. Co-morbid conditions such as pulmonary dysfunction, cardiovascular disease, neuropsychiatric conditions, autoimmunity, hypogammaglobulinemia, and cancers likely contribute to presentation and disease outcomes in both acute SARS-CoV-2 infection and PASC. In this review, we compare evolving information on clinical symptoms, pathophysiology, and co-morbid disease risk factors between acute COVID-19 and PASC.

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Abbott, Zachary; Summers, William; Niehaus, William

Fatigue in Postacute Sequelae of COVID-19

https://doi.org/10.1016/j.pmr.2023.04.006

Published

24-Apr-23

Review

https://www.pmr.theclinics.com/article/S1047-9651(23)00029-3/fulltext

Key Points
•
According to recent data from the U.S. Census Bureau and CDC’s National Center for Health Statistics (NCHS), 7.5% or 1 in 13 patients diagnosed with COVID-19 reported long-term symptoms
•
Because of the varied possible etiologies causing PASC symptoms, there does not appear to be a single laboratory evaluation, diagnostic test, or exam finding that will best identify the etiology of PASC symptoms.
•
At this time, there is continued investigation into which medication, therapy program, diet, infusion, or supplement that would best improve PASC symptoms.
Clinics Care Points
•
Collect a detailed fatigue history that includes information on the wide differential diagnoses that can impact PASC symptoms including the endocrinologic (HPA axis, adrenal gland), inflammatory, cardiac, pulmonary, myofascial, neuropsychiatric (including sleep), and gastrointestinal systems
•
If not already completed, perform a general work up that includes complete blood count comprehensive metabolic panel, and measurement of phosphorus, thyroid-stimulating hormone, and C-reactive protein.
•
If needed, refer to clinical sites and providers who have more experience assisting patients with PASC symptoms.
publisher: Elsevier

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Harky, Amer; Ala'Aldeen, Avesta; SundasButt; Duric, Bea; Roy, Sakshi; Zeinah, Mohamed

COVID-19 and Multiorgan Response: The Long-Term Impact

https://doi.org/10.1016/j.cpcardiol.2023.101756

Published

22-Apr-23

Article

https://www.sciencedirect.com/science/article/pii/S0146280623001731

In late December 2019, severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) was discovered following a cluster of pneumonia cases in Wuhan, China. During the early stages of the COVID-19 pandemic in 2020, it was unclear how this virus would manifest into a multiorgan impacting disease. After over 750 million cases worldwide, it has become increasingly evident that SARS-CoV-2 is a complex multifaceted disease we continue to develop our understanding of. The pathophysiology of COVID-19 and how it affects these systems has many theories, ranging from direct viral infection via ACE2 receptor binding, to indirect coagulation dysfunction, cytokine storm, and pathological activation of the complement system. Since the onset of the pandemic, disease presentation, management and manifestation have changed significantly. This paper intends to expand on the long-term impacts of COVID-19 on the cardiovascular, respiratory, urinary, gastrointestinal, and vascular systems of the body and the changes in clinical management. It is evident that the pharmacological, non-pharmacological and psychological management of COVID-19 patients require clearer guidelines to improve the survival odds and long-term clinical outcomes of those presenting with severe disease.

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Regunath, Hariharan; Goldstein, Nir M.; Guntur, Vamsi P.

Long COVID: Where Are We in 2023?

Published

1-Mar-23

Article

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10121126/

The term “COVID Long-Hauler” or “Long-Haul COVID” was first created by patients within few months of the onset of the pandemic.1,2 The first publication of persistent symptoms following acute COVID-19 was from Italy in July 2020, where-in, 143 hospitalized patients with acute COVID-19 between April and May 2020, who eventually tested negative by polymerase chain reaction (PCR), were followed for two months as out-patient and 87.4% had at least one persistent symptom.3 The database study from the United States (U.S.) Department of Veterans Affairs (VA) was the first largest study to show that beyond a month of illness, there existed a higher risk for death and healthcare utilization because of a variety of incident respiratory, cardiovascular, neurological, musculoskeletal, gastrointestinal and metabolic disorders.4 Subsequently, multiple other observational studies have been published.5–10 The systematic reviews that followed, were limited by the low quality of such studies, lack of standardized definition and representative biologic markers for the different organ systems involved as a part of this syndrome.

To date, “long COVID” remains loosely defined by the Centers for Disease Control and Prevention (CDC) as new-onset, persistent or evolving symptoms that linger beyond four weeks following recovery from a documented acute COVID illness or diagnosis, and characterized by persistent physical or mental health issues.11 The World Health Organization (WHO) uses a longer interval of 12 weeks in the absence of an alternative explanation or diagnosis.12, 13 Consensus continues to be lacking for a unified definition due to wide variations in study criteria, measures, and quality.14 Long COVID, post-COVID conditions, post-acute sequelae of SARS CoV-2 (PASC), chronic COVID-19, ongoing symptomatic COVID-19, post-COVD-19 persistent symptoms, and post COVID-19 syndrome are all merely different terms for a set of continued symptoms that linger after recovery from acute illness. Table 1 displays the different terms, definitions still in use as proposed by organizations and website references.14, 15 Clinically useful and meaningful definitions based on the organ system of greatest involvement, or prolonged manifestations from initial illness (e.g. post-ARDS, lack of pulmonary involvement, minimal URI involvement) are yet to be sorted out.

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Lippi, Giuseppe; Henry, Brandon; Favresse, Julien; Plebani, Mario

Addressing standardized definitions of post-COVID and long-COVID

https://doi.org/10.1515/cclm-2023-0390

Published

19-Apr-23

Article

https://www.degruyter.com/document/doi/10.1515/cclm-2023-0390/html

There is still large confusion and open debate as to what should be defined as a “pathological continuum of symptoms after recovering from an acute SARS-CoV-2 infection”, including confusion over appropriate terminology, such as differentiating between “post-COVID” and “long-COVID”. We are hence providing here a tentative (operative) definition, where we suggest to define “post-COVID” as continuation of signs, symptoms or even radiologic/laboratory abnormalities of an initial SARS-CoV-2 infection, irrespective of their duration, whilst we prefer to reserve the definition of “long-COVID” to those people with persistence of signs, symptoms or even radiologic/laboratory abnormalities of an initial SARS-CoV-2 infection for more than 3 months. We hope that these definitions could help harmonize the classification of patients with any type of post-COVID condition for both clinical and research purposes.

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Lenz, Christian; Slack, Mary P.E; Shea, Kimberly M.; Reinert, Ralf René; Taysi, Bülent N.; Swerdlow, David L.

Long-Term effects of COVID-19: a review of current perspectives and mechanistic insights

https://doi.org/10.1080/1040841X.2023.2190405

Published

19-Apr-23

Review

https://doi.org/10.1080/1040841X.2023.2190405

Although SARS-CoV-2, responsible for COVID-19, is primarily a respiratory infection, a broad spectrum of cardiac, pulmonary, neurologic, and metabolic complications can occur. More than 50 long-term symptoms of COVID-19 have been described, and as many as 80% of patients may develop ≥1 long-term symptom. To summarize current perspectives of long-term sequelae of COVID-19, we conducted a PubMed search describing the long-term cardiovascular, pulmonary, gastrointestinal, and neurologic effects post-SARS-CoV-2 infection and mechanistic insights and risk factors for the above-mentioned sequelae. Emerging risk factors of long-term sequelae include older age (≥65 years), female sex, Black or Asian race, Hispanic ethnicity, and presence of comorbidities. There is an urgent need to better understand ongoing effects of COVID-19. Prospective studies evaluating long-term effects of COVID-19 in all body systems and patient groups will facilitate appropriate management and assess burden of care. Clinicians should ensure patients are followed up and managed appropriately, especially those in at-risk groups. Healthcare systems worldwide need to develop approaches to follow-up and support patients recovering from COVID-19. Surveillance programs can enhance prevention and treatment efforts for those most vulnerable.

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Zhang, Harrison G.; Honerlaw, Jacqueline P.; Maripuri, Monika; Samayamuthu, Malarkodi Jebathilagam; Beaulieu-Jones, Brendin R.; Baig, Huma S.; L’Yi, Sehi; Ho, Yuk-Lam; Morris, Michele; Panickan, Vidul Ayakulangara; Wang, Xuan; Weber, Griffin M.; Liao, Katherine P.; Visweswaran, Shyam; Tan, Bryce W. Q.; Yuan, William; Gehlenborg, Nils; Muralidhar, Sumitra; Ramoni, Rachel B.; Kohane, Isaac S.; Xia, Zongqi; Cho, Kelly; Cai, Tianxi; Brat, Gabriel A.

Potential pitfalls in the use of real-world data for studying long COVID

https://doi.org/10.1038/s41591-023-02274-y

Published

13-Apr-23

Article

https://www.nature.com/articles/s41591-023-02274-y

A further challenge is the definition of cohorts of individuals with long COVID, as the syndrome is defined by a time to presentation and therefore requires an index date from which to observe clinical outcomes. The index date is usually an initial infection date, which may become increasingly difficult to ascertain with the use of at-home testing, the results of which are inconsistently reported in EHRs. Researchers should therefore carry out routine quality controls (such as checking the time period between initial infection and input of the ICD-10 code for long COVID), to better understand the biases present in the data. Researchers should also allow for some flexibility in defining index dates, such as considering an infection time period rather than a single date, which would help to account for delays in billing or data processing.

Researchers must remain cognizant of potential biases in patient selection in real-world data; using visits to a long-COVID clinic as a proxy for true disease status is problematic. We found that, on average, only 24.0% of patients assigned the U09.9 code visited a long-COVID clinic, suggesting that the majority of patients sampled were being coded by physicians who do not work at these clinics5. Among patients who met the WHO definition of long COVID, an average of just 35.6% visited a long-COVID clinic, suggesting that many patients are not being seen at these specialty care facilities5.

Studies should also account for differential data density and healthcare utilization. We found that individuals who visited a long-COVID clinic were, on average, annotated with more new-onset conditions when compared with individuals who never visited a long-COVID clinic5. Physicians working at long-COVID clinics could be more experienced with the syndrome and therefore document the disease more thoroughly. This contributes to a difference in data density and granularity, which can confound findings if not properly addressed.

Studies of long COVID using real-world data must be based on robust and comprehensive clinical data sets. The incorporation of narrative data obtained using natural-language-processing techniques should better capture symptoms, and researchers should take care when using only the ICD-10 code or a visit to a long-COVID clinic as surrogates for disease status.

Computational phenotypes (in which data elements are combined, using machine-learning algorithms, to describe a particular disorder) have the potential to account for the longitudinal persistence of symptoms while avoiding the misattribution of conditions that existed prior to initial infection9. Semi-supervised machine-learning algorithms are resistant to some of these challenges, and so may be powerful tools to capture complex underlying temporal patterns in the data using a small number of manually curated labels. Rule-based algorithms may be less suited for the inherent complexity of long COVID10.

Real-world data have an important role in supporting research into long COVID, but these pitfalls should be considered so that the most equitable clinical and policy decisions can be informed by population-level studies.
publisher: Nature Publishing Group

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Magnusson, Karin; Turkiewicz, Aleksandra; Flottorp, Signe Agnes; Englund, Martin

Prevalence of long COVID complaints in persons with and without COVID-19

https://doi.org/10.1038/s41598-023-32636-y

Published

13-Apr-23

Study

https://www.nature.com/articles/s41598-023-32636-y

We studied the prevalence and patterns of typical long COVID complaints in ~ 2.3 million individuals aged 18–70 years with and without confirmed COVID-19 in a Nation-wide population-based prospective cohort study in Norway. Our main outcome measures were the period prevalence of single-occurring or different combinations of complaints based on medical records: (1) Pulmonary (dyspnea and/or cough), (2) Neurological (concentration problems, memory loss), and/or (3) General complaints (fatigue). In persons testing positive (n = 75 979), 64 (95% confidence interval: 54 to 73) and 122 (111 to 113) more persons per 10 000 persons had pulmonary complaints 5–6 months after the test compared to 10 000 persons testing negative (n = 1 167 582) or untested (n = 1 084 578), respectively. The corresponding difference in prevalence of general complaints (fatigue) was 181 (168 to 195) and 224 (211 to 238) per 10 000, and of neurological complaints 5 (2 to 8) and 9 (6–13) per 10 000. Overlap between complaints was rare. Long COVID complaints were only slightly more prevalent in persons with than without confirmed COVID-19. Still, long COVID may pose a substantial burden to healthcare systems in the future given the lasting high incidence of symptomatic COVID-19 in both vaccinated and unvaccinated individuals.

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Vasilevskaya, Anna; Mushtaque, Asma; Tsang, Michelle Y.; Alwazan, Batoul; Herridge, Margaret; Cheung, Angela M.; Tartaglia, Maria Carmela

Sex and age affect acute and persisting COVID-19 illness

https://doi.org/10.1038/s41598-023-33150-x

Published

13-Apr-23

Study

https://www.nature.com/articles/s41598-023-33150-x

Long COVID is associated with neurological and neuropsychiatric manifestations. We conducted an observational study on 97 patients with prior SARS-CoV-2 infection and persisting cognitive complaints that presented to the University Health Network Memory Clinic between October 2020 and December 2021. We assessed the main effects of sex, age, and their interaction on COVID-19 symptoms and outcomes. We also examined the relative contribution of demographics and acute COVID-19 presentation (assessed retrospectively) on persistent neurological symptoms and cognition. Among our cohort, males had higher hospitalization rates than females during the acute COVID-19 illness (18/35 (51%) vs. 15/62 (24%); P = .009). Abnormal scores on cognitive assessments post-COVID were associated with older age (AOR = 0.84; 95% CI 0.74–0.93) and brain fog during initial illness (AOR = 8.80; 95% CI 1.76–65.13). Female sex (ARR = 1.42; 95% CI 1.09–1.87) and acute shortness of breath (ARR = 1.41; 95% CI 1.09–1.84) were associated with a higher risk of experiencing more persistent short-term memory symptoms. Female sex was the only predictor associated with persistent executive dysfunction (ARR = 1.39; 95% CI 1.12–1.76) and neurological symptoms (ARR = 1.66; 95% CI 1.19–2.36). Sex differences were evident in presentations and cognitive outcomes in patients with long COVID.

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Srikanth, Sujata; Boulos, Jessica R.; Dover, Tristan; Boccuto, Luigi; Dean, Delphine

Identification and diagnosis of long COVID-19: A scoping review

https://doi.org/10.1016/j.pbiomolbio.2023.04.008

Published

1-Sep-23

Review

https://www.sciencedirect.com/science/article/pii/S0079610723000421

Long COVID-19 (LC-19) is a condition that has affected a high percentage of the population that recovered from the initial disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). LC-19 diagnosis is currently poorly defined because of its variable, multisystem, episodic symptoms, and lack of uniformity in the critical time points associated with the disease. Considering the number of cases, workers’ compromised efficiency or inability to return to their duties can affect organizations and impact economies. LC-19 represents a significant burden on multiple levels and effectively reduces quality of life. These factors necessitate the establishment of firm parameters of diagnoses to provide a foundation for ongoing and future studies of clinical characteristics, epidemiology, risk factors, and therapy. In this scoping review, we conducted a literature search across multiple publication sites to identify papers of interest regarding the diagnosis of LC-19. We identified 225 records of interest and categorized them into seven categories. Based on our findings, there are only 11 original papers that outline the diagnostic process in detail with little overlap. This scoping review highlights the lack of consensus regarding the definition and, thereby, the LC-19 diagnosis processes. Due to no clear directive and considering the many unknowns surrounding the natural history of the disease and further recovery/sequelae from COVID-19, continued discussion and agreement on a definition/diagnosis will help future research and management of these patients.

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Levent-Krauskopff, Sandrine; Guedj, Myriam

Les conséquences psychologiques du COVID long. Effet des incertitudes, des stratégies de coping, du soutien social et de la qualité de vie sur la dépression

https://doi.org/10.1016/j.amp.2023.05.001

Published

13-May-23

Study

https://www.sciencedirect.com/science/article/pii/S0003448723001592

Résumé
Objectifs
De nombreuses personnes ont été infectées par le COVID-19 et pour une minorité d’entre elles, des symptômes multi-systémiques, fluctuants et impactant la qualité de vie, ont persisté au-delà de 20jours. Le COVID long a été d’abord défini par les patients eux-mêmes au printemps 2020 pour décrire leurs parcours de non-récupération. Plus précisément, le COVID long est défini comme « une constellation de symptômes physiques et mentaux qui peut persister ou émerger par la suite, façonnant un syndrome multi-systémique et invalidant, qui varie d’un patient à l’autre et qui fluctue dans le temps ». La persistance des symptômes du COVID, la diminution de la qualité de vie, l’incertitude quant à l’avenir, assorties parfois d’un faible soutien social perçu dans l’entourage médical et personnel, ont pu favoriser la survenue d’un trouble dépressif chez les patients atteints de COVID-long. L’objectif de cette recherche a été d’étudier l’effet des symptômes du COVID-long, des incertitudes et de l’altération de la qualité de vie sur les symptômes anxiodépressifs, tout en identifiant l’impact de variables modératrices comme les stratégies de coping et le soutien social.
Matériel et méthode
Deux cent quatorze participants atteints de COVID long (âgés de 18 à 68 ans, M=44ans, ET=11), dont 93 % de femmes (n=200) et 7 % d’hommes (n=14), ont participé à cette étude quantitative transversale entre les mois d’avril et de juin 2022. Ils ont décrit leurs symptômes et répondu à cinq échelles : l’échelle d’intolérance à l’incertitude (EII), l’échelle des stratégies de coping (WCC), l’échelle de mesure de la qualité de vie (MOS SF-36), l’échelle de soutien social perçu (QSSP), et l’échelle de mesure d’anxiété et de dépression (HADS).
Résultats
Les participants ont déclaré des symptômes de fatigue 91 % (n=171), de perte de concentration 52 % (n=111), de douleurs 51 % (n=110), de troubles du sommeil 49 % (n=104) et des difficultés de mémorisation 41 % (n=88). En comparaison avec la population générale, ils présentaient une qualité de vie dégradée, ainsi que des scores d’anxiété, de dépression et d’intolérance à l’incertitude élevés. Les scores aux stratégies de coping étaient également supérieurs aux normes relatives à la population générale, et ceux de la satisfaction du soutien social étaient généralement bons. Il est également apparu que les variables de l’intolérance à l’incertitude, de la qualité de vie et de la dépression étaient toutes corrélées entre elles. Par ailleurs, l’analyse de régression a permis de mettre en évidence les prédicteurs de la dépression. Ainsi les domaines de la qualité de vie Bien être émotionnel (β=–0,41, t (199)=–6,23, p<0,01) et Fatigue/énergie (β=–0,16, t (199)=–2,83, p<0,01) étaient des prédicteurs négatifs de la dépression, tout comme le score de coping centré sur le problème (β=–0,14, t (199)=–2,84, p<0,05). Les symptômes de la maladie en lien avec les difficultés de concentration (β=0,27, t (199)=5,16, p<0,01) et ceux impactant les projets (β=0,18, t (199)=3,31, p<0,01) étaient quant à eux des prédicteurs positifs de la dépression. Le deuxième constat de cette étude est que les personnes prises en charge spécifiquement pour leur COVID long présentaient des scores significativement moins élevés d’anxiété et d’intolérance à l’incertitude malgré des scores à certaines dimensions de la qualité de vie plus faibles. Également, les personnes prises en charge dans notre étude développaient davantage de stratégies de coping basées sur le problème et déclaraient davantage de disponibilité et de satisfaction liées au soutien social. Enfin, sur le plan de la qualité de vie, la population prise en charge a exprimé une meilleure santé psychique.
Conclusions
L’étude a montré, outre l’influence des symptômes du COVID long, de la qualité de vie, et des stratégies de coping sur les symptômes dépressifs, que la prise en charge spécifique des patients atteints de COVID long semble constituer en elle-même un facteur de protection de la dépression et de l’anxiété. Il apparaît donc essentiel que tout patient présentant un COVID long puisse bénéficier d’une prise en charge pluridisciplinaire spécifique à cette pathologie.
Objectives
Many people were infected by COVID-19 and for a minority of them, symptoms persisted beyond twenty days. These symptoms are multi-systemic, fluctuating, and impact the quality of life. Long COVID was first defined by patients themselves in the spring of 2020 to describe their recovery problems. Specifically, long COVID is defined as “a constellation of physical and mental symptoms which can persist or emerge afterwards, generating a multi-systemic and disabling syndrome, which varies from patient to patient and fluctuates over time”. The persistence of COVID symptoms, the decrease in the quality of life, the uncertainly about the future sometimes accompanied by a low level of social support perceived in the medical and personal entourage may have triggered the occurrence of a depressive disorder in patients with long COVID. The objective of this research was to study the effect of long COVID symptoms, of uncertainty and the impairment of quality of life on the development of depressive symptoms, while identifying the impact of moderating variables such as coping strategies and social support.
Materials and methods
Two hundred and fourteen participants with long COVID (aged 18–68, M=44, SD=11), including 93 % females (n=200) and 7% males (n=14), participated in this cross-sectional quantitative study between the months of April and June 2022. They described their symptoms and responded to five scales: the Evaluation of Intolerance of Uncertainty Scale (EII), the Coping Strategies Checklist (WCC), the Medical Outcome Study Short Form 36-item health survey (MOS SF-36), the Perceived Social Support Questionnaire (QSSP), and the Hospital Anxiety and Depression Scale (HADS).
Results
91% of the participants reported symptoms of fatigue (n=171), 52% a loss of concentration (n=111), 51% pain (n=110), 49 % trouble sleeping (n=104), and 41% memory problems (n=88). Compared with the general population, they presented a poorer quality of life, as well as high scores for anxiety, depression, and intolerance of uncertainty. Scores on coping strategies were also higher than the norms for the general population, and scores on satisfaction with social support were generally good. It was also found that the variables of intolerance of uncertainty, quality of life, and depression all correlated with each other. Furthermore, the regression analysis revealed predictors of depression. The areas of quality of life and emotional well-being (β=–0.41, t(199)=–6.23, P<0.01) and fatigue/energy (β=–0.16, t(199)=–2.83, P<0.01) were negative predictors of depression, as was the problem-focused coping score (β=–0.14, t(199)=–2.84, P<0.05). Symptoms of the disorder related to concentration difficulties (β=0.27, t(199)=5.16, P<0.01) and those impacting projects (β=0.18, t(199)=3.31, P<0.01) were positive predictors of depression. The second finding of this study is that people treated specifically for their long COVID had significantly lower scores for anxiety and intolerance of uncertainty despite lower scores for certain dimensions of quality of life. The individuals who took part in our study also developed more problem-based coping strategies and reported more availability of and satisfaction with social support. Lastly, in terms of quality of life, the treated population expressed better mental health.
Conclusions
The study showed that, in addition to the effects of long COVID symptoms, quality of life, and coping strategies on the onset of symptoms of depression, the specific treatment of patients with long COVID seemed to constitute in itself a protective factor against depression and anxiety. It therefore would seem essential that any patient suffering from long COVID should receive multidisciplinary care specific to this pathology.

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Navarro-Olivos, Efraín; Flores-Vargas, Gilberto; Morales-Reyes, Guadalupe Irazú; Plascencia-Roldán, Jéssica Paola; Gallardo-Luna, María de Jesús; Padilla-Raygoza, Nicolás; Navarro-Olivos, Efraín; Flores-Vargas, Gilberto; Morales-Reyes, Guadalupe Irazú; Plascencia-Roldán, Jéssica Paola; Gallardo-Luna, María de Jesús; Padilla-Raygoza, Nicolás

Post-COVID-19 Condition and Its Presence in Mexico

https://doi.org/10.5772/intechopen.111697

Published

12-May-23

Article

https://www.intechopen.com/online-first/87098

In this chapter, we discuss general information about the post-COVID-19 condition, also known as long COVID. Since it is still under research, many questions remain unanswered. Nevertheless, post-acute complications due to infections have been previously reported for other viruses. Among those complications that remain are anosmia, fatigue, cardiovascular, and pulmonary. The evidence so far suggests that these complications decrease with time. The most worrying persistent symptoms due to COVID-19 are related to neurological damage. Most post-COVID-19 complications can be treated in a standard way, but their impact on life quality is unknown. Finally, we present a rough landscape of long COVID-19 in Mexico and Latin America. More studies are needed to study this condition and its impact on public health.

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Baroni, Carolina; Potito, Jorge; Perticone, María Eugenia; Orausclio, Paola; Luna, Carlos Marcelo

How Does Long-COVID Impact Prognosis and the Long-Term Sequelae?

https://doi.org/10.3390/v15051173

Published

1-May-23

Review

https://www.mdpi.com/1999-4915/15/5/1173

Context: We reviewed what has been studied and published during the last 3 years about the consequences, mainly respiratory, cardiac, digestive, and neurological/psychiatric (organic and functional), in patients with COVID-19 of prolonged course. Objective: To conduct a narrative review synthesizing current clinical evidence of abnormalities of signs, symptoms, and complementary studies in COVID-19 patients who presented a prolonged and complicated course. Methods: A review of the literature focused on the involvement of the main organic functions mentioned, based almost exclusively on the systematic search of publications written in English available on PubMed/MEDLINE. Results: Long-term respiratory, cardiac, digestive, and neurological/psychiatric dysfunction are present in a significant number of patients. Lung involvement is the most common; cardiovascular involvement may happen with or without symptoms or clinical abnormalities; gastrointestinal compromise includes the loss of appetite, nausea, gastroesophageal reflux, diarrhea, etc.; and neurological/psychiatric compromise can produce a wide variety of signs and symptoms, either organic or functional. Vaccination is not associated with the emergence of long-COVID, but it may happen in vaccinated people. Conclusions: The severity of illness increases the risk of long-COVID. Pulmonary sequelae, cardiomyopathy, the detection of ribonucleic acid in the gastrointestinal tract, and headaches and cognitive impairment may become refractory in severely ill COVID-19 patients.

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Szabo, Sandor

The post-COVID stress syndrome: from the three-stage stress response of Hans Selye to COVID-19

https://doi.org/10.1007/s10787-023-01179-z

Published

15-May-23

Review

https://doi.org/10.1007/s10787-023-01179-z

Stress is the nonspecific response of the body to any demand made upon it, as defined by Hans Selye more than 80 years ago, based on his animal experiments at McGill University in Montreal, Canada. By emphasizing ‘nonspecificity’ he tried to underline that stress response is elicited my several factors, like nowadays in COVID-19, e.g., fear of infection, social isolation, death in family, loss of employment, etc. Thus, COVID-19 has been the largest new human stressor in the twenty-first century. Selye’s studies in rats also revealed 3 stages of stress response: the short initial “alarm reaction” is followed by a longer “stage of resistance”, associated with increased levels of corticosterone that is often terminated by a “stage of exhaustion”, referring to an exhausted adrenal cortex when the secretion of glucocorticoids drops. Fast forward, that is exactly what has been documented in severe cases of infections caused by the SARS-CoV-2 virus: in hospitalized COVID-19 patients initially the blood levels of cortisol not only have been elevated, but only those with high concentration of this natural anti-inflammatory corticosteroid survived vs. those who had low levels of cortisol, suggesting diminished adrenocortical functions. Furthermore, patients with very severe cases of COVID-19 who ended up in intensive care units had significantly low cortisol blood levels, compared to patients with equal severity of diseases due to other causes. Thus, these ‘natural phenomena’ in clinical medicine, unfortunately confirmed Selye’s studies in experimental animals several decades ago. Still, the good news is that astute clinicians empirically recognized this and started to give potent synthetic glucocorticoids such as dexamethasone to severe COVD-19 patients and this beneficial effect of exogenous corticoids has been extensively confirmed in the scientific literature.

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Kamanzi, Patrick; Mulundu, Gina; Mutale, Keagan; Mumba, Chibamba; Ngalamika, Owen

HIV and inflammatory markers are associated with persistent COVID‐19 symptoms

https://doi.org/10.1002/iid3.859

Published

8-May-23

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10165949/

Background
A proportion of COVID19 survivors may present with long‐COVID, which is persistent symptoms lasting four or more weeks post SARS‐CoV‐2 infection. These symptoms may be mild to severe, and may affect different organ‐systems of the body.

Aims
The main objective of this study was to determine the demographic, clinical and immunological factors associated with long COVID.

Materials & Methods
We conducted a nested case control study, with a total of 94 study participants initially included, and 64 participants matched for age and sex for biomarker analyses.

Results
32/94 (34.1%) of all the participants had long COVID. Respiratory symptoms were the most common (59.5%) followed by the musculoskeletal symptoms (28.1%). HIV was an independent predictor of long COVID (adjusted odds ratio = 2.7; p = .037). In all the 64 matched cases and controls, IFN‐β was significantly higher among controls than cases. After stratifying by HIV, IL6 was significantly higher among cases than controls in the HIV‐ group (2.06 vs. 0.81 pg/mL; p = .02). On the other hand, IFN‐β was significantly higher among controls than cases in the HIV+ group (251 vs. 0 pg/mL; p = .01).

Conclusion
HIV infection is a risk factor for long COVID, and inflammatory markers associated with long COVID may be slightly different for HIV− and HIV+ individuals.
PMID: null
PMCID: PMC10165949

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Yang, Chengliang; Zhao, Hedi; Espín, Estefanía; Tebbutt, Scott J.

Association of SARS-CoV-2 infection and persistence with long COVID

https://doi.org/10.1016/S2213-2600(23)00142-X

Published

10-May-23

Article

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00142-X/fulltext

The presented evidence suggests that the duration of SARS-CoV-2 infection in patients can persist considerably longer than suggested by PCR-negative tests on nasopharyngeal swabs or bronchoalveolar lavage fluids. A US study including 40 947 participants with SARS-CoV-2 reinfection (two or more infections), 443 588 participants with a single SARS-CoV-2 infection, and 5 334 729 participants with no SARS-CoV-2 infection indicated that reinfection further increases risks of death, hospitalisation, and sequelae in multiple organ systems in the acute and post-acute phases.14 Persistent low-grade multisystem injury in both adults and children might result from lingering SARS-CoV-2 infection or reinfection. In another study, the circulating SARS-CoV-2 components, spike protein, and viral RNA fragments persisted for up to 1 year or longer after SARS-CoV-2 acute infection in patients with long COVID, whereas these viral components decreased or were totally absent in convalescent patients with COVID-19, as shown by ddPCR and spike protein ELISA techniques.15
These findings provide further evidence that there might be a correlation between the length of time the virus stays in the body and the risk of long COVID (appendix p 1). Therefore, rapid viral elimination in patients with persistent SARS-CoV-2 virus could be crucial. We summarised the approved and ongoing, but unpublished, randomised trials on the nirmatrelvir with ritonavir (a SARS-CoV-2 main protease inhibitor) treatment for long COVID (appendix p 3) or persistence of SARS-CoV-2 in post-COVID-19 patients (appendix p 4) listed on ClinicalTrials.gov. The results of a recent observational study on nirmatrelvir with ritonavir and long COVID are promising and intriguing, and demand further investigation. The use of nirmatrelvir with ritonavir might eliminate viral reservoirs and alleviate long COVID symptoms.
Here we present a pathophysiological model of long COVID based on the persistence of SARS-CoV-2 virus that triggers a dysregulation of the immune system, followed by increased release of inflammatory cytokines and abnormal endothelial damage, ultimately leading to the development of chronic inflammation, vascular damage, hypercoagulability, microthrombosis, and multiorgan symptoms (figure). Anti-SARS-CoV-2 and other applicable therapies might contribute to viral clearance or to the reduction of inflammation to improve long COVID symptoms. Here, we present recommendations and future directions for a more effective response to long COVID (appendix p 5). We believe that a comprehensive understanding of the pathogenesis of long COVID will provide an opportunity for better outcomes for all patients experiencing similar conditions.
publisher: Elsevier
PMID: 37178694

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Voruz, Philippe; Assal, Frédéric; Péron, Julie A

The economic burden of the post-COVID-19 condition: Underestimated long-term consequences of neuropsychological deficits

https://doi.org/10.7189/jogh.13.03019

Published

5-May-23

Article

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10159592/

Thus, it is essential to estimate the economic burden of the post-COVID-19 condition according to its neuropsychological disorders and phenotypes, based on multidisciplinary approaches, and statistically validated simulation analyses, as had been done for other neurological pathologies. The implementation of such interdisciplinary studies for the neuropsychological post-COVID-19 condition could have effects on encouraging the search for the most prominent neuropsychological risk factors on direct and indirect costs (as it has already been done for multiple sclerosis), designing targeted rehabilitation programs (which are currently lacking) based on evidence-based medicine, and developing specific guidelines associating neuropsychological disorders and professional recovery. This would allow employers to reduce the impact of neuropsychological disorders on their employees' productivity and positively impact society by reducing the disability costs of these syndromes and the impact on the patients and their surroundings.

An external file that holds a picture, illustration, etc.
Object name is jogh-13-03019-Fa.jpg
Photo: Anamnesis of a simulated patient suffering from anosognosia following a SARS-CoV-2 infection and schematic explaining potential association between immunological variables and long-term cognitive disorders following a SARS-CoV-2 infection. Source: Extracted from videos produced by the Clinical and Experimental Neuropsychology Laboratory (CENLab) in the framework of the COVID-COG project (NRP 78_Swiss National Science Fondation). Available: https://www.youtube.com/@nrp7854. © CENLab. Used with permission.

Finally, based on patient testimonials, a gap exists between empirical evidence of post-COVID-19 symptoms and the knowledge of health care professionals and economists. The scientific community and civil society must work together to develop effective communication channels based on empirical evidence to ensure clear and unbiased transmission of scientific results to all layers of society (e.g. patients and health care professionals, employers, economic entities, insurers) to mitigate the potential global impact of the neuropsychological post-COVID-19 condition.
PMID: 37141527
PMCID: PMC10159592

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Chen, Benjamin; Julg, Boris; Mohandas, Sindhu; Bradfute, Steven B; RECOVER Mechanistic Pathways Task Force

Viral persistence, reactivation, and mechanisms of long COVID

https://doi.org/10.7554/eLife.86015

Published

4-May-23

Review

https://doi.org/10.7554/eLife.86015

The COVID-19 global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has infected hundreds of millions of individuals. Following COVID-19 infection, a subset can develop a wide range of chronic symptoms affecting diverse organ systems referred to as post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. A National Institutes of Health-sponsored initiative, RECOVER: Researching COVID to Enhance Recovery, has sought to understand the basis of long COVID in a large cohort. Given the range of symptoms that occur in long COVID, the mechanisms that may underlie these diverse symptoms may also be diverse. In this review, we focus on the emerging literature supporting the role(s) that viral persistence or reactivation of viruses may play in PASC. Persistence of SARS-CoV-2 RNA or antigens is reported in some organs, yet the mechanism by which they do so and how they may be associated with pathogenic immune responses is unclear. Understanding the mechanisms of persistence of RNA, antigen or other reactivated viruses and how they may relate to specific inflammatory responses that drive symptoms of PASC may provide a rationale for treatment.

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Yair Mina, Yoshimi Enose-Akahata, Dima A. Hammoud, Anthony J. Videckis, Sandeep R. Narpala, Sarah E. O'Connell, Robin Carroll, Bob C. Lin, Cynthia Chen McMahan, Govind Nair, Lauren B. Reoma, Adrian B. McDermott, Brian Walitt, Steven Jacobson, David S. Goldstein, Bryan R. Smith, Avindra Nath

Deep Phenotyping of Neurologic Postacute Sequelae of SARS-CoV-2 Infection | Neurology Neuroimmunology & Neuroinflammation

https://doi.org/10.1212/NXI.0000000000200097

Published

5-May-23

Study

https://nn.neurology.org/content/10/4/e200097.abstract

Background and Objectives SARS-CoV-2 infection has been associated with a syndrome of long-term neurologic sequelae that is poorly characterized. We aimed to describe and characterize in-depth features of neurologic postacute sequelae of SARS-CoV-2 infection (neuro-PASC).

Methods Between October 2020 and April 2021, 12 participants were seen at the NIH Clinical Center under an observational study to characterize ongoing neurologic abnormalities after SARS-CoV-2 infection. Autonomic function and CSF immunophenotypic analysis were compared with healthy volunteers (HVs) without prior SARS-CoV-2 infection tested using the same methodology.

Results Participants were mostly female (83%), with a mean age of 45 ± 11 years. The median time of evaluation was 9 months after COVID-19 (range 3–12 months), and most (11/12, 92%) had a history of only a mild infection. The most common neuro-PASC symptoms were cognitive difficulties and fatigue, and there was evidence for mild cognitive impairment in half of the patients (MoCA score <26). The majority (83%) had a very disabling disease, with Karnofsky Performance Status ≤80. Smell testing demonstrated different degrees of microsmia in 8 participants (66%). Brain MRI scans were normal, except 1 patient with bilateral olfactory bulb hypoplasia that was likely congenital. CSF analysis showed evidence of unique intrathecal oligoclonal bands in 3 cases (25%). Immunophenotyping of CSF compared with HVs showed that patients with neuro-PASC had lower frequencies of effector memory phenotype both for CD4+ T cells (p < 0.0001) and for CD8+ T cells (p = 0.002), an increased frequency of antibody-secreting B cells (p = 0.009), and increased frequency of cells expressing immune checkpoint molecules. On autonomic testing, there was evidence for decreased baroreflex-cardiovagal gain (p = 0.009) and an increased peripheral resistance during tilt-table testing (p < 0.0001) compared with HVs, without excessive plasma catecholamine responses.

Discussion CSF immune dysregulation and neurocirculatory abnormalities after SARS-CoV-2 infection in the setting of disabling neuro-PASC call for further evaluation to confirm these changes and explore immunomodulatory treatments in the context of clinical trials.

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Perumal, Rubeshan; Shunmugam, Letitia; Naidoo, Kogieleum; Abdool Karim, Salim S.; Wilkins, Dave; Garzino-Demo, Alfredo; Brechot, Christian; Parthasarathy, Sairam; Vahlne, Anders; Nikolich, Janko Ž.

Long COVID: a review and proposed visualization of the complexity of long COVID

https://doi.org/10.3389/fimmu.2023.1117464

Published

20-Apr-23

Review

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10157068/

Post-Acute Sequelae of Severe Acute Respiratory Syndrome Coronavirus – 2 (SARS-CoV-2) infection, or Long COVID, is a prevailing second pandemic with nearly 100 million affected individuals globally and counting. We propose a visual description of the complexity of Long COVID and its pathogenesis that can be used by researchers, clinicians, and public health officials to guide the global effort toward an improved understanding of Long COVID and the eventual mechanism-based provision of care to afflicted patients. The proposed visualization or framework for Long COVID should be an evidence-based, dynamic, modular, and systems-level approach to the condition. Furthermore, with further research such a framework could establish the strength of the relationships between pre-existing conditions (or risk factors), biological mechanisms, and resulting clinical phenotypes and outcomes of Long COVID. Notwithstanding the significant contribution that disparities in access to care and social determinants of health have on outcomes and disease course of long COVID, our model focuses primarily on biological mechanisms. Accordingly, the proposed visualization sets out to guide scientific, clinical, and public health efforts to better understand and abrogate the health burden imposed by long COVID.

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Bergmans, Rachel S.; Chambers-Peeple, Keiyana; Yu, Christine; Xiao, Lillian Z.; Wegryn-Jones, Riley; Martin, Allie; Dell'Imperio, Samantha; Aboul-Hassan, Deena; Williams, David A.; Clauw, Daniel J.; DeJonckheere, Melissa

‘I'm still here, I'm alive and breathing’: The experience of Black Americans with long COVID

https://doi.org/10.1111/jocn.16733

Published

4-May-23

Study

https://onlinelibrary.wiley.com/doi/abs/10.1111/jocn.16733

Aims and Objectives
In this study, we aimed to characterize the impact of long COVID on quality of life and approaches to symptom management among Black American adults.

Background
As a novel condition, qualitative evidence concerning long COVID symptoms and their impact on quality of life can inform the refinement of diagnostic criteria and care plans. However, the underrepresentation of Black Americans in long COVID research is a barrier to achieving equitable care for all long COVID patients.

Design
We employed an interpretive description study design.

Methods
We recruited a convenience sample of 15 Black American adults with long COVID. We analysed the anonymized transcripts from race-concordant, semi-structured interviews using an inductive, thematic analysis approach. We followed the SRQR reporting guidelines.

Results
We identified four themes: (1) The impact of long COVID symptoms on personal identity and pre-existing conditions; (2) Self-management strategies for long COVID symptoms; (3) Social determinants of health and symptom management; and (4) Effects on interpersonal relationships.

Conclusion
Findings demonstrate the comprehensive ramifications of long COVID on the lives of Black American adults. Results also articulate how pre-existing conditions, social risk factors, distrust due to systemic racism, and the nature of interpersonal relationships can complicate symptom management.

Relevance to Clinical Practice
Care approaches that support access to and implementation of integrative therapies may be best suited to meet the needs of long COVID patients. Clinicians should also prioritize eliminating patient exposure to discrimination, implicit bias, and microaggressions. This is of particular concern for long COVID patients who have symptoms that are difficult to objectively quantify, such as pain and fatigue.

No Patient or Public Contribution
While patient perspectives and experiences were the focus of this study, patients were not involved with the design or conduct of the study, data analysis or interpretation, or writing the manuscript.

What does this paper contribute to the wider global clinical community?
This study helps address the underrepresentation of Black Americans in long COVID research.
Findings highlight how pre-existing conditions, social risk factors, distrust due to systemic racism, and the nature of interpersonal relationships can complicate the management of long COVID symptoms.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/jocn.16733

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Petry Moecke, D.m.; Kwong, E.; Yao, J.; Turner, J.; Mclean, K.; den Breejen, S.; Cressman, S.; Camp, P.

Rehabilitation Needs of Adult British Columbians With Long COVID

Published

1-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A2167

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Scholkmann, Felix; May, Christian-Albrecht

COVID-19, post-acute COVID-19 syndrome (PACS, “long COVID”) and post-COVID-19 vaccination syndrome (PCVS, “post-COVIDvac-syndrome”): Similarities and differences

https://doi.org/10.1016/j.prp.2023.154497

Published

1-Jun-23

Review

https://www.sciencedirect.com/science/article/pii/S0344033823001978

Worldwide there have been over 760 million confirmed coronavirus disease 2019 (COVID-19) cases, and over 13 billion COVID-19 vaccine doses have been administered as of April 2023, according to the World Health Organization. An infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to an acute disease, i.e. COVID-19, but also to a post-acute COVID-19 syndrome (PACS, “long COVID”). Currently, the side effects of COVID-19 vaccines are increasingly being noted and studied. Here, we summarise the currently available indications and discuss our conclusions that (i) these side effects have specific similarities and differences to acute COVID-19 and PACS, that (ii) a new term should be used to refer to these side effects (post-COVID-19 vaccination syndrome, PCVS, colloquially “post-COVIDvac-syndrome”), and that (iii) there is a need to distinguish between acute COVID-19 vaccination syndrome (ACVS) and post-acute COVID-19 vaccination syndrome (PACVS) – in analogy to acute COVID-19 and PACS (“long COVID”). Moreover, we address mixed forms of disease caused by natural SARS-CoV-2 infection and COVID-19 vaccination. We explain why it is important for medical diagnosis, care and research to use the new terms (PCVS, ACVS and PACVS) in order to avoid confusion and misinterpretation of the underlying causes of disease and to enable optimal medical therapy. We do not recommend to use the term “Post-Vac-Syndrome” as it is imprecise. The article also serves to address the current problem of “medical gaslighting” in relation to PACS and PCVS by raising awareness among the medical professionals and supplying appropriate terminology for disease.

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Prashar, Jai

Long Covid: conceptualizing the challenges for public health

https://doi.org/10.1093/pubmed/fdac153

Published

2-May-23

Article

https://doi.org/10.1093/pubmed/fdac153

Long Covid has caused significant disruption to public services, economies and population health worldwide, but no single public health approach has proven effective in its management. This essay was the winning entry for the Faculty of Public Health’s Sir John Brotherston Prize 2022.In this essay, I synthesize existing literature on public health policy in long Covid, and discuss the challenges and opportunities posed by long Covid for the public health profession. The utility of specialist clinics and community care, in the UK and internationally, is examined, as well as key outstanding issues relating to evidence generation, health inequality and defining long Covid. I then use this information to inform a simple conceptual model.The generated conceptual model integrates community- and population-level interventions; key areas of identified policy need at both levels include ensuring equitable access to long Covid care, developing screening programmes for high-risk populations, co-production of research and clinical services with patients, and using interventions to generate evidence.Significant challenges remain in the management of long Covid from a public health policy perspective. Multidisciplinary community-level and population-level interventions should be employed with a view to achieving an equitable and scalable model of care.

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El-Maradny, Yousra A; Rubio-Casillas, Alberto; Uversky, Vladimir N; Redwan, Elrashdy M

Intrinsic factors behind long-COVID: I. Prevalence of the extracellular vesicles

https://doi.org/10.1002/jcb.30415

Published

1-May-23

Article

https://doi.org/10.1002/jcb.30415

It can be argued that the severity of COVID-19 has decreased in many countries. This could be a result of the broad coverage of the population by vaccination campaigns, which often reached an almost compulsory status in many places. Furthermore, significant roles were played by the multiple mutations in the body of the virus, which led to the emergence of several new SARS-CoV-2 variants with enhanced infectivity but dramatically reduced pathogenicity. However, the challenges associated with the development of various side effects and their persistence for long periods exceeding 20 months as a result of the SARS-CoV-2 infection, or taking available vaccines against it, are spreading horizontally and vertically in number and repercussions. For example, the World Health Organization announced that there are more than 17 million registered cases of long-COVID (also known as post-COVID syndrome) in the European Union countries alone. Furthermore, by using the PubMed search engine, one can find that more than 10 000 articles have been published focusing exclusively on long-COVID. In light of these enormous and ever-increasing numbers of cases and published articles, most of which are descriptive of the various long-COVID symptoms, the need to know the reasons behind this phenomenon raises several important questions. Is long-COVID caused by the continued presence of the virus or one/several of its components in the recovering individual body for long periods of time, which urges the body to respond in a way that leads to long-COVID development? Or are there some latent and limited reasons related to the recovering patients themselves? Or is it a sum of both? Many observations support a positive answer to the first question, whereas others back the second question but typically without releasing a fundamental reason/signal behind it. Whatever the answer is, it seems that the real reasons behind this widespread phenomenon remain unclear. This report opens a series of articles, in which we will try to shed light on the underlying causes that could be behind the long-COVID phenomenon.

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Tsilingiris, Dimitrios; Vallianou, Natalia G.; Karampela, Irene; Christodoulatos, Gerasimos Socrates; Papavasileiou, Georgios; Petropoulou, Dimitra; Magkos, Faidon; Dalamaga, Maria

Laboratory Findings and Biomarkers in Long COVID: What Do We Know So Far? Insights Into Epidemiology, Pathogenesis, Therapeutic Perspectives and Challenges

https://doi.org/10.20944/preprints202305.1487.v1

Published

22-May-23

Review

https://www.preprints.org/manuscript/202305.1487/v1

Long COVID (LC) encompasses a constellation of long-term symptoms experienced by at least 10% of people after the initial SARS-CoV-2 infection, and so far has affected about 65 million people. The etiology of LC remains unclear; however, many pathophysiological pathways may be involved, including viral persistence; chronic, low grade inflammatory response; immune dysregulation and defective immune response; reactivation of latent viruses; autoimmunity; persistent endothelial dysfunction and coagulopathy; gut dysbiosis; hormonal dysregulation, mitochondrial dysfunction; and autonomic nervous system dysfunction. There are no specific tests for the diagnosis of LC, and clinical features including laboratory findings and biomarkers may not specifically relate to LC. Therefore, it is of paramount importance to develop and validate biomarkers that can be employed for the prediction, diagnosis and prognosis of LC and its therapeutic response. Promising candidate biomarkers that are found in some patients are markers of systemic inflammation including acute phase proteins, cytokines and chemokines; biomarkers reflecting SARS-CoV-2 persistence, reactivation of herpesviruses and immune dysregulation; biomarkers of endotheliopathy, coagulation and fibrinolysis; microbiota alterations; diverse proteins and metabolites; hormonal and metabolic biomarkers; as well as cerebrospinal fluid biomarkers. At present, there are only two reviews summarizing relevant biomarkers; however, they do not cover the entire umbrella of current biomarkers or their link to etiopathogenetic mechanisms, and the diagnostic work-up in a comprehensive manner. Herein, we aim to appraise and synopsize the available evidence on the typical laboratory manifestations and candidate biomarkers of LC, their classification based on main LC symptomatology in the frame of the epidemiological and pathogenetic aspects of the syndrome, and furthermore assess limitations and challenges as well as potential implications in candidate therapeutic interventions.

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Del Carpio-Orantes, Luis; Aguilar-Silva, Andrés

[Intertwined long COVID theories to explain its etiopathogenesis]

Published

2-May-23

Editorial

https://pubmed.ncbi.nlm.nih.gov/37216305/

This editorial lists the main current theories on long COVID, such as the theory of viral persistence and the one of immunothrombosis associated with deregulation of the immune system; it is discussed as well their interrelation, which finally explains the etiopathogenesis and physiopathology of this new syndrome that afflicts the survivors of COVID-19; it is also discussed the link between viral persistence with the formation of amyloid microthrombi based on the hypothesis that the spike protein causes amyloidogenesis, inducing organic chronic damage that will characterize long COVID.

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Mattiuzzi, Camilla; Lippi, Giuseppe

Long COVID: An Epidemic within the Pandemic

https://doi.org/10.3390/covid3050057

Published

1-May-23

Article

https://www.mdpi.com/2673-8112/3/5/57

he use of a uniform, validated and trustworthy definition of the term “long COVID” is certainly the most important issue when it comes to this condition, because the use of different terms can only lead to great confusion. A specific ICD-10-CM (International Classification of Diseases, Tenth Revision, Clinical Modification) code has been developed for recognizing the post-viral clinical syndrome that develops after SARS-CoV-2 infection. Such a diagnosis code U09.9 (post-COVID-19 condition, unspecified) refers specifically to patients presenting suggestive symptoms that are new or persist for at least three months after diagnosis of a SARS-CoV-2 infection and that persist for more than two months without other reasonable explanations [5]. While this definition is certainly reasonable from a clinical standpoint, the spectrum of abnormalities and/or functional impairments that develop after recovering from an acute SARS-CoV-2 infection is broad and not necessarily limited to the—always obvious—clinical signs and symptoms. For this very reason, we recently proposed to also include “radiological/laboratory abnormalities” among the possible changes observed in patients with long COVID [6]. For example, fatigue is a paradigmatic symptom in patients with long COVID (in fact, it is the most common prolonged physical consequence), encompassing a multifactorial pathogenesis [7]. On the other hand, lower than normal hemoglobin levels have been described in a large number of patients after recovering from SARS-CoV-2 infections [8], and this lower hemoglobin level can therefore be considered an important cause of fatigue that could be misrecognized or misdiagnosed, especially when patients have sedentary habits. Nevertheless, anemia should always be considered as a long COVID condition when it develops after an acute SARS-CoV-2 infection. Consequently, anemic patients, whether symptomatic or not, should be classified as having long COVID. Similarly, a variety of fibrotic abnormalities have been reported in patients with long COVID [9]. Although many biological or functional anomalies may remain asymptomatic over a long period of time, they are very likely to become symptomatic with advancing age and physiological decline. Therefore, it seems appropriate to include a set of objectives (i.e., biochemical, metabolic and structural) but still asymptomatic signs of parenchymal injury in the definition of long COVID to allow a more timely and accurate identification of patients at risk of becoming symptomatic in the future.

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Perumal, Rubeshan; Shunmugam, Letitia; Naidoo, Kogieleum; Wilkins, Dave; Garzino-Demo, Alfredo; Brechot, Christian; Vahlne, Anders; Nikolich, Janko

Biological mechanisms underpinning the development of long COVID

https://doi.org/10.1016/j.isci.2023.106935

Published

16-Jun-23

Review

https://www.sciencedirect.com/science/article/pii/S258900422301012X

As COVID-19 evolves from a pandemic to an endemic disease, the already staggering number of people that have been or will be infected with SARS-CoV-2 is only destined to increase, and the majority of humanity will be infected. It is well understood that COVID-19, like many other viral infections, leaves a significant fraction of the infected with prolonged consequences. Continued high number of SARS-CoV-2 infections, viral evolution with escape from post-infection and vaccinal immunity, and reinfections heighten the potential impact of Long COVID. Hence, the impact of COVID-19 on human health will be seen for years to come until more effective vaccines and pharmaceutical treatments become available. To that effect, it is imperative that the mechanisms underlying the clinical manifestations of Long COVID be elucidated. In this article, we provide an in-depth analysis of the evidence on several potential mechanisms of Long COVID and discuss their relevance to its pathogenesis.

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Deng, Mario C.

An exercise immune fitness test to unravel mechanisms of Post-Acute Sequelae of COVID-19

https://doi.org/10.1080/1744666X.2023.2214364

Published

16-May-23

Editorial

https://doi.org/10.1080/1744666X.2023.2214364

Within an integrated cardio-respiratory-immunological fitness concept, sequential blood sampling during a standardized brief exercise regime after recovery from acute COVID-19 can be used to improve the understanding of mechanisms of Post-Acute Sequelae of COVID-19 (PASC) Syndrome. Longitudinal follow-up data based on this protocol is posed to provide fine-granular multi-omic mechanistic and predictive information and may allow for incorporation of quantifiable information in the assessment of the disabling socio-economic impact of PASC. In a broader perspective, this integrated cardio-respiratory-immunological fitness concept may be applicable as a predictive paradigm in other debilitating chronic disease conditions such as heart failure.
publisher: Taylor & Francis
_eprint: https://doi.org/10.1080/1744666X.2023.2214364
PMID: 37190994

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D478

Wang, Siwen; Huang, Tianyi; Weisskopf, Marc G.; Kang, Jae H.; Chavarro, Jorge E.; Roberts, Andrea L.

Multidimensional Sleep Health Prior to SARS-CoV-2 Infection and Risk of Post–COVID-19 Condition

https://doi.org/10.1001/jamanetworkopen.2023.15885

Published

30-May-23

Study

https://doi.org/10.1001/jamanetworkopen.2023.15885

Key Points
Question Is healthy sleep, both before and during the COVID-19 pandemic, prior to SARS-CoV-2 infection, protective against post–COVID-19 condition (PCC)?

Findings In this cohort study of 1979 women who reported testing positive for SARS-CoV-2, adherence to healthy sleep before infection was inversely associated with the risk of PCC. Compared with women who had a prepandemic sleep score of 0 or 1 (least healthy), those who scored 5 (most healthy) had a 30% lower risk of PCC.

Meaning These findings suggest that preinfection healthy sleep may be associated with a substantially decreased risk of PCC, indicating a need for further research on sleep health to prevent or improve symptoms of PCC.

Abstract
Importance The association of multiple healthy sleep dimensions with post–COVID-19 condition (PCC), also known as long COVID, has not been investigated.

Objective To examine whether multidimensional sleep health before and during the COVID-19 pandemic, prior to SARS-CoV-2 infection, was associated with the risk of PCC.

Design, Setting, and Participants This prospective cohort study (2015-2021) included Nurses’ Health Study II participants who reported testing positive (n = 2303) for SARS-CoV-2 infection in a substudy series of COVID-19–related surveys (n = 32 249) between April 2020 and November 2021. After exclusion for incomplete information about sleep health and nonresponse to a question about PCC, 1979 women were included in the analysis.

Exposures Sleep health was measured both before (June 1, 2015, to May 31, 2017) and early (April 1 to August 31, 2020) in the COVID-19 pandemic. Prepandemic sleep score was defined according to 5 dimensions: morning chronotype (assessed in 2015), 7 to 8 hours of sleep per day, low insomnia symptoms, no snoring, and no frequent daytime dysfunction (all assessed in 2017). On the first COVID-19 substudy survey (returned between April and August 2020), average daily sleep duration and sleep quality for the past 7 days were queried.

Main Outcomes and Measures SARS-CoV-2 infection and PCC (≥4 weeks of symptoms) were self-reported during 1 year of follow-up. Comparisons were examined between June 8, 2022, and January 9, 2023, using Poisson regression models.

Results Of the 1979 participants reporting SARS-CoV-2 infection (mean [SD] age, 64.7 [4.6] years; 1979 [100%] female; and 1924 [97.2%] White vs 55 [2.8%] other races and ethnicities), 845 (42.7%) were frontline health care workers, and 870 (44.0%) developed PCC. Compared with women who had a prepandemic sleep score of 0 or 1 (least healthy), those who scored 5 (most healthy) had a 30% lower risk of developing PCC (multivariable-adjusted relative risk, 0.70; 95% CI, 0.52-0.94; P for trend <.001). Associations did not differ by health care worker status. No or little daytime dysfunction prepandemic and good sleep quality during the pandemic were independently associated with a lower risk of PCC (relative risk, 0.83 [95% CI, 0.71-0.98] and 0.82 [95% CI, 0.69-0.99], respectively). Results were similar when PCC was defined as having 8 or more weeks of symptoms or as having ongoing symptoms at the time of PCC assessment.

Conclusions and Relevance The findings indicate that healthy sleep measured prior to SARS-CoV-2 infection, both before and during the COVID-19 pandemic, may be protective against PCC. Future research should investigate whether interventions on sleep health may prevent PCC or improve PCC symptoms.

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Iv, Edward J. Weldon; Hong, Bradon; Hayashi, Jeffrey; Goo, Connor; Carrazana, Enrique; Viereck, Jason; Liow, Kore; Iv, Edward J. Weldon; Hong, Bradon; Hayashi, Jeffrey; Goo, Connor; Carrazana, Enrique; Viereck, Jason; Liow, Kore

Mechanisms and Severity of Exercise Intolerance Following COVID-19 and Similar Viral Infections: A Comparative Review

https://doi.org/10.7759/cureus.39722

Published

30-May-23

Review

https://www.cureus.com/articles/153767-mechanisms-and-severity-of-exercise-intolerance-following-covid-19-and-similar-viral-infections-a-comparative-review

Approximately 19% of the population is suffering from “Long COVID”, also known as post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PASC), which often results in exercise intolerance. As COVID infections continue to be common, studying the long-term consequences of coronavirus disease (COVID) on physical function has become increasingly important. This narrative review will aim to summarize the current literature surrounding exercise intolerance following COVID infection in terms of mechanism, current management approaches, and comparison with similar conditions and will aim to define limitations in the current literature.

Multiple organ systems have been implicated in the onset of long-lasting exercise intolerance post-COVID, including cardiac impairment, endothelial dysfunction, decreased VO2 max and oxygen extraction, deconditioning due to bed rest, and fatigue. Treatment modalities for severe COVID have also been shown to cause myopathy and/or worsen deconditioning. Besides COVID-specific pathophysiology, general febrile illness as commonly experienced during infection will cause hypermetabolic muscle catabolism, impaired cooling, and dehydration, which acutely cause exercise intolerance. The mechanisms of exercise intolerance seen with PASC also appear similar to post-infectious fatigue syndrome and infectious mononucleosis. However, the severity and duration of the exercise intolerance seen with PASC is greater than that of any of the isolated mechanisms described above and thus is likely a combination of the proposed mechanisms. Physicians should consider post-infectious fatigue syndrome (PIFS), especially if fatigue persists after six months following COVID recovery. It is important for physicians, patients, and social systems to anticipate exercise intolerance lasting for weeks to months in patients with long COVID. These findings underscore the importance of long-term management of patients with COVID and the need for ongoing research to identify effective treatments for exercise intolerance in this population. By recognizing and addressing exercise intolerance in patients with long COVID, clinicians can provide proper supportive interventions, such as exercise programs, physical therapy, and mental health counseling, to improve patient outcomes.

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Wu, Qiao

Understanding the burden of post-covid-19 condition

https://doi.org/10.1136/bmj.p932

Published

31-May-23

Editorial

https://www.bmj.com/content/381/bmj.p932

Most patients with persistent covid symptoms after infection recovered between six months and 12 months, but those who did not recover seemed to develop chronic health problems and had very little improvement after month 12. People who were symptomatic at all follow-ups or reported worsened symptoms were more likely to be older and to have pre-existing health problems.

This new study identifies remaining uncertainties and indicates where future research is needed.7 Post-covid-19 condition may induce a wide variety of symptoms, each with independent courses and complex inter-relationships. The study did not aim to evaluate all possible symptoms but surveying for more in future studies might show a more complete picture of the experience of post-covid-19 condition. Another recent The BMJ article3 provides a good example. The authors examined 30 postacute covid symptoms and identified 13 combinations of symptom clusters, including patterns of cluster co-occurrence. The most prevalent symptom cluster observed was fatigue, which frequently co-occurred with neurocognitive impairment and chest symptoms.

An important limitation of Ballouz and colleagues’ study was its focus on only wild type SARS-CoV-2 in an unvaccinated population. Empirical evidence accounting for vaccination status and later virus strains is emerging. For example, another study8 found that vaccinated individuals with breakthrough infections had a significantly lower risk of persistent dyspnea and hair loss 30-90 days after infection when compared with unvaccinated individuals. Additionally, the risks of developing post-covid-19 condition were not significantly different among people who had an infection with wild type, alpha, or delta variants.

Post-covid-19 condition remains a global public health crisis. The design of future treatments, clinical trials, and policy interventions will depend on robust studies based on high quality population level data. Further studies focusing on more recent phases of the pandemic, and accounting for complexities (eg, more virus strains, vaccination statuses, and reinfections), will be particularly valuable. Additionally, in view of the complexity of symptom trajectories and the unique disease burden experienced by each individual patient with post-covid-19 condition, patients should be more closely involved in the design and conduct of these studies going forward.
publisher: British Medical Journal Publishing Group
section: Editorial
PMID: 37257892

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D481

Gallegos, Miguel; Morgan, Melissa L; Burgos-Videla, Carmen; Caycho-Rodríguez, Tomás; Martino, Pablo; Cervigni, Mauricio

The impact of long Covid on people’s capacity to work

https://doi.org/10.1093/annweh/wxad029

Published

30-May-23

Article

https://doi.org/10.1093/annweh/wxad029

This commentary addresses the post-COVID-19 syndrome and its implications for workers’ health. Post-COVID-19 syndrome consists of a set of physiological and psychological symptoms resulting from SARS-CoV-2 (COVID-19) infection, which occur continuously for several weeks or months. Therefore, it is an affectation that has multiple consequences for the recovery of people’s health, and compromises the ability to perform daily activities, including work, whether in person or remotely. Although several studies have been published so far, and several long-term consequences on people’s health have been demonstrated, most have not adequately delved into the implications for the health of workers, their families, and the socioeconomic cost for governments. The aim of this paper is to highlight this public health issue and to encourage more specialized research.

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Thaweethai, Tanayott; Jolley, Sarah E.; Karlson, Elizabeth W.; Levitan, Emily B.; Levy, Bruce; McComsey, Grace A.; McCorkell, Lisa; Nadkarni, Girish N.; Parthasarathy, Sairam; Singh, Upinder; Walker, Tiffany A.; Selvaggi, Caitlin A.; Shinnick, Daniel J.; Schulte, Carolin C. M.; Atchley-Challenner, Rachel; Horwitz, Leora I.; Foulkes, Andrea S.; RECOVER Consortium Authors for the RECOVER Consortium

Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection

https://doi.org/10.1001/jama.2023.8823

Published

25-May-23

Study

https://doi.org/10.1001/jama.2023.8823

Key Points
Question What symptoms are differentially present in SARS-CoV-2–infected individuals 6 months or more after infection compared with uninfected individuals, and what symptom-based criteria can be used to identify postacute sequelae of SARS-CoV-2 infection (PASC) cases?

Findings In this analysis of data from 9764 participants in the RECOVER adult cohort, a prospective longitudinal cohort study, 37 symptoms across multiple pathophysiological domains were identified as present more often in SARS-CoV-2–infected participants at 6 months or more after infection compared with uninfected participants. A preliminary rule for identifying PASC was derived based on a composite symptom score.

Meaning A framework for identifying PASC cases based on symptoms is a first step to defining PASC as a new condition. These findings require iterative refinement that further incorporates clinical features to arrive at actionable definitions of PASC.

Abstract
Importance SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals.

Objective To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections.

Design, Setting, and Participants Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling.

Exposure SARS-CoV-2 infection.

Main Outcomes and Measures PASC and 44 participant-reported symptoms (with severity thresholds).

Results A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months.

Conclusions and Relevance A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

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Gross, Robert; Lo Re, Vincent, III

Disentangling the Postacute Sequelae of SARS-CoV-2: E Unibus Pluram (From One, Many)

https://doi.org/10.1001/jama.2023.8961

Published

25-May-23

Editorial

https://doi.org/10.1001/jama.2023.8961

Early in the COVID-19 pandemic, patients and clinicians reported the persistence of initial symptoms and the onset of new symptoms after the acute phase of SARS-CoV-2 infection, collectively referred to as postacute sequelae of SARS-CoV-2 infection (PASC), or more colloquially called long COVID. Persistent anosmia as well as debilitating physical symptoms, such as chronic cough, gastrointestinal symptoms, fatigue, malaise, myalgias, pain, and lack of clarity of thought (“brain fog”), with or without obvious organ dysfunction, were prominent ailments identified by numerous patients after acute COVID-19. This phenomenon has been a major focus of research. Investigators have sought to determine the pathogenesis of illness with a goal of designing effective interventions to mitigate or resolve the symptoms.

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D484

Clauw, Daniel J.; Calabrese, Leonard

Rheumatology and Long COVID: lessons from the study of fibromyalgia

https://doi.org/10.1136/ard-2023-224250

Published

25-May-23

Article

https://ard.bmj.com/content/early/2023/05/24/ard-2023-224250

Rheumatology, such as other subspecialties, has both a unique perspective to offer as well as an evolving role to play in the global COVID-19 pandemic. Our field has already contributed meaningfully to the development and repurposing of many of the immune-based therapeutics which are now standard treatments for severe forms of the disease as well as to the understanding of the epidemiology, risk factors and natural history of COVID-19 in immune-mediated inflammatory diseases. Still in evolution is our potential to contribute to burgeoning research efforts in the next phase of the pandemic: the syndrome of postacute sequelae of COVID-19 or Long COVID. While our field brings many assets to the study of Long COVID including our expertise in the investigation of chronic inflammation and autoimmunity, our Viewpoint focuses on the strong similarities between fibromyalgia (FM) and Long COVID. While one can speculate on how embracing and confident practising rheumatologists already are regarding these interrelationships, we assert that in the emerging field of Long COVID the potential lessons from the field of fibromyalgia care and research have been underappreciated and marginalised and most importantly now deserve a critical appraisal.

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Faghy, Mark A.; Ashton, Ruth EM; Skipper, Lindsay; Kane, Binita

Long COVID – integrated approaches to chronic disease management?

https://doi.org/10.1016/j.amjmed.2023.04.037

Published

23-May-23

Article

https://www.amjmed.com/article/S0002-9343(23)00332-7/fulltext

This creates an important and timely opportunity to review the approaches taken to support Long COVID patients and more broadly the approach to managing and treating chronic disease. Utilising previous approaches there is a need to develop and implement a substantive pathways that are underpinned with whole system thinking approaches15, and enriched with interdisciplinary consideration and practice. In the context of Long COVID it feels appropriate to convene the relevant specialists to discuss the mechanistic and integrated issues that affect Long COVID patients. Again, acknowledge the broad challenges of Long COVID, it might be prudent to develop assessment services that incorporate objective triaging and monitoring to establish each patient's presentation and increase the understanding between the dynamic and the interrelating cause-effect factors that underpin Long COVID. This information obtained over time (i.e., whilst waiting for an appointment) can be used to direct patients towards the most important appropriate support services. Adopting such approaches will undoubtedly improve patient outcomes and experiences but it represents a step change in thinking that will cause logistical challenges as all parties will need to listen, learn, and collaborate with each other and seek a mutual understanding and approach. Moving towards a coordinated and integrated approach could lead to the design and implementation of efficient and effective services that can address a growing and significant burden to healthcare services which could be considered for adoption more broadly long-term conditions.
Long COVID is an unprecedented burden to healthcare systems and patients worldwide, and the long-term impacts for patients and healthcare providers are still to be realised16. The authors acknowledge that the development of Long COVID services is still very much embryonic, however, services are required at pace and scale to support the >2 million people in the UK and >150 million globally living with persistent and debilitating symptom profiles.
publisher: Elsevier
PMID: 37230401

490

MS01

Angelo Carfì, MD1; Roberto Bernabei, MD1; Francesco Landi,

Persistent Symptoms in Patients After Acute COVID-19

https://doi.org/10.1001/jama.2020.12603

9-Jul-20

Research Letter

https://jamanetwork.com/journals/jama/fullarticle/2768351

A letter in the prestigious JAMA on persistent symptoms after acute covid. Small sample, without control group nor study of confounding factors. his study found that in patients who had recovered from COVID-19, 87.4% reported persistence of at least 1 symptom, particularly fatigue and dyspnea.

Une lettre dans JAMA sur les symptômes persistants après une covid aiguë. Faible échantillon, sans groupe contrôle ni étude de facteurs confondants.

491

MS02

Hassaan Ahmed, Kajal Patel, Darren Greenwood, Stephen Halpin,

LONG-TERM CLINICAL OUTCOMES IN SURVIVORS OF CORONAVIRUS OUTBREAKS AFTER HOSPITALISATION OR ICU ADMISSION: A SYSTEMATIC REVIEW AND META-ANALYSIS OF FOLLOW-UP STUDIES

https://doi.org/10.1101/2020.04.16.20067975

pre-print

https://www.medrxiv.org/content/10.1101/2020.04.16.20067975v1

As a comparison with #COVID19, a *pre-print* meta-analysis (not peer-reviewed) of the long-term sequelae of *hospitalized* patients affected by the 2 coronaviruses SARS (SARS-CoV, 2003) and MERS (MERS-CoV , 2014-2016).

Pour comparaison avec la #COVID__19, une méta-analyse *en pré-print* (non évaluée) des séquelles à long terme des patients *hospitalisés* touchés par les 2 coronavirus SRAS (SARS-CoV, 2003) et MERS (MERS-CoV, 2014-2016).

492

MS03

AXD

Mark W. Tenforde, MD, PhD1; Sara S. Kim, MPH1,2; Christopher J. Lindsell, PhD3

Symptom Duration and Risk Factors for Delayed Return to Usual Health Among Outpatients with COVID-19 in a Multistate Health Care Systems Network — United States, March–June 2020

http://dx.doi.org/10.15585/mmwr.mm6930e1

published opinion

31-Jul-20

Article

https://www.cdc.gov/mmwr/volumes/69/wr/mm6930e1.htm

The US public health agency CDC details the persistence of symptoms of covid (including for young patients) in a study recently published.

In a multistate telephone survey of symptomatic adults who had a positive outpatient test result for SARS-CoV-2 infection, 35% had not returned to their usual state of health when interviewed 2–3 weeks after testing. Among persons aged 18–34 years with no chronic medical conditions, one in five had not returned to their usual state of health.
Nonhospitalized COVID-19 illness can result in prolonged illness and persistent symptoms, even in young adults and persons with no or few chronic underlying medical conditions. Public health messaging should target populations that might not perceive COVID-19 illness as being severe or prolonged, including young adults and those without chronic underlying medical conditions. Preventative measures, including social distancing, frequent handwashing, and the consistent and correct use of face coverings in public, should be strongly encouraged to slow the spread of SARS-CoV-2.

L'agence américaine de santé publique CDC détaille la persistance des symptômes du covid (y compris chez des patients jeunes) dans une étude publiée ce weekend.

493

MS04

Association française du syndrome de fatigue chronique

FATIGUE POST-COVID19

published opinion

Communiqué de presse

http://www.asso-sfc.org/documents/an-454-Communique-Post-covid-ASFC.pdf

The French Association of Chronic Fatigue Syndrome (@AssociationSfc) publishes a guide on post-covid fatigue19, discussing the hypothesis of the onset of myalgic encephalomyelitis (ME - chronic fatigue syndrome CFS).

L'Association française du syndrome de fatigue chronique (@AssociationSfc) publie un guide sur la fatigue post-covid19, évoquant l'hypothèse du déclenchement d'une encéphalomyélite myalgique (EM - syndrome de fatigue chronique SFC).

494

MS05

David T Arnold, Fergus W Hamilton, Alice Milne, Anna Morley, Jason Viner, Marie Attwood, et al.

Patient outcomes after hospitalisation with COVID-19 and implications for follow-up; results from a prospective UK cohort.

https://doi.org/10.1136/thoraxjnl-2020-216086

pre-print

https://www.medrxiv.org/content/10.1101/2020.08.12.20173526v1

British prospective longitudinal study (North Bristol NHS Trust) in pre-print (not yet reviewed) on August 14, carried out on 110 patients, 90 days of covid symptoms.

Étude longitudinale prospective anglaise (North Bristol NHS Trust) en pré-print (pas encore relue) le 14 août, effectuée sur 110 patients, #apresJ90 de symptômes covid.

495

MS06

Joseph R. Larsen1,2, Margaret R. Martin3, John D. Martin4, Peter Kuhn2* and James B. Hicks2*

Modeling the Onset of Symptoms of COVID-19

https://doi.org/10.3389/fpubh.2020.00473

published

13-Aug-20

ORIGINAL RESEARCH ARTICLE

https://www.frontiersin.org/articles/10.3389/fpubh.2020.00473/full

The most common order of symptoms of covid, in severe and non-severe cases.

The first two symptoms of COVID-19, SARS, and MERS are fever and cough. However, the upper GI tract (i.e., nausea/vomiting) seems to be affected before the lower GI tract (i.e., diarrhea) in COVID-19, which is the opposite from MERS and SARS.

L'ordre le plus fréquent des symptômes de la covid, dans les cas sévères et non-sévères.

496

MS07

Eve Garrigues
Paul Janvier
Yousra Kherabi
Vasco Honsel

Post-discharge persistent symptoms and health-related quality of life after hospitalization for COVID-19

https://doi.org/10.1016/j.jinf.2020.08.029

published opinion

24-Aug-20

LETTER TO THE EDITOR

https://www.journalofinfection.com/article/S0163-4453(20)30562-4/fulltext

A letter published 08/24 in Journal of Infection notes symptoms almost 4 months after hospitalization for covid for 120 patients (24 in intensive care unit). Beaujon Hospital (Paris).

Une lettre publiée le 24/08 dans Journal of Infection note les symptômes presque 4 mois après une hospitalisation pour covid pour 120 patients (24 passés en unité de soins intensifs). Hôp. Beaujon (Paris).

497

MS08

CIDRAP

COVID-19 symptoms can persist for months after hospital stay

published opinion

25-Aug-20

Article

https://www.cidrap.umn.edu/news-perspective/2020/08/covid-19-symptoms-can-persist-months-after-hospital-stay

_

498

MS09

Vellingiri Balachandar 1, Iyer Mahalaxmi 2, Mohandevi Subramaniam

Follow-up studies in COVID-19 recovered patients - is it mandatory?

https://doi.org/10.1016/j.scitotenv.2020.139021

published

10-Aug-20

Review

https://www.sciencedirect.com/science/article/abs/pii/S0048969720325389?via%3Dihub

Suivi en Inde

499

MS10

Survivor Corps

COVID-19 “Long Hauler” Symptoms
Survey Report

Survey

https://static1.squarespace.com/static/5e8b5f63562c031c16e36a93/t/5f25b5bfb3f4f86b1bf4d5f5/1596306894541/2020+Survivor+Corps+COVID-19+%27Long+Hauler%27+Symptoms+Survey+Report+%28revised+July+25.1%29.pdf

https://dig.abclocal.go.com/wls/documents/2020/072720-wls-covid-symptom-study-doc.pdf

Suivi "long-hauler" Indiana

500

MS11

Mark W. Tenforde, MD, PhD,corresponding author1 Sara S. Kim, MPH,1,2 Christopher

Symptom Duration and Risk Factors for Delayed Return to Usual Health Among Outpatients with COVID-19 in a Multistate Health Care Systems Network — United States, March–June 2020

https://doi.org/10.15585%2Fmmwr.mm6930e1

published

31-Jul-20

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392393/

Dans une étude US sur un panel randomisé de patients testés positifs non hospitalisés, l'état de santé antérieur n'est pas revenu au bout d'environ 20 jours pour plus d'un tiers des sondés. Toux, fatigue et essoufflement sont les symptômes les plus cités.

501

MS12

Mandal

‘Long-COVID’: a cross-sectional study of persisting
symptoms, biomarker and imaging abnormalities
following hospitalisation for COVID-19

http://dx.doi.org/10.1136/

21-Sep-20

https://thorax.bmj.com/content/thoraxjnl/early/2020/11/09/thoraxjnl-2020-215818.full.pdf

Initial reports are emerging of significant
ongoing symptom burden1
termed ‘Long-COVID’,
and of changes in lung function2
and imaging.3

while symptom burden in subjects recovering from hospital admission with COVID-19 had generally improved at early follow-up, 53% reported persistent breathlessness, 34% persistent cough and 69% persistent fatigue. Fifteen per cent were depressed.

502

MS13

Yes

Ladds

Persistent symptoms after Covid-19: qualitative study of 114 “long Covid” patients and draft quality criteria for services

https://doi.org/10.1186/s12913-020-06001-y

Published

14-Oct-20

Published after pre-print https://www.medrxiv.org/content/10.1101/2020.10.13.20211854v1

https://bmchealthservres.biomedcentral.com/articles/10.1186/s12913-020-06001-y

“Long” Covid is the name patients gave to Covid-19 infection that has not got better yet.1 Working definitions of ‘post-acute’ (symptoms beyond 3-4 weeks) and ‘chronic’ (symptoms beyond 12 weeks) Covid-19 are yet to be formally confirmed.23 A positive test for Covid-19 is not a prerequisite for diagnosis of post-acute or chronic disease, since many people were never tested.4 a heavy sense of loss and stigma; difficulty accessing and navigating services; difficulty being taken seriously and achieving a diagnosis; disjointed and siloed care (including inability to access specialist services); variation in standards (e.g. inconsistent criteria for seeing, investigating and referring patients); variable quality of the therapeutic relationship (some participants felt well supported while others felt “fobbed off”); and possible critical events (e.g. deterioration after being unable to access services). Emotional touch points in participants’ experiences informed ideas for improving services.

People with long Covid experience a confusing array of persistent and fluctuating symptoms including cough, breathlessness, fever, sore throat, chest pain, palpitations, cognitive deficits, myalgia, neurological symptoms, skin rashes, and diarrhoea; some also have persistent or intermittent low oxygen saturations.249-13 The cause of persisting symptoms is unknown, but probably involves several different disease mechanisms including an inflammatory reaction with a vasculitic component.14-16 Documented post-acute sequelae include myo- or pericarditis, heart failure, arrhythmias, and thrombo-embolic complications including myocardial infarction, stroke and venous thrombosis.1718

503

MS14

Cirulli

Long-term COVID-19 symptoms in a large unselected population

https://doi.org/10.1101/2020.10.07.20208702

under-review

24-Oct-20

https://www.medrxiv.org/content/10.1101/2020.10.07.20208702v2

The long-term symptoms most enriched in those with COVID-19 are anosmia, ageusia, difficulty concentrating, dyspnea, memory loss, confusion, headache, heart palpitations, chest pain, pain with deep breaths, dizziness, and tachycardia. We additionally observe that individuals who had an initial symptom of dyspnea are significantly more likely to develop long-term symptoms.

_

504

MS15

Maria Skaalum Petersen, Marnar Fríðheim Kristiansen, Katrin Dahl Hanusson,

Long COVID in the Faroe Islands - a longitudinal study among non-hospitalized patients

https://doi.org/10.1093/cid/ciaa1792

published

30-Nov-20

Study

https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1792/6012625

Une étude importante sur la prévalence du covid long.
Aux Îles Féroé, lors d'une campagne de tests PCR intense entre avril et juin, 187 personnes furent testées positives. 180 d'entre eux (soit 96%) ont accepté un suivi téléphonique jusqu'en août.
/ La moyenne d'âge est de 40 ans. Seuls 8 furent hospitalisés. Après 4 mois, plus de 50% gardent des symptômes. 33% ont 1 ou 2 symptômes, et 19% en ont 3 ou plus.
Les trois symptômes les plus fréquents sont la fatigue prolongée, la perte d'odorat et les douleurs articulaires. /La tranche d'âge intermédiaire (18 à 66 ans) est en proportion la plus touchée.
Même si elle est déclarative, cette étude est considérée comme l'une des moins impactées par les biais de sélection. NB : Selon ces données inédites par leur mode de sélection
Après 4 mois les symptômes persistants des testés positifs de la tranche 18-34 ans sont : légers : 32% Modérés : 14% Sévères : 11%
Après 4 mois, ceux de la tranche 35-49 ans sont : légers : 51% Modérés : 33% Sévères : 8%

505

MS16

Yes

Dominique Salmon MD, PhD , Dorsaf Slama MD ,
Thomas De Broucker MD , Marina Karmochkine MD ,

Clinical, virological and imaging profile in patients with Persistent or
Resurgent forms of COVID-19: a cross-sectional study

https://doi.org/10.1016/j.jinf.2020.12.002

published

2-Dec-20

Study

https://www.sciencedirect.com/science/article/pii/S0163445320307623

Une étude française sur une petite cohorte de patients infectés présentant des symptômes post-covid indique que pour la moitié d'entre eux, une période de 2 à 6 semaines s'est écoulée entre la phase aiguë et la réapparition de symptômes. L'étude émet des hypothèses sur le covid long :
1/ - une persistance virale active 2/ - une réponse immunitaire excessive menant à un état auto-inflammatoire chronique chez des personnes prédisposées génétiquement
3/ - le développement d'une encéphalomyélite myalgique, déjà observée pour le SRAS. Enfin, même si la cause de stress post-traumatique n'est pas exclue, l'étude précise que la répétition de troubles neurologiques et cardiothoraciques similaires, parfois objectivés par l'imagerie cardiaque, suggère une réelle entité post-covid.

N001B

___Multi-symptoms___

Published study on 2-Dec-20:
"Clinical, virological and imaging profile in patients with Persistent or
Resurgent forms of COVID-19: a cross-sectional study"
Une étude française sur une petite cohorte de patients infectés présentant des symptômes post-covid indique que pour la moitié d'entre eux, une période de 2 à 6 semaines s'est écoulée entre la phase aiguë et la réapparition de symptômes. L'étude émet des hypothèses sur le covid long :
1/ - une persistance virale active 2/ - une réponse immunitaire excessive menant à un état auto-inflammatoire chronique chez des personnes prédisposées génétiquement
3/ - le développement d'une encéphalomyélite myalgique, déjà observée pour le SRAS. Enfin, même si la cause de stress post-traumatique n'est pas exclue, l'étude précise que la répétition de troubles neurologiques et cardiothoraciques similaires, parfois objectivés par l'imagerie cardiaque, suggère une réelle entité post-covid.
Link: https://www.sciencedirect.com/science/article/pii/S0163445320307623
Extract: ""

506

MS17

Julie Walsh-Messinger, Hannah Manis, Alison Vrabec, Jenna Sizemore, Karyn Bishof, Marcella Debidda

The Kids Are Not Alright: A Preliminary Report of Post-COVID Syndrome in University Students

https://doi.org/10.1101/2020.11.24.20238261

pre-print

29-Nov-20

https://www.medrxiv.org/content/10.1101/2020.11.24.20238261v2

51% of participants who contracted COVID-19 (N=43) experienced symptoms ≥28 days and were classified as having post-COVID syndrome; all but one (96%) were female. During acute illness the post-COVID group, compared to those who fully recovered, experienced significantly more chest pain (64% vs 14%; P=.002), fatigue (86% vs 48%; P=.009), fever (82% vs 48%; P=.02), olfactory impairment (82% vs 52%; P=.04), headaches (32% vs 5%; P<.05), and diarrhea (32% vs 5%; P<.05).

_

507

MS18

Mayssam Nehme, MDOlivia Braillard, MDGabriel Alcoba, MDSigiriya Aebischer Perone, MD

COVID-19 Symptoms: Longitudinal Evolution and Persistence in Outpatient Settings

published

8-Dec-20

https://www.acpjournals.org/doi/10.7326/M20-5926

Les résultats de l'étude suisse COVICARE sur la persistance de symptômes covid long à un mois- un mois et demi. L'étude retrouve la symptomatologie déjà décrite ailleurs, même si ses biais de sélection importants empêchent une estimation de prévalence.

508

MS19

Office of National Statistics (GB)

The prevalence of long COVID symptoms and COVID-19 complications

published

16-Dec-20

Article

https://www.ons.gov.uk/news/statementsandletters/theprevalenceoflongcovidsymptomsandcovid19complications

L'Office national britannique des statistiques fait un point sur la prévalence des symptômes du covid long et indique que 10% des testés positifs ont des symptômes qui perdurent au delà de 3 mois.

509

MS20

PESE

Hannah E Davis, Gina S Assaf, Lisa McCorkel, Hannah Wei, Ryan J Low, Yochai Reem, Signe Redfield, Jared P Austin, Athena Akrami

Characterizing Long COVID in an International Cohort: 7 Months of Symptoms and Their Impact

https://doi.org/10.1101/2020.12.24.20248802

pre-print

26-Dec-20

Survey

https://www.medrxiv.org/content/10.1101/2020.12.24.20248802v2

Athena Akrami
@AthenaAkrami
>8k responded to our survey. In this work, we focus on 3762 cases w illness lasting >28 days & onset prior to June 2020, which gives us the chance to characterize symptom profile & time course over 7 months, along w the impact on daily life, work & return to baseline health
1/Of the 3762 respondents, 2454 experienced symptoms for at least 180 days (6 months). 257 respondents (6.8%) recovered after day 28 of illness. In this Long COVID cohort The probability of symptoms lasting beyond 35 weeks was 91.8%.
2/The majority of respondents reported “moderate” symptoms throughout the course. In those who recovered in less than 90 days, the average number of symptoms peaked at week2 (11.35); in those who did not recover in 90 days, the average # of symptoms peaked at month2 (17.16!)
3/Prevalence of 205 symptoms in 10 organ systems was estimated, with 66 symptoms traced over seven months. We had special focus on neurological/psychiatric symptoms (calling them neuropsychiatric) Here's symptom prevalence estimates for non-neuropsychiatric symptoms.
4/and prevalence estimates for neuropsychiatric symptoms in 9 groups: -Cognitive Functioning (>85%) -Memory (>70%) -Speech and Language (~50%) -Sensorimotor symptoms (>90%) -Sleep (~80%) -Headaches (~80%) -Emotion and Mood (~90%) -Taste and Smell (~60%) -Hallucinations (>15%)
5/88.0% of the total respondents (3310) experienced either cognitive dysfunction or memory loss, with substantial impact on daily life, particularly Work. These symptoms had similar impacts across all age groups.
6/To characterize the progression of the 66 symptoms over seven months, we estimated symptom time courses—the probability of experiencing each symptom at each time point, given that recovery has not yet occurred.
7/We also estimated the distribution of onset times for each symptom. White points and error bars show the mean onset time and 95% pointwise confidence intervals. As you can see, some symptoms are most likely to start in the 1st week, whereas others would start later (month 2)
8/To summarize general patterns in the progression of symptoms over time, we used a clustering algorithm to group theses symptms into 3 clusters, according to the shapes of their time courses (i.e. changes in relative amplitude over time, ignoring their overall prevalence)
9/Cluster 1: symptoms with early peak (the first 2 or 3 weeks), then a decreasing trend in probability over time Cluster 2: symptoms w a slow decrease, slow increase, or unchanging probability over time Cluster 3: symptoms w sharp ramp in the first 2 months, then plateau
10/The mean # of organ systems affected in each respondent was 9.08/10. Symptoms in the same organ-based category didn't necessarily cluster together & could appear across clusters Systemic & neuro/cognitive symptoms were most likely to persist from disease onset to month 7
11/Did all respondents test + for COVI19? No. 1730 tested negative & 600 tested positive (RT-PCR). Difference? The median number of days between first experiencing symptoms & being tested was 6 days for those who tested + and 43 days for those who tested -.
12/Out of 205 symptoms, only loss of smell/taste was significantly different between the two groups, after stratifying the data based on comparing populations with equal test times. This is consistent with what we found in our first study. See here:
13/Moreover, symptom probability time courses for participants with confirmed COVID-19 (n=1020, RT-PCR, antigen, or antibody tests) overlapped significantly with probability estimates from the whole population, except again for "Changes in smell/taste".
14/Going back to symptoms, 89.1% of participants reported experiencing either physical or mental Post-Exertional Malaise: "worsening or relapse of symptoms after physical or mental activity" one of the most demoralising features of #LongCOVID /
15Majority of respondents experienced PEM after a few hours or the following day, and it can last for a few days. Physical activity, stress, exercise, and mental activity were the most reported triggers of these relapses.
16/Those who still experience PEM after 6 month, on average experience a lot more symptoms, compared to those w no PEM. PEM is a mandatory symptom for ME/CFS. Intriguingly, among those still experiencing symptoms at month 6 w no PEM, fatigue was still the most common symptom
17/This suggests that while a subset of the #LongCOVID population may meet #MECFS diagnostic criteria, there remains a subpopulation w significant fatigue who do not meet the criteria & therefore the mechanisms of fatigue require further investigation.
18/A total of 2454 (65.2%) respondents were experiencing symptoms for at least 6 months. For this population, the top remaining symptoms after 6 months were primarily a combination of systemic and neurological symptoms.
19/You may wonder, do patients usually have break in their symptoms? Only 164 out of 3762 participants (4.4%) experienced a temporary break in symptoms (to the precision of our study, which is week 1-4, then month 2-7)
20/We also asked participants to answer the Fatigue Assessment Scale (FAS) questionnaire, based on their subjective report during the “past 1 week". Majority of unrecovered respondents fall in "Fatigued" and "Severely Fatigued", compared to recovered.
21/Respondents were also asked, “How would you rate how you feel today, on a scale of 0-100% (with 100% being your pre-COVID baseline)?" Unrecovered participants reported a mean score of 59.2, while recovered participants reported a mean score of 86.5.
22/AND most importantly, 45.2% of respondents reported requiring a reduced work schedule compared to pre-illness. 22.3% were not working due to their health conditions. Unrecovered ones were impacted stronger (68.9% reported reduced work hrs or not working at all). This is HUGE
23/We hope this work would help with valuable future research to answer: What are the biological underpinnings of #LongCOVID & what are potential treatments? What can be done to support the suffers, both medically & through policy, until treatments are identified?

@ahandvanish (co-author)
"While we had a few thousand more fill in the survey, this paper focuses on 3,762 #longhaulers (sick >28 days) who got sick between Dec-May (to look at an average of ~6 months of data). Some key findings:
1/We looked at 205 symptoms over 10 organs systems (Neuropsychiatric, Pulmonary, Head Ears Eyes Nose Throat (HEENT), Gastrointestinal, Cardiovascular, Musculoskeletal, Immunologic, Dermatologic, Reproductive/Genitourinary/Endocrine).
On average, 9 in 10 of these were affected!
2/Of the 205 symptoms, we looked at 74 over time, looking at Weeks 1-4 and Months 2-7.
These graphs show the % of respondents who have reached each month who have these symptoms. Some of them go down (fever*, dry cough) while others don't. (*tho some have fever for months!)
3/(Personal interpretation) there are a few symptoms that seem to increase or happen in later months (months 6+) that more research/investigation is worth looking into: bone ache/burning, tinnitus, hearing loss, and other ear symptoms, and possibly eye/vision symptoms.
4/A very cool graph showing the average *onset* of these #LongCovid symptoms.
5/~Half of our symptoms were Neuropsychiatric, so we divided them into 9 subgroups. Most of these were common: Cognitive dysfunction (85%), Sensorimotor issues (tremors, tingling, skin burning) (~91%), Sleep issues (79%), Headaches (77%).
Memory loss happened to 73%.
6/Our last survey found "brain fog" was common, but what is brain fog (referred to as cognitive dysfunction here) more concretely?
We found this to mean:
1. Poor attention/concentration (75% of respondents)
2. Difficulty thinking (70%)
3. Difficulty with executive...
7/3. ...functioning (planning, organizing,
figuring out the sequence of actions, abstracting) (58%)
4. Difficulty problem solving/decision making (54%)
5. Slowed thoughts (49%)
These still don't capture the full impact of how disorienting it is, so read these quotes! #LongCovid
8/We asked about the impact of this cognitive dysfunction and memory loss of everyday life.
The greatest area affected was work (86%), with 29% responding this impact was 'severe'. Other high areas included making serious decisions, communicating thoughts/needs,
9/difficulty having conversations, maintaining medication schedules, following simple instructions, and driving. #LongCovid
Memory issues were also high: 73% were affected overall. The most common was short-term memory loss, at 65%.
10/One of the biggest findings to me was that there was no difference on age for the cognitive dysfunction, memory loss, or impact of these on daily life!! These happened as often in the 18-29 year old group as the 70+ group. #LongCovid #longhaulers
11/There were high prevalences of fatigue (98%) and post-exertional malaise (worsening of symptoms after activity) at (89%). These went down over time, but ~73% of respondents in month 7 reported having post-exertional malaise. Charts a-c describe PEM/PENE severity/delay #pwme
12/Cognitive dysfunction, fatigue, & post-exertional malaise are the 1) most common symptoms overall, 2) three most debilitating symptoms reported by patients, & 3) most common persisting symptoms after 6 months (followed closely by sensorimotor & headaches). #LongCovid
13/Relapses happened to >86% of #LongCovid respondents. Physical activity & stress were the most common triggers, followed by exercise & mental activity.
Chart e describes relapses as well as symptom timecourses. ~50% said their symptoms got gradually better.
14/This paper includes many lesser known symptoms - even if infrequent, I want to highlight a few of them (Remember, with 80.5 million cases worldwide, & 10% of those (low estimate) with #LongCovid, that's 8 million people. A symptom prevalence of 1% is 800,000 people affected!)
15/Some serious symptoms are happening in #LongCovid: vision loss (1%), hearing loss (9%), new anaphalaxis (4%), new allergies (9%), facial paralysis (3%), suicidality (12%).
20% of respondents have changes in sensitivity to medications!! All doctors need to be aware of these.
16/On reproductive health in #LongCovid - I won't repeat everything but a few new datapoints:
15% of men reported sexual dysfunction. 11% of cis men and 3% of nonbinary respondents reported pain in testicles. 3% of cis men reported a decrease in genital size.
17/Post-menopausal bleeding/spotting happened to 4.5% of cis women over age 49. Early menopause happened to 3% of cis women in their 40s. #LongCovid
26% of people with periods had abnormal periods; 20% had abnormally heavy periods/clotting.
18/The impact of Long COVID is substantial.
68% either required a reduced work schedule or were no longer working due to #LongCovid.
For those with symptoms beyond 6 months, they continued to experience an average of 14 symptoms in month 7!
19/A key point - like last time, we accepted all suspected (positive, negative, and untested) #LongCovid patients, and compared the symptoms. Of 203 symptoms, 205 were statistically the same when comparing positive (orange in the chart here) & negative. The only difference
20/was loss of smell & taste, though altered smell/taste, heightened smell/taste, & phantom smell/tastes were all the same between positive & negative.
I think the loss of smell/taste may be bc: 1) Our dataset is mostly March or earlier, which was before smell/taste were known
21/2) there may be a testing bias for later months (if you had loss of smell/taste, you were more likely to get tested and therefore test positive) 3) it's also totally possible that in the negative cohort, the virus doesn't stay in the throat as long, for some reason #LongCovid
22/Importantly, the positive cohort was tested at a median of Day 6, and the negative cohort on Day 43 (!!!!) Whenever you hear 'negative test', especially for the spring wave, you should associated that with later or no testing availability.
23/We didn't write too much about treatments in this paper, but we did include "pacing", which stood out with the highest % considering it "significantly helpful" (23%) or "slightly helpful" (19%).
(For an understanding of pacing, check out https://meaction.net/stoprestpace/)
24/I could write about insights forever but I'll end there for now. Future papers will include antibody & diagnostic testing, mental health, symptom clustering, socioeconomic impact, & more. Please reach out to us at @patientled with any questions or collaborations! #LongCovid
25/We especially welcome BIPOC #LongCovid researchers who want to work with this data, & we plan to continue distributing this survey to #BIPOC communities. Please reach out if you'd like to collaborate!
26/This was only possible due to the most amazing team ever (all #LongCovid patients):@GinaAssaf @LisaAMcCorkell @herlifeinpixels & @AthenaAkrami (who got us IRB sponsorship at @ucl !) Forever grateful to @itsbodypolitic (our home!), to @long_covid, #pwme, & so many others!
27/We've been working on this for 7 months, immediately after we published our first #LongCovid survey in May, with every spare ounce of energy we have.
If you're able, please consider donating: https://gofund.me/f1acbf08
28/ should mention this was in a mostly non-hospitalized cohort (91.6% were not hospitalized). #LongCovid
29/ Tagging @YochaiReemMD who also worked on this paper and is on Twitter now!

> 8000 participants Ici, nous nous concentrons sur 3762 malades plus de 28 j et apparition avant juin 2020, ce qui nous permet de caractériser le profil des symptômes et l'évolution du temps sur 7 m, ainsi que l'impact sur la vie quotidienne, le travail et le retour à santé
1 /Sur les 3762 répondants, 2454 ont présenté des symptômes pendant au moins 180 jours (6 mois). 257 répondants (6,8%) se sont rétablis après le 28e jour de maladie. Dans cette cohorte COVID longue, la probabilité que les symptômes durent au-delà de 35 semaines était de 91,8%.
2 /La majorité des répondants ont signalé des symptômes «modérés» . Chez ceux qui se sont rétablis en moins de 90 j, le nombre moyen de symptômes a culminé à la semaine 2 ; chez ceux qui ne se sont pas rétablis en 90 j, le nombre moyen de symptômes a culminé au mois2
3 /Une prévalence de 205 symptômes dans 10 systèmes organiques a été estimée, avec 66 symptômes tracés sur 7mois. Nous nous sommes particulièrement concentrés sur les symptômes neuro psy. Ici les estimations de la prévalence des symptômes pour les symptômes non neuro psy.
4 /prévalence des symptômes neuropsychiatriques : -Fonctionnement cognitif (> 85%) -Mémoire (> 70%) -Parole et langage (~ 50%) -Symptômes sensorimoteurs (> 90%) -Dormir (~ 80%) -Maux de tête (~ 80%) -Émotion et humeur (~ 90%) -Goût et odeur (~ 60%) -Hallucinations (> 15%)
5 /88,0% du total des répondants (3310) ont connu un dysfonctionnement cognitif ou une perte de mémoire, avec un impact substantiel sur la vie quotidienne, en particulier le travail. Ces symptômes ont eu un impact similaire dans tous les groupes d'âge.
6 /Pour caractériser la progression des 66 symptômes sur sept mois, nous avons estimé l'évolution des symptômes dans le temps - la probabilité de ressentir chaque symptôme à chaque moment , tant que la guérison ne s'est pas encore produite.
7/Nous avons également estimé la distribution des temps d'apparition pour chaque symptôme. Comme vous pouvez le voir, certains symptômes sont plus susceptibles de commencer la 1ère semaine, tandis que d'autres commenceraient plus tard (mois 2)
8 /Pour résumer les tendances générales de la progression des symptômes au fil du temps, nous avons utilisé un algorithme de clustering pour regrouper ces symptômes en 3 groupes, en fonction de leur évolution dans le temps
9 /Gpe 1: symptômes avec pic précoce puis tendance à la baisse de la probabilité au fil du temps Gpe 2: symptômes avec une diminution lente, augmentation lente ou probabilité constante dans le temps Gpe 3: symptômes avec forte rampe au cours des 2 premiers mois, puis plateau 10/Le nombre moyen de systèmes organiques affectés chez chaque répondant était de 9,08 /
10. Les symptômes systémiques et neuro / cognitifs étaient les plus susceptibles de persister, du ébut de la maladie au mois 7
11 /Tous les participants n’ont pas eu un test + 1730 ont été testés négatifs et 600 ont été testés positifs (PCR). Différence? Le nombre médian de jours entre les premiers symptômes et le test était de 6 jours pour ceux qui ont testé + et de 43 jours pour ceux qui ont testé -.
12 / Sur 205 symptômes, seule la perte d'odeur / de goût était significativement différente entre les deux groupes, après stratification des données en comparant les populations à des temps de test égaux. Ceci est cohérent avec ce que nous avons trouvé dans notre première étude.
13 /En outre, le cours des symptômes pour les participants avec COVID19+ (n = 1020, RT-PCR, ou tests d'anticorps) se chevauchaient significativement avec les estimations de probabilité de l'ensemble de la population, sauf encore une fois pour «Changements d'odeur / goût». \
14Pour en revenir aux symptômes, 89,1% des participants ont déclaré avoir éprouvé un malaise post-effort physique ou mental: «aggravation ou rechute des symptômes après une activité physique ou mentale», l'une des caractéristiques les plus démoralisantes de #LongCOVID /
15La majorité des répondants ont fait l'expérience de MPE après quelques heures ou le lendemain, et cela peut durer quelques jours. L'activité physique, le stress, l'exercice et l'activité mentale étaient les déclencheurs les plus signalés de ces rechutes.
16 / Ceux qui souffrent encore de MPE après 6 m éprouvent plus de symptômes que ceux qui n'en ont pas. Le MPE est un symptôme obligatoire de l'EM / SFC. Pourtant, parmi ceux qui présentaient encore des symptômes au mois 6 sans MPE, la fatigue était tjs le symptôme le plus courant /
17Cela suggère que si un sous-ensemble de la population #LongCOVID peut répondre aux critères de diagnostic #MECFS, il reste une sous-population avec une fatigue importante qui ne répond pas aux critères,dc les mécanismes de la fatigue nécessitent une enquête plus approfondie.
18 /Un total de 2 454 répondants (65,2%) ont éprouvé des symptômes pendant au moins 6 mois. Pour cette population, les principaux symptômes restants après 6 mois étaient principalement une combinaison de symptômes systémiques et neurologiques.
19 /Vous vous demandez peut-être, est-ce que les patients ont généralement des pauses de leurs symptômes ? Seuls 164 participants sur 3762 (4,4%) ont connu une interruption temporaire des symptômes (selon la précision de notre étude, qui est la semaine 1-4, puis le mois 2-7)
20 / Nous avons également demandé aux participants de répondre au questionnaire de l'échelle d'évaluation de la fatigue (FAS). La majorité de « non guéris »se situent dans les catégories «fatigués» et «gravement fatigués», comparativement à ceux qui ont guéri .
21 /A la question: «Comment évalueriez-vous votre santé aujourd'hui, sur une échelle de 0 à 100% (100% étant votre base de référence pré-COVID)?» Les participants non guéris ont rapporté un score moyen de 59,2, alors que les guéris ont rapporté un score moyen de 86,5.
22 /45,2% des répondants ont déclaré ne pas pouvoir travailler autant qu’avant. 22,3% ne pouvaient pas travailler du tout. Les personnes non guéries ont été plus touchées (68,9% ont déclaré avoir réduit leurs heures de travail ou ne pas travailler du tout). C'est énorme
23 / Nous espérons que ce travail contribuera à de précieuses futures recherches sur la physiopatho de #LongCOVID et les traitements potentiels. Que peut-on faire pour aider les victimes, médicalement et par le biais de politiques, jusqu'à ce que des traitements soient identifiés?

510

MS21

Suspected of falsification

Chaolin Huang, Lixue Huang, Yeming Wang, Xia Li, Lili Ren, Xiaoying Gu

6-month consequences of COVID-19 in patients discharged from hospital: a cohort study

https://doi.org/10.1016/S0140-6736(20)32656-8

Published

8-Jan-21

Study

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32656-8/fulltext

Une étude à Wuhan a suivi une cohorte de 1733 malades de la covid sortis d'hôpital pendant 6 mois. Une large majorité garde des symptômes, dont une faiblesse musculaire générale, des troubles du sommeil, de l'anxiété et dépression.

*** Suspected of falsification ***

511

MS22

Sandra Lopez-Leon, Talia Wegman-Ostrosky, Carol Perelman, Rosalinda Sepulveda, Paulina A Rebolledo, Angelica Cuapio, Sonia Villapol

More than 50 long term effects of COVID-19: a systematic review and meta-analysis

https://doi.org/10.1101/2021.01.27.21250617

Published

27-Jan-21

systematic review and meta-analysis

https://www.medrxiv.org/content/10.1101/2021.01.27.21250617v2

The Preferred Reporting Items for Systematic Reviewers and Meta-analysis (PRISMA) reporting guideline was followed. A total of 18,251 publications were identified, of which 15 met the inclusion criteria. The prevalence of 55 long-term effects was estimated, 21 meta-analyses were performed, and 47,910 patients were included. The follow-up time ranged from 15 to 110 days post-viral infection. The age of the study participants ranged between 17 and 87 years. It was estimated that 80% (95% CI 65-92) of the patients that were infected with SARS-CoV-2 developed one or more long-term symptoms.

Une méta-analyse en relecture (pre-print), non publiée à ce jour, estime la prévalence de symptômes de la covid 15 à 110 jours post-infection à 4 patients sur 5. Elle présente une répartition sur 55 manifestations principales.

512

MS23

Chinwe Juliana Iwu, Chidozie Declan Iwu, Charles Shey Wiysonge

The occurrence of long COVID: a rapid review

https://doi.org/10.11604/pamj.2021.38.65.27366

Published

20-Jan-21

Review

https://www.panafrican-med-journal.com/content/article/38/65/full/

_

513

MS24

Dominik Menges, Tala Ballouz, Alexia Anagnostopoulos, Hélène E. Aschmann, Anja Domenghino, Jan S. Fehr, Milo A. Puhan

Estimating the Burden of Long COVID in the Canton of Zurich: Implications for Healthcare Service Planning

https://doi.org/10.1371/journal.pone.0254523

Pre-print

2-Mar-21

Study - intermediate results

https://www.corona-immunitas.ch/en/program/studies/e7-zurich-coronavirus-cohort-study/

Symptoms at diagnosis were reported by 90% of participants, of which 16%, 40%, 30% and 13% reported mild, moderate, severe and very severe symptoms, respectively. 20% of participants were hospitalized within two weeks of the infection. At 6 months, 26% reported not having returned to their normal health state; 31% among males and 21% among females. Furthermore, 23% among the non-hospitalized and 39% among the hospitalized reported not having fully recovered. Half of the participants reported at least one general practitioner visit post-infection. 54% of participants had fatigue in the FAS, and 26% and 32% had DASS-21 scores indicating depression and anxiety, respectively. One fourth had grade 1 dyspnea or higher based on mMRC scores.

Dans les résultats intermédiaires non publiés d'une étude menée dans le canton de Zurich, les patients infectés, dont 90% ont eu une forme initiale symptomatique, sont 26% à ne pas avoir retrouvé leur état de santé après 6 mois.
La fatigue selon les critères FAS touche 54% des participants, la dépression et l'anxiété 26 et 32% selon les critères DASS-21, 1/4 ont une dyspnée de grade 1 ou plus selon les scores mMRC.
Les auteurs notent que les prévalences peuvent être surestimées à cause d'une part de cas asymptomatiques.

N003

___Multi-symptoms___

Pre-Print study - intermediate results on 2-Mar-21:
"Estimating the Burden of Long COVID in the Canton of Zurich: Implications for Healthcare Service Planning"
Dans les résultats intermédiaires non publiés d'une étude menée dans le canton de Zurich, les patients infectés, dont 90% ont eu une forme initiale symptomatique, sont 26% à ne pas avoir retrouvé leur état de santé après 6 mois.
La fatigue selon les critères FAS touche 54% des participants, la dépression et l'anxiété 26 et 32% selon les critères DASS-21, 1/4 ont une dyspnée de grade 1 ou plus selon les scores mMRC.
Les auteurs notent que les prévalences peuvent être surestimées à cause d'une part de cas asymptomatiques.
Link: https://www.corona-immunitas.ch/en/program/studies/e7-zurich-coronavirus-cohort-study/
Extract: "Symptoms at diagnosis were reported by 90% of participants, of which 16%, 40%, 30% and 13% reported mild, moderate, severe and very severe symptoms, respectively. 20% of participants were hospitalized within two weeks of the infection. At 6 months, 26% reported not having returned to their normal health state; 31% among males and 21% among females. Furthermore, 23% among the non-hospitalized and 39% among the hospitalized reported not having fully recovered. Half of the participants reported at least one general practitioner visit post-infection. 54% of participants had fatigue in the FAS, and 26% and 32% had DASS-21 scores indicating depression and anxiety, respectively. One fourth had grade 1 dyspnea or higher based on mMRC scores."

514

MS25

Sofie Bliddal, Karina Banasik, Ole Birger Pedersen, Ioanna Nissen, Lisa Cantwell, Sisse Rye Ostrowski, Kirsten Grønbæk, Claus Henrik Nielsen, Susanne Dam Nielsen, Ulla Feldt-Rasmussen

Acute and persistent symptoms in non-hospitalized PCR-confirmed COVID-19 patients

https://doi.org/10.1101/2021.01.22.21249945

Pre-print

25-Jan-21

Study

https://www.medrxiv.org/content/10.1101/2021.01.22.21249945v1

445 participants were included, of whom 34% were asymptomatic. Most common acute symptoms
41 were fatigue, headache, and sneezing, while fatigue and reduced smell and taste were reported as most severe.
42 Persistent symptoms, most commonly fatigue and memory and concentration difficulties, were reported by
43 36% of 198 symptomatic participants with follow-up >four weeks. Risk factors for persistent symptoms
44 included female sex (women 44% vs. men 24%, odds ratio 2.7, 95%CI:1.4-5.1, p=0.003) and BMI (odds ratio
45 1.1, 95%CI:1.0-1.2, p=0.001).

Dans une étude danoise non encore relue ni publiée, les auteurs ont suivi des patients testés PCR + pour la covid mais n'ayant pas été hospitalisés. Un tiers se révèlent asymptomatiques et parmi les cas symptomatiques, plus d'un tiers témoignent de symptômes persistants aussi bien après 4 semaines que 12 semaines. Les femmes apparaissent comme étant plus touchées, un peu moins de 2 fois plus souvent que les hommes.

515

MS26

Jennifer K. Logue, BS1; Nicholas M. Franko, BS1; Denise J. McCulloch, MD, MPH1; Dylan McDonald, BA1; Ariana Magedson, BS1; Caitlin R. Wolf, BS1; Helen Y. Chu,

Sequelae in Adults at 6 Months After COVID-19 Infection

https://doi.org/10.1001/jamanetworkopen.2021.0830

Published

19-Feb-21

Research Letter

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2776560

The most common persistent symptoms were fatigue (24 of 177 patients [13.6%]) and loss of sense of smell or taste (24 patients [13.6%]). Overall, 23 patients (13.0%) reported other symptoms, including brain fog (4 [2.3%]). A total of 51 outpatients and hospitalized patients (30.7%) reported worse HRQoL compared with baseline vs 4 healthy participants and asymptomatic patients (12.5%); 14 patients (7.9%) reported negative impacts on at least 1 activity of daily living (ADL), the most common being household chores.

Une étude publiée dans JAMA note que près de 30% des patients souffrent encore de symptômes 6 mois après une infection covid. À cette échéance, 13% des patients seraient toujours touchés par de la fatigue, et le même pourcentage par une perte de goût et d'odorat, tandis que 13% rapporteraient d'autres symptômes. 1 à 5% continueraient de souffrir de "brouillard cérébral".

N002

___Multi-symptoms___

Published research letter on 19-Feb-21:
"Sequelae in Adults at 6 Months After COVID-19 Infection"
Une étude publiée dans JAMA note que près de 30% des patients souffrent encore de symptômes 6 mois après une infection covid. À cette échéance, 13% des patients seraient toujours touchés par de la fatigue, et le même pourcentage par une perte de goût et d'odorat, tandis que 13% rapporteraient d'autres symptômes. 1 à 5% continueraient de souffrir de "brouillard cérébral".
Link: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2776560
Extract: "The most common persistent symptoms were fatigue (24 of 177 patients [13.6%]) and loss of sense of smell or taste (24 patients [13.6%]). Overall, 23 patients (13.0%) reported other symptoms, including brain fog (4 [2.3%]). A total of 51 outpatients and hospitalized patients (30.7%) reported worse HRQoL compared with baseline vs 4 healthy participants and asymptomatic patients (12.5%); 14 patients (7.9%) reported negative impacts on at least 1 activity of daily living (ADL), the most common being household chores."

516

MS27

Bhakti Kundlik Lonkar*
and Ketakee Prakash Gosavi

A Review on Post COVID-19 Effects

Published

13-Feb-21

Review

https://d1wqtxts1xzle7.cloudfront.net/65655321/152.pdf?1612972663=&response-content-disposition=inline%3B+filename%3DA_Review_on_Post_COVID_19_Effects.pdf&Expires=1614283047&Signature=KuK-YCI3gwGMCZSa9k0ivqb1m6di-LnTlJiB2thnsU13Kf1JNUuVQPFHWiFSI2VcmE7jYH2RFpPaPiIaj08GFAw7jY~I-LCwmIhxRrvrLIK0s8PY6kdlhLyIzooxCCMMLs078JABgFxFv4kJG~gwcEdvmpGFDiIPFcbXWmJ~fl9XLXTGoRX862Rfy6-xlGpNNnJ2qfj9rA4reczUvgmCDqHELiRc3kVifbbseBut5kWei8tTIGeE7kDSnXrQcS5ZAC7sKKMgFDrAjZEAf0U~OAvmR-96bFQFROEtqze~mGWO3IxbYkkNP-wcv9DxYHIufOffqKhpt1LhzLlorHCfVw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA

A short review on post covid effects.

Une courte revue d'études sur les effets à long terme de la covid.

517

MS28

Bryan Oronsky, Christopher Larson, Terese C. Hammond, Arnold Oronsky, Santosh Kesari, Michelle Lybeck & Tony R. Reid

A Review of Persistent Post-COVID Syndrome (PPCS)

https://doi.org/10.1007/s12016-021-08848-3

Published

20-Feb-21

Review

https://link.springer.com/article/10.1007/s12016-021-08848-3

Inhibiting transforming growth factor beta (TGF-β), an immuno- and a fibrosis modulator, may attenuate these post-COVID sequelae. Current preclinical and clinical efforts are centered on the mechanisms and manifestations of COVID-19 and its presymptomatic and prodromal periods; by comparison, the postdrome, which occurs in the aftermath of COVID-19, which we refer to as persistent post-COVID-syndrome, has received little attention. Potential long-term effects from post-COVID syndrome will assume increasing importance as a surge of treated patients are discharged from the hospital, placing a burden on healthcare systems, patients’ families, and society in general to care for these medically devastated COVID-19 survivors. This review explores underlying mechanisms and possible manifestations of persistent post-COVID syndrome, and presents a framework of strategies for the diagnosis and management of patients with suspected or confirmed persistent post-COVID syndrome.

En comparant les symptômes persistants de la covid au syndrome post-septique (d'autres auteurs, comme le Pr J.-L. Vincent, assimilaient déjà la covid à une septicémie, cf https://www.futuremedicine.com/doi/full/10.2217/fmb-2020-0312), l'équipe du docteur américain Bryan Oronsky émet une hypothèse physiopathologique impliquant une surexpression du facteur de croissance transformant bêta (cytokine TGF-β). L'article formule en conséquence des pistes de traitements, notamment des inhibiteurs de TGF-β, qui pourraient concourir au rétablissement de l'homéostasie immunologique et à l'atténuation des séquelles des malades Covid longs.

N003R2

___Multi-symptoms___

Published review on 20-Feb-21:
"A Review of Persistent Post-COVID Syndrome (PPCS)"
En comparant les symptômes persistants de la covid au syndrome post-septique (d'autres auteurs, comme le Pr J.-L. Vincent, assimilaient déjà la covid à une septicémie, cf https://www.futuremedicine.com/doi/full/10.2217/fmb-2020-0312), l'équipe du docteur américain Bryan Oronsky émet une hypothèse physiopathologique impliquant une surexpression du facteur de croissance transformant bêta (cytokine TGF-β). L'article formule en conséquence des pistes de traitements, notamment des inhibiteurs de TGF-β, qui pourraient concourir au rétablissement de l'homéostasie immunologique et à l'atténuation des séquelles des malades Covid longs.
Link: https://link.springer.com/article/10.1007/s12016-021-08848-3
Extract: "Inhibiting transforming growth factor beta (TGF-β), an immuno- and a fibrosis modulator, may attenuate these post-COVID sequelae. Current preclinical and clinical efforts are centered on the mechanisms and manifestations of COVID-19 and its presymptomatic and prodromal periods; by comparison, the postdrome, which occurs in the aftermath of COVID-19, which we refer to as persistent post-COVID-syndrome, has received little attention. Potential long-term effects from post-COVID syndrome will assume increasing importance as a surge of treated patients are discharged from the hospital, placing a burden on healthcare systems, patients’ families, and society in general to care for these medically devastated COVID-19 survivors. This review explores underlying mechanisms and possible manifestations of persistent post-COVID syndrome, and presents a framework of strategies for the diagnosis and management of patients with suspected or confirmed persistent post-COVID syndrome."

518

MS29

Suneel Piryani1
, Rano Mal Piryani2*, Ganesh Dangal3

COVID-19 Course of Infection and Disease

https://doi.org/10.46405/ejms.v3i1.308

Published

25-Jan-21

Letter to Editor

http://scholar.google.fr/scholar_url?url=https://www.europasianjournals.org/ejms/index.php/ejms/article/download/208/139&hl=fr&sa=X&ei=08JCYM-SC4eUmAGinKG4CA&scisig=AAGBfm2O0Khf_xGE6ef0O4ExiY0JyJr7kA&nossl=1&oi=scholarr

Letter to Editor

Lettre à éditeur

519

MS30

Kent J. Nielsen, Jesper Medom Vestergaard, Vivi Schlünssen, Jens Peter Bonde, Kathrine Agergård Kaspersen, Karin Biering, Ole Carstensen, Thomas Greve, Karoline Kærgaard Hansen, Annett Dalbøge, Esben Meulengracht Flachs, Sanne Jespersen, Mette Lausten Hansen, Susan Mikkelsen, Marianne Kragh Thomsen, Jacob Dvinge Redder, Else Toft Würtz, Lars Østergaard, Christian Erikstrup, Henrik Albert Kolstad

Day by day symptoms following positive and negative PCR tests for SARS-CoV-2 in non-hospitalised health-care workers: a 90-day follow-up study

https://doi.org/10.1101/2021.03.02.21252437

pre-print

3-Mar-21

Study

https://www.medrxiv.org/content/10.1101/2021.03.02.21252437v1

Key messages

Reduced sense of taste and smell is present at a highly increased level of 30% during 90 days after testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2).

Test-positive participants experience dyspnoea persistently more often than test-negative participants but affect only few.

The prevalence of cough, sore throat, headache, muscle ache or pain, and fever following a positive test reach the level seen after a negative test within 30 days.

Women and participants aged 45 years or older tend to be more susceptible to symptoms following SARS-CoV-2 infection.

Un pré-print (étude non relue ni publiée) avec groupe contrôle remarque dans une cohorte de personnel médical que 5% des personnes infectées (210 patients) rapportent une dyspnée au bout de 30 j, tandis que toux, maux de tête, de gorge, et douleurs musculaires n'ont pas une prévalence significativement élevée.
L'anosmie reste le symptôme le plus constant (1/3 des positifs PCR) sur au moins 90 jours.

520

MS31

Yong Huang, Melissa D. Pinto, Jessica L. Borelli, Milad Asgari Mehrabadi, Heather Abrihim, Nikil Dutt, Natalie Lambert, Erika L. Nurmi, Rana Chakraborty, Amir M. Rahmani, Charles A. Downs

COVID Symptoms, Symptom Clusters, and Predictors for Becoming a Long-Hauler: Looking for Clarity in the Haze of the Pandemic

https://doi.org/10.1101/2021.03.03.21252086

pre-print

5-Mar-21

Study

https://www.medrxiv.org/content/10.1101/2021.03.03.21252086v1

27% reported persistent symptoms after 60 days. Women were more likely to become long-
haulers, and all age groups were represented with those aged 50 ± 20 years comprising 72% of
cases. Presenting symptoms included palpitations, chronic rhinitis, dysgeusia, chills, insomnia,
hyperhidrosis, anxiety, sore throat, and headache among others. We identified 5 symptom
clusters at day 61+: chest pain-cough, dyspnea-cough, anxiety-tachycardia, abdominal pain-
nausea, and low back pain-joint pain.

roughly 32% of those reporting symptoms at day 61+ in our study were initially asymptomatic at the time of SARS-CoV-2 testing

Une étude non publiée et non encore relue affirme que les femmes et patients de 30-79 ans sont plus à risque de symptômes persistants de covid. Dans le segment des 27% avec des symptômes à 2 mois, 32% étaient asymptomatiques initialement au moment du test.

521

MS32

Himmels JPW, Qureshi SA, Brurberg KG, Gravningen KM

COVID-19: Long-Term Effects of COVID-19

Published

SYSTEMATIC REVIEW

https://www.fhi.no/en/publ/2021/Long-Term-Effects-of-COVID-19/

Hospitalised COVID-19 patients report prevailing symptoms long after infection, with a large proportion continuing to experience one or more symptoms at six months of follow-up.

Le Norwegian Institute of Public Health publie une rapide revue d'études sur les effets et séquelles à plus d'un mois de la covid.

N003A

___Multi-symptoms___

Published systematic review on :
"COVID-19: Long-Term Effects of COVID-19"
Le Norwegian Institute of Public Health publie une rapide revue d'études sur les effets et séquelles à plus d'un mois de la covid.
Link: https://www.fhi.no/en/publ/2021/Long-Term-Effects-of-COVID-19/
Extract: "Hospitalised COVID-19 patients report prevailing symptoms long after infection, with a large proportion continuing to experience one or more symptoms at six months of follow-up."

522

MS33

Max Augustin, Philipp Schommers, Melanie Stecher, Felix Dewald, Lutz Gieselmann, Gerd Fätkenheuer, Michael Hallek, Florian Klein, Isabelle Suárez, Clara Lehmann

Recovered not restored: Long-term health consequences after mild COVID-19 in non-hospitalized patients

https://doi.org/10.1101/2021.03.11.21253207

pre-print

12-Mar-21

Study

https://www.medrxiv.org/content/10.1101/2021.03.11.21253207v1

We observed 442 and 353 patients over four and seven months after symptom onset, respectively. Four months post SARS-CoV-2 infection, 8.6% (38/442) of patients presented with shortness of breath, 12.4% (55/442) with anosmia, 11.1% (49/442) with ageusia and 9.7% (43/442) with fatigue. At least one of these characteristic symptoms was present in 27.8% (123/442) and 34.8% (123/353) at month 4 and 7 post-infection, respectively. This corresponds to 12.8% patients with long-lasting symptoms relative to the initial total cohort (123/958).

Dans une étude en peer-review, 12,8% des patients testés positivement suivis ont au moins un symptome après 7 mois. Après 4 mois, 8,6% souffraient d'essoufflement, 12,4% d'anosmie, 9,7% d'asthénie. Un faible taux d'anticoprs igG (immunoglobuline G) apparaît comme corrélé avec le risque de développer des symptômes durables.

523

MS34

Michael J. Peluso, J. Daniel Kelly, Scott Lu, Sarah A. Goldberg, Michelle C. Davidson, Sujata Mathur, Matthew S. Durstenfeld, Matthew A. Spinelli, Steven G. Deeks, Jeffrey N. Martin

Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19

https://doi.org/10.1101/2021.03.11.21252311

pre-print

13-Mar-21

Preliminary results

https://www.medrxiv.org/content/10.1101/2021.03.11.21252311v1.full

Among a cohort of participants enrolled in the post-acute phase of SARS-CoV-2 infection, we found many with persistent physical symptoms through 8 months following onset of COVID-19 with an impact on self-rated overall health.

_

524

MS35

The Writing Committee for the COMEBAC Study Group

Four-Month Clinical Status of a Cohort of Patients After Hospitalization for COVID-19

https://doi.org/10.1001/jama.2021.3331

Published

17-Mar-21

Original Investigation

https://jamanetwork.com/journals/jama/fullarticle/2777787

Four months after hospitalization, in an uncontrolled cohort study of 478 survivors of COVID-19, at least 1 new-onset symptom was reported by telephone interview by 244 patients (51%), including fatigue in 134 of 431 (31%), cognitive symptoms in 86 of 416 (21%), and dyspnea in 78 of 478 (16%). Computed tomographic lung scan abnormalities were reported in 63% of 171 patients assessed at an ambulatory visit, mainly subtle ground-glass opacities. Fibrotic lesions were observed in 19% of these 171 patients.

_

525

MS36

Anne M. Doherty, Gabrielle C. Colleran, Laura Durcan, Alan D. Irvine & Elizabeth Barrett

A pilot study of burnout and long covid in senior specialist doctors

https://doi.org/10.1007/s11845-021-02594-3

Published

13-Mar-21

Study

https://link.springer.com/article/10.1007/s11845-021-02594-3

To assess the effect of the ongoing Covid-19 pandemic on Irish doctors by investigating the incidence of burnout and long covid among senior medical staff in Ireland. A total of 114 responses were received. Three-quarters 77% (N = 88) screened positive for burnout on the MBS, with mean score of 5.6 (SD3.3), nearly double the cut-off for burnout. Nearly two-thirds (64%, n = 72) reported that Covid-19 has had an adverse effect on their mental health. One-quarter reported that they or colleagues had experience of ‘long-covid’ secondary to the virus.

_

526

MS37

Anna K. Taylor Tom Kingstone Tracy A. Briggs Catherine A. O'Donnell Helen Atherton David N. Blane Carolyn A. Chew‐Graham

Reluctant pioneer': A qualitative study of doctors' experiences as patients with long COVID

https://doi.org/10.1111/hex.13223

Published

22-Mar-21

Study

https://onlinelibrary.wiley.com/doi/10.1111/hex.13223

A qualitative study; interviews with doctors experiencing persistent symptoms were conducted by telephone or video call.
Thirteen doctors participated. The following themes are reported: making sense of symptoms, feeling let down, using medical knowledge and connections, wanting to help and be helped, combining patient and professional identity. Experiencing long COVID can be transformative: many expressed hope that good would come of their experiences. Distress related to feelings of being ‘let down’ and the hard work of trying to access care. Participants highlighted that they felt better able to care for, and empathize with, patients with chronic conditions, particularly where symptoms are unexplained.

_

527

MS38

Nida Ziauddeen, Deepti Gurdasani, Margaret E O'Hara, Claire Hastie, Paul Roderick, Guiqing Yao, Nisreen A Alwan

Characteristics of Long Covid: findings from a social media survey

https://doi.org/10.1101/2021.03.21.21253968

pre-print

27-Mar-21

Survey

https://www.medrxiv.org/content/10.1101/2021.03.21.21253968v2

We aimed to explore the initial and ongoing symptoms of Long Covid following SARS-CoV-2 infection and describe its impact on daily life in people who were not admitted to hospital during the first two weeks of the illness. We co-produced a survey with people living with Long Covid. We collected the data through an online survey using convenience non-probability sampling, with the survey posted both specifically on Long Covid support groups and generally on social media. The criteria for inclusion were adults with lab-confirmed (PCR or antibody) or suspected COVID-19 managed in the community (non-hospitalised) in the first two weeks of illness.

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528

MS39

Matthew Cadd & Maya Nunn

An A-E assessment of post-ICU COVID-19 recovery

https://doi.org/10.1186/s40560-021-00544-w

Published

20-Mar-21

Commentary

https://jintensivecare.biomedcentral.com/articles/10.1186/s40560-021-00544-w

A wide range of sequelae contribute to post intensive care syndrome (PICS); from our current knowledge of COVID-19, a few of these have the potential to be more prevalent following critical care admission. Follow-up assessment, diagnosis and treatment in an increasingly virtual setting will provide challenges but also opportunities to develop these services. Here, we propose an A to E approach to consider the potential long-term effects of COVID-19 following critical care admission.
Anxiety and other mental health diagnoses - Breathlessness - Central nervous system impairment - Dietary insufficiency and malnutrition - Embolic events

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529

MS40

Bodunrin Osikomaiya, Olufemi Erinoso, Kikelomo Ololade Wright, Olusegun Ogboye, Akin Osibogun & Akin Abayomi

‘Long COVID’: persistent COVID-19 symptoms in survivors managed in Lagos State, Nigeria

https://doi.org/10.1186/s12879-020-05716-x

Published

25-Mar-21

Research article

https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-020-05716-x

A total of 274 patients were enrolled in the study. A majority were within the age group > 35 to ≤49 years (38.3%), and male (66.1%). More than one-third (40.9%) had persistent COVID-19 symptoms after discharge, and 19.7% had more than three persistent COVID-like symptoms. The most persistent COVID-like symptoms experienced were easy fatigability (12.8%), headaches (12.8%), and chest pain (9.8%). Symptomatic COVID-19 disease with moderate severity compared to mild severity was a predictor of persistent COVID-like symptoms after discharge (p < 0.05). Our study identified neurologic symptoms in 39.1% of the COVID-19 survivors reviewed, symptoms such as headaches, insomnia, and attention deficits. These symptoms can potentially preclude a safe and effective return of survivors to usual life.

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530

MS41

ONS

Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the UK: 1 April 2021

Published

1-Apr-21

Survey

https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/prevalenceofongoingsymptomsfollowingcoronaviruscovid19infectionintheuk/1april2021#duration-of-reported-symptoms-following-confirmed-coronavirus-covid-19-infection

1.Main points
Over the four-week period ending 6 March 2021, an estimated 1.1 million people in private households in the UK reported experiencing long COVID (symptoms persisting more than four weeks after the first suspected coronavirus (COVID-19) episode that are not explained by something else).

The estimates presented in this analysis relate to self-reported long COVID, as experienced by study participants, rather than clinically diagnosed ongoing symptomatic COVID-19 or post-COVID-19 syndrome. There is no universally agreed definition of long COVID, but it covers a broad range of symptoms such as fatigue, muscle pain, and difficulty concentrating.

Self-reported long COVID symptoms were adversely affecting the day-to-day activities of 674,000 people in private households in the UK, with 196,000 of these individuals reporting that their ability to undertake their day-to-day activities had been limited a lot.

Of people with self-reported long COVID, 697,000 first had (or suspected they had) COVID-19 at least 12 weeks previously, and 70,000 first had (or suspected they had) COVID-19 at least one year previously.

Prevalence rates of self-reported long COVID were greatest in people aged 35 to 69 years, females, those living in the most deprived areas, those working in health or social care, and those with a pre-existing, activity-limiting health condition; however, it is not possible to say whether these patterns are because of differences in the risk of coronavirus infection or susceptibility to experiencing long COVID following infection.

These estimates provide a measure of the prevalence of self-reported long COVID across the whole population, and reflect both the risk of being infected with coronavirus and the risk of developing long COVID following infection; to investigate the second of these components, we examined the duration of self-reported symptoms following confirmed infection.

Among a sample of over 20,000 study participants who tested positive for COVID-19 between 26 April 2020 and 6 March 2021, 13.7% continued to experience symptoms for at least 12 weeks. This was eight times higher than in a control group of participants who are unlikely to have had COVID-19, suggesting that the prevalence of ongoing symptoms following coronavirus infection is higher than in the general population.

Of study participants who tested positive for COVID-19, symptom prevalence at 12 weeks post-infection was higher for female participants (14.7%) than male participants (12.7%) and was highest among those aged 25 to 34 years (18.2%).

Dans son rapport de décembre 2020, l'ONS (UK) estimait à 9,9% [95% CI : 6,7% - 14,7%] la proportion de personnes testées positives au SARS-CoV-2 qui continuent de présenter des symptômes 3 mois après l’infection.
Une nouvelle estimation parue aujourd'hui sur une plus grande cohorte donne 13,7% (95% CI 10,7% - 17,3%] d'infectés avec des symptômes à +3 mois.
Soit 11 points de plus qu'un groupe contrôle a priori non infecté.
Ces symptômes persistants à 3 mois sont :
L'asthénie (8,3%), les maux de tête (7,2%), la toux (7%), les maux de gorge (4%), l'anosmie/agueusie (3,7%), les douleurs musculaires (5,6%), l'essoufflement (3.4%), la diarrhée (1,7%) et les douleurs abdominales (1,5%).
L'ONS évalue à près de 700 000 le nombre de Britanniques souffrant toujours de symptômes plus de 3 mois après leur infection (1,1 million >4 semaines), pour une population de 66,6 millions d'habitants. L'étude est sur une base auto-declarative. Sur un critère de symptômes >4 semaines après l'infection, 420 000 disent n'être pas du tout gênés dans leurs activités quotidiennes, 478 000 l'être un peu, 196 000 l'être beaucoup.

N007

___Multi-symptoms___

Published survey on 1-Apr-21:
"Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the UK: 1 April 2021"
Dans son rapport de décembre 2020, l'ONS (UK) estimait à 9,9% [95% CI : 6,7% - 14,7%] la proportion de personnes testées positives au SARS-CoV-2 qui continuent de présenter des symptômes 3 mois après l’infection.
Une nouvelle estimation parue aujourd'hui sur une plus grande cohorte donne 13,7% (95% CI 10,7% - 17,3%] d'infectés avec des symptômes à +3 mois.
Soit 11 points de plus qu'un groupe contrôle a priori non infecté.
Ces symptômes persistants à 3 mois sont :
L'asthénie (8,3%), les maux de tête (7,2%), la toux (7%), les maux de gorge (4%), l'anosmie/agueusie (3,7%), les douleurs musculaires (5,6%), l'essoufflement (3.4%), la diarrhée (1,7%) et les douleurs abdominales (1,5%).
L'ONS évalue à près de 700 000 le nombre de Britanniques souffrant toujours de symptômes plus de 3 mois après leur infection (1,1 million >4 semaines), pour une population de 66,6 millions d'habitants. L'étude est sur une base auto-declarative. Sur un critère de symptômes >4 semaines après l'infection, 420 000 disent n'être pas du tout gênés dans leurs activités quotidiennes, 478 000 l'être un peu, 196 000 l'être beaucoup.
Link: https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/prevalenceofongoingsymptomsfollowingcoronaviruscovid19infectionintheuk/1april2021#duration-of-reported-symptoms-following-confirmed-coronavirus-covid-19-infection
Extract: "1.Main points
Over the four-week period ending 6 March 2021, an estimated 1.1 million people in private households in the UK reported experiencing long COVID (symptoms persisting more than four weeks after the first suspected coronavirus (COVID-19) episode that are not explained by something else).

The estimates presented in this analysis relate to self-reported long COVID, as experienced by study participants, rather than clinically diagnosed ongoing symptomatic COVID-19 or post-COVID-19 syndrome. There is no universally agreed definition of long COVID, but it covers a broad range of symptoms such as fatigue, muscle pain, and difficulty concentrating.

Self-reported long COVID symptoms were adversely affecting the day-to-day activities of 674,000 people in private households in the UK, with 196,000 of these individuals reporting that their ability to undertake their day-to-day activities had been limited a lot.

Of people with self-reported long COVID, 697,000 first had (or suspected they had) COVID-19 at least 12 weeks previously, and 70,000 first had (or suspected they had) COVID-19 at least one year previously.

Prevalence rates of self-reported long COVID were greatest in people aged 35 to 69 years, females, those living in the most deprived areas, those working in health or social care, and those with a pre-existing, activity-limiting health condition; however, it is not possible to say whether these patterns are because of differences in the risk of coronavirus infection or susceptibility to experiencing long COVID following infection.

These estimates provide a measure of the prevalence of self-reported long COVID across the whole population, and reflect both the risk of being infected with coronavirus and the risk of developing long COVID following infection; to investigate the second of these components, we examined the duration of self-reported symptoms following confirmed infection.

Among a sample of over 20,000 study participants who tested positive for COVID-19 between 26 April 2020 and 6 March 2021, 13.7% continued to experience symptoms for at least 12 weeks. This was eight times higher than in a control group of participants who are unlikely to have had COVID-19, suggesting that the prevalence of ongoing symptoms following coronavirus infection is higher than in the general population.

Of study participants who tested positive for COVID-19, symptom prevalence at 12 weeks post-infection was higher for female participants (14.7%) than male participants (12.7%) and was highest among those aged 25 to 34 years (18.2%)."

531

MS42

Francisco J.Barrantes

The Unfolding Palette of COVID-19Multisystemic Syndrome and its Neurological Manifestations

https://doi.org/10.1016/j.bbih.2021.100251

Published

3-Apr-21

Review

https://www.sciencedirect.com/science/article/pii/S2666354621000545

Highlights
•The original severe acute pulmonary syndrome is the main, but not the only manifestation of COVID-19
•One year of basic and clinical research indicate that COVID-19 is a much more complex multisystemic nosological entity
•SARS-CoV-2 tropism for vascular endothelium, epithelial mucosae and nervous tissue determines pathophysiological mechanisms

Une analyse invite à considérer la covid comme une entité nosologique (de classification) multi-systémique, et fait une revue d'études très complète du tableau neurologique de la maladie.

N007

___Multi-symptoms___

Published review on 3-Apr-21:
"The Unfolding Palette of COVID-19Multisystemic Syndrome and its Neurological Manifestations"
Une analyse invite à considérer la covid comme une entité nosologique (de classification) multi-systémique, et fait une revue d'études très complète du tableau neurologique de la maladie.
Link: https://www.sciencedirect.com/science/article/pii/S2666354621000545
Extract: "Highlights
•The original severe acute pulmonary syndrome is the main, but not the only manifestation of COVID-19
•One year of basic and clinical research indicate that COVID-19 is a much more complex multisystemic nosological entity
•SARS-CoV-2 tropism for vascular endothelium, epithelial mucosae and nervous tissue determines pathophysiological mechanisms"

532

MS43

Sebastian Havervall, MD1; Axel Rosell, MD1; Mia Phillipson, PhD2; Sara M. Mangsbo, PhD2; Peter Nilsson, PhD3; Sophia Hober, PhD3; Charlotte Thålin, MD, PhD1

Symptoms and Functional Impairment Assessed 8 Months After Mild COVID-19 Among Health Care Workers

https://doi.org/10.1001/jama.2021.5612

Published

7-Apr-21

Research Letter

https://jamanetwork.com/journals/jama/fullarticle/2778528

Approximately 80% of hospitalized patients with COVID-19 report persistent symptoms several months after infection onset.1,2 However, knowledge of long-term outcomes among individuals with mild COVID-19 is scarce, and prevalence data are hampered by selection bias and suboptimal control groups.3,4 This cohort study investigated COVID-19–related long-term symptoms in health care professionals.
Comparing seropositive vs seronegative participants, 26% vs 9% reported at least 1 moderate to severe symptom lasting for at least 2 months (RR, 2.9 [95% CI, 2.2-3.8]) and 15% vs 3% reported at least 1 moderate to severe symptom lasting for at least 8 months (RR, 4.4 [95% CI, 2.9-6.7]) (Table). The most common moderate to severe symptoms lasting for at least 2 months in the seropositive group were anosmia, fatigue, ageusia, and dyspnea.

Of the seropositive participants, 8% reported that their long-term symptoms moderately to markedly disrupted their work life, compared with 4% of the seronegative participants (RR, 1.8 [95% CI, 1.2-2.9]); 15% reported their long-term symptoms moderately to markedly disrupted their social life, compared with 6% of the seronegative participants (RR, 2.5 [95% CI, 1.8-3.6]); and 12% reported that their long-term symptoms moderately to markedly disrupted their home life, compared with 5% of the seronegative participants (RR, 2.3 [95% CI, 1.6-3.4]) (Figure). Furthermore, 11% of the seropositive participants reported moderate to marked disruption in any Sheehan Disability Scale category as well as having at least 1 moderate to severe symptom lasting for at least 8 months, compared with 2% of the seronegative participants (RR, 4.5 [95% CI, 2.7-7.3]).

Une étude dans JAMA évalue à 15% des patients, sur une cohorte de malades de la covid (testés positifs), qui rapportent au moins un symptôme d'intensité modérée à sévère à 8 mois de l'infection. 8, 15 et 12% considèrent que ces symptômes impactent significativement et respectivement leur vie professionnelle, leur vie sociale et leur vie dans leur foyer.

N010

___Multi-symptoms___

Published research letter on 7-Apr-21:
"Symptoms and Functional Impairment Assessed 8 Months After Mild COVID-19 Among Health Care Workers"
Une étude dans JAMA évalue à 15% des patients, sur une cohorte de malades de la covid (testés positifs), qui rapportent au moins un symptôme d'intensité modérée à sévère à 8 mois de l'infection. 8, 15 et 12% considèrent que ces symptômes impactent significativement et respectivement leur vie professionnelle, leur vie sociale et leur vie dans leur foyer.
Link: https://jamanetwork.com/journals/jama/fullarticle/2778528
Extract: "Approximately 80% of hospitalized patients with COVID-19 report persistent symptoms several months after infection onset.1,2 However, knowledge of long-term outcomes among individuals with mild COVID-19 is scarce, and prevalence data are hampered by selection bias and suboptimal control groups.3,4 This cohort study investigated COVID-19–related long-term symptoms in health care professionals.
Comparing seropositive vs seronegative participants, 26% vs 9% reported at least 1 moderate to severe symptom lasting for at least 2 months (RR, 2.9 [95% CI, 2.2-3.8]) and 15% vs 3% reported at least 1 moderate to severe symptom lasting for at least 8 months (RR, 4.4 [95% CI, 2.9-6.7]) (Table). The most common moderate to severe symptoms lasting for at least 2 months in the seropositive group were anosmia, fatigue, ageusia, and dyspnea.

Of the seropositive participants, 8% reported that their long-term symptoms moderately to markedly disrupted their work life, compared with 4% of the seronegative participants (RR, 1.8 [95% CI, 1.2-2.9]); 15% reported their long-term symptoms moderately to markedly disrupted their social life, compared with 6% of the seronegative participants (RR, 2.5 [95% CI, 1.8-3.6]); and 12% reported that their long-term symptoms moderately to markedly disrupted their home life, compared with 5% of the seronegative participants (RR, 2.3 [95% CI, 1.6-3.4]) (Figure). Furthermore, 11% of the seropositive participants reported moderate to marked disruption in any Sheehan Disability Scale category as well as having at least 1 moderate to severe symptom lasting for at least 8 months, compared with 2% of the seronegative participants (RR, 4.5 [95% CI, 2.7-7.3])."

533

MS44

Ziyad Al-Aly, Yan Xie & Benjamin Bowe

High-dimensional characterization of post-acute sequalae of COVID-19

https://doi.org/10.1038/s41586-021-03553-9

Published

22-Apr-21

Study

https://www.nature.com/articles/s41586-021-03553-9

We show that beyond the first 30 days of illness, people with COVID-19 exhibit higher risk of death and health resource utilization. Our high dimensional approach identifies incident sequalae in the respiratory system and several others including nervous system and neurocognitive disorders, mental health disorders, metabolic disorders, cardiovascular disorders, gastrointestinal disorders, malaise, fatigue, musculoskeletal pain, and anemia. We show increased incident use of several therapeutics including pain medications (opioids and non-opioids), antidepressants, anxiolytics, antihypertensives, and oral hypoglycemics and evidence of laboratory abnormalities in multiple organ systems. Analysis of an array of pre-specified outcomes reveals a risk gradient that increased across severity of the acute COVID-19 infection (non-hospitalized, hospitalized, admitted to intensive care). The findings show that beyond the acute illness, substantial burden of health loss — spanning pulmonary and several extrapulmonary organ systems — is experienced by COVID-19 survivors.

La revue Nature publie une très large étude rétrospective avec groupe contrôle sur les séquelles de la covid. Une surmortalité d'environ 60% est rapportée chez les patients qui n'avaient pas été hospitalisés. Ce qui représente 0,8% de mortalité à +6 mois.

N009

___Multi-symptoms___

Published study on 22-Apr-21:
"High-dimensional characterization of post-acute sequalae of COVID-19"
La revue Nature publie une très large étude rétrospective avec groupe contrôle sur les séquelles de la covid. Une surmortalité d'environ 60% est rapportée chez les patients qui n'avaient pas été hospitalisés. Ce qui représente 0,8% de mortalité à +6 mois.
Link: https://www.nature.com/articles/s41586-021-03553-9
Extract: "We show that beyond the first 30 days of illness, people with COVID-19 exhibit higher risk of death and health resource utilization. Our high dimensional approach identifies incident sequalae in the respiratory system and several others including nervous system and neurocognitive disorders, mental health disorders, metabolic disorders, cardiovascular disorders, gastrointestinal disorders, malaise, fatigue, musculoskeletal pain, and anemia. We show increased incident use of several therapeutics including pain medications (opioids and non-opioids), antidepressants, anxiolytics, antihypertensives, and oral hypoglycemics and evidence of laboratory abnormalities in multiple organ systems. Analysis of an array of pre-specified outcomes reveals a risk gradient that increased across severity of the acute COVID-19 infection (non-hospitalized, hospitalized, admitted to intensive care). The findings show that beyond the acute illness, substantial burden of health loss — spanning pulmonary and several extrapulmonary organ systems — is experienced by COVID-19 survivors. "

534

MS45

Bruno Silva Andrade 1 ,Sérgio Siqueira 1,Wagner Rodrigues de Assis Soares 1,2 ,Preetam Ghosh 7 andDebmalya Barh 8,*

Long-COVID and Post-COVID Health Complications: An Up-to-Date Review on Clinical Conditions and Their Possible Molecular Mechanisms

https://doi.org/10.3390/v13040700

Published

18-Apr-21

Review

https://www.mdpi.com/1999-4915/13/4/700/htm

We conducted a comprehensive review of adverse post-COVID health outcomes and potential long-COVID effects. We observed that such adverse outcomes were not localized. Rather, they affected different human systems, including: (i) immune system (e.g., Guillain–Barré syndrome, rheumatoid arthritis, pediatric inflammatory multisystem syndromes such as Kawasaki disease), (ii) hematological system (vascular hemostasis, blood coagulation), (iii) pulmonary system (respiratory failure, pulmonary thromboembolism, pulmonary embolism, pneumonia, pulmonary vascular damage, pulmonary fibrosis), (iv) cardiovascular system (myocardial hypertrophy, coronary artery atherosclerosis, focal myocardial fibrosis, acute myocardial infarction, cardiac hypertrophy), (v) gastrointestinal, hepatic, and renal systems (diarrhea, nausea/vomiting, abdominal pain, anorexia, acid reflux, gastrointestinal hemorrhage, lack of appetite/constipation), (vi) skeletomuscular system (immune-mediated skin diseases, psoriasis, lupus), (vii) nervous system (loss of taste/smell/hearing, headaches, spasms, convulsions, confusion, visual impairment, nerve pain, dizziness, impaired consciousness, nausea/vomiting, hemiplegia, ataxia, stroke, cerebral hemorrhage), (viii) mental health (stress, depression and anxiety). We additionally hypothesized mechanisms of action by investigating possible molecular mechanisms associated with these disease outcomes/symptoms. Overall, the COVID-19 pathology is still characterized by cytokine storm that results to endothelial inflammation, microvascular thrombosis, and multiple organ failures.

Revue d'études très technique des mécanismes pathologiques de la covid et des symptômes de covid long.

N009

___Multi-symptoms___

Published review on 18-Apr-21:
"Long-COVID and Post-COVID Health Complications: An Up-to-Date Review on Clinical Conditions and Their Possible Molecular Mechanisms"
Revue d'études très technique des mécanismes pathologiques de la covid et des symptômes de covid long.
Link: https://www.mdpi.com/1999-4915/13/4/700/htm
Extract: "We conducted a comprehensive review of adverse post-COVID health outcomes and potential long-COVID effects. We observed that such adverse outcomes were not localized. Rather, they affected different human systems, including: (i) immune system (e.g., Guillain–Barré syndrome, rheumatoid arthritis, pediatric inflammatory multisystem syndromes such as Kawasaki disease), (ii) hematological system (vascular hemostasis, blood coagulation), (iii) pulmonary system (respiratory failure, pulmonary thromboembolism, pulmonary embolism, pneumonia, pulmonary vascular damage, pulmonary fibrosis), (iv) cardiovascular system (myocardial hypertrophy, coronary artery atherosclerosis, focal myocardial fibrosis, acute myocardial infarction, cardiac hypertrophy), (v) gastrointestinal, hepatic, and renal systems (diarrhea, nausea/vomiting, abdominal pain, anorexia, acid reflux, gastrointestinal hemorrhage, lack of appetite/constipation), (vi) skeletomuscular system (immune-mediated skin diseases, psoriasis, lupus), (vii) nervous system (loss of taste/smell/hearing, headaches, spasms, convulsions, confusion, visual impairment, nerve pain, dizziness, impaired consciousness, nausea/vomiting, hemiplegia, ataxia, stroke, cerebral hemorrhage), (viii) mental health (stress, depression and anxiety). We additionally hypothesized mechanisms of action by investigating possible molecular mechanisms associated with these disease outcomes/symptoms. Overall, the COVID-19 pathology is still characterized by cytokine storm that results to endothelial inflammation, microvascular thrombosis, and multiple organ failures."

535

MS46

Y. Meije, A. Duarte-Borges, X. Sanz, M. Clemente, Ribera A, L. Ortega, R. González-Pérez, R. Cid, J. Pareja, I. Cantero, M. Ariño, T. Sagués, J. LLaberia, A. Ayestarán, N. Fernández-Hidalgo, B. Candás-Estébanez

Long-term outcomes of patients following hospitalization for COVID-19: a prospective observational study

https://doi.org/10.1016/j.cmi.2021.04.002

Published

22-Apr-21

Study

https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(21)00170-1/fulltext

Facility follow-up: 302 patients were enrolled. Median follow-up was 45 days after discharge; 78% (228/294) of patients had COVID-19-related symptoms (53% asthenia, 56% respiratory symptoms) and 40% (122/302) had residual pulmonary radiographic lesions. PaO2/FiO2 <200 was an independent predictor of persistent dyspnea; OR = 1.87 (1.38 to 2.52), (p <0.0001). PaO2/FiO2 >300 was associated with resolution of chest radiographic lesions; OR = 0.56 (0.42 to 0.74), (p <0.0001). Fifty per cent of patients required specific medical follow-up after the first consultation and were transferred to another physician. Telephone follow-up: 294 patients were contacted after a median time follow-up of 7 months. Fifty per cent of patients (147/294) still presented symptoms and 49% (145/294) psychological disorders. Asthenia was identified in 27% (78/294) and dyspnea in 10% (28/294) of patients independently of PaO2/FiO2.

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536

MS47

Stephen J Gamble

Are There Possible Long-Term Effects Of Covid-19?

Published

1-May-21

Article

https://istonline.org.uk/the-tech-magazine/vol-2-no-1/are-there-possible-long-term-effects-of-covid-19/

COVID-19 is a worldwide pandemic caused by the SARS-CoV-2 Corona virus. Following the acute phase of the infection, a number of people exhibit post infection symptoms that may last for a number of months. Evidence is presented that some other viral infections may cause effects which present a number of years after the initial infection either as re-activation of dormant virus or as delayed effects on other systems. There is a growing body of evidence that SARS-CoV-2 may also cause some of these long delayed effects. As this infection has only existed for just over one year, the full extent of these long delayed effects cannot yet be fully evaluated.

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537

MS48

Marcus Yu Bin Pai Andrew Seung Ho Park Bruno Fu Lon Chen Juliana Takiguti Toma Hong Jin Pai

Health Complications in Patients Recovering from COVID-19: A Narrative Review of Post-COVID Syndrome

https://doi.org/10.9734/jammr/2021/v33i1030916

Published

8-May-21

Review

https://journaljammr.com/index.php/JAMMR/article/view/30916

Results: Fatigue, myalgia (i.e., muscle pain), sleep disruptions, and mental health issues (e.g., anxiety and depression) are among the most reported post-recovery symptoms in patients recovering from the disease. The etiology and potential management of these health complications are discussed, considering recently published findings from COVID-19 patients as well as previous studies focusing on complications arising from other related pandemics.

Conclusion: Patients who have recovered from COVID-19 should be evaluated for signs of fatigue, muscle pain, mental health difficulties, and sleeping difficulties regardless of disease severity. Based on this review of the literature, complete clinical and psychiatric evaluation, and the use of validated indicators of the severity of COVID-19 disease, symptoms are recommended to develop efficient health management approaches that meet patients' needs.

_

538

MS49

Lars Christian Lund, MD, Prof Jesper Hallas, DMSc, Prof Henrik Nielsen, DMSc, Anders Koch, PhD, Stine Hasling Mogensen, PhD, Nikolai Constantin Brun, PhD, Christian Fynbo Christiansen, PhD, Reimar Wernich Thomsen, PhD, Prof Anton Pottegård, DMSc

Post-acute effects of SARS-CoV-2 infection in individuals not requiring hospital admission: a Danish population-based cohort study

https://doi.org/10.1016/S1473-3099(21)00211-5

Published

10-May-21

Study

https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00211-5/fulltext

This was a population-based cohort study using the Danish prescription, patient, and health insurance registries. All individuals with a positive or negative RT-PCR test for SARS-CoV-2 in Denmark between Feb 27 and May 31, 2020, were eligible for inclusion. Outcomes of interest were delayed acute complications, chronic disease, hospital visits due to persisting symptoms, and prescription drug use. We used data from non-hospitalised SARS-CoV-2-positive and matched SARS-CoV-2-negative individuals from 2 weeks to 6 months after a SARS-CoV-2 test to obtain propensity score-weighted risk differences (RDs) and risk ratios (RRs) for initiation of 14 drug groups and 27 hospital diagnoses indicative of potential post-acute effects. We also calculated prior event rate ratio-adjusted rate ratios of overall health-care use. This study is registered in the EU Electronic Register of Post-Authorisation Studies (EUPAS37658).
Findings
10 498 eligible individuals tested positive for SARS-CoV-2 in Denmark from Feb 27 to May 31, 2020, of whom 8983 (85·6%) were alive and not admitted to hospital 2 weeks after their positive test. The matched SARS-CoV-2-negative reference population not admitted to hospital consisted of 80 894 individuals. Compared with SARS-CoV-2-negative individuals, SARS-CoV-2-positive individuals were not at an increased risk of initiating new drugs (RD <0·1%) except bronchodilating agents, specifically short-acting β2-agonists (117 [1·7%] of 6935 positive individuals vs 743 [1·3%] of 57 206 negative individuals; RD +0·4% [95% CI 0·1–0·7]; RR 1·32 [1·09–1·60]) and triptans (33 [0·4%] of 8292 vs 198 [0·3%] of 72 828; RD +0·1% [0·0–0·3]; RR 1·55 [1·07–2·25]). There was an increased risk of receiving hospital diagnoses of dyspnoea (103 [1·2%] of 8676 vs 499 [0·7%] of 76 728; RD +0·6% [0·4–0·8]; RR 2·00 [1·62–2·48]) and venous thromboembolism (20 [0·2%] of 8785 vs 110 [0·1%] of 78 872; RD +0·1% [0·0–0·2]; RR 1·77 [1·09–2·86]) for SARS-CoV-2-positive individuals compared with negative individuals, but no increased risk of other diagnoses. Prior event rate ratio-adjusted rate ratios of overall general practitioner visits (1·18 [95% CI 1·15–1·22]) and outpatient hospital visits (1·10 [1·05–1·16]), but not hospital admission, showed increases among SARS-CoV-2-positive individuals compared with SARS-CoV-2-negative individuals.
Interpretation
The absolute risk of severe post-acute complications after SARS-CoV-2 infection not requiring hospital admission is low. However, increases in visits to general practitioners and outpatient hospital visits could indicate COVID-19 sequelae.

_

539

MS50

MaxAugustinMDabc1PhilippSchommersM.D. PhD.acd1MelanieStecherPh.D.ac1FelixDewaldM.D.dLutzGieselmannM.D.dHenningGruellM.D.dCarolaHornM.D.abcKanikaVanshyllaPh.D.dVeronica DiCristanzianoM.D.dLuiseOseboldaMariaRoventaaToqeerRiazaNikolaiTschernosterM.SceJanineAltmuellerM.D.eLeonardRoseM.D.fSusanneSalomonPh.D.dVanessaPriesnerM.D.aJan ChristofferLuersProf.gChristianAlbusProf.hStephanRosenkranzProf.bijBirgitGathofProf.fGerdFätkenheuerProf.acMichaelHallekProf.abklFlorianKleinProf.bdIsabelleSuárezM.D.ac2ClaraLehmannProf.a

Post-COVID syndrome in non-hospitalised patients with COVID-19: a longitudinal prospective cohort study

https://doi.org/10.1016/j.lanepe.2021.100122

Published

18-May-21

Study

https://www.sciencedirect.com/science/article/pii/S2666776221000995

We present a longitudinal, prospective analysis of health consequences in patients who initially presented with no or minor symptoms of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection. Hence, we focus on mild COVID-19 in non-hospitalised patients.
Methods
958 Patients with confirmed SARS-CoV-2 infection were observed from April 6th to December 2nd 2020 for long-term symptoms and SARS-CoV-2 antibodies. We identified anosmia, ageusia, fatigue or shortness of breath as most common, persisting symptoms at month 4 and 7 and summarised presence of such long-term health consequences as post-COVID syndrome (PCS). Predictors of long-term symptoms were assessed using an uni- and multivariable logistic regression model.
Findings
We observed 442 and 353 patients over four and seven months after symptom onset, respectively. Four months post SARS-CoV-2 infection, 8•6% (38/442) of patients presented with shortness of breath, 12•4% (55/442) with anosmia, 11•1% (49/442) with ageusia and 9•7% (43/442) with fatigue. At least one of these characteristic symptoms was present in 27•8% (123/442) and 34•8% (123/353) at month 4 and 7 post-infection, respectively. A lower baseline level of SARS-CoV-2 IgG, anosmia and diarrhoea during acute COVID-19 were associated with higher risk to develop long-term

Une étude constate que des symptômes de diarrhée et d'anosmie et un niveau faible d'immunoglobuline G (anticorps neutralisant) pendant la phase aiguë sont associés à un risque plus élevé de développer un covid long.

N011

___Multi-symptoms___

Published study on 18-May-21:
"Post-COVID syndrome in non-hospitalised patients with COVID-19: a longitudinal prospective cohort study"
Une étude constate que des symptômes de diarrhée et d'anosmie et un niveau faible d'immunoglobuline G (anticorps neutralisant) pendant la phase aiguë sont associés à un risque plus élevé de développer un covid long.
Link: https://www.sciencedirect.com/science/article/pii/S2666776221000995
Extract: "We present a longitudinal, prospective analysis of health consequences in patients who initially presented with no or minor symptoms of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection. Hence, we focus on mild COVID-19 in non-hospitalised patients.
Methods
958 Patients with confirmed SARS-CoV-2 infection were observed from April 6th to December 2nd 2020 for long-term symptoms and SARS-CoV-2 antibodies. We identified anosmia, ageusia, fatigue or shortness of breath as most common, persisting symptoms at month 4 and 7 and summarised presence of such long-term health consequences as post-COVID syndrome (PCS). Predictors of long-term symptoms were assessed using an uni- and multivariable logistic regression model.
Findings
We observed 442 and 353 patients over four and seven months after symptom onset, respectively. Four months post SARS-CoV-2 infection, 8•6% (38/442) of patients presented with shortness of breath, 12•4% (55/442) with anosmia, 11•1% (49/442) with ageusia and 9•7% (43/442) with fatigue. At least one of these characteristic symptoms was present in 27•8% (123/442) and 34•8% (123/353) at month 4 and 7 post-infection, respectively. A lower baseline level of SARS-CoV-2 IgG, anosmia and diarrhoea during acute COVID-19 were associated with higher risk to develop long-term"

540

MS51

Sarah E Daugherty, senior researcher1, Yinglong Guo, director1, Kevin Heath, national medical director for clinical intelligence and physician2 , Micah C Dasmariñas, data scientist1, Karol Giuseppe Jubilo, data scientist1, Jirapat Samranvedhya, principal data scientist1, Marc Lipsitch, professor3, Ken Cohen

Risk of clinical sequelae after the acute phase of SARS-CoV-2 infection: retrospective cohort study

https://doi.org/10.1136/bmj.n1098

Published

19-May-21

Study

https://www.bmj.com/content/373/bmj.n1098

Results 14% of adults aged ≤65 who were infected with SARS-CoV-2 (27 074 of 193 113) had at least one new type of clinical sequelae that required medical care after the acute phase of the illness, which was 4.95% higher than in the 2020 comparator group. The risk for specific new sequelae attributable to SARS-Cov-2 infection after the acute phase, including chronic respiratory failure, cardiac arrythmia, hypercoagulability, encephalopathy, peripheral neuropathy, amnesia (memory difficulty), diabetes, liver test abnormalities, myocarditis, anxiety, and fatigue, was significantly greater than in the three comparator groups (2020, 2019, and viral lower respiratory tract illness groups) (all P<0.001). Significant risk differences because of SARS-CoV-2 infection ranged from 0.02 to 2.26 per 100 people (all P<0.001), and hazard ratios ranged from 1.24 to 25.65 compared with the 2020 comparator group.

Conclusions The results indicate the excess risk of developing new clinical sequelae after the acute phase of SARS-CoV-2 infection, including specific types of sequelae less commonly seen in other viral illnesses. Although individuals who were older, had pre-existing conditions, and were admitted to hospital because of covid-19 were at greatest excess risk, younger adults (aged ≤50), those with no pre-existing conditions, or those not admitted to hospital for covid-19 also had an increased risk of developing new clinical sequelae. The greater risk for incident sequelae after the acute phase of SARS-CoV-2 infection is relevant for healthcare planning.

Une très vaste étude statistique établit que 14% des personnes âgées de 65 ans et moins, infectées par le SRAS-CoV-2, ont développé au moins un nouveau type de séquelle clinique nécessitant des soins médicaux après la phase aiguë de l'infection.

N011

___Multi-symptoms___

Published study on 19-May-21:
"Risk of clinical sequelae after the acute phase of SARS-CoV-2 infection: retrospective cohort study"
Une très vaste étude statistique établit que 14% des personnes âgées de 65 ans et moins, infectées par le SRAS-CoV-2, ont développé au moins un nouveau type de séquelle clinique nécessitant des soins médicaux après la phase aiguë de l'infection.
Link: https://www.bmj.com/content/373/bmj.n1098
Extract: "Results 14% of adults aged ≤65 who were infected with SARS-CoV-2 (27 074 of 193 113) had at least one new type of clinical sequelae that required medical care after the acute phase of the illness, which was 4.95% higher than in the 2020 comparator group. The risk for specific new sequelae attributable to SARS-Cov-2 infection after the acute phase, including chronic respiratory failure, cardiac arrythmia, hypercoagulability, encephalopathy, peripheral neuropathy, amnesia (memory difficulty), diabetes, liver test abnormalities, myocarditis, anxiety, and fatigue, was significantly greater than in the three comparator groups (2020, 2019, and viral lower respiratory tract illness groups) (all P<0.001). Significant risk differences because of SARS-CoV-2 infection ranged from 0.02 to 2.26 per 100 people (all P<0.001), and hazard ratios ranged from 1.24 to 25.65 compared with the 2020 comparator group.

Conclusions The results indicate the excess risk of developing new clinical sequelae after the acute phase of SARS-CoV-2 infection, including specific types of sequelae less commonly seen in other viral illnesses. Although individuals who were older, had pre-existing conditions, and were admitted to hospital because of covid-19 were at greatest excess risk, younger adults (aged ≤50), those with no pre-existing conditions, or those not admitted to hospital for covid-19 also had an increased risk of developing new clinical sequelae. The greater risk for incident sequelae after the acute phase of SARS-CoV-2 infection is relevant for healthcare planning."

541

MS52

Tahmina Nasserie, MPH; Michael Hittle, BS; Steven N. Goodman

Assessment of the Frequency and Variety of Persistent Symptoms
Among Patients With COVID-19
A Systematic Review

https://doi.org/10.1001/jamanetworkopen.2021.11417

Published

26-May-21

Study

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2780376

Key Points
Question What are the frequency and
variety of persistent symptoms after
COVID-19 infection?
Findings
In this systematic review of 45
studies including 9751 participants with
COVID-19, the median proportion of
individuals who experienced at least 1persistent symptom was 73%;
symptoms occurring most frequently
included shortness of breath or
dyspnea, fatigue or exhaustion, and
sleep disorders or insomnia. However,
the studies were highly heterogeneous
and needed longer follow-up and more
standardized designs.
Meaning
This systematic review found
that COVID-19 symptoms commonly
persisted beyond the acute phase of
infection, with implications for health-associated functioning and quality of
life; however, methodological
improvements are needed to reliably
quantify these risks.

Une revue systématique dans JAMA, qui rassemble des études aux résultats très hétérogènes et centrées le plus souvent sur des patients hospitalisés, rapporte qu'entre 55 et 80% d'entre eux présente au moins un symptôme persistant à 2 mois.

542

MS53

PESE

Leonard A. Jason, Mohammed F. Islam, Karl Conroy, Joseph Cotler, Chelsea Torres, Mady Johnson & Brianna Mabie

COVID-19 symptoms over time: comparing long-haulers to ME/CFS

https://doi.org/10.1080/21641846.2021.1922140

Published

5-May-21

Study

https://www.tandfonline.com/doi/full/10.1080/21641846.2021.1922140

Over time, the long-haulers reported an overall reduction of most symptoms including unrefreshing sleep and post-exertional malaise, but an intensification of neurocognitive symptoms. When compared to ME/CFS, the COVID-19 sample was initially more symptomatic for the immune and orthostatic domains but over time, the long-haulers evidenced significantly less severe symptoms than those with ME/CFS, except in the orthostatic domain. Among the COVID-19 long haulers, several neurocognitive symptoms got worse over time, whereas improvements occurred in most other areas.

Comparée à des malades d'encéphalomyélite myalgique (EM), la cohorte de malades du covid long était, dans une étude, initialement plus symptomatique sur les aspects immunitaire et orthostatique, mais au fil du temps, ils ont présenté des symptômes significativement moins graves que ceux atteints d'EM, sauf dans le domaine orthostatique. Les malades du covid long ont également plus de troubles neurologiques à 5 mois qu'aux deux premières semaines de leur maladie.

N011

___Multi-symptoms___

Published study on 5-May-21:
"COVID-19 symptoms over time: comparing long-haulers to ME/CFS"
Comparée à des malades d'encéphalomyélite myalgique (EM), la cohorte de malades du covid long était, dans une étude, initialement plus symptomatique sur les aspects immunitaire et orthostatique, mais au fil du temps, ils ont présenté des symptômes significativement moins graves que ceux atteints d'EM, sauf dans le domaine orthostatique. Les malades du covid long ont également plus de troubles neurologiques à 5 mois qu'aux deux premières semaines de leur maladie.
Link: https://www.tandfonline.com/doi/full/10.1080/21641846.2021.1922140
Extract: "Over time, the long-haulers reported an overall reduction of most symptoms including unrefreshing sleep and post-exertional malaise, but an intensification of neurocognitive symptoms. When compared to ME/CFS, the COVID-19 sample was initially more symptomatic for the immune and orthostatic domains but over time, the long-haulers evidenced significantly less severe symptoms than those with ME/CFS, except in the orthostatic domain. Among the COVID-19 long haulers, several neurocognitive symptoms got worse over time, whereas improvements occurred in most other areas."

543

MS54

Naresh Kumar, Dhiraj Wasnik, Harsh Vardhan, MK Daga

Long Term Health Sequelae of COVID-19: A Review

Published

1-Jun-21

Review

http://medical.advancedresearchpublications.com/index.php/MedicineJournal/article/view/584

This review describes the effects of SARS-CoV-2 taking into account the previous experiences with SARS-CoV-2 and the Middle East Respiratory Syndrome (MERS) coronavirus that caused SARS in 2003 and MERS in 2012 respectively. This review aims to update on the long-term sequelae of SARS-CoV-2 infection and highlight the necessity for patient monitoring following the acute stage of infection with SARS-CoV-2 to provide ground for the prevention, diagnosis, and management of these potential long-term sequelae and to complete the natural history of COVID-19.

_

544

MS55

Sarmin Sultana, Mohammad Tanvir Islam, Marium Salwa, Shah M. Zakir Hossain, Md Nazmul Hasan, Abdullah A. Masum, Abed H. Khan, Md Maruf Haque Khan, M Atiqul Haque

Duration and Risk Factors of Post-COVID Symptoms Following Recovery Among the Medical Doctors in Bangladesh

https://doi.org/10.7759/cureus.15351

Published

31-May-21

Study

https://www.cureus.com/articles/59394-duration-and-risk-factors-of-post-covid-symptoms-following-recovery-among-the-medical-doctors-in-bangladesh

A large number of coronavirus disease 2019 (COVID-19) recovered patients are suffering from related symptoms. We conducted telephone interviews with 186 COVID-19 recovered medical doctors to determine the post-COVID symptoms, duration, and associated risk factors. About 70% of participants had at least one acute post-COVID symptom, including fatigue (43.0%), sleep disturbance (13.4%), lack of concentration (11.8%), breathing difficulty (10.2%), headache (6.5%), and muscle pain (6.5%). However, about 24% of participants reported having long post-COVID symptoms. Logistic regression analysis showed that female sex (odds ratio {OR}, 2.79; 95% CI, 1.28-6.06; p-value: 0.010) and comorbid conditions (OR, 2.28; 95% CI, 1.08-4.79; p: value, 0.030) are risk factors for the long post-COVID symptoms.

_

545

MS56

Emma Westerlind, Annie Palstam, Katharina S. Sunnerhagen & Hanna C. Persson

Patterns and predictors of sick leave after Covid-19 and long Covid in a national Swedish cohort

https://doi.org/10.1186/s12889-021-11013-2

Published

31-May-21

Study

https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-021-11013-2

A substantial number of people are on sick leave due to Covid-19. Sick leave may be protracted, and sick leave for long Covid is quite common. The severity of Covid-19 (needing inpatient care), prior sick leave, and age all seem to predict the likelihood of longer sick leave. However, no socioeconomic factor could clearly predict longer sick leave, indicating the complexity of this condition. The group needing long sick leave after Covid-19 seems to be heterogeneous, indicating a knowledge gap.

_

546

MS57

Rosa María Wong-Chew , Edwin Xchel Rodríguez Cabrera , Carlos Alberto Rodríguez Valdez , Diego-Abelardo Álvarez-Hernández logo , Héctor Gallardo-Rincón * , German Fajardo Dolci , Roberto Tapia-Conyer , Rafael Ricardo Valdez Vazquez

Symptom Cluster Analysis of long COVID-19 in Patients Discharged from the Temporary COVID-19 Hospital in Mexico City: A Longitudinal Study

https://doi.org/10.20944/preprints202106.0011.v1

pre-print

1-Jun-21

Study

https://www.preprints.org/manuscript/202106.0011/v1

As further research is needed, we conducted a longitudinal observational study to report the prevalence and associated risk factors of long-term health consequences of COVID-19 by symptom clusters in patients discharged from the Temporary COVID-19 Hospital (TCH) in Mexico City. Self-reported clinical symptom data were collected via telephone calls over 90 days post-discharge. Among 4670 patients discharged from the TCH, we identified 45 symptoms across eight symptom clusters (neurological; mood disorders; systemic; respiratory; musculoskeletal; ear, nose, and throat; dermatological; and gastrointestinal). We observed that the neurological, dermatological, and mood disorder symptom clusters persisted in >30% of patients at 90 days post-discharge. Although most symptoms decreased in frequency between day 30 and 90, alopecia and the dermatological symptom cluster significantly increased (p<0·00001). Women were more prone than men to develop long-term symptoms and invasive mechanical ventilation also increased the frequency of symptoms at 30-days post-discharge. Overall, we observed that symptoms often persisted regardless of disease severity. We hope these findings will help promote public health strategies that ensure equity in the access to solutions focused on the long-term consequences of COVID-19.

_

547

MS58

Sherif M Shoucri1, Lawrence Purpura1, Clare DeLaurentis2, Matthew A Adan3, Deborah A Theodore1, Alexandria Lauren Irace3, Karthik Natarajan4, George Hripcsak4, Ruijun Chen4,5, Michael T Yin1, Magdalena E Sobieszczyk1, Delivette Castor1, Jason E Zucker1

Characterising the long-term clinical outcomes of 1190 hospitalised patients with COVID-19 in New York City: a retrospective case series

http://dx.doi.org/10.1136/bmjopen-2021-049488

Published

2-Jun-21

Study

https://bmjopen.bmj.com/content/11/6/e049488.full

Of the 1190 reviewed patients, 929 survived their initial hospitalisation and 261 died. Among survivors, 570 had follow-up encounters (488 at 3 months and 364 at 6 months). An additional 33 patients died in the follow-up period. In the first 3 months after admission, most encounters were telehealth visits (59%). Cardiopulmonary symptoms (35.7% and 28%), especially dyspnoea (22.1% and 15.9%), were the most common reported symptoms at 3-month and 6-month encounters, respectively. Additionally, a large number of patients reported generalised (26.4%) or neuropsychiatric (24.2%) symptoms 6 months after hospitalisation. Patients with severe COVID-19 were more likely to have reduced mobility, reduced independence or a new dialysis requirement in the 6 months after hospitalisation.

Conclusions Patients hospitalised with SARS-CoV-2 infection reported persistent symptoms up to 6 months after diagnosis. These results highlight the long-term morbidity of COVID-19 and its burden on patients and healthcare resources.

_

548

MS59

Sanjay Pujari 1, Sunil Gaikwad 1, Abhishek Chitalikar 1, Digamber Dabhade 1, Kedar Joshi 1, Vivek Bele 1

Long-coronavirus disease among people living with HIV in western India: An observational study

https://doi.org/10.1002/iid3.467

Published

2-Jun-21

Study

https://pubmed.ncbi.nlm.nih.gov/34078004/

Results: Ninety-four PLHIV were screened for long-COVID. Median (interquartile range [IQR]) age was 51 (47-56) years and 73.4% were males. The majority (76.6%) had a history of asymptomatic-mild COVID-19 illness. The prevalence of long-COVID was 43.6% (95% confidence interval [CI], 33.4-54.2). Moderate-severe COVID-19 illness was significantly associated with long-COVID (adjusted odds ratio, 4.7; 95% CI, 1.4-17.9; p = .016). Among individuals with long-COVID, cough (22.3%) and fatigue (19.1%) were the commonest symptoms. The median (IQR) duration for resolution of symptoms was 15 (7-30) days. Ten individuals (10.6%) had persistent symptoms at a median of 109 days since the onset of COVID-19.

Conclusion: Long-COVID is common among PLHIV with moderate-severe acute COVID-19 illness. There is a need for integration of long-COVID diagnosis and care services within antiretroviral therapy clinics for PLHIV with COVID-19.

_

549

MS60

Maddalena Peghin, Alvisa Palese, Margherita Venturini, Maria De Martino, Valentina Gerussin, Elena Graziano, Giulia Bontempo, Francesco Marrella, Alberto Tommasini, Martina Fabris, Francesco Curcio, Miriam Isola, Carlo Tascini

Post-COVID-19 symptoms 6 months after acute infection among hospitalized and non-hospitalized patients

https://doi.org/10.1016/j.cmi.2021.05.033

Published

6-Jun-21

Study

https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(21)00281-0/fulltext

A bidirectional prospective study. Interviews investigated symptoms potentially associated with COVID-19 six months after the disease onset of all consecutive adult in- and out-patients with COVID-19 attending Udine Hospital (Italy) from March to May 2020. IgG antibodies against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) were also evaluated six months after the onset of symptoms, at the time of the interview.
Results
A total of 599 individuals were included (320 female, 53.4%; mean age 53 years, SD 15.8) and interviewed 187 days (22 SD) after the onset. The prevalence of post-COVID-19 syndrome was 40.2% (241/599). The presence of IgG antibodies was significantly associated with the occurrence of post-COVID-19 syndrome (OR 2.56, 95% CI 1.48–4.38, p = 0.001) and median SARS-CoV-2 IgG titres were significantly higher in long-haulers than in patients without symptoms (42.1, IQR 17.1-78.4 vs. 29.1, IQR 12.1-54.2 kAU/L, p = 0.004). Female gender (OR 1.55, 95% CI 1.05–2.27), a proportional increase in the number of symptoms at the onset of COVID-19 (OR 1.81, 95% CI 1.59–2.05) and ICU admission OR 3.10, 95% CI 1.18–8.11) were all independent risk factors for post-COVID-19 syndrome. The same predictors also emerged in a subgroup of 231 patients with the serological follow-up available at the time of the interview alongside the proportional increase in anti-SARS-CoV-2 IgG (OR 1.01, 95% CI 1.00–1.02, p = 0.04).
Conclusions
Prospective follow-up could be offered to specific subgroups of COVID-10 patients, to identify typical symptoms and persistently high anti-SARS-CoV-2 IgG titers as a means of early detection of post-COVID-19 long-term sequelae.

_

550

MS61

Domingo FR, Waddell LA, Cheung AM, Cooper CL, Belcourt VJ, Zuckermann AME, Corrin T, Ahmad R, Boland L, Laprise C, Idzerda L, Khan A, Garcia AJ

Prevalence of long-term effects in individuals diagnosed with COVID-19: a living systematic review

https://doi.org/10.1101/2021.06.03.21258317

pre-print

6-Jun-21

Study

https://www.medrxiv.org/content/10.1101/2021.06.03.21258317v1

Of the 2807 unique citations, 36 observational studies met our inclusion criteria. Over 100 post COVID-19 conditions were reported in laboratory-confirmed individuals. Eighty-three percent (95%CI: 65-93%; low certainty ) and 56% (95%CI: 34-75%; very low certainty ) reported persistence or presence of one or more symptoms in the short- and long-term, respectively. The most prevalent symptoms in both periods included: fatigue, general pain or discomfort, sleep disturbances, shortness of breath and anxiety or depression (point estimates ranging from 22-51%; low to very low certainty ).

_

551

MS62

Anna Schandl 1 2 3, Anders Hedman 4 2, Patrik Lyngå 4 2, Sozan Fathi Tachinabad 5, Jessica Svefors 5, Mari Roël 5, Anne Geborek 5, Mikael Andersson Franko 2, Mårten Söderberg 5 2, Eva-Joelsson-Alm 1 2, Pernilla Darlington 5 2

Long-term consequences in critically ill COVID-19 patients: a prospective cohort study

https://doi.org/10.1111/aas.13939

Published

7-Jun-21

Study

https://pubmed.ncbi.nlm.nih.gov/34097753/

Results: Among 248 ICU patients, 200 patients survived. Of these, 113 patients came for follow-up. Seventy patients (62%) had received invasive ventilation. Most patients reported impaired health-related quality of life. Approximately one third suffered from posttraumatic stress, anxiety and depression. Twenty-six percent had reduced total lung capacity, 34% had reduced 6MWT and 50% worked fulltime. The outcomes were similar regardless of ventilatory support, but invasive ventilation was associated with more bodily pain (MSD -19, 95% CI: -32 to -5) and <80% total lung capacity (OR 4.1, 95% CI: 1.3-16.5).

_

552

MS63

A FAIR Health White Paper

A Detailed Study of Patients with
Long-Haul COVID - An Analysis of Private Healthcare Claims

Published

15-Jun-21

Study

https://s3.amazonaws.com/media2.fairhealth.org/whitepaper/asset/A%20Detailed%20Study%20of%20Patients%20with%20Long-Haul%20COVID--An%20Analysis%20of%20Private%20Healthcare%20Claims--A%20FAIR%20Health%20White%20Paper.pdf

_

553

MS64

Paolo Boscolo-Rizzo MD, Francesco Guida MD, Jerry Polesel ScD, Alberto Vito Marcuzzo MD, Vincenzo Capriotti MD, Nicoletta Gardenal MD, Martino Pengo MD, Giancarlo Tirelli MD

Sequelae in adults at 12 months after mild-to-moderate coronavirus disease 2019 (COVID-19)

https://doi.org/10.1002/alr.22832

Published

9-Jun-21

Study

https://onlinelibrary.wiley.com/doi/full/10.1002/alr.22832

Patients were considered mild-to-moderately symptomatic if they had less severe clinical symptoms, oxygen saturation (SpO2) ≥ 94%, not requiring hospitalization, and therefore considered suitable for being treated at home. Asymptomatic patients were not included in the study.

Of the 496 eligible patients, 354 (71.4%) completed the baseline telephone interview, which was conducted within 3 weeks after the first positive swab performed from March 1, 2020 to March 31, 2020. The median time from onset of symptoms to SARS-CoV-2 testing was 7 days (interquartile range [IQR], 4–12 days). The median age of the study cohort was 47 years (range, 18–76 years). Persistence of at least one symptom at 12 months was reported by 161 patients (53.0%) with the most frequent being "felt tired" (n = 83, 27.3%), followed by "smell or taste impairment" (n = 67, 22.0%), "shortness of breath" (n = 39, 12.8%), and "muscle pain" (n = 28, 9.2%).

Sur une cohorte de 304 patients qui ont accepté pendant un an de répondre à une enquête téléphonique pour le suivi de leurs symptômes de la covid (ni hospitalisés, ni asymptomatiques), sur 496 éligibles initialement, 161 patients déclarent garder au moins un symptôme à un an. Parmi les plus fréquents : fatigue (83), pertes d'odorat (67), essoufflement (39) douleurs musculaires (28).
Le fait d'être une femme, d'avoir entre 40 et 54 ans, d'avoir un IMC ≥ 25, d'avoir eu plus de 3, voire plus de 8 symptômes en phase initiale est corrélé avec un plus fort risque de conserver des symptômes.

N011

___Multi-symptoms___

Published study on 9-Jun-21:
"Sequelae in adults at 12 months after mild-to-moderate coronavirus disease 2019 (COVID-19)"
Sur une cohorte de 304 patients qui ont accepté pendant un an de répondre à une enquête téléphonique pour le suivi de leurs symptômes de la covid (ni hospitalisés, ni asymptomatiques), sur 496 éligibles initialement, 161 patients déclarent garder au moins un symptôme à un an. Parmi les plus fréquents : fatigue (83), pertes d'odorat (67), essoufflement (39) douleurs musculaires (28).
Le fait d'être une femme, d'avoir entre 40 et 54 ans, d'avoir un IMC ≥ 25, d'avoir eu plus de 3, voire plus de 8 symptômes en phase initiale est corrélé avec un plus fort risque de conserver des symptômes.
Link: https://onlinelibrary.wiley.com/doi/full/10.1002/alr.22832
Extract: "Patients were considered mild-to-moderately symptomatic if they had less severe clinical symptoms, oxygen saturation (SpO2) ≥ 94%, not requiring hospitalization, and therefore considered suitable for being treated at home. Asymptomatic patients were not included in the study.

Of the 496 eligible patients, 354 (71.4%) completed the baseline telephone interview, which was conducted within 3 weeks after the first positive swab performed from March 1, 2020 to March 31, 2020. The median time from onset of symptoms to SARS-CoV-2 testing was 7 days (interquartile range [IQR], 4–12 days). The median age of the study cohort was 47 years (range, 18–76 years). Persistence of at least one symptom at 12 months was reported by 161 patients (53.0%) with the most frequent being "felt tired" (n = 83, 27.3%), followed by "smell or taste impairment" (n = 67, 22.0%), "shortness of breath" (n = 39, 12.8%), and "muscle pain" (n = 28, 9.2%)."

554

MS65

Rebecca R Taylor 1, Bhavi Trivedi 1, Neena Patel 1, Richa Singh 1, William M Ricketts 2, Katharine Elliott 1, Marcus Yarwood 1, Veronica White 1, Hannah Hylton 1, Ruth Allen 1, Gavin Thomas 1, Vikas Kapil 3, Rachel McGuckin 1, Paul E Pfeffer 4

Post-COVID symptoms reported at asynchronous virtual review and stratified follow-up after COVID-19 pneumonia

https://doi.org/10.7861/clinmed.2021-0037

Published

8-Jun-21

Study

https://pubmed.ncbi.nlm.nih.gov/34103378/

Patients reviewed after hospitalisation for COVID pneumonia had a median of two ongoing physical health symptoms post-COVID. The most common was fatigue (50.3% of high-risk patients). Symptom burden did not vary significantly by severity of hospitalised COVID pneumonia but was highest in community referrals. Symptoms suggestive of depression, anxiety and post-traumatic stress disorder were common (depression occurred in 24.9% of high-risk patients). Asynchronous virtual review facilitated triage of patients at highest need of face-to-face review.

_

555

MS66

CésarFernández-de-las-PeñasPhD1DomingoPalacios-CeñaPhD1VíctorGómez-MayordomoMD2Lidiane LFlorencioPhD1María L.CuadradoPhD23GustavoPlaza-ManzanoPhD45MarcosNavarro-Santana

Prevalence of Post-COVID-19 Symptoms in Hospitalized and Non-Hospitalized COVID-19 Survivors: A Systematic Review and Meta-Analysis

https://doi.org/10.1016/j.ejim.2021.06.009

Published

16-Jun-21

Systematic Review and Meta-Analysis

https://www.sciencedirect.com/science/article/pii/S0953620521002089

Highlights
•This meta-analysis quantitively analysed data from 29 peer-reviewed studies and 4 preprints.
•The results showed that 63.2%, 71.9% and 45.9% of the sample exhibited ≥one post-COVID symptoms 30, 60, or ≥90days after onset or hospitalization.
•Fatigue and dyspnea were the most prevalent symptoms (pooled prevalence from 35% to 60%) depending on the follow-up period
•The prevalence of each post-COVID symptom in isolation dropped off 30days after (10-15%) but increased at 60days or longer after (40-60%) onset.

Une méta-analyse évalue la prévalence des symptômes sur le long terme de la covid depuis des études comprenant des malades hospitalisés et non hospitalisés. L'estimation note 46% de patients encore symptomatiques à 3 mois, avec un pic à 2 mois.

N011

___Multi-symptoms___

Published systematic review and meta-analysis on 16-Jun-21:
"Prevalence of Post-COVID-19 Symptoms in Hospitalized and Non-Hospitalized COVID-19 Survivors: A Systematic Review and Meta-Analysis"
Une méta-analyse évalue la prévalence des symptômes sur le long terme de la covid depuis des études comprenant des malades hospitalisés et non hospitalisés. L'estimation note 46% de patients encore symptomatiques à 3 mois, avec un pic à 2 mois.
Link: https://www.sciencedirect.com/science/article/pii/S0953620521002089
Extract: "Highlights
•This meta-analysis quantitively analysed data from 29 peer-reviewed studies and 4 preprints.
•The results showed that 63.2%, 71.9% and 45.9% of the sample exhibited ≥one post-COVID symptoms 30, 60, or ≥90days after onset or hospitalization.
•Fatigue and dyspnea were the most prevalent symptoms (pooled prevalence from 35% to 60%) depending on the follow-up period
•The prevalence of each post-COVID symptom in isolation dropped off 30days after (10-15%) but increased at 60days or longer after (40-60%) onset."

556

MS67

Sandra Ekström, Niklas Andersson, Alexandra Lövquist, André Lauber, Antonios Georgelis, Inger Kull, Erik Melén, Anna Bergström

COVID-19 among young adults in Sweden: self-reported long-term symptoms and associated factors

https://doi.org/10.1177%2F14034948211025425

Published

19-Jun-21

Study

https://journals.sagepub.com/doi/abs/10.1177/14034948211025425

The study population includes 1644 participants aged 23–26 years from the Swedish population-based birth cohort BAMSE. From August to November 2020, the participants answered a web questionnaire on COVID-19 symptoms, lifestyle and health. Information on tobacco use was compared against the previous study follow-up in 2016–2019.
Results: The prevalence of suspected COVID-19 symptoms was 45.3% (n=742), and 80 of these (10.8%) reported long-term symptoms (⩾4 weeks). There was no significant difference in sociodemographic or lifestyle factors in relation to the duration of suspected COVID-19 symptoms. Rhinitis, migraine and lower self-rated health before the pandemic was more common among participants with long-term symptoms. In addition, there was a tendency for higher prevalences of asthma, chronic bronchitis and depression in this group. The prevalence of smoking decreased from 18.9% before the pandemic to 14.7% during the pandemic, while snuff use increased from 12.7% to 22.4% (P<0.001).

Une étude suédoise qui suit des participants issus d'une cohorte nationale représentative de la population compte 11% des malades avec des symptômes persistants au moins un mois.

N011

___Multi-symptoms___

Published study on 19-Jun-21:
"COVID-19 among young adults in Sweden: self-reported long-term symptoms and associated factors"
Une étude suédoise qui suit des participants issus d'une cohorte nationale représentative de la population compte 11% des malades avec des symptômes persistants au moins un mois.
Link: https://journals.sagepub.com/doi/abs/10.1177/14034948211025425
Extract: "The study population includes 1644 participants aged 23–26 years from the Swedish population-based birth cohort BAMSE. From August to November 2020, the participants answered a web questionnaire on COVID-19 symptoms, lifestyle and health. Information on tobacco use was compared against the previous study follow-up in 2016–2019.
Results: The prevalence of suspected COVID-19 symptoms was 45.3% (n=742), and 80 of these (10.8%) reported long-term symptoms (⩾4 weeks). There was no significant difference in sociodemographic or lifestyle factors in relation to the duration of suspected COVID-19 symptoms. Rhinitis, migraine and lower self-rated health before the pandemic was more common among participants with long-term symptoms. In addition, there was a tendency for higher prevalences of asthma, chronic bronchitis and depression in this group. The prevalence of smoking decreased from 18.9% before the pandemic to 14.7% during the pandemic, while snuff use increased from 12.7% to 22.4% (P<0.001)."

557

MS68

Cecilie Delphin Amdal, Madeline Pe, Ragnhild Sørum Falk, Claire Piccinin, Andrew Bottomley, Juan Ignacio Arraras, Anne Sophie Darlington, Kristin Hofsø, Bernard Holzner, Nina Marie Høyning Jørgensen, Dagmara Kulis, Stein Arne Rimehaug, Susanne Singer, Katherine Taylor, Sally Wheelwright & Kristin Bjordal

Health-related quality of life issues, including symptoms, in patients with active COVID-19 or post COVID-19; a systematic literature review

https://doi.org/10.1007/s11136-021-02908-z

Published

19-Jun-21

Review

https://link.springer.com/article/10.1007/s11136-021-02908-z

This first comprehensive systematic review provides a detailed overview of the wide range of HRQoL issues experienced by patients with COVID-19 throughout the course of the disease. It demonstrates the devastating impact of the disease and provides critically important information for clinicians, to enable them to better recognize the disease and to provide knowledge important for treatment and follow-up. The results provided the foundation for the international development of a COVID-19 specific patient-reported HRQoL questionnaire.

Une revue systématique d'études entreprend de caractériser tous les impacts sur la qualité de vie liés à la persistance de symptômes de la covid, et s'intéresse aux différences par tranches d'âge et par sexe.

N011

___Multi-symptoms___

Published review on 19-Jun-21:
"Health-related quality of life issues, including symptoms, in patients with active COVID-19 or post COVID-19; a systematic literature review"
Une revue systématique d'études entreprend de caractériser tous les impacts sur la qualité de vie liés à la persistance de symptômes de la covid, et s'intéresse aux différences par tranches d'âge et par sexe.
Link: https://link.springer.com/article/10.1007/s11136-021-02908-z
Extract: "This first comprehensive systematic review provides a detailed overview of the wide range of HRQoL issues experienced by patients with COVID-19 throughout the course of the disease. It demonstrates the devastating impact of the disease and provides critically important information for clinicians, to enable them to better recognize the disease and to provide knowledge important for treatment and follow-up. The results provided the foundation for the international development of a COVID-19 specific patient-reported HRQoL questionnaire."

558

MS69

César Fernández-de-las-Peñas, Víctor Gómez-Mayordomo, María L Cuadrado, Domingo Palacios-Ceña, Lidiane L Florencio, Angel L Guerrero, David García-Azorín, Valentín Hernández-Barrera, Lars Arendt-Nielsen

The presence of headache at onset in SARS-CoV-2 infection is associated with long-term post-COVID headache and fatigue: A case-control study

https://doi.org/10.1177%2F03331024211020404

Published

16-Jun-21

Study

https://journals.sagepub.com/doi/full/10.1177/03331024211020404

Overall, 205 patients reporting headache and 410 patients without headache at hospitalisation were assessed 7.3 months (Standard Deviation 0.6) after hospital discharge. Patients with headache at onset presented a higher number of post-COVID symptoms (Incident Rate Ratio: 1.16, 95% CI: 1.03–1.30). Headache at onset was associated with a previous history of migraine (Odd Ratio: 2.90, 95% Confidence Interval: 1.41–5.98) and with the development of persistent tension-type like headache as a new post-COVID symptom (Odd Ratio: 2.65, 95% CI: 1.66–4.24). Fatigue as a long-term symptom was also more prevalent in patients with headache at onset (Odd Ratio: 1.55, 95% CI: 1.07–2.24). No between-group differences in the prevalence of anxiety/depressive symptoms or sleep quality were seen.

_

559

MS70

Malhotra P*
, Malhotra V, Gupta U, Sanwariya Y, Pahuja I and Akshay

Post Covid-19 Complications After First Wave in Haryana

Published

18-Jun-21

Research Article

https://www.researchgate.net/profile/Parveen-Malhotra/publication/352476274_Post_Covid-19_Complications_After_First_Wave_in_Haryana/links/60cac8e092851ca3aca738f2/Post-Covid-19-Complications-After-First-Wave-in-Haryana.pdf

Materials and Methods: It was a cross sectional study con-
ducted at Department of Medical Gastroenterology, Post Graduate
Institute of Medical Sciences (PGIMS), Rohtak, over a period of two
months i.e. from 01.03.2021 to 30.04.2021. The 25,000 confirmed
patients of first wave of Covid-19 infection who have recovered six
months prior from this illness, belonging to various parts of Haryana
were enrolled in the study.
1.4. Results: Out of these twenty-five thousand patients of Covid-19
infection, only Sixty-five (65) i.e. 0.26 % patients developed Post
Covid complications. It is pertinent to mention that these patients
belonged to first wave of Covid-19 infection in India which started
in March, 2020.

_

560

MS71

Bjørn Blomberg, Kristin Greve-Isdahl Mohn, Karl Albert Brokstad, Fan Zhou, Dagrun Waag Linchausen, Bent-Are Hansen, Sarah Lartey, Therese Bredholt Onyango, Kanika Kuwelker, Marianne Sævik, Hauke Bartsch, Camilla Tøndel, Bård Reiakvam Kittang, Bergen COVID-19 Research Group, Rebecca Jane Cox & Nina Langeland

Long COVID in a prospective cohort of home-isolated patients

https://doi.org/10.1038/s41591-021-01433-3

Published

23-Jun-21

Study

https://www.nature.com/articles/s41591-021-01433-3

We conducted a long-term follow-up in a prospective cohort study of 312 patients—247 home-isolated and 65 hospitalized—comprising 82% of total cases in Bergen during the first pandemic wave in Norway. At 6 months, 61% (189/312) of all patients had persistent symptoms, which were independently associated with severity of initial illness, increased convalescent antibody titers and pre-existing chronic lung disease. We found that 52% (32/61) of home-isolated young adults, aged 16–30 years, had symptoms at 6 months, including loss of taste and/or smell (28%, 17/61), fatigue (21%, 13/61), dyspnea (13%, 8/61), impaired concentration (13%, 8/61) and memory problems (11%, 7/61). Our findings that young, home-isolated adults with mild COVID-19 are at risk of long-lasting dyspnea and cognitive symptoms highlight the importance of infection control measures, such as vaccination.

561

MS72

Elda Righi, Massimo Mirandola, Fulvia Mazzaferri, Elisa Razzaboni, Amina Zaffagnini, Anna Erbogasto, Ilaria Dalla Vecchia, Nina Auerbach, Federico Ivaldi, Maria Mongardi, Pietro Minuz, Michele Milella, Sara Mehrabi, Oliviero Olivieri, Domenico Girelli, Enrico Polati, Claudio Micheletto & Evelina Tacconelli

Long-Term Patient-Centred Follow-up in a Prospective Cohort of Patients with COVID-19

https://doi.org/10.1007/s40121-021-00461-3

Published

21-Jun-21

Study

https://link.springer.com/article/10.1007/s40121-021-00461-3

A total of 448 patients (55% men, median age 56 years) were enrolled. WHO-CPS showed mild, moderate and severe disease in 48%, 42% and 10% of patients at admission and mild disease in all patients at follow-up, respectively. BI and aSGRQ were normal in 96% and 93% patients before COVID-19 but only in 47% and 16% at COVID-19 diagnosis and in 87% and 65% at 6-week follow-up. Male gender was identified by all three assessments as a predictor of impaired general health (BI, OR 2.14, p < 0.0001; aSGRQ, OR 0.53, p = 0.003; WHO-CPS, OR 1.56, p = 0.01). Other predictors included age, ICU admission and comorbidities (e.g. cardiovascular disease and cancer) for BI, hospital admission for aSGRQ, age and presence of comorbidities for WHO-CPS. At 6- and 12-week follow-up, 39% and 20% of patients, respectively, were still reporting symptoms. Fatigue and breathlessness were the most frequently reported symptoms.

562

MS73

Verena Hennig, Wolfgang Schuh, Antje Neubert, Dirk Mielenz, Hans-Martin Jäck, Holm Schneider

Increased risk of chronic fatigue and hair loss following COVID-19 in individuals with hypohidrotic ectodermal dysplasia

https://doi.org/10.21203/rs.3.rs-529105/v1

pre-print

25-Jun-21

Study

https://www.researchsquare.com/article/rs-529105/v1

HED appears to be associated with an increased risk of long-term consequences of a SARS-CoV-2 infection. Preventive vaccination against COVID-19 should be recommended for individuals affected by this rare genetic disorder.

_

563

MS74

Sandra Willi,a,b,∗ Renata Lüthold,b Adam Hunt,b Nadescha Viviane Hänggi,b Donikë Sejdiu,b Camila Scaff,b Nicole Bender,b,1 Kaspar Staub,b,c,1 and Patricia Schlagenhaufa,1

COVID-19 sequelae in adults aged less than 50 years: A systematic review

https://dx.doi.org/10.1016%2Fj.tmaid.2021.101995

Published

22-Feb-21

Review

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898978/

Study types included prospective and retrospective cohort studies, cross-sectional studies and case reports. Sequelae persistence since infection spanned 14 days to three months. Sequelae included persistent fatigue (39–73% of assessed persons), breathlessness (39–74%), decrease in quality of life (44–69%), impaired pulmonary function, abnormal CT findings including pulmonary fibrosis (39–83%), evidence of peri-/perimyo-/myocarditis (3–26%), changes in microstructural and functional brain integrity with persistent neurological symptoms (55%), increased incidence of psychiatric diagnoses (5.8% versus 2.5–3.4% in controls), incomplete recovery of olfactory and gustatory dysfunction (33–36% of evaluated persons).

564

MS75

Anup Bastola 1 ,Richa Nepal 2,* ,Bikesh Shrestha 2,Kijan Maharjan 2,Sanjay Shrestha 2 ,Bimal Sharma Chalise 2 andJenish Neupane 2

Persistent Symptoms in Post-COVID-19 Patients Attending Follow-Up OPD at Sukraraj Tropical and Infectious Disease Hospital (STIDH), Kathmandu, Nepal

https://doi.org/10.3390/tropicalmed6030113

Published

28-Jun-21

Study

https://www.mdpi.com/2414-6366/6/3/113/htm

All patients, presenting to the outpatient clinic during the study duration of six weeks, with history of positive reverse transcriptase- polymerase chain reaction for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) at least two weeks prior to presentation, were included. The duration of follow-up ranged from 15 till 150 days with the mean duration of 28 days after diagnosis of COVID-19. Of 118 patients, 43 (36.4%) had a history of mild COVID-19, 15 (12.8%) had moderate, and 60 (50.8%) had severe. At the time of presentation, 97 (82.2%) patients reported that they had at least one persistent/new symptom beyond two weeks from the diagnosis of COVID-19. Dyspnea, fatigue, chest heaviness, and cough were the commonest persistent complaints in 48 (40.7%), 39 (33.1%), 33 (28%), and 32 (27.1%) patients, respectively.

_

565

MS76

Francesca Reyes Domingo, Lisa A Waddell, Angela M. Cheung, Curtis L. Cooper, Veronica J. Belcourt, Alexandra M. E. Zuckermann, Tricia Corrin, Rukshanda Ahmad, Laura Boland, Claudie Laprise, Leanne Idzerda, Anam Khan, Alejandra Jaramillo Garcia

Prevalence of long-term effects in individuals diagnosed with COVID-19: a living systematic review

https://doi.org/10.1101/2021.06.03.21258317

pre-print

6-Jun-21

Study

https://www.medrxiv.org/content/10.1101/2021.06.03.21258317v1

Of the 2807 unique citations, 36 observational studies met our inclusion criteria. Over 100 post COVID-19 conditions were reported in laboratory-confirmed individuals. Eighty-three percent (95%CI: 65-93%; low certainty) and 56% (95%CI: 34-75%; very low certainty) reported persistence or presence of one or more symptoms in the short- and long-term, respectively. The most prevalent symptoms in both periods included: fatigue, general pain or discomfort, sleep disturbances, shortness of breath and anxiety or depression (point estimates ranging from 22-51%; low to very low certainty).

_

566

MS77

Louis Jacob MD-Ph Dabc Ai Koyanagi MD-PhDd Lee Smith Ph De Christian Tanislav MD-PhD f Marcel Konrad PhDg Susannevan der Beckh Karel Kostev PhDh

Prevalence of and factors associated with long-term COVID-19 sick leave in working-age patients followed in general practices in Germany

https://doi.org/10.1016/j.ijid.2021.06.063

Published

2-Jul-21

Study

https://www.sciencedirect.com/science/article/pii/S120197122100552X

Highlights
•This study included 30,950 patients diagnosed with COVID-19
•The prevalence of long-term sick leave was 5.8%.
•Women and elderly individuals had a higher risk of long-term sick leave.
•Seven chronical diseases were positively associated with long-term sick leave.
This study included 30,950 patients diagnosed with COVID-19 (51.7% women, mean [standard deviation] age 41.5 [13.0] years). The prevalence of long-term sick leave was 5.8%. Female sex, older age, and several conditions (i.e., noninfective enteritis and colitis, reaction to severe stress, and adjustment disorders, atopic dermatitis, mononeuropathies, reflux diseases, diabetes mellitus, and hypertension) were positively and significantly associated with long-term sick leave.

567

MS78

Jennifer M. Radin, PhD, MPH1; Giorgio Quer, PhD1; Edward Ramos, PhD1,2; Katie Baca-Motes, MBA1; Matteo Gadaleta, PhD1; Eric J. Topol, MD1; Steven R. Steinhubl, MD1

Assessment of Prolonged Physiological and Behavioral Changes Associated With COVID-19 Infection

https://doi.org/10.1001/jamanetworkopen.2021.15959

Published

7-Jul-21

Study

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2781687

We found a prolonged physiological impact of COVID-19 infection, lasting approximately 2 to 3 months, on average, but with substantial intraindividual variability, which may reflect various levels of autonomic nervous system dysfunction or potentially ongoing inflammation. Transient bradycardia has been noted in a case study6 approximately 9 to 15 days after symptom onset, which was also seen in our population. Our data suggest that early symptoms and larger initial RHR response to COVID-19 infection may be associated with the physiological length of recovery from this virus.

568

MS79

Neha Chopra, Mohit Chowdhury, Anupam K Singh, Khan MA, Arvind Kumar, Piyush Ranjan, Devashish Desai, Naveet Wig

Clinical predictors of long COVID-19 and phenotypes of mild COVID-19 at a tertiary care centre in India

https://doi.org/10.5582/ddt.2021.01014

Published

30-Jun-21

Study

https://www.jstage.jst.go.jp/article/ddt/15/3/15_2021.01014/_article

Follow up data at 30 days post-discharge was available for 53 patients. Among them, the most common persistent symptom was fatigue (22.6%), followed by cough (9.4%) and myalgias (7.5%). There was a significant association of persistent symptoms with diarrhoea at presentation [OR 14.26 (95% CI 2.30-142.47; p = 0.009] and gap between symptom onset and admission [OR 1.40 (95% CI 1.08-1.93; p = 0.020] on multivariate logistic regression analysis. On cluster analysis, three phenotypes of mild COVID-19 were identified, which may have implications on monitoring and management. There appears to be a positive association of diarrhoea as a presenting manifestation and gap between symptom onset and admission with the persistence of symptoms classified as long COVID-19, even in mild illness. We also identified multiple phenotypes of mild COVID-19 illness, which warrant further exploration.

569

MS80

Jessica Seeßle, Tim Waterboer, Theresa Hippchen, Julia Simon, Marietta Kirchner, Adeline Lim, Barbara Müller, Uta Merle

Persistent symptoms in adult patients one year after COVID-19: a prospective cohort study

https://doi.org/10.1093/cid/ciab611

Published

5-Jul-21

Study

https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab611/6315216?login=true

At month 12, only 22.9% of patients were completely free of symptoms and the most frequent symptoms were reduced exercise capacity (56.3%), fatigue (53.1%), dyspnoea (37.5%), concentration problems (39.6%), problems finding words (32.3%), and sleeping problems (26.0%). Females showed significantly more neurocognitive symptoms than males.

ANA titres were ≥1:160 in 43.6% of patients at 12 months post COVID-19 symptom onset, and neurocognitive symptom frequency was significantly higher in the group with an ANA titre ≥1:160 compared to <1:160. Compared to patients without symptoms, patients with at least one long COVID symptom at 12 months did not differ significantly with respect to their SARS-CoV-2-antibody levels, but had a significantly reduced physical and mental life quality compared to patients without symptoms.

Conclusions
Neurocognitive long COVID symptoms can persist at least for one year after COVID-19 symptom onset, and reduce life quality significantly. Several neurocognitive symptoms were associated with ANA titre elevations. This may indicate autoimmunity as cofactor in aetiology of long COVID.

570

MS81

Aiyegbusi, Olalekan Lee; Hughes, Sarah; Turner, Grace; Cruz Rivera, Samantha; McMullan,
Christel; Chandan, Joht; Haroon, Shamil; Price, Gary; Davies, Elin Haf ; Nirantharakumar,
Krishnarajah; Sapey, Elizabeth; Calvert, Melanie; on behalf of the TLC Study Group

Symptoms, complications and management of long
COVID – a review

Published

29-Jun-21

Review

https://research.birmingham.ac.uk/portal/files/136127534/AiyegbusiOL2021Symptoms.pdf

While the majority of infected individuals recover, a significant proportion continue to experience symptoms and complications after their acute illness. Patients with ‘long COVID’ experience a wide range of physical and mental/psychological symptoms. Pooled prevalence data showed the 10 most prevalent reported symptoms were fatigue, shortness of breath, muscle pain, joint pain, headache, cough, chest pain, altered smell, altered taste, and diarrhoea. Other common symptoms were cognitive impairment, memory loss, anxiety, and sleep disorders. Beyond symptoms and complications, people with long COVID often reported impaired quality of life, mental health and employment issues. These individuals may require multidisciplinary care involving the long-term monitoring of symptoms, to identify potential complications, physical rehabilitation, mental health
and social services support.

571

MS82

Mayssam Nehme, MD, Olivia Braillard, MD, François Chappuis, MD, PhD, Delphine S. Courvoisier, PhD, Idris Guessous, MD, PhD, on behalf of the CoviCare Study Team

Prevalence of Symptoms More Than Seven Months After Diagnosis of Symptomatic COVID-19 in an Outpatient Setting

https://doi.org/10.7326/M21-0878

Published

6-Jul-21

Study

https://www.acpjournals.org/doi/full/10.7326/M21-0878

Of the 629 participants in the study who completed the baseline interviews, 410 completed follow-up at 7 to 9 months after COVID-19 diagnosis; 39.0% reported residual symptoms. Fatigue (20.7%) was the most common symptom reported, followed by loss of taste or smell (16.8%), dyspnea (11.7%), and headache (10.0%).

572

MS83

Bircan Kayaaslan 1, Fatma Eser 1, Ayse Kaya Kalem 1, Gamze Kaya 2, Betül Kaplan 2, Duygu Kacar 2, Imran Hasanoglu 1, Belgin Coskun 2, Rahmet Guner

Post-covid Syndrome: A Single-Center Questionnaire Study On 1007 Participants Recovered from COVID-19

https://doi.org/10.1002/jmv.27198

Published

13-Jul-21

Study

https://pubmed.ncbi.nlm.nih.gov/34255355/

A total of 1007 participants, 39.0% had at least one comorbidity, and 47.5% had persistent symptoms. Fatigue/easy fatigability, myalgia, and loss of weight were the most frequent persistent symptoms (overall 29.3%) and followed by respiratory symptoms (25.4%). A total of 235 participants had visited outpatient clinics due to several reasons during the post-COVID-19 period, 17 of them were hospitalized. Severe acute COVID-19, hospitalization, and presence of comorbidity were independent factors for the development of persistent symptoms.

_

573

MS84

Hannah E. Davis 1
Gina S. Assaf 1
Lisa McCorkell 1
Hannah Wei 1
Ryan J. Low 1
Yochai Re'em 1
Signe Redfield
Jared P. Austin
Athena Akrami

Characterizing long COVID in an international cohort: 7 months of symptoms and their impact

https://doi.org/10.1016/j.eclinm.2021.101019

Published

15-Jul-21

Study

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00299-6/fulltext

Publication of MS20.

574

MS85

César Fernández-de-las-Peñas, Víctor Gómez-Mayordomo, David García-Azorín, Domingo Palacios-Ceña, Lidiane L. Florencio, Angel L. Guerrero, Valentín Hernández-Barrera & María L. Cuadrado

Previous History of Migraine Is Associated With Fatigue, but Not Headache, as Long-Term Post-COVID Symptom After Severe Acute Respiratory SARS-CoV-2 Infection: A Case-Control Study

https://doi.org/10.3389/fnhum.2021.678472

Published

8-Jul-21

Study

https://philpapers.org/go.pl?id=FERPHO

Overall, 57 patients with confirmed diagnosis of migraine and 144 non-migraine controls who had recovered from COVID-19 were assessed at 7.3 months after hospital discharge. The number of post-COVID symptoms in the migraine group was significantly greater than in the non-migraine group. Fatigue was significantly more prevalent in the migraine group. However, no between-groups difference in the prevalence of headache as a post-COVID symptom was detected.ConclusionPatients with a history of migraine who recovered from COVID-19 exhibited more long-term fatigue as post-COVID sequelae than those without migraine. Some of the pathophysiological changes associated with migraine could predispose to the occurrence of post-COVID symptoms.

575

MS86

Sophie A M van Kessel, Tim C Olde Hartman, Peter L B J Lucassen, Cornelia H M van Jaarsveld

Post-acute and long-COVID-19 symptoms in patients with mild diseases: a systematic review

https://doi.org/10.1093/fampra/cmab076

Published

16-Jul-21

Review

https://academic.oup.com/fampra/advance-article/doi/10.1093/fampra/cmab076/6322429

In total, nine articles were included in this literature review. The frequency of persistent symptoms in patients after mild COVID-19 infection ranged between 10% and 35%. Symptoms persisting after a mild COVID-19 infection can be distinguished into physical, mental and social symptoms. Fatigue was the most frequently described persistent symptom. Other frequently occurring persistent symptoms were dyspnoea, cough, chest pain, headache, decreased mental and cognitive status and olfactory dysfunction. In addition, it was found that persisting symptoms after a mild COVID-19 infection can have major consequences for work and daily functioning.

_

576

MS87

Thomas MDrakeMBChBa*Aya MRiadBMedScia*Cameron JFairfieldMBChBaConorEganMScaStephen RKnightMBChBaRiinuPiusPhDaHayley EHardwickeLisaNormanPhDaCatherine AShawPhDaKenneth AMcLeanMBChBaA A RogerThompsonPhDhAntoniaHoPhDiOlivia VSwannPhDbkMichaelSullivanMBChBjFelipeSoaresMPhilhKarl AHoldenMBChBelLauraMersonBScmDanielPlotkinBAmLouiseSigfridPhDmThushan Ide SilvaPhDhMichelleGirvanBScfClareJacksonfClark DRussellMBChBcdJakeDunningPhDenProfTomSolomonPhDegoGailCarsonMBChBmProfPieroOlliaroPhDmProfJonathan SNguyen-Van-TamDMpqLanceTurtlePhDeAnnemarie BDochertyPhDaProfPeter JMOpenshawPhDrJ KennethBailliePhDfProfEwen MHarrisonPhDa†Malcolm GSemple

Characterisation of in-hospital complications associated with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol UK: a prospective, multicentre cohort study

https://doi.org/10.1016/S0140-6736(21)00799-6

Published

17-Jul-21

Study

https://www.sciencedirect.com/science/article/pii/S0140673621007996

Between Jan 17 and Aug 4, 2020, 80 388 patients were included in the study. Of the patients admitted to hospital for management of COVID-19, 49·7% (36 367 of 73 197) had at least one complication. The mean age of our cohort was 71·1 years (SD 18·7), with 56·0% (41 025 of 73 197) being male and 81·0% (59 289 of 73 197) having at least one comorbidity. Males and those aged older than 60 years were most likely to have a complication (aged ≥60 years: 54·5% [16 579 of 30 416] in males and 48·2% [11 707 of 24 288] in females; aged <60 years: 48·8% [5179 of 10 609] in males and 36·6% [2814 of 7689] in females). Renal (24·3%, 17 752 of 73 197), complex respiratory (18·4%, 13 486 of 73 197), and systemic (16·3%, 11 895 of 73 197) complications were the most frequent. Cardiovascular (12·3%, 8973 of 73 197), neurological (4·3%, 3115 of 73 197), and gastrointestinal or liver (0·8%, 7901 of 73 197) complications were also reported.

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577

MS88

GillesDarcis1#AntoineBouquegneau2#NathalieMaes3Mariethys3MoniqueHenket4FlorenceLabye5Anne-FrançoiseRousseau6PerrineCanivet7ColinDesir7DorianeCalmes4RaphaelSchils1SophieDe Worm1PhilippeLéonard1PaulMeunier7MichelMoutschen1RenaudLouis4JulienGuiot

Long-term clinical follow up of patients suffering from moderate to severe COVID-19 infection: A monocentric prospective observational cohort study

https://doi.org/10.1016/j.ijid.2021.07.016

Published

14-Jul-21

Study

https://www.sciencedirect.com/science/article/pii/S1201971221005725

Highlights
•Post-COVID conditions are common
•The prevalence of tiredness up to 6 months after COVID-19 is high
•The prevalence of shortness of breath up to 6 months after COVID-19 is high
•Pulmonary function test improved during follow up
•Chest CT-scan at 3 months after discharge showed that most of images were improved

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578

MS89

ONS

Coronavirus and the social impacts of ‘long COVID’ on people’s lives in Great Britain: 7 April to 13 June 2021

Published

21-Jul-21

Study

https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/articles/coronavirusandthesocialimpactsoflongcovidonpeopleslivesingreatbritain/7aprilto13june2021

Over the period 7 April to 13 June 2021, 6.2% of adults said they may have experienced long COVID since the start of the pandemic; this includes 3.6% who said they had experienced long COVID, and 2.6% who said they were unsure if they had experienced long COVID; a further 10.1% reported they had at some point had a positive test for or believed they'd had coronavirus (COVID-19) but had not experienced long COVID.

Sur une base auto-déclarative, l'ONS (office de statistiques britannique) relève dans son rapport de juillet :
- 6,2% de la population adulte pensent avoir vécu un covid long depuis le début de la pandémie ; décomposés en 3,6% qui en sont sûrs et 2,6% qui n'en sont pas sûrs.
- 10,1% pensent avoir eu la covid (et/ou ont été testés positifs) mais déclarent ne pas avoir eu de covid long.

N012

___Multi-symptoms___

Published study on 21-Jul-21:
"Coronavirus and the social impacts of ‘long COVID’ on people’s lives in Great Britain: 7 April to 13 June 2021"
Sur une base auto-déclarative, l'ONS (office de statistiques britannique) relève dans son rapport de juillet :
- 6,2% de la population adulte pensent avoir vécu un covid long depuis le début de la pandémie ; décomposés en 3,6% qui en sont sûrs et 2,6% qui n'en sont pas sûrs.
- 10,1% pensent avoir eu la covid (et/ou ont été testés positifs) mais déclarent ne pas avoir eu de covid long.
Link: https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/articles/coronavirusandthesocialimpactsoflongcovidonpeopleslivesingreatbritain/7aprilto13june2021
Extract: "Over the period 7 April to 13 June 2021, 6.2% of adults said they may have experienced long COVID since the start of the pandemic; this includes 3.6% who said they had experienced long COVID, and 2.6% who said they were unsure if they had experienced long COVID; a further 10.1% reported they had at some point had a positive test for or believed they'd had coronavirus (COVID-19) but had not experienced long COVID. "

579

MS90

Diana C. Sanchez-Ramirez 1,* ,Kaylene Normand 1,Yang Zhaoyun 2 andRodrigo Torres-Castro

Long-Term Impact of COVID-19: A Systematic Review of the Literature and Meta-Analysis

https://doi.org/10.3390/biomedicines9080900

Published

27-Jul-21

Study

https://www.mdpi.com/2227-9059/9/8/900

This study aimed to explore post COVID-19 effects on patients chest computed tomography (CT), lung function, respiratory symptoms, fatigue, functional capacity, health-related quality of life (HRQoL), and the ability to return to work beyond 3 months post infection. Methods: A systematic search was performed on PubMed, Web of Science, and Ovid MEDLINE on 22 May 2021, to identify studies that reported persistent effects of COVID-19 beyond 3 months follow-up. Data on the proportion of patients who had the outcome were collected and analyzed using a one-group meta-analysis. Results: Data were extracted from 24 articles that presented information on a total of 5323 adults, post-infection, between 3 to 6 months after symptom onset or hospital discharge. The pooled prevalence of CT abnormalities was 59% (95% CI 44–73, I2 = 96%), abnormal lung function was 39% (95% CI 24–55, I2 = 94%), fatigue was 38% (95% CI 27–49, I2 = 98%), dyspnea was 32% (95% CI 24–40, I2 = 98%), chest paint/tightness was 16% (95% CI 12–21, I2 = 94%), and cough was 13%, (95% CI 9–17, I2 = 94%). Decreased functional capacity and HRQoL were found in 36% (95% CI 22–49, I2 = 97%) and 52% (95% CI 33–71, I2 = 94%), respectively. On average, 8 out of 10 of the patients had returned to work or reported no work impairment.

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580

MS91

Elisa Mantovani, Sara Mariotto, Daniele Gabbiani, Gianluigi Dorelli, Silvia Bozzetti, Angela Federico, Serena Zanzoni, Domenico Girelli, Ernesto Crisafulli, Sergio Ferrari & Stefano Tamburin

Chronic fatigue syndrome: an emerging sequela in COVID-19 survivors?

https://doi.org/10.1007/s13365-021-01002-x

Published

2-Aug-21

Study

https://link.springer.com/article/10.1007/s13365-021-01002-x

SARS-CoV-2 survivors may report persistent symptoms that resemble myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We explored (a) ME/CFS-like symptom prevalence and (b) whether axonal, inflammatory, and/or lung changes may contribute to ME/CFS-like symptoms in SARS-CoV-2 survivors through clinical, neuropsychiatric, neuropsychological, lung function assessment, and serum neurofilament light chain, an axonal damage biomarker. ME/CFS-like features were found in 27% of our sample. ME/CFS-like group showed worse sleep quality, fatigue, pain, depressive symptoms, subjective cognitive complaints, Borg baseline dyspnea of the 6-min walking test vs. those without ME/CFS-like symptoms. These preliminary findings raise concern on a possible future ME/CFS-like pandemic in SARS-CoV-2 survivors.

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581

MS92

Viet-Thi Tran, Raphael Porcher, Isabelle Pane, Philippe Ravaud

Course of long COVID symptoms over time in the ComPaRe long COVID prospective e-cohort

https://doi.org/10.21203/rs.3.rs-753615/v1

pre-print

3-Aug-21

Study

https://www.researchsquare.com/article/rs-753615/v1

About 10% of the people infected by the severe acute respiratory syndrome coronavirus 2 are reported to experience “long COVID,” that is, persistence of symptoms several weeks after infection. Day-by-day prevalence of long COVID symptoms was determined from responses to the Long COVID Symptom Tool by 837 patients (3075 person-months) with a confirmed infection and enrolled in the ComPaRe long COVID cohort, a prospective cohort of such patients in France. Nine months after disease onset, 88.7% patients reported persistent symptoms and 70% reported a high burden of disease. Over time, the prevalence progressively decreased for 19/53 symptoms (e.g., loss of taste/smell) and was stable for 29/53 symptoms (e.g., fatigue). For 5/53 symptoms (e.g., memory problems), prevalence increased rapidly over the first two months and then reached a plateau. These findings are important for understanding the underlying etiologies and mechanisms of long COVID.

582

MS93

Bridget M. Kuehn, MSJ

Post–COVID-19 Symptoms Were Worse Than Cancer’s Effects

https://doi.org/10.1001/jama.2021.12353

Published

Article

https://jamanetwork.com/journals/jama/fullarticle/2783410https://jamanetwork.com/journals/jama/fullarticle/2783410

583

MS94

Laura Catalina Cortes , Joseph Pergolizzi Jr, Sanim Choudhury, Charles Wollmuth, Peter Magnusson, Frank Breve, Giustino Varrassi

Chronic Pain Patients During/after COVID – Effects

pre-print

5-Aug-21

Review

https://www.cureus.com/abstracts/609-chronic-pain-patients-duringafter-covid---effects

With chronic pain affecting 15-30% of people across the globe, SARS-CoV-2 may have the potential to contribute to a rise in this statistic as patients report new onset pain symptoms after being infected with the virus. One study followed COVID-19 patients after being released from their hospital stay and demonstrated that 65.2% of patients reported new-onset pain compared to the control group, (11%, P=0.0001). These patients included those living with chronic pain and those living without pain. When exclusively considering patients without previous chronic pain, results were similar with 70% having new-onset pain and only 20% in control groups. Neuropathic syndromes have also been reported in COVID-19. Pain maybe part of the “long-haulers” syndrome reported with COVID-19.

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584

MS95

Arne Søraas ,Karl Trygve Kalleberg,John Arne Dahl,Camilla Lund Søraas,Tor Åge Myklebust,Eyvind Axelsen,Andreas Lind,Roar Bævre-Jensen,Silje Bakken Jørgensen,Mette S. Istre,Eyrun F. Kjetland,Giske Ursin

https://doi.org/10.1371/journal.pone.0256142

Published

26-Aug-21

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256142

Long-COVID-19 is a proposed syndrome negatively affecting the health of COVID-19 patients. We present data on self-rated health three to eight months after laboratory confirmed COVID-19 disease compared to a control group of SARS-CoV-2 negative patients. We followed a cohort of 8786 non-hospitalized patients who were invited after SARS-CoV-2 testing between February 1 and April 15, 2020 (794 positive, 7229 negative). Participants answered online surveys at baseline and follow-up including questions on demographics, symptoms, risk factors for SARS-CoV-2, and self-rated health compared to one year ago. Determinants for a worsening of self-rated health as compared to one year ago among the SARS-CoV-2 positive group were analyzed using multivariate logistic regression and also compared to the population norm. The follow-up questionnaire was completed by 85% of the SARS-CoV-2 positive and 75% of the SARS-CoV-2 negative participants on average 132 days after the SARS-CoV-2 test. At follow-up, 36% of the SARS-CoV-2 positive participants rated their health “somewhat” or “much” worse than one year ago. In contrast, 18% of the SARS-CoV-2 negative participants reported a similar deterioration of health while the population norm is 12%. Sore throat and cough were more frequently reported by the control group at follow-up. Neither gender nor follow-up time was associated with the multivariate odds of worsening of self-reported health compared to one year ago. Age had an inverted-U formed association with a worsening of health while being fit and being a health professional were associated with lower multivariate odds. A significant proportion of non-hospitalized COVID-19 patients, regardless of age, have not returned to their usual health three to eight months after infection.

585

MS96

ONS

Technical article: Updated estimates of the prevalence of post-acute symptoms among people with coronavirus (COVID-19) in the UK: 26 April 2020 to 1 August 2021

Published

16-Sep-21

Study

https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/articles/technicalarticleupdatedestimatesoftheprevalenceofpostacutesymptomsamongpeoplewithcoronaviruscovid19intheuk/26april2020to1august2021

Experimental estimates from three approaches to estimating the percentage of people testing positive for coronavirus (COVID-19) and who experience symptoms four or more weeks after infection, broken down by demographic and viral characteristics, using UK Coronavirus Infection Survey data.
Main points
Experimental estimates of the prevalence of symptoms that remain 12-weeks after coronavirus (COVID-19) infection (commonly referred to as "long COVID") range from 3.0% based on tracking specific symptoms, to 11.7% based on self-classification of long COVID, using data to 1 August 2021.
This analysis focusses on the number of Coronavirus Infection Survey (CIS) participants with post-acute symptoms out of those with laboratory-confirmed COVID-19, unlike our monthly prevalence publication where the denominator is the national population (irrespective of infection).
Approach 1: Prevalence of any symptom at a point in time after infection. Among study participants with COVID-19, 5.0% reported any of 12 common symptoms 12 to 16 weeks after infection; however, prevalence was 3.4% in a control group of participants without a positive test for COVID-19, demonstrating the relative commonness of these symptoms in the population at any given time.
Approach 2: Prevalence of continuous symptoms after infection. Among study participants with COVID-19, 3.0% experienced any of 12 common symptoms for a continuous period of at least 12 weeks from infection, compared with 0.5% in the control group; this estimate of 3.0% is based on a similar approach to the one we published in April 2021 (13.7%), but is substantially lower because of a combination of longer study follow-up time and updated statistical methodology. The corresponding prevalence estimate when considering only participants who were symptomatic at the acute phase of infection was 6.7%.
Approach 3: Prevalence of self-reported long COVID. An estimated 11.7% of study participants with COVID-19 would describe themselves as experiencing long COVID (based on self-classification rather than reporting one of the 12 common symptoms) 12 weeks after infection, and may therefore meet the clinical case definition of post-COVID-19 syndrome, falling to 7.5% when considering long COVID that resulted in limitation to day-to-day activities; these percentages increased to 17.7% and 11.8% respectively when considering only participants who were symptomatic at the acute phase of infection.
Irrespective of the approach to measurement, post-acute symptom prevalence was highest in females, adults aged 50 to 69 years, people with a pre-existing health condition, and those with signs of high viral load at the time of infection.

L'institut britannique de statistiques, l'ONS, publie une analyse ambitieuse d'estimation de la prévalence du covid long. Selon l'étude, entre 3 et 12% des personnes infectées (y compris asymptomatiques) présentent des symptômes évocateurs 3 mois après une infection de covid.
En considérant uniquement les personnes symptomatiques à la phase aiguë de l'infection, les auteurs évaluent une prévalence entre 7% et 18%. L'analyse utilise un groupe contrôle et plusieurs approches statistiques. Elle relève que la tranche d'âge 2-11 ans serait touchée dans une proportion difficile à distinguer d'un groupe contrôle, tandis que les symptômes d'au moins 3 à 4 mois toucherait environ 1,5-2% des infectés (y compris asymptomatiques) parmi les 12-16 ans. Après une infection symptomatique, environ 12% des patients estiment être limités dans leurs activités quotidiennes par leurs symptômes 3 mois après l'infection.

N013

___Multi-symptoms___

Published study on 16-Sep-21:
"Technical article: Updated estimates of the prevalence of post-acute symptoms among people with coronavirus (COVID-19) in the UK: 26 April 2020 to 1 August 2021"
L'institut britannique de statistiques, l'ONS, publie une analyse ambitieuse d'estimation de la prévalence du covid long. Selon l'étude, entre 3 et 12% des personnes infectées (y compris asymptomatiques) présentent des symptômes évocateurs 3 mois après une infection de covid.
En considérant uniquement les personnes symptomatiques à la phase aiguë de l'infection, les auteurs évaluent une prévalence entre 7% et 18%. L'analyse utilise un groupe contrôle et plusieurs approches statistiques. Elle relève que la tranche d'âge 2-11 ans serait touchée dans une proportion difficile à distinguer d'un groupe contrôle, tandis que les symptômes d'au moins 3 à 4 mois toucherait environ 1,5-2% des infectés (y compris asymptomatiques) parmi les 12-16 ans. Après une infection symptomatique, environ 12% des patients estiment être limités dans leurs activités quotidiennes par leurs symptômes 3 mois après l'infection.
Link: https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/articles/technicalarticleupdatedestimatesoftheprevalenceofpostacutesymptomsamongpeoplewithcoronaviruscovid19intheuk/26april2020to1august2021
Extract: "Experimental estimates from three approaches to estimating the percentage of people testing positive for coronavirus (COVID-19) and who experience symptoms four or more weeks after infection, broken down by demographic and viral characteristics, using UK Coronavirus Infection Survey data.
Main points
Experimental estimates of the prevalence of symptoms that remain 12-weeks after coronavirus (COVID-19) infection (commonly referred to as "long COVID") range from 3.0% based on tracking specific symptoms, to 11.7% based on self-classification of long COVID, using data to 1 August 2021.
This analysis focusses on the number of Coronavirus Infection Survey (CIS) participants with post-acute symptoms out of those with laboratory-confirmed COVID-19, unlike our monthly prevalence publication where the denominator is the national population (irrespective of infection).
Approach 1: Prevalence of any symptom at a point in time after infection. Among study participants with COVID-19, 5.0% reported any of 12 common symptoms 12 to 16 weeks after infection; however, prevalence was 3.4% in a control group of participants without a positive test for COVID-19, demonstrating the relative commonness of these symptoms in the population at any given time.
Approach 2: Prevalence of continuous symptoms after infection. Among study participants with COVID-19, 3.0% experienced any of 12 common symptoms for a continuous period of at least 12 weeks from infection, compared with 0.5% in the control group; this estimate of 3.0% is based on a similar approach to the one we published in April 2021 (13.7%), but is substantially lower because of a combination of longer study follow-up time and updated statistical methodology. The corresponding prevalence estimate when considering only participants who were symptomatic at the acute phase of infection was 6.7%.
Approach 3: Prevalence of self-reported long COVID. An estimated 11.7% of study participants with COVID-19 would describe themselves as experiencing long COVID (based on self-classification rather than reporting one of the 12 common symptoms) 12 weeks after infection, and may therefore meet the clinical case definition of post-COVID-19 syndrome, falling to 7.5% when considering long COVID that resulted in limitation to day-to-day activities; these percentages increased to 17.7% and 11.8% respectively when considering only participants who were symptomatic at the acute phase of infection.
Irrespective of the approach to measurement, post-acute symptom prevalence was highest in females, adults aged 50 to 69 years, people with a pre-existing health condition, and those with signs of high viral load at the time of infection."

586

MS97

Glenn Melnick, PhD | June F. O’Leary, PhD

After Their Initial Diagnosis, Many Adult COVID-19 Patients Continue Seeking Medical Care for up to Six Months or More

Published

1-Sep-21

Study

https://ehrn.org/articles/after-their-initial-diagnosis-many-adult-covid-19-patients-continue-seeking-medical-care-for-up-to-six-months-or-more

Depending on age group, 3-6% of patients first diagnosed during this 5-month window had at least one COVID-19 related health care claim 91-180 days later. These results are consistent with growing evidence suggesting it may take weeks to fully recover from COVID-19, and that 10% or more of patients may continue to experience symptoms for at least 3 months and some as long as 9 months or more.

587

MS98

Bérengère Davin-Casalena, Romain Lutaud, Dimitri Scronias, Valérie Guagliardo and Pierre Verger

French General Practitioners Frequently See Patients with Long-COVID

https://doi.org/10.3122/jabfm.2021.05.210142

Published

17-Sep-21

Study

https://www.jabfm.org/content/34/5/1010

Our study sought to identify the proportion of French GPs dealing with patients with potential long COVID syndrome and their symptoms in an online cross-sectional questionnaire-based survey among a representative national panel of GPs. The majority (53.8%) reported at least 1 patient with COVID-19 and persistent symptoms, and 33% 2 or more such patients. Their most frequent symptoms were respiratory difficulties (60.6%), psychological distress (42.8%), and anosmia-dysgeusia (40.8%). Long COVID syndrome's recognition, management, and rehabilitation are priorities requiring effective coordination between primary and secondary care.

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588

MS99

Melina Michelen1,2, Lakshmi Manoharan2, Natalie Elkheir3, Vincent Cheng4, Andrew Dagens2, Claire Hastie5, Margaret O'Hara5, Jake Suett6, Dania Dahmash2, Polina Bugaeva7, Ishmeala Rigby2, Daniel Munblit8,9,10, Eli Harriss11, Amanda Burls1, Carole Foote12, Janet Scott13, Gail Carson2, Piero Olliaro2, Louise Sigfrid2, Charitini Stavropoulou

Characterising long COVID: a living systematic review

http://dx.doi.org/10.1136/bmjgh-2021-005427

Published

27-Sep-21

Living systematic review

https://gh.bmj.com/content/6/9/e005427

Results A total of 39 studies were included: 32 cohort, 6 cross-sectional and 1 case–control. Most showed high or moderate risk of bias. None were set in low-income countries and few included children. Studies reported on 10 951 people (48% female) in 12 countries. Most included previously hospitalised people (78%, 8520/10 951). The longest mean follow-up time was 221.7 (SD: 10.9) days post COVID-19 onset. Over 60 physical and psychological signs and symptoms with wide prevalence were reported, most commonly weakness (41%; 95% CI 25% to 59%), general malaise (33%; 95% CI 15% to 57%), fatigue (31%; 95% CI 24% to 39%), concentration impairment (26%; 95% CI 21% to 32%) and breathlessness (25%; 95% CI 18% to 34%). 37% (95% CI 18% to 60%) of patients reported reduced quality of life; 26% (10/39) of studies presented evidence of reduced pulmonary function.

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589

MS100

Hossein Estiri, Zachary H. Strasser, Gabriel A. Brat, Yevgeniy R. Semenov, The Consortium for Characterization of COVID-19 by EHR (4CE), Chirag J. Patel & Shawn N. Murphy

Evolving phenotypes of non-hospitalized patients that indicate long COVID

https://doi.org/10.1186/s12916-021-02115-0

Published

27-Sep-21

Study

https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-021-02115-0

We identified 33 phenotypes among different age/gender cohorts or time windows that were positively associated with past SARS-CoV-2 infection. All identified phenotypes were newly recorded in patients’ medical records 2 months or longer after a COVID-19 RT-PCR test in non-hospitalized patients regardless of the test result. Among these phenotypes, a new diagnosis record for anosmia and dysgeusia (OR 2.60, 95% CI [1.94–3.46]), alopecia (OR 3.09, 95% CI [2.53–3.76]), chest pain (OR 1.27, 95% CI [1.09–1.48]), chronic fatigue syndrome (OR 2.60, 95% CI [1.22–2.10]), shortness of breath (OR 1.41, 95% CI [1.22–1.64]), pneumonia (OR 1.66, 95% CI [1.28–2.16]), and type 2 diabetes mellitus (OR 1.41, 95% CI [1.22–1.64]) is one of the most significant indicators of a past COVID-19 infection. Additionally, more new phenotypes were found with increased confidence among the cohorts who were younger than 65.

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590

MS101

Maxime Taquet ,Quentin Dercon,Sierra Luciano,John R. Geddes,Masud Husain,Paul J. Harrison

Incidence, co-occurrence, and evolution of long-COVID features: A 6-month retrospective cohort study of 273,618 survivors of COVID-19

https://doi.org/10.1371/journal.pmed.1003773

Published

28-Sep-21

Study

https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1003773

Among COVID-19 survivors (mean [SD] age: 46.3 [19.8], 55.6% female), 57.00% had one or more long-COVID feature recorded during the whole 6-month period (i.e., including the acute phase), and 36.55% between 3 and 6 months. The incidence of each feature was: abnormal breathing (18.71% in the 1- to 180-day period; 7.94% in the 90- to180-day period), fatigue/malaise (12.82%; 5.87%), chest/throat pain (12.60%; 5.71%), headache (8.67%; 4.63%), other pain (11.60%; 7.19%), abdominal symptoms (15.58%; 8.29%), myalgia (3.24%; 1.54%), cognitive symptoms (7.88%; 3.95%), and anxiety/depression (22.82%; 15.49%). All 9 features were more frequently reported after COVID-19 than after influenza (with an overall excess incidence of 16.60% and hazard ratios between 1.44 and 2.04, all p < 0.001), co-occurred more commonly, and formed a more interconnected network. Significant differences in incidence and co-occurrence were associated with sex, age, and illness severity. Besides the limitations inherent to EHR data, limitations of this study include that (i) the findings do not generalize to patients who have had COVID-19 but were not diagnosed, nor to patients who do not seek or receive medical attention when experiencing symptoms of long-COVID; (ii) the findings say nothing about the persistence of the clinical features; and (iii) the difference between cohorts might be affected by one cohort seeking or receiving more medical attention for their symptoms.

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591

MS102

Destin Groff, BA1; Ashley Sun, BA1; Anna E. Ssentongo, DrPH, MPH1,2; Djibril M. Ba, PhD, MPH2; Nicholas Parsons, MPhil3; Govinda R. Poudel, PhD4; Alain Lekoubou, MD, MSc2,5; John S. Oh, MD2; Jessica E. Ericson, MD, MPH6; Paddy Ssentongo, MD, PhD, MPH2,7; Vernon M. Chinchilli, PhD2

Short-term and Long-term Rates of Postacute Sequelae of SARS-CoV-2 Infection
A Systematic Review

https://doi.org/10.1001/jamanetworkopen.2021.28568

Published

13-Oct-21

Review

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2784918

From a total of 2100 studies identified, 57 studies with 250 351 survivors of COVID-19 met inclusion criteria. The mean (SD) age of survivors was 54.4 (8.9) years, 140 196 (56%) were male, and 197 777 (79%) were hospitalized during acute COVID-19. High-income countries contributed 45 studies (79%). The median (IQR) proportion of COVID-19 survivors experiencing at least 1 PASC was 54.0% (45.0%-69.0%; 13 studies) at 1 month (short-term), 55.0% (34.8%-65.5%; 38 studies) at 2 to 5 months (intermediate-term), and 54.0% (31.0%-67.0%; 9 studies) at 6 or more months (long-term). Most prevalent pulmonary sequelae, neurologic disorders, mental health disorders, functional mobility impairments, and general and constitutional symptoms were chest imaging abnormality (median [IQR], 62.2% [45.8%-76.5%]), difficulty concentrating (median [IQR], 23.8% [20.4%-25.9%]), generalized anxiety disorder (median [IQR], 29.6% [14.0%-44.0%]), general functional impairments (median [IQR], 44.0% [23.4%-62.6%]), and fatigue or muscle weakness (median [IQR], 37.5% [25.4%-54.5%]), respectively. Other frequently reported symptoms included cardiac, dermatologic, digestive, and ear, nose, and throat disorders.

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592

MS103

Eloara Vieira Machado Ferreira1, Rudolf K. F. Oliveira1

Mechanisms of exercise intolerance after COVID-19: new perspectives beyond physical deconditioning

https://dx.doi.org/10.36416/1806-3756/e20210406

Published

EDITORIAL

https://www.jornaldepneumologia.com.br/details/3604/en-US/mecanismos-de-intolerancia-ao-exercicio-apos-covid-19--novas-perspectivas-alem-do-descondicionamento-fisico;

Another possible cause for ventilatory inefficiency would be the increase in dead space as a fraction of tidal volume (VD/VT), which may be present in patients with endothelial and/or microvascular injury, poor alveoli perfusion, and/or destruction of the pulmonary vascular bed in fibrotic areas, associated with reduced O2 diffusion through the blood-alveolar barrier. (...)
Thus, considering the current pathophysiological knowledge of intolerance mechanisms and the range of systemic manifestations of the acute phase of COVID-19 infection, it would be simplistic for us to consider that all chronic symptoms of the long-COVID-19 syndrome are due to physical deconditioning by inactivity or prolonged hospitalization. The physical deconditioning theory does not explain the presence of persistent symptoms in patients who were affected by mild forms of the disease, many of whom did not even require hospitalization. Similarly, this theory does not explain the dissociation between the severity of hospitalization and the reduction in peak VO2 reported so far, nor does it explain the antagonism of the persistence of symptoms in patients with preserved peak VO2. (4-6) In light of the potential complexity and the lack of knowledge on the post-COVID-19 syndrome, it is unacceptable to be simplistic when attempting to unravel the post-COVID-19 syndrome exercise intolerance mechanisms. More robust scientific evidence is needed before drawing simple conclusions.

593

MS104

Antonella Serafini 1,*,Alberto Tagliaferro 2,3,* ,Francesco Balbi 1,Alberto Bordo 1,Stefano Bernardi 1,Giorgio Berta 1,Lorenzo Trucco 1,Enrico Perretta 1,Elisa Gualco 1,Patrizia Zoccali 1 andClaudio De Michelis

Screening of a Small Number of Italian COVID-19 Syndrome Survivors by Means of the Fatigue Assessment Scale: Long COVID Prevalence and the Role of Gender

https://doi.org/10.3390/covid1030044

Published

29-Oct-21

Study

https://www.mdpi.com/2673-8112/1/3/44/htm

The outcome of the two questionnaires were analyzed separately and compared. Females are more affected by fatigue than males. This results holds for both physical and mental fatigue. All the males’ fatigue scores were reduced at the second control, while 40% of females worsened it. Home-confined patients showed a higher fatigue score at the first check. In the initial stages of the recovery, patients are more affected by physical, rather than mental, fatigue. This is worth of further investigation as well as the reasons leading to a higher initial fatigue score for home cared patients.

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594

MS105

Anna Crispo, Sabrina Bimonte, Giuseppe Porciello, Cira Antonietta Forte, Gaia Cuomo, Concetta Montagnese, Melania Prete, Maria Grimaldi, Egidio Celentano, Alfonso Amore, Elvio de Blasio, Francesca Pentimalli, Antonio Giordano, Gerardo Botti, Giovanni Baglio, Pierpaolo Sileri, Marco Cascella & Arturo Cuomo

Strategies to evaluate outcomes in long-COVID-19 and post-COVID survivors

https://doi.org/10.1186/s13027-021-00401-3

Published

30-Oct-21

Review

https://link.springer.com/article/10.1186/s13027-021-00401-3

This narrative review is aimed at providing an updated overview of the impact of physical, cognitive, and psychological health disorders in COVID-19 survivors, by summarizing the data already published in literature in the last year. Studies cited were found through PubMed searches. We also presented an overview of the post-COVID-19 health consequences on three important aspects: nutritional status, neurological disorders, and physical health. Moreover, to activate a correct health planning policy, a multidisciplinary approach for addressing the post- COVID-19 issue, has been proposed. Finally, the involvement of health professionals is necessary even after the pandemic, to reduce expected post-pandemic psychosocial responses and mental health disorders.

_

595

MS106

Yan Xie,
Benjamin Bowe &
Ziyad Al-Aly

Burdens of post-acute sequelae of COVID-19 by severity of acute infection, demographics and health status

https://doi.org/10.1038/s41467-021-26513-3

Published

12-Nov-21

Study

https://www.nature.com/articles/s41467-021-26513-3

Here we used the healthcare databases of the US Department of Veterans Affairs to build a cohort of 181,384 people with COVID-19 and 4,397,509 non-infected controls and estimated that burden of PASC—defined as the presence of at least one sequela in excess of non-infected controls—was 73.43 (72.10, 74.72) per 1000 persons at 6 months. Burdens of individual sequelae varied by demographic groups (age, race, and sex) but were consistently higher in people with poorer baseline health and in those with more severe acute infection. In sum, the burden of PASC is substantial; PASC is non-monolithic with sequelae that are differentially expressed in various population groups. Collectively, our results may be useful in informing health systems capacity planning and care strategies of people with PASC.

596

MS107

Stephanie A Richard, Simon D Pollett, Charlotte A Lanteri, Eugene V Millar, Anthony C Fries, Ryan C Maves, Gregory C Utz, Tahaniyat Lalani, Alfred Smith, Rupal M Mody, Anuradha Ganesan, Rhonda E Colombo, Christopher J Colombo, David A Lindholm, Cristian Madar, Sharon Chi, Nikhil Huprikar, Derek T Larson, Samantha E Bazan, Caroline English, Edward Parmelee, Katrin Mende, Eric D Laing, Christopher C Broder, Paul W Blair, Josh Chenoweth, Mark P Simons, David R Tribble, Brian K Agan, Timothy H Burgess

COVID-19 outcomes among U.S. Military Health System beneficiaries include complications across multiple organ systems and substantial functional impairment

https://doi.org/10.1093/ofid/ofab556

Published

10-Nov-21

Study

https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab556/6425105?login=true

A total of 1,202 participants were enrolled. There were 1,070 laboratory confirmed SARS-CoV-2 cases and 132 SARS-CoV-2 negative participants. In the first month post-symptom onset among the SARS-CoV-2 positive cases, there were 214 hospitalizations, 79% requiring oxygen, 22 ICU admissions, and 9 deaths. Risk factors for COVID-19 associated hospitalization included race (increased for Asian, Black, and Hispanic compared to non-Hispanic White), age (age 45-64 and 65+ compared to <45), and obesity (BMI>=30 compared to BMI<30). Over 2% of survey respondents reported the need for supplemental oxygen and 31% had not returned to normal daily activities at one-month post-symptom onset.

Conclusions
Older age, reporting Asian, Black or Hispanic race/ethnicity, and obesity are associated with SARS-CoV-2 hospitalization. A proportion of acute SARS-CoV-2 infections require long-term oxygen therapy; the impact of SARS-CoV-2 infection on short-term functional status was substantial. A significant number of MHS beneficiaries had not yet returned to normal activities by one month.

597

MS108

Sumit Mukherjee, Meghana Kshirsagar, Nicholas Becker, Yixi Xu, William B Weeks, Shwetak Patel, Juan Lavista Ferres, Michael L. Jackson

Identifying Long-Term Effects of SARS-CoV-2 and Their Association with Social Determinants of Health in a Cohort of Over One Million COVID-19 Survivors

https://doi.org/10.21203/rs.3.rs-1032897/v1

pre-print

11-Nov-21

Study

https://www.researchsquare.com/article/rs-1032897/v1

Among the over 1.37 million COVID patients in our datasets we found 36 out of 1,724 3-digit ICD-10 codes to be statistically significantly increased in the post-COVID period (p-value <0.05). We also found one combination of ICD-10 codes, corresponding to ‘other anemias’ and ‘hypertension’, that was statistically significantly increased in the post-COVID period (p-value <0.05). Our logistic regression-based association analysis with social determinants of health variables, after adjusting for comorbidities and prior conditions, showed that age and gender were significantly associated with the multiple long-term effects. Race was only associated with ‘other sepsis’, income was only associated with ‘Alopecia areata’, while education level was only associated with ‘Maternal infectious and parasitic diseases’ (p-value <0.05).

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598

MS109

Mattia Bellan, Alessio Baricich, Filippo Patrucco, Patrizia Zeppegno, Carla Gramaglia, Piero Emilio Balbo, Alessandro Carriero, Roberta Rolla, Pier Paolo Sainaghi, Stefano Tricca & Mario Pirisi

Long-term sequelae are highly prevalent one year after hospitalization for severe COVID-19

https://doi.org/10.1038/s41598-021-01215-4

Published

22-Nov-21

Study

https://www.nature.com/articles/s41598-021-01215-4

We performed a prospective cohort study on 238 patients previously hospitalized for Covid-19 pneumonia in 2020 who already underwent clinical follow-up 4 months post-Covid-19. 200 consented to participate to a 12-months clinical assessment, including: pulmonary function tests with diffusing lung capacity for carbon monoxide (DLCO); post-traumatic stress (PTS) symptoms evaluation by the Impact of Event Scale (IES); motor function evaluation (by Short Physical Performance Battery and 2 min walking test); chest Computed Tomography (CT). After 366 [363–369] days, 79 patients (39.5%) reported at least one symptom. A DLCO < 80% was observed in 96 patients (49.0%). Severe DLCO impairment (< 60%) was reported in 20 patients (10.2%), related to extent of CT scan abnormalities. Some degree of motor impairment was observed in 25.8% of subjects. 37/200 patients (18.5%) showed moderate-to-severe PTS symptoms. In the time elapsed from 4 to 12 months after hospital discharge, motor function improves, while respiratory function does not, being accompanied by evidence of lung structural damage. Symptoms remain highly prevalent one year after acute illness.

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599

MS110

Yan-Jie Zhao
Wei Bai
Zhaohui Su
Chee H Ng
Yu-Tao Xiang

Long-term effects on survivors with COVID-19

https://doi.org/10.1016/S0140-6736(21)02283-2

Published

20-Nov-21

CORRESPONDENCE

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02283-2/fulltext

Lixue Huang and colleagues1 reported that patients discharged from hospital with COVID-19 showed good physical and functional recovery 1 year after symptom onset. Because of several concerns with the methods, we contend that the findings should be interpreted cautiously.
Quality of life (QOL) was measured using the EuroQol five-dimension five-level (EQ-5D-5L) questionnaire. However, the authors did not seem to use the validated Chinese version of the EQ-5D-5L, nor did they cite relevant studies.2 Additionally, the EQ-5D-5L item on anxiety or depression was used on its own as a major health outcome, which is not appropriate since the EQ-5D-5L item on anxiety or depression has not been validated in Chinese populations. Furthermore, depression and anxiety each consist of a cluster of different symptoms that cannot simply be assessed using one EQ-5D-5L item. The study findings on the anxiety or depression risk factors are therefore tentative.

600

MS111

L.Chiche1H.Faralli2C.Stavris1S.Rebaudet3J.Allemand3F.Cohen4D.Balma5H.Pegliasco6H.Drouet3M.Delord7P.Halfon1F.Retornaz1

Séquelles physiques et psychiques 3–6 mois après la COVID-19 : premiers résultats de la cohorte prospective ALCOVID

https://doi.org/10.1016/j.revmed.2021.10.298

Published

24-Nov-21

Study

https://www.sciencedirect.com/science/article/pii/S0248866321010225

les séquelles physiques et psychologiques sont fréquentes 3 à 6 mois après une COVID-19 quelle que soit sa gravité initiale. Les séquelles respiratoires et post-traumatiques pourraient être plus sévères chez les patients ayant nécessité respectivement une oxygénothérapie et de la réanimation. La gravité initiale semble aussi conditionner la réponse sérologique ultérieure.

_

601

MS112

Sudham Chand, MD, Sumit Kapoor, MD, Ali Naqvi, MD, Jyotsana Thakkar, MD, Melissa J. Fazzari, Ph.D, Deborah Orsi, MD, Vladyslav Dieiev, MD, David C. Lewandowski, MD, Peter V. Dicpinigaitis, MD

Long-Term Follow up of Renal and Other Acute Organ Failure in Survivors of Critical Illness Due to Covid-19

https://doi.org/10.1177%2F08850666211062582

Published

17-Dec-21

Study

https://journals.sagepub.com/doi/abs/10.1177/08850666211062582

126 out of 300 (42%) survived to 120-days post-hospital discharge. The median age of survivors was 54 (47-61) years. Seventy-eight (62%) patients developed acute kidney injury (AKI); thirty-five (44.9%) of them required renal replacement therapy (RRT). One hundred-five (83.3%) required invasive mechanical ventilation; ten of them required tracheotomy. 103 (81.7%) completed the telephone questionnaire-based study, at a median (IQR) of 216.5 (200-234.5) days after hospital discharge. 29 (28.2%) patients reported persistent shortness of breath, 24, (23.3%) complained of persistent cough, and persistent anosmia in 9 (8.8%). AKI resolved completely in 58 (74.4%) patients. Of 35 AKI patients who required initiation of RRT during hospitalization, 27 (77%) were liberated from RRT and 20 (57%) had resolution of AKI. Of 20 patients without AKI resolution, 12 developed chronic kidney disease, whereas 8 still require RRT. Thirty-three (32.4%) patients developed post-traumatic stress disorder (PTSD) and 10 (11.8%) reported major depression. Many of the patients (68%) regained baseline functional status. Readmissions occurred in 22.3% patients within first 6 months after discharge.

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602

MS113

CésarFernández-de-las-PeñasPhD1Oscar J.Pellicer-ValeroMSc2EsperanzaNavarro-PardoPhD3DomingoPalacios-CeñaPhD1Lidiane L.FlorencioPhD1CarlosGuijarroPhD45José D.Martín-GuerreroPhD2

Symptoms Experienced at the Acute Phase of SARS-CoV-2 Infection as Risk Factor of Long-term Post-COVID Symptoms: The LONG-COVID-EXP-CM Multicenter Study

https://doi.org/10.1016/j.ijid.2022.01.007

Published

10-Jan-22

Study

https://www.sciencedirect.com/science/article/pii/S1201971222000078

Highlights
•This multicentre study included 1,969 COVID-19 hospitalized patients.
•A higher number of onset symptoms was associated with more post-COVID symptoms
•Dyspnea and headache symptoms at onset are associated with post-COVID symptoms.
Results
Overall, 1,969 patients (46.5% women, age: 61, SD: 16 years) were randomly assessed at 8.4 months (SD 1.5) after hospital discharge. Female gender (OR1.82, 95%CI 1.57-2.10), number of morbidities (OR1.182, 95%CI 1.08-1.29), number of symptoms at hospital admission (OR1.309, 95%CI 1.15-1.49) and days at the hospital (OR1.01, 95%CI 1.007-1.017) were associated (all, P<0.001) with more long-term post-COVID symptoms. Further, vomiting (OR1.78, 95%CI 1.26-2.52), throat pain (OR1.36, 95%CI 1.02-1.81), diarrhoea (OR1.51, 95%CI 1.25-1.82), dyspnea (OR1.20, 95%CI 1.01-1.41), or headache (OR1.50, 95%CI 1.28-1.75) as symptoms at hospital admission were also associated (all, P<0.01) with a higher number of post-COVID symptoms.
Conclusion
This multicenter study found that a higher number of symptoms at hospital admission was the most relevant risk factor for developing more post-COVID symptoms, supporting the assumption that a higher symptom load at the acute phase is associated with a greater likelihood of long-term post-COVID symptoms.
Female gender (OR1.82, 95%CI 1.57-2.10), number of COVID-19 symptoms at hospital admission (OR1.309, 95%CI 1.15-1.49), number of pre-existing medical co-morbidities (OR1.182, 95%CI 1.08-1.29), and days at hospital (OR1.01, 95%CI 1.007-1.017) were independently associated (all, P<0.001) with more long-term post-COVID symptoms: the higher the number of COVID-19 onset symptoms or the higher the number of co-morbidities, the higher the number of post-COVID symptoms (Figure). No specific co-morbidity (e.g., obesity, hypertension) was associated with a greater number of post-COVID symptoms. Some specific symptoms at the acute phase were also independently associated (all, P<0.01) with a higher number of long-term post-COVID symptoms (Table): vomiting (OR1.78, 95%CI 1.26-2.52), throat pain (OR1.36, 95%CI 1.02-1.81), diarrhoea (OR1.51, 95%CI 1.25-1.82), dyspnea (OR1.20, 95%CI 1.01-1.41), or headache (OR1.50, 95%CI 1.28-1.75).

603

MS114

Marcel Ballin, MSc
Jonathan Bergman, BSc
Miia Kivipelto, MD, PhD
Anna Nordström, MD, PhD
Peter Nordström, MD, PhD

Excess Mortality After COVID-19 in Swedish Long-Term Care Facilities

https://doi.org/10.1016/j.jamda.2021.06.010

Published

23-Jun-21

Study

https://www.jamda.com/article/S1525-8610(21)00568-5/fulltext

Results
A total of 3731 residents (median age 87 years, 64.5% female) with COVID-19 were matched to 3731 controls without COVID-19. Thirty-day mortality was 39.9% in COVID-19 cases and 5.7% in controls [relative risk 7.05, 95% confidence interval (CI) 6.10-8.14]. In COVID-19 cases, the odds ratio (OR) for 30-day mortality was 2.44 (95% CI 1.57-3.81) in cases aged 80-84 years, 2.99 (95% CI 1.93-4.65) in cases aged 85-89 years, and 3.28 (95% CI 2.11-5.10) in cases aged ≥90 years, as compared with cases aged <70 years. Other risk factors for mortality among COVID-19 cases included male sex (OR, 2.60, 95% CI 2.22-3.05), neuropsychological conditions (OR, 2.18; 95% CI 1.76-2.71), impaired walking ability (OR, 1.45, 95% CI 1.17-1.78), urinary and bowel incontinence (OR 1.51, 95% CI 1.22-1.85), diabetes (OR 1.36, 95% CI 1.14-1.62), chronic kidney disease (OR 1.37, 95% CI 1.11-1.68) and previous pneumonia (OR 1.57, 95% CI 1.32-1.85). Nutritional factors, cardiovascular diseases, and antihypertensive medications were not significantly associated with mortality.
Conclusions and Implications
In Swedish LTCFs, COVID-19 was associated with a large excess in mortality after controlling for an extensive number of risk factors. Beyond older age and male sex, several prevalent clinical risk factors independently contributed to higher mortality. These findings suggest that reducing transmission of COVID-19 in LTCFs will likely prevent a considerable number of deaths.

604

MS115

Rosie Twomey, PhD, Jessica DeMars, BScPT, MSc, Kelli Franklin, BScPT, MSc, S Nicole Culos-Reed, PhD, Jason Weatherald, MD, James G Wrightson, PhD

Chronic Fatigue and Postexertional Malaise in People Living with Long COVID: An Observational Study

https://doi.org/10.1093/ptj/pzac005

Published

13-Jan-22

Study

https://academic.oup.com/ptj/advance-article-abstract/doi/10.1093/ptj/pzac005/6506311

Results
After data cleaning, 213 participants were included in the analysis. The total FACIT-F score was 18 (SD = 10) (where the score can range from 0 to 52 and a lower score indicates more severe fatigue), and 71.4% were experiencing chronic fatigue. Postexertional symptom exacerbation affected most participants, and 58.7% met the PEM scoring thresholds used in people living with myalgic encephalomyelitis/chronic fatigue syndrome.
Conclusion
Long COVID is characterized by chronic fatigue that is clinically relevant and at least as severe as fatigue in several other clinical conditions. PEM is a significant challenge for this patient group. Because of the potential for setbacks and deteriorated function following overexertion, fatigue and postexertional symptom exacerbation must be monitored and reported in clinical practice and in studies involving interventions for people with long COVID.
Impact
Physical therapists working with people with long COVID should measure and validate the patient’s experience. Postexertional symptom exacerbation must be considered, and rehabilitation needs to be carefully designed based on individual presentation. Beneficial interventions might first ensure symptom stabilization via pacing, a self-management strategy for the activity that helps minimize postexertional malaise.

605

MS116

Chiara Mariani
Fabio Borgonovo
Amedeo F Capetti
Letizia Oreni
Maria Vittoria Cossu
Martina Pellicciotta
Luciana Armiento
Simona Bocchio
Gianfranco Dedivitiis
Angelica Lupo
Massimo Galli
Giuliano Rizzardini

Persistence of Long-COVID symptoms in a heterogenous prospective cohort

https://doi.org/10.1016/j.jinf.2022.01.024

Published

22-Jan-22

Correspondence

https://www.journalofinfection.com/article/S0163-4453(22)00024-X/fulltext

Palpitations are disproportionate accelerations of the heartbeat during exercise or at rest that resolve slowly. Their estimated median time to resolution (95% CI) was 425 days (282-489). The estimated median time to resolution of anxiety and panic attacks was 391 days (313-NA). The median time to resolution of headache was estimated to be 379 days (264-505). For amnesia and insomnia the slow decay rate currently makes it impossible to foresee a median time of resolution. After one year less than 20% of our patients have resolved memory problems, and only about 15% have resolved insomnia. After median 35 days beyond the onset of COVID-19 phase of the disease 17.3% of the population reported telogen effluvium, the only truly post-COVID symptom, which had a median time to resolution of 299 days. What happens after COVID-19 disease cannot be summarily referred to a simple convalescence period in which symptoms gradually but linearly decrease.

606

MS117

CésarFernández-de-las-Peñas1José D.Martín-Guerrero2IgnacioCancela-Cilleruelo1PalomaMoro-López-Menchero1JorgeRodríguez-Jiménez1Oscar J.Pellicer-Valero2

Exploring the Trajectory Recovery Curve of the number of Post-COVID Symptoms: The LONG-COVID-EXP-CM Multicenter Study

https://doi.org/10.1016/j.ijid.2022.02.010

Published

9-Feb-22

Study

https://www.sciencedirect.com/science/article/pii/S1201971222000832

Highlights
•This multicentre study included 1,563 COVID-19 hospitalized patients
•Almost 50% of patients developed ≥3 post-COVID symptoms 6-months after infection
•A trajectory curve reveals overall decrease in the number of post-COVID symptoms
Results
A total of 1,593 COVID-19 survivors were assessed 8.4 (T1) and 13.2 (T2) months after hospitalization. The mean number of post-COVID symptoms was 2.6 (SD 2.0) at T1 and 1.5 (SD 1.4) at T2. The trajectory curve showed a decrease prevalence trend. The analysis also revealed that 985 (61.8%) subjects reported a greater number (T1>T2), 549 (34.5%) equal number (T1 =T2) and 59 (3.7%) lower number (T1<T2) of post-COVID symptoms in the first (T1: 8.4 months) in comparison with the second (T2: 13.2 months) assessment.
Conclusion
Current trajectory analysis revealed an overall decrease in the tendency in the number of post-COVID symptoms throughout the two years after the infection.

607

MS118

Cf MS119

Ingrid Torjesen

Covid-19 patients discharged from hospital have “substantially higher risk” of adverse outcomes and need monitoring

https://doi.org/10.1136/bmj.o265

Published

1-Feb-22

Article

https://www.bmj.com/content/376/bmj.o265.full

Patients who leave hospital after a stay for covid-19 are far more likely to need to be readmitted or to die than the general population, shows a UK study.1 The researchers said their findings emphasised that patients discharged after covid-19 were likely to pose a “substantial extra burden on healthcare.”
The findings support those of a study published in The BMJ in March 2021 that found that patients of all ages discharged after hospital treatment for covid-19 had higher than expected rates of multiorgan dysfunction.2
In the new study, researchers used linked primary care and hospital data in England to evaluate the risks of hospital admission and death among 24 673 patients who were treated in hospital for covid who survived for at least a week after discharge between February and December 2020. They were compared with 123 362 matched controls. Outcomes among the discharged patients were also compared with outcomes in 16 058 people who had been discharged after hospital treatment for influenza between 2017 and 2019.
The findings, reported in PLoS Medicine, showed that during a follow-up period of up to 315 days the covid patients were more than twice as likely to need readmission or to die as the general population (fully adjusted hazard ratio 2.22 (95% confidence interval 2.14 to 2.30, P<0.001)) but slightly less likely than the patients who had been admitted to hospital for flu (HR 0.95, 0.91 to 0.98, P=0.004).

608

MS119

Krishnan Bhaskaran ,Christopher T. Rentsch ,George Hickman ,William J. Hulme ,Anna Schultze,Helen J. Curtis,Kevin Wing,Charlotte Warren-Gash,Laurie Tomlinson,Chris J. Bates,Rohini Mathur,Brian MacKenna,Viyaasan Mahalingasivam,Angel Wong,Alex J. Walker,Caroline E. Morton,Daniel Grint,Amir Mehrkar,Rosalind M. Eggo,Peter Inglesby,Ian J. Douglas,Helen I. McDonald,Jonathan Cockburn,Elizabeth J. Williamson,David Evans,John Parry,Frank Hester,Sam Harper,Stephen JW Evans,Sebastian Bacon,Liam Smeeth ,Ben Goldacre

Overall and cause-specific hospitalisation and death after COVID-19 hospitalisation in England: A cohort study using linked primary care, secondary care, and death registration data in the OpenSAFELY platform

https://doi.org/10.1371/journal.pmed.1003871

Published

25-Jan-22

Study

https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1003871

Background
There is concern about medium to long-term adverse outcomes following acute Coronavirus Disease 2019 (COVID-19), but little relevant evidence exists. We aimed to investigate whether risks of hospital admission and death, overall and by specific cause, are raised following discharge from a COVID-19 hospitalisation.
Methods and findings
With the approval of NHS-England, we conducted a cohort study, using linked primary care and hospital data in OpenSAFELY to compare risks of hospital admission and death, overall and by specific cause, between people discharged from COVID-19 hospitalisation (February to December 2020) and surviving at least 1 week, and (i) demographically matched controls from the 2019 general population; and (ii) people discharged from influenza hospitalisation in 2017 to 2019. We used Cox regression adjusted for age, sex, ethnicity, obesity, smoking status, deprivation, and comorbidities considered potential risk factors for severe COVID-19 outcomes.
We included 24,673 postdischarge COVID-19 patients, 123,362 general population controls, and 16,058 influenza controls, followed for ≤315 days. COVID-19 patients had median age of 66 years, 13,733 (56%) were male, and 19,061 (77%) were of white ethnicity. Overall risk of hospitalisation or death (30,968 events) was higher in the COVID-19 group than general population controls (fully adjusted hazard ratio [aHR] 2.22, 2.14 to 2.30, p < 0.001) but slightly lower than the influenza group (aHR 0.95, 0.91 to 0.98, p = 0.004). All-cause mortality (7,439 events) was highest in the COVID-19 group (aHR 4.82, 4.48 to 5.19 versus general population controls [p < 0.001] and 1.74, 1.61 to 1.88 versus influenza controls [p < 0.001]). Risks for cause-specific outcomes were higher in COVID-19 survivors than in general population controls and largely similar or lower in COVID-19 compared with influenza patients. However, COVID-19 patients were more likely than influenza patients to be readmitted or die due to their initial infection or other lower respiratory tract infection (aHR 1.37, 1.22 to 1.54, p < 0.001) and to experience mental health or cognitive-related admission or death (aHR 1.37, 1.02 to 1.84, p = 0.039); in particular, COVID-19 survivors with preexisting dementia had higher risk of dementia hospitalisation or death (age- and sex-adjusted HR 2.47, 1.37 to 4.44, p = 0.002). Limitations of our study were that reasons for hospitalisation or death may have been misclassified in some cases due to inconsistent use of codes, and we did not have data to distinguish COVID-19 variants.
Conclusions
In this study, we observed that people discharged from a COVID-19 hospital admission had markedly higher risks for rehospitalisation and death than the general population, suggesting a substantial extra burden on healthcare. Most risks were similar to those observed after influenza hospitalisations, but COVID-19 patients had higher risks of all-cause mortality, readmission or death due to the initial infection, and dementia death, highlighting the importance of postdischarge monitoring.

609

MS120

Namrata Walia (1), Jessica Olivia Lat (2), Rabeet Tariq (3), Surbhi Tyagi (4), Adam Manzoor Qazi (5), Syeda Wajiha Salari (6), Amina Jafar (7), Tasneem Kousar (8), Sherrie Bieniek (9)

Post-acute sequelae of COVID-19 and the mental health implications

https://doi.org/10.15190/d.2021.19

Published

31-Dec-21

Review

https://discoveriesjournals.org/discoveries/D.2021.04.RA-Namrata.DOI

Post-acute sequelae of COVID-19 (PASC) or more commonly known as Long COVID-19, is the term given to persistent symptoms 12 weeks from the initial presentation of COVID-19 infection. Several multi-organ symptoms have been reported by patients. Some common symptoms include headaches, fatigue, memory impairment and mental health complications such as anxiety and depression. People with previous psychiatric diagnosis are at greater risk of developing longer mental health implications from persistent COVID-19 symptoms. Additionally, healthcare workers are at increased risk of being long haulers leading to burnout and exhaustion. The objective of this review article is to provide comprehensive evidence from existing literature on various symptoms reported by patients experiencing Long COVID-19 and the rate of occurrence of such symptoms in different populations. A long-term disease surveillance is required to further understand the persistent symptoms or the long-term impact of this infection.

610

MS121

ES

Dana Yelin 1,2,*,Ili Margalit 1,2,3 ,Mayssam Nehme 4,Jaume Bordas-Martínez 5,6 ,Francesco Pistelli 7,8 ,Dafna Yahav 2,3,Idris Guessous 4,9,Xavier Durà-Miralles 9,10,Laura Carrozzi 6,Irit Shapira-Lichter 2,11 ,Pauline Vetter 12,Dolores Peleato-Catalan 13,Giusy Tiseo 14,Eytan Wirtheim 15,Laurent Kaiser 12,Carlota Gudiol 6,16,17 ,Marco Falcone 14,Leonard Leibovici

Patterns of Long COVID Symptoms: A Multi-Center Cross Sectional Study

https://doi.org/10.3390/jcm11040898

Published

9-Feb-22

Study

https://www.mdpi.com/2077-0383/11/4/898/htm

Background: Long COVID has become a burden on healthcare systems worldwide. Research into the etiology and risk factors has been impeded by observing all diverse manifestations as part of a single entity. We aimed to determine patterns of symptoms in convalescing COVID-19 patients. Methods: Symptomatic patients were recruited from four countries. Data were collected regarding demographics, comorbidities, acute disease and persistent symptoms. Factor analysis was performed to elucidate symptom patterns. Associations of the patterns with patients’ characteristics, features of acute disease and effect on daily life were sought. Results: We included 1027 symptomatic post-COVID individuals in the analysis. The majority of participants were graded as having a non-severe acute COVID-19 (N = 763, 74.3%). We identified six patterns of symptoms: cognitive, pain-syndrome, pulmonary, cardiac, anosmia-dysgeusia and headache. The cognitive pattern was the major symptoms pattern, explaining 26.2% of the variance; the other patterns each explained 6.5–9.5% of the variance. The cognitive pattern was higher in patients who were outpatients during the acute disease. The pain-syndrome pattern was associated with acute disease severity, higher in women and increased with age. The pulmonary pattern was associated with prior lung disease and severe acute disease. Only two of the patterns (cognitive and cardiac) were associated with failure to return to pre-COVID occupational and physical activity status. Conclusion: Long COVID diverse symptoms can be grouped into six unique patterns. Using these patterns in future research may improve our understanding of pathophysiology and risk factors of persistent COVID, provide homogenous terminology for clinical research, and direct therapeutic interventions.

611

MS122

ES

Mohamad SalimAlkodaymiMBBS, MPH1∗∗Osama AliOmraniMBBS, BSc23∗∗Nader A.Fawzy4#Bader AbouShaar4#RaghedAlmamloukMBBS4#MuhammadRiazPhD5#MustafaObeidatMBBS, MBA4YasinObeidatMBBS6DanaGerberiMLS7Rand M.Taha4ZakariaKashourMBBS4TarekKashourMBChB8Elie F.BerbariMD9KhaledAlkattanMD4Imad M.TleyjehMD, MSc491011

Prevalence of post-acute COVID-19 syndrome symptoms at different follow-up periods: A systematic review and meta-analysis

https://doi.org/10.1016/j.cmi.2022.01.014

Published

3-Feb-22

Systematic Review

https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(22)00038-6/fulltext

Results
After screening 3209 studies, a total of 63 studies were eligible, with a total COVID-19 population of 257,348. The most commonly reported symptoms were fatigue, dyspnea, sleep disorder and concentration difficulty (32%, 25%, 24%, and 22% respectively at 3-<6 months follow-up), effort intolerance, fatigue, sleep disorder and dyspnea (45%, 36%, 29% and 25% respectively at 6-<9 months follow-up), fatigue (37%) and dyspnea (21%) at 9-<12 months and fatigue, dyspnea, sleep disorder, myalgia (41%, 31%, 30%, and 22% respectively at >12 months follow-up). There was substantial between-studies heterogeneity for all reported symptoms prevalence.
Meta-regressions identified statistically significant effect modifiers: world region, male gender, diabetes mellitus, disease severity and overall study quality score. Five of six studies including a comparator group consisting of COVID-19 negative cases observed significant adjusted associations between COVID-19 and several long-term symptoms.
Conclusions
This systematic review found that a large proportion of patients experience PACS 3 to 12 months after recovery from the acute phase of COVD-19. However, available studies of PACS are highly heterogeneous. Future studies need to have appropriate comparator groups, standardized symptoms definitions and measurements and longer follow-up.

612

MS123

ES

Saurabh Mehandru & Miriam Merad

Pathological sequelae of long-haul COVID

https://doi.org/10.1038/s41590-021-01104-y

Published

1-Feb-22

Review

https://www.nature.com/articles/s41590-021-01104-y

The world continues to contend with successive waves of coronavirus disease 2019 (COVID-19), fueled by the emergence of viral variants. At the same time, persistent, prolonged and often debilitating sequelae are increasingly recognized in convalescent individuals, named ‘post-COVID-19 syndrome’ or ‘long-haul COVID’. Clinical symptomatology includes fatigue, malaise, dyspnea, defects in memory and concentration and a variety of neuropsychiatric syndromes as the major manifestations, and several organ systems can be involved. The underlying pathophysiological mechanisms are poorly understood at present. This Review details organ-specific sequelae of post-COVID-19 syndromes and examines the underlying pathophysiological mechanisms available so far, elaborating on persistent inflammation, induced autoimmunity and putative viral reservoirs. Finally, we propose diagnostic strategies to better understand this heterogeneous disorder that continues to afflict millions of people worldwide.

613

MS124

Anuradhaa Subramanian, Krishnarajah Nirantharakumar, Sarah Hughes, Puja Myles, Tim Williams, Krishna Gokhale, Tom Taverner, Joht Chandan, Kirsty Brown, Nikita Simms-Williams, Anoop Shah, Megha Singh, Farah Kidy, Kelvin Okoth, Richard Hotham, Nasir Bashir, Neil Cockburn, Siang Lee, Grace Turner, Georgios Gkoutos, Olalekan Lee Aiyegbusi, Christel McMullan, Alastair Denniston, Elizabeth Sapey, Janet Lord, David Wraith, Edward Leggett, Clare Iles, Tom Marshall, Malcolm Price, Steven Marwaha, Elin Davies, Louise Jackson, Jenny Camaradou, Melanie Calvert, Shamil Haroon

Assessment of 115 symptoms for Long COVID (post-COVID-19 condition) and their risk factors in non-hospitalised individuals: a retrospective matched cohort study in UK primary care

10.21203/rs.3.rs-1343889/v1

Pre-print

15-Feb-22

Study

https://www.researchsquare.com/article/rs-1343889/v1

The objectives of this study were to assess which symptoms are associated with confirmed SARS CoV-2 beyond 12 weeks post-infection in non-hospitalised individuals, and the risk factors associated with developing persistent symptoms. We undertook a retrospective matched cohort study between 31st January 2020 and 15th April 2021 using data from a large database of UK-based primary care electronic health records, Clinical Practice Research Datalink (CPRD) Aurum. We selected 486,149 adult patients with a confirmed diagnosis of SARS CoV-2 infection that had not been hospitalised within 28 days of the diagnosis (infected cohort). We propensity score matched them to 1,944,580 patients without a coded record of either confirmed or suspected COVID-19 (uninfected cohort). Outcomes were the presence of 115 separate symptoms at ≥12 weeks post-infection, and Long COVID, defined as having at least one of the symptoms included in the World Health Organisation case definition. Separate Cox proportional hazards models were used to estimate adjusted hazard ratios (aHR) for individual symptoms and Long Covid. 62 symptoms were significantly associated with prior exposure to SARS CoV-2 after 12 weeks. The largest adjusted hazard ratios (aHR) were for anosmia (aHR 6.49, 95% CI 5.02 to 8.39), hair loss (3.99, 3.63 to 4.39), sneezing (2.77, 1.40 to 5.50), difficulties with ejaculation (2.63, 1.61 to 4.28), reduced libido (2.36, 1.61 to 3.47), shortness of breath at rest (2.20, 1.57 to 3.08), fatigue (1.92, 1.81 to 2.03), pleuritic chest pain (1.86, 1.41 to 2.46), hoarse voice (1.78, 1.44 to 2.20), and fever (1.75, 1.54 to 1.98). Among the infected cohort, risk factors for Long COVID included younger age (aHR 0.75, 95% CI 0.70 to 0.81, for those aged ≥70 years compared to those aged 18 to 30 years), female sex (1.52, 1.48 to 1.56), belonging to an ethnic minority group (1.14 [1.07 to 1.22] for mixed race, 1.21 [1.10 to 1.34] for black ethnic groups, and 1.06 [1.03 to 1.10] for other ethnic minority groups, compared to white ethnic groups), socioeconomic deprivation (1.11 [1.07 to 1.16] for the most compared to the least socioeconomically deprived quintile), smoking (1.12, 1.08 to 1.15), obesity (1.10, 1.07 to 1.14), and a wide range of comorbidities such as COPD. SARS CoV-2 in non-hospitalised individuals is associated with a plethora of symptoms being reported at ≥12 weeks post-infection, with a higher risk associated with younger age, female sex, ethnic minority groups, socioeconomic deprivation, smoking, obesity, and several comorbidities.

614

MS125

Han, Q.; Zheng, B.; Daines, L.; Sheikh, A.

Long-Term Sequelae of COVID-19: A Systematic Review and Meta-Analysis of One-Year Follow-Up Studies on Post-COVID Symptoms

https://doi.org/10.3390/pathogens11020269

Published

19-Feb-22

Systematic review

https://www.sciencedirect.com/science/article/pii/S0013935122002948

Highlights
•A long-term WBE was conducted using samples from four WWTP and four hospitals.
•WBE was capable of providing 2–7 days of early warning of clinical cases.
•The median detection rate of SARS-CoV-2 is one out of 14,300 reported new cases.
•Viral loads in influents and effluents of WWTPs were found similar.
•The COVID-19 point prevalence according to WBE ranged from 0.02 to 4.6%.
Abstract
Wastewater-based epidemiology offers a time- and cost-effective way to monitor SARS-CoV-2 spread in communities and therefore represents a complement to clinical testing. WBE applicability has been demonstrated in a number of cases over short-term periods as a method for tracking the prevalence of SARS-CoV-2 and an early-warning tool for predicting outbreaks in the population. This study reports SARS-CoV-2 viral loads from wastewater treatment plants (WWTPs) and hospitals over a 6-month period (June to December 2020). Results show that the overall range of viral load in positive tested samples was between 1.2 × 103 and 3.5 × 106 gene copies/l, unveiling that secondary-treated wastewaters mirrored the viral load of influents. The interpretation suggests that the viral titers found in three out of four WWTPs were associated to clinical COVID-19 surveillance indicators preceding 2–7 days the rise of reported clinical cases. The median wastewater detection rate of SARS-CoV-2 was one out of 14,300 reported new cases. Preliminary model estimates of prevalence ranged from 0.02 to 4.6% for the studied period. This comprehensive statistical and epidemiological analysis demonstrates that the applied wastewater-based approach to COVID-19 surveillance is in general consistent and feasible, although there is room for improvements.

615

MS126

Nicola Spiers

Reassessment of persistent symptoms, self-reported COVID-19 infection and SARS-CoV-2 serology in the SAPRIS-SERO cohort: identifying possible sub-syndromes of Long Covid

https://doi.org/10.1101/2022.02.25.22271499

Pre-print

26-Feb-22

Study

https://www.medrxiv.org/content/10.1101/2022.02.25.22271499v1.full-text

Background Long Covid remains a relatively new phenomenon with emerging understanding. Estimated UK prevalence of Long Covid with three or more symptoms lasting for 12 weeks or more was 2.2% at the end of 2021. The population-based French SAPRIS-SERO cohort has novel information about the pattern of symptoms of Long Covid that has been obscured by controversy around the original paper.
Methods Secondary analysis was used to describe and re-interpret the pattern of persistent symptoms by IgG seropositivity and self-reported Long Covid in the SAPRIS-SERO survey. Participants in the cross-sectional analysis were 26 823 individuals from the French population-based CONSTANCES cohort, included between 2012 and 2019, who took part in the nested SAPRIS and SAPRIS-SERO surveys. Between May and November 2020, the Euroimmun enzyme-linked immunosorbent assay was used to detect anti–SARS-CoV-2 antibodies. Surveyed online between December 2020 and January 2021, participants self-reported previous COVID-19 infection and physical symptoms during the previous four weeks that were new since March 2020, and had persisted for at least eight weeks.
Results There was similarity of prevalence over the majority of symptoms in those self-reporting COVID-19 infection, regardless of blood test result. Persistent symptoms significantly associated with self-reported COVID-19 infection and common in both groups include respiratory tract symptoms and a group of symptoms that might be related to chronic fatigue, malaise or postural issues. Seropositivity for IgG antibodies did not predict symptoms independently of self-reported Long Covid, except for anosmia.
Conclusions There may be three common sub-syndromes of Long Covid, one with persistent anosmia, another with other respiratory tract symptoms and a third, currently under researched, with symptoms relatable to chronic fatigue. Antibody tests are insufficient for case detection while Long Covid remains poorly understood.
Key Messages
- IgG seropositivity is insufficient to identify potential cases of Long Covid
- Persistent anosmia is very strongly associated with IgG seropositivity and may define a subsyndrome of Long Covid
- Other potential subsyndromes are those with persistent respiratory symptoms and those with persistent symptoms relatable to fatigue, malaise or postural issues
- The Long Covid research effort should be rebalanced towards understanding the fatigue/tiredness subsyndrome.

616

MS127

Anna Irene Vedel Sørensen, View ProfileLampros Spiliopoulos, View ProfilePeter Bager, View ProfileNete Munk Nielsen, View ProfileJørgen Vinsløv Hansen, View ProfileAnders Koch, View ProfileInger Kristine Meder, View ProfileSteen Ethelberg, View ProfileAnders Hviid

Post-acute symptoms, new onset diagnoses and health problems 6 to 12 months after SARS-CoV-2 infection: a nationwide questionnaire study in the adult Danish population

https://doi.org/10.1101/2022.02.27.22271328

Pre-print

28-Feb-22

Study

https://www.medrxiv.org/content/10.1101/2022.02.27.22271328v1.full-text

Background - A considerable number of individuals infected with SARS-CoV-2 continue to experience symptoms after the acute phase. More information on duration and prevalence of these symptoms in non-hospitalized populations is needed.
Methods - We conducted a nationwide cross-sectional study including 152 880 individuals aged 15-years or older, consisting of RT-PCR confirmed SARS-CoV-2 cases between September 2020-April 2021 (N=61 002) and a corresponding test-negative control group (N=91 878). Data were collected 6, 9 or 12 months after the test using web-based questionnaires. The questionnaire covered acute and post-acute symptoms, selected diagnoses, sick leave and general health, together with demographics and life style at baseline. Risk differences (RDs) between test-positives and -negatives were reported, adjusted for age, sex, single comorbidities, Charlson comorbidity score, obesity and healthcare-occupation.
Findings - Six to twelve months after the test date, the risks of 18 out of 21 physical symptoms were elevated among test-positives and one third (29.6%) of the test-positives experienced at least one physical post-acute symptom. The largest risk differences were observed for dysosmia (RD = 10.92%, 95%CI 10.68-11.21%), dysgeusia (RD=8.68%, 95%CI 8.43-8.93%), fatigue/exhaustion (RD=8.43%, 95%CI 8.14-8.74%), dyspnea (RD=4.87%, 95%CI 4.65-5.09%) and reduced strength in arms/legs (RD=4.68%, 95%CI 4.45-4.89%). More than half (53.1%) of test-positives reported at least one of the following conditions: concentration difficulties (RD=28.34%, 95%CI 27.34-28.78%), memory issues (RD=27.25%, 95%CI 26.80-27.71%), sleep problems (RD=17.27%, 95%CI 16.81-17.73%), mental (RD=32.58%, 95%CI 32.11-33.09%) or physical exhaustion (RD=40.45%, 95%CI 33.99-40.97%), compared to 11.5% of test-negatives. New diagnoses of anxiety (RD=1.15%, 95%CI 0.95-1.34%) or depression (RD=1.00%, 95%CI 0.81-1.19%) were also more common among test-positives.
Interpretation - At the population-level, where the majority of test-positives (96.0%) were not hospitalized during acute infection, a considerable proportion experience post-acute symptoms and sequelae 6-12 months after infection.

617

MS128

Kelly K O'BrienDarren A Brown5,6, Colm Bergin7,8, Kristine M Erlandson9, Jaime H Vera10,11, Lisa Avery12,13, Soo Chan Carusone14, Angela M Cheung2,12,15, Susie Goulding16, Richard Harding17, Lisa McCorkell18, Margaret O'Hara19, Larry Robinson20, Catherine Thomson6, Hannah Wei21, Natalie St Clair-Sullivan11, Brittany Torres1, Ciaran Bannan7,8, Niamh Roche22, Ruth Stokes22, Patriic Gayle23, Patricia Solomon

Long COVID and episodic disability: advancing the conceptualisation, measurement and knowledge of episodic disability among people living with Long COVID – protocol for a mixed-methods study

http://dx.doi.org/10.1136/bmjopen-2022-060826

Published

7-Mar-22

Study

https://bmjopen.bmj.com/content/12/3/e060826.abstract

Introduction As the prevalence of Long COVID increases, there is a critical need for a comprehensive assessment of disability. Our aims are to: (1) characterise disability experiences among people living with Long COVID in Canada, UK, USA and Ireland; and (2) develop a patient-reported outcome measure to assess the presence, severity and episodic nature of disability with Long COVID.
Methods and analysis In phase 1, we will conduct semistructured interviews with adults living with Long COVID to explore experiences of disability (dimensions, uncertainty, trajectories, influencing contextual factors) and establish an episodic disability (ED) framework in the context of Long COVID (n~10 each country). Using the conceptual framework, we will establish the Long COVID Episodic Disability Questionnaire (EDQ). In phase 2, we will examine the validity (construct, structural) and reliability (internal consistency, test–retest) of the EDQ for use in Long COVID. We will electronically administer the EDQ and four health status criterion measures with adults living with Long COVID, and readminister the EDQ 1 week later (n~170 each country). We will use Rasch analysis to refine the EDQ, and confirm structural and cross-cultural validity. We will calculate Cronbach’s alphas (internal consistency reliability), and intraclass correlation coefficients (test–retest reliability), and examine correlations for hypotheses theorising relationships between EDQ and criterion measure scores (construct validity). Using phase 2 data, we will characterise the profile of disability using structural equation modelling techniques to examine relationships between dimensions of disability and the influence of intrinsic and extrinsic contextual factors. This research involves an academic–clinical–community partnership building on foundational work in ED measurement, Long COVID and rehabilitation.

618

MS129

Nida Ziauddeen ,Deepti Gurdasani,Margaret E. O’Hara,Claire Hastie,Paul Roderick,Guiqing Yao,Nisreen A. Alwan

Characteristics and impact of Long Covid: Findings from an online survey

https://doi.org/10.1371/journal.pone.0264331

Published

8-Mar-22

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0264331

Results
We analysed data from 2550 participants with a median duration of illness of 7.6 months (interquartile range (IQR) 7.1–7.9). 26.5% reported lab-confirmation of infection. The mean age was 46.5 years (standard deviation 11 years) with 82.8% females and 79.9% of participants based in the UK. 89.5% described their health as good, very good or excellent before COVID-19. The most common initial symptoms that persisted were exhaustion, chest pressure/tightness, shortness of breath and headache. Cognitive dysfunction and palpitations became more prevalent later in the illness. Most participants described fluctuating (57.7%) or relapsing symptoms (17.6%). Physical activity, stress, and sleep disturbance commonly triggered symptoms. A third (32%) reported they were unable to live alone without any assistance at six weeks from start of illness. 16.9% reported being unable to work solely due to COVID-19 illness. 37.0% reported loss of income due to illness, and 64.4% said they were unable to perform usual activities/duties. Acute systems clustered broadly into two groups: a majority cluster (n = 2235, 88%) with cardiopulmonary predominant symptoms, and a minority cluster (n = 305, 12%) with multisystem symptoms. Similarly, ongoing symptoms broadly clustered in two groups; a majority cluster (n = 2243, 88.8%) exhibiting mainly cardiopulmonary, cognitive symptoms and exhaustion, and a minority cluster (n = 283, 11.2%) exhibiting more multisystem symptoms. Belonging to the more severe multisystem cluster was associated with more severe functional impact, lower income, younger age, being female, worse baseline health, and inadequate rest in the first two weeks of the illness, with no major differences in the cluster patterns when restricting analysis to the lab-confirmed subgroup.
Conclusion
This is an exploratory survey of Long Covid characteristics. Whilst this is a non-representative population sample, it highlights the heterogeneity of persistent symptoms, and the significant functional impact of prolonged illness following confirmed or suspected SARS-CoV-2 infection. To study prevalence, predictors and prognosis, research is needed in a representative population sample using standardised case definitions.

619

MS130

Chan Sui Ko Adrien
Candellier Alexandre
Mercier Marie
Joseph Cédric
Jean-Luc Schmit
Lanoix Jean-Philippe
Andrejak Claire

Number of initial symptoms is more related to long COVID-19 than acute severity of infection: a prospective cohort of hospitalized patients.

https://doi.org/10.1016/j.ijid.2022.03.006

Published

4-Mar-22

Study

https://www.ijidonline.com/article/S1201-9712(22)00141-2/fulltext

Post-COVID-19 symptoms experienced by many survivors after infection have a further devastating effect. Reports of risk factor of long COVID-19 are rising but data including reliable assessment of persistent symptoms by structured face to face follow up visit are scarce (Halpinet al. 2021). Here we report a study assessing post-COVID-19 associated risk factors in hospitalized patients including those requiring ICU four months after admission. We provide also data about objective measures of COVID-19 severity e.g., oxygen requirement, inflammatory biomarkers and radiological findings.
In univariate analysis, women had significantly increased risk (OR = 1.89 95% CI [1.16-3.03], p=0.01) than men. Patient with hypertension (OR = 1.64 95% CI [1.04-2.61], p=0.04) experienced persistent symptoms more frequently. The number of initial symptoms (OR = 1.27 95% CI [1.12-1.45], p<0.001) or patient with five or more initial symptoms showed greater risk for long-COVID-19 (OR = 2.47 95%CI [1.12-3.03]).
In multivariate logistic regression, female sex (OR = 1.94 95% CI [1.17-3.22], p=0.01) hypertension (OR = 2.01 95% CI [1.22-3.31], p<0.01) and the number of initial symptoms (OR = 1.35 95% CI [1.17-1.54], p<0.001) remained significantly associated with persistent symptoms (supplementary Table 1). Similarly, in multivariate Poisson regression, the number of persistent symptoms was significatively associated with the number of initial symptoms (adjusted incidence rate ratios, aIRR = 1.16 95% CI [1.11-1.22], p<0.001) as well as female sex (aIRR = 1.56 95% CI [1.29-1.87], p<0.001), hypertension (aIRR = 1.23 95% CI [1.02-1.50], p=0.03) and length of stay in hospital (aIRR = 1.01 95% CI [1.005-1.017], p<0.001)

620

MS131

Kenneth Fiala, Joshua Martens & Alaa Abd-Elsayed

Post-COVID Pain Syndromes

https://doi.org/10.1007/s11916-022-01038-6

Published

10-Mar-22

Commentary

https://link.springer.com/article/10.1007/s11916-022-01038-6

COVID-19 has taken the world by storm and there is a growing body of literature on how it can acutely manifest in patients. Now that COVID-19 has been affecting patients for approximately 2 years, we are discovering the potential long-term effects possible after contracting the virus. There appears to be an increase in the number of cases of long-term headaches, chest pain, testicular pain, and chronic pain being reported after COVID-19 infection. It has been postulated that secondary to the COVID-19 pandemic, chronic pain may be expected to rise in both the immediate and long-term [33]. Further analysis of the literature should be conducted in the future to continue to analyze the chronic effects of COVID-19.

621

MS132

Martha Spyridoula Katsarou , Eleni Iasonidou , Alexander Osarogue , Efthymios Kalafatis , Stylianos Gatzonis , Sofia Pappa logo , Athanasia Verentzioti , Maria Stefanatou , Pantelis Gounopoulos , Christos Demponeras , Eleni Konstantinidou , Nikolaos Drakoulis logo , Andreas Asimakos , Archontoula Antonoglou , Aspasia Mavronasou , Stavroula Spetsioti , Anastasia Kotanidou logo , Paraskevi Katsaounou * logo

Collaborative Research for Long COVID Haulers in Greece (Characteristics, Clinical Assessment and Rehabilitation). Non-hospitalized and Hospitalized Long COVID Patients Share Similar Symptom Patterns

https://doi.org/10.20944/preprints202203.0277.v1

Pre-print

21-Mar-22

Study

https://www.preprints.org/manuscript/202203.0277/v1

COVID-19 Long Haulers, an estimated 3% to 12% of people infected globally with coronavirus having latter devasting symptoms 12 weeks after the initial infection is on the rise. We conducted a collaborative study with the long covid patient organization in Greece in order to estimate the prevalence, symptoms and problems that adult long haulers experience and then propose a management plan for these patients. Symptoms were obtained from 208 patients using unstructured qualitative free text entries in an anonymized online questionnaire. The majority of respondents (68.8%) were not hospitalized and had been diagnosed more than six months ago with lingering symptoms (66,8%). Eighteen different symptoms (fatigue, tachycardia, shortness of breath, parosmia etc) were mentioned in both hospitalized and community patients. Interestingly, patients with initial mild symptoms suffer from the same persistent symptoms as those who were hospitalized. Awareness of long covid sequelae seems to be low even among medical doctors. Treatment options incorporating targeted rehabilitation programs are either not available or still excluded from the management plan of long covid patients. Since long COVID is a multi-systemic entity, we propose a holistic interventional approach using a multidisciplinary medical team in order to securely and effectively diagnose and treat these specific patients. Academic and medical community must collaborate with long covid patients’ organizations so as to provide personalized medicine.

622

MS133

Michele R.SchaefferabJuthapornCowancdeKathryn M.MilnebfJoseph H.PuyatgNhaVoduccVicenteCorrales-MedinadKim L.LavoiehiAndrewMulloycJulio A.ChirinosjSara J.AbdallahdJordan A.Guenetteab

Cardiorespiratory physiology, exertional symptoms, and psychological burden in post-COVID-19 fatigue

https://doi.org/10.1016/j.resp.2022.103898

Published

29-Mar-22

Study

https://www.sciencedirect.com/science/article/pii/S156990482200057X

Highlights
•Peak ⩒O2 (ml/kg/min) is lower in survivors with post-COVID-19 fatigue vs. without.
•Dyspnoea is elevated during exercise in COVID-19 survivors with fatigue vs. without.
•Higher psychological burden may contribute to post-COVID-19 fatigue symptomology.
Fatigue is a common, debilitating, and poorly understood symptom post-COVID-19. We sought to better characterize differences in those with and without post-COVID-19 fatigue using cardiopulmonary exercise testing. Despite elevated dyspnoea intensity ratings, V̇O2peak (ml/kg/min) was the only significant difference in the physiological responses to exercise (19.9 ± 7.1 fatigue vs. 24.4 ± 6.7 ml/kg/min non-fatigue, p = 0.04). Consistent with previous findings, we also observed a higher psychological burden in those with fatigue in the context of similar resting cardiopulmonary function. Our findings suggest that lower cardiorespiratory fitness and/or psychological factors may contribute to post-COVID-19 fatigue symptomology. Further research is needed for rehabilitation and symptom management following SARS-CoV-2 infection.

623

MS134

Jin H. Han,Kelsey N. Womack,Mark W. Tenforde,D. Clark Files,Kevin W. Gibbs,Nathan I. Shapiro,Matthew E. Prekker,Heidi L. Erickson,Jay S. Steingrub,Nida Qadir,Akram Khan,Catherine L. Hough,Nicholas J. Johnson,E. Wesley Ely,Todd W. Rice,Jonathan D. Casey,Christopher J. Lindsell,Michelle N. Gong,Vasisht Srinivasan,Nathaniel M. Lewis,Manish M. Patel,Wesley H. Self

Associations between persistent symptoms after mild COVID-19 and long-term health status, quality of life, and psychological distress

https://doi.org/10.1111/irv.12980

Published

28-Mar-22

Study

https://onlinelibrary.wiley.com/doi/10.1111/irv.12980

Background
We sought to assess whether persistent COVID-19 symptoms beyond 6 months (Long-COVID) among patients with mild COVID-19 is associated with poorer health status, quality of life, and psychological distress.
Methods
This was a multicenter prospective cohort study that included adult outpatients with acute COVID-19 from eight sites during 2-week sampling periods from April 1 and July 28, 2020. Participants were contacted 6–11 months after their first positive SARS-CoV-2 to complete a survey, which collected information on the severity of eight COVID-19 symptoms using a 4-point scale ranging from 0 (not present) to 3 (severe) at 1 month before COVID-19 (pre-illness) and at follow-up; the difference for each was calculated as an attributable persistent symptom severity score. A total attributable persistent COVID-19 symptom burden score was calculated by summing the attributable persistent severity scores for all eight symptoms. Outcomes measured at long-term follow-up comprised overall health status (EuroQol visual analogue scale), quality of life (EQ-5D-5L), and psychological distress (Patient Health Questionnaire-4). The association between the total attributable persistent COVID-19 burden score and each outcome was analyzed using multivariable proportional odds regression.
Results
Of the 2092 outpatients with COVID-19, 436 (21%) responded to the survey. The median (IQR) attributable persistent COVID-19 symptom burden score was 2 (0, 4); higher scores were associated with lower overall health status (aOR 0.63; 95% CI: 0.57–0.69), lower quality of life (aOR: 0.65; 95%CI: 0.59–0.72), and higher psychological distress (aOR: 1.40; 95%CI, 1.28–1.54) after adjusting for age, race, ethnicity, education, and income.
Conclusions
In participants with mild acute COVID-19, the burden of persistent symptoms was significantly associated with poorer long-term health status, poorer quality of life, and psychological distress.

624

MS135

Margherita Schiavi, Stefania Fugazzaro, Anna Bertolini, Monica Denti, Carlotta Mainini, Monia Allisen Accogli, Ginevra Bedogni, Daniele Ghizzoni, Otmen Esseroukh, Cecilia Gualdi & Stefania Costi

“Like before, but not exactly”: the Qualy-REACT qualitative inquiry into the lived experience of long COVID

https://doi.org/10.1186/s12889-022-13035-w

Published

28-Mar-22

Study

https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-022-13035-w

Background
Post-acute sequelae of SARS-CoV-2 infection (PASC) affect millions of individuals worldwide. Rehabilitation interventions could support individuals during the recovery phase of COVID-19, but a comprehensive understanding of this new disease and its associated needs is crucial. This qualitative study investigated the experience of individuals who had been hospitalized for COVID-19, focusing on those needs and difficulties they perceived as most urgent.
Methods
This naturalistic qualitative study was part of a single-center mix-method cross-sectional study (REACT) conducted in Italy during the first peak of the SARS-CoV-2 pandemic. The qualitative data collection took place through a telephone interview conducted 3 months after hospital discharge. The experience of individuals discharged after hospitalization for COVID-19 was investigated through the main research question – “Tell me, how has it been going since you were discharged?”. Two secondary questions investigated symptoms, activities, and participation. Data were recorded and transcribed verbatim within 48 h. An empirical phenomenological approach was used by the researchers, who independently analyzed the data and, through consensus, developed an interpretative model to answer the research question. Translation occurred after data was analyzed.
Results
During the first peak of the COVID-19 pandemic, 784 individuals with COVID-19 were discharged from the hospitals of the Local Health Authority of the Province of Reggio Emilia (Italy); 446 were excluded due to the presence of acute or chronic conditions causing disability other than COVID-19 (n. 339), inability to participate in the study procedures (n. 56), insufficient medical documentation to allow for screening (n. 21), discharge to residential facilities (n. 25), and pregnancy (n. 5). Overall, 150 individuals consented to participate in the REACT study, and 56 individuals (60.7% male, average age 62.8 years ±11.8) were interviewed in June–July 2020, up to data saturation.
Persistent symptoms, feelings of isolation, fear and stigma, emotional distress, a fatalistic attitude, and return to (adapted) life course were the key themes that characterized the participants’ experience after hospital discharge.
Conclusions
The experience as narrated by the participants in this study confirms the persistence of symptoms described in PASC and highlights the sense of isolation and psychological distress. These phenomena may trigger a vicious circle, but the participants also reported adaptation processes that allowed them to gradually return to their life course. Whether all individuals are able to rapidly activate these mechanisms and whether rehabilitation can help to break this vicious circle by improving residual symptoms remain to be seen.

625

MS136

Robineau, Olivier and Wiernik, Emmanuel and Lemogne, Cédric and de Lamballerie, Xavier and Ninove, Laetitia and Blanché, Hélène and Deleuze, Jean-François and Ribet, Céline and Kab, Sofiane and Goldberg, Marcel and Severi, Gianluca and Touvier, Mathilde and Zins, Marie and Carrat, Fabrice

Persistent Symptoms After the First Wave of COVID-19 in Relation to SARS-CoV-2 Serology and Experience of Acute Symptoms: A Nested Survey in a Population-Based Cohort

http://dx.doi.org/10.2139/ssrn.4016549

pre-print

24-Jan-22

Study

https://papers.ssrn.com/sol3/Delivery.cfm/e37b60e6-007d-4c5e-a222-dfe776deeae5-MECA.pdf?abstractid=4016549&mirid=1

Background: Many patients report persistent symptoms after COVID-19. Our aim was to determine whether some of these symptoms were more associated with past SARS-CoV-2 infection compared to other conditions.
Methods: This prospective survey was nested in CONSTANCES, a randomly selected French population-based cohort, started in 2012. All participants being followed-up by internet completed 2 questionnaires during the first wave of the pandemic (April-March 2020) focusing on the acute symptoms of their COVID-19-like illness. Serological tests for SARS-CoV-2 were then performed (May-Nov 2020). Between December 2020 and January 2021, participants completed a third questionnaire about symptoms that had lasted more than 2 months. Participants were classified into four groups according to European Center for Diseases Control (ECDC) criteria for SARS-CoV-2 infection (ECDC+ or ECDC-) and according to serological SARS-CoV-2 test results (Sero+ or Sero-). To compare the risk of each persistent symptom among the groups, logistic regression models were adjusted for age, sex, educational level, comorbidities, and the number of acute symptoms declared during the first wave of the epidemic. A mediation analysis was performed to estimate the direct effect of the infection on symptom persistence and its indirect effect via the initial clinical presentation.
Findings: The analysis was performed in 25910 participants. There was a higher risk of persistent persistent dysgeusia/anosmia, dyspnea and asthenia in the ECDC+/Sero+ group than in the ECDC+/Sero- group (OR: 6.83 [4.47-10.42], 1.69 [1.07-2.6] and 1.48 [1.05-2.07], respectively). Abdominal pain, sensitive symptoms or sleep disorders were at lower risk in the ECDC+/Sero+ group than in the ECDC+/Sero- group (0.51 [0.24-0.96], 0.40 [0.16-0.85], and 0.69 [0.49-0.95], respectively). The mediations analysis revealed that the association of infection with each symptom was mainly mediated by ECDC symptoms (proportion mediated range 50%-107%).
Conclusion: After COVID-19, persistent symptoms are very similar to those after other similar clinical conditions, apart from greater risk of anosmia, fatigue and dyspnea. The acute clinical presentation drives the risk of persistent symptoms.

626

MS137

Mike K.P. So
Amanda M.Y. Chu
Agnes Tiwari

Persistent symptoms after SARS-CoV-2 infection: Long-term implications for health and quality of life

https://doi.org/10.1016/j.lanepe.2022.100373

Published

29-Mar-22

Comment

https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(22)00066-7/fulltext

A positive serological result was regarded as “true SARS-CoV-2 infection” though there is the chance of false positives. The study was administrated longitudinally and participants were invited to complete three questionnaires online, around the time when their serological tests were taken, to self-report their symptoms. The third questionnaire was administered from December 2020 to February 2021 to collect information on persistent symptoms, defined as symptoms and effects that last for at least two months after the infection (“post-covid-19 syndrome” and “long-covid”). Using logistic regression models, the authors found a higher chance for people with SARS-CoV-2 infection, compared to those without the infection, in developing dysgeusia/anosmia, dyspnea and asthenia as persistent symptoms. Not only the authors presented useful information on persistent symptoms post COVID-19 in the French population, they have also provided a good reference for persistent symptoms in other populations. A natural extension of the longitudinal study is to consider changes in the severity of symptoms over time, from which we can learn how long the “long covid” will persist. Another future research direction is to investigate relationships among persistent symptoms, which may indicate suitable medical interventions for alleviating or removing the symptoms.
Many studies on persistent symptoms or “long covid” focused on physical symptoms which may be directly attributed to SARS-CoV-2 infection.2, 3, 4 Psychological or psychiatric symptoms, such as anxiety, depression, phobic anxiety disorder, however, have received relatively less attention in persistent symptom research despite some evidence pointing to the co-existence of depressive and even psychiatric disorders with the common physical COVID-19 symptoms.5,6 A possible concern is that psychological symptoms are more long-lasting than physical symptoms, and hence may affect health and quality of life for a long period of time. From the healthcare perspective, psychological symptoms can also be alarming as they may not be easily removed by medicine or medical treatments, and may therefore increase the burden for the healthcare and social welfare systems. Interestingly, post COVID-19 physical and psychological symptoms may be related. For example, insomnia can be a symptom of depression, and brain fog could progress to become long-term brain problems. Research has been devoted to the impact of COVID-19 on the brain and neurological diseases.7 There is speculation that after experiencing SARS-CoV-2 infection, people may have higher risk of cognitive decline, though more scientific evidence is needed. We also see mental health consequences from COVID-19 in the literature. For example, after SARS-CoV-2 infection, people are more vulnerable to having psychological distress, poor sleep quality and depression.8 Thus, the impact of the persistent symptoms on psychosocial health post COVID-19 infection should not be underestimated.
After the outbreak of the COVID-19 pandemic for more than two years, there is increasing research addressing persistent physical and psychological symptoms and their relationship and joint effects. We hope to see more longitudinal studies involving multiple regions to look into the typical “long-covid” symptoms including persistent psychological symptoms, and their impacts on psychosocial well-being and quality of life. Quantifying symptoms can also save lives in the pandemic.

627

MS138

ES

Viet-Thi Tran, Raphaël Porcher, Isabelle Pane & Philippe Ravaud

Course of post COVID-19 disease symptoms over time in the ComPaRe long COVID prospective e-cohort

https://doi.org/10.1038/s41467-022-29513-z

Published

5-Apr-22

Study

https://www.nature.com/articles/s41467-022-29513-z

About 10% of people infected by severe acute respiratory syndrome coronavirus 2 experience post COVID-19 disease. We analysed data from 968 adult patients (5350 person-months) with a confirmed infection enroled in the ComPaRe long COVID cohort, a disease prevalent prospective e-cohort of such patients in France. Day-by-day prevalence of post COVID-19 symptoms was determined from patients’ responses to the Long COVID Symptom Tool, a validated self-reported questionnaire assessing 53 symptoms. Among patients symptomatic after 2 months, 85% still reported symptoms one year after their symptom onset. Evolution of symptoms showed a decreasing prevalence over time for 27/53 symptoms (e.g., loss of taste/smell); a stable prevalence over time for 18/53 symptoms (e.g., dyspnoea), and an increasing prevalence over time for 8/53 symptoms (e.g., paraesthesia). The disease impact on patients’ lives began increasing 6 months after onset. Our results are of importance to understand the natural history of post COVID-19 disease.

628

MS139

Chen Chen, MA, Spencer R. Haupert, BS, Lauren Zimmermann, BSc, Xu Shi, PhD, Lars G. Fritsche, PhD, Bhramar Mukherjee

Global Prevalence of Post COVID-19 Condition or Long COVID: A Meta-Analysis and Systematic Review

https://doi.org/10.1093/infdis/jiac136

Published

16-Apr-22

Study

https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiac136/6569364?login=true

Introduction
This study aims to examine the worldwide prevalence of post COVID-19 condition, through a systematic review and meta-analysis.
Methods
PubMed, Embase, and iSearch were searched on July 5, 2021 with verification extending to March 13, 2022. Using a random effects framework with DerSimonian-Laird estimator, we meta-analyzed post COVID-19 condition prevalence at 28+ days from infection.
Results
50 studies were included, and 41 were meta-analyzed. Global estimated pooled prevalence of post COVID-19 condition was 0.43 (95% CI: 0.39,0.46). Hospitalized and non-hospitalized patients have estimates of 0.54 (95% CI: 0.44,0.63) and 0.34 (95% CI: 0.25,0.46), respectively. Regional prevalence estimates were Asia— 0.51 (95% CI: 0.37,0.65), Europe— 0.44 (95% CI: 0.32,0.56), and North America— 0.31 (95% CI: 0.21,0.43). Global prevalence for 30, 60, 90, and 120 days after infection were estimated to be 0.37 (95% CI: 0.26,0.49), 0.25 (95% CI: 0.15,0.38), 0.32 (95% CI: 0.14,0.57) and 0.49 (95% CI: 0.40,0.59), respectively. Fatigue was the most common symptom reported with a prevalence of 0.23 (95% CI: 0.17,0.30), followed by memory problems (0.14 [95% CI: 0.10,0.19]).
Discussion
This study finds post COVID-19 condition prevalence is substantial; the health effects of COVID-19 appear to be prolonged and can exert stress on the healthcare system.

629

MS140

The PHOSP-COVID Collaborative Group

Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study

https://doi.org/10.1016/S2213-2600(22)00127-8

Published

23-Apr-22

Study

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00127-8/fulltext

Background
No effective pharmacological or non-pharmacological interventions exist for patients with long COVID. We aimed to describe recovery 1 year after hospital discharge for COVID-19, identify factors associated with patient-perceived recovery, and identify potential therapeutic targets by describing the underlying inflammatory profiles of the previously described recovery clusters at 5 months after hospital discharge.
Methods
The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a prospective, longitudinal cohort study recruiting adults (aged ≥18 years) discharged from hospital with COVID-19 across the UK. Recovery was assessed using patient-reported outcome measures, physical performance, and organ function at 5 months and 1 year after hospital discharge, and stratified by both patient-perceived recovery and recovery cluster. Hierarchical logistic regression modelling was performed for patient-perceived recovery at 1 year. Cluster analysis was done using the clustering large applications k-medoids approach using clinical outcomes at 5 months. Inflammatory protein profiling was analysed from plasma at the 5-month visit. This study is registered on the ISRCTN Registry, ISRCTN10980107, and recruitment is ongoing.
Findings
2320 participants discharged from hospital between March 7, 2020, and April 18, 2021, were assessed at 5 months after discharge and 807 (32·7%) participants completed both the 5-month and 1-year visits. 279 (35·6%) of these 807 patients were women and 505 (64·4%) were men, with a mean age of 58·7 (SD 12·5) years, and 224 (27·8%) had received invasive mechanical ventilation (WHO class 7–9). The proportion of patients reporting full recovery was unchanged between 5 months (501 [25·5%] of 1965) and 1 year (232 [28·9%] of 804). Factors associated with being less likely to report full recovery at 1 year were female sex (odds ratio 0·68 [95% CI 0·46–0·99]), obesity (0·50 [0·34–0·74]) and invasive mechanical ventilation (0·42 [0·23–0·76]). Cluster analysis (n=1636) corroborated the previously reported four clusters: very severe, severe, moderate with cognitive impairment, and mild, relating to the severity of physical health, mental health, and cognitive impairment at 5 months. We found increased inflammatory mediators of tissue damage and repair in both the very severe and the moderate with cognitive impairment clusters compared with the mild cluster, including IL-6 concentration, which was increased in both comparisons (n=626 participants). We found a substantial deficit in median EQ-5D-5L utility index from before COVID-19 (retrospective assessment; 0·88 [IQR 0·74–1·00]), at 5 months (0·74 [0·64–0·88]) to 1 year (0·75 [0·62–0·88]), with minimal improvements across all outcome measures at 1 year after discharge in the whole cohort and within each of the four clusters.
Interpretation
The sequelae of a hospital admission with COVID-19 were substantial 1 year after discharge across a range of health domains, with the minority in our cohort feeling fully recovered. Patient-perceived health-related quality of life was reduced at 1 year compared with before hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials.

todo

630

MS141

Imad M.Tleyjehabcd1TarekKashoure1MuhammadRiazf2Samar A.Amergh2NourahAlSwaidanaLailaAlmutairigRabihHalwaniijAbdullahAssirig

Persistent COVID-19 symptoms at least one month after diagnosis: A national survey

https://doi.org/10.1016/j.jiph.2022.04.006

Published

25-Apr-22

Study

https://www.sciencedirect.com/science/article/pii/S1876034122000946

Background
Post-acute COVID-19 syndrome (PACS) is an important healthcare burden. We examined persistent symptoms in COVID-19 patients at least four weeks after the onset of infection, participants’ return to pre-COVID-19 health status and associated risk factors.
Methods
Cross-sectional study was conducted (December 2020 to January 2021). A validated online questionnaire was sent to randomly selected individuals aged more than 14 years from a total of 1397,386 people confirmed to have COVID-19 at least 4 weeks prior to the start of this survey. This sample was drawn from the Saudi ministry of health COVID-19 testing registry system.
Results
Out of the 9507 COVID-19 patients who responded to the survey, 5946 (62.5%) of them adequately completed it. 2895 patients (48.7%) were aged 35–44 years, 64.4% were males, and 91.5% were Middle Eastern or North African. 79.4% experienced unresolved symptoms for at least 4 weeks after the disease onset. 9.3% were hospitalized with 42.7% visiting healthcare facility after discharge and 14.3% requiring readmission. The rates of main reported persistent symptoms in descending order were fatigue 53.5%, muscle and body ache 38.2%, loss of smell 35.0%, joint pain 30.5%, and loss of taste 29.1%. There was moderate correlation between the number of symptoms at the onset and post-four weeks of COVID-19 infection. Female sex, pre-existing comorbidities, increased number of baseline symptoms, longer hospital-stay, and hospital readmission were predictors of delayed return to baseline health state (p < 0.05).
Conclusion
The symptoms of PACS are prevalent after contracting COVID-19 disease. Several risk factors could predict delayed return to baseline health state.

631

MS142

César Fernández-de-las-Peñas
José D. Martín-Guerrero
Ignacio Cancela-Cilleruelo
Paloma Moro-López-Menchero
Oscar J. Pellicer-Valero

Exploring the recovery curve for long-term post-COVID dyspnea and fatigue

https://doi.org/10.1016/j.ejim.2022.03.036

Published

28-Apr-22

Study

https://www.ejinme.com/article/S0953-6205(22)00136-4/fulltext

To the best of our knowledge, this is the first time analyzing the longitudinal curve of recovery of post-COVID dyspnea and fatigue in previously hospitalized COVID-19 survivors. The mosaic plots showed that a large number of patients developed “de novo” dyspnea, whereas fatigue was considered as a “de novo” post-COVID symptom. Despite this, more individuals recovered than those that developed dyspnea “de novo”, explaining the downwards prevalence trend observed. This decrease was, however, less pronounced in the case of post-COVID fatigue, which seems to be a long-lasting symptom.
Our prevalence rates of dyspnea and fatigue at the different follow-up periods are similar to those reported in current literature [[3],[4]]; however, we recognized that collecting fatigue as an onset symptom at hospital admission during the first wave of the pandemic was difficult because several subjects confused it with generalized viral-induced myalgias (general tiredness painful sensation). In fact, dyspnea and fever are the most bothersome COVID-19 symptoms self-reported by the patients at hospital admission.
Since lungs exhibit high levels of the angiotensin-converting enzyme II (ACE2) and transmembrane serine protease 2 (TMPRSS2) receptors, they are invaded by SARS-CoV-2 virus resulting in pulmonary affectation, and, hence, the development of post-COVID dyspnea and fatigue. The exponential recovery curve identified in our study suggests that post-COVID dyspnea could be present up to four years after the infection. This may be explained to the fact that almost 62% of COVID-19 survivors develop “de novo” dyspnea the following months after hospitalization. Similarly, the huge prevalence of post-COVID fatigue developed after hospitalization would explain the slow recovery curve presented by this symptom. Since recovery of post-COVID fatigue will be longer than expected, this could suggest an enhanced exposure and significant viral load for a prolonged time period. Nevertheless, evidence suggests complex mechanisms underlying post-COVID dyspnea and fatigue. For instance, the systemic immune response against SARS-CoV-2 virus, reflected by significant lower levels of antibodies, has been found to be strongly correlated with more severe post-COVID fatigue [[9]]. Therefore, identifying the risk factors associated with the development of post-COVID dyspnea and fatigue may help to better understand the management of these symptoms [[10]].
An important finding revealed by the mosaic plots is that the development of post-COVID symptoms, in this case dyspnea or fatigue, can appear at any time, e.g., almost 25% individuals without dyspnea at T1 self-reported this symptom at T2, suggesting that longitudinally evolution of post-COVID symptoms should be analyzed patient by patient and not just as the total sample [[8]].
We acknowledge potential weaknesses of the study. First, only hospitalized patients aged around 60-years old were included. Second, we collected self-reported dyspnea and fatigue. Although some tools are used for the assessment of fatigue, all consists of self-reported questionnaires. Third, we focused on these post-COVID symptoms. Interaction between different post-COVID symptoms is common. Future studies investigating the interactions between different post-COVID symptoms during the following years are now needed
In conclusion, our tendency analysis revealed that post-COVID dyspnea tend to slowly recover during the three years after SARS-CoV-2 infection, whereas the recovery of post-COVID fatigue is much slower in previously hospitalized COVID-19 survivors and could last several years after the infection.

632

MS143

Daniel A P de Miranda, Sarah V C Gomes, Priscilla S Filgueiras, Camila A Corsini, Nathalie B F Almeida, Raphael A Silva, Maria Izabella V A R C Medeiros, Raquel V R Vilela, Gabriel R Fernandes, Rafaella F Q Grenfell

Long COVID-19 syndrome: a 14-months longitudinal study during the two first epidemic peaks in Southeast Brazil

https://doi.org/10.1093/trstmh/trac030

Published

6-May-22

Study

https://academic.oup.com/trstmh/advance-article/doi/10.1093/trstmh/trac030/6581500?login=true

Background
A growing number of long COVID cases after infection have been reported. By definition, long COVID is the condition whereby affected individuals do not recover for several weeks or months following the onset of symptoms suggestive of COVID-19, the profile and timeline of which remains uncertain.
Methods
In this work, in-home, outpatient and hospitalized COVID-19 positive patients were monitored for up to 14 mo to establish the prevalence of long COVID symptoms and their correlation with age, pre-existing comorbidities and course of acute infection. The longitudinal study included 646 positive patients who were monitored once a month.
Results
From the whole population, 50.2% presented with long COVID syndrome. Twenty-three different symptoms were reported. Most frequent were fatigue (35.6%), persistent cough (34.0%), dyspnea (26.5%), loss of smell/taste (20.1%) and frequent headaches (17.3%). Mental disorders (20.7%), change in blood pressure (7.4%) and thrombosis (6.2%) were also reported. Most patients presented with 2–3 symptoms at the same time. Long COVID started after mild, moderate and severe infection in 60, 13 and 27% of cases, respectively, and it was not restricted to specific age groups.
Conclusions
Older patients tended to have more severe symptoms, leading to a longer post-COVID-19 period. The presence of seven comorbidities was correlated with the severity of infection, and severity itself was the main factor that determined the duration of symptoms in long COVID cases.

633

MS144

Carol Strahm, Marco Seneghini, Sabine Güsewell, Thomas Egger, Onicio Leal-Neto, Angela Brucher, Eva Lemmenmeier, Dorette Meier Kleeb, J Carsten Möller, Philip Rieder, Markus Ruetti, Remus Rutz, Hans-Ruedi Schmid, Reto Stocker, Danielle Vuichard-Gysin, Benedikt Wiggli, Ulrike Besold, Stefan P Kuster, Allison McGeer, Lorenz Risch, Andrée Friedl, Matthias Schlegel, Dagmar Schmid, Pietro Vernazza, Christian R Kahlert, Philipp Kohler

Symptoms Compatible With Long Coronavirus Disease (COVID) in Healthcare Workers With and Without Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection—Results of a Prospective Multicenter Cohort

https://doi.org/10.1093/cid/ciac054

Published

28-Jan-22

Study

https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac054/6516835

Background
The burden of long-term symptoms (ie, long COVID) in patients after mild COVID-19 is debated. Within a cohort of healthcare workers (HCWs), frequency and risk factors for symptoms compatible with long COVID are assessed.
Methods
Participants answered baseline (August/September 2020) and weekly questionnaires on SARS-CoV-2 nasopharyngeal swab (NPS) results and acute disease symptoms. In January 2021, SARS-CoV-2 serology was performed; in March, symptoms compatible with long COVID (including psychometric scores) were asked and compared between HCWs with positive NPS, seropositive HCWs without positive NPS (presumable asymptomatic/pauci-symptomatic infections), and negative controls. The effect of time since diagnosis and quantitative anti-spike protein antibodies (anti-S) was evaluated. Poisson regression was used to identify risk factors for symptom occurrence.
Results
Of 3334 HCWs (median, 41 years; 80% female), 556 (17%) had a positive NPS and 228 (7%) were only seropositive. HCWs with positive NPS more frequently reported ≥1 symptom compared with controls (73% vs 52%, P < .001); seropositive HCWs without positive NPS did not score higher than controls (58% vs 52%, P = .13), although impaired taste/olfaction (16% vs 6%, P < .001) and hair loss (17% vs 10%, P = .004) were more common. Exhaustion/burnout was reported by 24% of negative controls. Many symptoms remained elevated in those diagnosed >6 months ago; anti-S titers correlated with high symptom scores. Acute viral symptoms in weekly questionnaires best predicted long-COVID symptoms. Physical activity at baseline was negatively associated with neurocognitive impairment and fatigue scores.
Conclusions
Seropositive HCWs without positive NPS are only mildly affected by long COVID. Exhaustion/burnout is common, even in noninfected HCWs. Physical activity might be protective against neurocognitive impairment/fatigue symptoms after COVID-19.

634

MS145

Lara Bull-Otterson, PhD1; Sarah Baca1,2; Sharon Saydah, PhD1; Tegan K. Boehmer, PhD1; Stacey Adjei, MPH1; Simone Gray, PhD1; Aaron M. Harris

Post–COVID Conditions Among Adult COVID-19 Survivors Aged 18–64 and ≥65 Years — United States, March 2020–November 2021

https://doi.org/10.15585/mmwr.mm7121e1

Published

26-May-22

Study

https://www.cdc.gov/mmwr/volumes/71/wr/mm7121e1.htm

What is already known about this topic?
As more persons are exposed to and infected by SARS-CoV-2, reports of patients who experience persistent symptoms or organ dysfunction after acute COVID-19 and develop post-COVID conditions have increased.
What is added by this report?
COVID-19 survivors have twice the risk for developing pulmonary embolism or respiratory conditions; one in five COVID-19 survivors aged 18–64 years and one in four survivors aged ≥65 years experienced at least one incident condition that might be attributable to previous COVID-19.
What are the implications for public health practice?
Implementation of COVID-19 prevention strategies, as well as routine assessment for post-COVID conditions among persons who survive COVID-19, is critical to reducing the incidence and impact of post-COVID conditions, particularly among adults aged ≥65 years.

635

MS146

Bernardo Meza-Torres 1, Gayathri Delanerolle 1, Cecilia Okusi 1, Nikhil Mayer 2, Sneha Anand 1, Jack McCartney 1, Piers Gatenby 2, Ben Glampson 3, Martin Chapman 4, Vasa Curcin 4, Erik Mayer 3, Mark Joy 1, Trisha Greenhalgh 1, Brendan Delaney 5, Simon de Lusignan 6Bernardo Meza-Torres 1, Gayathri Delanerolle 1, Cecilia Okusi 1, Nikhil Mayer 2, Sneha Anand 1, Jack McCartney 1, Piers Gatenby 2, Ben Glampson 3, Martin Chapman 4, Vasa Curcin 4, Erik Mayer 3, Mark Joy 1, Trisha Greenhalgh 1, Brendan Delaney 5, Simon de Lusignan 6

Differences in clinical presentation with long covid following community and hospital infection, and associations with all-cause mortality: English sentinel network database study

https://doi.org/10.2196/37668

Published

17-May-22

Study

https://pubmed.ncbi.nlm.nih.gov/35605170/

Background: Most studies of long covid (symptoms of COVID-19 beyond 4 weeks) have focused on people hospitalised in their initial illness. Long covid is thought to be under-recorded in UK primary care electronic records.
Objective: We sought to determine which symptoms people present to primary care following COVID-19, and whether presentation differs in people who were not hospitalised, and post-long covid mortality.
Methods: We used routine data from the nationally representative Primary Care Sentinel Cohort of the Oxford-Royal College of General Practitioners Research and Surveillance Centre (N=7.4million), applying a pre-defined long covid phenotype and grouped by whether the illness index was in hospital or community. We included COVID-19 cases between 1st-March-2020 and 1st-April-2021. We conducted a before and after analysis of pre-specified long covid symptoms identified by the Office of National Statistics, comparing symptoms presented between one and six months after their index infection matched with the same months one year previously. We conducted logistic regression analysis, quoting odds ratios with 95% confidence intervals, reporting differences between those with an index community infection compared to those who had been hospitalised, and separately associations with all-cause mortality.
Results: 5.6% (416,505/7,396,702) and 1.8% (7,623/416,505) of patients respectively had a coded diagnosis of COVID-19 and diagnosis or referral for long covid. People coded as having long covid were significantly more likely to have presented the pre-specified symptoms after vs before COVID-19 infection (odds ratios 2.66 [2.46-2.88] for those with index community infection and 2.42 [2.03-2.89] for those hospitalised). Following an index community infection, patients were more likely to present with non-specific symptoms (odds ratio 3.44 [3.00-3.95], P<.001) than following a hospital admission (odds ratio 2.09 [1.56-2.80], P<.001). Mental health sequelae were more commonly associated with hospital admission index infections (odds ratio 2.21 [1.64-2.96]) compared to community (odds ratio 1.36 [1.21-1.53], P<.001). People presenting to primary care following hospital infection were more likely to be male (odds ratio 1.43 [1.25-1.64], P<.001), more socioeconomically deprived (odds ratio 1.42 [1.24-1.63], P<.001); and to have multi-morbidity (odds ratio 1.41 [1.26-1.57], P<.001) than those presenting after an index community infection. All-cause mortality in people with long covid was associated with increasing age; male gender (odds ratio 3.32 [1.34-9.24], P<.01) and higher multi-morbidity score (odds ratio 2.11 [1.34-3.29], P<.001). One or more vaccine doses was associated with reduced odds of mortality (odds ratio 0.10 [0.03-0.35], P<.001).
Conclusions: The low percentage of people recorded as having long covid following COVID-19 reflects either low prevalence or under-recording. The characteristics and comorbidities of those presenting with long covid following a community infection are different from those who were hospitalised with their index infection. This study provides insights into the presentation of long covid in primary care and implications for workload.

636

MS147

G.Gavazzi1C.Roubaud-Baudron2J.PLanoix3N.Baclet4C.Arlaud5T.fraisse6M.Paccalin7P.Caraux-Paz8A.Putot9E.Forestier10

Impact de COVID 19 sur le statut fonctionnel des populations françaises les plus âgées : Étude multicentrique COVID-OLD.

https://doi.org/10.1016/j.mmifmc.2022.03.030

Published

31-May-22

Study

https://www.sciencedirect.com/science/article/pii/S2772743222000484

Introduction
L'infection à COVID 19 est une maladie infectieuse sévère dans les populations âgées, induisant des taux de mortalité élevés. Cependant peu d'études ont exploré l'impact de COVID 19 chez les survivants. Les maladies aigues provoquent généralement un déclin fonctionnel de 20 à 50% dans ces populations. L'objectif de notre étude était de mesurer le taux de patients présentant un déclin fonctionnel à 3 mois après la COVID et d'en déterminer les facteurs associés.
Matériels et méthodes
60 centres français ont participé à cette étude prospective observationnelle incluant des patients âgés de 70 ans et plus, hospitalisés pour une COVID 19 entre le 04/10/2020 et le 10/12/20 dans des services de maladies infectieuses ou de gériatrie. Le déclin fonctionnel était défini par une perte d'au moins 0,5 sur le score d'activité de la vie quotidienne (ADL = capacité à transférer, manger, aller au toilette,se laver, s'habiller seul et être continent coté /6) ou/et une perte d'au moins 1 sur le score d'activité instrumentale de la vie quotidienne (IADL, cotés sur /8). Les données sociodémographiques, la sévérité du COVID 19, la présentation clinique, les traitements spécifiques et non spécifiques ont été recueillis. Des analyses univariées et multivariées (sans score de propension) ont été réalisées. Les différences entre les 2 vagues ont été déterminées.
Résultats
Sur les 1083 patients inclus 662 ont eu un suivi avec données complétées. L'âge moyen était de 84 ans. 56% présentaient un déclin fonctionnel à 3 mois, 40% sur les ADLs et 38% pour les IADLs. La perte moyenne était de 1,1 point pour les ADLs et de 1,6 point pour les IADLs. Tous les items des ADL étaient également affectés. La perte fonctionnelle était équivalente durant les 2 vagues.
En analyse univariée (n= 545), la perte d'ADL aiguë avant l'hospitalisation, la confusion, la durée du séjour, la chute, l'immobilisation sont des marqueurs prédictifs du déclin fonctionnel à 3 mois. En analyse multivariée (n=415), seuls La perte d'ADL avant l'hospitalisation et la présence d'une confusion au diagnostic sont prédicteurs de la perte fonctionnelle indépendamment des autres variables (gravité immédiate de la COVID, durée d'hospitalisation, de l'âge, sexe, syndrome d'immobilisation, chute, réhospitalisation dans les 3 Mois).
Conclusion
La majorité de la population survivante à une COVID 19 présente un déclin fonctionnel à 3 mois. La gravité de la perte fonctionnelle avant l'hospitalisation et la confusion au moment du diagnostic sont les 2 prédicteurs indépendants de la gravité immédiate de la COVID et de la durée d'hospitalisation . On ne sait pas ce qui est lié à la comorbidité, à l'absence de réadaptation ou à une longue infection Covid. L'impact de la COVID 19 sur la qualité de vie et les conséquences économiques de cet impact devraient être mesurés.

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MS148

Pierre Smith, Kristiaan Proesmans, Dieter Van Cauteren, Stefaan Demarest, Sabine Drieskens, Robby De Pauw, Laura Cornelissen, Karin De Ridder & Rana Charafeddine

Post COVID-19 condition and its physical, mental and social implications: protocol of a 2-year longitudinal cohort study in the Belgian adult population

https://doi.org/10.1186/s13690-022-00906-2

Published

4-Jun-22

Study

https://link.springer.com/article/10.1186/s13690-022-00906-2

Background
Since the onset of the COVID-19 pandemic, most research has focused on the pathophysiology and management of the acute symptoms of COVID-19, yet some people tend to experience symptoms beyond the acute phase of infection, that is, Post COVID-19 condition (PCC). However, evidence on the long-term health impacts of a COVID-19 infection are still scarce. The purpose of this paper is to describe the COVIMPACT study, which aims to set up a cohort of people who have been tested positive for COVID-19 and study the evolution of their physical, mental and social health over the medium (3 months) and long term (two years), and the factors associated with an (un)favorable evolution.
Methods
COVIMPACT is a longitudinal cohort study organised over a two-years period between April 2021 and April 2023. The eligible population is all people aged 18 years and older, living in Belgium, with a recent COVID-19 infection and contacted by the health authorities for contact tracing. Two questionnaires are used: a baseline questionnaire that aims to assess the initial health status of the participants and their status during the acute phase of the illness, and a follow-up questionnaire that is sent every three months after participants enter into the cohort. A matched non-COVID-19 control group was also selected. As of November 1, 2021, 10,708 people completed the baseline questionnaire (5% of the eligible population) and the follow-up participation rate was 79%. In total, 48% of the cohort participants appeared to fit the proposed case definition of PCC (i.e. report at least one symptom related to their COVID-19 infection three months afterwards).
Discussion
This study was designed to provide timely information on the short and long term impact of a COVID-19 infection, to stakeholders such as policymakers, health practitioners and people with PCC. Although the follow-up participation rate was good (79%), the participation rate of the eligible population was low (5%). Compared to other studies, this study has a large sample, of non-hospitalised and hospitalised people, who will be followed over a long period of 3 months to two years post infection, and with a global approach to their health.

638

MS149

Marta Rigoni, Emanuele Torri, Giandomenico Nollo, Livia Delle Donne, Sebastiano Rizzardo, Lorenza Lenzi, Andrea Falzone & Susanna Cozzio

“Long COVID” results after hospitalization for SARS-CoV-2 infection

https://doi.org/10.1038/s41598-022-13077-5

Published

10-Jun-22

Study

https://www.nature.com/articles/s41598-022-13077-5

Long-term sequelae of symptomatic infection caused by SARS-CoV-2 are largely undiscovered. We performed a prospective cohort study on consecutively hospitalized Sars-CoV-2 patients (March–May 2020) for evaluating COVID-19 outcomes at 6 and 12 months. After hospital discharge, patients were addressed to two follow-up pathways based on respiratory support needed during hospitalization. Outcomes were assessed by telephone consultation or ambulatory visit. Among 471 patients, 80.9% received no respiratory support during hospitalization; 19.1% received non-invasive ventilation (NIV) or invasive mechanical ventilation (IMV). 58 patients died during hospitalization, therefore 413 were enrolled for follow-up. At 6 months, among 355 patients, the 30.3% had any symptoms, 18.0% dyspnea, 6.2% neurological symptoms. Fifty-two out of 105 had major damages in interstitial computed tomography images. NIV/IMV patients had higher probability to suffer of symptoms (aOR = 4.00, 95%CI:1.99–8.05), dyspnea (aOR = 2.80, 95%CI:1.28–6.16), neurological symptoms (aOR = 9.72, 95%CI:2.78–34.00). At 12 months, among 344, the 25.3% suffered on any symptoms, 12.2% dyspnea, 10.1% neurological symptoms. Severe interstitial lesions were present in 37 out of 47 investigated patients. NIV/IMV patients in respect to no respiratory support, had higher probability of experiencing symptoms (aOR = 3.66, 95%CI:1.73–7.74), neurological symptoms (aOR = 8.96, 95%CI:3.22–24.90). COVID-19 patients showed prolonged sequelae up to 12 months, highlighting the need of follow-up pathways for post-COVID-19 syndrome.

639

MS150

Na Zeng, Yi-Miao Zhao, Wei Yan, Chao Li, Qing-Dong Lu, Lin Liu, Shu-Yu Ni, Huan Mei, Kai Yuan, Le Shi, Peng Li, Teng-Teng Fan, Jun-Liang Yuan, Michael V Vitiello, Thomas Kosten, Alexandra L Kondratiuk, Hong-Qiang Sun, Xiang-Dong Tang, Mei-Yan Liu, Ajit Lalvani, Jie Shi, Yan-Ping Bao & Lin Lu

A systematic review and meta-analysis of long term physical and mental sequelae of COVID-19 pandemic: call for research priority and action

https://doi.org/10.1038/s41380-022-01614-7

Published

6-Jun-22

Systematic Review

https://www.nature.com/articles/s41380-022-01614-7

The long-term physical and mental sequelae of COVID-19 are a growing public health concern, yet there is considerable uncertainty about their prevalence, persistence and predictors. We conducted a comprehensive, up-to-date meta-analysis of survivors’ health consequences and sequelae for COVID-19. PubMed, Embase and the Cochrane Library were searched through Sep 30th, 2021. Observational studies that reported the prevalence of sequelae of COVID-19 were included. Two reviewers independently undertook the data extraction and quality assessment. Of the 36,625 records identified, a total of 151 studies were included involving 1,285,407 participants from thirty-two countries. At least one sequelae symptom occurred in 50.1% (95% CI 45.4-54.8) of COVID-19 survivors for up to 12 months after infection. The most common investigation findings included abnormalities on lung CT (56.9%, 95% CI 46.2–67.3) and abnormal pulmonary function tests (45.6%, 95% CI 36.3–55.0), followed by generalized symptoms, such as fatigue (28.7%, 95% CI 21.0–37.0), psychiatric symptoms (19.7%, 95% CI 16.1–23.6) mainly depression (18.3%, 95% CI 13.3–23.8) and PTSD (17.9%, 95% CI 11.6–25.3), and neurological symptoms (18.7%, 95% CI 16.2–21.4), such as cognitive deficits (19.7%, 95% CI 8.8–33.4) and memory impairment (17.5%, 95% CI 8.1–29.6). Subgroup analysis showed that participants with a higher risk of long-term sequelae were older, mostly male, living in a high-income country, with more severe status at acute infection. Individuals with severe infection suffered more from PTSD, sleep disturbance, cognitive deficits, concentration impairment, and gustatory dysfunction. Survivors with mild infection had high burden of anxiety and memory impairment after recovery. Our findings suggest that after recovery from acute COVID-19, half of survivors still have a high burden of either physical or mental sequelae up to at least 12 months. It is important to provide urgent and appropriate prevention and intervention management to preclude persistent or emerging long-term sequelae and to promote the physical and psychiatric wellbeing of COVID-19 survivors.

640

MS151

Gunnhild Helmsdal, Katrin Dahl Hanusson, Marnar Fríðheim Kristiansen, Billa Mouritsardóttir Foldbo, Marjun Eivindardóttir Danielsen, Bjarni á Steig, Shahin Gaini, Marin Strøm, Pál Weihe, Maria Skaalum Petersen

Long COVID in the long run - 23 months follow-up study of persistent symptoms

https://doi.org/10.1093/ofid/ofac270

Published

6-Jun-22

Study

https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofac270/6603333

Symptoms of long COVID were found in 38% of 170 patients followed median 22.6 months. Most prevalent symptoms were fatigue, affected taste and smell, and difficulties remembering and concentrating. Predictors for long COVID were older age and number of symptoms in the acute phase. Long COVID may take many months, maybe years to resolve.

641

MS152

Quin Healey1, Aziz Sheikh2, Luke Daines2, Eleftheria Vasileiou2

Symptoms and signs of long COVID: A rapid review and meta-analysis

http://dx.doi.org/10.7189/jogh.12.05014

Published

21-May-22

Rapid review and meta-analysis

https://jogh.org/2022/jogh-12-05014

Background: Long COVID is defined as symptoms and signs related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that are present at least four weeks following acute infection. These symptoms and signs are poorly characterised but may be associated with significant morbidity. We sought to synthesise the evidence on their incidence to guide future research, policy and practice. Methods: We searched Medline and Embase for longitudinal cohort studies from January 2020 to July 2021 that investigated adults with long COVID at least four weeks after acute infection. Risk of bias was assessed using the Joanna Briggs Institute checklist for cohort studies. Random-effects meta-analyses were performed with subgroup analysis by follow-up time (4-12 vs more than 12 weeks). Results: 19 studies were included, 13 of which included patients hospitalised with COVID-19. The total sample size was 10 643 and the follow-up time ranged from 30 to 340 days. Risk of bias was assessed as high in one study, moderate in two studies and low in the remaining 16 studies. The most common symptoms and signs seen at any time point in long COVID were fatigue (37%; 95% confidence interval (CI) = 23-55), dyspnoea (21%; 95% CI = 14-30), olfactory dysfunction (17%; 95% CI = 9-29), myalgia (12%; 95% CI = 5-25), cough (11%; 95% CI = 6-20) and gustatory dysfunction (10%; 95% CI = 7-17). High heterogeneity was seen for all meta-analyses and the presence of some funnel plot asymmetry may indicate reporting bias. No effect of follow-up time was found for any symptom or sign included in the subgroup analysis. Conclusions: We have summarised evidence from longitudinal cohort studies on the most common symptoms and signs associated with long COVID. High heterogeneity seen in the meta-analysis means pooled incidence estimates should be interpreted with caution. This heterogeneity may be attributable to studies including patients from different health care settings and countries.

642

MS153

Christopher Millet
Spandana Narvaneni
Sherif Roman
George Horani
Suhail Chaudhry
Patrick Michael
Jin Suh
Humberto R. Jimenez

Symptoms Persist in Patients Two Years after COVID-19 infection: A Prospective Follow Up Study

https://doi.org/10.1016/j.cmi.2022.06.008

Published

16-Jun-22

Study

https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(22)00321-4/fulltext

This is a prospective, longitudinal, Institutional Review Board approved cohort study consisting of patients diagnosed with COVID-19 infection in March and April of 2020 in the St. Joseph’s Health Network. Individuals with confirmed SARS-CoV-2, who were either hospitalized or tested positive in the outpatient setting, were included. Patients under 18 years of age or those with cognitive impairment were excluded. Informed consent was obtained over telephone and participants were contacted during March and April of 2021 to complete a comprehensive questionnaire to evaluate for persistent symptoms following their initial diagnosis with COVID-19. Patients who reported persistence of symptoms at a one-year follow-up were contacted again at a two year follow-up in March of 2022 to assess for persistence of COVID-19 related symptoms. Logistic regression analysis was performed to identify predictors of symptom persistence and the McNemar test was used to compare the duration of symptoms among those surveyed both years.
500 patients were invited, of which 173 participated, including 91 patients who were previously hospitalized. The mean age was 51.5 years old, with an age range of 18-95, of whom 49.42% were male. The most common ethnicity was Hispanic (46.24%) and the most common comorbidity was hypertension (39.5%)(Table 1.). At 12 months follow up 50.8% of the patients experienced at least one persistent symptom (Figure 1A); the most common symptoms were shortness of breath (25%), fatigue (24%) anxiety (21%), difficulty focusing/brain fog (18%), body aches (18%) and headaches (16%)(Figure 1B.). At 24 months follow up, 23.1% of the patients experienced at least one persistent symptom (Figure 1A); the most common symptoms being shortness of breath (13.2%), fatigue (12.1%), difficulty focusing/brain fog (10.4%), memory loss (9.2%) and anxiety (8.1%)(Figure 1B.) 13 patients were lost to follow up from year 1 to year 2.
Two years after infection, 23.1% of patients still experienced at least one persistent symptom. At one and two years follow up, shortness of breath and fatigue were the most common symptoms. In other studies, fatigue and shortness of breath were similarly found to be amongst the most commonly reported symptoms after one year. [1, 2, 3, 4, 5] The symptoms most likely to improve between years one and two were anxiety, headaches, shortness of breath and fatigue. Women were more likely to have persistent symptoms at two years compared to men. Women have been found to experience more persistent symptoms in other studies as well. [4, 5].
To our knowledge this is the first US study to describe the duration and symptomatology of COVID-19 in patients over a two year follow up period. Most patients had reduction and resolution in their symptoms over the two year period, however nearly a quarter of patients still experience persistent symptoms. Study limitations include a small patient sample, self-recall bias, loss of patients to follow up and single center study. The study would have benefited from more frequent follow up intervals to provide a more accurate timeline of symptom recovery. The etiology and treatment of PACS remains poorly defined. With over half a billion people infected worldwide, thousands of new infections daily, and weaning protection from immunization or prior infection, a global public health crisis could be looming. For millions of patients, PACS can significantly impair cognitive function, quality of life and the ability to work at full capacity for years to come. [1, 2, 3, 4] These points highlight the urgent need for larger scale studies to better understand and effectively treat this post viral phenomenon.

643

MS154

Ahmet Naci Emecen, Salih Keskin, Oyku Turunc, Ahmet Furkan Suner, Neslisah Siyve, Ecem Basoglu Sensoy, Fatih Dinc, Oguz Kilinc, Vildan Avkan Oguz, Serdar Bayrak & Belgin Unal

The presence of symptoms within 6 months after COVID-19: a single-center longitudinal study

https://doi.org/10.1007/s11845-022-03072-0

Published

17-Jun-22

Study

https://link.springer.com/article/10.1007/s11845-022-03072-0

Background
Characterizing the post-COVID health conditions is helpful to direct patients to appropriate healthcare.
Aims
To describe the presence of symptoms in COVID-19 patients within 6 months after diagnosis and to investigate the associated factors in terms of reporting symptoms.
Methods
Data of DEU-COVIMER (a telephone interview-based COVID-19 follow-up center established in a tertiary care hospital) was analyzed for SARS-CoV-2 RNA positive participants aged ≥ 18 years from November 1st, 2020, to May 31st, 2021. Symptom frequencies were stratified by demographic and clinical characteristics at one, three, and 6 months after diagnosis. With the patients who had symptoms at baseline, generalized estimating equations were applied to identify the factors associated with reporting of symptoms.
Results
A total of 5610 patients agreed to participate in the study. Symptom frequency was 37.2%, 21.8%, and 18.2% for the first, third, and sixth months. Tiredness/fatigue, muscle or body aches, and dyspnea/difficulty breathing were the most common symptoms in all time frames. In multivariate analysis, older age, female gender (odds ratio OR 1.74, 95% confidence interval 1.57–1.93), bad economic status (OR 1.37, 1.14–1.65), current smoking (OR 1.15, 1.02–1.29), being fully vaccinated before COVID-19 (OR 0.53, 0.40–0.72), having more health conditions (≥ 3 conditions, OR 1.78, 1.33–2.37), having more symptoms (> 5 symptoms, OR 2.47, 2.19–2.78), and hospitalization (intensive care unit, OR 2.18, 1.51–3.14) were associated with reporting of symptoms.
Conclusions
This study identifies risk factors for patients who experience post-COVID-19 symptoms. Healthcare providers should appropriately allocate resources prioritizing the patients who would benefit from post-COVID rehabilitation.

644

MS155

Shirley V. Sylvester,Rada Rusu,Biankha Chan,Martha Bellows,Carly O’Keefe &Susan Nicholson

Sex differences in sequelae from COVID-19 infection and in long COVID syndrome: a review

https://doi.org/10.1080/03007995.2022.2081454

Published

20-Jun-22

Review

https://www.tandfonline.com/doi/full/10.1080/03007995.2022.2081454

Objective
We conducted literature reviews to uncover differential effects of sex on sequelae from coronavirus disease 2019 (COVID-19) and on long COVID syndrome.
Methods
Two authors independently searched OvidSP in Embase, Medline, Biosis, and Derwent Drug File. Publications reporting original, sex-disaggregated data for sequelae of COVID-19 (published before August 2020) and long COVID syndrome (published before June 2021) were included in the reviews. The association between COVID-19 sequelae (i.e. lasting <4 weeks after symptom onset) and sex, and between long COVID syndrome (i.e. lasting >4 weeks after symptom onset) and sex, was determined by odds ratio (OR) and 95% confidence interval (CI) (statistical significance defined by 95% CI not including 1).
Results
Of 4346 publications identified, 23 and 12 met eligibility criteria for COVID-19 sequelae and long COVID syndrome, respectively. COVID-19 sequelae in the categories of psychiatric/mood (OR = 1.80; 95% CI: 1.35–2.41), ENT (OR = 1.42; 95% CI: 1.39–1.46), musculoskeletal (OR = 1.15; 95% CI: 1.14–1.16), and respiratory (OR = 1.09; 95% CI: 1.08–1.11) were significantly more likely among females (vs. males), whereas renal sequelae (OR = 0.83; 95% CI: 0.75–0.93) were significantly more likely among males. The likelihood of having long COVID syndrome was significantly greater among females (OR = 1.22; 95% CI: 1.13–1.32), with the odds of ENT (OR = 2.28; 95% CI: 1.94–2.67), GI (OR = 1.60; 95% CI: 1.04–2.44), psychiatric/mood (OR = 1.58; 95% CI: 1.37–1.82), neurological (OR = 1.30; 95% CI: 1.03–1.63), dermatological (OR = 1.29; 95% CI: 1.05–1.58), and other (OR = 1.36; 95% CI: 1.25–1.49) disorders significantly higher among females and the odds of endocrine (OR = 0.75; 95% CI: 0.69–0.81) and renal disorders (OR = 0.74; 95% CI: 0.64–0.86) significantly higher among males.
Conclusions
Sex-disaggregated differences for COVID-19 sequelae and long COVID syndrome were observed. Few COVID-19 studies report sex-disaggregated data, underscoring the need for further sex-based research/reporting of COVID-19 disease.

645

MS156

S. PATIL
R. PATIL
G. GONDHALI

LONG COVID IN POST-COVID-19 CARE SETTING: PROSPECTIVE, OBSERVATIONAL, AND INTERVENTIONAL STUDY OF 6,000 CASES IN TERTIARY CARE SETTING IN INDIA

https://doi.org/10.1016/j.chest.2022.04.072

Published

1-Jun-22

Study

https://journal.chestnet.org/article/S0012-3692(22)00814-5/fulltext

TOPIC: Chest Infections
PURPOSE: our aim of this study is to analyze effects on organ system and its correlation with inflammatory markers and CT severity score.
METHODS: observational study, included 6000 COVID-19 indoor cases confirmed with RT-PCR. Retrospective analysis with treatment records, laboratory markers as IL-6, D-dimer, Ferritin, LDH, BSL, HBA1C. All cases undergone thorough interview in 'post covid care' outdoor setting regarding symptomatology, documnted vital signs abnormality, & workup as HBA1C,BSL,TFT,KFT,ECG, chest x-ray,HRCT thorax,BMD,Echocardiography,MRI brain whichever is necessary. Statistical analysis by using Chi square test and ANOVA.
RESULTS: Long covid manifestations were documented in 36.06% (2517/6000) post COVID cases, Fatigue 41.95%,dyspnea 35.98%,cough 31.96%,chest discomfort 26.95%,anosmia 8.76%,joint pain & headache 11.96%,dizziness,vertigo&insomnia 22.95% &alopecia 4.18% cases, Lung fibrosis in 16.66%, minimal lung abnormality 23.65%, pulmonary embolism 7.18% cases, palpitations 25.56%, chest pain 11.3%,arrythmias 5.53%,cardiac dysfunction 24.31%,PTSD 28%,Impaired memory with or without poor concentration (brain fog) 24.03%,Anxiety and or depression 6.33%,Reduction in quality of life 33%,Diabetes mellitus-new onset26%,transient34%,uncontrolled27%, Osteoporosis38.08%, thyroid dysfunction12.1%.CT severity score, Intensive care treatment with or without oxygen and or ventilator use & Laboratory parameters (D-dimer,IL-6,LDH,Ferritin) during hospitalization has significant association with long covid manifestations (p<0.00001)
CONCLUSIONS: Long covid in underestimated,improperly evaluated and halfheartedly treated during follow-up.All treated cases needs prompt evaluation, more awareness regrding its manifestations and its impact on quality of life is must
CLINICAL IMPLICATIONS: COVID-19 are heterogenous lung disease with pulmonary and extrapulmonary manifestations, and occurs irrespective of severity of illness. Timley workup and protoclised evaluation in these cases have positive impact on good symptom control and adequate quality of life.

646

MS157

Alison Jackes *,Michael Malfesi,Eleanor CurnowORCID,Vaibhav Tyagi andCathy Bulley

Living with and Breaking a Cycle of Illness: A Secondary Qualitative Data Analysis of Women’s Experiences with Long COVID

https://doi.org/10.3390/women2020017

Published

17-Jun-22

Study

https://www.mdpi.com/2673-4184/2/2/17/htm

Long COVID is an emerging condition, with early evidence suggesting it impacts women at a greater rate than men. As we seek to understand long COVID, it is important to consider the holistic impacts of this condition. Therefore, a qualitative perspective was used to explore the experience of those living with long COVID. Eight people from Scotland, who presented as women and Caucasian, participated in this study. A thematic analysis, from a phenomenological perspective, was conducted on data collected during two semi-structured focus groups. Five central themes emerged including: (1) a prolonged, varied, and debilitating illness; (2) barriers to care; (3) predominantly negative experiences of care; (4) fighting to carry the burden; and (5) looking to the future. These themes are linked through an explanatory theory describing a cycle of illness, the work required to break the cycle, and participant’s aims to regain their health and advocate for their condition. The thematic results are consistent with two prior qualitative studies on long COVID, creating a relatively consistent picture of individuals’ experiences during the pandemic. Additionally, the developed theory shares commonalities with individuals living with chronic illness, providing further insight into participants’ experiences.
Long COVID is an emerging condition with an incomplete understanding regarding pathology, epidemiology, and clinical management. There has been limited research into the experiences of those living with this illness. Therefore, this qualitative study sought to explore the experiences and perceptions of individuals who identified with the term long COVID. To meet this aim, data were collected by conducting semi-structured focus groups. A thematic analysis employing a phenomenological perspective revealed five central themes: (1) “It’s completely changed my life”: a prolonged, varied, and debilitating illness; (2) barriers to care, “there’s definitely a gap”; (3) “stay away, stay home”: predominantly negative experiences of care; (4) fighting to carry the burden is “a full-time job”; and (5) looking to the future and “those who come after”. An overarching explanatory theory was then proposed. This theory illustrates how participants found themselves in a cycle of illness where care-seeking behaviors were met with barriers, contributing to negative emotions. To break this cycle, participants undertook diverse activities. This was performed in response to their continued illness and out of concern for future long-COVID patients. Several of the thematic results that emerged in our study were consistent with prior qualitative work on long COVID. Additionally, several components described in our theory were consistent with pre-existing frameworks on chronic illness. As we continue to move forward in the pandemic timeline, understanding the holistic experiences of individuals with long COVID will allow for better illness management and healthcare provision.

647

MS158

TalalAlmasaJahanzebMalikbAbdulla K.AlsubaiaSyed MuhammadJawad ZaidicRaafeIqbaldKashifKhanbMuhammadAlibUzmaIshaqeMajidAlsufyaniaSebastianHadeedaReemaAlsufyaniaReemaAhmedaTusharThakurfMeettyAntonygIshanAntonyaAnhadBhullaraFaridaKotaitaLubabahAl-Ania

Post-acute COVID-19 syndrome and its prolonged effects: An updated systematic review

https://doi.org/10.1016/j.amsu.2022.103995

Published

15-Jun-22

Review

https://www.sciencedirect.com/science/article/pii/S2049080122007555

Highlights
•Clinical features of post-acute COVID-19 infection can manifest even after 60 days of initial infection.
•Prolonged symptoms and signs are being reported in observational studies and case reports every day. Although such symptoms are usually experienced in survivors of critical illness, the post-acute effects of COVID-19 are equally being reported in patients with mild severity of disease who do not require hospitalization.
•Necessary future research includes stratification of these post-acute effects with gender, age, and comorbid conditions in acute, subacute, and chronic phases of the disease.
Abstract
Objective
This systematic review aimed at estimating the prevalence of post-acute COVID-19 symptoms in view of published literature that studied prolonged clinical manifestations after recovery from acute COVID-19 infection.
Methods
Relevant databases were searched for extraction of articles. For data synthesis, based on the distribution of quantitative variables, they were expressed as mean ± standard deviation (SD) or median and interquartile range (IQR). Qualitative variables were presented as frequency (n) and percentages (%).
Results
Twenty-one articles qualified for the final analysis. The most common persistent clinical manifestations were fatigue (54.11%), dyspnea (24.38%), alopecia (23.21%), hyperhidrosis (23.6%), insomnia (25.98%), anxiety (17.29%), and arthralgia (16.35%). In addition to these symptoms, new-onset hypertension, diabetes, neuropsychiatric disorders, and bladder incontinence were also reported.
Conclusion
Clinical features of post-acute COVID-19 infection can manifest even after 60 days of initial infection. Multidisciplinary care along with regular follow-up must be provided to such patients.

648

MS159

FNU Shivani, Naina Kumari, Pinky Bai, FNU Rakesh, Muhammad Haseeb, Sunny Kumar, Amna Jamil, Maheen Zaidi, Faizan Shaukat, Amber Rizwan

Long-Term Symptoms of COVID-19: One-Year Follow-Up Study

https://doi.org/10.7759/cureus.25937

Published

14-Jun-22

Study

https://www.cureus.com/articles/91406-long-term-symptoms-of-covid-19-one-year-follow-up-study

Introduction: Persistent and prolonged symptoms, termed as long COVID (coronavirus disease), have been reported in several patients who recovered from the acute phase at different intervals. However, there has been largely unclear data regarding the full range of long-term sequelae of coronavirus disease 2019 (COVID-19) patients. This study aims to evaluate the prevalence of long COVID syndrome.
Methods: A long-term research was conducted in the COVID-19 unit of a tertiary care hospital in Pakistan from July 2020 to December 2021 in which 2,000 patients who had recovered from COVID-19 and had been discharged were included in the study. Symptoms were noted at the time of discharge and at follow-up after 12 months. Data were analyzed using Statistical Package for the Social Sciences (SPSS) v. 22.0 (IBM Corporation, Armonk, New York, United States).
Results: The mean age of the participants was 43 ± 10 years, 801 (53.8%) males and 688 (46.2%) females. At the time of discharge, the most common symptom was fatigue (26.93%), followed by dyspnea (20.34%) and muscle pain (8.86%). The most common symptom on follow-up was fatigue (6.78%).
Conclusion: We strongly emphasize discussing and exploring further knowledge on the post-infection syndrome, with an aim to bring healthcare professionals’ attention to the importance of handling COVID patients, their counseling, warning for alarming signs, and a long-term follow-up with necessary investigations and treatment.

649

MS160

Tore Bonsaksen 1,2,*ORCID,Janni Leung 3ORCID,Daicia Price 4ORCID,Mary Ruffolo 4ORCID,Gary Lamph 5,Isaac Kabelenga 6,Hilde Thygesen 7,8ORCID andAmy Østertun Geirdal 9ORCID

Self-Reported Long COVID in the General Population: Sociodemographic and Health Correlates in a Cross-National Sample

https://doi.org/10.3390/life12060901

Published

15-Jun-22

Study

https://www.mdpi.com/2075-1729/12/6/901/htm

We aimed to gain knowledge of possible sociodemographic predictors of long COVID and whether long COVID was associated with health outcomes almost two years after the pandemic outbreak. There were 1649 adults who participated in the study by completing a cross-sectional online survey disseminated openly in Norway, the UK, the USA, and Australia between November 2021 and January 2022. Participants were defined as having long COVID based on self-reports that they had been infected by COVID-19 and were experiencing long-lasting COVID symptoms. Logistic regression analyses were used to examine possible sociodemographic predictors, and multivariate analysis of variance was used to examine whether long COVID status was associated with health outcomes. None of the sociodemographic variables was significantly associated with reporting long COVID. Having long COVID was associated with higher levels of psychological distress, fatigue, and perceived stress. The effect of long COVID on health outcomes was greater among men than among women. In conclusion, long COVID appeared across sociodemographic groups. People with long COVID reported worsened health outcomes compared to those who had had COVID-19 but without long-term symptoms. Men experiencing long COVID appear to be particularly vulnerable to experiencing poorer health outcomes; health services may pay extra attention to potentially unnoticed needs for support among men experiencing long COVID.

650

MS161

Martha-Spyridoula Katsarou 1,2,3,Eleni Iasonidou 2,Alexander Osarogue 4,Efthymios Kalafatis 2,Maria Stefanatou 3,5,Sofia Pappa 6ORCID,Stylianos Gatzonis 3,5,Anastasia Verentzioti 3,5,Pantelis Gounopoulos 7,Christos Demponeras 8,Eleni Konstantinidou 7,Nikolaos Drakoulis 1,3ORCID,Andreas Asimakos 3,9,Archontoula Antonoglou 3,Aspasia Mavronasou 3,9,10,Stavroula Spetsioti 3,9,Anastasia Kotanidou 3,9ORCID andParaskevi Katsaounou 3,9,*ORCID

The Greek Collaborative Long COVID Study: Non-Hospitalized and Hospitalized Patients Share Similar Symptom Patterns

https://doi.org/10.3390/jpm12060987

Published

17-Jun-22

Study

https://www.mdpi.com/2075-4426/12/6/987/htm

Long COVID-19 syndrome refers to persisting symptoms (>12 weeks) after the initial coronavirus infection and is estimated to affect 3% to 12% of people diagnosed with the disease globally. Aim: We conducted a collaborative study with the Long COVID patient organization in Greece, in order to estimate the characteristics, symptoms, and challenges these patients confront. Methods: Data were collected from 208 patients using unstructured qualitative free-text entries in an anonymized online questionnaire. Results: The majority of respondents (68.8%) were not hospitalized and reported lingering symptoms (66.8%) for more than six months. Eighteen different symptoms (fatigue, palpitations, shortness of breath, parosmia, etc.) were mentioned in both hospitalized and community patients. Awareness of Long COVID sequelae seems to be low even among medical doctors. Treatment options incorporating targeted rehabilitation programs are either not available or still not included inthe management plan of Long COVID patients. Conclusions: Patients infected with coronavirus with initial mild symptoms suffer from the same persistent symptoms as those who were hospitalized. Long COVID syndrome appears to be a multi-systemic entity and a multidisciplinary medical approach should be adopted in order to correctly diagnose and successfully manage these patients.

651

MS162

Maria Skaalum Petersen 1
Marnar Fríðheim Kristiansen
Katrin Dahl Hanusson
Billa Mouritsardóttir Foldbo
Marjun Eivindardóttir Danielsen
Bjarni á Steig
Shahin Gaini
Marin Strøm
Pál Weihe

Prevalence of long COVID in a national cohort: longitudinal measures from disease onset until 8 months follow up

https://doi.org/10.1016/j.ijid.2022.06.031

Published

23-Jun-22

Study

https://www.ijidonline.com/article/S1201-9712(22)00364-2/fulltext

Highlights
•39% reported long COVID after median 168 days after the acute phase.
•The most prevalent long COVID symptoms were fatigue and taste and smell dysfunction.
•It may take months to resolve from COVID.
Abstract
Objectives
-206
Persistence of COVID-19 symptoms in non-hospitalised patients beyond a few months has not been well characterised. In this longitudinal study from the Faroe Islands, we present prevalence of long COVID in mainly non-hospitalised patients who were followed for up to 8 months.
Methods
All Faroese individuals with confirmed COVID-19 diagnosis from August to December 2020 were invited to participate in this study (n=297). Demographic and clinical characteristics and self-reported symptoms were ascertained prospectively using a detailed questionnaire administered at repeated phone interviews.
Results
A total of 226 individuals participated at baseline (226/297, 76% participation rate) of which 170 participants had more than 3 months follow-up. Of these, 39% (n=67/170, 95% CI [32-37%]) reported persistent symptoms median (range) 168 (93-231) days after the acute phase and 8% (n=14/170, 95% CI [5-13%]) reported severe persistent symptoms. The most prevalent symptoms were fatigue (16%) and smell (17%) and taste (14%) dysfunction. Long COVID was more common in people reporting daily medication use (OR 2.34, 95% CI [1.02-5.37]).
Conclusions
Our results show that symptoms may take months to resolve, even among non-hospitalised patients with a mild illness in the acute phase. Continued monitoring for long COVID is needed to evaluate the added risk of a potential public health concern.

652

MS163

Tianqi Yang, Michael Zhipeng Yan, Xingyi Li & Eric H. Y. Lau

Sequelae of COVID-19 among previously hospitalized patients up to 1 year after discharge: a systematic review and meta-analysis

https://doi.org/10.1007/s15010-022-01862-3

Published

24-Jun-22

Review

https://link.springer.com/article/10.1007/s15010-022-01862-3

Objective
Although complications and clinical symptoms of COVID-19 have been elucidated, the prevalence of long-term sequelae of COVID-19 is less clear in previously hospitalized COVID-19 patients. This review and meta-analysis present the occurrence of different symptoms up to 1 year of follow-up for previously hospitalized patients.
Methods
We performed a systematic review from PubMed and Web of Science using keywords such as “COVID-19”, “SARS-CoV-2”, “sequelae”, “long-term effect” and included studies with at least 3-month of follow-up. Meta-analyses using random-effects models were performed to estimate the pooled prevalence for different sequelae. Subgroup analyses were conducted by different follow-up time, regions, age and ICU admission.
Results
72 articles were included in the meta-analyses after screening 11,620 articles, identifying a total of 167 sequelae related to COVID-19 from 88,769 patients. Commonly reported sequelae included fatigue (27.5%, 95% CI 22.4–33.3%, range 1.5–84.9%), somnipathy (20.1%, 95% CI 14.7–26.9%, range 1.2–64.8%), anxiety (18.0%, 95% CI 13.8–23.1%, range 0.6–47.8%), dyspnea (15.5%, 95% CI 11.3–20.9%, range 0.8–58.4%), PTSD (14.6%, 95% CI 11.3–18.7%, range 1.2–32.0%), hypomnesia (13.4%, 95% CI 8.4–20.7%, range 0.6–53.8%), arthralgia (12.9%, 95% CI 8.4–19.2%, range 0.0–47.8%), depression (12.7%, 95% CI 9.3–17.2%, range 0.6–37.5%), alopecia (11.2%, 95% CI 6.9–17.6%, range 0.0–47.0%) over 3–13.2 months of follow-up. The prevalence of most symptoms reduced after > 9 months of follow-up, but fatigue and somnipathy persisted in 26.2% and 15.1%, respectively, of the patients over a year. COVID-19 patients from Asia reported a lower prevalence than those from other regions.
Conclusions
This review identified a wide spectrum of COVID-19 sequelae in previously hospitalized COVID-19 patients, with some symptoms persisting up to 1 year. Management and rehabilitation strategies targeting these symptoms may improve quality of life of recovered patients.

653

MS164

César Fernández-de-las-Peñas 1,2,*ORCID,Ignacio Cancela-Cilleruelo 1,Jorge Rodríguez-Jiménez 1,Victor Gómez-Mayordomo 3ORCID,Oscar J. Pellicer-Valero 4ORCID,José D. Martín-Guerrero 4ORCID,Valentín Hernández-Barrera 5,Lars Arendt-Nielsen 2,6 andJuan Torres-Macho 7,8

Associated-Onset Symptoms and Post-COVID-19 Symptoms in Hospitalized COVID-19 Survivors Infected with Wuhan, Alpha or Delta SARS-CoV-2 Variant

https://doi.org/10.3390/pathogens11070725

Published

25-Jun-22

Study

https://www.mdpi.com/2076-0817/11/7/725/htm

This study compared associated-symptoms at the acute phase of infection and post-COVID-19 symptoms between individuals hospitalized with the Wuhan, Alpha or Delta SARS-CoV-2 variant. Non-vaccinated individuals hospitalized because of SARS-CoV-2 infection in one hospital during three different waves of the pandemic (Wuhan, Alpha or Delta) were scheduled for a telephone interview. The presence of post-COVID-19 symptoms was systematically assessed. Hospitalization and clinical data were collected from medical records. A total of 201 patients infected with the Wuhan variant, 211 with the Alpha variant and 202 with Delta variant were assessed six months after hospitalization. Patients infected with the Wuhan variant had a greater number of symptoms at hospital admission (higher prevalence of fever, dyspnea or gastrointestinal problems) than those infected with Alpha or Delta variant (p < 0.01). A greater proportion of patients infected with the Delta variant reported headache, anosmia or ageusia as onset symptoms (p < 0.01). The mean number of post-COVID-19 symptoms was higher (p < 0.001) in individuals infected with the Wuhan variant (mean: 2.7 ± 1.3) than in those infected with the Alpha (mean: 1.8 ± 1.1) or Delta (mean: 2.1 ± 1.5) variant. Post-COVID-19 dyspnea was more prevalent (p < 0.001) in people infected with the Wuhan variant, whereas hair loss was higher in those infected with the Delta variant (p = 0.002). No differences in post-COVID-19 fatigue by SARS-CoV-2 variant were found (p = 0.594). Differences in COVID-19 associated onset symptoms and post-COVID-19 dyspnea were observed depending on the SARS-CoV-2 variant. The presence of fatigue was a common post-COVID-19 symptom to all SARS-CoV-2 variants.

654

MS165

Harrison G. Zhang, Arianna Dagliati, Zahra Shakeri Hossein Abad, Xin Xiong, Clara-Lea Bonzel, Zongqi Xia, Bryce W. Q. Tan, Paul Avillach, Gabriel A. Brat, Chuan Hong, Michele Morris, Shyam Visweswaran, Lav P. Patel, Alba Gutiérrez-Sacristán, David A. Hanauer, John H. Holmes, Malarkodi Jebathilagam Samayamuthu, Florence T. Bourgeois, Sehi L’Yi, Sarah E. Maidlow, Bertrand Moal, Shawn N. Murphy, Zachary H. Strasser, Antoine Neuraz, Kee Yuan Ngiam, Ne Hooi Will Loh, Gilbert S. Omenn, Andrea Prunotto, Lauren A. Dalvin, Jeffrey G. Klann, Petra Schubert, Fernando J. Sanz Vidorreta, Vincent Benoit, Guillaume Verdy, Ramakanth Kavuluru, Hossein Estiri, Yuan Luo, Alberto Malovini, Valentina Tibollo, Riccardo Bellazzi, Kelly Cho, Yuk-Lam Ho, Amelia L. M. Tan, Byorn W. L. Tan, Nils Gehlenborg, Sara Lozano-Zahonero, Vianney Jouhet, Luca Chiovato, Bruce J. Aronow, Emma M. S. Toh, Wei Gen Scott Wong, Sara Pizzimenti, Kavishwar B. Wagholikar, Mauro Bucalo, The Consortium for Clinical Characterization of COVID-19 by EHR (4CE), Tianxi Cai, Andrew M. South, Isaac S. Kohane & Griffin M. Weber

International electronic health record-derived post-acute sequelae profiles of COVID-19 patients

https://doi.org/10.1038/s41746-022-00623-8

Published

29-Jun-22

Study

https://www.nature.com/articles/s41746-022-00623-8

The risk profiles of post-acute sequelae of COVID-19 (PASC) have not been well characterized in multi-national settings with appropriate controls. We leveraged electronic health record (EHR) data from 277 international hospitals representing 414,602 patients with COVID-19, 2.3 million control patients without COVID-19 in the inpatient and outpatient settings, and over 221 million diagnosis codes to systematically identify new-onset conditions enriched among patients with COVID-19 during the post-acute period. Compared to inpatient controls, inpatient COVID-19 cases were at significant risk for angina pectoris (RR 1.30, 95% CI 1.09–1.55), heart failure (RR 1.22, 95% CI 1.10–1.35), cognitive dysfunctions (RR 1.18, 95% CI 1.07–1.31), and fatigue (RR 1.18, 95% CI 1.07–1.30). Relative to outpatient controls, outpatient COVID-19 cases were at risk for pulmonary embolism (RR 2.10, 95% CI 1.58–2.76), venous embolism (RR 1.34, 95% CI 1.17–1.54), atrial fibrillation (RR 1.30, 95% CI 1.13–1.50), type 2 diabetes (RR 1.26, 95% CI 1.16–1.36) and vitamin D deficiency (RR 1.19, 95% CI 1.09–1.30). Outpatient COVID-19 cases were also at risk for loss of smell and taste (RR 2.42, 95% CI 1.90–3.06), inflammatory neuropathy (RR 1.66, 95% CI 1.21–2.27), and cognitive dysfunction (RR 1.18, 95% CI 1.04–1.33). The incidence of post-acute cardiovascular and pulmonary conditions decreased across time among inpatient cases while the incidence of cardiovascular, digestive, and metabolic conditions increased among outpatient cases. Our study, based on a federated international network, systematically identified robust conditions associated with PASC compared to control groups, underscoring the multifaceted cardiovascular and neurological phenotype profiles of PASC.

655

MS166

Thomas Bahmer Christoph Borzikowsky
Wolfgang Lieb Anna Horn
Lilian Krist Julia Fricke Carmen Scheibenbogen
Klaus F. Rabe Walter Maetzler
Corina Maetzler Martin Laudien
Derk Frank Sabrina Ballhausen
Anne Hermes Olga Miljukov
Karl Georg Haeusler Nour Eddine El Mokhtari
Martin Witzenrath Jörg Janne Vehreschild
Dagmar Krefting Daniel Pape
Felipe A. Montellano Mirjam Kohls
Caroline Morbach Stefan Störk
Jens-Peter Reese Thomas Keil
Peter Heuschmann Michael Krawczak 1
Stefan Schreiber 1 on behalf of theNAPKON study group

Severity, predictors and clinical correlates of Post-COVID syndrome (PCS) in Germany: A prospective, multi-centre, population-based cohort study

https://doi.org/10.1016/j.eclinm.2022.101549

Published

15-Jul-22

Study

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(22)00279-6/fulltext

Background
Post-COVID syndrome (PCS) is an important sequela of COVID-19, characterised by symptom persistence for >3 months, post-acute symptom development, and worsening of pre-existing comorbidities. The causes and public health impact of PCS are still unclear, not least for the lack of efficient means to assess the presence and severity of PCS.
Methods
COVIDOM is a population-based cohort study of polymerase chain reaction (PCR) confirmed cases of SARS-CoV-2 infection, recruited through public health authorities in three German regions (Kiel, Berlin, Würzburg) between November 15, 2020 and September 29, 2021. Main inclusion criteria were (i) a PCR confirmed SARS-CoV-2 infection and (ii) a period of at least 6 months between the infection and the visit to the COVIDOM study site. Other inclusion criteria were written informed consent and age ≥18 years. Key exclusion criterion was an acute reinfection with SARS-CoV-2. Study site visits included standardised interviews, in-depth examination, and biomaterial procurement. In sub-cohort Kiel-I, a PCS (severity) score was developed based upon 12 long-term symptom complexes. Two validation sub-cohorts (Würzburg/Berlin, Kiel-II) were used for PCS score replication and identification of clinically meaningful predictors. This study is registered at clinicaltrials.gov (NCT04679584) and at the German Registry for Clinical Studies (DRKS, DRKS00023742).
Findings
In Kiel-I (n = 667, 57% women), 90% of participants had received outpatient treatment for acute COVID-19. Neurological ailments (61·5%), fatigue (57·1%), and sleep disturbance (57·0%) were the most frequent persisting symptoms at 6–12 months after infection. Across sub-cohorts (Würzburg/Berlin, n = 316, 52% women; Kiel-II, n = 459, 56% women), higher PCS scores were associated with lower health-related quality of life (EQ-5D-5L-VAS/-index: r = -0·54/ -0·56, all p < 0·0001). Severe, moderate, and mild/no PCS according to the individual participant's PCS score occurred in 18·8%, 48·2%, and 32·9%, respectively, of the Kiel-I sub-cohort. In both validation sub-cohorts, statistically significant predictors of the PCS score included the intensity of acute phase symptoms and the level of personal resilience.
Interpretation
PCS severity can be quantified by an easy-to-use symptom-based score reflecting acute phase disease burden and general psychological predisposition. The PCS score thus holds promise to facilitate the clinical diagnosis of PCS, scientific studies of its natural course, and the development of therapeutic interventions.

656

MS167

H. Shanthanna,A. M. Nelson,N. Kissoon,S. Narouze

The COVID-19 pandemic and its consequences for chronic pain: a narrative review

https://doi.org/10.1111/anae.15801

Published

18-Jul-22

Review

https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/full/10.1111/anae.15801

The COVID-19 pandemic transformed everyday life, but the implications were most impactful for vulnerable populations, including patients with chronic pain. Moreover, persistent pain is increasingly recognised as a key manifestation of long COVID. This narrative review explores the consequences of the COVID-19 pandemic for chronic pain. Publications were identified related to the COVID-19 pandemic influence on the burden of chronic pain, development of new-onset pain because of long COVID with proposed mechanisms and COVID-19 vaccines and pain interventions. Broadly, mechanisms underlying pain due to SARS-CoV-2 infection could be caused by ‘systemic inflammatory-immune mechanisms’, ‘direct neuropathic mechanisms’ or ‘secondary mechanisms due to the viral infection or treatment’. Existing chronic pain populations were variably impacted and social determinants of health appeared to influence the degree of effect. SARS-CoV-2 infection increased the absolute numbers of patients with pain and headache. In the acute phase, headache as a presenting symptom predicted a milder course. New-onset chronic pain was reportedly common and likely involves multiple mechanisms; however, its prevalence decreases over time and symptoms appear to fluctuate. Patients requiring intensive support were particularly susceptible to long COVID symptoms. Some evidence suggests steroid exposure (often used for pain interventions) may affect vaccine efficacy, but there is no evidence of clinical repercussions to date. Although existing chronic pain management could help with symptomatic relief, there is a need to advance research focusing on mechanism-based treatments within the domain of multidisciplinary care.

657

MS168

Anna Irene Vedel Sørensen, Lampros Spiliopoulos, Peter Bager, Nete Munk Nielsen, Jørgen Vinsløv Hansen, Anders Koch, Inger Kristine Meder, Steen Ethelberg & Anders Hviid

A nationwide questionnaire study of post-acute symptoms and health problems after SARS-CoV-2 infection in Denmark

https://doi.org/10.1038/s41467-022-31897-x

Published

21-Jul-22

Study

https://www.nature.com/articles/s41467-022-31897-x

A considerable number of individuals infected with SARS-CoV-2 continue to experience symptoms after the acute phase. Here, we report findings from a nationwide questionnaire study in Denmark including 61,002 RT-PCR confirmed SARS-CoV-2 cases and 91,878 test-negative controls aged 15-years or older. Six to twelve months after the test, the risks of 18 out of 21 symptoms were elevated among test-positives. The largest adjusted risk differences (RD) were observed for dysosmia (RD = 10.92%, 95% CI 10.68–11.21%), dysgeusia (RD = 8.68%, 95% CI 8.43–8.93%), fatigue/exhaustion (RD = 8.43%, 95%CI 8.14–8.74%), dyspnea (RD = 4.87%, 95% CI 4.65–5.09%) and reduced strength in arms/legs (RD = 4.68%, 95% CI 4.45–4.89%). During the period from the test and until completion of the questionnaire, new diagnoses of anxiety (RD = 1.15%, 95% CI 0.95–1.34%) or depression (RD = 1.00%, 95% CI 0.81–1.19%) were also more common among test-positives. Even in a population where the majority of test-positives were not hospitalized, a considerable proportion experiences symptoms up to 12 months after infection. Being female or middle-aged increases risks.

658

MS169

Qiao Wu, Jennifer A. Ailshire & Eileen M. Crimmins

Long COVID and symptom trajectory in a representative sample of Americans in the first year of the pandemic

https://doi.org/10.1038/s41598-022-15727-0

Published

8-Jul-22

Study

https://www.nature.com/articles/s41598-022-15727-0

People who have COVID-19 can experience symptoms for months. Studies on long COVID in the population lack representative samples and longitudinal data focusing on new-onset symptoms occurring with COVID while accounting for pre-infection symptoms. We use a sample representing the U.S. community population from the Understanding America Study COVID-19 Survey, which surveyed around 8000 respondents bi-weekly from March 2020 to March 2021. Our final sample includes 308 infected individuals who were interviewed one month before, around the time of, and 12 weeks after infection. About 23% of the sample experienced new-onset symptoms during infection which lasted for more than 12 weeks, and thus can be considered as having long COVID. The most common new-onset persistent symptoms among those included in the study were headache (22%), runny or stuffy nose (19%), abdominal discomfort (18%), fatigue (17%), and diarrhea (13%). Long COVID was more likely among obese individuals (OR = 5.44, 95% CI 2.12–13.96) and those who experienced hair loss (OR = 6.94, 95% CI 1.03–46.92), headache (OR = 3.37, 95% CI 1.18–9.60), and sore throat (OR = 3.56, 95% CI 1.21–10.46) during infection. There was a lack of evidence relating risk to age, gender, race/ethnicity, education, current smoking status, or comorbid chronic conditions. This work provides national estimates of long COVID in a representative sample after accounting for pre-infection symptoms.

659

MS170

Aranka V Ballering, MSc
Sander K R van Zon, PhD
Tim C olde Hartman, PhD
Prof Judith G M Rosmalen, PhD

Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study

https://doi.org/10.1016/S0140-6736(22)01214-4

Published

6-Aug-22

Study

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01214-4/fulltext

Background: Patients often report various symptoms after recovery from acute COVID-19. Previous studies on post-COVID-19 condition have not corrected for the prevalence and severity of these common symptoms before COVID-19 and in populations without SARS-CoV-2 infection. We aimed to analyse the nature, prevalence, and severity of long-term symptoms related to COVID-19, while correcting for symptoms present before SARS-CoV-2 infection and controlling for the symptom dynamics in the population without infection.
Methods: This study is based on data collected within Lifelines, a multidisciplinary, prospective, population-based, observational cohort study examining the health and health-related behaviours of people living in the north of the Netherlands. All Lifelines participants aged 18 years or older received invitations to digital COVID-19 questionnaires. Longitudinal dynamics of 23 somatic symptoms surrounding COVID-19 diagnoses (due to SARS-CoV-2 alpha [B.1.1.7] variant or previous variants) were assessed using 24 repeated measurements between March 31, 2020, and Aug 2, 2021. Participants with COVID-19 (a positive SARS-CoV-2 test or a physician's diagnosis of COVID-19) were matched by age, sex, and time to COVID-19-negative controls. We recorded symptom severity before and after COVID-19 in participants with COVID-19 and compared that with matched controls.
Findings: 76 422 participants (mean age 53·7 years [SD 12·9], 46 329 [60·8%] were female) completed a total of 883 973 questionnaires. Of these, 4231 (5·5%) participants had COVID-19 and were matched to 8462 controls. Persistent symptoms in COVID-19-positive participants at 90–150 days after COVID-19 compared with before COVID-19 and compared with matched controls included chest pain, difficulties with breathing, pain when breathing, painful muscles, ageusia or anosmia, tingling extremities, lump in throat, feeling hot and cold alternately, heavy arms or legs, and general tiredness. In 12·7% of patients, these symptoms could be attributed to COVID-19, as 381 (21·4%) of 1782 COVID-19-positive participants versus 361 (8·7%) of 4130 COVID-19-negative controls had at least one of these core symptoms substantially increased to at least moderate severity at 90–150 days after COVID-19 diagnosis or matched timepoint.
Interpretation: To our knowledge, this is the first study to report the nature and prevalence of post-COVID-19 condition, while correcting for individual symptoms present before COVID-19 and the symptom dynamics in the population without SARS-CoV-2 infection during the pandemic. Further research that distinguishes potential mechanisms driving post-COVID-19-related symptomatology is required.
Evidence before this study: We searched PubMed, Google Scholar, and preprint repositories from November, 2019, to February, 2022, for studies published in Dutch or English that investigated the course of post-COVID-19 condition (ie, long COVID) over time, the symptoms associated with post-COVID-19 condition, and the prevalence
of post-COVID-19 condition. Furthermore, we searched for studies and policy documents from (global) public health institutes (eg, WHO) that aimed to clinically define post-COVID-19 condition. A formal systematic review was not conducted. Most previous research that assessed the prevalence and symptoms associated with post-COVID-19 condition did not include an adequate control group, and so no adjustments for the prevalence of somatic symptoms in the population without COVID-19 could be made. Additionally, we found no studies that included patients’ symptom prevalence before COVID-19 diagnosis; therefore, the previous studies were unable to assess whether somatic symptoms reported after a COVID-19 diagnosis were already present before SARS-CoV-2 infection. Most research was conducted in a clinical setting, disregarding post-COVID-19 condition in the general population. In the context of these shortcomings, a systematic review estimated that the median proportion of patients with at least one somatic symptom after COVID-19 was 72∙5%.
Added value of this study: To our knowledge, this study is the first to include a control group matched for age, sex, and time, enabling us to adjust for
symptom presence in the general population and changes herein due to public health measures and seasonal influences.
Additionally, the repeated-measures nature of this study enabled us to assess symptom severity in patients with COVID-19 before they had SARS-CoV-2 infection. Therefore, we could assess whether symptom severity was truly increased after a COVID-19 diagnosis, or whether symptoms were a
continuation of pre-existing symptoms. Our approach allowed for identification of core symptoms that define post-COVID-19 condition, as these are increased in severity 90–150 days after a COVID-19 diagnosis compared with patient’s pre-existing symptom severity.
Implications of all the available evidence: Our unique approach allows us to present the core symptoms, namely chest pain, difficulties with breathing, pain when breathing, painful muscles, ageusia or anosmia, tingling extremities, lump in throat, feeling hot and cold alternately, heavy arms or legs, and general tiredness, which could define
post-COVID-19 condition. Additionally, we offer an improved working definition of post-COVID-19 condition and provide a reliable prevalence estimate in the general population corrected for pre-existing symptoms, and symptoms in COVID-19-negative controls. Taking into account the symptoms that increased in severity and could be attributed to COVID-19, while correcting for seasonal fluctuations and non-infectious health aspects of the pandemic on symptom dynamics, we estimated that 12∙7% of patients with COVID-19 in the general population will experience persistent somatic symptoms after COVID-19. Additionally, these core symptoms have major implications for future research, as these symptoms have the highest discriminative ability to distinguish between post-COVID-19 condition and non-COVID-19-related symptoms.

660

MS171

Christopher E Brightling
Rachael A Evans

Long COVID: which symptoms can be attributed to SARS-CoV-2 infection?

https://doi.org/10.1016/S0140-6736(22)01385-X

Published

6-Aug-22

Comment

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2822%2901385-X/fulltext

How many of the symptoms currently attributed to long COVID actually represent pre-existent disease or are unrelated to COVID-19 is uncertain. Symptoms that were present before SARS-CoV-2 infection are often not recorded or assessed by recall. In The Lancet, Aranka V Ballering and colleagues10 report the findings of a longitudinal cohort study conducted in the north of the Netherlands between April, 2020, and August, 2021, where 23 somatic symptoms were assessed using 24 repeated measurements in digital COVID-19 questionnaires. The study was embedded within the large, population-based Lifelines COVID-19 cohort. The main strengths of this study were that participants were their own control, with the pattern and severity of symptoms assessed before and 3–5 months after SARS-CoV-2 infection, and were also compared with a matched control group of COVID-19-negative participants. Of the 76 422 participants, 4231 (5·5%) had COVID-19 and were compared with 8462 matched controls. Participants had a mean age of 53·7 years (SD 12·9), 46 329 (60·8%) were female, and nearly all were of White ethnicity. The proportion of participants who had at least one core symptom of substantially increased severity to at least moderate was 21·4% (381 of 1782) in COVID-19-positive participants versus 8·7% (361 of 4130) in COVID-19-negative controls. Thus, this study found that core symptoms were attributed to COVID-19 in 12·7% of participants, or approximately one in eight. This is a major advance on previous long COVID prevalence estimates, as it includes a matched control group without SARS-CoV-2 infection and accounts for symptoms that were present before infection.
The pattern of symptomatology observed by Ballering and colleagues10 was similar to previous reports, with fatigue and breathlessness among the most common symptoms, but other symptoms such as chest pain were more common in people who had COVID-19 than in COVID-19-negative controls. Ballering and colleagues10 propose a core symptom set to be considered as part of the case definition for long COVID. Although an agreed diagnostic core symptom set would inform clinical pathways and research, the study by Ballering and colleagues10 did not fully consider the impact on mental health, it was conducted in one region in the Netherlands, and it did not include an ethnically diverse population; thus the concept of a core symptom set will require further validation.
Importantly, the study by Ballering and colleagues10 does not provide new mechanistic insights, which are key to uncovering new therapeutic targets. In other studies, clustering of patient-reported outcomes has identified different severity groups of long COVID and identified increased systemic inflammation in people with very severe long COVID.5, 6 How patient-centred outcomes, together with biomarkers, can further refine long COVID diagnosis and inform precision medicine approaches warrants further consideration.
Encouragingly, emerging data from other studies suggest that the proportion of newly infected people developing long COVID is reduced in people who have received vaccination before SARS-CoV-2 infection,11 and might be lower in people infected with the omicron variant than those infected with earlier variants.12 Findings from the ONS survey suggested that vaccination following infection might reduce the symptom burden of long COVID after the first dose, with sustained improvement after a second dose.13 Whether acute treatments for COVID-19 affect the likelihood of developing long COVID or its severity is unknown.
Current evidence supports the view that long COVID is common and can persist for at least 2 years after SARS-CoV-2 infection, although severe debilitating disease is present in a minority. The long COVID case definition needs to be further improved, potentially to describe different types of long COVID, of which better mechanistic understanding is crucial. This will lead to personalised multimodality treatments that can be implemented to manage the increasingly high number of people with long COVID.

661

MS172

Murray Dryden, MBBCh
Caroline Mudara, MSc
Caroline Vika, MSc
Prof Lucille Blumberg, DSc hc
Natalie Mayet, MPhil-CS
Prof Cheryl Cohen, PhD
Prof Stefano Tempia, PhD
Arifa Parker, MMed
Jeremy Nel, MBBCh
Rubeshan Perumal, MPH
Michelle J Groome, PhD
Francesca Conradie, MBBCh
Norbert Ndjeka, MMed
Louise Sigfrid, PhD
Laura Merson
Waasila Jassat, MMed

Post-COVID-19 condition 3 months after hospitalisation with SARS-CoV-2 in South Africa: a prospective cohort study

https://doi.org/10.1016/S2214-109X(22)00286-8

Published

1-Sep-22

Study

https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(22)00286-8/fulltext

Background
Post COVID-19 condition (PCC), as defined by WHO, refers to a wide range of new, returning, or ongoing health problems in people who have had COVID-19, and it represents a rapidly emerging public health priority. We aimed to establish how this developing condition has affected patients in South Africa and which population groups are at risk.
Methods
In this prospective cohort study, we used the DATCOV national hospital surveillance system to identify participants aged 18 years or older who had been hospitalised with laboratory-confirmed SARS-CoV-2 infection in South Africa. Participants underwent telephone follow-up assessment at 1 month and 3 months after hospital discharge. Participants were assessed using a standardised questionnaire for the evaluation of symptoms, functional status, health-related quality of life, and occupational status. We used negative binomial regression models to determine factors associated with PCC.
Findings
Of 241 159 COVID-19 admissions reported to DATCOV between Dec 1, 2020, and Aug 23, 2021, 8309 were randomly selected for enrolment. Of the 3094 patients that we were able to contact, 2410 (77·9%) consented to participate in the study at 1 month after discharge. Of these, 1873 (77·7%) were followed up at 3 months after hospital discharge. Participants had a median age of 52 years (IQR 41–62) and 960 (51·3%) were women. At 3 months of follow-up, 1249 (66·7%) of 1873 participants reported new or persistent COVID-19-related symptoms, compared with 1978 (82·1%) of 2410 at 1 month after hospital discharge. The most common symptoms reported at 3 months were fatigue (50·3%), shortness of breath (23·4%), confusion or lack of concentration (17·5%), headaches (13·8%), and problems seeing or blurred vision (10·1%). On multivariable analysis, the factors associated with persistent symptoms after acute COVID-19 were being female (adjusted incident rate ratio 1·20, 95% CI 1·04–1·38) and admission to an intensive care unit (1·17, 1·01–1·37).
Interpretation
Most participants in this cohort of individuals previously hospitalised with COVID-19 reported persistent symptoms 3 months after hospital discharge and a significant impact of PCC on their functional and occupational status. The large burden of PCC symptoms identified in this study emphasises the need for a national health strategy. This should include the development of clinical guidelines and training of health-care workers for identifying, assessing, and caring for patients affected by PCC; establishment of multidisciplinary health services; and provision of information and support to people who have PCC.

662

MS173

Pierre Smith
Rana Charafeddine
Sabine Drieskens
Robby De Pauw
Karin De Ridder
Stefaan Demarest
Dieter Van Cauteren

ETUDE COVIMPACT
INFECTION COVID-19 ET SES IMPLICATIONS
PHYSIQUES, MENTALES ET SOCIALES
À LONG TERME
Résultats du suivi à 3 et 6 mois suivant l’infection

https://doi.org/10.25608/gyzc-w673

Published

Study

https://www.sciensano.be/sites/default/files/report_2_final_fr.pdf

Parmi les guides de pratique clinique actuels du COVID de longue durée, ceux du NICE (National Institute for Health and Care Excellence) sont fortement utilisés (NICE, 2020): les symptômes persistent ou se développent plus de 3 mois après l’infection COVID-19 et ne peuvent être expliqués par un autre diagnostic. Sur base de cette
définition et dans le cadre de ce rapport sur l’impact d’une infection COVID-19 après 3 et 6 mois, nous avons choisi de travailler avec les deux définitions de cas suivantes de la COVID de longue durée : (1) Trois mois après l’infection, présenter au moins un symptôme lié à l’infection au COVID-19, (2) Six mois après l’infection, présenter encore au moins un symptôme persistant lié à l’infection au COVID-19. Selon ces définitions, 47% des participants déclarent après 3 mois encore avoir au moins un symptôme lié à leur infection, et 32% continuent d’en déclarer après 6 mois. Ces proportions sont similaires à celles observées dans d’autres études. Une métaanalyse a mis en évidence que 46% des personnes présentaient au moins un symptôme lié à l’infection au COVID19 trois mois après celle-ci (Fernández-de-Las-Peñas et al., 2021). Une autre étude a mis en avant que 6 mois après l’infection COVID-19, 30% des participants rapportaient encore au moins un symptôme persistant (Logue et al., 2021).
Tous les participants présentant un COVID long ne déclarent pas nécessairement un moins bon état de santé suite à leur infection COVID-19. En effet, environ 30% des participants présentant un COVID de longue durée après 3 et 6 mois se sentent complètement rétablis de leur infection COVID-19. Ce résultat montre que certaines
personnes peuvent avoir des symptômes persistants sans forcément se sentir en moins bonne santé suite à leur infection. Sur l’ensemble de l’échantillon, 33% des participants souffrent d’un COVID de longue durée et déclarent ne pas être complètement rétablis de leur infection après 3 mois, et 26% après 6 mois. Les femmes, les personnes avec un plus faible niveau d’éducation, les personnes avec un antécédent de maladie chronique, les personnes en situation d’obésité ou de surpoids, les personnes qui présentaient au moins un symptôme de la COVID-19 en phase aigüe de l’infection et les personnes hospitalisées suite à leur infection sont plus à risque de présenter un COVID de longue durée 3 mois et 6 mois après leur infection. L’âge et le nombre de doses de vaccins COVID-19 au moment de l’infection ne sont pas significativement associé au risque de présenter un COVID de longue durée. La fatigue ou épuisement est le symptôme persistant le plus fréquent chez les personnes présentant un COVID de longue durée à 3 mois (49%) et chez ceux le présentant à 6 mois (50%) après l’infection. Les autres symptômes persistants les plus fréquents sont les maux de tête (27% et 32%), les troubles de la mémoire et concentration (26% et 32%), les douleurs musculaires (22% et 28%), les difficultés respiratoires (21% et 27%) et les troubles du sommeil (19% et 22%). Les personnes avec un COVID de longue durée à 6 mois ont des proportions plus élevées des différents symptômes que ceux avec un COVID de longue durée à 3 mois, à l’exception de la perte de gout et perte d’odorat qui sont moins présents après 6 mois. En comparaison aux personnes ne présentant aucun symptôme de la COVID-19 trois et six mois après leur infection, les personnes présentant un COVID de longue durée à trois et six mois rapportent un score plus faible de qualité de vie liée à la santé, plus de difficultés respiratoires modérées et sévères, un niveau de fatigue plus élevé, plus de limitations fonctionnelles, des prévalences plus élevées d’anxiété et de dépression, et une activité physique diminuée. Nous observons également que l’état de santé globale sur ces différents résultats est plus défavorable pour les personnes qui présentent encore des symptômes persistants à 6 mois que chez ceux qui en présente à 3 mois après l’infection. Le COVID de longue durée a aussi des conséquences négatives sur la situation professionnelle et économique des individus. En comparaison aux personnes ne présentant plus de symptôme, les personnes avec un COVID de longue durée à 3 et 6 mois ont plus souvent été en arrêt maladie, avec un nombre de jours moyen en arrêt maladie plus élevé, et ont plus souvent rapporté une perte financière modérée et sévère due à leur état de santé lié au COVID-19.
Cette étude présente un certain nombre de limites et biais potentiels dont il est important de tenir compte. Premièrement, un biais de sélection peut survenir lors de la phase de recrutement car certaines personnes n'ont pas de GSM, elles n'auront donc pas accès au lien par SMS du premier questionnaire (voir 3. Méthodologie). De
plus, certaines personnes peuvent ne pas avoir accès à Internet ou les compétences nécessaires pour répondre par Internet. Les analyses ont été pondérées sur base de certaines caractéristiques de la population éligible (l’âge, le sexe, et le fait d’avoir au moins un symptôme en phase aigüe de l’infection) afin de tenir partiellement compte
de ce biais de sélection. Aussi, un biais lié aux participants perdus de vue (qui ne répondent plus aux questionnaires ou qui quittent l’étude) peut survenir car les personnes qui présentent des symptômes de la COVID de longue durée sont potentiellement plus susceptibles de continuer à participer et les personnes perdues de vue
pourraient plus vraisemblablement être des participants qui n'ont pas / plus de symptôme de la COVID-19, ou au contraire des personnes décédées. Enfin, une autre limite de cette étude et qu’elle n’a pas un groupe contrôle de personnes non infectées par la COVID-19.

663

MS174

Rehab Magdy, Alaa Elmazny, Shaimaa H. Soliman, Eman H. Elsebaie, Sara H. Ali, Ali M. Abdel Fattah, Mahmoud Hassan, Ahmed Yassien, Noha A. Mahfouz, Radwa M. Elsayed, Wael Fathy, Hoda M. Abdel-Hamid, Jehan Mohamed & Mona Hussein

Post-COVID-19 neuropsychiatric manifestations among COVID-19 survivors suffering from migraine: a case–control study

https://doi.org/10.1186/s10194-022-01468-y

Pubished

12-Aug-22

Study

https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-022-01468-y

Background
The burden of post-coronavirus disease (COVID)-19 symptoms has been increasing and is of great concern in patients with pre-existing chronic medical conditions.This study aimed to delineate the post-COVID-19 neuropsychiatric symptoms among migraine patients compared to the non-migraine control group.
Methods
Two groups, each of 204 COVID-19 survivors, were enrolled in the study after 3 months of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, one group fulfilling the episodic migraine criteria and the other serving as a matching control group. Subjects were evaluated through an in-person interview for post-COVID-19 neuropsychiatric symptoms, including detailed headache patterns and severity, using the visual analogue scale.
Results
The Frequency of headache during the acute phase of COVID-19 was more frequent in migraine patients (OR = 1.60, 95%CI = 1.04–2.45, P-value = 0.031). The reported significant post-COVID-19 neuropsychiatric symptoms in migraine patients compared to controls were fatigue (OR = 1.662, 95%CI = 1.064–2.596, P-value = 0.025), anosmia/hyposmia (OR = 2.06, 95%CI = 1.164- 3.645, P-value = 0.012), cacosmia (OR = 2.663, 95%CI = 1.145–6.195, P-value = 0.019), depression (OR = 2.259, 95%CI = 1.284- 3.975, P-value = 0.004), anxiety (OR = 3.267, 95%CI = 1.747- 6.108, P-value ≤ 0.001), insomnia (OR = 2.203, 95%CI = 1.298- 3.739, P-value = 0.003), and headache (OR = 3.148, 95%CI = 1.616–6.136, P-value = ≤ 0.001).While there was no statistically significant difference between migraine patients and controls regarding the post-COVID-19 functional status score (P-value = 0.102). The pattern of post-COVID-19 headache was reported as chronic headache transformation in 17.6% of the migraine group, with the median intensity rate being 5.5 and IQR (3–7). In the control group, 14% experienced chronic headache attributed to systemic viral infection with a median intensity rate of 2 and IQR (2–5), while 12% experienced a new daily persistent headache with a median intensity of 5 and IQR (1–6).
Conclusion
The study highlighted the importance of follow-up migraine patients upon recovery from COVID-19 infection, being more vulnerable to post-COVID-19 symptoms.

664

MS175

Aranka V Ballering, MSc
Sander K R van Zon, PhD
Tim C olde Hartman, PhD
Prof Judith G M Rosmalen, PhD

Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study

https://doi.org/10.1016/S0140-6736(22)01214-4

Published

6-Aug-22

Study

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01214-4/fulltext

Background
Patients often report various symptoms after recovery from acute COVID-19. Previous studies on post-COVID-19 condition have not corrected for the prevalence and severity of these common symptoms before COVID-19 and in populations without SARS-CoV-2 infection. We aimed to analyse the nature, prevalence, and severity of long-term symptoms related to COVID-19, while correcting for symptoms present before SARS-CoV-2 infection and controlling for the symptom dynamics in the population without infection.
Methods
This study is based on data collected within Lifelines, a multidisciplinary, prospective, population-based, observational cohort study examining the health and health-related behaviours of people living in the north of the Netherlands. All Lifelines participants aged 18 years or older received invitations to digital COVID-19 questionnaires. Longitudinal dynamics of 23 somatic symptoms surrounding COVID-19 diagnoses (due to SARS-CoV-2 alpha [B.1.1.7] variant or previous variants) were assessed using 24 repeated measurements between March 31, 2020, and Aug 2, 2021. Participants with COVID-19 (a positive SARS-CoV-2 test or a physician's diagnosis of COVID-19) were matched by age, sex, and time to COVID-19-negative controls. We recorded symptom severity before and after COVID-19 in participants with COVID-19 and compared that with matched controls.
Findings
76 422 participants (mean age 53·7 years [SD 12·9], 46 329 [60·8%] were female) completed a total of 883 973 questionnaires. Of these, 4231 (5·5%) participants had COVID-19 and were matched to 8462 controls. Persistent symptoms in COVID-19-positive participants at 90–150 days after COVID-19 compared with before COVID-19 and compared with matched controls included chest pain, difficulties with breathing, pain when breathing, painful muscles, ageusia or anosmia, tingling extremities, lump in throat, feeling hot and cold alternately, heavy arms or legs, and general tiredness. In 12·7% of patients, these symptoms could be attributed to COVID-19, as 381 (21·4%) of 1782 COVID-19-positive participants versus 361 (8·7%) of 4130 COVID-19-negative controls had at least one of these core symptoms substantially increased to at least moderate severity at 90–150 days after COVID-19 diagnosis or matched timepoint.
Interpretation
To our knowledge, this is the first study to report the nature and prevalence of post-COVID-19 condition, while correcting for individual symptoms present before COVID-19 and the symptom dynamics in the population without SARS-CoV-2 infection during the pandemic. Further research that distinguishes potential mechanisms driving post-COVID-19-related symptomatology is required.

665

MS176

Jonathan I. Silverberg ,Israel Zyskind ,Hiam Naiditch,Jason Zimmerman,Aaron E. Glatt,Abraham Pinter,Elitza S. Theel,Michael J. Joyner,D. Ashley Hill,Miriam R. Lieberman,Elliot Bigajer,Daniel Stok,Elliot Frank,Avi Z. Rosenberg

Predictors of chronic COVID-19 symptoms in a community-based cohort of adults

https://doi.org/10.1371/journal.pone.0271310

Published

4-Aug-22

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0271310

Background
COVID-19 can cause some individuals to experience chronic symptoms. Rates and predictors of chronic COVID-19 symptoms are not fully elucidated.
Objective
To examine occurrence and patterns of post-acute sequelae of SARS-CoV2 infection (PASC) symptomatology and their relationship with demographics, acute COVID-19 symptoms and anti-SARS-CoV-2 IgG antibody responses.
Methods
A multi-stage observational study was performed of adults (≥18 years) from 5 US states. Participants completed two rounds of electronic surveys (May-July 2020; April-May 2021) and underwent testing to anti-SARS-CoV-2 nucleocapsid protein IgG antibody testing. Latent Class Analysis was used to identify clusters of chronic COVID-19 symptoms.
Results
Overall, 390 adults (median [25%ile, 75%ile] age: 42 [31, 54] years) with positive SARS-CoV-2 antibodies completed the follow-up survey; 92 (24.7%) had ≥1 chronic COVID-19 symptom, with 11-month median duration of persistent symptoms (range: 1–12 months). The most common chronic COVID-19 symptoms were fatigue (11.3%), change in smell (9.5%) or taste (5.6%), muscle or joint aches (5.4%) and weakness (4.6%). There were significantly higher proportions of ≥1 persistent COVID-19 symptom (31.5% vs. 18.6%; Chi-square, P = 0.004), and particularly fatigue (15.8% vs. 7.3%, P = 0.008) and headaches (5.4% vs. 1.0%, P = 0.011) in females compared to males. Chronic COVID-19 symptoms were also increased in individuals with ≥6 acute COVID-19 symptoms, Latent class analysis revealed 4 classes of symptoms. Latent class-1 (change of smell and taste) was associated with lower anti-SARS-CoV-2 antibody levels; class-2 and 3 (multiple chronic symptoms) were associated with higher anti-SARS-CoV-2 antibody levels and more severe acute COVID-19 infection.
Limitations
Ambulatory cohort with less severe acute disease.
Conclusion
Individuals with SARS-CoV-2 infection commonly experience chronic symptoms, most commonly fatigue, changes in smell or taste and muscle/joint aches. Female sex, severity of acute COVID-19 infection, and higher anti-SARS-CoV-2 IgG levels were associated with the highest risk of having chronic COVID-19 symptoms.

666

MS177

Michał Chudzik 1,†ORCID,Mateusz Babicki 2,*,†ORCID,Joanna Kapusta 3ORCID,Żaneta Kałuzińska-Kołat 4,5ORCID,Damian Kołat 4,5ORCID,Piotr Jankowski 1ORCID andAgnieszka Mastalerz-Migas

Long-COVID Clinical Features and Risk Factors: A Retrospective Analysis of Patients from the STOP-COVID Registry of the PoLoCOV Study

https://doi.org/10.3390/v14081755

Published

11-Aug-22

Study

https://www.mdpi.com/1999-4915/14/8/1755/htm

Despite recovering from the acute phase of coronavirus disease (COVID-19), many patients report continuing symptoms that most commonly include fatigue, cough, neurologic problems, hair loss, headache, and musculoskeletal pain, a condition termed long-COVID syndrome. Neither its etiopathogenesis, nor its clinical presentation or risk factors are fully understood. Therefore, the purpose of this study was to retrospectively evaluate the most common symptoms of long-COVID among patients from the STOP COVID registry of the PoLoCOV study, and to search for risk factors for development of the syndrome. The registry includes patients who presented to the medical center for persistent clinical symptoms following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The analysis included data from initial presentation and at three-month follow-up. Of the 2218 patients, 1569 (70.7%) reported having at least one symptom classified as long-COVID syndrome three months after recovery from the initial SARS-CoV-2 infection. The most common symptoms included chronic fatigue (35.6%\), cough (23.0%), and a set of neurological symptoms referred to as brain fog (12.1%). Risk factors for developing long-COVID syndrome included female gender (odds ratio [OR]: 1.48, 95% confidence intervals [CI] [1.19–1.84]), severe COVID-19 (OR: 1.56, CI: 1.00–2.42), dyspnea (OR: 1.31, CI: 1.02–1.69), and chest pain (OR: 1.48, CI: 1.14–1.92). Long-COVID syndrome represents a significant clinical and social problem. The most common clinical manifestations are chronic fatigue, cough, and brain fog. Given the still-limited knowledge of long-COVID syndrome, further research and observation are needed to better understand the mechanisms and risk factors of the disease.

667

MS178

Zoe O Demko, Tong Yu, Sarika K. Mullapudi, M. Gabriela Varela Heslin, Chamia A. Dorsey, Christine B. Payton, Jeffrey A. Tornheim, Paul W. Blair, Shruti H. Mehta, David L. Thomas, Yukari C. Manabe, Annukka A.R. Antar, the OutSMART Study Team

Post-acute sequelae of SARS-CoV-2 (PASC) impact quality of life at 6, 12 and 18 months post-infection

https://doi.org/10.1101/2022.08.08.22278543

pre-print

9-Aug-22

Study

https://www.medrxiv.org/content/10.1101/2022.08.08.22278543v1.full-text

Little data exist on long COVID outcomes beyond one year. In a cohort enrolled with mild-moderate acute COVID-19, a wide range of symptoms manifest at 6, 12, and 18 months. Endorsing over 3 symptoms associates with poorer quality of life in 5 domains: physical, social, fatigue, pain, and general health.
We demonstrate in a prospective observational cohort that a high proportion of individuals with pre-delta variant, non-severe acute COVID-19 continue to report a wide range of symptoms at 6, 12, and 18 months post-infection, and that having multiple symptoms is associated with lower quality of life over a year after infection. This data extend to 18 months previously reported PASC symptoms and associations with QoL measures at earlier time points.[7-11] Fatigue, brain fog, nasal congestion and discharge, headache, sleep disturbances, and body aches were the most common symptoms. Neurological, mood, and systemic symptoms persisted in over half of participants surveyed at 18 months post-COVID-19. Almost one-quarter of participants reported not having returned to their usual pre-COVID health by 18 months, while some reported returning to work and other activities before feeling entirely recovered from COVID-19. Symptomatic participants reported that symptoms interfered with activities up to 18 months post-infection, and several quality of life domains were statistically significantly associated with multi-symptom morbidity.
Limitations of this study include the relatively small size of the cohort, the proportion of participants who missed survey timepoints, and attrition over the follow-up period, which may lead to sampling and attrition biases. Strengths of the study include prospective enrollment during acute COVID-19, prolonged follow-up with validated survey instruments, and a primarily non-hospitalized cohort.
More research is urgently needed to characterize and address the lasting morbidity associated with long COVID, especially in the face of omicron vaccine-breakthrough cases.

668

MS179

Jacqui Wise

Long covid: Hair loss and sexual dysfunction are among wider symptoms, study finds

https://doi.org/10.1136/bmj.o1887

Published

27-Jul-22

Article

https://www.bmj.com/content/378/bmj.o1887

People experiencing long covid have reported a wider set of symptoms than previously thought, including hair loss and sexual dysfunction.
Electronic health records of 2.4 million people in the UK from January 2020 to April 2021 were analysed for a study published in Nature Medicine.1 The cohort included 486 149 people with confirmed SARS-CoV-2 infection who were not admitted to hospital, matched with a control group of 1.9 million people with no recorded evidence of coronavirus infection.
People who tested positive for the virus reported at least one of 62 symptoms more frequently 12 weeks after initial infection with SARS-CoV-2 than those who had not contracted the virus. The symptoms with the largest adjusted hazard ratios were anosmia (6.49 (95% confidence interval 5.02 to 8.39)), hair loss (3.99 (3.63 to 4.39)), sneezing (2.77 (1.40 to 5.50)) ejaculation difficulty (2.63 (1.61 to 4.28)), reduced libido (2.36 (1.61 to 3.47)), and shortness of breath (2.20 (1.57 to 3.08)). Other common symptoms were chest pain, a hoarse voice, and fever.
Shamil Haroon, associate clinical professor in public health at the University of Birmingham and senior author, said, “This research validates what patients have been telling clinicians and policy makers throughout the pandemic, that the symptoms of long covid are extremely broad and cannot be fully accounted for by other factors such as lifestyle risk factors or chronic health conditions.
“The symptoms we identified should help clinicians and clinical guideline developers to improve the assessment of patients with long term effects from covid-19 and to subsequently consider how this symptom burden can be best managed.”

669

MS180

George N. Ioannou, BMBCh, MS1,2; Aaron Baraff, MS3; Alexandra Fox, MSIS3; Troy Shahoumian, PhD4; Alex Hickok, MS5; Ann M. O’Hare, MD6,7; Amy S. B. Bohnert, PhD8; Edward J. Boyko, MD, MPH9,10; Matthew L. Maciejewski, PhD11,12,13,14; C. Barrett Bowling, MD, MSPH15,16; Elizabeth Viglianti, MD17,18; Theodore J. Iwashyna, MD, PhD19,20; Denise M. Hynes, MPH, PhD, RN5,19,20

Rates and Factors Associated With Documentation of Diagnostic Codes for Long COVID in the National Veterans Affairs Health Care System

https://doi.org/10.1001/jamanetworkopen.2022.24359

Published

29-Jul-22

Study

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2794788

Key Points
Question What are the rates, clinical settings, and factors associated with documentation of care related to COVID-19 at 3 or more months after acute infection?
Findings In this cohort study of 198 601 persons with a positive SARS-CoV-2 test, COVID-19 care was documented in 13.5% of individuals 3 or more months after infection during a mean follow-up of 13.5 months and was documented more commonly in older persons, those with higher comorbidity burden, those with more severe acute COVID-19 presentation, and those who were unvaccinated at the time of infection.
Meaning These findings provide guidance for health care systems to develop systematic approaches to the evaluation and management of patients who may be experiencing long COVID.
Abstract
Importance Some persons infected with SARS-CoV-2 experience symptoms or impairments many months after acute infection.
Objectives To determine the rates, clinical setting, and factors associated with documented receipt of COVID-19–related care 3 or more months after acute infection.
Design, Setting, and Participants This retrospective cohort study used data from the US Department of Veterans Affairs health care system. Participants included persons with a positive SARS-CoV-2 test between February 1, 2020, and April 30, 2021, who were still alive 3 months after infection and did not have evidence of reinfection. Data analysis was performed from February 2020 to December 2021.
Exposures Positive SARS-CoV-2 test.
Main Outcomes and Measures Rates and factors associated with documentation of COVID-19–related International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes (U07.1, Z86.16, U09.9, and J12.82) 3 or more months after acute infection (hereafter, long-COVID care), with follow-up extending to December 31, 2021.
Results Among 198 601 SARS-CoV-2–positive persons included in the study, the mean (SD) age was 60.4 (17.7) years, 176 942 individuals (89.1%) were male, 133 924 (67.4%) were White, 44 733 (22.5%) were Black, and 19 735 (9.9%) were Hispanic. During a mean (SD) follow-up of 13.5 (3.6) months, long-COVID care was documented in a wide variety of clinics, most commonly primary care and general internal medicine (18 634 of 56 310 encounters [33.1%]), pulmonary (7360 of 56 310 encounters [13.1%]), and geriatrics (5454 of 56 310 encounters [9.7%]). Long-COVID care was documented in 26 745 cohort members (13.5%), with great variability across geographical regions (range, 10.8%-18.1%) and medical centers (range, 3.0%-41.0%). Factors significantly associated with documented long-COVID care included older age, Black or American Indian/Alaska Native race, Hispanic ethnicity, geographical region, high Charlson Comorbidity Index score, having documented symptoms at the time of acute infection (adjusted odds ratio [AOR], 1.71; 95% CI, 1.65-1.78) and requiring hospitalization (AOR, 2.60; 95% CI, 2.51-2.69) or mechanical ventilation (AOR, 2.46; 95% CI, 2.26-2.69). Patients who were fully vaccinated at the time of infection were less likely to receive long-COVID care (AOR, 0.78; 95% CI, 0.68-0.90).
Conclusions and Relevance Long-COVID care was documented in a variety of clinical settings, with great variability across regions and medical centers and was documented more commonly in older persons, those with higher comorbidity burden, those with more severe acute COVID-19 presentation and those who were unvaccinated at the time of infection. These findings provide support and guidance for health care systems to develop systematic approaches to the evaluation and management of patients who may be experiencing long COVID.

670

MS181

Aurélie Fischer, Lu Zhang, Abir Elbéji, Paul Wilmes, Pauline Oustric, Therese Staub, Petr V Nazarov, Markus Ollert, Guy Fagherazzi

Long COVID Symptomatology After 12 Months and Its Impact on Quality of Life According to Initial Coronavirus Disease 2019 Disease Severity

https://doi.org/10.1093/ofid/ofac397

Published

5-Aug-22

Study

https://academic.oup.com/ofid/article/9/8/ofac397/6656444

Background
“Long COVID” is characterized by a variety of symptoms and an important burden for affected people. Our objective was to describe long COVID symptomatology according to initial coronavirus disease 2019 (COVID-19) severity.
Methods
Predi-COVID cohort study participants, recruited at the time of acute COVID-19 infection, completed a detailed 12-month symptom and quality of life questionnaire. Frequencies and co-occurrences of symptoms were assessed.
Results
Among the 289 participants who fully completed the 12-month questionnaire, 59.5% reported at least 1 symptom, with a median of 6 symptoms. Participants with an initial moderate or severe acute illness declared more frequently 1 or more symptoms (82.6% vs 38.6%, P < .001) and had on average 6.8 more symptoms (95% confidence interval, 4.18–9.38) than initially asymptomatic participants who developed symptoms after the acute infection. Overall, 12.5% of the participants could not envisage coping with their symptoms in the long term. Frequently reported symptoms, such as neurological and cardiovascular symptoms, but also less frequent ones such as gastrointestinal symptoms, tended to cluster.
Conclusions
Frequencies and burden of symptoms present 12 months after acute COVID-19 infection increased with the severity of the acute illness. Long COVID likely consists of multiple subcategories rather than a single entity. This work will contribute to the better understanding of long COVID and to the definition of precision health strategies.

671

MS182

Bernardo Meza-Torres # 1, Gayathri Delanerolle 1, Cecilia Okusi 1, Nikhil Mayor 2, Sneha Anand 1, Jack Macartney 1, Piers Gatenby 2, Ben Glampson 3, Martin Chapman 4, Vasa Curcin 4, Erik Mayer 3, Mark Joy 1, Trisha Greenhalgh 1, Brendan Delaney 5, Simon de Lusignan 1

Differences in Clinical Presentation With Long COVID After Community and Hospital Infection and Associations With All-Cause Mortality: English Sentinel Network Database Study

https://doi.org/10.2196/37668

Published

16-Aug-22

Study

https://pubmed.ncbi.nlm.nih.gov/35605170/

Background: Most studies of long COVID (symptoms of COVID-19 infection beyond 4 weeks) have focused on people hospitalized in their initial illness. Long COVID is thought to be underrecorded in UK primary care electronic records.
Objective: We sought to determine which symptoms people present to primary care after COVID-19 infection and whether presentation differs in people who were not hospitalized, as well as post-long COVID mortality rates.
Methods: We used routine data from the nationally representative primary care sentinel cohort of the Oxford-Royal College of General Practitioners Research and Surveillance Centre (N=7,396,702), applying a predefined long COVID phenotype and grouped by whether the index infection occurred in hospital or in the community. We included COVID-19 infection cases from March 1, 2020, to April 1, 2021. We conducted a before-and-after analysis of long COVID symptoms prespecified by the Office of National Statistics, comparing symptoms presented between 1 and 6 months after the index infection matched with the same months 1 year previously. We conducted logistic regression analysis, quoting odds ratios (ORs) with 95% CIs.
Results: In total, 5.63% (416,505/7,396,702) and 1.83% (7623/416,505) of the patients had received a coded diagnosis of COVID-19 infection and diagnosis of, or referral for, long COVID, respectively. People with diagnosis or referral of long COVID had higher odds of presenting the prespecified symptoms after versus before COVID-19 infection (OR 2.66, 95% CI 2.46-2.88, for those with index community infection and OR 2.42, 95% CI 2.03-2.89, for those hospitalized). After an index community infection, patients were more likely to present with nonspecific symptoms (OR 3.44, 95% CI 3.00-3.95; P<.001) compared with after a hospital admission (OR 2.09, 95% CI 1.56-2.80; P<.001). Mental health sequelae were more strongly associated with index hospital infections (OR 2.21, 95% CI 1.64-2.96) than with index community infections (OR 1.36, 95% CI 1.21-1.53; P<.001). People presenting to primary care after hospital infection were more likely to be men (OR 1.43, 95% CI 1.25-1.64; P<.001), more socioeconomically deprived (OR 1.42, 95% CI 1.24-1.63; P<.001), and with higher multimorbidity scores (OR 1.41, 95% CI 1.26-1.57; P<.001) than those presenting after an index community infection. All-cause mortality in people with long COVID was associated with increasing age, male sex (OR 3.32, 95% CI 1.34-9.24; P=.01), and higher multimorbidity score (OR 2.11, 95% CI 1.34-3.29; P<.001). Vaccination was associated with reduced odds of mortality (OR 0.10, 95% CI 0.03-0.35; P<.001).
Conclusions: The low percentage of people recorded as having long COVID after COVID-19 infection reflects either low prevalence or underrecording. The characteristics and comorbidities of those presenting with long COVID after a community infection are different from those hospitalized. This study provides insights into the presentation of long COVID in primary care and implications for workload.

672

MS183

Catherine Paterson,Deborah Davis,Michael Roche,Bernie Bissett,Cara Roberts,Murray Turner,Emma Baldock,Imogen Mitchell

What are the long-term holistic health consequences of COVID-19 among survivors? An umbrella systematic review

https://doi.org/10.1002/jmv.28086

Published

24-Aug-22

Review

https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.28086

Many people who have survived COVID-19 have experienced negative persistent impacts on health. Impacts on health have included persistent respiratory symptoms, decreased quality of life, fatigue, impaired functional capacity, memory deficits, psychological impacts, and difficulties in returning to paid employment. Evidence is yet to be pooled to inform future directions in research and practice, to determine the physical, psychological, social, and spiritual impacts of the illness which extend beyond the acute phase of COVID-19 survivors. This umbrella review (review of systematic reviews) critically synthesized physical (including abnormal laboratory parameters), psychological, social, and spiritual impacts which extended beyond the acute phase of COVID-19 survivors. The search strategy was based on the sample, phenomena of interest, design, evaluation, research model and all publications were double screened independently by four review authors for the eligibility criteria. Data extraction and quality assessment were conducted in parallel independently. Eighteen systematic reviews were included, which represented a total of 493 publications. Sample sizes ranged from n = 15 to n = 44 799 with a total of n = 295 455 participants. There was incomplete reporting of several significant data points including the description of the severe acute respiratory syndrome coronavirus 2 variant, COVID-19 treatments, and key clinical and demographic data. A number of physical, psychological, and social impacts were identified for individuals grappling with post-COVID condition. The long term sequalae of acute COVID-19 and size of the problem is only beginning to emerge. Further investigation is needed to ensure that those affected by post-COVID condition have their informational, spiritual, psychological, social, and physical needs met in the future.

673

MS184

Mayssam Nehme, Olivia Braillard, François Chappuis, CoviCare Study Team & Idris Guessous

The chronification of post-COVID condition associated with neurocognitive symptoms, functional impairment and increased healthcare utilization

https://doi.org/10.1038/s41598-022-18673-z

Published

25-Aug-22

Study

https://www.nature.com/articles/s41598-022-18673-z

Post-COVID condition is prevalent in 10–35% of cases in outpatient settings, however a stratification of the duration and severity of symptoms is still lacking, adding to the complexity and heterogeneity of the definition of post-COVID condition and its oucomes. In addition, the potential impacts of a longer duration of disease are not yet clear, along with which risk factors are associated with a chronification of symptoms beyond the initial 12 weeks. In this study, follow-up was conducted at 7 and 15 months after testing at the outpatient SARS-CoV-2 testing center of the Geneva University Hospitals. The chronification of symptoms was defined as the continuous presence of symptoms at each evaluation timepoint (7 and 15 months). Adjusted estimates of healthcare utilization, treatment, functional impairment and quality of life were calculated. Logistic regression models were used to evaluate the associations between the chronification of symptoms and predictors. Overall 1383 participants were included, with a mean age of 44.3 years, standard deviation (SD) 13.4 years, 61.4% were women and 54.5% did not have any comorbidities. Out of SARS-CoV-2 positive participants (n = 767), 37.0% still had symptoms 7 months after their test of which 47.9% had a resolution of symptoms at the second follow-up (15 months after the infection), and 52.1% had persistent symptoms and were considered to have a chronification of their post-COVID condition. Individuals with a chronification of symptoms had an increased utilization of healthcare resources, more recourse to treatment, more functional impairment, and a poorer quality of life. Having several symptoms at testing and difficulty concentrating at 7 months were associated with a chronification of symptoms. COVID-19 patients develop post-COVID condition to varying degrees and duration. Individuals with a chronification of symptoms experience a long-term impact on their health status, functional capacity and quality of life, requiring a special attention, more involved care and early on identification considering the associated predictors.

674

MS185

Mohammed Samannodi 1,Hassan Alwafi 2,3,Abdallah Y. Naser 4ORCID,Abdullah A. Al Qurashi 5,6,Jumanah T. Qedair 5,6,Emad Salawati 7ORCID,Mohammed A. Almatrafi 8,Rakan Ekram 9,Rahaf I. Bukhari 2,Maryam Dahlawi 2ORCID,Bayan Hafiz 2,Roaa Mandora 2,Ranin K. Alsindi 2,Sarah Tayeb 10 andFaisal Minshawi 11,*ORCID

Determinants of Post-COVID-19 Conditions among SARS-CoV-2-Infected Patients in Saudi Arabia: A Web-Based Cross-Sectional Study

https://doi.org/10.3390/diseases10030055

Published

23-Aug-22

Study

https://www.mdpi.com/2079-9721/10/3/55/htm

Background: Large numbers of people infected with COVID-19 developed acute symptoms. Post-COVID-19 conditions have been reported after recovery or discharge from the hospital. However, little is known about the prevalence and possible risk factors of post-COVID-19 conditions in the Saudi community. Here, we describe the incidence of post-COVID-19 conditions among the general population of Saudi Arabia. Methods: We conducted a cross-sectional, nationwide study using an online survey in Saudi Arabia from 1 September 2021 to 28 February 2022. The survey was distributed using social media platforms, such as Twitter, WhatsApp, and Facebook. Patients with SARS-CoV-2 infection were included in the questionnaire adapted from published studies. Result: The study enrolled 7520 individuals who were previously infected with SARS-CoV-2. Most patients in our study were symptomatic and their acute symptoms may persist for more than six days. On the other hand, long-term complications may develop and continue for an extended period (post-COVID-19 conditions). Most of these complications are respiratory, neurological, psychological, or skin related. The proportion of long-term complications reported in this study is 36% among SARS-CoV-2-infected individuals. In addition, being female, old age, number of chronic complications, long-term medication, length of stay in hospital and intensive care unit, and duration of acute symptoms may be significant predictors of post-COVID-19 symptoms. Conclusion: In conclusion, the incidence of post-COVID-19 conditions among the Saudi population was high, which urges further investigation into the risk factors associated with post-COVID-19 symptoms.

675

MS186

Anuradhaa Subramanian,1 Krishnarajah Nirantharakumar,corresponding author1,2,3 Sarah Hughes,1,4,5,6,7 Puja Myles,8 Tim Williams,8 Krishna M. Gokhale,1 Tom Taverner,1 Joht Singh Chandan,1 Kirsty Brown,1,9 Nikita Simms-Williams,1 Anoop D. Shah,10 Megha Singh,1 Farah Kidy,1,11 Kelvin Okoth,1 Richard Hotham,1 Nasir Bashir,12 Neil Cockburn,1 Siang Ing Lee,1 Grace M. Turner,1,4,13 Georgios V. Gkoutos,2,3,14,15,16 Olalekan Lee Aiyegbusi,1,4,5,6,7,15 Christel McMullan,1,4,7,13,17 Alastair K. Denniston,2,3,4,6,15,16 Elizabeth Sapey,16,18,19 Janet M. Lord,13,15,18,20 David C. Wraith,15,21 Edward Leggett,8 Clare Iles,8 Tom Marshall,1 Malcolm J. Price,1,15 Steven Marwaha,22,23 Elin Haf Davies,24 Louise J. Jackson,1 Karen L. Matthews,25 Jenny Camaradou,25 Melanie Calvert,1,2,3,4,5,6,7,13,15,19 and Shamil Haroon1

Symptoms and risk factors for long COVID in non-hospitalized adults

https://doi.org/10.1038%2Fs41591-022-01909-w

Published

25-Jul-22

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9388369/

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with a range of persistent symptoms impacting everyday functioning, known as post-COVID-19 condition or long COVID. We undertook a retrospective matched cohort study using a UK-based primary care database, Clinical Practice Research Datalink Aurum, to determine symptoms that are associated with confirmed SARS-CoV-2 infection beyond 12 weeks in non-hospitalized adults and the risk factors associated with developing persistent symptoms. We selected 486,149 adults with confirmed SARS-CoV-2 infection and 1,944,580 propensity score-matched adults with no recorded evidence of SARS-CoV-2 infection. Outcomes included 115 individual symptoms, as well as long COVID, defined as a composite outcome of 33 symptoms by the World Health Organization clinical case definition. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) for the outcomes. A total of 62 symptoms were significantly associated with SARS-CoV-2 infection after 12 weeks. The largest aHRs were for anosmia (aHR 6.49, 95% CI 5.02–8.39), hair loss (3.99, 3.63–4.39), sneezing (2.77, 1.40–5.50), ejaculation difficulty (2.63, 1.61–4.28) and reduced libido (2.36, 1.61–3.47). Among the cohort of patients infected with SARS-CoV-2, risk factors for long COVID included female sex, belonging to an ethnic minority, socioeconomic deprivation, smoking, obesity and a wide range of comorbidities. The risk of developing long COVID was also found to be increased along a gradient of decreasing age. SARS-CoV-2 infection is associated with a plethora of symptoms that are associated with a range of sociodemographic and clinical risk factors.

676

MS187

Dan Cui, Simiao Chen, Luzhao Feng, Mengmeng Jia, Yeming Wang, Weijun Xiao, Yanxia Sun, Qiangru Huang, Libing Ma, Zhiwei Leng, Hao Wang, Bin Cao, Weizhong Yang, Juntao Yang, Chen Wang

Long-term outcomes in COVID-19 patients recovered from the first wave of the pandemic

https://doi.org/10.1093/nsr/nwac192

Published

20-Sep-22

Study

https://academic.oup.com/nsr/advance-article/doi/10.1093/nsr/nwac192/6706858

This cross-sectional study evaluated the long-term health effects of coronavirus disease 2019 (COVID-19) in Jianghan District (Wuhan, China). The results showed that 61.4% of COVID-19 patients reported at least one symptom, and 8.8% had depressive symptoms at the 17-month follow-up. The proportion of patients with chest radiographic abnormalities in Fangcang shelter hospitals and designated COVID-19 hospitals was 31.6% and 41.1%, respectively, and the proportion of patients with impaired pulmonary diffusion capacity in these hospitals was 52.8% and 60.9%, respectively. Female sex (odds ratio [OR]=1.48, 95% confidence interval [CI]: 1.16–1.88), severe disease (OR = 1.46, 95% CI: 1.01–2.10), and a higher number of initial symptoms (OR = 1.31, 95% CI: 1.23–1.40) were associated with the development of sequelae symptoms at 17 months. This study involving community-dwelling COVID-19 adults may help determine the long-term effects of COVID-19 during the first pandemic wave. Nonetheless, larger follow-up studies are needed to characterise post-COVID-19 condition.

677

MS188

ME - PESE

Frédérique Retornaz, Stanislas Rebaudet, Chloé Stavris & Yves Jammes

Long-term neuromuscular consequences of SARS-Cov-2 and their similarities with myalgic encephalomyelitis/chronic fatigue syndrome: results of the retrospective CoLGEM study

https://doi.org/10.1186/s12967-022-03638-7

Published

24-Sep-22

Study

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03638-7

Background
Patients with long-COVID often complain of continuous fatigue, myalgia, sleep problems, cognitive dysfunction, and post-exertional malaise. No data are available on EMG recording of evoked myopotentials (M-waves) or exercise-induced alterations in long-COVID patients, providing evidence of muscle membrane fatigue. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) develops in more than half of patients after an infectious disease, particularly viral diseases. A large proportion (around 70%) of these patients have neuromuscular disorders with M-wave alterations during and after exercise. Our hypothesis was that M-wave alterations would be also found in long-COVID patients, in association with neuromuscular symptoms, similar to ME/CFS.
Methods
This retrospective observational ColGEM (Covid LonG Encéphalomyelite Myalgique) study compared 59 patients with long-COVID and 55 ME/CFS patients with a history of severe infection who presented before the COVID pandemic. All of these patients underwent the same protocol consisting of a questionnaire focusing on neural and neuromuscular disorders and M-wave recording in the rectus femoris muscle before, during, and 10 min after a progressive cycling exercise. Maximal handgrip strength (MHGS) and maximal exercise power were also measured. The frequency of symptoms and magnitude of M-wave changes in the two groups were compared using non-parametric and parametric tests.
Results
The frequency of fatigue, myalgia, sleep problems, cognitive dysfunction, and post-exertional malaise as well as the magnitude of exercise-induced M-wave alterations were the same in the two groups. By contrast, digestive problems were less present in long-COVID. M-wave alterations were greater in ME/CFS patients as in those with long-COVID when the highest muscle strength and highest exercise performance were measured.
Conclusions
These high clinical and biological similarities between long-COVID and ME/CFS support the hypothesis that SARS-Cov-2 infection can cause ME/CFS symptoms.

678

MS189

TineBovilMScPHaChristian T.WesterMSc.aLasse L.Scheel-HinckeMScPHaKarenAndersen-RanbergMD

Risk factors of post-COVID-19 condition attributed to COVID-19 disease in people aged 50+ in Europe and Israel

https://doi.org/10.1016/j.puhe.2022.09.017

Published

27-Sep-22

Study

https://www.sciencedirect.com/science/article/pii/S0033350622002785

Objectives
High age, male sex, and pre-existing comorbidities are risk factors for a more severe development of COVID-19, and individuals surviving COVID-19 may experience persistent symptoms afterwards referred to as “Post COVID-19 condition”, which represents a range of symptoms after recovering from COVID-19. This study aims at identifying risk factors of post-COVID-19 conditions among 50+ year olds.
Study design
We conducted a cross-sectional study based on data from the Survey of Health, Ageing and Retirement in Europe.
Methods
A multiple logistic regression model was used to investigate age, sex, education, comorbidities, smoking, BMI, and COVID-19 hospitalisation as risk-factors of post-COVID-19 condition.
Results
Participants aged 70+ (OR 1.61), with medium (OR 2.38) and lower (OR 2.14) educational level have a higher risk of post-COVID-19 conditions. Additionally, when considering the severity of the COVID-19 disease, those who were hospitalised due to COVID-19 had a 26 times higher risk of post-COVID-19 conditions compared to those who were only tested positive (OR 25.9).
Conclusions
This study supports that health inequalities exist across educational levels with respect to post-COVID-19 conditions, although misclassification may be more common among lower educated participants. The results suggest that policy makers should increase educational interventions towards increasing health literacy.

679

MS190

VeredDaitch12#DanaYelin12#MuhammadAwwad3GiovanniGuaraldi45JovanaMilić5CristinaMussini45MarcoFalcone6GiusyTiseo6LauraCarrozzi7FrancescoPistelli7MayssamNehme8IdrisGuessous89LaurentKaiser10PaulineVetter10JaumeBordas-Martínez11XavierDurà-Miralles1213DoloresPeleato-Catalan14CarlotaGudiol1516IritShapira-Lichter217DonnaAbecasis17LeonardLeibovici18DafnaYahav219IliMargalit1219

Characteristics of long COVID among older adults: a cross-sectional study

https://doi.org/10.1016/j.ijid.2022.09.035

Published

1-Oct-22

Study

https://www.sciencedirect.com/science/article/pii/S1201971222005355

Highlights
•This study evaluated 2333 individuals at hospital-based COVID recovery clinics.
•Older adults are more likely to report on long COVID symptoms.
•The most common long COVID symptoms among older adults are fatigue and dyspnea.
•Older age does not correlate with long COVID fatigue or dyspnea.
•Obesity is an independent risk factors for both long COVID fatigue and dyspnea.
Abstract
Objective
To describe long-COVID symptoms among older adults, and to assess risk factors for two common long-COVID symptoms: fatigue and dyspnea.
Methods
Multicenter prospective cohort study, conducted in Israel, Switzerland, Spain, and Italy. Included were individuals at least 30 days since COVID-19 diagnosis. We compared long-COVID symptoms between elderly individuals (age>65 years) and younger population (18-65 years); and conducted univariate and multivariable analyses for predictors of long-COVID fatigue and dyspnea.
Results
2333 individuals were evaluated at an average of 5 months [146 days (95% CI 142-150)] following COVID-19 onset. Mean age was 51 and 20.5% were>65 years. Older adults were more likely to be symptomatic, with most common symptoms being fatigue (38%) and dyspnea (30%). They were more likely to complain of cough and arthralgia, and have abnormal chest imaging and pulmonary function tests. Independent risk factors for long-COVID fatigue and dyspnea included female gender, obesity, and closer proximity to COVID-19 diagnosis; older age was not an independent predictor.
Conclusions
Older individuals with long-COVID, have different persisting symptoms, with more pronounced pulmonary impairment. Women and individuals with obesity are at risk. Further research is warranted to investigate the natural history of long-COVID among the elderly population and to assess possible interventions aimed at promoting rehabilitation and well-being.

680

MS191

Antonio S. Menezes Jr., Silvia M. Botelho, Luciana R. Santos, Aline L. Rezende

Acute COVID-19 Syndrome Predicts Severe Long COVID-19: An Observational Study

https://doi.org/10.7759/cureus.29826

Published

2-Oct-22

Study

https://www.cureus.com/articles/116317-acute-covid-19-syndrome-predicts-severe-long-covid-19-an-observational-study

Introduction
Tissue damage, chronic dysfunction, and symptoms that last more than 12 weeks are hallmarks of long-term chronic opportunistic viral infection (COVID-19), and the disease may have a permanent, relapsing/remitting, or gradually improving course. This study aimed to determine the risk factors of severe long COVID-19.
Methods
In October 2021, primary care clinics enrolled consenting 18- to 89-year-olds to complete an online questionnaire on self-diagnosis, clinician diagnosis, testing, symptom presence, and duration of COVID-19. Long COVID-19 was identified if symptoms were beyond 12 weeks. Patients with long-lasting COVID-19 symptoms were assessed using multivariable regression to identify potential predictors of severe long COVID-19.
Results
Of the 220 respondents, 108 (49%) patients were self- or clinician-diagnosed with COVID-19 or had a confirmed positive laboratory test result. Patients aged >45 years and with at least 15 COVID-19 symptoms were 5.55 and 6.02 times, respectively, more likely to acquire severe long COVID-19. Most patients with severe and moderate post-acute COVID-19 syndrome had no relevant comorbidities (p=0.0402; odds ratio [OR]=0.4; 95% confidence interval [CI]=0.18-0.98). Obesity was a significant predictor (p=0.0307; OR=6.2; 95% CI=1.1-33.2).
Conclusion
The simultaneous presence of 15 or more COVID-19 symptoms, age >45 years, and obesity were related to a higher probability of severe long COVID-19.

681

MS192

Benjamin A. Abramoff, MD
Timothy Dillingham, MD
Lily A. Brown, PhD
Frank Caldera, MD
Mitra McLartney, MD
Emily McGinley, MS
Liliana E. Pezzin, PhD JD
Show less

Psychological and Cognitive Functioning Among Patients Receiving Outpatient Rehabilitation for post-COVID sequelae: An Observational Study

https://doi.org/10.1016/j.apmr.2022.09.013

Published

3-Oct-22

Study

https://www.archives-pmr.org/article/S0003-9993(22)01614-8/fulltext

Objectives
To describe the characteristics of individuals receiving outpatient rehabilitation for post-acute sequelae of SARS-CoV-2 infection (PASC). Further, to examine factors associated with variation in their psychological and cognitive functioning and health-related quality of life.
Design
Observational study.
Setting
Outpatient COVID-19 recovery clinic at a large, tertiary, urban health system in the U.S.
Participants
COVID-19 survivors with persistent sequelae (n=324).
Interventions
Not applicable.
Main Outcome Measures
Multivariable logistic and linear regression models were used to examine factors associated with COVID survivors’ experience of severe anxiety, severe depression, post-traumatic stress disorder (PTSD), cognitive impairment, and self-reported health-related quality of life.
Results
About 38% of survivors seeking care for their persistent COVID symptoms suffered from severe anxiety, 31.8% from severe depression, 43% experiencing moderate to severe PTSD symptomology, and 17.5% had cognitive impairment. Their health-related quality of life was substantially lower than that of the general population (-26%) and of persons with other chronic conditions. Poor and African American/Black individuals experienced worse psychological and cognitive sequelae following COVID19 infection, even after controlling for age, gender, initial severity of the acute infection, and time since diagnosis.
Conclusions
Evidence of consistent disparities in outcomes by the patients’ race and socioeconomic status, even among those with access to post-acute COVID rehabilitation care, are concerning and have significant implications for PASC policy and program development.

682

MS193

Asma S. Albtoosh, Ahmad A. Toubasi, Khaled Al Oweidat, Manar M. Hasuneh, Abdullah H. Alshurafa, Daniah L. Alfaqheri & Randa I. Farah

New symptoms and prevalence of postacute COVID-19 syndrome among nonhospitalized COVID-19 survivors

https://doi.org/10.1038/s41598-022-21289-y

Published

8-Oct-22

Study

https://www.nature.com/articles/s41598-022-21289-y

The aim of this study was to assess postacute coronavirus disease 2019 (COVID-19) syndrome (PACS) symptoms according to the onset of the infection while evaluating the effect of COVID-19 vaccination on the symptoms of PACS. We conducted a retrospective single-center cohort study in which nonhospitalized COVID-19 survivors and healthy controls were compared for the occurrence of PACS. The total number of patients in this study was 472. At 6–12 and > 12 months after the infection, COVID-19 survivors had a significantly higher incidence of posttraumatic stress disorder (PTSD) and anxiety than the non-COVID-19 cohort. Furthermore, depression, cognitive deficit, tics, impaired quality of life and general health impairment were significantly more prevalent among COVID-19 survivors at < 6 months, 6–12 months and > 12 months than in the non-COVID-19 cohort. However, respiratory symptoms were significantly more prevalent among COVID-19 survivors only in the first 6 months after infection. In addition, cognitive deficit (OR = 0.15; 95% CI 0.03–0.87) and impaired quality of life (B = − 2.11; 95% CI − 4.21 to − 0.20) were significantly less prevalent among vaccinated COVID-19 survivors than among nonvaccinated survivors. Longitudinal studies are needed to establish the time that should elapse after COVID-19 infection for the symptoms of PACS to appear. Randomized clinical trials are needed to assess the possibility that COVID-19 vaccines might relieve PACS symptoms.

683

MS194

M.C.MassicotteabC.ModeriecdS.MombelliabA.-S.Deshaies-RugamaabC.ThompsonaM.NigamafA.DesautelsafJ.MontplaisiraeN.Gosselinab

Distinguer la narcolepsie de type 2, l’hypersomnie idiopathique, la dépression et la somnolence dans le syndrome post-COVID-19Discriminating narcolepsy type-2, idiopathic hypersomnia, depression and hypersomnolence in post-acute COVID-19 syndrome

https://doi.org/10.1016/j.msom.2022.09.001

Published

8-Oct-22

Review

https://www.sciencedirect.com/science/article/abs/pii/S1769449322002655

Central disorders of hypersomnolence, including narcolepsy type-1 and type-2 as well as idiopathic hypersomnia, depression and a subtype of post-acute COVID-19 syndrome might be confused when establishing a diagnosis. This diagnostic challenge can be explained by the presence of excessive daytime sleepiness, a clinical symptom that is observed in all four conditions, an overlap in the phenotypic traits of narcolepsy type-2 and idiopathic hypersomnia, as well as the presence of depressive symptoms observed in central disorders of hypersomnolence and post-acute COVID-19 syndrome subtypes. Considering the importance of a valid diagnostic on treatment's efficacy and future interventions, it is essential to define those conditions with precision. In this review, we will discuss the diagnostic criteria, clinical presentation and current state of knowledge with regards to the pathophysiology of central disorders of hypersomnolence and post-acute COVID-19 syndrome. We will pay particular attention to the characteristics specific to narcolepsy type-2, idiopathic hypersomnia, depressive episodes with hypersomnolence, and post-acute COVID-19 syndrome with drowsiness. While many studies have assessed the ability of different tools used to diagnose central disorders of hypersomnolence, very few have focused on physiological markers. A better understanding and identification of biomarkers specific to narcolepsy type-1 and type-2, idiopathic hypersomnia and post-acute COVID-19 syndrome will reduce the possibility of misdiagnoses and allow the development of optimal treatment plans.

"Les syndromes d’hypersomnolence d’origine centrale (c.-à-d. narcolepsie de type-1, narcolepsie de type-2 et hypersomnie idiopathique), la dépression ainsi qu’un sous-type du syndrome post-COVID-19 peuvent être confondus lors de l’établissement d’un diagnostic. Ce défi diagnostique s’explique par un symptôme clinique caractéristique retrouvé dans les quatre conditions, la somnolence diurne excessive, un chevauchement phénotypique considérable entre la narcolepsie de type-2 et l’hypersomnie idiopathique ainsi qu’une symptomatologie dysphorique pouvant être présente autant dans les hypersomnolences centrales que dans un sous-type du syndrome post-COVID-19. Considérant l’importance d’un diagnostic valide sur l’efficacité des traitements et des interventions futures, il est essentiel de définir précisément ces quatre conditions. Dans cette revue, nous reprendrons les critères diagnostiques, les présentations cliniques et les connaissances actuelles en ce qui a trait à la pathophysiologie de ces troubles en portant une attention particulière aux éléments distinctifs de la narcolepsie de type-2, de l’hypersomnie idiopathique, des épisodes dépressifs avec hypersomnolence et du syndrome post-COVID-19 avec somnolence. Bien que de nombreuses études se soient penchées sur les valeurs diagnostiques des différents outils employés dans l’identification des hypersomnolences centrales, très peu de marqueurs physiologiques ont été identifiés. Une meilleure compréhension de ces conditions cliniques pourrait permettre l’identification de marqueurs objectifs spécifiques à chaque condition réduisant ainsi la possibilité d’une erreur diagnostique et optimisant les plans de traitement."

684

MS195

Ilona Merikanto,Yves Dauvilliers,Frances Chung,Yun Kwok Wing,Luigi De Gennaro,Brigitte Holzinger,Bjørn Bjorvatn,Charles M. Morin,Thomas Penzel,Christian Benedict,Adrijana Koscec Bjelajac,Ngan Yin Chan,Colin A. Espie,Harald Hrubos-Strøm,Yuichi Inoue,Maria Korman,Anne-Marie Landtblom,Damien Léger,Kentaro Matsui,Sergio Mota-Rolim,Michael R. Nadorff,Giuseppe Plazzi,Catia Reis,Juliana Yordanova,Markku Partinen

Sleep symptoms are essential features of long-COVID – Comparing healthy controls with COVID-19 cases of different severity in the international COVID sleep study (ICOSS-II)

https://doi.org/10.1111/jsr.13754

Published

8-Oct-22

Survey Study

https://onlinelibrary.wiley.com/doi/10.1111/jsr.13754

Many people report suffering from post-acute sequelae of COVID-19 or “long-COVID”, but there are still open questions on what actually constitutes long-COVID and how prevalent it is. The current definition of post-acute sequelae of COVID-19 is based on voting using the Delphi-method by the WHO post-COVID-19 working group. It emphasizes long-lasting fatigue, shortness of breath and cognitive dysfunction as the core symptoms of post-acute sequelae of COVID-19. In this international survey study consisting of 13,628 subjects aged 18–99 years from 16 countries of Asia, Europe, North America and South America (May–Dec 2021), we show that post-acute sequelae of COVID-19 symptoms were more prevalent amongst the more severe COVID-19 cases, i.e. those requiring hospitalisation for COVID-19. We also found that long-lasting sleep symptoms are at the core of post-acute sequelae of COVID-19 and associate with the COVID-19 severity when COVID-19 cases are compared with COVID-negative cases. Specifically, fatigue (61.3%), insomnia symptoms (49.6%) and excessive daytime sleepiness (35.8%) were highly prevalent amongst respondents reporting long-lasting symptoms after hospitalisation for COVID-19. Understanding the importance of sleep-related symptoms in post-acute sequelae of COVID-19 has a clinical relevance when diagnosing and treating long-COVID.

685

MS196

Dapeng Li,Xuejiao Liao,Zhi Liu,Zhenghua Ma,Jingke Dong,Guoqin Zheng,Mei ZiORCID Icon,Fang Wang,Qing He,Guobao Li,Zheng Zhang &Lei Liu

Healthy Outcomes of Patients with COVID-19 Two Years after the Infection: A Prospective Cohort Study

https://doi.org/10.1080/22221751.2022.2133639

Published

10-Oct-22

Study

https://www.tandfonline.com/doi/full/10.1080/22221751.2022.2133639

The long-term effect of coronavirus disease 2019 (COVID-19) has been rarely known. This study aimed to investigate healthy outcomes of COVID-19 survivors up to 2 years after the infection. A total of 155 COVID-19 patients, who were discharged from Shenzhen Third People's Hospital from February 2020 to April 2020, were enrolled and followed up until March 4, 2022. COVID-19 survivors received questionnaires of long COVID symptoms and psychological symptoms, pulmonary function tests, chest computed tomography (CT) scans, routine laboratory tests. Two years after infection, 36.6% of patients had at least one symptom of long COVID. Vision impairment and fatigue were the most common symptom. 35.0% of participants still had at least one psychological symptom of anxiety, depression, post-traumatic stress symptoms, and sleep difficulties. Radiographic abnormalities were presented in 50.7% of patients, with the most common features of fibrosis-like lesions and residual ground-glass opacity. Diffuse dysfunction (24.0%) was the main abnormalities of pulmonary function tests. Most laboratory parameters returned to normal range, while persistent abnormalities in kidney and liver function test were observed in a subset of participants after discharge. Two years after COVID-19 infection, persistent symptoms of long COVID and psychological symptoms, as well as abnormalities in pulmonary function test and CT, were still common in a subset of recovering individuals. These findings were limited by the lack of a healthy control group and pre-COVID assessments, which should be confirmed by further large-scale studies.

686

MS197

Claire E. Hastie, David J. Lowe, Andrew McAuley, Andrew J. Winter, Nicholas L. Mills, Corri Black, Janet T. Scott, Catherine A. O’Donnell, David N. Blane, Susan Browne, Tracy R. Ibbotson & Jill P. Pell

Outcomes among confirmed cases and a matched comparison group in the Long-COVID in Scotland study

https://doi.org/10.1038/s41467-022-33415-5

Published

12-Oct-22

Study

https://www.nature.com/articles/s41467-022-33415-5

With increasing numbers infected by SARS-CoV-2, understanding long-COVID is essential to inform health and social care support. A Scottish population cohort of 33,281 laboratory-confirmed SARS-CoV-2 infections and 62,957 never-infected individuals were followed-up via 6, 12 and 18-month questionnaires and linkage to hospitalization and death records. Of the 31,486 symptomatic infections,1,856 (6%) had not recovered and 13,350 (42%) only partially. No recovery was associated with hospitalized infection, age, female sex, deprivation, respiratory disease, depression and multimorbidity. Previous symptomatic infection was associated with poorer quality of life, impairment across all daily activities and 24 persistent symptoms including breathlessness (OR 3.43, 95% CI 3.29–3.58), palpitations (OR 2.51, OR 2.36–2.66), chest pain (OR 2.09, 95% CI 1.96–2.23), and confusion (OR 2.92, 95% CI 2.78–3.07). Asymptomatic infection was not associated with adverse outcomes. Vaccination was associated with reduced risk of seven symptoms. Here we describe the nature of long-COVID and the factors associated with it.

687

MS198

Michael A. Horberg, Eric Watson, Mamta Bhatia, Celeena Jefferson, Julia M. Certa, Seohyun Kim, Lily Fathi, Keri N. Althoff, Carolyn Williams & Richard Moore

Post-acute sequelae of SARS-CoV-2 with clinical condition definitions and comparison in a matched cohort

https://doi.org/10.1038/s41467-022-33573-6

Published

12-Oct-22

Study

https://www.nature.com/articles/s41467-022-33573-6

Disease characterization of Post-Acute Sequelae of SARS-CoV-2 (PASC) does not account for pre-existing conditions and time course of incidence. We utilized longitudinal data and matching to a COVID PCR-negative population to discriminate PASC conditions over time within our patient population during 2020. Clinical Classification Software was used to identify PASC condition groupings. Conditions were specified acute and persistent (occurring 0-30 days post COVID PCR and persisted 30–120 days post-test) or late (occurring initially 30-120 days post-test). We matched 3:1 COVID PCR-negative COVIDPCR-positive by age, sex, testing month and service area, controlling for pre-existing conditions up to four years prior; 28,118 PCR-positive to 70,293 PCR-negative patients resulted. We estimated PASC risk from the matched cohort. Risk of any PASC condition was 12% greater for PCR-positive patients in the late period with a significantly higher risk of anosmia, cardiac dysrhythmia, diabetes, genitourinary disorders, malaise, and nonspecific chest pain. Our findings contribute to a more refined PASC definition which can enhance clinical care.

688

MS199

KATHRYN W. HENDRICKSON
JORIE BUTLER
STEPHANIE C STOKES
DANIELLE GROAT
SAMUEL M BROWN
HIRSHBERG ELLIOTTE

PATIENT-REPORTED EXPERIENCES WITH SARS-COV-2: A SURVEY STUDY EXAMINING ACUTE- AND LONG-TERM SYMPTOMS AND HOW THEY RELATE TO AREA OF HOSPITALIZATION AND LONG-TERM DISEASE

https://doi.org/10.1016/j.chest.2022.08.899

Published

1-Oct-22

Study

https://journal.chestnet.org/article/S0012-3692(22)02259-0/fulltext

SESSION TITLE: Post-COVID-19 Outcomes
SESSION TYPE: Rapid Fire Original Inv
PRESENTED ON: 10/19/2022 11:15 am - 12:15 pm
PURPOSE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has caused an influx of hospitalized patients with acute disease, as well as an influx of outpatient visits for long-term symptoms. There is still much to learn about symptom patterns in different patient groups based on age, race, sex, and illness severity. Patients with post-acute COVID-19 syndrome (PACS), colloquially called long-haulers, are another group who may have unique symptom profiles. We conducted this study to characterize patients’ experiences with COVID-19 symptoms in both the acute and long-term phase.
METHODS: Participants were recruited using existing research panel through Qualtrics, a national consumer insights platform. Eligible participants included those who reported a positive COVID-19 test sometime in 2021 and sought some type of medical care. In an online survey, participants were asked about the three most bothersome physical symptoms they experienced out of body aches or joint pain, “brain fog”, chest pain, cough, fatigue or feeling tired/weak, fever/chills/sweating, GI issues such as vomiting/diarrhea, headache, loss of taste or smell, shortness of breath, and insomnia. This list of physical symptoms was sourced by qualitative, in-depth interviews with 55 hospitalized and recovered COVID-19 patients. In addition, participants reported basic demographics, hospitalizations, and whether they considered themselves long-haulers.
RESULTS: Of these patients, 29.8% considered themselves long-haulers. There were 2570 survey respondents who participated, of which 61% were female, 48% were male, and 1% were nonbinary. The patients were all age 18 years or older with 14% Hispanic/Latino/a/x/or Spanish origin, and 25% were non-white. Of those who sought medical treatment through a hospital, 59% reported that they sought treatment for COVID-19 in the emergency room, 32% were hospitalized, and 9% were hospitalized in the Intensive Care Unit (ICU). The most bothersome symptoms reported overall were cough, fatigue/feeling weak, and body aches. We compared bothersome symptoms by hospitalization location and long-haul status descriptively. For 18% of participants hospitalized in the ICU, the most bothersome symptom was shortness of breath compared to 11% of those hospitalized on the general floor, and 11% of those seen in the emergency room. Among participants who reported that they consider themselves long-haulers, the most common symptom reported most bothersome was cough.
CONCLUSIONS: Data indicate that symptom patterns may differ by illness severity, age, and race. Patients who consider themselves long-haulers also have a different symptom pattern from those who do not report long-term symptoms.
CLINICAL IMPLICATIONS: Our findings contribute to the understanding of patient experience with COVID-19 symptoms both in the acute and long-term phase.

689

MS200

ME

Frédérique Retornaz, Stanislas Rebaudet, Chloé Stavris & Yves Jammes

Long-term neuromuscular consequences of SARS-Cov-2 and their similarities with myalgic encephalomyelitis/chronic fatigue syndrome: results of the retrospective CoLGEM study

https://doi.org/10.1186/s12967-022-03638-7

Published

24-Sep-22

Study

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03638-7

Background
Patients with long-COVID often complain of continuous fatigue, myalgia, sleep problems, cognitive dysfunction, and post-exertional malaise. No data are available on EMG recording of evoked myopotentials (M-waves) or exercise-induced alterations in long-COVID patients, providing evidence of muscle membrane fatigue. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) develops in more than half of patients after an infectious disease, particularly viral diseases. A large proportion (around 70%) of these patients have neuromuscular disorders with M-wave alterations during and after exercise. Our hypothesis was that M-wave alterations would be also found in long-COVID patients, in association with neuromuscular symptoms, similar to ME/CFS.
Methods
This retrospective observational ColGEM (Covid LonG Encéphalomyelite Myalgique) study compared 59 patients with long-COVID and 55 ME/CFS patients with a history of severe infection who presented before the COVID pandemic. All of these patients underwent the same protocol consisting of a questionnaire focusing on neural and neuromuscular disorders and M-wave recording in the rectus femoris muscle before, during, and 10 min after a progressive cycling exercise. Maximal handgrip strength (MHGS) and maximal exercise power were also measured. The frequency of symptoms and magnitude of M-wave changes in the two groups were compared using non-parametric and parametric tests.
Results
The frequency of fatigue, myalgia, sleep problems, cognitive dysfunction, and post-exertional malaise as well as the magnitude of exercise-induced M-wave alterations were the same in the two groups. By contrast, digestive problems were less present in long-COVID. M-wave alterations were greater in ME/CFS patients as in those with long-COVID when the highest muscle strength and highest exercise performance were measured.
Conclusions
These high clinical and biological similarities between long-COVID and ME/CFS support the hypothesis that SARS-Cov-2 infection can cause ME/CFS symptoms.

690

MS201

Arjun M C 1, Arvind Kumar Singh 1, Payel Roy 1, Mythry Ravichandran 1, Srijani Mandal 1, Debkumar Pal 1, Kajal Das 1, G Alekhya 1, Mahalingam Venkateshan 2, Baijayantimala Mishra 3, Binod Kumar Patro 1, Prasanta Raghab Mohapatra 4, Sonu Hangma Subba 1

Long COVID following Omicron wave in Eastern India - A retrospective cohort study

https://doi.org/10.1002/jmv.28214

Published

12-Oct-22

Study

https://pubmed.ncbi.nlm.nih.gov/36224705/

Background and rationale: Long COVID or Post-acute sequelae of COVID-19 is widely reported but the data of Long COVID after infection with the Omicron variant is limited. This study was conducted to estimate the incidence, characteristics of symptoms and predictors of Long COVID among COVID-19 patients diagnosed during the Omicron wave in Eastern India.

Methodology: The cohort of COVID-19 patients included were adults (≥18 years) diagnosed as SARS-CoV-2 positive with Reverse Transcription Polymerase Chain Reaction (RT-PCR). After 28 days of diagnosis; participants were followed up with a telephonic interview to capture data on sociodemographic, clinical history, anthropometry, substance use, COVID-19 vaccination status, acute COVID-19 symptoms, and Long COVID symptoms. The Long COVID symptoms were self-reported by the participants. Logistic regression was used to determine the predictors of Long COVID.

Results: The median follow-up of participants was 73 days (Interquartile range (IQR); 67,83). The final analysis had 524 participants data; among them 8.2% (95% Confidence Interval (CI): 6%,10.9%) self-reported Long COVID symptoms. Fatigue (34.9%) was the most common reported symptom followed by cough (27.9%). In multivariable logistic regression only two predictors were statistically significant - number of acute COVID-19 symptoms ≥ five (Adjusted Odds ratio (aOR)=2.95, 95% CI:1.30,6.71) and past history of COVID-19 (aOR=2.66, 95% CI: 1.14,6.22).

Conclusion: The proportion of self-reported Long COVID is considerably low among COVID-19 patients diagnosed during the Omicron wave in Eastern India, when compared to estimates during Delta wave in the same setting.

691

MS202

Roy H. Perlis, MD, MSc1,2; Mauricio Santillana, PhD3; Katherine Ognyanova, PhD4; Alauna Safarpour, PhD3,5; Kristin Lunz Trujillo, PhD3,5; Matthew D. Simonson, PhD6; Jon Green, PhD3; Alexi Quintana, BA3; James Druckman, PhD7; Matthew A. Baum, PhD5; David Lazer, PhD3

Prevalence and Correlates of Long COVID Symptoms Among US Adults

https://doi.org/10.1001/jamanetworkopen.2022.38804

Published

27-Oct-22

Study

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2797782

Key Points
Question How common are COVID-19 symptoms lasting longer than 2 months, also known as long COVID, among adults in the United States, and which adults are most likely to experience long COVID?
Findings In this cross-sectional study of more than 16 000 individuals, 15% of US adults with a prior positive COVID-19 test reported current symptoms of long COVID. Those who completed a primary vaccination series prior to infection were less likely to report long COVID symptoms.
Meaning This study suggests that long COVID is prevalent and that the risk varies among individual subgroups in the United States; vaccination may reduce this risk.
Abstract
Importance - Persistence of COVID-19 symptoms beyond 2 months, or long COVID, is increasingly recognized as a common sequela of acute infection.
Objectives To estimate the prevalence of and sociodemographic factors associated with long COVID and to identify whether the predominant variant at the time of infection and prior vaccination status are associated with differential risk.
Design, Setting, and Participants - This cross-sectional study comprised 8 waves of a nonprobability internet survey conducted between February 5, 2021, and July 6, 2022, among individuals aged 18 years or older, inclusive of all 50 states and the District of Columbia.
Main Outcomes and Measures - Long COVID, defined as reporting continued COVID-19 symptoms beyond 2 months after the initial month of symptoms, among individuals with self-reported positive results of a polymerase chain reaction test or antigen test.
Results - The 16 091 survey respondents reporting test-confirmed COVID-19 illness at least 2 months prior had a mean age of 40.5 (15.2) years; 10 075 (62.6%) were women, and 6016 (37.4%) were men; 817 (5.1%) were Asian, 1826 (11.3%) were Black, 1546 (9.6%) were Hispanic, and 11 425 (71.0%) were White. From this cohort, 2359 individuals (14.7%) reported continued COVID-19 symptoms more than 2 months after acute illness. Reweighted to reflect national sociodemographic distributions, these individuals represented 13.9% of those who had tested positive for COVID-19, or 1.7% of US adults. In logistic regression models, older age per decade above 40 years (adjusted odds ratio [OR], 1.15; 95% CI, 1.12-1.19) and female gender (adjusted OR, 1.91; 95% CI, 1.73-2.13) were associated with greater risk of persistence of long COVID; individuals with a graduate education vs high school or less (adjusted OR, 0.67; 95% CI, 0.56-0.79) and urban vs rural residence (adjusted OR, 0.74; 95% CI, 0.64-0.86) were less likely to report persistence of long COVID. Compared with ancestral COVID-19, infection during periods when the Epsilon variant (OR, 0.81; 95% CI, 0.69-0.95) or the Omicron variant (OR, 0.77; 95% CI, 0.64-0.92) predominated in the US was associated with diminished likelihood of long COVID. Completion of the primary vaccine series prior to acute illness was associated with diminished risk for long COVID (OR, 0.72; 95% CI, 0.60-0.86).
Conclusions and Relevance - This study suggests that long COVID is prevalent and associated with female gender and older age, while risk may be diminished by completion of primary vaccination series prior to infection.

692

MS203

ME

Nader Salari, Yassaman Khodayari, Amin Hosseinian-Far, Hosna Zarei, Shabnam Rasoulpoor, Hakimeh Akbari & Masoud Mohammadi

Global prevalence of chronic fatigue syndrome among long COVID-19 patients: A systematic review and meta-analysis

https://doi.org/10.1186/s13030-022-00250-5

Published

23-Oct-22

Review and Meta-Analysis

https://bpsmedicine.biomedcentral.com/articles/10.1186/s13030-022-00250-5

Background
Chronic fatigue syndrome is a persistent and debilitating disorder. According to several studies, chronic fatigue syndrome has been identified among recovered COVID-19 patients as the most common symptom of long COVID. The aim of this systematic review and meta-analysis study was to obtain the prevalence of chronic fatigue syndrome in long COVID cases.
Methods
In this systematic review and meta-analysis, we analysed reported results of studies that assessed the occurrence of chronic fatigue syndrome among COVID-19 patients four weeks after the onset of symptoms. The study selection was commenced by searching PubMed, Web of Science, Science Direct, Scopus, Embase, and Google scholar using the keywords of Chronic fatigue syndrome, COVID-19, and post-COVID-19 syndrome. The searches were without a lower time limit and until April 2022. Heterogeneity of studies was assessed using the I2 index, and a random effects model was used for analysis. Data analysis was performed within the Comprehensive Meta-Analysis software (version 2).
Results
The pooled prevalence of chronic fatigue syndrome four weeks after the onset of COVID-19 symptoms, in 52 studies with a sample size of 127,117, was 45.2% (95% CI: 34.1-56.9%). Meta-regression analysis in examining the effects of the two factors of sample size, and year of study on the changes in the overall prevalence, showed that with increasing sample size, and year of study, the prevalence of chronic fatigue syndrome among long COVID patients (p < 0.05).
Conclusion
Our results show that the overall prevalence of chronic fatigue syndrome as a long COVID symptom is 45.2%. Chronic fatigue after infection with COVID-19 can negatively affect personal and social lives. Given such significant negative consequences caused by the syndrome, it is recommended that health policymakers allocate funds to reduce the adverse effects of this syndrome, by creating programs to support long COVID patients.

693

MS204

ME

C. (Linda) M. C. van Campen * andFrans C. Visser

Orthostatic Intolerance in Long-Haul COVID after SARS-CoV-2: A Case-Control Comparison with Post-EBV and Insidious-Onset Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

https://doi.org/10.3390/healthcare10102058

Published

17-Oct-22

Study

https://www.mdpi.com/2227-9032/10/10/2058/htm

Background: As complaints of long-haul COVID patients are similar to those of ME/CFS patients and as orthostatic intolerance (OI) plays an important role in the COVID infection symptomatology, we compared 14 long-haul COVID patients with 14 ME/CFS patients with a post-viral Ebstein-Barr (EBV) onset and 14 ME/CFS patients with an insidious onset of the disease. Methods: In all patients, OI analysis by history taking and OI assessed during a tilt test, as well as cerebral blood flow measurements by extracranial Doppler, and cardiac index measurements by suprasternal Doppler during the tilt test were obtained in all patients. Results: Except for disease duration no differences were found in clinical characteristics. The prevalence of POTS was higher in the long-haul patients (100%) than in post-EBV (43%) and in insidious-onset (50%) patients (p = 0.0002). No differences between the three groups were present in the prevalence of OI, heart rate and blood pressure changes, changes in cerebral blood flow or in cardiac index during the tilt test. Conclusion: OI symptomatology and objective abnormalities of OI (abnormal cerebral blood flow and cardiac index reduction during tilt testing) are comparable to those in ME/CFS patients. It indicates that long-haul COVID is essentially the same disease as ME/CFS.

694

MS205

Juan C. Pacho-Hernández 1ORCID,César Fernández-de-las-Peñas 2,*ORCID,Stella Fuensalida-Novo 2ORCID,Carmen Jiménez-Antona 2,Ricardo Ortega-Santiago 2ORCID andMargarita Cigarán-Mendez 1

Sleep Quality Mediates the Effect of Sensitization-Associated Symptoms, Anxiety, and Depression on Quality of Life in Individuals with Post-COVID-19 Pain

https://doi.org/10.3390/brainsci12101363

Published

8-Oct-22

Study

https://www.mdpi.com/2076-3425/12/10/1363/htm

A better understanding of biological and emotional variables associated with health-related quality of life in people with long-COVID is needed. Our aim was to identify potential direct and indirect effects on the relationships between sensitization-associated symptoms, mood disorders such as anxiety/depressive levels, and sleep quality on health-related quality of life in people suffering from post-COVID-19 pain. One hundred and forty-six individuals who were hospitalized due to COVID-19 during the first wave of the pandemic and suffering from long-term post-COVID-19 pain completed different patient-reported outcome measures (PROMs), including clinical features, symptoms associated with sensitization of the central nervous system (Central Sensitization Inventory), mood disorders (Hospital Anxiety and Depressive Scale), sleep quality (Pittsburgh Sleep Quality Index), and health-related quality of life (paper-based five-level version of EuroQol-5D) in a face-to-face interview conducted at 18.8 (SD 1.8) months after hospitalization. Different mediation models were conducted to assess the direct and indirect effects of the associations among the different variables. The mediation models revealed that sensitization-associated symptoms and depressive levels directly affected health-related quality of life; however, these effects were not statistically significant when sleep quality was included. In fact, the effect of sensitization-associated symptomatology on quality of life (β = −0.10, 95% CI −0.1736, −0.0373), the effect of depressive levels on quality of life (β= −0.09, 95% CI −0.1789, −0.0314), and the effect of anxiety levels on quality of life (β = −0.09, 95% CI −0.1648, −0.0337) were all indirectly mediated by sleep quality. This study revealed that sleep quality mediates the relationship between sensitization-associated symptoms and mood disorders (depressive/anxiety levels) with health-related quality of life in individuals who were hospitalized with COVID-19 at the first wave of the pandemic and reporting post-COVID-19 pain. Longitudinal studies will help to determine the clinical implications of these findings.

695

MS206

Endang Mutiawati 1,2,*,Hendrix Indra Kusuma 3,4,5ORCID,Marhami Fahriani 3,Harapan Harapan 3,6,7ORCID,Syahrul Syahrul 1,2 andNasrul Musadir 1,2

Headache in Post-COVID-19 Patients: Its Characteristics and Relationship with the Quality of Life

https://doi.org/10.3390/medicina58101500

Published

21-Oct-22

Study

https://www.mdpi.com/1648-9144/58/10/1500/htm

Little is known on the characteristics of headaches associated with coronavirus disease 2019 (COVID-19) in Indonesia. The objective of this study was to describe the characteristics of headache in post-COVID-19 patients, and its impact on the patients’ quality of life (QoL), as well as to determine the associated determinants of the poor QoL. A cross-sectional study was conducted in Banda Aceh, Indonesia. The demographic characteristics, clinical symptoms of COVID-19, characteristics of headache, and the QoL were collected and assessed. Headache was diagnosed and characterized using the International Classification of Headache Disorders, version 3 (ICHD-3). QoL was assessed using a Short Form 36 Health Survey (SF-36) tool. A logistic regression model was used to investigate the associated determinants of poor QoL in post-COVID-19 patients. A total of 215 post-COVID-19 patients were included in the final analysis, and 21.4% (46/215) of them had a poor QoL due to headache following COVID-19. Those who were unemployed and who contracted COVID-19 less than three months prior to the study had higher odds of having poor QoL compared to those who were employed and who contracted COVID-19 more than three months prior to the study. Low QoL was also related to headache that occurred less than one month after recovering from COVID-19 (compared to that which occurred longer than one month after); had a high frequency; had a combination sensation of pulsating, pressing, fiery, and stabbing pain; had a high severity score; and had additional symptoms accompanying the headache. In conclusion, headache related to COVID-19 is associated with low QoL among post-COVID-19 patients. A guideline on prevention measures of headache on COVID-19 patients, therefore, needs to be established to avoid long-term consequences.

696

MS207

ME

C. (Linda) M. C. van Campen * andFrans C. Visser

Orthostatic Intolerance in Long-Haul COVID after SARS-CoV-2: A Case-Control Comparison with Post-EBV and Insidious-Onset Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

https://doi.org/10.3390/healthcare10102058

Published

17-Oct-22

Study

https://www.mdpi.com/2227-9032/10/10/2058/htm

Background: As complaints of long-haul COVID patients are similar to those of ME/CFS patients and as orthostatic intolerance (OI) plays an important role in the COVID infection symptomatology, we compared 14 long-haul COVID patients with 14 ME/CFS patients with a post-viral Ebstein-Barr (EBV) onset and 14 ME/CFS patients with an insidious onset of the disease. Methods: In all patients, OI analysis by history taking and OI assessed during a tilt test, as well as cerebral blood flow measurements by extracranial Doppler, and cardiac index measurements by suprasternal Doppler during the tilt test were obtained in all patients. Results: Except for disease duration no differences were found in clinical characteristics. The prevalence of POTS was higher in the long-haul patients (100%) than in post-EBV (43%) and in insidious-onset (50%) patients (p = 0.0002). No differences between the three groups were present in the prevalence of OI, heart rate and blood pressure changes, changes in cerebral blood flow or in cardiac index during the tilt test. Conclusion: OI symptomatology and objective abnormalities of OI (abnormal cerebral blood flow and cardiac index reduction during tilt testing) are comparable to those in ME/CFS patients. It indicates that long-haul COVID is essentially the same disease as ME/CFS.

697

MS208

Limor Adler,Sivan Gazit,Yuval Pinto,Galit Perez,Miri Mizrahi Reuveni,Ilan Yehoshua,Robert Hoffman,Joseph Azuri &Tal Patalon

Long-COVID in patients with a history of mild or asymptomatic SARS-CoV-2 infection: a Nationwide Cohort Study

https://doi.org/10.1080/02813432.2022.2139480

Published

31-Oct-22

Study

https://www.tandfonline.com/doi/full/10.1080/02813432.2022.2139480

Objective
Evaluating the prevalence of long-COVID symptoms in patients with a history of mild or asymptomatic infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and the factors associated with developing long-COVID.
Design
A nationwide cohort study. Using a centralized database, we have identified patients with and without a history of SARS-CoV-2 infection 1–6 months before data collection. Patients were asked to fill out an online questionnaire through text messages.
Setting
Israeli general practice.
Subjects
2755 persons participated in the study in September 2021 (a response rate of 7.5%): 819 with and ,936 without a history of SARS-CoV-2 infection.
Main outcome measures
We asked patients to provide details about their demographic status, medical history, COVID-related variables and the presence of long-COVID symptoms.
Results
Most prevalent long-COVID symptoms were decreased smell sensation (35.1% vs. 4.3%, p < 0.001), decreased taste sensation (25.2% vs. 3.2%, p < 0.001), memory disturbances (36.9% vs. 14.4%, p < 0.001), dyspnea (24.2% vs. 10.7%, p < 0.001) and arthralgia (33% vs. 16.3%, p < 0.001). Risk factors associated with long-COVID included female gender, symptomatic COVID-19, overweight or obesity and the presence of dyslipidemia. About 34.6% of participants reported not returning to their baseline health condition after the acute illness.
Conclusion
Long-COVID is frequently seen following a mild symptomatic COVID-19 infection and, to a lesser extent, following an asymptomatic SARS-CoV-2 infection. Primary care physicians should be aware of these symptoms and consider this option in their differential diagnosis. Health policymakers should expect a significant impact of this syndrome on public health.
Key Points
Long-COVID has emerged as a significant health problem with a serious impact on normal daily function
• Long-COVID symptoms were evident in patients with mild symptomatic disease and in asymptomatic patients to a lesser extent.
• Risk factors for having Long-COVID symptoms include female gender, symptomatic disease, increased BMI, and the presence of dyslipidemia.
• Fatigue, dyspnea, weakness, decreased libido, weight changes, memory, and sleep disturbances were associated with not returning to the baseline health state.

698

MS209

Coen C.W.G. Bongers,Esmée A. Bakker,Laurien M. Buffart &Maria T.E. Hopman

Impact of a COVID-19 infection on exercise levels of recreational athletes one- and three-months post-infection

https://doi.org/10.1080/02640414.2022.2140919

Published

29-Oct-22

Study

https://www.tandfonline.com/doi/abs/10.1080/02640414.2022.2140919

We examined the effect of a COVID-19 infection on changes in exercise levels in recreational athletes in the first three months after infection, and identified personal factors associated with a larger change in exercise level and recovery time. Recreational athletes (n=4360) completed an online questionnaire on health and exercise levels. 601 Athletes have had a diagnostically confirmed COVID-19 infection, while 3479 athletes did not (non-COVID-19 group). Exercise levels (in MET-min/week) were examined prior to (2019) and during the COVID-19 pandemic (2020) for the non-COVID-19 group, and in 2019, 1-month pre-COVID-19 infection, 1-month post-COVID-19 infection and 3 months post-COVID-19 infection in the COVID-19 group. Median exercise level at baseline in the COVID-19 group was 3528 (IQR=1488–5760) MET-min/week. One-month post-COVID-19 infection, exercise level dropped 58% (2038 MET-min/week), which partly stabilized to 36% (1256 MET-min/week) below baseline values 3 months post-COVID-19 infection. Moreover, in both the COVID-19 (pre-COVID-19 infection) and non-COVID-19 group exercise levels during the pandemic decreased with ~260 MET-min/week. These results illustrate that even a relatively physically active population of recreational athletes is significantly affected by a COVID-19 infection, particularly those athletes who are overweight. COVID-19 disease burden, age, sex, comorbidities and smoking were not associated with reduced exercise levels.

699

MS210

Anouk Verveen, Elke Wynberg, Hugo D. G. van Willigen, Udi Davidovich, Anja Lok, Eric P. Moll van Charante, Menno D. de Jong, Godelieve de Bree, Maria Prins, Hans Knoop, Pythia T. Nieuwkerk & the RECoVERED Study Group

Health-related quality of life among persons with initial mild, moderate, and severe or critical COVID-19 at 1 and 12 months after infection: a prospective cohort study

https://doi.org/10.1186/s12916-022-02615-7

Published

2-Nov-22

Study

https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-022-02615-7

Background
Currently, there is limited evidence about the long-term impact on physical, social and emotional functioning, i.e. health-related quality of life (HRQL) after mild or moderate COVID-19 not requiring hospitalization. We compared HRQL among persons with initial mild, moderate or severe/critical COVID-19 at 1 and 12 months following illness onset with Dutch population norms and investigated the impact of restrictive public health control measures on HRQL.
Methods
RECoVERED, a prospective cohort study in Amsterdam, the Netherlands, enrolled adult participants after confirmed SARS-CoV-2 diagnosis. HRQL was assessed with the Medical Outcomes Study Short Form 36-item health survey (SF-36). SF-36 scores were converted to standard scores based on an age- and sex-matched representative reference sample of the Dutch population. Differences in HRQL over time were compared among persons with initial mild, moderate or severe/critical COVID-19 using mixed linear models adjusted for potential confounders.
Results
By December 2021, 349 persons were enrolled of whom 269 completed at least one SF-36 form (77%). One month after illness onset, HRQL was significantly below population norms on all SF-36 domains except general health and bodily pain among persons with mild COVID-19. After 12 months, persons with mild COVID-19 had HRQL within population norms, whereas persons with moderate or severe/critical COVID-19 had HRQL below population norms on more than half of the SF-36 domains. Dutch-origin participants had significantly better HRQL than participants with a migration background. Participants with three or more COVID-19 high-risk comorbidities had worse HRQL than part participants with fewer comorbidities. Participants who completed the SF-36 when restrictive public health control measures applied reported less limitations in social and physical functioning and less impaired mental health than participants who completed the SF-36 when no restrictive measures applied.
Conclusions
Twelve months after illness onset, persons with initial mild COVID-19 had HRQL within population norms, whereas persons with initial moderate or severe/critical COVID-19 still had impaired HRQL. Having a migration background and a higher number of COVID-19 high-risk comorbidities were associated with worse HRQL. Interestingly, HRQL was less impaired during periods when restrictive public health control measures were in place compared to periods without.

700

MS211

Lars Heubner, Paul Leon Petrick, Andreas Güldner, Lea Bartels, Maximillian Ragaller, Martin Mirus, Axel Rand, Oliver Tiebel, Jan Beyer-Westendorf, Martin Rößler, Jochen Schmitt, Thea Koch & Peter Markus Spieth

Extreme obesity is a strong predictor for in-hospital mortality and the prevalence of long-COVID in severe COVID-19 patients with acute respiratory distress syndrome

https://doi.org/10.1038/s41598-022-22107-1

Published

1-Nov-22

Study

https://www.nature.com/articles/s41598-022-22107-1

Acute Respiratory Distress Syndrome (ARDS) is common in COVID-19 patients and is associated with high mortality. The aim of this observational study was to describe patients’ characteristics and outcome, identifying potential risk factors for in-hospital mortality and for developing Long-COVID symptoms. This retrospective study included all patients with COVID-19 associated ARDS (cARDS) in the period from March 2020 to March 2021 who were invasively ventilated at the intensive care unit (ICU) of the University Hospital Dresden, Germany. Between October 2021 and December 2021 patients discharged alive (at minimum 6 months after hospital discharge—midterm survival) were contacted and interviewed about persistent symptoms possibly associated with COVID-19 as well as the quality of their lives using the EQ-5D-5L-questionnaire. Long-COVID was defined as the occurrence of one of the symptoms at least 6 months after discharge. Risk factors for mortality were assessed with Cox regression models and risk factors for developing Long-COVID symptoms by using relative risk (RR) regression. 184 Patients were included in this study (male: n = 134 (73%), median age 67 (range 25–92). All patients were diagnosed with ARDS according to the Berlin Definition. 89% of patients (n = 164) had severe ARDS (Horovitz-index < 100 mmHg). In 27% (n = 49) extracorporeal membrane oxygenation was necessary to maintain gas exchange. The median length of in-hospital stay was 19 days (range 1–60). ICU mortality was 51%, hospital mortality 59%. Midterm survival (median 11 months) was 83% (n = 55) and 78% (n = 43) of these patients presented Long-COVID symptoms with fatigue as the most common symptom (70%). Extreme obesity (BMI > 40 kg/m2) was the strongest predictor for in-hospital mortality (hazard ratio: 3.147, confidence interval 1.000–9.897) and for developing Long-COVID symptoms (RR 1.61, confidence interval 1.26–2.06). In-hospital mortality in severe cARDS patients was high, but > 80% of patients discharged alive survived the midterm observation period. Nonetheless, most patients developed Long-COVID symptoms. Extreme obesity with BMI > 40 kg/m2 was identified as independent risk factor for in-hospital mortality and for developing Long-COVID symptoms.

701

MS212

Mayssam Nehme MD, Francois Chappuis MD, PhD, Laurent Kaiser MD, PhD, Frederic Assal MD, PhD & Idris Guessous MD, PhD

The Prevalence, Severity, and Impact of Post-COVID Persistent Fatigue, Post-Exertional Malaise, and Chronic Fatigue Syndrome

https://doi.org/10.1007/s11606-022-07882-x

Published

10-Nov-22

Study

https://link.springer.com/article/10.1007/s11606-022-07882-x

Fatigue is the most common and persistent post-COVID symptom. The spectrum of fatigue severity in post-COVID individuals ranges from feeling tired to having severe fatigue, post-exertional malaise, or criteria for chronic fatigue syndrome with an increasing impact on health, functional capacity, and physical activity.
Almost half of individuals experiencing fatigue at 6 months after the infection had post-exertional malaise, and 6.2% had criteria for chronic fatigue syndrome, prompting physicians to consider pacing as a management option, in the absence of other treatment options at this stage. SARS-CoV-2 infection was positively associated with fatigue and post-exertional malaise. Results showed that individuals with fatigue were more likely to be vaccinated. This was partially explained by the baseline distribution as older individuals and those with more comorbidities were more likely to get vaccinated.
Results compare to recent reviews showing an overlap between post-COVID condition and chronic fatigue syndrome.6 Our study graded post-COVID fatigue by severity in correlation with functional capacity, and showed the high prevalence of post-exertional malaise.

702

MS213

Olivier Robineau, MD, PhD1,2; Marie Zins, MD, PhD3; Mathilde Touvier, MD, PhD4; Emmanuel Wiernik, PhD3; Cedric Lemogne, MD, PhD5; Xavier de Lamballerie, MD, PhD6; Hélène Blanché, PhD7; Jean-François Deleuze, PhD7; Paola Mariela Saba Villarroel, PhD6; Céline Dorival, PhD1; Jerome Nicol, PhD1; Roselyn Gomes-Rima, MPH8; Emmanuelle Correia, PhD8; Mireille Coeuret-Pellicer, MD, MPH3; Nathalie Druesne-Pecollo, PhD4; Younes Esseddik, PhD4; Céline Ribet, PhD3; Marcel Goldberg, MD, PhD3; Gianluca Severi, PhD8,9; Fabrice Carrat, MD, PhD1,10

Long-lasting Symptoms After an Acute COVID-19 Infection and Factors Associated With Their Resolution

https://doi.org/10.1001/jamanetworkopen.2022.40985

Published

9-Nov-22

Study

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2798224

Key Points
Question What is the duration of persistent symptoms after SARS-CoV-2 infection, and what factors are associated with their resolution?
Findings This cross-sectional study nested in 3 French population-based cohorts found that approximately 10% of individuals with acute COVID-19 infection still had symptoms after 1 year of follow-up. The risk factors associated with the duration of these symptoms vary depending on their persistence.
Meaning This study suggests that persistent symptoms after SARS-CoV-2 infection is a public health concern.
Abstract
Importance - Persistent symptoms after SARS-CoV-2 infection are an emerging public health problem. The duration of these symptoms remains poorly documented.
Objective - To describe the temporal dynamics of persistent symptoms after SARS-CoV-2 infection and the factors associated with their resolution.
Design, Setting, and Participants - This cross-sectional study involved 53 047 participants from 3 French adult population-based cohorts (CONSTANCES [Consultants des Centres d’Examens de Santé], E3N/E4N, and Nutrinet-Santé) who were included in a nationwide survey about SARS-CoV-2 infection. All participants were asked to complete self-administered questionnaires between April 1 and June 30, 2020. Variables included sociodemographic characteristics, comorbid conditions, COVID-19 diagnosis, and acute symptoms. Blood samples were obtained for serologic analysis between May 1 and November 30, 2020, from patients with SARS-CoV-2 infection defined as enzyme-linked immunosorbent assay immunoglobulin G antispike detection confirmed with a neutralization assay. A follow-up internet questionnaire was completed between June 1 and September 30, 2021, with details on persistent symptoms, their duration, and SARS-CoV-2 infection diagnosis by polymerase chain reaction.
Main Outcomes and Measures - Persistent symptoms were defined as symptoms occurring during the acute infection and lasting 2 or more months. Survival models for interval-censored data were used to estimate symptom duration from the acute episode. Multivariable adjusted hazard ratios (HRs) were estimated for age, sex, and comorbid conditions. Factors associated with the resolution of symptoms were assessed.
Results - A total of 3972 participants (2531 women [63.7%; 95% CI, 62.2%-65.2%]; mean [SD] age, 50.9 [12.7] years) had been infected with SARS-CoV-2. Of these 3972 participants, 2647 (66.6% [95% CI, 65.1%-68.1%]) reported at least 1 symptom during the acute phase. Of these 2647 participants, 861 (32.5% [95% CI, 30.8%-34.3%]) reported at least 1 persistent symptom lasting 2 or more months after the acute phase. After 1 year of follow-up, the estimated proportion of individuals with complete symptom resolution was 89.9% (95% CI, 88.7%-90.9%) with acute symptoms. Older age (>60 years; HR, 0.78; 95% CI, 0.68-0.90), female sex (HR, 0.64; 95% CI, 0.58-0.70), history of cancer (HR, 0.61; 95% CI, 0.47-0.79), history of tobacco consumption (HR, 0.80; 95% CI, 0.73-0.88), high body mass index (≥30: HR, 0.75; 95% CI, 0.63-0.89), and high number of symptoms during the acute phase (>4; HR, 0.43; 95% CI, 0.39-0.48) were associated with a slower resolution of symptoms.
Conclusions and Relevance - In this cross-sectional study, persistent symptoms were still present in 10.1% of infected individuals at 1 year after SARS-CoV-2 infection. Given the high level of cumulative incidence of COVID-19, the absolute prevalent number of people with persistent symptoms is a public health concern.

703

MS214

Mirembe Woodrow, Charles Carey, Nida Ziauddeen, Rebecca Thomas, Athena Akrami, Vittoria Lutje, Darren C Greenwood, Nisreen A Alwan

Systematic review of the prevalence of Long Covid

https://www.medrxiv.org/content/10.1101/2022.11.06.22281979v1.full-text

pre-print

7-Nov-22

Systematic review

https://www.medrxiv.org/content/10.1101/2022.11.06.22281979v1

Background Long Covid occurs in those infected with SARSCoV2 whose symptoms persist or develop beyond the acute phase. We conducted a systematic review to determine the prevalence of persistent symptoms, functional disability or pathological changes in adults or children at least 12 weeks post-infection.
Methods We searched MEDLINE (Ovid), Embase (OVID), the Cochrane Covid-19 Study register, WHO ICTRP, medRxiv, Cochrane CENTRAL, MEDLINE (PubMed), ClinicalTrials.gov, and the WHO Global research on coronavirus disease (COVID-19) database from 1st January 2020 to 2nd November 2021, limited to publications in English. We included studies with at least 100 participants. Studies where all participants were critically ill were excluded. Articles were screened independently by two reviewers, with disagreements resolved by a third. Long Covid (primary outcome) was extracted as prevalence of at least one symptom or pathology, or prevalence of the most common symptom or pathology, at 12 weeks or later. Heterogeneity was quantified in absolute terms and as a proportion of total variation and explored across pre-defined subgroups (PROSPERO ID CRD42020218351).
Findings In total 120 studies in 130 publications were included. Length of follow-up varied from 12 weeks to over 12 months. Few studies had low risk of bias. All complete and subgroup analyses except one had I2 ≥ 90%, with prevalence of persistent symptoms ranging between 0% and 93%. Studies using routine healthcare records tended to report lower prevalence of persistent symptoms/pathology than self-report. However, studies systematically investigating pathology in all participants at follow up tended to report the highest estimates of all three. Studies of hospitalised cases had generally higher estimates than community-based studies.
Interpretation The way in which Long Covid is defined and measured affects prevalence estimation. Given the widespread nature of SARSCoV2 infection globally, the burden of chronic illness is likely to be substantial even using the most conservative estimates.
Funding this systematic review received no specific funding.
Evidence before this study The chronic effects of COVID19 were accounted for in relation to the health, social and economic impacts at the start of the pandemic in 2020. Long Covid is now established as a serious outcome of infection with SARSCoV2 that influences the daily lives of many. To estimate the population-level burden, the prevalence of prolonged health effects from SARSCoV2 infection needs to be quantified. We conducted a systematic review of published studies to determine the prevalence of persistent symptoms, functional disability or pathological changes in adults or children at least 12 weeks post-infection.
Added value of this study We included 120 studies assessing Long Covid symptoms, functional status, or pathology published up to November 2021. There was significant heterogeneity between studies and wide variation in Long Covid prevalence estimates ranging between 0-93%. This is due to differences in Long Covid definition, required threshold of severity or impact on daily activities, study designs, sources of study samples, how the initial infection was defined, number of assessed symptoms and method of assessment. Despite large between-study heterogeneity, the studies with lowest risk of bias estimated prevalence between 3% and 37%. For studies that included comparison of cases to controls, there were significant methodological considerations to the choice of control groups including difficulty ascertaining the absence of exposure (SARSCoV2 infection). The review search timeline meant Long Covid prevalence in vaccinated populations could not be assessed.
Implication of all the available evidence Even with the most conservative estimates of prevalence among those infected, the chronic disease burden generated by SARSCoV2 infection seems substantial, particularly in countries where community transmission of SARSCoV2 is high.

704

MS215

Sonja H.Brunvoll1aAnders B.Nygaard1aMorten W.Fagerland2PetterHolland1MereteEllingjord-Dale1John ArneDahl1ArneSøraas1

Post-acute symptoms 3-15 months after COVID-19 among unvaccinated and vaccinated individuals with a breakthrough infection

https://doi.org/10.1016/j.ijid.2022.11.009

Published

12-Nov-22

Study

https://www.sciencedirect.com/science/article/pii/S1201971222005963

Highlights
•More symptoms in SARS-CoV-2 positive than negative participants ≥3 months post-COVID
•Most symptoms no different between vaccinated and unvaccinated positive participants
•No difference in EMQ-13 score comparing vaccinated to unvaccinated participants
•Less memory problems were reported among vaccinated than unvaccinated participants
Abstract
Objectives
We aimed to describe post-acute sequelae of SARS-CoV-2 infection (PASC) related symptoms 3-15 months after a positive test in SARS-CoV-2 unvaccinated and vaccinated participants with a breakthrough infection.
Methods
Participants of the Norwegian COVID-19 Cohort, without a positive SARS-CoV-2 test, filled in a questionnaire asking about PASC-related symptoms between November 2020 and January 2021. About a year later, a second questionnaire (which also included the Everyday Memory Questionnaire 13 (EMQ-13)) was filled in by the same participants, most still without a positive SARS-CoV-2 test, but also by unvaccinated and vaccinated participants with a positive test 3-15 months before the questionnaire. Laboratory-confirmed SARS-CoV-2 status (positive or negative swab test determined by reverse transcriptase quantitative polymerase chain reaction) at the time of completing questionnaires was ascertained from the Mandatory Norwegian Surveillance System for Communicable Diseases.
Results
No differences were found in the self-reported PASC-symptoms dyspnea, fatigue, smell/taste changes or concentration problems, or the EMQ-13 score between unvaccinated and vaccinated participants 3-15 months after the positive test. Less memory problems were reported among vaccinated than unvaccinated participants.
Conclusions
SARS-CoV-2 vaccines offer minor protection against PASC-symptoms, although less memory problems were reported among the vaccinated than the unvaccinated participants.

705

MS216

Emre Dirican
Open the ORCID record for Emre Dirican[Opens in a new window]
and
Tayibe Bal

COVID-19 disease severity to predict persistent symptoms: a systematic review and meta-analysis

https://doi.org/10.1017/S1463423622000585

Published

10-Nov-22

Systematic Review and Meta-Analysis

https://www.cambridge.org/core/journals/primary-health-care-research-and-development/article/covid19-disease-severity-to-predict-persistent-symptoms-a-systematic-review-and-metaanalysis/479FC1E900E22673895FDAC1CF5C12B2

Background:
It is unclear, whether the initial disease severity may help to predict which COVID-19 patients at risk of developing persistent symptoms.
Aim:
The aim of this study was to examine whether the initial disease severity affects the risk of persistent symptoms in post-acute COVID-19 syndrome and long COVID.
Methods:
A systematic search was conducted using PUBMED, Google Scholar, EMBASE, and ProQuest databases to identify eligible articles published after January 2020 up to and including 30 August 2021. Pooled odds ratio (OR) and confidence intervals (CIs) were calculated using random effects meta-analysis.
Findings:
After searching a total of 7733 articles, 20 relevant observational studies with a total of 7840 patients were selected for meta-analysis. The pooled OR for persistent dyspnea in COVID-19 survivors with a severe versus nonsevere initial disease was 2.17 [95%CI 1.62 to 2.90], and it was 1.33 [95%CI 0.75 to 2.33] for persistent cough, 1.30 [95%CI 1.06 to 1.58] for persistent fatigue, 1.02 [95%CI 0.73 to 1.40] for persistent anosmia, 1.22 [95%CI 0.69 to 2.16] for persistent chest pain, and 1.30 [95%CI 0.93 to 1.81] for persistent palpitation.
Conclusions:
Contrary to expectations, we did not observe an association between the initial COVID-19 disease severity and common persistent symptoms except for dyspnea and fatigue. In addition, it was found that being in the acute or prolonged post-COVID phase did not affect the risk of symptoms. Primary care providers should be alert to potential most prevalent persistent symptoms in all COVID-19 survivors, which are not limited to patients with critical–severe initial disease.

706

MS217

César Fernández-de-las-Peñas, PT, PhD1; Jorge Rodríguez-Jiménez, PT, MSc1; Ignacio Cancela-Cilleruelo, PT, MSc1; Angel Guerrero-Peral, MD, PhD2,3; José D. Martín-Guerrero, PhD4; David García-Azorín, MD, PhD2; Ana Cornejo-Mazzuchelli, MD5; Valentín Hernández-Barrera, PhD6; Oscar J. Pellicer-Valero, PhD4*

Post–COVID-19 Symptoms 2 Years After SARS-CoV-2 Infection Among Hospitalized vs Nonhospitalized Patients

https://doi.org/10.1001/jamanetworkopen.2022.42106

Published

15-Nov-22

Study

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2798446

Key Points
Question What is the prevalence of post–COVID-19 symptoms among hospitalized and nonhospitalized patients 2 years after acute infection?
Findings This cross-sectional study found that the proportion of patients with at least 1 post–COVID-19 symptom 2 years after acute infection was 59.7% for hospitalized patients and 67.5% for those not requiring hospitalization. No significant differences in post–COVID-19 symptoms were seen between hospitalized and nonhospitalized patients.
Meaning Similar rates of post–COVID-19 symptoms between hospitalized and nonhospitalized patients suggest that, among all patients who contract COVID-19, these sequelae deserve attention.
Abstract
Importance Identification of long-term post–COVID-19 symptoms among hospitalized and nonhospitalized patients is needed.
Objective To compare the presence of post–COVID-19 symptoms 2 years after acute SARS-CoV-2 infection between hospitalized and nonhospitalized patients.
Design, Setting, and Participants A cross-sectional cohort study was conducted at 2 urban hospitals and general practitioner centers from March 20 to April 30, 2020, among 360 hospitalized patients and 308 nonhospitalized patients with acute SARS-CoV-2 infection during the first wave of the pandemic. Follow-up was conducted 2 years later.
Main Outcomes and Measures Participants were scheduled for a telephone interview 2 years after acute infection. The presence of post–COVID-19 symptoms was systematically assessed, with particular attention to symptoms starting after infection. Hospitalization and clinical data were collected from medical records. Between-group comparisons and multivariate logistic regressions were conducted.
Results A total of 360 hospitalized patients (162 women [45.0%]; mean [SD] age, 60.7 [16.1] years) and 308 nonhospitalized patients (183 women [59.4%]; mean [SD] age, 56.7 [14.7] years) were included. Dyspnea was more prevalent at the onset of illness among hospitalized than among nonhospitalized patients (112 [31.1%] vs 36 [11.7%]; P < .001), whereas anosmia was more prevalent among nonhospitalized than among hospitalized patients (66 [21.4%] vs 36 [10.0%]; P = .003). Hospitalized patients were assessed at a mean (SD) of 23.8 (0.6) months after hospital discharge, and nonhospitalized patients were assessed at a mean (SD) of 23.4 (0.7) months after the onset of symptoms. The number of patients who exhibited at least 1 post–COVID-19 symptom 2 years after infection was 215 (59.7%) among hospitalized patients and 208 (67.5%) among nonhospitalized patients (P = .01). Among hospitalized and nonhospitalized patients, fatigue (161 [44.7%] vs 147 [47.7%]), pain (129 [35.8%] vs 92 [29.9%]), and memory loss (72 [20.0%] vs 49 [15.9%]) were the most prevalent post–COVID-19 symptoms 2 years after SARS-CoV-2 infection. No significant differences in post–COVID-19 symptoms were observed between hospitalized and nonhospitalized patients. The number of preexisting medical comorbidities was associated with post–COVID-19 fatigue (odds ratio [OR], 1.93; 95% CI, 1.09-3.42; P = .02) and dyspnea (OR, 1.91; 95% CI, 1.04-3.48; P = .03) among hospitalized patients. The number of preexisting medical comorbidities (OR, 3.75; 95% CI, 1.67-8.42; P = .001) and the number of symptoms at the onset of illness (OR, 3.84; 95% CI, 1.33-11.05; P = .01) were associated with post–COVID-19 fatigue among nonhospitalized patients.
Conclusions and Relevance This cross-sectional study suggested the presence of at least 1 post–COVID-19 symptom in 59.7% of hospitalized patients and 67.5% of nonhospitalized patients 2 years after infection. Small differences in symptoms at onset of COVID-19 were identified between hospitalized and nonhospitalized patients. Post–COVID-19 symptoms were similar between hospitalized and nonhospitalized patients; however, lack of inclusion of uninfected controls limits the ability to assess the association of SARS-CoV-2 infection with overall and specific post–COVID-19 symptoms 2 years after acute infection. Future studies should include uninfected control populations.

707

MS218

Mohammed Samannodi 1,Hassan Alwafi 2,3,Abdallah Y. Naser 4ORCID,Abdullah A. Al Qurashi 5,6,Jumanah T. Qedair 5,6,Emad Salawati 7ORCID,Mohammed A. Almatrafi 8,Rakan Ekram 9,Rahaf I. Bukhari 2,Maryam Dahlawi 2ORCID,Bayan Hafiz 2,Roaa Mandora 2,Ranin K. Alsindi 2,Sarah Tayeb 10 andFaisal Minshawi 11,*ORCID

Determinants of Post-COVID-19 Conditions among SARS-CoV-2-Infected Patients in Saudi Arabia: A Web-Based Cross-Sectional Study

https://doi.org/10.3390/diseases10030055

Published

23-Aug-22

Study

https://www.mdpi.com/2079-9721/10/3/55/htm

Background: Large numbers of people infected with COVID-19 developed acute symptoms. Post-COVID-19 conditions have been reported after recovery or discharge from the hospital. However, little is known about the prevalence and possible risk factors of post-COVID-19 conditions in the Saudi community. Here, we describe the incidence of post-COVID-19 conditions among the general population of Saudi Arabia. Methods: We conducted a cross-sectional, nationwide study using an online survey in Saudi Arabia from 1 September 2021 to 28 February 2022. The survey was distributed using social media platforms, such as Twitter, WhatsApp, and Facebook. Patients with SARS-CoV-2 infection were included in the questionnaire adapted from published studies. Result: The study enrolled 7520 individuals who were previously infected with SARS-CoV-2. Most patients in our study were symptomatic and their acute symptoms may persist for more than six days. On the other hand, long-term complications may develop and continue for an extended period (post-COVID-19 conditions). Most of these complications are respiratory, neurological, psychological, or skin related. The proportion of long-term complications reported in this study is 36% among SARS-CoV-2-infected individuals. In addition, being female, old age, number of chronic complications, long-term medication, length of stay in hospital and intensive care unit, and duration of acute symptoms may be significant predictors of post-COVID-19 symptoms. Conclusion: In conclusion, the incidence of post-COVID-19 conditions among the Saudi population was high, which urges further investigation into the risk factors associated with post-COVID-19 symptoms.

708

MS219

Mayssam Nehme MD, Francois Chappuis MD, PhD, Laurent Kaiser MD, PhD, Frederic Assal MD, PhD & Idris Guessous MD, PhD

The Prevalence, Severity, and Impact of Post-COVID Persistent Fatigue, Post-Exertional Malaise, and Chronic Fatigue Syndrome

https://doi.org/10.1007/s11606-022-07882-x

Published

10-Nov-22

Study

https://link.springer.com/article/10.1007/s11606-022-07882-x

Overall, 5515 individuals participated in this study (response rate 70.7%), with 5406 participants at 6 months or more after their test date. A total of 1497 (27.7%) participants had a documented positive SARS-CoV-2 test and were ultimately included in the study. The median time for follow-up was 225 days (interquartile range 207–398). Respectively, fatigue was reported by 17.2%, post-exertional malaise by 8.2%, and the presence of criteria for chronic fatigue syndrome by 1.1% of SARS-CoV-2-positive individuals, compared to 8.9%, 3.5%, and 0.5% of SARS-CoV-2-negative individuals. Characteristics are presented in Table 1.
Out of SARS-CoV-2-positive participants with fatigue (n = 258), 35.3% had moderate to severe limitations on the ECOG scale, and 83.0% had a score ≥ 4 on the Chalder fatigue scale. The Chalder fatigue scale revealed a mean score of 19 out of 33, SD 5.4, and a mean score of 6.7 out of 11, SD 3.3 using bimodal scoring. After adjusting for age and sex, 47.7% of SARS-CoV-2-positive individuals with fatigue at 6 months or more had the frequency and severity criteria for post-exertional malaise, and 6.2% had criteria for chronic fatigue syndrome.
Individuals had a higher prevalence of insomnia, cognitive impairment, headaches, generalized pain, functional impairment, reduced work capacity, and decreased physical activity, after SARS-CoV-2 infection. The prevalence of these sequelae was adjusted for age and sex and was increasingly higher with severe fatigue, with post-exertional malaise, or when criteria for chronic fatigue syndrome were present (Fig. 1).
Fatigue is the most common and persistent post-COVID symptom. The spectrum of fatigue severity in post-COVID individuals ranges from feeling tired to having severe fatigue, post-exertional malaise, or criteria for chronic fatigue syndrome with an increasing impact on health, functional capacity, and physical activity.
Almost half of individuals experiencing fatigue at 6 months after the infection had post-exertional malaise, and 6.2% had criteria for chronic fatigue syndrome, prompting physicians to consider pacing as a management option, in the absence of other treatment options at this stage. SARS-CoV-2 infection was positively associated with fatigue and post-exertional malaise. Results showed that individuals with fatigue were more likely to be vaccinated. This was partially explained by the baseline distribution as older individuals and those with more comorbidities were more likely to get vaccinated.
Results compare to recent reviews showing an overlap between post-COVID condition and chronic fatigue syndrome.6 Our study graded post-COVID fatigue by severity in correlation with functional capacity, and showed the high prevalence of post-exertional malaise.
Limitations include the self-reported nature of this follow-up with individuals infected in 2020 and follow-up in 2021, lacking comparisons to individuals infected with other variants. Additionally, this study considered having received at least 2 doses as full vaccination, a concept that continues to evolve with time.
Physicians, employers, and insurance companies should address fatigue on a spectrum, accounting for the correlated functional impairment, decreased activity levels, and potentially poorer quality of life.

709

MS220

ME

Nour Shaheen, MDcorresponding authora,* and Ahmed Shaheen, MDa

Long-term sequelae of COVID-19 (myalgic encephalomyelitis): An international cross-sectional study

https://doi.org/10.1097%2FMD.0000000000031819

Published

11-Nov-22

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9665887/

Background:
As a result of prolonged effects on multiple organs, recovery from COVID-19 caused by SARS-CoV-2 cannot be verified. This study seeks to understand chronic and acute long-term symptoms of COVID-19 lasting from a few weeks after diagnosis. The study also aims to gain insight into prevalence of chronic fatigue syndrome/myalgic encephalomyelitis, a potentially comorbid condition for several months after the infection, in addition to taking a broad perspective on rare symptoms that may have developed during or after the infection.
Study design:
Cross-sectional questionnaire\descriptive study.
Methods:
The questionnaire was developed to assess the long-term effects of the global pandemic of COVID-19 using DePaul Symptom Questionnaire-2. The DePaul Symptom Questionnaire, Patient Health Questionnaire, and other symptoms that have been introduced by literature review.
Discussion:
A large cohort of people from all over the world will be examined to understand the differential effects of people who have experienced COVID-19, as well as the potential occurrence of ME. In total, 20,000 COVID patients are expected to be included in the study by Sep 1, 2022. Patients who have experienced COVID-19 will be asked about their persistent symptoms from 1 week up to more than 6 months after catching or recovery from the infection.

710

MS221

Dávid Líška1, Erika Liptaková2, Adriana Babičová3, Ladislav Batalik4,5*, Patrícia Shtin Baňárová6 and Silvia Dobrodenková7

What is the quality of life in patients with long COVID compared to a healthy control group?

https://doi.org/10.3389/fpubh.2022.975992

Published

2-Nov-22

Study

https://www.frontiersin.org/articles/10.3389/fpubh.2022.975992/full

Introduction: Many patients have prolonged symptoms after COVID-19 infection, which can affect patient quality of life (QOL). The aim of this study is to determine the quality of life in patients with long COVID, compared with healthy controls.
Material and methods: The study was a prospective cross-sectional study using an anonymous online survey. The SF-36 questionnaire was chosen for quality of life measurement. The survey was distributed through the Facebook social media platform targeting groups of patients with long COVID. The control group was made up of physiotherapy and physical education students.
Results: There was a significant difference in physical function, with a mean score of 94.9 (±9.4) among the students, compared to long COVID patients with a mean score of 66.2 (±25.4) (p < 0.001). A similar result was found in the physical role (p < 0.001). The overall quality of life score for college students was 578.0 (±111.9), and the overall score for patients with long COVID was 331.9 (±126.9).
Conclusions: Patients with long COVID had a lower quality of life compared to the healthy control group, and this was associated with the negative effect of long-COVID. Lower quality of life in patients with long COVID is an important therapeutic goal, which requires attention.

711

MS222

Hi Sun Soh,1,2 and BeLong Cho3,4

Long COVID-19 and Health-Related Quality of Life of Mild Cases in Korea: 3-Months Follow-up of a Single Community Treatment Center

https://doi.org/10.3346/jkms.2022.37.e326

Published

9-Nov-22

Survey Study

https://www.jkms.kr/DOIx.php?id=10.3346/jkms.2022.37.e326

Background
Severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019 [COVID-19]) survivors mount as the pandemic continues. To date, studies on persistent symptoms and their effects on health-related quality of life (HRQoL) in mild COVID-19 cases have been limited.
Methods
A prospective online survey was conducted in COVID-19 patients who were admitted to Seongnam Community Treatment Center, an isolation center in South Korea, from November 23rd 2021 to January 2nd 2022. Patients above the age of 19 with no or mild symptoms were included in the study. Total of 147 patients returned to the follow-up survey 3 months after discharge. Baseline demographics, clinical characteristics, symptoms, and EuroQol-5 dimensions-5 levels (EQ-5D-5L) measures were investigated.
Results
The median (interquartile range [IQR]) interval period between the initial and follow-up survey was 96.0 (93.0–98.0) days. The median (IQR) age of participants was 51.0 (43.0–61.0). During isolation, 131 (89.1%) patients manifested symptoms. On follow-up, 82 (55.8%) participants remained symptomatic. Common symptoms were constitutional (fatigue, myalgia), neurological (memory impairment, hyposmia, hypogeusia, dizziness), and neuropsychiatric (anxiety) symptoms. Participants with remaining neuropsychiatric symptoms reported the lowest EQ-5D-5L index values. Factors associated with persistent symptoms and diminished HRQoL were identified as female sex, metabolic disease, and anxiety during acute COVID-19 phase.
Conclusions
Cardiopulmonary symptoms improved over time but constitutional, neurological, neuropsychiatric symptoms remained. Patients with neuropsychiatric symptoms (anxiety and insomnia) reported the worst HRQoL. Female sex, metabolic disease, and anxiety during the acute COVID-19 phase were associated with long COVID. Observations of long-term symptoms of COVID-19 with decline in HRQoL and integrated research in COVID-19 survivors are warranted.

712

MS223

Qiangru Huang, MD
Mengmeng Jia, PhD
Yanxia Sun, PhD
Binshan Jiang, BS
Dan Cui, MD
Luzhao Feng, PhD
Weizhong Yang, MD

One-year temporal changes in long COVID prevalence and characteristics: a systematic review and meta-analysis

https://doi.org/10.1016/j.jval.2022.11.011

Published

24-Nov-22

Systematic Review and Meta-analysis

https://www.valueinhealthjournal.com/article/S1098-3015(22)04743-X/pdf

Highlights
1.What is already known about this topic?
Long COVID shows multiorgan symptoms and persists for a long period in some post-acute patients.
2.What does the paper add to existing knowledge?
Our findings highlight the temporal change in prevalence of 44 specific long COVID symptoms. About two-thirds of the symptoms did not reduce during the 1-year follow-up. The influence of acute phase-related factors for long COVID gradually decreases over time.
3.What insights does the paper provide for informing health care-related decision making?
Long COVID may persist longer than expected and more attention should be paid to neuropsychiatric symptoms.
Abstract
Objectives
This study aimed to explore the 1-year temporal change in prevalence, variety, and potential risk factors of long COVID symptoms, and to further predict the prognostic trends of long COVID.
Methods
We searched electronic databases for related studies published from January 2020 to February 2022, and conducted one group meta-analysis and locally weighted regression explore the monthly temporal change in the prevalence of each long COVID symptom in 1-year follow-up period.
Results
A total of 137 studies were included in meta-analysis, including 134,093 participants. The temporal change of any long COVID symptom showed a steep decrease initially (from 92% at acute phase to 55% at 1-month follow-up), followed by stabilization at approximately 50% during 1-year follow-up. Six months or more after the acute phase, the odds ratio (OR) of population characteristic factors increased, such as female gender (from 1.62 to 1.82), while the OR value of acute phase-related factors (severe/critical and hospitalization) decreased. As for specific symptoms, about two-thirds of the symptoms did not significantly reduce during the 1-year follow-up, and the neuropsychiatric symptoms showed a higher long-term prevalence (approximately 25%) and longer persistence than physical-symptoms.
Conclusions
The temporal changes in the prevalence and characteristics speculate that long COVID may persist longer than expected. In particular, we should pay more attention to neuropsychiatric symptoms and other symptoms for which there is no significant downward trend in prevalence. The influence of acute phase-related factors for long COVID gradually decreases over time, while the influence of population characteristic-related gradually increases.

713

MS224

J.BaruchabcC.ZahraacT.CardonaaT.Melilloa

National long COVID impact and risk factors

https://doi.org/10.1016/j.puhe.2022.09.021

Published

23-Nov-22

Study

https://www.sciencedirect.com/science/article/pii/S0033350622002839

Objective
Our objective was to estimate the prevalence and risk factors for long COVID symptoms among polymerase chain reaction–confirmed COVID-19 patients (hospitalised and community) in Malta.
Study design
This was a national cross-sectional survey among COVID-19 patients in Malta during 2020.
Methods
Patients were sent a questionnaire 3–6 months after testing positive. Data were analysed descriptively to estimate symptom prevalence, and multivariable logistic regressions were used to determine the risk factors for long COVID symptoms. Age, sex, initial symptoms, hospitalisation, and healthcare worker status were used as risk factors and symptoms (cough, shortness of breath, fatigue, anxiety, sadness, and memory loss) 2.5 months or more after COVID-19 onset were used as outcomes.
Results
Of 8446 eligible participants, 2665 (31.55%) responded with a median age of 37 years. Initial symptoms were reported in 82% of responders, and 7.73% were hospitalised. Among the long COVID symptoms, fatigue persisted among most non-hospitalised responders, whereas anxiety, shortness of breath, and sadness were the most common symptoms. Female sex, hospitalisation, and initial symptoms were associated with higher odds of fatigue, shortness of breath, cough, anxiety, sadness, and memory loss as long COVID symptoms.
Conclusions
Our study is the first to highlight long COVID symptoms and risk factors in Malta, showing that long COVID is common among hospitalised and non-hospitalised patients. These data should increase awareness of long COVID and facilitate support to those affected nationally.

714

MS225

Jorge Vásconez-González 1,*,Juan S. Izquierdo-Condoy 1,2ORCID,Raul Fernandez-Naranjo 1 andEsteban Ortiz-Prado 1,3,*ORCID

A Systematic Review and Quality Evaluation of Studies on Long-Term Sequelae of COVID-19

https://doi.org/10.3390/healthcare10122364

Published

24-Nov-22

Systematic review

https://www.mdpi.com/2227-9032/10/12/2364

COVID-19 made its debut as a pandemic in 2020; since then, more than 607 million cases and at least 6.5 million deaths have been reported worldwide. While the burden of disease has been described, the long-term effects or chronic sequelae are still being clarified. The aim of this study was to present an overview of the information available on the sequelae of COVID-19 in people who have suffered from the infection. A systematic review was carried out in which cohort studies, case series, and clinical case reports were included, and the PubMed, Scielo, SCOPUS, and Web of Science databases were extracted. Information was published from 2020 to 1 June 2022, and we included 26 manuscripts: 9 for pulmonary, 6 for cardiac, 2 for renal, 8 for neurological and psychiatric, and 6 for cutaneous sequelae. Studies showed that the most common sequelae were those linked to the lungs, followed by skin, cutaneous, and psychiatric alterations. Women reported a higher incidence of the sequelae, as well as those with comorbidities and more severe COVID-19 history. The COVID-19 pandemic has not only caused death and disease since its appearance, but it has also sickened millions of people around the globe who potentially suffer from serious illnesses that will continue to add to the list of health problems, and further burden healthcare systems around the world.

715

MS226

Simon B. Larsson, Gustaf Stukát von Feilitzen, Maria E. Andersson, Per Sikora, Magnus Lindh, Rickard Nordén, Staffan Nilsson & Robert Sigström

Self-reported symptom severity, general health, and impairment in post-acute phases of COVID-19: retrospective cohort study of Swedish public employees

https://doi.org/10.1038/s41598-022-24307-1

Published

17-Nov-22

Study

https://www.nature.com/articles/s41598-022-24307-1

This study aimed to examine current symptom severity and general health in a sample of primarily non-hospitalized persons with polymerase chain reaction (PCR) confirmed COVID-19 in comparison to PCR negative controls. During the first quarter of 2021, we conducted an online survey among public employees in West Sweden, with a valid COVID-19 test result. The survey assessed past-month severity of 28 symptoms and signs, self-rated health, the WHO Disability Assessment Schedule (WHODAS) 2.0 and illness severity at the time of test. We linked participants’ responses to their SARS-CoV-2 PCR tests results. We compared COVID-19 positive and negative participants using univariable and multivariable regression analyses. Out of 56,221 invited, 14,222 (25.3%) responded, with a response rate of 50% among SARS-CoV-2 positive individuals. Analysis included 10,194 participants (86.4% women, mean age 45 years) who tested positive 4–12 weeks (N = 1425; subacute) and > 12 weeks (N = 1584; postcovid) prior to the survey, and 7185 PCR negative participants who did not believe that they had had COVID-19. Symptoms were highly prevalent in all groups, with worst symptoms in subacute phase participants, followed by postcovid phase and PCR negative participants. The most specific symptom for COVID-19 was loss of smell or taste. Both WHODAS 2.0 score and self-rated health were worst in subacute participants, and modestly worse in postcovid participants than in negative controls. Female gender, older age and acute illness severity had larger effects on self-rated health and WHODAS 2.0 score in PCR positive participants than in PCR negative. Studies with longer follow-up are needed to determine the long-term improvement after COVID-19.

716

MS227

Amélia Déguilhem 1 Author Orcid Image ; Joelle Malaab 1 Author Orcid Image ; Manissa Talmatkadi 1 Author Orcid Image ; Simon Renner 1 Author Orcid Image ; Pierre Foulquié 1 Author Orcid Image ; Guy Fagherazzi 2 Author Orcid Image ; Paul Loussikian 1 Author Orcid Image ; Tom Marty 1 Author Orcid Image ; Adel Mebarki 1 Author Orcid Image ; Nathalie Texier 1 Author Orcid Image ; Stephane Schuck 1 Author Orcid Image

Identifying Profiles and Symptoms of Patients With Long COVID in France: Data Mining Infodemiology Study Based on Social Media

https://doi.org/10.2196/39849

Published

Study

https://infodemiology.jmir.org/2022/2/e39849

Background:
Long COVID—a condition with persistent symptoms post COVID-19 infection—is the first illness arising from social media. In France, the French hashtag #ApresJ20 described symptoms persisting longer than 20 days after contracting COVID-19. Faced with a lack of recognition from medical and official entities, patients formed communities on social media and described their symptoms as long-lasting, fluctuating, and multisystemic. While many studies on long COVID relied on traditional research methods with lengthy processes, social media offers a foundation for large-scale studies with a fast-flowing outburst of data.
Objective:
We aimed to identify and analyze Long Haulers’ main reported symptoms, symptom co-occurrences, topics of discussion, difficulties encountered, and patient profiles.
Methods:
Data were extracted based on a list of pertinent keywords from public sites (eg, Twitter) and health-related forums (eg, Doctissimo). Reported symptoms were identified via the MedDRA dictionary, displayed per the volume of posts mentioning them, and aggregated at the user level. Associations were assessed by computing co-occurrences in users’ messages, as pairs of preferred terms. Discussion topics were analyzed using the Biterm Topic Modeling; difficulties and unmet needs were explored manually. To identify patient profiles in relation to their symptoms, each preferred term’s total was used to create user-level hierarchal clusters.
Results:
Between January 1, 2020, and August 10, 2021, overall, 15,364 messages were identified as originating from 6494 patients of long COVID or their caregivers. Our analyses revealed 3 major symptom co-occurrences: asthenia-dyspnea (102/289, 35.3%), asthenia-anxiety (65/289, 22.5%), and asthenia-headaches (50/289, 17.3%). The main reported difficulties were symptom management (150/424, 35.4% of messages), psychological impact (64/424,15.1%), significant pain (51/424, 12.0%), deterioration in general well-being (52/424, 12.3%), and impact on daily and professional life (40/424, 9.4% and 34/424, 8.0% of messages, respectively). We identified 3 profiles of patients in relation to their symptoms: profile A (n=406 patients) reported exclusively an asthenia symptom; profile B (n=129) expressed anxiety (n=129, 100%), asthenia (n=28, 21.7%), dyspnea (n=15, 11.6%), and ageusia (n=3, 2.3%); and profile C (n=141) described dyspnea (n=141, 100%), and asthenia (n=45, 31.9%). Approximately 49.1% of users (79/161) continued expressing symptoms after more than 3 months post infection, and 20.5% (33/161) after 1 year.
Conclusions:
Long COVID is a lingering condition that affects people worldwide, physically and psychologically. It impacts Long Haulers’ quality of life, everyday tasks, and professional activities. Social media played an undeniable role in raising and delivering Long Haulers’ voices and can potentially rapidly provide large volumes of valuable patient-reported information. Since long COVID was a self-titled condition by patients themselves via social media, it is imperative to continuously include their perspectives in related research. Our results can help design patient-centric instruments to be further used in clinical practice to better capture meaningful dimensions of long COVID.

717

MS228

IvanVargasaAlexandriaMuenchbMichael A.GrandnercMichael R.IrwindeMichael L.Perlisb

Insomnia symptoms predict longer COVID-19 symptom duration

https://doi.org/10.1016/j.sleep.2022.11.019

Published

23-Nov-22

Study

https://www.sciencedirect.com/science/article/pii/S1389945722012278

Highlights
•The prevalence of clinical insomnia remained high during the COVID-19 pandemic (>13%).
•Insomnia was not related to contracting COVID-19 or experiencing more severe symptoms.
•Insomnia was associated with a prolonged recovery from COVID-19 (i.e., more days sick).
Abstract
Objective
/Background: The goal of the present study was to assess the prevalence and incidence of insomnia in the United States during the COVID-19 pandemic, and whether, among those that contracted COVID-19, insomnia predicted worse outcomes (e.g., symptoms of greater frequency, duration, or severity).
Methods
A nationwide sample of 2980 adults living in the United States were surveyed online at two points during the COVID-19 pandemic (T1 = April–June 2020; T2 = January–March 2021). Insomnia symptoms were assessed at both time points using the Insomnia Severity Index (ISI). The T2 survey also asked questions regarding COVID-19 testing and symptoms.
Results
The prevalence of insomnia (defined as ISI ≥15) was 15% at T1 and 13% at T2. The incidence rate of insomnia (i.e., new cases from T1 to T2) was 5.6%. Participants with insomnia were not more likely to contract COVID-19 relative to those participants without insomnia. Among those participants in our sample that contracted the virus during the study interval (n = 149), there were no significant group differences in COVID-19 symptom outcomes, with one exception, participants with insomnia were more likely to report a longer symptom duration (insomnia = 24.8 sick days, no insomnia = 16.1 sick days).
Conclusions
The present study suggests the prevalence of insomnia in the U.S. population remained high during the COVID-19 pandemic. The data also support that insomnia may be related to experiencing more chronic COVID-19 symptoms. These findings have more general implications for the role of sleep and insomnia on immune functioning.

718

MS229

Terence Stephenson, Snehal M. Pinto Pereira, Manjula D. Nugawela, Kelsey McOwat, Ruth Simmons, Trudie Chalder, Tamsin Ford, Isobel Heyman, Olivia V Swann, Lana Fox-Smith, Natalia K Rojas, Emma Dalrymple, Shamez N. Ladhani, Roz Shafran

Long COVID - Six months of prospective follow-up of changes in symptom profiles of non-hospitalised children and young people after SARS-CoV-2 testing: a national matched cohort study

Published

18-Nov-22

Study

https://kclpure.kcl.ac.uk/portal/en/publications/long-covid--six-months-of-prospective-followup-of-changes-in-symptom-profiles-of-nonhospitalised-children-and-young-people-after-sarscov2-testing(a718e8cb-6970-44f1-befb-dd1fb32385df).html

Background: Little is known about the prevalence and natural trajectory of post-COVID symptoms in young people, despite very high numbers of young people having acute COVID. To date, there has been no prospective follow-up to establish the pattern of symptoms over a 6-month time period.

Methods: A non-hospitalised, national sample of 3,395 (1,737 SARS-COV-2 Negative;1,658 SARS65 COV-2 Positive at baseline) children and young people (CYP) aged 11-17 completed questionnaires 3 and 6 months after PCR-confirmed SARS-CoV-2 infection between January and March 2021 and were compared with age, sex and geographically-matched test-negative CYP.

Results: Three months after a positive SARS-CoV-2 PCR test, 11 of the 21 most common symptoms reported by >10% of CYP had reduced. There was a further decline at 6 months. By 3 and 6 months the prevalence of chills, fever, myalgia, cough and sore throat of CYP who tested positive for SARS71 CoV-2 reduced from 10-25% at testing to
Conclusions: In CYP, the prevalence of specific symptoms reported at time of PCR-testing declined with time. Similar patterns were observed among test-positives and test-negatives and new symptoms were reported six months post-test for both groups suggesting that symptoms are unlikely to exclusively be a specific consequence of SARS-COV-2 infection. Many CYP experienced unwanted symptoms that warrant investigation and potential intervention.

719

MS230

Anna Tisler ,Oliver Stirrup,Heti Pisarev,Ruth Kalda,Tatjana Meister,Kadri Suija,Raivo Kolde,Marko Piirsoo,Anneli Uusküla

Post-acute sequelae of COVID-19 among hospitalized patients in Estonia: Nationwide matched cohort study

https://doi.org/10.1371/journal.pone.0278057

Published

23-Nov-22

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0278057

Background
Post-acute COVID-19 sequelae refers to a variety of health complications involving different organ systems that have been described among individuals after acute phase of illness. Data from unselected population groups with long-time follow up is needed to comprehensively describe the full spectrum of post-acute COVID-19 complications.
Methods
In this retrospective nationwide cohort study, we used data obtained from electronic health record database. Our primary cohort were adults hospitalized with confirmed COVID-19 and matched (age, sex, Charlson Comorbidity Index) unaffected controls from general population. Individuals included from February 2020 until March 2021 were followed up for 12 months. We estimated risks of all-cause mortality, readmission and incidence of 16 clinical sequelae after acute COVID-19 phase. Using a frailty Cox model, we compared incidences of outcomes in two cohorts.
Results
The cohort comprised 3949 patients older than 18 years who were alive 30 days after COVID-19 hospital admission and 15511 controls. Among cases 40.3% developed at least one incident clinical sequelae after the acute phase of SARS-CoV-2 infection, which was two times higher than in general population group. We report substantially higher risk of all-cause mortality (adjusted hazard ratio (aHR) = 2.57 (95%CI 2.23–2.96) and hospital readmission aHR = 1.73 (95%CI 1.58–1.90) among hospitalized COVID-19 patients. We found that the risks for new clinical sequalae were significantly higher in COVID-19 patients than their controls, especially for dementia aHR = 4.50 (95% CI 2.35–8.64), chronic lower respiratory disease aHR = 4.39 (95% CI 3.09–6.22), liver disease aHR 4.20 (95% CI 2.01–8.77) and other (than ischemic) forms of heart diseases aHR = 3.39 (95%CI 2.58–4.44).
Conclusion
Our results provide evidence that the post-acute COVID-19 morbidity within the first year after COVID-19 hospitalization is substantial. Risks of all-cause mortality, hospitalisation and majority of clinical sequelae were significantly higher in hospitalized COVID-19 patients than in general population controls and warrant targeted prevention efforts.

720

MS231

Nike Walter 1,2,*ORCID,Markus Rupp 2ORCID,Siegmund Lang 2ORCID,Beate Leinberger 1,Volker Alt 2,Thilo Hinterberger 1 andThomas Loew 1

A Comprehensive Report of German Nationwide Inpatient Data on the Post-COVID-19 Syndrome Including Annual Direct Healthcare Costs

https://doi.org/10.3390/v14122600

Published

22-Nov-22

Study

https://www.mdpi.com/1999-4915/14/12/2600

Background: The aim of this study was to provide a comprehensive overview of German nationwide data including (i) the number of hospitalized Post-COVID Syndrome (PCS) cases including in-hospital mortality rates and intensive care unit treatments, (ii) the main common concomitant diagnoses associated with PCS, (iii) the most frequently performed treatment procedures, and (iv) the annual direct healthcare costs. Methods: The incidence was calculated based on annual ICD-10 diagnosis codes “U09.9!, Post-COVID-19 condition”. Data on concomitant diagnoses, treatment procedures, treatment in an intensive care unit (ICU), in-hospital mortality, the proportion of G-DRGs, and cumulative costs were assessed based on the Institute for the Hospital Remuneration System (InEK) data for 2019. Results: A total of 29,808 PCS inpatients could be identified yielding a prevalence of 5.5%. In total, 1330 (4.5%) in-hospital deaths were recorded, and 5140 (17.2%) patients required ICU treatment. The majority of patients (18.6%) were aged 65–74 years. The most common concomitant diagnoses included pneumonia, critical illness polyneuropathy, dyspnea, chronic fatigue syndrome, and pulmonary embolisms. The most frequently performed procedures were computed tomography of the thorax with contrast medium, whole-body plethysmography, and the monitoring of respiration, heart, and circulation. The cost per case of the G-DRG codes that were analyzed ranged from € 620 ± 377 (E64D, Respiratory insufficiency, one day of occupancy) to € 113,801 ± 27,939 (A06B, Ventilation > 1799 h with complex OR procedure). Total cumulative direct healthcare costs of € 136,608,719 were calculated, resulting in mean costs of € 4583 per case. Conclusion: Post-COVID Syndrome is of major public health importance with substantial financial implications. The present article can support stakeholders in health care systems to foresee future needs and adapt their resource management. Consensus diagnostic criteria and rehabilitation guidelines are highly warranted.

721

MS232

Mario GennaroMazzaabcMariagraziaPalladiniabcGaiaVillaaElenaAgnolettoaYasmineHarringtonabcBenedettaVaiabFrancescoBenedettiab

Prevalence of depression in SARS-CoV-2 infected patients: An umbrella review of meta-analyses

https://doi.org/10.1016/j.genhosppsych.2022.12.002

Published

7-Dec-22

Umbrella review of meta-analyses

https://www.sciencedirect.com/science/article/pii/S0163834322001438

Objective
The COVID-19 pandemic is still spreading worldwide two years after its outbreak. Depression has been reported in around 30% of SARS-CoV-2 infected patients. We aim to synthesize the available meta-analytical evidence in an umbrella review exploring the prevalence of depression during and after SARS-CoV-2 infection.
Methods
First, we performed a narrative umbrella review including only meta-analyses providing a quantitative summary of the prevalence of depression during or after SARS-CoV-2 infection. Then we extracted the prevalence and sample size from the original studies included in each meta-analysis, and after removing duplicate studies, we performed a random-effects model meta-analysis based on single original study estimates. Heterogeneity, publication bias, leave-one-out sensitivity, and subgroup analyses were performed.
Results
14 meta-analyses were included in the umbrella review. The prevalence of depression ranged from 12% to 55% in the presence of high heterogeneity. The meta-analysis based on 85 original studies derived from the included 14 meta-analyses showed a pooled prevalence of depression of 31% (95% CI:25–38%) in the presence of high and significant heterogeneity (Q = 8988; p < 10−6; I2 = 99%) and publication bias (p < 0.001).
Conclusion
The burden of post-COVID depression substantially exceeds the pre-pandemic prevalence. Health care services for COVID-19 survivors should monitor and treat emergent depression, reducing its potential detrimental long-term effects.

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Chen Chen, Spencer R Haupert, Lauren Zimmermann, Xu Shi, Lars G Fritsche, Bhramar Mukherjee

Global Prevalence of Post-Coronavirus Disease 2019 (COVID-19) Condition or Long COVID: A Meta-Analysis and Systematic Review

https://doi.org/10.1093/infdis/jiac136

Published

16-Apr-22

Meta-Analysis and Systematic Review

https://academic.oup.com/jid/article/226/9/1593/6569364?login=false

Background
This study aims to examine the worldwide prevalence of post-coronavirus disease 2019 (COVID-19) condition, through a systematic review and meta-analysis.
Methods
PubMed, Embase, and iSearch were searched on July 5, 2021 with verification extending to March 13, 2022. Using a random-effects framework with DerSimonian-Laird estimator, we meta-analyzed post-COVID-19 condition prevalence at 28+ days from infection.
Results
Fifty studies were included, and 41 were meta-analyzed. Global estimated pooled prevalence of post-COVID-19 condition was 0.43 (95% confidence interval [CI], .39–.46). Hospitalized and nonhospitalized patients had estimates of 0.54 (95% CI, .44–.63) and 0.34 (95% CI, .25–.46), respectively. Regional prevalence estimates were Asia (0.51; 95% CI, .37–.65), Europe (0.44; 95% CI, .32–.56), and United States of America (0.31; 95% CI, .21–.43). Global prevalence for 30, 60, 90, and 120 days after infection were estimated to be 0.37 (95% CI, .26–.49), 0.25 (95% CI, .15–.38), 0.32 (95% CI, .14–.57), and 0.49 (95% CI, .40–.59), respectively. Fatigue was the most common symptom reported with a prevalence of 0.23 (95% CI, .17–.30), followed by memory problems (0.14; 95% CI, .10–.19).
Conclusions
This study finds post-COVID-19 condition prevalence is substantial; the health effects of COVID-19 seem to be prolonged and can exert stress on the healthcare system.

723

MS234

Hao Zhang, Chengxi Zang, Zhenxing Xu, Yongkang Zhang, Jie Xu, Jiang Bian, Dmitry Morozyuk, Dhruv Khullar, Yiye Zhang, Anna S. Nordvig, Edward J. Schenck, Elizabeth A. Shenkman, Russell L. Rothman, Jason P. Block, Kristin Lyman, Mark G. Weiner, Thomas W. Carton, Fei Wang & Rainu Kaushal

Data-driven identification of post-acute SARS-CoV-2 infection subphenotypes

https://doi.org/10.1038/s41591-022-02116-3

Published

1-Dec-22

Study

https://www.nature.com/articles/s41591-022-02116-3

The post-acute sequelae of SARS-CoV-2 infection (PASC) refers to a broad spectrum of symptoms and signs that are persistent, exacerbated or newly incident in the period after acute SARS-CoV-2 infection. Most studies have examined these conditions individually without providing evidence on co-occurring conditions. In this study, we leveraged the electronic health record data of two large cohorts, INSIGHT and OneFlorida+, from the national Patient-Centered Clinical Research Network. We created a development cohort from INSIGHT and a validation cohort from OneFlorida+ including 20,881 and 13,724 patients, respectively, who were SARS-CoV-2 infected, and we investigated their newly incident diagnoses 30–180 days after a documented SARS-CoV-2 infection. Through machine learning analysis of over 137 symptoms and conditions, we identified four reproducible PASC subphenotypes, dominated by cardiac and renal (including 33.75% and 25.43% of the patients in the development and validation cohorts); respiratory, sleep and anxiety (32.75% and 38.48%); musculoskeletal and nervous system (23.37% and 23.35%); and digestive and respiratory system (10.14% and 12.74%) sequelae. These subphenotypes were associated with distinct patient demographics, underlying conditions before SARS-CoV-2 infection and acute infection phase severity. Our study provides insights into the heterogeneity of PASC and may inform stratified decision-making in the management of PASC conditions.

724

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Reinhold Kerbl

Wie häufig ist Long-COVID wirklich?
How frequent is long COVID really?

https://doi.org/10.1007/s00112-022-01660-z

Published

1-Dec-22

Study

https://link.springer.com/article/10.1007/s00112-022-01660-z

Originalpublikation
Global Burden of Disease Long COVID Collaborators, Wulf Hanson S, Abbafati C et al (2022) Estimated global proportions of individuals with persistent fatigue, cognitive, and respiratory symptom clusters following symptomatic COVID-19 in 2020 and 2021. JAMA 328(16):1604–1615. https://doi.org/10.1001/jama.2022.18931
Hintergrund.
Die Prävalenz von Long-COVID wird in verschiedenen Studien höchst unterschiedlich angegeben. Sie ist u. a. abhängig von der angewandten Definition, der Art der Studie, der untersuchten Fallzahl, aber auch der jeweiligen Infektionswelle (z. B. Delta vs. Omikron). Insbesondere in Fallserien ohne Kontrollgruppe werden teilweise sehr hohe Prävalenzzahlen berichtet; viele Studien berücksichtigen in ihrer Analyse auch das Vorliegen präexistenter Symptome nicht adäquat. Schließlich werden bis zu 300 verschiedene Symptome mit Long-COVID assoziiert und auch dadurch sehr hohe Prävalenzzahlen erzielt. Eine nunmehr im Journal of the American Medical Association (JAMA) publizierte Modellierungsstudie (Bayes-Metaregression) hat nun versucht, unter Anwendung der WHO-Definition und einheitlicher Kriterien die reale Prävalenz für Long-COVID zu erheben.
Methodik.
In die Metaregression eingeschlossen wurden 54 Studien aus 22 Ländern, die Gesamtzahl der inkludierten Patienten betrug 1,2 Mio. Für die Einstufung als Long-COVID wurde die WHO-Definition angewandt, die eine Symptomdauer von zumindest 3 Monaten voraussetzt. Berücksichtigt wurden nur Fälle mit vormals symptomatischem Verlauf, asymptomatische SARS-CoV-2-Infektionen wurden nicht eingeschlossen. Weiters wurden nur jene Fälle als „Long-COVID“ eingestuft, die zumindest einen der folgenden 3 Symptomenkomplexe zeigten: andauernde Müdigkeit mit Körperschmerz und Stimmungsschwankungen, kognitive Beeinträchtigung oder anhaltende respiratorische Probleme.
Ergebnisse.
Insgesamt erfüllten 6,2 % aller Patienten die Kriterien für Long-COVID. Vorherrschende Symptome waren respiratorische Probleme (bei 60,4 %), gefolgt von anhaltender Müdigkeit (51 %) und kognitiven Defiziten (35,4 %). Die Prävalenz war bei Personen nach dem 20. Lebensjahr signifikant höher als bei Personen unter 20 Jahren (Frauen 10,6 % vs. 5,4 %, Männer 5,4 % vs. 2,2 %). Die mittlere Symptomdauer betrug bei im Rahmen der Akuterkrankung hospitalisierten Patienten 9 Monate (Konfidenzintervall 7–12), bei vormals nichthospitalisierten Patienten 4 Monate (Konfidenzintervall 3,6–4,6).

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MS236

Krishna Mohan Surapaneni 1,2,3,*ORCID,Manmohan Singhal 1,*ORCID,Sofia Rani Saggu 4ORCID,Ashruti Bhatt 4,Priya Shunmathy 4 andAshish Joshi 2,5,*

A Scoping Review on Long COVID-19: Physiological and Psychological Symptoms Post-Acute, Long-Post and Persistent Post COVID-19

https://doi.org/10.3390/healthcare10122418

Published

30-Nov-22

Review

https://www.mdpi.com/2227-9032/10/12/2418

Background: The identification of persistent symptoms of chronic/long COVID-19 is crucial in understanding the management of long haulers of post COVID-19. Methods: Pub Med (Medline) database was scoped for original articles based on a search strategy related to the objectives. The selected articles post-screening were analyzed for variables relating to chronic/long COVID-19. Results were analyzed using descriptive statistics. Results: A total of 33 studies were reviewed. A total of 60% of the studies were observational studies and most of them were from high income countries. Almost half of the studies were in phase 3 of post-COVID-19, i.e., symptoms lasting >24 weeks. Among the physiological and psychological symptoms studied, fatigue, dyspnea, cough, headache, memory loss, depression, brain fog and lack of concentration were found to be the most frequently reported symptoms. Excessive sleep, constipation and neuropathic pain were among the least reported symptoms. Prior hospitalization, the female gender was found to be a risk factor. Limitations were reported by all studies. Conclusions: The major physiological and psychological symptoms of long COVID-19 have been explained with risk factors and its impact on patients’ lifestyles. The findings of this review hope to facilitate clinicians to draw conclusions to manage the long-term effects of post/chronic COVID-19.

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MS237

Lauren E. Wisk, PhD1,2; Michael A. Gottlieb, MD3; Erica S. Spatz, MD, MHS4,5; Huihui Yu, PhD4,5; Ralph C. Wang, MD, MAS6; Benjamin H. Slovis, MD, MA7; Sharon Saydah, PhD8; Ian D. Plumb, MBBS, MSc8; Kelli N. O’Laughlin, MD, MPH9,10; Juan Carlos C. Montoy, MD, PhD6; Samuel A. McDonald, MD, MS11,12; Zhenqiu Lin, PhD4,5; Jin-Mann S. Lin, PhD13; Katherine Koo, MS-HSM14; Ahamed H. Idris, MD11,15; Ryan M. Huebinger, MD16; Mandy J. Hill, DrPH, MPH16; Nicole L. Gentile, MD, PhD17,18; Anna Marie Chang, MD, MSCE7; Jill Anderson, BSN, RN19; Bala Hota, MD, MPH20; Arjun K. Venkatesh, MD, MBA, MHS5,21; Robert A. Weinstein, MD22,23; Joann G. Elmore, MD, MPH1,2; Graham Nichol, MD, MPH9,19; for the INSPIRE Group

Association of Initial SARS-CoV-2 Test Positivity With Patient-Reported Well-being 3 Months After a Symptomatic Illness

http://jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2022.44486

Published

1-Dec-22

Study

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2799116

Key Points
Question How do patient-reported physical, mental, and social well-being compare at 3 months after symptomatic illness among those who tested positive vs negative for SARS-CoV-2 infection?
Findings In this cohort study of 1000 US adults with symptomatic illness, poor well-being scores at follow-up were common in both those who tested positive and negative for SARS-CoV-2 infection. Despite some improvements over time, 39.6% of COVID-19–positive and 53.5% of COVID-19–negative patients reported residual symptoms.
Meaning These findings emphasize the importance of including a concurrent control group when studying sequelae of COVID-19 illness.
Abstract
Importance Long-term sequelae after symptomatic SARS-CoV-2 infection may impact well-being, yet existing data primarily focus on discrete symptoms and/or health care use.
Objective To compare patient-reported outcomes of physical, mental, and social well-being among adults with symptomatic illness who received a positive vs negative test result for SARS-CoV-2 infection.
Design, Setting, and Participants This cohort study was a planned interim analysis of an ongoing multicenter prospective longitudinal registry study (the Innovative Support for Patients With SARS-CoV-2 Infections Registry [INSPIRE]). Participants were enrolled from December 11, 2020, to September 10, 2021, and comprised adults (aged ≥18 years) with acute symptoms suggestive of SARS-CoV-2 infection at the time of receipt of a SARS-CoV-2 test approved by the US Food and Drug Administration. The analysis included the first 1000 participants who completed baseline and 3-month follow-up surveys consisting of questions from the 29-item Patient-Reported Outcomes Measurement Information System (PROMIS-29; 7 subscales, including physical function, anxiety, depression, fatigue, social participation, sleep disturbance, and pain interference) and the PROMIS Short Form–Cognitive Function 8a scale, for which population-normed T scores were reported.
Exposures SARS-CoV-2 status (positive or negative test result) at enrollment.
Main Outcomes and Measures Mean PROMIS scores for participants with positive COVID-19 tests vs negative COVID-19 tests were compared descriptively and using multivariable regression analysis.
Results Among 1000 participants, 722 (72.2%) received a positive COVID-19 result and 278 (27.8%) received a negative result; 406 of 998 participants (40.7%) were aged 18 to 34 years, 644 of 972 (66.3%) were female, 833 of 984 (84.7%) were non-Hispanic, and 685 of 974 (70.3%) were White. A total of 282 of 712 participants (39.6%) in the COVID-19–positive group and 147 of 275 participants (53.5%) in the COVID-19–negative group reported persistently poor physical, mental, or social well-being at 3-month follow-up. After adjustment, improvements in well-being were statistically and clinically greater for participants in the COVID-19–positive group vs the COVID-19–negative group only for social participation (β = 3.32; 95% CI, 1.84-4.80; P < .001); changes in other well-being domains were not clinically different between groups. Improvements in well-being in the COVID-19–positive group were concentrated among participants aged 18 to 34 years (eg, social participation: β = 3.90; 95% CI, 1.75-6.05; P < .001) and those who presented for COVID-19 testing in an ambulatory setting (eg, social participation: β = 4.16; 95% CI, 2.12-6.20; P < .001).
Conclusions and Relevance In this study, participants in both the COVID-19–positive and COVID-19–negative groups reported persistently poor physical, mental, or social well-being at 3-month follow-up. Although some individuals had clinically meaningful improvements over time, many reported moderate to severe impairments in well-being 3 months later. These results highlight the importance of including a control group of participants with negative COVID-19 results for comparison when examining the sequelae of COVID-19.

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MS238

Kokolevich, Zoe Mass; Crowe, Melissa; Mendez, Diana; Biros, Erik; Reznik, Jacqueline Elise

Most Common Long COVID Physical Symptoms in Working Age Adults Who Experienced Mild COVID-19 Infection: A Scoping Review

https://doi.org/10.3390/healthcare10122577

Published

Systematic Review

https://www.mdpi.com/2227-9032/10/12/2577

Background: One-third of patients who recover from COVID-19 present with long COVID. Their symptoms are broad, affecting their physical functioning and, ultimately, their quality of life. Many of those individuals who develop long COVID, possibly from a mild COVID-19 infection, are in the 18–65 age group. This prolongation of malaise directly influences national workforce economies. Objectives: To summarise the commonly reported physical symptoms of long COVID in order to inform potential adjustments in healthcare for the employable population. Methods: The Embase, CINAHL, Medline, SCOPUS, and WHO COVID-19 databases were searched. The study selection process was based on the PRISMA guidelines. The extracted data were synthesised and presented narratively. Results: 7403 studies were accessed, comprising 60 cohort studies and 10 case series/studies, representing 289,213 patients who met our criteria. The most frequently reported physical symptoms were fatigue (92%), shortness of breath (SOB) (81.8%), muscle pain (43.6%), and joint pain (34.5%). Conclusions: The range of reported physical symptoms was broad and varied; the main ones being fatigue, breathlessness/SOB, and pain. Similarities observed between long COVID and other post-acute infection syndromes may help formulate protocols to manage and promote recovery for long COVID patients. Inconsistencies were evident, particularly with a lack of adherence to the standardised definitions of long COVID.

728

MS239

Epsi, Nusrat J; Lindholm, David A; Ganesan, Anuradha; Lalani, Tahaniyat; Smith, Alfred G; Mody, Rupal; Jones, Milissa; Bazan, Samantha; Colombo, Rhonda E; Colombo, Christopher; Ewers, Evan C; Larson, Derek; Berjohn, Catherine M; Maves, Ryan C; Fries, Anthony C; Scher, Ann; Byrne, Celia; Rusiecki, Jennifer; Sanchez Edwards, Margaret; Rozman, Julia S; Mende, Katrin; Simons, Mark P; Tribble, David R; Agan, Brian; Burgess, Timothy; Pollett, Simon; Richard, Stephanie A

1066. Precision phenotyping of “long COVID” through machine learning

https://doi.org/10.1093/ofid/ofac492.907

Published

Study

https://doi.org/10.1093/ofid/ofac492.907

Characterizing, diagnosing, and caring for “long COVID” patients has proven to be challenging due to heterogenous symptoms and broad definitions of these post-acute sequelae. Here, we take a machine learning approach to identify discrete clusters of long COVID symptoms which may define specific long COVID phenotypes. Figure 1: (A) Principal component analysis followed by K-means clustering identified three groups of participants. (B) Heatmap depicting three distinct clusters (high values are in red and low value are in blue); Cluster 1 exhibits sensory symptoms (e.g., loss of smell and/or taste), Cluster 2 exhibits fatigue and difficulty thinking (e.g., changes in ability to think) symptoms, and Cluster 3 exhibits difficulty breathing and exercise intolerance symptoms. (C) Clinical and demographic characteristics of 97 military health system beneficiaries by identified clustersThe Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (EPICC) study is a longitudinal COVID-19 cohort study with data and biospecimens collected from 10 military treatment facilities and online recruitment. Demographic and clinical characteristics were collected using case report forms and surveys completed at enrollment and at 1, 3, 6, 9, and 12 months. For this analysis, we identified those who reported any moderate to severe persistent symptoms on surveys collected 6-months post-COVID-19 symptom onset. Using the survey responses, we applied principal component analysis (PCA) followed by unsupervised machine learning clustering algorithm K-means to identify groups with distinct clusters of symptoms.Of 1299 subjects with 6-month survey responses, 97 (7.47%) reported moderate to severe persistent symptoms. Among these subjects, three clusters were identified using PCA (Figure 1A). Cluster 1 is characterized by sensory symptoms (loss of taste and/or smell), Cluster 2 by fatigue and difficulty thinking, and Cluster 3 by difficulty breathing and exercise intolerance (Figure 1B). More than half of these subjects (57%) were female, 64% were 18-44 years old, and 64% had no comorbidities at enrollment (Figure 1C). Those in the sensory symptom cluster were all outpatients at the time of initial COVID-19 presentation (p < 0.01). The difficulty breathing and exercise intolerance symptom-clusters had a higher proportion of older participants (Age group ≥ 45-64) with more comorbidities (CCI ≥ 1-2).We identified three distinct ‘long COVID’ phenotypes among those with moderate to severe COVID-19 symptoms at 6-months post-symptom onset. With further validation and characterization, this framework may allow more precise classification of long COVID cases, and potentially improve the diagnosis, prognosis, and treatment of post- infectious sequelae.Ryan C. Maves, MD, AiCuris: Grant/Research Support|Sound Pharmaceuticals: Grant/Research Support|Trauma Insights, LLC: Advisor/Consultant Julia S. Rozman, n/a, Astra Zeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response Mark P. Simons, PhD, AstraZeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response David R. Tribble, DrPH, AstraZeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response Timothy Burgess, MD, MPH, AstraZeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response Simon Pollett, MBBS, Astra Zeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response.

729

MS240

Kenny, Grace; McCann, Kathleen; O'Brien, Conor; Savinelli, Stefano; O'Broin, Cathal; Tinago, Willard; Yousif, Obada; Lambert, John S; Feeney, Eoin; de Barra, Eoghan; Sadlier, Corinna; Landay, Alan; Doran, Peter; Mallon, Patrick W G

77. Demonstration of stable clusters of symptoms in long COVID

https://doi.org/10.1093/ofid/ofac492.002

Published

Study

https://doi.org/10.1093/ofid/ofac492.002

Long COVID is a heterogenous condition. We previously demonstrated distinct phenotypes of long COVID, but the impact of later waves caused by SARS-CoV-2 variants on long COVID presentations has not been described.Table 1Dates and variants of COVID-19 waves.We selected individuals with ongoing symptoms > 4 weeks from PCR-confirmed COVID-19 in a multicentre, prospective cohort study. We used multiple correspondence analysis and hierarchical clustering on self-reported symptoms to identify symptom clusters, in individuals recruited during two periods; cohort 1 from March 2020 to April 2021, and cohort 2 from April 2021 to March 2022. We explored differences in symptoms by mapping acute infection to one of four COVID-19 waves in Ireland (table 1) as well as vaccination status, and used Chi2 test to compare symptoms frequencies.Table 2Patient demographics and differences between the two cohorts.Figure 1- Heatmaps demonstrating the symptom clusters in the two cohortsEach line represents an individual, red represents the presence of a symptom, blue represents the absence of a symptom.Demographics are shown in Table 2. Cluster analysis of each cohort demonstrated 3 distinct clusters in both cohorts, which shared similar clinical characteristics; a musculoskeletal/pain symptom cluster, a cardiorespiratory cluster and a third less symptomatic cluster (Figure 1).While symptoms within clusters were similar across both periods, in the cardiorespiratory cluster, the frequency of palpitations decreased (56% vs 16%) and cough increased (14% vs 45%) between reporting periods (both P< 0.01). Furthermore, a greater proportion of palpitations were reported in those with COVID-19 from waves 1 and 2 (35% and 28%) compared to 3 and 4 (both 12%, P< 0.001), and a greater proportion of chest pain in waves 1, 2 and 4 compared to wave 3. There were no differences in other symptoms (Table 3). Additionally there were significantly less palpitations reported in those vaccinated at the time of review (17% vs 31% P=0.002), but not chest pain (30% vs 39% P=0.13). In multivariate analysis, infection in wave 3 and 4 but not vaccination status remained significantly associated with lower reported palpitations (OR (95% CI) 0.28 (0.13–0.97) and 0.5 (0.06–0.87) for waves 3 and 4, both P< 0.05), and wave 3 infection remained independently associated with lower reported chest pain (OR 0.3 (0.25–0.7)).Table 3Proportion of individuals reporting each long COVID symptom depending on timing of acute illness.Three symptom clusters define long COVID across the two cohorts, but characteristics of the cardiorespiratory phenotype have evolved over time with evolution of SARS-CoV-2 variants.All Authors: No reported disclosures.

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MS241

Logue, Jennifer; Franko, Nicholas M; Kemp, Megan M; McCulloch, Denise J; Chow, Eric J; Chu, Helen Y

284. Post-Acute Sequelae of COVID-19 Two Years After Acute Infection

https://doi.org/10.1093/ofid/ofac492.362

Published

Study

https://doi.org/10.1093/ofid/ofac492.362

The post-acute sequelae of COVID-19 (PASC) includes a constellation of debilitating symptoms after SARS-CoV-2 infection. Much remains unknown about the long-term health burden of COVID-19. We describe the symptom course and quality of life of adults up to 2 years after mild acute COVID-19.Adults within 30 days of laboratory-confirmed acute COVID-19 were enrolled as cases from January – September 2020 and followed for 2 years. Demographic and symptom data were collected in an enrollment survey and at 6, 12 and 24 months post-infection. Surveys included vaccination status, symptom course, and quality of life assessments (Fatigue Assessment Scale (FAS) and EuroQual visual analog scale (VAS)). A cohort of SARS-CoV-2 uninfected controls was concurrently enrolled and surveyed. We used descriptive statistics to compare cases and controls and defined a p-value < 0.05 as significant.A total of 112 of 239 enrolled cases and 44 of 59 controls completed all surveys. Of the 112 cases, 105 (94%) had mild disease. In the 6, 12 and 24 month surveys, 39 (35%), 48 (43%) and 56 (50%) cases indicated at least one persistent symptom, respectively, compared to 4 (9%), 5 (11%) and 6 (14%) controls (Table 1). In all 3 surveys, fatigue and altered smell or taste were the most common post-infection symptoms among cases (Figure 1). At 2 years, 40 (36%) cases reported symptoms were improving or resolved and 30 (27%) reported symptoms continued to wax and wane. Symptoms improved and worsened for 10 and 4 cases, respectively, following a complete SARS-CoV-2 vaccination. 46% reported seeking medical attention for persistent symptoms and 34% of those employed reported symptoms negatively impacted their ability to work. When compared to controls in the 12 and 24 month surveys, cases had a significantly higher mean FAS score (p-value < 0.001 and 0.01, respectively) and significantly lower VAS score (p-value = 0.01 and < 0.001, respectively).Demographic and Clinical Characteristics of the Study Cohort a. Time since symptom onset in infected cohort and time since enrollment in healthy controlsb. Other race/ethnicity included American Indian or Alaska Native, Black or African American, Native Hawaiian or other Pacific Islander, and more than 1 race.Percentage of participants reporting symptoms at 6-, 12-, and 24-months *Symptoms associated with PASC were reported up to 2 years after infection with significant impacts on quality of life. These findings underscore the healthcare and societal burdens even after recovery from acute infection. As studies seek to identify the underlying mechanisms of PASC, prevention of acute infection remains the mainstay of COVID-19 burden mitigation.Helen Y. Chu, MD, MPH, Cepheid: Reagents|Ellume: Advisor/Consultant|Gates Ventures: Grant/Research Support|Merck: Advisor/Consultant|Pfizer: Advisor/Consultant.

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MS242

Arjun, M. C.; Singh, Arvind Kumar; Pal, Debkumar; Das, Kajal; G, Alekhya; Venkateshan, Mahalingam; Mishra, Baijayantimala; Patro, Binod Kumar; Mohapatra, Prasanta Raghab; Subba, Sonu Hangma

Characteristics and predictors of Long COVID among diagnosed cases of COVID-19

https://doi.org/10.1371/journal.pone.0278825

Published

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0278825

Background Long COVID or long-term symptoms after COVID-19 has the ability to affect health and quality of life. Knowledge about the burden and predictors could aid in their prevention and management. Most of the studies are from high-income countries and focus on severe acute COVID-19 cases. We did this study to estimate the incidence and identify the characteristics and predictors of Long COVID among our patients. Methodology We recruited adult (≥18 years) patients who were diagnosed as Reverse Transcription Polymerase Chain Reaction (RTPCR) confirmed SARS-COV-2 infection and were either hospitalized or tested on outpatient basis. Eligible participants were followed up telephonically after four weeks and six months of diagnosis of SARS-COV-2 infection to collect data on sociodemographic, clinical history, vaccination history, Cycle threshold (Ct) values during diagnosis and other variables. Characteristics of Long COVID were elicited, and multivariable logistic regression was done to find the predictors of Long COVID. Results We have analyzed 487 and 371 individual data with a median follow-up of 44 days (Inter quartile range (IQR): 39,47) and 223 days (IQR:195,251), respectively. Overall, Long COVID was reported by 29.2% (95% Confidence interval (CI): 25.3%,33.4%) and 9.4% (95% CI: 6.7%,12.9%) of participants at four weeks and six months of follow-up, respectively. Incidence of Long COVID among patients with mild/moderate disease (n = 415) was 23.4% (95% CI: 19.5%,27.7%) as compared to 62.5% (95% CI: 50.7%,73%) in severe/critical cases(n = 72) at four weeks of follow-up. At six months, the incidence among mild/moderate (n = 319) was 7.2% (95% CI:4.6%,10.6%) as compared to 23.1% (95% CI:12.5%,36.8%) in severe/critical (n = 52). The most common Long COVID symptom was fatigue. Statistically significant predictors of Long COVID at four weeks of follow-up were—Pre-existing medical conditions (Adjusted Odds ratio (aOR) = 2.00, 95% CI: 1.16,3.44), having a higher number of symptoms during acute phase of COVID-19 disease (aOR = 11.24, 95% CI: 4.00,31.51), two doses of COVID-19 vaccination (aOR = 2.32, 95% CI: 1.17,4.58), the severity of illness (aOR = 5.71, 95% CI: 3.00,10.89) and being admitted to hospital (Odds ratio (OR) = 3.89, 95% CI: 2.49,6.08). Conclusion A considerable proportion of COVID-19 cases reported Long COVID symptoms. More research is needed in Long COVID to objectively assess the symptoms and find the biological and radiological markers.

732

MS243

Kröönström, Linda Ashman; Krause, Johanna; Larsson, Simon B.; Sigström, Robert; Sunnerhagen, Katharina Stibrant

Long-term self-reported health and disability after COVID-19 in public employees

https://doi.org/10.1186/s12889-022-14820-3

Published

Study

https://doi.org/10.1186/s12889-022-14820-3

Abstract
Background
Although the symptomatology has been assessed in multiple studies among persons recovering from coronavirus disease 2019 (COVID-19), less is known regarding long-term general health and disability. We aimed to assess long-term self-reported disability in public employees after predominantly mild COVID-19 in comparison with individuals who had negative COVID-19 polymerase chain reaction (PCR) test results.

Methods
Public employees within Region Västra Götaland were offered tests to identify SARS-CoV-2 infection (n = 56,221) and were invited to complete an online survey that included the World Health Organization Disability Assessment Schedule. Questionnaires were sent out between January 26 and March 5, 2021. A total of 14,222 (25.3%) employees responded, of which 10,194 (18%) were included (women n = 8749, 85.8%). Of these, 7185 (70.5%) participants had a negative PCR test result (controls). A total of 1425 (14%) had a positive PCR result and were categorized in the sub-acute phase (4–12 weeks post COVID-19), and 1584 (15.5%) had a positive PCR test and were categorized in the post COVID-19 phase (> 12 weeks).

Results
Fifty-two percent of controls rated disability of varying degrees, versus 73% and 64% of participants in the sub-acute and post COVID-19 phase, respectively. Being “emotionally affected” was the most frequently reported disability in the sub-acute phase, the post COVID-19 phase, as well as in controls. The proportion of participants reporting difficulties for 20–30 days was higher in the sub-acute phase than in the post COVID-19 phase (27.9% vs. 21.8%, p < 0.001) as well as in a comparison between participants in the post COVID-19 phase and controls (21.8% vs 14.2%, p < 0.001). Compared with controls, severe disability was more common in the post COVID-19 phase among both women (15.8% vs. 10.7%,), and men (9.8% vs. 6.8%).

Conclusions
Disability was present in all groups; however, reported disability was greater in the sub-acute phase than in the post COVID-19 phase. The higher levels of disability reported in the COVID-19 patient population may indicate a persisting need for rehabilitation and recovery. In general, women reported a greater degree of disability than men in the sub-acute and post COVID-19 phases.

733

MS244

Robertson, McKaylee M; Qasmieh, Saba A; Kulkarni, Sarah G; Teasdale, Chloe A; Jones, Heidi; McNairy, Margaret; Borrell, Luisa N; Nash, Denis

The epidemiology of long COVID in US adults

https://doi.org/10.1093/cid/ciac961

Published

Study

https://doi.org/10.1093/cid/ciac961

We estimated the prevalence of long COVID and impact on daily living among a representative sample of adults in the United States (US).We conducted a population-representative survey, June 30-July 2, 2022, of a random sample of 3,042 United States adults aged 18 years or older and weighted to the 2020 US population. Using questions developed by the United Kingdom’s Office of National Statistics, we estimated the prevalence of long COVID, by sociodemographics, adjusting for gender and age.An estimated 7.3% (95% CI: 6.1-8.5%) of all respondents reported long COVID, corresponding to approximately 18,828,696 adults. One-quarter (25.3% [18.2-32.4%]) of respondents with long COVID reported their day-to-day activities were impacted ‘a lot’ and 28.9% had SARS-CoV-2 infection >12 months ago. The prevalence of long COVID was higher among respondents who were female (aPR: 1.84 [1.40-2.42]), had comorbidities (aPR: 1.55 [1.19-2.00]) or were not (versus were) boosted (aPR: 1.67 [1.19-2.34]) or not vaccinated (versus boosted) (aPR: 1.41 (1.05-1.91)).We observed a high burden of long COVID, substantial variability in prevalence of SARS-CoV-2 and risk factors unique from SARS-CoV-2 risk, suggesting areas for future research. Population-based surveys are an important surveillance tool and supplement to ongoing efforts to monitor long COVID.

734

MS245

Khan, Nabeel; Mahmud, Nadim; Patel, Manthankumar; Sundararajan, Ramaswamy; Reinisch, Walter

Incidence of Long COVID and impact of medications on the risk of developing Long COVID in a nationwide cohort of IBD patients

https://doi.org/10.1016/j.cgh.2022.12.017

Published

Study

https://www.sciencedirect.com/science/article/pii/S1542356522011843

735

MS246

Mizrahi, Barak; Sudry, Tamar; Flaks-Manov, Natalie; Yehezkelli, Yoav; Kalkstein, Nir; Akiva, Pinchas; Ekka-Zohar, Anat; David, Shirley Shapiro Ben; Lerner, Uri; Bivas-Benita, Maytal; Greenfeld, Shira

Long covid outcomes at one year after mild SARS-CoV-2 infection: nationwide cohort study

https://doi.org/10.1136/bmj-2022-072529

Published

11-Jan-23

Study

https://www.bmj.com/content/380/bmj-2022-072529

Objectives To determine the clinical sequelae of long covid for a year after infection in patients with mild disease and to evaluate its association with age, sex, SARS-CoV-2 variants, and vaccination status.
Design Retrospective nationwide cohort study.
Setting Electronic medical records from an Israeli nationwide healthcare organisation.
Population 1 913 234 Maccabi Healthcare Services members of all ages who did a polymerase chain reaction test for SARS-CoV-2 between 1 March 2020 and 1 October 2021.
Main outcome measures Risk of an evidence based list of 70 reported long covid outcomes in unvaccinated patients infected with SARS-CoV-2 matched to uninfected people, adjusted for age and sex and stratified by SARS-CoV-2 variants, and risk in patients with a breakthrough SARS-CoV-2 infection compared with unvaccinated infected controls. Risks were compared using hazard ratios and risk differences per 10 000 patients measured during the early (30-180 days) and late (180-360 days) time periods after infection.
Results Covid-19 infection was significantly associated with increased risks in early and late periods for anosmia and dysgeusia (hazard ratio 4.59 (95% confidence interval 3.63 to 5.80), risk difference 19.6 (95% confidence interval 16.9 to 22.4) in early period; 2.96 (2.29 to 3.82), 11.0 (8.5 to 13.6) in late period), cognitive impairment (1.85 (1.58 to 2.17), 12.8, (9.6 to 16.1); 1.69 (1.45 to 1.96), 13.3 (9.4 to 17.3)), dyspnoea (1.79 (1.68 to 1.90), 85.7 (76.9 to 94.5); 1.30 (1.22 to 1.38), 35.4 (26.3 to 44.6)), weakness (1.78 (1.69 to 1.88), 108.5, 98.4 to 118.6; 1.30 (1.22 to 1.37), 50.2 (39.4 to 61.1)), and palpitations (1.49 (1.35 to 1.64), 22.1 (16.8 to 27.4); 1.16 (1.05 to 1.27), 8.3 (2.4 to 14.1)) and with significant but lower excess risk for streptococcal tonsillitis and dizziness. Hair loss, chest pain, cough, myalgia, and respiratory disorders were significantly increased only during the early phase. Male and female patients showed minor differences, and children had fewer outcomes than adults during the early phase of covid-19, which mostly resolved in the late period. Findings remained consistent across SARS-CoV-2 variants. Vaccinated patients with a breakthrough SARS-CoV-2 infection had a lower risk for dyspnoea and similar risk for other outcomes compared with unvaccinated infected patients.
Conclusions This nationwide study suggests that patients with mild covid-19 are at risk for a small number of health outcomes, most of which are resolved within a year from diagnosis.

736

MS247

Gil, Saulo; Gualano, Bruno; de Araújo, Adriana Ladeira; de Oliveira Júnior, Gersiel Nascimento; Damiano, Rodolfo Furlan; Pinna, Fabio; Imamura, Marta; Rocha, Vanderson; Kallas, Esper; Batistella, Linamara Rizzo; Forlenza, Orestes V.; de Carvalho, Carlos R. R.; Busatto, Geraldo Filho; Roschel, Hamilton

Post-acute sequelae of SARS-CoV-2 associates with physical inactivity in a cohort of COVID-19 survivors

https://doi.org/10.1038/s41598-022-26888-3

Published

5-Jan-23

Study

https://www.nature.com/articles/s41598-022-26888-3

The aim of this study was to determine whether Post-acute Sequelae of SARS-CoV-2 Infection (PASC) are associated with physical inactivity in COVID-19 survivors. This is a cohort study of COVID-19 survivors discharged from a tertiary hospital in Sao Paulo, Brazil. Patients admitted as inpatients due to laboratory-confirmed COVID-19 between March and August 2020 were consecutively invited for a follow-up in-person visit 6 to 11 months after hospitalization. Ten symptoms of PASC were assessed using standardized scales. Physical activity was assessed by questionnaire and participants were classified according to WHO Guidelines. 614 patients were analyzed (age: 56 ± 13 years; 53% male). Frequency of physical inactivity in patients exhibiting none, at least 1, 1–4, and 5 or more symptoms of PASC was 51%, 62%, 58%, and 71%, respectively. Adjusted models showed that patients with one or more persistent PASC symptoms have greater odds of being physically inactive than those without any persistent symptoms (OR: 1.57 [95% CI 1.04–2.39], P = 0.032). Dyspnea (OR: 2.22 [1.50–3.33], P < 0.001), fatigue (OR: 2.01 [1.40–2.90], P < 0.001), insomnia (OR: 1.69 [1.16–2.49], P = 0.007), post-traumatic stress (OR: 1.53 [1.05–2.23], P = 0.028), and severe muscle/joint pain (OR: 1.53 [95% CI 1.08–2.17], P = 0.011) were associated with greater odds of being physically inactive. This study suggests that PASC is associated with physical inactivity, which itself may be considered as a persistent symptom among COVID-19 survivors. This may help in the early identification of patients who could benefit from additional interventions tailored to combat inactivity (even after treatment of PASC), with potential beneficial impacts on overall morbidity/mortality and health systems worldwide.

737

MS248

Sansone, Donatella; Tassinari, Alice; Valentinotti, Romina; Kontogiannis, Dimitra; Ronchese, Federico; Centonze, Sandro; Maggiore, Adele; Cegolon, Luca; Filon, Francesca Larese

Persistence of Symptoms 15 Months since COVID-19 Diagnosis: Prevalence, Risk Factors and Residual Work Ability

https://doi.org/10.3390/life13010097

Published

1-Jan-23

Study

https://www.mdpi.com/2075-1729/13/1/97

Background: A proportion of patients’ ailments may last after recovering from acute COVID-19, with episodic and systemic symptoms of unclear etiology potentially involving different organs. Study aim: The aim of this study was to investigate the persistence of symptoms 15 months since COVID-19 diagnosis in patients referring to the post-COVID-19 clinic in Trieste (north-eastern Italy). Methods: Two-hundred-forty-seven patients were medically examined between 8 December 2020–6 April 2021, after a median time of 49 days since first positive swab test for SARS-CoV-2. After a median time of 15 months since COVID-19 diagnosis, the same patients were contacted over the phone and investigated by standardized questionnaire collecting information on any persisting symptoms and work ability index (WAI). Four multivariable logistic regression models were fitted to investigate factors associated with persistence of any respiratory, neurological, dysautonomic, or psychiatric symptoms at first (median time 49 days since COVID-19 diagnosis) as well as second (median 15 months since COVID-19 diagnosis) follow up. A multiple linear regression was also employed to investigate factors associated with higher mean WAI, assessed only at second follow up. Additionally, factors associated with persistence of symptoms 200+ days since COVID-19 diagnosis between first and second follow-up were investigated by multivariable Generalized Estimating Equation (GEE). Results: At first follow up (median time of 49 days since COVID-19 diagnosis) symptoms more frequently reported were fatigue (80.2%), shortness of breath (69.6%), concentration deficit (44.9%), headache (44.9%), myalgia (44.1%), arthralgia (43.3%), and anosmia (42.1%). At second follow-up (median time of 15 months since COVID-19 diagnosis) 75% patients returned to their baseline status preceding COVID-19. At first follow up males were less likely to experience neurological (OR = 0.16; 95% CI: 0.08; 0.35) as well as psychiatric (OR = 0.43; 95% CI: 0.23; 0.80) symptoms as compared to females. At first follow up, the risk of neurological symptoms increased also linearly with age (OR = 1.04; 95% CI: 1.01; 1.08) and pre-existing depression was a major risk factor for persisting dysautonomic (aOR = 6.35; 95% CI: 2.01; 20.11) as well as psychiatric symptoms (omitted estimate). Consistently, at second follow up only females experience psychiatric symptoms, whereas males exhibited significantly higher mean WAI (RC = 0.50; 95% CI: 0.11; 0.88). Additionally, neurological symptoms at second follow up were more likely in patients with pre-existing comorbidities (OR = 4.31; 95% CI: 1.27; 14.7). Finally, persistence of symptoms lasting 200+ days since COVID-19 diagnosis increased linearly with age (OR = 1.03; 95% CI 1.01–1.05) and were more likely in patients affected by pre-existing depression (OR = 2.68; 95% CI 1.60; 4.49). Conclusions: Following a median time of 15 months since first positive swab test, 75% patients with symptoms returned to their baseline health status preceding COVID-19. Females had a significantly lower WAI and were more likely to experience psychiatric symptoms at second follow up (15 months since COVID-19 diagnosis). Furthermore, the risk of symptoms persisting 200+ days since COVID-19 diagnosis increased with history of depression, endorsing the hypothesis that long-COVID-19 symptoms may be at least partially explained by pre-existing psychological conditions. Patient rehabilitation and psychological support may therefore play a key role in caring patients with the so called long COVID-19 syndrome.

738

MS249

Rosa, Regis Goulart; Cavalcanti, Alexandre Biasi; Azevedo, Luciano César Pontes; Veiga, Viviane Cordeiro; de Souza, Denise; dos Santos, Rosa da Rosa Minho; Schardosim, Raíne Fogliati de Carli; Rech, Gabriela Soares; Trott, Geraldine; Schneider, Daniel; Robinson, Caroline Cabral; Haubert, Tainá Aparecida; Pallaoro, Victoria Emanuele Lobo; Brognoli, Liége Gregoletto; de Souza, Ana Paula; Costa, Lauren Sezerá; Barroso, Bruna Machado; Pelliccioli, Melissa Pezzetti; Gonzaga, Janine; Studier, Nicole dos Santos; Dagnino, Ana Paula Aquistapase; Neto, Juliana de Mesquita; da Silva, Sabrina Souza; Gimenes, Bruna dos Passos; dos Santos, Vanessa Brzoskowski; Estivalete, Gabriel Pozza Muller; Pellegrino, Carolina de Moraes; Polanczyk, Carisi Anne; Kawano-Dourado, Letícia; Tomazini, Bruno Martins; Lisboa, Thiago Costa; Teixeira, Cassiano; Zampieri, Fernando Godinho; Zavascki, Alexandre Prehn; Gersh, Bernard J.; Avezum, Álvaro; Machado, Flávia Ribeiro; Berwanger, Otavio; Lopes, Renato Delascio; Falavigna, Maicon

Association between acute disease severity and one-year quality of life among post-hospitalisation COVID-19 patients: Coalition VII prospective cohort study

https://doi.org/10.1007/s00134-022-06953-1

Published

3-Jan-23

Study

https://doi.org/10.1007/s00134-022-06953-1

Purpose
To assess the association between acute disease severity and 1-year quality of life in patients discharged after hospitalisation due to coronavirus disease 2019 (COVID-19).

Methods
We conducted a prospective cohort study nested in 5 randomised clinical trials between March 2020 and March 2022 at 84 sites in Brazil. Adult post-hospitalisation COVID-19 patients were followed for 1 year. The primary outcome was the utility score of EuroQol five-dimension three-level (EQ-5D-3L). Secondary outcomes included all-cause mortality, major cardiovascular events, and new disabilities in instrumental activities of daily living. Adjusted generalised estimating equations were used to assess the association between outcomes and acute disease severity according to the highest level on a modified ordinal scale during hospital stay (2: no oxygen therapy; 3: oxygen by mask or nasal prongs; 4: high-flow nasal cannula oxygen therapy or non-invasive ventilation; 5: mechanical ventilation).

Results
1508 COVID-19 survivors were enrolled. Primary outcome data were available for 1156 participants. At 1 year, compared with severity score 2, severity score 5 was associated with lower EQ-5D-3L utility scores (0.7 vs 0.84; adjusted difference, − 0.1 [95% CI − 0.15 to − 0.06]); and worse results for all-cause mortality (7.9% vs 1.2%; adjusted difference, 7.1% [95% CI 2.5%–11.8%]), major cardiovascular events (5.6% vs 2.3%; adjusted difference, 2.6% [95% CI 0.6%–4.6%]), and new disabilities (40.4% vs 23.5%; adjusted difference, 15.5% [95% CI 8.5%–22.5]). Severity scores 3 and 4 did not differ consistently from score 2.

Conclusions
COVID-19 patients who needed mechanical ventilation during hospitalisation have lower 1-year quality of life than COVID-19 patients who did not need mechanical ventilation during hospitalisation.

Take-home message
After 1 year of follow-up, patients with more severe COVID-19, defined as need for mechanical ventilation during hospitalisation, had significantly lower health-related quality of life and worse results for mortality, major cardiovascular events, re-hospitalisation, new disabilities in instrumental activities of daily living, anxiety and post-traumatic stress symptoms, and return to work or study than COVID-19 patients who did not need mechanical ventilation during hospitalisation

739

MS250

Aubert, M.; Ohayon, R.; Freymond, N.; Catoire, S.; Couraud, S.; Fontaine-Delaruelle, C.

Exploration cardiorespiratoire à l’effort des patients présentant un syndrome post-COVID

https://doi.org/10.1016/j.rmra.2022.11.097

Published

1-Jan-23

Study

https://www.sciencedirect.com/science/article/pii/S1877120322002671

Introduction
Les symptômes du syndrome post-COVID, y compris respiratoires, sont souvent inexpliqués par les explorations fonctionnelles respiratoires de repos (EFR), le scanner thoracique et l’échographie cardiaque. L’épreuve d’effort maximale cardiorespiratoire (EFX) permet d’explorer ces symptômes.
Méthodes
Il s’agit d’une étude rétrospective monocentrique. Les résultats des EFX des patients présentant un syndrome post-COVID avec des EFR normales sont rapportés ainsi que les facteurs favorisant une altération de la VO2pic et un déconditionnement à l’effort.
Résultats
Cinquante patients ont été inclus, dont 62 % de femmes ; 60 % avaient bénéficié d’une prise en charge initiale ambulatoire. La moyenne de VO2pic était de 20,6mL/min/kg soit 81,1 % de la valeur maximale théorique. Une intolérance à l’effort a été mise en évidence chez 62 % des patients, et un déconditionnement périphérique chez 14 % des patients. La présence d’anomalies au scanner en post-COVID-19, la gravité initiale et l’obésité ne semblaient pas altérer la VO2pic.
Conclusion
Cette étude met en évidence une proportion significative d’intolérance à l’effort et de déconditionnement périphérique chez 50 patients atteints de syndrome post-COVID avec une fonction respiratoire normale. Cela suggère l’importance de la réhabilitation à l’effort et la nécessité d’études permettant l’analyse des EFX et de l’évolution des symptômes après réhabilitation.

740

MS251

da Costa e Silva, Grazielle Rosa; Moura, Winny Éveny Alves; dos Santos, Kamila Cardoso; Gomes, Davi Oliveira; Bandeira, Gabriela Nolasco; Guimarães, Rafael Alves; Rosso, Claci Fátima Weirich; Bazilio, Gabriela Silvério; Leite, Vanessa Rafaela Milhomem Cruz; Caetano, Karlla Antonieta Amorim; Carneiro, Megmar Aparecida dos Santos; Teles, Sheila Araújo

Long-Term Symptoms after Mild Coronavirus Disease in Healthy Healthcare Professionals: A 12-Month Prospective Cohort Study

https://doi.org/10.3390/ijerph20021483

Published

1-Jan-23

Study

https://www.mdpi.com/1660-4601/20/2/1483

The coronavirus disease 2019 (COVID-19) pandemic has changed the course of human history and killed millions of people worldwide. Its long-term consequences remain uncertain. This study aimed to describe the short- and long-term symptoms of COVID-19 among individuals in Goiás, central Brazil, who experienced acute mild or non-symptomatic SARS-CoV-2 infection during the first wave of the pandemic. This prospective cohort study included 110 healthcare workers, 18 safety workers, and 19 administrative support workers, who were followed up for 12 months after the onset of COVID-19. Most participants were healthy adult female healthcare professionals. At the onset of infection, the major symptoms were headache, myalgia, nasal congestion, cough, coryza, anosmia, ageusia, sore throat, fatigue, diarrhea, and dyspnea. Furthermore, 20.3% of the participants had three or more COVID-19 symptoms that persisted for at least 12 months. These included coryza, congestion, hair loss, sore throat, headache, myalgia, cough, memory loss, anosmia, and fatigue. This study revealed a high prevalence of persistent symptoms of COVID-19 in healthy individuals from central Brazil, which may present an additional burden on healthcare services. Further studies are required to investigate the sequelae of COVID-19 over periods greater than 12 months.

741

MS252

Muraro, Ana Paula; Rocha, Roseany; Boing, Alexandra Crispim; Oliveira, Ligia Regina de; Melanda, Francine Nesello; Andrade, Amanda Cristina de Souza

Deaths from post-COVID conditions in Brazil

https://doi.org/10.1590/1413-81232023282.16752022

Published

16-Jan-23

Study

https://www.scielosp.org/article/csc/2023.v28n2/331-336/en/

This paper aims to assess the magnitude and profile of deaths from post-COVID conditions in Brazil. Descriptive study based on preliminary data from the 2021 Mortality Information System. Records with ICD code B94.8 as the Basic Cause and with code U09 in some lines of part I or II of the declaration were considered for analysis. The distribution of deaths by geographic region, semester of occurrence, sex, age group, ethnicity/skin color, schooling, and place of occurrence was evaluated. We identified 2,948 deaths from conditions subsequent to COVID-19 were recorded, ranging from 0.5 deaths per 1,000 records in the Northeast Region to 3.6/1,000 in the Midwest Region. More than half occurred among males (58.0%), those aged 60 years or older (66.9%), and whites (51.8%). Conclusion: Deaths from post-COVID conditions had distinct sociodemographic characteristics between regions.
publisher: ABRASCO - Associação Brasileira de Saúde Coletiva

742

MS253

Ma, Yirui; Deng, Jie; Liu, Qiao; Du, Min; Liu, Min; Liu, Jue

Long-Term Consequences of Asymptomatic SARS-CoV-2 Infection: A Systematic Review and Meta-Analysis

https://doi.org/10.3390/ijerph20021613

Published

1-Jan-23

Review

https://www.mdpi.com/1660-4601/20/2/1613

Little is known about the long-term consequences of asymptomatic infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to review the data available to explore the long-term consequences of asymptomatic SARS-CoV-2 infection in the real world. We searched observational cohort studies that described the long-term health effects of asymptomatic SARS-CoV-2 infections. Random-effects inverse-variance models were used to evaluate the pooled prevalence (PP) and its 95% confidence interval (CI) of long-term symptoms. Random effects were used to estimate the pooled odds ratios (OR) and its 95%CI of different long-term symptoms between symptomatic and asymptomatic infections. Five studies involving a total of 1643 cases, including 597 cases of asymptomatic and 1043 cases of symptomatic SARS-CoV-2 infection were included in this meta-analysis. The PPs of long-term consequences after asymptomatic SARS-CoV-2 infections were 17.13% (95%CI, 7.55–26.71%) for at least one symptom, 15.09% (95%CI, 5.46–24.73%) for loss of taste, 14.14% (95%CI, −1.32–29.61%) for loss of smell, and 9.33% (95%CI, 3.07–15.60) for fatigue. Compared with symptomatic SARS-CoV-2 infection, asymptomatic infection was associated with a significantly lower risk of developing COVID-19-related sequelae (p < 0.05), with 80% lower risk of developing at least one symptom (OR = 0.20, 95%CI, 0.09–0.45), 81% lower risk of fatigue (OR = 0.19, 95%CI, 0.08–0.49), 90% lower risk of loss of taste/smell (OR = 0.10, 95%CI, 0.02–0.58). Our results suggested that there were long-term effects of asymptomatic SARS-CoV-2 infection, such as loss of taste or smell, fatigue, cough and so on. However, the risk of developing long-term symptoms in asymptomatic SARS-CoV-2 infected persons was significantly lower than those in symptomatic SARS-CoV-2 infection cases.

743

MS254

Burton, Christopher; Dawes, Helen; Goodwill, Simon; Thelwell, Michael; Dalton, Caroline

Within and between-day variation and associations of symptoms in Long Covid: Intensive longitudinal study

https://doi.org/10.1371/journal.pone.0280343

Published

19-Jan-23

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0280343

Background People with Long Covid (Post Covid-19 Condition) describe multiple symptoms which vary between and within individuals over relatively short time intervals. We aimed to describe the real-time associations between different symptoms and between symptoms and physical activity at the individual patient level. Methods and findings Intensive longitudinal study of 82 adults with self-reported Long Covid (median duration 12–18 months). Data collection involved a smartphone app with 5 daily entries over 14 days and continuous wearing of a wrist accelerometer. Data items included 7 symptoms (Visual Analog Scales) and perceived demands in the preceding period (Likert scales). Activity was measured using mean acceleration in the 3-hour periods preceding and following app data entry. Analysis used within-person correlations of symptoms pairs and both pooled and individual symptom networks derived from graphical vector autoregression. App data was suitable for analysis from 74 participants (90%) comprising 4022 entries representing 77.6% of possible entries. Symptoms varied substantially within individuals and were only weakly autocorrelated. The strongest between-subject symptom correlations were of fatigue with pain (partial coefficient 0.5) and cognitive difficulty with light-headedness (0.41). Pooled within-subject correlations showed fatigue correlated with cognitive difficulty (partial coefficient 0.2) pain (0.19) breathlessness (0.15) and light-headedness (0.12) but not anxiety. Cognitive difficulty was correlated with anxiety and light-headedness (partial coefficients 0.16 and 0.17). Individual participant correlation heatmaps and symptom networks showed no clear patterns indicative of distinct phenotypes. Symptoms, including fatigue, were inconsistently correlated with prior or subsequent physical activity: this may reflect adjustment of activity in response to symptoms. Delayed worsening of symptoms after the highest activity peak was observed in 7 participants. Conclusion Symptoms of Long Covid vary within individuals over short time scales, with heterogenous patterns of symptom correlation. The findings are compatible with altered central symptom processing as an additional factor in Long Covid.

744

MS255

Shanbehzadeh, Sanaz; Zanjari, Nasibeh; Yassin, Marzieh; Yassin, Zeynab; Tavahomi, Mahnaz

Association between long COVID, functional activity, and health-related quality of life in older adults

https://doi.org/10.1186/s12877-023-03757-w

Published

23-Jan-23

Study

https://doi.org/10.1186/s12877-023-03757-w

Background
Older adults experience persistent symptoms post-COVID-19, termed as Long COVID, affecting their physical and mental health. This study aimed to evaluate the effects of Long COVID, level of physical activity, and functional decline on older adults’ health-related quality of life post-COVID-19.

Methods
This cross-sectional study was conducted on 121 older adults with 60 to 90 years old post-coronavirus infection. The standardized metrics used in the study were Fatigue Severity Scale, Physical Activity Elderly, SF12, Post-COVID-19 functional status scale, and COVID-19 Yorkshire rehabilitation screening scale. The severity of coronavirus infection was evaluated by changes in chest CT scan images and O2 saturation at hospital admission. Data were analyzed using linear regression analyses.

Results
The results of regression analysis revealed six factors to be predictors of physical health at 6 months post-COVID-19 (F = 9.046, P < 0.001; explained variance 63%), which the significant factors were fatigue, level of physical activity, worsened pain, difficulties in activities of daily living and cognitive-communication problems. Among these factors, greater fatigue and worsened pain intensity were the strongest predictors. Mental health was associated with days of hospitalization and cognitive-communication problems (F = 2.866, P < 0.001; explained variance 35%).

Conclusions
Considering the negative impact of fatigue, pain, low physical activity, and cognitive-communication problems on health-related quality of life, early and accurate evaluation and management are required for recovered older adults post-COVID-19.

745

MS256

Vásconez-González, Jorge; Fernandez-Naranjo, Raul; Izquierdo-Condoy, Juan S.; Delgado-Moreira, Karen; Cordovez, Simone; Tello-De-la-Torre, Andrea; Paz, Clara; Castillo, Diana; Izquierdo-Condoy, Nathaly; Carrington, Sarah J; Ortiz-Prado, Esteban

Comparative analysis of long-term self-reported COVID-19 symptoms among pregnant women

https://doi.org/10.1016/j.jiph.2023.01.012

Published

20-Jan-23

Study

https://www.sciencedirect.com/science/article/pii/S1876034123000229

Background
The negative effects of COVID-19 infections during pregnancy have been amply described, however, the persistent sequels of this infection have not been explored so far.
Objective
The aim of this study was to describe persisting symptoms after COVID-19 infection in pregnant and non-pregnant women in Ecuador.
Methods
A cross-sectional analysis based on an online, self-reporting questionnaire was conducted in Ecuador from April to July 2022. Participants were invited by social media, radio, and TV to voluntarily participate in our study. A total of 457 surveys were included in this study. We compared risk factor variables and long-term persisting symptoms of pregnant and non-pregnant women in Ecuador.
Results
Overall, 247 (54.1%) responders claimed to have long-term symptoms after SARS-CoV-2 infection. Most of these symptoms were reported by non-pregnant women (94.0%). The most common Long-COVID symptoms in pregnant women were fatigue (10.6%), hair loss (9.6%), and difficulty concentrating (6.2%). We found that pregnant women who smoked had a higher risk of suffering fatigue.
Conclusions
The most frequent Long-COVID symptoms in pregnant women were fatigue, hair loss, and difficulty concentrating. Apparently, the patterns of presentation of long-term sequelae of SARS-CoV-2 infection in pregnant women do not differ significantly from reports available from studies in the general population.

746

MS257

Burton, Christopher; Dawes, Helen; Goodwill, Simon; Thelwell, Michael; Dalton, Caroline

Within and between-day variation and associations of symptoms in Long Covid: Intensive longitudinal study

https://doi.org/10.1371/journal.pone.0280343

Published

19-Jan-23

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0280343

Background People with Long Covid (Post Covid-19 Condition) describe multiple symptoms which vary between and within individuals over relatively short time intervals. We aimed to describe the real-time associations between different symptoms and between symptoms and physical activity at the individual patient level. Methods and findings Intensive longitudinal study of 82 adults with self-reported Long Covid (median duration 12–18 months). Data collection involved a smartphone app with 5 daily entries over 14 days and continuous wearing of a wrist accelerometer. Data items included 7 symptoms (Visual Analog Scales) and perceived demands in the preceding period (Likert scales). Activity was measured using mean acceleration in the 3-hour periods preceding and following app data entry. Analysis used within-person correlations of symptoms pairs and both pooled and individual symptom networks derived from graphical vector autoregression. App data was suitable for analysis from 74 participants (90%) comprising 4022 entries representing 77.6% of possible entries. Symptoms varied substantially within individuals and were only weakly autocorrelated. The strongest between-subject symptom correlations were of fatigue with pain (partial coefficient 0.5) and cognitive difficulty with light-headedness (0.41). Pooled within-subject correlations showed fatigue correlated with cognitive difficulty (partial coefficient 0.2) pain (0.19) breathlessness (0.15) and light-headedness (0.12) but not anxiety. Cognitive difficulty was correlated with anxiety and light-headedness (partial coefficients 0.16 and 0.17). Individual participant correlation heatmaps and symptom networks showed no clear patterns indicative of distinct phenotypes. Symptoms, including fatigue, were inconsistently correlated with prior or subsequent physical activity: this may reflect adjustment of activity in response to symptoms. Delayed worsening of symptoms after the highest activity peak was observed in 7 participants. Conclusion Symptoms of Long Covid vary within individuals over short time scales, with heterogenous patterns of symptom correlation. The findings are compatible with altered central symptom processing as an additional factor in Long Covid.

747

MS258

Squillace, Nicola; Cogliandro, Viola; Rossi, Emanuela; Bellelli, Giuseppe; Pozzi, Matteo; Luppi, Fabrizio; Lettino, Maddalena; Strepparava, Maria Grazia; Ferrarese, Carlo; Pollastri, Ester; Ricci, Elena; Bonfanti, Paolo; Bellani, Giacomo; Biondi, Andrea; Cazzaniga, Marina Elena; Citerio, Giuseppe; Contro, Ernesto; Foti, Giuseppe; Valsecchi, Maria Grazia; Rugova, Alban; Beretta, Eleonora Maria; Iannace, Marta; Spolti, Anna; Orsini, Valentina; Malafronte, Cristina; Valagussa, Laura; Ferlicca, Daniela; Bettini, Francesca; Bellin, Valeria; Meroni, Valeria; Calabria, Mariangela; Gatti, Stefano; Bronco, Alfio; Ripa, Claudio; Sosio, Simone; Faverio, Paola; Monzani, Anna; Ferrara, Maria Cristina; Zarcone, Cristina; Ferrarese, Carlo; Beretta, Simone; Salvarani, Valerio; Mauri, Ornella; Da Re, Carolina; Carrer, Andrea; for the STORM Long-COVID Team

A multidisciplinary approach to screen the post-COVID-19 conditions

https://doi.org/10.1186/s12879-023-08006-4

Published

24-Jan-23

Study

https://doi.org/10.1186/s12879-023-08006-4

Background
Post-COronaVIrus Disease 2019 (COVID-19) conditions (PCC) include multiple symptoms afflicting different organs and systems. To evaluate the frequency and type of them, we described our multidisciplinary approach with preliminary results of the first enrolled patients.
Methods
We included patients aged ≥ 18 years with hospital admission for confirmed SARS-CoV-2 infection. Symptoms were grouped in five macro groups hereafter referred to as "Symptoms Category" (SC): respiratory SC (dyspnoea or cough), neurological SC (peripheral neuropathies, headache, impaired mobility, behavioural disorders), psychological SC (sleep disorders, mood disorders), muscular SC (arthromyalgia, asthenia), other SC (fever, alopecia, diarrhoea, weight loss, smell and taste alterations, sexual dysfunctions). SC were evaluated at discharge and at follow-up. Association between patients’ characteristics and presence of SC at follow up was estimated by a logistic multivariable regression model.
Results
From June 2020 to July 2021, we followed up 361 patients: 128 (35.5%) who were previously admitted to Intensive Care Unit (ICU) and 233 patients to ordinary department. The median length of hospital stay was 20 days (Inter-Quartile-Range 13–32). Most patients (317/361, 87.8%) were still symptomatic at discharge, with one third referring three or more SC. At follow up, 67.3% (243/361) of patients still complained at least one SC. Moreover, 159 patients (44%) developed at least one new involved SC during follow up: 116 (72.9%) one SC, 39 (24.5%) two SC, 4 (2.5%) three or more SC. At follow up visit 130 of 361 (36%) were still with SC developed during follow up. At multivariable analysis presence of any SC at follow-up was associated with male gender (Odds Ratio [OR] 3.23, Confidence Interval [CI] 95% 1.46–7.15), ICU admission (OR 2.78, CI 95% 1.29–5.96) and presence of SC at discharge (OR 14.39, CI 95% 6.41–32.32).
Conclusions
In our sample of patients with severe COVID-19, we found that PCC are highly variable and fluctuating over time; in particular, in about 50% of our patients new SC appear during follow up. Moreover, presence of PCC also in patients without SC at discharge and the variability of symptoms underlining the advisability of our multidisciplinary approach.

748

MS259

O'Mahoney, Lauren L.; Routen, Ash; Gillies, Clare; Ekezie, Winifred; Welford, Anneka; Zhang, Alexa; Karamchandani, Urvi; Simms-Williams, Nikita; Cassambai, Shabana; Ardavani, Ashkon; Wilkinson, Thomas J.; Hawthorne, Grace; Curtis, Ffion; Kingsnorth, Andrew P.; Almaqhawi, Abdullah; Ward, Thomas; Ayoubkhani, Daniel; Banerjee, Amitava; Calvert, Melanie; Shafran, Roz; Stephenson, Terence; Sterne, Jonathan; Ward, Helen; Evans, Rachael A.; Zaccardi, Francesco; Wright, Shaney; Khunti, Kamlesh

The prevalence and long-term health effects of Long Covid among hospitalised and non-hospitalised populations: a systematic review and meta-analysis

https://doi.org/10.1016/j.eclinm.2022.101762

Published

1-Jan-23

Study

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(22)00491-6/fulltext

Background
The aim of this study was to systematically synthesise the global evidence on the prevalence of persistent symptoms in a general post COVID-19 population.
Methods
A systematic literature search was conducted using multiple electronic databases (MEDLINE and The Cochrane Library, Scopus, CINAHL, and medRxiv) until January 2022. Studies with at least 100 people with confirmed or self-reported COVID-19 symptoms at ≥28 days following infection onset were included. Patient-reported outcome measures and clinical investigations were both assessed. Results were analysed descriptively, and meta-analyses were conducted to derive prevalence estimates. This study was pre-registered (PROSPERO-ID: CRD42021238247).
Findings
194 studies totalling 735,006 participants were included, with five studies conducted in those <18 years of age. Most studies were conducted in Europe (n = 106) or Asia (n = 49), and the time to follow-up ranged from ≥28 days to 387 days. 122 studies reported data on hospitalised patients, 18 on non-hospitalised, and 54 on hospitalised and non-hospitalised combined (mixed). On average, at least 45% of COVID-19 survivors, regardless of hospitalisation status, went on to experience at least one unresolved symptom (mean follow-up 126 days). Fatigue was frequently reported across hospitalised (28.4%; 95% CI 24.7%–32.5%), non-hospitalised (34.8%; 95% CI 17.6%–57.2%), and mixed (25.2%; 95% CI 17.7%–34.6%) cohorts. Amongst the hospitalised cohort, abnormal CT patterns/x-rays were frequently reported (45.3%; 95% CI 35.3%–55.7%), alongside ground glass opacification (41.1%; 95% CI 25.7%–58.5%), and impaired diffusion capacity for carbon monoxide (31.7%; 95% CI 25.8%–3.2%).
Interpretation
Our work shows that 45% of COVID-19 survivors, regardless of hospitalisation status, were experiencing a range of unresolved symptoms at ∼ 4 months. Current understanding is limited by heterogeneous study design, follow-up durations, and measurement methods. Definition of subtypes of Long Covid is unclear, subsequently hampering effective treatment/management strategies.Publisher: Elsevier
PMID: 36474804

749

MS260

Morioka, S.; Tsuzuki, S.; Maruki, T.; Terada, M.; Miyazato, Y.; Kutsuna, S.; Saito, S.; Shimanishi, Y.; Takahashi, K.; Sanada, M.; Ashida, S.; Akashi, M.; Kuge, C.; Osanai, Y.; Tanaka, K.; Suzuki, M.; Hayakawa, K.; Ohmagari, N.

Epidemiology of post-COVID conditions beyond 1 year: a cross-sectional study

https://doi.org/10.1016/j.puhe.2023.01.008

Published

1-Mar-23

Study

https://www.sciencedirect.com/science/article/pii/S0033350623000173

Objective
The aim of this study was to investigate the epidemiology of post-COVID conditions beyond 12 months and identify factors associated with the persistence of each condition.
Study design
This was a cross-sectional questionnaire-based survey.
Methods
We conducted the survey among patients who had recovered from COVID-19 and visited our institute between February 2020 and November 2021. Demographic and clinical data and data regarding the presence and duration of post-COVID conditions were obtained. We identified factors associated with the persistence of post-COVID conditions using multivariable linear regression analyses.
Results
Of 1148 surveyed patients, 502 completed the survey (response rate, 43.7%). Of these, 393 patients (86.4%) had mild disease in the acute phase. The proportion of participants with at least one symptom at 6, 12, 18, and 24 months after symptom onset or COVID-19 diagnosis was 32.3% (124/384), 30.5% (71/233), 25.8% (24/93), and 33.3% (2/6), respectively. The observed associations were as follows: fatigue persistence with moderate or severe COVID-19 (β = 0.53, 95% confidence interval [CI] = 0.06–0.99); shortness of breath with moderate or severe COVID-19 (β = 1.39, 95% CI = 0.91–1.87); cough with moderate or severe COVID-19 (β = 0.84, 95% CI = 0.40–1.29); dysosmia with being female (β = −0.57, 95% CI = −0.97 to −0.18) and absence of underlying medical conditions (β = −0.43, 95% CI = −0.82 to −0.05); hair loss with being female (β = −0.61, 95% CI = −1.00 to −0.22), absence of underlying medical conditions (β = −0.42, 95% CI = −0.80 to 0.04), and moderate or severe COVID-19 (β = 0.97, 95% CI = 0.41–1.54); depressed mood with younger age (β = −0.02, 95% CI = −0.04 to −0.004); and loss of concentration with being female (β = −0.51, 95% CI = −0.94 to −0.09).
Conclusions
More than one-fourth of patients after recovery from COVID-19, most of whom had had mild disease in the acute phase, had at least one symptom at 6, 12, 18, and 24 months after onset of COVID-19, indicating that not a few patients with COVID-19 suffer from long-term residual symptoms, even in mild cases.

750

MS261

Jacobs, Molly M.; Evans, Elizabeth; Ellis, Charles

Racial, ethnic, and sex disparities in the incidence and cognitive symptomology of long COVID-19

https://doi.org/10.1016/j.jnma.2023.01.016

Published

13-Feb-23

Study

https://www.sciencedirect.com/science/article/pii/S0027968423000251

Background
The pandemic has highlighted and exacerbated health inequities in both acute coronavirus disease 2019 (COVID‐19) and its longer‐term sequelae. Given the heterogeneity in definitions of long COVID and the lack of centralized registries of patients with the disease, little is known about the differential prevalence among racial, ethnic, and sex subgroups. This study examines long COVID among Black, White, Asian, and Hispanic Americans and evaluates differences in the associated cognitive symptomology.
Method
Data from four releases of the Census Bureau's Household Pulse Survey detailing COVID-19 incidence and the duration and type of symptoms among a nationally representative sample of adults from June 1, 2022, through October 17, 2022, were combined. Binary logistic regression assessed the relative likelihood of long COVID among those who had been diagnosed COVID between racial, ethnic, and sex subgroups. Among those reporting long COVID, differences in the prevalence of difficulty understanding and difficulty remembering were assessed. Empirical models accounted for household, regional, vaccination, and insurance differences between respondents. Two-stage selection models were applied to test the robustness of the results.
Results
Among respondents who tested positive for COVID-19, Blacks (OR=1.097, CI=1.034-1.163), females (OR=1.849, CI=1.794-1.907), and Hispanics (OR=1.349, CI=1.286-1.414) were more likely to experience long COVID (symptoms lasting for 3 months or longer) compared to Whites, males, and non-Hispanics respectively. However, those with private health insurance (OR=0.634, CI=0.611-0.658) and who received the COVID vaccine (OR=0.901, CI=0.864-0.94) were less likely to have endured COVID symptoms than their counterparts. Symptoms of long COVID varied significantly between population subgroups. Compared to Whites, Blacks were more likely to have trouble remembering (OR=1.878, CI=1.765-1.808) while Hispanics were more likely to report difficult understanding (OR=1.827, CI=1.413, 2.362). Females, compared to males, were less likely to experience trouble understanding (OR=0.664, CI=0.537, 0.821), but more likely to report trouble remembering (OR=1.34, CI=1.237, 1.451).
Conclusions
Long COVID is more prevalent among Blacks, Hispanics, and females, but each group appears to experience long COVID differently. Therefore, additional research is needed to determine the best method to treat and manage this poorly understood condition.

751

MS262

Paradowska-Nowakowska, Elżbieta; Łoboda, Danuta; Gołba, Krzysztof S.; Sarecka-Hujar, Beata

Long COVID-19 Syndrome Severity According to Sex, Time from the Onset of the Disease, and Exercise Capacity—The Results of a Cross-Sectional Study

https://doi.org/10.3390/life13020508

Published

1-Feb-23

Study

https://www.mdpi.com/2075-1729/13/2/508

Symptoms of long COVID-19 syndrome (long COVID-19) are reported by 80% of convalescents up to several months after contracting the coronavirus-19 disease (COVID-19). The study aimed to assess the frequency and correlations of long COVID symptoms with sex, disease severity, time since the onset of the disease, and exercise capacity in a population of Polish convalescents hospitalized as a part of a rehabilitation program after COVID-19. The retrospective analysis was carried out based on medical records concerning reported symptoms, comorbidities, exercise capacity, fatigue and dyspnea on Borg’s scale, arterial oxygen saturation (SpO2), spirometric parameters, chest X-rays/computed tomography scans, systolic pulmonary artery pressure, and left ventricular ejection fraction. The study involved 471 patients aged 63.83 ± 9.93 years who had been hospitalized 191.32 ± 75.69 days from the onset of COVID-19, of which 269 (57.1%) were women. The most common symptoms were fatigue (99.57%), dyspnea (99.36%), and myalgia (97.03%). Women reported more symptoms than men (p < 0.001) and rated their fatigue as more severe (p = 0.021). Patients with depressed moods reported more physical symptoms than others (p < 0.001). Most long COVID symptoms, including dyspnea, fatigue, and depressive symptoms, were found with the same frequency in patients 12–24 weeks and >24 weeks after recovery (p = 0.874, p = 0.400, and p = 0.320, respectively), regardless of acute COVID-19 severity (p = 0.240, p = 0.826, and p = 0.108, respectively). Dyspnea severity correlated with forced vital capacity (FVC) (r = −0.153, p = 0.005), and forced expiratory volume in one second (FEV1) (r = −0.142, p = 0.008). Fatigue severity correlated with impaired FVC and FEV1 (both r = −0.162, p = 0.003). Fatigue and dyspnea inversely correlated with the distance in a six-minute walk test (r = −0.497, p < 0.001, and r = −0.327, p < 0.001). In conclusion, in our cohort, long COVID symptoms are more common in women. Dyspnea/fatigue and depressive symptoms do not tend to subside after an average six-month recovery period. The intensity of perceived fatigue may be exaggerated by the coexistence of neuropsychiatric disorders. Increased fatigue and dyspnea correlate with impaired spirometric parameters and significantly affects convalescents’ exercise capacity.

752

MS263

Jason, Leonard A.; Dorri, Joseph A.

ME/CFS and Post-Exertional Malaise among Patients with Long COVID

https://doi.org/10.3390/neurolint15010001

Published

1-Mar-23

Study

https://www.mdpi.com/2035-8377/15/1/1

This study sought to ascertain the prevalence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) among a sample of 465 patients with Long COVID. The participants completed three questionnaires: (1) a new questionnaire measuring both the frequency and severity of 38 common symptoms of COVID and Long COVID, (2) a validated short form questionnaire assessing ME/CFS, and (3) a validated questionnaire measuring post-exertional malaise. The population was predominantly white, female, and living in North America. The mean duration since the onset of COVID-19 symptoms was 70.5 weeks. Among the 465 participants, 58% met a ME/CFS case definition. Of respondents who reported that they had ME/CFS only 71% met criteria for ME/CFS and of those who did not report they had ME/CFS, 40% nevertheless did meet criteria for the disease: both over-diagnosis and under-diagnosis were evident on self-report. This study supports prior findings that ME/CFS occurs with high prevalence among those who have persistent COVID-19 symptoms.

753

MS264

Admon, Andrew J.; Iwashyna, Theodore J.; Kamphuis, Lee A.; Gundel, Stephanie J.; Sahetya, Sarina K.; Peltan, Ithan D.; Chang, Steven Y.; Han, Jin H.; Vranas, Kelly C.; Mayer, Kirby P.; Hope, Aluko A.; Jolley, Sarah E.; Caldwell, Ellen; Monahan, Max L.; Hauschildt, Katrina; Brown, Samuel M.; Aggarwal, Neil R.; Thompson, B. Taylor; Hough, Catherine L.; National Heart, Lung, and Blood Institute PETAL Network

Assessment of Symptom, Disability, and Financial Trajectories in Patients Hospitalized for COVID-19 at 6 Months

https://doi.org/10.1001/jamanetworkopen.2022.55795

Published

14-Feb-23

Study

https://doi.org/10.1001/jamanetworkopen.2022.55795

Key Points
Question How do symptoms, disabilities, and financial problems evolve in the 6 months after COVID-19-related hospitalization?
Findings In this national US cohort study that included 825 adults discharged from 44 hospitals, 75.4% of COVID-19 survivors experienced cardiopulmonary problems at 6 months compared with 67.3% at month 1. Decreases were noted at 6 months in financial problems (from 66.1% to 56.4%) and functional limitations (55.3% to 47.3%).
Meaning The findings of this study suggest that symptoms, disabilities, and financial problems remain highly prevalent—with some new problems—in the 6 months after COVID-19 hospitalization.
Abstract
Importance Individuals who survived COVID-19 often report persistent symptoms, disabilities, and financial consequences. However, national longitudinal estimates of symptom burden remain limited.
Objective To measure the incidence and changes over time in symptoms, disability, and financial status after COVID-19–related hospitalization.
Design, Setting, and Participants A national US multicenter prospective cohort study with 1-, 3-, and 6-month postdischarge visits was conducted at 44 sites participating in the National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Network's Biology and Longitudinal Epidemiology: COVID-19 Observational (BLUE CORAL) study. Participants included hospitalized English- or Spanish-speaking adults without severe prehospitalization disabilities or cognitive impairment. Participants were enrolled between August 24, 2020, and July 20, 2021, with follow-up occurring through March 30, 2022.
Exposure Hospitalization for COVID-19 as identified with a positive SARS-CoV-2 molecular test.
Main Outcomes and Measures New or worsened cardiopulmonary symptoms, financial problems, functional impairments, perceived return to baseline health, and quality of life. Logistic regression was used to identify factors associated with new cardiopulmonary symptoms or financial problems at 6 months.
Results A total of 825 adults (444 [54.0%] were male, and 379 [46.0%] were female) met eligibility criteria and completed at least 1 follow-up survey. Median age was 56 (IQR, 43-66) years; 253 (30.7%) participants were Hispanic, 145 (17.6%) were non-Hispanic Black, and 360 (43.6%) were non-Hispanic White. Symptoms, disabilities, and financial problems remained highly prevalent among hospitalization survivors at month 6. Rates increased between months 1 and 6 for cardiopulmonary symptoms (from 67.3% to 75.4%; P = .001) and fatigue (from 40.7% to 50.8%; P < .001). Decreases were noted over the same interval for prevalent financial problems (from 66.1% to 56.4%; P < .001) and functional limitations (from 55.3% to 47.3%; P = .004). Participants not reporting problems at month 1 often reported new symptoms (60.0%), financial problems (23.7%), disabilities (23.8%), or fatigue (41.4%) at month 6.
Conclusions and Relevance The findings of this cohort study of people discharged after COVID-19 hospitalization suggest that recovery in symptoms, functional status, and fatigue was limited at 6 months, and some participants reported new problems 6 months after hospital discharge.

754

MS265

Fabbri, Andrea; Voza, Antonio; Riccardi, Alessandro; Vanni, Simone; De Iaco, Fabio

Unfavorable Outcome and Long-Term Sequelae in Cases with Severe COVID-19

https://doi.org/10.3390/v15020485

Published

1-Feb-23

Review

https://www.mdpi.com/1999-4915/15/2/485

Emerging evidence shows that individuals with COVID-19 who survive the acute phase of illness may experience lingering symptoms in the following months. There is no clear indication as to whether these symptoms persist for a short time before resolving or if they persist for a long time. In this review, we will describe the symptoms that persist over time and possible predictors in the acute phase that indicate long-term persistence. Based on the literature available to date, fatigue/weakness, dyspnea, arthromyalgia, depression, anxiety, memory loss, slowing down, difficulty concentrating and insomnia are the most commonly reported persistent long-term symptoms. The extent and persistence of these in long-term follow-up is not clear as there are still no quality studies available. The evidence available today indicates that female subjects and those with a more severe initial disease are more likely to suffer permanent sequelae one year after the acute phase. To understand these complications, and to experiment with interventions and treatments for those at greater risk, we must first understand the physio-pathological mechanisms that sustain them.

755

MS266

Perisse, Anne; De Cacqueray, François; Delarbre, David; Marsaa, Hélène; Bergmann, Cedric; Da Silva, Virginie; Bronstein, Antoine; Paleiron, Nicolas; Menoud, Nastasia; Cobola, Jacques; Verret, Catherine; Mayet, Aurélie; Bylicki, Olivier

Symptoms of Long-COVID 1-Year After a COVID-19 Outbreak Among Sailors on a French Aircraft Carrier

https://doi.org/10.1016/j.idnow.2023.104673

Published

11-Feb-23

Study

https://www.sciencedirect.com/science/article/pii/S2666991923000350

Highlights
•Prevalence of Long-COVID symptoms was 53.7%, 55.2% and 54.3% in COVID-positive patients at months 6, 9 and 12.
•In COVID-negative patients, prevalence was 31.2%, 23.3% and 40.0% at months 6, 9 and 12.
•The main symptoms were concentration difficulties, asthenia and sleep disorders.
•Mild COVID-19 patients reported more symptoms than negative patients during the first 9 months.
•We should evoke a differential diagnosis in case of symptoms 1 year after mild-COVID.
Abstract
Objectives
While persistent symptoms have been reported after the coronavirus disease-2019 (COVID-19), long-term data on outpatients with mild COVID-19 are lacking. The objective was to describe symptoms persisting for 12 months.
Methods
This prospective cohort study on 1767 sailors of an aircraft carrier in which a Covid-19 outbreak occurred during a mission in April 2020 described predefined self-reported symptoms of Long-COVID at 6, 9 and 12 months. Logistic-regression analyses were used to identify correlates for Long-COVID at months 6, 9 and 12.
Results
Among the 641 participants, 619 (35%) completed at least one follow-up questionnaire (413 COVID-positive and 206 COVID-negative). Symptoms of Long-COVID were reported by 53.7%, 55.2% and 54.3% of COVID-positive participants vs. 31.2%, 23.3% and 40.0% in COVID-negative patients, at 6 (p<.002), 9 (p<.002) and 12 months (p=.13), respectively. The most frequent symptoms reported were concentration and memory difficulties, asthenia and sleep disorders.
Conclusion
In this study more than half of COVID-positive outpatients reported persistent symptoms up to 12 months post-quarantine. These findings suggests that all patients, including those with mild disease, can be affected by Long-COVID. A lack of difference at 12 months with COVID-negative patienys prompts caution. The symptoms of Long-COVID are so non-specific that they may be viewed as the consequence of multiple intercurrent factors.

756

MS267

Han, Emilie; Gyöngyösi, Mariann

Long COVID – eine neue Herausforderung in der Medizin: Fokus auf Schwangerschaft und Stillzeit

https://doi.org/10.1007/s41974-023-00250-5

Published

2-Feb-23

Article

https://doi.org/10.1007/s41974-023-00250-5

Long COVID wurde als eine neue Multiorganerkrankung beschrieben, die bei Frauen häufiger auftritt als bei Männern. Schwangere und stillende Frauen sind eine spezielle Untergruppe von Patienten, die bei einer Long-COVID-Erkrankung zu berücksichtigen sind, da bisher die Datenlage nur gering ausfällt. Menstruationsveränderungen werden häufig während oder nach einer akuten Erkrankung mit dem Coronavirus-2019 (COVID-19) beobachtet. Einige Studien stellen zudem einen Zusammenhang zwischen geringen Veränderungen der Zykluslänge und einer COVID-Impfung dar. Schwangere Frauen, die eine symptomatische Infektion mit dem schweren-akuten-Atemwegssyndrom-Coronavirus Typ 2 (SARS-CoV‑2) hatten, können ein höheres Risiko für Komplikationen in der Schwangerschaft, wie Frühgeburt oder Präeklampsie, haben. Darüber hinaus sind mehr Studien notwendig, um die Auswirkungen einer vertikalen Übertragung zu beurteilen. Das wirksamste Mittel gegen die Pandemie sind die verfügbaren COVID-Impfstoffe, da sie eine Infektion verhindern, aber auch Long-COVID-Symptome lindern können. Impfstoffe haben sich sowohl bei schwangeren als auch bei stillenden Frauen als sicher und wirksam erwiesen. Ziel dieses Artikels ist es, die aktuell verfügbaren Daten zu Long COVID bei schwangeren und stillenden Frauen darzustellen und die Risikofaktoren und therapeutischen Möglichkeiten aufzuzeigen.
Abstract
Long COVID (coronavirus disease) has been described as a new multi-organ disease, which appears to be more prevalent in women than in men. Pregnant and breastfeeding women are a special subgroup of patients to consider with long COVID, as only scarce data have been collected to date. Menstrual changes are commonly observed during or after COVID-19; some studies also attribute slight changes of cycle length to previous inoculation against the virus. Pregnant women who have a symptomatic infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are at a higher risk for adverse outcomes and pregnancy-associated complications. Moreover, more and robust data are required to evaluate vertical transmission. COVID vaccines are the most effective tool against the pandemic, as they prevent infection, but also appear to be able to ease long COVID symptoms. Vaccines have been proven safe and effective in both pregnant and breastfeeding women. This article aims to present current data on long COVID in pregnant and breastfeeding women and elucidate risk factors and possible treatment options.

757

MS268

Khullar, Dhruv; Zhang, Yongkang; Zang, Chengxi; Xu, Zhenxing; Wang, Fei; Weiner, Mark G.; Carton, Thomas W.; Rothman, Russell L.; Block, Jason P.; Kaushal, Rainu

Racial/Ethnic Disparities in Post-acute Sequelae of SARS-CoV-2 Infection in New York: an EHR-Based Cohort Study from the RECOVER Program

https://doi.org/10.1007/s11606-022-07997-1

Published

16-Feb-23

Study

https://doi.org/10.1007/s11606-022-07997-1

Background
Compared to white individuals, Black and Hispanic individuals have higher rates of COVID-19 hospitalization and death. Less is known about racial/ethnic differences in post-acute sequelae of SARS-CoV-2 infection (PASC).
Objective
Examine racial/ethnic differences in potential PASC symptoms and conditions among hospitalized and non-hospitalized COVID-19 patients.
Design
Retrospective cohort study using data from electronic health records.
Participants
62,339 patients with COVID-19 and 247,881 patients without COVID-19 in New York City between March 2020 and October 2021.
Main Measures
New symptoms and conditions 31–180 days after COVID-19 diagnosis.
Key Results
The final study population included 29,331 white patients (47.1%), 12,638 Black patients (20.3%), and 20,370 Hispanic patients (32.7%) diagnosed with COVID-19. After adjusting for confounders, significant racial/ethnic differences in incident symptoms and conditions existed among both hospitalized and non-hospitalized patients. For example, 31–180 days after a positive SARS-CoV-2 test, hospitalized Black patients had higher odds of being diagnosed with diabetes (adjusted odds ratio [OR]: 1.96, 95% confidence interval [CI]: 1.50—2.56, q<0.001) and headaches (OR: 1.52, 95% CI: 1.11—2.08, q=0.02), compared to hospitalized white patients. Hospitalized Hispanic patients had higher odds of headaches (OR: 1.62, 95% CI: 1.21—2.17, q=0.003) and dyspnea (OR: 1.22, 95% CI: 1.05—1.42, q=0.02), compared to hospitalized white patients. Among non-hospitalized patients, Black patients had higher odds of being diagnosed with pulmonary embolism (OR: 1.68, 95% CI: 1.20—2.36, q=0.009) and diabetes (OR: 2.13, 95% CI: 1.75—2.58, q<0.001), but lower odds of encephalopathy (OR: 0.58, 95% CI: 0.45—0.75, q<0.001), compared to white patients. Hispanic patients had higher odds of being diagnosed with headaches (OR: 1.41, 95% CI: 1.24—1.60, q<0.001) and chest pain (OR: 1.50, 95% CI: 1.35—1.67, q < 0.001), but lower odds of encephalopathy (OR: 0.64, 95% CI: 0.51—0.80, q<0.001).
Conclusions
Compared to white patients, patients from racial/ethnic minority groups had significantly different odds of developing potential PASC symptoms and conditions. Future research should examine the reasons for these differences.

758

MS269

Wahlgren, Carl; Forsberg, Gustaf; Divanoglou, Anestis; Balkhed, Åse Östholm; Niward, Katarina; Berg, Sören; Levi, Richard

Two-year follow-up of patients with post-COVID-19 condition in Sweden: a prospective cohort study

https://doi.org/10.1016/j.lanepe.2023.100595

Published

23-Feb-23

Study

https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(23)00013-3/fulltext

Background
Few studies have reported the long-term health effects of COVID-19. The regional population-based Linköping COVID-19 study (LinCoS) included all patients hospitalised due to COVID-19 during the first pandemic wave. Four months post-discharge, over 40% (185/433) experienced persisting symptoms and activity/participation limitations, indicating post-COVID-19 condition (PCC). The present follow-up study aimed to determine the long-term recovery among these patients 24 months post-admission.
Methods
This prospective cohort study included all patients from LinCoS with PCC at four months post-discharge. We repeated the same structured interview at a 24-month follow-up to identify persisting symptoms and their impact on daily life. Intercurrent health issues were identified by reviewing medical records.
Findings
Of 185 patients with PCC at 4 months post-discharge, 181 were alive at the 24-month assessment and 165 agreed to participate. Of those, 21% (35/165) had been readmitted to hospital for various causes in the interim period. The majority of patients (139/165, 84%) reported persisting problems affecting everyday life at 24 months. Significant improvements were seen in the prevalence and magnitude of some symptoms/limitations compared with four months post-discharge. Cognitive, sensorimotor, and fatigue symptoms were the most common persisting symptoms at 24 months. No clear difference was evident between individuals treated in the intensive care unit (ICU) and non-ICU-treated individuals. Approximately half of those who were on sick leave related to PCC at four months after infection were on sick leave at 24 months.
Interpretation
This is one of the first studies to report 2-year outcomes in patients with PCC following COVID-19 hospitalisation. Despite some improvements over time, we found a high prevalence of persisting symptoms and a need for long-term follow-up and rehabilitation post COVID-19 infection.
Funding
The study was funded by Region Östergötland.
publisher: Elsevier

759

MS270

Ranucci, Marco; Baryshnikova, Ekaterina; Anguissola, Martina; Pugliese, Sara; Ranucci, Luca; Falco, Mara; Menicanti, Lorenzo

The Very Long COVID: Persistence of Symptoms after 12–18 Months from the Onset of Infection and Hospitalization

https://doi.org/10.3390/jcm12051915

Published

1-Jan-23

Study

https://www.mdpi.com/2077-0383/12/5/1915

According to the World Health Organization’s definition, long COVID is the persistence or development of new symptoms 3 months after the initial infection. Various conditions have been explored in studies with up to one-year follow-up but very few looked further. This prospective cohort study addresses the presence of a wide spectrum of symptoms in 121 patients hospitalized during the acute phase of COVID-19 infection, and the association between factors related to the acute phase of the disease and the presence of residual symptoms after one year or longer from hospitalization. The main results are as follows: (i) post-COVID symptoms persist in up to 60% of the patient population at a mean follow-up of 17 months; (ii) the most frequent symptoms are fatigue and dyspnea, but neuropsychological disturbances persist in about 30% of the patients (iii) when corrected for the duration of follow-up with a freedom-from-event analysis; only complete (2 doses) vaccination at the time of hospital admission remained independently associated with persistence of the major physical symptoms, while vaccination and previous neuropsychological symptoms remained independently associated with persistence of major neuropsychological symptoms.

760

MS271

DeVries, Andrea; Shambhu, Sonali; Sloop, Sue; Overhage, J. Marc

One-Year Adverse Outcomes Among US Adults With Post–COVID-19 Condition vs Those Without COVID-19 in a Large Commercial Insurance Database

https://doi.org/10.1001/jamahealthforum.2023.0010

Published

3-Mar-23

Study

https://doi.org/10.1001/jamahealthforum.2023.0010

Key Points
Question Do postacute sequelae of SARS-CoV-2 increase risks of 1-year adverse outcomes?
Findings In this case-control study of 13 435 US adults with post–COVID-19 condition (PCC) and 26 870 matched adults without COVID-19, the adults with PCC experienced increased risks for a number of cardiovascular outcomes, such as ischemic stroke. During the 12-month follow-up period, 2.8% of the individuals with PCC vs 1.2% of the individuals without COVID-19 died, implying an excess death rate of 16.4 per 1000 individuals.
Meaning Individuals with PCC may be at increased risk for adverse outcomes in the year following initial infection.
Abstract
Importance Many individuals experience ongoing symptoms following the onset of COVID-19, characterized as postacute sequelae of SARS-CoV-2 or post–COVID-19 condition (PCC). Less is known about the long-term outcomes for these individuals.
Objective To quantify 1-year outcomes among individuals meeting a PCC definition compared with a control group of individuals without COVID-19.
Design, Setting, and Participants This case-control study with a propensity score–matched control group included members of commercial health plans and used national insurance claims data enhanced with laboratory results and mortality data from the Social Security Administration’s Death Master File and Datavant Flatiron data. The study sample consisted of adults meeting a claims-based definition for PCC with a 2:1 matched control cohort of individuals with no evidence of COVID-19 during the time period of April 1, 2020, to July 31, 2021.
Exposures Individuals experiencing postacute sequelae of SARS-CoV-2 using a Centers for Disease Control and Prevention–based definition.
Main Outcomes and Measures Adverse outcomes, including cardiovascular and respiratory outcomes and mortality, for individuals with PCC and controls assessed over a 12-month period.
Results The study population included 13 435 individuals with PCC and 26 870 individuals with no evidence of COVID-19 (mean [SD] age, 51 [15.1] years; 58.4% female). During follow-up, the PCC cohort experienced increased health care utilization for a wide range of adverse outcomes: cardiac arrhythmias (relative risk [RR], 2.35; 95% CI, 2.26-2.45), pulmonary embolism (RR, 3.64; 95% CI, 3.23-3.92), ischemic stroke (RR, 2.17; 95% CI, 1.98-2.52), coronary artery disease (RR, 1.78; 95% CI, 1.70-1.88), heart failure (RR, 1.97; 95% CI, 1.84-2.10), chronic obstructive pulmonary disease (RR, 1.94; 95% CI, 1.88-2.00), and asthma (RR, 1.95; 95% CI, 1.86-2.03). The PCC cohort also experienced increased mortality, as 2.8% of individuals with PCC vs 1.2% of controls died, implying an excess death rate of 16.4 per 1000 individuals.
Conclusions and Relevance This case-control study leveraged a large commercial insurance database and found increased rates of adverse outcomes over a 1-year period for a PCC cohort surviving the acute phase of illness. The results indicate a need for continued monitoring for at-risk individuals, particularly in the area of cardiovascular and pulmonary management.

761

MS272

Tran, Bach; Le Vu, Minh Ngoc; Le, Huong Thi; Nguyen, Tu Huu; Boyer, Laurent; Fond, Guillaume; Auquier, Pascal; Latkin, Carl A.; Ho, Roger C. M.; Ho, Cyrus S. H.; Zhang, Melvyn W. B.

Severity and geographical disparities of post-COVID-19 symptoms among the Vietnamese general population: a national evaluation

https://doi.org/10.1038/s41598-023-30790-x

Published

17-Mar-23

Study

https://www.nature.com/articles/s41598-023-30790-x

Post-COVID-19 symptoms have become a significant global health concern. This study focused on assessing the prevalence, severity, and care preference of post-COVID-19 symptoms, as well as identifying determinants to inform evidence-based policy on post-COVID-19 in Vietnam. A national cross-sectional study was conducted in May 2022 among 12,361 recovered COVID-19 patients, providing the largest dataset on health status after COVID-19 in Vietnam. The study utilized ordered logistic, Poisson regression, Multilevel linear random-effects models, and Multilevel random effects ordered logistic model to identify factors associated with various aspects of post-COVID-19 conditions. Results showed that the average number of post-COVID-19 symptoms was approximately 3, with fatigue and headache being the most common symptoms. The number of post-COVID-19 symptoms varied by province, decreased with age, and was significantly correlated with the duration of infection. Age, infection period, underlying conditions, telehealth utilization, and geographical location were identified as significant determinants of post-COVID-19 symptoms. The study concluded that improving resource allocation and health-seeking behavior in underserved areas could help address differences in health outcomes and improve post-COVID-19 control in Vietnam.

762

MS273

Bonilla, Hector; Quach, Tom C.; Tiwari, Anushri; Bonilla, Andres E.; Miglis, Mitchell; Yang, Phillip C.; Eggert, Lauren E.; Sharifi, Husham; Horomanski, Audra; Subramanian, Aruna; Smirnoff, Liza; Simpson, Norah; Halawi, Houssan; Sum-ping, Oliver; Kalinowski, Agnieszka; Patel, Zara M.; Shafer, Robert William; Geng, Linda C.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome is common in post-acute sequelae of SARS-CoV-2 infection (PASC): Results from a post-COVID-19 multidisciplinary clinic

https://doi.org/10.3389/fneur.2023.1090747

Published

15-Jul-05

Study

https://www.frontiersin.org/articles/10.3389/fneur.2023.1090747

BackgroundThe global prevalence of PASC is estimated to be present in 0·43 and based on the WHO estimation of 470 million worldwide COVID-19 infections, corresponds to around 200 million people experiencing long COVID symptoms. Despite this, its clinical features are not well-defined.MethodsWe collected retrospective data from 140 patients with PASC in a post-COVID-19 clinic on demographics, risk factors, illness severity (graded as one-mild to five-severe), functional status, and 29 symptoms and principal component symptoms cluster analysis. The Institute of Medicine (IOM) 2015 criteria were used to determine the Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) phenotype.FindingsThe median age was 47 years, 59.0% were female; 49.3% White, 17.2% Hispanic, 14.9% Asian, and 6.7% Black. Only 12.7% required hospitalization. Seventy-two (53.5%) patients had no known comorbid conditions. Forty-five (33.9%) were significantly debilitated. The median duration of symptoms was 285.5 days, and the number of symptoms was 12. The most common symptoms were fatigue (86.5%), post-exertional malaise (82.8%), brain fog (81.2%), unrefreshing sleep (76.7%), and lethargy (74.6%). Forty-three percent fit the criteria for ME/CFS, majority were female, and obesity (BMI > 30 Kg/m2) (P = 0.00377895) and worse functional status (P = 0.0110474) were significantly associated with ME/CFS.InterpretationsMost PASC patients evaluated at our clinic had no comorbid condition and were not hospitalized for acute COVID-19. One-third of patients experienced a severe decline in their functional status. About 43% had the ME/CFS subtype.

763

MS274

Wong, Martin Chi-Sang; Huang, Junjie; Wong, Yuet-Yan; Wong, Grace Lai-Hung; Yip, Terry Cheuk-Fung; Chan, Rachel Ngan-Yin; Chau, Steven Wai-Ho; Ng, Siew-Chien; Wing, Yun-Kwok; Chan, Francis Ka-Leung

Epidemiology, Symptomatology, and Risk Factors for Long COVID Symptoms: Population-Based, Multicenter Study

https://doi.org/10.2196/42315

Published

7-Mar-23

Study

https://publichealth.jmir.org/2023/1/e42315

Company: JMIR Public Health and Surveillance
Distributor: JMIR Public Health and Surveillance
Institution: JMIR Public Health and Surveillance
Label: JMIR Public Health and Surveillance
publisher: JMIR Publications Inc., Toronto, Canada

764

MS275

Patel, Ajay I.; Yadav, Anju; Patel, Ashok B.; Vyas, Amitkumar J.

Post Covid-19 Women Complications

https://doi.org/10.52711/2349-2996.2023.00017

Published

16-Mar-23

Review

https://ajner.com/AbstractView.aspx?PID=2023-13-1-17

Post-covid-19 women complications, Post covid-19 is Clinical symptoms that persist or worsen after acute COVID It is contains both ongoing symptomatic COVID-19 between 4 to 12 weeks or post COVID-19 more than 12 weeks. As of June 2020, given the terminology "post COVID-19". Reported studies are related to complications of the female patient, including effects on the immune system, physiology, or psychological health, and effects on pre-existing diseases, including hypertension, diabetes mellitus, neurodegenerative disease, rheumatoid arthritis, and tuberculosis (TB). However, six months after recovery from COVID-19, complications arise, including cough, fever, breathlessness, muscle aches, joint pain, fatigue, gastrointestinal complaints, anosmia, dyspepsia, sleep difficulties, anxiety or depression, higher stress levels, physical decline, post-activity polypnea, alopecia, chest tightness, palpitations, intestinal blockages, impaired respiratory functions, neurological issues, olfactory dysfunction, cognition, dexterity, conversation, disabilities of sight, or listening. Along with other miscellaneous complications such as Miller-Fisher syndrome. Overall, these reviews summarise studies conducted on pre-existing diseases in female patients after COVID-19, complications in female patients with immune dysfunction, including hormonal imbalances, and CSF-insufficiency in female patients with neurodegeneration complications. It observed high levels of molecular markers such as tau protein (t-tau, p-tau), plasma amyloid-beta (A42), glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neurofilament light chain protein. In Female patients with diabetes mellitus (Type 1 and Type 2) complications reported higher levels of sCr, C-reactive protein, TN-I, white blood cell, and erythrocyte sedimentation rate levels, enzymes, electrolytes, and coagulation factors, and female patients with tuberculosis (TB) complications had lower aggressive angiomyxoma (AAM) and E2 hormone levels.

765

MS276

Wang, Siwen; Farland, Leslie V.; Gaskins, Audrey J.; Mortazavi, Jasmine; Wang, Yi-Xin; Tamimi, Rulla M.; Rich-Edwards, Janet W.; Zhang, Dan; Terry, Kathryn L.; Chavarro, Jorge E.; Missmer, Stacey A.

Association of Laparoscopically-confirmed Endometriosis with Long COVID: A Prospective Cohort Study

https://doi.org/10.1016/j.ajog.2023.03.030

Published

25-Mar-23

Study

https://www.sciencedirect.com/science/article/pii/S0002937823001771

Background
Women are at greater risk than men of developing chronic inflammatory conditions and of developing ‘long COVID.’ However, few gynecologic health risk factors for long COVID have been identified. Endometriosis is a common gynecological disorder associated with chronic inflammation, immune dysregulation, and comorbid presentation with autoimmune and clotting disorders, all of which are pathophysiologic mechanisms proposed for long COVID. Therefore, we hypothesized that women with a history of endometriosis may be at greater risk of developing long COVID.
Objective
To investigate the association between history of endometriosis prior to SARS-CoV-2 infection and risk of long COVID.
Methods
We followed 46,579 women from two ongoing prospective cohort studies: the Nurses’ Health Study II and the Nurses’ Health Study 3, who participated in a series of COVID-19-related surveys administered from April 2020 to November 2022. Laparoscopic diagnosis of endometriosis was documented prospectively in main cohort questionnaires prior to the pandemic (1993–2020) with high validity. SARS-CoV-2 infection (confirmed by antigen, PCR, or antibody test) and CDC-defined long-term COVID-19 symptoms (≥4 weeks) were self-reported during follow-up. Among individuals with SARS-CoV-2 infection, we fit Poisson regression models to assess the associations between endometriosis and risk of long COVID-19 symptoms, with adjustment for potential confounding variables (demographics, body mass index, smoking status, history of infertility, and history of chronic diseases).
Results
Among 3650 women in our sample with self-reported SARS-CoV-2 infections during follow-up, 386 (10.6%) had a history of endometriosis with laparoscopic confirmation and 1598 (43.8%) reported experiencing long COVID symptoms. The majority of women were Non-Hispanic White (95.4%), with a median age of 59 years (interquartile range=44–65). Women with a history of laparoscopically-confirmed endometriosis had a 22% greater risk of developing long COVID (adjusted RR=1.22, 95% CI=1.05–1.42), compared to those who had never been diagnosed with endometriosis. The association was stronger when we defined long COVID as having symptoms ≥8 weeks (RR=1.28, 95% CI=1.09–1.50). We observed no statistically significant differences in the relationship between endometriosis and long COVID by age, infertility history, or comorbidity with uterine fibroids, although there was a suggestive trend that women <50 years may be at higher risk (<50 years, RR=1.37, 95% CI=1.00–1.88; ≥50 years, RR=1.19, 95% CI=1.01–1.41). Among persons who developed long COVID, women with endometriosis reported on average one additional long-term symptom compared to women without endometriosis.
Conclusions and relevance
Our findings suggest that those with a history of endometriosis may be at modestly increased risk for long COVID. Health care providers should be aware of endometriosis history when treating patients for signs of persisting symptoms post-SARS-CoV-2 infection. Future studies should investigate the potential biological pathways underlying these associations.

766

MS277

Bostanci, Aysegul; Gazi, Umut; Tosun, Ozgur; Suer, Kaya; Unal Evren, Emine; Evren, Hakan; Sanlidag, Tamer

Long-COVID-19 in Asymptomatic, Non-Hospitalized, and Hospitalized Populations: A Cross-Sectional Study

https://doi.org/10.3390/jcm12072613

Published

1-Jan-23

Study

https://www.mdpi.com/2077-0383/12/7/2613

A substantial proportion of coronavirus disease 2019 (COVID-19) survivors continue to suffer from long-COVID-19 (LC) symptoms. Our study aimed to determine the risk factors for LC by using a patient population from Northern Cyprus. Subjects who were diagnosed with severe acute respiratory syndrome-2 (SARS-CoV-2) infection in our university hospital were invited and asked to fill in an online questionnaire. Data from 296 survivors who had recovered from COVID-19 infection at least 28 days prior the study was used in the statistical analysis. For determination of risk factors for “ongoing symptomatic COVID-19 (OSC)” and “Post-COVID-19 (PSC)” syndromes, the patient population was further divided into group 1 (Gr1) and group 2 (Gr2), that included survivors who were diagnosed with COVID-19 within 4-12 weeks and at least three months prior the study, respectively. The number of people with post-vaccination SARS-CoV-2 infection was 266 (89.9%). B.1.617.2 (Delta) (41.9%) was the most common SARS-CoV-2 variant responsible for the infections, followed by BA.1 (Omicron) (34.8%), B.1.1.7 (Alpha) (15.5%), and wild-type SARS-CoV-2 (7.8%). One-hundred-and-nineteen volunteers (40.2%) stated an increased frequency of COVID-19-related symptoms and experienced the symptoms in the week prior to the study. Of those, 81 (38.8%) and 38 (43.7%) were from Gr1 and Gr2 groups, respectively. Female gender, chronic illness, and symptomatic status at PCR testing were identified as risk factors for developing OSC syndrome, while only the latter showed a similar association with PSC symptoms. Our results also suggested that ongoing and persistent COVID-19-related symptoms are not influenced by the initial viral cycle threshold (Ct) values of the SARS-CoV-2, SARS-CoV-2 variant as well as vaccination status and type prior to COVID-19. Therefore, strategies other than vaccination are needed to combat the long-term effect of COVID-19, especially after symptomatic SARS-CoV-2 infection, and their possible economic burden on healthcare settings.

767

MS278

da Silva, Rosilene; de Sarges, Kevin Matheus Lima; Cantanhede, Marcos Henrique Damasceno; da Costa, Flávia Póvoa; dos Santos, Erika Ferreira; Rodrigues, Fabíola Brasil Barbosa; de Nazaré do Socorro de Almeida Viana, Maria; de Meira Leite, Mauro; da Silva, Andréa Luciana Soares; de Brito, Mioni Thieli Magalhães; da Silva Torres, Maria Karoliny; Queiroz, Maria Alice Freitas; Vallinoto, Izaura Maria Vieira Cayres; Henriques, Daniele Freitas; dos Santos, Carla Pinheiro; Viana, Giselle Maria Rachid; Quaresma, Juarez Antônio Simões; Falcão, Luiz Fábio Magno; Vallinoto, Antonio Carlos Rosário; dos Santos, Eduardo José Melo

Thrombophilia and Immune-Related Genetic Markers in Long COVID

https://doi.org/10.3390/v15040885

Published

1-Apr-23

Study

https://www.mdpi.com/1999-4915/15/4/885

Aiming to evaluate the role of ten functional polymorphisms in long COVID, involved in major inflammatory, immune response and thrombophilia pathways, a cross-sectional sample composed of 199 long COVID (LC) patients and a cohort composed of 79 COVID-19 patients whose follow-up by over six months did not reveal any evidence of long COVID (NLC) were investigated to detect genetic susceptibility to long COVID. Ten functional polymorphisms located in thrombophilia-related and immune response genes were genotyped by real time PCR. In terms of clinical outcomes, LC patients presented higher prevalence of heart disease as preexistent comorbidity. In general, the proportions of symptoms in acute phase of the disease were higher among LC patients. The genotype AA of the interferon gamma (IFNG) gene was observed in higher frequency among LC patients (60%; p = 0.033). Moreover, the genotype CC of the methylenetetrahydrofolate reductase (MTHFR) gene was also more frequent among LC patients (49%; p = 0.045). Additionally, the frequencies of LC symptoms were higher among carriers of IFNG genotypes AA than among non-AA genotypes (Z = 5.08; p < 0.0001). Two polymorphisms were associated with LC in both inflammatory and thrombophilia pathways, thus reinforcing their role in LC. The higher frequencies of acute phase symptoms among LC and higher frequency of underlying comorbidities might suggest that acute disease severity and the triggering of preexisting condition may play a role in LC development.

768

MS279

Warren-Gash, Charlotte; Lacey, Andrea; Cook, Sarah; Stocker, Dylan; Toon, Samantha; Lelii, Ffion; Ford, Ben; Ireland, Georgina; Ladhani, Shamez N.; Stephenson, Terence; Nguipdop-Djomo, Patrick; Mangtani, Punam; McClenahan, Elliot; McKay, Gillian; Phelan, Jody; Lin, Liang-Yu; Lewin, Alex; Judd, Alison; Davies, Byron; Saib, Anisah; McCrae, James; Kelly, Joe; Diamond, Ian; Rourke, Emma; Dawe, Fiona; Jones, Pete; the COVID-19 Schools Infection Survey 2 Study Group

Post-COVID-19 condition and persisting symptoms in English schoolchildren: repeated surveys to March 2022

https://doi.org/10.1186/s12879-023-08203-1

Published

5-Apr-23

Study

https://doi.org/10.1186/s12879-023-08203-1

Background
Both post-COVID-19 condition (long COVID) and the presence of persisting symptoms that do not meet formal definitions of post-COVID-19-condition may adversely affect quality of life and function. However, their prevalence among children and young people in England is unclear.

Methods
We used data from repeated surveys in a large cohort of English schoolchildren from the COVID-19 Schools Infection Survey (SIS) for the school year 2021/22 to describe the weighted prevalence of post-COVID-19-condition and compare persisting symptoms between individuals with a positive SARS-CoV-2 test and those with neither a positive test history nor suspected infection.

Results
Among 7797 children from 173 schools, 1.8% of primary school pupils (aged 4 to 11 years), 4.5% of secondary school pupils in years 7–11 (aged 11 to 16 years) and 6.9% of those in years 12–13 (aged 16 to 18 years) met a definition of post-COVID-19 condition in March 2022. Specific persisting symptoms such as anxiety or difficulty concentrating were frequently reported regardless of prior infection status and increased with age: 48.0% of primary school pupils, 52.9% of secondary school pupils in years 7–11 and 79.5% in years 12–13 reporting at least one symptom lasting more than 12 weeks. Persisting loss of smell and taste, cardiovascular and some systemic symptoms were more frequently reported by those with a previous positive test.

Conclusions
We showed that ongoing symptoms were frequently reported by English schoolchildren regardless of SARS-CoV-2 test results and some specific symptoms such as loss of smell and taste were more prevalent in those with a positive test history. Our study emphasises the wide-ranging impacts of the COVID-19 pandemic on the health and wellbeing of children and young people.

769

MS280

Pena-Orbea, Cinthya; Lapin, Brittany; Li, Yadi; Englund, Kristin; Heinzinger, Catherine; Foldvary-Schaefer, Nancy; Mehra, Reena

Sleep Disturbance Severity and Correlates in Post-acute Sequelae of COVID-19 (PASC)

https://doi.org/10.1007/s11606-023-08187-3

Published

4-Apr-23

Study

https://doi.org/10.1007/s11606-023-08187-3

INTRODUCTION
Post-acute COVID-19 syndrome (PASC) is a global public health crisis in which patients experience lingering and debilitating symptoms beyond 4 weeks after the acute onset of SARS-CoV-2 infection.1 Sleep disturbance has a reported prevalence of 34–50% in PASC,2,3 but only a few studies have identified associated risk factors, and these have primarily described sleep quality and not symptom severity.3,4 Likewise, studies to date have not investigated the interaction of mood disorders and fatigue with sleep disturbance severity or the association of objective sleep study indices in PASC.

METHODS
Patients with PASC1 were evaluated at the Cleveland Clinic ReCOver Clinic between February 2021 and April 2022. Patients ≥ 18 years old who completed Patient-Reported Outcomes Measurement Information System (PROMIS)5 Sleep Disturbance within 90 days or during their initial ReCOver clinic visit were prospectively examined. Demographics and clinical characteristics were extracted from the COVID-19 Cleveland Clinic Registry. In a subset with pre-infection sleep studies available, Apnea Hypopnea Index (AHI) and hypoxia measures (mean oxygen saturation [SaO2%] and percentage of time spent < 90% oxygen saturation [T90]) were extracted. Patient-reported outcomes collected during the initial ReCOver clinic visit from the Electronic Medical Record included PROMIS Sleep Disturbance, Fatigue, and Global Health (PROMIS-GH) v1.2, Generalized Anxiety Disorder (GAD)-2, Patient Health Questionnaire (PHQ)-2, and the Quality of Life in Neurological Disorders (Neuro-QoL) v1.0 Cognitive Function. PROMIS scores were standardized on a T-scale with mean 50 (SD 10)6, with established cut-points at > 55, > 60, and > 70 for mild, moderate, and severe sleep disturbance respectively.6 Multivariable models were constructed to identify independent predictors of moderate to severe sleep disturbances based on clinically relevant variables determined a priori. Interactions between mood disorders and fatigue using PROMIS Fatigue, PHQ-2, and GAD-2 scores were tested.

RESULTS
A total of 962 of 1660 patients completed the PROMIS Sleep Disturbance; 565 (58.7%) had normal to mild sleep disturbance and 397 (41.3%) had moderate to severe sleep disturbance with characteristics shown in Table 1. After adjustment (Table 2), Black race (OR = 1.84, 95%CI: 1.10–3.08, p = 0.020), hospitalization for COVID-19 (OR = 1.59, 95%CI: 1.10–2.32, p < 0.015), greater anxiety severity (OR = 1.31, 95%CI: 1.18–1.45, p < 0.001), and moderate to severe fatigue (OR = 2.03, 95%CI: 1.33–3.11, p = 0.001) were significantly associated with moderate to severe sleep disturbance. Statistical interactions of anxiety severity and moderate to severe fatigue were not significant (p = 0.84).

Table 1 Patient Characteristics Stratified by Normal/Mild Versus Moderate/Severe Sleep Disturbance
Full size table
Table 2 Multivariable Logistic Regression Model for Predicting Moderate/Severe Sleep Disturbance
Full size table
Forty-eight patients had pre-COVID-19 sleep testing conducted 2.6 ± 2.1 years prior to the initial ReCOver Clinic appointment. AHI, the primary measure of obstructive sleep apnea (OSA) severity, was 15.4 ± 18.9 with mean SaO2 of 92 ± 2.3% and a median T90% of 12.1 [2.8,73.3] (Table 1). OSA (AHI:18.7 ± 24.4 vs 12.4 ± 11.8, p = 0.27) and hypoxia measures (mean SaO2%: 91.5 ± 2.8 vs 92.5 ± 1.6, p = 0.14; median T90% 16.5 [3.5, 83.2]vs 9.3 [1.8, 44.3], p = 0.32) were not statistically different between normal to mild and moderate to severe sleep disturbance.

DISCUSSION
Novel findings include a high prevalence of 41.3% of moderate to severe sleep disturbance in PASC associated with Black race, hospitalization for COVID-19, anxiety severity, and moderate to severe fatigue. There was no significant interaction between anxiety severity and moderate to severe fatigue; further studies are needed to investigate the interplay between mental and sleep disturbances in PASC physiologic pathways. Likewise, there was no association between objective sleep study measures of antecedent sleep apnea and hypoxia with sleep disturbance. This may be explained by the small sample size, testing indication biases, or limitations of sleep study type (i.e., home sleep apnea test), precluding assessment of objective sleep quality or quantity measures. With 58% of PASC patients completing PROMIS Sleep Disturbance, our study may suffer from selection bias. However, we observed that among patients of Black race who did not complete PROMIS Sleep Disturbance, 60% completed mood and fatigue questionnaires. As such, it is possible that the magnitude of association between Black race and moderate to severe sleep disturbances is even stronger. Study findings emphasize the importance of identification of sleep disturbance in PASC considering its impact on patients’ quality of life, daytime functioning, and medical health status. Results inform risk stratification and highlight the need to elucidate contributions of structural racism and socioeconomic inequities to PASC-related sleep disturbances with the goal of developing interventions to reduce PASC disparities.

770

MS281

Zhang, Xiaotong

Chronic Lung Disease as a Risk Factor for Long COVID in Patients Diagnosed with COVID-19: A Retrospective Cohort Study

Published

1-May-23

Study

https://digitalcommons.unmc.edu/coph_slce/237

Background: Patients with coronavirus disease 2019 (COVID-19) experience a wide range of ongoing symptoms after the acute phase of SARS-CoV-2 infection. Chronic lung disease has been shown to be a potential risk factor for persistent post-COVID conditions (PCC or long COVID).

Objective: This study aimed to examine the relationship between chronic lung disease before COVID infection and the incidence of long COVID.

Method: We conducted a retrospective cohort study to evaluate the association between chronic lung disease and the incidence of long COVID during a 6-month follow-up period after the acute phase of the infection. Data were sourced from the National COVID Cohort Collaborative (N3C) Data Enclave. Patients included were adults (18-65 years of age), 1) who were confirmed COVID positive during three consecutive SARS-CoV-2 variant dominance periods (Pre-Delta wave from December 29, 2020 to June 14, 2021; Delta wave from June 15, 2021 to November 29, 2021; Omicron wave from November 30, 2021 to June 15, 2022); 2) who completed the 6-month follow-up after acute phase; 3) who were diagnosed with long COVID within 6 months after acute phase but were lost to follow up thereafter. Otherwise, patients who were lost to follow up before the end of follow-up period were excluded. Patients who died from COVID during acute phase were also excluded. We used multivariate logistic regression to evaluate the association between long COVID and chronic lung disease as well as other risk factors. Sensitivity analysis was conducted by removing those who were lost to follow up after long COVID diagnosis.

Results: 970,707 patients were included in the study cohort. The overall incidence of long COVID was 1.2%. Chronic lung disease was significantly associated with long COVID (adjusted OR:1.4, 95% CI: 1.34 to 1.47). Reinfection after COVID increased the odds for long COVID by 17% (adjusted OR 1.17, 95% CI: 1.01 to 1.34) among patients with chronic lung disease, but it had no effect on long COVID risk among those without chronic lung disease (adjusted OR: 1.02, 95% CI: 0.93 to 1.12). Cardiomyopathy was also associated with long COVID among patients with chronic lung disease (adjusted OR 1.2, 95% CI: 1.01 to 1.43). Female sex and age of 40-65 years were related to higher odds for long COVID in both subgroups. Sensitivity analysis provided consistent results after removing the patients who were lost to follow up after being diagnosed with long COVID.

Conclusion: Underlying chronic lung disease is associated with a higher risk for long COVID during 6 months after acute phase of the infection. Precautions should be taken in this population, especially females, those at the age of 40 to 65 years, those with reinfections post COVID or cardiomyopathy.

771

MS282

Bamps, Laurence; Armenti, Jean-Philippe; Bojan, Mirela; Grandbastien, Bruno; von Garnier, Christophe; Du Pasquier, Renaud; Desgranges, Florian; Papadimitriou-Olivgeris, Matthaios; Alberio, Lorenzo; Preisig, Martin; Schwitter, Jurg; Guery, Benoit; The RegCOVID Study Group

Long-Term Consequences of COVID-19: A 1-Year Analysis

https://doi.org/10.3390/jcm12072673

Published

1-Jan-23

Study

https://www.mdpi.com/2077-0383/12/7/2673

Long-lasting symptoms after SARS-CoV-2 infection have been described many times in the literature and are referred to as Long COVID. In this prospective, longitudinal, monocentric, observational study, we collected the health complaints of 474 patients (252 ambulatory and 222 hospitalized) at Lausanne University Hospital 1 year after COVID-19 diagnosis. Using a self-reported health survey, we explored cardiopulmonary, vascular, neurological, and psychological complaints. Our results show that age, Charlson comorbidity index, and smoking habits were associated with hospital admission. Regarding the vascular system, we found that having had thromboembolism before SARS-CoV-2 infection was significantly associated with a higher risk of recurrence of thromboembolism at 1 year. In the neurologic evaluation, the most frequent symptom was fatigue, which was observed in 87.5% of patients, followed by “feeling slowed down”, headache, and smell disturbance in 71.5%, 68.5%, and 60.7% of cases, respectively. Finally, our cohort subjects scored higher overall in the STAI, CESD, Maastricht, and PSQI scores (which measure anxiety, depression, fatigue, and sleep, respectively) than the healthy population. Using cluster analysis, we identified two phenotypes of patients prone to developing Long COVID. At baseline, CCS score, prior chronic disease, stroke, and atrial fibrillation were associated with Long COVID. During COVID infection, mechanical ventilation and five neurological complaints were also associated with Long COVID. In conclusion, this study confirms the wide range of symptoms developed after COVID with the involvement of all the major systems. Early identification of risk factors associated with the development of Long COVID could improve patient follow-up; nevertheless, the low specificity of these factors remains a challenge to building a systematic approach.

772

MS283

Percze, Anna Reka; Nagy, Alexandra; Polivka, Lorinc; Barczi, Eniko; Czaller, Ibolya; Kovats, Zsuzsanna; Varga, Janos Tamas; Ballai, Judit H.; Muller, Veronika; Horvath, Gabor

Fatigue, sleepiness and sleep quality are SARS-CoV-2 variant independent in patients with long COVID symptoms

https://doi.org/10.1007/s10787-023-01190-4

Published

5-Apr-23

Study

https://doi.org/10.1007/s10787-023-01190-4

Acute infections with SARS-CoV-2 variants of concerns (VOCs) differ in clinical presentation. Discrepancies in their long-term sequelae, commonly referred to as long COVID, however, remain to be explored. We retrospectively analyzed data of 287 patients presented at the post-COVID care of the Pulmonology Department, Semmelweis University, Budapest, Hungary, and infected with SARS-CoV-2 during a period of 3 major epidemic waves in Hungary (February–July 2021, VOC: B.1.1.7, Alpha, N = 135; August–December 2021, VOC: B.1.617.2, Delta, N = 89; and January–June 2022, VOC: B.1.1.529, Omicron; N = 63), > 4 weeks after acute COVID-19. Overall, the ratio of long COVID symptomatic (LC) and asymptomatic (NS) patients was 2:1. Self-reported questionnaires on fatigue (Fatigue Severity Scale, FSS), sleepiness (Epworth Sleepiness Scale, ESS) and sleep quality (Pittsburgh Sleep Quality Index, PSQI) showed higher scores for LC (4.79 ± 0.12, 7.45 ± 0.33 and 7.46 ± 0.27, respectively) than NS patients (2.85 ± 0.16, 5.23 ± 0.32 and 4.26 ± 0.29, respectively; p < 0.05 for all vs. LC). By comparing data of the three waves, mean FSS and PSQI scores of LC patients, but not ESS scores, exceeded the normal range in all, with no significant inter-wave differences. Considering FSS ≥ 4 and PSQI > 5 cutoff values, LC patients commonly exhibited problematic fatigue (≥ 70%) and poor sleep quality (> 60%) in all three waves. Comparative analysis of PSQI component scores of LC patients identified no significant differences between the three waves. Our findings highlight the importance of concerted efforts to manage both fatigue and sleep disturbances in long COVID patient care. This multifaceted approach should be followed in all cases infected with either VOCs of SARS-CoV-2.

773

MS284

Chilunga, Felix Patience; Appelman, Brent; Vugt, Michele van; Kalverda, Kirsten; Smeele, Patrick; Es, Josien van; Wiersinga, Willem Joost; Rostila, Mikael; Prins, Maria; Stronks, Karien; Norredam, Marie; Agyemang, Charles

Differences in incidence, nature of symptoms, and duration of long COVID among hospitalised migrant and non-migrant patients in the Netherlands: a retrospective cohort study

https://doi.org/10.1016/j.lanepe.2023.100630

Published

6-Apr-23

Study

https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(23)00049-2/fulltext

Background
Comprehensive data on long COVID across ethnic and migrant groups are lacking. We investigated incidence, nature of symptoms, clinical predictors, and duration of long COVID among COVID-19 hospitalised patients in the Netherlands by migration background (Dutch, Turkish, Moroccan, and Surinamese origin, Others).
Methods
We used COVID-19 admissions and follow up data (January 2021–July 2022) from Amsterdam University Medical Centers. We calculated long COVID incidence proportions per NICE guidelines by migration background and assessed for clinical predictors via robust Poisson regressions. We then examined associations between migration background and long COVID using robust Poisson regressions and adjusted for derived clinical predictors, and other biologically relevant factors. We also assessed long COVID symptom persistence at one-year post-discharge.
Findings
1886 patients were included. 483 patients had long COVID (26%, 95% CI 24–28%) at 12 weeks post-discharge. Symptoms like dizziness, joint pain, insomnia, and headache varied by migration background. Clinical predictors of long COVID were female sex, hospital admission duration, intensive care unit admission, and receiving oxygen, or corticosteroid therapy. Long COVID risk was higher among patients with migration background than Dutch origin patients after adjustments for derived clinical predictors, age, smoking, vaccination status, comorbidities and remdesivir treatment. Only 14% of long COVID symptoms persisted at one-year post-discharge.
Interpretation
There are significant differences in occurrence, nature of symptoms, and duration of long COVID by migration background. Studies assessing the spectrum of functional limitation and access to post-COVID healthcare are needed to help plan for appropriate and accessible healthcare interventions.
publisher: Elsevier

774

MS285

Sedgley, Robert; Winer-Jones, Jessamine; Bonafede, Machaon

Long COVID Incidence in a Large US Ambulatory Electronic Health Record System

https://doi.org/10.1093/aje/kwad095

Published

19-Apr-23

Study

https://doi.org/10.1093/aje/kwad095

Estimates of the prevalence of long COVID vary widely. This retrospective cohort study describes the incidence of long COVID symptoms 12-20 weeks post-diagnosis in a US ambulatory care setting and identifies potential risk factors. We identified patients with and without a diagnosis of or positive test for COVID-19 between 1/1/2020 and 3/13/2022 in the Veradigm EHR database. We captured patient demographics, clinical characteristics, and COVID-19 comorbidities in the 12-month baseline period. We compared long COVID symptoms between matched cases and controls 12-20 weeks post-index (COVID-19 diagnosis date [cases] or median visit date [controls]). Multivariable logistic regression was used to examine associations between baseline COVID-19 comorbidities and long COVID symptoms. Among 916,894 patients with COVID-19, 14.8% had at least one long COVID symptom in the 12-20 weeks post-index compared to 2.9% of patients without documented COVID-19. Commonly reported symptoms were joint stiffness (4.5%), cough (3.0%), and fatigue (2.7%). Among patients with COVID-19, the adjusted odds of long COVID symptoms were significantly higher among patients with a baseline COVID-19 comorbidity (odds ratio: 1.91 [95% confidence interval: 1.88-1.95]). In particular, prior diagnosis of cognitive disorders, transient ischemic attack, hypertension, and obesity were associated with higher odds of long COVID symptoms.

775

MS286

Fung, Kin Wah; Baye, Fitsum; Baik, Seo H.; Zheng, Zhaonian; McDonald, Clement J.

Prevalence and characteristics of long COVID in elderly patients: An observational cohort study of over 2 million adults in the US

https://doi.org/10.1371/journal.pmed.1004194

Published

17-Apr-23

Study

https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004194

Background
Incidence of long COVID in the elderly is difficult to estimate and can be underreported. While long COVID is sometimes considered a novel disease, many viral or bacterial infections have been known to cause prolonged illnesses. We postulate that some influenza patients might develop residual symptoms that would satisfy the diagnostic criteria for long COVID, a condition we call “long Flu.” In this study, we estimate the incidence of long COVID and long Flu among Medicare patients using the World Health Organization (WHO) consensus definition. We compare the incidence, symptomatology, and healthcare utilization between long COVID and long Flu patients.

Methods and findings
This is a cohort study of Medicare (the US federal health insurance program) beneficiaries over 65. ICD-10-CM codes were used to capture COVID-19, influenza, and residual symptoms. Long COVID was identified by (a) the designated long COVID code B94.8 (code-based definition), or (b) any of 11 symptoms identified in the WHO definition (symptom-based definition), from 1 to 3 months post-infection. A symptom would be excluded if it occurred in the year prior to infection. Long Flu was identified in influenza patients from the combined 2018 and 2019 Flu seasons by the same symptom-based definition for long COVID. Long COVID and long Flu were compared in 4 outcome measures: (a) hospitalization (any cause); (b) hospitalization (for long COVID symptom); (c) emergency department (ED) visit (for long COVID symptom); and (d) number of outpatient encounters (for long COVID symptom), adjusted for age, sex, race, region, Medicare-Medicaid dual eligibility status, prior-year hospitalization, and chronic comorbidities. Among 2,071,532 COVID-19 patients diagnosed between April 2020 and June 2021, symptom-based definition identified long COVID in 16.6% (246,154/1,479,183) and 29.2% (61,631/210,765) of outpatients and inpatients, respectively. The designated code gave much lower estimates (outpatients 0.49% (7,213/1,479,183), inpatients 2.6% (5,521/210,765)). Among 933,877 influenza patients, 17.0% (138,951/817,336) of outpatients and 24.6% (18,824/76,390) of inpatients fit the long Flu definition. Long COVID patients had higher incidence of dyspnea, fatigue, palpitations, loss of taste/smell, and neurocognitive symptoms compared to long Flu. Long COVID outpatients were more likely to have any-cause hospitalization (31.9% (74,854/234,688) versus 26.8% (33,140/123,736), odds ratio 1.06 (95% CI 1.05 to 1.08, p < 0.001)), and more outpatient visits than long Flu outpatients (mean 2.9(SD 3.4) versus 2.5(SD 2.7) visits, incidence rate ratio 1.09 (95% CI 1.08 to 1.10, p < 0.001)). There were less ED visits in long COVID patients, probably because of reduction in ED usage during the pandemic. The main limitation of our study is that the diagnosis of long COVID in is not independently verified.

Conclusions
Relying on specific long COVID diagnostic codes results in significant underreporting. We observed that about 30% of hospitalized COVID-19 patients developed long COVID. In a similar proportion of patients, long COVID-like symptoms (long Flu) can be observed after influenza, but there are notable differences in symptomatology between long COVID and long Flu. The impact of long COVID on healthcare utilization is higher than long Flu.

Author summary
Why was this study done?
The quoted incidence of long COVID varies widely because of differences in definition and measurement method. Long COVID in the elderly is likely to be underreported because they are less likely to respond to surveys, and symptoms may be confused with other chronic diseases.
Lingering ill health after infections is not limited to COVID-19. We postulate that some patients may fit the diagnostic criteria of long COVID after a bout of influenza. We call this condition “long Flu.” Comparing and contrasting long COVID and long Flu may shed light on the understanding of long COVID, a disease still shrouded in mystery.
What did the researchers do and find?
We used the World Health Organization long COVID definition on 2 million Medicare patients with COVID-19 between April 2020 and June 2021. We applied the same definition to almost 900,000 influenza patients during the 2018 and 2019 Flu seasons to identify long Flu.
Long COVID occurred in 16.6% of outpatients and 29.2% of inpatients. The corresponding rates for long Flu were 17% and 24.6%. Using only the designated long COVID code, the estimated rates would be 0.5% and 2.6%, way below the reported rates in most studies.
Despite the similar overall incidence rates, long COVID patients suffered with notably different symptoms compared to long Flu patients and were also more likely to access inpatient and outpatient healthcare services.
What do these findings mean?
The use of designated long COVID diagnostic codes alone is likely to result in gross underreporting of long COVID in this population.
Long COVID is associated with greater healthcare utilization than long Flu, suggesting a bigger impact on individual health and well-being, as well as on healthcare expenditure.

776

MS287

Yao, Lan; Wang, Gang; Aleya, Lotfi; Maida, Marcello; Graff, J. Carolyn; Sun, Dianjun; Gu, Weikuan

Was the rate of Long Covid as high as 45%–a scary report with flaw

https://doi.org/10.1016/j.eclinm.2023.101949

Published

1-May-23

Letter to editor

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00126-8/fulltext

Long Covid has worried the public as the COVID-19 pandemic continues. We are interested in the report by O'Mahoney et al. on the systematic review and meta-analysis of the prevalence and long-term health effects of Long Covid among hospitalized and non-hospitalized populations.1 We were surprised that 45% of COVID-19 survivors, regardless of hospitalization status, experienced a range of unresolved symptoms at ∼ 4 months. First, these data suggest that a large population worldwide had Long Covid in the past two years up to the end of 2021. The authors collected data from publications until January 2022. Based on the report from World Health Organization (https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---31-August-2021), as of December 26, over 278 million cases were reported globally. If 45% of them have the Long Covid, 130 million people worldwide suffer from Long Covid after 4 months of COVID-19. Secondly, these data are significantly different from public perception. According to the December 15, 2022 report from the Centers for Disease Control and Prevention (https://www.cdc.gov/nchs/covid19/pulse/long-covid.htm), the prevalence of Long Covid was less than 20%. Most importantly, it differs from a credible recent publication.2 Based on the data of 486,149 non-hospitalized individuals, Subramanian and colleagues found that 5.3% of men and 9.8% of women had Long COVID symptoms 12 weeks after the index date.2 As such, we examined the data from the systematic review and found some discrepancies and would like to bring them to public attention.

publisher: Elsevier
PMID: 37125399

777

MS288

Malesevic, Stefan; Sievi, Noriane A.; Baumgartner, Patrick; Roser, Katharina; Sommer, Grit; Schmidt, Dörthe; Vallelian, Florence; Jelcic, Ilijas; Clarenbach, Christian F.; Kohler, Malcolm

Impaired health-related quality of life in long-COVID syndrome after mild to moderate COVID-19

https://doi.org/10.1038/s41598-023-34678-8

Published

12-May-23

Study

https://www.nature.com/articles/s41598-023-34678-8

A growing number of patients with SARS-CoV-2 infections experience long-lasting symptoms. Even patients who suffered from a mild acute infection show a variety of persisting and debilitating neurocognitive, respiratory, or cardiac symptoms (Long-Covid syndrome), consequently leading to limitations in everyday life. Because data on health-related quality of life (HRQoL) is scarce, we aimed to characterize the impact of Long-Covid symptoms after a mild or moderate acute infection on HRQoL. In this observational study, outpatients seeking counseling in the interdisciplinary Post-Covid consultation of the University Hospital Zurich with symptoms persisting for more than 4 weeks were included. Patients who received an alternative diagnosis or suffered from a severe acute Covid-19 infection were excluded. St. George’s Respiratory Questionnaire (SGRQ), Euroquol-5D-5L (EQ-5D-5L), and the Short form 36 (SF-36) were distributed to assess HRQoL. 112 patients were included, 86 (76.8%) were female, median (IQR) age was 43 (32.0, 52.5) years with 126 (91, 180) days of symptoms. Patients suffered frequently from fatigue (81%), concentration difficulties (60%), and dyspnea (60%). Patients mostly stated impairment in performing usual activities and having pain/discomfort or anxiety out of the EQ-5D-5L. EQ index value and SGRQ activity score component were significantly lower in females. SF-36 scores showed remarkably lower scores in the physical health domain compared to the Swiss general population before and during the COVID-19 pandemic. Long-Covid syndrome has a substantial impact on HRQoL. Long-term surveillance of patients must provide clarity on the duration of impairments in physical and mental health.

778

MS289

Cazé, Ana B; Cerqueira-Silva, Thiago; Bomfim, Adriele P; de Souza, Gisley L; Azevedo, Amanda CA; Brasil, Michelle QA; Santos, Nara R; Khouri, Ricardo; Dan, Jennifer; Bandeira, Antonio C; Cavalcanti, Luciano PG; Barral-Netto, Manoel; Barral, Aldina; Barbosa, Cynara G; Boaventura, Viviane S

Prevalence and risk factors for long COVID after mild disease: A cohort study with a symptomatic control group

https://doi.org/10.7189/jogh.13.06015

Published

12-May-23

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173895/

Background
There is limited data on the prevalence and risk factors for long COVID and few prospective studies with appropriate control groups and adequate sample sizes. We performed a prospective study to determine the prevalence and risk factors for long COVID.

Methods
We recruited individuals aged ≥15 years who were clinically suspected of having an acute SARS-CoV-2 infection from September 2020 to April 2021. We collected nasopharyngeal swabs three to five days following symptom onset for analysing using reverse transcriptase polymerase chain reaction (RT-PCR). We also collected clinical and sociodemographic characteristics from both SARS-CoV-2 positive and negative participants using structured questionnaires. We followed-up the participants via telephone interview to assess early outcomes and persistent symptoms. For COVID-19 cases, 5D-3L EuroQol questionnaire was used to assess the impact of symptoms on quality of life.

Results
We followed 814 participants (412 COVID-19 positive and 402 COVID-19 negative persons). Most (n = 741/814) had mild symptoms. Both groups had similar sociodemographic and clinical characteristics, except for the hospitalization rate (15.8% in the COVID-19 positive vs 1.5% in the COVID-19 negative group). One month after disease onset, 122/412 (29.6%) individuals in the COVID-19 positive (long COVID) and 24 (6%) in the COVID-19 negative group reported residual symptoms. In the long COVID group, fatigue, olfactory disorder, and myalgia were the most frequent symptoms in the acute phase. Compared to recovered individuals, older age and having more than five symptoms during the acute phase were risk factors for long COVID. Quality of life was evaluated in 102 out of 122 cases of long COVID, with 57 (55.9%) reporting an impact in at least one dimension of the European Quality of Life 5 Dimensions 3 Level (EQ-5D-3L) questionnaire.

Conclusions
In this prospective study consisting predominantly of individuals with mild disease, the persistence of symptoms after an acute respiratory illness was associated with a diagnosis of COVID-19. Polysymptomatic acute disease and older age were risk factors for long COVID.

779

MS290

Chelly, Souhir; Rouis, Sourour; Ezzi, Olfa; Ammar, Asma; Fitouri, Sami; Soua, Asma; Fathallah, Ines; Njah, Mansour; Mahjoub, Mohamed

Symptoms and risk factors for long COVID in Tunisian population

https://doi.org/10.1186/s12913-023-09463-y

Published

15-May-23

Study

https://doi.org/10.1186/s12913-023-09463-y

Background
The COVID-19 pandemic has presented various challenges, one of which is the discovery that after the acute episode, around 30% of patients experience persistent symptoms or develop new ones, now known as long COVID. This new disease has significant social and financial impacts. The objective is to determine the prevalence of long COVID in the Tunisian population and identify its predictive factors.

Methods
This was a cross-sectional study conducted among Tunisians who were infected with COVID-19 between March 2020 and February 2022. An online self-administered questionnaire was distributed through social media, radio, and television channels over the course of one month (February 2022). Long COVID was defined as the persistence of existing symptoms or the development of new symptoms within three months after onset, lasting for at least two months, and with no differential diagnosis. We performed univariate and multivariate analyses using binary stepwise logistic regression with a significance level set at 5%.

Results
A total of 1911 patients participated in our study, and the prevalence of long COVID was 46.5%. The two most frequent categories were general and neurological post-COVID syndrome, with a prevalence of 36.7% each. The most commonly observed symptoms were fatigue (63.7%) and memory problems (49.1%). In the multivariate analysis, the predictive factors for long COVID were female gender and age of 60 years or older, while complete anti-COVID vaccination was found to be a protective factor.

Conclusions
Our study found that complete vaccination was a protective factor against long COVID, while female gender and age of 60 years or older were identified as the main risk factors. These findings are consistent with studies conducted on other ethnic groups. However, many aspects of long COVID remain unclear, including its underlying mechanisms, the identification of which could guide the development of potential effective treatments.

780

MS291

Fong, Siew-Wai; Goh, Yun Shan; Torres-Ruesta, Anthony; Chang, Zi Wei; Chan, Yi-Hao; Neo, Vanessa Kexin; Lee, Bernett; Duan, Kaibo; Amrun, Siti Naqiah; Yeo, Nicholas Kim-Wah; Chen, Hsiuyi V.; Tay, Matthew Zirui; Carissimo, Guillaume; Group, COVID-19 Study; Group, NCID Study; Tan, Seow Yen; Leo, Yee-Sin; Lye, David C.; Renia, Laurent; Young, Barnaby Edward; Ng, Lisa F. P.

Prolonged inflammation in patients hospitalized for coronavirus disease 2019 (COVID-19) resolves 2 years after infection

https://doi.org/10.1002/jmv.28774

Published

13-May-23

Study

https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.28774

Long-term complications from coronavirus disease 2019 (COVID-19) are concerning, as survivors can develop subclinical multiorgan dysfunction. It is unknown if such complications are due to prolonged inflammation, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination may reduce sequela. We conducted a prospective longitudinal study on hospitalized patients over 24 months. Clinical symptoms were collected by self-reporting during follow-up, along with blood samples for quantification of inflammatory markers and immune cell frequencies. All patients were given one dose of mRNA vaccine at 12−16 months. Their immune profiles at 12 and 24 months were compared. Approximately 37% and 39% of our patients reported post-COVID-19 symptoms at 12 and 24 months, respectively. The proportion of symptomatic patients with more than one symptom decreased from 69% at 12 months to 56% at 24 months. Longitudinal cytokine profiling revealed a cluster of individuals with persistently high inflammatory cytokine levels 12 months after infection. Patients with prolonged inflammation showed elevated terminally differentiated memory T cells in their blood; 54% had symptoms at 12 months. The majority of inflammatory markers and dysregulated immune cells in vaccinated patients recovered to a healthy baseline at 24 months, even though symptoms persisted. Post-COVID-19 symptoms can linger for 2 years after the initial infection and are associated with prolonged inflammation. Prolonged inflammation in hospitalized patients resolves after 2 years. We define a set of analytes associated with persistent inflammation and presence of symptoms, which could be useful biomarkers for identifying and monitoring high-risk survivors.

781

MS292

Zorn, Jule; Vollrath, Shirin; Matits, Lynn; Schönfelder, Martin; Schulz, Sebastian V. W.; Jerg, Achim; Steinacker, Jürgen M.; Bizjak, Daniel A.

Relationship between physical performance and perception of stress and recovery in daily life post COVID-19—An explorative study

https://doi.org/10.1371/journal.pone.0285845

Published

15-May-23

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0285845

Introduction COVID-19 is a multi-systemic disease which can target the lungs and the cardiovascular system and can also affect parts of the brain for prolonged periods of time. Even healthy athletes without comorbidities can be psychologically affected long-term by COVID-19. Objective This study aimed to investigate athletes’ perceived mental stress and recovery levels in daily life, and their maximal aerobic power, at three different time points, post COVID-19. Methods In total, 99 athletes (62.6% male), who had been infected by COVID-19, filled out the Recovery Stress Questionnaire for Athletes (REST-Q-Sport) and completed cardiopulmonary exercise testing (endpoint maximal aerobic power output (Pmax)) at the initial screening (t1: 4 months after infection). Follow-up assessments occurred three (t2, n = 37) and seven months after t1 (t3, n = 19). Results Subgroup means from the Recovery category were significantly below the reference value of four at all three time points, except “General Recovery” (3.76 (± 0.96), p = 0.275, d = 0.968) at t3.”Overtiredness” (2.34 (± 1.27), p = 0.020, r = 0.224) was significantly above the reference value of two at t1, while all other Stress subgroups were not significantly different from the reference value or were significantly below the maximum threshold of two at t1, t2 and t3. Spearman’s ρ revealed a negative association between Pmax and the subcategories of stress (ρ = -0.54 to ρ = -0.11, p < 0.050), and positive correlations between Pmax and “Somatic Recovery” (ρ = 0.43, p < 0.001) and “General Recovery” (ρ = 0.23, p = 0.040) at t1. Pmax (t1: 3.83 (± 0.99), t2: 3.78 (± 1.14), β = 0.06, p < 0.003) increased significantly from t1 to t2. In addition, REST-Q-Sport indicated a decrease in "Sleep" (t2 = 2.35 (± 0.62), t3 = 2.28(± 0.61), β = -0.18, p < 0.023) at t3, when compared to t2. Conclusion The perceived recovery seems to be negatively affected in post COVID-19 athletes. Physical performance post COVID-19 correlates with both “Emotional and Somatic Stress” and “Somatic and General Recovery”, indicating potential mental and physical benefits of exercise. While it is evident that COVID-19, like other viral infections, may have an influence on physical performance, monitoring stress and recovery perceptions of athletes is critical to facilitate their return-to-sports, while minimizing long-term COVID-19 induced negative effects like the athletic objective and subjective perceived recovery and stress levels.

782

MS293

Roever, Leonardo; Cavalcante, Bruno Raphael Ribeiro; Improta-Caria, Alex Cleber

Long-term consequences of COVID-19 on mental health and the impact of a physically active lifestyle: a narrative review

https://doi.org/10.1186/s12991-023-00448-z

Published

11-May-23

Study

https://doi.org/10.1186/s12991-023-00448-z

Background
Coronavirus-19 disease (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Respiratory viruses damage not only the upper respiratory tract in humans, but also several different organs such as the brain. Some of the neurological consequences of COVID-19 reported are anosmia, headache, stroke, declined cognitive function, and impaired mental health, among others. People who had COVID-19 have a higher risk of sequelae in the central nervous system (CNS). However, it is not known which are all possible sequelae and how long will last the long-term effects of the COVID-19 pandemic on behavioral patterns and quality of life.

Aim
We intend to address the long-term impacts of COVID-19 on mental health and the relevance of physical exercise during the pandemic.

Methods
We conducted a literature search using PubMed to find the articles that were related to these themes.

Results
We found 23,489 papers initially, and then we applied the inclusion/exclusion criteria to narrow down our search to 3617 articles and selected 1380 eligible articles after a thorough reading of titles and abstracts. The findings indicated that COVID-19 impacted general mental health and led many not only hospitalized patients to develop cognitive decline, memory impairment, anxiety, sleep alterations, and depressive-like behavior. Furthermore, the fear of vaccines and their effects had negatively affected mental health and directly impacted mortality rates in unvaccinated COVID-19 patients.

Conclusions
Preventive measures must be undertaken, such as the vaccination of the entire population, vaccination hesitancy discouragement by creating awareness among individuals, and people’s engagement in a physically active lifestyle, since being physically active is a low-cost and effective measure to restore or inhibit the negative outcomes from COVID-19 on mental health.

783

MS294

Kuodi, Paul; Gorelik, Yanay; Gausi, Blessing; Bernstine, Tomer; Edelstein, Michael

Characterisation of post-COVID syndromes by symptom cluster and time period up to 12 months post-infection: A systematic review and meta-analysis

https://doi.org/10.1016/j.ijid.2023.05.003

Published

6-May-23

Systematic review and meta-analysis

https://www.sciencedirect.com/science/article/pii/S1201971223005490

Highlights
•A subset of individuals continues to report post-COVID symptoms beyond one year
•Studies reporting post-COVID symptom clusters remain rare in the literature
•We identified, systemic inflammatory, cardiorespiratory, and neurologic clusters
•Reporting of post-COVID symptom clusters is key to understanding long COVID
Abstract
Objectives
The objective of this study was to characterise post-COVID condition symptoms and symptom clusters, their duration and prevalence.
Methods
We conducted a systematic review and random-effects meta-analysis of studies reporting post-COVID-19 symptoms and clusters respectively. We searched MEDLINE (via PubMed), Scopus, Web of Science, Science direct, Google Scholar, EBSCOhost, EMBASE, PsycINFO, Cochrane Library, and Mednar for literature reporting on post-COVID condition up to August 2022.
Results
In the 76 included studies, we found that although most symptoms were reported less frequently 7-12 months following infection compared to earlier, over 20% of patients reported at least one post-COVID condition-compatible symptoms. In the seven studies reporting post-COVID symptom clusters, neurological clustering was the consistently identified, followed by cardiorespiratory and systemic/inflammatory.
Conclusions
Post-COVID symptom clustering provides direction for research into the etiology, diagnosis, and management of post-COVID condition. Studies reporting post-COVID symptom clusters remain rare due to focus on individual symptoms reporting. Studies on post-COVID symptom clusters should replace individual symptoms reporting to accelerate our understanding of this emerging public health issue.

784

MS295

Jothi, S.; Claessen, G.; Insel, M.; Kubba, S.; Howden, E.; Carmona, S.-R.; Rischard, F.p.

Post-acute Sequelae of SARS Co-V2 and Chronic Fatigue/Myalgic Encephalitis Share Similar Pathophysiologic Mechanisms of Exercise Limitation

Published

1-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A6470

785

MS296

J. Cirillo1, I. R. Young2, H. Remar1, R. Vakil3, D. Collazo4, A. Witzl5, R. Condos

Comparison of Patient-Reported Post-acute Sequelae SARS-CoV-2 (PASC) Respiratory Symptoms With Pulmonary Function Tests (PFTS) in a Post-COVID Patient Population | C66. VIRAL INFECTIONS, COVID, AND BEYOND

https://doi.org/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A5620

Published

23-May-23

Study

https://www.atsjournals.org/doi/epdf/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A5620?role=tab

786

MS297

Eschbach, E.; Parekh, A.; Rapoport, D.m.; Mancini, D.m.; Natelson, B.h.

Dysfunctional Breathing Patterns in Post-Acute Sequelae of SARS-CoV-2 (PASC) Patients Can Be Identified Using Approximate Entropy

Published

1-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A5838

787

MS298

Dierckx, W.; Ides, K.; De Meyer, Y.; Deckers, F.; De Backer, J.; Lavon, B.r.; Franck, E.; De Backer, W.

Pulmonary Vascular Effects of a Personalized Rehab Program in Patients With Post-Acute Sequelae of COVID-19 (PASC)

Published

1-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A5552

788

MS299

Dierckx, W.; Ides, K.; De Meyer, Y.; De Backer, J.; Lavon, B.r.; Franck, E.; De Backer, W.

Changes in Lung Function Following Personalized Pulmonary Rehabilitation Programs in Patients With Post-Acute Sequelae of COVID-19 (PASC)

Published

1-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A2159

789

MS300

Panda, A.; Hough, C.t.; Caldwell, E.; Gage, S.; Hope, A.a.

Fatigue Is Often Associated With Severe Headache, Dyspnea, and Insomnia in Adult Patients With Post-acute Sequelae of SARS-CoV-2 (PASC)

Published

1-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A2826

790

MS301

Witzl, A.; Young, I.r.; Remar, H.j.; Condos, R.

Vaccination Status During Acute COVID-19 Infection as a Predictor for Post-acute Sequelae of COVID-19 (PASC) Symptoms

Published

1-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A1619

791

MS302

Young, I.r.; Remar, H.j.; Cirillo, J.; Vakil, R.; Collazo, D.; Witzl, A.; Condos, R.

Longitudinal Generalized Anxiety Disorder 7-Item (GAD-7) Scale Outcomes as Compared to Other Post-acute Sequelae SARS-CoV-2 (PASC) Symptoms in a Post-COVID Patient Population

Published

1-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A3391

792

MS303

Jothi, S.; Claessen, G.; Insel, M.; Kubba, S.; Howden, E.; Carmona, S.-R.; Rischard, F.p.

Post-acute Sequelae of SARS Co-V2 and Chronic Fatigue/Myalgic Encephalitis Share Similar Pathophysiologic Mechanisms of Exercise Limitation

Published

1-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A6470

793

MS304

Bailey, J.; Phillips, A.; Herzog, K.; Sala, M.a.; Carnethon, M.; Kalhan, R.

Compared to the Wuhan Variant, Infection With Omicron and Delta Variants of SARS-CoV-2 Are Associated With Decreased Odds of Developing Post-Acute Sequelae of COVID-19

Published

1-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A3810

794

MS305

Jolley, S.e.; Gundel, S.; Ringwood, N.; Caldwell, E.; Mayer, K.p.; Palakshappa, J.a.; Rogers, A.; Peltan, I.d.; Qadir, N.; Andrews, J.; Tidswell, M.a.; Biehl, M.; Lynch, D.a.; Burnham, E.l.; Hope, A.a.; Hough, C.t.

One-Year Pulmonary Recovery in Patients Hospitalized for COVID-19

Published

1-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A2905

795

MS306

Litchman, T.d.; Maley, J.h.; Zibrak, J.d.

Characterizing Long COVID in Patients With Respiratory Symptoms Referred to a Multidisciplinary Long COVID Clinic

Published

1-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A2171

796

MS307

Hatte, L.; Preston, P.

Understanding Long COVID in Australia: Shaping Policy and Health Services to Support Long COVID Patients

Published

1-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A1831

797

MS308

Bailey, J.; Lavelle, B.; Miller, J.; Jimenez, M.; Lim, P.; Orban, Z.; Clark, J.; Tomar, R.; Ludwig, A.; Ali, S.; Lank, G.; Zielinski, A.; Mylvaganam, R.; El Muayed, M.; Mutharasan, K.; Liotta, E.; Sznajder, J.i.; Davidson, C.; Koralnik, I.; Sala, M.a.; Northwestern, Medicine Comprehensive COVID Center Investigators

Multidisciplinary Care for Long COVID Syndrome - a Single Center Experience

Published

1-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A4386

798

MS309

A.W. Wong 5, K.C. Tran 4, M. Binka 2, N.Z. Janjua 2, H. Sbihi 2, J.A. Russell 1, C. Carlsten 3, A. Levin 4, C.J. Ryerson

Use of Latent Class Analysis to Identify Distinct Phenotypes of Long COVID | D14. CUTTING EDGE CONCEPTS IN BEHAVIORAL SCIENCES AND HEALTH SERVICES RESEARCH

Published

2-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A6213

799

MS310

Stalker, G.; Tudas, R.a.; Villacreses, R.; Wilbin, T.; Hamzeh, N.y.; Graham, L.; Blount, R.j.; Zabner, J.; Garg, A.; Cho, J.l.; Comellas, A.p.; Pezzulo, A.

Long-COVID Improves After a Year in 50% of Subjects Enrolled in a Rural Cohort

Published

1-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A4391

800

MS311

Eddy, R.l.; Mummy, D.; Dai, H.; Bechtel, A.; Schmidt, A.; Frizzell, B.; Leipsic, J.a.; Leung, J.m.; Driehuys, B.; Que, L.g.; Sin, D.d.; Castro, M.; Niedbalski, P.j.

129Xe Magnetic Resonance Imaging-based Phenotypes of Long COVID: A Multi-center Evaluation

Published

1-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A6786

801

MS312

Bailey, Joseph; Lavelle, Bianca; Miller, Janet; Jimenez, Millenia; Lim, Patrick H.; Orban, Zachary S.; Clark, Jeffrey R.; Tomar, Ria; Ludwig, Amy; Ali, Sareen T.; Lank, Grace K.; Zielinski, Allison; Mylvaganam, Ruben; Kalhan, Ravi; Muayed, Malek El; Mutharasan, R. Kannan; Liotta, Eric M.; Sznajder, Jacob I; Davidson, Charles; Koralnik, Igor J.; Sala, Marc A.

Multidisciplinary Center Care for Long COVID Syndrome – a Retrospective Cohort Study

https://doi.org/10.1016/j.amjmed.2023.05.002

Published

22-May-23

Study

https://www.sciencedirect.com/science/article/pii/S0002934323003285

Structured Abstract
Background
Persistent multi-organ symptoms after COVID-19 have been termed “long COVID” or “post-acute sequelae of SARS-CoV-2 infection” (PASC). The complexity of these clinical manifestations posed challenges early in the pandemic as different ambulatory models formed out of necessity to manage the influx of patients. Little is known about the characteristics and outcomes of patients seeking care at multidisciplinary post-COVID centers.
Methods
We performed a retrospective cohort study of patients evaluated at our multidisciplinary Comprehensive COVID-19 Center (CCC) in Chicago, IL, between May 2020 and February 2022. We analyzed specialty clinic utilization and clinical test results according to severity of acute COVID-19.
Results
We evaluated 1802 patients a median of 8 months from acute COVID-19 onset, including 350 post-hospitalization and 1452 non-hospitalized patients. Patients were seen in 2361 initial visits in 12 specialty clinics, with 1151 (48.8%) in neurology, 591 (25%) in pulmonology, and 284 (12%) in cardiology. Among patients tested, 742/878(85%) reported decreased quality of life, 284/553(51%) had cognitive impairment, 195/434(44.9%) had alteration of lung function, 249/299(83.3%) had abnormal CT chest scans, and 14/116(12.1%) had elevated heart rate on rhythm monitoring. Frequency of cognitive impairment and pulmonary dysfunction was associated with severity of acute COVID-19. Non-hospitalized patients with positive SARS-CoV-2 testing had similar findings than those with negative or no test results.
Conclusions
The CCC experience shows common utilization of multiple specialists by long COVID patients, who harbor frequent neurologic, pulmonary, and cardiologic abnormalities. Differences in post-hospitalization and non-hospitalized groups suggest distinct pathogenic mechanisms of long COVID in these populations.

802

MS313

Mohtasham-Amiri, Zahra; Keihanian, Fatemeh; Rad, Enayatollah Homaie; Shakib, Reza Jafari; Vahed, Leila Kanafi; Kouchakinejad–Eramsadati, Leila; Rezvani, Seyed Mahmoud; Nikkar, Rastin

Long- COVID and general health status in hospitalized COVID-19 survivors

https://doi.org/10.1038/s41598-023-35413-z

Published

19-May-23

Study

https://www.nature.com/articles/s41598-023-35413-z

Despite advances in clinical research, the long-term effects of COVID-19 on patients are not clear. Many studies revealed persistent long-term signs and symptoms. In a survey study, 259 hospitalized confirmed COVID-19 patients between 18 and 59 years were interviewed. Demographic characteristics and complaints were studied through telephone interviews. Any patient-reported symptoms that continued or developed from 4 weeks up to 12 weeks after the onset of the disease were recorded only if they did not exist prior to infection. The 12-Item General Health Questionnaire was used for screening and assessing mental symptoms and psychosocial well-being. The mean age of participants was 43.8 ± 9.9 years. About 37% had at least one underlying disease. 92.5% showed ongoing symptoms that the most prevalent complications were hair loss (61.4%), fatigue (54.1%), shortness of breath (40.2%), altered smell (34.4%), and aggression (34.4%), respectively. In terms of factors affecting patients' complaints, there were significant differences between age, sex, and underlying disease with long-remaining complications. This study shows a high rate of long COVID-19 conditions that should be considered by physicians, policymakers, and managers.

803

MS314

Ballouz, Tala; Menges, Dominik; Anagnostopoulos, Alexia; Domenghino, Anja; Aschmann, Hélène E.; Frei, Anja; Fehr, Jan S.; Puhan, Milo A.

Recovery and symptom trajectories up to two years after SARS-CoV-2 infection: population based, longitudinal cohort study

https://doi.org/10.1136/bmj-2022-074425

Published

31-May-23

Study

https://www.bmj.com/content/381/bmj-2022-074425

Objective To evaluate longer term symptoms and health outcomes associated with post-covid-19 condition within a cohort of individuals with a SARS-CoV-2 infection.
Design Population based, longitudinal cohort.
Setting General population of canton of Zurich, Switzerland.
Participants 1106 adults with a confirmed SARS-CoV-2 infection who were not vaccinated before infection and 628 adults who did not have an infection.
Main outcome measures Trajectories of self-reported health status and covid-19 related symptoms between months six, 12, 18, and 24 after infection and excess risk of symptoms at six months after infection compared with individuals who had no infection.
Results 22.9% (95% confidence interval 20.4% to 25.6%) of individuals infected with SARS-CoV-2 did not fully recover by six months. The proportion of individuals who had an infection who reported not having recovered decreased to 18.5% (16.2% to 21.1%) at 12 months and 17.2% (14.0% to 20.8%) at 24 months after infection. When assessing changes in self-reported health status, most participants had continued recovery (68.4% (63.8% to 72.6%)) or had an overall improvement (13.5% (10.6% to 17.2%)) over time. Yet, 5.2% (3.5% to 7.7%) had a worsening in health status and 4.4% (2.9% to 6.7%) had alternating periods of recovery and health impairment. The point prevalence and severity of covid-19 related symptoms also decreased over time, with 18.1% (14.8% to 21.9%) reporting symptoms at 24 months. 8.9% (6.5% to 11.2%) of participants reported symptoms at all four follow-up time points, while in 12.5% (9.8% to 15.9%) symptoms were alternatingly absent and present. Symptom prevalence was higher among individuals who were infected compared with those who were not at six months (adjusted risk difference 17.0% (11.5% to 22.4%)). Excess risk (adjusted risk difference) for individual symptoms among those infected ranged from 2% to 10%, with the highest excess risks observed for altered taste or smell (9.8% (7.7% to 11.8%)), post-exertional malaise (9.4% (6.1% to 12.7%)), fatigue (5.4% (1.2% to 9.5%)), dyspnoea (7.8% (5.2% to 10.4%)), and reduced concentration (8.3% (6.0% to 10.7%)) and memory (5.7% (3.5% to 7.9%)).
Conclusions Up to 18% of individuals who were not vaccinated before infection had post-covid-19 condition up to two years after infection, with evidence of excess symptom risk compared with controls. Effective interventions are needed to reduce the burden of post-covid-19 condition. Use of multiple outcome measures and consideration of the expected rates of recovery and heterogeneity in symptom trajectories are important in the design and interpretation of clinical trials.
Study registration Current Controlled Trials ISRCTN14990068Current Controlled Trials ISRCTN18181860

804

MS315

Gottlieb, Michael; Spatz, Erica S; Yu, Huihui; Wisk, Lauren E; Elmore, Joann G; Gentile, Nicole L; Hill, Mandy; Huebinger, Ryan M; Idris, Ahamed H; Kean, Efrat R; Koo, Katherine; Li, Shu-Xia; McDonald, Samuel; Montoy, Juan Carlos C; Nichol, Graham; O’Laughlin, Kelli N; Plumb, Ian D; Rising, Kristin L; Santangelo, Michelle; Saydah, Sharon; Wang, Ralph C; Venkatesh, Arjun; Stephens, Kari A; Weinstein, Robert A; for the INSPIRE Group

Long COVID Clinical Phenotypes Up to Six Months After Infection Identified by Latent Class Analysis of Self-Reported Symptoms

https://doi.org/10.1093/ofid/ofad277

Published

31-May-23

Study

https://doi.org/10.1093/ofid/ofad277

The prevalence, incidence, and interrelationships of persistent symptoms after SARS-CoV-2 infection (Long COVID) vary. There are limited data on specific phenotypes of persistent symptoms. Using latent class analysis (LCA) modeling, we sought to identify whether specific phenotypes of COVID-19 were present three months and six months after acute infection.This was a multicenter, prospective study of symptomatic adults tested for SARS-CoV-2 with prospectively collected data on general symptoms and fatigue-related symptoms up to six-months post-diagnosis. Using LCA, we identified symptomatically homogenous groups among participants with COVID-19 (COVID-positive) and among others without COVID-19 (COVID-negative) at each time period for both general and fatigue-related symptoms.Among 5,963 baseline participants (4,504 COVID-positive and 1,459 COVID-negative), 4,056 had three-month and 2,856 had six-month data at the time of analysis. We identified four distinct phenotypes of post-COVID conditions at three- and six-months for both general and fatigue-related symptoms; minimal symptom groups represented 70% of participants at three and six months. When compared with the COVID-negative cohort, COVID-positive participants had higher occurrence of loss of taste and smell, as well cognition problems. There was substantial class-switching over time; those in one symptom class at three months were equally likely to remain or enter a new phenotype at six months.We identified distinct classes of post-COVID phenotypes for general and fatigue-related symptoms. Most participants had minimal or no symptoms at three and six months follow-up. Significant proportions of participants changed symptom groups over time, suggesting that symptoms present during the acute illness may differ from prolonged symptoms and that post-COVID conditions may have a more dynamic nature than previously recognized.NCT04610515

805

MS316

Carter, Isabelle; Strohl, Kingman; Rosenberg, David; Patil, Susheel; Torer, Juliane; Griggs, Stephanie; Decker, Michael; May, Anna

0967 Do Pre-existing Sleep Disorders Worsen Long COVID Fatigue and Brain Fog?

https://doi.org/10.1093/sleep/zsad077.0967

Published

1-May-23

Review

https://doi.org/10.1093/sleep/zsad077.0967

Long COVID is common after COVID-19 infection and leads to functional limitations with most reporting substantial symptom burden from fatigue. Symptoms in sleep disorders are attributed to inflammatory dysregulation and may predispose to fatigue expression. We hypothesize prior diagnoses of sleep disorders are associated with severity of long COVID fatigue.A retrospective EMR review was performed of 210 consecutive adult patients (9/2021 to 2/2022) referred at least 3 months after COVID-19 infection seen in a new community-based long COVID clinic. The intake process collected demographics, past medical history, functional questionnaires, and symptom checklists. Primary outcome was Fatigue Severity Scale (FSS) score. Sleep disorders were evaluated as a composite of self-reported insomnia, sleep disordered breathing, and restless legs syndrome as well as subset analyses of each disorder. Secondary outcome was physical functioning measured by ECOG performance scale. Linear analyses were used for FSS and ECOG analyses. Adjustors included age, sex, body mass index (BMI), and whether patient had COVID-19 hospitalization.Cohort was female (66.2%), aged 51.6±SD14.4 yrs, BMI 29.8 [IQR 26.2, 37.7]). Prior chronic insomnia was present in 9%, sleep disordered breathing in 23%, and RLS in 4%; the pooled history of sleep disorders was 30%. Fatigue was reported in 76% with mean FSS score of 5.44 [interquartile range, IQR: 4.11,6.44]; 48% reported brain fog. The interval between acute COVID infection and clinic evaluation was 10.4±5.34 months and had no association to FSS severity (r = 0.07, p = 0.30). Sleep disorders in aggregate, insomnia, and restless legs syndrome had no associations with fatigue or functional status. Sleep disordered breathing had an association to fatigue in unadjusted (β = 0.68, 95% confidence interval, [CI]:0.13,1.24), but not adjusted models (β = 0.53, 95%CI: -0.06,1.13). Sleep disorders both in aggregate and evaluated individually had no associations to brain fog.A prior history of sleep disorders contributed little to post-COVID fatigue reported in those presenting to a community-based Long COVID clinic.TEAMS institutional award, Department of Medicine, University Hospitals of Cleveland, VA CSRD IK2CX001882

806

MS317

Schilling, Claudia; Nieters, Alexandra; Schredl, Michael; Peter, Raphael S.; Rothenbacher, Dietrich; Brockmann, Stefan O.; Göpel, Siri; Kindle, Gerhard; Merle, Uta; Steinacker, Jürgen M.; Kern, Winfried; Group, the Epidemiology of Long COVID (EPILOC) Phase I. study

Pre-existing sleep problems as a predictor of post-acute sequelae of COVID-19

https://doi.org/10.1111/jsr.13949

Published

Study

https://onlinelibrary.wiley.com/doi/abs/10.1111/jsr.13949

Several months after COVID-19 many individuals still report persisting symptoms, the so-called ‘post-COVID-19 syndrome’. An immunological dysfunction is one of the main pathophysiological hypotheses. As sleep is central to the functioning of the immune system, we investigated whether self-reported pre-existing sleep disturbance might be an independent risk factor for the development of post-COVID-19 syndrome. A total of 11,710 participants of a cross-sectional survey (all tested positive for severe acute respiratory syndrome coronavirus-2) were classified into probable post-COVID-19 syndrome, an intermediate group, and unaffected participants at an average of 8.5 months after infection. The case definition was based on newly occurring symptoms of at least moderate severity and ≥20% reduction in health status and/or working capacity. Unadjusted and adjusted odds ratios were calculated to investigate the association between pre-existing sleep disturbances and subsequent development of post-COVID-19 syndrome while controlling for a variety of demographic, lifestyle, and health factors. Pre-existing sleep disturbances were found to be an independent predictor of subsequent probable post-COVID-19 syndrome (adjusted odds ratio 2.7, 95% confidence interval 2.27–3.24). Sleep disturbances as part of the post-COVID-19 syndrome were reported by more than half of the participants and appeared to be a new symptom and to occur independent of a mood disorder in most cases. Recognition of disturbed sleep as an important risk factor for post-COVID-19 syndrome should promote improved clinical management of sleep disorders in the context of COVID-19. Further, it may stimulate further research on the effect of improving sleep on the prognosis of COVID-19 long-term sequelae and other post-viral conditions.

807

MS318

Calvache-Mateo, Andrés; Navas-Otero, Alba; Heredia-Ciuró, Alejandro; Matín-Núñez, Javier; Torres-Sánchez, Irene; López-López, Laura; Valenza, Marie Carmen

Post-COVID Patients With New-Onset Chronic Pain 2 Years After Infection: Cross-Sectional Study

https://doi.org/10.1016/j.pmn.2023.04.010

Published

22-May-23

Study

https://www.sciencedirect.com/science/article/pii/S1524904223000954

Background
Although pain is common in non-hospitalized post-COVID-19 syndrome, only a few studies have provided information on the pain experience of these patients.
Aim
To identify the clinical and psychosocial profile associated with pain in non-hospitalized patients with post-COVID-19 syndrome.
Method
In this study there were three groups: healthy control group, successfully recovered group, and post-COVID syndrome group. Pain-related clinical profile and pain-related psychosocial variables were collected. Pain-related clinical profile included: pain intensity and interference (Brief Pain Inventory), central sensitization (Central Sensitization Scale), insomnia severity (Insomnia Severity Index), and pain treatment. Pain-related psychosocial variables were: fear of movement and (re)injury (Tampa Scale for Kinesiophobia), catastrophizing (Pain Catastrophizing Scale), depression, anxiety and stress (Depression, Anxiety and Stress Scale), and fear-avoidance beliefs (Fear Avoidance Beliefs Questionnaire).
Results
In all, 170 participants were included in the study (healthy control group n = 58, successfully recovered group n = 57, and post-COVID syndrome group n = 55). Post-COVID syndrome group obtained significantly worse punctuation in pain-related clinical profile and psychosocial variables than the other two groups (p < .05).
Conclusions
In conclusion, patients with post-COVID-19 syndrome have experienced high pain intensity and interference, central sensitization, increased insomnia severity, fear of movement, catastrophizing, fear-avoidance beliefs, depression, anxiety, and stress.

808

MS319

Schmidbauer, Lena; Kirchberger, Inge; Goßlau, Yvonne; Warm, Tobias D.; Hyhlik-Dürr, Alexander; Linseisen, Jakob; Meisinger, Christa

The association between the number of symptoms and the severity of Post-COVID-Fatigue after SARS-CoV-2 infection treated in an outpatient setting

https://doi.org/10.1007/s00415-023-11752-9

Published

23-May-23

Study

https://doi.org/10.1007/s00415-023-11752-9

Background
Post-COVID-Fatigue (PCF) is one of the most reported symptoms following SARS-CoV-2 infection. Currently, research on persistent symptoms focuses mainly on severe infections, while outpatients are rarely included in observations.

Objective
To investigate whether the severity of PCF is related to the number of acute and persistent symptoms due to mild-to-moderate COVID-19 and to compare the most common symptoms during acute infection with the persistent symptoms in PCF patients.

Methods
A total of 425 participants were examined after COVID-19 treated as an outpatient (median 249 days [IQR: 135; 322] after acute disease) at the site of University Hospital Augsburg, Germany. The Fatigue Assessment Scale (FAS) was used to quantify the severity of PCF. The number of symptoms (maximum 41) during acute infection and persistent symptoms (during the last 14 days before examination) were added up to sum scores. Multivariable linear regression models were used to show the association between the number of symptoms and PCF.

Results
Of the 425 participants, 37% (n = 157) developed PCF; most were women (70%). The median number of symptoms was significantly higher in the PCF group than in the non-PCF group at both time points. In multivariable linear regression models, both sum scores were associated with PCF (acute symptoms: β-estimate per additional symptom [95%-CI]: 0.48 [0.39; 0.57], p < 0.0001); persistent symptoms: β-estimate per additional symptom [95%-CI]: 1.18 [1.02; 1.34], p < 0.0001). The acute symptoms strongest associated with PCF severity were difficulty concentrating, memory problems, dyspnea or shortness of breath on exertion, palpitations, and problems with movement coordination.

Conclusion
Each additional symptom that occurs in COVID-19 increases the likelihood of suffering a higher severity of PCF. Further research is needed to identify the aetiology of PCF.

809

Ce01

Gemelli

Post-COVID-19 global health strategies: the need for an interdisciplinary approach

https://doi.org/10.1007/s40520-020-01616-x

published

11-Jun-20

https://pubmed.ncbi.nlm.nih.gov/32529595/

_

810

Ce02

Trisha Greenhalgh, Matthew Knight, , Christine A’Court, Maria Buxton, , Laiba Husain

Management of post-acute covid-19 in primary care

https://doi.org/10.1136/bmj.m3026

opinion

11-Aug-20

Practice Pointer

https://www.bmj.com/content/370/bmj.m3026

Suggested care approach for #LongCovid, published August 11 in the BMJ.
"About 10% of covid patients show symptoms for more than 3 months"

post-acute covid-19 as extending beyond three weeks from the onset of first symptoms and chronic covid-19 as extending beyond 12 weeks. Since many people were not tested, and false negative tests are common,4 we suggest that a positive test for covid-19 is not a prerequisite for diagnosis.

Management of covid-19 after the first three weeks is currently based on limited evidence
Approximately 10% of people experience prolonged illness after covid-19
Many such patients recover spontaneously (if slowly) with holistic support, rest, symptomatic treatment, and gradual increase in activity
Home pulse oximetry can be helpful in monitoring breathlessness
Indications for specialist assessment include clinical concern along with respiratory, cardiac, or neurological symptoms that are new, persistent, or progressive

Suggestions d'approche de soins pour les #LongCovid, publiées le 11 août dans le BMJ.
"Environ 10% des malades de la covid présentent des symptômes plus de 3 mois"

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Ce03

Advanced Wellbeing Research Centre (AWRC)

This is the first video in a series that aims to support people who have symptoms of fatigue during their recovery from Covid-19.

videos

https://www.youtube.com/watch?v=CIpXGB-8DWI&feature=youtu.be https://youtu.be/hIGYdjcZi7M

British hospital videos on persistent #LongCovid symptoms
The video introduces the team and provides a summary of fatigue and its potential causes
The series has been developed by the AWRC at Sheffield Hallam University in partnership with the CRESTA clinic at Newcastle Hospitals Foundation Trust, Newcastle University, and University of Northumbria. The work is part of the RICOVR unit at the AWRC (www.awrc.co.uk).

Vidéo 1 - Intro de présentation de l'équipe du centre de recherches et général sur le syndrôme de fatigue post-virale Vidéo 2 - Gestion de l'énergie et activités quotidiennes Vidéo 3 - Prendre soin de soi pendant la guérison Vidéo 4 - Activité et fatigue Vidéo 5 - Questions et réponses relatives à la guérison du Covid 19.

812

Ce04

Amy M. Lavery, PhD1; Leigh Ellyn Preston, DrPH1; Jean Y. Ko, PhD1; Jennifer R. Chevinsky, MD1; Carla L. DeSisto, PhD1;

Characteristics of Hospitalized COVID-19 Patients Discharged and Experiencing Same-Hospital Readmission — United States, March–August 2020

https://doi.org/10.15585/mmwr.mm6945e2

published

9-Nov-20

Study

https://www.cdc.gov/mmwr/volumes/69/wr/mm6945e2.htm

9% of patients hospitalized for covid need hospital readmission within 2 months, and 1.6% require multiple readmissions, according to a US study conducted between March and August 2020.

9% des patients hospitalisés pour la covid ont besoin d'une réadmission à l'hôpital dans les 2 mois, et 1,6% nécessitent des réadmissions multiples, selon une étude américaine réalisée entre les mois de mars et d'août 2020.

813

Ce004

Saoirse E. O'Sullivan, Carl W. Stevenson, and Steven R. Laviolette

Could Cannabidiol Be a Treatment for Coronavirus Disease-19-Related Anxiety Disorders?

https://doi.org/10.1089/can.2020.0102

opinion

5-Nov-20

opinion

https://www.liebertpub.com/doi/full/10.1089/can.2020.0102

The journal Cannabis and Cannabinoid Research publishes an article which questions the place of cannabidiol in the treatment of anxiety disorders linked to covid.

La revue Cannabis and Cannabinoid Research publie un article qui s'interroge sur la place du cannabidiol dans le traitement des troubles anxieux liés à la covid

814

Ce005

M Mendelson, J Nel, L Blumberg, S A Madhi, M Dryden, W Stevens, F W D Venter

Long-COVID: An evolving problem with an extensive impact

http://dx.doi.org/10.7196%2FSAMJ.2020.v111i11.15433

published

23-Nov-20

Article

http://www.samj.org.za/index.php/samj/article/view/13141

Une étude insiste sur la nécessité d'une approche holistique, multidisciplinaire, pour traiter le sujet du #longcovid.
Elle précise qu'il y a de plus en plus d'éléments pour dire que l'infection elle-même est cause de déficiences cognitives persistantes. En traitements, l'étude évoque l'entraînement olfactif, les exercices de contrôle de respiration, un "pacing" progressif pour la réadaptation à l'effort, ainsi que dans certains cas l'implication des professionnels de la santé mentale.

815

Ce006

Helen Humphreys, Laura Kilby, Nik Kudiersky, Robert Copeland

Long Covid and the role of physical activity: a qualitative study

https://doi.org/10.1101/2020.12.03.20243345

4-Dec-20

https://www.medrxiv.org/content/10.1101/2020.12.03.20243345v1

"It is imperative to establish consensus, regarding PA-related advice for people with Long Covid, including the identification of individual phenotypes for whom PA might or might not add value to their recovery"

Un pre-print évoque l'importance de définir des protocoles de reprise d'activités physiques chez lceux qui souffrent de séquelles de la covid.

816

Ce007

Mark Vink 1,* andAlexandra Vink-Niese

Could Cognitive Behavioural Therapy Be an Effective Treatment for Long COVID and Post COVID-19 Fatigue Syndrome? Lessons from the Qure Study for Q-Fever Fatigue Syndrome

https://doi.org/10.3390/healthcare8040552

published

11-Dec-20

Review

https://www.mdpi.com/2227-9032/8/4/552

It seems therefore unlikely that CBT will reduce disability or lead to objective improvement in long
COVID or in post-COVID-19 fatigue syndrome.

Une revue d'études indique que les thérapies cognitives et comportementales, n'ayant pas fait leur preuve dans des groupes hétérogènes pour l'encéphalomyélite myalgique, sont peu susceptibles d'être efficaces pour l'asthénie du #covidlong.

817

Ce008

Shin Jie Yong

Long-Haul COVID-19: Putative Pathophysiology, Risk Factors, and Treatments

https://doi.org/10.1080/23744235.2021.1924397

pre-print

10-Dec-20

Review

https://www.preprints.org/manuscript/202012.0242/v1

cf Ce35

Une revue d'études en preprint décrit les facteurs de risques suspectés du covid long, la physiopathologie et les pistes thérapeutiques. Sont évoqués le rintatolimod, les antihistamines (olopatadine, kétotifène), la clarithromycine et les corticostéroïdes.

818

Ce009

Sumathi Reddy (Wall Street Journal)

Experimental Drugs Aim to Treat Long-Haul Covid Patients
People suffering from debilitating symptoms for months after getting sick with Covid could get some relief if drugs prove effective in trials

press article

21-Dec-20

Press Article

https://www.wsj.com/articles/experimental-drugs-aim-to-treat-long-haul-covid-11608569400

Plusieurs médicaments sont prévus à l'essai aux États-Unis pour le covid long :
- L'anticorps monoclonal Leronlimab, développé par CytoDyn et qui vise le récepteur CCR5 des lymphocytes T, pour réduire l'inflammation cérébrale (pouvant causer fatigue, brouillard cérébral)---- Zofin, composé dérivé du liquide amniotique, développé par Organicell, vise à la régénération pulmonaire via un processus anti-inflammatoire
- LYT-100, développé par PureTech, pour la cicatrisation des lésions pulmonaires---- AIM ImmunoTech développe Ampligen (Rintatolimod), médicament immunomodulateur qui donnerait des résultats encourageants sur des patients atteints d'encéphalomyélite myalgique, et qui cible les symptômes "covid long" y ressemblant.

819

Ce010

M. Alawna, M. Amro, A.A. Mohamed

Aerobic exercises recommendations and specifications for patients with COVID-19: a systematic review

https://doi.org/10.26355/eurrev_202012_24211

published

1-Dec-20

Systematic Review

https://www.europeanreview.org/article/24211

Une revue systématique d'études sur les exercices de réadaptation physique post-covid.
Les recommandations citées font part de 2 à 3 séances hebdomadaires, à 55-80% VO2max et/ou 60-80% de fréquence cardiaque maximale.

820

Ce011

Sauvant, Céline, Bodet, Colin, MORICLET, Tommy, MANTO, Florence, BARTSCH, Valérie, PIRNAY, Laurence, Kellens, Isabelle, MAES, Nathalie, THYS, Marie, Kaux, Jean-François

Rôle de la médecine physique et réadaptation fonctionnelle dans les suites d’une atteinte au SARS-CoV-2

https://hdl.handle.net/2268/254170

published

1-Nov-20

Guideline

https://orbi.uliege.be/handle/2268/254170

_

821

Ce012

American Academy of Pediatrics

COVID-19 Interim Guidance: Return to Sports

published

17-Dec-20

Guidance

https://services.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/clinical-guidance/covid-19-interim-guidance-return-to-sports/

_

822

Ce013

George M. Anderson

Fluvoxamine, melatonin and COVID-19

https://doi.org/10.1007/s00213-020-05753-z

Published

4-Jan-21

Letter to the editor

https://link.springer.com/article/10.1007/s00213-020-05753-z

Parce que la fluvoxamine peut multiplier par 2 ou 3 les taux plasmatiques nocturnes de mélatonine, elle pourrait aider à la régulation des cycles chronobiologiques, et renforcer des effets anti-oxydants et anti-inflammatoires.

823

Ce014

Ankita Sagar, MD, MPH, FACP; Thomas McGinn

Patient-Centered Care in Post-COVID-19 Recovery

published

1-Jan-21

Article

https://connect.sgim.org/viewdocument/patient-centered-care-in-post-covid

Court article sur la prise en charge de la convalescence des patients covid, par l'institut Northwell de New-York.

824

Ce015

Ricardo Augusto Leoni De Sousa, Alex Cleber Improta-Caria, Roque Aras-Júnior, Edilamar Menezes de Oliveira, Úrsula Paula Reno Soci & Ricardo Cardoso Cassilhas

Physical exercise effects on the brain during COVID-19 pandemic: links between mental and cardiovascular health

https://doi.org/10.1007/s10072-021-05082-9

published

25-Jan-21

Review Article

https://link.springer.com/article/10.1007/s10072-021-05082-9

_

825

Ce016

Nicolas Hoertel, Marina Sánchez-Rico, Raphaël Vernet, Nathanaël Beeker, Anne-Sophie Jannot, Antoine Neuraz, Elisa Salamanca, Nicolas Paris, Christel Daniel, Alexandre Gramfort, Guillaume Lemaitre, Mélodie Bernaux, Ali Bellamine, Cédric Lemogne, Guillaume Airagnes, Anita Burgun & Frédéric Limosin

Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study

https://doi.org/10.1038/s41380-021-01021-4

published

4-Feb-21

Observationnel study

https://www.nature.com/articles/s41380-021-01021-4

This analysis showed a significant association between antidepressant use and reduced risk of intubation or death (HR, 0.56; 95% CI, 0.43–0.73, p < 0.001). This association remained significant in multiple sensitivity analyses. Exploratory analyses suggest that this association was also significant for SSRI and non-SSRI antidepressants, and for fluoxetine, paroxetine, escitalopram, venlafaxine, and mirtazapine (all p < 0.05).

La piste des ISRS, comme antiviraux et comme anti-inflammatoires pour la covid, dont la fluvoxamine et la fluoxétine, se trouve renforcée par une étude observationnelle en France. Une corrélation est relevée sur une réduction de l'aggravation de l'état.

826

Ce017

Phillip Joseph 1, Carlo Arevalo 2, Rudolf K F Oliveira 3, Mariana Faria-Urbina 4, Donna Felsenstein 5, Anne Louise Oaklander 6, David M Systrom

Insights from Invasive Cardiopulmonary Exercise Testing of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

https://doi.org/10.1016/j.chest.2021.01.082

published

9-Feb-21

Study

https://pubmed.ncbi.nlm.nih.gov/33577778/

During exercise, the 160 ME/CFS patients averaged lower RAP (1.9±2 vs. 8.3±1.5; P<0.0001) and peak VO2 (80%±21 vs. 101.4%±17; P<0.0001) than controls. The low-flow tertile had lower peak Qc than the normal and high-flow tertiles (88.4±19% vs. 99.5±23.8% vs. 99.9±19.5% predicted; P<0.01). In contrast, systemic oxygen extraction was impaired in high-flow versus low and normal-flow participants (0.74±0.1% vs. 0.88±0.11 vs. 0.86±0.1; P<0.0001) in association with peripheral left-to-right shunting. Among the 160 ME/CFS patient biopsies, 31% was consistent with SFN (epidermal innervation ≤5.0% of predicted; P < 0.0001). Denervation severity did not correlate with exertional measures.

Le malaise post-effort est un symptôme commun à de nombreux "covid long" et aux malades de l'encéphalomyélite myalgique. Une étude américaine en présente une physiopathologie possible. Les auteurs notent chez ces malades un retour veineux et une extraction périphérique d'oxygène altérés. La pression artérielle droite est inférieure à la moyenne. Pour ceux ayant une neuropathie à petites fibres, les dérégulations induites peuvent provoquer une dilatation microvasculaire, détournant le sang oxygéné des lits capillaires, ce qui réduit le retour cardiaque. Ces dérégulations neurovasculaires périphériques plaident pour une intolérance physiologique à l'effort qui va au-delà du seul déconditionnement.
Les auteurs écrivent que leurs observations permettent d'éliminer le déconditionnement physique comme facteur confondant des malaises post-effort, relevé comme incompatible avec le débit cardiaque plus élevé et les faibles pressions de remplissage biventriculaire.
"[Pour éviter les malaises post-effort] nous préconisons pour la rééducation physique un programme d'exercices prudents, gradués, pour aider à compenser les limitations cardiovasculaires associées à la maladie."

N001

___Care___

Published study on 9-Feb-21:
"Insights from Invasive Cardiopulmonary Exercise Testing of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome"
Le malaise post-effort est un symptôme commun à de nombreux "covid long" et aux malades de l'encéphalomyélite myalgique. Une étude américaine en présente une physiopathologie possible. Les auteurs notent chez ces malades un retour veineux et une extraction périphérique d'oxygène altérés. La pression artérielle droite est inférieure à la moyenne. Pour ceux ayant une neuropathie à petites fibres, les dérégulations induites peuvent provoquer une dilatation microvasculaire, détournant le sang oxygéné des lits capillaires, ce qui réduit le retour cardiaque. Ces dérégulations neurovasculaires périphériques plaident pour une intolérance physiologique à l'effort qui va au-delà du seul déconditionnement.
Les auteurs écrivent que leurs observations permettent d'éliminer le déconditionnement physique comme facteur confondant des malaises post-effort, relevé comme incompatible avec le débit cardiaque plus élevé et les faibles pressions de remplissage biventriculaire.
"[Pour éviter les malaises post-effort] nous préconisons pour la rééducation physique un programme d'exercices prudents, gradués, pour aider à compenser les limitations cardiovasculaires associées à la maladie."
Link: https://pubmed.ncbi.nlm.nih.gov/33577778/
Extract: "During exercise, the 160 ME/CFS patients averaged lower RAP (1.9±2 vs. 8.3±1.5; P<0.0001) and peak VO2 (80%±21 vs. 101.4%±17; P<0.0001) than controls. The low-flow tertile had lower peak Qc than the normal and high-flow tertiles (88.4±19% vs. 99.5±23.8% vs. 99.9±19.5% predicted; P<0.01). In contrast, systemic oxygen extraction was impaired in high-flow versus low and normal-flow participants (0.74±0.1% vs. 0.88±0.11 vs. 0.86±0.1; P<0.0001) in association with peripheral left-to-right shunting. Among the 160 ME/CFS patient biopsies, 31% was consistent with SFN (epidermal innervation ≤5.0% of predicted; P < 0.0001). Denervation severity did not correlate with exertional measures."

827

Ce018

Pam R. Taub, Adena Zadourian, Hannah C. Lo, Cameron K. Ormiston, Shahrokh Golshan, and Jonathan C. Hsu

Randomized Trial of Ivabradine in Patients With Hyperadrenergic Postural Orthostatic Tachycardia Syndrome

https://doi.org/10.1016/j.jacc.2020.12.029

published

15-Feb-21

RCT

https://www.sciencedirect.com/science/article/pii/S0735109720381316?dgcid=author

There was a significant reduction in heart rate between placebo and ivabradine (p < 0.001). Patients reported significant improvements in QOL with RAND 36-Item Health Survey 1.0 for physical functioning (p = 0.008) and social functioning (p = 0.021). There was a strong trend in reduction of NE levels upon standing with ivabradine (p = 0.056). Patients did not experience any significant side-effects, such as bradycardia or hypotension, with ivabradine.

Un essai clinique randomisé en double aveugle appuie fortement la possibilité que l'ivabradine, un médicament bradycardisant, soit efficace pour atténuer le syndrome de tachycardie orthostatique posturale (POTS en anglais), symptôme assez fréquent chez les malades du covid long, en lien particulier avec la dysautonomie.

Ivabradine pour traiter le syndrome de tachycardie orthostatique posturale : Un éditorial dans la revue Journal of the American College of Cardiology, qui publie l'étude de Taub et al. salue une avancée importante dans le traitement de ce syndrome.
https://www.jacc.org/doi/10.1016/j.jacc.2020.12.028

N001

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Published rct on 15-Feb-21:
"Randomized Trial of Ivabradine in Patients With Hyperadrenergic Postural Orthostatic Tachycardia Syndrome"
Un essai clinique randomisé en double aveugle appuie fortement la possibilité que l'ivabradine, un médicament bradycardisant, soit efficace pour atténuer le syndrome de tachycardie orthostatique posturale (POTS en anglais), symptôme assez fréquent chez les malades du covid long, en lien particulier avec la dysautonomie.

Ivabradine pour traiter le syndrome de tachycardie orthostatique posturale : Un éditorial dans la revue Journal of the American College of Cardiology, qui publie l'étude de Taub et al. salue une avancée importante dans le traitement de ce syndrome.
https://www.jacc.org/doi/10.1016/j.jacc.2020.12.028
Link: https://www.sciencedirect.com/science/article/pii/S0735109720381316?dgcid=author
Extract: "There was a significant reduction in heart rate between placebo and ivabradine (p < 0.001). Patients reported significant improvements in QOL with RAND 36-Item Health Survey 1.0 for physical functioning (p = 0.008) and social functioning (p = 0.021). There was a strong trend in reduction of NE levels upon standing with ivabradine (p = 0.056). Patients did not experience any significant side-effects, such as bradycardia or hypotension, with ivabradine."

828

Ce019

Luxmi Dhoonmoon

Self-management for patients with suspected ‘long COVID’

https://doi.org/10.12968/indn.2021.2.22

Published

18-Feb-21

https://www.magonlinelibrary.com/doi/abs/10.12968/indn.2021.2.22

Many long COVID patients will require rehabilitation services, which traditionally have long waiting times.7 In light of these new challenges posed on an already stretched healthcare system, nurses should be aware of digital and online health tools they can promote to long COVID patients. Self-management resources should be utilised to ease workload and ensure that patient’s conditions are effectively managed in between face-to-face and virtual consultations for which the wait will be longer than usual.

This article will explore the long-term respiratory, neuromuscular, cardiac, chronic wound and mental health effects of COVID-19 and the resources available to support these conditions in the community.

Un article britannique à destination des infirmières fait un rapide tour d'horizon des programmes de rééducation pour les patients atteints de séquelles de la covid.

N003R2

___Care___

Published article on 18-Feb-21:
"Self-management for patients with suspected ‘long COVID’"
Un article britannique à destination des infirmières fait un rapide tour d'horizon des programmes de rééducation pour les patients atteints de séquelles de la covid.
Link: https://www.magonlinelibrary.com/doi/abs/10.12968/indn.2021.2.22
Extract: "Many long COVID patients will require rehabilitation services, which traditionally have long waiting times.7 In light of these new challenges posed on an already stretched healthcare system, nurses should be aware of digital and online health tools they can promote to long COVID patients. Self-management resources should be utilised to ease workload and ensure that patient’s conditions are effectively managed in between face-to-face and virtual consultations for which the wait will be longer than usual.

This article will explore the long-term respiratory, neuromuscular, cardiac, chronic wound and mental health effects of COVID-19 and the resources available to support these conditions in the community."

829

Ce020

Victor FigueiredoLeiteMD1Danielle BianchiniRampimMD1Valeria ConceiçãoJorgePT1Maria do CarmoCorreia de LimaPT DPT1Leandro GonçalvesCezarinoPT1Cleber Nunesda RochaMD1Rodrigo BarbosaEsperMD PhD1Prevent Senior COVID-19 Rehabilitation Study

Persistent symptoms and disability after COVID-19 hospitalization: data from a comprehensive telerehabilitation program

https://doi.org/10.1016/j.apmr.2021.03.001

Published

10-Mar-21

Study

https://www.sciencedirect.com/science/article/pii/S0003999321002252

Individuals hospitalized due to COVID-19 present high levels of disability, dyspnea, dysphagia, and dependence for both ADLs and IADLs. Those admitted at the ICU presented more advanced disability parameters.

Etude sur les séquelles et les programmes de réadaptation pour des patients âgées (71,8±13,0 ans) covid hospitalisés.

830

Ce021

Manzur Kader, Md. Afzal Hossain, Vijayendar Reddy, Nirmala K. Panagodage Perera

Effects of short-term breathing exercises on respiratory recovery in patients with COVID-19- a quasi-experimental study

https://doi.org/10.21203/rs.3.rs-301294/v1

pre-print

8-Mar-21

RESEARCH ARTICLE

https://www.researchsquare.com/article/rs-301294/v1

After 4-5 days of respiratory rehabilitation SpO2 (96.7% ±2.1 vs 90.4% ±1.5), P<0.01), respiratory rate (20.5 ±2.4 vs 23.0 ±2.2) breaths/minute, P<0.01), heart rate (80.5 ±9.2 vs 91.2 ±8.6) beats/minute, P<0.01), and oxygen therapy requirement (0.4 ±0.98 vs 1.4 ±2.0) litre/min, P<0.01) improved in the intervention group compared to the control group. The mean days of hospitalisation for the intervention group and the control group were 7.1 days vs. 14.6 days, respectively.

Un préprint sur les effets d'exercices de respiration à court terme, pour la récupération respiratoire chez les patients hospitalisés atteints de covid.

831

Ce022

Praveen Kumar Kandakurti
Sampath Kumar Amaravadi

Management and Rehabilitation of COVID-19: A Physiotherapist Perspective

https://doi.org/10.1615/CritRevPhysRehabilMed.2021037383

Published

13-Jul-05

Review

http://www.dl.begellhouse.com/journals/757fcb0219d89390,4405326109887885,5aa2c5af68ed4859.html

We conclude that early physiotherapy rehabilitation should be started to avoid post-COVID complications and improve patients' quality of life. The current paper highlights the importance of physiotherapy rehabilitation service for patients with confirmed COVID-19 in the acute hospital setting, including screening to determine indications for physiotherapy, respiratory physiotherapy, exercise interventions, and postdischarge period.

_

832

Ce023

Polly Moffat

Recognising and treating long Covid

https://doi.org/10.12968/prma.2021.31.3.20

Published

12-Mar-21

https://www.magonlinelibrary.com/doi/abs/10.12968/prma.2021.31.3.20?journalCode=prma

Reports of continuing, long-term symptoms of Covid-19 after patients have recovered from infection have raised concerns among health professionals. What are the characteristics of the condition?

_

833

Ce024

Veronica LourençoWittmeraFlavia MariniParoaHalinaDuarteaVerena KiseCapellinibMarcela CangussuBarbalho-Moulim

Early mobilization and physical exercise in patients with COVID-19: A narrative literature review

https://doi.org/10.1016/j.ctcp.2021.101364

Published

13-Mar-21

Review

https://www.sciencedirect.com/science/article/pii/S1744388121000633

Highlights
•Mobilization plans must consider disease severity, contraindications and comorbidities.
•Early mobilization should start as soon as COVID-19 patients have clinical stability.
•Exercise prescription must consider clinical conditions and contraindications.
•Most of the studies recommended low-intensity exercise for patients with mild disease.
•Telerehabilitation should play a key role for patients in the recovery of COVID-19.

Une revue d'études sur la rééducation après une covid.

834

Ce025

Resat Cinar Malliga R. Iyer George Kunos

Dual inhibition of CB1R and iNOS as a potential novel approach to the pharmacological management of acute and long COVID‐19

https://doi.org/10.1111/bph.15461

Published

26-Mar-21

Article

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.15461

We discuss the potential pathologic function of increased activity of the endocannabinoid (EC)/CB1 receptor (CB1R) system and inducible NO synthase (iNOS). We advocate a polypharmacology approach wherein a single chemical entity simultaneously engages CB1R and iNOS for inhibition as a potential therapeutic strategy for COVID‐19 related health complications.

_

835

Ce026

Emmanuel Coudeyre (Pr) 1 Cédric Cormier 1 Frédéric Costes 2 Marie-Martine Lefevre-Colau 3 Maxime Grolier

Réadaptation musculaire après infection à COVID-19
Muscular rehabilitation post COVID-19 infection

https://doi.org/10.1016/j.monrhu.2021.03.002

Published

24-Mar-21

Article

https://www.sciencedirect.com/science/article/pii/S1878622721000412

Severe COVID 19 infection can cause a variety of respiratory and neuro-muscular damage both in the acute phase and at distance from the initial infection. Rehabilitation should be offered at every stages of the infection. Due to a lack of evidence based data, this management is based on published data for severe respiratory infections such as SARS and expert opinion. It should combine muscle strengthening, exercise reconditioning and more specific respiratory physiotherapy for certain patients.

L’infection sévère à COVID 19 peut-être à l’origine d’atteintes respiratoires et neuro-musculaires variées autant à la phase aigüe qu’à distance de l’infection initiale. Une prise en charge rééducative doit être proposée aux différentes phases de l’infection. Par manque de données probantes, cette prise en charge s’appuie sur les données publiées pour les infections respiratoires sévères comme le SARS et l’avis d’experts. Elle doit associer du renforcement musculaire, un reconditionnement à l’effort et une kinésithérapie respiratoire plus spécifique pour certains patients.

N006

___Care___

Published article on 24-Mar-21:
"Réadaptation musculaire après infection à COVID-19
Muscular rehabilitation post COVID-19 infection"
L’infection sévère à COVID 19 peut-être à l’origine d’atteintes respiratoires et neuro-musculaires variées autant à la phase aigüe qu’à distance de l’infection initiale. Une prise en charge rééducative doit être proposée aux différentes phases de l’infection. Par manque de données probantes, cette prise en charge s’appuie sur les données publiées pour les infections respiratoires sévères comme le SARS et l’avis d’experts. Elle doit associer du renforcement musculaire, un reconditionnement à l’effort et une kinésithérapie respiratoire plus spécifique pour certains patients.
Link: https://www.sciencedirect.com/science/article/pii/S1878622721000412
Extract: "Severe COVID 19 infection can cause a variety of respiratory and neuro-muscular damage both in the acute phase and at distance from the initial infection. Rehabilitation should be offered at every stages of the infection. Due to a lack of evidence based data, this management is based on published data for severe respiratory infections such as SARS and expert opinion. It should combine muscle strengthening, exercise reconditioning and more specific respiratory physiotherapy for certain patients."

836

Ce027

Thomas Hueso , Cécile Pouderoux , Hélène Péré ,Anne-Lise Beaumont ,Laure-Anne Raillon, Florence Ader ,Lucienne Chatenoud ,Déborah Eshagh ,Tali-Anne Szwebel ,Marc Garnier ,France Pirenne ,Pierre Tiberghien ,Karine Lacombe

Convalescent plasma therapy for B-cell–depleted patients with protracted COVID-19

https://doi.org/10.1182/blood.2020008423

Published

12-Nov-20

Study

https://ashpublications.org/blood/article/136/20/2290/463806

Key Points
As a proof of concept, COVID-19 convalescent plasma represents an interesting approach in B-cell–depleted patients with protracted COVID-19.

COVID-19 convalescent plasma induces a decrease in temperature and inflammatory parameters within 1 week associated with oxygen weaning.

Anti-CD20 monoclonal antibodies are widely used for the treatment of hematological malignancies or autoimmune disease but may be responsible for a secondary humoral deficiency. In the context of COVID-19 infection, this may prevent the elicitation of a specific SARS-CoV-2 antibody response. We report a series of 17 consecutive patients with profound B-cell lymphopenia and prolonged COVID-19 symptoms, negative immunoglobulin G (IgG)-IgM SARS-CoV-2 serology, and positive RNAemia measured by digital polymerase chain reaction who were treated with 4 units of COVID-19 convalescent plasma. Within 48 hours of transfusion, all but 1 patient experienced an improvement of clinical symptoms. The inflammatory syndrome abated within a week. Only 1 patient who needed mechanical ventilation for severe COVID-19 disease died of bacterial pneumonia. SARS-CoV-2 RNAemia decreased to below the sensitivity threshold in all 9 evaluated patients. In 3 patients, virus-specific T-cell responses were analyzed using T-cell enzyme-linked immunospot assay before convalescent plasma transfusion. All showed a maintained SARS-CoV-2 T-cell response and poor cross-response to other coronaviruses. No adverse event was reported. Convalescent plasma with anti–SARS-CoV-2 antibodies appears to be a very promising approach in the context of protracted COVID-19 symptoms in patients unable to mount a specific humoral response to SARS-CoV-2.

_

837

Ce028

D Liska, M Andreansky

Rehabilitation and physical activity for COVID-19 patients in the post infection period

https://doi.org/10.4149/bll_2021_052

Published

Study

https://pubmed.ncbi.nlm.nih.gov/33848179/

_

838

Ce029

PESE

Martine Nurek, Clare Rayner, Anette Freyer, Sharon Taylor, Linn Järte, Nathalie MacDermott,
Brendan C. Delaney

Recommendations for the Recognition, Diagnosis, and Management of Patients with Post COVID-19 Condition ('Long COVID'): A Delphi Study

https://dx.doi.org/10.2139/ssrn.3822279

pre-print

8-Apr-21

Guideline

https://ssrn.com/abstract=3822279

Recommendations pertaining to clinic organisation
1) Consider long covid in patients with a clinical diagnosis of covid-19 as per WHO criteria1 or test-positive history with new or fluctuating symptoms including but not limited to breathlessness, chest pain, palpitations, inappropriate tachycardia, wheeze, stridor, urticaria, abdominal pain, diarrhoea, arthralgia, neuralgia, dysphonia, fatigue including neurocognitive fatigue, cognitive impairment, prolonged pyrexia and neuropathy occurring beyond 4 weeks of initial covid-19.
2) Multispecialty long covid clinics should be led by a doctor with cross-specialty knowledge and experience of managing this condition.
3) Consider individualised investigations, management and rehabilitation planning via a multispecialty long covid assessment service as local services allow. Prioritise physician-led medical assessments and diagnostics initially, and consider allied health professionals including physiotherapy and OT input asadjuncts.
4) It is inappropriate for long covid clinics to be led by mental health specialists e.g., IAPT, clinical or health psychologist. They may be useful in supporting the multispecialty team but do not have the expertise to investigate and manage potential organ damage.
5) All under-18-year-olds need access to similar services run by paediatric specialists with knowledge of how presentations and treatments differ to adults and with close liaison with school.
6) Patients with comorbid mental health difficulties should have equal access to medical care as a patient without mental health difficulties and should not be triaged away from services.
Recommendations pertaining to diagnosis of underlying disorder
General approach:
7) In someone with long covid, symptoms of possible non-covid-19 related issues should be investigated and referred as per local guidelines. Long covid alone is not a sufficient diagnosis unless other causes have been excluded.
8) Carry out a face-to-face assessment including a thorough history and examination, consider other non-covid-19 related diagnoses, and measure FBC, renal function, CRP, LFT, thyroid function, HbA1c, Vitamin D, Magnesium, B12, folate, ferritin and bone studies.
Respiratory:
9) In those with respiratory symptoms, consider CXR at an early stage. Be aware that a normal appearance does not exclude respiratory pathology.
10) Be aware that simple spirometry may be normal but patients may have diffusion defects indicative of scarring, chronic PEs or microthrombi. Consider referral to respiratory for full lung function testing.
11) Measure oxygen saturation at rest and after an age-appropriate brief exercise test in people with breathlessness and refer for investigation if hypoxaemic or if any desaturation on exercise.
Cardiac:
12) Consider the possibility of a cardiac cause of breathlessness.
13) Be aware that a normal D-dimer may not exclude thromboembolism, especially in a chronic setting, and referral for investigation is therefore indicated if there is a clinical suspicion of pulmonary emboli. Additionally, be mindful that thromboembolism may occur at any stage during the disease course.
14) In patients with inappropriate tachycardia and/or chest pain, carry out ECG, troponin, Holter monitoring, and echocardiography. Be aware that myocarditis and pericarditis cannot be excluded on echocardiography alone.
15) In patients with chest pain consider a referral to cardiology as cardiac MRI may be indicated in a normal echo to rule out myopericarditis and microvascular angina.
16) In patients with palpitations and/or tachycardia, consider autonomic dysfunction.
Others:
17) In patients with urticaria, conjunctivitis, wheeze, inappropriate tachycardia, palpitations, shortness of breath, heartburn, abdominal cramps or bloating, diarrhoea, sleep disturbance, or neurocognitive fatigue,2 consider mast cell disorder.
18) In patients with cognitive difficulties sufficient to interfere with work or social functioning consider neurocognitive assessment.
19) In patients with joint swelling and arthralgia consider a diagnosis of reactive arthritis or new connective tissue disease and investigate and refer as appropriate.
Recommendations pertaining to management
General approach:
20) For patients with fatigue and worsening symptoms hours to days following an activity emphasise the importance of an initial phase of convalescence followed by careful pacing and rest.
21) Support patients in shifting their mental timeline of recovery to reflect the likely prolonged course, with a possibly long phased return to work.
22) Further support patients with signposting to patient resources. Applicable resources may include: management of post-exertional symptom exacerbation, activity pacing, acupuncture, diagnosis-specific management as relevant.
23) Provide patients with signposting to social prescribing, sickness certification and financial advice. Discuss with the patient whether sickness certification will state long covid as diagnosis.
24) Clinicians should ensure that the occupational status of patients with long covid is recorded (in/out of work, part/full time, student).
25) Follow patients up regularly to monitor progress from a full biopsychosocial and occupational perspective.
26) Encourage reporting of new symptoms (expected) and expectation of waxing-waning course.
27) Consider contributing patient data to research on long covid, using the WHO Case Report Form or similar.3
Management of specific conditions:
28) Patients with cardiac symptoms should be advised to limit their HR to 60% of maximum (usually around 100-110bpm) and investigated with at least ECG and echocardiogram before taking up exercise. Supervised exercise testing should be considered for this patient group as they may have perimyocarditis and exercise carries risk of arrhythmia and worsening cardiac function.4
29) For autonomic dysfunction including PoTS (Postural Orthostatic Tachycardia Syndrome), consider first increased fluids, salts, compression hosiery and specific rehabilitation.5
30) If PoTS and no or inadequate response to non-pharmacological therapy consider beta blocker, Ivabradine or Fludrocortisone (with BP and response monitoring).
31) In patients with possible mast cell disorder, consider a one-month trial of initial medical treatment and dietary advice. Higher than standard dose of antihistamines are commonly used for this indication. If partial effect consider adding second level treatment such as Montelukast, as well as referral to allergy or immunology specialists.6 7
32) Be aware that adverse drug reactions are more common in patients with mast cell disorder, for example to beta lactam antibiotics, NSAIDs, codeine, morphine or buprenorphine.
33) For breathing pattern disorder, consider specialist physiotherapy and/or using alternative therapies such as pranayama breathing and meditation.
34) In patients expressing distress, significant low mood, anxiety or symptoms of PTSD, consider mental health assessment.
35) Over the counter supplementation is common, including vitamin C, D, niacin (nicotinic acid) and quercetin. Be aware of significant drug interactions, such as with niacin or quercetin.

Un guide britannique de recommandations en pre-print (ni relu, ni encore publié) de prise en charge des malades du covid long, liste des conseils retenus par la méthode de Delphes ("Delphi", itérations de consensus par un groupe d'experts structuré).
Les recommandations portent sur l'organisation médicale, le diagnostic (notamment respiratoire, cardiaque, systémique) et la prise en charge.

839

Ce030

HAS

HAS - Webinaire : symptômes prolongés de la Covid-19 aiguë chez l'adulte

Webinar

https://youtu.be/lqPQbjeOyog

Lors du webinaire de la HAS sur les symptômes prolongés de la covid, le Dr Nicolas Barizien (à 57'05) insiste sur la nécessité de reprendre une petite activité quotidienne au plus tard quelques semaines après la phase aiguë. Il insiste pour faire impérativement précéder la rééducation sportive par une rééducation respiratoire, pour resynchroniser la respiration abdominale et la respiration thoracique. Il indique que, sans ce préalable, le patient risque un retour des dyspnées et une aggravation des symptômes. S'ensuit une réadaptation à l'effort avec de l'endurance douce, puis par "interval training" le retour à la capacité à changer de rythme et passer à des efforts plus soutenus. Le but est d'amener le patient à une activité physique en autonomie à domicile.

840

Ce031

Viet-Thi Tran, Caroline Riveros, Bérangère Clepier, Moïse Desvarieux, Camille Collet, Youri Yordanov, Philippe Ravaud

Development and validation of the long covid symptom and impact tools, a set of patient-reported instruments constructed from patients’ lived experience

https://doi.org/10.1093/cid/ciab352

Published

29-Apr-21

Study

https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab352/6252414

The long covid Symptom and Impact Tools (ST and IT) were constructed from the answers to a survey with open-ended questions to 492 patients with long COVID. Validation of the tools involved adult patients with suspected or confirmed COVID-19 and symptoms extending over three weeks after onset. Construct validity was assessed by examining the relations of the ST and IT scores with health related quality of life (EQ-5D-5L), function (PCFS, post-COVID functional scale), and perceived health (MYMOP2).

_

841

Ce032

Kamlesh Khunti, Melanie J. Davies, Mikhail N. Kosiborod & Michael A. Nauck

Long COVID — metabolic risk factors and novel therapeutic management

https://doi.org/10.1038/s41574-021-00495-0

Published

19-Apr-21

https://www.nature.com/articles/s41574-021-00495-0

Cardiometabolic conditions, including type 1 and type 2 diabetes mellitus, are associated with severe COVID-19 and long COVID. Interventions to target multiple risk factors, combined with use of novel glucose-lowering agents that improve metabolic function and the key processes that are impaired in COVID-19, should be the preferred therapeutic options for management of people with long COVID.

_

842

Ce033

Enya Daynes, Charlotte Gerlis, Emma Chaplin, Nikki Gardiner, Sally J Singh

Early experiences of rehabilitation for individuals post-COVID to improve fatigue, breathlessness exercise capacity and cognition – A cohort study

https://doi.org/10.1177%2F14799731211015691

Published

6-May-21

Study

https://journals.sagepub.com/doi/full/10.1177/14799731211015691

Individuals with lasting symptoms of COVID-19 should be offered a comprehensive recovery programme. 30 individuals (mean[SD] age 58[16]) that completed a 6 week, twice supervised rehabilitation programme demonstrated statistically significant improvements in exercise capacity, respiratory symptoms, fatigue and cognition. Participants improved by 112 m on the Incremental Shuttle Walking Test and 544 seconds on the Endurance Shuttle Walking Test. There were no serious adverse events recorded, and there were no dropouts related to symptom worsening. COVID-19 rehabilitation appears feasible and significantly improves clinical outcomes.

Un article décrit un programme de rééducation et réadaptation physique pour les patients ayant des symptômes persistants de la covid. Il se base sur les conseils donnés par ce site : https://www.yourcovidrecovery.nhs.uk/

N010

___Care___

Published study on 6-May-21:
"Early experiences of rehabilitation for individuals post-COVID to improve fatigue, breathlessness exercise capacity and cognition – A cohort study"
Un article décrit un programme de rééducation et réadaptation physique pour les patients ayant des symptômes persistants de la covid. Il se base sur les conseils donnés par ce site : https://www.yourcovidrecovery.nhs.uk/
Link: https://journals.sagepub.com/doi/full/10.1177/14799731211015691
Extract: "Individuals with lasting symptoms of COVID-19 should be offered a comprehensive recovery programme. 30 individuals (mean[SD] age 58[16]) that completed a 6 week, twice supervised rehabilitation programme demonstrated statistically significant improvements in exercise capacity, respiratory symptoms, fatigue and cognition. Participants improved by 112 m on the Incremental Shuttle Walking Test and 544 seconds on the Endurance Shuttle Walking Test. There were no serious adverse events recorded, and there were no dropouts related to symptom worsening. COVID-19 rehabilitation appears feasible and significantly improves clinical outcomes."

843

Ce034

Babita Yadav, Amit Rai, Pallavi Suresh Mundada, Richa Singhal, BCS Rao, Rakesh Rana, Narayanam Srikanth

Safety and Efficacy of Ayurvedic Interventions and Yoga on Long Term Effects of COVID-19: a Structured Summary of a Study Protocol for a Randomized Controlled Trial

https://doi.org/10.21203/rs.3.rs-490926/v1

pre-print

13-May-21

Study in progress

https://www.researchsquare.com/article/rs-490926/v1

Participants’ recruitment started on 1st May 2021. Anticipated end of recruitment is August 2021. Protocol number: CCRAS-01 Protocol version number: 1.1, 13th January 2021.

_

844

Ce035

Jaffer Shah, Hani Aiash, Maya Khodor, Sherief Ghozy, Ashraf Sheble, Adel Hassan, Said Abbadi, Khaled Sabry, Amany Abou Zeid, Akram Abdelbary

Integrated multidisciplinary post-COVID-19 care in Egypt

https://doi.org/10.1016/S2214-109X(21)00206-0

Published

18-May-21

Correspondance

https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(21)00206-0/fulltext

_

845

Ce036

Shin Jie Yong

Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments

https://doi.org/10.1080/23744235.2021.1924397

Published

22-May-21

Review

https://www.tandfonline.com/doi/full/10.1080/23744235.2021.1924397

Publication of Ce09

Cf Ce09

846

Ce037

Gutenbrunner, Christoph MD, PhD, FRCP; Nugraha, Boya MS, PhD; Martin, Lidia Teixido

Phase-Adapted Rehabilitation for Acute Coronavirus Disease-19 Patients and Patient With Long-term Sequelae of Coronavirus Disease-19

https://doi.org/10.1097/PHM.0000000000001762

Published

1-May-21

Article

https://journals.lww.com/ajpmr/Fulltext/2021/06000/Phase_Adapted_Rehabilitation_for_Acute_Coronavirus.3.aspx?context=LatestArticles

Since the beginning of the COVID-19 pandemic in early 2020, many papers have highlighted the need for the rehabilitation of patients with SARS-CoV-2 infection. Most papers refer to the need for respiratory rehabilitation in the acute phase; however, the fact that the infection also affects other organ systems has to be considered in rehabilitation interventions. Long-term symptoms in many cases severely limit activity and participation and alter quality of life, leading to rehabilitation needs. This article proposes a phase-adapted model of linking the acute, postacute, and long-term symptoms of COVID-19 with the well-established matrix of acute, postacute, and long-term rehabilitation services. A review of currently available recommendations for phase-adapted rehabilitation strategies, including the relevance of prehabilitation within this context, is provided.

_

847

Ce038

Martin Hensher, Mary Rose Angeles, Barbara de Graaff, Julie Campbell, Eugene Athan, Rebecca Haddock

Managing the long term health consequences of
COVID-19 in Australia

Published

Review

https://ahha.asn.au/system/files/docs/publications/deeble_issues_brief_no_40._managing_the_long_term_health_consequence_of_covid-19_in_australia.pdf

Primary prevention of COVID-19 should be prioritised as the most effective means of
mitigating the long-term health consequence of infection at population level. However
plans must be put in place to allow rapid scaling-up of long-term care were COVID-19
control measures to fail

_

848

Ce039

Zahra Alizadeh1, Nastaran Keyhanian2, Sara Ghaderkhani2, Simin Dashti-Khavidaki3, Raheleh Shokouhi Shoormasti1, and Zahra Pourpak

A Pilot Study on Controlling Coronavirus Disease 2019 (COVID-19)
Inflammation Using Melatonin Supplement

Published

10-Apr-21

https://ijaai.tums.ac.ir/index.php/ijaai/article/download/3086/1717/

No effective antiviral drugs and vaccines are available for the treatment of patients with
severe coronavirus 2019 (COVID-19). Therefore, available, safe, and inexpensive drugs and
supplements such as melatonin are among the proposed options for controlling inflammation.

_

849

Ce040

Abdel-Fattah

Long COVID-19 Syndrome Precaution and
Management

https://dx.doi.org/10.38125/OAJBS.000286

Published

27-May-21

Review

https://biomedscis.com/pdf/OAJBS.ID.000286.pdf

This is a review of COVID-19’s highly effects on almost all the organs and how we precaution and management as the COVID-19 causes many systemic abnormalities like inflammation, endotheliosis, vasoconstriction, hypercoagulability, edema and Lymphocytopenia, with elevated D-dimer, and disseminated intravascular coagulation.

_

850

Ce041

ME - PESE

Alaa Ghali 1,*,Carole Lacout 1,Maria Ghali 2,Aline Gury 1,Estelle Delattre 1,Christian Lavigne 1 andGeoffrey Urbanski 1

Warning Signals of Post-Exertional Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Retrospective Analysis of 197 Patients

https://doi.org/10.3390/jcm10112517

Published

7-Jun-21

Study

https://www.mdpi.com/2077-0383/10/11/2517/htm

Post-exertional malaise (PEM), the key feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is characterized by baseline symptom exacerbation after exposure to a stressor, and some patients can experience new or non-typical symptoms. We hypothesized that new or non-typical symptoms occurring long enough before onset of baseline symptom exacerbation could be warning signals predicting PEM. Adult ME/CFS patients who attended the internal medicine department of Angers University Hospital (France) between October 2011 and December 2019 were included in a retrospective medical records review. Patients who experienced one or more new or non-typical symptoms before baseline symptom exacerbation were compared with the rest of the study population for PEM features, epidemiological characteristics, fatigue features, and comorbidities. New or non-typical symptoms preceded baseline symptom exacerbation in 27/197 (13.7%) patients, and the most frequent ones were mood disorders (37%). When compared to the rest of the study population, only PEM intensity was significantly lower in these patients (p = 0.004), even after adjustment for sex and age at disease onset (p = 0.007). New or non-typical symptoms preceding baseline symptom exacerbation in some ME/CFS patients could be warning signals for PEM. Their identification could help preventing PEM occurrences or reducing their intensity leading to improving disease prognosis.

Une étude essaie de définir quels symptômes précurseurs peuvent annoncer un malaise post-effort chez les personnes souffrant d'encéphalomyélite myalgique.

N011

___Care___

Published study on 7-Jun-21:
"Warning Signals of Post-Exertional Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Retrospective Analysis of 197 Patients"
Une étude essaie de définir quels symptômes précurseurs peuvent annoncer un malaise post-effort chez les personnes souffrant d'encéphalomyélite myalgique.
Link: https://www.mdpi.com/2077-0383/10/11/2517/htm
Extract: "Post-exertional malaise (PEM), the key feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is characterized by baseline symptom exacerbation after exposure to a stressor, and some patients can experience new or non-typical symptoms. We hypothesized that new or non-typical symptoms occurring long enough before onset of baseline symptom exacerbation could be warning signals predicting PEM. Adult ME/CFS patients who attended the internal medicine department of Angers University Hospital (France) between October 2011 and December 2019 were included in a retrospective medical records review. Patients who experienced one or more new or non-typical symptoms before baseline symptom exacerbation were compared with the rest of the study population for PEM features, epidemiological characteristics, fatigue features, and comorbidities. New or non-typical symptoms preceded baseline symptom exacerbation in 27/197 (13.7%) patients, and the most frequent ones were mood disorders (37%). When compared to the rest of the study population, only PEM intensity was significantly lower in these patients (p = 0.004), even after adjustment for sex and age at disease onset (p = 0.007). New or non-typical symptoms preceding baseline symptom exacerbation in some ME/CFS patients could be warning signals for PEM. Their identification could help preventing PEM occurrences or reducing their intensity leading to improving disease prognosis."

851

Ce042

Funke-Chambour M.a,b · Bridevaux P.-O.c,d · Clarenbach C.F.e · Soccal P.M.d,f · Nicod L.P.g,h · von Garnier C.h

Guidelines
Swiss Recommendations for the Follow-Up and Treatment of Pulmonary Long COVID

https://doi.org/10.1159/000517255

Published

Review

https://www.karger.com/Article/FullText/517255

Results: The participants in the survey reached consensus and formulated a strong recommendation for regarding the following points. Patients hospitalized for COVID-19 should have a pulmonary assessment including pulmonary function tests. Symptomatic subjects affected by COVID-19, including those with mild disease, should benefit from a pulmonary follow-up. Persistent respiratory symptoms after COVID-19 should be investigated by a pulmonary follow-up including plethysmography, diffusion capacity measurement, and blood gases analysis. Individuals having suffered from COVID-19 and who present with persistent respiratory symptoms should be offered a rehabilitation. Additional questions were given moderateor weak recommendations for. The panel did not reach sufficient consensus for pharmacological therapy (e.g., therapy specifically targeting lung fibrosis) to formulate recommendations for LC drug treatment. Conclusion: The formulated recommendations should serve as an interim guidance to facilitate diagnosis and treatment of patients with pulmonary LC. As new evidence emerges, these recommendations may need to be adapted.

_

852

Ce043

Philippe Lepere, Bruno Escarguel, Selda Yolartiran, Claude Escarguel

COVID-19: Can early home treatment with Azithromycin alone or with Zinc help prevent hospitalisation, death, and long-COVID-19? A review

pre-print

22-Jan-21

Review

https://www.medrxiv.org/content/10.1101/2020.12.29.20248975v2

Many studies report on outpatient treatment with a combination of AZM + HCQ versus AZM alone, and few studies propose the addition of Zinc (Zn) to AZM. In addition, we identified 5 clinical trials currently recruiting individuals for early outpatient treatment with AZM. However, we failed in identifying any study or clinical trial conducted with family practitioners responding to our question.

_

853

Ce044

Maria Chiara Maccarone, Giacomo Magro, Lucrezia Tognolo & Stefano Masiero

Post COVID-19 persistent fatigue: a proposal for rehabilitative interventions in the spa setting

https://doi.org/10.1007/s00484-021-02158-1

Published

4-Jun-21

Correspondence

https://link.springer.com/article/10.1007/s00484-021-02158-1

In conclusion, respecting the hygiene and preventive measures, the spa setting could represent the appropriate environment to take care of post-COVID chronic fatigue, offering adequate and multidisciplinary rehabilitation protocols. Further, prospective trials on this topic are needed to fully evaluate the positive impact of a comprehensive rehabilitative treatment in the spa environment for subjects with post-COVID-19 fatigue

_

854

Ce045

Stefan R. Bornstein, Karin Voit-Bak, Timo Donate, Roman N. Rodionov, Raul R. Gainetdinov, Sergey Tselmin, Waldemar Kanczkowski, Gregor M. Müller, Martin Achleitner, Jun Wang, Julio Licinio, Michael Bauer, Allan H. Young, Sandrine Thuret, Nicole Bechmann & Richard Straube

Chronic post-COVID-19 syndrome and chronic fatigue syndrome: Is there a role for extracorporeal apheresis?

https://doi.org/10.1038/s41380-021-01148-4

Published

17-Jun-21

Article

https://www.nature.com/articles/s41380-021-01148-4

This overwhelming phenomenon has not been well defined and has been called “post-COVID syndrome” or “long-COVID” [1]. There are striking similarities to myalgic encephalomyelitis also called chronic fatigue syndrome linked to a viral and autoimmune pathogenesis. In both disorders neurotransmitter receptor antibodies against ß-adrenergic and muscarinic receptors may play a key role. We found similar elevation of these autoantibodies in both patient groups. Extracorporeal apheresis using a special filter seems to be effective in reducing these antibodies in a significant way clearly improving the debilitating symptoms of patients with chronic fatigue syndrome. Therefore, such a form of neuropheresis may provide a promising therapeutic option for patients with post-COVID-19 syndrome. This method will also be effective when other hitherto unknown antibodies and inflammatory mediators are involved.

En faisant le lien avec les thérapies testées pour l'encéphalomyélite myalgique, un article évoque dans Nature la possibilité d'expérimenter l'aphérèse extracorporelle pour les malades du covid long, en visant une diminution des taux d'auto-anticorps.

N011

___Care___

Published article on 17-Jun-21:
"Chronic post-COVID-19 syndrome and chronic fatigue syndrome: Is there a role for extracorporeal apheresis?"
En faisant le lien avec les thérapies testées pour l'encéphalomyélite myalgique, un article évoque dans Nature la possibilité d'expérimenter l'aphérèse extracorporelle pour les malades du covid long, en visant une diminution des taux d'auto-anticorps.
Link: https://www.nature.com/articles/s41380-021-01148-4
Extract: "This overwhelming phenomenon has not been well defined and has been called “post-COVID syndrome” or “long-COVID” [1]. There are striking similarities to myalgic encephalomyelitis also called chronic fatigue syndrome linked to a viral and autoimmune pathogenesis. In both disorders neurotransmitter receptor antibodies against ß-adrenergic and muscarinic receptors may play a key role. We found similar elevation of these autoantibodies in both patient groups. Extracorporeal apheresis using a special filter seems to be effective in reducing these antibodies in a significant way clearly improving the debilitating symptoms of patients with chronic fatigue syndrome. Therefore, such a form of neuropheresis may provide a promising therapeutic option for patients with post-COVID-19 syndrome. This method will also be effective when other hitherto unknown antibodies and inflammatory mediators are involved."

855

Ce046

Matthew T. Roe, Bray Patrick-Lake & Andrew C. von Eschenbach

Post-COVID-19 Syndrome: Leveraging the Patient Perspective and Technological Innovations to Enable the Delineation of Effective Treatments

https://doi.org/10.1007/s40265-021-01548-4

Published

16-Jun-21

Letter to the Editor

https://link.springer.com/article/10.1007/s40265-021-01548-4

A prospective registry that assimilates, aggregates, and curates data collected from both clinician-generated and person-generated sources can fully describe the patient journey for post-COVID survivors, delineate the long-term public health and financial impact of the COVID-19 pandemic after recovery from the acute infection, and serve as a discovery platform for identifying the most promising new and repurposed drugs to treat the long-term consequences of surviving an acute COVID infection

_

856

Ce047

Irfan Ahmed,
Aessa Tumi

When is it safe to return to exercise post COVID?

Published

2-Nov-20

Article

https://bjgp.org/content/when-it-safe-return-exercise-post-covid

We propose that patients and clinicians alike would benefit from primary care focused “graduated return to exercise” guidelines for the post-acute period of COVID-19.3. These guidelines could help patients to navigate milestones in their recovery, while outlining clear symptom-based criteria for stopping exercise, or when GP’s should refer patients on for further investigation due to a failure to progress during rehabilitation.

_

857

Ce048

CDC

Evaluating and Caring for Patients with Post-COVID Conditions: Interim Guidance

Published

14-Jun-21

Article

https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-index.html

Key Points
The term “Post-COVID Conditions” is an umbrella term for the wide range of physical and mental health consequences experienced by some patients that are present four or more weeks after SARS-CoV-2 infection, including by patients who had initial mild or asymptomatic acute infection.
Based on current information, many post-COVID conditions can be managed by primary care providers, with the incorporation of patient-centered approaches to optimize the quality of life and function in affected patients.
Objective laboratory or imaging findings should not be used as the only measure or assessment of a patient’s well-being; lack of laboratory or imaging abnormalities does not invalidate the existence, severity, or importance of a patient’s symptoms or conditions.
Healthcare professionals and patients are encouraged to set achievable goals through shared decision-making and to approach treatment by focusing on specific symptoms (e.g., headache) or conditions (e.g., dysautonomia); a comprehensive management plan focusing on improving physical, mental, and social wellbeing may be helpful for some patients.
Understanding of post-COVID conditions remains incomplete and guidance for healthcare professionals will likely change over time as the evidence evolves.

858

Ce049

SCOTT CHEATHAM

WORKING OUT AFTER COVID: RECOMMENDATIONS FOR POST-CORONAVIRUS EXERCISE

Published

1-Jul-21

Article

https://blog.nasm.org/working-out-after-covid

The fitness professional may play a vital role in helping post-COVID-19 clients return to physical activity. COVID-19 can have a significant impact on an individual’s health resulting in possible long-term complications.

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859

Ce050

G E Ivanova 1 2, A N Bogolepova 1 2, O S Levin 3, N A Shamalov 1 2, D R Khasanova 4, S N Yanishevsky 5, V V Zakharov 6, S E Khatkova 7, L V Stakhovskya 1

[Current issues of treatment and rehabilitation of patients with neurological disorders and the consequences of COVID-19. Resolution of Advisory Board] - Основные направления лечения и реабилитации неврологических проявлений COVID-19. Резолюция совета экспертов

https://doi.org/10.17116/jnevro2021121061145

Published

6-Jan-21

Article

https://pubmed.ncbi.nlm.nih.gov/34283545/

To designate such protracted clinical conditions, a new definition was introduced: «Post-COVID-19 Condition». Advisory Board of Neurologists and Rehabilitation Therapists met to, discuss of practical experience and taking into account scientific information about COVID-19, which was available at the time of the meeting, to develop unified approaches for the management of patients with neurological complications and the consequences of a new coronavirus infection. The Advisory Board worked out a resolution in which formulated the tactics of managing patients with neurological manifestations of COVID-19. The substantiation of the importance and expediency of the development and implementation of a special program of clinical examination of patients who have undergone COVID-19, which would include a clinical examination with a detailed assessment of cognitive functions to early identification and diagnosis of neurodegeneration and subsequent therapy, is given.

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860

Ce051

PieroClavarioa1VincenzoDe Marzobc1RobertaLottibcCristinaBarbaraaAnnalisaPorcileaCarmeloRussoaFedericaBeccariaaMarcoBonaviaaLuigi CarloBottaroaMartaCaltabellottaaFlaviaChioniaMonicaSantangeloaArto J.HautaladRaffaeleGriffoaGianfrancoParatifUgoCorràe2ItaloPorto

Cardiopulmonary exercise testing in COVID-19 patients at 3 months follow-up

https://doi.org/10.1016/j.ijcard.2021.07.033

Published

24-Jul-21

Study

https://www.sciencedirect.com/science/article/pii/S0167527321011785

Highlights
•Long-term effects of COVID-19 and their sustainability are of the utmost relevance.
•At 3-month, 50% of COVID-19 have significant reduction in peak oxygen consumption at CPET.
•1/3rd of them has no cardio-pulmonary cause as principal mechanism of CPET impairment.
•80% of COVID-19 experienced at least one disabling symptom at 3-month evaluation.
•Symptoms are not related with abnormal peak oxygen consumption or functional capacity.
Results
From 225 patients discharged from March to November 2020, we excluded 12 incomplete/missing cases, 13 unable to perform CPET leading to a final population of 200. Median percent-predicted peak oxygen uptake (%pVO2) was 88% (78.3–103.1).
Ninety-nine(49.5%) patients had %pVO2 below, whereas 101(50.5%) above the 85% predicted value (indicating normality).
Of 61/99 patients with reduced %pVO2 but normal anaerobic threshold, 9(14.8%) had respiratory, 21(34.4%) cardiac, and 31(50.8%) non-cardiopulmonary limitation of exercise. One-hundred sixty(80.0%) patients complain at least one symptom, without relationship with pVO2.
Multivariate linear regression analysis showed percent-predicted forced expiratory volume in one-second(β = 5.29,p = 0.023), percent-predicted diffusing capacity of lungs for carbon monoxide(β = 6.31,p = 0.001), and DLE maximal strength(β = 14.09,p = 0.008) independently associated with pVO2.
None adverse event was reported during/after CPET neither the involved health professionals developed COVID-19.
Conclusions
CPET after COVID-19 is safe and about 1/3rd of COVID-19 survivors show functional capacity limitation mainly explained by muscular impairment, calling for future research to identify patients at higher risk of long-term effects that may benefit from careful surveillance and targeted rehabilitation.

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861

Ce052

Shelley Lees1, Salla Sariola2, Megan Schmidt-Sane3, Luisa Enria1, Kit-Aun Tan4, Angel Aedo5, Koen Peeters Grietens6,7, David Kaawa-Mafigiri8

Key social science priorities for long-term COVID-19 response

http://dx.doi.org/10.1136/bmjgh-2021-006741

Published

26-Jul-21

Commentary

https://gh.bmj.com/content/6/7/e006741

The COVID-19 response continues to be driven by epidemiological priorities, and yet, the epidemic and responses are situated within specific political and health system contexts. Social science brings an understanding of context and draws attention to politics, power and social difference.
There are four critical social science priorities for COVID-19 research and policy in the long term. First, political-economic insights can support the design of public health measures and elucidate how public health responses are produced by political systems.
Second, a better understanding of the political and social structures that relate to vaccine confidence will improve public trust, acceptability, effectiveness and uptake of COVID-19 vaccines and therapeutics.
Third, development of social science perspectives on health and governance is vital to inform and untangle the complicated ways in which nationalism interacts with public health measures.
Finally, social science inquiry can reveal how individuals and communities perceive, understand and construct COVID-19 risk and severity and seek help.
These insights support building trust and good relations between local and international research and programme teams and between communities and researchers that will enhance confidence in the development, research and deployment of vaccines and other COVID-19 control measures.

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862

Ce053

Ce30

Nurek, Martine; Rayner, Clare; Freyer, Anette; Taylor, Sharon; Järte, Linn;
MacDermott, Nathalie; Delaney, Brendan

Recommendations for the recognition, diagnosis, and
management of long covid: A Delphi study

https://doi.org/10.3399/BJGP.2021.0265

Published

7-Jun-21

Study

https://bjgp.org/content/bjgp/early/2021/07/27/BJGP.2021.0265.full.pdf

Publication of Ce30a

863

Ce054

Zhipeng Yan 1,*,† ,Ming Yang 2,† andChing-Lung Lai 1,*

Long COVID-19 Syndrome: A Comprehensive Review of Its Effect on Various Organ Systems and Recommendation on Rehabilitation Plans

https://doi.org/10.3390/biomedicines9080966

Published

5-Aug-21

Review

https://www.mdpi.com/2227-9059/9/8/966/htm

The majority of people infected with SARS-CoV-2 fully recovered within a few weeks. However, a considerable number of patients of different ages still suffer from long-lasting problems similar to the multi-organ damage in its acute phase of infection, or experience symptoms continuously for a longer term after the recovery. The severity of the primary infection seems not to be associated with the possibility and severity of long-term symptoms. Various unresolved symptoms have been reported in COVID-19 survivors months after hospital discharge. Long COVID-19 Syndrome refers to survivors 4 months after initial symptoms onset. It is important to understand the systemic effects of Long COVID-19 Syndrome, its presentations, and the need for rehabilitations to restore functional recovery in survivors. Government, healthcare workers, and survivor groups should collaborate to establish a self-sustaining system to facilitate follow-up and rehabilitations, with prioritization of resources to more severely Long COVID-19 Syndrome survivors. This review looks into the systemic effects of Long COVID-19 Syndrome in various aspects: respiratory, cardiovascular, hematological, renal, gastrointestinal, neurological, and metabolic effects of Long COVID-19 Syndromes. Recommendations for follow-up and rehabilitations details have been explored to cope with the tremendous Long COVID-19 Syndrome patients.

864

Ce055

From this point on, the survey of studies is no longer as exhaustive as possible. Only those studies which seem to us to bring significant new elements will be listed.

865

Ce056

Gerard Pereira1*, Hunter Gillies1, Sanjay Chanda1, Michael Corbett1, Suzanne D. Vernon2, Tina Milani2 and Lucinda Bateman

Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

https://doi.org/10.3389/fnsys.2021.698240

Published

1-Sep-21

Study

https://www.frontiersin.org/articles/10.3389/fnsys.2021.698240/full

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multi-symptom disease with widespread evidence of disrupted systems. The authors hypothesize that it is caused by the upregulation of the corticotropin-releasing factor receptor type 2 (CRFR2) in the raphé nuclei and limbic system, which impairs the ability to maintain homeostasis. The authors propose utilizing agonist-mediated receptor endocytosis to downregulate CRFR2.

Materials and Methods: This open-label trial tested the safety, tolerability and efficacy of an acute dose of CT38s (a short-lived, CRFR2-selective agonist, with no known off-target activity) in 14 ME/CFS patients. CT38s was subcutaneously-infused at one of four dose-levels (i.e., infusion rates of 0.01, 0.03, 0.06, and 0.20 μg/kg/h), for a maximum of 10.5 h. Effect was measured as the pre-/post-treatment change in the mean 28-day total daily symptom score (TDSS), which aggregated 13 individual patient-reported symptoms.

Results: ME/CFS patients were significantly more sensitive to the transient hemodynamic effects of CRFR2 stimulation than healthy subjects in a prior trial, supporting the hypothesized CRFR2 upregulation. Adverse events were generally mild, resolved without intervention, and difficult to distinguish from ME/CFS symptoms, supporting a CRFR2 role in the disease. The acute dose of CT38s was associated with an improvement in mean TDSS that was sustained (over at least 28 days post-treatment) and correlated with both total exposure and pre-treatment symptom severity. At an infusion rate of 0.03 μg/kg/h, mean TDSS improved by −7.5 ± 1.9 (or −25.7%, p = 0.009), with all monitored symptoms improving.

Conclusion: The trial supports the hypothesis that CRFR2 is upregulated in ME/CFS, and that acute CRFR2 agonism

866

Ce057

Maria InesMitraniaMichael A.BellioaAllenMeglinbAishaKhancXiuminXucGwendolynHaskellaAlissaArangoaGeorge C.Shapiroa

Treatment of a COVID-19 long hauler with an amniotic fluid-derived extracellular vesicle biologic

https://doi.org/10.1016/j.rmcr.2021.101502

Published

30-Aug-21

Study

https://www.sciencedirect.com/science/article/pii/S2213007121001647

Zofin is an acellular biologic that contains the extracellular vesicle (EV) fraction of human amniotic fluid and is under investigation for use as a COVID-19 therapeutic. We obtained FDA and IRB approval to investigate the therapeutic use of Zofin in a single long hauler patient case experiencing prolonged shortness of breath and respiratory impairment. Administration of the EV product was shown to be safe. Furthermore, demonstrated respiratory improvements through chest X ray images and oxygen saturation measurement. The single patient IND studies were completed without any reported adverse events or safety concerns. Further-more, these completed studies demonstrate the feasibility and a therapeutic potential of amniotic fluid-derived EVs for COVID-19 long hauler intervention.

867

Ce058

A. N. Bogolepova, N. A. Osinovskaya, E. A. Kovalenko, E. V. Makhnovich

Fatigue and cognitive impairment in post-COVID syndrome: possible treatment approaches

https://doi.org/10.14412/2074-2711-2021-4-88-93

Published

Study

https://nnp.ima-press.net/nnp/article/view/1635

Objective: to evaluate the efficacy and safety of Cholytilin (choline alfoscerate) and the combined drug MexiB 6 in patients with post-COVID syndrome and fatigue, ADDs, and CI.

Patients and methods. The study included 100 patients aged 22 to 71 years who have had COVID-19 5.4 months ago. Inclusion criterion: cognitive complaints, fatigue, and emotional disturbances. The evaluation included neurological exam, Montreal Cognitive Assessment Scale (MoCA), Frontal Assessment Battery (FAB), 10-words list task, Multidimensional Fatigue Inventory (MFI-20), Hospital Anxiety and Depression Scale (HADS). Study participants were divided into two groups. Patients who had ADDs (anxiety/depression level according to HADS ≥8 points; n=50) were prescribed with MexiB 6 (1 tablet three times per day). Patients with CI (mean MoCA score ≤25 points; n=50) were prescribed with Cholytilin (2 capsules (800 mg) in the morning and 1 capsule (400 mg) at lunchtime). The follow-up period was 60 days.

Results and discussion. According to MoCA scores, a decrease in cognition was observed in 58% of participants, while 28% did not notice CI earlier. ADD fere present in 51%, and fatigue — in 100% of patients. We observed a significant reduction in fatigue severity (from 62.42±7.18 to 52.32±16.36 points; p<0.05) in patients prescribed with MexiB 6. The majority of patients noted a significant increase in physical activity, decreased fatigue, improvement of attention and physical well-being, and increased workplace efficiency. We also found a significant decrease in ADDs severity: ADDs either regressed completely (in 42% of participants) or became subclinical (in 48%; р<0.001). CI severity also reduced according to mean МоСА (from 26.60±1.31 to 27.28±1.39 points; p<0.05) and FAB (from 16.98±1.06 to 17.20±0.90 points; p<0.05) scores. In a subgroup of patients with mild CI treated with Cholytilin mean МоСА (from 23.50±0.99 to 26.36±1.34; р<0.001) and FAB (from 16.02±0.91 to 16.96±0.99; р<0.001) scores significantly increased. Complete regression of CI was observed in 74% of participants (р<0.001). We also found a decrease in ADDs (р<0.001) and fatigue (mean MFI-20 scores decreased from 42.28±10.73 to 35.60±8.10; р<0.001) severity in all study participants.

Conclusion. Patients who have had COVID-19, regardless of the disease severity, have a high prevalence of fatigue, ADDs and CI, and MexiB 6 and Cholytilin have a potential in their treatment.

868

Ce059

PESE

Maria G. Tanzi, PharmD

CDC releases guidance on caring for ‘COVID long-haulers’

https://doi.org/10.1016/j.ptdy.2021.08.009

Published

1-Sep-21

Article

https://www.pharmacytoday.org/article/S1042-0991(21)00636-8/fulltext

Health care providers can also consider already established symptom management approaches for patients experiencing post-COVID-19 conditions. For example, breathing exercises for dyspnea, OTC or prescription pain relievers for headaches, and activity management (pacing) for post-exertional malaise.
CDC reminds clinicians that there is no one-size-fits-all approach, and a treatment plan should always be customized to the patient’s conditions and treatment goals.

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869

Ce060

Maximilian Andreas Storz

Lifestyle Adjustments in Long-COVID Management: Potential Benefits of Plant-Based Diets

https://doi.org/10.1007/s13668-021-00369-x

Published

10-Sep-21

Review

https://link.springer.com/article/10.1007/s13668-021-00369-x

Thus, this review sought to investigate whether a plant-based diet could reduce the burden of long-COVID.

Recent Findings
The number of clinical trials investigating the role of plant-based nutrition in COVID-19 prevention and management is currently limited. Yet, there is evidence from pre-pandemic observational and clinical studies that a plant-based diet may be of general benefit with regard to several clinical conditions that can also be found in individuals with COVID-19. These include anxiety, depression, sleep disorders, and musculoskeletal pain. Adoption of a plant-based diet leads to a reduced intake in pro-inflammatory mediators and could be one accessible strategy to tackle long-COVID associated prolonged systemic inflammation.

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870

Ce061

Luke D Liu MD, Deborah L Duricka PhD

Stellate Ganglion Block Successfully Treats Long COVID/PASC: A Case Series

https://doi.org/10.21203/rs.3.rs-873830/v1

pre-print

10-Sep-21

Study

https://www.researchsquare.com/article/rs-873830/v1

Most of these symptoms are included in the “sickness behavior response” initiated from the brainstem when levels of circulating pro-inflammatory cytokines are high. Ordinarily a feedback loop prevents excessive production of these cytokines, however the SARS-CoV-2 virus has demonstrated the ability to induce the sympathetic nervous system (SNS), likely due to imbalance between ACE1 and ACE2 activity. Persistent sympathetic drive causes increased cytokine release, which interferes with the feedback loop that ends “sickness behaviors.” The stellate ganglion is a paravertebral collection of sympathetic nerves located in the cervical region that provides a convenient entry point to reduce activity of the SNS using local anesthetic blockade. The stellate ganglion block (SGB) has a well-established safety and efficacy profile for a variety of conditions involving the SNS. In this case report series, we treated three consecutive “Long COVID” patients with SGB. All three patients reported significant and durable improvement in symptoms including fatigue, “brain fog,” and smell and taste derangements. Our findings provide evidence implicating dysautonomia as the main etiology of Long COVID/PASC symptoms and suggest that SGB is an effective intervention for this condition with the potential to change the course of the second COVID pandemic, “Long COVID”/PASC.

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871

Ce062

Simon Décary, PT, PhD Michèle Dugas, MSc Théo Stefan, MSc
Léa Langlois, MSc Becky Skidmore, PhD Anne Bhéreur, MD
Annie LeBlanc, PhD

Care Models for Long COVID
A Rapid Systematic Review

Review

https://sporevidencealliance.ca/wp-content/uploads/2021/06/Care-Models-for-Long-COVID_Full-Report_2021.06.18.pdf

872

Ce063

Sergey N Gusev1*, Velichko LN2, Bogdanova AV2, Khramenko NI2, Konovalova NV2, Kovtun AV3

Clinical Examples of the Use of Mercureid Drug in Patients with Ischemic Neuropathy of the Optic Nerve That Appeared After Long COVID-19

Published

10-Sep-21

Study

https://athenaeumpub.com/clinical-examples-of-the-use-of-mercureid-drug-in-patients-with-ischemic-neuropathy-of-the-optic-nerve-that-appeared-after-long-covid-19/

For these purposes, an innovative multi-target immunotherapy drug, namely, Mercureid, has proven its advantages. Its intake during the period of hospitalization, in combination with vascular drugs, made it possible to achieve remission faster, stabilize the patients’ state, and achieve higher visual functions (synergism of action).
As a result, lower dosages of drugs used in combination therapy were required (there was less risk of side effects from their use).
After hospital discharge, Mercureid intake as a 3-month monotherapy brought to a complete restoration of vision (it needs reminding that upon inpatient hospital discharge, Right eye 0.01 does not have corrected visual acuity. 3 months later visual acuity became 1.0. Ischemic edema completely resolved. The foci of secondary degeneration were resorbed).

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873

Ce064

Gilmar Reis, PhD Eduardo Augusto dos Santos Moreira-Silva, PhD Daniela Carla Medeiros Silva, PhD Prof Lehana Thabane, PhD Aline Cruz Milagres, RN Thiago Santiago Ferreira, MD Castilho Vitor Quirino dos Santos Vitoria Helena de Souza Campos Ana Maria Ribeiro Nogueira, MD Alla V Glushchenko, MD Craig R Rayner, FRCPE Prof Eric J Lenze, MD Angela M Reiersen, MD
Prof Gordon H Guyatt, MD Prof Edward J Mills

Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial

https://doi.org/10.1016/S2214-109X(21)00448-4

Published

27-Oct-21

Study

https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(21)00448-4/fulltext

Recent evidence indicates a potential therapeutic role of fluvoxamine for COVID-19. In the TOGETHER trial for acutely symptomatic patients with COVID-19, we aimed to assess the efficacy of fluvoxamine versus placebo in preventing hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to a tertiary hospital due to COVID-19.
Methods
This placebo-controlled, randomised, adaptive platform trial done among high-risk symptomatic Brazilian adults confirmed positive for SARS-CoV-2 included eligible patients from 11 clinical sites in Brazil with a known risk factor for progression to severe disease. Patients were randomly assigned (1:1) to either fluvoxamine (100 mg twice daily for 10 days) or placebo (or other treatment groups not reported here). The trial team, site staff, and patients were masked to treatment allocation. Our primary outcome was a composite endpoint of hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to tertiary hospital due to COVID-19 up to 28 days post-random assignment on the basis of intention to treat. Modified intention to treat explored patients receiving at least 24 h of treatment before a primary outcome event and per-protocol analysis explored patients with a high level adherence (>80%). We used a Bayesian analytic framework to establish the effects along with probability of success of intervention compared with placebo. The trial is registered at ClinicalTrials.gov (NCT04727424) and is ongoing.
Findings
The study team screened 9803 potential participants for this trial. The trial was initiated on June 2, 2020, with the current protocol reporting randomisation to fluvoxamine from Jan 20 to Aug 5, 2021, when the trial arms were stopped for superiority. 741 patients were allocated to fluvoxamine and 756 to placebo. The average age of participants was 50 years (range 18–102 years); 58% were female. The proportion of patients observed in a COVID-19 emergency setting for more than 6 h or transferred to a teritary hospital due to COVID-19 was lower for the fluvoxamine group compared with placebo (79 [11%] of 741 vs 119 [16%] of 756); relative risk [RR] 0·68; 95% Bayesian credible interval [95% BCI]: 0·52–0·88), with a probability of superiority of 99·8% surpassing the prespecified superiority threshold of 97·6% (risk difference 5·0%). Of the composite primary outcome events, 87% were hospitalisations. Findings for the primary outcome were similar for the modified intention-to-treat analysis (RR 0·69, 95% BCI 0·53–0·90) and larger in the per-protocol analysis (RR 0·34, 95% BCI, 0·21–0·54). There were 17 deaths in the fluvoxamine group and 25 deaths in the placebo group in the primary intention-to-treat analysis (odds ratio [OR] 0·68, 95% CI: 0·36–1·27). There was one death in the fluvoxamine group and 12 in the placebo group for the per-protocol population (OR 0·09; 95% CI 0·01–0·47). We found no significant differences in number of treatment emergent adverse events among patients in the fluvoxamine and placebo groups.
Interpretation
Treatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19 reduced the need for hospitalisation defined as retention in a COVID-19 emergency setting or transfer to a tertiary hospital.

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874

Ce065

Betka Sophie, Kannape Oliver Alan, Fasola Jemina, Lance Florian, Cardin Sylvain, Schmid Aline, Similowski Thomas, Soccal Paola Marina, Herbelin Bruno, Adler Dan, Blanke Olaf

Virtual reality exercise to help COVID patients with refractory breathlessness

https://doi.org/10.1101/2021.10.26.21265510

pre-print

26-Oct-21

Study

https://www.medrxiv.org/content/10.1101/2021.10.26.21265510v1

Methods We performed a controlled, randomized, single-blind, cross-over clinical study to evaluate an iVR-based intervention to alleviate refractory breathlessness in patients recovering from COVID-19 pneumonia. The single-site study was conducted at the university hospital of Geneva, Switzerland. Patients reported refractory breathlessness (≥5 on a 10-point dyspnea scale) and had a MoCA score of ≥24. Cross-over groups were randomly assigned, concealed from the referring clinician. Participants received synchronous (intervention) or asynchronous (control) feedback of their breathing, embodied via a gender-matched avatar in iVR. Prior to the first exposure and following both experimental conditions, patients completed questionnaires. Breathing patterns were captured continuously. The COVVR clinical study is registered with ClinicalTrials.gov (NCT04844567) and is now closed.
Findings Study enrollment was open between November 2020 and April 2021. A total of 26 patients (27% women; age: mean=57, SD±12) were enrolled; 14 patients were randomly assigned to the “synchronous/asynchronous” sequence, 12 to the “asynchronous/synchronous” sequence. Data was available for all except two (7.7%) of 26 patients. The mean rating of breathing comfort was 0.1 at baseline, 0.8±1.8 for asynchronous, and 1.3±1.4 synchronous feedback (estimated difference of 0.5 (95%CI 0.05 to 1.04; p<0.05) between iVR conditions). Of all patients, 91.2% were satisfied with the intervention (1.8±1.6, t=5.201, p<0.0001, 95%CI 1.173 to inf) and 66.7% perceived it as beneficial for their breathing (0.7±1.9, t=1.806, p<0.05, 95%CI 0.036 to inf). No adverse events were reported.
Interpretation Based on these findings, we propose that our iVR-based DTx is a feasible and safe neuro-rehabilitation tool that improves breathing comfort in patients recovering from severe COVID-19 infection.

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Ce066

Stephen A Harrison 1, Seth J Baum 2, Nadege T Gunn 3, Ziad H Younes 4, Anita Kohli 5, Rashmee Patil 6, Margaret J Koziel 7, Harinder Chera 7, Jeff Zhao 7, Manu V Chakravarthy 7

Safety, Tolerability, and Biologic Activity of AXA1125 and AXA1957 in Subjects With Nonalcoholic Fatty Liver Disease

https://doi.org/10.14309/ajg.0000000000001375

Published

12-Aug-21

Study

https://pubmed.ncbi.nlm.nih.gov/34382947/

Axcella Therapeutics Launches Clinical Program to Develop Treatment for Patients with Long COVID https://www.businesswire.com/news/home/20211026005063/en/

La start-up Axcella Therapeutics va lancer un essai clinique sur son composé, AXA1125, qui vise les modulateurs endogènes du metabolisme et les mitochondries, comme potentiel traitement pour les malades du covid long. Le composé est un mélange d'acides aminés (Leucine 1g - Isoleucine 0,5g - Valine 0,5g - Arginine 1,81g - Glutamine 2g - n-acétyl-cystéine 0,15g). Les résultats sont attendus pour la mi-2022.

N015

___Care___

Published study on 12-Aug-21:
"Safety, Tolerability, and Biologic Activity of AXA1125 and AXA1957 in Subjects With Nonalcoholic Fatty Liver Disease"
La start-up Axcella Therapeutics va lancer un essai clinique sur son composé, AXA1125, qui vise les modulateurs endogènes du metabolisme et les mitochondries, comme potentiel traitement pour les malades du covid long. Le composé est un mélange d'acides aminés (Leucine 1g - Isoleucine 0,5g - Valine 0,5g - Arginine 1,81g - Glutamine 2g - n-acétyl-cystéine 0,15g). Les résultats sont attendus pour la mi-2022.
Link: https://pubmed.ncbi.nlm.nih.gov/34382947/
Extract: "Axcella Therapeutics Launches Clinical Program to Develop Treatment for Patients with Long COVID https://www.businesswire.com/news/home/20211026005063/en/"

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Ce067

Francisco Mera-Cordero, Sara Bonet Monne, Jesús Almeda Ortega, Ana García-Sangenís, Oriol Cunillera Puèrtolas, Sara Contreras-Martos, Gemma Alvarez Muñoz, Ramon Monfà Escolà, Marina Balanzó Joué, Rosa Morros Pedrós, Betlem Salvador-Gonzalez

Double-blind Placebo-controlled Randomized Clinical Trial to Assess the Efficacy of Montelukast in Mild to Moderate Respiratory Symptoms of Patients With Long COVID E-SPERANZA COVID PROJECT Study Protocol

https://doi.org/10.21203/rs.3.rs-845711/v1

pre-print

29-Oct-21

Study

https://www.researchsquare.com/article/rs-845711/v1

Phase III, randomized, double-blind clinical trial. We will include 18 to 80 year-old patients with SARS-CoV-2 infection and mild to moderate respiratory symptoms lasting more than 4 weeks. Participants will be randomly allocated in a 1:1 ratio to the intervention (experimental treatment with 10 mg/day montelukast) or the control group (placebo group), during a 28-day treatment. Follow up will finish 56 days after start of treatment. The primary outcome will be health-related quality of life associated with respiratory symptoms according to the COPD Assessment Test 4 weeks after starting treatment. Secondary outcomes a) Exercise capacity and oxygen saturation (1Min Sit-to-Stand test); b) Post-COVID-19 Functional Status scale; c) Other symptoms: asthenia, headache, mental confusion (brain fog), ageusia and anosmia (Likert scale); d) Use of healthcare resources; e) Mortality; f) Sick leave duration in days g) Side effects of montelukast.

Un médicament utilisé pour l'asthme, le montélukast, pressenti pour de possibles effets antiviraux et anti-inflammatoires, est en essai clinique de phase 3 sur des malades du covid long en Espagne.
Le rationnel pour l'utilisation du montélukast pour le covid long se base sur plusieurs études :
▶️https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321662/
▶️https://www.frontiersin.org/articles/10.3389/fphar.2020.01344/full
▶️https://pubmed.ncbi.nlm.nih.gov/32416408/

N014

___Care___

Pre-Print study on 29-Oct-21:
"Double-blind Placebo-controlled Randomized Clinical Trial to Assess the Efficacy of Montelukast in Mild to Moderate Respiratory Symptoms of Patients With Long COVID E-SPERANZA COVID PROJECT Study Protocol"
Un médicament utilisé pour l'asthme, le montélukast, pressenti pour de possibles effets antiviraux et anti-inflammatoires, est en essai clinique de phase 3 sur des malades du covid long en Espagne.
Le rationnel pour l'utilisation du montélukast pour le covid long se base sur plusieurs études :
▶️https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321662/
▶️https://www.frontiersin.org/articles/10.3389/fphar.2020.01344/full
▶️https://pubmed.ncbi.nlm.nih.gov/32416408/
Link: https://www.researchsquare.com/article/rs-845711/v1
Extract: "Phase III, randomized, double-blind clinical trial. We will include 18 to 80 year-old patients with SARS-CoV-2 infection and mild to moderate respiratory symptoms lasting more than 4 weeks. Participants will be randomly allocated in a 1:1 ratio to the intervention (experimental treatment with 10 mg/day montelukast) or the control group (placebo group), during a 28-day treatment. Follow up will finish 56 days after start of treatment. The primary outcome will be health-related quality of life associated with respiratory symptoms according to the COPD Assessment Test 4 weeks after starting treatment. Secondary outcomes a) Exercise capacity and oxygen saturation (1Min Sit-to-Stand test); b) Post-COVID-19 Functional Status scale; c) Other symptoms: asthenia, headache, mental confusion (brain fog), ageusia and anosmia (Likert scale); d) Use of healthcare resources; e) Mortality; f) Sick leave duration in days g) Side effects of montelukast."

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Hazar Abusalamah 1, Jessica M Reel 1, Christopher R Lupfer 2

Pyruvate affects inflammatory responses of macrophages during influenza A virus infection

https://doi.org/10.1016/j.virusres.2020.198088

1-Sep-20

Study

https://pubmed.ncbi.nlm.nih.gov/32634445/

We discovered that inclusion of sodium pyruvate in culture media during infection of mouse bone marrow derived macrophages with influenza A virus impaired cytokine production (IL-6, IL-1β, and TNF-α). Sodium pyruvate did not inhibit viral RNA replication. Instead, the addition of sodium pyruvate alters cellular metabolism and diminished mitochondrial reactive oxygen species (ROS) production and lowered immune signaling. Overall, sodium pyruvate affects the immune response produced by macrophages but does not inhibit virus replication.

Le pyruvate de sodium, un médicament qui modifie les réponses inflamamtoires et qui fut testée sur la grippe (https://pubmed.ncbi.nlm.nih.gov/32634445/), est à l'essai sur des malades du covid long dans cet essai clinique (https://clinicaltrials.gov/ct2/show/NCT04871815).

N014E

___Care___

study on 1-Sep-20:
"Pyruvate affects inflammatory responses of macrophages during influenza A virus infection"
Le pyruvate de sodium, un médicament qui modifie les réponses inflamamtoires et qui fut testée sur la grippe (https://pubmed.ncbi.nlm.nih.gov/32634445/), est à l'essai sur des malades du covid long dans cet essai clinique (https://clinicaltrials.gov/ct2/show/NCT04871815).
Link: https://pubmed.ncbi.nlm.nih.gov/32634445/
Extract: "We discovered that inclusion of sodium pyruvate in culture media during infection of mouse bone marrow derived macrophages with influenza A virus impaired cytokine production (IL-6, IL-1β, and TNF-α). Sodium pyruvate did not inhibit viral RNA replication. Instead, the addition of sodium pyruvate alters cellular metabolism and diminished mitochondrial reactive oxygen species (ROS) production and lowered immune signaling. Overall, sodium pyruvate affects the immune response produced by macrophages but does not inhibit virus replication."

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Anil Verma Chase E. Hawes Yashavanth Shaan Lakshmanappa Jamin W. Roh Brian A. Schmidt Joseph Dutra William Louie Hongwei Liu Zhong-Min Ma Jennifer K. Watanabe Jodie L. Usachenko Ramya Immareddy Rebecca L. Sammak Rachel Pollard J. Rachel Reader Katherine J. Olstad Lark L. Coffey Pamela A. Kozlowski Dennis J. Hartigan-O’Connor Michel Nussenzweig Koen K.A. Van Rompa John H. Morrison 9 Smita S. Iyer

Monoclonal antibodies protect aged rhesus macaques from SARS-CoV-2-induced immune activation and neuroinflammation

https://doi.org/10.1016/j.celrep.2021.109942

Published

18-Oct-21

Study

https://www.cell.com/cell-reports/fulltext/S2211-1247(21)01415-7

Highlights
•Neutralizing monoclonal antibodies (mAbs) block SARS-CoV-2 replication
•Neutralizing mAbs prevent SARS-CoV-2-induced interferon-induced chemokines
•Neutralizing mAbs limit effector CD4 T cell influx into cerebrospinal fluid
nti-viral monoclonal antibody (mAb) treatments may provide immediate but short-term immunity from coronavirus disease 2019 (COVID-19) in high-risk populations, such as people with diabetes and the elderly; however, data on their efficacy in these populations are limited. We demonstrate that prophylactic mAb treatment blocks viral replication in both the upper and lower respiratory tracts in aged, type 2 diabetic rhesus macaques. mAb infusion dramatically curtails severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-mediated stimulation of interferon-induced chemokines and T cell activation, significantly reducing development of interstitial pneumonia. Furthermore, mAb infusion significantly dampens the greater than 3-fold increase in SARS-CoV-2-induced effector CD4 T cell influx into the cerebrospinal fluid. Our data show that neutralizing mAbs administered preventatively to high-risk populations may mitigate the adverse inflammatory consequences of SARS-CoV-2 exposure.

879

Ce070

Heather Vance, Amelita Maslach, Emily Stoneman, Kathryn Harmes, Andrea Ransom, Katharine Seagly and Wendy Furst

Addressing Post-COVID Symptoms: A Guide for Primary Care Physicians

https://doi.org/10.3122/jabfm.2021.06.210254

Published

12-Nov-21

Review

https://www.jabfm.org/content/34/6/1229

Results: A quick-reference guide for management of post-COVID symptoms was created for PCPs. Educational materials were created for clinicians to share with patients. Our article reviews several common complaints including respiratory, cognitive, and neurological symptoms, chronic fatigue, dysautonomia, and anosmia and presents recommendations for management.

Conclusions: Data on long-term effects of COVID-19 are still emerging, and rapid dissemination of this data to front-line PCPs is crucial. This table was our effort to make the currently available evidence accessible for our PCPs in a simple, easy-to-use format.

todo

880

Ce071

Vicky van der Togt, Sammie Mcfarland, Marta Esperti, Elizabeth Semper, Sara Citrenbaum & Jeremy S. Rossman

Promotion of non-evidence-based therapeutics within patient-led Long COVID support groups

https://doi.org/10.1038/s41591-021-01589-y

Published

10-Dec-21

Correspondence

https://www.nature.com/articles/s41591-021-01589-y

Long COVID support groups began as a patient-led movement, providing safe spaces for patients (including children and their parents and caregivers) to discuss the disease and collectively advocate for awareness, research and support. However, in many groups, individuals and organizations have been promoting experimental treatments, ongoing clinical trials and for-profit treatment plans (examples are included in Table 1). Given the current lack of understanding of the disease etiology of Long COVID and lack of any proven treatment options, patients are desperate for any offered hope. The net result can be an unethical situation that endangers patient health and wellbeing and decreases the integrity and effectiveness of the patient-led movement.

_

881

Ce072

Tim Robbins, Michael Gonevski, Cain Clark, Sudhanshu Baitule, Kavi Sharma, Angel Magar, Kiran Patel, Sailesh Sankar, Ioannis Kyrou, Asad Ali and Harpal S Randeva

Hyperbaric oxygen therapy for the treatment of long COVID: early evaluation of a highly promising intervention

https://doi.org/10.7861/clinmed.2021-0462

Published

1-Nov-21

Study

https://www.rcpjournals.org/content/clinmedicine/21/6/e629

HBOT yielded a statistically significant improvement in the Chalder fatigue scale (p=0.0059; d=1.75 (very large)), global cognition (p=0.0137; d=–1.07 (large)), executive function (p=0.0039; d=–1.06 (large)), attention (p=0.0020; d=–1.2 (very large)), information processing (p=0.0059; d=–1.25 (very large)) and verbal function (p=0.0098; d=–0.92 (large)).

Conclusion Long COVID-related fatigue can be debilitating, and may affect young people who were previously in economic employment. The results presented here suggest potential benefits of HBOT, with statistically significant results following 10 sessions.

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Jake J.LeeaAndrew M.PetersonabDorinaKallogjeriaPawinaJiramongkolchaiaSaraKukuljanaJohn S.SchneideraCristine N.Klatt-CromwellaAndrew J.DrescheraJoseph D.BrunworthcJay F.Piccirilloa

Smell Changes and Efficacy of Nasal Theophylline (SCENT) irrigation: A randomized controlled trial for treatment of post-viral olfactory dysfunction

https://doi.org/10.1016/j.amjoto.2021.103299

Published

3-Dec-21

Study

https://www.sciencedirect.com/science/article/abs/pii/S0196070921004002

Twenty-two patients (n = 12, theophylline; n = 10, placebo) completed the study. Slightly more patients in the theophylline group (33%) reported improved smell compared to the placebo group (30%, difference 3.3%, 95% CI -35.6% to 42.3%). The median differences in pre- and post-treatment UPSIT and QOD-NS change between the two groups were 1 (95% CI -3 to 5) and -10 (95% CI -15 to -4), respectively in favor of theophylline. Three patients receiving theophylline and 2 receiving placebo had clinically meaningful improvements on the UPSIT (difference 5%, 95% CI -30% to 40%). There were no adverse events, and serum theophylline levels were undetectable in 10/10 patients.

Conclusions
While safe, there were no clinically meaningful differences in olfactory change between the two groups except for olfaction-related quality of life, which was better with theophylline. The imprecise estimates suggest future trials will need substantially larger sample sizes or treatment modifications, such as increasing the theophylline dose, to observe larger treatment effects.

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Ce074

T. A. Kuut, F. Müller, A. Aldenkamp, E. Assmann-Schuilwerve, A. Braamse, S. E. Geerlings, K. B. Gibney, R. A. A. Kanaan, P. Nieuwkerk, T. C. Olde Hartman, D. Pauëlsen, M. Prins, K. Slieker, M. Van Vugt, C. P. Bleeker-Rovers, S. P. Keijmel & H. Knoop

A randomised controlled trial testing the efficacy of Fit after COVID, a cognitive behavioural therapy targeting severe post-infectious fatigue following COVID-19 (ReCOVer): study protocol

https://doi.org/10.1186/s13063-021-05569-y

Published

2-Dec-21

Study

https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-021-05569-y

Discussion
This is the first trial testing a cognitive behavioural intervention targeting severe fatigue after COVID-19. If Fit after COVID is effective in reducing fatigue severity following COVID-19, this intervention could contribute to alleviating the long-term health consequences of COVID-19 by relieving one of its most prevalent and distressing long-term symptoms.

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Авторы: Юрко Е.В., Кучерявченко В.В., Соломенник А.О., Лесная А.С.

Methods of Correction of Neurological Disorders in Patients with Coronavirus Disease (COVID-19)

Published

1-Dec-21

Study

https://xavron.com.ua/en/publications/metody-korekcziyi-nevrologichnyh-porushen-u-pacziyentiv-iz-koronavirusnoyu-hvoroboyu-covid-19/

Neurological manifestations are typical of a new coronavirus disease. The incidence of certain neurological symptoms (impaired consciousness, headache, anxiety, worry, depression) depended on the severity of COVID-19 and was more common in patients with severe disease. The use of edaravon (Xavron), a combination of L-arginine and L-carnitine (Tivorel) and hyperosmolar balanced solution (Rheosorbilact) in the complex therapy of patients with COVID-19 promotes regression of clinical manifestations and normalization of laboratory parameters compared to standard pathogenetics.

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Dobri D. Kiprov1, Ahvie Herskowitz1, Daehwan Kim https:// .org/0000-0002-7273-99692, Michael Lieb2, Chao Liu https:// .org/0000-0001-8683-34732, Etsuko Watanabe2, Jan C. Hoffman3, Regina Rohe1, Michael J. Conboy2, Irina M. Conboy https:// .org/0000-0002-4276-06442
Author details

Case Report: Therapeutic and immunomodulatory effects of plasmapheresis in long-haul COVID [version 1; peer review: awaiting peer review]

https://doi.org/10.12688/f1000research.74534.1

pre-print

24-Nov-21

Study

https://f1000research.com/articles/10-1189

Many patients with COVID-19 experience a range of debilitating symptoms months after being infected, a syndrome termed long-haul COVID. A 68-year-old male presented with lung opacity, fatigue, physical and cognitive weaknesses, loss of smell and lymphocytopenia. After rounds of therapeutic plasma exchange (TPE), the patient returned to normal activities and work. Mechanistically in the patient’s peripheral blood mononuclear cells (PBMCs), markers of inflammatory macrophages diminished and markers of lymphocytes, including natural killer (NK) cells and cytotoxic CD8 T-cells, increased. Circulating inflammatory proteins diminished, while positive regulators of tissue repair increased. This case study suggests that TPE has the capacity to treat long-haul COVID.

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886

Ce077

L Boglione, G Meli, F Poletti, R Rostagno, R Moglia, M Cantone, M Esposito, C Scianguetta, B Domenicale, F Di Pasquale, S Borrè

Risk factors and incidence of long-COVID syndrome in hospitalized patients: does remdesivir have a protective effect?

https://doi.org/10.1093/qjmed/hcab297

Published

26-Nov-21

Study

https://academic.oup.com/qjmed/advance-article-abstract/doi/10.1093/qjmed/hcab297/6443168

Treatment with remdesivir leads to a 35.9% reduction in LCS rate in follow-up. Severity of illness, need of ICU admission and length of hospital stay were factor associated with the persistence of PCS at 6 months of follow-up.

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887

Ce078

Shin Jie Yong,Shiliang Liu

Proposed subtypes of post-COVID-19 syndrome (or long-COVID) and their respective potential therapies

https://doi.org/10.1002/rmv.2315

Published

9-Dec-21

Review

https://onlinelibrary.wiley.com/doi/10.1002/rmv.2315

Depending on the study referred, about 10%–30% (or more) of COVID-19 survivors may develop long-COVID or post-COVID-19 syndrome (PCS), characterised by persistent symptoms (most commonly fatigue, dyspnoea, and cognitive impairments) lasting for 3 months or more after acute COVID-19. While the pathophysiological mechanisms of PCS have been extensively described elsewhere, the subtypes of PCS have not. Owing to its highly multifaceted nature, this review proposes and characterises six subtypes of PCS based on the existing literature. The subtypes are non-severe COVID-19 multi-organ sequelae (NSC-MOS), pulmonary fibrosis sequelae (PFS), myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), postural orthostatic tachycardia syndrome (POTS), post-intensive care syndrome (PICS) and medical or clinical sequelae (MCS). Original studies supporting each of these subtypes are documented in this review, as well as their respective symptoms and potential interventions. Ultimately, the subtyping proposed herein aims to provide better clarity on the current understanding of PCS.

Dans une revue très complète de la littérature concernant les thérapies appliquées sur les malades du covid long, le chercheur Shin Jie Yong catégorise les symptômes et les thérapies proposées pour chacun d'entre eux.
Il aborde notamment :
1/ les séquelles non sévères multi-organes de la covid (NSC-MOS) :
La revue d'études indique que la rééducation peut être recommandée pour le NSC-MOS en raison de son approche holistique, qui n'a pas besoin d'être adaptée à une physiopathologie spécifique.
2/ les séquelles de la fibrose pulmonaire (PFS) :
Il est noté que certains médications sont approuvées, notamment les agents antifibrinolytiques comme le nintédanib et la pirfénidone. Sont également employés la réadaptation pulmonaire avec des exercices de respiration et d'aérobie, des techniques de dégagement des voies respiratoires, un soutien en oxygène et un contrôle nutritionnel.
3/ l'encéphalomyélite myalgique (syndrome de fatigue chronique ME/SFC),
Les revues systématiques ont identifié 3 traitements pharmaceutiques (vaccin Staphypan Berna, rintatolimod et coenzyme Q10 + NADH), ainsi que 5 non pharmaceutiques (thérapie cognitivo-comportementale TCC, thérapie par exercices gradués GET, rééducation, acupuncture et abdominoplastie).
Shin Jie Yong note que, concernant la TCC et la GET, leur efficacité et même leurs dommages potentiels ont été débattus, suite à des essais cliniques révélés comme faussés et par incompatibilité avec la physiopathologie sous-jacente.
L'auteur rappelle que récemment, les instances britanniques NICE ont cessé de recommander la GET et la TCC pour le traitement de l'EM/SFC, bien que la TCC puisse toujours être utilisée pour gérer les symptômes psychologiques des patients.
Il indique aussi que la pratique clinique a également suggéré d'utiliser d'autres traitements pharmaceutiques pour traiter des symptômes spécifiques de l'EM/SFC, plutôt que le syndrome lui-même, comme les médicaments contre les troubles du sommeil, la douleur et les antidépresseurs.
4/ le syndrome de tachycardie orthostatique posturale (POTS) :
L'article rapporte des études à faible niveau de preuve de traitements pharmaceutiques (c'est-à-dire propranolol, midodrine, ivabradine, fludrocortisone et antihistaminiques) ou non pharmaceutiques (c. exercice vertical).
Une étude sur une petite cohorte indique que l'ivabradine soulage la fréquence cardiaque de course plus efficacement que le carvédilol chez des survivants du covid avec des palpitations ou une tachycardie.
L'auteur renvoie à d'autres options pharmaceutiques pour le POTS comprennent une solution saline intraveineuse, la pyridostigmine, la clonidine, la méthyldopa, le vérapamil et la droxidopa.
Il est noté que cependant, la Heart Rhythm Society recommande d'abord des approches non pharmaceutiques pour le POTS, suivies d'options pharmaceutiques si nécessaire ; et que les thérapies doivent également être personnalisées car il n'y a pas d'approches universellement acceptées pour les POTS.
5/ le syndrome post-soins intensifs (PICS)
L'article indique qu'avec une présence d'inflammation chronique, une thrombose ou une fibrose chez les malades du covid long, les antagonistes de ces processus pathologiques peuvent aider. Ces antagonistes comprennent les statines, le dabigatran, les inhibiteurs du système rénine-angiotensine-aldostérone, les inhibiteurs du co-transporteur sodium-glucose-2, l'agoniste du récepteur du peptide-1 semblable au glucagon, la metformine et les inhibiteurs des récepteurs bêta-adrénergiques. Cependant, l'auteur noter que ces médicaments n'ont pas été testés dans des essais cliniques impliquant des patients covid long.
Plusieurs études ont souligné les besoins de réadaptation chez les personnes touchées par ce syndrome. Cependant, une méta-analyse a rapporté que la réadaptation physique sur ce syndrome n'améliore pas nécessairement la santé et la qualité mentale entre 6 et 12 mois. D'autres thérapies sont en test (stimulation électrique neuromusculaire, réalité virtuelle et programmes de réadaptation).
6/ les séquelles médicales ou cliniques (MCS)
Elles incluent une myriade de mécanismes spécifiques à la maladie, que la covid a créé ou aggravé s'ils étaient préexistants.
Les auteurs (@Shin63714105 et Dr Shiliang Liu) concluent que le covid long (ou syndrome post-covid) apparaît désormais comme le syndrome post-viral le plus fréquent à l'échelle mondiale.

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Abdul Mannan Baig

Loss of smell in COVID-19: reasons for variable recovery patterns from anosmia

https://doi.org/10.4103/1673-5374.330625

Published

10-Dec-21

Letter

https://www.nrronline.org/article.asp?issn=1673-5374;year=2022;volume=17;issue=7;spage=1623;epage=1624;aulast=Baig

Here I debate the possible mechanisms underlying the variable recovery from anosmia in COVID-19 and reasons why it continues in some patients with long-COVID?

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889

Ce080

Luke D.LiuDeborah L.Duricka

Stellate ganglion block reduces symptoms of Long COVID: A case series

https://doi.org/10.1016/j.jneuroim.2021.577784

Published

8-Dec-21

Short Communication

https://www.sciencedirect.com/science/article/pii/S0165572821003118

Highlights
•Long COVID symptoms include fatigue, brain fog, anosmia, dysgeusia, orthostatic intolerance.
•Long COVIDsymptoms overlap with those of chronic fatigue syndrome (ME/CFS) and POTS.
•Reduced cerebral blood flow is a feature of dysautonomia in ME/CFS and POTS.
•Stellate ganglion block increases cerebral blood flow and alleviates Long COVID symptoms.
•The interaction between nervous and immune systems is involved in Long COVID.
After recovering from COVID-19, a significant proportion of symptomatic and asymptomatic individuals develop Long COVID. Fatigue, orthostatic intolerance, brain fog, anosmia, and ageusia/dysgeusia in Long COVID resemble “sickness behavior,” the autonomic nervous system response to pro-inflammatory cytokines (Dantzer et al., 2008). Aberrant network adaptation to sympathetic/parasympathetic imbalance is expected to produce long-standing dysautonomia. Cervical sympathetic chain activity can be blocked with local anesthetic, allowing the regional autonomic nervous system to “reboot.” In this case series, we successfully treated two Long COVID patients using stellate ganglion block, implicating dysautonomia in the pathophysiology of Long COVID and suggesting a novel treatment.

Deux chercheurs de la société Neuroversion, à Anchorage en Alaska, rapportent dans une étude avoir traité 2 malades du covid long par bloc stellaire, une technique qui consiste en l'injection d'un anesthésique local sur le pourtour des nerfs du système sympathique (partie antérieure du cou), avec un supposé effet prolongé sur les nerfs. Les chercheurs indiquent avoir obtenu une diminution des symptômes très notable sur les deux patients traités.

890

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Esen Sefik, Benjamin Israelow, Haris Mirza, Jun Zhao, Rihao Qu, Eleanna Kaffe, Eric Song, Stephanie Halene, Eric Meffre, Yuval Kluger, Michel Nussenzweig, Craig B. Wilen, Akiko Iwasaki & Richard A. Flavell

A humanized mouse model of chronic COVID-19

https://doi.org/10.1038/s41587-021-01155-4

Published

17-Dec-21

Article

https://www.nature.com/articles/s41587-021-01155-4

Here we describe a humanized mouse model of COVID-19 that uses adeno-associated virus to deliver human ACE2 to the lungs of humanized MISTRG6 mice. This model recapitulates innate and adaptive human immune responses to severe acute respiratory syndrome coronavirus 2 infection up to 28 days after infection, with key features of chronic COVID-19, including weight loss, persistent viral RNA, lung pathology with fibrosis, a human inflammatory macrophage response, a persistent interferon-stimulated gene signature and T cell lymphopenia. We used this model to study two therapeutics on immunopathology, patient-derived antibodies and steroids and found that the same inflammatory macrophages crucial to containing early infection later drove immunopathology. This model will enable evaluation of COVID-19 disease mechanisms and treatments.

Une étude dans Nature Biotechnology présente un modèle de souris humanisé pour reproduire les symptômes prolongés de la covid chez l'homme (covid chronique ou covid long). Les souris présentent une perte de poids, la persistance d'un ARN viral, une pathologie pulmonaire avec fibrose, une réaction inflammatoire par activation des macrophages, une signature génique persistante stimulée par interféron ainsi qu'une lymphopénie des lymphocytes T. Ce modèle a permis de tester deux thérapies immunologiques, et fait dire aux auteurs que les glucocorticoïdes (ici la dexaméthasone) ne doivent être envisagés que lorsque les titres viraux sont indétectables, et permettent de réduire la morbidité sur la phase chronique.

891

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Vicky van der Togt, Sammie Mcfarland, Marta Esperti, Elizabeth Semper, Sara Citrenbaum & Jeremy S. Rossman

Promotion of non-evidence-based therapeutics within patient-led Long COVID support groups

https://doi.org/10.1038/s41591-021-01589-y

Published

17-Dec-21

Correspondence

https://www.nature.com/articles/s41591-021-01589-y

Long COVID support groups began as a patient-led movement, providing safe spaces for patients (including children and their parents and caregivers) to discuss the disease and collectively advocate for awareness, research and support. However, in many groups, individuals and organizations have been promoting experimental treatments, ongoing clinical trials and for-profit treatment plans (examples are included in Table 1). Given the current lack of understanding of the disease etiology of Long COVID and lack of any proven treatment options, patients are desperate for any offered hope. The net result can be an unethical situation that endangers patient health and wellbeing and decreases the integrity and effectiveness of the patient-led movement.

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Ontario and health care guidelines

Post COVID-19 Condition: Guidance for Primary Care

Published

30-Nov-21

Guidance

https://www.ontariohealth.ca/sites/ontariohealth/files/2021-12/PostCovidConditionsClinicalGuidance_EN.pdf

Assessment and Management of the Post-COVID-19 Condition
Content adapted from Centers for Disease Control and Prevention Interim Guidance

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Ce084

Christopher R. Lupfer1, Riley Nadler1, Ronald Amen2, Alain Martin*2

Inhalation of Sodium Pyruvate to Reduce the Symptoms and Severity of Respiratory Diseases Including COVID-19, Long COVID, and Pulmonary Fibrosis

https://doi.org/10.31488/EJRM.121

Published

29-Oct-21

Study

https://europeanjournalofrespiratorymedicine.com/inhalation-of-sodium-pyruvate-to-reduce-the-symptoms-and-severity-of-respiratory-diseases-including-COVID-19-long-COVID-and-pulmonary-fibrosis

Findings: During active COVID-19 infection, N115 decreased viral titers and produced a significant improvement over saline in coughing/sneezing and fatigue. In Long COVID patients, N115 significantly reduced headache, coughing/sneezing and increased SaO2 levels (decreased hypoxemia) and improved breathing (dyspnea). In patients with Pulmonary Fibrosis, there was a significant improvement in all lung functions, compared to baseline, as determined by changes in SaO2, FVC, FEV1, PEF, and FEV1/FVC ratio. Conclusions: N115 is safe and effective at reducing symptoms of active COVID-19 infection and improves disease condition in Long COVID patients. Furthermore, N115 significantly improves lung function in Pulmonary Fibrosis patients. As COVID-19 and Pulmonary Fibrosis are associated with each other, our clinical research demonstrates that N115 is a promising treatment for both and adds to the current 19 human clinical trials where N115 has shown efficacy in thousands of patients, regardless of the etiology of the lung disease (COPD, CF, allergic rhinitis, sinusitis, the flu, COVID-19 infected patients, Long COVID and patients with Pulmonary Fibrosis).

Une étude américaine souligne l'intérêt d'inhalations de pyruvate de sodium chez les malades du covid long pour atténuer les symptômes de maux de tête, de toux et permettre la diminution de l'hypoxémie et de la dyspnée, sur une cohorte de 22 patients. Chez les patients atteints de fibrose pulmonaire, les auteurs notent une amélioration significative de toutes les fonctions pulmonaires, quantifiée par les mesures et ratios SaO2, FVC, FEV1, PEF et FEV1/FVC.

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Etheresia Pretorius, Chantelle Venter, Gert Jacobus Laubscher, Maritha J. Kotze, Kelebogile Moremi, Sunday Oladejo, Liam R. Watson, Kanshu Rajaratnam, Bruce W. Watson, Douglas B. Kell

Combined triple treatment of fibrin amyloid microclots and platelet pathology in individuals with Long COVID/ Post-Acute Sequelae of COVID-19 (PASC) can resolve their persistent symptoms*

https://doi.org/10.21203/rs.3.rs-1205453/v1

pre-print

28-Dec-21

Study

https://www.researchsquare.com/article/rs-1205453/v1

A subset of 24 patients was treated with one month of dual antiplatelet therapy (DAPT) (Clopidogrel 75mg/Aspirin 75mg) once a day, as well as a direct oral anticoagulant (DOAC) (Apixiban) 5 mg twice a day. A proton pump inhibitor (PPI) pantoprazole 40 mg/day was also prescribed for gastric protection. Such a regime must only be followed under strict and qualified medical guidance to obviate any dangers, especially haemorrhagic bleeding, and of the therapy as a whole. Thromboelastography (TEG®) was used to assist in determining their clotting status. Each of the 24 treated cases reported that their main symptoms were resolved and fatigue as the main symptom was relieved, and this was also reflected in a decrease of both the fibrin amyloid microclots and platelet pathology scores. Nine patients were genotyped for genetic variation in homocysteine metabolism implicated in hypertension, a common COVID-19 co-morbidity reported in both patients found to be homozygous for the risk-associated MTHFR 677 T-allele. Fibrin amyloid microclots that block capillaries and inhibit the transport of O2 to tissues, accompanied by platelet hyperactivation, provide a ready explanation for the symptoms of Long COVID/PASC. The removal and reversal of these underlying endotheliopathies provide an important treatment option that seems to be highly efficacious, and warrants controlled clinical studies.

895

Ce086

S.Charfeddine12H.Ibn Hadjamor34S.Torjmen12S.Kraiem3R.Hammami12A.Bahloul12N.Kallel25N.Moussa25I.Touil6J.Jdidi27S.Abdesselem(Private cardiologist)48L.Abid12

Sulodexide in the treatment of patients with long COVID 19 symptoms and endothelial dysfunction: The results of TUN-EndCOV study

https://doi.org/10.1016/j.acvdsp.2021.10.007

Published

27-Dec-21

Study

https://www.sciencedirect.com/science/article/pii/S1878648021006455

Methods
We conducted a prospective multicenter longitudinal case-control study. Endothelial function was evaluated with DTM “E4-Diagnose” Polymath based on the Endothelium Quality Index (EQI). A group of patients with endothelial dysfunction (EQI < 2.0) received sulodexide. All the patients were followed-up 21 days after inclusion. Primary outcomes were defined as endothelial function amelioration (delta EQI) and long COVID-19 symptoms evolution during the follow-up.
Results
A total of 410 patients were included in this study. Patients were included at an average time of 1.89 ± 1.2 month after COVID-19 infection. At inclusion, 210 (51.2%) patients had an EQI < 2. The median age was 49 ± 13.8 (18–80) years. Among the patients with endothelial dysfunction, only 79 patients received sulodexide. Patients in sulodexide group had lower EQI than the non-medical intervention group (0.94 ± 0.6 vs. 1.52 ± 0.4; P < 10−3). They were more diabetic, hypertensive, had more coronary artery disease and received more long-term medications (aspirin, Bblockers and statins) than the others (P = 0.01, 0.002, 0.01, 0.009, 0.001 and 0.01, respectively). At the 21-days follow-up, patients in sulodexide group presented lower long COVID symptoms especially chest pain, palpitations, fatigue and neuro-cognitive difficulties associated to a significant amelioration of endothelial function (delta EQI 1.26 ± 1.07 vs. 0.22 ± 0.7; P < 10−3).
Conclusion
Sulodexide in patients with long COVID-19 may be a good intervention to ameliorate chest pain, palpitations, fatigue and neuro-cognitive difficulties associated to endothelial dysfunction.

896

Ce087

Etheresia Pretorius, Chantelle Venter, Gert Jacobus Laubscher, Maritha J. Kotze, Kelebogile Moremi, Sunday Oladejo, Liam R. Watson, Kanshu Rajaratnam, Bruce W. Watson, Douglas B. Kell

Combined triple treatment of fibrin amyloid microclots and platelet pathology in individuals with Long COVID/ Post-Acute Sequelae of COVID-19 (PASC) can resolve their persistent symptoms*

https://doi.org/10.21203/rs.3.rs-1205453/v1

pre-print

28-Dec-21

Study

https://www.researchsquare.com/article/rs-1205453/v1

A subset of 24 patients was treated with one month of dual antiplatelet therapy (DAPT) (Clopidogrel 75mg/Aspirin 75mg) once a day, as well as a direct oral anticoagulant (DOAC) (Apixiban) 5 mg twice a day. A proton pump inhibitor (PPI) pantoprazole 40 mg/day was also prescribed for gastric protection. Such a regime must only be followed under strict and qualified medical guidance to obviate any dangers, especially haemorrhagic bleeding, and of the therapy as a whole. Thromboelastography (TEG®) was used to assist in determining their clotting status. Each of the 24 treated cases reported that their main symptoms were resolved and fatigue as the main symptom was relieved, and this was also reflected in a decrease of both the fibrin amyloid microclots and platelet pathology scores. Nine patients were genotyped for genetic variation in homocysteine metabolism implicated in hypertension, a common COVID-19 co-morbidity reported in both patients found to be homozygous for the risk-associated MTHFR 677 T-allele. Fibrin amyloid microclots that block capillaries and inhibit the transport of O2 to tissues, accompanied by platelet hyperactivation, provide a ready explanation for the symptoms of Long COVID/PASC. The removal and reversal of these underlying endotheliopathies provide an important treatment option that seems to be highly efficacious, and warrants controlled clinical studies.

897

Ce088

Rosa María Wong-Chew, Edwin Xchel Rodríguez Cabrera, Carlos Alberto Rodríguez Valdez, Julieta Lomelin-Gascon, Linda Morales-Juárez, Liza Fernanda Contreras, Luis Rafael González de la Cerda, Arturo Juárez Flores, Luis Alberto Martínez-Juarez, Diego-Abelardo Álvarez-Hernández, Héctor Gallardo-Rincón, German Fajardo Dolci, Roberto Tapia-Conyer, Rafael Ricardo Valdez-Vázquez

Does anti-viral treatment in acute COVID infection decrease the risk of developing the Long-COVID Syndrome?

https://doi.org/10.1093/qjmed/hcab319

Published

8-Jan-22

Article

https://academic.oup.com/qjmed/article-abstract/114/12/841/6501564

A question that has often been asked is do vaccines prevent Long-COVID Syndrome? And, additionally, does anti-viral treatment of acute coronavirus disease-19 (COVID-19) infections reduce the risk of developing subsequently the Long-COVID Syndrome. We have some early epidemiological evidence that vaccines potentially do reduce the risk of the Long-COVID Syndrome but little evidence to date that specific anti-virals have the potential to also reduce the subsequent risk.

In a community population of 1.25 million individuals who downloaded a COVID symptom App, those who had dual vaccinations and experienced breakthrough COVID-19 infection—had significantly reduced disabling symptoms beyond ×28 days compared to unvaccinated individuals.1 In the unvaccinated population, 11% of individuals had persistent symptoms vs. 5% in the vaccinated population.

_

898

Ce089

Kirsty Brown
Asma Yahyouche
Shamil Haroon
Jenny Camaradou
Grace Turner

Long COVID and self-management

https://doi.org/10.1016/S0140-6736(21)02798-7

Published

22-Jan-22

Correspondence

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02798-7/fulltext

People with COVID-19 often have symptoms in the long term (ie, long COVID), including fatigue, breathlessness, and neurocognitive difficulties.1 The disease mechanisms causing long COVID are unknown, and there are no evidence-based treatment options. Clinical guidelines focus on symptom management, and various treatment options are being evaluated.1 The scarcity of advice has often left people with long COVID feeling isolated and frustrated in their search for therapies.
Studies have reported a wide range of self-prescribed medications being used for prevention and management of acute COVID-19, including anti-retrovirals, penicillin, vitamin C, traditional medicines, and chloroquine or hydroxychloroquine.2, 3, 4 Self-prescribing practices are unsurprising given the high incidence of and mortality from COVID-19, restricted access to health care during lockdowns, and few treatments and preventive therapies for COVID-19.

899

Ce090

PESE

Miwa K*

Oral Minocycline Challenge as a Potential First-Line Therapy for Myalgic
Encephalomyelitis and Long Covid-19 Syndrome

Published

28-Jan-22

Review

https://acmcasereport.com/wp-content/uploads/2022/01/ACMCR-v8-1710.pdf

Chronic fatigue syndrome characterized by severe disabling fatigue, prolonged post-exertional malaise, and unrefreshing sleep markedly reduces the activities of daily living and impairs the quality of life. Central nervous system dysfunction associated with myalgic encephalomyelitis (ME) has been postulated as the main cause of chronic fatigue syndrome. Recently, oral minocycline therapy has been reported to exert favorable therapeutic effects in some patients with ME, especially in the initial stage of the disease, although many patients discontinued treatment in the first few days because of acute adverse effects such as nausea and/or dizziness. Minocycline appeared to exert a variety of biologic actions against neural inflammation that are independent of their anti-microbial activity, including anti-inflammatory, immunomodulatory, and neuroprotective effects. In recent years, it has been noted that COVID-19 disease may cause persistent signs and symptoms described as post-COVID syndrome or long COVID, in which the clinical presentation is remarkably similar to those seen in patients with ME. A wide range of infectious agents have been suggested to trigger the development of ME, and one of such pathogens may be the COVID-19 virus. Recently, I had a valuable experience of a 22-year-old female patient with a 14-month duration of long COVID who completely recovered from ME-like symptoms after treatment with minocycline. This case suggests that oral minocycline could be an effective first-line therapy for long COVID-19, although a large scale of trial is obviously needed to justify the therapy.

900

Ce091

Gareth Iacobucci

Long covid: “Holistic” approach is best, given range of symptoms, say researchers

https://doi.org/10.1136/bmj.o336

Published

8-Feb-22

Article

https://www.bmj.com/content/376/bmj.o336.full

New research on long covid in adults and children supports the multidisciplinary approach to clinical care that is being provided at long covid clinics in England, experts have said.
“Long covid seems to be a condition where multiple symptoms are very common,” said Terence Stephenson, Nuffield professor of child health at the UCL Great Ormond Street Institute of Child Health in London, told a Science Media Centre briefing.
“I think the services that have been set up in England for young people do address that. They are holistic and comprehensive in their approach, rather than addressing single organs or single problems,” said Stephenson, who is the lead author of the Children and Young People with Long Covid (Clock) study, published in Lancet Adolescent and Child Health.1 “If you have a mixture of symptoms of headache, cough, and dizziness, you probably want to go to a service that can deal with you holistically with all your symptoms,” he added.
There are currently around 80 long covid clinics in England that take referrals from primary care for adults or children who are experiencing a range of symptoms that might include brain fog, anxiety, depression, breathlessness, and fatigue.

901

Ce092

Marc Blanchard 1 Author Image ; Lars Backhaus 1 Author Image ; Pedro Ming Azevedo 1 Author Image ; Thomas Hügle 1 Author Image

An mHealth App for Fibromyalgia-like Post–COVID-19 Syndrome: Protocol for the Analysis of User Experience and Clinical Data

https://doi.org/10.2196/32193

Published

Study

https://www.researchprotocols.org/2022/2/e32193/

Background:
Post–COVID-19 syndrome, also referred as “long covid,” describes persisting symptoms after SARS-CoV-2 infection, including myalgia, fatigue, respiratory, or neurological symptoms. Objective symptoms are often lacking, thus resembling a fibromyalgia-like syndrome. Digital therapeutics have shown efficiency in similar chronic disorders such as fibromyalgia, offering specific disease monitoring and interventions such as cognitive behavioral therapy or physical and respiratory exercise guidance.
Objective:
This protocol aims to study the requirements and features of a new mobile health (mHealth) app among patients with fibromyalgia-like post–COVID-19 syndrome in a clinical trial.
Methods:
We created a web application prototype for the post–COVID-19 syndrome called “POCOS,” as a web-based rehabilitation tool aiming to improve clinical outcomes. Patients without organ damage or ongoing inflammation will be included in the study. App use will be assessed through user experience questionnaires, focus groups, and clinical data analysis. Subsequently, we will analyze cross-sectional and longitudinal clinical data.
Results:
The developed mHealth app consists of a clinically adapted app interface with a simplified patient-reported outcome assessment, monitoring of medical interventions, and disease activity as well as web-based instructions for specific physical and respiratory exercises, stress reduction, and lifestyle instructions. The enrollment of participants is expected to be carried out in November 2021.
Conclusions:
User experience plays an important role in digital therapeutics and needs to be clinically tested to allow further improvement. We here describe this process for a new app for the treatment of the fibromyalgia-like post–COVID-19 syndrome and discuss the relevance of the potential outcomes such as natural disease course and disease phenotypes.

902

Ce093

Nikolay O. Kamenshchikov 1,* ,Lorenzo Berra 2,3 andRyan W. Carroll 3,4

Therapeutic Effects of Inhaled Nitric Oxide Therapy in COVID-19 Patients

https://doi.org/10.3390/biomedicines10020369

Published

3-Feb-22

Review

https://www.mdpi.com/2227-9059/10/2/369/htm

The global COVID-19 pandemic has become the largest public health challenge of recent years. The incidence of COVID-19-related acute hypoxemic respiratory failure (AHRF) occurs in up to 15% of hospitalized patients. Antiviral drugs currently available to clinicians have little to no effect on mortality, length of in-hospital stay, the need for mechanical ventilation, or long-term effects. Inhaled nitric oxide (iNO) administration is a promising new non-standard approach to directly treat viral burden while enhancing oxygenation. Along with its putative antiviral affect in COVID-19 patients, iNO can reduce inflammatory cell-mediated lung injury by inhibiting neutrophil activation, lowering pulmonary vascular resistance and decreasing edema in the alveolar spaces, collectively enhancing ventilation/perfusion matching. This narrative review article presents recent literature on the iNO therapy use for COVID-19 patients. The authors suggest that early administration of the iNO therapy may be a safe and promising approach for the treatment of COVID-19 patients. The authors also discuss unconventional approaches to treatment, continuous versus intermittent high-dose iNO therapy, timing of initiation of therapy (early versus late), and novel delivery systems. Future laboratory and clinical research is required to define the role of iNO as an adjunct therapy against bacterial, viral, and fungal infections.

903

Ce094

DebdootBasuaVivek P.ChavdabAnita A.Mehtaa

Therapeutics for COVID-19 and post COVID-19 complications: An update

https://doi.org/10.1016/j.crphar.2022.100086

Published

15-Feb-22

Review

https://www.sciencedirect.com/science/article/pii/S2590257122000062

Highlights
•With continuous mutation of SARS-CoV-2, there is a strong need for the potent therapeutic agent for covid management.
•Effectiveness of repurposed drugs used against COVID-19 till now it's not evident.
•List of US-FDA approved drugs for COVID-19 were summarized in the article.
•Several new drug molecules and biologics are engineered against SARS-CoV-2.
•A consolidated summary of the therapeutic development against SARS-CoV-2 is depicted along with an overview of effective management of postCOVID-19 complications.
Abstract
Since its inception in late December 2020 in China, novel coronavirus has affected the global socio-economic aspect. Currently, the world is seeking safe and effective treatment measures against COVID-19 to eradicate it. Many established drug molecules are tested against SARS-CoV-2 as a part of drug repurposing where some are proved effective for symptomatic relief while some are ineffective. Drug repurposing is a practical strategy for rapidly developing antiviral agents. Many drugs are presently being repurposed utilizing basic understanding of disease pathogenesis and drug pharmacodynamics, as well as computational methods. In the present situation, drug repurposing could be viewed as a new treatment option for COVID-19. Several new drug molecules and biologics are engineered against SARS-CoV-2 and are under different stages of clinical development. A few biologics drug products are approved by USFDA for emergency use in the covid management. Due to continuous mutation, many of the approved vaccines are not much efficacious to render the individual immune against opportunistic infection of SARS-CoV-2 mutants. Hence, there is a strong need for the cogent therapeutic agent for covid management. In this review, a consolidated summary of the therapeutic developments against SARS-CoV-2 are depicted along with an overview of effective management of post COVID-19 complications.

904

Ce095

Aisha M. Bhaiyat, Efrat Sasson, Zemer Wang, Sherif Khairy, Mouzayan Ginzarly, Umair Qureshi, Moin Fikree & Shai Efrati

Hyperbaric oxygen treatment for long coronavirus disease-19: a case report

https://doi.org/10.1186/s13256-022-03287-w

Published

15-Feb-22

Case Report

https://link.springer.com/article/10.1186/s13256-022-03287-w

Two potential mechanisms could be responsible for these long-term unremitting symptoms: hypercoagulability, which increases the risk of blood vessel occlusion, and an uncontrolled continuous inflammatory response. Currently, no known treatment is available for long COVID. One of the options to reverse hypoxia, reduce neuroinflammation, and induce neuroplasticity is hyperbaric oxygen therapy. In this article, we present the first case report of a previously healthy athletic individual who suffered from long COVID syndrome treated successfully with hyperbaric oxygen therapy.
Case presentation
A previously healthy 55-year-old Caucasian man presented 3 months after severe coronavirus disease 2019 infection with long COVID syndrome. His symptoms included a decline in memory, multitasking abilities, energy, breathing, and physical fitness. After evaluation that included brain perfusion magnetic resonance imaging, diffusion tensor imaging, computerized cognitive tests, and cardiopulmonary test, he was treated with hyperbaric oxygen therapy. Each session included exposure to 90 minutes of 100% oxygen at 2 atmosphere absolute pressure with 5-minute air breaks every 20 minutes for 60 sessions, 5 days per week. Evaluation after completing the treatment showed significant improvements in brain perfusion and microstructure by magnetic resonance imaging and significant improvement in memory with the most dominant effect being on nonverbal memory, executive functions, attention, information procession speed, cognitive flexibility, and multitasking. The improved cognitive functions correlated with the increased cerebral blood flow in brain regions as measured by perfusion magnetic resonance imaging. With regard to physical capacity, there was a 34% increase in the maximum rate of oxygen consumed during exercise and a 44% improvement in forced vital capacity. The improved physical measurements correlated with the regain of his pre-COVID physical capacity.
Conclusions
We report the first case of successfully treated long COVID symptoms with hyperbaric oxygen therapy with improvements in cognition and cardiopulmonary function. The beneficial effects of hyperbaric oxygen shed additional light on the pathophysiology of long COVID. As this is a single case report, further prospective randomized control studies are needed.

905

Ce096

MohanakrishnanSathyamoorthyaMonicaVerduzco-GutierrezbSwathiVaranasicRobynWarddJohnSpertuseSachinShahcf

Enhanced external counterpulsation for management of symptoms associated with long COVID

https://doi.org/10.1016/j.ahjo.2022.100105

Published

18-Feb-22

Study

https://www.sciencedirect.com/science/article/pii/S2666602222000222

Highlights
•This cohort of 16 Long COVID patients treated with EECP showed improvements in validated fatigue and cardiovascular markers.
•After EECP, patients had enhanced quality of life, allowing them to resume normal daily activities and return to work.
•These findings suggest that EECP may be beneficial for the management of Long COVID symptoms and warrants further studies.
Results
Compared to baseline, the PROMIS Fatigue, SAQ, DASI, and 6MWT improved by 4.63 ± 3.42 (p < 0.001), 21.44 ± 16.54 (p < 0.001), 18.08 ± 13.82 (p < 0.001), and 200.00 ± 180.14 (p = 0.002), respectively. CCS and RDS improved in 63% and 44% of patients, respectively. All patients unable to work prior to EECP were able to return post-therapy.
Conclusions and relevance
EECP significantly improved validated fatigue and cardiovascular-related markers in patients with Long COVID.

906

Ce097

Leonard Calabrese, Luana Colloca

Long COVID-19 and the Role of the Patient–Clinician Interaction in Symptom Management

https://doi.org/10.1177%2F23743735221077514

Published

9-Feb-22

Research Article

https://journals.sagepub.com/doi/full/10.1177/23743735221077514

We described the physical and psychological impact of Long COVID as well as detailed the neurobiology of the patient–clinician interaction and placebo science. While there are many unknowns we struggle with, placebo effects (and not mere placebo pills) can be potentially exploited as adjuvants for symptom managements. Namely, we recommend: (1) Educating the patient about her experience of sickness to align it with the clinician perspective of treating the symptoms and causes of the disease; (2) conveying awareness about the diagnosis itself of Long COVID and its strong personal dimension; (3) engaging with patients’ perspectives to expunge them of guilt; (4) dispelling fears surrounding the diagnosis of Long COVID; (5) establishing a genuine patient–clinician concordance and alliance to manage Long COVID; and (6) engaging with patients to identify their needs in order to minimize burn out deriving from Long COVID (Table 1).
Overall, the reflections presented here are based on current knowledge of Long COVID, the science of placebo effects with a focus on the neurobiology of the patient–clinician relationship with the scope to bridge these two research fields to translate the take-home messages helping patients cope and manage their Long COVID symptoms.

907

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Michal Botek 1,Jakub Krejčí 1,* ,Michal Valenta 1 ,Andrew McKune 2,3 ,Barbora Sládečková 1,Petr Konečný 4 ,Iva Klimešová 1 andDalibor Pastucha 5

Molecular Hydrogen Positively Affects Physical and Respiratory Function in Acute Post-COVID-19 Patients: A New Perspective in Rehabilitation

https://doi.org/10.3390/ijerph19041992

Published

10-Feb-22

Study

https://www.mdpi.com/1660-4601/19/4/1992/htm

Molecular hydrogen (H2) is potentially a novel therapeutic gas for acute post-coronavirus disease 2019 (COVID-19) patients because it has antioxidative, anti-inflammatory, anti-apoptosis, and antifatigue properties. The aim of this study was to determine the effect of 14 days of H2 inhalation on the respiratory and physical fitness status of acute post-COVID-19 patients. This randomized, single-blind, placebo-controlled study included 26 males (44 ± 17 years) and 24 females (38 ± 12 years), who performed a 6-min walking test (6 MWT) and pulmonary function test, specifically forced vital capacity (FVC) and expiratory volume in the first second (FEV1). Symptomatic participants were recruited between 21 and 33 days after a positive polymerase chain reaction test. The experiment consisted of H2/placebo inhalation, 2 × 60 min/day for 14 days. Results showed that H2 therapy, compared with placebo, significantly increased 6 MWT distance by 64 ± 39 m, FVC by 0.19 ± 0.24 L, and, in FEV1, by 0.11 ± 0.28 L (all p ≤ 0.025). In conclusion, H2 inhalation had beneficial health effects in terms of improved physical and respiratory function in acute post-COVID-19 patients. Therefore, H2 inhalation may represent a safe, effective approach for accelerating early function restoration in post-COVID-19 patients.

908

Ce099

Lucinda Bateman, MD Alison C. Bested, MD Hector F. Bonilla, MD Bela V. Chheda, MD Lily Chu, MD, MSHS Jennifer M. Curtin, MD Tania T. Dempsey, MD Mary E. Dimmock, BA Theresa G. Dowell, DNP, MPT Donna Felsenstein, MD David L. Kaufman, MD Nancy G. Klimas, MD Anthony L. Komaroff, MD Charles W. Lapp, MBME, MD Susan M. Levine, MD Jose G. Montoya, MD Benjamin H. Natelson, MD Daniel L. Peterson, MD Richard N. Podell, MD, MPH Irma R. Rey, MD Ilene S. Ruhoy, MD, PhD Maria A. Vera-Nunez, MD, MSBI Brayden P. Yellman, MD

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management

https://doi.org/10.1016/j.mayocp.2021.07.004

Published

25-Aug-21

Article

https://www.mayoclinicproceedings.org/article/S0025-6196(21)00513-9/fulltext

Despite myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affecting millions of people worldwide, many clinicians lack the knowledge to appropriately diagnose or manage ME/CFS. Unfortunately, clinical guidance has been scarce, obsolete, or potentially harmful. Consequently, up to 91% of patients in the United States remain undiagnosed, and those diagnosed often receive inappropriate treatment. These problems are of increasing importance because after acute COVID-19, a significant percentage of people remain ill for many months with an illness similar to ME/CFS. In 2015, the US National Academy of Medicine published new evidence-based clinical diagnostic criteria that have been adopted by the US Centers for Disease Control and Prevention. Furthermore, the United States and other governments as well as major health care organizations have recently withdrawn graded exercise and cognitive-behavioral therapy as the treatment of choice for patients with ME/CFS. Recently, 21 clinicians specializing in ME/CFS convened to discuss best clinical practices for adults affected by ME/CFS. This article summarizes their top recommendations for generalist and specialist health care providers based on recent scientific progress and decades of clinical experience. There are many steps that clinicians can take to improve the health, function, and quality of life of those with ME/CFS, including those in whom ME/CFS develops after COVID-19. Patients with a lingering illness that follows acute COVID-19 who do not fully meet criteria for ME/CFS may also benefit from these approaches.

909

Ce100

Pedro Cuevas, Antonio Manquillo, Javier Angulo, Guillermo Giménez-Gallego.

Dobesilate: A potential therapy for long-covid?

10.5455/IJMRCR.dobesilate-long-covid

Published

Study

http://www.mdpub.net/fulltext/172-1633990523.pdf?1646152427

On the basis of the involvement of fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) in inflammation and vascular changes in COVID-19, we hypothesized that Dobesilate, a demonstrated anti-FGF and anti-VEGF drug, might be beneficial for treating COVID-19 patients. We conducted a study and recruited 13 patients with long-COVID syndrome from one centre. Dobesilate (Doxium® 1g, twice a day for 15 days) shows clinical efficacy by improving symptoms in these patients.

910

Ce101

Maziar Malekzadeh Kebria, Peiman Brouki Milan, Noshad Peyravian, Jafar Kiani, Soheil Khatibi & Masoud Mozafari

Stem cell therapy for COVID-19 pneumonia

https://doi.org/10.1186/s43556-021-00067-8

Published

17-Feb-22

Review

https://link.springer.com/article/10.1186/s43556-021-00067-8

Researchers have tried different treatments to reduce the side effects of the COVID-19 symptoms. One of the most common and effective treatments now used is steroid therapy to reduce the complications of this disease. Long-term steroid therapy for chronic inflammation following COVID-19 is harmful and increases the risk of secondary infection, and effective treatment remains challenging owing to fibrosis and severe inflammation and infection. Sometimes our immune system can severely damage ourselves in disease. In the past, many researchers have conducted various studies on the immunomodulatory properties of stem cells. This property of stem cells led them to modulate the immune system of autoimmune diseases like diabetes, multiple sclerosis, and Parkinson's. Because of their immunomodulatory properties, stem cell-based therapy employing mesenchymal or hematopoietic stem cells may be a viable alternative treatment option in some patients. By priming the immune system and providing cytokines, chemokines, and growth factors, stem cells can be employed to build a long-term regenerative and protective response. This review addresses the latest trends and rapid progress in stem cell treatment for Acute Respiratory Distress Syndrome (ARDS) following COVID-19.

911

Ce102

Dana Yelin,Charalampos D. Moschopoulos,Ili Margalit,Effrossyni Gkrania-Klotsas,Francesco Landi,Jean-Paul Stahl,Dafna Yahav

ESCMID rapid guidelines for assessment and management of long COVID

https://doi.org/10.1016/j.cmi.2022.02.018

Published

17-Feb-22

Guideline

https://www.sciencedirect.com/science/article/abs/pii/S1198743X22000921

Evidence was insufficient to provide any recommendation other than conditional guidance. The panel recommends considering routine blood tests, chest imaging and pulmonary functions tests for patients with persistent respiratory symptoms at 3 months. Other tests should be performed mainly to exclude other conditions according to symptoms. For management, no evidence-based recommendations could be provided. Physical and respiratory rehabilitation should be considered. On the basis of limited evidence, the panel suggests designing high quality prospective clinical studies/trials, including a control group, to further evaluate assessment and management of individuals with persistent symptoms of COVID-19.

912

Ce103

Vink, M.; Vink-Niese, F.

Is It Useful to Question the Recovery Behaviour of Patients with ME/CFS or Long COVID?

https://doi.org/10.3390/healthcare10020392

Published

18-Feb-22

Review

https://www.mdpi.com/2227-9032/10/2/392

For the last few decades, medical guidelines have recommended treating patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with graded exercise therapy (GET) and cognitive behavioural therapy (CBT). Moreover, doctors have questioned the recovery behaviour of these patients and stimulated them to follow these treatments so that they would be able to go back to work. In this article, we reviewed trials of GET and CBT for ME/CFS that reported on work status before and after treatment to answer the question of whether doctors should continue to question the recovery behaviour of patients with ME/CFS. Our review shows that more patients are unable to work after treatment than before treatment with CBT and GET. It also highlights the fact that both treatments are unsafe for patients with ME/CFS. Therefore, questioning the recovery behaviour of patients with ME/CFS is pointless. This confirms the conclusion from the British National Institute for Health and Care Excellence (NICE), which has recently published its updated ME/CFS guideline and concluded that CBT and GET are not effective and do not lead to recovery. Studies on CBT and GET for long COVID have not yet been published. However, this review offers no support for their use in improving the recovery of patients with an ME/CFS-like illness after infection with COVID-19, nor does it lend any support to the practice of questioning the recovery behaviour of these patients.

913

Ce104

Ahmadi Hekmatikar, A.H.; Ferreira Júnior, J.B.; Shahrbanian, S.; Suzuki, K.

Functional and Psychological Changes after Exercise Training in Post-COVID-19 Patients Discharged from the Hospital: A PRISMA-Compliant Systematic Review

https://doi.org/10.3390/ijerph19042290

Published

17-Feb-22

Systematic review

https://www.mdpi.com/1660-4601/19/4/2290

Because reinfection is still possible in COVID-19 survivors, decreased physical function and increased stress and anxiety can lower immune function. However, the optimal exercise intensity and volume appear to remain unknown. Therefore, the current systematic review aimed to evaluate the effect of resistance or aerobic exercises in post-COVID-19 patients after hospital discharge. We conducted searches in the Scopus, SciELO, PubMed, Web of Science, Science Direct, and Google Scholar databases. Studies that met the following criteria were included: (i) English language, (ii) patients with COVID-19 involved with resistance or aerobic exercise programs after hospital discharge. Out of 381 studies reviewed, seven studies met the inclusion criteria. Evidence shows that exercise programs composed of resistance exercise (e.g., 1–2 sets of 8–10 repetitions at 30–80% of 1RM) along with aerobic exercise (e.g., 5 to 30 min at moderate intensity) may improve the functional capacity and quality of life (reduce stress and mental disorders) in post-COVID-19 patients. In addition, only one study reported reinfection of three subjects involved with the exercise program, suggesting that exercise programs may be feasible for the rehabilitation of the patients. A meta-analysis was not conducted because the included studies have methodological heterogeneities, and they did not examine a control group. Consequently, the results should be generalized with caution.

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Elizabeth Murray1, Henry Goodfellow2, Julia Bindman1, Ann Blandford3, Katherine Bradbury4, Tahreem Chaudhry2, Delmiro Fernandez-Reyes5, Manuel Gomes6, Fiona L Hamilton1, Melissa Heightman7, William Henley8, John R Hurst9, Hannah Hylton10, Stuart Linke11, Paul Pfeffer10, William Ricketts10, Chris Robson12, Richa Singh10, Fiona A Stevenson1, Sarah Walker8, Jonathan Waywell12

Development, deployment and evaluation of digitally enabled, remote, supported rehabilitation for people with long COVID-19 (Living With COVID-19 Recovery): protocol for a mixed-methods study

https://doi.org/10.1136/bmjopen-2021-057408

Published

7-Feb-22

Study

https://bmjopen.bmj.com/content/12/2/e057408

Introduction Long COVID-19 is a distressing, disabling and heterogeneous syndrome often causing severe functional impairment. Predominant symptoms include fatigue, cognitive impairment (‘brain fog’), breathlessness and anxiety or depression. These symptoms are amenable to rehabilitation delivered by skilled healthcare professionals, but COVID-19 has put severe strain on healthcare systems. This study aims to explore whether digitally enabled, remotely supported rehabilitation for people with long COVID-19 can enable healthcare systems to provide high quality care to large numbers of patients within the available resources. Specific objectives are to (1) develop and refine a digital health intervention (DHI) that supports patient assessment, monitoring and remote rehabilitation; (2) develop implementation models that support sustainable deployment at scale; (3) evaluate the impact of the DHI on recovery trajectories and (4) identify and mitigate health inequalities due to the digital divide.
Methods and analysis Mixed-methods, theoretically informed, single-arm prospective study, combining methods drawn from engineering/computer science with those from biomedicine. There are four work packages (WP), one for each objective. WP1 focuses on identifying user requirements and iteratively developing the intervention to meet them; WP2 combines qualitative data from users with learning from implementation science and normalisation process theory, to promote adoption, scale-up, spread and sustainability of the intervention; WP3 uses quantitative demographic, clinical and resource use data collected by the DHI to determine illness trajectories and how these are affected by use of the DHI; while WP4 focuses on identifying and mitigating health inequalities and overarches the other three WPs.

915

Ce106

E. Tucker, E. Fraser, A. Pick, R. Rogers, H. Salt, V. Masey

Long COVID rehabilitation: A collaborative approach to managing a new phenomenon

https://doi.org/10.1016/j.physio.2021.12.162

Published

1-Feb-22

Study

https://www.physiotherapyjournal.com/article/S0031-9406(21)00548-4/fulltext

Results: At time of writing, 434 patients had been referred to the Rehabilitation pathway of the Oxfordshire Post COVID Service, of whom 250 assessed and established on rehabilitation strategies. Patients referred are triaged by both leading Acute Trust Consultant and Community Trust AHP to identify the best place of care based on symptoms and functionality, utilising the Post COVID Functional Scale. At assessment, patients share their ‘story’, establish goals and identify most appropriate rehabilitative strategy. Clinicians involved in these processes include Respiratory and Rehabilitation Medicine Consultants, Psychiatrists, Psychologists, CBT Therapists, Physiotherapists and Occupational Therapists.
Processes are in place to offer patients an individualised approach to rehabilitation through the use of web based platform, symptom tracking application, development of virtual groups and encouraging use of external resources including ENO Breathe, Your COVID Recovery, NHS Yoga Platforms and we have linked locally with Age UK and Generation Games initiatives.
Patient feedback has been actively sought from the outset, ensuring that the patient voice is always heard and listened to. So far, it has been overwhelmingly positive.
Conclusion(s): Close collaboration between multiple professions, Trusts and Organisations resulted in seamless care, patient satisfaction and an excellent model of service delivery. Further work is required to support the recognition of health inequalities, with specific focus on BAME communities. We are in the process of collaborating with local GP's, inequality leads and local centres to develop focus groups ensuring that these voices are heard, and plans established to ensure equitable services are accessible to all.

916

Ce107

Lesley J.J.SorilabRonald W.DamantacGrace Y.LamcMaeve P.SmithcJasonWeatheralddJeanBourbeauePaulHernandezfMichael K.Sticklandac

The effectiveness of pulmonary rehabilitation for Post-COVID symptoms: A rapid review of the literature

https://doi.org/10.1016/j.rmed.2022.106782

Published

7-Mar-22

Review

https://www.sciencedirect.com/science/article/pii/S0954611122000476

Highlights
•Nine studies evaluating the clinical effectiveness of post-COVID pulmonary rehabilitation were identified.
•Most studies were small and of low quality.
•All studies reported improvements in post-COVID patients who had been hospitalized.
•No studies evaluated non-hospitalized patients or long-term outcomes (>3 months).
Nine studies evaluating the effectiveness of PR were identified; most were small, experimental or quasi-experimental studies, including 1 RCT, and were primarily of low quality. After attending PR, all studies reported improvements in exercise capacity, pulmonary function, and/or quality of life for individuals with post-COVID symptoms who had been hospitalized for their acute COVID-19 infection. Few studies evaluated changes in post-COVID symptom severity or frequency and, of these, improvements in dyspnea, fatigue, anxiety and depression were observed following PR. Further, no studies evaluated non-hospitalized patients or long-term outcomes beyond 3 months after initiating PR.
Conclusions
With limited high-quality evidence, any recommendations or practical guidance for PR programmes for those with post-COVID symptoms should consider factors such as feasibility, current PR capacity, and resource constraints.

917

Ce108

Tye, Joe MBA, MHA; Long, Kimberly DHA, MSN, RN, FNP, FACHE; Blake, Nancy PhD, RN, CCRN-K, NEA-BC, NHDP-BC, FAAN, FACHE; Luu, Allison MD, MS; Tye, Annie PhD

Caring for COVID's emotional long haulers

https://doi.org/10.1097/01.NUMA.0000821720.94922.5a

Published

1-Mar-22

Article

https://journals.lww.com/nursingmanagement/Fulltext/2022/03000/Caring_for_COVID_s_emotional_long_haulers.6.aspx

The COVID-19 pandemic has taken a toll on the emotional, psychological, and spiritual well-being of healthcare workers. This article presents 14 strategies nurse leaders can use to help safeguard nurses' mental health.
The COVID-19 pandemic is like Halley's Comet, which blazes a path across Earth's sky once every 75 years, pulling a long tail in its wake—a spectacle someone might see once in a lifetime and will never forget. Long after COVID-19 has become an endemic disease, the pandemic will leave behind a long tail of personal grief, emotional trauma, career dislocations, financial problems, anger, and anxiety. People living with long-term health problems associated with COVID-19 are called long haulers. We've borrowed that term to apply to healthcare workers who will experience long-term psychological, emotional, and spiritual pain because of their experiences during the pandemic. They're COVID's emotional long haulers.
In her final presidential message for Voice of Nursing Leadership, American Organization for Nursing Leadership (AONL) President Mary Ann Fuchs wrote: “At great personal cost, nurses provided hope, peace, and healing to patients and to each other... Because in times of uncertainty, nurses are there.”1 As the pandemic recedes, we must be there for the caregivers who were there for us as they cope with the likely second pandemic of posttrauma moral and emotional injury.

918

Ce109

Ramamurthy, Lakshmi B; Bhandari, Ridhi,; Kanakpur, Savitha; Thejaswini, P

Outcome of transcutaneous retrobulbar injection of liposomal amphotericin B in post-COVID-19 rhino-orbito-cerebral mucormycosis: Our experience

https://doi.org/10.4103/ijo.IJO_2356_21

Published

1-Mar-22

Study

https://journals.lww.com/ijo/Fulltext/2022/03000/Outcome_of_transcutaneous_retrobulbar_injection_of.66.aspx

Purpose:
To assess the outcome and response of transcutaneous retrobulbar injection of amphotericin B (TRAMB) in post-coronavirus disease of 2019 (COVID-19) rhino-orbito-cerebral mucormycosis (ROCM) and to establish a scoring system in guiding treatment modalities.
Results:
Out of 82 eyes, symptomatic improvement was seen in a major proportion (72%) of patients. A statistically significant improvement in scores was noted in group A (93% improved) with a P value of 0.002, while 68.4% showed improvement in group B (P-value- 0.0001). Group C with severe disease showed minimal improvement in post-injection scores of 41% (P-value 0.086), necessitating surgical intervention. No serious adverse effect of the drug or procedure was noted.
Conclusion:
Significant improvement in scores of groups A and B highlights TRAMB as an effective and safe treatment modality in mild to moderate ROCM. It is an effective adjunct in severe cases, along with other interventions. Also, the scoring system helps in assessing the severity and guiding in management strategies.

919

Ce110

Nopp S.a · Moik F.a · Klok F.A.b · Gattinger D.c · Petrovic M.c · Vonbank K.d · Koczulla A.R.e,f · Ay C.a · Zwick R.H.c,g

Outpatient Pulmonary Rehabilitation in Patients with Long COVID Improves Exercise Capacity, Functional Status, Dyspnea, Fatigue, and Quality of Life

https://doi.org/10.1159/000522118

Published

24-Feb-22

Study

https://www.karger.com/Article/FullText/522118

Background: COVID-19 survivors face the risk of long-term sequelae including fatigue, breathlessness, and functional limitations. Pulmonary rehabilitation has been recommended, although formal studies quantifying the effect of rehabilitation in COVID-19 patients are lacking. Methods: We conducted a prospective observational cohort study including consecutive patients admitted to an outpatient pulmonary rehabilitation center due to persistent symptoms after COVID-19. The primary endpoint was change in 6-min walk distance (6MWD) after undergoing a 6-week interdisciplinary individualized pulmonary rehabilitation program. Secondary endpoints included change in the post-COVID-19 functional status (PCFS) scale, Borg dyspnea scale, Fatigue Assessment Scale, and quality of life. Further, changes in pulmonary function tests were explored. Results: Of 64 patients undergoing rehabilitation, 58 patients (mean age 47 years, 43% women, 38% severe/critical COVID-19) were included in the per-protocol-analysis. At baseline (i.e., in mean 4.4 months after infection onset), mean 6MWD was 584.1 m (±95.0), and functional impairment was graded in median at 2 (IQR, 2–3) on the PCFS. On average, patients improved their 6MWD by 62.9 m (±48.2, p < 0.001) and reported an improvement of 1 grade on the PCFS scale. Accordingly, we observed significant improvements across secondary endpoints including presence of dyspnea (p < 0.001), fatigue (p < 0.001), and quality of life (p < 0.001). Also, pulmonary function parameters (forced expiratory volume in 1 s, lung diffusion capacity, inspiratory muscle pressure) significantly increased during rehabilitation. Conclusion: In patients with long COVID, exercise capacity, functional status, dyspnea, fatigue, and quality of life improved after 6 weeks of personalized interdisciplinary pulmonary rehabilitation. Future studies are needed to establish the optimal protocol, duration, and long-term benefits as well as cost-effectiveness of rehabilitation.

920

Ce111

Sebastián GarcíaMenéndezabVirna MargaritaMartín GiménezcMichael F.HolickdFrancisco J.BarranteseWalterManuchaab

COVID-19 and neurological sequelae: Vitamin D as a possible neuroprotective and/or neuroreparative agent

https://doi.org/10.1016/j.lfs.2022.120464

Published

7-Mar-22

Review

https://www.sciencedirect.com/science/article/pii/S0024320522001643

SARS-CoV-2 infection usually leads to bilateral atypical pneumonia with significant impairment of respiratory function. However, the infectious capacity of SARS-CoV-2 is not limited to the respiratory system, but may also affect other vital organs such as the brain. The central nervous system is vulnerable to cell damage via direct invasion or indirect virus-related effects leading to a neuroinflammatory response, processes possibly associated with a decrease in the activity of angiotensin II converting enzyme (ACE2), the canonical cell-surface receptor for SARS-CoV-2. This enzyme regulates neuroprotective and neuroimmunomodulatory functions and can neutralize both inflammation and oxidative stress generated at the cellular level. Furthermore, there is evidence of an association between vitamin D deficiency and predisposition to the development of severe forms of COVID-19, with its possible neurological and neuropsychiatric sequelae: vitamin D has the ability to down-modulate the effects of neuroinflammatory cytokines, among other anti-inflammatory/immunomodulatory effects, thus attenuating harmful consequences of COVID-19. This review critically analyzes current evidence supporting the notion that vitamin D may act as a neuroprotective and neuroreparative agent against the neurological sequelae of COVID-19.

921

Ce112

Rashudy F. Mahomedradja, Tessa O. van den Beukel, Maaike van den Bos, Steven Wang, Kirsten A. Kalverda, Birgit I. Lissenberg-Witte, Marianne A. Kuijvenhoven, Esther J. Nossent, Majon Muller, Kim C. E. Sigaloff, Jelle Tichelaar & Michiel A. van Agtmael

Prescribing errors in post - COVID-19 patients: prevalence, severity, and risk factors in patients visiting a post - COVID-19 outpatient clinic

https://doi.org/10.1186/s12873-022-00588-7

Published

5-Mar-22

Study

https://bmcemergmed.biomedcentral.com/articles/10.1186/s12873-022-00588-7

An acute increase in the number of hospitalized patients has necessitated a rigorous reorganization of hospital care, thereby creating circumstances that previously have been identified as facilitating prescribing errors (PEs), e.g. a demanding work environment, a high turnover of doctors, and prescribing beyond expertise. Hospitalized COVID-19 patients may be at risk of PEs, potentially resulting in patient harm. We determined the prevalence, severity, and risk factors for PEs in post–COVID-19 patients, hospitalized during the first wave of COVID-19 in the Netherlands, 3 months after discharge.
Methods
This prospective observational cohort study recruited patients who visited a post-COVID-19 outpatient clinic of an academic hospital in the Netherlands, 3 months after COVID-19 hospitalization, between June 1 and October 1 2020. All patients with appointments were eligible for inclusion. The prevalence and severity of PEs were assessed in a multidisciplinary consensus meeting. Odds ratios (ORs) were calculated by univariate and multivariate analysis to identify independent risk factors for PEs.
Results
Ninety-eight patients were included, of whom 92% had ≥1 PE and 8% experienced medication-related harm requiring an immediate change in medication therapy to prevent detoriation. Overall, 68% of all identified PEs were made during or after the COVID-19 related hospitalization. Multivariate analyses identified ICU admission (OR 6.08, 95% CI 2.16–17.09) and a medical history of COPD / asthma (OR 5.36, 95% CI 1.34–21.5) as independent risk factors for PEs.
Conclusions
PEs occurred frequently during the SARS-CoV-2 pandemic. Patients admitted to an ICU during COVID-19 hospitalization or who had a medical history of COPD / asthma were at risk of PEs. These risk factors can be used to identify high-risk patients and to implement targeted interventions. Awareness of prescribing safely is crucial to prevent harm in this new patient population.

922

Ce113

Giusto, Elisa DO1; Asplund, Chad A. MD, MPH2

Persistent COVID and a Return to Sport

https://doi.org/10.1249/JSR.0000000000000943

Published

1-Mar-22

Article

https://journals.lww.com/acsm-csmr/Fulltext/2022/03000/Persistent_COVID_and_a_Return_to_Sport.7.aspx

Coronavirus disease (COVID) has become a global pandemic that has widely impacted athletes at all levels of competition. For many athletes infected with COVID, the course is mild or asymptomatic, and most athletes are able to return to play in a matter of weeks. However, 10% to 15% of people infected with COVID will go on to have prolonged COVID symptoms that last for weeks to months and impact their ability to function and exercise. Not much is known about why certain people become “COVID long-haulers,” nor are there any predictive tools to predetermine who may have prolonged symptoms. However, many athletes will suffer from prolonged symptoms that may require further evaluation and may prolong their return to exercise, training, and competition. The purpose of this article is to discuss a framework in which sports medicine and primary care physicians can use to evaluate COVID long-haulers and help them return to sport.

923

Ce114

Salvi, Sundeep Santosh1,; Ghorpade, Deesha1; Dhoori, Sahajal2; Dhar, Raja3; Dumra, Harjit4; Chhajed, Prashant N5; Bhattacharya, Parathasarathi6; Rajan, Sujeet7; Talwar, Deepak8; Christopher, Devasahayam J9; Mohan, Murali10; Udwadia, Zarir11

Role of antifibrotic drugs in the management of post-COVID-19 interstitial lung disease: A review of literature and report from an expert working group

https://doi.org/10.4103/lungindia.lungindia_659_21

Published

1-Mar-22

Review

https://journals.lww.com/lungindia/Fulltext/2022/03000/Role_of_antifibrotic_drugs_in_the_management_of.14.aspx

The EWG recommended that the term post-COVID-19 pulmonary fibrosis is not appropriate because the term “fibrosis” implies a “permanent” nature, which is not the case in most patients with post-COVID-19 fibrotic lung disease. Post-COVID-19 ILD is a more appropriate terminology. Although post-COVID-19 ILD is known to resolve spontaneously in most cases, it does not happen in all patients and is therefore not a completely reversible form of the disease. The burden of post-COVID-19 ILD is estimated to be high and grow with time. The EWG recommended that antifibrotic drugs may be used to prevent pulmonary fibrosis or on compassionate grounds in a specific group of patients. Continued presence of respiratory symptoms and hypoxia, despite 2–4 weeks of treatment with systemic steroids, or presence of honeycombing, traction bronchiectasis, and distorted lung architecture were strong indications to consider the use of antifibrotic drugs. The presence of a high computed tomography score but mild symptoms and normal oxygen saturation are not indications for starting antifibrotic drugs. Although the expert group agreed that antifibrotic drugs should be used in the early course of the disease, the timing varied from immediately (ICU admission) to up to 4 weeks. There was no consensus on how long the antifibrotic drugs be given for, although most members agreed to using them for between 4 and 8 weeks, but less than 6 months, although the duration needs to be decided on a case-to-case basis. Both pirfenidone and nintedanib were equally good, although one-third of the expert group members believed nintedanib was better. Although the anti-inflammatory effects of antifibrotic drugs are known, this was not perceived to be an advantage to use them during the early course of the disease, as the evidence to support this was lacking.

924

Ce115

Huan Chen1,2, Hangyu Shi1,3, Xitong Liu4, Tianheng Sun1,3, Jiani Wu1 and Zhishun Liu1

Effect of Pulmonary Rehabilitation for Patients With Post-COVID-19: A Systematic Review and Meta-Analysis

https://doi.org/10.3389/fmed.2022.837420

Published

21-Feb-22

Systematic Review

https://www.frontiersin.org/articles/10.3389/fmed.2022.837420/full

Background: Evidence increasingly suggested that impaired respiratory function remained in about 40% of patients with coronavirus disease 2019 (COVID-19) after discharge, jeopardizing their activities of daily living and quality of life (QoL) in a long term. Pulmonary rehabilitation (PR) can improve exercise capacity and QoL in individuals with chronic lung disease; however, evidence on the effect of PR for patients with post-COIVD-19 was scarce. This study aimed to conduct a systematic review and meta-analysis to evaluate the effect of PR on lung impairment for patients with post-COVID-19
Results: Among 6,000 retrieved studies, 3 studies with 233 patients after COVID-19 were included. The pooled estimate of PR effect on 6-min walk test (6-MWT) (50.41, 95% CI 34.34 to 66.48; p < 0.0001) was in favor of the experiment group with clinical importance. It is found that PR could improve the symptom of dyspnea and QoL; however, its effect on pulmonary function test was inconsistent across studies. The risk of bias of included studies varied, with major concerns on the risk of blinding of participants and interventions performers.
Conclusion: The review showed that PR could improve exercise capacity measured by 6-MWT among patients with mild-to-moderate lung impairment after COVID-19. The interpretation of effects on lung function, dyspnea, and QoL should be cautious due to inadequate and conflicting data reported across studies.

925

Ce116

Robert J. Trager, Elise C. Brewka, Christine M. Kaiser, Andrew J. Patterson, Jeffery A. Dusek

Acupuncture in multidisciplinary treatment of post-COVID-19 Syndrome: A Case Report

https://doi.org/10.21203/rs.3.rs-1421933/v1

pre-print

8-Mar-22

Case Report

https://www.researchsquare.com/article/rs-1421933/v1

Background: Post-COVID syndrome (PCS) is a complex, multisystem illness that may follow SARS-CoV-2/COVID-19 infection. As there is limited evidence for individual therapies and no singular treatment for PCS, guidelines endorse a multidisciplinary approach. This case describes a post-COVID patient benefiting from acupuncture within a comprehensive approach alongside symptom-titrated physical activity (STPA).
Case: A 50-year-old woman presented upon Long-COVID Clinic referral to an outpatient hospital-affiliated acupuncturist with 8 months of fatigue, anosmia, chest pressure, palpitations, and other symptoms following mild assay-confirmed COVID-19. Prior/concurrent medical testing demonstrated multisystem-inflammatory involvement (pericardial effusion, thyroid dysfunction, elevated D-dimers). Cardiology/pulmonology cleared the patient for exercise to tolerance considering serious pathology was absent. The acupuncturist’s Traditional Chinese Medicine impression was of Qi deficiency of the Heart, Lung, Spleen, and Kidney. The patient received 7 sessions of scalp, auricular, and body acupuncture. Physical therapist (PT) led STPA began 1-week post-acupuncture, involving six 30-minute exercise sessions while monitoring heart rate, with as-needed rest.
Results: Chest pressure and palpitations resolved after 1 acupuncture treatment. With 6 additional treatments spanning 9 weeks, overlapping with physical therapist-led SPTA, the patient completely recovered and resumed normal exercise habits.
Conclusions: In this case, acupuncture appeared to facilitate PCS recovery. However, the independent effects of acupuncture are less clear given the concurrent STPA/exercise therapy, and should be explored using larger study designs. Acupuncture is an attractive potential PCS therapy, considering its holistic approach and that it may be added to a multidisciplinary, guideline-concordant regimen.

926

Ce117

Melitta A McNarry, Ronan M G Berg, James Shelley, Joanne Hudson, Zoe L Saynor, Jamie Duckers, Keir Lewis, Gwyneth A Davies, Kelly A Mackintosh

Inspiratory Muscle Training Enhances Recovery Post COVID-19: A Randomised Controlled Trial

https://doi.org/10.1183/13993003.03101-2021

Published

2-Mar-22

Study

https://erj.ersjournals.com/content/early/2022/02/24/13993003.03101-2021

Methods 281 adults (46.6±12.2 years; 88% female) recovering from self-reported COVID-19 (9.0±4.2 months post-acute infection) were randomised 4:1 to an 8-week IMT or a “usual care” wait list control arm. Health-related quality of life and breathlessness questionnaires (King's Brief Interstitial Lung Disease (KBILD) and Transition Dyspnoea Index (TDI)), respiratory muscle strength and fitness (Chester Step Test) were assessed pre- and post-intervention. The primary endpoint was KBILD total score, with the KBILD subdomains and TDI being key secondary outcomes.
Results According to intention to treat (ITT), there was no difference between groups in KBILD total score post-intervention (Control: 59.5±12.4; IMT: 58.2±12.3; p<0.05) but IMT elicited clinically meaningful improvements in the KBILD subdomains of breathlessness (Control: 59.8±12.6; IMT: 62.2±16.2; p<0.05) and chest symptoms (Control: 59.2±18.7; IMT: 64.5±18.2; p<0.05), along with clinically meaningful improvements in breathlessness according to TDI (Control: 0.9±1.7 versus 2.0±2.0; p<0.05). IMT also improved respiratory muscle strength and estimated aerobic fitness.
Conclusions IMT may represent an important home-based rehabilitation strategy for wider implementation as part of COVID-19 rehabilitative strategies. Given the diverse nature of long-COVID, further research is warranted on the individual responses to rehabilitation - the withdrawal rate herein highlights that no one strategy is likely to be appropriate for all.

927

Ce118

Felicia Ceban,Alexia Leber,Muhammad Youshay Jawad,Mathew Yu,Leanna M. W. Lui,Mehala Subramaniapillai,Joshua D. Di Vincenzo,Hartej Gill,Nelson B. Rodrigues,Bing Cao,Yena Lee,Kangguang Lin,Rodrigo B. Mansur,Roger Ho,Matthew J. Burke,Joshua D. Rosenblat &Roger S. McIntyre

Registered clinical trials investigating treatment of long COVID: a scoping review and recommendations for research

https://doi.org/10.1080/23744235.2022.2043560

Published

14-Mar-22

Review

https://www.tandfonline.com/doi/abs/10.1080/23744235.2022.2043560

A considerable proportion of individuals report persistent, debilitating and disparate symptoms despite resolution of acute COVID-19 infection (i.e. long COVID). Numerous registered clinical trials investigating treatment of long COVID are expected to be completed in 2021–2022. The aim of this review is to provide a scope of the candidate treatments for long COVID. A synthesis of ongoing long COVID clinical trials can inform methodologic approaches for future studies and identify key research vistas.
Methods
Scoping searches were conducted on multiple national and international clinical trial registries. Interventional trials testing treatments for long COVID were selected. The search timeline was from database inception to 28 July 2021.
Results
This scoping review included 59 clinical trial registration records from 22 countries with a total projected enrolment of 6718. Considerable heterogeneity was exhibited amongst component records with respect to the characterization of long COVID (i.e. name, symptoms- including frequency, intensity, trajectory and duration- mode of ascertainment, and definition of acute phase). In addition, the majority of proposed interventions were non-pharmacological and either targeted multiple long COVID symptoms simultaneously, or focussed on treatment of respiratory/pulmonary sequelae. Multiple interventions targeted inflammation, as well as tissue oxygenation and cellular recovery, and several interventions were repurposed from analogous conditions.
Conclusions
The results of this scoping review investigating ongoing clinical trials testing candidate treatments for long COVID suggest that a greater degree of definitional stringency and homogeneity is needed insofar as the characterization of long COVID and inclusion/exclusion criteria.

928

Ce119

Eric Asaba,Michael Sy,Roi Charles Pineda,Rebecca Aldrich,Tetsuya Anzai,Peter Bontje,Urša Bratun,Lisette Farias,Maria Kapanadze,Lea Šuc &Elisabet Åkesson

Return to work after COVID-19: an international perspective

https://doi.org/10.1080/14473828.2022.2045819

Published

9-Mar-22

Research Article

https://www.tandfonline.com/doi/full/10.1080/14473828.2022.2045819

Among individuals who have recovered from COVID-19 around the world, there is a substantial number who would need support in finding their way back to meaningful and productive work. The aims of this paper are to demonstrate the multitude of factors that shape return to work (RTW) practices across and within several countries, and argue for the need to explore RTW from an international perspective during an on-going pandemic, focusing on working age adults who have recovered from COVID-19. Conditions for RTW differ across countries. Occupational therapy has a central role in medical rehabilitation after injury and illness (including COVID-19), but the occupational therapy community has, to the best of our knowledge, yet to raise awareness and advance evidence regarding its role in post-COVID RTW processes. A robust evidence-based knowledge on RTW that can be utilised by occupational therapists during the present and future pandemics is needed.

929

Ce120

Irina Karosanidze 1,Ushangi Kiladze 1,Nino Kirtadze 1,Mikhail Giorgadze 1,Nana Amashukeli 1,Nino Parulava 1,Neli Iluridze 1,Nana Kikabidze 1,Nana Gudavadze 1,Lali Gelashvili 1,Vazha Koberidze 1,Eka Gigashvili 1,Natela Jajanidze 1,Naira Latsabidze 1,Nato Mamageishvili 2,Ramaz Shengelia 2,Areg Hovhannisyan 3 andAlexander Panossian

Efficacy of Adaptogens in Patients with Long COVID-19: A Randomized, Quadruple-Blind, Placebo-Controlled Trial

https://doi.org/10.3390/ph15030345

Published

11-Mar-22

Study

https://www.mdpi.com/1424-8247/15/3/345/htm

Currently, no effective treatment of comorbid complications or COVID-19 long-haulers during convalescence is known. This randomized, quadruple-blind, placebo-controlled trial aimed to assess the efficacy of adaptogens on the recovery of patients with Long COVID symptoms. One hundred patients with confirmed positive SARS-CoV-2 test, discharged from COVID Hotel isolation, Intensive Care Unit (ICU), or Online Clinics, and who experienced at least three of nine Long COVID symptoms (fatigue, headache, respiratory insufficiency, cognitive performance, mood disorders, loss of smell, taste, and hair, sweatiness, cough, pain in joints, muscles, and chest) in the 30 days before randomization were included in the study of the efficacy of Chisan®/ADAPT-232 (a fixed combination of adaptogens Rhodiola, Eleutherococcus, and Schisandra) supplementation for two weeks. Chisan® decreased the duration of fatigue and pain for one and two days, respectively, in 50% of patients. The number of patients with lack of fatigue and pain symptoms was significantly less in the Chisan® treatment group than in the placebo group on Days 9 (39% vs. 57%, pain relief, p = 0.0019) and 11 (28% vs. 43%, relief of fatigue, * p = 0.0157). Significant relief of severity of all Long COVID symptoms over the time of treatment and the follow-up period was observed in both groups of patients, notably decreasing the level of anxiety and depression from mild and moderate to normal, as well as increasing cognitive performance in patients in the d2 test for attention and increasing their physical activity and workout (daily walk time). However, the significant difference between placebo and Chisan® treatment was observed only with a workout (daily walk time) and relieving respiratory insufficiency (cough). A clinical assessment of blood markers of the inflammatory response (C-reactive protein) and blood coagulation (D-dimer) did not reveal any significant difference over time between treatment groups except significantly lower IL-6 in the Chisan® treatment group. Furthermore, a significant difference between the placebo and Chisan® treatment was observed for creatinine: Chisan® significantly decreased blood creatinine compared to the placebo, suggesting prevention of renal failure progression in Long COVID. In this study, we, for the first time, demonstrate that adaptogens can increase physical performance in Long COVID and reduce the duration of fatigue and chronic pain. It also suggests that Chisan®/ADAPT-232 might be useful for preventing the progression of renal failure associated with increasing creatinine.

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Győző Szolnoky, MD, PhD, Alejandro José González-Ochoa, MD

Sulodexide: A Benefit for Cardiovascular Sequelae of Long COVID Patients?

https://doi.org/10.1177%2F10760296221084300

Published

25-Mar-22

Article

https://journals.sagepub.com/doi/10.1177/10760296221084300

The elaborate and precise review of Harry N. Magnani didactically demonstrates the complex pathophysiological aspects of coronavirus disease 2019 (COVID-19) emphasizing the roles of vascular endothelial dysfunction and coagulation cascade as key features of disease progression.1 Moreover, this article brings up that glycosaminoglycane (GAG) antithrombotics likely interfere with inflammatory and coagulation activity in an effective fashion.1 Thereafter this postulate has become advocated as the application of sulodexide (Vessel Due F; ALFASIGMA, Italy) (SDX), an unexpensive and orally administrable GAG antithrombotic drug reduced the necessity for both hospital admission and oxygen supplementation in the early phase of SARS-Cov-2 infection under a randomized placebo-controlled out-patient trial.2 Interestingly, these patients also showed lower serum levels of C-reactive protein (CRP) and D-dimer as markers of inflammation and prothrombotic state. Of note, instead of regularly recommended and prescribed 250 RLU twice-daily dose, the clinical trial applied the higher, 500 RLU twice-daily dosing regimen in which an antithrombotic effect was safely achieved in a clinical setting.
Conversely, there is still a relatively little but emerging information “long hauler” sufferers who have recovered from the acute presentation and have a negative polymerase chain reaction (PCR) SARS-CoV-2 test yet still continue to have COVID-19 symptoms for weeks or even months later, or those who present cardiovascular complications weeks or months later.

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Aurelian ANGHELESCU
Ali-Osman SAGLAM
Simona STOICA
Gelu ONOSE

Rehabilitation of severe neurological complications post SARS-CoV-2 infection

https://doi.org/10.12680/balneo.2022.491

Published

18-Mar-22

Article

https://bioclima.ro/Journal/index.php/BRJ/article/view/82

Medical rehabilitation is a multi-professional / interdisciplinary process aimed at enhancing and restoring functional ability (activity and participation) and quality of life to people with impairments or disabilities. Rehabilitation is applied throughout the continuum of care. COVID-19 patients may develop a myriad of acute medical problems (linked to the virus per se, or as consequences of the invasive procedures), which can cause acute, post-acute and long-term consequences requiring rehabilitation. Information about short and long-term sequelae of COVID-19 indicate an increasing need for rehabilitation. The paper is focused on two main aspects: rehabilitation of the severe neurological disabilities that occurred during the acute phase and continuing in the chronic phase (i.e., different neurological sensory-motor and cognitive deficits secondary to stroke, encephalitis, seizures, encephalopathies). The other main issue is generated by the disruption of regular rehabilitation in people with neurological disabilities and chronic diseases (people living with sequels after stroke, Parkinson's disease, multiple sclerosis) due to quarantine, social isolation, movement restriction, and other healthcare systems ’disruptions. Methods Internet literature search (Lit Covid and PubMed) using the following keywords (Covid-19, Coronavirus, neurological complications, rehabilitation). During 2020-2021 were published 88 papers (in 2020 = 54, and in 2021= 54), with 21 reviewes (2020 = 15; 2021 = 8), and 2 systematic reviews, refearing neuroreabilitation in Covid-19 subacutre and long-term cases. Discussion REH-COVER Cochrane Rehabilitation WHO initiative (“Rapid Living Systematic Reviews Second Edition, called 2020”), contains the main cornerstones for a tailored rehabilitation programme, the best (current) available rehabilitation evidence on recovery interventions, for the patients living with sequelae of COVID-19. Conclusions More than two years since the outbreak of the COVID-19 pandemic, it is obvious that rehabilitation services play a crucial role in post-COVID recovery trajectories. A further achievement of research and evidence focussed on the clinical management, comprehensive treatments, and efficacy need to be targeted on short and long-term (neuro)-rehabilitation service models of care, for COVID-19 survivors.

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Annamária Bardelčíková,Andrej Miroššay,Jindřich Šoltýs,Ján Mojžiš

Therapeutic and prophylactic effect of flavonoids in post-COVID-19 therapy

https://doi.org/10.1002/ptr.7436

Published

18-Mar-22

Article

https://onlinelibrary.wiley.com/doi/full/10.1002/ptr.7436

The high incidence of post-covid symptoms in humans confirms the need for effective treatment. Due to long-term complications across several disciplines, special treatment programs emerge for affected patients, emphasizing multidisciplinary care. For these reasons, we decided to look at current knowledge about possible long-term complications of COVID-19 disease and then present the effect of flavonoids, which could help alleviate or eliminate complications in humans after overcoming the COVID-19 infection. Based on articles published from 2003 to 2021, we summarize the flavonoids-based molecular mechanisms associated with the post-COVID-19 syndrome and simultaneously provide a complex view regarding their prophylactic and therapeutic potential. Review clearly sorts out the outcome of post-COVID-19 syndrome according particular body systems. The conclusion is that flavonoids play an important role in prevention of many diseases. We suggest that flavonoids as critical nutritional supplements, are suitable for the alleviation and shortening of the period associated with the post-COVID-19 syndrome. The most promising flavonoid with noteworthy therapeutic and prophylactic effect appears to be quercetin.

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JessieHawkinsChristyHiresLindseyKeenanElizabethDunne

Aromatherapy Blend of Thyme, Orange, Clove Bud, and Frankincense Boosts Energy Levels in Post-COVID-19 Female Patients: A Randomized, Double-Blinded, Placebo Controlled Clinical Trial

https://doi.org/10.1016/j.ctim.2022.102823

Published

25-Mar-22

Study

https://www.sciencedirect.com/science/article/pii/S0965229922000255

Highlights
•Fatigue is the most common long-haul symptom among women who have recovered from an acute COVID-19 infection.
•This randomized, blinded, controlled clinical trial evaluated Longevity essential oil blend for energy boosting effects.
•Two weeks of twice-daily inhalation resulted in significant improvements to energy levels as compared to a placebo group.
•Aromatherapy provides a non-invasive approach to boosting quality of life among women who have recovered from COVID-19 but still experience low energy.
Background
A large proportion of individuals who have recovered from an acute COVID-19 infection continue to experience symptoms months later. Post-acute COVID-19 (long-haul COVID-19) can range from serious complications to quality of life symptoms such as fatigue or insomnia. The purpose of this study was to evaluate the potential for inhalation of essential oils to improve energy levels among otherwise healthy female survivors of acute COVID-19 who experience a lack of energy more than five months after recovery. This study was conducted in the United States in late 2021.
Method
This was a randomized double blind, placebo controlled trial to evaluate the potential for inhalation of Longevity™, a proprietary essential oil blend manufactured by Young Living Essential Oils (Lehi, Utah, USA), on energy levels among female survivors of COVID-19 who continue to experience fatigue more than 5 months recovery from the acute infection. Forty women were randomized to two groups: intervention and placebo. Both groups inhaled the assigned product twice daily for fourteen consecutive days. Fatigue scores were measured using the Multidimensional Fatigue Symptom Inventory (MFSI). Secondary outcomes included scores on each of the MFSI’s ten subscales.
Results
Individuals who inhaled the essential oil blend for 2 weeks had significantly lower fatigue scores after controlling for baseline scores, employment status, BMI, olfactory function, and time since diagnosis, with a large effect size (F (1,39) = 6.15, p =.020, partial eta squared =.198). Subscale analysis identified subscales of vigor, as well as global, behavioral, general, and mental fatigue as benefiting from the intervention. This study provides evidence that a proprietary aromatherapy blend can significantly improve energy levels among women who are experiencing fatigue after recovering from COVID-19.

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WeiZhenga1He-LiSunbcd1HongCaibcd1QingeZhange1Chee H.NgfYu-TaoXiangbcd

Antidepressants for COVID-19: A systematic review

https://doi.org/10.1016/j.jad.2022.03.059

Published

23-Mar-22

Review

https://www.sciencedirect.com/science/article/pii/S0165032722003068

Highlights
•Preliminary evidence showed that certain antidepressants appear to have potential as safe, inexpensive, and widely available medications that could improve COVID- 19-related outcomes such as mortality.
•The anti-inflammatory properties of antidepressants may be associated with decreased levels of proinflammatory cytokines, including interleukin (IL)-10 and tumor necrosis factor alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1), which are related to the severity of COVID-19.
Objective
To systematically examine the efficacy and safety of antidepressants for the treatment of coronavirus disease 2019 (COVID-19).
Methods
A systematic search was performed independently by two researchers based on Chinese Journal Net, WanFang, PsycINFO, Cochrane Library, PubMed, and EMBASE.
Results
Seven studies (n = 92,947) including three retrospective studies (n = 91,083), two randomized clinical trials (RCTs, n = 1649), two prospective cohort study (n = 215) involving (n = 92,947) patients with COVID-19 were examined. For RCTs, fluvoxamine outperformed placebo in reducing clinical deterioration and hospitalisation for COVID-19 patients. For retrospective studies, antidepressants (2 studies) and fluoxetine (1 study) possibly reduced the risk of mortality in patients with COVID-19. Results from two remaining studies supported the superiority of fluvoxamine in reducing risk of mortality in COVID-19 patients. The two RCTs that examined the safety of fluvoxamine for COVID-19 patients found inconsistent results but no significant group differences in the dropout rate.
Conclusion
This systematic review found emerging evidence for fluvoxamine in reducing the risk of mortality and hospitalisation in COVID-19 patients, but inconsistent evidence for the safety of fluvoxamine in COVID-19 patients. More studies are needed to determine the efficacy and safety of antidepressants for the treatment of COVID-19.

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ŞevkiAdemaVolkanEyupogluaIbrahim M.IbrahimbIqraSarfrazcAzharRasulcMuhammadAlidAbdo A.Elfikyb

Multidimensional in silico strategy for identification of natural polyphenols-based SARS-CoV-2 main protease (Mpro) inhibitors to unveil a hope against COVID-19

https://doi.org/10.1016/j.compbiomed.2022.105452

Published

29-Mar-22

Study

https://www.sciencedirect.com/science/article/pii/S001048252200244X

Highlights
•The phenolics were investigated by molecular docking, quantum mechanic and molecular dynamic over SARS-CoV-2 Mpro.
•All phenolics that have good binding potency are components of dietary foods can be used for therapeutics against COVID-19.
•Diosmin, Rutin, Hesperidin, and Apiin are available phenolics in nature and have inhibition potential SARS-CoV-2 Mpro .
SARS-CoV-2, a rapidly spreading new strain of human coronavirus, has affected almost all the countries around the world. The lack of specific drugs against SARS-CoV-2 is a significant hurdle towards the successful treatment of COVID-19. Thus, there is an urgent need to boost up research for the development of effective therapeutics against COVID-19. In the current study, we investigated the efficacy of 81 medicinal plant-based bioactive compounds against SARS-CoV-2 Mpro by using various in silico techniques. The interaction affinities of polyphenolic compounds towards SARS-CoV-2 Mpro was assessed via intramolecular (by Quantum Mechanic), intermolecular (by Molecular Docking), and spatial (by Molecular Dynamic) simulations. Our obtained result demonstrate that Hesperidin, rutin, diosmin, and apiin are most effective compounds agents against SARS-CoV-2 Mpro as compared to Nelfinavir (positive control). This study will hopefully pave a way for advanced experimental research to evaluate the in vitro and in vivo efficacy of these compounds for the treatment of COVID-19.

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TheresaMaitz1DominicParfianowicz1AshleyVojtek1YasothaRajeswaran2Apurva V.Vyas2RahulGupta

COVID-19 Cardiovascular Connection: A Review of Cardiac Manifestations in COVID-19 Infection and Treatment Modalities

https://doi.org/10.1016/j.cpcardiol.2022.101186

Published

26-Mar-22

Review

https://www.sciencedirect.com/science/article/pii/S0146280622000834

The coronavirus pandemic has crippled healthcare system since its outbreak in 2020, and has led to over 2.6 million deaths worldwide. Clinical manifestations of COVID-19 range from asymptomatic carrier to severe pneumonia, to life-threatening acute respiratory distress syndrome (ARDS). The early efforts of the pandemic surrounded treating the pulmonary component of COVID-19, however, there has been robust data surrounding the cardiac complications associated with the virus. This is suspected to be from a marked inflammatory response as well as direct viral injury. Arrhythmias, acute myocardial injury, myocarditis, cardiomyopathy, thrombosis, and myocardial fibrosis are some of the observed cardiac complications. There have been high morbidity and mortality rates in those affected by cardiac conditions associated with COVID-19. Additionally, there have been documented cases of patients presenting with typical cardiac symptoms who are subsequently discovered to have COVID-19 infection. In those who test positive for COVID-19, clinical awareness of the significant cardiac components of the virus is pertinent to prevent morbidity and mortality. Unfortunately, treatment and preventative measures developed for COVID-19 have been shown to be also be associated with cardiac complications. This is a comprehensive review of the cardiac complications and manifestations of COVID-19 infection in addition to those associated with both treatment and vaccination.

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Lamyae Benzakour 1,* andGuido Bondolfi 1,2

Update of the Potential Treatments for Psychiatric and Neuropsychiatric Symptoms in the Context of the Post-COVID-19 Condition: Still a Lot of Suffering and Many More Things to Learn

https://doi.org/10.3390/traumacare2020011

Published

24-Mar-22

Review

https://www.mdpi.com/2673-866X/2/2/11/htm

The World Health Organization (WHO) has defined a post-COVID-19 condition. Some of these symptoms can be categorized as psychiatric long COVID-19 if they appeared in the aftermath of COVID-19, including depression, anxiety, post-traumatic stress disorder, somatic symptoms disorders such as hyperventilation syndrome, fatigue, cognitive and sleep disorders. Psychiatric and neuropsychiatric post-COVID-19 present mental health specialists with difficult challenges because of its complexity and the multiple ways in which it integrates into a singular somatic context. Methods: We conducted a systematic research paradigm from SARS-CoV-2 using LitCOVID and Web of Science to search management strategies and potential treatments for psychiatric post-COVID-19 symptoms. Results: Management strategies must be based on a multidisciplinary approach to promote the global evaluation of psychiatric and physical symptoms, systematic detection and prevention. Selective serotonin reuptake inhibitors appear to be the best choice to treat post-COVID-19 depression and anxiety disorders, and tofisopam could be helpful for anxiety. Cognitive behavioral therapy techniques adjusted to post-COVID-19 fatigue, functional remediation, extracorporeal apheresis, transcutaneous auricular vagus nerve stimulation, monoclonal antibodies, flavonoids, oxytocin or L-carnitine all represent hypothetical therapeutic avenues that remain to be evaluated in clinical trials. Conclusions: Psychiatric and neuropsychiatric post-COVID-19 symptoms occur frequently and are debilitating. Attention should be paid to this condition and studies undertaken to specify the effective treatments.

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Claudia Cristina Ferreira Vasconcelos, Mariana Beiral Hammerle, Deborah Santos Sales, Fernanda Cristina Rueda Lopes, Patricia Gomes Pinheiro, Elisa Gutman Gouvea, Manuella Caroline Dutra Frazão Alves, Tayane Vasconcellos Pereira, Sergio Luis Schmidt, Regina Maria Papais Alvarenga & Karina Lebeis Pires

Post-COVID-19 olfactory dysfunction: carbamazepine as a treatment option in a series of cases

https://doi.org/10.1007/s13365-022-01066-3

Published

2-Apr-22

Case Series

https://link.springer.com/article/10.1007/s13365-022-01066-3

Olfactory dysfunction is reported frequently in patients with coronavirus disease 2019. However, an effective treatment for this dysfunction is unknown. The present study evaluated carbamazepine as a treatment option for olfactory dysfunction based on its use in cases of neuralgia, especially of the V cranial nerve. The study included 10 patients with coronavirus disease with olfactory complaints who were part of a cohort of 172 coronavirus disease patients monitored for late neurological manifestations. Carbamazepine was administered for 11 weeks. The adverse effects reported were drowsiness (9/10) and dizziness (2/10); 9 of the 10 patients reported improved olfactory function after carbamazepine treatment. While the role of carbamazepine in the control of post-coronavirus disease olfactory dysfunction could not be confirmed in this study, the satisfactory response observed in most patients in this series suggests that further studies are warranted.

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Florent Besnier 1,2 ,Béatrice Bérubé 1,3,4,Jacques Malo 1,2,Christine Gagnon 1,Catherine-Alexandra Grégoire 1,Martin Juneau 1,2,François Simard 1,2,Philippe L’Allier 1,2,Anil Nigam 1,2,Josep Iglésies-Grau 1,2,Thomas Vincent 1,Deborah Talamonti 1 ,Emma Gabrielle Dupuy 1,2,Hânieh Mohammadi 1 ,Mathieu Gayda 1,2,* andLouis Bherer 1,2,4

Cardiopulmonary Rehabilitation in Long-COVID-19 Patients with Persistent Breathlessness and Fatigue: The COVID-Rehab Study

https://doi.org/10.3390/ijerph19074133

Published

31-Mar-22

Protocol

https://www.mdpi.com/1660-4601/19/7/4133/htm

Background: Cardiopulmonary and brain functions are frequently impaired after COVID-19 infection. Exercise rehabilitation could have a major impact on the healing process of patients affected by long COVID-19. (2) Methods: The COVID-Rehab study will investigate the effectiveness of an eight-week cardiopulmonary rehabilitation program on cardiorespiratory fitness (V˙O2max) in long-COVID-19 individuals. Secondary objectives will include functional capacity, quality of life, perceived stress, sleep quality (questionnaires), respiratory capacity (spirometry test), coagulation, inflammatory and oxidative-stress profile (blood draw), cognition (neuropsychological tests), neurovascular coupling and pulsatility (fNIRS). The COVID-Rehab project was a randomised clinical trial with two intervention arms (1:1 ratio) that will be blindly evaluated. It will recruit a total of 40 individuals: (1) rehabilitation: centre-based exercise-training program (eight weeks, three times per week); (2) control: individuals will have to maintain their daily habits. (3) Conclusions: Currently, there are no specific rehabilitation guidelines for long-COVID-19 patients, but preliminary studies show encouraging results. Clinicaltrials.gov (NCT05035628).

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PESE

Roisin M. Cahalan, PhD, MA, BSc,corresponding author1,2 Ciara Meade, MA,3 and Sarah Mockler2,4

SingStrong—A singing and breathing retraining intervention for respiratory and other common symptoms of long COVID: A pilot study

https://dx.doi.org/10.29390%2Fcjrt-2021-074

Published

9-Mar-22

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8906430/

Background
Management of Long COVID (LC) is hugely challenging for clinicians. This pilot study evaluated a breathing retraining and singing programme (SingStrong for LC) to address common LC symptoms. The study hypothesized that this intervention would improve symptoms impacting disordered breathing and participant wellbeing.
Methods
The 10-week, bi-weekly online programme was comprised of a 45-min class of mindfulness, breathing retraining, vocal exercises, and singing. Sessions were recorded for non-attenders and conducted by a trained vocal coach experienced in respiratory cohorts. Persons with a confirmed COVID-19 diagnosis and persisting symptoms were invited to participate. Demographic and COVID-19 data were collected, and the DePaul Symptom Questionnaire Short Form (DSQ- SF) and COVID-19 Yorkshire Rehab Screen questionnaires were administered. Post-intervention focus groups were also conducted.
Results
Of 27 (F = 23(85%)) participants recruited, data from 21 who completed at least 10 (50%) classes were analysed. Participants showed significant pre–post-intervention improvements in all breathlessness symptoms (at rest: P < 0.001; dressing: P = 0.01; stairs: P < 0.001), fatigue (P = 0.03), usual activities (P = 0.04), pain/disability (P = 0.03), voice quality (P = 0.01), and communication/cognition (P = 0.04). Pre–post number of instances meeting DSQ-SF criteria for myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) decreased by a net of nine cases (14.3%). No association between COVID-19 hospitalisation status and diagnosis of ME/CFS was identified. Qualitative feedback from eight participants was overwhelmingly positive with all reporting improvements in breathing and general well-being.
Conclusion
The SingStrong programme shows promise as a viable treatment option for LC sufferers. Future studies are required to further investigate the efficacy of this intervention.

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Eren Ogut &Kutay Armagan

Evaluation of the Potential Impact of Medical Ozone Therapy on Covid-19: A Review Study

https://doi.org/10.1080/01919512.2022.2065242

Published

19-Apr-22

Review

https://www.tandfonline.com/doi/abs/10.1080/01919512.2022.2065242

The key objective of this review is to summarize the available information on the effects of medical ozone therapy in COVID-19 and its therapeutic potentials. An electronic literature search was performed using the PubMed, Cochrane, Web of Science, Science Direct, Scopus, Google Scholar, Ovid Medline, J Stage and China Knowledge Resource Integrated (CNKI) databases to September 2021. In total, 1833 articles were identified. Twenty-six articles were selected out of 667 articles. The most preferred and effective administration method for COVID-19 is major autohemotherapy (MAHT), followed by rectal insufflation and minor autohemotherapy (MiAHT). However, other methods, including ozonized oils and ozonated saline, are also used for COVID-19 due to ease of application, prophylactic and therapeutic effects. In studies, 850 patients were treated with ozone therapy as a complementary treatment. The effectiveness of ozone concentrations below 20 μg/mL or above 45 μg/mL for MAHT are yet to be proven in the COVID-19 patient population, and may be less effective. Complementary ozone therapy combined with antivirals increase the activity of antivirals against COVID-19. Large-scale, multicenter randomized clinical trials are needed to be able to isolate the effect of ozone therapy where the clinical variables are distributed more homogeneously. Also, an extended period of follow-up of COVID-19 patients may give more accurate indications about the effectiveness of the treatment in the long term.

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Elnaz Khani & Taher Entezari-Maleki

Fluvoxamine and long COVID-19; a new role for sigma-1 receptor (S1R) agonists

https://doi.org/10.1038/s41380-022-01545-3

Published

6-Apr-22

Article

https://www.nature.com/articles/s41380-022-01545-3

We read with interest Hashimoto et al. study about mechanisms of action of fluvoxamine in COVID-19 [1]. As they mentioned, fluvoxamine offers some key mechanisms against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It inhibits acid sphingomyelinase (ASM) activity, the formation of ceramide-enriched membrane domain, and attenuates SARS-CoV-2 cell entry. Interestingly, fluvoxamine acts as a potent sigma-1 receptor (S1R) agonist that may decrease SARS-CoV-2 replication and subsequent endoplasmic reticulum (ER) stress and inflammation.
Based on the evidence, S1R agonists prevent inositol requiring enzyme 1α (IRE1) from splicing of mRNA that encodes X-box binding protein-1 (XBP-1). Hence S1R-mediated reduction in XBP1 activation modulates the ER stress response pathway and reduces cytokine storm [2]. XBP1 plays a major role in the reactivation of the Epstein-Barr virus (EBV). It has been indicated that ER stress and unfolded-protein response induce the expression of lytic EBV gene in EBV-infected cells, suggesting a pathway in virus-associated complications [3, 4].
Gold et al. reported that ~70% of patients with long COVID-19 versus 10% of the control group were positive for EBV reactivation according to the early antigen-diffuse immunoglobulin G or EBV viral capsid antigen immunoglobulin M [5].
It has been suggested that more than 50% of patients who recovered from COVID-19 experienced long-term symptoms such as headache, fatigue, anxiety, depression, and cognitive features within 6 months [6].
These findings suggest that most of the long COVID-19 symptoms following the recovery from the acute disease might not be directly affected by SARS-CoV-2 but probably result from COVID-19-associated inflammation and EBV reactivation. Recently, infection with EBV was suggested as the possible leading cause for multiple sclerosis (MS), in which inflammation plays a key role [7].
Given the link between EBV replication and XBP1 activation and modulatory effects of S1R agonists in XBP1 and ER stress response, we proposed that fluvoxamine might have beneficial effects in reducing long-term symptoms of COVID-19. However, further clinical studies are required to confirm this hypothesis.

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Yaeko Hashimoto, Takuji Suzuki & Kenji Hashimoto

Comments to “Fluvoxamine and long COVID-19: a new role for sigma-1 receptor (S1R) agonists” by Khani and Entezari-Maleki

https://doi.org/10.1038/s41380-022-01546-2

Published

6-Apr-22

Comment

https://www.nature.com/articles/s41380-022-01546-2

The authors suggest that most of long-lasting symptoms in COVID-19 survivors following the recovery from SARS-CoV-2 infection might not be directly affected by the virus but probably result from SARS-CoV-2-associated inflammation and EBV reactivation [4].
In the issue, Khani and Entezari-Maleki proposed that fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), may be a new therapeutic drug for long-term consequences of COVID-19 survivors [5]. Fluvoxamine has been demonstrated to prevent clinical deterioration in early-stage subjects with COVID-19 [6]. In addition of serotonin transporter inhibition, sigma-1 receptor chaperone in the endoplasmic reticulum (ER) and acid sphingomyelinase might play a role in the mechanisms of beneficial action of fluvoxamine for patients with SARS-CoV-2 infection [6,7,8]. It is also reported that sigma-1 receptor agonists such as fluvoxamine could produce potent anti-inflammatory actions by the prevention of inositol requiring enzyme 1α (IRE1) and X-box binding protein-1 (XBP-1) pathway [9]. Collectively, it is likely that sigma-1 receptor agonists such as fluvoxamine could produce potent anti-inflammatory effects through sigma-1 receptor/IRE1/XBP-1 pathway in the ER [6,7,8,9].
Among the SSRIs, fluvoxamine was the most potent at sigma-1 receptor in the brain [6,7,8]. Given the link between EBV reactivation and XBP-1 [10], it is possible that the potent sigma-1 receptor agonist fluvoxamine may have beneficial effects for long-term consequences in COVID-19 survivors through sigma-1 receptor/IRE1/XBP-1 pathway [4]. Therefore, it is of great interest to examine whether fluvoxamine can improve long-term sequelae in COVID-19 survivors.

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Chun-PaiYangabChing-MaoChangcdeCheng-ChiaYangfCarmine M.PariantegKuan-PinSughij

Long COVID and long chain fatty acids (LCFAs): Psychoneuroimmunity implication of omega-3 LCFAs in delayed consequences of COVID-19

https://doi.org/10.1016/j.bbi.2022.04.001

Published

8-Apr-22

Review

https://www.sciencedirect.com/science/article/pii/S0889159122000952

Highlights
•SARS-CoV-2 has led to the lasting pandemic of COVID-19 and the post-acute phase sequelae of heterogeneous negative impacts in multiple systems known as the “long COVID.”
•The mechanisms of neuropsychiatric complications of long COVID damages from direct CNS viral involvement, unresolved systemic inflammation and oxidative stress, maladaptation of the renin-angiotensin-aldosterone system and coagulation system, dysregulated immunity, the dysfunction of neurotransmitters and HPA axis, and the psychosocial stress imposed by societal changes in response to this pandemic.
•Long chain omega-3 PUFAs might have favorable effects on immunity, inflammation, oxidative stress and psychoneuroimmunity at different stages of SARS-CoV-2 infection.
•Omega-3 PUFAs and their metabolites, including specialized pro-resolvin mediators, accelerate the process of cleansing chronic inflammation, altering the HPA axis, modulating neurotransmission via lipid rafts and restoring tissue homeostasis, and therefore offer a promising strategy for Long COVID.
Abstract
The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the lasting pandemic of coronavirus disease 2019 (COVID-19) and the post-acute phase sequelae of heterogeneous negative impacts in multiple systems known as the “long COVID.” The mechanisms of neuropsychiatric complications of long COVID are multifactorial, including long-term tissue damages from direct CNS viral involvement, unresolved systemic inflammation and oxidative stress, maladaptation of the renin-angiotensin-aldosterone system and coagulation system, dysregulated immunity, the dysfunction of neurotransmitters and hypothalamus–pituitaryadrenal (HPA) axis, and the psychosocial stress imposed by societal changes in response to this pandemic. The strength of safety, well-acceptance, and accumulating scientific evidence has now afforded nutritional medicine a place in the mainstream of neuropsychiatric intervention and prophylaxis. Long chain omega-3 polyunsaturated fatty acids (omega-3 or n-3 PUFAs) might have favorable effects on immunity, inflammation, oxidative stress and psychoneuroimmunity at different stages of SARS-CoV-2 infection. Omega-3 PUFAs, particularly EPA, have shown effects in treating mood and neurocognitive disorders by reducing pro-inflammatory cytokines, altering the HPA axis, and modulating neurotransmission via lipid rafts. In addition, omega-3 PUFAs and their metabolites, including specialized pro-resolvin mediators, accelerate the process of cleansing chronic inflammation and restoring tissue homeostasis, and therefore offer a promising strategy for Long COVID. In this article, we explore in a systematic review the putative molecular mechanisms by which omega-3 PUFAs and their metabolites counteract the negative effects of long COVID on the brain, behavior, and immunity.

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Carson, Erin PharmD*; Hemenway, Alice N. PharmD, MPH

A Scoping Review of Pharmacological Management of Postacute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 Infection in 2021

https://doi.org/10.1097/MJT.0000000000001486

Published

1-Apr-22

Review

https://journals.lww.com/americantherapeutics/Abstract/9900/A_Scoping_Review_of_Pharmacological_Management_of.8.aspx

Background:
Postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC), or long-COVID, are signs and symptoms that persist after the acute phase of Coronavirus disease 2019 infection has passed. PASC is newly recognized, and research is ongoing to answer questions about pathology, symptoms, diagnosis, and optimal treatment.
Areas of Uncertainty:
Use of pharmacologic treatment for symptoms of PASC is currently evolving. This scoping review aims to assess medical literature for any evidence supporting or refuting use of any medications to specifically treat PASC.
Data Sources:
PubMed, EMBASE, Web of Science, and gray literature sources were searched for any study of medication use for PASC. Studies were included if they described medication use in patients with PASC. There were no exclusion criteria based on study type or if results were reported. Studies were divided into completed works and ongoing research.
Results:
Fifty-two records were included in final analysis from an initial 3524 records found, including 2 randomized controlled trials, 7 prospective, open-label or observational studies, 14 case reports or case series, 1 survey, 1 correspondence, 1 retrospective analysis, and 26 studies in progress. Seven of the 26 completed works investigate ivabradine or beta-blockers, whereas 7 investigate local or systemic corticosteroids. Three investigate multi-ingredient nutritional supplements. The other 9 completed works as well as the 26 studies in progress investigate a wide variety of other treatments including drugs in development, drugs used for other conditions, herbals, supplements, and vitamins.
Conclusions:
There is limited, but evolving, literature on medication treatment for PASC. Providers who opt to use pharmacologic therapy for PASC need to be vigilant in their knowledge of these evolving data.

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H. Heald, Adriana,b; Perrin, Raymonda; Walther, Andreasc; Stedman, Miked; Hann, Marke; Mukherjee, Annicea; Riste, Lisaa,e,f

Reducing fatigue-related symptoms in Long COVID-19: a preliminary report of a lymphatic drainage intervention

https://doi.org/10.1097/XCE.0000000000000261

Published

12-Apr-22

Study

https://journals.lww.com/cardiovascularendocrinology/Fulltext/2022/06000/Reducing_fatigue_related_symptoms_in_Long.3.aspx?context=LatestArticles

Introduction
In the early days of the first global wave of the COVID-19 pandemic, the potential for a postviral syndrome to manifest following COVID-19 infection was first recognized. Here, we present an analysis of a case series of the first 20 patients’ data collected in clinical practice to evaluate the potential of a possible alternative treatment for Long COVID.
Methods
Face-to-face treatment sessions with Perrin technique practitioners occurred weekly involving effleurage/other manual articulatory techniques. The individuals being treated also undertook daily self-massage along with gentle mobility exercises. Patients recorded symptom severity using the self-report 54-item profile of fatigue-related states (PFRS) before and after treatment.
Results
The mean age of male patients was 41.8 years (range, 29–53 years), and for female patients, 39.3 years (range, 28–50 years). None of the participants had a prior diagnosis of chronic fatigue syndrome, and all were new attendees to the clinics at the time of initial assessment. The average number of treatment sessions was 9.7 in men and 9.4 in women. The reduction in PFRS scores was 45% in men and 52% in women. The highest subscale scores on average were for fatigue, with the lowest for somatic symptoms. All subscale scores showed, on average, a similar reduction of approximately 50% postintervention, with the reduction in score relating to a decrease in the severity of symptoms.
Conclusion
Our findings suggest that a specific manual lymphatic drainage intervention may help to reduce fatigue symptoms related to Long COVID. Perhaps preventing acute symptoms through early intervention.

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Arthur Melkumyants 1,2,*,Lyudmila Buryachkovskaya 1,Nikita Lomakin 3,Olga Antonova 1,Julia Docenko 1,Vladimir Ermishkin 1 andVictor Serebruany 4

Effect of Sulodexide on Circulating Blood Cells in Patients with Mild COVID-19

https://doi.org/10.3390/jcm11071995

Published

2-Apr-22

Study

https://www.mdpi.com/2077-0383/11/7/1995/htm

Background. Despite the fact that COVID-19 usually manifests with severe pneumonia, there is a growing body of evidence that life-threatening multiorgan damage is caused by vascular and hemostatic abnormalities. Since there is no established therapy, assessing antithrombotics is indeed important. Sulodexide, a compound derived from porcine intestinal mucosa is a mixture of fast-moving heparin fraction (80%) and dermatan sulfate (20%), is approved in Europe and currently in trials for COVID-19 indication. Methods. This single-center, prospective, observational study included 28 patients with mild COVID-19 hospitalized in the Central Clinical Hospital of the Presidential Administration of the Russian Federation. Patients in the control group (n = 14) were treated using routine therapy according to current guidelines, while patients in the experimental group (n = 14) had the routine treatment supplemented with daily intravenous injections of sulodexide in 600-unit doses. Scanning electron microscopy was utilized to examine the blood specimens derived from the cubital vein at admission and at 10 days after hospitalization, which was approximately the average duration of patients’ treatment in the hospital (11.6 ± 0.4 days). Results. Sulodexide significantly (by 40%) diminished the score of circulating endothelial cells, potentially indicating its antiviral endothelium-protective properties. It also prevented the extra activation of the platelets and the formation of erythrocytic sludges. Among patients in the control group, the share of activated platelets rose from 37 ± 5% to 45 ± 6% (p = 0.04) over the course of the study period, whereas among patients in the experimental group, the share of activated platelets remained practically unchanged (43 ± 6% vs. 38 ± 4%, p = 0.22). The score of erythrocytic sludges in the control group remained practically the same (4.8 ± 1.1 at admission vs. 3.9 ± 0.9 after 10 days, p = 0.67), whereas in the experimental group, it significantly decreased (from 5.7 ± 1.7 to 2.4 ± 0.9, p = 0.03). Conclusions. Sulodexide is able to defend endothelium, normalize blood, and, seemingly, prevent thrombosis. Therefore, it may be considered as a promising and effective agent for the treatment of patients with mild COVID-19. Broader randomized trials are needed to assess whether the observed findings will transform into sustained long-term clinical benefit.

948

Ce139

Norman B Gaylis, Angela Ritter, Scott A Kelly, Nader Z Pourhassan, Meenakshi Tiwary, Jonah B Sacha, Scott G Hansen, Christopher Recknor, Otto O Yang

Reduced Cell Surface Levels of C-C Chemokine Receptor 5 and Immunosuppression in Long Coronavirus Disease 2019 Syndrome

https://doi.org/10.1093/cid/ciac226

Published

22-Apr-22

Study

https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciac226/6572226

In an exploratory trial treating “long COVID” with the CCR5-binding antibody leronlimab, we observed significantly increased blood cell surface CCR5 in treated symptomatic responders but not in nonresponders or placebo-treated participants. These findings suggest an unexpected mechanism of abnormal immune downmodulation in some persons that is normalized by leronlimab.
Clinical Trials Registration. NCT04678830.

949

Ce140

Hannah L.S. Day

Exploring Online Peer Support Groups for Adults Experiencing Long COVID in the United Kingdom: Qualitative Interview Study

https://doi.org/10.2196/37674

Published

25-Apr-22

Study

https://preprints.jmir.org/preprint/37674/accepted

Background:
Long COVID is an emerging public health concern. A growing number of individuals are experiencing prolonged multifaceted health challenges and accompanying social impacts after COVID-19 infections. Support services in the United Kingdom remain insufficient and fraught with complexity. Responding to persistent gaps in care, patients joined forces in online peer support groups. However, little is known about how these groups impact long COVID patients and their lived experiences of the condition.
Objective:
The aim of this study is to explore the roles that online peer support groups take on, and the impact they have on patients experiencing and recovering from long COVID in the United Kingdom. In doing so, this study aims to identify ways to inform future long COVID care, including online peer support and broader long COVID care structures.
Methods:
I conducted 11 semi-structured interviews virtually on Zoom in July 2021. Participants had long COVID, were UK-based, and used long COVID online peer support groups. Topics discussed in interviews included what led participants to these groups, experiences within them, and feelings about the roles that the groups took on. I analyzed the results through manually conducting thematic analysis.
Results:
Long COVID online peer support groups had numerous roles, significantly impacting users. I identified 7 themes and 19 subthemes through thematic analysis. The identified themes were: (1) professional support, (2) societal awareness, (3) diversity of groups, (4) group format, (5) social connections, (6) engagement behavior, and (7) desired changes. Given the void of professional support, those experiencing long COVID gained some benefit from these groups. However, participants emphasized notable concerns about the all-encompassing roles these groups embody and speculated over potential improvements.
Conclusions:
If employed appropriately, online peer support groups could be immensely beneficial for patient wellbeing, beyond simply filling gaps in long COVID care. However, it appears many groups take on more than they can manage and become potentially harmful. Through prioritizing patient voices, long COVID care could be restructured to maximize peer support’s benefits within broader care structures.

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Kazuaki Imai 1,Takafumi Yamano 2,Soichiro Nishi 3,Ryushiro Nishi 3,Tatsuro Nishi 3,4,Hiroaki Tanaka 5,Toshiyuki Tsunoda 6,Shohei Yoshimoto 7,Ayaki Tanaka 8,Kenji Hiromatsu 9ORCID,Senji Shirasawa 6,Takashi Nakagawa 10 andKensuke Nishi 2,3,4,*

Epipharyngeal Abrasive Therapy (EAT) Has Potential as a Novel Method for Long COVID Treatment

https://doi.org/10.3390/v14050907

Published

27-Apr-22

Study

https://www.mdpi.com/1999-4915/14/5/907/htm

COVID-19 often causes sequelae after initial recovery, referred to collectively as long COVID. Long COVID is considered to be caused by the persistence of chronic inflammation after acute COVID-19 infection. We found that all long COVID patients had residual inflammation in the epipharynx, an important site of coronavirus replication, and some long COVID symptoms are similar to those associated with chronic epipharyngitis. Epipharyngeal abrasive therapy (EAT) is a treatment for chronic epipharyngitis in Japan that involves applying zinc chloride as an anti-inflammatory agent to the epipharyngeal mucosa. In this study, we evaluated the efficacy of EAT for the treatment of long COVID. The subjects in this study were 58 patients with long COVID who were treated with EAT in the outpatient department once a week for one month (mean age = 38.4 ± 12.9 years). The intensities of fatigue, headache, and attention disorder, which are reported as frequent symptoms of long COVID, were assessed before and after EAT using the visual analog scale (VAS). EAT reduced inflammation in the epipharynx and significantly improved the intensity of fatigue, headache, and attention disorder, which may be related to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These results suggest that EAT has potential as a novel method for long COVID treatment.

951

Ce142

Bin Wang, Lei Zhang, Yongqiang Wang, Tong Dai, Ziran Qin, Fangfang Zhou & Long Zhang

Alterations in microbiota of patients with COVID-19: potential mechanisms and therapeutic interventions

https://doi.org/10.1038/s41392-022-00986-0

Published

29-Apr-22

Review

https://www.nature.com/articles/s41392-022-00986-0

The global coronavirus disease 2019 (COVID-19) pandemic is currently ongoing. It is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A high proportion of COVID-19 patients exhibit gastrointestinal manifestations such as diarrhea, nausea, or vomiting. Moreover, the respiratory and gastrointestinal tracts are the primary habitats of human microbiota and targets for SARS-CoV-2 infection as they express angiotensin-converting enzyme-2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) at high levels. There is accumulating evidence that the microbiota are significantly altered in patients with COVID-19 and post-acute COVID-19 syndrome (PACS). Microbiota are powerful immunomodulatory factors in various human diseases, such as diabetes, obesity, cancers, ulcerative colitis, Crohn’s disease, and certain viral infections. In the present review, we explore the associations between host microbiota and COVID-19 in terms of their clinical relevance. Microbiota-derived metabolites or components are the main mediators of microbiota-host interactions that influence host immunity. Hence, we discuss the potential mechanisms by which microbiota-derived metabolites or components modulate the host immune responses to SARS-CoV-2 infection. Finally, we review and discuss a variety of possible microbiota-based prophylaxes and therapies for COVID-19 and PACS, including fecal microbiota transplantation (FMT), probiotics, prebiotics, microbiota-derived metabolites, and engineered symbiotic bacteria. This treatment strategy could modulate host microbiota and mitigate virus-induced inflammation.

952

Ce143

Eric Finkelstein, PT, DPT

Vestibular Physical Therapy for the Treatment of Brain Fog From Long COVID—A Case Report

https://doi.org/10.2519/josptcases.2022.10790

Published

30-Apr-22

Case Report

https://www.jospt.org/doi/abs/10.2519/josptcases.2022.10790

Background
Individuals with symptoms weeks or months following COVID-19 have been deemed “long haulers” or having long COVID (LC). COVID has a primary effect on the respiratory and cardiovascular systems; however, individuals diagnosed with LC have had a wide array of symptoms that span across all other body systems, including the nervous system.
Case Presentation
This case study describes the presentation of symptoms and treatment through physical therapy of an individual with LC who presented with cognitive fatigue and brain fog.
Outcome and Follow-up
The individual demonstrated improvements in cognitive fatigue, brain fog, and concentration as well as improvements in balance and vestibular function.
Discussion
This case highlights the importance of a thorough examination in individuals with LC as well as the potential role of physical therapy for those suffering from LC.

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Ce144

Michael J. Peluso1 ORCID Email Khamal Anglin1
Matthew S. Durstenfeld1 Jeffrey N. Martin1
J. Daniel Kelly1 Priscilla Y. Hsue1 Timothy J. Henrich1
Steven G. Deeks1

Effect of oral nirmatrelvir on Long COVID symptoms: a case series

https://doi.org/10.21203/rs.3.rs-1617822/v2

pre-print

5-May-22

Case Report

https://www.researchsquare.com/article/rs-1617822/v2

As the SARS-CoV-2 pandemic continues to evolve, efforts to understand variability in COVID-19 recovery, as well as the impact of factors including viral variants, vaccine status, and COVID-19 treatment on the development and persistence of Long COVID symptoms have intensified. We report three cases that demonstrate that variability in the timing of nirmatrelvir therapy may be associated with different outcomes and underscores the need for systematic study of antiviral therapy for this disease condition.

954

Ce145

Mohamed H. Abdelazim, Ahmed H. Abdelazim, Wael F. Ismaiel, Mahmoud E. Alsobky, Ahmed Younes, Abdelgawad M. Hadeya, Sherif Ramzy & Mohammed Shahin

Effect of intra-nasal nitrilotriacetic acid trisodium salt in lowering elevated calcium cations and improving olfactory dysfunction in COVID-19 patients

https://doi.org/10.1007/s00405-022-07424-5

Published

14-May-22

Study

https://link.springer.com/article/10.1007/s00405-022-07424-5

Purpose
An association between COVID-19 and olfactory dysfunction has been noted in many patients worldwide. The olfactory adaptation process leads to an increase in intracellular calcium cation levels. Nitrilotriacetic acid trisodium salt has high selective chelation for calcium cations from olfactory mucus. The aim of this work is to test the effect of an intranasal nitrilotriacetic acid trisodium salt to lower the elevated calcium cations in COVID-19 patients with relevant symptoms of olfactory dysfunction.
Methods
Fifty-eight COVID-19 adult patients with relevant symptoms of olfactory dysfunction were enrolled in a prospective randomized controlled trial. They received a nasal spray containing either 0.9% sodium chloride or 2% nitrilotriacetic acid trisodium salt. Olfactory function was assessed before and after treatment using the Sniffin’ Sticks test. Quantitative analysis of calcium cation concentration in nasal secretions was performed using a carbon paste ion-selective electrode.
Results
After the application of nitrilotriacetic acid trisodium salt compared to sodium chloride, a significant improvement from functional anosmia to healthy normosmia with significant decrease in calcium cation concentration was observed.
Conclusions
Further collaborative research is needed to fully investigate the effect of an intranasal nitrilotriacetic acid trisodium salt in the treatment of olfactory disorders.

955

Ce146

Summer Rolin, Ashley Chakales & Monica Verduzco-Gutierrez

Rehabilitation Strategies for Cognitive and Neuropsychiatric Manifestations of COVID-19

https://doi.org/10.1007/s40141-022-00352-9

Published

14-May-22

Review

https://link.springer.com/article/10.1007/s40141-022-00352-9

Purpose of Review
Extrapulmonary manifestations of COVID-19 are abundant, including after recovery of acute SARS-CoV-2 infection. This review seeks to explore the cognitive and neuropsychiatric manifestations of COVID-19 and post-acute sequelae of SARS-CoV-2 (PASC), including Long COVID syndromes. Furthermore, the review will discuss rehabilitation strategies for the emerging neurological consequences of COVID-19 to help those experiencing long-term effects of COVID-19.
Recent Findings
There is emerging evidence depicting the neural involvement of COVID-19. Health priorities have shifted from understanding pathogenesis and treatment of pulmonary symptoms to targeting the acute and chronic sequelae of COVID-19, including cognitive and neuropsychiatric symptoms. The sequelae of COVID-19 often co-occur with other medical problems and is best managed by assessment and care across multiple disciplines. Symptoms following infection are similar to those found by other syndromes and disorders that disrupt the central nervous system.
Summary
The acute and chronic sequelae of COVID-19 have become major targets of current health care providers given its significant public health impact, inclusive of cognitive and neuropsychiatric sequelae. Assessment and referral to rehabilitation based on each individual’s needs and symptoms can decrease morbidity and improve quality of life.

Intervention
Cognitive remediation and rehabilitation has been established as an effective treatment for ongoing sequelae of brain injury [34]. Common interventions that can be applied to PASC patients include compensatory strategies based on areas of deficit and training in metacognitive strategies and are outlined in recently published consensus guidance statements, which can be referenced [33].
Tele-rehabilitation, including home-based exercises tailored to the patients’ needs, can be implemented based on demonstrated areas of cognitive deficit [35]. Telemedicine services may not be available based on factors such as access to reliable internet connections, technology, and availability of providers. Thus, in-person therapies may be warranted, and these limitations should be particularly considered when treating patients from disparate health populations.
Exercise programs have been applied as a means to improve cognition, and cardiovascular exercise has been found to improve attention, processing speed, executive functioning, and memory [36]. Application-based exercise programs in other rehabilitation populations have been found to improve exercise engagement, but not functional outcomes such as motor ability and cognition [37]. In PASC patients, rehabilitation exercise programs focusing on resistance, endurance, and balance training, which include an education and pacing element, have yielded gains in cognition [38]. Improvements in symptoms of fatigue and breathlessness [38] have also been found, as well as an improvement in overall functional status [39]. Thus, it is recommended that exercise programs be applied that are in-person or virtual, and include education on pacing and psychoeducation of symptoms, as well as physical exertion.

956

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Shamil Haroon,corresponding author1 Krishnarajah Nirantharakumar,1,2 Sarah E Hughes,1,3 Anuradhaa Subramanian,1 Olalekan Lee Aiyegbusi,1,3 Elin Haf Davies,4 Puja Myles,5 Tim Williams,5 Grace Turner,1 Joht Singh Chandan,1 Christel McMullan,1 Janet Lord,6 David C Wraith,7 Kirsty McGee,6 Alastair K Denniston,8 Thomas Taverner,1 Louise J Jackson,1 Elizabeth Sapey,6 George Gkoutos,9 Krishna Gokhale,1 Edward Leggett,5 Clare Iles,5 Christopher Frost,4 Gary McNamara,4 Amy Bamford,8 Tom Marshall,1 Dawit T Zemedikun,1 Gary Price,10 Steven Marwaha,11 Nikita Simms-Williams,1 Kirsty Brown,1 Anita Walker,1 Karen Jones,1 Karen Matthews,10 Jennifer Camaradou,10 Michael Saint-Cricq,10 Sumita Kumar,10 Yvonne Alder,10 David E Stanton,10 Lisa Agyen,10 Megan Baber,10 Hannah Blaize,10 and Melanie Calvert1,2

Therapies for Long COVID in non-hospitalised individuals: from symptoms, patient-reported outcomes and immunology to targeted therapies (The TLC Study)

http://dx.doi.org/10.1136/bmjopen-2021-060413

Published

26-Apr-22

Protocol

https://bmjopen.bmj.com/content/12/4/e060413

Introduction: Individuals with COVID-19 frequently experience symptoms and impaired quality of life beyond 4–12 weeks, commonly referred to as Long COVID. Whether Long COVID is one or several distinct syndromes is unknown. Establishing the evidence base for appropriate therapies is needed. We aim to evaluate the symptom burden and underlying pathophysiology of Long COVID syndromes in non-hospitalised individuals and evaluate potential therapies.
Methods and analysis: A cohort of 4000 non-hospitalised individuals with a past COVID-19 diagnosis and 1000 matched controls will be selected from anonymised primary care records from the Clinical Practice Research Datalink, and invited by their general practitioners to participate on a digital platform (Atom5). Individuals will report symptoms, quality of life, work capability and patient-reported outcome measures. Data will be collected monthly for 1 year.
Statistical clustering methods will be used to identify distinct Long COVID-19 symptom clusters. Individuals from the four most prevalent clusters and two control groups will be invited to participate in the BioWear substudy which will further phenotype Long COVID symptom clusters by measurement of immunological parameters and actigraphy.
We will review existing evidence on interventions for postviral syndromes and Long COVID to map and prioritise interventions for each newly characterised Long COVID syndrome. Recommendations will be made using the cumulative evidence in an expert consensus workshop. A virtual supportive intervention will be coproduced with patients and health service providers for future evaluation.
Individuals with lived experience of Long COVID will be involved throughout this programme through a patient and public involvement group.
Strengths and limitations of this study
The study will generate a nationally representative cohort of individuals with Long COVID recruited from primary care.
We will recruit controls matched on a wide range of demographic and clinical factors to assess differences in symptoms between people with Long COVID and similar individuals without a history of COVID-19.
We will use a newly developed electronic patient-reported outcome measure (Symptom Burden Questionnaire) for Long COVID to comprehensively assess a wide range of symptoms highlighted by existing literature, patients and clinicians.
Immunological, proteomic, genetic and wearable data captured in the study will allow deep phenotyping of Long COVID syndromes to help better target therapies.
A limitation is that a significant proportion of non-hospitalised individuals affected by COVID-19 in the first wave of the pandemic will lack confirmatory testing and will be excluded from recruitment to the study.

957

Ce148

Talha Burki

The future of Paxlovid for COVID-19

https://doi.org/10.1016/S2213-2600(22)00192-8

Published

24-May-22

Article

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00192-8/fulltext

In comments to Bloomberg published on May 3, 2022, Pfizer chief executive officer Albert Bourla suggested that patients who experience a relapse of symptoms after finishing a course of the company's COVID-19 antiviral, Paxlovid, should take a second course of the drug. Yet the emergency use authorisation issued by the US Food and Drug Administration (FDA) stipulates that Paxlovid is “not authorized for use longer than five consecutive days”. On May 4, John Farley, director of the Office of Infectious Diseases at the FDA, reiterated this message. “There is no evidence of benefit at this time for a longer course of treatment...or repeating a treatment course of Paxlovid in patients with recurrent COVID-19 symptoms following completion of a treatment course”, stated Farley.
The US Government pays around US$530 for each 5-day course of Paxlovid. The drug is a combination of ritonavir plus the novel protease inhibitor PF-07321332. The emergency use authorisation was granted late last year, on the strength of results from the phase 2–3 trial showing that Paxlovid reduces the risk of hospitalisation or death for high-risk patients by 88%, compared with the placebo, if given within 5 days of symptom onset. The trial only recruited unvaccinated individuals. But three-quarters of the UK population and two-thirds of the US population are now fully vaccinated against COVID-19.

Whether or not antivirals will relieve long COVID hinges on the extent to which the condition is attributable to viral persistence. “At the moment, there is not enough evidence to support antiviral therapy for long COVID”, stressed Summers. “There have been reports that the genetic material from the virus has lingered in the guts of previously infected people, but we still do not know if this is live virus.” She added that symptoms of long COVID, such as blood clots and cardiovascular effects are indicative of a dysregulated host immune response, rather than viral persistence. “There could be some deep tissue persistence of hard-to-find virus that is driving a dysregulated inflammatory immune response”, countered Peluso. “I think there is enough compelling preliminary data to study this systematically.” The issue will only be resolved in large scale studies.
6 months have now elapsed since the FDA authorisation of Paxlovid, yet supplies to low-income settings remain suboptimal. “We have to work harder to ensure equitable access across the world”, said Summers. “It worries me that we could potentially be giving antiviral therapy for COVID-19 to patients in the UK or USA who are at low risk of hospitalisation, and who have been fully vaccinated, while there are large numbers of people who need them but have no access to these drugs.”

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Ce149

Huan Yang, Sam J. George, Dane A. Thompson, Harold A. Silverman, Téa Tsaava, Aisling Tynan, Valentin A. Pavlov, Eric H. Chang, Ulf Andersson, Michael Brines, Sangeeta S. Chavan & Kevin J. Tracey

Famotidine activates the vagus nerve inflammatory reflex to attenuate cytokine storm

https://doi.org/10.1186/s10020-022-00483-8

Published

16-May-22

Study

https://molmed.biomedcentral.com/articles/10.1186/s10020-022-00483-8

Background
Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and clinical studies suggest famotidine, a histamine 2 receptor (H2R) antagonist widely used to treat gastroesophageal reflux disease, attenuates the clinical course of COVID-19. Because evidence is lacking for a direct antiviral activity of famotidine, a proposed mechanism of action is blocking the effects of histamine released by mast cells. Here we hypothesized that famotidine activates the inflammatory reflex, a brain-integrated vagus nerve mechanism which inhibits inflammation via alpha 7 nicotinic acetylcholine receptor (α7nAChR) signal transduction, to prevent cytokine storm.
Methods
The potential anti-inflammatory effects of famotidine and other H2R antagonists were assessed in mice exposed to lipopolysaccharide (LPS)-induced cytokine storm. As the inflammatory reflex is integrated and can be stimulated in the brain, and H2R antagonists penetrate the blood brain barrier poorly, famotidine was administered by intracerebroventricular (ICV) or intraperitoneal (IP) routes.
Results
Famotidine administered IP significantly reduced serum and splenic LPS-stimulated tumor necrosis factor (TNF) and IL-6 concentrations, significantly improving survival. The effects of ICV famotidine were significantly more potent as compared to the peripheral route. Mice lacking mast cells by genetic deletion also responded to famotidine, indicating the anti-inflammatory effects are not mast cell-dependent. Either bilateral sub-diaphragmatic vagotomy or genetic knock-out of α7nAChR abolished the anti-inflammatory effects of famotidine, indicating the inflammatory reflex as famotidine’s mechanism of action. While the structurally similar H2R antagonist tiotidine displayed equivalent anti-inflammatory activity, the H2R antagonists cimetidine or ranitidine were ineffective even at very high dosages.
Conclusions
These observations reveal a previously unidentified vagus nerve-dependent anti-inflammatory effect of famotidine in the setting of cytokine storm which is not replicated by high dosages of other H2R antagonists in clinical use. Because famotidine is more potent when administered intrathecally, these findings are also consistent with a primarily central nervous system mechanism of action.

959

Ce150

April S. Caravaca, Alessandro L. Gallina, Laura Tarnawski, +6, Vladimir S. Shavva, Romain A. Colas, Jesmond Dalli, Stephen G. Malin, Henrik Hult, Hildur Arnardottir, and Peder S. Olofsson

Vagus nerve stimulation promotes resolution of inflammation by a mechanism that involves Alox15 and requires the α7nAChR subunit

https://doi.org/10.1073/pnas.2023285119

Published

27-May-22

Study

https://www.pnas.org/doi/10.1073/pnas.2023285119

Significance
Resolution of inflammation is an active process that restores tissue homeostasis and prevents the development of chronic inflammatory diseases. The mechanisms that regulate resolution of inflammation are only partially understood. Here, we showed that activation of the vagus nerve accelerated resolution of inflammation. Electrical stimulation of the vagus nerve in vivo increased levels of select specialized proresolving mediators in inflammation. Experiments in genetic mouse models revealed that the mechanism involved 12/15-lipoxgenase (Alox15), a key enzyme for biosynthesis of the identified mediators, and required the α7-nicotinic acetylcholine receptor subunit. The findings indicate that electrical signals in the vagus nerve activate a cholinergic signal promoting Alox15-dependent lipid mediator biosynthesis and accelerating resolution of inflammation, providing additional insights into neural regulation of inflammation.
Abstract
Nonresolving inflammation underlies a range of chronic inflammatory diseases, and therapeutic acceleration of resolution of inflammation may improve outcomes. Neural reflexes regulate the intensity of inflammation (for example, through signals in the vagus nerve), but whether activation of the vagus nerve promotes the resolution of inflammation in vivo has been unknown. To investigate this, mice were subjected to electrical vagus nerve stimulation (VNS) or sham surgery at the cervical level followed by zymosan-induced peritonitis. The duration of inflammation resolution was significantly reduced and efferocytosis was significantly increased in mice treated with VNS as compared with sham. Lipid mediator (LM) metabololipidomics revealed that mice treated with VNS had higher levels of specialized proresolving mediators (SPMs), particularly from the omega-3 docosahexaenoic (DHA) and docosapentaenoic (n-3 DPA) metabolomes, in peritoneal exudates. VNS also shifted the ratio between proinflammatory and proresolving LMs toward a proresolving profile, but this effect by VNS was inverted in mice deficient in 12/15-lipoxgenase (Alox15), a key enzyme in this SPM biosynthesis. The significant VNS-mediated reduction of neutrophil numbers in peritoneal exudates was absent in mice deficient in the cholinergic α7-nicotinic acetylcholine receptor subunit (α7nAChR), an essential component of the inflammatory reflex. Thus, VNS increased local levels of SPM and accelerated resolution of inflammation in zymosan-induced peritonitis by a mechanism that involves Alox15 and requires the α7nAChR.

960

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Joseph Colombo 1,*,Michael I. Weintraub 2,*,Ramona Munoz 1,Ashish Verma 1,Ghufran Ahmad 1,Karolina Kaczmarski 1,Luis Santos 3 andNicholas L. DePace 1

Long COVID and the Autonomic Nervous System: The Journey from Dysautonomia to Therapeutic Neuro-Modulation through the Retrospective Analysis of 152 Patients

https://doi.org/10.3390/neurosci3020021

Published

23-May-22

Study

https://www.mdpi.com/2673-4087/3/2/21/htm

Introduction. The severity and prevalence of Post-Acute COVID-19 Sequela (PACS) or long-COVID syndrome (long COVID) should not be a surprise. Long-COVID symptoms may be explained by oxidative stress and parasympathetic and sympathetic (P&S) dysfunction. This is a retrospective, hypothesis generating, outcomes study. Methods. From two suburban practices in northeastern United States, 152 long COVID patients were exposed to the following practices: (1) first, they were P&S tested (P&S Monitor 4.0; Physio PS, Inc., Atlanta, GA, USA) prior to being infected with COVID-19 due to other causes of autonomic dysfunction; (2) received a pre-COVID-19 follow-up P&S test after autonomic therapy; (3) then, they were infected with COVID-19; (4) P&S tested within three months of surviving the COVID-19 infection with long-COVID symptoms; and, finally, (5) post-COVID-19, follow-up P&S tested, again, after autonomic therapy. All the patients completed autonomic questionnaires with each test. This cohort included 88 females (57.8%), with an average age of 47.0 years (ranging from 14 to 79 years), and an average BMI of 26.9 #/in2. Results. More pre-COVID-19 patients presented with sympathetic withdrawal than parasympathetic excess. Post-COVID-19, these patients presented with this ratio reversed and, on average, 49.9% more autonomic symptoms than they did pre-COVID-19. Discussion. Both parasympathetic excess and sympathetic withdrawal are separate and treatable autonomic dysfunctions and autonomic treatment significantly reduces the prevalence of autonomic symptoms. Conclusion. SARS-CoV-2, via its oxidative stress, can lead to P&S dysfunction, which, in turn, affects the control and coordination of all systems throughout the whole body and may explain all of the symptoms of long-COVID syndrome. Autonomic therapy leads to positive outcomes and patient quality of life may be restored.

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Salma Charfeddine,corresponding author 1 , 2 , * Hassen Ibnhadjamor, 3 Jihen Jdidi, 2 , 4 Slim Torjmen, 2 , 5 Salma Kraiem, 3 Amine Bahloul, 1 , 2 Ahmed Makni, 1 , 2 Nesrine Kallel, 2 , 5 Nedia Moussa, 2 , 5 Mariem Boudaya, 2 , 6 Imen Touil, 7 Aiman Ghrab, 2 , 8 Jamel Elghoul, 2 , 9 Zeineb Meddeb, 10 Yamina Thabet, 10 Kais Ben Salem, 11 Faouzi Addad, 12 Kamel Bouslama, 10 Sami Milouchi, 2 , 8 Rania Hammami, 1 , 2 Salem Abdessalem, 13 and Leila Abid 1 , 2

Sulodexide Significantly Improves Endothelial Dysfunction and Alleviates Chest Pain and Palpitations in Patients With Long-COVID-19: Insights From TUN-EndCOV Study

https://doi.org/10.3389%2Ffcvm.2022.866113

Published

12-May-22

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133483/

Objective
Non-respiratory long-coronavirus disease 2019 (COVID-19) symptoms are mainly related to a long-lasting endothelial dysfunction and microcirculation impairment. We hypothesized that Sulodexide, a purified glycosaminoglycan mixture with a beneficial endothelial effect in arterial and venous peripheral diseases, may be effective in a subset of patients with long COVID-19.
Approach and Results
We conducted a multicenter prospective quasi-experimental study. A total of 290 patients from the TUN-EndCOV study with long-COVID-19 symptoms and endothelial dysfunction were included. The endothelial function was clinically assessed using a post-occlusive reactive hyperemia protocol with finger thermal monitoring device. Endothelial quality index (EQI) was assessed at inclusion and at 21 days later. The study population was assigned to a sulodexide group (144 patients) or a no-medical treatment group (146 patients). Clinical characteristics were similar at inclusion in the two groups. Fatigue, shortness of breath, and chest pain were the most common symptoms, respectively, 54.5, 53.8, and 28.3%. At 21 days, the sulodexide group improved significantly better than the no-medical treatment group in chest pain (83.7 vs. 43.6%, p < 10−3), palpitations (85.2 vs. 52.9%, p = 0.009), and endothelial function [median delta-EQI 0.66 (0.6) vs. 0.18 (0.3); p < 10−3]. Endothelial function improvement was significantly correlated with chest pain and palpitations recovery (AUC, i.e., area under the curve = 0.66, CI [0.57– 0.75], p = 0.001 and AUC = 0.60, CI [0.51– 0.69], p = 0.03, respectively).
Conclusion
Sulodexide significantly improves long-lasting post-COVID-19 endothelial dysfunction and alleviates chest pain and palpitations.

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Dario Cerasola, 1 , † Christiano Argano, 2 , 3 , 4 , † and Salvatore Corraocorresponding author 2 , 3 , 4 , *

Lessons From COVID-19: Physical Exercise Can Improve and Optimize Health Status

https://doi.org/10.3389%2Ffmed.2022.834844

Published

13-May-22

Article

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9136917/

The outbreak of Coronavirus Disease 2019 (COVID-19) has caused increasing challenges for healthcare systems globally. The disease spread rapidly from Wuhan to the rest of the world, involving more than 400 million individuals and including more than 5 million deaths. In dealing with the pandemic, China and other countries took protective measures such as promoting social distancing, canceling public gatherings, closing schools, quarantining, and imposing lockdowns. All these measures lead to physical inactivity. Being physically inactive has significant repercussions on the status of physical and mental wellbeing, and it is associated with anxiety, stress, increased chronic disease risk, and worsening of chronic conditions. In this sense, the relevance of maintaining a healthy lifestyle through physical exercise has been outlined by the World Health Organization (WHO). The aim of this mini review is to discuss the importance of physical activity in the context of the COVID-19 pandemic, highlighting the benefits of physical activity and exercise that could be potentially effective treatment strategies for comorbid chronic conditions, long covid syndrome (LCS), and symptoms such as depression and anxiety.

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Manabu Ohyama 1, Kiichi Matsudo 2, Toru Fujita 2

Management of hair loss after severe acute respiratory syndrome coronavirus 2 infection: Insight into the pathophysiology with implication for better management

https://doi.org/10.1111/1346-8138.16475

Published

27-May-22

Review

https://pubmed.ncbi.nlm.nih.gov/35633047/

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared a pandemic by the World Health Organization, and COVID-19 continues to have a major impact on society. Numerous studies have reported impaired health sequelae after COVID-19 recovery, one of which is hair loss. Individuals with hair loss experience a substantial mental burden, which potentially hinders their social life. However, few studies have systematically analyzed the details including hair loss. Therefore, we conducted a narrative review using PubMed on the frequency, associated comorbidities, disease characteristics, and treatment of hair loss after SARS-CoV-2 infection (HLASCI). Two search strings were used to identify 28 articles. Of note, most of the literature identified on COVID-19 sequelae reported an emergence/occurrence of hair loss. HLASCI is speculated to be composed of a heterogeneous population, with the onset or exacerbation of telogen effluvium (TE), anagen effluvium, androgenetic alopecia (AGA), and alopecia areata (AA) reported as possible underlying mechanisms. Among these, acute TE is thought to be the primary cause of HLASCI, with COVID-19 treatment and TE improvement being considered crucial for HLASCI management. An association between COVID-19 and AA exacerbation has also been implicated with still insufficient evidence. Spontaneous recovery of TE can be expected once infection reduces; however, faster improvement in symptoms is expected to reduce the mental and social burden of patients. An additional search string identified 11 articles about TE treatment which suggested that the use of minoxidil may be beneficial. Topical minoxidil has been widely used for AGA patients, who have been speculated to exhibit poor resistance to SARS-CoV-2. Topical minoxidil may provide relief from HLASCI, but future clinical research is warranted to confirm this observation.

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Ali Nouraeinejad

A proposal to apply brain injury recovery treatments for cognitive impairment in COVID-19 survivors

https://doi.org/10.1080/00207454.2022.2084091

Published

30-May-22

Article

https://www.tandfonline.com/doi/abs/10.1080/00207454.2022.2084091

There is still little information about the nature and broader prevalence of cognitive problems during post-infection in COVID-19 survivors. This is also the case for pathobiological findings related to these complications. In the meantime, there is mounting alarm regarding potential long-term outcomes of COVID-19, with descriptions of ‘long COVID’ symptoms keeping up into the chronic stage, which include ‘brain fog’. The cognitive impairment or brain fog creates many difficulties in daily activities and makes problems for those who wish to successfully return to their job. The author proposes to apply brain injury recovery treatments for cognitive impairment in COVID-19 survivors.

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ManabuNankakuPT, PhDaRyosukeIkeguchiMD, PhDabTomokiAoyamaMD, PhDcGakutoKitamuraPT, MSaAyumiOtagakiPT, BSaRyotaHamadaPT, MSaTakumaYuriOTR, PhDaShuichiMatsudaMD, PhDab

A first view of the effect of a trial of early mobilization on the muscle strength and activities of daily living in mechanically ventilated patients with COVID-19

https://doi.org/10.1016/j.arrct.2022.100201

Published

10-Jun-22

Study

https://www.sciencedirect.com/science/article/pii/S2590109522000258

Objective
To retrospectively investigate the effect of early mobilization on the muscle strength and activities of daily living in patients with coronavirus disease 2019 (COVID-19) under mechanical ventilation.
Design
This was a single-center, retrospective, observational study.
Setting
Inpatient rehabilitation care in Japan
Participants
The study subjects were divided based on the onset of mobilization: under mechanical ventilation (n =17; aged 68.5 ± 11.9, 13 male) and after extubation (n =11; aged 59.7 ± 7.1, 6 male).
Interventions
Mobilization, including dangle sitting, standing, walking, and muscle strengthening exercises
Main Outcome Measures
The outcome measures were Barthel Index, Medical Research Council Manual Muscle Test (MRC), and intensive care unit (ICU) Mobility Scale.
Results
The difference in the Barthel Index, MRC, and ICU Mobility Scale scores pre- and post-intervention were not statistically significant between the two groups, but all significantly improved after the intervention.
Conclusion
This small sample size study found no difference in the functional recovery of patients with severe COVID-19 who underwent early mobilization under mechanical ventilation relative to when it was begun after extubation.

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J. Kesavadev
S. Shijin
A. Shankar
G. Krishnan
A. Basanth
R.S. Joshi
A. Raveendran
I. Rajalakshmy
Y. Unes
S. Jothydev

IDF21-0234 The Virtual COVID In-patient (VCIP) Care and Post Covid Symptoms: a Comparison with Conventional Care

https://doi.org/10.1016/j.diabres.2022.109326

Published

1-Apr-22

Study

https://www.diabetesresearchclinicalpractice.com/article/S0168-8227(22)00138-3/fulltext

Background: VCIP is a home based interventional economic model wherein a consenting patient will remain in their home and consult the VCIP team via audio-video consultations to treat COVID-19 in a manner similar to inpatient care. While the widely prevalent home-based care that is currently available is often limited to monitoring of vital signs, the VCIP program described here involves active therapeutic intervention.
Aim: We assessed the impact of VCIP in the management of COVID and post COVID symptoms.
Method: Since September 2020, our center has been practicing VCIP for our patients with diabetes, already enrolled in our hospital, to treat COVID and Post COVID symptoms. This is a retrospective analysis of the data of 243 COVID-19 positive patients who enrolled in VCIP. A 24/7 dedicated WhatsApp group of patients, their relatives, doctors, nurses, dietitian and a psychologist was created for remote monitoring of temperature, blood pressure, blood glucose, respiratory and pulse rate along with the symptoms and then to follow up them for 4-6 months post-COVID. The vital parameters and general wellbeing of patients are monitored once every 4 hrs. Contrary to conventional domiciliary care, in VCIP, lab investigations, corticosteroids and other interventions were carried out as and when necessary, at home for the successful management of COVID-19. For patients with diabetes on insulin, the dosages were titrated based on SMBG values or real time CGM. We also assessed the post-COVID symptoms in these patients.
Results: Out of 243 patients who availed of the VCIP facility, all 243 of them recovered. However, 2 hospitalizations were there, one, due to the impending fear of death and the other one, due to intolerance to oral corticosteroids, yielding a 99.5% success rate in preventing hospitalization. There was a wide range of post-COVID-19 symptoms and illnesses experienced by <10% of the patients, which was very low compared to patients in conventional care, including headache(5%), generalized itching(7%), fatigue(20%), vertigo(<1%), urticaria(<1%), exacerbation of sinusitis(<1%), insomnia(15%), and bacterial infection(30%). The patients recovered from these symptoms within 2-3 months. Some patients who experienced more severe complications such as atrial fibrillation and ventricular ectopics (<1%) picked up in Apple watch ECG was referred to a cardiologist for evaluation. The arrhythmias disappeared spontaneously with clinical improvement in the majority of the patients.
Discussion: VCIP when compared to hospitalizations have proven to be cost effective, with significantly better immediate outcomes. With regular and structured teleconsultations and lab assessments, patients likely to deteriorate are identified quite early and treatment initiated without wasting any time. The comorbidities were also aggressively managed. The significantly less occurrence of post Covid symptoms in the VCIP group compared to hospitalized patients could have resulted from these early interventions.

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Pieter C. Goeminne, MD, PhD
Grant Waterer, MBBS, PhD

Post-COVID Care
Untying the Covidian Knot

https://doi.org/10.1016/j.chest.2022.02.036

Published

1-Jun-22

Editorial

https://journal.chestnet.org/article/S0012-3692(22)00403-2/fulltext

What then are the key questions that we need answers to so as to design appropriate, evidence-based post-COVID-19 care pathways in our health systems? First, are there any interventions in the acute phase of COVD-19 that reduce the risk of long-term complications? A recent analysis by Antonelli and colleagues12 showed that patients who had received two doses of vaccination had lower odds of developing post-COVID-19 syndrome (OR, 0.51; 95% CI, 0.32-0.82; P = .006). Because no other acute therapy has been shown to reduce post-COVID complications, this further emphasizes the need for vaccination campaigns. There is an urgent need to look at the impact of all current acute therapies on the long-term effects of COVID-19, including steroids, anti-IL-6 agents, anti-spike protein monoclonal antibodies, and the newer antivirals.
What is the most cost-effective and accurate diagnostic pathway to detect chronic organ damage from COVID-19, and does detection make a difference to therapy? Aside from long COVID-19 prevention, further research on its pathophysiology, identification, risk factors, diagnosis, treatment, and management is needed. As pointed out by Valley and colleagues,9 because there are a wide array of presentations with and without obvious organ pathology, multidisciplinary teams are crucial to address post-COVID-19 syndrome.
Does early intervention based on early diagnosis make a difference in patient outcomes or should we wait for patients to self-refer? Data from a broad group of patients with COVID-19 showed that patients who experienced more than five symptoms in the first week were more likely to develop post-COVID-19 syndrome (OR, 3.95; CI, 3.10-5.04). They also found that individuals with post-COVID-19 syndrome were more likely to have required hospital assessment.5 Looking further into the hospitalized patients, the recent PHOSP-COVID study found that factors associated with post-COVID-19 syndrome were female sex, two or more comorbidities, and more severe acute illness (WHO classes 7-9), whereas age groups < 30 and > 70 years had a better recovery. They also found four clusters of severity, with differences in severity regarding mental and physical health impairment.7 Although validating risk factors for post-COVID-19 syndrome is potentially useful, without effective interventions shown to improve outcomes, they remain an academic exercise rather than a clinically useful one.
A few attempts have already been made to formulate practical recommendations to tackle post-COVID-19 syndrome care, suggesting a multidisciplinary one-stop clinic to screen, diagnose, and treat patients with specialist expertise and interdisciplinary collaboration.13 Models have been developed and put into practice, such as the Multidisciplinary NHS COVID-19 service, with the establishment of a three-tier model.14 These approaches need confirmation and validation but provide a great basis to start further research. In the post-COVID world, the extent to which these clinics could be delivered virtually while achieving the same or better outcomes will undoubtedly be a major focus of study.15
We also should not forget lessons already learned in other analogous conditions. Post critical-illness syndrome is well recognized, and there has been extensive research into its pathology, diagnosis, and avenues of treatment.16 Although there is certainly a larger variety of pathologies and symptomatology reported post-COVID-19, lessons already learnt around the importance of exercise, nutrition, and psychological support should not have to be rediscovered.
In summary, specific guidelines are needed for all what entails post-COVID-19 care, but the evidence base for such recommendations is scant. In the absence of evidence, not surprisingly, a broad range of approaches are being taken across the United States (Valley et al9) and indeed the world. Although we are approaching some understanding of who is most at risk, the best approach to screening for pathology and which treatments (if any) modify long-term outcomes remains to be defined. Further well-designed research studies are urgently required for what is already a major health problem and likely to be so for some years to come.

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Santangelo Letizia
, Ginestra Angelo

PHYSIOTHERAPEUTIC
REHABILITATION IN THE TREATMENT
OF THE POST COVID-19 PATIENT

Published

1-Jun-22

Study

https://jahc.eu/wp-content/uploads/2022/03/JAHC2201-01.pdf

In the coronavirus emergency physiotherapy has had and continues to have a very important role in taking care of patients who, recovered from the disease, need an individualized path of recovery of respiratory and motor rehabilitation, to prevent complications of all kinds and, in general, improve the quality of life.
This study is the result of an accurate research conducted by means of the main research databases, including PubMed. For the drafting of the study, many studies were selected and included, including a position paper by AIPO (Italian Association of Hospital Pneumologists), ARIR (Association of Rehabilitators of Respiratory Insuffi ciency) and SIP (Italian Society of Pneumology) on respiratory rehabilitation, which accurately describes the different phases of treatment provided for each patient, based on the degree of severity of the pathology they suffer from, the SIAARTI recommendations for the management of the critical patient, reviews (SIMG) on physical rehabilitation, the results of a Delphi trial on pulmonary rehabilitation, indications for respiratory physiotherapy by ARIR in collaboration with AIFI (Italian Association of Physiotherapists), but also systematic reviews, some of which focus on the care of elderly patients, meta-analyses and randomised controlled clinical trials. In addition, the research group drew on the experience of a motor reconditioning programme of the U.O. of Rehabilitation Medicine of the Azienda Ospedaliera Marche Nord and on a clinical case of the Istituto Scientifi co Maugeri of Bari.

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Matteo Tosato, MD, PhD
Francesca Ciciarello, MD
Maria Beatrice Zazzara, MD
Cristina Pais, MD
Giulia Savera, MSc
Anna Picca, PhD
Vincenzo Galluzzo, MD
Hélio José Coelho-Júnior, PhD
Riccardo Calvani, PhD
Emanuele Marzetti, MD, PhD
Francesco Landi, MD, PhD

Nutraceuticals and Dietary Supplements for Older Adults with Long COVID

https://doi.org/10.1016/j.cger.2022.04.004

Published

20-Jun-22

Review

https://www.geriatric.theclinics.com/article/S0749-0690(22)00022-2/fulltext

Key points
•Long-term persistence of COVID-19–related symptoms after SARS-CoV-2 infection impacts quality of life.
•Several mechanisms may be involved in the persistence of COVID-19 symptoms, including chronic inflammation, immunometabolic processes, endothelial dysfunction, and gut dysbiosis.
•Bioactive foods, supplements, and nutraceuticals may be used for the management of long-term COVID-19 clinical sequelae.

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Bashar W Badran1
Sarah M Huffman1
Morgan Dancy1
Christopher W Austelle1
Marom Bikson2
Steven A Kautz1
Mark S George1

A pilot randomized controlled trial of supervised, at-home, self-administered transcutaneous auricular vagus nerve stimulation (taVNS) to manage long COVID symptoms

https://doi.org/10.21203/rs.3.rs-1716096/v1

pre-print

21-Jun-22

Study

https://www.researchsquare.com/article/rs-1716096/v1

Background
Although the coronavirus disease 19 (COVID-19) pandemic has now impacted the world for over two years, the persistent secondary neuropsychiatric effects are still not fully understood. These “long COVID” symptoms, also referred to as post-acute sequelae of SARS-CoV-2 infection (PASC), can persist for months after infection without any effective treatments. Long COVID involves a complex heterogenous symptomology and can lead to disability and limit work. Long COVID symptoms may be due to sustained inflammatory responses and prolonged immune response after infection. Interestingly, vagus nerve stimulation (VNS) may have anti-inflammatory effects, however, until recently, VNS could not be self-administered, at-home, noninvasively.
Methods
We created a double-blind, noninvasive transcutaneous auricular VNS (taVNS) system that can be self-administered at home with simultaneous remote monitoring of physiological biomarkers and video supervision by study staff. Subsequently, we carried out a pilot (n = 13) randomized, sham-controlled, trial with this system for four weeks to treat nine predefined long covid symptoms (anxiety, depression, vertigo, anosmia, ageusia, headaches, fatigue, irritability, brain fog). No in-person patient contact was needed, with informed consent, trainings, ratings, and all procedures being conducted remotely during the pandemic (2020–2021) and equipment being shipped to individuals’ homes. This trial was registered onClinicalTrials.gov under the identifier: NCT04638673.
Results
Four-weeks of at-home self-administered taVNS (two, one-hour sessions daily, delivered at suprathreshold intensities) was feasible and safe. Although our trial was not powered to determine efficacy as an intervention in a heterogenous population, the trends in the data suggest taVNS may have a mild to moderate effect in reducing mental fatigue symptoms in a subset of individuals. This innovative study demonstrates the safety and feasibility of supervised self-administered taVNS under a fully contactless protocol and suggests that future studies can safely investigate this novel form of brain stimulation at-home for a variety of neuropsychiatric and motor recovery applications.

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I.Lassouli1M.Benzakour2K.Echchilali3M.M.Moudatir3H.El Kabli3I.Lassouli1M.Benzakour2K.Echchilali3M.M.Moudatir3H.El Kabli3

Vascularite rétinienne post-Covid-19 et Molnupiravir

https://doi.org/10.1016/j.revmed.2022.03.121

Published

15-Jun-22

Study

https://www.sciencedirect.com/science/article/pii/S0248866322002053

Introduction
Le coronavirus du syndrome respiratoire aigu sévère 2 (SARS-CoV-2) est une nouvelle souche de coronavirus, a été détectée en fin décembre 2019 à Wuhan la capitale de la Chine centrale province du Hubei. Il a comme organe cible les poumons induisant une inflammation aiguë pouvant évoluer vers des troubles respiratoires et défaillance multiviscérale. Le spectre complet des présentations n’est pas entièrement élucidé car la pandémie est toujours en cours de progression. Les manifestations oculaires liées à la COVID-19 sont rares, dominées par la conjonctivite et la kératoconjonctivite, quelques rares cas de vascularite rétinienne ont été décrits. Le Molnupiravir est le premier antiviral oral appartenant au groupe des inhibiteurs de l’ARN polymérase qui a démontré un avantage significatif dans la réduction des hospitalisations ou des décès dans les cas légers de COVID-19. Nous rapportons un cas d’une vascularite rétinienne bilatérale post-infection au SARS-CoV 2 et qui a bien répondu au Molnupiravir chez une femme âgée de 30 ans suivie pour maladie de Takayasu.
Observation
Il s’agit d’une patiente âgée de 30 ans, non vaccinée contre le COVID-19, suivie pour maladie de Takayasu classe 5 évoluant depuis 2013 et retenue selon les critères ACR 1990. Admise pour bilan étiologique d’une vascularite rétinienne (VR) bilatérale évoluant depuis 20 jours avant son hospitalisation et concomitante à une infection SARS COV 2 confirmée. L’examen ophtalmologique initial objectivait une actuité visuelle à 3/10 à droit et 9/10 à gauche, le segment antérieur et le tonus intraoculaire étaient sans particularités et au fond d’œil (FO) des foyers de vascularite rétinienne avec des infiltrats blanchâtres et décollement séreux rétinien (DSR) en bilatérale. L’angiographie rétinienne à la fluoresceine retrouvait une vascularite active périmaculaire au niveau droit et normale au niveau gauche. La tomographie par cohérence optique (OCT) objectivait un DSR fovéolaire en bilatérale. Le bilan biologique complet comportant la recherche d’auto-immunité et de maladies infectieuses était négatif, même sa maladie n’était pas en poussée. Sur le plan thérapeutique, elle a été mise initialement sous corticothérapie 1 mg/kg/jour pendant 10 jours, l’évolution fut marquée par l’aggravation de l’acuité visuelle à 1/10 en bilatérale avec apparition au FO des plaques hémorragiques et persistance du DSR en bilatérale. En l’absence d’autre étiologie retrouvée et devant l’aggravation sous corticothérapie, la vascularite rétinienne a été attribuée au SARS COV2. Elle a été mise sous Molnupiravir à raison de 8 comprimés par jour pendant 5 jours avec bonne évolution, l’examen ophtalmologique de contrôle objectivait un acuité visuelle à 9/10 à droit et à 10/10 à gauche avec au FO remaniement maculaire séquelle de résorption du DSR sans oedème maculaire ni signes de vascularite rétinienne.
Conclusion
L’ARN viral du COVID-19 a été détecté dans la rétine des patients atteints et des publications récentes mettent en évidence la possibilité d’une microangiopathie rétinienne chez les patients dont l’infection au COVID-19 est confirmée. L’efficacité directe du Molnupiravir dans les vascularites rétiniennes post-COVID-19 est probable, elle doit encore être évaluée dans le cadre d’essais cliniques.

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Pallav Sengupta & Sulagna Dutta

N-acetyl cysteine as a potential regulator of SARS-CoV-2-induced male reproductive disruptions

https://doi.org/10.1186/s43043-022-00104-8

Published

15-Jun-22

Review

https://link.springer.com/article/10.1186/s43043-022-00104-8

Background
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19), has shown its persistent pandemic strength. This viral infectivity, kinetics, and the mechanisms of its actions in human body are still not completely understood. In addition, the infectivity and COVID-19 severity reportedly differ with patient’s gender with men being more susceptible to the disease. Thus, different studies have also suggested the adverse impact of COVID-19 on male reproductive functions, mainly emphasizing on high expressions of angiotensin-converting enzyme 2 (ACE2) in the testes that allows the viral entry into the cells.
Main body
The N-acetylcysteine (NAC), a potent therapeutic agent of COVID-19, may be effective in reducing the impairing impacts of this disease on male reproductive functions. NAC acts as mucolytic agent by reducing sulfide bonds in the cross-linked glycoprotein matrix in mucus owing to its free sulfhydryl group. Since NAC also breaks the viral disulfide bonds required for the host cell invasion, it may help to prevent direct SARS-CoV-2 invasion into the testicular cells as well. NAC also acts as a potent anti-inflammatory and antioxidant, directly scavenging reactive oxygen species (ROS) and regulating the redox state by maintaining the thiol pool being a precursor of cysteine (an essential substrate for glutathione synthesis). Since it is suggested that male reproductive impairment in COVID-19 patient may be caused by secondary immune responses owing to systemic inflammation and OS, the anti-inflammatory and antioxidant properties of NAC explained above may attribute in protecting the male reproduction functions from these COVID-19-mediated damages.
Conclusion
This article explains the mechanisms how NAC treatment for COVID-19 may prevent the infection-mediated disruptions in male reproduction.

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Kiran Pohar Manhas, PhD, Petra O’Connell, MHA, Jacqueline Krysa, PhD, Isabel Henderson, Chester Ho, MD, Elisavet Papathanassoglou, PhD

Development of a Novel Care Rehabilitation Pathway for Post-COVID Conditions (Long COVID) in a Provincial Health System in Alberta, Canada

https://doi.org/10.1093/ptj/pzac090

Published

29-Jun-22

Study

https://academic.oup.com/ptj/advance-article/doi/10.1093/ptj/pzac090/6619487?login=true

Objective. The purpose of this study was to describe the development and composition of a codesigned, multidisciplinary, integrated, systematic rehabilitation framework for post-COVID conditions (PCC) that spans the care continuum to streamline and standardize rehabilitation services to support persons with PCC in Alberta, Canada.
Methods. A collaborative, consensus-based approach was used, involving 2 iterative provincial taskforces in a Canadian provincial health system. The first taskforce (59 multidisciplinary stakeholders) sought to clarify the requisite facets of a sustainable, provincially coordinated rehabilitation approach for post-COVID rehabilitation needs, based on available research evidence. The second taskforce (129 multidisciplinary stakeholders) translated that strategy and criteria into an operational framework for provincial implementation. Both taskforces sought to align with operational realities of the provincial health system.
Results. The summation of this collaborative, consensus approach resulted in the Provincial Post COVID-19 Rehabilitation Response Framework (PCRF). The PCRF includes 3 care pathways across the care continuum, specifically targeting in-hospital care, continuing care, and community-based care, with 3 key elements: (1) the use of specific symptom screening and assessment tools to systematically identify PCC symptoms and functional impairments; (2) pathways to determine patients’ rehabilitation trajectory and to guide their transition between care settings; and, (3) self-management and education resources for patients and providers.
Conclusion. The PCRF aligns with international mandates for novel codesigned, multidisciplinary approaches to systematically address PCC and its myriad manifestations across the care continuum. The PCRF allows for local adaptation and highlights equity considerations allowing for further spread and scale provincially, nationally, and internationally.

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Suresh, Harshini; Nagaraja, Manjunatha S.

A study of clinical profile, sequelae of COVID, and satisfaction of inpatient care at a government COVID care hospital in Karnataka

https://doi.org/10.4103/jfmpc.jfmpc_1754_21

Published

1-Jun-22

Study

https://journals.lww.com/jfmpc/Fulltext/2022/06000/A_study_of_clinical_profile,_sequelae_of_COVID,.67.aspx

Background:
Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2 virus has increased the morbidity and mortality across the world. The most common symptoms are fever, dry cough, tiredness, and the least common symptoms are aches and pains, sore throat, diarrhoea, conjunctivitis, headache and loss of taste or smell. In this current pandemic, the number of COVID-19 survivors being discharged from the hospital is increasing day by day and the long-term effect among the survivors is also increasing. Fatigue and dyspnea were the most reported Post COVID symptoms. The presence of these symptoms is also known as “Long COVID”. COVID-19 disease has not only affected the physical health but also the mental health of the patients which also had led to decrease in their quality of life.
Material and Methods:
A retrospective cross-sectional study was conducted among 35 patients who were admitted in District hospital in Mysuru during the month of October 2020. Purposive Sampling was adopted for selecting the patients. Data was collected through telephone after their discharge. Data were entered in Microsoft Excel sheet and analysed using SPSS trial version 23. Descriptive statistics such as percentages and proportions were calculated. To see the association between the variables, Chi-square test, Fischer’s exact test was used. P < 0.05 was taken as statistically significant.
Results:
The mean age of the study participants was 49.1 years. Majority of them had fever (68.6%) followed by Myalgia (65.7%), cough (60%), fatigue (42.9%), headache (37.1%) Majority of the patients had no symptoms after discharge (65.7%). After being discharged from the hospital, 22.9% of patients had difficulty in sleeping, 17.1% had loss of taste/smell and fatigue, 8.6% of them had breathlessness and 5.7% of the patients had a change in voice and loss of appetite.
Conclusion:
With the increasing number of cases across the world, we will most likely face an ongoing wave of COVID-19 sequelae. To Prevent this, an extensive rehabilitation program is necessary for patients during hospitalization and after discharge.

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Alexander M. Matheson1,2, Marrissa J. McIntosh1,2, Harkiran K. Kooner1,2, Justin Lee3, Vedanth Desaigoudar1,2, Elianna Bier4, Bastiaan Driehuys4, Sarah Svenningsen5, Giles E. Santyr6,7, Miranda Kirby8, Mitchell S. Albert9,10,11, Yurii Shepelytskyi9,10, Vira Grynko9,10, Alexei Ouriadov12, Mohamed Abdelrazek13, Inderdeep Dhaliwal14, J. Michael Nicholson14, Grace Parraga1,2,3,13,14 See fewer authors

Oxaloacetate Treatment For Mental And Physical Fatigue In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID fatigue patients: a non-randomized controlled clinical trial

https://doi.org/10.1186/s12967-022-03488-3

Published

28-Jun-22

Study

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03488-3

Background
There is no approved pharmaceutical intervention for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS). Fatigue in these patients can last for decades. Long COVID may continue to ME/CFS, and currently, it is estimated that up to 20 million Americans have significant symptoms after COVID, and the most common symptom is fatigue. Anhydrous Enol-Oxaloacetate, (AEO) a nutritional supplement, has been anecdotally reported to relieve physical and mental fatigue and is dimished in ME/CFS patients. Here, we examine the use of higher dosage AEO as a medical food to relieve pathological fatigue.
Methods
ME/CFS and Long-COVID patients were enrolled in an open label dose escalating “Proof of Concept” non-randomized controlled clinical trial with 500 mg AEO capsules. Control was provided by a historical ME/CFS fatigue trial and supporting meta-analysis study, which showed average improvement with oral placebo using the Chalder Scale of 5.9% improvement from baseline. At baseline, 73.7% of the ME/CFS patients were women, average age was 47 and length of ME/CFS from diagnosis was 8.9 years. The Long-COVID patients were a random group that responded to social media advertising (Face Book) with symptoms for at least 6 months. ME/CFS patients were given separate doses of 500 mg BID (N = 23), 1,000 mg BID (N = 29) and 1000 mg TID (N = 24) AEO for six weeks. Long COVID patients were given 500 mg AEO BID (N = 22) and 1000 mg AEO (N = 21), again over a six-week period. The main outcome measure was to compare baseline scoring with results at 6 weeks with the Chalder Fatigue Score (Likert Scoring) versus historical placebo. The hypothesis being tested was formulated prior to data collection.
Results
76 ME/CFS patients (73.7% women, median age of 47) showed an average reduction in fatigue at 6 weeks as measured by the “Chalder Fatigue Questionnaire” of 22.5% to 27.9% from baseline (P < 0.005) (Likert scoring). Both physical and mental fatigue were significantly improved over baseline and historical placebo. Fatigue amelioration in ME/CFS patients increased in a dose dependent manner from 21.7% for 500 mg BID to 27.6% for 1000 mg Oxaloacetate BID to 33.3% for 1000 mg TID. Long COVID patients’ fatigue was significantly reduced by up to 46.8% in 6-weeks.
Conclusions
Significant reductions in physical and metal fatigue for ME/CFS and Long-COVID patients were seen after 6 weeks of treatment. As there has been little progress in providing fatigue relief for the millions of ME/CFS and Long COVID patients, anhydrous enol oxaloacetate may bridge this important medical need. Further study of oxaloacetate supplementation for the treatment of ME/CFS and Long COVID is warranted.

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Andrew G. Pliszka, B.S.A.

Modafinil: A Review and Its Potential Use in the Treatment of Long COVID Fatigue and Neurocognitive Deficits

https://doi.org/10.1176/appi.ajp-rj.2022.170402

Published

28-Jun-22

Drug Review

https://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp-rj.2022.170402

Key Points/Clinical Pearls
Long COVID refers to a constellation of persistent symptoms, most commonly fatigue and “brain fog,” often reported by individuals who have recovered from acute COVID-19 infection.
Modafinil is an eugeroic agent with a favorable safety profile and a low abuse potential, which has been approved for treating fatigue in narcolepsy and shift-work sleep disorder and shown to safely treat fatigue in populations with poststroke fatigue, multiple sclerosis, and HIV/AIDs neurocognitive dysfunction.
Modafinil could be a safe and effective agent in treating fatigue and neurocognitive deficits in patients with long COVID.
Modafinil is a eugeroic agent approved for treating fatigue in narcolepsy and shift-work sleep disorder. It has been shown to have antioxidant effects preclinically and clinical efficacy in treating neurocognitive symptoms. This article describes findings from a literature review that focused on modafinil’s mechanisms of action and its possible role in treating the fatigue and neurocognitive deficits of long COVID. PubMed was searched with the following key terms: “COVID-19-neuropsychiatric,” “long COVID,” modafinil,” “modafinil-fatigue,” “modafinil-inflammation,” and “modafinil–antioxidant.”
Coronavirus disease 2019 (COVID-19), the illness caused by severe acute respiratory syndrome–associated coronavirus type-2 (SARS-CoV-2) infection, has resulted in worldwide morbidity and mortality. Although the majority of COVID-19 infections result in mild disease, 5% of severe cases can lead to critical illness (1). A portion of recovered patients report persistent or new symptoms, even when polymerase chain reaction (PCR) test results are negative. “Long COVID” is a constellation of symptoms that includes fatigue, “brain fogginess,” autonomic dysfunction, headache, loss of smell or taste, cough, depression, low-grade fevers, palpitations, dizziness, muscle pain, and joint pains. One study reported that 87% of hospitalized COVID-19 patients endorsed the persistence of at least one symptom 60 days after discharge, the most common being fatigue (53.1%) (2).
Evidence suggests a neuropsychiatric component of coronavirus infection. Among patients hospitalized for SARS and Middle East respiratory syndrome, 30% to 40% reported neuropsychiatric symptoms during the acute illness, and 10%–20% reported persistent neuropsychiatric symptoms after recovery (3). COVID-19 infections involve increased serum levels of proinflammatory cytokines, which can cross the blood-brain barrier, promoting local inflammation resulting in neurotoxicity (4). Neuroinflammation’s relationship to neuropsychiatric disease and symptomatology is well established, illustrated by data demonstrating increased levels of inflammatory cytokines in depressed patients. These effects are thought to be mediated through down-regulation of monoamine neurotransmission and neurotropic factors (5).
There is limited literature regarding treatment of either the symptoms or the pathophysiology of long COVID. Established therapies targeted to the patient’s presentation are currently recommended (6), and immune modulation therapies have been recommended to target the inflammatory aspect of the disease (7). Evidence shows that depressed patients with abnormally elevated inflammation are less likely to respond to classical monoamine reuptake inhibitor therapy (8). Given the inflammatory nature of COVID-19 neuropathology, one could hypothesize a similar trend among long COVID patients.

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Kamran Abbasi

Long covid and apheresis: a miracle cure sold on a hypothesis of hope

https://doi.org/10.1136/bmj.o1733

Published

14-Jul-22

Article

https://www.bmj.com/content/378/bmj.o1733

A new BMJ investigation with ITN News finds that people are spending their life savings on apheresis, a treatment that claims to clear microthrombi from blood (doi:10.1136/bmj.o1671).20 There are no trials, only hypotheses. There is no research evidence of benefit, only anecdotal reports and the blind faith of vulnerable people seeking a miracle cure. We all need hope, but hope can sometimes be a dangerous thing.

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SilviaCompagnoaStefanoPalermiabValentinaPescatoreaEricaBruginaMarziaSartobRuggeroMarinaValliCalzavaraaManueleNizzettocMorenoScevoladAccursoAloicAlessandroBiffieCarloZanellaaGiovanniCarrettafSilviaGallofFrancoGiadaa

Physical and psychological reconditioning in long COVID syndrome: Results of an out-of-hospital exercise and psychological - based rehabilitation program

https://doi.org/10.1016/j.ijcha.2022.101080

Published

16-Jul-22

Study

https://www.sciencedirect.com/science/article/pii/S2352906722001294

Background
Long Covid Syndrome (LCS) is used to describe signs and symptoms that continue or develop after acute COVID-19 infection. Natural history and treatment of this syndrome are still poorly understood, even if evidences suggest the potential role of physical rehabilitation in improving symptoms in these patients.
Aim of the study
The aim of the present study was to evaluate effectiveness, safety and feasibility of an out-of-hospital multidisciplinary rehabilitation (MDR) program, based both on physical and psychological reconditioning, in reducing symptoms and improving physical fitness and psychological parameters in patients with LCS.
Methods
Thirty consecutive patients with LCS (18 males, mean age 58 years) underwent an accurate medical screening process including anthropometric and muscular strength evaluation, cardiopulmonary exercise test, quality of life (QoL) and psychological appraisal before and after a MDR program.
Results
At baseline, all LCS patients were strongly symptomatic and showed severe impairments in physical performance, QoL and psychological parameters. No adverse effects and dropouts were observed during the exercise training sessions. After the MDR program, COVID-19 residual symptoms significantly decreased, and significant improvements in upper and lower limb muscular strength, cardiopulmonary parameters, perceived physical and mental health, depression and anxiety were observed.
Conclusions
The present study confirms the severe physical and psychological impairment of patients with LCS and suggests that a MDR program is effective, safe and feasible in these patients and could promote their physical and psychological recovery.

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Andrey A. Lobanov, Irina A. Grishechkina, Sergei V. Andronov, Gleb N. Barashkov, Andrey I. Popov, Anatoliy D.Fesyun, Elena P. Ivanova, Maria Chiara Maccarone, Stefano Masiero

Can aquatic exercises contribute to the improvement of the gait stereotype function in patients with Long COVID outcomes?

https://doi.org/10.4081/ejtm.2022.10698

Published

14-Jul-22

Study

https://www.pagepressjournals.org/index.php/bam/article/view/10698

A variety of rehabilitation programmes can be offered to Long COVID patients, specifically physical training. Indeed 90% of these patients reports impairments of verticalization, stability and spatial orientation, making difficult exercise in the gym. The aim of our study was to assess the effectiveness and safety of aquatic exercise techniques as part of a comprehensive rehabilitation program for patients with Long COVID. The first of a two-stage program involved development of aquatic exercises technique, which was evaluated in 12 patients with impaired upright posture control before and after exercising by "Habilect" video gait analysis system. During the second phase, effectiveness and safety of aqua exercises were tested in water pool as part of a comprehensive rehabilitation programme conducted in 23 patients with Long COVID outcomes. Physical examination, 6-minute step test, Euro-QL-5D questionnaire, Borg scale, laser Doppler flowmetry, cardiointervalography, and spirometry were performed before and after the aquatic exercises program. After the training with aquatic exercises, indices of deviations of the main body axes of the head and the body mass centre ameliorated, as well as direction of body movement vector decreased (p<0.05). This study demonstrated a statistically significant improvement in exercise tolerance in both groups, as measured by the 6-minute step test after rehabilitation. The comparison group averaged 236.7 metres [126; 380] (T=8, p=0.047) after the rehabilitation course and the intervention group averaged 233.71 metres [150; 320] (T=8.0, p=0.047). When tested with the Euro-QL-5D questionnaire, a post-treatment improvement was noted in the comparison group on the anxiety/depression subscale (3 [3;3] (T=0, p=0.043)). In the intervention group, laser Doppler flowmetry revealed a statistically significant increase in microcirculation (6.36 standard units after rehabilitation) [5.54; 8.17] (T=7.0, p=0.004), and a decrease of oxidative metabolism index of 6.89 standard units. [4.76; 6.96] (T=4.0, p=0.03). No serious adverse events were reported. In conclusion, the developed aquatic exercises technique seems to contribute to recovery of impaired upright posture and motor function, normalizing the walking pattern.

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Chaitanya R Patil,Nilesh A Dhamne,Prasad K Tanawade,Namrata B Mestri

Megestrol Acetate in the Treatment of Post COVID-19 Fatigue in a Patient of Advanced Cancer: A Case Report and Mini Review of Literature

https://doi.org/10.1055/s-0042-1742616

Published

14-Apr-22

Case Report

https://www.ijmpo.org/ejournals/topic/megestrol-acetate-in-the-treatment-of-post-covid-19-fatigue-in-a-patient-of-advanced-cancer-a-case-report-and-mini-review-of-literature

Megestrol acetate is one of the pharmacological agents used for cancer-associated fatigue. To date, there are no studies on its use in the treatment of post-COVID-19 (coronavirus disease 2019) fatigue. So, we report a case of metastatic carcinoma lung with a partial response with three cycles of palliative chemotherapy. He was contracted with mild COVID-19 infection post three cycles of his chemotherapy. Post this episode, fatigue was his main and most troublesome symptom. After a thorough clinical history, physical examination, and investigations, type 2 post-COVID-19 syndrome was diagnosed. After explaining the risks and benefits, we started the patient on low-dose megestrol acetate (160 mg/d per oral) with low to moderate benefits. However, upon increasing the dose to 480 mg/d, the benefit on the subjective quality of life was significant. Studies with a larger sample and randomized controlled trials have to be conducted to substantiate the hypothesis and actual effect of megestrol acetate in the treatment of post-COVID-19 fatigue.

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RaffaeleIzzoa1ValentinaTrimarcob1PasqualeMonecTeresitaAloèdMassimo CapraMarzanieAntonioDianafGiovanniFaziogMarioMallardohMauroManiscalcoiGiuseppeMarazzijNunziaMessinakSimoneMininnilChiaraMussimGirolamoPelaianAlfioPennisioPierachilleSantuspFrancescoScarpelliqFrancescoTursir…BrunoTrimarcoa

Combining L-Arginine with Vitamin C Improves Long-COVID Symptoms: The Nationwide Multicenter LINCOLN Study

https://doi.org/10.1016/j.phrs.2022.106360

Published

19-Jul-22

Study

https://www.sciencedirect.com/science/article/pii/S104366182200305X

HIGHLIGHTS
•We hypothesized that a supplementation combining L-Arginine (to improve endothelial function) and Vitamin C (to reduce oxidation) could have beneficial effects in Long-COVID.
•We designed a nationwide multicenter clinical study, in which we administered to COVID-19 survivors a survey assessing several symptoms that have been associated with Long-COVID.
•1390 patients – divided in two groups L-Arginine + Vitamin C vs multivitaminic combinations (alternative treatment) – completed the study.
•After 1-month treatment, patients in the L-Arginine + Vitamin C group had significantly lower scores compared to the alternative treatment group.
ABSTRACT
Introduction
Recent evidence suggests that oxidative stress and endothelial dysfunction play critical roles in the pathophysiology of COVID-19 and Long-COVID. We hypothesized that a supplementation combining L-Arginine (to improve endothelial function) and Vitamin C (to reduce oxidation) could have favorable effects on Long-COVID symptoms.
Methods
We designed a nationwide multicenter clinical study (LINCOLN: L-Arginine and Vitamin C improves Long-COVID), in which a survey assessing several symptoms that have been associated with Long-COVID was administered to COVID-19 survivors; effort perception was measured using the Borg scale. Patients were divided in two groups, with a 2:1 ratio: the first group included patients treated with L-Arginine + Vitamin C, whereas the second group was treated with a multivitamin combination (alternative treatment). Before administering the survey, patients completed 30 days of treatment.
Results
1590 patients were initially enrolled, of which 1390 completed the study. Following a 30-day treatment with L-Arginine + Vitamin C, the survey revealed that patients in this treatment group had significantly lower scores compared to the other group. There were no other significant differences between the two groups. When examining effort perception, we observed a significantly lower value (p<0.0001) in patients receiving L-Arginine + Vitamin C compared to the alternative-treatment arm.
Conclusions
Taken together, our findings indicate that the supplementation with L-Arginine + Vitamin C has beneficial effects in Long-COVID, in terms of reducing its typical symptoms and improving effort perception.

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Beatriz Carpallo-Porcar,Laura Romo-Calvo,Sara Pérez-Palomares,Carolina Jiménez-Sánchez ,Pablo Herrero,Natalia Brandín-de la Cruz,Sandra Calvo

Efficacy of an asynchronous telerehabilitation program in post-COVID-19 patients: A protocol for a pilot randomized controlled trial

https://doi.org/10.1371/journal.pone.0270766

Published

19-Jul-22

Protocol

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0270766

Background
About 40% of patients who have had COVID-19 still have symptoms three months later whereas a 10% may experience physical and/or psychological consequences two years later. Therefore, it is necessary to perform preventive interventions when patients are discharged from the hospital to decrease the aforementioned sequelae. The purpose of this pilot-controlled trial will be to determine the efficacy of a rehabilitation program on functional status and psychosocial factors for post-COVID-19 patients when it is delivered through a tele-care platform versus a booklet-based rehabilitation.
Methods
The estimated sample size will be of 50 participants who have been discharged after COVID-19 and have a level of fatigue equal or greater than 4 on the Fatigue Severity Scale. The primary outcome will be the severity of fatigue. Participants will be randomly allocated to an “asynchronous telerehabilitation group” or to a “booklet-based rehabilitation group”. Treatment in both groups will be the same and will consist of a combination of therapeutic exercise and an educative program. Treatment outcomes will be evaluated the last day of the intervention and at three- and six-months follow-up.
Discussion
The telerehabilitation intervention appears to be a viable and efficacy option in decreasing severe fatigue and other fitness variables such as strength and aerobic capacity, similar to other traditional rehabilitation formats such as through an explanatory booklet.

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Edith L. Graham, Igor J. Koralnik & Eric M. Liotta

Therapeutic Approaches to the Neurologic Manifestations of COVID-19

https://doi.org/10.1007/s13311-022-01267-y

Published

21-Jul-22

Article

https://link.springer.com/article/10.1007/s13311-022-01267-y

As of May 2022, there have been more than 527 million infections with severe acute respiratory disease coronavirus type 2 (SARS-CoV-2) and over 6.2 million deaths from Coronavirus Disease 2019 (COVID-19) worldwide. COVID-19 is a multisystem illness with important neurologic consequences that impact long-term morbidity and mortality. In the acutely ill, the neurologic manifestations of COVID-19 can include distressing but relatively benign symptoms such as headache, myalgias, and anosmia; however, entities such as encephalopathy, stroke, seizures, encephalitis, and Guillain–Barre Syndrome can cause neurologic injury and resulting disability that persists long after the acute pulmonary illness. Furthermore, as many as one-third of patients may experience persistent neurologic symptoms as part of a Post-Acute Sequelae of SARS-CoV-2 infection (Neuro-PASC) syndrome. This Neuro-PASC syndrome can affect patients who required hospitalization for COVID-19 or patients who did not require hospitalization and who may have had minor or no pulmonary symptoms. Given the large number of individuals affected and the ability of neurologic complications to impair quality of life and productivity, the neurologic manifestations of COVID-19 are likely to have major and long-lasting personal, public health, and economic consequences. While knowledge of disease mechanisms and therapies acquired prior to the pandemic can inform us on how to manage patients with the neurologic manifestations of COVID-19, there is a critical need for improved understanding of specific COVID-19 disease mechanisms and development of therapies that target the neurologic morbidities of COVID-19. This current perspective reviews evidence for proposed disease mechanisms as they inform the neurologic management of COVID-19 in adult patients while also identifying areas in need of further research.

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Lavanya Visvabharathy Zachary S. Orban1
Igor J. Koralnik1

Treatment of Long COVID with nirmatrelvir/ritonavir and tocilizumab in a patient with rheumatoid arthritis and SARS-CoV-2 antigen persistence: a case report

https://doi.org/10.21203/rs.3.rs-1879380/v1

pre-print

22-Jul-22

Case Report

https://www.researchsquare.com/article/rs-1879380/v1

Background
Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC) in ~ 30% of all infected individuals. Here, we present a case of PASC in a patient with rheumatoid arthritis characterized by viral persistence in the nasopharynx for 6 months after acute infection. We demonstrate transient disappearance of antigen persistence and decreased antiviral and autoimmune T cell responses after nirmatrelvir/ritonavir and tocilizumab treatment.
Case Presentation:
A 37-year-old female with a 7-year history of rheumatoid arthritis enrolled in a COVID-19 research study was found to continuously test SARS-CoV-2 antigen positive in the nasopharynx for 6 months after acute infection. She simultaneously presented with new-onset PASC symptoms including chronic occipital headache and periods of intense fatigue 8 weeks after acute infection. The patient was prescribed nirmatrelvir/ritonavir to treat SARS-CoV-2 persistence at 3.5 months post-acute infection and observed a reduction in PASC symptoms 3 weeks after completing antiviral treatment. After resurgence of PASC symptoms, she stopped treatment with tocilizumab for rheumatoid arthritis to attempt complete SARS-CoV-2 viral clearance. The severity of the patient’s PASC symptoms subsequently increased, and she developed new-onset brain fog in addition to previous symptoms, which resolved after resumption of tocilizumab treatment. Assessment of adaptive immune responses demonstrated that nirmatrelvir/ritonavir and tocilizumab treatment decreased antiviral and autoreactive T cell activation. After resuming tocilizumab treatment, the patient’s PASC symptoms were significantly reduced, but nasopharyngeal antigen positivity remained.
Conclusions
These data suggest that nirmatrelvir/ritonavir should be considered in the treatment of PASC in patients who have SARS-CoV-2 antigen persistence, though care must be taken to monitor the patient for symptom resurgence or viral reactivation. In addition, the IL-6 inhibitor tocilizumab may ameliorate PASC symptoms in patients with persistent headache, fatigue, and brain fog.

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Aaron M. Gusdon1, Nauder Faraday2, John S. Aita3
, Sunil Kumar4, Ishan Mehta5 HuiMahn A. Choi1
, Jeffery L. Cleland6, Keith Robinson7, Louise D. McCullough8
, Derek K. Ng9 Rangaramanujam M. Kannan10, Sujatha Kannan

Dendrimer nanotherapy for severe COVID-19 attenuates inflammation and neurological injury markers and improves outcomes in a phase2a clinical trial

https://doi.org/10.1126/scitranslmed.abo2652

Published

20-Jul-22

Study

https://www.science.org/doi/10.1126/scitranslmed.abo2652

A dendrimer nanotherapy for COVID-19
OP-101, a hydroxyl-polyamidoamine dendrimer–N-acetyl cysteine conjugate, that specifically targets activated macrophages was evaluated in patients with severe COVID-19 in a phase 2a clinical trial. A single intravenous infusion of OP-101 was well tolerated and reduced the risk of death or mechanical ventilation at 30 and 60 days after treatment when compared to placebo. OP-101 treatment was associated with decreased serum concentrations of proinflammatory markers as well as markers of neurological injury (neurofilament light chain and glial fibrillary acidic protein). OP-101 may have potential for treating systemic hyperinflammation in severe COVID-19.
Abstract
Hyperinflammation triggered by SARS-CoV-2 is a major cause of disease severity, with activated macrophages implicated in this response. OP-101, a hydroxyl-polyamidoamine dendrimer–N-acetylcysteine conjugate that specifically targets activated macrophages, improves outcomes in preclinical models of systemic inflammation and neuroinflammation. In this multicenter, randomized, double-blind, placebo-controlled, adaptive phase 2a trial, we evaluated safety and preliminary efficacy of OP-101 in patients with severe COVID-19. Twenty-four patients classified as having severe COVID-19 with a baseline World Health Organization seven-point ordinal scale of ≥5 were randomized to receive a single intravenous dose of placebo (n = 7 patients) or OP-101 at 2 (n = 6), 4 (n = 6), or 8 mg/kg (n = 5 patients). All study participants received standard of care, including corticosteroids. OP-101 at 4 mg/kg was better than placebo at decreasing inflammatory markers; OP-101 at 4 and 8 mg/kg was better than placebo at reducing neurological injury markers, (neurofilament light chain and glial fibrillary acidic protein). Risk for the composite outcome of mechanical ventilation or death at 30 and 60 days after treatment was 71% (95% CI: 29%, 96%) for placebo and 18% (95% CI: 4%, 43%; P = 0.021) for the pooled OP-101 treatment arms. At 60 days, 3 of 7 patients given placebo and 14 of 17 OP-101–treated patients were surviving. No drug-related adverse events were reported. These data show that OP-101 was well tolerated and may have potential to treat systemic inflammation and neuronal injury, reducing morbidity and mortality in hospitalized patients with severe COVID-19.

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A. E. Tereshin, V. V. Kiryanova & D. A. Reshetnik

Correction of Mitochondrial Dysfunction in the Complex Rehabilitation of COVID-19 Patients

https://doi.org/10.1007/s11055-022-01269-5

Published

22-Jul-22

Study

https://link.springer.com/article/10.1007/s11055-022-01269-5

Objective. To study the efficacy of courses of i.v., Cytoflavin in combination with the standard rehabilitation program for postcovid syndrome for correction of postcovid asthenia. Materials and methods. Follow-up investigations were carried out in 45 patients with postcovid syndrome at the second stage of rehabilitation. Patients were divided into two groups of comparable sex and age. The volume of lung damage was also similar in both groups, at 25–80%. The 24 patients making up the comparison group received standard postcovid rehabilitation: pulsed magnetotherapy, inhalation therapy, aeroionotherapy, infrared laser therapy, courses of aerobic training, rational psychotherapy, and successive drug therapy. The 21 patients of the study group additionally received intravenous Cytoflavin daily for 10 days. The dynamics of increases in scores on the Rehabilitation Routing Scale, the Hamilton Depression Rating Scale (HDRS), the Asthenic Status Scale, and the 6-minute walk test at admission and discharge were also monitored. Results and conclusions. Addition of courses of intravenous Cytoflavin to the complex rehabilitation program for postcovid syndrome significantly improved the general functional state of the body, decreased levels of depression and asthenization, and increased physical exercise tolerance.

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Mateja Janković Makek1, Zdravko Babić2, Barbara Barun3 , Nikolina Bašić-Jukić4 Ervina Bilić3, Fran Borovečki3, Venija Cerovečki5, Rok Čivljak6, Viktor Domislović7 ,Ivo Darko Gabrić2, Mario Habek3, Irzal Hadžibegović8, Nenad Jakšić9, Tajana JalušićGlunčić1 , Željko Krznarić7, Ivica Lukšić10, Đivo Ljubičić11, Darko Marčinko9, Alemka Markotić6 , Ante Marušić12, Porin Perić13, Željka Petelin Gadže3 , Delfa Radić Krišto14, Gzim Redžepi15, Davor Sporiš16, Miroslav Samaržija

Overview and management of different
post-COVID conditions

https://doi.org/10.21857/mwo1vc32oy

Published

30-Jun-22

Review

https://hrcak.srce.hr/file/407088

Coronavirus disease 2019 (COVID-19) pandemic resulted in global healthcare crises and strained health resources, both in the acute and chronic phase of the disease. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged symptoms after acute COVID-19. These reports and studies have helped contribute to the recognition of post-COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of different manifestations of post-COVID conditions and propose a framework for the identification of patients at higher risk for post- COVID and their coordinated management through dedicated COVID-19 outpatient clinics.

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Bumi Herman ,Martin Chi-sang Wong ,Pramon Viwattanakulvanid

Vaccination status, favipiravir, and micronutrient supplementation roles in post-COVID symptoms: A longitudinal study

https://doi.org/10.1371/journal.pone.0271385

Published

21-Jul-22

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0271385

Introduction
Post-COVID symptoms are the new concern in the COVID-19 pandemic, where recovered patients experience residual symptoms affecting their quality of life. Therefore, it is imperative to evaluate the role of complete vaccination, prescribed medication, and micronutrients during COVID episodes in the occurrence of post-COVID symptoms.
Method
A longitudinal evaluation of Indonesia’s recovered COVID-19 patients was performed using the data collected from July 2021 and extracted in mid-February 2022. All participants were confirmed with a Real-Time Polymerase Chain Reaction test (PCR) and/or antigen test. This study collected demography and comorbidities information, symptoms and treatment of COVID-19, and collection of self-reported post-COVID symptoms every 30 days within 90 days after diagnosis/onset. Exposures of interest include vaccination status, Favipiravir administration, Vitamin C, Vitamin D, and Zinc. A Generalized Estimating Equation (GEE) was used to evaluate the longitudinal effect of exposures, presented with adjusted odds ratios and its 95% confidence interval.
Results
A total of 923 participants (18.2% fully-vaccinated) were involved in the study, with 79.7% being non-hospitalized. Only 25.7% did not develop any residual symptoms within 90 days. Fatigue was the most reported post-COVID symptom in each measurement time (39.5%, 16.3%, and 7.3%). Full-vaccination was effective against chronic cough (aOR 0.527, 95% CI 0.286–0.971), chronic headache (aOR 0.317, 95% CI 0.163–0.616), and chronic arthritis (aOR 0.285, 95% CI 0.116–0.703). The combination of micronutrient supplementations and Favipiravir gave no significant effect on all post-COVID symptoms. However, early initiation of Favipiravir and delaying vitamin D administration were associated with arthritis.
Conclusion
Full vaccination of COVID-19 prevents the disease and the development of residual symptoms when infected with SARS-COV-2. Hence, it is crucial to reconsider the prescription of micronutrient supplementation or adjust the dose of Favipiravir in the current guideline.

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Ícaro de A. T. Pires, MD, Sara T. Steffens, MD, Aurenzo G. Mocelin, MD, Debora E. Shibukawa, MD, Letícia Leahy, MD, Fernanda L. Saito, MD, Nicole T. Amadeu, MD, Natália M. D. Lopes, MSc, PhD, Ellen C. D. Garcia, MSc, PhD, Maria L. Albanese, MD, Laura F. De Mari, MD, Isabel M. Ferreira, MD, César A. Veiga, MSc, PhD, Yasser Jebahi, MD, PhD, Herton Coifman, MD, Marco A. Fornazieri, MD, PhD, Rogério Hamerschmidt, MD, PhD

Intensive Olfactory Training in Post-COVID-19 Patients: A Multicenter Randomized Clinical Trial

https://doi.org/10.1177%2F19458924221113124

Published

21-Jul-22

Study

https://journals.sagepub.com/doi/10.1177/19458924221113124

Background
Olfactory dysfunction (OD)—including anosmia and hyposmia—is a common symptom of COVID-19. Previous studies have identified olfactory training (OT) as an important treatment for postinfectious OD; however, little is known about its benefits and optimizations after SARS-CoV-2 infection.
Objective
This study aimed to assess whether olfactory training performance can be optimized using more fragrances over a shorter period of time in patients with persistent OD after COVID-19. In addition, we determined the presence of other variables related to OD and treatment response in this population.
Methods
This multicenter randomized clinical trial recruited 80 patients with persistent OD and prior COVID-19 infection for less than 3 months. The patients were divided into 2 groups receiving either 4 or 8 essences over 4 weeks. Subjective assessments and the University of Pennsylvania Smell Identification Test (UPSIT) were performed before and after the treatment.
Results
Significant olfactory improvement was measured subjectively and using the UPSIT in both groups; however, no significant differences between the groups were observed. Additionally, the presence of olfactory fluctuations was associated with higher UPSIT scores.
Conclusion
These data suggest that training intensification by increasing the number of essences for 4 weeks does not show superiority over the classical method. Moreover, fluctuant olfaction seems to be related to a higher score on the UPSIT.

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Loredana Raciti 1ORCID,Rosaria De Luca 2,Gianfranco Raciti 1,Francesca Antonia Arcadi 2 andRocco Salvatore Calabrò 2,*ORCID

The Use of Palmitoylethanolamide in the Treatment of Long COVID: A Real-Life Retrospective Cohort Study

https://doi.org/10.3390/medsci10030037

Published

14-Jul-22

Study

https://www.mdpi.com/2076-3271/10/3/37/htm

COVID-19 can cause symptoms that last weeks or months after the infection has gone, with a significant impairment of quality of life. Palmitoylethanolamide (PEA) is a naturally occurring lipid mediator that has an entourage effect on the endocannabinoid system mitigating the cytokine storm. The aim of this retrospective study is to evaluate the potential efficacy of PEA in the treatment of long COVID. Patients attending the Neurological Out Clinic of the IRCCS Centro Neurolesi Bonino-Pulejo (Messina, Italy) from August 2020 to September 2021 were screened for potential inclusion in the study. We included only long COVID patients who were treated with PEA 600 mg two times daily for about 3 months. All patients performed the post-COVID-19 Functional Status (PCFS) scale. Thirty-three patients (10 males, 43.5%, mean age 47.8 ± 12.4) were enrolled in the study. Patients were divided into two groups based on hospitalization or home care observation. A substantial difference in the PCFS score between the two groups at baseline and after treatment with PEA were found. We found that smoking was a risk factor with an odds ratio of 8.13 CI 95% [0.233, 1.167]. Our findings encourage the use of PEA as a potentially effective therapy in patients with long COVID.

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Shruti Gupta, MD1,2; Jake J. Lee, MD, MSCI1; Amber Perrin, BA1; Amish Khan, BS3; Harrison J. Smith, MD4; Nyssa Farrell, MD5; Dorina Kallogjeri, MD, MPH1; Jay F. Piccirillo, MD1

Efficacy and Safety of Saline Nasal Irrigation Plus Theophylline for Treatment of COVID-19–Related Olfactory Dysfunction
The SCENT2 Phase 2 Randomized Clinical Trial

https://doi.org/10.1001/jamaoto.2022.1573

Published

7-Jul-22

Study

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2793987

Key Points
Question Is the use of theophylline added to saline nasal irrigation efficacious and safe for treatment of COVID-19–related olfactory dysfunction?
Findings In this phase 2 randomized clinical trial of 51 adults with chronic COVID-19–related olfactory dysfunction, the number of participants who self-reported improvement in their olfactory function after using theophylline nasal irrigation was 16% higher than those receiving placebo (59% vs 43%). The theophylline arm had 24% more participants with a clinically meaningful change in their objective smell identification test score.
Meaning The use of theophylline added to saline nasal irrigations may result in clinically beneficial improvements in smell function compared with saline irrigation alone.
Abstract
Importance Recent studies suggest that theophylline added to saline nasal irrigation (SNI) can be an effective treatment for postviral olfactory dysfunction (OD), a growing public health concern during the COVID-19 pandemic.
Objective To evaluate the efficacy and safety of theophylline added to SNI compared with placebo for COVID-19–related OD.
Design, Setting, and Participants This triple-blinded, placebo-controlled, phase 2 randomized clinical trial was conducted virtually between March 15 and August 31, 2021. Adults residing in Missouri or Illinois were recruited during this time period if they had OD persisting for 3 to 12 months following suspected COVID-19 infection. Data analysis was conducted from October to December 2021.
Interventions Saline sinus rinse kits and bottles of identical-appearing capsules with either 400 mg of theophylline (treatment) or 500 mg of lactose powder (control) were mailed to consenting study participants. Participants were instructed to dissolve the capsule contents into the saline rinse and use the solution to irrigate their nasal cavities in the morning and at night for 6 weeks.
Main Outcomes and Measures The primary outcome was the difference in the rate of responders between the treatment and the control arms, defined as a response of at least slightly better improvement in the Clinical Global Impression-Improvement scale posttreatment. Secondary outcome measures included changes in the University of Pennsylvania Smell Identification Test (UPSIT), the Questionnaire for Olfactory Disorders, the 36-Item Short Form Health Survey on general health, and COVID-19–related questions.
Results A total of 51 participants were enrolled in the study; the mean (SD) age was 46.0 (13.1) years, and 36 (71%) participants were women. Participants were randomized to SNI with theophylline (n = 26) or to SNI with placebo (n = 25). Forty-five participants completed the study. At the end of treatment, 13 (59%) participants in the theophylline arm reported at least slight improvement in the Clinical Global Impression-Improvement scale (responders) compared with 10 (43%) in the placebo arm (absolute difference, 15.6%; 95% CI, −13.2% to 44.5%). The median difference for the UPSIT change between baseline and 6 weeks was 3.0 (95% CI, −1.0 to 7.0) for participants in the theophylline arm and 0.0 (95% CI, −2.0 to 6.0) for participants in the placebo arm. Mixed-model analysis revealed that the change in UPSIT scores through study assessments was not statistically significantly different between the 2 study arms. Eleven (50%) participants in the theophylline arm and 6 (26%) in the placebo arm had a change of 4 or more points in UPSIT scores from baseline to 6 weeks. The difference in the rate of responders as measured by the UPSIT was 24% (95% CI, −4% to 52%) in favor of theophylline.
Conclusions and Relevance This randomized clinical trial suggests that the clinical benefit of theophylline nasal irrigations on olfaction in participants with COVID-19–related OD is inconclusive, though suggested by subjective assessments. Larger studies are warranted to investigate the efficacy of this treatment more fully.

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Madlen Davies

Long covid patients travel abroad for expensive and experimental “blood washing”

https://doi.org/10.1136/bmj.o1671

Published

12-Jul-22

Article

https://www.bmj.com/content/378/bmj.o1671.full

Patients with long covid are travelling to private clinics in Cyprus, Germany, and Switzerland for blood filtering apheresis and anticoagulation drugs. Experts question whether these invasive treatments should be offered without sufficient evidence. Madlen Davies reports

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Alicia Gonzalez-Martinez, Ángel Luis Guerrero-Peral, Susana Arias-Rivas, Lorenzo Silva, Álvaro Sierra, Ana Beatriz Gago-Veiga & David García-Azorín

Amitriptyline for post-COVID headache: effectiveness, tolerability, and response predictors

https://doi.org/10.1007/s00415-022-11225-5

Published

12-Jul-22

Study

https://link.springer.com/article/10.1007/s00415-022-11225-5

Background
Headache is one of the most frequently reported symptoms in post-COVID patients. The clinical phenotype of COVID-19 headache combines phenotypic features of both tension-type headache (TTH) and migraine. We aimed to assess the effectiveness, side effects and predictors of amitriptyline (AMT) response in a real-world study setting.
Methods
We performed an observational multicentric study with a retrospective cohort. All consecutive patients with confirmed COVID-19 infection who received AMT for post-COVID headache from March 2020 to May 2021 were included. Response was evaluated by the reduction in the number of headache days per month (HDM) between weeks 8 and 12, compared with the baseline. We explored which variables were associated with a higher probability of response to AMT.
Results
Forty-eight patients were eligible for the study, 40/48 (83.3%) females, aged 46.85 (SD: 13.59) years. Patients had history of migraine 15/48 (31.3%) or TTH 5/48 (10.4%). The mean reduction of HDM was 9.6 (SD: 10.9; 95% CI 6.5, 12.7) days. Only 2/48 (5%) of patients discontinued AMT due to poor tolerability. History of TTH (10.9, 95% CI 1.3, 20.6) and nausea (− 8.5, 95% CI − 14.6, − 2.5) were associated with AMT response.
Conclusions
This study provides real-world evidence of the potential benefit of AMT in patients with post-COVID-19 headache, especially in patients with history of TTH and without concomitant nausea.

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Fabiola Cardoso Diniz, 1 , 2 , 3 Alan Roger Hipkiss, 4 and Gustavo Costa Ferreiracorresponding author 1 , 2 , 5 , *

The Potential Use of Carnosine in Diabetes and Other Afflictions Reported in Long COVID Patients

https://doi.org/10.3389%2Ffnins.2022.898735

Published

22-Jun-22

Article

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9257001/

Carnosine is a dipeptide expressed in both the central nervous system and periphery. Several biological functions have been attributed to carnosine, including as an anti-inflammatory and antioxidant agent, and as a modulator of mitochondrial metabolism. Some of these mechanisms have been implicated in the pathophysiology of coronavirus disease-2019 (COVID-19). COVID-19 is caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The clinical manifestation and recovery time for COVID-19 are variable. Some patients are severely affected by SARS-CoV-2 infection and may experience respiratory failure, thromboembolic disease, neurological symptoms, kidney damage, acute pancreatitis, and even death. COVID-19 patients with comorbidities, including diabetes, are at higher risk of death. Mechanisms underlying the dysfunction of the afflicted organs in COVID-19 patients have been discussed, the most common being the so-called cytokine storm. Given the biological effects attributed to carnosine, adjuvant therapy with this dipeptide could be considered as supportive treatment in patients with either COVID-19 or long COVID.

995

Ce186

Shani Zilberman-Itskovich, Merav Catalogna, Efrat Sasson, Karin Elman-Shina, Amir Hadanny, Erez Lang, Shachar Finci, Nir Polak, Gregory Fishlev, Calanit Korin, Ran Shorer, Yoav Parag, Marina Sova & Shai Efrati

Hyperbaric oxygen therapy improves neurocognitive functions and symptoms of post-COVID condition: randomized controlled trial

https://doi.org/10.1038/s41598-022-15565-0

Published

12-Jul-22

Study

https://www.nature.com/articles/s41598-022-15565-0

Post-COVID-19 condition refers to a range of persisting physical, neurocognitive, and neuropsychological symptoms after SARS-CoV-2 infection. The mechanism can be related to brain tissue pathology caused by virus invasion or indirectly by neuroinflammation and hypercoagulability. This randomized, sham-control, double blind trial evaluated the effect of hyperbaric oxygen therapy (HBOT or HBO2 therapy) on post-COVID-19 patients with ongoing symptoms for at least 3 months after confirmed infection. Seventy-three patients were randomized to receive daily 40 session of HBOT (n = 37) or sham (n = 36). Follow-up assessments were performed at baseline and 1–3 weeks after the last treatment session. Following HBOT, there was a significant group-by-time interaction in global cognitive function, attention and executive function (d = 0.495, p = 0.038; d = 0.477, p = 0.04 and d = 0.463, p = 0.05 respectively). Significant improvement was also demonstrated in the energy domain (d = 0.522, p = 0.029), sleep (d = − 0.48, p = 0.042), psychiatric symptoms (d = 0.636, p = 0.008), and pain interference (d = 0.737, p = 0.001). Clinical outcomes were associated with significant improvement in brain MRI perfusion and microstructural changes in the supramarginal gyrus, left supplementary motor area, right insula, left frontal precentral gyrus, right middle frontal gyrus, and superior corona radiate. These results indicate that HBOT can induce neuroplasticity and improve cognitive, psychiatric, fatigue, sleep and pain symptoms of patients suffering from post-COVID-19 condition. HBOT’s beneficial effect may be attributed to increased brain perfusion and neuroplasticity in regions associated with cognitive and emotional roles.

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Robin Green1 Julia Rybkina Nithin Jacob Brenda Colella David Gold Donna Stewart Lesley Ruttan Liesel-Ann Meusel Mary Pat McAndrews Susan Abbey

Self-Managing Symptoms of Long COVID: an Education and Strategies Research Protocol

https://doi.org/10.21203/rs.3.rs-1894964/v1

pre-print

11-Aug-22

Study

https://www.researchsquare.com/article/rs-1894964/v1

Post-acute sequelae of SARS-COV-2 (PASC) is growing in prevalence, and involves symptoms originating from the central neurological, cardiovascular, respiratory, gastrointestinal, autonomic nervous, or immune systems. There are non-specific symptoms such as fatigue, headaches, and brain fog, which cannot be ascribed to a single system/organ. PASC places a notable strain on our healthcare system, which is already laden with a large number of acute-COVID-19 patients. Furthermore, it impedes social, academic and vocational functioning, and impacts family life, relationships, and work/financial life. The treatment for PASC needs to target this non-specific etiology and wide-ranging sequelae. In conditions similar to PASC, such as “chemo brain”, and prolonged symptoms of concussion, the non-specific symptoms have shown to be effectively managed through education and strategies for self-management and Mindfulness interventions. However, such interventions have yet to be empirically evaluated in PASC to our knowledge. In response to this gap, we have developed a virtual education intervention synthesized by psychiatrists and clinical psychologists for the current study. We will undertake a two-phase randomized controlled trial to determine the feasibility (Phase 1; N = 90) and efficacy (Phase 2; sample sized based on phase 1 results) of the novel 8 week education and self-management strategies group compared to a mindfulness skills program, both delivered virtually. Main outcomes include confidence/ability to self-manage symptoms, quality of life, and healthcare utilization. This study stands to mitigate the deleterious intrusiveness of symptoms on everyday life in patients with PASC, and may also help to reduce the impact of PASC on the healthcare system.

997

Ce188

Sergey Tselmin , Ulrich Julius , Natalia Jarzebska , RomanN. Rodionov

COVID-19 and Therapeutic Apheresis

https://doi.org/10.1055/a-1864-9482

Published

9-Aug-22

Review

https://www.thieme-connect.com/products/ejournals/abstract/10.1055/a-1864-9482

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, is an unprecedented challenge for the global community. The pathogenesis of COVID-19, its complications and long term sequelae (so called Long/Post-COVID) include, in addition to the direct virus-induced tissues injury, multiple secondary processes, such as autoimmune response, impairment of microcirculation, and hyperinflammation. Similar pathological processes, but in the settings of neurological, cardiovascular, rheumatological, nephrological, and dermatological diseases can be successfully treated by powerful methods of Therapeutic Apheresis (TA). We describe here the rationale and the initial attempts of TA treatment in severe cases of acute COVID-19. We next review the evidence for the role of autoimmunity, microcirculatory changes and inflammation in pathogenesis of Long/Post COVID and the rationale for targeting those pathogenic processes by different methods of TA. Finally, we discuss the impact of COVID-19 pandemic on patients, who undergo regular TA treatments due to their underlying chronic conditions, with the specific focus on the patients with inherited lipid diseases being treated at the Dresden University Apheresis Center.

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Ce189

Gaurav Chauhan, Aman Upadhyay, Suchit Khanduja, Trent Emerick

Stellate Ganglion Block for Anosmia and Dysgeusia Due to Long COVID

https://doi.org/10.7759/cureus.27779

Published

8-Aug-22

Case Report

https://www.cureus.com/articles/106516-stellate-ganglion-block-for-anosmia-and-dysgeusia-due-to-long-covid

Anosmia and parosmia refer to the loss or dysfunction of smell, respectively. Dysgeusia refers to taste disturbance. The coronavirus disease 2019 (COVID-19) pandemic and the subsequent phenomenon of Long COVID syndrome have been associated with an increased incidence of anosmia and dysgeusia. Smell and taste disturbances associated with COVID-19 are usually self-limiting but can persist for longer periods in some cases. Imbalances of the autonomic nervous system, especially dysregulation of the sympathetic system, are implicated in the persistence of anosmia and dysgeusia post-COVID-19 infection. Stellate ganglion block (SGB) can diminish the increased sympathetic activity and potentially resolve anosmia and dysgeusia occurring due to Long COVID. The authors report the successful resolution of persistent anosmia and dysgeusia due to Long COVID in a female patient after she underwent SGB.

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Muchtaridi Muchtaridi 1,*ORCID,Siti Rafa Amirah 1,Jacko Abiwaqash Harmonis 1 andEmmy Hainida Khairul Ikram 2ORCID

Role of Nuclear Factor Erythroid 2 (Nrf2) in the Recovery of Long COVID-19 Using Natural Antioxidants: A Systematic Review

https://doi.org/10.3390/antiox11081551

Published

10-Aug-22

Review

https://www.mdpi.com/2076-3921/11/8/1551/htm

Coronavirus disease 2019 (COVID-19) is an infectious disease with approximately 517 million confirmed cases, with the average number of cases revealing that patients recover immediately without hospitalization. However, several other cases found that patients still experience various symptoms after 3–12 weeks, which is known as a long COVID syndrome. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can activate nuclear factor kappa beta (NF-κβ) and unbind the nuclear factor erythroid 2-related factor 2 (Nrf2) with Kelch-like ECH-associated protein 1 (Keap1), causing inhibition of Nrf2, which has an important role in antioxidant response and redox homeostasis. Disrupting the Keap1–Nrf2 pathway enhances Nrf2 activity, and has been identified as a vital approach for the prevention of oxidative stress and inflammation. Hence, natural antioxidants from various sources have been identified as a promising strategy to prevent oxidative stress, which plays a role in reducing the long COVID-19 symptoms. Oxygen-rich natural antioxidant compounds provide an effective Nrf2 activation effect that interact with the conserved amino acid residues in the Keap1-binding pocket, such as Ser602, Ser363, Ser508, and Ser555. In this review, the benefits of various natural antioxidant compounds that can modulate the Nrf2 signaling pathway, which is critical in reducing and curing long COVID-19, are highlighted and discussed.

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Ce191

Leah Conti, Rosa Kim, Amnon A. Berger, Lianne Ryan, Jonathan Eskander

Icosapent Ethyl (VASCEPA®) in the treatment of prolonged post-infectious COVID-19 symptoms

Published

1-Aug-22

Case Report

https://www.cureus.com/publish/articles/92742-icosapent-ethyl-vascepa-in-the-treatment-of-prolonged-post-infectious-covid-19-symptoms/preview?token=K_GvFLfprFB2cyqJukEg&utm_campaign=added_as_coauthor&utm_medium=email&utm_source=author_mailer

COVID-19, the SARS-CoV-2 disease, is a pandemic with devastating effects. Two years into the pandemic, few therapeutic options are available to treat the spectrum of disease. More recently a prolonged post-infectious syndrome, or “long COVID” has been described. This is a post-viral syndrome that persists after the acute infection, without any current available treatment. Emerging evidence attribute this syndrome to ongoing inflammatory response following resolution of acute symptoms.
An omega-three fatty acid derivative used in the treatment of hypertriglyceridemia, Icosapent Ethyl (IPE, VASCEPA®), was previously shown to reduce cardiovascular risk, likely via immunomodulatory effects. Following previous publications in treatment of severe acute COVID-19, we present three cases of resolution of long-COVID after treatment with IPE.

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Hansen, Kristoffer Skaalum and Mogensen, Trine Hyrup and Agergaard, Jane and Schiøttz-Christensen, Berit and Østergaard, Lars Jørgen and Vibholm, Line Khalidan and Leth, Steffen

Coenzyme Q10 as Treatment of Post COVID-19 Condition

http://dx.doi.org/10.2139/ssrn.4178044

pre-print

1-Aug-22

Trial

https://deliverypdf.ssrn.com/delivery.php?ID=466101127096068118004096017107017109028027010042065026093045039119019036059025067074127043001044014042091098031005098067070004076001031016105099052016092007118015037119081113091122104118116122125126054094010014019119087094107019010031064031023031103092064070066098004006106073021119064087107&EXT=pdf&INDEX=TRUE

Background
Post COVID-19 condition (PCC) is defined as symptoms lasting more than 12 weeks after developing COVID-19. Evidence of mitochondrial dysfunction has been reported in peripheral blood mononuclear cells obtained from patients with COVID-19. We hypothesized that PCC is caused by prolonged mitochondrial dysfunction. Given that coenzyme Q10 (CoQ10) can improve mitochondrial function, we examined whether high-dose CoQ10 can reduce the number and/or severity of PCC-related symptoms.
Methods In this placebo-controlled, double-blind, 2x2 crossover interventional trial, participants were recruited from two centres at Aarhus University Hospital and Gødstrup Hospital, Denmark. They were randomly assigned to receive either oral capsules of CoQ10 in a dose of 500 mg/day or placebo for six weeks, with crossover treatment after a four-week washout period. The ED-5Q and a PCC symptom specific questionnaire were completed by the participants at 5 visits during the 20-week study period. The primary endpoint was the change in the number and/or severity of PCC-related symptoms after the six-week intervention compared to placebo. Participants who completed the two-dosing period were included in the primary analysis, while all participants receiving one dose were included in safety assessment.
Findings From May 25th, 2021, to September 22nd, 2021, 121 participants underwent randomization, and 119 completed both dosing periods – 59 and 60 in group A and B, respectively. At baseline, the mean PCC-related symptom score was 43·06 (95% CI: 40·18;45·94), and the mean EQ-5D health index was 0·66 (95% CI: 0·64;0·68). The difference between CoQ10 and placebo was not significant with respect to either the change in EQ-5D health index (with a mean difference of 0·01; 95% CI:0·02;0·04; p=0·45) or the change in PCC-related symptom score (with a mean difference of -1·18; 95% CI: -3·54;1·17; p=0·32).
Interpretation We conclude that CoQ10 treatment does not appear to significantly reduce the number or severity of PCC-related symptoms when compared to placebo.
Funding Placebo and CoQ10 capsules were provided by Pharma Nord, and the trial was supported by grants from the Novo Nordisk Foundation (NNF21OC0066984). This trial is registered with EudraCT, 2020-005961-16 and ClinicalTrials.gov, NCT04960215. The trial is completed.

1002

Ce193

Mária Orendáčová ,Eugen Kvašňák,Jana Vránová

Effect of neurofeedback therapy on neurological post-COVID-19 complications (A pilot study)

https://doi.org/10.1371/journal.pone.0271350

Published

27-Jul-22

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0271350

Objective
Anxiety, fatigue and depression are common neurological manifestations after COVID-19. So far, post-COVID complications were treated by rehabilitation, oxygen therapy and immunotherapy. Effects of neurofeedback on post-COVID complications and their potential interrelatedness have not been studied yet. In this pilot study, we investigated the effectiveness of neurofeedback (Othmer method) for treatment of fatigue, anxiety, and depression after COVID-19.
Methods
10 participants met inclusion criteria for having positive anamnesis of at least one of the following complications following COVID-19: fatigue, anxiety, and depression which were measured by questionnaires. ANOVA was used for calculating differences in questionnaire score before and after neurofeedback. Pearson’s correlation coefficient was used to calculate correlations between anxiety, depression and fatigue.
Results
After five neurofeedback sessions, there came to significant reduction of severity of post-COVID anxiety and depression persisting for at least one month. Effect of neurofeedback on fatigue was insignificant. Severity of anxiety, fatigue and depression as well as reductions in depression and fatigue were positively correlated with each other.
Conclusion
These findings showed effectiveness neurofeedback for reducing anxiety and depression after COVID-19 and for studying correlations between neurological complications after COVID-19. However, since our pilot clinical trial was open-label, it is hard to differentiate between neurofeedback-specific and unspecific effects on our participants. Future randomized controlled trials with more robust sample are necessary to investigate feasibility of neurofeedback for post-COVID neurological complications. The study has identification number trial ID ISRCTN49037874 in ISRCTN register of clinical trials (Retrospectively registered).

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Ce194

Diana Araja, Angelika Krumina, Uldis Berkis, Zaiga Nora-Krukle and Modra Murovska

The Advantages of an Integrative Approach in the Primary Healthcare of Post-COVID-19 and ME/CFS Patients

https://doi.org/10.5772/intechopen.106013

Published

Article

https://www.intechopen.com/online-first/82708

The coronavirus disease caused by the SARS-CoV-2 virus (COVID-19) pandemic has changed not only global epidemiological and economic developments but also the lives of every individual, with particular severity for patients. The number of acute illness cases grew rapidly, significantly increasing the workload of hospitals, and simultaneously, new chronic diseases emerged, such as persistent post-COVID-19 syndrome (PPCS), with unclear etiology, symptoms, and complexity—similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Accordingly, the burden of chronic diseases poses new long-term challenges for primary healthcare and requires new approaches to patient care. This chapter provides insight into the integrative approach to healthcare and focuses on potentially new solutions by implementing an integrative attitude to the treatment of post-COVID-19 and ME/CFS patients in primary healthcare. Integrative health coaching contributes the holistic approach to patients’ overall health and resilience through cognitive practice and patient active engagement. The findings of this chapter can enrich the person-centered approach and healthcare system strengthening through holistic measures and systems thinking.

1004

Ce195

Albert Garcia-Quintanilla, Mario Rivera-Izquierdo2,3, Meritxell Garcia-Quintanilla4

Impact of evening carbohydrate intake on the resolution of persistent night sweats in patients with long COVID: a case series

https://doi.org/10.12688/f1000research.124505.1

pre-print

18-Aug-22

Study

https://f1000research.com/articles/11-950

Up to 25% of patients with long COVID experience persistent night sweats. However, in most cases they remain untreated until they disappear on their own. Since SARS-CoV-2 is known to disrupt glucose homeostasis, we hypothesized that impaired mitochondria would result in faster glycogen depletion at night due to reduced ATP production yield, inducing adrenaline production ultimately leading to the onset of persistent night sweats. To test our hypothesis we investigated whether incorporating carbohydrates into the diet of three non-diabetic patients with long COVID before bedtime would have any effect decreasing their night sweats. Remarkably, after one week with the dietary intervention, the patients reported that their night sweats had completely disappeared. Therefore, we propose carbohydrate supplementation as an affordable solution for night sweats in long COVID patients.

1005

Ce196

Dr BroughNicola1AbelSally2PriddleLucy3

A service evaluation of a community project combining psychoeducation and mind-body complementary approaches to support those with Long Covid in the UK

https://doi.org/10.1016/j.eujim.2022.102182

Published

21-Aug-22

Study

https://www.sciencedirect.com/science/article/pii/S187638202200083X

Introduction
: Post covid-19 syndrome or Long Covid has been estimated to impact 1.3 million individuals in the UK. This study evaluates the outcomes of delivering a complementary Long Covid support service using psycho-educational and mind-body approaches within a community setting.
Methods
: This study utilised quantitative methods to evaluate the outcomes of implementing a complementary approach to Long Covid support. The service offered a package of care including group sessions combining psychoeducation and mind-body complementary approaches and optional 1:2:1 sessions (physiotherapy and craniosacral therapy (CST)). Screening for the service and health information was obtained using the Covid-19-Yorkshire Rehabilitation Screening tool (C-19 YRS). The impact of the service was assessed using the patient reported outcome measure: Warwick Holistic Health Questionnaire (WHHQ-18), and a survey was designed for general evaluation and feedback about the service from participants.
Results
: N=25 participants engaged with the service. The C-19YRS proved to be a useful tool to screen service users. The WHHQ-18 highlighted a positive group change (n=16) in participants’ mental, physical, emotional, and spiritual wellbeing: mean group score at the start = 33.7 (SD=12.5), mean group score at the follow up = 39.5 (SD=10.8). In the feedback from the service evaluation, participants reported that the service was useful in supporting them with their health challenges because of Long Covid and was delivered to the standard expected.
Conclusion
: In conclusion the psycho-educational and mind-body complementary approaches used within this service were well received and the measures used to evaluate were suitable for a service delivered within a community setting.

1006

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Maxime Taquet, Paul J Harrison

Exposure to phenytoin associates with a lower risk of post-COVID cognitive deficits: a cohort study

https://doi.org/10.1093/braincomms/fcac206

Published

16-Aug-22

Study

https://academic.oup.com/braincomms/article/4/4/fcac206/6668727?login=false

Post-COVID cognitive deficits (often referred to as ‘brain fog’) are common and have large impacts on patients’ level of functioning. No specific intervention exists to mitigate this burden.

This study tested the hypothesis, inspired by recent experimental research, that post-COVID cognitive deficits can be prevented by inhibiting receptor-interacting protein kinase. Using electronic health record data, we compared the cognitive outcomes of propensity score-matched cohorts of patients with epilepsy taking phenytoin (a commonly used receptor-interacting protein kinase inhibitor) versus valproate or levetiracetam at the time of COVID-19 diagnosis. Patients taking phenytoin at the time of COVID-19 were at a significantly lower risk of cognitive deficits in the 6 months after COVID-19 infection than a matched cohort of patients receiving levetiracetam (hazard ratio 0.78, 95% confidence interval 0.63–0.97, P = 0.024) or valproate (hazard ratio 0.73, 95% confidence interval 0.58–0.93, P = 0.011). In secondary analyses, results were robust when controlling for subtype of epilepsy, and showed specificity to cognitive deficits in that similar associations were not seen with other ‘long-COVID’ outcomes such as persistent breathlessness or pain. These findings provide pharmacoepidemiological support for the hypothesis that receptor-interacting protein kinase signaling is involved in post-COVID cognitive deficits. These results should prompt empirical investigations of receptor-interacting protein kinase inhibitors in the prevention of post-COVID cognitive deficits.

1007

Ce198

Maria Angela Barletta, Gerardo Marino, Barbara Spagnolo, Francesco Paolo Bianchi, Paola Chiara Francesca Falappone, Luca Spagnolo & Pietro Gatti

Coenzyme Q10 + alpha lipoic acid for chronic COVID syndrome

https://doi.org/10.1007/s10238-022-00871-8

Published

22-Aug-22

Study

https://link.springer.com/article/10.1007/s10238-022-00871-8

Chronic COVID syndrome is characterized by chronic fatigue, myalgia, depression and sleep disturbances, similar to chronic fatigue syndrome (CFS) and fibromyalgia syndrome. Implementations of mitochondrial nutrients (MNs) with diet are important for the clinical effects antioxidant. We examined if use of an association of coenzyme Q10 and alpha lipoic acid (Requpero®) could reduce chronic covid symptoms. The Requpero study is a prospective observational study in which 174 patients, who had developed chronic-covid syndrome, were divided in two groups: The first one (116 patients) received coenzyme Q10 + alpha lipoic acid, and the second one (58 patients) did not receive any treatment. Primary outcome was reduction in Fatigue Severity Scale (FSS) in treatment group compared with control group. complete FSS response was reached most frequently in treatment group than in control group. A FSS complete response was reached in 62 (53.5%) patients in treatment group and in two (3.5%) patients in control group. A reduction in FSS core < 20% from baseline at T1 (non-response) was observed in 11 patients in the treatment group (9.5%) and in 15 patients in the control group (25.9%) (p < 0.0001). To date, this is the first study that tests the efficacy of coenzyme Q10 and alpha lipoic acid in chronic Covid syndrome. Primary and secondary outcomes were met. These results have to be confirmed through a double blind placebo controlled trial of longer duration.

1008

Ce199

Sarah Wolf, Ingrid Zechmeister-Koss & Judit Erdös

Possible long COVID healthcare pathways: a scoping review

https://doi.org/10.1186/s12913-022-08384-6

Published

23-Aug-22

Review

https://bmchealthservres.biomedcentral.com/articles/10.1186/s12913-022-08384-6

Background
Individuals of all ages and with all degrees of severity of the coronavirus disease (COVID) can suffer from persisting or reappearing symptoms called long COVID. Long COVID involves various symptoms, such as shortness of breath, fatigue, or organ damage. The growing number of long COVID cases places a burden on the patients and the broader economy and, hence, has gained more weight in political decisions. This scoping review aimed to give an overview of recommendations about possible long COVID healthcare pathways and requirements regarding decision-making and communication for healthcare professionals.
Methods
A systematic search in four databases and biweekly update-hand searches were conducted. In addition to guidelines and reviews, expert opinions in consensus statements or clinical perspectives were also considered. Data were systematically extracted and subsequently narratively and graphically summarised.
Results
Fourteen references, five guidelines, four reviews, one consensus paper, and four clinical perspectives were included. The evidence recommended that most long COVID-related healthcare should be in primary care. Patients with complex symptoms should be referred to specialized long COVID outpatient assessment clinics. In contrast, patients with one dominant symptom should be directed to the respective specialist for a second assessment. Depending on the patients’ needs, further referral options include, e.g. rehabilitation or non-medical health services. Self-management and good communication between healthcare professionals and patients are crucial aspects of the long COVID management recommendations.
Conclusions
The quality of the included guidelines and reviews is limited in the methods applied due to the novelty of this topic and the associated urgency for research. Hence, an update review with more rigorous data is recommended. Furthermore, the systematic collection of real-world data on long COVID surveillance needs to be set up soon to gather further information on the duration and severity of long COVID and thereby facilitate long COVID care planning.

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Masoumeh Hosseinpoor MD,Mona Kabiri PhD,Mohsen Rajati Haghi MD,Toktam Ghadam Soltani MD,Alireza Rezaei MD,Atiyeh Faghfouri MD,Zahra Poustchian Gholkhatmi MD,Mehdi Bakhshaee MD

Intranasal Corticosteroid Treatment on Recovery of Long-Term Olfactory Dysfunction Due to COVID-19

https://doi.org/10.1002/lary.30353

Published

25-Aug-22

Study

https://onlinelibrary.wiley.com/doi/full/10.1002/lary.30353

Background and Aims
Olfactory dysfunction is a recognized manifestation in patients infected with Coronavirus Disease 2019 (COVID-19). This investigation aimed to assess the effect of mometasone furoate intranasal spray on the improvement of smell dysfunction in post-COVID-19 patients.
Materials and Methods
This randomized placebo-controlled trial included 80 non-hospitalized adult patients who had persistent anosmia or severe microsmia for more than 4 weeks due to COVID-19 infection. The participants were randomly allocated to the intervention or placebo group to receive mometasone furoate nasal spray or sodium chloride intranasal spray during 4 weeks of follow-up, respectively. The patients' olfactory dysfunction was assessed in terms of visual analog scale (VAS), and smell test score according to the modified version of the University of Pennsylvania smell identification test for the Iranian population.
Results
A total of 70 participants completed the follow-up period and were analyzed in this study. By comparing the olfactory scores including smell test and VAS scores, no significant differences were found between case and control groups at baseline, 2, and 4 weeks intervals. However, the change of both olfactory scores at pre to post-treatment intervals and 2–4 weeks was significantly higher in the mometasone group relative to the placebo group. At post-treatment, the frequency of anosmia was 22.9% reduced in the case group compared to the control group.
Conclusion
Overall, there was no significant difference in olfactory dysfunction between the two groups during follow-up. However, based on the significant between-group difference in terms of olfactory scores changes, it seems that the nasal corticosteroids may be a positive effect on the recovery process of patients who received more than 2 weeks.

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NorbertoPericoMDa†MonicaCortinovisBiotechDa†ProfFredySuterMDb†ProfGiuseppeRemuzziMDab

Home as the new frontier for the treatment of COVID-19: the case for anti-inflammatory agents

https://doi.org/10.1016/S1473-3099(22)00433-9

Published

26-Aug-22

Review

https://www.sciencedirect.com/science/article/pii/S1473309922004339

COVID-19, caused by SARS-CoV-2, is characterised by a broad spectrum of symptom severity that requires varying amounts of care according to the different stages of the disease. Intervening at the onset of mild to moderate COVID-19 symptoms in the outpatient setting would provide the opportunity to prevent progression to a more severe illness and long-term complications. As early disease symptoms variably reflect an underlying excessive inflammatory response to the viral infection, the use of anti-inflammatory drugs, especially non-steroidal anti-inflammatory drugs (NSAIDs), in the initial outpatient stage of COVID-19 seems to be a valuable therapeutic strategy. A few observational studies have tested NSAIDs (especially relatively selective COX-2 inhibitors), often as part of multipharmacological protocols, for early outpatient treatment of COVID-19. The findings from these studies are promising and point to a crucial role of NSAIDs for the at-home management of people with initial COVID-19 symptoms.

1011

Ce202

Chia Siang Kow, Dinesh Sangarran Ramachandram & Syed Shahzad Hasan

Hyperbaric oxygen therapy to reverse post-COVID cognitive impairment

https://doi.org/10.1007/s10072-022-06365-5

Published

26-Aug-22

Comment

https://link.springer.com/article/10.1007/s10072-022-06365-5

The authors did not discuss the clinical implications of these findings in the article. Since the study [1] highlights the central role of hypoxemia in the pathophysiology of post-COVID cognitive impairment in patients with COVID-19, we believe the intervention to post-COVID cognitive impairment should be based on the improvement of tissue oxygenation, which can be directly achieved by oxygen therapy. Early oxygen therapy in patients with COVID-19 may be beneficial to prevent the development of post-COVID cognitive impairment, but most commonly, patients with COVID-19 receive oxygen therapy in the later stage of the disease upon presentation in the healthcare facilities, where tissue hypoxia has already occurred [2]. Therefore, the research focus should be placed on restoration of tissue oxygenation after the development of tissue hypoxia, which can be achieved with hyperbaric oxygen therapy.
Hyperbaric oxygen therapy involves inhaling 100% oxygen at pressures exceeding 1 atmosphere absolute (ATA), which aims to enhance the amount of oxygen dissolved in the body tissues. Even before the COVID-19 pandemic, evidence has been accumulated about the neuroplasticity effects of hyperbaric oxygen therapy, where the combined action of hyperoxia and hyperbaric pressure can improve tissue oxygenation by activating both oxygen- and pressure-sensitive genes [3]. It is evidenced that hyperbaric oxygen therapy, which explicitly utilizes the hyperoxic-hypoxic paradox through constant fluctuation in both pressure and oxygen concentrations, can induce gene expression and metabolic pathways involved in brain tissue regeneration. These pathways can promote neurogenesis and angiogenesis in injured brain tissue.
Hyperbaric oxygen therapy has been trialed in patients with COVID-19 with some success. In a case report [4] of a patient with post-COVID cognitive impairment, hyperbaric oxygen therapy led to improvements in brain perfusion and integrity of white matter brain microstructure, which are indicative of angiogenesis and neurogenesis, respectively. The patient also demonstrated improvement in cognitive performance after hyperbaric oxygen therapy [4]. Recently, a small-scale randomized controlled trial [5] of hyperbaric oxygen therapy in patients suffering from post-COVID-19 condition adds to the growing positive evidence of the intervention. There was a significant group-by-time interaction in the cognitive performance in patients randomized to hyperbaric oxygen therapy compared to patients randomized to sham therapy, which was accompanied by significant improvement in brain MRI perfusion and microstructural changes in frontal, parietal, and limbic regions of the brain involved in cognitive roles [5].
Based on the discovery that hypoxemia is the main driver of post-COVID cognitive impairment in patients with COVID-19, we believe larger scale trials should be performed to investigate the use of hyperbaric oxygen therapy in patients suffering from post-COVID cognitive impairment, especially when evidence to date has been reassuring. In fact, interventions for the post-COVID condition should not be sidelined since the post-COVID condition has been associated with deterioration in the quality of life, particularly the frail elderly patients who are more susceptible to post-COVID cognitive impairment [6].

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Nicola Veronese 1ORCID,Roberta Bonica 1,Sergio Cotugno 2,Ottavia Tulone 1,Michele Camporeale 2,Lee Smith 3ORCID,Mike Trott 4ORCID,Olivier Bruyere 5ORCID,Luigi Mirarchi 1,Giuseppina Rizzo 1,Davide Fiore Bavaro 1ORCID,Mario Barbagallo 1ORCID,Ligia J. Dominguez 1,6,Claudia Marotta 7,Andrea Silenzi 7ORCID,Emanuele Nicastri 8ORCID,Annalisa Saracino 2 andFrancesco Di Gennaro 2,*ORCID

Interventions for Improving Long COVID-19 Symptomatology: A Systematic Review

https://doi.org/10.3390/v14091863

Published

24-Aug-22

Systematic Review

https://www.mdpi.com/1999-4915/14/9/1863/htm

Introduction: Although the understanding of several aspects of long COVID-19 syndrome is increasing, there is limited literature regarding the treatment of these signs and symptoms. The aim of our systematic review was to understand which therapies have proved effective against the symptoms of long COVID-19. Methods: A systematic search for randomized controlled or clinical trials in several databases was conducted through 15 May 2022. Specific inclusion criteria included: (1) intervention studies, either randomized controlled (RCTs) or clinical trials; (2) diagnosis of long COVID-19, according to the World Health Organization criteria; (3) presence of long COVID-19 for at least 12 weeks after SARS-CoV-2 infection. Results: We initially found 1638 articles to screen. After removing 1602 works based on their title/abstract, we considered 35 full texts, and among them, two intervention studies were finally included. The first RCT focused on the greater improvement of treatment combining olfactory rehabilitation with oral supplementation with Palmitoylethanolamide and Luteolin in patients with olfactory dysfunction after COVID-19. The second study evaluated the positive impact of aromatherapy vs. standard care in adult females affected by fatigue. Conclusion: Our systematic review found only two intervention studies focused on patients affected by long COVID-19. More intervention studies are needed to investigate potentially positive interventions for long COVID-19 symptoms.

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Candace W. Burton,Charles A. Downs,Thomas Hughes,Natalie Lambert,Heather L. Abrahim,Maria Giraldo Herrera,Yong Huang,Amir Rahmani,Jung-Ah Lee,Rana Chakraborty,Melissa D. Pinto

A novel conceptual model of trauma-informed care for patients with post-acute sequelae of SARS-CoV-2 illness (PASC)

https://doi.org/10.1111/jan.15426

Published

29-Aug-22

DISCUSSION PAPER-METHODOLOGY

https://onlinelibrary.wiley.com/doi/10.1111/jan.15426

Aim
This paper proposes a novel, trauma-informed, conceptual model of care for Post-Acute Sequelae of COVID-19 illness (PASC).
Design
This paper describes essential elements, linkages and dimensions of the model that affect PASC patient experiences and the potential impact of trauma-informed care on outcomes.
Data sources
PASC is a consequence of the global pandemic, and a new disease of which little is known. Our model was derived from the limited available studies, expert clinical experience specific to PASC survivors and publicly available social media narratives authored by PASC survivors.
Implications for nursing
The model provides a critical and novel framework for the understanding and care of persons affected by PASC. This model is aimed at the provision of nursing care, with the intention of reducing the traumatic impacts of the uncertain course of this disease, a lack of defined treatment options and difficulties in seeking care. The use of a trauma-informed care approach to PASC patients can enhance nurses' ability to remediate and ameliorate both the traumatic burden of and the symptoms and experience of the illness.
Conclusion
Applying a trauma-informed perspective to care of PASC patients can help to reduce the overall burden of this complex condition. Owing to the fundamentally holistic perspective of the nursing profession, nurses are best positioned to implement care that addresses multiple facets of the PASC experience.
Impact
The proposed model specifically addresses the myriad ways in which PASC may affect physical as well as mental and psychosocial dimensions of health. The model particularly seeks to suggest means of supporting patients who have already experienced a life-threatening illness and are now coping with its long-term impact. Since the scope of this impact is not yet defined, trauma-informed care for PASC patients is likely to reduce the overall health and systems burdens of this complex condition.

1014

Ce205

Leah Shaffer

Lots of long COVID treatment leads, but few are proven

https://doi.org/10.1073/pnas.2213524119

Published

1-Sep-22

Article

https://www.pnas.org/doi/full/10.1073/pnas.2213524119

Lingering virus particles, microclots, and faulty immune signaling are likely culprits for many long-hauler symptoms. Anticoagulants, immune regulators, and antivirals show early promise.

1015

Ce206

Hui Zhang
Bin Cao

Post-infection rehabilitation of COVID-19 patients: Findings and prospects

https://doi.org/10.1016/j.lanepe.2022.100496

Published

1-Sep-22

Comment

https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(22)00192-2/fulltext

In the current issue of The Lancet Regional Health – Europe, Berentschot and colleagues provided results of a prospective multicenter cohort study (CO-FLOW) in the Netherlands revealing the changes of physical function across four different rehabilitation pathways within 12 months after discharge. The median age of patients enrolled in this study was 60 years, nearly 97% received supplemental oxygen, 40.7% were treated in ICU and 70.4% treated with steroids during hospitalization, indicating high risk for long COVID and rehabilitation training needs.6 Different from previous studies, this study not only focused on the rehabilitation of cardiopulmonary function, but also focused on changes in muscle strength and mobility. Among the three dimensions of assessed physical function, cardiorespiratory fitness and muscle strength improved most significantly within the first 6 months after discharge, suggesting that the first 6-month post-discharge is the optimal recovery period for COVID-19 patients. The findings also confirmed their hypothesis that patients who require more intensive rehabilitation have more impaired physical function at 3 months after hospital discharge and that these differences in physical function reduce over time. Although the improvement of physical function from 6-month to 1-year was not significant, it continued to improve till to 1-year, which means that the functional status requires longer follow-up observation.
Physical function, HRQoL, symptom, disability, activities of daily living and return to work have been identified as important recovery targets for long COVID rehabilitation, and a comprehensive assessment should be conducted before and after rehabilitation to provide more evidence for developing an appropriate plan for patients with long COVID or other illnesses.7,8 The current study was an interim analysis and approximately one-third of enrolled patients completed 3 visits; however, it is unclear which characteristics of patients should be treated by medical professionals and whether rehabilitation is feasible and beneficial for mild patients, who also reportedly have sequelae of long COVID. With the prevalence of the Omicron variants, the number of severe or critical COVID-19 patients has decreased, and the trajectory of rehabilitation may differ from that found in current study, so well-designed prospective cohort or randomized research focusing on recovery outcome of COVID-19 patients with various variants or severities is needed in the future to address the above gaps. In the context of limited medical resources, identifying patients who need rehabilitation treatment and classify them into appropriate rehabilitation sites will benefit for improving patients function level and allocating medical resources rationally. Due to the similarities between long COVID and other post-acute infection syndromes and PICS, appropriate control group needs to be considered in future study design to better elucidate the recovery characteristics of COVID-19 patients.9 In addition to focusing on the characteristics of patients with improved physical function, more attention should be paid to those patients without improvement or even declined continuously, and further study is crucial to uncover the underlying mechanism of long COVID in the future.

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Vengadesh Letchumanan1, Angel Yun-Kuan Thye1, Jodi Woan-Fei Law1, Priyia Pusparajah2, Sivakumar Thurairajasingam3, Loh Teng-Hern Tan3, Learn-Han Lee1

IDDF2022-ABS-0207 The potential use of probiotics in alleviating psychological symptoms of long covid-19

http://dx.doi.org/10.1136/gutjnl-2022-IDDF.63

Published

2-Sep-22

Review

https://gut.bmj.com/content/71/Suppl_2/A57.1.abstract

Background Neuropsychiatric implications could result from disease or brain damage due to direct central nervous system (CNS) infection or indirect effects on the CNS through an immune response. Symptoms of long COVID-19 can persist up to 1-year post-hospitalization. Rates surged for anxiety, depression, and post-traumatic stress in COVID-19 survivors. There is mounting evidence that probiotics could alleviate mental illnesses, which led to research on the application of probiotics as a potential COVID-19 prevention and treatment. This study explores the psychiatric manifestations, particularly anxiety, depression, and post-traumatic stress disorder (PTSD) post COVID-19 infection and the potential of probiotics as an adjunct treatment for COVID-19.
Methods Based on PRISMA guidelines, predefined MESH terms ‘COVID-19’ OR ‘long COVID’ AND ‘depression’ OR ‘psychological’ OR ‘anxiety’ OR ‘cognitive’ OR ‘neuropsychiatric’ OR ‘stress’ OR ‘mental health’ was used in databases (PubMed, Web of Science, Ovid Medline) to perform systematic literature searches. Google Scholar was also used. Studies reporting on the psychological sequelae among confirmed COVID-19 infected patients were included. Animal studies, studies without COVID-19 infected patients, and studies without evaluating psychological aspects, including reviews, commentaries/perspectives, conference abstracts, and editorials were excluded.
Results 73 studies in accordance with the inclusion criteria out of 391 articles were selected for qualitative analysis. The studies reported anxiety, depression, and PTSD are the persistent symptoms in COVID-19 survivors. Cytokine dysregulation is associated with these psychiatric illnesses presented by the patients. Hence, probiotic supplementation aids in stimulating and modulating the immune system and decreases inflammation. Its efficacy in improving mental illness has been proven in clinical trials. The proposed mechanisms in which probiotics exert its positive effects on the psychiatric symptoms of COVID-19 patients include modulating the kynurenine pathway, neurotransmitter production and the role of SCFAs in decreasing neuroinflammation, maintaining the gut and the blood-brain barrier’s integrity (IDDF2022-ABS-0207 Figure 1. Illustration of mechanisms of probiotics in the management of psychiatric symptoms in Covid19 patients).
Conclusions A potential connection exists between the psychiatric sequelae of COVID-19 and the gut microbiome. These findings also provide insights on probiotics as a potential adjunctive treatment to conventional psychotropic medications in alleviating psychiatric sequelae post COVID-19.

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Amaya Jimeno-Almazán,Francisco Franco-López,Ángel Buendía-Romero,Alejandro Martínez-Cava,José Antonio Sánchez-Agar,Bernardino J. Sánchez-Alcaraz Martínez,Javier Courel-Ibáñez,Jesús G. Pallarés

Rehabilitation for post-COVID-19 condition through a supervised exercise intervention: A randomized controlled trial

https://doi.org/10.1111/sms.14240

Published

15-Sep-22

Study

https://onlinelibrary.wiley.com/doi/10.1111/sms.14240

Purpose
The aim of the study was to compare the outcomes of patients with post-COVID-19 condition undergoing supervised therapeutic exercise intervention or following the self-management WHO (World Health Organization) rehabilitation leaflet.
Methods
A randomized controlled trial was carried out that included 39 participants with post-COVID-19 condition who had a chronic symptomatic phase lasting >12 weeks. Comprehensive medical screening, patient-reported symptoms, and cardiorespiratory fitness and muscular strength were assessed. Patients were randomly assigned to a tailored multicomponent exercise program based on concurrent training for 8 weeks (two supervised sessions per week comprised resistance training combined with aerobic training [moderate intensity variable training], plus a third day of monitored light intensity continuous training), or to a control group which followed the WHO guidelines for rehabilitation after COVID-19.
Results
After follow-up, there were changes in physical outcomes in both groups, however, the magnitude of the change pre–post intervention favored the exercise group in cardiovascular and strength markers: VO2max +5.7%, sit-to-stand −22.7% and load-velocity profiles in bench press +6.3%, and half squat +16.9%, (p < 0.05). In addition, exercise intervention resulted in a significantly better quality of life, less fatigue, less depression, and improved functional status, as well as in superior cardiovascular fitness and muscle strength compared to controls (p < 0.05). No adverse events were observed during the training sessions.
Conclusion
Compared to current WHO recommendations, a supervised, tailored concurrent training at low and moderate intensity for both resistance and endurance training is a more effective, safe, and well-tolerated intervention in post-COVID-19 conditions.

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Steenblock C1, Walther R1, Tselmin S2, Jarzebska N3, Voit-Bak K4, Toepfner N5, Siepmann T6, Passauer J1, Hugo C7, Wintermann G8, Julius U9, Babir M10, Khan TZ10, Puhan MA11, Straube R4, Hohenstein B1, Bornstein SR12, Rodionov R13

Long Covid and Apheresis - Where are we Standing?

https://doi.org/10.1055/a-1945-9694

Published

16-Sep-22

Study

https://europepmc.org/article/med/36113501

A continual increase in cases of Long Covid constitutes a medical and socioeconomic challenge to health systems around the globe. While the true extent of this problem cannot yet be fully evaluated, recent data suggests that up to 20% of people with confirmed with SARS-CoV-2 suffer from clinically relevant symptoms of Long Covid several weeks to months after the acute phase. The clinical presentation is highly variable with the main symptoms being chronic fatigue, dyspnea and cognitive symptoms. Extracorporeal apheresis has been suggested to alleviate symptoms of Long Covid. Thus, numerous patients are currently treated with apheresis. However, at present there is no data from randomized controlled trials available to confirm the efficacy. Therefore, physicians rely on the experience of practitioners and centers performing this treatment. Here, we summarize clinical experience on extracorporeal apheresis in patients with Long Covid from centers across Germany.

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Trisha Greenhalgh, professor of primary care health sciences1, Manoj Sivan, associate professor in rehabilitation medicine2, Brendan Delaney, professor of medical informatics and decision making3, Rachael Evans, associate professor in respiratory medicine, associate professor in respiratory medicine4, Ruairidh Milne

Long covid—an update for primary care

https://doi.org/10.1136/bmj-2022-072117

Published

22-Sep-22

Practice Pointer

https://www.bmj.com/content/378/bmj-2022-072117

What you need to know
Long covid (prolonged symptoms following covid-19 infection) is common
The mainstay of management is supportive, holistic care, symptom control, and detection of treatable complications
Many patients can be supported effectively in primary care by a GP with a special interest

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Mark Vink markvink.md@outlook.com and Alexandra Vink-Niese

Graded exercise therapy for myalgic encephalomyelitis/chronic fatigue syndrome is not effective and unsafe. Re-analysis of a Cochrane review

https://doi.org/10.1177/2055102918805187

Published

8-Oct-18

Review

https://journals.sagepub.com/doi/10.1177/2055102918805187

The analysis of the 2017 Cochrane review reveals flaws, which means that contrary to its findings, there is no evidence that graded exercise therapy is effective. Because of the failure to report harms adequately in the trials covered by the review, it cannot be said that graded exercise therapy is safe. The analysis of the objective outcomes in the trials provides sufficient evidence to conclude that graded exercise therapy is an ineffective treatment for myalgic encephalomyelitis/chronic fatigue syndrome.

1021

Ce212

Reinfeld, Samuel

Can bupropion treat COVID-19–induced brain fog? A case series

https://doi.org/10.1097/YIC.0000000000000436

Published

15-Sep-22

Case Series

https://journals.lww.com/intclinpsychopharm/Fulltext/9900/Can_bupropion_treat_COVID_19_induced_brain_fog__A.23.aspx

COVID-19–induced neurocognitive complications that include brain fog have affected a large portion of individuals who survived COVID-19. These symptoms can include inattention, mental fatigue, forgetfulness, amotivation, and distractibility. This can cause significant anxiety and depression, which may worsen disease progression. To date, there are no known specific treatments that target COVID-19-related brain fog. Here, two patients are presented that develop symptoms of brain fog that persisted after they recovered from an acute COVID-19 infection. Both had memory impairment, mental exhaustion, and inattention with associated depressed mood. They were given bupropion extended release and though varied with dosing and time to resolution, they recovered dramatically. The dopamine and norepinephrine reuptake inhibitor is known to have effects on the brain that may treat symptoms of brain fog including blocking hippocampal cell loss, increased neural activity in the cingulate cortex, and decreasing proinflammatory cytokines. Bupropion may be a possible option for those suffering from this growing and debilitating post-COVID-19 complication.

1022

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Anne Schrimpf,corresponding author * Annett Braesigk, Stefan Lippmann, and Markus Bleckwenn

Management and treatment of long COVID symptoms in general practices: An online-based survey

https://doi.org/10.3389%2Ffpubh.2022.937100

Published

13-Sep-22

Survey

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9513068/

Independent from initial severity, many patients develop persistent symptoms after infection with SARS-CoV-2, described as long COVID syndrome. Most of these patients are treated by general practitioners (GPs). As evidence-based treatment recommendations are still sparse, GPs must make their therapy decisions under uncertainty. We investigated (1) the most frequently observed long COVID symptoms in general practices and (2) GPs' applied treatment and rehabilitation plans for these symptoms. In total, 143 German GPs participated in an online-based survey between 05/2021 and 07/2021. We found that each GP practice was treating on average 12 patients with long COVID symptoms. Most frequently seen symptoms were fatigue and reduced performance. Current therapy options were rated as poor and loss of smell and taste, fatigue, or lack of concentration were perceived to be especially difficult to treat. The use of drug and non-drug therapies and specialist referrals focused primarily on physiological and less on psychosomatic/psychological rehabilitation and followed guidelines of similar conditions. Our results provide first insights into how GPs approach a newly emerging condition in the absence of guidelines, evidence-based recommendations, or approved therapies, and might inform about GP preparedness in future pandemics. Our results also emphasize a gap between the current knowledge of the long COVID manifestation and knowledge about effective rehabilitation.

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Hayley Wright 1 Author Orcid Image ; Andrew Turner 1 Author Orcid Image ; Stuart Ennis 2, 3, 4 Author Orcid Image ; Carol Percy 5 Author Orcid Image ; Garry Loftus 6 Author Orcid Image ; Wendy Clyne 7 Author Orcid Image ; Gabriela Matouskova 6 Author Orcid Image ; Faith Martin 1 Author Orcid Image

Digital Peer-Supported Self-Management Intervention Codesigned by People With Long COVID: Mixed Methods Proof-of-Concept Study

https://doi.org/10.2196/41410

Published

Study

https://formative.jmir.org/2022/10/e41410

Background:
There are around 1.3 million people in the United Kingdom with the devastating psychological, physical, and cognitive consequences of long COVID (LC). UK guidelines recommend that LC symptoms be managed pragmatically with holistic support for patients’ biopsychosocial needs, including psychological, emotional, and physical health. Self-management strategies, such as pacing, prioritization, and goal setting, are vital for the self-management of many LC symptoms.
Objective:
This paper describes the codevelopment and initial testing of a digital intervention combining peer support with positive psychology approaches for self-managing the physical, emotional, psychological, and cognitive challenges associated with LC. The objectives of this study were to (1) codesign an intervention with and for people with LC; (2) test the intervention and study methods; (3) measure changes in participant well-being, self-efficacy, fatigue, and loneliness; and (4) understand the types of self-management goals and strategies used by people with LC.
Methods:
The study used a pre-post, mixed methods, pragmatic, uncontrolled design. Digital intervention content was codeveloped with a lived-experience group to meet the needs uncovered during the intervention development and logic mapping phase. The resulting 8-week digital intervention, Hope Programme for Long COVID, was attended by 47 participants, who completed pre- and postprogram measures of well-being, self-efficacy, fatigue, and loneliness. Goal-setting data were extracted from the digital platform at the end of the intervention.
Results:
The recruitment rate (n=47, 83.9%) and follow-up rate (n=28, 59.6%) were encouraging. Positive mental well-being (mean difference 6.5, P<.001) and self-efficacy (mean difference 1.1, P=.009) improved from baseline to postcourse. All goals set by participants mapped onto the 5 goal-oriented domains in the taxonomy of everyday self-management strategies (TEDSS). The most frequent type of goals was related to activity strategies, followed by health behavior and internal strategies.
Conclusions:
The bespoke self-management intervention, Hope Programme for Long COVID, was well attended, and follow-up was encouraging. The sample characteristics largely mirrored those of the wider UK population with LC. Although not powered to detect statistically significant changes, the preliminary data show improvements in self-efficacy and positive mental well-being. Our next trial (ISRCTN: 11868601) will use a nonrandomized waitlist control design to further examine intervention efficacy.

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Vijay HaddaORCID Icon,Tejas M SuriORCID Icon,Hariharan Iyer,Avinash Jain,Saurabh MittalORCID Icon,Karan MadanORCID Icon,Anant MohanORCID Icon,Ashu Seith Bhalla,Girish Sindhwani,Naveen Dutt,Kavitha Venkatnarayan,Alok Nath,Sahajal DhooriaORCID Icon,Rohit Kumar,Vikas Marwah,Saurabh Karmakar,Dhruva Chaudhry,Irfan Ismail Ayub,Dharm Prakash Dwivedi,Pawan TiwariORCID Icon,Parvaiz Koul,Ajoy Kumar Behera,Puneet Saxena,Amitabha Sengupta,Prasanta R MohapatraORCID Icon,Abhishek Goyal,Devasahayam J Christopher &Randeep Guleria show less

A Delphi consensus statement for the management of post-COVID interstitial lung disease

https://doi.org/10.1080/17476348.2022.2128770

Published

30-Sep-22

Review

https://www.tandfonline.com/doi/full/10.1080/17476348.2022.2128770?scroll=top&needAccess=true

Introduction
As millions of people worldwide recover from COVID-19, a substantial proportion continue to have persistent symptoms, pulmonary function abnormalities, and radiological findings suggestive of post-COVID interstitial lung disease (ILD). To date, there is limited scientific evidence on the management of post-COVID ILD, necessitating a consensus-based approach.
Areas covered
A panel of experts in pulmonology and thoracic radiology was constituted. Key questions regarding the management of post-COVID ILD were identified. A search was performed on PubMed and EMBASE and updated till 1 March 2022. The relevant literature regarding the epidemiology, pathophysiology, diagnosis and treatment of post-COVID ILD was summarized. Subsequently, suggestions regarding the management of these patients were framed, and a consensus was obtained using the Delphi approach. Those suggestions which were approved by over 80% of the panelists were accepted. The final document was approved by all panel members.
Expert opinion
Dedicated facilities should be established for the care of patients with post-COVID ILD. Symptom screening, pulmonary function testing, and thoracic imaging have a role in the diagnosis. The pharmacologic and non-pharmacologic options for the management of post-COVID ILD are discussed. Further research into the pathophysiology and management of post-COVID ILD will improve our understanding of this condition.
Article highlights
Post-COVID interstitial lung disease (ILD) is a common sequela among patients hospitalized with acute COVID-19.
Symptom screening, pulmonary function testing, and thoracic imaging have a role in the diagnosis and follow-up for post-COVID ILD.
To date, there is limited scientific evidence on the management of post-COVID ILD.
This document uses the Delphi method to offer consensus-based suggestions on the diagnosis and management of post-COVID ILD.

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Svetlana Blitshteyn MD,Jonathan H. Whiteson MD,Benjamin Abramoff MD, MS,Alba Azola MD,Matthew N. Bartels MD, MPH,Ratna Bhavaraju-Sanka MD,Tae Chung MD,Talya K. Fleming MD,Ellen Henning PhD,Mitchell G. Miglis MD, FAAN,Sarah Sampsel MPH,Julie K. Silver MD,Jenna Tosto PT, DPT, NCS,Monica Verduzco-Gutierrez MD,David Putrino PT, PhD

Multi-disciplinary collaborative consensus guidance statement on the assessment and treatment of autonomic dysfunction in patients with post-acute sequelae of SARS-CoV-2 infection (PASC)

https://doi.org/10.1002/pmrj.12894

Published

28-Sep-22

Guidance

https://onlinelibrary.wiley.com/doi/10.1002/pmrj.12894

SUMMARY
Individuals with PASC commonly present with symptoms of autonomic dysfunction and should undergo a clinical evaluation for autonomic disorders. A comprehensive treatment program including non-pharmacologic, pharmacologic, and rehabilitative interventions is often needed to manage autonomic dysfunction and improve functional status. This guidance statement is designed to help clinicians currently treating individuals with PASC-related autonomic disorders by presenting evidence-based recommendations as well as recommendations based on the collective experience of the PASC Collaborative.
FUTURE DIRECTIONS
Although COVID vaccines may decrease the risk of PASC, breakthrough cases of COVID and subsequent PASC have been reported in fully vaccinated individuals, as well as observed in clinical practice.116, 117 It is important to note that a number of patients with PASC experience temporary or permanent improvement in symptoms after immunization with COVID vaccines.118-120 In an early post-vaccination study to assess changes in the trajectory of long COVID symptoms in adults infected with SARS-CoV-2, the incidence of symptoms decreased after both the first and second vaccination doses. This study suggests that vaccination may reduce the burden of both SARS-CoV-2 and PASC in adults.121 In contrast, a retrospective cohort study did not find COVID vaccines to be protective against PASC in breakthrough cases.122 Although further studies are needed to determine whether COVID vaccines decrease the incidence of PASC in vaccinated individuals after breakthrough infection, vaccination remains one of the most important public health measures to mitigate the pandemic.
These PASC Collaborative guidance statements are preliminary. Studies that investigate autonomic dysfunction in patients with post-COVID symptoms are needed to determine what subset of patients with PASC have autonomic dysfunction. At this time, it is unknown whether post-COVID autonomic disorders are similar to those that can arise after other viral infections or whether these represent a distinct phenotype unique to SARS-CoV-2 virus. Future studies are also needed to determine the biomarkers as well as appropriate diagnostic, prognostic, and therapeutic approaches to patients with post-COVID autonomic dysfunction. Specialized rehabilitation programs, non-pharmacologic management (including individualized dietary and exercise regimens), and pharmacologic treatment (including immunotherapy), require further investigation in clinical trials. As new studies emerge, the PASC Collaborative may require a re-evaluation of the assessment and treatment clinical recommendations in order to provide the most up-to-date evidence-based patient care for individuals with PASC.

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Laura A. Malone MD, PhD,Amanda Morrow MD,Yuxi Chen MD,Donna Curtis MD, MPH,Sarah D. de Ferranti MD, MPH,Monika Desai MD,Talya K. Fleming MD,Therese M. Giglia MD, FAHA,Trevor A. Hall PsyD, ABPdN,Ellen Henning PhD,Sneha Jadhav MD,Alicia M. Johnston MD,Dona Rani C. Kathirithamby MD,Christina Kokorelis MD,Catherine Lachenauer MD,Lilun Li MD,Henry C. Lin MD,Tran Locke MD,Carol MacArthur MD,Michelle Mann MD,Sharon A. McGrath-Morrow MD,Rowena Ng PhD,Laurie Ohlms MD,Sarah Risen MD,S. Christy Sadreameli MD, MHS,Sarah Sampsel MPH,S. Kristen Sexson Tejtel MD, PhD, MPH,Julie K. Silver MD,Tregony Simoneau MD,Rasha Srouji DNP,Sanjeev Swami MD,Souraya Torbey MD,Monica Verduzco Gutierrez MD,Cydni Nicole Williams MD, MCR,Lori Allison Zimmerman M.D.,Louise Elaine Vaz MD, MPH …

Multi-disciplinary collaborative consensus guidance statement on the assessment and treatment of postacute sequelae of SARS-CoV-2 infection (PASC) in children and adolescents

https://doi.org/10.1002/pmrj.12890

Published

28-Sep-22

Guidance

https://onlinelibrary.wiley.com/doi/10.1002/pmrj.12890

CONCLUSIONS
PASC in children and adolescents is increasing in recognition. Some children may have only one or two symptoms of PASC, whereas others may have a constellation of symptoms.86 Research is ongoing to better understand the pathogenesis behind PASC in both children and adults and optimal treatment approaches. Guidance regarding the evaluation and treatment of PASC in children and adolescents may change as further research is done to provide evidence-based recommendations, including the National Institutes of Health Recover trial.116, 117
It is important to note that not all the symptoms regarding PASC may be attributed to SARS-CoV-2 alone as recent studies have reported a high prevalence of symptoms similar to PASC in children who serve as healthy negative controls. This speaks to the impact of the pandemic as a co-contributor to some symptoms.3, 4, 118 Finally, given the demonstrated variability in COVID-19 outcomes secondary to social inequalities in health, researchers and clinicians must remain vigilant and address pediatric PASC in the context of preserving health equity, noting that particular vulnerable groups and populations may be disproportionately affected by the effects of the pandemic and systemic barriers to optimal health.

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Jennifer A. Frontera ,Lorna E. Thorpe,Naomi M. Simon,Adam de Havenon,Shadi Yaghi,Sakinah B. Sabadia,Dixon Yang,Ariane Lewis,Kara Melmed,Laura J. Balcer,Thomas Wisniewski,Steven L. Galetta

Post-acute sequelae of COVID-19 symptom phenotypes and therapeutic strategies: A prospective, observational study

https://doi.org/10.1371/journal.pone.0275274

Published

29-Sep-22

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0275274

Background
Post-acute sequelae of COVID-19 (PASC) includes a heterogeneous group of patients with variable symptomatology, who may respond to different therapeutic interventions. Identifying phenotypes of PASC and therapeutic strategies for different subgroups would be a major step forward in management.
Methods
In a prospective cohort study of patients hospitalized with COVID-19, 12-month symptoms and quantitative outcome metrics were collected. Unsupervised hierarchical cluster analyses were performed to identify patients with: (1) similar symptoms lasting ≥4 weeks after acute SARS-CoV-2 infection, and (2) similar therapeutic interventions. Logistic regression analyses were used to evaluate the association of these symptom and therapy clusters with quantitative 12-month outcome metrics (modified Rankin Scale, Barthel Index, NIH NeuroQoL).
Results
Among 242 patients, 122 (50%) reported ≥1 PASC symptom (median 3, IQR 1–5) lasting a median of 12-months (range 1–15) post-COVID diagnosis. Cluster analysis generated three symptom groups: Cluster1 had few symptoms (most commonly headache); Cluster2 had many symptoms including high levels of anxiety and depression; and Cluster3 primarily included shortness of breath, headache and cognitive symptoms. Cluster1 received few therapeutic interventions (OR 2.6, 95% CI 1.1–5.9), Cluster2 received several interventions, including antidepressants, anti-anxiety medications and psychological therapy (OR 15.7, 95% CI 4.1–59.7) and Cluster3 primarily received physical and occupational therapy (OR 3.1, 95%CI 1.3–7.1). The most severely affected patients (Symptom Cluster 2) had higher rates of disability (worse modified Rankin scores), worse NeuroQoL measures of anxiety, depression, fatigue and sleep disorder, and a higher number of stressors (all P<0.05). 100% of those who received a treatment strategy that included psychiatric therapies reported symptom improvement, compared to 97% who received primarily physical/occupational therapy, and 83% who received few interventions (P = 0.042).
Conclusions
We identified three clinically relevant PASC symptom-based phenotypes, which received different therapeutic interventions with varying response rates. These data may be helpful in tailoring individual treatment programs.

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Tamaradel Corral1Raúl FaberoGarrido2GustavoPlaza-Manzano3CésarFernández-de-las-Peñas4^MarcosNavarro-Santana5IbaiLópez-de-Uralde-Villanueva1

Home-based respiratory muscle training on quality of life and exercise tolerance in long-term post-COVID-19: Randomized controlled trial

https://doi.org/10.1016/j.rehab.2022.101709

Published

30-Sep-22

Trial

https://www.sciencedirect.com/science/article/pii/S1877065722000811

Highlights
•Respiratory muscle training increased quality of life in long-term COVID.
•Respiratory muscle training had no impact on exercise tolerance.
•Respiratory muscle training increased expiratory muscle function.
•Inspiratory and respiratory muscle training improved inspiratory muscle function.
•Inspiratory and respiratory muscle training improved lower limb muscle strength.
Abstract
Objective
To evaluate the effects of a home-based respiratory muscle training programme (inspiratory [IMT] or inspiratory/expiratory muscles [RMT]) supervised by telerehabilitation on quality of life and exercise tolerance in individuals with long-term post-COVID-19 symptoms. The secondary objective was to evaluate the effects of these programmes on respiratory muscle function, physical and lung function, and psychological state.
Methods
88 individuals with long-term symptoms of fatigue and dyspnoea after COVID-19 diagnosis were randomly (1:1 ratio) assigned to IMT, IMTsham, RMT or RMTsham groups for an 8-week intervention (40min/day, 6 times/week). Primary outcomes were quality of life (EuroQol-5D questionnaire) and exercise tolerance (Ruffier test). Secondary outcomes were respiratory muscle function (inspiratory/expiratory muscle strength; inspiratory muscle endurance), physical function (lower and upper limb strength [1-min Sit-to-Stand and handgrip force]), lung function (forced spirometry), and psychological status (anxiety/depression levels and post-traumatic stress disorder). All outcomes were measured pre-, intermediate- (4th week), and post-intervention.
Results
At post-intervention, there was a statistically significant and large (d>0.90) improvement in quality of life, but not in exercise tolerance, in the RMT group compared with the RMTsham group. Both of the real training groups produced a statistically significant and large increase in inspiratory muscle strength and endurance (d≥0.80) and in lower limb muscle strength (d≥0.77) compared with the 2 sham groups. Expiratory muscle strength and peak expiratory flow showed a statistically significant and large (d≥0.87) increase in the RMT group compared with the other 3 groups.
Conclusion
Only an 8-week supervised home-based RMT programme was effective in improving quality of life, but not exercise tolerance, in individuals with long-term post-COVID-19 symptoms. In addition, IMT and RMT programmes were effective in improving respiratory muscle function and lower limb muscle strength, but had no impact on lung function and psychological status.

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Yoonjung Kim,1 Seong Eun Kim,2 Tark Kim,3 Ki Wook Yun,4 So Hee Lee,5 Eunjung Lee,6 Jun-Won Seo,7 Young Hee Jung,8 and Yong Pil Chong9

Preliminary Guidelines for the Clinical Evaluation and Management of Long COVID

https://doi.org/10.3947/ic.2022.0141

Published

21-Jul-22

Guidelines

https://icjournal.org/search.php?where=aview&id=10.3947/ic.2022.0141&code=0086IC&vmode=FULL

Long-lasting coronavirus disease 2019 (COVID-19) symptoms beyond 12 weeks, the so-called ‘long COVID’ have been increasingly reported worldwide. Long COVID can be manifested in various forms, and there is an increasing demand for proper assessment and management. However, it is challenging when trying to determine the best-practice standards of care based on the current evidence because there is no internationally agreed clinical definition or clear treatment pathway. Therefore, the present guidelines have been drafted to provide advice on diagnosis and management based on the latest updated available evidence and the consensus of expert opinion. So far, no standard test and drug treatment can be strongly recommended for patients with long COVID because of a lack of evidence. The present guidelines provide advice based on 12 key questions, including appropriate interventions for long COVID that can be used in clinical practice. Continuous careful observation and studies related to long COVID are needed for the long-term impact of COVID-19 and proper management for long COVID to be determined.

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Grace Russell
University of the West of England
AD Thomas
University of the West of England
Alexander Nenov
University of the West of England
John T Hancock

The Influence of Molecular Hydrogen Therapies in Managing the Symptoms of Acute and Chronic COVID-19

https://doi.org/10.18103/mra.v10i9.3036

Published

20-Sep-22

Review

https://esmed.org/MRA/mra/article/view/3036

Coronavirus Infectious Disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) that emerged as a novel pathogen of global concern in the latter stages of 2019. COVID-19 is a highly contagious disease which can be transmitted through aerosol droplets and surface-to-host contact. Both symptomology and the severity of disease can vary wildly between individuals, from asymptomatic but infectious, to those that require critical care. Due to the neoteric emergence of SARS-CoV-2, current treatment strategies are not yet well developed and rely on the repurposing of such medications as antiviral, corticosteroid, immunosuppressant and oxygen (O2) therapies. However, the minimal efficacy of these interventions is concerning. In addition to the acute infection that prevails, it is estimated that up to 30% of adults who contract COVID-19 develop chronic symptoms lasting longer than 12 weeks. It is also estimated that 15% of children aged 2-16 years have developed long-lasting sequelae associated with SARS-CoV-2 infection.
According to recent clinical data, molecular hydrogen (H2) and oxy-hydrogen (H2/O2) therapies successfully remediated the debilitating effects of SARS-CoV-2 infection in adults. By acting as an effective anti-inflammatory and antioxidative agent, it is reported that H2 administration can improve recovery through abatement of the hyperinflammatory cytokine cascade and reduction of inhalation resistance in patients with mild-moderate disease symptoms.
In this review, the authors investigate the clinical and empirical evidence relating to treating the symptoms of both acute and chronic COVID-19 with H2-containing therapeutics.

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Beatriz A. Cavendish 1
Alisson Lima 1
Laiss Bertola
Leigh Charvet
Marom Bikson
Andre R. Brunoni 2
Kallene S. Vidal 2

Combination of transcranial direct current stimulation with online cognitive training improves symptoms of Post-acute Sequelae of COVID-19: A case series

https://doi.org/10.1016/j.brs.2022.09.008

Published

3-Oct-22

Study

https://www.brainstimjrnl.com/article/S1935-861X(22)00212-1/fulltext

Dear editor,
Given that there is accumulating evidence that one third of patients who develop COVID-19 experience enduring cognitive dysfunction with cumulative symptoms, there is an urgent need to develop treatment alternatives for Post-Acute Sequelae of Sars-Cov2 (PASC) [[1]]. Cross-sectional studies addressing the incidence of psychiatric and cognitive abnormalities in COVID-19 patients provided initial evidence on the occurrence of delirium, encephalopathy, persisting cognitive impairment, insomnia, psychotic and mood symptoms [[2]].
In this context, transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation intervention with potential as a PASC treatment as it modulates brain vascular function [[3]] and enhance ongoing synaptic plasticity [[4]], which can result in modulation of neural circuits underlying neurological, cognitive, and psychiatric disorders [[5]].
tDCS has been trialed in non-COVID-19 samples [[6]] and combined with cognitive tasks to boost neurorehabilitation and improve cognitive performance [[7]]. Therefore, this combination is a rational candidate for the treatment of PASC neuropsychiatric symptoms.
Here, we investigated the effects of this combined intervention in a case series of four patients with long COVID cognitive symptoms clinically evaluated using the Assessment of PASC inventory (A-PASC, Supplementary Materials Fig. 1) [[8]]. This is a pilot study that preceded an ongoing, double-blinded, randomized controlled trial comparing the effects of cognitive training combined with sham or active tDCS at University of São Paulo, Brazil.
Although this pilot study was not powered to show efficacy, several trends were observed: 1) An improvement in depression symptoms (QIDS); 2) A decrease of self-reported cognitive and emotional symptoms and functional abilities (A-PASC inventory); 3) An improvement in processing speed (FDT) and self-reported executive functioning (BDEFS); 4) An improvement in delayed and immediate recall (RAVLT).
To conclude, this case series suggest that tDCS combined with cognitive training might improve PASC cognitive symptoms, a condition with no currently available treatments. Notwithstanding, we could not exclude that this improvement occurred due to other factors, such as placebo effects, learning effects, and natural history of disease. Therefore, further randomized, controlled trials are warranted.

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Bjørn IngulfsvannHagenabAnnersLerdalbArneSøraascNils IngeLandrødRagnhildBødMilada CvancarovaSmåstuenbJacquelineBeckereJanStubberudbd

Cognitive rehabilitation in post-COVID-19 condition: A study protocol for a randomized controlled trial

https://doi.org/10.1016/j.cct.2022.106955

Published

5-Oct-22

Trial

https://www.sciencedirect.com/science/article/pii/S1551714422002816

Background
Post-COVID-19 condition is frequently comprised of persistent cognitive sequela, including deficits in attention and executive functions (EFs), which can act as a barrier for regaining pre-illness functional levels. Goal Management Training (GMT) is a cognitive rehabilitation (CR) intervention for improving attention and EFs that has received empirical support in studies of other patient groups. The present study aims to determine the efficacy of GMT for improving everyday attention and EFs in adults who experience persistent cognitive deficits after COVID-19.
Methods
This study protocol describes an open-label randomized controlled trial comparing the efficacy of GMT to a wait list control condition (WL), for improving persistent (> 2 months) cognitive sequela in post-COVID-19 condition. The study aims to recruit 240 participants aged 18 to 65 years with a history of SARS-CoV-2 infection and perceived attentional and EF difficulties in daily life. Participants will be block randomized (computer-algorithm) to either group-based GMT (n = 120) or WL (n = 120). GMT will be internet-delivered to groups of six participants in six two-hour sessions delivered once a week. The primary outcome will be the Metacognition Index of the Behavior Rating Inventory of Executive Function – Adult Version, a self-report measure assessing everyday EF difficulties, specifically metacognition, at six months post-treatment. Secondary outcomes include performance-based neurocognitive measures, and tertiary outcomes include rating scales of cognition, emotional health, quality of life, and fatigue.
Conclusion
Study findings could contribute to providing an evidence-based treatment option for symptoms that are frequent and debilitating following a prevalent condition.

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James Melrose1,2,3,*, Margaret M. Smith1

Natural and Semi-Synthetic Flavonoid Anti-SARS-CoV-2 Agents for the Treatment of Long COVID-19 Disease and Neurodegenerative Disorders of Cognitive Decline

https://doi.org/10.31083/j.fbe1404027

Published

9-Oct-22

Review

https://www.imrpress.com/journal/FBE/14/4/10.31083/j.fbe1404027/htm

The aim of this review is to highlight the beneficial attributes of flavonoids, a diverse family of widely-distributed polyphenolic phytochemicals that have beneficial cell and tissue protective properties. Phytochemicals are widely distributed in plants, herbs and shrubs used in traditional complimentary medical formulations for centuries. The bioactive components that convey beneficial medicinal effects in these complex herbal preparations are now being identified using network pharmacology and molecular docking procedures that identify their molecular targets. Flavonoids have anti-oxidant, anti-inflammatory, antiviral, antibacterial and anti-cancer properties that have inspired the development of potent multifunctional derivatised flavonoids of improved efficacy. The antiviral properties of flavonoids and the emergence of the severe acute respiratory syndrome (SARS-CoV-2) pandemic has resulted in a resurgence of interest in phytochemicals in the search for efficacious compounds that can prevent viral infection or replication, with many promising plant compounds identified. Promising semi-synthetic flavonoid derivatives have also been developed that inhibit multiple pathological neurodegenerative processes; these offer considerable promise in the treatment of diseases of cognitive decline. Clinical trials are currently being undertaken to evaluate the efficacy of dietary supplements rich in flavonoids for the treatment of virally-mediated diseases. Such trials are expected to identify flavonoids with cell and tissue protective properties that can be harnessed in biomedical applications that may serve as supportive adjunctive procedures to conventional anti-viral drug therapies against diseases such as COVID-19.

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ME

Neal C. Goldberg,Sabrina Poirier,Allison Kanas,Lisa McCorkell,Carrie Anna McGinn,Yochai Re’em,Kathi Kuehnel,Nina Muirhead,Tahlia Ruschioni,Susan Taylor-Brown &Leonard A. Jason

A new clinical challenge: supporting patients coping with the long-term effects of COVID-19

https://doi.org/10.1080/21641846.2022.2128576

Published

10-Oct-22

Article

https://www.tandfonline.com/doi/full/10.1080/21641846.2022.2128576

Mental Health Practitioners (MHPs) have a unique opportunity to provide resources and support to those suffering from Long COVID (LC), the post infectious illness that often follows an acute SARS-CoV-2 infection. In working with these individuals, MHPs can learn from the experiences of patients with another post-infectious disease known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS was once thought to be a psychologically mediated disorder caused by deconditioning and the fear of exertion following a precipitating event such as a viral infection. Research now shows that LC and ME/CFS are biomedical, multisystem, complex physiologic diseases. This article provides a framework to MHPs for the treatment of LC patients using knowledge derived from three decades of research on ME/CFS.

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Taku Harada,Kathryn Schmitz,Charles W. Helsper,Grace Campbell,Larissa Nekhlyudov

Long-COVID and long-term cancer survivorship—Shared lessons and opportunities

https://doi.org/10.1111/ecc.13712

Published

24-Sep-22

Commentary

https://onlinelibrary.wiley.com/doi/10.1111/ecc.13712

As of 2022, close to 90 million persons in the United States, 243 million persons in Europe and 585 million worldwide have been infected with the novel SARS-CoV-2 (COVID-19) virus and survived. Estimates vary but suggest that up to 50% may experience long-term sequelae, termed ‘Long-COVID’. While Long-COVID is a new condition, the phenomenon of disabling long-term effects following an illness requiring ongoing surveillance and management is not. In this commentary, we discuss how Long-COVID parallels the experiences of long-term cancer survivors, highlight shared challenges and offer opportunities to improve research and clinical care for both growing populations of patients as well as other long-term chronic, disabling conditions.

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Maha F. Alenazy 1,Haya I. Aljohar 2ORCID,Ashwag R. Alruwaili 3ORCID,Maha H. Daghestani 4,Mona A. Alonazi 5ORCID,Ranyah S. Labban 6,Afaf K. El-Ansary 7 andHanan A. Balto 8,*

Gut Microbiota Dynamics in Relation to Long-COVID-19 Syndrome: Role of Probiotics to Combat Psychiatric Complications

https://doi.org/10.3390/metabo12100912

Published

27-Sep-22

Review

https://www.mdpi.com/2218-1989/12/10/912/htm

Increasing numbers of patients who recover from COVID-19 report lasting symptoms, such as fatigue, muscle weakness, dementia, and insomnia, known collectively as post-acute COVID syndrome or long COVID. These lasting symptoms have been examined in different studies and found to influence multiple organs, sometimes resulting in life-threating conditions. In this review, these symptoms are discussed in connection to the COVID-19 and long-COVID-19 immune changes, highlighting oral and psychiatric health, as this work focuses on the gut microbiota’s link to long-COVID-19 manifestations in the liver, heart, kidney, brain, and spleen. A model of this is presented to show the biological and clinical implications of gut microbiota in SARS-CoV-2 infection and how they could possibly affect the therapeutic aspects of the disease. Probiotics can support the body’s systems in fighting viral infections. This review focuses on current knowledge about the use of probiotics as adjuvant therapies for COVID-19 patients that might help to prevent long-COVID-19 complications.

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Felipe Contreras-Briceño 1,2,3,4,*ORCID,Maximiliano Espinosa-Ramírez 1ORCID,Dmitry Rozenberg 5,6ORCID andW. Darlene Reid 7,8ORCID

Eccentric Training in Pulmonary Rehabilitation of Post-COVID-19 Patients: An Alternative for Improving the Functional Capacity, Inflammation, and Oxidative Stress

https://doi.org/10.3390/biology11101446

Published

1-Oct-22

Narrative Review

https://www.mdpi.com/2079-7737/11/10/1446/htm

Simple Summary
Exercise is the cornerstone of pulmonary rehabilitation (PR) programs. Although all exercise has concentric (CONC, where the muscle groups shorten to produce force) and eccentric (ECC, characterized by lengthening muscle during its muscle contraction) contractions or components, usually PR is focus on CONC as the main training modality. Data show that this exercise modality increases cardiopulmonary stress, eliciting higher ventilation and consequently exacerbating dyspnoea, been more stressful for patients with chronic respiratory diseases (e.g., COPD and interstitial lung diseases). Similarly, higher cardiopulmonary stress has been associated with more oxidative stress. This aspect has been proposed as the central pathophysiological mechanism involved in the functional limitation of post-COVID-19 patients with moderate-to-severe damage associated with SARS-CoV-2 infection and prolonged hospital stay. Thus, traditional PR programs with CONC as a primary exercise modality can exacerbate dyspnoea and leg fatigue in these patients, repercussing in early exercise intolerance and diminishing the adherence to PR. On the other hand, ECC training has increased the locomotor muscle mass without significant cardiopulmonary stress, improving functional capacity and self-autonomy. This review discusses the mechanism that supports aerobic ECC exercise as a novel alternative to conventional CONC exercise included in traditional PR for post-COVID-19 patients.
Abstract
The purpose of this narrative review is to highlight the oxidative stress induced in COVID-19 patients (SARS-CoV-2 infection), describe longstanding functional impairments, and provide the pathophysiologic rationale that supports aerobic eccentric (ECC) exercise as a novel alternative to conventional concentric (CONC) exercise for post-COVID-19 patients. Patients who recovered from moderate-to-severe COVID-19 respiratory distress demonstrate long–term functional impairment. During the acute phase, SARS-CoV-2 induces the generation of reactive oxygen species that can be amplified to a “cytokine storm”. The resultant inflammatory and oxidative stress process causes organ damage, particularly in the respiratory system, with the lungs as the tissues most susceptible to injury. The acute illness often requires a long-term hospital stay and consequent sarcopenia. Upon discharge, muscle weakness compounded by limited lung and cardiac function is often accompanied by dyspnea, myalgia, anxiety, depression, and sleep disturbance. Consequently, these patients could benefit from pulmonary rehabilitation (PR), with exercise as a critical intervention (including sessions of strength and endurance or aerobic exercises). Unfortunately, conventional CONC exercises induce significant cardiopulmonary stress and increase inflammatory and oxidative stress (OS) when performed at moderate/high intensity, which can exacerbate debilitating dyspnoea and muscle fatigue post-COVID-19. Eccentric training (ECC) is a well–tolerated alternative that improves muscle mass while mitigating cardiopulmonary stress in patients with COPD and other chronic diseases. Similar benefits could be realized in post-COVID-19 patients. Consequently, these patients could benefit from PR with exercise as a critical intervention.

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M. V. Kiselevskiy, N. Yu. Anisimova, M. I. Bilan, A. I. Usov, N. E. Ustyuzhanina, A. A. Petkevich, I. Zh. Shubina, G. E. Morozevich & N. E. Nifantiev

Prospects for the Use of Marine Sulfated Fucose-Rich Polysaccharides in Treatment and Prevention of COVID-19 and Post-COVID-19 Syndrome

https://doi.org/10.1134/S1068162022060152

Published

29-Oct-22

Review

https://link.springer.com/article/10.1134/S1068162022060152

Symptoms of the new coronavirus infection that appeared in 2019 (COVID-19) range from low fever and fatigue to acute pneumonia and multiple organ failure. The clinical picture of COVID-19 is heterogeneous and involves most physiological systems; therefore, drugs with a wide spectrum of mechanism of action are required. The choice of the treatment strategy for post-COVID-19 syndrome is still a challenge to be resolved. Polysaccharides with a high fucose content derived from seaweed and marine animals can form the basis for the subsequent development of promising agents for the treatment of COVID-19 and post-COVID-19 syndrome. This class of biopolymers is characterized by a variety of biological activities, including antiviral, antithrombotic, anticoagulant, hemo-stimulating, anti-inflammatory and immune-regulatory. Low molecular weight derivatives of these polysaccharides, as well as synthetic oligosaccharides with a sufficient amount and sulfation type may be considered as the most promising compounds due to their better bioavailability, which undoubtedly increases their therapeutic potential.

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Soha G. Elsheikh, Sally S. El-Mosallamy, Yasmin M. Fayez & Abeer M. E. Hassan

Smart stability indicating spectrophotometric methods for determination of modafinil: the promising treatment for post-covid neurological syndrome

https://doi.org/10.1186/s13065-022-00869-z

Published

21-Oct-22

Article

https://bmcchem.biomedcentral.com/articles/10.1186/s13065-022-00869-z

Modafinil (MDF) is one of the neurostimulants with a potential effect in the COVID-19 ICU ventilated patients and post-COVID neurological syndrome treatment. Four rapid, simple and cost-effective stability indicating spectrophotometric methods were used for estimation of MDF in the presence of its acidic degradation product, namely; ratio difference (RD), first derivative of the ratio spectra (1DD), mean centering (MCR) and ratio subtraction method (RS). These methods were validated according to ICH guidelines and all methods revealed a good linearity in concentration range of (5-30 µg/mL) in addition to a good accuracy and precision with mean percentage recovery of 99.97 ± 0.305 for (RD), 100.10 ± 0.560 for (1DD), 100.02 ± 0.483 for (MCR) & 99.18 ± 1.145 for (RS) method. Specificity of the proposed methods was assessed and MDF was determined in the presence of up to 80% of its acidic degradation product for RD, 1DD, MCR and RS methods. The proposed methods were successfully applied for the determination of MDF in bulk powder and its tablet dosage form with mean percentage recovery of 100.33 ± 0.915 for (RD), 100.62 ± 0.985 for (1DD), 99.70 ± 0.379 for (MCR) and 100.21 ± 0.313 for (RS) method. The results obtained were statistically compared with those of official HPLC method and showed no significant difference with relevance accuracy and precision.

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Melissa Suran, PhD, MSJ

VA Guidebook on Long COVID

https://doi.org/10.1001/jama.2022.15484

Published

25-Oct-22

Guidelines

https://jamanetwork.com/journals/jama/article-abstract/2797585

https://www.publichealth.va.gov/n-coronavirus/docs/Whole-Health-System-Approach-to-Long-COVID_080122_FINAL.pdf

The Department of Veterans Affairs (VA) published a new guidebook on caring for veterans with long COVID. Titled the Whole Health System Approach to Long COVID, the guidebook provides information about signs, symptoms, and treatments for the illness. The guidebook also includes metrics, such as surveys, to assess autonomic symptoms.

“From the first day of the pandemic, VA’s clinicians and researchers have been on the front lines—saving lives and learning how to treat COVID-19 and long COVID,” VA Secretary Denis McDonough, MSFS, said in a statement. “This guidebook packages up the best practices we’ve learned about treating long COVID, and it will help health care providers across America improve the lives of Veterans and non-Veterans alike.”

The guidebook’s whole health approach can be implemented to personalize a plan that considers individual goals, needs, and values. Moreover, this approach may help clinicians assess and manage long COVID symptoms and subsequent conditions. Clinicians can also use the whole health approach to prioritize treatment based on patient needs.

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Gita Shafiee, Tohid Arastou, Ramin Heshmat, Ahmad Reza Jamshidi, Bagher Larijani & Seyed Masoud Arzaghi

Post COVID-19 neuropsychiatric complications and therapeutic role for TNF-α inhibitors: a case series study

https://doi.org/10.1007/s40200-022-01138-5

Published

15-Oct-22

Case Series

https://link.springer.com/article/10.1007/s40200-022-01138-5

Background
The post-COVID syndrome is the various physical and neuropsychiatric symptoms after the acute phase of COVID-19. The understanding of pathophysiology of this syndrome and its treatment need to further studies. This study aimed to present three cases of neuropsychiatric symptoms after COVID-19 and effective treatments in these patients.
Case presentation
Three patients with new or progressively neuropsychiatric symptoms such as seizures, attention difficulties, insomnia, confusion and etc., were referred to our clinic about 8 months after severe COVID-19 infection. The patients were assessed with extensive workup includes a neurological exam, brain MRI, LORETA scan, and biochemical and levels of inflammatory serum markers. All patients had elevated levels of TNF-α, poor neurological exam, and abnormal reports of MRI or LORETA scan. Diagnosis of post- COVID neuropsychiatric complications was made for the patients.TNF inhibition with Adalimumab (40 mg/weekly for a month) was initiated for the patients and led to a dramatic improvement of all symptoms.
Conclusions
To our knowledge, this report is the first case series study that suggests TNF inhibitors in the treatment of post-COVID-19 syndrome, especially neuropsychological complications. However, future studies should evaluate the best therapeutic options for this syndrome.

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Clara Douin 1,*,Kevin Forton 2ORCID,Michel Lamotte 2,Alexis Gillet 2ORCID andPhilippe Van de Borne 2ORCID

Benefits of Cardio-Pulmonary Rehabilitation in Moderate to Severe Forms of COVID-19 Infection

https://doi.org/10.3390/healthcare10102044

Published

17-Oct-22

Study

https://www.mdpi.com/2227-9032/10/10/2044/htm

Our aim was to evaluate the benefits of cardio-pulmonary rehabilitation on severe to moderate COVID-19 patients. 25 discharged COVID-19 patients underwent a cardio-pulmonary test (CPET), a spirometry test and a measure of carbon monoxide lung diffusion capacity (DLCO) at the beginning of their rehabilitation program and after 23 ± 5 rehabilitation sessions. This rehabilitation program combined interval training exercises on a bike and resistance exercises for major muscle groups. We then compared their progress in rehabilitation to that obtained with cardiac patients. At the beginning of their rehabilitation program, COVID-19 patients presented a reduced physical capacity with a maximal aerobic capacity (VO2 max) at 71% of predicted value, a maximal workload at 70% of predicted value and an exercise hyperventilation measured by a higher VE/VCO2 slope. Exercise was mainly limited by muscle deconditioning. After rehabilitation, the VO2 max and maximal workload increased in COVID 19 patients by 18% and 26%, respectively. In patients with ischemic heart disease the post-rehabilitation gains in VO2 max and maximal workload were 22% and 25%, respectively. Moreover, exercise hyperventilation decreased by 10% in both groups. On the other hand, the intrinsic pulmonary function of COVID 19 patients improved following natural recovery. In conclusion, even if cardio-pulmonary rehabilitation is probably not the only parameter which explains the partial recovery of moderate to severe COVID-19 patients, it certainly helps to improve their physical capacity and reduce exercise hyperventilation.

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MeravCatalognaaEfratSassonaAmirHadannyabYoavParagaShaniZilberman-ItskovichabShaiEfratiabc

Effects of hyperbaric oxygen therapy on functional and structural connectivity in post-COVID-19 condition patients: A randomized, sham-controlled trial

https://doi.org/10.1016/j.nicl.2022.103218

Published

3-Oct-22

Trial

https://www.sciencedirect.com/science/article/pii/S2213158222002832

Highlights
•Resting state fMRI can detect longitudinal changes in post-COVID-19 patients.
•Effects of HBOT on cognitive recovery is most evident in internetwork connectivity.
•Emotional recovery correlated with alternation in the amygdala and insula networks.
•Structural efficacy enhancement of the amygdala circuit reflects lower psychiatric scores.
Abstract
Introduction
Post-COVID-19 condition refers to a range of persisting physical, neurocognitive, and neuropsychological symptoms after SARS-CoV-2 infection. Abnormalities in brain connectivity were found in recovered patients compared to non-infected controls. This study aims to evaluate the effect of hyperbaric oxygen therapy (HBOT) on brain connectivity in post-COVID-19 patients.
Methods
In this randomized, sham-controlled, double-blind trial, 73 patients were randomized to receive 40 daily sessions of HBOT (n = 37) or sham treatment (n = 36). We examined pre- and post-treatment resting-state brain functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) scans to evaluate functional and structural connectivity changes, which were correlated to cognitive and psychological distress measures.
Results
The ROI-to-ROI analysis revealed decreased internetwork connectivity in the HBOT group which was negatively correlated to improvements in attention and executive function scores (p < 0.001). Significant group-by-time interactions were demonstrated in the right hippocampal resting state function connectivity (rsFC) in the medial prefrontal cortex (PFWE = 0.002). Seed-to-voxel analysis also revealed a negative correlation in the brief symptom inventory (BSI-18) score and in the rsFC between the amygdala seed, the angular gyrus, and the primary sensory motor area (PFWE = 0.012, 0.002). Positive correlations were found between the BSI-18 score and the left insular cortex seed and FPN (angular gyrus) (PFWE < 0.0001). Tractography based structural connectivity analysis showed a significant group-by-time interaction in the fractional anisotropy (FA) of left amygdala tracts (F = 7.81, P = 0.007). The efficacy measure had significant group-by-time interactions (F = 5.98, p = 0.017) in the amygdala circuit.
Conclusions
This study indicates that HBOT improves disruptions in white matter tracts and alters the functional connectivity organization of neural pathways attributed to cognitive and emotional recovery in post-COVID-19 patients. This study also highlights the potential of structural and functional connectivity analysis as a promising treatment response monitoring tool.

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Kazuaki Imai 1,Takafumi Yamano 2,Soichiro Nishi 3,Ryushiro Nishi 3,Tatsuro Nishi 3,4,Hiroaki Tanaka 5,Toshiyuki Tsunoda 6,Shohei Yoshimoto 7,Ayaki Tanaka 8,Kenji Hiromatsu 9ORCID,Senji Shirasawa 6,Takashi Nakagawa 10 andKensuke Nishi 2,3,4,*ORCID

Epipharyngeal Abrasive Therapy (EAT) Has Potential as a Novel Method for Long COVID Treatment

https://doi.org/10.3390/v14050907

Published

27-Apr-22

Study

https://www.mdpi.com/1999-4915/14/5/907/htm

COVID-19 often causes sequelae after initial recovery, referred to collectively as long COVID. Long COVID is considered to be caused by the persistence of chronic inflammation after acute COVID-19 infection. We found that all long COVID patients had residual inflammation in the epipharynx, an important site of coronavirus replication, and some long COVID symptoms are similar to those associated with chronic epipharyngitis. Epipharyngeal abrasive therapy (EAT) is a treatment for chronic epipharyngitis in Japan that involves applying zinc chloride as an anti-inflammatory agent to the epipharyngeal mucosa. In this study, we evaluated the efficacy of EAT for the treatment of long COVID. The subjects in this study were 58 patients with long COVID who were treated with EAT in the outpatient department once a week for one month (mean age = 38.4 ± 12.9 years). The intensities of fatigue, headache, and attention disorder, which are reported as frequent symptoms of long COVID, were assessed before and after EAT using the visual analog scale (VAS). EAT reduced inflammation in the epipharynx and significantly improved the intensity of fatigue, headache, and attention disorder, which may be related to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These results suggest that EAT has potential as a novel method for long COVID treatment.

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Jessica DeMars, Darren A. Brown, Ippokratis Angelidis, Fiona Jones, Francis McGuire, Kelly K. O’Brien, Daria Oller, Sue Pemberton, Rachel Tarrant, Monica Verduzco-Gutierrez & Douglas P. Gross

What is Safe Long COVID Rehabilitation?

https://doi.org/10.1007/s10926-022-10075-2

Published

31-Oct-22

Editorial

https://link.springer.com/article/10.1007/s10926-022-10075-2

Long COVID is a term coined and preferred by people with the condition that describes persistent effects of Coronavirus Disease (COVID-19) [1]. Long COVID is known by other names including “Post COVID-19 Condition” (World Health Organization (WHO)[2] and “Post-Acute Sequelae of COVID-19” (United States). Long COVID is estimated to affect more than 145 million people around the globe[3] and results in wide diversity of symptoms,[4] episodic disability,[5] reduced quality of life,[6] and work loss,[7] irrespective of hospitalisation or acute disease severity [8]. Improved understanding of appropriate health care and rehabilitation interventions to reduce the burden of Long COVID have been identified as an international research priority.[9].
In September 2022, the patient-led association Long COVID Physio organized the two-day online Long COVID Physio International Forum, bringing lived experiences to Long COVID, disability, rehabilitation, and research. Long COVID Physio is an international, patient-led association of physiotherapists (physical therapists) living with Long COVID and allies, working internationally across peer support, education, research, and advocacy [10]. At the Forum, a discussion session was held to address the question, “What is Safe Long COVID Rehabilitation?” This topic was of critical importance given that some have experienced complications such as acute events, symptom exacerbation, or deterioration following traditional approaches to rehabilitation (i.e., involving progressive loading, physical or cognitive activity, or exercise), as well as perceived lack of support from health care providers who at times question the validity of symptom reports.
The discussion session involved people living with Long COVID, clinicians, and researchers with expertise and experiences related to Long COVID rehabilitation. The 10 speakers involved in this session met in advance of the Forum to share experiences and ideas, identify potential themes for discussion, and deliberate proposed recommendations. These were then presented to the international community at the Forum where themes and recommendations were discussed, debated, solidified, and are presented in this editorial (summary available in Table 1).
1) Safe Long COVID rehabilitation should include identifying red flags or complications where commencing rehabilitation could cause an acute event or deterioration.
2) Safe Long COVID rehabilitation should be personalized.
3) Safe Long COVID rehabilitation should be founded within accurate expectations.
4) Long COVID rehabilitation should be psychologically safe and supportive.

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Mohanakrishnan Sathyamoorthy, Rajkumar Sevak, Monica Verduzco-Gutierrez, Juan Cabrera, Marielisa Lopez and Sachin A Shah

Abstract 14980: Enhanced External Counterpulsation Improves Cognitive Function in Long Covid Patients

Published

30-Oct-22

Study

https://www.ahajournals.org/doi/abs/10.1161/circ.146.suppl_1.14980

INTRODUCTION: Enhanced External Counterpulsation (EECP) has been described to help Long Covid related cardiovascular (e.g. chest pain, fatigue) and neurocognitive (e.g. brain fog) symptoms. We sought to determine whether EECP improves cognitive function.
Methods: A retrospective evaluation of a contemporary consecutive patient cohort referred to Flow Therapy for management of Long Covid. All patients subjectively reporting brain fog were assessed using the BrainCheck tool to determine degree of cognitive impairment pre- and post EECP therapy. BrainCheck is an FDA-approved, web-based battery of standardized neuropsychological tests that includes the Trail Making Test (Trails A, Trails B) for assessing executive function (cognitive flexibility), the Digit Symbol Substitution Test (DSST) for assessing attention and processing speed, the Stroop Test for assessing executive function (response inhibition), and the List Learning Test for immediate/delayed verbal memory evaluation. BrainCheck scores have a normative mean of 100±15 with a clinically meaningful change ranging from 12-21 depending on age. Change from baseline to post-EECP were assessed using the paired student’s t-test.
Results: A total of 51 Long Covid patients were included (49.3±11.0 years, 60.8% female, 22% had CAD) with the average duration since Covid diagnosis being 9.9±6.1months. No patients were excluded. All patients completed 25-35 sessions of EECP. Baseline BrainCheck composite score was 88.0±22.1 which significantly improved to 100.1±16.4 post-EECP (+11.9±18.7, p<0.001). When limiting to baseline score under 85 (n=20; baseline average 66.7±17.6) the improvement was +26.0±20.9 (p<0.001). EECP therapy improved the patients’ performance across cognitive domains, as indicated by significant enhancements in scores from baseline in Trails A (+6.1±19.7), Trails B (+5.0±11.8), DSST (+12.9±24.1) and Stroop Test (+11.2±19.1) (all p-values<0.05).
Conclusion: This is the first evaluation showing significant improvement in Long Covid related cognitive impairment post-EECP therapy. Further study is needed to determine if the mechanistic basis may include EECP induced improved cerebral perfusion, change in endothelial function, or a yet unelucidated pathway.

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Simon Décary,corresponding author a Wouter De Groote, b Chiara Arienti, c Carlotte Kiekens, d Paolo Boldrini, e Stefano Giuseppe Lazzarini, c Michèle Dugas, f Théo Stefan, f Léa Langlois, f Frédérique Daigle, a Florian Naye, a Annie LeBlanc, f and Stefano Negrini g

Scoping review of rehabilitation care models for post COVID-19 condition

https://doi.org/10.2471%2FBLT.22.288105

Published

3-Oct-22

Review

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9589389/

Objective
To systematically map the current evidence about the characteristics of health systems, providers and patients to design rehabilitation care for post coronavirus disease 2019 (COVID-19) condition.
Methods
We conducted a scoping review by searching the databases: MEDLINE®, Embase®, Web of Science, Cochrane COVID-19 Registry and Cochrane Central Register of Controlled Trials, from inception to 22 April 2022. The search strategy included terms related to (i) post COVID-19 condition and other currently known terminologies; (ii) care models and pathways; and (iii) rehabilitation. We applied no language or study design restrictions. Two pairs of researchers independently screened title, abstracts and full-text articles and extracted data. We charted the evidence according to five topics: (i) care model components and functions; (ii) safe delivery of rehabilitation; (iii) referral principles; (iv) service delivery settings; and (v) health-care professionals.
Findings
We screened 13 753 titles and abstracts, read 154 full-text articles, and included 37 articles. The current evidence is conceptual and expert based. Care model components included multidisciplinary teams, continuity or coordination of care, people-centred care and shared decision-making between clinicians and patients. Care model functions included standardized symptoms assessment, telehealth and virtual care and follow-up system. Rehabilitation services were integrated at all levels of a health system from primary care to tertiary hospital-based care. Health-care workers delivering services within a multidisciplinary team included mostly physiotherapists, occupational therapists and psychologists.
Conclusion
Key policy messages include implementing a multilevel and multiprofessional model; leveraging country health systems’ strengths and learning from other conditions; financing rehabilitation research providing standardized outcomes; and guidance to increase patient safety.

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Kristoffer S.HansenabTrine H.MogensenabJaneAgergaardaBeritSchiøttz-ChristensenacLarsØstergaardabLine K.VibholmaeSteffenLethabde

High-dose coenzyme Q10 therapy versus placebo in patients with post COVID-19 condition: A randomized, phase 2, crossover trial

https://doi.org/10.1016/j.lanepe.2022.100539

Published

2-Nov-22

Trial

https://www.sciencedirect.com/science/article/pii/S2666776222002356

Background
Post COVID-19 condition (PCC) is defined as symptoms lasting more than 12 weeks after developing COVID-19. Evidence of mitochondrial dysfunction has been reported in peripheral blood mononuclear cells obtained from patients with COVID-19. We hypothesized that PCC is caused by prolonged mitochondrial dysfunction. Given that coenzyme Q10 (CoQ10) can improve mitochondrial function, we examined whether high-dose CoQ10 can reduce the number and/or severity of PCC-related symptoms.
Methods
In this placebo-controlled, double-blind, 2 × 2 crossover interventional trial, participants were recruited from two centres at Aarhus University Hospital and Gødstrup Hospital, Denmark. They were randomly assigned to receive either oral capsules of CoQ10 in a dose of 500 mg/day or placebo for 6 weeks, with crossover treatment after a 4-week washout period. The ED-5Q and a PCC-symptom specific questionnaire were completed by the participants at 5 visits during the 20-week study period. The primary endpoint was the change in the number and/or severity of PCC-related symptoms after the 6-week intervention compared to placebo. Participants who completed the two-dosing period were included in the primary analysis, while all participants receiving one dose were included in safety assessment.
Findings
From May 25th, 2021, to September 22nd, 2021, 121 participants underwent randomization, and 119 completed both dosing periods – 59 and 60 in group A and B, respectively. At baseline, the mean PCC-related symptom score was 43.06 (95% CI: 40.18; 45.94), and the mean EQ-5D health index was 0.66 (95% CI: 0.64; 0.68). The difference between CoQ10 and placebo was not significant with respect to either the change in EQ-5D health index (with a mean difference of 0.01; 95% CI: −0.02; 0.04; p = 0.45) or the change in PCC-related symptom score (with a mean difference of −1.18; 95% CI: −3.54; 1.17; p = 0.32).
Interpretation
Based on self-reported data, CoQ10 treatment does not appear to significantly reduce the number or severity of PCC-related symptoms when compared to placebo. However, we observed a significant spontaneous improvement on both scores regardless of treatment during 20 weeks observation.

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Hythem Sidky, View ORCID ProfileDavid K. Sahner, View ORCID ProfileAndrew T. Girvin, View ORCID ProfileNathan Hotaling, Sam G. Michael, Michael G. Kurilla, Ken Gersing the N3C consortium

Assessing the Effect of Selective Serotonin Reuptake Inhibitors in the Prevention of Post-Acute Sequelae of COVID-19

https://doi.org/10.1101/2022.11.09.22282142

pre-print

10-Nov-22

Study

https://www.medrxiv.org/content/10.1101/2022.11.09.22282142v1.full-text

Importance Post-acute sequelae of COVID-19 (PASC) produce significant morbidity, prompting evaluation of interventions that might lower risk. Selective serotonin reuptake inhibitors (SSRIs) potentially could modulate risk of PASC via their central hypothesized immunomodulatory, and/or antiplatelet properties and therefore have been hypothesized to be of potential benefit in patients with PASC, although clinical data are lacking.
Objectives The main objective was to evaluate whether SSRIs with agonist activity at the sigma-1 receptor lower the risk of PASC, since agonism at this receptor may serve as a mechanism by which SSRIs attenuate an inflammatory response. A secondary objective was to determine whether potential benefit could be traced to sigma-1 agonism by evaluating the risk of PASC among recipients of SSRIs that are not S1R agonists.
Design Retrospective study leveraging real-world clinical data within the National COVID Cohort Collaborative (N3C), a large centralized multi-institutional de-identified EHR database. Presumed PASC was defined based on a computable PASC phenotype trained on the U09.9 ICD-10 diagnosis code to more comprehensively identify patients likely to have the condition, since the ICD code has come into wide-spread use only recently.
Setting Population-based study at US medical centers.
Participants Adults (≥ 18 years of age) with a confirmed COVID-19 diagnosis date between October 1, 2021 and April 7, 2022 and at least one follow up visit 45 days post-diagnosis. Of the 17 933 patients identified, 2021 were exposed at baseline to a S1R agonist SSRI, 1328 to a non-S1R agonist SSRI, and 14 584 to neither.
Exposures Exposure at baseline (at or prior to COVID-19 diagnosis) to an SSRI with documented or presumed agonist activity at the S1R (fluvoxamine, fluoxetine, escitalopram, or citalopram), an SSRI without agonist activity at S1R (sertraline, an antagonist, or paroxetine, which does not appreciably bind to the S1R), or none of these agents.
Main Outcome and Measurement Development of PASC based on a previously validated XGBoost-trained algorithm. Using inverse probability weighting and Poisson regression, relative risk (RR) of PASC was assessed.
Results A 26% reduction in the RR of PASC (0.74 [95% CI, 0.63-0.88]; P = 5 × 10−4) was seen among patients who received an S1R agonist SSRI compared to SSRI unexposed patients and a 25% reduction in the RR of PASC was seen among those receiving an SSRI without S1R agonist activity (0.75 [95% CI, 0.62 - 0.90]; P = 0.003) compared to SSRI unexposed patients.
Conclusions and Relevance SSRIs with and without reported agonist activity at the S1R were associated with a significant decrease in the risk of PASC. Future prospective studies are warranted.
Question Do Selective Serotonin Reuptake Inhibitors with and without agonist activity at the sigma-1 receptor (S1R) prevent Post-Acute Sequelae of COVID-19?
Findings In this retrospective study leveraging real-world clinical data that included 17 933 patients, a 28% reduction in risk of PASC was observed for S1R agonist SSRIs and a 25% reduction in risk of PASC was observed for non-S1R agonist SSRIs, both versus controls, using a computable phenotype to define PASC.
Meaning SSRIs may play a role in managing the long term disease burden of COVID-19. Future prospective studies are warranted to confirm these findings and evaluate potential mechanisms of action.

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Ying Jie Chee,Bingwen Eugene Fan,Barnaby Edward Young,Rinkoo Dalan,David Chien Lye

Clinical trials on the pharmacological treatment of long COVID: a systematic review

https://doi.org/10.1002/jmv.28289

Published

8-Nov-22

Review

https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.28289

Background
The post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC), also known as post-acute coronavirus disease 19 (COVID-19) or the long COVID syndrome (long COVID) is an emerging public health concern. A substantial proportion of individuals may remain symptomatic months after initial recovery. An updated review of published and ongoing trials focusing on managing long COVID will help identify gaps and address the unmet needs of patients suffering from this potentially debilitating syndrome.
Methods
A comprehensive literature search was conducted on the international databases and clinical trial registries from inception to 31 July 2022.
Results
This review included 6 published trials and 54 trial registration records. There is significant heterogeneity in the characterization of long COVID and ascertainment of primary outcomes. Most of the trials are focused on individual symptoms of long COVID or isolated organ dysfunction, classified according to cardiovascular, respiratory and functional capacity, neurological and psychological, fatigue, and olfactory dysfunction. Most of the interventions are related to the mechanisms causing the individual symptoms. Although the 6 published trials showed significant improvement in the symptoms or organ dysfunction studied, these initial studies lack internal and external validity limiting the generalizability.
Conclusions
This review provides an update of the pharmacological agents that could be used to treat long COVID. Further standardization of the diagnostic criteria, inclusion of participants with concomitant chronic cardiometabolic diseases and standardization of outcomes will be essential in future clinical trials.

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NICE

COVID-19 rapid guideline: managing the longterm effects of COVID-19

Published

Guidelines

https://www.nice.org.uk/guidance/ng188/resources/covid19-rapid-guideline-managing-the-longterm-effects-of-covid19-pdf-51035515742

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VivianaVersaceaPaolaOrtelliaSabrinaDeziaDavideFerrazzoliaAlessiaAlibardiaIleniaBoniniaMichaelEnglbRobertoMaestricMartinaAssognadValentinaAjelloeElkePucks-FaesfLeopoldSaltuariaLucaSebastianelliaMarkusKoflerf1GiacomoKochdg1

Co-Ultramicronized Palmitoylethanolamide/Luteolin normalizes GABAB-ergic activity and cortical plasticity in long COVID-19 syndrome

https://doi.org/10.1016/j.clinph.2022.10.017

Published

11-Nov-22

Study

https://www.sciencedirect.com/science/article/pii/S1388245722009385

Highlights
•Long Covid patients with fatigue and cognitive problems show impairment of cortical GABAB activity and reduced plasticity in primary motor cortex.
•Co-ultramicronized palmitoylethanolamide with luteolin (PEA-LUT) 700+70 mg bid for 8 weeks restores GABAB neurotransmission and cortical plasticity.
•PEA-LUT is a candidate for the treatment of long Covid patients.
Abstract
Objective
Transcranial magnetic stimulation (TMS) studies showed that patients with cognitive dysfunction and fatigue after COVID-19 exhibit impaired cortical GABAB-ergic activity, as revealed by reduced long-interval intracortical inhibition (LICI).
Aim of this study was to test the effects of co-ultramicronized palmitoylethanolamide/luteolin (PEA-LUT), an endocannabinoid-like mediator able to enhance GABA-ergic transmission and to reduce neuroinflammation, on LICI.
Methods
Thirty-nine patients (26 females, mean age 49.9 ± 11.4 years, mean time from infection 296.7 ± 112.3 days) suffering from persistent cognitive difficulties and fatigue after mild COVID-19 were randomly assigned to receive either PEA-LUT 700mg + 70mg or PLACEBO, administered orally bid for eight weeks. The day before (PRE) and at the end of the treatment (POST), they underwent TMS protocols to assess LICI. We further evaluate short-latency afferent inhibition (SAI) and long-term potentiation (LTP)-like cortical plasticity.
Results
Patients treated with PEA-LUT but not with PLACEBO showed a significant increase of LICI and LTP-like cortical plasticity. SAI remained unaffected.
Conclusions
Eight weeks of treatment with PEA-LUT restore GABAB activity and cortical plasticity in long Covid patients.
Significance
This study confirms altered physiology of the motor cortex in long Covid and indicates PEA-LUT as a candidate for the treatment of this post-viral condition.

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DaniloBuonsenso

Pharmacological trials for long COVID: First light at the end of the tunnel

https://doi.org/10.1016/j.lanepe.2022.100544

Published

10-Nov-22

Article

https://www.sciencedirect.com/science/article/pii/S266677622200240X?via%3Dihub

Fourth, it is unlikely that a single intervention can be effective in treating such a complex systemic condition. Recent research considers long COVID to be a complex disease in which multiple different mechanisms triggered by the initial infection in a susceptible host, may play significant roles.8 Indeed, immunological imbalances, chronic endothelitis with circulating micro-clots, and intestinal dysbiosis have been documented in patients with long COVID.8 Therefore, it is crucial that trials involving a multipharmacological approach are implemented.
Finally, with the increasing number of cases different phenotypes of long COVID have been identified,7 as has also been described in Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS),9 a similar post-viral condition. It is possible that patients with specific phenotypes of long COVID (e.g. those with prevalent cardio-respiratory, gastrointestinal, musculoskeletal or neurocognitive impairments) may benefit from different interventions, and therefore trials should focus on defining better inclusion criteria to select patients according to their predominant symptomatology.
Hopefully, this trial will open a new era in long COVID care, which will probably also indirectly benefit the millions of neglected patients with ME/CFS. Importantly, there is clear evidence that long COVID can also affect children, although it is less frequent and usually less severe compared to adult long COVID, and efforts should be made to develop similar trials in children.7,10
The huge positive medical and psychological impact that trials can have on the long COVID community, will hopefully lead governments, public and private funders, and policy makers, to follow the path opened by Hansen and colleagues to conduct pharmacological trials for patients with Long Covid.

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SB Mistry1, AK Banerjee2

‘Endgame’ – Long term impacts of COVID-19
P229 Cardiopulmonary exercise testing in patients with long covid

http://dx.doi.org/10.1136/thorax-2022-BTSabstracts.361

Published

11-Nov-22

Trial

https://thorax.bmj.com/content/77/Suppl_1/A206.abstract

Objective Examine the relationship between symptoms and exercise physiological parameters in patients with long covid.
Methods Patients with long covid symptoms 6–12 months after covid19 infection referred to the long covid clinic were invited for Cardiopulmonary Exercise Testing (CPET). None had required ventilatory support during covid19 infection. All patients had normal transthoracic echocardiograms and normal resting flow-volume curves and gas transfer measurements. All patients underwent standard cycle ergometer symptom-limited CPET. Treatment guided by the CPET was offered and follow-up CPET was performed at 3 months.
Results 32 patients had a first CPET. The commonest symptoms were breathlessness (30/32), fatigue (26/32), cough (7/32), ‘brain fog’ (6/32) and chest pain (5/32). The main CPET physiological abnormalities were a borderline low peak oxygen uptake (mean 82.5% predicted), a low anaerobic threshold (AT, mean 47.6% of predicted maximal oxygen uptake) and a low oxygen uptake/work rate slope (mean 9.4 ml/min/W). The oxygen pulse curve flattened early in exercise, but peak oxygen pulse was normal (mean 88.9%).
20 patients underwent a second CPET. 14 patients had improved symptoms: breathlessness (11/20), fatigue (9/20), cough (2/20), ‘brain fog’ (3/20) and chest pain (0/20). Symptom improvement was associated with a rise in peak oxygen uptake (to mean 85.3% predicted) and oxygen pulse (to mean 94.1% predicted) although both remained within the normal range. The AT remained low (mean 46.4% predicted maximal oxygen uptake). The ventilatory equivalent for carbon dioxide (VE/VCO2) was normal 28.6 L/L at AT.
6 patients with unchanged symptoms had a reduction in oxygen pulse to mean 81.5% predicted compared to the first CPET but a rise in VE/VCO2 to 33.7 L/L at AT.
Conclusions
Long covid is associated with impaired peak oxygen uptake, AT and oxygen pulse. This suggests an oxygen delivery or uptake disorder or deconditioning. The transthoracic echocardiograms were normal suggesting a disorder at the muscle level.
A targeted treatment programme based on CPET improves symptoms and physiological parameters in long covid patients.
ConclusionsPatients with unchanged symptoms after 3 months of treatment had persistent physiological abnormalities but appeared to develop features of dysfunctional breathing syndrome.

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Pinar Mesci ,Janaina S. de Souza ,Laura Martin-Sancho ,Angela Macia ,Aurian Saleh,Xin Yin,Cedric Snethlage,Jason W. Adams,Simoni H. Avansini,Roberto H. Herai,Angels Almenar-Queralt,Yuan Pu,Ryan A. Szeto,Gabriela Goldberg,Patrick T. Bruck,Fabio Papes,Sumit K. Chanda,Alysson R. Muotri

SARS-CoV-2 infects human brain organoids causing cell death and loss of synapses that can be rescued by treatment with Sofosbuvir

https://doi.org/10.1371/journal.pbio.3001845

Published

3-Nov-22

Study

https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001845

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which was rapidly declared a pandemic by the World Health Organization (WHO). Early clinical symptomatology focused mainly on respiratory illnesses. However, a variety of neurological manifestations in both adults and newborns are now well-documented. To experimentally determine whether SARS-CoV-2 could replicate in and affect human brain cells, we infected iPSC-derived human brain organoids. Here, we show that SARS-CoV-2 can productively replicate and promote death of neural cells, including cortical neurons. This phenotype was accompanied by loss of excitatory synapses in neurons. Notably, we found that the U.S. Food and Drug Administration (FDA)-approved antiviral Sofosbuvir was able to inhibit SARS-CoV-2 replication and rescued these neuronal alterations in infected brain organoids. Given the urgent need for readily available antivirals, these results provide a cellular basis supporting repurposed antivirals as a strategic treatment to alleviate neurocytological defects that may underlie COVID-19- related neurological symptoms.

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D Boiskin, G Jayasekera

P220 Thoracic mobilisation techniques combined with stretches improves thoracic compliance and respiratory rate in long COVID

http://dx.doi.org/10.1136/thorax-2022-BTSabstracts.352

Published

11-Nov-22

Study

https://thorax.bmj.com/content/77/Suppl_1/A201.2.abstract

Background A number of patients with COVID-19 experience prolonged symptoms, known as ‘Long COVID’. Fatigue, dyspnoea and chest wall tightness are common symptoms. These symptoms limit exercise tolerance and cause anxiety. They require thorough and costly investigations that do not always provide a pathway to traditional treatments. We present the impact of thoracic mobilisation, a combination of stretches and general advice on abdominal breathing on long COVID symptoms.
Methods Consecutive adult long COVID patients attending a general respiratory physiotherapy clinic with breathlessness and chest wall tightness were included. All patients were assessed for thoracic expansion using a cloth tape, measuring at T6 level from resting expiration to maximum inspiration. Resting respiratory rate (RR) was also measured as breaths per minute (bpm). All patients were then treated with a single application of thoracic mobilisation techniques (muscle energy techniques and/or rib stacking) and combinations of muscle stretches including serratus anterior, pectoralis minor and diaphragm stretches. General advice regarding abdominal breathing was also demonstrated.
Results Thirty four consecutive long COVID patients were included (mean age 52 y, 16♂). Nine patients (26%) had pre-existing respiratory co-morbidities including asthma, COPD and sleep-disordered breathing and 12 patients (35%) had no past medical history. Prior to intervention mean thoracic expansion was 1.92 cm (±1.15) and mean RR was 17.6 bpm (±5.1). After intervention, thoracic expansion improved to 3.89 cm (±1.32) and RR to 11.2 bpm (±4.6). There were significant improvements in both thoracic expansion and respiratory rate (p<0.0001).
Conclusion Normal thoracic expansion is approximately 3.5 – 7 cm. This group of long COVID patients displayed suboptimal thoracic expansion at T6. This appears to have had an effect on resting respiratory rate. Post mobilisation both thoracic expansion and resting respiratory rate improved. This is likely due to improved thoracic compliance with mobilisations and stretches, reducing the work of breathing in these patients. The addition of simple breathing advice, rather than longer breathing re-education sessions helped to further reduce and correct respiratory rate.
A single application of thoracic mobilisation techniques combined with stretches and simple advice on breathing can improve thoracic expansion and resting respiratory rate in long COVID.

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J Gallois1, N McWirter2, A Windith2, D Barber1, S Pilsworth1, D Wat1

P225 Pulmonary Rehabilitation in Long COVID – The impact of social deprivation and treatment delay on outcomes

http://dx.doi.org/10.1136/thorax-2022-BTSabstracts.357

Published

11-Nov-22

Study

https://thorax.bmj.com/content/77/Suppl_1/A204.1.abstract

Introduction Post COVID-19 syndrome (Long COVID) is a new and emerging condition which affects up to 2.2 million patients in the UK as of April 2022. Physical deconditioning is a hallmark of Long COVID. Pulmonary Rehabilitation (PR) is a well-established treatment for many chronic respiratory diseases to improve physical conditioning. Delays in starting PR and socioeconomic factors could play a role in completion rate and efficacy. The validity of PR in Post COVID-19 Syndrome has not yet been clearly defined.
Methods We performed a retrospective observational study of patients undergoing PR between June 2020 and April 2021 for Post Covid-19 Syndrome to evaluate the change in exercise tolerance, as well as the effects of the Index of Multiple Deprivation (IMD) score and delay between infection and PR on patients’ outcomes.
Completion was defined as attainment of patient’s pre-PR defined personal goals. Pre- and Post-PR 6-minute Walk test (6MWT) results were used to measure exercise tolerance.
Results 86 patients participated in PR during the study period with 30 (34.9%) patients completing the program with a mean age of 59 years. The mean number of sessions attended was 10.6 (range 2–19). The number of sessions did not correlate with improvement in 6MWT. Completion of PR was associated with a statistically significant improvement of 6MWT distance (figure 1) using Wilcoxon rank test (p < 0.001). The mean delay between infection and starting PR was 200 days. IMD decile and time between diagnosis of COVID infection and starting PR did not have any influence on the change in 6MWT results.
Conclusions This study is a real-world delivery of PR in patients with Post COVID-19 syndrome, illustrating the improvements in physical conditioning. Unlike previous studies in the COPD population, socioeconomic status and the delays in starting PR did not affect the outcome of PR.1 As such this PR should be offered to any eligible patients following COVID-19 infection to improve their physical fitness.

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MA Faghy1, REM Ashton1, R Owen1, J Yates1, C Thomas1, T Maden-Wilkinson2, S Kumar3, R Gururaj3, C Ozemek4, R Arena4, T Bewick5

P227 Reduced respiratory muscle strength, lung function, and functional status and symptomology in patients referred to Long COVID clinics, an observational cohort analysis

http://dx.doi.org/10.1136/thorax-2022-BTSabstracts.359

Published

11-Nov-22

Study

https://thorax.bmj.com/content/77/Suppl_1/A205.1.abstract

Introduction One in ten people will develop Long COVID (LC) following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite broad-ranging and episodic symptomology, there are no data that demonstrate changes in functional status (FS), respiratory muscle strength and lung function over time. We conducted a sixteen-week cohort observation of LC patients to determine changes in FS, respiratory muscle strength and lung function.
Method Sixty-six patients (n=48 females, mean age 51 ± 10 years, n=8 hospitalised, mean time post-infection 6.2 ± 1.8 months) were recruited from LC clinics in the United Kingdom (CPMS ID: 52331). Patients completed five face-to-face visits (day 0, 28, 56, 84 and 110 ± 3 days) and bi-weekly telephone consultations (day 14, 42, 70 and 98 ± 3 days). FS was assessed via the post-COVID functional status scale (PCFS) and the six-minute walk test (6MWT). Maximum inspiratory (MIP) and expiratory (MEP) respiratory muscle pressure and lung function (forced vital capacity (FVC) and forced expired volume in one second (FEV1) were assessed during face-to-face visits according to published standards.
Results PCFS was 2.7 ± 0.4 AU, P=0.02 at baseline and improved at 16-weeks (2.1 ±1.1 AU) and still highlighted impaired FS. 6MWT was 322 ± 133 meters at baseline and improved at 16 weeks (430 ± 150 meters, P<0.01) but remained lower than normative values for healthy age-matched controls. MIP was 77 ± 21 cmH2O at baseline (86% predicted) and was unchanged post 16 weeks (88 ± 25 cmH2O, 92% predicted, P>0.05). Baseline MEP was 115 ± 41 cmH2O (96% and was unchanged post-16-weeks (119 ± 48 cmH2O, 92% predicted, P>0.05). Lung function data were below predicted values and unchanged over 16 weeks (baseline FVC: 3.10 ± 0.53 L.s-1, 72% predicted, post 16 weeks: 3.16 ± 0.34 L.s-1, 73% predicted, P>0.05 and baseline FEV1: 2.68 ± 0.39 L.s-1, 85% predicted, post 16 weeks: 2.75 ± 0.36 L.s-1, 85% predicted).
Conclusion LC patients demonstrate reduced respiratory muscle strength and lung function which could be associated with reduced FS and should be addressed via specific rehabilitation approaches.

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Daniel P. Cardinali 1,Gregory M. Brown 2 andSeithikurippu R. Pandi-Perumal 3,*ORCID

Possible Application of Melatonin in Long COVID

https://doi.org/10.3390/biom12111646

Published

7-Nov-22

Review

https://www.mdpi.com/2218-273X/12/11/1646

Clinical sequelae and symptoms for a considerable number of COVID-19 patients can linger for months beyond the acute stage of SARS-CoV-2 infection, “long COVID”. Among the long-term consequences of SARS-CoV-2 infection, cognitive issues (especially memory loss or “brain fog”), chronic fatigue, myalgia, and muscular weakness resembling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are of importance. Melatonin may be particularly effective at reducing the signs and symptoms of SARS-CoV-2 infection due to its functions as an antioxidant, anti-inflammatory, and immuno-modulatory agent. Melatonin is also a chronobiotic medication effective in treating delirium and restoring the circadian imbalance seen in COVID patients in the intensive care unit. Additionally, as a cytoprotector, melatonin aids in the prevention of several COVID-19 comorbidities, including diabetes, metabolic syndrome, and ischemic and non-ischemic cardiovascular diseases. This narrative review discusses the application of melatonin as a neuroprotective agent to control cognitive deterioration (“brain fog”) and pain in the ME/CFS syndrome-like documented in long COVID. Further studies on the therapeutic use of melatonin in the neurological sequelae of SARS-CoV-2 infection are warranted.

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PattonMcClellandM.D.aBruceGrayD.O.

Cilostazol as a Treatment for COVID Toes: A Case Report

https://doi.org/10.1016/j.avsg.2022.10.013

Published

25-Nov-22

Case Report

https://www.sciencedirect.com/science/article/pii/S0890509622007348

Highlights
1)Pictorial diagnosis of COVID toes
2)Simple medication to improve symptomatology
3)The association of a viral illness with a “vascular vasospastic condition”
Abstract
During the Coronavirus Disease 2019 (COVID-19) pandemic, skin lesions resembling those seen in pernio (chilblains) have been observed in patients with COVID-19 infection. The term “COVID toes” has been used when there is toe involvement. We describe the case of a fully vaccinated, 56-year-old woman with no prior diagnosis of COVID-19 who developed pernio-like lesions many months after being vaccinated. Her skin lesions resolved after treatment with cilostazol, suggesting that this medication may be a viable treatment for pernio in the setting of COVID-19 infection.

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ArmanFesharaki-ZadehabNaomiLoweaAmy F.T.Arnstenc

Clinical experience with the α2A-adrenoceptor agonist, guanfacine, and N-acetylcysteine for the treatment of cognitive deficits in “Long-COVID19”

https://doi.org/10.1016/j.nerep.2022.100154

Published

25-Nov-22

Study

https://www.sciencedirect.com/science/article/pii/S2667257X22001000

Highlights
•Combined treatment with the α2A-adrenoceptor agonist, guanfacine, and the anti-oxidant, N-acetylcysteine (NAC) reduced the cognitive deficits (“brain fog”) associated with long-COVID19 in eight out of twelve patients.
•Two patients stopped treatment due to hypotension and/or dizziness, common side effects of guanfacine, and two patients were lost to follow-up.
•The remaining eight patients reported improved working memory, concentration and executive function, including the resumption of normal workloads.
•One patient temporarily stopped guanfacine due to a hypotensive episode and reported a return of cognitive deficits that abated with resumed guanfacine treatment.
•Although placebo-controlled trials will be needed to demonstrate efficacy, the established safety of guanfacine and NAC suggests they may be immediately useful in treating the cognitive deficits of long-COVID19.
Abstract
Background
Prolonged cognitive deficits (“brain fog”) following COVID19 infection (long-COVID) are common and debilitating, yet there are currently no approved treatments. Cognitive impairment particularly targets the working memory and executive functions of the prefrontal cortex (PFC). The PFC has unusual neurotransmission and neuromodulation that render it vulnerable to stressors, and basic research has identified mechanisms that protect PFC connections. Based on the basic neuroscience data, we tried a combined open label treatment to bolster prefrontal function: the α2A-adrenoceptor agonist, guanfacine, which strengthens prefrontal connectivity, and the anti-oxidant, N- acetylcysteine (NAC), which protects mitochondria and reduces kynurenic acid blockade of NMDA receptors.
Case report
Twelve patients with “brain fog” including difficulties in executive functions were treated with guanfacine (1mg, PO bedtime for the first month, increased to 2mg after 1 month, if well-tolerated) and 600 mg NAC daily. Guanfacine+NAC improved cognitive abilities in eight of the twelve patients; four patients discontinued therapy, two for unspecified reasons and two due to hypotension and/or dizziness, common side effects of guanfacine. Those who stayed on guanfacine+NAC reported improved working memory, concentration, and executive functions, including a resumption of normal workloads. One patient briefly stopped taking guanfacine due to a hypotensive episode and reported a return of cognitive deficits that abated with resumed guanfacine treatment.
Conclusion
Although placebo-controlled trials will be needed to more rigorously demonstrate efficacy, as these agents have established safety, they may be immediately helpful in treating the large number of patients suffering from prolonged cognitive deficits following COVID19 infection.

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Fedor M. Zurabov 1,*ORCID,Ekaterina A. Chernevskaya 2ORCID,Natalia V. Beloborodova 2ORCID,Alexander Yu. Zurabov 1,Marina V. Petrova 2,Mikhail Ya. Yadgarov 2ORCID,Valentina M. Popova 1,Oleg E. Fatuev 2,Vladislav E. Zakharchenko 2,Marina M. Gurkova 1,Ekaterina A. Sorokina 2,Egor A. Glazunov 1,Tatiana A. Kochetova 1ORCID,Victoria V. Uskevich 1ORCID,Artem N. Kuzovlev 2 andAndrey V. Grechko 2

Bacteriophage Cocktails in the Post-COVID Rehabilitation

https://doi.org/10.3390/v14122614

Published

23-Nov-22

Study

https://digitalcommons.wku.edu/ijesab/vol14/iss2/139/

Increasing evidence suggests that gut dysbiosis is associated with coronavirus disease 2019 (COVID-19) infection and may persist long after disease resolution. The excessive use of antimicrobials in patients with COVID-19 can lead to additional destruction of the microbiota, as well as to the growth and spread of antimicrobial resistance. The problem of bacterial resistance to antibiotics encourages the search for alternative methods of limiting bacterial growth and restoring the normal balance of the microbiota in the human body. Bacteriophages are promising candidates as potential regulators of the microbiota. In the present study, two complex phage cocktails targeting multiple bacterial species were used in the rehabilitation of thirty patients after COVID-19, and the effectiveness of the bacteriophages against the clinical strain of Klebsiella pneumoniae was evaluated for the first time using real-time visualization on a 3D Cell Explorer microscope. Application of phage cocktails for two weeks showed safety and the absence of adverse effects. An almost threefold statistically significant decrease in the anaerobic imbalance ratio, together with an erythrocyte sedimentation rate (ESR), was detected. This work will serve as a starting point for a broader and more detailed study of the use of phages and their effects on the microbiome.

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Joan Stephenson, PhD1

Report on Long COVID Urges Actions to Address Needs of Patients, Caregivers

http://jamanetwork.com/article.aspx?doi=10.1001/jamahealthforum.2022.5254

Published

6-Dec-22

Editorial

https://jamanetwork.com/journals/jama-health-forum/fullarticle/2799427

To address this issue, the report urges sending clinicians the latest information on findings, testing, and treatments in the form of “Long COVID digests,” as well as enlisting academic partners to launch an “expansive outreach campaign” to train clinicians about long COVID and suggested care pathways through in-person and virtual presentations. In the longer term, it advised medical schools to increase training on long COVID and other infection-associated chronic conditions.

Other recommendations, based on experiences reported by patients, are aimed at nonclinicians. For example, the report said that educators and employers should develop and support accommodations that allow people with long COVID to continue to study and work.

The report also stresses that people with long COVID and those who care for them “feel marginalized, misunderstood, and isolated by a general public that is impatient for a return to business as usual.” It urged public messaging campaigns in multiple languages and formats to increase the public’s literacy and awareness regarding long COVID and said that government agency leaders should be encouraged “to amplify and share that Long COVID is real and a serious public health issue.”

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Mashfee H. Khan, Kennedy P. Kirkpatrick, Yi Deng, Krishna B. Shah

Stellate Ganglion Block for Long COVID Symptom Management: A Case Report

https://doi.org/10.7759/cureus.32295

Published

7-Dec-22

Case Report

https://www.cureus.com/articles/127985-stellate-ganglion-block-for-long-covid-symptom-management-a-case-report

Stellate ganglion block (SGB) is gaining increasing acceptance as a treatment modality for various medical conditions. It works by blocking neuronal transmissions which in turn alleviates sympathetically-driven disease processes. Many of the prolonged sequelae of long COVID are thought to be mediated by dysregulation of the autonomic nervous system, and SGB is being investigated as a potential option for symptomatic management of long COVID. This case report demonstrates the efficacy of SGB in a previously healthy patient for the management of long COVID symptoms including fatigue, post-exertional malaise, shortness of breath, and gastrointestinal symptoms. 

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Antonio Cimellaro 1,*ORCID,Desirée Addesi 1,Michela Cavallo 1,Francesco Spagnolo 1,Edoardo Suraci 1,Raffaella Cordaro 1,Ines Spinelli 1,Francesco Passafaro 2,Manuela Colosimo 3,Medea Pintaudi 4,Carmelo Pintaudi 1 andon behalf of the CATAnzaro LOng COVID (CATALOCO) Study Group †

Monoclonal Antibodies and Antivirals against SARS-CoV-2 Reduce the Risk of Long COVID: A Retrospective Propensity Score-Matched Case–Control Study

https://doi.org/10.3390/biomedicines10123135

Published

5-Dec-22

Study

https://www.mdpi.com/2227-9059/10/12/3135

Long COVID is a complex condition affecting quality of life, with limited therapeutic options. We investigated the occurrence of long COVID in subjects receiving early therapy with monoclonal antibodies (mAbs) or antivirals to reduce the risk of COVID-19 progression. In this retrospective study we enrolled 737 adult patients (aged 65.16 ± 13.46; 361F), who experienced COVID-19 between January 2021 and March 2022. Antiviral or mAbs were administered to symptomatic patients who did not require oxygen therapy or hospital admission for SARS-CoV-2 infection, and who were at high risk of progression to severe disease, as identified by age > 65 years or the presence of comorbidities. Long COVID, defined as newly or persistent long-term symptoms 4 weeks after the onset of the acute illness, was reported in 204 cases (28%). Age (OR 1.03; p < 0.001), gender (OR 1.88; p < 0.001) and at least three comorbidities (OR 3.49; p = 0.049) were directly associated with long COVID; conversely, vaccination (OR 0.59; p = 0.005) and mAbs/antivirals (OR 0.44; p = 0.002) were independently associated with a reduced risk of long COVID. At a propensity-score-matched analysis, the mAbs/antivirals group had a significantly lower occurrence of long COVID in comparison with untreated controls (11% vs. 34%; p = 0.001). In conclusion, mAbs and antivirals administered against the progression of COVID-19 were associated with a reduced risk of long COVID.

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Katie Chadd, Sophie Chalmers, Kate Harrall, Kathryn Moyse, Gemma Clunie

An evaluation of speech and language therapy services for people with long COVID in the UK: a call for integrated care

Published

30-Nov-22

Study

https://www.emerald.com/insight/content/doi/10.1108/JICA-07-2022-0038/full/html

Purpose
Long COVID is a complex and highly heterogeneous condition with a variable symptom profile, and calls have been made for an integrated care approach to be taken for its management. To date, no studies have explored speech and language therapy services or needs associated with long COVID. This service evaluation aimed to gauge the level of demand on speech and language therapy services for individuals with long COVID in the UK; their clinical needs, the organisational arrangements of services and the barriers and facilitators of delivering quality care.
Design/methodology/approach
A service evaluation was undertaken via distribution of an online survey to speech and language therapists (SLTs) receiving referrals for individuals with long COVID. Analysis was completed using descriptive statistics, with thematic analysis to evaluate qualitative data.
Findings
One hundred and eleven SLTs responded. Eighty-six percent were seeing individuals with long COVID in their “everyday” service, in uni- or multi-disciplinary teams, without any “dedicated” resource. Dysphagia and dysphonia were the most reported symptoms. Most respondents (66.7%) indicated the individuals they were seeing were of working age, and that an individuals' speech and language therapy needs were impacting their wellbeing. Perceived barriers to quality care included fragmented and non-integrated care pathways. Multi-disciplinary and integrated working was a key enabler.
Originality/value
This study provides novel insights into the current speech and language therapy needs of and care pathways for individuals with long COVID in the UK SLTs have unique expertise and are integral to supporting individuals with long COVID and should be a part of integrated care teams.

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VP

Yan Xie, Taeyoung Choi, View ORCID ProfileZiyad Al-Aly

Nirmatrelvir and the Risk of Post-Acute Sequelae of COVID-19

https://doi.org/10.1101/2022.11.03.22281783

pre-print

5-Nov-22

Study

https://www.medrxiv.org/content/10.1101/2022.11.03.22281783v1.full-text

Long Covid – the disease encompassing the post-acute sequelae of SARS-CoV-2 (PASC) —affects millions of people around the world. Prevention of PASC is an urgent public health priority. In this work, we aimed to examine whether treatment with nirmatrelvir in the acute phase of COVID-19 is associated with reduced risk of post-acute sequelae. We used the healthcare databases of the US Department of Veterans Affairs to identify users of the health system who had a SARS-CoV-2 positive test between March 01, 2022 and June 30, 2022, were not hospitalized on the day of the positive test, had at least 1 risk factor for progression to severe COVID-19 illness and survived the first 30 days after SARS-CoV-2 diagnosis. We identify those who were treated with oral nirmatrelvir within 5 days after the positive test (n=9217) and those who received no COVID-19 antiviral or antibody treatment during the acute phase of SARS-CoV-2 infection (control group, n= 47,123). Inverse probability weighted survival models were used to estimate the effect of nirmatrelvir (versus control) on a prespecified panel of 12 post-acute COVID-19 outcomes and reported as hazard ratio (HR) and absolute risk reduction (ARR) in percentage at 90 days. Compared to the control group, treatment with nirmatrelvir was associated with reduced risk of PASC (HR 0.74 95% CI (0.69, 0.81), ARR 2.32 (1.73, 2.91)) including reduced risk of 10 of 12 post-acute sequelae in the cardiovascular system (dysrhythmia and ischemic heart disease), coagulation and hematologic disorders (deep vein thrombosis, and pulmonary embolism), fatigue, liver disease, acute kidney disease, muscle pain, neurocognitive impairment, and shortness of breath. Nirmatrelvir was also associated with reduced risk of post-acute death (HR 0.52 (0.35, 0.77), ARR 0.28 (0.14, 0.41)), and post-acute hospitalization (HR 0.70 (0.61, 0.80), ARR 1.09 (0.72, 1.46)). Nirmatrelvir was associated with reduced risk of PASC in people who were unvaccinated, vaccinated, and boosted, and in people with primary SARS-CoV-2 infection and reinfection. In sum, our results show that in people with SARS-CoV-2 infection who had at least 1 risk factor for progression to severe COVID-19 illness, treatment with nirmatrelvir within 5 days of a positive SARS-CoV-2 test was associated with reduced risk of PASC regardless of vaccination status and history of prior infection. The totality of findings suggests that treatment with nirmatrelvir during the acute phase of COVID-19 reduces the risk of post-acute adverse health outcomes.

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Marasco, Giovanni; Cremon, Cesare; Barbaro, Maria Raffaella; Cacciari, Giulia; Falangone, Francesca; Kagramanova, Anna; Bordin, Dmitry; Drug, Vasile; Miftode, Egidia; Fusaroli, Pietro; Mohamed, Salem Youssef; Ricci, Chiara; Bellini, Massimo; Rahman, Mohammed Masudur; Melcarne, Luigi; Santos, Javier; Lobo, Beatriz; Bor, Serhat; Yapali, Suna; Akyol, Deniz; Sapmaz, Ferdane Pirincci; Urun, Yonca Yilmaz; Eskazan, Tugce; Celebi, Altay; Kacmaz, Huseyin; Ebik, Berat; Binicier, Hatice Cilem; Bugdayci, Mehmet Sait; Yağcı, Munkhtsetseg Banzragch; Pullukcu, Husnu; Kaya, Berrin Yalınbas; Tureyen, Ali; Hatemi, İbrahim; Koc, Elif Sitre; Sirin, Goktug; Calıskan, Ali Riza; Bengi, Goksel; Alıs, Esra Ergun; Lukic, Snezana; Trajkovska, Meri; Hod, Keren; Dumitrascu, Dan; Pietrangelo, Antonello; Corradini, Elena; Simren, Magnus; Sjölund, Jessica; Tornkvist, Navkiran; Ghoshal, Uday C.; Kolokolnikova, Olga; Colecchia, Antonio; Serra, Jordi; Maconi, Giovanni; Giorgio, Roberto De; Danese, Silvio; Portincasa, Piero; Sabatino, Antonio Di; Maggio, Marcello; Philippou, Elena; Lee, Yeong Yeh; Salvi, Daniele; Venturi, Alessandro; Borghi, Claudio; Zoli, Marco; Gionchetti, Paolo; Viale, Pierluigi; Stanghellini, Vincenzo; Barbara, Giovanni

Post COVID-19 irritable bowel syndrome

https://doi.org/10.1002/mco2.196

Published

8-Dec-22

Study

https://onlinelibrary.wiley.com/doi/abs/10.1002/mco2.196

COVID-19 caused by SARS-CoV-2 infection affects humans not only during the acute phase of the infection, but also several weeks to 2 years after the recovery. SARS-CoV-2 infects a variety of cells in the human body, including lung cells, intestinal cells, vascular endothelial cells, olfactory epithelial cells, etc. The damages caused by the infections of these cells and enduring immune response are the basis of long COVID. Notably, the changes in gene expression caused by viral infection can also indirectly contribute to long COVID. We summarized the occurrences of both common and uncommon long COVID, including damages to lung and respiratory system, olfactory and taste deficiency, damages to myocardial, renal, muscle, and enduring inflammation. Moreover, we provided potential treatments for long COVID symptoms manifested in different organs and systems, which were based on the pathogenesis and the associations between symptoms in different organs. Importantly, we compared the differences in symptoms and frequency of long COVID caused by breakthrough infection after vaccination and infection with different variants of concern, in order to provide a comprehensive understanding of the characteristics of long COVID and propose improvement for tackling COVID-19.

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Jimeno-Almazán, Amaya; Buendía-Romero, Ángel; Martínez-Cava, Alejandro; Franco-López, Francisco; Sánchez-Alcaraz, Bernardino; Courel-Ibáñez, Javier; Pallarés, Jesús G.

Effects of a concurrent training, respiratory muscle exercise and self-management recommendations on recovery from post-COVID-19 conditions: the RECOVE trial

https://doi.org/10.3390/life12122057

Published

Study

https://www.mdpi.com/2075-1729/12/12/2057

Vaccines against SARS-CoV-2 have saved millions of lives and played an important role in containing the COVID-19 pandemic. Vaccination against SARS-CoV-2 is also associated with reduced disease severity and, perhaps, with COVID-19 symptom burden. In this narrative review, we present, in a clinically relevant question-and-answer manner, the evidence regarding the association between vaccination against SARS-CoV-2 and long COVID-19. We discuss how the mechanism of action of vaccines could interplay with the pathophysiology of post-COVID-19 condition. Furthermore, we describe how specific factors, such as the number of vaccine doses and the type of SARS-CoV-2 variants, may affect post-COVID-19 condition. We also discuss the role of timing for vaccination in relation to the onset of long COVID-19 symptoms, as it seems to affect the frequency and severity of the condition. Additionally, we describe the potential modifying effect of age, as well as the association of type and level of immune response with long COVID-19. We also describe how system-specific long COVID-19 sequelae, namely neurocognitive-psychologic symptoms and cardiovascular pathology, could be altered by vaccination. Last, we address the question of whether seasonal influenza vaccination has a meaningful impact on the frequency of long COVID-19.

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Kohn, L; Dauvrin, M; Detollenaere, J; Primus-de Jong, C; Maertens de Noordhout, C; Castanares-Zapatero, D; Cleemput, I; Van den Heede, K

Long COVID and return to work: a qualitative study

https://doi.org/10.1152/japplphysiol.00489.2022

Published

Study

https://journals.physiology.org/doi/abs/10.1152/japplphysiol.00489.2022

The aim of this study was to determine the effectiveness of physical exercise, respiratory muscle training and the self-management WHO recommendations leaflet on the recovery of physical fitness, quality of life and symptom status in people with post COVID-19 conditions. Eighty non-hospitalized adults with a post-COVID-19 condition were randomly assigned to one of four 8-week parallel intervention groups: multicomponent exercise program based on concurrent training- CT (n= 20; 3 resistance and endurance supervised sessions per week at low-moderate intensity); b) inspiratory muscle training- RM (n= 17; 2 standardized daily sessions); c) a combination of both of the above- CTRM (n= 23); d) control group- CON (n= 20; following the WHO guidelines for post-COVID-19 related illness rehabilitation). No significant differences between groups were detected at baseline. While no significant differences between interventions were detected in the VO2max, significant individual improvements were identified in the CT (7.5%; ES=0.38) and CTRM (7.8%; ES=0.28) groups. Lower body muscle strength significantly improved in the CT and CTRM (14.5-32.6%; ES=0.27-1.13) groups compared to RM and CON (-0.3-11.3%; ES=0.19-0.00). The CT and CTRM groups improved significantly for dyspnea and fatigue, as did the health status. In addition, significant differences between interventions were described in fatigue and depression scales favouring CT and CTRM interventions. An individualized and supervised concurrent training with or without respiratory muscle training was safer and more effective than self-care recommendations and inspiratory muscle training alone, to regain cardiovascular and muscular fitness, improve symptom severity and health status in outpatients with post-COVID-19 conditions.

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Nevalainen, Olli P O; Horstia, Saana; Laakkonen, Sanna; Rutanen, Jarno; Mustonen, Jussi; Kalliala, Ilkka; Ansakorpi, Hanna; Kreivi, Hanna-Riikka; Kuutti, Pauliina; Paajanen, Juuso; Parkkila, Seppo; Paukkeri, Erja-Leena; Perola, Markus; Pourjamal, Negar; Renner, Andreas; Rosberg, Tuomas; Rutanen, Taija; Savolainen, Joni; Haukka, Jari K; Guyatt, Gordon H; Tikkinen, Kari A

1126. Effect of Remdesivir on Recovery, Quality of Life, and Long-COVID Symptoms One Year after Hospitalization for COVID-19 Infection: A Randomized Controlled SOLIDARITY Finland Trial

https://doi.org/10.1093/ofid/ofac492.965

Published

Trial

https://doi.org/10.1093/ofid/ofac492.965

Coronavirus disease 2019 (COVID-19) patients frequently suffer from long-term sequelae, often called “long COVID” or “post COVID-19 condition”. Remdesivir, given in early disease, decreases the risk of hospitalization and potentially mortality. No randomized trials have thus far published long-term follow-up data on any COVID-19 drug treatment. We investigated the effects of remdesivir on a range of patient-important outcomes at one year.Between July 2020 and January 2021, an open-label randomized multicenter trial in Finland recruited 208 adult patients from 11 Finnish hospitals. Patients were randomly assigned (1:1 ratio) to standard of care (SoC)with remdesivir (median duration of remdesivir treatment 5 days) or SoC alone. Primary outcomes were self-reported recovery, exertional dyspnea, fatigue, and quality of life at one year. Secondary outcomes were overall mortality and several potential long-COVID symptoms.At one year, 5 (4.4%) of 114 patients in the remdesivir and 5 (5.3%) of 94 in the SoC group had died (RR 0.82, 95% CI 0.25-2.76; absolute difference: -0.9%, 95% CI -7.9-5.3); 181 (92% of survivors) completed the follow-up. Self-reported recovery (fully or largely) occurred in 85% in remdesivir and in 86% in SoC (RR 0.94, 0.47-1.90; absolute difference: -0.9%, 95% CI -11%-10%). Exertional dyspnea occurred in 5% in remdesivir and 8% in SoC (OR 0.61, 95% CI 0.20-1.85; absolute difference -3.3%, 95% CI -12%-4.4%). We found no convincing difference between remdesivir and SoC groups in quality of life or symptom outcomes (p > 0.05 for all). Of the 21 potential long-COVID symptoms, patients often reported moderate or major bother from fatigue (26%), joint pain (22%), persistent respiratory mucus (21%), and problems with memory (19%) and attention/concentration (18%) (Figure).Bother from potential long-COVID symptoms at one year from COVID-19 hospitalization between the standard of care and standard of care plus remdesivir groups. After a one-year follow-up of hospitalized patients (with a very high participation rate), approximately one in four reported substantial bother from fatigue, and one in six reported that they had not recovered well from COVID-19. We found no convincing evidence of a remdesivir effect, but confidence intervals were wide and included possible substantial benefit and substantial harm.Hanna-Riikka Kreivi, MD, PhD, Pfizer: Advisor/Consultant|Roche: Advisor/Consultant Tuomas Rosberg, MD, PhD, AstraZeneca: Honoraria|Boehringer-Ingelheim: Honoraria|GSK: Honoraria.

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Monk, Phillip D; Evans, Rachael A; Tear, Victoria J; Brookes, Jody L; Batten, Toby; Mankowski, Marcin; Djukanovic, Ratko; Holgate, Stephen T; Brightling, Chris; Wilkinson, Tom

LB1533. Impact of Treatment of Hospitalised COVID-19 Patients With Inhaled Interferon Beta-1a (SNG001) on Long COVID Symptoms: Results From the SPRINTER trial

https://doi.org/10.1093/ofid/ofac492.1879

Published

Trial

https://doi.org/10.1093/ofid/ofac492.1879

People with post-COVID conditions can have a wide range of symptoms lasting months and it can affect as many as one in five infected people. Interferon beta (IFN-β) is key in host defence against viruses but can be suppressed by virus or host factors locally at the site of infection. Inhalation of SNG001 (IFN-β-1a nebuliser solution) aims to restore lung IFN-β levels. SPRINTER (NCT04732949) was a RCT of inhaled interferon beta in hospitalised COVID-19. There was no effect of SNG001 on the primary endpoints of time to discharge or recovery most likely due to improvements in the standard of care. However, there was an encouraging signal for the key secondary endpoint of prevention of progression to severe disease or death (ITT 26% relative risk reduction [RRR]; Odds Ratio [95% CI]: 0.71 [0.44, 1.15]; Per Protocol 36% RRR; OR 0.63 [0.35, 1.13]). Post hoc analyses showed enhanced effects favouring SNG001 in subgroups at higher risk of progression. We report on the impact of SNG001 on long COVID symptoms in SPRINTER.Patients requiring low-flow oxygen were randomized to receive SNG001 (314) or placebo (309) once daily for 14 days, plus standard-of-care. Long COVID symptoms were assessed as a secondary endpoint at follow-up visits via telephone/video call on Day 60 and Day 90. The following patient reported outcome (PRO) measures were also assessed: General Anxiety Disorder 7 Questionnaire (GAD-7), Patient Health Questionnaire-9 (PHQ-9), Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Scale and Brief Pain Inventory (Short Form).When compared to placebo, SNG001 reduced the relative risk of common symptoms of long COVID (fatigue/malaise [RRR=35.4%]; dyspnoea [RRR=28.3%]; loss of smell and/or taste [RRR=61.4%]). Analysis of the PROs is ongoing.Assessment of COVID symptoms at Day 60 and 90 follow up visits Effect of SNG001 treatment on long COVID symptoms Long COVID can leave patients with lingering cognitive, respiratory, and functional symptoms months after a SARS-CoV-2 infection. Given the shift from pandemic to endemic status for COVID-19 and the need for new treatments then these findings, suggesting SNG001 may be impacting common long COVID symptoms, provide additional support for the further investigation of SNG001.Phillip D. Monk, PhD, Synairgen Plc (Employed by Synairgen Research Ltd which is a subsidiary of Synairgen Plc, Stocks/Bonds): Board Member|Synairgen Plc (Employed by Synairgen Research Ltd which is a subsidiary of Synairgen Plc, Stocks/Bonds): Stocks/Bonds Victoria J. Tear, PhD, Synairgen Plc (Employed by Synairgen Research Ltd which is a subsidiary of Synairgen Plc, Stocks/Bonds): Stocks/Bonds Jody L. Brookes, BSc, Synairgen Plc (Employed by Synairgen Research Ltd which is a subsidiary of Synairgen Plc, Stocks/Bonds): Stocks/Bonds Marcin Mankowski, MD, MFPM (Dis), CytoDyn: Advisor/Consultant|Entasis: Advisor/Consultant|ImmuPharma: Advisor/Consultant|Menarini: Advisor/Consultant|Pfizer: Advisor/Consultant|Synairgen: Advisor/Consultant|Venatorx: Advisor/Consultant Ratko Djukanovic, MD, Synairgen: Advisor/Consultant|Synairgen: Honoraria|Synairgen: Stocks/Bonds Stephen T. Holgate, FMedSci, MD, Synairgen: Board Member|Synairgen: Non executive board director, patent on inhaled interferon beta|Synairgen: Stocks/Bonds chris brightling, FMedSci, Synairgen: Advisor/Consultant|Synairgen: Grant/Research Support Tom Wilkinson, PhD, PhD, AZ: Grant/Research Support|AZ: Honoraria|My mhealth: Board Member|My mhealth: Ownership Interest|My mhealth: Stocks/Bonds|Synairgen: Grant/Research Support|Synairgen: Honoraria.

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Writing Committee for the REMAP-CAP Investigators

Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial

https://doi.org/10.1001/jama.2022.23257

Published

Trial

https://doi.org/10.1001/jama.2022.23257

Key Points
Question What is the effect of treatment for critically ill patients with COVID-19 on longer-term mortality, disability, and health-related quality of life?

Findings In this bayesian adaptive randomized clinical platform trial that included 4869 critically ill patients with COVID-19, the probability was high that IL-6 receptor antagonists and antiplatelet agents improved survival at 6 months (posterior probabilities of superiority of >99.9% and 95.0%, respectively). Long-term outcomes were not improved with therapeutic anticoagulation (11.5%), convalescent plasma (54.7%), or lopinavir-ritonavir (31.9%) and were worsened with hydroxychloroquine (posterior probability of harm, 96.8%). Corticosteroids did not improve long-term outcomes, although enrollment had been terminated early in response to external evidence.

Meaning Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, there was a high likelihood of improved 180-day mortality among patients treated with IL-6 receptor antagonists and antiplatelet agents.

Abstract
Importance The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown.

Objective To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes.

Design, Setting, and Participants Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022.

Interventions Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401).

Main Outcomes and Measures The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83.

Results Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies.

Conclusions and Relevance Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.

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Lechien, Jerome R.; Le Bon, Serge D.; Saussez, Sven

Platelet-rich plasma injection in the olfactory clefts of COVID-19 patients with long-term olfactory dysfunction

https://doi.org/10.1007/s00405-022-07788-8

Published

Trial

https://doi.org/10.1007/s00405-022-07788-8

Abstract
Objective
To investigate safety, feasibility, and effectiveness of platelet-rich plasma (PRP) injection into the olfactory clefts of COVID-19 patients with persistent olfactory dysfunction (OD).

Methods
From March 2022 to July 2022, COVID-19 patients with persistent OD were consecutively recruited to benefit from PRP injection into the olfactory clefts. Patient pain, annoyance, time of procedure, and adverse events were evaluated. Olfactory function was evaluated at baseline and 2-month post-injection with the olfactory disorder questionnaire (ODQ) and threshold, discrimination, and identification (TDI) test.

Results
Eighty-seven patients with anosmia (N = 30), hyposmia (N = 40), or parosmia (N = 17) with a mean OD duration of 15.7 months completed the evaluations. The PRP injection was successfully performed in all patients with a mean procedure time of 18.4 ± 3.4 min. The adverse events included transient epistaxis (N = 31), parosmia related to xylocaine spray (N = 10), and vasovagal episode (N = 2). The injection procedure was evaluated as somewhat or moderately painful by 41 (47%) and 22 (25%) patients, respectively. Thirty-seven patients were assessed after 2 months post-injection. The mean ODQ and TDI scores significantly improved from baseline to 2-month post-injection (p < 0.01). The olfactory improvement occurred after a mean of 3.6 ± 1.9 weeks.

Conclusion
The injection of PRP into the olfactory clefts is safe and associated with adequate patient-reported outcomes. The findings of this preliminary study suggest possible efficacy on subjective and psychophysical evaluations, but future randomized controlled studies are needed to determine the superiority of PRP injection over placebo.

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Fernández-Lázaro, Diego; Santamaría, Gema; Sánchez-Serrano, Nerea; Lantarón Caeiro, Eva; Seco-Calvo, Jesús

Efficacy of Therapeutic Exercise in Reversing Decreased Strength, Impaired Respiratory Function, Decreased Physical Fitness, and Decreased Quality of Life Caused by the Post-COVID-19 Syndrome

https://doi.org/10.3390/v14122797

Published

Review

https://www.mdpi.com/1999-4915/14/12/2797

In the current global scenario, many COVID-19 survivors present a severe deterioration in physical strength, respiratory function, and quality of life due to persistent symptoms and post-acute consequences of SARS-CoV-2 infection. These alterations are known as post-COVID-19 syndrome for which there is no specific and effective treatment for their management. Currently, therapeutic exercise strategies (ThEx) are effective in many diseases by reducing the appearance of complications and side effects linked to treatment, and are consequently of great relevance. In this study, we review the effect of ThEX in reversing decreased strength, impaired respiratory function, decreased physical fitness, and decreased quality of life (QoL) caused by post-COVID-19 syndrome. A literature search was conducted through the electronic databases, Medline (PubMed), SciELO and Cochrane Library Plus for this structured narrative review for studies published from database retrieval up till 12 December 2022. A total of 433 patients with post-COVID-19 syndrome condition (60% women) were included in the nine studies which met the inclusion/exclusion criteria. Overall, post-COVID-19 syndrome patients who followed a ThEx intervention showed improvements in strength, respiratory function, physical fitness and QoL, with no exercise-derived side effects. Thus, ThEx based on strength, aerobic and respiratory training could be an adjuvant non-pharmacological tool in the modulation of post-COVID-19 syndrome.

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Russell, Peije; Esser, Lars; Hagemeyer, Christoph E.; Voelcker, Nicolas H.

The potential impact of nanomedicine on COVID-19-induced thrombosis

https://doi.org/10.1038/s41565-022-01270-6

Published

Review

https://www.nature.com/articles/s41565-022-01270-6

Extensive reports of pulmonary embolisms, ischaemic stroke and myocardial infarctions caused by coronavirus disease 2019 (COVID-19), as well as a significantly increased long-term risk of cardiovascular diseases in COVID-19 survivors, have highlighted severe deficiencies in our understanding of thromboinflammation and the need for new therapeutic options. Due to the complexity of the immunothrombosis pathophysiology, the efficacy of treatment with conventional anti-thrombotic medication is questioned. Thrombolytics do appear efficacious, but are hindered by severe bleeding risks, limiting their use. Nanomedicine can have profound impact in this context, protecting delicate (bio)pharmaceuticals from degradation en route and enabling delivery in a targeted and on demand manner. We provide an overview of the most promising nanocarrier systems and design strategies that may be adapted to develop nanomedicine for COVID-19-induced thromboinflammation, including dual-therapeutic approaches with antiviral and immunosuppressants. Resultant targeted and side-effect-free treatment may aid greatly in the fight against the ongoing COVID-19 pandemic.

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Uehara, Laura; Corrêa, João Carlos Ferrari; Ritti, Raphael; Leite, Paulo; de Faria, Deivide Rafael Gomes; Pacheco-Barrios, Kevin; Castelo-Branco, Luis; Fregni, Felipe; Corrêa, Fernanda Ishida

Transcutaneous auricular vagus nerve stimulation effects on inflammatory markers and clinical evolution of patients with COVID-19: a pilot randomized clinical trial

https://doi.org/10.1080/17434440.2022.2154147

Published

Trial

https://doi.org/10.1080/17434440.2022.2154147

Objective To evaluate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on inflammatory markers and clinical outcomes in patients with COVID-19.Methods A randomized blinded pilot study was carried out with 21 individuals hospitalized with COVID-19 who received 14 sessions of active (a-taVNS) or sham taVNS (s-taVNS). The level of interleukin-6 (IL-6), interleukin-10 (IL-10), cortisol, and C-reactive protein (CRP) in plasma and clinical evolution pre- and post-intervention were evaluated. The memory and attention levels were evaluated 14 days after the end of the treatment.Results After treatment, significant intragroup differences were found in the CRP (p = 0.01), IL-6 (p = 0.01), and cortisol (p = 0.01) levels; however, in the comparison between the groups, only the CRP level was statistically lower for the a-taVNS (p = 0.04). The impression of improvement in memory and attention was greater in the a-taVNS than in the s-taVNS (p = 0.01, p = 0.04, respectively). There was no difference between the other clinical outcomes.Conclusions taVNS is a viable and safe intervention in the acute care of patients with COVID-19, which can modulate their inflammatory profile and improve cognitive symptoms. However, improvements in overall clinical outcomes were not detected. Larger sample sizes and longer follow-ups are needed to confirm the anti-inflammatory and clinical effects of taVNS in patients with COVID-19.Trials Registry The Brazilian Registry of Clinical Trials (RBR–399t4g5).

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Ora, Josuel; Calzetta, Luigino; Frugoni, Chiara; Puxeddu, Ermanno; Rogliani, Paola

Expert guidance on the management and challenges of long-COVID syndrome: a systematic review

https://doi.org/10.1080/14656566.2022.2161365

Published

Systematic Review

https://doi.org/10.1080/14656566.2022.2161365

Introduction Long-COVID is the condition characterised by the permanence of symptoms beyond 4 weeks after initial infection. It affects 1 out of 5 people and is loosely related to the severity of acute infection and pathological mechanisms which are yet to be understood.Areas covered This article looks at currently available or under-study therapies for long-COVID syndrome. It particularly gives focus to ongoing trials and review the underlying mechanisms. A comprehensive literature search was performed on PubMed and clincaltrial.gov of clinical trials concerning the management of long-COVID syndrome.Expert opinion “Long-COVID” syndrome is a new emergency characterized by several symptoms such as fatigue, dyspnoea, cognitive and attention disorders, sleep disorders, post-traumatic stress disorder, muscle pain, and concentration problems. Despite the many guidelines available to date, there are no established treatments of long-COVID. Pharmacological research is studying known drugs that act on the reduction or modulation of systemic inflammation, or innovative drugs used in similar pathologies. Rehabilitation now seems to be the safest treatment to offer, whereas we will have to wait for the pharmacological research trials in progress as well as plan new trials based on a better understanding of the pathogenic mechanisms.

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Negro, Roberto W. Dal; Turco, Paola; Povero, Massimiliano

Nebivolol: an effective option against long-lasting dyspnoea following COVID-19 pneumonia - a pivotal double-blind, cross-over controlled study

https://doi.org/10.4081/mrm.2022.886

Published

Study

https://www.mrmjournal.org/mrm/article/view/886

Background: Pulmonary microvascular occlusions can aggravate SARS-CoV-2 pneumonia and result in a variable decrease in capillary blood volume (Vc). Dyspnoea may persist for several weeks after hospital discharge in many patients who have "radiologically recovered" from COVID-19 pneumonia. Dyspnoea is frequently "unexplained" in these cases because abnormalities in lung vasculature are understudied. Furthermore, even when they are identified, therapeutic options are still lacking in clinical practice, with nitric oxide (NO) supplementation being used only for severe respiratory failure in the hospital setting. Nebivolol is the only selective β1 adrenoceptor antagonist capable of inducing nitric oxide-mediated vasodilation by stimulating endothelial NO synthase via β3 agonism. The purpose of this study was to compare the effect of nebivolol versus placebo in patients who had low Vc and complained of dyspnoea for several weeks after COVID-19 pneumonia. Methods: Patients of both genders, aged ≥18 years, non-smokers, who had a CT scan that revealed no COVID-related parenchymal lesions but still complained of dyspnoea 12-16 weeks after hospital discharge, were recruited. Spirometrical volumes, blood haemoglobin, SpO2, simultaneous diffusing capacity for carbon monoxide (CO) and NO (DLCO and DLNO, respectively), DLNO/DLCO ratio, Vc and exhaled NO (eNO) were measured together with their dyspnoea score (DS), heart frequency (HF), and blood arterial pressure (BAP). Data were collected before and one week after both phosphorus (P) and nitrogen (N) (2.5 mg od) double-blind cross-over administered at a two-week interval. Data were statistically compared, and p<0.05 assumed as statistically significant.Results: Eight patients (3 males) were investigated. In baseline, their mean DS was 2.5±0.6 sd, despite the normality of lung volumes. DLCO and DLNO mean values were lower than predicted, while mean DLNO/DLCO ratio was higher. Mean Vc proved substantially reduced. Placebo did not modify any variable (all p=ns) while N improved DLCO and Vc significantly (+8.5%, p<0.04 and +17.7%, p<0.003, respectively). Also eNO was significantly increased (+17.6%, p<0.002). Only N lowered the dyspnoea score (-76%, p<0.001). Systolic and diastolic BAP were slightly lowered (-7.5%, p< 0.02 and -5.1% p< 0.04, respectively), together with HF (-16.8%, p<0.03).Conclusions: The simultaneous assessment of DLNO, DLCO, DLNO/DLCO ratio, and Vc confirmed that long-lasting dyspnoea is related to hidden abnormalities in the lung capillary vasculature. These abnormalities can persist even after the complete resolution of parenchymal lesions regardless of the normality of lung volumes. Nebivolol, but not placebo, improves DS and Vc significantly. The mechanism suggested is the NO-mediated vasodilation via the β3 adrenoceptor stimulation of endothelial NO synthase. This hypothesis is supported by the substantial increase of eNO only assessed after nebivolol. As the nebivolol tolerability in these post-COVID normotensive patients was very good, the therapeutic use of nebivolol against residual and symptomatic signs of long-COVID can be suggested in out-patients.

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Tartibian, Bakhtyar; Khayat, Sirwan Mohammad Amini; Maleki, Behzad Hajizadeh; Chehrazi, Mohammad

The Effects of Exercise Training on Recovery of Biochemical and Hematological Outcomes in Patients Surviving COVID-19: A Randomized Controlled Assessor-Blinded Trial

https://doi.org/10.1186/s40798-022-00546-4

Published

Trial

https://doi.org/10.1186/s40798-022-00546-4

Abstract
Background
No previous research has investigated the direct effects of exercise interventions on COVID-19 outcomes. The aim is to investigate the effect of 8 weeks of home-based moderate-intensity continuous training (MICT), resistance training (RT), and combined aerobic and resistance training (CET) on biochemical and hematologic markers associated with COVID-19 symptoms and severity in COVID-19 survivors.

Methods
A total of 547 male and female COVID-19 survivors were screened, and 296 (aged 20–93 years) were randomly assigned in a 1:1:1:1 ratio to one of four groups: MICT (n = 74), RT (n = 74), CET (n = 74), or non-exercise (NON-EX, n = 74). Blood samples were taken at baseline, at week 4, and week 8 after training.

Results
After the intervention, compared with the NON-EX group, all 3 MICT, RT, and CET interventions caused significant improvements in the levels of creatine kinase (CK), lactate dehydrogenase (LDH), C-reactive protein (CRP), troponin-I, d-dimer, creatinine, urea, potassium (K), sodium (Na), white blood cell (WBC), neutrophils, lymphocytes, red blood cells (RBC), platelets, hemoglobin, and hematocrit concentrations (P < 0.05). CET was effectively superior to MICT and RT in the improvements in the biochemical and hematological variables studied (P < 0.05).

Conclusions
Overall, the present study demonstrates that long-term MICT plus RT interventions have a synergistic effect in accelerating and enhancing the recovery in patients surviving COVID-19.

Trial registration IRCT20160605028270N3, 6 September 2020.

Key Points
No prior studies have investigated the direct impact of exercise interventions on COVID-19 outcomes.

Regular exercise training accelerates and improves recovery in COVID-19 survivors.

Eight weeks of aerobic training, resistance training, or combined aerobic and resistance training improved considerably the biochemical and hematologic indicators associated with COVID-19 symptoms and severity.

Combined aerobic and resistance training was substantially more effective in improving these biomarkers and indicators than aerobic training alone and resistance training alone.

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Noda, Yoshihiro; Sato, Akiko; Shichi, Misaki; Sato, Ayano; Fujii, Kyoshiro; Iwasa, Mio; Nagano, Yasuhiro; Kitahata, Ryosuke; Osawa, Ryota

Real world research on transcranial magnetic stimulation treatment strategies for neuropsychiatric symptoms with Long-COVID in Japan

https://doi.org/10.1016/j.ajp.2022.103438

Published

Study

https://www.sciencedirect.com/science/article/pii/S1876201822004361

Highlights
•
We developed the novel TMS therapeutic approach for patients with long-COVID.

•
The novel TMS treatment could improve depressive symptoms of long-COVID.

•
The novel TMS treatment could alleviate subjective chronic fatigue of long-COVID.

•
The novel TMS treatment could restore subjective cognitive decline of long-COVID.

Abstract
The number of patients suffering from long-COVID is currently increasing rapidly, even after the acute symptoms of COVID-19 have improved. The objective of this study was to investigate the effects of a pilot transcranial magnetic stimulation (TMS) treatment on neuropsychiatric symptoms caused by long-COVID. In this study, we examined the efficacy of the TMS treatment protocol, which has been established to be effective in depression, by applying it to patients who sought TMS treatment for neuropsychiatric symptoms caused by long-COVID at TMS clinics in Tokyo, Japan in the context of real world TMS registry study in Japan. Of the 23 patients (13 females) with long-COVID included in this case series, the main neuropsychiatric symptoms were chronic fatigue (n=12) and cognitive dysfunction (n=11), but most patients also showed mild depressive symptoms. The mean Montgomery-Åsberg Depression Rating Scale score before TMS treatment was 21.2 but improved to 9.8 after treatment. Similarly, the Performance Status score, which assesses the degree of fatigue, improved from 5.4 to 4.2, and the Perceived Deficits Questionnaire–Depression 5-item score, which reflects cognitive function, improved from 10.0 to 6.3. There were no serious adverse events, although a few patients complained of pain at the stimulation site during the TMS as a side effect. Despite the limitations of this open-label pilot study, the TMS protocol implemented in this study may have beneficial effects on neuropsychiatric symptoms caused by long-COVID, including depressive symptoms, chronic fatigue, and cognitive impairment. These preliminary findings warrant further validation in randomized controlled trials.

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Suran, Melissa

VA Finds Nirmatrelvir Associated With Lower Risk of Long COVID

https://doi.org/10.1001/jama.2022.20051

Published

Study

https://doi.org/10.1001/jama.2022.20051

The antiviral therapy nirmatrelvir, 1 of the medications used in Paxlovid, may mitigate the development of long COVID conditions, according to an observational study by the US Department of Veterans Affairs (VA). The study was posted to the preprint server medRxiv in early November and had not yet been peer-reviewed.

In the study of medical records from veterans who tested positive for SARS-CoV-2, about 9200 patients took oral nirmatrelvir within 5 days of their diagnosis while about 47 000 did not receive antiviral or antibody treatment during the first 30 days of infection. All patients had at least 1 risk factor for developing severe COVID-19. None were hospitalized on the day they tested positive, and all survived for at least 30 days.

About 3 months after diagnosis, patients who received nirmatrelvir were 26% less likely to develop long COVID conditions such as blood clots, fatigue, heart disease, kidney disease, liver disease, muscle pain, neurocognitive impairment, and shortness of breath. Such conditions occurred less often among these patients regardless of their vaccination status and prior history of SARS-CoV-2 infection. Nirmatrelvir use was also associated with a 30% and 48% reduction in postacute hospitalization and death, respectively. However, the drug wasn’t associated with a lower risk of new-onset diabetes or cough.

“This treatment could be an important asset to address the serious issue of long COVID,” the study’s corresponding author, Ziyad Al-Aly, MD, director of the Clinical Epidemiology Center at the VA St Louis Health Care System, said in a statement.

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Haque, Azizul; Pant, Anudeep B.

Long Covid: Untangling the Complex Syndrome and the Search for Therapeutics

https://doi.org/10.3390/v15010042

Published

Review

https://www.mdpi.com/1999-4915/15/1/42

Long Covid can affect anyone who has previously had acute COVID-19. The root causes of this syndrome are still unknown, and no effective therapeutics are available. This complex syndrome, with a wide array of symptoms, is still evolving. Given the dire situation, it is important to identify the causes of Long Covid and the changes occurring within the immune system of affected patients to figure out how to treat it. The immune system intersects with the persistent viral fragments and blood clots that are implicated in this syndrome; understanding how these complex systems interact may help in untangling the puzzling physiopathology of Long Covid and identifying mitigation measures to provide patients some relief. In this paper, we discuss evidence-based findings and formulate hypotheses on the mechanisms underlying Long Covid’s physiopathology and propose potential therapeutic options.

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Tanashyan, Marine M.; Мовсесовна, Танашян Маринэ; Raskurazhev, Anton A.; Алексеевич, Раскуражев Антон; Kuznetsova, Polina I.; Игоревна, Кузнецова Полина; Bely, Petr A.; Александрович, Белый Петр; Zaslavskaya, Kira Ia; Яковлевна, Заславская Кира

Prospects and possibilities for the treatment of patients with long COVID-19 syndrome

https://doi.org/10.26442/00403660.2022.11.201981

Published

Study

https://doi.org/10.26442/00403660.2022.11.201981

Aim. To study the efficacy and safety of a drug product based on the succinic acid complex with trimethylhydrazine used to treat patients with asthenic syndrome after a new coronavirus infection (COVID-19).Materials and methods. A prospective, multicenter, comparative, randomized, double-blind, placebo-controlled study of the safety and efficacy of sequential therapy with Brainmax® enrolled 160 patients 12–16 weeks after coronavirus infection (no more than 12 months). The study was conducted at 6 healthcare centers in different regions of the Russian Federation. At the enrollment, clinical and neurological examination and the following tests were performed: complete blood count, urinalysis, blood chemistry, coagulation test, pulse oximetry, electrocardiography, glomerular filtration rate calculation (according to Cockcroft–Gault formula) were performed. Also, the patients were assessed using the following tools: VAS headache rating scale, MFI-20 asthenia scale, PSQI index, FAS-10 fatigue assessment scale, Dizziness Handicap Inventory (DHI), MoCA-test for cognitive impairment assessment, Beck Anxiety Inventory, Kérdö Autonomic Index.Results. The primary endpoint was the mean reduction in the MFI-20 asthenia scale score after the therapy (Visit 5, 41st day of therapy) compared to data from Visit 0 (beginning of therapy). A clinically significant advantage of the study drug versus the placebo was demonstrated, with a median absolute change in the MFI-20 score of -19.5 [-27; -11] points in the Brainmax® drug group and -3 [-7; 1] score in the placebo group (p<0.001). A significant sleep quality improvement according to the PSQI index was shown in the study group: by -2.5 [-4; -1] points versus no improvement in the placebo group (0 [-3; 0], p<0,001). Significant differences were also noted for the following secondary endpoints: PSQI sleep quality scale, FAS-10 fatigue assessment scale, DHI, and Beck Anxiety and Depression Inventory. There was also a decrease in patients' complaints of cognitive deterioration according to the CGI scale.Conclusion. Our study clearly demonstrated the efficacy and high safety profile of Brainmax® in a representative sample of patients with the post-COVID syndrome.

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Valverde-Martínez, María Ángeles; López-Liria, Remedios; Martínez-Cal, Jesús; Benzo-Iglesias, María Jesús; Torres-Álamo, Lucía; Rocamora-Pérez, Patricia

Telerehabilitation, A Viable Option in Patients with Persistent Post-COVID Syndrome: A Systematic Review

https://doi.org/10.3390/healthcare11020187

Published

1-Jan-23

Review

https://www.mdpi.com/2227-9032/11/2/187

The number of patients with post-COVID-19 syndrome continues to increase considerably, having serious healthcare, social and economic repercussions. The objective of this study is to describe the effectiveness of telerehabilitation to alleviate the symptoms of post-COVID-19 syndrome. A systematic review was conducted using the information available on four databases (PubMed, Medline, Scielo and PEDRo) on these patients until November 2022. The MeSH search terms were: Post-COVID syndrome, Post-COVID-19, Long COVID, Telerehabilitation, Physiotherapy, Rehabilitation, Virtual, Home care. Six articles were included which provided information on 140 patients, detailing their symptomatology, assessment, treatment and monitoring. The variables measured were dyspnea, fatigue, physical performance and quality of life. All studies included aerobic and anaerobic exercises. Most notable among the techniques used were rib cage expansion exercises, respiratory control and thoracic cage stretching, patient education, Mindfulness and virtual reality games to address physical, mental and relaxation aspects. The use of telerehabilitation could be an effective tool for the treatment of persistent symptoms after suffering from COVID-19. It has been shown in these studies that patients improve both their physical performance and their quality of life.

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Ostrowska, Małgorzata; Rzepka-Cholasińska, Alicja; Pietrzykowski, Łukasz; Michalski, Piotr; Kosobucka-Ozdoba, Agata; Jasiewicz, Małgorzata; Kasprzak, Michał; Kryś, Jacek; Kubica, Aldona

Effects of Multidisciplinary Rehabilitation Program in Patients with Long COVID-19: Post-COVID-19 Rehabilitation (PCR SIRIO 8) Study

https://doi.org/10.3390/jcm12020420

Published

1-Jan-23

Study

https://www.mdpi.com/2077-0383/12/2/420

Up to 80% of COVID-19 survivors experience prolonged symptoms known as long COVID-19. The aim of this study was to evaluate the effects of a multidisciplinary rehabilitation program in patients with long COVID-19. The rehabilitation program was composed of physical training (aerobic, resistance, and breathing exercises), education, and group psychotherapy. After 6 weeks of rehabilitation in 97 patients with long COVID-19, body composition analysis revealed a significant decrease of abdominal fatty tissue (from 2.75 kg to 2.5 kg; p = 0.0086) with concomitant increase in skeletal muscle mass (from 23.2 kg to 24.2 kg; p = 0.0104). Almost 80% of participants reported dyspnea improvement assessed with the modified Medical Research Council scale. Patients’ physical capacity assessed with the 6 Minute Walking Test increased from 320 to 382.5 m (p < 0.0001), the number of repetitions in the 30 s Chair Stand Test improved from 13 to 16 (p < 0.0001), as well as physical fitness in the Short Physical Performance Battery Test from 14 to 16 (p < 0.0001). The impact of fatigue on everyday functioning was reduced in the Modified Fatigue Impact Scale from 37 to 27 (p < 0.0001). Cardiopulmonary exercise test did not show any change. The multidisciplinary rehabilitation program has improved body composition, dyspnea, fatigue and physical capacity in long COVID-19 patients.

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Khondakar, Kamil Reza; Kaushik, Ajeet

Role of Wearable Sensing Technology to Manage Long COVID

https://doi.org/10.3390/bios13010062

Published

1-Jan-23

Review

https://www.mdpi.com/2079-6374/13/1/62

Long COVID consequences have changed the perception towards disease management, and it is moving towards personal healthcare monitoring. In this regard, wearable devices have revolutionized the personal healthcare sector to track and monitor physiological parameters of the human body continuously. This would be largely beneficial for early detection (asymptomatic and pre-symptomatic cases of COVID-19), live patient conditions, and long COVID monitoring (COVID recovered patients and healthy individuals) for better COVID-19 management. There are multitude of wearable devices that can observe various human body parameters for remotely monitoring patients and self-monitoring mode for individuals. Smart watches, smart tattoos, rings, smart facemasks, nano-patches, etc., have emerged as the monitoring devices for key physiological parameters, such as body temperature, respiration rate, heart rate, oxygen level, etc. This review includes long COVID challenges for frequent monitoring of biometrics and its possible solution with wearable device technologies for diagnosis and post-therapy of diseases.

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Herman, Bumi; Bruni, Andrea; Zain, Ekachaeryanti; Dzulhadj, Azhar; Oo, Aye Chan; Viwattanakulvanid

Post-COVID depression and its multiple factors, does Favipiravir have a protective effect? A longitudinal study of indonesia COVID-19 patients

https://doi.org/10.1371/journal.pone.0279184

Published

30-Dec-22

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0279184

Background Coronavirus disease (COVID-19) not only has a long-term effect on its survivors, it also affects their quality of life, including inducing depression as a possible manifestation of central nervous system disruption. Favipiravir shows promising efficacy as an antiviral drug for the treatment of COVID-19. However, its effect on the sequelae of COVID-19 has not been explored. Therefore, this study aims to assess the impact of Favipiravir and address the factors associated with post-COVID depression in Indonesia. Method This cohort study conducted a post-COVID-19 survey on Indonesian patients who were diagnosed by using real-time polymerase chain reaction (RT-PCR) and antigen tests until January 2022. An online questionnaire was distributed to obtain information on demographics, comorbidities, health behavior, symptoms, and treatment. The propensity technique was used to allocate the participants into the favipiravir and nonrecipient groups (1:1). The Patient Health Questionnaire-9 (PHQ-9) was used for outcome measurement. The cohort was followed up biweekly for 60 days after onset/diagnosis to determine the occurrence of depression. Cox regression analysis with an adjusted odds ratio and 95% confidence interval was used to estimate the effect of favipiravir on post-COVID-19 depression. Results The data included the information of 712 participants, of whom 18.54% had depression within 60 days after onset/diagnosis. Depression was higher in the nonrecipient group (21.06%) than in the favipiravir group (16.01%). After adjustment by other factors, favipiravir prescription was found to be associated with depression (aOR 0.488, 95% CI 0.339–0.701 p < 0.001). In accordance with the PHQ-9 subset, favipiravir exerted a significant protective effect against depressive mood and loss of interest. However, patients living alone were prone to experiencing loss of interest (aOR 2.253, 95% CI 1.329–3.818, p = 0.003). Conclusion The data obtained in this preliminary survey suggested that favipiravir may be useful for preventing post-COVID depression. However, further study is needed. Moreover, the provision of mental health support, particularly to those who live alone, must be ensured. Trial registration Registry NCT05060562.

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Khan, Amish M.; Piccirillo, Jeffrey; Kallogjeri, Dorina; Piccirillo, Jay F.

Efficacy of Combined Visual-Olfactory Training With Patient-Preferred Scents as Treatment for Patients With COVID-19 Resultant Olfactory Loss: A Randomized Clinical Trial

https://doi.org/10.1001/jamaoto.2022.4112

Published

29-Dec-22

Trial

https://doi.org/10.1001/jamaoto.2022.4112

Key Points
Question Does bimodal visual-olfactory training with patient-preferred scents improve olfaction vs unimodal olfactory training with physician-assigned scents in individuals with COVID-19 postviral olfactory loss?

Findings In this randomized clinical trial that included 275 adults, the marginal mean difference for change in the UPSIT scores preintervention to postintervention between participants randomized to patient-preferred vs physician-assigned scents was 0.73, and between participants randomized to bimodal visual-olfactory vs unimodal olfactory training was 1.10. These were both insignificant differences.

Meaning No clinically meaningful improvement in UPSIT score was observed among individuals who underwent olfactory training, with no added benefit from bimodal visual-olfactory training or patient-preferred scents.

Abstract
Importance The number of olfactory dysfunction cases has increased dramatically because of the COVID-19 pandemic. Identifying therapies that aid and accelerate recovery is essential.

Objective To determine the efficacy of bimodal visual-olfactory training and patient-preferred scents vs unimodal olfactory training and physician-assigned scents in COVID-19 olfactory loss.

Design, Setting, and Participants This was a randomized, single-blinded trial with a 2-by-2 factorial design (bimodal, patient preferred; unimodal, physician assigned; bimodal, physician assigned; unimodal, patient preferred) and an independent control group. Enrollment occurred from February 1 to May 27, 2021. Participants were adults 18 to 71 years old with current olfactory loss defined as University of Pennsylvania Smell Identification Test (UPSIT) score less than 34 for men and less than 35 for women and duration of 3 months or longer. Olfactory loss was initially diagnosed within 2 weeks of COVID-19 infection.

Interventions Participants sniffed 4 essential oils for 15 seconds with a 30-second rest in between odors for 3 months. Participants in the physician-assigned odor arms trained with rose, lemon, eucalyptus, and clove. Participants randomized to the patient-preferred arms chose 4 of 24 available scents. If assigned to the bimodal arm, participants were shown digital images of the essential oil they were smelling.

Main Outcomes and Measures The primary end point was postintervention change in UPSIT score from baseline; measures used were the UPSIT (validated, objective psychometric test of olfaction), Clinical Global Impressions Impression–Improvement (CGI-I; self-report improvement scale), and Olfactory Dysfunction Outcomes Rating (ODOR; olfaction-related quality-of-life questionnaire).

Results Among the 275 enrolled participants, the mean (SD) age was 41 (12) years, and 236 (86%) were female. The change in UPSIT scores preintervention to postintervention was similar between the study arms. The marginal mean difference for change in UPSIT scores preintervention to postintervention between participants randomized to patient-preferred vs physician-assigned olfactory training was 0.73 (95% CI, −1.10 to 2.56), and between participants randomized to bimodal vs unimodal olfactory training was 1.10 (95% CI, −2.92 to 0.74). Five (24%) participants in the control arm had clinically important improvement on UPSIT compared with 18 (53%) in the bimodal, patient-preferred arm for a difference of 29% (95% CI, 4%-54%). Four (19%) participants in the control group self-reported improvement on CGI-I compared with 12 (35%) in the bimodal, patient-preferred arm for a difference of 16% (95% CI, −7% to 39%). The mean change in ODOR score preintervention to postintervention was 11.6 points (95% CI, 9.2-13.9), which was not deemed clinically important nor significantly different between arms.

Conclusions and Relevance Based on the change in UPSIT scores, this randomized clinical trial did not show any difference between intervention arms, but when exploring within-patient change in UPSIT as well as self-reported impression of improvement, active interventions were associated with larger improvement than controls with a potential advantage of bimodal intervention. While not definitive, these results suggest that patients with COVID-19 olfactory loss may benefit from bimodal visual-olfactory training with patient-preferred scents.

Trial Registration ClinicalTrials.gov Identifier: NCT04710394

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Kitala, Diana; Łabuś, Wojciech; Kozielski, Jerzy; Strzelec, Przemysław; Nowak, Mariusz; Knefel, Grzegorz; Dyjas, Piotr; Materniak, Krzysztof; Kosmala, Jolanta; Pająk, Jolanta; Czop, Jolanta; Janda-Kalus, Barbara; Marona, Barbara; Nowak-Wróżyna, Anna; Gierek, Marcin; Szczegielniak, Jan; Kucharzewski, Marek

Preliminary Research on the Effect of Hyperbaric Oxygen Therapy in Patients with Post-COVID-19 Syndrome

https://doi.org/10.3390/jcm12010308

Published

1-Jan-23

Study

https://www.mdpi.com/2077-0383/12/1/308

Negative consequences and medical complications of COVID-19 can persist for up to several months after initial recovery. These consequences can include stroke, diabetes, decreased lung diffusing capacity, sleep apnea, pulmonary fibrosis, arrhythmia, myocarditis, fatigue, headaches, muscle aches, heart rate fluctuations, sleep problems, memory problems, nervousness, anxiety, and other neurological disorders. Thirty-one patients who reported symptoms related to previous COVID-19 disease of both sexes were enrolled in the initial program. The patients underwent compression sessions in a multiplace hyperbaric chamber. Each patient underwent a cycle of 15 compressions. Before the first session, each participant completed a venous blood gas test, a Fullerton test, and two spirometry tests (one before the Fullerton test and one after the test). Patients completed psychotechnical tests, a questionnaire on quality of life (Polish version of EQ-5D-5L), and a questionnaire on specific symptoms accompanying the disease and post-infection symptoms. The results showed significant improvements in areas such as quality of life, endurance and strength, some spirometric parameters, the anion gap and lactate levels, working memory, and attention in the group of treated patients. In contrast, there were no changes in pH, pO2, pCO2, glucose, and excess alkaline values. A follow-up interview confirmed that the beneficial effects were maintained over time. Considering the results obtained, including the apparent improvement in the patient’s clinical condition, it can be concluded that the use of 15 compression sessions was temporarily associated with a noticeable improvement in health and performance parameters as well as improvement in certain blood gas parameters.

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Cavigli, Luna; Fusi, Chiara; Focardi, Marta; Mandoli, Giulia Elena; Pastore, Maria Concetta; Cameli, Matteo; Valente, Serafina; Zorzi, Alessandro; Bonifazi, Marco; D’Andrea, Antonello; D’Ascenzi, Flavio

Post-Acute Sequelae of COVID-19: The Potential Role of Exercise Therapy in Treating Patients and Athletes Returning to Play

https://doi.org/10.3390/jcm12010288

Published

1-Jan-23

Review

https://www.mdpi.com/2077-0383/12/1/288

Post-acute sequelae of coronavirus disease 19 (COVID-19) (PASC) describe a wide range of symptoms and signs involving multiple organ systems occurring after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, representing a growing health problem also in the world of sport and the athletic population. Patients with PASC have new, returning, or persisting symptoms four or more weeks after the infection. Among the most frequent symptoms, patients complain of fatigue, dyspnea, exercise intolerance, and reduced functional capacity that interfere with everyday life activity. The role of exercise programs in PASC patients will be identified, and upcoming studies will establish the magnitude of their benefits. However, the benefits of exercise to counteract these symptoms are well known, and an improvement in cardiopulmonary fitness, functional status, deconditioning, and quality of life can be obtained in these patients, as demonstrated in similar settings. Based on this background, this review aims to summarise the current evidence about the PASC syndrome and the benefit of exercise in these patients and to provide a practical guide for the exercise prescription in PASC patients to help them to resume their functional status, exercise tolerance, prior activity levels, and quality of life, also considering the athletic population and their return to play and sports competitions.

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Fawzy, Nader A.; Shaar, Bader Abou; Taha, RandM.; Arabi, Tarek Z.; Sabbah, Belal N.; Alkodaymi, Mohamad S.; Omrani, Osama A.; Makhzoum, Tariq; Almahfoudh, Najwa E.; Al-Hammad, Qasem A.; Hejazi, Wed; Obeidat, Yasin; Osman, Naden; Al-Kattan, Khaled M.; Berbari, Elie F.; Tleyjeh, Imad M.

A Systematic Review of Trials Currently Investigating Therapeutic Modalities for Post-Acute COVID-19 Syndrome and Registered on World Health Organization International Clinical Trials Platform

https://doi.org/10.1016/j.cmi.2023.01.007

Published

13-Jan-23

Review

https://www.sciencedirect.com/science/article/pii/S1198743X23000095

Background
Post-acute coronavirus 2019 (COVID-19) syndrome (PACS) is a well-recognized complex systemic disease that is associated with substantial morbidity. There is a paucity of established interventions to treat patients with this syndrome.
Objectives
To systematically review registered trials currently investigating therapeutic modalities for PACS.
Data sources
Search was conducted up to the 16th of September 2022 using the COVID-19 section of the World Health Organization (WHO) Internal Clinical Trials Registry Platform.
Study eligibility criteria, participants, and interventions
Interventional clinical trials of any sample size examining any therapeutic modality targeting persistent symptoms among individuals after diagnosis with COVID-19.
Methods
Data on trial characteristics and intervention characteristics were collected and summarized.
Results
After screening 17125 trials, 388 trials from 42 countries were eligible. 331 trials tested mono-therapeutic strategies, while 39 trials included a combination of interventions. Among the 824 primary outcomes identified, there were more than 300 different outcomes. Rehabilitation was the most employed class of intervention with 169 trials. We encountered 76 trials examining pharmacological agents of various classes with the most common agent being colchicine. Complementary and alternative medicine encompassed 64 trials exploring Traditional Chinese Medicine, Ayurveda, homeopathic medications, naturopathic medications, vitamins, dietary supplements, and botanicals. Psychotherapeutic and educational interventions were also employed with 12 and 4 trials, respectively. Other interventions including transcranial current direct stimulation, transcutaneous auricular vagus nerve stimulation, general electrical stimulation, cranial electrotherapy stimulation, various stem cell interventions, and oxygen therapy interventions were also employed.
Conclusion
We identified 388 registered trials with a high degree of heterogeneity exploring 144 unique interventions for PACS. Most target general alleviation of symptoms. There is a need for further high-quality and methodologically robust PACS treatment trials conducted with standardization of outcomes while following WHO’s recommendation for uniform evaluation and treatment.

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Hausswirth, Christophe; Schmit, Cyril; Rougier, Yann; Coste, Alexandre

Positive Impacts of a Four-Week Neuro-Meditation Program on Cognitive Function in Post-Acute Sequelae of COVID-19 Patients: A Randomized Controlled Trial

https://doi.org/10.3390/ijerph20021361

Published

1-Jan-23

Study

https://www.mdpi.com/1660-4601/20/2/1361

Study objective: Long COVID patients can experience high levels of impairment in their cognitive function and mental health. Using a parallel randomized control trial, we evaluated the effectiveness of a neuro-meditation program to reduce cognitive impairment in patients with long COVID. Methods: A total of 34 patients with long COVID were randomized to an intervention group (G-Int; n = 17) or a control group (G-Con; n = 17) and 15 healthy participants were constitutive of a normative group (G-Nor). The intervention consisted of ten 30-min sessions of Rebalance® over a period of five weeks. Each session included sound therapy and coach-guided meditation associated with light stimulations (i.e., chromotherapy). Primary outcomes were performance on five computerized cognitive tasks (choice response time, pattern comparison, Simon, pursuit rotor task, and Corsi block-tapping task), mental and physical fatigue (Chalder fatigue scale), perceived stress (perceived stress scale) and mood (profiles of mood states). Secondary outcomes were anxiety and depressive symptoms (hospital anxiety and depression scale), muscular pain, joint pain, and headaches using visual analog scales (VAS) as well as sleep quality (Spiegel sleep questionnaire). Assessments were conducted at baseline and at 1–2 and 7–8 days of follow-up. Results: Compared to healthy subjects, long COVID patients showed significant differences at baseline on all the self-report questionnaires, and a Rebalance® program improved all the subjective reports, as well as cognitive performances, especially on reaction time-based tasks. In particular, only the G-Int group revealed shortened reaction times in the choice reaction time (RTbaseline = 593 ± 121 ms vs. RTpost2 = 521 ± 86 ms, p < 0.001), Simon (RTbaseline = 539 ± 123 ms vs. RTpost2 = 494 ± 134 ms, p < 0.01), and pattern comparison tasks (RTbaseline = 1244 ± 315 ms vs. RTpost2 = 1079 ± 213 ms, p < 0.001). Conclusions) Initial evidence suggests that neuro-meditation reduces cognitive impairment and improves physical and mental fatigue, muscle and joint pain, symptoms of depression and anxiety, mood disturbances as well as sleep quality. The Rebalance® program hence constitutes a promising non-pharmacological intervention for the treatment of long-term psychological/cognitive outcomes of COVID-19.

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Berraies, A.; Sleiman, C.; Rabut, H.

Réhabilitation respiratoire dans la dyspnée chronique en post-COVID : expérience du service de pneumologie de Chartres

https://doi.org/10.1016/j.rmra.2022.11.095

Published

1-Jan-23

Study

https://www.sciencedirect.com/science/article/pii/S1877120322002658

Introduction
Certains patients gardent des séquelles plusieurs mois après une infection pulmonaire à SARS-CoV-2 indépendamment de la sévérité initiale de la maladie. La dyspnée, la fatigue et le retentissement psychologique sont les principaux symptômes rapportés. De plus en plus de données montrent l’intérêt de la réhabilitation respiratoire (RR) dans la dyspnée chronique post-COVID.
Méthodes
Nous rapportons les résultats de la RR en post-COVID à Chartres. Depuis septembre 2020, nous accueillons dans notre unité de RR ambulatoire des patients souffrant de dyspnée persistante en post-COVID pendant 6 semaines à raison de 3 séances hebdomadaires. Nous évaluons leur fonction respiratoire, leurs capacités à l’effort par un test de levers de chaise de 1 minute (TLC1) et une épreuve d’effort cardiorespiratoire (EFX) ainsi qu’une épreuve d’endurance et différents questionnaires.
Résultats
Quarante-six patients ont participé au programme avec un âge moyen de 55 ans (24–79 ans). Le sex-ratio est de 0,39. Parmi ces patients, 65 % ont été hospitalisés (30 patients) dont les 2/3 en réanimation et 28 % ont nécessité la ventilation mécanique. Le délai moyen de la RR était de 7,6 mois (3–24 mois). Treize patients (28 %) ont une restriction avec une CPT moyenne à 64 %. La DLCO était abaissée chez 58 % des patients avec une moyenne de 66 %. Dix-neuf patients (41 %) avaient des anomalies au scanner au moment de la réhabilitation dont 68 % avaient une fibrose. La VO2 moyenne était de 68 % (31–83 %). Un syndrome d’hyperventilation a été retrouvé chez 52 % des patients. L’anxiété et la dépression étaient présentes chez respectivement 74 % et 43 % des patients. Après réhabilitation, l’endurance est multipliée par 3 en moyenne (1,5 et 7,1). Amélioration du TLC1 chez 69 % des patients. L’anxiété s’améliore chez le tiers des patients et la dépression chez la moitié. Le syndrome d’hyperventilation a régressé dans 54 % des cas.
Conclusion
Comme pour les pathologies respiratoires chroniques, la RR permet d’améliorer les capacités à l’effort mais également le syndrome d’hyperventilation et le retentissement psychologique particulièrement importants dans cette pathologie.

1095

Ce286

Steinmetz, Anke; Bahlmann, Susanne; Bergelt, Corinna; Bröker, Barbara M.; Ewert, Ralf; Felix, Stephan B.; Flöel, Agnes; Fleischmann, Robert; Hoffmann, Wolfgang; Holtfreter, Silva; Nauck, Matthias; Riemann, Katja; Scheer, Christian; Stahl, Dana; Vogelgesang, Antje; Völker, Uwe; Wiesmann, Ulrich; Klinger-König, Johanna; Walk, René; Grabe, Hans J.; Gross, Stefan; Lehnert, Kristin; Fielitz, Jens; Dörr, Marcus

The Greifswald Post COVID Rehabilitation Study and Research (PoCoRe)–Study Design, Characteristics and Evaluation Tools

https://doi.org/10.3390/jcm12020624

Published

1-Jan-23

Protocol

https://www.mdpi.com/2077-0383/12/2/624

(1) Background: COVID-19 is often associated with significant long-term symptoms and disability, i.e., the long/post-COVID syndrome (PCS). Even after presumably mild COVID-19 infections, an increasing number of patients seek medical help for these long-term sequelae, which can affect various organ systems. The pathogenesis of PCS is not yet understood. Therapy has so far been limited to symptomatic treatment. The Greifswald Post COVID Rehabilitation Study (PoCoRe) aims to follow and deeply phenotype outpatients with PCS in the long term, taking a holistic and comprehensive approach to the analysis of their symptoms, signs and biomarkers. (2) Methods: Post-COVID outpatients are screened for symptoms in different organ systems with a standardized medical history, clinical examination, various questionnaires as well as physical and cardiopulmonary function tests. In addition, biomaterials are collected for the analysis of immunomodulators, cytokines, chemokines, proteome patterns as well as specific (auto)antibodies. Patients are treated according to their individual needs, adhering to the current standard of care. PoCoRe’s overall aim is to optimize diagnostics and therapy in PCS patients.

1096

Ce287

Shoaib, Shoaib; Ansari, Mohammad Azam; Kandasamy, Geetha; Vasudevan, Rajalakshimi; Hani, Umme; Chauhan, Waseem; Alhumaidi, Maryam S.; Altammar, Khadijah A.; Azmi, Sarfuddin; Ahmad, Wasim; Wahab, Shadma; Islam, Najmul

An Attention towards the Prophylactic and Therapeutic Options of Phytochemicals for SARS-CoV-2: A Molecular Insight

https://doi.org/10.3390/molecules28020795

Published

1-Jan-23

Review

https://www.mdpi.com/1420-3049/28/2/795

The novel pathogenic virus was discovered in Wuhan, China (December 2019), and quickly spread throughout the world. Further analysis revealed that the pathogenic strain of virus was corona but it was distinct from other coronavirus strains, and thus it was renamed 2019-nCoV or SARS-CoV-2. This coronavirus shares many characteristics with other coronaviruses, including SARS-CoV and MERS-CoV. The clinical manifestations raised in the form of a cytokine storm trigger a complicated spectrum of pathophysiological changes that include cardiovascular, kidney, and liver problems. The lack of an effective treatment strategy has imposed a health and socio-economic burden. Even though the mortality rate of patients with this disease is lower, since it is judged to be the most contagious, it is considered more lethal. Globally, the researchers are continuously engaged to develop and identify possible preventive and therapeutic regimens for the management of disease. Notably, to combat SARS-CoV-2, various vaccine types have been developed and are currently being tested in clinical trials; these have also been used as a health emergency during a pandemic. Despite this, many old antiviral and other drugs (such as chloroquine/hydroxychloroquine, corticosteroids, and so on) are still used in various countries as emergency medicine. Plant-based products have been reported to be safe as alternative options for several infectious and non-infectious diseases, as many of them showed chemopreventive and chemotherapeutic effects in the case of tuberculosis, cancer, malaria, diabetes, cardiac problems, and others. Therefore, plant-derived products may play crucial roles in improving health for a variety of ailments by providing a variety of effective cures. Due to current therapeutic repurposing efforts against this newly discovered virus, we attempted to outline many plant-based compounds in this review to aid in the fight against SARS-CoV-2.

1097

Ce288

Mullard, Jordan C. R.; Kawalek, Jessica; Parkin, Amy; Rayner, Clare; Mir, Ghazala; Sivan, Manoj; Greenhalgh, Trisha

Towards evidence-based and inclusive models of peer support for long covid: A hermeneutic systematic review

https://doi.org/10.1016/j.socscimed.2023.115669

Published

1-Mar-23

Review

https://www.sciencedirect.com/science/article/pii/S0277953623000242

Since the first wave of COVID-19 in March 2020 the number of people living with post-COVID syndrome has risen rapidly at global pace, however, questions still remain as to whether there is a hidden cohort of sufferers not accessing mainstream clinics. This group are likely to be constituted by already marginalised people at the sharp end of existing health inequalities and not accessing formal clinics. The challenge of supporting such patients includes the question of how best to organise and facilitate different forms of support. As such, we aim to examine whether peer support is a potential option for hidden or hardly reached populations of long COVID sufferers with a specific focus on the UK, though not exclusively. Through a systematic hermeneutic literature review of peer support in other conditions (57 papers), we evaluate the global potential of peer support for the ongoing needs of people living with long COVID. Through our analysis, we highlight three key peer support perspectives in healthcare reflecting particular theoretical perspectives, goals, and understandings of what is ‘good health’, we call these: biomedical (disease control/management), relational (intersubjective mutual support) and socio-political (advocacy, campaigning & social context). Additionally, we identify three broad models for delivering peer support: service-led, community-based and social media. Attention to power relations, social and cultural capital, and a co-design approach are key when developing peer support services for disadvantaged and underserved groups. Models from other long-term conditions suggest that peer support for long COVID can and should go beyond biomedical goals and harness the power of relational support and collective advocacy. This may be particularly important when seeking to reduce health inequalities and improve access for a potentially hidden cohort of sufferers.

1098

Ce289

Di Stadio, Arianna; Bernitsas, Evanthia; La Mantia, Ignazio; Brenner, Michael J.; Ralli, Massimo; Vaira, Luigi Angelo; Colizza, Andrea; Cavaliere, Carlo; Laudani, Matteo; Frohman, Teresa C.; De Vincentiis, Marco; Frohman, Elliot M.; Altieri, Marta

Targeting Neuroinflammation to Alleviate Chronic Olfactory Dysfunction in Long COVID: A Role for Investigating Disease-Modifying Therapy (DMT)?

https://doi.org/10.3390/life13010226

Published

1-Jan-23

Study

https://www.mdpi.com/2075-1729/13/1/226

Chronic olfactory dysfunction after SARS-CoV-2 infection occurs in approximately 10% of patients with COVID-19-induced anosmia, and it is a growing public health concern. A regimen of olfactory training and anti-neuroinflammatory therapy with co-ultramicronized palmitoylethanolamide with luteolin (um-PEA-LUT) has shown promising results in clinical trials; however, approximately 15% of treated patients do not achieve full recovery of a normal olfactory threshold, and almost 5% have no recovery. Disease-modifying therapies (DMTs), which are used to treat autoimmune neuroinflammation in multiple sclerosis (MS), have not been studied for treating persistent inflammation in refractory post-COVID-19 smell disorder. This study evaluated COVID-19-related smell loss and MS-related smell loss, comparing the responses to different therapies. Forty patients with MS and 45 reporting post-COVID-19 olfactory disorders were included in the study. All patients underwent nasal endoscopy and were evaluated by using validated Sniffin’ Sticks testing. The patients with long COVID were treated for three months with um-PEA-LUT plus olfactory training. The patients with MS were treated with DMTs. Olfactory functions before and after treatment were analyzed in both groups. At the experimental endpoint, 13 patients in the COVID-19 group treated with um-PEA-LUT had residual olfactory impairment versus 10 patients in the MS group treated with DMTs. The severity of the persistent olfactory loss was lower in the MS group, and the patients with MS treated with IFN-beta and glatiramer acetate had the preservation of olfactory function. These data provide a rationale for considering prospective trials investigating the efficacy of DMTs for post-COVID-19 olfactory disorders that are refractory to um-PEA-LUT with olfactory training. This study is the first to consider the role of DMT in treating refractory post-viral olfactory loss in patients with long COVID.

1099

Ce290

Liu, Ting-Hui; Wu, Jheng-Yan; Huang, Po-Yu; Tsai, Ya-Wen; Lai, Chih-Cheng

The effect of nirmatrelvir plus ritonavir on the long-term risk of epilepsy and seizure following COVID-19: A retrospective cohort study including 91,528 patients

https://doi.org/10.1016/j.jinf.2023.01.014

Published

13-Jan-23

Study

https://www.journalofinfection.com/article/S0163-4453(23)00017-8/fulltext

In summary, the results of this large retrospective cohort study suggest that non-hospitalized COVID-19 patients receiving NMV-r may have a lower long-term risk of epilepsy and seizure compared to those who did not receive anti-viral agents. This finding suggests that NMV-r may be effective in reducing the risk of post-acute COVID-19 sequelae, including epilepsy and seizure. Our findings were based on analyzing a large database involving multination, multi-institution, and multi-races. To minimize the potential effects of possible confounding factors, we exclude the patients with prior history of epilepsy or seizure, and the baseline characteristics were well-matched between groups. Therefore, our findings are generalizable, and the level of evidence is robust.
Our findings, in combination with those from a previous observational study,4 demonstrating the preventive effect of NMV-r on ten post-acute sequelae, suggest a potential role for NMV-r in preventing long COVID. These findings are extremely important because no effective measure can prevent the development of long COVID during this pandemic. If NMV-r can provide clinical benefits for acute COVID-19 and reduce the risk of post-acute sequelae, it may be worth considering changing clinical practice to encourage the use of NMV-r for patients with SARS-CoV-2 infection.Publisher: Elsevier
PMID: 36649824

1100

Ce291

Hansen, Kristoffer Skaalum; Leth, Steffen

Coenzyme Q10 therapy in patients with post COVID-19 condition – Authors’ response

https://doi.org/10.1016/j.lanepe.2022.100571

Published

1-Feb-23

Study

https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(22)00267-8/fulltext

A subgroup analysis on a cohort with BMI less than 26 was performed. The number of participants with BMI <26 was 51. In this sub-cohort, mean BMI was now 23.8, mean age 46 years and 39 (76.5%) were female. Group A and B consisted of 25 and 28 participants, respectively, and were still well-balanced. There was no significant difference between the subgroup of participants with BMI <26 and the original cohort with regards to baseline parameters (other than BMI).
There was no significant difference in reduction of PCC symptom score (−0.002 (95% CI -3.64; 3.66), P = 0.99) or increase in EQ-5D health index (−0.006 (95% CI -0.44; 0.032), P = 0.75) when comparing CoQ10 and placebo with a mixed-effect linear regression model in this subgroup. A subsequent analysis on symptom clusters did not show any significant difference between CoQ10 and placebo (Fig. 1). Importantly, subgroup analysis results should be interpreted with caution due to the risk of false positive by multiple comparisons and – especially in this case – limited power after reduction of the number of observations. Thus, larger cohort studies are needed to establish a connection between mitochondrial dysfunction in PCC and the involvement of interleukins.
publisher: Elsevier

1101

Ce292

Dannouf, Khaleedah

Management of Long COVID in the Primary Care Setting

Published

18-Jan-23

Review

https://digitalshowcase.lynchburg.edu/dmscjournal/vol5/iss1/55

Long COVID is a relatively new syndrome of uncertain chronicity. The syndrome presents in multiple fashions with one or more coronavirus-2 (COVID-19) symptoms persisting, reactivating, or beginning 12 weeks or more after the initial COVID-19 infection. Increasing survival rates from COVID-19 mean a growing number of patients at risk for developing long COVID. With more than 93 million confirmed COVID-19 cases in the United States by September 9, 2022, the likelihood of a primary care clinician treating patients with long COVID is significant. Clinicians must be poised to identify, treat and recognize when to refer care for their long COVID patients. This article reviews the etiology, complications, putative pathophysiology, diagnosis, differentials, treatments, and future direction of long COVID in managing primary care patients with previously mild-moderate COVID-19 illnesses.

1102

Ce293

Quinn, Kieran L.; Cheung, Angela M.; Razak, Fahad

Treating common and potentially modifiable symptoms of post-COVID-19 condition (long COVID) in adults

https://doi.org/10.1503/cmaj.220824

Published

17-Jan-23

Review

https://www.cmaj.ca/content/195/2/E80

Fatigue and postexertional malaise associated with long COVID should be treated with titrated structured activity and energy conservation strategies1
To avoid precipitating postexertional malaise, patients should be advised to begin a structured and symptom-guided return to activity program, tailored to their severity of fatigue. The 4 Ps (pacing; prioritizing which activities need to get done on specific days and which activities can be postponed; positioning to modify activities to make them easier to perform [e.g., while sitting]; and planning) is a helpful framework to educate people about how to apply physical, emotional and cognitive energy conservation strategies.1

Guideline-directed use of psychosocial interventions and medications can be used to treat mental health complications of long COVID
Anxiety, depression and posttraumatic stress disorder are among the most common mental health manifestations of long COVID and may be treated according to relevant guidelines in people with these conditions, which are similar to recommendations among people with myalgic encephalomyelitis (ME).2 The use of cognitive behavioural therapy for the treatment of fatigue is controversial and not currently endorsed by the ME Association.2

Breathing exercises, body positioning and pulmonary rehabilitation may improve dyspnea2
In people with mild dyspnea, pursed lip or deep breathing exercises may improve symptoms. Persistent hypoxemia is not a common manifestation of long COVID and may be caused by severe lung disease or organizing pneumonia. Its presence should prompt referral to a respirologist and consideration of pulmonary rehabilitation.2,3

People with sleep disturbances should receive counselling on sleep hygiene, relaxation techniques and stimulus control2
Sleep disturbances may be a result of their SARS-CoV-2 infection or the negative effects of the pandemic.2 They can be managed using cognitive behavioural therapy or 1 of the following medications currently available in Canada: eszopiclone, zolpidem or doxepin.4

Specific guidelines exist for the treatment of palpitations and tachycardia with particular causes
Current recommendations for the treatment of inappropriate sinus tachycardia and postural orthostatic tachycardia syndrome include behavioural modifications, oral fluids, salt, compression stockings, β-blockers, ivabradine and midodrine.5
publisher: CMAJ
section: Practice
PMID: 36649947

1103

Ce294

Bompani, Nicole; Bertella, Laura; Barbieri, Valentina; Scarabel, Luca; Scarpina, Federica; Perucca, Laura; Rossi, Paolo

The predictive role of fatigue and neuropsychological components on functional outcomes in COVID-19 after a multidisciplinary rehabilitation program

https://doi.org/10.1177/03000605221148435

Published

1-Jan-23

Study

https://doi.org/10.1177/03000605221148435

ObjectiveTo verify the impact of altered cognitive functioning and higher levels of mental fatigue, both reported after coronavirus disease 2019 (COVID-19), on rehabilitation treatment outcomes.MethodsIn this real-practice retrospective pre?post intervention cohort study, cognitive functioning, measured through standardized neuropsychological measures, and individual levels of fatigue, depression and anxiety symptoms, were evaluated at admission to a rehabilitation program in individuals who had been hospitalized for COVID-19. The rehabilitation program effectiveness was measured through the Functional Independence Measure.ResultsAmong the patient sample (n?=?66), 87.88% reported experiencing high levels of fatigue at admission, while 16.67% reported depressive symptoms, and 22.73% reported anxiety symptoms. After rehabilitation, the sample displayed a significant decrease in the level of disability, in both the motor and cognitive subscales. Neuropsychological and psychological functioning did not play a predictive role. The 45 patients who received mechanical ventilation during intensive care, representing 68.18% of the sample, benefited more from rehabilitation treatment.ConclusionsThe results support the importance of an early rehabilitation program after COVID-19 infection, independent of the initial neuropsychological and psychological functioning. Respiratory assistance may represent a crucial factor for short-term neuropsychological disease after-effects. Future studies on the long-term neuropsychological effect of COVID-19 infection on individual levels of disability are necessary.

1104

Ce295

Jimeno-Almazán, Amaya; Buendía-Romero, Ángel; Martínez-Cava, Alejandro; Franco-López, Francisco; Sánchez-Alcaraz, Bernardino Javier; Courel-Ibáñez, Javier; Pallarés, Jesús G.

Effects of a concurrent training, respiratory muscle exercise, and self-management recommendations on recovery from post-COVID-19 conditions: the RECOVE trial

https://doi.org/10.1152/japplphysiol.00489.2022

Published

1-Jan-23

Study

https://journals.physiology.org/doi/full/10.1152/japplphysiol.00489.2022

The aim of this study was to determine the effectiveness of physical exercise, respiratory muscle training, and the self-management World Health Organization (WHO) recommendations leaflet on the recovery of physical fitness, quality of life, and symptom status in people with post-COVID-19 conditions. Eighty nonhospitalized adults with a post-COVID-19 condition were randomly assigned to one of four 8-wk parallel intervention groups: 1) multicomponent exercise program based on concurrent training (CT, number of subjects (n) = 20; 3 resistance and endurance supervised sessions per week at low-moderate intensity); 2) inspiratory muscle training (RM, n = 17; 2 standardized daily sessions); 3) a combination of both of the above (CTRM, n = 23); and 4) control group (CON, n = 20; following the WHO guidelines for post-COVID-19-related illness rehabilitation). No significant differences between groups were detected at baseline. Although no significant differences between interventions were detected in the V̇o2max, significant individual improvements were identified in the CT (7.5%; effect size, ES = 0.28) and CTRM (7.8%; ES = 0.36) groups. Lower body muscle strength significantly improved in the CT and CTRM (14.5%–32.6%; ES = 0.27–1.13) groups compared with RM and CON (−0.3% to 11.3%; ES = 0.10–0.19). The CT and CTRM groups improved significantly for dyspnea and fatigue, as did the health status. In addition, significant differences between interventions were described in fatigue and depression scales favoring CT and CTRM interventions. An individualized and supervised concurrent training with or without inspiratory muscle training was safe and more effective than self-care recommendations and inspiratory muscle training alone, to regain cardiovascular and muscular fitness, improve symptom severity, and health status in outpatients with post-COVID-19 conditions.

NEW & NOTEWORTHY Eight weeks of concurrent training, with or without inspiratory muscle exercise, was better than WHO “Support for Rehabilitation: Self-Management after COVID-19-Related Illness” recommendations or inspiratory muscle training alone to improve cardiopulmonary fitness, strength, and symptom severity, in a safe and effective manner. The RECOVE trial proved the benefits and utility of a supervised exercise program in people with post-COVID-19 conditions after mild COVID-19 in an ambulatory setting.
publisher: American Physiological Society

1105

Ce296

Santana, Kelly; França, Eduardo; Sato, João; Silva, Ana; Queiroz, Maria; de Farias, Julia; Rodrigues, Danniely; Souza, Iara; Ribeiro, Vanessa; Caparelli-Dáquer, Egas; Teixeira, Antonio L.; Charvet, Leigh; Datta, Abhishek; Bikson, Marom; Andrade, Suellen

Non-invasive brain stimulation for fatigue in post-acute sequelae of SARS-CoV-2 (PASC)

https://doi.org/10.1016/j.brs.2023.01.1672

Published

1-Jan-23

Study

https://www.sciencedirect.com/science/article/pii/S1935861X23016741

Highlights
•Ten sessions of HD tDCS and rehabilitation program decreases symptoms associated with post-acute sequelae of COVID-19 (PASC).
•M1 HD tDCS modulates fatigue, anxiety, and quality of life on PASC-related fatigue.
•HD tDCS might be used as adjuvant therapeutic tool for PASC-related fatigue.
Abstract
Background
and purpose: Fatigue is among the most common persistent symptoms following post-acute sequelae of Sars-COV-2 infection (PASC). The current study investigated the potential therapeutic effects of High-Definition transcranial Direct Current Stimulation (HD-tDCS) associated with rehabilitation program for the management of PASC-related fatigue.
Methods
Seventy patients with PASC-related fatigue were randomized to receive 3 mA or sham HD-tDCS targeting the left primary motor cortex (M1) for 30 min paired with a rehabilitation program. Each patient underwent 10 sessions (2 sessions/week) over five weeks. Fatigue was measured as the primary outcome before and after the intervention using the Modified Fatigue Impact Scale (MFIS). Pain level, anxiety severity and quality of life were secondary outcomes assessed, respectively, through the McGill Questionnaire, Hamilton Anxiety Rating Scale (HAM-A) and WHOQOL.
Results
Active HD-tDCS resulted in significantly greater reduction in fatigue compared to sham HD-tDCS (mean group MFIS reduction of 22.11 points vs 10.34 points). Distinct effects of HD-tDCS were observed in fatigue domains with greater effect on cognitive (mean group difference 8.29 points; effect size 1.1; 95% CI 3.56–13.01; P < .0001) and psychosocial domains (mean group difference 2.37 points; effect size 1.2; 95% CI 1.34–3.40; P < .0001), with no significant difference between the groups in the physical subscale (mean group difference 0.71 points; effect size 0.1; 95% CI 4.47–5.90; P = .09). Compared to sham, the active HD-tDCS group also had a significant reduction in anxiety (mean group difference 4.88; effect size 0.9; 95% CI 1.93–7.84; P < .0001) and improvement in quality of life (mean group difference 14.80; effect size 0.7; 95% CI 7.87–21.73; P < .0001). There was no significant difference in pain (mean group difference −0.74; no effect size; 95% CI 3.66–5.14; P = .09).
Conclusion
An intervention with M1 targeted HD-tDCS paired with a rehabilitation program was effective in reducing fatigue and anxiety, while improving quality of life in people with PASC.

1106

Ce297

Wang, Samuel S. Y.; Xu, Chuanhui

Hydroxychloroquine: is there a role in long COVID?

https://doi.org/10.1007/s10067-023-06514-x

Published

25-Jan-23

Article

https://doi.org/10.1007/s10067-023-06514-x

HCQ could be explored as a potential therapeutic agent in long COVID for a few reasons.

First, a persistent residual virus may drive the unremitting inflammatory response in long COVID [5]. HCQ is an immunomodulatory drug by inhibits toll-like receptor (TLR) 7/9 sensing virus [6]. HCQ inhibits TLR signaling by altering the pH of endosomes involved in TLR processing and/or preventing TLR7/9 from binding to their respective ligands (RNA and DNA) [7]. HCQ can also exert its immunomodulatory effects through the inhibition of nucleic acid sensor cyclic GMP-AMP (cGAMP) synthase (cGAS) by interfering with cGAS binding to cytosolic DNA. cGAS stimulator of IFN genes (STING) pathway is a major source of the type I interferon (IFN) response, and through inhibition of this pathway, it can reduce the production of pro-inflammatory cytokines, including type I IFN [7]. HCQ is able to inhibit cytokine production in various immune cells, for example, the production of IL-1, IL-6, TNF, and IFNγ by mononuclear cells and the production of TNF, IFNα, and IL-6 by plasmacytoid dendritic cells and natural killer cells [7]. Therefore, HCQ may dampen the unremitting hyperinflammatory response seen in long COVID by suppressing TLR 7/9 activation, pro-inflammatory cytokine release, and also subsequent immune activation.

Second, long COVID has been associated with autoantibodies [5]. HCQ might address this problem through the prevention of MHC class II-mediated autoantigen presentation through inhibition of lysosomal activity [7]. HCQ inhibits the degradation of cargo derived externally (via endocytosis or phagocytosis) or internally (via the autophagy pathway) in autolysosomes by increasing the pH of endosomal compartments, impairing the maturation of lysosomes and autophagosomes, and inhibit auto-antigen presentation along the lysosomal pathway [7].

Another postulated mechanism of long COVID is a sustained endotheliopathy due to microthrombi; it was noted that in patients with long COVID, their plasma vWF antigen and propeptide levels correlated inversely with exercise capacity [8]. HCQ is well-proven to reduce thromboembolic events in SLE and improve endothelial dysfunction [9]. Assuming that the ongoing endotheliopathy is associated with immune-mediated microthromboses, HCQ could potentially improve endothelial dysfunction that is also found in the pathogenesis of long COVID.

Lastly, HCQ is safe and widely used in rheumatology for patients with SLE, and rheumatoid arthritis, which are prototypes of chronic inflammatory/autoimmune disease.

Hence, should long COVID be defined as a disease of a prolonged and dysregulated inflammatory state HCQ might be a suitable immunomodulatory agent to dampen and alter the hyperinflammatory response, given the above mechanisms of HCQ and the current understanding of the pathophysiology of long COVID.

It may be worthwhile to consider exploring treatment options/trials to evaluate the effectiveness and mechanisms of action of HCQ in long COVID patients. Ideally, a double-blind, randomized placebo-controlled trial should be carried out in patients with long COVID treated with HCQ and placebo. The outcome measures could be patient-reported outcomes, inflammatory markers, and endothelial function. This should be the future research agenda, and we are looking forward to it (Table 1).

1107

Ce298

Klocke, Carina; Valentini, Jan; Stolz, Regina; Gaßner, Lena; Joos, Stefanie; Förster, Christian

Patients’ Experiences With Therapeutic Approaches for Post-COVID Syndrome: Results of a Crowdsourced Research Survey

https://doi.org/10.1370/afm.2898

Published

1-Jan-23

Study

https://www.annfammed.org/content/21/1/73

Some patients develop multiple protracted sequelae after infection with SARS-CoV-2, collectively known as post-COVID syndrome or long COVID. To date, there is no evidence showing benefit of specific therapies for this condition, and patients likely resort to self-initiated therapies. We aimed to obtain information about therapies used by and needs of this population via inductive crowdsourcing research. Patients completed an online questionnaire about their symptoms and experiences with therapeutic approaches. Responses of 499 participants suggested few approaches (eg, mind-body medicine, respiratory therapy) had positive effects and showed a great need for patient-centered communication (eg, more recognition of this syndrome). Our findings can help design clinical studies and underscore the importance of the holistic approach to care provided by family medicine.

1108

Ce299

Jimeno-Almazán, Amaya; Buendía-Romero, Ángel; Martínez-Cava, Alejandro; Franco-López, Francisco; Sánchez-Alcaraz, Bernardino Javier; Courel-Ibáñez, Javier; Pallarés, Jesús G.

Effects of a concurrent training, respiratory muscle exercise, and self-management recommendations on recovery from post-COVID-19 conditions: the RECOVE trial

https://doi.org/10.1152/japplphysiol.00489.2022

Published

1-Jan-23

Study

https://journals.physiology.org/doi/full/10.1152/japplphysiol.00489.2022

The aim of this study was to determine the effectiveness of physical exercise, respiratory muscle training, and the self-management World Health Organization (WHO) recommendations leaflet on the recovery of physical fitness, quality of life, and symptom status in people with post-COVID-19 conditions. Eighty nonhospitalized adults with a post-COVID-19 condition were randomly assigned to one of four 8-wk parallel intervention groups: 1) multicomponent exercise program based on concurrent training (CT, number of subjects (n) = 20; 3 resistance and endurance supervised sessions per week at low-moderate intensity); 2) inspiratory muscle training (RM, n = 17; 2 standardized daily sessions); 3) a combination of both of the above (CTRM, n = 23); and 4) control group (CON, n = 20; following the WHO guidelines for post-COVID-19-related illness rehabilitation). No significant differences between groups were detected at baseline. Although no significant differences between interventions were detected in the V̇o2max, significant individual improvements were identified in the CT (7.5%; effect size, ES = 0.28) and CTRM (7.8%; ES = 0.36) groups. Lower body muscle strength significantly improved in the CT and CTRM (14.5%–32.6%; ES = 0.27–1.13) groups compared with RM and CON (−0.3% to 11.3%; ES = 0.10–0.19). The CT and CTRM groups improved significantly for dyspnea and fatigue, as did the health status. In addition, significant differences between interventions were described in fatigue and depression scales favoring CT and CTRM interventions. An individualized and supervised concurrent training with or without inspiratory muscle training was safe and more effective than self-care recommendations and inspiratory muscle training alone, to regain cardiovascular and muscular fitness, improve symptom severity, and health status in outpatients with post-COVID-19 conditions.

NEW & NOTEWORTHY Eight weeks of concurrent training, with or without inspiratory muscle exercise, was better than WHO “Support for Rehabilitation: Self-Management after COVID-19-Related Illness” recommendations or inspiratory muscle training alone to improve cardiopulmonary fitness, strength, and symptom severity, in a safe and effective manner. The RECOVE trial proved the benefits and utility of a supervised exercise program in people with post-COVID-19 conditions after mild COVID-19 in an ambulatory setting.
publisher: American Physiological Society

1109

Ce300

Müller, Thomas; Riederer, Peter; Kuhn, Wilfried

Aminoadamantanes: from treatment of Parkinson’s and Alzheimer’s disease to symptom amelioration of long COVID-19 syndrome?

https://doi.org/10.1080/17512433.2023.2176301

Published

1-Feb-23

Article

https://doi.org/10.1080/17512433.2023.2176301

Introduction
The aminoadamantanes amantadine and memantine are well known. They mainly act as N-methyl-D-aspartate antagonists.
Areas covered
The antiviral drug amantadine moderately ameliorates impaired motor behavior in patients with Parkinson’s disease. Memantine provides beneficial effects on memory function in patients with advanced Alzheimer’s disease already treated with acetylcholine esterase inhibitors. Both compounds counteract impaired monoamine neurotransmission with associated symptoms, such as depression. They improve vigilance, lack of attention and concentration, fatigue syndromes according to clinical findings in patients with chronic neurodegenerative processes. Their extrasynaptic N-methyl-D-Aspartate receptor blockade weakens a prolonged influx of Ca2+ ions as the main responsible components of neuronal excitotoxicity. This causes neuronal dying and associated functional deficits.
Expert opinion
We suggest aminoadamantanes as future therapies for amelioration of short- and long-term consequences of a COVID 19 infection. Particularly the extended-release amantadine formulations will be suitable. They showed better clinical efficacy compared with the conventional available compounds. Amantadine may particularly be suitable for amelioration of fatigue or chronic exhaustion, memantine for improvement of cognitive deficits. Clinical research in patients, who are affected by the short- and long-term consequences of a COVID 19 infection, is warranted to confirm these still hypothetical putative beneficial effects of aminoadamantanes.
Plain Language Summary
The drugs amantadine and memantine are known as aminoadamantanes. Amantadine improves motor skills in patients with Parkinson’s disease. It also reduces fatigue in individuals suffering from multiple sclerosis. Memantine improves memory dysfunction linked to Alzheimer’s disease. Aminoadamantanes affect communication between nerve cells by supporting neurotransmission of monoamines. Clinical studies have found that these drugs benefit patients with chronic neurodegenerative diseases, who have depression, fatigue, loss of attention or concentration deficits. These brain function problems may also appear to some extent due to COVID-19 infection. We suggest that aminoadamantanes could improve these problems in COVID-19 patients in both the short and long term. Clinical research is needed to confirm this hypothesis.
Article highlights
The aminoadamantanes, amantadine, and memantine, antagonize the neuronal N-methyl-D-aspartate receptor function and modify neurotransmission of monoamines.
Amantadine ameliorates impaired motor behavior in patients with Parkinson’s disease and improves fatigue syndromes
Memantine is well known for beneficial effects for some aspects of cognition and behavior, particularly in dementia.
COVID-19 infections may worsen alertness, attention, cognitive abilities, and mood as short- and long-term consequences. Therefore, amantadine and memantine may be beneficial for the treatment of long-covid syndrome
We suggest that intake of either amantadine or memantine as therapy for mental consequences of COVID-19 infections, but we emphasize that future clinical trials are needed to confirm these hypothetical considerations.
publisher: Taylor & Francis
_eprint: https://doi.org/10.1080/17512433.2023.2176301 PMID: 36726198

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Cavalcante, Tahissa Frota; Lourenço, Caroline Evaristo; Ferreira, José Erivelton de Souza Maciel; Oliveira, Lídia Rocha; Neto, João Cruz; Amaro, Josemberg Pereira; Moreira, Rafaella Pessoa

Models of Support for Caregivers and Patients with the Post-COVID-19 Condition: A Scoping Review

https://doi.org/10.3390/ijerph20032563

Published

1-Jan-23

Review

https://www.mdpi.com/1660-4601/20/3/2563

Background: In December 2019, an outbreak of the coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), occurred in the city of Wuhan, China. On 30 January 2020, the World Health Organization declared the outbreak a public health emergency of international concern. In October 2021, with the advancement of the disease, the World Health Organization defined the post-COVID-19 condition. The post-COVID-19 condition occurs in individuals with a history of probable or confirmed infection with SARS-CoV-2, usually 3 months after the onset of the disease. The chronicity of COVID-19 has increased the importance of recognizing caregivers and their needs. Methods: We conducted a scoping review following international guidelines to map the models of support for caregivers and patients with the post-COVID-19 condition. The searches were conducted in electronic databases and the grey literature. The Population, Concept, and Context framework was used: Population: patients with the post-COVID-19 condition and caregivers; Concept: models of caregiver and patient support; and Context: post-COVID-19 condition. A total of 3258 records were identified through the electronic search, and 20 articles were included in the final sample. Results: The studies approached existing guidelines and health policies for post-COVID-19 condition patients and support services for patients and home caregivers such as telerehabilitation, multidisciplinary care, hybrid models of care, and follow-up services. Only one study specifically addressed the home caregivers of patients with this clinical condition. Conclusions: The review indicates that strategies such as telerehabilitation are effective for training and monitoring the patient–family dyad, but the conditions of access and digital literacy must be considered.

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Wilmshurst, Peter; Bewley, Susan; Murray, Patricia

Hyperbaric oxygen therapy for the treatment of long COVID

https://doi.org/10.7861/clinmed.Let.23.1.2

Published

1-Jan-23

Article

https://www.rcpjournals.org/content/clinmedicine/23/1/99.2

A number of other hyperbaric facilities offer private HBOT for treatment of diseases for which there is neither evidence of efficacy nor a plausible hypothesis for a therapeutic mechanism. These include Alzheimer's disease, autism, cancers, depression, HIV/AIDS, Lyme disease and Parkinson's disease. Some facilities provide HBOT for multiple sclerosis although 12 randomised trials have identified no clinically significant benefit.2
This report states that 10 patients received 10 sessions of HBOT at 2.4 atmospheres. Only one author, who works at the Midlands Diving Chamber, treated the patients and he performed the pre- and post-treatment assessments of fatigue and cognitive scoring. The remaining 10 authors, who work at the University Hospitals Coventry and Warwickshire NHS Trust, analysed the data (which we estimate should have taken one person one day). The article reports that HBOT yielded significant improvements in fatigue scale, global cognition, executive function, attention, information processing and verbal function. The authors conclude that the results suggest potential benefits of HBOT in the treatment of long COVID.
We believe it is unacceptable that this experimental non-comparative efficacy trial had ethics approval only for the data analysis. It did not have ethics approval for the exposure of patients to the unproven use of HBOT in a clinical trial. If the patients were not told that they were participating in a research clinical trial, they did not give adequately informed consent.
HBOT involves risks of barotrauma to lungs and ears, and oxygen-induced pulmonary pneumonitis and neurological toxicity. The latter causes convulsions with the risk of aspiration for patients wearing a face mask or hood in the hyperbaric chamber.
The trial was not blinded for either patients or the treating doctor, who performed the assessment in the private facility. Whether the research was funded by the subjects paying for ‘private treatment’ is not stated.
Placebo effects are likely as HBOT facilities are highly technical. Patients are locked in a hyperbaric chamber and usually wear a mask or hood. They experience pressure sensations in their ears and temperature alterations as ambient pressure in the chamber changes.
The Midlands Diving Chamber now cites this paper on its website as evidence of efficacy of HBOT in long COVID to attract paying customers.3
We believe that Clinical Medicine should publish an expression of concern about this paper whilst the journal investigates whether there was ethical approval for the actual research and not just the analysis. If there was not, the article should be retracted.Publisher: Royal College of Physicians
section: Letters to the editor PMID: 36697009

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Marshall-Andon, Tess; Walsh, Sebastian; Berger-Gillam, Tara; Pari, Anees Ahmed Abdul

Systematic review of post-COVID-19 syndrome rehabilitation guidelines

https://doi.org/10.1136/ihj-2021-000100

Published

1-Feb-23

Review

https://ihj.bmj.com/content/4/1/e000100

Introduction Post-COVID-19 syndrome is associated with significant health and potential socioeconomic burden. Due to its novel nature, there is a lack of clarity over best practice for the rehabilitation of patients with ongoing or new symptoms following acute COVID-19 infection. We conducted a systematic review of clinical and service guidelines for post-COVID-19 syndrome rehabilitation.
Methods This review was registered on PROSPERO and is reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included guidelines formally published or endorsed by a recognised professional body, covering rehabilitation of people with symptoms following resolution of acute COVID-19 infection. We searched Medline, Embase, PsycINFO, CINAHL, Web of Science, NHS Evidence, MedRxiv, PsyArXiv and Google for terms related to COVID-19, rehabilitation and guideline. Two reviewers independently screened articles for inclusion, data extracted and quality assessed using the AGREE II and AGREE-REX tools for clinical guidelines and the AGREE-HS tool for service guidelines. We included guidelines of sufficient quality in a narrative synthesis.
Results We identified 12 790 articles, of which 37 guidelines (19 clinical only, 7 service only and 11 combined clinical and service) were included. Guidelines covered a range of countries, rehabilitation types, populations and rehabilitation settings. Synthesis of clinical guidelines (n=4) was structured following the patient pathway, from identification, to assessment, treatment and discharge, with consideration of specific patient groups. Synthesis of service guidelines (n=8) was structured according to the Donabedian framework.
Discussion Though the available post-COVID-19 syndrome rehabilitation guidelines were generally of poor quality, there was a high degree of consensus regarding the breadth of symptoms, the need for holistic assessment by a broad multidisciplinary team and person-centred care. There was less clarity on management options, measuring outcomes and discharge criteria.
PROSPERO registration number CRD42021236049.

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Conti, Valeria; Corbi, Graziamaria; Sabbatino, Francesco; De Pascale, Domenico; Sellitto, Carmine; Stefanelli, Berenice; Bertini, Nicola; De Simone, Matteo; Liguori, Luigi; Di Paola, Ilenia; De Bernardo, Maddalena; Tesse, Angela; Rosa, Nicola; Pagliano, Pasquale; Filippelli, Amelia

Long COVID: Clinical Framing, Biomarkers, and Therapeutic Approaches

https://doi.org/10.3390/jpm13020334

Published

1-Feb-23

Review

https://www.mdpi.com/2075-4426/13/2/334

More than two years after the onset of the COVID-19 pandemic, healthcare providers are facing an emergency within an emergency, the so-called long COVID or post-COVID-19 syndrome (PCS). Patients diagnosed with PCS develop an extended range of persistent symptoms and/or complications from COVID-19. The risk factors and clinical manifestations are many and various. Advanced age, sex/gender, and pre-existing conditions certainly influence the pathogenesis and course of this syndrome. However, the absence of precise diagnostic and prognostic biomarkers may further complicate the clinical management of patients. This review aimed to summarize recent evidence on the factors influencing PCS, possible biomarkers, and therapeutic approaches. Older patients recovered approximately one month earlier than younger patients, with higher rates of symptoms. Fatigue during the acute phase of COVID-19 appears to be an important risk factor for symptom persistence. Female sex, older age, and active smoking are associated with a higher risk of developing PCS. The incidence of cognitive decline and the risk of death are higher in PCS patients than in controls. Complementary and alternative medicine appears to be associated with improvement in symptoms, particularly fatigue. The heterogeneous nature of post-COVID symptoms and the complexity of patients with PCS, who are often polytreated due to concomitant clinical conditions, suggest a holistic and integrated approach to provide useful guidance for the treatment and overall management of long COVID.

1114

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Duñabeitia, Jon Andoni; Mera, Francisco; Baro, Óscar; Jadad-Garcia, Tamen; Jadad, Alejandro R.

Personalized Computerized Training for Cognitive Dysfunction after COVID-19: A Before-and-After Feasibility Pilot Study

https://doi.org/10.3390/ijerph20043100

Published

1-Jan-23

Study

https://www.mdpi.com/1660-4601/20/4/3100

The current pilot study was set to evaluate the feasibility and potential benefit of a personalized computerized cognitive training (CCT) intervention to improve cognitive function among people living with post-acute sequelae of COVID-19 (PASC). Seventy three adults who self-reported cognitive dysfunction more than 3 months after a diagnosis of COVID-19 took part in an 8-week training study. Participants’ general cognitive function was assessed before they completed as many cognitive daily training sessions as they wished during an 8-week period, using a personalized CCT application at home. At the end of this period, participants repeated the general cognitive function assessment. The differences between the scores at 8 weeks and baseline in five cognitive domains (attention, memory, coordination, perception, reasoning), complemented with analyses of the changes based on the participants’ age, training time, self-reported health level at baseline and time since the initial COVID-19 infection. Participants had significant cognitive dysfunction and self-reported negative health levels at baseline. Most of the participants obtained higher scores after CCT in each of the domains as compared with baseline. The magnitude of this score increase was high across domains. It is concluded that a self-administered CCT based on gamified cognitive tasks could be an effective way to ameliorate cognitive dysfunction in persons with PASC. The ClinicalTrials.gov identifier is NCT05571852.

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Mey, Jacob T.; Kirwan, John P.; Axelrod, Christopher L.

The Role of Nutrition in Mitigating the Effects of COVID-19 from Infection through PASC

https://doi.org/10.3390/nu15040866

Published

1-Jan-23

Review

https://www.mdpi.com/2072-6643/15/4/866

The expansive and rapid spread of the SARS-CoV-2 virus has resulted in a global pandemic of COVID-19 infection and disease. Though initially perceived to be acute in nature, many patients report persistent and recurrent symptoms beyond the infectious period. Emerging as a new epidemic, “long-COVID”, or post-acute sequelae of coronavirus disease (PASC), has substantially altered the lives of millions of people globally. Symptoms of both COVID-19 and PASC are individual, but share commonality to established respiratory viruses, which include but are not limited to chest pain, shortness of breath, fatigue, along with adverse metabolic and pulmonary health effects. Nutrition plays a critical role in immune function and metabolic health and thus is implicated in reducing risk or severity of symptoms for both COVID-19 and PASC. However, despite the impact of nutrition on these key physiological functions related to COVID-19 and PASC, the precise role of nutrition in COVID-19 infection and PASC onset or severity remains to be elucidated. This narrative review will discuss established and emerging nutrition approaches that may play a role in COVID-19 and PASC, with references to the established nutrition and clinical practice guidelines that should remain the primary resources for patients and practitioners.

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Di Nicola, Marco; Pepe, Maria; Montanari, Silvia; Spera, Maria Chiara; Panaccione, Isabella; Simonetti, Alessio; Sani, Gabriele

Vortioxetine improves physical and cognitive symptoms in patients with post-COVID-19 major depressive episodes

https://doi.org/10.1016/j.euroneuro.2023.02.006

Published

1-May-23

Study

https://www.sciencedirect.com/science/article/pii/S0924977X23000238

Major Depressive Episodes (MDE) following COVID-19 are frequent, can have a characteristic clinical picture, and are associated with immune-inflammatory changes. Vortioxetine is known to improve physical and cognitive performance in patients with depression and shows anti-inflammatory and anti-oxidative activities. This study aimed to retrospectively evaluate the effects of vortioxetine after 1 and 3 months of treatment in 80 patients (44.4% males, 54±17.2 years) with post-COVID-19 MDE. The primary outcome was improvement in physical and cognitive symptoms measured by specific items of Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale (HARS), Short Form-36 Health Survey Questionnaire (SF-36), Digit Symbol Substitution Test (DSST), Perceived Deficits Questionnaire for Depression (PDQ-D5). Changes in mood, anxiety, anhedonia, sleep, and quality of life were also investigated, as well as the underlying inflammatory status. Results show that, alongside reduction of depressive symptoms (HDRS, p<0.001), vortioxetine (mean dose: 10.1±4.1 mg/day) significantly improved physical features (all measurements p<0.001) and cognitive functioning (DDST, p=0.02; PDQ-D5, p<0.001) throughout treatment. We also observed significant reductions in inflammatory indexes. Therefore, vortioxetine might be a favorable therapeutic choice in post-COVID-19 patients with MDE because of its beneficial effects on physical complaints and cognition, features that appear to be specifically affected in relation to SARS-CoV-2 infection, and its good safety/tolerability profile. High prevalence and clinical and socioeconomic implications of COVID-19 consequences are a major public health concern and developing tailored, safe interventions is crucial to promote full functional recovery.

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Barnes, Henry W.; Demirdjian, Sally; Haddock, Naomi L.; Kaber, Gernot; Martinez, Hunter A.; Nagy, Nadine; Karmouty-Quintana, Harry; Bollyky, Paul L.

Hyaluronan in the pathogenesis of acute and post-acute COVID-19 infection

https://doi.org/10.1016/j.matbio.2023.02.001

Published

1-Feb-23

Review

https://www.sciencedirect.com/science/article/pii/S0945053X23000112

Highlights
•Hyaluronan (HA) is abundant in the sputum and serum of patients with COVID-19 acute respiratory distress syndrome (ARDS).
•There are suggestions that HA may also be present in post-acute SARS-CoV-2 infection (PASC), also known as “long COVID”.
•It may be possible to target HA in the lung therapeutically. Oral 4-MU has recently been shown to inhibit HA synthesis in the lung of healthy human patients and is under evaluation in a clinical trial in china in COVID-19.
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged as the cause of a global pandemic. Infection with SARS-CoV-2 can result in COVID-19 with both acute and chronic disease manifestations that continue to impact many patients long after the resolution of viral replication. There is therefore great interest in understanding the host factors that contribute to COVID-19 pathogenesis. In this review, we address the role of hyaluronan (HA), an extracellular matrix polymer with roles in inflammation and cellular metabolism, in COVID-19 and critically evaluate the hypothesis that HA promotes COVID-19 pathogenesis. We first provide a brief overview of COVID-19 infection. Then we briefly summarize the known roles of HA in airway inflammation and immunity. We then address what is known about HA and the pathogenesis of COVID-19 acute respiratory distress syndrome (COVID-19 ARDS). Next, we examine potential roles for HA in post-acute SARS-CoV-2 infection (PASC), also known as “long COVID” as well as in COVID-associated fibrosis. Finally, we discuss the potential therapeutics that target HA as a means to treat COVID-19, including the repurposed drug hymecromone (4-methylumbelliferone). We conclude that HA is a promising potential therapeutic target for the treatment of COVID-19.

1118

Ce309

Akanchise, Thelma; Angelova, Angelina

Potential of Nano-Antioxidants and Nanomedicine for Recovery from Neurological Disorders Linked to Long COVID Syndrome

https://doi.org/10.3390/antiox12020393

Published

1-Feb-23

Article

https://www.mdpi.com/2076-3921/12/2/393

Long-term neurological complications, persisting in patients who cannot fully recover several months after severe SARS-CoV-2 coronavirus infection, are referred to as neurological sequelae of the long COVID syndrome. Among the numerous clinical post-acute COVID-19 symptoms, neurological and psychiatric manifestations comprise prolonged fatigue, “brain fog”, memory deficits, headache, ageusia, anosmia, myalgias, cognitive impairments, anxiety, and depression lasting several months. Considering that neurons are highly vulnerable to inflammatory and oxidative stress damages following the overproduction of reactive oxygen species (ROS), neuroinflammation and oxidative stress have been suggested to dominate the pathophysiological mechanisms of the long COVID syndrome. It is emphasized that mitochondrial dysfunction and oxidative stress damages are crucial for the pathogenesis of neurodegenerative disorders. Importantly, antioxidant therapies have the potential to slow down and prevent disease progression. However, many antioxidant compounds display low bioavailability, instability, and transport to targeted tissues, limiting their clinical applications. Various nanocarrier types, e.g., liposomes, cubosomes, solid lipid nanoparticles, micelles, dendrimers, carbon-based nanostructures, nanoceria, and other inorganic nanoparticles, can be employed to enhance antioxidant bioavailability. Here, we highlight the potential of phytochemical antioxidants and other neuroprotective agents (curcumin, quercetin, vitamins C, E and D, melatonin, rosmarinic acid, N-acetylcysteine, and Ginkgo Biloba derivatives) in therapeutic strategies for neuroregeneration. A particular focus is given to the beneficial role of nanoparticle-mediated drug-delivery systems in addressing the challenges of antioxidants for managing and preventing neurological disorders as factors of long COVID sequelae.

1119

Ce310

Colzato, Lorenza S.; Elmers, Julia; Beste, Christian; Hommel, Bernhard

A Prospect to Ameliorate Affective Symptoms and to Enhance Cognition in Long COVID Using Auricular Transcutaneous Vagus Nerve Stimulation

https://doi.org/10.3390/jcm12031198

Published

1-Jan-23

Article

https://www.mdpi.com/2077-0383/12/3/1198

Long COVID, the postviral disorder caused by COVID-19, is expected to become one of the leading causes of disability in Europe. The cognitive consequences of long COVID have been described as “brain fog” and characterized by anxiety and depression, and by cognitive deficits. Long COVID is assumed to be a complex condition arising from multiple causes, including persistent brainstem dysfunction and disrupted vagal signaling. We recommend the potential application of auricular transcutaneous vagus nerve stimulation (atVNS) as an ADD-ON instrument to compensate for the cognitive decline and to ameliorate affective symptoms caused by long COVID. This technique enhances vagal signaling by directly activating the nuclei in the brainstem, which are hypoactive in long COVID to enhance mood and to promote attention, memory, and cognitive control—factors affected by long COVID. Considering that atVNS is a non-pharmacological intervention, its ADD-ON to standard pharmaceutical agents will be useful for non-responders, making of this method a suitable tool. Given that atVNS can be employed as an ecological momentary intervention (EMI), we outline the translational advantages of atVNS in the context of accelerating the cognitive and affective recovery from long COVID.

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Ce311

Souissi, Amine; Dergaa, Ismail; Romdhani, Mohamed; Ghram, Amine; Irandoust, Khadijeh; Chamari, Karim; Saad, Helmi Ben

Can melatonin reduce the severity of post-COVID-19 syndrome?

https://doi.org/10.17179/excli2023-5864

Published

2-Feb-23

Review

https://www.excli.de/index.php/excli/article/view/5864

This short review aimed at (i) providing an update on the health benefits associated with melatonin supplementation, while (ii) considering future potential research directions concerning melatonin supplementation use relative to Coronavirus disease of 2019 (COVID-19). A narrative review of the literature was undertaken to ascertain the effect of exogenous melatonin administration on humans. Night-time melatonin administration has a positive impact on human physiology and mental health. Indeed, melatonin (i) modulates the circadian components of the sleep-wake cycle; (ii) improves sleep efficiency and mood status; (iii) improves insulin sensitivity; and (iv) reduces inflammatory markers and oxidative stress. Melatonin has also remarkable neuroprotective and cardioprotective effects and may therefore prevent deterioration caused by COVID-19. We suggest that melatonin could be used as a potential therapy in the post-COVID-19 syndrome, and therefore call for action the research community to investigate on the potential use of exogenous melatonin to enhance the quality of life in patients with post-COVID-19 syndrome.

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Ce312

Buchhorn, Reiner

Therapeutic Approaches to Dysautonomia in Childhood, with a Special Focus on Long COVID

https://doi.org/10.3390/children10020316

Published

1-Feb-23

Study

https://www.mdpi.com/2227-9067/10/2/316

Background: Dysautonomia seems to be important for the pathophysiology of psychosomatic diseases and, more recently, for long COVID. This concept may explain the clinical symptoms and could help open new therapeutic approaches. Methods: We compared our data from an analysis of heart rate variability (HRV) in an active standing test in 28 adolescents who had developed an inappropriate sinus tachycardia (IST, n = 13) or postural orthostatic tachycardia syndrome (POTS, n = 15) after contracting COVID-19 disease and/or vaccination with 64 adolescents from our database who developed dysautonomia due to psychosomatic diseases prior to the COVID-19 pandemic. We prove the effects of our treatment: omega-3 fatty acid supplementation (O3-FA, n = 18) in addition to propranolol (low dose, up to 20-20-0 mg, n = 32) or ivabradine 5-5-0 mg (n = 17) on heart rate regulation and heart rate variability (HRV). Results: The HRV data were not different between the adolescents with SARS-CoV-2-related disorders and the adolescents with dysautonomia prior to the pandemic. The heart rate increases in children with POTS while standing were significantly lower after low-dose propranolol (27.2 ± 17.4 bpm***), ivabradine (23.6 ± 8.12 bpm*), and O-3-FA (25.6 ± 8.4 bpm*). The heart rate in children with IST while lying/standing was significantly lower after propranolol (81.6 ± 10.1 bpm**/101.8 ± 18.8***), ivabradine (84.2 ± 8.4 bpm***/105.4 ± 14.6**), and O-3-FA (88.6 ± 7.9 bpm*/112.1/14.9*). Conclusions: The HRV data of adolescents with dysautonomia after COVID-19 disease/vaccination are not significantly different from a historical control of adolescents with dysautonomia due to psychosomatic diseases prior to the pandemic. Low-dose propranolol > ivabradine > omega-3 fatty acids significantly decrease elevated heart rates in patients with IST and the heart rate increases in patients with POTS and may be beneficial in these children with dysautonomia.

1122

Ce313

Chandan, Joht Singh; Brown, Kirsty R.; Simms-Williams, Nikita; Bashir, Nasir Z.; Camaradou, Jenny; Heining, Dominic; Turner, Grace M.; Rivera, Samantha Cruz; Hotham, Richard; Minhas, Sonica; Nirantharakumar, Krishnarajah; Sivan, Manoj; Khunti, Kamlesh; Raindi, Devan; Marwaha, Steven; Hughes, Sarah E.; McMullan, Christel; Marshall, Tom; Calvert, Melanie J.; Haroon, Shamil; Aiyegbusi, Olalekan Lee

Non-Pharmacological Therapies for Post-Viral Syndromes, Including Long COVID: A Systematic Review

https://doi.org/10.3390/ijerph20043477

Published

1-Jan-23

Review

https://www.mdpi.com/1660-4601/20/4/3477

Background: Post-viral syndromes (PVS), including Long COVID, are symptoms sustained from weeks to years following an acute viral infection. Non-pharmacological treatments for these symptoms are poorly understood. This review summarises the evidence for the effectiveness of non-pharmacological treatments for PVS. Methods: We conducted a systematic review to evaluate the effectiveness of non-pharmacological interventions for PVS, as compared to either standard care, alternative non-pharmacological therapy, or placebo. The outcomes of interest were changes in symptoms, exercise capacity, quality of life (including mental health and wellbeing), and work capability. We searched five databases (Embase, MEDLINE, PsycINFO, CINAHL, MedRxiv) for randomised controlled trials (RCTs) published between 1 January 2001 to 29 October 2021. The relevant outcome data were extracted, the study quality was appraised using the Cochrane risk-of-bias tool, and the findings were synthesised narratively. Findings: Overall, five studies of five different interventions (Pilates, music therapy, telerehabilitation, resistance exercise, neuromodulation) met the inclusion criteria. Aside from music-based intervention, all other selected interventions demonstrated some support in the management of PVS in some patients. Interpretation: In this study, we observed a lack of robust evidence evaluating the non-pharmacological treatments for PVS, including Long COVID. Considering the prevalence of prolonged symptoms following acute viral infections, there is an urgent need for clinical trials evaluating the effectiveness and cost-effectiveness of non-pharmacological treatments for patients with PVS. Registration: The study protocol was registered with PROSPERO [CRD42021282074] in October 2021 and published in BMJ Open in 2022.

1123

Ce314

Adamová, Andrea; Laskov, Olga; Biačková, Nina; Novák, Tomáš; Voráčková, Veronika; Renka, Jiří; Klírová, Monika

Transcranial Direct Current Stimulation (TDCS) As A Therapeutic Intervention For Post-Acute Neuropsychiatric Sequelae Of SARS-COV-2

https://doi.org/10.1016/j.brs.2023.01.394

Published

1-Jan-23

Study

https://www.brainstimjrnl.com/article/S1935-861X(23)00396-0/fulltext

Background: There is a significant lack of effective treatment strategies for post-acute sequelae of SARS-Cov-2 (PASC). Neuropsychiatric (NP) symptoms, including functional impairment, emotional, and cognitive dysregulation, are among the most common manifestations of PASC. Non-invasive brain stimulation (NIBS) could represent a treatment method for post-acute and chronic stages of COVID-19. The first clinical results indicate the therapeutic potential of transcranial direct current stimulation (tDCS) in influencing NP symptoms of PASC associated with the advantage of portable devices with the possibility of home use.
Methods: A four-week, double-blind, randomized, placebo-controlled, parallel study was used to compare the efficacy (response to the treatment, effect duration) and safety of a 4-week active prefrontal cortex (PFC) tDCS (20 tDCS applications with anode placement at F3; 2 mA, 30 min/tDCS session) to placebo-tDCS in the treatment of NP symptoms of PASC. Patients were clinically assessed by “The Fatigue Impact Scale“ (FIS) and “The post-COVID-19 Symptoms Assessment Questionnaire“ (A-PASC), at baseline, after two weeks, and at the end of four weeks of treatment.
Results: 15 out of 34 enrolled patients were included in the Intention-to-treat (ITT) analysis. The treatment groups did not differ in age, gender, and at baseline FIS and A-PASC. PFC-tDCS (did not) showed better improvement (as assessed by FIS and A_PASC) compared to sham tDCS after four weeks. However, the study is still in progress and the results will be updated. No major side effects were observed during and after the treatment.
publisher: Elsevier

1124

Ce315

Vidal, Kallene; Cavendish, Beatriz; Lima, Alisson Lima; Bertola, Laiss; Charveth, Leigh; Bikson, Marom; Brunoni, Andre

Combination of transcranial direct current stimulation with online cognitive training improves symptoms of Post-acute Sequelae of COVID-19: a case series

https://doi.org/10.1016/j.brs.2023.01.348

Published

1-Jan-23

Study

https://www.brainstimjrnl.com/article/S1935-861X(23)00350-9/fulltext

Post-Acute Sequelae of COVID-19 (PASC) has been associated with cognitive impairment and complains in up to 90% of individuals after the infection by COVID 19. In this context, there is an urgent need to develop treatments for this disorder. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation intervention that can modulate neuronal excitability and improve PASC neurocognitive symptoms. Here, we investigated the effects of this intervention in a case series of four patients with cognitive symptoms using the Assessment of PASC (A-PASC) inventory. The intervention consisted of 20-minute, 2mA, 20 daily sessions of bilateral prefrontal (anodal-left/cathodal-right) tDCS (1x1 Mini-CT, Soterix Medical, New York, NY) plus online cognitive training using the BrainHQ platform (Posit Science, San Francisco, Glenn Smith). Several neuropsychological domains were assessed at baseline and endpoint. After treatment ,all participants described cognitive and emotional complaints decreasing. The neuropsychological assessment showed that the participants performed better for delayed and immediate recall in the verbal episodic memory task. They showed an improving trend in lexicon assessment, and in phonemic verbal fluency. The same was observed for the sustained attention task. Also, the participants showed a trend in becoming faster and more accurate in processing speed, and in executive function (inhibitory control, cognitive flexibility and time management). These are preliminary results from a pilot study that preceded an ongoing, double-blinded, randomized controlled trial comparing the effects of cognitive training combined with sham or active tDCS at University of São Paulo, Brazil.
publisher: Elsevier

1125

Ce316

Biačková, Nina; Klírová, Monika; Voráčková, Veronika; Adamová, Andrea; Novák, Tomáš; Renka, Jiří; Laskov, Olga

Treatment of cognitive symptoms in post-COVID-19 syndrome – a transcranial direct current stimulation (tDCS) approach

https://doi.org/10.1016/j.brs.2023.01.391

Published

1-Jan-23

Study

https://www.brainstimjrnl.com/article/S1935-861X(23)00393-5/fulltext

Background: Despite the acute infection's remission, COVID-19 is associated with clinically severe residual symptoms (i.e., post-COVID-19 syndrome). One of the most prevalent and incapacitating symptoms of the syndrome is fatigue, accompanied by cognitive impairment. Very few therapy options are effective for post-acute SARS-Cov-2 sequelae (PASC). There is a possibility that non-invasive brain stimulation methods could become successful and convenient treatment options for post-acute and chronic COVID-19. There are already the first clinical results for the use of transcranial direct current stimulation (tDCS) in the therapy of PASC. Our goal was to study the potential tDCS effect on cognitive impairment in patients with PASC.
Methods: We present a four-week, double-blind, randomized, placebo-controlled, parallel study with a 4-week active dorsolateral prefrontal cortex (DLPFC) tDCS (20 tDCS applications; anode on the F3; 2 mA, 30 min/tDCS session). Patients were evaluated with tests measuring attention (digit span forward), working memory (digit span backward), and psychomotor speed (digit symbol substitution test) at baseline, after two weeks, and at the end of four weeks of treatment. The tests were chosen according to previous studies on the assessment of cognitive function in patients after COVID-19.
Results: 15 out of 34 enrolled patients were included in Intention-to-treat (ITT) analysis. The treatment groups did not differ in age, gender, and baseline cognitive tests. There wasn’t a significant difference in cognitive tests results between active DLPFC tDCS and sham tDCS after four weeks. However, the study is still in progress and the results will be updated. No major side effects were observed during and after the treatment.
publisher: Elsevier

1126

Ce317

Seeley, Marie-Claire; Hooper, Matthew; Tan, Jason; Wells, Rachel; Gallagher, Celine; Lau, Dennis H.

Plasma exchange improves cognitive function in long-COVID related postural orthostatic tachycardia syndrome and autoimmune neurological dysfunction: Seeley et al. Plasmapheresis in long-COVID

https://doi.org/10.1016/j.amjmed.2023.01.043

Published

21-Feb-23

Study

https://www.amjmed.com/article/S0002-9343(23)00100-6/fulltext

1127

Ce318

Fang, Chao; Baz, Sarah; Carpentieri, JD; Sheard, Laura; Newlands, Fiona; Shafran, Roz

Understanding and supporting the long-term effects of COVID-19: A report from the Qualitative Long COVID Research Network in the United Kingdom

Published

1-Feb-33

Guidelines

https://www.convalescence.ac.uk/wp-content/uploads/2023/02/Briefing-report.pdf

1128

Ce319

Mińko, Alicja; Turoń-Skrzypińska, Agnieszka; Rył, Aleksandra; Szylińska, Aleksandra; Denisewicz, Iwona; Rotter, Iwona

Effects of Comprehensive Rehabilitation on Pulmonary Function in Patients Recovering from COVID-19

https://doi.org/10.3390/ijerph20053985

Published

1-Jan-23

Study

https://www.mdpi.com/1660-4601/20/5/3985

The aim of this study is to evaluate the effect of inpatient rehabilitation on pulmonary function in patients recovering from COVID-19, a multifaceted disease caused by the SARS-CoV-2 virus. This aspect of recovery is crucial, as pneumonia associated with this disease can cause lung-function abnormalities with varying degrees of hypoxemia. This study involved 150 patients qualified for inpatient rehabilitation following SARS-CoV-2 infection. Functional assessment of the lungs was performed by spirometry. The mean age of patients was 64.66 (±11.93) years, and the mean body mass index (BMI) was 29.16 (±5.68). The tests showed a statistically significant improvement in spirometric parameters. The rehabilitation program based on aerobic, strength, and endurance exercises improved lung-function parameters in the long term. The improvement in spirometric parameters in patients after COVID-19 may be related to body mass index (BMI).

1129

Ce320

Torres-Castro, Rodrigo; Núñez-Cortés, Rodrigo; Larrateguy, Santiago; Alsina-Restoy, Xavier; Barberà, Joan Albert; Gimeno-Santos, Elena; García, Agustin Roberto; Sibila, Oriol; Blanco, Isabel

Assessment of Exercise Capacity in Post-COVID-19 Patients: How Is the Appropriate Test Chosen?

https://doi.org/10.3390/life13030621

Published

1-Mar-23

Review

https://www.mdpi.com/2075-1729/13/3/621

There is a wide range of sequelae affecting COVID-19 survivors, including impaired physical capacity. These sequelae can affect the quality of life and return to work of the active population. Therefore, one of the pillars of following-up is the evaluation of physical capacity, which can be assessed with field tests (such as the six-minute walk test, the one-minute standing test, the Chester step test, and the shuttle walking test) or laboratory tests (such as the cardiopulmonary exercise test). These tests can be performed in different contexts and have amply demonstrated their usefulness in the assessment of physical capacity both in post-COVID-19 patients and in other chronic respiratory, metabolic, cardiologic, or neurologic diseases. However, when traditional tests cannot be performed, physical function can be a good substitute, especially for assessing the effects of an intervention. For example, the Short Physical Performance Battery assessment and the Timed Up and Go assessment are widely accepted in older adults. Thus, the test should be chosen according to the characteristics of each subject.

1130

Ce321

Sasaki, Nobuyuki; Yamatoku, Masato; Tsuchida, Tomoya; Sato, Hiroyuki; Yamaguchi, Keiichiro

Effect of Repetitive Transcranial Magnetic Stimulation on Long Coronavirus Disease 2019 with Fatigue and Cognitive Dysfunction

https://doi.org/10.2490/prm.20230004

Published

15-Jul-05

Study

Objectives: There is no established treatment for chronic fatigue and various cognitive dysfunctions (brain fog) caused by long coronavirus disease 2019 (COVID-19). We aimed to clarify the effectiveness of repetitive transcranial magnetic stimulation (rTMS) for treating these symptoms.Methods: High-frequency rTMS was applied to occipital and frontal lobes in 12 patients with chronic fatigue and cognitive dysfunction 3 months after severe acute respiratory syndrome coronavirus 2 infection. Before and after ten sessions of rTMS, Brief Fatigue Inventory (BFI), Apathy Scale (AS), and Wechsler Adult Intelligence Scale-fourth edition (WAIS4) were determined and N-isopropyl-p-[123I]iodoamphetamine single photon emission computed tomography (SPECT) was performed.Results: Twelve subjects completed ten sessions of rTMS without adverse events. The mean age of the subjects was 44.3 ± 10.7 years, and the mean duration of illness was 202.4 ± 114.5 days. BFI, which was 5.7 ± 2.3 before the intervention, decreased significantly to 1.9 ± 1.8 after the intervention. The AS was significantly decreased after the intervention from 19.2 ± 8.7 to 10.3 ± 7.2. All WAIS4 sub-items were significantly improved after rTMS intervention, and the full-scale intelligence quotient increased from 94.6 ± 10.9 to 104.4 ± 13.0. Hypoperfusion in the bilateral occipital and frontal lobes observed on SPECT improved in extent and severity after ten sessions of rTMS.Conclusions: Although we are still in the early stages of exploring the effects of rTMS, the procedure has the potential for use as a new non-invasive treatment for the symptoms of long COVID.

1131

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Sadeghdoust, Mohammadamin; Aligolighasemabadi, Farnaz; Dehesh, Tania; Taefehshokr, Nima; Sadeghdoust, Adel; Kotfis, Katarzyna; Hashemiattar, Amirhossein; Ravandi, Amir; Aligolighasemabadi, Neda; Vakili, Omid; Grabarek, Beniamin; Staszkiewicz, Rafał; Łos, Marek J.; Mokarram, Pooneh; Ghavami, Saeid

The Effects of Statins on Respiratory Symptoms and Pulmonary Fibrosis in COVID-19 Patients with Diabetes Mellitus: A Longitudinal Multicenter Study

https://doi.org/10.1007/s00005-023-00672-1

Published

28-Feb-23

Study

https://doi.org/10.1007/s00005-023-00672-1

The aim of this prospective cohort study was to explore the effect of statins on long-term respiratory symptoms and pulmonary fibrosis in coronavirus disease 2019 (COVID-19) patients with diabetes mellitus (DM). Patients were recruited from three tertiary hospitals, categorized into Statin or Non-statin groups, and assessed on days 0, 28, and 90 after symptoms onset to record the duration of symptoms. Pulmonary fibrosis was scored at baseline and follow-up time points by high-resolution computed tomography scans. Each group comprised 176 patients after propensity score matching. Data analysis revealed that the odds of having cough and dyspnea were significantly higher in the Non-statin group compared to the Statin group during the follow-up period. Overall, there was no significant difference in the change in pulmonary fibrosis score between groups. However, Non-statin patients with > 5 years of DM were more likely to exhibit a significantly higher fibrosis score during the follow-up period as compared to their peers in the Statin group. Our results suggest that the use of statins is associated with a lower risk of developing chronic cough and dyspnea in diabetic patients with COVID-19, and may reduce pulmonary fibrosis associated with COVID-19 in patients with long-term (> 5 years) DM.

1132

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Sova, Milan; Sovova, Eliska; Ozana, Jaromir; Moravcova, Katarina; Sovova, Marketa; Jelinek, Libor; Mizera, Jan; Genzor, Samuel

Post-COVID Syndrome and Cardiorespiratory Fitness—26-Month Experience of Single Center

https://doi.org/10.3390/life13030684

Published

1-Mar-23

Study

https://www.mdpi.com/2075-1729/13/3/684

Introduction: Persistent post-COVID syndrome, also referred to as long COVID, is a pathologic entity that involves persistent physical, medical, and cognitive sequelae following COVID-19. Decreased fitness has repeatedly been reported in numerous studies dealing with post-COVID syndrome, however, it is still not fully clear which groups of patients may be more susceptible for persisting symptoms. Aim: The aim of our study was to evaluate the number of post-COVID patients with cardiac symptoms, where these patients were evaluated by CPET and the results compared with a control group of patients. Methods: Follow-up of patients in post-COVID outpatient clinic from 1 March 2020 to 31 May 2022. Inclusion criteria were positive PCR test for SARS-CoV-2 and age 18–100. The initial examination was performed 4–12 weeks after the disease onset. All patients with possible cardiac symptoms had completed cardiopulmonary exercise testing. The control group was randomly selected from a database of clients in 2019, with the preventive reason for evaluation. Results: From 1 March 2020 to 31 May 2022, 2732 patients (45.7% males) were evaluated with a mean age of 54.6 ± 14.7. CPET was indicated only in 97 patients (3.5%). Seventy-four patients (26 male) achieved the exercise maximum and a comparison were made with a control group (same age (p = 0.801), BMI (p = 0.721), and sex ratio). No significant dependence between the parameter VO2 max mL/kg/min and post-COVID disability was demonstrated (p = 0.412). Spearman’s correlation analysis did not show a significant relationship between the parameter VO2 max mL/kg/min and the severity of COVID-19 (p = 0.285). Conclusions: Cardiac symptoms occurred in only a small percentage of patients in our study. There is a need for further studies that would objectively evaluate the effect of COVID-19 disease on the patient’s health.

1133

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Patterson, Bruce K.; Yogendra, Ram; Guevara-Coto, Jose; Mora-Rodriguez, Rodrigo A.; Osgood, Eric; Bream, John; Parikh, Purvi; Kreimer, Mark; Jeffers, Devon; Rutland, Cedric; Kaplan, Gary; Zgoda, Michael

Case series: Maraviroc and pravastatin as a therapeutic option to treat long COVID/Post-acute sequelae of COVID (PASC)

https://doi.org/10.3389/fmed.2023.1122529

Published

8-Feb-23

Case Series

https://www.frontiersin.org/articles/10.3389/fmed.2023.1122529

Post-acute sequelae of COVID (PASC), or long COVID, is a multisystem complication of SARS-CoV-2 infection that continues to debilitate millions worldwide thus highlighting the public health importance of identifying effective therapeutics to alleviate this illness. One explanation behind PASC may be attributed to the recent discovery of persistent S1 protein subunit of SARS-CoV-2 in CD16+ monocytes up to 15 months after infection. CD16+ monocytes, which express both CCR5 and fractalkine receptors (CX3CR1), play a role in vascular homeostasis and endothelial immune surveillance. We propose targeting these receptors using the CCR5 antagonist, maraviroc, along with pravastatin, a fractalkine inhibitor, could disrupt the monocytic-endothelial-platelet axis that may be central to the etiology of PASC. Using five validated clinical scales (NYHA, MRC Dyspnea, COMPASS-31, modified Rankin, and Fatigue Severity Score) to measure 18 participants’ response to treatment, we observed significant clinical improvement in 6 to 12 weeks on a combination of maraviroc 300 mg per oral twice a day and pravastatin 10 mg per oral daily. Subjective neurological, autonomic, respiratory, cardiac and fatigue symptoms scores all decreased which correlated with statistically significant decreases in vascular markers sCD40L and VEGF. These findings suggest that by interrupting the monocytic-endothelial-platelet axis, maraviroc and pravastatin may restore the immune dysregulation observed in PASC and could be potential therapeutic options. This sets the framework for a future double-blinded, placebo-controlled randomized trial to further investigate the drug efficacy of maraviroc and pravastatin in treating PASC.

1134

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Zulbaran-Rojas, Alejandro; Lee, Myeounggon; Bara, Rasha O.; Flores-Camargo, Areli; Spitz, Gil; Finco, M. G.; Bagheri, Amir Behzad; Modi, Dipaben; Shaib, Fidaa; Najafi, Bijan

Electrical stimulation to regain lower extremity muscle perfusion and endurance in patients with post-acute sequelae of SARS CoV-2: A randomized controlled trial

https://doi.org/10.14814/phy2.15636

Published

15-Jul-05

Trial

https://onlinelibrary.wiley.com/doi/abs/10.14814/phy2.15636

Muscle deconditioning and impaired vascular function in the lower extremities (LE) are among the long-term symptoms experienced by COVID-19 patients with a history of severe illness. These symptoms are part of the post-acute sequelae of Sars-CoV-2 (PASC) and currently lack evidence-based treatment. To investigate the efficacy of lower extremity electrical stimulation (E-Stim) in addressing PASC-related muscle deconditioning, we conducted a double-blinded randomized controlled trial. Eighteen (n = 18) patients with LE muscle deconditioning were randomly assigned to either the intervention (IG) or the control (CG) group, resulting in 36 LE being assessed. Both groups received daily 1 h E-Stim on both gastrocnemius muscles for 4 weeks, with the device functional in the IG and nonfunctional in the CG. Changes in plantar oxyhemoglobin (OxyHb) and gastrocnemius muscle endurance (GNMe) in response to 4 weeks of daily 1 h E-Stim were assessed. At each study visit, outcomes were measured at onset (t0), 60 min (t60), and 10 min after E-Stim therapy (t70) by recording ΔOxyHb with near-infrared spectroscopy. ΔGNMe was measured with surface electromyography at two time intervals: 0–5 min (Intv1) and: 55–60 min (Intv2). Baseline OxyHb decreased in both groups at t60 (IG: p = 0.046; CG: p = 0.026) and t70 (IG = p = 0.021; CG: p = 0.060) from t0. At 4 weeks, the IG's OxyHb increased from t60 to t70 (p < 0.001), while the CG's decreased (p = 0.003). The IG had higher ΔOxyHb values than the CG at t70 (p = 0.004). Baseline GNMe did not increase in either group from Intv1 to Intv2. At 4 weeks, the IG's GNMe increased (p = 0.031), whereas the CG did not change. There was a significant association between ΔOxyHb and ΔGNMe (r = 0.628, p = 0.003) at 4 weeks in the IG. In conclusion, E-Stim can improve muscle perfusion and muscle endurance in individuals with PASC experiencing LE muscle deconditioning.

1135

Ce326

Foss, Violeta; Maddie, Nicole; Frankini, Elisabeth; Landman, Scott; Maccagnano, Jennifer; Yao, Sheldon

Covid-19 Fatigue: Diagnosis and Treatment for the Osteopathic Physician

https://doi.org/10.33181/13090

Published

8-Mar-23

Review

https://www.ofpjournal.com/index.php/ofp/article/view/843

The novel coronavirus disease 2019 (COVID-19) has given rise to a global pandemic, as well as a multitude of long-term sequelae that continue to perplex physicians around the world, including in the United States. Among the most common and impactful long-haul symptoms experienced by survivors is COVID-19 fatigue. This review will use long COVID-19, post-acute COVID-19 syndrome (PCS), and Post-Acute Sequelae of COVID-19 (PASC) as synonymous terms to refer to the chronic symptomatology; chronic fatigue associated with PASC will be referred to as COVID-19 fatigue. While the knowledge and research on the exact pathophysiological mechanisms involved in the disease is still limited, parallels have been drawn between fatigue as a component of long COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Current studies suggest applying principles of pathophysiology, diagnosis, and treatment similar to those for ME/CFS in order to aid in managing chronic fatigue in COVID-19 survivors, particularly in the primary care setting. The osteopathic family physician can use the proposed pharmacologic agents, along with osteopathic manipulative treatment (OMT), as therapeutic modalities that can be tailored to each patient’s unique case. Nevertheless, research on proven successful treatments is still scarce. For that reason, it is essential that COVID-19 fatigue is recognized early, especially since its longitudinal impacts may be debilitating for many. This review of the available literature on COVID-19 fatigue aims to help provide quality care and lessen the disease burden experienced by patients.

1136

Ce327

Calvani, Riccardo; Gervasoni, Jacopo; Picca, Anna; Ciciarello, Francesca; Galluzzo, Vincenzo; Coelho-Júnior, Hélio José; Di Mario, Clara; Gremese, Elisa; Lomuscio, Sara; Paglionico, Anna Maria; Santucci, Lavinia; Tolusso, Barbara; Urbani, Andrea; Marini, Federico; Marzetti, Emanuele; Landi, Francesco; Tosato, Matteo

Effects of l-Arginine Plus Vitamin C Supplementation on l-Arginine Metabolism in Adults with Long COVID: Secondary Analysis of a Randomized Clinical Trial

https://doi.org/10.3390/ijms24065078

Published

1-Jan-23

Study

https://www.mdpi.com/1422-0067/24/6/5078

Altered l-arginine metabolism has been described in patients with COVID-19 and has been associated with immune and vascular dysfunction. In the present investigation, we determined the serum concentrations of l-arginine, citrulline, ornithine, monomethyl-l-arginine (MMA), and symmetric and asymmetric dimethylarginine (SDMA, ADMA) in adults with long COVID at baseline and after 28-days of l-arginine plus vitamin C or placebo supplementation enrolled in a randomized clinical trial, compared with a group of adults without previous history of SARS-CoV-2-infection. l-arginine-derived markers of nitric oxide (NO) bioavailability (i.e., l-arginine/ADMA, l-arginine/citrulline+ornithine, and l-arginine/ornithine) were also assayed. Partial least squares discriminant analysis (PLS–DA) models were built to characterize systemic l-arginine metabolism and assess the effects of the supplementation. PLS–DA allowed discrimination of participants with long COVID from healthy controls with 80.2 ± 3.0% accuracy. Lower markers of NO bioavailability were found in participants with long COVID. After 28 days of l-arginine plus vitamin C supplementation, serum l-arginine concentrations and l-arginine/ADMA increased significantly compared with placebo. This supplement may therefore be proposed as a remedy to increase NO bioavailability in people with long COVID.

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Quinn, Kieran L.; Cheung, Angela M.; Razak, Fahad

Traiter les symptômes courants et potentiellement modifiables du syndrome post-COVID-19 (COVID-19 de longue durée) chez l’adulte

https://doi.org/10.1503/cmaj.220824-f

Published

6-Mar-23

Article

https://www.cmaj.ca/content/195/9/e350

Un plan de reprise progressive des activités et une stratégie de conservation d’énergie sont indiqués pour traiter la fatigue et la malaise post-effort associés à la COVID-19 de longue durée1
Afin d’éviter le déclenchement d’épisodes de malaise post-effort, il faut conseiller aux patients de suivre un programme de reprise des activités structuré fondé sur les symptômes et le niveau de fatigue. Ils doivent apprendre à appliquer des stratégies physiques, émotionnelles et cognitives de conservation d’énergie, en particulier les 4 principes consistant à doser les activités au niveau d’énergie, à accorder la priorité aux activités les plus importantes (en déterminant celles qui doivent être exécutées le jour même et celles qui peuvent être retardées), à adopter une bonne posture pour modifier les activités et les rendre plus faciles à accomplir (p. ex., en position assise), et à planifier leur horaire1.

Des interventions psychosociales et des médicaments conformes aux lignes directrices peuvent être prescrits pour traiter les complications de santé mentale de la COVID-19 de longue durée
L’anxiété, la dépression et le trouble de stress post-traumatique font partie des manifestations de santé mentale les plus fréquentes de la COVID-19 de longue durée et peuvent être pris en charge en suivant les lignes directrices existantes, qui sont similaires à celles relatives à l’encéphalomyélite myalgique2. Le traitement de la fatigue par la thérapie cognitivo-comportementale est controversé et n’est pas approuvé par la ME Association2.

Des exercices de respiration, le positionnement du corps et la réadaptation pulmonaire peuvent atténuer la dyspnée2
Des exercices de respiration profonde ou avec la bouche à demi fermée peuvent atténuer les symptômes de dyspnée légère. L’hypoxémie persistante n’est pas une manifestation fréquente de la COVID-19 de longue durée, mais elle peut être provoquée par une pneumopathie grave ou une pneumonie organisée. Il faut donc orienter rapidement les patients concernés vers un pneumologue et envisager le recours à des services de réadaptation pulmonaire2,3.

Des conseils sur l’hygiène du sommeil, les techniques de relaxation et le contrôle des stimuli sont utiles pour les personnes atteintes de troubles du sommeil2
Les troubles du sommeil sont parfois secondaires à l’infection par le SRAS-CoV-2 ou aux effets négatifs de la pandémie2. Ils peuvent être pris en charge par une thérapie cognitivo-comportementale ou l’un des traitements offerts au Canada: eszopiclone, zolpidem ou doxépine4.

Des lignes directrices précises existent pour différentes causes de palpitations et tachycardie
Les recommandations actuelles pour traiter la tachycardie sinusale inappropriée et le syndrome de tachycardie orthostatique posturale (STOP) comprennent les modifications comportementales, l’apport liquidien, le sel, les bas de contention, les bêtabloquants, l’ivabradine et la midodrine5.
publisher: CMAJ
section: Pratique
PMID: 36878541

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Ce329

Heining, Dominic

Non-pharmacological therapies for post-viral syndromes, including long COVID: a systematic review.

https://doi.org/10.3390/ijerph20043477

Published

16-Feb-23

Review

https://rwt.dspace-express.com/handle/20.500.12687/1443

Background: Post-viral syndromes (PVS), including Long COVID, are symptoms sustained from weeks to years following an acute viral infection. Non-pharmacological treatments for these symptoms are poorly understood. This review summarises the evidence for the effectiveness of non-pharmacological treatments for PVS.

Methods: We conducted a systematic review to evaluate the effectiveness of non-pharmacological interventions for PVS, as compared to either standard care, alternative non-pharmacological therapy, or placebo. The outcomes of interest were changes in symptoms, exercise capacity, quality of life (including mental health and wellbeing), and work capability. We searched five databases (Embase, MEDLINE, PsycINFO, CINAHL, MedRxiv) for randomised controlled trials (RCTs) published between 1 January 2001 to 29 October 2021. The relevant outcome data were extracted, the study quality was appraised using the Cochrane risk-of-bias tool, and the findings were synthesised narratively.

Findings: Overall, five studies of five different interventions (Pilates, music therapy, telerehabilitation, resistance exercise, neuromodulation) met the inclusion criteria. Aside from music-based intervention, all other selected interventions demonstrated some support in the management of PVS in some patients.

Interpretation: In this study, we observed a lack of robust evidence evaluating the non-pharmacological treatments for PVS, including Long COVID. Considering the prevalence of prolonged symptoms following acute viral infections, there is an urgent need for clinical trials evaluating the effectiveness and cost-effectiveness of non-pharmacological treatments for patients with PVS.

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Saif-Ur-Rahman, K. M.; Kothari, Kavita; Sadlier, Corinna; Moriarty, Frank; Movsisyan, Ani; Whelan, Sean; Taneri, Petek E.; Blair, Matthew; Guyatt, Gordon; Devane, Declan

Effect of pharmacological interventions for the treatment of people with post-COVID-19 condition: A rapid review

https://doi.org/10.1002/cesm.12001

Published

15-Jul-05

Review

https://onlinelibrary.wiley.com/doi/abs/10.1002/cesm.12001

Objective Little is known about the treatment of post-coronavirus disease 2019 (COVID-19) condition (PCC). This article examines the effectiveness of pharmacological interventions for treating people with PCC. Methods We searched Medline, EMBASE, ClinicalTrials. gov, and the International Clinical Trials Registry Platform. Two independent review authors screened citations, extracted data, and assessed the quality of the included studies. Due to heterogeneity in participants, interventions, and outcomes, we synthesized data narratively. We assessed the certainty of evidence using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). Participants People with PCC. Interventions Pharmacological interventions include corticosteroids, ivabradine, and inhaled hydrogen. Outcome Measures Olfactory function, sinus tachycardia, respiratory function. Results We identified 5 completed studies and 41 ongoing studies. Oral corticosteroids and olfactory training had higher olfactory scores after 10 weeks (MD: 5.60, 95% confidence interval [CI]: 1.41 to 9.79). Patients allocated oral corticosteroid, and nasal irrigation demonstrated improved recovery of olfactory function compared with the control group at 40 days (median 60, interquartile range [IQR]: 40 vs. median 30, IQR: 25, p = 0.024). Patients allocated to topical corticosteroid nasal spray and olfactory training had improved recovery of olfactory function after 2 weeks (median 7, IQR: 5−10 vs. median 5, IQR: 2−8, p = 0.08). Participants allocated to ivabradine had a greater mean reduction in heart rate compared with participants randomized to carvedilol (MD: −4.24, 95% CI: −10.09 to 1.61). Participants allocated to inhaled hydrogen therapy had an improved vital capacity (MD: 0.20, 95% CI: 0.07 to 0.33), forced expiratory volume (MD: 0.19, 95% CI: 0.04 to 0.34), 6-minute walk test (MD: 55.0, 95% CI: 36.04 to 73.96). Conclusions The evidence is of low to very low certainty about the effect of all pharmacological interventions investigated for the treatment of people with PCC. There is currently a significant body of research underway that could expand the evidence to inform treatment decisions on pharmacological interventions for PCC.

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Hashimoto, Kenji

Overview of the potential use of fluvoxamine for COVID-19 and long COVID

https://doi.org/10.1007/s44192-023-00036-3

Published

21-Mar-23

Review

https://doi.org/10.1007/s44192-023-00036-3

Coronavirus disease 2019 (COVID-19) has presented a serious worldwide threat to public health since its emergence in late 2019. From a safety point of view, drug repurposing has received particular attention. Several clinical studies have demonstrated that the use of fluvoxamine, a selective serotonin reuptake inhibitor with potent sigma-1 receptor agonism, in the early-stage of infection might be associated with the prevention of clinical deterioration in individuals with SARS-CoV-2 infection, although several reports have shown that a low dose of fluvoxamine may be ineffective. There is increasing evidence that SARS-CoV-2 can cross the blood–brain barrier, resulting in a number of psychiatric and neurologic symptoms in COVID-19 survivors. Importantly, about half of COVID-19 survivors experience a variety of long-term sequelae, including psychiatric and neurologic symptoms, known as long COVID. In this priority review, the author presents an overview of the potential use of fluvoxamine in the treatment of COVID-19 and long COVID.

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Veliz, Philip T.; Zhou, Weijiao; Smith, Sheree; Larson, Janet L.

Substance Use and the Self-Management of Persistent Symptoms of COVID-19

https://doi.org/10.1080/10826084.2023.2184208

Published

21-Mar-23

Study

https://doi.org/10.1080/10826084.2023.2184208

Background: Understanding the self-management practices of persistent symptoms of SARS-Cov-2 (COVID-19) is critical given the misinformation that has been presented about this disease in the U.S. The purpose of this descriptive study is to assess the self-management of persistent symptoms of COVID-19 with commonly used and misused substances (i.e., alcohol, marijuana and commonly prescribed medications) among adults in the U.S. Methods: The data for this study comes from a cross-sectional survey of U.S. adults that was designed to broadly assess symptom burden, persistent symptom patterns, self-efficacy for symptom management and self-management strategies among people who experienced persistent/Long COVID. Multiple logistic regression analyses were used to assess how symptom length of COVID-19 was associated with the use of several substances to manage these persistent symptoms. Results: The analysis found that adults who had COVID-19 symptoms that persisted for 13 weeks or longer had higher rates of using alcohol (27.3%), marijuana (30.9%) and prescription tranquilizers (21.4%) to manage these symptoms when compared to their adult peers who had COVID-19 symptoms persist for only 4 weeks or less. For instance, the odds of indicating the use of marijuana (AOR = 4.21 95% CI = 1.68,10.5) to manage COVID-19 related symptoms was roughly four times higher for respondents who had COVID-19 symptoms persist for 13 weeks or longer when compared to respondents whose COVID-19 symptoms persisted for only 4 weeks or less. Conclusion: The findings suggest that screening of substance use disorders should be considered among healthcare providers who are treating adults who have persistent symptoms of COVID-19.

1142

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Kazama, Itsuro

Brain Leukocytes as the Potential Therapeutic Target for Post-COVID-19 Brain Fog

https://doi.org/10.1007/s11064-023-03912-0

Published

23-Mar-23

Article

https://doi.org/10.1007/s11064-023-03912-0

After recovering from the acute phase of coronavirus disease 2019 (COVID-19), many patients struggle with additional symptoms of long COVID during the chronic phase. Among them, the neuropsychiatric manifestations characterized by a short-term memory loss and inability to concentrate are called “brain fog”. Recent studies have revealed the involvement of “chronic neuro-inflammation” in the pathogenesis of brain fog following COVID-19 infection. In the COVID-related brain fog, similarly to neurodegenerative disorders caused by neuro-inflammation, brain leukocytes, such as microglia and lymphocytes, are hyperactivated, suggesting the overexpression of delayed rectifier K+-channels (Kv1.3) within the cells. In our previous patch-clamp studies, drugs, such as antihistamines, statins, nonsteroidal anti-inflammatory drugs, antibiotics and anti-hypertensive drugs, suppressed the Kv1.3-channel activity and reduced the production of pro-inflammatory cytokines. Additionally, newer generation antihistamines, antibiotics and corticosteroids strongly stabilize mast cells that directly activate microglia in the brain. Taking such pharmacological properties of these commonly used drugs into account, they may be useful in the treatment of COVID-related brain fog, in which the enhanced innate and adaptive immune responses are responsible for the pathogenesis.

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Galluzzo, Vincenzo; Zazzara, Maria Beatrice; Ciciarello, Francesca; Tosato, Matteo; Martone, Anna Maria; Pais, Cristina; Savera, Giulia; Calvani, Riccardo; Picca, Anna; Marzetti, Emanuele; Landi, Francesco; on behalf of Gemelli Against COVID-19 Post-Acute Care Team

Inadequate Physical Activity Is Associated with Worse Physical Function in a Sample of COVID-19 Survivors with Post-Acute Symptoms

https://doi.org/10.3390/jcm12072517

Published

1-Jan-23

Study

https://www.mdpi.com/2077-0383/12/7/2517

Background—Patients affected by Long COVID often report shorter times spent doing physical activity (PA) after COVID-19. The aim of the present study was to evaluate potential associations between PA levels and parameters of physical function in a cohort of COVID-19 survivors with post-acute symptoms, with a particular focus on individuals aged 65 and older. Materials and methods—PA levels before and after COVID-19 were assessed in a sample of patients that had recovered from COVID-19 and were admitted to a post-acute outpatient service at the Fondazione Policlinico Universitario Agostino Gemelli IRCCS (Rome, Italy). Participation in PA was operationalized as the engagement in leisure-time PA for at least 150 min per week in the last 3 months. Self-rated health and measures of physical performance and muscle strength were assessed. Results—Mean age of 1846 participants was 55.2 ± 14.4 years and 47% were women. Before COVID-19, inactivity was detected in 47% of the whole study population; only 28% maintained pre-COVID-19 PA engagement. Inactivity was more frequent in women. The stopping of physical activity was associated with increased BMI and CRP levels, lower vitamin D levels and a higher prevalence of post-COVID-19 fatigue, dyspnea, arthralgia, and myalgia. Active participants had higher handgrip strength and performed better on both the six-minute walking test (6MWT) and at the one-minute sit-to-stand test (1MSTST). In particular, at the 6MWT, participants 65 and older that were still active after COVID-19 walked 32 m more than sedentary peers. Moreover, the distance covered was 28 m more than those who were active only before COVID-19 (p = 0.05). Formerly active subjects performed similarly at the 6MWT to inactive participants. PA was associated with better self-rated health. Conclusions—Our findings reveal that inactivity is frequent in the post-acute COVID-19 phase. Stopping physical activity after COVID-19 results in measures of performance that are comparable to those who were never active. Relevant differences in the distance covered at the 6MWT were found between older active subjects and their sedentary peers.

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Hsu, Wan-Hsuan; Shiau, Bo-Wen; Tsai, Ya-Wen; Wu, Jheng-Yan; Liu, Ting-Hui; Chuang, Min-Hsiang; Lai, Chih-Cheng

The effect of molnupiravir on post-acute outcome of COVID-19 survivors

https://doi.org/10.1016/j.jinf.2023.03.016

Published

21-Mar-23

Article

https://www.journalofinfection.com/article/S0163-4453(23)00145-7/fulltext

Our study included 3600 patients for each cohort and we performed the final outcome analysis using these 7200 patients. We found that molnupiravir could reduce post-acute all-cause hospitalization or mortality among COVID-19 survivors. This finding was consistent with our previous study, in which patients receiving nirmatrelvir plus ritonavir could have a lower risk of all-cause hospitalization or mortality (HR, 0.543; 95% CI, 0.495-0.597) 30 to 180 days after a documented COVID-19 diagnosis.4 Both findings indicated that the novel oral anti-viral agents, including molnupiravir and nirmatrelvir plus ritonavir, are able to provide further clinical benefits for COVID-19 survivors during the post-acute phase. These findings suggested the promising effects of antivirals in the prevention of post-acute COVID-19 complications.
The association between molnupiravir and the post-acute outcome of patients with COVID-19 in this study could be explained by the following reasons. A significant portion of patients surviving acute COVID-19 would experience the post-acute sequelae of COVID-19 or long COVID, which was caused by SARS-CoV-2 direct injury or its associated immune/inflammatory response.6 However, early antiviral treatment may help facilitate the virological eradication and reduce further inflammatory or immunologic response. Thus, the risk of post-acute complications after SARS-CoV-2 infection could be reduced by anti-viral therapies.5, 7
With the TriNetX Research Network, our study was able to recruit cohort members from the large population-based database of over 120 HCOs. Propensity score matching was used to reduce confounding variables despite the retrospective nature of the database. However, our findings should be interpreted with the following limitations. First, our acquired data may be subjected to residual confounding variables such as vaccination status, COVID-19 severity, SARS-CoV-2 variants, and the use of other anti-COVID-19 treatments that were not listed in the cohort construction, particularly for corticosteroids and interleukin-6 blockade agents. Secondly, as with all coding-based studies, our results are susceptible to misdiagnosis, inaccurate coding, and errors in documentation. Hence, further study is warranted to clarify these issues.
In conclusion, in addition to the clinical benefit of molnupiravir for acute COVID-19,2, 3 our study demonstrated the extended effect of molnupiravir in reducing the risks of all-cause hospitalization and mortality in the post-acute phase following SARS-CoV-2 infection.
publisher: Elsevier
PMID: 36958635

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Minutolo, Antonella; Petrone, Vita; Fanelli, Marialaura; Maracchioni, Christian; Giudice, Martina; Teti, Elisabetta; Coppola, Luigi; Sorace, Chiara; Iannetta, Marco; Tony Miele, Martino; Bernardini, Sergio; Mastino, Antonio; Sinibaldi Vallebona, Paola; Balestrieri, Emanuela; Andreoni, Massimo; Sarmati, Loredana; Grelli, Sandro; Garaci, Enrico; Matteucci, Claudia

Thymosin alpha 1 restores the immune homeostasis in lymphocytes during Post-Acute sequelae of SARS-CoV-2 infection

https://doi.org/10.1016/j.intimp.2023.110055

Published

1-May-23

Study

https://www.sciencedirect.com/science/article/pii/S1567576923003764

Highlights
•Tα1 modulates the differentiation of T cells in PASC.
•Tα1 reduces the exhaustion of CD8 + T cells.
•Tα1 specifically reduces inflammation in activated lymphocytes.
•Higher immunomodulation by Tα1 in individuals with specific systemic and psychiatric PASC symptoms.
Abstract
The complex alterations of the immune system and the immune-mediated multiorgan injury plays a key role in host response to SARS-CoV-2 infection and in the pathogenesis of COVID-19, being also associated with adverse outcomes. Thymosin alpha 1 (Tα1) is one of the molecules used in the treatment of COVID-19, as it is known to restore the homeostasis of the immune system during infections and cancer. The use of Tα1 in COVID-19 patients had been widely used in China and in COVID-19 patients, it has been shown to decrease hospitalization rate, especially in those with greater disease severity, and reduce mortality by restoring lymphocytopenia and more specifically, depleted T cells. Persistent dysregulation with depletion of naive B and T cell subpopulations and expansion of memory T cells suggest a chronic stimulation of the immune response in individuals with post-acute sequelae of SARS-CoV-2 infection (PASC). Our data obtained from an ex vivo study, showed that in PASC individuals with a chronically altered immune response, Tα1 improve the restoration of an appropriate response, most evident in those with more severe illness and who need respiratory support during acute phase, and in those with specific systemic and psychiatric symptoms of PASC, confirming Tα1 treatment being more effective in compromised patients. The results obtained, along with promising reports on recent trials on Tα1 administration in patients with COVID-19, offer new insights into intervention also for those patients with long-lasting inflammation with post-infectious symptoms, some of which have a delayed onset.

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Schmidt, F.; Azar, C.; Goektas, O.

Treatment of Olfactory Disorders After SARS – CoViD 2 Virus Infection

https://doi.org/10.1177/01455613231168487

Published

28-Mar-23

Study

https://doi.org/10.1177/01455613231168487

ObjectiveThe benefit of a nasal corticosteroid in the treatment of persistent post-infectious smell disorders is not as clear in previous studies as is assumed for olfactory training. This study would therefore like to describe the treatment strategies using the example of a persistent olfactory dysfunction as a result of a proven infection with SARS-CoViD-2-virus.MethodsTwenty patients (average age of 33.9 ± 11.9 years) with hyposmia were included in this study from December 2020 to July 2021. Every second patient received additionally a nasal corticosteroid. The two resulting randomized groups of equal size were screened with the TDI test, a 20-item taste powder test for the assessment of retronasal olfaction and otorhinolaryngological examination. The patients were asked to train twice daily using a standardized odor training kit and followed up after 2 months and 3 months, respectively.ResultsWe documented a significant overall improvement in olfactory ability over the investigation period in both groups. While the TDI score steadily increased on average under the combination therapy, the rise under olfactory training alone was initially steeper. This short-term interaction effect over mean two months was not statistically significant. According to Cohen, however, a moderate effect (eta2 = 0.055, Cohen`s d = 0.5) can still be assumed. This effect could be explained by a possibly higher compliance at the beginning of the sole olfactory training due to the lack of further drug treatment offers. When the training intensity decreases, the recovery of the sense of smell stagnates. Adjunctive therapy ultimately outweighs this short-term benefit.ConclusionsThe results reinforce the recommendation of early and consistent olfactory training on patients with dysosmia due to COVID-19. For continuous improvement of the sense of smell, an accompanying topical treatment seems at least to be worth consideration. The results should be optimized with larger cohorts and using new objective olfactometric methods.

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Imam, Mohamed S.; Abdelazim, Mohamed H.; Abdelazim, Ahmed H.; Ismaiel, Wael F.; Gamal, Mohammed; Abourehab, Mohammed A. S.; Alghamdi, Saleh; Alghamdi, Mohamed A.; Ghoneim, Mohammed M.; Elwany, Samy

Efficacy of pentasodium diethylenetriamine pentaacetate in ameliorating anosmia post COVID-19

https://doi.org/10.1016/j.amjoto.2023.103871

Published

1-Jul-23

Trial

https://www.sciencedirect.com/science/article/pii/S0196070923000856

Highlights
•Reports demonstrated a relationship between anosmia and COVID-19
•Olfactory dysfunction causes an increase in intracellular calcium concentration.
•Pentasodium diethylenetriamine pentaacetate (DTPA) can decrease the concentration of calcium in the nasal secretion.
•Intranasal DTPA could be effective in treating anosmia.
Abstract
Background
COVID-19 has been frequently demonstrated to be associated with anosmia. Calcium cations are a mainstay in the transmission of odor. One of their documented effects is feedback inhibition. Thus, it has been advocated that reducing the free intranasal calcium cations using topical chelators such as pentasodium diethylenetriamine pentaacetate (DTPA) could lead to restoration of the olfactory function in patients with post-COVID-19 anosmia.
Methodology
This is a randomized controlled trial that investigated the effect of DTPA on post-COVID-19 anosmia. A total of 66 adult patients who had confirmed COVID-19 with associated anosmia that continued beyond three months of being negative for SARS-CoV-2 infection. The included patients were randomly allocated to the control group that received 0.9 % sodium chloride-containing nasal spray or the interventional group that received 2 % DTPA-containing nasal spray at a 1:1 ratio. Before treatment and 30 days post-treatment, the patients' olfactory function was evaluated using Sniffin' Sticks, and quantitative estimation of the calcium cations in the nasal mucus was done using a carbon paste ion-selective electrode test.
Results
Patients in the DTPA-treated group significantly improved compared to the control group in recovery from functional anosmia to hyposmia. Additionally, they showed a significant post-treatment reduction in the calcium concentration compared to the control group.
Conclusion
This study confirmed the efficacy of DTPA in treating post-COVID-19 anosmia.

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Quinn, Kieran L.; Lam, Grace Y.; Walsh, Jillian F.; Bhéreur, Anne; Brown, Adam D.; Chow, Chung Wai; Christie Chung, Kit Yan; Cowan, Juthaporn; Crampton, Noah; Décary, Simon; Falcone, Emilia L.; Graves, Lorraine; Gross, Douglas P.; Hanneman, Kate; Harvey, Paula J.; Holmes, Sheila; Katz, Gabrielle M.; Parhizgar, Parinaz; Sharkawy, Abdu; Tran, Karen C.; Waserman, Susan; Zannella, Vanessa E.; Cheung, Angela M.

Cardiovascular Considerations in the Management of People with Suspected Long COVID

https://doi.org/10.1016/j.cjca.2023.04.003

Published

6-Apr-23

Review

https://www.sciencedirect.com/science/article/pii/S0828282X23003033

Approximately 15% of adult Canadians with SARS-CoV-2 infection develop lingering symptoms beyond 12 weeks post-acute infection, known as post-COVID condition or long COVID. Some of the commonly reported long COVID cardiovascular symptoms include fatigue, shortness of breath, chest pain, and palpitations. Suspected long-term cardiovascular complications of SARS-CoV-2 infection may present as a constellation of symptoms that can be challenging for clinicians to diagnose and treat. When assessing patients with these symptoms, clinicians need to keep in mind Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), post-exertional malaise and post-exertional symptom exacerbation (PEM/PESE), cardiac dysautonomia such as Inappropriate Sinus Tachycardia (IST), and Postural Orthostatic Tachycardia Syndrome (POTS), and occasionally Mast Cell Activation Syndrome (MCAS). This paper summarizes the globally evolving evidence around management of cardiac sequelae of long COVID. In addition, this review includes a Canadian perspective, consisting of a panel of expert opinions from experienced clinicians across Canada who have been involved in management of long COVID. The objective of this review is to offer some practical guidance to cardiologists and generalist clinicians regarding diagnostic and treatment approaches for adult patients with suspected long COVID who continue to experience unexplained cardiac symptoms.

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Bertuccio, Paola; Degli Antoni, Melania; Minisci, Davide; Amadasi, Silvia; Castelli, Francesco; Odone, Anna; Quiros-Roldan, Eugenia

The impact of early therapies for COVID-19 on death, hospitalization and persisting symptoms: a retrospective study

https://doi.org/10.1007/s15010-023-02028-5

Published

6-Apr-23

Study

https://doi.org/10.1007/s15010-023-02028-5

Purpose
Oral antivirals (nirmatrelvir/ritonavir and molnupiravir), intravenous short treatment of remdesivir and anti-SARS-CoV-2 monoclonal antibodies (mAbs) have been used for early COVID-19 treatments in high risk of disease progression patients. The term long COVID has been used to refer to a range of new, returning, or ongoing symptoms after SARS-CoV-2 infection. Little is known about the impact of such therapies on long COVID.

Methods
This is a retrospective observational study, including all outpatients evaluated from April 2021 to March 2022 in Brescia, Lombardy, northern Italy. Patients were stratified in three groups: (a) treated with mAbs, (b) treated with antivirals drugs and (c) controls (patients eligible for a or b who refused treatment). Data were collected at baseline and at month 1 and 3 (data on self-reported symptoms were collected using a telephone-administered questionnaire). We assessed early COVID-19 therapies effectiveness in preventing hospitalization, death at 1 or 3 months and persisting symptoms at 3 months after the onset of SARS-CoV-2 infection.

Results
A total of 649 patients were included in the study, of which 242 (37.3%) were treated with mAbs, 197 (30.3%) with antiviral drugs and 210 (32.4%) were not treated. Patients most frequently reported cerebro-cardiovascular diseases (36.7%) followed by obesity (22%). Overall, 29 patients (4.5%) died or were hospitalized at 1 or 3-month follow-up. Death or hospitalization was positively associated with older ages, with a significant linear trend (OR 3.05; 95% CI 1.16–8.06, for patients aged 80 or more years compared to those aged less than 65). Data on long COVID at 3 months were available for 323 (49.8%) patients. A positive association emerged for females compared to men, with an OR of 2.14 (95% CI 1.30–3.53) for any symptoms. Conversely, inverse associations were found for treatment groups as compared to the control one, with significant estimates among patients treated with antiviral drugs for any symptoms (OR 0.43, 95% CI 0.21–0.87) and patients treated with mAbs for any neuro-behavioral symptoms (OR 0.48, 95% CI 0.25–0.92).

Conclusions
We report beneficial effect of early use of anti-SARS-CoV-2 antivirals and mAbs on long COVID.

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Seid, Abubeker Alebachew; Mohammed, Ahmed Adem; Hasen, Aragaw Asfaw

Progressive muscle relaxation exercises in patients with COVID-19: Systematic review and meta-analysis

https://doi.org/10.1097/MD.0000000000033464

Published

7-Apr-23

Systematic review and meta-analysis

https://journals.lww.com/md-journal/Fulltext/2023/04070/Progressive_muscle_relaxation_exercises_in.60.aspx

Background:
Patients with COVID-19 will experience high levels of anxiety and depression and poor levels of sleep and quality of life (QoL) due to isolation treatment and uncertain outcomes. Progressive muscle relaxation (PMR) exercises show promising treatment effects on mental health and sleep problems and overall QoL in COVID-19 patients. This study aimed to evaluate the efficacy and safety of PMR exercises in patients with COVID-19.
Methods:
Both experimental and non-experimental studies related to PMR and COVID-19 were systematically searched in the PubMed, Cochrane Library, PEDro and HINARI databases for studies published from the occurrence of the pandemic to December 2022. Study selection, methodological quality assessment and data extraction were carried out by 2 independent authors. Efficacy outcomes were evaluated for sleep quality, anxiety, depression, and QoL. The safety outcomes were evaluated based on adverse events reported. Review manager (RevMan 5.4, Cochrane collaboration) was used for the data analysis.
Results:
Four studies with 227 subjects were included in this systematic review. The pooled results indicated that PMR interventions improved the sleep quality score standardized mean difference (SMD): −0.23; 95% confidence interval (CI): −0.54, 0.07; P = .13, level of anxiety SMD: −1.35; 95% CI −2.38, −0.32; P = .01 compared to the usual care. Depression level, disease severity and QoL were also improved following PMR interventions. Only 1 study reported worsening of 1 patient clinical status while all other studies did not report any adverse events during the interventions.
Conclusions:
PMR interventions can improve the sleep quality, anxiety, depression, disease severity and QoL in patients with mild to moderate COVID-19 in a short-term period compared to the usual care. However, there was indecision about the safety and long-term effects of PMR.

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Heitmann, Juliane; Kreutz, Julian; Aldudak, Sümeya; Schieffer, Elisabeth; Schieffer, Bernhard; Schäfer, Ann-Christin

A practical approach for the treatment of post-COVID symptoms

https://doi.org/10.1007/s00059-023-05177-3

Published

23-Apr-23

Case Report

https://doi.org/10.1007/s00059-023-05177-3

For the past 3 years, our daily lives have been largely dictated by the coronavirus disease 2019 (COVID-19) pandemic. In many people, this infectious disease leads to long-lasting symptoms, which can vary greatly in form and intensity between individuals. This report describes the case of a young patient who had no health restrictions until she came into contact with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As part of a post-COVID syndrome, she not only temporarily lost her ability to work, but was also no longer able to manage her daily life independently. A crucial therapeutic approach, in this case, was the use of heparin-induced extracorporeal LDL/fibrinogen precipitation (H.E.L.P.) apheresis.

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Wacks, Michael; Wortley, Elizabeth; Gregorowski, Anna; Segal, Terry Y.; Whittaker, Elizabeth

Fifteen-minute consultation: Managing post-COVID-19 syndrome (long COVID) in children and young people

https://doi.org/10.1136/archdischild-2022-324950

Published

20-Apr-23

Article

https://ep.bmj.com/content/early/2023/04/20/archdischild-2022-324950

Post-COVID-19 syndrome is a new condition that can have a major impact on the physical and mental well-being of children and young people, affecting their ability to access activities including education. Paediatricians and general practitioners need to be able to assess and manage patients with this condition; making the diagnosis, excluding serious pathology, managing comorbidities and accessing appropriate management are crucial. This 15 minute consultation presents an approach to history taking, examination, investigations, management principles and referrals.

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Bachmeier, Beatrice E.; Hölzle, Salome; Gasser, Mohamed; van den Akker, Marjan

How do German General Practitioners Manage Long-/Post-COVID? A Qualitative Study in Primary Care

https://doi.org/10.3390/v15041016

Published

1-Apr-23

Study

https://www.mdpi.com/1999-4915/15/4/1016

Background: Many patients with ongoing complaints after a SARS-CoV-2 infection are treated in primary care. Existing medical guidelines on how to diagnose and treat Long-/Post-COVID are far from being comprehensive. This study aims to describe how German general practitioners (GPs) deal with this situation, what problems they experience when managing such patients, and how they solve problems associated with the diagnosis and treatment of Long-/Post-COVID. Methods and Findings: We conducted a qualitative study and interviewed 11 GPs. The most commonly described symptoms were ongoing fatigue, dyspnea, chest tightness and a decrease in physical capacity. The most common way to identify Long-/Post-COVID was by exclusion. Patients suffering from Long-/Post-COVID were generally treated by their GPs and rarely referred. A very common non-pharmacological intervention was to take a wait-and-see approach and grant sick leave. Other non-pharmacological interventions included lifestyle advices, physical exercise, acupuncture and exercises with intense aromas. Pharmacological treatments focused on symptoms, like respiratory symptoms or headaches. Our study’s main limitations are the small sample size and therefore limited generalizability of results. Conclusions: Further research is required to develop and test pharmaceutical and non-pharmaceutical interventions for patients with Long-/Post-COVID. In addition, strategies to prevent the occurrence of Long-/Post-COVID after an acute infection with SARS-CoV-2 have to be developed. The routine collection of data on the diagnosis and management of Long-/Post-COVID may help in the formulation of best practices. It is up to policymakers to facilitate the necessary implementation of effective interventions in order to limit the huge societal consequences of large groups of patients suffering from Long-/Post-COVID.

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Rinn, Robin; Gao, Lingling; Schoeneich, Sarah; Dahmen, Alina; Kumar, Vinayak Anand; Becker, Petra; Lippke, Sonia

Digital Interventions for Treating Post-COVID or Long-COVID Symptoms: Scoping Review

https://doi.org/10.2196/45711

Published

17-Apr-23

Review

https://www.jmir.org/2023/1/e45711

Background:
Patients with post-COVID/long-COVID symptoms need support, and health care professionals need to be able to provide evidence-based patient care. Digital interventions can meet these requirements, especially if personal contact is limited.

Objective:
We reviewed evidence-based digital interventions that are currently available to help manage physical and mental health in patients with post-COVID/long-COVID symptoms.

Methods:
A scoping review was carried out summarizing novel digital health interventions for treating post-COVID/long-COVID patients. Using the PICO (population, intervention, comparison, outcome) scheme, original studies were summarized, in which patients with post-COVID/long-COVID symptoms used digital interventions to help aid recovery.

Results:
From all scanned articles, 8 original studies matched the inclusion criteria. Of the 8 studies, 3 were “pretest” studies, 3 described the implementation of a telerehabilitation program, 1 was a post-COVID/long-COVID program, and 1 described the results of qualitative interviews with patients who used an online peer-support group. Following the PICO scheme, we summarized previous studies. Studies varied in terms of participants (P), ranging from adults in different countries, such as former hospitalized patients with COVID-19, to individuals in disadvantaged communities in the United Kingdom, as well as health care workers. In addition, the studies included patients who had previously been infected with COVID-19 and who had ongoing symptoms. Some studies focused on individuals with specific symptoms, including those with either post–COVID-19 or long-term symptoms, while other studies included patients based on participation in online peer-support groups. The interventions (I) also varied. Most interventions used a combination of psychological and physical exercises, but they varied in duration, frequency, and social dimensions. The reviewed studies investigated the physical and mental health conditions of patients with post-COVID/long-COVID symptoms. Most studies had no control (C) group, and most studies reported outcomes (O) or improvements in physiological health perception, some physical conditions, fatigue, and some psychological aspects such as depression. However, some studies found no improvements in bowel or bladder problems, concentration, short-term memory, unpleasant dreams, physical ailments, perceived bodily pain, emotional ailments, and perceived mental health.

Conclusions:
More systematic research with larger sample sizes is required to overcome sampling bias and include health care professionals’ perspectives, as well as help patients mobilize support from health care professionals and social network partners. The evidence so far suggests that patients should be provided with digital interventions to manage symptoms and reintegrate into everyday life, including work.
Company: Journal of Medical Internet Research
Distributor: Journal of Medical Internet Research
Institution: Journal of Medical Internet Research
Label: Journal of Medical Internet Research
publisher: JMIR Publications Inc., Toronto, Canada

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Chuang, Hung-Jui; Lin, Chia-Wei; Hsiao, Ming-Yen; Wang, Tyng-Guey; Liang, Huey-Wen

Long COVID and rehabilitation

https://doi.org/10.1016/j.jfma.2023.03.022

Published

13-Apr-23

Review

https://www.sciencedirect.com/science/article/pii/S0929664623001079

Coronavirus disease 2019 (COVID-19) has caused tremendous morbidity and mortality worldwide. The large number of post-COVID survivors has drawn attention to the management of post-COVID condition, known as long COVID. This review examines current knowledge of long COVID, regarding its epidemiology, mechanism, and clinical presentations in both adults and children. We also review the rehabilitation principles, modules, and effects, and share Taiwan's efforts to provide a top-down, nationwide care framework for long COVID patients. Dyspnea, chronic cough, and fatigue are the most commonly reported symptoms in the first 6 months after infection, but cognitive impairment and psychological symptoms may persist beyond this time. Several possible mechanisms behind these symptoms were proposed, but remained unconfirmed. These symptoms negatively impact individuals' function, activities, participation and quality of life. Rehabilitation is a key element of management to achieve functional improvement. Early management should start with comprehensive evaluation and identification of red flags. Exercise-based therapy, an essential part of management of long COVID, can be conducted with different modules, including telerehabilitation. Post-exertional symptom exacerbation and orthostatic hypotension should be carefully monitored during exercise. Randomized control trials with a large sample size are needed to determine the optimal timing, dosage, and modules.

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Finnigan, Lucy E. M.; Cassar, Mark Philip; Koziel, Margaret James; Pradines, Joel; Lamlum, Hanan; Azer, Karim; Kirby, Dan; Montgomery, Hugh; Neubauer, Stefan; Valkovič, Ladislav; Raman, Betty

Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised controlled phase 2a pilot study

https://doi.org/10.1016/j.eclinm.2023.101946

Published

14-Apr-23

Study

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00123-2/fulltext

Background
‘Long COVID’ describes persistent symptoms, commonly fatigue, lasting beyond 12 weeks following SARS-CoV-2 infection. Potential causes include reduced mitochondrial function and cellular bioenergetics. AXA1125 has previously increased β-oxidation and improved bioenergetics in preclinical models along with certain clinical conditions, and therefore may reduce fatigue associated with Long COVID. We aimed to assess the efficacy, safety and tolerability of AXA1125 in Long COVID.
Methods
Patients with fatigue-dominant Long COVID were recruited in this single-centre, double-blind, randomised controlled phase 2a pilot study completed in the UK. Patients were randomly assigned (1:1) using an Interactive Response Technology to receive either AXA1125 or matching placebo in a clinical-based setting. Each dose (33.9 g) of AXA1125 or placebo was administered orally in a liquid suspension twice daily for four weeks with a two-week follow-up period. The primary endpoint was the mean change from baseline to day 28 in the phosphocreatine (PCr) recovery rate following moderate exercise, assessed by 31P-magnetic resonance spectroscopy (MRS). All patients were included in the intention to treat analysis. This trial was registered at ClinicalTrials.gov, NCT05152849.
Findings
Between December 15th 2021, and May 23th 2022, 60 participants were screened, and 41 participants were randomised and included in the final analysis. Changes in skeletal muscle phosphocreatine recovery time constant (τPCr) and 6-min walk test (6MWT) did not significantly differ between treatment (n = 21) and placebo group (n = 20). However, treatment with AXA1125 was associated with significantly reduced day 28 Chalder Fatigue Questionnaire [CFQ-11] fatigue score when compared with placebo (least squares mean difference [LSMD] −4.30, 95% confidence interval (95% CI) −7.14, −1.47; P = 0.0039). Eleven (52.4%, AXA1125) and four (20.0%, placebo) patients reported treatment-emergent adverse events; none were serious or led to treatment discontinuation.
Interpretation
Although treatment with AXA1125 did not improve the primary endpoint (τPCr-measure of mitochondrial respiration), when compared to placebo, there were significant improvements in fatigue-based symptoms among patients living with Long COVID following a four-week treatment period. Further multicentre studies are needed to validate our findings in a larger cohort of patients with fatigue-dominant Long COVID.
publisher: Elsevier

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Thomas-Purcell, Kamilah; Davenport, Rosemary; Ayala, Victoria; Purcell, Donrie; Ownby, Raymond L.

Chronic Disease Self-Management of Post-Acute Sequelae of COVID-19 Among Older Adults: A Mixed-Methods Analysis

https://doi.org/10.2147/CIA.S393732

Published

14-Apr-23

Study

https://www.dovepress.com/chronic-disease-self-management-of-post-acute-sequelae-of-covid-19-amo-peer-reviewed-fulltext-article-CIA

Introduction: Approximately 20– 30% of individuals who contract acute coronavirus disease (COVID-19) infection develop longer term complications of their initial infection, referred to as Post-Acute Sequelae of SARS-CoV-2 infection (PASC). PASC is characterized by chronic, varying symptomatology.
Methods: Using a mixed methods study design, we aimed to gain insight into individuals’ experience with PASC, including cognitive issues, fatigue, and sleep disturbances. We explored whether our previously developed application (app), aimed at improving self-management skills among individuals with chronic diseases, is relevant for individuals with PASC and gained information to adapt the app for individuals with PASC. The study included 19 individuals, aged 40 years and older, recruited from our research participant database, Nova Southeastern University clinics, and community locations. We included this age range because older adults are more likely to have comorbid conditions, allowing us to better understand the impact of COVID-19 infection in these individuals. Participants completed seven standardized self-report questionnaires online, and an individual semi-structured interview via videoconferencing. Quantitative data were assessed using descriptive statistics and calculating individuals’ scores in relation to norms. Qualitative data were analyzed using a thematic analysis approach. Triangulation of the data was accomplished by calculating correlations between participants’ responses on self-report scales and themes found in semi-structured interviews.
Results: Themes included disruption of everyday life, diverse physical symptoms, and cognitive problems including brain fog, fatigue, coping, and emotional upset. Quantitative analysis demonstrated that participants experienced high levels of fatigue, negative mood, cognitive problems, and overall reduction in health-related quality of life (HRQOL). Correlation analyses revealed that individual interview responses were related to participants’ self-report of symptoms on standard questionnaires.
Discussion: Findings indicate that self-report questionnaires may reflect the experience of individuals with PASC and its impact. Additionally, further efforts to expand our prior mobile app are warranted among individuals with PASC.

1158

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Oliveira, Karla Cybele Vieira de; Ferreira, Ana Paula de Lima; Silva, Diana de Andrade; Monteiro, Janaína dos Santos; Silva, Kennedy Victor; Lucena, Larissa Coutinho de; Araújo, Maria das Graças Rodrigues de

The impact of post-COVID multicomponent rehabilitation

https://doi.org/10.1590/fm.2023.36112

Published

15-May-23

Study

https://www.scielo.br/j/fm/a/BssyDbNrSdCRjRzGmtXtnRs/

Abstract Introduction Post-COVID-19 syndrome is characterized by chronic fatigue and myalgia, among other symptoms, which can limit activities of daily living. Physical therapy protocols with multicomponent exercises combine strength, resistance, balance and gait, producing sig-nificant improvements in functional mobility. Objective Evaluate whether multicomponent rehabilitation is effective in improving functional mobility and quality of life in individuals with post-COVID-19 syndrome. Methods Randomized controlled trial with 59 volunteers, divided into an intervention (IG) and control group (CG), all of whom underwent initial assessment (T0). The IG performed 24 sessions over 12 weeks and the CG did not undergo training. Functional mobility was analyzed using the 6-minute walk test (6MWT) and the Berg balance scale, while the SF-36 questionnaire assessed quality of life. Results In the 6MWT, the IG covered 464.40 + 81.26 meters (T0) and 518.60 + 82.68 meters (T4). The IG Berg scale scores were 48.00 + 4.00 (T0) and 51.90 + 4.26 (T4). In terms of quality of life, the IG obtained mean scores of 96.26 + 10.14 (T0) and 102.60 + 5.53 (T4). None of these measures was statistically significant. Conclusion Individuals who underwent the multicomponent phys-iotherapy protocol showed statistically nonsignificant increases in the variables studied.

1159

Ce350

Nikolich, Janko Ž.; Rosen, Clifford J.

Toward Comprehensive Care for Long Covid

https://doi.org/10.1056/NEJMp2304550

Published

9-May-23

Article

https://doi.org/10.1056/NEJMp2304550

RECOVER is a building block for ultimately establishing the clinical definition of long Covid. We believe that over and above this research effort, the country needs additional structures that can provide the capacity for clinicians, patients, caregivers, advocacy groups, employers, and government officials to learn about, adapt, and implement interventions, therapeutics, and other best practices to combat long Covid.

We suggest that this effort include several key features. First, it should support people with long Covid by coordinating clinical care and rehabilitation, reducing health care disparities, and addressing ongoing and complex medical and psychosocial needs, with a particular focus on patients who currently receive fragmented care or no care at all. Such support could be provided by means of national long Covid centers of excellence. This program could begin by building out some centers involved in RECOVER so that they not only collect data and follow participants, but also provide comprehensive care for those patients and others with long Covid. RECOVER serves a cross section of underserved communities through research centers in both urban and rural areas and can act as a bridge to care provision for these patients.

Second, we need to define, continuously improve, and implement standards of care and best practices, built on evidence obtained through a coordinated exchange of information. Third, we can leverage innovative methods for disseminating information and providing support in order to educate clinicians, patients, and communities; broaden access to high-quality care; and further reduce disparities. And fourth, we will need to develop and implement workforce training programs for clinicians caring for patients with long Covid.

To implement such an ambitious program, we strongly urge Congress to consider appropriating funding in fiscal year 2024 for the Health Resources and Services Administration to competitively select centers of excellence in long Covid care by leveraging and expanding the initial investment in RECOVER hubs and other federally supported long Covid activities.

In addition, such centers could support and leverage, both nationally and throughout their states, greater educational initiatives from the CDC and the WHO for both clinicians and patients. Some examples include continuing education programs, grand rounds, and the Project ECHO (Extension for Community Healthcare Outcomes) model, a scalable and effective way of using electronic media to inform and facilitate changes in health and education for clinicians. These efforts should focus on symptom complexes, potential complications, and management strategies. We need to demystify the disease and empower affected people, involving them actively in their own care and in education and training. We also recommend that insurance providers reexamine criteria for disability claims and urge employers to gain a better understanding of this disorder and its wide-ranging implications. Most important, we need to put people and communities, not diseases, at the center of our health systems and empower them to take charge of their own health rather than be passive recipients of services.

If the prevalence of long Covid is indeed between 5 and 15%, we will continue to face an enormous challenge to our national health and our health care system moving forward. Innovative approaches will be needed to care for patients with long Covid, and these need to be backed by education, research, and support at all levels. It’s about time.
publisher: Massachusetts Medical Society
_eprint: https://doi.org/10.1056/NEJMp2304550

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Diem, Lara; Höfle, Oliver; Fregolente, Livia; Hoepner, Robert

The Role of Neurorehabilitation in Post-COVID-19 Syndrome

https://doi.org/10.3390/ctn7020013

Published

1-Jun-23

Article

https://www.mdpi.com/2514-183X/7/2/13

Post-COVID-19 syndrome is an ongoing challenge for healthcare systems as well as for society. The clinical picture of post-COVID-19 syndrome is heterogeneous, including fatigue, sleep disturbances, pain, hair loss, and gastrointestinal symptoms such as chronic diarrhea. Neurological complaints such as fatigue, cognitive impairment, and sleep disturbances are common. Due to the short timeframe of experience and small amount of evidence in this field, the treatment of post-COVID-19 syndrome remains a challenge. Currently, therapeutic options for post-COVID-19 syndrome are limited to non-pharmaceutical interventions and the symptomatic therapy of respective symptoms. In this article, we summarize the current knowledge about therapeutic options for the treatment of neurological symptoms of post-COVID-19 syndrome.

1161

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Barshikar, Surendra; Laguerre, Martin; Gordon, Patricia; Lopez, Marielisa

Integrated Care Models for Long Coronavirus Disease

https://doi.org/10.1016/j.pmr.2023.03.007

Published

8-May-23

Article

https://www.pmr.theclinics.com/article/S1047-9651(23)00023-2/fulltext

Key points
•
The wide range of persistent symptoms in long COVID requires a coordinated response from multiple medical specialties.
•
Formalized models of care systems and multidisciplinary collaborations began in early 2021 as health care providers recognized the needs of the affected population.
•
Multidisciplinary models largely exist in academic centers and larger cities; however, most care for PASC patients is provided by the primary care providers.
Introduction
As of July 2022, there have been more than 540 million confirmed cases of coronavirus disease (severe acute respiratory syndrome coronavirus 2 [SARS CoV-2], coronavirus disease 2019 [COVID-19]) during the global pandemic.1 Severe acute cases of SARS-CoV-2 respiratory illness continue to strain communities, health care systems, and nations. Evidence-based medical treatments have greatly improved patient outcomes; however, a growing population of survivors with persisting long-term complications has been recognized. This syndrome has been labeled as long COVID or the Post-Acute Sequelae of SARS CoV-2 (PASC).2,3
There is no single accepted definition of PASC. However, PASC is characterized by persistent and/or delayed symptoms or complications beyond 4 weeks of symptom onset or 3 months after a confirmed SARS CoV-2 infection.3 The population that experiences PASC is extremely heterogeneous, from those initially asymptomatic with no prior comorbidities to those with preexisting respiratory conditions and prolonged intensive care unit (ICU) stays. The exact prevalence of PASC in the population is unknown with reports of patients with PASC ranging from 10% to 81% of confirmed cases.4 Given this large population, treatment resource, health care needs, and social costs will continue to be a growing burden on already exhausted health care systems.5

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Kuut, Tanja A; Müller, Fabiola; Csorba, Irene; Braamse, Annemarie; Aldenkamp, Arnoud; Appelman, Brent; Assmann-Schuilwerve, Eleonoor; Geerlings, Suzanne E; Gibney, Katherine B; Kanaan, Richard A A; Mooij-Kalverda, Kirsten; Olde Hartman, Tim C; Pauëlsen, Dominique; Prins, Maria; Slieker, Kitty; van Vugt, Michele; Keijmel, Stephan P; Nieuwkerk, Pythia; Rovers, Chantal P; Knoop, Hans

Efficacy of cognitive behavioral therapy targeting severe fatigue following COVID-19: results of a randomized controlled trial

https://doi.org/10.1093/cid/ciad257

Published

8-May-23

Study

https://doi.org/10.1093/cid/ciad257

Background
Severe fatigue following COVID-19 is prevalent and debilitating. This study investigated the efficacy of cognitive behavioral therapy (CBT) for severe fatigue following COVID-19.

Methods
A multicenter, 2-arm randomized controlled trial was conducted in the Netherlands with patients being severely fatigued 3-12 months following COVID-19. Patients (n = 114) were randomly assigned (1:1) to CBT or care as usual (CAU). CBT, targeting perpetuating factors of fatigue, was provided for 17 weeks. The primary outcome was the overall mean difference between CBT and CAU on the fatigue severity subscale of the Checklist Individual Strength, directly post CBT or CAU (T1), and after six months (T2). Secondary outcomes were differences in proportions of patients meeting criteria for severe and/or chronic fatigue, differences in physical and social functioning, somatic symptoms and problems concentrating between CBT and CAU.

Results
Patients were mainly non-hospitalized and self-referred. Patients who received CBT were significantly less severely fatigued across follow-up assessments than patients receiving CAU (-8.8, (95% confidence interval (CI)) -11.9 to -5.8); P < 0.001), representing a medium Cohen’s d effect size (0.69). The between-group difference in fatigue severity was present at T1 -9.3 (95% CI -13.3 to -5.3) and T2 -8.4 (95% CI -13.1 to -3.7). All secondary outcomes favored CBT. Eight adverse events were recorded during CBT, and 20 during CAU. No serious adverse events were recorded.

Conclusions
Among patients, who were mainly non-hospitalized and self-referred, CBT was effective in reducing fatigue. The positive effect was sustained at six month follow-up.

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Shabaan, Alshaimaa Ahmed; Kassem, Islam; Mahrous, Aliaa Ibrahium; aboulmagd, Inass; Badrah, Mai; Attalla, Mohamed; Refahee, Shaimaa Mohsen

Diode laser in management of loss of taste sensation in patients with post-COVID syndrome: a randomized clinical trial

https://doi.org/10.1186/s12903-023-02952-w

Published

6-May-23

Study

https://doi.org/10.1186/s12903-023-02952-w

Objective
Loss of taste (ageusia) is a symptom observed following recovery from COVID-19 infection. The loss of taste and smell sensation may negatively affect patients’ quality of life (QoL). The present study aimed to evaluate the effectiveness of the Diode Laser in managing loss of taste sensation in patients with post-COVID syndrome versus the placebo.

Material and method
The study sample was 36 patients who complained of persistent loss of taste sensation following COVID-19. The patients were randomly assigned to one of the two groups according to the received treatment: Group I (laser treatment) and Group II (light treatment), with each patient receiving a diode laser treatment or placebo from the same operator. Taste sensation was subjectively measured after treatment for four weeks.

Results
The results demonstrated a significant difference between both groups regarding taste restoration after one month (p = 0.041), with Group II having a significantly higher percentage of cases 7 (38.9%) with partial taste restoration. In contrast, a significantly higher proportion of Group I 17 cases (94.4%) had complete taste restoration (p < 0.001).

Conclusion
The present study concluded that using a Diode laser 810 nm aided in a more rapid recovery from loss of taste dysfunction.

1164

Ce355

Moukayed, Meis

A Narrative Review on the Potential Role of Vitamin D3 in the Prevention, Protection, and Disease Mitigation of Acute and Long COVID-19

https://doi.org/10.1007/s13668-023-00471-2

Published

5-May-23

Review

https://doi.org/10.1007/s13668-023-00471-2

Purpose of Review
The coronavirus disease 2019 (COVID-19) pandemic has challenged global health systems and economies from January 2020. COVID-19 caused by the infectious severe acute respiratory syndrome coronavirus (SARS-CoV-2) has acute respiratory and cardiometabolic symptoms that can be severe and lethal. Long-term physiological and psychological symptoms, known as long COVID-19, persist affecting multiple organ systems. While vaccinations support the fight against SARS-CoV-2, other effective mechanisms of population protection should exist given the presence of yet unvaccinated and at-risk vulnerable groups, global disease comorbidities, and short-lived vaccine responses. The review proposes vitamin D3 as a plausible molecule for prevention, protection, and disease mitigation of acute and long COVID-19.

Recent Findings
Epidemiological studies have shown that individuals who were deficient in vitamin D3 had worse COVID-19 health outcomes and mortality rates. Higher doses of vitamin D3 supplementation may improve health and survivorship in individuals of various age groups, comorbidities, and severity of disease symptoms.

Summary
Vitamin D3’s biological effects can provide protection and repair in multiple organ systems affected by SARS-CoV-2. Vitamin D3 supplementation can potentially support disease-mitigation in acute and long COVID-19.

1165

Ce356

Jelinek, C.; Orozco-Bersoza, L.; Pini, S.; Melloy, S.; O'Connell, S.; Shaikh, H.; Collins, E.g.; Laghi, F.

A Home-based, Remotely Monitored Program to Improve Physical Activity in Patients With Long COVID

Published

1-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A2169

1166

Ce357

Achleitner, Martin; Steenblock, Charlotte; Dänhardt, Juliane; Jarzebska, Natalia; Kardashi, Romina; Kanczkowski, Waldemar; Straube, Richard; Rodionov, Roman N.; Bornstein, Nitzan; Tselmin, Sergey; Kaiser, Frank; Bucher, Ronald; Barbir, Mahmoud; Wong, Ma-Li; Voit-Bak, Karin; Licinio, Julio; Bornstein, Stefan R.

Clinical improvement of Long-COVID is associated with reduction in autoantibodies, lipids, and inflammation following therapeutic apheresis

https://doi.org/10.1038/s41380-023-02084-1

Published

2-May-23

Study

https://www.nature.com/articles/s41380-023-02084-1

In the aftermath of the COVID-19 pandemic, we are witnessing an unprecedented wave of post-infectious complications. Most prominently, millions of patients with Long-Covid complain about chronic fatigue and severe post-exertional malaise. Therapeutic apheresis has been suggested as an efficient treatment option for alleviating and mitigating symptoms in this desperate group of patients. However, little is known about the mechanisms and biomarkers correlating with treatment outcomes. Here, we have analyzed in different cohorts of Long-Covid patients specific biomarkers before and after therapeutic apheresis. In patients that reported a significant improvement following two cycles of therapeutic apheresis, there was a significant reduction in neurotransmitter autoantibodies, lipids, and inflammatory markers. Furthermore, we observed a 70% reduction in fibrinogen, and following apheresis, erythrocyte rouleaux formation and fibrin fibers largely disappeared as demonstrated by dark field microscopy. This is the first study demonstrating a pattern of specific biomarkers with clinical symptoms in this patient group. It may therefore form the basis for a more objective monitoring and a clinical score for the treatment of Long-Covid and other postinfectious syndromes.

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Ce358

Landhuis, Esther Wei-Yun

How Primary Care Physicians Can Recognize and Treat Long COVID

https://doi.org/10.1001/jama.2023.6604

Published

23-May-23

Article

https://doi.org/10.1001/jama.2023.6604

There are not enough long COVID specialty clinics to meet patient need, Ziyad Al-Aly, MD, chief of research and education service at the Veterans Affairs (VA) St Louis Health Care System, said in an interview. “We’re going to have to figure out a way to make sure the larger community of physician assistants, nurse practitioners, and primary care clinicians is educated to recognize and treat [long COVID].”

There’s also an urgent need for research. Last August, the US Department of Health and Human Services launched a research action plan for long COVID that includes the National Institutes of Health–funded Researching COVID to Enhance Recovery, or RECOVER, Initiative. Some have criticized RECOVER as inadequate and slow—to the extent that its principal investigators recently published a Call to Action urging Congress to include $37.5 million in fiscal year 2024 to speed research and disseminate learnings to other physicians.

The first RECOVER clinical trials are expected to launch in the coming months, a spokesperson from the National Heart, Lung, and Blood Institute told JAMA in an email, and will evaluate multiple interventions focused on 5 symptom types: viral persistence, autonomic dysfunction, sleep disturbances, cognitive dysfunction, and exercise intolerance or fatigue. Details of the interventions will appear on ClinicalTrials.gov once finalized, the spokesperson said.

Until results from those and other clinical trials arrive, guidance on managing long COVID in patients is available from the CDC, the VA, and the American Academy of Physical Medicine and Rehabilitation.

Experts interviewed for this story offered some basic guidance for primary care physicians:

Believe the patient. “Say it out loud. They need to hear it,” Palacio said of patients with long COVID symptoms, who are often not believed. If their physician says, “‘I believe you, and I will work with you to try to make you better even though I know very little about this,’ stress levels go down.”

Go beyond symptoms. Physicians are accustomed to checking off symptoms, but it’s also important to ask, “’How often do these occur?’ and ‘How do they affect your ability to carry out normal daily activities?’” Bateman said. “When you can’t perform physically and cognitively, it starts to really be disabling.”

Address fatigue. “If patients stop overexerting themselves, they start to feel better. It’s as simple as that,” Brode said. Physicians should discuss with patients “what they can honestly do in their daily activities.”

Look to familiar conditions. According to the CDC, long COVID can share symptoms with ME/CFS, fibromyalgia, posttreatment Lyme disease syndrome, dysautonomia, and mast cell activation syndrome. Approaches to managing these conditions can help some patients with long COVID. For example, POTS can be alleviated with fluids, compression garments, and graded horizontal exercise.

Primary care physicians “should be willing to think outside the box and use their medical training to provide sensible, supportive care,” Bateman said.

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Morgan, Sandra; Visovsky, Constance; Thomas, Bini; Klein, Aimee B.; Ji, Ming; Schwab, Lauren; Coury, Jillian

Home-Based Pilot Pulmonary Program for Dyspneic Patients Post-COVID-19

https://doi.org/10.1177/10547738231170496

Published

1-Jun-23

Study

https://doi.org/10.1177/10547738231170496

It is estimated that at least 10% of people who have had COVID-19 will experience ongoing symptoms such as shortness of breath, fatigue, and cognitive disturbances. Pulmonary exercise has demonstrated improved dyspnea outcomes in other respiratory conditions. Thus, the purpose of this study was to assess the efficacy of a home-based pulmonary rehabilitation program in post-COVID-19 survivors who continue to experience dyspnea. This was a longitudinal, single group pilot study in which 19 patients received a home-based expiratory muscle strength training program over 12 weeks. Outcomes measured at baseline, 6 weeks, and 12 weeks included pulmonary symptoms, functional performance, thoracic expansion, forced expiratory volume, and expiratory resistance measures. Significant improvements were found in pulmonary symptoms (p < .001), functional performance (p = .014), and progressive expiratory resistance capabilities (p < .001). A home-based pulmonary program may be an inexpensive strategy for post-COVID-19 survivors who continue to experience dyspnea.

1169

Ce360

Galvin, Vaughna; Cheek, Dennis J.; Zhang, Yan; Collins, Gregory; Gaskin, David

Short Communication: Stellate Ganglion Blockade for Persistent Olfactory and Gustatory Symptoms Post-COVID-19

https://doi.org/10.2147/LRA.S402197

Published

3-May-23

Study

https://www.dovepress.com/short-communication-stellate-ganglion-blockade-for-persistent-olfactor-peer-reviewed-fulltext-article-LRA

One hundred ninety-five patients presenting with post-COVID symptomology, including parosmia and dysgeusia, underwent reversible stellate ganglion blockade. Stellate ganglion blockade was performed at an outpatient facility, and patients were evaluated via survey at seven days post-injection. Of the 195 participants, ages ranged from 18– 69 years of age with the breakdown of sexes being females n = 157 and males n = 38. The most significant finding was a reported improvement in olfaction post-injection in 87.4% of subjects. The effectiveness of this novel treatment for post-COVID is promising and warrants further investigation.

1170

Ce361

Andrade, Sancler

Cognitive strategies and metacognition in occupational therapy for a long COVID-19 patient: a single case report

https://doi.org/10.1590/2526-8910.ctoRE265434642

Published

22-May-23

Case Report

https://www.scielo.br/j/cadbto/a/56B6TCcVFxNbJ8sWL59KDdH/?lang=en

Abstract Introduction The impact of COVID-19 on occupational and cognitive functioning deserves further exploration since clinicians have observed long COVID and neurological manifestations of COVID-19 long after the remission of respiratory symptoms. Patients with long COVID represent an underexplored population in need of quality occupational therapy interventions. Objectives (a) present an experience report on occupational therapy for assessment and intervention with this population in a hospital setting; (b) demonstrate how perceived occupational performance and health behavior can be improved by the adoption of cognitive strategies and strategies for changing habits. Method This was a single-case study of a long COVID patient in a hospital setting. A description of the framework for assessment and treatment is provided. The patient received a total of nine sessions focused on the use of cognitive strategies and metacognition. The data were analyzed descriptively. Results After exploring guided interventions, the client could create new habits and routines and have perceived occupational performance. Conclusion This experience report presents a framework for assessing and intervening in long COVID that highlights neurocognition. Prospective studies should evaluate if the effects of the proposed awareness assessment and treatment guidelines are reproducible in other settings and if this approach could be helpful for other COVID-19 survivors.

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Vontetsianos, A.; Chynkiamis, N.; Anagnostopoulou, C.; Vogiatzis, I.; Kaltsakas, G.; Koutsoukou, A.; Koulouris, N.; Kosmas, E.

Effect of hybrid rehabilitation on exercise tolerance and peripheral muscle strength in patients with long COVID-19 syndrome

https://doi.org/10.1183/23120541.LSC-2023.182

Published

9-Mar-23

Study

https://openres.ersjournals.com/content/9/suppl_10/182

Background: Exercise tolerance and quadriceps strength (QF) are reduced in patients with long COVID-19 syndrome several months after the acute phase of the disease. The effect of pulmonary rehabilitation (PR) on exercise tolerance and QF is inconclusive.
Aim: To investigate the effect of a hybrid PR program, combining outpatient and home-based PR, on exercise capacity and QF in long COVID-19 syndrome.
Methods: 38 patients (age (mean±SD): 57±12 yrs.) with excessive fatigue due to long COVID-19 syndrome (FACIT score (26±10) were allocated to PR (n=24) or usual care (UC) (n=14) groups, 132±75 days from hospital discharge. PR consisted of 8 outpatient sessions (twice weekly for 4 weeks), and 24 home- based sessions (3 times/week for 8 weeks). Patients in the UC were instructed to be physically active. Exercise tolerance was assessed by a ramp incremental CPET to the limit of tolerance. QF was assessed via an isometric strength test.
Results: Exercise tolerance was increased in the PR group (by 18±9 Watt, p<0.05) leading to greater oxygen consumption (by 2.3±1.6 ml/min/kg, p<0.05) following the completion of the PR programme. Leg fatigue at peak exercise was reduced by a clinically significant margin (1.0±3.0, Borg). Finally, QF was increased in the PR group (by 4.3±4.6 kg, p<0.05). There were no significant differences in the UC group. The change in exercise tolerance and oxygen consumption were positively associated with the change in QF when all patients were included in the analysis (r=0.315 (p=0.054) and r=0.353 (p=0.041), respectively).
Conclusions: A hybrid PR programme improves exercise tolerance and QF in patients with long COVID-19 syndrome.

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MCCarthy, Matthew W.

Metformin as a potential treatment for COVID-19

https://doi.org/10.1080/14656566.2023.2215385

Published

17-May-23

Study

https://doi.org/10.1080/14656566.2023.2215385

Introduction
Early treatment for SARS-CoV-2 infection is essential to limit the clinical progression of COVID-19. However, limited therapeutic options are available for standard-risk patients, including those under age 50 who have received the primary series of COVID-19 vaccination as well as a bivalent booster.

Areas covered
Metformin is a widely used, inexpensive antihyperglycemic for the treatment of diabetes mellitus type 2 as well as polycystic ovarian syndrome, with a well-described safety profile.

Expert opinion
Although the mechanism of action has not been fully elucidated, metformin is known to alter glucose metabolism and is under investigation as an antiviral agent, demonstrating in vitro and in vivo activity against SARS-CoV-2. Recent work suggests metformin may also serve as a therapeutic option for patients with COVID-19 as well as those with post-acute sequelae of SARS-CoV-2 infection, known more commonly as ‘long COVID-19.’ This manuscript examines what is known about metformin for the treatment of COVID-19 and explores how this drug may be used in the future to address the SARS-CoV-2 pandemic.

KEYWORDS: MetforminSARS-CoV-2antiviralCOVID-19diabetes mellitus
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Article highlights
Metformin is a widely used, inexpensive medication used for the treatment of diabetes, mellitus type 2, and polycystic ovarian syndrome.

Metformin exerts its effects in humans through a variety of mechanisms.

Metformin inhibits the mTOR pathway via AMP-kinase signaling, through the activation of tumor suppressor gene p53, inhibition of hypoxia inducible factor (HIF)-1α, and reduction of reactive oxygen species.

Metformin has antiviral and anti-inflammatory properties and may serve as a therapeutic option for outpatients infected with SARS-CoV-2

Metformin may also serve as a therapeutic option for patients with post-acute sequelae of SARS-CoV-2 infection (PASC).
publisher: Taylor & Francis
_eprint: https://doi.org/10.1080/14656566.2023.2215385
PMID: 37194484

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Samper-Pardo, M.; León-Herrera, S.; Oliván-Blázquez, B.; Méndez-López, F.; Domínguez-García, M.; Sánchez-Recio, R.

Effectiveness of a telerehabilitation intervention using ReCOVery APP of long COVID patients: a randomized, 3-month follow-up clinical trial

https://doi.org/10.1038/s41598-023-35058-y

Published

16-May-23

Study

https://www.nature.com/articles/s41598-023-35058-y

The main objective of this study is to analyze the clinical efficacy of telerehabilitation in the recovery of Long COVID patients through ReCOVery APP for 3 months, administered in the Primary Health Care context. The second objective is to identify significant models associated with an improvement in the study variables. An open-label randomized clinical trial was conducted using two parallel groups of a total of 100 Long COVID patients. The first group follows the treatment as usual methods established by their general practitioner (control group) and the second follows the same methods and also uses ReCOVery APP (intervention group). After the intervention, no significant differences were found in favour of the group intervention. Regarding adherence, 25% of the participants made significant use of the APP. Linear regression model establishes that the time of use of ReCOVery APP predicts an improvement in physical function (b = 0.001; p = 0.005) and community social support (b = 0.004; p = 0.021). In addition, an increase in self-efficacy and health literacy also contribute to improving cognitive function (b = 0.346; p = 0.001) and reducing the number of symptoms (b = 0.226; p = 0.002), respectively. In conclusion, the significant use of ReCOVery APP can contribute to the recovery of Long COVID patients.

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Ce365

Michi, Teresa; Mattana, Chiara; Menga, Luca S.; Bocci, Maria Grazia; Cesarano, Melania; Rosà, Tommaso; Gualano, Maria Rosaria; Montomoli, Jonathan; Spadaro, Savino; Tosato, Matteo; Rota, Elisabetta; Landi, Francesco; Cutuli, Salvatore L.; Tanzarella, Eloisa S.; Pintaudi, Gabriele; Piervincenzi, Edoardo; Bello, Giuseppe; Tonetti, Tommaso; Rucci, Paola; De Pascale, Gennaro; Maggiore, Salvatore M.; Grieco, Domenico Luca; Conti, Giorgio; Antonelli, Massimo; Maviglia, Riccardo; Mercurio, Giovanna; De Santis, Paolo; Pennisi, Mariano Alberto; Anzellotti, Gian Marco; Torrini, Flavia; Rubino, Carlotta; Morena, Tony C.; Gennenzi, Veronica; Postorino, Stefania; Vargas, Joel; Filetici, Nicoletta; Settanni, Donatella; Durante, Miriana; Cascarano, Laura; Di Muro, Mariangela; Scarascia, Roberta; Bitondo, Maria Maddalena; Murdolo, Martina; Mele, Alessandro; Silva, Serena; Zaccone, Carmelina; Pozzana, Francesca; Maccaglia, Alessio; Savino, Martina; Potalivo, Antonella; Ceccaroni, Francesca; Scavone, Angela; Lombardi, Gianmarco; Bello, Giuseppe; Montini, Luca; Dell’Anna, Antonio Maria; Volta, Carlo Alberto; Ranieri, Vito M.; Falò, Giulia; Carelli, Simone; Natalini, Daniele; Berardi, Cecilia; Delle Cese, Luca; Vetrugno, Luigi; Balzani, Eleonora; for the Gemelli COVID-ICU study group

Long-term outcome of COVID-19 patients treated with helmet noninvasive ventilation vs. high-flow nasal oxygen: a randomized trial

https://doi.org/10.1186/s40560-023-00669-0

Published

19-May-23

Trial

https://doi.org/10.1186/s40560-023-00669-0

Background
Long-term outcomes of patients treated with helmet noninvasive ventilation (NIV) are unknown: safety concerns regarding the risk of patient self-inflicted lung injury and delayed intubation exist when NIV is applied in hypoxemic patients. We assessed the 6-month outcome of patients who received helmet NIV or high-flow nasal oxygen for COVID-19 hypoxemic respiratory failure.

Methods
In this prespecified analysis of a randomized trial of helmet NIV versus high-flow nasal oxygen (HENIVOT), clinical status, physical performance (6-min-walking-test and 30-s chair stand test), respiratory function and quality of life (EuroQoL five dimensions five levels questionnaire, EuroQoL VAS, SF36 and Post-Traumatic Stress Disorder Checklist for the DSM) were evaluated 6 months after the enrollment.

Results
Among 80 patients who were alive, 71 (89%) completed the follow-up: 35 had received helmet NIV, 36 high-flow oxygen. There was no inter-group difference in any item concerning vital signs (N = 4), physical performance (N = 18), respiratory function (N = 27), quality of life (N = 21) and laboratory tests (N = 15). Arthralgia was significantly lower in the helmet group (16% vs. 55%, p = 0.002). Fifty-two percent of patients in helmet group vs. 63% of patients in high-flow group had diffusing capacity of the lungs for carbon monoxide < 80% of predicted (p = 0.44); 13% vs. 22% had forced vital capacity < 80% of predicted (p = 0.51). Both groups reported similar degree of pain (p = 0.81) and anxiety (p = 0.81) at the EQ-5D-5L test; the EQ-VAS score was similar in the two groups (p = 0.27). Compared to patients who successfully avoided invasive mechanical ventilation (54/71, 76%), intubated patients (17/71, 24%) had significantly worse pulmonary function (median diffusing capacity of the lungs for carbon monoxide 66% [Interquartile range: 47–77] of predicted vs. 80% [71–88], p = 0.005) and decreased quality of life (EQ-VAS: 70 [53–70] vs. 80 [70–83], p = 0.01).

Conclusions
In patients with COVID-19 hypoxemic respiratory failure, treatment with helmet NIV or high-flow oxygen yielded similar quality of life and functional outcome at 6 months. The need for invasive mechanical ventilation was associated with worse outcomes. These data indicate that helmet NIV, as applied in the HENIVOT trial, can be safely used in hypoxemic patients.

Trial registration Registered on clinicaltrials.gov NCT04502576 on August 6, 2020

1175

Ce366

Lejay, Noémie; Salvioni Chiabotti, Paolo; Ducrot, Aurélie; Allali, Gilles; Nehme, Mayssam

[Pharmacological trials evaluating treatment options for neuropsychiatric symptoms in post-COVID. A narrative review]

https://doi.org/10.53738/REVMED.2023.19.827.984

Published

17-May-23

Review

https://pubmed.ncbi.nlm.nih.gov/37195115/

Post-COVID prevalence's is estimated at 10 % in the general population. The neuropsychiatric symptoms, which are frequent (up to 30 %), can severely affect the quality of life of patients affected by this condition, notably by significantly reducing their working ability. To date, no pharmacologic treatment is available for post-COVID, apart from symptomatic treatments. A large number of pharmacological clinical trials for post-COVID are underway since 2021. A number of these trials targets neuropsychiatric symptoms, based on the various underlying pathophysiological hypotheses. The objective of this narrative review is to provide an overview of these ongoing trials targeting neuropsychiatric symptoms in post-COVID.

1176

Ce367

Sánchez-Solís, Alejandra Margarita; Peláez-Hernández, Viridiana; Santiago-Fuentes, Laura Mercedes; Luna-Rodríguez, Guadalupe Lizzbett; Reyes-Lagos, José Javier; Orea-Tejeda, Arturo

Induced Relaxation Enhances the Cardiorespiratory Dynamics in COVID-19 Survivors

https://doi.org/10.3390/e25060874

Published

1-Jun-23

Study

https://www.mdpi.com/1099-4300/25/6/874

Most COVID-19 survivors report experiencing at least one persistent symptom after recovery, including sympathovagal imbalance. Relaxation techniques based on slow-paced breathing have proven to be beneficial for cardiovascular and respiratory dynamics in healthy subjects and patients with various diseases. Therefore, the present study aimed to explore the cardiorespiratory dynamics by linear and nonlinear analysis of photoplethysmographic and respiratory time series on COVID-19 survivors under a psychophysiological assessment that includes slow-paced breathing. We analyzed photoplethysmographic and respiratory signals of 49 COVID-19 survivors to assess breathing rate variability (BRV), pulse rate variability (PRV), and pulse–respiration quotient (PRQ) during a psychophysiological assessment. Additionally, a comorbidity-based analysis was conducted to evaluate group changes. Our results indicate that all BRV indices significantly differed when performing slow-paced breathing. Nonlinear parameters of PRV were more appropriate for identifying changes in breathing patterns than linear indices. Furthermore, the mean and standard deviation of PRQ exhibited a significant increase while sample and fuzzy entropies decreased during diaphragmatic breathing. Thus, our findings suggest that slow-paced breathing may improve the cardiorespiratory dynamics of COVID-19 survivors in the short term by enhancing cardiorespiratory coupling via increased vagal activity.

1177

Ce368

Momtazmanesh, Sara; Ansari, Sahar; Izadi, Zahra; Shobeiri, Parnian; Vatankhah, Venus; Seifi, Arash; Ghiasvand, Fereshteh; Bahrami, Mahboobeh; Salehi, Mohammdreza; Noorbala, Ahmad Ali; Akhondzadeh, Shahin

Effect of famotidine on cognitive and behavioral dysfunctions induced in post-COVID-19 infection: A randomized, double-blind, and placebo-controlled study

https://doi.org/10.1016/j.jpsychores.2023.111389

Published

31-May-23

Trial

https://www.sciencedirect.com/science/article/pii/S0022399923002465

Highlights
•Post-COVID-19 complications persist in near 1/3 of the patients.
•Cognitive impairment and neuropsychiatric disorders are the most common complications.
•Few have assessed therapies for neuropsychiatric disorders caused by post-COVID-19 infection.
•A short-term treatment with famotidine improved cognitive functioning in post-COVID-19 infection.
Abstract
Objectives
This is an investigation of the efficacy and safety of famotidine, a selective histamine H2 receptor antagonist, on improvement of cognitive impairment, depression and anxiety symptoms developing post-COVID-19, in a 12-week, randomized controlled trial.

Methods
A total of 50 patients with a confirmed diagnosis of COVID-19 and a score ≤ 23 on the Mini-Mental State Examination (MMSE) test or a score ≤ 22 on the Montreal Cognitive Assessment (MoCA) were randomly assigned to either the famotidine (40 mg twice daily) or the placebo group. Changes in MMSE scores at weeks 6 and 12 were the primary outcome, while changes in other scales were the secondary outcomes. Participants and evaluators were blinded.

Results
At weeks 6 and 12, patients in the famotidine group had significantly higher MMSE scores (p = 0.014, p < 0.001, respectively). Regarding the MoCA scale, the famotidine group had a significantly higher score at weeks 6 and 12 (p = 0.001, p < 0.001, respectively). Considering the HAM-D scale (Hamilton Depression Rating Scale), at weeks 6 and 12, the famotidine group experienced a larger reduction (p = 0.009, p = 0.02, respectively). Additionally, comparison of the HAM-A scale scores (Hamilton Anxiety Rating Scale) at weeks 6 and 12 showed a statistically significant larger reduction in the famotidine group (p = 0.04, p = 0.02, respectively). The two groups did not differ in the frequency of adverse effects.

Conclusion
Our study supports safety and efficacy of famotidine in treating cognitive impairment, depression and anxiety symptoms induced by COVID-19.

1178

Ce369

Cerfoglio, Serena; Capodaglio, Paolo; Rossi, Paolo; Verme, Federica; Boldini, Gabriele; Cvetkova, Viktoria; Ruggeri, Graziano; Galli, Manuela; Cimolin, Veronica

Tele-Rehabilitation Interventions for Motor Symptoms in COVID-19 Patients: A Narrative Review

https://doi.org/10.3390/bioengineering10060650

Published

1-Jun-23

Review

https://www.mdpi.com/2306-5354/10/6/650

The COVID-19 pandemic brought new challenges to global healthcare systems regarding the care of acute patients and the delivery of rehabilitation programs to post-acute or chronic patients. Patients who survive severe forms of COVID-19 often report incomplete healing and long-term symptoms. The need of these patients for rehabilitation has been recognized as a public health problem. In this context, the application of tele-rehabilitation has been explored to reduce the burden on healthcare systems. The purpose of this narrative review is to present an overview of the state of the art regarding the application of remote motor rehabilitation programs for paucisymptomatic acute and post-acute COVID-19 patients, with a focus on the motor aspects of tele-rehabilitation. Following an extensive search on PubMed, the Web of Science, and Scopus, specific studies have been reviewed and compared in terms of study objectives and participants, experimental protocols and methods for home-based interventions, functional assessment, and rehabilitation outcomes. Overall, this review suggests the feasibility and the effectiveness of tele-rehabilitation as a promising tool to complement face-to-face rehabilitation interventions. However, further improvements are needed to overcome the limitations and the current lack of knowledge in the field.

1179

Ce370

Tomisti, Luca; Angelotti, Francesca; Lenzi, Mirco; Amadori, Francesco; Sarteschi, Giovanni; Porcu, Anna; Capria, Anna-Lisa; Bertacca, Gloria; Lombardi, Stefania; Bianchini, Guido; Vincenti, Antonella; Cesta, Novella

Efficacy of Convalescent Plasma to Treat Long-Standing COVID-19 in Patients with B-Cell Depletion

https://doi.org/10.3390/life13061266

Published

1-Jun-23

Case Report

https://www.mdpi.com/2075-1729/13/6/1266

The use of antivirals, corticosteroids, and IL-6 inhibitors has been recommended by the WHO to treat COVID-19. CP has also been considered for severe and critical cases. Clinical trials on CP have shown contradictory results, but an increasing number of patients, including immunocompromised ones, have shown benefits from this treatment. We reported two clinical cases of patients with prolonged COVID-19 infection and B-cell depletion who showed rapid clinical and virological recovery after the administration of CP. The first patient in this study was a 73-year-old female with a history of follicular non-Hodgkin lymphoma previously treated with bendamustine followed by maintenance therapy with rituximab. The second patient was a 68-year-old male with chronic obstructive pulmonary disease, bipolar disorder, alcoholic liver disease, and a history of mantellar non-Hodgkin lymphoma treated with rituximab and radiotherapy. After the administration of CP, both patients showed a resolution of symptoms, improvement of their clinical conditions, and a negative result of the nasopharyngeal swab test. The administration of CP might be effective in resolving symptoms and improving clinical and virological outcomes in patients with B-cell depletion and prolonged SARS-CoV2 infections.

1180

Ce371

Melamed, Esther; Rydberg, Leslie; Ambrose, Anne Felicia; Bhavaraju-Sanka, Ratna; Fine, Jeffrey S.; Fleming, Talya K.; Herman, Eric; Phipps Johnson, Jamie L.; Kucera, Jennifer Ryan; Longo, Michele; Niehaus, William; Oleson, Christina V.; Sampsel, Sarah; Silver, Julie K.; Smith, Martha M.; Verduzco-Gutierrez, Monica

Multidisciplinary collaborative consensus guidance statement on the assessment and treatment of neurologic sequelae in patients with post-acute sequelae of SARS-CoV-2 infection (PASC)

https://doi.org/10.1002/pmrj.12976

Published

29-Mar-23

Guidelines

https://onlinelibrary.wiley.com/doi/abs/10.1002/pmrj.12976

Despite the prevalence of neurological sequelae of COVID-19 infection and emerging data on longevity of symptoms, limited guidance exists regarding the assessment and treatment of neurologic sequelae in patients with PASC. The AAPM&R Multi-Disciplinary PASC Collaborative (PASC Collaborative), consisting of experts in PM&R, neurology, internal medicine, family practice, pediatric specialties, cardiology, physical therapy, occupational therapy, social work among other disciplines, was convened to address the pressing need for guidance in the care of patients with PASC.

The PASC Collaborative is following an iterative, modified Delphi process to achieve consensus on assessment and treatment recommendations for a series of consensus guidance statements focused on the most prominent PASC symptoms. These recommendations and guidance are informed by experts from established PASC centers with experience in managing individuals across the spectrum of sequelae experienced by patients with PASC.8-10, 13, 14 There is an intentional focus on health equity as disparities in care and outcomes are critically important to address. Beyond patient care, the hope is that a broadened understanding of current patient care practices will help identify areas of future research. A full description of the methodology has been published previously.15

We acknowledge that the definition of PASC is evolving, and there are various factors that contribute to diagnosis and management. Literature available at the time of our consensus process suggested that PASC be defined as the persistence of symptoms beyond 4 weeks from the onset of acute infection.16 Alternative definitions of PASC include symptoms lasting longer than 3 months.17 The World Health Organization released a definition of “post-COVID condition,” including describing the timing as “usually 3 months from the onset of COVID-19” and lasting “for at least 2 months.”18 Based on patient feedback during our consensus process, we agree that earlier evaluation, diagnosis, and management can improve access to beneficial interventions. For the purposes of this guidance statement, we recommend expanded assessment if symptoms are not improving 1 month after acute symptom onset.

At present, scientific evidence regarding effective assessment and treatment of PASC is limited, which prevents the creation of evidence-based clinical guidelines. This consensus guidance statement is intended to reflect current practice in patient assessment, testing, and treatments based on expert opinion from health care professionals who care for PASC patients regularly. It is intended as a resource and concise point of reference geared toward clinicians in different specialties caring for PASC patients. The recommendations should not preclude clinical judgment and must be applied in the context of the specific patient, with adjustments for patient preferences, comorbidities, and other factors.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1002/pmrj.12976

1181

Ce372

Widmann, Catherine Nichols; Kolano, Juliana; Peper, Martin

Improving Neuropsychological Rehabilitation for COVID-19 Patients

https://doi.org/10.1024/1016-264X/a000373

Published

1-Jun-23

Guidelines

https://econtent.hogrefe.com/doi/full/10.1024/1016-264X/a000373

: Cognitive sequelae after recovery from an initial COVID-19 disease are present in a subset of affected individuals, coalescing around several important issues such as effects of age, COVID-19 disease severity, comorbidities, and other factors. Some neuropsychological symptoms appear more common among certain patient populations. Comorbidities may complicate neuropsychological assessment as well. Hence, we need a guideline-based evaluation to guide neuropsychological rehabilitation. Drawing from the recent revision of the German National Guideline for the Long- and Post-COVID Syndrome and current advances in international guidance on neuropsychological assessment, this article provides practical and scientifically informed recommendations for the neuropsychological assessment of individuals recovering from coronavirus-related diseases.

1182

Ce373

Hasting, Anna S.; Herzig, Sabine; Obrig, Hellmuth; Schroeter, Matthias L.; Villringer, Arno; Thöne-Otto, Angelika I. T.

The Leipzig Treatment Program for Interdisciplinary Diagnosis and Therapy of Neurocognitive Post-COVID Symptoms

https://doi.org/10.1024/1016-264X/a000376

Published

1-Jun-23

Study

https://econtent.hogrefe.com/doi/full/10.1024/1016-264X/a000376

: This study introduces a 3-week group program designed for patients with neurocognitive post-COVID-19 syndrome (PCS). The program represents a combination of evidence-based components of neurorehabilitation and cognitive behavioral therapy (CBT). Following a detailed assessment, we develop a personalized bio-psycho-social model that integrates perceived complaints and identifies modifiable and influencing factors. We employed physiotherapeutic, cognitive, and communicative training methods to improve patients’ awareness of energy limits and implement compensatory strategies, including pacing and mindfulness techniques. N = 33 patients completed the program between June 2021 and November 2022. A pre-post comparison of questionnaire-based self-assessments revealed significant positive effects on mood, self-efficacy, and participation but not on fatigue symptoms. The study provides recommendations for the neuropsychological treatment of patients with PCS.

1183

Ce374

Albiach, C; Dominguez, E; Lopez, L; Sastre, C; Minguez, S; Nunez, J; Palau Sampio, P

Effect of a home-based inspiratory muscle training program on functional capacity in post-discharged patients with long COVID: The InsCOVID trial

https://doi.org/10.1093/eurjpc/zwad125.022

Published

1-Jun-23

Study

https://doi.org/10.1093/eurjpc/zwad125.022

Type of funding sources: Public Institution(s). Main funding source(s): Sociedad Española de Cardiología.Fatigue and exercise intolerance are the most common symptoms in patients with long COVID.This study aimed to evaluate whether a home-based inspiratory muscle training (IMT) program improves maximal functional capacity in patients long COVID after a previous admission due to SARS-CoV-2 pneumonia.This study was a single-centre, blinded assessor, randomised controlled trial. Twenty-six patients with long COVID and a previous admission due to SARS-CoV-2 pneumonia were randomly assigned to receive either a 12-week program of IMT or usual care alone. The physiotherapist and participants were not blinded. Patients allocated to the IMT arm were instructed to train at home twice daily using a threshold inspiratory muscle trainer and to maintain diaphragmatic breathing during the training session. The usual care arm received no intervention.The primary endpoint was changes in peak oxygen consumption (peakVO2). Secondary endpoints were changes in quality of life (QoL), ventilatory efficiency and chronotropic response during exercise (evaluated by chronotropic index-CIx- formula). We used linear mixed regression analysis for evaluating changes in primary and secondary endpoints.The median (interquartile range) age of the sample and time to first visit after discharge were 52 (42-59) years and 405 (301-435) days, respectively. A total of 11 (42.3%) were female. At baseline, the median of peakVO2, ventilatory efficiency and CIx were 17.4 (15.6-21.1) mL/kg/min, 29 (24.5-33.3), and 0.64 (0.54-0.87), respectively. The IMT arm improved their peakVO2 significantly compared to usual care (+Δ 4.46 mL/kg/min, 95% CI 3.10 to 5.81; p<0.001). Similar positive findings were found when evaluating changes for CIx and some QoL dimensions. We did not find significant changes in ventilatory efficiency.In long COVID patients with a previous admission due to SARS-CoV-2 pneumonia, IMT was associated with marked improvement in exercise capacity and QoL.

1184

Ce375

Freda, Colette

Biofeedback and Anxiety Reduction: An Occupational Therapy Intervention for Persons with Long Covid

Published

1-Jan-23

Study

https://encompass.eku.edu/otdcapstones/113

Background: People who acquire Covid 19 may have symptoms lasting over three months, called Long Covid. It is estimated that one in five people in the United States has Long Covid. Unpleasant symptoms of Long Covid are many including anxiety. People with Long Covid have a difficult time engaging in everyday activities and have a poor quality of life. Occupational therapy practitioners using heart rate variability (HRV) biofeedback may help decrease anxiety in the Long Covid population. There is limited research on occupational therapy and HRV biofeedback.

Purpose: The problem the study addressed was to investigate the use of HRV biofeedback therapy delivered by an occupational therapy practitioner and its effectiveness to decrease anxiety levels in people with Long Covid. The research aimed to discover if HRV biofeedback decreased anxiety and increased the quality of life in persons with Long Covid.

Methods: This study was quasi-experimental in the form of a pre-test-post-test design. Each participant was administered two pre-tests/posttests, the Generalized Anxiety Disorder (GAD) and the Quality of Life Scale (QOLS). Each participant received eight biofeedback sessions.

Results: The results of this study found that HRV biofeedback demonstrated potential in decreasing anxiety and improving quality of life in persons with Long Covid. This study yielded a low sample size; therefore, more data needs to be collected in order to determine if the results are statistically significant. A minimal clinical difference of a 4-point change is considered clinically meaningful. Ten out of eleven participants in this study reported a decrease in anxiety based on the post-test outcome measures of the GAD-7 which is considered clinically meaningful. An increase of 8-9 points in the QOLS is considered a 60% improvement in quality of life. Nine out of eleven participants reported an improvement in their quality of life and as a group mean score, which was found to be clinically meaningful.

Conclusions: The results of this pilot study appear promising for the use of HRV biofeedback to reduce anxiety and improve QOLS in persons with Long Covid. The study will continue to collect data until there are sufficient participants to perform paired-sample t-tests to determine the statistical significance of pre-test/post-test scores for both the GAD-7 and the QOLS.

1185

I01

Fan Wu, Aojie Wang, Mei Liu, Qimin Wang, Jun Chen, Shuai Xia, Yun Ling,

Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications

https://doi.org/10.1101/2020.03.30.20047365

pre-print

20-Apr-20

Study

https://www.medrxiv.org/content/10.1101/2020.03.30.20047365v2

Une mauvaise régulation des anticorps neutralisants pourrait expliquer d'autres symptômes.

1186

I02

Rajani Dube1, Subhranshu Sekhar Kar2

COVID-19 in pregnancy: the foetal perspective—a systematic review

http://dx.doi.org/10.1136/bmjpo-2020-000859

Published

1-Nov-20

Original research

https://bmjpaedsopen.bmj.com/content/4/1/e000859

Selon une revue de la littérature, le risque de bébé mort-né chez les mères infectées par la covid est à 0,99% et celui des morts néonatales à 0,55%. Cependant, cette majoration du risque (> x2) aurait des causes indirectes et non liées à l'infection. L'infection au SARS-CoV-2 de la mère ne semble pas présenter de caractère tératogène.
Le risque de transmission congénitale du virus est faible, entre 0,63 et 3% selon les études répertoriées dont certaines ont des biais de sélection.

1187

I03

N.Haddad1S.Oro2C.Ram-Wolff3M.Bagot34L.Rousset1S.Dalac5L.Laroche1E.Maubec1Groupe

COVID-19 et lymphomes cutanés

https://doi.org/10.1016/j.annder.2020.09.237

Published

25-Nov-20

Study

https://www.sciencedirect.com/science/article/pii/S0151963820306335

Les lymphomes cutanés primitifs à cellules B ou T (mycosis fongoïde), type de cancer du système lymphatique, sont décrits comme facteur de risque de covid sévère.

1188

I04

Carel W. le Roux

COVID-19 alters thinking and management in metabolic diseases

https://doi.org/10.1038/s41574-020-00449-y

Published

25-Nov-20

Article

https://www.nature.com/articles/s41574-020-00449-y

Les maladies métaboliques, sont décrites comme facteur de risque de covid sévère.

1189

I004

Muge Cevik, MRCP
Matthew Tate, MRCP
Ollie Lloyd, MRCP
Alberto Enrico Maraolo, MD
Jenna Schafers, MRCP
Antonia Ho, PhD

SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis

https://doi.org/10.1016/S2666-5247(20)30172-5

Published

19-Nov-20

Systematic review et méta-analyse

https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(20)30172-5/abstract

Une méta-analyse dans The Lancet (SRAS+MERS+SARS-CoV2, de 2003 à juin 2020) conclut que si l'excrétion d'ARN viral peut durer 126j dans les selles, aucun virus vivant de SARS-CoV-2 n'est présent dans les échantillons respiratoires après 9j de symptômes. "La transmission de la covid par voie respiratoire ne serait plus possible après 9 jours de symptômes, ce qui rendrait alors les tests PCR inutiles". La contagiosité serait plus courte pour les asymptomatiques. La possibilité de transmission par les selles est jugée incertaine.

1190

I005

Yes

Eric Y. Wang, Tianyang Mao, Jon Klein, Yile Dai, John D. Huck, Feimei Liu, Neil S. Zheng, Ting Zhou, Patrick Wong, Akiko Iwasaki, Aaron M. Ring

Diverse Functional Autoantibodies in Patients with COVID-19

https://doi.org/10.1101/2020.12.10.20247205

pre-print

12-Dec-20

https://www.medrxiv.org/content/10.1101/2020.12.10.20247205v2

One of the co-authors : "New exciting collaboration work with @Aaronmring lab reveals diverse and functional autoantibodies in #COVID patients.
Our findings provide clues for why COVID affects many organs, induce range of symptoms that are long lasting. A large fraction of #COVID patients had autoantibodies to multiple self antigens. The more severe the disease, more autoantibodies they had. So what are the targets of these autoantibodies? It turns out to be many. Some antibodies bound to interferons, chemokine and cytokines, while others bound to proteins expressed on the surface of immune and non-immune cells. ... These autoantibodies to IFN-I are likely functional - people who have them were unable to control viral load, compared to those without - matched for comparable average age, sex, and disease severity.

_

1191

I006

Questionable methodology

Bruce Patterson, Jose Guevara-Coto, Ram Yogendra, Edgar B. Francisco, emily long, Amruta Pise, Hallison Rodrigues, Purvi Parikh, Javier Mora, Rodrigo A. Mora-Rodriguez

Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning

https://doi.org/10.1101/2020.12.16.423122

pre-print

22-Dec-20

New Results

https://www.biorxiv.org/content/10.1101/2020.12.16.423122v1

Le quotient : S1= (interférons γ (IFNγ) + interleukine 2 (IL-2)) / protéines CCL4 (MIP-1β)
si supérieur à 0,4, permettrait de distinguer 97% des patients covid long sans faux positifs, selon un pre-print qui a utilisé un réseau neuronal...Ce qui signifie que les "covids longs" auraient un profil immunitaire efficace pour éliminer le virus mais sans les signaux de recrutement appropriés pour attirer les lymphocytes T activés. Cohorte de 144 patients, dont 64 covids longs et 25 sévères.
De la même façon, la différence de taux : S2 = (10*IL-10 + IL-6) – (IL-2 + IL-8)
si supérieur à 0, distinguerait les patients à covid sévère avec une sensibilité de 88% et une spécificité de 96%.Pour les patients à covid sévère, l'écart S2 traduit l'inflammation excessive, ainsi que l'activation dérégulée des lymphocytes T. L'étude a été menée par la société IncellDx, par analyse du plasma et isolation des cellules mononuclées du sang périphérique.

1192

I007

Catherine J. Reynolds1,, Leo Swadling2,, Joseph M. Gibbons3,, Corinna Pade3,, Melanie P. Jensen4, Maria

Discordant neutralizing antibody and T cell responses in asymptomatic and mild SARS-CoV-2 infection

https://doi.org/10.1126/sciimmunol.abf3698

Published

23-Dec-20

RESEARCH ARTICLE

https://immunology.sciencemag.org/content/5/54/eabf3698/

Une étude note des anomalies chez des malades asymptomatiques ou bénins de la covid, avec des réponses en anticorps et lymphocytes T parfois discordantes.

1193

I008

Laura Bergamaschi, Federica Mescia, Lorinda Turner, Aimee Hanson, Prasanti Kotagiri, Benjamin J. Dunmore, Helene Ruffieux, Aloka De Sa, Oisin Huhn, Mark R. Wills,

Early immune pathology and persistent dysregulation characterise severe COVID-19

https://doi.org/10.1101/2021.01.11.20248765

pre-print

15-Jan-21

Study

https://www.medrxiv.org/content/10.1101/2021.01.11.20248765v1

"Viral load does not correlate with the development of this pathological response, but does with its subsequent severity. Immune recovery is complex, with profound persi=stent cellular abnormalities correlating with a change in the nature of the inflammatory response, where signatures characteristic of increased oxidative phosphorylation and reactive-oxygen species-associated inflammation replace
those driven by TNF and IL-6. These late immunometabolic inflammatory changes and unresolved
immune cell defects, if persistent, may contribute to “long COVID”."

La façon dont le système immunitaire réagit *dès l'infection covid, au plus tard aux premiers symptômes*, permettrait de prédire une évolution bénigne ou non, selon une étude très qualitative encore non relue ni publiée. Selon ses auteurs, il n'y aurait pas de lien entre la charge virale aux premiers stades et la progression vers une maladie inflammatoire (covid sévère ou long). Mais une réponse immunitaire tardive serait signe d'une future évolution négative. Selon l'étude, une évolution vers un "covid long" peut résulter de modifications immuno-métaboliques inflammatoires tardives et d'altérations persistantes de certaines cellules immunitaires.

1194

I009

Petter Brodin

Immune determinants of COVID-19 disease presentation and severity

https://doi.org/10.1038/s41591-020-01202-8

published

13-Jan-21

Perspective

https://www.nature.com/articles/s41591-020-01202-8

Un article rappelle que le covid long est l'un des syndromes liés à la covid encore mal compris, avec le MIS-C (syndrome inflammatoire multisystémique chez l’enfant) et le MIS-A (le syndrome similaire chez l'adulte), et interroge le lien entre les 3.

N004

___Immunity___

Published perspective on 13-Jan-21:
"Immune determinants of COVID-19 disease presentation and severity"
Un article rappelle que le covid long est l'un des syndromes liés à la covid encore mal compris, avec le MIS-C (syndrome inflammatoire multisystémique chez l’enfant) et le MIS-A (le syndrome similaire chez l'adulte), et interroge le lien entre les 3.
Link: https://www.nature.com/articles/s41591-020-01202-8
Extract: ""

1195

I010

Alisa Pavel, Giusy del Giudice, Antonio Federico, Antonio Di Lieto, Pia A S Kinaret, Angela Serra, Dario Greco

Integrated network analysis reveals new genes suggesting COVID-19 chronic effects and treatment

https://doi.org/10.1093/bib/bbaa417

Published

11-Feb-21

Study

https://academic.oup.com/bib/advance-article/doi/10.1093/bib/bbaa417/6132618

•Integrated molecular network analysis can help to clarify the pathogenesis of complex diseases and suggest novel drug targets.
•By mapping SARS-CoV-2 first physical interactors and COVID-19 downstream differentially expressed genes on the integrated human molecular network, we identified a new set of intermediate genes.
•The newly discovered set of intermediate genes underlies important aspects of COVID-19 pathogenesis and long-term consequences, pointing to lung tissue remodelling and fibrosis.
• We highlighted immuno-modulatory and anti-angiogenic drugs targeting multiple genes in each and every relevant set: physical interactors, intermediate and downstream effectors.

Compilant plusieurs bases de données, une étude identifie des gènes susceptibles de favoriser une covid plus grave, et particulièrement les séquelles persistantes. Elle liste des médicaments qui pourraient atténuer ces prédispositions.

N002N

___Immunity___

Published study on 11-Feb-21:
"Integrated network analysis reveals new genes suggesting COVID-19 chronic effects and treatment"
Compilant plusieurs bases de données, une étude identifie des gènes susceptibles de favoriser une covid plus grave, et particulièrement les séquelles persistantes. Elle liste des médicaments qui pourraient atténuer ces prédispositions.
Link: https://academic.oup.com/bib/advance-article/doi/10.1093/bib/bbaa417/6132618
Extract: "•Integrated molecular network analysis can help to clarify the pathogenesis of complex diseases and suggest novel drug targets.
•By mapping SARS-CoV-2 first physical interactors and COVID-19 downstream differentially expressed genes on the integrated human molecular network, we identified a new set of intermediate genes.
•The newly discovered set of intermediate genes underlies important aspects of COVID-19 pathogenesis and long-term consequences, pointing to lung tissue remodelling and fibrosis.
• We highlighted immuno-modulatory and anti-angiogenic drugs targeting multiple genes in each and every relevant set: physical interactors, intermediate and downstream effectors."

1196

I011

Xiao-Lin Jiang, Guo-Lin Wang, Xiang-Na Zhao, Fei-Hu Yan, Lin Yao, Zeng-Qiang Kou, Sheng-Xiang Ji, Xiao-Li Zhang, Cun-Bao Li, Li-Jun Duan, Yan Li, Yu-Wen Zhang, Qing Duan, Tie-Cheng Wang, En-Tao Li, Xiao Wei, Qing-Yang Wang, Xue-Feng Wang, Wei-Yang Sun, Yu-Wei Gao, Dian-Min Kang, Ji-Yan Zhang & Mai-Juan Ma

Lasting antibody and T cell responses to SARS-CoV-2 in COVID-19 patients three months after infection

https://doi.org/10.1038/s41467-021-21155-x

Published

9-Feb-21

Study

https://www.nature.com/articles/s41467-021-21155-x

Our results thus provide critical evidence that IgG, NAb, and T cell responses persist in the majority of patients for at least 3–4 months after infection.

Cette étude indique que les anticorps neutralisants, d'autres comme l'immunoglobulines de type G, ainsi que les lymphocytes T restent présents chez une majorité de patients 3 à 4 mois après une infection de covid.

1197

I012

Erfan Taherifard,Ehsan Taherifard,Hamed Movahed &Mohammad Reza Mousavi

Hematologic autoimmune disorders in the course of COVID-19: a systematic review of reported cases

https://doi.org/10.1080/16078454.2021.1881225

Published

17-Feb-21

Systematic Review

https://www.tandfonline.com/doi/full/10.1080/16078454.2021.1881225

the most common hematologic autoimmune disorder was ITP in 55 cases (58%) followed by autoimmune hemolytic anemia (AIHA) in 22 cases (23%). Other hematologic autoimmune disorders observed in the literature include antiphospholipid syndrome (APLS) in 10 individuals, thrombotic thrombocytopenic purpura (TTP) in 3 individuals, Evans syndrome in 3 individuals and autoimmune neutropenia in one individual

Dans une revue d'études s'intéressant aux affections auto-immunes hématologiques qui sont parfois consécutives à la covid, une équipe de chercheurs remarquent que le purpura thrombopénique immunologique (une destruction périphérique des plaquettes dans le cadre d'un processus auto-immun médié par des autoanticorps) est le trouble le plus fréquent. Le second trouble en prévalence est l'anémie hémolytique autoimmune (les anticorps s'attaquant aux globules rouges).

1198

I013

Javier García-Abellán, Sergio Padilla, Marta Fernández-González, José A. García, Vanesa Agulló, María Andreo, Sandra Ruiz, Antonio Galiana, Félix Gutiérrez, Mar Masiá

Long-term clinical, virological and immunological outcomes in patients hospitalized for COVID-19: antibody response predicts long COVID

https://doi.org/10.1101/2021.03.08.21253124

pre-print

8-Mar-21

Study

https://www.medrxiv.org/content/10.1101/2021.03.08.21253124v1.article-info

Gender, severity of illness and weaker antibody responses, but not viral shedding, were associated with long-COVID.

Sur 146 patients covid hospitalisés, une étude non relue et non publiée note que 7,8% des patients rapportent des symptômes persistants modérés/sévères à 6 mois. Le sexe féminin et un faible taux d'anticorps Spike-IgG augmente le risque de symptômes à 6 mois. Aucune association n'est constatée avec une excrétion virale prolongée.

1199

I014

N. Winchester, BS1, C. Calabrese, DO2, L.H. Calabrese, DO2

The intersection of COVID-19 and autoimmunity: What is our current

https://doi.org/10.20411/pai.v6i1.417

Published

8-Mar-21

Study

https://www.paijournal.com/index.php/paijournal/article/download/417/325

The purpose of this review was not to provide a systematic review of this literature but rather to pose critical questions regarding the intersections of COVID-19 and autoimmunity and attempt to address them with a critical synthesis of select works that may provide insight or direction - at least for the moment.

Un article assez technique explore le lien entre les maladies auto-immune et la covid, et se demande comment celle-ci pourrait déclencher une maladies inflammatoire à médiation immunitaire.

N003A

___Immunity___

Published study on 8-Mar-21:
"The intersection of COVID-19 and autoimmunity: What is our current"
Un article assez technique explore le lien entre les maladies auto-immune et la covid, et se demande comment celle-ci pourrait déclencher une maladies inflammatoire à médiation immunitaire.
Link: https://www.paijournal.com/index.php/paijournal/article/download/417/325
Extract: "The purpose of this review was not to provide a systematic review of this literature but rather to pose critical questions regarding the intersections of COVID-19 and autoimmunity and attempt to address them with a critical synthesis of select works that may provide insight or direction - at least for the moment."

1200

I015

Florence WJ Chioh, Siew-Wai Fong, Barnaby E Young, Kan-Xing Wu, Anthony Siau, Shuba Krishnan, Yi-Hao Chan, Guillaume Carissimo, Louis LY Teo, Fei Gao, Ru San Tan, Liang Zhong, Angela S Koh, Seow-Yen Tan, Paul A Tambyah, Laurent Renia, Lisa FP Ng, David C Lye, Christine Cheung

Convalescent COVID-19 patients are susceptible to endothelial dysfunction due to persistent immune activation

https://doi.org/10.7554/eLife.64909

Published

23-Mar-21

Research Article

https://elifesciences.org/articles/64909

We found elevated levels of circulating endothelial cells (CECs), a biomarker of vascular injury, in COVID-19 convalescents compared to healthy controls. In particular, those with pre-existing conditions (e.g., hypertension, diabetes) had more pronounced endothelial activation hallmarks than non-COVID-19 patients with matched cardiovascular risk. Several proinflammatory and activated T lymphocyte-associated cytokines sustained from acute infection to recovery phase, which correlated positively with CEC measures, implicating cytokine-driven endothelial dysfunction. Notably, we found higher frequency of effector T cells in our COVID-19 convalescents compared to healthy controls. The activation markers detected on CECs mapped to counter receptors found primarily on cytotoxic CD8+ T cells, raising the possibility of cytotoxic effector cells targeting activated endothelial cells.

Une étude note un taux élevé de cellules endothéliales circulantes (CEC), un biomarqueur des lésions vasculaires, chez les convalescents de la covid par rapport aux témoins sains. Elle repère notamment des cytokines associées aux lymphocytes T pro-inflammatoires qui se maintiennent pendant la phase de récupération, impliquant un dysfonctionnement endothélial induit par celles-ci.

N006

___Immunity___

Published research article on 23-Mar-21:
"Convalescent COVID-19 patients are susceptible to endothelial dysfunction due to persistent immune activation"
Une étude note un taux élevé de cellules endothéliales circulantes (CEC), un biomarqueur des lésions vasculaires, chez les convalescents de la covid par rapport aux témoins sains. Elle repère notamment des cytokines associées aux lymphocytes T pro-inflammatoires qui se maintiennent pendant la phase de récupération, impliquant un dysfonctionnement endothélial induit par celles-ci.
Link: https://elifesciences.org/articles/64909
Extract: "We found elevated levels of circulating endothelial cells (CECs), a biomarker of vascular injury, in COVID-19 convalescents compared to healthy controls. In particular, those with pre-existing conditions (e.g., hypertension, diabetes) had more pronounced endothelial activation hallmarks than non-COVID-19 patients with matched cardiovascular risk. Several proinflammatory and activated T lymphocyte-associated cytokines sustained from acute infection to recovery phase, which correlated positively with CEC measures, implicating cytokine-driven endothelial dysfunction. Notably, we found higher frequency of effector T cells in our COVID-19 convalescents compared to healthy controls. The activation markers detected on CECs mapped to counter receptors found primarily on cytotoxic CD8+ T cells, raising the possibility of cytotoxic effector cells targeting activated endothelial cells."

1201

I016

Ales Macela andKlara Kubelkova

Why Does SARS-CoV-2 Infection Induce Autoantibody Production?

https://doi.org/10.3390/pathogens10030380

Published

22-Mar-21

Opinion

https://www.mdpi.com/2076-0817/10/3/380

SARS-CoV-2 infection induces the production of autoantibodies, which is significantly associated with complications during hospitalization and a more severe prognosis in COVID-19 patients. Such a response of the patient’s immune system may reflect (1) the dysregulation of the immune response or (2) it may be an attempt to regulate itself in situations where the non-infectious self poses a greater threat than the infectious non-self. Of significance may be the primary virus-host cell interaction where the surface-bound ACE2 ectoenzyme plays a critical role. Here, we present a brief analysis of recent findings concerning the immune recognition of SARS-CoV-2, which, we believe, favors the second possibility as the underlying reason for the production of autoantibodies during COVID-19.

Une analyse qualitative tente de comprendre pourquoi la covid entraîne une production d'auto-anticorps. Les auteurs appuient l'hypothèse que le corps entre dans une tentative de se réguler dans une situation où le soi non-infectieux représente une menace plus grande que le non-soi infectieux.

N006

___Immunity___

Published opinion on 22-Mar-21:
"Why Does SARS-CoV-2 Infection Induce Autoantibody Production?"
Une analyse qualitative tente de comprendre pourquoi la covid entraîne une production d'auto-anticorps. Les auteurs appuient l'hypothèse que le corps entre dans une tentative de se réguler dans une situation où le soi non-infectieux représente une menace plus grande que le non-soi infectieux.
Link: https://www.mdpi.com/2076-0817/10/3/380
Extract: "SARS-CoV-2 infection induces the production of autoantibodies, which is significantly associated with complications during hospitalization and a more severe prognosis in COVID-19 patients. Such a response of the patient’s immune system may reflect (1) the dysregulation of the immune response or (2) it may be an attempt to regulate itself in situations where the non-infectious self poses a greater threat than the infectious non-self. Of significance may be the primary virus-host cell interaction where the surface-bound ACE2 ectoenzyme plays a critical role. Here, we present a brief analysis of recent findings concerning the immune recognition of SARS-CoV-2, which, we believe, favors the second possibility as the underlying reason for the production of autoantibodies during COVID-19."

1202

I017

Rohan Ameratunga 1 2 3, See-Tarn Woon 2, Anthony Jordan 1, Hilary Longhurst 1 4, Euphemia Leung 5, Richard Steele 2 6, Klaus Lehnert 7, Russell Snell 7, Anna E S Brooks

Perspective: Diagnostic laboratories should urgently develop T cell assays for SARS-CoV-2 infection

https://doi.org/10.1080/1744666x.2021.1905525

Published

22-Mar-21

Perspective Article

https://pubmed.ncbi.nlm.nih.gov/33745411/

The role of T cells in acute illness is uncertain but long-term protection against the virus may rely on memory T cell responses. Measuring memory T cell responses is important for retrospective confirmation of cases, who may have been infected early in the pandemic before reliable RT-qPCR tests were available and whose SARS-CoV-2 antibodies may have become undetectable.

Dans la mesure où les anticorps suite à une infection à la covid peuvent parfois rapidement disparaître, voire être très peu présents même en première phase, un article plaide pour le développement rapide de tests de lymphocytes T pour déceler une infection passée.

N006

___Immunity___

Published perspective article on 22-Mar-21:
"Perspective: Diagnostic laboratories should urgently develop T cell assays for SARS-CoV-2 infection"
Dans la mesure où les anticorps suite à une infection à la covid peuvent parfois rapidement disparaître, voire être très peu présents même en première phase, un article plaide pour le développement rapide de tests de lymphocytes T pour déceler une infection passée.
Link: https://pubmed.ncbi.nlm.nih.gov/33745411/
Extract: "The role of T cells in acute illness is uncertain but long-term protection against the virus may rely on memory T cell responses. Measuring memory T cell responses is important for retrospective confirmation of cases, who may have been infected early in the pandemic before reliable RT-qPCR tests were available and whose SARS-CoV-2 antibodies may have become undetectable."

1203

I018

Kwang Su Kim ,Keisuke Ejima ,Shoya Iwanami,Yasuhisa Fujita,Hirofumi Ohashi,Yoshiki Koizumi,Yusuke Asai,Shinji Nakaoka,Koichi Watashi,Kazuyuki Aihara,Robin N. Thompson,Ruian Ke,Alan S. Perelson ,Shingo Iwami

A quantitative model used to compare within-host SARS-CoV-2, MERS-CoV, and SARS-CoV dynamics provides insights into the pathogenesis and treatment of SARS-CoV-2

https://doi.org/10.1371/journal.pbio.3001128

Published

22-Mar-21

https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001128

These findings suggest the difficulty of controlling SARS-CoV-2 infection by antivirals. We further used the viral dynamics model to predict the efficacy of potential antiviral drugs that have different modes of action. The efficacy was measured by the reduction in the viral load area under the curve (AUC). Our results indicate that therapies that block de novo infection or virus production are likely to be effective if and only if initiated before the viral load peak (which appears 2–3 days after symptom onset), but therapies that promote cytotoxicity of infected cells are likely to have effects with less sensitivity to the timing of treatment initiation. Furthermore, combining a therapy that promotes cytotoxicity and one that blocks de novo infection or virus production synergistically reduces the AUC with early treatment. Our unique modeling approach provides insights into the pathogenesis of SARS-CoV-2 and may be useful for development of antiviral therapies.

Une étude soutient l'idée que le contrôle de la covid est très délicat par des antiviraux. Elle affirme que seule une thérapie commencée avant le maximum de charge virale (soit 2 ou 3 jours après le début des symptômes) peut être efficace. L'alternative serait de conjuguer l'action avec une thérapie ciblant les cellules infectés en favorisant les effets cytotoxiques.

N006

___Immunity___

Published article on 22-Mar-21:
"A quantitative model used to compare within-host SARS-CoV-2, MERS-CoV, and SARS-CoV dynamics provides insights into the pathogenesis and treatment of SARS-CoV-2"
Une étude soutient l'idée que le contrôle de la covid est très délicat par des antiviraux. Elle affirme que seule une thérapie commencée avant le maximum de charge virale (soit 2 ou 3 jours après le début des symptômes) peut être efficace. L'alternative serait de conjuguer l'action avec une thérapie ciblant les cellules infectés en favorisant les effets cytotoxiques.
Link: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001128
Extract: "These findings suggest the difficulty of controlling SARS-CoV-2 infection by antivirals. We further used the viral dynamics model to predict the efficacy of potential antiviral drugs that have different modes of action. The efficacy was measured by the reduction in the viral load area under the curve (AUC). Our results indicate that therapies that block de novo infection or virus production are likely to be effective if and only if initiated before the viral load peak (which appears 2–3 days after symptom onset), but therapies that promote cytotoxicity of infected cells are likely to have effects with less sensitivity to the timing of treatment initiation. Furthermore, combining a therapy that promotes cytotoxicity and one that blocks de novo infection or virus production synergistically reduces the AUC with early treatment. Our unique modeling approach provides insights into the pathogenesis of SARS-CoV-2 and may be useful for development of antiviral therapies."

1204

I019

Quan-Xin Long, Yan-Jun Jia, Xin Wang, Hai-Jun Deng, Xiao-Xia Cao, Jun Yuan, Liang Fang, Xu-Rong Cheng, Chao Luo, An-Ran He, Xiao-Jun Tang, Jie-li Hu, Yuan Hu, Ni Tang, Xue-Fei Cai, De-Qiang Wang, Jie Hu, Jing-Fu Qiu, Bei-Zhong Liu, Juan Chen & Ai-long Huang

Immune memory in convalescent patients with asymptomatic or mild COVID-19

https://doi.org/10.1038/s41421-021-00250-9

Published

25-Mar-21

Article

https://www.nature.com/articles/s41421-021-00250-9

Here, we systematically evaluated the SARS-CoV-2-specific memory B cell and T cell responses in healthy controls and individuals recovered from asymptomatic or symptomatic infection approximately 6 months prior.

_

1205

I020

Lauren Eggert,Ziyuan He,William Collins,Alexandra Lee,Gopal Dhondalay,Shirley Jiang,Jessica Fitzpatrick,Theo Snow,Benjamin Pinsky,Maja Artandi,Linda Barman,Rajan Puri,Richard Wittman,Andra Blomkalns,Shu Cao,Ruth O'Hara,Neera Ahuja,Manisha Desai,Sayantani Sindher,Kari Nadeau,Sharon Chinthrajah

Asthma phenotypes, associated comorbidities, and long-term symptoms in COVID-19

https://doi.org/10.22541/au.161661725.56823358/v1

pre-print

24-Mar-21

Study

https://www.authorea.com/users/403836/articles/515192-asthma-phenotypes-associated-comorbidities-and-long-term-symptoms-in-covid-19

Asthma is not a risk factor for more severe COVID-19 disease. Allergic asthmatics were half as likely to be hospitalized with COVID-19 compared to non-allergic asthmatics. Lower levels of eosinophil counts (allergic biomarkers) were associated with more severe COVID-19 disease trajectory. Recovery was similar among asthmatics and non-asthmatics with over 50% of patients reporting ongoing lower respiratory symptoms three months post-infection.

Selon une étude, l'asthme n'apparaît pas comme un facteur de comorbidités pour une covid sévère, les allergies athmatiques pourraient même entrainer un risque moindre de complications.

1206

I021

Halima A.Shuwa111Tovah N.Shaw1211Sean B.Knight13KellyWemyss1Flora A.McClure1LaurencePearmain45IanPrise1ChristopherJagger1David J.Morgan1SabaKhan1OliverBrand1Elizabeth R.Mann16AndrewUstianowski7Nawar DiarBakerly3PaulDark510Christopher E.Brightling8SeemaBrij

Alterations in T and B cell function persist in convalescent COVID-19 patients

https://doi.org/10.1016/j.medj.2021.03.013

Published

31-Mar-21

https://www.sciencedirect.com/science/article/pii/S266663402100115X

We report that the alterations in B cell subsets observed in acute COVID-19 patients were largely recovered in convalescent patients. In contrast, T cells from convalescent patients displayed continued alterations with persistence of a cytotoxic program evident in CD8+ T cells as well as elevated production of type 1 cytokines and interleukin-17 (IL-17). Interestingly, B cells from patients with acute COVID-19 displayed an IL-6/IL-10 cytokine imbalance in response to Toll-like receptor activation, skewed toward a pro-inflammatory phenotype. Whereas the frequency of IL-6+ B cells was restored in convalescent patients irrespective of clinical outcome, the recovery of IL-10+ B cells was associated with the resolution of lung pathology.
Highlights
. Lymphocytes were examined during COVID-19 and at up to 6 months of convalescence
. B cell changes seen during acute COVID-19 were largely restored in convalescence
. T cells from convalescent COVID-19 patients displayed persistent changes
. Lymphocyte signatures defined 3 convalescent patient groups, one with poorer outcomes

Chez les malades de la covid présentant des symptômes persistants, une étude montre une activité cytotoxique des lymphocytes T CD8, et une production élevée de cytokines de type 1 et d'interleukine 17 (IL-17).

N010

___Immunity___

Published article on 31-Mar-21:
"Alterations in T and B cell function persist in convalescent COVID-19 patients"
Chez les malades de la covid présentant des symptômes persistants, une étude montre une activité cytotoxique des lymphocytes T CD8, et une production élevée de cytokines de type 1 et d'interleukine 17 (IL-17).
Link: https://www.sciencedirect.com/science/article/pii/S266663402100115X
Extract: "We report that the alterations in B cell subsets observed in acute COVID-19 patients were largely recovered in convalescent patients. In contrast, T cells from convalescent patients displayed continued alterations with persistence of a cytotoxic program evident in CD8+ T cells as well as elevated production of type 1 cytokines and interleukin-17 (IL-17). Interestingly, B cells from patients with acute COVID-19 displayed an IL-6/IL-10 cytokine imbalance in response to Toll-like receptor activation, skewed toward a pro-inflammatory phenotype. Whereas the frequency of IL-6+ B cells was restored in convalescent patients irrespective of clinical outcome, the recovery of IL-10+ B cells was associated with the resolution of lung pathology.
Highlights
. Lymphocytes were examined during COVID-19 and at up to 6 months of convalescence
. B cell changes seen during acute COVID-19 were largely restored in convalescence
. T cells from convalescent COVID-19 patients displayed persistent changes
. Lymphocyte signatures defined 3 convalescent patient groups, one with poorer outcomes"

1207

I022

Jean-Baptiste Dalmas

Éosinopénie et COVID-19

Published

Mémoire d'étudiant

https://hal-obspm.ccsd.cnrs.fr/MEM-UNIV-AMU/dumas-03193755v1

_

1208

I023

Elena Ortona, Danilo Buonsenso, Angelo Carfi, Walter Malorni & The Long Covid Kids study group

Long COVID: an estrogen-associated autoimmune disease?

https://doi.org/10.1038/s41420-021-00464-6

Published

13-Apr-21

Comment

https://www.nature.com/articles/s41420-021-00464-6

Organ damage caused by an excessive inflammatory response activated by the virus, but also an autoimmune reaction “unmasked” by the virus itself, perhaps due to molecular mimicry with some components of our body, could be responsible for the symptoms of Long COVID5. The autoimmune hypothesis could justify the higher incidence of this syndrome in women. In fact, the immune response for both genetic and hormonal factors is stronger in women than in men and this represents a double-edged sword: the outcome of acute COVID-19 is more severe in men but autoimmune reactions are more frequent in women6,7. Hence, the study of the appearance of autoantibodies in patient serum and the characterization of the specificity of these autoantibodies could be an important goal to begin to identify personalized and specific treatments also based on the sex of patients affected by Long COVID.

_

1209

I024

Yu Zuo, Srilakshmi Yalavarthi, Sherwin Navaz, Claire Hoy, Hui Shi, Alyssa Harbaugh, Kelsey Gockman, Melanie Zuo, Jacqueline A. Madison, Yogendra Kanthi, Jason S. Knight

Autoantibodies stabilize neutrophil extracellular traps in COVID-19

https://doi.org/10.1101/2021.03.31.21254692

pre-print

5-Apr-21

Study

https://www.medrxiv.org/content/10.1101/2021.03.31.21254692v1

The release of neutrophil extracellular traps (NETs) by hyperactive neutrophils is recognized to play an important role in the thromboinflammatory milieu inherent to severe presentations of COVID-19. At the same time, a variety of functional autoantibodies have been observed in individuals with severe COVID-19 where they likely contribute to immunopathology. Here, we aimed to determine the extent to which autoantibodies might target NETs in COVID-19 and, if detected, to elucidate their potential functions and clinical associations. We measured global anti-NET activity in 171 individuals hospitalized with COVID-19 alongside 48 healthy controls. We found high anti-NET activity in the IgG and IgM fractions of approximately 40% and 50% of patients, respectively. There was a strong correlation between anti-NET IgG and anti-NET IgM, with high anti-NET antibody levels in general associating with circulating markers of NETs such as myeloperoxidase-DNA complexes and calprotectin. Clinically, anti-NET antibodies tracked with impaired oxygenation efficiency and elevated levels of circulating D-dimer. Furthermore, patients who required mechanical ventilation had higher levels of anti-NET antibodies than those who did not require oxygen supplementation. Mechanistically, anti-NET antibodies of the IgG isotype impaired the ability of DNases in healthy serum to degrade NETs. In summary, these data reveal high levels of anti-NET antibodies in individuals hospitalized with COVID-19, where they likely impair NET clearance and thereby potentiate SARS-CoV-2 mediated thromboinflammation.

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1210

I025

GerdWallukatabBettinaHohbergercKatrinWenzelbJuliaFürstdSaraSchulze-RothebAnneWallukatbAnne-SophieHönickebJohannesMüller

Functional autoantibodies against G-protein coupled receptors in patients with persistent post-COVID-19 symptoms

https://doi.org/10.1016/j.jtauto.2021.100100

Published

16-Apr-21

Study

https://www.sciencedirect.com/science/article/pii/S2589909021000204

Highlights
•Sera from post-COVID syndrome patients contained functionally active autoantibodies which target G-protein coupled receptors.
•The list included pathogenic autoantibodies targeting the nociception receptor, the β2-and α1-adrenoceptors, angiotensin II AT1-, muscarinic M2-, MAS-, and ETA-receptors.
•Included syndromes were of neurological and cardiological origin, or a combination of both.
•This type of pathogenic autoantibody and specific autoantibody pattern were described before the first appearance of SARS-CoV2 in distinct neurological deficits and cardiovascular diseases.

Une étude renforce l'hypothèse que des symptômes de covid long pourrait traduire l'installation d'une maladie auto-immune.
Elle relève la présence d'autoanticorps pathogènes fonctionnellement actifs (fAAB) ciblant les récepteurs couplés aux protéines G (GPCR-fAAB) chez les malades à distance de l'infection. Un tel processus était, par le passé, déjà identifié comme favorisant des symptômes neurologiques et cardiaques, par une perturbation d'équilibre de mécanismes neuronaux et vasculaires.Selon les auteurs, ces éléments suggèrent qu'une combinaison de cofacteurs ischémiques ou inflammatoires, mais également d'autoanticorps, peut maintenir notamment un processus inflammatoire cardiaque.

N009

___Immunity___

Published study on 16-Apr-21:
"Functional autoantibodies against G-protein coupled receptors in patients with persistent post-COVID-19 symptoms"
Une étude renforce l'hypothèse que des symptômes de covid long pourrait traduire l'installation d'une maladie auto-immune.
Elle relève la présence d'autoanticorps pathogènes fonctionnellement actifs (fAAB) ciblant les récepteurs couplés aux protéines G (GPCR-fAAB) chez les malades à distance de l'infection. Un tel processus était, par le passé, déjà identifié comme favorisant des symptômes neurologiques et cardiaques, par une perturbation d'équilibre de mécanismes neuronaux et vasculaires.Selon les auteurs, ces éléments suggèrent qu'une combinaison de cofacteurs ischémiques ou inflammatoires, mais également d'autoanticorps, peut maintenir notamment un processus inflammatoire cardiaque.
Link: https://www.sciencedirect.com/science/article/pii/S2589909021000204
Extract: "Highlights
•Sera from post-COVID syndrome patients contained functionally active autoantibodies which target G-protein coupled receptors.
•The list included pathogenic autoantibodies targeting the nociception receptor, the β2-and α1-adrenoceptors, angiotensin II AT1-, muscarinic M2-, MAS-, and ETA-receptors.
•Included syndromes were of neurological and cardiological origin, or a combination of both.
•This type of pathogenic autoantibody and specific autoantibody pattern were described before the first appearance of SARS-CoV2 in distinct neurological deficits and cardiovascular diseases."

1211

I026

Liang Cheng, Zijun Zhu, Chao Wang, Ping Wang, Yongqun Oliver He, and Xue Zhang

COVID-19 induces lower levels of IL-8, IL-10, and MCP-1 than other acute CRS-inducing diseases

https://doi.org/10.1073/pnas.2102960118

Published

10-May-21

Letter

https://www.pnas.org/content/118/21/e2102960118

Overall, our MR analysis shows that COVID-19 induced lower levels of IL-8, IL-10, and MCP-1 than other acute diseases in CRS patients, suggesting a critical COVID-19 pathogenesis mechanism, that is, lowering the levels of these three cytokines in COVID-19 patients with CRS compared with the levels in those patents with other acute CRS-inducing diseases including bacterial sepsis, ARDS, and burns.

En comparaison avec d'autres maladies provoquant des orages de cytokines, la covid se distingue selon une étude par des niveaux plus faibles des trois cytokines suivantes : IL-8, IL-10 et MCP-1.

N010

___Immunity___

Published letter on 10-May-21:
"COVID-19 induces lower levels of IL-8, IL-10, and MCP-1 than other acute CRS-inducing diseases"
En comparaison avec d'autres maladies provoquant des orages de cytokines, la covid se distingue selon une étude par des niveaux plus faibles des trois cytokines suivantes : IL-8, IL-10 et MCP-1.
Link: https://www.pnas.org/content/118/21/e2102960118
Extract: "Overall, our MR analysis shows that COVID-19 induced lower levels of IL-8, IL-10, and MCP-1 than other acute diseases in CRS patients, suggesting a critical COVID-19 pathogenesis mechanism, that is, lowering the levels of these three cytokines in COVID-19 patients with CRS compared with the levels in those patents with other acute CRS-inducing diseases including bacterial sepsis, ARDS, and burns."

1212

I027

Andreas Wack

Monocyte and dendritic cell defects in COVID-19

https://doi.org/10.1038/s41556-021-00685-y

Published

10-May-21

Article

https://www.nature.com/articles/s41556-021-00685-y

Regarding therapeutic options, the results of this study suggest that boosting the pathways found to be impaired in patients with severe disease may be beneficial. IFN therapies have been hotly debated, and several versions have been tested with mixed results and controversial interpretations; this may not come as a surprise, given that both loss of IFN function and excessive IFNs were linked to severe COVID-19 (refs. 7,8,10). What seems clear is that IFN therapy may be most beneficial if given early, as later intervention may lead to complications due to the pro-inflammatory and anti-proliferative effects associated with IFNs6,10,14,15. In addition, whether or not patients with moderate disease should be regarded as prototypes of a successful antiviral response is unclear, as it could be argued that they still require hospital assistance and do not clear the virus with only minimal clinical symptoms, which is the assumed course of infection for many people infected by SARS-CoV-2 who remain below the clinical radar. Through the present study and many others, a coherent picture of severe COVID-19 is slowly emerging, and more work will be required to add higher resolution in time and space to the complex evolution of the immune response and its protective and pathogenic effects in COVID-19.

_

1213

I028

Chung-HsiangLiab1Hsin-YingClair Chiouc1Ming-HongLindChang-HungKuoeYu-ChihLinfgYi-ChingLinhij2Chih-HsingHungklmn2Chao-HungKuo

Immunological Map in COVID-19

https://doi.org/10.1016/j.jmii.2021.04.006

Published

12-May-21

Review

https://www.sciencedirect.com/science/article/pii/S1684118221000967

We constructed a brief summary comparison of SARS-CoV-2, SARS-CoV, and MERS-CoV infections regarding their immunological changes. In addition, we further investigated the immunological differences between severe and nonsevere COVID-19 cases, and we searched for possible immunological predictors of the patient outcome by reviewing case series studies to date. Possible immunological predictors of a poor outcome are leukocytosis, neutrophilia, lymphopenia (both CD4 and CD8 T cells), an increased neutrophil-to-lymphocyte ratio (NLR), and increased levels of pro-inflammatory cytokines (IL-6 and TNF-α), Th1 cytokines (IL-2 and IFN-γ), regulatory T cell cytokines (IL-10) and Th17 cytokines (IL-17). A more precise immunological map needs to be established, which may assist in diagnosing this disease and facilitate immunological precision medicine treatment.

_

1214

I029

Shengli Ma, Fan Zhang, Fengxia Zhou, Hui Li, Wenyu Ge, Rui Gan, Huan Nie, Biao Li, Yindong Wang, Meng Wu, Duo Li, Dongmei Wang, Zheng Wang, Yuhong You & Zhiwei Huang

Metagenomic analysis reveals oropharyngeal microbiota alterations in patients with COVID-19

https://doi.org/10.1038/s41392-021-00614-3

Published

13-May-21

Study

https://www.nature.com/articles/s41392-021-00614-3

Here, we present the oropharyngeal microbiota characteristics identified by shotgun metagenomic sequencing analyses of oropharynx swab specimens from 31 COVID-19 patients, 29 influenza B patients, and 28 healthy controls. Our results revealed a distinct oropharyngeal microbiota composition in the COVID-19 patients, characterized by enrichment of opportunistic pathogens such as Veillonella and Megasphaera and depletion of Pseudopropionibacterium, Rothia, and Streptococcus. Based on the relative abundance of the oropharyngeal microbiome, we built a microbial classifier to distinguish COVID-19 patients from flu patients and healthy controls with an AUC of 0.889, in which Veillonella was identified as the most prominent biomarker for COVID-19 group. Several members of the genus Veillonella, especially Veillonella parvula which was highly enriched in the oropharynx of our COVID-19 patients, were also overrepresented in the BALF of COVID-19 patients, indicating that the oral cavity acts as a natural reservoir for pathogens to induce co-infections in the lungs of COVID-19 patients. We also found the increased ratios of Klebsiella sp., Acinetobacter sp., and Serratia sp. were correlated with both disease severity and elevated systemic inflammation markers (neutrophil–lymphocyte ratio, NLR), suggesting that these oropharynx microbiota alterations may impact COVID-19 severity by influencing the inflammatory response. Moreover, the oropharyngeal microbiome of COVID-19 patients exhibited a significant enrichment in amino acid metabolism and xenobiotic biodegradation and metabolism. In addition, all 26 drug classes of antimicrobial resistance genes were detected in the COVID-19 group, and were significantly enriched in critical cases. In conclusion, we found that oropharyngeal microbiota alterations and functional differences were associated with COVID-19 severity.

Une publication dans Nature note des modifications spécifiques du microbiote dans le milieu oropharyngé des malades de la covid. Ces altérations pourraient selon les auteurs avoir un impact sur la réponse inflammatoire.

N011

___Immunity___

Published study on 13-May-21:
"Metagenomic analysis reveals oropharyngeal microbiota alterations in patients with COVID-19"
Une publication dans Nature note des modifications spécifiques du microbiote dans le milieu oropharyngé des malades de la covid. Ces altérations pourraient selon les auteurs avoir un impact sur la réponse inflammatoire.
Link: https://www.nature.com/articles/s41392-021-00614-3
Extract: "Here, we present the oropharyngeal microbiota characteristics identified by shotgun metagenomic sequencing analyses of oropharynx swab specimens from 31 COVID-19 patients, 29 influenza B patients, and 28 healthy controls. Our results revealed a distinct oropharyngeal microbiota composition in the COVID-19 patients, characterized by enrichment of opportunistic pathogens such as Veillonella and Megasphaera and depletion of Pseudopropionibacterium, Rothia, and Streptococcus. Based on the relative abundance of the oropharyngeal microbiome, we built a microbial classifier to distinguish COVID-19 patients from flu patients and healthy controls with an AUC of 0.889, in which Veillonella was identified as the most prominent biomarker for COVID-19 group. Several members of the genus Veillonella, especially Veillonella parvula which was highly enriched in the oropharynx of our COVID-19 patients, were also overrepresented in the BALF of COVID-19 patients, indicating that the oral cavity acts as a natural reservoir for pathogens to induce co-infections in the lungs of COVID-19 patients. We also found the increased ratios of Klebsiella sp., Acinetobacter sp., and Serratia sp. were correlated with both disease severity and elevated systemic inflammation markers (neutrophil–lymphocyte ratio, NLR), suggesting that these oropharynx microbiota alterations may impact COVID-19 severity by influencing the inflammatory response. Moreover, the oropharyngeal microbiome of COVID-19 patients exhibited a significant enrichment in amino acid metabolism and xenobiotic biodegradation and metabolism. In addition, all 26 drug classes of antimicrobial resistance genes were detected in the COVID-19 group, and were significantly enriched in critical cases. In conclusion, we found that oropharyngeal microbiota alterations and functional differences were associated with COVID-19 severity."

1215

I030

Sílvia Guerrero Caballeroa,*, Sonia Bilbao Fernándezb

Persistencia del virus SARS-CoV-2 como causa etiológica
de la sintomatología de larga duración en pacientes con
COVID-19 persistente - Persistence of the SARS-CoV-2 virus as etiological cause of long-term symptoms in persistent COVID-19 patients

http://dx.doi.org/10.24038/mgyf.2021.027

http://mgyf.org/persistencia-virus-sars-cov-2-causa-etiologica-sintomatologia-larga-duracion-en-pacientes-con-covid-19-persistente/

At present, there are significant gaps in knowledge regarding the COVID-19, result of infection due to SARS-CoV-2 virus, since a very short period of time has passed since its appearance.

This viral infection has presented with a wide range of clinical manifestations whose severity has varied greatly among the patients: persons who have required hospitalization, very ill patients with fatal consequences, subjects with long-term symptoms and others who are asymptomatic.

From the research group of Long COVID ACTS (patients with persistent symptoms of COVID-19) we have focused on the development of a scientific hypothesis in order to not rule out (and even strengthen) research projects based on the persistence of the SARS-CoV-2 virus as etiological cause of the symptoms in patients who present Persistent/Long COVID clinical symptoms (CP/LC).

_

1216

I031

David T. Arnold, MBChB, BSc, Alice Milne, MSc, Emma Samms, Louise Stadon, BSc, Nick A. Maskell, DM, Fergus W. Hamilton

Symptoms After COVID-19 Vaccination in Patients With Persistent Symptoms After Acute Infection: A Case Series

https://doi.org/10.7326/M21-1976

Published

25-May-21

Letter

https://www.acpjournals.org/doi/10.7326/M21-1976

Participants were telephoned a median of 30 days after vaccination (IQR, 26 to 36 days) to investigate changes in symptoms and quality of life. Among the 159 symptoms reported before vaccination, 37 (23.2%) had improved, 9 (5.6%) had worsened, and 113 (71.1%) were unchanged (Figure). There was no significant worsening in quality-of-life metrics before versus after vaccination (t test P > 0.1 for all SF-36 comparisons).

Dans une étude qui présente des limitations (cohorte d'une trentaine de patients et pas de double aveugle), davantage de malades du covid long observent une amélioration de leurs symptômes et quelques uns moins nombreux une dégradation. Les vaccins étaient Pfizer et AstraZeneca, aucun avantage de l'un sur l'autre n'est mesuré.

N010

___Immunity___

Published letter on 25-May-21:
"Symptoms After COVID-19 Vaccination in Patients With Persistent Symptoms After Acute Infection: A Case Series"
Dans une étude qui présente des limitations (cohorte d'une trentaine de patients et pas de double aveugle), davantage de malades du covid long observent une amélioration de leurs symptômes et quelques uns moins nombreux une dégradation. Les vaccins étaient Pfizer et AstraZeneca, aucun avantage de l'un sur l'autre n'est mesuré.
Link: https://www.acpjournals.org/doi/10.7326/M21-1976
Extract: "Participants were telephoned a median of 30 days after vaccination (IQR, 26 to 36 days) to investigate changes in symptoms and quality of life. Among the 159 symptoms reported before vaccination, 37 (23.2%) had improved, 9 (5.6%) had worsened, and 113 (71.1%) were unchanged (Figure). There was no significant worsening in quality-of-life metrics before versus after vaccination (t test P > 0.1 for all SF-36 comparisons)."

1217

I032

Chansavath Phetsouphanh, David Darley, Anette Howe, C. Mee Ling Munier, Sheila K Patel, Jenifer A Juno, Louise M Burrell, Stephen J Kent, Gregory J Dore, Anthony D Kelleher, Gail Matthews

Immunological dysfunction persists for 8 months following initial mild-moderate SARS-CoV-2 infection

https://doi.org/10.1101/2021.06.01.21257759

pre-print

3-Jun-21

Study

https://www.medrxiv.org/content/10.1101/2021.06.01.21257759v1.full-text

Here we studied a prospective cohort of individuals with long COVID (the ADAPT study) compared to age/gender matched subjects without long COVID, healthy donors and individuals infected with other non-SARS CoV2 human coronaviruses (the ADAPT-C study). We found an elevated diffuse serum inflammatory cytokine profile in symptomatic long COVID subjects that was maintained at 8 months post-infection and was not observed in asymptomatic COVID-19 survivors. This inflammatory profile consisted of 15 cytokines that positively correlated; revealing an apparent diffuse, potentially coordinated, low level up regulation of a spectrum of immune and inflammatory mediators. In addition, we found an absence of subsets of un-activated naїve T and B cells in peripheral blood of long COVID subjects, that did not reconstitute over time. In contrast, individual serum cytokines from the interferon I and III classes, T cell activation markers and plasma ACE2, while elevated in the serum of people previously infected with SARS-CoV-2 were not further elevated in subjects with long COVID symptoms. This work defines immunological parameters associated with long COVID and suggests future opportunities to prevention and treatment.

Une étude en pre-print note des modifications et dérégulations immunologiques particulières à 8 mois chez des patients covid long avec une phase initiale modérée.

1218

I033

Sanjay Pujari 1, Sunil Gaikwad 1, Abhishek Chitalikar 1, Digamber Dabhade 1, Kedar Joshi 1, Vivek Bele 1

Long-coronavirus disease among people living with HIV in western India: An observational study

https://doi.org/10.1002/iid3.467

Published

2-Jun-21

Study

https://pubmed.ncbi.nlm.nih.gov/34078004/

Long-COVID is common among PLHIV with moderate-severe acute COVID-19 illness. There is a need for integration of long-COVID diagnosis and care services within antiretroviral therapy clinics for PLHIV with COVID-19.

_

1219

I034

Jacob K. Files,1 Sanghita Sarkar,1 Timothy R Fram.,1 Sushma Boppana,1 Sarah Sterrett,1 Kai Qin,1 Anju Bansal,1 Dustin M. Long,2 Steffanie Sabbaj,1 James J. Kobie,1 Paul A. Goepfert,1 and Nathan Erdmann1

Duration of post-COVID-19 symptoms are associated with sustained SARS-CoV-2 specific immune responses

https://doi.org/10.1172/jci.insight.151544

Published

18-Jun-21

Study

https://insight.jci.org/articles/view/151544

We investigated longitudinal peripheral blood samples in 50 individuals with previously confirmed SARS-CoV-2 infection, including 20 who experienced prolonged duration of COVID-19 symptoms (lasting more than 30 days; median=74 days) compared to 30 who had symptom resolution in 20 days or less. Individuals with prolonged symptom duration maintained antigen-specific T-cell response magnitudes to SARS-CoV-2 spike protein in CD4+ and cTfh populations during late convalescence while those without persistent symptoms demonstrated an expected decline. The prolonged group also displayed increased IgG avidity to SARS-CoV-2 S-protein. Significant correlations between symptom duration and both SARS-CoV-2-specific T cells and antibodies were observed. Activation and exhaustion markers were evaluated in multiple immune cell types, revealing few phenotypic differences between prolonged and recovered groups suggesting that prolonged symptom duration is not due to persistent systemic inflammation. These findings demonstrate that SARS-CoV-2-specific immune responses are maintained in patients suffering from prolonged post-COVID-19 symptom duration in contrast to those with resolved symptoms and may suggest the persistence of viral antigens as an underlying etiology.

Une étude américaine note que les malades du covid long conservent des taux élevés de lymphocytes T spécifiques de l'antigène de la protéine Spike du SARS-CoV-2, tout comme une activité similaire des immunoglobulines de type G. Ces résultats appuient la possibilité que des réponses immunitaires spécifiques au SARS-CoV-2 sont maintenues chez les malades du covid long, et pourraient suggérer la persistance d'antigènes viraux comme étiologie sous-jacente, appuyant l'hypothèse de réservoirs viraux.

N011

___Immunity___

Published study on 18-Jun-21:
"Duration of post-COVID-19 symptoms are associated with sustained SARS-CoV-2 specific immune responses"
Une étude américaine note que les malades du covid long conservent des taux élevés de lymphocytes T spécifiques de l'antigène de la protéine Spike du SARS-CoV-2, tout comme une activité similaire des immunoglobulines de type G. Ces résultats appuient la possibilité que des réponses immunitaires spécifiques au SARS-CoV-2 sont maintenues chez les malades du covid long, et pourraient suggérer la persistance d'antigènes viraux comme étiologie sous-jacente, appuyant l'hypothèse de réservoirs viraux.
Link: https://insight.jci.org/articles/view/151544
Extract: "We investigated longitudinal peripheral blood samples in 50 individuals with previously confirmed SARS-CoV-2 infection, including 20 who experienced prolonged duration of COVID-19 symptoms (lasting more than 30 days; median=74 days) compared to 30 who had symptom resolution in 20 days or less. Individuals with prolonged symptom duration maintained antigen-specific T-cell response magnitudes to SARS-CoV-2 spike protein in CD4+ and cTfh populations during late convalescence while those without persistent symptoms demonstrated an expected decline. The prolonged group also displayed increased IgG avidity to SARS-CoV-2 S-protein. Significant correlations between symptom duration and both SARS-CoV-2-specific T cells and antibodies were observed. Activation and exhaustion markers were evaluated in multiple immune cell types, revealing few phenotypic differences between prolonged and recovered groups suggesting that prolonged symptom duration is not due to persistent systemic inflammation. These findings demonstrate that SARS-CoV-2-specific immune responses are maintained in patients suffering from prolonged post-COVID-19 symptom duration in contrast to those with resolved symptoms and may suggest the persistence of viral antigens as an underlying etiology."

1220

I035

Questionable methodology (preprin I07)

Bruce Patterson1*, Jose Guevara-Coto2, Ram Yogendra3, Edgar Francisco1, Emily Long1, Amruta Pise1, Hallison Rodrigues1, Purvi Parikh4, Javier Mora5 and Rodrigo A. Mora-Rodríguez5

Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning

https://doi.org/10.3389/fimmu.2021.700782

Published

10-Jun-21

Study

https://www.frontiersin.org/articles/10.3389/fimmu.2021.700782/abstract

Publication of pre-print I07. Cf above.

1221

I036

Bruce Patterson, Edgar B. Francisco, Ram Yogendra, Emily Long, Amruta Pise, Hallison Rodrigues, Eric Hall, onica Herrera, Purvi Parikh, Jose Guevara-Coto, Xaiolan Chang, Jonah B Sacha, Rodrigo Rodriguez, Javier Mora

Persistence of SARS CoV-2 S1 Protein in CD16+ Monocytes in Post-Acute Sequelae of COVID-19 (PASC) Up to 15 Months Post-Infection

https://doi.org/10.1101/2021.06.25.449905

pre-print

25-Jun-21

Study

https://www.biorxiv.org/content/10.1101/2021.06.25.449905v1

To be linked to I35.

1222

I037

Hannah Zacharias a Shirish Dubey ab Gouri Koduric David D'Cruz d

Rheumatological complications of Covid 19

https://doi.org/10.1016/j.autrev.2021.102883

Published

5-Jul-21

Review

https://www.sciencedirect.com/science/article/pii/S1568997221001567

Results
We found a number of reports of inflammatory arthritis after SARS-CoV-2 infection. SLE and renal disease have been described, and vasculitis also appears to be a common complication. Rhabdomyolysis and myositis has also been reported in a number of patients. We also found some evidence of large vessel vasculitis in ‘long COVID’ patients.
Conclusions
This review highlights a number of important complications such as inflammatory arthritis, lupus-like disease, myostis and vasculitis following SARS-CoV-2 infection.

Une revue d'études sur les rhumatismes et arthrites causées par la covid. Les auteurs rapportent les arthrites inflammatoires, les troubles du tissu conjonctif, les vascularites (à petits, gros vaisseaux, et à IgA), les manifestations cutanées, les atteintes du système nerveux central, et les syndromes inflammatoires multi-systémiques.

N014E

___Immunity___

Published review on 5-Jul-21:
"Rheumatological complications of Covid 19"
Une revue d'études sur les rhumatismes et arthrites causées par la covid. Les auteurs rapportent les arthrites inflammatoires, les troubles du tissu conjonctif, les vascularites (à petits, gros vaisseaux, et à IgA), les manifestations cutanées, les atteintes du système nerveux central, et les syndromes inflammatoires multi-systémiques.
Link: https://www.sciencedirect.com/science/article/pii/S1568997221001567
Extract: "Results
We found a number of reports of inflammatory arthritis after SARS-CoV-2 infection. SLE and renal disease have been described, and vasculitis also appears to be a common complication. Rhabdomyolysis and myositis has also been reported in a number of patients. We also found some evidence of large vessel vasculitis in ‘long COVID’ patients.
Conclusions
This review highlights a number of important complications such as inflammatory arthritis, lupus-like disease, myostis and vasculitis following SARS-CoV-2 infection."

1223

I038

Rolf F. Barth, MD; L. Maximillian Buja, MD; Alison L. Barth, PhD; David E. Carpenter, MA; Anil V. Parwani, MD, PhD

A Comparison of the Clinical, Viral, Pathologic, and Immunologic Features of Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and Coronavirus 2019 (COVID-19) Diseases

https://doi.org/10.5858/arpa.2020-0820-SA

Published

7-Jul-21

Review

https://meridian.allenpress.com/aplm/article/doi/10.5858/arpa.2020-0820-SA/467552/A-Comparison-of-the-Clinical-Viral-Pathologic-and

The SARS and MERS epidemics have been limited, involving 7,500 and 2,500 individuals, respectively. In contrast, COVID-19 has resulted in a worldwide pandemic with over 177 million cases and 3.9 million deaths as of June 15, 2021, and fatality rates ranging from <0.1% to ~10% depending upon the country. Ending on a positive note, the development of a number of vaccines, at least six of which now are in clinical use, should mitigate and eventually control the devastating COVID-19 pandemic.

1224

I039

Xu C, Fan J, Luo Y, Zhao Z, Tang P, Yang G, Pan Y, Guo S, Liu Y, Xiong Y, Xie W, Long X

Prevalence and Characteristics of Rheumatoid-Associated Autoantibodies in Patients with COVID-19

https://doi.org/10.2147/JIR.S312090

Published

12-Jul-21

Study

https://www.dovepress.com/prevalence-and-characteristics-of-rheumatoid-associated-autoantibodies-peer-reviewed-fulltext-article-JIR

Rheumatoid-associated autoantibodies were detected in 20.16% of patients (26/129) following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition, IgM-RF was primarily present in critically ill patients, while IgA-RF was mainly present in mild patients. Five patients were able to track for several months to monitor dynamic changes of these antibodies. Rheumatoid factor antibodies peaks in the later phase of the disease and last for longer time. Anti-Jo-1 antibody was found in one of the five patients.
Conclusion: This was the case series report that rheumatoid-associated autoantibodies are present in patients with COVID-19. The clinical significance of these antibodies was not fully understood and needed further characterization. These autoantibodies are related to the severity of the patient’s disease and exist for a long time in the patient’s body, while their impact on the patient’s health is unknown.

1225

I040

Carolina Lucas, Chantal B. F. Vogels, Inci Yildirim, Jessica E. Rothman, Peiwen Lu, Valter Monteiro, Jeff R. Gelhausen, Melissa Campbell, Julio Silva, Alexandra Tabachikova, M. Catherine Muenker, Mallery I. Breban, Joseph R. Fauver, Subhasis Mohanty, Jiefang Huang, Yale SARS-CoV-2 Genomic Surveillance Initiative, Claire Pearson, Anthony Muyombwe, Randy Downing, Jafar Razeq, Mary Petrone, Isabel Ott, Anne Watkins, Chaney Kalinich, Tara Alpert, Anderson Brito, Rebecca Earnest, Steven Murphy, Caleb Neal, Eva Laszlo, Ahmad Altajar, Irina Tikhonova, Christopher Castaldi, Shrikant Mane, Kaya Bilguvar, Nicholas Kerantzas, David Ferguson, Wade Schulz, Marie Landry, David Peaper, Albert C. Shaw, Albert I. Ko, Saad B. Omer, Nathan D. Grubaugh, Akiko Iwasaki

Impact of circulating SARS-CoV-2 variants on mRNA vaccine-induced immunity in uninfected and previously infected individuals

https://doi.org/10.1101/2021.07.14.21260307

pre-print

18-Jul-21

Study

https://www.medrxiv.org/content/10.1101/2021.07.14.21260307v1

We analysed the development of anti-SARS-CoV-2 antibody and T cell responses in previously infected (recovered) or uninfected (naive) individuals that received mRNA vaccines to SARS-CoV-2. While previously infected individuals sustained higher antibody titers than uninfected individuals post-vaccination, the latter reached comparable levels of neutralization responses to the ancestral strain than previously infected individuals 7 days after the second vaccine dose. T cell activation markers measured upon spike or nucleocapsid peptide in vitro stimulation showed a progressive increase after vaccination in the time-points analysed. Comprehensive analysis of plasma neutralization using 16 authentic isolates of distinct locally circulating SARS-CoV-2 variants revealed a range of reduction in the neutralization capacity associated with specific mutations in the spike gene: lineages with E484K and N501Y/T (e.g., B.1.351 and P.1) had the greatest reduction, followed by lineages with L452R (e.g., B.1.617.2) or with E484K (without N501Y/T). While both groups retained neutralization capacity against all variants, plasma from previously infected vaccinated individuals displayed overall better neutralization capacity when compared to plasma from uninfected individuals that also received two vaccine doses, pointing to vaccine boosters as a relevant future strategy to alleviate the impact of emerging variants on antibody neutralizing activity.

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1226

I041

MiriamMerad1234ArunaSubramanian5Taia T.Wang

An aberrant inflammatory response in severe COVID-19

https://doi.org/10.1016/j.chom.2021.06.018

Published

14-Jul-21

Forum

https://www.sciencedirect.com/science/article/pii/S1931312821003000

Severe COVID-19 arises from the convergence of inadequate pre-existing immunity and a host response that damages, rather than repairs, tissues. We outline clinical presentations of COVID-19 that are likely driven by dysregulated host immunity, discuss potential mechanisms underlying pathological responses, and highlight important areas for basic research on this topic.

_

1227

I042

Javier García-Abellán, Sergio Padilla, Marta Fernández-González, José A. García, Vanesa Agulló, María Andreo, Sandra Ruiz, Antonio Galiana, Félix Gutiérrez & Mar Masiá

Antibody Response to SARS-CoV-2 is Associated with Long-term Clinical Outcome in Patients with COVID-19: a Longitudinal Study

https://doi.org/10.1007/s10875-021-01083-7

Published

17-Jul-21

Study

https://link.springer.com/article/10.1007/s10875-021-01083-7

Of 146 patients (60% male, median age 64 years) followed-up, 20.6% required hospital readmission and 5.5% died. At 2 months and 6 months, 9.6% and 7.8% patients, respectively, reported moderate/severe persistent symptoms. SARS-CoV-2 RT-PCR was positive in NPS in 11.8% (median Ct = 38) and 3% (median Ct = 36) patients at 2 months and 6 months, respectively, but no reinfections were demonstrated. Antibody titers gradually waned, with seroreversion occurring at 6 months in 27 (27.6%) patients for N-IgG and in 6 (6%) for S-IgG. Adjusted 2-month predictors of the highest CSQ scores (OR [95%CI]) were lower peak S-IgG (0.80 [0.66–0.94]) and higher WHO severity score (2.57 [1.20–5.86]); 6-month predictors were lower peak S-IgG (0.89 [0.79–0.99]) and female sex (2.41 [1.20–4.82]); no association was found with prolonged viral RNA shedding.

Conclusions
Long-COVID is associated with weak anti-SARS-CoV-2 antibody response, severity of illness, and female gender. Late clinical events and persistent symptoms in the medium and long term occur in a significant proportion of patients hospitalized for COVID-19.

Une étude sur le profil immunologique de 146 malades du covid long montre une positivité aux tests PCR qui peut être maintenue sur 1 ou 2 mois, voire davantage, et une corrélation avec une baisse rapide des anticorps neutralisants S. Une séroreversion est intervenue à 6 mois pour plus d'un quart des patients pour les anticorps N-IgG, et pour 6% des patients concernant les S-IgG.

N012

___Immunity___

Published study on 17-Jul-21:
"Antibody Response to SARS-CoV-2 is Associated with Long-term Clinical Outcome in Patients with COVID-19: a Longitudinal Study"
Une étude sur le profil immunologique de 146 malades du covid long montre une positivité aux tests PCR qui peut être maintenue sur 1 ou 2 mois, voire davantage, et une corrélation avec une baisse rapide des anticorps neutralisants S. Une séroreversion est intervenue à 6 mois pour plus d'un quart des patients pour les anticorps N-IgG, et pour 6% des patients concernant les S-IgG.
Link: https://link.springer.com/article/10.1007/s10875-021-01083-7
Extract: "Of 146 patients (60% male, median age 64 years) followed-up, 20.6% required hospital readmission and 5.5% died. At 2 months and 6 months, 9.6% and 7.8% patients, respectively, reported moderate/severe persistent symptoms. SARS-CoV-2 RT-PCR was positive in NPS in 11.8% (median Ct = 38) and 3% (median Ct = 36) patients at 2 months and 6 months, respectively, but no reinfections were demonstrated. Antibody titers gradually waned, with seroreversion occurring at 6 months in 27 (27.6%) patients for N-IgG and in 6 (6%) for S-IgG. Adjusted 2-month predictors of the highest CSQ scores (OR [95%CI]) were lower peak S-IgG (0.80 [0.66–0.94]) and higher WHO severity score (2.57 [1.20–5.86]); 6-month predictors were lower peak S-IgG (0.89 [0.79–0.99]) and female sex (2.41 [1.20–4.82]); no association was found with prolonged viral RNA shedding.

Conclusions
Long-COVID is associated with weak anti-SARS-CoV-2 antibody response, severity of illness, and female gender. Late clinical events and persistent symptoms in the medium and long term occur in a significant proportion of patients hospitalized for COVID-19."

1228

I043

Vinod Nikhra

SARS-CoV-2 Infection, COVID-19, and Long Covid:
Saga of Erratic Immune Response, Waning Immunity, and Immune System Failure

http:// .org/0000-0003-0859-5232

Published

1-Jul-21

REVIEW ARTICLE

https://www.researchgate.net/profile/Vinod-Nikhra/publication/353170583_SARS-CoV-2_Infection_COVID-19_and_Long_Covid_Saga_of_Erratic_Immune_Response_Waning_Immunity_and_Immune_System_Failure/links/60ebb03ab8c0d5588cee6286/SARS-CoV-2-Infection-COVID-19-and-Long-Covid-Saga-of-Erratic-Immune-Response-Waning-Immunity-and-Immune-System-Failure.pdf

The role of the vaccine in protecting Long Covid manifestations is being assumed, though not backed by large clinical studies (41).

1229

I044

William David Strain Ondine Sherwood Amitava Banerjee Vicky van der Togt Lyth Hishmeh Jeremy Rossman

The Impact of COVID Vaccination on Symptoms of Long COVID. An International Survey of People with Lived Experience of Long COVID

pre-print

17-Jun-21

Study

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3868856

Results: 900 people participated in the questionnaire, of whom 45 had pre-existing myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) but no evidence of COVID infection and a further 43 did not complete the survey in full. The demographics and symptomology of the remaining 812 people were similar to Office of National Statistics. Following vaccination, 57.9% of participants reported improvements in symptoms, 17.9% reported deterioration and the remainder no change. There was considerable individual variation in responses. Larger improvements in symptom severity scores were seen in those receiving the mRNA vaccines compared to adenoviral vector vaccines.

1230

I045

Moriah Bergwerk, M.B., B.S., Tal Gonen, B.A., Yaniv Lustig, Ph.D., Sharon Amit, M.D., Marc Lipsitch, Ph.D., Carmit Cohen, Ph.D., Michal Mandelboim, Ph.D., Einav Gal Levin, M.D., Carmit Rubin, N.D., Victoria Indenbaum, Ph.D., Ilana Tal, R.N., Ph.D., Malka Zavitan, R.N., M.A., Neta Zuckerman, Ph.D., Adina Bar-Chaim, Ph.D., Yitshak Kreiss, M.D., and Gili Regev-Yochay

Covid-19 Breakthrough Infections in Vaccinated Health Care Workers

https://doi.org/10.1056/NEJMoa2109072

Published

28-Jul-21

Study

https://www.nejm.org/doi/full/10.1056/NEJMoa2109072

Among 1497 fully vaccinated health care workers for whom RT-PCR data were available, 39 SARS-CoV-2 breakthrough infections were documented. Neutralizing antibody titers in case patients during the peri-infection period were lower than those in matched uninfected controls (case-to-control ratio, 0.361; 95% confidence interval, 0.165 to 0.787). Higher peri-infection neutralizing antibody titers were associated with lower infectivity (higher Ct values). Most breakthrough cases were mild or asymptomatic, although 19% had persistent symptoms (>6 weeks). The B.1.1.7 (alpha) variant was found in 85% of samples tested. A total of 74% of case patients had a high viral load (Ct value, <30) at some point during their infection; however, of these patients, only 17 (59%) had a positive result on concurrent Ag-RDT. No secondary infections were documented.

Une étude israélienne relève que si la vaccination réduit bien le risque d'infection de façon conséquente, elle ne supprime pas la possibilité de développer un covid long en cas d'infection post-vaccinale. Sur 11453 soignants du centre hospitalier de Ramat Gan, complètement vaccinés au Pfizer, 39 ont été infectés au SARS-CoV-2 malgré leur vaccination, a priori tous par des non-vaccinés. 13 d'entre eux ont eu une infection asymptomatique, les 26 autres des symptômes légers. 31% de tous les soignants infectés ont déclaré avoir des symptômes résiduels 14 jours après leur diagnostic. Six semaines après leur diagnostic, 19% ont rapporté des symptômes de covid long : une perte d'odorat prolongée, une toux persistante, de la fatigue, une dyspnée ou une myalgie.
Neuf employés (23 %) ont pris un congé au-delà des 10 jours de quarantaine requis, et parmi ces soignants 4 ont repris le travail dans les 2 semaines. Un employé n'était pas encore revenu après 6 semaines.

N012

___Immunity___

Published study on 28-Jul-21:
"Covid-19 Breakthrough Infections in Vaccinated Health Care Workers"
Une étude israélienne relève que si la vaccination réduit bien le risque d'infection de façon conséquente, elle ne supprime pas la possibilité de développer un covid long en cas d'infection post-vaccinale. Sur 11453 soignants du centre hospitalier de Ramat Gan, complètement vaccinés au Pfizer, 39 ont été infectés au SARS-CoV-2 malgré leur vaccination, a priori tous par des non-vaccinés. 13 d'entre eux ont eu une infection asymptomatique, les 26 autres des symptômes légers. 31% de tous les soignants infectés ont déclaré avoir des symptômes résiduels 14 jours après leur diagnostic. Six semaines après leur diagnostic, 19% ont rapporté des symptômes de covid long : une perte d'odorat prolongée, une toux persistante, de la fatigue, une dyspnée ou une myalgie.
Neuf employés (23 %) ont pris un congé au-delà des 10 jours de quarantaine requis, et parmi ces soignants 4 ont repris le travail dans les 2 semaines. Un employé n'était pas encore revenu après 6 semaines.
Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2109072
Extract: "Among 1497 fully vaccinated health care workers for whom RT-PCR data were available, 39 SARS-CoV-2 breakthrough infections were documented. Neutralizing antibody titers in case patients during the peri-infection period were lower than those in matched uninfected controls (case-to-control ratio, 0.361; 95% confidence interval, 0.165 to 0.787). Higher peri-infection neutralizing antibody titers were associated with lower infectivity (higher Ct values). Most breakthrough cases were mild or asymptomatic, although 19% had persistent symptoms (>6 weeks). The B.1.1.7 (alpha) variant was found in 85% of samples tested. A total of 74% of case patients had a high viral load (Ct value, <30) at some point during their infection; however, of these patients, only 17 (59%) had a positive result on concurrent Ag-RDT. No secondary infections were documented."

1231

I046

Daisy Massey;1 Diana Berrent;2 Athena Akrami;3,4 Gina Assaf;4 Hannah Davis;4 Karen Harris;4 Lisa McCorkell;4 Aaron M Ring;5 Wade
L Schulz;1,6 Hannah Wei;4 Harlan M Krumholz;1,7,8 Akiko Iwasaki;5,9

Change in Symptoms and Immune Response in People with Post-Acute Sequelae of SARS-Cov-2 Infection (PASC) After
SARS-Cov-2 Vaccination

https://doi.org/10.1101/2021.07.21.21260391

pre-print

28-Jul-21

Study

https://www.medrxiv.org/content/10.1101/2021.07.21.21260391v2

As such, we are conducting a study that measures the changes in PASC symptoms after vaccination. We are collecting baseline self-report and biospecimens for immune assays and then are following up with participants to collect the same data at 2-weeks, 6-weeks, and 12-weeks post-vaccination (first dose). Immune assays using blood specimens will include B-cell, T-cell, and myeloid cell panels; evaluation of T-cell responsiveness to SARS-CoV-2 peptides and antigen specific response; autoantibody screening (of IgG, IgM, and IgA antibodies that attack human proteins); and TCR sequencing and antigen mapping of CD8+ T-cells. Mucosal immunity will
be measured using saliva specimens. The study aims to provide answers for people with PASC, especially regarding the causes of their symptoms and how the vaccine may affect them, and clues for PASC treatment.

1232

I047

Cf D88

Kevin Roe

A role for T-cell exhaustion in Long COVID-19 and severe outcomes for several categories of COVID-19 patients

https://doi.org/10.1002/jnr.24917

Published

19-Jul-21

Review

https://onlinelibrary.wiley.com/doi/full/10.1002/jnr.24917

It is now hypothesized that these differences in mortality rates and symptoms could be caused by a SARS-CoV-2 virus infection acting together with one or more latent pathogen infections in certain patients, through mutually beneficial induced immune cell dysfunctions, including T-cell exhaustion. A latent pathogen infection likely to be involved is the protozoan parasite Toxoplasma gondii, which infects approximately one third of the global human population. Furthermore, certain infections and cancers that cause T-cell exhaustion can also explain the more severe outcomes of other COVID-19 patients having several disease and cancer comorbidities.

1233

I048

Raghava S. Ambadapoodi1∗; Fnu Deepti1∗; Javaria Anwer1∗; Rafael Fernandez-Botran2†

Post-Acute Sequelae of COVID-19 (PASC): Association with
Inflammation and Autoimmunity

Published

27-Jul-21

Review

https://ir.library.louisville.edu/cgi/viewcontent.cgi?article=1213&context=jri

The exact causes for the symptoms observed in patients with PASC remain to be adequately characterized, but are likely to be associated with multiple factors, including residual disease and/or inflammation, organ damage, effects of hospitalization and/or prolonged ventilation, as well as effects of social isolation and stress. This mini-review discusses evidence that may link both inflammatory and auto-immune processes in the pathophysiology of PASC.

_

1234

I049

Tarek A-Z K Gaber, Abdul Ashish, Alison Unsworth & Jane Martindale

Are mRNA Covid 19 vaccines safe in Long Covid patients? A Health Care Workers perspective

pre-print

1-Aug-21

Study

https://www.bjmp.org/content/are-mrna-covid-19-vaccines-safe-long-covid-patients-health-care-workers-perspective

Method: A short questionnaire was sent to users of a long covid service supporting an NHS Trust staff in Wigan 2 weeks following the conclusion of a mRNA vaccine first dose roll out. The questionnaire explored acceptance and compliance with the vaccine and any change in the symptoms at least 2 weeks following the vaccination.
Results: 77 HCW were offered the vaccine. 10 respondents declined mainly because of concerns regarding worsening long covid symptoms. 67% of respondents did not experience any change in symptoms whilst 21% experienced improvement of symptoms. 12% experienced worsening of symptoms.
Conclusion: mRNA vaccines can influence long covid symptoms. However, patients seemed to be twice as likely to experience improvement than worsening of symptoms.

1235

I050

Michael J.Peluso16Amelia N.Deitchman26LeonelTorres136Nikita S.Iyer3Sadie E.Munter3Christopher C.Nixon3JoannaDonatelli3CassandraThanh3SakiTakahashi1JillHakim1KeirstinneTurcios1OwenJanson1RebeccaHoh1VivaTai1YanelHernandez1Emily A.Fehrman1Matthew A.Spinelli1MonicaGandhi1…Timothy J.Henrich

Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symptoms

https://doi.org/10.1016/j.celrep.2021.109518

Published

10-Aug-21

Study

https://www.sciencedirect.com/science/article/pii/S2211124721009487

We describe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell responses, soluble markers of inflammation, and antibody levels and neutralization capacity longitudinally in 70 individuals with PCR-confirmed SARS-CoV-2 infection. Participants represent a spectrum of illness and recovery, including some with persistent viral shedding in saliva and many experiencing post-acute sequelae of SARS-CoV-2 infection (PASC). T cell responses remain stable for up to 9 months. Whereas the magnitude of early CD4+ T cell immune responses correlates with severity of initial infection, pre-existing lung disease is independently associated with higher long-term SARS-CoV-2-specific CD8+ T cell responses. Among participants with PASC 4 months following coronavirus disease 2019 (COVID-19) symptom onset, we observe a lower frequency of CD8+ T cells expressing CD107a, a marker of degranulation, in response to Nucleocapsid (N) peptide pool stimulation, and a more rapid decline in the frequency of N-specific interferon-γ-producing CD8+ T cells. Neutralizing antibody levels strongly correlate with SARS-CoV-2-specific CD4+ T cell responses.

Highlights
•The magnitude of early CD4+ T cell responses correlates with severity of COVID-19
•Prior lung disease correlates with higher SARS-CoV-2-specific CD8+ T cell responses
•PASC is associated with a decline in N-specific interferon-γ-producing CD8+ T cells
•Neutralizing capacity correlates with SARS-CoV-2-specific CD4+ T cell responses

1236

I051

Feargal J. Ryan, Christopher M. Hope, Makutiro G. Masavuli, Miriam A. Lynn, Zelalem A. Mekonnen, Arthur Eng Lip Yeow, Pablo Garcia-Valtanen, Zahraa Al-Delfi, Jason Gummow, Catherine Ferguson, Stephanie O’Connor, Benjamin AJ Reddi, David Shaw, Chuan Kok-Lim, Jonathan M. Gleadle, Michael R. Beard, Simon C. Barry, Branka Grubor-Bauk, David J. Lynn

Long-term perturbation of the peripheral immune system months after SARS-CoV-2 infection

https://doi.org/10.1101/2021.07.30.21261234

pre-print

3-Aug-21

Study

https://www.medrxiv.org/content/10.1101/2021.07.30.21261234v1

Increasing evidence suggests immune dysregulation in individuals recovering from SARS- CoV-2 infection. We have undertaken an integrated analysis of immune responses at a transcriptional, cellular, and serological level at 12, 16, and 24 weeks post-infection (wpi) in 69 individuals recovering from mild, moderate, severe, or critical COVID-19. Anti-Spike and anti-RBD IgG responses were largely stable up to 24wpi and correlated with disease severity. Deep immunophenotyping revealed significant differences in multiple innate (NK cells, LD neutrophils, CXCR3+ monocytes) and adaptive immune populations (T helper, T follicular helper and regulatory T cells) in COVID-19 convalescents compared to healthy controls, which were most strongly evident at 12 and 16wpi. RNA sequencing suggested ongoing immune and metabolic dysregulation in convalescents months after infection. Variation in the rate of recovery from infection at a cellular and transcriptional level may explain the persistence of symptoms associated with long COVID in some individuals.

1237

I052

1238

I053

Michela Antonelli, PhD, Rose S Penfold, BMBCh, Jordi Merino, PhD, Carole H Sudre, PhD, Erika Molteni, PhD, Sarah Berry, PhD, Liane S Canas, PhD, Mark S Graham, PhD, Kerstin Klaser, MSc, Marc Modat, PhD, Benjamin Murray, MSc, Eric Kerfoot, PhD, Liyuan Chen, MSc, Jie Deng, PhD, Marc F Österdahl, MBBS, Nathan J Cheetham, PhD, David A Drew, PhD, Long H Nguyen, MD, Joan Capdevila Pujol, PhD, Christina Hu, MA, Somesh Selvachandran, MSc, Lorenzo Polidori, MS, Anna May, MSc, Jonathan Wolf, MA, Prof Andrew T Chan, MD, Prof Alexander Hammers, PhD, Prof Emma L Duncan, PhD, Prof Tim D Spector, PhD, Prof Sebastien Ourselin, PhD *, Claire J Steves

Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study

https://doi.org/10.1016/S1473-3099(21)00460-6

Published

1-Sep-21

Study

https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00460-6/fulltext

Between Dec 8, 2020, and July 4, 2021, 1 240 009 COVID Symptom Study app users reported a first vaccine dose, of whom 6030 (0·5%) subsequently tested positive for SARS-CoV-2 (cases 1), and 971 504 reported a second dose, of whom 2370 (0·2%) subsequently tested positive for SARS-CoV-2 (cases 2). In the risk factor analysis, frailty was associated with post-vaccination infection in older adults (≥60 years) after their first vaccine dose (odds ratio [OR] 1·93, 95% CI 1·50–2·48; p<0·0001), and individuals living in highly deprived areas had increased odds of post-vaccination infection following their first vaccine dose (OR 1·11, 95% CI 1·01–1·23; p=0·039). Individuals without obesity (BMI <30 kg/m2) had lower odds of infection following their first vaccine dose (OR 0·84, 95% CI 0·75–0·94; p=0·0030). For the disease profile analysis, 3825 users from cases 1 were included in cases 3 and 906 users from cases 2 were included in cases 4. Vaccination (compared with no vaccination) was associated with reduced odds of hospitalisation or having more than five symptoms in the first week of illness following the first or second dose, and long-duration (≥28 days) symptoms following the second dose. Almost all symptoms were reported less frequently in infected vaccinated individuals than in infected unvaccinated individuals, and vaccinated participants were more likely to be completely asymptomatic, especially if they were 60 years or older.

Selon une étude britannique, les chances d'avoir des symptômes qui se prolongent pendant 28 jours ou plus, après une infection de covid post-vaccinale, seraient approximativement réduites de moitié en ayant reçu deux doses de vaccin. La diminution de risque sur la population générale est estimée à 0,51 [CI 0,32-0,82], et même 0,21 [0,08-0,59] pour la tranche des 18-59 ans, c'est-à-dire de fortes chances de voir le risque diminuer bien davantage que de moitié.
La réduction de symptômes prolongés sur une plus longue durée que 28 jours n'est pas analysée dans l'étude, faute de recul encore suffisant (données collectées jusqu'au 18 juillet 2021).

N013

___Immunity___

Published study on 1-Sep-21:
"Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study"
Selon une étude britannique, les chances d'avoir des symptômes qui se prolongent pendant 28 jours ou plus, après une infection de covid post-vaccinale, seraient approximativement réduites de moitié en ayant reçu deux doses de vaccin. La diminution de risque sur la population générale est estimée à 0,51 [CI 0,32-0,82], et même 0,21 [0,08-0,59] pour la tranche des 18-59 ans, c'est-à-dire de fortes chances de voir le risque diminuer bien davantage que de moitié.
La réduction de symptômes prolongés sur une plus longue durée que 28 jours n'est pas analysée dans l'étude, faute de recul encore suffisant (données collectées jusqu'au 18 juillet 2021).
Link: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00460-6/fulltext
Extract: "Between Dec 8, 2020, and July 4, 2021, 1 240 009 COVID Symptom Study app users reported a first vaccine dose, of whom 6030 (0·5%) subsequently tested positive for SARS-CoV-2 (cases 1), and 971 504 reported a second dose, of whom 2370 (0·2%) subsequently tested positive for SARS-CoV-2 (cases 2). In the risk factor analysis, frailty was associated with post-vaccination infection in older adults (≥60 years) after their first vaccine dose (odds ratio [OR] 1·93, 95% CI 1·50–2·48; p<0·0001), and individuals living in highly deprived areas had increased odds of post-vaccination infection following their first vaccine dose (OR 1·11, 95% CI 1·01–1·23; p=0·039). Individuals without obesity (BMI <30 kg/m2) had lower odds of infection following their first vaccine dose (OR 0·84, 95% CI 0·75–0·94; p=0·0030). For the disease profile analysis, 3825 users from cases 1 were included in cases 3 and 906 users from cases 2 were included in cases 4. Vaccination (compared with no vaccination) was associated with reduced odds of hospitalisation or having more than five symptoms in the first week of illness following the first or second dose, and long-duration (≥28 days) symptoms following the second dose. Almost all symptoms were reported less frequently in infected vaccinated individuals than in infected unvaccinated individuals, and vaccinated participants were more likely to be completely asymptomatic, especially if they were 60 years or older."

1239

I054

Lavanya Visvabharathy, Barbara Hanson, Zachary Orban, Patrick H. Lim, Nicole Palacio, Rishi Jain, Eric Michael Liotta, Pablo Penaloza-MacMaster, Igor J. Koralnik

Neuro-COVID long-haulers exhibit broad dysfunction in T cell memory generation and responses to vaccination

https://doi.org/10.1101/2021.08.08.21261763

pre-print

9-Aug-21

Study

https://www.medrxiv.org/content/10.1101/2021.08.08.21261763v2.full-text

Here, we report that neuro-PASC patients have a specific signature composed of humoral and cellular immune responses that are biased towards different structural proteins compared to healthy COVID convalescents. Interestingly, the severity of cognitive deficits or quality of life markers in neuro-PASC patients are associated with reduced effector molecule expression in memory T cells. Furthermore, we demonstrate that T cell responses to SARS-CoV-2 mRNA vaccines are aberrantly elevated in longitudinally sampled neuro-PASC patients compared with healthy COVID convalescents. These data provide a framework for the rational design of diagnostics and predictive biomarkers for long-COVID disease, as well as a blueprint for improved therapeutics.

1240

I055

John P Haran 1, Evan Bradley 1, Abigail L Zeamer 2, Lindsey Cincotta 1, Marie-Claire Salive 1, Protiva Dutta 1, Shafik Mutaawe 1, Otuwe Anya 1, Mario Meza-Segura 2, Ann M Moormann 3, Doyle V Ward 2, Beth A McCormick 2, Vanni Bucci 2

Inflammation-type dysbiosis of the oral microbiome associates with the duration of COVID-19 symptoms and long-COVID

https://doi.org/10.1172/jci.insight.152346

Published

17-Aug-21

Study

https://insight.jci.org/articles/view/152346

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the pandemic Coronavirus Disease 2019 (COVID-19) and now many face the burden of prolonged symptoms-long-lasting COVID-19 symptoms or "long-COVID". Long-COVID is thought to be linked to immune dysregulation due to harmful inflammation, with the exact causes being unknown. Given the role of the microbiome in mediating inflammation, we aimed to examine the relationship between the oral microbiome and the duration of long-COVID symptoms. Tongue swabs were collected from patients presenting with symptoms concerning for COVID-19. Confirmed infections were followed until resolution of all symptoms. Bacterial composition was determined by metagenomic sequencing. We used random forest modeling to identify microbiota and clinical covariates that associated with long-COVID symptoms. Of the patients followed, 63% (17/27) developed ongoing symptomatic COVID-19 and 37% (10/27) went on to long-COVID. Patients with prolonged symptoms had significantly higher abundances of microbiota that induce inflammation, such as members of the genera Prevotella and Veillonella. Of note are species that produce lipopolysaccharides and the similarity of long-COVID patients' oral microbiome to those of patients with chronic fatigue syndrome. All together, we our findings suggest an association with the oral microbiome and long-COVID revealing the possibility that dysfunction of the oral microbiome may contribute to this draining disease.

1241

I056

John M. Arthur ,J. Craig Forrest ,Karl W. Boehme ,Joshua L. Kennedy,Shana Owens,Christian Herzog,Juan Liu,Terry O. Harville

Development of ACE2 autoantibodies after SARS-CoV-2 infection

https://doi.org/10.1371/journal.pone.0257016

Published

3-Sep-21

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257016

Activation of the immune system is implicated in the Post-Acute Sequelae after SARS-CoV-2 infection (PASC) but the mechanisms remain unknown. Angiotensin-converting enzyme 2 (ACE2) cleaves angiotensin II (Ang II) resulting in decreased activation of the AT1 receptor and decreased immune system activation. We hypothesized that autoantibodies against ACE2 may develop after SARS-CoV-2 infection, as anti-idiotypic antibodies to anti-spike protein antibodies.

Methods and findings
We tested plasma or serum for ACE2 antibodies in 67 patients with known SARS-CoV-2 infection and 13 with no history of infection. None of the 13 patients without history of SARS-CoV-2 infection and 1 of the 20 outpatients that had a positive PCR test for SARS-CoV-2 had levels of ACE2 antibodies above the cutoff threshold. In contrast, 26/32 (81%) in the convalescent group and 14/15 (93%) of patients acutely hospitalized had detectable ACE2 antibodies. Plasma from patients with antibodies against ACE2 had less soluble ACE2 activity in plasma but similar amounts of ACE2 protein compared to patients without ACE2 antibodies. We measured the capacity of the samples to inhibit ACE2 enzyme activity. Addition of plasma from patients with ACE2 antibodies led to decreased activity of an exogenous preparation of ACE2 compared to patients that did not have antibodies.

Conclusions
Many patients with a history of SARS-CoV-2 infection have antibodies specific for ACE2. Patients with ACE2 antibodies have lower activity of soluble ACE2 in plasma. Plasma from these patients also inhibits exogenous ACE2 activity. These findings are consistent with the hypothesis that ACE2 antibodies develop after SARS-CoV-2 infection and decrease ACE2 activity. This could lead to an increase in the abundance of Ang II, which causes a proinflammatory state that triggers symptoms of PASC.

Des chercheurs de la University of Arkansas for Medical Sciences (UAMS) publient une étude sur des auto-anticorps au récepteur ACE2 qui pourraient selon eux être déclencheurs du covid long. La présence de ces anticorps est relevée sur 26 des 32 malades convalescents de la covid, et sur 14 des 15 malades ayant été hospitalisés. Les anticorps sont suspectés être de type anti-idiotypique et d'inhiber l'activité enzymatique des récepteurs ACE2. Pour les auteurs, il s'agit d'un mécanisme assimilable à celui d'autres virus qui déclenchent des auto-anticorps et provoquent des maladies auto-immunes. Les effets positifs après la vaccination de malades du covid long s'expliqueraient par le fait que le vaccin incite le système immunitaire à équilibrer les anticorps idiotypiques et anti-idiotypiques pour le contrôle homéostatique. Ces élément seraient en cohérence avec une théorie de l'immunologiste danois Niels Kaj Jerne (https://pubmed.ncbi.nlm.nih.gov/4142565/). Les échantillons étant anonymisés, une corrélation avec les symptômes du covid long n'a pas pu être déterminée. Les résultats pourraient ouvrir la voie à des traitements. D'une part avec les bloqueurs des récepteurs de l'angiotensine, qui sont des molécules relativement sûres et largement utilisées, ainsi que la piste des inhibiteurs de l'ECA. Une thérapie plus ciblée sur le mécanisme d'inhibition de l'enzyme de conversion de l'angiotensine serait également possible selon l'équipe de recherche.

N013

___Immunity___

Published study on 3-Sep-21:
"Development of ACE2 autoantibodies after SARS-CoV-2 infection"
Des chercheurs de la University of Arkansas for Medical Sciences (UAMS) publient une étude sur des auto-anticorps au récepteur ACE2 qui pourraient selon eux être déclencheurs du covid long. La présence de ces anticorps est relevée sur 26 des 32 malades convalescents de la covid, et sur 14 des 15 malades ayant été hospitalisés. Les anticorps sont suspectés être de type anti-idiotypique et d'inhiber l'activité enzymatique des récepteurs ACE2. Pour les auteurs, il s'agit d'un mécanisme assimilable à celui d'autres virus qui déclenchent des auto-anticorps et provoquent des maladies auto-immunes. Les effets positifs après la vaccination de malades du covid long s'expliqueraient par le fait que le vaccin incite le système immunitaire à équilibrer les anticorps idiotypiques et anti-idiotypiques pour le contrôle homéostatique. Ces élément seraient en cohérence avec une théorie de l'immunologiste danois Niels Kaj Jerne (https://pubmed.ncbi.nlm.nih.gov/4142565/). Les échantillons étant anonymisés, une corrélation avec les symptômes du covid long n'a pas pu être déterminée. Les résultats pourraient ouvrir la voie à des traitements. D'une part avec les bloqueurs des récepteurs de l'angiotensine, qui sont des molécules relativement sûres et largement utilisées, ainsi que la piste des inhibiteurs de l'ECA. Une thérapie plus ciblée sur le mécanisme d'inhibition de l'enzyme de conversion de l'angiotensine serait également possible selon l'équipe de recherche.
Link: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257016
Extract: "Activation of the immune system is implicated in the Post-Acute Sequelae after SARS-CoV-2 infection (PASC) but the mechanisms remain unknown. Angiotensin-converting enzyme 2 (ACE2) cleaves angiotensin II (Ang II) resulting in decreased activation of the AT1 receptor and decreased immune system activation. We hypothesized that autoantibodies against ACE2 may develop after SARS-CoV-2 infection, as anti-idiotypic antibodies to anti-spike protein antibodies.

Methods and findings
We tested plasma or serum for ACE2 antibodies in 67 patients with known SARS-CoV-2 infection and 13 with no history of infection. None of the 13 patients without history of SARS-CoV-2 infection and 1 of the 20 outpatients that had a positive PCR test for SARS-CoV-2 had levels of ACE2 antibodies above the cutoff threshold. In contrast, 26/32 (81%) in the convalescent group and 14/15 (93%) of patients acutely hospitalized had detectable ACE2 antibodies. Plasma from patients with antibodies against ACE2 had less soluble ACE2 activity in plasma but similar amounts of ACE2 protein compared to patients without ACE2 antibodies. We measured the capacity of the samples to inhibit ACE2 enzyme activity. Addition of plasma from patients with ACE2 antibodies led to decreased activity of an exogenous preparation of ACE2 compared to patients that did not have antibodies.

Conclusions
Many patients with a history of SARS-CoV-2 infection have antibodies specific for ACE2. Patients with ACE2 antibodies have lower activity of soluble ACE2 in plasma. Plasma from these patients also inhibits exogenous ACE2 activity. These findings are consistent with the hypothesis that ACE2 antibodies develop after SARS-CoV-2 infection and decrease ACE2 activity. This could lead to an increase in the abundance of Ang II, which causes a proinflammatory state that triggers symptoms of PASC."

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Kangyun Wu,1 Kenji Kamimoto,2 Yong Zhang,1 Kuangying Yang,1 Shamus P. Keeler,1 Benjamin J. Gerovac,1 Eugene V. Agapov,1 Stephen P. Austin,1 Jennifer Yantis,1 Kelly A. Gissy,1 Derek E. Byers,1 Jennifer Alexander-Brett,1 Christy M. Hoffmann,1 Matthew Wallace,1 Michael E. Hughes,1 Erika C. Crouch,3 Samantha A. Morris,2 and Michael J. Holtzman

Basal-epithelial stem cells cross an alarmin checkpoint for post-viral lung disease

https://doi.org/10.1172/JCI149336

Published

24-Aug-21

Study

https://www.jci.org/articles/view/149336

Here we identify a pattern of imbalance marked by basal epithelial cell growth and differentiation that replaces normal airspaces in a mouse model of progressive post-viral lung disease due to Sendai virus. Single-cell and lineage-tracing technologies identify a distinct subset of basal epithelial stem cells (basal-ESCs) that extend into gas-exchange tissue to form long-term bronchiolar-alveolar remodeling regions. Moreover, this cell subset is selectively expanded by crossing a cell growth and survival checkpoint linked to the nuclear-localized alarmin IL-33 that is independent of IL-33-receptor signaling and instead connected to autocrine chromatin accessibility. This mechanism creates an activated stem-progenitor cell lineage with potential for physiological or pathological function. Thus, conditional loss of Il33 gene function in basal epithelial cells disrupts homeostasis of the epithelial barrier at skin and gut sites but also markedly attenuates post-viral disease in the lung based on down-regulation of remodeling and inflammation. We thereby identify a basal-ESC strategy to deploy innate-immune machinery that appears to overshoot the primordial goal of self-defense. The findings reveal new targets to stratify and correct chronic and often deadly post-viral disease.

1243

I058

Yukai Jing, Li Luo, Ying Chen, Lisa S. Westerberg, Peng Zhou, Zhiping Xu, Andrés A. Herrada, Chan-Sik Park, Masato Kubo, Heng Mei, Yu Hu, Pamela Pui-Wah Lee, Bing Zheng, Zhiwei Sui, Wei Xiao, Quan Gong, Zhongxin Lu & Chaohong Liu

SARS-CoV-2 infection causes immunodeficiency in recovered patients by downregulating CD19 expression in B cells via enhancing B-cell metabolism

https://doi.org/10.1038/s41392-021-00749-3

Published

22-Sep-21

Study

https://www.nature.com/articles/s41392-021-00749-3

The SARS-CoV-2 infection causes severe immune disruption. However, it is unclear if disrupted immune regulation still exists and pertains in recovered COVID-19 patients. In our study, we have characterized the immune phenotype of B cells from 15 recovered COVID-19 patients, and found that healthy controls and recovered patients had similar B-cell populations before and after BCR stimulation, but the frequencies of PBC in patients were significantly increased when compared to healthy controls before stimulation. However, the percentage of unswitched memory B cells was decreased in recovered patients but not changed in healthy controls upon BCR stimulation. Interestingly, we found that CD19 expression was significantly reduced in almost all the B-cell subsets in recovered patients. Moreover, the BCR signaling and early B-cell response were disrupted upon BCR stimulation. Mechanistically, we found that the reduced CD19 expression was caused by the dysregulation of cell metabolism. In conclusion, we found that SARS-CoV-2 infection causes immunodeficiency in recovered patients by downregulating CD19 expression in B cells via enhancing B-cell metabolism, which may provide a new intervention target to cure COVID-19.

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I059

Leonard B.WeinstockM.D. FACGaJill B.BrookMAbArthur S.WaltersMDcAshleighGorisRN, BSN, MPH, CIC, FAPICdLawrence B.AfrinMDeGerhard J.MolderingsMDf

Mast cell activation symptoms are prevalent in Long-COVID

https://doi.org/10.1016/j.ijid.2021.09.043

Published

23-Sep-21

Study

https://www.sciencedirect.com/science/article/pii/S1201971221007517

•Mast cell activation symptoms (MCAS) were increased in Long-COVID patients
•Long-COVID patients had similar severity of numerous MCAS symptoms
•Aberrant mast cells induced by SARS-CoV-2 infection is the likely triggering factor
•MC-directed therapy could help treat Long-COVID patients

1245

I060

Tran, Viet-Thi and Perrodeau, Elodie and Saldanha, Julia and Pane, Isabelle and Ravaud, Philippe

Efficacy of COVID-19 Vaccination on the Symptoms of Patients With Long COVID: A Target Trial Emulation Using Data From the ComPaRe e-Cohort in France

pre-print

29-Sep-21

Study

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3932953

Findings: In total, 455 patients were allocated to the vaccination group and 455 to the control group; 545 (60·1%) had confirmed infections, and 81 (8·9%) had been hospitalized during their acute COVID-19. By 120 days, vaccination reduced the long COVID symptoms (mean (SD) ST score in the vaccination group 13·0 (9·4) vs. 14·8 (9·8) in the control group; mean difference: -1·8, 95% CI -2·5 to -1·0) and doubled the rate of patients in complete remission (remission rate 16·6% vs 7·5%, HR: 1·97, 95% CI 1·23 to 3·15). Furthermore, vaccination reduced both disease impact on patients’ lives (mean (SD) IT score 24.3 (16·7) vs 27·6 (16·7); mean difference: -3·3, 95% CI -6·2 to -0·5) and the proportion of patients with an unacceptable symptom state (38.9% vs 46.4%, risk difference -7·5%, 95% CI -14·4 to -0·5). In the vaccination group, two (0·4%) patients reported serious adverse events leading to hospitalisation.

Interpretation: COVID-19 vaccination lowers the severity and life impact of long COVID at 120 days among patients with persistent symptoms.

1246

I061

Rogan A. Grant, Luisa Morales-Nebreda, Nikolay S. Markov, Suchitra Swaminathan, Melissa Querrey, Estefany R. Guzman, Darryl A. Abbott, Helen K. Donnelly, Alvaro Donayre, Isaac A. Goldberg, Zasu M. Klug, Nicole Borkowski, Ziyan Lu, Hermon Kihshen, Yuliya Politanska, Lango Sichizya, Mengjia Kang, Ali Shilatifard, Chao Qi, Jon W. Lomasney, A. Christine Argento, Jacqueline M. Kruser, Elizabeth S. Malsin, Chiagozie O. Pickens, Sean B. Smith, James M. Walter, Anna E. Pawlowski, Daniel Schneider, Prasanth Nannapaneni, Hiam Abdala-Valencia, Ankit Bharat, Cara J. Gottardi, G. R. Scott Budinger, Alexander V. Misharin, Benjamin D. Singer, Richard G. Wunderink

Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia

https://doi.org/10.1038/s41586-020-03148-w

pre-print

11-Jan-21

Study

https://www.nature.com/articles/s41586-020-03148-w

Here we investigate SARS-CoV-2 pathobiology by characterizing the immune response in the alveoli of patients infected with the virus. We collected bronchoalveolar lavage fluid samples from 88 patients with SARS-CoV-2-induced respiratory failure and 211 patients with known or suspected pneumonia from other pathogens, and analysed them using flow cytometry and bulk transcriptomic profiling. We performed single-cell RNA sequencing on 10 bronchoalveolar lavage fluid samples collected from patients with severe coronavirus disease 2019 (COVID-19) within 48 h of intubation. In the majority of patients with SARS-CoV-2 infection, the alveolar space was persistently enriched in T cells and monocytes. Bulk and single-cell transcriptomic profiling suggested that SARS-CoV-2 infects alveolar macrophages, which in turn respond by producing T cell chemoattractants. These T cells produce interferon-γ to induce inflammatory cytokine release from alveolar macrophages and further promote T cell activation. Collectively, our results suggest that SARS-CoV-2 causes a slowly unfolding, spatially limited alveolitis in which alveolar macrophages containing SARS-CoV-2 and T cells form a positive feedback loop that drives persistent alveolar inflammation.

1247

I062

VP

Esen Sefik, Rihao Qu, Eleanna Kaffe, Jun Zhao, Caroline Junqueira, Haris Mirza, Ricky Brewer, Ailin Han, Holly Steach, Benjamin Israelow, Y. Grace Chen, Stephanie Halene, Akiko Iwasaki, Eric Meffre, Michel Nussenzweig, Judy Lieberman, Craig B. Wilen, Yuval Kluger, Richard A. Flavell

Viral replication in human macrophages enhances an inflammatory cascade and interferon driven chronic COVID-19 in humanized mice

https://doi.org/10.1101/2021.09.27.461948

pre-print

27-Sep-21

Study

https://www.biorxiv.org/content/10.1101/2021.09.27.461948v1

Chronic COVID-19 is characterized by persistent viral RNA and sustained interferon (IFN) response which is recapitulated and required for pathology in SARS-CoV-2 infected MISTRG6-hACE2 humanized mice. As in the human disease, monocytes, and macrophages in SARS-CoV-2 infected MISTRG6-hACE2 are central to disease pathology. Here, we describe SARS-CoV-2 uptake in tissue resident human macrophages that is enhanced by virus specific antibodies. SARS-CoV-2 replicates in these human macrophages as evidenced by detection of double-stranded RNA, subgenomic viral RNA and expression of a virally encoded fluorescent reporter gene; and it is inhibited by Remdesivir, an inhibitor of viral replication. Although early IFN deficiency leads to enhanced disease, blocking either viral replication with Remdesivir or the downstream IFN stimulated cascade by injecting anti-IFNAR2 in vivo in the chronic stages of disease attenuates many aspects of the overactive immune-inflammatory response, especially the inflammatory macrophage response, and most consequentially, the chronic disease itself.

Dans un pre-print (non publié à ce jour) présenté par l'équipe du Pr. A. Iwasaki, l'hypothèse d'une persistance virale pour expliquer l'un des mécanismes du covid long est remise sur le devant de la scène. Selon l'étude, le SARS-CoV-2 pourrait persister dans l'organisme à l'intérieur des macrophages (type de globule blanc), continuer à s'y répliquer et provoquer une inflammation persistante. Le traitement de ce covid chronique par des antiviraux (dont le remdesivir) apparaît probant sur le modèle murin humanisé. Le mécanisme d'entrée dans les cellules serait constitutif d'une facilitation de l'infection par des anticorps (Antibody-dependant enhancement, ADE en anglais). Il ne concernerait pas les vaccins à ARNm selon plusieurs immunologues.

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I063

Lechien JR, Hopkins C, Vaira LA, Saussez S.

SARS-CoV-2 vaccination may help patients with persistent COVID-19 smell dysfunction

https://doi.org/10.1177%2F01455613211044770

Published

26-Sep-21

Study

https://journals.sagepub.com/doi/10.1177/01455613211044770

According to these findings and our clinical observations, we believe that the persistence of OD in COVID-19 patients could be related to the persistence of the virus in the olfactory region, which induces a chronic inflammatory reaction characterized by the destruction of re-infected cells throughout the recovery process, that is, neuroepithelium cells, sustentacular cells and olfactory neurons. Interestingly, it has been supported that inflammation may suppress regeneration of the olfactory stem cells.11 In this way, we believe that the administration of vaccine may stimulate the local and systemic immune response against the virus, ‘cleaning’ the olfactory region from the remaining viruses, allowing the regeneration of stem cells. Future controlled studies are needed to compare the evolution of olfactory outcomes of patients with persistent OD according to the vaccine status of patients. Recent studies have shown that SARS-CoV-2 can be detected in immunologically privileged tissues, such as the testicles, without significant immune response.12 Further studies are needed to test the hypothesis that the olfactory bulb could be considered as an additional anatomical region not exposed to a significant immune response, allowing for persistence of SARS-CoV-2.

1249

I064

Paul Glynne1, Natasha Tahmasebi2, Vanya Gant3, Rajeev Gupta

Long COVID following mild SARS-CoV-2 infection: characteristic T cell alterations and response to antihistamines

http://dx.doi.org/10.1136/jim-2021-002051

Published

5-Oct-21

Study

https://jim.bmj.com/content/early/2021/10/05/jim-2021-002051

Anecdotal reports of gradual clinical responses to histamine receptor antagonists (HRAs) suggest a histamine-dependent mechanism that is distinct from anaphylaxis, possibly mediated by T cells, which are also regulated by histamine. T cell perturbations have been previously reported in post-viral syndromes, but the T cell landscape in patients who have recovered from mild COVID-19 and its relationship to both long COVID symptoms and any symptomatic response to HRA remain underexplored. We addressed these questions in an observational study of 65 individuals who had recovered from mild COVID-19. Participants were surveyed between 87 and 408 days after the onset of acute symptoms; none had required hospitalization, 16 had recovered uneventfully, and 49 had developed long COVID. Symptoms were quantified using a structured questionnaire and T cell subsets enumerated in a standard diagnostic assay. Patients with long-COVID had reduced CD4+ and CD8+ effector memory (EM) cell numbers and increased PD-1 (programmed cell death protein 1) expression on central memory (CM) cells, whereas the asymptomatic participants had reduced CD8+ EM cells only and increased CD28 expression on CM cells. 72% of patients with long COVID who received HRA reported clinical improvement, although T cell profiling did not clearly distinguish those who responded to HRA. This study demonstrates that T cell perturbations persist for several months after mild COVID-19 and are associated with long COVID symptoms.

Une étude britannique note que les patients atteints de covid long ont un nombre réduit de lymphocytes T CD4+ et CD8+, ainsi qu'une expression accrue de protéines PD-1. Cette étude montre selon les auteurs que les perturbations des lymphocytes T persistent pendant plusieurs mois après une covid légère et sont associées à des symptômes de covid long.

N014E

___Immunity___

Published study on 5-Oct-21:
"Long COVID following mild SARS-CoV-2 infection: characteristic T cell alterations and response to antihistamines"
Une étude britannique note que les patients atteints de covid long ont un nombre réduit de lymphocytes T CD4+ et CD8+, ainsi qu'une expression accrue de protéines PD-1. Cette étude montre selon les auteurs que les perturbations des lymphocytes T persistent pendant plusieurs mois après une covid légère et sont associées à des symptômes de covid long.
Link: https://jim.bmj.com/content/early/2021/10/05/jim-2021-002051
Extract: "Anecdotal reports of gradual clinical responses to histamine receptor antagonists (HRAs) suggest a histamine-dependent mechanism that is distinct from anaphylaxis, possibly mediated by T cells, which are also regulated by histamine. T cell perturbations have been previously reported in post-viral syndromes, but the T cell landscape in patients who have recovered from mild COVID-19 and its relationship to both long COVID symptoms and any symptomatic response to HRA remain underexplored. We addressed these questions in an observational study of 65 individuals who had recovered from mild COVID-19. Participants were surveyed between 87 and 408 days after the onset of acute symptoms; none had required hospitalization, 16 had recovered uneventfully, and 49 had developed long COVID. Symptoms were quantified using a structured questionnaire and T cell subsets enumerated in a standard diagnostic assay. Patients with long-COVID had reduced CD4+ and CD8+ effector memory (EM) cell numbers and increased PD-1 (programmed cell death protein 1) expression on central memory (CM) cells, whereas the asymptomatic participants had reduced CD8+ EM cells only and increased CD28 expression on CM cells. 72% of patients with long COVID who received HRA reported clinical improvement, although T cell profiling did not clearly distinguish those who responded to HRA. This study demonstrates that T cell perturbations persist for several months after mild COVID-19 and are associated with long COVID symptoms."

1250

I065

Ryan C. Thompson, Nicole W. Simons, Lillian Wilkins, Esther Cheng, Diane Marie Del Valle, Gabriel E. Hoffman, Brian Fennessy, Konstantinos Mouskas, Nancy J. Francoeur, Jessica S. Johnson, , Robert Sebra, Miriam Merad, Sacha Gnjatic, Eric E. Schadt, Alexander W. Charney, Noam D. Beckmann

Acute COVID-19 gene-expression profiles show multiple etiologies of long-term sequelae

https://doi.org/10.1101/2021.10.04.21264434

pre-print

5-Oct-21

Study

https://www.medrxiv.org/content/10.1101/2021.10.04.21264434v1.full-text

Here, a transcriptome-wide investigation of this new condition was performed in a large cohort of acutely infected patients followed clinically into the post-acute period. Gene expression signatures of post-acute sequelae were already present in whole blood during the acute phase of infection, with both innate and adaptive immune cells involved. Plasma cells stood out as driving at least two distinct clusters of sequelae, one largely dependent on circulating antibodies against the SARS-CoV-2 spike protein and the other antibody-independent. Altogether, multiple etiologies of post-acute sequelae were found concomitant with SARS-CoV-2 infection, directly linking the emergence of these sequelae with the host response to the virus.

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1251

I066

Maya M.L. Poon, Ksenia Rybkina, Yu Kato, Masaru Kubota, Rei Matsumoto, Nathaniel I. Bloom, Zeli Zhang, Kathryn M. Hastie, Alba Grifoni, Daniela Weiskopf, Steven B. Wells, Basak B. Ural, Nora Lam, Peter A. Szabo, Pranay Dogra, Yoon S. Lee, Bradley, Marissa C, Brusko, Maigan A, Brusko, Todd M, Saphire, Erica O, Connors, Thomas J, Sette, Alessandro, Crotty, Shane, Farber, Donna L

SARS-CoV-2 infection generates tissue-localized immunological memory in humans

https://doi.org/10.1126/sciimmunol.abl9105

Published

7-Oct-21

Study

https://www.science.org/doi/10.1126/sciimmunol.abl9105

Here, we report from examination of SARS-CoV-2 seropositive organ donors (ages 10 – 74) that CD4+ T, CD8+ T, and B cell memory generated in response to infection is present in bone marrow, spleen, lung, and multiple lymph nodes (LNs) for up to 6 months post-infection. Lungs and lung-associated LNs were the most prevalent sites for SARS-CoV-2-specific memory T and B cells, with significant correlations between circulating and tissue-resident memory T and B cells in all sites. We further identified SARS-CoV-2-specific germinal centers in the lung-associated LNs up to 6 months post-infection. SARS-CoV-2-specific follicular helper T cells were also abundant in lung-associated LNs and lungs. Together, the results indicate local tissue coordination of cellular and humoral immune memory against SARS-CoV-2 for site-specific protection against future infectious challenges.

1252

I067

Maxime Taquet, Quentin Dercon, Paul J Harrison

Six-month sequelae of post-vaccination SARS-CoV-2 infection: a retrospective cohort study of 10,024 breakthrough infections

https://doi.org/10.1101/2021.10.26.21265508

pre-print

28-Oct-21

Study

https://www.medrxiv.org/content/10.1101/2021.10.26.21265508v2

Among 10,024 vaccinated individuals with SARS-CoV-2 infection, 9479 were matched to unvaccinated controls. Receiving at least one COVID-19 vaccine dose was associated with a significantly lower risk of respiratory failure, ICU admission, intubation/ventilation, hypoxaemia, oxygen requirement, hypercoagulopathy/venous thromboembolism, seizures, psychotic disorder, and hair loss (each as composite endpoints with death to account for competing risks; HR 0.70-0.83, Bonferroni-corrected p<.05), but not other outcomes, including long-COVID features, renal disease, mood, anxiety, and sleep disorders. Receiving 2 vaccine doses was associated with lower risks for most outcomes. Associations between prior vaccination and outcomes of SARS-CoV-2 infection were marked in those < 60 years-old, whereas no robust associations were observed in those ≥ 60 years-old.

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I068

RAPHAEL CARAPITORICHARD LIJULIE HELMSCHRISTINE CARAPITOSHARVARI GUJJAVÉRONIQUE ROLLIRAONY GUIMARAESJOSE MALAGON-LOPEZPERRINE SPINNHIRNY[...]SEIAMAK BAHRAM

Identification of driver genes for critical forms of COVID-19 in a deeply phenotyped young patient cohort

https://doi.org/10.1126/scitranslmed.abj7521

Published

26-Oct-21

Study

https://www.science.org/doi/10.1126/scitranslmed.abj7521

The cohort included 47 “critical” (in the intensive care unit under mechanical ventilation) and 25 “non-critical” (in a non-critical care ward) patients with COVID-19 and 22 healthy individuals. The analyses included whole-genome sequencing, whole-blood RNA sequencing, plasma and blood mononuclear cells proteomics, cytokine profiling, and high-throughput immunophenotyping. An ensemble of machine learning, deep learning, quantum annealing, and structural causal modeling were employed. Patients with critical COVID-19 were characterized by exacerbated inflammation, perturbed lymphoid and myeloid compartments, increased coagulation, and viral cell biology. Among differentially expressed genes, we observed up-regulation of the metalloprotease ADAM9. This gene signature was validated in a second independent cohort of 81 critical and 73 recovered patients with COVID-19, and were further confirmed at the transcriptional and protein level as well as by proteolytic activity. Ex vivo ADAM9 inhibition decreased severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uptake and replication in human lung epithelial cells. In conclusion, within a young, otherwise healthy, cohort of individuals with COVID-19, we provide the landscape of biological perturbations in vivo where a unique gene signature differentiated critical from non-critical patients. We further identified ADAM9 as a driver of disease severity and a candidate therapeutic target.

1254

I069

Benjamin A. Krishna, Eleanor Y. Lim, Lenette Mactavous, NIHR BioResource Team, Paul Lyons, Rainer Doffinger, John Bradley, Kenneth G. C. Smith, John Sinclair, Nicholas J. Matheson, Paul J. Lehner, Mark R. Wills, Nyaradzai Sithole

Retrospective diagnosis of SARS-CoV-2 infection in patients with Long COVID by measuring specific T cell mediated IL-2 release.

https://doi.org/10.21203/rs.3.rs-989434/v1

pre-print

21-Oct-21

Study

https://www.researchsquare.com/article/rs-989434/v1

Given the diagnostic conundrum of Long COVID, we set out to design a SARS-CoV-2 specific T cell assay, to follow up a cohort of undifferentiated mostly non-hospitalised patients with Long COVID for up to 13 months. Here, we show that IL-2 release from SARS-CoV-2-specific memory T cells shows >75% sensitivity and >88% specificity in identifying individuals with confirmed SARS-CoV-2 infection >6 months after a positive PCR test.

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I070

Stuart Stewart
Louise Newson
Tracy A Briggs
Dimitris Grammatopoulos
Lawrence Young
Paramjit Gill

Long COVID risk - a signal to address sex hormones and women's health

https://doi.org/10.1016/j.lanepe.2021.100242

Published

2-Nov-21

Article

https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(21)00228-3/fulltext

From a biological perspective, we propose the asymmetry in risk and outcomes between sexes, and an overlap of symptoms of Long COVID [[3]] with those of perimenopause and menopause [[6]] point towards sex hormone differences as targets for further investigation. Furthermore, the higher prevalence of Long COVID in women under the age of 50 years [[2]] is an important and supporting clue as the mean age of natural menopause (in the UK) is 51 years [[6]].
Oestrogen and androgen receptors are ubiquitous, present in almost all tissues in the body, evidencing the widespread and important roles of sex hormones [[7]], well beyond their obvious roles in the reproductive system. Viral-induced sex hormone dysfunction resulting in early menopause, menstruation abnormalities and miscarriage are documented in HIV and Hepatitis B and C infections [[8]]. In the context of viral infections, sex hormone dysfunction may be related to multisystem disruption or due to organ-specific effects [[8]]. The role of sex hormones in COVID-19 infection are now beginning to emerge. A recent study [[9]] highlights important clinical and immunological differences between sexes in acute COVID-19 infection; women had lower mortality, lower levels of inflammation, higher lymphocyte counts, and faster antibody responses than men.

todo

1256

I071

Krishna, Benjamin A. and Lim, Eleanor Y. and Mactavous, Lenette and Team, NIHR BioResource and Lyons, Paul A. and Doffinger, Rainer and Bradley, John and Smith, KGC and Sinclair, John and Matheson, Nicholas J. and Lehner, Paul and Wills, Mark R. and Sithole, Nyarie

Retrospective Diagnosis of SARS-CoV-2 Infection in Patients with Long COVID by Measuring Specific T Cell Mediated IL-2 Release.

http://dx.doi.org/10.2139/ssrn.3947817

pre-print

27-Oct-21

Study

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3947817

Given the diagnostic conundrum of Long COVID, we set out to design a SARS-CoV-2 specific T cell assay, to follow up a cohort of undifferentiated mostly non-hospitalised patients with Long COVID for up to 13 months. Here, we show that IL-2 release from SARS-CoV-2-specific memory T cells shows >75% sensitivity and >88% specificity in identifying individuals with confirmed SARS-CoV-2 infection >6 months after a positive PCR test.

1257

I072

Leo Swadling, Mariana O. Diniz, Nathalie M. Schmidt, Oliver E. Amin, Aneesh Chandran, Emily Shaw, Corinna Pade, Joseph M. Gibbons, Nina Le Bert, Lucy van Dorp, Francois Balloux, Áine McKnight, Mahdad Noursadeghi, Antonio Bertoletti & Mala K. Maini

Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2

https://doi.org/10.1038/s41586-021-04186-8

Published

10-Nov-21

Study

https://www.nature.com/articles/s41586-021-04186-8

Individuals with potential exposure to SARS-CoV-2 do not necessarily develop PCR or antibody positivity, suggesting some may clear sub-clinical infection before seroconversion. T-cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections1–3. We hypothesised that pre-existing memory T-cell responses, with cross-protective potential against SARS-CoV-24–11, would expand in vivo to support rapid viral control, aborting infection. We measured SARS-CoV-2-reactive T-cells, including those against the early transcribed replication transcription complex (RTC)12,13, in intensively monitored healthcare workers (HCW) remaining repeatedly negative by PCR, antibody binding, and neutralisation (seronegative HCW, SN-HCW). SN-HCW had stronger, more multispecific memory T-cells than an unexposed pre-pandemic cohort, and more frequently directed against the RTC than the structural protein-dominated responses seen post-detectable infection (matched concurrent cohort). SN-HCW with the strongest RTC-specific T-cells had an increase in IFI27, a robust early innate signature of SARS-CoV-214, suggesting abortive infection. RNA-polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and SARS-CoV-2 clades. RNA-polymerase was preferentially targeted (amongst regions tested) by T-cells from pre-pandemic cohorts and SN-HCW. RTC epitope-specific T-cells cross-recognising HCoV variants were identified in SN-HCW. Enriched pre-existing RNA-polymerase-specific T-cells expanded in vivo to preferentially accumulate in the memory response after putative abortive compared to overt SARS-CoV-2 infection. Our data highlight RTC-specific T-cells as targets for vaccines against endemic and emerging Coronaviridae.

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1258

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SARAH C. VICK MARIE FRUTOSO FLORIAN MAIR ANDREW J. KONECNYEVAN GREENECAITLIN R. WOLF JENNIFER K. LOGUE NICHOLAS M. FRANKO JIM BOONYARATANAKORNKIT RAPHAEL GOTTARDO JOSHUA T. SCHIFFER HELEN Y. CHUMARTIN PRLIC AND JENNIFER M. LUND

A regulatory T cell signature distinguishes the immune landscape of COVID-19 patients from those with other respiratory infections

https://doi.org/10.1126/sciadv.abj0274

Published

10-Nov-21

Study

https://www.science.org/doi/10.1126/sciadv.abj0274

We compare the immune signature from hospitalized SARS-CoV-2–infected patients to patients hospitalized prepandemic with influenza or respiratory syncytial virus (RSV). Our in-depth profiling indicates that the immune landscape in SARS-CoV-2 patients is largely similar to flu or RSV patients. Unique to patients infected with SARS-CoV-2 who had the most critical clinical disease were changes in the regulatory T cell (Treg) compartment. A Treg signature including increased frequency, activation status, and migration markers was correlated COVID-19 severity. These findings are relevant as Tregs are considered for therapy to combat the severe inflammation seen in COVID-19 patients. Likewise, having defined the overlapping immune landscapes in SARS-CoV-2, existing knowledge of flu and RSV infections could be leveraged to identify common treatment strategies.

1259

I074

I. V. Sarvilina, O. A. Gromova, A. V. Naumov

Pathobiochemical pathways of redox imbalance in the neurological long-term effects of COVID-19 and the role of chondroitin sulfate in the redox status restoration

https://doi.org/10.14412/2074-2711-2021-5-109-115

Published

1-Nov-21

Review

https://nnp.ima-press.net/nnp/article/view/1674/0

The review examines the epidemiology and clinical manifestations of COVID-19 long-term neurological effects, main pathobiochemical mechanisms, and integrated circuits of redox status impairment in COVID-19, such as the decrease of adenosine triphosphate production, fatty acids levels, acylcarnitine, and amino acids, impairment of oxidative phosphorylation and glycolysis, hypometabolic state, redox imbalance with the increase of peroxides and superoxides, isoprostanes, the decrease of α-tocopherol, substances reacting with thiobarbituric acid, increased nitrosative stress with the increase of inducible synthase of nitric oxide, nitric oxide, peroxynitrite, and nitrate. Neuroprotective approaches aimed at suppressing excitotoxicity, oxidative stress, and neuroinflammation are presented. Recent data on the relationship between mechanisms of chondroitin sulfate and its derivatives (chondroitin sulfate glycoprotein disaccharide) neuroprotective effects and characteristics of their chemical structure are analyzed. The mechanism of action and neuroprotective effects of chondroitin sulfate and its derivatives in fatigue syndrome in patients with SARS-CoV2 infection are discussed (regulation of the PKC/PI3K/Akt activity, the increase of heme oxygenase-1 level, the decrease of reactive oxygen species). The position that chondroitin sulfate and its derivatives can become promising drugs to prevent the long-term neurological effects of COVID-19 is reasoned.

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1260

I075

Ziyad Al-Aly, Benjamin Bowe, Yan Xie

Long Covid after Breakthrough COVID-19: the post-acute sequelae of breakthrough COVID-19

https://doi.org/10.21203/rs.3.rs-1062160/v1

pre-print

15-Nov-21

Study

https://www.researchsquare.com/article/rs-1062160/v1

We show that compared to people with no evidence of COVID-19, beyond the first 30 days of illness, people with breakthrough COVID-19 exhibit a higher risk of death and broad array of incident post-acute sequelae in the pulmonary system, as well as extrapulmonary sequelae that include cardiovascular disorders, coagulation disorders, gastrointestinal disorders, general disorders (e.g., fatigue), kidney disorders, mental health disorders, metabolic disorders, musculoskeletal disorders, and neurologic disorders.

People with breakthrough COVID-19 exhibited lower risk of death (HR 0.65 (0.55, 0.76); burden -12.97 (-16.58, -8.74); negative values denote reduced burden in breakthrough COVID-19 relative to COVID-19) and lower risk of post-acute sequelae (HR 0.87 (0.83, 0.92); burden -30.60 (-42.25, -18.49)) compared to those with COVID-19 and no prior history of vaccination (Figure 4 and Supplementary Table 9).
Comparatively, the risk of post-acute sequelae in the cardiovascular, coagulation, metabolic, and pulmonary organ systems, as well as risk of fatigue, was lower in people with breakthrough COVID-19 vs those with COVID-19 without prior vaccination. Lower risk was not statistically significant in kidney, gastrointestinal, mental health, and neurologic organ systems. None of the outcomes exhibited a higher risk among people with breakthrough COVID-19 compared to those with COVID-19 without prior vaccination.

1261

I076

JihaneEl KhalifaNourMekkiLydiaDeschampsVincentDescamps

Récidive des « COVID toes » après un nouveau contage avec le SARS-CoV-2

https://doi.org/10.1016/j.fander.2021.09.206

Published

19-Nov-21

Study

https://www.sciencedirect.com/science/article/pii/S2667062321004839

Nos 4 observations témoignent de la possibilité de récidive lors d’un nouveau contage témoignant de l’absence de réelle immunité spécifique et même la possibilité de développer une forme plus symptomatique. Il est probable que la sévérité clinique soit la conséquence de la balance entre l’importance de l’inoculum viral et de la capacité à développer une réponse immunitaire innée. Ainsi chez le 4e patient, le contage étant liée à sa partenaire avec vraisemblablement une charge virale de l’inoculum supérieure à celle du premier contage. Ceci confirme que les patients ayant eu un « COVID toes » justifient d’une vaccination car ces patients ne sont pas dans la majorité des cas immunisés.

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1262

I077

Heidi Ledford

Do vaccines protect against long COVID? What the data say
Vaccines reduce the risk of developing COVID-19 — but studies disagree on their protective effect against long COVID.

https://doi.org/10.1038/d41586-021-03495-2

Published

23-Nov-21

Article

https://www.nature.com/articles/d41586-021-03495-2

Vaccines reduce the risk of long COVID by lowering the chances of contracting COVID-19 in the first place. But for those who do experience a breakthrough infection, studies suggest that vaccination might only halve the risk of long COVID — or have no effect on it at all.

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1263

I078

Maxime Taquet, Quentin Dercon, Paul J Harrison

Six-month sequelae of post-vaccination SARS-CoV-2 infection: a retrospective cohort study of 10,024 breakthrough infections

https://doi.org/10.1101/2021.10.26.21265508

pre-print

8-Nov-21

Study

https://www.medrxiv.org/content/10.1101/2021.10.26.21265508v3.full-text

Receiving at least one COVID-19 vaccine dose was associated with a significantly lower risk of respiratory failure, ICU admission, intubation/ventilation, hypoxaemia, oxygen requirement, hypercoagulopathy/venous thromboembolism, seizures, psychotic disorder, and hair loss (each as composite endpoints with death to account for competing risks; HR 0.70-0.83, Bonferroni-corrected p<.05), but not other outcomes, including long-COVID features, renal disease, mood, anxiety, and sleep disorders. Receiving 2 vaccine doses was associated with lower risks for most outcomes. Associations between prior vaccination and outcomes of SARS-CoV-2 infection were marked in those < 60 years-old, whereas no robust associations were observed in those ≥ 60 years-old. In summary, COVID-19 vaccination is associated with lower risk of several, but not all, COVID-19 sequelae in those with breakthrough SARS-CoV-2 infection. These benefits of vaccination were clear in younger people but not in the over-60s. The findings may inform service planning, contribute to forecasting public health impacts of vaccination programmes, and highlight the need to identify additional interventions for COVID-19 sequelae.

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1264

I079

Kevin Roe

The role of polyspecific T-cell exhaustion in severe outcomes for COVID-19 patients having latent pathogen infections such as Toxoplasma gondii

https://doi.org/10.1016/j.micpath.2021.105299

Published

20-Nov-21

Article

https://www.sciencedirect.com/science/article/pii/S0882401021005738

Highlights
•COVID-19 patients exhibit mortality rate differences probably from latent pathogen infections.
•Toxoplasma gondii infects about one third of the global human population and it is likely involved.
•Latent pathogens have different genetic strains & different effects on later pathogen infections.
•Drug treatments affect pathogen infections causing immune dysfunctions, e.g. T-cell exhaustion.
•"Polyspecific T-cell exhaustion" enables concurrent multiple pathogen T-cell exhaustion.
The aims and purposes of this paper include providing explanations for the contradictions between these studies and introducing a significant new category of T-cell exhaustion. Latent pathogens can have different genetic strains with great differences in their effects on a second pathogen infection. Furthermore, depending on the timing and effectiveness of drug treatments, pathogen infections that become latent may or may not later induce immune cell dysfunctions, including T-cell exhaustion. Concurrent multiple pathogen T-cell exhaustion is herein called "polyspecific T-cell exhaustion."

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1265

I080

Elaine Holmes*, Julien Wist*, Reika Masuda, Samantha Lodge, Philipp Nitschke, Torben Kimhofer, Ruey Leng Loo, Sofina Begum, Berin Boughton, Rongchang Yang, Aude-Claire Morillon, Sung-Tong Chin, Drew Hall, Monique Ryan, Sze-How Bong, Melvin Gay, Dale W. Edgar, John C. Lindon, Toby Richards, Bu B. Yeap, Sven Pettersson, Manfred Spraul, Hartmut Schaefer, Nathan G. Lawler, Nicola Gray, Luke Whiley, and Jeremy K. Nicholson*

Incomplete Systemic Recovery and Metabolic Phenoreversion in Post-Acute-Phase Nonhospitalized COVID-19 Patients: Implications for Assessment of Post-Acute COVID-19 Syndrome

https://doi.org/10.1021/acs.jproteome.1c00224

Published

19-May-21

Article

https://pubs.acs.org/doi/abs/10.1021/acs.jproteome.1c00224

We present a multivariate metabotyping approach to assess the functional recovery of nonhospitalized COVID-19 patients and the possible biochemical sequelae of “Post-Acute COVID-19 Syndrome”, colloquially known as long-COVID. Blood samples were taken from patients ca. 3 months after acute COVID-19 infection with further assessment of symptoms at 6 months. Some 57% of the patients had one or more persistent symptoms including respiratory-related symptoms like cough, dyspnea, and rhinorrhea or other nonrespiratory symptoms including chronic fatigue, anosmia, myalgia, or joint pain. Plasma samples were quantitatively analyzed for lipoproteins, glycoproteins, amino acids, biogenic amines, and tryptophan pathway intermediates using Nuclear Magnetic Resonance (NMR) spectroscopy and mass spectrometry. Metabolic data for the follow-up patients (n = 27) were compared with controls (n = 41) and hospitalized severe acute respiratory syndrome SARS-CoV-2 positive patients (n = 18, with multiple time-points). Univariate and multivariate statistics revealed variable patterns of functional recovery with many patients exhibiting residual COVID-19 biomarker signatures. Several parameters were persistently perturbed, e.g., elevated taurine (p = 3.6 × 10–3 versus controls) and reduced glutamine/glutamate ratio (p = 6.95 × 10–8 versus controls), indicative of possible liver and muscle damage and a high energy demand linked to more generalized tissue repair or immune function. Some parameters showed near-complete normalization, e.g., the plasma apolipoprotein B100/A1 ratio was similar to that of healthy controls but significantly lower (p = 4.2 × 10–3) than post-acute COVID-19 patients, reflecting partial reversion of the metabolic phenotype (phenoreversion) toward the healthy metabolic state. Plasma neopterin was normalized in all follow-up patients, indicative of a reduction in the adaptive immune activity that has been previously detected in active SARS-CoV-2 infection. Other systemic inflammatory biomarkers such as GlycA and the kynurenine/tryptophan ratio remained elevated in some, but not all, patients. Correlation analysis, principal component analysis (PCA), and orthogonal-partial least-squares discriminant analysis (O-PLS-DA) showed that the follow-up patients were, as a group, metabolically distinct from controls and partially comapped with the acute-phase patients. Significant systematic metabolic differences between asymptomatic and symptomatic follow-up patients were also observed for multiple metabolites. The overall metabolic variance of the symptomatic patients was significantly greater than that of nonsymptomatic patients for multiple parameters (χ2p = 0.014). Thus, asymptomatic follow-up patients including those with post-acute COVID-19 Syndrome displayed a spectrum of multiple persistent biochemical pathophysiology, suggesting that the metabolic phenotyping approach may be deployed for multisystem functional assessment of individual post-acute COVID-19 patients.

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1266

I081

Winston A. Haynes, Kathy Kamath, Joel Bozekowski, Elisabeth Baum-Jones, Melissa Campbell, Arnau Casanovas-Massana, Patrick S. Daugherty, Charles S. Dela Cruz, Abhilash Dhal, Shelli F. Farhadian, Lynn Fitzgibbons, John Fournier, Michael Jhatro, Gregory Jordan, Jon Klein, Carolina Lucas, Debra Kessler, Larry L. Luchsinger, Brian Martinez, M. Catherine Muenker, Lauren Pischel, Jack Reifert, Jaymie R. Sawyer, Rebecca Waitz, Elsio A. Wunder Jr., Minlu Zhang, Yale IMPACT Team, Akiko Iwasaki, Albert Ko & John C. Shon

High-resolution epitope mapping and characterization of SARS-CoV-2 antibodies in large cohorts of subjects with COVID-19

https://doi.org/10.1038/s42003-021-02835-2

Published

22-Nov-21

Study

https://www.nature.com/articles/s42003-021-02835-2

Since traditional epitope identification tools are dependent upon pre-defined peptide sequences, they are not readily adaptable to diverse viral proteomes. The Serum Epitope Repertoire Analysis (SERA) platform leverages a high diversity random bacterial display library to identify proteome-independent epitope binding specificities which are then analyzed in the context of organisms of interest. When evaluating immune response in the context of SARS-CoV-2, we identify dominant epitope regions and motifs which demonstrate potential to classify mild from severe disease and relate to neutralization activity. We highlight SARS-CoV-2 epitopes that are cross-reactive with other coronaviruses and demonstrate decreased epitope signal for mutant SARS-CoV-2 strains. Collectively, the evolution of SARS-CoV-2 mutants towards reduced antibody response highlight the importance of data-driven development of the vaccines and therapies to treat COVID-19.

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1267

I082

M.ScherlingerL.PijnenburgE.ChatelusJ.SibiliaJ.E.GottenbergL.ArnaudR.Felten

Effet de la vaccination anti-SARS-CoV-2 sur les symptômes prolongés post-Covid : résultat de l’enquête nationale VAXILONG

https://doi.org/10.1016/j.rhum.2021.10.350

Published

26-Nov-21

Study

https://www.sciencedirect.com/science/article/abs/pii/S1169833021006098

L’absence d’effet de la vaccination va à l’encontre de l’hypothèse de persistance virale dans le COVID-long, d’autant que l’immunogénicité vaccinale y semble normale. Par ailleurs, des données suggèrent que la vaccination diminue le risque de développer un COVID-long [2].
Conclusion
La vaccination anti-SARS-CoV-2 ne semble pas influencer les symptômes de COVID-long rapportés par les patients.

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1268

I083

Pilar Brito-Zerón 1, Nihan Acar-Denizli 2, Vasco C Romão 3, Berkan Armagan 4, Raphaèle Seror 5, Francesco Carubbi 6, Sheila Melchor 7, Roberta Priori 8, Valeria Valim 9, Soledad Retamozo 10, Sandra G Pasoto 11, Virginia Fernandes Moça Trevisani 12, Benedikt Hofauer 13, Antonia Szántó 14, Nevsun Inanc 15, Gabriela Hernández-Molina 16, Agata Sebastian 17, Elena Bartoloni 18, Valerie Devauchelle-Pensec 19, Miriam Akasbi 20, Federico Giardina 21, Matilde Bandeira 3, Antoni Sisó-Almirall 22, Manuel Ramos-Casals 23

Post-COVID-19 syndrome in patients with primary Sjögren's syndrome after acute SARS-CoV-2 infection

PMID: 34874821.

Published

22-Nov-21

Study

https://pubmed.ncbi.nlm.nih.gov/34874821/

This is the first study that analyses the frequency and characteristics of post-COVID-19 syndrome in patients affected by a systemic autoimmune disease. We found that 57% of patients with pSS affected by COVID-19 remain symptomatic after a mean follow-up of 5 months. The risk of developing post-COVID-19 syndrome in patients who required hospitalisation was 8-times higher than in non-hospitalised patients, with baseline raised CRP levels and the use of hydroxychloroquine being independent risk factors for post-COVID-19.

1269

I084

Sabrina Kral 1
Chiara Banfi 1
Tobias Niedrist
Nazanin Sareban
Christian Guelly
Lisa Kriegl
Stefanie Schiffmann
Christoph Zurl
Markus Herrmann
Ivo Steinmetz
Peter Schlenke
Andrea Berghold
Robert Krause

Long-lasting immune response to a mild course of PCR-confirmed SARS-CoV-2 infection: A cohort study

https://doi.org/10.1016/j.jinf.2021.08.030

Published

21-Aug-21

Study

https://www.journalofinfection.com/article/S0163-4453(21)00419-9/fulltext

Taken together, our results indicate a strong and persistent immune response against SARS-CoV-2 infection in individuals who recovered from a mild course of COVID-19 for up to 8 months post infection. Importantly, our findings are in line with a recent study10 that used the very same quantitative anti-RBD antibody assay as we did and reported a robust and persistent antibody response after six months post infection. The titre at the baseline visit and its change through time was modulated by the time lag between infection and sampling. In line with Wells et al., we found that individuals without core symptoms developed immunity against COVID-19, although to a lower degree than individuals showing core symptoms, and it persisted through time.

1270

I085

Daniel Ayoubkhani, Charlotte Bermingham, Koen B. Pouwels, Myer Glickman, Vahé Nafilyan, Francesco Zaccardi, Kamlesh Khunti, Nisreen A. Alwan, A. Sarah Walker

Changes in the trajectory of Long Covid symptoms following COVID-19 vaccination: community-based cohort study

https://doi.org/10.1101/2021.12.09.21267516

pre-print

9-Dec-21

Study

https://www.medrxiv.org/content/10.1101/2021.12.09.21267516v1.full-text

Results Median follow-up was 141 days from first vaccination (among all participants) and 67 days from second vaccination (84% of participants). First vaccination was associated with an initial 12.8% decrease (95% confidence interval: −18.6% to −6.6%) in the odds of Long Covid, but increasing by 0.3% (−0.6% to +1.2%) per week after the first dose. Second vaccination was associated with an 8.8% decrease (−14.1% to −3.1%) in the odds of Long Covid, with the odds subsequently decreasing by 0.8% (−1.2% to −0.4%) per week. There was no statistical evidence of heterogeneity in associations between vaccination and Long Covid by socio-demographic characteristics, health status, whether hospitalised with acute COVID-19, vaccine type (adenovirus vector or mRNA), or duration from infection to vaccination.
Conclusions The likelihood of Long Covid symptoms reduced after COVID-19 vaccination, and the improvement was sustained over the follow-up period after the second dose. Vaccination may contribute to a reduction in the population health burden of Long Covid, though longer follow-up time is needed.
Summary box What is already known on this topic
COVID-19 vaccines are effective at reducing rates of SARS-CoV-2 infection, transmission, hospitalisation, and death
The incidence of Long Covid may be reduced if infected after vaccination, but the relationship between vaccination and pre-existing long COVID symptoms is unclear, as published studies are generally small and with self-selected participants
What this study adds
The likelihood of Long Covid symptoms reduced after COVID-19 vaccination, and the improvement was sustained over the follow-up period after the second dose
There was no evidence of differences in this relationship by socio-demographic characteristics, health-related factors, vaccine type, or duration from infection to vaccination
Although causality cannot be inferred from this observational evidence, vaccination may contribute to a reduction in the population health burden of Long Covid; further research is needed to understand the biological mechanisms that may ultimately contribute to the development of therapeutics for Long Covid

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I086

Daniel Chertow, Sydney Stein, Sabrina Ramelli, Alison Grazioli, Joon-Yong Chung, Manmeet Singh, Claude Kwe Yinda, Clayton Winkler, James Dickey, Kris Ylaya, Sung Hee Ko, Andrew Platt, Peter Burbelo, Martha Quezado, Stefania Pittaluga, Madeleine Purcell, Vincent Munster, Frida Belinky, Marcos Ramos-Benitez, Eli Boritz, Daniel Herr, Joseph Rabin, Kapil Saharia, Ronson Madathil, Ali Tabatabai, Shahabuddin Soherwardi, Michael McCurdy, Karin Peterson, Jeffrey Cohen, Emmie de Wit, Kevin Vannella, Stephen Hewitt, David Kleiner

SARS-CoV-2 infection and persistence throughout the human body and brain

https://doi.org/10.21203/rs.3.rs-1139035/v1

pre-print

20-Dec-21

Study

https://www.researchsquare.com/article/rs-1139035/v1

COVID-19 is known to cause multi-organ dysfunction1-3 in acute infection, with prolonged symptoms experienced by some patients, termed Post-Acute Sequelae of SARS-CoV-2 (PASC)4-5. However, the burden of infection outside the respiratory tract and time to viral clearance is not well characterized, particularly in the brain3,6-14. We performed complete autopsies on 44 patients with COVID-19 to map and quantify SARS-CoV-2 distribution, replication, and cell-type specificity across the human body, including brain, from acute infection through over seven months following symptom onset. We show that SARS-CoV-2 is widely distributed, even among patients who died with asymptomatic to mild COVID-19, and that virus replication is present in multiple extrapulmonary tissues early in infection. Further, we detected SARS-CoV-2 RNA in multiple anatomic sites, including regions throughout the brain, for up to 230 days following symptom onset. Despite extensive distribution of SARS-CoV-2 in the body, we observed a paucity of inflammation or direct viral cytopathology outside of the lungs. Our data prove that SARS-CoV-2 causes systemic infection and can persist in the body for months.

Il apparaît de plus en plus que le SARS-CoV-2 est un virus dont le corps ne se débarrasse peut-être jamais (pour au moins une part des infectés) complètement.
Vers des pistes thérapeutiques ?
Un article de @MarcGozlan sur son blog de @lemondefr
https://www.lemonde.fr/blog/realitesbiomedicales/2021/12/24/covid-19-le-sars-cov-2-peut-persister-dans-le-corps-pendant-des-mois-et-disseminer-precocement-dans-le-cerveau/
Dans cette étude, non encore relue et publiée et relue, 44 autopsies ont été réalisées sur des individus décédés de complications de la covid, jusqu'à 7 mois après l'infection, avec une moyenne de 35 jours. 95% d'entre eux présentaient une comorbidité, le plus souvent de l’hypertension artérielle, de l’obésité ou une maladie respiratoire chronique. Cependant, deux sont décédés sans formes sévère (par embolie pulmonaire tardive et par complications fatales liées à une comorbidité). Les 44 autopsiés sans exception conservaient des virions de SARS-CoV-2 dans de très nombreux sites anatomiques. L'ARN du SARS-CoV-2 a même été détecté dans le cerveau des six individus décédés tardivement, dont un décédé 7 mois après l'infection. Pour 5 d'entre eux, le virus était disséminé dans tous le système nerveux central.
Les chercheurs ont noté que chez certains patients, le virus s'était diversifié en différents variants selon la zone infectée (avec par ex un profil différent dans le cerveau et dans les poumons. L'ARN viral était également présent à l’intérieur de globules blancs (leucocytes mononucléés) dans la rate, l'appendice et l'épithélium du côlon, ce qui traduit des virions soit replicatifs, soit phagocytés dans des macrophages. Au total, l'ARN viral semble persister au long cours :
*** dans l'endothélium vasculaire (couche de la paroi de tous les vaisseaux sanguins), *** le cerveau pour 6 individus sur les 44 de la cohorte, dans le tissu cérébral dans 10 des 11 cas analysés, *** le poumon, les bronches, les fosses nasales (cornets nasaux) ; pour 43 des 44 cas autopsiques, l'ARN viral a été détecté dans le tissu respiratoire, *** le cœur (cellules musculaires, endothélium, muscles lisses des vaisseaux), dans le péricarde (enveloppe entourant le cœur), *** dans le tissu cardiovasculaire dans 35 cas sur 44, *** les ganglions lymphatiques intra-thoraciques (le tissu lymphoïde dans 38 cas), *** l'humeur aqueuse et tissu oculaire dans 22 cas, *** l'intestin grêle et les glandes surrénales, *** le tissu de l’appareil reproducteur dans 17 cas, *** le muscle, la peau et le tissu nerveux périphérique dans 30 cas,
La réplication virale était encore active chez une majorité de cas, dans tous les tissus, et même chez 42% des individus décédés plus de 30 jours après les premiers symptômes.
En détail, de l'ARN viral était retrouvé dans :
*** les cellules endocrines de la thyroïde et glandulaires du pancréas,*** cellules de l’appareil reproducteur (cellules de Leydig et de Sertoli dans les testicules, cellules germinales dans les tubes séminifères, *** l'épithélium glandulaire de l'endomètre, les cellules musculaires du muscle utérin,*** les myocytes (cellules du muscle squelettique),*** l'épithélium de l’œsophage, les cellules du foie (dont les hépatocytes et l'épithélium des canaux biliaires), les amas lymphoïdes du côlon,*** les cellules des tubules rénaux et vaisseaux des glomérules où a lieu la formation de l'urine primitive, élaborée à partir du sang filtré,*** les neurones, les cellules gliales, l'endothélium des vaisseaux cérébraux dans tous les lobes cérébraux, *** le cervelet (neurones, cellules de Purkinje, endothélium vasculaire).
Les chercheurs ont observé une atteinte alvéolaire diffuse au niveau pulmonaire et, au niveau cardiaque, des infiltrats inflammatoires dans le myocarde.
De minuscules caillots sanguins (micro-thrombi) ont été décrits, de même qu'un appauvrissement du nombre de lymphocytes (lymphodépletion) dans les ganglions lymphatiques et dans la rate. Peu de changements morphologiques ont été observés à l’examen histologique du cerveau.
Les auteurs notent qu'il y a peu d'inflammation significative hormis l'appareil pulmonaire.
Pour les auteurs, ces examens montrent que le virus peut se disséminer très précocement dans le corps, dont le cerveau, dès la première semaine. Comme des études précédentes l'avaient montré, le virus peut entrer dans le cerveau, et probablement en franchissant la barrière hémato-encéphalique.
Les auteurs concluent que le covid long pourrait notamment s'expliquer par cette persistance virale.
L'étude a été menée par une équipe des Instituts américains de la santé (NIH).

Les interprétations de la récente étude, qui analyse 44 autopsies de victimes de la covid et qui note une forte et persistante dissémination du virus dans le corps, sont critiquées par plusieurs experts. Notamment par l'immunologiste Andrew Croxford, qui explique pourquoi selon lui il n'est pas possible d'en tirer des conclusions sur le covid long. Il tient à rappeler que les malades avaient presque tous des comorbidités, que beaucoup ont été intubés, qu'il s'agit de malades non vaccinés et que l'essentiel étaient soit immunodéprimés, soit ont reçu des glucocorticoïdes (à même de favoriser la progression du virus). Pour Andrew Croxford, cette étude ne permet absolument pas de dire qu'une telle dissémination virale intervient fréquemment chez les personnes vaccinées ou les personnes sans comorbidités.

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Marc Scherlinger 1,2,3,* , Luc Pijnenburg 1,2, Emmanuel Chatelus 1,2, Laurent Arnaud 1,2,4,
Jacques-Eric Gottenberg 1,2,5, Jean Sibilia 1,2,4 and Renaud Felten

Effect of SARS-CoV-2 Vaccination on Symptoms from
Post-Acute Sequelae of COVID-19: Results from the
Nationwide VAXILONG Study

https://doi.org/10.3390/vaccines10010046

pre-print

30-Dec-21

Study

https://www.mdpi.com/2076-393X/10/1/46/htm

We conducted a nationwide online study among adult patients with PASC as defined by symptoms persisting over 4 weeks following a confirmed or probable COVID-19, without any identified alternative diagnosis. Information concerning PASC symptoms, vaccine type and scheme and its effect on PASC symptoms were studied. Results: 620 questionnaires were completed and 567 satisfied the inclusion criteria and were analyzed. The respondents’ median age was 44 (IQR 25–75: 37–50) and 83.4% were women. The initial infection was proven in 365 patients (64%) and 5.1% had been hospitalized to receive oxygen. A total of 396 patients had received at least one injection of SARS-CoV-2 vaccine at the time of the survey, after a median of 357 (198–431) days following the initially-reported SARS-CoV-2 infection. Among the 380 patients who reported persistent symptoms at the time of SARS-CoV-2 vaccination, 201 (52.8%) reported a global effect on symptoms following the injection, corresponding to an improvement in 21.8% and a worsening in 31%. There were no differences based on the type of vaccine used. After a complete vaccination scheme, 93.3% (28/30) of initially seronegative patients reported a positive anti-SARS-CoV-2 IgG. A total of 170 PASC patients had not been vaccinated. The most common reasons for postponing the SARS-CoV-2 vaccine were fear of worsening PASC symptoms (55.9%) and the belief that vaccination was contraindicated because of PASC (15.6%). Conclusion: Our study suggests that SARS-CoV-2 vaccination is well tolerated in the majority of PASC patients and has good immunogenicity. Disseminating these reassuring data might prove crucial to increasing vaccine coverage in patients with PASC.

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Jing Sun, MD, MPH, PhD1; Qulu Zheng, MS1; Vithal Madhira, MS2; Amy L. Olex, MS3; Alfred J. Anzalone, MS4; Amanda Vinson, MD5; Jasvinder A. Singh, MD6,7; Evan French, BS3; Alison G. Abraham, PhD8; Jomol Mathew, PhD9; Nasia Safdar, MD, PhD10; Gaurav Agarwal, MD, MSPH11; Kathryn C. Fitzgerald, ScD1,12; Namrata Singh, MD13; Umit Topaloglu, PhD14; Christopher G. Chute, MD, DrPH, MPH1,15; Roslyn B. Mannon, MD16; Gregory D. Kirk, MD, MPH, PhD1,17; Rena C. Patel, MD, MPH18;

Association Between Immune Dysfunction and COVID-19 Breakthrough Infection After SARS-CoV-2 Vaccination in the US

http://jamanetwork.com/article.aspx?doi=10.1001/jamainternmed.2021.7024

Published

28-Dec-21

Study

https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2787643

A total of 664 722 patients in the N3C sample were included. These patients had a median (IQR) age of 51 (34-66) years and were predominantly women (n = 378 307 [56.9%]). Overall, the incidence rate for COVID-19 breakthrough infection was 5.0 per 1000 person-months among fully vaccinated persons but was higher after the Delta variant became the dominant SARS-CoV-2 strain (incidence rate before vs after June 20, 2021, 2.2 [95% CI, 2.2-2.2] vs 7.3 [95% CI, 7.3-7.4] per 1000 person-months). Compared with partial vaccination, full vaccination was associated with a 28% reduced risk for breakthrough infection (adjusted IRR [AIRR], 0.72; 95% CI, 0.68-0.76). People with a breakthrough infection after full vaccination were more likely to be older and women. People with HIV infection (AIRR, 1.33; 95% CI, 1.18-1.49), rheumatoid arthritis (AIRR, 1.20; 95% CI, 1.09-1.32), and solid organ transplant (AIRR, 2.16; 95% CI, 1.96-2.38) had a higher rate of breakthrough infection.

Conclusions and Relevance This cohort study found that full vaccination was associated with reduced risk of COVID-19 breakthrough infection, regardless of the immune status of patients. Despite full vaccination, persons with immune dysfunction had substantially higher risk for COVID-19 breakthrough infection than those without such a condition. For persons with immune dysfunction, continued use of nonpharmaceutical interventions (eg, mask wearing) and alternative vaccine strategies (eg, additional doses or immunogenicity testing) are recommended even after full vaccination.

1274

I089

Svetlana P. Chapoval & Achsah D. Keegan

Perspectives and potential approaches for targeting neuropilin 1 in SARS-CoV-2 infection

https://doi.org/10.1186/s10020-021-00423-y

Published

27-Dec-21

Review

https://molmed.biomedcentral.com/articles/10.1186/s10020-021-00423-y

This perspective focuses on the contribution of the recently discovered interaction of SARS-CoV-2 Spike protein with neuropilin 1 (NRP1) receptor, NRP1 as a virus entry receptor for SARS-CoV-2, its role in different physiologic and pathologic conditions, and the potential to target the Spike–NRP1 interaction to combat virus infectivity and severe disease manifestations.
NRP1 has been shown to participate in the entry of SARS-CoV-2 into cells. Importantly, recent ‘omic’ analyses revealed a significant upregulation of NRP-1 in biological samples from COVID-19 patients compared to healthy controls (Xiong et al. 2020). Moreover, the increased levels of one NRP1 ligand, VEGF165, in bronchial alveolar lavage fluid from COVID-19 patients were also reported (Xiong et al. 2020). VEGF165 is a physiological ligand for the b1b2 pocket in NRP-1 (Moutal et al. 2021). Spike protein, the major surface antigen of SARS-CoV-2, could block VEGF165/NRP-1 signaling. Noteworthy, Sema3A and Sema4A also bind NRP-1 but into a1a2 pocket (Fig. 1). Nevertheless, Sema3A or Sema4A binding may modify the ability of NRP-1 to interact with Spike. The multiple roles of these ligand-receptor interactions in SARS-CoV-2 infection of different cells, tissues, and organs need to be further evaluated. This is an emerging field in research as the roles of NRP1 in different diseases are not well established. Nevertheless, published studies point to NRP1 as potential player in SARS-CoV-2 infection and recently developed approaches for NRP1 targeting provide a foundation for designing novel anti-viral therapies.

1275

I090

I33: pre-print ES

Chansavath Phetsouphanh, David R. Darley, Daniel B. Wilson, Annett Howe, C. Mee Ling Munier, Sheila K. Patel, Jennifer A. Juno, Louise M. Burrell, Stephen J. Kent, Gregory J. Dore, Anthony D. Kelleher & Gail V. Matthews

Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection

https://doi.org/10.1038/s41590-021-01113-x

Published

13-Jan-22

Study

https://www.nature.com/articles/s41590-021-01113-x

A proportion of patients surviving acute coronavirus disease 2019 (COVID-19) infection develop post-acute COVID syndrome (long COVID (LC)) lasting longer than 12 weeks. Here, we studied individuals with LC compared to age- and gender-matched recovered individuals without LC, unexposed donors and individuals infected with other coronaviruses. Patients with LC had highly activated innate immune cells, lacked naive T and B cells and showed elevated expression of type I IFN (IFN-β) and type III IFN (IFN-λ1) that remained persistently high at 8 months after infection. Using a log-linear classification model, we defined an optimal set of analytes that had the strongest association with LC among the 28 analytes measured. Combinations of the inflammatory mediators IFN-β, PTX3, IFN-γ, IFN-λ2/3 and IL-6 associated with LC with 78.5–81.6% accuracy. This work defines immunological parameters associated with LC and suggests future opportunities for prevention and treatment.

todo

1276

I091

SØREN R. PALUDAN AND TRINE H. MOGENSEN

Innate immunological pathways in COVID-19 pathogenesis

https://doi.org/10.1126/sciimmunol.abm5505

Published

7-Jan-22

Review

https://www.science.org/doi/10.1126/sciimmunol.abm5505

Coronavirus disease 2019 (COVID-19) is a disease characterized by a profound dysregulation of the innate immune system. This knowledge has emerged from the large body of single-cell omics studies of patients with COVID-19, which have provided one of the most detailed cellular atlases of a human disease ever. However, we are only beginning to understand the innate immunological pathways that govern host defense and immunopathology in COVID-19. In this review, we discuss the emerging understanding of how SARS-CoV-2 and host-derived molecules activate specific pattern recognition receptors to elicit protective interferon responses and pathological cytokine responses, with particular focus on acute infection of the lung and lung pathophysiology in critical COVID-19. In addition, we discuss how these pathways are modulated by virus-host interactions and host stress-sensing pathways. In-depth understanding of the disease mechanisms will likely uncover specific molecular targets for the treatment of COVID-19 and other emerging viral infections. In addition, it will reveal the fine balance between beneficial protective versus pathological disease causing immune responses.

1277

I092

Paul Kuodi, Yanay Gorelik, Hiba Zayyad, Ofir Wertheim, Karine Beiruti Wiegler, Kamal Abu Jabal, Amiel Dror, Saleh Nazzal, Daniel Glikman, Michael Edelstein

Association between vaccination status and reported incidence of post-acute COVID-19 symptoms in Israel: a cross-sectional study of patients tested between March 2020 and November 2021

https://doi.org/10.1101/2022.01.05.22268800

pre-print

17-Jan-22

Study

https://www.medrxiv.org/content/10.1101/2022.01.05.22268800v2

Long COVID is a post-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection syndrome characterised by not recovering for several weeks or months following the acute episode. The effectiveness of COVID-19 vaccines against long-term symptoms of COVID-19 is not well understood. We determined whether vaccination was associated with the incidence of reporting long-term symptoms post-SARS-CoV-2 infection Methods: We invited individuals who were PCR tested for SARS-CoV-2 infection at participating hospitals between March 2020-November 2021 to fill an online questionnaire that included baseline demographics, details of their acute episode and information about symptoms they were currently experiencing. Using binomial regression, we compared vaccinated individuals with those unvaccinated and those uninfected in terms of self-reported symptoms post-acute infection. Results: We included 951 infected and 2437 uninfected individuals. Of the infected, 637(67%) were vaccinated. The most commonly reported symptoms were; fatigue (22%), headache (20%), weakness (13%), and persistent muscle pain (10%). After adjusting for follow-up time and baseline symptoms, those who received two doses less likely than unvaccinated individuals to report any of these symptoms by 64%, 54%, 57%, and 68% respectively, (Risk ratios 0.36, 0.46, 0.43, 0.32, p<0.04 in the listed sequence). Those who received two doses were no more likely to report any of these symptoms than individuals reporting no previous SARS-CoV-2 infection. Conclusions: Vaccination with at least two doses of COVID-19 vaccine was associated with a substantial decrease in reporting the most common post-acute COVID-19 symptoms, bringing it back to baseline. Our results suggest that, in addition to reducing the risk of acute illness, COVID-19 vaccination may have a protective effect against long COVID.

Selon la version 2 d'un preprint d'une équipe israélienne (non encore revue par les pairs ni publiée), la vaccination avec 2 doses de Pfizer pourrait protéger très largement d'un covid long consécutif à une infection post-vaccinale. La prevalence de symptômes prolongées ne présente pas, pour cette cohorte, de différences significatives entre les double-vaccinés et les participants non infectés, ce qui suggère une protection forte d'un schéma vaccinal complet sur le covid long.

1278

I093

Benjamin Charvet, Joanna Brunel, Justine Pierquin, Mathieu Iampietro, Didier Decimo, Nelly Queruel, Alexandre Lucas, Maria del Mar Encabo-Berzosa, Izaskun Arenaz, Tania Perez Marmolejo, Francina Valezka Bolanos Morales, Arturo Ivan Gonzalez Gonzalez, Armando Castorena Maldonado, Cesar Luna Rivero, Cyrille Mathieu, Patrick Kury, Jose Flores-Rivera, Santiago Avila Rios, Gonzalo Salgado Montes de Oca, Jon Schoorlemmer, Branka Horvat, Herve JF Perron

SARS-CoV-2 induces human endogenous retrovirus type W envelope protein expression in blood lymphocytes and in tissues of COVID-19 patients.

https://doi.org/10.1101/2022.01.18.21266111

pre-print

18-Jan-22

Study

https://www.medrxiv.org/content/10.1101/2022.01.18.21266111v1

As viral infections may activate human endogenous retroviral elements (HERV), we studied the effect of SARS-CoV-2 on HERV-W and HERV-K envelope (ENV) expression, known to be involved in immunological and neurological pathogenesis of human diseases. Our results have showed that the exposure to SARS-CoV-2 virus activates early HERV-W and K transcription but only HERV-W ENV protein expression, in an infection- and ACE2-independent way within peripheral blood mononuclear cell cultures from one-third of healthy donors. Moreover, HERV-W ENV protein was significantly increased in serum and plasma of COVID-19 patients, correlating with its expression in CD3+ lymphocytes and with disease severity. Finally, HERV-W ENV was found expressed in post-mortem tissues of lungs, heart, brain olfactory bulb and nasal mucosa from acute COVID-19 patients in cell-types relevant for COVID-19-associated pathogenesis within affected organs, but different from those expressing of SARS-CoV-2 antigens. Altogether, the present study revealed that SARS-CoV-2 can induce HERV-W ENV expression in cells from individuals with symptomatic and severe COVID-19. Our data suggest that HERV-W ENV is likely to be involved in pathogenic features underlying symptoms of acute and post-acute COVID. It highlights the importance to further understand patients genetic susceptibility to HERV-W activation and the relevance of this pathogenic element as a prognostic marker and a therapeutic target in COVID-19 associated syndromes.

1279

I094

Samu N. Kurki, Jonas Kantonen, Karri Kaivola, Laura Hokkanen, Mikko I. Mäyränpää, Henri Puttonen, FinnGen, Juha Martola, Minna Pöyhönen, Mia Kero, Jarno Tuimala, Olli Carpén, Anu Kantele, Olli Vapalahti, Marjaana Tiainen, Pentti J. Tienari, Kai Kaila, Johanna Hästbacka & Liisa Myllykangas

APOE ε4 associates with increased risk of severe COVID-19, cerebral microhaemorrhages and post-COVID mental fatigue: a Finnish biobank, autopsy and clinical study

https://doi.org/10.1186/s40478-021-01302-7

Published

23-Dec-21

Study

https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-021-01302-7

Apolipoprotein E ε4 allele (APOE4) has been shown to associate with increased susceptibility to SARS-CoV-2 infection and COVID-19 mortality in some previous genetic studies, but information on the role of APOE4 on the underlying pathology and parallel clinical manifestations is scarce. Here we studied the genetic association between APOE and COVID-19 in Finnish biobank, autopsy and prospective clinical cohort datasets. In line with previous work, our data on 2611 cases showed that APOE4 carriership associates with severe COVID-19 in intensive care patients compared with non-infected population controls after matching for age, sex and cardiovascular disease status. Histopathological examination of brain autopsy material of 21 COVID-19 cases provided evidence that perivascular microhaemorrhages are more prevalent in APOE4 carriers. Finally, our analysis of post-COVID fatigue in a prospective clinical cohort of 156 subjects revealed that APOE4 carriership independently associates with higher mental fatigue compared to non-carriers at six months after initial illness. In conclusion, the present data on Finns suggests that APOE4 is a risk factor for severe COVID-19 and post-COVID mental fatigue and provides the first indication that some of this effect could be mediated via increased cerebrovascular damage. Further studies in larger cohorts and animal models are warranted.

1280

I095

ES

Carlo Cervia, Yves Zurbuchen, Patrick Taeschler, Tala Ballouz, Dominik Menges, Sara Hasler, Sarah Adamo, Miro E. Raeber, Esther Bächli, Alain Rudiger, Melina Stüssi-Helbling, Lars C. Huber, Jakob Nilsson, Ulrike Held, Milo A. Puhan & Onur Boyman

Immunoglobulin signature predicts risk of post-acute COVID-19 syndrome

https://doi.org/10.1038/s41467-021-27797-1

Published

25-Jan-22

Study

https://www.nature.com/articles/s41467-021-27797-1

Following acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) a significant proportion of individuals develop prolonged symptoms, a serious condition termed post-acute coronavirus disease 2019 (COVID-19) syndrome (PACS) or long COVID. Predictors of PACS are needed. In a prospective multicentric cohort study of 215 individuals, we study COVID-19 patients during primary infection and up to one year later, compared to healthy subjects. We discover an immunoglobulin (Ig) signature, based on total IgM and IgG3 levels, which – combined with age, history of asthma bronchiale, and five symptoms during primary infection – is able to predict the risk of PACS independently of timepoint of blood sampling. We validate the score in an independent cohort of 395 individuals with COVID-19. Our results highlight the benefit of measuring Igs for the early identification of patients at high risk for PACS, which facilitates the study of targeted treatment and pathomechanisms of PACS.

todo

1281

I096

ONS

Self-reported long COVID after two doses of a coronavirus (COVID-19) vaccine in the UK: 26 January 2022

Published

26-Jan-22

Study

https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/selfreportedlongcovidaftertwodosesofacoronaviruscovid19vaccineintheuk/26january2022

Odds ratios for symptoms reported at least 12 weeks after coronavirus (COVID-19) infection, comparing Coronavirus (COVID-19) Infection Survey participants who had received two doses of a COVID-19 vaccine before infection with those who were unvaccinated.
Main points
In a sample of UK adults aged 18 to 69 years, receiving two doses of a coronavirus (COVID-19) vaccine at least two weeks before a first test-confirmed COVID-19 infection was associated with a 41.1% decrease in the odds of self-reported long COVID at least 12 weeks later, relative to socio-demographically similar study participants who were not vaccinated when infected (Figure 1).
This analysis was based on data to 30 November 2021, and longer follow-up time is needed to assess the impact of booster doses and the Omicron variant; furthermore, the observational nature of the analysis means that we cannot say whether COVID-19 vaccination caused subsequent changes in the likelihood of self-reported long COVID.
Long COVID symptoms of any severity were reported by 9.5% of double-vaccinated study participants, compared with 14.6% of socio-demographically similar participants who were unvaccinated when infected; the corresponding estimates for long COVID symptoms severe enough to result in limitation to day-to-day activities were 5.5% and 8.7% respectively.
There was no statistical evidence that the relationship between vaccination status at the time of infection and the likelihood of subsequently reporting long COVID symptoms differed by whether participants received adenovirus vector (Oxford/AstraZeneca) or mRNA (Pfizer/BioNTech or Moderna) vaccines.

1282

I097

Qin Liu,1,2,3,4 Joyce Wing Yan Mak ,1,2,3 Qi Su,1,2,3 Yun Kit Yeoh ,1,5
Grace Chung-Yan Lui,2,6 Susanna So Shan Ng,2 Fen Zhang ,1,2,3 Amy Y L Li,1,2,3Wenqi Lu,1,2,3 David Shu-Cheong Hui, 6 Paul KS Chan,1,5 Francis K L Chan ,1,2,3Siew C Ng

Gut microbiota dynamics in a prospective cohort of patients with post-acute COVID-19 syndrome

http://dx.doi.org/10.1136/gutjnl-2021-325989

Published

26-Jan-22

Study

https://gut.bmj.com/content/early/2022/01/05/gutjnl-2021-325989

What is already known on this subject?
► Persistent symptoms after the convalescence period in patients with COVID-19 have been reported.
► Emerging evidence supports the potential role of gut dysbiosis in the severity of COVID-19 infection.
► The long-term impact of SARS-CoV-2 on the gut microbiome after the acute infection and whether gut microbiota composition affects risk of persistent symptoms in recovered patients with different severity of COVID-19 infection is unknown.
What are the new findings?
► Our results show that an individual’s gut microbiome profile may affect their susceptibility to long-term complications of COVID-19.
► Gut microbiome pattern reflects different symptoms in patients with post-acute COVID-19 syndrome (PACS).
► Distinct gut microbiota composition at admission is associated with occurrence of PACS at 6 months.
How might it impact on clinical practice in the foreseeable future?
► These findings provide new insights into the intricate association between the gut microbiome and the long-term sequelae after COVID-19 infection.
► Microbiome-based profiling might be used as a tool in early risk stratification for occurrence of post-acute COVID-19 syndrome.
Background Long-term complications after COVID-19 are common, but the potential cause for persistent symptoms after viral clearance remains unclear.
Objective To investigate whether gut microbiome composition is linked to post-acute COVID-19 syndrome (PACS), defined as at least one persistent symptom 4 weeks after clearance of the SARS-CoV-2 virus.
Methods We conducted a prospective study of 106 patients with a spectrum of COVID-19 severity followed up from admission to 6 months and 68 non-COVID-19 controls. We analysed serial faecal microbiome of 258 samples using shotgun metagenomic sequencing, and correlated the results with persistent symptoms at 6 months.
Results At 6 months, 76% of patients had PACS and the most common symptoms were fatigue, poor memory and hair loss. Gut microbiota composition at admission was associated with occurrence of PACS. Patients without PACS showed recovered gut microbiome profile at 6 months comparable to that of non-COVID-19 controls. Gut microbiome of patients with PACS were characterised by higher levels of Ruminococcus gnavus, Bacteroides vulgatus and lower levels of Faecalibacterium prausnitzii. Persistent respiratory symptoms were correlated with opportunistic gut pathogens, and neuropsychiatric symptoms and fatigue were correlated with nosocomial gut pathogens, including Clostridium innocuum and Actinomyces naeslundii (all p<0.05). Butyrate-producing bacteria, including Bifidobacterium pseudocatenulatum and Faecalibacterium prausnitzii showed the largest inverse correlations with PACS at 6 months.
Conclusion These findings provided observational evidence of compositional alterations of gut microbiome in patients with long-term complications of COVID-19. Further studies should investigate whether microbiota modulation can facilitate timely recovery from post-acute COVID-19 syndrome.

1283

I098

ES

YapengSu12328DanYuan1428Daniel G.Chen1528Rachel H.Ng14KaiWang1JongchanChoi1SarahLi1SungaHong1RongyuZhang14JingyiXie16Sergey A.Kornilov1KelseyScherler1Ana JimenaPavlovitch-Bedzyk7ShenDong8ChristopherLausted1InyoulLee1ShannonFallen1Chengzhen L.Dai1…James R.Heath

Multiple Early Factors Anticipate Post-Acute COVID-19 Sequelae

https://doi.org/10.1016/j.cell.2022.01.014

Published

25-Jan-22

Study

https://www.cell.com/cell/fulltext/S0092-8674(22)00072-1

Highlights
Longitudinal multiomics associate PASC with autoantibodies, viremia and comorbidities
Reactivation of latent viruses during initial infection may contribute to PASC
Subclinical autoantibodies negatively correlate with anti-SARS-CoV-2 antibodies
Gastrointestinal PASC uniquely present with post-acute expansion of cytotoxic T cells

Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk-factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data, and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific autoantibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.

1284

I099

Nabin K Shrestha, Patrick C Burke, Amy S Nowacki, Paul Terpeluk, Steven M Gordon

Necessity of COVID-19 Vaccination in Persons Who Have Already Had COVID-19

https://doi.org/10.1093/cid/ciac022

Published

13-Jan-22

Study

https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac022/6507165

Results
Among 52238 employees, 4718 (9%) were previously infected, and 36922 (71%) were vaccinated by the study’s end. Cumulative incidence of COVID-19 was substantially higher throughout for those previously uninfected who remained unvaccinated than for all other groups, lower for the vaccinated than unvaccinated, and lower for those previously infected than those not. Incidence of COVID-19 increased dramatically in all groups after the Omicron variant emerged. In multivariable Cox proportional hazards regression, both prior COVID-19 and vaccination were independently associated with significantly lower risk of COVID-19. Among previously infected subjects, a lower risk of COVID-19 overall was not demonstrated, but vaccination was associated with a significantly lower risk of symptomatic COVID-19 in both the pre-Omicron (HR 0.60, 95% CI 0.40–0.90) and Omicron (HR 0.36, 95% CI 0.23–0.57) phases.
Conclusions
Both previous infection and vaccination provide substantial protection against COVID-19. Vaccination of previously infected individuals does not provide additional protection against COVID-19 for several months, but after that provides significant protection at least against symptomatic COVID-19.

1285

I100

Priya Venkatesan

Do vaccines protect from long COVID?

https://doi.org/10.1016/S2213-2600(22)00020-0

Published

20-Jan-22

Article

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00020-0/fulltext

The data on long COVID are worrying, particularly during the current increase in global cases of COVID-19 infection. There are, however, encouraging emerging data that individuals who are vaccinated against COVID-19 are less likely to report long COVID symptoms. For example, a case-control study of 1·2 million users of a COVID symptom tracker app in the UK showed that there were lower odds of symptoms lasting 28 days or more in individuals who had received two vaccine doses (odds ratio 0·51 [95% CI 0·32–0·82]; p=0·0060)—ie, the risk of developing long COVID was reduced by around 50% in those who were double vaccinated. Wilder-Smith said “Even if COVID-19 did not cause deaths, the high morbidity as a result of this viral infection would justify vaccinating all. The reasons for vaccination beyond the most pressing need to avert severe disease and deaths are manifold, but foremost it is to prevent long COVID.” De Soyza added “Ideally preventing both acute severe COVID through vaccination and also reducing the chances of long COVID represents an additional driver to support people to get vaccinated.”

1286

I101

PabloPánicoPatriciaOstrosky-WegmanAna MaríaSalazar

The potential role of COVID-19 in the induction of DNA damage

https://doi.org/10.1016/j.mrrev.2022.108411

Published

21-Jan-22

Article

https://www.sciencedirect.com/science/article/pii/S1383574222000011

In some individuals, COVID-19 can cause a wide array of symptoms, affecting several organs, such as the lungs, heart, bowels, kidneys and brain, causing multiorgan failure, sepsis and death. These effects are related in part to direct viral infection of these organs, immunological deregulation, a hypercoagulatory state and the potential for development of cytokine storm syndrome. Since the appearance of COVID-19 is recent, the long-term effects on the health of recovered patients remain unknown. In this review, we focused on current evidence of the mechanisms of DNA damage mediated by coronaviruses. Data supports that these viruses can induce DNA damage, genomic instability, and cell cycle deregulation during their replication in mammalian cells. Since the induction of DNA damage and aberrant DNA repair mechanisms are related to the development of chronic diseases such as cancer, diabetes, neurodegenerative disorders, and atherosclerosis, it will be important to address similar effects and outcomes in recovered COVID-19 patients.

1287

I102

VP

Luis AntonioDíazMD1+TamaraGarcía-SalumPh.D2+EduardoFuentes-LópezPh.D3+DiegoReyesMD4JavierOrtizMD4JavierChahuanMD1JorgeLevicanPh.D2Leonardo I.AlmonacidPh.D2Gonzalo H.ValenzuelaMD2EileenSerranocPh.D2SigallBudnik5VicenteGandara5AndreaGallardo5María FranciscaSeydewitz5MarcelaFerrésMD2ColombaCofréMD6ManuelÁlvarezMD1CarolinaPavezMD1…ArnoldoRiquelmeMD M.Med.Ed Full Professor13

High prevalence of SARS-CoV-2 detection and prolonged viral shedding in stools: A Systematic Review and Cohort StudyElevada detección de SARS-CoV-2 y prolongada excreción viral en deposiciones: Estudio de cohorte y revisión sistemática

https://doi.org/10.1016/j.gastrohep.2021.12.009

Published

22-Jan-22

Study

https://www.sciencedirect.com/science/article/pii/S0210570522000012

Results: We included 32 patients; mean age was 43.7;17.7 years, 43.8% were female, and 40.6% reported gastrointestinal symptoms. Twenty-five percent (8/32) of patients had detectable viral RNA in stools. The median clearance time in stools of the cohort was 11[10-15] days. Systematic review included 30 studies (1,392 patients) with stool samples. Six studies were performed in children and 55% were male. The pooled prevalence of viral detection in stools was 34.6% (twenty-four studies, 1,393 patients; 95%CI:25.4-45.1); heterogeneity was high (I2:91.2%, Q:208.6; p=<0.001). A meta-regression demonstrates an association between female-gender and lower presence in stools (p=0.004). The median clearance time in stools was 22 days (nineteen studies, 140 patients; 95%CI:19–25). After 34 days, 19.9% (95%CI:11.3-29.7) of patients have a persistent detection in stools.
Conclusions: Detection of SARS-CoV-2 in stools is a frequent finding. The clearance of SARS-CoV-2 in stools is prolonged and it takes longer than nasopharyngeal secretions.

1288

I103

Artem Pliss, Andrey N. Kuzmin, Paras N. Prasad*, and Supriya D. Mahajan*

Mitochondrial Dysfunction: A Prelude to Neuropathogenesis of SARS-CoV-2

https://doi.org/10.1021/acschemneuro.1c00675

Published

20-Jan-22

Article

https://pubs.acs.org/doi/10.1021/acschemneuro.1c00675

The neuropathology of SARS-CoV-2 is increasingly attributed to mitochondrial dysfunction of brain microglia cells. However, the changes in biochemical content of mitochondria that drive the progression of neuro-COVID remain poorly understood. Here we introduce a Raman microspectrometry approach that enables the molecular profiling of single cellular organelles to characterize the mitochondrial molecular makeup in the infected microglia cells. We found that microglia treated with either spike protein or heat-inactivated SARS-CoV-2 trigger a dramatic reduction in mtDNA content and an increase in phospholipid saturation levels. At the same time, no significant changes were detected in Golgi apparatus and in lipid droplets, the organelles that accommodate biogenesis and storage of lipids. We hypothesize that transformations in mitochondria are caused by increased synthesis of reactive oxygen species in these organelles. Our findings call for the development of mitochondria-targeted therapeutic approaches to limit neuropathology associated with SARS-CoV-2.

1289

I104

Reka Varnai 1 ,Tihamer Molnar 2,* ,Laszlo Zavori 3 ,Margit Tőkés-Füzesi 4,Zsolt Illes 5,Andrea Kanizsai 6 andPeter Csecsei 7

Serum Level of Anti-Nucleocapsid, but Not Anti-Spike Antibody, Is Associated with Improvement of Long COVID Symptoms

https://doi.org/10.3390/vaccines10020165

Published

21-Jan-22

Article

https://www.mdpi.com/2076-393X/10/2/165/htm

Previous reports have suggested the role of an unsatisfactory immune response and impaired viral clearance in the pathogenesis of long COVID syndrome. We focused on potential associations between post-vaccination changes of antibody titers and the severity of long COVID symptoms and factors influencing the state of remission observed in patients with long COVID after vaccination. Methods: The severity of long COVID symptoms and serum anti-SARS-CoV-2 spike (S-Ig) and nucleocapsid (NC-Ig) levels were assessed in 107 post-COVID subjects at two time points: at baseline, and 17–24 weeks later. Besides, vaccination status was also assessed. Symptoms were evaluated based on the Chalder fatigue scale (CFQ-11) and visual analogue scale (VAS). Results: Serum level of S-Ig and NC-Ig at baseline were significantly higher in the patients with non-severe fatigue than those with severe fatigue, and this difference remained significant at follow-up in the case of NC-Ig. NC-Ig level above median was as an independent predictor for complete remission at follow-up. The difference in NC-Ig levels in subgroup analyses (severe fatigue vs. non-severe fatigue; complete remission vs. incomplete remission or progression) was found to be significant only in patients who received vaccination. Conclusions: The immune response against the SARS-CoV-2 nucleocapsid may play a more important role than the spike in the course of long-term COVID syndrome.

1290

I105

César Fernández-de-las-Peñas 1,2,* ,José D. Martín-Guerrero 3 ,Óscar J. Pellicer-Valero 3 ,Esperanza Navarro-Pardo 4 ,Víctor Gómez-Mayordomo 5 ,María L. Cuadrado 5,6,José A. Arias-Navalón 7 ,Margarita Cigarán-Méndez 8,Valentín Hernández-Barrera 9 andLars Arendt-Nielsen 2,10

Female Sex Is a Risk Factor Associated with Long-Term Post-COVID Related-Symptoms but Not with COVID-19 Symptoms: The LONG-COVID-EXP-CM Multicenter Study

https://doi.org/10.3390/jcm11020413

Published

14-Jan-22

Study

https://www.mdpi.com/2077-0383/11/2/413/htm

This multicenter cohort study investigated the differences between coronavirus disease 2019 (COVID-19) related symptoms and post-COVID symptoms between male and female COVID-19 survivors. Clinical and hospitalization data were collected from hospital medical records in a sample of individuals recovered from COVID-19 at five public hospitals in Spain. A predefined list of post-COVID symptoms was systematically assessed, but patients were free to report any symptom. Anxiety/depressive levels and sleep quality were also assessed. Adjusted multivariate logistic regressions were used to identify the association of sex with post-COVID related-symptoms. A total of 1969 individuals (age: 61, SD: 16 years, 46.4% women) were assessed 8.4 months after discharge. No overall significant sex differences in COVID-19 onset symptoms at hospital admission were found. Post-COVID symptoms were present in up to 60% of hospitalized COVID-19 survivors eight months after the infection. The number of post-COVID symptoms was 2.25 for females and 1.5 for males. After adjusting by all variables, female sex was associated with ≥3 post-COVID symptoms (adj OR 2.54, 95%CI 1.671–3.865, p < 0.001), the presence of post-COVID fatigue (adj OR 1.514, 95%CI 1.040–2.205), dyspnea (rest: adj OR 1.428, 95%CI 1.081–1.886, exertion: adj OR 1.409, 95%CI 1.109–1.791), pain (adj OR 1.349, 95%CI 1.059–1.720), hair loss (adj OR 4.529, 95%CI 2.784–7.368), ocular problems (adj OR 1.981, 95%CI 1.185–3.312), depressive levels (adj OR 1.606, 95%CI 1.002–2.572) and worse sleep quality (adj OR 1.634, 95%CI 1.097–2.434). Female sex was a risk factor for the development of some long-term post-COVID symptoms including mood disorders. Healthcare systems should consider sex differences in the management of long haulers.

1291

I106

C. Lazor-Blanchet, P. Zygoura, U. Dafni, F. Lamoth, Z. Tsourti, M.A. Lobritz, J. Regina, B. Grandbastien, C. Fenwick, G. Pantaleo, T. Calandra, S.d Meylan

Low neutralizing antibody titers after asymptomatic or non-severe SARS-CoV-2 infection over a 6-month assessment period

https://doi.org/10.1016/j.jinf.2022.02.001

Published

5-Feb-22

Letter to Editor

https://www.journalofinfection.com/article/S0163-4453(22)00062-7/fulltext

Highlights
•Patients with asymptomatic and mild SARS-CoV-2 infections are at risk of re-infection within the same year
•Neutralizing capacity remains more stable over time than do anti-S IgG titers.

1292

I107

NicoleBechmannPhDab*ProfAndreasBarthelMDac*ProfAndreasSchedlPhDadProfStephanHerzigPhDeProfZsuzsannaVargaMDfProfCatherineGebhardMDghProfManuelMayrPhDaiConstanzeHantelPhDakProfFelixBeuschleinMDklProfChristianWolfrumPhDmProfNikolaosPerakakisMDaProfLucillaPostonPhDnCynthia LAndoniadouPhDaoRichardSiowPhDijProfRaul RGainetdinovMDqAradDotanMDrProfYehudaShoenfeldMDrsProfGeltrudeMingroneMDptuProfStefan RBornsteinMDap

Sexual dimorphism in COVID-19: potential clinical and public health implications

https://doi.org/10.1016/S2213-8587(21)00346-6

Published

1-Feb-22

Personal View

https://www.sciencedirect.com/science/article/pii/S2213858721003466

Current evidence suggests that severity and mortality of COVID-19 is higher in men than in women, whereas women might be at increased risk of COVID-19 reinfection and development of long COVID. Differences between sexes have been observed in other infectious diseases and in the response to vaccines. Sex-specific expression patterns of proteins mediating virus binding and entry, and divergent reactions of the immune and endocrine system, in particular the hypothalamic–pituitary–adrenal axis, in response to acute stress might explain the higher severity of COVID-19 in men. In this Personal View, we discuss how sex hormones, comorbidities, and the sex chromosome complement influence these mechanisms in the context of COVID-19. Due to its role in the severity and progression of SARS-CoV-2 infections, we argue that sexual dimorphism has potential implications for disease treatment, public health measures, and follow-up of patients predisposed to the development of long COVID. We suggest that sex differences could be considered in future pandemic surveillance and treatment of patients with COVID-19 to help to achieve better disease stratification and improved outcomes.

1293

I108

RavindraGaneshMBBS, MDaStephanie L.GrachMD, MSdAditya K.GhoshMDeDennis M.BierleMDaBradley R.SalonenMDaNerissa M.CollinsMDaAvni Y.JoshiMD, MSbNeal D.BoederJr.MDaChristopher V.AnstineMDaMichael R.MuellerMD, MSaElizabeth C.WightMDaIvana T.CroghanPhDaAndrew D.BadleyMDcRickey E.CarterPhDfRyan T.HurtMD, PhDa

The Female-Predominant Persistent Immune Dysregulation of the Post-COVID Syndrome

https://doi.org/10.1016/j.mayocp.2021.11.033

Published

5-Feb-22

Study

https://www.sciencedirect.com/science/article/pii/S0025619621008880

Results
Most of the patients seen in our clinic were female (75%; 81/108), and the median age at presentation was 46 years (interquartile range, 37 to 55 years). All had post-acute sequelae of SARS-CoV-2 infection, with 6 clinical phenotypes being identified: fatigue predominant (n=69), dyspnea predominant (n=23), myalgia predominant (n=6), orthostasis predominant (n=6), chest pain predominant (n=3), and headache predominant (n=1). The fatigue-predominant phenotype was more common in women, and the dyspnea-predominant phenotype was more common in men. Interleukin 6 (IL-6) was elevated in 61% of patients (69% of women; P=.0046), which was more common than elevation in C-reactive protein and erythrocyte sedimentation rate, identified in 17% and 20% of cases, respectively.
Conclusion
In our PCOCC, we observed several distinct clinical phenotypes. Fatigue predominance was the most common presentation and was associated with elevated IL-6 levels and female sex. Dyspnea predominance was more common in men and was not associated with elevated IL-6 levels. IL-6 levels were more likely than erythrocyte sedimentation rate and C-reactive protein to be elevated in patients with post-acute sequelae of SARS-CoV-2 infection.

1294

I109

Dr. Carolina Diamandis,Olga Ivanova,Adrian Tudor Corresponding Author

From pandemic Covid-19 to endemic Sars-2 Omicron Disease: is Long Covid still an issue?

https://doi.org/10.22541/au.164364370.07687372/v1

pre-print

31-Jan-22

Review

https://www.authorea.com/doi/full/10.22541/au.164364370.07687372

Abstract
For many patients with severe Covid-19 disease of the pre-Omicron era, recovery is far from over with the end of acute symptoms. The authors of this paper have reviewed the currently available studies and conclude that Long-Covid appears to be a serious, sometimes even life-threatening syndrome. However, it seems to have good prospects for full recovery with multidisciplinary and evidence-based post-treatment care, which is, however, still lacking in Europe and North America. The Omicron variant appears to be a game changer in this regard as well. So far it seems that Long Covid is no common consequence of Sars-2-Omicron Disease.

1295

I110

Sara Ahmad Assiri
Raad M. M. Althaqafi
Taif University
Khaled Alswat
Ahmed Abdullah Alghamdi

Post COVID-19 Vaccination-Associated Neurological Complications

http://dx.doi.org/10.2147/NDT.S343438

Published

1-Feb-22

Study

https://www.researchgate.net/publication/358272064_Post_COVID-19_Vaccination-Associated_Neurological_Complications

Purpose: Neurological sequelae after COVID-19 vaccination are rare. We investigated the possible pathogenesis behind the development of neurological complications within a short period after Saudi residents received a COVID-19 vaccine. Patients and Methods: We evaluated 18 patients who recently received a COVID-19 vaccine (Comirnaty and Vaxzevria vaccines) and presented with neurological complications to the Saudi German Hospitals in Jeddah, Saudi Arabia. Neurologists assessed the patients’ clinical presentation, radiological investigations, and laboratory findings. Results: Three patients who received the first dose of the Vaxzevria vaccine experienced severe cerebral venous thrombosis, two of them were complicated by intracranial hemorrhage. Their laboratory investigations showed very high d-dimers and severe thrombocytopenia, which have been linked to higher mortality and poor outcome. Ischemic stroke occurred in eight cases (44.4%) with a predominance in older male patients. Three patients presented with seizures, two had optic neuritis. Guillain–Barré syndrome (GBS) and Miller Fisher syndrome (MFS) occurred in two male patients following vaccination with Comirnaty. Conclusion: Neurological complications after COVID-19 vaccinations are very rare, and only a few cases have been reported worldwide. The shared pathophysiological basis between COVID-19 viral infection and COVID-19 vaccines stands behind the very rare neurological complications resulting from the hypercoagulable state triggered by the general inflammatory condition. We suspect some differences in the pathogenesis of ischemic stroke caused by COVID-19 infection and COVID-19 vaccines, which render COVID-19 vaccine-associated ischemic stroke more responsive to treatment. To date, no definitive association between the vaccine and GBS has been proven by any strong evidence, but it has recently been added as a very rare side effect of the Janssen COVID-19 vaccine. No possible links of Miller Fisher syndrome to COVID-19 vaccines have been reported before the one reported in this study. Keywords: vaccine, ischemic stroke, cerebral venous thrombosis, seizures, optic neuritis.

1296

I111

Yang Yang, Minghui Yang, Yun Peng, Yanhua Liang, Jinli Wei, Li Xing, Liping Guo, Xiaohe Li, Jie Li, Jun Wang, Mianhuan Li, Zhixiang Xu, Mingxia Zhang, Fuxiang Wang, Yi Shi, Jing Yuan & Yingxia Liu

Longitudinal analysis of antibody dynamics in COVID-19 convalescents reveals neutralizing responses up to 16 months after infection

https://doi.org/10.1038/s41564-021-01051-2

Published

7-Feb-22

Article

https://www.nature.com/articles/s41564-021-01051-2

Elucidating the dynamics of the neutralizing antibody (nAb) response in coronavirus disease 2019 (COVID-19) convalescents is crucial in controlling the pandemic and informing vaccination strategies. Here we measured nAb titres across 411 sequential plasma samples collected during 1–480 d after illness onset or laboratory confirmation (d.a.o.) from 214 COVID-19 convalescents, covering the clinical spectrum of disease and without additional exposure history after recovery or vaccination against SARS-CoV-2, using authentic SARS-CoV-2 microneutralization (MN) assays. Forty-eight samples were also tested for neutralizing activities against the circulating variants using pseudotyped neutralization assay. Results showed that anti-RBD IgG and MN titres peaked at ~120 d.a.o. and subsequently declined, with significantly reduced nAb responses found in 91.67% of COVID-19 convalescents (≥50% decrease in current MN titres compared with the paired peak MN titres). Despite this decline, majority of the COVID-19 convalescents maintained detectable anti-RBD IgG and MN titres at 400–480 d.a.o., with undetectable neutralizing activity found in 14.41% (16/111) of the mild and 50% (5/10) of the asymptomatic infections at 330–480 d.a.o. Persistent antibody-dependent immunity could provide protection against circulating variants after one year, despite significantly decreased neutralizing activities against Beta, Delta and Mu variants. In conclusion, these data show that despite a marked decline in neutralizing activity over time, nAb responses persist for up to 480 d in most convalescents of symptomatic COVID-19, whereas a high rate of undetectable nAb responses was found in convalescents from asymptomatic infections.

1297

I112

Jin-Gyu Cheong, Arjun Ravishankar, Siddhartha Sharma, Christopher N. Parkhurst, Djamel Nehar-Belaid, Sai Ma, Lucinda Paddock, Benoit Fatou, Onur Karakaslar, Asa Thibodeau, Michael J. Bale, Vinay K. Kartha, Jim K Yee, Minh Yen Mays, Louise Leyre, Alexia Martinez de Paz, Andrew W. Daman, Sergio Alvarez Mullett, Lexi Robbins, Elyse LaFond, Karissa Weidman, View ProfileSabrina Racine-Brzostek, He S. Yang, David Price, Brad Jones, Edward J. Schenck, Robert J. Kaner, Amy Chadburn, Zhen Zhao, View ProfileHanno Steen, Virginia Pascual, Jason Buenrostro, Rachel E. Niec, Lindsay Lief, Duygu Ucar, View ProfileSteven Z. Josefowicz

Epigenetic Memory of COVID-19 in Innate Immune Cells and Their Progenitors

https://doi.org/10.1101/2022.02.09.479588

pre-print

10-Feb-22

Study

https://www.biorxiv.org/content/10.1101/2022.02.09.479588v1.full

Severe coronavirus disease 2019 (COVID-19) is characterized by systemic inflammation and can result in protracted symptoms. Robust systemic inflammation may trigger persistent changes in hematopoietic cells and innate immune memory through epigenetic mechanisms. We reveal that rare circulating hematopoietic stem and progenitor cells (HSPC), enriched from human blood, match the diversity of HSPC in bone marrow, enabling investigation of hematopoiesis and HSPC epigenomics. Following COVID-19, HSPC retain epigenomic alterations that are conveyed, through differentiation, to progeny innate immune cells. Epigenomic changes vary with disease severity, persist for months to a year, and are associated with increased myeloid cell differentiation and inflammatory or antiviral programs. Epigenetic reprogramming of HSPC may underly altered immune function following infection and be broadly relevant, especially for millions of COVID-19 survivors.

One Sentence Summary Transcriptomic and epigenomic analysis of blood reveal sustained changes in hematopoiesis and innate immunity after COVID-19.

1298

I113

Lydia L.Shook12Elinor L.Sullivan345Jamie O.Lo678Roy H.Perlis9Andrea G.Edlow12

COVID-19 in pregnancy: implications for fetal brain development

https://doi.org/10.1016/j.molmed.2022.02.004

Published

14-Feb-22

Review

https://www.sciencedirect.com/science/article/pii/S1471491422000454

Highlights
•SARS-CoV-2 infection in pregnancy is known to confer a risk of increased morbidity and mortality for the mother, but data are lacking regarding the impact of maternal SARS-CoV-2 infection on the developing fetal brain.
•Placental and fetal infection with SARS-CoV-2 have been rare to date; SARS-CoV-2 infection in pregnancy appears most likely to impact fetal brain development via maternal and placental immune activation.
•Maternal, placental, and fetal immune activation have been observed in SARS-CoV-2 infection during pregnancy, and adverse neurodevelopmental outcomes have been reported in early follow-up studies of offspring.
•Maternal and placental immune activation may impact the placenta and developing fetal brain via induction of immune activation and pro-inflammatory cytokine production, dysregulation of serotonin/other neurotransmitter signaling, and increased oxidative stress.
Abstract
The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy on the developing fetal brain is poorly understood. Other antenatal infections such as influenza have been associated with adverse neurodevelopmental outcomes in offspring. Although vertical transmission has been rarely observed in SARS-CoV-2 to date, given the potential for profound maternal immune activation, impact on the developing fetal brain is likely. Here we review evidence that SARS-CoV-2 and other viral infections during pregnancy can result in maternal, placental and fetal immune activation, and ultimately in offspring neurodevelopmental morbidity. Finally, we highlight the need for cellular models of fetal brain development to better understand potential short- and long-term impacts of maternal SARS-CoV-2 infection on the next generation.

1299

I114

MarySmallCharles N.SerhanStephaniaLibrerosRobertNshimiyimana

E-series Resolvin Metabolome, Biosynthesis and Critical Role of Stereochemistry of Specialized Pro-Resolving Mediators (SPMs) in Inflammation-Resolution: Preparing SPMs for Long COVID-19, Human Clinical Trials, and Targeted Precision Nutrition

https://doi.org/10.1016/j.smim.2022.101597

Published

16-Feb-22

Review

https://www.sciencedirect.com/science/article/pii/S1044532322000148

The COVID-19 pandemic has raised international awareness of the importance of rigorous scientific evidence and the havoc caused by uncontrolled excessive inflammation. Here we consider the evidence on whether the specialized pro-resolving mediators (SPMs) are ready to meet this challenge as well as targeted metabololipidomics of the resolution-inflammation metabolomes. Specific stereochemical mechanisms in the biosynthesis of SPMs from omega-3 essential fatty acids give rise to unique local-acting lipid mediators. SPMs possess stereochemically defined potent bioactive structures that are high-affinity ligands for cognate G protein-coupled surface receptors that evoke the cellular responses required for efficient resolution of acute inflammation. The SPMs biosynthesized from the major omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are coined Resolvins (resolution phase interaction products; E series and D-series), Protectins and Maresins (macrophage mediators in resolving inflammation). Their biosynthesis and stereochemical assignments are established and confirmed as well as their functional roles on innate immune cells and adaptive immune cells (both lymphocyte T-cell subsets and B-cells). The resolution of a protective acute inflammatory response is governed mainly by phagocytes that actively clear apoptotic cells, debris, blood clots and pathogens. These resolution phase functions of the acute inflammatory response are enhanced by SPMs, which together prepare the inflammatory loci for homeostasis and stimulate tissue regeneration via activating stem cells and the biosynthesis of novel cys-SPMs (e.g. MCTRs, PCTRs and RCTRs). These cys-SPMs also activate regeneration, are organ protective and stimulate resolution of local inflammation. Herein, we review the biosynthesis and functions of the E-series resolvins, namely resolvin E1 (the first n-3 resolvin identified), resolvin E2, resolvin E3 and resolvin E4 biosynthesized from their precursor eicosapentaenoic acid (EPA), and the critical role of total organic synthesis in confirming SPM complete stereochemistry, establishing their potent functions in resolution of inflammation, and novel structures. The physical properties of each biologically derived SPM, i.e., ultra-violet (UV) absorbance, chromatographic behavior, and tandem mass spectrometry (MS2) fragmentation, were matched to SPMs biosynthesized and prepared by stereospecific total organic synthesis. We briefly review this approach, also used with the endogenous D-series resolvins, protectins and maresins confirming their potent functions in resolution of inflammation, that paves the way for their rigorous evaluation in human tissues and clinical trials. The assignment of complete stereochemistry for each of the E and D series Resolvins, Protectins and Maresins was a critical and required step that enabled human clinical studies as in SPM profiling in COVID-19 infections and experimental animal disease models that also opened the promise of resolution physiology, resolution pharmacology and targeted precision nutrition as new areas for monitoring health and disease mechanisms.

1300

I115

Denise Goh1
Jeffrey Chun Tatt Lim1
Sonia Bilbao Fernández2
Justina Nadia Lee1
Craig Ryan Joseph1
Zhen Wei Neo1
Sílvia Guerrero2
Mai Chan Lau1
Joe Yeong Poh Sheng1

Persistence of residual SARS-CoV-2 viral antigen and RNA in tissues of patients with long COVID-19

https://doi.org/10.21203/rs.3.rs-1379777/v1

pre-print

22-Feb-22

Study

https://www.researchsquare.com/article/rs-1379777/new/v1

Since we have previously reported residual viral antigens in tissues of convalescent patients, we now aim to assess the presence of such antigens in post-convalescent tissues. Here, we established the presence of residual virus within the appendix and breast tissue of 2 patients who exhibited LC symptoms, 175 to 462 days upon positive diagnosis, using immunohistological techniques. We observed positive staining for viral nucleocapsid protein (NP) in the appendix, and tumour-adjacent region of the breast, but not within the tumour via multiplex immunohistochemistry. Notably, with RNAscope, both positive-sense and negative-sense (replicative intermediate) viral RNA were detected. As a single-stranded virus, SARS-CoV-2, have to produce a replicative intermediate as a template to synthesize new genomic RNAs. Thus, the detection of negative-sense viral RNA suggests ongoing viral replication. While viral RNA and antigen from gastrointestinal and stool samples of convalescent patients has been extensively reported, we believe this is the first study to detect viable virus. Furthermore, our positive finding in the breast tissue also corroborated with recent reports that immunocompromised patients had also experienced LC symptoms and persistent viral replication. Overall, our findings, along with emerging LC studies, question the possibility of the gastrointestinal tract functioning as a reservoir.

1301

I116

Daniel Ayoubkhani, View ProfileMatthew L Bosworth, Sasha King, View ProfileKoen B Pouwels, View ProfileMyer Glickman, View ProfileVahe Nafilyan, View ProfileFrancesco Zaccardi, View ProfileKamlesh Khunti, View ProfileNisreen A Alwan, View ProfileAnn Sarah Walker

Risk of Long Covid in people infected with SARS-CoV-2 after two doses of a COVID-19 vaccine: community-based, matched cohort study

https://doi.org/10.1101/2022.02.23.22271388

pre-print

24-Feb-22

Study

https://www.medrxiv.org/content/10.1101/2022.02.23.22271388v1

Participants who were double-vaccinated ≥14 days before infection were 1:1 propensity-score matched, based on socio-demographic characteristics and time from infection to follow-up for Long Covid, to those unvaccinated at time of infection. We estimated adjusted odds ratios (aOR) of Long Covid symptoms ≥12 weeks post-infection, comparing double-vaccinated with unvaccinated (reference group) participants. Results: The study sample comprised 3,090 double-vaccinated participants (mean age 49 years, 54% female, 92% white, median follow-up from infection 96 days) and matched control participants. Long Covid symptoms were reported by 294 double-vaccinated participants (prevalence 9.5%) compared with 452 unvaccinated participants (14.6%), corresponding to an aOR for Long Covid symptoms of 0.59 (95% CI: 0.50 to 0.69). There was no evidence of heterogeneity by adenovirus vector versus messenger ribonucleic acid vaccines (p=0.25). Conclusions: COVID-19 vaccination is associated with reduced risk of Long Covid, emphasising the need for public health initiatives to increase population-level vaccine uptake. Longer follow-up is needed, as is the assessment of further vaccine doses and the Omicron variant.

1302

I117

Tomonari Sumi, Kouji Harada

Immune Response To SARS-Cov-2 In Severe And Long COVID-19

https://doi.org/10.21203/rs.3.rs-1348061/v1

pre-print

17-Feb-22

Article

https://www.researchsquare.com/article/rs-1348061/v1

Here, we developed a mathematical model of the immune response to SARS-CoV-2 and revealed that typical age-related risk factors such as only a several 10 % decrease in innate immune cell activity and inhibition of type-I interferon signaling by autoantibodies drastically increased the viral load. It was reported that the numbers of certain dendritic cell subsets remained less than half those in healthy donors even seven months after infection. Hence, the inflammatory response was ongoing. Our model predicted the persistent DC reduction and showed that certain patients with severe and even mild symptoms could not effectively eliminate the virus and could potentially develop long COVID.

1303

I118

Elisabeth Mahase

Covid-19: Vaccinated people are less likely to get long covid, review finds

https://doi.org/10.1136/bmj.o407

Published

16-Feb-22

Article

https://www.bmj.com/content/376/bmj.o407.short

People who had been fully vaccinated against covid-19 were around half as likely to develop long covid symptoms as people who had received only one vaccine dose or were unvaccinated, the UK Health Security Agency has said.1
The agency conducted a rapid review of evidence, including 15 UK and international studies up to January 2022. Being vaccinated was defined as having two doses of the Pfizer-BioNTech, Oxford-AstraZeneca, or Moderna vaccine or one dose of the Janssen vaccine.
The review found that vaccine effectiveness against most post-covid symptoms in adults was highest in people over 60 and lowest in those aged 19 to 35.
Around 2% of the UK population have reported symptoms of long covid (or “post-covid syndrome”), which can last for more than four weeks after the initial SARS-CoV-2 infection. The most common symptoms are fatigue, shortness of breath, and muscle or joint pain.

1304

I119

Panagiotis Giannos,Konstantinos Prokopidis

Gut dysbiosis and long COVID-19: Feeling gutted

https://doi.org/10.1002/jmv.27684

Published

28-Feb-22

Article

https://onlinelibrary.wiley.com/doi/10.1002/jmv.27684

Emerging evidence has suggested that the pathology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may in part be explained by microbial species,1 contributing to the inflammatory phenotype commonly seen in patients with coronavirus disease (COVID-19).2, 3 Indeed, dysbiosis of the gut microbiota has been associated with poor clinical outcomes in mechanically ventilated COVID-19 patients. Specifically, Wu et al. observed elevated Granulicatella and Rothia mucilaginosa in the gut microbiome of COVID-19 hospitalized patients when compared to healthy individuals.4 Additionally, increased Burkholderia cepacia complex, Staphylococcus epidermidis, Mycoplasma hominis, and Mycroplasma orale species have been observed in severely ill COVID-19 patients as opposed to mildly affected ones.5 These findings hint at a possible yet prominent link between gut microbiota and SARS-CoV-2 repercussions, which may also be related to the imminent occurrence of long-term COVID-19 complications.
Contemporary research has revealed a disruption of the gut microbiota in stool samples of SARS-CoV-2 patients that may explain the well-described cytokine storm-induced ramifications post-infection.6 Interestingly, fecal transplantation may regenerate gut microbiota diversity, bolstering the respiratory system of patients suffering from COVID-19.7 Considering that long-term complications following recovery from SARS-CoV-2 persistently exhibit a damaged microbial microenvironment compared to uninfected controls,8 these changes may hint at alterations in the patients' microbiome. We describe recently published data on the relationship of the long COVID-19 phenomenon with gut microbiota dysbiosis, providing a mechanistic insight. Our aim is to raise awareness of the impact SARS-CoV-2 imposes on public health that in part may be explained through a gut-lung axis cascade.
The depletion of immunomodulatory microbiota from severe SARS-CoV-2 infection may prolong physiological repercussions (i.e., lung injury) during long COVID-19, induced by systemic inflammation.9 The recent study by Chen et al. showed significant reductions of microbial diversity in patients with COVID-19 during a 6-month follow-up, as opposed to the aseptic group.10 Particularly, following acute (30 days) and prolonged (3 months) SARS-CoV-2 recovery, suppression of anti-inflammatory bacteria such as Faecalibacterium prausnitzii, Eubacterium rectale, and Bifidobacterium adolescentis, and enrichment of pathogens, including Rothia, Erysipelatoclostridium, Ruminococcus gnavus, Ruminococcus torques, and Bacteroides dorei have been observed.8, 11 These changes may underlie the association between lower gut microbiota diversity and higher C-reactive protein levels in long COVID-19 patients (Figure 1).

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I120

Yasue Sakurada 1,Naruhiko Sunada 1,Hiroyuki Honda 1,Kazuki Tokumasu 1,Yuki Otsuka 1 ,Yasuhiro Nakano 1 ,Yoshihisa Hanayama 1,Masanori Furukawa 2,Hideharu Hagiya 1 andFumio Otsuka

Serial Changes of Long COVID Symptoms and Clinical Utility of Serum Antibody Titers for Evaluation of Long COVID

https://doi.org/10.3390/jcm11051309

Published

27-Feb-22

Study

https://www.mdpi.com/2077-0383/11/5/1309/htm

In February 2021, we established an outpatient clinic in a university hospital for patients with long COVID and started medical treatment for sequelae that persisted one month or more after infection. Methods: To determine the key factors that affect the onset and clinical course of sequelae, a retrospective analysis was performed at Okayama University Hospital (Japan) between February and July 2021. We focused on changes in the numbers of symptoms and the background of the patients during a three-month period from the first outpatient visit. We also examined the relationship with SARS-CoV-2 antibody titers. Results: Information was obtained from medical records for 65 patients. The symptoms of sequelae were diverse, with more than 20 types. The most frequent symptoms were general malaise, dysosmia, dysgeusia, sleeplessness, and headache. These symptoms improved in about 60% of the patients after 3 months. Patients who required hospitalization and had a poor condition in the acute phase and patients who received oxygen/dexamethasone therapy had higher antibody titers at the time of consultation. Patients with antibody titers ≥200 U/mL showed significantly fewer improvements in long COVID symptoms in 1 month, but they showed improvements at 3 months after the first visit. Conclusion: Long COVID symptoms were improved at 3 months after the initial visit in more than half of the patients. Serum antibody titers were higher in patients who experienced a severe acute phase, but the serum antibody titers did not seem to be directly related to the long-term persistence of long COVID symptoms.

1306

I121

Daniel Ayoubkhani, View ProfileMatthew L. Bosworth, Sasha King, View ProfileKoen B. Pouwels, View ProfileMyer Glickman, View ProfileVahé Nafilyan, View ProfileFrancesco Zaccardi, View ProfileKamlesh Khunti, View ProfileNisreen A. Alwan, View ProfileA. Sarah Walker

Risk of Long Covid in people infected with SARS-CoV-2 after two doses of a COVID-19 vaccine: community-based, matched cohort study

https://doi.org/10.1101/2022.02.23.22271388

pre-print

24-Feb-22

Study

https://www.medrxiv.org/content/10.1101/2022.02.23.22271388v1.full-text

Background It is unclear whether receiving two COVID-19 vaccinations before SARS-CoV-2 infection reduces the risk of developing Long Covid symptoms. We examined whether the likelihood of symptoms 12 weeks after infection differed by vaccination status.
Methods We included COVID-19 Infection Survey participants aged 18-69 years who tested positive for SARS-CoV-2 between 26 April 2020 and 30 November 2021; we excluded participants who, before their first test-confirmed infection, had suspected COVID-19 or Long Covid symptoms, or were single-vaccinated. Participants who were double-vaccinated ≥14 days before infection were 1:1 propensity-score matched, based on socio-demographic characteristics and time from infection to follow-up for Long Covid, to those unvaccinated at time of infection. We estimated adjusted odds ratios (aOR) of Long Covid symptoms ≥12 weeks post-infection, comparing double-vaccinated with unvaccinated (reference group) participants.
Results The study sample comprised 3,090 double-vaccinated participants (mean age 49 years, 54% female, 92% white, median follow-up from infection 96 days) and matched control participants. Long Covid symptoms were reported by 294 double-vaccinated participants (prevalence 9.5%) compared with 452 unvaccinated participants (14.6%), corresponding to an aOR for Long Covid symptoms of 0.59 (95% CI: 0.50 to 0.69). There was no evidence of heterogeneity by adenovirus vector versus messenger ribonucleic acid vaccines (p=0.25).
Conclusions COVID-19 vaccination is associated with reduced risk of Long Covid, emphasising the need for public health initiatives to increase population-level vaccine uptake. Longer follow-up is needed, as is the assessment of further vaccine doses and the Omicron variant.

1307

I122

Xu-Rui Shen, Rong Geng, Qian Li, Ying Chen, Shu-Fen Li, Qi Wang, Juan Min, Yong Yang, Bei Li, Ren-Di Jiang, Xi Wang, Xiao-Shuang Zheng, Yan Zhu, Jing-Kun Jia, Xing-Lou Yang, Mei-Qin Liu, Qian-Chun Gong, Yu-Lan Zhang, Zhen-Qiong Guan, Hui-Ling Li, Zhen-Hua Zheng, Zheng-Li Shi, Hui-Lan Zhang, Ke Peng & Peng Zhou

ACE2-independent infection of T lymphocytes by SARS-CoV-2

https://doi.org/10.1038/s41392-022-00919-x

Published

11-Mar-22

Study

https://www.nature.com/articles/s41392-022-00919-x

SARS-CoV-2 induced marked lymphopenia in severe patients with COVID-19. However, whether lymphocytes are targets of viral infection is yet to be determined, although SARS-CoV-2 RNA or antigen has been identified in T cells from patients. Here, we confirmed that SARS-CoV-2 viral antigen could be detected in patient peripheral blood cells (PBCs) or postmortem lung T cells, and the infectious virus could also be detected from viral antigen-positive PBCs. We next prove that SARS-CoV-2 infects T lymphocytes, preferably activated CD4 + T cells in vitro. Upon infection, viral RNA, subgenomic RNA, viral protein or viral particle can be detected in the T cells. Furthermore, we show that the infection is spike-ACE2/TMPRSS2-independent through using ACE2 knockdown or receptor blocking experiments. Next, we demonstrate that viral antigen-positive T cells from patient undergone pronounced apoptosis. In vitro infection of T cells induced cell death that is likely in mitochondria ROS-HIF-1a-dependent pathways. Finally, we demonstrated that LFA-1, the protein exclusively expresses in multiple leukocytes, is more likely the entry molecule that mediated SARS-CoV-2 infection in T cells, compared to a list of other known receptors. Collectively, this work confirmed a SARS-CoV-2 infection of T cells, in a spike-ACE2-independent manner, which shed novel insights into the underlying mechanisms of SARS-CoV-2-induced lymphopenia in COVID-19 patients.

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Tomoya Tsuchida,Masanori Hirose,Yoko Inoue,Hiroyuki Kunishima,Takehito Otsubo,Takahide Matsuda

Relationship between changes in symptoms and antibody titers after a single vaccination in patients with Long COVID

https://doi.org/10.1002/jmv.27689

Published

2-Mar-22

Study

https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.27689

This study evaluated postvaccination changes in symptoms and antibody titers in patients with Long COVID. Patients visiting the outpatient department specializing in Long COVID at our hospital were enrolled. Changes in symptoms were evaluated before and 14–21 days after first vaccination. Antibody titers were measured using ARCHITECT SARS-CoV-2 IgG II Quant at the same time. This study included 42 patients (median age: 45 years; 17 [40.5%] men). Median pre- and postvaccination antibody titers were 456 and 28,963 AU/ml, respectively. Postvaccination symptoms (fatigue, joint pain, and taste and olfactory abnormalities) were relieved, worsened, and unchanged in 7 (16.7%), 9 (21.4%), and 26 (61.9%) patients, respectively. Ratios of pre- and postvaccination antibody titers were 53, 40, and 174 in the unchanged, relief, and worsened groups, respectively. The worsened group had the significantly highest antibody titer ratio (p = 0.02). The higher increased rate of the antibody titer in the worsened group than in the nonworsened group suggests an excessive immune response to vaccination associated with worsening of sequelae. Although patients with Long COVID should be vaccinated, additional concerns should be addressed.

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Francisco Tejerina, Pilar Catalan, Cristina Rodriguez-Grande, Javier Adan, Carmen Rodriguez-Gonzalez, Patricia Muñoz, Teresa Aldamiz, Cristina Diez, Leire Perez, Chiara Fanciulli, Dario Garcia de Viedma

Post-COVID-19 syndrome. SARS-CoV-2 RNA detection in plasma, stool, and urine in patients with persistent symptoms after COVID-19

https://doi.org/10.1186/s12879-022-07153-4

Published

3-Mar-22

Study

https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-022-07153-4

Methods
We evaluated patients with symptoms that persisted for at least 4 weeks after COVID-19. Epidemiological and clinical data were collected. Blood tests, including inflammatory markers, were conducted, and imaging studies made if deemed necessary. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription polymerase chain reaction (RT-PCR) in plasma, stool, and urine were performed. Patients were offered antiviral treatment (compassionate use).
Results
We evaluated 29 patients who reported fatigue, muscle pain, dyspnea, inappropriate tachycardia, and low-grade fever. Median number of days from COVID-19 to positive RT-PCR in extra-respiratory samples was 55 (39–67). Previous COVID-19 was mild in 55% of the cases. Thirteen patients (45%) had positive plasma RT-PCR results and 51% were positive in at least one RT-PCR sample (plasma, urine, or stool). Functional status was severely reduced in 48% of the subjects. Eighteen patients (62%) received antiviral treatment. Improvement was seen in most patients (p = 0.000) and patients in the treatment group achieved better outcomes with significant differences (p = 0.01).
Conclusions
In a cohort of COVID-19 patients with persistent symptoms, 45% of them have detectable plasma SARS-CoV-2 RNA. Our results indicate possible systemic viral persistence in these patients, who may benefit of antiviral treatment strategies.

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ES

MIRIAM MERAD CATHERINE A. BLISH FEDERICA SALLUSTO AND AKIKO IWASAKI

The immunology and immunopathology of COVID-19

https://doi.org/10.1126/science.abm8108

Published

10-Mar-22

Review

https://www.science.org/doi/full/10.1126/science.abm8108

Considerable research effort has been made worldwide to decipher the immune response triggered upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, identify the drivers of severe and fatal COVID-19, and understand what leads to the prolongation of symptoms after disease resolution. We review the results of almost 2 years of COVID-19 immunology research and discuss definitive findings and remaining questions regarding our understanding of COVID-19 pathophysiology. We discuss emerging understanding of differences in immune responses seen in those with and without Long Covid syndrome, also known as post-acute sequelae of SARS-CoV-2. We hope that the knowledge gained from this COVID-19 research will be applied in studies of inflammatory processes involved in critical and chronic illnesses, which remain a major unmet need.

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Yaniv Lustig, Ph.D, Ella Mendelson, Ph.D, Michal Mandelboim, Ph.D, Asaf Biber, MD, Einav G Levin, MD, Carmit Cohen, DVM, Ph.D, Gili Regev-Yochay, MD, Eli Schwartz

Existence of immunological memory response in true sero-negative individuals post COVID-19 molecular diagnosis

https://doi.org/10.1093/cid/ciac196

Published

10-Mar-22

Study

https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac196/6546613

Approximately 1-8% of individuals do not develop antibodies following SARS-CoV-2 infection (sero-negatives). One BNT162b2 dose resulted in potent humoral response in 14 sero-negatives and 15 sero-positives, significantly higher than the response of 15 naïve-individuals, to two doses suggesting that COVID-19 provoked a memory response in individuals without detectable antibodies.

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Zheng Quan Toh, PhD1,2; Jeremy Anderson, BSc1,2; Nadia Mazarakis, PhD1; Melanie Neeland, PhD1,2; Rachel A. Higgins, BBiomed1; Karin Rautenbacher, BAppSc3; Kate Dohle, BSc1; Jill Nguyen, BSc1; Isabella Overmars, MPH1; Celeste Donato, PhD1,2; Sohinee Sarkar, PhD1,2; Vanessa Clifford, PhD4; Andrew Daley, PhD4; Suellen Nicholson, BSc5; Francesca L. Mordant, MSc6; Kanta Subbarao, MBBS6,7; David P. Burgner, PhD1,2,4; Nigel Curtis, MD1,2,4; Julie E. Bines, MD1,2,8; Sarah McNab, MD1,4; Andrew C. Steer, PhD1,2,4; Kim Mulholland, MD1,2,9; Shidan Tosif, PhD1,2,4; Nigel W. Crawford, MD1,2,4; Daniel G. Pellicci, PhD1,2,6; Lien Anh Ha Do, PhD1,2; Paul V. Licciardi, PhD1,2

Comparison of Seroconversion in Children and Adults With Mild COVID-19

https://doi.org/10.1001/jamanetworkopen.2022.1313

Published

9-Mar-22

Study

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2789845

Question - What proportion of children with mild SARS-CoV-2 infection undergo seroconversion compared with adults?
Findings In this cohort study of 57 children and 51 adults, the proportion of children with seroconversion to SARS-CoV-2 was half that found in adults despite similar viral load.
Meaning - These findings suggest that serology may provide a less reliable marker of prior SARS-CoV-2 infection in children and support strategies to protect children against COVID-19, including vaccination.
Abstract
Importance The immune response in children with SARS-CoV-2 infection is not well understood.
Objective - To compare seroconversion in nonhospitalized children and adults with mild SARS-CoV-2 infection and identify factors that are associated with seroconversion.
Design, Setting, and Participants - This household cohort study of SARS-CoV-2 infection collected weekly nasopharyngeal and throat swabs and blood samples during the acute (median, 7 days for children and 12 days for adults [IQR, 4-13] days) and convalescent (median, 41 [IQR, 31-49] days) periods after polymerase chain reaction (PCR) diagnosis for analysis. Participants were recruited at The Royal Children’s Hospital, Melbourne, Australia, from May 10 to October 28, 2020. Participants included patients who had a SARS-CoV-2–positive nasopharyngeal or oropharyngeal swab specimen using PCR analysis.
Main Outcomes and Measures - SARS-CoV-2 immunoglobulin G (IgG) and cellular (T cell and B cell) responses in children and adults. Seroconversion was defined by seropositivity in all 3 (an in-house enzyme-linked immunosorbent assay [ELISA] and 2 commercial assays: a SARS-CoV-2 S1/S2 IgG assay and a SARS-CoV-2 antibody ELISA) serological assays.
Results - Among 108 participants with SARS-CoV-2–positive PCR findings, 57 were children (35 boys [61.4%]; median age, 4 [IQR, 2-10] years) and 51 were adults (28 women [54.9%]; median age, 37 [IQR, 34-45] years). Using the 3 established serological assays, a lower proportion of children had seroconversion to IgG compared with adults (20 of 54 [37.0%] vs 32 of 42 [76.2%]; P < .001). This result was not associated with viral load, which was similar in children and adults (mean [SD] cycle threshold [Ct] value, 28.58 [6.83] vs 24.14 [8.47]; P = .09). In addition, age and sex were not associated with seroconversion within children (median age, 4 [IQR, 2-14] years for both seropositive and seronegative groups; seroconversion by sex, 10 of 21 girls [47.6%] vs 10 of 33 boys [30.3%]) or adults (median ages, 37 years for seropositive and 40 years for seronegative adults [IQR, 34-39 years]; seroconversion by sex, 18 of 24 women [75.0%] vs 14 of 18 men [77.8%]) (P > .05 for all comparisons between seronegative and seropositive groups). Symptomatic adults had 3-fold higher SARS-CoV-2 IgG levels than asymptomatic adults (median, 227.5 [IQR, 133.7-521.6] vs 75.3 [IQR, 36.9-113.6] IU/mL), whereas no differences were observed in children regardless of symptoms. Moreover, differences in cellular immune responses were observed in adults compared with children with seroconversion.
Conclusions and Relevance - The findings of this cohort study suggest that among patients with mild COVID-19, children may be less likely to have seroconversion than adults despite similar viral loads. This finding has implications for future protection after SARS-CoV-2 infection in children and for interpretation of serosurveys that involve children. Further research to understand why seroconversion and development of symptoms are potentially less likely in children after SARS-CoV-2 infection and to compare vaccine responses may be of clinical and scientific importance.

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Jialu Huang 1,Yubo Ding 2,Jingwei Yao 2,Minghui Zhang 1,Yu Zhang 1,Zhuoyi Xie 1 andJianhong Zuo

Nasal Nanovaccines for SARS-CoV-2 to Address COVID-19

https://doi.org/10.3390/vaccines10030405

Published

8-Mar-22

Review

https://www.mdpi.com/2076-393X/10/3/405/htm

COVID-19 is still prevalent around the globe. Although some SARS-CoV-2 vaccines have been distributed to the population, the shortcomings of vaccines and the continuous emergence of SARS-CoV-2 mutant virus strains are a cause for concern. Thus, it is vital to continue to improve vaccines and vaccine delivery methods. One option is nasal vaccination, which is more convenient than injections and does not require a syringe. Additionally, stronger mucosal immunity is produced under nasal vaccination. The easy accessibility of the intranasal route is more advantageous than injection in the context of the COVID-19 pandemic. Nanoparticles have been proven to be suitable delivery vehicles and adjuvants, and different NPs have different advantages. The shortcomings of the SARS-CoV-2 vaccine may be compensated by selecting or modifying different nanoparticles. It travels along the digestive tract to the intestine, where it is presented by GALT, tissue-resident immune cells, and gastrointestinal lymph nodes. Nasal nanovaccines are easy to use, safe, multifunctional, and can be distributed quickly, demonstrating strong prospects as a vaccination method for SARS-CoV-2, SARS-CoV-2 variants, or SARS-CoV-n.
SARS-CoV-2 nasal vaccines are being developed, and nine of them are in clinical trials. SARS-CoV-2 vaccines include inactivated vaccines, live attenuated vaccines, protein subunit vaccines, nucleic acid vaccines, viral vector-based vaccines, and other vaccines [39]. Inactivated vaccines are prepared using chemical stress or heat stress. In the process of heat stress or chemical stress, inactivated vaccines may lose immunogenicity, so these vaccines often need to be mixed with adjuvants. So far, a total of 28 inactivated vaccines for SARS-CoV-2 have been recorded by the WHO, of which 17 have entered clinical trials, and only one inactivated nasal vaccine has entered a phase I trial (NCT04871737) [40]. Live attenuated vaccines are vaccines made by removing or attenuating parts of the virus. Live attenuated vaccines have appropriate immunogenicity, although live attenuated vaccines require a long time to construct a suitable attenuated virus strain, and the constructed virus strain may undergo virulence reversal at any time. Only eight live attenuated vaccines have been recorded by the WHO. Among the eight vaccines, two nasal vaccines have entered clinical trials (NCT04798001, NCT04619628). Due to the long development time, live attenuated vaccines are not the preferred vaccine for SARS-CoV-2. Viral vector-based vaccines, on the other hand, are vital in the development of SARS-CoV-2 vaccines. This method is to insert antigens into existing successful and safe viral vectors (adenovirus, HIV, etc.) and enter the host through the viral vectors. It is easy for the viral vector to enter the host, causing a stronger host immune response and cross-reaction. In total, 70 viral vector-based vaccines have been recorded by the WHO and 26 viral vector-based vaccines have entered clinical trials, three of which are nasal vaccines (ChiCTR2000037782, discontinued test NCT04679909, NCT04751682, NCT04954287). Nucleic acid vaccines directly introduce the exogenous gene (DNA or RNA), transferring the antigen protein to the host cell to produce the antigen through the expression system of the host cell. The antigens can be recognized by the host immune system to produce anti-SARS-CoV-2 antibodies to achieve the purpose of prevention and treatment. Nucleic acid vaccines can select antigenic determinants by modifying the target gene carried by the gene expression vector. Moreover, the vaccine recipients can benefit from long-term immunity once vaccinated. A total of 76 nucleic acid vaccines have been recorded by the WHO, of which 36 have entered clinical trials. Among them, nasal mRNA vaccines can induce strong mucosal immunity and systemic immunity [41,42]. Protein subunit vaccines are made from one or more immunologically active fragments of SARS-CoV-2. Protein subunit vaccines discard some of the epitopes of SARS-CoV-2, whose immune effect is low and improves the effective antigen utilization efficiency of SARS-CoV-2. It needs to be used together with an adjuvant. In total, 122 protein subunit vaccines have been recorded by the WHO, and 47 have entered clinical trials, including two kinds of nasal protein subunit vaccines (RPCEC0000, IRCT20201214049709N2). All the SARS-CoV-2 vaccines data are from the WHO [23].

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Morley D.Hollenberg123MurrayEpstein4

The innate immune response, microenvironment proteinases, and the COVID-19 pandemic: pathophysiologic mechanisms and emerging therapeutic targets

https://doi.org/10.1016/j.kisu.2021.12.001

Published

18-Mar-22

Review

https://www.sciencedirect.com/science/article/pii/S2157171621000630

The coronavirus disease 2019 (COVID-19) pandemic, causing considerable mortality and morbidity worldwide, has fully engaged the biomedical community in attempts to elucidate the pathophysiology of COVID-19 and develop robust therapeutic strategies. To this end, the predominant research focus has been on the adaptive immune response to COVID-19 infections stimulated by mRNA and protein vaccines and on the duration and persistence of immune protection. In contrast, the role of the innate immune response to the viral challenge has been underrepresented. This overview focuses on the innate immune response to COVID-19 infection, with an emphasis on the roles of extracellular proteases in the tissue microenvironment. Proteinase-mediated signaling caused by enzymes in the extracellular microenvironment occurs upstream of the increased production of inflammatory cytokines that mediate COVID-19 pathology. These enzymes include the coagulation cascade, kinin-generating plasma kallikrein, and the complement system, as well as angiotensin-generating proteinases of the renin–angiotensin system. Furthermore, in the context of several articles in this Supplement elucidating and detailing the trajectory of diverse profibrotic pathways, we extrapolate these insights to explore how fibrosis and profibrotic pathways participate importantly in the pathogenesis of COVID-19. We propose that the lessons garnered from understanding the roles of microenvironment proteinases in triggering the innate immune response to COVID-19 pathology will identify potential therapeutic targets and inform approaches to the clinical management of COVID-19. Furthermore, the information may also provide a template for understanding the determinants of COVID-19–induced tissue fibrosis that may follow resolution of acute infection (so-called “long COVID”), which represents a major new challenge to our healthcare systems.

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MaddalenaPeghin12MariaDe Martino3AlvisaPalese4ValentinaGerussi1GiuliaBontempo1ElenaGraziano12EricaVisintini4Denise D’Elia1FabianaDellai1FrancescoMarrella1MartinaFabris5FrancescoCurcio5AssuntaSartor5MiriamIsola3CarloTascini1

Post-COVID-19 syndrome and humoral response association after one year in vaccinated and unvaccinated patients

https://doi.org/10.1016/j.cmi.2022.03.016

Published

23-Mar-22

Study

https://www.sciencedirect.com/science/article/pii/S1198743X22001550

Objectives
To describe the impact of vaccination and the role of humoral responses on post-coronavirus disease 2019 (COVID-19) syndrome one year after the onset of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Methods
A prospective study. Interviews investigated post-COVID-19 syndrome 6 and 12 months after the disease onset of all adult in- and outpatients with COVID-19 attending Udine Hospital (March–May 2020). Vaccination status and two different serological assays to distinguish between response to vaccination (receptor-binding domain –RBD SARS-CoV-2 IgG) and/or natural infection (non-RBD- SARS-CoV-2 IgG) were also assessed.
Results
479 individuals (52.6% female, mean age 53 years) were interviewed 13.5 months (0.6 SD) after acute infection. Post-COVID-19 syndrome was observed in 47.2% (226/479) of patients after one year. There were no significant differences in the worsening of post-COVID 19 symptoms (22.7% vs 15.8%, p = 0.209) among vaccinated (n=132) and unvaccinated (n=347) patients. The presence of non-RBD SARS-CoV-2 IgG induced by natural infection showed a significant association with post-COVID-19 syndrome (OR 1.35, 95% CI 1.11–1.64, p = 0.003), and median non-RBD SARS-CoV-2 IgG titres were significantly higher in long-haulers than in patients without symptoms 22 (IQR 9.7–37.2) vs 14.1 (IQR 5.4–31.3) kAU/L, p = 0.009) after one year. In contrast, the presence of RBD SARS-CoV-2 IgG was not associated with the occurrence of post-COVID-19 syndrome (>2500 U/mL vs 0.9–2500 U/mL, OR 1.36, 95% CI 0.62–3.00, p = 0.441) and RBD SARS-CoV-2 IgG titres were similar in long-haulers than in patients without symptoms (50% values > 2500 U/mL vs 55.6% values > 2500 U/mL, p = 0.451)
Conclusions
The SARS-CoV-2 vaccination is not associated with the emergence of post-COVID-19 symptoms over one year after acute infection. The persistence of high serological titres response induced by natural infection but not by vaccination, may play a role in long-COVID-19.

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Miguel Galán1†, Lorena Vigón1†, Daniel Fuertes2, María Aránzazu Murciano-Antón3, Guiomar Casado-Fernández1, Susana Domínguez-Mateos3, Elena Mateos1,4, Fernando Ramos-Martín1, Vicente Planelles5, Montserrat Torres1, Sara Rodríguez-Mora1,4, María Rosa López-Huertas1,4*‡ and Mayte Coiras1

Persistent Overactive Cytotoxic Immune Response in a Spanish Cohort of Individuals With Long-COVID: Identification of Diagnostic Biomarkers

https://doi.org/10.3389/fimmu.2022.848886

Published

25-Mar-22

Study

https://www.frontiersin.org/articles/10.3389/fimmu.2022.848886/full?s=03

The underlying mechanisms for Long-COVID are still undefined, but a sustained inflammatory response caused by the persistence of SARS-CoV-2 in organ and tissue sanctuaries or resemblance with an autoimmune disease are within the most considered hypotheses. In this study, we analyzed the usefulness of several demographic, clinical, and immunological parameters as diagnostic biomarkers of Long-COVID in one cohort of Spanish individuals who presented signs and symptoms of this syndrome after 49 weeks post-infection, in comparison with individuals who recovered completely in the first 12 weeks after the infection. We determined that individuals with Long-COVID showed significantly increased levels of functional memory cells with high antiviral cytotoxic activity such as CD8+ TEMRA cells, CD8±TCRγδ+ cells, and NK cells with CD56+CD57+NKG2C+ phenotype. The persistence of these long-lasting cytotoxic populations was supported by enhanced levels of CD4+ Tregs and the expression of the exhaustion marker PD-1 on the surface of CD3+ T lymphocytes. With the use of these immune parameters and significant clinical features such as lethargy, pleuritic chest pain, and dermatological injuries, as well as demographic factors such as female gender and O+ blood type, a Random Forest algorithm predicted the assignment of the participants in the Long-COVID group with 100% accuracy. The definition of the most accurate diagnostic biomarkers could be helpful to detect the development of Long-COVID and to improve the clinical management of these patients.

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I132

Julien Ramillon, Xavier de Lamballerie, Olivier Robineau, Helene Blanché, Gianluca Severi, Mathilde Touvier, Marie Zins, Fabrice Carrat, View ProfileNathanaël Lapidus, the SAPRIS-SERO study group

Humoral response, associated symptoms and profile of patients infected by SARS-CoV-2 with taste or smell disorders in the SAPRIS multicohort study

https://doi.org/10.1101/2022.02.01.22270250

pre-print

2-Feb-22

Study

https://www.medrxiv.org/content/10.1101/2022.02.01.22270250v1.full

Objectives Taste or smell disorders have been reported as strongly associated with COVID-19 diagnosis. We aimed to identify subject characteristics, symptom associations, and humoral response intensity associated with taste or smell disorders.
Patients and methods We used data from SAPRIS, a study based on a consortium of five prospective cohorts gathering 279,478 participants in the French general population. In the analysis, we selected participants who were presumably infected by SARS-CoV-2 during the first epidemic wave.
Results The analysis included 3,439 patients with a positive ELISA-Spike. Sex (OR = 1.28 [95% CI 1.05-1.58] for women), smoking (OR = 1.54 [95% CI 1.13-2.07]), consumption of more than 2 drinks of alcohol a day (OR = 1.37 [95% CI 1.06-1.76]) were associated with a higher probability of taste or smell disorders. The relationship between age and taste or smell disorders was non-linear. Serological titers were associated with taste or smell disorders: OR = 1.31 [95% CI 1.26-1.36], OR = 1.37 [95% CI 1.33-1.42] and OR = 1.34 [95% CI 1.29-1.39] for ELISA-Spike, ELISA-Nucleocapsid and seroneutralization, respectively. Among participants with taste or smell disorders, 90% reported a wide variety of other symptoms whereas 10% reported no other symptom or only rhinorrhea.
Conclusion Among patients with a positive ELISA-Spike test, women, smokers and people drinking more than 2 drinks a day were more likely to develop taste or smell disorders. This symptom was strongly associated with a humoral response. The overwhelming majority of patients with taste or smell disorders experienced a wide variety of symptoms.

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I133

Edda Russo, Lavinia Curini, Alessio Fabbrizzi & Amedeo Amedei

SARS-CoV-2 and Microbiota

https://doi.org/10.1007/978-981-16-8957-4_14

Published

26-Mar-22

Article

https://link.springer.com/chapter/10.1007/978-981-16-8957-4_14

This infectious disease is triggered by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and at lung level, like as intestine, there are different bacterial populations, named microbiota, that have a significant influence on the host’s immunological homeostasis.
But, to date, our understanding of bacterial flora and its symbiotic connection with immunological processes in the context of SARS-CoV-2 is, however, incomplete. A disturbed bacterial flora combined with too many opportunistic infections can trigger a cascade of inflammatory reactions dysregulating the immune system and resulting in multi-organ damage.
The involvement of the lung and intestinal microbiota in immune regulation of SARS-CoV-2 infection via multiple pathways will be discussed in this chapter. In addition, diet and lifestyle have a huge impact on the microbiota-inflammation crosstalk affecting both frequency and timing of this viral infection. So, in the last section we focus on the microbiota function in COVID-19, with an emphasis on immunological activation by the lung and gut bacteria and potential future therapies based on probiotic administration, able to regulate the microbiota–immunity axis.

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LiGuoPhDab*GengWangMSabd*YemingWangMDe*QiaoZhangPhDa*LiliRenPhDab*XiaoyingGuPhDe*TingxuanHuangMSadJingchuanZhongMSaYingWangMSaXinmingWangMSaLixueHuangMDeLiuhuiXuBSaConghuiWangPhDaLanChenBSaXiaXiaoPhDaYanchunPengPhDfgJulian CKnightPhDghTaoDongPhDfg…JianweiWangPhDab†

SARS-CoV-2-specific antibody and T-cell responses 1 year after infection in people recovered from COVID-19: a longitudinal cohort study

https://doi.org/10.1016/S2666-5247(22)00036-2

Published

23-Mar-22

Study

https://www.sciencedirect.com/science/article/pii/S2666524722000362

Background
The memory immune response is crucial for preventing reinfection or reducing disease severity. However, the robustness and functionality of the humoral and T-cell response to SARS-CoV-2 remains unknown 12 months after initial infection. The aim of this study is to investigate the durability and functionality of the humoral and T-cell response to the original SARS-CoV-2 strain and variants in recovered patients 12 months after infection.
Methods
In this longitudinal cohort study, we recruited participants who had recovered from COVID-19 and who were discharged from the Wuhan Research Center for Communicable Disease Diagnosis and Treatment at the Chinese Academy of Medical Sciences, Wuhan, China, between Jan 7 and May 29, 2020. Patients received a follow-up visit between Dec 16, 2020, and Jan 27, 2021. We evaluated the presence of IgM, IgA, and IgG antibodies against the SARS-CoV-2 nucleoprotein, Spike protein, and the receptor-binding domain 12 months after initial infection, using ELISA. Neutralising antibodies against the original SARS-CoV-2 strain, and the D614G, beta (B.1.351), and delta (B.1.617.2) variants were analysed using a microneutralisation assay in a subset of plasma samples. We analysed the magnitude and breadth of the SARS-CoV-2-specific memory T-cell responses using the interferon γ (IFNγ) enzyme-linked immune absorbent spot (ELISpot) assay and intracellular cytokine staining (ICS) assay. The antibody response and T-cell response (ie, IFN-γ, interleukin-2 [IL-2], and tumour necrosis factor α [TNFα]) were analysed by age and disease severity. Antibody titres were also analysed according to sequelae symptoms.
Findings
We enrolled 1096 patients, including 289 (26·4%) patients with moderate initial disease, 734 (67·0%) with severe initial disease, and 73 (6·7%) with critical initial disease. Paired plasma samples were collected from 141 patients during the follow-up visits for the microneutralisation assay. PBMCs were collected from 92 of 141 individuals at the 12-month follow-up visit, of which 80 were analysed by ELISpot and 92 by ICS assay to detect the SARS-CoV-2-specific memory T-cell responses. N-IgG (899 [82·0%]), S-IgG (1043 [95·2%]), RBD-IgG (1032 [94·2%]), and neutralising (115 [81·6%] of 141) antibodies were detectable 12 months after initial infection in most individuals. Neutralising antibodies remained stable 6 and 12 months after initial infection in most individuals younger than 60 years. Multifunctional T-cell responses were detected for all SARS-CoV-2 viral proteins tested. There was no difference in the magnitude of T-cell responses or cytokine profiles in individuals with different symptom severity. Moreover, we evaluated both antibody and T-cell responses to the D614G, beta, and delta viral strains. The degree of reduced in-vitro neutralising antibody responses to the D614G and delta variants, but not to the beta variant, was associated with the neutralising antibody titres after SARS-CoV-2 infection. We also found poor neutralising antibody responses to the beta variant; 83 (72·2%) of 115 patients showed no response at all. Moreover, the neutralising antibody titre reduction of the recovered patient plasma against the delta variant was similar to that of the D614G variant and lower than that of the beta variant. By contrast, T-cell responses were cross-reactive to the beta variant in most individuals. Importantly, T-cell responses could be detected in all individuals who had lost the neutralising antibody response to SARS-CoV-2 12 months after the initial infection.
Interpretation
SARS-CoV-2-specific neutralising antibody and T-cell responses were retained 12 months after initial infection. Neutralising antibodies to the D614G, beta, and delta viral strains were reduced compared with those for the original strain, and were diminished in general. Memory T-cell responses to the original strain were not disrupted by new variants. This study suggests that cross-reactive SARS-CoV-2-specific T-cell responses could be particularly important in the protection against severe disease caused by variants of concern whereas neutralising antibody responses seem to reduce over time.
Evidence before this study
We searched PubMed on Nov 2, 2021, using the following search terms [(“SARS-CoV-2” OR “COVID-19” OR “Coronavirus Disease 2019 Virus” OR “2019 Novel Coronavirus”) AND (“Adaptive Immunity” OR “Adoptive Immunity” OR “Immunity, Cellular” OR “Cellular Immunity” OR “Humoral Immunity” OR “Immunity, Humoral”)], with no date or language restrictions, and identified 793 results. Studies identified by the search reported that SARS-CoV-2-specific antibodies gradually decreased over several months. However, analyses of lymphocytes from COVID-19-convalescent individuals indicate that B cells and CD4 or CD8 T cells play an important role in mediating memory responses after natural infection. Therefore, it is important to explore these pathways to improve vaccination efficacy. The longest study spanned 12 months. However, the characteristics of adaptive immunity in patients 12 months after they contracted COVID-19 was not well understood. Given the rapid emergence of variants of concern, the ability of immunological memory to protect previously infected individuals from new variants has been examined, but no firm conclusions were reached.
Added value of this study
To our knowledge, this is the first comprehensive evaluation on the durability and robustness of antibody and T-cell responses against the SARS-CoV-2 original strain and its variants in recovered patients 1 year after natural infection without repeat exposure or vaccination in Wuhan, China. Our findings show that robust antibody and T-cell immunity against SARS-CoV-2 is present in the majority of recovered patients 12 months after moderate-to-critical infection. Total SARS-CoV-2-specific T-cell responses remain effective against variants, but neutralising antibodies diminish by 12 months.
Implications of all the available evidence
These data have important implications for vaccine efficacy against SARS-CoV-2 variants; the presence of cellular immune responses to SARS-CoV-2 variants and patients who lost their neutralising antibody responses provide additional important information on broad B-cell and T-cell immunity for future vaccine strategies targeting SARS-CoV-2. In particular, when neutralising antibody responses are reduced, cross-reactive SARS-CoV-2-specific T-cell responses could be important in protection against severe disease caused by variants of concern. Continuous surveillance is required to assess the duration of infection-induced immunity and the antibody and T-cell responses to these variants.

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Jacek M.Witkowskia1TamasFulopbEwaBrylc

Immunosenescence and COVID-19

https://doi.org/10.1016/j.mad.2022.111672

Published

8-Apr-22

Article

https://www.sciencedirect.com/science/article/pii/S0047637422000549

Highlights
•Aging is associated with increasing severity and mortality rates of COVID-19.
•The ability of immune system to fight SARS-CoV-2 depends in part on immunosenescence and inflammaging.
•Immunosenescence and inflammaging are the consequence of prior challenges called immunobiography.
•SARS-CoV-2 infection bears on individual immunobiography and might accelerate immunosenescence.
Ageing is associated with modified function of both innate and adaptive immunity. It is believed that changes occurring in ageing immune system are responsible for increased severity and deadliness of COVID-19 in the elderly. Although supported by statistics and epidemiology, these finding do not compute at the mechanistic level as depending solely on chronological and biological ageing. The phenomena describing changes in the aging immune system are immunosenescence and inflammageing, which develop in time depending on challenges to the individual immune system (immunobiography). Thus, “richer” immunobiography (in addition to other factors, including genetic, epigenetics or metabolic) may adversely affect the reactivity to the SARS-CoV-2 not only at later decades of life, but also earlier, in young and middle-aged individuals. On the other hand, infection with SARS-CoV-2 is affecting the function of both innate and adaptive branches of the immune system, adding to the individual immunobiography. Summarizing, immunosenescence and inflammaging may aggravate, but also may be aggravated by SARS-CoV-2 infection.

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C Mohan Rao, Pragyan Rout, Ashwini P. Pattnaik, Nipa Singh, Aarthi Rajendran, Shubhransu Patro

The Microbial Profile and Resistance Pattern of Pathogens Isolated From Long COVID Pneumonia Patients and Their Correlation to Clinical Outcome: Our Experience From a Tertiary Care Hospital

https://doi.org/10.7759/cureus.23644

Published

30-Mar-22

Study

https://www.cureus.com/articles/90127-the-microbial-profile-and-resistance-pattern-of-pathogens-isolated-from-long-covid-pneumonia-patients-and-their-correlation-to-clinical-outcome-our-experience-from-a-tertiary-care-hospital

Background
Coronavirus disease 2019 (COVID-19) patients with persistent symptoms for at least four weeks in spite of being reverse transcriptase-polymerase chain reaction (RTPCR) negative for COVID infection are defined as long COVID (wherein pulmonary involvement is seen in a significant proportion of cases). The history of prolonged use of corticosteroids, broad-spectrum antibiotics, and associated comorbid conditions in these patients increases the possibility of infection with multidrug-resistant microbial strains. It may lead to a grave prognosis, hence appropriate microbiological evaluation and management at the earliest can have a better outcome.
Methods
A retrospective observational study was carried out among long COVID patients admitted to the Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India, a tertiary care hospital. Eighty-four patients admitted to the ICU or non-ICU ward in the hospital from April to October 2021 were included in the study. Antibiotics, as prescribed by our hospital antibiotic policy, were administered wherever required and were subsequently changed according to culture and sensitivity reports of the samples (sputum, endotracheal aspirates, or blood). An analysis of the antibiotic sensitivity patterns of the pathogens isolated was performed. The outcome after optimum medical management was assessed for survivors, discharge, or death.
Results
Out of the total of 84 patients, 41 samples (sputum, endotracheal aspirates or blood) were collected and sent for culture, of which 32 (78.1%) were found to be culture positive for pathogens. Among the pathogens isolated, there were 22 (69%) drug-resistant and 10 (31%) sensitive organisms. Among the 22 resistant pathogen isolates, 18 were Gram-negative species, the most common species being Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumanii; two were Gram-positive species, one each from Staphylococcus aureus and Enterococcus faecalis, and three were Candida tropicalis. Of five deaths reported among 22 cases with resistant isolates, extensively drug-resistant (XDR), multi-drug resistance (MDR), and pan drug resistance (PDR) strains were detected in three, one, and one cases, respectively, and were harboured by K. pneumoniae, P. aeruginosa, and A. baumanii. Of the total eight deaths, there were two deaths among the 43 patients who received an empiric antibiotic in the wards, and six deaths were reported in the ICU. Despite raised biomarkers of inflammation, comorbid illnesses, renal impairment, and immunocompromised states, there was 91% survival and discharge, which was statistically significant (p-value = 0.00).
Conclusion
To conclude, K. pneumoniae, P. aeruginosa, A. baumanii, C. tropicalis, S. aureus, and E. faecalis were the most commonly isolated organisms among long COVID pneumonia cases, of which some were MDR, PDR and XDR strains. Early microbiological evaluation with targeted, proper antimicrobial usage along with optimized medical management and, wherever needed, critical care support in the ICU may lead to a better prognostic outcome in those groups of patients.

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Rachel M. Gittelman,1 Enrico Lavezzo,2 Thomas M. Snyder,1 H. Jabran Zahid,3 Cara L. Carty,1 Rebecca Elyanow,1 Sudeb C. Dalai,1 Ilan Kirsch,1 Lance Baldo,1 Laura Manuto,2 Elisa Franchin,2 Claudia Del Vecchio,2 Monia Pacenti,4 Caterina Boldrin,4 Margherita Cattai,4 Francesca Saluzzo,5 Andrea Padoan,6 Mario Plebani,6 Fabio Simeoni,7 Jessica Bordini,8 Nicola I. Lorè,5 Dejan Lazarević,7 Daniela Maria Cirillo,5 Paolo Ghia,9 Stefano Toppo,2 Jonathan M. Carlson,3 Harlan S. Robins,1 Andrea Crisanti,10 and Giovanni Tonon7

Longitudinal analysis of T-cell receptor repertoires reveals shared patterns of antigen-specific response to SARS-CoV-2 infection

https://doi.org/10.1172/jci.insight.151849

Published

19-Apr-22

Study

https://insight.jci.org/articles/view/151849

T cells play a prominent role in orchestrating the adaptive immune response to viral diseases and are a key component in understanding variability in SARS-CoV-2 infection severity and immunity. How the T cell response to SARS-CoV-2 infection and vaccination relates to clinical presentation, other components of the immune response, and subsequent immunity remains poorly understood. A population-based swab survey of the municipality of Vo’, Italy, conducted after the initial SARS-CoV-2 outbreak, uncovered a high frequency of asymptomatic infected individuals and their role in transmission. We sampled the T-cell receptor repertoire structure of the entire Vo’ population 2 months after the initial survey and followed up positive cases at 9 and 15 months post infection. We found that 97.0% (98/101) of cases had elevated levels of T-cell receptors associated with SARS-CoV-2 antigens at 2 months. T-cell frequency (depth) was increased in individuals with more severe disease. Both depth and diversity (breadth) of the T-cell receptor repertoire were also positively associated with neutralizing antibody titers, driven mostly by helper CD4+ T cells directed towards antigens from spike protein. At the later time points, detection of SARS-CoV-2 associated T cells remained high, with 90.7% (78/96) and 86.2% (25/29) of individuals having detectable signal at 9 and 15 months, respectively. Notably, at 9 months, T-cell signal was detectable in 84.6% (22/26) of cases who were initially asymptomatic. Forty-three individuals had been vaccinated by month fifteen, all presenting with a positive T-cell signal and showing a significant increase in T cells, specifically directed against spike protein. Taken together, these results demonstrate the central role of the T-cell response in mounting a comprehensive immune defense against SARS-CoV-2 that persists out to 15 months.

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Rebecca Elyanow,1 Thomas M. Snyder,1 Sudeb C. Dalai,1 Rachel M. Gittelman,1 Jim Boonyaratanakornkit,2 Anna Wald,2 Stacy Selke,3 Mark H. Wener,2 Chihiro Morishima,3 Alexander L. Greninger,3 Michael Gale Jr.,4 Tien-Ying Hsiang,4 Lichen Jing,2 Michael R. Holbrook,5 Ian M. Kaplan,1 H. Jabran Zahid,6 Damon H. May,1 Jonathan M. Carlson,6 Lance Baldo,1 Thomas Manley,1 Harlan S. Robins,1 and David M. Koelle3

T-cell receptor sequencing identifies prior SARS-CoV-2 infection and correlates with neutralizing antibodies and disease severity

https://doi.org/10.1172/jci.insight.150070

Published

19-Apr-22

Study

https://insight.jci.org/articles/view/150070

BACKGROUND. Measuring the immune response to SARS-CoV-2 enables assessment of past infection and protective immunity. SARS-CoV-2 infection induces humoral and T-cell responses, but these responses vary with disease severity and individual characteristics.
METHODS. A T-cell receptor (TCR) immunosequencing assay was conducted using small-volume blood samples from 302 individuals recovered from COVID-19. Correlations between the magnitude of the T-cell response and neutralizing antibody (nAb) titers or indicators of disease severity were evaluated. Sensitivity of T-cell testing was assessed and compared to serologic testing.
RESULTS. SARS-CoV-2–specific T-cell responses were significantly correlated with nAb titers and clinical indicators of disease severity, including hospitalization, fever, and difficulty breathing. Despite modest declines in depth and breadth of T-cell responses during convalescence, high sensitivity was observed until at least 6 months after infection, with overall sensitivity ~5% greater than serology tests for identifying prior SARS-CoV-2 infection. Improved performance of T-cell testing was most apparent in recovered, non-hospitalized individuals sampled >150 days after initial illness, suggesting greater sensitivity than serology at later timepoints and in individuals with less severe disease. T-cell testing identified SARS-CoV-2 infection in 68% (55/81) of samples with undetectable nAb titers (<1:40) and in 37% (13/35) of samples negative by 3 antibody assays.
CONCLUSION. These results support TCR-based testing as a scalable, reliable measure of past SARS-CoV-2 infection with clinical value beyond serology.

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Xue Cao, Wenjuan Li, Ting Wang, Dongzhi Ran, Veronica Davalos, Laura Planas-Serra, Aurora Pujol, Manel Esteller, Xiaolin Wang & Huichuan Yu

Accelerated biological aging in COVID-19 patients

https://doi.org/10.1038/s41467-022-29801-8

Published

19-Apr-22

Article

https://www.nature.com/articles/s41467-022-29801-8

Chronological age is a risk factor for SARS-CoV-2 infection and severe COVID-19. Previous findings indicate that epigenetic age could be altered in viral infection. However, the epigenetic aging in COVID-19 has not been well studied. In this study, DNA methylation of the blood samples from 232 healthy individuals and 413 COVID-19 patients is profiled using EPIC methylation array. Epigenetic ages of each individual are determined by applying epigenetic clocks and telomere length estimator to the methylation profile of the individual. Epigenetic age acceleration is calculated and compared between groups. We observe strong correlations between the epigenetic clocks and individual’s chronological age (r > 0.8, p < 0.0001). We also find the increasing acceleration of epigenetic aging and telomere attrition in the sequential blood samples from healthy individuals and infected patients developing non-severe and severe COVID-19. In addition, the longitudinal DNA methylation profiling analysis find that the accumulation of epigenetic aging from COVID-19 syndrome could be partly reversed at late clinic phases in some patients. In conclusion, accelerated epigenetic aging is associated with the risk of SARS-CoV-2 infection and developing severe COVID-19. In addition, the accumulation of epigenetic aging from COVID-19 may contribute to the post-COVID-19 syndrome among survivors.

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AravindNatarajan12∗SoumayaZlitni12∗Erin F.Brooks2∗Summer E.Vance2∗AlexDahlen3HaleyHedlin3Ryan M.ParkAlvinHan4Danica T.Schmidtke4RenuVerma5Karen B.Jacobson5JulieParsonnet67Hector F.Bonilla6UpinderSingh5Benjamin A.Pinsky58Jason R.Andrews5PrasannaJagannathan46Ami S.Bhatt12

Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA suggest prolonged gastrointestinal infection

https://doi.org/10.1016/j.medj.2022.04.001

Published

13-Apr-22

Study

https://www.sciencedirect.com/science/article/pii/S2666634022001672

Highlights
1.Approximately half of COVID-19 patients shed fecal RNA in the week after infection
2.4% patients with COVID-19 shed fecal viral RNA 10 months after diagnosis.
3.Presence of fecal SARS-CoV-2 RNA is associated with gastrointestinal symptoms.
4.SARS-CoV-2 likely infects gastrointestinal tissue.
Abstract
Background
COVID-19 manifests with respiratory, systemic, and gastrointestinal (GI) symptoms.1,2 SARS-CoV-2 RNA is detected in respiratory and fecal samples, and recent reports demonstrate viral replication in both the lung and intestinal tissue.3–5 Although much is known about early fecal RNA shedding, little is known about the long term shedding, especially in those with mild COVID-19. Furthermore, most reports of fecal RNA shedding do not correlate these findings with GI symptoms.6
Methods
We analyze the dynamics of fecal RNA shedding up to 10 months after COVID-19 diagnosis in 113 individuals with mild to moderate disease. We also correlate shedding with disease symptoms.
Findings
Fecal SARS-CoV-2 RNA is detected in 49.2% [95% Confidence interval = 38.2%-60.3%] of participants within the first week after diagnosis. Whereas there was no ongoing oropharyngeal SARS-CoV-2 RNA shedding in subjects at and after 4 months, 12.7% [8.5%-18.4%] of participants continued to shed SARS-CoV-2 RNA in the feces at 4 months after diagnosis and 3.8% [2.0%-7.3%] shed at 7 months. Finally, we find that GI symptoms (abdominal pain, nausea, vomiting) are associated with fecal shedding of SARS-CoV-2 RNA.
Conclusions
The extended presence of viral RNA in feces, but not respiratory samples, along with the association of fecal viral RNA shedding with GI symptoms suggest that SARS-CoV-2 infects the GI tract, and that this infection can be prolonged in a subset of individuals with COVID-19.

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LeilaMobasheriaMohammad HosseinNasirpourbElhamMasoumicdAfsaneh FooladyAzarnaminyeMozhdehJafarifgSeyed-AlirezaEsmaeilifg

SARS-CoV-2 triggering autoimmune diseases

https://doi.org/10.1016/j.cyto.2022.155873

Published

20-Apr-22

Review

https://www.sciencedirect.com/science/article/pii/S1043466622000825

Highlight
•SARS-CoV-2, the cause of the pandemic coronavirus disease, causes dysregulation of an immune response.
•Infection of respiratory epithelium by virus triggers both innate and acquired immunity that led to the immune system's hyperactivation.
•Therefore, triggering chronic inflammation can contribute to autoimmune disease.
•Post-Covid-19 autoimmunity may be due to molecular mimicry, bystander activation of T cells, transient immunosuppression, and pro-inflammatory cytokines, which might complicate SARS-CoV-2 vaccination.
Autoimmunity, hyperstimulation of the immune system, can be caused by a variety of reasons. Viruses are thought to be important environmental elements that contribute to the development of autoimmune antibodies. It seems that viruses cause autoimmunity with mechanisms such as molecular mimicry, bystander activation of T cells, transient immunosuppression, and inflammation, which has also been seen in post-Covid-19 autoimmunity. Infection of respiratory epithelium by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) dysregulates the immune response, triggers both innate and acquired immunity that led to the immune system's hyperactivation, excessive cytokine secretion known as “cytokine storm,” and finally acute respiratory distress syndrome (ARDS) associated with high mortality. Any factor in the body that triggers chronic inflammation can contribute to autoimmune disease, which has been documented during the Covid-19 pandemic. It has been observed that some patients produce autoantibody and autoreactive CD4+ and CD8+ T cells, leading to the loss of self-tolerance. However, there is a scarcity of evidence defining the precise molecular interaction between the virus and the immune system to elicit autoreactivity. Here, we present a review of the relevant immunological findings in Covid-19 and the current reports of autoimmune disease associated with the disease.

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Fernández-de-las-Peñas C.a,b · Ryan-Murua P.c · Rodríguez-Jiménez J.a · Palacios-Ceña M.a · Arendt-Nielsen L.b,d · Torres-Macho J.c,e

Serological Biomarkers at Hospital Admission Are Not Related to Long-Term Post-COVID Fatigue and Dyspnea in COVID-19 Survivors

https://doi.org/10.1159/000524042

Published

5-Apr-22

Study

https://www.karger.com/Article/FullText/524042

Objective: The aim of this study was to investigate the association between serological biomarkers at the acute phase of infection at hospital admission with the development of long-term post-COVID fatigue and dyspnea. Methods: A cohort study including patients hospitalized due to COVID-19 in one urban hospital of Madrid (Spain) during the first wave of the outbreak (from March 20 to June 30, 2020) was conducted. Hospitalization data, clinical data, and eleven serological biomarkers were systematically collected at hospital admission. Patients were scheduled for an individual telephone interview after hospital discharge for collecting data about the presence of post-COVID fatigue and dyspnea. Results: A total of 412 patients (age: 62 years, standard deviation: 15 years; 47.5% women) were assessed with a mean of 6.8 and 13.2 months after discharge. The prevalence of post-COVID fatigue and dyspnea was 72.8% and 17.2% at 6 months and 45.4% and 13.6% at 12 months after hospital discharge, respectively. Patients exhibiting post-COVID fatigue at 6 or 12 months exhibited a lower hemoglobin level, higher lymphocyte count, and lower neutrophil and platelets counts (all, p < 0.05), whereas those exhibiting post-COVID dyspnea at 6 or 12 months had a lower platelet count and lower alanine transaminase, aspartate transaminase, and lactate dehydrogenase (LDH) levels (all, p < 0.05) than those not developing post-COVID fatigue or dyspnea, respectively. The multivariate regression analyses revealed that a lower platelet count and lower LDH levels were associated but just explaining 4.5% of the variance, of suffering from post-COVID fatigue and dyspnea, respectively. Conclusion: Some serological biomarkers were slightly different in patients exhibiting post-COVID fatigue or dyspnea, but they could not explain the long-COVID problems in those patients.

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Lucía Beltrán-Camacho, Sara Eslava-Alcón, Marta Rojas-Torres, Daniel Sánchez-Morillo, Mª Pilar Martinez-Nicolás, Victoria Martín-Bermejo, Inés García de la Torre, Esther Berrocoso, Juan Antonio Moreno, Rafael Moreno-Luna & Mª Carmen Durán-Ruiz

The serum of COVID-19 asymptomatic patients up-regulates proteins related to endothelial dysfunction and viral response in circulating angiogenic cells ex-vivo

https://doi.org/10.1186/s10020-022-00465-w

Published

9-Apr-22

Study

https://molmed.biomedcentral.com/articles/10.1186/s10020-022-00465-w

Background
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has already caused 6 million deaths worldwide. While asymptomatic individuals are responsible of many potential transmissions, the difficulty to identify and isolate them at the high peak of infection constitutes still a real challenge. Moreover, SARS-CoV-2 provokes severe vascular damage and thromboembolic events in critical COVID-19 patients, deriving in many related deaths and long-hauler symptoms. Understanding how these processes are triggered as well as the potential long-term sequelae, even in asymptomatic individuals, becomes essential.
Methods
We have evaluated, by application of a proteomics-based quantitative approach, the effect of serum from COVID-19 asymptomatic individuals over circulating angiogenic cells (CACs). Healthy CACs were incubated ex-vivo with the serum of either COVID-19 negative (PCR −/IgG −, n:8) or COVID-19 positive asymptomatic donors, at different infective stages: PCR +/IgG − (n:8) and PCR −/IgG + (n:8). Also, a label free quantitative approach was applied to identify and quantify protein differences between these serums. Finally, machine learning algorithms were applied to validate the differential protein patterns in CACs.
Results
Our results confirmed that SARS-CoV-2 promotes changes at the protein level in the serum of infected asymptomatic individuals, mainly correlated with altered coagulation and inflammatory processes (Fibrinogen, Von Willebrand Factor, Thrombospondin-1). At the cellular level, proteins like ICAM-1, TLR2 or Ezrin/Radixin were only up-regulated in CACs treated with the serum of asymptomatic patients at the highest peak of infection (PCR + /IgG −), but not with the serum of PCR −/IgG + individuals. Several proteins stood out as significantly discriminating markers in CACs in response to PCR or IgG + serums. Many of these proteins particiArticle title: Kindly check and confirm the edit made in the article title.pate in the initial endothelial response against the virus.
Conclusions
The ex vivo incubation of CACs with the serum of asymptomatic COVID-19 donors at different stages of infection promoted protein changes representative of the endothelial dysfunction and inflammatory response after viral infection, together with activation of the coagulation process. The current approach constitutes an optimal model to study the response of vascular cells to SARS-CoV-2 infection, and an alternative platform to test potential inhibitors targeting either the virus entry pathway or the immune responses following SARS-CoV-2 infection.

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Zhongfang Wang, Xiaoyun Yang, Xinyue Mei, Yumin Zhou, Zhiqiang Tang, Guichang Li, Jiaying Zhong, Mengqiu Yu, Mingzhu Huang, Xiaoling Su, Bijia Lin, Pengxing Cao, Ji Yang & Pixin Ran

SARS-CoV-2-specific CD4+ T cells are associated with long-term persistence of neutralizing antibodies

https://doi.org/10.1038/s41392-022-00978-0

Published

23-Apr-22

Study

https://www.nature.com/articles/s41392-022-00978-0

Understanding the decay and maintenance of long-term SARS-CoV-2 neutralizing antibodies in infected or vaccinated people and how vaccines protect against other SARS-CoV-2 variants is critical for assessing public vaccination plans. Here, we measured different plasm antibody levels 2 and 12 months after disease onset, including anti-RBD, anti-N, total neutralizing antibodies, and two neutralizing-antibody clusters. We found that total neutralizing antibodies declined more slowly than total anti-RBD and anti-N IgG, and the two neutralizing-antibody clusters decayed even more slowly than total neutralizing antibodies. Interestingly, the level of neutralizing antibodies at 12 months after disease onset was significantly lower than that at 2 months but more broadly neutralized SARS-CoV-2 variants, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Lambda (C.37). Significant immune escape by the Omicron variant (B.1.1.529) was also observed 2 months post-recovery. Furthermore, we revealed that a high percentage of virus-specific CD4+ T cells and cTfh1 were associated with a slower decline in humoral immunity, accompanied by higher levels of CXCR3 ligands such as CXCL9 and CXCL10, higher frequency of cTfh1, and lower levels of cTfh2 and cTfh17. Our data highlight the importance of coordinating T-cell and humoral immunity to achieve long-term protective immunity.

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RYAN W. NELSON YUEZHOU CHEN OLIVIA L. VENEZIARICHARD M. MAJERUS DANIEL S. SHIN MGH COVID-19 COLLECTION & PROCESSING TEAM†MARY N. CARRINGTON XU G. YU DUANE R. WESEMANN JAMES J. MOON AND ANDREW D. LUSTER

SARS-CoV-2 epitope-specific CD4+ memory T cell responses across COVID-19 disease severity and antibody durability

https://doi.org/10.1126/sciimmunol.abl9464

Published

21-Apr-22

Study

https://www.science.org/doi/10.1126/sciimmunol.abl9464

CD4+ T cells are central to long-term immunity against viruses through the functions of T helper-1 (Th1) and T follicular helper (Tfh) cell subsets. To better understand the role of these subsets in COVID-19 immunity, we conducted a longitudinal study of SARS-CoV-2-specific CD4+ T cell and antibody responses in convalescent subjects who seroconverted during the first wave of the pandemic in Boston, Massachusetts, United States, across a range of COVID-19 disease severities. Analyses of spike (S) and nucleocapsid (N) epitope-specific CD4+ T cells using peptide and major histocompatibility complex class II (peptide:MHCII) tetramers demonstrated expanded populations of T cells recognizing the different SARS-CoV-2 epitopes in most subjects compared to pre-pandemic controls. Individuals who experienced a milder disease course not requiring hospitalization had a greater percentage of circulating Tfh (cTfh) and Th1 cells among SARS-CoV-2-specific cells. Analysis of SARS-CoV-2-specific CD4+ T cells responses in a subset of individuals with sustained anti-S antibody responses following viral clearance also revealed an increased proportion of memory cTfh cells. Our findings indicate efficient early disease control also predicts favorable long-term adaptive immunity.

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Arezoo Faramarzi 1, Reza Safaralizadeh 1, Narges Dastmalchi 2, Shahram Teimourian 3

Epigenetic-related effects of COVID-19 on the human cells

https://doi.org/10.2174/1871526522666220420093029

Published

20-Apr-22

Article

https://pubmed.ncbi.nlm.nih.gov/35450534/

Epigenetics related to the various pathways which show long-term impacts on the gene expression patterns without alterations in nucleotide sequences. Over the last decade, epigenetics advanced significantly in the science of biology, oncology, innate immunity as well as pathogens and infectious diseases. In the present review, we aimed to review the relationships between covid19 and epigenetic alterations of the infected cells. Corona virus is one of the known infectious diseases causes respiratory infection, such as pneumonia, and coughing while in animal, it causes diarrhea and upper respiratory disorders. This virus could be transmitted human to human or human to animal with droplets, it translocate via membrane ACE-2 exopeptidase in to the host cells. In conclusion, hypomethylation of Angiotensin II Converting Enzyme (ACE II) possibly upregulates its expression, which will enhance the possibility of SARS-CoV-2 infection.

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Hussein Kadhem Al-Hakeim, Haneen Tahseen Al-Rubaye, Dhurgham Shihab Al-Hadrawi, Abbas F. Almulla, Michael Maes

Long-COVID post-viral chronic fatigue syndrome and affective symptoms are associated with oxidative damage, lowered antioxidant defenses and inflammation: a proof of concept and mechanism study

https://doi.org/10.1101/2022.04.25.22274251

pre-print

27-Apr-22

Study

https://www.medrxiv.org/content/10.1101/2022.04.25.22274251v1.full-text

The immune-inflammatory response during the acute phase of COVID-19, as assessed using peak body temperature (PBT) and peripheral oxygen saturation (SpO2), predicts the severity of chronic fatigue, depression and anxiety (“physio-affective”) symptoms three to four months later. The present study was performed to characterize whether the effects of SpO2 and PBT on the physio-affective phenome of Long COVID are mediated by immune, oxidative and nitrosative stress (IO&NS) pathways. This study assayed SpO2 and PBT during acute COVID-19, and C-reactive protein (CRP), malondialdehyde (MDA), protein carbonyls (PCs), myeloperoxidase (MPO), nitric oxide (NO), zinc, and glutathione peroxidase (Gpx) in 120 Long COVID individuals and 36 controls. Cluster analysis showed that 31.7% of the Long COVID patients had severe abnormalities in SpO2, body temperature, increased oxidative toxicity (OSTOX) and lowered antioxidant defenses (ANTIOX), and increased total Hamilton Depression (HAMD) and Anxiety (HAMA) and Fibromylagia-Fatigue (FF) scores. Around 60% of the variance in the physio-affective phenome of Long COVID (a factor extracted from HAMD, HAMA and FF scores) was explained by OSTOX/ANTIOX ratio, PBT and SpO2. Increased PBT predicted increased CRP and lowered ANTIOX and zinc levels, while lowered SpO2 predicted lowered Gpx and increased NO production. Both PBT and SpO2 strongly predict OSTOX/ATIOX during Long COVID. In conclusion, the impact of acute COVID-19 on the physio-affective symptoms of Long COVID is partly mediated by OSTOX/ANTIOX, especially lowered Gpx and zinc, increased MPO and NO production and lipid peroxidation-associated aldehyde formation. Post-viral physio-affective symptoms have an inflammatory origin and are partly mediated by neuro-oxidative toxicity.

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Bin Wang, Lei Zhang, Yongqiang Wang, Tong Dai, Ziran Qin, Fangfang Zhou & Long Zhang

Alterations in microbiota of patients with COVID-19: potential mechanisms and therapeutic interventions

https://doi.org/10.1038/s41392-022-00986-0

Published

29-Apr-22

Review

https://www.nature.com/articles/s41392-022-00986-0

The global coronavirus disease 2019 (COVID-19) pandemic is currently ongoing. It is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A high proportion of COVID-19 patients exhibit gastrointestinal manifestations such as diarrhea, nausea, or vomiting. Moreover, the respiratory and gastrointestinal tracts are the primary habitats of human microbiota and targets for SARS-CoV-2 infection as they express angiotensin-converting enzyme-2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) at high levels. There is accumulating evidence that the microbiota are significantly altered in patients with COVID-19 and post-acute COVID-19 syndrome (PACS). Microbiota are powerful immunomodulatory factors in various human diseases, such as diabetes, obesity, cancers, ulcerative colitis, Crohn’s disease, and certain viral infections. In the present review, we explore the associations between host microbiota and COVID-19 in terms of their clinical relevance. Microbiota-derived metabolites or components are the main mediators of microbiota-host interactions that influence host immunity. Hence, we discuss the potential mechanisms by which microbiota-derived metabolites or components modulate the host immune responses to SARS-CoV-2 infection. Finally, we review and discuss a variety of possible microbiota-based prophylaxes and therapies for COVID-19 and PACS, including fecal microbiota transplantation (FMT), probiotics, prebiotics, microbiota-derived metabolites, and engineered symbiotic bacteria. This treatment strategy could modulate host microbiota and mitigate virus-induced inflammation.

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Carlo Brogna 1,*,†,Barbara Brogna 2ORCID,Domenico Rocco Bisaccia 1,Francesco Lauritano 1,Giuliano Marino 3,Luigi Montano 4,Simone Cristoni 5,Marina Prisco 6ORCID andMarina Piscopo 6,*,†ORCID

Could SARS-CoV-2 Have Bacteriophage Behavior or Induce the Activity of Other Bacteriophages?

https://doi.org/10.3390/vaccines10050708

Published

29-Apr-22

Review

https://www.mdpi.com/2076-393X/10/5/708/htm

SARS-CoV-2 has become one of the most studied viruses of the last century. It was assumed that the only possible host for these types of viruses was mammalian eukaryotic cells. Our recent studies show that microorganisms in the human gastrointestinal tract affect the severity of COVID-19 and for the first time provide indications that the virus might replicate in gut bacteria. In order to further support these findings, in the present work, cultures of bacteria from the human microbiome and SARS-CoV-2 were analyzed by electron and fluorescence microscopy. The images presented in this article, in association with the nitrogen (15N) isotope-labeled culture medium experiment, suggest that SARS-CoV-2 could also infect bacteria in the gut microbiota, indicating that SARS-CoV-2 could act as a bacteriophage. Our results add new knowledge to the understanding of the mechanisms of SARS-CoV-2 infection and fill gaps in the study of the interactions between SARS-CoV-2 and non-mammalian cells. These findings could be useful in suggesting specific new pharmacological solutions to support the vaccination campaign.

1335

I150

Mari E. K. Niemi, Mark J. Daly & Andrea Ganna

The human genetic epidemiology of COVID-19

https://doi.org/10.1038/s41576-022-00478-5

Published

2-May-22

Review

https://www.nature.com/articles/s41576-022-00478-5

Human genetics can inform the biology and epidemiology of coronavirus disease 2019 (COVID-19) by pinpointing causal mechanisms that explain why some individuals become more severely affected by the disease upon infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Large-scale genetic association studies, encompassing both rare and common genetic variants, have used different study designs and multiple disease phenotype definitions to identify several genomic regions associated with COVID-19. Along with a multitude of follow-up studies, these findings have increased our understanding of disease aetiology and provided routes for management of COVID-19. Important emergent opportunities include the clinical translatability of genetic risk prediction, the repurposing of existing drugs, exploration of variable host effects of different viral strains, study of inter-individual variability in vaccination response and understanding the long-term consequences of SARS-CoV-2 infection. Beyond the current pandemic, these transferrable opportunities are likely to affect the study of many infectious diseases.

1336

I151

Cristina Cerrada-Romero, Judith Berastegui-Cabrera, Pedro Camacho-Martínez, Josune Goikoetxea-Aguirre, Patricia Pérez-Palacios, Sonia Santibáñez, María José Blanco-Vidal, Adoración Valiente, Jorge Alba, Regino Rodríguez-Álvarez, Álvaro Pascual, José Antonio Oteo, José Miguel Cisneros, Jerónimo Pachón, Inmaculada Casas-Flecha, Elisa Cordero, Francisco Pozo & Javier Sánchez-Céspedes

Excretion and viability of SARS-CoV-2 in feces and its association with the clinical outcome of COVID-19

https://doi.org/10.1038/s41598-022-11439-7

Published

5-May-22

Study

https://www.nature.com/articles/s41598-022-11439-7

The main objective was to evaluate the viability of the SARS-CoV-2 viral particles excreted in stools. In addition, we aimed to identify clinical factors associated with the detection of SARS-CoV-2 RNA in feces, and to determine if its presence is associated with an unfavorable clinical outcome, defined as intensive care unit (ICU) admission and/or death. A prospective multicenter cohort study of COVID-19 adult patients, with confirmed SARS-CoV-2 infection by RT-PCR assay in nasopharyngeal (NP) swabs admitted to four hospitals in Spain, from March 2020 to February 2021. Sixty-two adult COVID-19 patients had stool samples collected at admission and/or during the follow up, with a total of 79 stool samples. SARS-CoV-2 RNA was detected in stool samples from 27 (43.5%) out of the 62 patients. Replicative virus, measured by the generation of cytopathic effect in cell culture and subsequent RT-PCR confirmation of a decrease in the Ct values, was not found in any of these stool samples. Fecal virus excretion was not associated with the presence of gastrointestinal symptoms, or with differences in the evolution of COVID-19 patients. Our results suggest that SARS-CoV-2 replicative capacity is null or very limited in stool samples, and thus, the fecal–oral transmission of SARS-CoV-2 as an alternative infection route is highly unlikely. In our study, the detection of SARS-CoV-2 RNA in feces at the beginning of the disease is not associated with any clinical factor nor with an unfavorable clinical outcome.

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Dejan Jakimovski 1ORCID,Karen Zakalik 2,Samreen Awan 2,Katelyn S. Kavak 2,Penny Pennington 2,David Hojnacki 2,Channa Kolb 2,Alexis A. Lizarraga 2,Svetlana P. Eckert 2ORCID,Rosila Sarrosa 3,Kamath Vineetha 3,Keith Edwards 3 andBianca Weinstock-Guttman 2,*ORCID

COVID-19 Vaccination in Multiple Sclerosis and Inflammatory Diseases: Effects from Disease-Modifying Therapy, Long-Term Seroprevalence and Breakthrough Infections

https://doi.org/10.3390/vaccines10050695

Published

28-Apr-22

Study

https://www.mdpi.com/2076-393X/10/5/695/htm

Background: To determine the effect of disease-modifying therapies (DMT) on humoral postvaccine seroconversion, long-term humoral response, and breakthrough COVID-19 infections in persons with multiple sclerosis (PwMS) and other neuroinflammatory disorders. Methods: A total of 757 PwMS and other neuroinflammatory disorders were recruited in two MS centers and vaccinated with one of the FDA-approved vaccines (BNT162b2, mRNA-1273, Ad26.COV2.S). The primary outcomes are the rate of humoral postvaccine seroconversion and anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) immunoglobulin G (IgG) differences between patients on different DMTs. Secondary measures include breakthrough infections and humoral response after six months. Other outcomes include differences in vaccine response between SARS-CoV-2 vaccines and the effects of age and comorbidities on the vaccine response. Results: A total of 465 (68.4%) PwMS and 55 (74.3%) patients with neuroinflammatory diseases were seropositive at 4–12 weeks after vaccination. A significant difference in seroconversion based on the DMT used at the time of vaccination (p < 0.001) was observed, with the lowest rates seen in patients treated with anti-CD20 antibodies (23.2%) and sphingosine-1-phosphate modulators (S1P) (30.8%). In seropositive patients, there was a significant decrease in anti-SARS IgG from mean 20.0 to 4.7 at six months (p = 0.004). Thirty-nine patients had breakthrough infection, but only two seronegative patients required hospitalization. mRNA vaccines resulted in significantly greater seroconversion compared to Ad26.COV2.S (p < 0.001). Older age and presence of cardiovascular comorbidities were associated with lower anti-SARS IgG (p = 0.021 and p = 0.003, respectively) Conclusions: PwMS and neuroinflammatory disorders treated with anti-CD20 and S1P medications have lower humoral response after anti-SARS-CoV-2 vaccination, even after booster dose. Waning of the humoral response puts vaccinated PwMS at a greater risk of COVID-19 breakthrough.

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Hussein Kadhem Al-Hakeim1 Haneen Tahseen Al-Rubaye2
Dhurgham Shihab Al-Hadrawi3 Abbas F. Almulla4 Michael Maes5

Long-COVID post-viral chronic fatigue and affective symptoms are associated with oxidative damage, lowered antioxidant defenses and inflammation: a proof of concept and mechanism study.

https://doi.org/10.21203/rs.3.rs-1610917/v1

pre-print

2-May-22

Study

https://www.researchsquare.com/article/rs-1610917/v1

The immune-inflammatory response during the acute phase of COVID-19, as assessed using peak body temperature (PBT) and peripheral oxygen saturation (SpO2), predicts the severity of chronic fatigue, depression and anxiety (“physio-affective”) symptoms three to four months later. The present study was performed to characterize whether the effects of SpO2 and PBT on the physio-affective phenome of Long COVID are mediated by immune, oxidative and nitrosative stress (IO&NS) pathways. This study assayed SpO2 and PBT during acute COVID-19, and C-reactive protein (CRP), malondialdehyde (MDA), protein carbonyls (PCs), myeloperoxidase (MPO), nitric oxide (NO), zinc, and glutathione peroxidase (Gpx) in 120 Long COVID individuals and 36 controls. Cluster analysis showed that 31.7% of the Long COVID patients had severe abnormalities in SpO2, body temperature, increased oxidative toxicity (OSTOX) and lowered antioxidant defenses (ANTIOX), and increased total Hamilton Depression (HAMD) and Anxiety (HAMA) and Fibromylagia-Fatigue (FF) scores. Around 60% of the variance in the physio-affective phenome of Long COVID (a factor extracted from HAMD, HAMA and FF scores) was explained by OSTOX/ANTIOX ratio, PBT and SpO2. Increased PBT predicted increased CRP and lowered ANTIOX and zinc levels, while lowered SpO2 predicted lowered Gpx and increased NO production. Both PBT and SpO2 strongly predict OSTOX/ATIOX during Long COVID. In conclusion, the impact of acute COVID-19 on the physio-affective symptoms of Long COVID is partly mediated by OSTOX/ANTIOX, especially lowered Gpx and zinc, increased MPO and NO production and lipid peroxidation-associated aldehyde formation. Post-viral physio-affective symptoms have an inflammatory origin and are partly mediated by neuro-oxidative toxicity.

1339

I154

Ibrahim Shnawa

Postinfection-Postvaccination autoimmune neural long covid

http://dx.doi.org/10.9734/jpri/2022/v34i36A36175

Published

2-May-22

Article

https://www.researchgate.net/publication/360317846_Postinfection-Postvaccination_autoimmune_neural_long_covid

Normal human subject can have baseline auto-antibodies and auto-reactive immune cells constituting the normal physiological autoimmune state. On, post- sars-cov-2 infection and post-vaccination periods either the virus built in spike protein in case of post-infection . Or the peptide expressed from the spike protein sequence within the human COVID -19 mRNA vaccines have an auto-reacting epitopes within the human vaccinee cells. Both of the virus spike protein and vaccinee cells are bearing either pan-sharing molecular mimicking or mono-specific molecular mimicking epitopes that initiate on continual exposure to the immune system cells mediating an autoimmune responses. Such responses may cause an immune conversion of the antibody and /or auto-reactive immune cells levels from the baseline limits to the clinically indicative levels of auto-antibody and/or auto-reacting cells. The immune conversion state may pose to an autoimmune tissue injuries as single or multiple organs defects expressing the patho-biologic features of autoimmune long COVID-19.This mechanistic view to the long Covid-19 is parallel with inclusion of long COVID-19 on the list of autoimmune registry 2021.Some workers holds the believe that autoimmune long COVID-19 is an auto-antibody mediated condition .Other workers are of the opinion that both auto-antibody and auto-reacting immune cells may be involved in, Though there is still existing some debate .A literature show case analysis of neural autoimmune long COVID-19 was tempted .A laboratory animal model for Post-infection-Post-vaccination autoimmune long COVID-19 was suggested .Both of these disease entities are being over-lapping.

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I155

Nermine Abdelwahab, MD #
Nicholas E Ingraham, MD #
Nguyen Nguyen
Lianne Siegel, PhD
Greg Silverman
Himanshu Shekhar Sahoo
Serguei Pakhomov, PhD
Leslie R Morse, DO
Joanne Billings, MD MPH
Michael G. Usher, MD PhD
Tanya E. Melnik, MD
Christopher J. Tignanelli, MD
Farha Ikramuddin, MD MHA

Predictors of Post-Acute Sequelae of COVID-19 Development and Rehabilitation: A Retrospective Study

https://doi.org/10.1016/j.apmr.2022.04.009

Published

12-May-22

Study

https://www.archives-pmr.org/article/S0003-9993(22)00397-5/fulltext

Main outcome measure
Descriptive analyses were conducted across the entire cohort along with an adult subgroup analysis. A logistic regression was performed to assess factors associated with PASC development and rehabilitation utilization.
Results
In an analysis of 19,792 patients, the frequency of PASC was 42.8% in the adult population. Patients with PASC compared to those without had a higher utilization of rehabilitation services (8.6% vs 3.8%, p<0.001). Risk factors for rehabilitation utilization in patients with PASC included younger age (OR 0.99, 95% CI 0.98-1.00; p=0.01). In addition to several comorbidities and demographics factors, risk factors for rehabilitation utilization solely in the inpatient population included male sex (OR 1.24, 95% CI 1.02-1.50; p=0.03) with patients on angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers three months prior to COVID-19 infections having a decreased risk of needing rehabilitation (OR 0.80, 95% CI 0.64-0.99; p=0.04).
Conclusion
Patients with PASC had higher rehabilitation utilization. We identified several clinical and demographic factors associated with the development of PASC and rehabilitation utilization.

1341

I156

Laurence Pearmain, Nicholas Scott, Sean B Knight, Oliver Brand, David J Morgan, Chris Jagger, Saba Khan, Pamela Hackney, Lara Smith, Madhvi Menon, Joanne E Konkel, Halima A Shuwa, Miriam Franklin, Verena Kästele, Sarah Harbach, Seema Brij, Andrew Ustianowski, Alexander G Mathoudiakis, Christopher E Brightling, Pilar Rivera Ortega, Nawar Diar Bakerly, Paul Dark, Kathryn Gray, Graham M Lord, Timothy W Felton, Circo, Karen Piper Hanley, Angela Simpson, John R Grainger, Tracy Hussell, Elizabeth R Mann

Monocyte migratory signatures identify acute and convalescent COVID-19 patients, and are associated with long COVID-19 symptoms

https://doi.org/10.1183/23120541.LSC-2022.172

Published

9-May-22

Study

https://openres.ersjournals.com/content/8/suppl_8/172.abstract

Background: Monocytes regulate the development and resolution of lung injury. We previously demonstrated dysregulation of blood monocytes in hospitalised COVID-19 patients. It is unknown whether monocyte abnormalities persist after discharge and their clinical significance to long COVID symptoms
Aims: We aimed to assess if monocyte dysfunction in COVID-19 is associated with long COVID symptoms.
Methods: Clinical data were collected from 72 patients with acute COVID-19 pneumonitis, 147 COVID-19 convalescent patients (range 8-36 weeks), and 38 healthy controls. Blood monocytes were characterised by flow cytometry.
Results: Monocytes from hospitalised, acute COVID-19 patients aberrantly expressed adhesion/migration molecules, including increased monocyte chemoattractant protein 1, chemokine receptor CXCR6 and adhesion molecules integrinβ7, PSGL-1. Notably chemokine receptor CXCR2 (decreased) and CD62L (increased) expression stratified with acute COVID-19 severity. In convalescence, increased monocyte CXCR6 and PSGL1 persisted; associating with patient breathlessness. Cyclo-oxygenase 2 expression was decreased on monocytes during acute COVID-19, stratifying with disease severity, and remained low during convalescence in patients with persistent fatigue. TNFα monocyte production was enhanced in patients with mild disease during the acute phase, and in patients without long COVID symptoms.
Conlusions: Persistent changes in monocytes during COVID-19 convalescence are associated with long COVID symptoms, where traditional tests of lung recovery are not. Targeting aberrant monocyte phenotypes throughout the COVID-19 time-course has biomarker & immunomodulatory therapy promise.

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I157

Buonsenso, Danilo 1 ; Piazza, Michele 2 ; Boner, Attilio L. 2 ; Bellanti, Joseph A. 3 ;

Long COVID: A proposed hypothesis-driven model of viral persistence for the pathophysiology of the syndrome

https://doi.org/10.2500/aap.2022.43.220018

Published

Article

https://www.ingentaconnect.com/content/ocean/aap/2022/00000043/00000003/art00003

Background:
Long COVID (coronavirus disease 2019) syndrome includes a group of patients who, after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibit lingering mild-to-moderate symptoms and develop medical complications that can have lasting health problems. In this report, we propose a model for the pathophysiology of the long COVID presentation based on increased proinflammatory cytokine production that results from the persistence of the SARS-CoV-2 virus or one of its molecular components. Associated with this hyperproduction of inflammatory cytokines is a heightened activity of nuclear factor κ B (NF-κB) and p38 mitogen-activated protein kinase signaling pathways that regulate cytokine production.
Objective:
The purpose of the present report was to review the causes of long COVID syndrome and suggest ways that can provide a basis for a better understanding of the clinical symptomatology for the of improved diagnostic and therapeutic procedures for the condition.
Methods:
Extensive research was conducted in medical literature data bases by applying terms such as “long COVID” associated with “persistence of the SARS-CoV-2 virus” “spike protein' “COVID-19” and “biologic therapies.”
Results and Conclusions:
In this model of the long COVID syndrome, the persistence of SARS-CoV-2 is hypothesized to trigger a dysregulated immune system with subsequent heightened release of proinflammatory cytokines that lead to chronic low-grade inflammation and multiorgan symptomatology. The condition seems to have a genetic basis, which predisposes individuals to have a diminished immunologic capacity to completely clear the virus, with residual parts of the virus persisting. This persistence of virus and resultant hyperproduction of proinflammatory cytokines are proposed to form the basis of the syndrome.

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I158

Daniel Ayoubkhani, Charlotte Bermingham, Koen B Pouwels, Myer Glickman, Vahé Nafilyan, Francesco Zaccardi, Kamlesh Khunti, , Nisreen A Alwan

Trajectory of long covid symptoms after covid-19 vaccination: community based cohort study

https://doi.org/10.1136/bmj-2021-069676

Published

18-May-22

Study

https://www.bmj.com/content/377/bmj-2021-069676

Objective: To estimate associations between covid-19 vaccination and long covid symptoms in adults with SARS-CoV-2 infection before vaccination.
Design: Observational cohort study.
Setting: Community dwelling population, UK.
Participants: 28 356 participants in the Office for National Statistics COVID-19 Infection Survey aged 18-69 years who received at least one dose of an adenovirus vector or mRNA covid-19 vaccine after testing positive for SARS-CoV-2 infection.
Main outcome measure; Presence of long covid symptoms at least 12 weeks after infection over the follow-up period 3 February to 5 September 2021.
Results: Mean age of participants was 46 years, 55.6% (n=15 760) were women, and 88.7% (n=25 141) were of white ethnicity. Median follow-up was 141 days from first vaccination (among all participants) and 67 days from second vaccination (83.8% of participants). 6729 participants (23.7%) reported long covid symptoms of any severity at least once during follow-up. A first vaccine dose was associated with an initial 12.8% decrease (95% confidence interval −18.6% to −6.6%, P<0.001) in the odds of long covid, with subsequent data compatible with both increases and decreases in the trajectory (0.3% per week, 95% confidence interval −0.6% to 1.2% per week, P=0.51). A second dose was associated with an initial 8.8% decrease (95% confidence interval −14.1% to −3.1%, P=0.003) in the odds of long covid, with a subsequent decrease by 0.8% per week (−1.2% to −0.4% per week, P<0.001). Heterogeneity was not found in associations between vaccination and long covid by sociodemographic characteristics, health status, hospital admission with acute covid-19, vaccine type (adenovirus vector or mRNA), or duration from SARS-CoV-2 infection to vaccination.
Conclusions: The likelihood of long covid symptoms was observed to decrease after covid-19 vaccination and evidence suggested sustained improvement after a second dose, at least over the median follow-up of 67 days. Vaccination may contribute to a reduction in the population health burden of long covid, although longer follow-up is needed.

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I159

Manoj Sivan, Trisha Greenhalgh, Ruairidh Milne, Brendan Delaney

Are vaccines a potential treatment for long covid?

https://doi.org/10.1136/bmj.o988

Published

18-May-22

Article

https://www.bmj.com/content/377/bmj.o988.full

Benefits are possible, but we need more evidence and a mechanism of action.
The mechanisms underpinning changes in long covid symptoms after vaccination are not fully understood. However, as Ayoubkhani and colleagues suggest, vaccination can increase antibody titres and potentially eliminate viral reservoirs.2 Given the small numbers of patients reported to benefit (an 8.8% reduction in odds of long covid after two vaccine doses) and the uncertainty around the true effect of vaccines relative to natural recovery, a clear explanation for how vaccines might reduce the multisystem manifestations of long covid is still lacking. Particularly for people already well past the stage of systemic inflammatory responses, and those with end organ damage from covid-19, such as lung fibrosis.
Several plausible mechanisms underlying long covid are currently being investigated, including the persistence of viral antigens and abnormalities in T cells, platelets, vascular endothelium, and clotting factors. People with long covid need timely investigation, management, and rehabilitation in specialist clinics, including identification of thrombotic phenomena, cardiac dysrhythmias, and dysautonomia.
Vaccination to reduce risk of reinfection remains important for people with long covid, and evidence so far suggests that benefits are likely to outweigh any harms. Three outcomes are possible after vaccination: no change in symptoms (most likely), improvement (best case), or deterioration (worst case).1 Unfortunately, many unknowns remain about the long term prognosis of long covid, including the effect of booster vaccines or recurrent covid-19. More research is needed on the link between antibody titres and symptoms over time before we can hope to predict the effects of vaccination on individuals.

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I160

Ngai Sze Wong, Shui Shan Lee, Denise P. C. Chan, Timothy C. M. Li, Tracy H. Y. Ho, Fion W. L. Luk, Kai Ming Chow, Eugene Y. K. Tso, Eng-Kiong Yeoh, Samuel Y. S. Wong, David S. C. Hui & Grace C. Y. Lui

Trajectory patterns of SARS-CoV-2 neutralising antibody response in convalescent COVID-19 patients

https://doi.org/10.1038/s43856-022-00119-2

Published

19-May-22

Study

https://www.nature.com/articles/s43856-022-00119-2

Background
The adaptive immune responses of COVID-19 patients contributes to virus clearance, restoration of health and protection from re-infection. The patterns of and the associated characteristics with longitudinal neutralising antibody (NAb) response following SARS-CoV-2 infection are important in their potential association with the population risks of re-infection.
Methods
This is a longitudinal study with blood samples and clinical data collected in adults aged 18 or above following diagnosis of SARS-CoV-2 infection. NAb levels were measured by the SARS-CoV-2 surrogate virus neutralisation test (sVNT). Anonymous clinical and laboratory data were matched with surveillance data for each subject for enabling analyses and applying latent class mixed models for trajectory delineation. Logistic regression models were performed to compare the characteristics between the identified classes.
Results
In 2020–2021, 368 convalescent patients in Hong Kong are tested for NAb. Their seroconversion occur within 3 months in 97% symptomatic patients, the level of which are maintained at 97% after 9 months. The NAb trajectories of 200 symptomatic patients are classified by the initial response and subsequent trend into high-persistent and waning classes in latent class mixed models. High-persistent (15.5%) class patients are older and most have chronic illnesses. Waning class patients (84.5%) are largely young adults who are mildly symptomatic including 2 who serorevert after 10 months.
Conclusions
Characteristic sub-class variabilities in clinical pattern are noted especially among patients with waning NAb. The heterogeneity of the NAb trajectory patterns and their clinical association can be important for informing vaccination strategy to prevent re-infection.

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I75 now published in Nature Medicine

Ziyad Al-Aly, Benjamin Bowe, Yan Xie

Long COVID after breakthrough SARS-CoV-2 infection

https://doi.org/10.1038/s41591-022-01840-0

Published

25-May-22

Study

https://www.nature.com/articles/s41591-022-01840-0

The post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection—also referred to as Long COVID—have been described, but whether breakthrough SARS-CoV-2 infection (BTI) in vaccinated people results in post-acute sequelae is not clear. In this study, we used the US Department of Veterans Affairs national healthcare databases to build a cohort of 33,940 individuals with BTI and several controls of people without evidence of SARS-CoV-2 infection, including contemporary (n = 4,983,491), historical (n = 5,785,273) and vaccinated (n = 2,566,369) controls. At 6 months after infection, we show that, beyond the first 30 days of illness, compared to contemporary controls, people with BTI exhibited a higher risk of death (hazard ratio (HR) = 1.75, 95% confidence interval (CI): 1.59, 1.93) and incident post-acute sequelae (HR = 1.50, 95% CI: 1.46, 1.54), including cardiovascular, coagulation and hematologic, gastrointestinal, kidney, mental health, metabolic, musculoskeletal and neurologic disorders. The results were consistent in comparisons versus the historical and vaccinated controls. Compared to people with SARS-CoV-2 infection who were not previously vaccinated (n = 113,474), people with BTI exhibited lower risks of death (HR = 0.66, 95% CI: 0.58, 0.74) and incident post-acute sequelae (HR = 0.85, 95% CI: 0.82, 0.89). Altogether, the findings suggest that vaccination before infection confers only partial protection in the post-acute phase of the disease; hence, reliance on it as a sole mitigation strategy may not optimally reduce long-term health consequences of SARS-CoV-2 infection. The findings emphasize the need for continued optimization of strategies for primary prevention of BTI and will guide development of post-acute care pathways for people with BTI.

We examined the risk of death and post-acute sequelae in those with BTI versus several controls of people without evidence of SARS-CoV-2 infection, including (1) a contemporary control of people exposed to the same broader forces of the pandemic (lockdowns and economic, social and environmental stressors); (2) a historical control from a pre-pandemic era that represents a baseline unaffected by the disruptions of the pandemic; and (3) a vaccinated control group. The results show two key findings: (1) Long COVID, including increased risks of death and myriad post-acute sequelae in the pulmonary and extrapulmonary organ systems, also manifests in vaccinated individuals who experience a BTI; and (2) the range of post-acute sequelae in various organ systems in BTI does not appear to be different than COVID-19 without prior vaccination. Our analyses of BTI versus SARS-CoV-2 infection without prior vaccination show that, comparatively, the magnitude of the risks of death and post-acute sequelae was lower in people with BTI versus those with SARS-CoV-2 infection who had not been previously vaccinated for it. These results show that, although vaccination may partially reduce the risks of post-acute death and disease, to most optimally reduce this burden requires continued emphasis on primary prevention of breakthrough SARS-CoV-2 infection as a goal of public health policy.
Although the absolute rates are smaller than in those with SARS-CoV-2 infection without prior vaccination, given the scale of the pandemic and the potential for breakthrough cases to continue to accumulate, the overall burden of death and disease after BTI will likely be substantial, will further add to the toll of this pandemic and will represent an additional strain on already overwhelmed health systems. In planning and development of health resources, governments and health systems should take into account the care needs of people with post-acute sequelae after BTI.
Our analyses suggest that this risk reduction (of post-acute sequelae) was most pronounced in recipients of BNT162b2 and mRNA-1273 vaccines (compared to Ad26.COV2.S). Although these results recapitulate evidence of vaccine effectiveness in the acute phase of COVID-19, the mechanism or mechanisms underlying this carry-through effect of risk reduction from the acute to the post-acute phase of the disease is not entirely clear. One putative interpretation of these results is that vaccine-induced reduction in severity of the acute infection may then translate into less long-term risk of post-acute health outcomes. In other analyses, we also show that the reduced risk of post-acute sequelae in people with BTIs was partially eroded in people with immunocompromised status, suggesting a putative immune-related mechanism in the expression of post-acute sequelae that may be influenced by vaccination.
We also show that the risk of post-acute sequelae is higher in people with BTI than in people with seasonal influenza—a well-characterized respiratory viral illness. This extends previous evidence showing that the risk of post-acute sequelae in people with SARS-CoV-2 infection was higher than those with seasonal influenza and again emphasizes the importance of prevention of both SARS-CoV-2 infection and BTI1.

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Katherine M. Littlefield, Renée O. Watson, Jennifer M. Schneider, Charles P. Neff, Eiko Yamada, Min Zhang, Thomas B. Campbell, Michael T. Falta, Sarah E. Jolley, Andrew P. Fontenot, Brent E. Palmer

SARS-CoV-2-specific T cells associate with inflammation and reduced lung function in pulmonary post-acute sequalae of SARS-CoV-2

https://doi.org/10.1371/journal.ppat.1010359

Published

26-May-22

Article

https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1010359

As of January 2022, at least 60 million individuals are estimated to develop post-acute sequelae of SARS-CoV-2 (PASC) after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While elevated levels of SARS-CoV-2-specific T cells have been observed in non-specific PASC, little is known about their impact on pulmonary function which is compromised in the majority of these individuals. This study compares frequencies of SARS-CoV-2-specific T cells and inflammatory markers with lung function in participants with pulmonary PASC and resolved COVID-19 (RC). Compared to RC, participants with respiratory PASC had between 6- and 105-fold higher frequencies of IFN-γ- and TNF-α-producing SARS-CoV-2-specific CD4+ and CD8+ T cells in peripheral blood, and elevated levels of plasma CRP and IL-6. Importantly, in PASC participants the frequency of TNF-α-producing SARS-CoV-2-specific CD4+ and CD8+ T cells, which exhibited the highest levels of Ki67 indicating they were activity dividing, correlated positively with plasma IL-6 and negatively with measures of lung function, including forced expiratory volume in one second (FEV1), while increased frequencies of IFN-γ-producing SARS-CoV-2-specific T cells associated with prolonged dyspnea. Statistical analyses stratified by age, number of comorbidities and hospitalization status demonstrated that none of these factors affect differences in the frequency of SARS-CoV-2 T cells and plasma IL-6 levels measured between PASC and RC cohorts. Taken together, these findings demonstrate elevated frequencies of SARS-CoV-2-specific T cells in individuals with pulmonary PASC are associated with increased systemic inflammation and decreased lung function, suggesting that SARS-CoV-2-specific T cells contribute to lingering pulmonary symptoms. These findings also provide mechanistic insight on the pathophysiology of PASC that can inform development of potential treatments to reduce symptom burden.

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Krista L.Newell1Adam T.Waickman121

Inflammation, immunity, and antigen persistence in post-acute sequelae of SARS-CoV-2 infection

https://doi.org/10.1016/j.coi.2022.102228

Published

24-May-22

Review

https://www.sciencedirect.com/science/article/pii/S0952791522000759

Highlights
•PASC impacts 7-10% of convalescent COVID-19 patients.
•PASC is associated with persistent inflammation after acute SARS-CoV-2 infection.
•The antigens or other immune stimuli driving PASC are still unclear.
•PASC severity and duration is reduced by SARS-CoV-2 vaccination.
SARS-CoV-2 infection is known to result in a range of symptoms with varying degrees of acute phase severity. In a subset of individuals an equally diverse collection of long-term sequelae has been reported after convalescence. As survivorship and therefore the number of individuals with “long-COVID” continues to grow, an understanding of the prevalence, origins, and mechanisms of post-acute sequelae manifestation is critically needed. Here, we will explore proposed roles of the anti-SARS-CoV-2 immune response in the onset, severity, and persistence of SARS-CoV-2 post-acute sequelae. We discuss the potential roles of persistent virus and autoantigens in this syndrome, as well as the contributions of unresolved inflammation and tissue injury. Furthermore, we highlight recent evidence demonstrating the potential benefits of vaccination and immunity in the resolution of post-acute symptoms.

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Sreus A.G. NaiduORCID Icon,Roger A. ClemensORCID Icon &A. Satyanarayan NaiduORCID Icon

SARS-CoV-2 Infection Dysregulates Host Iron (Fe)-Redox Homeostasis (Fe-R-H): Role of Fe-Redox Regulators, Ferroptosis Inhibitors, Anticoagulants, and Iron-Chelators in COVID-19 Control

https://doi.org/10.1080/19390211.2022.2075072

Published

22-May-22

Review

https://www.tandfonline.com/doi/abs/10.1080/19390211.2022.2075072

Severe imbalance in iron metabolism among SARS-CoV-2 infected patients is prominent in every symptomatic (mild, moderate to severe) clinical phase of COVID-19. Phase-I – Hypoxia correlates with reduced O2 transport by erythrocytes, overexpression of HIF-1α, altered mitochondrial bioenergetics with host metabolic reprogramming (HMR). Phase-II – Hyperferritinemia results from an increased iron overload, which triggers a fulminant proinflammatory response – the acute cytokine release syndrome (CRS). Elevated cytokine levels (i.e. IL6, TNFα and CRP) strongly correlates with altered ferritin/TF ratios in COVID-19 patients. Phase-III – Thromboembolism is consequential to erythrocyte dysfunction with heme release, increased prothrombin time and elevated D-dimers, cumulatively linked to severe coagulopathies with life-threatening outcomes such as ARDS, and multi-organ failure. Taken together, Fe-R-H dysregulation is implicated in every symptomatic phase of COVID-19. Fe-R-H regulators such as lactoferrin (LF), hemoxygenase-1 (HO-1), erythropoietin (EPO) and hepcidin modulators are innate bio-replenishments that sequester iron, neutralize iron-mediated free radicals, reduce oxidative stress, and improve host defense by optimizing iron metabolism. Due to its pivotal role in ‘cytokine storm’, ferroptosis is a potential intervention target. Ferroptosis inhibitors such as ferrostatin-1, liproxstatin-1, quercetin, and melatonin could prevent mitochondrial lipid peroxidation, up-regulate antioxidant/GSH levels and abrogate iron overload-induced apoptosis through activation of Nrf2 and HO-1 signaling pathways. Iron chelators such as heparin, deferoxamine, caffeic acid, curcumin, α-lipoic acid, and phytic acid could protect against ferroptosis and restore mitochondrial function, iron-redox potential, and rebalance Fe-R-H status. Therefore, Fe-R-H restoration is a host biomarker-driven potential combat strategy for an effective clinical and post-recovery management of COVID-19.

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Zion Congrave-Wilson 1,†ORCID,Wesley A. Cheng 1,†ORCID,Yesun Lee 1,Stephanie Perez 1,Lauren Turner 1,Carolyn Jennifer Marentes Ruiz 1,Shirley Mendieta 1ORCID,Adam Skura 1ORCID,Jaycee Jumarang 1ORCID,Jennifer Del Valle 1ORCID,John Kubale 2ORCID,Emma Kaitlynn Allen 3ORCID,Paul G. Thomas 3ORCID,Aubree Gordon 2ORCID andPia S. Pannaraj 1,4,*

Twelve-Month Longitudinal Serology in SARS-CoV-2 Naïve and Experienced Vaccine Recipients and Unvaccinated COVID-19-Infected Individuals

https://doi.org/10.3390/vaccines10050813

Published

20-May-22

Study

https://www.mdpi.com/2076-393X/10/5/813/htm

Longitudinal data comparing SARS-CoV-2 serology in individuals following infection and vaccination over 12 months are limited. This study compared the magnitude, decay, and variability in serum IgG, IgA, and neutralizing activity induced by natural infection (n = 218) or mRNA vaccination in SARS-CoV-2 naïve (n = 143) or experienced (n = 122) individuals over time using enzyme-linked immunosorbent assays and an in vitro virus neutralization assay. Serological responses were found to be highly variable after natural infection compared with vaccination but durable through 12 months. Antibody levels in vaccinated, SARS-CoV-2 naïve individuals peaked by 1 month then declined through 9 months, culminating in non-detectable SARS-CoV-2-specific serum IgA. Individuals with both infection and vaccination showed SARS-CoV-2-specific IgG and IgA levels that were more robust and slower to decline than the other groups; neutralizing activity remained highest in this group at 9 months past vaccination. These data reinforce the benefit of vaccination after SARS-CoV-2 recovery.

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Dominique GRANDJEAN,Caroline ELIE,Capucine GALLET,Clotilde JULIEN,Vinciane ROGER,Loïc DESQUILBET,Guillaume ALVERGNAT,Séverine DELARUE,Audrey GABASSI,Marine MINIER,Laure CHOUPEAUX,Solen KERNEIS,Constance DELAUGERRE,Jérôme LE GOFF,Jean-Marc TRELUYER

Diagnostic accuracy of non-invasive detection of SARS-CoV-2 infection by canine olfaction

https://doi.org/10.1371/journal.pone.0268382

Published

1-Jun-22

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0268382

Background
Throughout the COVID-19 pandemic, testing individuals remains a key action. One approach to rapid testing is to consider the olfactory capacities of trained detection dogs.
Methods
Prospective cohort study in two community COVID-19 screening centers. Two nasopharyngeal swabs (NPS), one saliva and one sweat samples were simultaneously collected. The dog handlers (and the dogs…) were blinded with regards to the Covid status. The diagnostic accuracy of non-invasive detection of SARS-CoV-2 infection by canine olfaction was assessed as compared to nasopharyngeal RT-PCR as the reference standard, saliva RT-PCR and nasopharyngeal antigen testing.
Results
335 ambulatory adults (143 symptomatic and 192 asymptomatic) were included. Overall, 109/335 participants tested positive on nasopharyngeal RT-PCR either in symptomatic (78/143) or in asymptomatic participants (31/192). The overall sensitivity of canine detection was 97% (95% CI, 92 to 99) and even reached 100% (95% CI, 89 to 100) in asymptomatic individuals compared to NPS RT-PCR. The specificity was 91% (95% CI, 72 to 91), reaching 94% (95% CI, 90 to 97) for asymptomatic individuals. The sensitivity of canine detection was higher than that of nasopharyngeal antigen testing (97% CI: 91 to 99 versus 84% CI: 74 to 90, p = 0.006), but the specificity was lower (90% CI: 84 to 95 versus 97% CI: 93 to 99, p = 0.016).
Conclusions
Non-invasive detection of SARS-CoV-2 infection by canine olfaction could be one alternative to NPS RT-PCR when it is necessary to obtain a result very quickly according to the same indications as antigenic tests in the context of mass screening.

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I167

Rita Rubin

From Positive to Negative to Positive Again—The Mystery of Why COVID-19 Rebounds in Some Patients Who Take Paxlovid

https://doi.org/10.1001/jama.2022.9925

Published

8-Jun-22

Article

https://jamanetwork.com/journals/jama/fullarticle/2793357

Ho likely is one of very few people who’ve relapsed after taking nirmatrelvir/ritonavir and then sequenced their own virus both the first and second time around. (At least 1 other leading virologist, Peter Hotez, MD, PhD, of the Baylor College of Medicine, has revealed that he also experienced a post-Paxlovid relapse.)
Both of Ho’s sequences were identical, ruling out a couple of possible explanations for his relapse, he said. It couldn’t have been due to a stroke of bad luck—a second SARS-CoV-2 infection just as he was getting over his first one. And it couldn’t have resulted from the virus becoming resistant to nirmatrelvir. If either were the case, the virus pair wouldn’t have been identical.
Scientists have proposed a few other possible explanations for rebounds after nirmatrelvir/ritonavir treatment. “Question number 1 in my mind is the timing. I think maybe we’re giving it too early,” del Rio said. Perhaps, Wachter speculated, “If you get started right away, maybe you suppress the virus [and] the immune system doesn’t rev up in the way it normally would.” He and others have also suggested that 5 days might not be a long enough treatment course. “All these theories are total handwaving,” Wachter acknowledged.
To answer the outstanding questions about relapses, “I’m not sure we need a clinical trial in the classical definition,” del Rio said. “We need post-approval data.” It’s being collected, he said, but the findings probably won’t be available for months. For now, there is no evidence that additional treatment with nirmatrelvir/ritonavir is needed when a rebound is suspected after a 5-day course, according to both the CDC’s advisory and FDA official Farley’s recent update.
Despite all the questions about the rebound phenomenon, “the biggest challenge we’re having with the drug is it’s not being used as frequently as it should,” del Rio said. “Primary care physicians are freaked out about the drug-drug interactions.” The people in whom COVID-19 is most likely to progress to a serious or even deadly infection are also the ones most likely to be taking multiple medications, he noted.
One thing is for sure, testing is more important than ever, given the availability of effective treatments for COVID-19, Cohen said. “I see a sea change in the management of respiratory infections.”
Nobody says, “Oh, I think I have a cold” anymore, he explained. “If we’re going to treat people with COVID, we need to know if they have COVID.”

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Alexandra Flemming

Vaccines only partially protect against Long COVID

https://doi.org/10.1038/s41577-022-00749-6

Published

10-Jun-22

Article

https://www.nature.com/articles/s41577-022-00749-6

COVID-19 vaccines have proven very successful in protecting against severe disease. However, they only provide partial protection against infection, and an increasing number of individuals suffer breakthrough infections (BTIs) after vaccination. Al-Aly and colleagues investigated the vast US department of Veterans Affairs national health-care database to determine the level of protection vaccines provide against post-acute COVID-19 sequelae (‘Long COVID’). They found that individuals with BTIs, compared with unvaccinated individuals, had a lower risk of death and Long COVID between of 1–6 months post-infection, particularly when comparing patients who had been hospitalized with COVID-19. However, the overall protection of the vaccine from Long COVID was only ~15%, which means that the burden of Long COVID is likely to be substantial even in fully vaccinated populations. Therefore, vaccination alone may not be enough to mitigate the long-term health consequences of SARS-CoV-2 infection.

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Juan-Manuel Anaya,María Herrán,Santiago Beltrán &Manuel Rojas

Is post-COVID syndrome an autoimmune disease?

https://doi.org/10.1080/1744666X.2022.2085561

Published

14-Jun-22

Perspective

https://www.tandfonline.com/doi/abs/10.1080/1744666X.2022.2085561

Article highlights
- Post-COVID syndrome (PCS) is a heterogeneous condition characterized by persistent inflammation and autoimmunity.
- PCS shares similarities with other post-infectious conditions but may last longer (> 6 months).
- The overlap between post-care syndromes and PCS may hinder differential diagnosis while suggesting clinical subphenotypes of PCS.
- In addition to an autoimmune-mediated mechanism, endotheliopathy, coagulopathy, autonomic, endocrine, neurological dysfunction, and viral persistence may contribute to PCS.
- Based on population data and new health and social care frameworks, personalized medicine should be considered to deal with PCS.
Post-COVID syndrome (PCS) is recognized as a new entity in the context of SARS-CoV-2 infection. Though its pathogenesis is not completely understood, persistent inflammation from acute illness and the development of autoimmunity play a critical role in its development.
Areas covered
The mechanisms involved in the emergence of PCS, their similarities with post-viral and post-care syndromes, its inclusion in the spectrum of autoimmunity and possible targets for its treatment.
Expert opinion
An autoimmune phenomenon plays a major role in most causative theories explaining PCS. There is a need for both PCS definition and classification criteria (including severity scores). Longitudinal and controlled studies are necessary to better understand this new entity, and to find what additional factors participate into its development. With the high prevalence of COVID-19 cases worldwide, together with the current evidence on latent autoimmunity in PCS, we may observe an increase of autoimmune diseases (ADs) in the coming years. Vaccination’s effect on the development of PCS and ADs will also receive attention in the future. Health and social care services need to develop a new framework to deal with PCS.

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I170

Raffaele Pagliuca, Maria Grazia Cupido, Giacomo Mantovani, Maura Bugada, Giulia Matteucci, Arturo Caffarelli, Federico Bellotti, Raffaella Cocchieri, Antonio Dentale, Federica Lozzi, Paola Malagoli, Pasquale Morabito, Gianluca Serra & Candida Andreati

Absence of negativization of nasal swab test and frailty as risk factors for mortality in elderly COVID-19 patients admitted in long-term care facilities

https://doi.org/10.1007/s41999-022-00657-x

Published

4-Jun-22

Study

https://link.springer.com/article/10.1007/s41999-022-00657-x

Aim: Focus of prognostic factors in elderly covid19 patients admitted in long term unit.
Findings: Nasal swab test at discharge, infection, age and frailty represented risk factors associated with increased mortality.
Message: Absence of negativization of nasal swab test is the major risk factor for mortality.
Methods
A limited amount of data is now available on prognostic factors and mortality among elderly people resident in Long-Term Care facilities and in post-acute units. These populations (in particular those with underlying chronic medical conditions) seem to have higher risk of morbidity and mortality related to COVID-19 disease, but further evidence is needed. The aim of our study is to investigate the impact of some well-known prognostic factors in elderly patients (≥ 65 years) with COVID-19 admitted in the Long-Term Care setting in AUSL Ferrara, Italy. We performed binary regression logistic analysis for some variables (demographic data, clinical data including nasal swab test (NST) at discharge and frailty assessments) to find potential predictors of mortality. We subsequently tested statistically significant variables using Kaplan–Meier curves and Cox-regression models to find survival outcomes and related hazard ratio.
Results
Risk factors associated with increased mortality resulted NST at discharge, infection, age and frailty. At a further secondary analysis carried out between NST at discharge, age and clinical frailty scale (CFS) < 5, we found a positive correlation between NST at discharge and CFS < 5. Kaplan–Meier curves showed a statistically significant difference regarding frailty and NST at discharge but not for age.
Conclusion
Our study showed that absence of negativization of NST at discharge and frailty are strong predictors for mortality in elderly COVID-19 patients admitted in Long-Term Care facilities, while age and the comorbidity burden are less important.

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I171

Svitlana Zubchenko, Iryna Kril, Olena Nadizhko, Oksana Matsyura & Valentyna Chopyak

Herpesvirus infections and post-COVID-19 manifestations: a pilot observational study

https://doi.org/10.1007/s00296-022-05146-9

Published

1-Jun-22

Study

https://link.springer.com/article/10.1007/s00296-022-05146-9

The global spread of SARS-CoV-2 points to unrivaled mutational variation of the virus, contributing to a variety of post-COVID sequelae in immunocompromised subjects and high mortality. Numerous studies have reported the reactivation of "sluggish" herpes virus infections in COVID-19, which exaggerate the course of the disease and complicate with lasting post-COVID manifestations CMV, EBV, HHV6). This study aimed to describe clinical and laboratory features of post-COVID manifestations accompanied by the reactivation of herpes virus infections (CMV, EBV, HHV6). 88 patients were recruited for this study, including subjects with reactivation of herpes viruses, 68 (72.3%) (main group) and 20 (27.7%) subjects without detectable DNA of herpesviruses (control group): 46 (52.3%) female and 42 (47.7%) male; median age was 41.4 ± 6.7 years. Patients with post-COVID manifestations presented with reactivation of EBV in 42.6%, HHV6 in 25.0%, and EBV plus HHV6 in 32.4%. Compared with controls, patients with herpes virus infections presented with more frequent slight fever temperature, headache, psycho-neurological disorders, pulmonary abnormalities and myalgia (p < 0.01), activation of liver enzymes, elevated CRP and D-dimer, and suppressed cellular immune response (p ≤ 0.05). Preliminary results indicate a likely involvement of reactivated herpes virus infections, primarily EBV infections in severe COVID-19 and the formation of the post-COVID syndrome. Patients with the post-COVID syndrome and reactivation of EBV and HHV6 infections are at high risk of developing various pathologies, including rheumatologic diseases.

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Nadia M. Hamdy, Fatma H. Shaker, Xianquan Zhan & Emad B. Basalious

Tangled quest of post-COVID-19 infection-caused neuropathology and what 3P nano-bio-medicine can solve?

https://doi.org/10.1007/s13167-022-00285-2

Published

2-Jun-22

Review

https://link.springer.com/article/10.1007/s13167-022-00285-2

COVID-19-caused neurological problems are the important post-CoV-2 infection complications, which are recorded in ~ 40% of critically ill COVID-19 patients. Neurodegeneration (ND) is one of the most serious complications. It is necessary to understand its molecular mechanism(s), define research gaps to direct research to, hopefully, design new treatment modalities, for predictive diagnosis, patient stratification, targeted prevention, prognostic assessment, and personalized medical services for this type of complication. Individualized nano-bio-medicine combines nano-medicine (NM) with clinical and molecular biomarkers based on omics data to improve during- and post-illness management or post-infection prognosis, in addition to personalized dosage profiling and drug selection for maximum treatment efficacy, safety with least side-effects. This review will enumerate proteins, receptors, and enzymes involved in CoV-2 entrance into the central nervous system (CNS) via the blood–brain barrier (BBB), and list the repercussions after that entry, ranging from neuroinflammation to neurological symptoms disruption mechanism. Moreover, molecular mechanisms that mediate the host effect or viral detrimental effect on the host are discussed here, including autophagy, non-coding RNAs, inflammasome, and other molecular mechanisms of CoV-2 infection neuro-affection that are defined here as hallmarks of neuropathology related to COVID-19 infection. Thus, a couple of questions are raised; for example, “What are the hallmarks of neurodegeneration during COVID-19 infection?” and “Are epigenetics promising solution against post-COVID-19 neurodegeneration?” In addition, nano-formulas might be a better novel treatment for COVID-19 neurological complications, which raises one more question, “What are the challenges of nano-bio-based nanocarriers pre- or post-COVID-19 infection?” especially in the light of omics-based changes/challenges, research, and clinical practice in the framework of predictive preventive personalized medicine (PPPM / 3P medicine).

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Noha Sharafeldin, Vithal Madhira, Qianqian Song, Benjamin Bates, Amit Kumar Mitra, Feifan Liu, Timothy Bergquist, Jing Su, Fang-Chi Hsu, Umit Topaloglu

Long COVID-19 in patients with cancer: Report from the National COVID Cohort Collaborative (N3C).

https://doi.org/10.1200/JCO.2022.40.16_suppl.1540

Published

2-Jun-22

Study

https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.1540

Background: Post-acute sequelae of SARS-CoV-2 or long COVID, is characterized by persistence of symptoms and/or emergence of new symptoms post COVID-19 infection. As evidence accumulates and national initiatives arise to address this increasingly prevalent syndrome, characterization of specific patient groups is still lacking including patients with cancer. Using a nationally representative sample of over 4.3M COVID-19 patients from the National COVID Cohort Collaborative (N3C), we aim to describe characteristics of patients with cancer and long COVID.
Methods: We employed two approaches to identify long COVID patients within N3C: i) patients presenting to a long COVID clinic at four N3C sites and ii) patients diagnosed using the recently introduced ICD-10 code: U09.9 Post COVID-19 condition, unspecified. We included patients with at least one positive COVID-19 diagnosis between 1/1/2020 and 2/3/2022. Patients had to survive at least 90 days from the date of their COVID-19 diagnosis. Analyses were performed in the N3C Data Enclave on the Palantir platform.
Results: A total of 1700 adult patients with long COVID were identified from the N3C cohort; 634 (37.3%) were cancer patients and 1066 were non-cancer controls. The most common represented cancers were skin (21.9%), breast (17.7%), prostate (8.3%), lymphoma (8.0%) and leukemia (5.7%). Median age of long-COVID cancer patients was 64 years (Interquartile Range: 54-72), 48.6% were 65 years or older, 60.4% females, 76.8% non-Hispanic White, 12.3% were Black, and 3% Hispanic. A total of 41.1% were current or former smokers, 27.7% had an adjusted Charlson Comorbidity Index score of 0, 18.6% score of 1 and 11.2% score of 2. A total of 57.2% were hospitalized for their initial COVID-19 infection, the average length of stay in the hospital was 9.6 days (SD: 16.7 days), 9.1% required invasive ventilation, and 13% had acute kidney injury during hospitalization. The most common diagnosis among the non-cancer long COVID patients was asthma (26%), diabetes (17%), chronic kidney disease (12%), heart failure (9.4%), and chronic obstructive pulmonary disease (7.8%). Among long COVID patients, compared to non-cancer controls, cancer patients were more likely to be older (OR = 2.4, 95%CI: 1.1-5.4, p = 0.03), have comorbidities (OR = 4.3, 95%CI: 2.9-6.2, p < 0.0001), and to be hospitalized for COVID-19 (OR = 1.3, 95%CI: 1.0-1.7, p = 0.05), adjusting for sex, race/ethnicity, body mass index and smoking history.
Conclusions: In a nationally representative sample of long COVID patients, there was a relative overrepresentation of patients with cancer. Compared to non-cancer controls, cancer patients were older, more likely to have more comorbidities and to be hospitalized for COVID-19 warranting further investigation to identify risk factors for long COVID in patients with cancer.

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I174

Viola Popov, Mihaela Andreescu, Catalina Pirvu, Andra Grigorie, Oana Constantin, Andreea Calen, Mihaela Dana Badoiu Niculae, Adriana Badea, Ana Rus, Lelia Iliescu

The importance of the long Covid-19 in the evolution of patients with neoplasms.

https://doi.org/10.1200/JCO.2022.40.16_suppl.e18647

2-Jun-22

https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.e18647

Background: Patients with comorbidities especially those with oncological diseases could have severe COVID-19 outcomes. OBJECTIVE: The aim of this study was to evaluate the role of prolonged positivity of SARS-Cov2 in evolution of patients with various neoplasia.
Methods: We analysed clinical and laboratory (hematological parameters and inflammatory markers: interleukin-6 and ferritin) data of COVID-19 patients admitted in intensive care unit (ICU) Department of our hospital, during 2020-2021 and presented in medical history solid tumors or haematological neoplasia . The cohort of patients included 78 patients with severe and critical form of COVID-19, 31 patients with solid tumors and 47 patients with hematologic malignancies. We consider long COVID-19 all cases with SARS Cov2 positivity more than 14 days.
Results: The frequency of long COVID-19 was quite equal between patients groups with solid tumors and hematologic malignancies, incidence rate 1:2, the incidence rate differences was 1:18, p = 0.75. Long COVID-19 was observed in 60% cases with favourable evolution, Chi-squared 5.35%, p = 0.02, these patients had moderate form and was admitted in hospital in 1 or more days after the onset, median value 3 (min 1, max 55) compared with patients with normal duration of positivity of SARS-Cov2 test- median value 2 (min 1, max 8), p = 0.01. The Kaplan Meyer survival analyses indicated long COVID-19 as predictive factor for unfavourable evolution, Chi-squared 17.97, p < 0.0001. Although we have not obtain significant differences, we observed more severe lymphopenia in patient without long COVID-19, probably because a part of these patients group died in the first 14 days of COVID-19 (0.765 (min 0.04, max 297.64) vs. 1.01 (min 0.09, max 254.35), p = 0.09). The rest of hematological and biochemistry parameters was not significant different between groups. Infectious and thrombotic complication was most frequent in patients with long COVID-19, Chi squared 8.6, p = 0.003.
Conclusions: Long Covid-19 is predictable for unfavourable evolution and is associated with sepsis and thrombotic complication. This diagnosis is frequent in patients who was admitted in hospital after the onset of COVID-19 symptoms, early treatment of COVID-19 in oncological patients being very important for favourable evolution.

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Guang-Ying Cui, Ben-Chen Rao, Zhao-Hai Zeng, Xue-Mei Wang, Tong Ren, Hai-Yu Wang, Hong Luo, Hong-Yan Ren, Chao Liu, Su-Ying Ding, Jun-Jie Tan, Zhen-Guo Liu, Ya-Wen Zou, Zhi-Gang Ren & Zu-Jiang Yu

Characterization of oral and gut microbiome and plasma metabolomics in COVID-19 patients after 1-year follow-up

https://doi.org/10.1186/s40779-022-00387-y

Published

17-Jun-22

Study

https://link.springer.com/article/10.1186/s40779-022-00387-y

Background
Due to the outbreak and rapid spread of coronavirus disease 2019 (COVID-19), more than 160 million patients have become convalescents worldwide to date. Significant alterations have occurred in the gut and oral microbiome and metabonomics of patients with COVID-19. However, it is unknown whether their characteristics return to normal after the 1-year recovery.
Methods
We recruited 35 confirmed patients to provide specimens at discharge and one year later, as well as 160 healthy controls. A total of 497 samples were prospectively collected, including 219 tongue-coating, 129 stool and 149 plasma samples. Tongue-coating and stool samples were subjected to 16S rRNA sequencing, and plasma samples were subjected to untargeted metabolomics testing.
Results
The oral and gut microbiome and metabolomics characteristics of the 1-year convalescents were restored to a large extent but did not completely return to normal. In the recovery process, the microbial diversity gradually increased. Butyric acid-producing microbes and Bifidobacterium gradually increased, whereas lipopolysaccharide-producing microbes gradually decreased. In addition, sphingosine-1-phosphate, which is closely related to the inflammatory factor storm of COVID-19, increased significantly during the recovery process. Moreover, the predictive models established based on the microbiome and metabolites of patients at the time of discharge reached high efficacy in predicting their neutralizing antibody levels one year later.
Conclusions
This study is the first to characterize the oral and gut microbiome and metabonomics in 1-year convalescents of COVID-19. The key microbiome and metabolites in the process of recovery were identified, and provided new treatment ideas for accelerating recovery. And the predictive models based on the microbiome and metabolomics afford new insights for predicting the recovery situation which benefited affected individuals and healthcare.

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Abhishek Thakur, Gaurav Sharma, Vishnu Nayak Badavath, Venkatesan Jayaprakash, Kenneth M. Merz Jr., Galia Blum*, and Orlando Acevedo*

Primer for Designing Main Protease (Mpro) Inhibitors of SARS-CoV-2

https://doi.org/10.1021/acs.jpclett.2c01193

Published

21-Jun-22

Study

https://pubs.acs.org/doi/10.1021/acs.jpclett.2c01193

The COVID-19 outbreak has been devastating, with hundreds of millions of infections and millions of deaths reported worldwide. In response, the application of structure–activity relationships (SAR) upon experimentally validated inhibitors of SARS-CoV-2 main protease (Mpro) may provide an avenue for the identification of new lead compounds active against COVID-19. Upon the basis of information gleaned from a combination of reported crystal structures and the docking of experimentally validated inhibitors, four “rules” for designing potent Mpro inhibitors have been proposed. The aim here is to guide medicinal chemists toward the most probable hits and to provide guidance on repurposing available structures as Mpro inhibitors. Experimental examination of our own previously reported inhibitors using the four “rules” identified a potential lead compound, the cathepsin inhibitor GB111-NH2, that was 2.3 times more potent than SARS-CoV-2 Mpro inhibitor N3.

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Sandra Ekstedt, Krzysztof Piersiala, Marianne Petro, Agneta Karlsson, Åsa Kågedal, Susanna Kumlien Georén & Lars Olaf Cardell Sandra Ekstedt, Krzysztof Piersiala, Marianne Petro, Agneta Karlsson, Åsa Kågedal, Susanna Kumlien Georén & Lars Olaf Cardell

A prolonged innate systemic immune response in COVID-19

https://doi.org/10.1038/s41598-022-13986-5

Published

15-Jun-22

Article

https://www.nature.com/articles/s41598-022-13986-5

Despite the introduction of vaccines, COVID-19 still affects millions of people worldwide. A better understanding of pathophysiology and the discovery of novel therapies are needed. One of the cells of interest in COVID-19 is the neutrophil. This cell type is being recruited to a site of inflammation as one of the first immune cells. In this project, we investigated a variety of neutrophils phenotypes during COVID-19 by measuring the expression of markers for migration, maturity, activation, gelatinase granules and secondary granules using flow cytometry. We show that neutrophils during COVID-19 exhibit altered phenotypes compared to healthy individuals. The activation level including NETs production and maturity of neutrophils seem to last longer during COVID-19 than expected for innate immunity. Neutrophils as one of the drivers of severe cases of COVID-19 are considered as potential treatment targets. However, for a successful implementation of treatment, there is a need for a better understanding of neutrophil functions and phenotypes in COVID-19. Our study answers some of those questions.

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I178

Jacqui Wise

Covid-19: Long covid risk is lower with omicron than delta, researchers find

https://doi.org/10.1136/bmj.o1500

Published

17-Jun-22

Article

https://www.bmj.com/content/377/bmj.o1500

The risk of developing long covid is lower among people with the omicron variant of SARS-CoV-2 than with delta, shows an analysis of self reported data to the UK ZOE covid app.1
Researchers from King’s College London looked at data logged by 56 003 adults who tested positive between 20 December 2021 and 9 March 2022, when the omicron variant was dominant. They compared these with 41 361 who tested positive between 1 June 2021 and 27 November 2021, when the delta variant was most common.
Among the cases in the omicron period, 2501 people (4.5%) reported they had experienced long covid, defined as having new or ongoing symptoms four weeks or more after they had tested positive. This compared with 4469 (10.8%) of people in the delta period, according to the analysis, published as a letter in the Lancet.
Overall the study found a reduction in odds of long covid with the omicron variant versus the delta variant of between 0.24 and 0.5, depending on age and time since vaccination. But because far more people have been infected during the omicron wave than during the delta wave, the total number with long covid will be higher. Earlier this month the Office for National Statistics estimated that the number of people experiencing long covid increased from 1.3 million in January 2022 to two million on 1 May 2022.23
Lead researcher Claire Steves said, “The omicron variant appears substantially less likely to cause long covid than previous variants—but still, one out of every 23 people who catches covid-19 goes on to have symptoms for more than four weeks.
“Given the numbers of people affected, it’s important that we continue to support them at work, at home, and within the NHS.”
Slightly more women than men log onto the ZOE app, and fewer people from the most deprived areas, so the samples are not fully generalisable to the UK population. But the researchers said the samples were similar in both study periods, allowing comparison.
The researchers said the strength of the study was the prospective logging of a wide range of symptoms. Limitations included no direct resting of infectious variants and no objective measures of illness duration. There were also insufficient data to estimate the odds of long covid in unvaccinated people, and the study did not estimate effects in children.

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Zoe Swank, View ORCID ProfileYasmeen Senussi, Galit Alter, View ORCID ProfileDavid R. Walt

Persistent circulating SARS-CoV-2 spike is associated with post-acute COVID-19 sequelae

https://doi.org/10.1101/2022.06.14.22276401

pre-print

16-Jun-22

Study

https://www.medrxiv.org/content/10.1101/2022.06.14.22276401v1.full-text

The diagnosis and management of post-acute sequelae of COVID-19 (PASC) poses an ongoing medical challenge. Identifying biomarkers associated with PASC would immensely improve the classification of PASC patients and provide the means to evaluate treatment strategies. We analyzed plasma samples collected from a cohort of PASC and COVID-19 patients (n = 63) to quantify circulating viral antigens and inflammatory markers. Strikingly, we detect SARS-CoV-2 spike antigen in a majority of PASC patients up to 12 months post-diagnosis, suggesting the presence of an active persistent SARS-CoV-2 viral reservoir. Furthermore, temporal antigen profiles for many patients show the presence of spike at multiple time points over several months, highlighting the potential utility of the SARS-CoV-2 full spike protein as a biomarker for PASC.

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Benjamin A. Krishna
Eleanor Y. Lim
Lenette Mactavous
NIHR BioResource Team
Paul A. Lyons
Rainer Doffinger
John R. Bradley
Kenneth G.C. Smith
John Sinclair
Nicholas J. Matheson
Paul J. Lehner
Mark R. Wills
Nyaradzai Sithole

Evidence of previous SARS-CoV-2 infection in seronegative patients with long COVID

https://doi.org/10.1016/j.ebiom.2022.104129

Published

27-Jun-22

Study

https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00310-3/fulltext

Background
There is currently no consensus on the diagnosis, definition, symptoms, or duration of COVID-19 illness. The diagnostic complexity of Long COVID is compounded in many patients who were or might have been infected with SARS-CoV-2 but not tested during the acute illness and/or are SARS-CoV-2 antibody negative.
Methods
Given the diagnostic conundrum of Long COVID, we set out to investigate SARS-CoV-2-specific T cell responses in patients with confirmed SARS-CoV-2 infection and/or Long COVID from a cohort of mostly non-hospitalised patients.
Findings
We discovered that IL-2 release (but not IFN-γ release) from T cells in response to SARS-CoV-2 peptides is both sensitive (75% +/−13%) and specific (88%+/−7%) for previous SARS-CoV-2 infection >6 months after a positive PCR test. We identified that 42–53% of patients with Long COVID, but without detectable SARS-CoV-2 antibodies, nonetheless have detectable SARS-CoV-2 specific T cell responses.
Interpretation
Our study reveals evidence (detectable T cell mediated IL-2 release) of previous SARS-CoV-2 infection in seronegative patients with Long COVID.

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Elena Azzolini, MD, PhD1; Riccardo Levi, MSc2; Riccardo Sarti, MSc2; Chiara Pozzi, PhD1; Maximiliano Mollura, MSc3; Alberto Mantovani, MD1; Maria Rescigno, PhD1

Association Between BNT162b2 Vaccination and Long COVID After Infections Not Requiring Hospitalization in Health Care Workers

https://doi.org/10.1001/jama.2022.11691

Published

1-Jul-22

Study

https://jamanetwork.com/journals/jama/fullarticle/2794072

Survivors of COVID-19 may present with long-lasting symptoms.1 Some factors have been associated with the development of post-COVID conditions (also referred to as “long COVID”),2 including hospitalization.3 A study of older US veterans showed 15% reduction of long COVID after vaccination; however, study limitations included the low number of women and suboptimal vaccination schedules.4
Methods
The study was approved by the Humanitas Research Hospital institutional review board. Each participant provided written informed consent.
We conducted an observational cohort study from March 2020 to April 2022 in individuals working in 9 Italian health care facilities.5,6 Polymerase chain reaction (PCR) tests for SARS-CoV-2 were conducted every week (in COVID wards) or 2 weeks (in other wards) for hospital personnel, or if they developed symptoms or were exposed to cases. All health care workers were required to receive 3 doses of vaccine (BNT162b2), with the first and second doses administered in January-February 2021 and the booster dose in November-December 2021.
Between February and April 2022, each participant completed a survey including demographics, comorbidities, a list of SARS-CoV-2–related symptoms at the time of infection and their duration (survey in the Supplement), and vaccination status. We defined long COVID as reporting at least 1 SARS-CoV-2–related symptom with a duration of more than 4 weeks. Hospitalized individuals were excluded to avoid bias related to severe disease, as were individuals with a date of infection less than 28 days before the survey. We included asymptomatic infections in the acute infection group (they could not have long COVID by definition) to avoid overestimating the prevalence of long COVID. The analysis was restricted to health care workers who were tested every 1 or 2 weeks with complete demographic data and a documented positive result for SARS-CoV-2 between March 2020 and March 2022.
By the date of infection, we divided the patients into 3 groups corresponding to the peaks in our data and circulation of variants of concern in Italy (wave 1, February-September 2020 [wild-type variant]; wave 2, October 2020-July 2021 [Alpha]; and wave 3, August 2021-March 2022 [Delta and Omicron]) (eFigure in the Supplement). A multivariable logistic regression model was used to assess the relationship between long COVID and characteristics, including participant sex, age, SARS-CoV-2 infection, wave, and vaccination status 14 days prior to infection. Time since second vaccination was assessed among vaccinated individuals.
The Clopper-Pearson method was used to calculate 95% CIs and the Mann-Whitney U test or the t test for continuous variables and the χ2-test for categorical variables to calculate P values. The significance threshold was defined as P < .05 (2-sided). Analyses were done in Python, version 3.8.3.
Results
Of 2560 participants, 739 individuals (29%) had COVID-19 (89 asymptomatic), of whom 229 (31.0%; 95% CI, 27.7%-34.5%) had long COVID (Table 1). The prevalence of long COVID varied across the pandemic waves, from 48.1% (95% CI, 39.9%-56.2%) in wave 1 to 35.9% (95% CI, 30.5%-41.6%) in wave 2 to 16.5% (95% CI, 12.4%-21.4%) in wave 3. The number of vaccine doses was associated with lower long COVID prevalence: 41.8% (95% CI, 37.0%-46.7%) in unvaccinated patients, 30.0% (95% CI, 6.7%-65.2%) with 1 dose, 17.4% (95% CI, 7.8%-31.4%) with 2 doses, and 16.0% (95% CI, 11.8%-21.0%) with 3 doses. Older age, higher body mass index, allergies, and obstructive lung disease were associated with long COVID.
With a reference group of unvaccinated females in wave 1 with no allergies or comorbidities (Table 2), male sex (odds ratio [OR], 0.65; 95% CI, 0.44-0.98, P = .04), 2 vaccine doses (OR, 0.25; 95% CI, 0.07-0.87, P = .03), and 3 vaccine doses (OR, 0.16; 95% CI, 0.03-0.84, P = .03) were associated with a lower probability of long COVID. Older age (OR, 1.23; 95% CI, 1.01-1.49, P = .04), allergies (OR, 1.50; 95% CI, 1.06-2.11, P = .02), and an increasing number of comorbidities (OR, 1.32; 95% CI, 1.04-1.68, P = .03) were associated with a higher probability. No statistically significant association with infection wave was found. Among vaccinated individuals (n = 265), time between the second vaccination dose and infection was not associated with long COVID (OR, 0.66; 95% CI, 0.34-1.29).
Discussion
In this longitudinal observational study conducted among health care workers with SARS-CoV-2 infections not requiring hospitalization, 2 or 3 doses of vaccine, compared with no vaccination, were associated with lower long COVID prevalence. Study limitations include that symptoms and duration were self-reported, and causality cannot be inferred.

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Anna Vicco ,Francesca Caccuri ,Serena Messali,Adriana Vitiello,Aron Emmi,Claudia Del Vecchio,Alberto Reale,Arnaldo Caruso,Giancarlo Ottaviano,Carla Mucignat,Cristina Parolin,Angelo Antonini ,Arianna Calistri Anna Vicco ,Francesca Caccuri ,Serena Messali,Adriana Vitiello,Aron Emmi,Claudia Del Vecchio,Alberto Reale,Arnaldo Caruso,Giancarlo Ottaviano,Carla Mucignat,Cristina Parolin,Angelo Antonini ,Arianna Calistri

Genomic surveillance of SARS-CoV-2 in patients presenting neurological manifestations

https://doi.org/10.1371/journal.pone.0270024

Published

30-Jun-22

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0270024

During the first wave of infections, neurological symptoms in Coronavirus Disease 2019 (COVID-19) patients raised particular concern, suggesting that, in a subset of patients, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could invade and damage cells of the central nervous system (CNS). Indeed, up to date several in vitro and in vivo studies have shown the ability of SARS-CoV-2 to reach the CNS. Both viral and/or host related features could explain why this occurs only in certain individuals and not in all the infected population. The aim of the present study was to evaluate if onset of neurological manifestations in COVID-19 patients was related to specific viral genomic signatures. To this end, viral genome was extracted directly from nasopharyngeal swabs of selected SARS-CoV-2 positive patients presenting a spectrum of neurological symptoms related to COVID-19, ranging from anosmia/ageusia to more severe symptoms. By adopting a whole genome sequences approach, here we describe a panel of known as well as unknown mutations detected in the analyzed SARS-CoV-2 genomes. While some of the found mutations were already associated with an improved viral fitness, no common signatures were detected when comparing viral sequences belonging to specific groups of patients. In conclusion, our data support the notion that COVID-19 neurological manifestations are mainly linked to patient-specific features more than to virus genomic peculiarities.

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Michelle D Cherne 1, Andrew B Gentry 2, Anna Nemudraia 1, Artem Nemudryy 1, Jodi F Hedges 1, Heather Walk 1, Karlin Blackwell 1, Deann T Snyder 1, Maria Jerome 1, Wyatt Madden 1 3, Marziah Hashimi 1, T Andrew Sebrell 1, David B King 2, Raina K Plowright 1, Mark A Jutila 1, Blake Wiedenheft 1, Diane Bimczok

SARS-CoV-2 is detected in the gastrointestinal tract of asymptomatic endoscopy patients but is unlikely to pose a significant risk to healthcare personnel

https://doi.org/10.1016/j.gastha.2022.06.002

Published

24-Jun-22

Study

https://pubmed.ncbi.nlm.nih.gov/35765598/

Background and aims: Recent evidence suggests that the gut is an additional target for SARS-CoV-2 infection. However, whether SARS-CoV-2 spreads via gastrointestinal secretions remains unclear. To determine the prevalence of gastrointestinal SARS-CoV-2 infection in asymptomatic subjects, we analyzed gastrointestinal biopsy and liquid samples from endoscopy patients for the presence of SARS-CoV-2.
Methods: We enrolled 100 endoscopic patients without known SARS-CoV-2 infection (cohort A) and 12 patients with a previous COVID-19 diagnosis (cohort B) in a cohort study performed at a regional hospital. Gastrointestinal biopsies and fluids were screened for SARS-CoV-2 by PCR, immunohistochemistry and virus isolation assay, and the stability of SARS-CoV-2 in gastrointestinal liquids in vitro was analyzed.
Results: SARS-CoV-2 RNA was detected by PCR in the colonic tissue of 1/100 patients in cohort A. In cohort, B, three colonic liquid samples tested positive for SARS-CoV-2 by PCR, and viral nucleocapsid protein was detected in the epithelium of the respective biopsy samples. However, no infectious virions were recovered from any samples. In vitro exposure of SARS-CoV-2 to colonic liquid led to a 4-log fold reduction of infectious SARS-CoV-2 within 1 hour (P ≤ 0.05).
Conclusions: Overall, the persistent detection of SARS-CoV-2 in endoscopy samples after resolution of COVID-19 points to the gut as a long-term reservoir for SARS-CoV-2. Since no infectious virions were recovered and SARS-CoV-2 was rapidly inactivated in the presence of colon liquids, it is unlikely that performing endoscopic procedures is associated with a significant infection risk due to undiagnosed asymptomatic or persistent gastrointestinal SARS-CoV-2 infections.

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Oya Ozlem Eren-Kutsoylu, Ozgur Appak, Arzu Nazli-Zeka, Gokcen Omeroglu-Simsek, Nil Tekin, Basak Bayram, Ayca Arzu Sayiner, Nesim Tanglay & Vildan Avkan-Oguz

Evaluation of SARS-CoV-2 antibody persistence and viral spread in stool: a long-term care experience before COVID-19 vaccination

https://doi.org/10.1007/s11845-022-03095-7

Published

12-Jul-22

Study

https://link.springer.com/article/10.1007/s11845-022-03095-7

Background
Due to elderly residents, nursing homes/assisted living facilities were the most affected places in COVID-19 pandemic. Besides symptomatic patients, asymptomatic patients were detected during routine screening.
Aim
This study aims to determine the factors that affect antibody response and viral shedding in stool samples after natural exposure to the virus in residents and staff who recovered from COVID-19 before the vaccine was available.
Methods
This prospective cross-sectional study was conducted at the nation’s highest-capacity Residential and Nursing Home. Blood samples were collected between December 15, 2020 and January 15, 2021 from participating residents and staff for anti-SARS-CoV-2 antibody testing. Stool samples were obtained for SARS-CoV-2 PCR testing 2 months after COVID-19. The Social Sciences (SPSS) program version 15.0 was used for statistical analysis. The Mann–Whitney U test compared SARS‐CoV‐2 antibody concentration between two groups.
Results
Four hundred sixty-four (52.3%) residents and 424 (47.7%) staff participated. Entirely 259 (29.2%) participants were anti-SARS-CoV-2 IgG (+) and 255 (28.7%) were SARS-CoV-2 PCR (+). Both antibody and PCR positivity was detected in 196 (76.9%). In PCR (−) group, 63 (10.0%) participants were SARS-CoV‐2 IgG (+). Antibody titers were found highest in SARS-CoV-2 PCR (+) male residents. SARS-CoV-2 IgG titers were significantly high in SARS-CoV-2 PCR (+) and hospitalized participants regardless of age. Stool samples were obtained from 61(23.9%) participants and were found negative.
Conclusion
A durable SARS-CoV‐2 IgG antibody response was monitored at least 9 months after the participants were diagnosed with COVID-19. SARS-CoV-2 antibody positivity was detected 76.9% in PCR (+) and 10.0% in PCR (−) participants. Knowing the duration of detectable antibodies is an important finding for developing disease prevention and public health strategies.

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Laracy, Justin C.a,b; Kamboj, Minia,b; Vardhana, Santosha A.c,d

https://journals.lww.com/co-infectiousdiseases/Abstract/2022/08000/Long_and_persistent_COVID_19_in_patients_with.3.aspx

https://doi.org/10.1097/QCO.0000000000000841

Published

5-Jul-22

Review

https://journals.lww.com/co-infectiousdiseases/Abstract/2022/08000/Long_and_persistent_COVID_19_in_patients_with.3.aspx

Purpose of review
Cancer patients, especially those with hematologic malignancies, are at increased risk for coronavirus disease 2019 (COVID-19)-related complications and mortality. We describe the incidence, clinical characteristics, risk factors, and outcomes of persistent COVID-19 infection in patients with hematologic malignancies.
Recent findings
The syndrome of persistent COVID-19 in patients with hematologic malignancies manifests as a chronic protracted illness marked by waxing and waning or progressive respiratory symptoms and prolonged viral shedding. Immunosuppressed patients with lymphoid malignancies may serve as partially immune reservoirs for the generation of immune-evasive viral escape mutants.
Summary
Persistent COVID-19 infection is a unique concern in patients with hematologic malignancies. While vaccination against severe acute respiratory syndrome coronavirus 2 has reduced the overall burden of COVID-19 in patients with hematologic cancers, whether vaccination or other novel treatments for COVID-19 prevent or alleviate this syndrome remains to be determined.

1371

I186

Aqsa Mumtaz 1,Abdul Ahad Ehsan Sheikh 2,Amin Moazzam Khan 3ORCID,Subaina Naeem Khalid 3ORCID,Jehanzaeb Khan 4,Adeel Nasrullah 5ORCID,Shazib Sagheer 6 andAbu Baker Sheikh 4,*ORCID

COVID-19 Vaccine and Long COVID: A Scoping Review

https://doi.org/10.3390/life12071066

Published

16-Jul-22

Review

https://www.mdpi.com/2075-1729/12/7/1066/htm

As the COVID-19 pandemic progresses, changing definitions and therapeutics regarding the post-acute sequela of COVID-19, particularly long COVID, have become a subject of great interest and study. The study aims to describe the pathophysiology and discuss different therapeutic agents currently available for long COVID. Another objective is to assess comparative efficacy between different types of vaccines on symptoms of long COVID. A preliminary search was conducted using Ovid Medline, Embase, medRxiv, and NIH COVID-19 portfolios. A total of 16 studies were included in our review. Despite some of the data showing variable results, most of the vaccinated patients reported improvement in long COVID symptoms with no significant difference between various types of vaccines. Further trials are needed to better identify the comparative efficacy of vaccines for long COVID and ascertain other therapeutic modalities.

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I187

Lisa M James, Apostolos P Georgopoulos

At the Root of 3 “Long” Diseases: Persistent Antigens Inflicting Chronic Damage on the Brain and Other Organs in Gulf War Illness, Long-COVID-19, and Chronic Fatigue Syndrome

https://doi.org/10.1177%2F26331055221114817

Published

22-Jul-22

Article

https://journals.sagepub.com/doi/full/10.1177/26331055221114817

Several foreign antigens such as those derived from viruses and bacteria have been linked to long-term deleterious effects on the brain and other organs; yet, health outcomes subsequent to foreign antigen exposure vary depending in large part on the host’s immune system, in general, and on human leukocyte antigen (HLA) composition, in particular. Here we first provide a brief description of 3 conditions characterized by persistent long-term symptoms, namely long-COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and Gulf War Illness (GWI), followed by a brief overview of the role of HLA in the immune response to foreign antigens. We then discuss our Persistent Antigen (PA) hypothesis and highlight associations between antigen persistence due to HLA-antigen incongruence and chronic health conditions in general and the 3 “long” diseases above in particular. This review is not intended to cover the breadth and depth of symptomatology of those diseases but is specifically focused on the hypothesis that the presence of persistent antigens underlies their pathogenesis.

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V. Lammi,1 H.M. Ollila,1,

Tackling Long COVID using international host genetics research collaboration

https://doi.org/10.1016%2Fj.sleep.2022.05.184

Published

21-Jul-22

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9300219/

Introduction: While the world is still fighting the spread and casualties of the acute disease caused by SARS-CoV-2 virus, there is also a need for mitigating the long-term effects of this pandemic. WHO has estimated that 10-20% of coronavirus disease 2019 (COVID-19) patients suffer from lingering symptoms, termed Long COVID (Post-acute sequelae of COVID-19, PASC / Post COVID-19 conditions). Various symptoms have been reported in virtually all organs, with debilitating fatigue, exercise intolerance, cognitive dysfunction, anxiety, depression, loss of smell or taste, and sleep difficulties among the most prevalent.
Several pathophysiological mechanisms ranging from prolonged infection to tissue damage and autoimmunity have been proposed. Studying human genetic variants predisposing to Long COVID can provide hypothesis-free information on the underlying biology.
Materials and methods: We have established an open world-wide collaboration for elucidating genetic risk factors for Long COVID. Currently, the Long COVID Host Genetics Initiative comprises 46 studies across 23 countries with genotype data combined to questionnaire information of symptoms and/or electronic health record (EHR) data of diagnoses.
Using questionnaire data, we have defined Long COVID as ‘any symptoms that cannot be explained by alternative diagnoses, or impact on everyday functioning, 3 months after the onset of COVID’. With EHR data, we have used specific diagnosis codes for Post COVID-19 conditions (ICD-10: U09) or Coronavirus as the cause of other diseases (B97.2).
In the first data freeze, we have data from 11 studies from 8 countries, with 1,534 Long COVID cases and 800,353 controls, of which 96,692 have had COVID but not Long COVID. Each contributing study has performed genome-wide association analyses (GWAS) comparing Long COVID to individuals who have recovered from COVID within 3 months, and to population controls. Also lifestyle measures and other diagnoses have been broadly assessed in some of the participating cohorts. This allowed us to examine the phenotypic associations with Long COVID using logistic regression.
Results: GWAS of individual cohorts have suggested potential variants associated with Long COVID but without genome-wide statistical significance. We are currently running meta-analyses to increase statistical power by combining data from these studies.
Using registry follow-up of 12 months in the FinnGen study after the beginning of the COVID-19 pandemic in Finland identified 2,018 participants with a PCR-verified SARS-CoV-2 infection. 50 (2.5%) of them had received a diagnosis for long COVID. Long COVID associated with autoimmune diseases (p = 0.026, OR[se] = 2.15[1.41]) but not with depression (p = 0.71, OR[se] = 1.20[1.75]) or asthma (p = 0.43, OR[se] = 1.55[1.74]).
Conclusions: Our findings indicate that Long COVID may be related to autoimmunity. The joint effort of the international Long COVID Host Genetics Initiative combining phenotypic and genetic data will allow us to identify genetic risk factors and test causality between autoimmunity and Long COVID.

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William J. Pandori,Lindsey E. Padgett,Ahmad Alimadadi,Norma A. Gutierrez,Daniel J. Araujo,Christine J. Huh,Claire E. Olingy,Huy Q. Dinh,Runpei Wu,Pandurangan Vijayanand,Serena J. Chee,Christian H. Ottensmeier,Catherine C. Hedrick

Single-cell immune profiling reveals long-term changes in myeloid cells and identifies a novel subset of CD9+ monocytes associated with COVID-19 hospitalization

https://doi.org/10.1002/JLB.4COVA0122-076R

Published

22-Jul-22

Study

https://jlb.onlinelibrary.wiley.com/doi/full/10.1002/JLB.4COVA0122-076R

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in severe immune dysfunction, hospitalization, and death. Many patients also develop long-COVID-19, experiencing symptoms months after infection. Although significant progress has been made in understanding the immune response to acute SARS-CoV-2 infection, gaps remain in our knowledge of how innate immunity influences disease kinetics and severity. We hypothesized that cytometry by time-of-flight analysis of PBMCs from healthy and infected subjects would identify novel cell surface markers and innate immune cell subsets associated with COVID-19 severity. In this pursuit, we identified monocyte and dendritic cell subsets that changed in frequency during acute SARS-CoV-2 infection and correlated with clinical parameters of disease severity. Subsets of nonclassical monocytes decreased in frequency in hospitalized subjects, yet increased in the most severe patients and positively correlated with clinical values associated with worse disease severity. CD9, CD163, PDL1, and PDL2 expression significantly increased in hospitalized subjects, and CD9 and 6-Sulfo LacNac emerged as the markers that best distinguished monocyte subsets amongst all subjects. CD9+ monocytes remained elevated, whereas nonclassical monocytes remained decreased, in the blood of hospitalized subjects at 3–4 months postinfection. Finally, we found that CD9+ monocytes functionally released more IL-8 and MCP-1 after LPS stimulation. This study identifies new monocyte subsets present in the blood of COVID-19 patients that correlate with disease severity, and links CD9+ monocytes to COVID-19 progression.

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Yu-Si Luo1,2†, www.frontiersin.orgLei Luo3†, www.frontiersin.orgWei Li4, www.frontiersin.orgYan Chen5, www.frontiersin.orgGuo-Feng Wu1, www.frontiersin.orgFang Chen2, www.frontiersin.orgHu-Yan Shen2, www.frontiersin.orgHong-Man Li6, www.frontiersin.orgMing-Yang Guo2, www.frontiersin.orgSha Yin3, www.frontiersin.orgKe Zhang2* and www.frontiersin.orgZhong-Shan Cheng7*

Evaluation of a Functional Single Nucleotide Polymorphism of the SARS-CoV-2 Receptor ACE2 That Is Potentially Involved in Long COVID

https://doi.org/10.3389/fgene.2022.931562

Published

18-Jul-22

Article

https://www.frontiersin.org/articles/10.3389/fgene.2022.931562/full

Since the occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, SARS-CoV-2 has led to a global coronavirus disease 2019 (COVID-19) pandemic. A better understanding of the SARS-CoV-2 receptor ACE2 at the genetic level would help combat COVID-19, particularly for long COVID. We performed a genetic analysis of ACE2 and searched for its common potential single nucleotide polymorphisms (SNPs) with minor allele frequency >0.05 in both European and Chinese populations that would contribute to ACE2 gene expression variation. We thought that the variation of the ACE2 expression would be an important biological feature that would strongly affect COVID-19 symptoms, such as “brain fog”, which is highlighted by the fact that ACE2 acts as a major cellular receptor for SARS-CoV-2 attachment and is highly expressed in brain tissues. Based on the human GTEx gene expression database, we found rs2106809 exhibited a significant correlation with the ACE2 expression among multiple brain and artery tissues. This expression correlation was replicated in an independent European brain eQTL database, Braineac. rs2106809*G also displays significantly higher frequency in Asian populations than in Europeans and displays a protective effect (p = 0.047) against COVID-19 hospitalization when comparing hospitalized COVID-19 cases with non-hospitalized COVID-19 or SARS-CoV-2 test-negative samples with European ancestry from the UK Biobank. Furthermore, we experimentally demonstrated that rs2106809*G could upregulate the transcriptional activity of ACE2. Therefore, integrative analysis and functional experiment strongly support that ACE2 SNP rs2106809 is a functional brain eQTL and its potential involvement in long COVID, which warrants further investigation.

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Soumya Arun, Abbie Storan, Bethan Myers

Mast cell activation syndrome and the link with long COVID

https://doi.org/10.12968/hmed.2022.0123

Published

26-Jul-22

Article

https://www.magonlinelibrary.com/doi/abs/10.12968/hmed.2022.0123

Mast cells are innate immune cells found in connective tissues throughout the body, most prevalent at tissue-environment interfaces. They possess multiple cell-surface receptors which react to various stimuli and, after activation, release many mediators including histamine, heparin, cytokines, prostaglandins, leukotrienes and proteases. In mast cell activation syndrome, excessive amounts of inflammatory mediators are released in response to triggers such as foods, fragrances, stress, exercise, medications or temperature changes. Diagnostic markers may be difficult to assess because of their rapid degradation; these include urinary N-methyl histamine, urinary prostaglandins D2, DM and F2α and serum tryptase (which is stable) in the UK. Self-management techniques, medications and avoiding triggers may improve quality of life. Treatments include mast cell mediator blockers, mast cell stabilisers and anti-inflammatory agents. ‘Long COVID’ describes post-COVID-19 syndrome when symptoms persist for more than 12 weeks after initial infection with no alternative diagnosis. Both mast cell activation syndrome and long COVID cause multiple symptoms. It is theorised that COVID-19 infection could lead to exaggeration of existing undiagnosed mast cell activation syndrome, or could activate normal mast cells owing to the persistence of viral particles. Other similarities include the relapse-remission cycle and improvements with similar treatments. Importantly, however, aside from mast cell disorders, long COVID could potentially be attributed to several other conditions.

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COA

Helen Fogarty,Soracha E. Ward,Liam Townsend,Ellie Karampini,Stephanie Elliott,Niall Conlon,Jean Dunne,Rachel Kiersey,Aifric Naughton,Mary Gardiner,Mary Byrne,Colm Bergin,Jamie M. O’Sullivan,Ignacio Martin-Loeches,Parthiban Nadarajan,Ciaran Bannan,Patrick W. Mallon,Gerard F. Curley,Roger J. S. Preston,Aisling M. Rehill,Ross I. Baker,Cliona Ni Cheallaigh,James S. O’Donnell,

Sustained VWF-ADAMTS13 axis imbalance and endotheliopathy in Long COVID syndrome is related to immune dysfunction

https://doi.org/10.1111/jth.15830

Published

25-Jul-22

Study

https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.15830

Background
Prolonged recovery is common after SARs-CoV-2 infection, however the pathophysiological mechanisms underpinning Long COVID syndrome remain unknown. VWF-ADAMTS13 imbalance, dysregulated angiogenesis and immuno-thrombosis are hallmarks of acute COVID-19. We hypothesized that VWF-ADAMTS13 imbalance persists in convalescence together with EC activation and angiogenic disturbance. Additionally, we postulate that ongoing immune cell dysfunction may be linked to sustained EC and coagulation activation.
Patients and Methods
Fifty patients were reviewed at a minimum of 6 weeks following acute COVID-19. ADAMTS13, WPB proteins and angiogenesis-related proteins were assessed and clinical evaluation and immunophenotyping performed. Comparisons were made with healthy controls (n=20) and acute COVID-19 patients (n=36).
Results
ADAMTS13 levels were reduced (p=0.009) and the VWF/ADAMTS13 ratio was increased in convalescence (p=0.0004). Levels of Platelet Factor 4 (PF4), a putative protector of VWF, were also elevated (p=0.0001). A non-significant increase in WPB proteins Angiopoietin-2 (Ang-2) and Osteoprotegerin (OPG) was observed in convalescent patients and WPB markers correlated with EC parameters. Enhanced expression of 21 angiogenesis-related proteins was observed in convalescent COVID-19. Finally, immunophenotyping revealed significantly elevated intermediate monocytes and activated CD4+ and CD8+ T cells in convalescence, which correlated with thrombin generation and endotheliopathy markers, respectively.
Conclusion
Our data provide insights into sustained EC activation, dysregulated angiogenesis and VWF/ADAMTS13 axis imbalance in convalescent COVID-19. In keeping with the pivotal role of immuno-thrombosis in acute COVID-19, our findings support the hypothesis that abnormal T cell and monocyte populations may be important in the context of persistent EC activation and hemostatic dysfunction during convalescence.

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Bruce K. Patterson1Email Edgar B. Francisco2 Ram Yogendra3 Emily Long4 Amruta Pise2 Christopher Beaty2 Eric Osgood5 John Bream6 Mark Kreimer7 Richard Vander Heide8 Jose Guevara-Coto9 Rodrigo Mora10 Javier Mora1

SARS-CoV-2 S1 Protein Persistence in SARS-CoV-2 Negative Post-Vaccination Individuals with Long COVID/ PASC-Like Symptoms

https://doi.org/10.21203/rs.3.rs-1844677/v1

pre-print

12-Jul-22

Study

https://www.researchsquare.com/article/rs-1844677/v1

Background
We sought to determine the immunologic abnormalities in patients following SARS-CoV-2 vaccines who experience post-acute sequelae of COVID-19 (PASC)-like symptoms > 4 weeks post vaccination. In addition, we investigated whether the potential etiology was similar to PASC.
Design:
We enrolled 50 post-vaccination individuals who experience PASC-like symptoms, 10 healthy individuals, and 35 individuals post-vaccination without symptoms. We performed multiplex cytokine/chemokine profiling with machine learning as well as SARS-CoV-2 S1 protein detection on monocyte subsets using flow cytometry and mass spectrometry.
Results
We determined that post-vaccination individuals with PASC-like symptoms had similar symptoms to PASC patients. When analyzing their immune profile, post-vaccination individuals had statistically significant elevations of sCD40L, CCL5, IL-6, and IL-8. SARS-CoV-2 S1 and S2 protein were detected in CD16 + monocytes using flow cytometry and mass spectrometry on sorted cells.
Conclusions
Post-vaccination individuals with PASC-like symptoms exhibit markers of platelet activation and pro-inflammatory cytokine production which may be driven by the persistence of SARS-CoV-2 S1 protein persistence in intermediate and non-classical monocytes.

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Xiaolin Jia,1,2 Shu Cao,1,3 Alexandra S. Lee,1,3 Monali Manohar,1,3 Sayantani B. Sindher,1,3 Neera Ahuja,1,2 Maja Artandi,1,4 Catherine A. Blish,1,5,6,7 Andra L. Blomkalns,8 Iris Chang,1,3 William J. Collins,1,2,3 Manisha Desai,1,3,9 Hena Naz Din,1,3 Evan Do,1,3 Andrea Fernandes,1,3 Linda N. Geng,1,4 Yael Rosenberg-Hasson,1,3 Megan Ruth Mahoney,1,4 Abigail L. Glascock,5 Lienna Y. Chan,5 Sharon Y. Fong,5 CLIAHUB Consortium,10 Chan Zuckerberg Biohub,5 Maira Phelps,5 Olivia Raeber,1,3 Stanford COVID-19 Biobank Study Group,10 Natasha Purington,1,3,9 Katharina Röltgen,11 Angela J. Rogers,1,12 Theo Snow,1,3 Taia T. Wang,1,6,7 Daniel Solis,11 Laura Vaughan,1,4 Michelle Verghese,11 Holden Maecker,13 Richard Wittman,1,4 Rajan Puri,1,4 Amy Kistler,5 Samuel Yang,8 Scott D. Boyd,1,3,11 Benjamin A. Pinsky,6,11 Sharon Chinthrajah,1,3 and Kari C. Nadeau1,3,12,13

Anti-nucleocapsid antibody levels and pulmonary comorbid conditions are linked to post–COVID-19 syndrome

https://doi.org/10.1172/jci.insight.156713

Published

8-Jul-22

Study

https://insight.jci.org/articles/view/156713

BACKGROUND. Prolonged symptoms after SARS-CoV-2 infection are well documented. However, which factors influence development of long-term symptoms, how symptoms vary across ethnic groups, and whether long-term symptoms correlate with biomarkers are points that remain elusive.
METHODS. Adult SARS-CoV-2 reverse transcription PCR–positive (RT-PCR–positive) patients were recruited at Stanford from March 2020 to February 2021. Study participants were seen for in-person visits at diagnosis and every 1–3 months for up to 1 year after diagnosis; they completed symptom surveys and underwent blood draws and nasal swab collections at each visit.
RESULTS. Our cohort (n = 617) ranged from asymptomatic to critical COVID-19 infections. In total, 40% of participants reported at least 1 symptom associated with COVID-19 six months after diagnosis. Median time from diagnosis to first resolution of all symptoms was 44 days; median time from diagnosis to sustained symptom resolution with no recurring symptoms for 1 month or longer was 214 days. Anti-nucleocapsid IgG level in the first week after positive RT-PCR test and history of lung disease were associated with time to sustained symptom resolution. COVID-19 disease severity, ethnicity, age, sex, and remdesivir use did not affect time to sustained symptom resolution.
CONCLUSION. We found that all disease severities had a similar risk of developing post–COVID-19 syndrome in an ethnically diverse population. Comorbid lung disease and lower levels of initial IgG response to SARS-CoV-2 nucleocapsid antigen were associated with longer symptom duration.

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Yunsung Lee, Espen Riskedal, Karl Trygve Kalleberg, Mette Istre, Andreas Lind, Fridtjof Lund-Johansen, Olaug Reiakvam, Arne V. L. Søraas, Jennifer R. Harris, John Arne Dahl, Cathrine L. Hadley & Astanand Jugessur

EWAS of post-COVID-19 patients shows methylation differences in the immune-response associated gene, IFI44L, three months after COVID-19 infection

https://doi.org/10.1038/s41598-022-15467-1

Published

7-Jul-22

Study

https://www.nature.com/articles/s41598-022-15467-1

Although substantial progress has been made in managing COVID-19, it is still difficult to predict a patient’s prognosis. We explored the epigenetic signatures of COVID-19 in peripheral blood using data from an ongoing prospective observational study of COVID-19 called the Norwegian Corona Cohort Study. A series of EWASs were performed to compare the DNA methylation profiles between COVID-19 cases and controls three months post-infection. We also investigated differences associated with severity and long-COVID. Three CpGs—cg22399236, cg03607951, and cg09829636—were significantly hypomethylated (FDR < 0.05) in COVID-19 positive individuals. cg03607951 is located in IFI44L which is involved in innate response to viral infection and several systemic autoimmune diseases. cg09829636 is located in ANKRD9, a gene implicated in a wide variety of cellular processes, including the degradation of IMPDH2. The link between ANKRD9 and IMPDH2 is striking given that IMPDHs are considered therapeutic targets for COVID-19. Furthermore, gene ontology analyses revealed pathways involved in response to viruses. The lack of significant differences associated with severity and long-COVID may be real or reflect limitations in sample size. Our findings support the involvement of interferon responsive genes in the pathophysiology of COVID-19 and indicate a possible link to systemic autoimmune diseases.

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PESE

Jon Klein, Jamie Wood, Jillian Jaycox, Peiwen Lu, Rahul M. Dhodapkar, Jeff R. Gehlhausen, Alexandra Tabachnikova, Laura Tabacof, Amyn A. Malik, Kathy Kamath, Kerrie Greene, Valter Silva Monteiro, Mario Peña-Hernandez, Tianyang Mao, Bornali Bhattacharjee, Takehiro Takahashi, Carolina Lucas, Julio Silva, Dayna Mccarthy, Erica Breyman, Jenna Tosto-Mancuso, Yile Dai, Emily Perotti, Koray Akduman, Tiffany J. Tzeng, Lan Xu, Inci Yildirim, Harlan M. Krumholz, John Shon, Ruslan Medzhitov, Saad B. Omer, David van Dijk, Aaron M. Ring, David Putrino, Akiko Iwasaki

Distinguishing features of Long COVID identified through immune profiling

https://doi.org/10.1101/2022.08.09.22278592

pre-print

10-Aug-22

Study

https://www.medrxiv.org/content/10.1101/2022.08.09.22278592v1.full-text

SARS-CoV-2 infection can result in the development of a constellation of persistent sequelae following acute disease called post-acute sequelae of COVID-19 (PASC) or Long COVID1–3. Individuals diagnosed with Long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions1–3; however, the basic biological mechanisms responsible for these debilitating symptoms are unclear. Here, 215 individuals were included in an exploratory, cross-sectional study to perform multi-dimensional immune phenotyping in conjunction with machine learning methods to identify key immunological features distinguishing Long COVID. Marked differences were noted in specific circulating myeloid and lymphocyte populations relative to matched control groups, as well as evidence of elevated humoral responses directed against SARS-CoV-2 among participants with Long COVID. Further, unexpected increases were observed in antibody responses directed against non-SARS-CoV-2 viral pathogens, particularly Epstein-Barr virus. Analysis of circulating immune mediators and various hormones also revealed pronounced differences, with levels of cortisol being uniformly lower among participants with Long COVID relative to matched control groups. Integration of immune phenotyping data into unbiased machine learning models identified significant distinguishing features critical in accurate classification of Long COVID, with decreased levels of cortisol being the most significant individual predictor. These findings will help guide additional studies into the pathobiology of Long COVID and may aid in the future development of objective biomarkers for Long COVID.

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Paul Farrell

Review 2: "Impact of Pre-Existing Chronic Viral Infection and Reactivation on the Development of Long COVID"

https://doi.org/10.1162/2e3983f5.67d7e320

Published

11-Aug-22

Study Review

https://rapidreviewscovid19.mitpress.mit.edu/pub/mjjeglr7/release/1

Reviewers were mixed on the overall reliability of this preprint. There is agreement that the study results are supported by the data, but some concern over the suggested explanation for the results.
Although descriptive, this is a well presented, valuable and worthwhile study.
Minor points to be addressed:
Table 1 is good but it does not allow the reader to know the distribution of the preexisting conditions in the patient cohort (were they all in different people, did the same 54 HIV+ people have most of the conditions etc?). It would be helpful to also have a more comprehensive supplementary table showing the distribution of the conditions in the patient population.
Since only some of the patients have raised antibodies to EBV, should the title of the paper be “Evidence of recent EBV reactivation in some individuals experiencing long COVID” ? The current title seems to imply that they all have raised EBV antibodies.

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PESE

Rohrhofer J 1 #, Graninger M 2#, Lettenmaier L 1, Schweighardt J 1, Gentile SA 1, Koidl L 1, Ret D 1, 3, Stingl M 4, Puchhammer-Stöckl E 2#*, Untersmayr E 1#

Association between EBV reactivation and development of Long-COVID fatigue

http://dx.doi.org/10.1111/all.15471

Published

8-Aug-22

Study

https://onlinelibrary.wiley.com/doi/epdf/10.1111/all.15471

To the Editor,Post-viral fatigue after S ARS-CoV-2 infection is a major concern in the ongoing COVID-19 pandemic. Up to 10% of patients develop Long-C O VID1, a syndrome defined by the National Institute for Health and Care Excellence as post-infectious long-term symptoms for more than 12 weeks, which cannot be explained by alternative pathologies1. While some Long-COVID symptoms, like shortness of breath or chest pain, might be associated with organdamage, the origin of post COVID fatigue, including debilitating fatigue and impaired memory and concentration, remains unclear. Several viruses were associated with post-viral fatigue, such as Epstein-Barr-Virus (EBV) or influenza viruses. Also, Myalgic encephalomyelitis / chronic fatigue syndrome, a WHO defined independent disease, may develop, amongst other triggers, after viral infections. However, the mechanisms leading to post-viral fatigue syndrome in overall and especially in Long-C O VID are unresolved 2. So far a higher frequency of EBV viremia was observed only in acute severe C O VID-19 infections 3. In the present prospective study, we analysed whether Long-C O VID fatigue may be triggered by SARS-CoV-2 persistence in the gastrointestinal or respirator y tract after acute disease 2, or by C O VID-19 associated reactivation of EBV. We tested for SARS-CoV-2 RNA in stool and throat washings, and for EBV D NA in stool, throat washings and blood by real time PCR (EBV) and real time RT-PCR (SARS-CoV-2) as described before 4,5. The exper imental procedures were performed with permission of the human ethics committee of the Medical University of Vienna (vote number: 2281/2020). All patients provided written informed consent. Samples were collected between 74 and 471 days (median: 235 days) after beginning of acute S ARS-CoV-2 infection in 30 Long-C O VIDpatients characterized by persistent fatigue, post-exertional malaise (PEM), autonomic dysfunction and/or orthostatic intolerance. Twenty age- and sex-matched patients, who have fully recovered after the S ARS-CoV-2 infection, were recruited for control pur poses. Samples were collected between 106 and 571 days (median: 275 days) after beginning of acute SARS-CoV-2 infection. All patients had mild infections, were not hospitalized and infected between spring 2020 and autumn 2021. We further analyzed virus-specific antibodies including SARS-CoV-2 IgA and IgG with commercial ELISA assays (Euroimmun, Germany). As Long-C O VID patients showed a higher frequency of positive titers for specific EBV antibodies compared to controls in earlier studies 6, the patients’ EBV IgM and IgG were tested by a commercial microarray (ViraMed, Germany). Demographic data as well as inclusion and exclusion criteria are depicted in Suppl. Table 1. More detailed information on the methodological procedures are listed in the supplementary information.At time point of sampling, SARS-CoV-2 RNA was detectable neither in throat washing nor stool in any of the study participants by real time RT-PCR. SARS-CoV-2 antibody titers (IgA and Ig G) did not differ between the cohorts (Suppl. Fig. 1). Most study participants had been vaccinated after COVID-19 disease prior to sampling (24/30 in Long-C O VID patients, 17/20 in controls). EBV real time PCR was negative in all blood or stool samples. However, EBV DNA was detected in throat washings in 15/30 (50%) of Long-C O VID patients while only in 4/20 (20%) of non-Long-C O VID patients who had recovered from their SARS-CoV-2 infection (p= 0.0411). EB V load levels were not significantly different between the two cohorts in EBV-specific real time PCR positive samples (Figure 1). All patients of both groups, except one patient in the fully convalescent COVID-19 group (SARS-CoV-2 – LC),had past EB V infections, as confirmed by EBV IgG seropositive and I g M seronegative status at the time of investigation, thus the EBV r eplication observed was due to EB V reactivationrather than primary infection. EBV specific antibody titers as assessed by microarray in blood were not different between the groups. (Suppl. Fig. 2) Taken together, SARS-CoV-2 persistence could not be detected in our study participants up to 10 weeks after infection, but EB V reactivation in the throat was more common in patientswith Long-C O VID fatigue, also months after acute S ARS-CoV-2 infection, compared to convalescent SARS-CoV-2 patients. This suggests that EBV replication may be a co-factor in a sub-group of patients developing Long-C O VID fatigue. However, contributing factors, such as HLA-subtype depending answers to latent EBV infection, have not been evaluated in this study and represent limitations. Earlier reports of differences in the EBV antibody profile of Long-C O VID patients6 could not be confirmed, possibly due to the small sample sizeanalyzed in our study. Further and larger studies are needed to clarify the impact and mechanism of EBV-associated Long-COVID fatigue.

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Icaro Bonyek-Silva1,2,3,4, Thiago Cerqueira-Silva1,2, Sara Nunes1,2, Antônio Fernando Araújo Machado5, Márcio Rivison Silva Cruz5, Blenda Pereira1,2, Leilane Estrela1, Jéssica Silva1,2, Ananda Isis1, Aldina Barral1,2,6, Pablo Rafael Silveira Oliveira7, Ricardo Khouri1,2, C. Henrique Serezani8, Cláudia Brodskyn1,2,6, Juliana Ribeiro Caldas5,9,10, Manoel Barral-Netto1,2,6, Viviane Boaventura1,2† and Natalia Machado Tavares

Prediabetes Induces More Severe Acute COVID-19 Associated With IL-6 Production Without Worsening Long-Term Symptoms

https://doi.org/10.3389/fendo.2022.896378

Published

8-Jul-22

Study

https://www.frontiersin.org/articles/10.3389/fendo.2022.896378/full

Aims: Pre-existing conditions, such as age, hypertension, obesity, and diabetes, constitute known risk factors for severe COVID-19. However, the impact of prediabetes mellitus (PDM) on COVID-19 severity is less clear. This study aimed to evaluate the influence of PDM in the acute and long-term phases of COVID-19.
Materials and methods: We compared inflammatory mediators, laboratory and clinical parameters and symptoms in COVID-19 patients with prediabetes (PDM) and without diabetes (NDM) during the acute phase of infection and at three months post-hospitalization.
Results: Patients with PDM had longer hospital stays and required intensive care unit admission more frequently than NDM. Upon hospitalization, PDM patients exhibited higher serum levels of interleukin 6 (IL-6), which is related to reduced partial pressure of oxygen (PaO2) in arterial blood, oxygen saturation (SpO2) and increased COVID-19 severity. However, at three months after discharge, those with PDM did not exhibit significant alterations in laboratory parameters or residual symptoms; however, PDM was observed to influence the profile of reported symptoms.
Conclusions: PDM seems to be associated with increased risk of severe COVID-19, as well as higher serum levels of IL-6, which may constitute a potential biomarker of severe COVID-19 risk in affected patients. Furthermore, while PDM correlated with more severe acute-phase COVID-19, no long-term worsening of sequelae was observed.

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Zhu Yang , Di Wu, Shanxin Lu, +9 , Yang Qiu, Zhengyi Hua, Fancheng Tan, Cixiong Zhang, Lei Zhang, Ding-Yu Zhang, Xi Zhou Zongwei Cai , You Shang you_shanghust@163.com, and Shu-Hai Lin

Plasma metabolome and cytokine profile reveal glycylproline modulating antibody fading in convalescent COVID-19 patients

https://doi.org/10.1073/pnas.2117089119

Published

9-Aug-22

Study

https://www.pnas.org/doi/full/10.1073/pnas.2117089119

Significance
Using absolute quantification of both cytokines and metabolites from the plasmas of convalescent COVID-19 patients, machine-learning approaches identified that a combination of cytokines and metabolites can clearly discriminate convalescent patients with rapidly faded antibodies (CO) from ordinary convalescents with antibodies (CA). We found glycylproline (gly-pro) accumulation in CO individuals compared with the CA group. Intriguingly, gly-pro contributes to the rapid fading of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–specific antibodies, whereas the inhibitor of its producing enzyme dipeptidyl peptidase 4, an antidiabetic drug, can counteract the gly-pro–down-regulated SARS-CoV-2-specific antibodies under physiological conditions. Therefore, our findings point to a novel mechanism for gly-pro–suppressed immune responses upon SARS-CoV-2 infection and provide therapeutic potentials for maintaining neutralizing antibody levels.
Abstract
The COVID-19 pandemic has incurred tremendous costs worldwide and is still threatening public health in the “new normal.” The association between neutralizing antibody levels and metabolic alterations in convalescent patients with COVID-19 is still poorly understood. In the present work, we conducted absolutely quantitative profiling to compare the plasma cytokines and metabolome of ordinary convalescent patients with antibodies (CA), convalescents with rapidly faded antibodies (CO), and healthy subjects. As a result, we identified that cytokines such as M-CSF and IL-12p40 and plasma metabolites such as glycylproline (gly-pro) and long-chain acylcarnitines could be associated with antibody fading in COVID-19 convalescent patients. Following feature selection, we built machine-learning–based classification models using 17 features (six cytokines and 11 metabolites). Overall accuracies of more than 90% were attained in at least six machine-learning models. Of note, the dipeptide gly-pro, a product of enzymatic peptide cleavage catalyzed by dipeptidyl peptidase 4 (DPP4), strongly accumulated in CO individuals compared with the CA group. Furthermore, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination experiments in healthy mice demonstrated that supplementation of gly-pro down-regulates SARS-CoV-2–specific receptor-binding domain antibody levels and suppresses immune responses, whereas the DPP4 inhibitor sitagliptin can counteract the inhibitory effects of gly-pro upon SARS-CoV-2 vaccination. Our findings not only reveal the important role of gly-pro in the immune responses to SARS-CoV-2 infection but also indicate a possible mechanism underlying the beneficial outcomes of treatment with DPP4 inhibitors in convalescent COVID-19 patients, shedding light on therapeutic and vaccination strategies against COVID-19.

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Cristina Solé, Sandra Domingo, Xavier Vidal & Josefina Cortés-Hernández

Humoral and cellular response in convalescent COVID-19 lupus patients

https://doi.org/10.1038/s41598-022-17334-5

Published

12-Aug-22

Study

https://www.nature.com/articles/s41598-022-17334-5

In SLE, underlying immune dysregulation and immunosuppression may increase the susceptibility to COVID-19 and impair the humoral and adaptive response. We aimed to characterize COVID-19 infection, identifying susceptibility and severity risk factors, assessing the presence of SARS-CoV-2 IgG antibodies and analyzing the cellular response. We established a prospective cohort of lupus patients to estimate the COVID-19 incidence compared to the reference general population. Data were collected via telephone interviews and medical record review. SARS-CoV-2 IgG antibodies were measured cross-sectionally as part of routine surveillance. Longitudinal changes in antibody titers and immunological profile from convalescent COVID-19 patients were evaluated at 6, 12 and 24 week after symptom onset. From immunological studies, PBMCs from convalescent patients were extracted and analyzed by flow cytometry and gene expression analysis. We included 725 patients, identifying 29 with PCR-confirmed COVID-19 infection and 16 with COVID-19-like symptoms without PCR-testing. Of the 29 confirmed cases, 7 had severe disease, 8 required hospital admission (27.6%), 4 intensive care, and 1 died. COVID-19 accumulated incidence was higher in lupus patients. Health care workers and anti-SSA/Ro52 antibody positivity were risk factors for COVID-19 susceptibility, and hypocomplementemia for severity. SARS-CoV-2 IgG antibodies were detected in 8.33% of patients. Three fourths of confirmed COVID-19 cases developed antibodies. High prednisone doses were associated with lack of antibody response. Antibody titers declined over time (39%). Convalescent patients at week 12 after symptom onset displayed a CD8+T cell reduction and predominant Th17 with a mild Th2 response, more pronounced in severe COVID-19 disease. Longitudinal immune response analysis showed a progressive sustained increase in CD8+ T and B memory cells with a decrease of Th17 signaling. Lupus patients are at higher risk of COVID-19 infection and new susceptibility and severity risk factors were identified. Lupus patients were able to mount humoral and cellular responses despite immunosuppressive therapy.

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I202

Juan Zhao,Madison Schank,Ling Wang,Xindi Dang,Dechao Cao,Sushant Khanal,Lam N.T. Nguyen,Yi Zhang,Xiao Y. Wu,James L. Adkins,Benjamin J. Pelton,Jinyu Zhang,Shunbin Ning,Mohamed El Gazzar,Jonathan P. Moorman,Zhi Q. Yao

Plasma biomarkers for systemic inflammation in COVID-19 survivors

https://doi.org/10.1002/prca.202200031

Published

5-Aug-22

Study

https://onlinelibrary.wiley.com/doi/full/10.1002/prca.202200031

Background
While the majority of COVID-19 patients fully recover from the infection and become asymptomatic, a significant proportion of COVID-19 survivors experience a broad spectrum of symptoms lasting weeks to months post-infection, a phenomenon termed “post-acute sequelae of COVID-19 (PASC).” The aim of this study is to determine whether inflammatory proteins are dysregulated and can serve as potential biomarkers for systemic inflammation in COVID-19 survivors.
Methods
We determined the levels of inflammatory proteins in plasma from 22 coronavirus disease 2019 (COVID-19) long haulers (COV-LH), 22 COVID-19 asymptomatic survivors (COV-AS), and 22 healthy subjects (HS) using an Olink proteomics assay and assessed the results by a beads-based multiplex immunoassay.
Results
Compared to HS, we found that COVID-19 survivors still exhibited systemic inflammation, as evidenced by significant changes in the levels of multiple inflammatory proteins in plasma from both COV-LH and COV-AS. CXCL10 was the only protein that significantly upregulated in COV-LH compared with COV-AS and HS.
Conclusions
Our results indicate that several inflammatory proteins remain aberrantly dysregulated in COVID-19 survivors and CXCL10 might serve as a potential biomarker to typify COV-LH. Further characterization of these signature inflammatory molecules might improve the understanding of the long-term impacts of COVID-19 and provide new targets for the diagnosis and treatment of COVID-19 survivors with PASC.

1388

I203

Muhammad G. Saleh ORCID logo, Linda Chang, Huajun Liang, Meghann C. Ryan, Eric Cunningham, Jonathan Garner, Eleanor Wilson, Andrea R. Levine, Shyamasundaran Kottilil and Thomas Ernst

Ongoing oxidative stress in individuals with post-acute sequelae of COVID-19

https://doi.org/10.1515/nipt-2022-0006

Published

15-Aug-22

Study

https://www.degruyter.com/document/doi/10.1515/nipt-2022-0006/html

Objectives
Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is associated with lower plasma glutathione (GSH) levels due to oxidative stress. However, plasma levels may not reflect brain GSH levels. Individuals with post-acute sequelae of COVID-19 (PASC) have a higher prevalence of cognitive fatigue, which might be related to altered brain γ-aminobutyric-acid (GABA) levels. Hence, our study aims to measure the brain GSH and GABA levels in PASC.
Methods
29 PASC participants and 24 uninfected controls were recruited for this study. Each was evaluated with detailed neuropsychiatric assessments and an edited proton MRS (Hadamard Encoding and Reconstruction of Mega-Edited Spectroscopy, HERMES) method to measure GABA and GSH concentrations in predominantly grey matter (GM) and predominantly white matter (WM) brain frontal voxels.
Results
PASC participants were 219 ± 137 days since their COVID-19 diagnosis. Nine individuals with PASC were hospitalized. Compared to controls, individuals with PASC had similar levels of GABA in both brain regions, but lower GSH and greater age-related GSH decline in the frontal GM region.
Conclusions
The lower-than-normal frontal GM GSH level in participants with PASC suggest that they have ongoing oxidative stress in the brain, and that older individuals may be even more vulnerable to oxidative stress.

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Marta Bertran1, Snehal M Pinto Pereira2, Manjula D Nugawela3, Terence Stephenson3, Roz Shafran3, Tamsin Ford4, Marta Buszewicz5, Elizabeth Whittaker6, Isobel Heyman3, Terry Y Segal 7, Emma Dalrymple3, Shamez N Ladhani

Association between parents experiencing ongoing problems from COVID-19 and adolescents reporting LONG COVID six months after a positive or negative SARS-CoV-2 PCR-test: prospective, national cohort study in England

pre-print

14-Aug-22

Study

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4192732

Abstract In a national cohort of 12,788 adolescents, those reporting parents experiencing ongoing problems from COVID-19 had 1.79-fold (95%CI: 1.58-2.02) higher odds of experiencing LONG COVID 6 months after a SARS-CoV-2 PCR-test than those reporting parents without ongoing symptoms, independent of age, sex, deprivation and SARS-CoV-2 infection status. Funding: This work was supported by the Department of Health and Social Care, in their capacity as the National Institute for Health Research (NIHR), and by the UK Research and Innovation (UKRI) who have awarded funding grant number COVLT0022. All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. SMPP is supported by a UK Medical Research Council Career Development Award (ref: MR/P020372/1).

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Michael J. Peluso, Tyler-Marie Deveau, Sadie E. Munter, Dylan Ryder, Amanda Buck, Gabriele Beck-Engeser, Fay Chan, Scott Lu, Sarah A. Goldberg, Rebecca Hoh, Viva Tai, Leonel Torres, Nikita S. Iyer, Monika Deswal, Lynn H. Ngo, Melissa Buitrago, Antonio Rodriguez, Jessica Y. Chen, Brandon C. Yee, Ahmed Chenna, John W. Winslow, Christos J. Petropoulos, Amelia N. Deitchman, Joanna Hellmuth, Matthew A. Spinelli, Matthew S. Durstenfeld, Priscilla Y. Hsue, J. Daniel Kelly, Jeffrey N. Martin, Steven G. Deeks, Peter W. Hunt, Timothy J. Henrich

Impact of Pre-Existing Chronic Viral Infection and Reactivation on the Development of Long COVID

https://doi.org/10.1101/2022.06.21.22276660

pre-print

22-Jul-22

Study

https://www.medrxiv.org/content/10.1101/2022.06.21.22276660v2.full-text

The presence and reactivation of chronic viral infections such as Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human immunodeficiency virus (HIV) have been proposed as potential contributors to Long COVID (LC), but studies in well-characterized post-acute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited. In a cohort of 280 adults with prior SARS-CoV-2 infection, we observed that LC symptoms such as fatigue and neurocognitive dysfunction at a median of 4 months following initial diagnosis were independently associated with serological evidence of recent EBV reactivation (early antigen-D [EA-D] IgG positivity) or high nuclear antigen IgG levels, but not with ongoing EBV viremia. Evidence of EBV reactivation (EA-D IgG) was most strongly associated with fatigue (OR 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR 0.52) and tended to have less severe (>5 symptoms reported) LC (OR 0.44). Overall, these findings suggest differential effects of chronic viral co-infections on the likelihood of developing LC and predicted distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted.

SUMMARY The authors found that Long COVID symptoms in a post-acute cohort were associated with serological evidence of recent EBV reactivation and pre-existing HIV infection when adjusted for participant factors, sample timing, comorbid conditions and prior hospitalization, whereas underlying CMV infection was associated with a decreased risk of Long COVID.

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ShuangLiuaYasuyukiSuzukiabcErikaTakemasaaRyusukeWatanabeaMasakiMogia

Mast cells promote viral entry of SARS-CoV-2 via formation of chymase/spike protein complex

https://doi.org/10.1016/j.ejphar.2022.175169

Published

31-Jul-22

Study

https://www.sciencedirect.com/science/article/pii/S0014299922004307

The pulmonary pathological findings associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) result from the release of multiple proinflammatory cytokines, which causes the subsequential damage of the lungs. The current study was undertaken to investigate the responses of mast cells to viral inoculation and their contribution to host defenses from the point of view of viral entry. Pseudovirions, in which the spike glycoprotein of SARS-CoV-2 was incorporated, triggered activation of mast cells, and a mast cell-derived chymase, MCP2, formed a complex with spike protein, which promoted protease-dependent viral entry. According to the quantification results of viral entry, 10 μM quercetin, a mast cell stabilizer, potentially potently inhibited 41.3% of viral entry, while 100 μM chymostatin, which served as a chymase inhibitor, suppressed 52.1% of viral entry, compared to non-treated cells. Study using mast cell-deficient mice showed that the absence of mast cells may influence early viral loading in the upper respiratory tract, which consequently increases the risk of viral invasion into the lower respiratory system. Furthermore, mast cell-deficient mice exhibited ongoing infection in the late phase post-viral inoculation, while clearance of virus-positive cells was observed in wild-type mice. In conclusion, mast cells act as a multifaceted immune modulator that is equipped with both protective effects and pathogenic influences on viral entry of SARS-CoV-2. The utility of mast cell stabilizers and chymase inhibitors in the treatment of SARS-CoV-2-induced acute respiratory syndrome should be optimized regarding the infection stage and the risk of cytokine storm.

1392

I207

VP

Daniel Benharroch* and Karen Nalbandyan

Sars-Cov-2 Persistent Infection May Evolve into Malignancy, Possibly
Curbed by Vaccination: A Hypothesis

https://doi.org/10.47363/JIRR/2022(2)114

Published

13-Jul-22

Review

https://onlinescientificresearch.com/articles/sarscov2-persistent-infection-may-evolve-into-malignancy-possibly-curbed-by-vaccination-a-hypothesis.pdf

The three coronavirus variant infections which evolve onto severe respiratory conditions, have occasionally been associated with persistence. The viral RNA might be solely affected, or else, new symptoms might represent the only disease manifestations, often systemic and neurological. At times, it may associate with variable immunity. A persistent COVID-19 may initiate a “long COVID” episode. It has been hypothesized that, pending an expanded follow-up, the persistence of the SARS-CoV-2 might advance into a cancer: TMPRSS2 gene might develop into prostate cancer, while ground glass lung opacities might lead to lung cancer. In contrast, vaccines may impede the development of a malignancy. Among these, the BCG vaccine predominates, together with the MMR vaccine; mumps and measles being possibly responsible for tumor handicap. It is too early to discern a similar role for COVID-19 with anti-SARSCoV-2 vaccines, as they may relate to cancer.

1393

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Paul Kuodi, Yanay Gorelik, Hiba Zayyad, Ofir Wertheim, Karine Beiruti Wiegler, Kamal Abu Jabal, Amiel A. Dror, Saleh Nazzal, Daniel Glikman & Michael Edelstein

Association between BNT162b2 vaccination and reported incidence of post-COVID-19 symptoms: cross-sectional study 2020-21, Israel

https://doi.org/10.1038/s41541-022-00526-5

Published

26-Aug-22

Study

https://www.nature.com/articles/s41541-022-00526-5

The effectiveness of Coronavirus disease 2019 (COVID-19) vaccines against the long-term COVID-19 symptoms expressed by a substantial proportion of patients is not well understood. We determined whether vaccination with the BNT162b2 mRNA vaccine was associated with incidence of reporting long-term symptoms post-SARS-CoV-2 infection. We invited individuals PCR-tested for SARS-CoV-2 infection at participating hospitals between March 2020 and November 2021 to fill an online questionnaire that included information about demographics, acute COVID-19 episode and symptoms they were currently experiencing. Using binomial regression, we compared vaccinated individuals with those unvaccinated and those uninfected, in terms of post-acute self-reported symptoms. Of the 951 infected, 637(67%) were vaccinated. In the study population, the most prevalent symptoms were: fatigue (22%), headache (20%), weakness of limbs (13%), and persistent muscle pain (10%). After adjusting for age, time from beginning of symptoms to responding to the survey, and baseline symptoms, those who received two vaccine doses were less likely than unvaccinated individuals to report any of these symptoms (fatigue, headache, weakness of limbs, persistent muscle pain) by 62%, 50%, 62%, and 66% respectively, (Risk ratios 0.38, 0.50, 0.38, 0.34, p < 0.04 in the listed sequence). Compared to the 2447 included individuals who never reported SARS-CoV-2 infection, double-vaccinated participants were no more likely to report any of the mentioned symptoms. Vaccination with 2+ doses of BNT162b2 was associated with a reduced risk of reporting most of the common post-acute COVID-19 symptoms. Our results suggest that BNT162b2 vaccination may have a protective effect against longer term COVID-19 symptoms.

1394

I209

Kin IsraelNotarteaJesus AlfonsoCatahaybJacqueline VeronicaVelascocAdrielPastranacAbbygail ThereseVercFlos CarmeliPangilinancPrincess JuneirePeligrocMichaelCasimirocJonathan JaimeGuerrerodMa. Margarita LeticiaGellacocGiuseppeLippieBrandon MichaelHenryfCésarFernández-de-las-Peñasg

Impact of COVID-19 vaccination on the risk of developing long-COVID and on existing long-COVID symptoms: A systematic review

https://doi.org/10.1016/j.eclinm.2022.101624

Published

27-Aug-22

Systematic review

https://www.sciencedirect.com/science/article/pii/S2589537022003546

Background
Although COVID-19 vaccination decreases the risk of severe illness, it is unclear whether vaccine administration may impact the prevalence of long-COVID. The aim of this systematic review is to investigate the association between COVID-19 vaccination and long-COVID symptomatology.
Methods
MEDLINE, CINAHL, PubMed, EMBASE, and Web of Science databases, as well as medRxiv and bioRxiv preprint servers were searched up to June 20, 2022. Peer-reviewed studies or preprints monitoring multiple symptoms appearing after acute SARS-CoV-2 infection either before or after COVID-19 vaccination collected by personal, telephone or electronic interviews were included. The methodological quality of the studies was assessed using the Newcastle-Ottawa Scale.
Findings
From 2584 studies identified, 11 peer-reviewed studies and six preprints were included. The methodological quality of 82% (n=14/17) studies was high. Six studies (n=17,256,654 individuals) investigated the impact of vaccines before acute SARS-CoV-2 infection (vaccine-infection-long-COVID design). Overall, vaccination was associated with reduced risks or odds of long-COVID, with preliminary evidence suggesting that two doses are more effective than one dose. Eleven studies (n=36,736 COVID-19 survivors) investigated changes in long-COVID symptoms after vaccination (infection-long-COVID-vaccine design). Seven articles showed an improvement in long-COVID symptoms at least one dose post-vaccination, while four studies reported no change or worsening in long-COVID symptoms after vaccination.
Interpretation
Low level of evidence (grade III, case-controls, cohort studies) suggests that vaccination before SARS-CoV-2 infection could reduce the risk of subsequent long-COVID. The impact of vaccination in people with existing long-COVID symptoms is still controversial, with some data showing changes in symptoms and others did not. These assumptions are limited to those vaccines used in the studies.

1395

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Sara Díaz-Salazar,Raquel Navas,Laura Sainz-Maza,Patricia Fierro,Meryam Maamar,Arancha Artime,Héctor Basterrechea,Benedetta Petitta,Stefanie Pini,José Manuel OlmosORCID Icon,Carmen RamosORCID Icon,Emilio ParienteORCID Icon &José Luis Hernández

Blood group O is associated with post-COVID-19 syndrome in outpatients with a low comorbidity index

https://doi.org/10.1080/23744235.2022.2115548

Published

27-Aug-22

Study

https://www.tandfonline.com/doi/abs/10.1080/23744235.2022.2115548

Background
ABO blood group system modulates the inflammatory response and has been implicated in COVID-19. Group O protects against SARS-CoV-2 infection, but there are no data regarding post-COVID-19 syndrome (PCS). Our aim was to assess this possible association.
Methods
Case–control study in a community setting, with subjects who had experienced mild COVID-19. Cases were PCS+, controls were PCS-, and the exposure variable, group O. We collected age, sex, BMI, smoking, comorbidities, inflammatory markers, anti-SARS-CoV-2 IgG antibodies, blood type and clinical data. Five composite inflammatory indices were developed. Multivariate analyses were performed.
Results
We analysed 121 subjects (56.2% women), mean age 45.7 ± 16 years. Blood group frequencies were 41.5%, 7.9%, 5.9%, and 44.5% for A, B, AB and O, respectively. Thirty-six patients were PCS+, without significant differences between cases and controls. Compared to non-O, a higher prevalence of PCS (p = .036), and number of symptoms of PCS (p = .017) were noted in group O. Concerning biomarkers, PCS + and PCS- showed no differences in A, B, and AB groups. In contrast, group O PCS + patients had significantly lower albumin-to-globulin ratio and higher lymphocyte count, fibrinogen, CRP levels, and higher percentages of 3 composite indices, than PCS- subjects. Group O showed a 6-fold increased risk of PCS, compared to non-O (adjusted OR = 6.25 [95%CI, 1.6-23]; p = .007).
Conclusions
Group O has shown a consistent relationship with PCS, characterised by a more intense inflammatory burden than the other blood groups. Blood group O could be part of the immunological link between acute COVID-19 and PCS.

1396

I211

C. Kedor, H. Freitag, L. Meyer-Arndt, K. Wittke, L. G. Hanitsch, T. Zoller, F. Steinbeis, M. Haffke, G. Rudolf, B. Heidecker, T. Bobbert, J. Spranger, H. D. Volk, C. Skurk, F. Konietschke, F. Paul, U. Behrends, J. Bellmann-Strobl & C. Scheibenbogen

A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity

https://doi.org/10.1038/s41467-022-32507-6

Published

30-Aug-22

Study

https://www.nature.com/articles/s41467-022-32507-6

A subset of patients has long-lasting symptoms after mild to moderate Coronavirus disease 2019 (COVID-19). In a prospective observational cohort study, we analyze clinical and laboratory parameters in 42 post-COVID-19 syndrome patients (29 female/13 male, median age 36.5 years) with persistent moderate to severe fatigue and exertion intolerance six months following COVID-19. Further we evaluate an age- and sex-matched postinfectious non-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome cohort comparatively. Most post-COVID-19 syndrome patients are moderately to severely impaired in daily live. 19 post-COVID-19 syndrome patients fulfill the 2003 Canadian Consensus Criteria for myalgic encephalomyelitis/chronic fatigue syndrome. Disease severity and symptom burden is similar in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome and non-COVID-19/myalgic encephalomyelitis/chronic fatigue syndrome patients. Hand grip strength is diminished in most patients compared to normal values in healthy. Association of hand grip strength with hemoglobin, interleukin 8 and C-reactive protein in post-COVID-19 syndrome/non-myalgic encephalomyelitis/chronic fatigue syndrome and with hemoglobin, N-terminal prohormone of brain natriuretic peptide, bilirubin, and ferritin in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome may indicate low level inflammation and hypoperfusion as potential pathomechanisms.

1397

I212

Vladimir V. Klimov

Allergies in COVID-19 and Post-COVID Syndrome

https://doi.org/10.1007/978-3-031-04309-3_10

Published

2-Sep-22

Article

https://link.springer.com/chapter/10.1007/978-3-031-04309-3_10

This chapter focuses on the immunity and atopic allergies in COVID and post-COVID syndrome. The pandemic SARS-CoV-2 infection has added to our knowledge about immune reactions and responses, uncommon clinical situations, risk factors for poor outcomes, and promoted novel treatment approaches. We consider the process of viral entry in a host cell and how Th2-cytokines can inhibit it, and corticosteroids suppress SARS-CoV-2 replication. There are controversial data concerning atopic allergies, mainly asthma, during COVID-19, and multifactorial influence on disease outcomes and residual changes. Systematic reviews, meta-analyses, and online surveys allow us a vision of the whole panorama.

1398

I213

Mohd Arish,Wei Qian,Harish Narasimhan,Jie Sun

COVID-19 immunopathology: From acute diseases to chronic sequelae

https://doi.org/10.1002/jmv.28122

Published

3-Sep-22

Review

https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.28122

The clinical manifestation of coronavirus disease 2019 (COVID-19) mainly targets the lung as a primary affected organ, which is also a critical site of immune cell activation by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, recent reports also suggest the involvement of extrapulmonary tissues in COVID-19 pathology. The interplay of both innate and adaptive immune responses is key to COVID-19 management. As a result, a robust innate immune response provides the first line of defense, concomitantly, adaptive immunity neutralizes the infection and builds memory for long-term protection. However, dysregulated immunity, both innate and adaptive, can skew towards immunopathology both in acute and chronic cases. Here we have summarized some of the recent findings that provide critical insight into the immunopathology caused by SARS-CoV-2, in acute and post-acute cases. Finally, we further discuss some of the immunomodulatory drugs in preclinical and clinical trials for dampening the immunopathology caused by COVID-19.

1399

I214

Bellanti, Joseph A.

The long COVID syndrome: A conundrum for the allergist/immunologist

https://doi.org/10.2500/aap.2022.43.220059

Published

25-Sep-22

Article

https://www.ingentaconnect.com/content/ocean/aap/2022/00000043/00000005/art00007

Background:
The long coronavirus disease 2019 (COVID-19) syndrome includes a group of patients who, after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibit lingering mild-to-moderate symptoms and develop medical complications that can have lasting health problems.
Objective:
The purpose of this report was to examine the current body of evidence that deals with the relationship of COVID-19 infection with the long COVID syndrome to define the possible immunologic mechanisms involved in the pathogenesis of long COVID and to describe potential strategies for the diagnosis and clinical management of the condition.
Methods:
Extensive research was conducted in medical literature data bases by applying terms such as long COVID, post‐COVID-19 condition, pathogenesis of long COVID, management of the long COVID syndrome.
Results:
The post-COVID conditions, a more recent and less anxiety-inducing term for the patient than long COVID or “long haul,” is an umbrella term for a wide range of physical and mental health symptoms similar to those seen in patients with the myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), experienced by some patients and are present ≥ 4 weeks after SARS-CoV-2 infection. Although the precise reason why long COVID develops is unknown, one of the major causes is thought to be related to chronic inflammation with overproduction of inflammatory cytokines responsible for the symptoms of the disorder.
Conclusion:
Long COVID is a growing burden for millions of patients, health-care providers, and global health-care systems, and is a particular challenge for the allergist/immunologist. Many survivors of COVID-19 struggle with multiple symptoms, increased disability, reduced function, and poor quality of life. The allergist/immunologist can assist the total health-care team's efforts in providing a comprehensive and coordinated approach to the management of these patients by promoting comprehensive vaccination and rehabilitation and social services that focus on improving physical, mental, and social well-being, and by establishing partnerships with specialists and other health-care professionals who can provide behavioral, lifestyle, and integrative approaches that may have much to offer in helping patients cope with their symptoms.

1400

I215

Bailey Brooks 1,2ORCID,Christina Tancredi 2,Yufeng Song 2,Alemu Tekewe Mogus 2,Meei-Li W. Huang 3ORCID,Haiying Zhu 3,Tuan L. Phan 4,5,Harrison Zhu 5,6ORCID,Alexandra Kadl 7,8,Judith Woodfolk 7,9,Keith R. Jerome 3,10 andSteven L. Zeichner 2,9,*

Epstein–Barr Virus and Human Herpesvirus-6 Reactivation in Acute COVID-19 Patients

https://doi.org/10.3390/v14091872

Published

25-Aug-22

Study

https://www.mdpi.com/1999-4915/14/9/1872/htm

Beyond their pulmonary disease, many COVID-19 patients experience a complex constellation of characteristics, including hyperinflammatory responses, autoimmune disorders, and coagulopathies. However, the pathogenesis of these aspects of COVID-19 is obscure. More than 90% of people are latently infected with the lymphotropic herpesviruses Epstein–Barr Virus (EBV) and/or Human Herpesvirus-6 (HHV-6). Some of the inflammatory features of COVID-19 resemble clinical syndromes seen during EBV and HHV-6 infection, and these latent viruses can be reactivated by inflammatory mediators. We hypothesized that EBV and HHV-6 reactivation might be a common feature of early COVID-19, particularly in patients with more inflammation. We tested for EBV and HHV-6 reactivation in 67 patients acutely hospitalized with COVID-19 using previously validated quantitative PCR assays on the plasma. In our cohort, we found that 15/67 (22.4%) patients had detectable EBV and 3/67 (4.5%) had detectable HHV-6. This frequency of activation is somewhat more than the frequency reported for some healthy cohorts, such as blood donors and other healthy control cohorts. There was no association between EBV or HHV-6 and markers indicative of more inflammatory disease. We conclude that EBV and HHV-6 activation at about day 7 of hospitalization occurred in a modest fraction of our cohort of COVID-19 patients and was not associated with high levels of inflammation. In the modest fraction of patients, EBV and HHV-6 reactivation could contribute to some features of acute disease and pre-disposition to post-acute sequelae in a subset of patients.

1401

I216

César Fernández-de-las-Peñas 1,*ORCID,Ricardo Ortega-Santiago 1,Stella Fuensalida-Novo 1ORCID,José D. Martín-Guerrero 2ORCID,Oscar J. Pellicer-Valero 2ORCID andJuan Torres-Macho 3,4ORCID

Differences in Long-COVID Symptoms between Vaccinated and Non-Vaccinated (BNT162b2 Vaccine) Hospitalized COVID-19 Survivors Infected with the Delta Variant

https://doi.org/10.3390/vaccines10091481

Published

6-Sep-22

Study

https://www.mdpi.com/2076-393X/10/9/1481/htm

This study compared differences in the presence of post-COVID symptoms among vaccinated and non-vaccinated COVID-19 survivors requiring hospitalization due to the Delta (B.1.617.2) variant. This cohort study included hospitalized subjects who had survived SARS-CoV-2 infection (Delta variant) from July to August 2021 in an urban hospital in Madrid, Spain. Individuals were classified as vaccinated if they received full administration (i.e., two doses) of BNT162b2 (“Pfizer-BioNTech”) vaccines. Other vaccines were excluded. Those with just one dose of the BNT162b2 vaccine were considered as non-vaccinated. Patients were scheduled for a telephone interview at a follow-up around six months after infection for assessing the presence of post-COVID symptoms with particular attention to those symptoms starting after acute infection and hospitalization. Anxiety/depressive levels and sleep quality were likely assessed. Hospitalization and clinical data were collected from medical records. A total comprising 109 vaccinated and 92 non-vaccinated COVID-19 survivors was included. Vaccinated patients were older and presented a higher number of medical comorbidities, particular cardiorespiratory conditions, than non-vaccinated patients. No differences in COVID-19 onset symptoms at hospitalization and post-COVID symptoms six months after hospital discharge were found between vaccinated and non-vaccinated groups. No specific risk factor for any post-COVID symptom was identified in either group. This study observed that COVID-19 onset-associated symptoms and post-COVID symptoms six-months after hospitalization were similar between previously hospitalized COVID-19 survivors vaccinated and those non-vaccinated. Current data can be applied to the Delta variant and those vaccinated with BNT162b2 (Pfizer-BioNTech) vaccine.

1402

I217

VP

Denise Goh1†, Jeffrey Chun Tatt Lim1†, Sonia Bilbao Fernaíndez2†, Craig Ryan Joseph1, Sara Gil Edwards3, Zhen Wei Neo1, Justina Nadia Lee1, Sílvia Guerrero Caballero2, Mai Chan Lau1 and Joe Poh Sheng Yeong

Case report: Persistence of residual antigen and RNA of the SARS-CoV-2 virus in tissues of two patients with long COVID

https://doi.org/10.3389/fimmu.2022.939989

Published

5-Sep-22

Case Report

https://www.frontiersin.org/articles/10.3389/fimmu.2022.939989/full

The World Health Organization has defined long COVID-19 (LC) as a condition that occurs in individuals with a history of SARS-CoV-2 infection who exhibit persistent symptoms after its acute phase that last for at least two months and cannot be explained by an alternative diagnosis. Since we had previously reported residual viral antigens in tissues of convalescent patients, we aimed to assess the presence of such antigens in long COVID tissues. Here, we established the presence of the residual virus in the appendix, skin, and breast tissues of 2 patients who exhibited LC symptoms 163 and 426 days after symptom onset. With multiplex immunohistochemistry, we detected viral nucleocapsid protein in all three tissues. The nucleocapsid protein was further observed to colocalize with macrophage marker CD68, suggesting that immune cells were direct targets of SARS-CoV-2. Additionally, using RNAscope, the presence of viral RNA was also detected. Our positive finding in the breast tissue is corroborated by the recent reports of immunocompromised patients experiencing LC symptoms and persistent viral replication. Overall, our findings and emerging LC studies raise the possibility that the gastrointestinal tract may function as a reservoir for SARS-CoV-2.

1403

I218

Miklós Fagyas, Béla Nagy Jr., Arnold Péter Ráduly, Ivetta Siket Mányiné, Lilla Mártha, Gábor Erdősi, Sándor Sipka Jr., Enikő Enyedi, Attila Ádám Szabó, Zsófia Pólik, János Kappelmayer, Zoltán Papp, Attila Borbély, Tamás Szabó, József Balla, György Balla, Péter Bai, Attila Bácsi & Attila Tóth

The majority of severe COVID-19 patients develop anti-cardiac autoantibodies

https://doi.org/10.1007/s11357-022-00649-6

Published

16-Sep-22

Study

https://link.springer.com/article/10.1007/s11357-022-00649-6

Severe cases of COVID-19 are characterized by an inflammatory burst, which is accompanied by multiorgan failure. The elderly population has higher risk for severe or fatal outcome for COVID-19. Inflammatory mediators facilitate the immune system to combat viral infection by producing antibodies against viral antigens. Several studies reported that the pro-inflammatory state and tissue damage in COVID-19 also promotes autoimmunity by autoantibody generation. We hypothesized that a subset of these autoantibodies targets cardiac antigens. Here we aimed to detect anti-cardiac autoantibodies in severe COVID-19 patients during hospitalization. For this purpose, 104 COVID-19 patients were recruited, while 40 heart failure patients with dilated cardiomyopathy and 20 patients with severe aortic stenosis served as controls. Patients were tested for anti-cardiac autoantibodies, using human heart homogenate as a bait. Follow-up samples were available in 29 COVID-19 patients. Anti-cardiac autoantibodies were detected in 68% (71 out of 104) of severe COVID-19 patients. Overall, 39% of COVID-19 patients had anti-cardiac IgG autoantibodies, while 51% had anti-cardiac autoantibodies of IgM isotype. Both IgG and IgM anti-cardiac autoantibodies were observed in 22% of cases, and multiple cardiac antigens were targeted in 38% of COVID-19 patients. These anti-cardiac autoantibodies targeted a diverse set of myocardial proteins, without apparent selectivity. As controls, heart failure patients (with dilated cardiomyopathy) had similar occurrence of IgG (45%, p = 0.57) autoantibodies, while significantly lower occurrence of IgM autoantibodies (30%, p = 0.03). Patients with advanced aortic stenosis had significantly lower number of both IgG (11%, p = 0.03) and IgM (10%, p < 0.01) type anti-cardiac autoantibodies than that in COVID-19 patients. Furthermore, we detected changes in the anti-cardiac autoantibody profile in 7 COVID-19 patients during hospital treatment. Surprisingly, the presence of these anti-cardiac autoantibodies did not affect the clinical outcome and the prevalence of the autoantibodies did not differ between the elderly (over 65 years) and the patients younger than 65 years of age. Our results demonstrate that the majority of hospitalized COVID-19 patients produce novel anti-cardiac IgM autoantibodies. COVID-19 also reactivates resident IgG autoantibodies. These autoantibodies may promote autoimmune reactions, which can complicate post-COVID recuperation, contributing to post-acute sequelae of COVID-19 (long COVID).

1404

I219

Shahrooz AminMozaffariaAliSalehibElnazMousavicBurhan AbdullahZamandAli EslambolNassajeFarnooshEbrahimzadehfHadiNasiriaZahraValedkarimiaAliAdilighGhazalehAsemaniaMortezaAkbariia

SARS-CoV-2-associated gut microbiome alteration; a new contributor to colorectal cancer pathogenesis

https://doi.org/10.1016/j.prp.2022.154131

Published

16-Sep-22

Review

https://www.sciencedirect.com/science/article/pii/S0344033822003752

The emergence of a novel coronavirus, COVID-19, in December 2019 led to a global pandemic with more than 170 million confirmed infections and more than 6 million deaths (by July 2022). Studies have shown that infection with SARS-CoV-2 in cancer patients has a higher mortality rate than in people without cancer. Here, we have reviewed the evidence showing that gut microbiota plays an important role in health and is linked to colorectal cancer development. Studies have shown that SARS-CoV-2 infection leads to a change in gut microbiota, which modify intestinal inflammation and barrier permeability and affects tumor-suppressor or oncogene genes, proposing SARS-CoV-2 as a potential contributor to CRC pathogenesis

1405

I220

Javier García-Abellán, 1 , 2 , 3 Marta Fernández, 1 , 3 Sergio Padilla, 1 , 2 , 3 José Alberto García, 1 , 3 Vanesa Agulló, 1 , 3 Valle Lozano, 4 Nuria Ena, 1 Lidia García-Sánchez, 1 Félix Gutiérrez,corresponding author 1 , 2 , 3 , * , † and Mar Masiácorresponding author 1

Immunologic phenotype of patients with long-COVID syndrome of 1-year duration

https://doi.org/10.3389%2Ffimmu.2022.920627

Published

24-Aug-22

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9451924/

Background
The pathophysiology of long-COVID remains unknown, and information is particularly limited for symptoms of very long duration. We aimed to assess the serological, T-cell immune responses and ANA titers of patients with long-COVID-19 syndrome of 1-year duration.
Methods
Prospective, longitudinal study of hospitalized COVID-19 patients followed-up for 12 months. Sequential blood samples and COVID-19 symptom questionnaires (CSQ) were obtained, and humoral and cellular immune responses, antinuclear antibodies (ANA) and inflammation biomarkers were analyzed.
Results
Of 154 patients discharged from hospital, 72 non-vaccinated with available CSQ in all visits were included. Of them, 14 (19.4%) reported persistent symptoms both at 6-months and 12-months, mainly asthenia (15.3%), myalgia (13.9%), and difficulty concentrating/memory loss (13.9%). Symptomatic patients were more frequently women, smokers, showed higher WHO severity score, and a trend to higher ICU admission. In the adjusted analysis, long-COVID syndrome was associated with lower frequency of detectable neutralizing antibodies (adjusted hazard ratio [aHR] 0.98; 95% confidence interval [CI], 0.97-0.99) and lower SARS-CoV-2-S1/S2 titers (aHR [95%CI] 0.14 [0.03–0.65]). T-cell immune response measured with a SARS-CoV-2-interferon-γ release assay was not different between groups. There was a higher frequency of positive ANA titers (≥160) in symptomatic patients (57.1% vs 29.3%, p=0.04), that was attenuated after adjustment aHR [95% CI] 3.37 [0.84-13.57], p=0.087. Levels of C-reactive protein and D-dimer were higher during follow-up in symptomatic patients, but with no differences at 12 months.
Conclusion
Patients with 1-year duration long-COVID-19 syndrome exhibit a distinct immunologic phenotype that includes a poorer SARS-CoV-2 antibody response, low-degree chronic inflammation that tends to mitigate, and autoimmunity.

1406

I221

Soumya Arun, Abbie Storan, Bethan Myers

Mast cell activation syndrome and the link with long COVID

https://doi.org/10.12968/hmed.2022.0123

Published

26-Jul-22

Review

https://www.magonlinelibrary.com/doi/abs/10.12968/hmed.2022.0123

Mast cells are innate immune cells found in connective tissues throughout the body, most prevalent at tissue-environment interfaces. They possess multiple cell-surface receptors which react to various stimuli and, after activation, release many mediators including histamine, heparin, cytokines, prostaglandins, leukotrienes and proteases. In mast cell activation syndrome, excessive amounts of inflammatory mediators are released in response to triggers such as foods, fragrances, stress, exercise, medications or temperature changes. Diagnostic markers may be difficult to assess because of their rapid degradation; these include urinary N-methyl histamine, urinary prostaglandins D2, DM and F2α and serum tryptase (which is stable) in the UK. Self-management techniques, medications and avoiding triggers may improve quality of life. Treatments include mast cell mediator blockers, mast cell stabilisers and anti-inflammatory agents. ‘Long COVID’ describes post-COVID-19 syndrome when symptoms persist for more than 12 weeks after initial infection with no alternative diagnosis. Both mast cell activation syndrome and long COVID cause multiple symptoms. It is theorised that COVID-19 infection could lead to exaggeration of existing undiagnosed mast cell activation syndrome, or could activate normal mast cells owing to the persistence of viral particles. Other similarities include the relapse-remission cycle and improvements with similar treatments. Importantly, however, aside from mast cell disorders, long COVID could potentially be attributed to several other conditions.

1407

I222

Michael J Peluso, Anthea Mitchell, Chung Yu Wang, Saki Takahashi, Rebecca Hoh, Viva Tai, Matthew S Durstenfeld, Priscilla Y Hsue, J Daniel Kelly, Jeffrey N Martin, Michael R Wilson, Bryan Greenhouse, Steven G Deeks, Joseph L DeRisi, Timothy J Henrich

Low Prevalence of Interferon-α Autoantibodies in People Experiencing Long COVID Symptoms

https://doi.org/10.1093/infdis/jiac372

Published

12-Sep-22

Study

https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiac372/6696027

Interferon (IFN)-specific autoantibodies have been implicated in severe COVID-19 and have been proposed as a potential driver of the persistent symptoms characterizing Long COVID, a type of post-acute sequelae of SARS-CoV-2 infection (PASC). We report than only two of 215 SARS-CoV-2 convalescent participants tested over 394 timepoints, including 121 people experiencing Long COVID symptoms, had detectable IFN-α2 antibodies. Both had been hospitalized during the acute phase of the infection. These data suggest that persistent anti-IFN antibodies, although a potential driver of severe COVID-19, are unlikely to contribute to Long COVID symptoms in the post-acute phase of the infection.

1408

I223

Rupert Donald Holms

Long COVID (PASC) Is Maintained by a Self-Sustaining Pro-Inflammatory TLR4/RAGE-Loop of S100A8/A9 > TLR4/RAGE Signalling, Inducing Chronic Expression of IL-1b, IL-6 and TNFa: Anti-Inflammatory Ezrin Peptides as Potential Therapy

https://doi.org/10.3390/immuno2030033

Published

8-Sep-22

Review

https://www.mdpi.com/2673-5601/2/3/33/htm

Long COVID, also referred to as Post-Acute Sequelae of COVID (PASC), is probably triggered during SARS-CoV-2 infection and acute COVID-19 by SARS-CoV-2 Spike-protein binding and hyper-activating the cell-membrane expressed Receptor for Advance Glycation End-products (mRAGE) and Toll-Like Receptor 4 (TLR4). SARS-CoV-2 infects lung monocytes by Spike binding to mRAGE (not ACE2). During acute COVID-19, high levels of IL-6 hyper-stimulate S100A8/A9 expression and secretion. Although no viral protein nor mRNA can be detected in half of long COVID (PASC) patients, there is a significant elevation of serum levels of IL-1b, IL-6, TNFa, and S100A8/A9. It appears that a pathological pro-inflammatory feedback loop (the TLR4/RAGE-loop) is established during acute COVID-19, which is maintained by S100A8/A9 > RAGE/TLR4 chronic inflammatory signalling, even after SARS-CoV-2 has been cleared from the body. During long COVID/PASC, Ca2+-binding protein S100A8/A9 chronically stimulates TLR4/RAGE-signalling to induce chronic expression of IL-1b, IL-6 and TNFa. Secreted IL-6 binds to its IL-6R receptor on the surface of other cells and signals via STAT3 and C/EBPb for more S100A8/A9 expression. Secreted IL-1b binds to its receptor IL-1R on other cells, and signals via NFkB for more mRAGE and TLR4 expression. New S100A8/A9 can bind and activate cell-surface mRAGE and TLR4 to stimulate expression of more IL-1b, IL-6 and TNFa. This process establishes a pathogenic pro-inflammatory TLR4/RAGE-loop: IL-1b + IL-6 > IL-1R + IL-6R > TLR4/mRAGE + S100A8/A9 > IL-1b + IL-6, which generates multi-organ inflammation that persists in the blood vessels, the brain, the liver, the heart, the kidneys, the gut and the musculo-skeletal system, and is responsible for all the complex pathologies associated with long COVID/PASC. Chronic expression of IL-1, IL-6 and TNFa is critical for the maintenance of the TLR4/RAGE-loop and persistence of long COVID/PASC. Ezrin peptides are inhibitors of IL-1, IL-6, IL-8 and TNFa expression, so are now being investigated as potential therapy for long COVID/PASC. There is preliminary anecdotal evidence of symptomatic relief (not confirmed yet by formal clinical trials) from a few long COVID/PASC patient volunteers, after treatment with ezrin peptide therapy.

1409

I224

Gabriella Captur 1 James C. Moon 1 Constantin-Cristian Topriceanu George Joy Leo Swadling Jenny Hallqvist Ivan Doykov Nina Patel Justyna Spiewak Tomas Baldwin Matt Hamblin Katia Menacho Marianna Fontana Thomas A. Treibel Charlotte Manisty Ben O'Brien Joseph M. Gibbons Corrina Pade Tim Brooks Daniel M. Altmann Rosemary J. Boyton Áine McKnight Mala K. Maini Mahdad Noursadeghi Kevin Mills 2 Wendy E. Heywood

Plasma proteomic signature predicts who will get persistent symptoms following SARS-CoV-2 infection

https://doi.org/10.1016/j.ebiom.2022.104293

Published

28-Sep-22

Study

https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00475-3/fulltext

Background
The majority of those infected by ancestral Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) during the UK first wave (starting March 2020) did not require hospitalisation. Most had a short-lived mild or asymptomatic infection, while others had symptoms that persisted for weeks or months. We hypothesized that the plasma proteome at the time of first infection would reflect differences in the inflammatory response that linked to symptom severity and duration.
Methods
We performed a nested longitudinal case-control study and targeted analysis of the plasma proteome of 156 healthcare workers (HCW) with and without lab confirmed SARS-CoV-2 infection. Targeted proteomic multiple-reaction monitoring analysis of 91 pre-selected proteins was undertaken in uninfected healthcare workers at baseline, and in infected healthcare workers serially, from 1 week prior to 6 weeks after their first confirmed SARS-CoV-2 infection. Symptom severity and antibody responses were also tracked. Questionnaires at 6 and 12 months collected data on persistent symptoms.
Findings
Within this cohort (median age 39 years, interquartile range 30–47 years), 54 healthcare workers (44% male) had PCR or antibody confirmed infection, with the remaining 102 (38% male) serving as uninfected controls. Following the first confirmed SARS-CoV-2 infection, perturbation of the plasma proteome persisted for up to 6 weeks, tracking symptom severity and antibody responses. Differentially abundant proteins were mostly coordinated around lipid, atherosclerosis and cholesterol metabolism pathways, complement and coagulation cascades, autophagy, and lysosomal function. The proteomic profile at the time of seroconversion associated with persistent symptoms out to 12 months. Data are available via ProteomeXchange with identifier PXD036590.
Interpretation
Our findings show that non-severe SARS-CoV-2 infection perturbs the plasma proteome for at least 6 weeks. The plasma proteomic signature at the time of seroconversion has the potential to identify which individuals are more likely to suffer from persistent symptoms related to SARS-CoV-2 infection.

1410

I225

Daniel Ayoubkhani, Matthew L Bosworth, Sasha King, Koen B Pouwels, Myer Glickman, Vahé Nafilyan, Francesco Zaccardi, Kamlesh Khunti, Nisreen A Alwan, A Sarah Walker

Risk of Long COVID in People Infected With Severe Acute Respiratory Syndrome Coronavirus 2 After 2 Doses of a Coronavirus Disease 2019 Vaccine: Community-Based, Matched Cohort Study

https://doi.org/10.1093/ofid/ofac464

Published

12-Sep-22

Study

https://academic.oup.com/ofid/article/9/9/ofac464/6696170

We investigated long COVID incidence by vaccination status in a random sample of UK adults from April 2020 to November 2021. Persistent symptoms were reported by 9.5% of 3090 breakthrough severe acute respiratory syndrome coronavirus 2 infections and 14.6% of unvaccinated controls (adjusted odds ratio, 0.59 [95% confidence interval, .50–.69]), emphasizing the need for public health initiatives to increase population-level vaccine uptake.

1411

I226

Eva Schulte1

68. UNTANGLING GENETIC RISK FACTORS OF LONG COVID: WORK OF THE INTERNATIONAL COVID-19 HOST GENETICS INITIATIVE

https://doi.org/10.1016%2Fj.euroneuro.2022.07.155

Published

23-Sep-22

International Initiative

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9502139/

Background: WHO has published a clinical definition of the post COVID-19 condition, “Long COVID”, as a condition occurring “usually 3 months from the onset of COVID-19 with symptoms” “that cannot be explained by an alternative diagnosis”. Debilitating fatigue, exercise intolerance, cognitive dysfunction, disturbed sleep, anxiety, and depression are among the most prevalent symptoms, making the Long COVID phenotype of special interested to mental health professionals.

Methods: We have established an open global collaboration for elucidating genetic risk factors of Long COVID. The Long COVID Host Genetics Initiative currently comprises 46 studies across 23 countries with genotype data combined with Long COVID phenotype definitions based on questionnaire information on symptoms and/or electronic health record (EHR) data. For the first data freeze, contributing studies (N=11) performed genome-wide association analyses (GWAS) comparing Long COVID (N=1,588) to individuals who have recovered from COVID within 3 months (N=96,714), and to population controls (N=800,478).

Results: GWAS of individual cohorts have suggested potential variants associated with Long COVID but short of genome-wide statistical significance. We are currently running meta-analyses combining data from these studies. Further, data from individual studies have further detailed associations with other phenotypes in individuals with Long COVID. For example, in the FinnGen sample from Finland with 2,018 participants with a PCR-verified SARS-CoV-2 infection, and 50 (2.4%) with a Long COVID diagnosis, Long COVID associated with previous autoimmune diseases (p = 0.026, OR[se] = 2.15 [1.41]) but not with depression (p = 0.71, OR [se] = 1.20 [1.75]) or asthma (p = 0.43, OR[se] = 1.55 [1.74]). Data from the currently ongoing second GWAS data freeze and corresponding meta-analyses will be presented at the meeting.

Discussion: Current global GWAS efforts for Long COVID seem promising in that they can further inform the underlying disease pathophysiology through genetics. Although no locus of genome-wide significance has been identified to date, the global collaboration in the COVID-19 Host Genetics Initiative allows us–through stark increases in sample sizes in the ongoing meta-analyses–to assume that this will change in the near future. The identification of genetic risk factors for COVID-19 is important because it furthers understanding about the underlying pathophysiology of the disorder, which is currently only incompletely understood, and because it could, in the future, aid in identifying at-risk individuals.

1412

I227

Gabriella Captur 1James C. Moon 1 Constantin-Cristian Topriceanu George Joy Leo Swadling Jenny Hallqvist Ivan Doykov Nina Patel Justyna Spiewak Tomas Baldwin Matt Hamblin Katia Menacho Marianna Fontana Thomas A. Treibel Charlotte ManistyBen O'Brien Joseph M. Gibbons Corrina Pade Tim Brooks Daniel M. Altmann Rosemary J. Boyton Áine McKnight
Mala K. Maini Mahdad Noursadeghi Kevin Mills 2 Wendy E. Heywood

Plasma proteomic signature predicts who will get persistent symptoms following SARS-CoV-2 infection

https://doi.org/10.1016/j.ebiom.2022.104293

Published

28-Sep-22

Study

https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00475-3/fulltext

Background
The majority of those infected by ancestral Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) during the UK first wave (starting March 2020) did not require hospitalisation. Most had a short-lived mild or asymptomatic infection, while others had symptoms that persisted for weeks or months. We hypothesized that the plasma proteome at the time of first infection would reflect differences in the inflammatory response that linked to symptom severity and duration.
Methods
We performed a nested longitudinal case-control study and targeted analysis of the plasma proteome of 156 healthcare workers (HCW) with and without lab confirmed SARS-CoV-2 infection. Targeted proteomic multiple-reaction monitoring analysis of 91 pre-selected proteins was undertaken in uninfected healthcare workers at baseline, and in infected healthcare workers serially, from 1 week prior to 6 weeks after their first confirmed SARS-CoV-2 infection. Symptom severity and antibody responses were also tracked. Questionnaires at 6 and 12 months collected data on persistent symptoms.
Findings
Within this cohort (median age 39 years, interquartile range 30–47 years), 54 healthcare workers (44% male) had PCR or antibody confirmed infection, with the remaining 102 (38% male) serving as uninfected controls. Following the first confirmed SARS-CoV-2 infection, perturbation of the plasma proteome persisted for up to 6 weeks, tracking symptom severity and antibody responses. Differentially abundant proteins were mostly coordinated around lipid, atherosclerosis and cholesterol metabolism pathways, complement and coagulation cascades, autophagy, and lysosomal function. The proteomic profile at the time of seroconversion associated with persistent symptoms out to 12 months. Data are available via ProteomeXchange with identifier PXD036590.
Interpretation
Our findings show that non-severe SARS-CoV-2 infection perturbs the plasma proteome for at least 6 weeks. The plasma proteomic signature at the time of seroconversion has the potential to identify which individuals are more likely to suffer from persistent symptoms related to SARS-CoV-2 infection.

1413

I228

Sophia Stromberg1, Bridget A. Baxter2, Gregory Dooley2, Stephanie M. LaVergne2, Emily Gallichotte3, Taru Dutt3, Madison Tipton2, Kailey Berry2, Jared Haberman2, Nicole Natter2, Tracy L. Webb4, Kim McFann5, Marcela Henao-Tamayo3, Greg Ebel3, Sangeeta Rao4, Julie Dunn5 and Elizabeth P. Ryan2

Relationships between plasma fatty acids in adults with mild, moderate, or severe COVID-19 and the development of post-acute sequelae

https://doi.org/10.3389/fnut.2022.960409

Published

14-Sep-22

Study

https://www.frontiersin.org/articles/10.3389/fnut.2022.960409/full

Background: SARS-CoV-2 has infected millions across the globe. Many individuals are left with persistent symptoms, termed post-acute sequelae of COVID-19 (PASC), for months after infection. Hyperinflammation in the acute and convalescent stages has emerged as a risk factor for poor disease outcomes, and this may be exacerbated by dietary inadequacies. Specifically, fatty acids are powerful inflammatory mediators and may have a significant role in COVID-19 disease modulation.
Objective: The major objective of this project was to pilot an investigation of plasma fatty acid (PFA) levels in adults with COVID-19 and to evaluate associations with disease severity and PASC.
Methods and procedures: Plasma from adults with (N = 41) and without (N = 9) COVID-19 was analyzed by gas chromatography-mass spectrometry (GC-MS) to assess differences between the concentrations of 18 PFA during acute infection (≤14 days post-PCR + diagnosis) in adults with varying disease severity. Participants were grouped based on mild, moderate, and severe disease, alongside the presence of PASC, a condition identified in patients who were followed beyond acute-stage infection (N = 23).
Results: Significant differences in PFA profiles were observed between individuals who experienced moderate or severe disease compared to those with mild infection or no history of infection. Palmitic acid, a saturated fat, was elevated in adults with severe disease (p = 0.04), while behenic (p = 0.03) and lignoceric acid (p = 0.009) were lower in adults with moderate disease. Lower levels of the unsaturated fatty acids, γ-linolenic acid (GLA) (p = 0.03), linoleic (p = 0.03), and eicosapentaenoic acid (EPA) (p = 0.007), were observed in adults with moderate disease. Oleic acid distinguished adults with moderate disease from severe disease (p = 0.04), and this difference was independent of BMI. Early recovery-stage depletion of GLA (p = 0.02) and EPA (p = 0.0003) was associated with the development of PASC.
Conclusion: Pilot findings from this study support the significance of PFA profile alterations during COVID-19 infection and are molecular targets for follow-up attention in larger cohorts. Fatty acids are practical, affordable nutritional targets and may be beneficial for modifying the course of disease after a COVID-19 diagnosis. Moreover, these findings can be particularly important for overweight and obese adults with altered PFA profiles and at higher risk for PASC.

1414

I229

Maria P.YavropoulouaGeorge C.TsokosbGeorge P.Chrousosc1Petros P.Sfikakisa1

Protracted stress-induced hypocortisolemia may account for the clinical and immune manifestations of Long COVID

https://doi.org/10.1016/j.clim.2022.109133

Published

29-Sep-22

Comment

https://www.sciencedirect.com/science/article/pii/S1521661622002145

About one out of eight people to convalesce from COVID-19 suffer from the so called Long COVID, a syndrome of non-specific symptoms with unclear pathogenesis. In a recent study published in Cell Long COVID participants reporting respiratory symptoms had low cortisol levels. In an as yet unpublished analysis from Yale University low plasma cortisol levels discriminated Long COVID from asymptomatic convalescent or healthy non-infected controls. Although various immune perturbations were present in Long COVID, low levels of cortisol were prominent and strikingly, depression and anxiety were increased. It has become clear that Long COVID features may be similar to those described in myalgic encephalomyelitis/chronic fatigue syndrome, post-SARS sickness syndrome, and various chronic stress syndromes which have been linked to hypocortisolemia. Notably, lack of response of the hypothalamic–pituitary–adrenal axis to hypocortisolemia shows a suppressed axis in Long COVID. We suggest that the inability of hypothalamic–pituitary–adrenal axis to recover after the acute illness, perhaps due to protracted stress in predisposed individuals, may represent the pathogenetic basis of the Long COVID-associated clinical and immunological manifestations.

1415

I230

John Kee, Samuel Thudium, David M. Renner, Karl Glastad, Katherine Palozola, Zhen Zhang, Yize Li, Yemin Lan, Joseph Cesare, Andrey Poleshko, Anna A. Kiseleva, Rachel Truitt, Fabian L. Cardenas-Diaz, Xianwen Zhang, Xuping Xie, Darrell N. Kotton, Konstantinos D. Alysandratos, Johnathan A. Epstein, Pei-Yong Shi, Wenli Yang, Edward Morrisey, Benjamin A. Garcia, Shelley L. Berger, Susan R. Weiss & Erica Korb

SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry

https://doi.org/10.1038/s41586-022-05282-z

Published

5-Oct-22

Study

https://www.nature.com/articles/s41586-022-05282-z

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and caused the devastating global pandemic of coronavirus disease 2019 (COVID-19), in part because of its ability to effectively suppress host cell responses1,2,3. In rare cases, viral proteins dampen antiviral responses by mimicking critical regions of human histone proteins4,5,6,7,8, particularly those containing post-translational modifications required for transcriptional regulation9,10,11. Recent work has demonstrated that SARS-CoV-2 markedly disrupts host cell epigenetic regulation12,13,14. However, how SARS-CoV-2 controls the host cell epigenome and whether it uses histone mimicry to do so remain unclear. Here we show that the SARS-CoV-2 protein encoded by ORF8 (ORF8) functions as a histone mimic of the ARKS motifs in histone H3 to disrupt host cell epigenetic regulation. ORF8 is associated with chromatin, disrupts regulation of critical histone post-translational modifications and promotes chromatin compaction. Deletion of either the ORF8 gene or the histone mimic site attenuates the ability of SARS-CoV-2 to disrupt host cell chromatin, affects the transcriptional response to infection and attenuates viral genome copy number. These findings demonstrate a new function of ORF8 and a mechanism through which SARS-CoV-2 disrupts host cell epigenetic regulation. Further, this work provides a molecular basis for the finding that SARS-CoV-2 lacking ORF8 is associated with decreased severity of COVID-19.

1416

I231

Clemens A. Schmitt, Tamar Tchkonia, Laura J. Niedernhofer, Paul D. Robbins, James L. Kirkland & Soyoung Lee

COVID-19 and cellular senescence

https://doi.org/10.1038/s41577-022-00785-2

Published

5-Oct-22

Article

https://www.nature.com/articles/s41577-022-00785-2

The clinical severity of coronavirus disease 2019 (COVID-19) is largely determined by host factors. Recent advances point to cellular senescence, an ageing-related switch in cellular state, as a critical regulator of SARS-CoV-2-evoked hyperinflammation. SARS-CoV-2, like other viruses, can induce senescence and exacerbates the senescence-associated secretory phenotype (SASP), which is comprised largely of pro-inflammatory, extracellular matrix-degrading, complement-activating and pro-coagulatory factors secreted by senescent cells. These effects are enhanced in elderly individuals who have an increased proportion of pre-existing senescent cells in their tissues. SASP factors can contribute to a ‘cytokine storm’, tissue-destructive immune cell infiltration, endothelialitis (endotheliitis), fibrosis and microthrombosis. SASP-driven spreading of cellular senescence uncouples tissue injury from direct SARS-CoV-2-inflicted cellular damage in a paracrine fashion and can further amplify the SASP by increasing the burden of senescent cells. Preclinical and early clinical studies indicate that targeted elimination of senescent cells may offer a novel therapeutic opportunity to attenuate clinical deterioration in COVID-19 and improve resilience following infection with SARS-CoV-2 or other pathogens.

1417

I232

Marta Bertran
Snehal M Pinto Pereira
Manjula D Nugawela
Terence Stephenson
Roz Shafran
Tamsin Ford
Marta Buszewicz
Elizabeth Whittaker
Isobel Heyman
Terry Y Segal
Emma Dalrymple
Shamez N Ladhani

The relationship between Post COVID symptoms in young people and their parents

https://doi.org/10.1016/j.jinf.2022.10.005

Published

7-Oct-22

Letter to the Editor

https://www.journalofinfection.com/article/S0163-4453(22)00560-6/fulltext

We read with interest the recent study on risk factors for long COVID. 1 Similar risk factors, including female gender, older age and higher number of symptoms, have been reported in children and young people (CYP). 2 In England, the CLoCk study was established to investigate long COVID in a cohort of >30,000 CYP aged 11–17 years with PCR-confirmed SARS-CoV-2 infection and a contemporaneous PCR-negative group, matched by age, sex, geography and time. 3 Outcomes at 3 months follow-up have been published. 4 Anecdotal information suggested many CYP with ongoing symptoms had other household members with symptoms after COVID-19. We hypothesised that CYP reporting long COVID were more likely to have a parent with ongoing symptoms.

1418

I233

Gaber El-Saber Batiha, Hayder M. Al-kuraishy, Ali I. Al-Gareeb & Nermeen N. Welson

Pathophysiology of Post-COVID syndromes: a new perspective

https://doi.org/10.1186/s12985-022-01891-2

Published

9-Oct-22

Review

https://virologyj.biomedcentral.com/articles/10.1186/s12985-022-01891-2

Most COVID-19 patients recovered with low mortality; however, some patients experienced long-term symptoms described as “long-COVID” or “Post-COVID syndrome” (PCS). Patients may have persisting symptoms for weeks after acute SARS-CoV-2 infection, including dyspnea, fatigue, myalgia, insomnia, cognitive and olfactory disorders. These symptoms may last for months in some patients. PCS may progress in association with the development of mast cell activation syndrome (MCAS), which is a distinct kind of mast cell activation disorder, characterized by hyper-activation of mast cells with inappropriate and excessive release of chemical mediators. COVID-19 survivors, mainly women, and patients with persistent severe fatigue for 10 weeks after recovery with a history of neuropsychiatric disorders are more prone to develop PCS. High D-dimer levels and blood urea nitrogen were observed to be risk factors associated with pulmonary dysfunction in COVID-19 survivors 3 months post-hospital discharge with the development of PCS. PCS has systemic manifestations that resolve with time with no further complications. However, the final outcomes of PCS are chiefly unknown. Persistence of inflammatory reactions, autoimmune mimicry, and reactivation of pathogens together with host microbiome alterations may contribute to the development of PCS. The deregulated release of inflammatory mediators in MCAS produces extraordinary symptoms in patients with PCS. The development of MCAS during the course of SARS-CoV-2 infection is correlated to COVID-19 severity and the development of PCS. Therefore, MCAS is treated by antihistamines, inhibition of synthesis of mediators, inhibition of mediator release, and inhibition of degranulation of mast cells.

1419

I234

Kevin Roe

SARS-CoV-2 and Toxoplasma gondii shared symptoms suggest muscle cells and neurons are their chronic infection reservoirs

https://doi.org/10.1007/s13577-022-00809-y

Published

10-Oct-22

Letter to the Editor

https://link.springer.com/article/10.1007/s13577-022-00809-y

In conclusion, the post-infection symptoms of Long COVID/PASC are sometimes experienced after active SARS-CoV-2 virus infections. Long COVID/PASC exhibits several neurological and muscular symptoms that substantially parallel T. gondii infection symptoms. T. gondii is known to use central nervous system neurons and muscle cells to maintain chronic infections. It is therefore plausible that in some cases SARS-CoV-2 and T. gondii both use central nervous system neurons and muscle cells as reservoirs to maintain chronic infections. There may also be other pathways without a chronic infection viral reservoir that could explain the remaining Long COVID/PASC cases that lack SARS-CoV-2 antigens.

1420

I235

Charles-Edouard Luyt, Sonia Burrel, David Mokrani, Marc Pineton de Chambrun, Domitille Luyt, Juliette Chommeloux, Vincent Guiraud, Nicolas Bréchot, Matthieu Schmidt, Guillaume Hekimian, Alain Combes & David Boutolleau

Herpesviridae lung reactivation and infection in patients with severe COVID-19 or influenza virus pneumonia: a comparative study

https://doi.org/10.1186/s13613-022-01062-0

Published

24-Sep-22

Study

https://annalsofintensivecare.springeropen.com/articles/10.1186/s13613-022-01062-0

Background
Lung reactivations of Herpesviridae, herpes simplex virus (HSV) and cytomegalovirus (CMV) have been reported in COVID-19 patients. Whether or not those viral reactivations are more frequent than in other patients is not known.
Methods
Retrospective monocentric cohort study of 145 patients with severe COVID-19 pneumonia requiring invasive mechanical ventilation and who were tested for HSV and CMV in bronchoalveolar lavage performed during fiberoptic bronchoscopy for ventilator-associated pneumonia suspicion. Rates of HSV and CMV lung reactivations, and HSV bronchopneumonitis were assessed and compared with an historical cohort of 89 patients with severe influenza pneumonia requiring invasive mechanical ventilation.
Results
Among the 145 COVID-19 patients included, 50% and 42% had HSV and CMV lung reactivations, respectively, whereas among the 89 influenza patients, 63% and 28% had HSV and CMV lung reactivations, respectively. Cumulative incidence of HSV lung reactivation (taking into account extubation and death as competing events) was higher in influenza than in COVID-19 patients (p = 0.03), whereas the rate of HSV bronchopneumonitis was similar in both groups (31% and 25%, respectively). Cumulative incidence of CMV lung reactivation (taking into account extubation and death as competing events) was similar in COVID-19 and influenza patients (p = 0.07). Outcomes of patients with HSV or CMV lung reactivations were similar to that of patients without, whatever the underlying conditions, i.e., in COVID-19 patients, in influenza patients, or when all patients were grouped.
Conclusions
HSV and CMV lung reactivations are frequent in COVID-19 patients, but not more frequent than in patients with influenza-associated severe pneumonia, despite a higher severity of illness at intensive care unit admission of the latter and a longer duration of mechanical ventilation of the former. Although no impact on outcome of HSV and CMV lung reactivations was detected, the effect of antiviral treatment against these Herpesviridae remains to be determined in these patients.

1421

I236

Vamsi P. Guntur 1,2,†,Travis Nemkov 3,†ORCID,Esther de Boer 1,2,Michael P. Mohning 1,2,David Baraghoshi 4ORCID,Francesca I. Cendali 3ORCID,Inigo San-Millán 5,6,7,Irina Petrache 1,2,‡ORCID andAngelo D’Alessandro 3

Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC)

https://doi.org/10.3390/metabo12111026

Published

26-Oct-22

Study

https://www.mdpi.com/2218-1989/12/11/1026/htm

Exercise intolerance is a major manifestation of post-acute sequelae of severe acute respiratory syndrome coronavirus infection (PASC, or “long-COVID”). Exercise intolerance in PASC is associated with higher arterial blood lactate accumulation and lower fatty acid oxidation rates during graded exercise tests to volitional exertion, suggesting altered metabolism and mitochondrial dysfunction. It remains unclear whether the profound disturbances in metabolism that have been identified in plasma from patients suffering from acute coronavirus disease 2019 (COVID-19) are also present in PASC. To bridge this gap, individuals with a history of previous acute COVID-19 infection that did not require hospitalization were enrolled at National Jewish Health (Denver, CO, USA) and were grouped into those that developed PASC (n = 29) and those that fully recovered (n = 16). Plasma samples from the two groups were analyzed via mass spectrometry-based untargeted metabolomics and compared against plasma metabolic profiles of healthy control individuals (n = 30). Observational demographic and clinical data were retrospectively abstracted from the medical record. Compared to plasma of healthy controls or individuals who recovered from COVID-19, PASC plasma exhibited significantly higher free- and carnitine-conjugated mono-, poly-, and highly unsaturated fatty acids, accompanied by markedly lower levels of mono-, di- and tricarboxylates (pyruvate, lactate, citrate, succinate, and malate), polyamines (spermine) and taurine. Plasma from individuals who fully recovered from COVID-19 exhibited an intermediary metabolic phenotype, with milder disturbances in fatty acid metabolism and higher levels of spermine and taurine. Of note, depletion of tryptophan—a hallmark of disease severity in COVID-19—is not normalized in PASC patients, despite normalization of kynurenine levels—a tryptophan metabolite that predicts mortality in hospitalized COVID-19 patients. In conclusion, PASC plasma metabolites are indicative of altered fatty acid metabolism and dysfunctional mitochondria-dependent lipid catabolism. These metabolic profiles obtained at rest are consistent with previously reported mitochondrial dysfunction during exercise, and may pave the way for therapeutic intervention focused on restoring mitochondrial fat-burning capacity.

1422

I237

Sarah E Turbett, MD, Christopher H Tomkins-Tinch, BS, Melis N Anahtar, MD, PhD, Caitlin M Dugdale, MD, Emily P Hyle, MD, MSc, Erica S Shenoy, MD, PhD, Bennett Shaw, BS, Kenechukwu Egbuonu, BS, Kathryn A Bowman, MD, Kimon C Zachary, MD, Gordon C Adams, BA, David C Hooper, MD, Edward T Ryan, MD, Regina C LaRocque, MD, MPH, Ingrid V Bassett, MD, MPH, Virginia A Triant, MD, MPH, Katherine J Siddle, PhD, Eric Rosenberg, MD, PhD, Pardis C Sabeti, MD, DPhil, Stephen F Schaffner, PhD, Bronwyn L MacInnis, PhD, Jacob E Lemieux, MD, PhD, Richelle C Charles, MD

Distinguishing SARS-CoV-2 persistence and reinfection: A retrospective cohort study

https://doi.org/10.1093/cid/ciac830

Published

21-Oct-22

Study

https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac830/6765222

Background
SARS-CoV-2 reinfection is poorly understood, partly because few studies have systematically applied genomic analysis to distinguish reinfection from persistent RNA detection related to initial infection. We aimed to evaluate the characteristics of SARS-CoV-2 reinfection and persistent RNA detection using independent genomic, clinical, and laboratory assessments.
Methods
All individuals at a large academic medical center who underwent a SARS-CoV-2 nucleic acid amplification test (NAAT) ≥ 45 days after an initial positive test, with both tests between March 14th and December 30th, 2020, were analyzed for potential reinfection. Inclusion criteria required having ≥2 positive NAATs collected ≥45 days apart with a cycle threshold (Ct) value <35 at repeat testing. For each included subject, likelihood of reinfection was assessed by viral genomic analysis of all available specimens with a Ct value <35, structured Ct trajectory criteria, and case-by-case review by infectious diseases physicians.
Results
Among 1,569 individuals with repeat SARS-CoV-2 testing ≥45 days after an initial positive NAAT, 65 (4%) met cohort inclusion criteria. Viral genomic analysis characterized mutations present, and was successful for 14/65 (22%) subjects. Six subjects had genomically-supported reinfection and eight subjects had genomically-supported persistent RNA detection. Compared to viral genomic analysis, clinical and laboratory assessments correctly distinguished reinfection from persistent RNA detection in 12/14 (86%) subjects but missed 2/6 (33%) genomically-supported reinfections.
Conclusion
Despite good overall concordance with viral genomic analysis, clinical and Ct value-based assessments failed to identify 33% of genomically-supported reinfections. Scaling-up genomic analysis for clinical use would improve detection of SARS-CoV-2 reinfections.

1423

I238

Arjun MC1, Singh AK1, Roy P1, Ravichandran M1, Mandal S1, Pal D1, Das K1, Gajjala A1, Venkateshan M2, Mishra B3, Patro BK1, Mohapatra PR4, Subba SH1

Long COVID following Omicron wave in Eastern India-A retrospective cohort study.

https://doi.org/10.1002/jmv.28214

Published

12-Oct-22

Study

https://europepmc.org/article/med/36224705

Long coronavirus disease (COVID) or postacute sequelae of coronavirus disease of 2019 (COVID-19) is widely reported but the data of long COVID after infection with the Omicron variant is limited. This study was conducted to estimate the incidence, characteristics of symptoms, and predictors of long COVID among COVID-19 patients diagnosed during the Omicron wave in Eastern India. The cohort of COVID-19 patients included were adults (≥18 years) diagnosed as severe acute respiratory syndrome coronavirus 2 positive with Reverse Transcription Polymerase Chain Reaction. After 28 days of diagnosis; participants were followed up with a telephonic interview to capture data on sociodemographic, clinical history, anthropometry, substance use, COVID-19 vaccination status, acute COVID-19 symptoms, and long COVID symptoms. The long COVID symptoms were self-reported by the participants. Logistic regression was used to determine the predictors of long COVID. The median follow-up of participants was 73 days (Interquartile range; 67-83). The final analysis had 524 participants' data; among them 8.2% (95% Confidence Interval [CI]: 6%-10.9%) self-reported long COVID symptoms. Fatigue (34.9%) was the most common reported symptom followed by cough (27.9%). In multivariable logistic regression only two predictors were statistically significant-number of acute COVID-19 symptoms ≥ five (Adjusted odds ratio (aOR) = 2.95, 95% CI: 1.30-6.71) and past history of COVID-19 (aOR = 2.66, 95% CI: 1.14-6.22). The proportion of self-reported long COVID is considerably low among COVID-19 patients diagnosed during the Omicron wave in Eastern India when compared with estimates during Delta wave in the same setting.

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EthanDavittaColinDavittbMonty B.MazerceSathya S.AretidRichard S.HotchkissabKenneth E.Remybcde

COVID-19 disease and immune dysregulation

https://doi.org/10.1016/j.beha.2022.101401

Published

15-Oct-22

Review

https://www.sciencedirect.com/science/article/pii/S1521692622000561

The SARS-CoV-2 virus has complex and divergent immune alterations in differing hosts and over disease evolution. Much of the nuanced COVID-19 disease immune dysregulation was originally dominated by innate cytokine changes, which has since been replaced with a more complex picture of innate and adaptive changes characterized by simultaneous hyperinflammatory and immunosuppressive phenomena in effector cells. These intricacies are summarized in this review as well as potential relevance from acute infection to a multisystem inflammatory syndrome commonly seen in children. Additional consideration is made for the influence of variant to variant host cellular changes and the impact of potential vaccination upon these phenotypes. Finally, therapeutic benefit for immune alterations are discussed.

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Yasuhiro Nakano 1ORCID,Yuki Otsuka 1ORCID,Hiroyuki Honda 1,Naruhiko Sunada 1,Kazuki Tokumasu 1ORCID,Yasue Sakurada 1,Yui Matsuda 1,Toru Hasegawa 1,Kanako Ochi 2,Hideharu Hagiya 1ORCID,Hitomi Kataoka 1,Keigo Ueda 1 andFumio Otsuka 1,*ORCID

Transitional Changes in Fatigue-Related Symptoms Due to Long COVID: A Single-Center Retrospective Observational Study in Japan

https://doi.org/10.3390/medicina58101393

Published

5-Oct-22

Study

https://www.mdpi.com/1648-9144/58/10/1393/htm

Background and Objectives: Changes in post COVID-19 condition (PCC) characteristics caused by viral variants have yet to be clarified. We aimed to characterize the differences between clinical backgrounds and manifestations in long COVID patients who were infected with the Delta variant and those who were infected with the Omicron variants. Materials and Methods: This study was a single-center retrospective observational study for patients who visited our COVID-19 aftercare outpatient clinic (CAC) established in Okayama University Hospital (Japan) during the period from 15 February 2021 to 15 July 2022. We classified the onset of COVID-19 in the patients into three groups, the preceding, Delta-dominant, and Omicron-dominant periods, based on the prevalent periods of the variants in our prefecture. Results: In a total of 353 patients, after excluding 8 patients, 110, 130, and 113 patients were classified into the preceding, Delta-dominant, and Omicron-dominant periods, respectively. Patients infected in the Omicron-dominant period had significantly fewer hospitalizations, milder illnesses, more vaccinations and earlier visit to the CAC than did patients infected in the Delta-dominant period. Patients infected in the Omicron-dominant period had significantly lower frequencies of dysosmia (12% vs. 45%, ** p < 0.01), dysgeusia (14% vs. 40%, ** p < 0.01) and hair loss (7% vs. 28%, ** p < 0.01) but had higher frequencies of fatigue (65% vs. 50%, * p < 0.05), insomnia (26% vs. 13%, * p < 0.05) and cough (20% vs. 7%, ** p < 0.01) than did patients infected in the Delta-dominant period. Conclusions: The transitional changes in long COVID symptoms caused by the two variants were characterized.

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Maria J Monroy-Iglesias , Kathryn Tremble, Beth Russell, Charlotte Moss , Saoirse Dolly, Ailsa Sita-Lumsden, Alessio Cortellini, David James Pinato, Anne Rigg, Sophia N Karagiannis & Mieke Van Hemelrijck

Long-term effects of COVID-19 on cancer patients: the experience from Guy's Cancer Centre

https://doi.org/10.2217/fon-2022-0088

Published

29-Sep-22

Study

https://www.futuremedicine.com/doi/10.2217/fon-2022-0088

Background: Few studies have investigated the long-term effects of COVID-19 on cancer patients. Materials & methods: The authors conducted a telephone survey on the long-term symptoms of cancer patients from Guy's Cancer Centre. They compared patients whose symptoms occurred/got worse over 4 weeks after COVID-19 diagnosis (classified as long COVID) with patients who did not develop symptoms or whose symptoms occurred/got worse in the first 4 weeks after diagnosis. Results: The authors analyzed responses from 80 patients with a previous COVID-19 diagnosis; 51.3% (n = 41) developed long COVID. The most common symptoms were fatigue, breathlessness and cognitive impairment. Conclusion: Findings suggest that over half of the cancer population will experience long-term effects after their initial COVID-19 diagnosis. Further studies are required to validate the findings of this study.

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Marialaura Fanelli 1,Vita Petrone 1,Margherita Buonifacio 1,Elisabetta Delibato 2,Emanuela Balestrieri 1,Sandro Grelli 1,3,Antonella Minutolo 1ORCID andClaudia Matteucci 1,*

Multidistrict Host–Pathogen Interaction during COVID-19 and the Development Post-Infection Chronic Inflammation

https://doi.org/10.3390/pathogens11101198

Published

18-Oct-22

Review

https://www.mdpi.com/2076-0817/11/10/1198/htm

Due to the presence of the ACE2 receptor in different tissues (nasopharynx, lung, nervous tissue, intestine, liver), the COVID-19 disease involves several organs in our bodies. SARS-CoV-2 is able to infect different cell types, spreading to different districts. In the host, an uncontrolled and altered immunological response is triggered, leading to cytokine storm, lymphopenia, and cellular exhaustion. Hence, respiratory distress syndrome (ARDS) and systemic multi-organ dysfunction syndrome (MODS) are established. This scenario is also reflected in the composition of the microbiota, the balance of which is regulated by the interaction with the immune system. A change in microbial diversity has been demonstrated in COVID-19 patients compared with healthy donors, with an increase in potentially pathogenic microbial genera. In addition to other symptoms, particularly neurological, the occurrence of dysbiosis persists after the SARS-CoV-2 infection, characterizing the post-acute COVID syndrome. This review will describe and contextualize the role of the immune system in unbalance and dysbiosis during SARS-CoV-2 infection, from the acute phase to the post-COVID-19 phase. Considering the tight relationship between the immune system and the gut–brain axis, the analysis of new, multidistrict parameters should be aimed at understanding and addressing chronic multisystem dysfunction related to COVID-19.

1428

I243

César Fernández-de-las-Peñas 1,2,*ORCID,Lars Arendt-Nielsen 2,3,Gema Díaz-Gil 4ORCID,Francisco Gómez-Esquer 4ORCID,Antonio Gil-Crujera 4ORCID,Stella M. Gómez-Sánchez 4ORCID,Silvia Ambite-Quesada 1ORCID,María A. Palomar-Gallego 4ORCID,Oscar J. Pellicer-Valero 5ORCID andRocco Giordano 2,*ORCID

Genetic Association between ACE2 (rs2285666 and rs2074192) and TMPRSS2 (rs12329760 and rs2070788) Polymorphisms with Post-COVID Symptoms in Previously Hospitalized COVID-19 Survivors

https://doi.org/10.3390/genes13111935

Published

24-Oct-22

Study

https://www.mdpi.com/2073-4425/13/11/1935/htm

The aim of the study was to identify the association between four selected COVID-19 polymorphisms of ACE2 and TMPRSS2 receptors genes with the presence of long-COVID symptomatology in COVID-19 survivors. These genes were selected as they associate with the entry of the SARS-CoV-2 virus into the cells, so polymorphisms could be important for the prognoses of long-COVID symptoms. Two hundred and ninety-three (n = 293, 49.5% female, mean age: 55.6 ± 12.9 years) individuals who had been previously hospitalized due to COVID-19 were included. Three potential genotypes of the following single nucleotide polymorphisms (SNPs) were obtained from non-stimulated saliva samples of participants: ACE2 (rs2285666), ACE2 (rs2074192), TMPRSS2 (rs12329760), TMPRSS2 (rs2070788). Participants were asked to self-report the presence of any post-COVID defined as a symptom that started no later than one month after SARS-CoV-2 acute infection and whether the symptom persisted at the time of the study. At the time of the study (mean: 17.8, SD: 5.2 months after hospital discharge), 87.7% patients reported at least one symptom. Fatigue (62.8%), pain (39.9%) or memory loss (32.1%) were the most prevalent post-COVID symptoms. Overall, no differences in long-COVID symptoms were dependent on ACE2 rs2285666, ACE2 rs2074192, TMPRSS2 rs12329760, or TMPRSS2 rs2070788 genotypes. The four SNPs assessed, albeit previously associated with COVID-19 severity, do not predispose for developing long-COVID symptoms in people who were previously hospitalized due to COVID-19 during the first wave of the pandemic

1429

I244

Karen Giménez-Orenga1†, Justine Pierquin2†, Joanna Brunel2, Benjamin Charvet2, Eva Martín-Martínez3, Hervé Perron2,4*† and Elisa Oltra5,6*†

HERV-W ENV antigenemia and correlation of increased anti-SARS-CoV-2 immunoglobulin levels with post-COVID-19 symptoms

https://doi.org/10.3389/fimmu.2022.1020064

Published

27-Oct-22

Study

https://www.frontiersin.org/articles/10.3389/fimmu.2022.1020064/full

Due to the wide scope and persistence of COVID-19´s pandemic, post-COVID-19 condition represents a post-viral syndrome of unprecedented dimensions. SARS-CoV-2, in line with other infectious agents, has the capacity to activate dormant human endogenous retroviral sequences ancestrally integrated in human genomes (HERVs). This activation was shown to relate to aggravated COVID-19 patient´s symptom severity. Despite our limited understanding of how HERVs are turned off upon infection clearance, or how HERVs mediate long-term effects when their transcription remains aberrantly on, the participation of these elements in neurologic disease, such as multiple sclerosis, is already settling the basis for effective therapeutic solutions. These observations support an urgent need to identify the mechanisms that lead to HERV expression with SARS-CoV-2 infection, on the one hand, and to answer whether persistent HERV expression exists in post-COVID-19 condition, on the other. The present study shows, for the first time, that the HERV-W ENV protein can still be actively expressed long after SARS-CoV-2 infection is resolved in post-COVID-19 condition patients. Moreover, increased anti-SARS-CoV-2 immunoglobulins in post-COVID-19 condition, particularly high anti-SARS-CoV-2 immunoglobulin levels of the E isotype (IgE), seem to strongly correlate with deteriorated patient physical function (r=-0.8057, p<0.01). These results indicate that HERV-W ENV antigenemia and anti-SARS-CoV-2 IgE serology should be further studied to better characterize post-COVID-19 condition pathogenic drivers potentially differing in subsets of patients with various symptoms. They also point out that such biomarkers may serve to design therapeutic options for precision medicine in post-COVID-19 condition.

1430

I245

Laura C. Chambers, PhD, MPH and Francesca L. Beaudoin, MD, PhD, MS

A Longitudinal Study of COVID-19 Sequelae and Immunity

https://doi.org/10.7326/L22-0330

Published

1-Nov-22

Study

https://www.acpjournals.org/doi/full/10.7326/L22-0330

TO THE EDITOR: Sneller and colleagues' article (1) received controversial coverage on social media for the authors' conclusions that extensive diagnostic evaluation did not identify a cause of postacute sequelae of SARS-CoV-2 infection (PASC) and that persons with a history of anxiety disorder are at increased risk for PASC. Although we may be apt to dismiss such critiques in the age of misinformation, it is worth further examination lest we draw erroneous inferences about anxiety and PASC.
The authors' primary analyses included 189 participants with a history of COVID-19 (104 with PASC and 85 without). Ignoring power lost because of (appropriate) correction of the false discovery rate, the study sample was sufficiently powered to detect an odds ratio of 4.6 (assuming 5% prevalence of the characteristic among control participants). An effect size of this magnitude is large and probably unreasonable given that PASC may represent multiple distinct conditions with different causes and risk factors. Exploratory immunologic and virologic evaluations included an even smaller subset of participants, further limiting power. The noted absence of associations may be true or simply due to limited power.
Of note, the study measured prevalent PASC at study enrollment, which occurred approximately 5 months after COVID-19 onset. Given that some patients experience symptom resolution within 5 months (2), participants with resolved PASC at enrollment would have been misclassified as control participants “without PASC,” biasing results toward the null. The design was also subject to recall and selection bias that would have been mitigated with a prospective design or different sampling scheme. It is not surprising that persons with a history of anxiety who believed they had PASC might have been more apt to volunteer for a study about PASC. The authors acknowledge the limitations of self-referral, but it is also important to highlight how this sample differs from the general population. For example, 48% of participants had an advanced degree versus 13% of the U.S. population (3). Finally, analyses of risk factors for PASC were unadjusted, so associations may have been confounded by measured (such as female sex is associated with both PASC and anxiety disorders) and unmeasured (such as genetics) characteristics (4).
This study contributes much-needed data on PASC and highlights critical areas for future research. However, we must not draw broad conclusions from a small study with important limitations, and appropriate messaging around the science is critical. Patients with PASC already experience stigma and difficulty accessing care (5); our early work on PASC should not exacerbate this.

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I246

Javier Jurado Velez, Nita Kanney, Sadeep Shrestha and Bertha Hidalgo

Abstract 14914: Post-Acute Sequelae of SARS-CoV-2 and Mortality Among Individuals With Breakthrough Infections in Alabama

https://doi.org/10.1161/circ.146.suppl_1.14914

Published

30-Oct-22

Study

https://www.ahajournals.org/doi/abs/10.1161/circ.146.suppl_1.14914

Introduction: While breakthrough SARS-CoV-2 infections were expected among vaccinated individuals, less is known about the incidence of post-acute SARS-CoV-2 sequelae (PASC) and mortality among vaccinated individuals.
Methods: A retrospective analysis of Alabama Health System electronic health record (EHR) data was performed for 4,274 individuals with vaccination, clinical, medical, and mortality information between December 2020 and December 2021. The study population consisted of patients who had documented evidence of vaccination (e.g., two doses of Pfizer-BioNTech, two doses of Moderna, or a single dose of Janssen/Johnson & Johnson vaccines).
Results: Out of 4,274 individuals with EHR data in our cohort, 2,177 were female (51%), with a mean age equal to 56 ± 16.2; 1,245 individuals had received one or more doses of a COVID-19 vaccine. There were 640 COVID-19 related deaths, of which were 265 women (41%), 487 (76%) had obesity/overweight, and 133 patients (21%) that had an organ transplant or had a history of cancer. A greater percentage of unvaccinated individuals had documented COVID-19 deaths compared to individuals who were vaccinated (N=57, 5% and 583, 19%, respectively). The odds of mortality were lower among those who were vaccinated, compared to those who were unvaccinated (OR = 0.2, 95% CI = 0.15, 0.27). Sensitivity analyses showed that mortality among vaccinated individuals comprised of 6% (13) of patients with 1 dose, 5% (42) of patients with 2 doses, and <1% (2) of patients with 3 doses. One hundred and eighteen individuals had a PASC diagnosis, with 57% (67) of patients having received at least 1 dose. PASC occurred in 6% (13) of patients with 1 dose, 10% (84) of patients with 2 doses, and 3% (6) of patients with 3 doses. The odds of having PASC were higher among those vaccinated, compared to those unvaccinated (OR = 3.32, 95% CI = 2.29, 4.81). Among those who were vaccinated and had PASC (N=67), a greater proportion were female than male (69% compared to 31%, respectively).
Conclusions: At least 1 dose of a COVID-19 vaccine provided a lower odds of mortality in individuals with a breakthrough infection; however, in our population, vaccinated individuals had equal odds of post-acute SARS-CoV-2 sequelae (PASC) as unvaccinated individuals.

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Marianna Spatola, Nadège Nziza, Wonyeong Jung, Yixiang Deng, Dansu Yuan, View ORCID ProfileAlessandro Dinoto, View ORCID ProfileSilvia Bozzetti, View ORCID ProfileVanessa Chiodega, Sergio Ferrari, View ORCID ProfileDouglas A Lauffenburger, View ORCID ProfileSara Mariotto, View ORCID ProfileGalit Alter

Neurologic sequalae of COVID-19 are determined by immunologic imprinting from previous Coronaviruses

https://doi.org/10.1101/2022.11.07.22282030

pre-print

10-Nov-22

Study

https://www.medrxiv.org/content/10.1101/2022.11.07.22282030v1.full-text

Coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health emergency. Although SARS-CoV-2 is primarily a respiratory pathogen, extra-respiratory organs, including the central nervous system (CNS), can also be affected. Neurologic symptoms have been observed not only during acute SARS-CoV-2 infection, but also at distance from respiratory disease, also known as long-COVID or neurological post-acute sequelae of COVID-19 (neuroPASC). The pathogenesis of neuroPASC is not well understood, but hypotheses include SARS-CoV-2-induced immune dysfunctions, hormonal dysregulations, and persistence of SARS-CoV-2 reservoirs. In this study, we used a high throughput systems serology approach to dissect the humoral response to SARS-CoV-2 (and other common Coronaviruses - 229E, HKU1, NL63, OC43) in the serum and cerebrospinal fluid (CSF) from 112 infected individuals who developed or did not develop neuroPASC. Unique SARS-CoV-2 humoral profiles were observed in the CSF of neuroPASC. All antibody isotypes (IgA, IgM, IgA) and subclasses (IgA1-2; IgG1-4) were detected in serum, whereas CSF was characterized by focused IgG1 (and absence of IgM). These data argue in favor of compartmentalized brain-specific responses against SARS-CoV-2 through selective transfer of antibodies from the serum to the CSF across the blood-brain-barrier, rather than intrathecal synthesis, where more diversity in antibody classes/subclasses would be expected. Moreover, compared to individuals who did not develop post-acute neurological complications following infection (n=94), those with neuroPASC (n=18) exhibited attenuated systemic antibody responses against SARS-CoV-2, characterized by decreased capacity to activate antibody-dependent complement deposition (ADCD), NK cell activation (ADNKA) and to bind Fcγ receptors. However, surprisingly, neuroPASC showed significantly expanded antibody responses to other common Coronaviruses, including 229E, HKU1, NL63, and OC43. This biased humoral activation across coronaviruses was particularly enriched in neuroPASC individuals with poor outcome, suggesting an original antigenic sin (or immunologic imprinting), where pre-existing immune responses against related viruses shape the response to current infection, as a key prognostic marker of neuroPASC disease. Overall, these findings point to a pathogenic role for compromised anti-SARS-CoV-2 responses in the CSF, likely resulting in incomplete virus clearance from the brain and persistent neuroinflammation, in the development of post-acute neurologic complications of SARS-CoV-2 infection.

1433

I248

Benjamin Bowe, Yan Xie & Ziyad Al-Aly

Acute and postacute sequelae associated with SARS-CoV-2 reinfection

https://doi.org/10.1038/s41591-022-02051-3

Published

10-Nov-22

Study

https://www.nature.com/articles/s41591-022-02051-3

First infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with increased risk of acute and postacute death and sequelae in various organ systems. Whether reinfection adds to risks incurred after first infection is unclear. Here we used the US Department of Veterans Affairs’ national healthcare database to build a cohort of individuals with one SARS-CoV-2 infection (n = 443,588), reinfection (two or more infections, n = 40,947) and a noninfected control (n = 5,334,729). We used inverse probability-weighted survival models to estimate risks and 6-month burdens of death, hospitalization and incident sequelae. Compared to no reinfection, reinfection contributed additional risks of death (hazard ratio (HR) = 2.17, 95% confidence intervals (CI) 1.93–2.45), hospitalization (HR = 3.32, 95% CI 3.13–3.51) and sequelae including pulmonary, cardiovascular, hematological, diabetes, gastrointestinal, kidney, mental health, musculoskeletal and neurological disorders. The risks were evident regardless of vaccination status. The risks were most pronounced in the acute phase but persisted in the postacute phase at 6 months. Compared to noninfected controls, cumulative risks and burdens of repeat infection increased according to the number of infections. Limitations included a cohort of mostly white males. The evidence shows that reinfection further increases risks of death, hospitalization and sequelae in multiple organ systems in the acute and postacute phase. Reducing overall burden of death and disease due to SARS-CoV-2 will require strategies for reinfection prevention.

1434

I249

Qin Liu, Qi Su, Fen Zhang, Hein M. Tun, Joyce Wing Yan Mak, Grace Chung-Yan Lui, Susanna So Shan Ng, Jessica Y. L. Ching, Amy Li, Wenqi Lu, Chenyu Liu, Chun Pan Cheung, David S. C. Hui, Paul K. S. Chan, Francis Ka Leung Chan & Siew C. Ng

Multi-kingdom gut microbiota analyses define COVID-19 severity and post-acute COVID-19 syndrome

https://doi.org/10.1038/s41467-022-34535-8

Published

10-Nov-22

Study

https://www.nature.com/articles/s41467-022-34535-8

Our knowledge of the role of the gut microbiome in acute coronavirus disease 2019 (COVID-19) and post-acute COVID-19 is rapidly increasing, whereas little is known regarding the contribution of multi-kingdom microbiota and host-microbial interactions to COVID-19 severity and consequences. Herein, we perform an integrated analysis using 296 fecal metagenomes, 79 fecal metabolomics, viral load in 1378 respiratory tract samples, and clinical features of 133 COVID-19 patients prospectively followed for up to 6 months. Metagenomic-based clustering identifies two robust ecological clusters (hereafter referred to as Clusters 1 and 2), of which Cluster 1 is significantly associated with severe COVID-19 and the development of post-acute COVID-19 syndrome. Significant differences between clusters could be explained by both multi-kingdom ecological drivers (bacteria, fungi, and viruses) and host factors with a good predictive value and an area under the curve (AUC) of 0.98. A model combining host and microbial factors could predict the duration of respiratory viral shedding with 82.1% accuracy (error ± 3 days). These results highlight the potential utility of host phenotype and multi-kingdom microbiota profiling as a prognostic tool for patients with COVID-19.

1435

I250

Veronica Dioverti, Sonsoles Salto-Alejandre & Ghady Haidar

Immunocompromised Patients with Protracted COVID-19: a Review of “Long Persisters”

https://doi.org/10.1007/s40472-022-00385-y

Published

12-Nov-22

Review

https://link.springer.com/article/10.1007/s40472-022-00385-y

Purpose of Review
Certain immunocompromised individuals are at risk for protracted COVID-19, in which SARS-CoV-2 leads to a chronic viral infection. However, the pathogenesis, diagnosis, and management of this phenomenon remain ill-defined.
Recent Findings
Herein, we review key aspects of protracted SARS-CoV-2 infection in immunocompromised individuals, or the so-called long persisters, and describe the clinical presentation, risk factors, diagnosis, and treatment modalities of this condition, as well as intra-host viral evolution. Based on the available data, we also propose a framework of criteria with which to approach this syndrome.
Summary
Protracted COVID-19 is an uncharacterized syndrome affecting patients with B-cell depletion; our proposed diagnostic approach and definitions will inform much needed future research.

1436

I251

Benjamin Bowe, Yan Xie & Ziyad Al-Aly

Acute and postacute sequelae associated with SARS-CoV-2 reinfection

https://doi.org/10.1038/s41591-022-02051-3

Published

10-Nov-22

Study

https://www.nature.com/articles/s41591-022-02051-3

First infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with increased risk of acute and postacute death and sequelae in various organ systems. Whether reinfection adds to risks incurred after first infection is unclear. Here we used the US Department of Veterans Affairs’ national healthcare database to build a cohort of individuals with one SARS-CoV-2 infection (n = 443,588), reinfection (two or more infections, n = 40,947) and a noninfected control (n = 5,334,729). We used inverse probability-weighted survival models to estimate risks and 6-month burdens of death, hospitalization and incident sequelae. Compared to no reinfection, reinfection contributed additional risks of death (hazard ratio (HR) = 2.17, 95% confidence intervals (CI) 1.93–2.45), hospitalization (HR = 3.32, 95% CI 3.13–3.51) and sequelae including pulmonary, cardiovascular, hematological, diabetes, gastrointestinal, kidney, mental health, musculoskeletal and neurological disorders. The risks were evident regardless of vaccination status. The risks were most pronounced in the acute phase but persisted in the postacute phase at 6 months. Compared to noninfected controls, cumulative risks and burdens of repeat infection increased according to the number of infections. Limitations included a cohort of mostly white males. The evidence shows that reinfection further increases risks of death, hospitalization and sequelae in multiple organ systems in the acute and postacute phase. Reducing overall burden of death and disease due to SARS-CoV-2 will require strategies for reinfection prevention.

1437

I252

Sindhu Vangeti, Sivakumar Periasamy, Peifang Sun, Corey A. Balinsky, Avinash S. Mahajan, Natalia A. Kuzmina, Alessandra Soares-Schanoski, Elizabeth Cooper, Charmagne Beckett, Jan Marayag, Amethyst Marrone, Edgar Nunez, Yongchao Ge, Chad K. Porter, Carl W. Goforth, Stephen E. Lizewski, Rhonda Lizewski, Vihasi Jani, Victor A. Sugiharto https://orcid.org/0000-0002-9505-7303, Megan Schilling, Xuechen B. Yu, Nada Marjanovic, Mary Catherine George, Alexander Bukreyev, Stuart C. Sealfon stuart.sealfon@mssm.edu, Andrew G. Letizia andrew.g.letizia.mil@mail.mil, Irene Ramos

Serum Fc-Mediated Monocyte Phagocytosis Activity Is Stable for Several Months after SARS-CoV-2 Asymptomatic and Mildly Symptomatic Infection

https://doi.org/10.1128/spectrum.01837-22

Published

14-Nov-22

Study

https://journals.asm.org/doi/10.1128/spectrum.01837-22

We investigated the temporal profile of multiple components of the serological response after asymptomatic or mildly symptomatic SARS-CoV-2 infection, in a cohort of 67 previously SARS-CoV-2 naive young adults, up to 8.5 months after infection. We found a significant decrease of spike IgG and neutralization antibody titers from early (11 to 56 days) to late (4 to 8.5 months) time points postinfection. Over the study period, S1-specific IgG levels declined significantly faster than that of the S2-specific IgG. Further, serum antibodies from PCR-confirmed participants cross-recognized S2, but not S1, of the betacoronaviruses HKU1 and OC43, suggesting a greater degree of cross-reactivity of S2 among betacoronaviruses. Antibody-Dependent Natural Killer cell Activation (ADNKA) was detected at the early time point but significantly decreased at the late time point. Induction of serum Antibody-Dependent Monocyte Phagocytosis (ADMP) was detected in all the infected participants, and its levels remained stable over time. Additionally, a reduced percentage of participants had detectable neutralizing activity against the Beta (50%), Gamma (61 to 67%), and Delta (90 to 94%) variants, both early and late postinfection, compared to the ancestral strain (100%). Antibody binding to S1 and RBD of Beta, Gamma, Delta (1.7 to 2.3-fold decrease), and Omicron (10 to 16-fold decrease) variants was also significantly reduced compared to the ancestral SARS-CoV-2 strain. Overall, we found variable temporal profiles of specific components and functionality of the serological response to SARS-CoV-2 in young adults, which is characterized by lasting, but decreased, neutralizing activity and antibody binding to S1, stable ADMP activity, and relatively stable S2-specific IgG levels.
IMPORTANCE Adaptive immunity mediated by antibodies is important for controlling SARS-CoV-2 infection. While vaccines against COVID-19 are currently widely distributed, a high proportion of the global population is still unvaccinated. Therefore, understanding the dynamics and maintenance of the naive humoral immune response to SARS-CoV-2 is of great importance. In addition, long-term responses after asymptomatic infection are not well-characterized, given the challenges in identifying such cases. Here, we investigated the longitudinal humoral profile in a well-characterized cohort of young adults with documented asymptomatic or mildly symptomatic SARS-CoV-2 infection. By analyzing samples collected preinfection, early after infection and during late convalescence, we found that, while neutralizing activity decreased over time, high levels of serum S2 IgG and Antibody-Dependent Monocyte Phagocytosis (ADMP) activity were maintained up to 8.5 months after infection. This suggests that a subset of antibodies with specific functions could contribute to long-term protection against SARS-CoV-2 in convalescent unvaccinated individuals.

1438

I253

Stefanie N. Bernas,Henning Baldauf,Ruben Real,Jürgen Sauter,Jan Markert,Sarah Trost,Kristin Tausche,Uta Behrends,Alexander H. Schmidt,Johannes Schetelig

Post-COVID-19 condition in the German working population: A cross-sectional study of 200k registered stem cell donors

https://doi.org/10.1111/joim.13587

Published

13-Nov-22

Study

https://onlinelibrary.wiley.com/doi/abs/10.1111/joim.13587

Background
The SARS-CoV-2 pandemic has strained health systems worldwide, and infection numbers continue to rise. While previous data have already shown that many patients suffer from symptoms for months after an acute infection, data on risk factors and long-term outcomes are incomplete, particularly for the working population.
Objectives
We aimed to provide information on the prevalence of post COVID-19 conditions in a subset of the German working-age population (18-61 years old) and to analyze risk-factors.
Methods
We conducted an online survey with a health questionnaire among registered potential stem cell donors with or without a self-reported history of PCR-confirmed SARS-CoV-2 infection. Logistic regression models were used to examine the risks of severity of acute infection, sex, age, body mass index, diabetes mellitus and arterial hypertension medication on post COVID-19 symptoms.
Results
199,377 donors reported evaluable survey questionnaires: 12,609 cases had a history of SARS-CoV-2 infection and 186,768 controls had none. Overall, cases reported physical, cognitive and psychological complaints more frequently compared to controls. Increased rates of complaints persisted throughout 15 months post infection, e.g. 28.4/19.3% of cases/controls reported fatigue (p<0.0001) and 9.5/3.6% of cases/controls reported loss of concentration (p<0.0001). No significant differences were observed in the frequency of reported symptoms between three- and 15-months post-infection. Multivariate analysis revealed a strong influence of the severity of the acute SARS-CoV-2 infection episode and age on the risk for post-COVID-19 conditions.
Conclusion
We report the prevalence of post-COVID-19 conditions in mainly unvaccinated individuals with SARS-CoV-2 infections between February 2020 and August 2021. Severity of the acute course and age were major risk factors. Vaccinations may reduce the risk of post-COVID-19 conditions by reducing the risk for severe infections.

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V. Rossini,V. Tolosa-Enguis,C. Frances-Cuesta &Y. Sanz

Gut microbiome and anti-viral immunity in COVID-19

https://doi.org/10.1080/10408398.2022.2143476

Published

16-Nov-22

Review

https://www.tandfonline.com/doi/full/10.1080/10408398.2022.2143476

SARS-CoV-2 mainly affects the respiratory system, but the gastrointestinal tract is also a target. Prolonged gut disorders, in COVID-19 patients, were correlated with decreased richness and diversity of the gut microbiota, immune deregulation and delayed viral clearance. Although there are no definitive conclusions, ample evidence would suggest that the gut microbiome composition and function play a role in COVID-19 progression. Microbiome modulation strategies for population stratification and management of COVID-19 infection are under investigation, representing an area of interest in the ongoing pandemic. In this review, we present the existing data related to the interaction between gut microbes and the host’s immune response to SARS-CoV-2 and discuss the implications for current disease management and readiness to face future pandemics.

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Pierre Dudouet, Philippe Colson, Sarah Aherfi, Anthony Levasseur, Mamadou Beye, Jeremy Delerce, Emilie Burel, Philippe Lavrard, Wahiba Bader, Jean-Christophe Lagier, Pierre-Edouard Fournier, Bernard La Scola & Didier Raoult

SARS-CoV-2 quasi-species analysis from patients with persistent nasopharyngeal shedding

https://doi.org/10.1038/s41598-022-22060-z

Published

4-Nov-22

Study

https://www.nature.com/articles/s41598-022-22060-z

At the time of a new and unprecedented viral pandemic, many questions are being asked about the genomic evolution of SARS-CoV-2 and the emergence of different variants, leading to therapeutic and immune evasion and survival of this genetically highly labile RNA virus. The nasopharyngeal persistence of infectious virus beyond 17 days proves its constant interaction with the human immune system and increases the intra-individual mutational possibilities. We performed a prospective high-throughput sequencing study (ARTIC Nanopore) of SARS-CoV-2 from so-called "persistent" patients, comparing them with a non-persistent population, and analyzing the quasi-species present in a single sample at time t. Global intra-individual variability in persistent patients was found to be higher than in controls (mean 5.3%, Standard deviation 0.9 versus 4.6% SD 0.3, respectively, p < 0.001). In the detailed analysis, we found a greater difference between persistent and non-persistent patients with non-severe COVID 19, and between the two groups infected with clade 20A. Furthermore, we found minority N501Y and P681H mutation clouds in all patients, with no significant differences found both groups. The question of the SARS-CoV-2 viral variants’ genesis remains to be further investigated, with the need to prevent new viral propagations and their consequences, and quasi-species analysis could be an important key to watch out.

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Lucy Kundura1*, Renaud Cezar2, Sonia André3, Mauricio Campos-Mora4, Claire Lozano5, Thierry Vincent5, Laurent Muller6, Jean-Yves Lefrant6, Claire Roger6, Pierre-Géraud Claret7, Sandra Duvnjak8, Paul Loubet9, Albert Sotto9, Tu-Ahn Tran10, Jérôme Estaquier3,11† and Pierre Corbeau

Low perforin expression in CD8+ T lymphocytes during the acute phase of severe SARS-CoV-2 infection predicts long COVID

https://doi.org/10.3389/fimmu.2022.1029006

Published

20-Oct-22

Study

https://www.frontiersin.org/articles/10.3389/fimmu.2022.1029006/full

T cell cytotoxicity plays a major role in antiviral immunity. Anti-SARS-CoV-2 immunity may determine acute disease severity, but also the potential persistence of symptoms (long COVID). We therefore measured the expression of perforin, a cytotoxic mediator, in T cells of patients recently hospitalized for SARS-CoV-2 infection. We recruited 54 volunteers confirmed as being SARS-CoV-2-infected by RT-PCR and admitted to Intensive Care Units (ICUs) or non-ICU, and 29 age- and sex-matched healthy controls (HCs). Amounts of intracellular perforin and granzyme-B, as well as cell surface expression of the degranulation marker CD107A were determined by flow cytometry. The levels of 15 cytokines in plasma were measured by Luminex. The frequency of perforin-positive T4 cells and T8 cells was higher in patients than in HCs (9.9 ± 10.1% versus 4.6 ± 6.4%, p = 0.006 and 46.7 ± 20.6% vs 33.3 ± 18.8%, p = 0.004, respectively). Perforin expression was neither correlated with clinical and biological markers of disease severity nor predictive of death. By contrast, the percentage of perforin-positive T8 cells in the acute phase of the disease predicted the onset of long COVID one year later. A low T8 cytotoxicity in the first days of SARS-CoV-2 infection might favor virus replication and persistence, autoimmunity, and/or reactivation of other viruses such as Epstein-Barr virus or cytomegalovirus, paving the way for long COVID. Under this hypothesis, boosting T cell cytotoxicity during the acute phase of the infection could prevent delayed sequelae.

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Kamille Fogh https://orcid.org/0000-0002-6669-6894 kamille.fogh.01@regionh.dk, Tine Graakjær Larsen, Cecilie B. Hansen, Rasmus B. Hasselbalch, Alexandra R. R. Eriksen, Henning Bundgaard, Ruth Frikke-Schmidt, Linda M. Hilsted, Lars Østergaard, Isik S. Johansen, Ida Hageman, Peter Garred https://orcid.org/0000-0002-2876-8586, Kasper Iversen

Self-Reported Long COVID and Its Association with the Presence of SARS-CoV-2 Antibodies in a Danish Cohort up to 12 Months after Infection

https://doi.org/10.1128/spectrum.02537-22

Published

9-Nov-22

Study

https://journals.asm.org/doi/10.1128/spectrum.02537-22

The majority of long coronavirus disease (COVID) symptoms are not specific to COVID-19 and could be explained by other conditions. The present study aimed to explore whether Danish individuals with a perception that they suffer from long COVID have antibodies against the nucleocapsid antigen, as a proxy for detecting previous infection. The study was conducted in February and March 2021, right after the second surge of the COVID-19 pandemic in Denmark. All members of the social media group on Facebook “Covidramte med senfølger” (“long COVID sufferers'') above the age of 17 years and living in Denmark were invited to participate in a short electronic questionnaire about long COVID risk factors and symptoms. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N) protein was detected in blood samples as a proxy for natural SARS-CoV-2 infection. The final study population comprised 341 participants (90.6% females) who completed blood sampling and answered the questionnaire. A total of 232 (68%) were seropositive (median age, 49.5 years; interquartile range [IQR], 41 to 55 years; 90.1% females). There was no significant difference between sexes and serostatus. Seronegative and seropositive individuals had a similar burden of symptoms that could be attributed to long COVID. Time since perceived COVID-19 was significantly longer in the group of seronegative individuals than the seropositive ones (P < 0.001). This study suggests that long-COVID sufferers are mostly women and showed that a third of the participants did not have detectable anti-N-protein antibodies. It emphasizes the importance of early confirmation of COVID-19, as this study indicates an overlap between long-COVID symptoms and symptoms that are possibly of another origin.
IMPORTANCE This cohort study included questionnaire data as well as anti-nucleocapsid antibody analysis, allowing us to determine whether participants were seropositive due to vaccination or natural infection. The study emphasizes the importance of early confirmation of COVID-19, as antibodies recede with time, and it indicates an overlap between long COVID symptoms and symptoms possibly of another origin.

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Bhupesh K. Prusty1*, Francesca Kasimir1, Danny Toomey2, Zheng Liu1, Agnes Kaiping1 and Maria Eugenia Ariza3

Tissue specific signature of HHV-6 infection in ME/CFS

https://doi.org/10.3389/fmolb.2022.1044964

Published

5-Dec-22

Study

https://www.frontiersin.org/articles/10.3389/fmolb.2022.1044964/abstract?s=31

First exposure to various human herpesviruses (HHVs) including HHV-6, HCMV and EBV does not cause a life-threatening disease. In fact, most individuals are frequently unaware of their first exposure to such pathogens. These herpesviruses acquire lifelong latency in the human body where they show minimal genomic activity required for their survival. We hypothesized that it is not the latency itself but a timely, regionally restricted viral reactivation in a sub-set of host cells that plays a key role in disease development. HHV-6 (HHV-6A and HHV-6B) and HHV-7 are unique HHVs that acquire latency by integration of the viral genome into sub-telomeric region of human chromosomes. HHV-6 reactivation has been linked to Alzheimer’s Disease, Chronic Fatigue Syndrome, and many other diseases. However, lack of viral activity in commonly tested biological materials including blood or serum strongly suggests tissue specific localization of active HHV-6 genome. Here in this paper, we attempted to analyze active HHV-6 transcripts in postmortem tissue biopsies from a small cohort of ME/CFS patients and matched controls by fluorescence in situ hybridization using a probe against HHV-6 microRNA (miRNA), miR-aU14. Our results show abundant viral miRNA in various regions of the human brain and associated neuronal tissues including the spinal cord that is only detected in ME/CFS patients and not in controls. Our findings provide evidence of tissue-specific active HHV-6 and EBV infection in ME/CFS, which along with recent work demonstrating a possible relationship between herpesvirus infection and ME/CFS, provide grounds for renewed discussion on the role of herpesviruses in ME/CFS.

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Michael J. Peluso, Tyler-Marie Deveau, Sadie E. Munter, Dylan Ryder, Amanda Buck, Gabriele Beck-Engeser, Fay Chan, Scott Lu, Sarah A. Goldberg, Rebecca Hoh, Viva Tai, Leonel Torres, Nikita S. Iyer, Monika Deswal, Lynn H. Ngo, Melissa Buitrago, Antonio Rodriguez, Jessica Y. Chen, Brandon C. Yee, Ahmed Chenna, John W. Winslow, Christos J. Petropoulos, Amelia N. Deitchman, Joanna Hellmuth, Matthew A. Spinelli, Matthew S. Durstenfeld, Priscilla Y. Hsue, J. Daniel Kelly, Jeffrey N. Martin, Steven G. Deeks, Peter W. Hunt, Timothy J. Henrich

Impact of Pre-Existing Chronic Viral Infection and Reactivation on the Development of Long COVID

https://doi.org/10.1101/2022.06.21.22276660

pre-print

22-Jul-22

Study

https://www.medrxiv.org/content/10.1101/2022.06.21.22276660v2.full-text

The presence and reactivation of chronic viral infections such as Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human immunodeficiency virus (HIV) have been proposed as potential contributors to Long COVID (LC), but studies in well-characterized post-acute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited. In a cohort of 280 adults with prior SARS-CoV-2 infection, we observed that LC symptoms such as fatigue and neurocognitive dysfunction at a median of 4 months following initial diagnosis were independently associated with serological evidence of recent EBV reactivation (early antigen-D [EA-D] IgG positivity) or high nuclear antigen IgG levels, but not with ongoing EBV viremia. Evidence of EBV reactivation (EA-D IgG) was most strongly associated with fatigue (OR 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR 0.52) and tended to have less severe (>5 symptoms reported) LC (OR 0.44). Overall, these findings suggest differential effects of chronic viral co-infections on the likelihood of developing LC and predicted distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted.

SUMMARY The authors found that Long COVID symptoms in a post-acute cohort were associated with serological evidence of recent EBV reactivation and pre-existing HIV infection when adjusted for participant factors, sample timing, comorbid conditions and prior hospitalization, whereas underlying CMV infection was associated with a decreased risk of Long COVID.

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Partha Chattopadhyay1,2, Kriti Khare1,2†, Manish Kumar2,3†, Pallavi Mishra1†, Alok Anand4†, Ranjeet Maurya1,2, Rohit Gupta1, Shweta Sahni3, Ayushi Gupta4, Saruchi Wadhwa3, Aanchal Yadav1,2, Priti Devi1,2, Kishore Tardalkar5, Meghnad Joshi5*, Tavpritesh Sethi4* and Rajesh Pandey1,2*

Single-cell multiomics revealed the dynamics of antigen presentation, immune response and T cell activation in the COVID-19 positive and recovered individuals

https://doi.org/10.3389/fimmu.2022.1034159

Published

2-Dec-22

Study

https://www.frontiersin.org/articles/10.3389/fimmu.2022.1034159/full

Introduction: Despite numerous efforts to describe COVID-19's immunological landscape, there is still a gap in our understanding of the virus's infections after-effects, especially in the recovered patients. This would be important to understand as we now have huge number of global populations infected by the SARS-CoV-2 as well as variables inclusive of VOCs, reinfections, and vaccination breakthroughs. Furthermore, single-cell transcriptome alone is often insufficient to understand the complex human host immune landscape underlying differential disease severity and clinical outcome.
Methods: By combining single-cell multi-omics (Whole Transcriptome Analysis plus Antibody-seq) and machine learning-based analysis, we aim to better understand the functional aspects of cellular and immunological heterogeneity in the COVID-19 positive, recovered and the healthy individuals.
Results: Based on single-cell transcriptome and surface marker study of 163,197 cells (124,726 cells after data QC) from the 33 individuals (healthy=4, COVID-19 positive=16, and COVID-19 recovered=13), we observed a reduced MHC Class-I-mediated antigen presentation and dysregulated MHC Class-II-mediated antigen presentation in the COVID-19 patients, with restoration of the process in the recovered individuals. B-cell maturation process was also impaired in the positive and the recovered individuals. Importantly, we discovered that a subset of the naive T-cells from the healthy individuals were absent from the recovered individuals, suggesting a post-infection inflammatory stage. Both COVID-19 positive patients and the recovered individuals exhibited a CD40-CD40LG-mediated inflammatory response in the monocytes and T-cell subsets. T-cells, NK-cells, and monocyte-mediated elevation of immunological, stress and antiviral responses were also seen in the COVID-19 positive and the recovered individuals, along with an abnormal T-cell activation, inflammatory response, and faster cellular transition of T cell subtypes in the COVID-19 patients. Importantly, above immune findings were used for a Bayesian network model, which significantly revealed FOS, CXCL8, IL1β, CST3, PSAP, CD45 and CD74 as COVID-19 severity predictors.
Discussion: In conclusion, COVID-19 recovered individuals exhibited a hyper-activated inflammatory response with the loss of B cell maturation, suggesting an impeded post-infection stage, necessitating further research to delineate the dynamic immune response associated with the COVID-19. To our knowledge this is first multi-omic study trying to understand the differential and dynamic immune response underlying the sample subtypes.

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Michael J. Peluso,1 Tyler-Marie Deveau,2 Sadie E. Munter,2 Dylan M. Ryder,2 Amanda M. Buck,2 Gabriele Beck-Engeser,2 Fay Chan,2 Scott Lu,3 Sarah A. Goldberg,3 Rebecca Hoh,1 Viva Tai,1 Leonel Torres,2 Nikita S. Iyer,2 Monika Deswal,1 Lynn H. Ngo,1 Melissa Buitrago,1 Antonio E. Rodriguez,1 Jessica Y. Chen,1 Brandon C. Yee,4 Ahmed Chenna,5 John W. Winslow,5 Christos J. Petropoulos,5 Amelia N. Deitchman,6 Joanna Hellmuth,7 Matthew A. Spinelli,1 Matthew S. Durstenfeld,8 Priscilla Y. Hsue,8 John Daniel Kelly,3 Jeffrey N. Martin,3 Steven G. Deeks,1 Peter W. Hunt,2 and Timothy J. Henrich2

Impact of pre-existing chronic viral infection and reactivation on the development of long COVID

https://doi.org/10.1172/JCI163669

Published

1-Dec-22

Study

https://www.jci.org/articles/view/163669

BACKGROUND. The presence and reactivation of chronic viral infections such as Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human immunodeficiency virus (HIV) have been proposed as potential contributors to Long COVID (LC), but studies in well-characterized post-acute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited.

METHODS. In a cohort of 280 adults with prior SARS-CoV-2 infection, we assessed the presence and types of LC symptoms and prior medical history (including COVID-19 history and HIV status), and performed serological testing for EBV and CMV using a commercial laboratory. We used covariate-adjusted binary logistic regression models to identify independent associations between variables and LC symptoms.

RESULTS. We observed that LC symptoms such as fatigue and neurocognitive dysfunction at a median of 4months following initial diagnosis were independently associated with serological evidence suggesting recent EBV reactivation (early antigen-D [EA-D] IgG positivity) or high nuclear antigen (EBNA) IgG levels, but not with ongoing EBV viremia. Serological evidence suggesting recent EBV reactivation (EA-D IgG) was most strongly associated with fatigue (OR 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR 0.52).

CONCLUSION. Overall, these findings suggest differential effects of chronic viral co-infections on the likelihood of developing LC and predicted distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted.

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César Fernández-de-las-Peñas 1,2,*ORCID,Kin Israel Notarte 3ORCID,Princess Juneire Peligro 4,Jacqueline Veronica Velasco 4ORCID,Miguel Joaquín Ocampo 4,Brandon Michael Henry 5,Lars Arendt-Nielsen 2,6,Juan Torres-Macho 7,8 andGustavo Plaza-Manzano 9ORCID

Long-COVID Symptoms in Individuals Infected with Different SARS-CoV-2 Variants of Concern: A Systematic Review of the Literature

https://doi.org/10.3390/v14122629

Published

25-Nov-22

Systematic Review

https://www.mdpi.com/1999-4915/14/12/2629

The association of SARS-CoV-2 variants with long-COVID symptoms is still scarce, but new data are appearing at a fast pace. This systematic review compares the prevalence of long-COVID symptoms according to relevant SARS-CoV-2 variants in COVID-19 survivors. The MEDLINE, CINAHL, PubMed, EMBASE and Web of Science databases, as well as the medRxiv and bioRxiv preprint servers, were searched up to 25 October 2022. Case-control and cohort studies analyzing the presence of post-COVID symptoms appearing after an acute SARS-CoV-2 infection by the Alpha (B.1.1.7), Delta (B.1.617.2) or Omicron (B.1.1.529/BA.1) variants were included. Methodological quality was assessed using the Newcastle–Ottawa Scale. From 430 studies identified, 5 peer-reviewed studies and 1 preprint met the inclusion criteria. The sample included 355 patients infected with the historical variant, 512 infected with the Alpha variant, 41,563 infected with the Delta variant, and 57,616 infected with the Omicron variant. The methodological quality of all studies was high. The prevalence of long-COVID was higher in individuals infected with the historical variant (50%) compared to those infected with the Alpha, Delta or Omicron variants. It seems that the prevalence of long-COVID in individuals infected with the Omicron variant is the smallest, but current data are heterogeneous, and long-term data have, at this stage, an obviously shorter follow-up compared with the earlier variants. Fatigue is the most prevalent long-COVID symptom in all SARS-CoV-2 variants, but pain is likewise prevalent. The available data suggest that the infection with the Omicron variant results in fewer long-COVID symptoms compared to previous variants; however, the small number of studies and the lack of the control of cofounders, e.g., reinfections or vaccine status, in some studies limit the generality of the results. It appears that individuals infected with the historical variant are more likely to develop long-COVID symptomatology.

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Huan-ping Zhang,Yuan-li Sun,Yan-fen Wang,Duygu Yazici,Dilek Azkur,Ismail Ogulur,Ahmet Kursat Azkur,Zhao-wei Yang,Xiao-xue Chen,Ai-Zhi Zhang,Jia-qian Hu,Guang-Hui Liu,Mübeccel Akdis,Cezmi A. Akdis,Ya-dong Gao

Recent developments in the immunopathology of COVID-19

https://doi.org/10.1111/all.15593

Published

24-Nov-22

Review

https://onlinelibrary.wiley.com/doi/10.1111/all.15593

There has been an important change in the clinical characteristics and immune profile of Coronavirus disease 2019 (COVID-19) patients during the pandemic thanks to the extensive vaccination programs. Here, we highlight recent studies on COVID-19, from the clinical and immunological characteristics to the protective and risk factors for severity and mortality of COVID-19. The efficacy of the COVID-19 vaccines and potential allergic reactions after administration are also discussed. The occurrence of new variants of concerns such as Omicron BA.2, BA.4, and BA.5 and the global administration of COVID-19 vaccines have changed the clinical scenario of COVID-19. Multisystem inflammatory syndrome in children (MIS-C) may cause severe and heterogeneous disease but with a lower mortality rate. Perturbations in immunity of T cells, B cells, and mast cells, as well as autoantibodies and metabolic reprogramming may contribute to the long-term symptoms of COVID-19. There is conflicting evidence about whether atopic diseases, such as allergic asthma and rhinitis, are associated with a lower susceptibility and better outcomes of COVID-19. At the beginning of pandemic, the European Academy of Allergy and Clinical Immunology (EAACI) developed guidelines that provided timely information for the management of allergic diseases and preventive measures to reduce transmission in the allergic clinics. The global distribution of COVID-19 vaccines and emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with reduced pathogenic potential dramatically decreased the morbidity, severity, and mortality of COVID-19. Nevertheless, breakthrough infection remains a challenge for disease control. Hypersensitivity reactions (HSR) to COVID-19 vaccines are low compared to other vaccines, and these were addressed in EAACI statements that provided indications for the management of allergic reactions, including anaphylaxis to COVID-19 vaccines. We have gained a depth knowledge and experience in the over 2 years since the start of the pandemic, and yet a full eradication of SARS-CoV-2 is not on the horizon. Novel strategies are warranted to prevent severe disease in high-risk groups, the development of MIS-C and long COVID-19.

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Chiara Ambaglio,1,* Marina Marchetti, PhD,1,* Simone V Benatti,2,* Carmen J Tartari, PhD,1,* Cinzia Giaccherini,1,* Laura Russo,1,* Sara Gamba, MD,1,* Cristina Verzeroli,1,* Silvia Bolognini,1,* Chiara Ticozzi,1,* Francesca Schieppati, MD,1,* Serena Venturelli,2,* Luca Barcella, MD,1,* Marco Rizzi,2,* and Anna Falanga, MD1,3

Role of Hemostatic Biomarkers for the Identification of Patients with LONG-COVID19 Syndrome: Results from the 'Accordi' Study

https://doi.org/10.1182%2Fblood-2022-162206

Published

15-Nov-22

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9665220/

Introduction: Hemostatic alterations of patients with acute Covid-19 are well described, while post-Covid-19 clinical and laboratory consequences are less clear. Survivors of Covid-19 exhibit a complex array of symptoms, whose underlying pathology is still to be elucidated. The term 'long-Covid' is used to describe this condition developing after acute Covid-19.
Materials and Methods: After the first wave of the pandemic, we started an ad hoc multidisciplinary follow-up project for Covid-19 patients discharged from our Institution (ACCORDI STUDY). The program was run from July to November 2020. Patients were reassessed one time for clinical, instrumental, and laboratory parameters. Blood samples were collected from each participant for the measurement of hemostatic biomarkers. Here we present the first interim analysis of the biomarkers study.
The laboratory study included complete blood cell count, liver and renal functional tests, LDH, C-reactive protein, fibrinogen, D-dimer (DD), von Willebrand factor antigen (vWF:Ag), thrombomodulin (TM), tissue plasminogen activator (tPA) and plasminogen activator inhibitor PAI-1, prothrombin fragment 1+2 (F1+2).
Results: A cohort of 1471 (554F/917M) patients was recruited in the ACCORDI program with a median age of 60 (19-93). The median time from Covid-19 onset was 107 days (range 65-142). At the onset of disease, patients had the following symptoms: cardiopulmonary (94%), flu-like (91%), respiratory (82%), and neurological (57%). At the follow-up visit, cardiopulmonary symptoms persisted in 88%, flu-like in 64%, respiratory in 42%, and neurological in 13%. No differences in symptoms' distribution were present in relation to age and gender at either disease onset or follow-up visit. Based on the time of symptom persistence, 771 (53%) patients were classified as long-Covid, while the remaining 700 (47%) were symptoms-free. The median age of long-Covid patients was 59 (range 38-80) years, 55% male, with cardiopulmonary as the prevalent symptoms.
In a subgroup of 468 patients [322M/146F, age range 65 (38-83) years], 231 long-Covid and 237 symptoms-free, an interim analysis of hemostatic biomarker test results was performed. The analysis (Table 1) showed that, compared to symptoms-free subjects, long-Covid patients had significantly (p<0.05) higher levels of vWF:Ag and PAI-1. In addition, among subjects evaluated within 12 weeks from disease onset, the symptomatic subjects (n=48) had significantly higher levels of PAI-1 and TM (p<0.05) than the symptoms-free ones (n=78), whereas, among subjects evaluated after 12 weeks of disease onset (n=184), i.e. the post-Covid syndrome patients, had significantly (p<0.05) higher levels of vWF:Ag as compared to symptoms-free subjects (n=159). No significant differences were observed in the levels of tPA, DD, fibrinogen, F1+2 of symptomatic vs asymptomatic individuals. In a model of logistic regression analysis corrected for age and gender, having at least one among TM and PAI-1 biomarkers above the 75th percentile within 12 weeks from the disease onset, was significantly associated with a diagnosis of long-Covid (OR 2.425; 95% CI:1.037-5.671; p=0.041).
Conclusions: In conclusion, in this study cohort, patients with long-Covid syndrome are characterized by the persistence of cardiopulmonary symptoms. Preliminary results on hemostatic biomarkers analysis show that endothelial (TM and vWF:Ag) and fibrinolytic (PAI) biomarkers are associated with long-Covid symptoms and may be useful for the identification of affected subjects.

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LorenzThurneraNatalieFadleaEviRegitzaKlaus-DieterPreussaFrankNeumannaOnurCetinaClaudiaSchormannaMarie-ChristinHoffmannaChristianHerrbParastooKheiroddincTorben MillardRixeckerbRobertBalsbdSylvianeMullereBernhardThurnerfChristophKesselgMichaelKabeschcMoritzBewarderaKristinaHeyneaChristianLenschb1Igor AgeKosa1

Autoantibodies against SUMO1-DHX35 in long-COVID

https://doi.org/10.1016/j.jtauto.2022.100171

Published

20-Nov-22

Study

https://www.sciencedirect.com/science/article/pii/S2589909022000326

Highlights
•IgG autoantobodies against SUMO1-DHX35 occur in a subset of patients with long-COVID.
•Lysine 53 was identified as SUMOylation site of DHX35
•SUMOylation of DHX-35 is a necessary prerequisite for reactivity of autoantibodies
Abstract
Long COVID is a collection of symptoms as a late sequelae of SARS-CoV-2 infection. It often includes mental symptoms such as cognitive symptoms, persisting loss of smell and taste, in addition to exertional dyspnea. A role of various autoantibodies (autoAbs) has been postulated in long-COVID and is being further investigated. With the goal of identifying potentially unknown autoAbs, we screened plasma of patients with long COVID on in-house post-translationally modified protein macroarrays including citrullinated, SUMOylated and acetylated membranes. SUMO1ylated isoform DEAD/H (Asp-Glu-Ala-Asp/His) box helicase 35 (SUMO1-DHX35) was identified as only candidate antigen. In adult patients with long COVID, IgG autoAbs against SUMO1-DHX35 of IgG class were found in seven of 71 (9.8%) plasma samples, of IgM and IgG class in one of 69 (1.4%) samples, not in 200 healthy adult controls, not in 442 healthy children, and 146 children after SARS-CoV-2 infection. All autoAb-positive seven patients were female. AutoAb titers ranged between 200 to up to 400 By point mutagenesis and expression of FLAG-tagged mutants of DHX35 in HEK293 cells, and subsequent SUMOylation of purified constructs, lysine 53 was identified as a unique, never yet identified, SUMOylation site. The autoAbs had no reactivity against the non-SUMO1ylated mutant (K53R) of DHX35. To summarize, autoAbs against SUMO1-DHX35 were identified in adult female patients with long-COVID. Further studies are needed to verify the frequency of occurrence. The function of DHX35 has not yet been determined and there is no available information in relation to disease implication. The molecular mechanism causing the SUMOylation, the potential functional consequences of this post-translational modification on DHX35, and a potential pathogenicity of the autoAbs against SUMO1-DHX35 in COVID-19 and other possible contexts remain to be elucidated.

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AsimaKarimaTahirMuhammadbM. ShahidIqbalcRizwanQaisara

Elevated plasma CAF22 are incompletely restored six months after COVID-19 infection in older men

https://doi.org/10.1016/j.exger.2022.112034

Published

21-Nov-22

Study

https://www.sciencedirect.com/science/article/pii/S0531556522003436?ref=pdf_download&fr=RR-2&rr=775595db0de8f124

Highlights
•Covid-19 infection is associated with sarcopenia in old age.
•Muscle weakness and elevated plasma CAF22 occur one week after COVID-19 infection.
•Muscle strength and CAF22 are partly restored six months after COVID-19 infection.
•COVID-19 may cause muscle loss by degrading neuromuscular junctions.
•Evaluation and prevention of muscle loss may help treat COVID-19 infection.
Abstract
Introduction
The long-term complications of COVID-19 appear as significant health problems. However, the long-term muscle decline in these patients is poorly characterized.
Methods
We investigated the age-related muscle decline, termed sarcopenia, before and following the COVID-19 infection in older male patients (n = 87). We evaluated handgrip strength (HGS) and functional capacity (short physical performance battery; SPPB) in COVID-19 patients 7–42 days before and one week and 6-month after COVID-19 infection. We used ELISA tests to measure plasma c-terminal agrin fragment-22 (CAF22), c-reactive protein (CRP), and 8-isoprostanes as markers of degraded neuromuscular junctions, inflammation, and oxidative stress, respectively.
Results
Before the COVID-19 infection, 54 patients were non-sarcopenic, and 25 patients were sarcopenic, while eight patients subsequently developed sarcopenia. All patients exhibited reduced HGS and SPPB, while elevated CAF22, CRP, and 8-isoprostane levels one week post-COVID-19 infection (all p < 0.05). At six months post-COVID-19 infection, the HGS, SPPB, CAF22, CRP, and 8-isoprostanes were partly restored to baseline levels (all p < 0.05). Correlation analysis revealed that the plasma CAF22 had a significant correlation with HGS, SPPB, and COVID-19 disease severity. CAF22 also demonstrated significant areas under the curves in diagnosing sarcopenia at all three time-points.
Conclusion
Altogether, the muscle detriment due to COVID-19 persists six months post-infection, and plasma CAF22 may be helpful to detect muscle and functional decline in these patients. Timely evaluation and intervention of sarcopenia may be critical in COVID-19 treatment.

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Mahdi Taghadosi,Elham Safarzadeh,Ali Asgarzadeh,Seyed Askar Roghani,Afsaneh Shamsi,Cyrus Jalili,Shirin Assar,Parviz Soufivand,Mehran Pournazari,Parisa Feizollahi,Mohammad Hossein Nicknam,Vahid Asghariazar,Siavash Vaziri,Hossein Shahriari,Asadollah Mohammadi

Partners in crime: Autoantibodies complicit in COVID-19 pathogenesis

https://doi.org/10.1002/rmv.2412

Published

5-Dec-22

Review

https://onlinelibrary.wiley.com/doi/10.1002/rmv.2412

Autoantibodies (AABs) play a critical role in the pathogenesis of autoimmune diseases (AIDs) and serve as a diagnostic and prognostic tool in assessing these complex disorders. Viral infections have long been recognized as a principal environmental factor affecting the production of AABs and the development of autoimmunity. COVID-19 has primarily been considered a hyperinflammatory syndrome triggered by a cytokine storm. In the following, the role of maladaptive B cell response and AABs became more apparent in COVID-19 pathogenesis. The current review will primarily focus on the role of extrafollicular B cell response, Toll-like receptor-7 (TLR-7) activation, and neutrophil extracellular traps (NETs) formation in the development of AABs following SARS-CoV-2 infection. In the following, this review will clarify how these AABs dysregulate immune response to SARS-CoV-2 by disrupting cytokine function and triggering neutrophil hyper-reactivity. Finally, the pathologic effects of these AABs will be further described in COVID-19 associate clinical manifestations, including venous and arterial thrombosis, a multisystem inflammatory syndrome in children (MIS-C), acute respiratory distress syndrome (ARDS), and recently described post-acute sequelae of COVID-19 (PASC) or long-COVID.

1453

I268

Alistair V. W. Nunn 1,*ORCID,Geoffrey W. Guy 2,Wolfgang Brysch 3 andJimmy D. Bell 1ORCID

Understanding Long COVID; Mitochondrial Health and Adaptation—Old Pathways, New Problems

https://doi.org/10.3390/biomedicines10123113

Published

2-Dec-22

Review

https://www.mdpi.com/2227-9059/10/12/3113

Many people infected with the SARS-CoV-2 suffer long-term symptoms, such as “brain fog”, fatigue and clotting problems. Explanations for “long COVID” include immune imbalance, incomplete viral clearance and potentially, mitochondrial dysfunction. As conditions with sub-optimal mitochondrial function are associated with initial severity of the disease, their prior health could be key in resistance to long COVID and recovery. The SARs virus redirects host metabolism towards replication; in response, the host can metabolically react to control the virus. Resolution is normally achieved after viral clearance as the initial stress activates a hormetic negative feedback mechanism. It is therefore possible that, in some individuals with prior sub-optimal mitochondrial function, the virus can “tip” the host into a chronic inflammatory cycle. This might explain the main symptoms, including platelet dysfunction. Long COVID could thus be described as a virally induced chronic and self-perpetuating metabolically imbalanced non-resolving state characterised by mitochondrial dysfunction, where reactive oxygen species continually drive inflammation and a shift towards glycolysis. This would suggest that a sufferer’s metabolism needs to be “tipped” back using a stimulus, such as physical activity, calorie restriction, or chemical compounds that mimic these by enhancing mitochondrial function, perhaps in combination with inhibitors that quell the inflammatory response.

1454

I269

Ekaterina Pisareva, Stephanie Badiou, Lucia Mihalovičová, Alexia Mirandola, Brice Pastor, Andrei Kudriavtsev, Marie Berger, Camille Roubille, Pierre Fesler, Kada Klouche, Jean-Paul Cristol, Alain R. Thierry

Persistence of neutrophil extracellular traps and anticardiolipin auto-antibodies in post-acute phase COVID-19 patients

https://doi.org/10.1002/jmv.28209

Published

13-Oct-22

Study

https://onlinelibrary.wiley.com/doi/10.1002/jmv.28209

In the early phase of the pandemic, we were among the first to postulate that neutrophil extracellular traps (NETs) play a key role in COVID-19 pathogenesis. This exploratory prospective study based on 279 individuals showed that plasma levels of neutrophil elastase, myeloperoxidase and circulating DNA of nuclear and mitochondrial origins in nonsevere (NS), severe (S) and postacute phase (PAP) COVID-19 patients were statistically different as compared to the levels in healthy individuals, and revealed the high diagnostic power of these NETs markers in respect to the disease severity. The diagnostic power of NE, MPO, and cir-nDNA as determined by the Area Under Receiver Operating Curves (AUROC) was 0.95, 097, and 0.64; 0.99, 1.0, and 0.82; and 0.94, 1.0, and 0.93, in NS, S, and PAP patient subgroups, respectively. In addition, a significant fraction of NS, S as well as of PAP patients exhibited aCL IgM/IgG and anti-B2GP IgM/IgG positivity. We first demonstrate persistence of these NETs markers in PAP patients and consequently of sustained innate immune response imbalance, and a prolonged low-level pro-thrombotic potential activity highlighting the need to monitor these markers in all COVID-19 PAP individuals, to investigate postacute COVID-19 pathogenesis following intensive care, and to better identify which medical resources will ensure complete patient recovery.

TO Zotero

1455

I270

Thompson, Ryan C.; Simons, Nicole W.; Wilkins, Lillian; Cheng, Esther; Del Valle, Diane Marie; Hoffman, Gabriel E.; Cervia, Carlo; Fennessy, Brian; Mouskas, Konstantinos; Francoeur, Nancy J.; Johnson, Jessica S.; Lepow, Lauren; Le Berichel, Jessica; Chang, Christie; Beckmann, Aviva G.; Wang, Ying-chih; Nie, Kai; Zaki, Nicholas; Tuballes, Kevin; Barcessat, Vanessa; Cedillo, Mario A.; Yuan, Dan; Huckins, Laura; Roussos, Panos; Marron, Thomas U.; Glicksberg, Benjamin S.; Nadkarni, Girish; Heath, James R.; Gonzalez-Kozlova, Edgar; Boyman, Onur; Kim-Schulze, Seunghee; Sebra, Robert; Merad, Miriam; Gnjatic, Sacha; Schadt, Eric E.; Charney, Alexander W.; Batchelor, Craig; Beckmann, Noam D.

Molecular states during acute COVID-19 reveal distinct etiologies of long-term sequelae

https://doi.org/10.1186/s10020-022-00583-5

Published

Study

https://doi.org/10.1186/s10020-022-00583-5

Background
Multisystem Inflammatory Syndrome in Children (MIS-C) is a life-threatening complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which manifests as a hyper inflammatory process with multiorgan involvement in predominantly healthy children in the weeks following mild or asymptomatic coronavirus disease 2019 (COVID-19). However, host monogenic predisposing factors to MIS-C remain elusive.

Methods
Herein, we used whole exome sequencing (WES) on 16 MIS-C Brazilian patients to identify single nucleotide/InDels variants as predisposition factors associated with MIS-C.

Results
We identified ten very rare variants in eight genes (FREM1, MPO, POLG, C6, C9, ABCA4, ABCC6, and BSCL2) as the most promising candidates to be related to a higher risk of MIS-C development. These variants may propitiate a less effective immune response to infection or trigger the inflammatory response or yet a delayed hyperimmune response to SARS-CoV-2. Protein–Protein Interactions (PPIs) among the products of the mutated genes revealed an integrated network, enriched for immune and inflammatory response mechanisms with some of the direct partners representing gene products previously associated with MIS-C and Kawasaki disease (KD). In addition, the PPIs direct partners are also enriched for COVID-19-related gene sets. HLA alleles prediction from WES data allowed the identification of at least one risk allele in 100% of the MIS-C patients.

Conclusions
This study is the first to explore host MIS-C-associated variants in a Latin American admixed population. Besides expanding the spectrum of MIS-C-associated variants, our findings highlight the relevance of using WES for characterising the genetic interindividual variability associated with COVID-19 complications and ratify the presence of overlapping/convergent mechanisms among MIS-C, KD and COVID-19, crucial for future therapeutic management.

1456

I271

Tofarides, Andreas G.; Christaki, Eirini; Milionis, Haralampos; Nikolopoulos, Georgios K.

Effect of Vaccination against SARS-CoV-2 on Long COVID-19: A Narrative Review

https://doi.org/10.1038/s41591-022-02107-4

Published

Study

https://www.nature.com/articles/s41591-022-02107-4

Post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are debilitating, clinically heterogeneous and of unknown molecular etiology. A transcriptome-wide investigation was performed in 165 acutely infected hospitalized individuals who were followed clinically into the post-acute period. Distinct gene expression signatures of post-acute sequelae were already present in whole blood during acute infection, with innate and adaptive immune cells implicated in different symptoms. Two clusters of sequelae exhibited divergent plasma-cell-associated gene expression patterns. In one cluster, sequelae associated with higher expression of immunoglobulin-related genes in an anti-spike antibody titer-dependent manner. In the other, sequelae associated independently of these titers with lower expression of immunoglobulin-related genes, indicating lower non-specific antibody production in individuals with these sequelae. This relationship between lower total immunoglobulins and sequelae was validated in an external cohort. Altogether, multiple etiologies of post-acute sequelae were already detectable during SARS-CoV-2 infection, directly linking these sequelae with the acute host response to the virus and providing early insights into their development.

1457

I272

He, Shi-ting; Wu, Kexin; Cheng, Zixuan; He, Mengjie; Hu, Ruolan; Fan, Ning; Shen, Lin; Li, Qirui; Fan, Huahao; Tong, Yigang

Long COVID: The latest manifestations, mechanisms, and potential therapeutic interventions

https://doi.org/10.1038/s41577-022-00815-z

Published

Study

https://www.nature.com/articles/s41577-022-00815-z

Tissue-resident memory T (TRM) cells were originally identified as a tissue-sequestered population of memory T cells that show lifelong persistence in non-lymphoid organs. That definition has slowly evolved with the documentation of TRM cells having variable terms of tissue residency combined with a capacity to return to the wider circulation. Nonetheless, reductionist experiments have identified an archetypical population of TRM cells showing intrinsic permanent residency in a wide range of non-lymphoid organs, with one notable exception: the lungs. Despite the fact that memory T cells generated during a respiratory infection are maintained in the circulation, local TRM cell numbers in the lung decline concomitantly with a decay in T cell-mediated protection. This Perspective describes the mechanisms that underpin long-term T cell lodgement in non-lymphoid tissues and explains why residency is transient for select TRM cell subsets. In doing so, it highlights the unusual nature of memory T cell egress from the lungs and speculates on the broader disease implications of this process, especially during infection with SARS-CoV-2.

1458

I273

Nehme, Mayssam; Vetter, Pauline; Chappuis, François; Kaiser, Laurent; Guessous, Idris; the CoviCare Study team

Prevalence of post-COVID Condition 12 Weeks after Omicron Infection Compared to Negative Controls and Association with Vaccination Status

https://doi.org/10.1093/cid/ciac947

Published

Study

https://doi.org/10.1093/cid/ciac947

Post-COVID symptoms can persist several months after SARS-CoV-2 infection. Little is known, however, about the prevalence of post-COVID condition following infections from Omicron variants and how this varies according to vaccination statusThis study evaluates the prevalence of symptoms and functional impairment 12 weeks after an infection by Omicron variants (BA.1 and BA.2) compared to negative controls tested during the same period.Outpatient individuals tested positive or negative for COVID-19 infection between December 2021 and February 2022 at the Geneva University Hospitals were followed 12 weeks after their test date.Overall, 11.7% of Omicron cases had symptoms 12 weeks after the infection compared to 10.4% of individuals who tested negative during the same period (p < 0.001), and symptoms were much less common in vaccinated vs non-vaccinated individuals with Omicron infection (9.7% vs 18.1%, p < 0.001). There were no significant differences in functional impairment at 12 weeks between Omicron cases and negative controls even after adjusting for multiple potential confounders.The differential prevalence of post-COVID symptoms and functional impairment attributed to Omicron BA.1 and BA.2 infection is low when compared to negative controls. Vaccination is associated with lower prevalence of post-COVID symptoms.

1459

I274

Thompson, JY; Nnate, DA; Mussad, M; Carroll, S; Buck, P; Strain, WD; Banerjee, A; Van de Velde, N

EPH155 A Systematic Review of the Impact of Vaccination on Long COVID

https://doi.org/10.1016/j.jval.2022.09.1076

Published

Systematic Review

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9747389/

PMID: null
PMCID: PMC9747389
Objectives
Coronavirus disease 2019 (COVID-19) has multisystem effects, with a myriad of symptoms that may persist beyond four weeks (i.e., “long COVID”) but may be amenable to vaccination. This review systematically synthesised evidence to evaluate the health and economic burden of long COVID, specifically its relationship to vaccines.

Go to:
Methods
Relevant databases were searched for experimental randomized controlled trials (RCTs) and non-interventional studies. No language restrictions were applied. Estimates from 29 studies were narratively synthesised from Canada (2), United States (6), Australia (1), United Kingdom (9), France (2), India (2), Europe (1), Indonesia (1), Israel (1), Egypt (1), and international (3). Of the 29 studies identified, only 11 studies considered fully vaccinated vs partially vaccinated or unvaccinated groups before they were infected. Most studies were conducted among community-dwelling individuals (n=20), four among hospitalized patients, and five in either setting. Seven studies considered participants that were vaccinated post-infection. In comparison, eleven studies did not provide adequate information about vaccination status.

Go to:
Results
Of the 29 studies, 17 explored the relationship between vaccination and symptoms of long-COVID; 1 study reported worsening of symptoms, 11 studies reported improvement of symptoms, and 5 reported no difference in symptom profile following vaccination. Only two studies provided information on the economic benefit of vaccination strategies.

Go to:
Conclusions
The COVID-19 and long COVID evidence base is evolving, and additional data may be presented at the conference. Data collected to date suggest that the prevalence of long COVID is a crude approximation, which underestimates the burden of the disease and the impact of vaccines and findings may also be limited by the reporting and quality of eligible studies. Furthermore, we would not be able to evaluate the impact of risk aversion via adherence to public health guidelines or non-pharmacological interventions due to measurement error, thereby increasing the possibility of bias.

1460

I275

Thompson, J. Y.; Nnate, D. A.; Mussad, M.; Carroll, S.; Buck, P.; Strain, W. D.; Banerjee, A.; Velde, N. Van de

EPH155 A Systematic Review of the Impact of Vaccination on Long COVID

https://doi.org/10.1016/j.jval.2022.09.1076

Published

Systematic Review

https://www.valueinhealthjournal.com/article/S1098-3015(22)03281-8/fulltext

publisher: Elsevier
Objectives
Coronavirus disease 2019 (COVID-19) has multisystem effects, with a myriad of symptoms that may persist beyond four weeks (i.e., “long COVID”) but may be amenable to vaccination. This review systematically synthesised evidence to evaluate the health and economic burden of long COVID, specifically its relationship to vaccines.
Methods
Relevant databases were searched for experimental randomized controlled trials (RCTs) and non-interventional studies. No language restrictions were applied. Estimates from 29 studies were narratively synthesised from Canada (2), United States (6), Australia (1), United Kingdom (9), France (2), India (2), Europe (1), Indonesia (1), Israel (1), Egypt (1), and international (3). Of the 29 studies identified, only 11 studies considered fully vaccinated vs partially vaccinated or unvaccinated groups before they were infected. Most studies were conducted among community-dwelling individuals (n=20), four among hospitalized patients, and five in either setting. Seven studies considered participants that were vaccinated post-infection. In comparison, eleven studies did not provide adequate information about vaccination status.
Results
Of the 29 studies, 17 explored the relationship between vaccination and symptoms of long-COVID; 1 study reported worsening of symptoms, 11 studies reported improvement of symptoms, and 5 reported no difference in symptom profile following vaccination. Only two studies provided information on the economic benefit of vaccination strategies.
Conclusions
The COVID-19 and long COVID evidence base is evolving, and additional data may be presented at the conference. Data collected to date suggest that the prevalence of long COVID is a crude approximation, which underestimates the burden of the disease and the impact of vaccines and findings may also be limited by the reporting and quality of eligible studies. Furthermore, we would not be able to evaluate the impact of risk aversion via adherence to public health guidelines or non-pharmacological interventions due to measurement error, thereby increasing the possibility of bias.

1461

I276

Stein, Sydney R.; Ramelli, Sabrina C.; Grazioli, Alison; Chung, Joon-Yong; Singh, Manmeet; Yinda, Claude Kwe; Winkler, Clayton W.; Sun, Junfeng; Dickey, James M.; Ylaya, Kris; Ko, Sung Hee; Platt, Andrew P.; Burbelo, Peter D.; Quezado, Martha; Pittaluga, Stefania; Purcell, Madeleine; Munster, Vincent J.; Belinky, Frida; Ramos-Benitez, Marcos J.; Boritz, Eli A.; Lach, Izabella A.; Herr, Daniel L.; Rabin, Joseph; Saharia, Kapil K.; Madathil, Ronson J.; Tabatabai, Ali; Soherwardi, Shahabuddin; McCurdy, Michael T.; Peterson, Karin E.; Cohen, Jeffrey I.; de Wit, Emmie; Vannella, Kevin M.; Hewitt, Stephen M.; Kleiner, David E.; Chertow, Daniel S.

SARS-CoV-2 infection and persistence in the human body and brain at autopsy

https://doi.org/10.1038/s41586-022-05542-y

Published

Study

https://www.nature.com/articles/s41586-022-05542-y

Coronavirus disease 2019 (COVID-19) is known to cause multi-organ dysfunction1–3 during acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with some patients experiencing prolonged symptoms, termed post-acute sequelae of SARS-CoV-2 (refs. 4,5). However, the burden of infection outside the respiratory tract and time to viral clearance are not well characterized, particularly in the brain3,6–14. Here we carried out complete autopsies on 44 patients who died with COVID-19, with extensive sampling of the central nervous system in 11 of these patients, to map and quantify the distribution, replication and cell-type specificity of SARS-CoV-2 across the human body, including the brain, from acute infection to more than seven months following symptom onset. We show that SARS-CoV-2 is widely distributed, predominantly among patients who died with severe COVID-19, and that virus replication is present in multiple respiratory and non-respiratory tissues, including the brain, early in infection. Further, we detected persistent SARS-CoV-2 RNA in multiple anatomic sites, including throughout the brain, as late as 230 days following symptom onset in one case. Despite extensive distribution of SARS-CoV-2 RNA throughout the body, we observed little evidence of inflammation or direct viral cytopathology outside the respiratory tract. Our data indicate that in some patients SARS-CoV-2 can cause systemic infection and persist in the body for months.

1462

I277

Ogura, Hideki; Gohda, Jin; Lu, Xiuyuan; Yamamoto, Mizuki; Takesue, Yoshio; Son, Aoi; Doi, Sadayuki; Matsushita, Kazuyuki; Isobe, Fumitaka; Fukuda, Yoshihiro; Huang, Tai-Ping; Ueno, Takamasa; Mambo, Naomi; Murakami, Hiromoto; Kawaguchi, Yasushi; Inoue, Jun-ichiro; Shirai, Kunihiro; Yamasaki, Sho; Hirata, Jun-Ichi; Ishido, Satoshi

Dysfunctional Sars-CoV-2-M protein-specific cytotoxic T lymphocytes in patients recovering from severe COVID-19

https://doi.org/10.1038/s41467-022-34655-1

Published

Study

https://www.nature.com/articles/s41467-022-34655-1

Although the importance of virus-specific cytotoxic T lymphocytes (CTL) in virus clearance is evident in COVID-19, the characteristics of virus-specific CTLs related to disease severity have not been fully explored. Here we show that the phenotype of virus-specific CTLs against immunoprevalent epitopes in COVID-19 convalescents might differ according to the course of the disease. We establish a cellular screening method that uses artificial antigen presenting cells, expressing HLA-A*24:02, the costimulatory molecule 4-1BBL, SARS-CoV-2 structural proteins S, M, and N and non-structural proteins ORF3a and nsp6/ORF1a. The screen implicates SARS-CoV-2 M protein as a frequent target of IFNγ secreting CD8+ T cells, and identifies M198–206 as an immunoprevalent epitope in our cohort of HLA-A*24:02 positive convalescent COVID-19 patients recovering from mild, moderate and severe disease. Further exploration of M198–206-specific CD8+ T cells with single cell RNA sequencing reveals public TCRs in virus-specific CD8+ T cells, and shows an exhausted phenotype with less differentiated status in cells from the severe group compared to cells from the moderate group. In summary, this study describes a method to identify T cell epitopes, indicate that dysfunction of virus-specific CTLs might be an important determinant of clinical outcomes.

1463

I278

Lu, Scott; Anglin, Khamal; Tassetto, Michel; Garcia-Knight, Miguel; Pineda-Ramirez, Jesus; Sanchez, Ruth Diaz; Zhang, Amethyst; Romero, Mariela; Goldberg, Sarah A; Chen, Jessica Y; Donohue, Kevin; Davidson, Michelle; Lugtu, Kara; Yee, Brandon; Chenna, Ahmed; Winslow, John; Petropoulos, Christos J; Briggs-Hagen, Melissa; Peluso, Michael J; Andino, Raul; Midgley, Claire; Martin, Jeffrey; Saydah, Sharon; Kelly, Dan; Deeks, Steve

1048. Biological Determinants of Post-Acute Sequelae of SARS-CoV-2

https://doi.org/10.1093/ofid/ofac492.889

Published

Study

https://doi.org/10.1093/ofid/ofac492.889

The biological determinants of post-acute sequelae of SARS-CoV-2 infection (PASC), defined as the persistence or recurrence of symptoms not explained by an alternative medical diagnosis, are poorly understood. We assessed viral and immunological determinants during acute SARS-CoV-2 infection for an association with PASC at 4 to 8 months.From September 2020 to February 2022, symptomatic non-hospitalized individuals with laboratory-confirmed SARS-CoV-2 infection were identified within 5 days of symptom onset. We used anterior nasal biospecimens to measure the magnitude and duration of RNA and infectious viral shedding as well as blood samples to measure soluble markers of inflammation during the acute phase (first 28 days post-enrollment). PASC was defined as self-report of 1 or more COVID-19 attributed symptoms between 4 and 8 months after initial illness. We compared virologic and inflammatory markers, GFAP (a marker of neuronal damage) and neutralizing antibody levels from the acute phase between those with and without PASC using Mann-Whitney U tests or repeated measures mixed effects linear models.Among 71 SARS-CoV-2-positive participants with a completed follow-up visit between 4 to 8 months, we included 69 with virologic data and 61 with inflammatory marker data. Median age was 37 (IQR: 29 to 48) Overall, 16/72 (23%) reported at least one qualifying PASC symptom. Report of PASC was associated with >9 days of RNA shedding (p=0.04); all participants stopped RNA shedding by day 20. During acute illness, those with subsequent PASC had increased levelsof INF-alpha, INF-gamma, IP-10, IL-10, and MCP-1; these differences were greatest in the early period and normalized over 2 to 3 weeks post-illness onset. Compared to those without PASC, during the acute illness those with PASC had increased levels of GFAP and decreased levels of neutralizing antibodies but these differences were not statistically significant.We found indications that viral and immunological factors during acute illness may be associated with PASC, suggesting acute immunologic response to SARS-CoV-2 may have longer term effects and play a role in PASC. Further understanding of the clinically significance of these observations is needed.Ahmed Chenna, PhD, LabCorp: Employee John Winslow, PhD, Labcorp-Monogram Bioscience: Issued patents on VeraTag immunoassay-not applicable to present work|Labcorp-Monogram Bioscience: Employee|Labcorp-Monogram Biosciences: Issued patents on VeraTag immunoassay-not applicable to present work|Labcorp-Monogram Biosciences: Employee of Labcorp-Monogram Biosciences Christos J. Petropoulos, PhD, Labcorp-Monogram Biosciences: employee, corporate officer|Labcorp-Monogram Biosciences: Stocks/Bonds.

1464

I279

McDonald, Dylan; Logue, Jennifer; Franko, Nicholas M; Kemp, Megan M; McCulloch, Denise J; Chow, Eric J; Chu, Helen Y

1054. Comparison of Post-Acute COVID-19 Symptoms in Infected Individuals Pre- and Post-Vaccination

https://doi.org/10.1093/ofid/ofac492.895

Published

Study

https://doi.org/10.1093/ofid/ofac492.895

A constellation of debilitating symptoms, known as post-acute sequelae of COVID-19 (PASC), has been described in those in those with prior SARS-CoV-2 infection. While SARS-CoV-2 vaccination remains an effective way to prevent severe illness, PASC in individuals infected after vaccination is not well characterized.A cohort of adults with laboratory confirmed SARS-CoV-2 infection were enrolled as cases and longitudinally followed between March 2020-March 2022 in the greater Seattle region. Demographic and acute illness surveys capturing baseline symptoms, infection severity and medical care were administered at enrollment (Table). Controls with no history of SARS-CoV-2 infection were concurrently followed.Symptom surveys were given at 6 months post-infection. Vaccination status was self-reported. We defined PASC as the presence of one or more symptoms that persisted for at least 4 weeks after acute SARS-CoV-2 infection. Table.Demographic and Illness Characteristics of Study Participants*Days since illness onset refers to the days passed since infection date. **Comorbidities included hypertension, diabetes mellitus, chronic obstructive pulmonary disease, cardiovascular disease, chronic liver disease, chronic kidney disease, HIV, current use of immunosuppressants or diagnosis of cancer.Of 369 cases and 93 controls 57% (median age 44.7 years; 59.3% female) and 30% (median age 50.0 years; 50.0% female), completed the 6-month survey, respectively (Table). A total of 174 cases were infected prior to vaccination and 35 were post-vaccination.A total of 58 (28%) cases reported symptoms at 6 months, compared to 5 (18%) controls (Figure). In participants infected pre-vaccination, 32% reported PASC symptoms, compared to 6% of those infected post-vaccination (Figure; P=0.001). Our study found that the proportion of individuals reporting PASC at 6 months after infection was significantly higher among those infected before SARS-CoV-2 vaccination than those who were infected after. This suggests that timing of vaccination relative to SARS-CoV-2 infection may be associated with the development of PASC symptoms. Symptoms were still reported among many individuals with PASC who were vaccinated after their infection. Further research is required to understand the underlying mechanisms of PASC, and to characterize PASC in those infected after vaccination and with variant of concerns.Helen Y. Chu, MD, MPH, Cepheid: Reagents|Ellume: Advisor/Consultant|Gates Ventures: Grant/Research Support|Merck: Advisor/Consultant|Pfizer: Advisor/Consultant.

1465

I280

LaVergne, Stephanie; LaVergne, Stephanie; Dutt, Taru; McFann, Kim; Baxter, Bridget; Webb, Tracy; Berry, Kailey; Stomberg, Sophia; Dunn, Julie; Henao-Tamayo, Marcela; Ryan, Elizabeth

78. Longitudinal Analysis of T cells in COVID-19 Survivors with Post-Acute Sequelae of COVID-19 Reveals Associations between Individual Symptoms and Inflammatory Indexes

https://doi.org/10.1093/ofid/ofac492.003

Published

Study

https://doi.org/10.1093/ofid/ofac492.003

Many individuals infected with SARS-CoV-2 are left with persistent symptoms of COVID-19. Post-acute sequelae of COVID-19 (PASC) can affect quality of life and functionality. The mechanism underlying PASC is unknown but elevated inflammatory markers several months post infection have been found in those with PASC.Individuals diagnosed with COVID-19 were evaluated longitudinally for PASC and persistent symptoms. CD4+ and CD8+ cellular markers and intracellular cytokines were assessed at each follow-up time point and analyzed by individual PASC symptoms reported.Participants who reported persistent dyspnea, forgetfulness, confusion, and chest pain had significantly higher levels of CD8+Ki67+ cells. Those with dyspnea also had significantly higher levels of CD8+CD38+, CD8+Granzyme B+, and CD8+IL10+ cells. Those who suffered from forgetfulness, chest pain, and joint pain had significantly higher levels of CD4+CD25+ cells.Table 1Baseline participant characteristics and demographic data.Figure 1Differences in CD8 T cell markers and inflammatory cytokines in participants reporting symptoms of: a) dyspnea (N=20) and without dyspnea (N=104), b) fatigue (N=35) and without fatigue (N=89), c) confusion (N=17) and without confusion (N=107), d) difficulty concentrating (DC) (N=26) and without difficulty concentrating (N= 98), and e) forgetfulness or absent-mindedness (N=28) and without forgetfulness or absent-mindedness (N=96). *p<0.05.Figure 2Inflammatory indexes measured at 15–44, 45–89, 90–174, and > 175 days post PCR by symptom: A) dyspnea B) fatigue C) confusion D) DC=difficulty concentrating E) forgetfulness.These findings suggest continued CD8+ T cell and CD4+CD25+ T cell activation and response following SARS-CoV-2 infection in patients with PASC. An increase in T regulatory cells suggests an ongoing attempt to control host inflammation in a subset of these patients. These results shed further light on continued immune system activation and chronic inflammation as a link to symptoms in COVID-19 survivors suffering from PASC.All Authors: No reported disclosures.

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I281

Klimova, Elena M.; Bozhkov, Anatoly I.; Lavinska, Olena V.; Drozdova, Larisa A.; Kurhuzova, Nataliia I.

Low molecular weight cytotoxic components (DAMPs) form the post-COVID-19 syndrome

https://doi.org/10.1016/j.imbio.2022.152316

Published

Study

https://www.sciencedirect.com/science/article/pii/S0171298522001425

Highlights
•
The duration of post-COVID-19 symptoms is associated with neutrophil dysfunction and the formation of a specific humoral immunological pattern that performs an adaptive function and at the same time provides additional DAMPs production.

•
The DAMPs formed in the body of SARS-CoV-2 infection are not species-specific.

•
The possibility of modeling post-COVID-19 manifestations in an experiment on rats is shown.

•
The preliminary administaration of the biologically active substance MF into the body “modifies” the subsequent adaptive response of the body to the actions of cytotoxic components of the patient's serum in such a way that the studied parameters are similar or close to the control values.

Abstract
We studied the role of cytotoxic components (DAMPs) formed in the body of patients with COVID-19 in ensuring the long-term preservation of post-COVID-19 manifestations and the possibility of creating an experimental model by transferring DAMPs to rats. In patients with post-COVID-19 syndrome (PCS) 2 months after SARS-CoV-2 infection we determined the presence of cytotoxic components in the blood serum (Terasaki test, Dunaliella viridis test and content of DAMPs). In post-COVID-19 syndrome patients with a high content of serum cytotoxic oligopeptide fraction (selective group, n = 16) we determined the number of leukocytes, lymphocytes, neutrophil granulocytes and monocytes in the blood, the content of C-reactive protein (CRP), the concentration of C3 and C4 complement components and circulating immune complexes, the serum content of IL-6, IL −10, IL-18, TNF-α, phagocytic activity of neutrophils, presence of neutrophil traps and autoantibodies ANA.

It has been shown that in patients with PCS, there are components with cytotoxicity in the blood serum, form specific immunopathological patterns, which are characterized by: an increased content of CRP, complement system components C3 and C4 and cytokines (TNF-α, IL-6, IL-10, IL-18) activation, the formation of a wide range of autoantibodies ANA, the low efficiency of endocytosis in oxygen-independent phagocytosis; their phagocytic activity reaches its functional limit, and against this background, activation of neutrophil traps occurs, which can contribute to further induction of DAMPs. This self-sustaining cell-killing activation provided long-term preservation of PCS symptoms.

The transfer of blood serum components from selective group patients with PCS to rats was accompanied by the appearance of cytotoxic components in them which induced sensitization and immunopathological reactions. Preventive administration of a biologically active substance with polyfunctional properties MF to experimental animals “corrected” the initial functional state of the body's immune-metabolic system and eliminated or facilitated immuno-inflammatory reactions.

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Maher, Allison K.; Burnham, Katie L.; Jones, Emma M.; Tan, Michelle M. H.; Saputil, Rocel C.; Baillon, Laury; Selck, Claudia; Giang, Nicolas; Argüello, Rafael; Pillay, Clio; Thorley, Emma; Short, Charlotte-Eve; Quinlan, Rachael; Barclay, Wendy S.; Cooper, Nichola; Taylor, Graham P.; Davenport, Emma E.; Dominguez-Villar, Margarita

Transcriptional reprogramming from innate immune functions to a pro-thrombotic signature by monocytes in COVID-19

https://doi.org/10.1038/s41467-022-35638-y

Published

Study

https://www.nature.com/articles/s41467-022-35638-y

Although alterations in myeloid cells have been observed in COVID-19, the specific underlying mechanisms are not completely understood. Here, we examine the function of classical CD14+ monocytes in patients with mild and moderate COVID-19 during the acute phase of infection and in healthy individuals. Monocytes from COVID-19 patients display altered expression of cell surface receptors and a dysfunctional metabolic profile that distinguish them from healthy monocytes. Secondary pathogen sensing ex vivo leads to defects in pro-inflammatory cytokine and type-I IFN production in moderate COVID-19 cases, together with defects in glycolysis. COVID-19 monocytes switch their gene expression profile from canonical innate immune to pro-thrombotic signatures and are functionally pro-thrombotic, both at baseline and following ex vivo stimulation with SARS-CoV-2. Transcriptionally, COVID-19 monocytes are characterized by enrichment of pathways involved in hemostasis, immunothrombosis, platelet aggregation and other accessory pathways to platelet activation and clot formation. These results identify a potential mechanism by which monocyte dysfunction may contribute to COVID-19 pathology.

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Behura, Assirbad; Naik, Lincoln; Patel, Salina; Das, Mousumi; Kumar, Ashish; Mishra, Abtar; Nayak, Dev Kiran; Manna, Debraj; Mishra, Amit; Dhiman, Rohan

Involvement of epigenetics in affecting host immunity during SARS-CoV-2 infection

https://doi.org/10.1016/j.bbadis.2022.166634

Published

Article

https://www.sciencedirect.com/science/article/pii/S0925443922003052

Highlights
•SARS-CoV-2 regulates the epigenetic machinery of the host.
•miRNAs and virulent proteins help in hijacking the primary immune response.
•The host epigenetic landscape regulates SARS-CoV-2 mediated cytokine storm.
•Vitamins and minerals control SARS-CoV-2 infection by regulating the epigenetic module.
•Treatment approaches targeting epigenetic mechanisms can potentially combat COVID-19.
Abstract
Coronavirus disease 19 (COVID-19) is caused by a highly contagious RNA virus Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2), originated in December 2019 in Wuhan, China. Since then, it has become a global public health concern and leads the disease table with the highest mortality rate, highlighting the necessity for a thorough understanding of its biological properties. The intricate interaction between the virus and the host immune system gives rise to diverse implications of COVID-19. RNA viruses are known to hijack the host epigenetic mechanisms of immune cells to regulate antiviral defence. Epigenetics involves processes that alter gene expression without changing the DNA sequence, leading to heritable phenotypic changes. The epigenetic landscape consists of reversible modifications like chromatin remodelling, DNA/RNA methylation, and histone methylation/acetylation that regulates gene expression. The epigenetic machinery contributes to many aspects of SARS-CoV-2 pathogenesis, like global DNA methylation and receptor angiotensin-converting enzyme 2 (ACE2) methylation determines the viral entry inside the host, viral replication, and infection efficiency. Further, it is also reported to epigenetically regulate the expression of different host cytokines affecting antiviral response. The viral proteins of SARS-CoV-2 interact with various host epigenetic enzymes like histone deacetylases (HDACs) and bromodomain-containing proteins to antagonize cellular signalling. The central role of epigenetic factors in SARS-CoV-2 pathogenesis is now exploited as promising biomarkers and therapeutic targets against COVID-19. This review article highlights the ability of SARS-CoV-2 in regulating the host epigenetic landscape during infection leading to immune evasion. It also discusses the ongoing therapeutic approaches to curtail and control the viral outbreak.

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Fernández-de-las-Peñas, César; Arendt-Nielsen, Lars; Díaz-Gil, Gema; Gil-Crujera, Antonio; Gómez-Sánchez, Stella M.; Ambite-Quesada, Silvia; Palomar-Gallego, Maria A.; Pellicer-Valero, Oscar J.; Giordano, Rocco

ACE1 rs1799752 Polymorphism is not Associated with Long-COVID Symptomatology in Previously Hospitalized COVID-19 Survivors

https://doi.org/10.1016/j.jinf.2022.12.026

Published

Study

https://www.journalofinfection.com/article/S0163-4453(22)00752-6/fulltext

publisher: Elsevier
PMID: 36584771
Viral mechanisms of infection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent responsible of the coronavirus disease, 2019 (COVID-19), suggest the involvement of surface receptor for S1 of the angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine-2 (TMPRSS2) receptors [[1]]. Single studies have found that single nucleotide polymorphisms (SNP), e.g., ACE2 rs2285666, ACE2 rs2074192, or TMPRSS2 rs12329760, seem to be potentially associated with severity of COVID-19; however, current evidence is still not conclusive [[2]]. Another potential SNP that could be implicated in various clinical diseases (e.g., renal damage, pneumonia, ischemic stroke) and also immunological reaction (i.e., cytokine storm) induced by SARS-CoV-2 is ACE1 rs1799752 [[3]]. In fact, evidence suggests that the D allele of this SNP is associated with higher severity of SARS-CoV-2 [[4]].
Although ACE2, TMPRSS2 and ACE1 receptors are highly expressed in the lungs and respiratory tract, these receptors are also present in several other tissues explaining the heterogeneity clinical presentation of COVID-19. Accordingly, it could be proposed that these receptors are potentially also associated with the presence of symptoms after the acute phase of the infection, i.e., long-COVID. Mariani et al have recently observed that post-COVID symptoms are present for up to one year in a heterogeneous population [[5]]. Additionally, a recent meta-analysis reported that post-COVID fatigue can be present in up to 51% of COVID-19 survivors [[6]]. Our group has recently identified that ACE2 rs2285666, ACE2 rs2074192, TMPRSS2 rs12329760 and TMPRSS2 rs2070788 polymorphisms do not predispose for long-COVID symptoms in previously hospitalized COVID-19 survivors [[7]].
We present here a secondary analysis, genetic part of THE LONG COVID EXPERIENCE STUDY [[7]], of the potential association between ACE1 rs1799752 polymorphism and the presence of long-COVID symptomatology.
Briefly, unstimulated whole saliva samples were collected from 288 COVID-19 survivors who were hospitalized at three urban hospitals in Madrid (Spain) during the first wave of the pandemic (March-May 2020). All participants provided written informed consent. The study was approved by the Institutional Ethics Committees of all involved institutions (HSO25112020; URJC0907202015920; HUFA20/126; HUIL/092-20). Genotyping collection and procedures have been previously published [[7]]. Identification of each possible genotype of ACE1 rs1799752 polymorphism was conducted by using specific fluorescent dyes. The ACE1 rs1799752 is an insertion/deletion of an Alu repeat sequence that is interrogated using a pair of assays. The possible variants of the ACE1 rs1799752 (the mutant Alu insertion allele -I allele- and the wild type of deletion allele -D allele-) SNP lead to the following genotypes (D/D, D/I, I/I) derived from the sequence:
CCCATTTCTCTAGACCTGCTGCCT [-/ALU] ATACAGTCACTTTTATGTGGTTTC
Demographic, medical comorbidities, and hospitalization data were collected from hospital medical records. Post-COVID symptomatology was collected during a face-to-face appointment conducted by experienced healthcare professionals at 17.8 (SD 5.2) months after hospitalization [[7]]. Dyspnea at exertion (n=196, 68%) and fatigue (n=181, 63%) were the most prevalent post-COVID symptoms in the total sample. Other post-COVID symptoms included pain (n=117, 40.6%), memory loss (n=92, 32%) or hair loss (n=77, 26.7%). The genotype distribution (D/D genotype n=109, 37%; D/I genotype n=173, 60%; I/I genotype n=6, 3%) deviated from that expected based on the Hardy-Weinberg equilibrium, a result also extensively found in published COVID-19 studies. Overall, no significant differences in long-COVID symptoms were observed depending on the genotypes of ACE1 rs1799752 SNP (Table). No sex differences in the genotype distribution (P=0.723) were either found.
TablePre-Infection data and post-COVID symptoms according to the ACE1 rs1799752 Polymorphism Genotype (n=288)

The results of this secondary analysis reveal that ACE1 rs1799752 polymorphism does not predispose to developing long-COVID symptoms when evaluated in previously hospitalized COVID-19 survivors. Current results would agree with our previous report on ACE2 and TMPRSS2 polymorphisms [[7]]. The lack of association between these SNPs and long-COVID could be explained by the significant gene variability existing (i.e., ethnic differences) across populations [[8]]. Further, the lack of relationship among SNPs associated with COVID-19 severity and the presence of long-COVID reinforce the idea that the severity of the disease is not associated with the development of post-COVID symptoms since the presence of these symptoms is similar between hospitalized and non-hospitalized patients [[9]]. Similarly, the D allele of the ACE1 rs1799752 polymorphism has been associated with a higher risk of hospitalization in patients with co-morbidities at the acute phase of the infection since these individuals are at a higher risk for developing acute respiratory distress syndrome (ARDS) [[10]]. In our study, no differences in previous medical co-morbidities depending on the ACE1 rs1799752 genotype were observed.
Some limitations of the current data should be recognized. First, only previously hospitalized COVID-19 survivors were included, therefore, the role of these SNPs in non-hospitalized patients is yet to be invetigated. Second, it could be possible that larger samples could identify genotype differences, accordingly, our data should be considered exploratory. Population-based cohort studies and a whole genome SNPs analysis might help to validate current results and identify other genes potentially related to long-COVID symptoms.

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Altmann, Daniel M.

The COVID-19 immunology masterclass enters its third year

https://doi.org/10.1038/s41590-022-01393-x

Published

5-Jan-23

Article

https://www.nature.com/articles/s41590-022-01393-x

publisher: Nature Publishing Group
The other topic within this throwing down of the gauntlet to immunology researchers and funders is the huge challenge of long COVID, often correctly referred to as the ‘pandemic within the pandemic’. We cannot accurately count how many on the planet have experienced COVID-19 infection, but estimate that around one-tenth suffer persistent symptoms — the lives of a significant minority of these remain changed at two and half years and counting. This is a disease process that is destroying lives and has potential to destroy health services and damage economies, imposing a societal disease burden as large as that of rheumatic or cardiac disease. Most agree that defining an etiology, whatever the mix of autoimmunity, immunopathology, endotheliitis, viral persistence and hypercoagulation, lies within the remit of immunologists. Given the huge successes over past decades of translational immunology across areas from cancer to autoimmune disease, there is reason for optimism that with knowledge of long-COVID mechanisms, the well-stocked immunology toolkit would have the wherewithal to supply solutions. We just need the resources to fight this next battle.

So, as immunologists return to the day job and rightly go back to the countless research questions that occupied us prior to the end of 2019, let us also keep reminding ourselves of the only half-done COVID-19 job and the need for us, with the help of appropriate funding, to now show what can be achieved if we really let rip with all that hard-fought immunological knowledge.

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Adnot, S.; Bernard, D.; Lipskaia, L.; Trottein, F.

La sénescence cellulaire, nouvelle cible des infections virales respiratoires : du virus influenza au SARS-CoV-2

https://doi.org/10.1016/j.banm.2022.11.011

Published

4-Jan-23

Review

https://www.sciencedirect.com/science/article/pii/S0001407922003727

Résumé
L’accumulation de cellules sénescentes dans les tissus est un processus clé du vieillissement et des maladies chroniques liées à l’âge, notamment les maladies pulmonaires telles la bronchopneumopathie chronique obstructive, la fibrose pulmonaire, ou le cancer. Ces dernières années ont permis d’élargir le spectre des maladies respiratoires associées à une sénescence cellulaire, en particulier les infections pulmonaires aiguës virales, au premier rang desquelles la maladie à coronavirus 2019 (COVID19), particulièrement sévère chez le sujet âgé ou atteint de comorbidités. L’infection par le virus influenza qui frappe plus sévèrement les âges extrêmes de la vie est également associée à une forte sénescence pulmonaire. La sénescence cellulaire représente potentiellement une cible originale pour s’attaquer à ces maladies, bien que ses mécanismes spécifiques restent largement incompris. De nouvelles approches thérapeutiques à visée anti-sénescente sont ainsi proposées au cours des infections pulmonaires virales sévères, dans un but de prévention des effets aigus et/ou, à plus long terme, des séquelles pulmonaires.
Summary
The accumulation of senescent cells in tissues is a key process of aging and age-related diseases, including lung diseases such as chronic obstructive pulmonary disease, lung fibrosis, or cancer. In recent years, the spectrum of respiratory diseases associated with cellular senescence has been broadened, in particular acute viral pulmonary infections, foremost among which is coronavirus disease 2019 (COVID19), which is particularly severe in the elderly or in subjects with comorbidities. Influenza virus infection, which strikes more severely at the extreme ages of life, is also associated with severe pulmonary senescence. Cellular senescence potentially represents an original target for attacking these diseases, although its specific mechanisms remain largely misunderstood. New anti-senescent therapeutic approaches are thus proposed during severe viral pulmonary infections, with the aim of preventing acute effects and/or, in the longer term, pulmonary sequelae.

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Torres-Ruiz, Jiram; Lomelín-Gascón, Julieta; Lira Luna, Jaquelin; Vargas- Castro, Ana Sofia; Pérez-Fragoso, Alfredo; Nuñez-Aguirre, Miroslava; Alcalá-Carmona, Beatriz; Absalón-Aguilar, Abdiel; Balderas-Miranda, Jennifer T.; Maravillas-Montero, José Luis; Mejía-Domínguez, Nancy R.; Núñez-Álvarez, Carlos; Llorente, Luis; Romero-Ramírez, Sandra; Sosa-Hernández, Victor Andrés; Cervantes-Díaz, Rodrigo; Juárez-Vega, Guillermo; Meza-Sánchez, David; Rull-Gabayet, Marina; Martínez-Juárez, Luis Alberto; Morales, Linda; López-López, Lizeth Naomi; Negrete-Trujillo, José Adrián; Falcón-Lezama, Jorge Abelardo; Valdez-Vázquez, Rafael Ricardo; Gallardo-Rincón, Héctor; Tapia-Conyer, Roberto; Gómez-Martín, Diana

Novel clinical and immunological features associated with persistent post-acute sequelae of COVID-19 after six months of follow-up: a pilot study

https://doi.org/10.1080/23744235.2022.2158217

Published

13-Jan-23

Study

https://doi.org/10.1080/23744235.2022.2158217

Background Currently, there is scant information regarding the features associated to the persistence of post-COVID-19 syndrome, which is the main aim of the present study.Methods A cohort study of 102 COVID-19 patients was conducted. The post-COVID-19 symptoms were assessed by a standardised questionnaire. Lymphocyte immunophenotyping was performed by flow cytometry and chemokines/cytokines, neutrophil extracellular traps, the tripartite motif 63, anti-cellular, and anti-SARS-CoV-2 IgG antibodies were addressed in serum. The primary outcome was the persistence of post-COVID-19 syndrome after six months follow-up.Results Thirteen patients (12.7%) developed the primary outcome and had a more frequent history of post-COVID-19 syndrome 3 months after infection onset (p = .044), increased levels of IL-1α (p = .011) and IP-10 (p = .037) and increased CD57 expression in CD8+ T cells (p = .003). There was a trend towards higher levels of IFN-γ (p = .051), IL-1β (p = .062) and IL-6 (p = .087). The history of post COVID-19 in the previous 3 months, obesity, baseline serum MIP-1α and IP-10, and CD57 expression in CD8+ T cells were independently associated with the persistence of post-COVID-19 syndrome.Conclusion Our data suggest an important relationship between a pro-inflammatory state mediated through metabolic pathways related to obesity and increased cellular senescence as a key element in the persistence of post-COVID-19 syndrome at six months of follow-up.

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Abel, T.; Gueant-Rodriguez, R. M.; Regnault, V.; Gueant, J. L.; Chaouat, A.; Chabot, F.; Valentin, S.

Rôle prédictif des marqueurs de l’activation des neutrophiles dans les complications respiratoires résiduelles des pneumonies à SARS-CoV-2

https://doi.org/10.1016/j.rmra.2022.11.353

Published

1-Jan-23

Study

https://www.sciencedirect.com/science/article/pii/S1877120322005237

Introduction
L’infection par le SARS-CoV-2 s’exprime au niveau respiratoire par des formes très diverses allant de l’absence de symptômes à un syndrome de détresse respiratoire aiguë. Ces différences sont expliquées par différents mécanismes physiopathologiques. Notamment, certains marqueurs impliqués dans la régulation de l’immunité innée (élastase des polynucléaires neutrophiles, myélopéroxydase-DNA et histone-DNA) sont associés à la gravité de l’atteinte respiratoire à la phase aiguë de l’infection [1]. Les conséquences à court et moyen terme de l’infection sont maintenant bien connues. Cependant, l’évolution de l’immunité innée des neutrophiles à distance de l’infection n’est pas bien décrite. Ainsi, l’objectif était de décrire l’évolution de ces biomarqueurs dans les six mois suivants une infection sévère à SARS-CoV-2 et de les comparer avec les données de sujets sains.
Méthodes
Nous avons recueilli les données cliniques, biologiques, fonctionnelles et radiologiques de patients lors du suivi à trois et six mois d’une hospitalisation pour une infection sévère à SARS-CoV-2 au CHRU de Nancy entre mars et décembre 2020. Les données biologiques de sujets sains, antérieures à la pandémie à SARS-CoV-2 ont également été colligées.
Résultats
Sur les 98 patients inclus, 82 ont été réévalués à trois mois et 66 à six mois de la sortie d’hospitalisation. L’âge médian était de 65,5 [56–73] avec 72 (73,5 %) hommes et un indice de masse corporelle médian de 27,8 [24,6–31,0] kg/m2. À la première réévaluation, 65 patients (66,3 %) avaient des séquelles respiratoires de l’infection à SARS-CoV-2 (Tableau 1). Le taux médian d’élastase des neutrophiles à trois mois était de 419,5 [269,3–629,0] ng/mL et 504,0 [234,8–811,0] ng/mL à six mois, significativement plus élevé que chez les sujets sains 32,8 [21,0–78,5] ng/mL (p<0,0001) ng/mL. Les taux de myéloperoxydase-DNA et d’histones-DNA sont également significativement plus élevés à six mois de l’infection que chez les sujets sains (p<0,0001) (Tableau 1). À trois mois, on ne notait pas de différence significative du taux de ces biomarqueurs entre patients gardant ou non des séquelles respiratoires.
Conclusion
Les patients ayant présenté une infection sévère à SARS-CoV-2 conservent une élévation significative du taux d’élastase des neutrophiles, de myélopéroxydase-DNA et d’histone-DNA dans le suivi jusqu’à 6 mois par rapport à des sujets sains. Ces résultats préliminaires pourraient suggérer une implication de l’immunité innée dans la persistance de séquelles respiratoire et ouvrir la voie à de nouvelles thérapeutiques spécifiques.

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Sin, Don D.

Is long COVID an autoimmune disease?

https://doi.org/10.1183/13993003.02272-2022

Published

1-Jan-23

Article

https://erj.ersjournals.com/content/61/1/2202272

Extract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the novel coronavirus disease of 2019 (COVID-19), has, to date (27 December, 2022), infected over 662 million people and been directly responsible for 6.6 million deaths worldwide [1]. Millions of patients who have recovered from COVID-19 continue to experience one or more COVID-19-related symptoms, including fatigue, intractable headaches, exertional dyspnoea, olfactory and taste disturbances, myalgia and cognitive dysfunction (also called “brain fog”) for many weeks to months following their acute illness [2].
Tweetable abstract @ERSpublications
click to tweetThe findings from the study reported by Mukherjee and co-workers suggest that autoreactive antibodies may be responsible for driving the inflammatory process that persist in patients with long COVID https://bit.ly/3hAnDkt

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Giannitrapani, Lydia; Mirarchi, Luigi; Amodeo, Simona; Licata, Anna; Soresi, Maurizio; Cavaleri, Francesco; Casalicchio, Salvatore; Ciulla, Gregorio; Ciuppa, Maria Elena; Cervello, Melchiorre; Barbagallo, Mario; Veronese, Nicola; the COMEPA Group

Can Baseline IL-6 Levels Predict Long COVID in Subjects Hospitalized for SARS-CoV-2 Disease?

https://doi.org/10.3390/ijms24021731

Published

1-Jan-23

Study

https://www.mdpi.com/1422-0067/24/2/1731

The immune response to infection plays a crucial role in the pathogenesis of COVID-19, but several patients develop a wide range of persistent symptoms, which is becoming a major global health and economic burden. However, reliable indicators are not yet available to predict the persistence of symptoms typical of the so-called long COVID. Our study aims to explore an eventual role of IL-6 levels as a marker of long COVID. Altogether, 184 patients admitted to the COVID Medicine Unit of the University Hospital in Palermo, Italy, from the 1st of September 2020, were analyzed. Patients were divided into two groups according to the IL-6 serum levels (normal or elevated), considering the serum IL-6 levels measured during the first four days of hospitalization. In our study, higher serum IL-6 levels were associated with a doubled higher risk of long COVID (OR = 2.05; 95% CI: 1.04–4.50) and, in particular, they were associated with a higher incidence of mobility decline (OR = 2.55; 95% CI: 1.08–9.40) and PTSD (OR = 2.38; 95% CI: 1.06–8.61). The analysis of our case series confirmed the prominent role of IL-6 levels in response to SARS-CoV-2 infection, as predictors not only of COVID-19 disease severity and unfavorable outcomes, but also long COVID development trends.

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Prasada Kabekkodu, Shama; Chakrabarty, Sanjiban; Jayaram, Pradyumna; Mallya, Sandeep; Thangaraj, Kumarasamy; Singh, Keshav K; Satyamoorthy, Kapaettu

Severe acute respiratory syndrome coronaviruses contributing to mitochondrial dysfunction: Implications for post-COVID complications

https://doi.org/10.1016/j.mito.2023.01.005

Published

1-Mar-23

Review

https://www.sciencedirect.com/science/article/pii/S1567724923000053

Highlights
•Mitochondria are vital cellular organelles linked to the production of ATP, biosynthesis of fatty acids, calcium signaling, regulation of cell cycle, apoptosis, and innate immune response among others.
•Several RNA viruses target mitochondria leading to abnormal anterograde and retrograde grade signaling to facilitate growth and survival.
•Mitochondria plays a role in controlling immunity against SARS-CoV-2, and its infection leads to alteration in both structure and function of the mitochondria.
•SARS-CoV participates in stress response, apoptosis pathways and mitochondrial fusion in host cells.
•Research concentrating on SARS-CoV-2 modulation of essential mitochondrial activities should close the gap in COVID-19 prevention and treatment.
Abstract
Mitochondria play a central role in oxidative phosphorylation (OXPHOS), bioenergetics linked with ATP production, fatty acids biosynthesis, calcium signaling, cell cycle regulation, apoptosis, and innate immune response. Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) infection manipulates the host cellular machinery for its survival and replication in the host cell. The infectiaon causes perturbed the cellular metabolism that favours viral replication leading to mitochondrial dysfunction and chronic inflammation. By localizing to the mitochondria, SARS CoV proteins increase reactive oxygen species (ROS) levels, perturbation of Ca2+ signaling, changes in mtDNA copy number, mitochondrial membrane potential (MMP), mitochondrial mass, and induction of mitophagy. These proteins also influence the fusion and fission kinetics, size, structure, and distribution of mitochondria in the infected host cells. This results in compromised bioenergetics, altered metabolism, and innate immune signaling, and hence can be a key player in determining the outcome of SARS-CoV infection. SARS-CoV infection contributes to stress and activates apoptotic pathways. This review summarizes how mitochondrial function and dynamics are affected by SARS-CoV and how the mitochondria-SARS-CoV interaction benefits viral survival and growth by evading innate host immunity. We also highlight how the SARS-CoV-mediated mitochondrial dysfunction contributes to post-COVID complications. Besides, a discussion on targeting virus-mitochondria interactions as a therapeutic strategy is presented.

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Zhu, JingJing; Wilding, John P. H.; Hu, Ji

Adipocytes in obesity: A perfect reservoir for SARS-CoV-2?

https://doi.org/10.1016/j.mehy.2023.111020

Published

1-Feb-23

Article

https://www.sciencedirect.com/science/article/pii/S0306987723000166

Research evidence suggests that adipocytes in obesity might facilitate SARS-CoV-2 replication, for it was only found in adipose tissue of individuals with overweight or obesity but not lean individuals who died from COVID-19. As lipid metabolism is key to adipocyte function, and viruses are capable of exploiting and manipulating lipid metabolism of host cells for their own benefit of infection, we hypothesize that adipocytes could not only impair host immune defense against viral infection, but also facilitate SARS-CoV-2 entry, replication and assembly as a reservoir to boost the viral infection in obesity. The latter of which could mainly be mediated by SARS-CoV-2 hijacking the abnormal lipid metabolism in the adipocytes. If these were to be confirmed, an approach to combat COVID-19 in people with obesity by taking advantage of the abnormal lipid metabolism in adipocytes might be considered, as well as modifying lipid metabolism of other host cells as a potential adjunctive treatment for COVID-19.

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Parodi, Josefina B.; Indavere, Agustín; Bobadilla Jacob, Pamela; Toledo, Guillermo C.; Micali, Rubén G.; Waisman, Gabriel; Masson, Walter; Epstein, Eduardo D.; Huerin, Melina S.

Impact of COVID-19 vaccination in post-COVID cardiac complications

https://doi.org/10.1016/j.vaccine.2023.01.052

Published

27-Jan-23

Study

https://www.sciencedirect.com/science/article/pii/S0264410X23000841

Highlights
•1883 vaccinated and unvaccinated post-COVID patients evaluated by echocardiogram.
•2.92% presented pathological TTE findings consistent with post-COVID cardiac injury.
•Unvaccinated patients presented more cardiac injury than vaccinated (4.1% vs 1.3%)
•15% of the patients reported persistent symptoms at the post-COVID control.
•Complete vaccination was associated with 48% reduction in risk of long-COVID symptoms.
Abstract
Background
After the acute infection, COVID-19 can produce cardiac complications as well as long-COVID persistent symptoms. Although vaccination against COVID-19 represented a clear reduction in both mortality and ICU admissions, there is very little information on whether this was accompanied by a decrease in the prevalence of post-COVID cardiac complications. The aim of this study was to analyze the relationship between COVID-19 vaccination and the prevalence of post-COVID cardiac injury assessed by echocardiogram, and long-COVID persistent cardiac symptoms. Methods: All patients who consulted for post-COVID evaluation 14 days after discharge from acute illness were included. Patients with heart disease were excluded. The relationship between complete vaccination scheme (at least two doses applied with 14 days or more since the last dose) and pathological echocardiographic findings, as well as the relationship of vaccination with persistent long-COVID symptoms, were evaluated by multivariate analysis, adjusting for age, sex and clinical variables that would have shown significant differences in univariate analysis. Results: From 1883 patients, 1070 patients (56.8%) suffered acute COVID-19 without a complete vaccination scheme. Vaccination was associated with lower prevalence of cardiac injury (1.35% versus 4.11%, adjusted OR 0.33; 95% CI 0.17–0.65, p=0.01). In addition, vaccinated group had a lower prevalence of persistent long-COVID symptoms compared to unvaccinated patients (10.7% versus 18.3%, adjusted OR 0.52; 95% CI 0.40–0.69, p<0.001). Conclusion: Vaccination against COVID-19 was associated with lower post-COVID cardiac complications and symptoms, reinforcing the importance of fully vaccinating the population.

1479

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Rabaan, Ali A.; Aljeldah, Mohammed; Shammari, Basim R. Al; Alsubki, Roua A.; Alotaibi, Jawaher; Alhashem, Yousef N.; Alali, Neda A.; Sulaiman, Tarek; Alsalem, Zainab; Bajunaid, Huda A.; Garout, Mohammed; Alsaffar, Heba A.; Almuthree, Souad A.; Hudhaiah, Doha; Alzaher, Azhar M.; Alshaikh, Fatimah A.; Alshengeti, Amer; Najim, Mustafa A.; Farahat, Ramadan Abdelmoez; Mohapatra, Ranjan K.

Epigenetic Targets and Pathways Linked to SARS-CoV-2 Infection and Pathology

https://doi.org/10.3390/microorganisms11020341

Published

1-Feb-23

Review

https://www.mdpi.com/2076-2607/11/2/341

The scale at which the SARS-CoV-2/COVID-19 pandemic has spread remains enormous. Provided the genetic makeup of the virus and humans is readily available, the quest for knowing the mechanism and epidemiology continues to prevail across the entire scientific community. Several aspects, including immunology, molecular biology, and host-pathogen interaction, are continuously being dug into for preparing the human race for future pandemics. The exact reasons for vast differences in symptoms, pathophysiological implications of COVID-infections, and mortality differences remain elusive. Hence, researchers are also looking beyond traditional genomics, proteomics, and transcriptomics approach, especially entrusting the environmental regulation of the genetic landscape of COVID–human interactions. In line with these questions lies a critical process called epigenetics. The epigenetic perturbations in both host and parasites are a matter of great interest to unravel the disparities in COVID-19 mortalities and pathology. This review provides a deeper insight into current research on the epigenetic landscape of SARS-CoV-2 infection in humans and potential targets for augmenting the ongoing investigation. It also explores the potential targets, pathways, and networks associated with the epigenetic regulation of processes involved in SARS-CoV-2 pathology.

1480

I295

Cron, Randy Q.

Immunologic prediction of long COVID

https://doi.org/10.1038/s41590-022-01396-8

Published

1-Feb-23

Article

https://www.nature.com/articles/s41590-022-01396-8

In addition to the acute phase of SARS-CoV-2 infection, a significant percentage of patients experience a prolonged illness with varying symptomatology. Longitudinal SARS-CoV-2 patient-centric immunologic, inflammatory and metabolic data collection has allowed the generation of a composite signature to predict recovery.

1481

I296

Ruffieux, Hélène; Hanson, Aimee L.; Lodge, Samantha; Lawler, Nathan G.; Whiley, Luke; Gray, Nicola; Nolan, Tui H.; Bergamaschi, Laura; Mescia, Federica; Turner, Lorinda; de Sa, Aloka; Pelly, Victoria S.; Kotagiri, Prasanti; Kingston, Nathalie; Bradley, John R.; Holmes, Elaine; Wist, Julien; Nicholson, Jeremy K.; Lyons, Paul A.; Smith, Kenneth G. C.; Richardson, Sylvia; Bantug, Glenn R.; Hess, Christoph

A patient-centric modeling framework captures recovery from SARS-CoV-2 infection

https://doi.org/10.1038/s41590-022-01380-2

Published

1-Feb-23

Study

https://www.nature.com/articles/s41590-022-01380-2

The biology driving individual patient responses to severe acute respiratory syndrome coronavirus 2 infection remains ill understood. Here, we developed a patient-centric framework leveraging detailed longitudinal phenotyping data and covering a year after disease onset, from 215 infected individuals with differing disease severities. Our analyses revealed distinct ‘systemic recovery’ profiles, with specific progression and resolution of the inflammatory, immune cell, metabolic and clinical responses. In particular, we found a strong inter-patient and intra-patient temporal covariation of innate immune cell numbers, kynurenine metabolites and lipid metabolites, which highlighted candidate immunologic and metabolic pathways influencing the restoration of homeostasis, the risk of death and that of long COVID. Based on these data, we identified a composite signature predictive of systemic recovery, using a joint model on cellular and molecular parameters measured soon after disease onset. New predictions can be generated using the online tool http://shiny.mrc-bsu.cam.ac.uk/apps/covid-19-systemic-recovery-prediction-app, designed to test our findings prospectively.

1482

I297

Bogard, Gemma; Barthelemy, Johanna; Hantute-Ghesquier, Aline; Sencio, Valentin; Brito-Rodrigues, Patricia; Séron, Karin; Robil, Cyril; Flourens, Anne; Pinet, Florence; Eberlé, Delphine; Trottein, François; Duterque-Coquillaud, Martine; Wolowczuk, Isabelle

SARS-CoV-2 infection induces persistent adipose tissue damage in aged golden Syrian hamsters

https://doi.org/10.1038/s41419-023-05574-w

Published

1-Feb-23

Study

https://www.nature.com/articles/s41419-023-05574-w

Coronavirus disease 2019 (COVID-19, caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2)) is primarily a respiratory illness. However, various extrapulmonary manifestations have been reported in patients with severe forms of COVID-19. Notably, SARS-CoV-2 was shown to directly trigger white adipose tissue (WAT) dysfunction, which in turn drives insulin resistance, dyslipidemia, and other adverse outcomes in patients with COVID-19. Although advanced age is the greatest risk factor for COVID-19 severity, published data on the impact of SARS-CoV-2 infection on WAT in aged individuals are scarce. Here, we characterized the response of subcutaneous and visceral WAT depots to SARS-CoV-2 infection in young adult and aged golden hamsters. In both age groups, infection was associated with a decrease in adipocyte size in the two WAT depots; this effect was partly due to changes in tissue’s lipid metabolism and persisted for longer in aged hamsters than in young-adult hamsters. In contrast, only the subcutaneous WAT depot contained crown-like structures (CLSs) in which dead adipocytes were surrounded by SARS-CoV-2-infected macrophages, some of them forming syncytial multinucleated cells. Importantly, older age predisposed to a unique manifestation of viral disease in the subcutaneous WAT depot during SARS-CoV-2 infection; the persistence of very large CLSs was indicative of an age-associated defect in the clearance of dead adipocytes by macrophages. Moreover, we uncovered age-related differences in plasma lipid profiles during SARS-CoV-2 infection. These data suggest that the WAT’s abnormal response to SARS-CoV-2 infection may contribute to the greater severity of COVID-19 observed in elderly patients.

1483

I298

Xue, Pei; Merikanto, Ilona; Chung, Frances; Morin, Charles M.; Espie, Colin; Bjorvatn, Bjørn; Cedernaes, Jonathan; Landtblom, Anne-Marie; Penzel, Thomas; De Gennaro, Luigi; Holzinger, Brigitte; Matsui, Kentaro; Hrubos-Strøm, Harald; Korman, Maria; Leger, Damien; Mota-Rolim, Sérgio; Bolstad, Courtney J.; Nadorff, Michael; Plazzi, Giuseppe; Reis, Catia; Chan, Rachel Ngan Yin; Wing, Yun Kwok; Yordanova, Juliana; Bjelajac, Adrijana Koscec; Inoue, Yuichi; Partinen, Markku; Dauvilliers, Yves; Benedict, Christian

Persistent short nighttime sleep duration is associated with a greater post-COVID risk in fully mRNA-vaccinated individuals

https://doi.org/10.1038/s41398-023-02334-4

Published

1-Feb-23

Study

https://www.nature.com/articles/s41398-023-02334-4

Short nighttime sleep duration impairs the immune response to virus vaccination, and long nighttime sleep duration is associated with poor health status. Thus, we hypothesized that short (<6 h) and long (>9 h) nighttime sleepers have a higher post-COVID risk than normal nighttime sleepers, despite two doses of mRNA vaccine (which has previously been linked to lower odds of long-lasting COVID-19 symptoms). Post-COVID was defined as experiencing at least one core COVID-19 symptom for at least three months (e.g., shortness of breath). Multivariate logistic regression adjusting for age, sex, BMI, and other factors showed in 9717 respondents (age span 18–99) that two mRNA vaccinations lowered the risk of suffering from post-COVID by about 21% (p < 0.001). When restricting the analysis to double-vaccinated respondents (n = 5918), short and long sleepers exhibited a greater post-COVID risk than normal sleepers (adjusted OR [95%-CI], 1.56 [1.29, 1.88] and 1.87 [1.32, 2.66], respectively). Among respondents with persistent sleep duration patterns during the pandemic compared to before the pandemic, short but not long sleep duration was significantly associated with the post-COVID risk (adjusted OR [95%-CI], 1.59 [1.24, 2.03] and 1.18 [0.70, 1.97], respectively). No significant association between sleep duration and post-COVID symptoms was observed in those reporting positive SARS-CoV-2 test results (n = 538). Our findings suggest that two mRNA vaccinations against SARS-CoV-2 are associated with a lower post-COVID risk. However, this protection may be less pronounced among those sleeping less than 6 h per night. Our findings warrant replication in cohorts with individuals with confirmed SARS-CoV-2 infection.

1484

I299

Vojdani, Aristo; Vojdani, Elroy; Saidara, Evan; Maes, Michael

Persistent SARS-CoV-2 Infection, EBV, HHV-6 and Other Factors May Contribute to Inflammation and Autoimmunity in Long COVID

https://doi.org/10.3390/v15020400

Published

1-Feb-23

Review

https://www.mdpi.com/1999-4915/15/2/400

A novel syndrome called long-haul COVID or long COVID is increasingly recognized in a significant percentage of individuals within a few months after infection with SARS-CoV-2. This disorder is characterized by a wide range of persisting, returning or even new but related symptoms that involve different tissues and organs, including respiratory, cardiac, vascular, gastrointestinal, musculo-skeletal, neurological, endocrine and systemic. Some overlapping symptomatologies exist between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Very much like with long ME/CFS, infections with herpes family viruses, immune dysregulation, and the persistence of inflammation have been reported as the most common pattern for the development of long COVID. This review describes several factors and determinants of long COVID that have been proposed, elaborating mainly on viral persistence, reactivation of latent viruses such as Epstein–Barr virus and human herpesvirus 6 which are also associated with the pathology of ME/CFS, viral superantigen activation of the immune system, disturbance in the gut microbiome, and multiple tissue damage and autoimmunity. Based on these factors, we propose diagnostic strategies such as the measurement of IgG and IgM antibodies against SARS-CoV-2, EBV, HHV-6, viral superantigens, gut microbiota, and biomarkers of autoimmunity to better understand and manage this multi-factorial disorder that continues to affect millions of people in the world.

1485

I300

Fogh, Kamille; Garred, Peter; Hansen, Cecilie B.; Iversen, Kasper K.

Reply to Brandt et al., “Antibodies to Nucleocapsid Are Not Diagnostic for Long COVID”

https://doi.org/10.1128/spectrum.00065-23

Published

14-Feb-23

Article

https://journals.asm.org/doi/10.1128/spectrum.00065-23

The first question posed by Brandt et al. concerns the small number of respondents (less than 5%) and skewed gender distribution. We had a target population of 8,000 members of the social media group, but likely due to logistics, as blood samples could only be taken at 3 different hospitals in Denmark, our study population ended up with 350 participants, which is 5% of the target population. We did not anticipate that the entire target group would participate. In total, 926 social media users expressed an interest in participating, and 350 (38%) of them had a blood sample taken, with sampling bias as a limitation. As stated in the article’s limitations section, participation bias cannot be ruled out because members of the social media group were more often women than men.
The second question posed by Brandt et al. concerns the long-term persistence of nucleocapsid protein (N protein). According to Brandt et al., 30 to 40% of patients will not have persisting antibodies at the time of recruitment, and antibody decay is faster with mild COVID. In our study, we are looking at observations and measuring the qualitative outcome (seropositive or seronegative) rather than the quantitative outcome. The presence of SARS-CoV-2 N protein total Ig was determined using Roche electrochemiluminescence and a COBAS analyzer system, as mentioned in the article. This assay has been shown to be reliable, with a specificity of 98.1% compared to prepandemic samples and a sensitivity of 99.1% in patients with a confirmed PCR-positive test 14 days after symptom start (2). There was no significant difference in assay sensitivity by disease severity. Thus, the gray area of whether we oversee true-positive samples appears to be negligible. According to a published study, detectable N protein can be found up to 6 months after infection, with an increasing tendency due to improved affinity (3). The same system was used in an unpublished study of hospital employees from our group who were mostly infected but not hospitalized. In this study, N protein was found in 90% of previously infected participants after 12 months. It should be noted that N protein seropositivity and decline over time may vary between different studies, as other studies have shown around 80% seropositivity 9 months after virologically confirmed SARS-CoV-2 infection (4).
The third question posed by Brandt et al. concerns the inclusion of PCR test-positive patients in the characterization of long COVID. Brandt et al. mention that 90% of the participants reported a previous PCR test, and the inclusion of the PCR result could be used as a reliable factor in the characterization of long COVID. Unfortunately, the questionnaire design only allowed participants to report the most recent PCR test, which was not always related to the first reported infection with SARS-CoV-2. As a result, we chose not to include self-reported PCR test results.
publisher: American Society for Microbiology

1486

I301

Reyes-Long, Samuel; Cortés-Altamirano, Jose Luis; Bandala, Cindy; Avendaño-Ortiz, Karina; Bonilla-Jaime, Herlinda; Bueno-Nava, Antonio; Ávila-Luna, Alberto; Sánchez-Aparicio, Pedro; Clavijo-Cornejo, Denise; Dotor-LLerena, Ana Lilia; Cabrera-Ruiz, Elizabeth; Alfaro-Rodríguez, Alfonso

Role of the MicroRNAs in the Pathogenic Mechanism of Painful Symptoms in Long COVID: Systematic Review

https://doi.org/10.3390/ijms24043574

Published

1-Jan-23

Review

https://www.mdpi.com/1422-0067/24/4/3574

The ongoing pandemic of COVID-19 has caused more than 6.7 million tragic deaths, plus, a large percentage of people who survived it present a myriad of chronic symptoms that last for at least 6 months; this has been named as long COVID. Some of the most prevalent are painful symptoms like headache, joint pain, migraine, neuropathic-like pain, fatigue and myalgia. MicroRNAs are small non-coding RNAs that regulate genes, and their involvement in several pathologies has been extensively shown. A deregulation of miRNAs has been observed in patients with COVID-19. The objective of the present systematic review was to show the prevalence of chronic pain-like symptoms of patients with long COVID and based on the expression of miRNAs in patients with COVID-19, and to present a proposal on how they may be involved in the pathogenic mechanisms of chronic pain-like symptoms. A systematic review was carried out in online databases for original articles published between March 2020 to April 2022; the systematic review followed the PRISMA guidelines, and it was registered in PROSPERO with registration number CRD42022318992. A total of 22 articles were included for the evaluation of miRNAs and 20 regarding long COVID; the overall prevalence of pain-like symptoms was around 10 to 87%, plus, the miRNAs that were commonly up and downregulated were miR-21-5p, miR-29a,b,c-3p miR-92a,b-3p, miR-92b-5p, miR-126-3p, miR-150-5p, miR-155-5p, miR-200a, c-3p, miR-320a,b,c,d,e-3p, and miR-451a. The molecular pathways that we hypothesized to be modulated by these miRNAs are the IL-6/STAT3 proinflammatory axis and the compromise of the blood–nerve barrier; these two mechanisms could be associated with the prevalence of fatigue and chronic pain in the long COVID population, plus they could be novel pharmacological targets in order to reduce and prevent these symptoms.

1487

I302

Yin, Kailin; Peluso, Michael J.; Thomas, Reuben; Shin, Min-Gyoung; Neidleman, Jason; Luo, Xiaoyu; Hoh, Rebecca; Anglin, Khamal; Huang, Beatrice; Argueta, Urania; Lopez, Monica; Valdivieso, Daisy; Asare, Kofi; Ibrahim, Rania; Ständker, Ludger; Lu, Scott; Goldberg, Sarah A.; Lee, Sulggi A.; Lynch, Kara L.; Kelly, J. Daniel; Martin, Jeffrey N.; Münch, Jan; Deeks, Steven G.; Henrich, Timothy J.; Roan, Nadia R.

Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2

https://doi.org/10.1101/2023.02.09.527892

pre-print

10-Feb-23

Study

https://www.biorxiv.org/content/10.1101/2023.02.09.527892v1

Long COVID (LC), a type of post-acute sequelae of SARS-CoV-2 infection (PASC), occurs after at least 10% of SARS-CoV-2 infections, yet its etiology remains poorly understood. Here, we used multiple “omics” assays (CyTOF, RNAseq, Olink) and serology to deeply characterize both global and SARS-CoV-2-specific immunity from blood of individuals with clear LC and non-LC clinical trajectories, 8 months following infection and prior to receipt of any SARS-CoV-2 vaccine. Our analysis focused on deep phenotyping of T cells, which play important roles in immunity against SARS-CoV-2 yet may also contribute to COVID-19 pathogenesis. Our findings demonstrate that individuals with LC exhibit systemic inflammation and immune dysregulation. This is evidenced by global differences in T cell subset distribution in ways that imply ongoing immune responses, as well as by sex-specific perturbations in cytolytic subsets. Individuals with LC harbored increased frequencies of CD4+ T cells poised to migrate to inflamed tissues, and exhausted SARS-CoV-2-specific CD8+ T cells. They also harbored significantly higher levels of SARS-CoV-2 antibodies, and in contrast to non-LC individuals, exhibited a mis-coordination between their SARS-CoV-2-specific T and B cell responses. Collectively, our data suggest that proper crosstalk between the humoral and cellular arms of adaptive immunity has broken down in LC, and that this, perhaps in the context of persistent virus, leads to the immune dysregulation, inflammation, and clinical symptoms associated with this debilitating condition.

1488

I303

Craddock, Vaughn; Mahajan, Aatish; Spikes, Leslie; Krishnamachary, Balaji; Ram, Anil K.; Kumar, Ashok; Chen, Ling; Chalise, Prabhakar; Dhillon, Navneet K.

Persistent circulation of soluble and extracellular vesicle-linked Spike protein in individuals with postacute sequelae of COVID-19

https://doi.org/10.1002/jmv.28568

Published

9-Feb-23

Study

https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.28568

SARS-CoV-2, the causative agent of COVID-19 disease, has resulted in the death of millions worldwide since the beginning of the pandemic in December 2019. While much progress has been made to understand acute manifestations of SARS-CoV-2 infection, less is known about post-acute sequelae of COVID-19 (PASC). We investigated the levels of both Spike protein (Spike) and viral RNA circulating in patients hospitalized with acute COVID-19 and in patients with and without PASC. We found that Spike and viral RNA were more likely to be present in patients with PASC. Among these patients, 30% were positive for both Spike and viral RNA; whereas, none of the individuals without PASC were positive for both. The levels of Spike and/or viral RNA in the PASC+ve patients were found to be increased or remained the same as in the acute phase; whereas, in the PASC−ve group, these viral components decreased or were totally absent. Additionally, this is the first report to show that part of the circulating Spike is linked to extracellular vesicles without any presence of viral RNA in these vesicles. In conclusion, our findings suggest that Spike and/or viral RNA fragments persist in the recovered COVID-19 patients with PASC up to 1 year or longer after acute SARS-CoV-2 infection.

1489

I304

Peluso, Michael J.; Deveau, Tyler-Marie; Munter, Sadie E.; Ryder, Dylan; Buck, Amanda; Beck-Engeser, Gabriele; Chan, Fay; Lu, Scott; Goldberg, Sarah A.; Hoh, Rebecca; Tai, Viva; Torres, Leonel; Iyer, Nikita S.; Deswal, Monika; Ngo, Lynn H.; Buitrago, Melissa; Rodriguez, Antonio; Chen, Jessica Y.; Yee, Brandon C.; Chenna, Ahmed; Winslow, John W.; Petropoulos, Christos J.; Deitchman, Amelia N.; Hellmuth, Joanna; Spinelli, Matthew A.; Durstenfeld, Matthew S.; Hsue, Priscilla Y.; Kelly, J. Daniel; Martin, Jeffrey N.; Deeks, Steven G.; Hunt, Peter W.; Henrich, Timothy J.

Chronic viral coinfections differentially affect the likelihood of developing long COVID

https://doi.org/10.1172/JCI163669

Published

1-Feb-23

Study

https://www.jci.org/articles/view/163669

BACKGROUND. The presence and reactivation of chronic viral infections, such as EBV, CMV, and HIV, have been proposed as potential contributors to long COVID (LC), but studies in well-characterized postacute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited.

METHODS. In a cohort of 280 adults with prior SARS-CoV-2 infection, we assessed the presence and types of LC symptoms and prior medical history (including COVID-19 history and HIV status) and performed serological testing for EBV and CMV using a commercial laboratory. We used covariate-adjusted binary logistic regression models to identify independent associations between variables and LC symptoms.

RESULTS. We observed that LC symptoms, such as fatigue and neurocognitive dysfunction, at a median of 4 months following initial diagnosis were independently associated with serological evidence suggesting recent EBV reactivation (early antigen–diffuse IgG positivity) or high nuclear antigen (EBNA) IgG levels but not with ongoing EBV viremia. Serological evidence suggesting recent EBV reactivation (early antigen–diffuse IgG positivity) was most strongly associated with fatigue (OR = 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR = 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR = 0.52).

CONCLUSION. Overall, these findings suggest differential effects of chronic viral coinfections on the likelihood of developing LC and association with distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted.Publisher: American Society for Clinical Investigation
PMID: 0

1490

I305

Watanabe, Atsuyuki; Iwagami, Masao; Yasuhara, Jun; Takagi, Hisato; Kuno, Toshiki

Protective effect of COVID-19 vaccination against long COVID syndrome: A systematic review and meta-analysis

https://doi.org/10.1016/j.vaccine.2023.02.008

Published

8-Feb-23

Review

https://www.sciencedirect.com/science/article/pii/S0264410X23001342

Highlights
•The effects of COVID-19 vaccination on long COVID remains inconclusive.
•Vaccination before SARS-CoV-2 infection was associated with a lower risk of long COVID.
•Vaccination after SARS-CoV-2 infection was not associated with symptomatic changes of long COVID.
•Vaccination before SARS-CoV-2 infection can be recommended to reduce long COVID.
Abstract
Background
The relationship between coronavirus disease 2019 (COVID-19) vaccination and long COVID has not been firmly established. We conducted a systematic review and meta-analysis to evaluate the association between COVID-19 vaccination and long COVID.
Methods
PubMed and EMBASE databases were searched on September 2022 without language restrictions (CRD42022360399) to identify prospective trials and observational studies comparing patients with and without vaccination before severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. We also included studies reporting symptomatic changes of ongoing long COVID following vaccination among those with a history of SARS-CoV-2 infection. Odds ratios (ORs) for each outcome were synthesized using a random-effects model. Symptomatic changes after vaccination were synthesized by a one-group meta-analysis.
Results
Six observational studies involving 536,291 unvaccinated and 84,603 vaccinated (before SARS-CoV-2 infection) patients (mean age, 41.2–66.6; female, 9.0–67.3%) and six observational studies involving 8,199 long COVID patients (mean age, 40.0 to 53.5; female, 22.2–85.9%) who received vaccination after SARS-CoV-2 infection were included. Two-dose vaccination was associated with a lower risk of long COVID compared to no vaccination (OR, 0.64; 95% confidence interval [CI], 0.45–0.92) and one-dose vaccination (OR, 0.60; 95% CI, 0.43–0.83). Two-dose vaccination compared to no vaccination was associated with a lower risk of persistent fatigue (OR, 0.62; 95% CI, 0.41–0.93) and pulmonary disorder (OR, 0.50; 95% CI, 0.47–0.52). Among those with ongoing long COVID symptoms, 54.4% (95% CI, 34.3–73.1%) did not report symptomatic changes following vaccination, while 20.3% (95% CI, 8.1–42.4%) experienced symptomatic improvement after two weeks to six months of COVID-19 vaccination.
Conclusions
COVID-19 vaccination before SARS-CoV-2 infection was associated with a lower risk of long COVID, while most of those with ongoing long COVID did not experience symptomatic changes following vaccination.

1491

I306

Feng, Allan; Yang, Emily Y.; Moore, Andrew Reese; Dhingra, Shaurya; Chang, Sarah Esther; Yin, Xihui; Pi, Ruoxi; Mack, Elisabeth K. M.; Völkel, Sara; Geßner, Reinhard; Gündisch, Margrit; Neubauer, Andreas; Renz, Harald; Tsiodras, Sotirios; Fragkou, Paraskevi C.; Asuni, Adijat A.; Levitt, Joseph E.; Wilson, Jennifer G.; Leong, Michelle; Lumb, Jennifer H.; Mao, Rong; Pinedo, Kassandra; Roque, Jonasel; Richards, Christopher M.; Stabile, Mikayla; Swaminathan, Gayathri; Salagianni, Maria L.; Triantafyllia, Vasiliki; Bertrams, Wilhelm; Blish, Catherine A.; Carette, Jan E.; Frankovich, Jennifer; Meffre, Eric; Nadeau, Kari Christine; Singh, Upinder; Wang, Taia T.; Prak, Eline T. Luning; Herold, Susanne; Andreakos, Evangelos; Schmeck, Bernd; Skevaki, Chrysanthi; Rogers, Angela J.; Utz, Paul J.

Autoantibodies are highly prevalent in non–SARS-CoV-2 respiratory infections and critical illness

https://doi.org/10.1172/jci.insight.163150

Published

8-Feb-23

Study

https://insight.jci.org/articles/view/163150

The widespread presence of autoantibodies in acute infection with SARS-CoV-2 is increasingly recognized, but the prevalence of autoantibodies in non–SARS-CoV-2 infections and critical illness has not yet been reported. We profiled IgG autoantibodies in 267 patients from 5 independent cohorts with non–SARS-CoV-2 viral, bacterial, and noninfectious critical illness. Serum samples were screened using Luminex arrays that included 58 cytokines and 55 autoantigens, many of which are associated with connective tissue diseases (CTDs). Samples positive for anti-cytokine antibodies were tested for receptor blocking activity using cell-based functional assays. Anti-cytokine antibodies were identified in > 50% of patients across all 5 acutely ill cohorts. In critically ill patients, anti-cytokine antibodies were far more common in infected versus uninfected patients. In cell-based functional assays, 11 of 39 samples positive for select anti-cytokine antibodies displayed receptor blocking activity against surface receptors for Type I IFN, GM-CSF, and IL-6. Autoantibodies against CTD-associated autoantigens were also commonly observed, including newly detected antibodies that emerged in longitudinal samples. These findings demonstrate that anti-cytokine and autoantibodies are common across different viral and nonviral infections and range in severity of illness.
publisher: American Society for Clinical Investigation
PMID: 0

1492

I307

Gerhards, Catharina; Kittel, Maximilian; Ast, Volker; Bugert, Peter; Froelich, Matthias F.; Hetjens, Michael; Haselmann, Verena; Neumaier, Michael; Thiaucourt, Margot

Humoral SARS-CoV-2 Immune Response in COVID-19 Recovered Vaccinated and Unvaccinated Individuals Related to Post-COVID-Syndrome

https://doi.org/10.3390/v15020454

Published

1-Feb-23

Study

https://www.mdpi.com/1999-4915/15/2/454

Background: The duration of anti-SARS-CoV-2-antibody detectability up to 12 months was examined in individuals after either single convalescence or convalescence and vaccination. Moreover, variables that might influence an anti-RBD/S1 antibody decline and the existence of a post-COVID-syndrome (PCS) were addressed. Methods: Forty-nine SARS-CoV-2-qRT-PCR-confirmed participants completed a 12-month examination of anti-SARS-CoV-2-antibody levels and PCS-associated long-term sequelae. Overall, 324 samples were collected. Cell-free DNA (cfDNA) was isolated and quantified from EDTA-plasma. As cfDNA is released into the bloodstream from dying cells, it might provide information on organ damage in the late recovery of COIVD-19. Therefore, we evaluated cfDNA concentrations as a biomarker for a PCS. In the context of antibody dynamics, a random forest-based logistic regression with antibody decline as the target was performed and internally validated. Results: The mean percentage dynamic related to the maximum measured value was 96 (±38)% for anti-RBD/S1 antibodies and 30 (±26)% for anti-N antibodies. Anti-RBD/S1 antibodies decreased in 37%, whereas anti-SARS-CoV-2-anti-N antibodies decreased in 86% of the subjects. Clinical anti-RBD/S1 antibody decline prediction models, including vascular and other diseases, were cross-validated (highest AUC 0.74). Long-term follow-up revealed no significant reduction in PCS prevalence but an increase in cognitive impairment, with no indication for cfDNA as a marker for a PCS. Conclusion: Long-term anti-RBD/S1-antibody positivity was confirmed, and clinical parameters associated with declining titers were presented. A fulminant decrease in anti-SARS-CoV-2-anti-N antibodies was observed (mean change to maximum value 30 (±26)%). Anti-RBD/S1 antibody titers of SARS-CoV-2 recovered subjects boosted with a vaccine exceeded the maximum values measured after single infection by 235 ± 382-fold, with no influence on preexisting PCS. PCS long-term prevalence was 38.6%, with an increase in cognitive impairment compromising the quality of life. Quantified cfDNA measured in the early post-COVID-19 phase might not be an effective marker for PCS identification.

1493

I308

Williams, Elizabeth SCP; Martins, Thomas B.; Shah, Kevin S.; Hill, Harry R.; Coiras, Mayte; Spivak, Adam M.; Planelles, Vicente

Cytokine Deficiencies in Patients with Long-COVID

Published

18-Nov-22

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894377/

Up to half of individuals who contract SARS-CoV-2 develop symptoms of long-COVID approximately three months after initial infection. These symptoms are highly variable, and the mechanisms inducing them are yet to be understood. We compared plasma cytokine levels from individuals with long-COVID to healthy individuals and found that those with long-COVID had 100% reductions in circulating levels of Interferon Gamma (IFNγ) and Interleukin-8 (IL-8). Additionally, we found significant reductions in levels of IL-6, IL-2, IL-17, IL-13, and IL-4 in individuals with long-COVID. We propose immune exhaustion as the driver of long-COVID, with the complete absence of IFNγ and IL-8preventing the lungs and other organs from healing after acute infection, and reducing the ability to fight off subsequent infections, both contributing to the myriad of symptoms suffered by those with long-COVID.

1494

I309

Frasca, Loredana; Ocone, Giuseppe; Palazzo, Raffaella

Safety of COVID-19 Vaccines in Patients with Autoimmune Diseases, in Patients with Cardiac Issues, and in the Healthy Population

https://doi.org/10.3390/pathogens12020233

Published

1-Feb-23

Review

https://www.mdpi.com/2076-0817/12/2/233

The coronavirus disease 2019 (COVID-19) has been a challenge for the whole world since the beginning of 2020, and COVID-19 vaccines were considered crucial for disease eradication. Instead of producing classic vaccines, some companies pointed to develop products that mainly function by inducing, into the host, the production of the antigenic protein of SARS-CoV-2 called Spike, injecting an instruction based on RNA or a DNA sequence. Here, we aim to give an overview of the safety profile and the actual known adverse effects of these products in relationship with their mechanism of action. We discuss the use and safety of these products in at-risk people, especially those with autoimmune diseases or with previously reported myocarditis, but also in the general population. We debate the real necessity of administering these products with unclear long-term effects to at-risk people with autoimmune conditions, as well as to healthy people, at the time of omicron variants. This, considering the existence of therapeutic interventions, much more clearly assessed at present compared to the past, and the relatively lower aggressive nature of the new viral variants.

1495

I310

Lavi, Yael; Vojdani, Aristo; Halpert, Gilad; Sharif, Kassem; Ostrinski, Yuri; Zyskind, Israel; Lattin, Miriam T.; Zimmerman, Jason; Silverberg, Jonathan I.; Rosenberg, Avi Z.; Shoenfeld, Yehuda; Amital, Howard

Dysregulated Levels of Circulating Autoantibodies against Neuronal and Nervous System Autoantigens in COVID-19 Patients

https://doi.org/10.3390/diagnostics13040687

Published

1-Jan-23

Study

https://www.mdpi.com/2075-4418/13/4/687

Background: COVID-19 is a heterogenous disease resulting in long-term sequela in predisposed individuals. It is not uncommon that recovering patients endure non-respiratory ill-defined manifestations, including anosmia, and neurological and cognitive deficit persisting beyond recovery—a constellation of conditions that are grouped under the umbrella of long-term COVID-19 syndrome. Association between COVID-19 and autoimmune responses in predisposed individuals was shown in several studies. Aim and methods: To investigate autoimmune responses against neuronal and CNS autoantigens in SARS-CoV-2-infected patients, we performed a cross-sectional study with 246 participants, including 169 COVID-19 patients and 77 controls. Levels of antibodies against the acetylcholine receptor, glutamate receptor, amyloid β peptide, alpha-synucleins, dopamine 1 receptor, dopamine 2 receptor, tau protein, GAD-65, N-methyl D-aspartate (NMDA) receptor, BDNF, cerebellar, ganglioside, myelin basic protein, myelin oligodendrocyte glycoprotein, S100-B, glial fibrillary acidic protein, and enteric nerve were measured using an Enzyme-Linked Immunosorbent Assay (ELISA). Circulating levels of autoantibodies were compared between healthy controls and COVID-19 patients and then classified by disease severity (mild [n = 74], severe [n = 65], and requiring supplemental oxygen [n = 32]). Results: COVID-19 patients were found to have dysregulated autoantibody levels correlating with the disease severity, e.g., IgG to dopamine 1 receptor, NMDA receptors, brain-derived neurotrophic factor, and myelin oligodendrocyte glycoprotein. Elevated levels of IgA autoantibodies against amyloid β peptide, acetylcholine receptor, dopamine 2 receptor, myelin basic protein, and α-synuclein were detected in COVID-19 patients compared with healthy controls. Lower IgA autoantibody levels against NMDA receptors, and IgG autoantibodies against glutamic acid decarboxylase 65, amyloid β peptide, tau protein, enteric nerve, and S100-B were detected in COVID-19 patients versus healthy controls. Some of these antibodies have known clinical correlations with symptoms commonly reported in the long COVID-19 syndrome. Conclusions: Overall, our study shows a widespread dysregulation in the titer of various autoantibodies against neuronal and CNS-related autoantigens in convalescent COVID-19 patients. Further research is needed to provide insight into the association between these neuronal autoantibodies and the enigmatic neurological and psychological symptoms reported in COVID-19 patients

1496

I311

Bamidis, Anna D; Koehler, Philipp; Di Cristanziano, Veronica; Rasche, Kurt; Demirel, Baris; Bacher, Petra; Hallek, Michael; Kochanek, Matthias; Klein, Florian; Hofmann, Silke C; Wesselmann, Ulrich; Kofler, David M

First manifestation of adult-onset Still's disease after COVID-19

https://doi.org/10.1016/S2665-9913(21)00072-2

Published

1-May-21

Case Report

https://linkinghub.elsevier.com/retrieve/pii/S2665991321000722

Adult-onset Still's disease (AOSD) is a rare inflammatory disorder that usually affects young adults, with a bimodal peak at ages 15–25 years and 36–46 years. The disease is characterised by fever of more than 39°C, transient skin rash, leucocytosis, arthralgia, arthritis, or a combination of these symptoms.1 In addition to at least two of the aforementioned major criteria, the Yamaguchi criteria for the diagnosis of AOSD require the presence of minor criteria—ie, sore throat, lymphadenopathy, hepatomegaly or splenomegaly, abnormal liver function tests, and negative tests for antinuclear antibodies and rheumatoid factor.1 Infections, malignancies, and other rheumatic diseases need to be excluded. The cytokine interleukin (IL)-1 has a central role in the pathogenesis of AOSD and inhibition of IL-1β by monoclonal antibodies, and blockade of the IL-1 receptor by antagonists significantly ameliorates the disease.2 IL-1 drives the intense innate immune response by activating neutrophils, macrophages, and mast cells, and by leading to overexpression of several proinflammatory cytokines, including IL-6, IL-8, IL-17, IL-18, and TNF.3 Viral or bacterial infections have been proposed as potential trigger, but the exact mechanisms underlying AOSD onset remain largely unknown.4
SARS-CoV-2 emerged in late 2019, causing the COVID-19 pandemic. AOSD and COVID-19 share several clinical and laboratory features, including systemic inflammation, unremitting fever, high serum ferritin, and a potentially life-threatening cytokine release syndrome. Data obtained from single-cell analysis revealed IL-1β-associated inflammasome signatures and a significant expansion of CD14-positive, IL-1β-positive monocytes in the peripheral blood of patients with severe COVID-19.5, 6 Thus, AOSD and the severe immune over-reaction which occurs in some patients with COVID-19 might be triggered by the same mechanisms.
Here, we report a case of severe AOSD manifestations emerging in a patient suffering from long-term sequelae of COVID-19 for 6 months. In Germany, in March, 2020, a 29-year-old White woman with no notable medical history developed signs of SARS-CoV-2 infection including sore throat, headache, anosmia, ageusia, generalised weakness, shortness of breath, diarrhoea, and chilblain-like skin eruptions of the toes. The patient tested positive for SARS-CoV-2 by RT-PCR from a nasopharyngeal swab. There was no need for therapy or hospitalisation. RT-PCR tests for SARS-CoV-2 were negative on day 15 after the onset of first symptoms. The patient continued to have elevated temperatures of up to 38·0°C for another 8 days.

1497

I312

Karbalaeimahdi, Mohammad; Farajnia, Safar; Bargahi, Nasrin; Ghadiri-Moghaddam, Farzaneh; Rasouli Jazi, Hamid Reza; Bakhtiari, Nasim; Ghasemali, Samaneh; Zarghami, Nosratollah

The Role of Interferons in Long Covid Infection

https://doi.org/10.1089/jir.2022.0193

Published

1-Feb-23

Review

https://www.liebertpub.com/doi/10.1089/jir.2022.0193

Although the new generation of vaccines and anti-COVID-19 treatment regimens facilitated the management of acute COVID-19 infections, concerns about post-COVID-19 syndrome or Long Covid are rising. This issue can increase the incidence and morbidity of diseases such as diabetes, and cardiovascular, and lung infections, especially among patients suffering from neurodegenerative disease, cardiac arrhythmias, and ischemia. There are numerous risk factors that cause COVID-19 patients to experience post-COVID-19 syndrome. Three potential causes attributed to this disorder include immune dysregulation, viral persistence, and autoimmunity. Interferons (IFNs) are crucial in all aspects of post-COVID-19 syndrome etiology. In this review, we discuss the critical and double-edged role of IFNs in post-COVID-19 syndrome and how innovative biomedical approaches that target IFNs can reduce the occurrence of Long Covid infection.

1498

I313

Joung, Sandy; Weber, Brittany; Wu, Min; Liu, Yunxian; Tang, Amber B.; Driver, Matthew; Sternbach, Sarah; Wynter, Timothy; Hoang, Amy; Barajas, Denisse; Kao, Yu Hung; Khuu, Briana; Bravo, Michelle; Masoom, Hibah; Tran, Teresa; Sun, Nancy; Botting, Patrick G.; Claggett, Brian L.; Prostko, John C.; Frias, Edwin C.; Stewart, James L.; Robertson, Jackie; Kwan, Alan C.; Torossian, Mariam; Pedraza, Isabel; Sterling, Carina; Goldzweig, Caroline; Oft, Jillian; Zabner, Rachel; Fert-Bober, Justyna; Ebinger, Joseph E.; Sobhani, Kimia; Cheng, Susan; Le, Catherine N.

Serological response to vaccination in post-acute sequelae of COVID

https://doi.org/10.1186/s12879-023-08060-y

Published

16-Feb-23

Study

https://doi.org/10.1186/s12879-023-08060-y

Background
Individuals with post-acute sequelae of COVID (PASC) may have a persistence in immune activation that differentiates them from individuals who have recovered from COVID without clinical sequelae. To investigate how humoral immune activation may vary in this regard, we compared patterns of vaccine-provoked serological response in patients with PASC compared to individuals recovered from prior COVID without PASC.

Methods
We prospectively studied 245 adults clinically diagnosed with PASC and 86 adults successfully recovered from prior COVID. All participants had measures of humoral immunity to SARS-CoV-2 assayed before or after receiving their first-ever administration of COVID vaccination (either single-dose or two-dose regimen), including anti-spike (IgG-S and IgM-S) and anti-nucleocapsid (IgG-N) antibodies as well as IgG-S angiotensin-converting enzyme 2 (ACE2) binding levels. We used unadjusted and multivariable-adjusted regression analyses to examine the association of PASC compared to COVID-recovered status with post-vaccination measures of humoral immunity.

Results
Individuals with PASC mounted consistently higher post-vaccination IgG-S antibody levels when compared to COVID-recovered (median log IgG-S 3.98 versus 3.74, P < 0.001), with similar results seen for ACE2 binding levels (median 99.1 versus 98.2, P = 0.044). The post-vaccination IgM-S response in PASC was attenuated but persistently unchanged over time (P = 0.33), compared to in COVID recovery wherein the IgM-S response expectedly decreased over time (P = 0.002). Findings remained consistent when accounting for demographic and clinical variables including indices of index infection severity and comorbidity burden.

Conclusion
We found evidence of aberrant immune response distinguishing PASC from recovered COVID. This aberrancy is marked by excess IgG-S activation and ACE2 binding along with findings consistent with a delayed or dysfunctional immunoglobulin class switching, all of which is unmasked by vaccine provocation. These results suggest that measures of aberrant immune response may offer promise as tools for diagnosing and distinguishing PASC from non-PASC phenotypes, in addition to serving as potential targets for intervention.

1499

I314

Bhatia-Dey, Naina; Csoka, Antonei B.; Heinbockel, Thomas

Chemosensory Ability and Sensitivity in Health and Disease: Epigenetic Regulation and COVID-19

https://doi.org/10.3390/ijms24044179

Published

1-Jan-23

Review

https://www.mdpi.com/1422-0067/24/4/4179

Throughout the animal kingdom, our two chemical senses, olfaction and gustation, are defined by two primary factors: genomic architecture of the organisms and their living environment. During the past three years of the global COVID-19 pandemic, these two sensory modalities have drawn much attention at the basic science and clinical levels because of the strong association of olfactory and gustatory dysfunction with viral infection. Loss of our sense of smell alone, or together with a loss of taste, has emerged as a reliable indicator of COVID-19 infection. Previously, similar dysfunctions have been detected in a large cohort of patients with chronic conditions. The research focus remains on understanding the persistence of olfactory and gustatory disturbances in the post-infection phase, especially in cases with long-term effect of infection (long COVID). Also, both sensory modalities show consistent age-related decline in studies aimed to understand the pathology of neurodegenerative conditions. Some studies using classical model organisms show an impact on neural structure and behavior in offspring as an outcome of parental olfactory experience. The methylation status of specific odorant receptors, activated in parents, is passed on to the offspring. Furthermore, experimental evidence indicates an inverse correlation of gustatory and olfactory abilities with obesity. Such diverse lines of evidence emerging from basic and clinical research studies indicate a complex interplay of genetic factors, evolutionary forces, and epigenetic alterations. Environmental factors that regulate gustation and olfaction could induce epigenetic modulation. However, in turn, such modulation leads to variable effects depending on genetic makeup and physiological status. Therefore, a layered regulatory hierarchy remains active and is passed on to multiple generations. In the present review, we attempt to understand the experimental evidence that indicates variable regulatory mechanisms through multilayered and cross-reacting pathways. Our analytical approach will add to enhancement of prevailing therapeutic interventions and bring to the forefront the significance of chemosensory modalities for the evaluation and maintenance of long-term health.

1500

I315

Zavori, Laszlo; Molnar, Tihamer; Varnai, Reka; Kanizsai, Andrea; Nagy, Lajos; Vadkerti, Bence; Szirmay, Balazs; Schwarcz, Attila; Csecsei, Peter

Cystatin-c May Indicate Subclinical Renal Involvement, While Orosomucoid Is Associated with Fatigue in Patients with Long-COVID Syndrome

https://doi.org/10.3390/jpm13020371

Published

1-Feb-23

Study

https://www.mdpi.com/2075-4426/13/2/371

Long-COVID syndrome is associated with high healthcare costs, but its pathophysiology is not yet fully understood. Inflammation, renal impairment or disturbance of the NO system emerge as potential pathogenetic factors. We aimed to investigate the relationship between symptoms of long-COVID syndrome and serum levels of cystatin-c (CYSC), orosomucoid (ORM), l-arginine, symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA). A total of 114 patients suffering from long-COVID syndrome were included in this observational cohort study. We found that serum CYSC was independently associated with the anti-spike immunoglobulin (S-Ig) serum level (OR: 5.377, 95% CI: 1.822–12.361; p = 0.02), while serum ORM (OR: 9.670 (95% CI: 1.34–9.93; p = 0.025) independently predicted fatigue in patients with long-COVID syndrome, both measured at baseline visit. Additionally, the serum CYSC concentrations measured at the baseline visit showed a positive correlation with the serum SDMA levels. The severity of abdominal and muscle pain indicated by patients at the baseline visit showed a negative correlation with the serum level of L-arginine. In summary, serum CYSC may indicate subclinical renal impairment, while serum ORM is associated with fatigue in long-COVID syndrome. The potential role of l-arginine in alleviating pain requires further studies.

1501

I316

Ballouz, Tala; Menges, Dominik; Kaufmann, Marco; Amati, Rebecca; Frei, Anja; Wyl, Viktor von; Fehr, Jan S.; Albanese, Emiliano; Puhan, Milo A.

Post COVID-19 condition after Wildtype, Delta, and Omicron SARS-CoV-2 infection and prior vaccination: Pooled analysis of two population-based cohorts

https://doi.org/10.1371/journal.pone.0281429

Published

22-Feb-23

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0281429

Background Post COVID-19 condition (PCC) is an important complication of SARS-CoV-2 infection, affecting millions worldwide. This study aimed to evaluate the prevalence and severity of post COVID-19 condition (PCC) with novel SARS-CoV-2 variants and after prior vaccination. Methods We used pooled data from 1350 SARS-CoV-2-infected individuals from two representative population-based cohorts in Switzerland, diagnosed between Aug 5, 2020, and Feb 25, 2022. We descriptively analysed the prevalence and severity of PCC, defined as the presence and frequency of PCC-related symptoms six months after infection, among vaccinated and non-vaccinated individuals infected with Wildtype, Delta, and Omicron SARS-CoV-2. We used multivariable logistic regression models to assess the association and estimate the risk reduction of PCC after infection with newer variants and prior vaccination. We further assessed associations with the severity of PCC using multinomial logistic regression. To identify groups of individuals with similar symptom patterns and evaluate differences in the presentation of PCC across variants, we performed exploratory hierarchical cluster analyses. Results We found strong evidence that vaccinated individuals infected with Omicron had reduced odds of developing PCC compared to non-vaccinated Wildtype-infected individuals (odds ratio 0.42, 95% confidence interval 0.24–0.68). The odds among non-vaccinated individuals were similar after infection with Delta or Omicron compared to Wildtype SARS-CoV-2. We found no differences in PCC prevalence with respect to the number of received vaccine doses or timing of last vaccination. The prevalence of PCC-related symptoms among vaccinated, Omicron-infected individuals was lower across severity levels. In cluster analyses, we identified four clusters of diverse systemic, neurocognitive, cardiorespiratory, and musculoskeletal symptoms, with similar patterns across variants. Conclusion The risk of PCC appears to be lowered with infection by the Omicron variant and after prior vaccination. This evidence is crucial to guide future public health measures and vaccination strategies.

1502

I317

Patel, Maitray A.; Knauer, Michael J.; Nicholson, Michael; Daley, Mark; Van Nynatten, Logan R.; Cepinskas, Gediminas; Fraser, Douglas D.

Organ and cell-specific biomarkers of Long-COVID identified with targeted proteomics and machine learning

https://doi.org/10.1186/s10020-023-00610-z

Published

21-Feb-23

Study

https://doi.org/10.1186/s10020-023-00610-z

Background
Survivors of acute COVID-19 often suffer prolonged, diffuse symptoms post-infection, referred to as “Long-COVID”. A lack of Long-COVID biomarkers and pathophysiological mechanisms limits effective diagnosis, treatment and disease surveillance. We performed targeted proteomics and machine learning analyses to identify novel blood biomarkers of Long-COVID.

Methods
A case–control study comparing the expression of 2925 unique blood proteins in Long-COVID outpatients versus COVID-19 inpatients and healthy control subjects. Targeted proteomics was accomplished with proximity extension assays, and machine learning was used to identify the most important proteins for identifying Long-COVID patients. Organ system and cell type expression patterns were identified with Natural Language Processing (NLP) of the UniProt Knowledgebase.

Results
Machine learning analysis identified 119 relevant proteins for differentiating Long-COVID outpatients (Bonferonni corrected P < 0.01). Protein combinations were narrowed down to two optimal models, with nine and five proteins each, and with both having excellent sensitivity and specificity for Long-COVID status (AUC = 1.00, F1 = 1.00). NLP expression analysis highlighted the diffuse organ system involvement in Long-COVID, as well as the involved cell types, including leukocytes and platelets, as key components associated with Long-COVID.

Conclusions
Proteomic analysis of plasma from Long-COVID patients identified 119 highly relevant proteins and two optimal models with nine and five proteins, respectively. The identified proteins reflected widespread organ and cell type expression. Optimal protein models, as well as individual proteins, hold the potential for accurate diagnosis of Long-COVID and targeted therapeutics.

1503

I318

Brandt, C. T.; Wiese, L.; Christiansen, K. M.; Agergaard, J.

Antibodies to Nucleocapsid Are Not Diagnostic for Long COVID

https://doi.org/10.1128/spectrum.04900-22

Published

21-Feb-23

Letter to editor

https://journals.asm.org/doi/10.1128/spectrum.04900-22

Studying the long-term effects of COVID-19 (long COVID) among members of a Facebook group dedicated to individuals who suspect they may have sequelae from COVID-19 is innovative (1).
The study by Fogh et al. emphasizes the importance of thorough investigation of patients with symptoms resembling long COVID to rule out other causes of malaise. Fogh et al. used antibodies against the nucleocapsid antigen as a proxy for detecting previous COVID infection among Danish individuals with a perception that they suffer from long COVID. The finding that 32% of the participants did not have detectable antinucleocapsid antibodies leads to the conclusion that their symptoms were most likely not related to COVID-19. The low number of respondents—below 5%—is likely to have introduced a bias of uncertain significance besides skewed gender distribution.
The acquired data do, however, only to a limited extent support the study conclusions.
The study premises where Facebook group members with negative screening to SARS-CoV-2 nucleocapsid protein are considered not to have had COVID is challenging since 30 to 40% of patients will not have persisting antibodies at the time of recruitment (2). Furthermore, patients with mild COVID have an antibody response with an even more rapid decay (2, 3). The results presented by Fogh et al. confirm these results by showing significantly increased time from COVID in seronegative individuals compared to seropositive (317 versus 214 days). Close to 90% of the included group members had COVID PCR tests performed. These results could be included as confirmative data for infection as a more reliable indicator of COVID disease status. All available data are important in order to characterize long COVID, and a positive SARS-CoV-2 test is part of the long COVID diagnosis. It is important to use test-positive patients when we characterize long COVID symptoms and search for new treatment options for long COVID patients.
Footnote
For the author reply, see https://doi.org/10.1128/spectrum.00065-23.
publisher: American Society for Microbiology

1504

I319

Hernández-Aceituno, Ana; García-Hernández, Abigail; Larumbe-Zabala, Eneko

COVID-19 long-term sequelae: Omicron versus Alpha and Delta variants

https://doi.org/10.1016/j.idnow.2023.104688

Published

28-Feb-23

Study

https://www.sciencedirect.com/science/article/pii/S2666991923000507

Highlights
•The Omicron variant was associated with a lower risk of COVID-19long-term sequelae.
•Severity of illness indicators increased the risk (ICU length of stay and antiviral or immunomodulatory treatment).
•Vaccination, age, sex, and comorbidities were not found to predict risk of sequelae.
Abstract
Background
The study aimed to assess the association between three predominant SARS-CoV-2 variants (Alpha, Delta, and Omicron) and the risk of developing long COVID (persistence of physical, medical, and cognitive symptoms more than 4 weeks after infection), post-COVID-19 syndrome (symptoms extending beyond 12 weeks), and viral persistence (testing positive beyond 4 weeks despite clinical resolution).
Methods
Retrospective study of 325 patients hospitalized for COVID-19 with genomic sequencing information. For each SARS-CoV-2 variant, sample characteristics, frequency of symptoms, and long-term sequelae were compared using Chi-squared test, Fisher’s exact test, Kruskal-Wallis test, and Dunn's test as appropriate. Odds ratios (OR) were calculated using logistic regression models to assess the association of risk factors and sequelae.
Results
The adjusted model showed that the Omicron (vs Alpha) variant (OR, 0.30; 95% CI 0.16–0.56), admission to ICU (OR, 1.14; 95% CI 1.05–1.23), and being treated with antiviral or immunomodulatory drugs (OR, 2.01; 95% CI 1.23–3.27) predicted long COVID and post-COVID-19 syndrome. Viral persistence showed no difference between variants.
Conclusions
The Omicron variant was associated with significantly lower odds of developing long-term sequelae from COVID-19 compared with previous variants, while severity of illness indicators increased the risk. Vaccination status, age, sex, and comorbidities were not found to predict sequelae development. This information has implications for both health managers and clinicians when deciding on the appropriate clinical management and subsequent outpatient follow-up of these patients. More studies with non-hospitalized patients are still necessary.

1505

I320

Sher, Emina Karahmet; Ćosović, Adnan; Džidić-Krivić, Amina; Farhat, Esma Karahmet; Pinjić, Emma; Sher, Farooq

Covid-19 a triggering factor of autoimmune and multi-inflammatory diseases

https://doi.org/10.1016/j.lfs.2023.121531

Published

15-Apr-23

Review

https://www.sciencedirect.com/science/article/pii/S0024320523001650

SARS-CoV-2 virus has attracted a lot of attention globally due to the autoimmune and inflammatory processes that were observed during the development of Covid-19 disease. Excessive activation of immune response and triggering of autoantibodies synthesis as well as an excessive synthesis of inflammatory cytokines and the onset of cytokine storm has a vital role in the disease outcome and the occurring autoimmune complications. This scenario is reminiscent of infiltration of lymphocytes and monocytes in specific organs and the increased production of autoantibodies and chemoattractants noted in other inflammatory and autoimmune diseases. The main goal of this study is to investigate the complex inflammatory processes that occur in Covid-19 disease and to find similarities with other inflammatory diseases such as multiple sclerosis (MS), acute respiratory distress syndrome (ARDS), rheumatoid arthritis (RA) and Kawasaki syndrome to advance existing diagnostic and therapeutic protocols. The therapy with Interferon-gamma (IFN-γ) and the use of S1P receptor modulators showed promising results. However, there are many unknowns about these mechanisms and possible novel therapies. Therefore, the inflammation and autoimmunity triggered by Covid-19 should be further investigated to improve existing diagnostic procedures and therapeutic protocols for Covid-19.

1506

I321

Huang, Mengwen; Pan, Xingchao; Wang, Xinling; Ren, Qingfei; Tong, Bei; Dong, Xianchi; Ge, Gaoxiang; Lu, Lu; Jiang, Shibo; Chen, Jianfeng

Lymphocyte integrins mediate entry and dysregulation of T cells by SARS-CoV-2

https://doi.org/10.1038/s41392-023-01348-0

Published

27-Feb-23

Study

https://www.nature.com/articles/s41392-023-01348-0

T-cell infection by SARS-CoV-2 and associated immune responses are correlated with disease severity and prognosis of COVID-19. Lymphopenia is associated with increased disease severity in COVID-19. Significantly lower circulating T and B cell counts were observed in patients who died from COVID-19 compared with survivors. Moreover, SARS-CoV-2 infection causes aberrant lymphocyte activation and dysfunction. COVID-19 patients displayed hyperactivated T cells which are prone to apoptosis and dysregulated cytokine responses.1 Some evidence suggests the infection of lymphocytes by SARS-CoV-2, including colocalization of SARS-CoV-2 spike (S) protein and lymphocytes in lung tissues of COVID-19 patients and strands of SARS-CoV-2 sub-genomes in immune cells from bronchoalveolar lavage fluid (BALF) and sputum samples of severe COVID-19 patients.2 Angiotensin-converting enzyme 2 (ACE2) and some other reported S protein receptors are barely expressed in lymphocytes. Some recent studies suggest that integrins may act as SARS-CoV-2 receptors, shedding light on the dysregulation of lymphocyte functions by SARS-CoV-2. However, a clear-cut mechanism underlying the crosstalk between SARS-CoV-2 and lymphocyte integrins remains elusive.
Lymphopenia and cytokine storm are associated with disease severity in most COVID-19 patients. Our data showed that the binding of S-RBD to integrins on T cells not only suppressed T cell proliferation but also promoted T cell activation and proinflammatory cytokine secretion. The dysregulation of T cells by S-RBD binding may therefore result in aberrant T cell immune responses and increase the severity of COVID-19.
In summary, our study demonstrates that integrins act as SARS-CoV-2 receptors on T cells and mediate entry and dysregulation of T cells by SARS-CoV-2. Blocking S-RBD‒integrin interaction may be a strategy for preventing SARS-CoV-2 entry into T cells and associated immune dysregulation in COVID-19 patients.
number: 1
publisher: Nature Publishing Group

1507

I322

Edwards, Frances; Hamilton, Fergus W.

Impact of covid-19 vaccination on long covid

https://doi.org/10.1136/bmjmed-2022-000470

Published

1-Feb-23

Article

https://bmjmedicine.bmj.com/content/2/1/e000470

> Some beneficial effects are likely but estimating the size of the effect currently remains a challenge

Vaccines have had an important role in reducing mortality and morbidity from the covid-19 pandemic, with an estimated 14.4 million lives saved globally over the first year of vaccination.

Where do these data leave us with vaccines and long covid? Given new and existing evidence, covid-19 vaccination is likely to have some beneficial effect on long covid through reducing case severity as well as incidence. However, estimating the size of the effect (and the effect of further vaccine doses) remains a challenge in observational data. The evidence of benefit after infection is much more unclear and harder to interpret given the current rate of seropositivity and vaccine uptake in many countries. While these studies are encouraging, trials comparing vaccination with placebo in patients with long covid (as defined by WHO criteria) are required to definitively recommend for or against vaccination to improve symptoms of long covid. Until then, vaccination should continue to be based on the most up-to-date evidence available for the prevention of covid-19 related infection, hospital admission, and death.

publisher: BMJ Specialist Journals
section: Editorial

1508

I323

Taylor, Luke

Covid-19: Vaccination reduces severity and duration of long covid, study finds

https://doi.org/10.1136/bmj.p491

Published

1-Mar-23

Article

https://www.bmj.com/content/380/bmj.p491

Vaccination against covid-19 reduces both the severity and the duration of long covid, a study published in BMJ Medicine has found.1

The paper adds to the evidence that patients infected with SARS CoV-2 who experience persistent covid-19 symptoms should be encouraged to be vaccinated against the virus, the authors said.

Lasting covid-19 symptoms that persist more than three months after infection affect an estimated one in 10 people in the UK. The condition can end a patient’s social life and put them out of work because of the many associated symptoms, ranging from breathlessness and muscle pain to brain fog and headaches.

An estimated two million to four million people in the US are out of work because of long covid, costing $170bn-$230bn (£141bn-£191bn; €159bn-€215bn) a year in lost wages.2

One of the remaining questions over the poorly understood condition is whether covid-19 vaccination affects recovery, which is made more difficult by the fact …

1509

I324

Lee, A. Ram; Woo, Jin Seok; Lee, Seon-Yeong; Lee, Yeon Su; Jung, Jooyeon; Lee, Chae Rim; Park, Sung-Hwan; Cho, Mi-La

SARS-CoV-2 spike protein promotes inflammatory cytokine activation and aggravates rheumatoid arthritis

https://doi.org/10.1186/s12964-023-01044-0

Published

2-Mar-23

Study

https://doi.org/10.1186/s12964-023-01044-0

Background
Coronavirus disease 2019 (COVID-19) induces inflammation, autoantibody production, and thrombosis, which are common symptoms of autoimmune diseases, including rheumatoid arthritis (RA). However, the effect of COVID-19 on autoimmune disease is not yet fully understood.

Methods
This study was performed to investigate the effects of COVID-19 on the development and progression of RA using a collagen-induced arthritis (CIA) animal model. Human fibroblast-like synoviocytes (FLS) were transduced with lentivirus carrying the SARS-CoV-2 spike protein gene in vitro, and the levels of inflammatory cytokine and chemokine expression were measured. For in vivo experiments, CIA mice were injected with the gene encoding SARS-CoV-2 spike protein, and disease severity, levels of autoantibodies, thrombotic factors, and inflammatory cytokine and chemokine expression were assessed. In the in vitro experiments, the levels of inflammatory cytokine and chemokine expression were significantly increased by overexpression of SARS-CoV-2 spike protein in human FLS.

Results
The incidence and severity of RA in CIA mice were slightly increased by SARS-CoV-2 spike protein in vivo. In addition, the levels of autoantibodies and thrombotic factors, such as anti-CXC chemokine ligand 4 (CXCL4, also called PF4) antibodies and anti-phospholipid antibodies were significantly increased by SARS-CoV-2 spike protein. Furthermore, tissue destruction and inflammatory cytokine level in joint tissue were markedly increased in CIA mice by SARS-CoV-2 spike protein.

Conclusions
The results of the present study suggested that COVID-19 accelerates the development and progression of RA by increasing inflammation, autoantibody production, and thrombosis.

1510

I325

Tran, Viet-Thi; Perrodeau, Elodie; Saldanha, Julia; Pane, Isabelle; Ravaud, Philippe

Efficacy of first dose of covid-19 vaccine versus no vaccination on symptoms of patients with long covid: target trial emulation based on ComPaRe e-cohort

https://doi.org/10.1136/bmjmed-2022-000229

Published

1-Feb-23

Study

https://bmjmedicine.bmj.com/content/2/1/e000229

Objective To evaluate the effect of covid-19 vaccination on the severity of symptoms in patients with long covid.
Design Target trial emulation based on ComPaRe e-cohort.
Data source ComPaRe long covid cohort, a nationwide e-cohort (ie, a cohort where recruitment and follow-up are performed online) of patients with long covid, in France.
Methods Adult patients (aged ≥18 years) enrolled in the ComPaRe cohort before 1 May 2021 were included in the study if they reported a confirmed or suspected SARS-CoV-2 infection, symptoms persistent for >3 weeks after onset, and at least one symptom attributable to long covid at baseline. Patients who received a first covid-19 vaccine injection were matched with an unvaccinated control group in a 1:1 ratio according to their propensity scores. Number of long covid symptoms, rate of complete remission of long covid, and proportion of patients reporting an unacceptable symptom state at 120 days were recorded.
Results 910 patients were included in the analyses (455 in the vaccinated group and 455 in the control group). By 120 days, vaccination had reduced the number of long covid symptoms (mean 13.0 (standard deviation 9.4) in the vaccinated group v 14.8 (9.8) in the control group; mean difference −1.8, 95% confidence interval −3.0 to −0.5) and doubled the rate of patients in remission (16.6% v 7.5%, hazard ratio 1.93, 95% confidence interval 1.18 to 3.14). Vaccination reduced the effect of long covid on patients' lives (mean score on the impact tool 24.3 (standard deviation 16.7) v 27.6 (16.7); mean difference −3.3, 95% confidence interval −5.7 to −1.0) and the proportion of patients with an unacceptable symptom state (38.9% v 46.4%, risk difference −7.4%, 95% confidence interval −14.5% to −0.3%). In the vaccinated group, two (0.4%) patients reported serious adverse events requiring admission to hospital.
Conclusion In this study, covid-19 vaccination reduced the severity of symptoms and the effect of long covid on patients' social, professional, and family lives at 120 days in those with persistent symptoms of infection.

1511

I326

Qi, Furong; Li, Dapeng; Zhang, Zheng

The kinetics of chemokine autoantibodies in COVID-19

https://doi.org/10.1038/s41590-023-01455-8

Published

15-Mar-23

Article

https://www.nature.com/articles/s41590-023-01455-8

First, it will be of importance to validate the presence of chemokine autoantibody patterns in a larger population, although the authors have validated their observation in two additional cohorts. Longitudinal follow-up of cohorts should be conducted to explore whether the elevation of chemokine autoantibodies that are associated with the absence of long COVID are already present in the acute phase or the early recovery stages and to further study their predictive value. In addition, it is not clear whether various patterns of chemokine autoantibodies can be defined in patients with long COVID with different organ-specific symptoms (for example, respiratory symptoms versus neurological symptoms), given the heterogeneity of symptoms, and even in long-term sequelae caused by other viral infections.

Second, it remains to be determined what drives the elevation of these autoantibodies in patients with favorable outcomes. A simple model would be that chemokines proportionally induce autoantibodies, but such a correlation was not found by Muri et al4. This may be partly owing to different sampling times and the variable half-lives for the chemokines and the autoantibodies in plasma. It will be important to determine whether the level of chemokine autoantibodies in the blood correlates with the amount of chemokines in the tissues. In autoimmune diseases, chemokines at autoimmune sites could cause the breakthrough of B cell tolerance to generate autoantibodies against the dominant chemokine at these sites9. A subset of patients with COVID-19 and individuals with long COVID can present inflammation- and autoimmune-related symptoms10. However, the chemokine autoantibody signature in COVID-19 is different from that in the autoimmune diseases that authors have investigated here. Future studies should elaborately investigate the mechanisms underlying the elevated chemokine autoantibodies in individuals post-COVID-19 infection without long COVID.

Third, given that the chemokine autoantibodies associated with long COVID are involved in sustaining lymphocyte recruitment, understanding the kinetics of these lymphocytes could help to clarify the mechanisms underlying the various COVID-19 outcomes. Research in the dynamics of antibody-producing cells and T cells through single-cell transcriptomic analysis might lead to better understanding of these complex regulatory mechanisms8. Considering that naturally arising chemokine autoantibodies associated with COVID-19 may be beneficial in regulating inflammatory responses, the development of targeted therapies to the chemokine system will be critical in the treatment of long COVID.
publisher: Nature Publishing Group

1512

I327

Schloss, John V.

Nutritional deficiencies that may predispose to long COVID

https://doi.org/10.1007/s10787-023-01183-3

Published

15-Mar-23

Review

https://doi.org/10.1007/s10787-023-01183-3

Multiple nutritional deficiencies (MND) confound studies designed to assess the role of a single nutrient in contributing to the initiation and progression of disease states. Despite the perception of many healthcare practitioners, up to 25% of Americans are deficient in five-or-more essential nutrients. Stress associated with the COVID-19 pandemic further increases the prevalence of deficiency states. Viral infections compete for crucial nutrients with immune cells. Viral replication and proliferation of immunocompetent cells critical to the host response require these essential nutrients, including zinc. Clinical studies have linked levels of more than 22 different dietary components to the likelihood of COVID-19 infection and the severity of the disease. People at higher risk of infection due to MND are also more likely to have long-term sequelae, known as Long COVID.

1513

I328

Worku, Dominic

Multisystem Inflammatory Syndrome in Adults (MIS-A) and SARS-CoV2: An Evolving Relationship

https://doi.org/10.3390/biomed3010016

Published

1-Mar-23

Article

https://www.mdpi.com/2673-8430/3/1/16

The SARS-CoV2 pandemic is the most significant global health emergency of the last century. While the pathophysiology of SARS-CoV2 is understood, the early and long-term outcomes of natural infection are increasingly being recognised. Multisystem inflammatory syndrome (MIS) represents a manifestation of the extreme immune dysfunction that SARS-CoV2 infection heralds and has been described in both children (MIS-C) and adults (MIS-A). Here, we discuss current knowledge of MIS-A and the vast questions that remain unanswered.

1514

I329

Hackenbruch, Christopher; Maringer, Yacine; Tegeler, Christian M.; Walz, Juliane S.; Nelde, Annika; Heitmann, Jonas S.

Elevated SARS-CoV-2-Specific Antibody Levels in Patients with Post-COVID Syndrome

https://doi.org/10.3390/v15030701

Published

1-Mar-23

Study

https://www.mdpi.com/1999-4915/15/3/701

With the routine use of effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, the number of life-threatening coronavirus disease 2019 (COVID-19) courses have largely been reduced. However, multiple COVID-19 convalescents, even after asymptomatic to moderate disease, suffer from post-COVID syndrome, with relevant limitations in daily life. The pathophysiologic mechanisms of post-COVID syndrome are still elusive, with dysregulation of the immune system suggested as a central mechanism. Here, we assessed COVID-19 post-infectious symptoms (5–6 months after PCR-confirmed acute infection) together with the humoral immune response against SARS-CoV-2 in non-hospitalized COVID-19 convalescents, early (5–6 weeks) and late (5–6 months) after their first positive SARS-CoV-2 PCR result. Convalescents reporting several post-infectious symptoms (>3) showed higher anti-spike and anti-nucleocapsid antibody levels 5–6 weeks after PCR-confirmed infection with the latter remained increased 5–6 months after positive PCR. Likewise, a higher post-infectious symptom score was associated with increased antibody levels. Of note, convalescents displaying neuro-psychiatric symptoms such as restlessness, palpitations, irritability, and headache, as well as general symptoms such as fatigue/reduced power had higher SARS-CoV-2-specific antibody levels compared with asymptomatic cases. The increased humoral immune response in convalescents with post-COVID syndrome might be useful for the detection of individuals with an increased risk for post-COVID syndrome.

1515

I330

Gioia, Ubaldo; Tavella, Sara; Martínez-Orellana, Pamela; Cicio, Giada; Colliva, Andrea; Ceccon, Marta; Cabrini, Matteo; Henriques, Ana C.; Fumagalli, Valeria; Paldino, Alessia; Presot, Ettore; Rajasekharan, Sreejith; Iacomino, Nicola; Pisati, Federica; Matti, Valentina; Sepe, Sara; Conte, Matilde I.; Barozzi, Sara; Lavagnino, Zeno; Carletti, Tea; Volpe, Maria Concetta; Cavalcante, Paola; Iannacone, Matteo; Rampazzo, Chiara; Bussani, Rossana; Tripodo, Claudio; Zacchigna, Serena; Marcello, Alessandro; d’Adda di Fagagna, Fabrizio

SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence

https://doi.org/10.1038/s41556-023-01096-x

Published

9-Mar-23

Article

https://www.nature.com/articles/s41556-023-01096-x

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the RNA virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Although SARS-CoV-2 was reported to alter several cellular pathways, its impact on DNA integrity and the mechanisms involved remain unknown. Here we show that SARS-CoV-2 causes DNA damage and elicits an altered DNA damage response. Mechanistically, SARS-CoV-2 proteins ORF6 and NSP13 cause degradation of the DNA damage response kinase CHK1 through proteasome and autophagy, respectively. CHK1 loss leads to deoxynucleoside triphosphate (dNTP) shortage, causing impaired S-phase progression, DNA damage, pro-inflammatory pathways activation and cellular senescence. Supplementation of deoxynucleosides reduces that. Furthermore, SARS-CoV-2 N-protein impairs 53BP1 focal recruitment by interfering with damage-induced long non-coding RNAs, thus reducing DNA repair. Key observations are recapitulated in SARS-CoV-2-infected mice and patients with COVID-19. We propose that SARS-CoV-2, by boosting ribonucleoside triphosphate levels to promote its replication at the expense of dNTPs and by hijacking damage-induced long non-coding RNAs’ biology, threatens genome integrity and causes altered DNA damage response activation, induction of inflammation and cellular senescence.

1516

I331

Kahlert, Christian R; Strahm, Carol; Güsewell, Sabine; Cusini, Alexia; Brucher, Angela; Goppel, Stephan; Möller, Elisabeth; Möller, J Carsten; Ortner, Manuela; Ruetti, Markus; Stocker, Reto; Vuichard-Gysin, Danielle; Besold, Ulrike; McGeer, Allison; Risch, Lorenz; Friedl, Andrée; Schlegel, Matthias; Vernazza, Pietro; Kuster, Stefan P; Kohler, Philipp; SURPRISE Study Group

Post-acute sequelae after SARS-CoV-2 infection by viral variant and vaccination status: a multicenter cross-sectional study

https://doi.org/10.1093/cid/ciad143

Published

11-Mar-23

Study

https://doi.org/10.1093/cid/ciad143

Disentangling the effects of SARS-CoV-2 variants and vaccination on the occurrence of post-acute sequelae of SARS-CoV-2 (PASC) is crucial to estimate and reduce the burden of PASC.We performed a cross-sectional analysis (May/June 2022) within a prospective multicenter healthcare worker (HCW) cohort in North-Eastern Switzerland. HCW were stratified by viral variant and vaccination status at time of their first positive SARS-CoV-2 nasopharyngeal swab. HCW without positive swab and with negative serology served as controls. The sum of eighteen self-reported PASC symptoms was modeled with univariable and multivariable negative-binomial regression to analyse the association of mean symptom number with viral variant and vaccination status.Among 2’912 participants (median age 44 years, 81.3% female), PASC symptoms were significantly more frequent after wild-type infection (estimated mean symptom number 1.12, p<0.001; median time since infection 18.3 months), after Alpha/Delta infection (0.67 symptoms, p<0.001; 6.5 months), and after Omicron BA.1 infections (0.52 symptoms, p=0.005; 3.1 months) compared to uninfected controls (0.39 symptoms). After Omicron BA.1 infection, the estimated mean symptom number was 0.36 for unvaccinated individuals, compared to 0.71 with 1-2 vaccinations (p=0.028) and 0.49 with ≥3 prior vaccinations (p=0.30). Adjusting for confounders, only wild-type (adjusted rate ratio [aRR] 2.81, 95% confidence interval [CI] 2.08-3.83) and Alpha/Delta infection (aRR 1.93, 95% CI 1.10-3.46) were significantly associated with the outcome.Previous infection with pre-Omicron variants was the strongest risk factor for PASC symptoms among our HCW. Vaccination prior to Omicron BA.1 infection was not associated with a clear protective effect against PASC symptoms in this population.

1517

I332

Opsteen, Skye; Files, Jacob K.; Fram, Tim; Erdmann, Nathan

The role of immune activation and antigen persistence in acute and long COVID

https://doi.org/10.1177/10815589231158041

Published

6-Mar-23

Review

https://doi.org/10.1177/10815589231158041

In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered the global coronavirus disease 2019 (COVID-19) pandemic. Although most infections cause a self-limited syndrome comparable to other upper respiratory viral pathogens, a portion of individuals develop severe illness leading to substantial morbidity and mortality. Furthermore, an estimated 10%?20% of SARS-CoV-2 infections are followed by post-acute sequelae of COVID-19 (PASC), or long COVID. Long COVID is associated with a wide variety of clinical manifestations including cardiopulmonary complications, persistent fatigue, and neurocognitive dysfunction. Severe acute COVID-19 is associated with hyperactivation and increased inflammation, which may be an underlying cause of long COVID in a subset of individuals. However, the immunologic mechanisms driving long COVID development are still under investigation. Early in the pandemic, our group and others observed immune dysregulation persisted into convalescence after acute COVID-19. We subsequently observed persistent immune dysregulation in a cohort of individuals experiencing long COVID. We demonstrated increased SARS-CoV-2-specific CD4+ and CD8+ T-cell responses and antibody affinity in patients experiencing long COVID symptoms. These data suggest a portion of long COVID symptoms may be due to chronic immune activation and the presence of persistent SARS-CoV-2 antigen. This review summarizes the COVID-19 literature to date detailing acute COVID-19 and convalescence and how these observations relate to the development of long COVID. In addition, we discuss recent findings in support of persistent antigen and the evidence that this phenomenon contributes to local and systemic inflammation and the heterogeneous nature of clinical manifestations seen in long COVID.

1518

I333

Dhawan, Manish; Rabaan, Ali A.; Alwarthan, Sara; Alhajri, Mashael; Halwani, Muhammad A.; Alshengeti, Amer; Najim, Mustafa A.; Alwashmi, Ameen S. S.; Alshehri, Ahmad A.; Alshamrani, Saleh A.; AlShehail, Bashayer M.; Garout, Mohammed; Al-Abdulhadi, Saleh; Al-Ahmed, Shamsah H.; Thakur, Nanamika; Verma, Geetika

Regulatory T Cells (Tregs) and COVID-19: Unveiling the Mechanisms, and Therapeutic Potentialities with a Special Focus on Long COVID

https://doi.org/10.3390/vaccines11030699

Published

1-Mar-23

Review

https://www.mdpi.com/2076-393X/11/3/699

The COVID-19 pandemic has caused havoc all around the world. The causative agent of COVID-19 is the novel form of the coronavirus (CoV) named SARS-CoV-2, which results in immune system disruption, increased inflammation, and acute respiratory distress syndrome (ARDS). T cells have been important components of the immune system, which decide the fate of the COVID-19 disease. Recent studies have reported an important subset of T cells known as regulatory T cells (Tregs), which possess immunosuppressive and immunoregulatory properties and play a crucial role in the prognosis of COVID-19 disease. Recent studies have shown that COVID-19 patients have considerably fewer Tregs than the general population. Such a decrement may have an impact on COVID-19 patients in a number of ways, including diminishing the effect of inflammatory inhibition, creating an inequality in the Treg/Th17 percentage, and raising the chance of respiratory failure. Having fewer Tregs may enhance the likelihood of long COVID development in addition to contributing to the disease’s poor prognosis. Additionally, tissue-resident Tregs provide tissue repair in addition to immunosuppressive and immunoregulatory activities, which may aid in the recovery of COVID-19 patients. The severity of the illness is also linked to abnormalities in the Tregs’ phenotype, such as reduced expression of FoxP3 and other immunosuppressive cytokines, including IL-10 and TGF-beta. Hence, in this review, we summarize the immunosuppressive mechanisms and their possible roles in the prognosis of COVID-19 disease. Furthermore, the perturbations in Tregs have been associated with disease severity. The roles of Tregs are also explained in the long COVID. This review also discusses the potential therapeutic roles of Tregs in the management of patients with COVID-19.

1519

I334

Amiama-Roig, Ana; Pérez-Martínez, Laura; Rodríguez Ledo, Pilar; Verdugo-Sivianes, Eva M.; Blanco, José-Ramón

Should We Expect an Increase in the Number of Cancer Cases in People with Long COVID?

https://doi.org/10.3390/microorganisms11030713

Published

1-Mar-23

Review

https://www.mdpi.com/2076-2607/11/3/713

The relationship between viral infections and the risk of developing cancer is well known. Multiple mechanisms participate in and determine this process. The COVID-19 pandemic caused by the SARS-CoV-2 virus has resulted in the deaths of millions of people worldwide. Although the effects of COVID-19 are limited for most people, a large number of people continue to show symptoms for a long period of time (long COVID). Several studies have suggested that cancer could also be a potential long-term complication of the virus; however, the causes of this risk are not yet well understood. In this review, we investigated arguments that could support or reject this possibility.

1520

I335

Liu, Ziqi; Yin, Ziqiao; Mi, Zhilong; Guo, Binghui

Long-COVID Inducement Mechanism Based on the Path Module Correlation Coefficient

https://doi.org/10.3390/math11061368

Published

1-Jan-23

Study

https://www.mdpi.com/2227-7390/11/6/1368

As the number of COVID-19 cases increases, the long-COVID symptoms become the focus of clinical attention. Based on the statistical analysis of long-COVID symptoms in European and Chinese populations, this study proposes the path module correlation coefficient, which can estimate the correlation between two modules in a network, to evaluate the correlation between SARS-CoV-2 infection and long-COVID symptoms, providing a theoretical support for analyzing the frequency of long-COVID symptoms in European and Chinese populations. The path module correlation coefficients between specific COVID-19-related genes in the European and Chinese populations and genes that may induce long-COVID symptoms were calculated. The results showed that the path module correlation coefficients were completely consistent with the frequency of long-COVID symptoms in the Chinese population, but slightly different in the European population. Furthermore, the cathepsin C (CTSC) gene was found to be a potential COVID-19-related gene by a path module correlation coefficient correction rate. Our study can help to explore other long-COVID symptoms that have not yet been discovered and provide a new perspective to research this syndrome. Meanwhile, the path module correlation coefficient correction rate can help to find more species-specific genes related to COVID-19 in the future.

1521

I336

Byambasuren, Oyungerel; Stehlik, Paulina; Clark, Justin; Alcorn, Kylie; Glasziou, Paul

Effect of covid-19 vaccination on long covid: systematic review

https://doi.org/10.1136/bmjmed-2022-000385

Published

1-Feb-23

Review

https://bmjmedicine.bmj.com/content/2/1/e000385

Objective To determine the effect of covid-19 vaccination, given before and after acute infection with the SARS-CoV-2 virus, or after a diagnosis of long covid, on the rates and symptoms of long covid.
Design Systematic review.
Data sources PubMed, Embase, and Cochrane covid-19 trials, and Europe PubMed Central (Europe PMC) for preprints, from 1 January 2020 to 3 August 2022.
Eligibility criteria for selecting studies Trials, cohort studies, and case-control studies reporting on patients with long covid and symptoms of long covid, with vaccination before and after infection with the SARS-CoV-2 virus, or after a diagnosis of long covid. Risk of bias was assessed with the ROBINS-I tool.
Results 1645 articles were screened but no randomised controlled trials were found. 16 observational studies from five countries (USA, UK, France, Italy, and the Netherlands) were identified that reported on 614 392 patients. The most common symptoms of long covid that were studied were fatigue, cough, loss of sense of smell, shortness of breath, loss of taste, headache, muscle ache, difficulty sleeping, difficulty concentrating, worry or anxiety, and memory loss or confusion. 12 studies reported data on vaccination before infection with the SARS-CoV-2 virus, and 10 showed a significant reduction in the incidence of long covid: the odds ratio of developing long covid with one dose of vaccine ranged from 0.22 to 1.03; with two doses, odds ratios were 0.25-1; with three doses, 0.16; and with any dose, 0.48-1.01. Five studies reported on vaccination after infection, with odds ratios of 0.38-0.91. The high heterogeneity between studies precluded any meaningful meta-analysis. The studies failed to adjust for potential confounders, such as other protective behaviours and missing data, thus increasing the risk of bias and decreasing the certainty of evidence to low.
Conclusions Current studies suggest that covid-19 vaccines might have protective and therapeutic effects on long covid. More robust comparative observational studies and trials are needed, however, to clearly determine the effectiveness of vaccines in preventing and treating long covid.
Protocol registration Open Science Framework https://osf.io/e8jdy.

1522

I337

Muri, Jonathan; Cecchinato, Valentina; Cavalli, Andrea; Shanbhag, Akanksha A.; Matkovic, Milos; Biggiogero, Maira; Maida, Pier Andrea; Moritz, Jacques; Toscano, Chiara; Ghovehoud, Elaheh; Furlan, Raffaello; Barbic, Franca; Voza, Antonio; De Nadai, Guendalina; Cervia, Carlo; Zurbuchen, Yves; Taeschler, Patrick; Murray, Lilly A.; Danelon-Sargenti, Gabriela; Moro, Simone; Gong, Tao; Piffaretti, Pietro; Bianchini, Filippo; Crivelli, Virginia; Podešvová, Lucie; Pedotti, Mattia; Jarrossay, David; Sgrignani, Jacopo; Thelen, Sylvia; Uhr, Mario; Bernasconi, Enos; Rauch, Andri; Manzo, Antonio; Ciurea, Adrian; Rocchi, Marco B. L.; Varani, Luca; Moser, Bernhard; Bottazzi, Barbara; Thelen, Marcus; Fallon, Brian A.; Boyman, Onur; Mantovani, Alberto; Garzoni, Christian; Franzetti-Pellanda, Alessandra; Uguccioni, Mariagrazia; Robbiani, Davide F.

Autoantibodies against chemokines post-SARS-CoV-2 infection correlate with disease course

https://doi.org/10.1038/s41590-023-01445-w

Published

6-Mar-23

Study

https://www.nature.com/articles/s41590-023-01445-w

Infection with severe acute respiratory syndrome coronavirus 2 associates with diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse coronavirus disease 2019 (COVID-19) outcomes. Here we discovered that antibodies against specific chemokines were omnipresent post-COVID-19, were associated with favorable disease outcome and negatively correlated with the development of long COVID at 1 yr post-infection. Chemokine antibodies were also present in HIV-1 infection and autoimmune disorders, but they targeted different chemokines compared with COVID-19. Monoclonal antibodies derived from COVID-19 convalescents that bound to the chemokine N-loop impaired cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising chemokine antibodies may modulate the inflammatory response and thus bear therapeutic potential.

1523

I338

Horne, Benjamin Davies; Knowlton, Kirk U.; Le, Viet T.; Bair, Tami L.; May, Heidi Thomas; Knight, Stacey; Anderson, Jeffrey L.

Is exposure to epstein-barr virus a risk factor for long-covid?

https://doi.org/10.1016/S0735-1097(23)02228-3

Published

7-Mar-23

Study

https://www.jacc.org/doi/full/10.1016/S0735-1097%2823%2902228-3

Background
A viral etiology to chronic fatigue syndrome (CFS) has long been postulated, and Epstein-Barr Virus (EBV) was the first CFSassociated virus. CFS and Long-COVID share features, potentially implicating a similar etiology. This study evaluated if EBV exposure is associated with post-COVID syndrome (Long-COVID).

Methods
Intermountain Healthcare electronic health records were queried to identify patients diagnosed with COVID-19 and tested for EBV between March 6, 2020 and April 13, 2022. A subsequent diagnosis of Long-COVID (ICD-10 U09.9) was evaluated using survival methods.

Results
Overall, 296,959 patients had COVID-19 and 590 had concurrent EBV test results [207 (35.1%) were EBV positive]. Subjects averaged 27.4±18.4 years of age (range: 0-86); 57.6% were female. Hospitalization occurred in 61 subjects (10.3%) within 30 days of COVID-19 diagnosis, with 17 (2.9%) requiring intensive care. Long-COVID was found in 29 (4.9%) subjects (just 10 were among the 61 hospitalized for COVID-19), with 15 (7.2%) EBV positive (Figure) and 14 (3.7%) EBV negative (HR=2.09, 95% CI=1.01, 4.34; p=0.042). EBV risk remained in multivariable analyses. Race, hyperlipidemia, and tobacco use also predicted Long-COVID, with histories of anticoagulant and vitamin D use were protective.

Conclusion
In a large prospectively-collected registry, EBV positivity was associated with an elevated risk of Long-COVID. This suggests that EBV may be a predisposing risk factor for or co-precipitant of Long-COVID.
publisher: American College of Cardiology Foundation

1524

I339

Abu Hamdh, Bayan; Nazzal, Zaher

A prospective cohort study assessing the relationship between long-COVID symptom incidence in COVID-19 patients and COVID-19 vaccination

https://doi.org/10.1038/s41598-023-30583-2

Published

25-Mar-23

Study

https://www.nature.com/articles/s41598-023-30583-2

Current studies about the long-term effects of COVID-19 show a wide range of symptoms. This prospective cohort study aimed to find the incidence of long-COVID symptoms and the associated risk factors. We followed 669 confirmed COVID-19 patients. Sociodemographic and clinical data were extracted from medical records and collected via semi-structured telephone interviews on days 10, 30, 60, and 90. The incidence of long-COVID symptoms was 41.6% (95% CI 37.8–45.4%). Females [aOR = 1.5 (95% CI 1.1–2.3)], the elderly [aOR = 4.9 (95% CI 2.0–11.3)], and those who required hospitalization [aOR = 5.0 (95% CI 1.3–3.7)] were at a higher risk of developing long-COVID. Patients with dyspnea at day 10 [aOR: 2.4 (95% CI 1.6–3.7] and fatigue at day 60 [aOR: 3.1 (95% CI 1.5–6.3] were also at risk. While non-vaccinated patients were almost seven times more likely to report long-COVID symptoms than vaccinated patients [aOR: 6.9 (95% CI 4.2–11.3)]. In conclusion, long-COVID was common among COVID-19 patients, with higher rates among females, older age groups, hospitalized patients, and those with dyspnea and fatigue, while vaccination provided protection. Interventions should educate health professionals, raise general public awareness about the risks and consequences of Long COVID, and the value of vaccination.

1525

I340

Ceban, Felicia; Kulzhabayeva, Dana; Rodrigues, Nelson B.; Di Vincenzo, Joshua D.; Gill, Hartej; Subramaniapillai, Mehala; Lui, Leanna M. W.; Cao, Bing; Mansur, Rodrigo B.; Ho, Roger C.; Burke, Matthew J.; Rhee, Taeho Greg; Rosenblat, Joshua D.; McIntyre, Roger S.

COVID-19 Vaccination for the Prevention and Treatment of Long COVID: A Systematic Review and Meta-analysis

https://doi.org/10.1016/j.bbi.2023.03.022

Published

27-Mar-23

Systematic review and meta-analysis

https://www.sciencedirect.com/science/article/pii/S088915912300079X

Highlights
•At least one dose of a SARS-CoV-2 vaccine was associated with a protective effect against long COVID.
•Long COVID trajectory following vaccination was mixed, with most patients reporting no changes.
•Evidence supports SARS-CoV-2 vaccination for the prevention of long COVID.
Abstract
Empirical evidence addressing the association between SARS-CoV-2 vaccination and long COVID would guide public health priorities and inform personal health decisions. Herein, the co-primary objectives are to determine the differential risk of long COVID in vaccinated versus unvaccinated patients, and the trajectory of long COVID following vaccination. Of 2775 articles identified via systematic search, 17 were included, and 6 were meta-analyzed. Meta-analytic results determined that at least one vaccine dose was associated with a protective effect against long COVID (OR 0.539, 95% CI 0.295-0.987, p = 0.045, N= 257 817). Qualitative analysis revealed that trajectories of pre-existing long COVID following vaccination were mixed, with most patients reporting no changes. The evidence herein supports SARS-CoV-2 vaccination for the prevention of long COVID, and recommends long COVID patients adhere to standard SARS-CoV-2 vaccination schedules.

1526

I341

Xie, Yan; Choi, Taeyoung; Al-Aly, Ziyad

Association of Treatment With Nirmatrelvir and the Risk of Post–COVID-19 Condition

https://doi.org/10.1001/jamainternmed.2023.0743

Published

23-Mar-23

Study

https://doi.org/10.1001/jamainternmed.2023.0743

Key Points
Question Is treatment with nirmatrelvir in the acute phase of SARS-CoV-2 infection associated with a lower risk of post–COVID-19 condition (PCC)?

Findings In this cohort study of 281 793 people with SARS-CoV-2 infection who had at least 1 risk factor for progression to severe COVID-19 illness, compared with 246 076 who had no treatment, nirmatrelvir use in the acute phase (n = 35 717) was associated with reduced risk of PCC, including reduced risk of 10 of 13 post–acute sequelae in various organ systems, as well as reduced risk of post–acute death and post–acute hospitalization. Nirmatrelvir was associated with reduced risk of PCC in people who were unvaccinated, vaccinated, and boosted, and in people with primary SARS-CoV-2 infection and reinfection.

Meaning In people with SARS-CoV-2 infection and at least 1 risk factor for progression to severe COVID-19 illness, treatment with nirmatrelvir during the acute phase of COVID-19 was associated with reduced risk of PCC.

Abstract
Importance Post–COVID-19 condition (PCC), also known as long COVID, affects many individuals. Prevention of PCC is an urgent public health priority.

Objective To examine whether treatment with nirmatrelvir in the acute phase of COVID-19 is associated with reduced risk of PCC.

Design, Setting, and Participants This cohort study used the health care databases of the US Department of Veterans Affairs (VA) to identify patients who had a SARS-CoV-2 positive test result between January 3, 2022, and December 31, 2022, who were not hospitalized on the day of the positive test result, who had at least 1 risk factor for progression to severe COVID-19 illness, and who had survived the first 30 days after SARS-CoV-2 diagnosis. Those who were treated with oral nirmatrelvir within 5 days after the positive test (n = 35 717) and those who received no COVID-19 antiviral or antibody treatment during the acute phase of SARS-CoV-2 infection (control group, n = 246 076) were identified.

Exposures Treatment with nirmatrelvir or receipt of no COVID-19 antiviral or antibody treatment based on prescription records.

Main Outcomes and Measures Inverse probability weighted survival models were used to estimate the association of nirmatrelvir (vs control) with post–acute death, post–acute hospitalization, and a prespecified panel of 13 post–acute COVID-19 sequelae (components of PCC) and reported in relative scale as relative risk (RR) or hazard ratio (HR) and in absolute scale as absolute risk reduction in percentage at 180 days (ARR).

Results A total of 281 793 patients (mean [SD] age, 61.99 [14.96]; 242 383 [86.01%] male) who had a positive SARS-CoV-2 test result and had at least 1 risk factor for progression to severe COVID-19 illness were studied. Among them, 246 076 received no COVID-19 antiviral or antibody treatment during the acute phase of SARS-CoV-2 infection, and 35 717 received oral nirmatrelvir within 5 days after the positive SARS-CoV-2 test result. Compared with the control group, nirmatrelvir was associated with reduced risk of PCC (RR, 0.74; 95% CI, 0.72-0.77; ARR, 4.51%; 95% CI, 4.01-4.99), including reduced risk of 10 of 13 post–acute sequelae (components of PCC) in the cardiovascular system (dysrhythmia and ischemic heart disease), coagulation and hematologic disorders (pulmonary embolism and deep vein thrombosis), fatigue and malaise, acute kidney disease, muscle pain, neurologic system (neurocognitive impairment and dysautonomia), and shortness of breath. Nirmatrelvir was also associated with reduced risk of post–acute death (HR, 0.53; 95% CI, 0.46-0.61); ARR, 0.65%; 95% CI, 0.54-0.77), and post–acute hospitalization (HR, 0.76; 95% CI, 0.73-0.80; ARR, 1.72%; 95% CI, 1.42-2.01). Nirmatrelvir was associated with reduced risk of PCC in people who were unvaccinated, vaccinated, and boosted, and in people with primary SARS-CoV-2 infection and reinfection.

Conclusions and Relevance This cohort study found that in people with SARS-CoV-2 infection who had at least 1 risk factor for progression to severe disease, treatment with nirmatrelvir within 5 days of a positive SARS-CoV-2 test result was associated with reduced risk of PCC across the risk spectrum in this cohort and regardless of vaccination status and history of prior infection; the totality of findings suggests that treatment with nirmatrelvir during the acute phase of COVID-19 may reduce the risk of post–acute adverse health outcomes.

1527

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Kurian, Shilia Jacob; Mathews, Sara Poikayil; Paul, Abin; Viswam, Subeesh K.; Nagri, Shivashankara Kaniyoor; Miraj, Sonal Sekhar; Karanth, Shubhada

Association of serum ferritin with severity and clinical outcome in COVID-19 patients: An observational study in a tertiary healthcare facility

https://doi.org/10.1016/j.cegh.2023.101295

Published

1-May-23

Study

https://cegh.net/article/S2213-3984(23)00082-9/fulltext

Highlights
•Evidence show hyperferritinemia has been associated with higher disease severity and adverse clinical outcomes in COVID-19.
•Median ferritin levels were significantly high in moderate to severe COVID-19 infection compared to mild infection.
•Median ferritin levels were notably high in patients with COVID-19-related complications than those without complications.
•
Patients with more than 287.4 ng/ml ferritin value have greater chances of developing moderate to severe COVID-19 infections.
Abstract
Background
Ferritin, an intracellular protein, has a pivotal role in immune dysregulation. Hyperferritinemia has been associated with higher disease severity and adverse clinical outcomes in COVID-19, including mortality. We aimed to study the association of serum ferritin levels with disease severity and clinical outcomes and its severity prediction potential in COVID-19 patients.
Methods
This retrospective study included 870 adult patients with symptomatic COVID-19 infection hospitalized between July 1, 2020 to December 21, 2020. All the patients had a positive polymerase chain reaction test result of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Results
The median age was 55 (IQR:40, 65) years with a male predominance [66.32% (n = 577)], among 870 COVID-19. Of these, 413 (47.47%) had mild COVID-19, and 457 (52.53%) had moderate plus severe COVID-19 disease. Median ferritin levels were significantly high in moderate to severe COVID-19 infection compared to mild [545.8 (326.0, 1046.0) vs 97.3 (52.65–155.5) (p = 0.001)], and in patients who developed a complication compared to without complications [380 (177.05, 863.15) vs 290 (110.9, 635) (p = 0.002). A slight elevation in median ferritin levels was observed in patients who had an ICU stay than non-ICU [326 (129.8, 655) vs 309 (119.1, 684) (p = 0.872)]. The cut-off for ferritin was identified at >287.4 ng/ml for mild versus moderate plus severe COVID-19 infections.
Conclusion
Moderate to severe COVID-19 patients have elevated ferritin levels. Patients with more than 287.4 ng/ml ferritin value would have greater chances of developing moderate to severe COVID-19 infections.
publisher: Elsevier
PMID: 37012977

1528

I343

Santa Cruz, André; Mendes-Frias, Ana; Azarias-da-Silva, Marne; André, Sónia; Oliveira, Ana Isabel; Pires, Olga; Mendes, Marta; Oliveira, Bárbara; Braga, Marta; Lopes, Joana Rita; Domingues, Rui; Costa, Ricardo; Silva, Luís Neves; Matos, Ana Rita; Ângela, Cristina; Costa, Patrício; Carvalho, Alexandre; Capela, Carlos; Pedrosa, Jorge; Castro, António Gil; Estaquier, Jérôme; Silvestre, Ricardo

Post-acute sequelae of COVID-19 is characterized by diminished peripheral CD8+β7 integrin+ T cells and anti-SARS-CoV-2 IgA response

https://doi.org/10.1038/s41467-023-37368-1

Published

30-Mar-23

Study

https://www.nature.com/articles/s41467-023-37368-1

Several millions of individuals are estimated to develop post-acute sequelae SARS-CoV-2 condition (PASC) that persists for months after infection. Here we evaluate the immune response in convalescent individuals with PASC compared to convalescent asymptomatic and uninfected participants, six months following their COVID-19 diagnosis. Both convalescent asymptomatic and PASC cases are characterised by higher CD8+ T cell percentages, however, the proportion of blood CD8+ T cells expressing the mucosal homing receptor β7 is low in PASC patients. CD8 T cells show increased expression of PD-1, perforin and granzyme B in PASC, and the plasma levels of type I and type III (mucosal) interferons are elevated. The humoral response is characterized by higher levels of IgA against the N and S viral proteins, particularly in those individuals who had severe acute disease. Our results also show that consistently elevated levels of IL-6, IL-8/CXCL8 and IP-10/CXCL10 during acute disease increase the risk to develop PASC. In summary, our study indicates that PASC is defined by persisting immunological dysfunction as late as six months following SARS-CoV-2 infection, including alterations in mucosal immune parameters, redistribution of mucosal CD8+β7Integrin+ T cells and IgA, indicative of potential viral persistence and mucosal involvement in the etiopathology of PASC.

1529

I344

Fedorchenko, Yuliya; Zimba, Olena

Long COVID in autoimmune rheumatic diseases

https://doi.org/10.1007/s00296-023-05319-0

Published

30-Mar-23

Review

https://doi.org/10.1007/s00296-023-05319-0

Consequences of Corona Virus Disease-19 (COVID-19) in patients with rheumatic diseases (RDs) are clinically diverse. SARS-CoV-2 infection has been associated with various autoimmune and rheumatic manifestations over the past three years. Emerging evidence points to the possibility of Long COVID predisposition in rheumatic patients due to the changes in immune regulatory response. The aim of this article was to overview data on the pathobiology of Long COVID in patients with RDs. Related risk factors, clinical characteristics, and prognosis of Long COVID in RDs were analyzed. Relevant articles were retrieved from Medline/PubMed, Scopus, and Directory of Open Access Journals (DOAJ). Diverse mechanisms of viral persistence, chronic low-grade inflammation, lasting production of autoantibodies, endotheliopathy, vascular complications, and permanent tissue damage have been described in association with Long COVID. Patients with RDs who survive COVID-19 often experience severe complications due to the immune disbalance resulting in multiple organ damage. Regular monitoring and treatment are warranted in view of the accumulating evidence.

1530

I345

Hulme, John

COVID-19 and Diarylamidines: The Parasitic Connection

https://doi.org/10.3390/ijms24076583

Published

1-Jan-23

Review

https://www.mdpi.com/1422-0067/24/7/6583

As emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants (Omicron) continue to outpace and negate combinatorial vaccines and monoclonal antibody therapies targeting the spike protein (S) receptor binding domain (RBD), the appetite for developing similar COVID-19 treatments has significantly diminished, with the attention of the scientific community switching to long COVID treatments. However, treatments that reduce the risk of “post-COVID-19 syndrome” and associated sequelae remain in their infancy, particularly as no established criteria for diagnosis currently exist. Thus, alternative therapies that reduce infection and prevent the broad range of symptoms associated with ‘post-COVID-19 syndrome’ require investigation. This review begins with an overview of the parasitic–diarylamidine connection, followed by the renin-angiotensin system (RAS) and associated angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSSR2) involved in SARS-CoV-2 infection. Subsequently, the ability of diarylamidines to inhibit S-protein binding and various membrane serine proteases associated with SARS-CoV-2 and parasitic infections are discussed. Finally, the roles of diarylamidines (primarily DIZE) in vaccine efficacy, epigenetics, and the potential amelioration of long COVID sequelae are highlighted.

1531

I346

Sumantri, Stevent; Rengganis, Iris

Immunological dysfunction and mast cell activation syndrome in long COVID

https://doi.org/10.5415/apallergy.0000000000000022

Published

1-Mar-23

Review

https://journals.lww.com/apallergy/Fulltext/2023/03000/Immunological_dysfunction_and_mast_cell_activation.8.aspx

At least 65 million people around the world suffer from long COVID-19, with the majority of cases occurring in the productive age (36–50 years old). Individuals with long COVID-19 are confounded with multiple organ system dysfunctions, long-term organ injury sequelae, and a decreased quality of life. There is an overlapping of risk factors between long COVID-19 and other postviral infection syndromes, so advances in research could also benefit other groups of patients. Long COVID-19 is the consequence of multiple immune system dysregulation, such as T-cell depletion, innate immune cell hyperactivity, lack of naive T and B cells, and elevated signature of pro-inflammatory cytokines, together with persistent severe acute respiratory syndrome-coronavirus 2 reservoir and other consequences of acute infection. There is an activated condition of mast cells in long COVID-19, with abnormal granulation and excessive inflammatory cytokine release. A study by Weinstock et al. indicates that patients with long COVID-19 suffer the same clinical syndrome as patients with mast cell activation syndrome (MCAS). Diagnosis and treatment of MCAS in patients with long COVID-19 will provide further symptomatic relief, and manage mast cell-mediated hyperinflammation states, which could be useful in the long-term control and recovery of such patients.

1532

I347

Savchenko, Andrei A.; Kudryavtsev, Igor V.; Isakov, Dmitry V.; Sadowski, Ivan S.; Belenyuk, Vasily D.; Borisov, Alexandr G.

Recombinant Human Interleukin-2 Corrects NK Cell Phenotype and Functional Activity in Patients with Post-COVID Syndrome

https://doi.org/10.3390/ph16040537

Published

1-Apr-23

Study

https://www.mdpi.com/1424-8247/16/4/537

Post-COVID syndrome develops in 10–20% of people who have recovered from COVID-19 and it is characterized by impaired function of the nervous, cardiovascular, and immune systems. Previously, it was found that patients who recovered from infection with the SARS-CoV-2 virus had a decrease in the number and functional activity of NK cells. The aim of the study was to assess the effectiveness of recombinant human IL-2 (rhIL-2) administered to correct NK cell phenotype and functional activity in patients with post-COVID syndrome. Patients were examined after 3 months for acute COVID-19 of varying severity. The phenotype of the peripheral blood NK cells was studied by flow cytometry. It was found that disturbances in the cell subset composition in patients with post-COVID syndrome were characterized by low levels of mature (p = 0.001) and cytotoxic NK cells (p = 0.013), with increased release of immature NK cells (p = 0.023). Functional deficiency of NK cells in post-COVID syndrome was characterized by lowered cytotoxic activity due to the decreased count of CD57+ (p = 0.001) and CD8+ (p < 0.001) NK cells. In the treatment of patients with post-COVID syndrome with recombinant IL-2, peripheral blood NK cell count and functional potential were restored. In general, the effectiveness of using rhIL-2 in treatment of post-COVID syndrome has been proven in patients with low levels of NK cells.

1533

I348

Tannous, Jonika; Pan, Alan P.; Potter, Thomas; Bako, Abdulaziz T.; Dlouhy, Katharine; Drews, Ashley; Sostman, Henry Dirk; Vahidy, Farhaan S.

Real-world effectiveness of COVID-19 vaccines and anti-SARS-CoV-2 monoclonal antibodies against postacute sequelae of SARS-CoV-2: analysis of a COVID-19 observational registry for a diverse US metropolitan population

https://doi.org/10.1136/bmjopen-2022-067611

Published

1-Apr-23

Study

https://bmjopen.bmj.com/content/13/4/e067611

Objectives We evaluated the effectiveness of COVID-19 vaccines and monoclonal antibodies (mAbs) against postacute sequelae of SARS-CoV-2 infection (PASC).
Design and setting A retrospective cohort study using a COVID-19 specific, electronic medical record-based surveillance and outcomes registry from an eight-hospital tertiary hospital system in the Houston metropolitan area. Analyses were replicated across a global research network database.
Participants We identified adult (≥18) patients with PASC. PASC was defined as experiencing constitutional (palpitations, malaise/fatigue, headache) or systemic (sleep disorder, shortness of breath, mood/anxiety disorders, cough and cognitive impairment) symptoms beyond the 28-day postinfection period.
Statistical analysis We fit multivariable logistic regression models and report estimated likelihood of PASC associated with vaccination or mAb treatment as adjusted ORs with 95% CIs.
Results Primary analyses included 53 239 subjects (54.9% female), of whom 5929, 11.1% (95% CI 10.9% to 11.4%), experienced PASC. Both vaccinated breakthrough cases (vs unvaccinated) and mAb-treated patients (vs untreated) had lower likelihoods for developing PASC, aOR (95% CI): 0.58 (0.52–0.66), and 0.77 (0.69–0.86), respectively. Vaccination was associated with decreased odds of developing all constitutional and systemic symptoms except for taste and smell changes. For all symptoms, vaccination was associated with lower likelihood of experiencing PASC compared with mAb treatment. Replication analysis found identical frequency of PASC (11.2%, 95% CI 11.1 to 11.3) and similar protective effects against PASC for the COVID-19 vaccine: 0.25 (0.21–0.30) and mAb treatment: 0.62 (0.59–0.66).
Conclusion Although both COVID-19 vaccines and mAbs decreased the likelihood of PASC, vaccination remains the most effective tool for the prevention of long-term consequences of COVID-19.

1534

I349

Hansen, Cecilie Bo; Dvoncova, Kristina; Pérez-Alós, Laura; Fogh, Kamille; Madsen, Johannes Roth; Garred, Caroline Hartwell; Jarlhelt, Ida; Nielsen, Pernille Brok; Petersen, Steffan Svejgaard; Fjordager, Charlotte Gandsø; Lauritsen, Klara Tølbøll; Hilsted, Linda; Boding, Lasse; Iversen, Kasper Karmark; Hyveled, Liselotte; Garred, Peter

SARS-CoV-2 antibody dynamics over time and risk factors associated with infection and long COVID-19 symptoms in large working environments

https://doi.org/10.1111/joim.13637

Published

1-Apr-23

Study

https://doi.org/10.1111/joim.13637

BackgroundFactors influencing SARS-CoV-2 antibody dynamics, transmission, waning and long COVID-19 symptomatology are still not fully understood.MethodsIn the Danish section of the Novo Nordisk Group, we performed a prospective seroepidemiological study during the first and second waves of the COVID-19 pandemic. All employees and their household members (>18 years) were invited to participate in a baseline (June-August 2020), 6-month follow-up (December 2020-January 2021), and 12-month follow-up (August 2021) sampling. In total, 18,614 accepted and provided at least one blood sample and completed a questionnaire regarding socioeconomic background, health status, previous SARS-CoV-2 infection, and persistent symptoms. Total antibody and specific IgM, IgG and IgA levels against recombinant receptor binding domain were tested.ResultsAt baseline, the SARS-CoV-2-antibody seroprevalence was 3.9%. At 6-month follow-up, the seroprevalence was 9.1%, while at 12-month follow-up, the seroprevalence was 94.4% (after the vaccine roll-out). Male sex and younger age (18-40 years) were significant risk factors for seropositivity. From baseline to the 6-month sampling, we observed a substantial waning of IgM, IgG and IgA levels (p ConclusionThe study provides a comprehensive insight into SARS-CoV-2 antibody seroprevalence following infection and vaccination, waning, persistent COVID-19 symptomatology and risk factors for seropositivity in large working environments.

1535

I350

Sen, Parikshit; R, Naveen; Nune, Arvind; Day, Jessica; Joshi, Mrudula; Agarwal, Vikas; Aggarwal, Rohit; Gupta, Latika

Post-COVID-19 condition in patients with autoimmune rheumatic diseases: the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study

https://doi.org/10.1016/S2665-9913(23)00066-8

Published

1-May-23

Study

https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(23)00066-8/fulltext

Literature regarding post-COVID-19 condition in patients with autoimmune rheumatic diseases is scarce. One large, global study reported that post-COVID-19 condition developed in nearly one in ten people with systemic autoimmune rheumatic diseases and outlined the demographics of individuals with post-COVID-19 condition.6 Regional database studies have reported that belonging to a minority ethnic group, including Black and Hispanic, is a risk factor for post-COVID-19 condition—a finding that we could not replicate in our data. The presence of comorbidities has been more consistently identified as a risk factor for the condition in published reports.7, 8
Notably, in our analysis, patients with severe COVID-19 who required oxygen supplementation, intensive care, or advanced treatment appeared to be at higher risk of developing post-COVID-19 condition than patients who did not, which is consistent with data from a single-centre study.9 Our finding of poorer physical health outcomes in individuals who develop the condition further aligns with previous studies on long-term outcomes of COVID-19 (eg 10).
Our study is one of few to study risk factors for post-COVID-19 condition in patients with diverse rheumatic and non-rheumatic autoimmune diseases, including patients from understudied regions of Africa and South America. A strength of the study was the relatively high rate of completion of the survey (62%). The study also had limitations, including the self-reported nature of the questionnaire, which could result in recall and reporting bias, and underrepresentation of some groups because of convenience sampling. However, we have tried to minimise these limitations through the inclusion of patients from the outpatient clinics, the inclusion of control groups, and the analysis of stratified subsets. We did not confirm SARS-CoV-2 serology or vaccine immunogenicity, nor did we explore the full symptomatology, severity, and the duration of post-COVID-19 condition, which might be an avenue for future exploration. Given the limitations of screening for the condition with the WHO definition, caution is warranted in deriving strong conclusions in the absence of more well accepted diagnostic criteria. We studied risk factors for post-COVID-19 condition in a relatively small subgroup of patients with autoimmune rheumatic diseases, and additional characterisation of the condition and its risk factors in the general population is needed in larger-structured cohorts.
Our study provides information on risk factors for post-COVID-19 condition that might help to inform local guidelines. We found that individuals with autoimmune rheumatic diseases are at greater risk of developing post-COVID-19 condition than are healthy individuals. Associated comorbid conditions and advanced treatment or admission to an intensive care unit for severe COVID-19 confer a heightened risk of post-COVID-19 condition. Referring people with autoimmune rheumatic diseases and a recent SARS-CoV-2 infection for post-exposure treatment in a timely way is imperative, particularly in the presence of the identified risk factors, to facilitate close monitoring and multidisciplinary management in anticipation of poorer physical and mental outcomes.
publisher: Elsevier

1536

I351

Jarupan, Muttharat; Jantarabenjakul, Watsamon; Jaruampornpan, Peera; Subchartanan, Jarujan; Phasomsap, Chayapa; Sritammasiri, Taweesak; Cartledge, Sapphire; Suchartlikitwong, Pintip; Anugulruengkitt, Suvaporn; Kawichai, Surinda; Puthanakit, Thanyawee

Long COVID and Hybrid Immunity among Children and Adolescents Post-Delta Variant Infection in Thailand

https://doi.org/10.3390/vaccines11050884

Published

1-May-23

Study

https://www.mdpi.com/2076-393X/11/5/884

This study aimed to assess long COVID, and describe immunogenicity against Omicron variants following BNT162b2 vaccination. A prospective cohort study was conducted among children (aged 5–11) and adolescents (aged 12–17) who had SARS-CoV-2 infection from July to December 2021 (Delta predominant period). Long COVID symptoms were assessed by questionnaires at 3 months after infection. Immunogenicity was evaluated by using a surrogate virus-neutralizing antibody test (sVNT) against the Omicron variant. We enrolled 97 children and 57 adolescents. At 3 months, 30 children (31%) and 34 adolescents (60%) reported at least one long COVID symptom, with respiratory symptoms prevailing (25% children and 32% adolescents). The median time from infection to vaccination was 3 months in adolescents and 7 months in children. At 1 month following vaccination, in children who received one-dose and two-dose BNT162b2 vaccines, the median (IQR) sVNT against Omicron was 86.2% inhibition (71.1–91.8) and 79.2% inhibition (61.5–88.9), respectively (p = 0.26). Among adolescents who received one-dose and two-dose BNT162b2 vaccines, the median (IQR) sVNT against Omicron was 64.4% inhibition (46.8–88.8) and 68.8% inhibition (65.0–91.2) (p = 0.64). Adolescents had a higher prevalence of long COVID than children. Immunogenicity against the Omicron variant after vaccination was high and did not vary between one or two doses of the vaccine in either children or adolescents.

1537

I352

Price, Jillian Kallman; Gerber, Lynn H.; Stepanova, Maria; Avila, Leyla de; Weinstein, Ali A.; Pham, Huong; Nader, Fatema; Afendy, Mariam; Terra, Kathy; Austin, Patrick; Keo, Wisna’odom; Racila, Andrei; Estep, James Michael; Gerber, Suzannah; Verma, Manisha; Golabi, Pegah; Lam, Brian P.; Younossi, Zobair

Post-Acute SARS-CoV-2 Symptoms are Fewer, Less Intense Over Time in People Treated with Mono-Clonal Antibodies for Acute Infection

https://doi.org/10.2147/IJGM.S406571

Published

24-Apr-23

Study

https://www.dovepress.com/post-acute-sars-cov-2-symptoms-are-fewer-less-intense-over-time-in-peo-peer-reviewed-fulltext-article-IJGM

Introduction: Many with post-acute SARS-CoV-2 (PASC) have persistent symptoms impacting physical and cognitive function, decreased health and health-related life quality. Monoclonal antibody (mAb) treatment was available to acutely infected patients which might improve these outcomes.
Purpose: To compare patient perception of PASC symptoms for those receiving bamlanivimab or casirivimab and imdevimab (mAbs) to those not receiving this treatment (non-mAbs). To compare changes between these groups in symptoms, function and quality of life over a 6-month follow-up.
Patients and Methods: Consented adults > 28 days post-infection with positive SARS-CoV-2 qPCR or antigen test and SARS-CoV-2 infection between March of 2020 and July of 2022 were enrolled. This prospective, repeated measure observational study reports baseline through 6-month follow-up. Extensive sociodemographic data, detailed medical history, COVID-19 symptom history, and standardized measures of well-being, depression, anxiety, stigma, cognition, symptom assessment, distress, and health status were collected.
Results: 323 participants [101 mAb, 221 non-mAb, 52.7± 15.5 years, 47.7% male, body mass index (BMI) 31.4± 8.4] were analyzed. Fewer symptoms at baseline were reported in mAb versus non-mAb participants (1.06± 1.31 vs 1.78± 2.15, respectively p=0.0177) 6 months: (0.911± 1.276 mAb vs.1.75± 2.22 non-mAb, p=0.0427). Both groups showed significant within-group decreases in symptom number (52 to 21 mAb, 126 to 63 non-mAb) and symptom burden (p=0.0088 mAb, p< 0.00001 non-mAb). mAb patients had significantly shorter infection-to-baseline interval (days) (120.4± 55.3 mAb vs 194.0± 89.3 non-mAb, p< 0.00001); less frequent history of myocardial infarction (0.0 vs 3.9%, p=0.0464); headache (2.0% vs.11.8%, p=0.0046), rash (3.1% vs 9.9%, p=0.0377), and miscellaneous muscle complaints (2.0% vs 12.3%, p=0.0035), plus significantly better 6-month mood. (2.2% vs 13.2%, p=0.0390).
Conclusion: mAb treated participants had reduced symptom burden and consistently reported fewer symptoms than non-mAb at all time points despite less time since acute illness. Both groups reported a statistically significant decrease in symptoms by 6-month visit with no statistically significant differences between them at follow-up.
publisher: Dove Press

1538

I353

Yin, Jing-Xian; Agbana, Yannick Luther; Sun, Zhi-Shan; Fei, Si-Wei; Zhao, Han-Qing; Zhou, Xiao-Nong; Chen, Jun-Hu; Kassegne, Kokouvi

Increased interleukin-6 is associated with long COVID-19: a systematic review and meta-analysis

https://doi.org/10.1186/s40249-023-01086-z

Published

24-Apr-23

Review

https://doi.org/10.1186/s40249-023-01086-z

Background
Coronavirus disease 2019 (COVID-19) can involve persistence, sequelae, and other clinical complications that last weeks to months to evolve into long COVID-19. Exploratory studies have suggested that interleukin-6 (IL-6) is related to COVID-19; however, the correlation between IL-6 and long COVID-19 is unknown. We designed a systematic review and meta-analysis to assess the relationship between IL-6 levels and long COVID-19.

Methods
Databases were systematically searched for articles with data on long COVID-19 and IL-6 levels published before September 2022. A total of 22 published studies were eligible for inclusion following the PRISMA guidelines. Analysis of data was undertaken by using Cochran's Q test and the Higgins I-squared (I2) statistic for heterogeneity. Random-effect meta-analyses were conducted to pool the IL-6 levels of long COVID-19 patients and to compare the differences in IL-6 levels among the long COVID-19, healthy, non-postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (non-PASC), and acute COVID-19 populations. The funnel plot and Egger's test were used to assess potential publication bias. Sensitivity analysis was used to test the stability of the results.

Results
An increase in IL-6 levels was observed after SARS-CoV-2 infection. The pooled estimate of IL-6 revealed a mean value of 20.92 pg/ml (95% CI = 9.30–32.54 pg/ml, I2 = 100%, P < 0.01) for long COVID-19 patients. The forest plot showed high levels of IL-6 for long COVID-19 compared with healthy controls (mean difference = 9.75 pg/ml, 95% CI = 5.75–13.75 pg/ml, I2 = 100%, P < 0.00001) and PASC category (mean difference = 3.32 pg/ml, 95% CI = 0.22–6.42 pg/ml, I2 = 88%, P = 0.04). The symmetry of the funnel plots was not obvious, and Egger’s test showed that there was no significant small study effect in all groups.

Conclusions
This study showed that increased IL-6 correlates with long COVID-19. Such an informative revelation suggests IL-6 as a basic determinant to predict long COVID-19 or at least inform on the “early stage” of long COVID-19.

1539

I354

Chen, Yi-Chen; Ho, Chung-Han; Liu, Ting-Hui; Wu, Jheng-Yan; Huang, Po-Yu; Tsai, Ya-Wen; Lai, Chih-Cheng

Long-term risk of herpes zoster following COVID-19: A retrospective cohort study of 2 442 686 patients

https://doi.org/10.1002/jmv.28745

Published

18-Apr-23

Study

https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.28745

The long-term risk of herpes zoster (HZ) after recovery from a SARS-CoV-2 infection is unclear. This retrospective cohort study assessed the risk of HZ in patients following a COVID-19 diagnosis. This retrospective, propensity score-matched cohort study was based on the multi-institutional research network TriNetX. The risk of incident HZ in patients with COVID-19 was compared with that of those not infected with SARS-CoV-2 during a 1-year follow-up period. Hazard ratios (HRs) and 95% confidence intervals (CIs) of HZ and its subtypes were calculated. This study identified 1 221 343 patients with and without COVID-19 diagnoses with matched baseline characteristics. During the 1-year follow-up period, patients with COVID-19 had a higher risk of HZ compared with those without COVID-19 (HR: 1.59; 95% CI: 1.49–1.69). In addition, compared with the control group patients, those with COVID-19 had a higher risk of HZ ophthalmicus (HR: 1.31; 95% CI: 1.01–1.71), disseminated zoster (HR: 2.80; 95% CI: 1.37–5.74), zoster with other complications (HR: 1.46; 95% CI: 1.18–1.79), and zoster without complications (HR: 1.66; 95% CI: 1.55–1.77). Kaplan–Meier curve analysis (log-rank p < 0.05) results indicated that the risk of HZ remained significantly higher in patients with COVID-19 compared with those without COVID-19. Finally, the higher risk of HZ in the COVID-19 cohort compared with that in the non-COVID-19 cohort remained consistent across subgroup analyses regardless of vaccine status, age, or sex. The risk of HZ within a 12-month follow-up period was significantly higher in patients who had recovered from COVID-19 compared with that in the control group. This result highlights the importance of carefully monitoring HZ in this population and suggests the potential benefit of the HZ vaccine for patients with COVID-19.

1540

I355

Basaran, M. Mert; Hazar, Merve; Aydın, Mehtap; Uzuğ, Gülsüm; Özdoğan, İlkima; Pala, Emin; Aydın Dilsiz, Sevtap; Basaran, Nursen

Effects of COVID-19 Disease on DNA Damage, Oxidative Stress and Immune Responses

https://doi.org/10.3390/toxics11040386

Published

1-Apr-23

Study

https://www.mdpi.com/2305-6304/11/4/386

Coronavirus disease 2019 (COVID-19) has posed a great threat to public health and has caused concern due to its fatal consequences over the last few years. Most people with COVID-19 show mild-to-moderate symptoms and recover without the need for special treatment, while others become seriously ill and need medical attention. Additionally, some serious outcomes, such as heart attacks and even stroke, have been later reported in patients who had recovered. There are limited studies on how SARS-CoV-2 infection affects some molecular pathways, including oxidative stress and DNA damage. In this study, we aimed to evaluate DNA damage, using the alkaline comet assay, and its relationship with oxidative stress and immune response parameters in COVID-19-positive patients. Our results show that DNA damage, oxidative stress parameters and cytokine levels significantly increased in SARS-CoV-2-positive patients when compared with healthy controls. The effects of SARS-CoV-2 infection on DNA damage, oxidative stress and immune responses may be crucial in the pathophysiology of the disease. It is suggested that the illumination of these pathways will contribute to the development of clinical treatments and to reduce adverse effects in the future.

1541

I356

Goetzl, Edward J.; Yao, Pamela J.; Kapogiannis, Dimitrios

Prediction of Post-Acute-Sequelae of COVID-19 by Cargo Protein Biomarkers of Blood Total Extracellular Vesicles in Acute COVID-19

https://doi.org/10.1016/j.amjmed.2023.03.026

Published

17-Apr-23

Study

https://www.sciencedirect.com/science/article/pii/S0002934323002589

Background
SARS-CoV-2 invades mitochondria of infected cells resulting in disordered metabolism, mitophagy and abnormal levels of mitochondrial proteins in extracellular vesicles. Blood extracellular vesicle SARS-CoV-2 proteins and mitochondrial proteins were quantified in COVID-19 to assess possible roles as biomarkers.
Methods
Total extracellular vesicles were precipitated from blood of age- and gender-matched participants with no infection (n=10), acute COVID-19 (n=16), post-acute sequelae of COVID-19 (PASC or long-COVID) (n=30) or post-acute COVID without PASC (n=8) and their extracted proteins quantified by enzyme-linked immunosorbent assays (ELISAs).
Results
Total extracellular vesicle levels of S1(RBD) protein were significantly higher in acute infections than in uninfected controls, post-acute infection without PASC and PASC. Total extracellular vesicle levels of N protein were significantly higher in PASC than in uninfected controls, acute infections and post-acute infection without PASC. Neither acute levels of S1(RBD) or N proteins predicted progression to PASC. Levels of neither SARS-CoV-2 protein in established PASC correlated with neuropsychiatric manifestations. Significant decreases in total extracellular vesicle levels of the mitochondrial proteins MOTS-c, VDAC-1 and humanin, as well as elevations of levels of SARM-1, were observed in acutely infected patients who would develop PASC. Significant decreases in total extracellular vesicle levels of MOTS-c and humanin, but not VDAC-1, as well as elevations of total extracellular vesicle levels of SARM-1, were characteristic of PASC patients with neuropsychiatric manifestations.
Conclusions
Total extracellular vesicle levels of SARS-CoV-2 proteins in COVID-19 indicate intracellular presence of SARS-CoV-2. Abnormal total extracellular vesicles levels of mitochondrial proteins in acute infections predict a high risk of PASC and later in established PASC are indicative of neuropsychiatric manifestations.

1542

I357

Ren, Zhigang; Liu, Shanshuo; Wang, Qiong; Rao, Benchen; Zeng, Zhaohai; Xu, Yakun; Wang, Haiyu; Luo, Hong; Gou, Jianjun; Yu, Zujiang

Alterations of the oral and gut mycobiome and cytokines during long-term follow-up of COVID-19 convalescents

https://doi.org/10.1038/s41392-023-01417-4

Published

17-Apr-23

Study

https://www.nature.com/articles/s41392-023-01417-4

A large number of COVID-19 patients experience body-specific conditions such as fatigue, sleep disturbances, anxiety, depression, and dyspnea after the disease has subsided, which is called “long COVID-19”.1 Studies have confirmed reduced microbial diversity, enrichment of opportunistic pathogens and depletion of beneficial symbiotic bacteria in patients with COVID-19.2,3 Long-term dysregulation of the microbiota has also been observed in recovered patients.4 Nevertheless, long-term fungal microbiota follow-up was still blank. The microecology is closely associated with altered immune status and physical health and may be a potential cause of symptoms. We collected tongue coating, feces, and serum samples from 35 COVID-19 confirmed patients who were recovery (CPR0) and followed up for 1 year (CPR1) and 90 age- and sex-matched healthy controls (HC) for internal transcribed spacer (ITS) sequencing (Supplementary Fig. 1, Supplementary Table S1). The blood routine, liver and kidney function, and cytokines of CPR1 and HC were all within the normal range, but a few indicators were different, and most of them in the HC group were lower (Supplementary Tables S2–3).

During COVID-19 recovery, the α diversity of oral (Fig. 1a) and fecal (Fig. 1b) fungal microbiota increased to varying degrees, but did not fully return to normal levels after 1 year. The Venn diagram indicated the shared and unique operational taxonomy units (OTUs) between the three groups (Fig. 1c, d). In the β diversity analysis, non-metric multidimensional scale (NMDS) analysis and principal coordinate analysis (PCoA) revealed that the oral (Fig. 1e, f) and fecal (Fig. 1g, h) fungal microbiota of CPR1 group was between CPR0 and HC, and tended to converge to the latter, and the difference between groups was statistically significant.

Fig. 1
figure 1
Alterations of the oral and gut mycobiome and cytokines of COVID-19 convalescents after 1-year follow-up. a As estimated by the Shannon index, the α diversity of oral mycobiome gradually increased. b As estimated by the Simpson index, the α diversity of gut mycobiome gradually increased. c With a total of 2912 OTUs found and 271 OTUs shared between the three groups in oral, the HC group had 1560 unique OTUs, significantly higher than the CPR0 and CPR1 groups. d 631 OTUs of a total of 6811 OTUs were shared between the three groups, while 5021 OTUs appeared only in the HC group. The NMDS (e) and PCoA (f) analysis indicated the oral fungal taxonomic composition was conspicuously different in the three groups, and CPR1 gradually approached HC. The NMDS (g) and PCoA (h) analysis showed the gut fungal taxonomic composition was conspicuously different in the three groups, and CPR1 gradually approached HC. Composition of gut mycobiome at the phylum (i) and genus (j) levels in different groups. Comparison of fecal mycobiome at the phylum (k), genus (l) and species (m) levels among three groups. (n) Compared with the CPR0-H group, the POD value of the CPR0-L group in tongue coating samples increased significantly and achieved great diagnostic results in the training set, with an AUC value of 0.8095 (o) (P < 0.05). p Compared with the CPR0-H group, the POD value of the CPR0-L group in fecal samples increased significantly and achieved great diagnostic results in the training set, with an AUC value of 0.9667 (q) (P < 0.05). r Gradual recovery of the cytokines among three groups. OTUs operational taxonomy units; HC healthy controls, CPR0 confirmed patients recover at discharge, CPR1 confirmed patients recover 1 year, NMDS non-metric multidimensional scale analysis, PCoA principal coordinate analysis, POD probability of disease, AUC area under the curve. Data were represented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001. ns not significant

Full size image
When analyzing the average composition and comparison of oral and fecal fungal microbiome at different levels (Supplementary Data S1–10), we found that the dominant phylum of oral and fecal fungi was the same, which were Ascomycota, Basidiomycota and Mucoromycota (Fig. 1i). At the genus level, Zanclospora, Aspergillus, Acrodictys, Entorrhiza and Candida were co-dominant genera, Malassezia, Actinomucor, Cladosporium and Blumeria were more abundant in the oral cavity, and Ascomycota_gen_Incertae_ Sedis and Saccharomyces were more abundant in feces (Fig. 1j). In the between-group differential fungal analysis at the phylum level, the abundance of Ascomycota in the oral cavity gradually increased and Mucoromycota in feces (Fig. 1k) gradually decreased during disease recovery. At the genus level, there were 21 genera in oral cavity and 11 genera in feces gradually increased, while 8 genera in oral cavity and 11 genera in feces (Fig. 1l) gradually decreased. Tuber, Chrysosphaeria, and Angustimassarina gradually increased in abundance in both environments, while Actinomucor, Rhodotorula, and Micor decreased. At the species level, the abundance of 25 species in the oral cavity and 13 species in the feces gradually increased, and the abundance of 13 species in oral cavity and 13 species in feces (Fig. 1m) gradually decreased. The heatmap can visualize the abundance of different OTUs between three groups of fungal microbes during disease recovery (Supplementary Fig. 2).

Linear discriminant analysis (LDA) effect size (LEfSe) was used to compare the phylogenetic distribution of fungal microorganisms in three groups. We set LDA score (log10)>3 to select differential species, and compared with CPR0 and HC, the number of species significantly enriched in tongue samples in CPR1 was the smallest. Nevertheless, the CPR0 group had the largest number of species significantly enriched in fecal samples, more than the CPR1 group and HC group. Interestingly, we found that the CPR0 group had Dipodascus, Candida, Rhodotorula, Mucor, Cladosporium and Actinomucor as the dominant fungi in both tongue and fecal samples (Supplementary Data S11–12). Candida causes opportunistic infections when immunocompromised and is the most cited COVID-19-associated fungal infections. Cladosporium infections can develop into diseases such as pneumonia if not treated promptly. The MetaCyc database was used to determine possible enrichment pathways for fungal influences on COVID-19. We found that oral and fecal fungi were enriched in tryptophan degradation, guanosine nucleotides degradation, pantothenate and coenzyme A biosynthesis, and sucrose biosynthesis in CPR0 group. Nevertheless, guanosine nucleotides biosynthesis was observed in feces in the CPR1 group. We also found that the amino acid and nucleotide degradation pathways were more enriched in the CPR0 group, while the synthesis pathways were more obvious in the CPR1 group, which was like that in the HC group (Supplementary Data S13–14).

We selected patients with complete clinical information and samples from both CPR0 and CPR1 to establish the prediction model, and finally included 16 patients who provided oral samples and 11 patients who provided fecal samples. After 1-year follow-up, neutralizing antibody inhibition rates below 70% were classified as CPR0-L group, and those above 70% were divided to CPR0-H group. Subsequently, a random forest model was constructed and a five-fold cross-validation was carried out. Finally, 3 oral fungal biomarkers and 18 fecal fungal biomarkers were determined (Supplementary Data S15–16). The probability of disease (POD) index of the CPR0-L group was significantly higher than that of the CPR0-H group in both samples (Fig. 1n, p). The area under the curve (AUC) of the oral prediction model was 0.8095 (95% CI: 0.5261-1, P = 0.0418) (Fig. 1o) and the AUC of the fecal prediction model was 0.9667 (95% CI: 0.8743-1, P = 0.0087) (Fig. 1q).

Most cytokines, such as IL-1b, MIP-3a, IL-5, and IL-10, tended to decline during disease recovery, while IL-8 concentrations gradually increased (Fig. 1r, Supplementary Data S17). To explore the relationship between fungal flora and immunity during COVID-19 recovery, key oral and fecal fungi and cytokines that showed increasing or decreasing trend among CPR0, CPR1 and HC with statistical difference were selected for Spearman correlation analysis (Supplementary Table S3). In the association analysis between 37 oral OTUs, 23 fecal OTUs and 11 cytokines (Supplementary Fig. 3), IL-8 and MIP-1b were negatively correlated with other cytokines, and were negatively correlated with OTU5, OTU50, OTU67, OTU119, OTU157 in oral fungal microorganisms and OTU5, OTU19, OTU29, OTU69, OTU8088 in fecal fungal microorganisms. In the association analysis of 18 oral fungal OTUs and 8 fecal fungal OTUs with 10 clinical indicators, we found that neutralizing antibody and IgG were negatively correlated with monocytes and total bile acids, and positively correlated with albumin. In addition, OTU5 in oral fungal microorganisms was positively correlated with SARS-CoV-2 binding IgG and IgM during disease recovery. In the association analysis of fungi and bacteria, we found that OTU4, OTU12, OTU19, OTU69, OTU5910 in fecal fungi were negatively correlated with key bacteria (Supplementary Data S18–20). This confirmed that bacteria in the gastrointestinal tract may limit fungal colonization and invasion.

In this study, we reported for the first time that oral and gut fungal microbiome diversity was restored 1 year after discharge from COVID-19 patients, and cytokine concentrations associated with inflammatory storms were gradually reduced. Moreover, the CPR1 neutralizing antibody prediction models based on oral and intestinal fungal flora obtained excellent prediction effects. Spearman correlation analysis also showed significant correlations between oral fungi and bacteria, fecal fungi and bacteria, cytokines, and clinical indicators. However, there are certain shortcomings in this study. Although the predictive model achieves high efficiency, the sample size is small, and large sample validation is required before clinical practice. In addition, the study is observational and requires more in-depth design experiments to validate the findings.

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Allan-Blitz, Lao-Tzu; Akbari, Omid; Kojima, Noah; Saavedra, Edwyn; Chellamuthu, Prithivi; Denny, Nicholas; MacMullan, Melanie A.; Hess, Victoria; Shacreaw, Maria; Brobeck, Matthew; Turner, Frederick; Slepnev, Vladimir I.; Ibrayeva, Albina; Klausner, Jeffrey D.

Unique immune and inflammatory cytokine profiles may define long COVID syndrome

https://doi.org/10.1007/s10238-023-01065-6

Published

16-Apr-23

Study

https://doi.org/10.1007/s10238-023-01065-6

Purpose
Long COVID is estimated to occur in 5–10% of individuals after acute SARS-CoV-2 infection. However, the pathophysiology driving the disease process is poorly understood.

Methods
We evaluated urine and plasma inflammatory and immune cytokine profiles in 33 individuals with long COVID compared to 33 who were asymptomatic and recovered, and 34 without prior infection.

Results
Mean urinary leukotriene E4 was significantly elevated among individuals with long COVID compared to asymptomatic and recovered individuals (mean difference 774.2 pg/mL; SD 335.7) and individuals without prior SARS-CoV-2 infection (mean difference 503.1 pg/ml; SD 467.7). Plasma chemokine ligand 6 levels were elevated among individuals with long COVID compared to individuals with no prior SARS-CoV-2 infection (mean difference 0.59 units; SD 0.42). We found no significant difference in angiotensin-converting enzyme 2 antibody levels. Plasma tumor necrosis factor receptor-associated factor 2 (TRAF2) levels were reduced among individuals with long COVID compared to individuals who were asymptomatic and recovered (mean difference = 0.6 units, SD 0.46). Similarly, the mean level of Sarcoma Homology 2-B adapter protein 3 was 3.3 units (SD 1.24) among individuals with long COVID, lower than 4.2 units (SD 1.1) among individuals with recovered, asymptomatic COVID.

Conclusion
Our findings suggest that further studies should be conducted to evaluate the role of leukotriene E4 as a potential biomarker for a diagnostic test. Furthermore, based on reductions in TRAF2, long COVID may be driven in part by impaired TRAF2-dependent immune-mediated inflammation and potentially immune exhaustion.

1544

I359

Fudge, Jared B.

Long COVID immune phenotypes identified for blockade

https://doi.org/10.1038/s41587-023-01765-0

Published

1-Apr-23

Article

https://www.nature.com/articles/s41587-023-01765-0

Symptoms of severe long COVID may include lung fibrosis, and a precise, detailed profile of associated immunopathology has been missing until now. Writing in Proceedings of the National Academy of Sciences USA, Cui et al. use published single-cell transcriptomics data from human lung-tissue samples to explore the onset of fibrosis, alongside a new humanized mouse model for long COVID. A series of unique immune hallmarks serve as a basis to investigate potential therapeutic strategies for the ever-growing cohort of patients with long COVID.

Leukocytes and pulmonary fibroblasts from patients with long COVID had unique gene-expression profiles compared to those from healthy, matched control individuals. Pathways related to the pro-inflammatory cytokine and anti-inflammatory myokine interleukin-6 (IL-6) were upregulated in alveolar macrophages from these patients, consistent with previous reports of cytokine storms. Neutrophils and lung fibroblasts were enriched for profibrotic pathways and associated with increased deposition of extracellular matrix proteins. Immunofluorescence assays validated the enrichment of proteins involved in innate immune activation and profibrosis pathways in lung tissue from patients with long COVID, probably mediated by the transcription factor JUN.

Next, the authors developed a humanized mouse model of SARS-CoV-2 infection. Fibrosis symptoms appeared in 75% of treated mice four weeks after exposure. Neutrophil and macrophage recruitment further recapitulated patient pathology in the mouse model. Treatments using anti-IL-6 and anti-CD47 antibodies were administered for two weeks, and this was sufficient to restore lung morphology, reduce fibrosis and ameliorate recruitment of neutrophils and macrophages to the affected tissue.

This study pinpoints the role of fibrosis and inflammation pathways in initial long-COVID pathology and offers clinical targets related to the innate immune response.
number: 4
publisher: Nature Publishing Group

1545

I360

Guiot, Julien; Henket, Monique; Remacle, Claire; Cambier, Maureen; Struman, Ingrid; Winandy, Marie; Moermans, Catherine; Louis, Edouard; Malaise, Michel; Ribbens, Clio; Louis, Renaud; Njock, Makon-Sébastien

Systematic review of overlapping microRNA patterns in COVID-19 and idiopathic pulmonary fibrosis

https://doi.org/10.1186/s12931-023-02413-6

Published

15-Apr-23

Review

https://doi.org/10.1186/s12931-023-02413-6

Background
Pulmonary fibrosis is an emerging complication of SARS-CoV-2 infection. In this study, we speculate that patients with COVID-19 and idiopathic pulmonary fibrosis (IPF) may share aberrant expressed microRNAs (miRNAs) associated to the progression of lung fibrosis.

Objective
To identify miRNAs presenting similar alteration in COVID-19 and IPF, and describe their impact on fibrogenesis.

Methods
A systematic review of the literature published between 2010 and January 2022 (PROSPERO, CRD42022341016) was conducted using the key words (COVID-19 OR SARS-CoV-2) AND (microRNA OR miRNA) or (idiopathic pulmonary fibrosis OR IPF) AND (microRNA OR miRNA) in Title/Abstract.

Results
Of the 1988 references considered, 70 original articles were appropriate for data extraction: 27 studies focused on miRNAs in COVID-19, and 43 on miRNAs in IPF. 34 miRNAs were overlapping in COVID-19 and IPF, 7 miRNAs presenting an upregulation (miR-19a-3p, miR-200c-3p, miR-21-5p, miR-145-5p, miR-199a-5p, miR-23b and miR-424) and 9 miRNAs a downregulation (miR-17-5p, miR-20a-5p, miR-92a-3p, miR-141-3p, miR-16-5p, miR-142-5p, miR-486-5p, miR-708-3p and miR-150-5p).

Conclusion
Several studies reported elevated levels of profibrotic miRNAs in COVID-19 context. In addition, the balance of antifibrotic miRNAs responsible of the modulation of fibrotic processes is impaired in COVID-19. This evidence suggests that the deregulation of fibrotic-related miRNAs participates in the development of fibrotic lesions in the lung of post-COVID-19 patients.

What is already known on this topic
An emerging complications of SARS-CoV-2 infection is pulmonary fibrosis. In this study, we speculate that patients with COVID-19 and idiopathic pulmonary fibrosis (IPF) may share aberrant expressed miRNAs associated to the progression of lung fibrosis.

What this study adds
This is the first review to identify miRNAs presenting similar alteration in COVID-19 and IPF. Interestingly, these miRNAs are key regulators of fibrosis processes. The deregulation of these fibrotic-related miRNAs may participate in the development of fibrotic lesions in the lung of post-COVID-19 patients.

How this study might affect research, practice or policy
The study of these miRNAs may help to decipher molecular pathways involved in the development of lung fibrosis in post-COVID-19 patients.

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I361

di Filippo, Luigi; Frara, Stefano; Nannipieri, Fabrizio; Cotellessa, Alice; Locatelli, Massimo; Rovere Querini, Patrizia; Giustina, Andrea

Low Vitamin D Levels Are Associated With Long COVID Syndrome in COVID-19 Survivors

https://doi.org/10.1210/clinem/dgad207

Published

13-Apr-23

Study

https://doi.org/10.1210/clinem/dgad207

Context
Long COVID is an emerging syndrome affecting 50% to 70% of COVID-19 survivors that still lacks predicting factors.

Objective
Due to the extraskeletal effects of vitamin D, we retrospectively assessed the association between 25(OH) vitamin D levels and long COVID in COVID-19 survivors 6 months after hospitalization.

Methods
Long COVID was defined according to NICE guidelines. Fifty long COVID and 50 non–long-COVID subjects matched on a 1:1 basis were enrolled from an outpatient clinic post-COVID cohort seen from August to November 2020. Therapies/comorbidities affecting calcium/vitamin D/bone metabolism, and/or admission to the intensive care unit during hospitalization were exclusion criteria. 25(OH) Vitamin D was measured at hospital admission and 6 months after discharge.

Results
We observed lower 25(OH) vitamin D levels, evaluated at follow-up, in subjects with long COVID than those without (20.1 vs 23.2 ng/mL, P = .03). Regarding the affected health areas evaluated in the entire cohort, we observed lower 25(OH) vitamin D levels in those with neurocognitive symptoms at follow-up (n = 7) than those without (n = 93) (14.6 vs 20.6 ng/mL, P = .042). In patients presenting vitamin D deficiency (<20 ng/mL), both at admission and at follow-up (n = 42), those affected by long COVID (n = 22) presented lower 25(OH) vitamin D levels at follow-up than those not affected (n = 20) (12.7 vs 15.2 ng/mL, P = .041). In multiple regression analyses, lower 25(OH) vitamin D levels at follow-up were the only variable significantly associated with long COVID in our cohort (P = .008, OR 1.09, CI 1.01-1.16).

Conclusion
COVID-19 survivors with long COVID have lower 25(OH) vitamin D levels than matched patients without long COVID. Our data suggest that vitamin D levels should be evaluated in COVID-19 patients after hospital discharge. The role of vitamin D supplementation as a preventive strategy of COVID-19 sequelae should be tested in randomized controlled trials.

1547

I362

Nguyen, Nhu Ngoc; Nguyen, Y. Ngoc; Hoang, Van Thuan; Million, Matthieu; Gautret, Philippe

SARS-CoV-2 Reinfection and Severity of the Disease: A Systematic Review and Meta-Analysis

https://doi.org/10.3390/v15040967

Published

1-Apr-23

Systematic review and meta-analysis

https://www.mdpi.com/1999-4915/15/4/967

Since the discovery of SARS-CoV-2, changes in genotype and reinfection with different variants have been observed in COVID-19-recovered patients, raising questions around the clinical pattern and severity of primary infection and reinfection. In this systematic review, we summarize the results of 23 studies addressing SARS-CoV-2 reinfections. A total of 23,231 reinfected patients were included, with pooled estimated reinfection rates ranging from 0.1 to 6.8%. Reinfections were more prevalent during the Omicron variant period. The mean age of reinfected patients was 38.0 ± 6. years and females were predominant among reinfected patients (M/F = 0.8). The most common symptoms during the first and second infection were fever (41.1%), cough (35.7% and 44.6%), myalgia (34.5% and 33.3%), fatigue (23.8% and 25.6%), and headaches (24.4% and 21.4%). No significant differences of clinical pattern were observed between primary infection and reinfection. No significant differences in the severity of infection were observed between primary infection and reinfection. Being female, being a patient with comorbidities, lacking anti-nucleocapsid IgG after the first infection, being infected during the Delta and Omicron wave, and being unvaccinated were associated with a higher risk of reinfection. Conflicting age-related findings were found in two studies. Reinfection with SARS-CoV-2 suggests that natural immunity is not long-lasting in COVID-19 patients.

1548

I363

Liang, Weifeng; Gu, Ming; Zhu, Lingxiang; Yan, Ziqi; Schenten, Dominik; Herrick, Shelby; Li, Hongmin; Samrat, Subodh Kumar; Zhu, Jiapeng; Chen, Yin

The main protease of SARS-CoV-2 downregulates innate immunity via a translational repression

https://doi.org/10.1038/s41392-023-01418-3

Published

13-Apr-23

Study

https://www.nature.com/articles/s41392-023-01418-3

SARS-CoV-2 is the etiological cause of COVID-19. RIG-I-like receptor (RLR) signaling pathway appeared to be responsible for SARS-CoV-2 induced IFN,1 a major antiviral pathway. IFN deficiency2,3 was identified to be a significant risk factor of severe COVID-19, highlighting an important role of IFN in the defense against SARS-CoV-2 and in the pathogenesis of severe COVID-19. Since SARS-CoV-2 is highly susceptible to IFN treatment,3,4 it has to evade host IFN-mediated immune surveillance to establish an active infection,

To identify viral regulators of IFN, we designed a screening strategy, in which MAVS, the common adaptor protein, was overexpressed to initiate the downstream IFN signaling. Each viral protein encoded by SARS-CoV-2 was introduced into the system to examine its effect on MAVS-IFN signaling. We found that NSP5, the main protease of SARS-CoV-2, is among the five viral proteins (NSP1, 3, 5, ORF6, and 8) that significantly repressed MAVS-IFN (Supplementary Fig. 1a). In contrast, NSP5 (C145A), an enzymatic inactive NSP5, could not inhibit MAVS-induced ISRE reporter activity (Supplementary Fig. 1b). Furthermore, NSP5 was able to inhibit IFN promoter reporter (PRDIII) and this inhibition was mostly restored by a protease inhibitor of NSP5 (GC376) (Supplementary Fig. 1c). Next, we extended the study of reporter assay (Supplementary Fig. 1) to cellular RLR signaling pathway. MAVS overexpression induced MAVS aggregation (a pre-requisite for MAVS activation) and STAT1 phosphorylation (Fig. 1c), confirming that MAVS overexpression indeed activated the downstream IFN pathway. We further tested if overexpression of upstream RNA sensors (MDA5 and RIG-I) or downstream signaling proteins (TBK1 and IRF3) could also activate IFN pathway. Indeed, an overexpression of MDA5 (Fig. 1a), RIG-I (Fig. 1b), TBK1 (Fig. 1d) and IRF3 (Fig. 1e) robustly induced STAT1 phosphorylation. At the mRNA level, we tested MAVS (Fig. 1f) or TBK1 (Fig. 1g) overexpression and found that both could increase the expression of selected interferon stimulated genes (or ISGs) (e.g. IFNβ, and ISG15). The cellular protease activity of transfected NSP5 was verified by flipGFP model system (Supplementary Fig. 2), in which an inactive flipGFP could be activated by a specific cleavage of NSP5 recognition site. Indeed, transfected NSP5, but not NSP5 (C145A), elicited a strong protease activity as demonstrated by a robust GFP signal (Supplementary Fig. 2). Consistent with the results from the reporter gene assay (Supplementary Fig. 1), co-transfection with NSP5, but not with NSP5 (C145A), significantly repressed STAT1 activation (Fig. 1a-e, Supplementary Fig. 3) and MAVS aggregation (Fig. 1c). Additionally, increased expressions of ISGs (IFNβ and ISG15) were almost completely repressed by NSP5, but not by NSP5 (C145A) (Fig. 1f, g). We also tested two other common IFN stimuli: poly (I:C) and Sendai virus (SeV) infection. Indeed, their downstream IFN signaling pathways were also repressed by NSP5, but not by NSP5 (C145A) (Supplementary Fig. 4a, b). Taken together, NSP5 significantly repressed RLR pathway in a protease-dependent manner.

In summary, we have discovered a novel translational mechanism that is likely responsible for NSP5-mediated IFN repression. eIF4G, a key component of translational initiation complex, was identified to be a specific NSP5 substrate in vitro as well as in a cell model of SARS-CoV-2 infection. Ectopic eIF4G expression was able to partly rescue NSP5-mediated repression of RLR-IFN pathway. Our finding provides a unique angle to the research of innate immunity against SARS-CoV-2 infection. Since IFN repression is a major mechanism of viral evasion and a determinant of severe COVID-19, our finding may reveal a new target (eIF4G) for research on COVID-19 pathogenesis.

number: 1
publisher: Nature Publishing Group

1549

I364

Kriebs, Anna

SARS-CoV-2-induced loss of CHK1 causes DNA damage

https://doi.org/10.1038/s43587-023-00414-0

Published

14-Apr-23

Article

https://www.nature.com/articles/s43587-023-00414-0

SARS-CoV-2 infection promotes cellular phenotypes that are associated with aging, such as senescence and proinflammatory cytokine release. However, the molecular pathways that link SARS-CoV-2 with these phenotypes are not fully understood. Now, a study by Ubaldo Gioia, Sara Tavella and colleagues shows that SARS-CoV-2 infection leads to a loss of CHK1, which causes a shortage in dNTP and impairs DNA replication, thus initiating a DNA damage response (DDR), inflammation and senescence.

Credit: Zhengshun tang/Moment/Getty
“The idea of a mechanism clicked in my head when I attended an RNA conference in the earliest days of the pandemic, before any lockdown”, says corresponding author Fabrizio d’Adda di Fagagna. “Narry Kim from Seoul National University showed her preliminary results from nanopore RNA sequencing of infected cells. Staggeringly, two out of three sequenced RNAs were of viral origin! Such an amount of RNA synthesis immediately meant to me that the cell was getting into trouble: where would the cell find three times the amount of rNTP than normally needed?”

The researchers began by infecting human cells with SARS-CoV-2. They observed that SARS-CoV-2 infection causes DNA damage and an altered DDR associated with a proinflammatory phenotype and senescence; it was also associated with a downregulation of effector kinase CHK1. As loss of CHK1 is sufficient to cause replication stress and DNA damage accumulation, the team measured dNTP levels and cell cycle progression. They observed that SARS-CoV-2 infection decreases dNTP concentrations and impairs S-phase progression. Deoxynucleotide supplementation in the culture medium of infected cells reduces DDR activation, DNA damage accumulation and proinflammatory cytokine expression.

“Our study shows that SARS-CoV-2 infections causes the degradation of CHK1, thus reducing ribonucleoside-diphosphate reductase subunit M2 (RRM2) expression and ribonucleotide reductase (RNR) activity and thereby shifting the balance of cellular nucleotide metabolism in favor of rNTP and in disfavor of dNTP. This generates DNA damage”, explains d’Adda di Fagagna. “In addition, DNA damage repair is impaired: surprisingly, 53BP1 foci cannot assemble. This is because they depend on the function of damage-induced long noncoding RNA (dilncRNA) generated at sites of DNA damage. We discovered that viral N protein binds to dilncRNA and blocks 53BP1 condensation.”

The researchers also measured the DDR markers 53BP1, CHK1 and RRM2 in lungs from mice infected with SARS-CoV-2 and in lung and nasal mucosa sections from patients who died of COVID-19. These results are consistent with their in vitro data.

“Key to this study was the collaboration with experts in the field, like Alessandro Marcello’s group, to perform all real viral infections (no pseudoviruses)”, continues d’Adda di Fagagna. “Also essential was access to infected tissues form mice and patients, and a great pathologist, Claudio Tripodo, who assessed DDR in these tissues.”

In future studies, the authors note it will be interesting to establish whether the mechanisms they uncovered contribute to long-COVID pathology.

Overall, this study sheds light on the mechanisms that underlie the cellular effects of SARS-CoV-2 infection, particularly DNA damage, inflammation and senescence.
publisher: Nature Publishing Group

1550

I365

Gioia, Ubaldo; Tavella, Sara; Martínez-Orellana, Pamela; Cicio, Giada; Colliva, Andrea; Ceccon, Marta; Cabrini, Matteo; Henriques, Ana C.; Fumagalli, Valeria; Paldino, Alessia; Presot, Ettore; Rajasekharan, Sreejith; Iacomino, Nicola; Pisati, Federica; Matti, Valentina; Sepe, Sara; Conte, Matilde I.; Barozzi, Sara; Lavagnino, Zeno; Carletti, Tea; Volpe, Maria Concetta; Cavalcante, Paola; Iannacone, Matteo; Rampazzo, Chiara; Bussani, Rossana; Tripodo, Claudio; Zacchigna, Serena; Marcello, Alessandro; d’Adda di Fagagna, Fabrizio

SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence

https://doi.org/10.1038/s41556-023-01096-x

Published

1-Apr-23

Study

https://www.nature.com/articles/s41556-023-01096-x

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the RNA virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Although SARS-CoV-2 was reported to alter several cellular pathways, its impact on DNA integrity and the mechanisms involved remain unknown. Here we show that SARS-CoV-2 causes DNA damage and elicits an altered DNA damage response. Mechanistically, SARS-CoV-2 proteins ORF6 and NSP13 cause degradation of the DNA damage response kinase CHK1 through proteasome and autophagy, respectively. CHK1 loss leads to deoxynucleoside triphosphate (dNTP) shortage, causing impaired S-phase progression, DNA damage, pro-inflammatory pathways activation and cellular senescence. Supplementation of deoxynucleosides reduces that. Furthermore, SARS-CoV-2 N-protein impairs 53BP1 focal recruitment by interfering with damage-induced long non-coding RNAs, thus reducing DNA repair. Key observations are recapitulated in SARS-CoV-2-infected mice and patients with COVID-19. We propose that SARS-CoV-2, by boosting ribonucleoside triphosphate levels to promote its replication at the expense of dNTPs and by hijacking damage-induced long non-coding RNAs’ biology, threatens genome integrity and causes altered DNA damage response activation, induction of inflammation and cellular senescence.

1551

I366

Basaran, M. Mert; Hazar, Merve; Aydın, Mehtap; Uzuğ, Gülsüm; Özdoğan, İlkima; Pala, Emin; Aydın Dilsiz, Sevtap; Basaran, Nursen

Effects of COVID-19 Disease on DNA Damage, Oxidative Stress and Immune Responses

https://doi.org/10.3390/toxics11040386

Published

1-Apr-23

Study

https://www.mdpi.com/2305-6304/11/4/386

Coronavirus disease 2019 (COVID-19) has posed a great threat to public health and has caused concern due to its fatal consequences over the last few years. Most people with COVID-19 show mild-to-moderate symptoms and recover without the need for special treatment, while others become seriously ill and need medical attention. Additionally, some serious outcomes, such as heart attacks and even stroke, have been later reported in patients who had recovered. There are limited studies on how SARS-CoV-2 infection affects some molecular pathways, including oxidative stress and DNA damage. In this study, we aimed to evaluate DNA damage, using the alkaline comet assay, and its relationship with oxidative stress and immune response parameters in COVID-19-positive patients. Our results show that DNA damage, oxidative stress parameters and cytokine levels significantly increased in SARS-CoV-2-positive patients when compared with healthy controls. The effects of SARS-CoV-2 infection on DNA damage, oxidative stress and immune responses may be crucial in the pathophysiology of the disease. It is suggested that the illumination of these pathways will contribute to the development of clinical treatments and to reduce adverse effects in the future.

1552

I367

Augustin, Max; Heyn, Ferdinand; Ullrich, Stella; Sandaradura de Silva, Ute; Albert, Marie-Christine; Linne, Viktoria; Schlotz, Maike; Schommers, Philipp; Pracht, Elisabeth; Horn, Carola; Suarez, Isabelle; Simonis, Alexander; Picard, Lea Katharina; Zoufaly, Alexander; Wenisch, Christoph; Fätkenheuer, Gerd; Gruell, Henning; Klein, Florian; Hallek, Michael; Walczak, Henning; Rybniker, Jan; Theobald, Sebastian J.; Lehmann, Clara

Immunological fingerprint in coronavirus disease-19 convalescents with and without post-COVID syndrome

https://doi.org/10.3389/fmed.2023.1129288

Published

24-Apr-23

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10165999/

Background
Symptoms lasting longer than 12 weeks after severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection are called post-coronavirus disease (COVID) syndrome (PCS). The identification of new biomarkers that predict the occurrence or course of PCS in terms of a post-viral syndrome is vital. T-cell dysfunction, cytokine imbalance, and impaired autoimmunity have been reported in PCS. Nevertheless, there is still a lack of conclusive information on the underlying mechanisms due to, among other things, a lack of controlled study designs.

Methods
Here, we conducted a prospective, controlled study to characterize the humoral and cellular immune response in unvaccinated patients with and without PCS following SARS-CoV-2 infection over 7 months and unexposed donors.

Results
Patients with PCS showed as early as 6 weeks and 7 months after symptom onset significantly increased frequencies of SARS-CoV-2-specific CD4+ and CD8+ T-cells secreting IFNγ, TNF, and expressing CD40L, as well as plasmacytoid dendritic cells (pDC) with an activated phenotype. Remarkably, the immunosuppressive counterparts type 1 regulatory T-cells (TR1: CD49b/LAG-3+) and IL-4 were more abundant in PCS+.

Conclusion
This work describes immunological alterations between inflammation and immunosuppression in COVID-19 convalescents with and without PCS, which may provide potential directions for future epidemiological investigations and targeted treatments.
PMID: 37168268
PMCID: PMC10165999

1553

I368

El-Akkad, S.-E.-D.; Shao, S.; Tran, K.c.w.; Russell, J.a.; Carlsten, C.; Ryerson, C.j.; Levin, A.; Wong, A.w.

COVID-19 Vaccination Is Not Associated With Abnormal Patient Reported Outcome Measures in Patients With Long-COVID: A Prospective Cohort Study

Published

1-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A3846

1554

I369

Di, Filippo Luigi; Frara, Stefano; Nannipieri, Fabrizio; Cotellessa, Alice; Locatelli, Massimo; Rovere-Querini, Patrizia; Giustina, Andrea

Low 25(OH) vitamin D levels are associated with Long COVID syndrome in COVID-19 survivors

https://doi.org/10.1530/endoabs.90.EP150

Published

2-May-23

Study

https://www.endocrine-abstracts.org/ea/0090/ea0090ep150

Low vitamin D levels were consistently reported as a risk factor for worse outcomes in hospitalized COVID-19 patients. Emerging evidences suggest that in 50–70% of COVID-19 survivors several post-COVID symptoms can be observed up to 3 months after acute-disease, representing a novel clinical condition defined Long-COVID syndrome. To date, the predisposing factors for this syndrome are still poorly understood. We retrospectively aimed at evaluating the influence of 25(OH) vitamin D levels on Long-COVID occurrence in patients previously hospitalized for COVID-19, re-assessed 6-months after discharge. Long-COVID was defined based on the National Institute for Health and Care Excellence-guidelines and approximately 500 patients were re-evaluated after the first pandemic-wave. While excluding patients with therapies/comorbidities affecting bone metabolism, and/or those admitted in ICU during hospitalization, only 50 Long-COVID patients were eligible for enrolment and compared in an age, sex, comorbidities and acute-disease characteristics-matched 1:1 ratio with non-Long-COVID patients. 25(OH) vitamin D was measured at hospital-admission and after 6-months. Median 25(OH) vitamin D levels were 14.7 and 20.6 ng/ml, at hospital-admission and at 6-month follow-up, respectively. At admission, vitamin D deficiency (25(OH) vitamin D <20 ng/ml) was found in 71 patients, and, at 6-month follow-up, in 46 patients. We observed lower 25(OH) vitamin D levels, evaluated at follow-up visit, in Long-COVID group than those without (20.1 vs 23.2 ng/ml, P=0.03). No statistically significant differences were observed regarding prevalence of vitamin D deficiency between those with and without Long-COVID. Regarding the different affected health areas evaluated in the entire cohort, we observed lower 25(OH) vitamin D levels in those with neurocognitive symptoms at 6-month visit (n.7) as compared to those without (n.93) (14.6 vs 20.6 ng/ml, P=0.042). In patients presenting vitamin D deficiency both at admission and at follow-up (n.42), those affected by Long-COVID (n.22) were characterized by lower 25(OH) vitamin D levels, evaluated at follow-up, compared to those not affected (n.20) (12.7 vs 15.2 ng/ml, P=0.041). In multiple regression analyses, lower 25(OH) vitamin D levels, evaluated at follow-up, resulted as the only variable significantly associated with the Long-COVID occurrence (P=0.016, OR 1.08-CI 1.01-1.15). In conclusion, COVID-19 survivors with Long-COVID have lower 25(OH) vitamin D levels as compared to matched patients without Long-COVID. Moreover, lower vitamin D resulted as an independent risk factor for the occurrence of this syndrome. Our data suggest that evaluating vitamin D levels in COVID-19 patients after hospital discharge and improving their vitamin D status when needed may be helpful in reducing the burden of COVID-19 sequelae.
ISSN: 1470-3947, 1479-6848

1555

I370

Ambrus, Mira; Fodor, Eszter; Berki, Timea; Müller, Veronika; Uhlár, Ádám; Hornyák, István; Lacza, Zsombor

Professional Athletes Maintain High TNF-Alpha or IFN-Gamma Related Inflammatory Status after Recovering from COVID-19 Infection without Developing a Neutralizing Antibody Response

https://doi.org/10.3390/sports11050097

Published

1-May-23

Study

https://www.mdpi.com/2075-4663/11/5/97

Introduction: Professional athletes are endangered by COVID-19 and belong to the high-risk population due to their lifestyle. To obtain information on the behavior of COVID-19 in professional athletes, serological, cytokine, and virus neutralization capacities were analyzed. Materials and methods: Hungarian national teams participated in international sports events during the early phases of the COVID-19 epidemic in 2020. Altogether, 29 professional athletes volunteered to donate plasma. Their serological status was evaluated by IgA, IgM, and IgG ELISAs and the highest virus neutralization titer in an in vitro live tissue assay. Plasma cytokine patterns were analyzed with a Bioplex multiplex ELISA system. Results: Surprisingly, only one athlete (3%) had anti-SARS-CoV-2 IgG, while IgA was more common (31%). Neither plasma showed direct virus neutralization in a titer over 1:10; hence, they were not suitable for reconvalescent treatment. The ‘cytokine storm’ markers IL-6 and IL-8 were at baseline levels. In contrast, either the TNF-alpha-related cytokines or the IFN-gamma-associated cytokines were elevated. There was a strong negative correlation between the TNF-alpha- or IFN-gamma-related cytokines. Conclusions: Professional athletes are susceptible to the SARS-CoV-2 infection without developing long-term immunity through neutralizing immunoglobulins. Elevated secretory and cellular immunity markers indicate that these systems are probably responsible for virus elimination in this subpopulation.

1556

I371

Baalbaki, N.; Cornelissen, M.; Drunen, C. Van; Houweling, L.; Noij, L.; Werken, M. Van De; Korneliusz, G.; Zee, A. Maitland-Van Der

Activated -inflammatory states of airway cells in Long COVID

https://doi.org/10.1183/23120541.LSC-2023.124

Published

9-Mar-23

Study

https://openres.ersjournals.com/content/9/suppl_10/124

Introduction: Long COVID is described as the persistence of symptoms following acute COVID-19 for >12 weeks and occurs in about 30% of all cases. Nasal epithelium is a primary target for SARS-CoV-2 and involved in the early phase immune response.
Aims: To assess the role of nasal epithelium and a local tissue micro-environment in long COVID.
Methods: Phenotype and function of nasal epithelium and innate lymphoid cells(ILC) were analyzed from long COVID patients and healthy controls(HC) using quantitative polymerase chain reaction, transepithelial resistance, scratch assays and flow cytometry. Long COVID samples were collected from Precision Medicine for more Oxygen (P4O2)– COVID-19 participants at 3-6 months post-COVID. Nasal epithelium was cultured at air-liquid-interface and exposed to viral mimic poly(I:C).
Results: An activated inflammatory state of nasal epithelium in long COVID (n=10) compared to HC(n=5) was found. In nasal epithelium, the relative gene expression of pro-inflammatory cytokines, including interleukin (IL)6, IL8, CXCL10, CCL5, TNFA and IL1B, was increased at baseline and after 24-hour exposure to poly(I:C). Furthermore, increased frequencies of IFN-gamma producing ILCs were found in the blood of long COVID patients, that in vitro produced more IFN-gamma after exposure to epithelium-derived IL-1beta compared to HC. Ex vivo, this inflammatory state resulted in a reduced barrier function and increased regeneration potential of long COVID nasal epithelium.
Conclusions: In Long COVID, epithelium-derived IL-1beta is potentially a key mediator in shaping the inflammatory airway tissue micro-environment by inducing IFN-gamma production in immune cells and consequently disturbing the epithelial barrier function.

1557

I372

Barco, N. Mendoza; Cruz, T.; Lledó, G.; Perea, L.; Albacar, N.; Hernandez-Gonzalez, F.; Agustí, A.; Sellarés, J.; Sibila, O.; Faner, R.

Persistence of specific T-cell response in patients with Long COVID and pulmonary sequelae

https://doi.org/10.1183/23120541.LSC-2023.207

Published

9-Mar-23

Study

https://openres.ersjournals.com/content/9/suppl_10/207

Background: A significant proportion of patients that survive COVID19 may develop LongCOVID or pulmonary sequelae(DLCO<80%).The mechanisms underlying these alterations are not described.Objectives:To determine if there is an association of the virus specific T cell response and the presence of LongCOVID or pulmonary sequelae at 12 months of convalescence.
Methods: T lymphocytes were stimulated with specific SARSCoV2 peptides(N and S) in 40 patients (11 with LongCOVID, 17 pulmonary sequelae) at 12 months postCOVID.Tcell populations and IFNg production in stimulated lymphocytes were measured by flow cytometry. Lung function was measured at 6 and 12 months to evaluate the progression.
Results: After comparing the prevalence of SARSCoV2 specific T cells(>2%IFNg+Tcells) across study groups at 12 months we observed that:1)50% of the recovered patients presented an in vitro Tcell response against SARSCoV2;2)72% of the patients with LongCOVID and 82% of the patients with lung sequelae responded.Th1 cells were increased in patients with LongCOVID in response to both peptides.Patients with pulmonary sequelae only presented an increase in Th1 in response to the S peptide. An in-depth characterization of the T lymphocytes in patients with LongCOVID,showed reduced expression of HLADR in CD4/CD8 T cells, and overall reduction of the frequencies of Th1 response.The frequency of CD4 HLADR,Th1,Th17,Th1/17 correlated with the change in DLCO in patients with pulmonary sequelae.
Conclusions: Patients with LongCOVID or pulmonary sequelae have an increased persistence of virus specific Tcell response after 12 months. Findings suggest the presence of long-term altered immune profile in patients with LongCOVID.

1558

I373

Patil, S. V.; Patil, S.; Toshniwal, S.; Gondhali, G.; Patil, R.; Acharya, A.; Patil, D.

“Clinical and immunological phenotypes” in ‘Long COVID’: The tsunami of multisystem syndrome of this decade!

https://doi.org/10.1183/23120541.LSC-2023.1

Published

9-Mar-23

Study

https://openres.ersjournals.com/content/9/suppl_10/1

Background: Clinical presentation and immunological patterns are different in all three waves & still evolving.
Methods: Prospective,observational study done in all three waves of COVID-19 pandemic & enrolled 8000 symptomatic, RT PCR confirmed cases in post COVID Unit. Clinical & immunological phenotypes were categorised in four types, Duration of illness (DOI) classified into transient or evolved, persistent, progressive, Topographical classification into vague or nonspecific and systemic or organic as per involvement of organ systems, Treatment responsive classified as per response into easy to treat and difficult to treat or refractory to treatment & Fourth is according genetic makeup patterns or strain patterns observed in first, second and third wave as pulmonary, extrapulmonary and pulmonary-extrapulmonary combo. Investigated with LDH, Uric acid, CRP, D-dimer, antinuclear antibody & retrospective analysis of antigenic cross reactivity/mimicry, markers as IL-6, Ferritin and interventions required during hospitalization including follow up HRCT thorax.
Results: Clinical phenotypes as per DOI & Topographical phenotypes has documented significant association with immunological markers (p<0.00001) Treatment response phenotypes has documented significant association with DOI before hospitalisation, interventions required and inflammatory marker (p<0.00001) Clinical phenotypes in three waves has documented significant association with four pathophysiological pathways (p<0.00001)
Conclusion: Clinical-Immunological Phenotypes of ‘Long COVID’ can be predicted at entry point, and sequential titers of inflammatory marker has 'vital role' during management in post covid care setting.

1559

I374

Bellinghausen, C.; Grünewaldt, A.; Khodamoradi, Y.; Du, W.; Azem, T.; Lask, C.; Vehreschild, M.; Rohde, G.

Serum markers of chronic inflammation and pulmonary remodelling in patients with long COVID up to one year after infection

https://doi.org/10.1183/23120541.LSC-2023.42

Published

9-Mar-23

Study

https://openres.ersjournals.com/content/9/suppl_10/42

Clinical sequelae following COVID19 can persist months after initial infection and significantly affect patients’ quality of life. The pathomechanisms and predictors for their course remain unclear. Here, we explored markers of systemic inflammation and pulmonary damage, and their association with clinical characteristics in patients with long COVID.
Outpatients presenting with persisting symptoms after SARS-CoV2 infection were prospectively recruited. Serum markers of inflammation and pulmonary damage, and their association with symptom burden, clinical and lung function parameters were assessed for up to one year after infection.
We included data from 235 patients (median age 48 [IQR 38-56] y, 65% female) during 503 visits. Acute COVID19 had mostly been mild to moderate, yet symptom burden at inclusion was high, with fatigue (81.7%) and shortness of breath (75.3%) being most common. FEV1% was below 80% in 11.6% of visits. Maximum inspiratory muscle strength (MIP) was impaired during 54.5% of visits, and negatively correlated with fatigue (ρ=-0.16, p=0.001) and cumulative symptom scores (ρ=-0.14, p=0.024). Levels of IL8, IL1β, IL10, TGFβ, surfactant protein D, and club cell protein 16 (CC16) showed little to no change over time and did not differ depending on severity of acute COVID19. CC16 levels were lower in patients with fatigue (7.1 [IQR 5.2-8.9] vs. 7.7 [IQR 6.4-10.8] ng/ml, p=0.008), and negatively correlated with symptom scores (ρ=-0.16, p=0.025).
Our results confirm the high burden and heterogeneity of symptoms in patients with long COVID. Lack of anti-inflammatory proteins such as CC16 associated with symptoms may represent a pathogenetic factor.

1560

I375

Hoang, Huy-Dung; Naeli, Parisa; Alain, Tommy; Jafarnejad, Seyed Mehdi

Mechanisms of impairment of interferon production by SARS-CoV-2

https://doi.org/10.1042/BST20221037

Published

18-May-23

Review

https://doi.org/10.1042/BST20221037

Interferons (IFNs) are crucial components of the cellular innate immune response to viral infections. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown a remarkable capacity to suppress the host IFN production to benefit viral replication and spread. Thus far, of the 28 known virus-encoded proteins, 16 have been found to impair the host's innate immune system at various levels ranging from detection and signaling to transcriptional and post-transcriptional regulation of expression of the components of the cellular antiviral response. Additionally, there is evidence that the viral genome encodes non-protein-coding microRNA-like elements that could also target IFN-stimulated genes. In this brief review, we summarise the current state of knowledge regarding the factors and mechanisms by which SARS-CoV-2 impairs the production of IFNs and thereby dampens the host's innate antiviral immune response.

1561

I376

Knight, S.; Menon, M.; Pott, B.; Hussell, T.; Bakerly, N.; Williams, T.; Grainger, J.; Konkel, J.; Mann, E.; Simpson, A.; Pearmain, L.; Mathioudakis, A.; Lowman, G.; Sarda, S.; Turkoglu, A.; Pickle, L.; Toro, M.

Resolution of inflammation in long COVID

https://doi.org/10.1183/23120541.LSC-2023.30

Published

9-Mar-23

Study

https://openres.ersjournals.com/content/9/suppl_10/30

As the cases of severe COVID-19 decline, long COVID is emerging as the major complication of SARS CoV2 infection. We have reasoned that the dysregulated immune response characterising acute COVID-19 is unlikely to resolve in an orderly fashion and that persistence of some features may be present in patients with long COVID. We have extended our landmark acute COVID-19 studies [1, 2], following up 53 patients one year into convalescence. This unique cohort includes 30 people who are fully recovered and 23 with long COVID. All have been evaluated by multi-parameter flow cytometry and a subset have had B cell receptor repertoire sequencing. The main perturbations of B/T cell phenotypes in acute COVID-19 resolve, however, there was an unexpected peak in the complementarity determining region of the B cell receptor repertoire in long COVID patients. Interestingly, the consensus sequence is an 82% match to spike protein monoclonal antibody sequences (Figure 1) and only present in IgM and IgD receptors. This implies that patients with long COVID have a different humoral response to those with a full recovery from acute COVID-19.
References:
[1] Mann ER, Menon M, Knight SB, et al. Longitudinal immune profiling reveals key myeloid signatures associated with COVID-19. Sci Immunol. 2020;5(51).
[2] Shuwa HA, Shaw TN, Knight SB, et al. Alterations in T and B cell function persist in convalescent COVID-19 patients. Med (N Y). 2021;2(6):720-35 e4.

1562

I377

Neves, Pablo Fabiano Moura das; Quaresma, Juarez Antônio Simões; Queiroz, Maria Alice Freitas; Silva, Camilla Costa; Maia, Enzo Varela; Oliveira, João Sergio de Sousa; Neves, Carla Manuela Almeida das; Mendonça, Suellen da Silva; Falcão, Aline Semblano Carreira; Melo, Giovana Salomão; Santos, Isabella Boechat Faria; Sousa, Jorge Rodrigues de; Santos, Eduardo José Melo dos; Vasconcelos, Pedro Fernando da Costa; Vallinoto, Antonio Carlos Rosário; Falcão, Luiz Fábio Magno

Imbalance of Peripheral Temperature, Sympathovagal, and Cytokine Profile in Long COVID

https://doi.org/10.3390/biology12050749

Published

1-May-23

Study

https://www.mdpi.com/2079-7737/12/5/749

Simple Summary
In this study, we looked at how persistent inflammation affects peripheral body temperature and sympathovagal balance in individuals with long COVID. Increased temperature and reduced heart rate variability were directly related to the increase in inflammatory cytokines and reduction in anti-inflammatory cytokines. We identified a possible “molecular signature” for long COVID, characterised by a Th17 inflammatory profile with a reduced anti-inflammatory response, resulting in alterations in homeostatic functions and sympathovagal balance.
Abstract
A persistent state of inflammation has been reported during the COVID-19 pandemic. This study aimed to assess short-term heart rate variability (HRV), peripheral body temperature, and serum cytokine levels in patients with long COVID. We evaluated 202 patients with long COVID symptoms categorized them according to the duration of their COVID symptoms (≤120 days, n = 81; >120 days, n = 121), in addition to 95 healthy individuals selected as controls. All HRV variables differed significantly between the control group and patients with long COVID in the ≤120 days group (p < 0.05), and participants in the long COVID ≤120 days group had higher temperatures than those in the long COVID >120 days group in all regions analysed (p < 0.05). Cytokine analysis showed higher levels of interleukin 17 (IL-17) and interleukin 2 (IL-2), and lower levels of interleukin 4 (IL-4) (p < 0.05). Our results suggest a reduction in parasympathetic activation during long COVID and an increase in body temperature due to possible endothelial damage caused by the maintenance of elevated levels of inflammatory mediators. Furthermore, high serum levels of IL-17 and IL-2 and low levels of IL-4 appear to constitute a long-term profile of COVID-19 cytokines, and these markers are potential targets for long COVID-treatment and prevention strategies.

1563

I378

Espindola, M.; Hohman, M.; Sá, Y.; Garcia, S.; Creyns, B.; Coelho, A. L.; Yao, C.; Chiang, G.; Parimon, T.; Strip, B.; Chen, P.; Hogaboam, C.

Biomarker identification in fatal and post-acute sequelae of SARS-CoV-2 (PASC) lungs leads to epigenetic targeting in PASC-related fibrosis

https://doi.org/10.1183/23120541.LSC-2023.201

Published

9-Mar-23

Study

https://openres.ersjournals.com/content/9/suppl_10/201

A percentage of COVID-19 affected patients develop post-acute sequalae of SARS-CoV-2, with evidence that SARS-CoV-2 causes ARDS leading to lung fibrosis (PASC-Fibrosis) that shares similarities with idiopathic pulmonary fibrosis (IPF). Herein, we addressed the hypothesis that fatal COVID-19, PASC, and IPF share key biomarkers of interest in lung fibrosis. Autopsy and explanted lung samples were subjected to histopathological and immunohistochemical (IHC) analysis for key biomarkers of interest in fibrosis. PASC-fibrosis-derived 2D and 3D cell cultures were treated with BRD4 inhibitors to evaluate proliferation and differentiation of fibroblasts, airway epithelial cells and lung bronchospheres. Single-cell RNA sequencing determined altered immune subpopulations. PASC-Fibrosis survivors had diffuse interstitial fibrosis, with organization into a non-specific interstitial fibrosis (NSIP) pattern. Transcriptomic analysis from fatal COVID-19 lungs showed BRD4, GDF15, IFNα2 and IL11 pathways markedly active. These findings were confirmed by IHC on PASC-fibrosis, with increased expression in myeloid cells. Altered frequencies in lung PASC-fibrosis subpopulations included loss of FABP4+ and increase of MERTK+SSP1+ macrophages and monocytes. Pharmacological inhibition of PASC-Fibrosis lung cultures and bronchospheres with BRD4 inhibitors limited outgrowth and differentiation of fibroblasts, airway epithelial cells and the formation of lung bronchospheres. In conclusion, shared profibrotic pathways among COVID-19 and chronic fibrotic ILDs provides the impetus to further explore treatment strategies to chronically ventilated COVID-19 patients.

1564

I379

Boekel, Laura; Atiqi, Sadaf; Leeuw, Maureen; Hooijberg, Femke; Besten, Yaëlle R.; Wartena, Rosa; Steenhuis, Maurice; Vogelzang, Erik; Webers, Casper; Boonen, Annelies; Gerritsen, Martijn; Lems, Willem F.; Tas, Sander W.; Vollenhoven, Ronald F. van; Voskuyl, Alexandre E.; Horst-Bruinsma, Irene van der; Nurmohamed, Mike; Rispens, Theo; Wolbink, Gertjan

Post-COVID condition in patients with inflammatory rheumatic diseases: a prospective cohort study in the Netherlands

https://doi.org/10.1016/S2665-9913(23)00127-3

Published

31-May-23

Study

https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(23)00127-3/fulltext

Background
Studies on long-term consequences of COVID-19, commonly referred to as post-COVID condition, in patients with inflammatory rheumatic diseases are scarce and inconclusive. Furthermore, classifying patients with inflammatory rheumatic diseases as having post-COVID condition is complicated because of overlapping symptoms. Therefore, we investigated the risk of post-COVID condition and time until recovery, and compared the prevalence of symptoms seen in post-COVID condition, between patients with inflammatory rheumatic diseases and healthy controls, with and without a history of COVID-19.
Methods
In this substudy we used data from an ongoing prospective cohort study in the Netherlands. All adult patients with inflammatory rheumatic diseases from the Amsterdam Rheumatology and Immunology Center in Amsterdam, the Netherlands, were invited to participate in the study between April 26, 2020, and March 1, 2021. All patients were asked, but not obliged, to recruit their own control participant of the same sex, of comparable age (< 5 years), and without an inflammatory rheumatic disease. Demographic and clinical data, including data on the occurrence of SARS-CoV-2 infections, were collected via online questionnaires. On March 10, 2022, all study participants received a questionnaire on the occurrence, onset, severity, and duration of persistent symptoms during the first 2 years of the COVID-19 pandemic, independent of their history of SARS-CoV-2 infection. Additionally, we prospectively monitored a subset of participants who had a PCR or antigen confirmed SARS-CoV-2 infection in the 2-month period surrounding the questionnaire in order to assess COVID-19 sequelae. In line with WHO guidelines, post-COVID condition was defined as persistent symptoms that lasted at least 8 weeks, started after the onset and within 3 months of a PCR or antigen-confirmed SARS-CoV-2 infection, and could not be explained by an alternative diagnosis. Statistical analyses included descriptive statistics, logistic regression analyses, logistic-based causal mediation analyses, and Kaplan-Meier survival analyses for time until recovery from post-COVID condition. In exploratory analyses, E-values were calculated to investigate unmeasured confounding.
Findings
A total of 1974 patients with inflammatory rheumatic disease (1268 [64%] women and 706 [36%] men; mean age 59 years [SD 13]) and 733 healthy controls (495 [68%] women and 238 [32%] men; mean age 59 years [12]) participated. 468 (24%) of 1974 patients with inflammatory rheumatic disease and 218 (30%) of 733 healthy controls had a recent SARS-CoV-2 omicron infection. Of those, 365 (78%) of 468 patients with inflammatory rheumatic disease and 172 (79%) of 218 healthy controls completed the prospective follow-up COVID-19 sequelae questionnaires. More patients than controls fulfilled post-COVID condition criteria: 77 (21%) of 365 versus 23 (13%) of 172 (odds ratio [OR] 1·73 [95% CI 1·04–2·87]; p=0·033). The OR was attenuated after adjusting for potential confounders (adjusted OR 1·53 [95% CI 0·90–2·59]; p=0·12). Among those without a history of COVID-19, patients with inflammatory diseases were more likely to report persistent symptoms consistent with post-COVID condition than were healthy controls (OR 2·52 [95% CI 1·92–3·32]; p<0·0001). This OR exceeded the calculated E-values of 1·74 and 1·96. Recovery time from post-COVID condition was similar for patients and controls (p=0·17). Fatigue and loss of fitness were the most frequently reported symptoms in both patients with inflammatory rheumatic disease and healthy controls with post-COVID condition.
Interpretation
Post-COVID condition after SARS-CoV-2 omicron infections was higher in patients with inflammatory rheumatic disease than in healthy controls based on WHO classification guidelines. However, because more patients with inflammatory rheumatic disease than healthy controls without a history of COVID-19 reported symptoms that are commonly used to define a post-COVID condition during the first 2 years of the pandemic, it is likely that the observed difference in post-COVID condition between patients and controls might in part be explained by clinical manifestations in the context of underlying rheumatic diseases. This highlights the limitations of applying current criteria for post-COVID condition in patients with inflammatory rheumatic disease, and suggests it might be appropriate for physicians to keep a nuanced attitude when communicating the long-term consequences of COVID-19.
publisher: Elsevier

1565

I380

Calabrese, Leonard H.

Long COVID in inflammatory rheumatic diseases—what's in a name?

https://doi.org/10.1016/S2665-9913(23)00134-0

Published

31-May-23

Article

https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(23)00134-0/fulltext

The impact of COVID-19 from the perspective of disease severity and overall mortality appears to be subsiding; however, what the future holds in terms of the post-COVID condition, commonly referred to as long COVID, remains uncertain. Although the effect of acute COVID-19 on patients with immune-mediated inflammatory diseases and inflammatory rheumatic diseases in particular has been extensively investigated, it is somewhat surprising that we still know relatively little regarding whether patients with immune-mediated inflammatory diseases are more or less susceptible to experiencing long COVID and, if it does occur, whether it is similar or different in severity and clinical expression to patients without immune-mediated inflammatory diseases.
In The Lancet Rheumatology, Laura Boekel and colleagues1 have contributed considerably to efforts to address unanswered questions regarding long COVID in patients with inflammatory rheumatic diseases by reporting on an extension of a prospective cohort study that was originally designed to assess the severity of incident COVID-19 in patients with inflammatory rheumatic diseases and healthy controls in the Netherlands. Boekel and colleagues further exploited the original data, which was utilised to assess the frequency and characteristics of long COVID sequelae. Employing an assessment tool in line with WHO guidelines defining long COVID,2 they were able to explore prevalent and incident symptomatology in those with and without inflammatory rheumatic diseases, both with and without a history of COVID-19. Their top line results revealed that patients with inflammatory rheumatic diseases were more likely than healthy controls to experience new onset and persistent long COVID (21% vs 13%; odds ratio [OR] 1·73 [95% CI 1·04–2·87]; p=0·033), yet this was attenuated after adjusting for potential confounders (adjusted OR 1·53 [95% CI 0·90–2·59]; p=0·12). They also documented that symptoms of long COVID and recovery time were similar between patients with inflammatory rheumatic diseases and healthy controls. Thus, based on this first prospective and controlled investigation, the impact of long COVID on patients with inflammatory rheumatic diseases might be greater than in healthy controls, but appears likely to be similar in clinical expression and natural history when comparing the two groups.
• View related content for this article

Beyond these observations, and perhaps of even more importance, is the exploratory analysis revealing that patients with inflammatory rheumatic diseases, but without a history of COVID-19, were more likely to report common long COVID symptoms during the first 2 years of the pandemic than were healthy controls without a history of COVID-19. Most studies, including the study by Boekel and colleagues, rely on WHO guidelines2 which define long COVID as any symptom lasting 8 weeks (and starting after the onset of and within 3 months of a SARS-CoV-2 infection) that cannot be explained by an alternative diagnosis. Among the most prevalent symptoms identified in the current study, in those both with and without inflammatory rheumatic diseases or COVID-19, were fatigue, loss of fitness, difficulties with concentration, sleep disturbances, and pain. Such symptoms are common among patients with inflammatory rheumatic diseases, especially in those with concomitant fibromyalgia,3, 4 and thus might confound efforts to identify affected patients on the basis of one unexplained symptom. At the same time it must also be emphasised that these limitations of case definition should not in any way diminish the reality of those suffering from long COVID, but rather should serve to remind us that at this stage of the pandemic we unfortunately still lack validated classification criteria for long COVID and of the importance of including non-SARS-CoV-2 infected controls in all studies.
From a wider perspective, beyond the epidemiologic challenges of studying long COVID in patients with inflammatory rheumatic diseases, are the challenges of studying long COVID in the general population using clinical signs and symptoms. An assertion from a recent review5 that the number of symptoms which might occur in the wake of COVID-19 might exceed 200 should raise concern regarding the challenges of specificity when attempting to use the presence of medically unexplained symptoms to assign causality. Previous data from multiple studies in the pre-COVID era using community surveys showed that respondents reported a median of five symptoms in the past week, with 23% of the population reporting ten or more symptoms including the variable presence of fatigue, headache, sleep disturbances, dizziness, and back pain, which are largely medically unexplained.6, 7 Such symptomatology might constitute a reservoir of distress in our daily lives, challenging their utility in assigning causality from an infection with the magnitude of the global prevalence of COVID-19.
Validated classification criteria for long COVID that can be used for comparative epidemiologic investigations and biomarker discovery are now urgently required. The field of rheumatology has extensive experience in the development of disease-state classification criteria for disorders that are complex and have many overlapping features with long COVID that could serve as a model for such efforts. For now it appears that long COVID, while an important reality affecting the lives of millions of individuals, remains incompletely defined and still in search of becoming a nosologically defined disease state.
publisher: Elsevier

1566

I381

Mohandas, Sindhu; Jagannathan, Prasanna; Henrich, Timothy J; Sherif, Zaki A; Bime, Christian; Quinlan, Erin; Portman, Michael A; Gennaro, Marila; Rehman, Jalees; RECOVER Mechanistic Pathways Task Force

Immune mechanisms underlying COVID-19 pathology and post-acute sequelae of SARS-CoV-2 infection (PASC)

https://doi.org/10.7554/eLife.86014

Published

26-May-23

Review

https://doi.org/10.7554/eLife.86014

With a global tally of more than 500 million cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections to date, there are growing concerns about the post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Recent studies suggest that exaggerated immune responses are key determinants of the severity and outcomes of the initial SARS-CoV-2 infection as well as subsequent PASC. The complexity of the innate and adaptive immune responses in the acute and post-acute period requires in-depth mechanistic analyses to identify specific molecular signals as well as specific immune cell populations which promote PASC pathogenesis. In this review, we examine the current literature on mechanisms of immune dysregulation in severe COVID-19 and the limited emerging data on the immunopathology of PASC. While the acute and post-acute phases may share some parallel mechanisms of immunopathology, it is likely that PASC immunopathology is quite distinct and heterogeneous, thus requiring large-scale longitudinal analyses in patients with and without PASC after an acute SARS-CoV-2 infection. By outlining the knowledge gaps in the immunopathology of PASC, we hope to provide avenues for novel research directions that will ultimately lead to precision therapies which restore healthy immune function in PASC patients.

1567

I382

Sahni, Dimple; Singh, Parvinder; kaur, Rajwant; Aggarwal, Sangeeta; kaur, Amandeep

Rising Incidence of Post Covid Rhinocerebral Mucormycosis: An Otolaryngologists Prospective

https://doi.org/10.1007/s12070-023-03886-z

Published

29-May-23

Study

https://doi.org/10.1007/s12070-023-03886-z

Mucormycosis or grimmer popular name, “black fungus” has evolved public concern in context of covid-19 pandemic, Covid Associated Mucormycosis (CAM) seen in Covid-19 pandemic and as a post covid sequelae. The present study was conducted to find out the incidence of the Mucormycosis, and to study its association with post-covid status and co-morbidities. A retrospective study conducted at tertiary care centre over a period of four months, involving all patients with mucormycosis of the paranasal sinuses suffering from or having a history of coronavirus disease. 59 patients had CAM, 47 patients had rhino-orbital Mucormycosis, followed by nasal and paranasal Mucormycosis in 8 patients, 3 patients with rhino-orbital-cerebral Mucormycosis, and one patient with pulmonary Mucormycosis. Diabetes mellitus was present in all 59 patients, 60.41% who had HbA1c > 10 (range 7–15), and 39.58% had HbA1c < 10 with range 6–13. Only 8.33% had controlled diabetes status, uncontroled hypertension and diabetes was seen in 34.02%. All patients were started with IV amphotericin B anti-fungal drug, and followed by oral posaconazole. Depending upon the extent of the disease surgical debridement was done in 52 patients. All patients had history of steroid intake. 7 mortality was there. Uncontrolled diabetes, over-zealous use of steroids, uncontrolled underlying primary disease or co-morbidities, prolonged hospitalization in intensive care unit or normal wards, and hyperventilation all these factors together aggravated the CAM. So it’s proper management based on, prompt diagnosis, reversal of predisposing condition with proper medical and aggressive surgical debridement remain the corner stone for this deadly CAM.

1568

I383

Jahankhani, Kasra; Ahangari, Fatemeh; Adcock, Ian M.; Mortaz, Esmaeil

Possible cancer-causing capacity of COVID-19: Is SARS-CoV-2 an oncogenic agent?

https://doi.org/10.1016/j.biochi.2023.05.014

Published

1-Oct-23

Review

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10202899/

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown diverse life-threatening effects, most of which are considered short-term. In addition to its short-term effects, which has claimed many millions of lives since 2019, the long-term complications of this virus are still under investigation. Similar to many oncogenic viruses, it has been hypothesized that SARS-CoV-2 employs various strategies to cause cancer in different organs. These include leveraging the renin angiotensin system, altering tumor suppressing pathways by means of its nonstructural proteins, and triggering inflammatory cascades by enhancing cytokine production in the form of a “cytokine storm” paving the way for the emergence of cancer stem cells in target organs. Since infection with SARS-CoV-2 occurs in several organs either directly or indirectly, it is expected that cancer stem cells may develop in multiple organs. Thus, we have reviewed the impact of coronavirus disease 2019 (COVID-19) on the vulnerability and susceptibility of specific organs to cancer development. It is important to note that the cancer-related effects of SARS-CoV-2 proposed in this article are based on the ability of the virus and its proteins to cause cancer but that the long-term consequences of this infection will only be illustrated in the long run.

1569

I384

Moynan, David; Barkat, Rizwan; Avramovic, Gordana; Morley, Deirdre; O'Kelly, Brendan; Lambert, John S.

The reactivation of herpesviruses in severe COVID-19; a retrospective analysis of a critical care cohort

https://doi.org/10.1016/j.clinpr.2023.100232

Published

1-Jul-23

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10204275/

While this study is limited in its retrospective design, we have found that the reactivation of CMV (22.3%), EBV (26%), and HSV/VZV (9%) in this cohort is in line with what has previously been documented (Saade et al., 2021). CMV infection in particular was associated with invasive ventilation and longer ventilation times, as previously described (Niitsu et al., 2021, Gatto et al., 2022). However, contrary to results from other studies, there was no association with lymphopaenia and CMV infection, although the measurement of a single nadir lymphocyte count likely underestimates the time spent in a lymphopenic state. Furthermore, while not fully elucidated, the reactivation of latent viral infections is certainly multifactorial. The cytokine storm caused by SARS-CoV-2 infection is thought to induce herpesvirus reactivation via TNF-alpha and IL-6 among others, while the transcripts of SARS-CoV-2 are thought to interact with herpesvirus elements directly (Chen et al., 2022).

Viral reactivation is not exclusive to SARS-CoV-2 infection, with herpesvirus reactivation documented prior to the onset of the pandemic in critically unwell patients in the ICU (Coşkun et al., 2017). As seen in our study, it is often associated with higher CRP values, mechanical ventilation and lymphopaenia. However, recent data from a non-critical care cohort has implicated EBV reactivation in the pathophysiology of long-COVID. In a study by Gold et al that investigated the prevalence of EBV reactivation in a long-COVID cohort, as defined by a positive titre for EBV EA-D IgG or EBV VCA IgM, 66.7% of long-term long-COVID patients were found to be positive for EBV reactivation (Gold et al., 2021). With many of these patients documented as asymptomatic to their initial infection, it strengthens the argument that SARS-CoV-2 infection itself plays a role in viral reactivation, independent of disease severity.

In conclusion, we believe that the reactivation of herpesviruses in the setting of SARS-CoV-2 infection warrants further research, with the virus itself capable of stimulating other infections and potentially contribute to an enhanced disease severity and a protracted symptom course, as seen in long-COVID.
PMID: 37251495
PMCID: PMC10204275

1570

CaV01

ENDO

Valentina O. Puntmann, MD, PhD1; M. Ludovica Carerj, MD1,2; Imke Wieters, MD3; et al

Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19)

https://doi.org/10.1001/jamacardio.2020.3557

Published

27-Jul-20

Original Investigation

https://jamanetwork.com/journals/jamacardiology/fullarticle/2768916

A study in JAMA Cardiology highlights the frequent cardiovascular sequelae in people who have been affected by covid, even without hospitalization. Nevertheless, a group of cardiologists warns against misinterpretations of cardiac abnomalies : https://cvctcardiobrief.com/letter-warns-against-clinical-role-for-cardiac-mri-in-asymptomatic-covid-patients/

In this cohort study including 100 patients recently recovered from COVID-19 identified from a COVID-19 test center, cardiac magnetic resonance imaging revealed cardiac involvement in 78 patients (78%) and ongoing myocardial inflammation in 60 patients (60%), which was independent of preexisting conditions, severity and overall course of the acute illness, and the time from the original diagnosis

Une étude dans JAMA Cardiology souligne les fréquentes séquelles cardio-vasculaires chez les personnes ayant été touchées par le covid, même sans hospitalisation. Cependant, un collectif de cardiologues publient une lettre mettant en garde contre les interprétations hâtives des anomalies aux images et déconseillent les IRM sur les patients asymptomatiques. https://cvctcardiobrief.com/letter-warns-against-clinical-role-for-cardiac-mri-in-asymptomatic-covid-patients/

1571

CaV02

No

Diana Lindner, PhD1,2; Antonia Fitzek, MD3; Hanna Bräuninger, MS1,2; et al

Association of Cardiac Infection With SARS-CoV-2 in Confirmed COVID-19 Autopsy Cases

https://doi.org/10.1001/jamacardio.2020.3551

Published

27-Jul-20

Brief Report

https://jamanetwork.com/journals/jamacardiology/fullarticle/2768914

Another study (JAMA Cardiology) examines the cardiac damages observed during autopsies of patients who died from covid, and the viral load of SARS-CoV-2 RNA in the myocardium.

Une autre étude (JAMA Cardiology) s'intéresse aux atteintes cardiaques constatées lors d'autopsies de patients morts du covid, et de la charge virale d'ARN SARS-CoV-2 dans le myocarde.

1572

CaV03

?

By ELIZABETH COONEY

Covid-19 infections leave an impact on the heart, raising concerns about lasting damage

Opinion

27-Jul-20

Editorial

https://www.statnews.com/2020/07/27/covid19-concerns-about-lasting-heart-damage/

An article from the US health news site STAT reviews these two studies from JAMA Cardiology.
"biomarker evidence pointing to heart lesions typical of those seen after a heart attack" "It is premature to say whether the heart damage seen in patients recovering from covid is transient or permanent, but cardiologists are concerned."

Un article du site d'information américain consacré à la santé STAT revient sur ces deux études du JAMA Cardiology.
"des preuves de biomarqueurs mettant en évidence des lésions cardiaques typiques de celles observées après une crise cardiaque" "Il est trop tôt pour dire si les lésions cardiaques observées chez les patients en convalescence du covid sont transitoires ou permanentes, mais les cardiologues sont inquiets"

1573

CaV04

?

Juan A. Pérez-Bermejo, Serah Kang, Sarah J. Rockwood, Camille R. Simoneau,

SARS-CoV-2 infection of human iPSC-derived cardiac cells predicts novel cytopathic features in hearts of COVID-19 patients

https://doi.org/10.1101/2020.08.25.265561

pre-print

12-Sep-20

New Results

https://www.biorxiv.org/content/10.1101/2020.08.25.265561v2

Very qualitative study (https://biorxiv.org/content/10.1101/2020.08.25.265561v1) not yet peer-reviewed, which can explain the MRIs of cardiac attacks, from JAMA Cardiology (https://jamanetwork.com/journals/jamacardiology/fullarticle/2768916, end of July).
Infection and spread of the virus in cardiomyocytes (contractile cells).

Étude très qualitative (biorxiv.org/content/10.110…) non encore relue, qui peut expliquer les IRM d'atteintes cardiaques du JAMA Cardiology (jamanetwork.com/journals/jamac…, fin juillet).
Infection et propagation du virus dans les cardiomyocytes (cellules contractiles).

1574

CaV05

Rocio Eiros, Manuel Barreiro-Perez, Ana Martin-Garcia, Julia Almeida, Eduardo Villacorta,

Pericarditis and myocarditis long after SARS-CoV-2 infection: a cross-sectional descriptive study in health-care workers

https://doi.org/10.1101/2020.07.12.20151316

pre-print

14-Jul-20

cross-sectional descriptive study

https://www.medrxiv.org/content/10.1101/2020.07.12.20151316v1

Myocarditis (inflammation of the heart) and pericarditis due to covid, *even for asymptomatic patients*, worry cardiologists, and raise fears of an increase in the incidence of heart failure. Detectable by cardiac MRI, myocarditis "is often cured without incident".
"It is accompanied by symptoms such as shortness of breath, chest pain, fever and fatigue, but can also be asymptomatic."

Les myocardites (inflammation du cœur) et péricardites dues à la covid, *même chez des asymptomatiques*, inquiètent les cardiologues, et fait craindre une hausse de l'incidence des insuffisances cardiaque. Détectables par IRM cardiaque, les myocardites "se guérissent souvent sans incident".
"Elle s'accompagnent de symptômes tels que l'essoufflement, les douleurs thoraciques, de la fièvre et de la fatigue, mais peuvent aussi être asymptomatiques."

1575

CaV06

ENDO

Richard C. Becker

Anticipating the long-term cardiovascular effects of COVID-19

https://doi.org/10.1007/s11239-020-02266-6

Published

3-Sep-20

Editorial

https://link.springer.com/article/10.1007/s11239-020-02266-6

What we know so far about the cardiac impacts of covid: a very comprehensive editorial by renowned cardiologist Richard Becker, to be put in the hands of all practitioners who follow #LongCovid patients.

Ce que l'on sait à ce jour des impacts cardiaques de la covid : un éditorial très complet du cardiologue réputé Richard Becker, à mettre dans les mains de tous les praticiens qui suivent des patients #LongCovid.

1576

CaV07

Alessandro Di Minno, Pasquale Ambrosino, Ilenia Calcaterra, Matteo Nicola Dario Di Minno

COVID-19 and Venous Thromboembolism: A Meta-analysis of Literature Studies

https://doi.org/10.1055/s-0040-1715456

Published

3-Sep-20

Review Article

https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0040-1715456

Venous thromboembolic disorders

Troubles thromboemboliques veineux

1577

CaV08

Eric J. Topol

COVID-19 can affect the heart

https://doi.org/10.1126/science.abe2813

Published

23-Oct-20

PERSPECTIVE

https://science.sciencemag.org/content/370/6515/408

Synthetic article by the well-known American cardiologist @EricTopol on the current state of knowledge concerning heart attacks linked to covid.

Article synthétique du très renommé cardiologue américain @EricTopol sur l'état actuel des connaissances concernant les atteintes cardiaques liées à la covid.

1578

CaV09

Robert O. Bonow, MD, MS1,2; Patrick T. O’Gara, MD3,4; Clyde W. Yancy, MD, MSc1,4

Cardiology and COVID-19

https://doi.org/10.1001/jama.2020.15088

Published

Viewpoint

https://jamanetwork.com/journals/jama/fullarticle/2770858

JAMA publishes abstracts of specialists on different aspects of covid pathologies.
Cardiological: https://jamanetwork.com/journals/jama/fullarticle/2770858
"There remain important unknowns regarding the intermediate and long-term sequelae of COVID-19 infection"

Le JAMA publie des synthèses de spécialistes sur différents aspects des pathologies covid.
Cardiologiques "There remain important unknowns regarding the intermediate and long-term sequelae of COVID-19 infection"

1579

CaV007

Gennaro Giustino, MD,a,∗∗ Lori B. Croft, MD,a,∗ Giulio G. Stefanini, MD, PhD,b,∗∗ Renato Bragato, MD,b

Characterization of Myocardial Injury in Patients With COVID-19

https://doi.org/10.1016%2Fj.jacc.2020.08.069

Published

26-Oct-20

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588179/

A technical article which details myocardial damage in patients with covid.

Un article technique qui détaille les atteintes du myocarde chez les malades de la covid.

1580

CaV008

Yes

Daniel Brito, Scott Meester, Naveena Yanamala, Heenaben B. Patel, Brenden J. Balcik,

High Prevalence of Pericardial Involvement in College Student Athletes Recovering From COVID-19

https://doi.org/10.1016/j.jcmg.2020.10.023

Published

25-Nov-20

Clinical Research

https://www.jacc.org/doi/10.1016/j.jcmg.2020.10.023

In a cohort of 160 young athletes affected by covid, 48 of whom had extensive cardiac examinations, a West Virginia study to appear in JACC: Cardiovascular Imaging finds heart damage in 27 patients.

Dans une cohorte de 160 jeunes athlètes touchés par la covid dont 48 ont eu des examens cardiaques poussés, une étude en Virginie-Occidentale à paraître dans JACC: Cardiovascular Imaging constate des lésions cardiaques pour 27 patients.

1581

CaV009

ENDO

Bingwen Eugene Fan, Thirugnanam Umapathi, Karen Chua, Yew Woon Chia

Delayed catastrophic thrombotic events in young and asymptomatic post COVID-19 patients

https://doi.org/10.1007/s11239-020-02332-z

Published

7-Nov-20

Case Letter to the Editor

https://link.springer.com/article/10.1007/s11239-020-02332-z

Four cases in Singapore of severe delayed vascular damage, avg. 38 years old, who were asymptomatic, including 3 without risk factors.

Quatre cas à Singapour de graves dégâts vasculaires différés, moy. 38 ans, qui étaient asymptomatiques dont 3 sans facteur de risques.

1582

CaV010

ENDO

Yu Zuo1, Shanea K. Estes1, Ramadan A. Ali1, Alex A. Gandhi1

Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19

https://doi.org/10.1126/scitranslmed.abd3876

Published

18-Nov-20

RESEARCH ARTICLE

https://stm.sciencemag.org/content/12/570/eabd3876

The cycle of inflammation and coagulation that creates blood clots in covid patients, linked to autoantibodies and similar to Hughes syndrome, better understood thanks to a 🇺🇲 study. The reaction causes thrombosis, pulmonary embolism and stroke. The team is launching a clinical trial (https://clinicaltrials.gov/ct2/show/NCT04391179) on dipyridamole, an anticoagulant showing promise for blocking this specific type of inflammation.

Le cycle d'inflammation et de coagulation qui crée des caillots sanguins chez des malades covid, lié à des auto-anticorps et proche du syndrome de Hughes, mieux compris grâce à une étude 🇺🇲. La réaction provoque thromboses, embolies pulmonaires et AVC. L'équipe lance un essai clinique (clinicaltrials.gov/ct2/show/NCT04…) sur le dipyridamole, anticoagulant prometteur pour bloquer ce type spécifique d’inflammation.

1583

CaV011

Kathleen M. Capaccione
Jay S. Leb
Belinda D'souza

Acute myocardial infarction secondary to COVID-19 infection: A case report and review of the literature

https://doi.org/10.1016/j.clinimag.2020.11.030

Published

14-Nov-20

Case report and review

https://www.clinicalimaging.org/article/S0899-7071(20)30462-9/fulltext#%20

An unprecedented case of acute coronary syndrome (obstruction of a coronary artery, precursor of myocardial infarction) following a covid infection, reported by a New York team, supplemented by a review of the literature on this subject.

Un cas inédit de syndrome coronarien aigu (obstruction d'une artère coronaire, précurseur d'infarctus du myocarde) consécutif à une infection covid, rapporté par une équipe new-yorkaise, complété d'une revue de la littérature sur ce sujet.

1584

CaV012

Marijke Linschoten, Sanne Peters, Maarten van Smeden, ...

Cardiac complications in patients hospitalised with COVID-19

https://doi.org/10.1177%2F2048872620974605

Published

21-Nov-20

Research Article

https://journals.sagepub.com/doi/full/10.1177/2048872620974605

A very large international study (CAPACITY-COVID) intended to quantify the incidence of cardiac complications, on a cohort of patients with a median age of 67 (63% men.), found 20% of deaths and 11.6% of cardiac complications during hospitalization.

Une très large étude internationale (CAPACITY-COVID) destinée à quantifier l'incidence des complications cardiaques, sur une cohorte de patients de médiane 67 ans (63% h.), relève 20% de décès et 11,6% de complications cardiaques pendant l'hospitalisation.

1585

CaV013

Moutal, Aubin1; Martin, Laurent F.2,; Boinon, Lisa1,; Gomez, Kimberly

SARS-CoV-2 Spike protein co-opts VEGF-A/Neuropilin-1 receptor signaling to induce analgesia

https://doi.org/10.1097/j.pain.0000000000002097

Published

1-Oct-20

RESEARCH PAPER

https://journals.lww.com/pain/Abstract/9000/SARS_CoV_2_Spike_protein_co_opts.98244.aspx

Une étude avance l'hypothèse que la protéine Spike du SARS-CoV-2 pourrait bloquer sur l'endothélium vasculaire A (VEGF-A) les récepteurs de neuropiline-1 (NRP-1), et donc inhiber la douleur. Les auteurs évoque une douleur "mise en sourdine" ("silencing").

1586

CaV014

Puneet Kaur Randhawa1 , Kaylyn Scanlon1 , Jay Rappaport2 and Manish K. Gupta

Modulation of Autophagy by SARS-CoV-2: A Potential Threat for Cardiovascular System

https://doi.org/10.3389/fphys.2020.611275

Published

30-Nov-20

Mini-review article

https://www.frontiersin.org/articles/10.3389/fphys.2020.611275/full

Une revue de la littérature sur les effets cardiovasculaires de la covid, et l'impact du dérèglement de l'autophagie par le virus.

1587

CaV015

Geraldine Martorella, Suzanne Fredericks, Julie Sanders, Rochelle Wynne

Breaking pandemic chain reactions: telehealth psychosocial support in cardiovascular disease during COVID-19

https://doi.org/10.1093/eurjcn/zvaa011

Published

1-Dec-20

Editorial

https://academic.oup.com/eurjcn/advance-article/doi/10.1093/eurjcn/zvaa011/6013085

La possibilité de lésions cardiaques provoquées par la covid, associée aux conditions socio-économiques de la crise, majorent le risque de maladies cardiovasculaires, selon une étude qui met en avant des thérapies de santé mentale et la télémédecine.

1588

CaV016

Young Joo Suh, Hyunsook Hong, Hasti Robbie, Soon Ho Yoon

Pulmonary Embolism and Deep Vein Thrombosis in COVID-19: A Systematic Review and Meta-Analysis

https://doi.org/10.1148/radiol.2020203557

Published

15-Dec-20

Systematic Review and Meta-Analysis

https://pubs.rsna.org/doi/10.1148/radiol.2020203557

_

1589

CaV017

Patrick S. Buckley, MD and Catherine A. Logan MD, MBA, MSPT

COVID-19 Related Cardiology for the Sports Medicine Physician

Published

1-Dec-20

Opinion

https://www.sportsmed.org/aossmimis/STOP/Downloads/Posts/CardiacCovid_Buckley_Logan.pdf

Un article d'opinion de médecins du sport sur les risques pour les athlètes avec la covid, qui renvoit notamment à ce guide : https://jamanetwork.com/journals/jamacardiology/fullarticle/2772399
ainsi qu'à ce guide de retour à l'activité sportive : https://services.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/clinical-guidance/covid-19-interim-guidance-return-to-sports/

1590

CaV018

Linghua Fu, Xiao Liu, Yuhao Su, Jianyong Ma, Kui Hong

Prevalence and impact of cardiac injury on COVID‐19: A systematic review and meta‐analysis

https://doi.org/10.1002/clc.23540

Published

31-Dec-20

Systematic review and meta‐analysis

https://onlinelibrary.wiley.com/doi/full/10.1002/clc.23540

Une méta-analyse retrouve un quart de patients hospitalisés pour covid avec des lésions cardiaques, avec une forte corrélation entre l'importance de ces lésions et le risque létal.

1591

CaV019

COVID-19 vasculitis and novel vasculitis mimics

https://doi.org/10.1016/S2665-9913(20)30420-3

Published

1-Jul-21

https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(20)30420-3/fulltext

suggèrent que ce mécanisme représente une nouvelle vascularite-like liée au COVID-19 qui pourrait conduire à des accidents vasculaires cérébraux cryptogéniques à travers les territoires à plusieurs vaisseaux, à une lésion rénale aiguë avec hématurie, à une vascularite cutanée mimétique, à une ischémie intestinale et à d'autres manifestations ischémiques d'organes.

1592

CaV020

Kurz David J., Eberli Franz R.

Cardiovascular aspects of COVID-19

https://doi.org/10.4414/smw.2020.20417

Published

Review

https://smw.ch/article/doi/smw.2020.20417

Dans la Swiss Medical Weekly, une revue d'études particulièrement documentée évalue et analyse les conséquences possibles cardio-vasculaires de la covid. Les principaux mécanismes d'attaque du virus y sont documentés, notamment avec le rôle du système rénine-angiotensine-aldostérone, la susceptibilité aux antécédents cardiaques et les mécanismes à long terme des lésions cardiaques.

1593

CaV021

DAVE FORNELL

The Long-term Cardiovascular Impact of COVID-19

Published

22-Jan-21

Opinion

https://www.dicardiology.com/article/long-term-cardiovascular-impact-covid-19

Un article d'opinion décrit les séquelles cardiovasculaires de la covid et détaille les orientations que la recherche prend et devra prendre sur le sujet.

1594

CaV022

Visesha Kakarla, Naoki Kaneko, May Nour, Kasra Khatibi, Fanny Elahi, David S Liebeskind, Jason D Hinman

Pathophysiologic mechanisms of cerebral endotheliopathy and stroke due to Sars-CoV-2

https://doi.org/10.1177%2F0271678X20985666

Published

2-Feb-21

Review Article

https://journals.sagepub.com/doi/full/10.1177/0271678X20985666

Cerebrovascular events have emerged as a central feature of the clinical syndrome associated with Sars-CoV-2 infection. This increase in infection-related strokes is marked by atypical presentations including stroke in younger patients and a high rate of hemorrhagic transformation after ischemia. A variety of pathogenic mechanisms may underlie this connection. Efforts to identify synergism in the pathophysiology underlying stroke and Sars-CoV-2 infection can inform the understanding of both conditions in novel ways. In this review, the molecular cascades connected to Sars-CoV-2 infection are placed in the context of the cerebral vasculature and in relationship to pathways known to be associated with stroke. Cytokine-mediated promotion of systemic hypercoagulability is suggested while direct Sars-CoV-2 infection of cerebral endothelial cells may also contribute. Endotheliopathy resulting from direct Sars-CoV-2 infection of the cerebral vasculature can modulate ACE2/AT1R/MasR signaling pathways, trigger direct viral activation of the complement cascade, and activate feed-forward cytokine cascades that impact the blood-brain barrier. All of these pathways are already implicated as independent mechanisms driving stroke and cerebrovascular injury irrespective of Sars-CoV-2. Recognizing the overlap of molecular pathways triggered by Sars-CoV-2 infection with those implicated in the pathogenesis of stroke provides an opportunity to identify future therapeutics targeting both Sars-CoV-2 and stroke thereby reducing the impact of the global pandemic.

Une revue d'études s'intéresse à la physiopathologie des endothéliopathies cérébrales et des AVC consécutifs à la covid. Elle décrit de possibles mécanismes viraux et inflammatoires qui entrent en jeu à la frontière cerveau / système sanguin.

N002

___Cardio-Vascular___

Published review article on 2-Feb-21:
"Pathophysiologic mechanisms of cerebral endotheliopathy and stroke due to Sars-CoV-2"
Une revue d'études s'intéresse à la physiopathologie des endothéliopathies cérébrales et des AVC consécutifs à la covid. Elle décrit de possibles mécanismes viraux et inflammatoires qui entrent en jeu à la frontière cerveau / système sanguin.
Link: https://journals.sagepub.com/doi/full/10.1177/0271678X20985666
Extract: "Cerebrovascular events have emerged as a central feature of the clinical syndrome associated with Sars-CoV-2 infection. This increase in infection-related strokes is marked by atypical presentations including stroke in younger patients and a high rate of hemorrhagic transformation after ischemia. A variety of pathogenic mechanisms may underlie this connection. Efforts to identify synergism in the pathophysiology underlying stroke and Sars-CoV-2 infection can inform the understanding of both conditions in novel ways. In this review, the molecular cascades connected to Sars-CoV-2 infection are placed in the context of the cerebral vasculature and in relationship to pathways known to be associated with stroke. Cytokine-mediated promotion of systemic hypercoagulability is suggested while direct Sars-CoV-2 infection of cerebral endothelial cells may also contribute. Endotheliopathy resulting from direct Sars-CoV-2 infection of the cerebral vasculature can modulate ACE2/AT1R/MasR signaling pathways, trigger direct viral activation of the complement cascade, and activate feed-forward cytokine cascades that impact the blood-brain barrier. All of these pathways are already implicated as independent mechanisms driving stroke and cerebrovascular injury irrespective of Sars-CoV-2. Recognizing the overlap of molecular pathways triggered by Sars-CoV-2 infection with those implicated in the pathogenesis of stroke provides an opportunity to identify future therapeutics targeting both Sars-CoV-2 and stroke thereby reducing the impact of the global pandemic."

1595

CaV023

Marketa Kubankova, Bettina Hohberger, Jakob Hoffmanns, Julia Fuerst, Martin Hermann, Jochen Guck, Martin Krater

Physical phenotype of blood cells is altered in COVID-19

https://doi.org/10.1101/2021.02.12.429482

pre-print

12-Feb-21

New Results

https://www.biorxiv.org/content/10.1101/2021.02.12.429482v1

"We found significant changes in erythrocyte deformability, lymphocyte stiffness, monocyte size, and neutrophil size and deformability. While some of these changes recovered to normal values after hospitalization, others persisted for months after hospital discharge, evidencing the long-term imprint of COVID-19 on the body."
"neutrophil alterations observed in our recovered cohort were induced after the successful displacement of the virus by the immune system. This might be indicative for SARS-CoV-2 causing long-term immunological signals or even targeting bone marrow stem cells, as viral RNA was found post-mortem in patient bone marrow"
"These alterations could be connected with long term symptoms of the recovered patients"

Sur une cohorte assez réduite, une étude allemande en relecture (pre-print) note chez les patients guéris de la phase aiguë de la covid des altérations des globules rouges et des granulocytes neutrophiles qui pourraient avoir des effets à long terme.
Des changements dans la déformabilité érythrocytaire ainsi que celle des neutrophiles et de leur taille, se retrouvent avec des écarts statistiquement significatifs, sur une médiane de 7 mois après l'infection au SARS-CoV-2.

1596

CaV024

ENDO

Mi Zhou,Chun-Ka Wong ,Ka-Chun Un ,Yuk-Ming Lau,Jeffrey Chun-Yin Lee,Frankie Chor-Cheung Tam,Yee-Man Lau,Wing-Hon Lai,Anthony Raymond Tam,Yat-Yin Lam,Polly Pang,Teresa Tong,Milky Tang, [ ... ],Chung-Wah Siu

Cardiovascular sequalae in uncomplicated COVID-19 survivors

https://doi.org/10.1371/journal.pone.0246732

Published

11-Feb-21

RESEARCH ARTICLE

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246732

The mean age was 46.5 ± 18.6 years; 53.6% were men. All were classified with non-severe disease without overt cardiac manifestations and did not require intensive care. Median hospitalization stay was 17 days and median duration from discharge to screening was 11 days. Cardiac abnormalities were detected in 42.3% including sinus bradycardia (29.9%), newly detected T-wave abnormality (8.2%), elevated troponin level (6.2%), newly detected atrial fibrillation (1.0%), and newly detected left ventricular systolic dysfunction with elevated NT-proBNP level (1.0%). Significant sinus bradycardia with heart rate below 50 bpm was detected in 7.2% COVID-19 survivors, which appeared to be self-limiting and recovered over time.

Première étude systémique d'évaluation cardio-vasculaire pour détecter les atteintes cardiaques subcliniques et/ou latentes parmi des cas hospitalisés de la covid non sévères. Les atteintes non directement perceptibles sont fréquentes, parfois seulement révélées par IRM cardiaque (CRM).

N002N

___Cardio-Vascular___

Published research article on 11-Feb-21:
"Cardiovascular sequalae in uncomplicated COVID-19 survivors"
Première étude systémique d'évaluation cardio-vasculaire pour détecter les atteintes cardiaques subcliniques et/ou latentes parmi des cas hospitalisés de la covid non sévères. Les atteintes non directement perceptibles sont fréquentes, parfois seulement révélées par IRM cardiaque (CRM).
Link: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246732
Extract: "The mean age was 46.5 ± 18.6 years; 53.6% were men. All were classified with non-severe disease without overt cardiac manifestations and did not require intensive care. Median hospitalization stay was 17 days and median duration from discharge to screening was 11 days. Cardiac abnormalities were detected in 42.3% including sinus bradycardia (29.9%), newly detected T-wave abnormality (8.2%), elevated troponin level (6.2%), newly detected atrial fibrillation (1.0%), and newly detected left ventricular systolic dysfunction with elevated NT-proBNP level (1.0%). Significant sinus bradycardia with heart rate below 50 bpm was detected in 7.2% COVID-19 survivors, which appeared to be self-limiting and recovered over time."

1597

CaV025

Ehsan Zaboli1 , Roya Ghasemian2 , Mahdi Abounoori3 , Mohammad Zahedi4 , Seyyed Abbas Hashemi * 5

Deep Vein Thrombosis Associated With COVID-19

http://pbr.mazums.ac.ir/article-1-360-en.html

Published

12-Jul-05

Case Report

http://pbr.mazums.ac.ir/article-1-360-en.html

Deep vein thrombosis (DVT) is a devastating condition that usually involves the lower extremities. The typical course of DVT is associated with an episode of enormous limb swelling and pain. In this case report, we aimed to present one of the COVID-19 possible complications: DVT in a 38 years old man infected with SARS-CoV-2. A 38 years old man presented with leg pain. He had a dry cough and fatigue suspicious symptoms of COVID-19.

Un cas rapporté de thrombose veineuse profonde consécutif à une infection de covid.

1598

CaV026

ENDO

Tushar Kotecha, Daniel S Knight, Yousuf Razvi, Kartik Kumar, Kavitha Vimalesvaran, George Thornton, Graham D Cole, Marianna Fontana

Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance

https://doi.org/10.1093/eurheartj/ehab075

Published

18-Feb-21

Study

https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab075/6140994

Multi-organ involvement in COVID-19 is recognized, with many patients having troponin release indicative of acute myocardial injury.6–11 Here, in a multicentre study across six acute hospitals, we show that myocardial injury during acute COVID-19 infection requiring acute hospital admission is associated with a CMR abnormality in approximately half of patients, with three patterns of injury being observed: non-infarct, myocarditis-pattern injury (27%), ischaemic pathology (22%), and non-ischaemic non-specific scar (5%). Dual pathology with ischaemic and non-ischaemic features was observed in 6%. The different patterns of abnormalities found suggest multiple possible underlying mechanisms including myocarditis (with limited extent and no functional consequence), MI (type 1 or type 2), and inducible myocardial ischaemia.

Dans une étude multicentrique, une équipe montre que les lésions myocardiques (avec niveau élevé de troponine) chez les patients covid hospitalisés sont associées à une anomalie visible à l'IRM cardiovasculaire chez environ la moitié d'entre eux.

N003A

___Cardio-Vascular___

Published study on 18-Feb-21:
"Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance"
Dans une étude multicentrique, une équipe montre que les lésions myocardiques (avec niveau élevé de troponine) chez les patients covid hospitalisés sont associées à une anomalie visible à l'IRM cardiovasculaire chez environ la moitié d'entre eux.
Link: https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab075/6140994
Extract: "Multi-organ involvement in COVID-19 is recognized, with many patients having troponin release indicative of acute myocardial injury.6–11 Here, in a multicentre study across six acute hospitals, we show that myocardial injury during acute COVID-19 infection requiring acute hospital admission is associated with a CMR abnormality in approximately half of patients, with three patterns of injury being observed: non-infarct, myocarditis-pattern injury (27%), ischaemic pathology (22%), and non-ischaemic non-specific scar (5%). Dual pathology with ischaemic and non-ischaemic features was observed in 6%. The different patterns of abnormalities found suggest multiple possible underlying mechanisms including myocarditis (with limited extent and no functional consequence), MI (type 1 or type 2), and inducible myocardial ischaemia."

1599

CaV027

ENDO

Alan D.KayeMD, PhD(Professor, Provost, Allyson L.Spence, MariahMayerlecNitishSardana, Claire M.Clay, Matthew R.EngMD,Markus M.LuediMDgPh.DMichelle A.Carroll Turpin, Richard D.Urman, Elyse M.Cornett

The impact of COVID-19 infection on the cardiovascular system: an evidence-based analysis of risk factors and outcomes

https://doi.org/10.1016/j.bpa.2021.02.003

Published

1-Mar-21

Analysis

https://www.sciencedirect.com/science/article/pii/S1521689621000082

In this evidence-based review, we discuss risk factors of cardiovascular involvement in COVID-19 infection, pathophysiology of COVID-19-related cardiovascular infection and injury, COVID-19 effects on the cardiovascular system and corresponding treatments, and hematologic effects of COVID-19 and COVID-19 in heart transplant patients.

Une revue des facteurs de risque cardiovasculaire pour la covid, de la physiopathologie des blessures cardiovasculaires liées, des atteintes hématologiques et sur le système cardiovasculaire, et enfin évocation des traitements correspondants. La dysfonction endothéliale est présentée comme un élément parmi plusieurs autres de dommages vasculaires pouvant être causés par le SARS-CoV-2.

N003A

___Cardio-Vascular___

Published analysis on 1-Mar-21:
"The impact of COVID-19 infection on the cardiovascular system: an evidence-based analysis of risk factors and outcomes"
Une revue des facteurs de risque cardiovasculaire pour la covid, de la physiopathologie des blessures cardiovasculaires liées, des atteintes hématologiques et sur le système cardiovasculaire, et enfin évocation des traitements correspondants. La dysfonction endothéliale est présentée comme un élément parmi plusieurs autres de dommages vasculaires pouvant être causés par le SARS-CoV-2.
Link: https://www.sciencedirect.com/science/article/pii/S1521689621000082
Extract: "In this evidence-based review, we discuss risk factors of cardiovascular involvement in COVID-19 infection, pathophysiology of COVID-19-related cardiovascular infection and injury, COVID-19 effects on the cardiovascular system and corresponding treatments, and hematologic effects of COVID-19 and COVID-19 in heart transplant patients."

1600

CaV028

ENDO

Federica Catapano, Livia Marchitelli, Giulia Cundari, Francesco Cilia, Giuseppe Mancuso, Giacomo Pambianchi, Nicola Galea, Paolo Ricci, Carlo Catalano & Marco Francone

Role of advanced imaging in COVID-19 cardiovascular complications

https://doi.org/10.1186/s13244-021-00973-z

Published

24-Feb-21

Critical Review

https://insightsimaging.springeropen.com/articles/10.1186/s13244-021-00973-z

Present article aims to review the value of advanced multimodality imaging in patients with suspected SARS-CoV-2-related cardiovascular involvement and its essential role in risk stratification and tailored treatment strategies. Based on our experience, we also sought to suggest possible diagnostic algorithms for the rationale utilization of advanced imaging tools, such as cardiac CT and CMR, avoiding unnecessary examinations and diagnostic delays.

Une étude examine la valeur de l'imagerie multimodale avancée chez les patients avec des séquelles cardiovasculaires liées à la covid. Les auteurs suggèrent des algorithmes de diagnostic possibles pour justifier l'utilisation d'outils d'imagerie avancés.

N004

___Cardio-Vascular___

Published critical review on 24-Feb-21:
"Role of advanced imaging in COVID-19 cardiovascular complications"
Une étude examine la valeur de l'imagerie multimodale avancée chez les patients avec des séquelles cardiovasculaires liées à la covid. Les auteurs suggèrent des algorithmes de diagnostic possibles pour justifier l'utilisation d'outils d'imagerie avancés.
Link: https://insightsimaging.springeropen.com/articles/10.1186/s13244-021-00973-z
Extract: "Present article aims to review the value of advanced multimodality imaging in patients with suspected SARS-CoV-2-related cardiovascular involvement and its essential role in risk stratification and tailored treatment strategies. Based on our experience, we also sought to suggest possible diagnostic algorithms for the rationale utilization of advanced imaging tools, such as cardiac CT and CMR, avoiding unnecessary examinations and diagnostic delays."

1601

CaV029

Satish R. Raj, Amy C. Arnold, Alexandru Barboi, Victoria E. Claydon, Jacqueline K. Limberg, Vera-Ellen M. Lucci, Mohammed Numan, Amanda Peltier, Howard Snapper, Steven Vernino

Long-COVID postural tachycardia syndrome: an American Autonomic Society statement

Published

19-Mar-21

Review Article

https://link.springer.com/article/10.1007/s10286-021-00798-2

There is much that is not known about Long-COVID POTS. While not exhaustive, the list includes:
1. Natural history of Long-COVID POTS. Is this a self-limiting disorder that will resolve in several months, or one that will last for years?
2. Underlying pathophysiology of Long-COVID POTS.
3. Are patients with Long-COVID POTS different from patients with POTS unrelated to COVID-19?
4. Best treatments for Long-COVID POTS.

Une analyse américaine s'intéresse au syndrome de tachycardie posturale (PoTS) dans le cadre de la covid. Elle évalue toutes les inconnues actuelles liées à ce symptôme de la covid et esquisse des hypothèses explicatives.

N006

___Cardio-Vascular___

Published review article on 19-Mar-21:
"Long-COVID postural tachycardia syndrome: an American Autonomic Society statement"
Une analyse américaine s'intéresse au syndrome de tachycardie posturale (PoTS) dans le cadre de la covid. Elle évalue toutes les inconnues actuelles liées à ce symptôme de la covid et esquisse des hypothèses explicatives.
Link: https://link.springer.com/article/10.1007/s10286-021-00798-2
Extract: "There is much that is not known about Long-COVID POTS. While not exhaustive, the list includes:
1. Natural history of Long-COVID POTS. Is this a self-limiting disorder that will resolve in several months, or one that will last for years?
2. Underlying pathophysiology of Long-COVID POTS.
3. Are patients with Long-COVID POTS different from patients with POTS unrelated to COVID-19?
4. Best treatments for Long-COVID POTS."

1602

CaV030

Dr. Lázaro Alfonso Pérez Cabrera. *
Dra. Natalia L. Planas Sliuntiaeva. **
Dr. Ronald Aroche Aportela

Miocarditis post Covid-19 a propósito de un caso tratado con
Jusvinza
Post Covid-19 myocarditiscase treated with Jusvinza

Published

Case Report

https://aniversariocimeq2021.sld.cu/index.php/ac2021/Cimeq2021/paper/viewFile/91/43

or https://aniversariocimeq2021.sld.cu/index.php/ac2021/Cimeq2021/paper/view/91
SARSCov 2 disease (Covid-19) manifests with a broad spectrum of clinical
presentation, ranging from asymptomatic disease to severe respiratory failure,
myocardial injury, and death. As more patients recover from the acute stage,
reports of cardiovascular manifestations such as: heart failure, arrhythmias,
myocarditis, among others that could be considered as a disease sequel,
increase. Existing reports of coronavirus myocarditis are scarce, but it appears
that more heart damage occurs in patients affected by Covid-19 than by other
coronaviruses. A 50-year-old patient is presented, with a history of Covid-19
diagnosed 23 days ago, who comes in due to palpitations. In the emergency
room the exam revealed arrhythmic heart sounds and elevated heart rate,
corroborating atrial fibrillation in the electrocardiogram with rapid ventricular
response, accompanied by increased cardiac enzymes. He was diagnosed as
Post Covid-19 myocarditis and was admitted to intensive care unit, antiarrhythmic
and immunomodulatory treatment with Jusvinza was started.

_

1603

CaV031

LeylaHazaraMineKarahanaEsraVuralbSedatAvaaSeyfettinErdemaMehmet EminDursunaUğurKeklikçi

Macular vessel density in patients recovered from COVID-19 disease

https://doi.org/10.1016/j.pdpdt.2021.102267

Published

27-Mar-21

Study

https://www.sciencedirect.com/science/article/pii/S1572100021000934

Highlights
•COVID-19, lead to vasculopathy and retinal vascular pathologies.
•The ability of OCTA to provide vascular mapping of separate layers is an important advantage.
•Very limited report is available about superficial and deep capillary plexus in patients with COVID 19 disease.
•Vascular densities of both superficial and deep capillary network are affected in COVID 19 disease.
•Foveal avascular zone is not affected in patients who have recovered from mild to moderate COVID-19 disease.

Une étude s'intéresse aux vasculopathies consécutives à la covid qui peuvent affecter la vision. La mesure de densité vasculaire rétinienne maculaire peut être étudiée par tomographie par cohérence optique (TCO), qui permet une cartographie vasculaire de couches séparées. L'étude explique que la covid peut affecter le réseau capillaire superficiel et profond de l'oeil, même si la zone avasculaire fovéale n'est pas affectée chez les patients qui se sont rétablis d'une covid légère à modérée.

N006

___Cardio-Vascular___

Published study on 27-Mar-21:
"Macular vessel density in patients recovered from COVID-19 disease"
Une étude s'intéresse aux vasculopathies consécutives à la covid qui peuvent affecter la vision. La mesure de densité vasculaire rétinienne maculaire peut être étudiée par tomographie par cohérence optique (TCO), qui permet une cartographie vasculaire de couches séparées. L'étude explique que la covid peut affecter le réseau capillaire superficiel et profond de l'oeil, même si la zone avasculaire fovéale n'est pas affectée chez les patients qui se sont rétablis d'une covid légère à modérée.
Link: https://www.sciencedirect.com/science/article/pii/S1572100021000934
Extract: "Highlights
•COVID-19, lead to vasculopathy and retinal vascular pathologies.
•The ability of OCTA to provide vascular mapping of separate layers is an important advantage.
•Very limited report is available about superficial and deep capillary plexus in patients with COVID 19 disease.
•Vascular densities of both superficial and deep capillary network are affected in COVID 19 disease.
•Foveal avascular zone is not affected in patients who have recovered from mild to moderate COVID-19 disease."

1604

CaV032

Carole Émile

Risque thrombotique de la Covid-19

https://dx.doi.org/10.1016%2FS0992-5945(21)00048-9

Published

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006242/

La fréquence des embolies pulmonaires au cours de la Covid-19 est élevée, voisine de 20 %. La physiopathologie des événements thromboemboliques est complexe et reste mal connue, notamment pour les thromboses artérielles. Une prophylaxie anti-thrombotique est proposée chez les patients hospitalisés en l’absence de risque hémorragique, à doses habituelles ou élevées, ainsi que chez les patients à domicile en cas de réduction de la mobilité associée à un facteur de risque.

_

1605

CaV033

ENDO

Aldo Bonaventura, Alessandra Vecchié, Lorenzo Dagna, Kimberly Martinod, Dave L. Dixon, Benjamin W. Van Tassell, Francesco Dentali, Fabrizio Montecucco, Steffen Massberg, Marcel Levi & Antonio Abbate

Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19

https://doi.org/10.1038/s41577-021-00536-9

Published

6-Apr-21

Article

https://www.nature.com/articles/s41577-021-00536-9

Here, we propose that SARS-CoV-2 infection induces a process known as immunothrombosis, in which activated neutrophils and monocytes interact with platelets and the coagulation cascade, leading to intravascular clot formation in small and larger vessels. Microthrombotic complications may contribute to acute respiratory distress syndrome (ARDS) and other organ dysfunctions. Therapeutic strategies aimed at reducing immunothrombosis may therefore be useful. Several antithrombotic and immunomodulating drugs have been proposed as candidates to treat patients with SARS-CoV-2 infection.

Un article de recherche très qualitatif dans Nature explore l'hypothèse physiopathologique des micro-thromboses consécutives à une infection de SARS-CoV-2. L'étude pose l'idée que la covid entraîne un processus d'immunothrombose, dans lequel les neutrophiles et les monocytes activés interagissent avec les plaquettes et la cascade de la coagulation, conduisant à la formation de caillots intravasculaires dans des petits vaisseaux mais aussi de plus grande taille. L'étude y voit un impact sur les conséquences à long terme de la covid.

N007

___Cardio-Vascular___

Published article on 6-Apr-21:
"Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19"
Un article de recherche très qualitatif dans Nature explore l'hypothèse physiopathologique des micro-thromboses consécutives à une infection de SARS-CoV-2. L'étude pose l'idée que la covid entraîne un processus d'immunothrombose, dans lequel les neutrophiles et les monocytes activés interagissent avec les plaquettes et la cascade de la coagulation, conduisant à la formation de caillots intravasculaires dans des petits vaisseaux mais aussi de plus grande taille. L'étude y voit un impact sur les conséquences à long terme de la covid.
Link: https://www.nature.com/articles/s41577-021-00536-9
Extract: "Here, we propose that SARS-CoV-2 infection induces a process known as immunothrombosis, in which activated neutrophils and monocytes interact with platelets and the coagulation cascade, leading to intravascular clot formation in small and larger vessels. Microthrombotic complications may contribute to acute respiratory distress syndrome (ARDS) and other organ dysfunctions. Therapeutic strategies aimed at reducing immunothrombosis may therefore be useful. Several antithrombotic and immunomodulating drugs have been proposed as candidates to treat patients with SARS-CoV-2 infection."

1606

CaV034

Fuad-Tahsin Abbas, Wayne State University School Of Medicine

The Ticking Time Bomb: COVID-19's hidden, long-term impact: permanent cardiovascular disease

Published

31-Mar-21

https://digitalcommons.wayne.edu/covidinfographics/38/

_

1607

CaV035

Bingwen Eugene Fan , Christine Cheung

Post COVID-19 Arterial Thromboembolism: A Clear and Present Danger

https://doi.org/10.1055/s-0041-1728717

Published

Letter to the Editor

https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0041-1728717

The evidence of persistent endothelial dysfunction in post COVID-19 patients, including those with either no or minimal symptoms during initial infection, raises pressing concerns about the potential long-term cardiovascular effects. Besides arterial thromboembolism, COVID-19 survivors developing endothelial dysfunction may experience chronic cardiovascular complications such as heart failure, sudden cardiac death, arrhythmias (especially atrial fibrillation), accelerated arteriosclerosis,[21] pulmonary hypertension,[22] and arterial aneurysms.[23] Moreover, the incidence of vascular events due to endothelial dysfunction from COVID-19 in survivors is likely to be exacerbated by comorbidities such as hypertension and diabetes. Immunomodulatory therapy targeting thromboinflammation in COVID-19,[24] such as tocilizumab (anti–interleukin-6 receptor monoclonal antibodies) or the use of high-dose steroid therapy, may have benefits in reducing the inflammatory cascade in COVID-19 and endotheliitis in at-risk patients, and requires further evaluation.

Un article note que les preuves d'un dysfonctionnement endothélial persistant chez les patients postcovid, y compris les paucisymptomatiques en phase initiale, soulèvent des inquiétudes quant aux effets cardiovasculaires potentiels à long terme. Les auteurs remarquent que l'incidence des événements vasculaires dus au dysfonctionnement endothélial lié à la covid est susceptible d'être exacerbée par des comorbidités telles que l'hypertension et le diabète. Ils suggèrent qu'une thérapie immunomodulatrice ciblant la thromboinflammation (citant le tocilizumab), ou une corticothérapie à haute dose, peuvent présenter des avantages pour réduire les effets inflammatoires et l'endothélite chez les patients à risque.

N011

___Cardio-Vascular___

Published letter to the editor on :
"Post COVID-19 Arterial Thromboembolism: A Clear and Present Danger"
Un article note que les preuves d'un dysfonctionnement endothélial persistant chez les patients postcovid, y compris les paucisymptomatiques en phase initiale, soulèvent des inquiétudes quant aux effets cardiovasculaires potentiels à long terme. Les auteurs remarquent que l'incidence des événements vasculaires dus au dysfonctionnement endothélial lié à la covid est susceptible d'être exacerbée par des comorbidités telles que l'hypertension et le diabète. Ils suggèrent qu'une thérapie immunomodulatrice ciblant la thromboinflammation (citant le tocilizumab), ou une corticothérapie à haute dose, peuvent présenter des avantages pour réduire les effets inflammatoires et l'endothélite chez les patients à risque.
Link: https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0041-1728717
Extract: "The evidence of persistent endothelial dysfunction in post COVID-19 patients, including those with either no or minimal symptoms during initial infection, raises pressing concerns about the potential long-term cardiovascular effects. Besides arterial thromboembolism, COVID-19 survivors developing endothelial dysfunction may experience chronic cardiovascular complications such as heart failure, sudden cardiac death, arrhythmias (especially atrial fibrillation), accelerated arteriosclerosis,[21] pulmonary hypertension,[22] and arterial aneurysms.[23] Moreover, the incidence of vascular events due to endothelial dysfunction from COVID-19 in survivors is likely to be exacerbated by comorbidities such as hypertension and diabetes. Immunomodulatory therapy targeting thromboinflammation in COVID-19,[24] such as tocilizumab (anti–interleukin-6 receptor monoclonal antibodies) or the use of high-dose steroid therapy, may have benefits in reducing the inflammatory cascade in COVID-19 and endotheliitis in at-risk patients, and requires further evaluation."

1608

CaV036

Sabrine Zieda Mariem Messelmani Manel Akkari Hajer Derbali Malek Mansour Jamel Zaouali Ridha Mrissa

Accident vasculaire cérébral inaugural d’une infection COVID-19 : étude de 9 cas

https://doi.org/10.1016/j.neurol.2021.02.294

Published

11-Apr-21

Study

https://www.sciencedirect.com/science/article/pii/S0035378721003362

_

1609

CaV037

RichardChocronaBaptisteDuceaubNicolasGendroncNacimEzzouhairidLinaKhidereAntoninTrimaillefGuillaumeGoudoteOrianneWeizmangJean MarcAlsachThibaultPommieriOlivierBoryjJoffreyCellierkAurélienPhilippecLauraGenestelIannisBen AbdallahhVassiliPanagidesmSalmaEl BattihWassimaMarsounPhilippeJuvinjAntoineDeneyoEmmanuelMessaspSabirAttouqBenjaminPlanquetterDelphineMikasPascaleGaussemtCharlesFauveluJean-LucDiehlvTheoPezelwTristanMiraultpWillySutterbOlivierSanchezrGuillaumeBonnetbArielCohenx1David M.Smadjac1forthe Critical COVID-19 France investigators

D-dimer at hospital admission for COVID-19 are associated with in-hospital mortality, independent of venous thromboembolism: Insights from a French multicenter cohort studyLes D-dimères à l’admission pour COVID-19 sont associés à la mortalité hospitalière indépendamment du risque de thrombose veineuse

https://doi.org/10.1016/j.acvd.2021.02.003

Published

9-Mar-21

Study

https://www.sciencedirect.com/science/article/pii/S1875213621000516

Highlights
•COVID-19 has been associated with micro- and macrothrombotic events.
•D-dimer measurement on admission is recommended in patients with COVID-19.
•The optimum D-dimer cut-off has been a matter of debate.
•We identified > 1128 ng/mL as the optimum cut-off to predict in-hospital mortality.
•This cut-off predicts mortality independent of venous thromboembolism occurrence.

_

1610

CaV038

Liam Townsend Helen Fogarty Adam Dyer Ignacio Martin‐Loeches Ciaran Bannan Parthiban Nadarajan Colm Bergin Cliona O’Farrelly Niall Conlon Nollaig M. Bourke Soracha E. Ward Mary Byrne Kevin Ryan Niamh O’Connell Jamie M. O’Sullivan Cliona Ni Cheallaigh James S. O’Donnell

Prolonged elevation of D‐dimer levels in convalescent COVID‐19 patients is independent of the acute phase response

https://doi.org/10.1111/jth.15267

Published

15-Feb-21

BRIEF REPORT

https://onlinelibrary.wiley.com/doi/full/10.1111/jth.15267

ESSENTIALS
Persistent fatigue, breathlessness, and reduced exercise tolerance following acute COVID‐19 infection has been termed long COVID syndrome.
We observed sustained elevated D‐dimer levels in 25% of patients reviewed a minimum of 6 weeks following initial diagnosis. Although D‐dimers remained elevated, other coagulation and inflammation markers had returned to normal in the majority of patients.
Despite ongoing symptoms and elevated D‐dimers, computed tomography pulmonary angiogram screening in eight patients failed to demonstrate pulmonary embolism.
Further adequately powered studies will be required to elucidate the mechanisms underlying elevated D‐dimer levels during COVID‐19 convalescence.

Des niveaux accrus de D-dimères (marqueurs de coagulation) sont observés chez un quart des personnes infectées par le SARS-CoV-2 jusqu'à 4 mois après l'infection. L'étude lie ces examens à la pathogenèse du covid long.

N014E

___Cardio-Vascular___

Published brief report on 15-Feb-21:
"Prolonged elevation of D‐dimer levels in convalescent COVID‐19 patients is independent of the acute phase response"
Des niveaux accrus de D-dimères (marqueurs de coagulation) sont observés chez un quart des personnes infectées par le SARS-CoV-2 jusqu'à 4 mois après l'infection. L'étude lie ces examens à la pathogenèse du covid long.
Link: https://onlinelibrary.wiley.com/doi/full/10.1111/jth.15267
Extract: "ESSENTIALS
Persistent fatigue, breathlessness, and reduced exercise tolerance following acute COVID‐19 infection has been termed long COVID syndrome.
We observed sustained elevated D‐dimer levels in 25% of patients reviewed a minimum of 6 weeks following initial diagnosis. Although D‐dimers remained elevated, other coagulation and inflammation markers had returned to normal in the majority of patients.
Despite ongoing symptoms and elevated D‐dimers, computed tomography pulmonary angiogram screening in eight patients failed to demonstrate pulmonary embolism.
Further adequately powered studies will be required to elucidate the mechanisms underlying elevated D‐dimer levels during COVID‐19 convalescence."

1611

CaV039

Nathaniel Moulson, Bradley J. Petek, Jonathan A. Drezner, Kimberly G. Harmon, Stephanie A. Kliethermes, Manesh R. Patel, and Aaron L. Baggish

SARS-CoV-2 Cardiac Involvement in Young Competitive Athletes

https://doi.org/10.1161/CIRCULATIONAHA.121.054824

17-Apr-21

https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.054824

Among 19,378 athletes tested for SARS-CoV-2 infection, 3018 (mean age 20 years [SD,1 year]; 32% female) tested positive and underwent cardiac evaluation. A total of 2820 athletes underwent at least one element of cardiac 'triad' testing [12-lead electrocardiography (ECG), troponin, and/or transthoracic echocardiography(TTE)] followed by cardiac magnetic resonance (CMR) if clinically indicated. In contrast, primary screening CMR was performed in 198 athletes. Abnormal findings suggestive of SARS-CoV-2 cardiac involvement were detected by ECG (21/2999,0.7%), cardiac troponin (24/2719,0.9%), and TTE (24/2556,0.9%). Definite, probable, or possible SARS-COV-2 cardiac involvement was identified in 21/3018 (0.7%) athletes, including 15/2820 (0.5%) who underwent clinically indicated CMR (n=119) and 6/198 (3.0%) who underwent primary screening CMR. Accordingly, the diagnostic yield of CMR for SARS-COV-2 cardiac involvement was 4.2 times higher for a clinically indicated CMR (15/119,12.6%) versus a primary screening CMR (6/198,3.0%). After adjustment for race and sex, predictors of SARS-CoV-2 cardiac involvement included cardiopulmonary symptoms (OR:3.1,95% CI:1.2,7.7) or at least one abnormal triad test (OR:37.4,95% CI:13.3,105.3). Five (0.2%) athletes required hospitalization for non-cardiac complications of SARS-CoV-2. During clinical surveillance (median follow-up 113 days [IQR=90,146]), there was one (0.03%) adverse cardiac event likely unrelated to SARS-CoV-2 infection.

Chez les jeunes athlètes, les complications et séquelles cardiovasculaires semblent relativement rare. L'âge et les facteurs de comorbidité comme un terrain auto-immun favorable pourraient jouer.

1612

CaV040

ENDO

Mina K. Chung,corresponding author1,2,3 David A. Zidar,3,4 Michael R. Bristow,5 Scott J. Cameron,1,2,3 Timothy Chan,1,2,3 Clifford V. Harding, III,3 Deborah H. Kwon,1,2,3 Tamanna Singh,1,2,3 John C. Tilton,3 Emily J. Tsai,6 Nathan R. Tucker,7,8 John Barnard,1,2 and Joseph Loscalzo

COVID-19 and Cardiovascular Disease
From Bench to Bedside

https://dx.doi.org/10.1161%2FCIRCRESAHA.121.317997

Published

16-Apr-21

Review

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048382/

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can infect the heart, vascular tissues, and circulating cells through ACE2 (angiotensin-converting enzyme 2), the host cell receptor for the viral spike protein. Acute cardiac injury is a common extrapulmonary manifestation of COVID-19 with potential chronic consequences. This update provides a review of the clinical manifestations of cardiovascular involvement, potential direct SARS-CoV-2 and indirect immune response mechanisms impacting the cardiovascular system, and implications for the management of patients after recovery from acute COVID-19 infection.

Les lésions cardiaques aiguës sont une manifestation extrapulmonaire courante de la covid avec des conséquences chroniques potentielles, décrit une revue d'études qui répertorie les impacts cardio-vasculaires à long terme de la maladie.

N014E

___Cardio-Vascular___

Published review on 16-Apr-21:
"COVID-19 and Cardiovascular Disease
From Bench to Bedside"
Les lésions cardiaques aiguës sont une manifestation extrapulmonaire courante de la covid avec des conséquences chroniques potentielles, décrit une revue d'études qui répertorie les impacts cardio-vasculaires à long terme de la maladie.
Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048382/
Extract: "Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can infect the heart, vascular tissues, and circulating cells through ACE2 (angiotensin-converting enzyme 2), the host cell receptor for the viral spike protein. Acute cardiac injury is a common extrapulmonary manifestation of COVID-19 with potential chronic consequences. This update provides a review of the clinical manifestations of cardiovascular involvement, potential direct SARS-CoV-2 and indirect immune response mechanisms impacting the cardiovascular system, and implications for the management of patients after recovery from acute COVID-19 infection."

1613

CaV041

ENDO

Paul C Evans, G Ed Rainger, Justin C Mason, Tomasz J Guzik, Elena Osto, Zania Stamataki, Desley Neil, Imo E Hoefer, Maria Fragiadaki, Johannes Waltenberger, Christian Weber, Marie-Luce Bochaton-Piallat, Magnus Bäck

Endothelial dysfunction in COVID-19: a position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science

https://doi.org/10.1093/cvr/cvaa230

Published

4-Aug-20

https://academic.oup.com/cardiovascres/article/116/14/2177/5880580

[We] provide a Position Statement on the importance of the endothelium in the underlying pathophysiology behind the clinical presentation in COVID-19 and identify key questions for future research to address. We propose that endothelial biomarkers and tests of function (e.g. flow-mediated dilatation) should be evaluated for their usefulness in the risk stratification of COVID-19 patients. A better understanding of the effects of SARS-CoV-2 on endothelial biology in both the micro- and macrovasculature is required, and endothelial function testing should be considered in the follow-up of convalescent COVID-19 patients for early detection of long-term cardiovascular complications.

Le Council on Basic Cardiovascular Science de la Société européenne de cardiologie recommande :
"Nous proposons que les biomarqueurs endothéliaux et les tests de fonction endothéliale (par exemple la dilatation à médiation par le flux) soient évalués pour leur utilité dans la stratification du risque des patients COVID-19. Une meilleure compréhension des effets du SRAS-CoV-2 sur la biologie endothéliale à la fois dans le domaine micro et macro-vasculaire est nécessaire, et des tests de la fonction endothéliale doivent être envisagés dans le suivi des patients convalescents COVID-19 pour la détection précoce des complications cardiovasculaires de la maladie à long terme."

1614

CaV042

ENDO

Peter Libby, Thomas Lüscher

COVID-19 is, in the end, an endothelial disease

https://doi.org/10.1093/eurheartj/ehaa623

Published

3-Sep-20

https://academic.oup.com/eurheartj/article/41/32/3038/5901158

This essay explores the hypothesis that COVID-19, particularly in the later complicated stages, represents an endothelial disease. Cytokines, protein pro-inflammatory mediators, serve as key danger signals that shift endothelial functions from the homeostatic into the defensive mode. The endgame of COVID-19 usually involves a cytokine storm, a phlogistic phenomenon fed by well-understood positive feedback loops that govern cytokine production and overwhelm counter-regulatory mechanisms. The concept of COVID-19 as an endothelial disease provides a unifying pathophysiological picture of this raging infection, and also provides a framework for a rational treatment strategy at a time when we possess an indeed modest evidence base to guide our therapeutic attempts to confront this novel pandemic.

_

1615

CaV043

ENDO

Zsuzsanna Varga,a Andreas J Flammer,b Peter Steiger,c Martina Haberecker,a Rea Andermatt,c Annelies S Zinkernagel,d Mandeep R Mehra,e Reto A Schuepbach,c Frank Ruschitzka,b and Holger Moch

Endothelial cell infection and endotheliitis in COVID-19

https://dx.doi.org/10.1016%2FS0140-6736(20)30937-5

Published

21-Apr-20

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172722/

Our findings show the presence of viral elements within endothelial cells and an accumulation of inflammatory cells, with evidence of endothelial and inflammatory cell death. These findings suggest that SARS-CoV-2 infection facilitates the induction of endotheliitis in several organs as a direct consequence of viral involvement (as noted with presence of viral bodies) and of the host inflammatory response. In addition, induction of apoptosis and pyroptosis might have an important role in endothelial cell injury in patients with COVID-19. COVID-19-endotheliitis could explain the systemic impaired microcirculatory function in different vascular beds and their clinical sequelae in patients with COVID-19. This hypothesis provides a rationale for therapies to stabilise the endothelium while tackling viral replication, particularly with anti-inflammatory anti-cytokine drugs, ACE inhibitors, and statins.7, 8, 9, 10, 11 This strategy could be particularly relevant for vulnerable patients with pre-existing endothelial dysfunction, which is associated with male sex, smoking, hypertension, diabetes, obesity, and established cardiovascular disease, all of which are associated with adverse outcomes in COVID-19.

Dans The Lancet, des chercheurs rapportent que le recrutement de cellules immunitaires lors d'une covid, soit par infection virale directe de l'endothélium, soit à médiation immunitaire, peut entraîner un dysfonctionnement endothélial généralisé associé à l'apoptose (mort cellulaire). Cela renforce selon les auteurs l'intérêt de thérapies comprenant des médicaments anti-inflammatoires anti-cytokines, des inhibiteurs de l'ACE2 et des statines.

N014E

___Cardio-Vascular___

Published study on 21-Apr-20:
"Endothelial cell infection and endotheliitis in COVID-19"
Dans The Lancet, des chercheurs rapportent que le recrutement de cellules immunitaires lors d'une covid, soit par infection virale directe de l'endothélium, soit à médiation immunitaire, peut entraîner un dysfonctionnement endothélial généralisé associé à l'apoptose (mort cellulaire). Cela renforce selon les auteurs l'intérêt de thérapies comprenant des médicaments anti-inflammatoires anti-cytokines, des inhibiteurs de l'ACE2 et des statines.
Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172722/
Extract: "Our findings show the presence of viral elements within endothelial cells and an accumulation of inflammatory cells, with evidence of endothelial and inflammatory cell death. These findings suggest that SARS-CoV-2 infection facilitates the induction of endotheliitis in several organs as a direct consequence of viral involvement (as noted with presence of viral bodies) and of the host inflammatory response. In addition, induction of apoptosis and pyroptosis might have an important role in endothelial cell injury in patients with COVID-19. COVID-19-endotheliitis could explain the systemic impaired microcirculatory function in different vascular beds and their clinical sequelae in patients with COVID-19. This hypothesis provides a rationale for therapies to stabilise the endothelium while tackling viral replication, particularly with anti-inflammatory anti-cytokine drugs, ACE inhibitors, and statins.7, 8, 9, 10, 11 This strategy could be particularly relevant for vulnerable patients with pre-existing endothelial dysfunction, which is associated with male sex, smoking, hypertension, diabetes, obesity, and established cardiovascular disease, all of which are associated with adverse outcomes in COVID-19."

1616

CaV044

ENDO

Florence WJ Chioh, Siew-Wai Fong, Barnaby E Young, Kan-Xing Wu, Anthony Siau, Shuba Krishnan, Yi-Hao Chan, Guillaume Carissimo, Louis LY Teo, Fei Gao, Ru San Tan, Liang Zhong, Angela S Koh, Seow-Yen Tan, Paul A Tambyah, Laurent Renia, Lisa FP Ng, David C Lye, Christine Cheung

Convalescent COVID-19 patients are susceptible to endothelial dysfunction due to persistent immune activation

https://doi.org/10.7554/eLife.64909

Published

23-Mar-21

Research Article

https://elifesciences.org/articles/64909

We found elevated levels of circulating endothelial cells (CECs), a biomarker of vascular injury, in COVID-19 convalescents compared to healthy controls. In particular, those with pre-existing conditions (e.g., hypertension, diabetes) had more pronounced endothelial activation hallmarks than non-COVID-19 patients with matched cardiovascular risk. Several proinflammatory and activated T lymphocyte-associated cytokines sustained from acute infection to recovery phase, which correlated positively with CEC measures, implicating cytokine-driven endothelial dysfunction. Notably, we found higher frequency of effector T cells in our COVID-19 convalescents compared to healthy controls. The activation markers detected on CECs mapped to counter receptors found primarily on cytotoxic CD8+ T cells, raising the possibility of cytotoxic effector cells targeting activated endothelial cells.

Une étude note un taux élevé de cellules endothéliales circulantes (CEC), un biomarqueur des lésions vasculaires, chez les convalescents de la covid par rapport aux témoins sains. Elle repère notamment des cytokines associées aux lymphocytes T pro-inflammatoires qui se maintiennent pendant la phase de récupération, impliquant un dysfonctionnement endothélial induit par celles-ci.

N009

___Cardio-Vascular___

Published research article on 23-Mar-21:
"Convalescent COVID-19 patients are susceptible to endothelial dysfunction due to persistent immune activation"
Une étude note un taux élevé de cellules endothéliales circulantes (CEC), un biomarqueur des lésions vasculaires, chez les convalescents de la covid par rapport aux témoins sains. Elle repère notamment des cytokines associées aux lymphocytes T pro-inflammatoires qui se maintiennent pendant la phase de récupération, impliquant un dysfonctionnement endothélial induit par celles-ci.
Link: https://elifesciences.org/articles/64909
Extract: "We found elevated levels of circulating endothelial cells (CECs), a biomarker of vascular injury, in COVID-19 convalescents compared to healthy controls. In particular, those with pre-existing conditions (e.g., hypertension, diabetes) had more pronounced endothelial activation hallmarks than non-COVID-19 patients with matched cardiovascular risk. Several proinflammatory and activated T lymphocyte-associated cytokines sustained from acute infection to recovery phase, which correlated positively with CEC measures, implicating cytokine-driven endothelial dysfunction. Notably, we found higher frequency of effector T cells in our COVID-19 convalescents compared to healthy controls. The activation markers detected on CECs mapped to counter receptors found primarily on cytotoxic CD8+ T cells, raising the possibility of cytotoxic effector cells targeting activated endothelial cells."

1617

CaV045

ENDO

Douglas Alexandre do Espírito Santo, Anna Cristina Bertoldi Lemos & Carlos Henrique Miranda

In vivo demonstration of microvascular thrombosis in severe COVID-19

https://doi.org/10.1007/s11239-020-02245-x

Published

13-Aug-20

Study

https://link.springer.com/article/10.1007/s11239-020-02245-x

We report preliminary results of an in vivo evaluation of sublingual microcirculation in thirteen patients with severe COVID-19 requiring mechanical ventilation. We observed multiple filling defects moving within the microvessels indicative of thrombi in most of the cases 11/13 (85%). Microthrombi in pulmonary circulation is a common finding in autopsies of severe COVID-19 patients.

In vivo evaluation of sublingual microcirculation of severe COVID-19 patients showed multiple filling defects moving within the microvessels indicative of thrombi in most of the cases.

This is the first imaging documentation of microvascular thrombosis in living severe COVID-19 patients.

The clinical relevance of microvascular thrombosis in COVID-19 requires further research.

_

1618

CaV046

ENDO

Alexandros Rovas # 1, Irina Osiaevi # 1, Konrad Buscher 1, Jan Sackarnd 2, Phil-Robin Tepasse 3, Manfred Fobker 4, Joachim Kühn 5, Stephan Braune 6, Ulrich Göbel 7, Gerold Thölking 1 8, Andreas Gröschel 9, Hermann Pavenstädt 1, Hans Vink 10, Philipp Kümpers

Microvascular dysfunction in COVID-19: the MYSTIC study

https://doi.org/10.1007/s10456-020-09753-7

Published

14-Oct-20

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556767/

Pre-clinical and autopsy studies have fueled the hypothesis that a dysregulated vascular endothelium might play a central role in the pathogenesis of ARDS and multi-organ failure in COVID-19. COVID-19 patients showed an up to 90% reduction in vascular density, almost exclusively limited to small capillaries (diameter 4–6 µm), and also significant reductions of VRBC. Especially, patients on mechanical ventilation showed severe glycocalyx damage as indicated by higher PBR values (i.e., thinner glycocalyx) and increased blood levels of shed glycocalyx constituents. Several markers of endothelial dysfunction were increased and correlated with disease severity in COVID-19. PBR (AUC 0.75, p = 0.01), ADAMTS13 (von Willebrand factor-cleaving protease; AUC 0.74, p = 0.02), and vascular endothelial growth factor A (VEGF-A; AUC 0.73, p = 0.04) showed the best discriminatory ability to predict 60-day in-hospital mortality.

Conclusions
Our data clearly show severe alterations of the microcirculation and the endothelial glycocalyx in patients with COVID-19. Future therapeutic approaches should consider the importance of systemic vascular involvement in COVID-19.

(Étude qui se concentre sur la fonction endothéliale pour comprendre les atteintes vasculaires.)

1619

CaV047

ENDO

Gerlando Natalello,a,⁎ Giacomo De Luca,b Laura Gigante,a Corrado Campochiaro,b Enrico De Lorenzis,a,c Lucrezia Verardi,a Annamaria Paglionico,a Luca Petricca,a Anna Maria Martone,f Stefania Calvisi,d Marco Ripa,e Giulio Cavalli,b Emanuel Della-Torre,b Moreno Tresoldi,d Francesco Landi,f Silvia Laura Bosello,a Elisa Gremese,a and Lorenzo Dagna

Nailfold capillaroscopy findings in patients with coronavirus disease 2019: Broadening the spectrum of COVID-19 microvascular involvement

https://dx.doi.org/10.1016%2Fj.mvr.2020.104071

Published

17-Sep-20

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494493/

Increasing evidence points to endothelial dysfunction as a key pathophysiological factor in coronavirus disease-2019 (COVID-19). No specific methods have been identified to predict, detect and quantify the microvascular alterations during COVID-19. Our aim was to assess microvasculature through nailfold videocapillaroscopy (NVC) in COVID-19 patients.

Methods
We performed NVC in patients with a confirmed diagnosis of COVID-19 pneumonia. Elementary alterations were reported for each finger according to a semi-quantitative score. Capillary density, number of enlarged and giant capillaries, number of micro-hemorrhages and micro-thrombosis (NEMO score) were registered.

Results
We enrolled 82 patients (mean age 58.8 ± 13.2 years, male 68.3%) of whom 28 during the hospitalization and 54 after recovery and hospital discharge. At NVC examination we found abnormalities classifiable as non-specific pattern in 53 patients (64.6%). Common abnormalities were pericapillary edema (80.5%), enlarged capillaries (61.0%), sludge flow (53.7%), meandering capillaries and reduced capillary density (50.0%). No pictures suggestive of scleroderma pattern have been observed. Acute COVID-19 patients, compared to recovered patients, showed a higher prevalence of hemosiderin deposits as a result of micro-hemorrhages (P = .027) and micro-thrombosis (P < .016), sludge flow (P = .001), and pericapillary edema (P < .001), while recovered patients showed a higher prevalence of enlarged capillaries (P < .001), loss of capillaries (P = .002), meandering capillaries (P < .001), and empty dermal papillae (P = .006).

Conclusion
COVID-19 patients present microvascular abnormalities at NVC. Currently ill and recovered subjects are characterized by a different distribution of elementary capillaroscopic alterations, resembling acute and post-acute microvascular damage. Further studies are needed to assess the clinical relevance of NVC in COVID-19.

Cette étude préconise d'utiliser la vidéo-capillaroscopie, qui enregistre nombre de microhémorragies et de micro-thromboses (score NEMO), pendant et après une hospitalisation.

1620

CaV048

Elliot Akama-Garren, Praveen Anand, Tudor Cristea-Platon, Patrick Lenehan, Emily Lindemer, Sairam Bade, Saran Liukasemsarn, John C. O’Horo, Ryan T. Hurt, Amy W. Williams, Gregory J. Gores, Andrew D. Badley, Samir Awasthi, Venky Soundararajan

Hair loss in females and thromboembolism in males are significantly enriched in post-acute sequelae of COVID (PASC) relative to recent medical history

https://doi.org/10.1101/2021.01.03.20248997

Pre-print

13-Apr-21

Study

https://www.medrxiv.org/content/10.1101/2021.01.03.20248997v2

Through comparison of the frequency of 10,039 signs and symptoms before and after diagnosis, we identified an increase in hypertensive chronic kidney disease (OR 47.3, 95% CI 23.9-93.6, p=3.50×10−9), thromboembolism (OR 3.84, 95% CI 3.22-4.57, p=1.18×10−4), and hair loss (OR 2.44, 95% CI 2.15-2.76, p=8.46×10−3) in COVID-19 patients three to six months after diagnosis. The sequelae associated with long COVID were notably different among male vs female patients and patients above vs under 55 years old, with the hair loss enrichment found primarily in females and the thromboembolism enrichment in males.

_

1621

CaV049

Nishant R. Tiwari 1
Sanat Phatak
Vivek R. Sharma
Sanjay K. Agarwal

COVID-19 and thrombotic microangiopathies

https://doi.org/10.1016/j.thromres.2021.04.012

Published

19-Apr-21

REVIEW ARTICLE

https://www.thrombosisresearch.com/article/S0049-3848(21)00297-8/fulltext

Highlights
•COVID – 19 infection can be associated with and complicated by the presence of thrombotic microangiopathies (TMAs).
•Available evidence points to higher incidence of TMAs in seriously ill COVID-19 infected patients.
•Treatment strategies for various TMAs including TPE, Eculizumab and immunosuppression in carefully selected patients can be lifesaving.
•Retrospective studies for defining the incidence of TMAs in and RCTs for guiding the therapy of such patients are required.

_

1622

CaV050

Louie F. Dy, Ryan C. V. Lintao, Cynthia P. Cordero, Ian Theodore G. Cabaluna & Leonila F. Dans

Prevalence and prognostic associations of cardiac abnormalities among hospitalized patients with COVID-19: a systematic review and meta-analysis

https://doi.org/10.1038/s41598-021-87961-x

Published

19-Apr-21

Review

https://www.nature.com/articles/s41598-021-87961-x

This study aims to estimate the proportion of COVID-19 patients with cardiac abnormalities and to determine the association between the cardiac abnormalities in COVID-19 patients and disease severity and mortality. Pooled prevalence of cardiac abnormalities in 20 studies was calculated to be 0.31 [95% Confidence Intervals (CI) of (0.23; 0.41)], with statistically significant heterogeneity (percentage of variation or I-squared statistic I2 = 97%, p < 0.01). Pooled analysis of 19 studies showed an overall odds ratio (OR) of 6.87 [95%-CI (3.92; 12.05)] for cardiac abnormalities associated with disease severity and mortality, with statistically significant heterogeneity (I2 = 85%, between-study variance or tau-squared statistic τ2 = 1.1485, p < 0.01). Due to the high uncertainty in the pooled prevalence of cardiac abnormalities and the unquantifiable magnitude of risk (although an increased risk is certain) for severity or mortality among COVID-19 patients, much more long-term prognostic studies are needed to check for the long-term complications of COVID-19 and formalize definitive criteria of “COVID-19 associated cardiomyopathy”.

Une analyse reprenant les données de plusieurs études suggère que les atteintes cardiaques chez les patients hospitalisées pour la covid peuvent concerner un quart des malades. Elles multiplieraient par 7 le risque de décès.

N011

___Cardio-Vascular___

Published review on 19-Apr-21:
"Prevalence and prognostic associations of cardiac abnormalities among hospitalized patients with COVID-19: a systematic review and meta-analysis"
Une analyse reprenant les données de plusieurs études suggère que les atteintes cardiaques chez les patients hospitalisées pour la covid peuvent concerner un quart des malades. Elles multiplieraient par 7 le risque de décès.
Link: https://www.nature.com/articles/s41598-021-87961-x
Extract: "This study aims to estimate the proportion of COVID-19 patients with cardiac abnormalities and to determine the association between the cardiac abnormalities in COVID-19 patients and disease severity and mortality. Pooled prevalence of cardiac abnormalities in 20 studies was calculated to be 0.31 [95% Confidence Intervals (CI) of (0.23; 0.41)], with statistically significant heterogeneity (percentage of variation or I-squared statistic I2 = 97%, p < 0.01). Pooled analysis of 19 studies showed an overall odds ratio (OR) of 6.87 [95%-CI (3.92; 12.05)] for cardiac abnormalities associated with disease severity and mortality, with statistically significant heterogeneity (I2 = 85%, between-study variance or tau-squared statistic τ2 = 1.1485, p < 0.01). Due to the high uncertainty in the pooled prevalence of cardiac abnormalities and the unquantifiable magnitude of risk (although an increased risk is certain) for severity or mortality among COVID-19 patients, much more long-term prognostic studies are needed to check for the long-term complications of COVID-19 and formalize definitive criteria of “COVID-19 associated cardiomyopathy”."

1623

CaV051

Santiago Garcia, Payam Dehghani, Cindy Grines, Laura Davidson, Keshav R. Nayak, Jacqueline Saw, Ron Waksman, John Blair, Bagai Akshay, Ross Garberich, David A. Wood, Frederick G. Welt, Jay Giri, Ehtisham Mahmud, Timothy D. Henry

Initial Findings From the North American COVID-19 Myocardial Infarction Registry

Published

1-Apr-21

Study

https://www.jacc.org/doi/abs/10.1016/j.jacc.2021.02.055

The coronavirus disease 2019 (COVID-19) pandemic has impacted many aspects of ST-segment elevation myocardial infarction (STEMI) care, including timely access to primary percutaneous coronary intervention (PPCI).
As of December 6, 2020, 1,185 patients were included in the NACMI registry (230 COVID+ patients, 495 PUIs, and 460 control patients). COVID+ patients were more likely to have minority ethnicity (Hispanic 23%, Black 24%) and had a higher prevalence of diabetes mellitus (46%) (all p < 0.001 relative to PUIs). COVID+ patients were more likely to present with cardiogenic shock (18%) but were less likely to receive invasive angiography (78%) (all p < 0.001 relative to control patients). Among COVID+ patients who received angiography, 71% received PPCI and 20% received medical therapy (both p < 0.001 relative to control patients). The primary outcome occurred in 36% of COVID+ patients, 13% of PUIs, and 5% of control patients (p < 0.001 relative to control patients).
Conclusions
COVID+ patients with STEMI represent a high-risk group of patients with unique demographic and clinical characteristics. PPCI is feasible and remains the predominant reperfusion strategy, supporting current recommendations.

Related pocast:
https://www.jacc.org/do/10.1016/podcast-jacc-77-16-3/full/

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1624

CaV052

LÁZARO ALFONSO PÉREZ CABRERA, NATALIA L. PLANAS SLIUNTIAEVA, RONALD AROCHE APORTELA

Miocarditis post COVID-19: a propósito de un caso tratado con Jusvinza

Published

28-Apr-21

Article

http://www.revcimeq.sld.cu/index.php/imq/article/view/716

La enfermedad causada por el coronavirus SARSCoV-2 (Covid - 19) se manifiesta por un amplio espectro en su presentación clínica, que va de la enfermedad asintomática hasta la insuficiencia respiratoria grave, lesión miocárdica y muerte. A medida que una mayor cantidad de pacientes se recuperan de la etapa aguda, aumentan los reportes de manifestaciones clínicas cardiovasculares como: insuficiencia cardíaca, arritmias, miocarditis, entre otras, que podrían ser consideradas como secuelas de la enfermedad. Los reportes existentes sobre miocarditis por coronavirus son escasos, pero al parecer se producen mayores daños cardiacos en los pacientes afectados por SARSCoV-2 que por otros coronavirus. Se presenta un paciente de 50 años, que acude por presentar palpitaciones, con el antecedente de Covid-19 diagnosticada hace 23 días. En urgencias se constatan, ruidos cardíacos arrítmicos y frecuencia cardiaca elevada, corroborándose en electrocardiograma fibrilación auricular con respuesta ventricular rápida, acompañado de una elevación de las enzimas cardíacas. Se diagnóstica como miocarditis Post Covid-19, se ingresa en cuidados intensivos y se comienza tratamiento antiarrítmico e inmunomodulador con Jusvinza.

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1625

CaV053

Rachel E. Szeghy Valesha M. Province Nina L. Stute Marc A. Augenreich Laurel K. Koontz Jonathon L. Stickford Abigail S. L. Stickford Stephen M. Ratchford

Carotid stiffness, intima media thickness, and aortic augmentation index among adults with SARS‐CoV‐2

https://doi.org/10.1113/EP089481

Published

26-Apr-21

Study

https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/EP089481

New Findings
What is the central question of this study?
This study sought to investigate whether carotid stiffness and cIMT, as well as aortic augmentation index, are altered in young adults 3–4 weeks following contraction of SARS‐CoV‐2 compared with young healthy adults.
What is the main finding and its importance?
The main findings were carotid stiffness, Young's modulus, and aortic augmentation index were greater in young adults who tested positive for SARS‐CoV‐2 compared with healthy young adults. These findings provide additional evidence for detrimental effects of SARS‐CoV‐2 on young adult vasculature, which may have implications for cardiovascular health.

Une étude sur 15 patients de 20 ans, 3 à 4 semaines après un test positif au SARS-CoV-2, constate une modification importante de l’état des artères par rapport à un groupe contrôle. Une rigidité plus nette et une moindre élasticité est notée. Notamment, l'artère carotide présente une capacité de gonflement inférieure à 27% et une élasticité moindre de 22%. L'artère aortique est également atteinte. Les auteurs estiment que l'augmentation constatée du module d'élasticité de Young, de plus d'un écart-type, pourrait représenter un surrisque supérieur à 15% de développer de l'hypertension dans les 3 ans si l'élasticité ne s'améliore pas. L'index d'augmentation AIx (heightened radial artery) correspond en moyenne à celui de sujets 10 and plus âgés. L'article précise enfin que la persistance à long terme de ces altérations demeure inconnue.

N009

___Cardio-Vascular___

Published study on 26-Apr-21:
"Carotid stiffness, intima media thickness, and aortic augmentation index among adults with SARS‐CoV‐2"
Une étude sur 15 patients de 20 ans, 3 à 4 semaines après un test positif au SARS-CoV-2, constate une modification importante de l’état des artères par rapport à un groupe contrôle. Une rigidité plus nette et une moindre élasticité est notée. Notamment, l'artère carotide présente une capacité de gonflement inférieure à 27% et une élasticité moindre de 22%. L'artère aortique est également atteinte. Les auteurs estiment que l'augmentation constatée du module d'élasticité de Young, de plus d'un écart-type, pourrait représenter un surrisque supérieur à 15% de développer de l'hypertension dans les 3 ans si l'élasticité ne s'améliore pas. L'index d'augmentation AIx (heightened radial artery) correspond en moyenne à celui de sujets 10 and plus âgés. L'article précise enfin que la persistance à long terme de ces altérations demeure inconnue.
Link: https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/EP089481
Extract: "New Findings
What is the central question of this study?
This study sought to investigate whether carotid stiffness and cIMT, as well as aortic augmentation index, are altered in young adults 3–4 weeks following contraction of SARS‐CoV‐2 compared with young healthy adults.
What is the main finding and its importance?
The main findings were carotid stiffness, Young's modulus, and aortic augmentation index were greater in young adults who tested positive for SARS‐CoV‐2 compared with healthy young adults. These findings provide additional evidence for detrimental effects of SARS‐CoV‐2 on young adult vasculature, which may have implications for cardiovascular health."

1626

CaV054

Samantha M. Morrissey, Anne E. Geller, Xiaoling Hu, David Tieri, Chuanlin Ding, Christopher K. Klaes, Elizabeth A. Cooke, Silvia M. Uriarte, Corey T. Watson, Jiapeng Huang, and Jun Yan

A specific low-density neutrophil population correlates with hypercoagulation and disease severity in hospitalized COVID-19 patients

https://doi.org/10.1172/jci.insight.148435

Published

10-May-21

Study

https://insight.jci.org/articles/view/148435

SARS coronavirus 2 (SARS-CoV-2) is a novel viral pathogen that causes a clinical disease called coronavirus disease 2019 (COVID-19). Although most COVID-19 cases are asymptomatic or involve mild upper respiratory tract symptoms, a significant number of patients develop severe or critical disease. Patients with severe COVID-19 commonly present with viral pneumonia that may progress to life-threatening acute respiratory distress syndrome (ARDS). Patients with COVID-19 are also predisposed to venous and arterial thromboses that are associated with a poorer prognosis. The present study identified the emergence of a low-density inflammatory neutrophil (LDN) population expressing intermediate levels of CD16 (CD16Int) in patients with COVID-19. These cells demonstrated proinflammatory gene signatures, activated platelets, spontaneously formed neutrophil extracellular traps, and enhanced phagocytic capacity and cytokine production. Strikingly, CD16Int neutrophils were also the major immune cells within the bronchoalveolar lavage fluid, exhibiting increased CXCR3 but loss of CD44 and CD38 expression. The percentage of circulating CD16Int LDNs was associated with D-dimer, ferritin, and systemic IL-6 and TNF-α levels and changed over time with altered disease status. Our data suggest that the CD16Int LDN subset contributes to COVID-19–associated coagulopathy, systemic inflammation, and ARDS. The frequency of that LDN subset in the circulation could serve as an adjunct clinical marker to monitor disease status and progression.

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1627

CaV055

Saikat Mitra 1, Ryan Ruiyang Ling, Isabelle Xiaorui Yang, Wynne Hsing Poon, Chuen Seng Tan, Paul Monagle, Graeme MacLaren, Kollengode Ramanathan

Severe COVID-19 and coagulopathy: A systematic review and meta-analysis

https://doi.org/10.47102/annals-acadmedsg.2020420

Published

1-Apr-21

Review

https://pubmed.ncbi.nlm.nih.gov/33990820/

Methods: We conducted a systematic review of the literature (until 1 June 2020) to assess CIC and disease severity during the early COVID-19 pandemic. Primary outcomes were pooled mean differences in platelet count, D-dimer level, prothrombin time, activated partial thromboplastin time (aPTT) and fibrinogen level between non-severe and severe patients, stratified by degree of hypoxaemia or those who died. The risk factors for CIC were analysed. Random-effects meta-analyses and meta-regression were performed using R version 3.6.1, and certainty of evidence was rated using the Grading of Recommendation, Assessment, Development, and Evaluation approach.
Results: Of the included 5,243 adult COVID-19 patients, patients with severe COVID-19 had a significantly lower platelet count, and higher D-dimer level, prothrombin time and fibrinogen level than non-severe patients. Pooled mean differences in platelet count (-19.7×109 /L, 95% confidence interval [CI] -31.7 to -7.6), D-dimer level (0.8μg/mL, 95% CI 0.5–1.1), prothrombin time (0.4 second, 95% CI 0.2–0.6) and fibrinogen level (0.6g/L, 95% CI 0.3–0.8) were significant between the groups. Platelet count and D-dimer level were significant predictors of disease severity on meta-regression analysis. Older men had higher risks of severe coagulopathic disease.
Conclusion: Significant variability in CIC exists between non-severe and severe patients, with platelet count and D-dimer level correlating with disease severity. Routine monitoring of all coagulation parameters may help to assess CIC and decide on the appropriate management.
This systematic review and meta-analysis demonstrated significant variability of the coagulation parameters in non-severe versus severe COVID-19. COVID-19 patients manifest a dynamic coagulation profile with the progression of disease severity. Both platelet count and D-dimer level significantly correlated with the severity.

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1628

CaV056

Sujin Kang, Toshio Tanaka, Hitomi Inoue, Chikako Ono, Shoji Hashimoto, Yoshiyuki Kioi, Hisatake Matsumoto, Hiroshi Matsuura, Tsunehiro Matsubara, Kentaro Shimizu, Hiroshi Ogura, Yoshiharu Matsuura, and Tadamitsu Kishimoto

Reply to Cheng et al.: COVID-19 induces lower extent of cytokines, but damages vascular endothelium by IL-6 signaling

https://doi.org/10.1073/pnas.2105040118

Published

25-May-21

Reply

https://www.pnas.org/content/118/21/e2105040118

The IL-6 concentrations in patients with COVID-19 are significantly lower than those in patients with sepsis or ARDS patients (2, 3). COVID-19 patients were heterogeneous, from critical to severe cases, in the primary analysis, with a broad range of IL-6 concentrations, from 6.5 pg/mL to 357.2 pg/mL (3). Notably, severe acute respiratory syndrome coronavirus 2 infection causes pulmonary endothelial injury and increases IL-6 production by endothelial cells (4). Moreover, several in vitro data from multiple studies indicate that IL-6 trans-signaling in vascular endothelial cells can induce the production of IL-6, IL-8, and MCP-1. The extent to which severe COVID-19 causes endothelial injury can depend on the site of insult and the basis of systemic inflammatory profiles (5, 6). Importantly, the levels of acute-phase proteins such as C-reactive protein, which is induced by IL-6, and D-dimer were elevated in patients with COVID-19, and the concentrations of these proteins were comparable between patients with COVID-19 and those with sepsis. Increasing IL-6 levels might function in endothelial activation and the coagulation cascade in pulmonary tissue; this possibility supports the findings of recent clinical trials indicating that IL-6 signaling-inhibiting therapeutics are beneficial for treating severe cases of COVID-19 (7, 8).

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1629

CaV057

Questionable methodology

Lize M. Grobbelaar, Chantelle Venter, Mare Vlok, Malebogo Ngoepe, Gert Jacobus Laubscher, Petrus Johannes Lourens, Janami Steenkamp, Douglas B. Kell, Etheresia Pretorius

SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: Implications for microclot formation in COVID-19

https://doi.org/10.1101/2021.03.05.21252960

pre-print

8-Mar-21

Study

https://www.medrxiv.org/content/10.1101/2021.03.05.21252960v1

Here we suggest that, in part, the presence of spike protein in circulation may contribute to the hypercoagulation in COVID-19 positive patients and may cause substantial impairment of fibrinolysis. Such lytic impairment may result in the persistent large microclots we have noted here and previously in plasma samples of COVID-19 patients. This observation may have important clinical relevance in the treatment of hypercoagulability in COVID-19 patients.

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1630

CaV058

Sebastian Fridman, Maria Bres Bullrich, Amado Jimenez-Ruiz, Pablo Costantini, Palak Shah, Caroline Just, Daniel Vela-Duarte, Italo Linfante, Athena Sharifi-Razavi, Narges Karimi, Rodrigo Bagur, Derek B. Debicki, Teneille E. Gofton, David A. Steven, Luciano A. Sposato

Stroke risk, phenotypes, and death in COVID-19
Systematic review and newly reported cases

https://doi.org/10.1212/WNL.0000000000010851

Published

15-Dec-20

Study

https://n.neurology.org/content/95/24/e3373

The proportions of patients with COVID-19 with stroke (1.8%, 95% confidence interval [CI] 0.9%–3.7%) and in-hospital mortality (34.4%, 95% CI 27.2%–42.4%) were exceedingly high. Mortality was 67% lower in patients <50 years of age relative to those >70 years of age (odds ratio [OR] 0.33, 95% CI 0.12–0.94, p = 0.039). Large vessel occlusion was twice as frequent (46.9%) as previously reported and was high across all age groups, even in the absence of risk factors or comorbid conditions. A clinical phenotype characterized by older age, a higher burden of comorbid conditions, and severe COVID-19 respiratory symptoms was associated with the highest in-hospital mortality (58.6%) and a 3 times higher risk of death than the rest of the cohort (OR 3.52, 95% CI 1.53–8.09, p = 0.003).

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1631

CaV059

Curt J. Daniels, Saurabh Rajpal, Joel T. Greenshields, Geoffrey L. Rosenthal, Eugene H. Chung, Michael Terrin, Jean Jeudy, Scott E. Mattson, Ian H. Law, James Borchers, Richard Kovacs, Jeffrey Kovan, Sami F. Rifat, Christopher J. Kratochvil, Lawrence D. Rink, for the Big Ten COVID-19 Cardiac Registry Investigators

Prevalence of Clinical and Subclinical Myocarditis in Competitive Athletes With Recent SARS-CoV-2 Infection
Results From the Big Ten COVID-19 Cardiac Registry

http://jamanetwork.com/article.aspx?doi=10.1001/jamacardio.2021.2065

Published

27-May-21

Study

https://jamanetwork.com/journals/jamacardiology/fullarticle/2780548

In this cohort study of 1597 US competitive collegiate athletes undergoing comprehensive cardiovascular testing, the prevalence of clinical myocarditis based on a symptom-based screening strategy was only 0.31%. Screening with cardiovascular magnetic resonance imaging increased the prevalence of clinical and subclinical myocarditis by a factor of 7.4 to 2.3%.

These cardiac magnetic resonance imaging findings provide important data on the prevalence of clinical and subclinical myocarditis in college athletes recovering from symptomatic and asymptomatic COVID-19 infections.
At present, we do not know the natural history or the short- and long-term implications to an athlete with COVID-19 clinical or subclinical myocarditis. To address these concerns, we must find ways to minimize the variability in performance among academic centers to diagnose myocarditis, perhaps through standardized evidence-based diagnostic algorithms and testing protocols, and when indicated, standardization of CMR protocols and interpretation.

Sur 1597 athlètes américains testés positifs à la covid, 2,3% avaient une myocardite clinique ou subclinique selon une étude. Les patients pour qui des symptômes étaient visibles représentaient 0,3%.

N011

___Cardio-Vascular___

Published study on 27-May-21:
"Prevalence of Clinical and Subclinical Myocarditis in Competitive Athletes With Recent SARS-CoV-2 Infection
Results From the Big Ten COVID-19 Cardiac Registry"
Sur 1597 athlètes américains testés positifs à la covid, 2,3% avaient une myocardite clinique ou subclinique selon une étude. Les patients pour qui des symptômes étaient visibles représentaient 0,3%.
Link: https://jamanetwork.com/journals/jamacardiology/fullarticle/2780548
Extract: "In this cohort study of 1597 US competitive collegiate athletes undergoing comprehensive cardiovascular testing, the prevalence of clinical myocarditis based on a symptom-based screening strategy was only 0.31%. Screening with cardiovascular magnetic resonance imaging increased the prevalence of clinical and subclinical myocarditis by a factor of 7.4 to 2.3%.

These cardiac magnetic resonance imaging findings provide important data on the prevalence of clinical and subclinical myocarditis in college athletes recovering from symptomatic and asymptomatic COVID-19 infections.
At present, we do not know the natural history or the short- and long-term implications to an athlete with COVID-19 clinical or subclinical myocarditis. To address these concerns, we must find ways to minimize the variability in performance among academic centers to diagnose myocarditis, perhaps through standardized evidence-based diagnostic algorithms and testing protocols, and when indicated, standardization of CMR protocols and interpretation."

1632

CaV060

Farnaz Farshidfar, Navid Koleini, and Hossein Ardehali

Cardiovascular complications of COVID-19

Published

1-Jun-21

Review

https://df6sxcketz7bb.cloudfront.net/manuscripts/148000/148980/jci.insight.148980.v1.pdf

The presence of pre-existing cardiovascular disease increases mortality in COVID-19 patients, and cardiovascular injuries, including myocarditis, cardiac rhythm abnormalities, endothelial cell injury, thrombotic events, and myocardial interstitial fibrosis, are observed in some COVID-19 patients. The underlying pathophysiology of COVID-19-associated cardiovascular complications is not fully understood, although direct viral infection of myocardium and cytokine storm have been suggested as possible mechanisms of myocarditis. In this review, we summarize available data on SARS-
2 CoV-2-related cardiac damage and discuss potential mechanisms of cardiovascular implications of this rapidly spreading virus.

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1633

CaV061

Ian Paterson 1, Krishnan Ramanathan 2, Rakesh Aurora 3, David Bewick 4, Chi-Ming Chow 5, Brian Clarke 6, , Larry Sterns 18, Ricky Turgeon 19, Sean Virani 20, Kenny K Wong 21, Shelley Zieroth 22

Long COVID-19: A Primer for Cardiovascular Health Professionals On Behalf of the CCS Rapid Response Team

https://doi.org/10.1016/j.cjca.2021.05.011

Published

3-Jun-21

Guidance

https://pubmed.ncbi.nlm.nih.gov/34090980/

It is now widely recognized that COVID-19 illness can be associated with significant intermediate and potentially longer-term physical limitations. The term “Long COVID-19” is used to define any patient with persistent symptoms after acute COVID-19 (i.e. after 4 weeks). It is postulated that cardiac injury may be linked to symptoms that persist following resolution of acute infection, as part of this syndrome. The Canadian Cardiovascular Society Rapid Response Team has generated this document to provide guidance to health care providers on the optimal management of patients with suspected cardiac complications of Long COVID-19.

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1634

CaV062

Jenna Stephanie O'Sullivan1, Andrew Lyne2 and Carl J Vaughan1

COVID-19-induced postural orthostatic tachycardia syndrome treated with ivabradine

http://dx.doi.org/10.1136/bcr-2021-243585

Published

14-Jun-21

Case Report

https://casereports.bmj.com/content/14/6/e243585

Evaluation revealed a resting sinus tachycardia and criteria for postural orthostatic tachycardia syndrome were met. After non-pharmacological interventions failed to yield symptomatic improvement, ivabradine was commenced. This intervention was followed by a substantial improvement in the patient’s exercise tolerance and energy levels and an objective reduction in supine and standing heart rate.

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1635

CaV063

Marketa Kubankova, Bettina Hohberger, Jakob Hoffmanns, Julia Fuerst, Martin Hermann, Jochen Guck, Martin Krater

Physical phenotype of blood cells is altered in COVID-19

Publication of CaV26
https://doi.org/10.1016/j.bpj.2021.05.025

Published

2-Jun-21

New Results

https://www.sciencedirect.com/science/article/pii/S0006349521004549

"We found significant changes in erythrocyte deformability, lymphocyte stiffness, monocyte size, and neutrophil size and deformability. While some of these changes recovered to normal values after hospitalization, others persisted for months after hospital discharge, evidencing the long-term imprint of COVID-19 on the body."
"neutrophil alterations observed in our recovered cohort were induced after the successful displacement of the virus by the immune system. This might be indicative for SARS-CoV-2 causing long-term immunological signals or even targeting bone marrow stem cells, as viral RNA was found post-mortem in patient bone marrow"
"These alterations could be connected with long term symptoms of the recovered patients"

Sur une cohorte assez réduite, une étude allemande note chez les patients guéris de la phase aiguë de la covid des altérations des globules rouges et des granulocytes neutrophiles qui pourraient avoir des effets à long terme.
Des changements dans la déformabilité érythrocytaire ainsi que celle des neutrophiles et de leur taille, se retrouvent avec des écarts statistiquement significatifs, sur une médiane de 7 mois après l'infection au SARS-CoV-2.

N014E

___Cardio-Vascular___

Published new results on 2-Jun-21:
"Physical phenotype of blood cells is altered in COVID-19"
Sur une cohorte assez réduite, une étude allemande note chez les patients guéris de la phase aiguë de la covid des altérations des globules rouges et des granulocytes neutrophiles qui pourraient avoir des effets à long terme.
Des changements dans la déformabilité érythrocytaire ainsi que celle des neutrophiles et de leur taille, se retrouvent avec des écarts statistiquement significatifs, sur une médiane de 7 mois après l'infection au SARS-CoV-2.
Link: https://www.sciencedirect.com/science/article/pii/S0006349521004549
Extract: ""We found significant changes in erythrocyte deformability, lymphocyte stiffness, monocyte size, and neutrophil size and deformability. While some of these changes recovered to normal values after hospitalization, others persisted for months after hospital discharge, evidencing the long-term imprint of COVID-19 on the body."
"neutrophil alterations observed in our recovered cohort were induced after the successful displacement of the virus by the immune system. This might be indicative for SARS-CoV-2 causing long-term immunological signals or even targeting bone marrow stem cells, as viral RNA was found post-mortem in patient bone marrow"
"These alterations could be connected with long term symptoms of the recovered patients""

1636

CaV064

David M. Smadja, Steven J. Mentzer, Michaela Fontenay, Mike A. Laffan, Maximilian Ackermann, Julie Helms, Danny Jonigk, Richard Chocron, Gerald B. Pier, Nicolas Gendron, Stephanie Pons, Jean-Luc Diehl, Coert Margadant, Coralie Guerin, Elisabeth J. M. Huijbers, Aurélien Philippe, Nicolas Chapuis, Patrycja Nowak-Sliwinska, Christian Karagiannidis, Olivier Sanchez, Philipp Kümpers, David Skurnik, Anna M. Randi & Arjan W. Griffioen

COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects

https://doi.org/10.1007/s10456-021-09805-6

Published

28-Jun-21

Review

https://link.springer.com/article/10.1007/s10456-021-09805-6

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is presenting as a systemic disease associated with vascular inflammation and endothelial injury. Severe forms of SARS-CoV-2 infection induce acute respiratory distress syndrome (ARDS) and there is still an ongoing debate on whether COVID-19 ARDS and its perfusion defect differs from ARDS induced by other causes. Beside pro-inflammatory cytokines (such as interleukin-1 β [IL-1β] or IL-6), several main pathological phenomena have been seen because of endothelial cell (EC) dysfunction: hypercoagulation reflected by fibrin degradation products called D-dimers, micro- and macrothrombosis and pathological angiogenesis. Direct endothelial infection by SARS-CoV-2 is not likely to occur and ACE-2 expression by EC is a matter of debate. Indeed, endothelial damage reported in severely ill patients with COVID-19 could be more likely secondary to infection of neighboring cells and/or a consequence of inflammation. Endotheliopathy could give rise to hypercoagulation by alteration in the levels of different factors such as von Willebrand factor. Other than thrombotic events, pathological angiogenesis is among the recent findings. Overexpression of different proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) or placental growth factors (PlGF) have been found in plasma or lung biopsies of COVID-19 patients. Finally, SARS-CoV-2 infection induces an emergency myelopoiesis associated to deregulated immunity and mobilization of endothelial progenitor cells, leading to features of acquired hematological malignancies or cardiovascular disease, which are discussed in this review. Altogether, this review will try to elucidate the pathophysiology of thrombotic complications, pathological angiogenesis and EC dysfunction, allowing better insight in new targets and antithrombotic protocols to better address vascular system dysfunction. Since treating SARS-CoV-2 infection and its potential long-term effects involves targeting the vascular compartment and/or mobilization of immature immune cells, we propose to define COVID-19 and its complications as a systemic vascular acquired hemopathy.

La covid est une 𝗵𝗲́𝗺𝗼𝗽𝗮𝘁𝗵𝗶𝗲 (𝗺𝗮𝗹𝗮𝗱𝗶𝗲 𝗱𝘂 𝘀𝗮𝗻𝗴) 𝘃𝗮𝘀𝗰𝘂𝗹𝗮𝗶𝗿𝗲 𝘀𝘆𝘀𝘁𝗲́𝗺𝗶𝗾𝘂𝗲 acquise, résume un groupe de chercheurs français dans le journal Angiogenesis. L'étude explore la physiopathlogie de la covid et note que l'infection induit une myélopoïèse d'urgence associée à une immunité dérégulée et à une mobilisation des cellules progénitrices endothéliales, conduisant à des caractéristiques de malignités hématologiques acquises ou de maladies cardiovasculaires.

N014E

___Cardio-Vascular___

Published review on 28-Jun-21:
"COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects"
La covid est une 𝗵𝗲́𝗺𝗼𝗽𝗮𝘁𝗵𝗶𝗲 (𝗺𝗮𝗹𝗮𝗱𝗶𝗲 𝗱𝘂 𝘀𝗮𝗻𝗴) 𝘃𝗮𝘀𝗰𝘂𝗹𝗮𝗶𝗿𝗲 𝘀𝘆𝘀𝘁𝗲́𝗺𝗶𝗾𝘂𝗲 acquise, résume un groupe de chercheurs français dans le journal Angiogenesis. L'étude explore la physiopathlogie de la covid et note que l'infection induit une myélopoïèse d'urgence associée à une immunité dérégulée et à une mobilisation des cellules progénitrices endothéliales, conduisant à des caractéristiques de malignités hématologiques acquises ou de maladies cardiovasculaires.
Link: https://link.springer.com/article/10.1007/s10456-021-09805-6
Extract: "Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is presenting as a systemic disease associated with vascular inflammation and endothelial injury. Severe forms of SARS-CoV-2 infection induce acute respiratory distress syndrome (ARDS) and there is still an ongoing debate on whether COVID-19 ARDS and its perfusion defect differs from ARDS induced by other causes. Beside pro-inflammatory cytokines (such as interleukin-1 β [IL-1β] or IL-6), several main pathological phenomena have been seen because of endothelial cell (EC) dysfunction: hypercoagulation reflected by fibrin degradation products called D-dimers, micro- and macrothrombosis and pathological angiogenesis. Direct endothelial infection by SARS-CoV-2 is not likely to occur and ACE-2 expression by EC is a matter of debate. Indeed, endothelial damage reported in severely ill patients with COVID-19 could be more likely secondary to infection of neighboring cells and/or a consequence of inflammation. Endotheliopathy could give rise to hypercoagulation by alteration in the levels of different factors such as von Willebrand factor. Other than thrombotic events, pathological angiogenesis is among the recent findings. Overexpression of different proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) or placental growth factors (PlGF) have been found in plasma or lung biopsies of COVID-19 patients. Finally, SARS-CoV-2 infection induces an emergency myelopoiesis associated to deregulated immunity and mobilization of endothelial progenitor cells, leading to features of acquired hematological malignancies or cardiovascular disease, which are discussed in this review. Altogether, this review will try to elucidate the pathophysiology of thrombotic complications, pathological angiogenesis and EC dysfunction, allowing better insight in new targets and antithrombotic protocols to better address vascular system dysfunction. Since treating SARS-CoV-2 infection and its potential long-term effects involves targeting the vascular compartment and/or mobilization of immature immune cells, we propose to define COVID-19 and its complications as a systemic vascular acquired hemopathy."

1637

CaV065

Anna Giulia Falchi
Sergio Leonardi
Giovanni Cappa
Stefano Perlini

Subclinical pericarditis long after SARS-CoV-2 infection: a case report

https://doi.org/10.4081/ecj.2021.9782

Published

28-Jun-21

Case Report

https://www.pagepressjournals.org/index.php/ecj/article/view/9782

We describe a rare complication of COVID-19 long after infection in a 76-years-old man presented to the Emergency Department with dyspnea and palpitations. A 12-lead Electrocardiogram (ECG) showed sinus tachycardia PR depression in the inferior leads associated with an apparent pseudo ST elevation. In the absence of elevation of inflammatory indices, considering the lack of symptoms neither NSAIDs nor colchicine were prescribed, and the patient was referred for clinical follow-up. After ten days ECG documented initial reduction of the widespread concave STE and PR depression, and the 1-month follow- up visit, the patient was asymptomatic with unremarkable physical examination, and a 12-lead ECG showed almost complete normalization of the ST and PR segments.

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1638

CaV066

Clement C. E. Lee,Kashan Ali,David Connell,Ify R. Mordi ,Jacob George ,Elizabeth MSL Lang andChim C. Lang *

COVID-19-Associated Cardiovascular Complications

https://doi.org/10.3390/diseases9030047

Published

29-Jun-21

Review

https://www.mdpi.com/2079-9721/9/3/47/htm

Coronavirus disease 2019 (COVID-19) has been reported to cause cardiovascular complications such as myocardial injury, thromboembolic events, arrhythmia, and heart failure. Multiple mechanisms—some overlapping, notably the role of inflammation and IL-6—potentially underlie these complications. The reported cardiac injury may be a result of direct viral invasion of cardiomyocytes with consequent unopposed effects of angiotensin II, increased metabolic demand, immune activation, or microvascular dysfunction. Thromboembolic events have been widely reported in both the venous and arterial systems that have attracted intense interest in the underlying mechanisms. These could potentially be due to endothelial dysfunction secondary to direct viral invasion or inflammation. Additionally, thromboembolic events may also be a consequence of an attempt by the immune system to contain the infection through immunothrombosis and neutrophil extracellular traps. Cardiac arrhythmias have also been reported with a wide range of implicated contributory factors, ranging from direct viral myocardial injury, as well as other factors, including at-risk individuals with underlying inherited arrhythmia syndromes. Heart failure may also occur as a progression from cardiac injury, precipitation secondary to the initiation or withdrawal of certain drugs, or the accumulation of des-Arg9-bradykinin (DABK) with excessive induction of pro-inflammatory G protein coupled receptor B1 (BK1). The presenting cardiovascular symptoms include chest pain, dyspnoea, and palpitations. There is currently intense interest in vaccine-induced thrombosis and in the treatment of Long COVID since many patients who have survived COVID-19 describe persisting health problems. This review will summarise the proposed physiological mechanisms of COVID-19-associated cardiovascular complications.

1639

CaV067

Sanjay R Agarwala1, Mayank Vijayvargiya2 and Prashant Pandey2

Avascular necrosis as a part of ‘long COVID-19’

http://dx.doi.org/10.1136/bcr-2021-242101

Published

2-Jul-21

Case report

https://casereports.bmj.com/content/14/7/e242101

We report a series of three cases in which patients developed AVN of the femoral head after being treated for COVID-19 infection. The mean dose of prednisolone used in these cases was 758 mg (400–1250 mg), which is less than the mean cumulative dose of around 2000 mg steroid, documented in the literature as causative for AVN. Patients were symptomatic and developed early AVN presentation at a mean of 58 days after COVID-19 diagnosis as compared with the literature which shows that it generally takes 6 months to 1 year to develop AVN post steroid exposure.

1640

CaV068

Lee Stoner1, 2, *(), Mark Faghy2, 3, 4, Ryan Conners2, 5

COVID-19 infection and cardiometabolic complications: short- and long-term treatment and management considerations

https://doi.org/10.31083/j.rcm2202031

Published

30-Jun-21

Review

https://rcm.imrpress.com/EN/10.31083/j.rcm2202031

Below we pose some of the many questions of interest to chronic disease management (summarized in Fig. 1), with an emphasis on cardiometabolic disease, during and following COVID-19. On behalf of HL-PIVOT (Healthy Living for Pandemic Event Protection) and Exercise is Medicine® (EIM) Underserved & Community Health, this special issue aims to expand the discourse related to the short- and long-term impact of COVID19 on individual and public health. Below we pose some of the many topics of interest to chronic disease management, with an emphasis on cardiometabolic disease. during and following COVID-19. The intention of this section is to ignite interest in this special issue and spur continued discourse from authors across the biomedical spectrum.

1641

CaV069

Fatih Akkaya,1 Feyza Nur Topçu Yenerçağ,2 Ahmet Kaya,1 Yusuf Ziya Şener,corresponding author3 and Ali Bağcı4

Long term effects of mild severity COVID‑19 on right ventricular functions

https://dx.doi.org/10.1007%2Fs10554-021-02340-x

Published

12-Jul-21

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274467/

The aim of our study was to evaluate the right ventricular functions of mild severity COVID-19 patients 3 months after, and compare them to the right ventricular functions of healthy volunteers. For this single-center study, data from 105 patients who were treated for mild severity COVID-19 between September 15, 2020 and December 31, 2020 were collected. 105 age and sex matched healthy subjects were included in the study. Right ventricular (RV) functions were evaluated using conventional two-dimensional (2D) echocardiography and 2D speckle-tracking echocardiography (STE) for all patients. 2D-E parameters indicating RV functions were compared between the two groups. RV diamaters, systolic pulmonary artery pressure (sPAP) and RV myocardial performance index (RV MPI) were significantly higher in the COVID-19 patients compared to control group (p < 0.05). Tricuspid annular plane systolic motion (TAPSE), right ventricular fractional area change (RVFAC) and RV S’ were significantly lower in the COVID-19 group compared to control group (p < 0.05). RV global longitudinal strain (RV-GLS) (− 19.6 ± 5.2 vs. − 15.1 ± 3.4, p < 0.001) and RV free wall longitudinal strain RV-FWLS (− 19.6 ± 5.2 vs. − 17.2 ± 4.4, p < 0.001) values were significantly lower in the COVID-19 group than the control group. There was a significant negative correlation between RV-FWLS, RV-GLS and C-reactive protein (CRP), neutrophil to lymphocyte ratio (NLR), d-dimer, ferritin, platelet to lymphocyte ratio (PLR) in patients with mild severity COVID-19. This results suggested that RV-GLS and RV-FWLS decreased in the long term (third month) follow-up of patients treated for mild severity COVID-19 disease. Subclinical RV dysfunction may be observed in patients after mild severity COVID-19.

1642

CaV070

Katherine Chenevey, William Murdoch, A. Vincent Songco

COVID-19-Induced Cardiomyopathy in a Young Nulliparous Woman

https://doi.org/10.7759/cureus.16516

Published

20-Jul-21

Case Report

https://www.cureus.com/articles/64043-covid-19-induced-cardiomyopathy-in-a-young-nulliparous-woman

A young nulliparous woman presented with new-onset heart failure several weeks after an asymptomatic coronavirus disease 2019 (COVID-19) infection. Investigation revealed non-ischemic cardiomyopathy without apical ballooning. A literature review demonstrates other reported cases of COVID-19-induced cardiomyopathy; however, our patient was demographically unique from previously described cases, presented later, and did not have Takotsubo-like findings. Our patient continued to have evidence of cardiac remodeling and a reduced ejection fraction months after presentation. This case highlights the importance of surveilling for the post-infectious sequelae of COVID-19, along with the wide demographic range of patients susceptible to such outcomes.

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1643

CaV071

Jayanta Kumar Biswal, Sujit Kumar Mohanty, Satya Narayan Behera, Santanu Kumar Swain, Ashok Kumar Sahoo

Acute Limb Ischemia: A Catastrophic COVID-19 Sequel Leading to Amputation

https://doi.org/10.7759/cureus.16456

Published

18-Jul-21

Case Report

https://www.cureus.com/articles/64302-acute-limb-ischemia-a-catastrophic-covid-19-sequel-leading-to-amputation

A positive-sense single-stranded ribonucleic acid (RNA) virus causes the novel coronavirus illness 2019 (COVID-19). COVID-19 symptoms range from mild to moderate to severe and very severe. Fever, cough, headache, anosmia, ageusia, body ache, and diarrhoea are mild to moderate grade symptoms, whereas systemic involvements (pneumonia, myocarditis, stroke, and other coagulation abnormalities) are more serious. Except for a few patients who have mild complaints of cough and shortness of breath, the majority of patients are recuperating entirely from the viral infection. Patients with severe to very severe illnesses experience significant lung damage and fibrosis. These are the patients who are more likely to experience extrapulmonary complications after COVID-19. The disease's aberrant presentation may be related to systemic involvement and a hypercoagulable condition with micro and macro-angiopathy. Acute limb ischemia is one of the symptoms of the hypercoagulable condition. Its presentation can be in the form of chilblains, bullae, acral cyanosis, bruising, blood blisters, dry gangrene, or life-threatening acute limb ischemia. Unfortunately, most patients have to undergo amputation due to a delay in presentation or rapidly progressing disease. Here we present a case series of two COVID-19 infected patients who were initially discharged from the hospital after proper treatment but developed acute limb ischemia within the home isolation period and their treatment strategy.

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1644

CaV072

Damsara Nandadeva 1, Benjamin E Young 1, Brandi Y Stephens 1, Ann-Katrin Grotle 1, Rachel J Skow 1, Angela J Middleton 2, Florence P Haseltine 3, Paul J Fadel 1

Blunted peripheral but not cerebral vasodilator function in young otherwise healthy adults with persistent symptoms following COVID-19

https://doi.org/10.1152/ajpheart.00368.2021

Published

23-Jul-21

Study

https://pubmed.ncbi.nlm.nih.gov/34296966/

Recent findings suggest that COVID-19 causes vascular dysfunction during the acute phase of the illness in otherwise healthy young adults. To date, no studies have investigated the longer-term effects of COVID-19 on vascular function. Herein, we hypothesized that young, otherwise healthy adults who are past the acute phase of COVID-19 would exhibit blunted peripheral (brachial artery flow-mediated dilation (FMD) and reactive hyperemia) and cerebral vasodilator function (cerebral vasomotor reactivity to hypercapnia; CVMR) and increased central arterial stiffness. Sixteen young adults who were at least 4 weeks past a COVID-19 diagnosis and 12 controls who never had COVID-19 were studied. Eight COVID subjects were symptomatic (SYM) and 8 were asymptomatic (ASYM) at the time of testing. FMD and reactive hyperemia were not different between COVID and Control groups. However, FMD was lower in SYM (3.8 ± 0.6%) compared to ASYM (6.8 ± 0.9%; P = 0.007) and Control (6.8 ± 0.6%; P = 0.003) with no difference between ASYM and Control. Similarly, peak blood velocity following cuff release was lower in SYM (47 ± 8 cm/s) compared to ASYM (64 ± 19 cm/s; P = 0.025) and Control (61 ± 14 cm/s; P = 0.036). CVMR and arterial stiffness were not different between any groups. In summary, peripheral macro- and microvascular function, but not cerebral vascular function or central arterial stiffness were blunted in young adults symptomatic beyond the acute phase of COVID-19. In contrast, those who were asymptomatic had similar vascular function compared to controls who never had COVID.

Une étude relève que la vasodilatation macrovasculaire et microvasculaire périphérique est considérablement émoussée chez les jeunes adultes encore symptomatiques du covid au-delà de la phase aiguë. Les chercheurs réalisent ces mesures par la technique de la dilatation liée au flux (FMD : Flow mediated-dilatation) de l'artère brachiale.

N014E

___Cardio-Vascular___

Published study on 23-Jul-21:
"Blunted peripheral but not cerebral vasodilator function in young otherwise healthy adults with persistent symptoms following COVID-19"
Une étude relève que la vasodilatation macrovasculaire et microvasculaire périphérique est considérablement émoussée chez les jeunes adultes encore symptomatiques du covid au-delà de la phase aiguë. Les chercheurs réalisent ces mesures par la technique de la dilatation liée au flux (FMD : Flow mediated-dilatation) de l'artère brachiale.
Link: https://pubmed.ncbi.nlm.nih.gov/34296966/
Extract: "Recent findings suggest that COVID-19 causes vascular dysfunction during the acute phase of the illness in otherwise healthy young adults. To date, no studies have investigated the longer-term effects of COVID-19 on vascular function. Herein, we hypothesized that young, otherwise healthy adults who are past the acute phase of COVID-19 would exhibit blunted peripheral (brachial artery flow-mediated dilation (FMD) and reactive hyperemia) and cerebral vasodilator function (cerebral vasomotor reactivity to hypercapnia; CVMR) and increased central arterial stiffness. Sixteen young adults who were at least 4 weeks past a COVID-19 diagnosis and 12 controls who never had COVID-19 were studied. Eight COVID subjects were symptomatic (SYM) and 8 were asymptomatic (ASYM) at the time of testing. FMD and reactive hyperemia were not different between COVID and Control groups. However, FMD was lower in SYM (3.8 ± 0.6%) compared to ASYM (6.8 ± 0.9%; P = 0.007) and Control (6.8 ± 0.6%; P = 0.003) with no difference between ASYM and Control. Similarly, peak blood velocity following cuff release was lower in SYM (47 ± 8 cm/s) compared to ASYM (64 ± 19 cm/s; P = 0.025) and Control (61 ± 14 cm/s; P = 0.036). CVMR and arterial stiffness were not different between any groups. In summary, peripheral macro- and microvascular function, but not cerebral vascular function or central arterial stiffness were blunted in young adults symptomatic beyond the acute phase of COVID-19. In contrast, those who were asymptomatic had similar vascular function compared to controls who never had COVID."

1645

CaV073

Arthur Melkumyants, Ludmila Buryachkovskaya, Nikita Lomakin, Olga Antonova, Victor Serebruany

Mild COVID-19 and Impaired Cell-Endothelial Crosstalk: Considering Long-Term Antithrombotics and Vascular Protection?
COVID and vascular-endothelial injury

https://doi.org/10.1055/a-1551-9911

Published

16-Jul-21

https://www.thieme-connect.com/products/ejournals/abstract/10.1055/a-1551-9911

We analyzed blood erythrocytes (RBC), endotheliocytes, and echinocytes by electron microscopy and flow cytometry in patients with confirmed COVID-19 (n=31) and matched controls (n=32) on admission and at hospital discharge. Results All patients experienced mild disease, none required pulmonary support, and all survived. Admission number of circulating endotheliocytes was significantly (40-100 times) higher in COVID-19 patients. Cells were massively damaged by multiple fenestrae in membranes with diameter comparable to the size of supercapsid in SARS CoV-2 virus. COVID-19 also provoked formation of stacked aggregated RBC capable to clog microvascular bed and to diminish oxygen supply. In some patients, such abnormalities persisted at hospital discharge revealing remaining penetration of COVID-19 intracellular where it may be replicated and returned to circulation. Conclusion Cell-endothelial injury cause blood vessels denuded; their increased permeability resulted in tissue edema, inflammation, platelet activation, and augmented thrombosis. Such sequelae can provoke long-term delayed vascular complications following COVID-19. Controlled outcome-driven trials are urgently needed for exploring optimal antithrombotic and vascular protection strategies following even mild COVID-19.

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1646

CaV074

Umit Arslan MD, Ferhat Borulu MD, İbrahim Sarac MD, Bilgehan Erkut Prof

Chronic intracardiac thrombus, a long-term complication of COVID-19: Case reports

https://doi.org/10.1111/jocs.15836

Published

26-Jul-21

Case Report

https://onlinelibrary.wiley.com/doi/full/10.1111/jocs.15836

Our study describes two patients who recovered from COVID-19 and presented with chronic intracardiac thrombus.
To date, reports of intracardiac thrombosis in COVID-19 patients with normal cardiac anatomy and function are rare and may cause major cardiovascular complications. Therefore, patients are recommended standard prophylactic anticoagulation doses for at least 3 months during and after the illness. In addition, patients must follow up with monthly echocardiography to check for cardiac thrombus.

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1647

CaV075

Arthur Melkumyants, Ludmila Buryachkovskaya, Nikita Lomakin, Olga Antonova, Victor Serebruany

Mild COVID-19 and Impaired Cell-Endothelial Crosstalk: Considering Long-Term Antithrombotics and Vascular Protection?
COVID and vascular-endothelial injury

https://doi.org/10.1055/a-1551-9911

Published

16-Jul-21

Study

https://www.thieme-connect.com/products/ejournals/abstract/10.1055/a-1551-9911

We analyzed blood erythrocytes (RBC), endotheliocytes, and echinocytes by electron microscopy and flow cytometry in patients with confirmed COVID-19 (n=31) and matched controls (n=32) on admission and at hospital discharge. Results All patients experienced mild disease, none required pulmonary support, and all survived. Admission number of circulating endotheliocytes was significantly (40-100 times) higher in COVID-19 patients. Cells were massively damaged by multiple fenestrae in membranes with diameter comparable to the size of supercapsid in SARS CoV-2 virus. COVID-19 also provoked formation of stacked aggregated RBC capable to clog microvascular bed and to diminish oxygen supply. In some patients, such abnormalities persisted at hospital discharge revealing remaining penetration of COVID-19 intracellular where it may be replicated and returned to circulation. Conclusion Cell-endothelial injury cause blood vessels denuded; their increased permeability resulted in tissue edema, inflammation, platelet activation, and augmented thrombosis. Such sequelae can provoke long-term delayed vascular complications following COVID-19. Controlled outcome-driven trials are urgently needed for exploring optimal antithrombotic and vascular protection strategies following even mild COVID-19.

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1648

CaV076

Victor Arévalos ,Luis Ortega-Paz ,Diego Fernandez-Rodríguez,Víctor Alfonso Jiménez-Díaz,Jordi Bañeras Rius,Gianluca Campo,Miguel Rodríguez-Santamarta,Armando Pérez de Prado,Antonio Gómez-Menchero,José Francisco Díaz Fernández,Claudia Scardino,Nieves Gonzalo,Alberto Pernigotti,Fernando Alfonso,Ignacio Jesús Amat-Santos,Antonio Silvestro,Alfonso Ielasi,José María de la Torre,Gabriela Bastidas,Josep Gómez-Lara,Manel Sabaté,Salvatore Brugaletta

Long-term effects of coronavirus disease 2019 on the cardiovascular system, CV COVID registry: A structured summary of a study protocol

https://doi.org/10.1371/journal.pone.0255263

Published

29-Jul-21

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255263

The primary outcome will be cardiovascular mortality at 1 year. The secondary outcomes will be acute myocardial infarction, stroke, heart failure hospitalization, pulmonary embolism, and serious cardiac arrhythmias, at 1 year. Outcomes will be compared between the two groups. Events will be adjudicated by an independent clinical event committee.
Conclusion
The results of this registry will contribute to a better understanding of the long-term cardiovascular implications of the COVID19.

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1649

CaV077

Ioannis Katsoularis, MD †
Osvaldo Fonseca-Rodríguez, PhD †
Paddy Farrington, PhD
Krister Lindmark, PhD
Anne-Marie Fors Connolly

Risk of acute myocardial infarction and ischaemic stroke following COVID-19 in Sweden: a self-controlled case series and matched cohort study

https://doi.org/10.1016/S0140-6736(21)00896-5

Published

29-Jul-21

Study

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00896-5/fulltext

86 742 patients with COVID-19 were included in the SCCS study, and 348 481 matched control individuals were also included in the matched cohort study. When day of exposure was excluded from the risk period in the SCCS, the IRR for acute myocardial infarction was 2·89 (95% CI 1·51–5·55) for the first week, 2·53 (1·29–4·94) for the second week, and 1·60 (0·84–3·04) in weeks 3 and 4 following COVID-19. When day of exposure was included in the risk period, IRR was 8·44 (5·45–13·08) for the first week, 2·56 (1·31–5·01) for the second week, and 1·62 (0·85–3·09) for weeks 3 and 4 following COVID-19. The corresponding IRRs for ischaemic stroke when day of exposure was excluded from the risk period were 2·97 (1·71–5·15) in the first week, 2·80 (1·60–4·88) in the second week, and 2·10 (1·33–3·32) in weeks 3 and 4 following COVID-19; when day of exposure was included in the risk period, the IRRs were 6·18 (4·06–9·42) for the first week, 2·85 (1·64–4·97) for the second week, and 2·14 (1·36–3·38) for weeks 3 and 4 following COVID-19. In the matched cohort analysis excluding day 0, the odds ratio (OR) for acute myocardial infarction was 3·41 (1·58–7·36) and for stroke was 3·63 (1·69–7·80) in the 2 weeks following COVID-19. When day 0 was included in the matched cohort study, the OR for acute myocardial infarction was 6·61 (3·56–12·20) and for ischaemic stroke was 6·74 (3·71–12·20) in the 2 weeks following COVID-19.
Interpretation
Our findings suggest that COVID-19 is a risk factor for acute myocardial infarction and ischaemic stroke. This indicates that acute myocardial infarction and ischaemic stroke represent a part of the clinical picture of COVID-19, and highlights the need for vaccination against COVID-19.

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1650

CaV078

Sanjay R Agarwala
Orthopaedics, PD Hinduja National Hospital, Mumbai, Maharashtra, India
PubMed articlesGoogle scholar articles
Mayank Vijayvargiya
Orthopaedics, PD Hinduja National Hospital and Medical Research Centre, Mumbai, Maharashtra, India
PubMed articlesGoogle scholar articles
Prashant Pandey

Avascular necrosis as a part of ‘long COVID-19’

http://dx.doi.org/10.1136/bcr-2021-242101

Published

2-Jul-21

Study

https://casereports.bmj.com/content/14/7/e242101

We report a series of three cases in which patients developed AVN of the femoral head after being treated for COVID-19 infection. The mean dose of prednisolone used in these cases was 758 mg (400–1250 mg), which is less than the mean cumulative dose of around 2000 mg steroid, documented in the literature as causative for AVN. Patients were symptomatic and developed early AVN presentation at a mean of 58 days after COVID-19 diagnosis as compared with the literature which shows that it generally takes 6 months to 1 year to develop AVN post steroid exposure.

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1651

CaV079

Helen Fogarty,Liam Townsend,Hannah Morrin,Azaz Ahmad,Claire Comerford,Ellie Karampini,Hanna Englert,Mary Byrne,Colm Bergin,Jamie M. O’Sullivan,Ignacio Martin-Loeches,Parthiban Nadarajan,Ciaran Bannan,Patrick W. Mallon,Gerard F. Curley,Roger J.S. Preston,Aisling M. Rehill,Dennis McGonagle,Cliona Ni Cheallaigh,Ross I. Baker,Thomas Renné,Soracha E. Ward,James S. O’ Donnell

Persistent Endotheliopathy in the Pathogenesis of Long COVID Syndrome

https://doi.org/10.1111/jth.15490

Published

10-Aug-21

BRIEF REPORT

https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.15490

Persistent symptoms including breathlessness, fatigue and decreased exercise tolerance have been reported in patients after acute SARS-CoV-2 infection. The biological mechanisms underlying this ‘Long COVID’ syndrome remain unknown. However, autopsy studies have highlighted the key roles played by pulmonary endotheliopathy and microvascular immunothrombosis in acute COVID-19. We hypothesized that endothelial cell activation may be sustained in convalescent COVID-19 patients and contribute to Long COVID pathogenesis.

Patients and Methods
Fifty patients were reviewed at a median of 68 days following SARS-CoV-2 infection. In addition to clinical workup, acute phase markers, EC activation and NETosis parameters and thrombin generation were assessed.

Results
Thrombin generation assays revealed significantly shorter lag times (p<0.0001, 95% CI -2.57– -1.02min), increased endogenous thrombin potential (ETP) (p=0.04, 95% CI 15–416nM/min) and peak thrombin (p<0.0001, 95% CI 39–93nM) in convalescent COVID-19 patients. These pro-thrombotic changes were independent of ongoing acute phase response or active NETosis. Importantly, EC biomarkers including VWF:Ag, VWF propeptide (VWFpp) and Factor VIII (FVIII:C) were significantly elevated in convalescent COVID-19 compared to controls (p=0.004, 95% CI 0.09–0.57IU/ml; p=0.009, 95% CI 0.06–0.5IU/ml; p=0.04, 95% CI 0.03–0.44IU/ml, respectively). In addition, plasma soluble thrombomodulin (sTM) levels were significantly elevated in convalescent COVID-19 (p=0.02, 95% CI 0.01–2.7ng/ml). Sustained endotheliopathy was more frequent in older, comorbid patients and those requiring hospitalization. Finally, both plasma VWF:Ag and VWFpp levels correlated inversely with 6-minute walk tests.

Conclusions
Collectively, our findings demonstrate that sustained endotheliopathy is common in convalescent COVID-19 and raise the intriguing possibility that this may contribute to Long COVID pathogenesis.

1652

CaV080

1653

CaV081

Damsara Nandadeva, 1 Benjamin E. Young, 1 Brandi Y. Stephens, 1 Ann-Katrin Grotle, 1 Rachel J. Skow, 1 Angela J. Middleton, 2 Florence P. Haseltine, 3 and Paul J. Fadel

Blunted peripheral but not cerebral vasodilator function in young otherwise healthy adults with persistent symptoms following COVID-19

https://dx.doi.org/10.1152%2Fajpheart.00368.2021

Published

1-Sep-21

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384473/

Recent findings suggest that COVID-19 causes vascular dysfunction during the acute phase of the illness in otherwise healthy young adults. To date, to our knowledge, no studies have investigated the longer-term effects of COVID-19 on vascular function. Herein, we hypothesized that young, otherwise healthy adults who are past the acute phase of COVID-19 would exhibit blunted peripheral [brachial artery flow-mediated dilation (FMD) and reactive hyperemia] and cerebral vasodilator function (cerebral vasomotor reactivity to hypercapnia; CVMR) and increased central arterial stiffness. Sixteen young adults who were at least 4 wk past a COVID-19 diagnosis and 12 controls who never had COVID-19 were studied. Eight subjects with COVID-19 were symptomatic (SYM) and eight were asymptomatic (ASYM) at the time of testing. FMD and reactive hyperemia were not different between COVID and control groups. However, FMD was lower in SYM (3.8 ± 0.6%) compared with ASYM (6.8 ± 0.9%; P = 0.007) and control (6.8 ± 0.6%; P = 0.003) with no difference between ASYM and control. Similarly, peak blood velocity following cuff release was lower in SYM (47 ± 8 cm/s) compared with ASYM (64 ± 19 cm/s; P = 0.025) and control (61 ± 14 cm/s; P = 0.036). CVMR and arterial stiffness were not different between any groups. In summary, peripheral macrovascular and microvascular function, but not cerebral vascular function or central arterial stiffness were blunted in young adults symptomatic beyond the acute phase of COVID-19. In contrast, those who were asymptomatic had similar vascular function compared with controls who never had COVID-19.

This study was the first to investigate the persistent effects of COVID-19 on vascular function in otherwise healthy young adults. We demonstrated that peripheral macrovascular and microvascular vasodilation was significantly blunted in young adults still symptomatic from COVID-19 beyond the acute phase (>4 wk from diagnosis), whereas those who become asymptomatic have similar vascular function compared with controls who never had COVID-19. In contrast, cerebral vascular function and central arterial stiffness were unaffected irrespective of COVID-19 symptomology.

1654

CaV082

Pierre Dudouet
Serge Cammilleri
Eric Guedj
Alexis Jacquier
Didier Raoult
Carole Eldin

Aortic [18F] FDG-PET/CT hypermetabolism in patients with long COVID: a retrospective study

https://doi.org/10.1016/j.cmi.2021.09.020

Published

26-Sep-21

LETTER TO THE EDITOR

https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(21)00542-5/fulltext

To resume, we retrospectively found aortic hypermetabolism in 10 out of 47 patients with long COVID who had a 18F-FDG PET/CT scan, with more frequent chest pain in this group (6/10; 60% vs 7/37; 19%, p=0.017). The high proportion of aortic hypermetabolism in our cohort (21%) makes us think that this phenomenon is not incidental. To have an idea of the prevalence of incidental finding of thoracic aortic hypermetabolism, we compared thoracic aortic uptakes between our long COVID patients, and a non-COVID-19 control group of 20 randomly selected patients with negative SARS-CoV-2 RT-PCR and serology, who had 18 F-FDG PET/CT scan for oncologic indications. No patient of this control group had visually detected aortic hypermetabolism and comparative analysis with non-parametric Kruskall-Wallis test showed significant differences in mean aortic SUVmax between our 10 patients with aortic hypermetabolism and non-COVID-19 control group (3.36, SD 0.63 and 2.15 (SD 0.59), respectively; p< 0.0001).

Une lettre faisant part de résultats en imagerie #TEP métabolique corps-entier au 18FDG, publiée dans Clinical Microbiology & Infection en collaboration avec l’IHU Méditerranée Infection, portant sur 47 patients souffrant de COVID long et 20 sujets contrôles non-COVID :
- 21% d’inflammation des gros vaisseaux (aortite) vs 0% dans le groupe contrôle non-COVID
- Une association significative entre l’hypermétabolisme aortique et douleurs thoraciques chez les patients avec COVID long (douleurs thoraciques 3 fois plus fréquentes en cas d’hypermétabolisme aortique par rapport aux patients post-COVID avec TEP négatif)

N014E

___Cardio-Vascular___

Published letter to the editor on 26-Sep-21:
"Aortic [18F] FDG-PET/CT hypermetabolism in patients with long COVID: a retrospective study"
Une lettre faisant part de résultats en imagerie #TEP métabolique corps-entier au 18FDG, publiée dans Clinical Microbiology & Infection en collaboration avec l’IHU Méditerranée Infection, portant sur 47 patients souffrant de COVID long et 20 sujets contrôles non-COVID :
- 21% d’inflammation des gros vaisseaux (aortite) vs 0% dans le groupe contrôle non-COVID
- Une association significative entre l’hypermétabolisme aortique et douleurs thoraciques chez les patients avec COVID long (douleurs thoraciques 3 fois plus fréquentes en cas d’hypermétabolisme aortique par rapport aux patients post-COVID avec TEP négatif)
Link: https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(21)00542-5/fulltext
Extract: "To resume, we retrospectively found aortic hypermetabolism in 10 out of 47 patients with long COVID who had a 18F-FDG PET/CT scan, with more frequent chest pain in this group (6/10; 60% vs 7/37; 19%, p=0.017). The high proportion of aortic hypermetabolism in our cohort (21%) makes us think that this phenomenon is not incidental. To have an idea of the prevalence of incidental finding of thoracic aortic hypermetabolism, we compared thoracic aortic uptakes between our long COVID patients, and a non-COVID-19 control group of 20 randomly selected patients with negative SARS-CoV-2 RT-PCR and serology, who had 18 F-FDG PET/CT scan for oncologic indications. No patient of this control group had visually detected aortic hypermetabolism and comparative analysis with non-parametric Kruskall-Wallis test showed significant differences in mean aortic SUVmax between our 10 patients with aortic hypermetabolism and non-COVID-19 control group (3.36, SD 0.63 and 2.15 (SD 0.59), respectively; p< 0.0001)."

1655

CaV083

Questionable methodology

Etheresia Pretorius, Mare Vlok, Chantelle Venter, Johannes A. Bezuidenhout, Gert Jacobus Laubscher, Janami Steenkamp & Douglas B. Kell

Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin

https://doi.org/10.1186/s12933-021-01359-7

Published

23-Aug-21

Study

https://cardiab.biomedcentral.com/articles/10.1186/s12933-021-01359-7

We use techniques including proteomics and fluorescence microscopy to study plasma samples from healthy individuals, individuals with Type 2 Diabetes Mellitus (T2DM), with acute COVID-19, and those with Long COVID/PASC symptoms.
Results
We show that plasma samples from Long COVID/PASC still contain large anomalous (amyloid) deposits (microclots). We also show that these microclots in both acute COVID-19 and Long COVID/PASC plasma samples are resistant to fibrinolysis (compared to plasma from controls and T2DM), even after trypsinisation. After a second trypsinization, the persistent pellet deposits (microclots) were solubilized. We detected various inflammatory molecules that are substantially increased in both the supernatant and trapped in the solubilized pellet deposits of acute COVID-19 and Long COVID/PASC, versus the equivalent volume of fully digested fluid of the control samples and T2DM. Of particular interest was a substantial increase in α(2)-antiplasmin (α2AP), various fibrinogen chains, as well as Serum Amyloid A (SAA) that were trapped in the solubilized fibrinolytic-resistant pellet deposits.
Conclusions
Clotting pathologies in both acute COVID-19 infection and in Long COVID/PASC might benefit from following a regime of continued anticlotting therapy to support the fibrinolytic system function.

todo ------ les échantillons de plasma de Long COVID/PASC contiennent toujours de gros dépôts anormaux (amyloïdes) (microcaillots).

1656

CaV084

Francesco Carubbi 1,2,*,† ,Alessia Alunno 1,† ,Silvia Leone 1,Nicoletta Di Gregorio 1,2,Bernardina Mancini 1,2,Angelo Viscido 1 ,Rita Del Pinto 1 ,Sabrina Cicogna 2,3,Davide Grassi 1 andClaudio Ferri 1

Pericarditis after SARS-CoV-2 Infection: Another Pebble in the Mosaic of Long COVID?

https://doi.org/10.3390/v13101997

Published

4-Oct-21

Study

https://www.mdpi.com/1999-4915/13/10/1997/htm

Here, we reported a series of 7 patients developing pericarditis after a median of 20 days from clinical and virological recovery from SARS-CoV-2 infection. We excluded specific identifiable causes of pericarditis, hence we speculate that these cases can be contextualized within the clinical spectrum of long COVID. All our patients were treated with a combination of colchicine and either ASA or NSAIDs, but four of them did not achieve a clinical response. When switched to glucocorticoids, these four patients recovered with no recurrence during drug tapering. Based on this observation and on the latency of pericarditis occurrence (a median of 20 days after a negative nasopharyngeal swab), could be suggested that post-COVID pericarditis may be linked to ongoing inflammation sustained by the persistence of viral nucleic acid without virus replication in the pericardium. Therefore, glucocorticoids may be a suitable treatment option in patients not responding or intolerant to conventional therapy and who require to counteract the pericardial inflammatory component rather than direct an acute viral injury to the pericardial tissue.

_

1657

CaV085

Jae Kyu Ryu, Elif G. Sozmen, Karuna Dixit, Mauricio Montano, Yusuke Matsui, Yixin Liu, Ekram Helmy, Thomas J. Deerinck, Zhaoqi Yan, Renaud Schuck, Rosa Meza Acevedo, Collin M. Spencer, Reuben Thomas, Alexander R. Pico, Scott S. Zamvil, Kara L. Lynch, Mark H. Ellisman, Warner C. Greene, Katerina Akassoglou

SARS-CoV-2 spike protein induces abnormal inflammatory blood clots neutralized by fibrin immunotherapy

https://doi.org/10.1101/2021.10.12.464152

pre-print

13-Oct-21

Study

https://www.biorxiv.org/content/10.1101/2021.10.12.464152v1

Here we report that the Spike protein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the blood coagulation factor fibrinogen and induces structurally abnormal blood clots with heightened proinflammatory activity. SARS-CoV-2 Spike virions enhanced fibrin-mediated microglia activation and induced fibrinogen-dependent lung pathology. COVID-19 patients had fibrin autoantibodies that persisted long after acute infection. Monoclonal antibody 5B8, targeting the cryptic inflammatory fibrin epitope, inhibited thromboinflammation. Our results reveal a procoagulant role for the SARS-CoV-2 Spike and propose fibrin-targeting interventions as a treatment for thromboinflammation in COVID-19.

One-Sentence Summary SARS-CoV-2 spike induces structurally abnormal blood clots and thromboinflammation neutralized by a fibrin-targeting antibody.

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1658

CaV086

G Artemyeva, A Kalinskaya, O Dukhin, A Lebedeva, A Rozin, A Shpektor, E Vasilieva

Long-term post-discharge coagulation abnormalities in patients with moderate to severe COVID-19

https://doi.org/10.1093/eurheartj/ehab724.3428

Published

14-Oct-21

Study

https://academic.oup.com/eurheartj/article/42/Supplement_1/ehab724.3428/6392448

In the deferred period (2–5 months) of COVID-19 the fibrinolysis process remains still active whereas the process of clot formation is mostly suppressed. Endothelial function assessed via the FMD test is within the normal range in the post COVID period.

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1659

CaV087

C Espejo, H Mejia-Renteria, A Travieso, N Gonzalo, S Fernandez, M L Capote, O Vedia, L Wang, I Nunez-Gil, J M Grande Ingelmo, I Fernandez Rozas, C Olmos, D Vivas, J Escaned

Myocardial ischaemia of non-obstructive origin as a cause of new onset anginal chest pain in the long COVID syndrome

https://doi.org/10.1093/eurheartj/ehab724.1078

Published

14-Oct-21

Study

https://academic.oup.com/eurheartj/article/42/Supplement_1/ehab724.1078/6392359?login=true

Myocardial ischaemia of non-obstructive origin is common in patients with chest pain and LCS. Vasomotor abnormalities related to endothelial dysfunction occurred in 82% of patients, frequently associated to impaired microvascular vasodilation or high microvascular resistance. Stratified medical treatment led to significant improvement in angina stability and frequency.

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1660

CaV088

ES

Benjamin A. Satterfield, Deepak L. Bhatt & Bernard J. Gersh

Cardiac involvement in the long-term implications of COVID-19

https://doi.org/10.1038/s41569-021-00631-3

Published

22-Oct-21

Perspective

https://www.nature.com/articles/s41569-021-00631-3

In this Perspectives article, we highlight what is known about the cardiovascular sequelae in survivors of COVID-19 and discuss important questions that need to be addressed in prospective studies to understand and mitigate these lasting cardiovascular consequences, including in post-acute COVID-19 syndrome.
Of note, the manifestations of acute cardiovascular injury associated with SARS-CoV-2 infection are diverse, including acute myocardial infarction, myocarditis, stress cardiomyopathy, pericarditis, arrhythmias, multisystem inflammatory syndrome in both adults (MIS-A) and children (MIS-C), stroke, macrothrombotic disease including arterial and venous thromboembolism, microthrombotic disease and bleeding diathesis2,3,4 (Fig. 1). The pathogenic mechanisms underlying these clinical manifestations are not well understood and are likely to be multifactorial, including primary causes such as elevated local (endotheliitis) and systemic (cytokine storm) inflammation, resulting in coagulopathy, myocardial infarction, stroke, MIS-A, MIS-C and arrhythmias, direct viral cytopathic effects possibly resulting in myocarditis, and autoantibodies5,6,7. In addition, hypoxaemia can occur secondary to lung injury, and myocardial oedema can develop secondary to the inflammatory states mentioned above5,6,7.

Review Cardiaque.

Dans Nature Reviews Cardiology, une riche synthèse sur les dommages et séquelles cardiaques de la covid pouvant être à l'origine de symptômes du covid long. Les vascularites/aortites, récemment objectivées par PET-SCAN, ne sont cependant pas ici évoquées.

N014

___Cardio-Vascular___

Published perspective on 22-Oct-21:
"Cardiac involvement in the long-term implications of COVID-19"
Review Cardiaque.

Dans Nature Reviews Cardiology, une riche synthèse sur les dommages et séquelles cardiaques de la covid pouvant être à l'origine de symptômes du covid long. Les vascularites/aortites, récemment objectivées par PET-SCAN, ne sont cependant pas ici évoquées.
Link: https://www.nature.com/articles/s41569-021-00631-3
Extract: "In this Perspectives article, we highlight what is known about the cardiovascular sequelae in survivors of COVID-19 and discuss important questions that need to be addressed in prospective studies to understand and mitigate these lasting cardiovascular consequences, including in post-acute COVID-19 syndrome.
Of note, the manifestations of acute cardiovascular injury associated with SARS-CoV-2 infection are diverse, including acute myocardial infarction, myocarditis, stress cardiomyopathy, pericarditis, arrhythmias, multisystem inflammatory syndrome in both adults (MIS-A) and children (MIS-C), stroke, macrothrombotic disease including arterial and venous thromboembolism, microthrombotic disease and bleeding diathesis2,3,4 (Fig. 1). The pathogenic mechanisms underlying these clinical manifestations are not well understood and are likely to be multifactorial, including primary causes such as elevated local (endotheliitis) and systemic (cytokine storm) inflammation, resulting in coagulopathy, myocardial infarction, stroke, MIS-A, MIS-C and arrhythmias, direct viral cytopathic effects possibly resulting in myocarditis, and autoantibodies5,6,7. In addition, hypoxaemia can occur secondary to lung injury, and myocardial oedema can develop secondary to the inflammatory states mentioned above5,6,7."

1661

CaV089

Rossana Rauti, Meishar Shahoha, Yael Leichtmann-Bardoogo, Rami Nasser, Eyal Paz, Rina Tamir, Victoria Miller, Tal Babich, Kfir Shaked, Avner Ehrlich, Konstantinos Ioannidis, Yaakov Nahmias, Roded Sharan, Uri Ashery, Ben Meir Maoz

Effect of SARS-CoV-2 proteins on vascular permeability

https://doi.org/10.7554/eLife.69314

pre-print

25-Oct-21

Research Article

https://elifesciences.org/articles/69314

It affects several vital organs, seemingly through a pathological effect on endothelial cells. The SARS-CoV-2 genome encodes 29 proteins, whose contribution to the disease manifestations, and especially endothelial complications, is unknown. We cloned and expressed 26 of these proteins in human cells and characterized the endothelial response to overexpression of each, individually. Whereas most proteins induced significant changes in endothelial permeability, nsp2, nsp5_c145a (catalytic dead mutant of nsp5), and nsp7 also reduced CD31, and increased von Willebrand factor expression and IL-6, suggesting endothelial dysfunction. Using propagation-based analysis of a protein–protein interaction (PPI) network, we predicted the endothelial proteins affected by the viral proteins that potentially mediate these effects. We further applied our PPI model to identify the role of each SARS-CoV-2 protein in other tissues affected by coronavirus disease (COVID-19). While validating the PPI network model, we found that the tight junction (TJ) proteins cadherin-5, ZO-1, and β-catenin are affected by nsp2, nsp5_c145a, and nsp7 consistent with the model prediction. Overall, this work identifies the SARS-CoV-2 proteins that might be most detrimental in terms of endothelial dysfunction, thereby shedding light on vascular aspects of COVID-19.

1662

CaV090

HernanMejia-RenteriaaAlejandroTraviesoaAdamSagirbEduardoMartínez-GómezaAngelaCarrascosa-GranadaaTakumiToyacIván J.Núñez-GilaVicenteEstradaaAmirLermancJavierEscaneda

In-vivo evidence of systemic endothelial vascular dysfunction in COVID-19

https://doi.org/10.1016/j.ijcard.2021.10.140

Published

24-Oct-21

Study

https://www.sciencedirect.com/science/article/pii/S0167527321016946

Highlights
•Endothelium-mediated vasodilator function is markedly reduced in COVID-19 post-infection stage compared to active infection and controls.
•These findings suggest that endothelial vascular dysfunction may be a chronic complication of the SARS-CoV-2 infection.
•This study opens new venues to investigate the clinical implication of vascular endothelial dysfunction in post-COVID syndrome using non-invasive techniques.
This study suggests a deleterious effect of SARS-CoV-2 infection on systemic vascular endothelial function.
By a measure of endothelium-mediated dilation of peripheral arteries.

1663

CaV091

Yogesh Acharya, Aqeel Alameer, Gavin Calpin, Maha Alkhattab & Sherif Sultan

A comprehensive review of vascular complications in COVID-19

https://doi.org/10.1007/s11239-021-02593-2

Published

1-Nov-21

Review

https://link.springer.com/article/10.1007/s11239-021-02593-2

This study aims to review the available literature pertinent to vascular complications in COVID-19. A systematic search was performed using PubMed and Google Scholar to identify all relevant studies based on our study objective. Multiple studies have reported widespread systemic inflammation and procoagulant/hypercoagulable state in COVID-19, including thrombotic microangiopathy, endothelial dysfunction, bleeding disorder, and thrombosis. However, large specialised studies on vascular complications are lacking despite current evidence indicating dysfunctional coagulation pathways. Furthermore, there are no clear and definitive recommendations regarding thromboprophylaxis or full therapeutic anticoagulation in COVID-19. Several studies have reported hypercoagulability and vascular complications as important predictors of patient outcome in COVID-19.

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1664

CaV092

Giovanna Pelà 1,2,* ,Matteo Goldoni 1 ,Chiara Cavalli 1,Felice Perrino 1,Sara Tagliaferri 1 ,Annalisa Frizzelli 1,3,Pier Anselmo Mori 4,Maria Majori 4,Marina Aiello 1,3 ,Nicola Sverzellati 1,5,Massimo Corradi 1 andAlfredo Chetta 1,3

Long-Term Cardiac Sequelae in Patients Referred into a Diagnostic Post-COVID-19 Pathway: The Different Impacts on the Right and Left Ventricles

https://doi.org/10.3390/diagnostics11112059

Published

6-Nov-21

Study

https://www.mdpi.com/2075-4418/11/11/2059/htm

This monocentric cohort study included 160 consecutive patients who had been discharged from the ward or from the outpatient clinic after a diagnosis of COVID-19 and subsequently referred for a follow-up visit. Clinical features’ data about the acute phase along with information about the follow-up visit, including ECG and Echocardiographic parameters, were recorded. At an average follow-up of 5 months, echocardiography showed morpho-functional characteristics of both right (RV) and left (LV) ventricles, such as RV dilation, increased pressure in the pulmonary circulation, and bi-ventricular systolic–diastolic dysfunction. When examined using multivariate analysis, independent of age, sex, and co-morbidities, RV and LV changes were significantly associated with chest High-Resolution computed tomography score and hemodynamic Instability (HI), and with C-reactive protein, respectively. Our results suggest that COVID-19 may impact RV and LV differently. Notably, the extent of the pneumonia and HI may affect RV, whereas the inflammatory status may influence LV. A long-term follow-up is warranted to refine and customize the most appropriate therapeutic strategies.

1665

CaV093

Helen Fogarty,Ellie Karampini,Andrew S. O’Donnell,Soracha E. Ward,Jamie M O’Sullivan,James S. O’Donnell

More on Persistent Endotheliopathy in the Pathogenesis of Long COVID Syndrome

https://doi.org/10.1111/jth.15578

Published

4-Nov-21

Study

https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.15578

These findings provide further evidence that sustained endotheliopathy and coagulopathy are both common in patients following acute COVID-19 [2-5]. The longitudinal data presented provide additional insights into the duration of specific aspects of COVID-19-induced hemostatic dysfunction. Previous studies have reported elevated D-dimer levels in 25% of patients in the first few months post-SARS-CoV-2 infection [2, 5]. Notwithstanding differences in patient cohorts and study design, von Meijenfeldt et al show that these elevated D-dimer levels after acute COVID appear to normalize by 4 months [1]. Given that convalescent COVID-19 patients commonly present with respiratory symptoms, this observation has important clinical implications with respect to the utility of D-dimer testing in pulmonary embolism testing algorithms.

todo

1666

CaV094

Salma Charfeddine1,2*, Hassen Ibn Hadj Amor3, Jihen Jdidi2,4, Slim Torjmen1,2, Salma Kraiem3, Rania Hammami1,2, Amine Bahloul1,2, Nesrine Kallel2,5, Nedia Moussa2,5, Imen Touil6, Aiman Ghrab7, Jamel Elghoul2,8, Zineb Meddeb9, Yamina Thabet9, Samir Kammoun1,2, Kamel Bouslama9, Sami Milouchi2,7, Salem Abdessalem10 and Leila Abid1,2

Long COVID 19 Syndrome: Is It Related to Microcirculation and Endothelial Dysfunction? Insights From TUN-EndCOV Study

https://doi.org/10.3389/fcvm.2021.745758

Published

30-Nov-21

Study

https://www.frontiersin.org/articles/10.3389/fcvm.2021.745758/full

Our study focused on the evaluation of endothelial quality index (EQI) by finger thermal monitoring with E4 diagnosis Polymath in a large cohort of long COVID-19 patients to determine whether long-covid 19 symptoms are associated with endothelial dysfunction. This is a cross-sectional multicenter observational study with prospective recruitment of patients. A total of 798 patients were included in this study. A total of 618 patients (77.4%) had long COVID-19 symptoms. The mean EQI was 2.02 ± 0.99 IC95% [1.95–2.08]. A total of 397 (49.7%) patients had impaired EQI. Fatigue, chest pain, and neuro-cognitive difficulties were significantly associated with endothelium dysfunction with an EQI <2 after adjustment for age, sex, diabetes, hypertension, dyslipidemia, coronary heart disease, and the severity of acute COVID-19 infection. In multivariate analysis, endothelial dysfunction (EQI <2), female gender, and severe clinical status at acute COVID-19 infection with a need for oxygen supplementation were independent risk factors of long COVID-19 syndrome. Long COVID-19 symptoms, specifically non-respiratory symptoms, are due to persistent endothelial dysfunction. These findings allow for better care of patients with long COVID-19 symptoms.

todo

1667

CaV095

Jozica Šikić 1,2,* ,Zrinka Planinić 1 ,Vid Matišić 2 ,Tea Friščić 1,Vilim Molnar 2,Dorijan Jagačić 2,Lovro Vujičić 2,Neven Tudorić 2,Lana Postružin Gršić 3,Đivo Ljubičić 2,4 andDragan Primorac

COVID-19: The Impact on Cardiovascular System

https://doi.org/10.3390/biomedicines9111691

Published

15-Nov-21

Review

https://www.mdpi.com/2227-9059/9/11/1691/htm

SARS-CoV-2 has been circulating in population worldwide for the past year and a half, and thus a vast amount of scientific literature has been produced in order to study the biology of the virus and the pathophysiology of COVID-19, as well as to determine the best way to prevent infection, treat the patients and eliminate the virus. SARS-CoV-2 binding to the ACE2 receptor is the key initiator of COVID-19. The ability of SARS-CoV-2 to infect various types of cells requires special attention to be given to the cardiovascular system, as it is commonly affected. Thorough diagnostics and patient monitoring are beneficial in reducing the risk of cardiovascular morbidity and to ensure the most favorable outcomes for the infected patients, even after they are cured of the acute disease. The multidisciplinary nature of the fight against the COVID-19 pandemic requires careful consideration from the attending clinicians, in order to provide fast and reliable treatment to their patients in accordance with evidence-based medicine principles. In this narrative review, we reviewed the available literature on cardiovascular implications of COVID-19; both the acute and the chronic.

1668

CaV096

Giandomenico Bisaccia 1,† ,Fabrizio Ricci 1,2,3,*,† ,Vittoria Recce 1,Antonio Serio 1,Giovanni Iannetti 4,Anwar A. Chahal 5,6,7,8 ,Marcus Ståhlberg 9,Mohammed Yunus Khanji 8,10,11,Artur Fedorowski 2,9,† andSabina Gallina 1,†

Post-Acute Sequelae of COVID-19 and Cardiovascular Autonomic Dysfunction: What Do We Know?

https://doi.org/10.3390/jcdd8110156

Published

15-Nov-21

Review

https://www.mdpi.com/2308-3425/8/11/156/htm

Post-acute sequelae of SARS-CoV-2 (PASC), or long COVID syndrome, is emerging as a major health issue in patients with previous SARS-CoV-2 infection. Symptoms commonly experienced by patients include fatigue, palpitations, chest pain, dyspnea, reduced exercise tolerance, and “brain fog”. Additionally, symptoms of orthostatic intolerance and syncope suggest the involvement of the autonomic nervous system. Signs of cardiovascular autonomic dysfunction appear to be common in PASC and are similar to those observed in postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia. In this review, we report on the epidemiology of PASC, discuss current evidence and possible mechanisms underpinning the dysregulation of the autonomic nervous system, and suggest nonpharmacological and pharmacological interventions to treat and relieve symptoms of PASC-associated dysautonomia.

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1669

CaV097

Vallejo Camazón N1, Teis A2, Martínez Membrive MJ1, Llibre C1, Bayés-Genís A1, Mateu L3

Long COVID-19 and microvascular disease-related angina

https://doi.org/10.1016/j.rec.2021.10.010

Published

28-Oct-21

Study

https://www.sciencedirect.com/science/article/pii/S1885585721003224

However, many patients report persistent symptoms after recovery, a condition known as persistent or long-coronavirus disease 2019 (COVID-19) syndrome. In some series, chest pain has been described in ∼20% of patients with long-COVID-19 syndrome,1 but the mechanisms for these symptoms have not been adequately explored. Some of these patients have angina-like chest pain. Adenosine stress perfusion cardiac magnetic resonance (CMR) imaging is a useful noninvasive diagnostic tool for assessing myocardial perfusion and distinguishing epicardial from microvascular impairment according to perfusion patterns.2 CMR could play a role in the evaluation of this syndrome.
These first consecutive cases in this observational study strongly suggest that coronary microvascular ischemia is the underlying mechanism of angina-like persistent chest pain in patients who have recovered from COVID-19. As noted, the patients reported here are part of a broader study (ANGI-Covid) in which special CMR sequences for noninvasive quantification of myocardial perfusion and coronary flow reserve are also being studied and evaluated in these patients. Future work will have to elucidate the incidence and prevalence and compare these data with controls. However, at this point, we believe the results provided are of clinical importance.

todo

1670

CaV098

Iana Simova, Denislava Hristova, Hristina Tzanovska, Denis Nikolov, Diliana Iakova, Anyuta Ivanova, Maria-Magdalena Pintova, Pavlin Pavlov, Ognyan Matkov, Todor Samardjiev, Vladimir Kornovski, Jordan Krasnaliev, Todor Kundurzhiev, Nikolay Dimitrov and Toni Vekov

Post COVID-19 Conditions and the Cardiovascular System

https://doi.org/10.5772/intechopen.99197

Published

Review

https://www.intechopen.com/chapters/77664

The cardiovascular system is one of the key targets for the Post COVID-19 syndrome, given the pathogenesis of the virus and prevalence of ACE-2 receptors. According to our initial personal experience via the campaign “Life after COVID” of the Bulgarian Cardiac Institute, a substantial proportion of patients having suffered from COVID-19 develop long-term cardiovascular consequences. They could range from rhythm disorder and blood pressure variation, through impairment of myocardial mechanics and heart failure, and to acute vascular manifestations of Post COVID-19 conditions, such as acute coronary syndrome, acute pulmonary embolism, and acute limb ischemia. These cardiovascular complications require special and dedicated medical attention, and we could share our personal experience on the matter.

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1671

CaV099

S.Charfeddine12H.Ibnhadjamor34S.Torjmen12S.Kraiem3R.Hammami12A.Bahloul12N.Kallel25N.Moussa25I.Touil6S.Milouchi27J.Elghoul28Z.Meddeb49Y.Thabet9J.Jdidi210K.Bouslema45S.Abdesselem(Private cardiologist)411L.Abid12

Endothelial dysfunction is the key of long COVID-19 symptoms: The results of TUN-EndCOV study

https://doi.org/10.1016/j.acvdsp.2021.10.004

Published

27-Dec-21

Study

https://www.sciencedirect.com/science/article/pii/S187864802100642X

A total of 798 patients were included in this study. Patients were included at an average time of 68.93 ± 43.1 days. The mean EQI was 2.02 ± 0.99 [0–5]. A total of 397 (49.7%) patients had poor or very poor EQI and 211 (26.4%) patients had very poor EQI. The median age was 49.94 ± 14.2 (18–80) years. A total of 618 patients (77.4%) had long COVID-19 symptoms. Patients with long COVID-19 symptoms had a reduced EQI (1.99 ± 0.97 vs. 2.09 ± 1.05, P = 0.24). Among long COVID-19 symptoms, fatigue was the most common symptom reported in 42.2%. Fatigue and chest pain were significantly associated to the endothelial dysfunction (P = 0.04 and 0.001 respectively). Patients with chest pain had significantly lower EQI (1.74 ± 1.0 vs. 2.09 ± 0.9, P ≤ 10−3) and LVGLS (−16.35 ± 3.0 vs. −17.16 ± 2.5, P = 0.04).
Conclusion
Long COVID-19 symptoms specifically chest pain and fatigue are due to persistent poor endothelial quality index. These findings allow a better care of patients with long COVID-19 symptoms.

1672

CaV100

I.Hassen1S.Charfeddine2K.Salma1T.Imen3T.Slim2H.Rania2A.Bahloul2K.Nesrine4M.Nadia4S.Milouchi5G.Jamel6M.Zeinab7T.Yemina7J.Jihen8B.Kamel7A.Salem(Private cardiologist)9L.Abid2

Left ventricular global longitudinal strain alteration in young patient and correlation with post-COVID syndrome (TUN END COV Study)

https://doi.org/10.1016/j.acvdsp.2021.09.120

Published

27-Dec-21

Study

https://www.sciencedirect.com/science/article/pii/S187864802100478X

Patients and methods
A prospective multicentric study including a total of 630 patients diagnosed with COVID-19, 2 weeks to one month after recovering from COVID-19. Young patients without any medical history other than recent SARS-CoV2 infection are selected. A meticulous interrogation and clinical examination as well as an echocardiography are performed in all of patients. In addition to symptoms, we assessed echocardiographic parameters including initial left ventricular global longitudinal strain (initial SLG: SLGi) and after one month (SLG control: SLGc).
Results
Mean SLGi was −18.1 ± 2.4 in study group (−19.6 ± 1.5; P < 0.001). Forty-two patients (52.5%) had initially altered strain versus 38 patients (47.5%) with normal strain. The threshold value for SLG in our study has been established using ROC curve which was −17.95% with sensibility (52.5%) and specificity (83.7%). we found a statistically significative correlation between the initial alteration of SLG and persistent symptoms in multivariate test: dyspnea (P < 0.002); chest pain (P = 0.031). At one month of follow-up, 87.5% of patients improved their SLG. And there was a correlation between control GS value (mean SLGc was −18.91 ± 3.33; P = 0.002) associated with a marked improvement in symptoms (P = 0.001).
Conclusion
We reported here an original case series of SLG alteration induced by SARS-CoV2 infection that is correlated with the presence of chest pain and dyspnea. However, this affection seems to be spontaneously significantly reversible and associated with significant clinical improvement.

1673

CaV101

Xi Liu, Yan-Zi Wen, Zi-Liang Huang, Xia Shen, Jun-Hao Wang, Yi-Hai Luo, Wen-Xin
Chen, Zhao-Rong Lun, Hui-Bin Li, Liang-Hu Qu, Hong Shan, Ling-Ling Zheng

SARS-CoV-2 Causes a Significant Stress Response Mediated by Small RNAs in the
Blood of COVID-19 Patients

https://doi.org/10.1016/j.omtn.2021.12.034

Published

29-Dec-21

Study

https://www.cell.com/molecular-therapy-family/nucleic-acids/pdf/S2162-2531(21)00337-1.pdf

SARS-CoV-2 has had a serious impact on the world. In this study, small RNAs from the blood of COVID-19 patients with moderate or severe symptoms were extracted for high-throughput sequencing and analysis. Interestingly, the levels of a special group of tRNA-derived small RNAs (tsRNAs) were found to be dramatically upregulated after SARS-CoV-2 infection, particularly in COVID-19 patients with severe symptoms. In particular, the 3'CCA tsRNAs from Gly-tRNA were highly consistent with the inflammation indicator C-reactive protein (CRP). In addition, we found that the majority of significantly changed microRNAs (miRNAs) were associated with endoplasmic reticulum (ER)/unfolded protein response (UPR) sensors, which may lead to the induction of proinflammatory cytokine and immune responses. This study found that SARS-CoV-2 infection caused significant changes in the levels of stress44 associated small RNAs in patient blood and their potential functions. Our research revealed that the cells of COVID-19 patients undergo tremendous stress and respond, which can be reflected or regulated by sncRNAs, thus providing potential thought for therapeutic intervention in COVID-19 by modulating small RNA levels or activities.

1674

CaV102

Elsi S. Tryfou, Peggy M. Kostakou, Christos G. Chasikidis, Vassilios S. Kostopoulos, Ioannis I. Serafetinidis, Efterpi K. Ferdianaki, Constantinos Mihas, Christoforos D. Olympios & Nikos T. Kouris

Biventricular myocardial function in Covid-19 recovered patients assessed by speckle tracking echocardiography: a prospective cohort echocardiography study

https://doi.org/10.1007/s10554-021-02498-4

Published

23-Dec-21

Study

https://link.springer.com/article/10.1007/s10554-021-02498-4

The aim of our study was to evaluate prospectively cardiac involvement in patients after the recovery from Covid-19, using two-dimensional speckle tracking echocardiography. 100 Covid-19 recovered patients with preserved left ventricular ejection fraction, were included, divided based upon clinical manifestation into two groups, those who were treated ambulant and those who were hospitalized. All patients underwent echocardiographic evaluation after their recovery. Although overall LV systolic function expressed by EF was normal, left ventricular global longitudinal strain (LVGLS) was significantly lower in Covid-19 recovered patients (33.28 ± 9.4 days after diagnosis) compared to controls (− 18.47 ± − 2.4 vs. − 21.07 ± − 1.76% respectively, p < 0.0001). Εspecially the lateral wall longitudinal strain (LATLS) and posterior wall longitudinal strain (POSTLS) were significantly reduced in all patients compared to controls (− 17.77 ± − 3.48 vs. − 20.97 ± − 2.86%, p < 0.0001 and − 19.52 ± − 5.3 vs. − 22.23 ± − 2.65%, p = 0.01). right ventricular global longitudinal strain (RVGLS) was significantly diminished only in the hospitalized group of Covid-19 recovered patients, compared to controls (− 18.17 ± − 3.32 vs. − 26.03 ± − 4.55% respectively, p < 0.0001). LVGLS is affected in almost all individuals after Covid-19 infection independently of the infection severity, with LATLS being the most sensitive marker of LV impairment and with POSTLS to follow. RV shows impaired GLS in severely ill patients highlighting RVGLS as a helpful tool of prognosis. Recovered patients from Covid-19 infection have to be monitored for a long time, since the term “long Covid disease” might also include the cardiac function.

1675

CaV103

Lesley Kavi

Postural tachycardia syndrome and long COVID: an update

https://doi.org/10.3399/bjgp22X718037

Published

31-Dec-21

Editorial

https://bjgp.org/content/72/714/8.full

Autonomic dysregulation causes inadequate vasoconstriction when standing, resulting in blood pooling within the splanchnic vasculature and limbs, and consequent reduced venous return to the heart. An excessive compensatory tachycardia and increased plasma noradrenaline levels contribute to symptoms, the commonest of which are fatigue, palpitations, light-headedness, headache, and nausea.3,4 See Table 1 for a list of symptoms. If not adequately treated, PoTS can become a debilitating disorder that can lead to significant disability and impaired quality of life.
Exercise intolerance resulting in prolonged post-exercise fatigue is a common symptom of both PoTS and long COVID, and may hinder ability to engage in an exercise regimen.5 The role of physical activity including exercise in severely exercise-intolerant patients remains unclear and should be undertaken with great caution. Physiotherapists and occupational therapists treating patients with long COVID and PoTS should be familiar with managing these conditions.
Like long COVID, PoTS severity can fluctuate unpredictably, making rehabilitation and return to work challenging.
Medication that was recommended pre-pandemic for PoTS is being prescribed in long COVID PoTS when self-management measures are insufficient to control symptoms.5 Although unlicensed for use in PoTS, many of these drugs such as propranolol, ivabradine, midodrine, fludrocortisone, pyridostigmine, clonidine, and methyldopa are familiar to GPs through use in other conditions and may be prescribed provided that the General Medical Council’s guidance for good practice in prescribing unlicensed medicines is followed. Where possible, withdraw drugs that can exacerbate symptoms such as those that lower blood pressure or induce tachycardia.

1676

CaV104

Maria-Luiza Luchian 1,* ,Andreea Motoc 1,Stijn Lochy 1,Julien Magne 2,3,Dries Belsack 4,Johan De Mey 4,Bram Roosens 1 ,Karen Van den Bussche 1 ,Sven Boeckstaens 1,Hadischat Chameleva 5,Jolien Geers 1,Laura Houard 1 ,Tom De Potter 5,Sabine Allard 6 ,Caroline Weytjens 1,Steven Droogmans 1 andBernard Cosyns 1

Subclinical Myocardial Dysfunction in Patients with Persistent Dyspnea One Year after COVID-19

https://doi.org/10.3390/diagnostics12010057

Published

28-Dec-21

Study

https://www.mdpi.com/2075-4418/12/1/57/htm

We investigated the presence of subclinical cardiac dysfunction, assessed by transthoracic echocardiography (TTE), in recovered COVID-19 patients with or without dyspnea, after exclusion of previous cardiopulmonary diseases. A total of 310 consecutive COVID-19 patients were prospectively included. Of those, 66 patients (mean age 51.3 ± 11.1 years, almost 60% males) without known cardiopulmonary diseases underwent one-year follow-up consisting of clinical evaluation, spirometry, chest computed tomography, and TTE. From there, 23 (34.8%) patients reported dyspnea. Left ventricle (LV) ejection fraction was not significantly different between patients with or without dyspnea (55.7 ± 4.6 versus (vs.) 57.6 ± 4.5, p = 0.131). Patients with dyspnea presented lower LV global longitudinal strain, global constructive work (GCW), and global work index (GWI) compared to asymptomatic patients (−19.9 ± 2.1 vs. −21.3 ± 2.3 p = 0.039; 2183.7 ± 487.9 vs. 2483.1 ± 422.4, p = 0.024; 1960.0 ± 396.2 vs. 2221.1 ± 407.9, p = 0.030). GCW and GWI were inversely and independently associated with dyspnea (p = 0.035, OR 0.998, 95% CI 0.997–1.000; p = 0.040, OR 0.998, 95% CI 0.997–1.000). Persistent dyspnea one-year after COVID-19 was present in more than a third of the recovered patients. GCW and GWI were the only echocardiographic parameters independently associated with symptoms, suggesting a decrease in myocardial performance and subclinical cardiac dysfunction.

1677

CaV105

Radu Tanacli, 1 , 2 Patrick Doeblin, 1 Collin Götze, 1 Victoria Zieschang, 1 Alessandro Faragli, 1 , 2 Christian Stehning, 3 Grigorios Korosoglou, 4 Jennifer Erley, 1 Jakob Weiss, 1 , 5 Alexander Berger, 1 Felix Pröpper, 1 Fridolin Steinbeis, 6 Titus Kühne, 1 , 7 Franziska Seidel, 1 , 7 Dominik Geisel, 8 Thula Cannon Walter-Rittel, 8 Philipp Stawowy, 1 , 5 Martin Witzenrath, 6 Karin Klingel, 9 Sophie Van Linthout, 5 , 10 Burkert Pieske, 1 , 2 , 5 Carsten Tschöpe, 2 , 5 , 10 , † and Sebastian Kelle 1 , 2 , 5 , * , †

COVID-19 vs. Classical Myocarditis Associated Myocardial Injury Evaluated by Cardiac Magnetic Resonance and Endomyocardial Biopsy

https://dx.doi.org/10.3389%2Ffcvm.2021.737257

Published

24-Dec-21

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8739473/

Methods: In total, 32 patients with persistent cardiac symptoms after a COVID-19 infection, 22 patients with acute classic myocarditis not related to COVID-19, and 16 healthy volunteers were included in this study and underwent a comprehensive baseline CMR scan. Of these, 10 patients post COVID-19 and 13 with non-COVID-19 myocarditis underwent a follow-up scan. In 10 of the post-COVID-19 and 15 of the non-COVID-19 patients with myocarditis endomyocardial biopsy (EMB) with histological, immunohistological, and molecular analysis was performed.
Results: In total, 10 (31%) patients with COVID-19 showed evidence of myocardial injury, eight (25%) presented with myocardial oedema, eight (25%) exhibited global or regional systolic left ventricular (LV) dysfunction, and nine (28%) exhibited impaired right ventricular (RV) function. However, only three (9%) of COVID-19 patients fulfilled updated CMR–Lake Louise criteria (LLC) for acute myocarditis. Regarding EMB, none of the COVID-19 patients but 87% of the non-COVID-19 patients with myocarditis presented histological findings in keeping with acute or chronic inflammation. COVID-19 patients with severe disease on the WHO scale presented with reduced biventricular longitudinal function, increased RV mass, and longer native T1 times compared with those with only mild or moderate disease.
Conclusions: In our cohort, CMR and EMB findings revealed that SARS-CoV-2 infection was associated with relatively mild but variable cardiac involvement. More symptomatic COVID-19 patients and those with higher clinical care demands were more likely to exhibit chronic inflammation and impaired cardiac function compared to patients with milder forms of the disease.

1678

CaV106

Gordon T. Snowden, Nick D. Clement, Shenqi Zhang, Qingyun Xue, A. Hamish R. W. Simpson

Orthopaedic long COVID - the unknown unknowns
are we facing a pandemic of avascular necrosis following COVID-19?

https://doi.org/10.1302/2046-3758.111.BJR-2021-0505

Published

11-Jan-22

Article

https://online.boneandjoint.org.uk/doi/full/10.1302/2046-3758.111.BJR-2021-0505

The detrimental effects of steroids are well documented, and the link between these drugs and the occurrence of femoral head avascular necrosis (AVN) is increasingly recognized.9,10 AVN involves progressive destruction of bone as a result of compromise of bone vasculature,11,12 death of osteocytes and fat cells, and alteration of bone architecture. Following the SARS epidemic in 2003, high rates of femoral head AVN (up to 23%) were noted in patients recovering from the condition who had received steroid treatment.13 The link between COVID-19 and AVN in those who have received steroids has been reported.14 If the rates of AVN reach the heights of those reported following SARS, then orthopaedic services may be subject to a pandemic of AVN, and result in a significant increase in the burden of musculoskeletal disease in the community.

1679

CaV107

Maciej Koźlik 1,* ,Adrianna Błahuszewska 2 andMaciej Kaźmierski 1

Cardiovascular System during SARS-CoV-2 Infection

https://doi.org/10.3390/ijerph19031184

Published

21-Jan-22

Review

https://www.mdpi.com/1660-4601/19/3/1184/htm

SARS-CoV-2 virus can not only damage the respiratory system but may also pose a threat to other organs, such as the heart or vessels. This review focuses on cardiovascular complications of COVID-19, including acute cardiac injury, arrhythmias, biomarkers, accompanying comorbidities and outcomes in patients diagnosed with SARS-CoV-2 infection. The research was conducted on the databases: PubMed, Springer, ScienceDirect, UpToDate, Oxford Academic, Wiley Online Library, ClinicalKey. Fifty-six publications from 1 November 2020 till 15 August 2021 were included in this study. The results show that cardiac injury is present in about 1 in 4 patients with COVID-19 disease, and it is an independent risk factor, which multiplies the death rate several times in comparison to infected patients without myocardial injury. New-onset cardiac injury occurs in nearly every 10th patient of the COVID-19-suffering population. Comorbidities (such as hypertension, cardiovascular disease and diabetes) severely deteriorate the outcome. Therefore, patients with SARS-CoV-2 infection should be carefully assessed in terms of cardiac medical history and possible cardiological complications.

1680

CaV108

Yan Xie, Evan Xu, Benjamin Bowe & Ziyad Al-Aly

Long-term cardiovascular outcomes of COVID-19

https://doi.org/10.1038/s41591-022-01689-3

Published

7-Feb-22

Study

https://www.nature.com/articles/s41591-022-01689-3

We show that, beyond the first 30 d after infection, individuals with COVID-19 are at increased risk of incident cardiovascular disease spanning several categories, including cerebrovascular disorders, dysrhythmias, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure and thromboembolic disease. These risks and burdens were evident even among individuals who were not hospitalized during the acute phase of the infection and increased in a graded fashion according to the care setting during the acute phase (non-hospitalized, hospitalized and admitted to intensive care). Our results provide evidence that the risk and 1-year burden of cardiovascular disease in survivors of acute COVID-19 are substantial. Care pathways of those surviving the acute episode of COVID-19 should include attention to cardiovascular health and disease.

todo

1681

CaV109

Lale Dinc Asarcikli, Mert İlker Hayiroglu, Altug Osken, Kivanc Keskin, Zeynep Kolak & Tolga Aksu

Heart rate variability and cardiac autonomic functions in post-COVID period

https://doi.org/10.1007/s10840-022-01138-8

Published

1-Feb-22

Study

https://link.springer.com/article/10.1007/s10840-022-01138-8

Results
Time domain indices of HRV analysis (standard deviation of normal RR intervals in 24 h (SDNN 24 h) and root mean square of successive RR interval differences (RMSSD)) were significantly higher in post-COVID patients (p < 0.05 for all). Among frequency domain indices, high frequency and low frequency/high frequency ratio was significantly higher in post-COVID patients (p = 0.037 and p = 0.010, respectively). SDNN >60 ms [36 (60.0%) vs. 12 (36.4%), p = 0.028)] and RMSSD >40 ms [31 (51.7%) vs. 7 (21.2%), p = 0.003)] were more prevalent in post-COVID patients. Logistic regression models were created to evaluate parasympathetic overtone in terms of SDNN >60 ms and RMSSD >40 ms. After covariate adjustment, post-COVID patients were more likely to have SDNN >60 msn (OR: 2.4, 95% CI:1.2–12.8) and RMSSD >40 ms (OR: 2.5, 95% CI: 1.4–9.2).
Conclusion
This study revealed parasympathetic overtone and increased HRV in patients with history of COVID-19. This may explain the unresolved orthostatic symptoms occurring in post-COVID period which may be associated with autonomic imbalance.

1682

CaV110

JS.TascaG.BianchiAGirardelloA.LucchiniC.Cappelli

Atteinte cardiaque chez les athlètes infectés par le SARS COV-2 - Cardiac involvement in athletes infected by SARS COV-2 disease

https://doi.org/10.1016/j.scispo.2021.05.009

Published

7-Feb-22

Article

https://www.sciencedirect.com/science/article/pii/S0765159722000314

News: The COVID-19 pandemic has resulted in the inevitable cancellation of most sports activities, practiced at both a professional and amateur level, in order to minimize the risk of spreading the infection. Since the number of athletes who tested positive was rather high, the potential cardiac involvement in this peculiar population of subjects contracting the disease in a mild (asymptomatic, slightly symptomatic) or moderate form, has recently raised concerns following the observation of cases of recorded myocardial damage, myocarditis, arrhythmias and a first reported case of Sudden Cardiac Death (SCD) in a 27-year-old professional basketball player. Several studies even seem to confirm the possibility of permanent impairment of the cardiorespiratory system following the infection. Medical history, biomarkers, electrocardiographical and cardiac imaging features appear to be crucial in distinguishing cardiovascular alterations related to COVID-19 infection from typical adaptations to exercise related to athletes’ heart.
Prospects and Projects: Clarifications and prospective data based on long-term follow-ups on larger populations of athletes are still needed to exclude the development of myocardial damage capable of negatively affecting prognosis and increasing cardiovascular risk in athletes recovered from COVID-19 in asymptomatic (simple positivity to SARS-COV-2) or in a mild form.

1683

CaV111

E Yaroslavskaya, D Krinochkin, N Shirokov, E Gultyaeva, N Osokina, E Gorbatenko, T Petelina

One-year cardiac follow-up of COVID-19 pneumonia: dynamics of right heart echocardiographic parameters three months and one year after discharge

https://doi.org/10.1093/ehjci/jeab289.348

Published

4-Feb-22

Study

https://academic.oup.com/ehjcimaging/article/23/Supplement_1/jeab289.348/6522650?login=true

Purpose
To compare EchoCG parameters of right heart in patients with proven COVID-19 pneumonia 3 months and one year after discharge.
Methods
A total of 116 patients with confirmed COVID-19 pneumonia were included from April 2020 to July 2021. All patients underwent clinical examination including transthoracic EchoCG 3 months ±2 weeks and one year ±3 weeks after discharge. Mean age of patients was 49.0 ± 14.4 years (19-84 years), females were 49.6%. During hospitalization, chest computed tomography (CT) detected mild lesions in 31.3%, moderate lesions in 33.3%, severe lesions in 29.3% and critical lesions in 6.1%.
Results
The rate of resolution of lung abnormalities according to CT was 55.9%. Mean body mass index was 28.7 ± 5.8 kg/m2 3 months after discharge, and it significantly increased to one year after discharge – 29.4 ± 6.1 kg/m2 (p < 0,001). The mean anteroposterior right ventricular (RV) diameter index decreased over the observation period (13.5 ± 1.9 vs 13.0 ± 1.5 mm/m2, p <0.001), as well as the indices of end-diastolic and end-systolic RV area (8.0 ± 1.8 vs 7.5 ± 1.5 cm2/m2 and 3.8 ± 1.1 vs 3.3 ± 0.8 cm2/m2, respectively, both p < 0.001). The basal RV diameter increased (30.4 ± 5.4 versus 31.1 ± 4.1 mm, p = 0.045), the mid-cavitary RV diameter did not change (25.8 ± 5.4 and 25.8 ± 4.2 mm, p = 0.852), and the base to apex RV length decreased (69.5 ± 8.8 vs 63.9 ± 8.3 mm, p < 0.001). Basal and mid RV sphericity indices (RVSI) increased (0.44 ± 0.07 vs 0.49 ± 0.07 and 0.37 ± 0.07 vs 0.41 ± 0.07, respectively, both p < 0.001). The systolic excursion of the fibrous ring of the tricuspid valve (TAPSE) (22.7 ± 3.2 and 22.8 ± 2.3 mm, p = 0.637) and the tricuspid annular peak systolic velocity S" did not change significantly (10.4 ± 2.6 and 10,1 ± 3.0 cm/s, p = 0.289). The fraction of change in the RV area (FAC RV) increased (52.6 ± 8.2 vs 55.0 ± 8.9%, p = 0.019). The right ventricular outflow tract velocity time integral (RVOT VTI) decreased (18.1 ± 4.0 vs 16.4 ± 3.7 cm, p < 0.001). There were tendencies to increase in the systolic pulmonary artery pressure (PAPs) (22.5 ± 7.1 and 23.3 ± 6.3 mm Hg, p = 0.076) and to increase of the right atrium (RA) long axis dimension (48.7 ± 6.5 vs 49.5 ± 6.3 mm, p = 0.074).
Conclusions
Compared to three months after discharge, in patients one year after COVID-19 pneumonia EchoCG showed the anteroposterior RV diameter and the end-diastolic RV area decreased, the FAC RV increased. However, increase of the basal and mid RVSI, decrease in the RVOT VTI and tendencies to increase of the PAPs and the RA long axis dimension was observed. A subgroup analysis is planned depending on the severity of lung damage during hospitalization.

1684

CaV112

M Akbulut, TS Tan, DM Gerede, V Kozluca, I Dincer

Evaluation of cardiac function by two-dimensional speckle tracking echocardiography in uncomplicated COVID-19 survivors

https://doi.org/10.1093/ehjci/jeab289.155

Published

4-Feb-22

Study

https://academic.oup.com/ehjcimaging/article/23/Supplement_1/jeab289.155/6522343

COVID-19 is a multi-systemic infectious disease. Nearly 20-30% of hospitalized patients have evidence of acute myocardial involvement, portending a poorer prognosis. However, not much is known about the long-term cardiac effects of the disease. Also, there is a growing concern about the cardiac sequelae of COVID-19 among survivors. In this study, we aimed to investigate the long-term cardiac effects in patients with prior mild-moderate COVID-19 infection, using both conventional and speckle tracking echocardiographic imaging modalities. A total number of 58 patients who have been diagnosed with COVID-19 within the previous six months and 20 age-, sex- and risk factor-matched healthy adults were included. All patients underwent a comprehensive echocardiographic examination. Both conventional and two-dimensional speckle tracking echocardiographic measurements were done. Also, serum cardiac biomarkers were obtained on the day of echocardiographic examination. Compared with healthy controls, COVID-19 survivors had similar left and right ventricular systolic function at six months. Also, left and right atrial peak systolic strain values did not differ between the groups. Long-term cardiac sequelae of COVID-19 infection are still widely unknown, resulting in concern among survivors. This study is valuable in putting forth the unaffected systolic and diastolic myocardial function on long-term in uncomplicated COVID-19 cases and may decrease the survivors’ anxiety and the number of unnecessary applications to cardiology clinics.

1685

CaV113

Mitchell G. Miglis, Nicholas Larsen & Srikanth Muppidi

Inappropriate sinus tachycardia in long-COVID and other updates on recent autonomic research

https://doi.org/10.1007/s10286-022-00854-5

Published

7-Feb-22

Editorial

https://link.springer.com/article/10.1007/s10286-022-00854-5

As the COVID-19 pandemic continues to affect hundreds of millions of people worldwide, autonomic complications are being recognized with increasing frequency in both the acute and chronic form of the illness, the latter now designated as post-acute sequelae of SARS-CoV-2 (PASC), colloquially termed long-COVID. Tachycardia is a common symptom of PASC, and some patients may be diagnosed with postural tachycardia syndrome (POTS) or inappropriate sinus tachycardia (IST). While post-COVID POTS has garnered more attention from the scientific and popular press, IST may be equally or more common and has been reported in survivors of the prior SARS coronavirus pandemic [1]. The etiology of IST is unknown; however, the proposed mechanisms overlap with those of POTS, including increased sympathetic and/or reduced cardiovagal activity.

1686

CaV114

ES

Douglas B. Kell
Gert Jacobus Laubscher;
Etheresia Pretorius

A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications

https://doi.org/10.1042/BCJ20220016

Published

23-Feb-22

Review

https://academic.oup.com/jmp/article-abstract/21/3/303/902332

Post-acute sequelae of COVID (PASC), usually referred to as ‘Long COVID’ (a phenotype of COVID-19), is a relatively frequent consequence of SARS-CoV-2 infection, in which symptoms such as breathlessness, fatigue, ‘brain fog’, tissue damage, inflammation, and coagulopathies (dysfunctions of the blood coagulation system) persist long after the initial infection. It bears similarities to other post-viral syndromes, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Many regulatory health bodies still do not recognize this syndrome as a separate disease entity, and refer to it under the broad terminology of ‘COVID’, although its demographics are quite different from those of acute COVID-19. A few years ago, we discovered that fibrinogen in blood can clot into an anomalous ‘amyloid’ form of fibrin that (like other β-rich amyloids and prions) is relatively resistant to proteolysis (fibrinolysis). The result, as is strongly manifested in platelet-poor plasma (PPP) of individuals with Long COVID, is extensive fibrin amyloid microclots that can persist, can entrap other proteins, and that may lead to the production of various autoantibodies. These microclots are more-or-less easily measured in PPP with the stain thioflavin T and a simple fluorescence microscope. Although the symptoms of Long COVID are multifarious, we here argue that the ability of these fibrin amyloid microclots (fibrinaloids) to block up capillaries, and thus to limit the passage of red blood cells and hence O2 exchange, can actually underpin the majority of these symptoms. Consistent with this, in a preliminary report, it has been shown that suitable and closely monitored ‘triple’ anticoagulant therapy that leads to the removal of the microclots also removes the other symptoms. Fibrin amyloid microclots represent a novel and potentially important target for both the understanding and treatment of Long COVID and related disorders.

1687

CaV115

Betty Raman, David A. Bluemke, Thomas F. Lüscher, Stefan Neubauer

Long COVID: post-acute sequelae of COVID-19 with a cardiovascular focus

https://doi.org/10.1093/eurheartj/ehac031

Published

18-Feb-22

Review

https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehac031/6529562

Cardiopulmonary symptoms including chest pain, shortness of breath, fatigue, and autonomic manifestations such as postural orthostatic tachycardia are common and associated with significant disability, heightened anxiety, and public awareness. A range of cardiovascular (CV) abnormalities has been reported among patients beyond the acute phase and include myocardial inflammation, myocardial infarction, right ventricular dysfunction, and arrhythmias. Pathophysiological mechanisms for delayed complications are still poorly understood, with a dissociation seen between ongoing symptoms and objective measures of cardiopulmonary health. COVID-19 is anticipated to alter the long-term trajectory of many chronic cardiac diseases which are abundant in those at risk of severe disease. In this review, we discuss the definition of long COVID and its epidemiology, with an emphasis on cardiopulmonary symptoms. We further review the pathophysiological mechanisms underlying acute and chronic CV injury, the range of post-acute CV sequelae, and impact of COVID-19 on multiorgan health. We propose a possible model for referral of post-COVID-19 patients to cardiac services and discuss future directions including research priorities and clinical trials that are currently underway to evaluate the efficacy of treatment strategies for long COVID and associated CV sequelae.

1688

CaV116

Berenice Martínez-Salazar1,2†, Melle Holwerda2†, gChiara Stüdle3†, Indre Piragyte2,4†, Nadia Mercader2,4,5,6*, Britta Engelhardt3*, Robert Rieben2* and Yvonne Döring1,2,7,8*

COVID-19 and the Vasculature: Current Aspects and Long-Term Consequences

https://doi.org/10.3389/fcell.2022.824851

Published

15-Feb-22

Review

https://www.frontiersin.org/articles/10.3389/fcell.2022.824851/full

Early on during this pandemic, it became apparent that SARS-CoV-2 was not only restricted to infecting the respiratory tract, but the virus was also found in other tissues, including the vasculature. Individuals with underlying pre-existing co-morbidities like diabetes and hypertension have been more prone to develop severe illness and fatal outcomes during COVID-19. In addition, critical clinical observations made in COVID-19 patients include hypercoagulation, cardiomyopathy, heart arrythmia, and endothelial dysfunction, which are indicative for an involvement of the vasculature in COVID-19 pathology. Hence, this review summarizes the impact of SARS-CoV-2 infection on the vasculature and details how the virus promotes (chronic) vascular inflammation. We provide a general overview of SARS-CoV-2, its entry determinant Angiotensin-Converting Enzyme II (ACE2) and the detection of the SARS-CoV-2 in extrapulmonary tissue. Further, we describe the relation between COVID-19 and cardiovascular diseases (CVD) and their impact on the heart and vasculature. Clinical findings on endothelial changes during COVID-19 are reviewed in detail and recent evidence from in vitro studies on the susceptibility of endothelial cells to SARS-CoV-2 infection is discussed. We conclude with current notions on the contribution of cardiovascular events to long term consequences of COVID-19, also known as “Long-COVID-syndrome”. Altogether, our review provides a detailed overview of the current perspectives of COVID-19 and its influence on the vasculature.

1689

CaV117

Annamaria Russo 1,Ester Tellone 2,* ,Davide Barreca 2,* ,Silvana Ficarra 2 andGiuseppina Laganà 2

Implication of COVID-19 on Erythrocytes Functionality: Red Blood Cell Biochemical Implications and Morpho-Functional Aspects

https://doi.org/10.3390/ijms23042171

Published

16-Feb-22

Review

https://www.mdpi.com/1422-0067/23/4/2171/htm

In this review, the hematological changes are evaluated, with particular focus on the morphology and metabolic aspects of erythrocytes. Changes in the functionality of such cells may, in fact, help provide important information about disease severity and progression. The viral infection causes significant damage to the blood cells that are altered in size, rigidity, and distribution width. Lower levels of hemoglobin and anemia have been reported in several studies, and an alteration in the concentration of antioxidant enzymes has been shown to promote a dangerous state of oxidative stress in red blood cells. Patients with severe COVID-19 showed an increase in hematological changes, indicating a progressive worsening as COVID-19 severity progressed. Therefore, monitored hematological alterations in patients with COVID-19 may play an important role in the management of the disease and prevent the risk of a severe course of the disease. Finally, monitored changes in erythrocytes and blood, in general, may be one of the causes of the condition known as Long COVID.

1690

CaV118

Gille-Johnson, Patrik MD, PhD; Kessler, Irene; Tehrani, Sara

Impaired Microvascular Function in Patients With Critical COVID-19

https://doi.org/10.1097/CCE.0000000000000643

Published

1-Feb-22

Study

https://journals.lww.com/ccejournal/Fulltext/2022/02000/Impaired_Microvascular_Function_in_Patients_With.15.aspx

MAIN RESULTS:
Patients with critical COVID-19 had higher basal skin perfusion during both the acute (34 ± 9 perfusion unit; p = 0.0003) and the postinfectious phase (29 ± 8 perfusion unit; p = 0.04), compared with noncoronavirus disease controls (23 ± 7 perfusion unit). In addition, endothelial-dependent and endothelial-independent vasodilation were reduced in patients with critical COVID-19 during the acute disease phase (p < 0.001 for both), whereas no significant differences between patients and controls were found during the postinfectious phase. In patients with severe COVID-19, basal skin perfusion and endothelial-dependent vasodilatation were not significantly changed, whereas endothelial-independent vasodilatation was reduced (p = 0.02) compared with controls.
CONCLUSIONS:
Changes in skin microcirculation in patients with critical COVID-19 indicate that the infection induces a systemic microvascular impairment with persisting long-term effects on the microvascular function.

1691

CaV119

William T. Gunning 1,* ,Paula M. Kramer 1,Jacob A. Cichocki 1,Beverly L. Karabin 2,Sadik A. Khuder 2 andBlair P. Grubb

Platelet Storage Pool Deficiency and Elevated Inflammatory Biomarkers Are Prevalent in Postural Orthostatic Tachycardia Syndrome

https://doi.org/10.3390/cells11050774

Published

23-Feb-22

Study

https://www.mdpi.com/2073-4409/11/5/774/htm

A significant number of postural orthostatic tachycardia syndrome (POTS) patients have platelet delta granule storage pool deficiency (δ-SPD). The etiology of POTS is unknown but a number of laboratories, including ours, have reported elevations of G-protein-coupled adrenergic receptor and muscarinic acetylcholine receptor autoantibodies in POTS patients, detected by a variety of techniques, suggesting that the disorder is an autoimmune condition. Thus, it could also be considered an inflammatory disease. In a pilot study, we investigated a limited number of platelet-related cytokines and chemokines and discovered many that were elevated. This case–control study validates our pilot study results that POTS patients have an activated innate immune system. Plasma of 35 POTS patients and 35 patients with unexplained bleeding symptoms and categorized as “non-POTS” subjects was analyzed by multiplex flow cytometry to quantify 16 different innate immune system cytokines and chemokines. Electron microscopy was used to quantify platelet dense granules. Ten of 16 biomarkers of inflammation were elevated in plasma from POTS patients compared to non-POTS subjects, with most of the differences extremely significant, with p values < 0.0001. Of particular interest were elevations of IL-1β and IL-18 and decreased or normal levels of type 1 interferons in POTS patients, suggesting that the etiology of POTS might be autoinflammatory. All POTS patients had δ-SPD. With a growing body of evidence that POTS is an autoimmune disease and having elevations of the innate immune system, our results suggest a potential T-cell-mediated autoimmunity in POTS characteristic of a mixed-pattern inflammatory disease similar to rheumatoid arthritis.

1692

CaV120

Chi-Ju Hsu, Wen-Chin Lin, Yu-Ching Chou, Chuen-Mi Yang, Hsueh-Ling Wu, Yun-Hsiang Cheng, Ping-Cheng Liu, Jia-Yu Chang, Hsing-Yu Chen, Jun-Ren Sun

Dynamic Changes of the Blood Chemistry in Syrian Hamsters Post-Acute COVID-19

https://doi.org/10.1128/spectrum.02362-21

Published

23-Feb-22

Study

https://journals.asm.org/doi/10.1128/spectrum.02362-21

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that causes coronavirus disease 2019 (COVID-19). However, the long-term health consequences of COVID-19 are not fully understood. We aimed to determine the long-term lung pathology and blood chemistry changes in Syrian hamsters infected with SARS-CoV-2. Syrian hamsters (Mesocricetus auratus) were inoculated with 105 PFU of SARS-CoV-2, and changes post-infection (pi) were observed for 20 days. On days 5 and 20 pi, the lungs were harvested and processed for pathology and viral load count. Multiple blood samples were collected every 3 to 5 days to observe dynamic changes in blood chemistry. Infected hamsters showed consistent weight loss until day 7 pi At day 5 pi, histopathology of the lungs showed moderate to severe inflammation and the virus could be detected. These results indicate that SARS-CoV-2 has an acute onset and recovery course in the hamster infection model. During the acute onset, blood triglyceride levels increased significantly at day 3 pi During the recovery course, uric acid and low-density lipoprotein levels increased significantly, but the total protein and albumin levels decreased. Together, our study suggests that SARS-CoV-2 infection in hamsters not only causes lung damage but also causes long-term changes in blood biochemistry during the recovery process.

1693

CaV121

Vignesh Chidambaram
Amudha Kumar
Giuseppe Calcaterra
Jawahar L. Mehta

Persistent cardiac injury – An important component of long COVID-19 syndrome

https://doi.org/10.1016/j.ebiom.2022.103892

Published

23-Feb-22

Study

https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00076-7/fulltext

As the COVID-19 pandemic goes on, we continue to identify the long-term complications or symptoms among patients who recovered from this infection, be it mild or severe.1 These complications are collectively recognized as “COVID-19 long-hauler syndrome”.1 It is crucial to understand the factors leading to the development of these long-term sequelae to identify, prevent and manage them using appropriate interventions.
Acute cardiac injury (ACI), marked by elevation of troponin levels in the blood over the 99th percentile, is an important phenomenon shown to occur in nearly 30% of patients admitted to the hospital with COVID-19 infection.2 ACI has been shown to be associated with an elevated risk of critical illness, increased duration of hospital stay and mortality.2,3 Multiple processes, both ischaemic and non-ischaemic, have been shown to contribute to the development of ACI in COVID-19 patients. The most important among them is the direct myocardial injury caused by SARS-CoV-2.4 Tavazzi et al. demonstrated direct viral infection in the interstitial cells of the myocardium on endomyocardial biopsy, accompanied by low-grade inflammation.4 But to date, there has been no demonstration of COVID-19 genome in the cardiac tissue in patients with clinical myocarditis. Other mechanisms postulated to increase myocardial injury include systemic inflammation, vascular endothelial damage, cardiomyocyte apoptosis, abnormal myocardial strain, microthrombi formation and supply-demand mismatch (Figure 1).2 The precise mechanisms of myocardial injury in patients with COVID-19 are still unclear. It is also unknown if the myocardial injury is a direct effect of the virus or a response to systemic inflammation or both.
As we continue to obtain long-term data on COVID-19 survivors, it is imperative to look at how the patients with troponin elevation during their hospital admission fair after discharge. We read with interest the article by Lu et al.5 on the importance of persistent cardiac injury in patients with previous COVID-19 and the factors associated with its development. Among the 673 patients who developed ACI and had a follow-up visit, 371 patients (55.1%) had persistent elevation in troponin levels over a median follow-up of 2.5 months. The authors have made a significant case that COVID-19 is associated with persistent cardiac injury in some patients even after the primary infection has resolved. This highlights the long-term cardiac involvement in patients with COVID-19 in the convalescent period. The clinical relevance of these persistently elevated troponin levels on left ventricular function and other cardiovascular outcomes is still to be determined. A retrospective study from the SWEDEHEART database showed that, among 48,482 COVID 19 patients with elevated cardiac troponin levels (>99 percentile) without a diagnosis of acute coronary syndrome, 7529 patients (15.4%) developed long-term major adverse cardiac events, defined as the composite of all-cause mortality, myocardial infarction, readmission for heart failure, or stroke, over a median follow-up of 4.9 years.6 Kotecha et al. performed cardiac magnetic resonance (CMR) studies in 148 patients with severe COVID-19 and persistent troponin elevation at a median of 68 days post-discharge and observed late gadolinium enhancement and/or ischaemia in 54% of patients.7 Though multiple studies have shown a high frequency of abnormalities on CMR within 1-2 months following SARS-CoV-2 infection, Joy et al. demonstrated that the CMR features are similar in patients with mild COVID-19 illness compared with seronegative healthy individuals, 6 months after SARS-CoV-2 infection.8 However, the long-term CMR abnormalities and their clinical relevance remain to be ascertained.9 Even when the COVID-19 infection has resolved and the individual is no longer infective, he/she might still harbor SARS-CoV-2 RNA in various tissues in the body for up to 230 days.10 This could be one of the mechanisms leading to persistent cardiac injury.10 There are yet major gaps in our understanding of the mechanisms by which SARS-CoV-2 affects the blood vessels and the myocardium, and in turn affects the development of important clinical syndromes like atherosclerosis and heart failure.
Although most of current treatment measures have concentrated on the management of acute illness, multiple trials on the use of various medications and their effects on outcomes in patients with COVID-19 are ongoing.9 Prospective studies are essential to better appreciate the lasting cardiovascular consequences of the long COVID-19 syndrome. It is important to formulate the surveillance guidelines among select groups of patients to identify electrophysiologic, morphologic and functional abnormalities. Consideration should be given for advanced imaging such as CMR, particularly in high-risk patients during follow-up. In that context, whether persistent elevation of troponin points towards a high risk of development of long-term cardiac complications and whether elevated troponin levels is a useful and cost-effective method of screening is to be tested. Optimal screening guidelines for patients after recovery from COVID-19 should be determined to prevent cardiovascular complications in a vast majority of the population.

1694

CaV122

Reika Masuda, Samantha Lodge, Luke Whiley, Nicola Gray, Nathan Lawler, Philipp Nitschke, Sze-How Bong, Torben Kimhofer, Ruey Leng Loo, Berin Boughton, Annie X. Zeng, Drew Hall, Hartmut Schaefer, Manfred Spraul, Girish Dwivedi, Bu B. Yeap, Tammo Diercks, Ganeko Bernardo-Seisdedos, José M. Mato, John C. Lindon, Elaine Holmes*, Oscar Millet*, Julien Wist*, and Jeremy K. Nicholson*

Exploration of Human Serum Lipoprotein Supramolecular Phospholipids Using Statistical Heterospectroscopy in n-Dimensions (SHY-n): Identification of Potential Cardiovascular Risk Biomarkers Related to SARS-CoV-2 Infection

https://doi.org/10.1021/acs.analchem.1c05389

Published

1-Mar-22

Study

https://pubs.acs.org/doi/full/10.1021/acs.analchem.1c05389

SARS-CoV-2 infection causes a significant reduction in lipoprotein-bound serum phospholipids give rise to supramolecular phospholipid composite (SPC) signals observed in diffusion and relaxation edited 1H NMR spectra. To characterize the chemical structural components and compartmental location of SPC and to understand further its possible diagnostic properties, we applied a Statistical HeterospectroscopY in n-dimensions (SHY-n) approach. This involved statistically linking a series of orthogonal measurements made on the same samples, using independent analytical techniques and instruments, to identify the major individual phospholipid components giving rise to the SPC signals. Thus, an integrated model for SARS-CoV-2 positive and control adults is presented that relates three identified diagnostic subregions of the SPC signal envelope (SPC1, SPC2, and SPC3) generated using diffusion and relaxation edited (DIRE) NMR spectroscopy to lipoprotein and lipid measurements obtained by in vitro diagnostic NMR spectroscopy and ultrahigh-performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS). The SPC signals were then correlated sequentially with (a) total phospholipids in lipoprotein subfractions; (b) apolipoproteins B100, A1, and A2 in different lipoproteins and subcompartments; and (c) MS-measured total serum phosphatidylcholines present in the NMR detection range (i.e., PCs: 16.0,18.2; 18.0,18.1; 18.2,18.2; 16.0,18.1; 16.0,20.4; 18.0,18.2; 18.1,18.2), lysophosphatidylcholines (LPCs: 16.0 and 18.2), and sphingomyelin (SM 22.1). The SPC3/SPC2 ratio correlated strongly (r = 0.86) with the apolipoprotein B100/A1 ratio, a well-established marker of cardiovascular disease risk that is markedly elevated during acute SARS-CoV-2 infection. These data indicate the considerable potential of using a serum SPC measurement as a metric of cardiovascular risk based on a single NMR experiment. This is of specific interest in relation to understanding the potential for increased cardiovascular risk in COVID-19 patients and risk persistence in post-acute COVID-19 syndrome (PACS).

1695

CaV123

doublon CaV114

Douglas B. Kell
ORCHID logo
; Gert Jacobus Laubscher; Etheresia Pretorius
ORCHID logo

A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications

https://doi.org/10.1042/BCJ20220016

Published

23-Feb-22

Review

https://portlandpress.com/biochemj/article/479/4/537/230829

Post-acute sequelae of COVID (PASC), usually referred to as ‘Long COVID’ (a phenotype of COVID-19), is a relatively frequent consequence of SARS-CoV-2 infection, in which symptoms such as breathlessness, fatigue, ‘brain fog’, tissue damage, inflammation, and coagulopathies (dysfunctions of the blood coagulation system) persist long after the initial infection. It bears similarities to other post-viral syndromes, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Many regulatory health bodies still do not recognize this syndrome as a separate disease entity, and refer to it under the broad terminology of ‘COVID’, although its demographics are quite different from those of acute COVID-19. A few years ago, we discovered that fibrinogen in blood can clot into an anomalous ‘amyloid’ form of fibrin that (like other β-rich amyloids and prions) is relatively resistant to proteolysis (fibrinolysis). The result, as is strongly manifested in platelet-poor plasma (PPP) of individuals with Long COVID, is extensive fibrin amyloid microclots that can persist, can entrap other proteins, and that may lead to the production of various autoantibodies. These microclots are more-or-less easily measured in PPP with the stain thioflavin T and a simple fluorescence microscope. Although the symptoms of Long COVID are multifarious, we here argue that the ability of these fibrin amyloid microclots (fibrinaloids) to block up capillaries, and thus to limit the passage of red blood cells and hence O2 exchange, can actually underpin the majority of these symptoms. Consistent with this, in a preliminary report, it has been shown that suitable and closely monitored ‘triple’ anticoagulant therapy that leads to the removal of the microclots also removes the other symptoms. Fibrin amyloid microclots represent a novel and potentially important target for both the understanding and treatment of Long COVID and related disorders.

1696

CaV124

EvangelosOikonomouab1NektariosSouvaliotisaaStamatiosLampsasaaGerasimosSiasosabGaryphalliaPoulakoucPanagiotisTheofilisbTheodore G.PapaioannoubAnna-BettinaHaidichdGeorgiaTsaousieVasileiosNtousopouloscVissariaSakkacGeorgiosCharalambousfVasilikiRapticSylviaRaftopoulougKonstantinosSyrigoscCostasTsioufisbDimitrisTousoulisbManolisVavuranakisa

Endothelial dysfunction in acute and long standing COVID−19: A prospective cohort study

https://doi.org/10.1016/j.vph.2022.106975

Published

3-Mar-22

Study

https://www.sciencedirect.com/science/article/pii/S1537189122000246

Background
Coronavirus disease-19 (COVID-19) is implicated by active endotheliitis, and cardiovascular morbidity. The long-COVID-19 syndrome implications in atherosclerosis have not been elucidated yet. We assessed the immediate, intermediate, and long-term effects of COVID-19 on endothelial function.
Results
Seventy-three patients diagnosed with COVID-19 (37% admitted in ICU) were recruited. FMD was significantly (p < 0.001) impaired in the COVID-19 group (1.65 ± 2.31%) compared to the control (6.51 ± 2.91%). ICU-treated subjects presented significantly impaired (p = 0.001) FMD (0.48 ± 1.01%) compared to those treated in the medical ward (2.33 ± 2.57%). During hospitalization, FMD was inversely associated with Interleukin-6 and Troponin I (p < 0.05 for all). Although, a significant improvement in FMD was noted during the follow-up (acute: 1.75 ± 2.19% vs. 1 month: 4.23 ± 2.02%, vs. 6 months: 5.24 ± 1.62%; p = 0.001), FMD remained impaired compared to control (6.48 ± 3.08%) at 1 month (p < 0.001) and 6 months (p = 0.01) post-hospital discharge.
Conclusion
COVID-19 patients develop a notable endothelial dysfunction, which is progressively improved over a 6-month follow-up but remains impaired compared to healthy controls subjects. Whether chronic dysregulation of endothelial function following COVID-19 could be accompanied by a residual risk for cardiovascular and thrombotic events merits further research.

1697

CaV125

Nan Liu,Hui Long,Jianhua Sun,Huan Li,Yunting He,Qiang Wang,Kai Pan,Yongliang Tong,Bingshun Wang,Qingming Wu,Likun Gong

New laboratory evidence for the association between endothelial dysfunction and COVID-19 disease progression

https://doi.org/10.1002/jmv.27693

Published

5-Mar-22

Study

https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.27693

There is growing evidence that ACE2 is highly expressed on endothelial cells, endothelial dysfunction plays a critical role in COVID-19 disease progression, but laboratory evidence is still lacking. This study established a multicenter retrospective cohort of 966 COVID-19 patients from three hospitals in Wuhan, China. We found that male (62.8% vs 46.5%), old age (72 (17) vs 60.5 (21)), and coexisting chronic diseases (88.5% vs 60.0%) were associated with poor clinical prognosis in COVID-19. Furthermore, the deteriorated patients exhibited more severe multi-organ damage, coagulation dysfunction, and extensive inflammation. Additionally, a cross-sectional study including 41 non-COVID-19 controls and 39 COVID-19 patients assayed endothelial function parameters in plasma and showed that COVID-19 patients exhibited elevated VCAM-1 (odds ratio, 1.000; 95% CI, 1.000-1.000; P=0.002), E-selectin (odds ratio, 1.000; 95% CI, 1.000-1.001; P<0.001), tPA (odds ratio, 1.024; 95% CI, 1.014-1.035; P<0.001), and decreased PAI-1 (odds ratio, 0.995; 95% CI, 0.990-1.000; P=0.059). Moreover, VCAM-1 was positively correlated with D-dimer (R=0.544, P<0.001); tPA was positively correlated with D-dimer (R=0.800, P<0.001) and BUN (R=0.638, P<0.001). Our findings further confirm the strong association between endothelial dysfunction and poor prognosis of COVID-19, which offers a rationale for targeting endothelial dysfunction as a therapeutic strategy for COVID-19.

1698

CaV126

Christoph C. Kaufmann 1,*,Amro Ahmed 1,Achim Leo Burger 1,Marie Muthspiel 1,Bernhard Jäger 1,2,Johann Wojta 3,4,5 andKurt Huber 1,2,5

Biomarkers Associated with Cardiovascular Disease in COVID-19

https://doi.org/10.3390/cells11060922

Published

8-Mar-22

Review

https://www.mdpi.com/2073-4409/11/6/922/htm

While the respiratory system is the primary target of disease manifestation, COVID-19 has been shown to also affect several other organs, making it a rather complex, multi-system disease. As such, cardiovascular involvement has been a topic of discussion since the beginning of the COVID-19 pandemic, primarily due to early reports of excessive myocardial injury in these patients. Treating physicians are faced with multiple challenges in the management and early triage of patients with COVID-19, as disease severity is highly variable ranging from an asymptomatic infection to critical cases rapidly deteriorating to intensive care treatment or even fatality. Laboratory biomarkers provide important prognostic information which can guide decision making in the emergency department, especially in patients with atypical presentations. Several cardiac biomarkers, most notably high-sensitive cardiac troponin (hs-cTn) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), have emerged as valuable predictors of prognosis in patients with COVID-19. The purpose of this review was to offer a concise summary on prognostic cardiac biomarkers in COVID-19 and discuss whether routine measurements of these biomarkers are warranted upon hospital admission.

1699

CaV127

CPET

Pasquale Ambrosino 1,*,† ,Paolo Parrella 2,†,Roberto Formisano 1,Giovanni Perrotta 1,Silvestro Ennio D’Anna 3,Marco Mosella 3,Antimo Papa 1,‡ andMauro Maniscalco

Cardiopulmonary Exercise Performance and Endothelial Function in Convalescent COVID-19 Patients

https://doi.org/10.3390/jcm11051452

Published

7-Mar-22

Study

https://www.mdpi.com/2077-0383/11/5/1452/htm

Background: Endothelial dysfunction has been proposed as the common pathogenic background of most manifestations of coronavirus disease 2019 (COVID-19). Among these, some authors also reported an impaired exercise response during cardiopulmonary exercise testing (CPET). We aimed to explore the potential association between endothelial dysfunction and the reduced CPET performance in COVID-19 survivors. Methods: 36 consecutive COVID-19 survivors underwent symptom-limited incremental CPET and assessment of endothelium-dependent flow-mediate dilation (FMD) according to standardized protocols. Results: A significantly higher FMD was documented in patients with a preserved, as compared to those with a reduced, exercise capacity (4.11% ± 2.08 vs. 2.54% ± 1.85, p = 0.048), confirmed in a multivariate analysis (β = 0.899, p = 0.038). In the overall study population, FMD values showed a significant Pearson’s correlation with two primary CPET parameters, namely ventilation/carbon dioxide production (VE/VCO2) slope (r = −0.371, p = 0.026) and end-tidal carbon dioxide tension (PETCO2) at peak (r = 0.439, p = 0.007). In multiple linear regressions, FMD was the only independent predictor of VE/VCO2 slope (β = −1.308, p = 0.029) and peak PETCO2 values (β = 0.779, p = 0.021). Accordingly, when stratifying our study population based on their ventilatory efficiency, patients with a ventilatory class III-IV (VE/VCO2 slope ≥ 36) exhibited significantly lower FMD values as compared to those with a ventilatory class I-II. Conclusions: The alteration of endothelial barrier properties in systemic and pulmonary circulation may represent a key pathogenic mechanism of the reduced CPET performance in COVID-19 survivors. Personalized pharmacological and rehabilitation strategies targeting endothelial function may represent an attractive therapeutic option.

1700

CaV128

He Li ,Yixiang Deng ,Zhen Li,Ander Dorken Gallastegi,Christos S. Mantzoros,Galit H. Frydman,George E. Karniadakis

Multiphysics and multiscale modeling of microthrombosis in COVID-19

https://doi.org/10.1371/journal.pcbi.1009892

Published

7-Mar-22

Study

https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1009892

Because of the infectious nature of SARS-CoV-2, patients’ fresh blood samples are limited to access for in vitro experimental investigations. Herein, we employ a novel multiscale and multiphysics computational framework to perform predictive modeling of the pathological thrombus formation in the microvasculature using data from patients with COVID-19. This framework seamlessly integrates the key components in the process of blood clotting, including hemodynamics, transport of coagulation factors and coagulation kinetics, blood cell mechanics and adhesive dynamics, and thus allows us to quantify the contributions of many prothrombotic factors reported in the literature, such as stasis, the derangement in blood coagulation factor levels and activities, inflammatory responses of endothelial cells and leukocytes to the microthrombus formation in COVID-19. Our simulation results show that among the coagulation factors considered, antithrombin and factor V play more prominent roles in promoting thrombosis. Our simulations also suggest that recruitment of WBCs to the endothelial cells exacerbates thrombogenesis and contributes to the blockage of the blood flow. Additionally, we show that the recent identification of flowing blood cell clusters could be a result of detachment of WBCs from thrombogenic sites, which may serve as a nidus for new clot formation. These findings point to potential targets that should be further evaluated, and prioritized in the anti-thrombotic treatment of patients with COVID-19. Altogether, our computational framework provides a powerful tool for quantitative understanding of the mechanism of pathological thrombus formation and offers insights into new therapeutic approaches for treating COVID-19 associated thrombosis.
Author summary
Emerging clinical evidence suggests that thrombosis in the microvasculature of patients with Coronavirus disease 2019 (COVID-19) plays an essential role in dictating the disease progression. We employ a novel multiphysics and multiscale computational framework to investigate the underlying mechanism of the pathological formation of microthrombi and circulating cell clusters in COVID-19. We quantify the contributions of many prothrombotic factors reported in the literature, such as stasis, the derangement in blood coagulation factor levels and activities, inflammatory responses of endothelial cells and leukocytes to the microthrombus formation in COVID-19, through which we identify the potential targets that should be further evaluated, and prioritized in the anti-thrombotic treatment of patients with COVID-19.

1701

CaV129

Jennifer Abbasi

The COVID Heart—One Year After SARS-CoV-2 Infection, Patients Have an Array of Increased Cardiovascular Risks

https://doi.org/10.1001/jama.2022.2411

Published

2-Mar-22

Study

https://jamanetwork.com/journals/jama/fullarticle/2789793

An analysis of data from nearly 154 000 US veterans with SARS-CoV-2 infection provides a grim preliminary answer to the question: What are COVID-19’s long-term cardiovascular outcomes? The study, published in Nature Medicine by researchers at the Veterans Affairs (VA) St Louis Health Care System, found that in the year after recovering from the illness’s acute phase, patients had increased risks of an array of cardiovascular problems, including abnormal heart rhythms, heart muscle inflammation, blood clots, strokes, myocardial infarction, and heart failure. What’s more, the heightened risks were evident even among those who weren’t hospitalized with acute COVID-19.

1702

CaV130

Michael Tarasev, Sabrina Mota, Xiufeng Gao, Marta Ferranti, Aliya U. Zaidi, Bryan Hannan, Patrick Hines

Possible Role of P-selectin Adhesion in Long-COVID: A Comparative Analysis of a Long-COVID Case Versus an Asymptomatic Post-COVID Case

https://doi.org/10.1101/2022.03.09.22271297

pre-print

12-Mar-22

Study

https://www.medrxiv.org/content/10.1101/2022.03.09.22271297v1.full-text

The pathophysiology of Long-COVID remains to be established. Functional P-selectin activity, implicated in COVID-19 sequalae, was measured between two convalescent COVID-19 subjects, one with (Long-COVID subject) and another without Long-COVID symptoms.
Methods - Flow adhesion of whole blood or isolated white blood cells to P-selectin (FA-WB-Psel and FA-WBC-Psel) was measured using a standardized microfluidics clinical assay; impedance aggregometry with a collagen agonist was measured using model 590 Chrono-Log impedance aggregometer; standard laboratory assays were performed to evaluate changes in blood chemistries.
Results - For both subjects, hemoglobin, WBC, platelet counts, electrolytes and ferritin were within normal reference ranges, with FA-WB-Psel significantly elevated compared to healthy controls (p< 0.01). In vitro treatment of whole blood samples with crizanlizumab (anti-p-selectin monoclonal antibody) within the clinical dose range (10 μg/ml) mL) inhibited FA-WB-Psel only in samples from asymptomatic post-COVID subject, with the Long-COVID subject sample requiring close to 5-fold elevated dose to achieve a response. Pronounced inhibition of P-selectin adhesion of isolated leukocytes was observed for both subjects in autologous platelet-poor plasma and buffer. Impedance aggregometry showed greater baseline platelet aggregation to collagen in the Long-COVID sample, although both samples responded similarly to aspirin-induced platelet inhibition.
Conclusions - Presented results suggest that elevated platelet activation in Long-COVID subject may be associated with increased P-Selectin activity. The results are discussed in terms of possible use on P-selectin inhibition therapies in treating Long-COVID.

1703

CaV131

Sara Díaz-Salazar, Raquel Navas, Laura Sainz-Maza, Patricia Fierro, Meryam Maamar, Arancha Artime, Héctor Basterrechea, Benedetta Petitta, Carlota Lamadrid, Lucía Pedraja, Claudia Gándara-Samperio, Stefanie Pini, View ProfileJosé Manuel Olmos, View ProfileCarmen Ramos, View ProfileEmilio Pariente, View ProfileJosé Luis Hernández

Blood group O and post-COVID-19 syndrome

https://doi.org/10.1101/2022.03.10.22272197

pre-print

17-Mar-22

Study

https://www.medrxiv.org/content/10.1101/2022.03.10.22272197v3.full-text

The ABO blood group system modulates the inflammatory response and has been involved in COVID-19. O-group protects against SARS-CoV-2 infection, but there are no data regarding post-COVID-19 syndrome (PCS). Our aim was to assess this possible association.
Subjects and methods - Case-control study in a community setting, with subjects who had experienced mild COVID-19. Cases were PCS+, controls were PCS-, and the exposure variable, O-group. Epidemiological data (age, sex, BMI, smoking, comorbidities), laboratory parameters (inflammatory markers, IgG antibodies, blood type) and clinical data were collected. Composite inflammatory indices were developed. Multivariate analyses were performed.
Results - We analyzed 121 subjects (56.2% women), mean age 45.7 ± 16 years. Blood group frequencies were 43.3%, 7.7%, 5.7%, and 43.3% for A, B, AB and O, respectively. Thirty-six patients were PCS+. There were no significant differences between cases and controls. Compared to non-O, a higher prevalence of PCS (p=0.036), number of symptoms (p=0.017) and myalgia (p=0.030) were noted in O-group. Concerning inflammatory markers, PCS+ and PCS-showed no differences in A, B, and AB groups. In contrast, O-group PCS+ patients had significantly higher lymphocyte count, higher levels of fibrinogen and CRP, and higher percentages of 3 composite indices, than PCS-subjects. The O-group showed a 4-fold increased risk of PCS compared to non-O (adjusted OR=4.20 [95%CI, 1.2-14]; p=0.023).
Conclusion - An increased risk of PCS has shown to be associated with O-group, after controlling for confounders. In O-group subjects with PCS, slightly albeit significant, raised levels of fibrinogen, CRP, and lymphocyte count, have been demonstrated.

1704

CaV132

Shokrollah Elahi

Hematopoietic responses to SARS-CoV-2 infection

https://doi.org/10.1007/s00018-022-04220-6

Published

13-Mar-22

Review

https://link.springer.com/article/10.1007/s00018-022-04220-6

Under physiological conditions, hematopoietic stem and progenitor cells (HSPCs) in the bone marrow niches are responsible for the highly regulated and interconnected hematopoiesis process. At the same time, they must recognize potential threats and respond promptly to protect the host. A wide spectrum of microbial agents/products and the consequences of infection-induced mediators (e.g. cytokines, chemokines, and growth factors) can have prominent impact on HSPCs. While COVID-19 starts as a respiratory tract infection, it is considered a systemic disease which profoundly alters the hematopoietic system. Lymphopenia, neutrophilia, thrombocytopenia, and stress erythropoiesis are the hallmark of SARS-CoV-2 infection. Moreover, thrombocytopenia and blood hypercoagulability are common among COVID‐19 patients with severe disease. Notably, the invasion of erythroid precursors and progenitors by SARS-CoV-2 is a cardinal feature of COVID-19 disease which may in part explain the mechanism underlying hypoxia. These pieces of evidence support the notion of skewed steady-state hematopoiesis to stress hematopoiesis following SARS-CoV-2 infection. The functional consequences of these alterations depend on the magnitude of the effect, which launches a unique hematopoietic response that is associated with increased myeloid at the expense of decreased lymphoid cells. This article reviews some of the key pathways including the infectious and inflammatory processes that control hematopoiesis, followed by a comprehensive review that summarizes the latest evidence and discusses how SARS-CoV-2 infection impacts hematopoiesis.

1705

CaV133

Filippo Crea

European Society of Cardiology guidance for the management of cardiovascular disease during the pandemic and a focus on long COVID

https://doi.org/10.1093/eurheartj/ehac087

Published

17-Feb-22

Guidance

https://academic.oup.com/eurheartj/article/43/11/1017/6547843?login=true

This focus issue on COVID-19 opens with two guidance documents produced by the Task Force for the management of COVID-19 of the European Society of Cardiology.6,7 The aim of this two-part series is to provide practical knowledge and guidance to aid clinicians in the diagnosis and management of cardiovascular disease (CVD) in association with COVID-19. The authors point out that they have reviewed the available evidence and have organized the resulting information into two parts. The first focuses on the epidemiology, pathophysiology, and diagnosis of CV conditions that may be manifest in patients with COVID-19. The second part addresses the topics of care pathways, treatment, and follow-up of CV conditions in patients with COVID-19. The Task Force concludes that these documents provide a summary of current knowledge and guidance to practising clinicians managing patients with CVD and COVID-19. The recommendations are mainly the result of observations and personal experience from healthcare providers. Therefore, the information provided may be subject to change with increasing knowledge, evidence from prospective studies, and changes in the pandemic. Likewise, the guidance provided in the document should not interfere with recommendations provided by local and national healthcare authorities.

1706

CaV134

Ismaheel O. Lawal, Mankgopo M. Kgatle, Kgomotso Mokoala, Abubakar Farate & Mike M. Sathekge

Cardiovascular disturbances in COVID-19: an updated review of the pathophysiology and clinical evidence of cardiovascular damage induced by SARS-CoV-2

https://doi.org/10.1186/s12872-022-02534-8

Published

9-Mar-22

Review

https://bmccardiovascdisord.biomedcentral.com/articles/10.1186/s12872-022-02534-8

Severe acute respiratory coronavirus-2 (SARS-Co-2) is the causative agent of coronavirus disease-2019 (COVID-19). COVID-19 is a disease with highly variable phenotypes, being asymptomatic in most patients. In symptomatic patients, disease manifestation is variable, ranging from mild disease to severe and critical illness requiring treatment in the intensive care unit. The presence of underlying cardiovascular morbidities was identified early in the evolution of the disease to be a critical determinant of the severe disease phenotype. SARS-CoV-2, though a primarily respiratory virus, also causes severe damage to the cardiovascular system, contributing significantly to morbidity and mortality seen in COVID-19. Evidence on the impact of cardiovascular disorders in disease manifestation and outcome of treatment is rapidly emerging. The cardiovascular system expresses the angiotensin-converting enzyme-2, the receptor used by SARS-CoV-2 for binding, making it vulnerable to infection by the virus. Systemic perturbations including the so-called cytokine storm also impact on the normal functioning of the cardiovascular system. Imaging plays a prominent role not only in the detection of cardiovascular damage induced by SARS-CoV-2 infection but in the follow-up of patients’ clinical progress while on treatment and in identifying long-term sequelae of the disease.

1707

CaV135

Sina Bohnacker, Franziska Hartung, Fiona Henkel, Alessandro Quaranta, Johan Kolmert, Alina Priller, Minhaz Ud-Dean, Johanna Giglberger, Luisa M. Kugler, Lisa Pechtold, Sarah Yazici, Antonie Lechner, Johanna Erber, Ulrike Protzer, Paul Lingor, Percy Knolle, Adam M. Chaker, Carsten B. Schmidt-Weber, Craig E. Wheelock & Julia Esser-von Bieren

Mild COVID-19 imprints a long-term inflammatory eicosanoid- and chemokine memory in monocyte-derived macrophages

https://doi.org/10.1038/s41385-021-00482-8

Published

15-Mar-22

Study

https://www.nature.com/articles/s41385-021-00482-8

Monocyte-derived macrophages (MDM) drive the inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and they are a major source of eicosanoids in airway inflammation. Here we report that MDM from SARS-CoV-2-infected individuals with mild disease show an inflammatory transcriptional and metabolic imprint that lasts for at least 5 months after SARS-CoV-2 infection. MDM from convalescent SARS-CoV-2-infected individuals showed a downregulation of pro-resolving factors and an increased production of pro-inflammatory eicosanoids, particularly 5-lipoxygenase-derived leukotrienes. Leukotriene synthesis was further enhanced by glucocorticoids and remained elevated at 3–5 months, but had returned to baseline at 12 months post SARS-CoV-2 infection. Stimulation with SARS-CoV-2 spike protein or LPS triggered exaggerated prostanoid-, type I IFN-, and chemokine responses in post COVID-19 MDM. Thus, SARS-CoV-2 infection leaves an inflammatory imprint in the monocyte/ macrophage compartment that drives aberrant macrophage effector functions and eicosanoid metabolism, resulting in long-term immune aberrations in patients recovering from mild COVID-19.

1708

CaV136

Writing Committee, Ty J. Gluckman, Nicole M. Bhave, Larry A. Allen, Eugene H. Chung, Erica S. Spatz, Enrico Ammirati, Aaron L. Baggish, Biykem Bozkurt, William K. Cornwell, Kimberly G. Harmon, Jonathan H. Kim, Anuradha Lala, Benjamin D. Levine, Matthew W. Martinez, Oyere Onuma, Dermot Phelan, Valentina O. Puntmann, Saurabh Rajpal, Pam R. Taub, and Amanda K. Verma

2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19 in Adults: Myocarditis and Other Myocardial Involvement, Post-Acute Sequelae of SARS-CoV-2 Infection, and Return to Play: A Report of the American College of Cardiology Solution Set Oversight Committee
EXPERT CONSENSUS DECISION PATHWAY

https://doi.org/10.1016/j.jacc.2022.02.003

Published

16-Mar-22

EXPERT CONSENSUS DECISION PATHWAY

https://www.jacc.org/doi/full/10.1016/j.jacc.2022.02.003

The novel coronavirus disease 2019 (COVID-19) pandemic has had an unprecedented impact worldwide. In the United States alone, more than 78 million cases have been reported, with greater than 948,000 deaths attributed directly to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as of the writing of this ECDP.2 Among patients hospitalized for COVID-19, various abnormalities in cardiac testing (eg, electrocardiographic abnormalities, elevated cardiac biomarkers)3-5 and a wide range of cardiovascular complications (eg, myocardial injury, thrombosis, arrhythmia) have been reported.4-7
For some patients infected with SARS-CoV-2, cardiac symptoms (eg, chest pain, shortness of breath, fatigue, and palpitations) persist, lasting months after the initial illness.8,9 Laboratory and imaging evidence of myocardial injury and involvement has also been observed in both symptomatic and asymptomatic individuals,4,10,11 as well as after receipt of the COVID-19 mRNA vaccine.12 For clinicians treating these individuals, a growing number of questions exist related to evaluation and management of these conditions, as well as safe resumption of physical activity.
To help gather further insights, the ACC held a virtual Heart House Roundtable in May 2021, bringing together experts in the following areas: 1) myocarditis; 2) post-acute sequelae of SARS-CoV-2 infection (PASC); and 3) sports cardiology. This ECDP represents a key output from that meeting and is intended to serve as a resource for clinicians caring for these patients, largely in the outpatient setting. More specifically, this document attempts to address commonly asked questions regarding the care of adults (aged ≥18 years) with cardiac symptoms (eg, chest pain, dyspnea, palpitations, syncope) after SARS-CoV-2 infection. In the absence of robust clinical trial data, it is intended to provide practical guidance related to evaluation and management.

1709

CaV137

ME - PESE

Milan Haffke, Helma Freitag, Gordon Rudolf, Martina Seifert, Wolfram Doehner, Nadja Scherbakov, Leif Hanitsch, Kirsten Wittke, Sandra Bauer, Frank Konietschke, Friedemann Paul, Judith Bellmann-Strobl, Claudia Kedor, Carmen Scheibenbogen & Franziska Sotzny

Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS)

https://doi.org/10.1186/s12967-022-03346-2

Published

22-Mar-22

Study

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03346-2

Background
Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS.
Methods
We studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs). 14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS. Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs. In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers.
Results
Five of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding. A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs.
Conclusion
A subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups.

1710

CaV138

Mauro Giacca & Ajay M. Shah

The pathological maelstrom of COVID-19 and cardiovascular disease

https://doi.org/10.1038/s44161-022-00029-5

Published

16-Mar-22

Review

https://www.nature.com/articles/s44161-022-00029-5

Coronavirus disease 2019 (COVID-19) is a consequence of infection of the upper and lower respiratory tract with severe acute respiratory syndrome coronavirus 2 but often becomes a systemic disease, with important involvement of other organs. A bidirectional relationship exists between COVID-19 and cardiovascular disease. On the one hand, preexisting comorbidities, in particular high prevalence of cardiovascular risk factors such as hypertension and diabetes and chronic cardiovascular conditions predispose to severe disease. On the other hand, biomarkers of myocardial injury are frequently raised in patients with COVID-19, along with arrhythmia and heart failure. Localized thrombosis is a common finding in the lungs but can also increase the occurrence of thrombotic events systemically. Thrombosis is consequent to different pathogenic mechanisms, which include endothelial dysfunction and immunothrombosis. Thrombocytopenia is common in patients with COVID-19 and alterations in platelet function participate in the pro-thrombotic phenotype. Involvement of the cardiovascular system in COVID-19 has important consequences during recovery from infection and the development of long COVID.

1711

CaV139

Francesco Nappi 1,*,† ,Omar Giacinto 2,†,Omar Ellouze 3,Antonio Nenna 2 ,Sanjeet Singh Avtaar Singh 4 ,Massimo Chello 2 ,Assine Bouzguenda 3 andXavier Copie 5

Association between COVID-19 Diagnosis and Coronary Artery Thrombosis: A Narrative Review

https://doi.org/10.3390/biomedicines10030702

Published

18-Mar-22

Review

https://www.mdpi.com/2227-9059/10/3/702/htm

Coronavirus disease 2019 is characterized by its severe respiratory effects. Data early on indicated an increased risk of mortality in patients with cardiovascular comorbidities. Early reports highlighted the multisystem inflammatory syndrome, cytokine storm, and thromboembolic events as part of the disease processes. The aim of this review is to assess the association between COVID-19 and its thrombotic complications, specifically related to the cardiovascular system. The role of neutrophil extracellular traps (NETs) is explored in the pathogenesis of the disease. The structure and anatomy of the virus are pivotal to its virulence in comparison to other α and β Coronaviridae (HCoV-229E, HCoV-OC43, HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1). In particular, the host interaction and response may explain the variability of severity in patients. Angio tensin-converting enzyme 2 (ACE2) activation may be implicated in the cardiovascular and throm bogenic potential of the disease. The virus may also have direct effects on the endothelial lining affecting hemostasis and resulting in thrombosis through several mechanisms. Dipyridamole may have a therapeutic benefit in NET suppression. Therapeutic avenues should be concentrated on the different pathophysiological steps involving the virus and the host.

1712

CaV140

Michael S. Nirenberg,Luis Requena,Carlos Santonja,Gregory T. Smith,Steve A. McClain

Histopathology of Persistent Long COVID Toe: A Case Report

https://doi.org/10.1111/cup.14240

Published

2-Apr-22

Case Report

https://onlinelibrary.wiley.com/doi/10.1111/cup.14240

During the 2020 coronavirus (SARS-CoV-2) pandemic, several cutaneous lesions were identified, including: pseudo-chilblain, vesicular, urticarial, maculopapular, and livedo/necrosis. A 59-year-old obese man with probable COVID-19 developed painful cyanosis with histopathologic capillary thrombosis of toes, and the cyanosis persisted for nearly 22 months. Shortly after initial exposure to family members with documented SARS-CoV-2, he developed upper respiratory symptoms, yet his anti-SARS-CoV-2 antibody and nasal swab RT-PCR tests were repeatedly negative. Two family members were hospitalized and one of them succumbed with documented SARS-CoV-2 pneumonia within ten days of exposure. Biopsy of the distal toe 16 weeks after initial exposure demonstrated papillary dermal capillary thrombosis with endothelial swelling, telangiectasia, and peri-eccrine lymphocytic infiltrates resembling pernio. Overall, this is the first case of biopsy of “long COVID toe” following presumed SARS-Cov-2 exposure, with demonstration of thrombotic vasculopathy, toe cyanosis, and pernio-like pathology.

1713

CaV141

Mohamed O. Mohamed & Amitava Banerjee

Long COVID and cardiovascular disease: a learning health system approach

https://doi.org/10.1038/s41569-022-00697-7

Published

24-Mar-22

Article

https://www.nature.com/articles/s41569-022-00697-7

Cardiovascular disease is both a risk factor and potential outcome of the direct, indirect and long-term effects of COVID-19. A recent analysis in >150,000 survivors of COVID-19 demonstrates an increased 1-year risk of numerous cardiovascular diseases. Preventing and managing this new disease burden presents challenges to health systems and requires a learning health system approach.
To summarize, bidirectional relationships exist between CVD and COVID-19. Multimorbidity and CVD are key considerations in patients with long COVID, who require multidisciplinary and integrated care. Long COVID, including cardiovascular complications, has potentially far-reaching implications for health system resources, including staffing, infrastructure and funding. The knowledge gaps in basic research, clinical evidence and patient care need to be addressed together to enable effective and timely management of long COVID. Future pandemic planning and preparedness should include modelling and consideration of CVDs and noncommunicable diseases, as well as potential long-term disease sequelae.

1714

CaV142

Pietro Enea Lazzerini, Franco Laghi-Pasini, Mohamed Boutjdir & Pier Leopoldo Capecchi

Inflammatory cytokines and cardiac arrhythmias: the lesson from COVID-19

https://doi.org/10.1038/s41577-022-00714-3

Published

28-Mar-22

Article

https://www.nature.com/articles/s41577-022-00714-3

Although inflammatory cytokines are implicated in the pathogenesis of cardiac arrhythmias, inflammation is still largely overlooked in the current management of heart rhythm disorders. Now, COVID-19, a systemic inflammatory disease, causes an unexpectedly high prevalence of arrhythmic events, emphasizing the relevance of inflammation in the pathogenesis of cardiac arrhythmias.
Conclusion
COVID-19 has provided us with the unique opportunity to observe how systemic cytokine release increases arrhythmic risk. It is increasingly evident that a very similar increase of arrhythmic events is also found in other inflammatory conditions. Although some clinical studies show beneficial effects of targeting inflammation and inflammatory cytokines to reduce arrhythmic risk1, this field is still largely unexplored. Notably, a large meta-analysis of randomized controlled trials recently demonstrated that therapy with glucocorticoid and/or IL-6 receptor antagonist significantly reduced short-term mortality in patients with severe COVID-19, including cardiovascular death10. Therefore, it is important to consider inflammation as an essential contributor to cardiac arrhythmic events, especially given that its clinical impact is likely to be relevant in conditions beyond COVID-19.

1715

CaV143

Luca Santoro 1,†,Lorenzo Falsetti 2,† ,Vincenzo Zaccone 2,*,Antonio Nesci 1,Matteo Tosato 3 ,Bianca Giupponi 4,Maria Cristina Savastano 5 ,Gianluca Moroncini 6,Antonio Gasbarrini 7,8,Francesco Landi 3,8,Angelo Santoliquido 1,8

Impaired Endothelial Function in Convalescent Phase of COVID-19: A 3 Month Follow Up Observational Prospective Study

https://doi.org/10.3390/jcm11071774

Published

23-Mar-22

Study

https://www.mdpi.com/2077-0383/11/7/1774/htm

Endothelial dysfunction has a role in acute COVID-19, contributing to systemic inflammatory syndrome, acute respiratory distress syndrome, and vascular events. Evidence regarding COVID-19 middle- and long-term consequences on endothelium are still lacking. Our study aimed to evaluate if COVID-19 severity could significantly affect the endothelial function after three months from the acute phase. Methods: We assessed endothelial function in outpatients with previous COVID-19 three months after negative SARS-CoV-2 molecular test by measuring flow-mediated dilation (FMD) in patients categorized according to a four-variable COVID-19 severity scale (“home care”; “hospital, no oxygen”; “hospital, oxygen”; “hospital requiring high-flow nasal canula, non-invasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation”). FMD difference among COVID-19 severity categories was assessed with analysis of variance; we further clarified the relationship between FMD and previous COVID-19 severity with multivariate logistic models. Results: Among 658 consecutive COVID-19 subjects, we observed a significant linear trend of FMD reduction with the increase of the COVID-19 category (p < 0.0001). The presence of endothelial dysfunction was more frequent among hospitalized patients (78.3%) with respect to home-care patients (21.7%; p < 0.0001). COVID-19 severity was associated with increased endothelial dysfunction risk (OR: 1.354; 95% CI: 1.06–1.71; p = 0.011) at multivariate binary logistic analysis. FMD showed a significant direct correlation with PaO2 (p = 0.004), P/F ratio (p = 0.004), FEV1 (p = 0.008), and 6MWT (p = 0.0001). Conclusions: Hospitalized COVID-19 subjects showed an impaired endothelial function three months after the acute phase that correlated with pulmonary function impairment. Further studies are needed to evaluate if these subjects are at higher risk of developing pulmonary disease or future cardiovascular events.

1716

CaV144

Ioannis Katsoularis, Osvaldo Fonseca-Rodríguez, Paddy Farrington, Hanna Jerndal, Erling Häggström Lundevaller, Malin Sund, Krister Lindmark, Anne-Marie Fors Connolly

Risks of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19: nationwide self-controlled cases series and matched cohort study

https://doi.org/10.1136/bmj-2021-069590

Published

6-Apr-22

Study

https://www.bmj.com/content/377/bmj-2021-069590

Objective To quantify the risk of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19.
Design Self-controlled case series and matched cohort study.
Setting National registries in Sweden.
Participants 1 057 174 people who tested positive for SARS-CoV-2 between 1 February 2020 and 25 May 2021 in Sweden, matched on age, sex, and county of residence to 4 076 342 control participants.
Main outcomes measures Self-controlled case series and conditional Poisson regression were used to determine the incidence rate ratio and risk ratio with corresponding 95% confidence intervals for a first deep vein thrombosis, pulmonary embolism, or bleeding event. In the self-controlled case series, the incidence rate ratios for first time outcomes after covid-19 were determined using set time intervals and the spline model. The risk ratios for first time and all events were determined during days 1-30 after covid-19 or index date using the matched cohort study, and adjusting for potential confounders (comorbidities, cancer, surgery, long term anticoagulation treatment, previous venous thromboembolism, or previous bleeding event).
Results Compared with the control period, incidence rate ratios were significantly increased 70 days after covid-19 for deep vein thrombosis, 110 days for pulmonary embolism, and 60 days for bleeding. In particular, incidence rate ratios for a first pulmonary embolism were 36.17 (95% confidence interval 31.55 to 41.47) during the first week after covid-19 and 46.40 (40.61 to 53.02) during the second week. Incidence rate ratios during days 1-30 after covid-19 were 5.90 (5.12 to 6.80) for deep vein thrombosis, 31.59 (27.99 to 35.63) for pulmonary embolism, and 2.48 (2.30 to 2.68) for bleeding. Similarly, the risk ratios during days 1-30 after covid-19 were 4.98 (4.96 to 5.01) for deep vein thrombosis, 33.05 (32.8 to 33.3) for pulmonary embolism, and 1.88 (1.71 to 2.07) for bleeding, after adjusting for the effect of potential confounders. The rate ratios were highest in patients with critical covid-19 and highest during the first pandemic wave in Sweden compared with the second and third waves. In the same period, the absolute risk among patients with covid-19 was 0.039% (401 events) for deep vein thrombosis, 0.17% (1761 events) for pulmonary embolism, and 0.101% (1002 events) for bleeding.
Conclusions The findings of this study suggest that covid-19 is a risk factor for deep vein thrombosis, pulmonary embolism, and bleeding. These results could impact recommendations on diagnostic and prophylactic strategies against venous thromboembolism after covid-19.

1717

CaV145

Ahmed Ibrahim Ahmed, Jean Michel Saad, Yushui Han, Maan Malahfji, Faisal Nabi, John J. Mahmarian, William A. Zoghbi, and Mouaz H. Al-Mallah

CORONARY MICROVASCULAR HEALTH IN PATIENTS WITH PRIOR COVID-19 INFECTION: IMPLICATIONS FOR LONG-COVID SYNDROME

Published

1-Mar-22

Study

https://www.jacc.org/doi/full/10.1016/S0735-1097%2822%2902813-3

Background:
SARS-CoV-2 infection has been shown to directly infect coronary vascular endothelium, causing inflammation and plaque instability. We aimed to assess the vascular health of patients with prior COVID-19 using Positron emission tomography (PET) derived coronary flow reserve (CFR).
Methods:
A prospective cohort of consecutive patients with PCR confirmed prior COVID-19 infection undergoing clinically indicated PET myocardial perfusion imaging were included and compared to patients with no prior COVID19. CFR was determined by PET and microvascular dysfunction (CMD) was defined as CFR<2.
Results:
The study population consisted of 2316 patients (4.4% prior COVID 19, 52% male, mean age 67±12 years, 55% hypertensive, 32% diabetic, 41% dyslipidemia). The mean duration between COVID19 diagnosis and PET was 191 (±131) days. CMD was more prevalent in those with prior COVID19 (58% vs 46%, p=0.012). After adjusting for baseline and clinical characteristics, patients with prior COVID19 had statistically significant higher odds of CMD (OR 1.8, p=0.008). Results were consistent in subgroups of patients with no clinical risk factors and normal stress tests.
Conclusion:
Our analysis shows that patients with prior COVID19 have higher rates of CMD. This may in part explain the long-COVID symptoms. The prognostic implications of these findings need to be determined.

1718

CaV146

Christopher Werlein, Maximilian Ackermann, Harshit R. Shah, Helge Stark, Florian Laenger, Tim Salditt, Tobias Welte, Johann Bauersachs, Axel Haverich, Saskia von Stillfried, Mark Kuehnel, Roman Buelow, Peter Boor, Stephen M. Black, Steven J. Mentzer, and Danny Jonigk

INFLAMMATION AND VASCULAR REMODELING IN COVID-19 HEARTS

Published

2-Mar-22

Study

https://www.jacc.org/doi/full/10.1016/S0735-1097%2822%2902814-5

Background:
Cardiac involvement in COVID-19 infection is a common clinical finding and can determine the clinical outcome; however the underlying pathomechanisms are largely unknown.
Methods:
We performed a comprehensive analysis of heart-tissue samples of 24 autopsies with confirmed COVID-19 disease and compared them to samples of age-matched Influenza A (n=16) as well as conventional viral myocarditis cases (n=8) and control tissue (n=9). We employed conventional histopathology, microvascular corrosion casting, scanning electron microscopy, phase-contrast synchrotron x-ray tomography, direct multiplexed measurements of gene expression, multiplexed immunohistochemistry (MPX) and Synchrotron radiation tomographic microscopy.
Results:
On conventional histopathology, none of the COVID-19 samples fulfilled the criteria for lymphocytic myocarditis; however quantification via MPX showed a significant increase in perivascular CD11b/Tie2+-macrophages in COVID-19 over hospitalisation time. Ultrastructurally, an altered microvascularity, an increase of intussusceptive angiogenesis as well as multifocal ultrastructurally detectable thrombi (uTh) could be demonstrated, unapparent in conventional morphology. On a molecular level, COVID-19 hearts displayed a distinct expression pattern coding mainly for angiogenesis and epithelial-mesenchymal transition (EMT) and lesser for inflammation.
Conclusion:
Cardiac involvement in COVID-19 is not a conventional viral myocarditis but a rather qualitative than quantitative increase in CD11b+/Tie2+ monocytes/ macrophages contributing to cardiac neoangiogenesis and remodeling in COVID-19 cardiomyopathy. COVID-19 cardiomyopathy is substantially underappreciated upon light-microscopy observation and requires a multimodal approach. Our comparative morphological and transcriptional data indicate that the neovascularization by intussusceptive angiogenesis is the main driver for a specific COVID-19 induced cardiac response facilitated by interactions between the incorporation of blood-borne CD11b+/Tie2+ monocytes/macrophages and damaged and activated endothelial cells in COVID-19 hearts.

1719

CaV147

Vishal Khetpal, Julia Berkowitz, Lan Jiang, Shilpa Vijayakumar, Khansa Ahmad, Justin Echouffo Tcheugui, Anupama Menon, Daithi S. Heffernan, Gaurav Choudhary, James Rudolph, Wen-Chih Wu, and Sebhat Erqou

LONG-TERM OUTCOMES OF VETERANS WITH A DIAGNOSIS OF HEART FAILURE AFTER CORONAVIRUS-2019 (COVID-19) INFECTION

Published

3-Mar-22

Study

https://www.jacc.org/doi/full/10.1016/S0735-1097%2822%2903146-1

Background:
Patients with heart failure (HF) are at risk for continued symptoms after recovery from acute COVID-19, termed in a growing body of literature as ‘long COVID’. However, limited data have examined whether COVID-19 is associated with higher long-term risk for mortality and hospital admission for HF patients.
Methods:
We conducted a retrospective cohort study of HF patients using Veterans’ Affairs (VA) data from February 1, 2020, to July 31, 2021. Patients with a diagnosis of HF, defined by ICD-10 codes in the year prior to study entry, and COVID-19 infection during the study period were age-, sex- and race-matched with HF patients without COVID-19 infection. We calculated 90-, 180- and 270-day hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause mortality and hospital admissions using Cox-regression models with adjustment for comorbidities. To assess for long-term sequelae of infection, only outcomes taking place beyond the first 30 days after diagnosis of COVID-19 infection were included in analyses.
Results:
Analyses included 85,818 (mean [SD]; 72.5 [10.3] years, 97.6% male, 71.7% White) HF patients. Compared with the subset of HF patients without COVID-19 infection (n=71,515), the subset of HF patients with COVID-19 infection (n=14,303) had significantly higher risk of 90-, 180-, and 270-day mortality, with exclusion of events taking place within the first 30 days of COVID-19 diagnosis (adjusted HR [95% CIs]: 2.15 [1.96-2.37], 1.63 [1.53-1.75], 1.48 [1.39-1.57], respectively). HF patients with COVID-19 infection also had significantly higher 90-, 180-, and 270-day hospital admission rates with exclusion of events taking place within the first 30 days of COVID-19 diagnosis (adjusted HR [95% CIs]: 1.73 [1.56-1.92], 1.51 [1.42-1.60], 1.44 [1.37-1.52], respectively).
Conclusion:
COVID-19 is associated with higher long-term all-cause mortality rate and hospital admission rates for HF patients persisting beyond the acute phase of infection.

1720

CaV148

Sameer M. Jamal, David Landers, Zoltan G. Turi, Steven M. Hollenberg, Taya V. Glotzer, Jana Tancredi, and Joseph E. Parrillo

NEUROCARDIOGENIC SYNCOPE DURING HEAD-UP TILT TABLE (HUTT) TESTING IN PATIENTS WITH POST-ACUTE SEQUELA OF COVID-19 (PASC): A PROSPECTIVE EVALUATION

Published

4-Mar-22

Study

https://www.jacc.org/doi/full/10.1016/S0735-1097%2822%2903106-0

Background:
There is increasing recognition of “Long COVID” or Post-Acute Sequela of COVID-19 (PASC) occurring well after recovery from the initial acute illness. Symptoms may include palpitations, fatigue, and perceived heart rate increase upon standing or on minimal exertion. Somewhat less commonly, patients experience syncope. Autonomic dysfunction may explain these findings, and we have previously shown orthostatic intolerance (OI) on head-up tilt table (HUTT) in 22 of 24 prospectively studied subjects with PASC symptoms. Our objective was to investigate if autonomic dysfunction causes neurocardiogenic syncope on HUTT in PASC patients.
Methods:
This was an IRB approved, prospective, longitudinal, observational study. We included PASC patients complaining of tachycardia with standing or minimal activity, palpitations, and fatigue with exertion. Patients with an alternate medical explanation for these symptoms, pre-existing autonomic dysfunction, or history of syncope prior to PASC symptom development were excluded. Subjects underwent HUTT testing using a standard protocol. OI, postural orthostatic tachycardia syndrome (POTS), and neurocardiogenic syncope were classically defined.
Results:
HUTT was performed on 24 consecutive patients (4 males, mean age 43 years), reporting PASC symptoms for 6 + 4 months. Three demonstrated pure neurocardiogenic syncope. Four demonstrated POTS, with 1 progressing to neurocardiogenic syncope. Fifteen developed OI after sublingual nitroglycerin, and five of these subjects progressed to neurocardiogenic syncope. Neurocardiogenic syncope occurred in 9 of 24 (38%) PASC patients during HUTT testing.
Conclusion:
Neurocardiogenic syncope was demonstrated in 38% of PASC study patients. Our findings suggest autonomic dysfunction contributes to PASC symptom development. In patients with PASC, OI is commonly seen on HUTT.

1721

CaV149

Rachana Raghupathy, Umar Khalid, Sathwika Thodeti, Brandon M. Mikolich, Tahir Kuraan, and J Ronald Mikolich

PREVALENCE OF RIGHT AND LEFT VENTRICULAR DYSFUNCTION AMONG PATIENTS WITH POST-COVID INFLAMMATORY HEART DISEASE

Published

5-Mar-22

Study

https://www.jacc.org/doi/full/10.1016/S0735-1097%2822%2903057-1

Background:
Recently published data suggests that inflammatory heart disease (IHD) is more prevalent in COVID-19 patients than initially expected. There have been reports of greater than expected right ventricular (RV) dysfunction during the post COVID-19 recovery period. This study was designed to assess and compare the prevalence of RV hypokinesis and LV hypokinesis in patients with post COVID-19 related IHD using CMR, which is the “gold” standard for ejection fraction assessment, given its full field of view and spatial resolution. Also, CMR is not limited by intercostal space size, obesity or breast artifact.
Methods:
An institutional cardiac imaging database was queried for all patients with post-COVID-19 IHD documented by CMR. IHD was defined as pericarditis and/or myocarditis using the recent Lake Louise criteria, including T1 and T2 relaxation mapping. Left ventricular global ejection fraction (LVEF) and right ventricular ejection fraction (RVEF) were computed using PRECESSION software (Heart IT) for each patient with post-COVID-19 IHD. The prevalence of RV dysfunction (EF<40%) and LV dysfunction (EF<55%) were computed and statistically analyzed using an unpaired t-test.
Results:
Query of the institutional cardiac imaging database identified 109 patients with post-COVID IHD using state of the art CMR pulse sequences. All had excellent CMR visualization of the RV. Of these 109 patients, 61 (56.0%) were females and 47 (44.0%) were male. Of the 109 post-COVID patients with IHD, 90 (82.6%) showed evidence of RV hypokinesis on CMR with RVEF<40%. Only 25 (22.9%) showed evidence of LV hypokinesis on CMR with LVEF<55. There was a statistically significant difference between the prevalence of RV hypokinesis and LV hypokinesis (p-value < 0.001) among patients with post-COVID IHD.
Conclusion:
These data demonstrate a significantly higher prevalence of RV dysfunction in post-COVID patients with IHD using CMR imaging with both T1 and T2 relaxation mapping to detect myocardial and pericardial edema/inflammation. If a patient with symptoms of post-COVID IHD has a 2-D echo which does not fully visualize the RV structures, this study suggests that CMR should be considered to assess the RVEF.

1722

CaV150

Karina Janice Guadalupe Díaz-Resendiz,Alma Betsaida Benitez-Trinidad,Carlos Eduardo Covantes-Rosales,Gladys Alejandra Toledo-Ibarra,Pablo Cesar Ortiz-Lazareno,Daniel Alberto Girón-Pérez,Adela Yolanda Bueno-Durán,Daniela Alejandra Pérez-Díaz,Rocío Guadalupe Barcelos-García,Manuel Iván Girón-Pérez … See fewer authors

Loss of mitochondrial membrane potential (ΔΨm) in leucocytes as post-COVID-19 sequelae

https://doi.org/10.1002/JLB.3MA0322-279RRR

Published

31-Mar-22

Study

https://jlb.onlinelibrary.wiley.com/doi/full/10.1002/JLB.3MA0322-279RRR

The mitochondrial membrane potential (ΔΨm) is a parameter often used to determine mitochondrial function; therefore, it can be used to determine the integrity and functionality of cells. A decrement of ΔΨm is implicated in several inflammatory-related pathologies, such phenomena can be related to COVID-19 infection. The present work aimed to compare the ΔΨm in leucocytes (human PBMCs; HPBMC) isolated from healthy control (HC) subjects, patients with COVID-19 (C-19), recovered subjects at 40 ± 13 (R1) and 335 ± 20 (R2) days after infection (dai). Obtained data showed that ΔΨm decreased in HPBMC of subjects with C-19, R1, and R2 compared with HC. When analyzing the ΔΨm data by sex, in females, a significant decrease was observed in R1 and R2 groups versus HC. Regarding men, a significant decrease of ΔΨm was observed in R1, with respect to HC, contrary to R2 group, who reestablished this parameter. Obtained results suggest that the loss of ΔΨm could be related to the long-COVID.

1723

CaV151

Sandeep A. Saha MD, MS, FHRS, Andrea M. Russo MD, FHRS, Mina K. Chung MD, FHRS, Thomas F. Deering MD, FHRS, Dhanunjaya Lakkireddy MD, FHRS & Rakesh Gopinathannair MD, MA, FHRS

COVID-19 and Cardiac Arrhythmias: a Contemporary Review

https://doi.org/10.1007/s11936-022-00964-3

Published

19-Apr-22

Review

https://link.springer.com/article/10.1007/s11936-022-00964-3

Purpose of Review
A significant proportion of patients infected by the severe acute respiratory syndrome-coronavirus (SARS-CoV2) (COVID-19) also have disorders affecting the cardiac rhythm. In this review, we provide an in-depth review of the pathophysiological mechanisms underlying the associated arrhythmic complications of COVID-19 infection and provide pragmatic, evidence-based recommendations for the clinical management of these conditions.
Recent Findings
Arrhythmic manifestations of COVID-19 include atrial arrhythmias such as atrial fibrillation or atrial flutter, sinus node dysfunction, atrioventricular conduction abnormalities, ventricular tachyarrhythmias, sudden cardiac arrest, and cardiovascular dysautonomias including the so-called long COVID syndrome. Various pathophysiological mechanisms have been implicated, such as direct viral invasion, hypoxemia, local and systemic inflammation, changes in ion channel physiology, immune activation, and autonomic dysregulation. The development of atrial or ventricular arrhythmias in hospitalized COVID-19 patients has been shown to portend a higher risk of in-hospital death.
Summary
Arrhythmic complications from acute COVID-19 infection are commonly encountered in clinical practice, and COVID-19 patients with cardiac complications tend to have worse clinical outcomes than those without. Management of these arrhythmias should be based on published evidence-based guidelines, with special consideration of the acuity of COVID-19 infection, concomitant use of antimicrobial and anti-inflammatory drugs, and the transient nature of some rhythm disorders. Some manifestations, such as the long COVID syndrome, may lead to residual symptoms several months after acute infection. As the pandemic evolves with the discovery of new SARS-CoV2 variants, development and use of newer anti-viral and immuno-modulator drugs, and the increasing adoption of vaccination, clinicians must remain vigilant for other arrhythmic manifestations that may occur in association with this novel but potentially deadly disease.

1724

CaV152

Fabian Heinrich 1,*,† ,Kevin Roedl 2,† ,Dominik Jarczak 2 ,Hanna-Lisa Goebels 1,Axel Heinemann 1,Ulrich Schäfer 3,Frank Ludwig 4,Martin Bachmann 5,Berthold Bein 6,Christian Friedrich Weber 7,Karsten Sydow 8,Marc Bota 9 ,Hans-Richard Paschen 10,Andreas de Weerth 11,Carsten Veit 12,Oliver Detsch 13,Philipp-Alexander Brand 14,Stefan Kluge 2,Benjamin Ondruschka 1,‡ andDominic Wichmann 2,*,‡

New Insights in the Occurrence of Venous Thromboembolism in Critically Ill Patients with COVID-19—A Large Postmortem and Clinical Analysis

https://doi.org/10.3390/v14040811

Published

14-Apr-22

Study

https://www.mdpi.com/1999-4915/14/4/811/htm

Critically ill COVID-19 patients are at high risk for venous thromboembolism (VTE), namely deep vein thrombosis (DVT) and/or pulmonary embolism (PE), and death. The optimal anticoagulation strategy in critically ill patients with COVID-19 remains unknown. This study investigated the ante mortem incidence as well as postmortem prevalence of VTE, the factors predictive of VTE, and the impact of changed anticoagulation practice on patient survival. We conducted a consecutive retrospective analysis of postmortem COVID-19 (n = 64) and non-COVID-19 (n = 67) patients, as well as ante mortem COVID-19 (n = 170) patients admitted to the University Medical Center Hamburg-Eppendorf (Hamburg, Germany). Baseline patient characteristics, parameters related to the intensive care unit (ICU) stay, and the clinical and autoptic presence of VTE were evaluated and statistically compared between groups. The occurrence of VTE in critically ill COVID-19 patients is confirmed in both ante mortem (17%) and postmortem (38%) cohorts. Accordingly, comparing the postmortem prevalence of VTE between age- and sex-matched COVID-19 (43%) and non-COVID-19 (0%) cohorts, we found the statistically significant increased prevalence of VTE in critically ill COVID-19 cohorts (p = 0.001). A change in anticoagulation practice was associated with the statistically significant prolongation of survival time (HR: 2.55, [95% CI 1.41–4.61], p = 0.01) and a reduction in VTE occurrence (54% vs. 25%; p = 0.02). In summary, in the autopsy as well as clinical cohort of critically ill patients with COVID-19, we found that VTE was a frequent finding. A change in anticoagulation practice was associated with a statistically significantly prolonged survival time.

1725

CaV153

Manuela De Michele, Joshua Kahan , Irene Berto, Oscar G. Schiavo , Marta Iacobucci , Danilo Toni ,* Alexander E. Merkler

Cerebrovascular Complications of COVID-19 and
COVID-19 Vaccination

https://doi.org/10.1161/CIRCRESAHA.122.319954

Published

23-Apr-22

Review

https://www.ahajournals.org/doi/pdf/10.1161/CIRCRESAHA.122.319954

The risk of stroke and cerebrovascular disease complicating infection with SARS-CoV-2 has been extensively
reported since the onset of the pandemic. The striking efforts of many scientists in cooperation with regulators and
governments worldwide have rapidly brought the development of a large landscape of vaccines against SARS-CoV-2. The novel DNA and mRNA vaccines have offered great flexibility in terms of antigen production and led to an unprecedented rapidity in effective and safe vaccine production. However, as mass vaccination has progressed, rare but catastrophic cases of thrombosis have occurred in association with thrombocytopenia and antibodies against PF4 (platelet factor 4). This catastrophic syndrome has been named vaccine-induced immune thrombotic thrombocytopenia. Rarely, ischemic stroke can be the symptom onset of vaccine-induced immune thrombotic thrombocytopenia or can complicate the course of the disease. In this review, we provide an overview of stroke and cerebrovascular disease as a complication of the SARS-CoV-2 infection and outline the main clinical and radiological characteristics of cerebrovascular complications of vaccinations, with a focus on vaccine-induced immune thrombotic thrombocytopenia. Based on the available data from the literature and from our experience, we propose a therapeutic protocol to manage this challenging condition. Finally, we highlight the overlapping pathophysiologic mechanisms of SARS-CoV-2 infection and vaccination leading to thrombosis.

1726

CaV154

Rachel E. Szeghy, Nina L. Stute, Valesha M. Province, Marc A. Augenreich, Jonathon L.
4 Stickford, Abigail S.L. Stickford, Stephen M. Ratchford

Six-Month Longitudinal Tracking of Arterial Stiffness and Blood Pressure
2 in Young Adults Following SARS-CoV-2 Infection
Short Title: Improvement From SARS-CoV-2: Arterial Stiffness

-

Published

23-Apr-22

Study

https://journals.physiology.org/doi/pdf/10.1152/japplphysiol.00793.2021

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can increase arterial stiffness 3-4 weeks following infection, even among young, healthy adults. However, the long-term impacts of SARS-CoV-2 infection on cardiovascular health and the duration of recovery remains unknown. Purpose: The purpose of this study was to elucidate potential long lasting effects of SARS-CoV-2 infection on markers of arterial stiffness among young adults during the six months following infection. Methods: Assessments were performed at months 1, 2, 3, 4, and ~6 following SARS-CoV-2 infection. Doppler ultrasound was utilized to measure carotid-femoral pulse wave velocity (cfPWV) and carotid stiffness, and arterial tonometry was used to measure central blood pressures and aortic augmentation index at a heart rate of 75
beats∙min-1 (AIx@HR75). Vascular (VCAM-1) and intracellular (ICAM-1) adhesion molecules were analyzed as circulating markers of arterial stiffness. Results: From months 1-6, a significant reduction in cfPWV was observed (month1: 5.70±0.73m·s-1; month6: 4.88±0.65m·s-1 31 ; p<0.05) without any change in carotid stiffness measures. Reductions in systolic blood pressure (month1: 123±8mmHg; month6: 112±11mmHg) and mean arterial pressure (month1: 97±6mmHg; month6: 86±7mmHg) were observed (p<0.05), although AIx@HR75 did not change over time. The month1-6 change in cfPWV and MAP were correlated (r=0.894; p<0.001). A reduction in VCAM-1 was observed at month 3 compared with month 1 (month1: 5575±2242pg·ml-1; month3: 4636±1621pg·ml-1 37 ; p<0.05) without a change in ICAM-1. Conclusion: A reduction in cfPWV was related with MAP, and some indicators of arterial stiffness remain elevated for several months following SARS-CoV-2 infection, possibly contributing to prolonged recovery and increased cardiovascular health risks.

1727

CaV155

Paul J. Hanson, Felicia Liu-Fei, Coco Ng, Taylor A. Minato, Chi Lai, Al Rohet Hossain, Rebecca Chan, Bobby Grewal, Harpreet Rai, Jeremy Hirota, Daniel R. Anderson, Stanley J. Radio & Bruce M. McManus

Characterization of COVID-19-associated cardiac injury: evidence for a multifactorial disease in an autopsy cohort

https://doi.org/10.1038/s41374-022-00783-x

Published

18-Apr-22

Study

https://www.nature.com/articles/s41374-022-00783-x

As the coronavirus disease 2019 (COVID-19) pandemic evolves, much evidence implicates the heart as a critical target of injury in patients. The mechanism(s) of cardiac involvement has not been fully elucidated, although evidence of direct virus-mediated injury, thromboembolism with ischemic complications, and cytokine storm has been reported. We examined suggested mechanisms of COVID-19-associated heart failure in 21 COVID-19-positive decedents, obtained through standard autopsy procedure, compared to clinically matched controls and patients with various etiologies of viral myocarditis. We developed a custom tissue microarray using regions of pathological interest and interrogated tissues via immunohistochemistry and in situ hybridization. Severe acute respiratory syndrome coronavirus 2 was detected in 16/21 patients, in cardiomyocytes, the endothelium, interstitial spaces, and percolating adipocytes within the myocardium. Virus detection typically corresponded with troponin depletion and increased cleaved caspase-3. Indirect mechanisms of injury—venous and arterial thromboses with associated vasculitis including a mixed inflammatory infiltrate—were also observed. Neutrophil extracellular traps (NETs) were present in the myocardium of all COVID-19 patients, regardless of injury degree. Borderline myocarditis (inflammation without associated myocyte injury) was observed in 19/21 patients, characterized by a predominantly mononuclear inflammatory infiltrate. Edema, inflammation of percolating adipocytes, lymphocytic aggregates, and large septal masses of inflammatory cells and platelets were observed as defining features, and myofibrillar damage was evident in all patients. Collectively, COVID-19-associated cardiac injury was multifactorial, with elevated levels of NETs and von Willebrand factor as defining features of direct and indirect viral injury.

1728

CaV156

R.SiglerB.ChenA.BhartiS.Aslam

Long COVID-19 in Heart Transplant Recipients

https://doi.org/10.1016/j.healun.2022.01.682

Published

7-Apr-22

Study

https://www.sciencedirect.com/science/article/pii/S1053249822007008

Purpose
The goal of this study was to assess the frequency and common symptoms of post-acute COVID-19 syndrome (Long COVID-19) in heart transplant recipients (HTR).
Methods
After obtaining IRB approval, we conducted telephone surveys of HTR (n=30) who had tested positive for SARS-CoV-2 to evaluate their experience with acute COVID-19 illness and assess symptoms of Long COVID-19. Symptoms at onset and also beyond 6, 12, and 24 weeks of the initial diagnosis were recorded. Additionally, medical charts were reviewed for detailed information regarding transplant history, immunosuppression, COVID-19 management and hospitalization, and COVID-19 vaccination status.
Results
As noted in Table 1, among the 30 participants, 10 (33%) had symptoms consistent with Long COVID-19. Those with Long COVID-19 were more symptomatic during acute illness, with 40% of patients reporting cough, fevers or chills, and headaches, compared with 15%, 25%, and 20% respectively in those without Long COVID-19. Emergency department visits at initial illness (80% vs. 20%) and admission to the intensive care unit were more frequent (60% vs. 5%) in the Long COVID-19. Symptoms of Long COVID-19 lasted for a median of 9 weeks with 30% reporting ongoing symptoms at week 24. The most common persistent symptoms were depression, confusion, and difficulty concentrating.
Conclusion
This study is an early investigation of a complex syndrome of Long COVID-19 in transplant patients. Long COVID-19 is not well described in the transplant setting. HTR at our center with Long COVID-19 were sicker at their initial COVID-19 diagnosis and had more emergency room visits, hospital admissions, and longer hospital stays than those without subsequent Long COVID-19. Although, recall bias could affect participants’ ability to remember details and symptoms, this would have impacted both groups similarly as the time since COVID-19 diagnosis to study enrollment was similar between the two groups. These are preliminary findings and the study is currently ongoing.

1729

CaV157

Ioannis Katsoularis, cardiologist, internist, and doctoral student1, Osvaldo Fonseca-Rodríguez, senior research assistant of epidemiology and statistics2, Paddy Farrington, professor emeritus of statistics3, Hanna Jerndal, doctoral student and medical intern2, Erling Häggström Lundevaller, associate professor of statistics4, Malin Sund, professor of general surgery5 6, Krister Lindmark, associate professor of cardiology1, Anne-Marie Fors Connolly

Risks of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19: nationwide self-controlled cases series and matched cohort study

https://doi.org/10.1136/bmj-2021-069590

Published

6-Apr-22

Study

https://www.bmj.com/content/377/bmj-2021-069590

Abstract
Objective - To quantify the risk of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19.
Design Self-controlled case series and matched cohort study.
Setting National registries in Sweden.
Participants - 1 057 174 people who tested positive for SARS-CoV-2 between 1 February 2020 and 25 May 2021 in Sweden, matched on age, sex, and county of residence to 4 076 342 control participants.
Main outcomes measures - Self-controlled case series and conditional Poisson regression were used to determine the incidence rate ratio and risk ratio with corresponding 95% confidence intervals for a first deep vein thrombosis, pulmonary embolism, or bleeding event. In the self-controlled case series, the incidence rate ratios for first time outcomes after covid-19 were determined using set time intervals and the spline model. The risk ratios for first time and all events were determined during days 1-30 after covid-19 or index date using the matched cohort study, and adjusting for potential confounders (comorbidities, cancer, surgery, long term anticoagulation treatment, previous venous thromboembolism, or previous bleeding event).
Results - Compared with the control period, incidence rate ratios were significantly increased 70 days after covid-19 for deep vein thrombosis, 110 days for pulmonary embolism, and 60 days for bleeding. In particular, incidence rate ratios for a first pulmonary embolism were 36.17 (95% confidence interval 31.55 to 41.47) during the first week after covid-19 and 46.40 (40.61 to 53.02) during the second week. Incidence rate ratios during days 1-30 after covid-19 were 5.90 (5.12 to 6.80) for deep vein thrombosis, 31.59 (27.99 to 35.63) for pulmonary embolism, and 2.48 (2.30 to 2.68) for bleeding. Similarly, the risk ratios during days 1-30 after covid-19 were 4.98 (4.96 to 5.01) for deep vein thrombosis, 33.05 (32.8 to 33.3) for pulmonary embolism, and 1.88 (1.71 to 2.07) for bleeding, after adjusting for the effect of potential confounders. The rate ratios were highest in patients with critical covid-19 and highest during the first pandemic wave in Sweden compared with the second and third waves. In the same period, the absolute risk among patients with covid-19 was 0.039% (401 events) for deep vein thrombosis, 0.17% (1761 events) for pulmonary embolism, and 0.101% (1002 events) for bleeding.
Conclusions - The findings of this study suggest that covid-19 is a risk factor for deep vein thrombosis, pulmonary embolism, and bleeding. These results could impact recommendations on diagnostic and prophylactic strategies against venous thromboembolism after covid-19.

1730

CaV158

Samit M. Shah,Natalija Odanovic,Steffne Kunnirickal,Attila Feher,Steven E. Pfau,Erica S. Spatz

Chest pain and coronary endothelial dysfunction after recovery from COVID-19: A case series

https://doi.org/10.1002/ccr3.5612

Published

8-Apr-22

Case Series

https://onlinelibrary.wiley.com/doi/full/10.1002/ccr3.5612

Endothelial cell damage related to coronavirus disease 2019 (COVID-19) has been described in multiple vascular beds, and many survivors of COVID-19 report chest pain. This case series describes two previously healthy middle-aged individuals who survived COVID-19 and were subsequently found to have symptomatic coronary endothelial dysfunction months after initial infection.

1731

CaV159

Harneet Bhatti, Andres Cordova Sanchez, Rajat Dhungana, Christos Carvounis, Avneet Singh

Left Ventricular Global Longitudinal Strain in Patients With COVID-19 Infection

https://doi.org/10.7759/cureus.23986

Published

9-Apr-22

Study

https://www.cureus.com/articles/86618-left-ventricular-global-longitudinal-strain-in-patients-with-covid-19-infection

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2, is an ongoing pandemic that has affected millions globally. Many infected patients have been noted to have cardiovascular damage. Prior to the development of clinical symptoms, the use of transthoracic echocardiography, specifically with measurements of left ventricular global longitudinal strain (LVGLS), may provide an additional prognostic marker for patients infected with COVID-19. We sought to determine whether patients with COVID-19 and reduced LVGLS have an increased risk for mortality. The mean LVGLS was determined to be significantly lower in the non-survivors compared to the survivors (−11.6 ± 1.8 vs −15.4 ± 0.74, p<0.05). It should be noted, however, that even those that survived were found to have reduced LVGLS (<−18.5%). A multivariate logistic regression analysis was also performed that demonstrated a relationship between reduced LVGLS and an increased risk for mortality. Overall, our data indicate that COVID-19 patients may have subclinical left ventricular dysfunction, and that critically ill patients may have a greater decline in cardiac dysfunction.

1732

CaV160

Bingwen Eugene Fan,Shiun Woei Wong,Christina Lai Lin Sum,Gek Hsiang Lim,Bernard PuiLam Leung,Chuen Wen Tan,Kollengode Ramanathan,Rinkoo Dalan,Christine Cheung,Xin Rong Lim,Mucheli Shravan Sadasiv,David Chien Lye,Barnaby Edward Young,Eng Soo Yap,Yew Woon Chia

Hypercoagulability, endotheliopathy, and inflammation approximating 1 year after recovery: Assessing the long-term outcomes in COVID-19 patients

https://doi.org/10.1002/ajh.26575

Published

28-Apr-22

Study

https://onlinelibrary.wiley.com/doi/10.1002/ajh.26575

Sustained hypercoagulability and endotheliopathy are present in convalescent COVID-19 patients for up to 4 months from recovery. The hemostatic, endothelial, and inflammatory profiles of 39 recovered COVID-19 patients were evaluated up to 16 months after recovery from COVID-19. These values were compared with a control group of healthy volunteers (n = 124). 39 patients (71.8% males, median age 43 years) were reviewed at a mean of 12.7 ± 3.6 months following recovery. One patient without cardiovascular risk factors had post COVID-19 acute ischaemic limb. Elevated D-dimer and Factor VIII levels above normal ranges were noted in 17.9% (7/39) and 48.7% (19/39) of patients respectively, with a higher median D-dimer 0.34 FEU μg/mL (IQR 0.28, 0.46) (p < .001) and Factor VIII 150% (IQR 171, 203) (p = .004), versus controls. Thrombin generation (Thromboscreen) showed a higher median endogenous thrombin potential (ETP) of 1352 nM*min (IQR 1152, 1490) (p = .002) and a higher median peak height of 221.4 nM (IQR 170.2, 280.4) (p = 0.01) and delayed lag time 2.4 min (1.42–2.97) (p = 0.0002) versus controls. Raised vWF:Ag and ICAM-1 levels were observed in 17.9% (7/39) and 7.7% (3/39) of patients respectively, with a higher median VWF:Ag 117% (IQR 86, 154) (p = 0.02) and ICAM-1 54.1 ng/mL (IQR 43.8, 64.1) (p = .004) than controls. IL-6 was noted to be raised in 35.9% (14/39) of patients, with a higher median IL-6 of 1.5 pg/mL (IQR 0.6, 3.0) (p = 0.004) versus controls. Subgroup analysis stratifying patients by COVID-19 severity and COVID-19 vaccination preceding SARS-CoV-2 infection did not show statistically significant differences. Hypercoagulability, endothelial dysfunction, and inflammation are still detectable in some patients approximately 1 year after recovery from COVID-19.

1733

CaV161

Charalambos Vlachopoulos MD, Dimitrios Terentes-Printzios MD, Paraskevi Katsaounou MD, Eirini Solomou MD, Vasiliki Gardikioti MD, Dimitrios Exarchos MD, Dimitrios Economou MD, Georgia Christopoulou MD, Antonios-Dimosthenis Kalkinis MD, Pavlos Kafouris MD, Alexios Antonopoulos MD, Georgios Lazaros MD, Anastasia Kotanidou MD, Ioannis Datseris MD, Konstantinos Tsioufis MD & Constantinos Anagnostopoulos

Time-related aortic inflammatory response, as assessed with 18F-FDG PET/CT, in patients hospitalized with severely or critical COVID-19: the COVAIR study

https://doi.org/10.1007/s12350-022-02962-1

Published

2-May-22

Study

https://link.springer.com/article/10.1007/s12350-022-02962-1

Aim
Arterial involvement has been implicated in the coronavirus disease of 2019 (COVID-19). Fluorine 18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging is a valuable tool for the assessment of aortic inflammation and is a predictor of outcome. We sought to prospectively assess the presence of aortic inflammation and its time-dependent trend in patients with COVID-19.
Methods
Between November 2020 and May 2021, in this pilot, case-control study, we recruited 20 patients with severe or critical COVID-19 (mean age of 59 ± 12 years), while 10 age and sex-matched individuals served as the control group. Aortic inflammation was assessed by measuring 18F-FDG uptake in PET/CT performed 20-120 days post-admission. Global aortic target to background ratio (GLA-TBR) was calculated as the sum of TBRs of ascending and descending aorta, aortic arch, and abdominal aorta divided by 4. Index aortic segment TBR (IAS-TBR) was designated as the aortic segment with the highest TBR.
Results
There was no significant difference in aortic 18F-FDG PET/CT uptake between patients and controls (GLA-TBR: 1.46 [1.40-1.57] vs. 1.43 [1.32-1.70], respectively, P = 0.422 and IAS-TBR: 1.60 [1.50-1.67] vs. 1.50 [1.42-1.61], respectively, P = 0.155). There was a moderate correlation between aortic TBR values (both GLA and IAS) and time distance from admission to 18F-FDG PET-CT scan (Spearman’s rho = − 0.528, P = 0.017 and Spearman’s rho = − 0.480, p = 0.032, respectively). Patients who were scanned less than or equal to 60 days from admission (n = 11) had significantly higher GLA-TBR values compared to patients that were examined more than 60 days post-admission (GLA-TBR: 1.53 [1.42-1.60] vs. 1.40 [1.33-1.45], respectively, P = 0.016 and IAS-TBR: 1.64 [1.51-1.74] vs. 1.52 [1.46-1.60], respectively, P = 0.038). There was a significant difference in IAS- TBR between patients scanned ≤ 60 days and controls (1.64 [1.51-1.74] vs. 1.50 [1.41-1.61], P = 0.036).
Conclusion
This is the first study suggesting that aortic inflammation, as assessed by 18F-FDG PET/CT imaging, is increased in the early post COVID phase in patients with severe or critical COVID-19 and largely resolves over time. Our findings may have important implications for the understanding of the course of the disease and for improving our preventive and therapeutic strategies.

1734

CaV162

Diana L. Tobler, Alix J. Pruzansky, Sahar Naderi, Andrew P. Ambrosy & Justin J. Slade

Long-Term Cardiovascular Effects of COVID-19: Emerging Data Relevant to the Cardiovascular Clinician

https://doi.org/10.1007/s11883-022-01032-8

Published

4-May-22

Review

https://link.springer.com/article/10.1007/s11883-022-01032-8

Purpose of Review
COVID-19 is now a global pandemic and the illness affects multiple organ systems, including the cardiovascular system. Long-term cardiovascular consequences of COVID-19 are not yet fully characterized. This review seeks to consolidate available data on long-term cardiovascular complications of COVID-19 infection.
Recent Findings
Acute cardiovascular complications of COVID-19 infection include myocarditis, pericarditis, acute coronary syndrome, heart failure, pulmonary hypertension, right ventricular dysfunction, and arrhythmia. Long-term follow-up shows increased incidence of arrhythmia, heart failure, acute coronary syndrome, right ventricular dysfunction, myocardial fibrosis, hypertension, and diabetes mellitus. There is increased mortality in COVID-19 patients after hospital discharge, and initial myocardial injury is associated with increased mortality.
Summary
Emerging data demonstrates increased incidence of cardiovascular illness and structural changes in recovered COVID-19 patients. Future research will be important in understanding the clinical significance of these structural abnormalities, and to determine the effect of vaccines on preventing long-term cardiovascular complications.

1735

CaV163

Zainab AlDuhailibabSimonOczkowskicdKamilPolokeJakubFronczekeWojciechSzczeklikeJoshuaPiticarucManoj J.MammenfFayezAlshamsigJohnEikelboomhiEmilie P.Belley-CotehiWaleedAlhazzanicd

Venous and Arterial Thrombosis in COVID-19: An updated Narrative Review

https://doi.org/10.1016/j.jiph.2022.05.003

Published

14-May-22

Review

https://www.sciencedirect.com/science/article/pii/S187603412200123X

Hospitalized patients with coronavirus disease 2019 (COVID-19), particularly those admitted to the intensive care unit (ICU) are at high risk of morbidity and mortality. Several observational studies have described hemostatic derangements and thrombotic complications in patients with COVID-19. The aim of this review article is to summarize the current evidence on pathologic findings, pathophysiology, coagulation and hemostatic abnormalities, D-dimer’s role in prognostication epidemiology and risk factors of thrombotic complications, and the role of prophylactic and therapeutic anticoagulation in patients with COVID-19.
While existing evidence is limited in quality, COVID-19 appears to increase micro-and macro-vascular thrombosis rates in hospitalized and critically ill patients, which may contribute to the burden of disease. D-dimer can be used for risk stratification of hospitalized patients, but its role to guide anticoagulation therapy remains unclear. Evidence of higher quality is needed to address the role of therapeutic anticoagulation or high-intensity venous thromboembolism prophylaxis in COVID-19 patients.
Take-home points
•The prevalence of venous thromboembolism (VTE) in hospitalized COVID-19 patients is high, therefore, clinicians should have a high index of suspicion.
•The pathophysiology of thrombosis is likely related to a combination of SARS-CoV-2 direct endothelial injury and dysregulated inflammation causing coagulation activation.
•The current evidence on the value of D-dimer guided therapy is limited.
•The rate of VTE post-hospital discharge is very low, supporting the safety of current discharge practice without VTE prophylaxis in most patients.
•The role of higher-intensity VTE prophylaxis or therapeutic anticoagulation in critically ill COVID-19 patients without documented or suspected VTE remains uncertain.
•Therapeutic anticoagulation in hospitalized non-critically ill patients with COVID-19 may improve outcomes but more research is warranted.

1736

CaV164

Pretorius E, Venter C, Laubscher GJ, Kotze MJ, Oladejo S, Watson LR, Rajaratnam K, Watson BW, Kell DB

Prevalence of symptoms, comorbidities, fibrin amyloid microclots and platelet pathology in individuals with Long COVID/ Post-Acute Sequelae of COVID-19 (PASC)

https://doi.org/10.21203/rs.3.rs-1205453/v2

pre-print

9-May-22

Study

https://europepmc.org/article/ppr/ppr490705

Background:
Fibrin(ogen) amyloid microclots and platelet hyperactivation previously reported as a novel finding in South African patients with the coronavirus 2019 disease (COVID-19) and Long COVID/Post-Acute Sequelae of COVID-19 (PASC), might form a suitable set of foci for the clinical treatment of the symptoms of long COVID/PASC. A Long COVID/PASC Registry was subsequently established as an online platform where patients can report Long COVID/PASC symptoms and previous comorbidities.
Methods:
: In this study, we report on the comorbidities and persistent symptoms, using data obtained from 845 South African Long COVID/PASC patients. By using a previously published scoring system for fibrin amyloid microclots and platelet pathology, we also analysed blood samples from 80 patients, and report the presence of significant fibrin amyloid microclots and platelet pathology in all cases.
Results:
: Hypertension, high cholesterol levels (dyslipidaemia), cardiovascular disease and type 2 diabetes mellitus (T2DM) were found to be the most important comorbidities. The gender balance (70% female) and the most commonly reported Long COVID/PASC symptoms (fatigue, brain fog, loss of concentration and forgetfulness, shortness of breath, as well as joint and muscle pains) were comparable to those reported elsewhere. These findings confirmed that our sample was not atypical. Microclot and platelet pathologies were associated with Long COVID/PASC symptoms that persisted after the recovery from acute COVID-19.
Conclusions:
: Fibrin amyloid microclots that block capillaries and inhibit the transport of O 2 to tissues, accompanied by platelet hyperactivation, provide a ready explanation for the symptoms of Long COVID/PASC. Removal and reversal of these underlying endotheliopathies provide an important treatment option that urgently warrants controlled clinical studies to determine efficacy in patients with a diversity of comorbidities impacting on SARS-CoV-2 infection and COVID-19 severity. We suggest that our platelet and clotting grading system provides a simple and cost-effective diagnostic method for early detection of long COVID/PASC as a major determinant of effective treatment regimens, including those focusing on reducing clot burden and platelet hyperactivation.

1737

CaV165

Sofia Romagnoli,Agnese SbrolliniORCID,Ilaria Marcantoni,Micaela MorettiniORCID andLaura Burattini *ORCID

Review on Cardiorespiratory Complications after SARS-CoV-2 Infection in Young Adult Healthy Athletes

https://doi.org/10.3390/ijerph19095680

Published

6-May-22

Review

https://www.mdpi.com/1660-4601/19/9/5680/htm

This review analyzes scientific data published in the first two years of the COVID-19 pandemic with the aim to report the cardiorespiratory complications observed after SARS-CoV-2 infection in young adult healthy athletes. Fifteen studies were selected using PRISMA guidelines. A total of 4725 athletes (3438 males and 1287 females) practicing 19 sports categories were included in the study. Information about symptoms was released by 4379 (93%) athletes; of them, 1433 (33%) declared to be asymptomatic, whereas the remaining 2946 (67%) reported the occurrence of symptoms with mild (1315; 45%), moderate (821; 28%), severe (1; 0%) and unknown (809; 27%) severity. The most common symptoms were anosmia (33%), ageusia (32%) and headache (30%). Cardiac magnetic resonance identified the largest number of cardiorespiratory abnormalities (15.7%). Among the confirmed inflammations, myocarditis was the most common (0.5%). In conclusion, the low degree of symptom severity and the low rate of cardiac abnormalities suggest that the risk of significant cardiorespiratory involvement after SARS-CoV-2 infection in young adult athletes is likely low; however, the long-term physiologic effects of SARS-CoV-2 infection are not established yet. Extensive cardiorespiratory screening seems excessive in most cases, and classical pre-participation cardiovascular screening may be sufficient.

1738

CaV166

Laura P.M.H. de Rooij, Lisa M. Becker and Peter Carmeliet

A Role for the Vascular Endothelium in Post–Acute COVID-19?

https://doi.org/10.1161/CIRCULATIONAHA.122.059231

Published

16-May-22

Article

https://www.ahajournals.org/doi/abs/10.1161/CIRCULATIONAHA.122.059231

While the war against acute coronavirus disease 2019 (COVID-19) is still raging, reports of a long-lasting post-COVID-19 syndrome are surging. "Long COVID" progressed from a mere oddity to an acknowledged public health issue worldwide. A formal definition of post-acute COVID-19 syndrome (ie, long COVID) is evolving, and for the purposes of this review, we consider as persistent symptoms or complications lasting more than 30 days after severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) infection. Symptoms of long COVID involve multiple organs and include shortness of breath, wae storiess breath fatigue, chest pain, loss of taste and/or smell, and nitive dysfunction. Studies investigating the incidence of long COVID report broad heterogeneity (likely attrib and cog utable to variations in study cohorts and long COVID definition/symptoms), and its manifestation may from 30% to a staggering 280% of all SARS-CoV-2 infected patients. Although there is reduce the risk of developing long COVID, nation may reduce the risk of here is hope that vacci studies remain inconclusive thus far. Breakthrough infections frequently occur in vaccinated people and may unfortunately still cause an escalation in long COVID cases. Detection and treatment of long COVID is challenging because the molecular underpinnings of the condition remain largely unknown.

1739

CaV167

Jorge H. Ulloa 1
Oscar Y. Moreno Rocha 1
Paula Pinto 1
Maria C. Consuegra
Sebastian Cifuentes 2
Andrés Figueroa 1
Antonio Solano 1
Javier Bravo 1
Jairo Ramirez

Post–COVID-19 Arterial Thrombosis: A Systematic Review

https://doi.org/10.1016/j.jvs.2022.03.158

Published

19-May-22

Review

https://www.jvascsurg.org/article/S0741-5214(22)00652-8/fulltext

Objectives
COVID-19 (coronavirus disease 2019) is associated with coagulation defects, including endothelial dysfunction, inflammation, hypoxia, cytokine release, and hypercoagulability. We aimed to summarize the available cases of arterial peripheral thrombosis in the setting of post–COVID-19 infection and the use of biomarkers and related pharmacologic therapies to describe the better medical and surgical treatments based on the reported outcomes.
Methods
We executed a systematic review following the 2020 PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. We searched PubMed, Embase, Scopus, and the Cochrane Library for studies reported from March 2020 to September 2021 with serologic confirmation of a resolved SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection. Related questions regarding high-yield end points included the location of the thrombosis, amputation, reintervention rates, mortality, anticoagulant therapy, and biomarkers.
Results
Of the 398 matching results, 23 reports met the inclusion criteria of post–COVID-19 thrombosis, arterial, venous, peripheral, and cured. The literature review included 12 case reports, 3 incidence reports, 3 literature reviews, 2 meta-analyses, 1 observational cohort study, and 2 prospective analyses. The overall presentation consisted of peripheral arterial thrombosis (33.3%), venous thrombosis (63.2%), and mixed events (3.5%). Most of the studies had used low-molecular-weight heparin monotherapy as a part of the medical management. There was no difference in the use of clopidogrel and aspirin as antiplatelet agents. Other pharmacologic alternatives were nonfractionated heparin, enoxaparin, warfarin, rivaroxaban, and apixaban. Open thrombectomy was the most common procedure used for COVID-19 thrombosis complications (40%), with mortality of 27.2%, followed by endovascular thrombectomy (15%), amputation (12.5%), exploratory laparotomy (5%), and endarterectomy (2.5%). We found 38 reported biomarkers, which were classified into seven categories related to an inflammatory process, coagulation time, clotting factors, cardiorespiratory function, kidney function, metabolic profile, and autoimmunity. An initial D-dimer level >1.250 ng/mL might identify COVID-19 patients at risk of arterial thrombotic events. Additional end points were associated with increased creatinine, interleukin-6, interferon gamma-induced protein-10, D-dimer, and C-reactive protein levels.
Conclusions
COVID-19 infection is associated with a high risk of arterial and venous post-thrombotic complications, with a variable clinical and anatomic presentation, high mortality, and high amputation risk. Microcirculatory alterations can be reflected by a panel of biomarkers. The medical and surgical management of these patients could depend on the availability of resources regarding the context of medical attention. Nevertheless, considering the highly inflammatory context, endovascular interventions with less systemic stress should be considered in addition to thromboprophylaxis measures.

1740

CaV168

Justin J. Frere & Benjamin R. tenOever

Cardiometabolic syndrome — an emergent feature of Long COVID?

https://doi.org/10.1038/s41577-022-00739-8

Published

24-May-22

Comment

https://www.nature.com/articles/s41577-022-00739-8

Large-scale clinical studies on the post-infectious impacts of SARS-CoV-2 have suggested that patients who have recovered from acute infection have increased risk for cardiometabolic syndrome-associated morbidities such as diabetes, chronic kidney disease and heart failure. Initial studies have taken the first steps towards unravelling the molecular processes that may be driving these findings, including the role of immune and inflammatory factors, but a comprehensive aetiology remains unclear. Given that cardiometabolic syndrome progression in patients with Long COVID may pose a significant global health and economic burden post pandemic, there is an emergent need to identify therapeutic targets and treatment options.

1741

CaV169

Pascal Bauer, Lutz Kraushaar, Oliver Dörr, Stanislav Keranov, Holger Nef, Christian W. Hamm & Astrid Most

Vascular alterations among male elite athletes recovering from SARS-CoV-2 infection

https://doi.org/10.1038/s41598-022-12734-z

Published

23-May-22

Study

https://www.nature.com/articles/s41598-022-12734-z

SARS-CoV-2 may affect the cardiovascular system and vascular impairment has been reported in healthy young adults recovering from COVID-19. However, the impact of SARS-CoV-2 infection on the vascular function of elite athletes is unknown. We examined 30 healthy male elite athletes (age 25.8 ± 4.6 years) pre-season and at a 6-month follow-up (182 ± 10 days). Vascular function and central blood pressure were calculated using transfer function-based analysis of peripheral arterial waveforms obtained by oscillometry. We performed a two-way repeated-measures ANOVA on the biomarker data, with SARS-CoV-2 status as the between-groups factor and time as the within-groups factor. Subjects who tested positive for SARS-CoV-2 were studied 18 ± 4 days after their positive testing date at follow-up. Of 30 athletes, 15 tested positive for SARS-CoV-2 after the first examination and prior to the follow-up. None had severe COVID-19 or reported any persisting symptoms. The results of the two-way repeated measures ANOVA revealed that there was no significant main effect of COVID-19 on any of the investigated biomarkers. However, there was a significant interaction between the effects of SARS-CoV-2 exposure and time on augmentation index (Aix) (p = 0.006) and augmentation index normalized to a heart rate of 75 beats per minute (Aix@75), (p = 0.0018). The observation of an interaction effect on Aix and Aix@75 in the absence of any main effect indicates a cross-over interaction. Significant vascular alterations in male elite athletes recovering from COVID-19 were observed that suggest vascular impairment. Whether these alterations affect athletic performance should be evaluated in future studies.

1742

CaV170

Gabriela Trifan & Fernando D. Testai

Neurological Manifestations of Myocarditis

https://doi.org/10.1007/s11910-022-01203-9

Published

19-May-22

Review

https://link.springer.com/article/10.1007/s11910-022-01203-9

Purpose of Review
The present review discusses the neurological complications associated with myocarditis of different etiologies.
Recent Findings
Myocarditis can be idiopathic or caused by different conditions, including toxins, infections, or inflammatory diseases. Clinical findings are variable and range from mild self-limited shortness of breath or chest pain to hemodynamic instability which may result in cardiogenic shock and death. Several neurologic manifestations can be seen in association with myocarditis. Tissue remodeling, fibrosis, and myocyte dysfunction can result in heart failure and arrhythmias leading to intracardiac thrombus formation and cardioembolism. In addition, peripheral neuropathies, status epilepticus, or myasthenia gravis have been reported in association with specific types of myocarditis.
Summary
Multiple studies suggest the increasing risk of neurologic complications in patients with myocarditis. Neurologists should maintain a high suspicion of myocarditis in cases presenting with both cardiovascular and neurological dysfunction without a clear etiology.

1743

CaV171

Fizzah A.ChoudryKrishnaraj S.RathodAndreasBaumbachAnthonyMathurDaniel A.Jones

Long-term outcomes of COVID-19 associated ST-elevation myocardial infarction treated with primary PCI

https://doi.org/10.1016/j.carrev.2022.05.029

Published

25-May-22

Study

https://www.sciencedirect.com/science/article/pii/S1553838922002809

Coronavirus disease 2019 (COVID-19) is known to significantly increase the risk of arterial thrombosis (1*). In patients with type I or ST-elevation myocardial infarction (STEMI) who have COVID-19 infection there is data to suggest a poorer in-hospital outcome compared with patients who are COVID negative and suffer from STEMI (with higher thrombus burden, increased incidence of delayed presentation, cardiogenic shock, left ventricular (LV) dysfunction and need for intensive care) [1], [2], [3], [4], [5]. However, there is a paucity of comparative long-term outcome data in this cohort of patients. Here we examine the characteristics and long terms outcomes of a cohort of COVID positive STEMI patients treated with primary percutaneous coronary intervention (PCI) comparing long-term outcomes with a COVID negative group from the first and second waves of the pandemic.
Results
Over a 1-year period between 01/03/2020 and 01/03/2021, 101 consecutive patients with COVID-19 presenting with confirmed STEMI and 465 confirmed STEMI patients without COVID 19 infection were included (Table 1). Of patients with COVID-19, 12 had established infection undergoing inpatient treatment at time of presentation whereas the remaining 89 were first diagnosed at the time of STEMI presentation.

1744

CaV172

A.Menard1L.Meddeb1M.Chine2A.Meilhac3P.Rossi2F.Thuny3

Symptômes cardiaques en Post Covid : bilan cardiaque ? Pour qui ? Quand ? Comment ?

https://doi.org/10.1016/j.mmifmc.2022.03.025

Published

31-May-22

Study

https://www.sciencedirect.com/science/article/pii/S2772743222000435

Introduction
Dans le contexte de pandémie de Sars-Cov-19 avec des atteintes cardiovasculaires mal caractérisées, nous réalisons depuis mai 2020 une étude prospective, observationnelle, de cohorte centrée sur une évaluation et un suivi cardiovasculaire systématique chez des patients, quel que soit leur profil cardiovasculaire, ayant survécu à un épisode de Covid-19 modéré ou sévère (IDRCB: 2020-A01576-33)
Matériels et méthodes
A S4, S24 et S48 d'une infection avec PCRSars-Cov-19 positive, les patients inclus bénéficient d'une consultation clinique de cardiologie avec 1) ECG 2)Prélèvement sanguin troponine T, NT-proBNP, D-Dimères, bilan d'hémostase 3)Échocardiographie trans-thoracique (ETT) + écho-doppler veineux « 3 points » à 1 et 12 mois 4)IRM cardiaque et Angioscanner thoracique selon les recommandations internationales. Nous proposons ici une analyse intermédiaire de nos résultats après 18 mois du début de l'etude.
Résultats
124 patients ont été inclus, avec un sex ratio de 1/2, d'âge médian de 55 ans, 58% avec une comorbidité à risque de forme sévère dont 38% de pathologie cardio-vasculaire, tabagisme actif dans 13% des cas .La prise en charge initiale était en ambulatoire (42.2%)en hospitalisation conventionnelle(37.8%) ou en soins intensif/réanimation(20%). Une maladie chronique a décompensé chez 24.4%des patients ou a été découverte chez 7% et 8% ont présenté une maladie thrombo-embolique et 2 patients une pericardite et 3 un trouble du rythme en phase aigüe. Dans le suivi, la présence de signes cardiologiques (douleur thoracique, syncope, palpitation, dyspnée de classe III ou IV NYHA, signes congestifs d'insuffisance cardiaque gauche ou droite, frottement péricardique, anomalies ECG du segment ST, des ondes T, élargissement du QRS, bloc atrio-ventriculaire du 2ème ou 3ème degré) était retrouvée chez 33% des patients à S4, 28% àS12, 22% àS24 et 14% à S48. Une ETT a été réalisée chez 60 patients et anormale chez 12 (20%) avec hypokinésie septale (8) une pericardite (2) ou HVG (2), une IRM cardiaque chez 41 patients et anormale chez 12 (29%) avec 10 myocardites et 2 péricardites. Tous les holter-ECG étaient normaux (4/4). Entre S4 etS12, 28% des patients avaient des D-Dimeres élevés (>0,5) et 25% une anomalie de la tropo/ NT-proBNP. Tous les patients avec une elevation des DDimeres avec une imagerie cardiaque anormale. Aucun lien n'est retrouvé entre le degré de sévérité initial, les co morbidités et les complications cardio-vasculaires post Covid sur le long terme.
Conclusion
Notre étude retrouve une importante prévalence des symptômes cardiaques même si ces derniers semblent disparaitre spontanément après 1 an de suivi. Nous ne disposons pas, à ce jour, de stratégie rentable pour exclure une pathologie CV sévére (myocadite pericardite) mais les consensus d'expert (https://doi.org/10.1093/eurheartj/ehac031) considèrent comme raisonnable de dépister les personnes à haut risque d'atteinte cardiaque ou avec un nouveau diagnostic CVpost-COVID-19 ainsi que les athlètes.

1745

CaV173

Michael Hultström, Robert Frithiof, Jonathan Grip, Linnea Lindelöf, Olav Rooijackers, Sara Pigazzini, Mari Niemi, Mattia Cordioli, Lindo Nkambule, Tomislav Maricic, Kristina Nilsson Ekdahl, Bo Nilsson, Miklós Lipcsey, Hugo Zeberg & Oskar Eriksson

Genetic determinants of mannose-binding lectin activity predispose to thromboembolic complications in critical COVID-19

https://doi.org/10.1038/s41590-022-01227-w

Published

27-May-22

Study

https://www.nature.com/articles/s41590-022-01227-w

A recent study demonstrated that the complement recognition protein mannose-binding lectin (MBL) can bind to glycosylated SARS-CoV-2 spike protein. Binding activated complement in a spike-dependent manner and inhibited severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in in vitro models1. Furthermore, genetic variants near or in the MBL2 gene that encodes MBL in humans were suggested as being associated with COVID-19 requiring hospitalization.
In the present study, we carried out genetic and biochemical analyses of MBL activity in plasma in a multicenter cohort of critically ill COVID-19 patients and interrogated the publicly available summary statistics from the COVID-19 Human Genetics Initiative (COVID-19 HGI)2. We found no evidence that genetic variants that determine activity of the MBL pathway are associated with hospitalization or intensive care admission due to SARS-CoV-2 infection. Instead, we demonstrated that MBL2 haplotypes determine risk for thrombotic complications in critically ill COVID-19 patients. Specifically, genetically determined MBL activity confers risk for pulmonary embolism in a U-shaped manner, where haplotypes associated with intermediate MBL activity are protective. Our results demonstrate a complement-dependent mechanism for COVID-19-associated thrombosis and provide an example of how genetic variation in the innate immune system modulates thrombosis risk.
The unique polymorphic nature of the MBL2 locus, with a high frequency of naturally occurring knockouts devoid of functional MBL, allows for an assessment of the role of MBL activity in observational studies. We show that genetically determined MBL deficiency does not influence the risk of COVID-19 requiring hospitalization or admission to intensive care. Instead, our results demonstrate that the interaction between genetic variation in the MBL2 gene and SARS-CoV-2 infection determines thrombosis risk in critically ill patients, a finding with important clinical implications given the high rate of thrombotic complications in COVID-19 patients.

1746

CaV174

Ioana Mădălina Zota 1ORCID,Cristian Stătescu 1ORCID,Radu Andy Sascău 1,Mihai Roca 1,Larisa Anghel 1,Alexandra Maștaleru 1,Maria Magdalena Leon-Constantin 1,Cristina Mihaela Ghiciuc 2,*ORCID,Sebastian Romica Cozma 3ORCID,Lucia Corina Dima-Cozma 1,Irina Mihaela Esanu 1,* andFlorin Mitu 1ORCID

Acute and Long-Term Consequences of COVID-19 on Arterial Stiffness—A Narrative Review

https://doi.org/10.3390/life12060781

Published

25-May-22

Review

https://www.mdpi.com/2075-1729/12/6/781/htm

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing global coronavirus (COVID-19) pandemic. Although initially viewed as an acute respiratory illness, COVID-19 is clearly a complex multisystemic disease with extensive cardiovascular involvement. Emerging evidence shows that the endothelium plays multiple roles in COVID-19 physiopathology, as both a target organ that can be directly infected by SARS-CoV-2 and a mediator in the subsequent inflammatory and thrombotic cascades. Arterial stiffness is an established marker of cardiovascular disease. The scope of this review is to summarize available data on the acute and long-term consequences of COVID-19 on vascular function. COVID-19 causes early vascular aging and arterial stiffness. Fast, noninvasive bedside assessment of arterial stiffness could optimize risk stratification in acute COVID-19, allowing for early escalation of treatment. Vascular physiology remains impaired at least 12 months after infection with SARS-CoV-2, even in otherwise healthy adults. This raises concerns regarding the extent of arterial remodeling in patients with preexisting vascular disease and the potential development of a persistent, chronic COVID-19 vasculopathy. Long-term follow up on larger cohorts is required to investigate the reversibility of COVID-19-induced vascular changes and their associated prognostic implications.

1747

CaV175

Oleksandr Dmytrenko 1ORCID andKory J. Lavine 1,2,3,*ORCID

Cardiovascular Tropism and Sequelae of SARS-CoV-2 Infection

https://doi.org/10.3390/v14061137

Published

25-May-22

Review

https://www.mdpi.com/1999-4915/14/6/1137/htm

The extrapulmonary manifestation of coronavirus disease-19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), became apparent early in the ongoing pandemic. It is now recognized that cells of the cardiovascular system are targets of SARS-CoV-2 infection and associated disease pathogenesis. While some details are emerging, much remains to be understood pertaining to the mechanistic basis by which SARS-CoV-2 contributes to acute and chronic manifestations of COVID-19. This knowledge has the potential to improve clinical management for the growing populations of patients impacted by COVID-19. Here, we review the epidemiology and pathophysiology of cardiovascular sequelae of COVID-19 and outline proposed disease mechanisms, including direct SARS-CoV-2 infection of major cardiovascular cell types and pathogenic effects of non-infectious viral particles and elicited inflammatory mediators. Finally, we identify the major outstanding questions in cardiovascular COVID-19 research.

1748

CaV176

Massimo Nunes1 Arneaux Kruger1 Amy Proal2 Douglas Kell3 Etheresia Pretorius1

The occurrence of hyperactivated platelets and fibrinaloid microclots in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

https://doi.org/10.21203/rs.3.rs-1727226/v1

pre-print

8-Jun-22

Study

https://www.researchsquare.com/article/rs-1727226/v1

We have previously demonstrated that platelet poor plasma (PPP) obtained from patients with LongCovid/Post-Acute Sequelae of COVID-19 (PASC) is characterized by a hypercoagulable state reflected in hyperactivated platelets and the presence of considerable numbers of fibrin(ogen) amyloid microclots or fibrinaloid microclots. Due to substantial overlap in symptoms and aetiology between PASC and ME/CFS, we investigated whether coagulopathies, platelet hyperactivation and/or fibrin amyloid formation differed between individuals exhibiting ME/CFS and gender- and age-matched healthy controls. ME/CFS patients were statistically far more hypercoagulable as judged by thromboelastography of both whole blood and platelet-poor plasma. The area of plasma images containing fibrinaloid microclots was commonly more than 10-fold greater in untreated platelet-poor plasma from individuals with ME/CFS than in that of healthy controls. A similar difference was found when the plasma samples were treated with thrombin. Using fluorescently labelled PAC-1, which recognizes glycoprotein IIb/IIIa, and CD62P, which binds P-selectin, we observed massive hyperactivation and spreading of platelets in samples from individuals with ME/CFS. Using a quantitative scoring system, this was found to have a score of 2.72 ± 1.24 vs 1.00 (activation with pseudopodia formation) for healthy controls. We conclude that ME/CFS is accompanied by substantial and measurable changes in coagulability, platelet hyperactivation, and fibrinaloid microclot formation. However, fibrinaloid microclot load was not as prevalent as was previously noted in PASC. Fibrinaloid microclots, in particular can provide a ready explanation, via (temporary) blockage of microcapillaries and hence ischaemia, for many of the symptoms, such as fatigue, seen in patients with ME/CFS. The discovery of these biomarkers pointing to significant and systemic endothelial inflammation, represents an important development in ME/CFS research. It also points at novel treatment strategies using known drugs and/or nutraceuticals that target systemic vascular pathology and endothelial inflammation.

1749

CaV177

Andrea Izquierdo-Marquisá,corresponding author 1 , 2 , * Hector Cubero-Gallego, 1 , 3 Álvaro Aparisi, 1 , 3 Beatriz Vaquerizo, 1 , 2 , 3 , 4 and Núria Ribas-Barquet 1 , 2 , 4

Myocardial Injury in COVID-19 and Its Implications in Short- and Long-Term Outcomes

https://doi.org/10.3389%2Ffcvm.2022.901245

Published

26-May-22

Review

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9204594/

COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still a pandemic with high mortality and morbidity rates. Clinical manifestation is widely variable, including asymptomatic or mild respiratory tract illness to severe pneumonia and death. Myocardial injury is a significant pathogenic feature of COVID-19 and it is associated with worse in-hospital outcomes, mainly due to a higher number of hospital readmissions, with over 50% mortality. These findings suggest that myocardial injury would identify COVID-19 patients with higher risk during active infection and mid-term follow-up. Potential contributors responsible for myocardial damage are myocarditis, vasculitis, acute inflammation, type 1 and type 2 myocardial infarction. However, there are few data about cardiac sequelae and its long-term consequences. Thus, the optimal screening tool for residual cardiac sequelae, clinical follow-up, and the benefits of a specific cardiovascular therapy during the convalescent phase remains unknown. This mini-review explores the different mechanisms of myocardial injury related to COVID-19 and its short and long-term implications.

1750

CaV178

Raul DMitrania*NitikaDabasa*JarrahAlfadhliaMaureen HLoweryaThomas MBestbJoshua MHareacRobert JMyerburgaJeffrey JGoldbergera

Long-Term Cardiac Surveillance and Outcomes of COVID-19 Patients

https://doi.org/10.1016/j.tcm.2022.06.003

Published

16-Jun-22

Article

https://www.sciencedirect.com/science/article/pii/S1050173822000871

Acute cardiac manifestions of COVID-19 have been well described, while chronic cardiac sequelae remain less clear. Various studies have shown conflicting data on the prevalence of new or worsening cardiovascular disease, myocarditis or cardiac dysrhythmias among patients recovered from COVID-19. Data are emerging that show that patients recovering from COVID-19 have an increased incidence of myocarditis and arrhythmias after recovery from COVID-19 compared with the control groups without COVID-19. The incidence of myocarditis after COVID-19 infection is low but is still significantly greater than the incidence of myocarditis from a COVID-19 vaccine. There have been several studies of athletes who underwent a variety of screening protocols prior to being cleared to return to exercise and competition. The data show possible, probable or definite myocarditis or cardiac injury among 0.4-3.0% of the athletes studied. Recent consensus statements suggest that athletes with full recovery and absence of cardiopulmonary symptoms may return to exercise and competition without cardiovascular testing. In conclusion, patients with COVID-19 may be expected to have an increased risk of cardiovascular disease, myocarditis or arrhythmias during the convalescent phase. Fortunately, the majority of patients, including athletes may return to their normal activity after recovery from COVID 19, in the absence of persisting cardiovascular symptoms.

1751

CaV179

M.Pineton De Chambrun1P.Barhoum1K.Dorgham2M.Kerneis3Q.Moyon4P.Quentric4J.L.Charuel5M.Schmidt1G.Lebreton6C.E.Luyt1M.Miyara5Z.Amoura4A.Combes1G.Gorochov7G.Hekimian1

Hétérogénéité phénotypique des myocardites fulminantes induites par la COVID-19 chez l’adulte

https://doi.org/10.1016/j.revmed.2022.03.316

Published

15-Jun-22

Study

https://www.sciencedirect.com/science/article/pii/S0248866322004003

Introduction
L’infection par le SARS-CoV-2 peut induire chez l’adulte un syndrome inflammatoire multisystémique (MIS-A). La myocardite fulminante est l’une des complications les plus graves du MIS-A. Des critères internationaux ont été établis par le Center for Disease Control and Prevention américain (US-CDC) pour faciliter son diagnostic. Cependant, certains patients présentant une myocardite fulminante dans un contexte de la COVID-19 ne répondent pas aux critères de l’US-CDC, suggérant l’existence de plusieurs phénotypes de myocardites fulminantes associées à la COVID-19. L’objectif de cette étude était de comparer les caractéristiques cliniques et l’évolution des myocardites fulminantes induites par la COVID-19 selon qu’elles répondent, ou non, aux critères du MIS-A établis par l’US-CDC.
Patients et méthodes
Etude rétrospective monocentrique incluant toutes les myocardites fulminantes induites par la COVID-19 admises dans un service de Médecine Intensive-Réanimation entre mars 2020 et juin 2021. Le critère de jugement principal était la mortalité intra-hospitalière.
Résultats
Pendant la durée de l’étude, 38 patients ont été admis en réanimation pour une myocardite fulminante (homme 66 %, âge moyen à l’admission ± DS 32 ± 15 ans) induite par la COVID-19. Les traitements des défaillances d’organes reçus par les patients étaient : dobutamine 79 %, noradrénaline 60 %, ventilation invasive 50 %, ECMO-VA 42 % et épuration extra-rénale 29 %. La mortalité intra-hospitalière était de 13 %. Vingt-cinq patients (66 %) répondaient aux critères du MIS-A (MIS-A + ). Les patients MIS-A- présentaient : un délai plus court entre le début de la COVID-19 et la survenue de la myocardite ; une fraction d’éjection du ventricule gauche plus basse ; une plus grande fréquence des défaillance d’organes et avaient un risque plus important de recevoir une ECMO-VA (92 % vs. 16 %, p < 0,0001). La mortalité intra-hospitalière était plus élevée chez les MIS-A- (31 % vs. 4 %). Les MIS-A+ présentaient des taux circulants plus élevées d’IL-17, d’IL-22 et de TNFa alors que les MIS-A- présentaient des taux circulants plus important d’IFNa2 et d’IL-8. De plus, les anticorps anti-ARN polymérases III étaient présents chez 54 % des patients MIS-A- mais chez aucun patient MIS-A+.
Conclusion
Les critères de MIS-A permettent d’identifier deux phénotypes au sein des myocardites fulminantes induites par la COVID-19. Les patients MIS-A+ et MIS-A- ont une présentation clinique, un pronostic et un profil immunologique très différents. Différencier ces deux entités semble important pour leurs traitements et pour mieux en comprendre la physiopathologie.

1752

CaV180

Akash Srinivasan 1ORCID,Felyx Wong 1ORCID,Liam S. Couch 2 andBrian X. Wang 3,*ORCIDAkash Srinivasan 1ORCID,Felyx Wong 1ORCID,Liam S. Couch 2 andBrian X. Wang 3,*ORCID

Cardiac Complications of COVID-19 in Low-Risk Patients

https://doi.org/10.3390/v14061322

Published

17-Jun-22

Review

https://www.mdpi.com/1999-4915/14/6/1322/htm

The coronavirus disease 2019 (COVID-19) pandemic has resulted in over 6 million deaths and significant morbidity across the globe. Alongside common respiratory symptoms, COVID-19 is associated with a variety of cardiovascular complications in the acute and post-acute phases of infection. The suggested pathophysiological mechanisms that underlie these complications include direct viral infection of the myocardium via the angiotensin-converting enzyme 2 (ACE2) protein and a cytokine release syndrome that results in indirect inflammatory damage to the heart. Patients with pre-existing cardiovascular disease and co-morbidities are generally more susceptible to the cardiac manifestations of COVID-19. However, studies have identified a variety of complications in low-risk individuals, including young adults and children. Myocarditis and paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS) are among the adverse events reported in the acute phase of infection. Furthermore, patients have reported cardiac symptoms persisting beyond the acute phase in post-COVID syndrome. This review summarises the acute and chronic cardiac consequences of COVID-19 in low-risk patients, explores the pathophysiology behind them, and discusses new predictive factors for poor outcomes.

1753

CaV181

Vincenzo Nuzzi, Eva Del Mestre, Alessia Degrassi, Daniel I. Bromage, Paolo Manca, Susan Piper, Jessica Artico, Piero Gentile, Paul A. Scott, Mario Chiatto, Marco Merlo, Nilesh Pareek, Mauro Giacca, Gianfranco Sinagra, Theresa A. McDonagh & Antonio Cannata

Cardiovascular Damage in COVID-19: What We Know Two Years Later

https://doi.org/10.1007/s11886-022-01730-4

Published

25-Jun-22

Review

https://link.springer.com/article/10.1007/s11886-022-01730-4

Purpose of the Review
The Coronavirus disease 2019 (COVID-19) pandemic has profoundly influenced cardiological clinical and basic research in the past two years. In the present review, we summarize the current knowledge on myocardial involvement in COVID-19, providing an overview on the incidence, the pathogenetic mechanisms, and the clinical implications of cardiac injury in this setting.
Recent Findings
The possibility of heart involvement in patients with COVID-19 has received great attention since the beginning of the pandemic. After more than two years, several steps have been taken in understanding the mechanisms and the incidence of cardiac injury during COVID-19 infection. Similarly, studies globally have clarified the implications of co-existing heart disease and COVID-19.
Summary
Severe COVID-19 infection may be complicated by myocardial injury. To date, a direct damage from the virus has not been demonstrated. The presence of myocardial injury should be systematically assessed for a prognostication purpose and for possible therapeutic implications.

1754

CaV182

Pratima Chowdary

COVID-19 coagulopathy – what should we treat?

https://doi.org/10.1113/EP089404

Published

22-Jun-22

Review

https://physoc.onlinelibrary.wiley.com/doi/full/10.1113/EP089404

New Findings
What is the topic of this review?
Overview of the coagulation abnormalities, including elevated D-dimers widely reported with COVID-19, often labelled as COVID coagulopathy.
What advances does it highlight?
The review highlights the changes in bronchoalveolar haemostasis due to apoptosis of alveolar cells, which contributes to acute lung injury and acute respiratory distress syndrome; the pathophysiological mechanisms, including endothelial dysfunction and damage responsible for thrombosis of pulmonary microcirculation and potential contribution to the hypoxaemia of COVID-19 acute lung injury; and changes in coagulation proteins responsible for the hypercoagulability and increased risk of thrombosis in other venous and arterial beds. The rationale for anticoagulation and fibrinolytic therapies is detailed, and potential confounders that might have led to less than expected improvement in the various randomised controlled trials are considered.
Abstract
Coronavirus disease 19 (COVID-19) causes acute lung injury with diffuse alveolar damage, alveolar–capillary barrier disruption, thrombin generation and alveolar fibrin deposition. Clinically, hypoxaemia is associated with preserved lung compliance early in the disease, suggesting the lack of excessive fluid accumulation typical of other lung injuries. Notably, autopsy studies demonstrate infection of the endothelium with extensive capillary thrombosis distinct from the embolic thrombi in pulmonary arteries. The inflammatory thrombosis in pulmonary vasculature secondary to endothelial infection and dysfunction appears to contribute to hypoxaemia. This is associated with elevated D-dimers and acquired hypercoagulability with an increased risk of deep vein thrombosis. Hypercoagulability is secondary to elevated plasma tissue factor levels, von Willebrand factor, fibrinogen, reduced ADAMTS-13 with platelet activation and inhibition of fibrinolysis. Multi-platform randomised controlled studies of systemic therapeutic anticoagulation with unfractionated and low molecular mass heparins demonstrated a survival benefit over standard care with full-dose anticoagulation in patients with non-severe disease who require supplemental oxygen, but not in severe disease requiring ventilatory support. Late intervention and the heterogeneous nature of enrolled patients can potentially explain the apparent lack of benefit in severe disease. Improvement in oxygenation has been demonstrated with intravenous fibrinolytics in small studies. Inhaled anticoagulants, thrombolytic agents and non-specific proteolytic drugs in clinical trials for decreasing alveolar fibrin deposition might benefit early disease. Essentially, COVID-19 is a multi-system disorder with pulmonary vascular inflammatory thrombosis that requires an interdisciplinary approach to combination therapies addressing both inflammation and intravascular thrombosis or alveolar fibrin deposits to improve outcomes.

1755

CaV183

Yicheng Yang, Zhiyao Wei, Changming Xiong & Haiyan Qian

Direct mechanisms of SARS-CoV-2-induced cardiomyocyte damage: an update

https://doi.org/10.1186/s12985-022-01833-y

Published

25-Jun-22

Review

https://virologyj.biomedcentral.com/articles/10.1186/s12985-022-01833-y

Myocardial injury induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is reportedly related to disease severity and mortality, attracting attention to exploring relevant pathogenic mechanisms. Limited by insufficient evidence, myocardial injury caused by direct viral invasion of cardiomyocytes (CMs) is not fully understood. Based on recent studies, endosomal dependence can compensate for S protein priming to mediate SARS-CoV-2 infection of CMs, damage the contractile function of CMs, trigger electrical dysfunction, and tip the balance of the renin–angiotensin–aldosterone system to exert a myocardial injury effect. In this review, we shed light on the direct injury caused by SARS-CoV-2 to provide a comprehensive understanding of the cardiac manifestations of coronavirus disease 2019 (COVID-19).

1756

CaV184

O Shchudro, L Konopkina, T Pertseva, L Botvinikova, K Bielosludtseva

The role of NT-proBNP in patients discharged after COVID-19 pneumonia

https://doi.org/10.1093/eurjcn/zvac060.019

Published

2-Jul-22

Study

https://academic.oup.com/eurjcn/article-abstract/21/Supplement_1/zvac060.019/6627402

Aims
The long-term health effects after SARS-CoV-2 infection remain poorly understood. The aim of our study was to define the cardiac disorders in the early postCOVID period.
Methods and resuts
Was observed 85 patients (40 (47,1%) men, 45 (52,9%) women, average age – 44,2 (39,3; 47,1)) on 48,3 (45,0; 56,2) days after the onset of the first symptoms of COVID-19. The main group were divided into 3 subgroups: 1 – 39 patients after moderate COVID-19 pneumonia, 2 – 36 patients after severe COVID-19 pneumonia, 3 – 10 patients after critical COVID-19 pneumonia. The subgroups were comparable in gender and age. All patients before COVID-19 were virtually healthy and had no history of cardiovascular disease, including arrhythmias. All patients underwent general clinical methods of examination, determination of SpO2, echocardiography and measured NT-proBNP concentration in serum. In 100% patients was the level of SpO2 more than 95% (average 97,5 (96,3; 98,8)%) and preserved left ventricular ejection fraction (LVEF) (average 62,3 (60,2; 74,3)%). In patients after moderate COVID-19 pneumonia, the level of NT-proBNP was significantly lower (79,4 (59,9; 75,3) pg/ml) than in patients after severe (145,0 (66,9; 170,9) pg/ml) and critical (149,7 (79,3; 138,5) pg/ml) COVID-19 pneumonia (p < 0,01). But concentration NT-proBNP in patients after severe and critical COVID-19 pneumonia didn’t differ significantly (p > 0,05).
Conclusions
Patients after severe and critical COVID-19 pneumonia are at risk for developing cardiac disorders in the early postCOVID period. Determining the level of NT-proBNP, and not just performing echocardiography, after discharged in such patients will help to customize the most appropriate therapeutic strategies.

1757

CaV185

Cameron K.OrmistonBSabIwonaŚwiątkiewiczMD, PhDacPam R.TaubMDa

Postural Orthostatic Tachycardia Syndrome as a Sequela of COVID-19

https://doi.org/10.1016/j.hrthm.2022.07.014

Published

16-Jul-22

Review

https://www.sciencedirect.com/science/article/pii/S1547527122021853

Postural Orthostatic Tachycardia Syndrome (POTS) is a complex, multisystem disorder characterized by orthostatic intolerance and tachycardia and may be triggered by viral infection. Recent reports indicate 2-14% of COVID-19 survivors develop POTS and 9-61% experience POTS-like symptoms, such as tachycardia, orthostatic intolerance, fatigue, and cognitive impairment within 6-8 months following a SARS-CoV-2 infection. Pathophysiological mechanisms of Post-COVID-19 POTS are not well understood. Current hypotheses include autoimmunity related to SARS-CoV-2 infection, autonomic dysfunction, direct toxic injury by SARS-CoV-2 to the autonomic nervous system, and invasion of the central nervous system by SARS-CoV-2. Practitioners should actively assess for POTS in patients with post-acute COVID syndrome symptoms. Given symptoms of Post-COVID-19 POTS are predominantly chronic orthostatic tachycardia, lifestyle modifications in combination with the use of heart rate-lowering medications along with other pharmacotherapies should be considered. For example, ivabradine or beta-blockers in combination with compression stockings and increasing salt and fluid intake has shown potential. Treatment teams should be multidisciplinary, including physicians of various specialties, nurses, psychologists, and physiotherapists. Additionally, more resources to adequately care for this patient population are urgently needed given the increased demand for autonomic specialists and clinics since the start of the COVID-19 pandemic. Considering our limited understanding of Post-COVID-19 POTS, further research on topics such as its natural history, pathophysiological mechanisms, and ideal treatment is warranted. This review evaluates the current literature available on the associations between COVID-19 and POTS, possible mechanisms, patient assessment, treatments, and future directions to improving our understanding of Post-COVID-19 POTS.

1758

CaV186

Emma Rezel-Potts,Abdel Douiri,Xiaohui Sun,Phillip J. Chowienczyk,Ajay M. Shah,Martin C. Gulliford Emma Rezel-Potts,Abdel Douiri,Xiaohui Sun,Phillip J. Chowienczyk,Ajay M. Shah,Martin C. Gulliford

Cardiometabolic outcomes up to 12 months after COVID-19 infection. A matched cohort study in the UK

https://doi.org/10.1371/journal.pmed.1004052

Published

19-Jul-22

Study

https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004052

Background
Acute Coronavirus Disease 2019 (COVID-19) has been associated with new-onset cardiovascular disease (CVD) and diabetes mellitus (DM), but it is not known whether COVID-19 has long-term impacts on cardiometabolic outcomes. This study aimed to determine whether the incidence of new DM and CVDs are increased over 12 months after COVID-19 compared with matched controls.
Methods and findings
We conducted a cohort study from 2020 to 2021 analysing electronic records for 1,356 United Kingdom family practices with a population of 13.4 million. Participants were 428,650 COVID-19 patients without DM or CVD who were individually matched with 428,650 control patients on age, sex, and family practice and followed up to January 2022. Outcomes were incidence of DM and CVD. A difference-in-difference analysis estimated the net effect of COVID-19 allowing for baseline differences, age, ethnicity, smoking, body mass index (BMI), systolic blood pressure, Charlson score, index month, and matched set. Follow-up time was divided into 4 weeks from index date (“acute COVID-19”), 5 to 12 weeks from index date (“post-acute COVID-19”), and 13 to 52 weeks from index date (“long COVID-19”). Net incidence of DM increased in the first 4 weeks after COVID-19 (adjusted rate ratio, RR 1.81, 95% confidence interval (CI) 1.51 to 2.19) and remained elevated from 5 to 12 weeks (RR 1.27, 1.11 to 1.46) but not from 13 to 52 weeks overall (1.07, 0.99 to 1.16). Acute COVID-19 was associated with net increased CVD incidence (5.82, 4.82 to 7.03) including pulmonary embolism (RR 11.51, 7.07 to 18.73), atrial arrythmias (6.44, 4.17 to 9.96), and venous thromboses (5.43, 3.27 to 9.01). CVD incidence declined from 5 to 12 weeks (RR 1.49, 1.28 to 1.73) and showed a net decrease from 13 to 52 weeks (0.80, 0.73 to 0.88). The analyses were based on health records data and participants’ exposure and outcome status might have been misclassified.
Conclusions
In this study, we found that CVD was increased early after COVID-19 mainly from pulmonary embolism, atrial arrhythmias, and venous thromboses. DM incidence remained elevated for at least 12 weeks following COVID-19 before declining. People without preexisting CVD or DM who suffer from COVID-19 do not appear to have a long-term increase in incidence of these conditions.
Author summary
Why was this study done?
➢ Acute Coronavirus Disease 2019 (COVID-19) may be associated with cardiovascular complications and disorders of blood glucose.
➢ It is not known whether patients recovering from COVID-19 remain at increased risk of cardiovascular disease (CVD) or diabetes mellitus (DM).
➢ This study aimed to find out whether new diagnoses of DM and CVDs are increased over 12 months after COVID-19 compared with matched control patients who did not have COVID-19.
What did the researchers do and find?
➢ We analysed electronic records for 428,650 COVID-19 patients who were matched with 428,650 control patients and followed up to January 2022. We evaluated new diagnoses of DM and CVD up to 12 months after COVID-19 infection. We compared COVID-19 patients with controls and adjusted for baseline differences in risk.
➢ DM diagnoses were increased by 81% in acute COVID-19 and remained elevated by 27% from 4 to 12 weeks after the infection.
➢ Acute COVID-19 was associated with a 6-fold increase in cardiovascular diagnoses overall, including an 11-fold increase in pulmonary embolism, a 6-fold increase in atrial arrythmias, and a 5-fold increase in venous thromboses. CVD diagnoses declined from 4 to 12 weeks after COVID-19 and returned to baseline levels or below from 12 weeks to 1 year after the infection.
What do these findings mean?
➢ Acute COVID-19 is associated with increased risk of cardiovascular disorders, but risk generally returns to background levels soon after the infection.
➢ The risk of new DM remains increased for at least 12 weeks following COVID-19 before declining.
➢ Patients recovering from COVID-19 should be advised to consider measures to reduce diabetes risk including healthy diet and taking exercise.
➢ People without preexisting CVD or DM who suffer from COVID-19 do not appear to have a long-term increase in incidence of these conditions.

1759

CaV187

Jessica Nye, PhD

Are Amyloid Fibrin Microclots Central to Long COVID?

Published

8-Jul-22

Article

https://www.hematologyadvisor.com/home/topics/thrombotic-disorders/covid-amyloid-fibrin-micro-clots-central-treatment-risk/

Analysis of patient blood samples found that microclots and platelet pathologies were present in all 80 patients. Using a spreading, clumping, and microclot scoring system, 30 of the 80 patients were found to have moderate activation.6

One of the possible treatments will be to prevent microclots from forming and to prevent platelet hyperactivation. Oral anticoagulants or nutraceuticals might be an option to investigate, and some clinicians have embarked upon clinician-initiated treatment regimens that include such treatments.11 However, such treatment regimens should be tested in randomized controlled trials to determine dosage, as well as efficacy in large patient populations. Various adjuvant medications may also assist in patient symptom relief and other research groups have suggested a combination of statins and antihistamines.6,11

Going forward there are still many aspects of SARS-CoV-2 infections that remain elusive. Prof Kell explained that symptoms of COVID-19 can persist for months, or even longer ¾ much as with myalgic encephalomyelitis/chronic fatigue syndrome ¾ after recovery and viral clearance. This suggests that there may be a replicating viral reservoir remaining long term, in some cases. Finding that reservoir ¾ most likely in the gut microbiome that may well contain microbial hosts for the virus ¾ should be the next mystery to investigate.

1760

CaV188

Kyya, Yulian; Barnett, Olga; Halkevych, Marta; Labinska, Olha

RED BLOOD CELL COLOUR VARIATION AS A MARKER OF CALCIUM DISTRIBUTION: WHAT ROLE DOES IT HAVE IN HEART FAILURE PATIENTS WITH HYPERTENSION AND LONG COVID?

https://doi.org/10.1097/01.hjh.0000837240.96681.96

Published

1-Jun-22

Study

https://journals.lww.com/jhypertension/Abstract/2022/06001/RED_BLOOD_CELL_COLOUR_VARIATION_AS_A_MARKER_OF.487.aspx

Objective:
Red blood cell (RBC) role is both passive action, oxygen delivery to the tissues as well as carbon dioxide to the lungs and active action involvement in the regulation of vascular tone.
The aim was to investigate pathophysiological and ultrastructural changes of RBC in heart failure (HF) patients with hypertension (HT) and long Covid.
Design and method:
In total 12 patients with HF of Coronary Artery Disease origin, HT, and long Covid were examined. Mean age of patients was 62 ± 5.8 years. The control group consisted of 10 apparently healthy people. The functional state and ultrastructure of RBC were studied using electron microscopy.
Results:
During ultrastructure examination, structural pathologies of RBC in HF patients with HT and long Covid were revealed. RBC anisocytosis and poikilocytosis as structural damage variations in size and shape were found respectively. Reticulocytes were found much more often in HF patients with HT and long Covid than in the control group. In healthy control group, RBC had a typical discoid shape. In the presence of long Covid, both calcification as a marker of RBC apoptosis and destruction was also detected (Fig.1). Neutrophil extracellular traps (NETs) were found in RBC surrounding (Fig.1).
Conclusions:
Altered RBC function has important implications for HF patients with HT and long Covid. RBC has been shown to induce endothelial cell dysfunction and to increase cardiac injury as well as increased inflammatory processes in long Covid. The presence of HF, HT and long Covid leads to RBC calcification and activation of blood cell apoptosis. Prognostic role of RBC calcium distribution in combination with other important prognostic measures, such as biomarkers like Thrombospondin - 1, NT-proBNP and ST2 is subject of interest and requires further research.

1761

CaV189

Petra Barhoum, Marc Pineton de Chambrun, Karim Dorgham, Mathieu Kerneis, Sonia Burrel, Paul Quentric, Christophe Parizot, Juliette Chommeloux, Nicolas Bréchot, Quentin Moyon, Guillaume Lebreton, Samia Boussouar, Matthieu Schmidt, Hans Yssel, Lucie Lefevre, Makoto Miyara, Jean-Luc Charuel, Stéphane Marot, Anne-Geneviève Marcelin, Charles-Edouard Luyt, Pascal Leprince, Zahir Amoura, Gilles Montalescot, Alban Redheuil, Alain Combes, Guy Gorochov, and Guillaume Hékimian

Phenotypic Heterogeneity of Fulminant COVID-19--Related Myocarditis in Adults

https://doi.org/10.1016/j.jacc.2022.04.056

Published

18-Jul-22

Study

https://www.jacc.org/doi/full/10.1016/j.jacc.2022.04.056

Background
Adults who have been infected with SARS-CoV-2 can develop a multisystem inflammatory syndrome (MIS-A), including fulminant myocarditis. Yet, several patients fail to meet MIS-A criteria, suggesting the existence of distinct phenotypes in fulminant COVID-19–related myocarditis.
Objectives
This study sought to compare the characteristics and clinical outcome between patients with fulminant COVID-19–related myocarditis fulfilling MIS-A criteria (MIS-A+) or not (MIS-A−).
Methods
A monocentric retrospective analysis of consecutive fulminant COVID-19–related myocarditis in a 26-bed intensive care unit (ICU).
Results
Between March 2020 and June 2021, 38 patients required ICU admission (male 66%; mean age 32 ± 15 years) for suspected fulminant COVID-19–related myocarditis. In-ICU treatment for organ failure included dobutamine 79%, norepinephrine 60%, mechanical ventilation 50%, venoarterial extracorporeal membrane oxygenation 42%, and renal replacement therapy 29%. In-hospital mortality was 13%. Twenty-five patients (66%) met the MIS-A criteria. MIS-A− patients compared with MIS-A+ patients were characterized by a shorter delay between COVID-19 symptoms onset and myocarditis, a lower left ventricular ejection fraction, and a higher rate of in-ICU organ failure, and were more likely to require mechanical circulatory support with venoarterial extracorporeal membrane oxygenation (92% vs 16%; P < 0.0001). In-hospital mortality was higher in MIS-A− patients (31% vs 4%). MIS-A+ had higher circulating levels of interleukin (IL)-22, IL-17, and tumor necrosis factor-α (TNF-α), whereas MIS-A− had higher interferon-α2 (IFN-α2) and IL-8 levels. RNA polymerase III autoantibodies were present in 7 of 13 MIS-A− patients (54%) but in none of the MIS-A+ patients.
Conclusion
MIS-A+ and MIS-A− fulminant COVID-19–related myocarditis patients have 2 distinct phenotypes with different clinical presentations, prognosis, and immunological profiles. Differentiating these 2 phenotypes is relevant for patients’ management and further understanding of their pathophysiology.

1762

CaV190

Rachel E. Szeghy, Nina L. Stute, Valesha M. Province, Marc A. Augenreich, Jonathon L. Stickford, Abigail S. L. Stickford, and Stephen M. Ratchford

Six-month longitudinal tracking of arterial stiffness and blood pressure in young adults following SARS-CoV-2 infection

https://doi.org/10.1152/japplphysiol.00793.2021

Published

17-May-22

Study

https://journals.physiology.org/doi/full/10.1152/japplphysiol.00793.2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can increase arterial stiffness 3–4 wk following infection, even among young, healthy adults. However, the long-term impacts of SARS-CoV-2 infection on cardiovascular health and the duration of recovery remain unknown. The purpose of this study was to elucidate potential long-lasting effects of SARS-CoV-2 infection on markers of arterial stiffness among young adults during the 6 mo following infection. Assessments were performed at months 1, 2, 3, 4, and ∼6 following SARS-CoV-2 infection. Doppler ultrasound was used to measure carotid-femoral pulse wave velocity (cfPWV) and carotid stiffness, and arterial tonometry was used to measure central blood pressures and aortic augmentation index at a heart rate of 75 beats·min−1 (AIx@HR75). Vascular (VCAM-1) and intracellular (ICAM-1) adhesion molecules were analyzed as circulating markers of arterial stiffness. From months 1–6, a significant reduction in cfPWV was observed (month 1: 5.70 ± 0.73 m·s−1; month 6: 4.88 ± 0.65 m·s−1; P < 0.05) without any change in carotid stiffness measures. Reductions in systolic blood pressure (month 1: 123 ± 8 mmHg; month 6: 112 ± 11 mmHg) and mean arterial pressure (MAP; month 1: 97 ± 6 mmHg; month 6: 86 ± 7 mmHg) were observed (P < 0.05), although AIx@HR75 did not change over time. The month 1–6 change in cfPWV and MAP were correlated (r = 0.894; P < 0.001). A reduction in VCAM-1 was observed at month 3 compared with month 1 (month 1: 5,575 ± 2,242 pg·mL−1; month 3: 4,636 ± 1,621 pg·mL−1; P < 0.05) without a change in ICAM-1. A reduction in cfPWV was related with MAP, and some indicators of arterial stiffness remain elevated for several months following SARS-CoV-2 infection, possibly contributing to prolonged recovery and increased cardiovascular health risks.

NEW & NOTEWORTHY We sought to investigate potential long-lasting effects of SARS-CoV-2 infection on markers of arterial stiffness among young adults for 6 mo following infection. Carotid femoral pulse wave velocity was significantly reduced while carotid stiffness measures remained unaltered over the 6-mo period. These findings suggest several months of recovery from infection may be necessary for young adults to improve various markers of arterial stiffness, possibly contributing to cardiovascular health and recovery among those infected with SARS-CoV-2.

1763

CaV191

Larisa G.TereshchenkoMD, PhDabAdamBishopBSaNoraFisher-CampbellBAaJacquelineLeveneDOaCraig C.MorrisMDaHetalPatelMScacErynnBeesonMDaJessica A.BlankMDaJG N.BradnerBSaMichelleCoblensBAaJacob W.CorpronBSaJenna M.DavisonMPHaKathleenDennyBAaMary S.EarpBSaSimeonFloreaaHowardFreemanMDaOliviaFusonBSaFlorian H.GuillotBSaKazi T.HaqPhDaMorrisKimMDaClintonKolsethMDaOliviaKrolBScLisaLinBSaLiatLitwinMDaAneeqMalikMDaEvanMitchellBSaAmanMohapatraBSacCassandraMullenMDaChad DNixMScaAyodeleOyeyemiMDaChristineRutlenMD, MPHaAshley E.TamBAaIngaVan BurenBAaJessicaWallaceBAaAkramKhanMDd

Risk of Cardiovascular Events After COVID-19

https://doi.org/10.1016/j.amjcard.2022.06.023

Published

15-Jul-22

Study

https://www.sciencedirect.com/science/article/pii/S0002914922006555

We aimed to determine absolute and relative risks of either symptomatic or asymptomatic SARS-CoV-2 infection for late cardiovascular (CV) events and all-cause mortality. We conducted a retrospective double cohort study of patients with either symptomatic or asymptomatic SARS-CoV-2 infection (COVID-19+ cohort) and its documented absence (COVID-19− cohort). The study investigators drew a simple random sample of records from all patients under the Oregon Health & Science University Healthcare (n = 65,585), with available COVID-19 test results, performed March 1, 2020 to September 13, 2020. Exclusion criteria were age <18 years and no established Oregon Health & Science University care. The primary outcome was a composite of CV morbidity and mortality. All-cause mortality was the secondary outcome. The study population included 1,355 patients (mean age 48.7 ± 20.5 years; 770 women [57%], 977 White non-Hispanic [72%]; 1,072 ensured [79%]; 563 with CV disease history [42%]). During a median 6 months at risk, the primary composite outcome was observed in 38 of 319 patients who were COVID-19+ (12%) and 65 of 1,036 patients who were COVID-19− (6%). In the Cox regression, adjusted for demographics, health insurance, and reason for COVID-19 testing, SARS-CoV-2 infection was associated with the risk for primary composite outcome (hazard ratio 1.71, 95% confidence interval 1.06 to 2.78, p = 0.029). Inverse probability-weighted estimation, conditioned for 31 covariates, showed that for every patient who was COVID-19+, the average time to all-cause death was 65.5 days less than when all these patients were COVID-19−: average treatment effect on the treated −65.5 (95% confidence interval −125.4 to −5.61) days, p = 0.032. In conclusion, either symptomatic or asymptomatic SARS-CoV-2 infection is associated with an increased risk for late CV outcomes and has a causal effect on all-cause mortality in a late post-COVID-19 period.

1764

CaV192

Ryota Urata, Koji Ikeda, Ekura Yamazaki, Daisuke Ueno, Akiko Katayama, Masaharu Shin-Ya, Eriko Ohgitani, Osam Mazda & Satoaki Matoba

Senescent endothelial cells are predisposed to SARS-CoV-2 infection and subsequent endothelial dysfunction

https://doi.org/10.1038/s41598-022-15976-z

Published

25-Jul-22

Study

https://www.nature.com/articles/s41598-022-15976-z

The coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains to spread worldwide. COVID-19 is characterized by the striking high mortality in elderly; however, its mechanistic insights remain unclear. Systemic thrombosis has been highlighted in the pathogenesis of COVID-19, and lung microangiopathy in association with endothelial cells (ECs) injury has been reported by post-mortem analysis of the lungs. Here, we experimentally investigated the SARS-CoV-2 infection in cultured human ECs, and performed a comparative analysis for post-infection molecular events using early passage and replicative senescent ECs. We found that; (1) SARS-CoV-2 infects ECs but does not replicate and disappears in 72 hours without causing severe cell damage, (2) Senescent ECs are highly susceptible to SARS-CoV-2 infection, (3) SARS-CoV-2 infection alters various genes expression, which could cause EC dysfunctions, (4) More genes expression is affected in senescent ECs by SARS-CoV-2 infection than in early passage ECs, which might causes further exacerbated dysfunction in senescent ECs. These data suggest that sustained EC dysfunctions due to SARS-CoV-2 infection may contribute to the microangiopathy in the lungs, leading to deteriorated inflammation and thrombosis in COVID-19. Our data also suggest a possible causative role of EC senescence in the aggravated disease in elder COVID-19 patients.

1765

CaV193

Husam M. Salah, Marat Fudim, Shawn T. O’Neil, Amin Manna, Christopher G. Chute & Melissa C. Caughey

Post-recovery COVID-19 and incident heart failure in the National COVID Cohort Collaborative (N3C) study

https://doi.org/10.1038/s41467-022-31834-y

Published

15-Jul-22

Study

https://www.nature.com/articles/s41467-022-31834-y

Cardiac involvement has been noted in COVID-19 infection. However, the relationship between post-recovery COVID-19 and development of de novo heart failure has not been investigated in a large, nationally representative population. We examined post-recovery outcomes of 587,330 patients hospitalized in the United States (257,075 with COVID-19 and 330,255 without), using data from the National COVID Cohort Collaborative study. Patients hospitalized with COVID-19 were older (51 vs. 46 years), more often male (49% vs. 42%), and less often White (61% vs. 69%). Over a median follow up of 367 days, 10,979 incident heart failure events occurred. After adjustments, COVID-19 hospitalization was associated with a 45% higher hazard of incident heart failure (hazard ratio = 1.45; 95% confidence interval: 1.39–1.51), with more pronounced associations among patients who were younger (P-interaction = 0.003), White (P-interaction = 0.005), or who had established cardiovascular disease (P-interaction = 0.005). In conclusion, COVID-19 hospitalization is associated with increased risk of incident heart failure.

1766

CaV194

Zainab Mahmoud 1 Lauren East 1 Marye Gleva Pamela K. Woodard Kory Lavine Amanda K. Verma

Cardiovascular symptom phenotypes of post-acute sequelae of SARS-CoV-2

https://doi.org/10.1016/j.ijcard.2022.07.018

Published

13-Jul-22

Study

https://www.internationaljournalofcardiology.com/article/S0167-5273(22)01086-5/fulltext

Highlights:
•Cardiovascular post-acute sequelae occur in some patients after acute COVID-19 infection
•The most common symptoms are chest pain, palpitations, and dyspnea on exertion
•Patients were found to have a significant burden of sinus tachycardia that correlated with symptoms
•Elevated blood pressures compared to pre-COVID-19 infection were also seen
•Cardiac imaging showed reduced strain, increased left ventricular volume, and myocardial involvement on cardiac MRI
Abstract
Background
Acute COVID-19 infection has been shown to have significant effects on the cardiovascular system. Post-acute sequelae of SARS-CoV-2 (PASC) are being identified in patients; however, the cardiovascular effects are yet to be well-defined. The Post-COVID Cardiology Clinic at Washington University evaluates and treats patients with ongoing cardiovascular PASC.
Objectives
This investigation aims to describe the phenotypes of cardiovascular symptoms of PASC in patients presenting to the Post-COVID Cardiology Clinic, including their demographics, symptoms, and the clinical phenotypes observed.
Methods
This was a retrospective analysis of symptoms, clinical findings, and test results from the first 100 consecutive adult patients who presented to the Post-COVID Cardiology Clinic at Washington University in St. Louis, between September 2020 to May 2021 with cardiovascular symptoms following COVID-19 infection.
Results
The population (n = 100) had a mean age of 46.3 years and was 81% female. Most patients had mild acute illness, with only 23% of patients requiring hospitalization during acute COVID-19 infection. The most commonly reported PASC symptoms were chest pain (66%), palpitations (59%), and dyspnea on exertion (56%). Of those presenting with these symptoms, 74/98 patients (75.5%) were found to have a significant blood pressure elevation, considerable sinus tachycardia burden, reduced global longitudinal strain, increased indexed left-ventricular end-diastolic volume (LVEDVi) by echocardiogram, and/or cMRI findings consistent with possible active or healing myocarditis.
Conclusions
Our findings highlight clinical phenotypes of the cardiovascular manifestations of PASC. Further studies are needed to evaluate the pathophysiology, treatment options and long-term outcomes for these patients.

1767

CaV195

Stefanie Lip1, Linsay Mccallum1,2, Christian Delles1, John D McClure1, Tomasz Guzik1, Colin Berry1, Rhian Touyz1,3 and Sandosh Padmanabhan1

Rationale and Design for the LOnger-term effects of SARS-CoV-2 INfection on blood Vessels And blood pRessure (LOCHINVAR): an observational phenotyping study

http://dx.doi.org/10.1136/openhrt-2022-002057

Published

24-Jun-22

Protocol

https://openheart.bmj.com/content/9/1/e002057

Introduction COVID-19 may lead to long-term endothelial consequences including hypertension, stroke and myocardial infarction. A pilot study ‘COVID-19 blood pressure endothelium interaction study’, which found that patients with normal blood pressure (BP) at the time of hospital admission with COVID-19 showed an 8.6 mm Hg higher BP ≥12 weeks after recovery, compared with a group without COVID-19. The ‘LOnger-term effects of SARS-CoV-2 INfection on blood Vessels And blood pRessure’(LOCHINVAR) study is designed to provide definitive evidence of the long-term impact of COVID-19 on BP.

Methods and analysis The LOCHINVAR study is an observational clinical phenotyping study comparing longitudinal BP change between individuals with and without COVID-19 infection. 150 participants (30–60 years) with no history of hypertension and not on BP lowering medications will be recruited to the study to attend three visits (baseline, 12 months, 18 months). Cases will be patients who were admitted to the Queen Elizabeth University Hospital (QEUH), Glasgow, UK, with suspected/confirmed COVID-19 until 31 December 2021 and who were alive at discharge. Controls will be those who have never had confirmed COVID-19 infection. All participants will undergo clinical and vascular phenotyping studies which will include 24-hour ambulatory BP monitoring systolic BP (ABPM SBP), brachial flow-mediated dilatation urine and blood samples to assess the renin-angiotensin system, vascular inflammation and immune status. The primary outcome is the change in systolic 24-hour ABPM (ABPM SBP) between the cases and controls. Sample size was calculated to detect a mean difference of 5 mm Hg ABPM SBP at 80% power.

1768

CaV196

Maria Pia Borrelli
Adelaide Buora
Paolo Frigatti

The long haul COVID-19 arterial thrombosis

https://doi.org/10.1016/j.thromres.2022.07.008

Published

26-Jul-22

Letter to the Editor

https://www.thrombosisresearch.com/article/S0049-3848(22)00324-3/fulltext

The presence of a coexisting hypercoagulable state associated with Covid-19 infection has gained attention and several studies have already described acute limb ischemia (ALI) and peripheral arterial disease in critically ill patients, as well as coronary artery disease and ischemic stroke as manifestations usually associated with respiratory distress. Actually no information is currently available on how long inflammation and thrombotic derangements can last after recovery from Covid-19 symptoms and which patients are prone to develop acute arterial thrombosis.

Considering the high rates of in-hospital thrombosis in Covid-19 patients, an aggressive thromboprophylaxis is recommended during hospitalization [[7]].
The International Society on Thrombosis and Haemostasis recommend to administer low molecular-weight heparin (LMWH) to all patients who need to be hospitalized for Covid-19 infection, unless contraindicated [[8]]. Beyond its anticoagulant action, heparin has also anti-inflammatory, cytoprotective and anti-viral effects: in fact it is able to bind to Sars-CoV-2 and block replication of the virus [[9]].
Besides LMWH and UFH, direct oral anticoagulants, antiplatelet drugs and fibrinolytic agents are also useful in management of Covid-19 patients.
Abciximab (ReoPro) is a monoclonal antibody against the GPIIb/IIIa receptor, inhibiting platelet aggregation and thrombus formation. Evidence from the coronary literature suggest its use to enhance microperfusion likely because of prevention of downstream microembolization and platelet aggregation. The PROMPT Study, a randomized pilot trial [[10]], has demonstrated that in patients with ALI who underwent urokinase thrombolysis an adjunctive abciximab infusion resulted in faster thrombus dissolution and improved amputation free-survival.
Our rationale for using adjunctive intra-arterial infusion of abciximab in Covid-19 patients with ALI was based on the histologic analysis of thrombi extracted in these kind of patients, which revealed platelet-fibrin thrombi and not just simple clot.
Although prophylactic anticoagulation in active Covid-19 patients is largely accepted, there is no agreement on the dosage to be employed. Furthermore, whether and how long the pro-thrombotic state of Covid-19 persists after symptoms resumption is unknown and the utility of post-discharge tromboprophylaxis is debated.
Our analysis underlines that delayed arterial thrombotic sequela of Covid-19 can also occur in susceptible patients after the index infection. From this perspective, vascular screening and followup should be discussed both during and after Covid-19 systemic symptoms resumption, to detect vascular manifestations which could be silent during viral infection.
A better understanding of the coagulopathy in Covid-19 could have an essential role to guide prevention and treatment of arterial thromboembolic events, both during and after the viral infection.
Further investigations are required to establish the type, dose and duration of anticoagulant/antiplatelet therapy not just during but also after Covid-19 infection.

1769

CaV197

Irina Osiaevi, Arik Schulze, Georg Evers, Kimon Harmening, Hans Vink, Philipp Kümpers, Michael Mohr & Alexandros Rovas

Persistent capillary rarefication in long COVID syndrome

https://doi.org/10.1007/s10456-022-09850-9

Published

11-Aug-22

Study

https://link.springer.com/article/10.1007/s10456-022-09850-9

Background
Recent studies have highlighted Coronavirus disease 2019 (COVID-19) as a multisystemic vascular disease. Up to 60% of the patients suffer from long-term sequelae and persistent symptoms even 6 months after the initial infection.
Methods
This prospective, observational study included 58 participants, 27 of whom were long COVID patients with persistent symptoms > 12 weeks after recovery from PCR-confirmed SARS-CoV-2 infection. Fifteen healthy volunteers and a historical cohort of critically ill COVID-19 patients (n = 16) served as controls. All participants underwent sublingual videomicroscopy using sidestream dark field imaging. A newly developed version of Glycocheck™ software was used to quantify vascular density, perfused boundary region (PBR-an inverse variable of endothelial glycocalyx dimensions), red blood cell velocity (VRBC) and the microvascular health score (MVHS™) in sublingual microvessels with diameters 4–25 µm.
Measurements and main results
Although dimensions of the glycocalyx were comparable to those of healthy controls, a µm-precise analysis showed a significant decrease of vascular density, that exclusively affected very small capillaries (D5: − 45.16%; D6: − 35.60%; D7: − 22.79%). Plotting VRBC of capillaries and feed vessels showed that the number of capillaries perfused in long COVID patients was comparable to that of critically ill COVID-19 patients and did not respond adequately to local variations of tissue metabolic demand. MVHS was markedly reduced in the long COVID cohort (healthy 3.87 vs. long COVID 2.72 points; p = 0.002).
Conclusions
Our current data strongly suggest that COVID-19 leaves a persistent capillary rarefication even 18 months after infection. Whether, to what extent, and when the observed damage might be reversible remains unclear.

1770

CaV198

Weijie Wang
Chi-Yen Wang
Shiow-Ing Wang 1
James Cheng-Chung Wei

Long-term cardiovascular outcomes in COVID-19 survivors among non-vaccinated population: A retrospective cohort study from the TriNetX US collaborative networks

https://doi.org/10.1016/j.eclinm.2022.101619

Published

11-Aug-22

Study

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(22)00349-2/fulltext

Background
The long-term cardiovascular outcomes in COVID-19 survivors remain largely unclear. The aim of this study was to investigate the long-term cardiovascular outcomes in COVID-19 survivors.
Methods
This study used the data from the US Collaborative Network in TriNetX. From a cohort of more than 42 million records between 1 January 2019 and 31 March 2022, a total of 4,131,717 participants who underwent SARS-CoV-2 testing were recruited. Study population then divided into two groups based on COVID-19 test results. To avoid reverse causality, the follow-up initiated 30 days after the test, and continued until 12 months. Hazard ratios (HRs) and 95% Confidence intervals (CIs) of the incidental cardiovascular outcomes were calculated between propensity score–matched patients with versus without SARS-CoV-2 infection. Subgroup analyses on sex, and age group were also conducted. Sensitivity analyses were performed using different network, or stratified by hospitalization to explore the difference of geography and severity of COVID-19 infection.
Findings
The COVID-19 survivors were associated with increased risks of cerebrovascular diseases, such as stroke (HR [95% CI] = 1.618 [1.545-1.694]), arrhythmia related disorders, such as atrial fibrillation (HR [95% CI] = 2.407 [2.296-2.523]), inflammatory heart disease, such as myocarditis (HR [95% CI] =4.406 [2.890-6.716]), ischemic heart disease(IHD), like ischemic cardiomyopathy (HR [95% CI] = 2.811 [2.477-3.190]), other cardiac disorders, such as heart failure (HR [95% CI] =2.296 [2.200-2.396]) and thromboembolic disorders (e.g. pulmonary embolism: HR [95% CI] =2.648 [2.443-2.870]). The risks of two composite endpoints, major adverse cardiovascular event (HR [95% CI] = 1.871 [1.816–1.927]) and any cardiovascular outcome (HR [95% CI] = 1.552 [1.526–1.578]), were also higher in the COVID-19 survivors than in the controls. Moreover, the survival probability of the COVID-19 survivors dramatically decreased in all the cardiovascular outcomes. The risks of cardiovascular outcomes were evident in both male and female COVID-19 survivors. Furthermore, the risk of mortality was higher in the elderly COVID-19 survivors (age ≥ 65 years) than in the young ones. Sensitivity analyses presented roughly similar results globally. Furthermore, the impact of COVID-19 on cardio-related outcomes appeared to be more pronounced in inpatients than in outpatients.
Interpretation
The 12-month risk of incidental cardiovascular diseases is substantially higher in the COVID-19 survivors than the non-COVID-19 controls. Clinicians and patients with a history of COVID-19 should pay attention to their cardiovascular health in long term.

1771

CaV199

Edward M. Conway, Nigel Mackman, Ronald Q. Warren, Alisa S. Wolberg, Laurent O. Mosnier, Robert A. Campbell, Lisa E. Gralinski, Matthew T. Rondina, Frank L. van de Veerdonk, Karin M. Hoffmeister, John H. Griffin, Diane Nugent, Kyung Moon & James H. Morrissey

Understanding COVID-19-associated coagulopathy

https://doi.org/10.1038/s41577-022-00762-9

Published

5-Aug-22

Article

https://www.nature.com/articles/s41577-022-00762-9

COVID-19-associated coagulopathy (CAC) is a life-threatening complication of SARS-CoV-2 infection. However, the underlying cellular and molecular mechanisms driving this condition are unclear. Evidence supports the concept that CAC involves complex interactions between the innate immune response, the coagulation and fibrinolytic pathways, and the vascular endothelium, resulting in a procoagulant condition. Understanding of the pathogenesis of this condition at the genomic, molecular and cellular levels is needed in order to mitigate thrombosis formation in at-risk patients. In this Perspective, we categorize our current understanding of CAC into three main pathological mechanisms: first, vascular endothelial cell dysfunction; second, a hyper-inflammatory immune response; and last, hypercoagulability. Furthermore, we pose key questions and identify research gaps that need to be addressed to better understand CAC, facilitate improved diagnostics and aid in therapeutic development. Finally, we consider the suitability of different animal models to study CAC.

1772

CaV200

Mirawati, D. K., Budianto, P., Danuaji, R., Subandi, S., Ristinawati, I., & Prabaningtyas, H. R.

Long-COVID neurological symptoms are associated with D-dimer levels in COVID-19 patients

https://doi.org/10.18051/UnivMed.2022.v41.169-175

Published

13-Aug-22

Study

https://univmed.org/ejurnal/index.php/medicina/article/view/1246

Background
Coronavirus disease 2019 (COVID-19) is a disease designated as a global pandemic by the WHO that can manifest clinically as neurological disorders that can occur in the acute phase or after the acute phase (long COVID-19), such as headache, myalgia, anosmia, and cognitive impairment. These neurological disorders as symptoms of long COVID-19 are presumably caused by hypercoagulable conditions characterized by an increase in D-dimer level. This study aims to determine the correlation of long COVID-19 neurological symptoms with hypercoagulable conditions and the role of D-dimer as a biomarker of long COVID-19 neurological symptoms.
Methods
This was a cross-sectional study involving 31 patients with long COVID-19 symptoms. Admitted long COVID-19 cases with recorded D-dimer levels and definitive outcomes were included consecutively. Long COVID-19 neurological symptoms were collected. D-dimer level was measured using immunofluorescence assay and reported in fibrinogen equivalent units (ìg/mL). The correlation between D-dimer levels and neurological clinical manifestations was assessed by using ordinal regression analysis. The p-value of <0.05 was considered statistically significant.
Results
The mean age of the subjects was 38.81 ± 11.58 years and 18 (58.06%) were female. Long COVID neurological symptoms comprised myalgia, anosmia and cephalgia, and most subjects complained of myalgia (80.65%). On multivariable analysis, long-COVID-19 neurological symptoms were significantly correlated with D-dimer [odds ratio (OR) = 1.05; p=0.020].
Conclusion
The number of neurological long COVID symptoms were significantly correlated with level of D-Dimer. Ultimately, more clarity is needed on the neurological impact of COVID-19, its diagnosis, and its treatment.

1773

CaV201

Sebastián Garcia-Zamora, José M. Picco, Augusto J. Lepori, Marcela I. Galello, Ariel K. Saad, Miguel Ayón, Nancy Monga-Aguilar, Issam Shehadeh, Carlos F. Manganiello, Cintia Izaguirre, Luciano N. Fallabrino, Matias Clavero, Flavia Mansur, Sebastián Ghibaudo, Daniela Sevilla, Cesar A. Cado, Mauricio Priotti, Kiera Liblik, Natalio Gastaldello & Pablo M. Merlo

Abnormal echocardiographic findings after COVID-19 infection: a multicenter registry

https://doi.org/10.1007/s10554-022-02706-9

Published

13-Aug-22

Study

https://link.springer.com/article/10.1007/s10554-022-02706-9

The Coronavirus Disease 2019 (COVID-19) pandemic has transformed health systems worldwide. There is conflicting data regarding the degree of cardiovascular involvement following infection. A registry was designed to evaluate the prevalence of echocardiographic abnormalities in adults recovered from COVID-19. We prospectively evaluated 595 participants (mean age 45.5 ± 14.9 years; 50.8% female) from 10 institutions in Argentina and Brazil. Median time between infection and evaluation was two months, and 82.5% of participants were not hospitalized for their infection. Echocardiographic studies were conducted with General Electric equipment; 2DE imaging and global longitudinal strain (GLS) of both ventricles were performed. A total of 61.7% of the participants denied relevant cardiovascular history and 41.8% had prolonged symptoms after resolution of COVID-19 infection. Mean left ventricular ejection fraction (LVEF) was 61.0 ± 5.5% overall. In patients without prior comorbidities, 8.2% had some echocardiographic abnormality: 5.7% had reduced GLS, 3.0% had a LVEF below normal range, and 1.1% had wall motion abnormalities. The right ventricle (RV) was dilated in 1.6% of participants, 3.1% had a reduced GLS, and 0.27% had reduced RV function. Mild pericardial effusion was observed in 0.82% of participants. Male patients were more likely to have new echocardiographic abnormalities (OR 2.82, p = 0.002). Time elapsed since infection resolution (p = 0.245), presence of symptoms (p = 0.927), or history of hospitalization during infection (p = 0.671) did not have any correlation with echocardiographic abnormalities. Cardiovascular abnormalities after COVID-19 infection are rare and usually mild, especially following mild infection, being a low GLS of left and right ventricle, the most common ones in our registry. Post COVID cardiac abnormalities may be more frequent among males.

1774

CaV202

Helen Fogarty,Soracha E. Ward,Liam Townsend,Ellie Karampini,Stephanie Elliott,Niall Conlon,Jean Dunne,Rachel Kiersey,Aifric Naughton,Mary Gardiner,Aisling M. Rehill,Ross I. Baker,Cliona Ni Cheallaigh,James S. O'Donnell,

Sustained VWF-ADAMTS-13 axis imbalance and endotheliopathy in long COVID syndrome is related to immune dysfunction

https://doi.org/10.1111/jth.15830

Published

25-Jul-22

Study

https://onlinelibrary.wiley.com/doi/10.1111/jth.15830

Background
Prolonged recovery is common after acute SARS-CoV-2 infection; however, the pathophysiological mechanisms underpinning Long COVID syndrome remain unknown. VWF/ADAMTS-13 imbalance, dysregulated angiogenesis, and immunothrombosis are hallmarks of acute COVID-19. We hypothesized that VWF/ADAMTS-13 imbalance persists in convalescence together with endothelial cell (EC) activation and angiogenic disturbance. Additionally, we postulate that ongoing immune cell dysfunction may be linked to sustained EC and coagulation activation.
Patients and methods
Fifty patients were reviewed at a minimum of 6 weeks following acute COVID-19. ADAMTS-13, Weibel Palade Body (WPB) proteins, and angiogenesis-related proteins were assessed and clinical evaluation and immunophenotyping performed. Comparisons were made with healthy controls (n = 20) and acute COVID-19 patients (n = 36).
Results
ADAMTS-13 levels were reduced (p = 0.009) and the VWF-ADAMTS-13 ratio was increased in convalescence (p = 0.0004). Levels of platelet factor 4 (PF4), a putative protector of VWF, were also elevated (p = 0.0001). A non-significant increase in WPB proteins Angiopoietin-2 (Ang-2) and Osteoprotegerin (OPG) was observed in convalescent patients and WPB markers correlated with EC parameters. Enhanced expression of 21 angiogenesis-related proteins was observed in convalescent COVID-19. Finally, immunophenotyping revealed significantly elevated intermediate monocytes and activated CD4+ and CD8+ T cells in convalescence, which correlated with thrombin generation and endotheliopathy markers, respectively.
Conclusion
Our data provide insights into sustained EC activation, dysregulated angiogenesis, and VWF/ADAMTS-13 axis imbalance in convalescent COVID-19. In keeping with the pivotal role of immunothrombosis in acute COVID-19, our findings support the hypothesis that abnormal T cell and monocyte populations may be important in the context of persistent EC activation and hemostatic dysfunction during convalescence.
Essentials
- Reduced plasma ADAMTS-13 levels and an increased VWF/ADAMTS13 ratio are common in convalescentCOVID-19 patients.
- Levels of Platelet Factor 4, a putative VWF protector, are elevated in convalescent COVID-19 patients compared to healthy controls.
- Elevated levels of pro-angiogenic proteins, including Weibel Palade Body constituents Angiopoietin-2 and Osteoprotegerin, are observed in a subset of patients.
- Intermediate monocytes and activated CD4+ and CD8+ T cell subsets are increased in convalescent COVID-19 and correlate with thrombin generation and endotheliopathy markers, respectively.

1775

CaV203

Saima May Sidik

Heart disease after COVID: what the data say

Published

2-Aug-22

Editorial

https://www.nature.com/articles/d41586-022-02074-3

Some studies suggest that the risk of cardiovascular problems, such as a heart attack or stroke, remains high even many months after a SARS-CoV-2 infection clears up. Researchers are starting to pin down the frequency of these issues and what is causing the damage.

1776

CaV204

Ahmed Ibrahim Ahmed, Jean Michel Saad, Yushui Han, Fares Alahdab, Maan Malahfji, Faisal Nabi, John J. Mahmarian, John P. Cooke, William A. Zoghbi, and Mouaz H. Al-Mallah

Coronary Microvascular Health in Patients With Prior COVID-19 Infection: IMPLICATIONS FOR LONG-COVID SYNDROME

https://doi.org/10.1016/j.jcmg.2022.07.006

Published

17-Aug-22

Study

https://www.jacc.org/doi/10.1016/j.jcmg.2022.07.006

Background: SARS-CoV-2 infection has been shown to directly infect coronary vascular endothelium, causing inflammation and plaque instability. We aimed to assess the vascular health of patients with prior COVID-19 using Positron emission tomography (PET) derived coronary flow reserve (CFR). Methods: A prospective cohort of consecutive patients with PCR confirmed prior COVID-19 infection undergoing clinically indicated PET myocardial perfusion imaging were included and compared to patients with no prior COVID19. CFR was determined by PET and microvascular dysfunction (CMD) was defined as CFR<2. Results: The study population consisted of 2316 patients (4.4% prior COVID 19, 52% male, mean age 67±12 years, 55% hypertensive, 32% diabetic, 41% dyslipidemia). The mean duration between COVID19 diagnosis and PET was 191 (±131) days. CMD was more prevalent in those with prior COVID19 (58% vs 46%, p=0.012). After adjusting for baseline and clinical characteristics, patients with prior COVID19 had statistically significant higher odds of CMD (OR 1.8, p=0.008). Results were consistent in subgroups of patients with no clinical risk factors and normal stress tests. Conclusion: Our analysis shows that patients with prior COVID19 have higher rates of CMD. This may in part explain the long-COVID symptoms. The prognostic implications of these findings need to be determined.

1777

CaV205

VP

Vaughn Craddock, Aatish Mahajan, Balaji Krishnamachary, Leslie Spikes, Prabhakar Chalise, View ORCID ProfileNavneet K. Dhillon

Persistent Presence of Spike protein and Viral RNA in the Circulation of Individuals with Post-Acute Sequelae of COVID-19

https://doi.org/10.1101/2022.08.07.22278520

pre-print

9-Aug-22

Study

https://www.medrxiv.org/content/10.1101/2022.08.07.22278520v1.full-text

SARS-CoV-2, the causative agent of COVID-19 disease has resulted in the death of millions worldwide since the beginning of the pandemic in December 2019. While much progress has been made to understand acute manifestations of SARS-CoV-2 infection, less is known about post-acute sequelae of COVID-19 (PASC). We investigated the levels of circulating SARS-CoV-2 components, Spike protein and viral RNA, in patients hospitalized with acute COVID-19 and in patients with and without PASC. In hospitalized patients with acute COVID-19 (n=116), we observed a positive correlation of Spike protein with D-dimer, length of hospitalization, and peak WHO score while viral RNA correlated with a tissue injury marker, lactate dehydrogenase (LDH). When comparing patients with post-COVID symptoms (n=33) and patients without (n=14), we found that Spike protein and viral RNA were more likely to be present in patients with PASC and in some cases at higher levels compared to acute COVID-19 patients. We also observed that the percent positivity of circulating viral RNA increased in the PASC positive individuals compared to acute COVID-19 group while Spike protein positivity remained the same. Additionally, we report that part of the circulating Spike protein is linked to extracellular vesicles without any presence of viral RNA in these vesicles. In conclusion, our findings suggest that Spike protein and/or viral RNA fragments persist in the recovered COVID-19 patients with PASC, regardless of their presence or absence during the acute COVID-19 phase. These results may help in understanding the reason(s) for why patients experience PASC symptoms and may offer potential therapeutic targets.

1778

CaV206

VP

Manuela De Michele, Giulia d’Amati, Martina Leopizzi, Marta Iacobucci, Irene Berto, Svetlana Lorenzano, Laura Mazzuti, Ombretta Turriziani, Oscar G. Schiavo & Danilo Toni

Evidence of SARS-CoV-2 spike protein on retrieved thrombi from COVID-19 patients

https://doi.org/10.1186/s13045-022-01329-w

Published

16-Aug-22

Study

https://jhoonline.biomedcentral.com/articles/10.1186/s13045-022-01329-w

The pathophysiology of COVID-19-associated coagulopathy is complex and not fully understood. SARS-CoV-2 spike protein (SP) may activate platelets and interact with fibrin(ogen). We aimed to investigate whether isolated SP can be present in clots retrieved in COVID-19 patients with acute ischemic stroke (by mechanical thrombectomy) and myocardial infarction. In this pilot study, we could detect SP, but not nucleocapsid protein, on platelets of COVID-19 patients’ thrombi. In addition, in all three COVID-19 thrombi analyzed for molecular biology, no SARS-CoV-2 RNA could be detected by real-time polymerase chain reaction. These data could support the hypothesis that free SP, besides the whole virus, may be the trigger of platelet activation and clot formation in COVID-19.

1779

CaV207

Jasimuddin Ahamed1 and Jeffrey Laurence2

Long COVID endotheliopathy: hypothesized mechanisms and potential therapeutic approaches

https://doi.org/10.1172/JCI161167

Published

1-Aug-22

Review

https://www.jci.org/articles/view/161167

SARS-CoV-2–infected individuals may suffer a multi–organ system disorder known as “long COVID” or post-acute sequelae of SARS-CoV-2 infection (PASC). There are no standard treatments, the pathophysiology is unknown, and incidence varies by clinical phenotype. Acute COVID-19 correlates with biomarkers of systemic inflammation, hypercoagulability, and comorbidities that are less prominent in PASC. Macrovessel thrombosis, a hallmark of acute COVID-19, is less frequent in PASC. Female sex at birth is associated with reduced risk for acute COVID-19 progression, but with increased risk of PASC. Persistent microvascular endotheliopathy associated with cryptic SARS-CoV-2 tissue reservoirs has been implicated in PASC pathology. Autoantibodies, localized inflammation, and reactivation of latent pathogens may also be involved, potentially leading to microvascular thrombosis, as documented in multiple PASC tissues. Diagnostic assays illuminating possible therapeutic targets are discussed.

1780

CaV208

Cheng-I. Wu, MD
Peter J. Schwartz, MD, FHRS
Michael J. Ackerman, MD, PhD
Arthur A.M. Wilde, MD, PhD, FHRS

COVID-19 vaccination in patients with long QT syndrome

https://doi.org/10.1016/j.hroo.2022.07.011

Published

2-Aug-22

Article

https://www.heartrhythmopen.com/article/S2666-5018(22)00168-4/fulltext

Patients with long QT syndrome (LQTS) face potential threats from COVID-19 vaccination. Fever is one of the issues that is not uncommon after vaccination, and it usually takes place within 2 days. In particular, patients with type 2 LQTS based on trafficking-deficient variants are probably vulnerable to arrhythmogenicity under febrile conditions. Furthermore, myocarditis is one of the rare complications that is possibly associated with acquired QT prolongation and puts patients with LQTS at risk of life-threatening arrhythmia. Moreover, postural orthostatic tachycardia syndrome is another rare condition that, perhaps, poses LQTS patients susceptible to life-threatening arrhythmia when QT interval does not shorten optimally during tachycardia. In this review, we recommended prudent measurements to beneficially reduce the risk for patients with LQTS when vaccination or booster doses are eligible.
Key Findings
▪Patients with type 2 long QT syndrome (LQTS) are probably vulnerable to arrhythmogenicity under febrile conditions.
▪In the extremely rare event that an LQTS patient experiences myocarditis following either the infection itself or the vaccination, monitoring the QTc seems a reasonable precaution.
▪If patients with type 1 LQTS have any sign of postural orthostatic tachycardia syndrome after COVID-19 vaccination, monitoring the electrocardiogram may be reasonable in the initial phase.

1781

CaV209

Timothy L Wiemken, Ph.D, Leah J McGrath, Ph.D, Kathleen M Andersen, Ph.D, Farid Khan, MPH, Deepa Malhotra, MS MBA, Tamuno Alfred, Ph.D, Jennifer L Nguyen, ScD MPH, Laura Puzniak, Ph.D, Elizabeth Thoburn, MPH, Luis Jodar, Ph.D, John M McLaughlin, PhD

COVID-19 severity and risk of subsequent cardiovascular events

https://doi.org/10.1093/cid/ciac661

Published

19-Aug-22

Study

https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac661/6671924

Background
Little is known about the relationship between COVID-19 severity and subsequent risk of experiencing a cardiovascular event (CVE) after COVID-19 recovery. We evaluated this relationship in a large cohort of US adults.
Methods
Using a claims database, we performed a retrospective cohort study of adults diagnosed with COVID-19 between April 1, 2020 and May 31, 2021. We evaluated the association between COVID-19 severity and risk of CVE >30 days after COVID-19 diagnosis using inverse probability of treatment weighted competing risks regression. Severity was based on level of care required for COVID-19 treatment: intensive care unit (ICU) admission, non-ICU hospitalization, or outpatient care only.
Results
1,357,518 COVID-19 patients were included (2% ICU, 3% non-ICU hospitalization, and 95% outpatient only). Compared to outpatients, there was an increased risk of any CVE for patients requiring ICU admission (adjusted hazard ratio [HR]: 1.80 [95%CI: 1.71−1.89]) or non-ICU hospitalization (HR: 1.28 [1.24−1.33]). Risk of subsequent hospitalization for CVE was even higher (HR: 3.47 [3.20–3.76] for ICU and HR: 1.96 [1.85–2.09] for non-ICU hospitalized vs. outpatient only).
Conclusions
COVID-19 patients hospitalized or requiring critical care had a significantly higher risk of experiencing and being hospitalized for post-COVID-19 CVE than patients with milder COVID-19 who were managed solely in the outpatient setting even after adjusting for differences between these groups. These findings underscore the continued importance of preventing SARS-CoV-2 infection from progressing to severe illness to reduce potential long-term cardiovascular complications.

1782

CaV210

Georgios Mavraganis,Maria-Angeliki Dimopoulou,Dimitrios Delialis,Dimitrios Bampatsias,Raphael Patras,Alexandros Sianis,Eleni Maneta,Kimon Stamatelopoulos,Georgios Georgiopoulos

Clinical implications of vascular dysfunction in acute and convalescent COVID-19: a systematic review

https://doi.org/10.1111/eci.13859

Published

20-Aug-22

Systematic Review

https://onlinelibrary.wiley.com/doi/abs/10.1111/eci.13859

Background
Accumulating evidence suggests that endothelial dysfunction is implicated in the pathogenesis and severity of coronavirus disease 2019 (COVID-19). In this context, vascular impairment in COVID-19 might be associated with clinical manifestations and could refine risk stratification in these patients.
Methods
This systematic review aims to synthesize current evidence on the frequency and the prognostic value of vascular dysfunction during acute and post-recovery COVID-19. After systematically searching the MEDLINE, clinicaltrials.gov and the Cochrane Library from 1/12/19 until 05/03/22, we identified 24 eligible studies with laboratory confirmed COVID-19 and a thorough examination of vascular function. Flow mediated dilation (FMD) was assessed in 5 and 12 studies in acute and post-recovery phase respectively; pulse wave velocity (PWV) was the marker of interest in 3 studies in the acute and 4 studies in the post-recovery phase.
Results
All studies except for one in the acute and in the post-recovery phase showed positive association between vascular dysfunction and COVID-19 infection. Endothelial dysfunction in 2 studies and increased arterial stiffness in 3 studies were related to inferior survival in COVID-19.
Discussion
Overall, a detrimental effect of COVID-19 on markers of endothelial function and arterial stiffness that could persist even for months after the resolution of the infection and provide prognostic value was congruent across published studies. Further research is warranted to elucidate clinical implications of this association.

1783

CaV211

Narendra N. Khanna,Mahesh Maindarkar,Anudeep Puvvula,Sudip Paul ,Mrinalini Bhagawati ,Puneet Ahluwalia,Zoltan Ruzsa ,Aditya Sharma Smiksha Munjral,Raghu Kolluri,Padukone R. Krishnan,Inder M. Singh,John R. Laird,Mostafa Fatemi ,Azra Alizad,Surinder K. Dhanjil,Luca Saba,Antonella Balestrieri,Gavino Faa ,Kosmas I. Paraskevas

Vascular Implications of COVID-19: Role of Radiological Imaging, Artificial Intelligence, and Tissue Characterization: A Special Report

https://doi.org/10.3390/jcdd9080268

Published

15-Aug-22

Study

https://www.mdpi.com/2308-3425/9/8/268/htm

The SARS-CoV-2 virus has caused a pandemic, infecting nearly 80 million people worldwide, with mortality exceeding six million. The average survival span is just 14 days from the time the symptoms become aggressive. The present study delineates the deep-driven vascular damage in the pulmonary, renal, coronary, and carotid vessels due to SARS-CoV-2. This special report addresses an important gap in the literature in understanding (i) the pathophysiology of vascular damage and the role of medical imaging in the visualization of the damage caused by SARS-CoV-2, and (ii) further understanding the severity of COVID-19 using artificial intelligence (AI)-based tissue characterization (TC). PRISMA was used to select 296 studies for AI-based TC. Radiological imaging techniques such as magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound were selected for imaging of the vasculature infected by COVID-19. Four kinds of hypotheses are presented for showing the vascular damage in radiological images due to COVID-19. Three kinds of AI models, namely, machine learning, deep learning, and transfer learning, are used for TC. Further, the study presents recommendations for improving AI-based architectures for vascular studies. We conclude that the process of vascular damage due to COVID-19 has similarities across vessel types, even though it results in multi-organ dysfunction. Although the mortality rate is ~2% of those infected, the long-term effect of COVID-19 needs monitoring to avoid deaths. AI seems to be penetrating the health care industry at warp speed, and we expect to see an emerging role in patient care, reduce the mortality and morbidity rate.

1784

CaV212

Jyotpal Singh,Lanishen Bhagaloo,Eric Sy,Andrea J. Lavoie,Payam Dehghani,Holly A. Bardutz,Cameron S. Mang,Josef Buttigieg,J. Patrick Neary

Cardiac impairments in postacute COVID-19 with sustained symptoms: A review of the literature and proof of concept

https://doi.org/10.14814/phy2.15430

Published

22-Aug-22

Review

https://physoc.onlinelibrary.wiley.com/doi/10.14814/phy2.15430

Although acute COVID-19 is known to cause cardiac damage in some cases, there is still much to learn about the duration and relative permanence of the damage that may occur. Long COVID is a condition that can occur when COVID-19 symptoms remain in the postviral acute period. Varying accounts of long COVID have been described across the literature, however, cardiac impairments are sustained in many individuals and cardiovascular assessment is now considered to be an expected follow-up examination. The purpose of this review and proof of concept is to summarize the current research related to the assessment of cardiac function, including echocardiography and blood biomarker data, during the follow-up period in patients who recovered from COVID-19. Following a literature review, it was found that right ventricular dysfunction along with global longitudinal strain and diastolic dysfunction are common findings. Finally, more severe acute myocardial injury during the index hospitalization appears to exacerbate cardiac function. The available literature implies that cardiac function must be monitored in patients recovered from COVID-19 who remain symptomatic and that the impairments and severity vary from person-to-person. The proof-of-concept analysis of patients with cardiac disease and respiratory disease in comparison to those with sustained symptoms from COVID-19 suggests elevated systolic time interval in those with sustained symptoms from COVID-19, thus reducing heart performance indices. Future research must consider the details of cardiac complications during the acute infection period and relate this to the cardiac function in patients with long COVID during mid- and long-term follow-up.

1785

CaV213

Ignas Badaras and Agnė Laučytė-Cibulskienė

Vascular Aging and COVID-19

https://doi.org/10.1177/00033197221121007

Published

28-Aug-22

Article

https://journals.sagepub.com/doi/full/10.1177/00033197221121007

Vascular age is determined by functional and structural changes in the arterial wall. When measured by its proxy, pulse wave velocity, it has been shown to predict cardiovascular and total mortality. Disconcordance between chronological and vascular age might represent better or worse vascular health. Cell senescence is caused by oxidative stress and sustained cell replication. Senescent cells acquire senescence-associated secretory phenotype. Oxidative stress, endothelial dysfunction, dysregulation of coagulation and leucocyte infiltration are observed in the aging endothelium. All of these mechanisms lead to increased vascular calcification and stiffness. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can involve the vascular endothelium. It enters cells using angiotensin-converting enzyme 2 (ACE-2) receptors, which are abundant in endothelial cells. The damage this virus does to the endothelium can be direct or indirect. Indirect damage is caused by hyperinflammation. Direct damage results from effects on ACE-2 receptors. The reduction of ACE-2 levels seen during coronavirus disease 2019 (COVID-19) infection might cause vasoconstriction and oxidative stress. COVID-19 and vascular aging share some pathways. Due to the novelty of the virus, there is an urgent need for studies that investigate its long-term effects on vascular health.

1786

CaV214

Suzana E. Tanni
Carolina R. Tonon
Mariana Gatto
Gustavo A.F. Mota
Marina P. Okoshi

Post-COVID-19 syndrome: Cardiovascular manifestations

https://doi.org/10.1016/j.ijcard.2022.08.054

Published

31-Aug-22

Editorial

https://www.internationaljournalofcardiology.com/article/S0167-5273(22)01265-7/fulltext

In this issue of International Journal of Cardiology, Mahmoud et al. [[9]] present a valuable study analyzing cardiovascular changes in patients with post-acute sequelae of SARS-CoV-2 infection. The authors performed a retrospective analysis from medical records of 100 consecutive adult patients referred to the Post-COVID Cardiology Clinic at Washington University School of Medicine in St. Louis, Missouri, USA, between September 2020 and May 2021. The Clinic had been established to evaluate and treat individuals with previous or new cardiovascular symptoms following acute COVID-19. Baseline data were collected from a chart review of previous visits when available. Cardiovascular symptoms, vital signs, treatments, and follow-up were evaluated. Laboratory analyzes included inflammatory and cardiac biomarkers, electrocardiogram, Holter monitoring, and transthoracic echocardiogram (TTE).

1787

CaV215

PESE

Douglas B. Kell
ORCID logo
; Etheresia Pretorius
ORCID logo

The potential role of ischaemia–reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implications

https://doi.org/10.1042/BCJ20220154

Published

31-Aug-22

Review

https://portlandpress.com/biochemj/article/479/16/1653/231696/The-potential-role-of-ischaemia-reperfusion-injury

Ischaemia–reperfusion (I–R) injury, initiated via bursts of reactive oxygen species produced during the reoxygenation phase following hypoxia, is well known in a variety of acute circumstances. We argue here that I–R injury also underpins elements of the pathology of a variety of chronic, inflammatory diseases, including rheumatoid arthritis, ME/CFS and, our chief focus and most proximally, Long COVID. Ischaemia may be initiated via fibrin amyloid microclot blockage of capillaries, for instance as exercise is started; reperfusion is a necessary corollary when it finishes. We rehearse the mechanistic evidence for these occurrences here, in terms of their manifestation as oxidative stress, hyperinflammation, mast cell activation, the production of marker metabolites and related activities. Such microclot-based phenomena can explain both the breathlessness/fatigue and the post-exertional malaise that may be observed in these conditions, as well as many other observables. The recognition of these processes implies, mechanistically, that therapeutic benefit is potentially to be had from antioxidants, from anti-inflammatories, from iron chelators, and via suitable, safe fibrinolytics, and/or anti-clotting agents. We review the considerable existing evidence that is consistent with this, and with the biochemical mechanisms involved.

1788

CaV216

Dr. xing chang, Dr. Nur Izzah Ismail, Dr. Attaur Rahman, Prof. Dachun Xu, Prof. Renee Wan Yi Chan, Prof. Sang-Ging Ong, and Prof. SANG-BING ONG

Long COVID-19 and the heart: is cardiac mitochondria the missing link?

https://doi.org/10.1089/ars.2022.0126

Published

2-Sep-22

Article

https://www.liebertpub.com/doi/abs/10.1089/ars.2022.0126

Significance: Although COVID-19 has now gradually been categorized as an endemic, the long-term effect of COVID-19 in causing multi-organ disorders, including a perturbed cardiovascular system, is beginning to gain attention. Nonetheless, the underlying mechanism triggering post-COVID-19 cardiovascular dysfunction remains enigmatic. Are cardiac mitochondria the key to mediating cardiac dysfunction post-SARS-CoV-2 infection? Recent Advances: Cardiovascular complications post-SARS-CoV-2 infection include myocarditis, myocardial injury, microvascular injury, pericarditis, acute coronary syndrome, and arrhythmias (fast or slow). Different types of myocardial damage or reduced heart function can occur after a lung infection or lung injury. Myocardial/coronary injury or decreased cardiac function is directly associated with increased mortality after hospital discharge in patients with COVID-19. The incidence of adverse cardiovascular events increases even in recovered COVID-19 patients. Disrupted cardiac mitochondria post-infection have been postulated to lead to cardiovascular dysfunction in the COVID-19 patients. Further studies are crucial to unravel the association between SARS-CoV-2 infection, mitochondrial dysfunction and ensuing cardiovascular disorders. Critical Issues: The relationship between COVID-19 and myocardial injury or cardiovascular dysfunction has not been elucidated. In particular, the role of the cardiac mitochondria in this association remains to be determined. Future Directions: Elucidating the cause of cardiac mitochondrial dysfunction post-SARS-CoV-2 infection may allow a deeper understanding of long COVID-19 and resulting cardiovascular disorders, thus providing a potential therapeutic target

1789

CaV217

Valentina O. Puntmann, Simon Martin, Anastasia Shchendrygina, Jedrzej Hoffmann, Mame Madjiguène Ka, Eleni Giokoglu, Byambasuren Vanchin, Niels Holm, Argyro Karyou, Gerald S. Laux, Christophe Arendt, Philipp De Leuw, Kai Zacharowski, Yascha Khodamoradi, Maria J. G. T. Vehreschild, Gernot Rohde, Andreas M. Zeiher, Thomas J. Vogl, Carsten Schwenke & Eike Nagel

Long-term cardiac pathology in individuals with mild initial COVID-19 illness

https://doi.org/10.1038/s41591-022-02000-0

Published

5-Sep-22

Study

https://www.nature.com/articles/s41591-022-02000-0

Cardiac symptoms are increasingly recognized as late complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in previously well individuals with mild initial illness, but the underlying pathophysiology leading to long-term cardiac symptoms remains unclear. In this study, we conducted serial cardiac assessments in a selected population of individuals with Coronavirus Disease 2019 (COVID-19) with no previous cardiac disease or notable comorbidities by measuring blood biomarkers of heart injury or dysfunction and by performing magnetic resonance imaging. Baseline measurements from 346 individuals with COVID-19 (52% females) were obtained at a median of 109 days (interquartile range (IQR), 77–177 days) after infection, when 73% of participants reported cardiac symptoms, such as exertional dyspnea (62%), palpitations (28%), atypical chest pain (27%) and syncope (3%). Symptomatic individuals had higher heart rates and higher imaging values or contrast agent accumulation, denoting inflammatory cardiac involvement, compared to asymptomatic individuals. Structural heart disease or high levels of biomarkers of cardiac injury or dysfunction were rare in symptomatic individuals. At follow-up (329 days (IQR, 274–383 days) after infection), 57% of participants had persistent cardiac symptoms. Diffuse myocardial edema was more pronounced in participants who remained symptomatic at follow-up as compared to those who improved. Female gender and diffuse myocardial involvement on baseline imaging independently predicted the presence of cardiac symptoms at follow-up. Ongoing inflammatory cardiac involvement may, at least in part, explain the lingering cardiac symptoms in previously well individuals with mild initial COVID-19 illness.

1790

CaV218

Stefano Rigo, Vasile Urechie, Andre Diedrich, Luis E Okamoto, Italo Biaggioni and Cyndya A Shibao

Abstract 022: Impaired Parasympathetic Cardiac Modulation In Long-COVID Postural Tachycardia Syndrome

https://doi.org/10.1161/hyp.79.suppl_1.022

Published

7-Sep-22

Study

https://www.ahajournals.org/doi/abs/10.1161/hyp.79.suppl_1.022

About 1 out of 10 patients infected with Sars-CoV2 have persistent symptoms beyond 4 weeks and some of them meet diagnostic criteria for postural tachycardia syndrome (Long-COVID POTS). The pathophysiology of Long-COVID POTS is unknown, but autonomic dysfunction may play a role. We hypothesize Long-COVID POTS patients have impaired cardiovascular autonomic reflexes and cardiac sympathovagal balance. We conducted a case-control study with patients recruited from the Vanderbilt Autonomic Dysfunction Center and an historical population of healthy controls. Hemodynamic parameters were measured before and during 75° head up tilt. Supine ECG and finger blood pressure were continuously measured for spontaneous heart rate variability analysis. The Low Frequency (0.04-0.15Hz, LFRR) and High Frequency (0.15-0.4 Hz, HFRR) oscillatory modulations of sino-atrial node discharge were computed. We included 14 Long-COVID POTS patients and 15 controls matched by age (34±11 vs 28±7; p=0.09) and BMI (26.1±5.3 vs 23.0±2.6; p=0.06). As expected, the orthostatic HR increase was higher in Long-COVID POTS compared to controls (40±18 vs 21±1, p<0.05). Spectral analysis of heart rate variability in 9 patients and 15 controls (Figure) showed that Long-COVID POTS had reduced HFRR (363±420 vs 933±1000 ms2; p<0.05) and similar LFRR (798±596 vs 962±1075 ms2; p=0.68), resulting in a greater LF/HF ratio (3.7±2.9 vs 1.4±1.3; p<0.05). Patients with Long-COVID POTS have reduced markers of cardiovagal modulation, but normal cardiac sympathetic activation. Our results suggest that parasympathetic dysfunction contributes to the pathophysiology of Long-COVID POTS.

1791

CaV219

Amanda Verma,Tarun Ramayya,Anand Upadhyaya,Ines Valenta,Maureen Lyons,Jonas Marschall,Farrokh Dehdashti,Robert J. Gropler,Pamela K. Woodard,Thomas Hellmut Schindler

Post COVID-19 syndrome with impairment of flow-mediated epicardial vasodilation and flow reserve

https://doi.org/10.1111/eci.13871

Published

9-Sep-22

Study

https://onlinelibrary.wiley.com/doi/full/10.1111/eci.13871

Aims
The aim of this study is to evaluate whether post-acute sequelae of COVID-19 cardiovascular syndrome (PASC-CVS) is associated with alterations in coronary circulatory function.
Materials and Methods
In individuals with PASC-CVS but without known cardiovascular risk factors (n = 23) and in healthy controls (CON, n = 23), myocardial blood flow (MBF) was assessed with 13N-ammonia and PET/CT in mL/g/min during regadenoson-stimulated hyperemia, at rest, and the global myocardial flow reserve (MFR) was calculated. MBF was also measured in the mid and mid-distal myocardium of the left ventricle (LV). The Δ longitudinal MBF gradient (hyperemia minus rest) as a reflection of an impairment of flow-mediated epicardial vasodilation, was calculated.
Results
Resting MBF was significantly higher in PASC-CVS than in CON (1.29 ± 0.27 vs. 1.08 ± 0.20 ml/g/min, p ≤ .024), while hyperemic MBFs did not differ significantly among groups (2.46 ± 0.53 and 2.40 ± 0.34 ml/g/min, p = .621). The MFR was significantly less in PASC-CVS than in CON (1.97 ± 0.54 vs. 2.27 ± 0.43, p ≤ .031). In addition, there was a Δ longitudinal MBF gradient in PASC-CVS, not observed in CON (−0.17 ± 0.18 vs. 0.04 ± 0.11 ml/g/min, p < .0001).
Conclusions
Post-acute sequelae of COVID-19 cardiovascular syndrome may be associated with an impairment of flow-mediated epicardial vasodilation, while reductions in coronary vasodilator capacity appear predominantly related to increases in resting flow in women deserving further investigations.

1792

CaV220

Miroslawa Gorecka, Nicholas Jex, Sharmaine Thirunavukarasu, Amrit Chowdhary, Joanna Corrado, Jennifer Davison, Rachel Tarrant, Ana-Maria Poenar, Noor Sharrack, Amy Parkin, Manoj Sivan, Peter P. Swoboda, Hui Xue, Vassilios Vassiliou, Peter Kellman, Sven Plein, Stephen J. Halpin, Alexander D. Simms, John P. Greenwood & Eylem Levelt

Cardiovascular magnetic resonance imaging and spectroscopy in clinical long-COVID-19 syndrome: a prospective case–control study

https://doi.org/10.1186/s12968-022-00887-9

Published

12-Sep-22

Study

https://link.springer.com/article/10.1186/s12968-022-00887-9

Background
The underlying pathophysiology of post-coronavirus disease 2019 (long-COVID-19) syndrome remains unknown, but increased cardiometabolic demand and state of mitochondrial dysfunction have emerged as candidate mechanisms. Cardiovascular magnetic resonance (CMR) provides insight into pathophysiological mechanisms underlying cardiovascular disease and 31-phosphorus CMR spectroscopy (31P-CMRS) allows non-invasive assessment of the myocardial energetic state. The main aim of the study was to assess whether long COVID-19 syndrome is associated with abnormalities of myocardial structure, function, perfusion and energy metabolism.
Methods
Prospective case–control study. A total of 20 patients with a clinical diagnosis of long COVID-19 syndrome (seropositive) and no prior underlying cardiovascular disease (CVD) and 10 matching healthy controls underwent 31P-CMRS and CMR at 3T at a single time point. All patients had been symptomatic with acute COVID-19, but none required hospital admission.
Results
Between the long COVID-19 syndrome patients and matched contemporary healthy controls there were no differences in myocardial energetics (phosphocreatine to ATP ratio), in cardiac structure (biventricular volumes), function (biventricular ejection fractions, global longitudinal strain), tissue characterization (T1 mapping and late gadolinium enhancement) or perfusion (myocardial rest and stress blood flow, myocardial perfusion reserve). One patient with long COVID-19 syndrome showed subepicardial hyperenhancement on late gadolinium enhancement imaging compatible with prior myocarditis, but no accompanying abnormality in cardiac size, function, perfusion, extracellular volume fraction, native T1, T2 or cardiac energetics.
Conclusions
In this prospective case–control study, the overwhelming majority of patients with a clinical long COVID-19 syndrome with no prior CVD did not exhibit any abnormalities in myocardial energetics, structure, function, blood flow or tissue characteristics.

1793

CaV221

Arneaux Kruger, Mare Vlok, Simone Turner, Chantelle Venter, Gert Jacobus Laubscher, Douglas B. Kell & Etheresia Pretorius

Proteomics of fibrin amyloid microclots in long COVID/post-acute sequelae of COVID-19 (PASC) shows many entrapped pro-inflammatory molecules that may also contribute to a failed fibrinolytic system

https://doi.org/10.1186/s12933-022-01623-4

Published

21-Sep-22

Study

https://cardiab.biomedcentral.com/articles/10.1186/s12933-022-01623-4

Background
Post-acute sequelae of COVID-19 (PASC), also now known as long COVID, has become a major global health and economic burden. Previously, we provided evidence that there is a significant insoluble fibrin amyloid microclot load in the circulation of individuals with long COVID, and that these microclots entrap a substantial number of inflammatory molecules, including those that might prevent clot breakdown. Scientifically, the most challenging aspect of this debilitating condition is that traditional pathology tests such as a serum CRP (C-reactive protein) may not show any significant abnormal inflammatory markers, albeit these tests measure only the soluble inflammatory molecules. Elevated, or abnormal soluble biomarkers such as IL-6, D-Dimer or fibrinogen indicate an increased risk for thrombosis or a host immune response in COVID-19. The absence of biomarkers in standard pathology tests, result in a significant amount of confusion for patients and clinicians, as patients are extremely sick or even bed-ridden but with no regular identifiable reason for their disease. Biomarkers that are currently available cannot detect the molecules present in the microclots we identified and are therefore unable to confirm their presence or the mechanisms that drive their formation.
Methods
Here we analysed the protein content of double-digested microclots of 99 long COVID patients and 29 healthy controls. The patients suffering from long COVID reported their symptoms through a questionnaire completed by themselves or their attending physician.
Results
Our long COVID cohort’s symptoms were found to be in line with global findings, where the most prevalent symptoms were constant fatigue (74%,) cognitive impairment (71%) and depression and anxiety (30%). Our most noteworthy findings were a reduced level of plasma Kallikrein compared to our controls, an increased level of platelet factor 4 (PF4) von Willebrand factor (VWF), and a marginally increased level of α-2 antiplasmin (α-2-AP). We also found a significant presence of antibodies entrapped inside these microclots.
Conclusion
Our results confirm the presence of pro-inflammatory molecules that may also contribute to a failed fibrinolysis phenomenon, which could possibly explain why individuals with long COVID suffer from chronic fatigue, dyspnoea, or cognitive impairment. In addition, significant platelet hyperactivation was noted. Hyperactivation will result in the granular content of platelets being shed into the circulation, including PF4. Overall, our results provide further evidence of both a failed fibrinolytic system in long COVID/PASC and the entrapment of many proteins whose presence might otherwise go unrecorded. These findings might have significant implications for individuals with pre-existing comorbidities, including cardiovascular disease and type 2 diabetes.

1794

CaV222

Valentina Puntmann and Eike Nagel

Lingering cardiac involvement in previously well people after mild COVID-19

https://doi.org/10.1038/s41591-022-02002-y

Published

26-Sep-22

Study

https://www.nature.com/articles/s41591-022-02002-y

Serial heart MRI scans conducted in previously well people with mild initial COVID-19 illness suggest that lingering cardiac symptoms may be explained, at least in part, by ongoing mild cardiac inflammation.

1795

CaV223

DurreAdenaSufianZaheerbRohitKumarcSwatiRajdTaibaKhaneShilpiVarshneyf

Beyond COVID-19 and SARS-CoV-2, cardiovascular outcomes of “long covid” from a pathological perspective – a look back and road ahead

https://doi.org/10.1016/j.prp.2022.154144

Published

29-Sep-22

Review

https://www.sciencedirect.com/science/article/pii/S0344033822003880

With the decrease in severity of COVID-19 there is a sense of relief in the general population. However, there has been an increased incidence of cardiovascular and other organ complications post-infection, which have raised concerns about long COVID. The term “long COVID” was first used by Perego on social media to denote the persistence of symptoms weeks or months after initial SARS-CoV-2 infection and the term ‘long haulers’ was first described by Watson and by Yong to identify post-COVID conditions. There has been an increased incidence of sudden cardiac death and MI post-COVID-19 in healthy individuals, sports persons and prominent movie stars. Potential mechanisms contributing to the pathophysiology of post-acute COVID-19 may include 1) Damage to tissues and cells that are important for blood flow, so clotting of blood is increased. 2) Persistence of fragments of virus or its sub-particles/ protein material in a wide range of body sites and, 3) an immune system gone haywire. As the majority of countries across the globe are easing coronavirus precautionary measures, there is an urgent need by health care organizations and policymakers worldwide to generate awareness by educating the public at large, about the ill effects of long-COVID and varied types of post-acute sequelae of COVID-19.

1796

CaV224

Pin Li, Yi Lee, Qasim Jehangir, Chun-Hui Lin, Geetha Krishnamoorthy, Anupam A. Sule, Abdul R. Halabi, Kiritkumar Patel, Laila Poisson & Girish B. Nair

SARS-COV-ATE risk assessment model for arterial thromboembolism in COVID-19

https://doi.org/10.1038/s41598-022-18510-3

Published

28-Sep-22

Study

https://www.nature.com/articles/s41598-022-18510-3

Patients with SARS-CoV-2 infection are at an increased risk of cardiovascular and thrombotic complications conferring an extremely poor prognosis. COVID-19 infection is known to be an independent risk factor for acute ischemic stroke and myocardial infarction (MI). We developed a risk assessment model (RAM) to stratify hospitalized COVID-19 patients for arterial thromboembolism (ATE). This multicenter, retrospective study included adult COVID-19 patients admitted between 3/1/2020 and 9/5/2021. Among 3531 patients from the training cohort, 15.5% developed acute in-hospital ATE, including stroke, MI, and other ATE, compared to 13.4% in the validation cohort. The 16-item final score was named SARS-COV-ATE (Sex: male = 1, Age [40–59 = 2, > 60 = 4], Race: non-African American = 1, Smoking = 1 and Systolic blood pressure elevation = 1, Creatinine elevation = 1; Over the range: leukocytes/lactate dehydrogenase/interleukin-6, B-type natriuretic peptide = 1, Vascular disease (cardiovascular/cerebrovascular = 1), Aspartate aminotransferase = 1, Troponin-I [> 0.04 ng/mL = 1, troponin-I > 0.09 ng/mL = 3], Electrolytes derangement [magnesium/potassium = 1]). RAM had a good discrimination (training AUC 0.777, 0.756–0.797; validation AUC 0.766, 0.741–0.790). The validation cohort was stratified as low-risk (score 0–8), intermediate-risk (score 9–13), and high-risk groups (score ≥ 14), with the incidence of ATE 2.4%, 12.8%, and 33.8%, respectively. Our novel prediction model based on 16 standardized, commonly available parameters showed good performance in identifying COVID-19 patients at risk for ATE on admission.

1797

CaV225

ManuelSerranoaGerardEspinosabAntonioSerranoaRicardCerverab

COVID-19 and the antiphospholipid syndrome

https://doi.org/10.1016/j.autrev.2022.103206

Published

3-Oct-22

Review

https://www.sciencedirect.com/science/article/pii/S1568997222001768

Highlights
•Coagulopathy secondary to COVID-19 occurs in the context of an uncontrolled inflammatory response, reminiscent of APS, especially in its catastrophic form.
•During the first days of infection, there is an aPL-independent mechanism secondary to SARS-CoV2 infection.
•The aPL carriers would have an additional later risk of thrombosis.
Abstract
Coronavirus disease 2019 (COVID-19) has resulted in a global pandemic. Most COVID-19 patients are asymptomatic or have flu-like symptoms. However, around 15% of the patients may have severe disease, including unilateral or bilateral pneumonia with acute respiratory distress syndrome and progressive hypoxemia that may require mechanical ventilation assistance. A systemic inflammatory response syndrome occurs in the most severe forms of COVID-19, with multiorgan involvement which can be life threatening caused by a cytokine storm. Although what best characterizes COVID-19 are the manifestations of the respiratory system, it has been shown that it also acts at the cardiovascular level, producing coagulation abnormalities, which causes thrombotic events mainly in the arteries/arterioles, microcirculation and venous system, and potentially increased mortality risk. This multiorgan vascular disease overlaps with other known microangiopathies, such as thrombotic microangiopathy or paroxysmal nocturnal hemoglobinuria, where complement overactivation plays an important role in the pathophysiology of thrombosis. Furthermore, coagulopathy secondary to COVID-19 occurs in the context of an uncontrolled inflammatory response, reminiscent of APS, especially in its catastrophic form. This review summarizes the current knowledge regarding the relationship between COVID-19 and the APS.

1798

CaV226

Maitray A. Patel, Michael J. Knauer, Michael Nicholson, Mark Daley, Logan R. Van Nynatten, Claudio Martin, Eric K. Patterson, Gediminas Cepinskas, Shannon L. Seney, Verena Dobretzberger, Markus Miholits, Brian Webb & Douglas D. Fraser

Elevated vascular transformation blood biomarkers in Long-COVID indicate angiogenesis as a key pathophysiological mechanism

https://doi.org/10.1186/s10020-022-00548-8

Published

10-Oct-22

Study

https://link.springer.com/article/10.1186/s10020-022-00548-8

Background
Long-COVID is characterized by prolonged, diffuse symptoms months after acute COVID-19. Accurate diagnosis and targeted therapies for Long-COVID are lacking. We investigated vascular transformation biomarkers in Long-COVID patients.
Methods
A case–control study utilizing Long-COVID patients, one to six months (median 98.5 days) post-infection, with multiplex immunoassay measurement of sixteen blood biomarkers of vascular transformation, including ANG-1, P-SEL, MMP-1, VE-Cad, Syn-1, Endoglin, PECAM-1, VEGF-A, ICAM-1, VLA-4, E-SEL, thrombomodulin, VEGF-R2, VEGF-R3, VCAM-1 and VEGF-D.
Results
Fourteen vasculature transformation blood biomarkers were significantly elevated in Long-COVID outpatients, versus acutely ill COVID-19 inpatients and healthy controls subjects (P < 0.05). A unique two biomarker profile consisting of ANG-1/P-SEL was developed with machine learning, providing a classification accuracy for Long-COVID status of 96%. Individually, ANG-1 and P-SEL had excellent sensitivity and specificity for Long-COVID status (AUC = 1.00, P < 0.0001; validated in a secondary cohort). Specific to Long-COVID, ANG-1 levels were associated with female sex and a lack of disease interventions at follow-up (P < 0.05).
Conclusions
Long-COVID patients suffer prolonged, diffuse symptoms and poorer health. Vascular transformation blood biomarkers were significantly elevated in Long-COVID, with angiogenesis markers (ANG-1/P-SEL) providing classification accuracy of 96%. Vascular transformation blood biomarkers hold potential for diagnostics, and modulators of angiogenesis may have therapeutic efficacy.

1799

CaV227

S Lampsas, E Oikonomou, N Souvaliotis, A Goliopoulou, G A Papamikroulis, A Anastasiou, P Theofilis, G Zakynthinos, I Gialamas, P Pantelidis, M A Gounaridi, A Tsatsaragkou, G Siasos, D Tousoulis, M Vavuranakis

Impaired heart rate variability one and six months post acute COVID-19

https://doi.org/10.1093/eurheartj/ehac544.402

Published

3-Oct-22

Study

https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.402/6743966

Background
Long COVID-19 syndrome is an increasingly recognized problem. Post-infectious cardiac autonomic dysfunction is commonly reported. This study aims to evaluate autonomic dysfunction by means of Heart rate variability (HRV) on post-COVID-19 patients.
Methods
Hospitalized patients for COVID-19 (either at the medical ward or Intensive Care Unit (ICU)) were followed up at 1 and 6 months after hospital discharge. Medical history and clinical information were collected. HRV was assessed by 24-hour ambulatory electrocardiography Holter, with the measure of the standard deviation of normal RR intervals in 24 h, ms (SDNN). The comparison was conducted with age and sex-matched non-COVID-19 controls.
Results
Thirty-four patients hospitalized with COVID-19 (20.6% admitted in ICU) were examined 1-month and 6-months post-hospital discharge. SDNN was significantly (p<0.001) reduced in the COVID-19 group (111±23 ms) compared to the control subjects (152±24 ms) 1-month after discharge. Subgroup analysis between COVID-19 group revealed that ICU subjects presented significantly (p<0.001) reduced SDNN compared to the medical ward, respectively (83±20 ms vs. 118±17 ms). At 6-months, an improvement was noted at SDNN 24h (6-month: 133±24 vs. control: 151±24 ms, p=0.004; 1-month: 111±23 ms vs. 6-month: 133±24 ms, p<0.001). Also at 6-months, ICU subjects noted significantly (p=0.003) reduced SDNN 24h compared to medical ward subjects (107±17 ms vs. 140±20 ms). On the 6-months follow-up, 32% of the subjects had “long-COVID-19” symptoms. Subjects with long COVID-19 symptoms had low SDNN values (“long-COVID-19”: 112±17 ms vs. non-“long-COVID-19”: 142±20 ms, p=0.001)
Conclusion
Patients hospitalized for COVID-19 have reduced SDNN, at one month post-hospital discharge which is improved at the six months follow-up. These findings emphasize the increased sympathetic drive activity in the post-acute COVID-19 phase and imply a link between autonomic dysfunction and long COVID-19.

1800

CaV228

V Arevalos Rivas, L Ortega-Paz, D Fernandez-Rodriguez, V A Jimenez-Diaz, J Baneras Rius, G Campo, J F Diaz, C Scardino, M Rodriguez-Santamarta, N Gonzalo, A Perginotti, F Alfonso, I Amat-Santos, M Sabate, S Brugaletta

Long-term effects of coronavirus disease 2019 on the cardiovascular system: the CV COVID-19 registry

https://doi.org/10.1093/eurheartj/ehac544.2859

Published

3-Oct-22

Study

https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.2859/6745820

Background
Patients with COVID-19 have an increased risk of cardiovascular adverse events during the acute phase. However, the long-term cardiovascular outcomes are unknown.
Objective
We aimed to determine the long-term effects of COVID-19 in the cardiovascular system.
Methods
This is a multicenter, observational, retrospective registry conducted at 17 centers in Spain and Italy. Consecutive patients older than 18 years who underwent a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) for SARS-CoV2 in the participating institutions were included. Patients were classified into two groups, according to the results of the RT-PCR: COVID-19 positive or negative. The primary outcome was cardiovascular (CV) death at 1-year. The secondary outcomes included acute myocardial infarction, stroke, heart failure hospitalization, pulmonary embolism, and serious cardiac arrhythmias at 1-year. Outcomes were compared between the two groups. An independent clinical event committee adjudicated events.
Results
A total of 4427 patients were included, 3578 (80.8%) patients with COVID-19 and 849 (19.2%) without COVID-19. COVID-19 patients were older, had a higher rate of classical cardiovascular risk factors, except for active smoking, and had fewer comorbidities. At a median time of 13.5 (IQR 11.8–15.8) months, after an adjustment by baseline characteristics, there was no difference in CV death (1.4% vs. 1.1%; HR 1.03 [0.49–2.18]; p=0.941) between patients with COVID-19 and without. However, COVID-19 patients experienced higher rate of venous thromboembolism (VTE) (3.9% vs. 0.6%, HR 6.11 [2.46–15.16]; p=0.001), major bleeding (2.9% vs. 0.5%, HR 5.38 [1.95–14.84]; p=0.001), and serious cardiac arrhythmias (2.6% vs. 0.9%, HR 2.25 [1.07–4.73]; p=0.033). During follow-up, between discharge and end of follow-up, COVID-19 patients did not experience a higher risk of adverse cardiovascular outcomes (composite of CV death, any MI, ischemic stroke, systemic arterial thrombosis, VTE, heart failure hospitalization, or any serious arrhythmia) compared to patients without (HR 0.80; [0.53–1.21]; p=0.298).
Conclusions
At 1-year follow-up, COVID-19 was not associated with an increased risk of cardiovascular death but with a higher risk of VTE events, major bleeding, and serious cardiac arrhythmias. COVID-19 was not associated with a higher risk of adverse cardiovascular events during follow-up.

1801

CaV229

Suo-wen Xu, Iqra Ilyas & Jian-ping Weng

Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies

https://doi.org/10.1038/s41401-022-00998-0

Published

17-Oct-22

Review

https://www.nature.com/articles/s41401-022-00998-0

The fight against coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is still raging. However, the pathophysiology of acute and post-acute manifestations of COVID-19 (long COVID-19) is understudied. Endothelial cells are sentinels lining the innermost layer of blood vessel that gatekeep micro- and macro-vascular health by sensing pathogen/danger signals and secreting vasoactive molecules. SARS-CoV-2 infection primarily affects the pulmonary system, but accumulating evidence suggests that it also affects the pan-vasculature in the extrapulmonary systems by directly (via virus infection) or indirectly (via cytokine storm), causing endothelial dysfunction (endotheliitis, endothelialitis and endotheliopathy) and multi-organ injury. Mounting evidence suggests that SARS-CoV-2 infection leads to multiple instances of endothelial dysfunction, including reduced nitric oxide (NO) bioavailability, oxidative stress, endothelial injury, glycocalyx/barrier disruption, hyperpermeability, inflammation/leukocyte adhesion, senescence, endothelial-to-mesenchymal transition (EndoMT), hypercoagulability, thrombosis and many others. Thus, COVID-19 is deemed as a (micro)vascular and endothelial disease. Of translational relevance, several candidate drugs which are endothelial protective have been shown to improve clinical manifestations of COVID-19 patients. The purpose of this review is to provide a latest summary of biomarkers associated with endothelial cell activation in COVID-19 and offer mechanistic insights into the molecular basis of endothelial activation/dysfunction in macro- and micro-vasculature of COVID-19 patients. We envisage further development of cellular models and suitable animal models mimicking endothelial dysfunction aspect of COVID-19 being able to accelerate the discovery of new drugs targeting endothelial dysfunction in pan-vasculature from COVID-19 patients.

1802

CaV230

F Santoro, N Di Nunno, A Centola, R Cetera, V Le Rose, J Perez-Villacastin, A Fernandez-Ortiz, I Nunez Gil, N D Brunetti

Long-term mayor adverse cardiovascular events after COVID-19 infection: a clinical score from a cohort of 2575 patients enrolled in the multicenter international HOPE 2 registry

https://doi.org/10.1093/eurheartj/ehac544.1334

Published

3-Oct-22

Study

https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.1334/6744487

Background
Long-term consequences of COVID-19 infection are still partly known. According to some studies several patients may experience long term symptoms; however, predictors of long-term mayor adverse cardiovascular events among (MACE) patients with previous COVID-19 infection are .
Aim of the study
To derive a simple clinical score for risk prediction of long-term MACE among patients with previous covid-19 infection.
Methods
2575 consecutive patients were enrolled in a multicenter, international registry (HOPE-2) from February 2020 to April 2021, and followed-up at long-term. A risk score was developed using a stepwise multivariable regression analysis.
Results
Out of 2575 patients enrolled in the HOPE-2 registry, 1481 (58%) were male, with mean age of 60±16 years. At long-term follow-up overall rate of MACE was 7.9% (202 of 2545 pts, 3.3% death, 2.4% inflammatory myocardial disease, 1.3% arterial thrombosis, 0.7% venous thrombosis). After multivariable regression analysis, independent predictors of MACE were used to derive a simple prognostic score: The HOPE-2 prognostic score may be calculated by giving: ½ point for every 10 years of age, 2 points for previous cardiovascular disease, 1 point for increased troponin serum levels during hospitalization, 2.5 points for heart failure and 3 points for sepsis during hospitalization, −1.5 points for vaccination at follow-up. Score accuracy at receiver operating characteristic curve analysis was 0.81.
Stratification into 3 risk groups (0–2, 3–5, and >5 points) classified into low, intermediate and high risk. The observed MACE rates were 0.5% for low-risk patients, 4% for intermediate-risk patients, and 19.5% for high-risk patients (log-Rank p<0.001, Figure 1).
Conclusions
The HOPE-2 prognostic score may be useful for long-term risk stratification in patients with previous COVID-19 infection. High-risk patients may require a strict cardiological follow-up.

1803

CaV231

M Camera, M Brambilla, P Canzano, A Becchetti, M Conti, P G Agostoni, M Pengo, E Tortorici, M E Mancini, D Andreini, A Bonomi, G F Parati

Long COVID-19 syndrome: association of cardiopulmonary impairment with a persistent platelet activation

https://doi.org/10.1093/eurheartj/ehac544.3038

Published

3-Oct-22

Study

https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.3038/6746301

Background
A considerable proportion of patients do not fully recover from COVID-19 infection and report symptoms that persist beyond the initial phase of infection: this condition is defined long-COVID-19 syndrome (LCS). LCS can involve lungs as well as several extrapulmonary organs, including the cardiovascular system. The risk and 1-year burden of cardiovascular diseases (CVD) is increased in COVID-19 survivors, even in subjects at low risk of CVD. Recently, we documented that acute COVID-19 infection induces altered platelet activation state characterized by a prothrombotic phenotype and by the formation of platelet-leukocyte aggregates (PLA), that may be involved in the pulmonary microthrombi found in autoptic specimens. No data are yet available on the contribution of platelet activation to residual pulmonary impairment and procoagulant potential in LCS patients.
Purpose
To study platelet activation status, microvesicle (MV) profile, platelet thrombin generation capacity (pTGC) in LCS patients enrolled at 6 months after resolution of the acute phase (6mo-FU), compared to acute COVID-19 infection patients.
Methods
6mo-FU COVID-19 patients (n=24) with established LCS were enrolled at Centro Cardiologico Monzino. Residual pulmonary impairment was assessed by Cardiopulmonary Exercise Testing (CPET) and 64-rows-CT scan evaluation. Platelet activation (P-selectin, Tissue Factor [TF] and PLA) and MV profile were assessed by flow cytometry; pTGC by calibrated automated thrombogram. 46 patients enrolled during acute COVID-19 infection and 46 healthy subjects (HS) were used for comparison.
Results
Dispnea in LCS patients was confirmed by CPET showing compromised alveolus-capillary membrane diffusion and residual pulmonary impairment. TF+-platelet and -MV levels were 3-fold (1.5% [1.2–2.9] vs 2.4% [1.6–5.7]) and 2-fold (217/μl [137–275] vs 435/μl [275–633]) lower at 6mo-FU compared to acute phase, being comparable to HS. pTGC behaved similarly. At 6mo-FU, the MV profile, in terms of total number and cell origin, returned to physiological levels. Conversely, although lower than that measured in acute phase, a 2.5-fold higher platelet P-selectin expression (6.9% [3–13.5] vs 11.7% [5.2–18.9]) and PLA formation (35.5% [27.4–46.8] vs 67.7% [45.7–85.3]) was observed at 6mo-FU compared to HS. Interestingly, a significant correlation between PLA formation and residual pulmonary impairment was observed (r=−0.423; p=0.02).
Conclusion
These data strengthen the hypothesis that the presence of PLA in the bloodstream, and thus also in the pulmonary microcirculation, may contribute to support pulmonary dysfunction still observed in LCS patients.

1804

CaV232

R A Xuereb, A Gatt, K Vella, R G Xuereb, C J Barbara, S Fava, C J Magri

Long COVID syndrome: a case-control study

https://doi.org/10.1093/eurheartj/ehac544.2836

Published

3-Oct-22

Study

https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.2836/6745876

Background
Cardiovascular complications are rapidly emerging as a major threat in COVID-19 infection. Nonetheless, the mechanisms underlying the disproportionate effect of SARS-CoV-2 infection on patients with cardiovascular comorbidities remain incompletely understood.
Purpose
To assess whether COVID-19 infection has an adverse clinical outcome at medium-term follow-up.
Methods
A case-control study was performed. Cases were subjects who were diagnosed with COVID-19 infection following nasopharyhngeal swabbing. Controls were age- and gender-matched subjects who were not found to be infected with COVID-19 following swabbing and were negative on testing for COVID-19 IgG antibodies. All participants were submitted a standardised questionnaire regarding past medical history. Baseline blood investigations were taken including N-terminal pro–B-type natriuretic peptide (NT-proBNP) and troponin levels. High-sensitivity C-reactive protein (hsCRP) was taken as marker of inflammation and von Willebrand factor (vWF) was taken as marker of endothelial dysfunction.
Results
270 subjects were recruited, comprising 174 cases and 96 controls. Of the latter, 21 were found to be COVID-19 IgG positive and were excluded from the analysis. Hence, the study cohort comprised 174 cases and 75 controls. The mean age of the participants was 46.1±13.8 years. The median follow-up was of 173.5 days (IQR 129–193.25 days). There was no statistically significant difference in the baseline demographics between cases and controls with regards age, gender as well as cardiovascular risk factors and underlying medical conditions. Regarding symptomatology at follow-up, there was a statistically significant difference between the groups in deterioration in general condition (p<0.001), shortness of breath (SOB) (p=0.008), fatigue (p=0.044), arthralgia (p<0.001), abnormal taste (p<0.001) and anosmia (p<0.001), all being more frequent in subjects with prior COVID-19 infection. At follow-up, the blood investigations showed that only hsCRP was statistically significantly higher in the cases as compared to the controls (p=0.03, Figure 1). Correlation analysis consequently revealed a negative correlation in both troponin (p=0.013, r=−0.19) and vWF levels (p=0.026, r=−0.169) with time. Finally, the association between the cases experiencing dyspnoea and the blood investigations at follow-up was assessed. Multivariate analysis revealed that COVID-19 positive cases experiencing dyspnoea have significantly higher white cell count (WCC) (OR 1.22, 95% CI 1.02–1.46, p=0.029) and troponin levels (OR 1.15, 95% CI 1.02–1.29, p=0.015) and lower haemoglobin levels at follow-up (OR 0.66, 95% CI 0.5–0.86, p<0.002), Figure 2.
Conclusion
Patients previously infected with COVID-19 have persistent symptomatology at medium-term follow-up. The role of troponin, together with markers of inflammation and endothelial dysfunction at long-term follow-up merit further investigation.

1805

CaV233

P Rasmus, J D Kasprzak, M Chudzik, A Lipert

Anxiety and depression among ambulatory and hospitalized patients with cardiovascular long-COVID-19 presentation referred to cardiology consultation after COVID-19 infection

https://doi.org/10.1093/eurheartj/ehac544.2426

Published

3-Oct-22

Study

https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.2426/6746291

Introduction
COVID-19 is connected with varying degrees of emotional stress. Patients (pts) who are hospitalized with severe COVID-19 (C19) are located in single rooms without a permanent attendant to prevent contamination. All personnel serving these pts come into contact with patients with personal full-body protective garment. Ambulatory C19 pts, usually with less severe presentation, are treated in more comfortable conditions.
Purpose
To evaluate the impact of the psychosocial changing conditions on individuals' psyche and to analyse the differences in terms of experienced anxiety and depression among the ambulatory and hospital patients referred to post-C19 cardiology consultation.
Methods
The study involved 388 pts with persistent cardiovascular symptoms, including 198 ambulatory patients (130 females and 68 males) and 190 hospital patients (128 females and 62 males) referred to the cardiology consultation (mean age 4.9±12.9 and 50.5±14.4 years, respectively). The data were collected using the specially designed questionnaire related to descriptive characteristics of the patients and to standardized questionnaires: the State-Trait Anxiety Inventory (STAI) and Beck's Depression Inventory (BDI).
Results
Abnormal psychological metrics was common in the study pts. Indicators of anxiety were lower in the ambulatory than in hospitalized pts (p<0.001). Depression level was also lower in the ambulatory pts (p<0.001). The same differences were statistically significant in both female and male pts subsets. However, anxiety and depression were more pronounced among female than male pts. Very strong positive correlation was observed between anxiety - state and depression among ambulatory patients, both females and males (p<0.05).
Conclusions
C19 convalescents with persistent symptoms of presumed cardiovascular origin present with abnormal psychological traits including increased anxiety and depression especially in individuals requiring hospital treatment. For this reason, it is necessary to plan the interventions particularly in hospitalized pts to reduce their anxiety and depression levels and to create psychological support programs.

1806

CaV234

M Chudzik, M Banach, J Lewek, J Kapusta, A Bielecka-Dabrowa, P Jankowski

Independent predictors of long-COVID in patients without comorbidities. Data from the Polish long-COVID cardiovascular (PoLoCOV-CVD) study

https://doi.org/10.1093/eurheartj/ehac544.2392

Published

3-Oct-22

Study

https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.2392/6745656

Coronavirus disease 2019 (COVID-19) is a serious respiratory disease that results from infection with a newly discovered coronavirus (SARS-COV-2). Patients recovering from SARS-COV2 infection complain of persisting symptoms which may lead to chronic fatigue syndrome and as well as many other complications. The vast majority of COVID-19 patients remaining in isolation/quarantine, due to the mild course of the disease, do not require hospitalization. There are many studies describing the course and complications of patients hospitalized due to COVID-19. There is little published data on how nonhospitalized patients get sick and what are the early and late complications of SARS-CoV-2 infection. Little is also known about Long-COVID (LC) in patients without comorbidities. Therefore, the aim of our analysis was to assess the predictors of long-lasting symptoms in patients without comorbidities suffering from COVID-19.
Methods
Patients ≥18 years of age diagnosed with COVID-19, were examined after full recovery (resolution of clinical symptoms, minimum 14 days after last symptoms). Patient information, course of the disease with symptoms, post-COVID-19 complaints were collected within 4–8 weeks after the COVID-19 recovery. We followed patients for at least 3 months. Patients were ordered the following tests: 12-lead ECG, 24-hour Holter ECG monitoring, 24-hour Holter blood pressure monitoring, Echocardiographic of the Heart assessment, Biochemical tests: lipid profile, glucose or glycosylated hemoglobin level, D-dimers. In patients with indications, the following were additionally performed: Magnetic resonance imaging of the heart, Computed tomography angiography (CTA) of pulmonary vessels, Angio CT of coronary vessels or other diagnostic tests.
Results
We identified 701 consecutive patients without comorbidities of whom 488 pts completed 3 month follow-up. Comparisons were made between LC group (n=218) and non-LC group (n=270). The demographic and laboratory characteristics of the studied group are presented in Table 1. Patients with severe course of acute phase of COVID-19 developed LC more often (72 vs. 28%, p<0.001). Significant differences regarding sex, weight, height, body mass index were observed. Patients with LC more often presented with dyspnoea, significant fatigue, chest pain, leg muscle pain, headache, arthralgia and chills. No statistically significant difference was observed regarding laboratory tests, 24-hour systolic and diastolic BP and echocardiographic parameters. LC group had higher 24-hour heart rate (77 [72–83] vs. 75 [70–81], p=0.021). Multivariate regression analysis showed that LC patients had higher BMI (odds ratio 1.057, 95% confidence intervals 1.016–1.100) and almost twice as often had a severe course (1.736, 1.071–2.814) and presented with arthralgia in the acute phase (1.901, 1.225–2.950).
Conclusions
Severe course of COVID-19, BMI, and arthralgia are independently related to long-COVID in patients without comorbidities.

1807

CaV235

J Lewek, B Sosnowska, W Adach, K Gryglewska, A Bielecka-Dabrowa, M Maciejewski, M Banach

Post-COVID-19 cardiovascular complications and their association with clinical characteristics, symptoms and comorbidities – the LATE-COVID study

https://doi.org/10.1093/eurheartj/ehac544.2335

Published

3-Oct-22

Study

https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.2335/6746129

Background
Among many complications of coronavirus disease 2019 (COVID-19) there is a wide range of cardiovascular (CV) problems ranging from mild to severe ones. Even asymptomatic patients and those with mild course of COVID-19 may develop severe CV complications. Factors leading to such state have not been extensively studied so far.
Purpose
We aimed to assess which factors were linked to the severe complications of COVID-19.
Methods
We included 200 consecutive patients admitted to the Department of Cardiology and Adult Congenital Heart Diseases of the Polish Mother's Memorial Research Institute (PMMHRI) due to post-Covid cardiovascular complications. SARS-CoV2 infection was confirmed with real-life PCR testing. Laboratory tests, 24-hour ECG monitoring and echocardiography were performed in all patients from the investigated group. For the purposes of our study severe complications were defined as: myocarditis, a decrease of ejection fraction >10% from the pre-disease value, thromboembolic complications, angina pectoris requiring myocardial revascularization and the new onset of atrial fibrillation of supraventricular tachycardia. Some patients presented more than one of the above. Statistical analysis was performed using the software Statistica v.13 (TIBCO Software Inc., Palo Alto, CA, USA). Data were presented as mean ±SD or median (25th-75th percentile) for continuous variables and as proportions for categorical variables. Comparisons between groups were performed using Student's t-test for independent variables and the Mann-Whitney U test or χ2 test with Yates's correction, as appropriate. For all calculations p-values <0.05 were considered statistically significant.
Results
Finally, we included 200 consecutive patients (aged 54±16 years, 76 males – 38%), hospitalized for COVID-19 complications after a median 3 (2–6) months following the acute phase of infection. On admission patients presented with dyspnea (23%), impairment of exercise tolerance (47%), chest pain (32%), increase in blood pressure (29%), palpitations (25%), weight loss (13%), brain fog (6%), general malaise (11%), headache (5%), limb pain (13%), swelling (14%). Severe complications of COVID-19 were diagnosed in 31 patients (16%).Taking into consideration symptoms, the presence of severe COVID-19 complications was significantly associated with dyspnoea and deterioration of exercise tolerance. In comparison to patients with mild complications, severe ones were linked to age (the older patients, the higher risk), previous history of heart failure and diabetes mellitus. We did not observe statistically significant differences in severity of complications depending on smoking status (Tables 1 and 2).
Conclusions
Previous history of heart failure and diabetes mellitus as well as symptoms (dyspnoea and deterioration of exercise tolerance) along with older age are related to more severe complications following COVID-19.

1808

CaV236

R A Xuereb, R G Xuereb, C Barbara, S Fava, C J Magri

COVID-19 and the autonomic nervous system

https://doi.org/10.1093/eurheartj/ehac544.2422

Published

3-Oct-22

Study

https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.2422/6746061

Background
COVID-19 infection has been shown to have an adverse impact on the cardiovascular system. Cardiac injury, as indicated by elevated cardiac troponin and NT-proBNP levels have been confirmed in COVID-19 cases. There is still ambivalent data on the effect of left ventricular function. Cases of left ventricular impairment, persistent hypotension, acute myopericarditis, myocarditis, arrhythmia and heart failure have been reported in the short term, but there is a significant lacuna when it comes to medium and long-term follow-up of subjects previously infected with COVID-19.
Purpose
To assess any residual myocardial and autonomic injury in subjects previously infected with COVID-19 at a median follow-up of 5 months.
Methods
A case-control study was performed. Cases were randomly selected subjects who were previously diagnosed with COVID-19 infection following nasopharyngeal swabbing. Controls were subjects who had not been found to be infected with COVID-19 following swabbing and were negative for COVID-19 IgG antibodies. All participants were submitted a standardised questionnaire regarding past medical history. Blood investigations were taken including NT-proBNP and troponin I levels. In addition, all participants underwent 24-hour ambulatory blood pressure monitoring (ABPM) and 24-hour ECG monitoring. The latter was used to assess both for underlying arrhythmias as well as heart rate variability (HRV), a measure of autonomic regulation of the heart. All data was analysed using SPSS version 23.0.
Results
The study comprised 259 subjects, whereby cases included 174 participants while 75 subjects were age- and gender-matched controls. The study cohort was relatively young with a mean age of 46.1±13.8 years. The median follow-up was of approximately 5 months (median 173.5 days, IQR 129–193.25 days). There was no statistically significant difference between cases and controls with regards cardiovascular risk factors and underlying medical conditions. Likewise, there was no difference in blood investigations, including troponin I and NT-proBNP levels at 5-months follow-up. No difference was noted between the two groups in both awake and asleep blood pressure (BP) readings, as well as dipping BP status. No significant arrhythmias were noted in both groups on 24-hour ECG monitoring. However, when assessing for heart rate variability, it was shown that subjects who had been previously infected with COVID-19 exhibited lower root-mean square differences of successive R-R intervals (RMSSD), p=0.028. This indicates poor vagus nerve-mediated autonomic control of the heart.
Conclusion
Subjects previously infected with COVID-19 exhibited lower HRV as exhibited by low RMSSD as compared to controls. Reduced HRV is a known biomarker for mortality and sudden death in cardiac disease. The possible long-term implications of reduced HRV in subjects previously infected with COVID-19 merits further investigation.

1809

CaV237

M L Luchian, A Motoc, B Roosens, J Magne, K Van Den Bussche, H Chameleva, T De Potter, L Houard, S Droogmans, B Cosyns

The impact of long COVID on myocardial work performance

https://doi.org/10.1093/eurheartj/ehac544.012

Published

3-Oct-22

Study

https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.012/6743492

Background
Long COVID emerged as a new condition, following the acute episode of coronavirus disease 2019 (COVID-19),exerting a significant impact on patients' quality of life [1]. Several studies involving COVID-19 survivors emphasized the presence of cardiac abnormalities following the acute infection. However, data on possible mechanisms associated to long COVID remain limited. Clinical applications of myocardial work (MW) analysis, assessed by transthoracic echocardiography (TTE) have expended recently, showing an additional value in detecting cardiac dysfunction compared to standard parameters such as left ventricle ejection fraction (LVEF) or global longitudinal strain (GLS) in various pathologies, including COVID-19 [2]. Nevertheless, its potential role in detecting subclinical cardiac dysfunction in long COVID remained unexplored.
Purpose
We assessed the association between subclinical cardiac dysfunction evaluated by global work index (GWI) and global constructive work (GCW) and long COVID.
Methods
We included 310 COVID-19 patients hospitalized between March and April 2020. All patients were invited to a systematic one-year follow-up, including clinical evaluation, TTE with MW assessment, chest-computed tomography and spirometry. 140 patients completed the follow-up. Normal values for GWI and GCW were defined as 1926±247 mmHg% and 2224±229 mmHg% [3]. The primary endpoint was long COVID, characterized by a cluster of symptoms such as fatigue or dyspnea more than 3 months after the acute infection, without any other explanation.
Results
140 patients (57.1±13.9 years, 90 (64.3%) males) had a mean follow-up of 337.1±34.5 days.The mean values of LVEF, GWI and GCW were 55.2±3.2%, 2105.9±403.3 mmHg% and 2377.8±446.2 mmHg%. 83 (61%) patients had long COVID. No significant differences in terms of comorbidities, clinical evaluation and COVID-19 severity were found between patients with and without long COVID. GCW (2276.7±410.3 vs 2516.5±458.6, p=0.006) and GWI (2008.5±358.9 vs 2242.2±427.0, p=0.003) were the only TTE parameters different between patients with and without long COVID. Multivariable regression analysis showed that GWI <1926 mmHg% (OR 6.095; CI: 2.024–18.355, p=0.001) and GCW <2224 mmHg% (OR 3.205; CI: 1.181–8.694, p=0.022) were the only MW parameters independently associated with long COVID, irrespective of age or the severity of the acute infection, at one year. In a subgroup analysis of 77 patients without previous cardiovascular diseases, long COVID was diagnosed in 45 (58.4%)patients. GWI <1926 mmHg% (OR 8.015; CI: 2.149–29.887, p=0.002) remained independently associated with long COVID at 1 year follow-up.
Conclusions
Long COVID, frequently observed in recovered COVID-19 patients may indicate the presence of subclinical cardiac dysfunction, reflected by a decrease of the left ventricle performance, assessed by GWI and GCW.Long-term follow-up including cardiac screening should be performed in order to identify patients at risk who would benefit from cardiac rehabilitation programs.

1810

CaV238

J Niebauer, C Binder, A Iscel, S Klenk, C Capelle, M Kahr, S Cadjo, M Lichtenauer, A Toma, A Zoufaly, S Hoffman, S Charwat-Resl, C Krestan, C Wenisch, D Bonderman

Cardiopulmonary long-term effects in patients after hospitalization due to COVID-19 infection

https://doi.org/10.1093/eurheartj/ehac544.249

Published

3-Oct-22

Study

https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.249/6743527

Background
Multiple studies have described acute effects of the Covid-19 infection on the heart, but little is known about the long-term cardiac and pulmonary effects and complications after recovery. The aim of this analysis was to deliver a comprehensive report of symptoms and possible long-term impairments after hospitalization because of Covid-19 infection as well as to try to identify predictors for Long-Covid.
Methods
This was a prospective, multicenter registry study. Patients with verified Covid-19 infection, who were treated as in-patients at our dedicated Covid hospital (Clinic Favoriten), have been included in this study. In all patients, testing was performed approximately 6 months post discharge. During the study visit the following tests and investigations were performed: detailed patient history and clinical examination, transthoracic echocardiography, electrocardiography, cardiac magnetic resonance imaging (MRI), chest computed tomography (CT) scan, lung function test and a comprehensive list of laboratory parameters including cardiac bio markers.
Results
Between July 2020 and October 2021, 150 patients were recruited. Sixty patients (40%) were female and the average age was 53.5±14.5 years. Of all patients, 92% had been admitted to our general ward and 8% had a severe course of disease, requiring admission to our intensive care unit. Six months after discharge the majority of patients still experienced symptoms and 75% fulfilled the criteria for Long-Covid. Only 24% were completely asymptomatic (figure 1).
Echocardiography detected reduced global longitudinal strain (GLS) in 11%. Cardiac MRI revealed pericardial effusion in 18%. Furthermore, cardiac MRI showed signs of former peri- or myocarditis in 4%. Pulmonary CT scans identified post-infectious residues, such as bilateral ground glass opacities and fibrosis in 22%. Exertional dyspnea was associated with either reduced forced vital capacity measured during pulmonary function tests in 11%, with reduced GLS and/or diastolic dysfunction, thus providing evidence for a cardiac and/or pulmonary cause.
Independent predictors for Long-Covid were markers of a more severe disease course like length of in-hospital stay, admission to an intensive care unit, type of ventilation as well as higher NT-proBNP and/or troponin levels.
Conclusion
Even 6 months after recovery from Covid-19 infection, the majority of previously hospitalized patients still suffer from at least one symptom, such as chronic fatigue and/or exertional dyspnea. While there was no association between fatigue and cardiopulmonary abnormalities, impaired lung function, reduced GLS and/or diastolic dysfunction were significantly more prevalent in patients presenting with exertional dyspnea. On chest CT approximately one fifth of all patients showed post infectious changes in chest CT including evidence for myo- and pericarditis as well as accumulation of pericardial effusions.

1811

CaV239

L Simonini, S Sbrana, I Foffa, M Baroni, G Catapano, D Chiappino, C Grigoratos, C Marrone, P Losi, F Mannucci, S Salvadori, G Todiere, E Valenti, L Ait-Ali, G D Aquaro

Relationships between plasma cytokine balance and cardiac magnetic resonance imaging in long-term post-COVID follow-up: a cross-sectional preliminary study

https://doi.org/10.1093/eurheartj/ehac544.245

Published

3-Oct-22

Study

https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.245/6744716

Background
COVID-19 infection can lead to a constellation of long-lasting post-infectious sequelae, including myocardial dysfunction, whose outcome is strongly affected by a fine-tuned balance between pro- and anti-inflammatory systemic immune responses. Plasma cytokines are key mediators of this immunological balance. In this preliminary study we evaluated the cross-sectional association between the circulating levels of the main pro- and anti-inflammatory cytokines and cardiac magnetic resonance (CMR) abnormalities.
Methods
71 subjects (59% female, mean age 52±14) with previous diagnosis of COVID-19 infection were enrolled at our institution for MULTICOVID protocol, comprehensive of CMR and biomarkers assessment performed >3 months and <1 year following the first negative swab test. CMR protocols consisted of conventional sequences (cine, T2-weighted imaging, and late gadolinium enhancement [LGE]) and quantitative mapping sequences (T1, T2, and extracellular volume [ECV] mapping). Plasma levels of cytokines TNF-α, IL-1β, IL-1α, IFN-α2, IL-6, IL-8, IL-13, IL-10, IL-17A, IL-18, IP-10, MIG and MCP-1 were quantified by Multiplex Immunoassays on the Luminex technology platform. Soluble cardiologic and biochemical biomarkers were measured by routine laboratory analysis.
Results
After a median of 9 (IQR 6–11) months following negative swab, CMR was normal in 48 subjects, while in 23 (32%) it revealed tissue characterization abnormalities (myocardial late enhancement and/or edema). By multivariate regression analysis (adjusted for age, sex, vaccination, severity degrees of the initial COVID disease, presence of comorbidities, smoke, time interval between COVID diagnosis and CMR assessment) the cytokine ratio TNF-α/(IL-10+IL-13) was independently associated (OR=2.89, 95% CI 1.19–7.04, p=0.02) with CMR abnormalities. Interestingly, the cumulative pro-/anti-inflammatory cytokine ratio (IL-1β+TNF-α+IFN-α2+IL-6+IL-17A+IL-8)/(IL-10+IL-13) showed a positive (OR=1.70, 95% CI: 1.04–2.75) and significant (p=0.03) association with CMR imaging aspects. Also, the ratio IFN-α2/(IL-10+IL-13), although without achieving a complete statistical significance (p=0.09), was associated positively with CMR findings.
Conclusions
The preliminary results of this cross-sectional study suggest that the systemic inflammatory environment, long-lasting unbalanced towards a prevalent cytokine-driven pro-inflammatory condition following COVID infection, could affect the development of CMR-detectable myocardial edema and fibrosis in long-term post-COVID subjects.

1812

CaV240

T L F Sousa, M J N N Alves, M D T Melo, A L P Albuquerque, J G Martins, L F B Botelho

Evaluation of myocardial work in patients recovered from the severe form of COVID-19

https://doi.org/10.1093/eurheartj/ehac544.073

Published

3-Oct-22

Study

https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.073/6743486

Background/Introduction
The impact of COVID-19 goes beyond its acute form, and can lead to the persistence of symptoms and the emergence of systemic disorders, defined as Post-Covid or Long-Covid.
Purpose
Assess the late impact on the cardiorespiratory system of patients recovered from severe Covid.
Methods
We performed cross-sectional study that included patients over 18 years of age who recovered from the severe form of COVID-19 after at least 60 days of their discharge. Patients and healthy controls were enrolled to perform transthoracic echocardiography (TTE) and cardiopulmonary exercise testing (CPET).
Results
A total of 52 patients and 24 controls were enrolled. The standard TTE parameters (end diastolic diameters, left ventricular ejection fraction, diastolic function and right ventricular systolic function) showed no difference when compared to the control group. When analyzing the myocardial work, there was a higher Wasted MW (GWW): 135 mmHg% vs 84.5 mmHg% (p=0.002), with lower MW Efficiency (GWE): 94 vs. 96 (p=0.003); as well as lower values of global strain: cases = 18.6% vs. 20.1% (p=0.009). No differences were found in the Constructive MW (GWC) and MW Global Index (GWI). In the CPET data we found lower peak values for the VO2: 24 ml/kg/min vs. 32.75 ml/kg/min (p<0.001); for the Heart Rate: 162 bpm vs. 175 bpm (p<0.001); for the Ventilation: 79.3 L/min vs. 109.85 L/min (p<0.001) and Respiratory Exchange Ratio: 1.12 vs. 1.19 (p=0.004). There was no difference in the maximum load reached, neither in the oxygen pulse values and in the Ve/CO2 slope. In relation to the oxygen kinetics, there was a significant reduction in OUES%: 85% vs. 98% (p=0.03); as well as an extended T½: 112 s vs. 88.5 s (p<0.001); and a slowing of the fall in heart rate in recovery time, as measured by the Heart Rate decay: −17.32 bpm vs. −22.08 bpm (p=0.005).
Conclusion
Patients recovered from the severe form of COVID-19 had higher GWW with lower efficiency (GWE). Such findings, added to changes in oxygen kinetics during exercise, may point to a possible cardiocirculatory mechanism associated with decreased aerobic capacity.

1813

CaV241

P Theofilis, E Oikonomou, S Lampsas, G Siasos, K Tsioufis, D Tousoulis

Endothelial dysfunction in the post-COVID-19 period: a meta-analysis

https://doi.org/10.1093/eurheartj/ehac544.2833

Published

3-Oct-22

Meta-Analysis

https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.2833/6746530

Background
Coronavirus disease (COVID)-19 is an entity characterized by a cytokine storm and profound endotheliitis. Although several reports have pointed to the presence of endothelial dysfunction in the acute phase, data is accumulating regarding a possible prolonged adverse effect of COVID-19 on endothelial function.
Purpose
This systematic review and meta-analysis aims to evaluate the degree of endothelial impairment, assessed by flow-mediated dilation (FMD) of the brachial artery, in individuals recovering from COVID-19.
Methods
We conducted a systematic literature search for studies assessing FMD between in patients post-COVID-19 and controls. Exclusion criteria consisted of the absence of a control group, measurement of FMD only during the acute phase of the disease, and not reporting FMD in % change. Effect sizes were pooled via random-effect model and the results are expressed as uncorrected standardized mean difference (SMD), using the Cohen's d as the effect size metric, with 95% confidence intervals (CI). Between-study heterogeneity was assessed through the calculation of I2. Subgroup analysis according to follow-up duration and the presence of cardiovascular risk factor-matched controls was also carried out.
Results
Database search identified 51 studies. Following the application of the exclusion criteria, 7 studies were included in the meta-analysis (post-COVID-19: 342 subjects, Control: 273 subjects). Compared to controls, patients post-COVID-19 had significantly lower FMD% values (SMD: −1.06, 95% CI: −1.74 to −0.38, p<0.01, I2: 86%) (Figure 1). Results remained unaffected after exclusion of any single study using the leave-one-out method. Subgroup analysis revealed no significant differences in FMD between post-COVID-19 patients and controls according to follow-up duration or the presence of cardiovascular risk factor-matched control group.
Conclusion
Flow-mediated dilation of the brachial artery, indicative of endothelial dysfunction, was significantly reduced in post-COVID-19 subjects compared to non-infected controls. This finding may be an alarming sign towards a higher risk of incident cardiovascular events.

1814

CaV242

M Klinceva, L V Veljanovska-Kiridzievska, P Z Zafirovska, E I Idoski, V A Ampova-Sokolov, T A Angjusheva, I M Milev, S I Idrizi, I N Neshkovski, Z M Mitrev

Post COVID-19 cardiac magnetic resonance findings among inpatients vs outpatients

https://doi.org/10.1093/eurheartj/ehac544.250

Published

3-Oct-22

Study

https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.250/6743526

Background
Myocardial injury and myopericarditis constitute an important complication after viral infection. The prevalence of myocardial injury among patients that survived COVID – 19 infections and its causes are still not clear.
The purpose of this study is to estimate whether there is a difference in the prevalence of cardiac magnetic findings between patients treated in a hospital vs patients treated at an outpatient clinic.
Methods
We evaluated 360 cardiac magnetic resonance examinations, performed from 1st of June 2020 until the 31st of August, 2021. Out of them, 141 patients (39%) underwent cardiac magnetic resonance due to persistent symptoms after a SARS-CoV-2 infection. A conventional CMR protocol was performed to rule out myocarditis. Revised 2018 Lake Louise Criteria were used to diagnose myocarditis. All scans were performed by Phillips Medical Systems Ingenia 1.5T. T1 native values were estimated elevated when mapping values measured above 1030ms, T2 mapping values were estimated elevated when greater than 55 ms. Mid wall or subepicardial late gadolinium enhancement, pericardial effusions and extracardiac findings were evaluated. Chi-square test was used.
Results
Out of 141 patients, 78 patients (55%) had at least one cardiac magnetic resonance finding: either increased T1 (22%), T2 mapping (7%), T2 STIR (1.4%), left gadolinium enhancement (30%), small pericardial effusion (26%) or lung parenchymal changes (12%) after COVID-19. Twenty out of 141 patients (14%) fulfilled the criteria for myocarditis. Out of these 20 patients, 14 patients (70%) received treatment at an outpatient clinic, while 6 patients (30%) were treated from COVID-19 in a hospital (p<0.053). The most prevalent symptoms were effort intolerance and palpitations (50% and 26% respectively).
There was no statistical difference in myocarditis prevalence, between hospitalized patients treated with or without corticosteroids (p=0.65), as well as between patients treated with hemodiafiltration (Oxiris filter) and patients without hemodiafiltration (p=0.95). Also, there was no statistical difference between T1 mapping among the inpatients and outpatients (p=0.58), as well as the severity of the clinical picture (p=0.72). There was no statistical difference between the in- and outpatient groups according to age (p=0.46). None of these patients had signs of fulminant myocarditis.
Conclusion
The prevalence of myopericardial and/or lung involvement after SARS-CoV-2 infection is present in every other cardiac magnetic resonance examination performed for persistent symptoms after a survived COVID-19. Myocarditis after SARS-CoV-2 infection develops regardless of the severity of the symptoms or the treatment method. We can conclude that we have to look for the reasons for myocarditis, beyond the clinical picture and the treatment strategies.

1815

CaV243

Renin Chang 1
Cheuk-Kwan Sun 1
Yao-Min Hung

Concerns about Long-term cardiovascular outcomes in COVID-19 survivors among non-vaccinated population: A retrospective cohort study from the TriNetX US collaborative networks

https://doi.org/10.1016/j.eclinm.2022.101701

Published

20-Oct-22

Correspondance

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(22)00431-X/fulltext

A recent study of eClinicalMedicine found that COVID-19 survivors, compared with non-COVID-19 controls, had a significantly higher risk of cardiovascular events within 12-month follow-up.1 This study offered timely information to readers. However, we have several concerns.
First, this study excluded patients who died within 30 days of the index date, a method that could lead to a Neyman bias that tends to distort survival analyses.2 Thus, critically ill patients who had new cardiovascular events within 30 days of the diagnosis of COVID-19 were intentionally excluded, which may lead to an underestimation or overestimation of the true risk of cardiovascular events.
Second, this study conducted by the TriNetX EHR database is retrospective and observational, and the authors have mentioned the possibility of residual unmeasured confounders such as smoking, exercise, or family history of cardiovascular disease. We recommend a self-matched study design, which may reduce the interference caused by unmeasured confounders.3
Third, as the investigators recognized, there may be inaccuracies in this study caused by the diagnosis and coding of myocardial injury or myocarditis into myocardial infarction and vice versa. Here, we would like to emphasize the importance of reporting case ascertainment, providing positive predictive rates or performing sensitivity analyses (using a rigorous definition of cardiovascular outcomes rather than just ICD-10) to make study results more reliable.
Although vaccination and antiviral therapy have produced positive results,4 further research is needed to prevent sequelae such as long-term cardiovascular events among COVID-19 survivors.

1816

CaV244

R. Hira
T. Siddiqui
J. Baker
S. Ranada
A. Soroush
K. Karalasingham
H. Ahmad
C. Morillo
R. Sheldon
S. Raj

OBJECTIVE CARDIOVASCULAR AUTONOMIC ABNORMALITIES IN POST-ACUTE SEQUELAE OF COVID-19 (PASC): OVERALL AND SEX-BASED PREVALENCE

https://doi.org/10.1016/j.cjca.2022.08.085

Published

1-Oct-22

Study

https://www.onlinecjc.ca/article/S0828-282X(22)00619-5/fulltext

Background
The novel coronavirus has negatively impacted the health and economy of Canada and the world. While most patients recover, many patients are left with residual symptoms even several months after resolution of the acute illness (“Post-Acute Sequalae of COVID-19” [PASC]; or “Long COVID). Symptoms can include fatigue, light-headedness, and achycardia/palpitations, which are common in cardiovascular autonomic disorders such as Postural Orthostatic Tachycardia Syndrome (POTS), Initial Orthostatic Hypotension (IOH), Orthostatic Hypotension (OH), and Inappropriate Sinus Tachycardia (IST). Currently, we do not know the prevalence of objective autonomic abnormalities in patients with PASC, nor if there are sex differences. We aimed to determine the prevalence of objective autonomic abnormalities, and whether there was a sex-difference, among patients with PASC.
Methods and Results
Patients with PASC (n=61; F=49; Age=45±11 years) underwent autonomic function testing with beat-to-beat hemodynamics for 10 min supine followed by a 10 min active stand 397±131 days after their COVID infection. Patients were evaluated for hemodynamic criterion for POTS (ΔHR≥30 bpm within 10 min), IOH (transient ΔSBP≥40mmHg within 45s), OH (ΔSBP≥20mmHg within 3 min), and IST (supine HR>100 bpm). Categorical data were analyzed with a Fisher’s Exact test. The POTS criterion was met in 18 (30%) patients with PASC, while the IOH criterion was met in 40 (66%) patients. The IST and OH criteria were each seen in 1 patient. Overall, 44 (72%) patients met the criterion for at least 1 of these disorders. When analyzed by sex, the POTS criterion was met in 18 (37%) females, but no males (P=0.01). IOH criterion was met in females (69%) and males (50%; P=0.2) at a similar frequency. The single OH and IST patients were female. Overall, there was a non-significant trend for more females (78%) than males (50%; P=0.06) meeting the criterion for at least 1 of these disorders.
Conclusion
Many patients with PASC have objective evidence of autonomic cardiovascular abnormalities. The most common abnormality is IOH, followed by POTS. IOH will be missed unless an active standing protocol is used. POTS was much more common in females than males, but IOH was evenly split between sexes. Overall, there is a trend toward increased frequency of autonomic cardiovascular disorders in females than males. On behalf of the Canadian Long Covid Autonomic Network (CaLoCAN).

1817

CaV245

Zahra Raisi-Estabragh1,2, Jackie Cooper1, Ahmed Salih1, Betty Raman3, Aaron Mark Lee1, Stefan Neubauer3, Nicholas C. Harvey4,5, http://orcid.org/0000-0003-4622-5160Steffen E. Petersen

Cardiovascular disease and mortality sequelae of COVID-19 in the UK Biobank

http://dx.doi.org/10.1136/heartjnl-2022-321492

Published

24-Oct-22

Study

https://heart.bmj.com/content/early/2022/09/21/heartjnl-2022-321492

Objective To examine association of COVID-19 with incident cardiovascular events in 17 871 UK Biobank cases between March 2020 and 2021.
Methods COVID-19 cases were defined using health record linkage. Each case was propensity score-matched to two uninfected controls on age, sex, deprivation, body mass index, ethnicity, diabetes, prevalent ischaemic heart disease (IHD), smoking, hypertension and high cholesterol. We included the following incident outcomes: myocardial infarction, stroke, heart failure, atrial fibrillation, venous thromboembolism (VTE), pericarditis, all-cause death, cardiovascular death, IHD death. Cox proportional hazards regression was used to estimate associations of COVID-19 with each outcome over an average of 141 days (range 32–395) of prospective follow-up.
Results Non-hospitalised cases (n=14 304) had increased risk of incident VTE (HR 2.74 (95% CI 1.38 to 5.45), p=0.004) and death (HR 10.23 (95% CI 7.63 to 13.70), p<0.0001). Individuals with primary COVID-19 hospitalisation (n=2701) had increased risk of all outcomes considered. The largest effect sizes were with VTE (HR 27.6 (95% CI 14.5 to 52.3); p<0.0001), heart failure (HR 21.6 (95% CI 10.9 to 42.9); p<0.0001) and stroke (HR 17.5 (95% CI 5.26 to 57.9); p<0.0001). Those hospitalised with COVID-19 as a secondary diagnosis (n=866) had similarly increased cardiovascular risk. The associated risks were greatest in the first 30 days after infection but remained higher than controls even after this period.
Conclusions Individuals hospitalised with COVID-19 have increased risk of incident cardiovascular events across a range of disease and mortality outcomes. The risk of most events is highest in the early postinfection period. Individuals not requiring hospitalisation have increased risk of VTE, but not of other cardiovascular-specific outcomes.

1818

CaV246

Ian M. Kronish & Ari Shechter

COVID-19 and the amplification of cardiovascular risk by psychological distress

https://doi.org/10.1038/s44161-022-00153-2

Published

24-Oct-22

Comment

https://www.nature.com/articles/s44161-022-00153-2

The COVID-19 pandemic has unleashed a tidal wave of psychological distress. Here we discuss the biobehavioral mechanisms through which psychological distress amplifies the adverse effects of SARS-CoV-2 infection on cardiovascular outcomes. We also examine how the stress of caring for patients with COVID-19 increases cardiovascular risk in healthcare workers.

1819

CaV247

C. (Linda) M. C. van Campen *ORCID andFrans C. Visser

Long-Haul COVID Patients: Prevalence of POTS Are Reduced but Cerebral Blood Flow Abnormalities Remain Abnormal with Longer Disease Duration

https://doi.org/10.3390/healthcare10102105

Published

21-Oct-22

Study

https://www.mdpi.com/2227-9032/10/10/2105/htm

Background: Postural orthostatic tachycardia syndrome (POTS) has been described early after the onset of the COVID-19 infection, but also orthostatic hypotension (OH). In the present study, we hypothesized that orthostatic intolerance decreases over time. Methods: In 29 long-haul COVID-19 (LHC) patients, a tilt test was performed, including measurements of cerebral blood flow (CBF) by extracranial Doppler. The time interval between the onset of infection and the tilt test varied between 3 and 28 months. Results: In the first 12 months after the infection, 71% of the LHC patients showed POTS and after 24 months none of them. In the first 12 months, 29% of patients had a normal heart rate and blood pressure response (normHRBP) and after 24 months 75% (distribution of POTS, OH, and a normHRBP over time: p < 0.0001). Linear regression showed that, over time, there was a decrease in the abnormal CBF during the tilt (p = 0.024) but remained abnormal. Conclusion: In LHC patients, hemodynamic abnormalities of a tilt test change over time. Patients studied early after the onset of the disease mainly exhibit POTS, but patients studied later in the time course mainly show a normHRBP or OH. In addition, the abnormal CBF reduction improves over time, but CBF remains abnormal.

1820

CaV248

Rute Pires 1ORCID,Miguel Pedrosa 2,Maria Marques 3,4,*,Margarida Goes 3,4ORCID,Henrique Oliveira 5,6ORCID andHélder Godinho 1

Cardiometabolic Risk after SARS-CoV-2 Virus Infection: A Retrospective Exploratory Analysis

https://doi.org/10.3390/jpm12111758

Published

24-Oct-22

Study

https://www.mdpi.com/2075-4426/12/11/1758/htm

Objective: The aim of this study is to characterize the cardiometabolic risk of individuals who were infected with the SARS-CoV-2 virus and subsequently admitted to a hospital in a major city in mainland Portugal. Methods: This is a retrospective exploratory study using a sample of 102 patients, with data analysis including descriptive statistics, nonparametric measures of association between variables based on Spearman’s rank-order correlation, a logistic regression model for predicting the likelihood that an individual might eventually pass away, and a multiple linear regression model to predict a likely increase in the number of days an infected patient remained in the hospital. Results: About 62.7% of the individuals required intensive care on the second day of hospitalization, remaining 14.2 days in the intensive care unit (ICU) on average. The likelihood that an individual might eventually pass away due to SARS-CoV-2 virus infection increases for the older than younger ones and increases even more if he/she suffers from cardiometabolic disorders such as obesity, especially cardiovascular disease. Older individuals and those with obesity and hypertension remained more days in the ICU. Conclusions: A later age and the prevalence of cardiometabolic disorders severely affect the care pathway of individuals infected with the SARS-CoV-2 virus.

1821

CaV249

Austin Culver, Peter Ju, Daniel Kim, Brandon Benefield, Li-Yueh Hsu, Suvai Gunasekaran, Michael Ison, Ravi Kalhan, Bradley D Allen, Michael Markl, Clyde Yancy and Daniel C Lee

Abstract 11734: Myocardial Perfusion Reserve Quantified by Stress Cardiovascular Magnetic Resonance Imaging is Reduced in Long COVID Patients Presenting With Chest Pain

Published

30-Oct-22

Study

https://www.ahajournals.org/doi/abs/10.1161/circ.146.suppl_1.11734

Introduction: Chest pain is common in patients with Post-acute Sequelae of SARS-CoV-2 (PASC), also known as long COVID, but the mechanism is unknown.
Hypothesis: We hypothesized that PASC patients with chest pain have impaired myocardial perfusion reserve (MPR) measured by stress perfusion cardiovascular magnetic resonance (CMR) imaging.
Methods: We retrospectively identified the first 30 consecutive patients who underwent clinically ordered adenosine stress perfusion CMR for chest pain persisting >4 weeks after SARS-CoV-2 infection (PASC). Patients with a history of coronary artery disease (CAD) or left ventricular ejection fraction (LVEF) <50% were excluded. Patients without a history of SARS-CoV-2 infection who had a normal clinically ordered perfusion CMR served as controls. A previously-described automated pixel-wise quantitative perfusion tool was used to calculate stress and rest myocardial blood flow (MBF) in mL/min/g, and MPR as the ratio of stress MBF/rest MBF. The cutoff for reduced MPR was >2 SD below mean MPR for controls.
Results: In 30 PASC (67% female, age 43±13) and 13 controls (54% female, age 50±12), with LVEF (61±6% vs 59±8%), native T1 (1001±49 vs 992±57 ms), T2 (49.5±3.7 vs 48.0±3.3 ms), and ECV (24.6±2.9 vs 24.6±2.6%) were similar (p>0.2 for all). Prior pericarditis (n=2) or prior myocarditis (n=3) were infrequent, with no acute disease by CMR. PASC patients had significantly lower global MPR than controls (1.54±0.25 vs. 2.20±0.36, p<0.001), and 16/30 (53%) PASC patients had reduced MPR (<1.49). Clinical ischemia evaluation revealed obstructive CAD in only 2 PASC patients.
Conclusions: In PASC patients with chest pain undergoing stress perfusion CMR, global MPR is frequently reduced and is significantly lower than in patients with normal clinical perfusion CMR and no history of SARS-CoV-2 infection. This study raises the possibility that microvascular dysfunction is an important cause of chest pain in patients with long COVID.

1822

CaV250

Ali Mahdi, Ulrika Reistam, Jannike Nickander, Artur Fedorowski, Liyew Desta, Malin Nygren-Bonnier, Michael Runold, Judith Bruchfeld, John Pernow and Marcus Stahlberg

Abstract 12760: Microvascular Endothelial Dysfunction in Postural Orthostatic Tachycardia Syndrome Associated With Post-Acute Sequelae of COVID-19

Published

30-Oct-22

Study

https://www.ahajournals.org/doi/abs/10.1161/circ.146.suppl_1.12760

Introduction: Post-acute sequelae of COVID-19 (PASC) is a novel clinical syndrome. We have previously reported that PASC patients can develop postural orthostatic tachycardia syndrome (POTS) and that COVID-19 induce microvascular endothelial dysfunction in acutely ill, hospitalized patients, that persist up to four months post discharge. Whether microvascular endothelial dysfunction contributes to POTS pathophysiology in PASC remains unclear.
Hypothesis: Patients with PACS combined with POTS have impaired microvascular endothelial function.
Methods: PASC patients (n=44) with mild SARS-CoV-2 infection (not hospitalized) were recruited from the post-COVID multidisciplinary clinic at Karolinska University Hospital. PASC diagnosis was based on the WHO PASC criteria. POTS was diagnosed in 21 patients (PASC + POTS) while 23 had a negative head-up tilt test (PASC - POTS). Age- and gender-matched healthy subjects (n=15) served as controls. Microvascular endothelial function was quantified as reactive hyperemia index (RHI) determined from the changes in pulse amplitude tonometry before and after a 5 min episode of arterial occlusion. Stress-perfusion cardiac magnetic resonance imaging (cMRI) with adenosine was performed in a subset of patients.
Results: Mean age was 42±11 years and 95 % were women among PACS patients. Time from COVID-19 symptom onset to study inclusion was 18±3 months. RHI was significantly lower in PASC + POTS than in healthy controls and PASC - POTS (Figure 1). The prevalence of cardiac microvascular dysfunction on cMRI did not differ between the PASC groups (8% in PASC + POTS vs. 13% in PASC - POTS, p=1.00). All subjects with microvascular dysfunction on cMRI except one had a RHI below the cutoff (1.67) indicating microvascular dysfunction.
Conclusions: Microvascular endothelial dysfunction is common in patients with PACS-associated POTS and may cause stress-induced myocardial ischemia up to 18 months after a mild primary infection.

1823

CaV251

Melanie Walker, Emma M Federico, Douglas B Kell, Christopher Dupont, Amy Proal and Etheresia Pretorius

Abstract 15637: Detection and Characterization of Fibrin/Amyloid Microclots in Patients With Post-Acute Sequelae of Covid-19

Published

30-Oct-22

Study

https://www.ahajournals.org/doi/abs/10.1161/circ.146.suppl_1.15637

LongCovid or Post-Acute Sequelae of COVID-19 (PASC) is a diagnosis given to patients who experience a wide range of debilitating chronic symptoms after infection with SARS-CoV-2. The majority of individuals are PCR negative, indicating microbiological recovery. There are currently few LongCovid/PASC blood-based biomarkers. We used fluorescence microcopy to identify unique fibrin/amyloid micro-thrombosis and hyperactivated platelets in individuals with PASC. These fibrin/amyloid microclots may impede blood flow to tissue.
Methods: Whole blood was collected in citrate tubes from 30 matched healthy subjects and 30 PASC subjects. Platelet poor plasma (PPP) was prepared by centrifugation and stored at -80 °C. PPP was then exposed to thioflavin T (ThT), a fluorescence marker known to bind to and open hydrophobic areas on damaged amyloidogenic protein. Samples were viewed with fluorescence microscopy using a 63x/1.4 Oil DIC M27 objective (excitation wavelength 450nm-488nm, emission 499nm- 529nm). After a double-trypsin PPP digestion method, proteomic analysis of the PPP samples was performed.
Results: Significant microclot load was observed in the PPP of participants with PASC compared to healthy participants (Fig. 1). Proteomic analysis revealed the presence of inflammatory molecules within digested microclots.
Conclusion: Preliminary results suggest that the presence of microclots in PPP may be used as a diagnostic biomarker for the PASC. Characterization of inflammatory molecules and antibodies trapped within microclots might provide insight into the pathogenesis of PASC and serve as a basis for novel treatment strategies or preventative medicine. Figure: Representative specimens A) Microclots in healthy plasma. B) Microclots in PASC plasma.

1824

CaV252

Mark C Beatty and Amanda K Verma

Abstract 11491: Clinical Time Course of Post-Acute Sequelae of SARS-CoV-2 Cardiovascular Syndrome

Published

30-Oct-22

Study

https://www.ahajournals.org/doi/abs/10.1161/circ.146.suppl_1.11491

Introduction: Post-acute sequelae of SARS-CoV-2 cardiovascular syndrome (PASC-CVS) is a heterogeneous disorder of post-COVID syndrome that involves a wide range of cardiovascular symptoms including palpitations, chest pain, dyspnea and dizziness. The clinical time-course of PASC-CVS is not well characterized. We sought to understand predictors of time to symptom improvement for patients with PASC-CVS.
Methods: Patients with PASC-CVS undergoing evaluation in a dedicated post-COVID cardiology clinic were recruited after informed consent. Information was obtained from chart review and included demographics, comorbidities, symptoms, time of infection to time of presentation to the clinic and time to improvement in symptoms. A multivariate linear regression model was used to determine predictors of time to improvement.
Results: A total of 144 consecutive patients were included that had complete records available for review. Average age was 46 years, 74% were female and 94% were Caucasian. Comorbities included obesity (49%), mental health disorder (25%), hypertension (24%), hyperlipidemia (24%), pulmonary disease (18%), type II diabetes (9%), atrial arrhythmia (5%) and coronary artery disease (3%). Time from infection to presentation (p <0.001), chest pain (p 0.002) and dyspnea (<0.001) demonstrated significant associations with time to improvement of symptoms and were used in the multivariate regression model (F 27.8, p<0.001). The time to presentation predicted the longest time to symptom improvement, followed by dyspnea, chest pain, and dizziness.
Conclusions: This analysis of a large group of PASC-CVS patients suggests those who wait longer to seek care for PASC-CVS symptoms may have longer duration of post-COVID symptoms. Additionally, specific symptoms may take longer to improve than others. Patients with PASC-CVS should therefore consider early medical care to mitigate symptoms and reduce duration of post-COVID syndrome.

1825

CaV253

Khan O. Mohammad, Andrew Lin & Jose B. Cruz Rodriguez

Cardiac Manifestations of Post-Acute COVID-19 Infection

https://doi.org/10.1007/s11886-022-01793-3

Published

2-Nov-22

Review

https://link.springer.com/article/10.1007/s11886-022-01793-3

Purpose of Review
There is emerging evidence that the post-acute and chronic phases of COVID-19 infection are associated with various significant cardiovascular sequelae.
Recent Findings
Long COVID has been shown to be associated with multiple cardiovascular sequelae including direct myocardial injury, arrhythmias, and cardiomyopathies. Hypotheses on the mechanism of myocardial injury include direct viral infiltration and autoimmune dysregulation. Long COVID is associated with persistent cardiac ischemia in patients with no previous history of coronary disease, atrial and ventricular arrhythmias, and the development of new-onset heart failure in previously healthy patients. Onset of long COVID may be related to severity of the initial SARS-CoV2 infection. Cardiac MRI is a valuable tool in assessing myocarditis and the development of cardiomyopathies in the setting of long COVID.
Summary
Both patients with and without pre-existing cardiovascular disease are at risk of developing myocardial injury in the setting of long COVID. Future studies will elucidate both cardiovascular mortality and cardiac rehabilitation in the post-acute and chronic phases of COVID-19.

1826

CaV254

Darius A. Gerlach, Andrea Maier, Jorge Manuel, Anja Bach, Alex Hoff, Jan‐Niklas Hönemann, Karsten Heusser, Dirk Voit, Jens Frahm, Jens Jordan and Jens Tank

Real‐Time Magnetic Resonance Imaging to Study Orthostatic Intolerance Mechanisms in Human Beings: Proof of Concept

https://doi.org/10.1161/JAHA.122.026437

Published

27-Oct-22

Proof‐of‐concept study

https://www.ahajournals.org/doi/10.1161/JAHA.122.026437

Background
Discerning the mechanisms driving orthostatic symptoms in human beings remains challenging. Therefore, we developed a novel approach combining cardiac and cerebral real‐time magnetic resonance imaging, beat‐to‐beat physiological monitoring, and orthostatic stress testing through lower‐body negative pressure (LBNP). We conducted a proof‐of‐concept study in a patient with severe orthostatic hypotension.
Methods and Results
We included a 46‐year‐old man with pure autonomic failure. Without and during −30 mmHg LBNP, we obtained 3T real‐time magnetic resonance imaging of the cardiac short axis and quantitative flow measurements in the pulmonary trunk and middle cerebral artery. Blood pressure was 118/74 mmHg during supine rest and 58/35 mmHg with LBNP. With LBNP, left ventricular stroke volume decreased by 44.6%, absolute middle cerebral artery flow by 37.6%, and pulmonary trunk flow by 40%.
Conclusions
Combination of real‐time magnetic resonance imaging, LBNP, and continuous blood pressure monitoring provides a promising new approach to study orthostatic intolerance mechanisms in human beings.

1827

CaV255

Sarah Schlick 1,†,Marianna Lucio 2,†,Gerd Wallukat 3,Alexander Bartsch 1ORCID,Adam Skornia 1,Jakob Hoffmanns 1,Charlotte Szewczykowski 1,Thora Schröder 1,Franziska Raith 1,Lennart Rogge 1,Felix Heltmann 1,Michael Moritz 1,Lorenz Beitlich 1,Julia Schottenhamml 1,Martin Herrmann 4,5ORCID,Thomas Harrer 4,5ORCID,Marion Ganslmayer 6,Friedrich E. Kruse 1,Robert Lämmer 1ORCID,Christian Mardin 1,*,‡ andBettina Hohberger 1,*,‡

Post-COVID-19 Syndrome: Retinal Microcirculation as a Potential Marker for Chronic Fatigue

https://doi.org/10.3390/ijms232213683

Published

8-Nov-22

Study

https://www.mdpi.com/1422-0067/23/22/13683

Post-COVID-19 syndrome (PCS) is characterized by persisting sequelae after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). PCS can affect patients with all COVID-19 disease severities. As previous studies have revealed impaired blood flow as a provoking factor triggering PCS, it was the aim of the present study to investigate the potential association between self-reported chronic fatigue and retinal microcirculation in patients with PCS, potentially indicating an objective biomarker. A prospective study was performed, including 201 subjects: 173 patients with PCS and 28 controls. Retinal microcirculation was visualized by OCT angiography (OCT-A) and quantified using the Erlangen-Angio-Tool as macula and peripapillary vessel density (VD). Chronic fatigue (CF) was assessed according to the variables of Bell’s score, age and gender. VDs in the superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP) were analyzed, considering the repetitions (12 times). Seropositivity for autoantibodies targeting G protein-coupled receptors (GPCR-AAbs) was determined by an established cardiomyocyte bioassay. Taking account of the repetitions, a mixed model was performed to detect possible differences in the least square means between the different groups included in the analysis. An age effect in relation to VD was observed between patients and controls (p < 0.0001). Gender analysis showed that women with PCS showed lower VD levels in the SVP compared to male patients (p = 0.0015). The PCS patients showed significantly lower VDs in the ICP as compared to the controls (p = 0.0001 (CI: 0.32; 1)). Moreover, considering PCS patients, the mixed model revealed a significant difference between those with chronic fatigue (CF) and those without CF with respect to VDs in the SVP (p = 0.0033 (CI: −4.5; −0.92)). The model included variables of age, gender and Bell’s score, representing a subjective marker for CF. Consequently, retinal microcirculation might serve as an objective biomarker in subjectively reported chronic fatigue in patients with PCS.

1828

CaV256

Jaroslav Pelisek
ORCID logo
; Benedikt Reutersberg; Urs F Greber; Alexander Zimmermann

Vascular dysfunction in COVID-19 patients: update on SARS-CoV-2 infection of endothelial cells and the role of long non-coding RNAs

https://doi.org/10.1042/CS20220235

Published

11-Nov-22

Review

https://portlandpress.com/clinsci/article/136/21/1571/232077/Vascular-dysfunction-in-COVID-19-patients-update

Although COVID-19 is primarily a respiratory disease, it may affect also the cardiovascular system. COVID-19 patients with cardiovascular disorder (CVD) develop a more severe disease course with a significantly higher mortality rate than non-CVD patients. A common denominator of CVD is the dysfunction of endothelial cells (ECs), increased vascular permeability, endothelial-to-mesenchymal transition, coagulation, and inflammation. It has been assumed that clinical complications in COVID-19 patients suffering from CVD are caused by SARS-CoV-2 infection of ECs through the angiotensin-converting enzyme 2 (ACE2) receptor and the cellular transmembrane protease serine 2 (TMPRSS2) and the consequent dysfunction of the infected vascular cells. Meanwhile, other factors associated with SARS-CoV-2 entry into the host cells have been described, including disintegrin and metalloproteinase domain-containing protein 17 (ADAM17), the C-type lectin CD209L or heparan sulfate proteoglycans (HSPG). Here, we discuss the current data about the putative entry of SARS-CoV-2 into endothelial and smooth muscle cells. Furthermore, we highlight the potential role of long non-coding RNAs (lncRNAs) affecting vascular permeability in CVD, a process that might exacerbate disease in COVID-19 patients.

1829

CaV257

Pasquale AmbrosinoORCID Icon,Stefano Sanduzzi ZamparelliORCID Icon,Marco Mosella,Roberto FormisanoORCID Icon,Antonio MolinoORCID Icon,Giorgio Alfredo SpedicatoORCID Icon,Antimo PapaORCID Icon,Andrea MottaORCID Icon,Matteo Nicola Dario Di MinnoORCID Icon &Mauro ManiscalcoORCID Icon show less

Clinical assessment of endothelial function in convalescent COVID-19 patients: a meta-analysis with meta-regressions

https://doi.org/10.1080/07853890.2022.2136403

Published

16-Nov-22

Meta-Analysis

https://www.tandfonline.com/doi/full/10.1080/07853890.2022.2136403

Background
Endothelial dysfunction has been proposed to play a key role in the pathogenesis of coronavirus disease 2019 (COVID-19) and its post-acute sequelae. Flow-mediated dilation (FMD) is recognized as an accurate clinical method to assess endothelial function. Thus, we performed a meta-analysis of the studies evaluating FMD in convalescent COVID-19 patients and controls with no history of COVID-19.
Methods
A systematic literature search was conducted in the main scientific databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Using the random effects method, differences between cases and controls were expressed as mean difference (MD) with 95% confidence intervals (95% CI). The protocol was registered on PROSPERO with reference number CRD42021289684.
Results
Twelve studies were included in the final analysis. A total of 644 convalescent COVID-19 patients showed significantly lower FMD values as compared to 662 controls (MD: −2.31%; 95% CI: −3.19, −1.44; p < 0.0001). Similar results were obtained in the sensitivity analysis of the studies that involved participants in either group with no cardiovascular risk factors or history of coronary artery disease (MD: −1.73%; 95% CI: −3.04, −0.41; p = 0.010). Interestingly, when considering studies separately based on enrolment within or after 3 months of symptom onset, results were further confirmed in both short- (MD: −2.20%; 95% CI: −3.35, −1.05; p < 0.0001) and long-term follow-up (MD: −2.53%; 95% CI: −4.19, −0.86; p = 0.003). Meta-regression models showed that an increasing prevalence of post-acute sequelae of COVID-19 was linked to a higher difference in FMD between cases and controls (Z-score: −2.09; p = 0.037).
Conclusions
Impaired endothelial function can be documented in convalescent COVID-19 patients, especially when residual clinical manifestations persist. Targeting endothelial dysfunction through pharmacological and rehabilitation strategies may represent an attractive therapeutic option.
Key messages
The mechanisms underlying the post-acute sequelae of coronavirus disease 2019 (COVID-19) have not been fully elucidated.
Impaired endothelial function can be documented in convalescent COVID-19 patients for up to 1 year after infection, especially when residual clinical manifestations persist.
Targeting endothelial dysfunction may represent an attractive therapeutic option in the post-acute phase of COVID-19.

1830

CaV258

Paul Baum, Lisa Do, Lea Deterding, Julia Lier, Ines Kunis, Dorothee Saur, Joseph Classen, Hubert Wirtz & Ulrich Laufs

Cardiac function in relation to functional status and fatigue in patients with post-COVID syndrome

https://doi.org/10.1038/s41598-022-24038-3

Published

15-Nov-22

Study

https://www.nature.com/articles/s41598-022-24038-3

Patients with Post-COVID syndrome (PCS) are frequently referred for cardiologic evaluation. We assessed cardiac function and biomarkers in relation to functional status and fatigue in patients with PCS. This prospective single-center cohort study included 227 patients with persisting symptoms after COVID-19 infection. Most frequent complaints were fatigue (70%), dyspnea (56%), neurocognitive symptoms (34%) and chest pain (28%). Standardized questionnaires were used to assess Post-COVID-Functional-Scale (PCFS) and fatigue (MFI-20). The fatigue severity was inversely related to age and did not correlate with cardiovascular diseases, echocardiographic findings, or biomarkers. Similarly, mild to moderate functional impairment (PCFS 1–3) did not correlate with cardiovascular alterations. However, the subgroup of patients with significant functional impairment (PCFS = 4) had more frequent cardiovascular comorbidities, biomarkers and impaired global longitudinal strain (GLS). Patients with elevated troponin T showed abnormal GLS, reduced left ventricular ejection fraction and impaired tricuspid annular plane systolic excursion. The majority of patients with PCS shows a normal cardiac function. Only the small subgroup of patients with severe functional impairment and patients with elevated troponin T is at risk for impaired cardiac function and likely to benefit from specialized care by a cardiologist.

1831

CaV259

Lukas Fiedler 1,2,†ORCID,Lukas J. Motloch 1,†,Peter Jirak 1,Ruslan Gumerov 3,Paruir Davtyan 3,Diana Gareeva 3,Irina Lakman 3,4ORCID,Alexandr Tataurov 5,Gulnaz Lasinova 3,Valentin Pavlov 6,Laurenz Hauptmann 1ORCID,Kristen Kopp 1ORCID,Uta C. Hoppe 1,Michael Lichtenauer 1,Rudin Pistulli 7ORCID,Anna-Maria Dieplinger 8,9,† andNaufal Zagidullin

Investigation of hs-TnI and sST-2 as Potential Predictors of Long-Term Cardiovascular Risk in Patients with Survived Hospitalization for COVID-19 Pneumonia

https://doi.org/10.3390/biomedicines10112889

Published

10-Nov-22

Study

https://www.mdpi.com/2227-9059/10/11/2889

Introduction: COVID-19 survivors reveal an increased long-term risk for cardiovascular disease. Biomarkers like troponins and sST-2 improve stratification of cardiovascular risk. Nevertheless, their prognostic value for identifying long-term cardiovascular risk after having survived COVID-19 has yet to be evaluated. Methods: In this single-center study, admission serum biomarkers of sST-2 and hs-TnI in a single cohort of 251 hospitalized COVID-19 survivors were evaluated. Concentrations were correlated with major cardiovascular events (MACE) defined as cardiovascular death and/or need for cardiovascular hospitalization during follow-up after hospital discharge [FU: 415 days (403; 422)]. Results: MACE was a frequent finding during FU with an incidence of 8.4% (cardiovascular death: 2.8% and/or need for cardiovascular hospitalization: 7.2%). Both biomarkers were reliable indicators of MACE (hs-TnI: sensitivity = 66.7% & specificity = 65.7%; sST-2: sensitivity = 33.3% & specificity = 97.4%). This was confirmed in a multivariate proportional-hazards analysis: besides age (HR = 1.047, 95% CI = 1.012–1.084, p = 0.009), hs-TnI (HR = 4.940, 95% CI = 1.904–12.816, p = 0.001) and sST-2 (HR = 10.901, 95% CI = 4.509–29.271, p < 0.001) were strong predictors of MACE. The predictive value of the model was further improved by combining both biomarkers with the factor age (concordance index hs-TnI + sST2 + age = 0.812). Conclusion: During long-term FU, hospitalized COVID-19 survivors, hs-TnI and sST-2 at admission, were strong predictors of MACE, indicating both proteins to be involved in post-acute sequelae of COVID-19.

1832

CaV260

Elamein Yousif, Sarah Premraj

A Review of Long COVID With a Special Focus on Its Cardiovascular Manifestations

https://doi.org/10.7759/cureus.31933

Published

27-Nov-22

Review

https://www.cureus.com/articles/124983-a-review-of-long-covid-with-a-special-focus-on-its-cardiovascular-manifestations

Abstract
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has been the cause of the century’s worst pandemic so far: coronavirus disease 2019 (COVID-19). It has led to unprecedented mortality and morbidity, resulting in devastating consequences worldwide. The acute manifestations of COVID-19 including respiratory as well as multisystem involvement have been causes of great concern among physicians. However, the long-term effects of the coronavirus have left many patients battling with chronic symptoms, ranging from extreme fatigue to cardiomyopathy. In this article, we review the chronic manifestations of COVID-19 with a focus on cardiovascular manifestations. We discuss the pathophysiology, post-acute sequelae, clinical manifestations, approach to the laboratory diagnosis of cardiovascular manifestations of long COVID, and a proposed multidisciplinary treatment method. We also explore the relationship between vaccination and the long COVID syndrome.
Introduction & Background
According to the WHO’s weekly report of coronavirus disease 2019 (COVID-19) on October 30, 2022, over 627 million confirmed cases and over 6.5 million deaths have been reported globally [1]. Although the incidence of new cases is on the decline, the long-term sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have sparked a growing interest among clinicians and researchers. This is due to the fact that survivors of COVID-19 have now been reported to have a higher risk of mortality, and health loss due to a wide spectrum of pulmonary and extra-pulmonary manifestations [2]. In this review, we discuss the definition of post-acute sequelae of COVID-19 (PASC), the epidemiology, pathophysiology, clinical characteristics, and proposed management strategies. Our review touches briefly on the wide spectrum of long COVID while paying special attention to its cardiovascular manifestations.

1833

CaV261

Thomas A. Dewland & Gregory M. Marcus

SARS-CoV-2 infection and cardiac arrhythmias

https://doi.org/10.1038/s44161-022-00166-x

Published

23-Nov-22

Comment

https://www.nature.com/articles/s44161-022-00166-x

Although cardiac arrhythmias have been observed and described during and after SARS-CoV-2 infection, rigorous studies designed to untangle the complex relationship between this proinflammatory illness and arrhythmogenesis are limited. Despite a pervasive opinion to the contrary, there is presently no definitive data to establish a causal, viral-specific association between COVID-19 and incident arrhythmia.

1834

CaV262

Thiago A. Laranjeira, Antonio S. Menezes Jr.

A Systematic Review of Post-COVID Electrocardiographic Changes in Young Athletes

https://doi.org/10.7759/cureus.31829

Published

23-Nov-22

Review

https://www.cureus.com/articles/124860-a-systematic-review-of-post-covid-electrocardiographic-changes-in-young-athletes

Post-coronavirus disease (COVID) syndrome involves the presentation of various new, returning, or ongoing symptoms, more than four weeks after COVID-19 infection. Post-infectious myocarditis is a potential sequela, associated with greater arrhythmogenic potential. Thus, it is an outcome that should be considered in athletes. An undiagnosed heart condition associated with adrenergic stimulus caused by high-intensity exercises can lead to sudden cardiac death. Electrocardiography (ECG) plays a role in cardiac screening for potential cardiac changes associated with myocarditis. Therefore, this study aimed to evaluate the occurrence of electrocardiographic alterations in athletes during the post-COVID period.

A systematic review of longitudinal observational studies in the PubMed, LILACS, and CENTRAL databases that evaluated athletes in the post-COVID period with ECG was performed. A total of four articles involving 5371 patients were included in the analysis. The athletes mostly presented with mild asymptomatic or symptomatic COVID-19. A low prevalence of electrocardiographic alterations suggestive of cardiac involvement by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in this population.

Electrocardiographic abnormalities indicative of myocarditis are uncommon in young athletes throughout the post-COVID era. However, anomalies that may signify and need further cardiovascular testing were found.

1835

CaV263

LeenAlblaihedMBBS, MHAaWilliam J.BradyMDbTareqAl-SalamahMBBS, MPHcAmalMattuMDa

Dysrhythmias associated with COVID-19: Review and management considerations

https://doi.org/10.1016/j.ajem.2022.12.004

Published

5-Dec-22

Review

https://www.sciencedirect.com/science/article/pii/S0735675722007446

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), is known to affect the cardiovascular system. Cardiac manifestations in COVID-19 can be due to direct damage to the myocardium and conduction system as well as by the disease's effect on the various organ systems. These manifestations include acute coronary syndrome, ST- segment elevations, cardiomyopathy, and dysrhythmias. Some of these dysrhythmias can be detrimental to the patient. Therefore, it is important for the emergency physician to be aware of the different arrhythmias associated with COVID-19 and how to manage them. This narrative review discusses the pathophysiology underlying the various arrhythmias associated with COVID-19 and their management considerations.

1836

CaV264

Zachary V.RezlerBHScabEmmaKoBMScbElaineJinBHScbMishaIshtiaqBHScabChristinaPapaioannoubHelenaKimBHScbKyobinHwangaYu-Hsin (Sophy)LinBSccJakeColauttiBHScabKaren M.DavisonMSc, PhDcVidhiThakkarMSc, PhDac

The impact of COVID-19 on the cardiovascular health of emerging adults aged 18-25: findings from a scoping review

https://doi.org/10.1016/j.cjcpc.2022.11.005

Published

1-Dec-22

Review

https://www.sciencedirect.com/science/article/pii/S277281292200118X

There is limited knowledge regarding the cardiovascular impact of coronavirus disease 2019 (COVID-19) on emerging adults aged 18-25, a group which disproportionately contracts COVID-19. To guide future cardiovascular disease (CVD) research, policy, and practice, a scoping review was conducted to: i) examine the impact of the COVID-19 pandemic on the cardiovascular health of emerging adults; and ii) identify strategies to screen for and manage COVID-19-related cardiovascular complications in this age group. A comprehensive search strategy was applied to several academic databases and grey literature sources. An updated search yielded 6738 articles, 147 of which were extracted and synthesized. Reports identified COVID-19-associated cardiac abnormalities, vascular alterations, and multisystem inflammatory syndrome in emerging adults; based on data from student-athlete samples, prevalence estimates of myocarditis and cardiac abnormalities were 0.5-3% and 0-7%, respectively. Obesity, hypertension, CVD, congenital heart disease, and marginalization are potential risk factors for severe COVID-19, related cardiovascular complications, and mortality in this age group. As a screening modality for COVID-19-associated cardiac involvement, it is recommended that cardiac magnetic resonance imaging be indicated by a positive cardiac history and/or abnormal ‘triad’ testing (cardiac troponin, electrocardiogram, and transthoracic echocardiogram) to improve diagnostic utility. To foster long-term cardiovascular health among emerging adults, cardiorespiratory fitness, health literacy and education, and telehealth accessibility should be priorities of health policy and clinical practice. Ultimately, surveillance data from the broader emerging adult population will be crucial to assess the long-term cardiovascular impact of both COVID-19 and vaccination, guide screening and management protocols, and inform CVD prevention efforts.

1837

CaV265

Dini, Frank Lloyd; Baldini, Umberto; Bytyçi, Ibadete; Pugliese, Nicola Riccardo; Bajraktari, Gani; Henein, Michael Y.

Acute pericarditis as a major clinical manifestation of long COVID-19 syndrome

https://doi.org/10.3390/medicina58121807

Published

Study

https://www.mdpi.com/1648-9144/58/12/1807

Following COVID-19 infection, a substantial proportion of patients suffer from persistent symptoms known as Long COVID. Among the main symptoms are fatigue, cognitive dysfunction, muscle weakness and orthostatic intolerance (OI). These symptoms also occur in myalgic encephalomyelitis/chronic fatigue (ME/CFS). OI is highly prevalent in ME/CFS and develops early during or after acute COVID-19 infection. The causes for OI are unknown and autonomic dysfunction is hypothetically assumed to be the primary cause, presumably as a consequence of neuroinflammation. Here, we propose an alternative, primary vascular mechanism as the underlying cause of OI in Long COVID. We assume that the capacitance vessel system, which plays a key role in physiologic orthostatic regulation, becomes dysfunctional due to a disturbance of the microvessels and the vasa vasorum, which supply large parts of the wall of those large vessels. We assume that the known microcirculatory disturbance found after COVID-19 infection, resulting from endothelial dysfunction, microthrombus formation and rheological disturbances of blood cells (altered deformability), also affects the vasa vasorum to impair the function of the capacitance vessels. In an attempt to compensate for the vascular deficit, sympathetic activity overshoots to further worsen OI, resulting in a vicious circle that maintains OI. The resulting orthostatic stress, in turn, plays a key role in autonomic dysfunction and the pathophysiology of ME/CFS.

1838

CaV266

Wirth, Klaus J.; Löhn, Matthias

Orthostatic Intolerance after COVID-19 Infection: Is Disturbed Microcirculation of the Vasa Vasorum of Capacitance Vessels the Primary Defect?

https://doi.org/10.1016/j.ijcard.2022.12.019

Published

Study

https://www.internationaljournalofcardiology.com/article/S0167-5273(22)01891-5/fulltext

Publisher: Elsevier
PMID: 36513284
Highlights
•Acute pericarditis is an important manifestation of long COVID-19 syndrome.
•Thickened and bright pericardial layers with small effusions was the most frequent finding.
•History of autoimmune and allergic disorders, and palpitations/arrhythmias were risk factors.
Abstract
Background
The long COVID-19 syndrome has been recently described and some reports have suggested that acute pericarditis represents important manifestation of long COVID-19 syndrome. The aim of this study was to identify the prevalence and clinical characteristics of patients with long COVID-19, presenting with acute pericarditis.
Methods
We retrospectively included 180 patients (median age 47 years, 62% female) previously diagnosed with COVID-19, exhibiting persistence or new-onset symptoms ≥12 weeks from a negative naso-pharyngeal SARS CoV2 swamp test. The original diagnosis of COVID-19 infection was determined by a positive swab. All patients had undergone a thorough physical examination. Patients with suspected heart involvement were referred to a complete cardiovascular evaluation. Echocardiography was performed based on clinical need and diagnosis of acute pericarditis was achieved according to current guidelines.
Results
Among the study population, shortness of breath/fatigue was reported in 52%, chest pain/discomfort in 34% and heart palpitations/arrhythmias in 37%. Diagnosis of acute pericarditis was made in 39 patients (22%). Mild-to-moderate pericardial effusion was reported in 12, while thickened and bright pericardial layers with small effusions (< 5 mm) with or without comet tails arising from the pericardium (pericardial B-lines) in 27. Heart palpitations/arrhythmias (OR:3.748, p = 0.0030), and autoimmune disease and allergic disorders (OR:4.147, p = 0.0073) were independently related to the diagnosis of acute pericarditis, with a borderline contribution of less likelihood of hospitalization during COVID-19 (OR: 0.100, p = 0.0512).
Conclusion
Our findings suggest a high prevalence of acute pericarditis in patients with long COVID-19 syndrome. Autoimmune and allergic disorders, and palpitations/arrhythmias were frequently associated with pericardial disease.

1839

CaV267

Carbone, Francis R.

Unique properties of tissue-resident memory T cells in the lungs: implications for COVID-19 and other respiratory diseases

https://doi.org/10.1016/j.cjca.2022.12.003

Published

Study

https://www.sciencedirect.com/science/article/pii/S0828282X22010923

Background
Acute myocarditis has been described as a relatively rare cardiovascular complication of COVID-19 infection. However, data regarding the risk of myocarditis during the post-acute phase of COVID-19 are scant. We assess the risk of incident myocarditis in COVID-19 survivors within one year from the index infection by a systematic review and meta-analysis of the available data.
Methods
Data were obtained searching MEDLINE and Scopus for all studies published at any time up to September 1, 2022, and reporting the long-term risk of incident myocarditis in COVID-19 survivors. Myocarditis risk data were pooled using the Mantel–Haenszel random effects models with Hazard ratio (HR) as the effect measure with 95% confidence interval (CI). Heterogeneity among studies was assessed using Higgins and Thomson I2 statistic.
Results
Overall, 20.875.843 patients (mean age 56.1 years, 59.1% males) were included in this analysis. Of them, 1.245.167 survived to COVID-19 infection. Over a mean follow-up of 9.5 months, myocarditis occurred to 0.21 [95% CI: 0.13- 0.42) out of 1000 patients survived to COVID-19 infection compared to 0.09 [95% CI: 0.07-0.12] out of 1000 control subjects. Pooled analysis revealed that recovered COVID-19 patients presented an increased risk of incident myocarditis (HR: 5.16, 95% CI: 3.87-6.89, p<0.0001, I2=7.9%) within one year from the index infection. The sensitivity analysis confirmed yielded results.
Conclusion
Our findings suggest that myocarditis represents a relatively rare but important post-acute COVID-19 sequelae.

1840

CaV268

Abdulla, Maheeba; Mohammed, Nafeesa; AlQamish, Jehad; Mosli, Mahmoud

Inflammatory bowel disease and COVID-19 outcomes: a meta-analysis

https://doi.org/10.1016/j.cjca.2022.12.002

Published

Study

https://www.sciencedirect.com/science/article/pii/S0828282X22010911

Background
Many COVID-19 patients are left with symptoms several months after resolution of the acute illness (“Post-Acute Sequalae of COVID-19” [PASC]). We aimed to determine the prevalence of objective hemodynamic cardiovascular autonomic abnormalities (CAA), explore sex differences, and assess the prevalence of CAA among hospitalized vs non-hospitalized PASC patients.
Methods
Patients with PASC (n=70; F=56; 42 years 95% CI [40,48]) completed standard autonomic tests, including an active stand test 399 days [338,455] after their COVID-19 infection. Clinical autonomic abnormalities were evaluated.
Results
Most patients with PASC met the criteria for at least one CAA (51; 73%; F=43). The Postural Orthostatic Tachycardia Syndrome hemodynamic criterion (POTSHR) of a heart rate increase of >30bpm within 5-10mins of standing was seen in 21 patients (30%; F=20; p=0.037 [by sex]). The Initial Orthostatic Hypotension hemodynamic criterion (IOH40) of a transient SBP change of >40mmHg in the first 15s of standing was seen in 43 (61%) patients and equally among females and males (63% vs. 57%; p=0.7). Only 9 (13%) patients were hospitalized; hospitalized vs. non-hospitalized patients had similar frequencies of abnormalities (67% vs. 74%; p=0.7).
Conclusions
Patients with PASC have evidence of CAA, most commonly IOH40, which will be missed unless an active stand test is used. Females have increased frequency of POTSHR, but IOH40 is equally prevalent between sexes. Finally, even non-hospitalized “mild” infections can result in long-term CAA.

1841

CaV269

Hira, Rashmin; Baker, Jacquie R.; Siddiqui, Tanya; Ranada, Shaun I.; Soroush, Ateyeh; Karalasingham, Kavithra; Ahmad, Hyeqa; Mavai, Vibhuti; Ayala Valani, Luciano Martin; Ambreen, Sakina; Bourne, Kate M.; Lloyd, Matthew G.; Morillo, Carlos A.; Sheldon, Robert S.; Raj, Satish R.

Objective Hemodynamic Cardiovascular Autonomic Abnormalities in Post-Acute Sequelae of COVID-19

https://doi.org/10.1016/j.cjca.2022.12.002

Published

Study

https://www.sciencedirect.com/science/article/pii/S0828282X22010911

Background: The long-term sequela of COVID-19 on young people is still unknown. This systematic review explored the effect of COVID-19 on lung imaging and function, cardiorespiratory symptoms, fatigue, exercise capacity and functional capacity in children and adolescents ≥ 3 months after infection. Methods: A systemic search was completed in the electronic databases of PubMed, Web of Science and Ovid MEDLINE on 27 May 2022. Data on the proportion of participants who had long-term effects were collected, and one-group meta-analysis were used to estimate the pooled prevalence of the outcomes studied. Results: 17 articles met the inclusion criteria, presented data on 124,568 children and adolescents. The pooled prevalence of abnormalities in lung imaging was 10% (95% CI 1–19, I2 = 73%), abnormal pulmonary function was 24% (95% CI 4–43, I2 = 90%), chest pain/tightness was 6% (95% CI 3–8, I2 = 100%), heart rhythm disturbances/palpitations was 6% (95% CI 4–7, I2 = 98%), dyspnea/breathing problems was 16% (95% CI 14–19, I2 = 99%), and fatigue was 24% (95% CI 20–27, I2 = 100%). Decreased exercise capacity and functional limitations were found in 20% (95% CI 4–37, I2 = 88%) and 48% (95% CI 25–70, I2 = 91%) of the participants studied, respectively. Conclusion: Children and adolescents may have persistent abnormalities in lung imaging and function, cardiorespiratory symptoms, fatigue, and decreased functional capacity between 3 to 12 months after infection. More research is needed to understand the long-term effect of COVID-19 on young people, and to clarify its causes and effective management.

1842

CaV270

Constantinescu-Bercu, Adela; Kessler, Anna; Groot, Rens de; Dragunaite, Bertina; Heightman, Melissa; Hillman, Toby; Price, Laura C.; Brennan, Ewan; Sivera, Raphael; Vanhoorelbeke, Karen; Singh, Deepak; Scully, Marie

Analysis of thrombogenicity under flow reveals new insights into the prothrombotic state of patients with post-COVID syndrome

https://doi.org/10.1016/j.jtha.2022.10.013

Published

Study

https://www.jthjournal.org/article/S1538-7836(22)07182-3/fulltext

publisher: Elsevier
Essentials
•
Post-COVID syndrome is an emerging condition linked to an uncharacterized prothrombotic state.
•
We studied thrombogenicity using a range of tests, including a novel microfluidic assay.
•
Post-COVID syndrome can lead to increased platelet recruitment and larger thrombi under flow.
•
The median time of 23 months from symptom onset suggests potential long-term thrombogenicity.
Abstract
Background
Post-COVID syndrome (PCS) affects millions of people worldwide, causing a multitude of symptoms and impairing quality of life months or even years after acute COVID-19. A prothrombotic state has been suggested; however, underlying mechanisms remain to be elucidated.
Objectives
To investigate thrombogenicity in PCS using a microfluidic assay, linking microthrombi, thrombin generation, and the von Willebrand factor (VWF):a Disintegrin and Metalloproteinase with a Thrombospondin Type 1 motif, member 13 (ADAMTS13) axis.
Methods
Citrated blood was perfused through microfluidic channels coated with collagen or an antibody against the VWF A3 domain, and thrombogenicity was monitored in real time. Thrombin generation assays were performed and α(2)-antiplasmin, VWF, and ADAMTS13 activity levels were also measured.
Results
We investigated thrombogenicity in a cohort of 21 patients with PCS with a median time following symptoms onset of 23 months using a dynamic microfluidic assay. Our data show a significant increase in platelet binding on both collagen and anti-VWF A3 in patients with PCS compared with that in controls, which positively correlated with VWF antigen (Ag) levels, the VWF(Ag):ADAMTS13 ratio (on anti-VWF A3), and inversely correlated with ADAMTS13 activity (on collagen). Thrombi forming on collagen presented different geometries in patients with PCS vs controls, with significantly increased thrombi area mainly attributable to thrombi length in the patient group. Thrombi length positively correlated with VWF(Ag):ADAMTS13 ratio and thrombin generation assay results, which were increased in 55.5% of patients. α(2)-Antiplasmin levels were normal in 89.5% of patients.
Conclusion
Together, these data present a dynamic assay to investigate the prothrombotic state in PCS, which may help unravel the mechanisms involved and/or establish new therapeutic strategies for this condition.

1843

CaV271

Szoltysek-Boldys, Izabela; Zielinska-Danch, Wioleta; Loboda, Danuta; Wilczek, Jacek; Gibinski, Michal; Paradowska-Nowakowska, Elzbieta; Golba, Krzysztof S.; Sarecka-Hujar, Beata

Photoplethysmographic Measurement of Arterial Stiffness in Polish Patients with Long-COVID-19 Syndrome—The Results of a Cross-Sectional Study

https://doi.org/10.3390/diagnostics12123189

Published

Study

https://www.mdpi.com/2075-4418/12/12/3189

The coronavirus disease 2019 (COVID-19) is associated with an increase in the incidence of cardiovascular diseases (CVD) that persists even several months after the onset of infection. COVID-19 may also have an impact on arterial stiffness, which is a risk factor for CVD. We aimed to analyze if and to what extent arterial stiffness measured by photoplethysmography differed among COVID-19 convalescents depending on the acute phase severity and time elapsed since disease onset. A total of 225 patients (mean age 58.98 ± 8.57 years, 54.7% women) were analyzed after COVID-19 hospitalization at the Cardiac Rehabilitation Department of the Ustron Health Resort (Poland). In the entire study population, no differences were found in the mean values of stiffness index (SI) and reflection index (RI) depending on the severity of the acute COVID-19 and the time since the onset of the disease. There were no differences in the heart rate (HR) according to the severity of acute COVID-19; the mean HR was higher in patients who had COVID-19 less than 12 weeks before the study than in convalescents more than 24 weeks after the acute disease (p = 0.002). The mean values of SI and RI were higher in men than in women (p < 0.001), while the heart rate (HR) was similar in both sexes (p = 0.286). However, multiple linear regression analyses after adjusting for factors influencing arterial stiffness, i.e., sex, age, body mass index, smoking status, hypertension, diabetes, the severity of the acute COVID-19, and the time from the disease onset, confirmed that age, sex, time from disease onset, and diabetes are the most important determinants that could influence arterial stiffness.

1844

CaV272

Moscucci, Federica; Gallina, Sabina; Bucciarelli, Valentina; Aimo, Alberto; Pelà, Giovanna; Cadeddu-Dessalvi, Christian; Nodari, Savina; Maffei, Silvia; Meloni, Antonella; Deidda, Martino; Mercuro, Giuseppe; Pedrinelli, Roberto; Penco, Maria; Sciomer, Susanna; Vittoria Mattioli, Anna

Impact of COVID-19 on the cardiovascular health of women: a review by the Italian Society of Cardiology Working Group on ‘gender cardiovascular diseases’

https://doi.org/10.2459/JCM.0000000000001398

Published

Review

https://journals.lww.com/jcardiovascularmedicine/Fulltext/9900/Impact_of_COVID_19_on_the_cardiovascular_health_of.81.aspx

The coronavirus disease 19 (COVID-19), due to coronavirus 2 (SARS-CoV-2) infection, presents with an extremely heterogeneous spectrum of symptoms and signs. COVID-19 susceptibility and mortality show a significant sex imbalance, with men being more prone to infection and showing a higher rate of hospitalization and mortality than women.
In particular, cardiovascular diseases (preexistent or arising upon infection) play a central role in COVID-19 outcomes, differently in men and women. This review will discuss the potential mechanisms accounting for sex/gender influence in vulnerability to COVID-19.
Such variability can be ascribed to both sex-related biological factors and sex-related behavioural traits.
Sex differences in cardiovascular disease and COVID-19 involve the endothelial dysfunction, the innate immune system and the renin-angiotensin system (RAS). Furthermore, the angiotensin-converting enzyme 2 (ACE2) is involved in disease pathogenesis in cardiovascular disease and COVID-19 and it shows hormone-dependent actions.
The incidence of myocardial injury during COVID-19 is sex-dependent, predominantly in association with a greater degree of inflammation and coagulation disorders among men. Its pathogenesis is not fully elucidated, but the main theories foresee a direct role for the ACE2 receptor, the hyperimmune response and the RAS imbalance, which may also lead to isolated presentation of COVID-19-mediated myopericarditis.
Moreover, the latest evidence on cardiovascular diseases and their relationship with COVID-19 during pregnancy will be discussed.
Finally, authors will analyse the prevalence of the long-covid syndrome between the two sexes and its impact on the quality of life and cardiovascular health.

1845

CaV273

Ruberg, Frederick L.; Baggish, Aaron L.; Hays, Allison G.; Jerosch-Herold, Michael; Kim, Jiwon; Ordovas, Karen G.; Reddy, Gautham; Shenoy, Chetan; Weinsaft, Jonathan W.; Woodard, Pamela K.

Utilization of cardiovascular magnetic resonance (CMR) imaging for resumption of athletic activities following COVID-19 infection: an expert consensus document on behalf of the American Heart Association Council on Cardiovascular Radiology and Intervention (CVRI) Leadership and endorsed by the Society for Cardiovascular Magnetic Resonance (SCMR)

https://doi.org/10.1186/s12968-022-00907-8

Published

Review

https://doi.org/10.1186/s12968-022-00907-8

The global pandemic of coronavirus disease 2019 (COVID-19) caused by infection with severe acute respiratory suyndrome coronavirus 2 (SARS-CoV-2) is now entering its 4th year with little evidence of abatement. As of December 2022, the World Health Organization Coronavirus (COVID-19) Dashboard reported 643 million cumulative confirmed cases of COVID-19 worldwide and 98 million in the United States alone as the country with the highest number of cases. While pneumonia with lung injury has been the manifestation of COVID-19 principally responsible for morbidity and mortality, myocardial inflammation and systolic dysfunction though uncommon are well-recognized features that also associate with adverse prognosis. Given the broad swath of the population infected with COVID-19, the large number of affected professional, collegiate, and amateur athletes raises concern regarding the safe resumption of athletic activity (return to play, RTP) following resolution of infection. A variety of different testing combinations that leverage the electrocardiogram, echocardiography, circulating cardiac biomarkers, and cardiovascular magnetic resonance (CMR) imaging have been proposed and implemented to mitigate risk. CMR in particular affords high sensitivity for myocarditis but has been employed and interpreted non-uniformly in the context of COVID-19 thereby raising uncertainty as to the generalizability and clinical relevance of findings with respect to RTP. This consensus document synthesizes available evidence to contextualize the appropriate utilization of CMR in the RTP assessment of athletes with prior COVID-19 infection to facilitate informed, evidence-based decisions, while identifying knowledge gaps that merit further investigation.

1846

CaV274

Ståhlberg, Marcus; Fedorowski, Artur

Cardiovascular autonomic abnormalities in patients with Post-acute Sequalae of COVID-19: don’t miss that target!

https://doi.org/10.1016/j.cjca.2022.12.021

Published

Editorial

https://www.onlinecjc.ca/article/S0828-282X(22)01117-5/fulltext

publisher: Elsevier
PMID: 36586481
A massive and sustained world-wide spread of the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has triggered a pandemic that has lasted for three years now and generated > 600 million reported cases around the globe. It has been increasingly evident that a substantial portion of patients who develop Corona Virus Disease 2019 (COVID-19) do not recover completely but rather experience lingering symptoms for months to years. This novel clinical syndrome is has been termed Long COVID or Post-acute Sequalae of COVID-19 (PASC), and has been defined by the World Health Organization as ongoing symptoms beyond three months from the acute illness due to confirmed or suspected SARS-CoV-2 infection that cannot be explained by other diseases1. The prevalence of PASC in patients with COVID-19 varies based on definition and setting and has been reported to be between 68% in hospitalized 2 and 13% in non-hospitalized patients 3. It’s beyond any doubt that this novel clinical syndrome has profound negative effects on individual patients, healthcare sectors and whole societies.
Case reports and smaller observational cohort studies have indicated that PASC can be associated with cardiovascular (CV) autonomic dysfunction including postural orthostatic tachycardia syndrome (POTS), inappropriate sinus tachycardia (IST), and orthostatic hypotension (OH)4, 5, 6, 7. This is important since CV dysautonomias are conditions that often can be successfully treated with substantial symptom improvement, while virtually no evidence exists for effective treatment of PASC itself. The prevalence of CV autonomic dysfunction in PASC remains largely unknown but is important to comprehend since it will highlight dysautonomia as a specific sequalae of acute COVID-19, establish pre-test likelihood and guide the development of diagnostic work-up protocols for unsorted PASC patients.
Cardiovascular dysautonomia is common in PACS: more women but no difference between hospitalized and non-hospitalized patients
Hira and colleagues should be complimented for the effort to determine the occurrence of cardiovascular autonomic abnormalities in PACS patients. In their study published in this issue8, 70 PASC patients completed a thorough investigation including active standing test, autonomic function testing (quantitative sudomotor axon reflex testing, deep breathing, and Valsalva maneuver) as well as symptom reports at a median of 399 days after a primary PCR-confirmed SARS-CoV-2 infection. A majority of included patients were females (80%) and did not require hospital treatment during the acute COVID-19 disease (87%). However, comorbidities, disease history and current medications as well as the exact inclusion criteria were not detailed. The authors report a high prevalence of CV dysautonomia in the overall cohort (73%), with the most prevalent abnormality being initial orthostatic hypotension (61%) and POTS (30%). Inappropriate sinus tachycardia was uncommon (1.4%) but it should be emphasized that prolonged ECG monitoring was not a part of study protocol, thus reducing the diagnostic accuracy for this specific abnormality.9 Moreover, tilt testing and 24-hour ambulatory blood pressure monitoring were not performed, which potentially may have affected the detection rate of delayed orthostatic hypotension and vasovagal syncope susceptibility, common dysautonomic conditions.7,10,11 POTS was found more frequently in females (36%) compared to males (7%, p=0.0037), and the overall prevalence of cardiovascular dysautonomia was similar in hospitalized and non-hospitalized patients which implies that initial disease severity is not a risk factor for developing dysautonomia in PASC patients.
Strengths and weaknesses of the study
The study has several strengths. Previous data on the prevalence of specific forms of CV dysautonomia in PASC relied mostly on case reports, case series, smaller observational studies, and symptom questionnaires. In contrast, the current paper includes a fairly large patient cohort that are well characterized in terms of hemodynamic response to active standing test, and by other autonomic tests as well as by presence and severity of symptoms common in dysautonomia. Patients were evaluated on average one year after the primary SARS-CoV-2 infection which is important when interpreting the results. Persistence of CV dysautonomia long time after initial infection suggests that these symptoms and hemodynamic findings are in many unlikely to resolve shortly after the initial infection. One might suspect that the number of patients affected by CV autonomic abnormalities may have been higher at three or six months after acute illness but that some may have recovered before the evaluation one year after. It is also our clinical experience that symptoms and hemodynamic findings during orthostatic tests may change over a longer follow-up period. Therefore, an important study limitation is that testing for CV dysautonomia was performed only once.
In general, to describe accurately prevalence of a disease in population, a larger number of evaluated subjects is needed. The study by Hira and colleagues is therefore limited by the relatively small number of included patients. It is additionally difficult to draw conclusions on sex differences (only 20% males) and importance of hospitalization (only 13% were hospitalized) as these subgroups were even smaller. Furthermore, most patients were recruited from referral centers (dedicated PASC centers and/or dysautonomia clinics) which likely makes the study population highly selected. Consequently, it’s difficult to extrapolate these findings onto general PASC population. One can assume that patients evaluated at these centers experienced longer PASC duration and more severe functional impairment compared with an average PASC patient thus biasing the study toward a sicker population. Therefore, the prevalence numbers reported by Hira and colleagues should be interpreted with caution as representative for specialized post-COVID centers, not the general PASC population. The proportions of POTS, for instance, reported here are however in line with our personal experience from a similar tertiary center, and find support in previous reports.12 Importantly, the present study included only Caucasians from the same geographical region and hence, studies in other races and geographical regions are needed to establish the global impact of CV dysautonomia on PASC.
Two other aspects we wish to highlight as important when interpreting these results are that 80% of patients were evaluated before COVID-19 vaccination and that data on when the initial COVID-19 disease occurred were not presented. First, COVID-19 vaccination itself can induce prolonged symptoms and physical findings consistent with CV dysautonomia although POTS is diagnosed at a much lower rate after vaccination than after contracting the virus13. Second, the SARS-CoV-2 has mutated several times during the pandemic, and it is unknown whether different SARS-CoV-2 strains are more prone to trigger CV dysautonomia. Thus, the prevalence of dysautonomia in PASC population may change after vaccination or according to the viral strand causing the primary infection. However, we consider it unlikely that these factors would have a decisive effect on the overall incidence of autonomic disturbances in the study.
Conclusion
Although some limitations exist, the study constitutes an important contribution to our understanding of the role of cardiovascular autonomic dysfunction in the post-COVID condition. Patients were systematically evaluated and majority were diagnosed with at least one objective, symptomatic and potentially treatable autonomic abnormality. These findings highlight the need for specialized autonomic clinics and imply that a high suspicion of cardiovascular dysautonomia should be raised in patients not recovering swiftly from acute COVID-19.

1847

CaV275

Matsumoto, Chisa; Shibata, Shigeru; Kishi, Takuya; Morimoto, Satoshi; Mogi, Masaki; Yamamoto, Koichi; Kobayashi, Kazuo; Tanaka, Masami; Asayama, Kei; Yamamoto, Eiichiro; Nakagami, Hironori; Hoshide, Satoshi; Mukoyama, Masashi; Kario, Kazuomi; Node, Koichi; Rakugi, Hiromi

Long COVID and hypertension-related disorders: a report from the Japanese Society of Hypertension Project Team on COVID-19

https://doi.org/10.1038/s41440-022-01145-2

Published

Review

https://www.nature.com/articles/s41440-022-01145-2

The coronavirus disease 2019 (COVID-19) affects infected patients even after the acute phase and impairs their health and quality of life by causing a wide variety of symptoms, referred to as long COVID. Although the evidence is still insufficient, hypertension is suspected to be a potential risk factor for long COVID, and the occurrence of cardiovascular diseases seems to be a key facet of multiple conditions observed in long COVID. Nonetheless, there are few reports that comprehensively review the impacts of long COVID on hypertension and related disorders. As a sequel to our previous report in 2020 which reviewed the association of COVID-19 and hypertension, we summarize the possible influences of long COVID on hypertension-related organs, including the cardiovascular system, kidney, and endocrine system, as well as the pathophysiological mechanisms associated with the disorders in this review. Given that the clinical course of COVID-19 is highly affected by age and sex, we also review the impacts of these factors on long COVID. Lastly, we discuss areas of uncertainty and future directions, which may lead to better understanding and improved prognosis of clinical problems associated with COVID-19.

1848

CaV276

Zuin, Marco; Rigatelli, Gianluca; Roncon, Loris; Pasquetto, Gianpaolo; Bilato, Claudio

Risk of incident heart failure after COVID-19 recovery: a systematic review and meta-analysis

https://doi.org/10.1007/s10741-022-10292-0

Published

Study

https://doi.org/10.1007/s10741-022-10292-0

Patients recovered from COVID-19 have an increased incidence of cardiovascular disease and heart structural changes. The aim of the present manuscript is to assess the risk of incident heart failure (HF) after COVID-19 infection. Data were obtained searching MEDLINE and Scopus for all studies published at any time up to September 1, 2022 reporting the risk of incident HF in COVID-19 recovered patients. The cumulative post-COVID-19 incidence and risk of incident HF were pooled using a random effects model and presented with the corresponding 95% confidence interval (CI). Statistical heterogeneity was measured using the Higgins I2 statistic. Overall, 21,463,173 patients (mean age 54.5 years, 58.7% males) were analyzed. Among them, 1,628,424 had confirmed COVID-19 infection while the remaining 19,834,749 represented the controls. The mean length of follow-up was 9.2 months. A random effect model revealed a pooled incidence of post COVID-19 HF in 1.1% of cases (95% CI: 0.7–1.6, I2: 99.8%). Moreover, recovered COVID-19 patients showed an increased risk of incident HF (HR: 1.90, 95% CI: 1.54–3.24, p < 0.0001, I2 = 96.5%) in the same follow-up period. Meta-regression showed a direct relationship for the risk of incident HF using age (p = 0.001) and hypertension (HT) (p = 0.02) as moderators, while an inverse association was observed when the follow-up length was adopted as moderating variable (p = 0.01). COVID-19 survivors had an additional 90% risk of developing HF after COVID-19 infection in the long-term period. This risk was directly related with age and previous history of HT especially in the early post-acute phase of the infection.

1849

CaV277

Płazak, Wojciech; Drabik, Leszek

SARS-CoV-2 infection and SLE: endothelial dysfunction, atherosclerosis, and thrombosis

https://doi.org/10.1007/s10067-022-06497-1

Published

9-Jan-23

Review

https://doi.org/10.1007/s10067-022-06497-1

Abstract
An increased risk of atherosclerotic and thrombotic complications characterizes connective tissue diseases. Endothelial dysfunction is the basis for the initiation and progression of atherosclerosis and thrombosis. We present systemic lupus erythematosus (SLE) as a model rheumatic disease with endothelial dysfunction and discuss its mechanisms, factors that influence the early onset and rapid progression of atherosclerosis, and the increased risk of thromboembolic events. We focus on established methods to improve endothelium function, including statins, antiplatelet, and antithrombotic therapy. Hypercoagulable and hypofibrinolitic states and a hyperinflammatory response characterize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Several pathogenic mechanisms are typical for an acute phase of Covid-19 post-Covid syndrome and connective tissue diseases: endothelial dysfunction, elevated antiphospholipid antibody titer, activation of the complement system, and formation of extracellular neutrophil traps (NET). The current review discusses the mechanisms underlying SLE and the COVID-19 in the context of endothelial function, atherosclerosis, and thrombosis (Graphical abstract).

Key Points
• The pathophysiology of systemic lupus erythematosus (SLE) and Covid-19 shows some similarities, such as endothelial cell activation and dysfunction, the activation of complementary systems, the presence of antiphospholipid antibodies, and the formation of extracellular neutrophil traps.
• Autoimmunity in both diseases creates the basis for hyperinflammatory, hypercoagulable, and hypofibrinolitic states and their thromboembolic complications.
• This paper presents our perspective on the mechanisms behind the cardiovascular manifestations of SLE and COVID-19, with a particular emphasis on endothelial dysfunction.
Graphical abstract
Covid-19 and systemic lupus erythematosus—potential similarities in pathophysiology. Figures of the panel illustrate the clinical manifestations of endothelial dysfunction, atherosclerosis, and thromboembolism, including coronary artery disease ([A] coronary angiography with left anterior descending artery stenosis and [B] scintigraphy with reduced perfusion in the myocardial apical segments), stroke ([C] carotid angiography, left carotid artery occlusion) and pulmonary embolism ([D]computed tomography with thrombus in the right pulmonary artery).

1850

CaV278

Martingano, Daniel; Santana, Eddie; Mehta, Prutha; Ngyuen, Ashley; Al-Dulaimi, Marwa; Robertson, Katie; Menefee, Christopher; Ouyang, Andrea; Herben, Camilla; Singh, Shailini; Marecheau, Jacqueline; Dribus, Benjamin F.

Effect of Respiratory and Anticoagulation Medications on Long Covid in the Postpartum Period

https://doi.org/10.1016/j.ajog.2022.11.254

Published

1-Jan-23

Study

https://www.ajog.org/article/S0002-9378(22)01138-3/fulltext

publisher: Elsevier
Objective
Long Covid (LC) is a collective term referring to the persistence of symptoms and complications related to those acquiring an acute SARS-CoV-2 infection. This study sought to evaluate the potential benefits of certain medications often employed empirically in the management of LC for pregnant patients in the 3rd trimester and postpartum periods.
Study Design
We conducted a multi-center, prospective observational study from 7/2021 to 7/2022 comparing all pregnant women diagnosed with SARS-CoV-2 infection (CoV-2) in the 3rd trimester through 6 weeks postpartum. The primary outcomes included the development of LC and improvement following treatment. Patients with preexisting respiratory, hematological, or neurological disorders or preterm delivery < 37 weeks-gestation, were excluded. Medications including any CoV-2 antiviral treatment, enoxaparin, aspirin, inhaled corticosteroids with or without a long-acting beta blocker, theophylline, leukotriene receptor antagonists, and 1st generation antihistamines were included as covariates. Primary outcomes were determined by patient-reported symptoms and provider interpretation in the immediate postpartum, 1-week postpartum (1P), and 6-week postpartum (6P) periods.
Results
The study included 444 patients diagnosed with LC. 291 (65.6%) patients received enoxaparin at time of diagnosis continued weekly until 6 weeks postpartum. Patients who received enoxaparin were less likely to report LC at the 1P and 6P visits (39.2% v. 54.9%, p = 0.02). LC was not significantly different when comparing patients who received antiviral therapies to those who did not. Patients with LC were more likely to report improvement when taking aspirin 325mg (19.8% v. 11.3%, p = 0.003) or when taking theophylline (22.9% v. 14.2%, p = 0.01). After adjusting for confounding factors these differences remained significant.
Conclusion
These findings suggest that treatments targeting the circulatory system may prove more useful for LC in the 3rd trimester and postpartum period than other types of medications.

1851

CaV279

Durrington, Paul

Blood lipids after COVID-19 infection

https://doi.org/10.1016/S2213-8587(22)00389-8

Published

6-Jan-23

Commentary

https://www.thelancet.com/journals/landia/article/PIIS2213-8587(22)00389-8/fulltext

publisher: Elsevier
PMID: 36623516
The report by Xu and colleagues3 raises fundamental questions about the origins of dyslipidaemia in general. We know that the acute effect of infection or serious illnesses from other causes is to lower LDL cholesterol, sometimes profoundly.4, 5 At the same time there is a tendency for triglycerides to rise and for HDL cholesterol to decrease. LDL cholesterol is usually restored to premorbid concentrations as the acute illness abates, but in chronic inflammation the increase in triglyceride and decreased HDL persists probably due to the effect of inflammatory cytokines.4, 5 Although the aetiology of long COVID remains speculative, clear evidence that a state of chronic inflammation can persist even in asymptomatic survivors is accruing.6, 7 During such inflammation, the composition and functional capacity of HDL also changes and it has thus been called pro-inflammatory or pro-atherogenic HDL. Serum amyloid A, released during inflammation, interferes with the ability of HDL to protect LDL from pro-atherogenic modifications such as oxidation and glycation. Furthermore, decreases in apolipoprotein A1 in HDL reduce its capacity to receive excess tissue cholesterol, which is believed to occur through the ATP binding cassette A1 and to be an important early phase of reverse cholesterol transport.5
• View related content for this article

The effects of chronic inflammation on lipoprotein metabolism have been extensively investigated in obesity. Adipose tissue, particularly when it is centrally located (metabolic syndrome), contains inflammatory cells that release cytokines causing dyslipidaemia. Reversal by bariatric surgery restores triglyceride and HDL metabolism towards normality, but has little effect on LDL cholesterol.8 Persisting effects on LDL after the apparent resolution of inflammation are unexplained and remind us just how imperfect our knowledge is of what determines LDL cholesterol concentrations in adulthood. Recently, because of their potential to lower LDL cholesterol by pharmacological inhibition, interest has sparked in two factors that influence the balance between LDL catabolism and production. These are proprotein convertase subtilisin or kexin type 9 (PCSK9), which has a major effect on hepatic receptor-mediated LDL catabolism9 and angiopoietin-like protein 3 (ANGPTL3), which regulates the production of LDL from its precursor very low density lipoprotein.10 It has been hypothesised that both can increase during inflammation.9, 10, 11
We clearly need to learn more about how cholesterol metabolism is permanently imprinted by nutrition and infection or inflammation.

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Krug, Ethan; Geckeler, Keara C.; Frishman, William H.

Cardiovascular Manifestations of Long COVID: A Review

https://doi.org/10.1097/CRD.0000000000000520

Published

6-Jan-23

Review

https://journals.lww.com/cardiologyinreview/Abstract/9900/Cardiovascular_Manifestations_of_Long_COVID__A.65.aspx

The acute phase of severe acute respiratory syndrome coronavirus 2 [coronavirus disease (COVID)] infection has many well-documented cardiovascular manifestations, however, the long-term sequelae are less understood. In this focused review, we explore the risk factors, character, and rates of cardiovascular events in patients with Long COVID, which is defined as symptoms occurring more than 4 weeks following initial infection. Research has identified increased rates of cerebrovascular disease, dysrhythmias, ischemic and inflammatory heart disease, cardiopulmonary symptoms, and thrombotic events among those with Long COVID, though the risk rates and potential mechanisms behind each cardiovascular event vary. Finally, we discuss the current gaps in the literature as well as how COVID compares to other viral infections when it comes to causing long-term cardiovascular sequelae.

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Ortega-Paz, Luis; Arévalos, Victor; Fernández-Rodríguez, Diego; Jiménez-Díaz, Víctor; Bañeras, Jordi; Campo, Gianluca; Rodríguez-Santamarta, Miguel; Díaz, José Francisco; Scardino, Claudia; Gómez-Álvarez, Zaira; Pernigotti, Alberto; Alfonso, Fernando; Amat-Santos, Ignacio J.; Silvestro, Antonio; Rampa, Lorenzo; Hernández, José M. de la Torre; Bastidas, Gabriela; Gómez-Lara, Josep; Bikdeli, Behnood; García-García, Hector M.; Angiolillo, Dominick J.; Rodés-Cabau, Josep; Sabaté, Manel; Brugaletta, Salvatore; Investigators, on behalf of the CV COVID-19 registry

One-year cardiovascular outcomes after coronavirus disease 2019: The cardiovascular COVID-19 registry

https://doi.org/10.1371/journal.pone.0279333

Published

30-Dec-22

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0279333

Background The long-term cardiovascular (CV) outcomes of COVID-19 have not been fully explored. Methods This was an international, multicenter, retrospective cohort study conducted between February and December 2020. Consecutive patients ≥18 years who underwent a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) for SARS-CoV2 were included. Patients were classified into two cohorts depending on the nasopharyngeal swab result and clinical status: confirmed COVID-19 (positive RT-PCR) and control (without suggestive symptoms and negative RT-PCR). Data were obtained from electronic records, and clinical follow-up was performed at 1-year. The primary outcome was CV death at 1-year. Secondary outcomes included arterial thrombotic events (ATE), venous thromboembolism (VTE), and serious cardiac arrhythmias. An independent clinical event committee adjudicated events. A Cox proportional hazards model adjusted for all baseline characteristics was used for comparing outcomes between groups. A prespecified landmark analysis was performed to assess events during the post-acute phase (31–365 days). Results A total of 4,427 patients were included: 3,578 (80.8%) in the COVID-19 and 849 (19.2%) control cohorts. At one year, there were no significant differences in the primary endpoint of CV death between the COVID-19 and control cohorts (1.4% vs. 0.8%; HRadj 1.28 [0.56–2.91]; p = 0.555), but there was a higher risk of all-cause death (17.8% vs. 4.0%; HRadj 2.82 [1.99–4.0]; p = 0.001). COVID-19 cohort had higher rates of ATE (2.5% vs. 0.8%, HRadj 2.26 [1.02–4.99]; p = 0.044), VTE (3.7% vs. 0.4%, HRadj 9.33 [2.93–29.70]; p = 0.001), and serious cardiac arrhythmias (2.5% vs. 0.6%, HRadj 3.37 [1.35–8.46]; p = 0.010). During the post-acute phase, there were no significant differences in CV death (0.6% vs. 0.7%; HRadj 0.67 [0.25–1.80]; p = 0.425), but there was a higher risk of deep vein thrombosis (0.6% vs. 0.0%; p = 0.028). Re-hospitalization rate was lower in the COVID-19 cohort compared to the control cohort (13.9% vs. 20.6%; p = 0.001). Conclusions At 1-year, patients with COVID-19 experienced an increased risk of all-cause death and adverse CV events, including ATE, VTE, and serious cardiac arrhythmias, but not CV death. Study registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT04359927.

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Kusumawardhani, Nuraini Yasmin; Putra, Iwan Cahyo Santosa; Kamarullah, William; Afrianti, Rien; Pramudyo, Miftah; Iqbal, Mohammad; Prameswari, Hawani Sasmaya; Achmad, Chaerul; Tiksnadi, Badai Bhatara; Akbar, Mohammad Rizki

Cardiovascular Disease in Post-Acute COVID-19 Syndrome: A Comprehensive Review of Pathophysiology and Diagnosis Approach

https://doi.org/10.31083/j.rcm2401028

Published

13-Jan-23

Review

https://www.imrpress.com/journal/RCM/24/1/10.31083/j.rcm2401028

Long COVID or post-acute Coronavirus disease 2019 (COVID-19), a malady defined by the persistence of COVID-19 symptoms for weeks or even months, is expected to affect the lives of millions of individuals worldwide significantly. Cardiopulmonary symptoms such as chest discomfort, shortness of breath, fatigue, and autonomic manifestations such as postural orthostatic tachycardia syndrome, and arrhythmias are prevalent and widely recognized. A variety of cardiovascular problems, including myocardial inflammation, myocardial infarction, ventricular dysfunction, and endothelial dysfunction, have been described in individuals following the initial acute phase. With over 10,000 published publications on COVID-19 and the cardiovascular system, presenting an unbiased thorough analysis of how SARS-CoV-2 affects the system is essentially challenging. This review will provide an overview of frequent cardiovascular manifestations, emphasizing consequences, proposed pathophysiology, and clinical diagnostic manifestation strategy.

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Kumar, Rahul; Aktay-Cetin, Öznur; Craddock, Vaughn; Morales-Cano, Daniel; Kosanovic, Djuro; Cogolludo, Angel; Perez-Vizcaino, Francisco; Avdeev, Sergey; Kumar, Ashok; Ram, Anil Kumar; Agarwal, Stuti; Chakraborty, Ananya; Savai, Rajkumar; Perez, Vinicio de Jesus; Graham, Brian B.; Butrous, Ghazwan; Dhillon, Navneet K.

Potential long-term effects of SARS-CoV-2 infection on the pulmonary vasculature: Multilayered cross-talks in the setting of coinfections and comorbidities

https://doi.org/10.1371/journal.ppat.1011063

Published

12-Jan-23

Review

https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1011063

The Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its sublineages pose a new challenge to healthcare systems worldwide due to its ability to efficiently spread in immunized populations and its resistance to currently available therapies. COVID-19, although targeting primarily the respiratory system, is also now well established that later affects every organ in the body. Most importantly, despite the available therapy and vaccine-elicited protection, the long-term consequences of viral infection in breakthrough and asymptomatic individuals are areas of concern. In the past two years, investigators accumulated evidence on how the virus triggers our immune system and the molecular signals involved in the cross-talk between immune cells and structural cells in the pulmonary vasculature to drive pathological lung complications such as endothelial dysfunction and thrombosis. In the review, we emphasize recent updates on the pathophysiological inflammatory and immune responses associated with SARS-CoV-2 infection and their potential long-term consequences that may consequently lead to the development of pulmonary vascular diseases.

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Zanini, Giada; Selleri, Valentina; Roncati, Luca; Coppi, Francesca; Nasi, Milena; Farinetti, Alberto; Manenti, Antonio; Pinti, Marcello; Mattioli, Anna Vittoria

Vascular “Long COVID”: A New Vessel Disease?

https://doi.org/10.1177/00033197231153204

Published

18-Jan-23

Review

https://doi.org/10.1177/00033197231153204

Vascular sequelae following (SARS-CoV-2 coronavirus disease) (COVID)-19 infection are considered as ?Long Covid (LC)? disease, when occurring 12 weeks after the original infection. The paucity of specific data can be obviated by translating pathophysiological elements from the original Severe Acute Respiratory Syndrome-Corona Virus (SARS-CoV-2) infection (In a microcirculatory system, a first ?endotheliitis,? is often followed by production of ?Neutrophil Extracellular Trap,? and can evolve into a more complex leukocytoklastic-like and hyperimmune vasculitis. In medium/large-sized vessels, this corresponds to endothelial dysfunction, leading to an accelerated progression of pre-existing atherosclerotic plaques through an increased deposition of platelets, circulating inflammatory cells and proteins. Associated dysregulated immune and pro-coagulant conditions can directly cause thrombo-embolic arterial or venous complications. In order to implement appropriate treatment, physicians need to consider vascular pathologies observed after SARS-Cov-2 infections as possible ?LC? disease.

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Wan, Eric Yuk Fai; Mathur, Sukriti; Zhang, Ran; Yan, Vincent Ka Chun; Lai, Francisco Tsz Tsun; Chui, Celine Sze Ling; Li, Xue; Wong, Carlos King Ho; Chan, Esther Wai Yin; Yiu, Kai Hang; Wong, Ian Chi Kei

Association of COVID-19 with short- and long-term risk of cardiovascular disease and mortality: a prospective cohort in UK Biobank

https://doi.org/10.1093/cvr/cvac195

Published

19-Jan-23

Study

https://doi.org/10.1093/cvr/cvac195

This study aims to evaluate the short- and long-term associations between COVID-19 and development of cardiovascular disease (CVD) outcomes and mortality in the general population.A prospective cohort of patients with COVID-19 infection between 16 March 2020 and 30 November 2020 was identified from UK Biobank, and followed for up to 18 months, until 31 August 2021. Based on age (within 5 years) and sex, each case was randomly matched with up to 10 participants without COVID-19 infection from two cohorts—a contemporary cohort between 16 March 2020 and 30 November 2020 and a historical cohort between 16 March 2018 and 30 November 2018. The characteristics between groups were further adjusted with propensity score-based marginal mean weighting through stratification. To determine the association of COVID-19 with CVD and mortality within 21 days of diagnosis (acute phase) and after this period (post-acute phase), Cox regression was employed. In the acute phase, patients with COVID-19 (n = 7584) were associated with a significantly higher short-term risk of CVD {hazard ratio (HR): 4.3 [95% confidence interval (CI): 2.6– 6.9]; HR: 5.0 (95% CI: 3.0–8.1)} and all-cause mortality [HR: 81.1 (95% CI: 58.5–112.4); HR: 67.5 (95% CI: 49.9–91.1)] than the contemporary (n = 75 790) and historical controls (n = 75 774), respectively. Regarding the post-acute phase, patients with COVID-19 (n = 7139) persisted with a significantly higher risk of CVD in the long-term [HR: 1.4 (95% CI: 1.2–1.8); HR: 1.3 (95% CI: 1.1– 1.6)] and all-cause mortality [HR: 5.0 (95% CI: 4.3–5.8); HR: 4.5 (95% CI: 3.9–5.2) compared to the contemporary (n = 71 296) and historical controls (n = 71 314), respectively.COVID-19 infection, including long-COVID, is associated with increased short- and long-term risks of CVD and mortality. Ongoing monitoring of signs and symptoms of developing these cardiovascular complications post diagnosis and up till at least a year post recovery may benefit infected patients, especially those with severe disease.

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Ashton, Ruth E.; Philips, Bethan E.; Faghy, Mark

The acute and chronic implications of the COVID-19 virus on the cardiovascular system in adults: A systematic review

https://doi.org/10.1016/j.pcad.2023.01.003

Published

20-Jan-23

Review

https://www.sciencedirect.com/science/article/pii/S003306202300004X

Despite coronavirus disease 2019 (COVID-19) primarily being identified as a respiratory illness, some patients who seemingly recovered from initial infection, developed chronic multi-system complications such as cardiovascular (CV), pulmonary and neurological issues leading to multiple organ injuries. However, to date, there is a dearth of understanding of the acute and chronic implications of a COVID-19 infection on the CV system in adults. A systematic review of the literature was conducted according to PRISMA guidelines and prospectively registered via Prospero (ID: CRD42022360444). The MEDLINE Ovid, Cochrane Library and PubMed databases were searched from inception to August 2022. The search strategy keywords and MeSH terms used included: 1) COVID; 2) coronavirus; 3) long COVID; 4) cardiovascular; and 5) cardiovascular disease. Reference lists of all relevant systematic reviews identified were searched for additional studies. A total of 11,332 records were retrieved from database searches, of which 310 records were duplicates. A further 9887 were eliminated following screening of titles and abstracts. After full-text screening of 1135 articles, 9 manuscripts were included for review. The evidence of CV implications post-COVID-19 infection is clear, and this must be addressed with appropriate management strategies that recognise the acute and chronic nature of cardiac injury in COVID-19 patients. Efficacious management strategies will be needed to address long standing issues and morbidity.

1859

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Gyöngyösi, Mariann; Alcaide, Pilar; Asselbergs, Folkert W; Brundel, Bianca J J M; Camici, Giovanni G; Martins, Paula da Costa; Ferdinandy, Péter; Fontana, Marianna; Girao, Henrique; Gnecchi, Massimiliano; Gollmann-Tepeköylü, Can; Kleinbongard, Petra; Krieg, Thomas; Madonna, Rosalinda; Paillard, Melanie; Pantazis, Antonis; Perrino, Cinzia; Pesce, Maurizio; Schiattarella, Gabriele G; Sluijter, Joost P G; Steffens, Sabine; Tschöpe, Carsten; Van Linthout, Sophie; Davidson, Sean M

Long COVID and the cardiovascular system—elucidating causes and cellular mechanisms in order to develop targeted diagnostic and therapeutic strategies: a joint Scientific Statement of the ESC Working Groups on Cellular Biology of the Heart and Myocardial and Pericardial Diseases

https://doi.org/10.1093/cvr/cvac115

Published

25-Jul-22

Review

https://doi.org/10.1093/cvr/cvac115

Long COVID has become a world-wide, non-communicable epidemic, caused by long-lasting multiorgan symptoms that endure for weeks or months after SARS-CoV-2 infection has already subsided. This scientific document aims to provide insight into the possible causes and therapeutic options available for the cardiovascular manifestations of long COVID. In addition to chronic fatigue, which is a common symptom of long COVID, patients may present with chest pain, ECG abnormalities, postural orthostatic tachycardia, or newly developed supraventricular or ventricular arrhythmias. Imaging of the heart and vessels has provided evidence of chronic, post-infectious perimyocarditis with consequent left or right ventricular failure, arterial wall inflammation, or microthrombosis in certain patient populations. Better understanding of the underlying cellular and molecular mechanisms of long COVID will aid in the development of effective treatment strategies for its cardiovascular manifestations. A number of mechanisms have been proposed, including those involving direct effects on the myocardium, microthrombotic damage to vessels or endothelium, or persistent inflammation. Unfortunately, existing circulating biomarkers, coagulation, and inflammatory markers, are not highly predictive for either the presence or outcome of long COVID when measured 3 months after SARS-CoV-2 infection. Further studies are needed to understand underlying mechanisms, identify specific biomarkers, and guide future preventive strategies or treatments to address long COVID and its cardiovascular sequelae.

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Yong, Shin Jie; Halim, Alice; Halim, Michael; Liu, Shiliang; Aljeldah, Mohammed; Al Shammari, Basim R.; Alwarthan, Sara; Alhajri, Mashael; Alawfi, Abdulsalam; Alshengeti, Amer; Khamis, Faryal; Alsalman, Jameela; Alshukairi, Abeer N.; Abukhamis, Nujoud A.; Almaghrabi, Fatimah S.; Almuthree, Souad A.; Alsulaiman, Abdulrahman M.; Alshehail, Bashayer M.; Alfaraj, Amal H.; Alhawaj, Shorouq A.; Mohapatra, Ranjan K.; Rabaan, Ali A.

Inflammatory and vascular biomarkers in post-COVID-19 syndrome: A systematic review and meta-analysis of over 20 biomarkers

https://doi.org/10.1002/rmv.2424

Published

27-Jan-23

Study

https://onlinelibrary.wiley.com/doi/abs/10.1002/rmv.2424

Severe acute respiratory syndrome coronavirus 2 may inflict a post-viral condition known as post-COVID-19 syndrome (PCS) or long-COVID. Studies measuring levels of inflammatory and vascular biomarkers in blood, serum, or plasma of COVID-19 survivors with PCS versus non-PCS controls have produced mixed findings. Our review sought to meta-analyse those studies. A systematic literature search was performed across five databases until 25 June 2022, with an updated search on 1 November 2022. Data analyses were performed with Review Manager and R Studio statistical software. Twenty-four biomarkers from 23 studies were meta-analysed. Higher levels of C-reactive protein (Standardized mean difference (SMD) = 0.20; 95% CI: 0.02–0.39), D-dimer (SMD = 0.27; 95% CI: 0.09–0.46), lactate dehydrogenase (SMD = 0.30; 95% CI: 0.05–0.54), and leukocytes (SMD = 0.34; 95% CI: 0.02–0.66) were found in COVID-19 survivors with PCS than in those without PCS. After sensitivity analyses, lymphocytes (SMD = 0.30; 95% CI: 0.12–0.48) and interleukin-6 (SMD = 0.30; 95% CI: 0.12–0.49) were also significantly higher in PCS than non-PCS cases. No significant differences were noted in the remaining biomarkers investigated (e.g., ferritin, platelets, troponin, and fibrinogen). Subgroup analyses suggested the biomarker changes were mainly driven by PCS cases diagnosed via manifestation of organ abnormalities rather than symptomatic persistence, as well as PCS cases with duration of <6 than ≥6 months. In conclusion, our review pinpointed certain inflammatory and vascular biomarkers associated with PCS, which may shed light on potential new approaches to understanding, diagnosing, and treating PCS.

1861

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Reis Carneiro, Diogo; Rocha, Isabel; Habek, Mario; Helbok, Raimund; Sellner, Johann; Struhal, Walter; Wenning, Gregor; Fanciulli, Alessandra

Clinical presentation and management strategies of cardiovascular autonomic dysfunction following a COVID-19 infection – A systematic review

https://doi.org/10.1111/ene.15714

Published

24-Jan-23

Review

https://onlinelibrary.wiley.com/doi/abs/10.1111/ene.15714

Background Cardiovascular autonomic dysfunction may reportedly occur after a coronavirus-disease-2019 (COVID-19) infection, but the available evidence is scattered. Here we sought to understand the acute and mid-term effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on cardiovascular autonomic function. Methods We performed a systematic PubMed, Embase, Web of Science, medRxiv, and bioRxiv search for cases of cardiovascular autonomic dysfunction during an acute SARS-CoV-2 infection or post-COVID-19 condition. The clinical-demographic characteristics of individuals in the acute versus post-COVID-19 phase were compared. Results We screened 6470 titles and abstracts. Fifty-four full-length articles were included in the data synthesis. One-hundred and thirty-four cases were identified: 81 during the acute SARS-CoV-2 infection (24 thereof diagnosed by history) and 53 in the post-COVID-19 phase. Post-COVID-19 cases were younger than those with cardiovascular autonomic disturbances in the acute SARS-CoV-2 phase (42 vs. 51 years old, p = 0.002) and were more frequently women (68% vs. 49%, p = 0.034). Reflex syncope was the most common cardiovascular autonomic disorder in the acute phase (p = 0.008) and postural orthostatic tachycardia syndrome (POTS) the most frequent diagnosis in individuals with post-COVID-19 orthostatic complaints (p < 0.001). Full recovery was more frequent in individuals with acute versus post-COVID-19 onset of cardiovascular autonomic disturbances (43% vs. 15%, p = 0.002). Conclusions There is evidence from the scientific literature about different types of cardiovascular autonomic dysfunction developing during and after COVID-19. More data about the prevalence of autonomic disorders associated with a SARS-CoV-2 infection are needed to quantify its impact on human health.

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Shrestha, Abhigan Babu; Mehta, Aashna; Pokharel, Pashupati; Mishra, Aakash; Adhikari, Lukash; Shrestha, Sajina; Yadav, Randhir Sagar; Khanal, Surakshya; Sah, Ranjit; Nowrouzi-Kia, Behdin; Padhi, Bijaya Kumar; Chattu, Vijay Kumar

Long COVID Syndrome and Cardiovascular Manifestations: A Systematic Review and Meta-Analysis

https://doi.org/10.3390/diagnostics13030491

Published

1-Jan-23

Systematic review and meta-analysis

https://www.mdpi.com/2075-4418/13/3/491

(1) Background: Long COVID syndrome is a significant cause of morbidity in COVID-19 patients who remain symptomatic with varied clinical presentations beyond three weeks. Furthermore, the relevance of considering cardiovascular outcomes in post-COVID-19 syndrome is important in the current COVID-19 pandemic; (2) Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed for this systematic review and meta-analysis. Systematic searches were conducted from multiple databases without language restrictions until October 8, 2022, to find studies evaluating cardiovascular outcomes such as arrhythmias, myocardium and pericardium diseases, coronary vessel disease, and thromboembolic disorders in post-COVID cases. The pooled odds ratio (OR), and standard mean difference (SMD) with their corresponding 95% confidence intervals (CI) were computed to find the association; (3) Results: Altogether, seven studies with a total of 8,126,462 (cases: 1,321,305; controls: 6,805,157) participants were included in the meta-analysis. Pooled odds ratios of cardiovascular outcomes were significantly higher in post-COVID cases (OR > 1, p < 0.05) than in controls. However, the mortality (OR: 4.76, p = 0.13), and heart rate variability (SMD: −0.06, p = 0.91) between cases and controls were not statistically significant; (4) Conclusions: Significant cardiovascular sequelae in long COVID syndrome highlight the importance of careful cardiac monitoring of COVID-19 patients in the post-COVID phase to address cardiovascular complications as soon as possible; larger-scale prospective studies are required for accurate estimation.

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Huseynov, Aydin; Akin, Ibrahim; Duerschmied, Daniel; Scharf, Rüdiger E.

Cardiac Arrhythmias in Post-COVID Syndrome: Prevalence, Pathology, Diagnosis, and Treatment

https://doi.org/10.3390/v15020389

Published

1-Feb-23

Review

https://www.mdpi.com/1999-4915/15/2/389

An increase in post-COVID patients with late sequelae of acute COVID-19 infection is emerging as an ongoing challenge for physicians and healthcare professionals. Since the beginning of the pandemic, it has rapidly become evident that the acute infection is not limited to the respiratory tract but that several organs, including the cardiovascular system, can be affected. Moreover, in a significant proportion of patients (ranging from about 10 to up to 50%) with former COVID-19, cardiopulmonary symptoms such as dyspnea, palpitations, restricted physical capacity, and cardiac arrhythmias can persist weeks and months after the acute SARS-CoV-2 infection. The spectrum of COVID-19-associated arrhythmias is rather wide, most likely due to various pathomechanisms. In this article, the prevalence of cardiac arrhythmias and underlying pathologies are reviewed, including direct myocardial injury and abnormal consequences with an impact on cardiac electric instability. The hyperinflammatory reaction of the host immune system is specifically considered. Moreover, several distinct rhythm disorders occurring in post-COVID patients are discussed with regard to their clinical management.

1864

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Doğan, Hasan; Kara, Aslı; Çankaya, Erdem; Balkan, Eda; Gürbüz, Muhammet Ali; Kızılkaya, Murat; Aykaç, Merve

Clinical Investigation of Leukocyte DNA Damage in COVID-19 Patients

https://doi.org/10.3390/cimb45020062

Published

1-Feb-23

Study

https://www.mdpi.com/1467-3045/45/2/62

This prospective cross-sectional study aimed to evaluate leukocyte DNA damage in coronavirus disease (COVID-19) patients. In this study, 50 COVID-19-positive patients attending the Erzurum City Hospital Internal Medicine Outpatient Clinic and 42 control group patients were included. DNA damage was detected in living cells through leukocyte isolation in 50 COVID-19-positive patients using the comet assay method. DNA tail/head (olive) moments were evaluated and compared. White blood cells (WBC), red blood cells (RBC), hemoglobin (HGB), neutrophils (NEU), lymphocytes (LYM), eosinophils (EO), monocytes (MONO), basophils (BASO), platelets (PLT), and the neutrophil/lymphocyte ratio (NLR) were analyzed. The RBC, lymphocyte, eosinophil, and monocyte means were significantly higher in the control group (p < 0.05), whereas the HGB and neutrophile means were significantly higher in the study group (p < 0.05). There were significant negative correlations between COVID-19 and RBC (r = −0.863), LYM (r = −0.542), EO (r = −0.686), and MONO (r = −0.385). Meanwhile, there were significant positive correlations between COVID-19 and HGB (r = 0.863), NEU (r = 0.307), tail moment (r = 0.598), and olive moment (r = 0.582). Both the tail and olive moment mean differences were significantly higher in the study group, with higher ranges (p < 0.05). COVID-19 infection caused statistically significant increases in both the tail and olive damage percentage in patients, causing DNA damage. Lastly, the NLR rate was associated with the presence and progression of COVID-19.

1865

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ZeinElabdeen, Shimaa Gamal; Sherif, Abdelsalam; Kandil, Nader Talaat; Altabib, Abdalaali Mohammed Omar; abdelrashid, Mahmoud Abdelaziz

Left atrial longitudinal strain analysis in long Covid-19 syndrome

https://doi.org/10.1007/s10554-023-02801-5

Published

14-Feb-23

Study

https://doi.org/10.1007/s10554-023-02801-5

It is known that during the active course of Coronavirus disease 2019 (COVID-19), myocardial injury has an established pathological base, while its myocardial injury post-recovery is still obscured.The aim of this study was to evaluate the longitudinal left atrial strain (LAS) using speckle tracking echocardiography (STE) in COVID-19-recovered patients who are previously healthy without confounder comorbidities to detect the potential cardiac dysfunction.200 patients were prospectively included and examined 4?12 weeks after recovery from COVID-19 infection. 137 participants with comorbidities or previous history of cardiopulmonary disease were excluded from the analysis. A total of 63 patients who fulfilled our inclusion criteria were recruited into two groups according to thepresence or absence of persistent dyspnoea and exercise intolerance. Clinical, laboratory & comprehensive echocardiographic examinations were done for all. We observed that 31.7% of the previously healthy individuals developed dyspnoea & exercise intolerance post-COVID-19 infection. There were significantly impaired LAS parameters in the symptomatic group (LA reservoir, contraction & conduit strain, 22.7%, -6.6% & -16.1% versus 40%, -12%, and ? 27% in the asymptomatic group with P < 0.000). Only LA reservoir strain and LA stiffness can independently predict the development of dyspnoea & exercise intolerance post-COVID-19 at cut-off values of 30% & 24.5% respectively with a sensitivity of 90% and a specificity of 91%, P < 0.001. These impaired LAS parameters could explain the developed symptoms post-COVID-19 recovery, even before disturbed conventional diastolic echocardiographic parameters.LAS parameters are significantly associated with the developed exertional dyspnoea & exercise intolerance post-COVID-19. LA reservoir strain & LA stiffness could provide a simple, easily available tool that points to early LV diastolic dysfunction and may direct the therapy in this subset of the population.

1866

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Akhtar, Zubair; Trent, Mallory; Moa, Aye; Tan, Timothy C; Fröbert, Ole; MacIntyre, C Raina

The impact of COVID-19 and COVID vaccination on cardiovascular outcomes

https://doi.org/10.1093/eurheartjsupp/suac123

Published

15-Feb-23

Review

https://doi.org/10.1093/eurheartjsupp/suac123

COVID-19 is an independent risk factor for cardiovascular disease. COVID-19 vaccination may prevent this, but in some cases, COVID-19 vaccination may cause myocarditis or pericarditis. Patients with COVID-19 may present with non-specific symptoms that have a cardiac origin. This review examines the cardiovascular complications of COVID-19 infection and the impact of COVID-19 vaccination. COVID-19 cardiovascular complications include myocardial injury, pericarditis, coagulopathy, myocardial infarction, heart failure, arrhythmias, and persistent post-acute risk of adverse cardiovascular outcomes. Diagnostic and referral pathways for non-specific symptoms, such as dyspnoea and fatigue, remain unclear. COVID-19 vaccination is cardioprotective overall but is associated with myopericarditis in young males, though at a lower rate than following SARS-CoV-2 infection. Increased awareness among primary care physicians of potential cardiovascular causes of non-specific post-COVID-19 symptoms, including in younger adults, such as fatigue, dyspnoea, and chest pain, is essential. We recommend full vaccination with scheduled booster doses, optimal management of cardiovascular risk factors, rapid treatment of COVID-19, and clear diagnostic, referral, and management pathways for patients presenting with non-specific symptoms to rule out cardiac complications.

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Willems, Loes H.; Jacobs, Lotte M. C.; Groh, Laszlo A.; ten Cate, Hugo; Spronk, Henri M. H.; Wilson-Storey, Boden; Hannink, Gerjon; van Kuijk, Sander M. J.; Ghossein-Doha, Chahinda; Nagy, Magdi; Thijssen, Dick H. J.; van Petersen, André S.; Warlé, Michiel C.

Vascular Function, Systemic Inflammation, and Coagulation Activation 18 Months after COVID-19 Infection: An Observational Cohort Study

https://doi.org/10.3390/jcm12041413

Published

1-Jan-23

Study

https://www.mdpi.com/2077-0383/12/4/1413

Introduction: Among its effect on virtually all other organs, COVID-19 affects the cardiovascular system, potentially jeopardizing the cardiovascular health of millions. Previous research has shown no indication of macrovascular dysfunction as reflected by carotid artery reactivity, but has shown sustained microvascular dysfunction, systemic inflammation, and coagulation activation at 3 months after acute COVID-19. The long-term effects of COVID-19 on vascular function remain unknown. Materials and Methods: This cohort study involved 167 patients who participated in the COVAS trial. At 3 months and 18 months after acute COVID-19, macrovascular dysfunction was evaluated by measuring the carotid artery diameter in response to cold pressor testing. Additionally, plasma endothelin-1, von Willebrand factor, Interleukin(IL)-1ra, IL-6, IL-18, and coagulation factor complexes were measured using ELISA techniques. Results: The prevalence of macrovascular dysfunction did not differ between 3 months (14.5%) and 18 months (11.7%) after COVID-19 infection (p = 0.585). However, there was a significant decrease in absolute carotid artery diameter change, 3.5% ± 4.7 vs. 2.7% ± 2.5, p—0.001, respectively. Additionally, levels of vWF:Ag were persistently high in 80% of COVID-19 survivors, reflecting endothelial cell damage and possibly attenuated endothelial function. Furthermore, while levels of the inflammatory cytokines interleukin(IL)-1RA and IL-18 were normalized and evidence of contact pathway activation was no longer present, the concentrations of IL-6 and thrombin:antithrombin complexes were further increased at 18 months versus 3 months (2.5 pg/mL ± 2.6 vs. 4.0 pg/mL ± 4.6, p = 0.006 and 4.9 μg/L ± 4.4 vs. 18.2 μg/L ± 11.4, p < 0.001, respectively). Discussion: This study shows that 18 months after COVID-19 infection, the incidence of macrovascular dysfunction as defined by a constrictive response during carotid artery reactivity testing is not increased. Nonetheless, plasma biomarkers indicate sustained endothelial cell activation (vWF), systemic inflammation (IL-6), and extrinsic/common pathway coagulation activation (FVII:AT, TAT) 18 months after COVID-19 infection.

1868

CaV296

Carbone, Roberto G.; Puppo, Francesco

Pericarditis in long COVID-19

https://doi.org/10.1016/j.ijcard.2023.01.087

Published

6-Feb-23

Editorial

https://www.internationaljournalofcardiology.com/article/S0167-5273(23)00170-5/fulltext

In summary the investigation by Llyod Dini et al. [[1]] confirms the data reported in the literature showing that pericarditis is a major cardiac complication in COVID-19 infection. However large prospective clinical trials are required for a more accurate assessment of the incidence of pericarditis in acute and long COVID-19 infection.
publisher: Elsevier
PMID: 36758864

1869

CaV297

Parhizgar, Parinaz; Yazdankhah, Nima; Rzepka, Anna M.; Chung, Kit Yan Christie; Ali, Irfan; Lai, Rachel; Russell, Victoria; Cheung, Angela M.

Beyond acute COVID-19: A review of long-term cardiovascular outcomes

https://doi.org/10.1016/j.cjca.2023.01.031

Published

6-Feb-23

Review

https://www.sciencedirect.com/science/article/pii/S0828282X23000776

Statistics Canada estimates that approximately 1.4 million Canadians suffer from long COVID. While cardiovascular changes during acute SARS-CoV-2 infection are well documented, long-term cardiovascular sequelae are less understood. In this review, we sought to characterize adult cardiovascular outcomes seen in the months following acute COVID-19 illness. Our search identified reports of outcomes including cardiac dysautonomia, myocarditis, ischemic injuries, and ventricular dysfunction. Even in patients without overt cardiac outcomes, subclinical changes have been observed. Cardiovascular sequelae following SARS-CoV-2 infection can stem from exacerbation of pre-existing conditions, ongoing inflammation, or as a result of damage occurring during acute infection. For example, myocardial fibrosis has been reported months after hospital admission for COVID-19 illness, and may be a consequence of myocarditis and myocardial injury during acute disease. In turn, myocardial fibrosis can contribute to further outcomes including dysrhythmias and heart failure. Severity of acute infection may be a risk factor for long-term cardiovascular consequences, however, cardiovascular changes have also been reported in young, healthy individuals who had asymptomatic or mild acute disease. Although evolving evidence suggests that prior SARS-CoV-2 infection may be a risk factor for cardiovascular disease, there is heterogeneity in existing evidence, and some studies are marred by both measured and unmeasured confounders. Many investigations have also been limited by relatively short follow up. Future studies should focus on longer term outcomes (beyond 1 year) and identifying the prevalence of outcomes in different populations based on acute and long COVID disease severity.

1870

CaV298

Moulson, Nathaniel; Petek, Bradley J.; Baggish, Aaron L.; Harmon, Kimberly G.; Kliethermes, Stephanie A.; Patel, Manesh R.; Churchill, Timothy W.; Drezner, Jonathan A.

The Cardiac Effects of COVID-19 on Young Competitive Athletes: Results from the Outcomes Registry for Cardiac Conditions in Athletes (ORCCA)

https://doi.org/10.3390/jcdd10020072

Published

1-Feb-23

Review

https://www.mdpi.com/2308-3425/10/2/72

The Outcomes Registry for Cardiac Conditions in Athletes (ORCCA) study is a large-scale prospective investigation evaluating the cardiovascular effects and outcomes of SARS-CoV-2 infection on young competitive athletes. This review provides an overview of the key results from the ORCCA study. Results from the ORCCA study have provided important insights into the clinical impact of SARS-CoV-2 infection on the cardiovascular health of young competitive athletes and informed contemporary screening and return to sport practices. Key results include defining a low prevalence of both cardiac involvement and adverse cardiovascular outcomes after SARS-CoV-2 infection and evaluating the utility of a return-to-play cardiac evaluation. Future aims of the ORCCA study include the longer-term evaluation of cardiovascular outcomes among athletes post-SARS-CoV-2 infection and the transition to investigating outcomes in young athletes with potentially high-risk genetic or structural cardiac diagnoses.

1871

CaV299

Espinosa-Gonzalez, Ana B.; Master, Harsha; Gall, Nicholas; Halpin, Stephen; Rogers, Natalie; Greenhalgh, Trisha

Orthostatic tachycardia after covid-19

https://doi.org/10.1136/bmj-2022-073488

Published

24-Feb-23

Article

https://www.bmj.com/content/380/bmj-2022-073488

### What you need to know

Patients with long covid—defined by the National Institute for Health and Care Excellence (NICE) as signs and symptoms that persist for more than four weeks (and especially more than 12 weeks) following acute covid-1912—may present in primary care with symptoms of palpitations (tachycardia) triggered by standing or minimal exertion.3 These may be accompanied by dizziness, breathlessness, chest pain, sweating, bloating, fatigue, and other symptoms which may be caused by a dysfunction of the autonomic nervous system (dysautonomia).45678910111213 Patients can find these symptoms debilitating and they can affect function and mood. Limited evidence, variable diagnostic criteria, uncertainty around cause and pathogenesis, and the absence of licensed medications, have all contributed to making this a difficult condition to diagnose and manage. In this practice pointer, we offer an overview of orthostatic tachycardia following covid-19, including a summary of the key steps for diagnosis and management.

Prevalence estimates vary depending on sample and setting, but indicate that about 25% of long covid patients may have dysautonomia14 and 2-14% will develop orthostatic tachycardia (postural orthostatic tachycardia syndrome) six to eight months after infection.341516Box 1 provides more information on these conditions. The assessment and management is summarised in the infographic.

Box 1
### Dysautonomia and postural orthostatic tachycardia syndromes

The autonomic nervous system is responsible for the unconscious regulation of many physiological processes, including heart rate, blood pressure, respiration, and digestion. The broad category of “dysautonomia” encompasses several conditions, from the intermittent “faint” (neurocardiogenic syncope) through more pervasive dysregulation (postural … RETURN TO TEXT

1872

CaV300

Han, Lefei; Zhao, Shi; Li, Siyuan; Gu, Siyu; Deng, Xiaobei; Yang, Lin; Ran, Jinjun

Excess cardiovascular mortality across multiple COVID-19 waves in the United States from March 2020 to March 2022

https://doi.org/10.1038/s44161-023-00220-2

Published

1-Mar-23

Study

https://www.nature.com/articles/s44161-023-00220-2

The COVID-19 pandemic has limited the access of patients with cardiovascular diseases to healthcare services, causing excess deaths. However, a detailed analysis of temporal variations of excess cardiovascular mortality during the COVID-19 pandemic has been lacking. Here we estimate time-varied excess cardiovascular deaths (observed deaths versus expected deaths predicted by the negative binomial log-linear regression model) in the United States. From March 2020 to March 2022 there were 90,160 excess cardiovascular deaths, or 4.9% more cardiovascular deaths than expected. Two large peaks of national excess cardiovascular mortality were observed during the periods of March–June 2020 and June–November 2021, coinciding with two peaks of COVID-19 deaths, but the temporal patterns varied by state, age, sex and race and ethnicity. The excess cardiovascular death percentages were 5.7% and 4.0% in men and women, respectively, and 3.6%, 8.8%, 7.5% and 7.7% in non-Hispanic White, Black, Asian and Hispanic people, respectively. Our data highlight an urgent need for healthcare services optimization for patients with cardiovascular diseases in the COVID-19 era.

1873

CaV301

Philip, Bejoy; Mukherjee, Prerona; Khare, Yuti; Ramesh, Pranav; Zaidi, Sara; Sabry, Haytham; Harky, Amer

COVID-19 and its long-term impact on the cardiovascular system

https://doi.org/10.1080/14779072.2023.2184800

Published

1-Mar-23

Review

https://doi.org/10.1080/14779072.2023.2184800

Introduction
TheSARS-CoV-2 virus caused a pandemic affecting healthcare deliveryglobally. Despite the presentation of COVID-19 infection beingfrequently dominated by respiratory symptoms; it is now notorious tohave potentially serious cardiovascular sequelae. This articleexplores current data to provide a comprehensive overview of thepathophysiology, cardiovascular risk factors, and implications ofCOVID-19.

Areas covered
Inherentstructure of SARS-CoV-2, and its interaction with both ACE-2 andnon-ACE-2 mediated pathways have been implicated in the developmentof cardiovascular manifestations, progressively resulting in acuterespiratory distress syndrome, multiorgan failure, cytokine releasesyndrome, and subsequent myocardial damage. The interplay betweenexisting and de novo cardiac complications must be noted. Forindividuals taking cardiovascular medications, pharmacologicinteractions are a crucial component. Short-term cardiovascularimpacts include arrhythmia, myocarditis, pericarditis, heart failure,and thromboembolism, whereas long-term impacts include diabetes andhypertension. To identify suitable studies, a PubMed literaturesearch was performed including key words such as ‘Covid 19,’‘Cardiovascular disease,’ ‘Long covid,’ etc.

Expert opinion
Moresophisticated planning and effective management for cardiologyhealthcare provision is crucial, especially for accommodatingchallenges associated with Long-COVID. With the potential applicationof AI and automated data, there are many avenues and sequelae thatcan be approached for investigation.

Plain Language Summary
Deemed the pandemic of the century, COVID-19 is an illness affecting multiple organ systems. Although the virus is best known for its lung-related complications, its adverse effects on the heart and blood vessels are now becoming more apparent. Rapidly mutating and evolving, its unique structure enables it to undergo interactions with various proteins in the body, resulting in complications of both the heart itself and blood vessels throughout the body. Numerous risk factors have been identified to facilitate these manifestations, including existing heart disease, medication usage, and age. Research has shown that certain drug interactions induce disturbances of the heart rhythm and function. In addition to this, they can also exacerbate preexisting heart-related complications, resulting in severe manifestations. The effects on the heart and blood vessels can be divided into acute and chronic complications. Acute complications include heart failure, rhythm disturbances, heart muscle weakness, and inflammation. In addition to this, chronic complications such as high blood pressure and the new onset of diabetes could also be a consequence. Further research is necessary to improve and enhance both our understanding of the virus and our ability to anticipate heart-related symptoms early on.
publisher: Taylor & Francis
_eprint: https://doi.org/10.1080/14779072.2023.2184800
PMID: 36856339

1874

CaV302

Zharkikh, Elena V.; Loktionova, Yulia I.; Fedorovich, Andrey A.; Gorshkov, Alexander Y.; Dunaev, Andrey V.

Assessment of Blood Microcirculation Changes after COVID-19 Using Wearable Laser Doppler Flowmetry

https://doi.org/10.3390/diagnostics13050920

Published

1-Jan-23

Study

https://www.mdpi.com/2075-4418/13/5/920

The present work is focused on the study of changes in microcirculation parameters in patients who have undergone COVID-19 by means of wearable laser Doppler flowmetry (LDF) devices. The microcirculatory system is known to play a key role in the pathogenesis of COVID-19, and its disorders manifest themselves long after the patient has recovered. In the present work, microcirculatory changes were studied in dynamics on one patient for 10 days before his disease and 26 days after his recovery, and data from the group of patients undergoing rehabilitation after COVID-19 were compared with the data from a control group. A system consisting of several wearable laser Doppler flowmetry analysers was used for the studies. The patients were found to have reduced cutaneous perfusion and changes in the amplitude–frequency pattern of the LDF signal. The obtained data confirm that microcirculatory bed dysfunction is present in patients for a long period after the recovery from COVID-19.

1875

CaV303

Czeisler, Mark É.; Ibrahim, Said A.

Cardiovascular Risks in Patients With Post–COVID-19 Condition

https://doi.org/10.1001/jamahealthforum.2022.4664

Published

3-Mar-23

Article

https://doi.org/10.1001/jamahealthforum.2022.4664

Post–COVID-19 condition (PCC) following SARS-CoV-2 infection (also known as long COVID) describes a variety of symptoms and health conditions, including both direct and indirect effects of the virus. The constellation of symptoms was initially identified by members of the public on social media in May 2020.1 As recurrent waves of COVID-19 have led to large numbers of infections and reinfections, PCC has garnered increased attention from policy makers, clinicians, and the public.
To date, more than 200 signs and symptoms and 50 health conditions have been identified in PCC.2 In a US Centers for Disease Control and Prevention study, new-onset symptoms consistent with PCC were reported by 38.2% of adults with and 16.0% of adults without prior SARS-CoV-2 infection—greater than a 2-fold increased risk after prior infection.3 Beyond impaired health and suffering, the enormous medical spending and earning losses attributable to PCC in the US may measure in the trillions of dollars.4 Therefore, PCC is a defining challenge for health care systems.
A study in this issue of JAMA Health Forum by DeVries and colleagues directly addresses this evolving public health challenge.5 The study of US adults in a large commercial insurance database describes markedly increased risks of adverse cardiovascular events and excess all-cause mortality in the postacute phase of COVID-19. These findings, together with increasing evidence of long-term consequences of SARS-CoV-2 infections spanning a wide range of organ systems,6 call for enhanced and extended health monitoring of individuals with SARS-CoV-2 infections and raise questions about public health goals at this stage of the pandemic.
DeVries and colleagues used propensity score matching on a comprehensive set of variables in commercial insurance claims to compare a cohort of 13 435 persons who had experienced PCC symptoms with a cohort of 26 870 persons without evidence of COVID-19.5 Additional analyses were conducted among persons who had experienced PCC and been hospitalized within a month of SARS-CoV-2 infection. For both analyses, claims-based utilization tied to cardiovascular disorders, chronic respiratory disorders, and mortality over 12 months were compared between cohorts.
Between 1 month and 12 months postinfection, individuals who had experienced COVID-19 exhibited increased incident cardiovascular disease relative to those who had not, including more than a doubling in the relative risk (RR) of pulmonary embolism or deep vein thrombosis (8.0% vs 2.2%; RR, 3.64), cardiac arrhythmias (29.5% vs 12.5%; RR, 2.35), and ischemic stroke (3.9% vs 1.8%; RR, 2.17). Individuals with SARS-CoV-2 infections also experienced a comparable relative increase in all-cause mortality (2.8% vs 1.2%) during the 12-month follow-up period. Even greater increases in the RRs of these adverse outcomes were observed among individuals hospitalized within a month of SARS-CoV-2 infection.
The findings of DeVries and colleagues5 extend those of several recently published studies of postacute cardiovascular sequelae of SARS-CoV-2 infection. Other notable studies identifying a prolonged increased risk of incident cardiovascular disease between 1 month and 12 months following SARS-CoV-2 infection include those by Xie and colleagues7 and Wang and colleagues.8 However, their findings may be less generalizable; the former study reported on a cohort that was more than 90% male with a mean age older than 60 years, and the latter study analyzed a cohort that excluded persons who had received COVID-19 vaccines. DeVries and colleagues build on these studies by demonstrating findings of similar magnitude in a cohort that was 58% female with a mean age of 50 years and had representation across US racial and ethnic groups and geographic regions.5
Perhaps the most comparable published study is an analysis of UK Biobank participants by Raisi-Estabragh and colleagues, which primarily highlighted markedly increased cardiovascular and mortality risks among individuals hospitalized within 30 days of infection.9 The authors also reported sustained elevated risks of venous thromboembolism and of heart failure similar to those of DeVries and colleagues5 across the overall study cohort (ie, both hospitalized and nonhospitalized participants). However, contrary to the spectrum of cardiovascular-specific risk outcomes reported by DeVries and colleagues, Raisi-Estabragh and colleagues reported that the only postacute cardiovascular-specific risk outcome for nonhospitalized participants was venous thromboembolism.9 This difference could be related to the shorter follow-up interval in the UK Biobank study compared with the study by DeVries and colleagues.5

1876

CaV304

Ranucci, Marco; Baryshnikova, Ekaterina; Anguissola, Martina; Pugliese, Sara; Falco, Mara; Menicanti, Lorenzo

The Long Term Residual Effects of COVID-Associated Coagulopathy

https://doi.org/10.3390/ijms24065514

Published

1-Jan-23

Study

https://www.mdpi.com/1422-0067/24/6/5514

During the acute phase of COVID-19, many patients experience a complex coagulopathy characterized by a procoagulant pattern. The present study investigates the persistence of hemostatic changes in post-COVID patients at a long-term follow up, and the link with the persistence of physical and neuropsychological symptoms. We completed a prospective cohort study on 102 post-COVID patients. Standard coagulation and viscoelastic tests were performed, along with an assessment of persistent symptoms and recording of acute phase details. A procoagulant state was adjudicated in the presence of fibrinogen > 400 mg/dL, or D-dimer > 500 ng/mL, or platelet count > 450,000 cells/µL, or a maxim clot lysis at viscoelastic test < 2%. A procoagulant state was identified in 75% of the patients at 3 months follow up, 50% at 6 months, and 30% at 12–18 months. Factors associated with the persistence of a procoagulant state were age, severity of the acute phase, and persistence of symptoms. Patients with major physical symptoms carry a procoagulant state relative risk of 2.8 (95% confidence interval 1.17–6.7, p = 0.019). The association between persistent symptoms and a procoagulant state raises the hypothesis that an ongoing process of thrombi formation and/or persistent microthrombosis may be responsible for the main physical symptoms in long-COVID patients.

1877

CaV305

Mabila, Sithembile; Patel, Deven; Fan, Michael; Stahlman, Shauna; Seliga, Nicholas; Nowak, Gosia; Wells, Natalie

Post –acute sequalae of COVID-19 and cardiac outcomes in U. S. military members

https://doi.org/10.1016/j.ijcrp.2023.200183

Published

1-Jun-23

Study

https://www.sciencedirect.com/science/article/pii/S2772487523000168

Post –acute sequalae of COVID-19 (PASC) among U.S. military members remains unexplored. A cohort study of U. S. military members who had a COVID-19 test result, with the specimen collected between March 1, 2020 and November 30, 2021 was conducted. Demographic, inpatient and outpatient data including cardiac event diagnoses were extracted from electronic medical records and compared COVID-19 test-positive and COVID-19 test-negative service members. We used univariate and multivariable logistic regression methods to determine the effect PASC on select cardiac events. Among 997,785 service members, 15,779 (1.6%) were diagnosed with a cardiac event. In fully adjusted models, PASC was significantly associated with increased odds of any cardiac event [OR =1.64 (95% CI: 1.57, 1.71]. PASC was associated with increased odds of myocarditis [OR = 5.86 (95% CI: 4.22, 8.15)], pericarditis [OR =3.08 (95% CI: 2.31, 4.11)], syncope [OR =1.52 (95% CI: 1.41, 1.63)], tachycardia [OR =1.72 (95% CI: 1.56, 1.89)], heart failure [OR =2.15 (95% CI: 1.76, 2.63)], bradycardia [OR =1.71 (95% CI: 1.50, 1.96)], and atrial fibrillation [OR =1.33(95% CI: 1.02, 1.74)] in fully adjusted models. In a sensitivity analysis of military members with no history of cardiac events, PASC was still significantly associated with increased odds of any cardiac event [OR =1.75 (95% CI: 1.67, 1.84)]. In conclusion, we observed a significant association between PASC and cardiac outcomes including; myocarditis, pericarditis, and heart failure. These associations were observed in a relatively young and healthy population and among those without pre-existing cardiac diagnoses.

1878

CaV306

Ball, Erin E.; Weiss, Christopher M.; Liu, Hongwei; Jackson, Kenneth; Keel, M. Kevin; Miller, Christopher J.; Van Rompay, Koen K. A.; Coffey, Lark L.; Pesavento, Patricia A.

Severe Acute Respiratory Syndrome Coronavirus 2 Vasculopathy in a Syrian Golden Hamster Model

https://doi.org/10.1016/j.ajpath.2023.02.013

Published

10-Mar-23

Study

https://www.sciencedirect.com/science/article/pii/S0002944023000822

Clinical evidence of vascular dysfunction and hypercoagulability as well as pulmonary vascular damage and microthrombosis are frequently reported in severe cases of human coronavirus disease 2019 (COVID-19). Syrian golden hamsters recapitulate histopathologic pulmonary vascular lesions reported in patients with COVID-19. Here, special staining techniques and transmission electron microscopy further define vascular pathologies in a Syrian golden hamster model of human COVID-19. The results show that regions of active pulmonary inflammation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are characterized by ultrastructural evidence of endothelial damage with platelet marginalization and both perivascular and subendothelial macrophage infiltration. SARS-CoV-2 antigen/RNA was not detectable within affected blood vessels. Taken together, these findings suggest that the prominent microscopic vascular lesions in SARS-CoV-2–inoculated hamsters are likely due to endothelial damage followed by platelet and macrophage infiltration.

1879

CaV307

Sewanan, Lorenzo R.; Clerkin, Kevin J.; Tucker, Nathan R.; Tsai, Emily J.

How Does COVID-19 Affect the Heart?

https://doi.org/10.1007/s11886-023-01841-6

Published

1-Mar-23

Review

https://doi.org/10.1007/s11886-023-01841-6

Purpose of Review
Cardiac consequences occur in both acute COVID-19 and post-acute sequelae of COVID-19 (PASC). Here, we highlight the current understanding about COVID-19 cardiac effects, based upon clinical, imaging, autopsy, and molecular studies.

Recent Findings
COVID-19 cardiac effects are heterogeneous. Multiple, concurrent cardiac histopathologic findings have been detected on autopsies of COVID-19 non-survivors. Microthrombi and cardiomyocyte necrosis are commonly detected. Macrophages often infiltrate the heart at high density but without fulfilling histologic criteria for myocarditis. The high prevalences of microthrombi and inflammatory infiltrates in fatal COVID-19 raise the concern that recovered COVID-19 patients may have similar but subclinical cardiac pathology. Molecular studies suggest that SARS-CoV-2 infection of cardiac pericytes, dysregulated immunothrombosis, and pro-inflammatory and anti-fibrinolytic responses underlie COVID-19 cardiac pathology. The extent and nature by which mild COVID-19 affects the heart is unknown. Imaging and epidemiologic studies of recovered COVID-19 patients suggest that even mild illness confers increased risks of cardiac inflammation, cardiovascular disorders, and cardiovascular death. The mechanistic details of COVID-19 cardiac pathophysiology remain under active investigation.

Summary
The ongoing evolution of SARS-CoV-2 variants and vast numbers of recovered COVID-19 patients portend a burgeoning global cardiovascular disease burden. Our ability to prevent and treat cardiovascular disease in the future will likely depend on comprehensive understanding of COVID-19 cardiac pathophysiologic phenotypes.

1880

CaV308

Yar, Aria; Uusitalo, Valtteri; Vaara, Satu M.; Holmström, Miia; Vuorinen, Aino-Maija; Heliö, Tiina; Paakkanen, Riitta; Kivistö, Sari; Syväranta, Suvi; Hästbacka, Johanna

Cardiac magnetic resonance -detected myocardial injury is not associated with long-term symptoms in patients hospitalized due to COVID-19

https://doi.org/10.1371/journal.pone.0282394

Published

8-Mar-23

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0282394

Background Long-term symptoms are frequent after coronavirus disease 2019 (COVID-19). We studied the prevalence of post-acute myocardial scar on cardiac magnetic resonance imaging (CMR) in patients hospitalized due to COVID-19 and its association with long-term symptoms. Materials and methods In this prospective observational single-center study, 95 formerly hospitalized COVID-19 patients underwent CMR imaging at the median of 9 months after acute COVID-19. In addition, 43 control subjects were imaged. Myocardial scar characteristic of myocardial infarction or myocarditis were noted from late gadolinium enhancement images (LGE). Patient symptoms were screened using a questionnaire. Data are presented as mean ± standard deviation or median (interquartile range). Results The presence of any LGE was higher in COVID-19 patients (66% vs. 37%, p<0.01) as was the presence of LGE suggestive of previous myocarditis (29% vs. 9%, p = 0.01). The prevalence of ischemic scar was comparable (8% vs. 2%, p = 0.13). Only two COVID-19 patients (7%) had myocarditis scar combined with left ventricular dysfunction (EF <50%). Myocardial edema was not detected in any participant. The need for intensive care unit (ICU) treatment during initial hospitalization was comparable in patients with and without myocarditis scar (47% vs. 67%, p = 0.44). Dyspnea, chest pain, and arrhythmias were prevalent in COVID-19 patients at follow-up (64%, 31%, and 41%, respectively) but not associated with myocarditis scar on CMR. Conclusions Myocardial scar suggestive of possible previous myocarditis was detected in almost one-third of hospital-treated COVID-19 patients. It was not associated with the need for ICU treatment, greater symptomatic burden, or ventricular dysfunction at 9 months follow-up. Thus, post-acute myocarditis scar on COVID-19 patients seems to be a subclinical imaging finding and does not commonly require further clinical evaluation.

1881

CaV309

Nunes, Jean M.; Kell, Douglas B.; Pretorius, Etheresia

Cardiovascular and haematological pathology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A role for viruses

https://doi.org/10.1016/j.blre.2023.101075

Published

20-Mar-23

Review

https://www.sciencedirect.com/science/article/pii/S0268960X2300036X

ME/CFS is a debilitating chronic condition that often develops after viral or bacterial infection. Insight from the study of Long COVID/Post Acute Sequelae of COVID-19 (PASC), the post-viral syndrome associated with SARS-CoV-2 infection, might prove to be useful for understanding pathophysiological mechanisms of ME/CFS. Disease presentation is similar between the two conditions, and a subset of Long COVID patients meet the diagnostic criteria for ME/CFS. Since Long COVID is characterized by significant vascular pathology – including endothelial dysfunction, coagulopathy, and vascular dysregulation – the question of whether or not the same biological abnormalities are of significance in ME/CFS arises. Cardiac abnormalities have for a while now been documented in ME/CFS cohorts, with recent studies demonstrating major deficits in cerebral blood flow, and hence vascular dysregulation. A growing body of research is demonstrating that ME/CFS is accompanied by platelet hyperactivation, anomalous clotting, a procoagulant phenotype, and endothelial dysfunction. Endothelial damage and dysregulated clotting can impair substance exchange between blood and tissues, and result in hypoperfusion, which may contribute to the manifestation of certain ME/CFS symptoms. Here we review the ME/CFS literature to summarize cardiovascular and haematological findings documented in patients with the condition, and, in this context, briefly discuss the potential role of previously-implicated pathogens. Overall, cardiac and haematological abnormalities are present within ME/CFS cohorts. While atherosclerotic heart disease is not significantly associated with ME/CFS, suboptimal cardiovascular function defined by reduced cardiac output, impaired cerebral blood flow, and vascular dysregulation are, and these abnormalities do not appear to be influenced by deconditioning. Rather, these cardiac abnormalities may result from dysfunction in the (autonomic) nervous system. Plenty of recently published studies are demonstrating significant platelet hyperactivity and endothelial dysfunction in ME/CFS, as well as anomalous clotting processes. It is of particular importance to determine to what extent these cardiovascular and haematological abnormalities contribute to symptom severity, and if these two systems can be targeted for therapeutic purposes. Viral reservoirs of herpesviruses exist in ME/CFS, and most likely contribute to cardiovascular and haematological dysfunction directly or indirectly. This review highlights the potential of studying cardiac functioning, the vasculature, and coagulation system in ME/CFS.

1882

CaV310

Podrug, Mario; Koren, Pjero; Dražić Maras, Edita; Podrug, Josip; Čulić, Viktor; Perissiou, Maria; Bruno, Rosa Maria; Mudnić, Ivana; Boban, Mladen; Jerončić, Ana

Long-Term Adverse Effects of Mild COVID-19 Disease on Arterial Stiffness, and Systemic and Central Hemodynamics: A Pre-Post Study

https://doi.org/10.3390/jcm12062123

Published

1-Jan-23

Study

https://www.mdpi.com/2077-0383/12/6/2123

COVID-19-associated vascular disease complications are primarily associated with endothelial dysfunction; however, the consequences of disease on vascular structure and function, particularly in the long term (>7 weeks post-infection), remain unexplored. Individual pre- and post-infection changes in arterial stiffness as well as central and systemic hemodynamic parameters were measured in patients diagnosed with mild COVID-19. As part of in-laboratory observational studies, baseline measurements were taken up to two years before, whereas the post-infection measurements were made 2–3 months after the onset of COVID-19. We used the same measurement protocol throughout the study as well as linear and mixed-effects regression models to analyze the data. Patients (N = 32) were predominantly healthy and young (mean age ± SD: 36.6 ± 12.6). We found that various parameters of arterial stiffness and central hemodynamics—cfPWV, AIx@HR75, and cDBP as well as DBP and MAP—responded to a mild COVID-19 disease. The magnitude of these responses was dependent on the time since the onset of COVID-19 as well as age (pregression_models ≤ 0.013). In fact, mixed-effects models predicted a clinically significant progression of vascular impairment within the period of 2–3 months following infection (change in cfPWV by +1.4 m/s, +15% in AIx@HR75, approximately +8 mmHg in DBP, cDBP, and MAP). The results point toward the existence of a widespread and long-lasting pathological process in the vasculature following mild COVID-19 disease, with heterogeneous individual responses, some of which may be triggered by an autoimmune response to COVID-19.

1883

CaV311

Lee, Joanna; Kothari, Aditi S.; Bhatt, Gaurang; Gupta, Navneet; Ali, Ahmed Elsaid; Najam, Nadia; Mazroua, Muhammad; Mansoor, Taha; Amal, Tanya; Elsaban, Mariam; Deo, Rohan; Bansal, Vikas; Kashyap, Rahul

Cardiac complications among long covid patients: a systematic review and meta-analysis

https://doi.org/10.1016/S0735-1097(23)02559-7

Published

7-Mar-23

Review

https://www.jacc.org/doi/full/10.1016/S0735-1097%2823%2902559-7

Background
Long COVID is a novel phenomenon of persistent or new symptoms affecting multiple organ systems including the cardiovascular system. The long-term implications of long COVID, particularly its cardiac complications remain uncertain. We performed a systematic review and meta-analysis of studies that reported cardiac complications among long COVID patients.

Methods
We searched PUBMED, EMBASE, and SCOPUS databases and included 982 eligible studies from January 2020 to July 2022. After applying exclusion criteria, 74 studies were included for the detailed review. The meta-analysis included cohort and case control studies comparing the cardiac complications among long COVID vs. control. Total 11 studies were eligible for meta-analysis on full text review. It was registered on PROSPERO with the ID CRD42022338488.

Results
A total of 5,885,453 patients were included, and a total of 449,599 patients had cardiac complications (18,956 patients in long COVID-19 arm and 430,272 patients in control arm). The unadjusted odds of cardiac complications in long COVID-19 were significantly higher (OR 2.35, p=0.01) with high heterogeneity (I2=91%). We performed sensitivity analysis by excluding study by Galloway et al to reduce the heterogeneity and the odds of cardiac complications remained same with moderate heterogeneity (OR 2.57, p=<0.001, I2=51%).
Conclusion
Patients with long COVID have significantly higher odds of developing cardiac complications compared to those who do not.

publisher: American College of Cardiology Foundation

1884

CaV312

Howick, James; Saric, Petar; Elwazir, Mohamed; Gersh, Bernard J.; Bois, John P.

Cardiac sequelae of long-covid

https://doi.org/10.1016/S0735-1097(23)02684-0

Published

7-Mar-23

Study

https://www.jacc.org/doi/full/10.1016/S0735-1097%2823%2902684-0

Background
Cardiac injury from COVID-19 is likely the result of a bidirectional interaction with various pathophysiologic mechanisms coupled with modifying factors such as delayed presentation resulting in several clinical outcomes. The spectrum of long-term cardiovascular sequelae and incidence of structural cardiac damage remains unclear.

Methods
Advanced Text Explorer was utilized to search for COVID-19 long-haulers, defined as symptoms lasting greater than 4 weeks after initial infection, who presented to Cardiology Clinics at Mayo from April 2020 to March 2022. Additional patients diagnosed with COVID with possible cardiac sequelae seen in Chest Pain Clinic, Infectious Disease, and Radiology departments were also manually assessed for potential inclusion. These patients were evaluated for ongoing symptoms including chest pain, fatigue, dyspnea, palpitations, and syncope thought to represent cardiac sequelae related to COVID-19. All patients were manually reviewed to verify long-haul status and to determine whether these symptoms were indeed due to cardiovascular effects from COVID-19 versus a different etiology.

Results
78,202 unique patients were diagnosed with COVID-19 at Mayo Clinic from April 2020 to March 2022. 336 (0.4%) long-haulers evaluated by Cardiology for ongoing symptoms that may represent cardiac sequelae from COVID were identified. 216 (61.6%) of these patients were vaccinated and 42 (12.5%) had severe initial infection receiving inpatient treatment for COVID prior to developing long-haul symptoms. 116 (34.5%) likely had symptoms from a cardiac cause and 220 (65.5%) were non-cardiac. Of the 116 with a cardiac etiology, 76 (22.6%) were thought to have symptoms largely driven by COVID; 59 with new cardiac disease and 17 with worsening of existing disease secondary to COVID. There were 7 cases of myocarditis, 5 suspected cases of endothelial dysfunction, and 31 cases of autonomic dysfunction/POTS.

Conclusion
In a sample of COVID-19 long-haulers with possible cardiac symptoms, the incidence of true structural cardiac sequelae as an explanation is rare.
publisher: American College of Cardiology Foundation

1885

CaV313

May, Heidi Thomas; Knight, Stacey; Horne, Benjamin Davies; Bair, Tami L.; Anderson, Jeffrey L.; Le, Viet T.; Muhlestein, J. Brent; Knowlton, Kirk U.

A comparison of cardiovascular outcomes among sars-cov-2 positive patients, sars-cov-2 negative patients, and a historical cohort

https://doi.org/10.1016/S0735-1097(23)02286-6

Published

7-Mar-23

Study

https://www.jacc.org/doi/full/10.1016/S0735-1097%2823%2902286-6

Background
Recovery from a SARS-CoV-2 infection varies among individuals. Some report symptoms for weeks or months after the acute infection, and in some, new symptoms emerge. Symptoms range from mild to incapacitating and can involve multiple organ systems. Such symptoms and damage have been termed post-acute sequelae of SARS-CoV-2 infection (PASC). COVID-19 infection has been shown to affect the cardiovascular (CV) system, but whether symptoms and organ damage have yet resulted in an increase in diagnoses and events has not been entirely determined.

Methods
Outpatients >18 yrs with 30-days survival testing positive for SARS-CoV-2 were matched to SARS-CoV-2 negative and historical patients by age (±1 yrs), sex, and index month seen. Pts were followed for 6-month and 1-year CV outcomes occurring >30 days after index.

Results
The baseline characteristics of the 444,474 (148,158/group) pts are shown in Table 1. Event rates were low and generally similar between the groups after adjustment, with chest pain being significantly greater in SARS-CoV-2 positive pts (Table 2 and 3).

Conclusion
This study found chest pain to be more common among SARS-CoV-2 positive pts, but no other increases in CV outcomes. It may be that the lasting effects of infection on the CV system are hard to quantify in terms of diagnoses or other events in the short-term and won't be realized until longer follow-up. Therefore, ongoing CV outcome monitoring will be critical in determining the true effect of a SARS-CoV-2 infection on CV disease.
publisher: American College of Cardiology Foundation

1886

CaV314

Fontana, Gregory Paul; Egloff, Shanna Arnold; Kar, Kar Saibal; Lakkireddy, Dhanunjaya R.; Huneycutt, David; Misch, Amanda; Williamson, Weldon Kent; Sands, Kenneth; Manoukian, Steven Vahe

Trends in long-term cardiovascular-related hospital admissions after covid-19 hospitalization

https://doi.org/10.1016/S0735-1097(23)02839-5

Published

7-Mar-23

Study

https://www.jacc.org/doi/full/10.1016/S0735-1097%2823%2902839-5

Background
Evidence exists that cardiovascular (CV) disease risk is increased in patients following COVID-19 (C19) infection and these risks may be sustained and manifest long after symptoms have resolved (long-COVID syndrome). This study sought to assess trends and timing of long-term CV-related admissions following C19 hospitalization and identify associated risks.

Methods
A retrospective multisite observational cohort study of a large private U.S. hospital network was performed of patients >18 years of age who survived an index C19 hospitalization (>24 hours) between 3/2/2020 and 7/31/2021, allowing for 1-year follow-up for CV-related admissions. Autoregressive integrated moving average (ARIMA) models were used to assess trends and compare expected vs. observed CV admissions for those having prior C19 hospitalization. Independent effects of clinicodemographics at time of C19 index hospitalization on future CV admission were assessed using multivariable logistic regression models with intent to expand models to include comorbidities as well as facility and C19 admission attributes.

Results
The C19 cohort (n=134,235) was compared to total monthly CV admission diagnoses from 2016 to 2021. Deep vein thrombosis, cardiac arrest, atrial fibrillation, and cardiogenic shock were concentrated within 30 days of C19 discharge. In contrast, stroke, myocardial infarction (MI), hypertension (HTN), and heart valve disorders peaked from 180 to 365+ days after C19 admission. HTN and cardiomyopathy accounted for 50% of all CV inpatient diagnoses. The largest peak in CV admissions occurred 8 months past the C19 delta wave; a pattern that remained consistent for stroke and MI. Current smoking, Black race, and age >50 years were associated with increased odds of having a CV-related admission; male sex, Asian race, and Hispanic ethnicity were associated with reduced odds.

Conclusion
In the year following admission for C19 infection, CV hospital admissions are elevated and exhibit a bimodal distribution. Numerous subgroups exist which are at increased risk of CV admission following C19 admission; greater understanding of these populations will aid in CV evaluation, surveillance and follow-up.
publisher: American College of Cardiology Foundation

1887

CaV315

Puntmann, Valentina O.; Nagel, Eike

Toward Better Understanding of Cardiac Involvement Post COVID∗

https://doi.org/10.1016/j.jcmg.2023.02.004

Published

23-Mar-23

Editorial

https://www.sciencedirect.com/science/article/pii/S1936878X23000980

Owing to the new disease entity and wide spectrum of potential myocardial involvement that may be seen with COVID-19, the 2022 American College of Cardiology Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19 in Adults1 focused on myocarditis and other forms of inflammatory cardiac involvement and provides the following definitions:
•Myocarditis: Condition defined by the presence of cardiac symptoms (eg, chest pain, dyspnea, palpitations, syncope), an elevated cardiac troponin (cTn), and abnormal electrocardiographic, echocardiographic, CMR, and/or histopathologic findings on biopsy or postmortem evaluation in the absence of flow-limiting coronary artery disease.
•Myocardial involvement: Condition defined by abnormal myocardium manifest by electrocardiographic, echocardiographic, CMR, and/or histopathologic findings, with or without symptoms and with or without an elevated cTn.
•Myocardial injury: Condition defined by a cTn level above the 99th percentile upper reference limit.
We urge the CMR field to use this classification, as it may help to underpin the many faces of heterogeneous clinical presentation because of SARS-CoV-2 infection, and by that help to better understand some of the highly variable prevalences. The technical issues to diagnosis of post-COVID cardiac involvement by CMR aside, the management of the complex condition requires dedicated expert knowledge and a multidisciplinary approach.
In summary, our understanding of cardiac involvement post COVID-19 continues to evolve and remains an important issue both for clinicians as well as for researchers. The use of CMR is relevant to better understand patients with symptoms or abnormal ECG or laboratory values post COVID-19. However, for routine use, more standardization of imaging and reporting is required.

1888

CaV316

Tijmes, Felipe Sanchez; Marschner, Constantin; Thavendiranathan, Paaladinesh; Hanneman, Kate

Magnetic Resonance Imaging of Cardiovascular Manifestations Following COVID-19

https://doi.org/10.1002/jmri.28677

Published

Review

https://onlinelibrary.wiley.com/doi/abs/10.1002/jmri.28677

Globally, over 650 million people have had COVID-19 due to infection with the SARS-Cov-2 virus. Cardiac complications in the acute infectious and early recovery phase were recognized early in the pandemic, including myocardial injury and inflammation. With a decrease in the number of acute COVID-19 related deaths, there has been increased interest in postacute sequela of COVID-19 (PASC) and other longer-term cardiovascular complications. A proportion of patients recovered from COVID-19 have persistent cardiac symptoms and are at risk of cardiovascular disease. Cardiovascular imaging, including MRI, plays an important role in the detection of cardiovascular manifestations of COVID-19 in both the acute and longer-term phases after COVID-19. The purpose of this review is to highlight the role of cardiovascular imaging in the diagnosis and risk stratification of patients with acute and chronic cardiovascular manifestations of COVID-19 with a focus on cardiac MRI. Evidence Level 4. Technical Efficacy Stage 3.

1889

CaV317

Ferreira, Vanessa M.; Plein, Sven; Wong, Timothy C.; Tao, Qian; Raisi-Estabragh, Zahra; Jain, Supriya S.; Han, Yuchi; Ojha, Vineeta; Bluemke, David A.; Hanneman, Kate; Weinsaft, Jonathan; Vidula, Mahesh K.; Ntusi, Ntobeko A. B.; Schulz-Menger, Jeanette; Kim, Jiwon

Cardiovascular magnetic resonance for evaluation of cardiac involvement in COVID-19: recommendations by the Society for Cardiovascular Magnetic Resonance

https://doi.org/10.1186/s12968-023-00933-0

Published

27-Mar-23

Recommendations

https://doi.org/10.1186/s12968-023-00933-0

Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic that has affected nearly 600 million people to date across the world. While COVID-19 is primarily a respiratory illness, cardiac injury is also known to occur. Cardiovascular magnetic resonance (CMR) imaging is uniquely capable of characterizing myocardial tissue properties in-vivo, enabling insights into the pattern and degree of cardiac injury. The reported prevalence of myocardial involvement identified by CMR in the context of COVID-19 infection among previously hospitalized patients ranges from 26 to 60%. Variations in the reported prevalence of myocardial involvement may result from differing patient populations (e.g. differences in severity of illness) and the varying intervals between acute infection and CMR evaluation. Standardized methodologies in image acquisition, analysis, interpretation, and reporting of CMR abnormalities across would likely improve concordance between studies. This consensus document by the Society for Cardiovascular Magnetic Resonance (SCMR) provides recommendations on CMR imaging and reporting metrics towards the goal of improved standardization and uniform data acquisition and analytic approaches when performing CMR in patients with COVID-19 infection.

1890

CaV318

Simone Turner

Rapid flow cytometric analysis of fibrin amyloid microclots in Long COVID

https://doi.org/10.2139/ssrn.4405265

Published

29-Mar-23

Study

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4405265

Long COVID has become a significant global health and economic burden, yet there are currently no established diagnostic tools to identify which patients might benefit from specific treatments. One of the major pathophysiological factors contributing to Long COVID is the presence of hypercoagulability; this results in insoluble amyloid microclots that are resistant to fibrinolysis. Our previous research using fluorescence microscopy has demonstrated a significant amyloid microclot load in Long COVID patients. However, this approach lacked statistical robustness, objectivity, and rapid throughput. In the current study, we have used imaging flow cytometry for the first time to show significantly increased concentration and size of these microclots. We identified notable variations in size and fluorescence between microclots in Long COVID and those of controls even using a 20x objective. By combining cell imaging and the high-event-rate nature of a conventional flow cytometer, imaging flow cytometry can eliminate erroneous results and increase accuracy in gating and analysis beyond what pure quantitative measurements from conventional flow cytometry can provide. Although imaging flow cytometry was used in our study, our results suggest that the signals indicating the presence of microclots should be easily detectable using a conventional flow cytometer. Flow cytometry is a more widely available technique which has been used in pathology laboratories for decades, rendering it a potentially more suitable and accessible method for detecting microclots in individuals suffering from both Long COVID and other conditions with similar pathology, such as myalgic encephalomyelitis.
DOI: 10.21203/rs.3.rs-2731434/v1

1891

CaV319

Émile, Carole

Atteintes myocardiques au cours de la Covid-19, utilité des biomarqueurs cardiaques

https://doi.org/10.1016/S0992-5945(23)00050-8

Published

1-Mar-23

Article

https://www.sciencedirect.com/science/article/pii/S0992594523000508

La Covid-19 est une pandémie sans précédent, par son ampleur, sa gravité et ses conséquences sociétales. Dans nos hôpitaux, elle a conduit à un afflux massif de patients, une saturation des capacités des services de réanimation et la création d’unités spécialisées. Les patients les plus sévères avaient des marqueurs biologiques très perturbés, en faveur d’une atteinte multiviscérale et, parmi ceux-ci, une augmentation des CK-MB, de la troponine et du BNP, stigmates d’une atteinte myocardique.
À retenir
20 % des patients qui développent une forme sévère de la Covid-19 ont une atteinte myocardique (troponine [I ou T] supérieure au 99e percentile de la limite supérieure de référence). Une troponine élevée est associée à un mauvais pronostic et permet d’identifier les patients à risque, nécessitant une prise en charge intensive.

Toutefois, dans la majorité des cas, l’élévation de la troponine n’est pas associée à une atteinte coronarienne aiguë, mais reflète de nombreuses atteintes cardiaques ou à retentissement cardiaque.

Les patients qui ont développé une forme sévère de la Covid-19, mais également une forme modérée, ont un risque cardiovasculaire à un an augmenté. Enfin, dans plus de 50 % des cas d’atteintes myocardiques, la troponine reste élevée plusieurs mois après l’infection, ce qui pourrait expliquer ce risque cardio-vasculaire plus important.

1892

CaV320

Kalinskaya, Anna; Vorobyeva, Daria; Rusakovich, George; Maryukhnich, Elena; Anisimova, Alexandra; Dukhin, Oleg; Elizarova, Antonina; Ivanova, Oxana; Bugrova, Anna; Brzhozovskiy, Alexander; Kononikhin, Alexey; Nikolaev, Evgeny; Vasilieva, Elena

Targeted Blood Plasma Proteomics and Hemostasis Assessment of Post COVID-19 Patients with Acute Myocardial Infarction

https://doi.org/10.3390/ijms24076523

Published

1-Jan-23

Study

https://www.mdpi.com/1422-0067/24/7/6523

The molecular mechanisms underlying cardiovascular complications after the SARS-CoV-2 infection remain unknown. The goal of our study was to analyze the features of blood coagulation, platelet aggregation, and plasma proteomics in COVID-19 convalescents with AMI. The study included 66 AMI patients and 58 healthy volunteers. The groups were divided according to the anti-N IgG levels (AMI post-COVID (n = 44), AMI control (n = 22), control post-COVID (n = 31), and control (n = 27)). All participants underwent rotational thromboelastometry, thrombodynamics, impedance aggregometry, and blood plasma proteomics analysis. Both AMI groups of patients demonstrated higher values of clot growth rates, thrombus size and density, as well as the elevated levels of components of the complement system, proteins modifying the state of endothelium, acute-phase and procoagulant proteins. In comparison with AMI control, AMI post-COVID patients demonstrated decreased levels of proteins connected to inflammation and hemostasis (lipopolysaccharide-binding protein, C4b-binding protein alpha-chain, plasma protease C1 inhibitor, fibrinogen beta-chain, vitamin K-dependent protein S), and altered correlations between inflammation and fibrinolysis. A new finding is that AMI post-COVID patients opposite the AMI control group, are characterized by a less noticeable growth of acute-phase proteins and hemostatic markers that could be explained by prolonged immune system alteration after COVID-19.

1893

CaV321

Nandadeva, Damsara; Skow, Rachel J.; Stephens, Brandi Y.; Grotle, Ann-Katrin; Georgoudiou, Stephanie; Barshikar, Surendra; Seo, Yaewon; Fadel, Paul J.

Cardiovascular and Cerebral Vascular Health in Females with Post-Acute Sequelae of COVID-19 (PASC)

https://doi.org/10.1152/ajpheart.00018.2023

Published

31-Mar-23

Study

https://journals.physiology.org/doi/abs/10.1152/ajpheart.00018.2023

Many individuals who had COVID-19 develop detrimental persistent symptoms; a condition known as post-acute sequelae of COVID-19 (PASC). Despite the elevated risk of cardiovascular disease following COVID-19, limited studies have examined vascular function in PASC with equivocal results reported. Moreover, the role of PASC symptom burden on vascular health has not been examined. We tested the hypothesis that peripheral and cerebral vascular function would be blunted, and central arterial stiffness would be elevated in patients with PASC compared to age-matched controls. Furthermore, we hypothesized that impairments in vascular health would be greater in those with higher PASC symptom burden. Resting blood pressure (BP; brachial and central), brachial artery flow-mediated dilation (FMD), forearm reactive hyperemia, carotid-femoral pulse wave velocity (PWV), and cerebral vasodilator function were measured in 12 females with PASC and 11 age matched female controls without PASC. The severity of persistent symptoms in those with PASC was reported on a scale of 1-10 (higher score: greater severity). Brachial BP (e.g., systolic BP, 126±19 vs.109±8 mmHg; P=0.010), central BP (P<0.050) and PWV (7.1±1.2 vs. 6.0±0.8 m/s; P=0.015) were higher in PASC compared to controls. However, FMD, reactive hyperemia, and cerebral vasodilator function were not different between groups (P>0.050 for all). Total symptom burden was not correlated with any measure of cardiovascular health (P>0.050 for all). Collectively, these findings indicate that BP and central arterial stiffness are elevated in females with PASC, whereas peripheral and cerebral vascular function appear to be unaffected; effects that appear independent of symptom burden.

1894

CaV322

Singh, Inderjit; Leitner, Brooks P.; Wang, Yiwei; Zhang, Hanming; Joseph, Phillip; Lutchmansingh, Denyse D.; Gulati, Mridu; Possick, Jennifer D.; Damsky, William; Hwa, John; Heerdt, Paul M.; Chun, Hyung J.

Proteomic profiling demonstrates inflammatory and endotheliopathy signatures associated with impaired cardiopulmonary exercise hemodynamic profile in Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome

https://doi.org/10.1002/pul2.12220

Published

1-Apr-23

Study

https://onlinelibrary.wiley.com/doi/abs/10.1002/pul2.12220

Approximately 50% of patients who recover from the acute SARS-CoV-2 experience Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome. The pathophysiological hallmark of PASC is characterized by impaired system oxygen extraction (EO2) on invasive cardiopulmonary exercise test (iCPET). However, the mechanistic insights into impaired EO2 remain unclear. We studied 21 consecutive iCPET in PASC patients with unexplained exertional intolerance. PASC patients were dichotomized into mildly reduced (EO2peak-mild) and severely reduced (EO2peak-severe) EO2 groups according to the median peak EO2 value. Proteomic profiling was performed on mixed venous blood plasma obtained at peak exercise during iCPET. PASC patients as a group exhibited depressed peak exercise aerobic capacity (peak VO2; 85 ± 18 vs. 131 ± 45% predicted; p = 0.0002) with normal systemic oxygen delivery, DO2 (37 ± 9 vs. 42 ± 15 mL/kg/min; p = 0.43) and reduced EO2 (0.4 ± 0.1 vs. 0.8 ± 0.1; p < 0.0001). PASC patients with EO2peak-mild exhibited greater DO2 compared to those with EO2peak-severe [42.9 (34.2–41.2) vs. 32.1 (26.8–38.0) mL/kg/min; p = 0.01]. The proteins with increased expression in the EO2peak-severe group were involved in inflammatory and fibrotic processes. In the EO2peak-mild group, proteins associated with oxidative phosphorylation and glycogen metabolism were elevated. In PASC patients with impaired EO2, there exist a spectrum of PASC phenotype related to differential aberrant protein expression and cardio-pulmonary physiologic response. PASC patients with EO2peak-severe exhibit a maladaptive physiologic and proteomic signature consistent with persistent inflammatory state and endothelial dysfunction, while in the EO2peak-mild group, there is enhanced expression of proteins involved in oxidative phosphorylation-mediated ATP synthesis along with an enhanced cardiopulmonary physiological response.

1895

CaV323

Gomes, Shayane Martins Rodrigues; Brito, Andréia Carolinne de Souza; Manfro, Wânia Ferraz Pereira; Ribeiro-Alves, Marcelo; Ribeiro, Roberto Stefan de Almeida; Cal, Mariana Soares da; Lisboa, Vinicius da Cunha; Abreu, Daniel Paiva Barros de; Castilho, Leda dos Reis; Porto, Luís Cristóvão de Moares Sobrino; Mafort, Thiago Thomáz; Lopes, Agnaldo José; Silva, Silvia Amaral Gonçalves da; Dutra, Patrícia Maria Lourenço; Rodrigues, Luciana Silva

High levels of pro-inflammatory SARS-CoV-2-specific biomarkers revealed by in vitro whole blood cytokine release assay (CRA) in recovered and long-COVID-19 patients

https://doi.org/10.1371/journal.pone.0283983

Published

5-Apr-23

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0283983

Background Cytokines induced by SARS-CoV-2 infection play a crucial role in the pathophysiology of COVID-19 and hyperinflammatory responses have been associated with poor clinical outcomes, with progression to severe conditions or long-term subacute complications named as long-COVID-19. Methods In this cross-sectional study, we aimed to evaluate a set of antigen-specific inflammatory cytokines in blood from recovered COVID-19 individuals or who suffered a post-acute phase of SARS-CoV-2 infection compared to healthy individuals with no history of COVID-19 exposition or infection. Interferon-gamma (IFN-γ), IFN-γ-induced protein 10 (IP-10), tumor necrosis factor (TNF), IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, and IL-17A were quantified by multiplex cytometric bead assay and enzyme-linked immunosorbent assay after stimulation of whole blood with recombinant Spike protein from SARS-CoV-2. Additionally, all participants have evaluated for anti-(S) protein-specific IgG antibodies. Clinical specimens were collected within two months of COVID-19 diagnosis. Results A total of 47 individuals were enrolled in the study, a median age of 43 years (IQR = 14.5), grouped into healthy individuals with no history of infection or exposure to SARS-CoV-2 (unexposed group; N = 21); and patients from the Health Complex of the Rio de Janeiro State University (UERJ), Brazil, who were SARS-CoV-2 positive by RT-PCR (COVID-19 group)–categorized as recovered COVID-19 (N = 11) or long-COVID-19 (N = 15). All COVID-19 patients presented at least one signal or symptom during the first two weeks of infection. Six patients were hospitalized and required invasive mechanical ventilation. Our results showed that COVID-19 patients had significantly higher levels of IFN-γ, TNF, IL-1β, IL-2, IL-6, IL-8, and IP-10 than the unexposed group. The long-COVID-19 group has presented significantly high levels of IL-1β and IL-6 compared to unexposed individuals, but not from recovered COVID-19. A principal-component analysis demonstrated 84.3% of the total variance of inflammatory-SARS-CoV-2 response in the first two components, and it was possible to stratify IL-6, TNF, IL-1β, IL-10, and IL-2 as the top-five cytokines which are candidates to discriminate COVID-19 group (including long-COVID-19 subgroup) and healthy unexposed individuals. Conclusion We revealed important S protein-specific differential biomarkers in individuals affected by COVID-19, bringing new insights into the inflammatory status or SARS-CoV-2 exposition determination.

1896

CaV324

Martins-Gonçalves, Remy; Hottz, Eugenio D.; Bozza, Patricia T.

Acute to post-acute COVID-19 thromboinflammation persistence: Mechanisms and potential consequences

https://doi.org/10.1016/j.crimmu.2023.100058

Published

1-Jan-23

Review

https://www.sciencedirect.com/science/article/pii/S2590255523000045

Concerns for the long-term effects of COVID-19 infection have grown due to frequently reported persisting symptoms that can affect multiple systems for longer than 4 weeks after initial infection, a condition known as long-COVID-19 or post-acute COVID-19 syndrome (PACS). Even nonhospitalized survivors have an elevated risk for the development of thromboinflammatory-associated events, such as ischemic stroke and heart failure, pulmonary embolism and deep vein thrombosis. Recent findings point to the persistence of many mechanisms of hypercoagulability identified to be associated with disease severity and mortality in the acute phase of the disease, such as sustained inflammation and endotheliopathy, accompanied by abnormal fibrin generation and impaired fibrinolysis. Platelets seem to be central to the sustained hypercoagulable state, displaying hyperreactivity to stimuli and increased adhesive capacity. Platelets also contribute to elevated levels of thromboinflammatory mediators and pro-coagulant extracellular vesicles in individuals with ongoing PACS. Despite new advances in the understanding of mechanisms sustaining thromboinflammation in PACS, little is known about what triggers this persistence. In this graphical review, we provide a schematic representation of the known mechanisms and consequences of persisting thromboinflammation in COVID-19 survivors and summarize the hypothesized triggers maintaining this prothrombotic state.

1897

CaV325

Sattar, Yasar; Taha, Amro; Patel, Neel; Victor, Varun; Titus, Anoop; Aziz, Shazia; Gonuguntla, Karthik; Thyagaturu, Harshith; Atti, Lalitsiri; Micho, Tarec; Almas, Talal; Tarun, Tushar; Alraies, M. Chadi; Balla, Sudarshan

Cardiovascular outcomes of type 2 myocardial infarction among COVID-19 patients: a propensity matched national study

https://doi.org/10.1080/14779072.2023.2200933

Published

10-Apr-23

Study

https://doi.org/10.1080/14779072.2023.2200933

Background Myocardial infarction Type II (T2MI) is a prevalent cause of troponin elevation secondary to a variety of conditions causing stress/demand mismatch. The impact of T2MI on outcomes in patients hospitalized with COVID-19 is not well studied.Methods The Nationwide Inpatient Sample database from the year 2020 was queried to identify COVID-19 patients with T2MI during the index hospitalization. Clinical Modification (ICD-10-CM) codes ‘U07.1’ and ‘I21.A1’ were used as disease identifiers for COVID-19 and T2MI respectively. Multivariate adjusted Odds ratio (aOR) and propensity score matching (PSM) was done to compare outcomes among COVID patients with and without T2MI. The primary outcome was in-hospital mortality.Results A total of 1,678,995 COVID-19-weighted hospitalizations were identified in the year 2020, of which 41,755 (2.48%) patients had T2MI compared to 1,637,165 (97.5%) without T2MI. Patients with T2MI had higher adjusted odds of in-hospital mortality (aOR 1.44, PSM 32.27%, 95% CI 1.34–1.54) sudden cardiac arrest (aOR 1.29, PSM 6.6%, 95% CI 1.17–1.43) and CS (aOR 2.16, PSM 2.73%, 95% CI 1.85–2.53) compared to patients without T2MI. The rate of coronary angiography (CA) in T2MI with COVID was 1.19%, with significant use of CA among patients with T2MI complicated by CS compared to those without CS (4% vs 1.1%, p < 0.001). Additionally, COVID-19 patients with T2MI had an increased prevalence of sepsis compared to COVID-19 without T2MI (48% vs 24.1%, p < 0.001).Conclusion COVID-19 patients with T2MI had worse cardiovascular outcomes with significantly higher in-hospital mortality, SCA, and CS compared to those without T2MI. Long-term mortality and morbidity among COVID-19 patients who had T2MI will need to be clarified in future studies.

1898

CaV326

Krinsky, Nitzan; Sizikov, Sofia; Nissim, Sivan; Dror, Adi; Sas, Anna; Prinz, Hodaya; Pri-Or, Ester; Perek, Shay; Raz-Pasteur, Ayelet; Lejbkowicz, Izabella; Cohen-Matsliah, Sivan Ida; Almog, Ronit; Chen, Nikanor; Kurd, Ramzi; Jarjou'i, Amir; Rokach, Ariel; Ben-Chetrit, Eli; Schroeder, Avi; Caulin, Aleah F.; Yost, Christian Con; Schiffman, Joshua D.; Goldfeder, Mor; Martinod, Kimberly

NETosis induction reflects COVID-19 severity and Long COVID: insights from a two-center patient cohort study in Israel

https://doi.org/10.1016/j.jtha.2023.02.033

Published

11-Apr-23

Study

https://www.jthjournal.org/article/S1538-7836(23)00274-X/fulltext

Background
COVID-19 severity and its late complications continue to be poorly understood. Neutrophil extracellular traps (NETs) form in acute COVID-19, likely contributing to morbidity and mortality. This study evaluated immunothrombosis markers in a comprehensive cohort of acute and recovered COVID-19 patients, including the association of NETs with LongCOVID.
Methods
One-hundred-seventy-seven patients were recruited from clinical cohorts at two Israeli centers: acute COVID-19 (mild/moderate, severe/critical), convalescent COVID-19 (recovered and Long COVID), along with 54 non-COVID controls. Plasma was examined for markers of platelet activation, coagulation, and NETs. Ex vivo NETosis induction capability was evaluated after neutrophil incubation with patient plasma.
Results
Soluble P-selectin, Factor VIII, von Willebrand factor, and platelet factor 4 were significantly elevated in COVID-19 patients versus controls. Myeloperoxidase (MPO)-DNA complex levels were increased only in severe COVID-19 and did not differentiate between COVID-19 severities or correlate with thrombotic markers. NETosis induction levels strongly correlated with illness severity/duration, platelet activation markers, and coagulation factors, and were significantly reduced upon dexamethasone treatment and recovery. Long COVID patients maintained higher NETosis induction, but not NET fragments, compared to recovered convalescent patients.
Conclusions
Increased NETosis induction can be detected in Long COVID patients. NETosis induction appears to be a more sensitive NET measurement than MPO-DNA levels in COVID-19, differentiating between disease severity and Long COVID patients. Ongoing NETosis induction capability in Long COVID may provide insights into pathogenesis and serve as a surrogate marker for persistent pathology. This study emphasizes the need to explore neutrophil-targeted therapies in acute and chronic COVID-19.
publisher: Elsevier
PMID: 37054916

1899

CaV327

Balas, Reka Borka; Meliț, Lorena Elena; Mărginean, Cristina Oana

COVID-19 and Cardiac Implications—Still a Mystery in Clinical Practice

https://doi.org/10.31083/j.rcm2405125

Published

24-Apr-23

Review

https://www.imrpress.com/journal/RCM/24/5/10.31083/j.rcm2405125

Although initially the evolution of Coronavirus disease 2019 (COVID-19) seemed less severe in pediatric patients, in the three years since the beginning of the pandemics, several severe cases have been described, pediatric inflammatory multisystem syndrome (PIMS) has been defined, pathogenesis is being continuously studied, and many aspects regarding the long-term evolution and multi-organ damage are still unexplained. Cardiac injuries in COVID-19 represent most-likely the second cause of mortality associated with the infection. A wide-spectrum of cardiac abnormalities were reported to be associated with COVID-19 in children including ventricular dysfunction, acute myocardial dysfunction, arrhythmias, conduction abnormalities, coronary artery dilation or aneurysms, and less common pericarditis and valvulitis. Risk factors for severe COVID-19 in children should be identified, laboratory tests and imaging techniques should be performed to reveal cardiac injury as soon as possible. The aim of this review was to highlight the great value of repeated cardiological monitoring in patients with COVID-19, underlining also the peculiarities in terms of pediatric population. This review is looking for answers on questions like ‘Why do some, but not all, patients with COVID-19 develop cardiac injury or severe hyperinflammatory status?’, ‘Which factors are involved in triggering COVID-19 associated cardiac injury?’, ‘What are the mechanisms involved in the etiology of cardiac injury?’, ‘Is there a clear relationship between hyperinflammation and cardiac injury?’, ‘Is hyperinflammatory status the pre-stage of cardiac injury in COVID-19 patients?’ which still lack clear answers. The understanding of mechanisms involved in the development of COVID-19 associated cardiac injury might shed light on all the above-mentioned mysteries and might increase the likelihood of favorable evolution even in severe cases.

1900

CaV328

González-Hermosillo G, J. Antonio; Galarza, Esteban Jorge; Fermín, Onasis Vicente; González, José Manuel Núñez; Tostado, Lucia Mariel Félix Álvarez; Lozano, Marco Antonio Estrada; Rabasa, Claudia Ruíz; Martínez Alvarado, María del Rocio

Exaggerated blood pressure elevation in response to orthostatic challenge, a post-acute sequelae of SARS-CoV-2 infection (PASC) after hospitalization

https://doi.org/10.1016/j.autneu.2023.103094

Published

1-Jul-23

Study

https://www.sciencedirect.com/science/article/pii/S1566070223000231

Highlights
•Head-up tilt may unmask an exaggerated blood pressure response after COVID-19.
•Renin-angiotensin imbalance enhancing sympathetic tone may be the mechanism.
•Preclinical hypertension could be a sequelae of COVID-19.
Abstract
Objective
Post-acute sequelae of SARS-COV-2 (PASC) are emerging as a major health challenge. Orthostatic intolerance secondary to autonomic failure has been found in PASC patients. This study investigated the effect of COVID-19 after recovery on blood pressure (BP) during the orthostatic challenge.

Research design and methods
Thirty-one out of 45 patients hospitalized due to COVID-19-related pneumonia that developed PASC and did not have hypertension at discharge were studied. They underwent a head-up tilt test (HUTT) at 10.8 ± 1.9 months from discharge. All met the PASC clinical criteria, and an alternative diagnosis did not explain the symptoms. This population was compared with 32 historical asymptomatic healthy controls.

Results
Exaggerated orthostatic blood pressure response (EOPR)/orthostatic hypertension (OHT) was detected in 8 out of 23 (34.7 %) patients, representing a significantly increased prevalence (7.67-fold increase p = 0.009) compared to 2 out of 32 (6.4 %) asymptomatic healthy controls matched by age, who underwent HUTT and were not infected with SARS-CoV-2.

Conclusions
This prospective evaluation in patients with PASC revealed abnormal blood pressure rise during the orthostatic challenge, suggesting of autonomic dysfunction in a third of the studied subjects. Our findings support the hypothesis that EOPR/OHT may be a phenotype of neurogenic hypertension. Hypertension in PASC patients may adversely affect the cardiovascular burden in the world.

1901

CaV329

Lorente-Ros, Marta; Das, Subrat; Elias, Joseph; Frishman, William H; Aronow, Wilbert S

Cardiovascular Manifestations of the Long COVID Syndrome

https://doi.org/10.1097/crd.0000000000000552

Published

1-Apr-23

Review

https://doi.org/10.1097/CRD.0000000000000552

While most coronavirus 2019 (COVID-19) survivors have had complete resolution of symptoms, a significant proportion have suffered from incomplete recovery. Cardiopulmonary symptoms, such as dyspnea, chest pain, and palpitations are responsible for a substantial symptom burden in COVID-19 survivors. Studies have revealed persistent myocardial injury with late gadolinium enhancement and myocardial scar on cardiac magnetic resonance in a significant proportion of patients. Evidence of myocardial edema, active inflammation, left ventricular dysfunction, and right ventricular dysfunction, is limited to a minority of patients. Large observational studies of COVID-19 survivors have indicated an increased risk of cardiovascular disease compared to the general population, including the risk of coronary artery disease, cardiomyopathy, and arrhythmias. Management of long COVID is focused on supportive therapy to reduce systemic inflammation. Patients with high cardiovascular risk, namely, those who had cardiovascular complications during acute illness, patients who have new onset cardiopulmonary symptoms in the postinfectious period, and competitive athletes, should be evaluated by a cardiovascular specialist. Management of cardiovascular sequelae is currently based on general expert guideline recommendations given the lack of evidence specific to long COVID syndrome. In this review, we outline the cardiovascular manifestations of long COVID, the current evidence supporting cardiac abnormalities in the postinfectious period, and the recommended management of these patients.

1902

CaV330

Cecchetto, Antonella; Torreggiani, Gianpaolo; Guarnieri, Gabriella; Vianello, Andrea; Baroni, Giulia; Palermo, Chiara; Bertagna De Marchi, Leonardo; Lorenzoni, Giulia; Bartolotta, Patrizia; Bertaglia, Emanuele; Donato, Filippo; Aruta, Patrizia; Iliceto, Sabino; Mele, Donato

Subclinical Myocardial Injury in Patients Recovered from COVID-19 Pneumonia: Predictors and Longitudinal Assessment

https://doi.org/10.3390/jcdd10040179

Published

1-Apr-23

Study

https://www.mdpi.com/2308-3425/10/4/179

(1) Background: Emerging data regarding patients recovered from COVID-19 are reported in the literature, but cardiac sequelae have not yet been clarified. To quickly detect any cardiac involvement at follow-up, the aims of the research were to identify: elements at admission predisposing subclinical myocardial injury at follow up; the relationship between subclinical myocardial injury and multiparametric evaluation at follow-up; and subclinical myocardial injury longitudinal evolution. (2) Methods and Results: A total of 229 consecutive patients hospitalised for moderate to severe COVID-19 pneumonia were initially enrolled, of which 225 were available for follow-up. All patients underwent a first follow-up visit, which included a clinical evaluation, a laboratory test, echocardiography, a six-minute walking test (6MWT), and a pulmonary functional test. Of the 225 patients, 43 (19%) underwent a second follow-up visit. The median time to the first follow-up after discharge was 5 months, and the median time to the second follow-up after discharge was 12 months. Left ventricular global longitudinal strain (LVGLS) and right ventricular free wall strain (RVFWS) were reduced in 36% (n = 81) and 7.2% (n = 16) of the patients, respectively, at first the follow-up visit. LVGLS impairment showed correlations with patients of male gender (p 0.008, OR 2.32 (95% CI 1.24–4.42)), the presence of at least one cardiovascular risk factor (p < 0.001, OR 6.44 (95% CI 3.07–14.9)), and final oxygen saturation (p 0.002, OR 0.99 (95% CI 0.98–1)) for the 6MWTs. Subclinical myocardial dysfunction had not significantly improved at the 12-month follow-ups. (3) Conclusions: in patients recovered from COVID-19 pneumonia, left ventricular subclinical myocardial injury was related to cardiovascular risk factors and appeared stable during follow-up.

1903

CaV331

Soysal, G. G.; Kimyon, S.; Mete, A.; Güngör, K.

Evaluation of the retina with optical coherence tomography angiography (OCTA) in patients with coronavirus (COVID-19) infection

https://doi.org/10.1016/j.jfo.2023.02.006

Published

17-Apr-23

Study

https://www.sciencedirect.com/science/article/pii/S0181551223002280

Purpose
The goal of this study is to compare the optical coherence tomography angiography (OCTA) findings in Coronavirus (COVID-19) positive adult and pediatric patients with those of healthy volunteers with the same demographic characteristics.
Methods
The right eye of 157 adults infected with covid, 168 healthy adult volunteers, 40 children (6–18 years of age) infected with covid, and 44 healthy children (6–18 years of age) were included in this prospective study. All participants underwent ophthalmological examination and OCTA. The OCTA findings were evaluated.
Results
Deep nasal density (DND), deep inferior density (DID), and deep parafoveal density (DPD) were significantly lower in the pediatric covid-affected group (PCAG) than in the pediatric healthy control group (PHCG) (P=0.034, P=0.029, P=0.022 respectively). On the other hand, radial peripapillary capillary vessel density (RPCVD) intra-disc measurements were significantly higher in the PCAG compared to the PHCG (P=0.025). There was no significant difference between the OCTA measurements of the adult covid-affected group (ACAG) and the adult healthy control group (AHCG).
Conclusion
In our study, significant differences were found in OCTA measurements between the covid group and the healthy control group in children. Retinal microvascular changes may occur in patients with covid infection, and these patients might be followed for long-term retinal changes.
Résumé
Objectif
L’objectif de cette étude est de comparer les résultats de l’angiographie par tomographie à cohérence optique (OCTA) de patients adultes et pédiatriques positifs au coronavirus (COVID-19) avec des volontaires sains présentant les mêmes caractéristiques démographiques.
Méthodes
L’œil droit de 157 adultes infectés par la covid, 168 volontaires adultes sains, 40 enfants (6–18 ans) infectés par la covid et 44 enfants sains (6–18 ans) ont été inclus dans cette étude prospective. Tous les participants ont subi un examen ophtalmologique et une OCTA a été réalisée. Les résultats de l’OCTA ont été évalués.
Résultats
La densité nasale profonde (DND), la densité inférieure profonde (DID) et la densité parafovéale profonde (DPD) étaient significativement plus faibles dans le groupe pédiatrique atteint de la covid (PCAG) que dans le groupe témoin sain (PHCG) (p=0,034, p=0,029, p=0,022 respectivement). D’autre part, les mesures de la densité des vaisseaux capillaires péripapillaires radiaux (RPCVD) à l’intérieur du disque étaient significativement plus élevées dans le PCAG que dans le PHCG (p=0,025). Il n’y avait pas de différence significative entre les mesures OCTA du groupe d’adultes atteints de la covid (ACAG) et du groupe de contrôle adulte sain (AHCG).
Conclusion
Dans notre étude, des différences significatives ont été trouvées dans les mesures OCTA entre le groupe covid et le groupe de contrôle sain chez les enfants. Des changements microvasculaires rétiniens peuvent se produire chez les patients atteints d’une infection de la covid, et ces patients peuvent être suivis pour des changements rétiniens à long terme.

1904

CaV332

Machado, Nicolle R.; Dias, Karina T.; Cortes, Bryan F.S.; Rodrigues, Stephen F.

Effect of coronaviruses on blood vessel permeability: potential therapeutic targets

https://doi.org/10.1177/17534666231162252

Published

1-Jan-23

Study

https://doi.org/10.1177/17534666231162252

Coronavirus-induced diseases have afflicted humanity for several decades. This scenario was aggravated by the emergence of the coronavirus disease 2019 (named COVID-19) in Wuhan, China, in December 2019. Since then, COVID-19 has killed millions of people worldwide, probably the most devastating pandemic since HIV/AIDS. This review aimed to bring together important updated aspects related to coronavirus-induced diseases and the enhanced vascular permeability observed mainly in the lungs of affected people. The dysregulated vascular permeability in the lungs is of fundamental importance for coronaviruses-caused morbidity and mortality. Thus, as described in this review, it is a target of new and old drugs.

1905

CaV333

Kersten, Johannes; Schellenberg, Jana; Jerg, Achim; Kirsten, Johannes; Persch, Hasema; Liu, Yuefei; Steinacker, Jürgen M.

Strain Echocardiography in Acute COVID-19 and Post-COVID Syndrome: More than Just a Snapshot

https://doi.org/10.3390/biomedicines11041236

Published

1-Apr-23

Review

https://www.mdpi.com/2227-9059/11/4/1236

Speckle-tracking echocardiography (STE) has become an established, widely available diagnostic method in the past few years, making its value clear in cases of COVID-19 and the further course of the disease, including post-COVID syndrome. Since the beginning of the pandemic, many studies have been published on the use of STE in this condition, enabling, on the one hand, a better understanding of myocardial involvement in COVID-19 and, on the other, a better identification of risk to patients, although some questions remain unanswered in regard to specific pathomechanisms, especially in post-COVID patients. This review takes a closer look at current findings and potential future developments by summarising the extant data on the use of STE, with a focus on left and right ventricular longitudinal strain.

1906

CaV334

Turner, Simone; Khan, M. Asad; Putrino, David; Woodcock, Ashley; Kell, Douglas B.; Pretorius, Etheresia

Long COVID: pathophysiological factors and abnormalities of coagulation

https://doi.org/10.1016/j.tem.2023.03.002

Published

1-Jun-23

Study

https://www.cell.com/trends/endocrinology-metabolism/abstract/S1043-2760(23)00055-3

Highlights
Long COVID has a multifactorial nature with multiple pathophysiological factors at play.
Viral factors, host factors (including systemic inflammation, and metabolic, endocrine, and endothelial dysfunction) and downstream impacts (tissue damage from the initial infection, hypoxia, dysbiosis, and autonomic nervous system dysfunction) are key elements underpinning the condition.
Various factors culminate in the long-term persistence of the disorder (i.e., a thrombotic endothelialitis characterized by endothelial inflammation, hyperactivated platelets, and fibrinaloid microclots).
We suggest a multipronged treatment agenda for Long COVID treatment trials, incorporating drugs targeting all potential mechanisms, including viral persistence, autoimmunity, immune dysregulation, and gut dysbiosis; with endothelialitis and coagulation abnormalities as two priorities.
Abstract
Acute COVID-19 infection is followed by prolonged symptoms in approximately one in ten cases: known as Long COVID. The disease affects ~65 million individuals worldwide. Many pathophysiological processes appear to underlie Long COVID, including viral factors (persistence, reactivation, and bacteriophagic action of SARS CoV-2); host factors (chronic inflammation, metabolic and endocrine dysregulation, immune dysregulation, and autoimmunity); and downstream impacts (tissue damage from the initial infection, tissue hypoxia, host dysbiosis, and autonomic nervous system dysfunction). These mechanisms culminate in the long-term persistence of the disorder characterized by a thrombotic endothelialitis, endothelial inflammation, hyperactivated platelets, and fibrinaloid microclots. These abnormalities of blood vessels and coagulation affect every organ system and represent a unifying pathway for the various symptoms of Long COVID.
publisher: Elsevier
PMID: 37080828

1907

CaV335

Nicolai, Leo; Kaiser, Rainer; Stark, Konstantin

Thrombo-inflammation in Long COVID – the elusive key to post-infection sequelae?

https://doi.org/10.1016/j.jtha.2023.04.039

Published

11-May-23

Review

https://www.sciencedirect.com/science/article/pii/S1538783623004002

Long COVID is a public health emergency affecting millions of people worldwide, characterized by heterogenous symptoms across multiple organs systems. Here, we discuss the current evidence linking thrombo-inflammation to Post-acute sequelae of COVID-19 (PASC). Studies have found persistence of vascular damage with increased circulating markers of endothelial dysfunction, coagulation abnormalities with increased thrombin generation capacity, and abnormalities in platelet counts in PASC. Neutrophil phenotype resembles acute COVID-19 with an increase in activation and NETosis. These insights are potentially linked by elevated platelet-neutrophil aggregate formation. This hypercoagulable state in turn can lead to microvascular thrombosis, evidenced by microclots and elevated D-Dimer in the circulation, as well as perfusion abnormalities in the lung and brain of Long COVID patients. Also, COVID-19 survivors suffer from an increased rate of arterial and venous thrombotic events. We discuss three important, potentially intertwined hypotheses, that might contribute to thromboinflammation in Long COVID: Lasting structural changes, most prominently endothelial damage, caused during initial infection, a persistent viral reservoir, and immunopathology driven by a misguided immune system. Lastly, we outline the necessity for large, well-characterized clinical cohorts and mechanistic studies to clarify the contribution of thromboinflammation to Long COVID.

1908

CaV336

Koupenova, Milka; Chung, Mina K.; Bristow, Michael R.

COVID-19 and the Cardiovascular System: Requiem for a Medical Minotaur

https://doi.org/10.1161/CIRCRESAHA.123.322935

Published

12-May-23

Article

https://www.ahajournals.org/doi/full/10.1161/CIRCRESAHA.123.322935

Sophisticated imaging methodology has contributed enormously to our understanding of how a respiratory viral infection caused by SARS-CoV-2 may seriously impact cardiovascular disease. Cardiac magnetic resonance imaging is instrumental in the detection of myocardial injury and the clinical diagnosis of myocarditis in COVID-19 patients, in addition to the evaluation of coronary microvascular dysfunction particularly in patients recovered from COVID-19 infection. In this compendium, Holby et al14 provide an overview of the multimodality imaging that has been used to diagnose and evaluate COVID-19. As we dive deeper into the mechanisms of disease, murine models and mouse adaptable strains have proved valuable, which is briefly discussed by Sciaudone et al.5 However, mice including those that express human ACE2, lack a full set of sequelae presented by human COVID-19. In that sense the usefulness of iPS-derived systems, particularly cardiomyocytes, are also reviewed by Satta et al,15 including the benefits and limitations in advancements in microfluidics, organ-on-a-chip and human stem-cell derived models to study SARS-CoV-2 infection in the physiological organ microenvironment. Overall, many tools have been developed in COVID-19 investigations, and we are beginning to understand the unique roles of these model systems.Three years following the onset of the pandemic, we have gained a vast amount of knowledge as to how one virus as small as 100 µm can collapse an entire multiorgan system. We can now conclusively say that certain respiratory coronaviruses increase the risk of macrothrombotic events, organ microthrombosis, myocardial injury including myocarditis, and arrhythmias. We have learned there are factors, such as hypertension, atrial fibrillation, heart failure, diabetes and obesity, that predispose to cardiac involvement in COVID-19. We have increased our understanding of how the immune response to SARS-CoV-2 may contribute to the pathophysiology of CVD in addition to its roles in inflammation and thrombosis signaling. Nevertheless, we have just scratched the surface and many questions remain unanswered. For instance, what are the exact mechanisms that cannot be controlled by anticoagulation and antiplatelet therapy that contribute to treatment-refractory macro- and microthrombosis; what are the precise mechanisms that underline myocardial injury in cases where myocarditis is not detected, what are the factors responsible for development of prolonged fatigue and other symptoms that underlie long-COVID/PASC, and in CV research and training should there be a greater emphasis on immunology and infectious disease? History has shown that pandemics will continue to occur, and the more we understand how viruses and infections in general impact human cardiovascular pathophysiology, the better prepared we will be for the next outbreak, which may occur sooner rather than later in this age of global connectivity. Areas where we will need to do better include recognizing and preventing the consequences of cardiovascular clinical risks, understanding and avoiding postinfection sequelae, and designing better therapeutic agents and vaccines. We as a community must continue to address the remaining questions and elucidate the relevant mechanisms; only then will we be able to more effectively confront the next Minotaur of infectious impact on cardiovascular disease.

1909

CaV337

Singh, Tamanna K.; Zidar, David A.; McCrae, Keith; Highland, Kristin B.; Englund, Kristin; Cameron, Scott J.; Chung, Mina K.

A Post-Pandemic Enigma: The Cardiovascular Impact of Post-Acute Sequelae of SARS-CoV-2

https://doi.org/10.1161/CIRCRESAHA.122.322228

Published

12-May-23

Review

https://www.ahajournals.org/doi/abs/10.1161/CIRCRESAHA.122.322228

COVID-19 has become the first modern-day pandemic of historic proportion, affecting >600 million individuals worldwide and causing >6.5 million deaths. While acute infection has had devastating consequences, postacute sequelae of SARS-CoV-2 infection appears to be a pandemic of its own, impacting up to one-third of survivors and often causing symptoms suggestive of cardiovascular phenomena. This review will highlight the suspected pathophysiology of postacute sequelae of SARS-CoV-2, its influence on the cardiovascular system, and potential treatment strategies.
publisher: Lippincott Williams & Wilkins
Hagerstown, MD

1910

CaV338

Lopes, Leilani A.; Agrawal, Devendra K.

Thromboembolism in the Complications of Long COVID-19

https://doi.org/

Published

20-Apr-23

Review

http://www.fotunejournals.com/thromboembolism-in-the-complications-of-long-covid19.html

SARS-CoV-2 is a +ssRNA helical coronavirus responsible for the global pandemic caused by coronavirus disease 19 (COVID-19). Classical clinical symptoms from primary COVID-19 when symptomatic include cough, fever, pneumonia or even ARDS; however, they are limited primarily to the respiratory system. Long-COVID-19 sequalae is responsible for many pathologies in almost every organ system and may be present in up to 30% of patients who have developed COVID-19. Our review focuses on how long-COVID-19 (3 -24 weeks after primary symptoms) may lead to an increased risk for stroke and thromboembolism. Patients who were found to be primarily at risk for thrombotic events included critically ill and immunocompromised patients. Additional risk factors for thromboembolism and stroke included diabetes, hypertension, respiratory and cardiovascular disease, and obesity. The etiology of how long-COVID-19 leads to a hypercoagulable state are yet to be definitively elucidated. However, anti-phospholipid antibodies and elevated D-dimer are present in many patients who develop thromboembolism. In addition, chronic upregulation and exhaustion of the immune system may lead to a pro-inflammatory and hypercoagulable state, increasing the likelihood for induction of thromboembolism or stroke. This article provides an up-to-date review on the proposed etiologies for thromboembolism and stroke in patients with long-COVID-19 and to assist health care providers in examining patients who may be at a higher risk for developing these pathologies.

1911

CaV339

Chouairi, Fouad; Pinsker, Bret; Miller, P. Elliott; Fudim, Marat

Effects of COVID-19 on heart failure admissions

https://doi.org/10.1016/j.ahj.2023.05.001

Published

6-May-23

Study

https://www.sciencedirect.com/science/article/pii/S0002870323001114

Despite significant investigation into the effects of COVID-19 on cardiovascular disease, there is a paucity of national data specifically examining its effects on heart failure (HF) hospitalizations. Previous cohort study data demonstrate worsened outcomes in HF patients with recent COVID-19 infection. To better understand this association, this study aimed to utilize a nationally representative database to examine demographics, outcomes, and health care utilization in hospitalizations for HF with a codiagnosis of COVID-19.

1912

CaV340

Sayegh, Michael N.; Goins, Allie E.; Hall, Mary Ann Kirkconnell; Shin, Yoo Mee; Sayegh, Michael N.; Goins, Allie E.; Hall, Mary Ann Kirkconnell; Shin, Yoo Mee

Presentations, Diagnosis, and Treatment of Post-COVID Viral Myocarditis in the Inpatient Setting: A Narrative Review

https://doi.org/10.7759/cureus.39338

Published

22-May-23

Review

https://www.cureus.com/articles/153448-presentations-diagnosis-and-treatment-of-post-covid-viral-myocarditis-in-the-inpatient-setting-a-narrative-review

While coronavirus disease 2019 (COVID-19) infection rates have declined, and mortality outcomes have improved with vaccines, targeted antiviral therapies, and improved care practices over the course of the pandemic, post-acute sequelae of SARS CoV-2 infection (PASC, also referred to as “long COVID”) has emerged as a significant concern, even among individuals who appear to have fully recovered from their initial infection. Acute COVID-19 infection is associated with myocarditis and cardiomyopathies, but the prevalence and presentation of post-infectious myocarditis are unclear. We provide a narrative review of post-COVID myocarditis, including symptoms and signs, physical exam findings, diagnosis, and treatment strategies.

Post-COVID myocarditis has a wide range of presentations, from very mild symptoms to severe ones that can include sudden cardiac death. Several studies have noted what appears to be a bimodal distribution of affected patients, with individuals under age 16 (particularly males) most affected, followed by those over age 50. The gold standard of diagnosis for myocarditis is endomyocardial biopsy and cardiac magnetic resonance imaging with a confirmed diagnosis of COVID-19. However, if these are not available, other studies such as electrocardiogram, echocardiography, and inflammatory markers can guide clinicians to diagnose post-COVID myocarditis when appropriate. Treatment is largely supportive and may include oxygen therapy, intravenous hydration, diuretics, steroids, and antivirals. Post-COVID myocarditis is rare but important to recognize as more patients present with this condition in the inpatient setting.

1913

CaV341

Diekman, Sarah; Chung, Tae

Post-acute sequelae of SARS-CoV-2 syndrome presenting as postural orthostatic tachycardia syndrome

https://doi.org/10.15441/ceem.22.409

Published

30-Jan-23

Review

http://www.ceemjournal.org/journal/view.php?doi=10.15441/ceem.22.409

What is already known
Postural orthostatic tachycardic syndrome (POTS) is increasingly recognized among patients with post-acute sequelae of SARS-CoV-2 syndrome (PASC).
What is new in the current study
We have reviewed all the case reports and prospective studies of POTS or dysautonomia among patients with PASC.
The novel SARS-CoV-2 emerged in 2019, and the global COVID-19 pandemic continues into 2022. It has been known that a subset of patients develops chronic, debilitating symptoms after otherwise complete recovery from acute infection of COVID-19. Multiple terms have been used to describe this constellation of symptoms, including long COVID, long-haul COVID, and postacute sequelae of SARS-CoV-2 syndrome (PASC). PASC is broadly defined as a wide range of new, returning, or ongoing symptoms at least four weeks after infection. Those patients are often seen in emergency departments after acute COVID-19 infection, but their symptoms are not adequately managed because the underlying pathophysiology of PASC is not well understood. Among patients with PASC, postural orthostatic tachycardic syndrome (POTS) has been increasingly recognized. POTS is one of the most common forms of autonomic dysfunction and defined by a sustained orthostatic tachycardia during active standing or head-up tilt test in the absence of orthostatic hypotension or other cardiopulmonary diseases. Because POTS is a treatable condition, it is important to recognize POTS among PASC patients. Herein, we reviewed the current literature on POTS and dysautonomia in PASC in order to better understand the overlap and distinction between these pathologies.
publisher: The Korean Society of Emergency Medicine

1914

CaV342

Gotelli, E.; Ingegnoli, F.; Angelis, R. De; Guiducci, S.; Giuggioli, D.; Pizzorni, C.; Riccieri, V.; Sebastiani, M.; Sulli, A.; Smith, V.; Cutolo, M.

Ab1310 Utilization and Attitudes Towards Nailfold Videocapillaroscopy for the Assessment of Microvascular Status in Patients with Long-Covid: A Multicenter Online Survey

https://doi.org/10.1136/annrheumdis-2023-eular.3345

Published

1-Jun-23

Study

https://ard.bmj.com/content/82/Suppl_1/1883.3

Background Human SARS-CoV-2 infection is responsible for a large variety of clinical manifestations related to Coronavirus disease-19 (COVID-19) [1]. SARS-CoV-2 can induce microvascular damage, that can be safely detected by nailfold videocapillaroscopy (NVC), as recently demonstrated [2-4]. Virus-induced endothelial dysfunction has been implicated in the pathogenesis of both active infection and long-COVID clinical manifestations (the last as persistence of disease symptoms after at least three months from onset) [5]. The study group on capillaroscopy and microcirculation in rheumatic diseases of the Italian Society of Rheumatology (CAPSIR) carried out an internal survey on the interest of the Italian Centers that perform NVC in participating in a detailed capillaroscopic and clinical data collection in long-COVID patients.
Objectives To carry out an Italian multicenter cognitive survey on the interest in collecting NVC and clinical data of patients affected by long-COVID with or without previous rheumatological diseases.
Methods The steering committee of the CAPSIR study group formulated a cognitive questionnaire, entitled “Study on the role of capillaroscopy in patients with long-COVID” (CAPSIR_2 Study), consisting of 27 open or multiple-choice questions. A Google Form of the questionnaire was emailed to all the member of the study group between September and October 2022. Data are reported with a descriptive analysis.
Results The online questionnaire was completed by 41 CAPSIR members, belonging to 33 different Italian centers. Of note, 63% of participants had already experienced NVC in patients with long-COVID. The primary indication to perform the NVC was the onset of a new Raynaud’s phenomenon (46% of cases) and the requests come mainly from General Practitioners (33% of cases). In 2/3 of the cases, patients with long-COVID and previous rheumatic diseases, who underwent NVC examination, represented less than 20% of the total. It should be noted that always in 2/3 of the cases there was no preferential channel for the study of the microcirculation in patients affected by long-COVID nor a NVC investigation prior to the SARS-CoV-2 infection. According to the previous experience of the participants in the interview, the most important NVC parameters considered to be evaluated in long-COVID patients were number of capillaries per linear millimeter (24% of cases), presence of hemorrhages (34% of cases) and giant capillaries (22% of capillaries). All participants (100%) therefore agreed to participate in a further collection of NVC and clinical data in this cohort of patients.
Conclusion This survey highlighted the interest of Italian Rheumatologists in assessing by NVC the COVID-related microvascular involvement. A consensus has emerged that future research is needed. After this pilot survey, the second part of the CAPSIR_2 Study will concern the collection/analysis before and after the SARS-CoV-2 infection of NVC and clinical data in patients with primary and secondary (to rheumatic diseases) Raynaud’s phenomenon and affected by long-COVID versus adequate controls. The aim is to investigate if the presence/severity of the microvascular damage might be involved in the pathogenesis of the clinical manifestations observed in COVID-19 patients after the active infection. CAPSIR_2 Study will be open to all Italian rheumatological centers that participated in the previous national CAPSIR_1 Project [6].
References [1]Fernandes Q et al. Ann Med. 2022;54:524-540.[2]Cutolo M et al. Nat Rev Rheumatol. 2021;17:665-677.[3]Sulli A et al. Microvasc Res 2022;142:104361.[4]Natalello G et al. Microvasc Res. 2021;133:104071.[5]Charfeddine S et al. Front Cardiovasc Med. 2021;8:745758.[6]Ingegnoli F et al. Reumatismo. 2022;74.
Acknowledgements Authors wrote the abstract on behalf of the study group on capillaroscopy and microcirculation in rheumatic diseases of the Italian Society of Rheumatology (SIR) - CAPSIR.CAPSIR Study Group thanks the EULAR Study Group of Microcirculation in Rheumatic Diseases for the continuous cultural support.
Disclosure of Interests None Declared.

1915

CaV343

Hovornyan, A; Ilashchuk, T O

Analysis of long-term cardiovascular outcomes of COVID-19. Artificial Intelligence model for risk evaluation

https://doi.org/10.1093/eurjpc/zwad125.328

Published

1-Jun-23

Study

https://doi.org/10.1093/eurjpc/zwad125.328

Type of funding sources: None.The COVID-19 pandemic has caused a serious worldwide health crisis with wide-reaching consequences. According to current studies, COVID-19 may contribute to the emergence of various problems, including cardiovascular disorders [1-3]. However, there are currently no strategies for predicting the cardiovascular post-acute COVID-19 consequences, nor is there any scientific examination of these effects [3]. This knowledge gap must be filled in order to improve post-acute COVID-19 care [4].To conduct a 12-month follow-up longitudinal observation study to explore potential long-term cardiovascular outcomes of COVID-19 and develop an AI-based model to predict them.We included 328 COVID-19 patients who were admitted to the hospital between February and April 2021. The average age of the studied population was 56.1, while 51% of the population was male. Patients with severe comorbidities, major adverse cardiovascular events (MACE) in anamnesis, and intra-hospital mortality were not included. After discharge, patients were monitored for 12 months. The data were randomly divided into derivation (n=201), validation (n=81), and external cohort (n=47). The obtained data include clinical data, results of laboratory and instrumental investigations, and medical records during the 1-year period. Our AI model is a convolutional neural network (CNN) consisting of sigmoid-activation-function neurons, trained by using outcome results, received in follow-ups, and evaluated on the external cohort.Due to the analysis of clinical data, higher levels of C-reactive protein, D-dimer, neutrophil/lymphocyte ratio, and lower levels of thyrotropin were associated with a higher 12-month risk of cardiovascular consequences. The longitudinal study showed that 16.4% of patients experienced MACE (8.5% - myocardial infarction, 5.2% - cerebrovascular disorders, 2.7% - pulmonary embolism) leading to cardiovascular death in 2.4% of the studied population. The total count of cardiovascular complications was 25.9% including first-detected hypertension, arrhythmias, heart failure etc.The derivation and validation datasets were used for the training of the CNN. The ROC analysis indicated that our AI model had a high predictive value for cardiovascular events during follow-up (AUC=0.891, 95% CI=0.869–0.913, p<0.001, sensitivity 92.4%, specificity 90.1%). The external cohort data analysis showed accurate results in 41/47 patients (87.2% accuracy), which significantly outperformed any other known methods of cardiovascular outcomes prediction during 12 months after COVID-19.Cardiovascular health in COVID-19 survivors needs special attention since COVID-19 is linked to an elevated risk of post-acute cardiovascular consequences. Long-term outcomes for COVID-19 can be predicted using AI-driven models.

1916

CaV344

Noniashvili, M; Tamar Saralidze, T S; Tamar Svanidze, T S; Tamar Kandashvili, T K; David Malidze, D M

Cardiovascular pathologies in post-covid syndrome

https://doi.org/10.1093/eurjpc/zwad125.337

Published

1-Jun-23

Study

https://doi.org/10.1093/eurjpc/zwad125.337

Type of funding sources: None.Problems of cardiovascular system and kidney function often follows the disease of Covid-19. Our aim was revealing and evaluation of cardiovascular disorders and kidney problems in patients who recovered from Covid-19.46 patients with Covid-19 infection, aged 29 to 64, were examined upon entering the clinic and after 2 months in outpatient department. (38 were women and 8 men, average age was 46, 1+_10.3 years). Along with clinical laboratory examination, echocardiography and ECG-Holter monitoring was performed in dynamic. Daily proteinuria, creatinine clearance and glomerular filtration rate were calculated. Patients who previously had arterial hypertension or any other disease of the cardiovascular system were not included in the study.Results of the study: Among the complaints that patients revealed 2 months after clinical onset of Covid-19, most frequent was discomfort and stinging pain in precordial area without irradiation that was not related to physical exertion. Cardialgia was observed in acute period and after two months in 30% and 25% of patients, respectively. 15% of patients revealed shortness of breath and palpitations during slight physical exertion in the acute period, while at repeated examination the specified symptom remained in 6%.Special attention was paid in our study to the dynamics of blood pressure. 24% of patients had elevated blood pressure at baseline. Blood pressure readings was increased in 28% of patients after 14 days. The average values of blood pressure during two months were 135, 5+_14.3 mmHg - systolic and 89.7+_10.7 mmHg- diastolic. After 2 months 26% of patients maintained arterial hypertention (AH) within the first stage. According to echocardiographic data, ventricular diastolic dysfunction was observed in 58% of patients in acute period and in 44% after two months. There were no signs of myocardial systolic dysfunction in dynamics.During the initial examination, diminished creatinine clearance (<90ml/min) and glomerular filtration rate (<90ml/min/1.73m2) disorders were observed in 42% and 62% of patients, respectively and microalbuminuria in 69% of patients. After 2 months microalbuminuria was maintained in 60% of patients, while decreased renal function (creatinine clearance and GFR) was observed in 33% of patients.Cardialgia, AH and signs of diastolic dysfunction were the main clinical manifestations of cardiovascular system dysfunction. The data of our study shows that probability of the formation of AH is highly increased after Covid-19 infection. Long-lasting microalbuminuria and a decrease in the renal filtering capabilities can also be revealed in every third patient after Covid-19 infection.The results of the study indicate the necessity of the monitoring of the patients after Covid-19 for timely diagnosis of AH and kidney disfunction to prevent development of unexpected cardiovascular events and kidney failure.

1917

CaV345

Hira, Rashmin; Siddiqui, Tanya; Baker, Jacquie; Bourne, Kate; Ranada, Shaun; Soroush, Ateyeh; Karalasingham, Kavithra; Ahmad, Hyeqa; Morillo, Carlos; Sheldon, Robert; Raj, Satish

Objective cardiovascular autonomic abnormalities persist over time in patients with Post-Acute Sequelae of COVID-19 (PASC)

https://doi.org/10.1152/physiol.2023.38.S1.5735031

Published

1-May-23

Study

https://journals.physiology.org/doi/abs/10.1152/physiol.2023.38.S1.5735031

BACKGROUND: The novel coronavirus (SARS-CoV-2) has negatively impacted the health and economy of the world. While most patients recover, many are suffering from symptoms several months after resolution of the acute illness (“Post-Acute Sequalae of COVID-19” [PASC]). Symptoms include fatigue, light-headedness, and tachycardia/palpitations, similar to symptoms of cardiovascular autonomic disorders such as Postural Orthostatic Tachycardia Syndrome (POTS), Initial Orthostatic Hypotension (IOH), Orthostatic Hypotension (OH), and Inappropriate Sinus Tachycardia (IST). We have previously shown a high prevalence of autonomic abnormalities among PASC patients. We currently do not know if these autonomic abnormalities are chronic and persist in PASC patients over time. OBJECTIVE: We aimed to determine if the autonomic abnormalities seen in patients after COVID-19 infection are persistent or transient, by comparing hemodynamic criterion between baseline and follow-up visits. We hypothesize that patients will recover, and abnormalities will not persist between the visits. METHODS: PASC patients (n=64; F=51; 46±12y) completed baseline visits 411±133 days after their initial COVID-19 infection and follow-up visits 97±9 days later. Patients underwent autonomic function testing with beat-to-beat hemodynamics during 10min supine rest followed by a 10min active stand. Patients were evaluated for hemodynamic criterion for POTS (↑HR≥30bpm within 10min), IOH (transient ↓SBP≥40mmHg within 15s), OH (↓SBP≥20mmHg within 3min), and IST (supine HR>100bpm). Categorical data were analyzed with a McNemar’s test. RESULTS: 19 (30%) participants met POTS criterion at baseline vs. 15 (23%) at follow-up (p=0.1). 43 (67%) participants met IOH criterion at baseline vs. 37 (58%) at follow-up (p=0.08). The OH criterion was seen in 2 (3.1%) vs 5 (7.8%) patients (p=0.2) and IST was seen in 1 patient at both visits (1.6%). Overall, 48 (75%) patients met the hemodynamic criterion for at least one autonomic disorder at baseline and 43 (67%) patients met at least one criterion at follow-up (p=0.09). CONCLUSION: Many patients with PASC have evidence of cardiovascular autonomic abnormalities, most commonly IOH, followed by POTS. The prevalence of these abnormalities does not decrease over time. These findings suggest patients with PASC are not recovering from autonomic complications due to their COVID-19 infections. Treatment and management strategies for autonomic abnormalities are needed to improve the quality of life for these patients.

Funding: Canadian Institutes of Health Research (CIHR)

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

1918

CaV346

Hupin, D; Pichot, V; Back, M; Nygren Bonnier, M; Reistam, U; Runold, M; Bruchfeldt, J; Barthelemy, J C; Stahlberg, M; Fedorowski, A; Nickander, J

Diagnostic value of 24-h ECG recording in Long COVID patients with postural orthostatic tachycardia syndrome

https://doi.org/10.1093/europace/euad122.626

Published

1-Jun-23

Study

https://doi.org/10.1093/europace/euad122.626

Type of funding sources: None.Cardiovascular autonomic dysfunction (CVAD) is a major complication for a large proportion of Long COVID (LC) patients. The main phenotype of CVAD is postural orthostatic tachycardia syndrome (POTS), commonly observed as a sequalae of COVID infection, thus defining a subset of LC patients. POTS is a cardiovascular autonomic disorder characterized by an excessive heart rate (HR) increase and symptoms of orthostatic intolerance when assuming upright posture, occurring predominantly in young and middle-aged women. Since the start of COVID-19 pandemic it has been observed that up to 30% of patients with post-COVID-19 syndrome develop POTS with such symptoms as tachycardia, orthostatic intolerance, fatigue, and cognitive impairment. The heterogeneity of POTS symptoms makes the diagnosis and appropriate management of POTS more difficult and one of the first steps for clinicians is to develop and test relevant diagnostic methods for POTS.Patients with persistent symptoms, 3 months after an acute SARS-CoV-2 infection were referred to the multi-disciplinary LC unit at a hospital in Sweden. Consecutive patients seen at this unit from 2021 to 2022 underwent a 24-h ECG recording. LC patients with POTS verified by active standing test and/or head-up tilt testing were prospectively enrolled in the study database and were compared with LC patients without POTS according to 3 specific analyses based on 24-h ECG recording : (1) cardiac autonomic activity expressed by heart rate variability, HRV (SDNN and RMSSD in ms) parameters, (2) awakening HR increase (HR mean 10 min before vs. 30 min after awakening) and (3) HR spikes (number/h if at least over than 30 bpm and at least during 30 s). Control group consisted of healthy subjects from 24-h ECG recordings database (HRV analysis) of a hospital in France. Data were expressed as mean (± standard deviation, SD) and frequencies (%).A total of 120 LC patients (mean age: 42.7 +/-9.97 y, 88% women) and 100 healthy subjects (mean age: 46.4 +/-10.2 y, 82% women) were included. LC with POTS (42%) was associated with (1) a decrease in most HRV parameters (mean SDNN: 86.8 +/-24.3 vs. 108.7 +/-24.1 ms, p=0.03), and the most reduced components were those related to the parasympathetic tone (mean RMSSD: 34,5 +/-20.4 vs. 45.6 +/-22.1 ms, p=0.04), (2) an abrupt and sustained increase in HR during the first 30 min after awakening (+30%, p<0.05) and (3) a higher number of HR spikes per h (1.4 +/-0.8 vs. 0.8 +/-0.7/h, p<0.001) compared with healthy subjects (HRV) and LC patients without POTS (awakenings and HR peaks) respectively.A triple analysis of 24-h ECG recordings revealed presence of autonomic dysfunction in LC patients with POTS compared with those without POTS. This novel analysis may be introduced in the clinic for screening and therapy monitoring.

1919

L01

BMJ

Long term respiratory complications of covid-19

https://doi.org/10.1136/bmj.m3001

opinion

3-Aug-20

editorial

https://www.bmj.com/content/370/bmj.m3001

An editorial in the BMJ notes that, like with SARS and MERS diseases, covid-19 is likely to cause respiratory symptoms in many patients that persist for at least several months.

Un éditorial dans BMJ remarque que, comme pour les maladies SRAS et MERS, la covid-19 est susceptible d'entraîner chez de nombreux patients des symptômes respiratoires persistants au moins plusieurs mois.

1920

L02

Brian Shaw, Mahyar Daskareh & Ali Gholamrezanezhad

The lingering manifestations of COVID-19 during and after convalescence: update on long-term pulmonary consequences of coronavirus disease 2019 (COVID-19)

https://doi.org/10.1007/s11547-020-01295-8

Published

1-Oct-20

Article

https://link.springer.com/article/10.1007/s11547-020-01295-8

A review of the literature on the pulmonary sequelae of covid. The authors recommend regular checks and examinations of lung function.

Une revue de la littérature sur les séquelles pulmonaires de la covid. Les auteurs conseillent des contrôles et examens réguliers de la fonction pulmonaire.

1921

L03

Ahmadreza Zarifian
Mohammad Ghasemi Nour
Arash Akhavan Rezayat

Chest CT findings of coronavirus disease 2019 (COVID-19): A comprehensive meta-analysis of 9907 confirmed patients

https://doi.org/10.1016/j.clinimag.2020.10.035

Published

24-Oct-20

CARDIOTHORACIC IMAGING

https://www.clinicalimaging.org/article/S0899-7071(20)30402-2/fulltext

A meta-analysis of lung scans of covid patients lists abnormalities by prevalence of onset: ground glass infiltrates with / without union, crosslinks, air bronchograms, pleural thickening and bronchial wall thickening.

Une méta-analyse de scans pulmonaires de patients covid répertorie les anomalies par prévalence d'apparition : infiltrats en verre dépoli avec/sans consolidation, réticulations, bronchogrammes aériens, épaississements pleuraux et des parois bronchiques.

1922

L04

Jenny C. NGAI Fanny W. KO Susanna S. NG Kin‐Wang

The long‐term impact of severe acute respiratory syndrome on pulmonary function, exercise capacity and health status

https://doi.org/10.1111/j.1440-1843.2010.01720.x

Published

29-Mar-10

Study

https://onlinelibrary.wiley.com/doi/10.1111/j.1440-1843.2010.01720.x

_

1923

L05

Jonathan E Aviv1*, Sujana Chandrasekhar2 and Byron Thomashow3

Covid-19 Era Post Viral Vagal Neuropathy Presenting as Persistent Shortness of Breath with Normal Pulmonary Imaging

https://dx.doi.org/10.19080/IJOPRS.2020.04.555641

Published

6-Oct-20

Opinion

https://juniperpublishers.com/ijoprs/IJOPRS.MS.ID.555641.php

A team of New York doctors indicates having detected, for a cohort of a few long covid patients with persistent shortness of breath despite normal pulmonary imaging, post-viral vagal neuropathy. It would be revealed by a dysfunction of the vocal cords, and could be cured by respiratory rehabilitation and a modification of the diet (in particular by the exclusion of acidic foods).

Une équipe de médecins new-yorkais indique avoir détecté, pour une cohorte de quelques patients covid long avec un essoufflement persistant malgré une imagerie pulmonaire normale, une neuropathie vagale post-virale. Elle serait révélée par un dysfonctionnement des cordes vocales, et pourrait être soignée par rééducation respiratoire et une modification du régime alimentaire (notamment par l'exclusion d'aliments acides).

1924

L06

Srikanth Kasturi, Arvind Muthirevula, Rohan R Chinthareddy

Delayed COVID-19 sequel - A challenging case of recurrent spontaneous pneumothorax

https://doi.org/10.21203/rs.3.rs-100043/v1

pre-print

20-Nov-20

Case report

https://www.researchsquare.com/article/rs-100043/v1

A study of a case of pneumothorax in a 55-year-old man, exceptional for its delayed appearance (30 days after a covid hospitalization, which lasted 35 days) which the authors attribute to persistent inflammation, and to lung damage and lesions.

Une étude d'un cas de pneumothorax chez un homme de 55 ans, exceptionnel par son aspect différé (30 j après une hospitalisation covid, qui avait duré 35j) que les auteurs attribuent à une inflammation persistante, et à des atteintes et lésions pulmonaires.

1925

L07

Bram van den Borst, MD, PhD, Jeannette B Peters, PhD, Monique Brink, MD, PhD,

Comprehensive health assessment three months after recovery from acute COVID-19

https://doi.org/10.1093/cid/ciaa1750

Published

21-Nov-20

Study

https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1750/5998118

En pratiquant des tomodensitométries thoraciques haute résolution (0,5 mm), une étude montre, 3 mois après, une récupération encourageante des capacités respiratoires des malades hospitalisés, malgré des anomalies résiduelles du parenchyme pulmonaire. L'étude néerlandaise remarque une part non négligeable de patients non hospitalisés qui gardent des séquelles importantes sur différents aspects, toujours à 3 mois, comme pour certains un échec au test de marche de 6 min.

1926

L08

University of Sheffield

Hidden damage to lungs from Covid-19 revealed in new study from University of Sheffield

New imagery

1-Dec-20

New imagery

https://www.sheffield.ac.uk/news/hidden-damage-lungs-covid-19-revealed-new-study-university-sheffield

En faisant inhaler du xénon hyperpolarisé (¹²⁹Xe) aux patients pendant les IRM pulmonaires, les équipes de l'Université de Sheffield pensent tenir une technique révolutionnaire pour mieux repérer les lésions causées par la covid, quand les autres scans IRM classiques semblent normaux. Cette technique pourrait répondre à certains paradoxes du #covidlong.

1927

L09

Federico Giovannoni & Francisco J. Quintana

SARS-CoV-2-induced lung pathology: AHR as a candidate therapeutic target

https://doi.org/10.1038/s41422-020-00447-9

Published

1-Dec-20

Article

https://www.nature.com/articles/s41422-020-00447-9

Un article dans Nature décrit une piste thérapeutique pour les atteintes pulmonaires de la covid, qui consiste à cibler par un antagoniste (CH223191) le récepteur d'aryl hydrocarbone (AhR), perçu comme facteur pro-viral. L'article de Nature cite notamment une étude publiée le mois dernier. https://www.nature.com/articles/s41422-020-00435-z

1928

L10

Paul Hofman, Marie-Christine Copin

Les lésions histologiques pulmonaires associées à l’infection par le Sars-CoV-2 Histological pulmonary features due to the Sars-CoV-2

https://doi.org/10.1016/S1773-035X(20)30391-9

Published

1-Jan-21

Article

https://www.sciencedirect.com/science/article/pii/S1773035X20303919

Une revue d'articles répertorie les lésions tissulaires pulmonaires dues à la covid et note qu'une maladie vasculaire se traduisant par des thrombi sur des vaisseaux de calibre varié est souvent observée au niveau pulmonaire.

1929

L11

Revue des maladies respiratoires - Actualités

Résultats préliminaires d'études
Pneumopathie à SARS-CoV-2: évolution fonctionnelle à 3 mois et corrélation avec les anomalies radiologiques (étude post Covid M3)
Fonction pulmonaire à 3 mois des patients survivants à la réanimation du SARS-CoV-2
Pneumonie à SARS-COV-2 en réanimation : quelles séquelles respiratoires chez les patients guéris de la COVID-19 ?
Bilan COVID à 3 mois : retour d’expérience par le trinôme médical, paramédical et AMA
Impact cardiorespiratoire de l’infection à SARS-CoV-2 : données à 3 mois
Prévalence du trouble de diffusion après infection à SARS-CoV-2 : comparaison entre les normes CECA/ERS 1993 et GLI
Récupération respiratoire à distance d’une pneumonie sévère à SARS-CoV-2 (COVID-19) : résultats préliminaires de l’étude de cohorte multicentrique prospective RE2COVERI

Published

Preliminary results from studies

https://www.sciencedirect.com/science/article/abs/pii/S1877120320306376
https://www.sciencedirect.com/science/article/abs/pii/S1877120320306479
https://www.sciencedirect.com/science/article/abs/pii/S1877120320302706
https://www.sciencedirect.com/science/article/abs/pii/S1877120320302391
https://www.sciencedirect.com/science/article/abs/pii/S1877120320302676
https://www.sciencedirect.com/science/article/abs/pii/S1877120320306406
https://www.sciencedirect.com/science/article/abs/pii/S1877120320306418

Dans le numéro de janvier 2021 de la Revue des maladies respiratoires - Actualités, plusieurs résultats intermédiaires d'études sur les séquelles pulmonaires de la covid à 3 mois sont publiées.

1930

L12

James P Hayes

Considering the long-term respiratory effects of Covid-19

https://doi.org/10.1093/occmed/kqaa224

Published

22-Jan-21

Editorial

https://academic.oup.com/occmed/advance-article/doi/10.1093/occmed/kqaa224/6105804

Un éditorial dans Occupational Medicine décrit les séquelles pulmonaires qui peuvent se retrouver chez des malades covid, aussi bien modérés que sévères, et se traduisent par des opacités en verre dépoli, des atélectasies et divers stades de dysfonctionnement pulmonaire, obstructif ou restrictif. L'éditorial rappelle que le NIHR (agence de recherche médicale britannique) estime que le covid long et l'ensemble des symptômes persistants pourraient en réalité recouvrir jusqu'à 4 syndromes différents.

1931

L13

Bavaharan Rajalingam1, Ethirajan Narayanan2, Praveen Nirmalan3, Kamalanthan Muthukrishnan4, Vivek Sundaram5, Saravanan Kumaravelu6, Mukundhan Gopalan7, Senthil Jeyapal8, Baskaran Rajalingam9, Vijay Khanna10, Praveen Dhoss11, Gopinath

Pattern recognition of high-resolution computer tomography (HRCT) chest to guide clinical management in patients with mild to moderate COVID-19

Published

23-Jan-21

Study

https://www.ijri.org/text.asp?2021/31/5/110/307734

_

1932

L14

Srikanth Kasturi, Arvind Muthirevula, Rohan Reddy Chinthareddy & Vijay Cholenahalli Lingaraju

Delayed recurrent spontaneous pneumothorax post-recovery from COVID-19 infection

https://doi.org/10.1007/s12055-021-01145-w

Published

2-Feb-21

Case Report

https://link.springer.com/article/10.1007/s12055-021-01145-w

We present a case of delayed recurrent spontaneous pneumothorax, presenting 4 weeks after recovery from COVID-19 in a previously healthy middle-aged gentleman, for which uniportal video-assisted thoracoscopic surgery (VATS) pleurectomy was performed, but the cause of pneumothorax could not be ascertained.

Un cas de pneumothorax retardé et attribué à l'infection (4 semaines après une guérison de phase aiguë de la covid).

N004

___Respiratory___

Published case report on 2-Feb-21:
"Delayed recurrent spontaneous pneumothorax post-recovery from COVID-19 infection"
Un cas de pneumothorax retardé et attribué à l'infection (4 semaines après une guérison de phase aiguë de la covid).
Link: https://link.springer.com/article/10.1007/s12055-021-01145-w
Extract: "We present a case of delayed recurrent spontaneous pneumothorax, presenting 4 weeks after recovery from COVID-19 in a previously healthy middle-aged gentleman, for which uniportal video-assisted thoracoscopic surgery (VATS) pleurectomy was performed, but the cause of pneumothorax could not be ascertained."

1933

L15

J.R. Blanco, M.J. Cobos-Ceballos, F. Navarro, I. Sanjoaquin, F. Arnaiz de las RevillasE. Bernal, L. Buzon-Martin, 0, M. Viribay, L. Romero, S. Espejo-Pérez, B. Valencia, 0, D. Ibañez, D. Ferrer-Pargada, D. Malia, F.G. Gutierrez-Herrero, J. Olalla, B. Jurado-Gamez, J. Ugedo

Pulmonary long-term consequences of COVID-19 infections after hospital discharge

https://doi.org/10.1016/j.cmi.2021.02.019

Published

1-Mar-21

ORIGINAL ARTICLE

https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(21)00101-4/fulltext

In summary, this study has shown that a high proportion of severely affected COVID-19 patients show impairment in DLCO measurements in the first few months after symptoms onset. Although its long-term impact is still unknown, DLCO could be considered a useful tool to identify individuals at risk for pulmonary sequelae.

Une publication étudie les pertes de capacité pulmonaire de diffusion du monoxyde de carbone (DLCO) sur le long terme après une infection au SARS-CoV-2.

N004

___Respiratory___

Published original article on 1-Mar-21:
"Pulmonary long-term consequences of COVID-19 infections after hospital discharge"
Une publication étudie les pertes de capacité pulmonaire de diffusion du monoxyde de carbone (DLCO) sur le long terme après une infection au SARS-CoV-2.
Link: https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(21)00101-4/fulltext
Extract: "In summary, this study has shown that a high proportion of severely affected COVID-19 patients show impairment in DLCO measurements in the first few months after symptoms onset. Although its long-term impact is still unknown, DLCO could be considered a useful tool to identify individuals at risk for pulmonary sequelae."

1934

L16

Naybandi Atashi S, Naderpour Z, Goharimpghadam K, Saeedi M.

An Eight-week Follow-up Study in Patients With COVID-19 Respiratory Failure: Delayed Recovery or Lung Sequel

https://doi.org/10.18502/crcp.v5iS1.6240

Published

7-Mar-21

CASE REPORT

https://crcp.tums.ac.ir/index.php/crcp/article/view/411

CT imaging techniques have an important role in the primary diagnosis of pneumonia secondary to COVID-19; moreover, the level of pulmonary involvement in CT scan is one of the criteria for disease severity in the acute phase of COVID-19 pneumonia. Still, the role of CT scan in the follow-up period is unknown.

Une présentation de 4 cas de patients avec des séquelles pumlonaires de la covid suivis sur 8 semaines.

1935

L17

Laura Fabbri, Samuel Moss, Fasihul Khan, Wenjie Chi, Jun Xia, Karen Robinson, Alan Smyth, Gisli Jenkins, Iain Stewart

Post-viral parenchymal lung disease of COVID-19 and viral pneumonitis: A systematic review and meta-analysis

https://doi.org/10.1101/2021.03.15.21253593

pre-print

17-Mar-21

Systematic review and meta-analysis

https://www.medrxiv.org/content/10.1101/2021.03.15.21253593v1

On follow up CT scans, the overall estimated proportion was 0·56 (95%CI 0·44 to 0·66, I2= 94·44%) for inflammatory changes, and 0·40 (95%CI 0·29 to 0·52, I2=95·19%) for fibrotic findings. In SARS-CoV-2 specifically, proportions were estimated at 0·43 (95%CI 0·32 to 0·56, I2=94.60%) and 0·30 (95%CI 0·19 to 0·43, I2=94.89%) for inflammatory and fibrotic findings, respectively. Overall proportion for restrictive impairment was 0·19 (95%CI 0·12 to 0·27, I2=94·46%), DLCO reduction was estimated at 0·45 (95%CI 0·38 to 0·52, I2=90·10). Elevated radiological and functional estimates persisted across follow-up times.

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1936

L18

MaurizioBalbiabCaterinaConticGianlucaImericAnnaCarolidAlessandraSuraceabAndreaCorsiabElisaMercanzinabAlbertoArrigonieGiuliaVilladFabianoDi MarcocfPietro AndreaBonaffiniabSandroSironi

Post-discharge chest CT findings and pulmonary function tests in severe COVID-19 patients

https://doi.org/10.1016/j.ejrad.2021.109676

Published

20-Mar-21

Study

https://www.sciencedirect.com/science/article/pii/S0720048X2100156X

Highlights
•Severe COVID-19 survivors can still have chest CT abnormalities after discharge, even beyond three months after the disease onset
•The percentage of compromised lung volume on CT correlates with pulmonary function tests and dyspnea severity
•Pulmonary function tests indicate an impairment of diffusion capacity and a tendency toward restrictive physiology in most cases. An underlying pulmonary vasculopathy is possibly implied in a minor proportion of patients

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1937

L19

Hiroaki Ogata Taisuke Nakagawa Soichiro Sakoda Akiko Ishimatsu Kazuhito Taguchi Masako Kadowaki Atsushi Moriwaki Makoto Yoshida

Nintedanib treatment for pulmonary fibrosis after coronavirus disease 2019

https://doi.org/10.1002/rcr2.744

Published

30-Mar-21

Case Report

https://onlinelibrary.wiley.com/doi/10.1002/rcr2.744

A 78‐year‐old Japanese woman with no smoking history suffered from near‐fatal coronavirus disease 2019 (COVID‐19) requiring four‐week invasive mechanical ventilation, with subsequent radiological features of pulmonary fibrosis. Although methylprednisolone gradually improved her respiratory condition, her oxygenation and exercise tolerance had drastically deteriorated, necessitating high‐flow nasal cannula oxygen therapy. In parallel with tapering systemic steroid, the patient was treated with nintedanib. Three months later, the patient was able to walk with a walking aid using oxygen at 4 L/min. The present case is an indication that nintedanib might provide a novel therapeutic approach for managing post‐COVID‐19 fibrosis, although further studies are warranted.

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1938

L20

Federico Mento, Tiziano Perrone, Anna Fiengo, Francesco Tursi, Veronica Narvena Macioce, Andrea Smargiassi, Riccardo Inchingolo & Libertario Demi

Limiting the areas inspected by lung ultrasound leads to an underestimation of COVID-19 patients’ condition

https://doi.org/10.1007/s00134-021-06407-0

Published

11-May-21

Correspondence

https://link.springer.com/article/10.1007/s00134-021-06407-0

In a recent work, we compared the impact of different imaging protocols in the evaluation of COVID-19 patients by LUS and found that a minimum of 10 areas was necessary to avoid a significant underestimation of the patient’s condition.
Results show a 43, 63, and 80% agreement with our fourteen-area protocol for protocols 1, 2 and 3, respectively, when inspecting the data for bilateral large consolidations and/or areas of white lung (large hyperechoic bands). Moreover, a 77, 87, and 87% agreement was found for protocols 1, 2, and 3, respectively, when inspecting the data for bilateral small or large consolidations and/or areas of white lung. These results would imply an underestimation, according to the classification presented in [1], of HighLUS patients as IntLUS patients. Moreover, as previously reported in [3], these results confirm the importance of the basal areas for a correct evaluation of LUS data from COVID-19 patients.

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1939

L21

Elia Bari 1 ,Ilaria Ferrarotti 2,Laura Saracino 3,Sara Perteghella 1,4 ,Maria Luisa Torre 1,4,* ,Luca Richeldi 5 andAngelo Guido Corsico

Mesenchymal Stromal Cell Secretome for Post-COVID-19 Pulmonary Fibrosis: A New Therapy to Treat the Long-Term Lung Sequelae?

https://doi.org/10.3390/cells10051203

Published

14-May-21

Article

https://www.mdpi.com/2073-4409/10/5/1203/htm

Available antifibrotic therapies, namely nintedanib and pirfenidone, might have a role in attenuating profibrotic pathways in SARS-CoV-2 infection but are not economically sustainable by national health systems and have critical adverse effects. It is our opinion that the mesenchymal stem cell secretome could offer a new therapeutic approach in treating COVID-19 fibrotic lungs through its anti-inflammatory and antifibrotic factors.

Un article évoque la thérapie par sécrétome des cellules mésenchymateuses stromales pour traiter les fibroses pulmonaires, séquelles à long terme de la covid.

Les auteurs évoquent un avantage par rapport aux thérapies antifibrotiques habituellement disponibles, à savoir le nintédanib et la pirfénidone, qui pourraient jouer un rôle dans l'atténuation des voies profibrotiques dans l'infection par le SARS-CoV-2, mais ne sont pas économiquement viables et ont des effets indésirables critiques.

N011

___Respiratory___

Published article on 14-May-21:
"Mesenchymal Stromal Cell Secretome for Post-COVID-19 Pulmonary Fibrosis: A New Therapy to Treat the Long-Term Lung Sequelae?"
Un article évoque la thérapie par sécrétome des cellules mésenchymateuses stromales pour traiter les fibroses pulmonaires, séquelles à long terme de la covid.

Les auteurs évoquent un avantage par rapport aux thérapies antifibrotiques habituellement disponibles, à savoir le nintédanib et la pirfénidone, qui pourraient jouer un rôle dans l'atténuation des voies profibrotiques dans l'infection par le SARS-CoV-2, mais ne sont pas économiquement viables et ont des effets indésirables critiques.
Link: https://www.mdpi.com/2073-4409/10/5/1203/htm
Extract: "Available antifibrotic therapies, namely nintedanib and pirfenidone, might have a role in attenuating profibrotic pathways in SARS-CoV-2 infection but are not economically sustainable by national health systems and have critical adverse effects. It is our opinion that the mesenchymal stem cell secretome could offer a new therapeutic approach in treating COVID-19 fibrotic lungs through its anti-inflammatory and antifibrotic factors."

1940

L22

Pallab Chakraborty * and Kaustav Chakraborty

Anti-Fibrotic Agents Could Be the Game Changer for Post‑COVID Pulmonary Fibrosis Treatment – A Mini Review

https://doi.org/10.20944/preprints202105.0423.v1

pre-print

18-May-21

Review

https://www.preprints.org/manuscript/202105.0423/v1

Due to COVID-19, dysregulated immune response and wound repair mainly in elderly patients causes this secondary pulmonary fibrosis. Thus using anti-fibrotic agents could be meaningful in these circumstances although their efficacy in treating COVID-19 is subject to more detailed laboratory research works. In this review article you will get to know about the lung fibrosis generation due to COVID-19 infection, about anti-fibrotic agents and the currents challenges of this field.

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1941

L23

James T. Grist1,2,3,4, Mitchell Chen3, Guilhem J. Collier5, Betty Raman2, Gabriele AbuEid3, Anthony McIntyre3, Violet Matthews3, Emily Fraser7, Ling-Pei Ho6,7, Jim M. Wild5, Fergus Gleeson

Hyperpolarized 129Xe MRI Abnormalities in Dyspneic Participants 3 Months after COVID-19 Pneumonia: Preliminary Results

https://doi.org/10.1148/radiol.2021210033

Published

25-May-21

Study

https://pubs.rsna.org/doi/10.1148/radiol.2021210033

9 patients (mean age 57±7 years, Male = 6) and 5 volunteers (29 ± 3 years, Female = 5) were enrolled. Patient mean time from hospital discharge was 169, range 116-254 days. There was a difference in RBC:TP between patients and controls (0.3 ± 0.1 versus 0.5 ± 0.1, respectively, p = 0.001, effect size = 1.36). There was significant difference between the RBC and gas phase spectral full width at half maximum (FWHM) between volunteers and patients (median ± 95 % confidence interval, 567 ± 1 vs 507 ± 81, p = 0.002 and 104 ± 2 vs 122 ± 17, p = 0.004, respectively). Results were reproducible with Intraclass Correlation Coefficients of 0.82 and 0.88 for patients and volunteers respectively. Participants had normal or near normal CT scans, mean 7/25, range 0-10/25.

Conclusion
Xe MRI showed alveolar-capillary diffusion limitation in all 9 post COVID-19 pneumonia patients despite normal or nearly normal CT scans.

Une étude à Oxford sur 9 patients suggère que l'IRM au xénon hyperpolarisée peut être un mode d'imagerie potentiellement utile chez les patients atteints de covid et dyspnéiques 3 mois après la phase aigue ou la sortie de l'hôpital.

N011

___Respiratory___

Published study on 25-May-21:
"Hyperpolarized 129Xe MRI Abnormalities in Dyspneic Participants 3 Months after COVID-19 Pneumonia: Preliminary Results"
Une étude à Oxford sur 9 patients suggère que l'IRM au xénon hyperpolarisée peut être un mode d'imagerie potentiellement utile chez les patients atteints de covid et dyspnéiques 3 mois après la phase aigue ou la sortie de l'hôpital.
Link: https://pubs.rsna.org/doi/10.1148/radiol.2021210033
Extract: "9 patients (mean age 57±7 years, Male = 6) and 5 volunteers (29 ± 3 years, Female = 5) were enrolled. Patient mean time from hospital discharge was 169, range 116-254 days. There was a difference in RBC:TP between patients and controls (0.3 ± 0.1 versus 0.5 ± 0.1, respectively, p = 0.001, effect size = 1.36). There was significant difference between the RBC and gas phase spectral full width at half maximum (FWHM) between volunteers and patients (median ± 95 % confidence interval, 567 ± 1 vs 507 ± 81, p = 0.002 and 104 ± 2 vs 122 ± 17, p = 0.004, respectively). Results were reproducible with Intraclass Correlation Coefficients of 0.82 and 0.88 for patients and volunteers respectively. Participants had normal or near normal CT scans, mean 7/25, range 0-10/25.

Conclusion
Xe MRI showed alveolar-capillary diffusion limitation in all 9 post COVID-19 pneumonia patients despite normal or nearly normal CT scans."

1942

L24

YohAritaM.D., Ph.D.aShoheiYamamotoM.D.aManabuNagataM.D., Ph.D.bNobuyukiOgasawaraM.D.aShinjiHasegawaM.D., Ph.D.a

Long COVID presenting with intermittent fever after COVID-19 pneumonia

https://doi.org/10.1016/j.radcr.2021.05.081

Published

4-Jun-21

Case Report

https://www.sciencedirect.com/science/article/pii/S1930043321003769

A 72-year-old man presented to our hospital with a fever. Chest computed tomography showed typical coronavirus disease 2019 (COVID-19) pneumonia. The fever normalized after a few days, and the pneumonia was alleviated. However, the intermittent fever subsequently re-occurred and persisted for over a month. Various tests, including blood tests, culture tests, and image evaluations, were performed. However, the conclusion was that long COVID was the cause of the intermittent fever as an exclusion diagnosis. Many patients suffer from persistent symptoms of COVID-19, but the symptoms and their durations vary. Here we report a case of prolonged fever after COVID-19 pneumonia.

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1943

L25

Alberto Fortini, Arianna Torrigiani, Serena Sbaragli, Aldo Lo Forte, Andrea Crociani, Paolo Cecchini, Giulia Innocenti Bruni & Antonio Faraone

COVID-19: persistence of symptoms and lung alterations after 3–6 months from hospital discharge

https://doi.org/10.1007/s15010-021-01638-1

Published

6-Jun-21

Study

https://link.springer.com/article/10.1007/s15010-021-01638-1

Results
22% of patients reported no residual symptoms, 28.8% 1 or 2 symptoms and 49.2% 3 or more symptoms. The most frequently symptoms were fatigue, exertional dyspnea, insomnia, and anxiety. Among the inflammatory and coagulation parameters, only the median value of fibrinogen was slightly above normal. A deep vein thrombosis was detected in 1 patient (1.7%). Thoracic US detected mild pulmonary changes in 15 patients (25.4%), 10 of which reported exertional dyspnea. DLCO was mildly or moderately reduced in 19 patients (37.2%), 13 of which complained of exertional dyspnea.
Conclusion
These results highlight that a substantial percentage of COVID-19 patients (77.8%) continue to complain of symptoms 3–6 months after hospital discharge. Exertional dyspnea was significantly associated with the persistence of lung US abnormalities and diffusing capacity alterations. Extended follow-up is required to assess the long-term evolution of postacute sequelae of COVID-19.

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1944

L26

Saeki, Takuya RPT, MSc1,2; Ogawa, Fumihiro MD, PhD3; Matsumiya, Mina RPT2; Yamamura, Mei RPT2; Oritsu, Hideyuki RPT2; Nonogaki, Manabu MD1; Uesugi, Jo RPT2; Takeuchi, Ichiro MD, PhD3; Nakamura, Takeshi

Long Term Decreased Exercise Capacity of COVID-19 Patients Who Received Mechanical Ventilation in Japan
A Case Series

https://doi.org/10.1097/PHM.0000000000001803

28-May-21

Cases Report

https://journals.lww.com/ajpmr/Abstract/9000/Long_Term_Decreased_Exercise_Capacity_of_COVID_19.97657.aspx

However, the 6MWD of the four patients remained shorter than those of healthy persons of the same age at 6 months after admission to the hospital. Furthermore, the minimum SpO2 during the 6-minute walking test remained below 96%. It is possible that patients who receive mechanical ventilation due to COVID-19-associated ARDS have decreased long-term exercise capacity, despite muscle power and activities of daily living recovering completely.

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1945

L27

Vinod Nikhra

Pulmonary Involvement in COVID-19 and'Long Covid': The Morbidity, Complications and Sequelae

https://doi.org/10.29328/journal.jprr.1001022

Published

15-Jun-21

Study

https://www.heighpubs.org/jprr/jprr-aid1022.php

Pulmonary Involvement in COVID-19 and ‘Long Covid’: The Morbidity, Complications and Sequelae

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1946

L28

Sonay Aydina 1 Edhem Unver b 1 Erdal Karavasa 1 Seven Yalcin b1 Mecit Kantarci ac2

Computed tomography at every step: Long coronavirus disease

https://doi.org/10.1016/j.resinv.2021.05.014

Published

29-Jun-21

Study

https://www.sciencedirect.com/science/article/pii/S221253452100112X

Highlights
•Persistent long COVID symptoms of shortness of breath, chest pain, cough, and muscle weakness are correlated with CT severity values.
•CT severity is related with more persistent symptoms than laboratory parameters.
•Knowing the relationsgip between CT severity and long COVID can help to identify risky patients and create follow up programs to support these cases.
Levels of C-reactive protein and fibrinogen, anemia, and female sex were associated with some of the persistent symptoms., the severity of the disease seen on CT was a successful predictor for the disease severity/prognosis and was also correlated with prolonged COVID infection and more persistent symptoms.

1947

L29

Shengding Zhang, Wenxue Bai, Junqing Yue, Lu Qin, Cong Zhang, Shuyun Xu, Xiansheng Liu, Wang Ni & Min Xie

Eight months follow-up study on pulmonary function, lung radiographic, and related physiological characteristics in COVID-19 survivors

https://doi.org/10.1038/s41598-021-93191-y

Published

5-Jul-21

Study

https://www.nature.com/articles/s41598-021-93191-y

At follow-up, severe cases had higher incidences of persistent symptoms, DLCO impairment, and higher abnormal CT score as compared with mild cases. CT score at follow-up was positively correlated with age, LDH level, cumulative days of oxygen treatment, total dosage of glucocorticoids used, and CT peak score during hospitalization. DLCO% at follow-up was negatively correlated with cumulative days of oxygen treatment during hospitalization. DLCO/VA% at follow-up was positively correlated with BMI, and TNF-α level. Among the three groups categorized as survivors with normal DLCO, abnormal DLCO but normal DLCO/VA, and abnormal DLCO and DLCO/VA, survivors with abnormal DLCO and DLCO/VA had the lowest serum IL-2R, IL-8, and TNF-α level, while the survivors with abnormal DLCO but normal DLCO/VA had the highest levels of inflammatory cytokines during hospitalization. Altogether, COVID-19 had a greater long-term impact on the lung physiology of severe cases. The long-term radiological abnormality maybe relate to old age and the severity of COVID-19. Either absent or excess of inflammation during COVID-19 course would lead to the impairment of pulmonary diffusion function.

1948

L30

Salem AM, Al Khathlan N, Alharbi AF, Alghamdi T, AlDuilej S, Alghamdi M, Alfudhaili M, Alsunni A, Yar T, Latif R, Rafique N, Al Asoom L, Sabit H

The Long-Term Impact of COVID-19 Pneumonia on the Pulmonary Function of Survivors

https://doi.org/10.2147/IJGM.S319436

Published

9-Jul-21

Study

https://www.dovepress.com/the-long-term-impact-of-covid-19-pneumonia-on-the-pulmonary-function-o-peer-reviewed-fulltext-article-IJGM

Significant reduction in total lung capacity (TLC), forced vital capacity (FVC), forced expiratory volume (FEV1), FEV1/FEV, and diffusing capacity for carbon monoxide (DLCO) was observed in post-COVID-19 subjects compared to controls. Restrictive lung impairment was observed in 50% of post-COVID-19 cases (n = 10) compared to 20% in the control group (n = 6, P = 0.026). In addition, mild diffusion defect was detected in 35% (n = 7) of the post-COVID-19 group compared to 23.3% (n = 7) in the controls (P = 0.012).
Conclusion: COVID-19 pneumonia has an impact on the lung functions in terms of restrictive lung impairment and mild diffusion defect after three months from recovery.

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1949

L31

NiclaOrzesa1LauraPiniab1GuidoLeviaSilviaUccelliaFrancescaCettoloaClaudioTantucci

A prospective evaluation of lung function at three and six months in patients with previous SARS-COV-2 pneumonia

https://doi.org/10.1016/j.rmed.2021.106541

Published

10-Jul-21

Study

https://www.sciencedirect.com/science/article/pii/S095461112100247X

Highlights
•After COVID-19 pneumonia, nearly 50% of patients fully recovered lung function.
•Most of those with abnormal pulmonary function tests at 3 months improved later.
•However, only another 29% reached normal values at 6 months.
•Lung function recovery is faster at first and occurs more slowly thereafter.
•More than one-third of patients keep abnormal lung function tests at 6 months.

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1950

L32

Nannan Shi, Chao Huang, Qi Zhang, Chunzi Shi, Fengjun Liu, Fengxiang Song, Qinguo Hou, Jie Shen, Fei Shan, Xiaoming Su, Cheng Liu, Zhiyong Zhang, Lei Shi & Yuxin Shi

Longitudinal trajectories of pneumonia lesions and lymphocyte counts associated with disease severity among convalescent COVID-19 patients: a group-based multi-trajectory analysis

https://doi.org/10.1186/s12890-021-01592-6

Published

13-Jul-21

Study

https://bmcpulmmed.biomedcentral.com/articles/10.1186/s12890-021-01592-6

We characterised four distinct trajectory subgroups. (1) Group 1 (13.9%), pneumonia increased until a peak lesion percentage of 1.9% (IQR 0.7–4.4) before absorption. The slightly decreased lymphocyte rapidly recovered to the top half of the normal range. (2) Group 2 (44.7%), the peak lesion percentage was 7.2% (IQR 3.2–12.7). The abnormal lymphocyte count restored to normal soon. (3) Group 3 (26.0%), the peak lesion percentage reached 14.2% (IQR 8.5–19.8). The lymphocytes continuously dropped to 0.75 × 109/L after one day post-onset before slowly recovering. (4) Group 4 (15.4%), the peak lesion percentage reached 41.4% (IQR 34.8–47.9), much higher than other groups. Lymphopenia was aggravated until the lymphocytes declined to 0.80 × 109/L on the fourth day and slowly recovered later. Patients in the higher order groups were older and more likely to have hypertension and diabetes (all P values < 0.05), and have more severe disease.
Conclusions
Our findings provide new insights to understand the heterogeneous natural courses of COVID-19 patients and the associations of distinct trajectories with disease severity, which is essential to improve the early risk assessment, patient monitoring, and follow-up schedule.

1951

L33

Rebecca C. Robey, Katie Kemp, Philip Hayton, Dalia Mudawi, Ran Wang, Melanie Greaves, Veronica Yioe, Pilar Rivera-Ortega, Cristina Avram & Nazia Chaudhuri

Pulmonary Sequelae at 4 Months After COVID-19 Infection: A Single-Centre Experience of a COVID Follow-Up Service

https://doi.org/10.1007/s12325-021-01833-4

Published

18-Jul-21

Study

https://link.springer.com/article/10.1007/s12325-021-01833-4

A total of 221 patients were followed-up: all patients who had been admitted to ICU (n = 44) and 38 of 177 (21%) non-ICU patients who had persistent symptoms and/or persistent radiographic changes on chest X-ray at their initial 8-week follow-up visit required further pulmonary function testing and thoracic imaging.
An overall prevalence of PFT abnormalities were seen in around 24% of the entire cohort and radiological evidence of fibrosis was seen in around 7% of the entire cohort at 4 months after discharge.

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1952

L34

Carlos Toufen JuniorPaulo Manuel Pêgo-Fernandes

COVID-19: long-term respiratory consequences

https://doi.org/10.1590/1516-3180.2021.139526052021

Published

16-Jul-21

Editorial

https://www.scielo.br/j/spmj/a/VHR5DZBxcb6Gh5z5wjWb36Q/?lang=en

Although COVID-19 was initially identified as a pneumonia-like illness, its pathophysiology in severe cases can include destruction of lung epithelial cells, thrombosis, hypercoagulation and vascular leakage. These events lead to acute respiratory distress syndrome (ARDS).

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1953

L35

Ranju T Dhawan, FRCR
Deepa Gopalan, FRCR
Luke Howard, DPhil
Angelito Vicente, BSc
Mirae Park, MRCP
Kavina Manalan, MRCP
Ingrid Wallner, BSc
Prof Peter Marsden, PhD
Surendra Dave, MSc
Howard Branley, MD
Georgina Russell, MRCP
Nishanth Dharmarajah, MSc
Prof Onn M Kon

Beyond the clot: perfusion imaging of the pulmonary vasculature after COVID-19

https://doi.org/10.1016/S2213-2600(20)30407-0

Published

17-Nov-20

Article

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30407-0/fulltext

Although the long-term outcomes of COVID-19 are not known, should pulmonary vascular sequelae prove to be clinically significant, these have the potential to become a public health problem. In this Personal View, we propose a proactive follow-up strategy to evaluate residual clot burden, small vessel injury, and potential haemodynamic sequelae. A nuanced and physiological approach to follow-up imaging that looks beyond the clot, at the state of perfusion of lung tissue, is proposed as a key triage tool, with the potential to inform therapeutic strategies.

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1954

L36

Damiano Caruso1, Gisella Guido1, Marta Zerunian1, Tiziano Polidori1, Elena Lucertini1, Francesco Pucciarelli1, Michela Polici1, Carlotta Rucci1, Benedetta Bracci1, Matteo Nicolai1, Antonio Cremona1, Chiara De Dominicis1, Andrea Laghi1

Postacute Sequelae of COVID-19 Pneumonia: 6-month Chest CT Follow-up

https://doi.org/10.1148/radiol.2021210834

Published

27-Jul-21

https://pubs.rsna.org/doi/10.1148/radiol.2021210834

One-hundred-eighteen patients, with both baseline and six-month follow-up Chest CT, were included in the study (62 female, mean age 65±12 years). At follow-up Chest CT, 85/118 (72%) patients showed fibrotic-like changes and 49/118 (42%) showed GGOs. Baseline LSS (>14), QCCT (≤3.75L and ≤80%) showed an excellent performance in predicting fibrotic-like changes at Chest CT follow-up. In the multivariable analysis, AUC was .89 (95%CI .77-.96) for the clinical model, .81 (95%CI .68-.9) for the radiological model and .92 (95%CI .81-.98)for the combined model.

Conclusion
At six-month follow-up Chest CT, 72% of patients showed late sequelae, in particular fibrotic-like changes. Baseline LSS and QCCT of well-aerated lung showed an excellent performance in predicting fibrotic-like changes at six-month Chest CT (AUC>.88). Male sex, cough, lymphocytosis and QCCT well-aerated lung were significant predictors of fibrotic-like changes at six-month with an inverse correlation (AUC .92).

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1955

L37

AshleyDiazBS1DanielBujnowskiBS2PhillipMcMullenMD, PhD3MariaLysandrouBA1VijayalakshmiAnanthanarayananMD4Aliya N.HusainMBBS3RichardFreemanMD, MBA5Wickii T.VigneswaranMD, MBA5Mark K.FergusonMD6JessicaDoningtonMD6Maria LuciaMadariagaMD6Zaid M.Abdelsattar

Pulmonary parenchymal changes in COVID-19 survivors

https://doi.org/10.1016/j.athoracsur.2021.06.076

Published

31-Jul-21

Study

https://www.sciencedirect.com/science/article/pii/S0003497521013072

Results
Eleven COVID-19 survivors with asymptomatic (n=4), moderate (n=4), and severe (n=3) COVID-19 infections underwent elective lung resection at a median 68.5 days (range 24-142) after COVID-19 diagnosis. The most common operation was lobectomy (75%). On histopathological examination, no differences were identified between the lung parenchyma of COVID-19 survivors and controls across all compartments examined. Conversely, patients in the end-stage COVID-19 group showed fibrotic diffuse alveolar damage with intra-alveolar macrophages, organizing pneumonia, and focal interstitial emphysema.

Conclusions
In this first study to examine the lung parenchyma of COVID-19 survivors, we did not find distinct post-acute histopathological changes to suggest permanent pulmonary damage. These results are reassuring for COVID-19 survivors who recover and become asymptomatic.

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1956

L38

Grace Y. Lam, A. Dean Befus, Ronald W. Damant, Giovanni Ferrara, Desi P. Fuhr, Michael K. Stickland, Rhea A. Varughese, Eric Y. Wong & Maeve P. Smith

Exertional intolerance and dyspnea with preserved lung function: an emerging long COVID phenotype?

https://doi.org/10.1186/s12931-021-01814-9

Published

6-Aug-21

Letter to the Editor

https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-021-01814-9

There is now a growing recognition of the longer-term sequelae of this infection, termed “long COVID”. However, little is known about this condition. Here, we describe a distinct phenotype seen in a subset of patients with long COVID who have reduced exercise tolerance as measured by the 6 min walk test. They are associated with significant exertional dyspnea, reduced health-related quality of life and poor functional status. However, surprisingly, they do not appear to have any major pulmonary function abnormalities or increased burden of neurologic, musculoskeletal or fatigue symptoms.

?

1957

L39

Inderjit Singh, MD
Phillip Joseph, MD
Paul M. Heerdt, MD, PhD
Marjorie Cullinan, RT
Denyse D. Lutchmansingh, MBBS
Mridu Gulati, MD, MPH
Jennifer D. Possick, MD
David M. Systrom, MD
Aaron B. Waxman, MD, PhD

Persistent Exertional Intolerance After COVID-19
Insights From Invasive Cardiopulmonary Exercise Testing

https://doi.org/10.1016/j.chest.2021.08.010

Published

10-Aug-21

Study

https://journal.chestnet.org/article/S0012-3692(21)03635-7/fulltext

This study examined the systemic and pulmonary hemodynamics, ventilation, and gas exchange in 10 patients who recovered from COVID-19 and were without cardiopulmonary disease during invasive cardiopulmonary exercise testing (iCPET) and compared the results with those from 10 age- and sex-matched control participants. These data then were used to define potential reasons for exertional limitation in the cohort of patients who had recovered from COVID-19.
Results
The patients who had recovered from COVID-19 exhibited markedly reduced peak exercise aerobic capacity (oxygen consumption [VO2]) compared with control participants (70 ± 11% predicted vs 131 ± 45% predicted; P < .0001). This reduction in peak VO2 was associated with impaired systemic oxygen extraction (ie, narrow arterial-mixed venous oxygen content difference to arterial oxygen content ratio) compared with control participants (0.49 ± 0.1 vs 0.78 ± 0.1; P < .0001), despite a preserved peak cardiac index (7.8 ± 3.1 L/min vs 8.4±2.3 L/min; P > .05). Additionally, patients who had recovered from COVID-19 demonstrated greater ventilatory inefficiency (ie, abnormal ventilatory efficiency [VE/VCO2] slope: 35 ± 5 vs 27 ± 5; P = .01) compared with control participants without an increase in dead space ventilation.
Interpretation
Patients who have recovered from COVID-19 without cardiopulmonary disease demonstrate a marked reduction in peak VO2 from a peripheral rather than a central cardiac limit, along with an exaggerated hyperventilatory response during exercise.

1958

L40

Salman Siddiqui
Christopher E Brightling

Pathological disease in the lung periphery after acute COVID-19

https://doi.org/10.1016/S2213-2600(21)00378-7

Published

7-Sep-21

COMMENT

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00378-7/fulltext

First, there is little evidence to show a meaningful persistent impairment in the large or small conducting airways, although longer-term studies that incorporate imaging in a more mixed population, including patients who were ventilated, are required. Second, there might be pulmonary capillary disease alone (particularly given the common vascular effects of COVID-19 infection), in which case DLCO might decrease, consistent with the abnormal DLCO levels that have been identified across several studies. This fall in DLCO might be associated with parenchymal destruction, in which case the total lung capacity, FVC, and residual volume would also decrease. However, without more detailed reporting of the carbon monoxide transfer coefficient and alveolar volume—the two components that define the single-breath carbon monoxide diffusion test—it is difficult to dissect fully the pathological abnormality in the lung periphery in long COVID. An exploratory hyperpolarised 129Xenon MRI study in patients approximately 6 months after acute COVID-19 infection showed striking reductions in the ratio of 129Xe in red blood cells to tissue plasma, despite near-normal CT imaging and preserved lung function.10 These observations further support the notion that damage to the alveolar–capillary interface might be a hallmark of the longer-term pathogenesis of COVID-19 lung disease.

1959

L41

Konstantina Kitsou, Anastasia Kotanidou, Dimitrios Paraskevis , Timokratis Karamitros, Aris Katzourakis, Richard Tedder, Tara Hurst, , Spyros Sapounas, Athanassios Kotsinas, Vassilis Gorgoulis , Vana Spoulou, Sotirios Tsiodras, Pagona Lagiou, and Gkikas Magiorkinis

Upregulation of Human Endogenous Retroviruses in Bronchoalveolar Lavage Fluid of COVID-19 Patients

https://doi.org/10.1128/Spectrum.01260-21

Published

6-Oct-21

Study

https://journals.asm.org/doi/10.1128/Spectrum.01260-21

Given that human endogenous retroviruses (HERVs) are known to be activated during and participate in inflammatory processes, we examined whether HERV dysregulation signatures are present in COVID-19 patients. By comparing transcriptomes of bronchoalveolar lavage fluid (BALF) of COVID-19 patients and healthy controls, and peripheral blood monocytes (PBMCs) from patients and controls, we have shown that HERVs are intensely dysregulated in BALF of COVID-19 patients compared to those in BALF of healthy control patients but not in PBMCs. In particular, upregulation in the expression of specific HERV families was detected in BALF samples of COVID-19 patients, with HERV-FRD being the most highly upregulated family among the families analyzed. In addition, we compared the expression of HERVs in human bronchial epithelial cells (HBECs) without and after senescence induction in an oncogene-induced senescence model in order to quantitatively measure changes in the expression of HERVs in bronchial cells during the process of cellular senescence. This apparent difference of HERV dysregulation between PBMCs and BALF warrants further studies in the involvement of HERVs in inflammatory pathogenetic mechanisms as well as exploration of HERVs as potential biomarkers for disease progression. Furthermore, the increase in the expression of HERVs in senescent HBECs in comparison to that in noninduced HBECs provides a potential link for increased COVID-19 severity and mortality in aged populations.

1960

L42

Felice D’Agnillo†, Kathie-Anne Walters†, Yongli Xiao‡, Zong-Mei Sheng‡, Kelsey Scherler, Jaekeun Park, ,Charles A. BlattiIII Ruoqing Zhu, Lisa Gatzke, Colleen Bushell, Matthew J. Memoli, Steven J. O’Day, Trevan D. Fischer, Terese C. Hammond, Raymond C. Lee, J. Christan Cash, Matthew E. Powers, , Grant E. O’Keefe, Kelly J. Butnor, Amy V. Rapkiewicz, William D. Travis, Scott P. Layne, John C. Kash, Jeffery K. Taubenberger

Lung epithelial and endothelial damage, loss of tissue repair, inhibition of fibrinolysis, and cellular senescence in fatal COVID-19

https://doi.org/10.1126/scitranslmed.abj7790

Published

14-Oct-21

Study

https://www.science.org/doi/10.1126/scitranslmed.abj7790

Lung autopsy samples from 18 patients with fatal COVID-19, with symptom onset-to-death times ranging from 3 to 47 days, and antemortem plasma samples from 6 of these cases were evaluated using deep sequencing of SARS-CoV-2 RNA, multiplex plasma protein measurements, and pulmonary gene expression and imaging analyses. Prominent histopathological features in this case series included progressive diffuse alveolar damage with excessive thrombosis and late onset pulmonary tissue and vascular remodeling. Acute damage at the alveolar-capillary barrier was characterized by the loss of surfactant protein expression with injury to alveolar epithelial cells, endothelial cells, respiratory epithelial basal cells, and defective tissue repair processes. Other key findings included impaired clot fibrinolysis with increased concentrations of plasma and lung plasminogen activator inhibitor-1 (PAI-1), and modulation of cellular senescence markers, including p21 and sirtuin-1, in both lung epithelial and endothelial cells. Together, these findings further define the molecular pathological features underlying the pulmonary response to SARS-CoV-2 infection and provide important insights into signaling pathways that may be amenable to therapeutic intervention.

1961

L43

BenoitBouteleuxaPaulineHenrotbcRachelErnstaLéoGrassiondChantalRaherison-SemjendeFabienBeaufilsbcMaévaZysmanbd1MathieuDelormeaf1

Respiratory rehabilitation for Covid-19 related persistent dyspnoea: A one-year experience

https://doi.org/10.1016/j.rmed.2021.106648

Published

13-Oct-21

Study

https://www.sciencedirect.com/science/article/pii/S0954611121003565

Most prevalent symptoms were dyspnoea (n = 35(90%)) and fatigue (n = 30(77%)). Hyperventilation syndrome was highly frequent (n = 12(34%)). 29(74%) patients presented with prolonged functional sequelae, which was associated with younger age (43 ± 14 vs. 50 ± 10yr; p = 0.002), greater prevalence of hyperventilation syndrome (n = 12(41%) vs. 0(0%); p = 0.255) and poorer quality of life (VQ-11; 31 ± 10 vs. 23 ± 9; p = 0.030). Over the course of rehabilitation, exertional dyspnoea, 6-min walking distance, 3-min sit-to-stand test, hyperventilation syndrome prevalence and quality of life significantly improved.
Conclusion
Hyperventilation is frequent in long Covid and may explain persistent dyspnoea as well as altered quality of life. Our data support screening of hyperventilation syndrome and functional impairment in mild Covid-19 out-patients as both of these components may improve with ambulatory rehabilitation.
•COVID-19 out patients without severe initial manifestation may have prolonged sequelae.
•Main symptoms in COVID-19 out patients are dyspnoea and fatigue.
•Prevalence of hyperventilation syndrome is substantial in Covid-19 out patients.
•Respiratory rehabilitation may improve dysfunctional breathing, functional capacities and quality of life.

_

1962

L44

Larissa Lipskaia 1 2, Pauline Maisonnasse 3 4, Charles Fouillade 5 6 7, Valentin Sencio 8, Quentin Pascal 4, Jean-Michel Flaman 9, Emmanuelle Born 10 11, Arturo London-Vallejo 5 6 7, Roger Le Grand 3 4, David Bernard 9, François Trottein 12, Serge Adnot 13

Evidence that SARS-CoV-2 Induces Lung-Cell Senescence: Potential Impact on COVID-19 Lung Disease

https://doi.org/10.1165/rcmb.2021-0205le

Published

14-Oct-21

Study

https://pubmed.ncbi.nlm.nih.gov/34648725/

Cell senescence is usually viewed as a response to chronic stressors that severely impedes healthy aging and promotes age-related noncommunicable diseases (11). Here, BALF cells from patients with severe COVID-19 expressed high levels of senescent-cell markers. This original observation was confirmed in a macaque COVID-19 model: early massive senescent lung-cell
accumulation occurred in areas of severe COVID-19-related lung damage. Moreover, senescent cells persisted in the lungs over time, and many of them appeared concomitantly with the development of long-term lung alterations including remodeling of the alveolar septa and pulmonary vessels. Given the deleterious effect of cell senescence on tissue repair and
inflammation, these results suggest that senescent-cell accumulation may contribute to the early lung alterations caused by SARS-CoV-2 infection and, potentially, to the post-viral lung pathology seen in a substantial proportion of patients (12). Most ECs in thrombosed vessels were senescent, suggesting a causal relationship between EC senescence and vascular thrombosis. Thus, counteracting the cell-senescence process or eliminating senescent lung cells might lessen lung damage severity. This may be of therapeutic importance since strategies are now proposed to control senescence in various lung diseases, as well as in ARDS due to other causes (13,14). A recent study in mice showed that lung inflammation caused by a mouse -oronavirus was markedly reduced by senolytic treatment, which also decreased mortality in old mice (7). These findings also support senescence as a major mechanism in the pathogenesis of COVID-19 and of other viral infections (15) and suggest that senescent lung-cell persistence after virus clearance may contribute to post-viral lung disease, namely emphysema or fibrosis.

1963

L45

Behnam Rabiee,Liesl S. Eibschutz,Shadi Asadollahi,Amit Gupta,Shahram Akhlaghpoor &Ali Gholamrezanezhad

The Role of Imaging Techniques in Understanding and Evaluating the Long-term Pulmonary Effects of COVID-19

https://doi.org/10.1080/17476348.2021.2001330

Published

3-Nov-21

Review

https://www.tandfonline.com/doi/abs/10.1080/17476348.2021.2001330

Article highlights
- Many COVID-19 patients suffer from long-term sequelae months after initial disease recovery.
- Imaging plays a pivotal role in the non-invasive assessment of the extent of pulmonary involvement during long-term follow-up.
- Although the diagnostic utility is suboptimal due to limited field of view in lungs and operator expertise dependency, the feasibility, affordability, and lack of ionizing radiation associated with lung ultrasonography create a potential niche for this imaging modality in certain patient populations, such as pregnant women and those in low-income countries.
- Although useful in initial presentation and readily available, CXR is not optimal for long-term follow-up of COVID-19 due to limited sensitivity in detecting the primary abnormality and evolving changes.
- Chest CT can be very useful in long-term follow-up, due to its high contrast and spatial resolution in assessing lung tissue.
- Main Chest CT findings include residual ground-glass opacities, scar, and organizing pneumonia, along with fibrotic change as evidenced by interstitial septal thickening and honeycombing.
- Abnormal findings have reported on chest CT months after COVID-19 recovery.
- While MRI is not utilized routinely for lung imaging, low field MRI not only shows relatively higher signal intensity of the lung parenchyma, but also is comparable to CT regarding image acquisition, and thus may be useful in investigating the long-term pathophysiological findings of COVID-19.
- Although not practical for daily clinical practice of medicine (due to radiation burden, costs, and time-consuming imaging protocols), 18F-FDG-PET/CT can also be useful in detection of the extra-pulmonary COVID-19 infection and may be beneficial in long-term follow-up of both pulmonary and systemic sequelae of this disease in certain cases.
- V/Q SPECT-CT scans may have great utility in diagnosing small vessel obstruction, identifying parenchymal damage, and monitoring COVID-19 survivors struggling with persistent dyspnea.

_

1964

L46

Max J Biondi, Phillip Joseph, Mridu Gulati, Jennifer Possick, Denyse Lutchmansingh, Marjorie Cullinan, Paul M Heerdt, Inderjit Singh

Abstract 6991: Impaired Systemic Oxygen Extraction Relates to Reduced Exercise Capacity in Post-COVID-19 Long Hauler Syndrome

Published

8-Nov-21

Case Reports

https://www.ahajournals.org/doi/abs/10.1161/circ.144.suppl_1.6991

Results: All patients had normal biventricular and valvular function on resting echocardiogram, no evident parenchymal lung disease on CT, and normal PFTs. Resting mean pulmonary arterial pressure was ≤20 mmHg for all patients with pulmonary vascular resistance <3 Woods units. At maximum exercise, all patients exhibited normal respiratory, cardiac output (% predicted), and total pulmonary vascular resistance responses, but demonstrated clearly depressed aerobic capacity (peak VO2 <80% predicted). Reduced peak VO2 was associated with impaired systemic O2 extraction as indicated by an arterial-venous O2 content difference (adjusted for hemoglobin) of <80% (Figure 1).

Conclusion: This case series provides preliminary evidence that reduced peak aerobic capacity among long haulers is primarily attributable to a peripheral (i.e., impaired systemic O2 extraction), rather than central cardiopulmonary, limitation. These results suggest that systemic microcirculatory dysfunction contributes to exercise limitation.

_

1965

L47

Jong Hyuk Lee, Jae-Joon Yim, Jimyung Park

Impaired Diffusion Capacity and Pulmonary Fibrosis after Recovery from COVID-19: A Systematic Review and Meta-Analysis

https://doi.org/10.21203/rs.3.rs-1089533/v1

pre-print

22-Nov-21

Systematic Review

https://www.researchsquare.com/article/rs-1089533/v1

Results: Of the 8159 studies identified, 29 met our eligibility criteria. Among these studies, 25 and 20 had data on follow-up pulmonary function testing and chest computed tomography (CT), respectively. Impaired diffusion capacity (<80% of predicted values or lower limit of normal) was the most common pulmonary abnormality (pooled prevalence 34%, 95% CI 27%–41%). When classified according to the severity of index infection, patients with severe COVID-19 were more likely to display impaired diffusion capacity than those with non-severe COVID-19 (pooled odds ratio 2.97, 95% CI 2.10–4.20). On follow-up chest CT, pulmonary fibrosis was found in 26% (95% CI 17%–36%) of the patients.

Conclusions: A substantial number of patients recovering from COVID-19 displayed impaired diffusion capacity and pulmonary fibrosis. The severity of index COVID-19 was associated with impaired diffusion capacity, highlighting the importance of respiratory follow-up in patients recovering from severe COVID-19.

_

1966

L48

Luigi Angelo Vaira, MD, Giovanni Salzano, MD, Serge Le Bon, MD, Angelantonio Maglio, MD, Marzia Petrocelli, MD, Younes Steffens, MD, Enrica Ligas, MSN, Fabio Maglitto, MD, Jerome R. Lechien, MD, PhD, Sven Saussez, MD, PhD, Alessandro Vatrella, MD, Francesco Antonio Salzano, MD, Paolo Boscolo-Rizzo, MD, Claire Hopkins, FRSC (ORLHNS), DM (Oxon), Giacomo De Riu

Levels of end-tidal carbon dioxide are low despite normal respiratory rate in individuals with Long COVID

https://doi.org/10.1088/1752-7163/ac3c18

Published

22-Nov-21

Letter

https://iopscience.iop.org/article/10.1088/1752-7163/ac3c18

In total, 82 patients with Long COVID completed the assessment (Table 1). The most common comorbidities reported were anxiety (n=19, 23%), asthma (n=11, 13%), depression (n=10, 12%) and inflammatory bowel disease (n=7, 9%). Six (7%) patients were hospitalized during acute COVID-19 infection, one (1%) patient had a pulmonary embolism, and three (3%) patients had subsequently developed pulmonary fibrosis. The median and interquartile range (IQR) for ETCO2 were 32 and 8 mmHg respectively (Table 1). The median (IQR) RR was 13 (6) breaths per minute. ETCO2 was below 35mmHg in 61 (74%) patients. The level of ETCO2 and RR were moderately negatively correlated (r=-0.4, p<0.01). In summary, the ETCO2 levels observed were lower than the expected range of 35 to 45 mmHg, despite on average, RR falling within the normal range. It is apparent that hypocapnia is present in the absence of hyperventilation in patients with Long COVID following less severe acute infection, potentially contributing to or as a manifestation of the underlying pathophysiology.

The possible causes of hypocapnia in this cohort may include increases in baseline respiration rate compared to pre-COVID-19 infection, disruption of the autonomic nervous system that may also be the cause of many Long COVID symptoms, or organ damage that may not be detectable on routine clinical imaging and assessment.

1967

L49

Andrea Vianello logo, Gabriella Guarnieri, Fausto Braccioni, Sara Lococo, Beatrice Molena, Antonella Cecchetto, Chiara Giraudo, Leonardo Bertagna De Marchi, Marco Caminati and Gianenrico Senna

The pathogenesis, epidemiology and biomarkers of susceptibility of pulmonary fibrosis in COVID-19 survivors

https://doi.org/10.1515/cclm-2021-1021

Published

16-Nov-21

Review

https://www.degruyter.com/document/doi/10.1515/cclm-2021-1021/html

Pulmonary fibrosis (PF), a pathological outcome of chronic and acute interstitial lung diseases associated to compromised wound healing, is a key component of the “post-acute COVID-19 syndrome” that may severely complicate patients’ clinical course. Although inconclusive, available data suggest that more than a third of hospitalized COVID-19 patients develop lung fibrotic abnormalities after their discharge from hospital. The pathogenesis of PF in patients recovering from a severe acute case of COVID-19 is complex, and several hypotheses have been formulated to explain its development. An analysis of the data that is presently available suggests that biomarkers of susceptibility could help to identify subjects with increased probability of developing PF and may represent a means to personalize the management of COVID-19’s long-term effects. Our review highlights the importance of both patient-related and disease-related contributing risk factors for PF in COVID-19 survivors and makes it definitely clear the possible use of acute phase and follow-up biomarkers for identifying the patients at greatest risk of developing this disease.

1968

L50

Sarah Halawa, Soni S. Pullamsetti, Charles R. M. Bangham, Kurt R. Stenmark, Peter Dorfmüller, Maria G. Frid, Ghazwan Butrous, Nick W. Morrell, Vinicio A. de Jesus Perez, David I. Stuart, Kevin O’Gallagher, Ajay M. Shah, Yasmine Aguib & Magdi H. Yacoub

Potential long-term effects of SARS-CoV-2 infection on the pulmonary vasculature: a global perspective

https://doi.org/10.1038/s41569-021-00640-2

Published

6-Dec-21

Review

https://www.nature.com/articles/s41569-021-00640-2

The lungs are the primary target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, with severe hypoxia being the cause of death in the most critical cases. Coronavirus disease 2019 (COVID-19) is extremely heterogeneous in terms of severity, clinical phenotype and, importantly, global distribution. Although the majority of affected patients recover from the acute infection, many continue to suffer from late sequelae affecting various organs, including the lungs. The role of the pulmonary vascular system during the acute and chronic stages of COVID-19 has not been adequately studied. A thorough understanding of the origins and dynamic behaviour of the SARS-CoV-2 virus and the potential causes of heterogeneity in COVID-19 is essential for anticipating and treating the disease, in both the acute and the chronic stages, including the development of chronic pulmonary hypertension. Both COVID-19 and chronic pulmonary hypertension have assumed global dimensions, with potential complex interactions. In this Review, we present an update on the origins and behaviour of the SARS-CoV-2 virus and discuss the potential causes of the heterogeneity of COVID-19. In addition, we summarize the pathobiology of COVID-19, with an emphasis on the role of the pulmonary vasculature, both in the acute stage and in terms of the potential for developing chronic pulmonary hypertension. We hope that the information presented in this Review will help in the development of strategies for the prevention and treatment of the continuing COVID-19 pandemic.

1969

L51

Tøri Vigeland Lerum, Niklas Nyboe Maltzahn, Pål Aukrust, Marius Trøseid, Katerina Nezvalova Henriksen, Trine Kåsine, Anne-Ma Dyrhol-Riise, Birgitte Stiksrud, Mette Haugli, Bjørn Blomberg, Bård Reiakvam Kittang, Asgeir Johannessen, Raisa Hannula, Saad Aballi, Anders Benjamin Kildal, Ragnhild Eiken, Tuva Børresdatter Dahl, Fridtjof Lund-Johansen, Fredrik Müller, Jezabel Rivero Rodriguez, Carin Meltzer, Gunnar Einvik, Thor Ueland, Inge Christoffer Olsen, NOR-SOLIDARITY Consortium, Andreas Barratt-Due, Trond Mogens Aaløkken & Ole Henning Skjønsberg

Persistent pulmonary pathology after COVID-19 is associated with high viral load, weak antibody response, and high levels of matrix metalloproteinase-9

https://doi.org/10.1038/s41598-021-02547-x

Published

1-Dec-21

Study

https://www.nature.com/articles/s41598-021-02547-x

he association between pulmonary sequelae and markers of disease severity, as well as pro-fibrotic mediators, were studied in 108 patients 3 months after hospital admission for COVID-19. The COPD assessment test (CAT-score), spirometry, diffusion capacity of the lungs (DLCO), and chest-CT were performed at 23 Norwegian hospitals included in the NOR-SOLIDARITY trial, an open-labelled, randomised clinical trial, investigating the efficacy of remdesivir and hydroxychloroquine (HCQ). Thirty-eight percent had a CAT-score ≥ 10. DLCO was below the lower limit of normal in 29.6%. Ground-glass opacities were present in 39.8% on chest-CT, parenchymal bands were found in 41.7%. At admission, low pO2/FiO2 ratio, ICU treatment, high viral load, and low antibody levels, were predictors of a poorer pulmonary outcome after 3 months. High levels of matrix metalloproteinase (MMP)-9 during hospitalisation and at 3 months were associated with persistent CT-findings. Except for a negative effect of remdesivir on CAT-score, we found no effect of remdesivir or HCQ on long-term pulmonary outcomes. Three months after hospital admission for COVID-19, a high prevalence of respiratory symptoms, reduced DLCO, and persistent CT-findings was observed. Low pO2/FiO2 ratio, ICU-admission, high viral load, low antibody levels, and high levels of MMP-9 were associated with a worse pulmonary outcome.

1970

L52

Nhu Ngoc Nguyen Van Thuan Hoang Thi Loi Dao Line Meddeb Jean-Christophe Lagier Matthieu Million Didier Raoult Philippe Gautret

Long-term persistence of symptoms of dyspnoea in COVID-19 patients

https://doi.org/10.1016/j.ijid.2021.11.035

Published

26-Nov-21

Short Communication

https://www.ijidonline.com/article/S1201-9712(21)00882-1/fulltext

Highlights
•Out of 838 contacted patients, 496 (59.2%) answered the questionnaire.
•123/496 (24.8%) patients reported persistent dyspnoea.
•Age ≥ 45 years old is associated with persistent dyspnoea.

1971

L53

Chiara Colarusso 1,Angelantonio Maglio 2 ,Michela Terlizzi 1,Carolina Vitale 2,Antonio Molino 3,Aldo Pinto 1,Alessandro Vatrella 2 andRosalinda Sorrentino 1,*

Post-COVID-19 Patients Who Develop Lung Fibrotic-like Changes Have Lower Circulating Levels of IFN-β but Higher Levels of IL-1α and TGF-β

https://doi.org/10.3390/biomedicines9121931

Published

17-Dec-21

Study

https://www.mdpi.com/2227-9059/9/12/1931/htm

The purpose of this study was to identify blood biomarkers to predict PC patients undergoing pulmonary fibrosis. Patients and Methods: We analyzed blood samples of healthy, anti-SARS-CoV-2 vaccinated (VAX) subjects and PC patients who were stratified according to the severity of the disease and chest computed tomography (CT) scan data. Results: The inflammatory C reactive protein (CRP), complement complex C5b-9, LDH, but not IL-6, were higher in PC patients, independent of the severity of the disease and lung fibrotic areas. Interestingly, PC patients with ground-glass opacities (as revealed by chest CT scan) were characterized by higher plasma levels of IL-1α, CXCL-10, TGF-β, but not of IFN-β, compared to healthy and VAX subjects. In particular, 19 out of 23 (82.6%) severe PC and 8 out of 29 (27.6%) moderate PC patients presented signs of lung fibrosis, associated to lower levels of IFN-β, but higher IL-1α and TGF-β. Conclusions: We found that higher IL-1α and TGF-β and lower plasma levels of IFN-β could predict an increased relative risk (RR = 2.8) of lung fibrosis-like changes in PC patients.

1972

L54

Joseph M. Rohr, MD, PhD, Heather Strah, MD, David Berkheim, MD, Aleem Siddique, MBBS, Stanley J. Radio, MD, Benjamin J. Swanson, MD, PhD

Pulmonary Hypertensive Changes Secondary to COVID-19 Pneumonia in a Chronically SARS-CoV-2-Infected Bilateral Lung Explant

https://doi.org/10.1177%2F10668969211064208

Published

13-Dec-21

Case Report

https://journals.sagepub.com/doi/abs/10.1177/10668969211064208

We performed a bilateral lung transplant on a 31-year-old male patient for chronic hypoxic respiratory failure, severe pulmonary hypertension and radiographically identified pulmonary fibrosis five months after an acute COVID-19 infection. The explant demonstrated moderate pulmonary vascular remodeling with intimal thickening and medial hypertrophy throughout, consistent with pulmonary hypertension. The parenchyma demonstrated an organizing lung injury in the proliferative phase, with severe fibrosis, histiocytic proliferation, type II pneumocyte hyperplasia, and alveolar loss consistent with known COVID-19 pneumonia complications.
This report highlights a novel histologic finding in severe, chronic COVID-19. Although the findings in acute COVID-19 pneumonia have been well-examined at autopsy, the chronic course of this complex disease is not yet understood. The case presented herein suggests that COVID-induced pulmonary hypertension may become more common as more patients survive severe SARS-CoV-2-related pneumonia.

_

1973

L55

panelPaul M.Heerdt1BenShelley2InderjitSingh

Impaired systemic oxygen extraction long after mild COVID-19: potential perioperative implications

https://doi.org/10.1016/j.bja.2021.12.036

Published

27-Dec-21

Correspondence

https://www.sciencedirect.com/science/article/abs/pii/S0007091221008564

1974

L56

VP

Olivia M. Patania, Shiho Chiba, Peter J. Halfmann, Masato Hatta, Tadashi Maemura, Kristen A. Bernard, Yoshihiro Kawaoka, LaTasha K. Crawford

Pulmonary lesions induced by SARS-CoV-2 infection in domestic cats

https://doi.org/10.1177%2F03009858211066840

Published

29-Dec-21

Study

https://journals.sagepub.com/doi/10.1177/03009858211066840

Our objective was to describe histologic lung lesions and viral loads following experimental SARS-CoV-2 infection in 11 cats. Microscopic evaluation at 3, 6, 10, or 28 days postinoculation (DPI) identified mild to moderate patchy interstitial pneumonia, bronchiolar epithelial damage, and occlusive histiocytic bronchiolitis. Based on immunohistochemistry, alveolar septal thickening was due to CD204-positive macrophages, fewer B and T lymphocytes, type II pneumocytes, and capillary proliferation with a relative dearth of fibrosis. In blood vessel endothelium, there was reactive hypertrophy or vacuolar degeneration and increased MHC II expression at all time points. Unexpectedly, one cat from the 28 DPI group had severe subacute regionally extensive lymphohistiocytic pneumonia with multifocal consolidation, vasculitis, and alveolar fibrin. Reverse transcriptase-quantitative polymerase chain reaction identified SARS-CoV-2 RNA within the lung at 3 and 6 DPI, and viral RNA was below the limit of detection at 10 and 28 DPI, suggesting that pulmonary lesions persist beyond detection of viral RNA. These findings clarify our comparative understanding of disease induced by SARS-CoV-2 and suggest that cats can serve as an informative model to study post-acute pulmonary sequelae.

Les chats infectés par la covid peuvent subir des lésions pulmonaires persistantes, pouvant amener à une détérioration de la fonction pulmonaire, selon une étude dans Veterinary Pathology.

1975

L57

Chad S. Clancy, Carl Shaia, Vincent Munster, Emmie de Wit, David Hawman, Atsushi Okumura, Heinz Feldmann, Greg Saturday, Dana Scott

Histologic pulmonary lesions of SARS-CoV-2 in 4 nonhuman primate species: An institutional comparative review

https://doi.org/10.1177%2F03009858211067468

Published

29-Dec-21

Study

https://journals.sagepub.com/doi/full/10.1177/03009858211067468

Nonhuman primate models have previously been shown to be valuable in evaluation of emerging respiratory coronaviruses with pandemic potential (ie, SARS-CoV and Middle East respiratory syndrome coronavirus). In this article, we review the pulmonary histopathologic characteristics and immunohistochemical evaluation of experimental SARS-CoV-2 infection in the rhesus macaque, pigtail macaque, African green monkey, and squirrel monkey. Our results indicate that all evaluated nonhuman primate species developed variably severe histopathologic changes typical of coronavirus respiratory disease characterized by interstitial pneumonia with or without syncytial cell formation, alveolar fibrin, and pulmonary edema that progressed to type II pneumocyte hyperplasia. Lesion distribution was multifocal, frequently subpleural, and often more severe in lower lung lobes. However, squirrel monkeys showed the least severe and least consistent lesions of the evaluated nonhuman primates. Additionally, our results highlight the disparate physical relationship between viral antigen and foci of pulmonary lesions. While classic respiratory coronaviral lesions were observed in the lungs of all nonhuman primates evaluated, none of the primates exhibited severe lesions or evidence of diffuse alveolar damage and therefore are unlikely to represent the severe form of SARS-CoV-2 infection observed in fatal human cases.

Certains primates, notamment le Macaque rhésus, le Grivet d'Éthiopie, le Macaque à queue de cochon, le Singe-écureuil, peuvent, à différents niveaux selon les espèces, souffrir de lésions pulmonaires lorsqu'ils sont infectées au SARS-CoV-2.

1976

L58

E.M.Jutant1O.Meyrignac2A.Beurnier3X.Jais1T.Pham4L.Morin5A.Boucly1S.Bulifon1F.Samy6A.Harrois6M.Jevnikar1N.Noël7J.Pichon1A.Roche1A.Seferian1S.Soliman2J.Duranteau6L.Becquemont8X.Monnet4O.Sitbon1M.F.Bellin2M.Humbert1L.Savale1D.Montani1

Symptômes respiratoires et anomalies radiologiques dans le COVID long

https://doi.org/10.1016/j.rmra.2021.11.203

Published

25-Dec-21

Study

https://www.sciencedirect.com/science/article/pii/S1877120321008132

Résultats
Parmi les 478 patients, 78 (16,3 %) ont signalé une dyspnée et 23 (4,8 %) une toux, apparues depuis la COVID-19. Les patients présentant une dyspnée d’apparition récente étaient significativement plus jeunes (56,1 ± 12,3 versus 61,9 ± 16,6 ans), avaient eu une COVID-19 plus sévère (admission en USI 56,4 % versus 24,5 %) et un antécédent d’embolie pulmonaire pendant la COVID-19 plus fréquente (18,0 % versus 6,8 %) (tous les p ≤ 0,001) que les patients sans nouvelle dyspnée et parmi eux 23 (29,5 %) avaient un score de Nijmegen > 22. Parmi les patients réévalués en HDJ, la prévalence des lésions fibrosantes pulmonaires était de 19,3 %, avec une étendue lésionnelle < 25 % dans 97 % des cas. Les patients présentant des lésions fibrosantes étaient plus âgés (61 ± 11 versus 56 ± 14 ans, p = 0,03), plus fréquemment pris en charge en USI (87,9 versus 47,4 %, p < 0,001) et avaient une capacité pulmonaire totale inférieure (74,1 ± 13,7 versus 84,9 ± 14,8 %, p < 0,001) et une DLCO plus basse (73,3 ± 17,9 versus 89,7 ± 22,8 %, p < 0,001). L’association d’une nouvelle dyspnée, de lésions fibrosantes et d’une DLCO < 70 % était rarement observée (8/478 patients).
Conclusion
La dyspnée d’apparition récente et les lésions fibrosantes pulmonaire peu étendues sont fréquentes 4 mois après COVID-19 mais l’association d’une dyspnée avec des lésions fibrosantes et des troubles de la diffusion est rarement retrouvée.

1977

L59

Bo Xu 1
Fu-qiang Ma 1
Cong He 1
Zi-qi Wu
Cun-yu Fan
He-rong Mao
Ji-xian Zhang
Min Yang
Zuo-wei Hu

Incidence and affecting factors of pulmonary diffusing capacity impairment with COVID-19 survivors 18 months after discharge in Wuhan, China

https://doi.org/10.1016/j.jinf.2021.12.020

Published

25-Dec-21

Study

https://www.journalofinfection.com/article/S0163-4453(21)00642-3/fulltext

In this study, we discovered the factors affecting COVID-19 patients’ PDCI. The multivariate logistic regression analysis showed that gender, Hb, PLT, MVV and the disease severity levels were correlated with the declined pulmonary diffusing capacity. Furthermore, we found that the incidence of PDCI in female patients was significantly higher than that of males, which are in agreement with the previous studies on COVID-19 patients 1 year after discharge.3,5
In the acute phase, PLT activation and aggregation of COVID-19 patients were increased.6,7 Histopathological assessment on the autopsy of COVID-19 cases revealed presence of PLT-involved inflammatory microvascular thrombosis in the patients’ lungs, kidneys and hearts, confirming that respiratory failure of COVID-19 patients was connected with inflammatory thrombosis.8, 9, 10 Our study also showed that pulmonary diffusing capacity was negatively correlated with PLT, that is, the diffusing capacity would be obviously impaired when PLTs were at the normal high value, and pulmonary diffusing capacity would be greatly improved when PLTs were at the normal low value.
Moreover, our findings exhibited that after the correction of hemoglobin that affected pulmonary diffusing capacity, the normal high value of hemoglobin was positively correlated with diffusing capacity of the lungs, which could be probably associated with the enhanced capacity of oxygen-carrying of hemoglobin when increased, and with the improved gas exchange in the lungs.
However, FVC and MVV of most COVID-19 survivors with PDCI were normal, which is consistent with other scholars’ findings2. It should be noted that severity of the disease was closely linked to the survivors’ PDCI as shown in Table 2.
As a cross-sectional study, limitations of this study still exist, and the baseline data are insufficient about the survivors’ pulmonary functions prior to the onset of COVID-19.
In summary, our study revealed that 57.92% of COVID-19 patients had PDCI, which was correlated with gender, PLTs, hemoglobin, MVV and severity of COVID-19. The potential factors affecting pulmonary diffusing capacity of COVID-19 patients and the complicated mechanisms behind remain to be further investigated in the future.

1978

L60

CPET

Paul M. Heerdt
Ben Shelley
Inderjit Singh

Impaired systemic oxygen extraction long after mild COVID-19: potential perioperative implications

https://doi.org/10.1016/j.bja.2021.12.036

Published

27-Dec-21

Correspondence

https://www.bjanaesthesia.org/article/S0007-0912(21)00856-4/fulltext

Singh and colleagues4 performed invasive cardiopulmonary exercise testing (iCPET) on 10 patients (mean age 48 yr, range: 28 to 79 yr, 9/10 female) with persistent exertional limitation 11 (1) months following mild COVID-19. None of the patients had abnormalities evident on chest computed tomographic imaging, pulmonary function testing, or resting echocardiogram, and all had normal haemoglobin levels. Study results were compared to a matched control group of 10 patients with normal exercise capacity and no history of COVID-19. As shown in table 1, relative to control patients at rest, DO2 was the same for post-COVID-19 patients but VO2 and systemic EO2 were modestly reduced. At peak exercise, when functional reserve mechanisms normally increase both DO2 and EO2, the difference in VO2 and EO2 between control and post-COVID-19 patients was more profound. Importantly, this disparity occurred despite a peak exercise response for heart rate and DO2 that was similar for both groups. These results indicate that exercise capacity was primarily limited by impaired systemic EO2 of such severity that what should have been an adequate increase in DO2 was insufficient to allow for an increase in VO2. While patients who are deconditioned can exhibit impaired EO2 with exercise12, preservation of the capacity to increase heart rate and cardiac output adequately at peak exercise in post-COVID-19 patients makes deconditioning a less likely singular explanation for their exercise limitation. In fact, several patients included in the study had already completed supervised exercise rehabilitation programs by the time of their iCPET. The lack of objective evidence for the presence of other factors such as anaemia, impaired cardiac or pulmonary function, or superimposed non-COVID infection suggests a possible microvascular/molecular abnormality. It is worth noting the overlap between the clinical presentations of patients with post-COVID-19 exercise limitation and patients with myalgic encephalitis/chronic fatigue syndrome13. The causal hypothesis of myalgic encephalitis/chronic fatigue syndrome has also been linked to preceding infection including human herpes virus, enterovirus, influenzae, Epstein-Barr virus (EBV), and Borrelia burgdorferi14, 15.
Given the broad heterogeneity of symptoms associated with COVID-19, the complexity of accurately measuring EO2, and the fact that a substantial number of people have undoubtedly experienced mild but undiagnosed SARS-CoV-2 infection1, it is difficult (if not impossible) to define the incidence, much less the consequences, of impaired EO2 reserve following mild COVID-19 in the surgical population. Ultimately, we agree with Silvapulle and colleagues2, that at present the best approach to perioperative risk assessment in post-COVID-19 patients is tangible, objective evaluation of multiorgan sequelae. Nonetheless, clinicians should be aware that a deficit may exist that can mimic impaired tissue DO2 despite normal cardiopulmonary function and haemoglobin level, and potentially enhance the adverse consequences of perioperative hypoxaemia, anaemia, or impaired tissue perfusion. We are just beginning to learn of the long-term sequelae of even mild COVID-19, underscoring the need to be vigilant to the potential for a broader perioperative impact of prior SARS-CoV-2 infection.

1979

L61

VP

Akmaljon Odilov 1,* ,Alexey Volkov 1,2 ,Adhamjon Abdullaev 3 ,Tatiana Gasanova 4 ,Tatiana Lipina 5 andIgor Babichenko 1

COVID-19: Multiorgan Dissemination of SARS-CoV-2 Is Driven by Pulmonary Factors

https://doi.org/10.3390/v14010039

Published

26-Dec-21

Study

https://www.mdpi.com/1999-4915/14/1/39/htm

SARS-CoV-2 VL in the lungs, heart, liver, kidneys, brain, spleen and lymph nodes have been measured by RT qPCR using the following formula: NSARS-CoV−2/NABL1 × 100. Dissemination of SARS-CoV-2 in 30.5% of cases was mono-organ, and in 63.9% of cases, it was multi-organ. The average SARS-CoV-2 VL in the exudative phase of diffuse alveolar damage (DAD) was 60 times higher than in the proliferative phase. The SARS-CoV-2 VL in the lungs ranged from 0 to 250,281 copies. The “pulmonary factors” of SARS-CoV-2 multi-organ dissemination are the high level of SARS-CoV-2 VL (≥4909) and the exudative phase of DAD. The frequency of SARS-CoV-2 dissemination to lymph nodes was 86.9%, heart–56.5%, spleen–52.2%, liver–47.8%, kidney–26%, and brain–13%. We found no link between the SARS-CoV-2 VL level in the liver, kidneys, and heart and the serum level of CPK, LDH, ALP, ALT, AST and Cr of COVID-19 patients. Isolated detection of SARS-CoV-2 RNA in the myocardium of COVID-19 patients who died from heart failure is possible. The pathogenesis of COVID-19-associated multi-organ failure requires further research in a larger cohort of patients.

1980

L62

Akmaljon Odilov 1,* ,Alexey Volkov 1,2 ,Adhamjon Abdullaev 3 ,Tatiana Gasanova 4 ,Tatiana Lipina 5 andIgor Babichenko 1

COVID-19: Multiorgan Dissemination of SARS-CoV-2 Is Driven by Pulmonary Factors

https://doi.org/10.3390/v14010039

Published

26-Dec-21

Study

https://www.mdpi.com/1999-4915/14/1/39/htm

Multi-organ failure is one of the common causes of fatal outcome in COVID-19 patients. However, the pathogenetic association of the SARS-CoV-2 viral load (VL) level with fatal dysfunctions of the lungs, liver, kidneys, heart, spleen and brain, as well as with the risk of death in COVID-19 patients remains poorly understood. SARS-CoV-2 VL in the lungs, heart, liver, kidneys, brain, spleen and lymph nodes have been measured by RT qPCR using the following formula: NSARS-CoV−2/NABL1 × 100. Dissemination of SARS-CoV-2 in 30.5% of cases was mono-organ, and in 63.9% of cases, it was multi-organ. The average SARS-CoV-2 VL in the exudative phase of diffuse alveolar damage (DAD) was 60 times higher than in the proliferative phase. The SARS-CoV-2 VL in the lungs ranged from 0 to 250,281 copies. The “pulmonary factors” of SARS-CoV-2 multi-organ dissemination are the high level of SARS-CoV-2 VL (≥4909) and the exudative phase of DAD. The frequency of SARS-CoV-2 dissemination to lymph nodes was 86.9%, heart–56.5%, spleen–52.2%, liver–47.8%, kidney–26%, and brain–13%. We found no link between the SARS-CoV-2 VL level in the liver, kidneys, and heart and the serum level of CPK, LDH, ALP, ALT, AST and Cr of COVID-19 patients. Isolated detection of SARS-CoV-2 RNA in the myocardium of COVID-19 patients who died from heart failure is possible. The pathogenesis of COVID-19-associated multi-organ failure requires further research in a larger cohort of patients.

1981

L63

James T. Grist, Guilhem J. Collier, Huw Walters, Mitchell Chen, Gabriele Abu Eid, Aviana Laws, Violet Matthews, Kenneth Jacob, Susan Cross, Alexandra Eves, Marianne Durant, Anthony Mcintyre, Roger Thompson, Rolf F. Schulte, Betty Raman, Peter A. Robbins, Jim M. Wild, Emily Fraser, Fergus Gleeson

The Investigation of Pulmonary Abnormalities using Hyperpolarised Xenon Magnetic Resonance Imaging in Patients with Long-COVID

https://doi.org/10.1101/2022.02.01.22269999

pre-print

2-Feb-22

Study

https://www.medrxiv.org/content/10.1101/2022.02.01.22269999v1

Methods Eleven non-hospitalised Long-COVID (NHLC, 4 male), 12 post-hospitalised COVID-19 (PHC, 10 male) patients were recruited from a Post-COVID Assessment clinic, and thirteen healthy controls (6 female) were recruited to undergo Hyperpolarized Xenon Magnetic Resonance Imaging (Hp-XeMRI). NHLC and PHC participants underwent contemporaneous CT, Hp-XeMRI, lung function tests, 1-minute sit-to-stand test and breathlessness questionnaires. Statistical analysis included group and pair-wise comparisons between patients and controls, and correlations between patient clinical and imaging data.
Results NHLC and PHC patients were 287 ± 79 [range 190-437] and 149 ± 68 [range 68-269] days from infection, respectively. All NHLC patients had normal CT scans, and the PHC had normal or near normal CT scans (0.3/25 ± 0.6 [range 0-2] and 7/25 ± 5 [range 4-8], respectively). There was a significant difference in TLco (%) between NHLC and PHC patients (76 ± 8 % vs 86 ± 8%, respectively, p = 0.04) but no differences in other measurements of lung function. There were significant differences in RBC:TP mean between volunteers (0.45 ± 0.07, range [0.33-0.55]) and PHC (0.31 ± 0.11, [range 0.16-0.37]) and NHLC (0.35 ± 0.09, [range 0.26-0.58]) patients, but not between NHLC and PHC (p = 0.26).
Conclusion There are RBC:TP abnormalities in NHLC and PHC patients, with NHLC patients also demonstrating lower TLco than PHC patients despite their having normal CT scans. These abnormalities are present many months after the initial infection.

1982

L64

about L63

NIHR

Lung abnormalities found in long COVID patients with breathlessness

Published

Article

https://www.nihr.ac.uk/news/lung-abnormalities-found-in-long-covid-patients-with-breathlessness/29798

Researchers have identified abnormalities in the lungs of long COVID patients with breathlessness but whose other tests are normal.
The EXPLAIN study is using hyperpolarised xenon MRI scans to investigate possible lung damage in long COVID patients who experience breathlessness and were not hospitalised when they had COVID-19.
These early results suggest that COVID-19 may result in persistent impairment in gas transfer and underlying lung abnormalities. However, the extent to which these abnormalities contribute to breathlessness is currently unclear.

In the initial results, published on the medRxiv pre-print server, the long COVID patients had abnormal hyperpolarised xenon MRI scans, indicating ‘significantly impaired gas transfer’ from the lungs to the bloodstream. However their CT scans showed normal results.
The pilot study involves teams in Oxford, Sheffield, Cardiff and Manchester and is funded by the NIHR. It is one of 19 studies that have received nearly £40 million investment from NIHR to improve understanding of long COVID, from diagnosis and treatment through to rehabilitation and recovery. The research is also supported by the NIHR Oxford Biomedical Research Centre.

1983

L65

Erkan Celik ,Christian Nelles,Jonathan Kottlors,Philipp Fervers,Lukas Goertz,Daniel Pinto dos Santos,Tobias Achenbach,David Maintz,Thorsten Persigehl

Quantitative determination of pulmonary emphysema in follow-up LD-CTs of patients with COVID-19 infection

https://doi.org/10.1371/journal.pone.0263261

Published

3-Feb-22

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0263261

Methods
Consecutive patients with proven COVID-19 infection and a follow-up CT were retrospectively reviewed. The severity of pulmonary involvement was classified as mild, moderate and severe. Total lung volume, emphysema volume and the ratio of emphysema/-to-lung volume were quantified semi-automatically and compared inter-individually between initial and follow-up CT and to a control group of healthy, age- and sex-matched patients. Lung density was further assessed by drawing circular regions of interest (ROIs) into non-affected regions of the upper lobes.
Results
A total of 32 individuals (mean age: 64 ± 13 years, 12 females) with at least one follow-up CT (mean: 52 ± 66 days, range: 5–259) were included. In the overall cohort, total lung volume, emphysema volume and the ratio of lung-to-emphysema volume did not differ significantly between the initial and follow-up scans. In the subgroup of COVID-19 patients with > 30 days of follow-up, the emphysema volume was significantly larger as compared to the subgroup with a follow-up < 30 days (p = 0.045). Manually measured single ROIs generally yielded lower attenuation values prior to COVID-19 pneumonia, but the difference was not significant between groups (all p > 0.05).
Conclusion
COVID-19 patients with a follow-up CT >30 days showed significant emphysematous lung alterations. These findings may help to explain the long-term effect of COVID-19 on pulmonary function and warrant validation by further studies.

1984

L66

Fuxiaonan Zhao, Qingwen Ma, Qing Yue, Huaiyong Chen

SARS-CoV-2 Infection and Lung Regeneration

https://doi.org/10.1128/cmr.00188-21

Published

2-Feb-22

Review

https://journals.asm.org/doi/full/10.1128/cmr.00188-21

The lung is the primary site of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced immunopathology whereby the virus enters the host cells by binding to angiotensin-converting enzyme 2 (ACE2). Sophisticated regeneration and repair programs exist in the lungs to replenish injured cell populations. However, known resident stem/progenitor cells have been demonstrated to express ACE2, raising a substantial concern regarding the long-term consequences of impaired lung regeneration after SARS-CoV-2 infection. Moreover, clinical treatments may also affect lung repair from antiviral drug candidates to mechanical ventilation. In this review, we highlight how SARS-CoV-2 disrupts a program that governs lung homeostasis. We also summarize the current efforts of targeted therapy and supportive treatments for COVID-19 patients. In addition, we discuss the pros and cons of cell therapy with mesenchymal stem cells or resident lung epithelial stem/progenitor cells in preventing post-acute sequelae of COVID-19. We propose that, in addition to symptomatic treatments being developed and applied in the clinic, targeting lung regeneration is also essential to restore lung homeostasis in COVID-19 patients.

1985

L67

Cheng Wang, Haidong Li, Sa Xiao, Zimeng Li, Xiuchao Zhao, Junshuai Xie, Chaohui Ye, Liming Xia, Xin Lou & Xin Zhou

Abnormal dynamic ventilation function of COVID-19 survivors detected by pulmonary free-breathing proton MRI

https://doi.org/10.1007/s00330-022-08605-w

Published

Study

https://link.springer.com/article/10.1007/s00330-022-08605-w

Objectives
To visualize and quantitatively assess regional lung function of survivors of COVID-19 who were hospitalized using pulmonary free-breathing 1H MRI.
Methods
A total of 12 healthy volunteers and 27 COVID-19 survivors (62.4 ± 8.1 days between infection and image acquisition) were recruited in this prospective study and performed chest 1H MRI acquisitions with free tidal breathing. Then, conventional Fourier decomposition ventilation (FD-V) and global fractional ventilation (FVGlobal) were analyzed. Besides, a modified PREFUL (mPREFUL) method was developed to adapt to COVID-19 survivors and generate dynamic ventilation maps and parameters. All the ventilation maps and parameters were analyzed using Student’s t-test. Pearson’s correlation and a Bland-Altman plot between FVGlobal and mPREFUL were analyzed.
Results
There was no significant difference between COVID-19 and healthy groups regarding a static FD-V map (0.47 ± 0.12 vs 0.42 ± 0.08; p = .233). However, mPREFUL demonstrated lots of regional high ventilation areas (high ventilation percentage (HVP): 23.7% ± 10.6%) existed in survivors. This regional heterogeneity (i.e., HVP) in survivors was significantly higher than in healthy volunteers (p = .003). The survivors breathed deeper (flow-volume loop: 5375 ± 3978 vs 1688 ± 789; p = .005), and breathed more air in respiratory cycle (total amount: 62.6 ± 19.3 vs 37.3 ± 9.9; p < .001). Besides, mPREFUL showed both good Pearson’s correlation (r = 0.74; p < .001) and Bland-Altman consistency (mean bias = −0.01) with FVGlobal.
Conclusions
Dynamic ventilation imaging using pulmonary free-breathing 1H MRI found regional abnormity of dynamic ventilation function in COVID-19 survivors.

1986

L68

Tomás Franquet, Ana Giménez, Loren Ketai, Sandra Mazzini, Andrea Rial, Virginia Pomar & Pere Domingo

Air trapping in COVID-19 patients following hospital discharge: retrospective evaluation with paired inspiratory/expiratory thin-section CT

https://doi.org/10.1007/s00330-022-08580-2

Published

28-Feb-22

Study

https://link.springer.com/article/10.1007/s00330-022-08580-2

The study reports our experience with paired inspiration/expiration thin-section computed tomographic (CT) scans in the follow-up of COVID-19 patients with persistent respiratory symptoms.
Results
Parenchymal abnormality was found in 50% (24/48) of patients and included air trapping (37/48, 77%), ground-glass opacities (19/48, 40%), reticulation (18/48, 38%), parenchymal bands (15/48, 31%), traction bronchiectasis (9/48, 19%), mosaic attenuation pattern (9/48, 19%), bronchial wall thickening (6/48, 13%), and consolidation (2/48, 4%). The absence of air trapping was observed in 11/48 (23%), mild air trapping in 20/48 (42%), moderate in 13/48 (27%), and severe in 4/48 (8%). Independent predictors of air trapping were, in decreasing order of importance, gender (p = 0.0085), and age (p = 0.0182).
Conclusions
Our results, in a limited number of patients, suggest that follow-up with paired inspiratory/expiratory CT in long-COVID patients with persistent respiratory symptoms commonly displays air trapping.

1987

L69

Asma Mohammadi, Irina Balan, Shikha Yadav, Wanessa F. Matos, Amrin Kharawala, Mrunanjali Gaddam, Noemi Sarabia, Sri Charitha Koneru, Siva K. Suddapalli, Sima Marzban

Post-COVID-19 Pulmonary Fibrosis

https://doi.org/10.7759/cureus.22770

Published

2-Mar-22

Review

https://www.cureus.com/articles/87859-post-covid-19-pulmonary-fibrosis

Despite having a wide range of clinical features, acute respiratory distress syndrome (ARDS) has emerged as the primary cause of mortality in these patients. Risk factors and comorbidities like advanced age with limited lung function, pre-existing diabetes, hypertension, cardiovascular diseases, and obesity have increased the risk for severe COVID-19 infection. Rise in inflammatory markers like transforming growth factor β (TGF-β), interleukin-6 (IL-6), and expression of matrix metalloproteinase 1 and 7 (MMP-1, MMP-7), along with collagen deposition at the site of lung injury, results in extensive lung scarring and fibrosis. Anti-fibrotic drugs, such as Pirfenidone and Nintedanib, have emerged as potential treatment options for post-COVID-19 pulmonary fibrosis. A lung transplant might be the only life-saving treatment. Despite the current advances in the management of COVID-19, there is still a considerable knowledge gap in the management of long-term sequelae in such patients, especially concerning pulmonary fibrosis. Follow up on the current clinical trials and research to test the efficacy of various anti-inflammatory drugs is needed to prevent long-term sequelae early mortality in these patients.

1988

L70

I Stewart, J Jacob, PM George, PL Molyneaux, JC Porter, RJ Allen, JK Baillie, SL Barratt, P Beirne, SM Bianchi, JF Blaikley, J Chalmers, RC Chambers, N Chadhuri, C Coleman, G Collier, EK Denneny, A Docherty, O Elneima, RA Evans, L Fabbri, MA Gibbons, FV Gleeson, B Gooptu, NJ Greening, B Guillen Guio, IP Hall, NA Hanley, V Harris, EM Harrison, M Heightman, TE Hillman, A Horsley, L Houchen-Wolloff, I Jarrold, SR Johnson, MG Jones, F Khan, R Lawson, OC Leavy, N Lone, M Marks, H McAuley, P Mehta, E Omer, D Parekh, K Piper Hanley, M Platé, J Pearl, K Poinasamy, JK Quint, B Raman, M Richardson, P Rivera-Ortega, LC Saunders, R Saunders, MG Semple, M Sereno, A Shikotra, AJ Simpson, A Singapuri, DJF Smith, M Spears, LG Spencer, S Stanel, D Thickett, AAR Thompson, M Thorpe, R Thwaites, SLF Walsh, S Walker, ND Weatherley, M Weeks, JM Wild, DG Wootton, CE Brightling, LP Ho, LV Wain, RG Jenkins

Interstitial lung damage following COVID-19 hospitalisation: an interim analysis of the UKILD Post-COVID study

https://doi.org/10.1101/2022.03.10.22272081

pre-print

16-Mar-22

Study

https://www.medrxiv.org/content/10.1101/2022.03.10.22272081v2.full-text

Introduction Shared characteristics between COVID-19 and pulmonary fibrosis, including symptoms, genetic architecture, and circulating biomarkers, suggests interstitial lung disease (ILD) development may be associated with SARS-CoV-2 infection.
Methods - The UKILD Post-COVID study planned interim analysis was designed to stratify risk groups and estimate the prevalence of Post-COVID Interstitial Lung Damage (ILDam) using the Post-HOSPitalisation COVID-19 (PHOSP-COVID) Study. Demographics, radiological patterns and missing data were assessed descriptively. Bayes binomial regression was used to estimate the risk ratio of persistent lung damage >10% involvement in linked, clinically indicated CT scans. Indexing thresholds of percent predicted DLco, chest X-ray findings and severity of admission were used to generate risk strata. Number of cases within strata were used to estimate the amount of suspected Post-COVID ILDam.
Results - A total 3702 people were included in the UKILD interim cohort, 2406 completed an early follow-up research visit within 240 days of discharge and 1296 had follow-up through routine clinical review. We linked the cohort to 87 clinically indicated CTs with visually scored radiological patterns (median 119 days from discharge; interquartile range 83 to 155, max 240), of which 74 people had ILDam. ILDam was associated with abnormal chest X-ray (RR 1.21 95%CrI 1.05; 1.40), percent predicted DLco<80% (RR 1.25 95%CrI 1.00; 1.56) and severe admission (RR 1.27 95%CrI 1.07; 1.55). A risk index based on these features suggested 6.9% of the interim cohort had moderate to very-high risk of Post-COVID ILDam. Comparable radiological patterns were observed in repeat scans >90 days in a subset of participants.
Conclusion - These interim data highlight that ILDam was not uncommon in clinically indicated thoracic CT up to 8 months following SARS-CoV-2 hospitalisation. Whether the ILDam will progress to ILD is currently unknown, however health services should radiologically and physiologically monitor individuals who have Post-COVID ILDam risk factors.

1989

L71

C.Bensaid1H.Guerrouj2I.Ghfir2M.Çaoui2N.Ben Rais Aouad2

Les profils scintigraphiques de la perfusion pulmonaire des patients post COVID-19

https://doi.org/10.1016/j.mednuc.2022.01.075

Published

11-Mar-22

Study

https://www.sciencedirect.com/science/article/pii/S0928125822000754

L’incidence des complications thromboemboliques dans l’infection COVID-19 est bien connue, même chez les patients recevant une anticoagulation prophylactique. La scintigraphie pulmonaire est un examen fonctionnel permettant d’étudier les processus physiologiques de la perfusion et d’éliminer une embolie.
Matériels et méthodes
Nous avons analysé rétrospectivement la scintigraphie pulmonaire de perfusion de 60 patients post-COVID-19, cette exploration consiste à l’injection intraveineuse de macro-agrégats d’albumine marqués au technétium (MAA-99mTc). Notre étude porte sur la présence ou non de défects de perfusion évocateurs de processus embolique ainsi que leurs différents aspects au niveau des deux champs pulmonaires.
Résultats
En plus de l’étude épidémiologique, des signes cliniques et paracliniques, nos résultats scintigraphiques sont exprimés en probabilité (de faible à forte) à défaut de couplage de la scintigraphie perfusion/ventilation et en confrontation avec les images scanographiques.
Conclusion
La scintigraphie pulmonaire de perfusion reste un examen incontournable dans le diagnostic de l’embolie, surtout si l’angioscanner est négatif. En cette pandémie, elle occupe une place importante dans le suivi post-COVID.

1990

L72

Klaus J. Wirth 1,2 andCarmen Scheibenbogen

Dyspnea in Post-COVID Syndrome following Mild Acute COVID-19 Infections: Potential Causes and Consequences for a Therapeutic Approach

https://doi.org/10.3390/medicina58030419

Published

12-Mar-22

Review

https://www.mdpi.com/1648-9144/58/3/419/htm

Dyspnea, shortness of breath, and chest pain are frequent symptoms of post-COVID syndrome (PCS). These symptoms are unrelated to organ damage in most patients after mild acute COVID infection. Hyperventilation has been identified as a cause of exercise-induced dyspnea in PCS. Since there is a broad overlap in symptomatology with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), causes for dyspnea and potential consequences can be deduced by a stringent application of assumptions made for ME/CFS in our recent review papers. One of the first stimuli of respiration in exercise is caused by metabolic feedback via skeletal muscle afferents. Hyperventilation in PCS, which occurs early on during exercise, can arise from a combined disturbance of a poor skeletal muscle energetic situation and autonomic dysfunction (overshooting respiratory response), both found in ME/CFS. The exaggerated respiratory response aggravating dyspnea does not only limit the ability to exercise but further impairs the muscular energetic situation: one of the buffering mechanisms to respiratory alkalosis is a proton shift from intracellular to extracellular space via the sodium–proton-exchanger subtype 1 (NHE1), thereby loading cells with sodium. This adds to two other sodium loading mechanisms already operative, namely glycolytic metabolism (intracellular acidosis) and impaired Na+/K+ATPase activity. High intracellular sodium has unfavorable effects on mitochondrial calcium and metabolism via sodium–calcium-exchangers (NCX). Mitochondrial calcium overload by high intracellular sodium reversing the transport mode of NCX to import calcium is a key driver for fatigue and chronification. Prevention of hyperventilation has a therapeutic potential by keeping intracellular sodium below the threshold where calcium overload occurs.

1991

L73

P D Mitchell, J Olaniyi, C Buckley, S C Donnelly

Long COVID syndrome and the lung: how long will it last?

https://doi.org/10.1093/qjmed/hcac070

Published

22-Mar-22

SHORT COMMENTARY

https://academic.oup.com/qjmed/advance-article-abstract/doi/10.1093/qjmed/hcac070/6551992

The prevalence and duration of the long-term respiratory complications of COVID-19 infection remains to be elucidated. This short commentary reports on recently published studies in patients post-acute COVID-19 infection in terms of symptom prevalence, physiological and radiological sequela and where only symptoms are present despite investigation. Pulmonary function testing, 6-min walk tests, computed tomography chest and more advanced imaging modalities have been incorporated to reveal the underlying pathophysiology that cause such disabling symptoms in patient with post-acute COVID-9 syndrome (PACS). PACS has a serious impact on people’s ability to return to work, affecting the physical, mental, social sphere and with significant healthcare and general economic consequences for them, their families and society.

1992

L74

GuillermoCueto-Robledo123ErnestoRoldan-Valadez45Luis-EugenioGraniel-Palafox6MarisolGarcia-Cesar1Maria-BereniceTorres-Rojas1RocioEnriquez-Garcia6Hector-DanielCueto-Romero2NathalyRivera-Sotelo2Angel-AugustoPerez-Calatayud7

Chronic thromboembolic pulmonary hypertension (CTEPH): a review of another sequel of severe post-Covid-19 pneumonia.

https://doi.org/10.1016/j.cpcardiol.2022.101187

Published

25-Mar-22

Review

https://www.sciencedirect.com/science/article/pii/S0146280622000846

The spectrum of pulmonary parenchymal and vascular pathologies related to the COVID-19 have emerged. There is evidence of a specific susceptibility related to thrombotic microangiopathy in situ and a complex immune-inflammatory cascade, especially in the pulmonary vascular bed. The potential to lead to transient or self-correcting sequelae of pulmonary vascular injury will only become apparent with longer-term follow-up.
In this review, we aimed to present the findings in a group of patients with severe pneumonia due to covid-19 complicated by acute pe documented by chest angiography, who during a follow-up of more than three months with oral anticoagulant met clinical, hemodynamic, and imaging criteria of chronic thromboembolic pulmonary hypertension. We present a brief review of the epidemiology, pathophysiology, clinical findings, comorbidities, treatment, and imaging findings of chronic thromboembolic pulmonary hypertension as a sequel of severe post-covid-19 pneumonia; and compared and discussed these findings with similar reports from the medical literature.

1993

L75

Andreia L. Pinto, Ranjit K. Rai, Jonathan C. Brown, Paul Griffin, James R. Edgar, Anand Shah, Aran Singanayagam, Claire Hogg, Wendy S. Barclay, Clare E. Futter & Thomas Burgoyne

ltrastructural insight into SARS-CoV-2 entry and budding in human airway epithelium

https://doi.org/10.1038/s41467-022-29255-y

Published

25-Mar-22

Study

https://www.nature.com/articles/s41467-022-29255-y

Ultrastructural studies of SARS-CoV-2 infected cells are crucial to better understand the mechanisms of viral entry and budding within host cells. Here, we examined human airway epithelium infected with three different isolates of SARS-CoV-2 including the B.1.1.7 variant by transmission electron microscopy and tomography. For all isolates, the virus infected ciliated but not goblet epithelial cells. Key SARS-CoV-2 entry molecules, ACE2 and TMPRSS2, were found to be localised to the plasma membrane including microvilli but excluded from cilia. Consistently, extracellular virions were seen associated with microvilli and the apical plasma membrane but rarely with ciliary membranes. Profiles indicative of viral fusion where tomography showed that the viral membrane was continuous with the apical plasma membrane and the nucleocapsids diluted, compared with unfused virus, demonstrate that the plasma membrane is one site of entry where direct fusion releasing the nucleoprotein-encapsidated genome occurs. Intact intracellular virions were found within ciliated cells in compartments with a single membrane bearing S glycoprotein. Tomography showed concentration of nucleocapsids round the periphery of profiles strongly suggestive of viral budding into these compartments and this may explain how virions gain their S glycoprotein containing envelope.

1994

L76

Swarnakar, Rajesh1,; Garje, Yogesh2; Markandeywar, Neeraj3; Mehta, Suyog3

Exploring the common pathophysiological links between IPF, SSc-ILD and post-COVID fibrosis

https://doi.org/10.4103/lungindia.lungindia_89_22

Published

20-Apr-22

Article

https://journals.lww.com/lungindia/Fulltext/2022/05000/Exploring_the_common_pathophysiological_links.11.aspx

In coronavirus disease 2019 (COVID-19) patients, dysregulated release of matrix metalloproteinases occurs during the inflammatory phase of acute respiratory distress syndrome (ARDS), resulting in epithelial and endothelial injury with excessive fibroproliferation. COVID-19 resembles idiopathic pulmonary fibrosis (IPF) in several aspects. The fibrotic response in IPF is driven primarily by an abnormally activated alveolar epithelial cells (AECs) which release cytokines to activate fibroblasts. Endoplasmic reticulum (ER) stress is postulated to be one of the early triggers in both diseases. Systemic sclerosis (SSc) is a heterogeneous autoimmune rare connective tissue characterised by fibrosis of the skin and internal organs. Interstitial lung disease (ILD) is a common complication and the leading cause of SSc-related death. Several corollaries have been discussed in this paper for new drug development based on the pathogenic events in these three disorders associated with pulmonary fibrosis. A careful consideration of the similarities and differences in the pathogenic events associated with the development of lung fibrosis in post-COVID patients, IPF patients and patients with SSc-ILD may pave the way for precision medicine. Several questions need to be answered through research, which include the potential role of antifibrotics in managing IPF, SSc-ILD and post-COVID fibrosis. Many trials that are underway will ultimately shed light on their potency and place in therapy.

1995

L77

Charles N. S. Allen 1ORCID,Maryline Santerre 1ORCID,Sterling P. Arjona 1,Lea J. Ghaleb 1,Muna Herzi 1,Megan D. Llewellyn 1,Natalia Shcherbik 2 andBassel E. Sawaya 1,3,4,5,*ORCID

SARS-CoV-2 Causes Lung Inflammation through Metabolic Reprogramming and RAGE

https://doi.org/10.3390/v14050983

Published

6-May-22

Study

https://www.mdpi.com/1999-4915/14/5/983/htm

Clinical studies indicate that patients infected with SARS-CoV-2 develop hyperinflammation, which correlates with increased mortality. The SARS-CoV-2/COVID-19-dependent inflammation is thought to occur via increased cytokine production and hyperactivity of RAGE in several cell types, a phenomenon observed for other disorders and diseases. Metabolic reprogramming has been shown to contribute to inflammation and is considered a hallmark of cancer, neurodegenerative diseases, and viral infections. Malfunctioning glycolysis, which normally aims to convert glucose into pyruvate, leads to the accumulation of advanced glycation end products (AGEs). Being aberrantly generated, AGEs then bind to their receptor, RAGE, and activate several pro-inflammatory genes, such as IL-1b and IL-6, thus, increasing hypoxia and inducing senescence. Using the lung epithelial cell (BEAS-2B) line, we demonstrated that SARS-CoV-2 proteins reprogram the cellular metabolism and increase pyruvate kinase muscle isoform 2 (PKM2). This deregulation promotes the accumulation of AGEs and senescence induction. We showed the ability of the PKM2 stabilizer, Tepp-46, to reverse the observed glycolysis changes/alterations and restore this essential metabolic process.

1996

L78

Josalyn L. Cho1,*, Raul Villacreses1,*, Prashant Nagpal2, Junfeng Guo2,3, Alejandro A. Pezzulo1, Andrew L. Thurman1, Nabeel Y. Hamzeh1, Robert J. Blount1, Spyridon Fortis1,4, Eric A. Hoffman1,2,3, Joseph Zabner1, Alejandro P. Comellas1

Quantitative Chest CT Assessment of Small Airways Disease in Post-Acute SARS-CoV-2 Infection

https://doi.org/10.1148/radiol.212170

Published

15-Mar-22

Study

https://pubs.rsna.org/doi/10.1148/radiol.212170

Background
The long-term effects of SARS-CoV-2 infection on pulmonary structure and function remain incompletely characterized.
Purpose
To test whether SARS-CoV-2 infection leads to small airways disease in patients with persistent symptoms.
Materials and Methods
In this single center study at a university teaching hospital, adults with confirmed COVID-19 who remained symptomatic >30 days following diagnosis were prospectively enrolled between June and December 2020 and compared to healthy participants (controls) prospectively enrolled between March and August 2018. Participants with post-acute sequelae of COVID-19 (PASC) were classified as ambulatory, hospitalized, or requiring the intensive care unit (ICU) based on the highest level of care received during acute infection. Symptoms, pulmonary function tests, and chest CT images were collected, and quantitative CT analysis was performed using supervised machine-learning to measure regional ground glass opacities (GGO) and inspiratory and expiratory image-matching to measure regional air trapping. Univariable analyses and multivariable linear regression were used to compare groups.
Results
100 participants with PASC (median age, 48 years; 66 women) were evaluated and compared with 106 matched healthy controls. Sixty-seven percent (67/100) of the participants with PASC were classified as ambulatory, 17% (17/100) wer e hospitalized and 16% (16/100) required care in the ICU. Among the hospitalized and ICU groups, the mean percent of total lung classified as GGO was 13.2% and 28.7%, respectively, and was higher than in the ambulatory group (3.7%, p<.001 for both comparisons). The mean percentage of total lung affected by air trapping was 25.4%, 34.6%, and 27.3% in the ambulatory, hospitalized, and ICU groups and 7.2% in healthy controls (p<.001). Air trapping correlated with the residual volume to total lung capacity rati o (RV/TLC; r=0.6, p<.001).
Conclusions
In survivors of COVID-19, small airways disease occurred independently of initial infection severity. The long-term consequences are unknown.

1997

L79

about L78

McGraw, Mark

A Connection Between Long COVID & Small Airways Disease

https://doi.org/10.1097/01.COT.0000831992.95100.43

Published

20-May-22

Article

https://journals.lww.com/oncology-times/Fulltext/2022/05200/A_Connection_Between_Long_COVID___Small_Airways.18.aspx

The results the study produced are the product of implementing an expiratory CT. “In the absence of this breathing maneuver, we would have missed this finding,” Comellas noted. “At this time, we are unclear if the small airway disease is due to inflammation versus fibrosis of the airway. The former could be reversible, while the latter is not.”
A critical message to emerge from the study is that health care providers “should obtain expiratory CTs in patients who are still symptomatic months later, after initial SARS CoV-2 infection. A normal inspiratory CT, normal lung function, or initial severity of illness are not predictive of whether patients could be suffering from small airways diseases manifested as air trapping,” he said. “In addition, this finding can help in deciding some therapies and referral to pulmonary rehabilitation.”

1998

L80

James T. Grist1,,2,,3,,4, Guilhem J. Collier5, Huw Walters1, Minsuok Kim6, Mitchell Chen1, Gabriele Abu Eid1, Aviana Laws1, Violet Matthews1, Kenneth Jacob1, Susan Cross1, Alexandra Eves1, Marianne Durant1, Anthony Mcintyre1, Roger Thompson7, Rolf F. Schulte8, Betty Raman3, Peter A. Robbins2, Jim M. Wild5, Emily Fraser9, Fergus Gleeson

Lung Abnormalities Depicted with Hyperpolarized Xenon MRI in Patients with Long COVID

https://doi.org/10.1148/radiol.220069

Published

24-May-22

Study

https://pubs.rsna.org/doi/10.1148/radiol.220069

Background
Post-Covid-19 condition describes symptoms following COVID-19 infection after four weeks. Symptoms are wide-ranging but breathlessness is common.
Purpose
The purpose of this study was to determine whether the previously described lung abnormalities on Hp-XeMRI in post-hospitalised COVID-19 participants are also present in non-hospitalised participants with Post-Covid-19 condition.
Methods
In this prospective study, non-hospitalised Post-Covid-19 condition (NHLC) and post-hospitalised COVID-19 (PHC) participants were enrolled from 06/2020 to 08/2021. Participants had chest CT, hyperpolarized pulmonary 129Xenon MRI (Hp-XeMRI), pulmonary function tests, 1-minute sit-to-stand test and breathlessness questionnaires. Control subjects underwent HP-XeMRI only. CT scans were analysed for post COVID interstitial lung disease severity using a previously published scoring system, and Full-scale Airway Network (FAN) modelling. Analysis used group and pair-wise comparisons between participants and controls, and correlations between participant clinical and imaging data.
Results
A total of 11 NHLC (4:7 Male: Female, 44 ± 11 years, [37-50], (mean ± SD, [95% CI]) and 12 PHC (10:2, Male: Female, 58 ± 10 years, [52-64]) participants were included, with a significant difference in age between groups, p = 0.05. NHLC participants were 287 ± 79, [240-334] and PHC 143 ± 72, [105-190] days from infection, respectively. NHLC and PHC participants had normal or near normal CT scans (0.3/25 ± 0.6, [0-0.63] and 7/25 ± 5, [4-10], respectively). Gas transfer (DLCO (%)) was different between NHLC and PHC participants (76 ± 8%, [73-83] vs 86 ± 8%, [80-91] respectively, p = 0.04) but there was no evidence of other differences in lung function. Red Blood Cell:Tissue Plasma (RBC:TP) mean was different between volunteers vs PHC (0.45 ± 0.07, [0.43-0.47] vs (0.31 ± 0.10, [0.24-0.37], respectively, p = 0.02) and volunteers vs NHLC (0.37 ± 0.10, [0.31-0.44], p = 0.03) participants, but not between NHLC and PHC participants (p = 0.26). FAN results did not correlate with DLCO or Hp- XeMRI.
Conclusion
NHLC and PHC subjects showed Hp-XeMRI RBC:TP abnormalities, with NHLC participants demonstrating lower DLCO than PHC participants despite having normal CT scans.

1999

L81

About L80

Grace Parraga , Alexander M. Matheson

Step on the 129Xe Gas: The MRI Race to Uncover Drivers of Post-COVID-19 Symptoms

https://doi.org/10.1148/radiol.221098

Published

24-May-22

Editorial

https://pubs.rsna.org/doi/10.1148/radiol.221098

Previous 129Xe MRI studies focused on ever-hospitalized post-COVID-19 participants which limited our understanding of the post-COVID condition to those with the most severe disease. Alarmingly, here Grist and colleagues reported that both PHC and NHLC participants had significantly lower MRI RBC:barrier ratio compared to healthy volunteers. This important finding tells us that even mild disease can result in persistent symptoms and gas-exchange differences. An exact timepoint at which COVID infection may resolved is still a matter of debate, however here data in never-hospitalized participants was acquired at least six months following infection. It is therefore unlikely that these changes were due to residual infection, and more likely they reflect temporally persistent gas-exchange abnormalities that stem from the pulmonary vasculature or alveolar membrane.
Taken together, these results emphasize the power and sensitivity of pulmonary functional imaging and the fact that gas-exchange abnormalities that stem either from the alveolar membrane or pulmonary vasculature may be important pathophysiological drivers of symptoms in post-COVID-19 patients. Moreover, Grist and colleagues reported MRI gas-exchange findings that were beyond the sensitivity of pulmonary function tests including DLCO and were not flagged as obvious abnormalities in chest CT images either.
The COVID-19 pandemic has provided unprecedented challenges and important opportunities to better understand the natural history of viral lung infection in millions of patients. These hyperpolarized 129Xe MRI findings reveal new valuable clues about lung abnormalities that endure, months post-infection, perhaps putting post-COVID patients back in the driver's seat of their recovery.

2000

L82

Abdelfattah Touman, Mohammed Kahyat, Adeeb Bulkhi, Mutaz Khairo, Wael Alyamani, Ahmad M. Aldobyany, Nabil Ghaleb, Hadeel Ashi, Mohammed Alsobaie, Eid Alqurashi

Post COVID-19 Chronic Parenchymal Lung Changes

https://doi.org/10.7759/cureus.25197

Published

21-May-22

Study

https://www.cureus.com/articles/97696-post-covid-19-chronic-parenchymal-lung-changes

Introduction: Persistent parenchymal lung changes are an important long-term sequela of COVID-19. There are limited data on this COVID-19 infection sequela characteristics and trajectories. This study aims to evaluate persistent COVID-19-related parenchymal lung changes 10 weeks after acute viral pneumonia and to identify associated risk factors.
Methods: This is a retrospective case-control observational study involving 38 COVID-19 confirmed cases using nasopharyngeal swab reverse transcriptase-polymerase chain reaction (RT-PCR) at King Abdullah Medical City (KAMC) Hospital, Makkah. Patients were recruited from the post-COVID-19 interstitial lung disease (ILD) clinic. Referral to this clinic was based on the pulmonology consultant’s assessment of hospitalized patients suspected of developing COVID-19-related ILD changes during hospitalization.
Results: Thirty-eight patients with parenchymal lung changes were evaluated at the ILD clinic. Nineteen patients who had persistent parenchymal changes 10 weeks after the acute illness (group 1) were compared with 19 control patients who had accelerated clinical and/or radiological improvement (group 2). Group 1 was found to have the more severe clinical and radiological disease, with a higher peak value of inflammatory biomarkers. Two risk factors were identified, neutrophil-lymphocyte ratio (NLR) > 3.13 at admission increases the odds ratio (OR) of chronic parenchymal changes by 6.42 and 5.92 in the univariate and multivariate analyses, respectively. Invasive mechanical ventilation had a more profound effect with ORs of 13.09 and 44.5 in the univariate and multivariate analyses, respectively.
Conclusion: Herein, we found that only receiving invasive mechanical ventilation and having NLR >3.13 at admission were strong risk factors for persistent parenchymal lung changes. Neither the clinical severity of the acute illness nor the radiological one is found to predict this outcome. None of the medications received during the acute illness were found to alter the risk for this post-COVID-19 infection sequelae.

2001

L83

Johannes Kersten, Alexander Wolf, Luis Hoyo, Elina Hüll, Marijana Tadic, Stefanie Andreß, Sascha d’Almeida, Dominik Scharnbeck, Eva Roder, Petra Beschoner, Wolfgang Rottbauer & Dominik Buckert

Symptom burden correlates to impairment of diffusion capacity and exercise intolerance in long COVID patients

https://doi.org/10.1038/s41598-022-12839-5

Published

25-May-22

Study

https://www.nature.com/articles/s41598-022-12839-5

After acute infection with the SARS-CoV-2 virus, a considerable number of patients remains symptomatic with pathological changes in various organ systems. This study aimed to relate the physical and mental burden of symptoms of long COVID patients to the findings of a somatic evaluation. In patients with persistent long COVID symptoms three months after acute infection we assessed physical and mental health status using the SF-36 questionnaire. The cohort was dichotomised by the results (upper two quartiles vs. lower to quartiles) and compared with regard to transthoracic echocardiography, body plethysmography (including diffusion capacity), capillary blood gas analysis and 6-min walk test (6-MWT). From February 22 to September 13, 2021, 463 patients were prospectively examined, of which 367 completed the SF-36 questionnaire. A positive correlation between initial disease severity (need for hospitalization, intensive care medicine) and resulting symptom burden at follow-up could be demonstrated. Patients with impaired subjective physical and mental status were significantly more likely to be women. There was a significant correlation between symptom severity and reduced exercise tolerance in the 6-MWT (495.6 ± 83.7 m vs 549.7 ± 71.6 m, p < 0.001) and diffusion capacity for carbon monoxide (85.6 ± 14.3% of target vs 94.5 ± 14.4, p < 0.001). In long COVID patients, initial disease severity is correlated with symptom burden after at least 3 months of follow-up. Highly symptomatic long COVID patients show impaired diffusion capacity and 6-MWT despite average or mildly affected mechanical lung parameters. It must be further differentiated whether this corresponds to a transient functional impairment or whether it is a matter of defined organ damage.

2002

L84

Valentina Ruggiero 1,2,Rita P. Aquino 1,Pasquale Del Gaudio 1ORCID,Pietro Campiglia 1ORCID andPaola Russo 1,*ORCID

Post-COVID Syndrome: The Research Progress in the Treatment of Pulmonary sequelae after COVID-19 Infection

https://doi.org/10.3390/pharmaceutics14061135

Published

26-May-22

Review

https://www.mdpi.com/1999-4923/14/6/1135/htm

Post-COVID syndrome or long COVID is defined as the persistence of symptoms after confirmed SARS-CoV-2 infection, the pathogen responsible for coronavirus disease. The content herein presented reviews the reported long-term consequences and aftereffects of COVID-19 infection and the potential strategies to adopt for their management. Recent studies have shown that severe forms of COVID-19 can progress into acute respiratory distress syndrome (ARDS), a predisposing factor of pulmonary fibrosis that can irreversibly compromise respiratory function. Considering that the most serious complications are observed in the airways, the inhalation delivery of drugs directly to the lungs should be preferred, since it allows to lower the dose and systemic side effects. Although further studies are needed to optimize these techniques, recent studies have also shown the importance of in vitro models to recreate the SARS-CoV-2 infection and study its sequelae. The information reported suggests the necessity to develop new inhalation therapies in order to improve the quality of life of patients who suffer from this condition.

2003

L85

Katherine M. Littlefield,Renée O. Watson,Jennifer M. Schneider,Charles P. Neff,Eiko Yamada,Min Zhang,Thomas B. Campbell,Michael T. Falta,Sarah E. Jolley,Andrew P. Fontenot,Brent E. Palmer

SARS-CoV-2-specific T cells associate with inflammation and reduced lung function in pulmonary post-acute sequalae of SARS-CoV-2

https://doi.org/10.1371/journal.ppat.1010359

Published

26-May-22

Study

https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1010359

As of January 2022, at least 60 million individuals are estimated to develop post-acute sequelae of SARS-CoV-2 (PASC) after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While elevated levels of SARS-CoV-2-specific T cells have been observed in non-specific PASC, little is known about their impact on pulmonary function which is compromised in the majority of these individuals. This study compares frequencies of SARS-CoV-2-specific T cells and inflammatory markers with lung function in participants with pulmonary PASC and resolved COVID-19 (RC). Compared to RC, participants with respiratory PASC had between 6- and 105-fold higher frequencies of IFN-γ- and TNF-α-producing SARS-CoV-2-specific CD4+ and CD8+ T cells in peripheral blood, and elevated levels of plasma CRP and IL-6. Importantly, in PASC participants the frequency of TNF-α-producing SARS-CoV-2-specific CD4+ and CD8+ T cells, which exhibited the highest levels of Ki67 indicating they were activity dividing, correlated positively with plasma IL-6 and negatively with measures of lung function, including forced expiratory volume in one second (FEV1), while increased frequencies of IFN-γ-producing SARS-CoV-2-specific T cells associated with prolonged dyspnea. Statistical analyses stratified by age, number of comorbidities and hospitalization status demonstrated that none of these factors affect differences in the frequency of SARS-CoV-2 T cells and plasma IL-6 levels measured between PASC and RC cohorts. Taken together, these findings demonstrate elevated frequencies of SARS-CoV-2-specific T cells in individuals with pulmonary PASC are associated with increased systemic inflammation and decreased lung function, suggesting that SARS-CoV-2-specific T cells contribute to lingering pulmonary symptoms. These findings also provide mechanistic insight on the pathophysiology of PASC that can inform development of potential treatments to reduce symptom burden.

2004

L86

AlessiaVerduri1JonathanHewitt2BenCarter3RobertoTonelli4EnricoClini1BiancaBeghè1

Prevalence of asthma and COPD in a cohort of patients at the follow up after COVID-19 pneumonia

https://doi.org/10.1016/j.pulmoe.2022.05.005

Published

10-Jun-22

Study

https://www.sciencedirect.com/science/article/pii/S2531043722001271

According to the study purpose, we were able to show interesting findings.
First, data collection helped quantify the proportion of patients with diagnosis of asthma and COPD in a large cohort of people at the follow up after COVID-19 pneumonia. The prevalence of asthmatic patients is in line with that observed in the general population in Italy,10 but it seems larger than previously reported data in a large cohort of COVID-19 patients.11,12 On the other hand, COPD patients in our study cohort are less prevalent than in the general population, 13 which may support a different epidemiology within COVID-19 patients.3 Notwithstanding, the follow-up service provided a new diagnosis of chronic respiratory disease, particularly COPD. This provided patients with an opportunity for an appropriate disease identification and care plan.
Second, a clinically meaningful post-COVID mMRC dyspnea score observed in 41.5% of the COPD patients, who were in mild GOLD grade of severity, confirms the findings of Huang et al in a large population of patients discharged in Wuhan and assessed six months later.14 This emphasises that older age is not the only responsible factor for long-term residual dyspnea in COPD survivors.
Third, the reduction in DLCO (mean 73.6% pred with <80%pred in 57.3% of cases) as a marker of residual lung damage following interstitial pneumonia was similar to that observed in unselected patients treated with respiratory support therapies (HFNC, NIV, intubation),14, 15, 16 even though more frequent in COPD (75.6%) than in patients with asthma in our cohort.
Finally, the great proportion of people with asthma and obesity (43.9%), confirmed that this comorbidity makes asthma difficult to treat17 and may also impact negatively on the patient's perception of good health in individuals recovering from COVID-19.
Considering major limitations (i.e. the single-center analysis and the lack of pre-to-post comparison of pulmonary function test in patients with existing diagnosis of asthma and COPD), the study results are informative. Indeed, the patients with asthma and COPD is a representative real-word disease-group, and the follow up assessment can be useful for unknown diagnoses of chronic respiratory disease. Therefore, the findings highlight the importance of a tight respiratory follow-up assessment in individuals recovering from COVID-19 pneumonia who should be investigated for long-term symptoms including dyspnea, especially those underdiagnosed for having asthma or COPD.

2005

L87

Marco Chilosi 1,Claudio Doglioni 2ORCID,Claudia Ravaglia 3,*,Guido Martignoni 1,4,Gian Luca Salvagno 5,6,Giovanni Pizzolo 7,Vincenzo Bronte 8 andVenerino Poletti 3,9

Unbalanced IDO1/IDO2 Endothelial Expression and Skewed Keynurenine Pathway in the Pathogenesis of COVID-19 and Post-COVID-19 Pneumonia

https://doi.org/10.3390/biomedicines10061332

Published

6-Jun-22

Review

https://www.mdpi.com/2227-9059/10/6/1332/htm

Despite intense investigation, the pathogenesis of COVID-19 and the newly defined long COVID-19 syndrome are not fully understood. Increasing evidence has been provided of metabolic alterations characterizing this group of disorders, with particular relevance of an activated tryptophan/kynurenine pathway as described in this review. Recent histological studies have documented that, in COVID-19 patients, indoleamine 2,3-dioxygenase (IDO) enzymes are differentially expressed in the pulmonary blood vessels, i.e., IDO1 prevails in early/mild pneumonia and in lung tissues from patients suffering from long COVID-19, whereas IDO2 is predominant in severe/fatal cases. We hypothesize that IDO1 is necessary for a correct control of the vascular tone of pulmonary vessels, and its deficiency in COVID-19 might be related to the syndrome’s evolution toward vascular dysfunction. The complexity of this scenario is discussed in light of possible therapeutic manipulations of the tryptophan/kynurenine pathway in COVID-19 and post-acute COVID-19 syndromes.
The complex involvement of the TKP activation in the diverse presentations of COVID-19 and PACS poses relevant issues when the possible manipulation of this pathway is considered as a therapeutic option [117]. The complex roles (protective versus harmful) of endothelial TKP activation in different physiological systems and tissues need to be carefully considered in therapeutic planning in different clinical contexts. In COVID-19, the TKP activation may be considered harmful in increasing the systemic concentration of kynurenines and toxic Trp-metabolites, potentially interfering with immune and neurological functions, as previously described. Nevertheless, the endothelial IDO1 expression likely exerts significant protection against vascular dysfunction in the lung, and under this context the inhibition of IDO1 does not appear to be safe, which means that alternative interventions are needed to correct metabolic abnormalities. The correct balance of Trp-metabolites is relevant for maintaining healthful functions, and specific approaches should be selected for treating different COVID-19 clinical presentations. This can be particularly true in PACS, where mild “supportive” therapeutic interventions may ameliorate symptoms and shorten the disease course.
Trp supplementation, either dietary or non-nutritional, has been experimentally investigated and proposed to ameliorate neurological disturbances and social behavior in humans by increasing 5-HT production, but its clinical effect is still controversial and prone to genetic variations [257,258,259,260,261,262,263,264,265]. In addition, potential side effects of excessive Trp intake should be evaluated in different clinical settings [266]. Deranged activation of the TKP is common in COVID-19, and Trp supplementation may potentially increase the systemic concentration of harmful Trp metabolites [267].
Melatonin supplementation. Divergence from the serotonin pathway of Trp metabolism induces a defective production of melatonin in COVID-19 patients, and this decrease has prognostic significance [268]. This deficiency may be either indirectly related to the over-activation of the TKP (eventually leading to lower available 5-HT), to the well-documented anti-oxidant and anti-inflammatory roles of melatonin, or both [134,269,270,271,272]. A possible role in protecting pulmonary endothelial cells can be also hypothesized, as observed in pre-eclampsia [273]. Several authors have proposed melatonin as a useful therapeutic tool in contrasting neurological complications and super-infections for both COVID-19 and PACS patients [274,275,276,277,278], and a significant vantage in mortality and recovery rate has been observed in severe cases [279,280,281]. Validation of the therapeutic role of melatonin and its metabolites in COVID-19 and PACS is needed, and clinical trials and the use of reliable animal models are warranted [282,283,284,285,286,287].
IDO inhibitors. The relevant pathogenic and prognostic roles of the different Trp-metabolites in COVID-19 suggest the possible use of specific inhibitors to modulate the enzymes that regulate the TKP [117,288,289]. IDOs and TDO are involved in tumor immunosurveillance and the potential use of inhibitors of these enzymes to restore antitumor immunity is a matter of intense clinical investigation [96,290,291]. Different specific inhibitors are in fact available, and clinical trials are ongoing on a variety of human neoplastic and non-neoplastic diseases [292,293,294,295]. If the pathogenic shift from early/mild to severe COVID-19 pneumonias is in part determined by the modulation of IDO1 and IDO2 expression in the pulmonary microenvironment as here hypothesized, the availability and selective use of specific IDO1 or IDO2 inhibitors might be crucial. A range of selective and potent TDO, IDO1, and IDO2 inhibitors are currently under investigation in cancer research and information from this field may be translationally utilized for new personalized therapies for patients suffering from COVID-19 and PACS [52,86,296,297,298,299].
The inhibition of AHR is feasible, and this approach might be safer in severe cases [300].

2006

L88

Mickael Rejaudry Lacavalerie, Sandrine Pierre-Francois, Moustapha Agossou, Jocelyn Inamo, André Cabie, José Luis Barnay & Rémi Neviere

Obese patients with long COVID-19 display abnormal hyperventilatory response and impaired gas exchange at peak exercise

https://doi.org/10.2217/fca-2022-0017

Published

6-Jun-22

Study

https://www.futuremedicine.com/doi/full/10.2217/fca-2022-0017

Aim: To analyze the impact of obesity on cardiopulmonary response to exercise in people with chronic post-coronavirus disease 2019 (COVID-19) syndrome. Patients & methods: Consecutive subjects with chronic post-COVID syndrome 6 months after nonsevere acute infection were included. All patients received a complete clinical evaluation, lung function tests and cardiopulmonary exercise testing. A total of 51 consecutive patients diagnosed with chronic post-COVID-19 were enrolled in this study. Results: More than half of patients with chronic post-COVID-19 had a significant alteration in aerobic exercise capacity (VO2peak) 6 months after hospital discharge. Obese long-COVID-19 patients also displayed a marked reduction of oxygen pulse (O2pulse). Conclusion: Obese patients were more prone to have pathological pulmonary limitation and pulmonary gas exchange impairment to exercise compared with nonobese COVID-19 patients.

2007

L89

Maria T. Tsakok1,*,+ , Robert A. Watson1,2,3,*, Shyamal J. Saujani1, Mark Kong1, Cheng Xie1, Heiko Peschl1, Louise Wing1, Fiona K. MacLeod1, Brian Shine1, Nick P. Talbot1,5, Rachel E. Benamore1, David W. Eyre1,4,**, Fergus Gleeson1

Chest CT and Hospital Outcomes in Patients with Omicron Compared with Delta Variant SARS-CoV-2 Infection

https://doi.org/10.1148/radiol.220533

Published

21-Jun-22

Study

https://pubs.rsna.org/doi/full/10.1148/radiol.220533

Background
The SARS-Cov-2 Omicron variant demonstrates rapid spread but with reduced disease severity. Studies evaluating the lung imaging findings of Omicron infection versus non-Omicron variants remain lacking.
Purpose
To compare Omicron and Delta variants of SARS-CoV-2 by their chest CT radiological pattern, biochemical parameters, clinical severity and hospital outcomes after adjusting for vaccination status.
Materials and Methods
Retrospective study of hospitalized adult patients rt-PCR positive for SARS-CoV-2 with CT pulmonary angiography performed within 7 days of admission between December 1, 2021 and January 14, 2022. Blinded radiological analysis with multiple readers including RSNA CT classification, chest CT severity score (CT-SS, range 0 least severe to 25 most severe) and CT imaging features including bronchial wall thickening.
Results
106 patients (Delta n=66, Omicron n=40) were evaluated (mean age, 58 years ± 18, 58 men). In the Omicron group, 37% (15/40) of CT pulmonary angiograms were categorized as normal compared with 15% (10/66) in the Delta group (p=.016). Using a generalized linear model to control for confounding variables, including vaccination status, Omicron variant infection was associated with a CT-SS that was lower by 7.2 points compared to infection with Delta variant (β=-7.2, 95%CI: -9.9, -4.5; p <.001). Bronchial wall thickening was more common with Omicron than with the Delta variant (odds ratio [OR] 2.4, 95%CI: 1.01, 5.92, p=.04). Vaccination with a booster shot was associated with a protective effect on chest infection compared with the unvaccinated (CT-SS median 5 (IQR 0-11), CT-SS median 11 (IQR 7.5-14), respectively; p = .03). The Delta variant was associated with a higher odds ratio of severe disease (OR 4.6, 95%CI: 1.2, 26, p=.01) and critical care admission (OR 7.0, 95%CI: 1.5, 66, p=.004) than the Omicron variant.
Conclusion
The SARS-COV-2 Omicron variant was associated with fewer and less severe changes on chest CT compared with the Delta variant. Patients with Omicron had greater frequency of bronchial wall thickening but lower clinical severity and improved hospital outcomes than those with Delta.
Summary
SARS-CoV-2 Omicron variant chest infections are radiologically and clinically less severe than Delta variant infections and are associated with improved hospital outcomes.
Key Results
■ In 106 hospitalized adult patients with Omicron (n=40) and Delta variants (n=66) of SARSCoV-2, patients with Omicron had lower median chest CT severity scores (CT-SS) (median, 3.5) compared with Delta (median, 11.8) (p<.001).
■ Patients who had received a vaccine booster dose had lower median CT-SS (median, 5) than the unvaccinated patients (median, 11) (p=.03).
■ Bronchial wall thickening was more common with Omicron than Delta SARS-CoV-2 (odds ratio [OR] 2.4, p=.04).

2008

L90

Aurelien Justet, Amy Y. Zhao & Naftali Kaminski

From COVID to fibrosis: lessons from single-cell analyses of the human lung

https://doi.org/10.1186/s40246-022-00393-0

Published

13-Jun-22

Review

https://humgenomics.biomedcentral.com/articles/10.1186/s40246-022-00393-0

The increased resolution of single-cell RNA-sequencing technologies has led to major breakthroughs and improved our understanding of the normal and pathologic conditions of multiple tissues and organs. In the study of parenchymal lung disease, single-cell RNA-sequencing has better delineated known cell populations and identified novel cells and changes in cellular phenotypes and gene expression patterns associated with disease. In this review, we aim to highlight the advances and insights that have been made possible by applying these technologies to two seemingly very different lung diseases: fibrotic interstitial lung diseases, a group of relentlessly progressive lung diseases leading to pulmonary fibrosis, and COVID-19 pneumonia, an acute viral disease with life-threatening complications, including pulmonary fibrosis. We discuss changes in cell populations and gene expression, highlighting potential common features, such as alveolar cell epithelial injury and aberrant repair and monocyte-derived macrophage populations, as well as relevance and implications to mechanisms of disease and future directions.

2009

L91

Thomas Sonnweber 1,*ORCID,Philipp Grubwieser 1ORCID,Sabina Sahanic 1,Anna Katharina Böhm 1,Alex Pizzini 1,Anna Luger 2ORCID,Christoph Schwabl 2ORCID,Sabine Koppelstätter 1,Katharina Kurz 1,Bernhard Puchner 1,Barbara Sperner-Unterweger 3ORCID,Katharina Hüfner 3ORCID,Ewald Wöll 4,Manfred Nairz 1,Gerlig Widmann 2,Ivan Tancevski 1,Judith Löffler-Ragg 1 andGünter Weiss 1,5,*ORCID

The Impact of Iron Dyshomeostasis and Anaemia on Long-Term Pulmonary Recovery and Persisting Symptom Burden after COVID-19: A Prospective Observational Cohort Study

https://doi.org/10.3390/metabo12060546

Published

14-Jun-22

Study

https://www.mdpi.com/2218-1989/12/6/546/htm

Coronavirus disease 2019 (COVID-19) is frequently associated with iron dyshomeostasis. The latter is related to acute disease severity and COVID-19 convalescence. We herein describe iron dyshomeostasis at COVID-19 follow-up and its association with long-term pulmonary and symptomatic recovery. The prospective, multicentre, observational cohort study “Development of Interstitial Lung Disease (ILD) in Patients With Severe SARS-CoV-2 Infection (CovILD)” encompasses serial extensive clinical, laboratory, functional and imaging evaluations at 60, 100, 180 and 360 days after COVID-19 onset. We included 108 individuals with mild-to-critical acute COVID-19, whereas 75% presented with severe acute disease. At 60 days post-COVID-19 follow-up, hyperferritinaemia (35% of patients), iron deficiency (24% of the cohort) and anaemia (9% of the patients) were frequently found. Anaemia of inflammation (AI) was the predominant feature at early post-acute follow-up, whereas the anaemia phenotype shifted towards iron deficiency anaemia (IDA) and combinations of IDA and AI until the 360 days follow-up. The prevalence of anaemia significantly decreased over time, but iron dyshomeostasis remained a frequent finding throughout the study. Neither iron dyshomeostasis nor anaemia were related to persisting structural lung impairment, but both were associated with impaired stress resilience at long-term COVID-19 follow-up. To conclude, iron dyshomeostasis and anaemia are frequent findings after COVID-19 and may contribute to its long-term symptomatic outcome.

2010

L92

Chiara Gattoni,Emanuele Conti,Andrea Casolo,Stefano Nuccio,Carmine Baglieri,Carlo Capelli,Michele Girardi

COVID-19 disease in professional football players: symptoms and impact on pulmonary function and metabolic power during matches

https://doi.org/10.14814/phy2.15337

Published

14-Jun-22

Study

https://physoc.onlinelibrary.wiley.com/doi/10.14814/phy2.15337

This study aimed at: (1) Reporting COVID-19 symptoms and duration in professional football players; (2) comparing players’ pulmonary function before and after COVID-19; (3) comparing players’ metabolic power (Pmet) before and after COVID-19. Thirteen male players (Age: 23.9 ± 4.0 years, V̇O2peak: 49.7 ± 4.0 mL/kg/min) underwent a medical screening and performed a running incremental step test and a spirometry test after COVID-19. Spirometric data were compared with the ones collected at the beginning of the same season. Players’ mean Pmet of the 10 matches played before COVID-19 was compared with mean Pmet of the 10 matches played after COVID-19. Players completed a questionnaire on COVID-19 symptoms and duration 6 months following the disease. COVID-19 positivity lasted on average 15 ± 5 days. “General fatigue” and “muscle fatigue” symptoms were reported by all players during COVID-19 and persisted for 77% (general fatigue) and 54% (muscle fatigue) of the players for 37 ± 28 and 38 ± 29 days after the disease, respectively. No significant changes in spirometric measurements were found after COVID-19, even though some impairments at the individual level were observed. Conversely, a linear mixed-effects model analysis showed a significant reduction of Pmet (−4.1 ± 3.5%) following COVID-19 (t = −2.686, p < 0.05). “General fatigue” and “muscle fatigue” symptoms may persist for several weeks following COVID-19 in professional football players and should be considered for a safer return to sport. Players’ capacity to compete at high intensities might be compromised after COVID-19.

2011

L93

Mary M. Salvatore
Kathleen M. Capaccione
Anjali Saqi
Jonathan B. Overdevest
Rebecca Patrizio
David A. Gudis

Characteristic patterns of SARS-CoV-2 on chest CT suggests a hematologic pathway for viral entry into the lung

https://doi.org/10.1016/j.clinimag.2022.06.011

Published

25-Jun-22

Editorial

https://www.clinicalimaging.org/article/S0899-7071(22)00167-X/fulltext

Highlights
•Imaging supports that the pulmonary capillaries may be important for transmission of the virus and/or inflammatory mediators to the lung epithelium.
•SARS-CoV-2 is about 0.1 microns, however, respiratory droplets are generally 5 microns. The nose would be highly effective at retaining respiratory droplets containing the virus.
•spread of virus from endothelium to epithelium explains the vulnerability of those with endothelial instability to worse outcomes and supports stabilizing the vascular endothelium.
Abstract
Many SARS-CoV-2 studies have supported the theory that the Type II alveolar epithelial cells (AEC-2) are the primary portal of entry of the virus into the lung following its brief nasal occupation. However, the theory of inhalational transmission of the virus from the ciliated and goblet nasal cells to the lung parenchyma is not supported by the imaging findings on chest computerized tomography (CT), leading the authors to consider an alternative pathway from the nose to the lung parenchyma that could explain the peripheral, basilar predominant pattern of early disease. Imaging supports that the pulmonary capillaries may be an important vehicle for transmission of the virus and/or associated inflammatory mediators to the lung epithelium.

2012

L94

Harkiran K Kooner1,2, Marrissa J McIntosh1,2, Alexander M Matheson1,2, Carmen Venegas3,4, Nisarg Radadia4, Terence Ho3,4, Ehsan Ahmed Haider5, Norman B Konyer6, Giles E Santyr7,8, Mitchell S Albert9,10, http://orcid.org/0000-0002-0920-2528Alexei Ouriadov11, Mohamed Abdelrazek12, Miranda Kirby13, Inderdeep Dhaliwal14, http://orcid.org/0000-0003-1560-7967J Michael Nicholson14, Parameswaran Nair3,4, Sarah Svenningsen3,4 and http://orcid.org/0000-0002-5619-4145Grace Parraga

129Xe MRI ventilation defects in ever-hospitalised and never-hospitalised people with post-acute COVID-19 syndrome

http://dx.doi.org/10.1136/bmjresp-2022-001235

Published

18-May-22

Study

https://bmjopenrespres.bmj.com/content/9/1/e001235

Background Patients often report persistent symptoms beyond the acute infectious phase of COVID-19. Hyperpolarised 129Xe MRI provides a way to directly measure airway functional abnormalities; the clinical relevance of 129Xe MRI ventilation defects in ever-hospitalised and never-hospitalised patients who had COVID-19 has not been ascertained. It remains unclear if persistent symptoms beyond the infectious phase are related to small airways disease and ventilation heterogeneity. Hence, we measured 129Xe MRI ventilation defects, pulmonary function and symptoms in ever-hospitalised and never-hospitalised patients who had COVID-19 with persistent symptoms consistent with post-acute COVID-19 syndrome (PACS).
Methods Consenting participants with a confirmed diagnosis of PACS completed 129Xe MRI, CT, spirometry, multi-breath inert-gas washout, 6-minute walk test, St. George’s Respiratory Questionnaire (SGRQ), modified Medical Research Council (mMRC) dyspnoea scale, modified Borg scale and International Physical Activity Questionnaire. Consenting ever-COVID volunteers completed 129Xe MRI and pulmonary function tests only.
Results Seventy-six post-COVID and nine never-COVID participants were evaluated. Ventilation defect per cent (VDP) was abnormal and significantly greater in ever-COVID as compared with never-COVID participants (p<0.001) and significantly greater in ever-hospitalised compared with never-hospitalised participants who had COVID-19 (p=0.048), in whom diffusing capacity of the lung for carbon-monoxide (p=0.009) and 6-minute walk distance (6MWD) (p=0.005) were also significantly different. 129Xe MRI VDP was also related to the 6MWD (p=0.02) and post-exertional SpO2 (p=0.002). Participants with abnormal VDP (≥4.3%) had significantly worse 6MWD (p=0.003) and post-exertional SpO2 (p=0.03).
Conclusion 129Xe MRI VDP was significantly worse in ever-hospitalised as compared with never-hospitalised participants and was related to 6MWD and exertional SpO2 but not SGRQ or mMRC scores.

2013

L95

Hannah Hylton, Alex Long, Charlotte Francis, Rebecca R Taylor, William M Ricketts, Richa Singh and Paul E Pfeffer

Real-world use of the Breathing Pattern Assessment Tool in assessment of breathlessness post-COVID-19

https://doi.org/10.7861/clinmed.2021-0759

Published

27-Jun-22

Study

https://www.rcpjournals.org/content/clinmedicine/early/2022/06/22/clinmed.2021-0759

Introduction Breathing pattern disorders (BPDs) are a common cause of chronic breathlessness, including after acute respiratory illnesses such as COVID pneumonia. BPD is however underdiagnosed, partly as a result of difficulty in clinically assessing breathing pattern. The Breathing Pattern Assessment Tool (BPAT) has been validated for use in diagnosing BPD in patients with asthma but to date has not been validated in other diseases.
Methods Patients undergoing face-to-face review in a post-COVID clinic were assessed by a respiratory physician and specialist respiratory physiotherapist. Assessment included a Dyspnoea-12 (D12) questionnaire to assess breathlessness, physiotherapist assessment of breathing pattern including manual assessment of respiratory motion, and BPAT assessment. The sensitivity and specificity of BPAT for diagnosis of BPD in post-COVID patients was assessed.
Results BPAT had a sensitivity of 89.5% and specificity of 78.3% for diagnosing BPD in post-COVID breathlessness. Patients with a BPAT score above the diagnostic cut-off had higher levels of breathlessness than those with lower BPAT scores (D12 score mean average 19.4 vs 13.2).
Conclusion BPAT has high sensitivity and moderate specificity for BPD in patients with long COVID. This would support its use as a screening test in clinic, and as a diagnostic tool for large cohort studies.

2014

L96

Alexander M. Matheson1,2, Marrissa J. McIntosh1,2, Harkiran K. Kooner1,2, Justin Lee3, Vedanth Desaigoudar1,2, Elianna Bier4, Bastiaan Driehuys4, Sarah Svenningsen5, Giles E. Santyr6,7, Miranda Kirby8, Mitchell S. Albert9,10,11, Yurii Shepelytskyi9,10, Vira Grynko9,10, Alexei Ouriadov12, Mohamed Abdelrazek13, Inderdeep Dhaliwal14, J. Michael Nicholson14, Grace Parraga1,2,3,13,14 See fewer authors

Persistent 129Xe MRI Pulmonary and CT Vascular Abnormalities in Symptomatic Individuals with Post-Acute COVID-19 Syndrome

https://doi.org/10.1148/radiol.220492

Published

28-Jun-22

Study

https://pubs.rsna.org/doi/full/10.1148/radiol.220492

Background
In patients with post-acute COVID-19-syndrome (PACS), abnormal gas-transfer and pulmonary vascular density have been reported, but such findings have not been related to each other, or to symptoms and exercise limitation. The pathophysiological drivers of PACS in ever- and never-hospitalized patients are not well-understood.
Purpose
To determine the relationship of persistent symptoms and exercise limitation with 129Xe MRI and CT pulmonary vascular measurements in individuals with PACS.
Materials and Methods
In this prospective study, patients with PACS aged 18-80 years with a positive PCR COVID test were recruited from a quaternary-care COVID-19 clinic between April and October 2021. Participants with PACS underwent spirometry, diffusing-capacity-of-the-lung- for-carbon-monoxide (DLCO), 129Xe MRI, and chest CT. Healthy controls had no prior history of COVID-19 underwent spirometry, DLCO, and 129Xe MRI. The 129Xe MRI red-blood-cell (RBC) to alveolar-barrier signal ratio, RBC area-under-the-curve (AUC), CT volume-of-pulmonary-vessels with cross-sectional-area <5mm2 (BV5), and total-blood-volume (TBV) were quantified. St. George's Respiratory Questionnaire (SGRQ), International Physical Activity Questionnaire (IPAQ) and modified Borg Dyspnea Scale (mBDS) measured quality-of-life, exercise limitation and dyspnea. Differences between groups were compared using Welch's T-tests or Welch's ANOVA. Relationships were evaluated using Pearson (r) and Spearman (ρ) correlations.
Results
Forty participants were evaluated including six controls (mean age, 35±15 years[standard deviation], 3 women) and 34 participants with PACS (mean age, 53±13 years[SD], 18 women), of which 22 were never-hospitalized. The 129Xe MRI RBC:barrier ratio was lower in ever- hospitalized participants (P=.04) compared to controls. BV5 correlated with RBC AUC (ρ=.44,P=.03). The 129Xe MRI RBC:barrier ratio was related to DLCO (r=.57,P=.002) and FEV1 (ρ=.35,P=.03); RBC AUC was related to dyspnea (ρ=-.35,P=.04) and IPAQ score (ρ=.45,P=.02).
Conclusion
129Xe MRI measurements were lower in ever- hospitalized participants with post- acute COVID-19-syndrome, 34±25 weeks post-infection compared to controls. 129Xe MRI measures were associated with CT pulmonary vascular density, DLCO, exercise capacity, and dyspnea.

2015

L97

Pınar YıldızGülhanAssoc. Prof1Peri MeramArbakProf. Dr.1Ali NihatAnnakkayaProf. Dr1Ege GüleçBalbayProf. Dr.1Öner AbidinBalbayProf. Dr.1

An assessment of post-COVID-19 infection pulmonary functions in healthcare professionals

https://doi.org/10.1016/j.ajic.2022.07.003

Published

20-Jul-22

Study

https://www.sciencedirect.com/science/article/pii/S019665532200534X

Highlights
•The medium- and long-term effects of COVID-19 infection on pulmonary function are still unknown.
•The COVID-19 pandemic adversely affected healthcare professionals, inflicting a heavy burden on the healthcare systems of countries.
•Healthcare professionals with persistent complaints who contracted COVID-19 and returned to work using pulmonary function tests, the 6-minute walk test (6MWT), and the diffusing capacity of the lungs for carbon monoxide (DLCO) test.
Abstract
Introduction and Purpose
The medium- and long-term effects of COVID-19 infection on pulmonary function are still unknown. The present study aimed to investigate the pulmonary functions in healthcare professionals who had persistent complaints after contracting COVID-19 and returning to work.
Methods
The study included COVID-19-infected healthcare professionals from the Düzce University Medical Faculty Hospital who volunteered to participate. Medical histories, medical records, pulmonary function tests, the diffusing capacity of the lungs for carbon monoxide (DLCO) test, and the 6-minute walk test (6MWT) were used to collect data from all participants.
Results
The study included 53 healthcare professionals, with an average age of 38 ± 10 years (min: 24 years and max: 71 years), including 29 female (54.7%) and 24 male (45.3%) participants. Of the participants, 22.6% were smokers, 35.8% (19 individuals) had comorbidities, and 17% (9 individuals) were hospitalized. The mean length of stay was 9 ± 4 days (mean ± standard deviation). The most prevalent symptoms were weakness (88.7%), muscle aches (67.9%), inability to smell/taste (60.4%), headache (54.7%), fever (45.3%), cough (41.5%), and shortness of breath (37.7%). The mean time to return to work after a positive polymerase chain reaction (PCR) test for COVID-19 was 18 ± 13 days. The average time among post-disease pulmonary function, 6MW, and DLCO tests was 89 ± 36 days (min: 15 and max: 205). The DLCO level decreased in 39.6% (21) of the participants. Female participants had a significantly higher rate of decreased DLCO levels than male participants (25% vs. 55.2%, p = 0.026). DLCO levels were significantly higher in participants with long-term persistent complaints (p = 0.043). The later the time to return to work, the lower the DLCO value (r = −0.290 and p = 0.035). The 6MWT distance was positively correlated with hemoglobin and lymphocyte levels at the time of the disease onset and negatively correlated with D-dimer levels. The most prevalent symptoms during the control visits were shortness of breath/effort dyspnea (24.6%), weakness (9.5%), and muscle aches (7.6%).
Conclusion
Significant persistent complaints (47.2%) and low DLCO levels (39.6%) were observed in healthcare professionals during control visits at a mean time of 3 months after the COVID-19 infection. Symptoms and spirometry measurements, including DLCO, may be helpful in the follow-up of healthcare professionals who contracted COVID-19. Further comprehensive studies with long-term follow-up periods are required.

2016

L98

Koulla Parpa & Marcos Michaelides

Aerobic capacity of professional soccer players before and after COVID-19 infection

https://doi.org/10.1038/s41598-022-16031-7

Published

13-Jul-22

Study

https://www.nature.com/articles/s41598-022-16031-7

This investigation aimed to assess the aerobic capacity of professional soccer players pre-and post-COVID-19 infection. Twenty-one division-1 elite soccer players (age 24.24 ± 5.75 years, height 178.21 ± 5.44 cm, weight 74.12 ± 5.21 kg) participated in this study. This observational study compared the same players' aerobic capacity pre-, and 60-days post COVID-19 recovery. The statistical analysis demonstrated that the infected players had significantly lower VO2max values [t(20) = 5.17, p < 0.01, d = 0.613 (medium effect)], and significantly lower VO2 values at respiratory compensation point (RC) [t(20) = 2.97, p < 0.05, d = 0.39 (small effect)] after recovery. Furthermore, results indicated a significantly lower running time (RT) on the treadmill [t(20) = 4.84, p < 0.01, d = 0.46 (small effect)] when compared to the results that were obtained before they got infected. In addition, velocity at VO2max (VVO2max) was significantly lower [t(20) = 2.34, p < 0.05, d = 0.41 (small effect)] and the heart rate values at ventilatory threshold (VT) [t(20) = −2.79, p < 0.01, d = 0.55 (medium effect)] and RC [t(20) = −3.72, p < 0.01, d = 0.52 (medium effect)] were significantly higher post-recovery. The aforementioned findings indicate that post COVID-19 soccer players may not reach full recovery at two months. Therefore, our results highlight that further adaptations and improvements are needed with regard to aerobic capacity before soccer players return to professional games.

2017

L99

Kenneth H Dinnon 3rd # 1, Sarah R Leist # 2, Kenichi Okuda # 3, Hong Dang # 3, Ethan J Fritch # 1, Kendra L Gully 2, Gabriela De la Cruz 4, Mia D Evangelista 4, Takanori Asakura 3, Rodney C Gilmore 3, Padraig Hawkins 3, Satoko Nakano 3, Ande West 2, Alexandra Schäfer 2, Lisa E Gralinski 2, Jamie L Everman 5, Satria P Sajuthi 5, Mark R Zweigart 2, Stephanie Dong 2, Jennifer McBride 2, Michelle R Cooley 2, Jesse B Hines 6, Miriya K Love 3, Steve D Groshong 7, Alison VanSchoiack 8, Stefan J Phelan 8, Yan Liang 8, Tyler Hether 8, Michael Leon 8, Ross E Zumwalt 9, Lisa M Barton 10, Eric J Duval 10, Sanjay Mukhopadhyay 11, Edana Stroberg 10, Alain Borczuk 12, Leigh B Thorne 13, Muthu K Sakthivel 14, Yueh Z Lee 14 15, James S Hagood 3 16, Jason R Mock 3 17, Max A Seibold 5 18 19, Wanda K O'Neal # 3, Stephanie A Montgomery # 4 13, Richard C Boucher # 3, Ralph S Baric # 1 2 20

SARS-CoV-2 infection produces chronic pulmonary epithelial and immune cell dysfunction with fibrosis in mice

https://doi.org/10.1126/scitranslmed.abo5070

Published

7-Jul-22

Study

https://www.science.org/doi/10.1126/scitranslmed.abo5070

A subset of individuals who recover from coronavirus disease 2019 (COVID-19) develop post-acute sequelae of SARS-CoV-2 (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal tissue samples. The mouse-adapted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain MA10 produces an acute respiratory distress syndrome (ARDS) in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute to clinical recovery phases. At 15 to 120 days post-virus clearance, pulmonary histologic findings included subpleural lesions composed of collagen, proliferative fibroblasts, and chronic inflammation, including tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal up-regulation of pro-fibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early anti-fibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC.

2018

L100

Peter Ladlow, Oliver O’Sullivan, Alexander N. Bennett, Robert Barker-Davies, Andrew Houston, Rebecca Chamley, Samantha May, Daniel Mills, Dominic Dewson, Kasha Rogers-Smith, Christopher Ward, John Taylor, Joseph Mulae, Jon Naylor, Edward D. Nicol, and David A. Holdsworth

The effect of medium-term recovery status after COVID-19 illness on cardiopulmonary exercise capacity in a physically active adult population

https://doi.org/10.1152/japplphysiol.00138.2022

Published

9-Jun-22

Study

https://journals.physiology.org/doi/full/10.1152/japplphysiol.00138.2022

A failure to fully recover following coronavirus disease 2019 (COVID-19) may have a profound impact on high-functioning populations ranging from frontline emergency services to professional or amateur/recreational athletes. The aim of the study is to describe the medium-term cardiopulmonary exercise profiles of individuals with “persistent symptoms” and individuals who feel “recovered” after hospitalization or mild-moderate community infection following COVID-19 to an age, sex, and job-role matched control group. A total of 113 participants underwent cardiopulmonary functional tests at a mean of 159 ± 7 days (∼5 mo) following acute illness; 27 hospitalized with persistent symptoms (hospitalized-symptomatic), 8 hospitalized and now recovered (hospitalized-recovered); 34 community managed with persistent symptoms (community-symptomatic); 18 community managed and now recovered (community-recovered); and 26 controls. Hospitalized groups had the least favorable body composition (body mass, body mass index, and waist circumference) compared with controls. Hospitalized-symptomatic and community-symptomatic individuals had a lower oxygen uptake (V̇o2) at peak exercise (hospitalized-symptomatic, 29.9 ± 5.0 mL/kg/min; community-symptomatic, 34.4 ± 7.2 mL/kg/min; vs. control 43.9 ± 3.1 mL/kg/min, both P < 0.001). Hospitalized-symptomatic individuals had a steeper V̇e/V̇co2 slope (lower ventilatory efficiency) (30.5 ± 5.3 vs. 25.5 ± 2.6, P = 0.003) versus. controls. Hospitalized-recovered had a significantly lower oxygen uptake at peak (32.6 ± 6.6 mL/kg/min vs. 43.9 ± 13.1 mL/kg/min, P = 0.015) compared with controls. No significant differences were reported between community-recovered individuals and controls in any cardiopulmonary parameter. In conclusion, medium-term findings suggest that community-recovered individuals did not differ in cardiopulmonary fitness from physically active healthy controls. This suggests their readiness to return to higher levels of physical activity. However, the hospitalized-recovered group and both groups with persistent symptoms had enduring functional limitations, warranting further monitoring, rehabilitation, and recovery.

2019

L101

Jimmy Yu,Tobias Granberg,Roya Shams,Sven Petersson,Magnus Sköld,Sven Nyrén,Johan Lundberg

Lung perfusion disturbances in non-hospitalized post-COVID with dyspnea – An MRI feasibility study

https://doi.org/10.1111/joim.13558

Published

10-Aug-22

Study

https://onlinelibrary.wiley.com/doi/abs/10.1111/joim.13558

Background
Dyspnea is common after COVID-19. Though the underlying mechanisms are largely unknown, lung perfusion abnormalities could contribute to lingering dyspnea.
Objectives
To detect pulmonary perfusion disturbances in non-hospitalized individuals with post-COVID condition and persistent dyspnea 4–13 months after the disease onset.
Methods
Individuals with dyspnea and matched healthy controls were recruited for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), a six-minute walk test, and an assessment of dyspnea. The DCE-MRI was quantified using two parametric values: mean time-to-peak (TTP) and TTP ratio, reflecting the total lung perfusion resistance and the fraction of lung with delayed perfusion, respectively.
Results
Twenty-eight persons with persistent dyspnea (mean age 46.5±8.0 years, 75% women) and 22 controls (mean age 44.1±10.8 years, 73% women) were included. There was no systematic sex difference in dyspnea. The post-COVID group had no focal perfusion deficits but had higher mean pulmonary TTP (0.43±0.04 vs. 0.41±0.03, P = 0.011) and TTP ratio (0.096±0.052 vs. 0.068±0.027, P = 0.032). Post-COVID males had the highest mean TTP 0.47±0.02 and TTP ratio of 0.160±0.039; compared to male controls and post-COVID females (P = 0.001 and P<0.001 respectively). Correlations between dyspnea and perfusion parameters were demonstrated in males (r = 0.83, P<0.001 for mean TTP; r = 0.76, P = 0.003 for TTP ratio), but not in females.
Conclusions
DCE-MRI demonstrated late contrast bolus arrival in males with post-COVID dyspnea, suggestive of primary vascular lesions or secondary effects of hypoxic vasoconstriction. Since this effect was not regularly observed in female patients, our findings suggest sex differences in the mechanisms underlying post-COVID dyspnea, which warrants further investigation in dedicated trials.

2020

L102

Monika Fagevik Olsén,Louise Lannefors,Malin Nygren-BonnierORCID Icon &Ewa-Lena Johansson

Long COVID – respiratory symptoms in non-hospitalised subjects – a cross-sectional study

https://doi.org/10.1080/21679169.2022.2101692

Published

1-Aug-22

Study

https://www.tandfonline.com/doi/full/10.1080/21679169.2022.2101692

Background
The aim of this study was to describe and analyse the variety of respiratory appearances in Long COVID subjects who were not hospitalised during the acute phase of the infection.
Methods
A consecutive series of 60 subjects participated x¯10.8 months (SD 4.5) after the acute phase of the infection. Respiratory function was tested concerning lung volumes, expiratory flow, muscle strength, physical capacity including concurrent oxygen saturation, chest expansion, lung sounds, pain and breathing pattern. Differences between those with or without positive test and duration of symptoms more or less than 6 months were analysed with T-test, Chi-square test and Fisher’s exact test.
Results
Decreased forced vital capacity was found in 6/60 (10%), and forced expiratory volume in 1 s and 7/60 (12%), low maximal inspiratory pressure in 38/58 (54%) and low maximal expiratory pressure in 10/58 (17%). Decreased physical capacity was registered in 36/52 (69%), and thoracic expansion in 26/46 (56%). Pathologic lung sounds had 15/58 (26%) and six patients desaturated during the test of physical capacity. A majority (36/58, 67%) presented pain in the ribcage. All but three patients (95%) showed a dysfunctional breathing pattern in sitting and standing. Only poor and fair correlations were found between age, duration and level of physical capacity compared to spirometry, respiratory muscle strength and thoracic expansion.
Conclusion
Abnormal breathing pattern and respiratory movements as well as pain, and reduced lung volumes, flow, respiratory muscle strength, physical capacity and thoracic expansion may be involved in Long COVID. The breathing symptoms should therefore be looked for in a wider picture beyond spirometry and oximetry.

2021

L103

CPET

Esther L van Voorthuizen, MD, Hanneke A C van Helvoort, PhD, Jeanette B Peters, PhD, Michel M van den Heuvel, MD, PhD, Bram van den Borst, MD, PhD

Persistent Exertional Dyspnea and Perceived Exercise Intolerance After Mild COVID-19: A Critical Role for Breathing Dysregulation?

https://doi.org/10.1093/ptj/pzac105

Published

28-Jul-22

Study

https://academic.oup.com/ptj/advance-article/doi/10.1093/ptj/pzac105/6651031

Objective
After mild COVID-19, a subgroup of patients reported post–acute-phase sequelae of COVID-19 (PASC), in which exertional dyspnea and perceived exercise intolerance were common. Underlying pathophysiological mechanisms remain incompletely understood. The purpose of this study was to examine outcomes from cardiopulmonary exercise testing (CPET) in these patients.
Methods
In this observational study, participants were patients who were referred for the analysis of PASC after mild COVID-19 and in whom CPET was performed after standard clinical workup turned out unremarkable. Cardiocirculatory, ventilatory, and metabolic responses to and breathing patterns during exercise at physiological limits were analyzed.
Results
Twenty-one patients (76% women; mean age = 40 years) who reported severe disability in physical functioning underwent CPET at 32 weeks (interquartile range [IQR] = 22–52) after COVID-19. Mean peak O2 uptake was 99% of predicted with normal anaerobic thresholds. No cardiovascular or gas exchange abnormalities were detected. Twenty of the 21 patients (95%) demonstrated breathing dysregulation (ventilatory inefficiency [29%], abnormal course of breathing frequency and tidal volume [57%], absent increase of end-tidal PCO2 [57%], and abnormal resting blood gases [67%]).
Conclusion
Breathing dysregulation may explain exertional dyspnea and perceived exercise intolerance in patients with PASC after mild COVID-19 and can be present in the absence of deconditioning. This finding warrants further study on the levels of neural control of breathing and muscle function, and simultaneously provides a potential treatment opportunity.

2022

L104

Tove LekvaORCID Icon,Thor Ueland,Bente HalvorsenORCID Icon,Sarah Louise Murphy,Anne Ma Dyrhol-Riise,Anders Tveita,Ane-Kristine Finbråten,Alexander Mathiessen,Karl Erik Müller,Trond Mogens Aaløkken,Ole Henning Skjønsberg,Tøri Vigeland Lerum,Pål Aukrust &Tuva Børresdatter Dahl

Markers of cellular senescence is associated with persistent pulmonary pathology after COVID-19 infection

https://doi.org/10.1080/23744235.2022.2113135

Published

19-Aug-22

Study

https://www.tandfonline.com/doi/full/10.1080/23744235.2022.2113135

Background
The lungs are the organ most likely to sustain serious injury from coronavirus disease 2019 (COVID-19). However, the mechanisms for long-term complications are not clear. Patients with severe COVID-19 have shorter telomere lengths and higher levels of cellular senescence, and we hypothesized that circulating levels of the telomere-associated senescence markers chitotriosidase, β-galactosidase, cathelicidin antimicrobial peptide and stathmin 1 (STMN1) were elevated in hospitalized COVID-19 patients compared to controls and could be associated with pulmonary sequelae following hospitalization.
Methods
Ninety-seven hospitalized patients with COVID-19 who underwent assessment for pulmonary sequelae at three-month follow-up were included in the study. β-Galactosidase and chitotriosidase were analysed by fluorescence; stathmin 1 and cathelicidin antimicrobial peptide were analysed by enzyme immuno-assay in plasma samples from the acute phase and after three-months. In addition, the classical senescence markers cyclin-dependent kinase inhibitor 1A and 2A were analysed by enzyme immuno-assay in peripheral blood mononuclear cell lysate after three months.
Results
We found elevated plasma levels of the senescence markers chitotriosidase and stathmin 1 in patients three months after hospitalization with COVID-19, and these markers in addition to protein levels of cyclin-dependent kinase inhibitor 2A in cell lysate, were associated with pulmonary pathology. The elevated levels of these markers seem to reflect both age-dependent (chitotriosidase) and age-independent (stathmin 1, cyclin-dependent kinase inhibitor 2A) processes.
Conclusions
We suggest that accelerated ageing or senescence could be important for long-term pulmonary complications of COVID-19, and our findings may be relevant for future research exploring the pathophysiology and management of these patients.

2023

L105

Tanyalak Parimon, M.D, Milena Espindola, Ph.D, Alberto Marchevsky, M.D, Reinaldo Rampolla, M.D, Peter Chen, M.D, Cory M Hogaboam, Ph.D

Potential Mechanisms for Lung Fibrosis Associated with COVID-19 Infection

https://doi.org/10.1093/qjmed/hcac206

Published

26-Aug-22

Article

https://academic.oup.com/qjmed/advance-article/doi/10.1093/qjmed/hcac206/6677237

Pulmonary fibrosis is a sequalae of SARS-CoV-2 infection that currently lacks effective preventative or therapeutic measures. Post-viral lung fibrosis due to SARS-CoV-2 has been shown to be progressive on selected patients using imaging studies. Persistent infiltration of macrophages and monocytes, a main feature of SARS-CoV-2 pulmonary fibrosis, and long-lived circulating inflammatory monocytes might be driving factors promoting the profibrotic milieu in the lung. The upstream signal (s) that regulates the presence of these immune cells (despite complete viral clearance) remains to be explored. Current data indicate that much of the stimulating signals are localized in the lungs. However, an ongoing low-grade systemic inflammation in long COVID-19 symptoms suggests that certain non-pulmonary regulators such as epigenetic changes in hematopoietic stem cells might be critical to the chronic inflammatory response. Since nearly one-third of the world population have been infected, a timely understanding of the underlying pathogenesis leading to tissue remodeling is required. Herein, we review the potential pathogenic mechanisms driving lung fibrosis following SARS-CoV-2 infection based upon available studies and our preliminary findings.

2024

L106

Jeffrey P. Kanne , Brent P. Little, Jefree J. Schulte, Adina Haramati, Linda B. Haramati

Long-Term Lung Abnormalities Associated with COVID-19 Pneumonia

https://doi.org/10.1148/radiol.221806

Published

30-Aug-22

Review

https://pubs.rsna.org/doi/full/10.1148/radiol.221806

In the third year of the SARS-CoV-2 pandemic, much has been learned about the long- term effect of COVID-19 pneumonia on the lungs. Approximately one-third of patients with moderate-to-severe pneumonia, especially those requiring intensive care therapy or mechanical ventilation, have residual abnormalities on chest CT one year after presentation. Abnormalities range from parenchymal bands to bronchial dilation to frank fibrosis. Less is known about the long-term pulmonary vascular sequelae, but there appears to be a persistent, increased risk of venothromboembolic events in a small cohort of patients. Finally, the associated histologic abnormalities resulting from SARS- CoV-2 infection are similar to those of patients with other causes of acute lung injury.
Summary
Some patients with moderate to severe COVID-19 have chest CT abnormalities that persist at least 1 year after infection and may be associated with symptoms. These CT abnormalities show similarities to those described in the 2002–2003 SARS epidemic.
Essentials
■ Approximately one-third of patients hospitalized with COVID-19 pneumonia have abnormalities at chest CT 12 months after infection.
■ CT abnormalities range from residual parenchymal bands to fibrosis as well as air trapping and bronchiectasis.
■ A very small number of patients have a persistently elevated risk of venothromboembolic disease after acute infection.
■ The late histopathologic findings of COVID-19 are similar to those of other causes of acute lung injury with a mix of organizing and chronic fibrosing histologic patterns. Additionally, these findings are comparable to those reported with the SARS epidemic.

2025

L107

Jong Hyuk Lee, Jae-Joon Yim & Jimyung Park

Pulmonary function and chest computed tomography abnormalities 6–12 months after recovery from COVID-19: a systematic review and meta-analysis

https://doi.org/10.1186/s12931-022-02163-x

Published

6-Sep-22

Systematic Review and Meta-analysis

https://link.springer.com/article/10.1186/s12931-022-02163-x

Background
Some coronavirus disease 2019 (COVID-19) survivors experience prolonged and varying symptoms, a condition termed post-acute COVID-19 syndrome (PACS). However, the prevalence of chronic pulmonary sequelae of PACS during long-term follow-up remains unclear. Several studies have examined this issue and reported heterogeneous results.
Methods
We conducted a systematic review and meta-analysis using a random-effects model to estimate the pooled prevalence of the pulmonary sequelae of COVID-19, as demonstrated by pulmonary function testing (PFT) and chest computed tomography (CT) performed at least 6 months after initial infection. PubMed, Embase, and Cochrane Library databases were searched from January 1, 2020 to December 31, 2021 to identify related studies. We investigated whether the prevalence of pulmonary sequelae decreased over time and attempted to identify the factors associated with their development by performing multiple subgroup and meta-regression analyses.
Results
Of the 18,062 studies identified, 30 met our eligibility criteria. Among these studies, 25 and 22 had follow-up PFT and chest CT data, respectively. The follow-up durations were approximately 6 and 12 months in 18 and 12 studies, respectively. Impaired diffusion capacity was the most common abnormality on PFT (pooled prevalence 35%, 95% confidence interval [CI] 30–41%) with a prevalence of 39% (95% CI 34–45%) and 31% (95% CI 21–40%) in the 6-month and 12-month follow-up studies, respectively (P = 0.115). Restrictive pulmonary dysfunction evident as reduced forced vital capacity was less frequent (pooled prevalence 8%, 95% CI 6–11%); however, its prevalence was lower in the 12-month follow-up studies than in the 6-month follow-up studies (5% [95% CI 3–7%] vs. 13% [95% CI 8–19%], P = 0.006). On follow-up chest CT, the pooled prevalence of persistent ground-glass opacities and pulmonary fibrosis was 34% (95% CI 24–44%) and 32% (95% CI 23–40%), respectively, and the prevalence did not decrease over time. As every meta-analysis showed significant between-study heterogeneity, subgroup and meta-regression analyses were performed to identify potential effect modifiers; the severity of index infection was associated with the prevalence of impaired diffusion capacity and pulmonary fibrosis.
Conclusions
A substantial number of COVID-19 survivors displayed pulmonary sequelae as part of PACS. Except for restrictive pulmonary dysfunction, the prevalence of these sequelae did not decrease until 1 year after initial infection. Considering the association between the severity of acute COVID-19 and risk of pulmonary sequelae, patients who recover from severe COVID-19 require close respiratory follow-up.

2026

L108

Puja Mehta, Ivan O. Rosas & Mervyn Singer

Understanding post-COVID-19 interstitial lung disease (ILD): a new fibroinflammatory disease entity

https://doi.org/10.1007/s00134-022-06877-w

Published

8-Sep-22

Article

https://link.springer.com/article/10.1007/s00134-022-06877-w

Immunomodulation and immunity from vaccination and natural infection have reduced mortality from coronavirus disease 2019 (COVID-19). However, there are ongoing concerns regarding emerging variants and residual pulmonary sequelae in survivors, given that the lungs are the principal site for the triumvirate of infection, inflammation and injury. The initial waves of acute, severe COVID-19 were profoundly inflammatory, usually manifest as organising pneumonia ± acute respiratory distress syndrome (ARDS). The extent of the fibrogenic potential of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the modifiability of the pathogenic processes and disease course are unclear. Interestingly patients can develop ‘post-COVID interstitial lung disease’ (PC-ILD) irrespective of having ARDS during the acute phase. Here, we describe our evolving understanding of PC-ILD and the critical need to identify risk factors, including within the critical care setting. We also discuss immunopathomechanisms that may facilitate early intervention to prevent, slow or arrest progression of lung damage e.g. with immunomodulatory and/or anti-fibrotic agents.
Future directions
The prevalence, severity and impact on healthcare systems of PC-ILD are currently unknown. The influence of viral load, new variants (with varying lung tropism), vaccination, ventilatory strategies, systemic hyperinflammation and immunomodulation [15] (e.g. corticosteroids or cytokine blockade (e.g. interleukin-6 antagonism) in the acute phase of PC-ILD are unknown. The role of immunomodulatory or anti-fibrotic therapies in PC-ILD is currently unresolved. It is tempting to speculate that immunomodulation (used for autoimmune ILD) may have a role in accelerating reversal of “inflammatory” changes, and anti-fibrotics (e.g. nintedanib used in progressive-fibrosing ILD) may attenuate “fibrotic-like” changes. However thus far PC-ILD appears to be non-progressive and clinical trial outcome data are eagerly awaited (Fig. 1).
Systematic, longitudinal data capture and deep phenotyping of patients with both persisting and resolving respiratory symptoms post-COVID are critical to unpick the aetiopathogenesis of PC-ILD. This should include clinical, physiological and radiological correlates with paired bio-sampling of both the lung microenvironment (e.g. BAL) and peripheral blood compartments to enable comparison to established f-ILDs. Serial CTs (ideally with in- or pre-hospital baselines) quantifying the extent and character of parenchymal change are needed to understand the relationship, reciprocity and evolution of radiological regions of inflammation and fibrosis. Understanding PC-ILD has global public health implications, but is also a unique opportunity to better understand molecular and cellular mechanisms of initiation, propagation and resolution of lung fibrosis. This may uncover novel therapeutic targets of wider relevance for multi-organ fibrotic diseases.

2027

L109

Tony H Ruppert, Zahra Alkhamees, Lydia Hulshizer and Luminita Tudor

Dyspnea Correlations in Patients With Post-Acute Sequelae of COVID-19 Infection

Published

3-Oct-22

Study

https://rc.rcjournal.com/content/67/Suppl_10/3773902.short

Background: COVID-19 is a respiratory disease that has caused a modern global pandemic. A subset of patients continues to complain of dyspnea several weeks and months after the initial acute COVID-19 infection. This project was a retrospective analysis of patients diagnosed with Post-Acute Sequelae of COVID-19 infection (PASC) within an Outpatient COVID Care Center in Central PA. This study focused on identifying any correlations between the breathlessness of long COVID-19 patients and multiple other factors.
Methods: After IRB approval, a retrospective study using electronic data from Wellspan Health (York PA) Outpatient COVID Care Center was conducted. 97 patients with pulmonary function testing recorded in the electronic medical record from June 2021 to March 2022 were included in the study. The retrospective study analyzed factors including age, prior to COVID smoking history, rest and/or exercise hypoxemia, history of prior pulmonary diseases, post-bronchodilator spirometry, total lung capacity, diffusing capacity, intubation history due to acute COVID-19, current symptoms of depression as shown by patient health care questionnaire (PHQ6), current symptoms of anxiety as shown by the general anxiety disorder score (GAD7), and cognitive function as shown by Montreal cognitive assessment (MoCA0).
Results: 78/97 patients identified dyspnea as a complaint 4-6 weeks after acute COVID-19 infection. Statistical analysis with Chi-square, independent T-test and Mann-Whitney U test demonstrated a P-value greater than 0.05 in all analyses indicating no statistical predictor of post-COVID-19 shortness of breath among the tested considerations. Although they were not statistically significant in this study, factors such as abnormal DLCO, TLC, and elevated scores of PHQ6, and GAD7 showed an interesting trend towards a correlation with post-COVID-19 shortness of breath
Conclusions: COVID-19 continues to affect patients, even after the initial infection. This study on long COVID-19 patients showed no statistically significant factors that predicted or correlated with ongoing dyspnea. Limitations to our study include small sample size and only the use of single-center patients. Further research should be conducted with larger sample size and continued factors such as DLCO, TLC, anxiety, depression, and other factors that could predict or influence dyspnea in long COVID-19 patients.

2028

L110

A M Bielecka-Dabrowa, A Sakowicz, M Banach, M Maciejewski, K Gryglewska

Diagnostic usefulness of spiroergometry and risk factors of long -COVID in patients with normal left ventricular ejection fraction

https://doi.org/10.1093/eurheartj/ehac544.2464

Published

3-Oct-22

Study

https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.2464/6745489

Background
Recent evidence has shown that patients with acute SARS-CoV-2 infection might present symptoms of infection a long time after a recovery.
Purpose
To investigate the risk factors and assess the utility of spiroergometry parameters in differential diagnosing patients presenting the symptoms (dyspnea, fatique, pain in chest, muscle pain, cognitive impairment, taste and smell disturbances) persisting for a few months after recovery from COVID 19 (symptoms of long COVID).
Methods and results
The 146 patients (pts) with normal left ventricular ejection fraction and without respiratory diseases, hospitalised in Cardiology Department recovering from COVID-19 at three to six months after confirmed diagnosis were included. The clinical examination, laboratory results, echocardiography using Vivid E95–GE Healthcare, non-invasive body mass analysis using Body Composition Analyzer (Tanita Pro), spiroergometry using The MetaSoft® Studio application were analyzed. The subjects were divided into the two following groups: group demonstrating long COVID symptoms (i.e. suffering from one of the following dyspnea, fatique, pain in chest, muscle pain, cognitive impairment, taste or smell disturbances) [N=44 pts] and the group without long COVID symptoms [N=102 pts]. Pts with long COVID symptoms presented significantly higher age (58 versus [vs] 44 years; p<0.0001), higher metabolic age (53 vs 45 years; p=0.01), higher left atrial diameter (37 vs 35 mm; p=0.04), higher left ventricular mass index (LVMI) (83 vs 74 g/m2, p=0.03), higher E/E' (7.3 vs 6; p<0.001) compared to control group. In CPET long COVID pts presented lower forced vital capacity (FVC) (3.6 vs 4.3 L; p=0.009), lower maximal oxygen consumption measured during incremental exercise indexed per kilogram (VO2max) (21 vs 23 ml/min/kg; p=0.04), lower respiratory exchange ratio (RER) (1.0 vs 1.1; p=0.04); lower forced expiratory volume in one second (FEV1) (2.9 vs 3.25 L; p=0,03); higher ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC) (106 vs 100%; p=0.0002) – Figure 1, there were no significant changes in electrocardiogram between groups. The laboratory results pointed that pts with long COVID symptoms had also lower rate of red blood cells (RBC) (4,4 vs 4,6 mln; p=0.01); higher level of glucose (92 vs 90 mg%; p=0.02); lower glomerular filtration rate (GFR) estimate by Modification of Diet in Renal Disease (MDRD) (88 vs 95; p=0.02); higher level of hypersensitive cardiac Troponin T (hsTnT) (6.1 vs 3.9 ng/L; p=0.03). The parameters significant in univariate analyses were included to the multivariate model. The results of multiple logistic regression were as follows: age (OR 4.6, 95% CI: 1.7–11.5; p=0.001) and LVMI (OR 2.5, 95% CI: 1.0–6.6; p=0.04).
Conclusions
Persistent symptoms in long COVID can mimic those of cardiovascular disease. Spiroergometric parameters are useful in making a proper diagnosis.

2029

L111

Aysegul GencerORCID Icon,Buket Caliskaner Ozturk,Sermin BorekciORCID Icon &Bilun Gemicioglu

Bronchodilator Reversibility Testing in Long-Term Cough and Dyspnea after Covid-19 Viral Infection: A Trigger for Asthma?

https://doi.org/10.1080/02770903.2022.2139719

Published

24-Oct-22

Study

https://www.tandfonline.com/doi/abs/10.1080/02770903.2022.2139719

Background
This study aims to investigate the presence of underlying chronic airway disease in individuals with chronic cough and dyspnea lasting longer than eight weeks and who had previously Coronavirus disease 2019(COVID-19) and had no known lung disease.
Methods
A total of 151 patients admitted to the respiratory diseases outpatient room with the complaint of cough and/or dyspnea that persisted for at least eight weeks following COVID-19 infection were accrued to the study. Demographic characteristics, smoking history, the severity of lung involvement on chest computed tomography in the acute phase of Covid-19 infection, and bronchodilator reversibility test results were recorded. Smoking history and forced expiratory volume in the first second (FEV1) were compared.
Results
FEV1 increase ≥200 ml was observed in 40(26.5%) patients. In 24(15.9%) patients, an increase in FEV1 was found to be 200 ml and above, and the percentage of FEV1 was 12% or more. While 14(9.3%) patients were diagnosed with asthma, 13(8,6%) patients were diagnosed with nonreversible airflow obstruction (NRAO), and 1(0.7%) patient was diagnosed with chronic obstructive pulmonary disease (COPD).
Conclusion
COVID-19 infection may play a vital role in initiating asthma pathogenesis. It should be kept in mind that viral infection-related asthma may be the underlying cause of prolonged cough and dyspnea after COVID-19 infection.

2030

L112

T VasileiosStavrouabAstaraKyriakiacD GeorgeVavougiosadG IoannisFatouroseS GeorgeMetsiosfKonstantinosKalabakasbDimitriosKaragiannisbZoeDaniilaI KonstantinosGourgoulianisaGeorgeΒasdekisb

Athletes with mild post-COVID-19 symptoms experience increased respiratory and metabolic demands: Α cross-sectional study

https://doi.org/10.1016/j.smhs.2022.10.004

Published

23-Oct-22

Study

https://www.sciencedirect.com/science/article/pii/S2666337622000634

Coronavirus Disease 2019 (COVID-19) has significantly affected different physiological systems, with a potentially profound effect on athletic performance. However, to date, such effect has not been neither addressed, nor investigated. Therefore, the aim of this study was to investigate fitness indicators, along with the respiratory and metabolic profile, in post-COVID-19 athletes. Forty male soccer players, were divided into two groups: non-hospitalized COVID-19 (n = 20, Age: 25.2 ± 4.1 years, Body Surface Area (BSA): 1.9 ± 0.2 m2, body fat: 11.8 ± 3.4%) versus (vs) healthy (n = 20, Age: 25.1 ± 4.4 years, BSA: 2.0 ± 0.3 m2, body fat: 10.8 ± 4.5%). For each athlete, prior to cardiopulmonary exercise testing (CPET), body composition, spirometry and lactate blood levels, were recorded. Differences between groups were assessed with the independent samples t-test (<0.05). Several differences were detected between the two groups: ventilation (VE: Resting: 14.7 ± 3.1 vs. 11.5 ± 2.6, p = 0.001; Maximal Effort: 137.1 ± 15.5 vs. 109.1 ± 18.4 L/min, p < 0.001), ratio VE/maximal voluntary ventilation (Resting: 7.9 ± 1.8 vs. 5.7 ± 1.7%, p < 0.001; Maximal Effort: 73.7 ± 10.8 vs. 63.1 ± 9.0, p = 0.002), ratio VE/BSA (Resting: 7.9 ± 2.0 vs. 5.9 ± 1.4%, p = 0.001; Maximal Effort: 73.7 ± 11.1 vs. 66.2 ± 9.2%, p = 0.026), heart rate (Maximal Effort: 191.6 ± 7.8 vs. 196.6 ± 8.6 bpm, p = 0.041), and lactate acid (Resting: 1.8 ± 0.8 vs. 0.9 ± 0.1 mmol/L, p < 0.001; Maximal Effort: 11.0 ± 1.6 vs. 9.8 ± 1.2 mmol/L, p = 0.009), during CPET. No significant differences were identified regarding maximal oxygen uptake (55.7 ± 4.4 vs. 55.4 ± 4.6 ml/min/kg, p = 0.831). Our findings demonstrate a pattern of compromised respiratory function in post-COVID-19 athletes characterized by increased respiratory work at both rest and maximum effort as well as hyperventilation during exercise, which may explain the reported increased metabolic needs.

2031

L113

Nagel C.Access ORCID a,b,c,d · Olschewski H.e · Sorichter S.f · Uezgoer G.d · Diehm C.g · Huppert P.h · Iber T.i · Herth F.c,j · Harutyunova S.b,c · Marra A.M.b,k · Benjamin N.b,c · Salkić A.b,c · Grünig E.b,c · Egenlauf B.b,c,j

Impairment of Inspiratory Muscle Function after COVID-19

https://doi.org/10.1159/000527361

Published

28-Oct-22

Study

https://www.karger.com/Article/Abstract/527361

Background: Persistent symptoms after acute coronavirus-disease-2019 (COVID-19) are common, and there is no significant correlation with the severity of the acute disease. In long-COVID (persistent symptoms >4 weeks after acute COVID-19), respiratory symptoms are frequent, but lung function testing shows only mild changes that do not explain the symptoms. Although COVID-19 may lead to an impairment of the peripheral nervous system and skeletal muscles, respiratory muscle function has not been examined in this setting. Methods: In this study, we assessed the severity of dyspnea (NYHA-function class) in long-COVID patients and analyzed its association with body mass index (BMI), FEV1, forced vital capacity, other parameters of body plethysmography, diffusing capacity for carbon monoxide (DLCO), arterial blood gases, and inspiratory muscle function, assessed by airway occlusion pressure (P0.1) and maximal inspiratory pressure (PImax) in two respiratory clinics in Germany between Oct 2020 and Aug 2021. Results: A total of 116 patients were included in the study. The mean age was 50.2 ± 14.5 years; BMI, 26.7 ± 5.87 kg/m2; NYHA class I, 19%; II, 27%; III, 41%; and IV, 14%. While lung function values and computed tomography or conventional X-ray of the chest were in the normal range, inspiratory muscle function was markedly impaired. P01 was elevated to 154 ± 83%predicted and PImax was reduced to 41 ± 25%predicted. PImax reduction was strongly associated with the severity of dyspnea but independent of BMI, time after acute COVID-19 and most of the other parameters. Conclusions: This study shows that in long-COVID patients, respiratory symptoms may be mainly caused by reduced inspiratory muscle strength. Assessment of PImax and P0.1 might better explain dyspnea than classical lung function tests and DLCO. A prospective study is needed to confirm these results.

2032

L114

Pasquale Maria Parrella, Marco Rumolo, Roberto Bianco, Giada Annarumma, Eugenio di Vaia, and Guido Iaccarino

Alterations of basal spirometry in long COVID patients. Effects of physical activity

https://doi.org/10.1016%2Fj.vph.2022.107065

Published

14-Oct-22

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9560753/

The long-term sequelae of the COVID-19 (Long Covid, LC), includes of fatigue, exercise intolerance, dyspnea and palpitations 30 days after negative swab. Little is known about the determinants of LC. We verified the impact of physical activity (PA), focusing on lung function, evaluated with traditional spirometry. Out of 73 COVID-19 healed patients referred to the Sports Medicine Clinic of the Federico II University Hospital from December 2020 to May 2021 for sports fitness certification, we selected 19 patients aged between 40 and 65 years, mean age 52.9 ± 6.9 years, 6/13 females/males, BMI 29.3 ± 5.7. Inclusion criteria were COVID severity >1, compliance to spirometry testing, absence of other conditions and medications that could interfere with spirometry. Patients were divided into sportsmen (S, n = 7, practicing PA > 2 h/w) and non- sportsmen (NS, n = 12, practicing PA < 2 h/w,) and subjected to traditional spirometry (Spirostick blue, Gerotherm), for the evaluation of forced vital capacity (FVC), tidal volume (CV), maximum expiratory volume in the first second (FEV1), and FEV1/FVC calculated with reference to the expected theoretical values. Considering the population as whole, we observed the increase in FEV1/FVC comparedto the theoretical value (87.9 ± 1.5 vs. 79.9 ± 0.6%, p < 0.001). This difference was confirmed in both subgroups (S:89.1 ± 2.2 vs. 79.4 ± 1.0%, p < 0.001; NS:87.2 ± 2.0 vs. 80.2 ± 0.8%, p < 0.001). In NS patients the increase is due to the reduction in FVC (3.7 ± 0.2 vs. 4.0 ± 0.2 L, p < 0.05) but not in S patients (4.2 ± 0.4 vs. 4.2 ± 0.3 L, ns). Also, CV reduction is observed in NS patients (3.6 ± 0.2 vs. 4.0 ± 0.2 L, p < 0.05), but not in S patients (4.5 ± 0.3 vs. 4.3 ± 0.3 L, ns). LC is characterized by remodeling of lung function 1 month after negative swab. In NS patients, this is accompanied by structural changes, prevented in S patients. Our data support the importance of PA in the prevention and treatment of LC outcomes.

2033

L115

Iqbal, Nousheen, Iffat Khanum, Muhammad Ali Ibrahim Kazi, Syeda Urooj Riaz, Uzzam Ahmed Khawaja, Safia Awan, Muhammad Irfan, Ali Bin Sarwar Zubairi, and Javaid Ahmed Khan

Post COVID-19 sequelae of the respiratory system. A single center experience reporting the compromise of the airway, alveolar and vascular components

https://doi.org/10.4081/monaldi.2022.2412

Published

11-Oct-22

Study

https://www.monaldi-archives.org/index.php/macd/article/view/2412

The long-term sequelae of COVID-19 have now become more common and appreciable. The SARS-CoV-2 virus can cause a variety of infectious and non-infectious pulmonary complications. The purpose of this study is to raise awareness about post-COVID-19 pulmonary sequelae, both infectious and non-infectious, in this geographical area. A retrospective study was conducted from July 1st 2020 to December 20th 2020. A total of 1200 patients were evaluated, with 83 suffering from post-COVID-19 pulmonary complications. The patients' mean age was 62 years (IQR 55-69), with 63 (75.9%) being male. The most common co-morbid illnesses were hypertension (49, 59%) and diabetes (45, 54.2%). The majority of them (37, 44.6%) had severe COVID-19, followed by critical COVID-19 (33, 39.8%). There was no statistically significant difference in recurrence of respiratory symptoms or duration of current illness between non-severe, severe, and critical COVID-19 patients. Non-infectious complications were observed in the majority of patients (n=76, 91.5%), including organizing pneumonia/ground glass opacities in 71 (88%) patients, fibrosis in 44 (55%), pulmonary embolism in 10 (12.5%), pneumomediastinum in 6 (7.4%) and pneumothorax in 7 (8.6%). Infective complications (25, 30.1%) included aspergillus infection in 10 (12.0%) and bacterial infection in 5 (8.47%), with more gram-negative infections and one patient developing Mycobacterium tuberculosis. Post COVID-19 mortality was 11 (13.3%). The long-term pulmonary sequelae of COVID-19 are not rare. Cryptogenic organizing pneumonia, ground glass opacities, and fibrosis were common post-COVID-19 sequelae in our patients. This necessitates frequent close monitoring of these patients in order to initiate early appropriate management and prevent further morbidity and eventual mortality.

2034

L116

Udwadia, Zarir F.1; Pawar, Unmesha Prakash2; Nanda, Viral Jayshinh2

Severe interstitial lung disease persisting 2 years post-COVID-19 despite anti-fibrotic therapy

https://doi.org/10.4103/lungindia.lungindia_355_22

Published

25-Oct-22

Case Report

https://journals.lww.com/lungindia/Fulltext/2022/11000/Severe_interstitial_lung_disease_persisting_2.17.aspx

This case is presented to highlight the fact that not all patients with COVID pneumonia resolve over time and persistent fibrosis and established severe ILD may be a long-term sequel in some patients. It emphasizes that careful serial follow-up of all such patients is needed till they reach stable lung function. It also suggests that antifibrotics may not have a specific role and till the results of large trials emerge their routine use in the anticipation that they will prevent fibrosis may need to be reconsidered. A recent study shed mechanistic insight and suggests pulmonary PASC is driven by inflammatory cytokines produced by activated SARS CoV-2 specific T cells. These patients also demonstrated 6–105 fold increased frequency of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) producing SARS CoV-2 specific cluster of differentiation-4 (CD4) and CD8 T cells which also co-related with the decline in PFT.[1]

2035

L117

ÖzgürBostancıaEmreKaradumanaYunusÇolakbcAli KerimYılmazaMenderesKabadayıaSaitBilgiç

Respiratory muscle strength and pulmonary function in unvaccinated athletes before and after COVID-19 infection: A prospective cohort study

https://doi.org/10.1016/j.resp.2022.103983

Published

11-Nov-22

Study

https://www.sciencedirect.com/science/article/pii/S1569904822001422

Highlights
•Athletes with COVID-19 infection report fatigue, muscle/joint pain, and headache as the most frequent symptoms, whereas dyspnoea and cough are less reported.
•COVID-19 decreases respiratory muscle strength and pulmonary function in unvaccinated athletes despite reporting few respiratory symptoms.
•Athletes may need a longer recovery time before being able to return to training and competition.
Abstract
Purpose
We investigated abnormalities and recovery in respiratory function after COVID-19 infection in an unvaccinated elite athlete population.
Methods
Measurements included maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and peak expiratory flow (PEF).
Results
The most frequent reported symptoms were fatigue with 80% and muscle/joint pain and headache with 50%, whereas only 10% reported dyspnoea and 30% cough. During follow-up, MIP was up to 13% and MEP up to 8% lower following COVID-19 infection. Likewise, FEV1 was up to 2% and FVC up to 5% lower. While MEP and FEV1 rapidly normalised, MIP and FVC still remained abnormal after 52 days of COVID-19 infection, thereby leading to a restrictive ventilatory pattern. PEF seemed unaffected during follow-up.
Conclusions
COVID-19 decreases respiratory function in unvaccinated athletes despite reporting few respiratory symptoms and having mild disease. An initiative aimed at reducing the long-term adverse effects following COVID-19 infection seems warranted, which perhaps may be avoided through vaccination.

2036

L118

André F. Rendeiro, View ORCID ProfileHiranmayi Ravichandran, View ORCID ProfileJunbum Kim, View ORCID ProfileAlain C. Borczuk, View ORCID ProfileOlivier Elemento, View ORCID ProfileRobert E. Schwartz

Persistent alveolar type 2 dysfunction and lung structural derangement in post-acute COVID-19

https://doi.org/10.1101/2022.11.28.22282811

pre-print

29-Nov-22

Study

https://www.medrxiv.org/content/10.1101/2022.11.28.22282811v1.full-text

SARS-CoV-2 infection can manifest as a wide range of respiratory and systemic symptoms well after the acute phase of infection in over 50% of patients. Key questions remain on the long-term effects of infection on tissue pathology in recovered COVID-19 patients. To address these questions we performed multiplexed imaging of post-mortem lung tissue from 12 individuals who died post-acute COVID-19 (PC) and compare them to lung tissue from patients who died during the acute phase of COVID-19, or patients who died with idiopathic pulmonary fibrosis (IPF), and otherwise healthy lung tissue. We find evidence of viral presence in the lung up to 359 days after the acute phase of disease, including in patients with negative nasopharyngeal swab tests. The lung of PC patients are characterized by the accumulation of senescent alveolar type 2 cells, fibrosis with hypervascularization of peribronchial areas and alveolar septa, as the most pronounced pathophysiological features. At the cellular level, lung disease of PC patients, while distinct, shares pathological features with the chronic pulmonary disease of IPF. which may help rationalize interventions for PC patients. Altogether, this study provides an important foundation for the understanding of the long-term effects of SARS-CoV-2 pulmonary infection at the microanatomical, cellular, and molecular level.

2037

L119

Stettner, Mark; Fleischer, Michael; Skoda, Eva-Maria; Teufel, Martin; Kleinschnitz, Christoph

Response Letter to Vink et al. ‘Neurological Study Does Not Provide Any Evidence that Long COVID is Psychosomatic’

https://doi.org/10.1016/j.mri.2022.12.002

Published

Study

https://www.sciencedirect.com/science/article/pii/S0730725X22002120

Patients recovered from COVID-19 may develop long-COVID symptoms in the lung. For this patient population (post-COVID patients), they may benefit from longitudinal, radiation-free lung MRI exams for monitoring lung lesion development and progression. The purpose of this study was to investigate the performance of a spiral ultrashort echo time MRI sequence (Spiral-VIBE-UTE) in a cohort of post-COVID patients in comparison with CT and to compare image quality obtained using different spiral MRI acquisition protocols. Lung MRI was performed in 36 post-COVID patients with different acquisition protocols, including different spiral sampling reordering schemes (line in partition or partition in line) and different breath-hold positions (inspiration or expiration). Three experienced chest radiologists independently scored all the MR images for different pulmonary structures. Lung MR images from spiral acquisition protocol that received the highest image quality scores were also compared against corresponding CT images in 27 patients for evaluating diagnostic image quality and lesion identification. Spiral-VIBE-UTE MRI acquired with the line in partition reordering scheme in an inspiratory breath-holding position achieved the highest image quality scores (score range = 2.17–3.69) compared to others (score range = 1.7–3.29). Compared to corresponding chest CT images, three readers found that 81.5% (22 out of 27), 81.5% (22 out of 27) and 37% (10 out of 27) of the MR images were useful, respectively. Meanwhile, they all agreed that MRI could identify significant lesions in the lungs. The Spiral-VIBE-UTE sequence allows for fast imaging of the lung in a single breath hold. It could be a valuable tool for lung imaging without radiation and could provide great value for managing different lung diseases including assessment of post-COVID lesions.

2038

L120

Laorden, Daniel; Domínguez-Ortega, Javier; Carpio, Carlos; Barranco, Pilar; Villamañán, Elena; Romero, David; Quirce, Santiago; Álvarez-Sala, Rodolfo; Camperos, Ricardo; Agrela, Isamar De; Fernández-Concha, Inés; Freund, Paul Kent Ernesto; Pavón, Jaime; Pose, Katherine

Long COVID outcomes in an asthmatic cohort and its implications for asthma control

https://doi.org/10.1016/j.rmed.2022.107092

Published

Study

https://www.resmedjournal.com/article/S0954-6111(22)00357-2/fulltext

Highlights
•
COVID-19 infection had not an influence on asthma outcomes.
•
There is a potential protection of T2-asthma against acute COVID infection.
•
The severity of asthma was associated with worse long-term outcomes of COVID-19.
The findings observed in this study help us better understand post-acute COVID-19 complications in patients with asthma. Patients with T2-asthma had less chest pain after 12 months post-COVID (OR = 0.319) (table-3). These results are consistent with previous studies, suggesting the potential protection of T2-asthma against acute COVID infection [8, 9, 10, 11].
Viral infections clearly affect asthma outcomes [[3],[8],[11]]. Interestingly, and consistent with previous papers, we have not found that COVID-19 infection had an influence on asthma outcomes at the time of observation in our investigation. Exacerbations, asthma control (measured by ACT), and lung function parameters appeared to be unaffected by COVID-19, at least in most patients (table-3). Unfortunately, we could not perform spirometry on all the study patients because of the pandemic situation.
Given that the severity of acute COVID-19 was associated with the development of worse long-term outcomes of COVID-19, it is noteworthy that we found an increased risk of pneumonia in men (OR = 2.828), smokers (OR = 2.568) and subjects previously treated with ICS + LABA (OR = 3.119), it was confirmed by multivariant regression model) (table-2). In line with these findings, we have also observed a higher risk of hospitalization among patients with the same clinical characteristics: men (OR = 2), smokers (OR = 4.803) and treated with ICS + LABA (OR = 2.793). We found less risk in patients previously treated with ICS alone (OR = 0.272) than with an ICS + LABA combination (OR = 2.793), probably explained by severity of asthma in the acute phase of COVID-19, since more severe asthma has been associated with a worse prognosis [[11]]. In contrast, and, as expected, T2-asthma patients had a lower risk of acute SARS-CoV-2 pneumonia (OR = 0.320), which probably influenced the clinical presentation of prolonged COVID.
The major drawback of this study is its retrospective design, in several waves of evolution of the pandemic. These circumstances make up the major limitation of the study, which is the absence of a prospective design that allows greater validation of these results. We also believe that some trends seen in our results might have been confirmed by a larger sample, which could have helped to better explore the impact of COVID-19 on asthma outcomes. However, it seems difficult to design this type of study because of the evolution of the pandemic after vaccination.
Among the strengths of this study, it includes many non-vaccinated patients with asthma and COVID infection. To our knowledge, this is the first study with a longitudinal evaluation after at least 6 months from the acute infection, including data from interviews and current physical examinations that others studies do not include [[10]].
In conclusion, patients with severe asthma are at an increased risk of developing long COVID, while eosinophilic and T2-asthma could protect against complications of prolonged COVID.

2039

L121

Jha, Manika; Gupta, Richa; Saxena, Rajiv

A Precise Method to Detect Post-COVID-19 Pulmonary Fibrosis Through Extreme Gradient Boosting

https://doi.org/10.1007/s42979-022-01526-x

Published

Study

https://doi.org/10.1007/s42979-022-01526-x

The association of pulmonary fibrosis with COVID-19 patients has now been adequately acknowledged and caused a significant number of mortalities around the world. As automatic disease detection has now become a crucial assistant to clinicians to obtain fast and precise results, this study proposes an architecture based on an ensemble machine learning approach to detect COVID-19-associated pulmonary fibrosis. The paper discusses Extreme Gradient Boosting (XGBoost) and its tuned hyper-parameters to optimize the performance for the prediction of severe COVID-19 patients who developed pulmonary fibrosis after 90 days of hospital discharge. A dataset comprising Electronic Health Record (EHR) and corresponding High-resolution computed tomography (HRCT) images of chest of 1175 COVID-19 patients has been considered, which involves 725 pulmonary fibrosis cases and 450 normal lung cases. The experimental results achieved an accuracy of 98%, precision of 99% and sensitivity of 99%. The proposed model is the first in literature to help clinicians in keeping a record of severe COVID-19 cases for analyzing the risk of pulmonary fibrosis through EHRs and HRCT scans, leading to less chance of life-threatening conditions.

2040

L122

Tyagi, Suresh C.; Pushpakumar, Sathnur; Sen, Utpal; Mokshagundam, Sri Prakash L.; Kalra, Dinesh K.; Saad, Mohamed A.; Singh, Mahavir

COVID-19 Mimics Pulmonary Dysfunction in Muscular Dystrophy as a Post-Acute Syndrome in Patients

https://doi.org/10.3390/ijms24010287

Published

Review

https://www.mdpi.com/1422-0067/24/1/287

Although progressive wasting and weakness of respiratory muscles are the prominent hallmarks of Duchenne muscular dystrophy (DMD) and long-COVID (also referred as the post-acute sequelae of COVID-19 syndrome); however, the underlying mechanism(s) leading to respiratory failure in both conditions remain unclear. We put together the latest relevant literature to further understand the plausible mechanism(s) behind diaphragm malfunctioning in COVID-19 and DMD conditions. Previously, we have shown the role of matrix metalloproteinase-9 (MMP9) in skeletal muscle fibrosis via a substantial increase in the levels of tumor necrosis factor-α (TNF-α) employing a DMD mouse model that was crossed-bred with MMP9-knockout (MMP9-KO or MMP9-/-) strain. Interestingly, recent observations from clinical studies show a robust increase in neopterin (NPT) levels during COVID-19 which is often observed in patients having DMD. What seems to be common in both (DMD and COVID-19) is the involvement of neopterin (NPT). We know that NPT is generated by activated white blood cells (WBCs) especially the M1 macrophages in response to inducible nitric oxide synthase (iNOS), tetrahydrobiopterin (BH4), and tetrahydrofolate (FH4) pathways, i.e., folate one-carbon metabolism (FOCM) in conjunction with epigenetics underpinning as an immune surveillance protection. Studies from our laboratory, and others researching DMD and the genetically engineered humanized (hACE2) mice that were administered with the spike protein (SP) of SARS-CoV-2 revealed an increase in the levels of NPT, TNF-α, HDAC, IL-1β, CD147, and MMP9 in the lung tissue of the animals that were subsequently accompanied by fibrosis of the diaphragm depicting a decreased oscillation phenotype. Therefore, it is of interest to understand how regulatory processes such as epigenetics involvement affect DNMT, HDAC, MTHFS, and iNOS that help generate NPT in the long-COVID patients.

2041

L123

Peroy-Badal, Renata; Sevillano-Castaño, Ana; Núñez-Cortés, Rodrigo; García-Fernández, Pablo; Torres-Castro, Rodrigo; Vilaró, Jordi; Blanco, Isabel; Gimeno-Santos, Elena

The Chester Step Test Is a Reproducible Tool to Assess Exercise Capacity and Exertional Desaturation in Post-COVID-19 Patients

https://doi.org/10.3390/healthcare11010051

Published

Study

https://www.mdpi.com/2227-9032/11/1/51

Many people recovering from an acute episode of coronavirus disease (COVID-19) experience prolonged symptoms. Exercise testing is a feasible and cost-effective option for assessing exercise tolerance, fatigue, and dyspnea related to effort. Being that the Chester step test (CST) is a progressive, submaximal test for predicting aerobic capacity, it could be a good option to explore. This study aimed to determine the reproducibility of CST for assessing exertional desaturation and exercise capacity in patients post-COVID-19 disease. A cross-sectional study was conducted on post-COVID-19 patients. Two attempts of the CST were performed. The intraclass correlation coefficient (ICC) was used to assess agreement between the two tests. Forty-two symptomatic post-COVID-19 patients were included, the mean age was 53.8 ± 10.3 years, and 52% were female. There was no significant difference between both tests (p = 0.896). Twenty-four percent of participants (10 cases) had a clinically significant decrease in SpO2 at the first assessment, compared to 30.1% (13 cases) at the second, with no significant difference. An ICC of 0.993 (95% CI: 0.987 to 0.996) was obtained for the total number of steps in the CST.

2042

L124

Altersberger, Martin; Grafeneder, Anna; Cho, Yerin; Winkler, Roland; Zwick, Ralf Harun; Mathis, Gebhard; Genger, Martin

One-Year Follow-Up Lung Ultrasound of Post-COVID Syndrome—A Pilot Study

https://doi.org/10.3390/diagnostics13010070

Published

Study

https://www.mdpi.com/2075-4418/13/1/70

(1) Background: Millions of people worldwide were infected with COVID-19. After the acute phase of the disease, many suffer from prolonged symptoms, the post-COVID syndrome, especially the phenotype with lung residuals. Many open questions regarding lung ultrasound (LUS) have to be answered. One essential question is the means for optimal following-up of patients with post-COVID-19 residuals with LUS; (2) Methods: A retrospective data analysis of patients after acute COVID-19 infection diagnosed with post-COVID syndrome in the state hospital of Steyr and the rehabilitation center of Hochegg was performed. LUS examinations following a 12-zone scanning protocol were performed, and the LUS score quantified comet tail artifacts. A total of 16 patients were evaluated twice with LUS from May 2020 until June 2021. (3) Results: All patients’ reverberation artifacts were reduced over time. The initial LUS score of 17.75 (SD 4.84) points was decreased over the duration of the second rehabilitation to 8,2 (SD 5.94). The difference in the Wilcoxon test was significant (p < 0.001); (4) Conclusions: Lung ultrasound was a valuable tool in the follow-up of post-COVID-syndrome with lung residuals in the first wave of COVID-19. A reduction in reverberation artifacts was demonstrated. Further studies about the clinical significance have to follow.

2043

L125

Siekacz, Kamil; Kumor-Kisielewska, Anna; Miłkowska-Dymanowska, Joanna; Pietrusińska, Małgorzata; Bartczak, Krystian; Majewski, Sebastian; Stańczyk, Adam; Piotrowski, Wojciech J.; Białas, Adam J.

Soluble ITGaM and ITGb2 Integrin Subunits Are Involved in Long-Term Pulmonary Complications after COVID-19 Infection

https://doi.org/10.3390/jcm12010342

Published

1-Jan-23

Study

https://www.mdpi.com/2077-0383/12/1/342

(1) Introduction: The role of soluble integrins in post-COVID-19 complications is unclear, especially in long-term pulmonary lesions. The purpose of this study was to investigate the association between soluble ITGa2, ITGaM and ITGb2 integrin subunits and long COVID-19 pulmonary complications. (2) Methodology: Post-COVID-19 patients were enrolled. According to the evidence of persistent interstitial lung lesions on CT, patients were divided into a long-term pulmonary complications group (P(+)) and a control group without long-term pulmonary complications (P(−)). We randomly selected 80 patients for further investigation (40 subjects for each group). Levels of ITGa2, ITGaM and ITGb2 integrin subunits were determined by ELISA assay. (3) Results: The serum concentration of sITGaM and sITGb2 were significantly higher in the P(+) group (sITGaM 18.63 ng/mL [IQR 14.17–28.83] vs. 14.75 ng/mL [IQR 10.91–20] p = 0.01 and sITGb2 10.55 ng/mL [IQR 6.53–15.83] vs. 6.34 ng/mL [IQR 4.98-9.68] p = 0.002). We observed a statistically significant correlation between sITGaM and sITGb2 elevation in the P(+) group (R = 0.42; p = 0.01). Patients from the P(+) group had a lower (1.82 +/−0.84 G/L) lymphocyte level than the P(−)group (2.28 +/−0.79 G/L), p = 0.03. Furthermore, we observed an inverse correlation in the P(−) group between blood lymphocyte count and sITGb2 integrin subunit levels (R = −0.49 p = 0.01). (4) Conclusions: Elevated concentrations of sITGaM and sITGb2 were associated with long-term pulmonary complications in post-COVID-19 patients. Both sITGaM and sITGb2 may be promising biomarkers for predicting pulmonary complications and could be a potential target for therapeutic intervention in post-COVID-19 patients.

2044

L126

Matheson, Alexander M.; McIntosh, Marrissa J.; Kooner, Harkiran K.; Abdelrazek, Mohamed; Albert, Mitchell S.; Dhaliwal, Inderdeep; Nicholson, J. Michael; Ouriadov, Alexei; Svenningsen, Sarah; Parraga, Grace

Longitudinal follow-up of postacute COVID-19 syndrome: DLCO, quality-of-life and MRI pulmonary gas-exchange abnormalities

https://doi.org/10.1136/thorax-2022-219378

Published

3-Jan-23

Study

https://thorax.bmj.com/content/early/2023/01/03/thorax-2022-219378

129Xe MRI red blood cell to alveolar tissue plasma ratio (RBC:TP) abnormalities have been observed in ever-hospitalised and never-hospitalised people with postacute COVID-19 syndrome (PACS). But, it is not known if such abnormalities resolve when symptoms and quality-of-life scores improve. We evaluated 21 participants with PACS, 7±4 months (baseline) and 14±4 months (follow-up) postinfection. Significantly improved diffusing capacity of the lung for carbon monoxide (DLCO, Δ=14%pred ;95%CI 7 to 21, p<0.001), postexertional dyspnoea (Δ=−0.7; 95%CI=−0.2 to –1.2, p=0.019), St George’s Respiratory Questionnaire-score (SGRQ Δ=−6; 95% CI=−1 to –11, p=0.044) but not RBC:TP (Δ=0.03; 95% CI=0.01 to 0.05, p=0.051) were observed at 14 months. DLCO correlated with RBC:TP (r=0.60, 95% CI=0.22 to 0.82, p=0.004) at 7 months. While DLCO and SGRQ measurements improved, these values did not normalise 14 months post-infection. ClinicalTrials.gov NCT04584671.

2045

L127

Rusu, D.

Lésions pulmonaires cavitaires post-COVID-19

https://doi.org/10.1016/j.rmra.2022.11.116

Published

1-Jan-23

Study

https://www.sciencedirect.com/science/article/pii/S1877120322002865

Introduction
Les lésions pulmonaires cavitaires sont des complications rares et généralement tardives de l’infection SARS-CoV-2. La fréquence de la cavitation pulmonaire au cours de la COVID-19 reste incertaine : l’incidence a été estimée à 1,7 % parmi tous les patients traités pour la COVID-19 à l’hôpital, 3,3 % parmi les patients ayant développé pneumonie COVID-19 et jusqu’à 11 % chez les patients hospitalisés en unité de soins intensif [1], [2].
Méthodes
Une série de 14 patients avec des cavitations pulmonaires post-COVID-19 a été analysée. Tous les patients ont été évalués par scanner thoracique, examen microbiologique pour confirmer une co-infection bactérienne ou fongique, ou mycobactérienne, par bronchoscopie avec BAL, examen sérologique pour Aspergillus, marqueurs immuns (ANA, ANCA), test VIH, analyses de laboratoire de routine.
Résultats
L’âge des patients variait entre 32 et 69 ans. Les lésions pulmonaires cavitaires étaient des complications tardives, la plupart des patients se présentant 2 mois après la COVID-19. Les principaux symptômes associés étaient dyspnée, douleurs thoraciques, toux, hémoptysie, fièvre. La cavitation pulmonaire peut survenir après la maladie COVID-19, même en cas de COVID-19 léger. Parmi les patients évalués, 6 avaient des formes sévères de COVID-19, 5 patients des formes modérées et 3 patients des formes légères. La présentation d’imagerie des cavités était diverse, mais surtout ce sont de cavités avec des parois épaisses, contenant des détritus. Chez les patients évalués, les causes des cavités pulmonaires étaient les surinfections bactériennes (Staphylococcus aureus, Pseudomonas aeruginosae) et fongiques (Aspergillus), les infections mycobactériennes (tuberculose, mycobactéries non tuberculeuses), thromboembolie pulmonaire avec infarctus, les bronchectasies, le néoplasme. Onze patients ont reçu une antibiothérapie et un traitement à la dexaméthasone pendant la COVID-19. Un mécanisme iatrogénique avec l’introduction de traitements corticoïdes pourrait favoriser les surinfections bactériennes ou fongiques et la formation d’abcès pulmonaires.
Conclusion
La présence de cavitation est considérée comme une manifestation atypique du COVID-19, suggérant un diagnostic alternatif. Lésions cavitaires chez les patients atteints de COVID-19 nécessite un diagnostic différentiel pour des infections superposées, des néoplasmes, des mycobactérioses, d’embolie pulmonaire, de tuberculose, des maladies fongiques, d’infarctus pulmonaire ou de maladie vasculaire thrombembolique associée à COVID-19.

2046

L128

Kouri, Andrew; Gupta, Samir

Respiratory manifestations of long COVID

https://doi.org/10.1080/24745332.2022.2156407

Published

13-Jan-23

Review

https://doi.org/10.1080/24745332.2022.2156407

As we near the third year of the COVID-19 pandemic, greater attention is now being paid to the potential long-term consequences of SARS-CoV-2 in the hundreds of millions of people infected globally. A syndrome termed “long COVID” has emerged, which predominantly manifests as persistent fatigue, dyspnea, chest pain, and cognitive dysfunction following acute infection. The incidence of long COVID is in the range of 15% based on current best evidence, and symptoms are likely a result of several different pathophysiological mechanisms including multi-organ injury from acute infection, systemic viral persistence, immune dysregulation, and/or autoimmunity. Pulmonary symptoms represent a significant component of long COVID, and there is a growing body of research describing the epidemiology, risk factors, physiology, and radiology of the respiratory manifestations of long COVID. In this clinical review, we examine the most recent evidence relating to “respiratory long COVID,” discuss how innovative technologies such as Xenon-129 gas transfer magnetic resonance imaging (MRI) and respiratory oscillometry are helping to elucidate its unique pathophysiology, and consider the role of preventative strategies and possible treatments such as adapted pulmonary rehabilitation. The burden of respiratory long COVID is likely to continue to grow, and all healthcare professionals who care for patients with respiratory disease must prepare for this emerging chronic condition. This will require increased resources from healthcare decision makers, inventive approaches to healthcare delivery, further research, and the same spirit of collaboration that has enabled the many success stories to date in the global effort against COVID-19.

2047

L129

Krueger, Tina; van den Heuvel, Janelle; van Kampen-van den Boogaart, Vivian; van Zeeland, Roel; Mehagnoul-Schipper, D. Jannet; Barten, Dennis G.; Knarren, Lieve; Maas, Arno F. G.; Wyers, Caroline E.; Gach, Debbie; Schols, Annemie M. W. J.; Beijers, Rosanne J. H. C. G.; van den Bergh, Joop P.; van Osch, Frits H. M.

Pulmonary function three to five months after hospital discharge for COVID-19: a single centre cohort study

https://doi.org/10.1038/s41598-023-27879-8

Published

13-Jan-23

Study

https://www.nature.com/articles/s41598-023-27879-8

Some COVID-19 survivors suffer from persistent pulmonary function impairment, but the extent and associated factors are unclear. This study aimed to characterize pulmonary function impairment three to five months after hospital discharge and the association with disease severity. Survivors of COVID-19 after hospitalization to the VieCuri Medical Centre between February and December 2020 were invited for follow-up, three to five months after discharge. Dynamic and static lung volumes, respiratory muscle strength and diffusion capacity were measured. The cohort comprised 257 patients after a moderate (n = 33), severe (n = 151) or critical (n = 73) COVID-19 infection with a median follow-up of 112 days (interquartile range 96–134 days). The main sequelae included reduced diffusion capacity (36%) and reduced maximal expiratory pressure (24%). Critically ill patients were more likely to have reduced diffusion capacity than moderate (OR 8.00, 95% CI 2.46–26.01) and severe cases (OR 3.74, 95% CI 1.88–7.44) and lower forced vital capacity (OR 3.29, 95% CI 1.20–9.06) compared to severe cases. Many COVID-19 survivors, especially after a critical disease course, showed pulmonary function sequelae, mainly DLCO impairments, three to five months after discharge. Monitoring is needed to investigate the persistence of these symptoms and the longer-term implications of the COVID-19 burden.

2048

L130

Franco-Moreno, A.; Brown-Lavalle, D.; Campos-Arenas, M.; Rodríguez-Ramírez, N.; Muñoz-Roldán, C.; Rubio-Aguilera, A. I.; Muñoz-Rivas, N.; de Girón, J. Bascuñana-Morejón; Fernández-Vidal, E.; Palma-Huerta, E.; Estévez-Alonso, S.; Rodríguez-Gómez, B.; Manzano-Valera, S.; Pedrero-Tomé, R.; Casado-Suela, M.; Bibiano-Guillén, C.; Mir-Montero, M.; Torres-Macho, J.; Bustamante-Fermosel, A.; Moya-Mateo, E.; Mestre-Gómez, B.; Lorente-Ramos, R. M.; Rogado, J.; Obispo, B.; Salazar-Chiriboga, D.; Sáez-Vaquero, T.; Abad-Motos, A.; Cortina-Camarero, C.; Such-Díaz, A.; Ruiz-Velasco, E.; Sierra-Hidalgo, F.; de Carranza-López, M.; Herrera-Morueco, M. A.; Akasbi-Montalvo, M.; Medrano-Izquierdo, P.; Mariscal-Gómez, E.; Marín-Mori, K.; Figueras-González, C.; López-Lallave, S.; Díaz-Díaz, D.; Mauleón-Fernández, C.; Martín-Navarro, J.; Torres-Rubio, P.; Matesanz, C.; Moro-Álvarez, M. J.; Hernández-Rivas, J. A.; the Infanta Leonor Thrombosis Research Group

Acute phase characteristics and long-term complications of pulmonary embolism in COVID-19 compared to non-COVID-19 cohort: a large single-centre study

https://doi.org/10.1186/s12890-023-02323-9

Published

18-Jan-23

Study

https://doi.org/10.1186/s12890-023-02323-9

Background
To compare the severity of pulmonary embolism (PE) and the long-term complications between patients with and without COVID-19, and to investigate whether the tools for risk stratification of death are valid in this population.
Methods
We retrospectively included hospitalized patients with PE from 1 January 2016 to 31 December 2022. Comparisons for acute episode characteristics, risk stratification of the PE, outcomes, and long-term complications were made between COVID and non-COVID patients.
Results
We analyzed 116 (27.5%) COVID patients and 305 (72.4%) non-COVID patients. In patients with COVID-19, the traditional risk factors for PE were absent, and the incidence of deep vein thrombosis was lower. COVID patients showed significantly higher lymphocyte count, lactate dehydrogenase, lactic acid, and D-dimer levels. COVID patients had PE of smaller size (12.3% vs. 25.5% main pulmonary artery, 29.8% vs. 37.1% lobar, 44.7% vs. 29.5% segmental and 13.2% vs. 7.9% subsegmental, respectively; p < 0.001), less right ventricular dysfunction (7.7% vs. 17.7%; p = 0.007) and higher sPESI score (1.66 vs. 1.11; p < 0.001). The need for mechanical ventilation was significantly higher in COVID patients (8.6% vs. 1.3%; p < 0.001); However, the in-hospital death was less (5.2% vs. 10.8%; p = 0.074). The incidence of long-term complications was lower in COVID cohort (p < 0.001). PE severity assessed by high sPESI and intermediate and high-risk categories were independently associated with in-hospital mortality in COVID patients.
Conclusion
The risk of in-hospital mortality and the incidence of long-term complications were lower in COVID-19. The usual tools for risk stratification of PE are valid in COVID patients.

2049

L131

Carvalho, Carlos Roberto Ribeiro; Lamas, Celina Almeida; Chate, Rodrigo Caruso; Salge, João Marcos; Sawamura, Marcio Valente Yamada; Albuquerque, André L. P. de; Junior, Carlos Toufen; Lima, Daniel Mario; Garcia, Michelle Louvaes; Scudeller, Paula Gobi; Nomura, Cesar Higa; Gutierrez, Marco Antonio; Baldi, Bruno Guedes; Group, HCFMUSP Covid-19 Study

Long-term respiratory follow-up of ICU hospitalized COVID-19 patients: Prospective cohort study

https://doi.org/10.1371/journal.pone.0280567

Published

20-Jan-23

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0280567

Background Coronavirus disease (COVID-19) survivors exhibit multisystemic alterations after hospitalization. Little is known about long-term imaging and pulmonary function of hospitalized patients intensive care unit (ICU) who survive COVID-19. We aimed to investigate long-term consequences of COVID-19 on the respiratory system of patients discharged from hospital ICU and identify risk factors associated with chest computed tomography (CT) lesion severity. Methods A prospective cohort study of COVID-19 patients admitted to a tertiary hospital ICU in Brazil (March-August/2020), and followed-up six-twelve months after hospital admission. Initial assessment included: modified Medical Research Council dyspnea scale, SpO2 evaluation, forced vital capacity, and chest X-Ray. Patients with alterations in at least one of these examinations were eligible for CT and pulmonary function tests (PFTs) approximately 16 months after hospital admission. Primary outcome: CT lesion severity (fibrotic-like or non-fibrotic-like). Baseline clinical variables were used to build a machine learning model (ML) to predict the severity of CT lesion. Results In total, 326 patients (72%) were eligible for CT and PFTs. COVID-19 CT lesions were identified in 81.8% of patients, and half of them showed mild restrictive lung impairment and impaired lung diffusion capacity. Patients with COVID-19 CT findings were stratified into two categories of lesion severity: non-fibrotic-like (50.8%-ground-glass opacities/reticulations) and fibrotic-like (49.2%-traction bronchiectasis/architectural distortion). No association between CT feature severity and altered lung diffusion or functional restrictive/obstructive patterns was found. The ML detected that male sex, ICU and invasive mechanic ventilation (IMV) period, tracheostomy and vasoactive drug need during hospitalization were predictors of CT lesion severity(sensitivity,0.78±0.02;specificity,0.79±0.01;F1-score,0.78±0.02;positive predictive rate,0.78±0.02; accuracy,0.78±0.02; and area under the curve,0.83±0.01). Conclusion ICU hospitalization due to COVID-19 led to respiratory system alterations six-twelve months after hospital admission. Male sex and critical disease acute phase, characterized by a longer ICU and IMV period, and need for tracheostomy and vasoactive drugs, were risk factors for severe CT lesions six-twelve months after hospital admission.

2050

L132

Zheng, Zhen; Peng, Fei; Zhou, Yong

Pulmonary fibrosis: A short- or long-term sequelae of severe COVID-19?

https://doi.org/10.1016/j.pccm.2022.12.002

Published

23-Jan-23

Review

https://www.sciencedirect.com/science/article/pii/S277255882300004X

The pandemic of coronavirus disease 2019 (COVID‑19), caused by a novel severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), has caused an enormous impact on the global healthcare. SARS-CoV-2 infection primarily targets the respiratory system. Although most individuals testing positive for SARS-CoV-2 present mild or no upper respiratory tract symptoms, patients with severe COVID-19 can rapidly progress to acute respiratory distress syndrome (ARDS). ARDS-related pulmonary fibrosis is a recognized sequelae of COVID-19. Whether post-COVID-19 lung fibrosis is resolvable, persistent, or even becomes progressive as seen in human idiopathic pulmonary fibrosis (IPF) is currently not known and remains a matter of debate. With the emergence of effective vaccines and treatments against COVID-19, it is now important to build our understanding of the long-term sequela of SARS-CoV-2 infection, to identify COVID-19 survivors who are at risk of developing chronic pulmonary fibrosis, and to develop effective anti-fibrotic therapies. The current review aims to summarize the pathogenesis of COVID-19 in the respiratory system and highlights ARDS-related lung fibrosis in severe COVID-19 and the potential mechanisms. It envisions the long-term fibrotic lung complication in COVID-19 survivors, in particular in the aged population. The early identification of patients at risk of developing chronic lung fibrosis and the development of anti-fibrotic therapies are discussed.

2051

L133

Carvalho, Carlos Roberto Ribeiro; Lamas, Celina Almeida; Chate, Rodrigo Caruso; Salge, João Marcos; Sawamura, Marcio Valente Yamada; Albuquerque, André L. P. de; Junior, Carlos Toufen; Lima, Daniel Mario; Garcia, Michelle Louvaes; Scudeller, Paula Gobi; Nomura, Cesar Higa; Gutierrez, Marco Antonio; Baldi, Bruno Guedes; Group, HCFMUSP Covid-19 Study

Long-term respiratory follow-up of ICU hospitalized COVID-19 patients: Prospective cohort study

https://doi.org/10.1371/journal.pone.0280567

Published

20-Jan-23

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0280567

Background Coronavirus disease (COVID-19) survivors exhibit multisystemic alterations after hospitalization. Little is known about long-term imaging and pulmonary function of hospitalized patients intensive care unit (ICU) who survive COVID-19. We aimed to investigate long-term consequences of COVID-19 on the respiratory system of patients discharged from hospital ICU and identify risk factors associated with chest computed tomography (CT) lesion severity. Methods A prospective cohort study of COVID-19 patients admitted to a tertiary hospital ICU in Brazil (March-August/2020), and followed-up six-twelve months after hospital admission. Initial assessment included: modified Medical Research Council dyspnea scale, SpO2 evaluation, forced vital capacity, and chest X-Ray. Patients with alterations in at least one of these examinations were eligible for CT and pulmonary function tests (PFTs) approximately 16 months after hospital admission. Primary outcome: CT lesion severity (fibrotic-like or non-fibrotic-like). Baseline clinical variables were used to build a machine learning model (ML) to predict the severity of CT lesion. Results In total, 326 patients (72%) were eligible for CT and PFTs. COVID-19 CT lesions were identified in 81.8% of patients, and half of them showed mild restrictive lung impairment and impaired lung diffusion capacity. Patients with COVID-19 CT findings were stratified into two categories of lesion severity: non-fibrotic-like (50.8%-ground-glass opacities/reticulations) and fibrotic-like (49.2%-traction bronchiectasis/architectural distortion). No association between CT feature severity and altered lung diffusion or functional restrictive/obstructive patterns was found. The ML detected that male sex, ICU and invasive mechanic ventilation (IMV) period, tracheostomy and vasoactive drug need during hospitalization were predictors of CT lesion severity(sensitivity,0.78±0.02;specificity,0.79±0.01;F1-score,0.78±0.02;positive predictive rate,0.78±0.02; accuracy,0.78±0.02; and area under the curve,0.83±0.01). Conclusion ICU hospitalization due to COVID-19 led to respiratory system alterations six-twelve months after hospital admission. Male sex and critical disease acute phase, characterized by a longer ICU and IMV period, and need for tracheostomy and vasoactive drugs, were risk factors for severe CT lesions six-twelve months after hospital admission.

2052

L134

Núñez-Fernández, Marta; Ramos-Hernández, Cristina; García-Río, Francisco; Pérez-González, Alexandre; Tilve-Gómez, Amara; Rodríguez-Fernández, Paula; Nodar-Germiñas, Andrés; Fernández-García, Alberto; Ruano-Raviña, Alberto; Fernández-Villar, Alberto

Evolution and long‑term respiratory sequelae after severe COVID-19 pneumonia: nitric oxide diffusion measurement value

https://doi.org/10.1186/s12931-023-02344-2

Published

13-Feb-23

Study

https://doi.org/10.1186/s12931-023-02344-2

Introduction
There are no published studies assessing the evolution of combined determination of the lung diffusing capacity for both nitric oxide and carbon monoxide (DLNO and DLCO) 12 months after the discharge of patients with COVID-19 pneumonia.
Methods
Prospective cohort study which included patients who were assessed both 3 and 12 months after an episode of SARS-CoV-2 pneumonia. Their clinical status, health condition, lung function testings (LFTs) results (spirometry, DLNO-DLCO analysis, and six-minute walk test), and chest X-ray/computed tomography scan images were compared.
Results
194 patients, age 62 years (P25–75, 51.5–71), 59% men, completed the study. 17% required admission to the intensive care unit. An improvement in the patients’ exercise tolerance, the extent of the areas of ground-glass opacity, and the LFTs between 3 and 12 months following their hospital discharge were found, but without a decrease in their degree of dyspnea or their self-perceived health condition. DLNO was the most significantly altered parameter at 12 months (19.3%). The improvement in DLNO-DLCO mainly occurred at the expense of the recovery of alveolar units and their vascular component, with the membrane factor only improving in patients with more severe infections.
Conclusions
The combined measurement of DLNO-DLCO is the most sensitive LFT for the detection of the long-term sequelae of COVID-19 pneumonia and it explain better their pathophysiology.

2053

L135

Kooner, Harkiran K; McIntosh, Marrissa J; Matheson, Alexander M; Abdelrazek, Mohammed; Albert, Mitchell S; Dhaliwal, Inderdeep; Kirby, Miranda; Ouriadov, Alexei; Santyr, Giles E; Venegas, Carmen; Radadia, Nisarg; Svenningsen, Sarah; Nicholson, J Michael; Parraga, Grace

Post-Acute COVID-19 Syndrome: 129Xe MRI Ventilation Defects and Respiratory Outcomes One Year Later

https://doi.org/10.1148/radiol.222557

Published

7-Feb-23

Study

https://pubs.rsna.org/doi/10.1148/radiol.222557

Background
In people with post-acute COVID-19 syndrome (PACS) and normal pulmonary function, 129Xe MRI ventilation defects, abnormal quality-of-life scores, and exercise limitation were reported 3-months after infection; the longitudinal trajectory remains unclear.
Purpose
To measure and compare pulmonary function, exercise capacity, quality-of-life, and 129Xe MRI ventilation defect percent (VDP) in people with PACS evaluated 3- and 15-months post-infection.
Materials and Methods
In this prospective study, participants with PACS aged 18-80 years were enrolled between July 2020 and August 2021 from two quaternary care centers. They were evaluated 3-months and 15-months post-infection for: 129Xe MRI VDP, diffusing capacity of the lung for carbon monoxide (DLCO), spirometry, oscillometry, six-minute walk distance (6MWD), and St. George's Respiratory Questionnaire (SGRQ). Differences between time-points were evaluated using paired t-tests. Multivariable models were generated to explain exercise capacity and quality-of-life improvements. Odds ratios (OR) were used to evaluate potential treatment influences.
Results
Fifty-three participants (mean age, 55 years ±18[SD]; 26 male; 27 female) attended both 3- and 15-month visits and were included in analysis. 129Xe MRI VDP (5.4%, 4.2%; P=.003), forced expiratory volume in 1-second (85%pred, 90%pred; P=.001), DLCO (89%pred, 99%pred; P=.002) and SGRQ (35, 25; P<.001) improved between the 3- and 15-month visit. VDP measured at 3- months post-COVID predicted the change in 6MWD (β=-.643, P=.001) while treatment with respiratory medication at 3-months predicted improved 15-month quality-of-life score (OR=4.0; 95%CI:1.2,13.8, P=.03).
Conclusion
Pulmonary function, gas-exchange, exercise capacity, quality-of-life, and 129Xe MRI ventilation defect percent (VDP) improved in participants with post-acute COVID-19 syndrome evaluated at 15-months as compared to 3-months post-infection. VDP measured at 3-months post-infection correlated with improved exercise capacity, whilst treatment with respiratory medication was associated with improved quality-of-life score at 15-months post-infection.
Clinical Trial Registration: www.clinicaltrials.gov NCT05014516
See also the editorial by Vogel-Claussen in this issue.

2054

L136

Lalwani, Muskan; Taksande, Avinash B.; Mukku3652008@gmail.com, Muskan; Taksande, Avinash B.

Pulmonary Function Test as a Diagnostic Tool for Post-COVID-19 Effects

https://doi.org/10.7759/cureus.34751

Published

7-Feb-23

Review

https://www.cureus.com/articles/116773-pulmonary-function-test-as-a-diagnostic-tool-for-post-covid-19-effects

COVID-19-infected survivors are reporting persistent anomalies upon hospital discharge. After one year, a sizable percentage of COVID-19 survivors still have persistent symptoms affecting different bodily systems. Evidence suggests that the lungs are the most affected organs by COVID-19. It may also cause corollary and other medical issues. The literature on preceding COVID-19 infections reviews that patients may also experience chronic impairment in breathing characteristics after discharge. The outcome of COVID-19 may remain for weeks to months after the initial recovery. Our goal is to determine the superiority of the restrictive pattern, obstructive pattern, and adjusted diffusion in patients post-COVID-19 contamination and to explain the distinctive opinions of breathing characteristics used with those patients. Therefore, lung function tests were measured post-discharge for three to 12 months. According to estimates, 80% of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-infected patients experienced one or more chronic symptoms. Multidisciplinary teams are required to develop preventive measures, rehabilitation methods, and scientific control plans with a completely patient-centered attitude for long-term COVID-19 care. Clarifying the pathophysiologic mechanisms, creating and testing specific interventions, and treating patients with long-term COVID-19 are urgently needed. The goal of this review is to locate research evaluating COVID-19's long-term effects. A person who has suffered from COVID-19 in the past showed changes in their pulmonary function test. So, we have to notice the changes and recovery from post-COVID-19 effects. COVID-19 survivors were observed in an eventual observational study and continuously examined three, six, and 12 months after having COVID-19 infections. We evaluated the clinical features and concentrations of circulating pulmonary epithelial and endothelial markers in COVID-19 survivors with normal or lower diffusion capacity for carbon monoxide (DLCO) six months after discharge to analyze risk factors and underlying pathophysiology.

2055

L137

Bazdar, Somayeh; Kwee, Anastasia K. A. L.; Houweling, Laura; de Wit-van Wijck, Yolanda; Mohamed Hoesein, Firdaus A. A.; Downward, George S.; Nossent, Esther J.; Maitland-van der Zee, Anke H.

A Systematic Review of Chest Imaging Findings in Long COVID Patients

https://doi.org/10.3390/jpm13020282

Published

1-Feb-23

Review

https://www.mdpi.com/2075-4426/13/2/282

Long COVID is the persistence of one or more COVID-19 symptoms after the initial viral infection, and there is evidence supporting its association with lung damage. In this systematic review, we provide an overview of lung imaging and its findings in long COVID patients. A PubMed search was performed on 29 September 2021, for English language studies in which lung imaging was performed in adults suffering from long COVID. Two independent researchers extracted the data. Our search identified 3130 articles, of which 31, representing the imaging findings of 342 long COVID patients, were retained. The most common imaging modality used was computed tomography (CT) (N = 249). A total of 29 different imaging findings were reported, which were broadly categorized into interstitial (fibrotic), pleural, airway, and other parenchymal abnormalities. A direct comparison between cases, in terms of residual lesions, was available for 148 patients, of whom 66 (44.6%) had normal CT findings. Although respiratory symptoms belong to the most common symptoms in long COVID patients, this is not necessarily linked to radiologically detectable lung damage. Therefore, more research is needed on the role of the various types of lung (and other organ) damage which may or may not occur in long COVID.

2056

L138

Björsell, Tove; Sundh, Josefin; Lange, Anna; Ahlm, Clas; Forsell, Mattias N.E.; Tevell, Staffan; Blomberg, Anders; Edin, Alicia; Normark, Johan; Cajander, Sara

Risk factors for impaired respiratory function post COVID-19: A prospective cohort study of nonhospitalized and hospitalized patients

https://doi.org/10.1111/joim.13614

Published

23-Feb-23

Study

https://onlinelibrary.wiley.com/doi/abs/10.1111/joim.13614

Background Severe COVID-19 increases the risk for long-term respiratory impairment, but data after mild COVID-19 are scarce. Our aims were to determine risk factors for reduced respiratory function 3–6 months after COVID-19 infection and to investigate if reduced respiratory function would relate to impairment of exercise performance and breathlessness. Methods Patients with COVID-19 were enrolled at the University Hospitals of Umeå and Örebro, and Karlstad Central Hospital, Sweden. Disease severity was defined as mild (nonhospitalized), moderate (hospitalized with or without oxygen treatment), and severe (intensive care). Spirometry, including diffusion capacity (DLCO), was performed 3–6 months after hospital discharge or study enrollment (for nonhospitalized patients). Breathlessness (defined as ≥1 according to the modified Medical Research Council scale) and functional exercise capacity (1-min sit-to-stand test; 1-MSTST) were assessed. Results Between April 2020 and May 2021, 337 patients were enrolled in the study. Forced vital capacity and DLCO were significantly lower in patients with severe COVID-19. Among hospitalized patients, 20% had reduced DLCO, versus 4% in nonhospitalized. Breathlessness was found in 40.6% of the participants and was associated with impaired DLCO. A pathological desaturation or heart rate response was observed in 17% of participants during the 1-MSTST. However, this response was not associated with reduced DLCO. Conclusion Reduced DLCO was the major respiratory impairment 3–6 months following COVID-19, with hospitalization as the most important risk factor. The lack of association between impaired DLCO and pathological physiological responses to exertion suggests that these physiological responses are not primarily related to decreased lung function.

2057

L139

Cui, Lu; Fang, Zhuoqing; De Souza, Cristabelle Madona; Lerbs, Tristan; Guan, Yuan; Li, Irene; Charu, Vivek; Chen, Shih-Yu; Weissman, Irving; Wernig, Gerlinde

Innate immune cell activation causes lung fibrosis in a humanized model of long COVID

https://doi.org/10.1073/pnas.2217199120

Published

7-Mar-23

Study

https://www.pnas.org/doi/full/10.1073/pnas.2217199120

Significance
Post COVID-19 induced pulmonary fibrosis is the most severe of a number of clinical symptoms associated with “long COVID”, a condition which is currently incompletely understood but affects millions given the ongoing COVID-19 pandemic. Using systems biology and mechanistic studies in a humanized mouse model of COVID lung fibrosis, we identify the essential genetic and immunologic perturbations occurring in patients with long COVID lung fibrosis and reveal promising therapeutic targets.
Abstract
COVID-19 remains a global pandemic of an unprecedented magnitude with millions of people now developing “COVID lung fibrosis.” Single-cell transcriptomics of lungs of patients with long COVID revealed a unique immune signature demonstrating the upregulation of key proinflammatory and innate immune effector genes CD47, IL-6, and JUN. We modeled the transition to lung fibrosis after COVID and profiled the immune response with single-cell mass cytometry in JUN mice. These studies revealed that COVID mediated chronic immune activation reminiscent to long COVID in humans. It was characterized by increased CD47, IL-6, and phospho-JUN (pJUN) expression which correlated with disease severity and pathogenic fibroblast populations. When we subsequently treated a humanized COVID lung fibrosis model by combined blockade of inflammation and fibrosis, we not only ameliorated fibrosis but also restored innate immune equilibrium indicating possible implications for clinical management of COVID lung fibrosis in patients.
publisher: Proceedings of the National Academy of Sciences

2058

L140

Mulet, Alba; Tarrasó, Julia; Rodríguez-Borja, Enrique; Carbonell-Asins, Juan A; Lope-Martínez, Amaia; Martí-Martinez, Arancha; Murria, Rosa; Safont, Belén; Fernandez-Fabrellas, Estrella; Ros, José A; Rodriguez-Portal, Juan A; Andreu, Ada L; Soriano, Joan B.; Signes-Costa, Jaime

Fibrosis Biomarkers in a Cohort of COVID-19 Patients One Year after Hospital Discharge

https://doi.org/10.1165/rcmb.2022-0474OC

Published

27-Feb-23

Study

https://www.atsjournals.org/doi/abs/10.1165/rcmb.2022-0474OC

Beyond the acute infection of coronavirus disease (COVID-19), concern has arisen about long-term effects of SARS-CoV-2 infection. The aim of our study was to analyze if there is any biomarker of fibrogenesis in COVID-19 pneumonia patients capable of predicting post-COVID pulmonary sequelae. We conducted a multicenter, prospective, observational cohort study of patients admitted to hospital with bilateral COVID-19 pneumonia. We classified patients in two groups according to severity, and blood samples to measure MMP1, MMP7, periostin and VEGF, respiratory function tests and HRCT imaging were obtained at 2 and 12 months after hospital discharge. A total of 135 patients were evaluated at 12 months. Median age was 61 (IQR: 19) years and 58.5% were men. We found between-group differences in age, radiological involvement, length of hospital stay and inflammatory laboratory parameters. Differences were found between 2 and 12 months in all functional tests, including improvements in FVC% (98.0 vs. 103.9; p=0.001) and DLCO<80% (60.9% vs. 39.7%; p=0.001). At 12 months, 63% of patients had complete HRTC resolution, but fibrotic changes persisted in 29.4%. Biomarker analysis demonstrated differences at 2 months in periostin (ng/mL) (0.8893 vs. 1.437; p<0.001) and MMP-7 (ng/mL) (8.7249 vs. 15.2181; p<0.001). No differences were found at 12 months. In multivariable analysis, only 2-month periostin was associated with 12-month fibrotic changes (OR: 1.0013 95% CI: 1.0006–1.00231; p=0.003) and 12-month DLCO impairment (OR: 1.0006 95% CI: 1.0000–1.0013; p=0.047). Our data suggest that early periostin post-discharge could predict the presence of fibrotic pulmonary changes.

2059

L141

Kewalramani, Namrata; Heenan, Kerri-Marie; McKeegan, Denise; Chaudhuri, Nazia

Post-COVID Interstitial Lung Disease—The Tip of the Iceberg

https://doi.org/10.1016/j.iac.2023.01.004

Published

3-Mar-23

Review

https://www.immunology.theclinics.com/article/S0889-8561(23)00004-8/fulltext

Key points
•Some patients have persistent symptoms, lung function impairment, and radiological abnormalities post-severe acute respiratory syndrome coronavirus 2 infection.
•Post-COVID-fibrotic changes have shown resolution at 12 months, however, in a cohort of patients, the changes persist.
•The long-term impact of post-COVID fibrosis remains unknown and ongoing studies are aimed at assessing the frequency and consequences of this new disease entity.
•Post-COVID interstitial lung disease may represent a significant burden on the health care systems.
Introduction
On the March 11, 2020, the World Health Organization (WHO) declared the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a global pandemic, commonly referred to as coronavirus 2019 (COVID-19).1 The first documented case was recognized in Wuhan, China, in December 2019.2 As of November 2022, there have been over 550 million cases worldwide and over 6 million deaths associated with COVID-19.3 The spectrum of presentations and symptoms of COVID-19 can vary widely from asymptomatic carriers to life-threatening respiratory and multi-organ failure. The risk factors for the severity of COVID-19 are thought to correlate with increasing age, body mass index (BMI), and comorbidities such as diabetes, obesity, cardiovascular disease, hypertension, and chronic kidney disease.4, 5, 6, 7
The widespread collaborative efforts of governments, public health, pharmaceutical industry, and researchers have led to a wealth of expertise in tackling the pandemic over a relatively short time. We have effective therapies that can reduce the symptom burden and risk of hospitalization and in-hospital mortality with COVID-19. Antivirals, monoclonal antibodies, and immunomodulatory drugs have emerged through robust trials as treatments for SARS-CoV-2 infection.8,9 Several therapies have been shown to reduce the risk of hospitalization in patients with mild to moderate disease. Treatment of symptomatic COVID-19 with Paxlovid, a SARS-CoV-2 protease inhibitor consisting of nirmatrelvir and ritonavir, has led to a reduction of severe COVID-19 by 89%, without evident safety concerns.10 In non-hospitalized patients with mild to moderate COVID-19 disease, Molnupiravir reduces the risk of hospitalization or death by approximately 50%.11, 12, 13 Coupled with the rollout of mass vaccination programs worldwide, we have seen the mortality from COVID-19 declining despite continued high rates of infection.14,15
Although we are grappling with the changing nature of the virus and attempting to rebuild our lives and economies, we are now faced with an emerging yet unquantifiable health epidemic –post-COVID-19 condition (long COVID). This review will discuss the emerging evidence for the development of post-COVID interstitial lung disease (PC-ILD) focusing on the pathophysiological mechanisms, incidence, diagnosis, and impact of this potentially new and emerging respiratory disease.
publisher: Elsevier

2060

L142

Barash, Mark; Ramalingam, Vijaya

Post-COVID Interstitial Lung Disease and Other Lung Sequelae

https://doi.org/10.1016/j.ccm.2022.11.019

Published

3-Mar-23

Review

https://www.chestmed.theclinics.com/article/S0272-5231(22)00135-6/fulltext

Key points
•Post-acute sequelae of SARS-COV-2 or post-COVID conditions are a poorly defined syndrome, possibly with long-lasting effects.
•Respiratory failure is one of the most serious complications of COVID-19 infection and contributes to major morbidity and mortality.
•Several studies have demonstrated abnormal lung function tests and radiological findings in patients who recovered from COVID-19 infection.
•Evidence on post-COVID pulmonary fibrosis is evolving.
Introduction
Respiratory failure is one of the most serious complications of COVID-19 infection and contributes to significant morbidity and mortality. Illness severity ranges from mild/asymptomatic disease to critical illness requiring mechanical ventilation. There has been increasing concern about pulmonary sequelae, including symptoms, pulmonary function testing (PFT) abnormalities, and pulmonary fibrosis.1 Our knowledge about the natural history of recovery after COVID-19 infection is limited.
This article focuses on two concepts. First, the authors seek to describe available knowledge of post-COVID lung disease including pulmonary physiologic changes, imaging characteristics, fibrotic lung disease, and other complications. Next, the authors discuss the post-acute sequelae of SARS-CoV-2 (PASC): a poorly understood syndrome comprising a conglomerate of “head-to-toe” symptoms that afflicts a subset of patients recovering from COVID-19.
publisher: Elsevier

2061

L143

Grewal, Japnam S.; Carlsten, Christopher; Johnston, James C.; Shah, Aditi S.; Wong, Alyson W.; Ryerson, Christopher J.

Post-COVID dyspnea: prevalence, predictors, and outcomes in a longitudinal, prospective cohort

https://doi.org/10.1186/s12890-023-02376-w

Published

13-Mar-23

Study

https://doi.org/10.1186/s12890-023-02376-w

Background
The pathophysiology, evolution, and associated outcomes of post-COVID dyspnea remain unknown. The aim of this study was to determine the prevalence, severity, and predictors of dyspnea 12 months following hospitalization for COVID-19, and to describe the respiratory, cardiac, and patient-reported outcomes in patients with post-COVID dyspnea.

Methods
We enrolled a prospective cohort of all adult patients admitted to 2 academic hospitals in Vancouver, Canada with PCR-confirmed SARS-CoV-2 during the first wave of COVID between March and June 2020. Dyspnea was measured 3, 6, and 12 months after initial symptom onset using the University of California San Diego Shortness of Breath Questionnaire.

Results
A total of 76 patients were included. Clinically meaningful dyspnea (baseline score > 10 points) was present in 49% of patients at 3 months and 46% at 12 months following COVID-19. Between 3 and 12 months post-COVID-19, 24% patients had a clinically meaningful worsening in their dyspnea, 49% had no meaningful change, and 28% had a clinically meaningful improvement in their dyspnea. There was worse sleep, mood, quality of life, and frailty in patients with clinically meaningful dyspnea at 12 months post-COVID infection compared to patients without dyspnea. There was no difference in PFT findings, troponin, or BNP comparing patients with and without clinically meaningful dyspnea at 12 months. Severity of dyspnea and depressive symptoms at 3 months predicted severity of dyspnea at 12 months.

Conclusions
Post-COVID dyspnea is common, persistent, and negatively impacts quality of life. Mood abnormalities may play a causative role in post-COVID dyspnea in addition to potential cardiorespiratory abnormalities. Dyspnea and depression at initial follow-up predict longer-term post-COVID dyspnea, emphasizing that standardized dyspnea and mood assessment following COVID-19 may identify patients at high risk of post-COVID dyspnea and facilitating early and effective management.

2062

L144

Rai, Deependra K.; Sharma, Priya; Karmakar, Saurabh; Thakur, Somesh; Ameet, H.; Yadav, Rajesh; Gupta, Vatsal B.

Approach to post COVID-19 persistent cough: A narrative review

https://doi.org/10.4103/lungindia.lungindia_250_22

Published

1-Apr-23

Review

https://journals.lww.com/lungindia/Fulltext/2023/03000/Approach_to_post_COVID_19_persistent_cough__A.10.aspx

A large proportion of patients who completely recovered from acute coronavirus disease 2019 (COVID-19) infection later continued to experience symptoms even after recovery, irrespective of the severity of the disease. Various terms with varying duration were used for those who had persistent symptoms, of which cough was the most common. We systematically searched the published literature concerning post-COVID-19 cough, its prevalence, and the potential ways to reduce it in clinical practice. The aim of this review was to provide an overview of existing literature concerning post-COVID-19 cough. Literature shows that augmented cough reflex sensitivity is responsible for persistent cough after acute viral upper respiratory infection (URI). Overall, the heightened cough reflex associated with SARSCoV2 induces neurotropism, neuroinflammation, and neuroimmunomodulation via the vagal sensory nerves. Therapies for post-COVID-19 cough aim at the suppression of cough reflex. For a patient who does not respond to early symptomatic treatment, Inhaled corticosteroids can be given a trial to suppress airway inflammation. More trials of novel cough therapies in patients with post-COVID-19 cough using various outcome measures need to be studied in future research. Several agents are currently available for symptomatic relief. However, non-response or refractory cough continues to preclude adequate symptom relief.

2063

L145

Hamdy, Rehab M.; Abdelaziz, Ola Hassan; Shamsseldain, Hager Elsayed; Eltrawy, Heba H.

Functional outcomes in post Covid-19 patients with persistent dyspnea: multidisciplinary approach

https://doi.org/10.1007/s10554-023-02819-9

Published

6-Mar-23

Study

https://doi.org/10.1007/s10554-023-02819-9

Background: Post-acute sequelae of SARS-CoV-2 (PASC) have emerged as a major health issue in patients who have previously been infected with Covid-19 virus. Purpose: we aimed at the assessment of functional outcomes in post Covid-19 patients with persistent dyspnea using a multidisciplinary approach including clinical assessment, laboratory investigations, exercise ECG, and different echo-Doppler modalities, including left atrial functions. Methods: The current observational randomized controlled study conducted on 60- patients one month after recovery from Covid-19 infection presented with persistent dyspnea compared to 30 healthy volunteers. All participants were subjected to evaluation of dyspnea by different scores, laboratory investigations, stress ECG, and echo-Doppler examination to measure LV dimensions, volumes, systolic and diastolic functions by M-mode, 2D, and tissue Doppler imaging in addition to 2-D speckle tacking LA strain. Results: Post Covid-19 patients had persistent elevation of inflammatory markers, low functional capacity (evidenced by a higher NYHA class, m MRC score, PCFS scale) and decreased METs by stress ECG compared to control group. Post Covid-19 patients showed LV diastolic dysfunction and impairment of 2D-STE LA functions compared to control group. We found negative correlations between LA strain with NYHA class, mMRC scale, LAVI, ESR and CRP; meanwhile, there were significant positive correlations between LA strain with exercise duration and METs. Conclusion: post Covid patients presented with persistent dyspnea demonstrated low functional capacity evidenced by different scores and stress ECG. Moreover, patients with post Covid syndrome showed elevated inflammatory biomarkers, LV diastolic dysfunction in addition to impaired LA strain functions. Impairment of LA strain was closely correlated to different functional scores, inflammatory biomarkers, exercise duration, and METs suggesting that these could to be the possible etiologies for the persistence of post Covid symptoms.

2064

L146

Fesu, Dorottya; Polivka, Lorinc; Barczi, Eniko; Foldesi, Marcell; Horvath, Gabor; Hidvegi, Edit; Bohacs, Aniko; Muller, Veronika

Post-COVID interstitial lung disease in symptomatic patients after COVID-19 disease

https://doi.org/10.1007/s10787-023-01191-3

Published

24-Mar-23

Study

https://doi.org/10.1007/s10787-023-01191-3

COVID-19 is often associated with long-lasting pulmonary symptoms. Data are scarce about interstitial lung disease (ILD) in patients following COVID-19 hospitalization with persistent symptoms. We retrospectively reviewed all cases sent to pulmonary post-COVID evaluation due to persistent symptoms between February 2021 and February 2022 (N = 318). All patients with suspected ILD (N = 44) were reviewed at the multidisciplinary discussion. Patient characteristics, symptoms, time since hospitalization, detailed lung function measurements and 6-min walk test (6MWT) were evaluated. The post-COVID ILD suspected group included more men (68.2 vs. 31.8%) with significantly older age compared to the control group (64.0 ± 12.3 vs. 51.3 ± 14.9 years). Most patient needed hospital care for COVID-19 pneumonia (68.6% of all patients and 84.1% of ILD suspected group) and average time since hospitalization was 2.4 ± 2.3 months. Persisting symptoms included fatigue (34%), dyspnoea (25.2%), cough (22.6%), and sleep disorders (insomnia 13.2%; sleepiness 8.2%). Post-COVID ILD presented more often with new symptoms of cough and sleepiness. Functional impairment, especially decreased walking distance and desaturation during 6-min walk test (6MWT) were detected in the ILD-suspected group. Respiratory function test in the post-COVID ILD group showed slight restrictive ventilatory pattern (FVC: 76.7 ± 18.1%, FEV1: 83.5 ± 19.1%, TLC: 85.6 ± 28.1%) and desaturation during 6MWT were detected in 41% of patients. LDCT changes were mainly ground glass opacities (GGO) and/or reticular abnormalities in most cases affecting < 10% of the lungs. Our data indicate that suspected post-COVID ILD is affecting 13.8% of symptomatic patients. High resolution chest CT changes were mainly low extent GGO/reticulation, while long-term lung structural changes need further evaluation.

2065

L147

Patrucco, Filippo; Solidoro, Paolo; Gavelli, Francesco; Apostolo, Daria; Bellan, Mattia

Idiopathic Pulmonary Fibrosis and Post-COVID-19 Lung Fibrosis: Links and Risks

https://doi.org/10.3390/microorganisms11040895

Published

1-Apr-23

Review

https://www.mdpi.com/2076-2607/11/4/895

Idiopathic pulmonary fibrosis (IPF) is considered the paradigmatic example of chronic progressive fibrosing disease; IPF does not result from a primary immunopathogenic mechanism, but immune cells play a complex role in orchestrating the fibrosing response. These cells are activated by pathogen-associated or danger-associated molecular patterns generating pro-fibrotic pathways or downregulating anti-fibrotic agents. Post-COVID pulmonary fibrosis (PCPF) is an emerging clinical entity, following SARS-CoV-2 infection; it shares many clinical, pathological, and immune features with IPF. Similarities between IPF and PCPF can be found in intra- and extracellular physiopathological pro-fibrotic processes, genetic signatures, as well as in the response to antifibrotic treatments. Moreover, SARS-CoV-2 infection can be a cause of acute exacerbation of IPF (AE-IPF), which can negatively impact on IPF patients’ prognosis. In this narrative review, we explore the pathophysiological aspects of IPF, with particular attention given to the intracellular signaling involved in the generation of fibrosis in IPF and during the SARS-CoV-2 infection, and the similarities between IPF and PCPF. Finally, we focus on COVID-19 and IPF in clinical practice.

2066

L148

del Corral, Tamara; Fabero-Garrido, Raúl; Plaza-Manzano, Gustavo; Fernández-de-las-Peñas, César; Navarro-Santana, Marcos José; López-de-Uralde-Villanueva, Ibai

Minimal Clinically Important Differences in Inspiratory Muscle Function Variables after a Respiratory Muscle Training Programme in Individuals with Long-Term Post-COVID-19 Symptoms

https://doi.org/10.3390/jcm12072720

Published

1-Jan-23

Study

https://www.mdpi.com/2077-0383/12/7/2720

Objective: To establish the minimal clinically important difference (MCID) for inspiratory muscle strength (MIP) and endurance (IME) in individuals with long-term post-COVID-19 symptoms, as well as to ascertain which of the variables has a greater discriminatory capacity and to compare changes between individuals classified by the MCID. Design: Secondary analysis of randomised controlled trial of data from 42 individuals who performed an 8-week intervention of respiratory muscle training programme. Results: A change of at least 18 cmH2O and 22.1% of that predicted for MIP and 328.5s for IME represented the MCID. All variables showed acceptable discrimination between individuals who classified as “improved” and those classified as “stable/not improved” (area under the curve ≥0.73). MIP was the variable with the best discriminative ability when expressed as a percentage of prediction (Youden index, 0.67; sensitivity, 76.9%; specificity, 89.7%). Participants classified as “improved” had significantly greater improvements in quality of life and lung function compared with the participants classified as “stable/not improved”. Conclusion: In individuals with long-term post-COVID-19 symptoms, the inspiratory muscle function variables had an acceptable discriminative ability to assess the efficacy of a respiratory muscle training programme. MIP was the variable with the best discriminative ability, showing better overall performance when expressed as a percentage of prediction.

2067

L149

Kooner, Harkiran K.; McIntosh, Marrissa J.; Matheson, Alexander M.; Svenningsen, Sarah; Parraga, Grace

More Data about 129Xe MRI Ventilation Defects in Long COVID-19

https://doi.org/10.1148/radiol.230479

Published

18-Apr-23

Study

https://pubs.rsna.org/doi/full/10.1148/radiol.230479

We appreciated the editorial (1) about our study (2), published in Radiology on February 7, 2023. We thank Dr Vogel-Claussen for his insightful analysis and commentary. He correctly pointed out that abnormal xenon 129 (129Xe) MRI ventilation defect percent (VDP) at 15 months after infection (n = 53; 4.2% ± 6.8 [SD]) may derive from patients with post-acute COVID-19 syndrome who self-identified with prior respiratory disease (n = 22; 7.4% ± 9.1).

Based on his excellent comments, we thought it would be important to dig deeper into the data, so we performed additional analyses on the subgroups with and without prior respiratory disease.

In the subgroup with no self-reported previous lung disease, airways-disease medication at 3 months after COVID-19 infection was associated with a significant and clinically meaningful improvement in the St George Respiratory Questionnaire (SGRQ) score (odds ratio [OR], 3.7; 95% CI: 1.02, 13.14; P = .046) at 15 months compared with 3 months after infection. This was consistent with results in the entire group (OR, 4.0; 95% CI: 1.2, 13.8; P = .03) (2) and the smaller group of participants with prior respiratory illness (OR, 4.5; 95% CI: 0.97, 20.83; P = .05). Therefore, it appears that both subgroups showed an SGRQ improvement, which correlated with airways-disease treatment at 3 months. This finding supports the notion that there is an airways-disease component of post-acute COVID-19 syndrome (3), even in patients with no previous diagnosis of asthma or chronic obstructive pulmonary disease.

In the subgroup without respiratory disease, there was significantly improved forced expiratory volume in 1 second (FEV1; from 89% predicted to 97% predicted; P = .009), ratio of FEV1 to forced vital capacity (from 79% to 84%; P = .008), diffusing capacity of the lungs for carbon monoxide (from 88% predicted to 105% predicted; P = .009), SGRQ score (from 35 to 21; P = .003), and MRI VDP (from 3.2% to 1.5%; P < .001) at 15 months after COVID compared with at 3 months (2). Although trending in a similar versus “the right” direction, there were no significant improvements in participants with self-reported prior respiratory disease (FEV1, from 76% predicted to 82% predicted [P = .6]; diffusing capacity of the lungs for carbon monoxide, from 83% predicted to 92% predicted [P > .99]; SGRQ score, from 37 to 30 [P = .2]; and VDP, from 9.4% to 7.4% [P = .2]).

As Dr Vogel-Claussen (1) appropriately articulated, patients with post-acute COVID-19 syndrome without previous lung disease may be normalizing and improving over time, whereas those with respiratory disease (mainly asthma in this group) may well be improving, but perhaps to a different baseline.
publisher: Radiological Society of North America

2068

L150

Norweg, Anna; Yao, Lanqiu; Barbuto, Scott; Nordvig, Anna S.; Tarpey, Thaddeus; Collins, Eileen; Whiteson, Jonathan; Sweeney, Greg; Haas, Francois; Leddy, John

Exercise intolerance associated with impaired oxygen extraction in patients with long COVID

https://doi.org/10.1016/j.resp.2023.104062

Published

1-Jul-23

Study

https://www.sciencedirect.com/science/article/pii/S1569904823000502

Highlights
•Reduced O2 pulse peak % predicted (impaired oxygen extraction) may be a mechanism of chronic fatigue and exercise intolerance in long COVID.
•Our study identified chronotropic intolerance as a potential biomarker in long COVID.
•Impaired O2 extraction may have contributed to both mental and peripheral muscle fatigue and early exercise termination in long COVID.
•We recommend low-intensity, sub-symptom aerobic exercise to treat long COVID.
Abstract
Objective
Chronic mental and physical fatigue and post-exertional malaise are the more debilitating symptoms of long COVID-19. The study objective was to explore factors contributing to exercise intolerance in long COVID-19 to guide development of new therapies. Exercise capacity data of patients referred for a cardiopulmonary exercise test (CPET) and included in a COVID-19 Survivorship Registry at one urban health center were retrospectively analyzed. Results:

Most subjects did not meet normative criteria for a maximal test, consistent with suboptimal effort and early exercise termination. Mean O2 pulse peak % predicted (of 79 ± 12.9) was reduced, supporting impaired energy metabolism as a mechanism of exercise intolerance in long COVID, n = 59. We further identified blunted rise in heart rate peak during maximal CPET. Our preliminary analyses support therapies that optimize bioenergetics and improve oxygen utilization for treating long COVID-19.

2069

L151

Cui, Lu; Fang, Zhuoqing; De Souza, Cristabelle Madona; Lerbs, Tristan; Guan, Yuan; Li, Irene; Charu, Vivek; Chen, Shih-Yu; Weissman, Irving; Wernig, Gerlinde

Innate immune cell activation causes lung fibrosis in a humanized model of long COVID

https://doi.org/10.1073/pnas.2217199120

Published

7-Mar-23

Study

https://www.pnas.org/doi/10.1073/pnas.2217199120

Significance
Post COVID-19 induced pulmonary fibrosis is the most severe of a number of clinical symptoms associated with “long COVID”, a condition which is currently incompletely understood but affects millions given the ongoing COVID-19 pandemic. Using systems biology and mechanistic studies in a humanized mouse model of COVID lung fibrosis, we identify the essential genetic and immunologic perturbations occurring in patients with long COVID lung fibrosis and reveal promising therapeutic targets.
Abstract
COVID-19 remains a global pandemic of an unprecedented magnitude with millions of people now developing “COVID lung fibrosis.” Single-cell transcriptomics of lungs of patients with long COVID revealed a unique immune signature demonstrating the upregulation of key proinflammatory and innate immune effector genes CD47, IL-6, and JUN. We modeled the transition to lung fibrosis after COVID and profiled the immune response with single-cell mass cytometry in JUN mice. These studies revealed that COVID mediated chronic immune activation reminiscent to long COVID in humans. It was characterized by increased CD47, IL-6, and phospho-JUN (pJUN) expression which correlated with disease severity and pathogenic fibroblast populations. When we subsequently treated a humanized COVID lung fibrosis model by combined blockade of inflammation and fibrosis, we not only ameliorated fibrosis but also restored innate immune equilibrium indicating possible implications for clinical management of COVID lung fibrosis in patients.
publisher: Proceedings of the National Academy of Sciences

2070

L152

Becker, Richard C.

Evaluating chest pain in patients with post COVID conditions permission to think outside of the box

https://doi.org/10.1007/s11239-023-02808-8

Published

1-May-23

Article

https://doi.org/10.1007/s11239-023-02808-8

Chest pain is among the most common symptoms of post-COVID-19 Conditions (PCC) that prompts medical attention. Because the SARS-CoV-2 virus has proclivity for many organs and organ systems in the chest, ranging from the heart, lungs, great vessels, lymphatics, and peripheral nerves, clinicians evaluating patients with chest pain must consider a broad differential diagnosis and take a comprehensive approach to management.

2071

L153

Fedorowski, Artur; Olsén, Monika Fagevik; Nikesjö, Frida; Janson, Christer; Bruchfeld, Judith; Lerm, Maria; Hedman, Kristofer

Cardiorespiratory dysautonomia in post-COVID-19 condition: Manifestations, mechanisms and management

https://doi.org/10.1111/joim.13652

Published

1-May-23

Review

https://doi.org/10.1111/joim.13652

A significant proportion of COVID-19 patients experience debilitating symptoms for months after the acute infection. According to recent estimates, approximately one out of ten COVID-19 convalescents reports persistent health issues more than three months after initial recovery. This "post-COVID-19 condition" may include a large variety of symptoms from almost all domains and organs, and for some patients it may mean prolonged sick-leave, homestay, and strongly limited activities of daily life. In this narrative review, we focus on the symptoms and signs of post-COVID-19 condition in adults-particularly those associated with cardiovascular and respiratory systems, such as postural orthostatic tachycardia syndrome (POTS) or airway disorders-and explore the evidence for chronic autonomic dysfunction as a potential underlying mechanism. The most plausible hypotheses regarding cellular and molecular mechanisms behind the wide spectrum of observed symptoms-such as lingering viruses, persistent inflammation, impairment in oxygen sensing systems and circulating antibodies directed to blood pressure regulatory components-are discussed. In addition, an overview of currently available pharmacological and non-pharmacological treatment options is presented. This article is protected by copyright. All rights reserved.

2072

L154

Ides, K.; De Meyer, Y.; Dierckx, W.; Lauwers, E.; De Backer, W.

Hyperventilation in Long COVID Patients Is Part of the Clinical Picture

Published

1-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A2156

2073

L155

Baalbaki, N.; Cornelissen, M.; Drunen, C.; Houweling, L.; Noij, L.; Golebski, K.; Maitland-van der Zee, A.-H.

Long COVID Patients Show Abnormalities and Activated -inflammatory States of Airway Cells

Published

1-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A1245

2074

L156

Back, G.d.; Camargo, P.f.; Silva, R.n.; Oliveira, M.r.; Goulart, C.d.l.; Caruso, F.r.; Silva, A.b.

Long COVID-19 Severity and Its Impacts on Pulmonary Function A 1 Year Follow-Up Study

Published

1-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A6799

2075

L157

Morgan, Sandra; Visovsky, Constance; Thomas, Bini; Klein, Aimee B.; Ji, Ming; Schwab, Lauren; Coury, Jillian

Home-Based Pilot Pulmonary Program for Dyspneic Patients Post-COVID-19

https://doi.org/10.1177/10547738231170496

Published

1-Jun-23

Study

https://doi.org/10.1177/10547738231170496

It is estimated that at least 10% of people who have had COVID-19 will experience ongoing symptoms such as shortness of breath, fatigue, and cognitive disturbances. Pulmonary exercise has demonstrated improved dyspnea outcomes in other respiratory conditions. Thus, the purpose of this study was to assess the efficacy of a home-based pulmonary rehabilitation program in post-COVID-19 survivors who continue to experience dyspnea. This was a longitudinal, single group pilot study in which 19 patients received a home-based expiratory muscle strength training program over 12 weeks. Outcomes measured at baseline, 6 weeks, and 12 weeks included pulmonary symptoms, functional performance, thoracic expansion, forced expiratory volume, and expiratory resistance measures. Significant improvements were found in pulmonary symptoms (p < .001), functional performance (p = .014), and progressive expiratory resistance capabilities (p < .001). A home-based pulmonary program may be an inexpensive strategy for post-COVID-19 survivors who continue to experience dyspnea.

2076

L158

Sandra Morgan, RN, MSN, Constance Visovsky, RN, PhD, FAAN, Bini Thomas, PT, DPT, MSA, EdD, Aimee B. Klein, PT, DPT, DSc, Ming Ji, PhD, Lauren Schwab, RN, MSN, FNP, Jillian Coury, MPH, CRA

Home Health Care or Hospitalization for Adults With Chronic Respiratory Diseases and Post-COVID Syndrome: A Systematic Review | C37. ONGOING IMPACT OF THE COVID-19 PANDEMIC

https://doi.org/10.1164/ajrccm-conference.2023.207.1

Published

1-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A4890

2077

L159

Kleemann, Detlef; Menschikowski, Jörg; Wellhausen, Elisabeth; Prechtl, Anselm; Fritz, Alexander; Jablowski, Silke; Frommhold, Jördis

Prevalence of chronic rhinosinusitis in patients with a Long Covid course

https://doi.org/10.1055/s-0043-1767141

Published

1-May-23

Study

http://www.thieme-connect.de/DOI/DOI?10.1055/s-0043-1767141

Introduction Assuming that disorders of the sense of smell are an important symptom of chronic rhinosinusitis (CRS), CRS is an exclusion criterion in various studies on olfactory and gustatory disorders associated with Covid-19 and in particular the long-term courses. A few reports in the literature on the prevalence of CRS in covid-19 sufferers showed controversial results.

Material and method We report on the collection of anamnestic data and symptom questionnaires from a total of 354 patients from two ENT practices and one rehabilitation clinic. All respondents were confirmed to have a SARS-COV-2 infection. Of this study group, 127 patients (97 of them from the rehabilitation clinic) had a Long Covid course. In addition to the prevalence of chronic sinus problems in the history of the patients group, the focus of this evaluation was the recording of symptoms at the beginning of the illnesses (semiquantitative) and in the post covid phase.

Results 43.3% of the surveyed patients with a Long Covid course reported chronic sinus problems in their medical history. The difference to the whole study group was significant. Olfactory and gustatory disturbances, but also headache, dizziness and fever in the early phase of SARS-COV-2 disease were reported as more pronounced by patients with chronic sinus problems than by patients without such a history. The pronounced olfactory and gustatory dysfunction proved to be an early cardinal symptom for a later long covid progression. A significant risk for severe acute courses of SARS-Cov-2 infection in the sense of necessary hospital treatment could not be secured for this group of patients in our study.
ISSN: 0935-8943, 1438-8685
issue: S 2
journalAbbreviation: Laryngorhinootologie

2078

L160

Duong-Quy, Sy; Vo-Pham-Minh, Thu; Tran-Xuan, Quynh; Huynh-Anh, Tuan; Vo-Van, Tinh; Vu-Tran-Thien, Quan; Nguyen-Nhu, Vinh

Post-COVID-19 Pulmonary Fibrosis: Facts—Challenges and Futures: A Narrative Review

https://doi.org/10.1007/s41030-023-00226-y

Published

20-May-23

Review

https://doi.org/10.1007/s41030-023-00226-y

Patients with coronavirus disease 2019 (COVID-19) usually suffer from post-acute sequelae of coronavirus disease 2019 (PASC). Pulmonary fibrosis (PF) has the most significant long-term impact on patients’ respiratory health, called post-COVID-19 pulmonary fibrosis (PC19-PF). PC19- PF can be caused by acute respiratory distress syndrome (ARDS) or pneumonia due to COVID-19. The risk factors of PC19-PF, such as older age, chronic comorbidities, the use of mechanical ventilation during the acute phase, and female sex, should be considered. Individuals with COVID-19 pneumonia symptoms lasting at least 12 weeks following diagnosis, including cough, dyspnea, exertional dyspnea, and poor saturation, accounted for nearly all disease occurrences. PC19-PF is characterized by persistent fibrotic tomographic sequelae associated with functional impairment throughout follow-up. Thus, clinical examination, radiology, pulmonary function tests, and pathological findings should be done to diagnose PC19-PF patients. PFT indicated persistent limitations in diffusion capacity and restrictive physiology, despite the absence of previous testing and inconsistency in the timeliness of assessments following acute illness. It has been hypothesized that PC19-PF patients may benefit from idiopathic pulmonary fibrosis treatment to prevent continued infection-related disorders, enhance the healing phase, and manage fibroproliferative processes. Immunomodulatory agents might reduce inflammation and the length of mechanical ventilation during the acute phase of COVID-19 infection, and the risk of the PC19-PF stage. Pulmonary rehabilitation, incorporating exercise training, physical education, and behavioral modifications, can improve the physical and psychological conditions of patients with PC19-PF.

2079

L161

Singh, Sally J.; Baldwin, Molly M.; Daynes, Enya; Evans, Rachael A.; Greening, Neil J.; Jenkins, R. Gisli; Lone, Nazir I.; McAuley, Hamish; Mehta, Puja; Newman, Joseph; Novotny, Petr; Smith, David J. F.; Stanel, Stefan; Toshner, Mark; Brightling, Christopher E.

Respiratory sequelae of COVID-19: pulmonary and extrapulmonary origins, and approaches to clinical care and rehabilitation

https://doi.org/10.1016/S2213-2600(23)00159-5

Published

19-May-23

Article

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00159-5/fulltext

Although the exact prevalence of post-COVID-19 condition (also known as long COVID) is unknown, more than a third of patients with COVID-19 develop symptoms that persist for more than 3 months after SARS-CoV-2 infection. These sequelae are highly heterogeneous in nature and adversely affect multiple biological systems, although breathlessness is a frequently cited symptom. Specific pulmonary sequelae, including pulmonary fibrosis and thromboembolic disease, need careful assessment and might require particular investigations and treatments. COVID-19 outcomes in people with pre-existing respiratory conditions vary according to the nature and severity of the respiratory disease and how well it is controlled. Extrapulmonary complications such as reduced exercise tolerance and frailty might contribute to breathlessness in post-COVID-19 condition. Non-pharmacological therapeutic options, including adapted pulmonary rehabilitation programmes and physiotherapy techniques for breathing management, might help to attenuate breathlessness in people with post-COVID-19 condition. Further research is needed to understand the origins and course of respiratory symptoms and to develop effective therapeutic and rehabilitative strategies.
publisher: Elsevier
PMID: 37216955

2080

L162

Faria, Nuno; Oliveira, Tiago; Pinto, Paula; Almeida, Vânia; Carvalho, Raquel; Fernandes, Maria José; Sucena, Maria; Gomes, Joana

Role of the one-minute sit-to-stand test in the diagnosis of post COVID-19 condition: a prospective cohort study

https://doi.org/10.36416/1806-3756/e20230027

Published

26-May-23

Study

https://www.scielo.br/j/jbpneu/a/dHckCvsqzfxjFbwmmcL3h8q/

ABSTRACT Objective: To analyze the relationship between one-minute sit-to-stand test (1MSTST) parameters and a diagnosis of post COVID-19 condition in a cohort of patients who previously had COVID-19. Methods: This was a prospective cohort study of patients with post COVID-19 condition referred for body plethysmography at a tertiary university hospital. Post COVID-19 condition was defined in accordance with the current WHO criteria. Results: Fifty-three patients were analyzed. Of those, 25 (47.2%) met the clinical criteria for post COVID-19 condition. HR was lower in the patients with post COVID-19 condition than in those without it at 30 s after initiation of the 1MSTST (86.2 ± 14.3 bpm vs. 101.2 ± 14.7 bpm; p < 0.001) and at the end of the test (94.4 ± 18.2 bpm vs. 117.3 ± 15.3 bpm; p < 0.001). The ratio between HR at the end of the 1MSTST and age-predicted maximal HR (HRend/HRmax) was lower in the group of patients with post COVID-19 condition (p < 0.001). An HRend/HRmax of < 62.65% showed a sensitivity of 78.6% and a specificity of 82.0% for post COVID-19 condition. Mean SpO2 at the end of the 1MSTST was lower in the patients with post COVID-19 condition than in those without it (94.9 ± 3.6% vs. 96.8 ± 2.4%; p = 0.030). The former group of patients did fewer repetitions on the 1MSTST than did the latter (p = 0.020). Conclusions: Lower SpO2 and HR at the end of the 1MSTST, as well as lower HR at 30 s after initiation of the test, were associated with post COVID-19 condition. In the appropriate clinical setting, an HRend/HRmax of < 62.65% should raise awareness for the possibility of post COVID-19 condition.

2081

L163

Zaremba, Solomiia; Miller, Alex; Ovrom, Erik; Senefeld, Jonathon; Wiggins, Chad; Dominelli, Paolo; Joyner, Michael; Welch, Brian; Ramsook, Andrew

Airway luminal area in long COVID patients compared to acute COVID-19 patients

https://doi.org/10.1152/physiol.2023.38.S1.5731335

Published

1-May-23

Study

https://journals.physiology.org/doi/abs/10.1152/physiol.2023.38.S1.5731335

Background: Patients with respiratory manifestations of acute COVID-19 infection have enlarged luminal areas of central conducting airways demonstrated on computed tomography imaging and abnormal pulmonary function. In some cases, COVID-19 symptoms may persist for more than 4 weeks, referred to as long COVID, and the effect on airway luminal area remains unknown. Herein, we report airway luminal cross-sections areas among a long COVID group, compared to individuals with an acute COVID-19. We aim to investigate if large conducting airways sizes are different between acute COVID-19 and long COVID patients. Methods: A cohort of 181 people with long COVID were screened, of which 20 people (9 men, 11 women; 55.9 ± 14.1 years) were included in analyses. Twenty age, height, and sex matched patients with an acute (< 4 weeks of persistent symptoms from diagnosis) COVID-19 infection (55.7 ± 15.2 years) served as a comparison group. We used a three-dimensional reconstruction of computed tomography imaging to measure luminal areas of the trachea, right and left main bronchi, bronchus intermediate, right and left upper lobe, and left lower lobe bronchi at proximal, middle, and distal cross-sectional points in both groups. Airway luminal area was taken as the average of the three points. We compared average lumen area of long COVID patients with acute COVID-19 individuals, using an independent samples t-test. Results: We found no significant difference comparing measurements of the following airway luminal cross-sectional areas: trachea (277.7 ± 100.4 vs. 268.0 ± 70.5 mm2 p=0.73), right main bronchus (191.0 ± 66.1 vs. 190.1 ± 49.0 mm2, p=0.96), bronchus intermediate (112.3 ± 33.4 vs. 109.3 ± 27.9 mm2, p=0.76), right upper lobe bronchus (74.4 ± 21.0 vs. 73.7 ± 25.5 mm2, p=0.92), left main bronchus (129.1 ± 50.1 vs. 136.9 ± 38.0 mm2, p=0.58), left lower lobe bronchus (57.8 ± 18.2 vs. 59.0 ± 13.4 mm2, p=0.82), and left upper lobe bronchus (80.1 ± 19.5 vs. 77.9 ± 22.9 mm2, p=0.75) in the long COVID and acute COVID-19 groups respectively. Conclusion: In patients with long COVID, compared to those with an acute COVID-19 infection, we did not see differences in central airway luminal areas. Further analysis of a larger cohort is needed to determine whether enlarged airway luminal areas, associated with acute COVID-19, persist in long COVID. This research will expand knowledge on functional consequences for patients with long COVID.

Funding: F32HL154320 to JWS; 5R35HL139854 to MJJ.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

2082

N01

Heneka

Immediate and long-term consequences of COVID-19 infections for the development of neurological disease

https://doi.org/10.1186/s13195-020-00640-3

published

4-Jun-20

https://alzres.biomedcentral.com/articles/10.1186/s13195-020-00640-3

Prospective studies are needed to investigate potential correlations between acute and sub-acute COVID-19 infections and long-term neurological sequalae in this patient cohort.

_

2083

N02

Yiping Lu, MD Xuanxuan Li, MD, Daoying Geng, MD, Nan Mei, MD, Pu-Yeh Wu, PhD, Chu-Chung Huang, PhD et al.

Cerebral Micro-Structural Changes in COVID-19 Patients – An MRI-based 3-month Follow-up Study

https://doi.org/10.1016/j.eclinm.2020.100484

Published

3-Aug-20

RESEARCH PAPER

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(20)30228-5/fulltext

The Lancet, August, the 4th :
"The study reveals a possible disruption to micro-structural and functional brain integrity in the recovery stages of COVID-19, suggesting long-term consequences of SARSCoV2." "The abnormalities in these brain areas might cause long-term burden to COVID-19 patients after recovery, which was thus worth public attention"
British Thoracic Society recommends chest x-ray three months after discharge for all patients admitted to hospital with covid-19

The Lancet, 4 août :
"L'étude révèle une possible perturbation de l'intégrité micro-structurelle et fonctionnelle du cerveau dans les stades de récupération du COVID-19, suggérant des conséquences à long terme du SRASCoV2." "Les anomalies dans ces zones cérébrales pourraient entraîner un fardeau à long terme pour les patients atteints de COVID-19 après la guérison, ce qui mérite donc l'attention du public." "La British Thoracic Society recommande une radiographie thoracique trois mois après la sortie pour tous les patients admis à l'hôpital avec covid-19"

2084

N03

Beth Rabinovitz,Abhishek Jaywant &Chaya B. Fridman

Neuropsychological functioning in severe acute respiratory disorders caused by the coronavirus: Implications for the current COVID-19 pandemic

https://doi.org/10.1080/13854046.2020.1803408

Published

9-Sep-20

Article

https://www.tandfonline.com/doi/full/10.1080/13854046.2020.1803408

Neurological impacts

Impacts neurologiques

2085

N04

Eric Song, Ce Zhang, Benjamin Israelow, Alice Lu-Culligan

Neuroinvasion of SARS-CoV-2 in human and mouse brain

https://doi.org/10.1101/2020.06.25.169946

pre-print

8-Sep-20

New Results

https://www.biorxiv.org/content/10.1101/2020.06.25.169946v2

Research on the entry of the virus into the brain

Recherche sur l'entrée du virus dans le cerveau

2086

N05

Martin Sylvester Otte ,Hans Nikolaus Caspar Eckel,Leonard Poluschkin,Jens Peter Klussmann

Olfactory dysfunction in patients after recovering from COVID-19

https://doi.org/10.1080/00016489.2020.1811999

published

27-Aug-20

Research Article

https://www.tandfonline.com/doi/full/10.1080/00016489.2020.1811999

A German study on 91 symptomatic PCR+ patients reports, after 8 weeks, that 45% of them still have a relative loss of smell (hyposmia).

Half of the patients with an olfactory loss as a symptom of COVID-19 still have olfactory impairments after two months, although not all of these patients subjectively notice a restriction.

Une étude allemande sur 91 patients PCR+ symptomatiques rapporte, après 8 semaines, que 45% d'entre ont toujours une perte relative d'odorat (hyposmie).

2087

N06

Jason C. Lee, MD, PhD, Rohit Nallani, MD, Lauren Cass, MD, MPH, ...

A Systematic Review of the Neuropathologic Findings of Post-Viral Olfactory Dysfunction: Implications and Novel Insight for the COVID-19 Pandemic

https://doi.org/10.1177%2F1945892420957853

published

11-Sep-20

Systematic Review

https://journals.sagepub.com/doi/full/10.1177/1945892420957853

On post-viral olfactory pathologies

Sur les pathologies olfactives post-virales

2088

N07

Christos Pantelis*, Mahesh Jayaram*, Anthony J Hannan, ...

Neurological, neuropsychiatric and neurodevelopmental complications of COVID-19

https://doi.org/10.1177%2F0004867420961472

Published

1-Oct-20

Research Article

https://journals.sagepub.com/doi/full/10.1177/0004867420961472

Neurological, psychiatric, and prenatal complications of covid.
"Maternal viral (and other) infections during pregnancy can affect the offspring, with greater incidence of neurodevelopmental disorders, such as autism, schizophrenia and epilepsy."

Complications neurologiques, psychiatriques, et prénatales de la covid.
"Maternal viral (and other) infections during pregnancy can affect the offspring, with greater incidence of neurodevelopmental disorders, such as autism, schizophrenia and epilepsy."

2089

N08

S. Andrew Josephson, MD1,2; Hooman Kamel, MD3,4

Neurology and COVID-19

https://doi.org/10.1001/jama.2020.14254

Published

Viewpoint

https://jamanetwork.com/journals/jama/fullarticle/2770855

_

2090

N09

Daniela Costa Martins 1, Sofia Branco Ribeiro, Isabel Jesus Pereira, Susana Mestre, Jonathan Rios

Unilateral Hypoglossal Nerve Palsy as a COVID-19 Sequel

https://doi.org/10.1097/phm.0000000000001607

Published

1-Oct-20

Case

https://pubmed.ncbi.nlm.nih.gov/33002915/

In Portugal, a case of unilateral hypoglossal (tongue) nerve palsy reported in a patient with a severe form of covid.

Au Portugal, un cas de paralysie unilatérale du nerf hypoglosse (langue) rapporté chez un patient atteint d'une forme sévère de covid.

2091

N10

Foteini Stefania Koumpa1,2, Cillian T Forde2 and Joseph G Manjaly2

Sudden irreversible hearing loss post COVID-19

http://dx.doi.org/10.1136/bcr-2020-238419

Published

1-Oct-20

Case report

https://casereports.bmj.com/content/13/11/e238419

Extremely rare case of a priori definitive deafness caused by covid in a 45-year-old British patient, reported in BMJ Case Reports. Hearing loss and tinnitus are temporary sequelae already reported for influenza.

Cas rarissime d'une surdité définitive a priori causée par la covid chez un patient britannique de 45 ans, rapporté dans le BMJ Case Reports. Perte auditive et acouphènes sont des séquelles temporaires déjà rapportées pour la grippe.

2092

N11

Butler

Neuropsychiatric complications of covid-19

https://doi.org/10.1136/bmj.m3871

published

13-Oct-20

https://www.bmj.com/content/371/bmj.m3871

o date, most research on long covid has been led by patients, and it suggests this is a common and disabling disorder.21 Further research informing clinical guidelines and our understanding of the mechanisms underlying this disorder is urgently required.22

_

2093

N12

Adam Hampshire, William Trender, Samuel R Chamberlain, Amy Jolly, Jon E. Grant

Cognitive deficits in people who have recovered from COVID-19 relative to controls: An N=84,285 online study

https://doi.org/10.1101/2020.10.20.20215863

pre-print

21-Oct-20

Study

https://www.medrxiv.org/content/10.1101/2020.10.20.20215863v1

A large-scale study, not yet reviewed or published, would tend to show a worrying cognitive underperformance of people who had covid, significantly pronounced in hospitalized people.

Une étude de grande ampleur, non encore relue ni publiée, tendrait à montrer une sous-performance cognitive inquiétante des personnes ayant eu la covid, significativement prononcée chez les personnes hospitalisées.

2094

N13

Yes

Arun Raj Antony
Zulfi Haneef

Systematic review of EEG findings in 617 patients diagnosed with COVID-19

https://doi.org/10.1016/j.seizure.2020.10.014

Published

18-Oct-20

Systematic review

https://www.seizure-journal.com/article/S1059-1311(20)30332-0/abstract

According to a study, covid could be at the origin of attacks in particular in the frontal lobe (more observed in severe covid), some of which could be irreversible (speech, confusion ...). Median in the study: 61 years. The mechanism could be direct (viral) or indirect (decrease in oxygenation caused by covid). The publication is a systematic american study of electroencephalography performed on covid patients, (part of this study at N-Y): The anomalies are notably non-convulsive epileptic states (the prevalence of these epileptic attacks is according to the NY study of 30% in patients who have had a severe form of covid).

Selon une étude, la covid pourrait être à l'origine d'atteintes notamment dans le lobe frontal (davantage observées sur covid sévère), dont certaines risqueraient d'être irréversibles (élocution, confusion...). Médiane dans l'étude: 61 ans. Le mécanisme pourrait être direct (viral) ou indirect (baisse d'oxygénation causée par la covid). La publication est une étude systématique américaine d'électroencéphalographies effectuées sur des malades covid, une partie issus de cette étude à N-Y: Les anomalies sont notamment des états épileptiques non convulsifs (la prévalence de ces atteintes épilep. est selon l'étude de NY de 30% chez les malades ayant eu une forme grave de la covid).

2095

N14

Jacob Pellinen Elizabeth Carroll Daniel Friedman Michael Boffa Patricia Dugan David E. Manisha Holmes

Continuous EEG findings in patients with COVID‐19 infection admitted to a New York academic hospital system

https://doi.org/10.1111/epi.16667

Published

2-Sep-20

FULL‐LENGTH ORIGINAL RESEARCH

https://onlinelibrary.wiley.com/doi/10.1111/epi.16667

Study in N-Y

étude à N-Y

2096

N15

Siukan Law email 1; Albert Wingnang Leung2; Chuanshan Xu3

Do COVID-19 infection among patients increase the risk of Alzheimer’s disease?

https://dx.doi.org/10.21608/mid.2020.46935.1073

Published

1-Nov-20

Letter to the Editor

https://mid.journals.ekb.eg/article_120300.html

An article in Microbes and Infectious Deseases indicates that there is no evidence that covid increases the risk of Alzheimer's disease, and that the virus itself is unlikely to enter the central nervous system.

Un article dans Microbes and Infectious Deseases indique qu'aucun élément ne permet de dire que la covid augmente le risque de maladie d'Alzheimer, et qu'il est improbable que le virus lui-même puisse entrer dans le système nerveux central.

2097

N16

Pasquale Viola, Massimo Ralli, Davide Pisani, Donatella Malanga, Domenico Sculco, Luigi Messina, Carla

Tinnitus and equilibrium disorders in COVID-19 patients: preliminary results

https://doi.org/10.1007/s00405-020-06440-7

Published

23-Oct-20

Study

https://link.springer.com/article/10.1007/s00405-020-06440-7

Tinnitus and balance problems appear with a notable incidence in patients with covid, according to this Italian study.

Acouphènes et problèmes d'équilibre apparaissent avec une incidence notable chez les malades de la covid, selon cette étude italienne.

2098

N17

Beauchamp, Leah C.a; b | Finkelstein, David I.a | Bush, Ashley I.a; c | Evans, Andrew H.d | Barnham, Kevin J.a; b; c;

Parkinsonism as a Third Wave of the COVID-19 Pandemic?

https://doi.org/10.3233/JPD-202211

Published

27-Oct-20

Research Article

https://content.iospress.com/articles/journal-of-parkinsons-disease/jpd202211

An Australian research article wonders if the neurotropic aspect of SARS-CoV-2 could be at the origin of a wave of Parkinson's diseases, and warns of the possible disastrous consequences of betting on natural herd immunity. The article notes the still unknown origin of the lethargic encephalitis pandemic that affected 5 million people between 1916 and 1926, causing an outbreak of parkinsonism. Studies had advanced the viral hypothesis (Spanish flu).

Un article de recherche australien se demande si l'aspect neurotrope du SARS-CoV-2 pourrait être à l'origine d'une vague de maladies de Parkinson, et met en garde contre les possibles conséquences désastreuses du pari d'une immunité collective naturelle./. L'article note l'origine toujours inconnue de la pandémie d'encéphalite léthargique qui toucha 5 millions de personnes entre 1916 et 1926, causant une flambée de troubles parkinsoniens. Des études avaient avancé l'hypothèse virale (grippe espagnole).

2099

N18

Yes

Elodie Meppiel, M.D.
Nathan Peiffer-Smadja, M.D.
Alexandra Maury
Pierre Tattevin, M.D. Ph.D.

Neurological manifestations associated with COVID-19: a multicentric registry

https://doi.org/10.1016/j.cmi.2020.11.005

Published

12-Nov-20

multicentric registry

https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(20)30698-4/abstract

A French study lists the possible neurological damage from covid. Out of 222 hospitalized patients (median age 63 years) with neurological symptoms, 30% presented with encephalopathy, 25% with ischemic stroke, 9% with encephalitis. One of the authors, @nathanpsmad, presents the results of the study (Meppiel & al, @elomepiel) in this thread https://twitter.com/nathanpsmad/status/1326992035098877958. An important part of the symptoms would be linked more to post-infectious inflammatory mechanisms, even if the direct role of SARS-CoV-2 virions is not ruled out.

Une étude française liste les atteintes neurologiques possibles de la covid. Sur 222 patients hospitalisés (âge médian 63 ans) avec symptômes neurolog., 30% présentent une encéphalopathie, 25% un AVC ischémique, 9% une encéphalite. L'un des auteurs, @nathanpsmad, présente les résultats de l'étude (Meppiel & al, @elomepiel) dans ce thread. https://twitter.com/nathanpsmad/status/1326992035098877958 Une part importante des symptômes serait davantage liée à des mécanismes inflammatoires post-infectieux, même si le rôle direct de virions de SARS-CoV-2 n'est pas écarté.

2100

N19

Guilherme Dias De Melo, Françoise Lazarini, Sylvain Levallois, Charlotte Hautefort,

COVID-19-associated olfactory dysfunction reveals SARS-CoV-2 neuroinvasion and persistence in the olfactory system

https://doi.org/10.1126/scitranslmed.abf8396

Published

18-Nov-20

New Results

https://www.science.org/doi/10.1126/scitranslmed.abf8396

First pre-print: https://www.biorxiv.org/content/10.1101/2020.11.18.388819v1.full
Finally, olfactory mucosa sampling in COVID-19 patients presenting with persistent loss of smell reveals the presence of virus transcripts and of SARS-CoV-2-infected cells, together with protracted inflammation

Étude finalement bien publiée - Elle n'est pas encore révisée par les pairs ni publiée, mais cette étude 🇨🇵 d'une équipe de l'Institut Pasteur sur l'homme et l'animal montre des charges virales SARS-CoV-2 dans l'épithélium olfactif à même d'expliquer l'anosmie prolongée.

2101

N20

SanazKatalaAliGholamrezanezhadbc

COVID-19–related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters
Neuroimaging findings in COVID-19: A narrative review

https://doi.org/10.1016/j.neulet.2020.135529

Published

25-Nov-20

review

https://www.sciencedirect.com/science/article/pii/S0304394020307990

Brain imaging should be considered in the diagnostic work up of those COVID-19 patients who present with neurological symptoms. In this regard, radiologists and clinicians should be familiar with the spectrum of neuroimaging findings in COVID-19 to detect and understand the disease process, and to evaluate its progression during the course of treatment. Yet, further studies are still warranted regarding the long-term neurological sequel and prognostic implications in COVID-19.

Une rapide revue de la littérature fait le point sur les symptômes neurologiques de la covid, insiste sur l'apport de l'imagerie cérébrale, et appelle à des études plus poussées sur les séquelles neurologiques à long terme.

2102

N21

Yes

LIVIA NG

COVID-19 Damages the CNS

opinion

10-Jul-20

opinion

https://neucruit.com/journal/covid19-cns

Neucruit, plateforme 🇬🇧 pour essais cliniques résume : "la covid abîme le système nerveux central" : "le virus peut infecter le liquide cérébro-spinal, causer des œdèmes cérébraux, des vasodilatations méningées et des neurodégénérescences partielles".

2103

N22

AvindraNathBryanSmith

Neurological issues during COVID-19: An Overview

https://doi.org/10.1016/j.neulet.2020.135533

Published

25-Nov-20

Article

https://www.sciencedirect.com/science/article/pii/S030439402030803X

Séquelles neurologiques de la covid : les auteurs voient cette catégorie de symptômes persistants (qui peut toucher selon eux 10 à 35% des malades) comme la plus lourde sur le long terme, et affirment que les conséquences socio-éco. sont insondables.

2104

N23

ES

Jenny Meinhardt, Josefine Radke, […]Frank L. Heppner

Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19

https://doi.org/10.1038/s41593-020-00758-5

Published

30-Nov-20

Article

https://www.nature.com/articles/s41593-020-00758-5

Cette étude dans Nature décrit comment le SARS-CoV-2 peut entrer dans le système nerveux central en traversant la muqueuse olfactive, exploitant la proximité immédiate des tissus muqueux olfactifs, endothéliaux et nerveux.

2105

N24

Yes

Abdul Mannan Baig

Deleterious Outcomes in Long-Hauler COVID-19: The Effects of
SARS-CoV‑2 on the CNS in Chronic COVID Syndrome

https://doi.org/10.1021/acschemneuro.0c00725

Published

13-Nov-20

Viewpoint

https://dx.doi.org/10.1021/acschemneuro.0c00725

Un point de vue sur les impacts neurologiques lors des covids longs ("neuro-covid chronique"). L'auteur évoque des hypothèses de thérapies, notamment anti-inflammatoires, pour lesquelles il préconise des tests cliniques.

2106

N25

Fatemeh Sadat Mirfazeli, Atiye Sarabi-Jamab, Amin Jahanbakhshi, Alireza Kordi, Parisa Javadnia Seyed Hamid Reza Faiz

Neuropsychiatric manifestations of COVID-19 can be clustered in three distinct symptom categories

https://doi.org/10.1038/s41598-020-78050-6

Published

1-Dec-20

Article

https://www.nature.com/articles/s41598-020-78050-6

Une étude distingue 3 types de troubles neuro. covid :
- anosmie/hypogeusie
- étourdissemts, maux de tête, réduction de la force des membres
- photophobie, état mental modifié, hallucinations, pb vision/élocution, convulsions, AVC, troubles de l'équilibre.

2107

N26

Michael Eliezer, Anne-Laurel Hamel, Emmanuel Houdart, Philippe Herman, Juliette Housset, Clement Jourdaine, Corinne Eloit, Benjamin Verillaud, Charlotte Hautefort

Loss of smell in patients with COVID-19
MRI data reveal a transient edema of the olfactory clefts

https://doi.org/10.1212/WNL.0000000000010806

Published

8-Dec-20

Article

https://n.neurology.org/content/95/23/e3145

Des radiologues et ORL français rapportent dans un article publié en ligne le 11 septembre dans la revue Neurology les résultats d’une étude évaluant l’aspect à l’imagerie par résonance magnétique (IRM) de la partie supérieure des fosses nasales de patients anosmiques au début de leur maladie Covid-19. Elle met clairement en évidence que la perte d’odorat (anosmie) dont se plaignent de nombreux patients Covid-19 est fréquemment associée à un gonflement transitoire au niveau de la partie supérieure des fosses nasales, ce que les spécialistes ORL appellent un œdème des fentes olfactives. Suite sur https://www.lemonde.fr/blog/realitesbiomedicales/tag/fente-olfactive/

2108

N27

Yes

Rachel Wells, Varun Malik, Anthony G. Brooks, Dominik Linz, Adrian D. Elliott, Prashanthan Sanders, Amanda Page, Mathias Baumert, and Dennis H. Lau

Cerebral Blood Flow and Cognitive Performance in Postural Tachycardia Syndrome: Insights from Sustained Cognitive Stress Test

https://doi.org/10.1161/JAHA.120.017861

Published

5-Dec-20

RESEARCH ARTICLE

https://www.ahajournals.org/doi/10.1161/JAHA.120.017861

A very important study that demonstrates abnormal cerebral blood flow in patients with POTS during a cognitive test suggesting that "brain fog" has a pathophysiologic basis.

Une base physiopathologique du «brouillard cérébral» («brain fog», l'un des symptômes du covid long) suspectée par l'observation de flux sanguins cérébraux anormaux chez des patients atteints de syndrome de tachycardie orthostatique posturale (POTS).

2109

N28

Michael Lange
Riyi Shi

Possible Neuroinflammatory Mechanisms Which May Lead to Long-Term Neurological Disorders in COVID-19 Patients

https://doi.org/10.18060/24687

Viewpoint

15-Dec-20

Abstract only

https://journals.iupui.edu/index.php/IMPRS/article/view/24687

_

2110

N29

Yes

Myoung-Hwa Lee, Ph.D, Daniel P. Perl, M.D., Govind Nair, Ph.D., Wenxue Li, Ph.D., Dragan Maric, Ph.D., Avindra Nath

Microvascular Injury in the Brains of Patients with Covid-19

https://doi.org/10.1056/NEJMc2033369

Published

30-Dec-20

Correspondance

https://www.nejm.org/doi/full/10.1056/NEJMc2033369

Lors d'IRM post-mortem de résolution 25μm-100μm sur des victimes de la covid, sont fréquemment relevées des micro-lésions vasculaires dans le cerveau et le bulbe olfactif, sans atteinte virale directe de neurones.

2111

N29

Yes

Lee MH, Perl DP, Nair G, Li W, Maric D, Murray H, Dodd SJ, Koretsky AP, Watts JA, Cheung V, Masliah E, Horkayne-Szakaly I, Jones R, Stram MN, Moncur J, Hefti M, Folkerth RD, Nath A.

NIH study uncovers blood vessel damage and inflammation in COVID-19 patients’ brains but no infection

Results from a study of 19 deceased patients suggests brain damage is a byproduct of a patient’s illness.

https://doi.org/10.1056/NEJMc2033369

Published

30-Dec-20

Article

https://www.nih.gov/news-events/news-releases/nih-study-uncovers-blood-vessel-damage-inflammation-covid-19-patients-brains-no-infection

Les données de l'étude menée par le NIH ont surpris l'équipe. "Originally, we expected to see damage that is caused by a lack of oxygen. Instead, we saw multifocal areas of damage that is usually associated with strokes and neuroinflammatory diseases""Our results suggest that this may be caused by the body's inflammatory response to the virus" "We plan to study how COVID-19 harms the brain's blood vessels and whether that produces some of the short- and long-term symptoms we see in patients."

2112

N30

Yes

Peter Wostyn

COVID-19 and chronic fatigue syndrome: Is the worst yet to come?

https://doi.org/10.1016/j.mehy.2020.110469

Published

2-Jan-21

Hypothesis

https://pubmed.ncbi.nlm.nih.gov/33401106/

Selon le chercheur en psychiatrie Peter Wostyn, le syndrome de fatigue chronique associé au covid long pourrait résulter de dommages aux neurones sensoriels olfactifs, entraînant une réduction de l'écoulement du liquide céphalo-rachidien à travers la lame criblée. Cela conduirait à une congestion du système glymphatique avec une accumulation de toxicité ultérieure dans le système nerveux central.
Le chercheur envisage une amélioration des symptômes en drainant le liquide céphalo-rachidien pour rétablir le transport glymphatique et l'élimination des déchets du cerveau.

2113

N31

Andrea Pilotto, MD, Stefano Masciocchi, MD, Irene Volonghi, MD, Valeria De Giuli, MD, Francesca Caprioli, MD, Sara Mariotto, MD, Sergio Ferrari, MD, Silvia Bozzetti, MD, Alberto Imarisio, MD, Barbara Risi

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Encephalitis Is a Cytokine Release Syndrome: Evidences From Cerebrospinal Fluid Analyses

https://doi.org/10.1093/cid/ciaa1933

Published

4-Jan-21

Major article

https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1933/6062486?

SARS-CoV-2-related encephalitis were associated with prominent glial activation and neuroinflammatory markers, whereas neuronal markers were increased in severe cases only. The pattern of CSF alterations suggested a cytokine-release syndrome as the main inflammatory mechanism of SARS-CoV-2 related encephalitis.

Les encéphalites déclenchées par la covid trouveraient leur origine, selon cette étude, dans la libération de cytokines qui devient le principal effet inflammatoire.

2114

N32

Yes

Eric Song, Ce Zhang, Benjamin Israelow, Alice Lu-Culligan, Anita Huttner, Danielle Seilhean, Nicolas Renier, Kaya Bilguvar, Akiko Iwasaki

Neuroinvasion of SARS CoV 2 in human and mouse

https://doi.org/10.1084/jem.20202135

Published

12-Jan-21

Article

https://rupress.org/jem/article/218/3/e20202135/211674/Neuroinvasion-of-SARS-CoV-2-in-human-and-mouse

Tweet by @EricTopol : "There's been controversy as to whether #SARSCoV2 directly attacks brain cells. This new @JExpMed paper supports that it occurs via brain organoids, mouse models, and patient autopsy. And lack of IFN response."

Il y a un débat pour savoir si le SARS-CoV2 peut directement attaquer les cellules cérébrales. En utilisant des organoïdes cérébraux, un modèle animal (souris) et via des autopsies de victimes de la covid, une étude appuie cette possibilité.

2115

N33

Yes

Tissa Wijeratne Sheila Crewther

COVID-19 and long-term neurological problems: Challenges ahead with Post-COVID-19 Neurological Syndrome

https://doi.org/10.31128/AJGP-COVID-43

Published

12-Jan-21

Article

https://www1.racgp.org.au/ajgp/coronavirus/covid-19-and-long-term-neurological-problems

"The COVID-19-associated neurological disorders reported to date fit into five main categories: encephalopathies, inflammatory central nervous system (CNS) syndromes, ischaemic strokes, peripheral neurological disorders and miscellaneous other CNS disorders. The number of articles reporting longer-term post-COVID-19 neurological effects and symptoms makes an undeniable case for medicine to recognise the Post-COVID-19 Neurological Syndrome (PCNS)". "The pandemic statistics highlight the need for ongoing, careful follow-up of all patients with COVID-19, even those formerly regarded as asymptomatic, with regular screening for likely long-term persistent neurological involvements."

Un article australien classifie les troubles neurologiques associés à la covid :
"ils entrent dans 5 catégories : encéphalopathies, syndromes inflammatoires du système nerveux central (SNC), accidents vasculaires cérébraux ischémiques,troubles neurologiques périphériques et divers autres troubles du SNC."
"Ces symptômes nous obligent à reconnaître un «syndrome neurologique post-covid» (Post-COVID-19 Neurological Syndrome - PCNS)". "Il y a nécessité d'un suivi continu de tous les patients atteints de la covid, y compris ceux qui étaient considérés auparavant comme asymptomatiques, avec un dépistage régulier des probables implications neurologiques persistantes à long terme".

2116

N34

Françoise Chapon

Syndrome de Guillain-Barré et infection au SARS-CoV-2
Guillain-Barré syndrome associated with SARS-CoV-2

https://doi.org/10.1051/medsci/2020210

Published

11-Jan-21

Case study

https://www.medecinesciences.org/en/articles/medsci/full_html/2020/12/medsci200210s/medsci200210s.html

Une étude de cas sur des syndromes de Guillain-Barré consécutifs à une infection au SARS-CoV-2.

2117

N35

Pratima Kumari, Hussin A. Rothan, Janhavi P. Natekar, Shannon Stone, Heather Pathak, Philip G. Strate, Komal Arora, Margo A. Brinton and Mukesh Kumar

Neuroinvasion and Encephalitis Following Intranasal Inoculation of SARS-CoV-2 in K18-hACE2 Mice

https://doi.org/10.3390/v13010132

Published

19-Jan-21

Study on animal model

https://www.mdpi.com/1999-4915/13/1/132/htm

A study on six week old transgenic mice (for susceptibility to SARS-CoV-2," "K18-hACE2-transgenic" "), infected with the covid virus intranasally, revealed neurological symptoms and infection central nervous system. The study notes that unlike the lungs where virions disappear by immune action, the brain is subject to strong kinetics of late infection, which triggers an inflammatory response. Tissue analyzes reveal the presence perivascular hemorrhages, leukocyte infiltrations and the death of some neuronal cells. Antigens of the virus are detected throughout the murine brain, including the cortex, cerebellum and hippocampus. The authors believe that the brain is a site major SARS-CoV-2 infection following intranasal infection: first through the olfactory bulb, then by propagation in the brain by following the axons of neurons in the brain that connect to it. According to Mukesh Kumar, one of the co-authors of the study, is where the virus can take refuge because there is not the same level of immune response as in other organs. This tropism is correlated according to him to systemic symptoms, in particular cardiac, to anosmia, and to other neurological disorders which are characteristic of the long covid. "

Une étude sur des souris de six semaines transgéniques (pour une susceptibilité au SARS-CoV-2, "K18-hACE2-transgenic"), infectées au virus de la covid par voie intranasale, relève des symptômes neurologiques et l'infection du système nerveux central. L'étude note que contrairement aux poumons où les virions disparaissent par l'action immunitaire, le cerveau est sujet à une cinétique forte d'infection plus tardive, qui déclenche une réponse inflammatoire. Des analyses tissulaires, ressort la présence d'hémorragies périvasculaires, des infiltrations de leucocytes et la mort de certaines cellules neuronales. Les antigènes du virus sont détectés dans tout le cerveau murin, y compris le cortex, le cervelet et l'hippocampe. Les auteurs estiment que le cerveau est un site majeur d'infection au SARS-CoV-2 suite à une infection par voie intranasale : d'abord le bulbe olfactif, puis par propagation dans le cerveau en suivant les axones des neurones du cerveau qui s'y connectent. Selon Mukesh Kumar, l'un des co-auteurs de l'étude, c'est là où le virus peut se réfugier parce qu'il n'y a pas le même niveau de réponse immunitaire que dans d'autres organes. Ce tropisme est corrélé selon lui aux symptômes systémiques, notamment cardiaques, à l'anosmie, et à d'autres troubles neurologiques qui sont caractéristiques du covid long.

2118

N36

E Guedj, M Million, P Dudouet, H Tissot-Dupont, F Bregeon, S Cammilleri & D Raoult

18F-FDG brain PET hypometabolism in post-SARS-CoV-2 infection: substrate for persistent/delayed disorders?

https://doi.org/10.1007/s00259-020-04973-x

Published

30-Jul-20

Short Communication

https://link.springer.com/article/10.1007%2Fs00259-020-04973-x

_

2119

N37

Yes

E. Guedj, J. Y. Campion, P. Dudouet, E. Kaphan, F. Bregeon, H. Tissot-Dupont, S. Guis, F. Barthelemy, P. Habert, M. Ceccaldi, M. Million, D. Raoult, S. Cammilleri & C. Eldin

18F-FDG brain PET hypometabolism in patients with long COVID

https://doi.org/10.1007/s00259-021-05215-4

Published

26-Jan-21

Study

https://link.springer.com/article/10.1007/s00259-021-05215-4

In comparison to healthy subjects, patients with long COVID exhibited bilateral hypometabolism in the bilateral rectal/orbital gyrus, including the olfactory gyrus; the right temporal lobe, including the amygdala and the hippocampus, extending to the right thalamus; the bilateral pons/medulla brainstem; the bilateral cerebellum

Une étude suggère qu'un hypométabolisme (activité plus basse qu'attendue) dans les zones du cerveau proches du bulbe olfactif, relevé par TEP-scanner cérébral, pourrait être un biomarqueur des malades du covid long. L'étude note que le neurotropisme de certains coronavirus (SRAS, MERS) avait déjà été évoqué (https://sciencedirect.com/science/article/abs/pii/S0889159120303573). Elle relève cependant un hypométabolisme moindre chez 3 patients qui avaient utilisé en traitement initial un spray nasal décongestionnant, et plus important chez les patients ayant une utilisation récente d'inhibiteurs ACE (médicaments contre l'hypertension). L'étude est réalisée sur une cohorte de 35 patients, infectés au SARS-CoV-2 et présentant des séquelles usuelles du covid long. Au sujet de l'étude Guedj & al., l'auteur décrit, dans des commentaires vidéo des résultats, des symptômes neurologiques inversement corrélés avec l'âge, et une corrélation avec le temps écoulé après l'infection, pouvant résulter d'un biais de sélection.
Le Dr Guedj (hôpital La Timone) note qu'"on ne peut pas raccrocher l'atteinte du tronc cérébral, très atypique, à un éventuel syndrome de stress post-traumatique".
[2/2]
https://youtu.be/E5yQEhB-qRA

N001

___Neurologic___

Published study on 26-Jan-21:
"18F-FDG brain PET hypometabolism in patients with long COVID"
Une étude suggère qu'un hypométabolisme (activité plus basse qu'attendue) dans les zones du cerveau proches du bulbe olfactif, relevé par TEP-scanner cérébral, pourrait être un biomarqueur des malades du covid long. L'étude note que le neurotropisme de certains coronavirus (SRAS, MERS) avait déjà été évoqué (https://sciencedirect.com/science/article/abs/pii/S0889159120303573). Elle relève cependant un hypométabolisme moindre chez 3 patients qui avaient utilisé en traitement initial un spray nasal décongestionnant, et plus important chez les patients ayant une utilisation récente d'inhibiteurs ACE (médicaments contre l'hypertension). L'étude est réalisée sur une cohorte de 35 patients, infectés au SARS-CoV-2 et présentant des séquelles usuelles du covid long. Au sujet de l'étude Guedj & al., l'auteur décrit, dans des commentaires vidéo des résultats, des symptômes neurologiques inversement corrélés avec l'âge, et une corrélation avec le temps écoulé après l'infection, pouvant résulter d'un biais de sélection.
Le Dr Guedj (hôpital La Timone) note qu'"on ne peut pas raccrocher l'atteinte du tronc cérébral, très atypique, à un éventuel syndrome de stress post-traumatique".
[2/2]
https://youtu.be/E5yQEhB-qRA
Link: https://link.springer.com/article/10.1007/s00259-021-05215-4
Extract: "In comparison to healthy subjects, patients with long COVID exhibited bilateral hypometabolism in the bilateral rectal/orbital gyrus, including the olfactory gyrus; the right temporal lobe, including the amygdala and the hippocampus, extending to the right thalamus; the bilateral pons/medulla brainstem; the bilateral cerebellum"

2120

N38

Chiara Pizzanelli, Chiara Milano, Silvia Canovetti, Mirco Cosottini, Gabriele Siciliano

Autoimmune limbic encephalitis related to SARS-CoV-2 infection: Case-report and review of the literature

https://doi.org/10.1016/j.bbih.2021.100210

Published

24-Jan-21

Short Communication

https://www.sciencedirect.com/science/article/pii/S2666354621000132

Une étude évoque un cas d'encéphalite limbique autoimmune attribuée à une infection de covid, et répertorie 5 autres cas de cette association dans les publications médicales.

2121

N39

Biyan Nathanael Harapan & Hyeon Joo Yoo

Neurological symptoms, manifestations, and complications associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 19 (COVID-19)

https://doi.org/10.1007/s00415-021-10406-y

Published

23-Jan-21

Review

https://link.springer.com/article/10.1007/s00415-021-10406-y

Dans Journal of Neurology, une riche revue d'études des connaissances acquises sur les séquelles neurologiques de la covid, avec les mécanismes suspectés, impliquant les systèmes nerveux central et périphérique, ainsi que le musculosquelettique.

N003

___Neurologic___

Published review on 23-Jan-21:
"Neurological symptoms, manifestations, and complications associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 19 (COVID-19)"
Dans Journal of Neurology, une riche revue d'études des connaissances acquises sur les séquelles neurologiques de la covid, avec les mécanismes suspectés, impliquant les systèmes nerveux central et périphérique, ainsi que le musculosquelettique.
Link: https://link.springer.com/article/10.1007/s00415-021-10406-y
Extract: ""

2122

N40

Tamar Wildwing, Nicole Holt

The neurological symptoms of COVID-19: a systematic overview of systematic reviews, comparison with other neurological conditions and implications for healthcare services

https://doi.org/10.1177%2F2040622320976979

Published

28-Jan-21

Review Article

https://journals.sagepub.com/doi/full/10.1177/2040622320976979

Un aperçu des revues d'études sur les symptômes neurologiques de la covid note que ceux-ci présentent des similarités avec d'autres conditions neurologiques telles que le syndrome de fatigue chronique (SFC) et les troubles neurologiques fonctionnels (TNF).

2123

N41

E. Leslie Cameron, Per Møller, Keith S. Karn

Effects of COVID-19 on Sense of Smell: Human Factors/Ergonomics Considerations

https://doi.org/10.1177%2F0018720821990162

Published

1-Feb-21

Research Article

https://journals.sagepub.com/doi/full/10.1177/0018720821990162

COVID-19 is known to reduce the olfactory sense (smell) in people who contract the disease. The duration of the loss is not well characterized at this time, but some may experience permanent dysfunction in the sense of smell.
Human factors/ergonomics professionals should be aware of the increased number of people with olfactory dysfunction and consider ways to accommodate them.
While the sense of smell is not commonly thought of as a primary means of human-system communication, we rely on smell in many important ways that relate to both quality of life and safety.
Olfaction has received relatively little attention from human factors/ergonomics professionals. Product research and development teams have just begun to tap into the sense of smell to augment human system communication.

Un article de recherche s'intéresse à la perte d'odorat dans la covid. Rapportée par 35% des patients, elle est en réalité mesurable dans 98% des cas. L'étude souligne que l'anosmie a d'importantes répercussions dans la vie quotidienne.

2124

N42

Yes

Shin Jie Yong

Persistent Brainstem Dysfunction in Long-COVID: A Hypothesis

https://doi.org/10.1021/acschemneuro.0c00793

Published

4-Feb-21

Article

https://pubs.acs.org/doi/10.1021/acschemneuro.0c00793

While the possible causes of long-COVID include long-term tissue damage, viral persistence, and chronic inflammation, the review proposes, perhaps for the first time, that persistent brainstem dysfunction may also be involved. This hypothesis can be split into two parts. The first is the brainstem tropism and damage in COVID-19. As the brainstem has a relatively high expression of ACE2 receptor compared with other brain regions, SARS-CoV-2 may exhibit tropism therein. Evidence also exists that neuropilin-1, a co-receptor of SARS-CoV-2, may be expressed in the brainstem. Indeed, autopsy studies have found SARS-CoV-2 RNA and proteins in the brainstem. The brainstem is also highly prone to damage from pathological immune or vascular activation, which has also been observed in autopsy of COVID-19 cases. The second part concerns functions of the brainstem that overlap with symptoms of long-COVID. The brainstem contains numerous distinct nuclei and subparts that regulate the respiratory, cardiovascular, gastrointestinal, and neurological processes, which can be linked to long-COVID. As neurons do not readily regenerate, brainstem dysfunction may be long-lasting and, thus, is long-COVID. Indeed, brainstem dysfunction has been implicated in other similar disorders, such as chronic pain and migraine and myalgic encephalomyelitis or chronic fatigue syndrome.

Le neurobiologiste Shin Jie Yong (@Shin63714105) détaille une hypothèse sur le covid long. Selon lui, un dysfonctionnement persistant du tronc cérébral, qui régule des processus respiratoire, cardiovasculaire, gastro-intestinal et neurologique, pourrait expliquer une partie des symptômes fonctionnels.
Cette atteinte serait alors liée à l'expression de récepteurs ACE2 et neuropiline 1 dans le tronc cérébral, ou à la vulnérabilité de celui-ci aux pathologies immunitaires ou vasculaires. À lire : l'intégralité de l'article de @Shin63714105 sur l'hypothèse d'un dysfonctionnement persistent du tronc cérébral pour expliquer les symptômes neurologiques du covid long.
https://drive.google.com/file/d/1p0vtb0pDJx-dvNHGOVbwW4a1u6-1J-cI/view?usp=drivesdk L'auteur avance que ce dysfonctionnement pourrait expliquer la dysautonomie et autres troubles cardiaques, respiratoires, intestinaux, ou systémiques. La faible faculté des neurones du tronc cérébral à se régénérer pourrait laisser présager des symptômes au très long cours.

N001

___Neurologic___

Published article on 4-Feb-21:
"Persistent Brainstem Dysfunction in Long-COVID: A Hypothesis"
Le neurobiologiste Shin Jie Yong (@Shin63714105) détaille une hypothèse sur le covid long. Selon lui, un dysfonctionnement persistant du tronc cérébral, qui régule des processus respiratoire, cardiovasculaire, gastro-intestinal et neurologique, pourrait expliquer une partie des symptômes fonctionnels.
Cette atteinte serait alors liée à l'expression de récepteurs ACE2 et neuropiline 1 dans le tronc cérébral, ou à la vulnérabilité de celui-ci aux pathologies immunitaires ou vasculaires. À lire : l'intégralité de l'article de @Shin63714105 sur l'hypothèse d'un dysfonctionnement persistent du tronc cérébral pour expliquer les symptômes neurologiques du covid long.
https://drive.google.com/file/d/1p0vtb0pDJx-dvNHGOVbwW4a1u6-1J-cI/view?usp=drivesdk L'auteur avance que ce dysfonctionnement pourrait expliquer la dysautonomie et autres troubles cardiaques, respiratoires, intestinaux, ou systémiques. La faible faculté des neurones du tronc cérébral à se régénérer pourrait laisser présager des symptômes au très long cours.
Link: https://pubs.acs.org/doi/10.1021/acschemneuro.0c00793
Extract: "While the possible causes of long-COVID include long-term tissue damage, viral persistence, and chronic inflammation, the review proposes, perhaps for the first time, that persistent brainstem dysfunction may also be involved. This hypothesis can be split into two parts. The first is the brainstem tropism and damage in COVID-19. As the brainstem has a relatively high expression of ACE2 receptor compared with other brain regions, SARS-CoV-2 may exhibit tropism therein. Evidence also exists that neuropilin-1, a co-receptor of SARS-CoV-2, may be expressed in the brainstem. Indeed, autopsy studies have found SARS-CoV-2 RNA and proteins in the brainstem. The brainstem is also highly prone to damage from pathological immune or vascular activation, which has also been observed in autopsy of COVID-19 cases. The second part concerns functions of the brainstem that overlap with symptoms of long-COVID. The brainstem contains numerous distinct nuclei and subparts that regulate the respiratory, cardiovascular, gastrointestinal, and neurological processes, which can be linked to long-COVID. As neurons do not readily regenerate, brainstem dysfunction may be long-lasting and, thus, is long-COVID. Indeed, brainstem dysfunction has been implicated in other similar disorders, such as chronic pain and migraine and myalgic encephalomyelitis or chronic fatigue syndrome."

2125

N43

ES

Jakob Matschke, Marc Lütgehetmann, Christian Hagel, Ann Sophie Schröder, Carolin Edler, Herbert Mushumba, Stefan Bonn, Marco Prinz, Christian Gerloff, Markus Glatzel

Neuropathology of patients with COVID-19 in Germany: a post-mortem case series

https://doi.org/10.1016/S1474-4422(20)30308-2

Published

1-Nov-20

Cases Series

https://www.sciencedirect.com/science/article/abs/pii/S1474442220303082

Cette étude, par autopsies, indique une détection de protéines virales du SARS-CoV-2 dans le tronc cérébral chez certaines victimes de la covid.

N001R

___Neurologic___

Published cases series on 1-Nov-20:
"Neuropathology of patients with COVID-19 in Germany: a post-mortem case series"
Cette étude, par autopsies, indique une détection de protéines virales du SARS-CoV-2 dans le tronc cérébral chez certaines victimes de la covid.
Link: https://www.sciencedirect.com/science/article/abs/pii/S1474442220303082
Extract: ""

2126

N44

Jan Remsik 9
Jessica A. Wilcox 9
N. Esther Babady
Edward K. Avila
Bianca Santomasso
Adrienne Boire

Inflammatory Leptomeningeal Cytokines Mediate COVID-19 Neurologic Symptoms in Cancer Patients

https://doi.org/10.1016/j.ccell.2021.01.007

Published

16-Jan-21

Prospective study

https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00051-9

- Inflammatory cytokines are detected in the CSF weeks after SARS-CoV-2 infection
- Levels of IFN-β and IL-8 are specifically enriched in the CSF compared with plasma
- CSF markers of senescence and neurodegeneration are consistent with neuronal injury
- Intracranial levels of MMP-10 correlate with the degree of neurologic disability Here, we present the clinical neurologic characterization of cancer patients with neurologic toxicity after SARS-CoV-2 infection correlated with biochemical analysis of CSF. As comparators, we analyzed CSF collected from cancer patients with an array of neuroinflammatory conditions, including autoimmune encephalitis and chimeric-antigen-receptor T cell (CAR T)-associated neurotoxicity. We correlated CSF composition with degree of neurologic dysfunction. In doing so, we have found evidence for a sustained neuroinflammation and subsequent neuronal damage as a key pathway in the pathogenesis of COVID-19-associated encephalopathy.

Une étude sur des patients cancéreux atteints de la covid et présentant des troubles neurologiques oriente vers un mécanisme de neuroinflammation prolongée et des lésions neuronales consécutives à l'infection. Ce mécanisme est décrit comme élément clé dans la pathogenèse de l'encéphalopathie associée à la covid. Les auteurs notent également que les taux de MMP-10 dans le liquide cérébrospinal sont corrélés avec l'importance des manifestations neurologiques.

N001R

___Neurologic___

Published prospective study on 16-Jan-21:
"Inflammatory Leptomeningeal Cytokines Mediate COVID-19 Neurologic Symptoms in Cancer Patients"
Une étude sur des patients cancéreux atteints de la covid et présentant des troubles neurologiques oriente vers un mécanisme de neuroinflammation prolongée et des lésions neuronales consécutives à l'infection. Ce mécanisme est décrit comme élément clé dans la pathogenèse de l'encéphalopathie associée à la covid. Les auteurs notent également que les taux de MMP-10 dans le liquide cérébrospinal sont corrélés avec l'importance des manifestations neurologiques.
Link: https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00051-9
Extract: "- Inflammatory cytokines are detected in the CSF weeks after SARS-CoV-2 infection
- Levels of IFN-β and IL-8 are specifically enriched in the CSF compared with plasma
- CSF markers of senescence and neurodegeneration are consistent with neuronal injury
- Intracranial levels of MMP-10 correlate with the degree of neurologic disability Here, we present the clinical neurologic characterization of cancer patients with neurologic toxicity after SARS-CoV-2 infection correlated with biochemical analysis of CSF. As comparators, we analyzed CSF collected from cancer patients with an array of neuroinflammatory conditions, including autoimmune encephalitis and chimeric-antigen-receptor T cell (CAR T)-associated neurotoxicity. We correlated CSF composition with degree of neurologic dysfunction. In doing so, we have found evidence for a sustained neuroinflammation and subsequent neuronal damage as a key pathway in the pathogenesis of COVID-19-associated encephalopathy."

2127

N45

Ruqaiyyah Siddiqui,Mohammad Ridwane Mungroo &Naveed Ahmed Khan

SARS-CoV-2 invasion of the central nervous: a brief review

https://doi.org/10.1080/21548331.2021.1887677

Published

8-Feb-21

Review Article

https://www.tandfonline.com/doi/full/10.1080/21548331.2021.1887677

Une brève revue d'études entreprend de faire le point sur les mécanismes qui permettent au SARS-CoV2 d'entrer dans le système nerveux central.

2128

N46

David W. Nauen, MD, PhD1; Jody E. Hooper, MD1; C. Matthew Stewart, MD, PhD2; Isaac H. Solomon

Assessing Brain Capillaries in Coronavirus Disease 2019

https://doi.org/10.1001/jamaneurol.2021.0225

Published

12-Feb-21

Research Letter

https://jamanetwork.com/journals/jamaneurology/fullarticle/2776455

Hannah Davis @ahandvanish (Twitter) :
A new possible theory of COVID/#LongCOVID brain fog from Johns Hopkins - large megakaryocyte (bone marrow) cells found in the brain. These could block blood flow through individual capillaries, "resulting in an atypical form of neurologic impairment." 1/
Layman's translation from https://www.medscape.com/viewarticle/945774 "I was taken aback; I couldn't figure out what they were. Then I realized these cells were megakaryocytes from the bone marrow. I have never seen these cells in the brain before." 2/"This might alter the hemodynamics & put pressure on other vessels." None of the samples he examined came from patients with COVID-19 who had had a stroke. Other than the megakaryocytes, the brain looked normal. He examined 15 brains...megakaryocytes were found in 5 cases. 3/"Megakaryocytes are bone marrow cells, not immune cells. Their job is to produce platelets to help the blood clot. They are not normally found outside bone marrow, but they have been reported in other organs in COVID-19 patients." 4/"The big puzzle with finding them in the brain is how they get through the very fine network of blood vessels in the lungs. The geometry just doesn't work. We don't know which part of the COVID inflammatory response makes this happen," said Nauen. 5/Another mention of endothelial dysfunction: The authors suggest one possibility is that altered endothelial or other signaling is recruiting megakaryocytes into the circulation." 6/

Une étude effectuée à partir d'autopsies de victimes de covid retrouve des cellules identifiées comme des mégakaryocytes (cellules de moelle osseuse fabriquant les plaquettes) dans certains échantillons du cerveau, emplacement inédit pour ces cellules. Ceux-ci pourraient bloquer la circulation sanguine à travers les capillaires, entraîner une forme atypique de déficience neurologique, et jouer un rôle dans les troubles de coagulation souvent observés dans la covid.

N002N

___Neurologic___

Published research letter on 12-Feb-21:
"Assessing Brain Capillaries in Coronavirus Disease 2019"
Une étude effectuée à partir d'autopsies de victimes de covid retrouve des cellules identifiées comme des mégakaryocytes (cellules de moelle osseuse fabriquant les plaquettes) dans certains échantillons du cerveau, emplacement inédit pour ces cellules. Ceux-ci pourraient bloquer la circulation sanguine à travers les capillaires, entraîner une forme atypique de déficience neurologique, et jouer un rôle dans les troubles de coagulation souvent observés dans la covid.
Link: https://jamanetwork.com/journals/jamaneurology/fullarticle/2776455
Extract: "Hannah Davis @ahandvanish (Twitter) :
A new possible theory of COVID/#LongCOVID brain fog from Johns Hopkins - large megakaryocyte (bone marrow) cells found in the brain. These could block blood flow through individual capillaries, "resulting in an atypical form of neurologic impairment." 1/
Layman's translation from https://www.medscape.com/viewarticle/945774 "I was taken aback; I couldn't figure out what they were. Then I realized these cells were megakaryocytes from the bone marrow. I have never seen these cells in the brain before." 2/"This might alter the hemodynamics & put pressure on other vessels." None of the samples he examined came from patients with COVID-19 who had had a stroke. Other than the megakaryocytes, the brain looked normal. He examined 15 brains...megakaryocytes were found in 5 cases. 3/"Megakaryocytes are bone marrow cells, not immune cells. Their job is to produce platelets to help the blood clot. They are not normally found outside bone marrow, but they have been reported in other organs in COVID-19 patients." 4/"The big puzzle with finding them in the brain is how they get through the very fine network of blood vessels in the lungs. The geometry just doesn't work. We don't know which part of the COVID inflammatory response makes this happen," said Nauen. 5/Another mention of endothelial dysfunction: The authors suggest one possibility is that altered endothelial or other signaling is recruiting megakaryocytes into the circulation." 6/"

2129

N47

Anand Ramani, Pranty AbidaIslam1Jay Gopalakrishnan

Neurotropic effects of SARS-CoV-2 modeled by the human brain organoids

https://doi.org/10.1016/j.stemcr.2021.02.007

Published

12-Feb-21

Perspective

https://www.sciencedirect.com/science/article/pii/S2213671121000874

Here, we summarize the neurotoxic effects of SARS-CoV-2 using brain organoids and comprehensively discuss how brain organoids could further improve our understanding when they are fine-tuned.

Un article fait le point sur l'utilisation d'organoïdes de cerveaux humains pour comprendre le neurotropisme du virus SARS-CoV-2 à travers différentes études.

2130

N48

Roberta Ferrucci, Michelangelo Dini, Elisabetta Groppo, Chiara Rosci, Maria Rita Reitano, Francesca Bai, Barbara Poletti, Agostino Brugnera, Vincenzo Silani, Antonella D’Arminio Monforte and Alberto Priori

Long-Lasting Cognitive Abnormalities after COVID-19

https://doi.org/10.3390/brainsci11020235

Published

13-Feb-21

Study

https://www.mdpi.com/2076-3425/11/2/235

We recruited 38 (aged 22–74 years; 27 males) patients hospitalized for complications of SARS-CoV-2
infection in nonintensive COVID units. Participants underwent neuropsychological testing about
5 months after hospital discharge. Of all patients, 42.1% had processing speed deficits, while 26.3% showed delayed verbal recall deficits. Twenty-one percent presented with deficits in both processing speed and verbal memory. Bivariate analysis revealed a positive correlation between the lowest
arterial oxygen partial pressure (PaO2) to fractional inspired oxygen (FiO2) (P/F) ratio during hospitalization and verbal memory consolidation performance (SRT-LTS score, r = 0.404, p = 0.027),
as well as a positive correlation between SpO2
levels upon hospital arrival and delayed verbal recall
performance (SRT-D score, rs = 0.373, p = 0.042). Acute respiratory distress syndrome (ARDS) during
hospitalization was associated with worse verbal memory performance (ARDS vs. no ARDS: SRT-LTS
mean score = 30.63 ± 13.33 vs. 44.50 ± 13.16, p = 0.007; SRT-D mean score = 5.95 ± 2.56 vs. 8.10 ±
2.62, p = 0.029). Cognitive abnormalities can frequently be found in COVID-19 patients 5 months after
hospital discharge. Increased fatigability, deficits of concentration and memory, and overall decreased
cognitive speed months after hospital discharge can interfere with work and daily activities.

Dans une étude sur une petite cohorte de malades de la covid hospitalisés mais sans passage en réanimation, des chercheurs retrouvent après 5 mois, chez 42%, des lenteurs cognitives anormales et chez 26% des déficits de remémoration verbale.

N003

___Neurologic___

Published study on 13-Feb-21:
"Long-Lasting Cognitive Abnormalities after COVID-19"
Dans une étude sur une petite cohorte de malades de la covid hospitalisés mais sans passage en réanimation, des chercheurs retrouvent après 5 mois, chez 42%, des lenteurs cognitives anormales et chez 26% des déficits de remémoration verbale.
Link: https://www.mdpi.com/2076-3425/11/2/235
Extract: "We recruited 38 (aged 22–74 years; 27 males) patients hospitalized for complications of SARS-CoV-2
infection in nonintensive COVID units. Participants underwent neuropsychological testing about
5 months after hospital discharge. Of all patients, 42.1% had processing speed deficits, while 26.3% showed delayed verbal recall deficits. Twenty-one percent presented with deficits in both processing speed and verbal memory. Bivariate analysis revealed a positive correlation between the lowest
arterial oxygen partial pressure (PaO2) to fractional inspired oxygen (FiO2) (P/F) ratio during hospitalization and verbal memory consolidation performance (SRT-LTS score, r = 0.404, p = 0.027),
as well as a positive correlation between SpO2
levels upon hospital arrival and delayed verbal recall
performance (SRT-D score, rs = 0.373, p = 0.042). Acute respiratory distress syndrome (ARDS) during
hospitalization was associated with worse verbal memory performance (ARDS vs. no ARDS: SRT-LTS
mean score = 30.63 ± 13.33 vs. 44.50 ± 13.16, p = 0.007; SRT-D mean score = 5.95 ± 2.56 vs. 8.10 ±
2.62, p = 0.029). Cognitive abnormalities can frequently be found in COVID-19 patients 5 months after
hospital discharge. Increased fatigability, deficits of concentration and memory, and overall decreased
cognitive speed months after hospital discharge can interfere with work and daily activities."

2131

N49

Edwin Estefan Reza-Zaldívar, Mercedes Azucena Hernández-Sapiéns, Benito Minjarez, Ulises Gómez-Pinedo, Ana Laura Márquez-Aguirre, Juan Carlos Mateos-Díaz, Jorge Matias-Guiu, and Alejandro Arturo Canales-Aguirre

Infection Mechanism of SARS-COV-2 and Its Implication on the Nervous System

https://doi.org/10.3389%2Ffimmu.2020.621735

Published

29-Jan-21

Review

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878381/

it has been demonstrated that SARS-CoV-2 affects the CNS. As overwhelming proof, there is the isolation of SARS-CoV-2 from cerebrospinal fluid, the colocalization within the olfactory system, the ultrastructural evidence of frontal lobe budding SARS-CoV-2, and the list of neurologic manifestations in the COVID-19 patients. Unfortunately, it is unclear if the neurological symptoms of COVID-19 result from cytokine storm-induced neuroinflammation or some brain areas’ infection. Nevertheless, the CNS and immune system involvement might have remarkably neurologic long-term consequences, including the development of neuropsychiatric disorders.

Une revue d'études entreprend d'établir les voies possibles de la neuroinvasion du SARS-CoV-2, notamment la voie synaptique depuis le bulbe olfactif ainsi que celles des terminaisons nerveuses périphériques, et l'impact sur le système nerveux central. Les auteurs notent qu'il est établi que la covid peut endommager le système nerveux central, et qu'il reste la question de savoir s'il s'agit d'une neuroinflammaiton ou d'une infection directe du tissu cérébral.

N002N

___Neurologic___

Published review on 29-Jan-21:
"Infection Mechanism of SARS-COV-2 and Its Implication on the Nervous System"
Une revue d'études entreprend d'établir les voies possibles de la neuroinvasion du SARS-CoV-2, notamment la voie synaptique depuis le bulbe olfactif ainsi que celles des terminaisons nerveuses périphériques, et l'impact sur le système nerveux central. Les auteurs notent qu'il est établi que la covid peut endommager le système nerveux central, et qu'il reste la question de savoir s'il s'agit d'une neuroinflammaiton ou d'une infection directe du tissu cérébral.
Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878381/
Extract: "it has been demonstrated that SARS-CoV-2 affects the CNS. As overwhelming proof, there is the isolation of SARS-CoV-2 from cerebrospinal fluid, the colocalization within the olfactory system, the ultrastructural evidence of frontal lobe budding SARS-CoV-2, and the list of neurologic manifestations in the COVID-19 patients. Unfortunately, it is unclear if the neurological symptoms of COVID-19 result from cytokine storm-induced neuroinflammation or some brain areas’ infection. Nevertheless, the CNS and immune system involvement might have remarkably neurologic long-term consequences, including the development of neuropsychiatric disorders."

2132

N50

Bing Sun, Norina Tang, Michael J. Peluso, Nikita S. Iyer, Leonel Torres, Joanna L. Donatelli, Sadie E. Munter, Christopher C. Nixon, Rachel L. Rutishauser, Isabel Rodriguez-Barraquer, Bryan Greenhouse, John D. Kelly, Jeffrey N. Martin, Steven G. Deeks, Timothy J. Henrich and Lynn Pulliam

Characterization and Biomarker Analyses of Post-COVID-19 Complications and Neurological Manifestations

https://doi.org/10.3390/cells10020386

Published

13-Feb-21

Study

https://www.mdpi.com/2073-4409/10/2/386

Plasma from 24 individuals recovering from COVID-19 at 1 to 3 months after initial infection were collected for cytokine and antibody levels and neuronal-enriched extracellular vesicle (nEV) protein cargo analyses. Plasma cytokine IL-4 was increased in all COVID-19 participants. Volunteers with self-reported neurological problems (nCoV, n = 8) had a positive correlation of IL6 with age or severity of the sequalae, at least one co-morbidity and increased SARS-CoV-2 antibody compared to those COVID-19 individuals without neurological issues (CoV, n = 16). Protein markers of neuronal dysfunction including amyloid beta, neurofilament light, neurogranin, total tau, and p-T181-tau were all significantly increased in the nEVs of all participants recovering from COVID-19 compared to historic controls. This study suggests ongoing peripheral and neuroinflammation after COVID-19 infection that may influence neurological sequelae by altering nEV proteins. Individuals recovering from COVID-19 may have occult neural damage while those with demonstrative neurological symptoms additionally had more severe infection.

Une étude s'intéresse aux biomarqueurs neurologiques liés à une infection de covid. Elle suggère une neuroinflammation périphérique continue avec des séquelles neurologiques par la dégradation des vésicules extracellulaires enrichies en neurones.

N004R

___Neurologic___

Published study on 13-Feb-21:
"Characterization and Biomarker Analyses of Post-COVID-19 Complications and Neurological Manifestations"
Une étude s'intéresse aux biomarqueurs neurologiques liés à une infection de covid. Elle suggère une neuroinflammation périphérique continue avec des séquelles neurologiques par la dégradation des vésicules extracellulaires enrichies en neurones.
Link: https://www.mdpi.com/2073-4409/10/2/386
Extract: "Plasma from 24 individuals recovering from COVID-19 at 1 to 3 months after initial infection were collected for cytokine and antibody levels and neuronal-enriched extracellular vesicle (nEV) protein cargo analyses. Plasma cytokine IL-4 was increased in all COVID-19 participants. Volunteers with self-reported neurological problems (nCoV, n = 8) had a positive correlation of IL6 with age or severity of the sequalae, at least one co-morbidity and increased SARS-CoV-2 antibody compared to those COVID-19 individuals without neurological issues (CoV, n = 16). Protein markers of neuronal dysfunction including amyloid beta, neurofilament light, neurogranin, total tau, and p-T181-tau were all significantly increased in the nEVs of all participants recovering from COVID-19 compared to historic controls. This study suggests ongoing peripheral and neuroinflammation after COVID-19 infection that may influence neurological sequelae by altering nEV proteins. Individuals recovering from COVID-19 may have occult neural damage while those with demonstrative neurological symptoms additionally had more severe infection."

2133

N51

Maria Rosaria Rizzo*, Giuseppe Paolisso

SARS-CoV-2 Emergency and Long-Term Cognitive Impairment in Older People

https://doi.org/10.14336/AD.2021.0109

Published

27-Jan-21

Article

http://www.aginganddisease.org/EN/10.14336/AD.2021.0109

"data on potential long-term damages generally and on long-term cognitive functions impairment of older COVID-19 survivors have yet to be investigated."
"we wanted to explore the brain mechanisms of SARS-CoV-2, in order to provide more in-depth analysis and to draw attention to a topic relevant to basic scientific research and, more generally, to the elderly population.Looking forward, we argue that an early clinical and instrumental cognitive assessment can help prevent and slow down this possible complication or at least improve the quality of life for older people Covid-19 survivor."

Un article d'analyse explore les différents mécanismes de dommages cérébraux de la covid, notamment chez les personnes âgées. Il insiste sur l'invalidité chronique qui peut résulter de ces dommages cérébraux.

N003R

___Neurologic___

Published article on 27-Jan-21:
"SARS-CoV-2 Emergency and Long-Term Cognitive Impairment in Older People"
Un article d'analyse explore les différents mécanismes de dommages cérébraux de la covid, notamment chez les personnes âgées. Il insiste sur l'invalidité chronique qui peut résulter de ces dommages cérébraux.
Link: http://www.aginganddisease.org/EN/10.14336/AD.2021.0109
Extract: ""data on potential long-term damages generally and on long-term cognitive functions impairment of older COVID-19 survivors have yet to be investigated."
"we wanted to explore the brain mechanisms of SARS-CoV-2, in order to provide more in-depth analysis and to draw attention to a topic relevant to basic scientific research and, more generally, to the elderly population.Looking forward, we argue that an early clinical and instrumental cognitive assessment can help prevent and slow down this possible complication or at least improve the quality of life for older people Covid-19 survivor.""

2134

N52

Amr El-Sayed, Lotfi Aleya & Mohamed Kamel

COVID-19: a new emerging respiratory disease from the neurological perspective

https://doi.org/10.1007/s11356-021-12969-9

Published

15-Feb-21

Review

https://link.springer.com/article/10.1007/s11356-021-12969-9

"The involvement of the central nervous system is now suspected to be among the main causes of death."

L'implication des dommages au système nerveux central est désormais suspectée être l'une des principales causes de décès de covid, selon cette revue d'études.

2135

N53

Amruta Narayanappa Wesley H.Chastain Meshi Paza Rebecca J.Solch Isabel C. Murray-Brown Jaime B.Befelera Timothy E.Gressetta Michele T. Longo Elizabeth B. Engler-Chiurazzi Gregory Bix

SARS-CoV-2 mediated neuroinflammation and the impact of COVID-19 in neurological disorders

https://doi.org/10.1016/j.cytogfr.2021.02.002

Published

19-Feb-21

https://www.sciencedirect.com/science/article/pii/S1359610121000186

Review : Highlights
•SARS-CoV-2, a novel coronavirus that severely affects the respiratory system, is the cause of the COVID-19 pandemic.
•Illustrates immune cell infiltration, cytokine storm, and inflammation.
•Discusses SARS-CoV-2 mediates neuroinflammation and the impact of COVID-19 in neurological disorders.
•ATN-161 inhibits SARS-CoV-2 spike protein binding to both integrin α5β1 and α5β1/hACE2.
•Summarizes available treatments and vaccines to treat COVID-19 patients.

Une revue d'études très générale aborde la question de la neuro-inflammation induite possible lors d'une infection au SARS-CoV-2.

2136

N54

Mazza Mario Gennaro a b Palladini Maria grazia aRebecca De Lorenzo b c Magnaghi Cristiano c Poletti Sara a b Furlan Roberto b d Ciceri Fabio b c 1 Rovere-Querini Patrizia b c Benedetti Francesco a b

Persistent psychopathology and neurocognitive impairment in COVID-19 survivors: effect of inflammatory biomarkers at three-month follow-up

https://doi.org/10.1016/j.bbi.2021.02.021

Published

24-Feb-21

Study

https://www.sciencedirect.com/science/article/pii/S0889159121000866

Highlights
•COVID-19 is associated with acute and short-term psychiatric implications.
•We found depressive symptomatology and neurocognitive impairment at three months.
•Systemic inflammation predicted depressive symptomatology and cognitive impairment.
•Attention and information processing were strictly related to depression.
•COVID-19 related inflammation leads to depression and cognitive dysfunction.

Les résultats d'une étude à 3 mois de l'hospitalisation font suggérer aux auteurs que la covid pourrait causer une inflammation systémique prolongée qui prédispose les patients à une dépression persistante et à un dysfonctionnement neurocognitif associé.

2137

N55

Yuanyuan Qin,1 Jinfeng Wu,2 Tao Chen,3 Jia Li,1 Guiling Zhang,1 Di Wu,1 Yiran Zhou,1 Ning Zheng,4 Aoling Cai,2 Qin Ning,5 Anne Manyande,6 Fuqiang Xu,4 Jie Wang,7 and Wenzhen Zhu

Long-term micro-structure and cerebral blood flow changes in patients recovered from COVID-19 without neurological manifestations

https://doi.org/10.1172/JCI147329

Published

25-Feb-21

Study

https://www.jci.org/articles/view/147329

Here, two subtypes (mild type-MG and severe type-SG) with no specific neurological manifestations at the acute stage and no obvious lesions on the conventional MRI three months after discharge were recruited. Changes in gray matter morphometry, cerebral blood flow (CBF) and white matter (WM) microstructure were investigated using MRI. The relationship between brain imaging measurements and inflammation markers were further analyzed. Compared with healthy controls, the decrease in cortical thickness/CBF, and the changes in WM microstructure were observed to be more severe in the SG than MG, especially in the frontal and limbic systems. Furthermore, changes in brain microstructure, CBF and tracts parameters were significantly correlated with inflammatory markers. The indirect injury related to inflammatory storm may damage the brain, that led to these interesting observations. There are also other likely potential causes, such as hypoxemia and dysfunction of vascular endothelium, et al.

Comparé à un groupe contrôle sain, une étude note que la circulation cérébrovasculaire et l'épaisseur corticale a tendance à avoir diminué à 3 mois chez les personnes atteintes de la covid, en particulier dans les systèmes frontal et limbique. Ces constatations se retrouvent corrélées à des marqueurs inflammatoires et à la sévérité de la phase de covid aiguë.

N003A

___Neurologic___

Published study on 25-Feb-21:
"Long-term micro-structure and cerebral blood flow changes in patients recovered from COVID-19 without neurological manifestations"
Comparé à un groupe contrôle sain, une étude note que la circulation cérébrovasculaire et l'épaisseur corticale a tendance à avoir diminué à 3 mois chez les personnes atteintes de la covid, en particulier dans les systèmes frontal et limbique. Ces constatations se retrouvent corrélées à des marqueurs inflammatoires et à la sévérité de la phase de covid aiguë.
Link: https://www.jci.org/articles/view/147329
Extract: "Here, two subtypes (mild type-MG and severe type-SG) with no specific neurological manifestations at the acute stage and no obvious lesions on the conventional MRI three months after discharge were recruited. Changes in gray matter morphometry, cerebral blood flow (CBF) and white matter (WM) microstructure were investigated using MRI. The relationship between brain imaging measurements and inflammation markers were further analyzed. Compared with healthy controls, the decrease in cortical thickness/CBF, and the changes in WM microstructure were observed to be more severe in the SG than MG, especially in the frontal and limbic systems. Furthermore, changes in brain microstructure, CBF and tracts parameters were significantly correlated with inflammatory markers. The indirect injury related to inflammatory storm may damage the brain, that led to these interesting observations. There are also other likely potential causes, such as hypoxemia and dysfunction of vascular endothelium, et al."

2138

N56

Michael Fleischer, Martin Köhrmann, Sebastian Dolff, Fabian Szepanowski, Karsten Schmidt, Frank Herbstreit, Cansu Güngör, Benjamin Stolte, Katharina Marie Steiner, Christine Stadtler, Joachim Riße, Melanie Fiedler, Gerd Meyer zu Hörste, Anne-K. Mausberg, Clemens Kill, Michael Forsting, Ulrich Sure, Ulf Dittmer, Oliver Witzke, Thorsten Brenner, Christoph Kleinschnitz*, Mark Stettner

Observational cohort study of neurological involvement among patients with SARS-CoV-2 infection

https://doi.org/10.1177%2F1756286421993701

Published

26-Feb-21

Research Article

https://journals.sagepub.com/doi/full/10.1177/1756286421993701

"Cerebrovascular events were the most frequent severe NIV and severe NIV
was associated with high mortality. Incidence of NIV increased with respiratory symptoms
and NIV and pre-existing neurological morbidities were independent risk factors for fatality.
Inflammatory involvement due to BBB disruption and cytokine release drives NIV, rather
than direct viral invasion."

Une étude rapporte que dans 75% des décès de covid, les patients présentaient des dysfonctions neurologiques aggravées par la covid ou consécutives à celle-ci. Les analyses du liquide cérébrospinal et du sang suggèrent que la perturbation de la barrière hémato-encéphalique, la libération de cytokines ainsi que des mécanismes auto-immuns sont impliqués dans le développement des troubles neurologiques de la covid. Ces mécanismes tendraient à écarter l'invasion virale directe au niveau cérébral.

2139

N57

Martina Sollini 1 2, Silvia Morbelli 3 4, Michele Ciccarelli 1, Maurizio Cecconi 1 2, Alessio Aghemo 1 2, Paola Morelli 1 2, Silvia Chiola 1 2, Fabrizia Gelardi 5 6, Arturo Chiti

Long COVID hallmarks on [18F]FDG-PET/CT: a case-control study

https://doi.org/10.1007/s00259-021-05294-3

Published

7-Mar-21

Study

https://link.springer.com/article/10.1007/s00259-021-05294-3

Results: In 4/13 long COVID patients, CT images showed lung abnormalities presenting mild [18F]FDG uptake. Many healthy organs/parenchyma SUVs and SUV ratios significantly differed between the two groups (p ≤ 0.05). Long COVID patients exhibited brain hypometabolism in the right parahippocampal gyrus and thalamus (uncorrected p < 0.001 at voxel level). Specific area(s) of hypometabolism characterised patients with persistent anosmia/ageusia, fatigue, and vascular uptake (uncorrected p < 0.005 at voxel level).
Conclusion: [18F]FDG PET/CT acknowledged the multi-organ nature of long COVID, supporting the hypothesis of underlying systemic inflammation. Whole-body images showed increased [18F]FDG uptake in several "target" and "non-target" tissues. We found a typical pattern of brain hypometabolism associated with persistent complaints at the PET time, suggesting a different temporal sequence for brain and whole-body inflammatory changes. This evidence underlined the potential value of whole-body [18F]FDG PET in disclosing the pathophysiology of long COVID.

En effectuant un PET-SCAN "corps entier" sur une cohorte de 13 patients qui souffrent de symptômes persistants après une infection de covid, et en comparant avec un groupe contrôle, une équipe italienne confirme les résultats d'une étude française. Un hypométabolisme est noté dans certaines régions cérébrales, notamment le gyrus parahippocampique et le thalamus droits. Des anomalies d'hypermétabolisme sont également retrouvées sur certains organes et tissus, et traduisent un syndrome inflammatoire multi-systémique. Une absorption anormale au niveau du foie, et parfois, de façon plus inquiétante pour les auteurs, de la moelle osseuse, est relevée dans cette cohorte covid long, âgée de 46 à 79 ans, la moitié sans hospitalisation. Les observations de cette étude font dire aux auteurs que les PET-SCAN "corps entier" pourraient devenir un examen de référence dans l'étude des atteintes organiques et systémiques chez les malades covid longs.

N003A

___Neurologic___

Published study on 7-Mar-21:
"Long COVID hallmarks on [18F]FDG-PET/CT: a case-control study"
En effectuant un PET-SCAN "corps entier" sur une cohorte de 13 patients qui souffrent de symptômes persistants après une infection de covid, et en comparant avec un groupe contrôle, une équipe italienne confirme les résultats d'une étude française. Un hypométabolisme est noté dans certaines régions cérébrales, notamment le gyrus parahippocampique et le thalamus droits. Des anomalies d'hypermétabolisme sont également retrouvées sur certains organes et tissus, et traduisent un syndrome inflammatoire multi-systémique. Une absorption anormale au niveau du foie, et parfois, de façon plus inquiétante pour les auteurs, de la moelle osseuse, est relevée dans cette cohorte covid long, âgée de 46 à 79 ans, la moitié sans hospitalisation. Les observations de cette étude font dire aux auteurs que les PET-SCAN "corps entier" pourraient devenir un examen de référence dans l'étude des atteintes organiques et systémiques chez les malades covid longs.
Link: https://link.springer.com/article/10.1007/s00259-021-05294-3
Extract: "Results: In 4/13 long COVID patients, CT images showed lung abnormalities presenting mild [18F]FDG uptake. Many healthy organs/parenchyma SUVs and SUV ratios significantly differed between the two groups (p ≤ 0.05). Long COVID patients exhibited brain hypometabolism in the right parahippocampal gyrus and thalamus (uncorrected p < 0.001 at voxel level). Specific area(s) of hypometabolism characterised patients with persistent anosmia/ageusia, fatigue, and vascular uptake (uncorrected p < 0.005 at voxel level).
Conclusion: [18F]FDG PET/CT acknowledged the multi-organ nature of long COVID, supporting the hypothesis of underlying systemic inflammation. Whole-body images showed increased [18F]FDG uptake in several "target" and "non-target" tissues. We found a typical pattern of brain hypometabolism associated with persistent complaints at the PET time, suggesting a different temporal sequence for brain and whole-body inflammatory changes. This evidence underlined the potential value of whole-body [18F]FDG PET in disclosing the pathophysiology of long COVID."

2140

N58

Michelle A. Erickson 1,2,* ,Elizabeth M. Rhea 1,2 ,Rachel C. Knopp 1,2 andWilliam A. Banks 1,2,*

Interactions of SARS-CoV-2 with the Blood–Brain Barrier

https://doi.org/10.1007/s00259-021-05294-3

Published

6-Mar-21

Review

https://www.mdpi.com/1422-0067/22/5/2681

Emerging data indicate that neurological complications occur as a consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The blood–brain barrier (BBB) is a critical interface that regulates entry of circulating molecules into the CNS, and is regulated by signals that arise from the brain and blood compartments. In this review, we discuss mechanisms by which SARS-CoV-2 interactions with the BBB may contribute to neurological dysfunction associated with coronavirus disease of 2019 (COVID-19), which is caused by SARS-CoV-2. We consider aspects of peripheral disease, such as hypoxia and systemic inflammatory response syndrome/cytokine storm, as well as CNS infection and mechanisms of viral entry into the brain. We also discuss the contribution of risk factors for developing severe COVID-19 to BBB dysfunction that could increase viral entry or otherwise damage the brain.

Une analyse très technique sur la façon dont le virus SARS-CoV-2 pourrait franchir la barrière hémato-encéphalique (vaisseaux sanguins / système cérébral). Une recherche est faite sur les facteurs de risque favorisant cette entrée.

N004

___Neurologic___

Published review on 6-Mar-21:
"Interactions of SARS-CoV-2 with the Blood–Brain Barrier"
Une analyse très technique sur la façon dont le virus SARS-CoV-2 pourrait franchir la barrière hémato-encéphalique (vaisseaux sanguins / système cérébral). Une recherche est faite sur les facteurs de risque favorisant cette entrée.
Link: https://www.mdpi.com/1422-0067/22/5/2681
Extract: "Emerging data indicate that neurological complications occur as a consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The blood–brain barrier (BBB) is a critical interface that regulates entry of circulating molecules into the CNS, and is regulated by signals that arise from the brain and blood compartments. In this review, we discuss mechanisms by which SARS-CoV-2 interactions with the BBB may contribute to neurological dysfunction associated with coronavirus disease of 2019 (COVID-19), which is caused by SARS-CoV-2. We consider aspects of peripheral disease, such as hypoxia and systemic inflammatory response syndrome/cytokine storm, as well as CNS infection and mechanisms of viral entry into the brain. We also discuss the contribution of risk factors for developing severe COVID-19 to BBB dysfunction that could increase viral entry or otherwise damage the brain."

2141

N59

Zheng Li, Xingye Li, Jianxiong Shen, Matthew T.V. Chan & William Ka Kei Wu

Miller Fisher syndrome associated with COVID-19: an up-to-date systematic review

https://doi.org/10.1007/s11356-021-13233-w

Published

6-Mar-21

Review Article

https://link.springer.com/article/10.1007/s11356-021-13233-w

Recently, during the pandemic infection of the novel SARS-CoV-2, some cases of Miller Fisher syndrome (MFS) have been reported. We want to summarize the main features of patients with MFS and COVID-19. A PubMed search was performed on 8 October to identify references reporting cases with MFS associated with COVID-19 from the first report of COVID-19 to 8 October 2020 using the following keywords: “Miller Fisher syndrome” AND “COVID-19” OR “SARS-CoV-2”. A systematic review from the first report of coronavirus disease 2019 (COVID-19) to 8 October 2020 revealed 7 cases with Miller Fisher syndrome (MFS) associated with COVID-19. The 7 cases came from 5 countries but most of these patients were from Europe (85.7%), especially Spain. There are 5 cases of MFS diagnosed after the laboratory confirmation of SARS-CoV-2 infection. The mean onset time of MFS-associated neurological symptoms was 14.75 days after the diagnosis of COVID-19. However, the two remaining cases presented initially with MFS-associated neurological symptoms followed by the diagnosis of COVID-19. The most common symptoms of COVID-19-associated MFS were perioral paresthesias (57.1%), ataxia (57.1%), blurred vision (42.9), ophthalmoplegia (42.9), and generalized areflexia (42.9). However, more cohort and case-control studies are required to establish the epidemiological linkage.

Une étude systématique de publications sur les interactions entre la covid et le syndrome (rare) de Miller-Fisher (une maladie auto-immune neurologique).

2142

N60

Thông Hua-Huy , Christine Lorut , Frédérique Aubourg , Caroline Morbieu , Jonathan Marey , Joëlle Texereau , Isabelle Fajac , Luc Mouthon , Nicolas Roche , and Anh Tuan Dinh-Xuan

Persistent Nasal Inflammation Five Months After Acute Anosmia in Patients with COVID-19

https://doi.org/10.1164/rccm.202011-4258LE

Published

4-Mar-21

Study

https://www.atsjournals.org/doi/10.1164/rccm.202011-4258LE

there is clear evidence of persistent inflammation 5 months after onset of symptoms in COVID patients who have recovered from their OD. Whether this will lead to chronic rhino-sinus diseases is yet to be investigated.

Le point sur les inflammations nasales persistantes, consécutives à la covid, menant à un dysfonctionnement olfactif (anosmie), qui peuvent se prolonger de nombreux mois après l'infection.

2143

N61

Ali Al-Ramadan 1,2 ,Omar Rabab’h 1,2 ,Jawad Shah 1,2,3,4,5 andAbeer Gharaibeh

Acute and Post-Acute Neurological Complications of COVID-19

https://doi.org/10.3390/neurolint13010010

Published

9-Mar-21

Review

https://www.mdpi.com/2035-8377/13/1/10

we have summarized the most common neurological complications and reported neurological case studies associated with COVID-19, and neurological side effects associated with COVID-19 treatments. Additionally, the post-acute COVID-19 syndrome and long-term neurological complications were discussed. We also explained the proposed mechanisms that are involved in the pathogenesis of these neurological complications.

Une revue d'études fait le point sur les complications neurologiques de la covid. L'analyse rappelle également les différents scénarios qui pourraient expliquer ces séquelles et la façon dont le système nerveux central est affecté.

N004

___Neurologic___

Published review on 9-Mar-21:
"Acute and Post-Acute Neurological Complications of COVID-19"
Une revue d'études fait le point sur les complications neurologiques de la covid. L'analyse rappelle également les différents scénarios qui pourraient expliquer ces séquelles et la façon dont le système nerveux central est affecté.
Link: https://www.mdpi.com/2035-8377/13/1/10
Extract: "we have summarized the most common neurological complications and reported neurological case studies associated with COVID-19, and neurological side effects associated with COVID-19 treatments. Additionally, the post-acute COVID-19 syndrome and long-term neurological complications were discussed. We also explained the proposed mechanisms that are involved in the pathogenesis of these neurological complications."

2144

N62

Shibani S.MukerjiaIsaac H.Solomon

What can we learn from brain autopsies in COVID-19?

https://doi.org/10.1016/j.neulet.2020.135528

Published

25-Nov-20

Minireview

https://www.sciencedirect.com/science/article/pii/S0304394020307989

•Chronic neurological disease and acute abnormalities are present in COVID-19 brain autopsies.
•Acute hypoxic-injury, hemorrhage, and minimal inflammation are frequently observed.
•Low levels of viral SARS-CoV-2 RNA are present; cellular source remains unknown.

There remains no clear understanding of the mechanisms that underlie neurological symptoms in COVID-19 and whether SARS-CoV-2 has the potential for neuroinvasion in humans. In this minireview, we discuss what is known from human autopsies in fatal COVID-19, including highlighting studies that investigate for the presence of SARS-CoV-2 in brain and olfactory tissue, and summarize the neuropathological consequences of infection.

Une courte revue d'études s'intéresse aux symptômes neurologiques de la covid.

N006

___Neurologic___

Published minireview on 25-Nov-20:
"What can we learn from brain autopsies in COVID-19?"
Une courte revue d'études s'intéresse aux symptômes neurologiques de la covid.
Link: https://www.sciencedirect.com/science/article/pii/S0304394020307989
Extract: "•Chronic neurological disease and acute abnormalities are present in COVID-19 brain autopsies.
•Acute hypoxic-injury, hemorrhage, and minimal inflammation are frequently observed.
•Low levels of viral SARS-CoV-2 RNA are present; cellular source remains unknown.

There remains no clear understanding of the mechanisms that underlie neurological symptoms in COVID-19 and whether SARS-CoV-2 has the potential for neuroinvasion in humans. In this minireview, we discuss what is known from human autopsies in fatal COVID-19, including highlighting studies that investigate for the presence of SARS-CoV-2 in brain and olfactory tissue, and summarize the neuropathological consequences of infection."

2145

N63

Dipak Kumar, Sadaf Jahan, Andleeb Khan, Arif Jamal Siddiqui, Neeru Singh Redhu, Wahajuddin, Johra Khan, Saeed Banwas, Bader Alshehri & Mohammed Alaidarous

Neurological Manifestation of SARS-CoV-2 Induced Inflammation and Possible Therapeutic Strategies Against COVID-19

https://doi.org/10.1007/s12035-021-02318-9

Published

14-Mar-21

Review

https://link.springer.com/article/10.1007/s12035-021-02318-9

This review discusses the concerns regarding the neuronal complications of COVID-19 and the possible mechanisms of amelioration.

_

2146

N64

Lisa Bauer, Bas Lendemeijer, Lonneke Leijten, Carmen W. E. Embregts, Barry Rockx, Steven A. Kushner, Femke M.S. de Vrij, Debby van Riel

Replication kinetic, cell tropism and associated immune responses in SARS-CoV-2 and H5N1 virus infected human iPSC derived neural models

https://doi.org/10.1101/2021.03.15.435472

pre-print

16-Mar-21

New Results

https://www.biorxiv.org/content/10.1101/2021.03.15.435472v1

Our findings support the hypothesis that neurological complications might result from local immune responses triggered by virus invasion, rather than abundant SARS-CoV-2 replication in the CNS.

_

2147

N65

Amit Mahajan1 and Graeme F. Mason

A sobering addition to the literature on COVID-19 and the brain

https://doi.org/10.1172/JCI148376

Published

16-Mar-21

Commentary

https://www.jci.org/articles/view/148376

Several COVID-19 studies have focused on neuropathology. In this issue of the JCI, Qin, Wu, and Chen, et al. focused specifically on people whose acute infection lacked obvious neurological involvement. Severely infected patients showed abnormal grey matter volumes, white matter diffusion, and cerebral blood flow compared with healthy controls and those with mild infection. The data remain associative rather than mechanistic, but correlations with systemic immune markers suggest effects of inflammation, hypercoagulation, or other aspects of disease severity. Mechanistic research is warranted. Given the lack of obvious neurological symptoms, neurocognitive assessments were not performed, but the findings suggest that such assessments may be warranted in severely affected patients, even without obvious symptoms. Further, studying CNS involvement of other disorders with overlapping pathophysiologies, such as inflammation, coagulation, hypoxia, or direct viral infection may reveal the causes for COVID-19 related neuropathology.

_

2148

N66

BrycePolascikB.S.JeffreyBrowndykePh.D.SimonDavisPh.D.AndyLiu

Cognitive consequences of COVID-19 in older adults with cognitive impairment

https://doi.org/10.1016/j.jagp.2021.01.066

Published

16-Mar-21

Cases Report

https://www.sciencedirect.com/science/article/pii/S1064748121000920

This case series describes the exacerbation of pre-existing psychiatric and cognitive conditions after COVID-19 recovery in 3 older adults with formal neuropsychological evaluation data.

_

2149

N67

Edith L Graham Jeffrey R Clark Zachary S Orban Patrick H Lim April L Szymanski Carolyn Taylor Rebecca M DiBiase Dan Tong Jia Roumen Balabanov Sam U Ho Ayush Batra Eric M Liotta Igor J Koralnik

Persistent neurologic symptoms and cognitive dysfunction in non‐hospitalized Covid‐19 “long haulers”

https://doi.org/10.1002/acn3.51350

Published

23-Mar-21

Study

https://onlinelibrary.wiley.com/doi/10.1002/acn3.51350

This is a prospective study of the first 100 consecutive patients (50 SARS‐CoV‐2 laboratory‐positive and 50 laboratory‐negative individuals) presenting to our Neuro‐Covid‐19 clinic between May and November 2020. Due to early pandemic testing limitations, patients were included if they met Infectious Diseases Society of America symptoms of Covid‐19, were never hospitalized for pneumonia or hypoxemia and had neurologic symptoms lasting over 6 weeks.

Whereas hypoxemia, systemic inflammation, coagulopathy, and neuroinvasion have been implicated in hospitalized Covid‐19 patients who develop encephalopathy,3 it appears more likely that post‐infectious, autoimmune mechanisms may be at play in “long Covid.” The long‐term impact of “long Covid” on quality of life and potential return to normalcy, through lost productivity and lingering cognitive dysfunction, may be substantial as the pandemic continues to escalate.

_

2150

N68

Ritwick Mondal ShramanaDebb Gourav Shom e c Upasan a Ganguly a Durjoy Lahiri a d Julián Benito-Leon

COVID-19 and emerging spinal cord complications: A systematic review

https://doi.org/10.1016/j.msard.2021.102917

Published

21-Mar-21

Original article

https://www.sciencedirect.com/science/article/pii/S221103482100184X

Highlights
•Spinal cord demyelination in COVID-19 might be an under-recognized neurological complication.
•Concerning the prognosis, most of the patients improved and the mortality rate was low.
•Spinal cord demyelination should be added to the plethora of immune mediated neurologic complications associated with COVID-19

Une revue d'études fait le point sur les maladies démyélinisantes déclenchées par une covid. Les auteurs concluent que la démyélinisation de la moelle épinière doit être ajoutée à la pléthore de complications neurologiques à médiation immunitaire associées à la maladie.

N006

___Neurologic___

Published original article on 21-Mar-21:
"COVID-19 and emerging spinal cord complications: A systematic review"
Une revue d'études fait le point sur les maladies démyélinisantes déclenchées par une covid. Les auteurs concluent que la démyélinisation de la moelle épinière doit être ajoutée à la pléthore de complications neurologiques à médiation immunitaire associées à la maladie.
Link: https://www.sciencedirect.com/science/article/pii/S221103482100184X
Extract: "Highlights
•Spinal cord demyelination in COVID-19 might be an under-recognized neurological complication.
•Concerning the prognosis, most of the patients improved and the mortality rate was low.
•Spinal cord demyelination should be added to the plethora of immune mediated neurologic complications associated with COVID-19"

2151

N69

Maura Boldrini, MD, PhD1,2; Peter D. Canoll, MD, PhD3; Robyn S. Klein

How COVID-19 Affects the Brain

https://doi.org/10.1001/jamapsychiatry.2021.0500

Published

26-Mar-21

Article

http://jamanetwork.com/article.aspx?doi=10.1001/jamapsychiatry.2021.0500

Entering through angiotensin-converting enzyme 2 receptors,2 SARS-CoV-2 can damage endothelial cells leading to inflammation, thrombi, and brain damage. Moreover, systemic inflammation leads to decreased monoamines and trophic factors and activation of microglia, resulting in increased glutamate and N-methyl-d-aspartate (NMDA)3 and excitotoxicity (Figure). These insults induce new-onset or re-exacerbation of preexisting neuro-psychiatric symptoms.

Un article dans JAMA Psychiatry dresse un point concis et étayé sur la façon dont le SARS-CoV-2 peut endommager le cerveau, vraisemblablement par des processus indirects d'inflammation et de détérioration de la barrière hémato-encéphalique. "Les symptômes neuro-psychiatriques de la covid pourraient résulter de micro-AVC et de lésions neuronales, ces symptômes diffèrent par conséquent en fonction de la région cérébrale impliquée."
L'analyse explore les traitements possibles : les antagonistes des cytokines (étanercept, infliximab), des récepteurs NMDA (kétamine), de TNF-α, ainsi que les voies anti-inflammatoires (aspirine, célécoxib) et les modulateurs des voies de la kynurénine (minocycline).

N006

___Neurologic___

Published article on 26-Mar-21:
"How COVID-19 Affects the Brain"
Un article dans JAMA Psychiatry dresse un point concis et étayé sur la façon dont le SARS-CoV-2 peut endommager le cerveau, vraisemblablement par des processus indirects d'inflammation et de détérioration de la barrière hémato-encéphalique. "Les symptômes neuro-psychiatriques de la covid pourraient résulter de micro-AVC et de lésions neuronales, ces symptômes diffèrent par conséquent en fonction de la région cérébrale impliquée."
L'analyse explore les traitements possibles : les antagonistes des cytokines (étanercept, infliximab), des récepteurs NMDA (kétamine), de TNF-α, ainsi que les voies anti-inflammatoires (aspirine, célécoxib) et les modulateurs des voies de la kynurénine (minocycline).
Link: http://jamanetwork.com/article.aspx?doi=10.1001/jamapsychiatry.2021.0500
Extract: "Entering through angiotensin-converting enzyme 2 receptors,2 SARS-CoV-2 can damage endothelial cells leading to inflammation, thrombi, and brain damage. Moreover, systemic inflammation leads to decreased monoamines and trophic factors and activation of microglia, resulting in increased glutamate and N-methyl-d-aspartate (NMDA)3 and excitotoxicity (Figure). These insults induce new-onset or re-exacerbation of preexisting neuro-psychiatric symptoms."

2152

N70

Lis Høy Marbjerg, Christina Jacobsen, Jannik Fonager, Claus Bøgelund, Morten Rasmussen, Anders Fomsgaard, Jytte Banner, Veronika Vorobieva Solholm Jensen

Possible Involvement of Central Nervous System in COVID-19 and Sequence Variability of SARS-CoV-2 Revealed in Autopsy Tissue Samples: A Case Report

https://doi.org/10.1177%2F2632010X211006096

Published

27-Mar-21

Case Report

https://journals.sagepub.com/doi/full/10.1177/2632010X211006096

A forensic autopsy was performed. This revealed severely condensed, almost airless, firm lungs, and the cause of death was severe acute respiratory distress syndrome-associated with COVID-19 (SARS-CoV-2). In addition, SARS-CoV-2 was detected with reverse transcription polymerase chain reaction (RT-PCR) in cerebrospinal fluid, lung tissue, and tracheal sample and specific antibodies for SARS-CoV-2 were detected in cerebrospinal fluid and serum. Subsequent sequencing of the SARS-CoV-2 virus showed variation in nucleotides at 3 sites between SARS-CoV-2 isolates recovered from the tracheal sample, cerebrospinal fluid, and tissues from both lungs, and phylogenetic analysis revealed that the spinal fluid sample differed the most from the other 3 samples.

Lors d'une autopsie d'une victime de la covid, la présence de virions a été confirmée dans le liquide cérébro-spinal, et un séquençage a montré que les particules virales portaient des mutations par rapport à celles des poumons et de la trachée. Pour les auteurs, cette étude appuie l'idée que le SARS-CoV-2 peut être neuroinvasif et provoquer une infection du système nerveux central.

N006

___Neurologic___

Published case report on 27-Mar-21:
"Possible Involvement of Central Nervous System in COVID-19 and Sequence Variability of SARS-CoV-2 Revealed in Autopsy Tissue Samples: A Case Report"
Lors d'une autopsie d'une victime de la covid, la présence de virions a été confirmée dans le liquide cérébro-spinal, et un séquençage a montré que les particules virales portaient des mutations par rapport à celles des poumons et de la trachée. Pour les auteurs, cette étude appuie l'idée que le SARS-CoV-2 peut être neuroinvasif et provoquer une infection du système nerveux central.
Link: https://journals.sagepub.com/doi/full/10.1177/2632010X211006096
Extract: "A forensic autopsy was performed. This revealed severely condensed, almost airless, firm lungs, and the cause of death was severe acute respiratory distress syndrome-associated with COVID-19 (SARS-CoV-2). In addition, SARS-CoV-2 was detected with reverse transcription polymerase chain reaction (RT-PCR) in cerebrospinal fluid, lung tissue, and tracheal sample and specific antibodies for SARS-CoV-2 were detected in cerebrospinal fluid and serum. Subsequent sequencing of the SARS-CoV-2 virus showed variation in nucleotides at 3 sites between SARS-CoV-2 isolates recovered from the tracheal sample, cerebrospinal fluid, and tissues from both lungs, and phylogenetic analysis revealed that the spinal fluid sample differed the most from the other 3 samples."

2153

N71

Philippe Tellier

SARS-CoV-2, un neurotropisme sous-estimé, peut-être

Published

Article

https://www.researchgate.net/publication/340772093_SARS-CoV-2_un_neurotropisme_sous-estime_peut-etre

Selon le docteur Philippe Tellier, il faut s'intéresser à l'hypothèse que l’atteinte du tronc cérébral par le SARS-CoV-2 pourrait contribuer à l’insuffisance respiratoire aiguë de certains patients atteints de la covid.

2154

N72

I. Conejero,corresponding author1,2 B. Nobile,1,2 E. Olié,1,2,3 and Ph. Courtet1,2,3

How Does COVID-19 Affect the Neurobiology of Suicide?

https://dx.doi.org/10.1007%2Fs11920-021-01227-x

Published

3-Mar-21

Review

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927764/

We hypothesize that SARS-CoV-2 interacts with multiple biological processes that underlie suicidal behavior, such as the renin-angiotensin system, nicotinic receptors, and central and systemic inflammation. Social distancing measures may also worsen subjective or objective social disconnection, thus increasing the risk of suicide. Interestingly, the drugs used to prevent suicide could be promising options to counteract brain damage caused by this coronavirus.

Une étude suggère que l'attaque du SARS-CoV-2 sur l'organisme, et notamment sur le système nerveux central, pourrait contribuer à des mécanismes d'inflammation chronique de faible intensité qui augmentent le risque de suicide chez les malades.

2155

N73

Samir Djemli*, Abdelkrim Tahraoui, Mabrouk Boussena, Faiza Rouag, Ines Refes, Samia Messikh, Ibtissem Chouba, Mohamed Kouadria and Rouya Memouni

The Neuroinvasive Potential of SARS-CoV-2 on the Central Nervous System (lesions in the brain)

Published

8-Apr-21

Editorial Article

https://www.researchgate.net/publication/350500546_The_Neuroinvasive_Potential_of_SARS-CoV-2_on_the_Central_Nervous_System_lesions_in_the_brain

The coronavirus that causes Covid-19 could infect the central nervous system like other coronaviruses. Is this related to the cases of anosmia reported by doctors among infected people? The more than 340,000 people suffering from Covid-19 complain of a triad of symptoms typical of infection: fever, cough, and difficulty breathing. But some also complain of rarer ailments like headaches, nausea and vomiting. These symptoms are usually associated with a neurological condition. Are they witnessing the invasion by the coronavirus responsible for Covid-19 of the central nervous system?

Un éditorial dans Medical & Clinical Research interroge les différentes possibilités expliquant les symptômes neurologiques de la covid. S'il est confirmé que la défense du corps contre le virus cause un phénomène inflammatoire dans le cerveau, l'intrusion du virus lui-même n'est pas à ce jour confirmée.

N007

___Neurologic___

Published editorial article on 8-Apr-21:
"The Neuroinvasive Potential of SARS-CoV-2 on the Central Nervous System (lesions in the brain)"
Un éditorial dans Medical & Clinical Research interroge les différentes possibilités expliquant les symptômes neurologiques de la covid. S'il est confirmé que la défense du corps contre le virus cause un phénomène inflammatoire dans le cerveau, l'intrusion du virus lui-même n'est pas à ce jour confirmée.
Link: https://www.researchgate.net/publication/350500546_The_Neuroinvasive_Potential_of_SARS-CoV-2_on_the_Central_Nervous_System_lesions_in_the_brain
Extract: "The coronavirus that causes Covid-19 could infect the central nervous system like other coronaviruses. Is this related to the cases of anosmia reported by doctors among infected people? The more than 340,000 people suffering from Covid-19 complain of a triad of symptoms typical of infection: fever, cough, and difficulty breathing. But some also complain of rarer ailments like headaches, nausea and vomiting. These symptoms are usually associated with a neurological condition. Are they witnessing the invasion by the coronavirus responsible for Covid-19 of the central nervous system?"

2156

N74

Maxime Taquet, PhD
Prof John R Geddes, MD
Prof Masud Husain, FRCP
Sierra Luciano, BA
Prof Paul J Harrison

6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records

https://doi.org/10.1016/S2215-0366(21)00084-5

Published

6-Apr-21

Retrospective Study

https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(21)00084-5/fulltext

Among 236 379 patients diagnosed with COVID-19, the estimated incidence of a neurological or psychiatric diagnosis in the following 6 months was 33·62% (95% CI 33·17–34·07), with 12·84% (12·36–13·33) receiving their first such diagnosis. For patients who had been admitted to an ITU, the estimated incidence of a diagnosis was 46·42% (44·78–48·09) and for a first diagnosis was 25·79% (23·50–28·25). Regarding individual diagnoses of the study outcomes, the whole COVID-19 cohort had estimated incidences of 0·56% (0·50–0·63) for intracranial haemorrhage, 2·10% (1·97–2·23) for ischaemic stroke, 0·11% (0·08–0·14) for parkinsonism, 0·67% (0·59–0·75) for dementia, 17·39% (17·04–17·74) for anxiety disorder, and 1·40% (1·30–1·51) for psychotic disorder, among others. In the group with ITU admission, estimated incidences were 2·66% (2·24–3·16) for intracranial haemorrhage, 6·92% (6·17–7·76) for ischaemic stroke, 0·26% (0·15–0·45) for parkinsonism, 1·74% (1·31–2·30) for dementia, 19·15% (17·90–20·48) for anxiety disorder, and 2·77% (2·31–3·33) for psychotic disorder.

The severity of COVID-19 had a clear effect on subsequent neurological diagnoses.
Compared with neurological disorders, common psychiatric disorders (mood and anxiety disorders) showed a weaker relationship with the markers of COVID-19 severity in terms of incidence (table 2) or HRs (table 5). This might indicate that their occurrence reflects, at least partly, the psychological and other implications of a COVID-19 diagnosis rather than being a direct manifestation of the illness.

La plus large étude rétrospective sur les manifestations neurologiques et psychiatriques de la covid entreprend de quantifier la prévalence des symptômes 6 mois après une infection.
Les auteurs remarquent que la sévérité de la covid a un effet conséquent sur le diagnostic neurologique ultérieur.
Les 4/5e de la cohorte n'ont pas été hospitalisés. Un tiers des patients présente un diagnostic neurologique ou psychiatrique à 6 mois, et 13% pour qui cela constitue le premier diagnostic de ce type.
L'étude compte 0,6% qui ont eu une hémorragie intracrânienne, 2,1% un AVC ischémique, 0,7% souffrent de démence, 17,4% de troubles anxieux, 1,4% de troubles psychotiques.

Les auteurs remarquent que les troubles psychiatriques habituels (troubles d'anxiété et d'humeur), comparés aux troubles neurologiques, sont moins corrélés avec la sévérité de la phase aiguë. Il est fait la supposition que leur occurence reflète, au moins partiellement, l'impact psychologique d'un diagnostic de covid, davantage qu'une manifestation directe de la maladie.
La survenue d'une encéphalopathie, au delà d'un marqueur de sévérité, apparaît comme un possible signal de futurs symptômes neuropsychiatriques et neurodégénératifs.
Enfin, des craintes sont émises sur une augmentation de troubles parkinsoniens consécutifs à ces atteintes.

N007

___Neurologic___

Published retrospective study on 6-Apr-21:
"6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records"
La plus large étude rétrospective sur les manifestations neurologiques et psychiatriques de la covid entreprend de quantifier la prévalence des symptômes 6 mois après une infection.
Les auteurs remarquent que la sévérité de la covid a un effet conséquent sur le diagnostic neurologique ultérieur.
Les 4/5e de la cohorte n'ont pas été hospitalisés. Un tiers des patients présente un diagnostic neurologique ou psychiatrique à 6 mois, et 13% pour qui cela constitue le premier diagnostic de ce type.
L'étude compte 0,6% qui ont eu une hémorragie intracrânienne, 2,1% un AVC ischémique, 0,7% souffrent de démence, 17,4% de troubles anxieux, 1,4% de troubles psychotiques.

Les auteurs remarquent que les troubles psychiatriques habituels (troubles d'anxiété et d'humeur), comparés aux troubles neurologiques, sont moins corrélés avec la sévérité de la phase aiguë. Il est fait la supposition que leur occurence reflète, au moins partiellement, l'impact psychologique d'un diagnostic de covid, davantage qu'une manifestation directe de la maladie.
La survenue d'une encéphalopathie, au delà d'un marqueur de sévérité, apparaît comme un possible signal de futurs symptômes neuropsychiatriques et neurodégénératifs.
Enfin, des craintes sont émises sur une augmentation de troubles parkinsoniens consécutifs à ces atteintes.
Link: https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(21)00084-5/fulltext
Extract: "Among 236 379 patients diagnosed with COVID-19, the estimated incidence of a neurological or psychiatric diagnosis in the following 6 months was 33·62% (95% CI 33·17–34·07), with 12·84% (12·36–13·33) receiving their first such diagnosis. For patients who had been admitted to an ITU, the estimated incidence of a diagnosis was 46·42% (44·78–48·09) and for a first diagnosis was 25·79% (23·50–28·25). Regarding individual diagnoses of the study outcomes, the whole COVID-19 cohort had estimated incidences of 0·56% (0·50–0·63) for intracranial haemorrhage, 2·10% (1·97–2·23) for ischaemic stroke, 0·11% (0·08–0·14) for parkinsonism, 0·67% (0·59–0·75) for dementia, 17·39% (17·04–17·74) for anxiety disorder, and 1·40% (1·30–1·51) for psychotic disorder, among others. In the group with ITU admission, estimated incidences were 2·66% (2·24–3·16) for intracranial haemorrhage, 6·92% (6·17–7·76) for ischaemic stroke, 0·26% (0·15–0·45) for parkinsonism, 1·74% (1·31–2·30) for dementia, 19·15% (17·90–20·48) for anxiety disorder, and 2·77% (2·31–3·33) for psychotic disorder.

The severity of COVID-19 had a clear effect on subsequent neurological diagnoses.
Compared with neurological disorders, common psychiatric disorders (mood and anxiety disorders) showed a weaker relationship with the markers of COVID-19 severity in terms of incidence (table 2) or HRs (table 5). This might indicate that their occurrence reflects, at least partly, the psychological and other implications of a COVID-19 diagnosis rather than being a direct manifestation of the illness."

2157

N75

R

Jonas A Hosp, Andrea Dressing, Ganna Blazhenets, Tobias Bormann, Alexander Rau, Marius Schwabenland, Johannes Thurow, Dirk Wagner, Cornelius Waller, Wolf D Niesen, Lars Frings, Horst Urbach, Marco Prinz, Cornelius Weiller, Nils Schroeter, Philipp T Meyer

Cognitive impairment and altered cerebral glucose metabolism in the subacute stage of COVID-19

https://doi.org/10.1093/brain/awab009

Published

5-Apr-21

https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awab009/6209743

In this prospective cohort study, we assessed neurological and cognitive symptoms in hospitalized coronavirus disease-19 (COVID-19) patients and aimed to determine their neuronal correlates. Patients with reverse transcription-PCR-confirmed COVID-19 infection who required inpatient treatment primarily because of non-neurological complications were screened between 20 April 2020 and 12 May 2020. Patients (age > 18 years) were included in our cohort when presenting with at least one new neurological symptom (defined as impaired gustation and/or olfaction, performance < 26 points on a Montreal Cognitive Assessment and/or pathological findings on clinical neurological examination). Patients with ≥2 new symptoms were eligible for further diagnostics using comprehensive neuropsychological tests, cerebral MRI and 18fluorodeoxyglucose (FDG) PET as soon as infectivity was no longer present. Exclusion criteria were: premorbid diagnosis of cognitive impairment, neurodegenerative diseases or intensive care unit treatment. Of 41 COVID-19 inpatients screened, 29 patients (65.2 ± 14.4 years; 38% female) in the subacute stage of disease were included in the register. Most frequently, gustation and olfaction were disturbed in 29/29 and 25/29 patients, respectively. Montreal Cognitive Assessment performance was impaired in 18/26 patients (mean score 21.8/30) with emphasis on frontoparietal cognitive functions. This was confirmed by detailed neuropsychological testing in 15 patients. 18FDG PET revealed pathological results in 10/15 patients with predominant frontoparietal hypometabolism. This pattern was confirmed by comparison with a control sample using voxel-wise principal components analysis, which showed a high correlation (R2 = 0.62) with the Montreal Cognitive Assessment performance. Post-mortem examination of one patient revealed white matter microglia activation but no signs of neuroinflammation. Neocortical dysfunction accompanied by cognitive decline was detected in a relevant fraction of patients with subacute COVID-19 initially requiring inpatient treatment. This is of major rehabilitative and socioeconomic relevance.

Une nouvelle étude constate des hypométabolismes cérébraux par PET-SCAN chez des malades de la covid un mois après la phase aiguë. Les résultats témoignent d'infarctus subaigus microemboliques et de la présence de marqueurs de lésion axonale. Selon les auteurs, l'hypométabolisme pourrait être une séquelle d'un processus distant dû à une pathologie du tronc cérébral ou de la substance blanche, plutôt qu'à des dommages corticaux directs (par exemple, découplage ou dysfonctionnement de régions stratégiques comme les noyaux aminergiques du tronc cérébral). Cette hypothèse suggérerait que la détérioration neurologique peut être réversible.

N007

___Neurologic___

Published article on 5-Apr-21:
"Cognitive impairment and altered cerebral glucose metabolism in the subacute stage of COVID-19"
Une nouvelle étude constate des hypométabolismes cérébraux par PET-SCAN chez des malades de la covid un mois après la phase aiguë. Les résultats témoignent d'infarctus subaigus microemboliques et de la présence de marqueurs de lésion axonale. Selon les auteurs, l'hypométabolisme pourrait être une séquelle d'un processus distant dû à une pathologie du tronc cérébral ou de la substance blanche, plutôt qu'à des dommages corticaux directs (par exemple, découplage ou dysfonctionnement de régions stratégiques comme les noyaux aminergiques du tronc cérébral). Cette hypothèse suggérerait que la détérioration neurologique peut être réversible.
Link: https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awab009/6209743
Extract: "In this prospective cohort study, we assessed neurological and cognitive symptoms in hospitalized coronavirus disease-19 (COVID-19) patients and aimed to determine their neuronal correlates. Patients with reverse transcription-PCR-confirmed COVID-19 infection who required inpatient treatment primarily because of non-neurological complications were screened between 20 April 2020 and 12 May 2020. Patients (age > 18 years) were included in our cohort when presenting with at least one new neurological symptom (defined as impaired gustation and/or olfaction, performance < 26 points on a Montreal Cognitive Assessment and/or pathological findings on clinical neurological examination). Patients with ≥2 new symptoms were eligible for further diagnostics using comprehensive neuropsychological tests, cerebral MRI and 18fluorodeoxyglucose (FDG) PET as soon as infectivity was no longer present. Exclusion criteria were: premorbid diagnosis of cognitive impairment, neurodegenerative diseases or intensive care unit treatment. Of 41 COVID-19 inpatients screened, 29 patients (65.2 ± 14.4 years; 38% female) in the subacute stage of disease were included in the register. Most frequently, gustation and olfaction were disturbed in 29/29 and 25/29 patients, respectively. Montreal Cognitive Assessment performance was impaired in 18/26 patients (mean score 21.8/30) with emphasis on frontoparietal cognitive functions. This was confirmed by detailed neuropsychological testing in 15 patients. 18FDG PET revealed pathological results in 10/15 patients with predominant frontoparietal hypometabolism. This pattern was confirmed by comparison with a control sample using voxel-wise principal components analysis, which showed a high correlation (R2 = 0.62) with the Montreal Cognitive Assessment performance. Post-mortem examination of one patient revealed white matter microglia activation but no signs of neuroinflammation. Neocortical dysfunction accompanied by cognitive decline was detected in a relevant fraction of patients with subacute COVID-19 initially requiring inpatient treatment. This is of major rehabilitative and socioeconomic relevance."

2158

N76

Markus Ameres, Susanne Brandstetter, Antoaneta A. Toncheva, Michael Kabesch, David Leppert, Jens Kuhle & Sven Wellmann

Association of neuronal injury blood marker neurofilament light chain with mild-to-moderate COVID-19

https://doi.org/10.1007/s00415-020-10050-y

Published

9-Jul-20

Letter to the Editors

https://link.springer.com/article/10.1007/s00415-020-10050-y

a neuronal biomarker would be extremely useful to elucidate neuro-axonal injury during an infection with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and in the post-infection follow-up period. Serum neurofilament light chain (sNfL) has recently been considered as a specific biomarker to quantitate neuro-axonal damage in several disorders of the peripheral and central nervous system [5]. Hence, sNfL might also serve as a sensitive screening and follow-up marker for neuronal injury in COVID-19 patients.

Dans une correspondance publiée dans Journal of Neurology, des chercheurs estiment que la chaîne légère du neurofilament sérique (sNfL, déjà utilisée dans plusieurs troubles du système nerveux périphérique et central) devrait être un marqueur sensible de dépistage et de suivi des lésions neuronales chez les patients atteints de la covid.

N009

___Neurologic___

Published letter to the editors on 9-Jul-20:
"Association of neuronal injury blood marker neurofilament light chain with mild-to-moderate COVID-19"
Dans une correspondance publiée dans Journal of Neurology, des chercheurs estiment que la chaîne légère du neurofilament sérique (sNfL, déjà utilisée dans plusieurs troubles du système nerveux périphérique et central) devrait être un marqueur sensible de dépistage et de suivi des lésions neuronales chez les patients atteints de la covid.
Link: https://link.springer.com/article/10.1007/s00415-020-10050-y
Extract: "a neuronal biomarker would be extremely useful to elucidate neuro-axonal injury during an infection with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and in the post-infection follow-up period. Serum neurofilament light chain (sNfL) has recently been considered as a specific biomarker to quantitate neuro-axonal damage in several disorders of the peripheral and central nervous system [5]. Hence, sNfL might also serve as a sensitive screening and follow-up marker for neuronal injury in COVID-19 patients."

2159

N77

Gabriele Melegari 1,*,Veronica Rivi 2 ,Gabriele Zelent 3,Vincenzo Nasillo 4 ,Elena De Santis 4,Alessandra Melegari 4,Claudia Bevilacqua 5,Michele Zoli 2,Stefano Meletti 6 andAlberto Barbier

Mild to Severe Neurological Manifestations of COVID-19: Cases Reports

https://doi.org/10.3390/ijerph18073673

Published

1-Apr-21

Cases Reports

https://www.mdpi.com/1660-4601/18/7/3673

Here, we present two different case-reports of COVID-19 patients, describing neurological complications, diagnostic imaging such as olfactory bulb damage (a mild and unclear underestimated complication) and a severe and sudden thrombotic stroke complicated with hemorrhage with a low-level cytokine storm and respiratory symptom resolution. We discuss the possible mechanisms of virus entrance, together with the causes of COVID-19-related encephalitis, olfactory bulb damage, ischemic stroke, and intracranial hemorrhage.

_

2160

N78

Matteo Foschi, Lucio D'Anna, Ahmed Abdelhak, Benjamin Mayer, Hayrettin Tumani, Markus Otto, Samir Abu-Rumeileh

Ongoing challenges in unravelling the association between COVID-19 and Guillain-Barré syndrome

https://doi.org/10.1093/brain/awab069

Published

3-Apr-21

Letter to the Editor

https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awab069/6209733

To conclude, we believe that the definitive proof of a possible causal association between COVID-19 and GBS could derive from two different efforts: (i) the conduction of rigorous case-control studies; and (ii) the systematic testing of all patients with GBS for anti-SARS-CoV-2 antibodies. This would allow us to avoid possible underestimation of COVID-19-related GBS by including patients tested negative with PCR whilst positive for untested anti-SARS-CoV-2 antibodies (a bias which reasonably cannot be excluded in the cohort by Keddie et al.1).

_

2161

N79

William Camargo-Martínez
Ivan Lozada-Martínez
Angie Escobar-Collazos
Aura Navarro-Coronado
Luis Moscote-Salazar
Alfonso Pacheco-Hernández
Tariq Janjua
Pilar Bosque-Varela

Post-COVID 19 Neurological Syndrome: Implications for sequelae’s treatment

https://doi.org/10.1016/j.jocn.2021.04.001

Published

8-Apr-21

REVIEW ARTICLE

https://www.jocn-journal.com/article/S0967-5868(21)00163-6/fulltext

Neurological complications caused by COVID-19 are frequent and represent a risk that compromises the functional capacity and the life of patients. The suspicion of these conditions, the strict control of metabolic alterations and cardiovascular risk factors, the effective and safe treatment of these entities, are a current challenge throughout the pandemic. The rehabilitation process in these patients is a challenge. This is due to the limitations generated by multi-organ damage, as well as risk of brain death. The prognosis of recovery from post-COVID neurological syndrome must be evaluated in a personalized way, depending on target organ damage, especially lungs and heart, which intervene in the process of physical activity and maintenance of daily life activities.

Une revue d'études souligne le défi que représente la rééducation des malades de la covid présentant des séquelles neurologiques, et s'inquiète des difficultés pour la mise en œuvre de ces programmes dans les pays pauvres.

N009

___Neurologic___

Published review article on 8-Apr-21:
"Post-COVID 19 Neurological Syndrome: Implications for sequelae’s treatment"
Une revue d'études souligne le défi que représente la rééducation des malades de la covid présentant des séquelles neurologiques, et s'inquiète des difficultés pour la mise en œuvre de ces programmes dans les pays pauvres.
Link: https://www.jocn-journal.com/article/S0967-5868(21)00163-6/fulltext
Extract: "Neurological complications caused by COVID-19 are frequent and represent a risk that compromises the functional capacity and the life of patients. The suspicion of these conditions, the strict control of metabolic alterations and cardiovascular risk factors, the effective and safe treatment of these entities, are a current challenge throughout the pandemic. The rehabilitation process in these patients is a challenge. This is due to the limitations generated by multi-organ damage, as well as risk of brain death. The prognosis of recovery from post-COVID neurological syndrome must be evaluated in a personalized way, depending on target organ damage, especially lungs and heart, which intervene in the process of physical activity and maintenance of daily life activities."

2162

N80

Finsterer, Josef

Presentation of Neuro-COVID is Broad and Pathogenesis Diverse

Published

8-Apr-21

Letter to the editor

https://escholarship.org/uc/item/01z8q12d

There was no discussion about the putative delineation between neurological disorders due to direct attack of the virus (primary manifestations), secondary CNS/PNS disorders due to the immune response (secondary manifestations), and those occurring as a side effect of the treatment or involvement of other organs than the CNS (tertiary manifestations). Whether such a distinction is truly permissible is under debate. Limited data from animal and basic science research are currently available. Disregarding this debate, there are indications that the virus enters the CNS via the blood brain barrier (BBB) or via retrograde invasion along peripheral nerves, as mentioned in the review.1,15 There are even indications that the virus disrupts the BBB.16 Interestingly, in most of the CNS disorders claimed to have been triggered by direct contact of the virus Klinik Landstrasse, Messerli Institute, Department of Neurology, Vienna, Austriawith CNS structures, investigations of the cerebro-spinal fluid (CSF) did not confirm the presence of the virus in the CSF. Absence of the virus in the CSF has been explained by rapid entering of the virus intra-cellularly, thus being present in the CSF only temporarily for a short time. Accordingly, virus-RNA has been found inside neurons and glial cells.
The spectrum of neurological disease triggered by SARS-CoV-2 is broader than anticipated. Neurological disease possibly results from a direct virus attack, from the immune response, or from side effects of the treatment of pulmonary manifestations.

Une lettre publiée dans Western Journal of Emergency Medicine insiste sur le spectre plus large qu'attendu des maladies neurologiques déclenchées par le SRAS-CoV-2. Les affections touchant les systèmes nerveux central et périphérique peuvent résulter d'une attaque virale directe, de la réponse immunitaire, et parfois même des effets secondaires des traitements administrés (hydroxychloroquine, stéroïdes, tocilizumab, azithromycine).

N010

___Neurologic___

Published letter to the editor on 8-Apr-21:
"Presentation of Neuro-COVID is Broad and Pathogenesis Diverse"
Une lettre publiée dans Western Journal of Emergency Medicine insiste sur le spectre plus large qu'attendu des maladies neurologiques déclenchées par le SRAS-CoV-2. Les affections touchant les systèmes nerveux central et périphérique peuvent résulter d'une attaque virale directe, de la réponse immunitaire, et parfois même des effets secondaires des traitements administrés (hydroxychloroquine, stéroïdes, tocilizumab, azithromycine).
Link: https://escholarship.org/uc/item/01z8q12d
Extract: "There was no discussion about the putative delineation between neurological disorders due to direct attack of the virus (primary manifestations), secondary CNS/PNS disorders due to the immune response (secondary manifestations), and those occurring as a side effect of the treatment or involvement of other organs than the CNS (tertiary manifestations). Whether such a distinction is truly permissible is under debate. Limited data from animal and basic science research are currently available. Disregarding this debate, there are indications that the virus enters the CNS via the blood brain barrier (BBB) or via retrograde invasion along peripheral nerves, as mentioned in the review.1,15 There are even indications that the virus disrupts the BBB.16 Interestingly, in most of the CNS disorders claimed to have been triggered by direct contact of the virus Klinik Landstrasse, Messerli Institute, Department of Neurology, Vienna, Austriawith CNS structures, investigations of the cerebro-spinal fluid (CSF) did not confirm the presence of the virus in the CSF. Absence of the virus in the CSF has been explained by rapid entering of the virus intra-cellularly, thus being present in the CSF only temporarily for a short time. Accordingly, virus-RNA has been found inside neurons and glial cells.
The spectrum of neurological disease triggered by SARS-CoV-2 is broader than anticipated. Neurological disease possibly results from a direct virus attack, from the immune response, or from side effects of the treatment of pulmonary manifestations."

2163

N81

Josef Finsterer & Fulvio A Scorza

Clinical and Pathophysiologic Spectrum of Neuro-COVID

https://doi.org/10.1007/s12035-021-02383-0

Published

8-Apr-21

Mini-Review

https://link.springer.com/article/10.1007/s12035-021-02383-0

The spectrum of central nervous system disease in COVID-19 patients is much broader than so far anticipated. Peripheral nerves and the skeletal muscle are less predominantly affected. In the vast majority of the cases, there is no direct attack of the virus towards vulnerable structures, which explains why various manifestations of the nervous system manifest favourably to immune suppression or immune modulation. Overall, the pathophysiology and clinical presentation of CNS/PNS involvement in COVID-19 is wider than believed. All patients with COVID-19 should be investigated by the neurologist for primary or secondary involvement of the CNS/PNS in the infection. neuro-COVID responds favourably to immune suppressants or immune modulation.

Un article académique note la grande diversité des possibles atteintes au système nerveux central occasionnées par la covid. Les auteurs remarquent que ces atteintes répondent favorablement aux immunosuppresseurs ou à la modulation immunitaire.

N009

___Neurologic___

Published mini-review on 8-Apr-21:
"Clinical and Pathophysiologic Spectrum of Neuro-COVID"
Un article académique note la grande diversité des possibles atteintes au système nerveux central occasionnées par la covid. Les auteurs remarquent que ces atteintes répondent favorablement aux immunosuppresseurs ou à la modulation immunitaire.
Link: https://link.springer.com/article/10.1007/s12035-021-02383-0
Extract: "The spectrum of central nervous system disease in COVID-19 patients is much broader than so far anticipated. Peripheral nerves and the skeletal muscle are less predominantly affected. In the vast majority of the cases, there is no direct attack of the virus towards vulnerable structures, which explains why various manifestations of the nervous system manifest favourably to immune suppression or immune modulation. Overall, the pathophysiology and clinical presentation of CNS/PNS involvement in COVID-19 is wider than believed. All patients with COVID-19 should be investigated by the neurologist for primary or secondary involvement of the CNS/PNS in the infection. neuro-COVID responds favourably to immune suppressants or immune modulation."

2164

N82

Hicham El Otmani

Controverse : le Neuro-Covid-19 existe-t-il ?

https://doi.org/10.1016/j.neurol.2021.02.059

Published

11-Apr-21

Opinion

https://www.sciencedirect.com/science/article/pii/S0035378721001016

Cette maladie, dont les manifestations respiratoires et systémiques sont prévalantes, serait responsable de plusieurs manifestations neurologiques. Toutefois, l’analyse critique des données actuellement disponibles montre que les atteintes neurologiques restent mal caractérisées voire difficile à affirmer. En effet, des manifestations comme les céphalées, les vertiges et les myalgies sont celles d’une « forte » grippe et n’ont aucune spécificité, l’anosmie qui est un symptôme très fréquent semble plus liée à une atteinte muqueuse olfactive, le neurotropisme du SARS-Cov-2 semble (à la différence d’autres virus comme celui de la rage ou de l’herpès), très marginal au vu des données biologiques et histologiques actuellement disponibles, les manifestations neurologiques immune-médiées comme le syndrome de Guillain-Barré et les EMAD… sont très rares (au nombre de quelques dizaines) au regard de la grande fréquence de la maladie, pouvant suggérer des coïncidences. Ailleurs, les manifestations neurologiques les plus fréquentes comme le delirium (plus fréquent chez les personnes âgées et en présence d’une atteinte cognitive sous jacente), la maladie cérébrovasculaire (généralement chez des personnes ayant des facteurs de risque vasculaire) sont habituellement retrouvées chez des patients admis en Neuro-réanimation, pour une atteinte respiratoire importante ou une défaillance multi-organes. Il semble que l’essentiel de la Neurologie de la Covid-19 ne soit finalement que le témoin d’une maladie systémique grave…

_

2165

N83

Dominique Caparros

Amélioration neurologique inattendue après infection Covid : rôle des anticorps anti-covid sur la microglie de cerveaux endommagés ?

https://doi.org/10.1016/j.neurol.2021.02.015

Published

11-Apr-21

Opinion

https://www.sciencedirect.com/science/article/pii/S0035378721000576

L’amélioration neurologique pour ces 4 patients objectivée 2 à 4 semaines après le début de l’infection COVID persiste sur le long terme. L’hypothèse de l’activation des cellules microgliales par les anticorps anti COVID est évoquée. L’effet de la vaccination anti COVID sur le SNC chez les patients cérébro-lésés devra donc êtré analysée.

_

2166

N84

Yannick FogangFogoum1Ahmed VessahNjoya2MichelNoubom3JosephKamtchum-Tatuene4Callixte KuateTegueu

Manifestations neurologiques de la COVID-19 à l’hôpital régional de Bafoussam, Cameroun

https://doi.org/10.1016/j.neurol.2021.02.242

Published

11-Apr-21

Study

https://www.sciencedirect.com/science/article/pii/S0035378721002848

Il s’agissait d’une étude transversale rétrospective menée de mars à septembre 2020 à l’hôpital régional de Bafoussam, dans l’Ouest Cameroun. Étaient inclus les patients symptomatiques avec un test RT-PCR positif au SARS-CoV-2. Les données sociodémographiques et cliniques notamment les manifestations neurologiques en relation temporelle avec le diagnostic étaient extraites des dossiers des patients à leur sortie.

Résultats
Nous avons inclus 177 patients. L’âge moyen était de 54,60 ± 17,8 ans. Les manifestations neurologiques étaient retrouvées chez 113 (63,84 %) patients. Les plus fréquentes étaient : les céphalées (58,41 %), les myalgies (50,44 %), l’anosmie (18,58 %), les troubles de la conscience (16,8 %), le délirium (15,04 %), une hémiplégie (4,42 %), l’agueusie (4,42 %). Une hypersialorrhée (2 cas) et un tremblement intentionnel (1 cas). Les diagnostics posés étaient la méningo-encéphalite (11,50 %), l’encéphalopathie (20,35 %) et l’AVC ischémique (4,42 %).

_

2167

N85

Svetlana Blitshteyn

Is postural orthostatic tachycardia syndrome (POTS) a central nervous system disorder?

https://doi.org/10.1007/s00415-021-10502-z

Published

7-Mar-21

Review

https://link.springer.com/article/10.1007/s00415-021-10502-z

This review outlines existing evidence of POTS as a CNS disorder and proposes a hypothetical model combining key mechanisms in the pathophysiology of POTS. Redefining POTS as a CNS disorder can lead to new possibilities in pharmacotherapy and non-pharmacologic therapeutic interventions in patents affected by this disabling syndrome.

Une chercheuse américaine pense que le syndrome de tachycardie orthostatique posturale (POTS en anglais), un dysfonctionnement du système nerveux autonome, devrait également être considéré comme un trouble du système nerveux central. Cette nouvelle perspective permet selon l'auteure d'envisager d'autres traitements comme les thérapies immunomodulatrices (immunoglobuline intraveineuse, immunoglobuline sous-cutanée ou plasmaphérèse) pour ce symptôme fréquent chez les malades du covid long. Ces thérapies sont utilisées pour les POTS réfractaires au traitement avec des marqueurs auto-immuns positifs, et pourraient être bénéfiques en réduisant la neuroinflammation dans le système nerveux central.

N009

___Neurologic___

Published review on 7-Mar-21:
"Is postural orthostatic tachycardia syndrome (POTS) a central nervous system disorder?"
Une chercheuse américaine pense que le syndrome de tachycardie orthostatique posturale (POTS en anglais), un dysfonctionnement du système nerveux autonome, devrait également être considéré comme un trouble du système nerveux central. Cette nouvelle perspective permet selon l'auteure d'envisager d'autres traitements comme les thérapies immunomodulatrices (immunoglobuline intraveineuse, immunoglobuline sous-cutanée ou plasmaphérèse) pour ce symptôme fréquent chez les malades du covid long. Ces thérapies sont utilisées pour les POTS réfractaires au traitement avec des marqueurs auto-immuns positifs, et pourraient être bénéfiques en réduisant la neuroinflammation dans le système nerveux central.
Link: https://link.springer.com/article/10.1007/s00415-021-10502-z
Extract: "This review outlines existing evidence of POTS as a CNS disorder and proposes a hypothetical model combining key mechanisms in the pathophysiology of POTS. Redefining POTS as a CNS disorder can lead to new possibilities in pharmacotherapy and non-pharmacologic therapeutic interventions in patents affected by this disabling syndrome."

2168

N86

Elbakal Ayoub Bourazza Ahmed

Manifestations neurologiques au cours de l’infection au virus COVID-19 : étude prospective à propos de 713 patients

https://doi.org/10.1016/j.neurol.2021.02.236

Published

11-Apr-21

Study

https://www.sciencedirect.com/science/article/pii/S0035378721002782

Au total, 713 patients ont été suivis, l’âge moyen était de 31,95 ans avec un faible taux de comorbidités (2,1 %). Les manifestations neurologiques étaient présentes chez 12,8 % des patients (n = 91) notamment les céphalées 5,8 % (n = 41), l’anosmie 5,6 % (n = 40), myalgies 1,4 % (n = 10).

Discussion
Selon les études les manifestations neurologiques associées à la COVID-19 sont présentes chez 25 % des patients tout au plus, et sont généralement bénignes.

_

2169

N87

Woo-Jung Song, MD
Christopher K M Hui, MD
James H Hull, PhD
Prof Surinder S Birring, MD
Prof Lorcan McGarvey
Prof Stuart B Mazzone, PhD
Prof Kian Fan Chung

Confronting COVID-19-associated cough and the post-COVID syndrome: role of viral neurotropism, neuroinflammation, and neuroimmune responses

https://doi.org/10.1016/S2213-2600(21)00125-9

Published

12-Apr-21

Personal View

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00125-9/fulltext

Cough is one of the most common presenting symptoms of COVID-19, along with fever and loss of taste and smell. Cough can persist for weeks or months after SARS-CoV-2 infection, often accompanied by chronic fatigue, cognitive impairment, dyspnoea, or pain—a collection of long-term effects referred to as the post-COVID syndrome or long COVID. We hypothesise that the pathways of neurotropism, neuroinflammation, and neuroimmunomodulation through the vagal sensory nerves, which are implicated in SARS-CoV-2 infection, lead to a cough hypersensitivity state. The post-COVID syndrome might also result from neuroinflammatory events in the brain. We highlight gaps in understanding of the mechanisms of acute and chronic COVID-19-associated cough and post-COVID syndrome, consider potential ways to reduce the effect of COVID-19 by controlling cough, and suggest future directions for research and clinical practice. Although neuromodulators such as gabapentin or opioids might be considered for acute and chronic COVID-19 cough, we discuss the possible mechanisms of COVID-19-associated cough and the promise of new anti-inflammatories or neuromodulators that might successfully target both the cough of COVID-19 and the post-COVID syndrome.

Dans The Lancet, des chercheurs font l'hypothèse que les voies du neurotropisme, de la neuroinflammation et de la neuro-immunomodulation à travers les nerfs sensoriels vagaux, qui sont impliqués dans l'infection par le SRAS-CoV-2, conduisent à un état d'hypersensibilité à la toux. Pour les auteurs, la compréhension de cette toux persistante est un enjeu pour choisir de nouveaux anti-inflammatoires ou neuromodulateurs qui pourraient cibler avec succès à la fois la toux de la covid et le syndrome post-covid.

N010

___Neurologic___

Published personal view on 12-Apr-21:
"Confronting COVID-19-associated cough and the post-COVID syndrome: role of viral neurotropism, neuroinflammation, and neuroimmune responses"
Dans The Lancet, des chercheurs font l'hypothèse que les voies du neurotropisme, de la neuroinflammation et de la neuro-immunomodulation à travers les nerfs sensoriels vagaux, qui sont impliqués dans l'infection par le SRAS-CoV-2, conduisent à un état d'hypersensibilité à la toux. Pour les auteurs, la compréhension de cette toux persistante est un enjeu pour choisir de nouveaux anti-inflammatoires ou neuromodulateurs qui pourraient cibler avec succès à la fois la toux de la covid et le syndrome post-covid.
Link: https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00125-9/fulltext
Extract: "Cough is one of the most common presenting symptoms of COVID-19, along with fever and loss of taste and smell. Cough can persist for weeks or months after SARS-CoV-2 infection, often accompanied by chronic fatigue, cognitive impairment, dyspnoea, or pain—a collection of long-term effects referred to as the post-COVID syndrome or long COVID. We hypothesise that the pathways of neurotropism, neuroinflammation, and neuroimmunomodulation through the vagal sensory nerves, which are implicated in SARS-CoV-2 infection, lead to a cough hypersensitivity state. The post-COVID syndrome might also result from neuroinflammatory events in the brain. We highlight gaps in understanding of the mechanisms of acute and chronic COVID-19-associated cough and post-COVID syndrome, consider potential ways to reduce the effect of COVID-19 by controlling cough, and suggest future directions for research and clinical practice. Although neuromodulators such as gabapentin or opioids might be considered for acute and chronic COVID-19 cough, we discuss the possible mechanisms of COVID-19-associated cough and the promise of new anti-inflammatories or neuromodulators that might successfully target both the cough of COVID-19 and the post-COVID syndrome."

2170

N88

Yes

Igor C Fontana 1, Débora Guerini Souza 1, Luc Pellerin 2, Diogo O Souza 1 3, Eduardo R Zimmer

About the source and consequences of 18 F-FDG brain PET hypometabolism in short and long COVID-19

https://doi.org/10.1007/s00259-021-05342-y

Published

4-Apr-21

Letter to the Editor

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019399/

Indeed, it seems that astrocytes substantially contribute to 18F-FDG PET signal [8–10]. Moreover, it is known that astrocytes play pivotal roles in the brain defence against peripheral inflammatory changes [11]. Guedj and colleagues [1] mentioned that acute systemic inflammation and SARS-CoV-2 neurotropism could be related to brain inflammatory alterations. Complementary, other groups identified signs of reactive astrogliosis in post-mortem tissue of COVID-19 patients [12], in cellular models and in brain organoids [13]. In keeping with this, one could not neglect astrocyte dysfunction as the possible cellular origin of brain 18F-FDG PET hypometabolism in COVID-19. In vivo brain imaging of COVID-19 individuals using specific PET radiotracers targeting reactive astrocytes (e.g. 11C-DED and 11C-BU99008) could help settling this matter.

While the cellular origins of brain 18F-FDG PET hypometabolism in COVID-19 remain to be defined, it seems clear that we are dealing with persistent synaptic dysfunction. Guedj et al. [1] demonstrated that multiple brain regions are hypometabolic in long COVID. In addition, it seems that there is a link between clinical manifestations and regional glucose hypometabolism. For instance, decreased glucose consumption in the cerebellum was linked to hyposmia/anosmia and cognitive impairment. Another recent study followed up the 18F-FDG brain profile of seven patients in the early phase of infection, 1 month and 6 months after COVID-19 onset. Interestingly, the abnormal cognitive function associated with pre-frontal cortex hypometabolism persisted in all patients for ~6 months [14]. Remarkably, 18F-FDG brain hypometabolism in the pre-frontal cortex is present in multiple neurodegenerative disorders [15] and neuropsychiatric conditions [16], sometimes even preceding the first symptoms.

Thus, the cellular origins of COVID-19 18F-FDG PET hypometabolism in short- and long-term scenario remain to be explored, with mounting evidence suggesting an astroglial contribution. Furthermore, persistent 18F-FDG PET hypometabolism in long COVID patients should be carefully monitored in terms of potential sequelae, such as the development of brain disorders.

Un article d'analyse revient sur les hypométabolismes dans le système nerveux central fréquemment relevés chez les malades du covid long. Une 1e hypothèse émise est une dysfonction des astrocytes (cellules gliales du cerveau), qui pourrait selon les auteurs être étudiée par des PET-SCAN utilisant d'autres radiotraceurs comme le ¹¹C-DED et le ¹¹C-BU99008.
De plus, les auteurs rappellent que l'hypométabolisme dans le cervelet est ici bien lié à des anosmies et des troubles cognitifs.Ils notent qu'il semble clair qu'il est question d'un dysfonctionnement synaptique persistant. Cette persistance au delà de plusieurs mois est interrogée au regard des maladies neurodégénératives qui font apparaître très tôt des hypométabolismes.

N009

___Neurologic___

Published letter to the editor on 4-Apr-21:
"About the source and consequences of 18 F-FDG brain PET hypometabolism in short and long COVID-19"
Un article d'analyse revient sur les hypométabolismes dans le système nerveux central fréquemment relevés chez les malades du covid long. Une 1e hypothèse émise est une dysfonction des astrocytes (cellules gliales du cerveau), qui pourrait selon les auteurs être étudiée par des PET-SCAN utilisant d'autres radiotraceurs comme le ¹¹C-DED et le ¹¹C-BU99008.
De plus, les auteurs rappellent que l'hypométabolisme dans le cervelet est ici bien lié à des anosmies et des troubles cognitifs.Ils notent qu'il semble clair qu'il est question d'un dysfonctionnement synaptique persistant. Cette persistance au delà de plusieurs mois est interrogée au regard des maladies neurodégénératives qui font apparaître très tôt des hypométabolismes.
Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019399/
Extract: "Indeed, it seems that astrocytes substantially contribute to 18F-FDG PET signal [8–10]. Moreover, it is known that astrocytes play pivotal roles in the brain defence against peripheral inflammatory changes [11]. Guedj and colleagues [1] mentioned that acute systemic inflammation and SARS-CoV-2 neurotropism could be related to brain inflammatory alterations. Complementary, other groups identified signs of reactive astrogliosis in post-mortem tissue of COVID-19 patients [12], in cellular models and in brain organoids [13]. In keeping with this, one could not neglect astrocyte dysfunction as the possible cellular origin of brain 18F-FDG PET hypometabolism in COVID-19. In vivo brain imaging of COVID-19 individuals using specific PET radiotracers targeting reactive astrocytes (e.g. 11C-DED and 11C-BU99008) could help settling this matter.

While the cellular origins of brain 18F-FDG PET hypometabolism in COVID-19 remain to be defined, it seems clear that we are dealing with persistent synaptic dysfunction. Guedj et al. [1] demonstrated that multiple brain regions are hypometabolic in long COVID. In addition, it seems that there is a link between clinical manifestations and regional glucose hypometabolism. For instance, decreased glucose consumption in the cerebellum was linked to hyposmia/anosmia and cognitive impairment. Another recent study followed up the 18F-FDG brain profile of seven patients in the early phase of infection, 1 month and 6 months after COVID-19 onset. Interestingly, the abnormal cognitive function associated with pre-frontal cortex hypometabolism persisted in all patients for ~6 months [14]. Remarkably, 18F-FDG brain hypometabolism in the pre-frontal cortex is present in multiple neurodegenerative disorders [15] and neuropsychiatric conditions [16], sometimes even preceding the first symptoms.

Thus, the cellular origins of COVID-19 18F-FDG PET hypometabolism in short- and long-term scenario remain to be explored, with mounting evidence suggesting an astroglial contribution. Furthermore, persistent 18F-FDG PET hypometabolism in long COVID patients should be carefully monitored in terms of potential sequelae, such as the development of brain disorders."

2171

N89

R

Aurélie Kas,corresponding author1 Marine Soret,1 Nadya Pyatigoskaya,2 Marie-Odile Habert,1 Adèle Hesters,3 Loic Le Guennec,3 Olivier Paccoud,4 Stéphanie Bombois,#5 Cécile Delorme,#3 and on the behalf of CoCo-Neurosciences study group and COVID SMIT PSL study group

The cerebral network of COVID-19-related encephalopathy: a longitudinal voxel-based 18F-FDG-PET study

https://dx.doi.org/10.1007%2Fs00259-020-05178-y

Published

15-Jan-21

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810428/

All patients had a consistent pattern of hypometabolism in a widespread cerebral network including the frontal cortex, anterior cingulate, insula and caudate nucleus. Six months after COVID-19 onset, the majority of patients clinically had improved but cognitive and emotional disorders of varying severity remained with attention/executive disabilities and anxio-depressive symptoms, and lasting prefrontal, insular and subcortical 18F-FDG-PET/CT abnormalities.

En suivant 7 patients touchés par une encéphalopathie déclenchée par une infection au SARS-CoV-2, des équipes françaises de l'hôpital de la Pitié Salpêtrière ont noté leurs constatations par imagerie cérébrale.
Des PET-SCAN cérébraux jusqu'à 6 mois ont montré l'évolution, généralement favorable, des hypométabolismes et hypermétabolismes dans différentes régions du système nerveux central. Les analyses étaient menées dans le cadre des groupes d'études CoCo-Neurosciences et COVID SMIT PSL.

N010

___Neurologic___

Published study on 15-Jan-21:
"The cerebral network of COVID-19-related encephalopathy: a longitudinal voxel-based 18F-FDG-PET study"
En suivant 7 patients touchés par une encéphalopathie déclenchée par une infection au SARS-CoV-2, des équipes françaises de l'hôpital de la Pitié Salpêtrière ont noté leurs constatations par imagerie cérébrale.
Des PET-SCAN cérébraux jusqu'à 6 mois ont montré l'évolution, généralement favorable, des hypométabolismes et hypermétabolismes dans différentes régions du système nerveux central. Les analyses étaient menées dans le cadre des groupes d'études CoCo-Neurosciences et COVID SMIT PSL.
Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810428/
Extract: "All patients had a consistent pattern of hypometabolism in a widespread cerebral network including the frontal cortex, anterior cingulate, insula and caudate nucleus. Six months after COVID-19 onset, the majority of patients clinically had improved but cognitive and emotional disorders of varying severity remained with attention/executive disabilities and anxio-depressive symptoms, and lasting prefrontal, insular and subcortical 18F-FDG-PET/CT abnormalities."

2172

N90

Melanie Dani, consultant geriatrician,A Andreas Dirksen, specialist nurse in syncope,B Patricia Taraborrelli, specialist nurse in syncope,B Miriam Torocastro, syncope research nurse,C Dimitrios Panagopoulos, clinical research fellow in cardiology,D Richard Sutton, professor of clinical cardiology,E and Phang Boon Lim, consultant cardiologistF

Autonomic dysfunction in ‘long COVID’: rationale, physiology and management strategies

https://dx.doi.org/10.7861%2Fclinmed.2020-0896

Published

1-Jan-21

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850225/

We describe a series of individuals with symptoms of ‘long COVID’, and we posit that this condition may be related to a virus- or immune-mediated disruption of the autonomic nervous system resulting in orthostatic intolerance syndromes. We suggest that all physicians should be equipped to recognise such cases, appreciate the symptom burden and provide supportive management. We present our rationale for an underlying impaired autonomic physiology post-COVID-19 and suggest means of management.

Individual analyses confirmed a severe, bilateral prefrontal hypometabolism in 7/7 patients, including the rectus gyrus (p < 0.05 FWE corrected, Fig. Fig.2,2, Table Table4).4). In every patient, hypometabolism expanded bilaterally to the anterior cingulate and insula (p < 0.05 FWE corrected, Table Table4).4). A mild to moderate parietotemporal associative hypometabolism was observed in 4/7 patients, whereas two others had a severe, spread parietotemporooccipital hypometabolism (#6, 7). Hypermetabolism was found in the visual cortex in patient #1 due to visual stimulation after 18F-FDG injection and in the left frontal cortex in patient #4 due to focal seizure. Notably, bilateral mesiotemporal hypermetabolism was found in one patient (#6) without T2-MRI hyperintensity, whereas hypometabolism was observed in patient #3 with known hippocampal sclerosis and in patient #5 having hippocampal atrophy. Metabolism was decreased in the caudate nucleus in five patients (#2–5, 7) and thalamus in two (#2, 3) (p < 0.05 corrected). Metabolism was decreased in the bilateral cerebellar hemispheres in all patients except one (#4) but increased in the vermis in 5/7 patients (p < 0.05).

Dans une étude qui décrit les dérèglements du système autonome consécutifs à la covid, et notamment le syndrome de tachycardie orthostatique posturale, les auteurs proposent une méthodologie de diagnostic et des pistes de traitements.

N010

___Neurologic___

Published study on 1-Jan-21:
"Autonomic dysfunction in ‘long COVID’: rationale, physiology and management strategies"
Dans une étude qui décrit les dérèglements du système autonome consécutifs à la covid, et notamment le syndrome de tachycardie orthostatique posturale, les auteurs proposent une méthodologie de diagnostic et des pistes de traitements.
Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850225/
Extract: "We describe a series of individuals with symptoms of ‘long COVID’, and we posit that this condition may be related to a virus- or immune-mediated disruption of the autonomic nervous system resulting in orthostatic intolerance syndromes. We suggest that all physicians should be equipped to recognise such cases, appreciate the symptom burden and provide supportive management. We present our rationale for an underlying impaired autonomic physiology post-COVID-19 and suggest means of management.

Individual analyses confirmed a severe, bilateral prefrontal hypometabolism in 7/7 patients, including the rectus gyrus (p < 0.05 FWE corrected, Fig. Fig.2,2, Table Table4).4). In every patient, hypometabolism expanded bilaterally to the anterior cingulate and insula (p < 0.05 FWE corrected, Table Table4).4). A mild to moderate parietotemporal associative hypometabolism was observed in 4/7 patients, whereas two others had a severe, spread parietotemporooccipital hypometabolism (#6, 7). Hypermetabolism was found in the visual cortex in patient #1 due to visual stimulation after 18F-FDG injection and in the left frontal cortex in patient #4 due to focal seizure. Notably, bilateral mesiotemporal hypermetabolism was found in one patient (#6) without T2-MRI hyperintensity, whereas hypometabolism was observed in patient #3 with known hippocampal sclerosis and in patient #5 having hippocampal atrophy. Metabolism was decreased in the caudate nucleus in five patients (#2–5, 7) and thalamus in two (#2, 3) (p < 0.05 corrected). Metabolism was decreased in the bilateral cerebellar hemispheres in all patients except one (#4) but increased in the vermis in 5/7 patients (p < 0.05)."

2173

N91

Theoharis C. Theoharides Christos Cholevas Konstantinos Polyzoidis Antonios Politis

Long‐COVID syndrome‐associated brain fog and chemofog: Luteolin to the rescue

https://doi.org/10.1002/biof.1726

Published

12-Apr-21

Review

https://iubmb.onlinelibrary.wiley.com/doi/10.1002/biof.1726

Long‐COVID syndrome symptoms, especially brain fog, are similar to those experienced by patients undertaking or following chemotherapy for cancer (chemofog or chemobrain), as well in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or mast cell activation syndrome (MCAS). The pathogenesis of brain fog in these illnesses is presently unknown but may involve neuroinflammation via mast cells stimulated by pathogenic and stress stimuli to release mediators that activate microglia and lead to inflammation in the hypothalamus. These processes could be mitigated by phytosomal formulation (in olive pomace oil) of the natural flavonoid luteolin.

Une revue d'études compare le brouillard cérébral (symptôme fréquent dans le covid long) à celui qui suit des chimiothérapie anti-cancer, à celui des encéphalomyélites myalgiques, et à celui des troubles des troubles des mastocytes. L'article indique que la pathogenèse de cet état est encore inconnue, mais pourrait impliquer une neuroinflammation via des mastocytes stimulés par des stimuli pathogènes et du stress, libérant des médiateurs qui activent la microglie et conduisent à une inflammation de l'hypothalamus.
L'auteur principal, par ailleurs directeur scientifique de la société Algonot qui produit des compléments alimentaires à base de flavonoïdes, évoque une possibilité de traitement par une formulation phytosomale (dans l'huile de grignons d'olive) de la lutéoline flavonoïde naturelle ou de la quercétine.

N010

___Neurologic___

Published review on 12-Apr-21:
"Long‐COVID syndrome‐associated brain fog and chemofog: Luteolin to the rescue"
Une revue d'études compare le brouillard cérébral (symptôme fréquent dans le covid long) à celui qui suit des chimiothérapie anti-cancer, à celui des encéphalomyélites myalgiques, et à celui des troubles des troubles des mastocytes. L'article indique que la pathogenèse de cet état est encore inconnue, mais pourrait impliquer une neuroinflammation via des mastocytes stimulés par des stimuli pathogènes et du stress, libérant des médiateurs qui activent la microglie et conduisent à une inflammation de l'hypothalamus.
L'auteur principal, par ailleurs directeur scientifique de la société Algonot qui produit des compléments alimentaires à base de flavonoïdes, évoque une possibilité de traitement par une formulation phytosomale (dans l'huile de grignons d'olive) de la lutéoline flavonoïde naturelle ou de la quercétine.
Link: https://iubmb.onlinelibrary.wiley.com/doi/10.1002/biof.1726
Extract: "Long‐COVID syndrome symptoms, especially brain fog, are similar to those experienced by patients undertaking or following chemotherapy for cancer (chemofog or chemobrain), as well in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or mast cell activation syndrome (MCAS). The pathogenesis of brain fog in these illnesses is presently unknown but may involve neuroinflammation via mast cells stimulated by pathogenic and stress stimuli to release mediators that activate microglia and lead to inflammation in the hypothalamus. These processes could be mitigated by phytosomal formulation (in olive pomace oil) of the natural flavonoid luteolin."

2174

N92

KuaikuaiDuanabEnricoPremicdAndreaPilottodVivianaCristillodAlbertoBenussidIleniaLibridMarcelloGiuntadH. JeremyBockholtbJingyuLiubeRiccardoCamporafAlessandroPezzinidRobertoGasparottifMauroMagonicAlessandroPadovanidVinceCalhoun

Alterations of frontal-temporal gray matter volume associate with clinical measures of older adults with COVID-19

https://doi.org/10.1016/j.ynstr.2021.100326

Published

13-Apr-21

https://www.sciencedirect.com/science/article/pii/S2352289521000345

Highlights
•We identified gray matter alterations underlying COVID-19 using source-based morphometry.
•. Lower gray matter volume (GMV) in frontal regions linked to more severe disability.
•Patients receiving oxygen therapy had lower GMV in widespread frontal regions.
•Patients with fever presented reduced GMV in temporal and fusiform gyri.

_

2175

N93

Sara LaHue, Nina Escueta, Elan Guterman, Vanja Douglas, John Newman

Delirium in Hospitalized Adults with Confirmed SARS-CoV-2 Infection (1973)

Published

13-Apr-21

https://n.neurology.org/content/96/15_Supplement/1973

We included 99 patients diagnosed with COVID-19, of whom 46 patients were only on a medical-surgical ward. Forty-three percent of patients were delirious. Delirious patients were older than non-delirious patients: median(IQR) 62(47–81) vs. 48(38–63) years old (Z=−3.3, p=0.001). Seventy percent of delirious patients were cared for in the ICU at any point during hospitalization, compared with 25% of non-delirious patients (p <0.001). Compared with non-delirious patients, delirious patients had a longer median length of stay in days [8(4–13) vs 14(11–27); Z=−4.2, p<0.001], more likely to have a safety attendant (28% vs 7%, p=0.01), restraints (58% vs 5%, p<0.001), and less likely to be discharged home (39% vs 84%, p<0.001).

_

2176

N94

Sachi Gianchandani, Sarah Addison, Yousef Hannawi, Archana Hinduja

Prevalence of Delirium and its Risk Factors in Hospitalized Patients with SARS-CoV-2 Infection (1577)

Published

13-Apr-21

https://n.neurology.org/content/96/15_Supplement/1577

Data of 145 patients with confirmed SARS-CoV-2 infection were available (age 61.4±18.1 years, 41% female, and 29% African American). Delirium occurred in 33.8% of the patients. Patients with delirium were older, and had higher rates of hypertension, hyperlipidemia, diabetes mellitus, dementia, and psychiatric illness compared to those without delirium (P< 0.05). Furthermore, patients with delirium more frequently received supplemental oxygen, had lower PaO2/FiO2 ratio on admission, and higher levels of LDH, CRP and IL-6 compared to those without delirium (P<0.05). In logistic regression models, among the patients’ baseline characteristics, dementia was associated with greater odds of developing delirium (OR 4.25, 95% CI: 1.17–15.37, P=0.027). Additionally, among in-hospital complications, only cardiac complications and sepsis were independently associated with delirium in the logistic regression analysis (OR 9.02, 95% CI: 1.63–50.03, P=0.012, and OR 5.1 95%, CI: 1.88–13.84, P=0.001, respectively).

_

2177

N95

Sachi Gianchandani, Sarah Addison, Yousef Hannawi, Archana Hinduja

Impact of Delirium on Outcomes in Hospitalized Patients with SARS-CoV-2 Infection (4871)

Published

13-Apr-21

https://n.neurology.org/content/96/15_Supplement/4871

Data of 145 patients with confirmed SARS-CoV-2 infection were available (age 61.4±18.1 years, 41% female, and 29% African American). Delirium occurred in 33.8% of patients. Patients with delirium had increased length of hospital stay, intensive care unit (ICU) stay, longer duration of mechanical ventilation and higher likelihood of discharge to hospice or death (P<0.05). In Linear regression analyses, longer hospital stay was significantly associated with delirium (B=0.377, 95% CI: 0.723–1.25), renal complications (B=0.203, 95% CI: 0.051–0.355), acute respiratory distress syndrome (ARDS) (B=0.152, 95% CI: 0.0069–0.308) and hyperlipidemia (B=−0.17, 95% CI: −0.327–0.009). Longer ICU stay was also significantly associated with delirium (B=0.39, 95% CI: 0.11–0.67). In ordered logistic regression, older age, ARDS, presence of renal complications, and delirium were independently associated with unfavorable discharge disposition to hospice or nursing home (B=0.046, 95% CI: 0.123–0.079; B=1.48, 95% CI: 0.538–2.441; B=0.902, 95% CI: 0.016–1.789; B=1.207, 95% CI: 0.227–2.188, respectively).

_

2178

N96

Niyatee Samudra, Shawniqua Williams Roberson

Electroencephalographic findings in hospitalized patients with SARS-COV-2 (COVID-19) encephalopathy (1672)

Published

13-Apr-21

https://n.neurology.org/content/96/15_Supplement/1672.abstract

The most common indication for EEG monitoring was altered mental status (15/16 patients). Mean age was 59.5, and all patients had non-neurologic medical comorbidities. 7/16 patients were deceased. All EEGs demonstrated continuous generalized slow activity, consistent with encephalopathy, and EEG findings did not appear to relate to mortality outcome. Focal non-epileptiform abnormalities (slow activity or attenuation of faster frequencies) were present in 6/16 patients. Definitive sharp waves were seen in 2/16 patients, both of whom had a history of epilepsy. Whole-brain basic spectral composition (delta, theta, alpha, beta and average band power) did not demonstrate a difference between survivors and non-survivors in this cohort. A history of seizures or epilepsy was more common in deceased patients (42.8% vs 22.2%).

Conclusions: EEG findings in patients with COVID-19 encephalopathy were nonspecific. An EEG signature related to mortality was not identified, but a history of seizures or epilepsy was associated with a worse prognosis.

_

2179

N97

Keith J.Kincaida1 Justin ChiKunga1 Alexander J.Senetara 1 David Mendoz aa Daniel A.Bonnina Windy L.Purtlebaugha Rainier idhu Kariyawasama Maria Bruzzone aAlexis N.Simpkinsa

Post-COVID seizure: A new feature of “long-COVID”

https://doi.org/10.1016/j.ensci.2021.100340

Published

18-Apr-21

Case Report

https://www.sciencedirect.com/science/article/pii/S2405650221000320

Highlights
•Patients with COVID-19 can develop multiple neurologic disorders.
•Seizure can be a manifestation of the “Long-COVID” syndrome.
•Longitudinal studies of neurologic disease in COVID-19 survivors are needed.

_

2180

N98

Abu Baker Sheikha Prabal Kumar Chourasi a b Nismat Javed c Mehul Kumar Chourasi a d Sajid S.Suriyae Shubhra Upadhyaya FatimaIjaza Suman Pala Narges Moghimie Rahul Shekhara

Association of Guillain-Barre syndrome with COVID-19 infection: An updated systematic review

Published

18-Apr-21

Review Article

https://www.sciencedirect.com/science/article/pii/S0165572821001041

Highlights
•AIDP is the common form that can occur concomitant with COVID-19 infection.
•Clinical features of GBS with COVID-19 were similar to classical GBS.
•Up to date systematic review of 94 cases of GBS with COVID-19 infection.

_

2181

N99

Michael Connerney, Rohit Gummi, Catherine Yim, Christopher DeGiorgio

Seizure and Dural Sinus Thrombosis in setting of COVID-19 with 3 and 6 Month Outcomes after Long-Term Anticoagulation (5145)

Published

13-Apr-21

Case Report

https://n.neurology.org/content/96/15_Supplement/5145.abstract

To report how a case of coronavirus-19 (COVID-19) can lead to seizure and dural sinus thrombosis with subsequent clinical outcome after several months of long-term anticoagulation.

_

2182

N100

Marjolaine Uginet MD Gautier Breville MD Frédéric Assal MD Karl‐Olof Lövblad MD Maria Isabel Vargas MD Jérôme Pugin MD Jacques Serratrice MD Francois R. Herrmann MD, MPH Patrice H. Lalive MD Gilles Allali

COVID‐19 encephalopathy: Clinical and neurobiological features

https://doi.org/10.1002/jmv.26973

Published

30-Mar-21

RESEARCH ARTICLE

https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.26973

On May 10, 2020, 707 patients infected by SARS‐CoV‐2 were hospitalized at the Geneva University Hospitals; 31 (4.4%) consecutive patients with an acute encephalopathy (64.6 ± 12.1 years; 6.5% female) were included in this series, after exclusion of comorbid neurological conditions, such as stroke or meningitis. The severity of the COVID‐19 encephalopathy was divided into severe and mild based on the Richmond Agitation Sedation Scale (RASS): severe cases (n = 14, 45.2%) were defined on a RASS < −3 at worst presentation. The severe form of this so‐called COVID‐19 encephalopathy presented more often a headache. The severity of the pneumonia was not associated with the severity of the COVID‐19 encephalopathy: 28 of 31 (90%) patients did develop an acute respiratory distress syndrome, without any difference between groups (p = .665). Magnetic resonance imaging abnormalities were found in 92.0% (23 of 25 patients) with an intracranial vessel gadolinium enhancement in 85.0% (17 of 20 patients), while an increased cerebrospinal fluid/serum quotient of albumin suggestive of blood‐brain barrier disruption was reported in 85.7% (6 of 7 patients). Reverse transcription‐polymerase chain reaction for SARS‐CoV‐2 was negative for all patients in the cerebrospinal fluid. Although different pathophysiological mechanisms may contribute to this acute encephalopathy, our findings suggest the hypothesis of disturbed brain homeostasis and vascular dysfunction consistent with a SARS‐CoV‐2‐induced endotheliitis.

_

2183

N101

AmeenBiadseeacOrDagancZeevOrmianerbFirasKassemacShchadaMasarwabAmeerBiadsee

Eight-month follow-up of olfactory and gustatory dysfunctions in recovered COVID-19 patients

https://doi.org/10.1016/j.amjoto.2021.103065

Published

20-Apr-21

Study

https://www.sciencedirect.com/science/article/pii/S0196070921001666

Highlights
•52% of patients had full recovery of olfactory sense after 8 months.
•38.5% reported only a partial recovery of olfactory sense.
•61.5% of patients had full recovery of gustatory function after 8 months.
•38.5% reported only a partial recovery of gustatory sense.
•Gender did not affect the recovery of olfactory/gustatory functions.

En utilisant des tests gradués olfactifs, une étude note que plus d'un tiers l'une cohorte de malades de la covid n'ont retrouvé que partiellement leur odorat à 8 mois.

N010

___Neurologic___

Published study on 20-Apr-21:
"Eight-month follow-up of olfactory and gustatory dysfunctions in recovered COVID-19 patients"
En utilisant des tests gradués olfactifs, une étude note que plus d'un tiers l'une cohorte de malades de la covid n'ont retrouvé que partiellement leur odorat à 8 mois.
Link: https://www.sciencedirect.com/science/article/pii/S0196070921001666
Extract: "Highlights
•52% of patients had full recovery of olfactory sense after 8 months.
•38.5% reported only a partial recovery of olfactory sense.
•61.5% of patients had full recovery of gustatory function after 8 months.
•38.5% reported only a partial recovery of gustatory sense.
•Gender did not affect the recovery of olfactory/gustatory functions."

2184

N102

Eric Song, Christopher M. Bartley, Ryan D. Chow, Thomas T. Ngo, Ruoyi Jiang, Colin R. Zamecnik, Ravi Dandekar, Rita P. Loudermilk, Yile Dai, Feimei Liu, Sara Sunshine, Jamin Liu, Wesley Wu, Isobel A. Hawes, Bonny D. Alvarenga, Trung Huynh, Lindsay McAlpine, Nur-Taz Rahman, Bertie Geng, Jennifer Chiarella, Benjamin Goldman-Israelow, Chantal B.F. Vogels, Nathan D. Grubaugh, Arnau Casanovas-Massana, Brett S. Phinney, Michelle Salemi, Jessa R. Alexander, Juan A. Gallego, Todd Lencz, Hannah Walsh, Anne E. Wapniarski, Subhasis Mohanty, Carolina Lucas, Jon Klein, Tianyang Mao, Jieun Oh, Aaron Ring, Serena Spudich, Albert I. Ko, Steven H. Kleinstein, John Pak, Joseph L. DeRisi, Akiko Iwasaki, Samuel J. Pleasure, Michael R. Wilson, Shelli F. Farhadian

Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms

https://doi.org/10.1016/j.xcrm.2021.100288

Published

27-Apr-21

Study

https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00116-6

Highlights
•Immune cell scRNA-seq showed divergent T cell activation in the CNS during COVID-19
•COVID-19 patients had a compartmentalized cytokine response in the CNS
•All COVID-19 patients had anti-SARS-CoV-2 antibodies in their CSF,
•Five out of seven COVID-19 patients had anti-neural autoantibodies in their CSF
"This humoral response included indirect evidence for neuroinvasion of SARS-CoV-2 through the presence of anti-viral antibodies in the CNS during acute SARS-CoV-2 infection"
"These data therefore suggest that [this] presence may similarly reflect viral infection of the CNS"

Une étude éditée dans Cell, la plus prestigieuse publication en biologie, remarque que les malades de la covid ont une réponse inflammatoire cytokinique dans le système nerveux central spécifique et compartimentalisée, indépendante des atteintes pulmonaires. Les anticorps au SARS-CoV-2 semblent systématiquement présents dans le liquide cérébrospinal (LCS). Et celui-ci présente une activation spécifique des lymphocytes T et, chez une partie des malades, des auto-anticorps neuraux. Ces anticorps ont des cibles (épitopes) différentes des anticorps sériques de la covid. Les auteurs relient ces constatations aux dommages neurologiques de la covid, qui seraient alors en lien avec ces auto-anticorps. Un complément d'approche sur un modèle murin appuie l'hypothèse selon laquelle la présence d'anticorps dans le LCS ne reflète pas uniquement le transfert passif des anticorps de la circulation systémique, suggérant une possible infection cérébrale, dont les autoanticorps du LCR pourraient être les déclencheurs.Le LCS est le seul substitut de tissu aisément échantillonné chez les humains vivants. Cette étude remet sur le devant de la scène la possibilité que les dommages neurologiques soient en partie liés à une neuroinvasion virale, plutôt que seulement des processus indirects."This humoral response included indirect evidence for neuroinvasion of SARS-CoV-2 through the presence of anti-viral antibodies in the CNS during acute SARS-CoV-2 infection"/"These data therefore suggest that [this] presence may similarly reflect viral infection of the CNS"

N009

___Neurologic___

Published study on 27-Apr-21:
"Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms"
Une étude éditée dans Cell, la plus prestigieuse publication en biologie, remarque que les malades de la covid ont une réponse inflammatoire cytokinique dans le système nerveux central spécifique et compartimentalisée, indépendante des atteintes pulmonaires. Les anticorps au SARS-CoV-2 semblent systématiquement présents dans le liquide cérébrospinal (LCS). Et celui-ci présente une activation spécifique des lymphocytes T et, chez une partie des malades, des auto-anticorps neuraux. Ces anticorps ont des cibles (épitopes) différentes des anticorps sériques de la covid. Les auteurs relient ces constatations aux dommages neurologiques de la covid, qui seraient alors en lien avec ces auto-anticorps. Un complément d'approche sur un modèle murin appuie l'hypothèse selon laquelle la présence d'anticorps dans le LCS ne reflète pas uniquement le transfert passif des anticorps de la circulation systémique, suggérant une possible infection cérébrale, dont les autoanticorps du LCR pourraient être les déclencheurs.Le LCS est le seul substitut de tissu aisément échantillonné chez les humains vivants. Cette étude remet sur le devant de la scène la possibilité que les dommages neurologiques soient en partie liés à une neuroinvasion virale, plutôt que seulement des processus indirects."This humoral response included indirect evidence for neuroinvasion of SARS-CoV-2 through the presence of anti-viral antibodies in the CNS during acute SARS-CoV-2 infection"/"These data therefore suggest that [this] presence may similarly reflect viral infection of the CNS"
Link: https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00116-6
Extract: "Highlights
•Immune cell scRNA-seq showed divergent T cell activation in the CNS during COVID-19
•COVID-19 patients had a compartmentalized cytokine response in the CNS
•All COVID-19 patients had anti-SARS-CoV-2 antibodies in their CSF,
•Five out of seven COVID-19 patients had anti-neural autoantibodies in their CSF
"This humoral response included indirect evidence for neuroinvasion of SARS-CoV-2 through the presence of anti-viral antibodies in the CNS during acute SARS-CoV-2 infection"
"These data therefore suggest that [this] presence may similarly reflect viral infection of the CNS""

2185

N103

Mary Kelley, Katrina Samson

Bipallidal lesions in COVID 19 patients: Case series and review of literature. (1583)

Published

13-Apr-21

Case Report

https://n.neurology.org/content/96/15_Supplement/1583

Bipallidal lesions are specific to a handful of conditions and their presence in patients with COVID 19 provides us with insight into how the virus can effect the brain. These findings may reflect liver damage in individuals and/or may be the result of chronic hypoxia, blood glucose variability or vasculitis. Damage to these areas of the brain may be irreversible and create long term disability due to neurological dysfunction of the individuals infected and therefore it is important to identify them early.

_

2186

N104

Li Jiao, Yun Yang, Wenhai Yu, Yuan Zhao, Haiting Long, Jiahong Gao, Kaiyun Ding, Chunxia Ma, Jingmei Li, Siwen Zhao, Haixuan Wang, Haiyan Li, Mengli Yang, Jingwen Xu, Junbin Wang, Jing Yang, Dexuan Kuang, Fangyu Luo, Xingli Qian, Longjiang Xu, Bin Yin, Wei Liu, Hongqi Liu, Shuaiyao Lu & Xiaozhong Peng

The olfactory route is a potential way for SARS-CoV-2 to invade the central nervous system of rhesus monkeys

https://doi.org/10.1038/s41392-021-00591-7

Published

24-Apr-21

Study

https://www.nature.com/articles/s41392-021-00591-7

In this study, we explored the mechanisms of SARS-CoV-2 neurotropism via our established non-human primate model of COVID-19. In rhesus monkey, SARS-CoV-2 invades the CNS primarily via the olfactory bulb. Thereafter, viruses rapidly spread to functional areas of the central nervous system, such as hippocampus, thalamus, and medulla oblongata. The infection of SARS-CoV-2 induces the inflammation possibly by targeting neurons, microglia, and astrocytes in the CNS. Consistently, SARS-CoV-2 infects neuro-derived SK-N-SH, glial-derived U251, and brain microvascular endothelial cells in vitro. To our knowledge, this is the first experimental evidence of SARS-CoV-2 neuroinvasion in the NHP model, which provides important insights into the CNS-related pathogenesis of SARS-CoV-2.

Chez le singe, le SARS-CoV-2 peut infecter le cerveau puis de proche en proche d'autres parties du système nerveux central en entrant par le bulbe olfactif (étude dans Nature). Cette neuroinvasion provoque des inflammations cytokiniques visant les neurones, les astrocytes et la microglie. Elle n'apparaît pas corrélée à une invasion virale pulmonaire. Les auteurs remarquent que l'importance de la neuroinvasion pourrait être différence chez la souris, le primate ou l'homme. Chez le singe, la réplication virale n'est cependant pas efficace, ce qui suggère que les dommages pathologiques sur le SNC sont causés par des facteurs indirects tels que les «tempêtes de cytokines». L'étude n'exclut pas que la neuro-inflammation puisse être aussi provoquée via la barrière hémato-encéphalique. La troisième voie d'entrée du virus vers le SNC pourrait être la voie gastro-intestinale (système nerveux entérique).

N009

___Neurologic___

Published study on 24-Apr-21:
"The olfactory route is a potential way for SARS-CoV-2 to invade the central nervous system of rhesus monkeys"
Chez le singe, le SARS-CoV-2 peut infecter le cerveau puis de proche en proche d'autres parties du système nerveux central en entrant par le bulbe olfactif (étude dans Nature). Cette neuroinvasion provoque des inflammations cytokiniques visant les neurones, les astrocytes et la microglie. Elle n'apparaît pas corrélée à une invasion virale pulmonaire. Les auteurs remarquent que l'importance de la neuroinvasion pourrait être différence chez la souris, le primate ou l'homme. Chez le singe, la réplication virale n'est cependant pas efficace, ce qui suggère que les dommages pathologiques sur le SNC sont causés par des facteurs indirects tels que les «tempêtes de cytokines». L'étude n'exclut pas que la neuro-inflammation puisse être aussi provoquée via la barrière hémato-encéphalique. La troisième voie d'entrée du virus vers le SNC pourrait être la voie gastro-intestinale (système nerveux entérique).
Link: https://www.nature.com/articles/s41392-021-00591-7
Extract: "In this study, we explored the mechanisms of SARS-CoV-2 neurotropism via our established non-human primate model of COVID-19. In rhesus monkey, SARS-CoV-2 invades the CNS primarily via the olfactory bulb. Thereafter, viruses rapidly spread to functional areas of the central nervous system, such as hippocampus, thalamus, and medulla oblongata. The infection of SARS-CoV-2 induces the inflammation possibly by targeting neurons, microglia, and astrocytes in the CNS. Consistently, SARS-CoV-2 infects neuro-derived SK-N-SH, glial-derived U251, and brain microvascular endothelial cells in vitro. To our knowledge, this is the first experimental evidence of SARS-CoV-2 neuroinvasion in the NHP model, which provides important insights into the CNS-related pathogenesis of SARS-CoV-2."

2187

N105

Artemios Artemiadis,Andreas Liampas,Loizos Hadjigeorgiou &Panagiotis Zis

Myelopathy associated with SARS-COV-2 infection. A systematic review

https://doi.org/10.1080/01616412.2021.1915078

Published

17-Apr-21

Research Article

https://www.tandfonline.com/doi/abs/10.1080/01616412.2021.1915078

More than one-third of COVID-19 patients report neurological symptoms and cases of neurological diseases are increasingly accumulating. The aim of this systematic review was to characterize all – to date – reported cases with COVID-19 related myelopathy. Methods׃Eighteen papers were included in this review. Patients of all ages could be affected, although there is a predilection for middle-aged people. Results׃There were no significant co-morbidities or immunodeficiencies in the affected patients. COVID-19 related myelopathy started roughly within the first month after COVID-19 onset, either concomitantly with COVID-19 symptoms or within 10 days after their remission. The vast majority of cases fulfilled our criteria for postinfectious transverse myelitis. However, some cases were considered to have had parainfectious or infectious myelitis or, in one case, vascular myelopathy. Motor, sensory and bowel and/or bladder symptoms predominated the clinical presentation of myelopathies, explained mainly by centrally localized and longitudinally extensive lesions within the cervical and/or thoracic segments of the spinal cord. Occasionally lesions were complicated by necrosis and hemorrhages. Treatment with corticosteroids, intravenous immunoglobulin or plasma exchange was offered mostly a mild to marked improvement within a period of some weeks. Conclusions׃ Considering the imminent arrival of new vaccines against COVID-19 pandemic, and their potential risk for postvaccination transverse myelitis, this characterization of COVID-19 related myelopathy is of utmost importance.

_

2188

N106

ES

Guilherme Dias de Melo1,, Françoise Lazarini2,, Sylvain Levallois3,, Charlotte Hautefort4,, Vincent Michel2,5, Florence Larrous1, Benjamin Verillaud4, Caroline Aparicio6, Sebastien Wagner2, Gilles Gheusi2,7, Lauriane Kergoat1, Etienne Kornobis8,9, Flora Donati10,11, Thomas Cokelaer8,9, Rémi Hervochon12, Yoann Madec13, Emmanuel Roze14, Dominique Salmon15, Hervé Bourhy1,*, Marc Lecuit3,16,* and Pierre-Marie Lledo2,

COVID-19-related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters

https://doi.org/10.1126/scitranslmed.abf8396

Published

3-May-21

Research Article

https://stm.sciencemag.org/content/early/2021/04/30/scitranslmed.abf8396

Whereas recent investigations have revealed viral, inflammatory and vascular factors involved in SARS-CoV-2 lung pathogenesis, the pathophysiology of neurological disorders in COVID-19 remains poorly understood. Olfactory and taste dysfunction are common in COVID-19, especially in mildly symptomatic patients. Here, we conducted a virologic, molecular, and cellular study of the olfactory neuroepithelium of seven patients with COVID-19 presenting with acute loss of smell. We report evidence that the olfactory neuroepithelium may be a major site of SARS-CoV2 infection with multiple cell types, including olfactory sensory neurons, support cells, and immune cells, becoming infected. SARS-CoV-2 replication in the olfactory neuroepithelium was associated with local inflammation. Furthermore, we showed that SARS-CoV-2 induced acute anosmia and ageusia in golden Syrian hamsters, lasting as long as the virus remained in the olfactory epithelium and the olfactory bulb. Finally, olfactory mucosa sampling from patients showing long-term persistence of COVID-19-associated anosmia revealed the presence of virus transcripts and of SARS-CoV-2-infected cells, together with protracted inflammation. SARS-CoV-2 persistence and associated inflammation in the olfactory neuroepithelium may account for prolonged or relapsing symptoms of COVID-19, such as loss of smell, which should be considered for optimal medical management of this disease.

Une étude sur des hamsters montre sur cet animal une anosmie (perte d'odorat) qui perdure aussi longtemps que le virus reste dans le bulbe et l'épithélium olfactifs. L'analyse sur 7 patients révèle également la présence de cellules infectées par le SRAS-CoV-2 ainsi qu'une inflammation prolongée.

N010

___Neurologic___

Published research article on 3-May-21:
"COVID-19-related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters"
Une étude sur des hamsters montre sur cet animal une anosmie (perte d'odorat) qui perdure aussi longtemps que le virus reste dans le bulbe et l'épithélium olfactifs. L'analyse sur 7 patients révèle également la présence de cellules infectées par le SRAS-CoV-2 ainsi qu'une inflammation prolongée.
Link: https://stm.sciencemag.org/content/early/2021/04/30/scitranslmed.abf8396
Extract: "Whereas recent investigations have revealed viral, inflammatory and vascular factors involved in SARS-CoV-2 lung pathogenesis, the pathophysiology of neurological disorders in COVID-19 remains poorly understood. Olfactory and taste dysfunction are common in COVID-19, especially in mildly symptomatic patients. Here, we conducted a virologic, molecular, and cellular study of the olfactory neuroepithelium of seven patients with COVID-19 presenting with acute loss of smell. We report evidence that the olfactory neuroepithelium may be a major site of SARS-CoV2 infection with multiple cell types, including olfactory sensory neurons, support cells, and immune cells, becoming infected. SARS-CoV-2 replication in the olfactory neuroepithelium was associated with local inflammation. Furthermore, we showed that SARS-CoV-2 induced acute anosmia and ageusia in golden Syrian hamsters, lasting as long as the virus remained in the olfactory epithelium and the olfactory bulb. Finally, olfactory mucosa sampling from patients showing long-term persistence of COVID-19-associated anosmia revealed the presence of virus transcripts and of SARS-CoV-2-infected cells, together with protracted inflammation. SARS-CoV-2 persistence and associated inflammation in the olfactory neuroepithelium may account for prolonged or relapsing symptoms of COVID-19, such as loss of smell, which should be considered for optimal medical management of this disease."

2189

N107

Siu Wa Tang, Daiga Helmeste and Brian Leonard

Inflammatory Neuropsychiatric Disorders and COVID-19 Neuroinflammation

https://doi.org/10.1017/neu.2021.13

Published

30-Apr-21

Review

https://www.cambridge.org/core/journals/acta-neuropsychiatrica/article/abs/inflammatory-neuropsychiatric-disorders-and-covid19-neuroinflammation/DE79FA11E7111CDFC6478C9DD3925926#

Neuropsychiatric sequalae to COVID-19 infection are beginning to emerge, like previous Spanish influenza and SARS episodes. Streptococcal infection in pediatric patients causing OCD (PANDAS) is another recent example of an infection-based psychiatric disorder. Inflammation associated with neuropsychiatric disorders has been previously reported but there is no standard clinical management approach established. Part of the reason is that it is unclear what factors determine the specific neuronal vulnerability and the efficacy of anti-inflammatory treatment in neuroinflammation. The emerging COVID-19 data suggested that in the acute stage, wide-spread neuronal damage appears to be the result of abnormal and overactive immune responses and cytokine storm is associated with poor prognosis. It is still too early to know if there are long term specific neuronal or brain regional damages associated with COVID-19, resulting in distinct neuropsychiatric disorders. In several major psychiatric disorders where neuroinflammation is present, patients with abnormal inflammatory markers may also experience less than favorable response or treatment resistance when standard treatment is used alone. Evidence regarding the benefits of co-administered anti-inflammatory agents such as COX-2 inhibitor is encouraging in selected patients though may not benefit others. Disease modifying therapies are increasingly being applied to neuropsychiatric diseases characterized by abnormal or hyperreactive immune responses. Adjunct anti-inflammatory treatment may benefit selected patients and is definitely an important component of clinical management in the presence of neuroinflammation.

Une revue d'études dresse un résumé très complet sur la neuro-inflammation que peut causer la covid, en comparaison avec d'autres maladies infectieuses, les pistes thérapeutiques possibles, les techniques d'imagerie pertinentes, et la question des effets à long terme en tant que troubles neuro-psychiatriques inflammatoires.

N010

___Neurologic___

Published review on 30-Apr-21:
"Inflammatory Neuropsychiatric Disorders and COVID-19 Neuroinflammation"
Une revue d'études dresse un résumé très complet sur la neuro-inflammation que peut causer la covid, en comparaison avec d'autres maladies infectieuses, les pistes thérapeutiques possibles, les techniques d'imagerie pertinentes, et la question des effets à long terme en tant que troubles neuro-psychiatriques inflammatoires.
Link: https://www.cambridge.org/core/journals/acta-neuropsychiatrica/article/abs/inflammatory-neuropsychiatric-disorders-and-covid19-neuroinflammation/DE79FA11E7111CDFC6478C9DD3925926#
Extract: "Neuropsychiatric sequalae to COVID-19 infection are beginning to emerge, like previous Spanish influenza and SARS episodes. Streptococcal infection in pediatric patients causing OCD (PANDAS) is another recent example of an infection-based psychiatric disorder. Inflammation associated with neuropsychiatric disorders has been previously reported but there is no standard clinical management approach established. Part of the reason is that it is unclear what factors determine the specific neuronal vulnerability and the efficacy of anti-inflammatory treatment in neuroinflammation. The emerging COVID-19 data suggested that in the acute stage, wide-spread neuronal damage appears to be the result of abnormal and overactive immune responses and cytokine storm is associated with poor prognosis. It is still too early to know if there are long term specific neuronal or brain regional damages associated with COVID-19, resulting in distinct neuropsychiatric disorders. In several major psychiatric disorders where neuroinflammation is present, patients with abnormal inflammatory markers may also experience less than favorable response or treatment resistance when standard treatment is used alone. Evidence regarding the benefits of co-administered anti-inflammatory agents such as COX-2 inhibitor is encouraging in selected patients though may not benefit others. Disease modifying therapies are increasingly being applied to neuropsychiatric diseases characterized by abnormal or hyperreactive immune responses. Adjunct anti-inflammatory treatment may benefit selected patients and is definitely an important component of clinical management in the presence of neuroinflammation."

2190

N108

A. L. Ren, R. J. Digby & E. J. Needham

Neurological update: COVID-19

https://doi.org/10.1007/s00415-021-10581-y

Published

30-Apr-21

Review

https://link.springer.com/article/10.1007/s00415-021-10581-y

Coronavirus Disease 2019 is predominantly a disorder of the respiratory system, but neurological complications have been recognised since early in the pandemic. The major pathophysiological processes leading to neurological damage in COVID-19 are cerebrovascular disease, immunologically mediated neurological disorders and the detrimental effects of critical illness on the nervous system. It is still unclear whether direct invasion of the nervous system by the Severe Acute Respiratory Syndrome Coronavirus 2 occurs; given the vast numbers of people infected at this point, this uncertainty suggests that nervous system infection is unlikely to represent a significant issue if it occurs at all. In this review, we explore what has been learnt about the neurological complications of COVID-19 over the course of the pandemic, and by which mechanisms these complications most commonly occur.

Cette revue d'études discute des 4 causes principales de dommages neurologiques attribués à la covid :
- l'invasion directe du système nerveux central par le SRAS-CoV-2
- les troubles neurologiques à médiation immunologique
- la maladie neurovasculaire et thromboembolique
- les séquelles neurologiques d'une phase aiguë grave de la maladie

N010

___Neurologic___

Published review on 30-Apr-21:
"Neurological update: COVID-19"
Cette revue d'études discute des 4 causes principales de dommages neurologiques attribués à la covid :
- l'invasion directe du système nerveux central par le SRAS-CoV-2
- les troubles neurologiques à médiation immunologique
- la maladie neurovasculaire et thromboembolique
- les séquelles neurologiques d'une phase aiguë grave de la maladie
Link: https://link.springer.com/article/10.1007/s00415-021-10581-y
Extract: "Coronavirus Disease 2019 is predominantly a disorder of the respiratory system, but neurological complications have been recognised since early in the pandemic. The major pathophysiological processes leading to neurological damage in COVID-19 are cerebrovascular disease, immunologically mediated neurological disorders and the detrimental effects of critical illness on the nervous system. It is still unclear whether direct invasion of the nervous system by the Severe Acute Respiratory Syndrome Coronavirus 2 occurs; given the vast numbers of people infected at this point, this uncertainty suggests that nervous system infection is unlikely to represent a significant issue if it occurs at all. In this review, we explore what has been learnt about the neurological complications of COVID-19 over the course of the pandemic, and by which mechanisms these complications most commonly occur."

2191

N109

Alexios-Fotios A. Mentis

What neurological and psychiatric effects does COVID-19 have on its survivors?

https://doi.org/10.1186/s12916-021-01986-7

Published

29-Apr-21

Review

https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-021-01986-7

Furthermore, when compared to neurological disorders, the hazard ratios for psychiatric disorders, such as anxiety and mood disorders, showed a less strong association with encephalopathy and hospitalization. This observation suggests that mental health deterioration due to social distancing and pandemic-related anxiety may have partly contributed to psychiatric illness; thus, it is unlikely they represent a direct manifestation of the COVID-19 illness. Moreover, the underlying mechanisms for such associations include direct effects of viral tropism on the central nervous system, angiotensin-converting enzyme-2 receptor-related neuronal damage, cytokine overproduction and toxicity-related neuronal injury, and immune response-related neuronal injury [1, 5].

The study by Taquet et al. indicates severe neurological and psychiatric illness following infection with COVID-19. The knowledge reaped from this study can assist in health services planning and in identifying future research goals. Globally, the cohort approach reported offers useful, timely, and critically required information for other researchers and funding providers to guide the future steps in the COVID-19 research related to clinical neurosciences and mental health strategy.

_

2192

N110

Flavia Mattioli, Chiara Stampatori, […]Giuseppe De Palma

Neurological and cognitive sequelae of Covid-19: a four month follow-up

Published

1-May-21

Study

https://link.springer.com/article/10.1007/s00415-021-10579-6

The aim of this study is to investigate if objective neurological or cognitive impairment is detect-able four months after SARS-CoV-2 infection, in a group of patients who had mild–moderate COVID-19. A cohort of 120 health care workers previously afected by COVID-19 was examined 4 months after the diagnosis by means of neurological and extensive cognitive evaluation and compared to a group of 30 health care workers who did not have COVID-19 and were similar for age and co morbidities. At 4 month follow-up, 118/120 COVID-19 cases had normal neurological examination, two patients had neurological defcits. COVID-19 patients did not show general cognitive impairment at MMSE. In COVID-19 cases the number of impaired neuropsychological tests was not signifcantly diferent from non COVID-19 cases (mean 1.69 and 1 respectively, Mann–Whitney p=n.s.), as well as all the mean tests’ scores. Anxiety, stress and depression scores resulted to be signifcantly higher in COVID-19 than in non COVID-19 cases. The results do not support the presence of neurological defcits or cognitive impairment in this selected population of mild–moderate COVID-19 patients four months after the diagnosis. Severe emotional disorders in patients who had COVID-19 in the past are confrmed.

Une étude a mesuré les scores cognitifs sur une cohorte de 120 patients d'un personnel hospitalier PCR+ avec seulement des cas légers à modérés de la covid pendant la phase aiguë (2 seulement ayant eu besoin d'une oxygénothérapie). Il n'apparaît pas d'écarts significatifs avec un groupe contrôle (très légèrement moins bon sans écart stat. significatif). Les tests comprenaient des évaluations de fluidité verbale, mémoire, attention, réactivité, et notamment un MMSE (mini-mental state examination).

N010

___Neurologic___

Published study on 1-May-21:
"Neurological and cognitive sequelae of Covid-19: a four month follow-up"
Une étude a mesuré les scores cognitifs sur une cohorte de 120 patients d'un personnel hospitalier PCR+ avec seulement des cas légers à modérés de la covid pendant la phase aiguë (2 seulement ayant eu besoin d'une oxygénothérapie). Il n'apparaît pas d'écarts significatifs avec un groupe contrôle (très légèrement moins bon sans écart stat. significatif). Les tests comprenaient des évaluations de fluidité verbale, mémoire, attention, réactivité, et notamment un MMSE (mini-mental state examination).
Link: https://link.springer.com/article/10.1007/s00415-021-10579-6
Extract: "The aim of this study is to investigate if objective neurological or cognitive impairment is detect-able four months after SARS-CoV-2 infection, in a group of patients who had mild–moderate COVID-19. A cohort of 120 health care workers previously afected by COVID-19 was examined 4 months after the diagnosis by means of neurological and extensive cognitive evaluation and compared to a group of 30 health care workers who did not have COVID-19 and were similar for age and co morbidities. At 4 month follow-up, 118/120 COVID-19 cases had normal neurological examination, two patients had neurological defcits. COVID-19 patients did not show general cognitive impairment at MMSE. In COVID-19 cases the number of impaired neuropsychological tests was not signifcantly diferent from non COVID-19 cases (mean 1.69 and 1 respectively, Mann–Whitney p=n.s.), as well as all the mean tests’ scores. Anxiety, stress and depression scores resulted to be signifcantly higher in COVID-19 than in non COVID-19 cases. The results do not support the presence of neurological defcits or cognitive impairment in this selected population of mild–moderate COVID-19 patients four months after the diagnosis. Severe emotional disorders in patients who had COVID-19 in the past are confrmed."

2193

N111

George B. Stefano, Pascal Büttiker, Simon Weissenberger, Anders Martin, Radek Ptacek, Richard M. Kream

Editorial: The Pathogenesis of Long-Term Neuropsychiatric COVID-19 and the Role of Microglia, Mitochondria, and Persistent Neuroinflammation: A Hypothesis

https://doi.org/10.12659/MSM.933015

Published

10-May-21

Article

https://www.medscimonit.com/download/index/idArt/933015

Persistent comorbidities occur in patients who initially recover from acute coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ‘Long COVID’ involves the central nervous system (CNS), resulting in neuropsychiatric symptoms and signs, including cognitive impairment or ‘brain fog’ and chronic fatigue syndrome. There are similarities in these persistent complications between SARS-CoV-2 and the Ebola, Zika, and influenza A viruses. Normal CNS neuronal mitochondrial function requires high oxygen levels for oxidative phosphorylation and ATP production. Recent studies have shown that the SARS-CoV-2 virus can hijack mitochondrial function. Persistent changes in cognitive functioning have also been reported with other viral infections. SARS-CoV-2 infection may result in long-term effects on immune processes within the CNS by causing microglial dysfunction. This short opinion aims to discuss the hypothesis that the pathogenesis of long-term neuropsychiatric COVID-19 involves microglia, mitochondria, and persistent neuroinflammation.

Des chercheurs élaborent une hypothèse sur les séquelles neurologiques de la covid. Selon eux, un état chronique de pro-inflammation dans les structures du système nerveux central pourrait être perpétué par une activation chronique des lymphocytes T et B due aux épitopes viraux, ciblant au final la microglie cérébrale. Les auteurs proposent des analyses bioinformatiques adaptées sur les peptides concernés pour valider cette hypothèse.

N010

___Neurologic___

Published article on 10-May-21:
"Editorial: The Pathogenesis of Long-Term Neuropsychiatric COVID-19 and the Role of Microglia, Mitochondria, and Persistent Neuroinflammation: A Hypothesis"
Des chercheurs élaborent une hypothèse sur les séquelles neurologiques de la covid. Selon eux, un état chronique de pro-inflammation dans les structures du système nerveux central pourrait être perpétué par une activation chronique des lymphocytes T et B due aux épitopes viraux, ciblant au final la microglie cérébrale. Les auteurs proposent des analyses bioinformatiques adaptées sur les peptides concernés pour valider cette hypothèse.
Link: https://www.medscimonit.com/download/index/idArt/933015
Extract: "Persistent comorbidities occur in patients who initially recover from acute coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ‘Long COVID’ involves the central nervous system (CNS), resulting in neuropsychiatric symptoms and signs, including cognitive impairment or ‘brain fog’ and chronic fatigue syndrome. There are similarities in these persistent complications between SARS-CoV-2 and the Ebola, Zika, and influenza A viruses. Normal CNS neuronal mitochondrial function requires high oxygen levels for oxidative phosphorylation and ATP production. Recent studies have shown that the SARS-CoV-2 virus can hijack mitochondrial function. Persistent changes in cognitive functioning have also been reported with other viral infections. SARS-CoV-2 infection may result in long-term effects on immune processes within the CNS by causing microglial dysfunction. This short opinion aims to discuss the hypothesis that the pathogenesis of long-term neuropsychiatric COVID-19 involves microglia, mitochondria, and persistent neuroinflammation."

2194

N112

Courtney L.McMahon124HilaryStaples34MichalGazi3RicardoCarrion3JennyHsieh

SARS-CoV-2 targets glial cells in human cortical organoids

https://doi.org/10.1016/j.stemcr.2021.01.016

Published

11-May-21

Study

https://www.sciencedirect.com/science/article/pii/S2213671121000461

Highlights
•SARS-CoV-2 infects human cortical organoids at low viral loads within 6 h
•Replication of SARS-CoV-2 does not occur within 4 days post infection
•SARS-CoV-2 preferentially targets glia and choroid plexus cells in vitro
•Cleaved caspase-3 co-localizes with SARS-CoV-2 in cells at 14 days post infection

Dans une étude publiée dans Stem Cell Reports, des chercheurs notent grâce à des organoïdes humains cérébraux que le virus SARS-CoV-2 semblent cibler non pas les neurones mais les cellules gliales et les cellules du plexus choroïde.

N010

___Neurologic___

Published study on 11-May-21:
"SARS-CoV-2 targets glial cells in human cortical organoids"
Dans une étude publiée dans Stem Cell Reports, des chercheurs notent grâce à des organoïdes humains cérébraux que le virus SARS-CoV-2 semblent cibler non pas les neurones mais les cellules gliales et les cellules du plexus choroïde.
Link: https://www.sciencedirect.com/science/article/pii/S2213671121000461
Extract: "Highlights
•SARS-CoV-2 infects human cortical organoids at low viral loads within 6 h
•Replication of SARS-CoV-2 does not occur within 4 days post infection
•SARS-CoV-2 preferentially targets glia and choroid plexus cells in vitro
•Cleaved caspase-3 co-localizes with SARS-CoV-2 in cells at 14 days post infection"

2195

N113

Eric GUEDJ
Françoise LAZARINI
Silvia MORBELLI
Mathieu CECCALDI
Charlotte HAUTEFORT
Aurélie KAS
Thomas RADULESCO
Dominique SALMON-CERON
Carole ELDIN

Long COVID and the brain network of Proust's madeleine: targeting the olfactory pathway

https://doi.org/10.1016/j.cmi.2021.05.015

Published

17-May-21

Article

https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(21)00238-X/fulltext

Interestingly, the identified pathway seems to describe the limbic network of Proust's famous madeleine: the smell is quickly followed by the taste, recognition (and, more broadly, the memory), and associated emotions. This limbic system is known to be closely linked on brainstem nuclei to the autonomic nervous system, that is also involved during emotional memory processing, and whose dysregulation can lead to cardiovascular, muscular, gastrointestinal and respiratory symptoms (e.g., diarrhoea, dizziness, hypertension, palpitations, or tremor) The fronto-basal cortex is involved in attention and short-term memory linked to the olfactory sense. After being processed and refined in the olfactory bulb and piriform cortex, the olfactory sensory input is processed in the amygdala and hippocampus (two key brain areas involved in emotion and memory), thus making olfaction a privileged sense for accessing memories. Perturbations of the olfactory circuit and functioning can thus result in emotional and cognitive dysfunctions, as described in animal models such as olfactory bulbectomy, a relevant model of depression. Accordingly, loss of olfaction is associated with depressed mood and anxiety in long COVID more strongly than life-threatening symptoms such as shortness of breath do The profile of hypometabolism identified in patients with long COVID does not seem to correspond to those in depression, post-traumatic stress disorder, or even fibromyalgia. If limbic alterations have also been described in these conditions, the association with concomitant hypometabolism of the brainstem and cerebellum is more atypical Nevertheless, we believe that the functional aspect of this remote effect is important since most patients recover after a few months in the absence of obvious brain lesions on brain MRI. This functional recovery could thus be accelerated by different strategies of rehabilitationIf the hypothesis is borne out, the development of new therapeutic strategies must target the olfactory clefts in the most severely impaired patients who will have little or no recovery after rehabilitation, for example, by using intranasally administered anti-inflammatory or antiviral drugs to act [7], beyond functional effects, on the pathological impairment of Proust’s madeleine brain network.

Dans une hypothèse qu'elle dresse sur la neuro-inflammation qui peut être déclenchée par le virus SARS-CoV-2, une équipe française note que le profil d'hypométabolisme cérébral identifié chez les patients atteints de covid long ne semble pas correspondre à ceux en dépression, en état de stress post-traumatique, ou en fibromyalgie. Les auteurs remarquent que, même si des altérations limbiques ont également été décrites dans ces conditions, l'association avec un hypométabolisme concomitant du tronc cérébral et du cervelet est plus atypique. L'équipe table notamment sur une hypothèse liée aux zones afférentes à la mémoire des odeurs ("le chemin de la madeleine de Proust"). En l'absence de lésions distantes connues, l'altération du bulbe olfactif pourrait être selon eux à l'origine d'effets localisés plus en arrière sur la fonction cérébrale d'autres régions limbiques (dont l'amygdale et l'hippocampe), ainsi que le tronc cérébral et le cervelet, par diaschisis (diminution de l'activité fonctionnelle des régions cérébrales des zones cérébrales endommagées connectées) en raison de désafférentation (perte d'entrée).

N009

___Neurologic___

Published article on 17-May-21:
"Long COVID and the brain network of Proust's madeleine: targeting the olfactory pathway"
Dans une hypothèse qu'elle dresse sur la neuro-inflammation qui peut être déclenchée par le virus SARS-CoV-2, une équipe française note que le profil d'hypométabolisme cérébral identifié chez les patients atteints de covid long ne semble pas correspondre à ceux en dépression, en état de stress post-traumatique, ou en fibromyalgie. Les auteurs remarquent que, même si des altérations limbiques ont également été décrites dans ces conditions, l'association avec un hypométabolisme concomitant du tronc cérébral et du cervelet est plus atypique. L'équipe table notamment sur une hypothèse liée aux zones afférentes à la mémoire des odeurs ("le chemin de la madeleine de Proust"). En l'absence de lésions distantes connues, l'altération du bulbe olfactif pourrait être selon eux à l'origine d'effets localisés plus en arrière sur la fonction cérébrale d'autres régions limbiques (dont l'amygdale et l'hippocampe), ainsi que le tronc cérébral et le cervelet, par diaschisis (diminution de l'activité fonctionnelle des régions cérébrales des zones cérébrales endommagées connectées) en raison de désafférentation (perte d'entrée).
Link: https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(21)00238-X/fulltext
Extract: "Interestingly, the identified pathway seems to describe the limbic network of Proust's famous madeleine: the smell is quickly followed by the taste, recognition (and, more broadly, the memory), and associated emotions. This limbic system is known to be closely linked on brainstem nuclei to the autonomic nervous system, that is also involved during emotional memory processing, and whose dysregulation can lead to cardiovascular, muscular, gastrointestinal and respiratory symptoms (e.g., diarrhoea, dizziness, hypertension, palpitations, or tremor) The fronto-basal cortex is involved in attention and short-term memory linked to the olfactory sense. After being processed and refined in the olfactory bulb and piriform cortex, the olfactory sensory input is processed in the amygdala and hippocampus (two key brain areas involved in emotion and memory), thus making olfaction a privileged sense for accessing memories. Perturbations of the olfactory circuit and functioning can thus result in emotional and cognitive dysfunctions, as described in animal models such as olfactory bulbectomy, a relevant model of depression. Accordingly, loss of olfaction is associated with depressed mood and anxiety in long COVID more strongly than life-threatening symptoms such as shortness of breath do The profile of hypometabolism identified in patients with long COVID does not seem to correspond to those in depression, post-traumatic stress disorder, or even fibromyalgia. If limbic alterations have also been described in these conditions, the association with concomitant hypometabolism of the brainstem and cerebellum is more atypical Nevertheless, we believe that the functional aspect of this remote effect is important since most patients recover after a few months in the absence of obvious brain lesions on brain MRI. This functional recovery could thus be accelerated by different strategies of rehabilitationIf the hypothesis is borne out, the development of new therapeutic strategies must target the olfactory clefts in the most severely impaired patients who will have little or no recovery after rehabilitation, for example, by using intranasally administered anti-inflammatory or antiviral drugs to act [7], beyond functional effects, on the pathological impairment of Proust’s madeleine brain network."

2196

N114

Ingrid H.C.H.M. Philippens, Kinga P. Böszörményi, Jacqueline A. Wubben, Zahra C. Fagrouch, Nikki van Driel, Amber Q. Mayenburg, Diana Lozovagia, Eva Roos, Bernadette Schurink, Marianna Bugiani, Ronald E. Bontrop, Jinte Middeldorp, Willy M. Bogers, Lioe-Fee de Geus-Oei, Jan A.M. Langermans, Marieke A. Stammes, Babs E. Verstrepen, Ernst J. Verschoor

SARS-CoV-2 causes brain inflammation and induces Lewy body formation in macaques

https://doi.org/10.1101/2021.02.23.432474

pre-print

5-May-21

Study

https://www.biorxiv.org/content/10.1101/2021.02.23.432474v2.full

Here we show that SARS-CoV-2 infection causes brain inflammation in the macaque model. An increased metabolic activity in the pituitary gland of two macaques was observed by longitudinal positron emission tomography-computed tomography (PET-CT). Post-mortem analysis demonstrated infiltration of T-cells and activated microglia in the brain, and viral RNA was detected in brain tissues from one animal. We observed Lewy bodies in brains of all rhesus macaques. These data emphasize the virus’ capability to induce neuropathology in this nonhuman primate model for SARS-CoV-2 infection. As in humans, Lewy body formation is an indication for the development of Parkinson’s disease, this data represents a warning for potential long-term neurological effects after SARS-CoV-2 infection.

Selon un pre-print (étude ni relue ni publiée), les infections à la covid chez les macaques peuvent causer des inflammations neurologiques et les analyses post-mortem revèlent la présence de corps de Lewy (indicateur de neurodégénérescence de type parkinsonien).

N011

___Neurologic___

Pre-Print study on 5-May-21:
"SARS-CoV-2 causes brain inflammation and induces Lewy body formation in macaques"
Selon un pre-print (étude ni relue ni publiée), les infections à la covid chez les macaques peuvent causer des inflammations neurologiques et les analyses post-mortem revèlent la présence de corps de Lewy (indicateur de neurodégénérescence de type parkinsonien).
Link: https://www.biorxiv.org/content/10.1101/2021.02.23.432474v2.full
Extract: "Here we show that SARS-CoV-2 infection causes brain inflammation in the macaque model. An increased metabolic activity in the pituitary gland of two macaques was observed by longitudinal positron emission tomography-computed tomography (PET-CT). Post-mortem analysis demonstrated infiltration of T-cells and activated microglia in the brain, and viral RNA was detected in brain tissues from one animal. We observed Lewy bodies in brains of all rhesus macaques. These data emphasize the virus’ capability to induce neuropathology in this nonhuman primate model for SARS-CoV-2 infection. As in humans, Lewy body formation is an indication for the development of Parkinson’s disease, this data represents a warning for potential long-term neurological effects after SARS-CoV-2 infection."

2197

N115

R

Lucas Scardua Silva, Rafael Batista Joao, Mateus Henrique Nogueira, Italo Karmann Aventurato, Brunno Machado de Campos, Mariana Rabelo de Brito, Marina Koutsodontis Machado Alvim, Guilherme Vieira Nunes Ludwig, André Schwambach Vieira, Leonilda Maria Barbosa Santos, Alessandro dos Santos Farias, Fernando Cendes, Clarissa Lin Yasuda

Functional and microstructural brain abnormalities, fatigue, and cognitive dysfunction after mild COVID-19

https://doi.org/10.1101/2021.03.20.21253414

pre-print

24-Mar-21

Study

https://www.medrxiv.org/content/10.1101/2021.03.20.21253414v1.full

We conducted a cross-sectional study of 87 non-hospitalized recovered individuals 54 days after the laboratory confirmation of COVID-19. We performed structured interviews, neurological examination, 3T-MRI scans with diffusion tensor images (DTI) and functional resting-state images (fMRI). Also, we investigated fatigue, anxiety, depression, somnolence, language, memory, and cognitive flexibility, using validated instruments.

Individuals self-reported a high frequency of headache (40%) and memory difficulties (33%). The quantitative analyses confirmed symptoms of fatigue (68%), excessive somnolence (35%), anxiety (29%), impaired cognitive flexibility (40%) and language impairment (33%). There were widespread cerebral white matter alterations (mainly characterized by increased fractional anisotropy), which correlated with abnormal attention and cognitive flexibility. The resting-state fMRI networks analysis showed severely disrupted brain hyperconnectivity and loss of resting-state networks specificity.

Une étude non relue et non encore publiée (pre-print) utilise l'imagerie du tenseur de diffusion sur des patients souffrant de séquelles neurologiques de la covid deux mois après l'infection. Des altérations de la substance blanche cérébrale semblent répandues et corrélées avec une attention anormale et une flexibilité cognitive. La connectivité cérébrale peut être fortement perturbée, avec des régions excessivement et chaotiquement connectées, associées à une perte significative de spécificité.

2198

N116

R

M. Almeria J.C. Cejudo J.Sotoca J.Deus J .Krupinski

Cognitive profile following COVID-19 infection: Clinical predictors leading to neuropsychological impairment

https://doi.org/10.1016/j.bbih.2020.100163

Published

22-Oct-20

Study

https://www.sciencedirect.com/science/article/pii/S2666354620301289

Highlights
•Neuropsychological deficits related to COVID-19 infection were seen in attention, memory and executive function domains.
•Presenting neurological symptoms during COVID-19 infection were risk factors for cognitive deficit.
•Oxygen therapy, headache and diarrhea were symptoms associated to poor performance in neuropsychological tests.
•Cognitive complains in patients with COVID-19 were associated with anxiety and depressive symptoms.

Une étude indique que le symptôme de diarrhée et la nécessité d'oxygénothérapie chez les malades de la covid sont des facteurs de risque pour de possibles séquelles de déficience neurocognitive.

N010

___Neurologic___

Published study on 22-Oct-20:
"Cognitive profile following COVID-19 infection: Clinical predictors leading to neuropsychological impairment"
Une étude indique que le symptôme de diarrhée et la nécessité d'oxygénothérapie chez les malades de la covid sont des facteurs de risque pour de possibles séquelles de déficience neurocognitive.
Link: https://www.sciencedirect.com/science/article/pii/S2666354620301289
Extract: "Highlights
•Neuropsychological deficits related to COVID-19 infection were seen in attention, memory and executive function domains.
•Presenting neurological symptoms during COVID-19 infection were risk factors for cognitive deficit.
•Oxygen therapy, headache and diarrhea were symptoms associated to poor performance in neuropsychological tests.
•Cognitive complains in patients with COVID-19 were associated with anxiety and depressive symptoms."

2199

N117

R

P. Voruz, G. Allali, L. Benzakour, A. Nuber-Champier, M. Thomasson, I. Jacot, J. Pierce, P. Lalive, K-O. Lövblad, O. Braillard, M. Coen, J. Serratrice, J. Pugin, R. Ptak, I. Guessous, B.N. Landis, F. Assal, J.A. Péron

Long COVID neuropsychological deficits after severe, moderate or mild infection

https://doi.org/10.1101/2021.02.24.21252329

pre-print

26-Feb-21

Study

https://www.medrxiv.org/content/10.1101/2021.02.24.21252329v1

Methods Standardized neuropsychological, psychiatric, neurological and olfactory tests were administered to 45 patients (categorized according to the severity of their respiratory symptoms during the acute phase) 236.51 ± 22.54 days post-discharge following SARS-CoV-2 infection.
Results Deficits were found in all the domains of cognition and the prevalence of psychiatric symptoms was also high in the three groups. The severe performed more poorly on long-term episodic memory and exhibited greater anosognosia. The moderate had poorer emotion recognition, which was positively correlated with persistent olfactory dysfunction. The mild were more stressed, anxious and depressed.
Conclusion The data support the hypothesis that the virus targets the central nervous system (and notably the limbic system), and support the notion of different neuropsychological phenotypes.
"Our third level of analysis enabled us to go further in characterizing the hypothesized clinical phenotypes. Quantified results pointed to the presence of at least three profiles (patient clusters), corroborating the clinical impressions we had when interviewing and assessing the patients for this study. Patients with the first (neurological) profile were typically aged about 55 years, mostly men, of average educational level, and a small proportion of them had a history of diabetes, cardiovascular disease, or sleep apnea syndrome. At the cognitive level, these patients displayed long-term memory, executive and language disorders. They had more severe anosognosia for their memory difficulties. Nearly all of them reported sleep disorders and emotional apathy. Patients with the second (psychiatric) profile were aged about 45-50 years, and there were equal numbers of men and women. No significant medical antecedents were noted, and the majority of them had had mild or moderate respiratory disease. At the cognitive level, they displayed executive and attentional dysfunctions, which could influence other cognitive domains (e.g., memory recall strategies). At the psychiatric level, they had high scores for depressive symptoms, anxiety, insomnia and stress, and more sporadically exhibited PTSD and dissociative disorders. Our results also indicated the presence of a third (mixed) profile combining the symptoms and clinical characteristics of the two previously described profiles."
"This study unambiguously demonstrates the presence of long-term neuropsychological sequelae following SARS-CoV-2 infection, regardless of the severity of the respiratory disease in the acute phase. Some of the cognitive deficits could be explained by psychiatric variables, emphasizing the importance of considering a broad range of psychiatric symptoms. However, not all neuropsychological sequelae could be explained by these variables. The presence of correlations between olfaction, emotion recognition and episodic memory, which share common functional and anatomical substrates, reinforces the hypothesis that the virus targets the CNS (and notably the limbic system). Finally, the data support the notion of different clinical phenotypes, paving the way for clinical guidelines and recommendations for the management of long-term neurological impairment following SARS-CoV-2 infection."

Une étude en pre-print (non relue et non publiée) a suivi sur 6-9 mois des patients atteints d'une covid légère, modérée et sévère avec des tests neurologiques et psychiatriques standardisés. Les auteurs notent que certaines séquelles neurologiques sont liées sans ambiguïté à l'infection au SARS-CoV-2. Enfin, l'étude distingue trois profils de patients, selon des phénotypes neuropsychiatriques, mais rappelle que des biais de sélection peuvent affecter les résultats.

Les patients présentant le premier profil (neurologique) étaient généralement âgés d'environ 55 ans, principalement des hommes, d'un niveau d'éducation moyen, et une petite proportion d'entre eux avaient des antécédents de diabète, de maladie cardiovasculaire ou de syndrome d'apnée du sommeil. Au niveau cognitif, ces patients présentaient des troubles de la mémoire, de l'exécutif et du langage à long terme. Ils avaient une anosognosie plus sévère en raison de leurs difficultés de mémoire. Presque tous ont signalé des troubles du sommeil et une apathie émotionnelle. Les patients avec le deuxième profil (psychiatrique) étaient âgés d'environ 45 à 50 ans, et il y avait un nombre égal d'hommes et de femmes. Aucun antécédent médical significatif n'a été noté et la majorité d'entre eux avaient une maladie respiratoire légère ou modérée. Au niveau cognitif, ils présentaient des dysfonctionnements exécutifs et attentionnels, qui pouvaient influencer d'autres domaines cognitifs (par exemple, les stratégies de rappel de mémoire). Au niveau psychiatrique, ils avaient des scores élevés pour les symptômes dépressifs, l'anxiété, l'insomnie et le stress, et présentaient plus sporadiquement le SSPT et les troubles dissociatifs. Nos résultats indiquent également la présence d'un troisième profil (mixte) combinant les symptômes et les caractéristiques cliniques des deux profils précédemment décrits.

Cette étude démontre sans ambiguïté la présence de séquelles neuropsychologiques à long terme suite à une infection par le SRAS-CoV-2, quelle que soit la gravité de la maladie respiratoire en phase aiguë. Certains des déficits cognitifs pourraient être expliqués par des variables psychiatriques, soulignant l'importance de considérer un large éventail de symptômes psychiatriques. Cependant, toutes les séquelles neuropsychologiques ne peuvent être expliquées par ces variables. La présence de corrélations entre l'olfaction, la reconnaissance des émotions et la mémoire épisodique, qui partagent des substrats fonctionnels et anatomiques communs, renforce l'hypothèse que le virus cible le SNC (et notamment le système limbique). Enfin, les données soutiennent la notion de différents phénotypes cliniques, ouvrant la voie à des lignes directrices cliniques et des recommandations pour la gestion des troubles neurologiques à long terme suite à une infection par le SRAS-CoV-2.

2200

N118

RitwikGhoshaDipayanRoybArpanMandalaShyamal KantiPalaBikashChandra SwaikaaDinabandhuNagaaAlakPanditcBiman KantiRaycJuliánBenito-León

Cerebral venous thrombosis in COVID-19

https://doi.org/10.1016/j.dsx.2021.04.026

Published

18-May-21

Review

https://www.sciencedirect.com/science/article/pii/S1871402121001387

Highlights
•CVT should be listed among the neurological manifestations of COVID-19.
•The hypercoagulable state is thought to be the main mechanism in COVID-19 related CVT.
•Headache, seizures, and stroke-like/encephalopathy symptoms in the setting of COVID-19 should prompt to rule out CVT.

_

2201

N119

Jonathan P Rogers, MRCPsych †
Edward Chesney, MRCPsych †
Dominic Oliver, MSc
Thomas A Pollak, PhD
Prof Philip McGuire, FMedSci
Paolo Fusar-Poli, PhD
Michael S Zandi, PhD
Prof Glyn Lewis, PhD
Prof Anthony S David, FMedSci

Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic

https://doi.org/10.1016/S2215-0366(20)30203-0

Published

18-May-20

Meta-analysis

https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(20)30203-0/fulltext

If infection with SARS-CoV-2 follows a similar course to that with SARS-CoV or MERS-CoV, most patients should recover without experiencing mental illness. SARS-CoV-2 might cause delirium in a significant proportion of patients in the acute stage. Clinicians should be aware of the possibility of depression, anxiety, fatigue, post-traumatic stress disorder, and rarer neuropsychiatric syndromes in the longer term.

Une méta-analyse sur les séquelles neurologiques et psychiatriques comparées du SRAS, du MERS, au regard du SARS-CoV-2.

2202

N120

Arvid Edén, Nelly Kanberg, Johanna Gostner, Dietmar Fuchs, Lars Hagberg, Lars-Magnus Andersson, Magnus Lindh, Richard W. Price, Henrik Zetterberg, Magnus Gisslén

CSF Biomarkers in Patients With COVID-19 and Neurologic Symptoms
A Case Series

https://doi.org/10.1212/WNL.0000000000010977

Published

12-Jan-21

Case Series

https://n.neurology.org/content/96/2/e294

Our results in patients with COVID-19 and neurologic symptoms suggest an unusual pattern of marked CSF inflammation in which soluble markers were increased but white cell response and other immunologic features typical of CNS viral infections were absent. While our initial hypothesis centered on CNS SARS-CoV-2 invasion, we could not convincingly detect SARS-CoV-2 as the underlying driver of CNS inflammation. These features distinguish COVID-19 CSF from other viral CNS infections and raise fundamental questions about the CNS pathobiology of SARS-CoV-2 infection.

Une étude de cas dans la revue Neurology remarque chez les malades de la covid souffrant de troubles neurologiques un schéma inhabituel d'inflammation marquée du liquide cérébro-spinal, mais sans caractéristiques typiques des infections virales.

N011

___Neurologic___

Published case series on 12-Jan-21:
"CSF Biomarkers in Patients With COVID-19 and Neurologic Symptoms
A Case Series"
Une étude de cas dans la revue Neurology remarque chez les malades de la covid souffrant de troubles neurologiques un schéma inhabituel d'inflammation marquée du liquide cérébro-spinal, mais sans caractéristiques typiques des infections virales.
Link: https://n.neurology.org/content/96/2/e294
Extract: "Our results in patients with COVID-19 and neurologic symptoms suggest an unusual pattern of marked CSF inflammation in which soluble markers were increased but white cell response and other immunologic features typical of CNS viral infections were absent. While our initial hypothesis centered on CNS SARS-CoV-2 invasion, we could not convincingly detect SARS-CoV-2 as the underlying driver of CNS inflammation. These features distinguish COVID-19 CSF from other viral CNS infections and raise fundamental questions about the CNS pathobiology of SARS-CoV-2 infection."

2203

N121

Jennifer A. Frontera, Sakinah Sabadia, Rebecca Lalchan, Taolin Fang, Brent Flusty, Patricio Millar-Vernetti, Thomas Wisniewski, Andrea B. Troxel, Laura Balcer, Steven Galetta

A Prospective Study of Neurologic Disorders in Hospitalized Patients With COVID-19 in New York City

https://doi.org/10.1212/WNL.0000000000010979

Published

26-Jan-21

Study

https://n.neurology.org/content/96/4/e575

Neurologic disorders were detected in 13.5% of patients with COVID-19 and were associated with increased risk of in-hospital mortality and decreased likelihood of discharge home. Many observed neurologic disorders may be sequelae of severe systemic illness.

_

2204

N122

Abhishek Jaywant, W. Michael Vanderlind, George S. Alexopoulos, Chaya B. Fridman, Roy H. Perlis & Faith M. Gunning

Frequency and profile of objective cognitive deficits in hospitalized patients recovering from COVID-19

https://doi.org/10.1038/s41386-021-00978-8

Published

15-Feb-21

Study

https://www.nature.com/articles/s41386-021-00978-8

We evaluated the frequency, severity, and profile of cognitive dysfunction in patients recovering from prolonged COVID-19 hospitalization who required acute inpatient rehabilitation prior to discharge. We analyzed cross-sectional scores from the Brief Memory and Executive Test (BMET) in a cohort of N = 57 COVID-19 patients undergoing inpatient rehabilitation, calculating the frequency of impairment based on neuropsychologist diagnosis and by age-normed BMET subtests. In total, 43 patients (75%) were male, 35 (61%) were non-white, and mean age was 64.5 (SD = 13.9) years. In total, 48 (84%) were previously living at home independently. Two patients had documented preexisting cognitive dysfunction; none had known dementia. Patients were evaluated at a mean of 43.2 (SD = 19.2) days after initial admission. In total, 50 patients (88%) had documented hypoxemic respiratory failure and 44 (77%) required intubation. Forty-six patients (81%) had cognitive impairment, ranging from mild to severe. Deficits were common in working memory (26/47 [55%] of patients), set-shifting (21/44 [47%]), divided attention (18/39 [46%]), and processing speed (14/35 [40%]).

_

2205

N123

Stéphane Kremer, François Lersy, Mathieu Anheim, Hamid Merdji, Maleka Schenck, Hélène Oesterlé, Federico Bolognini, Olivier Collange, Paul Michel Mertes, Francis Schneider, Samira Fafi-Kremer, Mickael Ohana, Ferhat Meziani, Nicolas Meyer, Julie Helms, François Cotton

Neurologic and neuroimaging findings in patients with COVID-19
A retrospective multicenter study

https://doi.org/10.1212/WNL.0000000000010112

Published

29-Sep-20

Study

https://n.neurology.org/content/95/13/e1868

Patients with COVID-19 may develop a wide range of neurologic symptoms, which can be associated with severe and fatal complications such as ischemic stroke or encephalitis. In terms of meningoencephalitis involvement, even if a direct effect of the virus cannot be excluded, the pathophysiology seems to involve an immune or inflammatory process given the presence of signs of inflammation in both CSF and neuroimaging but the lack of virus in CSF.

_

2206

N124

R. Méndez, V. Balanzá-Martínez, S.C. Luperdi, I. Estrada, A. Latorre, P. González-Jiménez, L. Feced, L. Bouzas, K. Yépez, A. Ferrando, D. Hervás, E. Zaldívar, S. Reyes, M. Berk, R. Menéndez

Short-term neuropsychiatric outcomes and quality of life in COVID-19 survivors

https://doi.org/10.1111/joim.13262

Published

3-Feb-21

Study

https://onlinelibrary.wiley.com/doi/10.1111/joim.13262

Results
Of the 229 screened patients, 179 were included in the final analysis. Amongst survivors, the prevalence of moderately impaired immediate verbal memory and learning was 38%, delayed verbal memory (11.8%), verbal fluency (34.6%) and working memory (executive function) (6.1%), respectively. Moreover, 58.7% of patients had neurocognitive impairment in at least one function. Rates of positive screening for anxiety, depression and post-traumatic stress disorder were 29.6%, 26.8% and 25.1%, respectively. In addition, 39.1% of the patients had psychiatric morbidity. Low QoL for physical and mental components was detected in 44.1% and 39.1% of patients respectively. Delirium and psychiatric morbidity were associated with neurocognitive impairment, and female gender was related with psychiatric morbidity.

Conclusion
Hospitalized COVID-19 survivors showed a considerable prevalence of neurocognitive impairment, psychiatric morbidity and poor QoL in the short term. It is uncertain if these impacts persist over the long term.

_

2207

N125

Domenico Nuzzo , Gaetano Cambula 3 ,Ignazio Bacile, Manfredi Rizzo 4, Massimo Galia , Paola Mangiapane 6, Pasquale Picone 1,2, Daniela Giacomazza 7 and Luca Scalisi

Long-Term Brain Disorders in Post Covid-19 Neurological Syndrome (PCNS) Patient

https://doi.org/10.3390/brainsci11040454

Published

2-Apr-21

Case Report

https://www.mdpi.com/2076-3425/11/4/454/htm

The aim of this article is to describe the prolonged neurological clinical consequences related to COVID-19. We believe it is clinically clear that we can define a post-acute COVID-19 neurological syndrome. Therefore, in patients after a severe clinical condition of COVID-19, a deepening of persistent neurological signs is necessary.

_

2208

N126

Maithili Sashindranath, Harshal H. Nandurkar

Endothelial Dysfunction in the Brain
Setting the Stage for Stroke and Other Cerebrovascular Complications of COVID-19

https://doi.org/10.1161/STROKEAHA.120.032711

Published

2-Apr-21

Study

https://www.ahajournals.org/doi/10.1161/STROKEAHA.120.032711

Together with findings of fibrin-rich microthrombi, widespread extracellular fibrin deposition in affected various organs and hypercytokinemia, this suggests that COVID-19 is more than a pulmonary viral infection. Evidently, COVID-19 is a thrombo-inflammatory disease. Endothelial cells that constitute the lining of blood vessels are the primary targets of a thrombo-inflammatory response, and severe acute respiratory syndrome coronavirus 2 also directly infects endothelial cells through the ACE2 (angiotensin-converting enzyme 2) receptor. Being highly heterogeneous in their structure and function, differences in the endothelial cells may govern the susceptibility of organs to COVID-19. Here, we have explored how the unique characteristics of the cerebral endothelium may be the underlying reason for the increased rates of cerebrovascular pathology associated with COVID-19.

Des chercheurs dans une étude australienne évoquent le rôle particulier de l'endothélium vasculaire et les dommages qu'il subit. Ces derniers sont, selon les auteurs, impliqués dans les symptômes neurologiques.

N011

___Neurologic___

Published study on 2-Apr-21:
"Endothelial Dysfunction in the Brain
Setting the Stage for Stroke and Other Cerebrovascular Complications of COVID-19"
Des chercheurs dans une étude australienne évoquent le rôle particulier de l'endothélium vasculaire et les dommages qu'il subit. Ces derniers sont, selon les auteurs, impliqués dans les symptômes neurologiques.
Link: https://www.ahajournals.org/doi/10.1161/STROKEAHA.120.032711
Extract: "Together with findings of fibrin-rich microthrombi, widespread extracellular fibrin deposition in affected various organs and hypercytokinemia, this suggests that COVID-19 is more than a pulmonary viral infection. Evidently, COVID-19 is a thrombo-inflammatory disease. Endothelial cells that constitute the lining of blood vessels are the primary targets of a thrombo-inflammatory response, and severe acute respiratory syndrome coronavirus 2 also directly infects endothelial cells through the ACE2 (angiotensin-converting enzyme 2) receptor. Being highly heterogeneous in their structure and function, differences in the endothelial cells may govern the susceptibility of organs to COVID-19. Here, we have explored how the unique characteristics of the cerebral endothelium may be the underlying reason for the increased rates of cerebrovascular pathology associated with COVID-19."

2209

N127

Matteo Bocci, Clara Oudenaarden, Xavier Sàenz-Sardà, Joel Simrén, Arvid Edén, Jonas Sjölund, Christina Möller, Magnus Gisslén, Henrik Zetterberg, Elisabet Englund, Kristian Pietras

Infection of brain pericytes underlying neuropathology of COVID-19 patients

https://doi.org/10.1101/2021.05.24.445532

pre-print

25-May-21

Study

https://www.biorxiv.org/content/10.1101/2021.05.24.445532v1

Here, we used state-of-the-art multiplexed immunostaining of human brains (n = 6 COVID-19, median age = 69,5 years; and n = 7 control, median age = 68 years), and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in peri-vascular cells. Viral particles were identified in the vascular wall and paralleled by peri-vascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood-brain barrier. Notably, cerebrospinal fluid from an additional 16 individuals (n = 8 COVID-19, median age = 67 years; and n = 8 control, median age = 69,5 years) exhibited significantly lower levels of the pericyte marker PDGFRβ in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis.

We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to peri-vascular inflammation and a locally compromised blood-brain barrier.

Un travail en pre-print (étude non encore relue ni publiée) estime que l'infection par le SARS-CoV-2 des péricytes (cellules qui entourent les capillaires) permet l'entrée du virus dans le système nerveux central, et explique la symptomatologie neurologique.
Selon les auteurs, les symptômes neurologiques sont notamment dus à l'inflammation périvasculaire et aux dommages sur la barrière hémato-encéphalique.

2210

N128

Benjamin, Butler, Matthew, Song, Jia, Hafeez, Danish, Morrin, Hamilton, Rengasamy, Emma Rachel, Thomas, Lucretia, Ralovska, Silviya, Smakowski, Abigail, Sundaram, Ritika Dilip, Hunt, Camille Kaitlyn, Lim, Mao Fong, Aniwattanapong, Daruj, Singh, Vanshika, Hussain, Zain, Chakraborty, Stuti, Burchill, Ella, Jansen, Katrin, Holling, Heinz, Walton, Dean, Pollak, Thomas A, Ellul, Mark, Koychev, Ivan, Solomon, Tom, Michael, Benedict Daniel, Nicholson, Timothy R, Rooney, Alasdair G

Neurology and neuropsychiatry of COVID-19: a systematic review and meta-analysis of the early literature reveals frequent CNS manifestations and key emerging narratives

https://doi.org/10.1136/jnnp-2021-326405

Published

3-Jun-21

Systematic review and meta-analysis

https://jnnp.bmj.com/content/early/2021/06/03/jnnp-2021-326405

In our review, we summarise point prevalence of 20 neurological and neuropsychiatric complications of COVID-19. The most frequently studied symptoms were heavily weighted towards non-specific features of systemic illness, such as headache, myalgia, fatigue, anosmia and dysgeusia, which are unlikely to be ‘primary’ neurological symptoms. It was predominantly these more non-specific symptoms that were found to have the highest prevalences, ranging from 20.7% (16.1% to 26.1%) to 43.1% (35.2% to 51.3%) (headache and anosmia, respectively). Of note, more specific neurological and neuropsychiatric symptoms such as altered mental status, depression, anxiety, sleep disorder, stroke and seizures were less frequently studied. However, the core psychiatric disorders of depression (23.0% (11.8% to 40.2%)) and anxiety (15.9% (5.6% to 37.7%)) appeared to be highly prevalent. The reported prevalence of major neurological disorders such as ischaemic stroke (1.9% (1.3% to 2.8%)), haemorrhagic stroke (0.4% (0.3% to 0.7%)) and seizure (0.06% (0.06% to 0.07%)) were substantially lower.

Dans le BMJ, une revue systématique d'études et une très large méta-analyse sur les manifestations neurologiques et psychiatriques de la covid. les auteurs notent qu'il pourrait y avoir une sous-estimation de la prévalence de ces symptômes. L'étude conclut que le covid long est susceptible d'être une entité hétérogène avec une étiologie multifactorielle, comprenant la persistance virale, des dérèglements inflammatoires, un déconditionnement physique et des facteurs psychologiques.

N011

___Neurologic___

Published systematic review and meta-analysis on 3-Jun-21:
"Neurology and neuropsychiatry of COVID-19: a systematic review and meta-analysis of the early literature reveals frequent CNS manifestations and key emerging narratives"
Dans le BMJ, une revue systématique d'études et une très large méta-analyse sur les manifestations neurologiques et psychiatriques de la covid. les auteurs notent qu'il pourrait y avoir une sous-estimation de la prévalence de ces symptômes. L'étude conclut que le covid long est susceptible d'être une entité hétérogène avec une étiologie multifactorielle, comprenant la persistance virale, des dérèglements inflammatoires, un déconditionnement physique et des facteurs psychologiques.
Link: https://jnnp.bmj.com/content/early/2021/06/03/jnnp-2021-326405
Extract: "In our review, we summarise point prevalence of 20 neurological and neuropsychiatric complications of COVID-19. The most frequently studied symptoms were heavily weighted towards non-specific features of systemic illness, such as headache, myalgia, fatigue, anosmia and dysgeusia, which are unlikely to be ‘primary’ neurological symptoms. It was predominantly these more non-specific symptoms that were found to have the highest prevalences, ranging from 20.7% (16.1% to 26.1%) to 43.1% (35.2% to 51.3%) (headache and anosmia, respectively). Of note, more specific neurological and neuropsychiatric symptoms such as altered mental status, depression, anxiety, sleep disorder, stroke and seizures were less frequently studied. However, the core psychiatric disorders of depression (23.0% (11.8% to 40.2%)) and anxiety (15.9% (5.6% to 37.7%)) appeared to be highly prevalent. The reported prevalence of major neurological disorders such as ischaemic stroke (1.9% (1.3% to 2.8%)), haemorrhagic stroke (0.4% (0.3% to 0.7%)) and seizure (0.06% (0.06% to 0.07%)) were substantially lower."

2211

N129

Thomas Müller

Long COVID - Langzeitfolgen durch chronische Neuroinflammation?

https://doi.org/10.1007/s15202-021-4692-8

Published

10-Jun-21

Review

https://link.springer.com/article/10.1007/s15202-021-4692-8

Es trifft nicht nur die Alten und Schwerkranken: Die meisten Patienten mit Long COVID sind relativ jung und haben die Infektion zuhause durchgemacht. Experten vermuten eine chronische Neuroinflammation als Ursache.

2212

N130

Maria A. Garcia Paula V. Barreras Allie Lewis Gabriel Pinilla Lori J. Sokoll Thomas Kickler Heba Mostafa Mario Caturegli Abhay Moghekar Kathryn C. Fitzgerald Hopkins Neuro-COVID-19 Group Carlos A. Pardo

Cerebrospinal fluid in COVID-19 neurological complications: Neuroaxonal damage, anti-SARS-Cov2 antibodies but no evidence of cytokine storm

https://doi.org/10.1016/j.jns.2021.117517

Published

31-May-21

Study

https://www.jns-journal.com/article/S0022-510X(21)00211-2/fulltext

Highlights
•A case-control study of CSF showed a paucity of neuroinflammation changes in CSF of COVID-19 neurological complications.
•No evidence of “cytokine storm” was observed in COVID-19 complications such as stroke and encephalopathy
•Subsets of CSF cytokine increases are not exclusive of COVID-19 strokes as they are present in non-COVID-19 stroke controls.
•No evidence of SARS-CoV2 viral RNA was observed in the CSF.
•A high frequency of anti-SARS-CoV2 spike protein IgG antibodies (77% of cases) was observed in CSF from COVID-19 neurological complications
•Increase of CSF neurofilament light chain and C-reactive protein was prominent in critical and severe COVID-19 cases
CSF from COVID-19 subjects showed absence of pleocytosis or specific increases in pro-inflammatory markers (IL-6, ferritin, or D-dimer). Although pro-inflammatory cytokines (IL-6, TNFα, IL-12p70) and IL-10 were increased in CSF of stroke COVID-19 subjects, a similar increase was observed in non-COVID-19 stroke subjects. Anti-SARS-CoV2 antibodies in CSF of COVID-19 subjects (77%) were observed despite no evidence of SARS-CoV2 viral RNA. CSF-NF-L was elevated in subjects with stroke and critical COVID-19 as compared to controls and other COVID-19 severity categories. CSF-hsCRP was present in all subjects with critical stages of COVID-19 (7/18) but only in 1/82 controls.

2213

N131

Don A. Davies, Aida Adlimoghaddam & Benedict C. Albensi

The Effect of COVID-19 on NF-κB and Neurological Manifestations of Disease

https://doi.org/10.1007/s12035-021-02438-2

Published

1-Jun-21

Article

https://link.springer.com/article/10.1007/s12035-021-02438-2

Neurological symptoms in COVID-19 patients may arise due to a cytokine storm and a heighten state of inflammation. The nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) is a central pathway involved with inflammation and is shown to be elevated in a dose-dependent matter in response to coronaviruses. NF-κB has a role in cytokine storm syndrome, which is associated with greater severity in COVID-19-related symptoms. Therefore, therapeutics that reduce the NF-κB pathway should be considered in the treatment of COVID-19. Neuro-COVID-19 units have been established across the world to examine the neurological symptoms associated with COVID-19. Neuro-COVID-19 is increasingly becoming an accepted term among scientists and clinicians, and interdisciplinary teams should be created to implement strategies for treating the wide range of neurological symptoms observed in COVID-19 patients.

Une étude suggère que des thérapies visant à réduire la voie de la protéine NF-κB devraient être envisagées dans le traitement de la covid, pour limiter les séquelles neurologiques ("le neuro-covid").

N011

___Neurologic___

Published article on 1-Jun-21:
"The Effect of COVID-19 on NF-κB and Neurological Manifestations of Disease"
Une étude suggère que des thérapies visant à réduire la voie de la protéine NF-κB devraient être envisagées dans le traitement de la covid, pour limiter les séquelles neurologiques ("le neuro-covid").
Link: https://link.springer.com/article/10.1007/s12035-021-02438-2
Extract: "Neurological symptoms in COVID-19 patients may arise due to a cytokine storm and a heighten state of inflammation. The nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) is a central pathway involved with inflammation and is shown to be elevated in a dose-dependent matter in response to coronaviruses. NF-κB has a role in cytokine storm syndrome, which is associated with greater severity in COVID-19-related symptoms. Therefore, therapeutics that reduce the NF-κB pathway should be considered in the treatment of COVID-19. Neuro-COVID-19 units have been established across the world to examine the neurological symptoms associated with COVID-19. Neuro-COVID-19 is increasingly becoming an accepted term among scientists and clinicians, and interdisciplinary teams should be created to implement strategies for treating the wide range of neurological symptoms observed in COVID-19 patients."

2214

N132

Nils Kappelmann,a,b,⁎ Robert Dantzer,c and Golam M. Khandakerd,e,f,g

Interleukin-6 as potential mediator of long-term neuropsychiatric symptoms of COVID-19

https://dx.doi.org/10.1016%2Fj.psyneuen.2021.105295

Published

3-Jun-21

Article

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172271/

The majority of COVID-19 survivors experience long-term neuropsychiatric symptoms such as fatigue, sleeping difficulties, depression and anxiety. We propose that neuroimmune cross-talk via inflammatory cytokines such as interleukin-6 (IL-6) could underpin these long-term COVID-19 symptoms. This hypothesis is supported by several lines of research, including population-based cohort and genetic Mendelian Randomisation studies suggesting that inflammation is associated with fatigue and sleeping difficulties, and that IL-6 could represent a possible causal driver for these symptoms. Immune activation following COVID-19 can disrupt T helper 17 (TH17) and regulatory T (Treg) cell responses, affect central learning and emotional processes, and lead to a vicious cycle of inflammation and mitochondrial dysfunction that amplifies the inflammatory process and results in immuno-metabolic constraints on neuronal energy metabolism, with fatigue being the ultimate result. Increased cytokine activity drives this process and could be targeted to interrupt it. Therefore, whether persistent IL-6 dysregulation contributes to COVID-19-related long-term fatigue, sleeping difficulties, depression, and anxiety, and whether targeting IL-6 pathways could be helpful for treatment and prevention of long COVID are important questions that require investigation. This line of research could inform new approaches for treatment and prevention of long-term neuropsychiatric symptoms of COVID-19. Effective treatment and prevention of this condition could also help to stem the anticipated rise in depression and other mental illnesses ensuing this pandemic.

Des chercheurs font la supposition que les échanges neuro-immuns d'interleukine-6 (IL-6) qui marquent l'inflammation cytokinique participent aux symptômes neuropsychiatriques prolongés. Viser cette voie des IL-6 serait un possible traitement du covid long.

N011

___Neurologic___

Published article on 3-Jun-21:
"Interleukin-6 as potential mediator of long-term neuropsychiatric symptoms of COVID-19"
Des chercheurs font la supposition que les échanges neuro-immuns d'interleukine-6 (IL-6) qui marquent l'inflammation cytokinique participent aux symptômes neuropsychiatriques prolongés. Viser cette voie des IL-6 serait un possible traitement du covid long.
Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172271/
Extract: "The majority of COVID-19 survivors experience long-term neuropsychiatric symptoms such as fatigue, sleeping difficulties, depression and anxiety. We propose that neuroimmune cross-talk via inflammatory cytokines such as interleukin-6 (IL-6) could underpin these long-term COVID-19 symptoms. This hypothesis is supported by several lines of research, including population-based cohort and genetic Mendelian Randomisation studies suggesting that inflammation is associated with fatigue and sleeping difficulties, and that IL-6 could represent a possible causal driver for these symptoms. Immune activation following COVID-19 can disrupt T helper 17 (TH17) and regulatory T (Treg) cell responses, affect central learning and emotional processes, and lead to a vicious cycle of inflammation and mitochondrial dysfunction that amplifies the inflammatory process and results in immuno-metabolic constraints on neuronal energy metabolism, with fatigue being the ultimate result. Increased cytokine activity drives this process and could be targeted to interrupt it. Therefore, whether persistent IL-6 dysregulation contributes to COVID-19-related long-term fatigue, sleeping difficulties, depression, and anxiety, and whether targeting IL-6 pathways could be helpful for treatment and prevention of long COVID are important questions that require investigation. This line of research could inform new approaches for treatment and prevention of long-term neuropsychiatric symptoms of COVID-19. Effective treatment and prevention of this condition could also help to stem the anticipated rise in depression and other mental illnesses ensuing this pandemic."

2215

N133

Medha Karnik, Narasimha M. Beeraka, Chinnappa A. Uthaiah, Suma M. Nataraj, Anjali Devi S. Bettadapura, Gjumrakch Aliev & SubbaRao V. Madhunapantula

A Review on SARS-CoV-2-Induced Neuroinflammation, Neurodevelopmental Complications, and Recent Updates on the Vaccine Development

https://doi.org/10.1007/s12035-021-02399-6

Published

5-Jun-21

Review

https://link.springer.com/article/10.1007/s12035-021-02399-6

In this review, we have attempted to highlight the landmark discoveries that lead to the development of various vaccines that are currently under different stages of clinical progression. Besides, a brief account of various drug candidates that are being tested to mitigate the burden of COVID-19 was also covered. Further, in a dedicated section, the impact of SARS-CoV-2 infection on neuronal inflammation and neuronal disorders was discussed. In summary, it is expected that the content covered in this article help to understand the pathophysiology of COVID-19 and the impact on neuronal complications induced by SARS-CoV-2 infection while providing an update on the vaccine development.

2216

N134

Amarnath Sen

Does serotonin deficiency lead to anosmia, ageusia, dysfunctional chemesthesis and increaed severity of illness in COVID-19?

https://dx.doi.org/10.1016%2Fj.mehy.2021.110627

Published

6-Jun-21

Article

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180092/

Different mechanisms forwarded to understand anosmia and ageusia in coronavirus patients are not adequate to explain reversible anosmia and ageusia, which are resolved quickly. In addition, the reason behind the impaired chemesthetic sensations in some coronavirus patients remains unknown. In the present paper it is proposed that SARS-CoV-2 patients suffer from depletion of tryptophan, as ACE2, a key element in the process of absorption of tryptophan from the food, is significantly reduced in the patients as coronavirus uses ACE2 as the receptor to enter the host cells. The tryptophan depletion leads to a deficit of serotonin (5-HT) in SARS-COV-2 patients because tryptophan is the precursor in the synthesis of 5-HT. Such 5-HT deficiency can explain anosmia, ageusia and dysfunctional chemesthesis in COVID-19, given the fact that 5-HT is an important neuromodulator in the olfactory neurons, taste receptor cells and transient receptor potential channels (TRP channels) involved in chemesthesis. In addition, 5-HT deficiency worsens silent hypoxemia and depresses hypoxic pulmonary vasoconstriction leading to increased severity of the disease. Also, the levels of anti-inflammatory melatonin (synthesized from 5-HT) and nicotinamide adenine dinucleotide (NAD+, produced from niacin whose precursor is the tryptophan) might decrease in coronavirus patients resulting in the aggravation of the disease. Interestingly, selective serotonin reuptake inhibitors (SSRIs) may not be of much help in correcting the 5-HT deficiency in COVID-19 patients, as their efficacy goes down significantly when there is depletion of tryptophan in the system. Hence, tryptophan supplementation may herald a radical change in the treatment of COVID-19 and accordingly, clinical trials (therapeutic / prophylactic) should be conducted on coronavirus patients to find out how tryptophan supplementation (oral or parenteral, the latter in severe cases where there is hardly any absorption of tryptophan from the food) helps in curing, relieving or preventing the olfactory, gustatory and chemesthetic dysfunctions and in lessening the severity of the disease.

Une étude émet l'hypothèse que l'anosmie et la réactivité chimique des membranes, observés comme symptômes prolongés de la covid, trouvent leur origine dans un déficit en sérotonine qui serait déclenché par l'appauvrissement en tryptophane, un acide aminé.

N014E

___Neurologic___

Published article on 6-Jun-21:
"Does serotonin deficiency lead to anosmia, ageusia, dysfunctional chemesthesis and increaed severity of illness in COVID-19?"
Une étude émet l'hypothèse que l'anosmie et la réactivité chimique des membranes, observés comme symptômes prolongés de la covid, trouvent leur origine dans un déficit en sérotonine qui serait déclenché par l'appauvrissement en tryptophane, un acide aminé.
Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180092/
Extract: "Different mechanisms forwarded to understand anosmia and ageusia in coronavirus patients are not adequate to explain reversible anosmia and ageusia, which are resolved quickly. In addition, the reason behind the impaired chemesthetic sensations in some coronavirus patients remains unknown. In the present paper it is proposed that SARS-CoV-2 patients suffer from depletion of tryptophan, as ACE2, a key element in the process of absorption of tryptophan from the food, is significantly reduced in the patients as coronavirus uses ACE2 as the receptor to enter the host cells. The tryptophan depletion leads to a deficit of serotonin (5-HT) in SARS-COV-2 patients because tryptophan is the precursor in the synthesis of 5-HT. Such 5-HT deficiency can explain anosmia, ageusia and dysfunctional chemesthesis in COVID-19, given the fact that 5-HT is an important neuromodulator in the olfactory neurons, taste receptor cells and transient receptor potential channels (TRP channels) involved in chemesthesis. In addition, 5-HT deficiency worsens silent hypoxemia and depresses hypoxic pulmonary vasoconstriction leading to increased severity of the disease. Also, the levels of anti-inflammatory melatonin (synthesized from 5-HT) and nicotinamide adenine dinucleotide (NAD+, produced from niacin whose precursor is the tryptophan) might decrease in coronavirus patients resulting in the aggravation of the disease. Interestingly, selective serotonin reuptake inhibitors (SSRIs) may not be of much help in correcting the 5-HT deficiency in COVID-19 patients, as their efficacy goes down significantly when there is depletion of tryptophan in the system. Hence, tryptophan supplementation may herald a radical change in the treatment of COVID-19 and accordingly, clinical trials (therapeutic / prophylactic) should be conducted on coronavirus patients to find out how tryptophan supplementation (oral or parenteral, the latter in severe cases where there is hardly any absorption of tryptophan from the food) helps in curing, relieving or preventing the olfactory, gustatory and chemesthetic dysfunctions and in lessening the severity of the disease."

2217

N135

Virginia F. J. Newcombe, Neha S. Dangayach & Romain Sonneville

Neurological complications of COVID-19

https://doi.org/10.1007/s00134-021-06439-6

Published

7-Jun-21

Article

https://link.springer.com/article/10.1007/s00134-021-06439-6

We discuss the neurological complications associated with COVID-19 (NeuroCOVID) for general intensivists with an emphasis on key symptoms and signs to look for which may change management and/or provide a potential avenue for targeted therapies to improve outcomes.

2218

N136

Bassetti Claudio L. A., Jung Simon, Helbok Raimund

«Le spectre neurologique du COVID-19»

https://doi.org/10.4414/fms.2021.08813

Published

Review

https://medicalforum.ch/fr/detail/doi/fms.2021.08813

Afin d’obtenir un aperçu objectif des manifestations neurologiques durant la maladie aiguë et de pouvoir évaluer les conséquences à long terme potentielles du COVID-19, à la fois l’Organisation mondiale de la santé (OMS) et, plus tôt déjà, diverses sociétés de neurologie («World Federation of Neurology», EAN, «Österreichische Gesellschaft für Neurologie», «Deutsche Gesellschaft für Neurologie», «Deutsche Gesellschaft für Neurointensiv- und Notfallmedizin», «Neurocritical Care Society») ont appelé à recenser le mieux possible les patients dans un registre prospectif [7, 39]. L’objectif de ces initiatives est de parvenir à une définition exacte des manifestations neurologiques. Il convient de mentionner le registre ENERGY de l’EAN, qui se focalise sur les manifestations neurologiques durant la maladie aiguë avec un suivi allant jusqu’à un an (covidregistry@ean.org). Plus de 1100 cas de patients issus de 30 pays situés sur trois continents ont déjà été entrés dans le registre. L’EAN a en outre établi une coopération avec la «Neurocritical Care Society» («Global Consortium Study of Neurological Dysfunction in COVID-19» [GCS-NeuroCOVID]) et dispose ainsi de la plus longue portée à ce jour pour évaluer les complications neurologiques [39]. L’intérêt de la communauté neurologique a ainsi certainement été éveillé [40].

De cette façon, il sera possible de remédier aux incertitudes qui persistent encore: Lesquels des symptômes et maladies neurologiques rapportés jusqu’à présent correspondent à une atteinte spécifique du système nerveux? Quels symptômes ou maladies correspondent à un effet non spécifique du COVID-19 sur le système nerveux? Et quels symptômes correspondent à une manifestation concomitante fortuite?

Un article en français dresse un état des connaissances sur les atteintes neurologiques liées à la covid.
Il évoque la pathogenèse, les manifestations, et souligne le peu de traitements spécifiques proposés concernant ces symptômes.

N011

___Neurologic___

Published review on :
"«Le spectre neurologique du COVID-19»"
Un article en français dresse un état des connaissances sur les atteintes neurologiques liées à la covid.
Il évoque la pathogenèse, les manifestations, et souligne le peu de traitements spécifiques proposés concernant ces symptômes.
Link: https://medicalforum.ch/fr/detail/doi/fms.2021.08813
Extract: "Afin d’obtenir un aperçu objectif des manifestations neurologiques durant la maladie aiguë et de pouvoir évaluer les conséquences à long terme potentielles du COVID-19, à la fois l’Organisation mondiale de la santé (OMS) et, plus tôt déjà, diverses sociétés de neurologie («World Federation of Neurology», EAN, «Österreichische Gesellschaft für Neurologie», «Deutsche Gesellschaft für Neurologie», «Deutsche Gesellschaft für Neurointensiv- und Notfallmedizin», «Neurocritical Care Society») ont appelé à recenser le mieux possible les patients dans un registre prospectif [7, 39]. L’objectif de ces initiatives est de parvenir à une définition exacte des manifestations neurologiques. Il convient de mentionner le registre ENERGY de l’EAN, qui se focalise sur les manifestations neurologiques durant la maladie aiguë avec un suivi allant jusqu’à un an (covidregistry@ean.org). Plus de 1100 cas de patients issus de 30 pays situés sur trois continents ont déjà été entrés dans le registre. L’EAN a en outre établi une coopération avec la «Neurocritical Care Society» («Global Consortium Study of Neurological Dysfunction in COVID-19» [GCS-NeuroCOVID]) et dispose ainsi de la plus longue portée à ce jour pour évaluer les complications neurologiques [39]. L’intérêt de la communauté neurologique a ainsi certainement été éveillé [40].

De cette façon, il sera possible de remédier aux incertitudes qui persistent encore: Lesquels des symptômes et maladies neurologiques rapportés jusqu’à présent correspondent à une atteinte spécifique du système nerveux? Quels symptômes ou maladies correspondent à un effet non spécifique du COVID-19 sur le système nerveux? Et quels symptômes correspondent à une manifestation concomitante fortuite?"

2219

N137

Lian Yang, Mei Zhou, Lingli Li, Ping Luo, Wenliang Fan, Juanjuan Xu, Qing Chen, Feng Pan, Ping Lei, Chuansheng Zheng & Yang Jin

Characteristics of mental health implications and plasma metabolomics in patients recently recovered from COVID-19

https://doi.org/10.1038/s41398-021-01426-3

Published

21-May-21

Study

https://www.nature.com/articles/s41398-021-01426-3

Our results also demonstrated significantly different plasma metabolic profiling in recovered COVID-19 patients even at 3 months after their hospital discharge, which was mainly related to purine pathways, amino acids, lipids, and amine metabolism. Certain regions with cerebral WM alterations in the recovered patients showed significant correlations with different metabolites and the mental health scores. We observed multiple alterations in both WM integrity and plasma metabolomics that may explain the deteriorated mental health of recovered COVID-19 patients. These findings may provide potential biomarkers for the mental health evaluation for the recovered COVID-19 patients and potential targets for novel therapeutics.

Une analyse très poussée sur 28 patients hospitalisés et guéris de la covid, utilisant de l'imagerie IRM du tenseur de diffusion, relève des modifications de la substance blanche cérébrale parfois plusieurs mois avec l'hospitalisation. Les relevés montrent des anisotropies fractionnelles réduites et des diffusions pondérées ou radiales augmentées dans certains zones.
Les altérations observées sont souvent corrélées aux modifications métaboliques et aux détails des examens standardisés neuropsychiatriques.

N011

___Neurologic___

Published study on 21-May-21:
"Characteristics of mental health implications and plasma metabolomics in patients recently recovered from COVID-19"
Une analyse très poussée sur 28 patients hospitalisés et guéris de la covid, utilisant de l'imagerie IRM du tenseur de diffusion, relève des modifications de la substance blanche cérébrale parfois plusieurs mois avec l'hospitalisation. Les relevés montrent des anisotropies fractionnelles réduites et des diffusions pondérées ou radiales augmentées dans certains zones.
Les altérations observées sont souvent corrélées aux modifications métaboliques et aux détails des examens standardisés neuropsychiatriques.
Link: https://www.nature.com/articles/s41398-021-01426-3
Extract: "Our results also demonstrated significantly different plasma metabolic profiling in recovered COVID-19 patients even at 3 months after their hospital discharge, which was mainly related to purine pathways, amino acids, lipids, and amine metabolism. Certain regions with cerebral WM alterations in the recovered patients showed significant correlations with different metabolites and the mental health scores. We observed multiple alterations in both WM integrity and plasma metabolomics that may explain the deteriorated mental health of recovered COVID-19 patients. These findings may provide potential biomarkers for the mental health evaluation for the recovered COVID-19 patients and potential targets for novel therapeutics."

2220

N138

Gwenaëlle Douaud, Soojin Lee, Fidel Alfaro-Almagro, Christoph Arthofer, Chaoyue Wang, Frederik Lange, Jesper L.R. Andersson, Ludovica Griffanti, Eugene Duff, Saad Jbabdi, Bernd Taschler, Anderson Winkler, Thomas E. Nichols, Rory Collins, Paul M. Matthews, Naomi Allen, Karla L. Miller, Stephen M. Smith

Brain imaging before and after COVID-19 in UK Biobank

https://doi.org/10.1101/2021.06.11.21258690

pre-print

15-Jun-21

Study

https://www.medrxiv.org/content/10.1101/2021.06.11.21258690v1.full-text

There is strong evidence for brain-related pathologies in COVID-19, some of which could be a consequence of viral neurotropism. The vast majority of brain imaging studies so far have focused on qualitative, gross pathology of moderate to severe cases, often carried out on hospitalised patients. It remains unknown however whether the impact of COVID-19 can be detected in milder cases, in a quantitative and automated manner, and whether this can reveal a possible mechanism for the spread of the disease. UK Biobank scanned over 40,000 participants before the start of the COVID-19 pandemic, making it possible to invite back in 2021 hundreds of previously-imaged participants for a second imaging visit. Here, we studied the effects of the disease in the brain using multimodal data from 782 participants from the UK Biobank COVID-19 re-imaging study, with 394 participants having tested positive for SARS-CoV-2 infection between their two scans. We used structural and functional brain scans from before and after infection, to compare longitudinal brain changes between these 394 COVID-19 patients and 388 controls who were matched for age, sex, ethnicity and interval between scans. We identified significant effects of COVID-19 in the brain with a loss of grey matter in the left parahippocampal gyrus, the left lateral orbitofrontal cortex and the left insula. When looking over the entire cortical surface, these results extended to the anterior cingulate cortex, supramarginal gyrus and temporal pole. We further compared COVID-19 patients who had been hospitalised (n=15) with those who had not (n=379), and while results were not significant, we found comparatively similar findings to the COVID-19 vs control group comparison, with, in addition, a greater loss of grey matter in the cingulate cortex, central nucleus of the amygdala and hippocampal cornu ammonis (all |Z|>3). Our findings thus consistently relate to loss of grey matter in limbic cortical areas directly linked to the primary olfactory and gustatory system. Unlike in post hoc disease studies, the availability of pre-infection imaging data helps avoid the danger of pre-existing risk factors or clinical conditions being mis-interpreted as disease effects. Since a possible entry point of the virus to the central nervous system might be via the olfactory mucosa and the olfactory bulb, these brain imaging results might be the in vivo hallmark of the spread of the disease (or the virus itself) via olfactory and gustatory pathways.

Careful: The plots for Figure "Left orbitofrontal cortex (thickness)" are the same that one's for "Left superior insula (thickness)". This red flag has to be checked.
This point has been corrected.

2221

N139

Hannah A.B.Whitmore1†Leo A.Kim

Understanding the Role of Blood Vessels in the Neurological Manifestations of COVID-19

https://doi.org/10.1016/j.ajpath.2021.04.017

Published

11-Jun-21

Review

https://www.sciencedirect.com/science/article/pii/S0002944021002601

Originally identified as a respiratory disease, similar to previously discovered SARS and MERS type viruses, concern has since been raised about the effects of SARS-CoV-2 infection on the vasculature. This viral-vascular involvement is of particular concern with regards to the small vessels present in the brain, with mounting evidence demonstrating that SARS-CoV-2 is capable of crossing the blood-brain-barrier.

_

2222

N140

Raphael Bernard-Valnet, Sylvain Perriot, Mathieu Canales, Beatrice Pizzarotti, Leonardo Caranzano, Mayté Castro-Jiménez, Jean-Benoit Epiney, Sergiu Vijiala, Paolo Salvioni-Chiabotti, Angelica Anichini, Alexander Salerno, Katia Jaton, Julien Vaucher, Matthieu Perreau, Gilbert Greub, Giuseppe Pantaleo, Renaud A. Du Pasquier

Encephalopathies Associated With Severe COVID-19 Present Neurovascular Unit Alterations Without Evidence for Strong Neuroinflammation

https://doi.org/10.1212/NXI.0000000000001029

Published

16-Jun-21

Study

https://nn.neurology.org/content/8/5/e1029

We detected anti–SARS-CoV-2 immunoglobulin G in patients with severe COVID-19 with signs of intrathecal synthesis for some of them. Of the 4 categories of tested patients, the CSF of IND exhibited the highest level of cytokines, chemokines, and growth factors. By contrast, patients with COVID-19 did not present overall upregulation of inflammatory mediators in the CSF. However, patients with severe COVID-19 (intensive care unit patients) exhibited higher concentrations of CCL2, CXCL8, and vascular endothelium growth factor A (VEGF-A) in the CSF than patients with a milder form of COVID-19. In addition, we could show that intrathecal CXCL8 synthesis was linked to an elevated albumin ratio and correlated with the increase of peripheral inflammation (serum hepatocyte growth factor [HGF] and CXCL10). Conclusions Our results do not indicate active replication of SARS-CoV-2 in the CSF or signs of massive inflammation in the CSF compartment but highlight a specific impairment of the neurovascular unit linked to intrathecal production of CXCL8.

Un article s'interroge sur le rôle éventuel d'un déficit de sérotonine dans la sévérité de la covid et certains symptômes neurologiques.

N011

___Neurologic___

Published study on 16-Jun-21:
"Encephalopathies Associated With Severe COVID-19 Present Neurovascular Unit Alterations Without Evidence for Strong Neuroinflammation"
Un article s'interroge sur le rôle éventuel d'un déficit de sérotonine dans la sévérité de la covid et certains symptômes neurologiques.
Link: https://nn.neurology.org/content/8/5/e1029
Extract: "We detected anti–SARS-CoV-2 immunoglobulin G in patients with severe COVID-19 with signs of intrathecal synthesis for some of them. Of the 4 categories of tested patients, the CSF of IND exhibited the highest level of cytokines, chemokines, and growth factors. By contrast, patients with COVID-19 did not present overall upregulation of inflammatory mediators in the CSF. However, patients with severe COVID-19 (intensive care unit patients) exhibited higher concentrations of CCL2, CXCL8, and vascular endothelium growth factor A (VEGF-A) in the CSF than patients with a milder form of COVID-19. In addition, we could show that intrathecal CXCL8 synthesis was linked to an elevated albumin ratio and correlated with the increase of peripheral inflammation (serum hepatocyte growth factor [HGF] and CXCL10). Conclusions Our results do not indicate active replication of SARS-CoV-2 in the CSF or signs of massive inflammation in the CSF compartment but highlight a specific impairment of the neurovascular unit linked to intrathecal production of CXCL8."

2223

N141

Yidan Xu, Yu Zhuang, Lumei Kang

A Review of Neurological Involvement in Patients with SARS-CoV-2 Infection

https://doi.org/10.12659/MSM.932962

Published

19-Jun-21

Review

https://www.medscimonit.com/abstract/index/idArt/932962

This review aims to provide an update on what is currently known about neurological involvement in patients with COVID-19 due to SARS-CoV-2 infection. In this review, we demonstrate invasion routes of SARS-CoV-2, provide evidence to support the neurotropism hypothesis of the virus, and investigate the pathological mechanisms that underlie neurological complications associated with SARS-CoV-2.

_

2224

N142

Jeffrey E. Gold 1,*,Ramazan A. Okyay 2,Warren E. Licht 3 andDavid J. Hurley

Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation

https://doi.org/10.3390/pathogens10060763

Published

17-Jun-21

Study

https://www.mdpi.com/2076-0817/10/6/763/htm

Our aim was to first determine long COVID prevalence in 185 randomly surveyed COVID-19 patients and, subsequently, to determine if there was an association between occurrence of long COVID symptoms and reactivation of Epstein–Barr virus (EBV) in 68 COVID-19 patients recruited from those surveyed. We found the prevalence of long COVID symptoms to be 30.3% (56/185), which included 4 initially asymptomatic COVID-19 patients who later developed long COVID symptoms. Next, we found that 66.7% (20/30) of long COVID subjects versus 10% (2/20) of control subjects in our primary study group were positive for EBV reactivation based on positive titers for EBV early antigen-diffuse (EA-D) IgG or EBV viral capsid antigen (VCA) IgM. The difference was significant (p < 0.001, Fisher’s exact test). A similar ratio was observed in a secondary group of 18 subjects 21–90 days after testing positive for COVID-19, indicating reactivation may occur soon after or concurrently with COVID-19 infection. These findings suggest that many long COVID symptoms may not be a direct result of the SARS-CoV-2 virus but may be the result of COVID-19 inflammation-induced EBV reactivation.

Est-ce que le neuro-covid pourrait s'expliquer par une réactivation d'une précédente infection au virus d'Epstein-Barr (EBV) ? C'est l'hypothèse que soulève une étude qui remarque que les 2/3 (20 patients sur 30) des malades du covid long testés présentaient une sérologie positive aux antigènes de l'EBV, contre 10% pour le groupe contrôle (2 patients sur 20), soit une corrélation statistiquement significative.

N011

___Neurologic___

Published study on 17-Jun-21:
"Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation"
Est-ce que le neuro-covid pourrait s'expliquer par une réactivation d'une précédente infection au virus d'Epstein-Barr (EBV) ? C'est l'hypothèse que soulève une étude qui remarque que les 2/3 (20 patients sur 30) des malades du covid long testés présentaient une sérologie positive aux antigènes de l'EBV, contre 10% pour le groupe contrôle (2 patients sur 20), soit une corrélation statistiquement significative.
Link: https://www.mdpi.com/2076-0817/10/6/763/htm
Extract: "Our aim was to first determine long COVID prevalence in 185 randomly surveyed COVID-19 patients and, subsequently, to determine if there was an association between occurrence of long COVID symptoms and reactivation of Epstein–Barr virus (EBV) in 68 COVID-19 patients recruited from those surveyed. We found the prevalence of long COVID symptoms to be 30.3% (56/185), which included 4 initially asymptomatic COVID-19 patients who later developed long COVID symptoms. Next, we found that 66.7% (20/30) of long COVID subjects versus 10% (2/20) of control subjects in our primary study group were positive for EBV reactivation based on positive titers for EBV early antigen-diffuse (EA-D) IgG or EBV viral capsid antigen (VCA) IgM. The difference was significant (p < 0.001, Fisher’s exact test). A similar ratio was observed in a secondary group of 18 subjects 21–90 days after testing positive for COVID-19, indicating reactivation may occur soon after or concurrently with COVID-19 infection. These findings suggest that many long COVID symptoms may not be a direct result of the SARS-CoV-2 virus but may be the result of COVID-19 inflammation-induced EBV reactivation."

2225

N143

Jacques Hugon, Eva-Flore Msika, Mathieu Queneau, Karim Farid & Claire Paquet

Long COVID: cognitive complaints (brain fog) and dysfunction of the cingulate cortex

https://doi.org/10.1007/s00415-021-10655-x

Published

18-Jun-21

Study

https://link.springer.com/article/10.1007/s00415-021-10655-x

This long COVID status can include “brain fog” and cognitive deficits that can disturb activities of daily living and can delay complete recovery. Here, we report two cases of neurological long COVID with abnormal FDG PET findings marked by hypometabolic regions of the cingulate cortex.

Des chercheurs font l'hypothèse que le symptôme de brouillard cérébral de deux patients suivis pour un covid long pourrait être lié à un hypométabolisme dans la zone du gyrus cingulaire du cortex cérébral, révélé au PET-SCAN.

N011

___Neurologic___

Published study on 18-Jun-21:
"Long COVID: cognitive complaints (brain fog) and dysfunction of the cingulate cortex"
Des chercheurs font l'hypothèse que le symptôme de brouillard cérébral de deux patients suivis pour un covid long pourrait être lié à un hypométabolisme dans la zone du gyrus cingulaire du cortex cérébral, révélé au PET-SCAN.
Link: https://link.springer.com/article/10.1007/s00415-021-10655-x
Extract: "This long COVID status can include “brain fog” and cognitive deficits that can disturb activities of daily living and can delay complete recovery. Here, we report two cases of neurological long COVID with abnormal FDG PET findings marked by hypometabolic regions of the cingulate cortex."

2226

N144

Andrew C. Yang, Fabian Kern, Patricia M. Losada, Maayan R. Agam, Christina A. Maat, Georges P. Schmartz, Tobias Fehlmann, Julian A. Stein, Nicholas Schaum, Davis P. Lee, Kruti Calcuttawala, Ryan T. Vest, Daniela Berdnik, Nannan Lu, Oliver Hahn, David Gate, M. Windy McNerney, Divya Channappa, Inma Cobos, Nicole Ludwig, Walter J. Schulz-Schaeffer, Andreas Keller & Tony Wyss-Coray

Dysregulation of brain and choroid plexus cell types in severe COVID-19

https://doi.org/10.1038/s41586-021-03710-0

Published

21-Jun-21

Study

https://www.nature.com/articles/s41586-021-03710-0

Here, we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control (including 1 terminal influenza) and 8 COVID-19 patients. While a systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations which predict that choroid plexus barrier cells sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover COVID-19 disease-associated microglia and astrocyte subpopulations that share features with pathological cell states reported in human neurodegenerative disease4–6. Synaptic signaling of upper-layer excitatory neurons—evolutionarily expanded in humans7 and linked to cognitive function8—are preferentially affected in COVID-19. Across cell types, COVID-19 perturbations overlap with those in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia, and depression. Our findings and public dataset provide a molecular framework to understand COVID-19 related neurological disease observed now and which may emerge later.

2227

N145

Olivia Swain, Sofia K. Romano, Ritika Miryala, Jocelyn Tsai, Vinnie Parikh and George K. E. Umanah

SARS-CoV-2 Neuronal Invasion and Complications: Potential Mechanisms and Therapeutic Approaches

https://doi.org/10.1523/JNEUROSCI.3188-20.2021

Published

23-Jun-21

Review

https://www.jneurosci.org/content/41/25/5338

Autopsies of patients confirm the presence of the coronaviruses in the CNS, especially in the brain. The invasion and transmission of SARS-CoV-2 in the CNS is not clearly defined, but, because the endocytic pathway has become an important target for the development of therapeutic strategies for COVID-19, it is necessary to understand endocytic processes in the CNS. In addition, mitochondria and mechanistic target of rapamycin (mTOR) signaling pathways play a critical role in the antiviral immune response, and may also be critical for endocytic activity. Furthermore, dysfunctions of mitochondria and mTOR signaling pathways have been associated with some high-risk conditions such as diabetes and immunodeficiency for developing severe complications observed in COVID-19 patients. However, the role of these pathways in SARS-CoV-2 infection and spread are largely unknown. In this review, we discuss the potential mechanisms of SARS-CoV-2 entry into the CNS and how mitochondria and mTOR pathways might regulate endocytic vesicle–mitochondria interactions and dynamics during SARS-CoV-2 infection. The mechanisms that plausibly account for severe neurologic complications with COVID-19 and potential treatments with Food and Drug Administration-approved drugs targeting mitochondria and the mTOR pathways are also addressed.

2228

N146

Rodolfo Furlan Damiano, Bruno F. Guedes, Cristiana Castanho de Rocca, Antonio de Pádua Serafim, Luiz Henrique Martins Castro, Carolina Demarchi Munhoz, Ricardo Nitrini, Geraldo Busatto Filho, Eurípedes Constantino Miguel, Giancarlo Lucchetti & Orestes Forlenza

Cognitive decline following acute viral infections: literature review and projections for post-COVID-19

https://doi.org/10.1007/s00406-021-01286-4

Published

25-Jun-21

Review

https://link.springer.com/article/10.1007/s00406-021-01286-4

This article aims to review the state of the art regarding the knowledge about the impact of acute viral infections on human cognition, laying a foundation to explore the possible cognitive decline followed coronavirus disease 2019 (COVID-19). To reach this goal, we conducted a narrative review systematizing six acute viral infections as well as the current knowledge about COVID-19 and its impact on human cognition. Recent findings suggest probable short- and long-term COVID-19 impacts in cognition, even in asymptomatic individuals, which could be accounted for by direct and indirect pathways to brain dysfunction. Understanding this scenario might help clinicians and health leaders to deal better with a wave of neuropsychiatric issues that may arise following COVID-19 pandemic as well as with other acute viral infections, to alleviate the cognitive sequelae of these infections around the world.

2229

N147

Ravindra K Garg 1

Spectrum of Neurological Manifestations in Covid-19: A Review

https://doi.org/10.4103/0028-3886.289000

Published

6-Jul-20

Review

https://www.neurologyindia.com/article.asp?issn=0028-3886;year=2020;volume=68;issue=3;spage=560;epage=572;aulast=Garg

The SARS-CoV-2 virus causes the disease COVID-19 and has the potential to invade the brain. The SARS-CoV-2 virus enters the brain either via a hematogenous route or olfactory system. Angiotensin-converting enzyme two receptors, present on endothelial cells of cerebral vessels, are a possible viral entry point. The most severe neurological manifestations, altered sensorium (agitation, delirium, and coma), are because of hypoxic and metabolic abnormalities. Characteristic cytokine storm incites severe metabolic changes and multiple organ failure. Profound coagulopathies may manifest with ischemic or hemorrhagic stroke. Rarely, SARS-CoV-2 virus encephalitis or pictures like acute disseminated encephalomyelitis or acute necrotizing encephalopathy have been reported. Nonspecific headache is a commonly experienced neurological symptom. A new type of headache “personal protection equipment-related headache” has been described. Complete or partial anosmia and ageusia are common peripheral nervous system manifestations. Recently, many cases of Guillain-Barré syndrome in COVID-19 patients have been observed, and a postinfectious immune-mediated inflammatory process was held responsible for this. Guillain-Barré syndrome does respond to intravenous immunoglobulin. Myalgia/fatigue is also common, and elevated creatine kinase levels indicate muscle injury. Most of the reports about neurological complications are currently from China. COVID-19 pandemic is spreading to other parts of the world; the spectrum of neurological complications is likely to widen further.

2230

N148

Narges Moghimi, Mario Di Napoli, José Biller, James E. Siegler, Rahul Shekhar, Louise D. McCullough, Michelle S. Harkins, Emily Hong, Danielle A. Alaouieh, Gelsomina Mansueto & Afshin A. Divani

The Neurological Manifestations of Post-Acute Sequelae of SARS-CoV-2 Infection

https://doi.org/10.1007/s11910-021-01130-1

Published

28-Jun-21

Review

https://link.springer.com/article/10.1007/s11910-021-01130-1

This review aims to summarize the incidence, risk factors, possible pathophysiology, and proposed management of neurological manifestations of post-acute sequelae of SARS-CoV-2 infection (PASC) or neuro-PASC based on the published literature.

2231

N149

Pablo Najta Helen L.Richards b Dónal G. Fortunea

Brain imaging in patients with COVID-19: A systematic review

https://doi.org/10.1016/j.bbih.2021.100290

Published

2-Jul-21

Review

https://www.sciencedirect.com/science/article/pii/S2666354621000934

Highlights
•A spectrum of brain changes particularly at advanced stage relates to SARS-CoV-2
•Across severity phases SARS-CoV-2 affects olfactory structures
•Emerging abnormalities in COVID-19 is associated with the olfactory brain network
Twenty-seven studies were included in the review, including 5 case series, 8 cohort studies and 14 case control studies. The findings revealed predominant involvement of the olfactory system with disruptions across four olfactory structures. Abnormalities also extended to the corpus callosum, cingulate cortex, and insula, jointly implicating the olfactory brain network.

2232

N150

Mayuri Gupta and Donald F. Weaver

COVID-19 as a Trigger of Brain Autoimmunity

https://doi.org/10.1021/acschemneuro.1c00403

Published

2-Jul-21

Article

https://pubs.acs.org/doi/full/10.1021/acschemneuro.1c00403

Entry of SARS-CoV-2 into the central nervous system (CNS) activates microglia, triggering chronic neuroinflammation and possibly neurodegeneration. The complex transcriptome of SARS-CoV-2 shares molecular similarities with diverse human CNS protein epitopes, leading to a cytokine storm and various autoantibodies, potentially culminating in an autoimmune state. A COVID-19 initiated CNS autoimmune cascade may occur via multiple pathways including molecular mimicry, bystander activation, epitope spreading, production of autoantibodies, and immortalization of effector B-cells.

2233

N151

Nicholas W.LarsenaLauren E.StilesbMitchell G.Miglisa

Preparing for the long-haul: Autonomic complications of COVID-19

https://doi.org/10.1016/j.autneu.2021.102841

Published

3-Jul-21

Review

https://www.sciencedirect.com/science/article/pii/S1566070221000710

Many symptoms of post-acute COVID syndrome appear autonomic in nature, suggesting that autonomic impairment may play a central role in the underlying pathophysiology. In this review, we discuss the autonomic symptoms and manifestations of post-acute COVID syndrome, potential mechanisms involved, and future directions for a better understanding of this novel condition.

2234

N152

Qing Ye, Jia Zhou, Qi He, Rui-Ting Li, Guan Yang, Yao Zhang, Shu-Jia Wu, Qi Chen, Jia-Hui Shi, Rong-Rong Zhang, Hui-Ming Zhu, Hong-Ying Qiu, Tao Zhang, Yong-Qiang Deng, Xiao-Feng Li, Jian-Feng Liu, Ping Xu, Xiao Yang & Cheng-Feng Qin

SARS-CoV-2 infection in the mouse olfactory system

https://doi.org/10.1038/s41421-021-00290-1

Published

6-Jul-21

Study

https://www.nature.com/articles/s41421-021-00290-1

Herein, we demonstrate that intranasal inoculation with SARS-CoV-2 induces robust viral replication in the olfactory epithelium (OE), not the olfactory bulb (OB), resulting in transient olfactory dysfunction in humanized ACE2 (hACE2) mice. The sustentacular cells and Bowman’s gland cells in the OE were identified as the major target cells of SARS-CoV-2 before invasion into olfactory sensory neurons (OSNs). Remarkably, SARS-CoV-2 infection triggers massive cell death and immune cell infiltration and directly impairs the uniformity of the OE structure. Combined transcriptomic and quantitative proteomic analyses revealed the induction of antiviral and inflammatory responses, as well as the downregulation of olfactory receptor (OR) genes in the OE from the infected animals. Overall, our mouse model recapitulates olfactory dysfunction in COVID-19 patients and provides critical clues for understanding the physiological basis for extrapulmonary manifestations of COVID-19.

Sur des souris humanisées (avec réc. hACE2), une équipe montre une forte réplication virale dans l'épithélium olfactif à la suite d'une inoculation intranasale de covid. L'uniformité de l'épithélium et les neurones des récepteurs olfactifs sont touchés.

N014E

___Neurologic___

Published study on 6-Jul-21:
"SARS-CoV-2 infection in the mouse olfactory system"
Sur des souris humanisées (avec réc. hACE2), une équipe montre une forte réplication virale dans l'épithélium olfactif à la suite d'une inoculation intranasale de covid. L'uniformité de l'épithélium et les neurones des récepteurs olfactifs sont touchés.
Link: https://www.nature.com/articles/s41421-021-00290-1
Extract: "Herein, we demonstrate that intranasal inoculation with SARS-CoV-2 induces robust viral replication in the olfactory epithelium (OE), not the olfactory bulb (OB), resulting in transient olfactory dysfunction in humanized ACE2 (hACE2) mice. The sustentacular cells and Bowman’s gland cells in the OE were identified as the major target cells of SARS-CoV-2 before invasion into olfactory sensory neurons (OSNs). Remarkably, SARS-CoV-2 infection triggers massive cell death and immune cell infiltration and directly impairs the uniformity of the OE structure. Combined transcriptomic and quantitative proteomic analyses revealed the induction of antiviral and inflammatory responses, as well as the downregulation of olfactory receptor (OR) genes in the OE from the infected animals. Overall, our mouse model recapitulates olfactory dysfunction in COVID-19 patients and provides critical clues for understanding the physiological basis for extrapulmonary manifestations of COVID-19."

2235

N153

Michael Marshall

COVID and the brain: researchers zero in on how damage occurs

https://doi.org/10.1038/d41586-021-01693-6

Published

7-Jul-21

Article

https://www.nature.com/articles/d41586-021-01693-6

How COVID-19 damages the brain is becoming clearer. New evidence suggests that the coronavirus’s assault on the brain could be multipronged: it might attack certain brain cells directly, reduce blood flow to brain tissue or trigger production of immune molecules that can harm brain cells. These pathways — astrocytes, pericytes and autoantibodies — are not mutually exclusive, and are probably not the only ones: it is likely that people with COVID-19 experience neurological symptoms for a range of reasons. Prüss says a key question is what proportion of cases is caused by each of the pathways. “That will determine treatment,” he says.

Même si le virus du SARS-CoV-2 se réplique peu dans le système nerveux central, il peut néanmoins infecter les astrocytes, cellules qui ont un rôle crucial dans le fonctionnement du cerveau, et provoque des troubles neurologiques par différents mécanismes.

N014E

___Neurologic___

Published article on 7-Jul-21:
"COVID and the brain: researchers zero in on how damage occurs"
Même si le virus du SARS-CoV-2 se réplique peu dans le système nerveux central, il peut néanmoins infecter les astrocytes, cellules qui ont un rôle crucial dans le fonctionnement du cerveau, et provoque des troubles neurologiques par différents mécanismes.
Link: https://www.nature.com/articles/d41586-021-01693-6
Extract: "How COVID-19 damages the brain is becoming clearer. New evidence suggests that the coronavirus’s assault on the brain could be multipronged: it might attack certain brain cells directly, reduce blood flow to brain tissue or trigger production of immune molecules that can harm brain cells. These pathways — astrocytes, pericytes and autoantibodies — are not mutually exclusive, and are probably not the only ones: it is likely that people with COVID-19 experience neurological symptoms for a range of reasons. Prüss says a key question is what proportion of cases is caused by each of the pathways. “That will determine treatment,” he says."

2236

N154

Lu Wang, David Sievert, Alex E. Clark, Sangmoon Lee, Hannah Federman, Benjamin D. Gastfriend, Eric V. Shusta, Sean P. Palecek, Aaron F. Carlin & Joseph G. Gleeson

A human three-dimensional neural-perivascular ‘assembloid’ promotes astrocytic development and enables modeling of SARS-CoV-2 neuropathology

https://doi.org/10.1038/s41591-021-01443-1

Published

9-Jul-21

Study

https://www.nature.com/articles/s41591-021-01443-1

Here we show that pericyte-like cells (PLCs), when integrated into a cortical organoid, are capable of infection with authentic SARS-CoV-2. Before infection, PLCs elicited astrocytic maturation and production of basement membrane components, features attributed to pericyte functions in vivo. While traditional cortical organoids showed little evidence of infection, PLCs within cortical organoids served as viral ‘replication hubs’, with virus spreading to astrocytes and mediating inflammatory type I interferon transcriptional responses. Therefore, PLC-containing cortical organoids (PCCOs) represent a new ‘assembloid’ model that supports astrocytic maturation as well as SARS-CoV-2 entry and replication in neural tissue; thus, PCCOs serve as an experimental model for neural infection.

Une étude dans Nature sur des organoïdes cérébraux montre les capacités neuropathologiques du SARS-CoV-2, sa capacité à se répliquer dans les astrocytes, ainsi que des réponses inflammatoires transcriptionnelles par l'interféron de type I.

N014E

___Neurologic___

Published study on 9-Jul-21:
"A human three-dimensional neural-perivascular ‘assembloid’ promotes astrocytic development and enables modeling of SARS-CoV-2 neuropathology"
Une étude dans Nature sur des organoïdes cérébraux montre les capacités neuropathologiques du SARS-CoV-2, sa capacité à se répliquer dans les astrocytes, ainsi que des réponses inflammatoires transcriptionnelles par l'interféron de type I.
Link: https://www.nature.com/articles/s41591-021-01443-1
Extract: "Here we show that pericyte-like cells (PLCs), when integrated into a cortical organoid, are capable of infection with authentic SARS-CoV-2. Before infection, PLCs elicited astrocytic maturation and production of basement membrane components, features attributed to pericyte functions in vivo. While traditional cortical organoids showed little evidence of infection, PLCs within cortical organoids served as viral ‘replication hubs’, with virus spreading to astrocytes and mediating inflammatory type I interferon transcriptional responses. Therefore, PLC-containing cortical organoids (PCCOs) represent a new ‘assembloid’ model that supports astrocytic maturation as well as SARS-CoV-2 entry and replication in neural tissue; thus, PCCOs serve as an experimental model for neural infection."

2237

N155

FatimaKhatoonKartikayPrasadVijayKumar

COVID-19 associated nervous system manifestations

https://doi.org/10.1016/j.sleep.2021.07.005

Published

9-Jul-21

Review

https://www.sciencedirect.com/science/article/pii/S1389945721003877

Highlights
•Neurological complications observed in COVID-19.
•COVID-19 associated central nervous system manifestations.
•COVID-19 associated peripheral nervous system manifestations.
•COVID-19 and neurodegenerative diseases.
•COVID-19 and sleep dysfunction.
•SARS-CoV-2-2 prey human genes are involved in sleep apnea.
SARS-CoV-2 enters the brain through the olfactory bulb, retrograde axonal transport from peripheral nerve endings, or via hematogenous or lymphatic routes. Notably, COVID-19 infection can cause or even present with different neurological features including encephalopathy, impaired consciousness, confusion, agitation, seizure, ataxia, headache, anosmia, ageusia, neuropathies, and neurodegenerative diseases. In this paper, we provide a brief review of observed neurological manifestations associated with COVID-19.

_

2238

N156

AntonJohanssonaMohamed S.MohamedaThiago C.MoulinaHelgi B.Schiöth

Neurological manifestations of COVID-19: A comprehensive literature review and discussion of mechanisms

https://doi.org/10.1016/j.jneuroim.2021.577658

Published

10-Jul-21

Review

https://www.sciencedirect.com/science/article/pii/S0165572821001855

Here, we review the literature describing SARS-CoV-2-induced neurological manifestations and provide a comprehensive discussion of proposed mechanisms underlying the neurological pathophysiology. First, we analyse the neuroinvasiveness potential of the coronavirus family based on previous SARS-CoV-1 studies. Then, we describe the current evidence on COVID-19-induced nervous tissue damage, including processes behind brain vasculopathy and cytokine storm. We also discuss in detail anosmia and Guillain-Barré syndrome. Finally, we provide a summarised timeline of the main findings in the field. Future perspectives are presented, and suggestions of further investigations to clarify how SARS-COV-2 can affect the CNS.

_

2239

N157

Jai Mathur1, Alan Carson

#3125 Novel framework for neurocognitive COVID-19 assessment

http://dx.doi.org/10.1136/jnnp-2021-BNPA.32

Published

11-Mar-21

Review

https://jnnp.bmj.com/content/92/8/A14.abstract

Conclusion Cognitive symptoms are common after confirmed and assumed COVID exposure. We propose a framework for neuropsychiatric assessment and the use of adjuvant imaging and potential biomarkers.
Neuropsychiatric history- Part 1 symptoms at onset- in particular disruptions of consciousness and altered mental state. Acute memory impairment, anterograde/retrograde and with/without a temporal gradient. neurocognitive function. ITU admission and oxygen requirements.

Part 2 Current cognitive and mental state- in addition to standard history seek evidence of internal inconsistency of memory symptoms and attentional dysregulation. Has social cognition and meta-cognition been affected. Note attribution bias i.e. no Im not depressed, I cant enjoy anything because of my symptoms

Background history- subtle suggestion of neurodegeneration and depression, anxiety and functional symptoms should be explored.

MRI findings- signal changes in the medial temporal lobe, nonconfluent multifocal white matter hyperintense lesions, and isolated white matter microhemorrhages.

Novel biomarkers IL-6, MCP-1, and IP-10.

_

2240

N158

Iqra Athar

“Cerebral venous sinus thrombosis sequel of COVID Encephalitis; a rare presentation”

https://doi.org/10.1016/j.hest.2021.07.003

Published

16-Jul-21

Case Report

https://www.sciencedirect.com/science/article/pii/S2589238X2100036X

However, its popularity as neuropathogen has increased dramatically. Patient presents a wide range of symptoms. We report a case of Covid-19 encephalitis which was incidentally found to have cerebral venous sinus thrombosis, presented with acute delirium and then developed new onset seizures.

_

2241

N159

Adam Hampshire
William Trender
Samuel R Chamberlain
Amy E. Jolly
Jon E. Grant
Fiona Patrick
Ndaba Mazibuko
Steve CR Williams
Joseph M Barnby
Peter Hellyer
Mitul A Mehta

Cognitive deficits in people who have recovered from COVID-19

https://doi.org/10.1016/j.eclinm.2021.101044

Published

22-Jul-21

RESEARCH PAPER

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00324-2/fulltext

Findings
People who had recovered from COVID-19, including those no longer reporting symptoms, exhibited significant cognitive deficits versus controls when controlling for age, gender, education level, income, racial-ethnic group, pre-existing medical disorders, tiredness, depression and anxiety. The deficits were of substantial effect size for people who had been hospitalised (N = 192), but also for non-hospitalised cases who had biological confirmation of COVID-19 infection (N = 326). Analysing markers of premorbid intelligence did not support these differences being present prior to infection. Finer grained analysis of performance across sub-tests supported the hypothesis that COVID-19 has a multi-domain impact on human cognition.
Interpretation
Interpretation. These results accord with reports of ‘Long Covid’ cognitive symptoms that persist into the early-chronic phase. They should act as a clarion call for further research with longitudinal and neuroimaging cohorts to plot recovery trajectories and identify the biological basis of cognitive deficits in SARS-COV-2 survivors.

Selon une étude publiée dans The Lancet, les malades qui se sont remis d'une covid, y compris ceux qui ne rapportent plus de symptômes, présentent des déficits cognitifs, dont l'importance est liée à la gravité de la phase aiguë. Selon l'étude, la différence est faible, mais statistiquement significative, pour les malades avec des symptômes résolus non respiratoires.
On retrouve chez les patients qui ont été hospitalisés et ventilés une perte cognitive (0,47 SD) plus importante que chez les patients victimes d'attaque cérébrale (0,24 SD) ou ceux ayant des handicaps d'apprentissage (0,38 SD). Cette perte peut être comparée à 7 pts de QI.
L'analyse et le groupe contrôle ont été faits pour prendre en compte les facteurs confondants d'âge, de sexe, de niveau d'éducation, niveau d'éducation, revenu, d'ethnicité, de troubles préexistants, de fatigue, de dépression et d'anxiété.

N012

___Neurologic___

Published research paper on 22-Jul-21:
"Cognitive deficits in people who have recovered from COVID-19"
Selon une étude publiée dans The Lancet, les malades qui se sont remis d'une covid, y compris ceux qui ne rapportent plus de symptômes, présentent des déficits cognitifs, dont l'importance est liée à la gravité de la phase aiguë. Selon l'étude, la différence est faible, mais statistiquement significative, pour les malades avec des symptômes résolus non respiratoires.
On retrouve chez les patients qui ont été hospitalisés et ventilés une perte cognitive (0,47 SD) plus importante que chez les patients victimes d'attaque cérébrale (0,24 SD) ou ceux ayant des handicaps d'apprentissage (0,38 SD). Cette perte peut être comparée à 7 pts de QI.
L'analyse et le groupe contrôle ont été faits pour prendre en compte les facteurs confondants d'âge, de sexe, de niveau d'éducation, niveau d'éducation, revenu, d'ethnicité, de troubles préexistants, de fatigue, de dépression et d'anxiété.
Link: https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00324-2/fulltext
Extract: "Findings
People who had recovered from COVID-19, including those no longer reporting symptoms, exhibited significant cognitive deficits versus controls when controlling for age, gender, education level, income, racial-ethnic group, pre-existing medical disorders, tiredness, depression and anxiety. The deficits were of substantial effect size for people who had been hospitalised (N = 192), but also for non-hospitalised cases who had biological confirmation of COVID-19 infection (N = 326). Analysing markers of premorbid intelligence did not support these differences being present prior to infection. Finer grained analysis of performance across sub-tests supported the hypothesis that COVID-19 has a multi-domain impact on human cognition.
Interpretation
Interpretation. These results accord with reports of ‘Long Covid’ cognitive symptoms that persist into the early-chronic phase. They should act as a clarion call for further research with longitudinal and neuroimaging cohorts to plot recovery trajectories and identify the biological basis of cognitive deficits in SARS-COV-2 survivors."

2242

N160

Yu-Hui Liu, Ye-Ran Wang, Qing-Hua Wang, Yang Chen, Xian Chen, Ying Li, Yuan Cen, Cheng Xu, Tian Hu, Xu-Dong Liu, Ling-Li Yang, Si-Jing Li, Xue-Fei Liu, Chun-Mei Liu, Jie Zhu, Wei Li, Li-Li Zhang, Juan Liu & Yan-Jiang Wang

Post-infection cognitive impairments in a cohort of elderly patients with COVID-19

https://doi.org/10.1186/s13024-021-00469-w

Published

19-Jul-21

Study

https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-021-00469-w

Compared with controls, COVID-19 patients had lower TICS-40 scores and higher IQCODE scores [TICS-40 median (IQR): 29 (25 to 32) vs. 30 (26 to 33), p < 0.001; IQCODE median (IQR): 3.19 (3.00 to 3.63) vs. 3.06 (3.00 to 3.38), p < 0.001]. Severe COVID-19 patients had lower TICS-40 scores and higher IQCODE scores than non-severe COVID-19 patients [TICS-40 median (IQR): 24 (18 to 28) vs. 30 (26 to 33), p < 0.001; IQCODE median (IQR): 3.63 (3.13 to 4.31) vs. 3.13 (3.00 to 3.56), p < 0.001] and controls [TICS-40 median (IQR): 24 (18 to 28) vs. 30 (26 to 33), p < 0.001; IQCODE median (IQR) 3.63 (3.13 to 4.31) vs. 3.06 (3.00 to 3.38), p < 0.001]. Severe COVID-19 patients had a higher proportion of cases with current cognitive impairment and longitudinal cognitive decline than non-severe COVID-19 patients [dementia: 25 (10.50 %) vs. 9 (0.69 %), p < 0.001; Mild cognitive impairment (MCI): 60 (25.21 %) vs. 63 (4.84 %), p < 0.001] and controls [dementia: 25 (10.50 %) vs. 0 (0 %), p < 0.001; MCI: 60 (25.21 %) vs. 20 (4.29 %), p < 0.001)]. COVID-19 severity, delirium and COPD were risk factors of current cognitive impairment. Low education level, severe COVID-19, delirium, hypertension and COPD were risk factors of longitudinal cognitive decline.

_

2243

N161

Wen-Rong Zhan, Jing Huang, Peng-Ming Zeng, Wei-Ya Tian, Zhen-Ge Luo

Emerging neurotropic features of SARS-CoV-2

https://doi.org/10.1093/jmcb/mjab044

Published

21-Jul-21

Review

https://academic.oup.com/jmcb/advance-article/doi/10.1093/jmcb/mjab044/6325086

Although several cell types in the brain express angiotensin converting enzyme-2 (ACE2), the main SARS-CoV-2 receptor, and other related proteins, it remains unclear whether the observed neurological manifestations are attributed to virus invasion into the brain or just comorbidities caused by dysregulation of systemic factors. Here, we briefly review the neurological manifestations of SARS-CoV-2, summarize recent evidence for the potential neurotropism of SARS-CoV-2, and discuss the potential mechanisms of COVID-19-associated neurological diseases.

_

2244

N162

Neelakshi Pal and Kuntal Gupta*

NEUROLOGICAL MANIFESTATION OF COVID-19: A SHORT
REVIEW

https://doi.org/10.20959/wjpr20218-20957

Published

26-Jun-21

Review

https://wjpr.s3.ap-south-1.amazonaws.com/article_issue/1625102026.pdf

This review which attempts at understanding the causes, mechanisms and symptoms of various neurological diseases manifested post-COVID infection is one such aspect. SARSCoV-2 virus invades the human systems through receptors namely ACE-2 and TMPSS2, through haematological, neurological or the inflammatory route. The epithelial cells for olfaction and sensory ciliated neurons are affected, impairing smell perception. The viral replication within the taste buds and peripheral chemoreceptors damages the cranial nerves responsible for gustation. Encephalopathy occurs in various forms including lesion of the right temporal lobe, delirium, corpus callosum injury, oedema, nystagmus and cerebritis. The clumping of blood within the vessels is common. Since endothelium is spread all over the body, no organs, except a few, are spared from viral infection. GBS characterized by weakness of lower limbs, paralysis, myelitis and MillerFisher syndrome are prominent. Blurred vision, pupillary defects, retinal vasculitis occur during optic neuritis damaging optic nerves of the orbital cortex. Hearing loss, clot-formation in cochlea and auditory pathway occur during sensorineural impairment. Nociceptors get hyper-stimulated causing pain. The cytokine storm releasing inflammatory mediators is another manifestation.

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2245

N163

Michael S Xydakis, MD
Mark W Albers, MD
Eric H Holbrook, MD
Dina M Lyon, MS
Robert Y Shih, MD
Prof Johannes A Frasnelli, MD
Prof Axel Pagenstecher, MD
Alexandra Kupke, DVM
Prof Lynn W Enquist, PhD †
Prof Stanley Perlman

Post-viral effects of COVID-19 in the olfactory system and their implications

https://doi.org/10.1016/S1474-4422(21)00182-4

Published

30-Jul-21

RAPID REVIEW

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(21)00182-4/fulltext

The prevalence of CNS and olfactory bulb pathosis in patients with COVID-19 is not known. We postulate that, in people who have recovered from COVID-19, a chronic, recrudescent, or permanent olfactory deficit could be prognostic for an increased likelihood of neurological sequelae or neurodegenerative disorders in the long term. An inflammatory stimulus from the nasal olfactory epithelium to the olfactory bulbs and connected brain regions might accelerate pathological processes and symptomatic progression of neurodegenerative disease. Persistent olfactory impairment with or without perceptual distortions (ie, parosmias or phantosmias) after SARS-CoV-2 infection could, therefore, serve as a marker to identify people with an increased long-term risk of neurological disease.

Les troubles olfactifs (anosmie) de la covid sont vus comme des premiers signes de dommages neurologiques. Lorsque ces troubles sont prolongés, ils pourraient être le signe d'un risque de maladie neurologique ultérieure.

N014E

___Neurologic___

Published rapid review on 30-Jul-21:
"Post-viral effects of COVID-19 in the olfactory system and their implications"
Les troubles olfactifs (anosmie) de la covid sont vus comme des premiers signes de dommages neurologiques. Lorsque ces troubles sont prolongés, ils pourraient être le signe d'un risque de maladie neurologique ultérieure.
Link: https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(21)00182-4/fulltext
Extract: "The prevalence of CNS and olfactory bulb pathosis in patients with COVID-19 is not known. We postulate that, in people who have recovered from COVID-19, a chronic, recrudescent, or permanent olfactory deficit could be prognostic for an increased likelihood of neurological sequelae or neurodegenerative disorders in the long term. An inflammatory stimulus from the nasal olfactory epithelium to the olfactory bulbs and connected brain regions might accelerate pathological processes and symptomatic progression of neurodegenerative disease. Persistent olfactory impairment with or without perceptual distortions (ie, parosmias or phantosmias) after SARS-CoV-2 infection could, therefore, serve as a marker to identify people with an increased long-term risk of neurological disease."

2246

N164

B.Rodríguez-AlfonsoaS.Ruiz SolísbL.Silva-HernándezcI.Pintos PascualdS.Aguado IbáñezeC.Salas Antónf

18F-FDG-PET/CT in SARS-CoV-2 infection and its sequelae18F-FDG-PET/TC ante la infeccion por sars-cov-2 y sus secuelas

https://doi.org/10.1016/j.remnie.2021.07.005

Published

28-Jul-21

Review

https://www.sciencedirect.com/science/article/abs/pii/S2253808921001269

To date, knowledge about the usefulness of 18F-FDG-PET/CT in the acute phase has been limited to the incidental detection of SARS-CoV-2 unsuspected pneumonia. Recent studies have been appearing collecting the findings of 18F-FDG-PET/CT in long COVID-19 or persistent COVID-19 state as well as the alterations caused after mass vaccination of the population in the metabolic studies. This work aims to review the existing literature focusing on these three issues and to briefly present our own preliminary experience.

2247

N165

Esther S. Oh, MD, PhD1,2,3,4; Tracy D. Vannorsdall, PhD2,5; Ann M. Parker, MD, PhD6,7

Post-acute Sequelae of SARS-CoV-2 Infection and Subjective Memory Problems

http://jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2021.19335

Published

29-Jul-21

Invited Commentary

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2782534

Limitations of the study by Søraas et al2 include the low overall response rate (24%) and potential bias in both participation and responses to survey questions introduced by knowing their SARS-CoV-2 test results. Additionally, there are no data on race or ethnicity, and the results are from a single country in Scandinavia.

To advance the current knowledge of cognitive impairment among COVID-19 survivors, longer prospective cohort studies that include individuals from different races and ethnicities are needed to determine symptom persistence, and more importantly, the potential association between subjective cognitive impairment and rate of objective cognitive impairment compared with age-, sex-, and education-adjusted norms. Moreover, the functional consequences of persistent cognitive dysfunction among individuals who may have been at the height of their work productivity before SARS-CoV-2 infection is an important area in need of further investigation. Finally, ongoing efforts to understand the underlying biological mechanism of the effect of SARS-CoV-2 on the brain will be important in identifying those at high risk of developing subsequent cognitive impairment.

_

2248

N166

Nelly Kanberg 1 Joel Simrén 1 Arvid Edén Lars-Magnus Andersson Staffan Nilsson Nicholas J. Ashton Pär-Daniel Sundvall Bengt Nellgård Kaj Blennow Henrik Zetterberg Magnus Gisslén

Neurochemical signs of astrocytic and neuronal injury in acute COVID-19 normalizes during long-term follow-up

https://doi.org/10.1016/j.ebiom.2021.103512

Published

29-Jul-21

RESEARCH PAPER

https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(21)00305-4/fulltext

One hundred patients with mild (n = 24), moderate (n = 28), and severe (n = 48) COVID-19 were followed for a median (IQR) of 225 (187–262) days. In the acute phase, patients with severe COVID-19 had higher concentrations of NfL than all other groups (all p < 0·001), and higher GFAp than controls (p < 0·001). GFAp was also significantly increased in moderate disease (p < 0·05) compared with controls. NfL (r = 0·53, p < 0·001) and GFAp (r = 0·39, p < 0·001) correlated with GDF-15 during the acute phase. After six months, NfL and GFAp concentrations had normalized, with no persisting group differences. Despite this, 50 patients reported persistent neurological symptoms, most commonly fatigue (n = 40), “brain-fog” (n = 29), and changes in cognition (n = 25). We found no correlation between persistent neurological symptoms and CNS injury biomarkers in the acute phase.
Interpretation
The normalization of CNS injury biomarkers in all individuals, regardless of previous disease severity or persisting neurological symptoms, indicates that post COVID-19 neurological sequelae are not accompanied by ongoing CNS injury.

2249

N167

Arne Søraas, PhD1; Ragnhild Bø, PhD2; Karl Trygve Kalleberg, PhD3; Nathalie C. Støer, PhD4; Merete Ellingjord-Dale, PhD1; Nils Inge Landrø, PhD5

Self-reported Memory Problems 8 Months After COVID-19 Infection

http://jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2021.18717

Published

29-Jul-21

Research Letter

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2782531

At follow-up, a mean (SD) of 257 (32) days after baseline, 9705 of 13 001 participants (75%) responded, and 72 of 651 of the participants (11%) in the SARS-CoV-2–positive group reported memory problems. In contrast, 254 of 5712 participants (4%) in the SARS-CoV-2–negative group or 80 of 3342 participants (2%) in the untested randomly selected reported memory problems (Figure).

In the multiple logistic regression model, SARS-CoV-2 positivity at baseline was strongly associated with reporting memory problems at 8 months follow-up (odds ratio [OR], 4.66; 95% CI, 3.25-6.66) compared to the untested randomly selected group. At follow-up, 267 of 649 participants (41%) in the SARS-CoV-2–positive group reported a significant worsening of health compared with 1 year prior, and 81 of 651 participants (12%) in the SARS-CoV-2–positive group also reported problems concentrating. Additionally, 59 of 267 participants (82%) in the SARS-CoV-2–positive group who reported memory problems also reported a worsening of health. Feeling depressed, having less energy, or pain were reported relatively equally by the different groups.
The lack of objective memory tests limits strong conclusions. However, subjective memory concerns have been shown to reflect objective problems and observable changes in everyday function even when controlling for associated factors, such as depression.5 Self-reported memory problems are also a risk factor for later mild cognitive impairment or dementia.6 Nevertheless, a more detailed examination of what type of memory problems are specific for PASC, like working memory vs long-term memory, is warranted in future studies.

Huit mois après l'infection, sur une large cohorte norvégienne de patients testés positifs au SARS-CoV-2, 11% rapportent encore des troubles mnésiques, 12% des difficultés de concentration, et une part importante considère que son état s'est dégradé.

N014E

___Neurologic___

Published research letter on 29-Jul-21:
"Self-reported Memory Problems 8 Months After COVID-19 Infection"
Huit mois après l'infection, sur une large cohorte norvégienne de patients testés positifs au SARS-CoV-2, 11% rapportent encore des troubles mnésiques, 12% des difficultés de concentration, et une part importante considère que son état s'est dégradé.
Link: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2782531
Extract: "At follow-up, a mean (SD) of 257 (32) days after baseline, 9705 of 13 001 participants (75%) responded, and 72 of 651 of the participants (11%) in the SARS-CoV-2–positive group reported memory problems. In contrast, 254 of 5712 participants (4%) in the SARS-CoV-2–negative group or 80 of 3342 participants (2%) in the untested randomly selected reported memory problems (Figure).

In the multiple logistic regression model, SARS-CoV-2 positivity at baseline was strongly associated with reporting memory problems at 8 months follow-up (odds ratio [OR], 4.66; 95% CI, 3.25-6.66) compared to the untested randomly selected group. At follow-up, 267 of 649 participants (41%) in the SARS-CoV-2–positive group reported a significant worsening of health compared with 1 year prior, and 81 of 651 participants (12%) in the SARS-CoV-2–positive group also reported problems concentrating. Additionally, 59 of 267 participants (82%) in the SARS-CoV-2–positive group who reported memory problems also reported a worsening of health. Feeling depressed, having less energy, or pain were reported relatively equally by the different groups.
The lack of objective memory tests limits strong conclusions. However, subjective memory concerns have been shown to reflect objective problems and observable changes in everyday function even when controlling for associated factors, such as depression.5 Self-reported memory problems are also a risk factor for later mild cognitive impairment or dementia.6 Nevertheless, a more detailed examination of what type of memory problems are specific for PASC, like working memory vs long-term memory, is warranted in future studies. "

2250

N168

AaronJesuthasanaFlaviaMasseybHadiManjicMichael S.ZandicSarahWiethoff

Emerging potential mechanisms and predispositions to the neurological manifestations of COVID-19

https://doi.org/10.1016/j.jns.2021.117608

Published

4-Aug-21

Review

https://www.jns-journal.com/article/S0022-510X(21)00302-6/fulltext

Highlights
•The pathophysiology of NeuroCOVID is complex, likely entailing a combination of separate and overlapping mechanisms.
•There is increasing evidence for genetic predispositions to NeuroCOVID.
•The longer-term symptoms of COVID-19 are being increasingly described and represent an impending burden on healthcare services.
•It is pivotal for future studies to further explore demographic and genetic risk factors for developing long COVID, particularly with regard to chronic neurological symptoms, which remain poorly understood.
The present review subsequently attempts to address the evolving molecular, cellular and systemic mechanisms of NeuroCOVID, which we have classified as the acute and long-term neurological effects of COVID-19. We place particular emphasis on cerebrovascular, demyelinating and encephalitic presentations, which have been reported. Several mechanisms are presented, especially the involvement of a “cytokine storm”. We explore the genetic and demographic factors that may predispose individuals to NeuroCOVID. The increasingly evident long-term neurological effects are also presented, including the impact of the virus on cognition, autonomic function and mental wellbeing, which represent an impending burden on already stretched healthcare services. We subsequently reinforce the need for cautious surveillance, especially for those with predisposing factors, with effective clinical phenotyping, appropriate investigation and, if possible, prompt treatment. This will be imperative to prevent downstream neurological sequelae, including those related to the long COVID phenotypes that are being increasingly recognised.

Une revue d'études du 𝗻𝗲𝘂𝗿𝗼𝗰𝗼𝘃𝗶𝗱, la pathologie neurologique associée à la covid, entreprend d'en décrire la physiopathologie et les possibles facteurs génétiques prédisposants, tels les variants rs73635825 et rs143936283 de la protéine ACE2. L'article évoque la neuro-inflammation chez l'adulte, celle retrouvée selon un spectre similaire chez l'enfant, et s'interroge sur les séquelles à long terme.

N014E

___Neurologic___

Published review on 4-Aug-21:
"Emerging potential mechanisms and predispositions to the neurological manifestations of COVID-19"
Une revue d'études du 𝗻𝗲𝘂𝗿𝗼𝗰𝗼𝘃𝗶𝗱, la pathologie neurologique associée à la covid, entreprend d'en décrire la physiopathologie et les possibles facteurs génétiques prédisposants, tels les variants rs73635825 et rs143936283 de la protéine ACE2. L'article évoque la neuro-inflammation chez l'adulte, celle retrouvée selon un spectre similaire chez l'enfant, et s'interroge sur les séquelles à long terme.
Link: https://www.jns-journal.com/article/S0022-510X(21)00302-6/fulltext
Extract: "Highlights
•The pathophysiology of NeuroCOVID is complex, likely entailing a combination of separate and overlapping mechanisms.
•There is increasing evidence for genetic predispositions to NeuroCOVID.
•The longer-term symptoms of COVID-19 are being increasingly described and represent an impending burden on healthcare services.
•It is pivotal for future studies to further explore demographic and genetic risk factors for developing long COVID, particularly with regard to chronic neurological symptoms, which remain poorly understood.
The present review subsequently attempts to address the evolving molecular, cellular and systemic mechanisms of NeuroCOVID, which we have classified as the acute and long-term neurological effects of COVID-19. We place particular emphasis on cerebrovascular, demyelinating and encephalitic presentations, which have been reported. Several mechanisms are presented, especially the involvement of a “cytokine storm”. We explore the genetic and demographic factors that may predispose individuals to NeuroCOVID. The increasingly evident long-term neurological effects are also presented, including the impact of the virus on cognition, autonomic function and mental wellbeing, which represent an impending burden on already stretched healthcare services. We subsequently reinforce the need for cautious surveillance, especially for those with predisposing factors, with effective clinical phenotyping, appropriate investigation and, if possible, prompt treatment. This will be imperative to prevent downstream neurological sequelae, including those related to the long COVID phenotypes that are being increasingly recognised."

2251

N169

Marco Ruggiero

Application of Ultrasonography to Neuro-COVID-19

https://doi.org/10.21203/rs.3.rs-776630/v1

Pre-print

2-Aug-21

Study

https://www.researchsquare.com/article/rs-776630/v1

Here, it is demonstrated that application of ultrasonography
to Neuro-COVID-19 requires a specific adaptation that takes into account brain movements
synchronous with breathing as well as the sensitivity of SARS-CoV-2 to ultrasounds.

_

2252

N170

E. Guedj CampionJ.DudouetP.KaphanE.BregeonF.CeccaldiM.MillionD.RaoultS.CammilleriC.Eldin

Hypométabolisme TEP cérébral chez les patients atteints de COVID long

https://doi.org/10.1016/j.mednuc.2021.06.023

Published

2-Aug-21

Study

https://www.sciencedirect.com/science/article/pii/S0928125821000735

Par rapport aux sujets sains, les patients avec COVID long présentaient un hypométabolisme bilatéral fronto-basal incluant le bulbe olfactif, le lobe temporal droit comprenant l’amygdale et l’hippocampe s’étendant jusqu’au thalamus droit, le tronc cérébral bulbo-protubérantiel et le cervelet bilatéral (p-voxel < 0,001, p-cluster < 0,05 FWE corrigé). Ces clusters métaboliques étaient discriminants pour distinguer les patients des sujets sains (classification correcte à 100 %). Ils étaient associés à des plaintes fonctionnelles plus nombreuses et à la survenue des symptômes (anosmie, troubles cognitifs, douleurs, insomnie) (p < 0,05). Le métabolisme du cluster frontal, qui comprenait le bulbe olfactif, était encore plus diminué chez les 7 patients traités par des médicaments ciblant ACE dans un contexte d’HTA (p = 0,032) et moins diminué chez les 3 patients ayant effectué des irrigations nasales au stade inital (p < 0,001). Cette étude démontre un profil d’hypométabolisme cérébral TEP chez des patients COVID long avec une infection SARS-CoV-2 démontrée biologiquement et des plaintes fonctionnelles persistantes plus de 3 semaines. Cet hypométabolisme implique le gyrus olfactif et les régions limbiques/paralimbiques connectées, étendues au tronc cérébral et au cervelet. Ces hypométabolismes sont associés aux symptômes, avec une valeur de biomarqueur pour identifier et potentiellement suivre ces patients.

Conclusions
L’hypométabolisme du cluster frontal, qui comprenait le bulbe olfactif, semblait être lié aux médicaments ciblant ACE, avec également un meilleur métabolisme de cette région olfactive chez les patients ayant pratiqué des irrigations nasales décongestionnantes, suggérant un rôle possible des récepteurs ACE en tant que passerelle olfactive de ce neurotropisme.

Communication orale d'une étude déjà publiée (cf supra).

2253

N171

Eric Guedj,1 Silvia Morbelli,2,3 Elsa Kaphan,4 Jacques-Yves Campion,1
Pierre Dudouet,5 Mathieu Ceccaldi,6 Serge Cammilleri,1 Flavio Nobili2,7 and
Carole Eldin

From early limbic inflammation to long COVID sequelae

https://doi.org/10.1093/brain/awab215

Published

17-Jun-21

Article

https://academic.oup.com/brain/advance-article-abstract/doi/10.1093/brain/awab215/6303604

Given the demonstration of viral persistence and inflammation in human olfactory epithelium, with diffusion to brain cortex, brainstem and cerebellum after intranasal inoculation in hamsters, 4 we interpreted the results in long COVID as hypometabolic dysfunction of a brain network connected to the olfactory pathway, through a propagation mechanism previously proposed for other coronaviruses, across the lamina cribrosa, from nose to olfactory bulb,5 where ACE2 receptors are strongly expressed. Of note, both RNA and protein of the virus have been found in neurons of COVID-19 patients, with T cell inflammatory infiltration and microglial activation in macaques after apparent remission (for a review, see Guedj et al.6). Hypometabolism of deeper connected regions in the limbic system, brainstem and cerebellum could at least partially correspond to a diaschisis phenomenon in relation to olfactory pathway deafferentation. An alternative explanation would be the diffusion of inflammation/infection to these more posterior regions through a trans-synaptic mechanism previously reported for other coronaviruses,4 possibly in patients with more severe presentation or those with little recovery after rehabilitation. Further multi-modal imaging studies will be needed to determine the possible contributions of each hypothesis. 18F-FDG PET might also be used to identify hypermetabolism within this network at earlier stages, since this feature has already been reported during the acute phase of COVID-19 (either in the presence or absence of encephalitis), especially by Kas et al.,7 and may more directly reflect inflammation/infection.

Qu'est-ce qui peut faire basculer une infection subaiguë de covid vers les séquelles neurologiques retrouvées dans le covid long ?

Dans un article publié dans Brain, des chercheurs remarquent que les zones d'hypométabolisme cérébral, observées chez l'essentiel des patients de covid long, sont des zones en hypermétabolisme au stade initial d'une infection subaiguë de covid.
Les auteurs interprètent ce résultat comme la marque d'une inflammation cérébrale précoce avec pour conséquence des désordres fonctionnels plus tardif au stade de covid long. Ils notent que cette transition de l’hyper- vers l’hypométabolisme, sur des régions cérébrales spécifiques, est analogue à celle retrouvée dans d'autres modèles inflammatoires et dysimmunitaires comme l’encéphalite.
Une explication avancée est une propagation (précédemment proposée pour d'autres coronavirus), à travers la lame criblée de l'ethmoïde, du nez au bulbe olfactif, où les récepteurs ACE2 sont fortement exprimés. Un rapprochement est fait avec des précédent relevés d'ARN et de protéines du virus dans les neurones chez des patients covid, ainsi qu'une infiltration inflammatoire des lymphocytes T et une activation microgliale chez le singe après une rémission apparente. L'hypométabolisme de régions connectées plus profondément dans le système limbique, le tronc cérébral et le cervelet, pourrait correspondre, au moins partiellement, à un phénomène de diaschisis en relation avec la désafférentation des voies olfactives. Une explication alternative est une diffusion de l'inflammation/infection à des régions davantage postérieures, par un mécanisme trans-synaptique précédemment signalés pour d'autres coronavirus, notamment chez les patients plus sévèrement affectés en phase aiguë.

N014E

___Neurologic___

Published article on 17-Jun-21:
"From early limbic inflammation to long COVID sequelae"
Qu'est-ce qui peut faire basculer une infection subaiguë de covid vers les séquelles neurologiques retrouvées dans le covid long ?

Dans un article publié dans Brain, des chercheurs remarquent que les zones d'hypométabolisme cérébral, observées chez l'essentiel des patients de covid long, sont des zones en hypermétabolisme au stade initial d'une infection subaiguë de covid.
Les auteurs interprètent ce résultat comme la marque d'une inflammation cérébrale précoce avec pour conséquence des désordres fonctionnels plus tardif au stade de covid long. Ils notent que cette transition de l’hyper- vers l’hypométabolisme, sur des régions cérébrales spécifiques, est analogue à celle retrouvée dans d'autres modèles inflammatoires et dysimmunitaires comme l’encéphalite.
Une explication avancée est une propagation (précédemment proposée pour d'autres coronavirus), à travers la lame criblée de l'ethmoïde, du nez au bulbe olfactif, où les récepteurs ACE2 sont fortement exprimés. Un rapprochement est fait avec des précédent relevés d'ARN et de protéines du virus dans les neurones chez des patients covid, ainsi qu'une infiltration inflammatoire des lymphocytes T et une activation microgliale chez le singe après une rémission apparente. L'hypométabolisme de régions connectées plus profondément dans le système limbique, le tronc cérébral et le cervelet, pourrait correspondre, au moins partiellement, à un phénomène de diaschisis en relation avec la désafférentation des voies olfactives. Une explication alternative est une diffusion de l'inflammation/infection à des régions davantage postérieures, par un mécanisme trans-synaptique précédemment signalés pour d'autres coronavirus, notamment chez les patients plus sévèrement affectés en phase aiguë.
Link: https://academic.oup.com/brain/advance-article-abstract/doi/10.1093/brain/awab215/6303604
Extract: "Given the demonstration of viral persistence and inflammation in human olfactory epithelium, with diffusion to brain cortex, brainstem and cerebellum after intranasal inoculation in hamsters, 4 we interpreted the results in long COVID as hypometabolic dysfunction of a brain network connected to the olfactory pathway, through a propagation mechanism previously proposed for other coronaviruses, across the lamina cribrosa, from nose to olfactory bulb,5 where ACE2 receptors are strongly expressed. Of note, both RNA and protein of the virus have been found in neurons of COVID-19 patients, with T cell inflammatory infiltration and microglial activation in macaques after apparent remission (for a review, see Guedj et al.6). Hypometabolism of deeper connected regions in the limbic system, brainstem and cerebellum could at least partially correspond to a diaschisis phenomenon in relation to olfactory pathway deafferentation. An alternative explanation would be the diffusion of inflammation/infection to these more posterior regions through a trans-synaptic mechanism previously reported for other coronaviruses,4 possibly in patients with more severe presentation or those with little recovery after rehabilitation. Further multi-modal imaging studies will be needed to determine the possible contributions of each hypothesis. 18F-FDG PET might also be used to identify hypermetabolism within this network at earlier stages, since this feature has already been reported during the acute phase of COVID-19 (either in the presence or absence of encephalitis), especially by Kas et al.,7 and may more directly reflect inflammation/infection."

2254

N172

Riccardo Manca 1, Matteo De Marco 1, Paul G Ince 1, Annalena Venneri

Heterogeneity in Regional Damage Detected by Neuroimaging and Neuropathological Studies in Older Adults With COVID-19: A Cognitive-Neuroscience Systematic Review to Inform the Long-Term Impact of the Virus on Neurocognitive Trajectories

https://doi.org/10.3389/fnagi.2021.646908

Published

3-Jun-21

Article

https://pubmed.ncbi.nlm.nih.gov/34149394/

Results: Ninety studies, mainly single cases and case series, were included. Several neuroimaging and neuropathological findings in older patients with COVID-19 emerged from these studies, with cerebrovascular damage having a prominent role. Abnormalities (hyperintensities, hypoperfusion, inflammation, and cellular damage) were reported in most brain areas. The most consistent cross-aetiology findings were in white matter, brainstem and fronto-temporal areas. Viral DNA was detected mainly in olfactory, orbitofrontal and brainstem areas. Conclusion: Studies on COVID-19 related neural damage are rich and diverse, but limited to description of hospitalised patients with fatal outcome (i.e., in neuropathological studies) or severe symptoms (i.e., in neuroimaging studies). The damage seen in this population indicates acute and largely irreversible dysfunction to neural regions involved in major functional networks that support normal cognitive and behavioural functioning. It is still unknown whether the long-term impact of the virus will be limited to chronic evolution of acute events, whether sub-clinical pathological processes will be exacerbated or whether novel mechanisms will emerge. Based on current literature, future theoretical frameworks describing the long-term impact of COVID-19 infection on mental abilities will have to factor in major trends of aetiological and topographic heterogeneity.

2255

N173

Garrett M. Timmons, Torge Rempe, Elizabeth A. Bevins, Vanessa Goodwill, Annalise Miner, Arthur Kavanaugh, Michele Ritter, Jennifer S. Graves

CNS Lymphocytic Vasculitis in a Young Woman With COVID-19 Infection

https://doi.org/10.1212/NXI.0000000000001048

Published

28-Jul-21

Case Report

https://nn.neurology.org/content/8/5/e1048

Here, we report additional evidence for COVID-19–related CNS vasculitis, confirmed by biopsy, in a young healthy patient with otherwise mild COVID-19 infection.

_

2256

N174

Luana M. Manosso 1,Camila O. Arent 1,Laura A. Borba 1 ,Luciane B. Ceretta 2,João Quevedo 1,3,4,5 andGislaine Z. Réus

Microbiota-Gut-Brain Communication in the SARS-CoV-2 Infection

https://doi.org/10.3390/cells10081993

Published

6-Aug-21

Review

https://www.mdpi.com/2073-4409/10/8/1993/htm

An exacerbated inflammatory state can lead to the blood–brain barrier (BBB) damage as well as to intestinal dysbiosis. These changes, in turn, are associated with microglial activation and reactivity of astrocytes that can promote the degeneration of neurons and be associated with the development of psychiatric disorders and neurodegenerative diseases. Studies also have been shown that SARS-CoV-2 alters the composition and functional activity of the gut microbiota. The microbiota-gut-brain axis provides a bidirectional homeostatic communication pathway. Thus, this review focuses on studies that show the relationship between inflammation and the gut microbiota–brain axis in SARS-CoV-2 infection.

2257

N175

Melvin R. Hayden

Hypothesis: Neuroglia Activation Due to Increased Peripheral and CNS Proinflammatory Cytokines/Chemokines with Neuroinflammation May Result in Long COVID

https://doi.org/10.3390/neuroglia2010004

Published

30-Aug-21

Review

https://www.mdpi.com/2571-6980/2/1/4/htm

This review aims to summarize many of the cumulated findings associated with LC/PASC and provides supportive and representative illustrations and transmission electron micrographic remodeling changes within brain tissues associated with a stress type of injury as occurs in the classic db/db and novel BTBR ob/ob obesity and diabetes mellitus mice models. These models are utilized to merely provide a response to metabolic stress injury wound healing mechanisms that are also present in humans. This review posits that neuroglial activation and chronic neuroinflammation may be a common denominator for the development of the complex LC/PASC syndrome following acute COVID-19 due to SARS-CoV-2.

2258

N176

Yiping Lu, MD 1
Xuanxuan Li, MD 1
Daoying Geng, MD 1
Nan Mei, MD 1
Pu-Yeh Wu, PhD
Chu-Chung Huang, PhD
Tianye Jia, PhD
Yajing Zhao, MD
Dongdong Wang, MD
Anling Xiao, MD
Bo Yin

Cerebral Micro-Structural Changes in COVID-19 Patients – An MRI-based 3-month Follow-up Study

https://doi.org/10.1016/j.eclinm.2020.100484

Published

3-Aug-20

Study

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(20)30228-5/fulltext

In this prospective study, diffusion tensor imaging (DTI) and 3D high-resolution T1WI sequences were acquired in 60 recovered COVID-19 patients (56.67% male; age: 44.10 ± 16.00) and 39 age- and sex-matched non-COVID-19 controls (56.41% male; age: 45.88 ± 13.90). Registered fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were quantified for DTI, and an index score system was introduced. Regional volumes derived from Voxel-based Morphometry (VBM) and DTI metrics were compared using analysis of covariance (ANCOVA). Two sample t-test and Spearman correlation were conducted to assess the relationships among imaging indices, index scores and clinical information.
• View related content for this article

Findings
In this follow-up stage, neurological symptoms were presented in 55% COVID-19 patients. COVID-19 patients had statistically significantly higher bilateral gray matter volumes (GMV) in olfactory cortices, hippocampi, insulas, left Rolandic operculum, left Heschl's gyrus and right cingulate gyrus and a general decline of MD, AD, RD accompanied with an increase of FA in white matter, especially AD in the right CR, EC and SFF, and MD in SFF compared with non-COVID-19 volunteers (corrected p value <0.05). Global GMV, GMVs in left Rolandic operculum, right cingulate, bilateral hippocampi, left Heschl's gyrus, and Global MD of WM were found to correlate with memory loss (p value <0.05). GMVs in the right cingulate gyrus and left hippocampus were related to smell loss (p value <0.05). MD-GM score, global GMV, and GMV in right cingulate gyrus were correlated with LDH level (p value <0.05).
Interpretation
Study findings revealed possible disruption to micro-structural and functional brain integrity in the recovery stages of COVID-19, suggesting the long-term consequences of SARS-CoV-2.

2259

N177

J. J. Merino, A. Macho-González, J. Benedi & M. P. González

Neurological manifestations of COVID-19 in patients: from path physiology to therapy

https://doi.org/10.1007/s10072-021-05505-7

Published

21-Aug-21

Review

https://link.springer.com/article/10.1007/s10072-021-05505-7

In this review, we update the neurological mechanisms by which coronavirus-19 causes neurological manifestation in patients such as encephalomyelitis, Guillain-Barré syndrome, lacunars infarcts, neuropsychiatry disorders such as anxiety and depression, and vascular alterations. This review explains (a) the possible pathways by which coronavirus-19 can induce the different neurological manifestations, (b) the strategies used by the virus to cross the barrier system, (c) how the immune system responds to the infection, and (d) the treatment than can be administered to the COVID-19 patients.

2260

N178

Bindu D. Paul, Marian D. Lemle, Anthony L. Komaroff, and Solomon H. Snyder

Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome

https://doi.org/10.1073/pnas.2024358118

Published

16-Aug-21

PERSPECTIVE

https://www.pnas.org/content/118/34/e2024358118

Although most patients recover from acute COVID-19, some experience postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC). One subgroup of PASC is a syndrome called “long COVID-19,” reminiscent of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a debilitating condition, often triggered by viral and bacterial infections, leading to years-long debilitating symptoms including profound fatigue, postexertional malaise, unrefreshing sleep, cognitive deficits, and orthostatic intolerance. Some are skeptical that either ME/CFS or long COVID-19 involves underlying biological abnormalities. However, in this review, we summarize the evidence that people with acute COVID-19 and with ME/CFS have biological abnormalities including redox imbalance, systemic inflammation and neuroinflammation, an impaired ability to generate adenosine triphosphate, and a general hypometabolic state. These phenomena have not yet been well studied in people with long COVID-19, and each of them has been reported in other diseases as well, particularly neurological diseases. We also examine the bidirectional relationship between redox imbalance, inflammation, energy metabolic deficits, and a hypometabolic state. We speculate as to what may be causing these abnormalities. Thus, understanding the molecular underpinnings of both PASC and ME/CFS may lead to the development of novel therapeutics.

Dans une revue d'études, un groupe de chercheurs décrit les éléments communs au covid long et à l'encéphalomyélite myalgique. Ils listent notamment un déséquilibre antioxydants/pro-oxydants, une inflammation systémique et une neuro-inflammation, une capacité altérée à générer de l'adénosine triphosphate et un état hypométabolique général.

N014E

___Neurologic___

Published perspective on 16-Aug-21:
"Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome"
Dans une revue d'études, un groupe de chercheurs décrit les éléments communs au covid long et à l'encéphalomyélite myalgique. Ils listent notamment un déséquilibre antioxydants/pro-oxydants, une inflammation systémique et une neuro-inflammation, une capacité altérée à générer de l'adénosine triphosphate et un état hypométabolique général.
Link: https://www.pnas.org/content/118/34/e2024358118
Extract: "Although most patients recover from acute COVID-19, some experience postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC). One subgroup of PASC is a syndrome called “long COVID-19,” reminiscent of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a debilitating condition, often triggered by viral and bacterial infections, leading to years-long debilitating symptoms including profound fatigue, postexertional malaise, unrefreshing sleep, cognitive deficits, and orthostatic intolerance. Some are skeptical that either ME/CFS or long COVID-19 involves underlying biological abnormalities. However, in this review, we summarize the evidence that people with acute COVID-19 and with ME/CFS have biological abnormalities including redox imbalance, systemic inflammation and neuroinflammation, an impaired ability to generate adenosine triphosphate, and a general hypometabolic state. These phenomena have not yet been well studied in people with long COVID-19, and each of them has been reported in other diseases as well, particularly neurological diseases. We also examine the bidirectional relationship between redox imbalance, inflammation, energy metabolic deficits, and a hypometabolic state. We speculate as to what may be causing these abnormalities. Thus, understanding the molecular underpinnings of both PASC and ME/CFS may lead to the development of novel therapeutics."

2261

N179

Richard C. Becker

Autonomic dysfunction in SARS-COV-2 infection acute and long-term implications COVID-19 editor’s page series

https://doi.org/10.1007/s11239-021-02549-6

Published

17-Aug-21

Review

https://link.springer.com/article/10.1007/s11239-021-02549-6

The autonomic nervous system (ANS) is a complex network of nerves originating in the brain, brain stem, spinal cord, heart and extracardiac organs that regulates neural and physiological responses to internal and external environments and conditions. A common observation among patients with the 2019 Coronavirus (CoV) (SARS-severe acute respiratory syndrome CoV-2) (SARS-CoV-2) or COVID-19 [CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019)] in the acute and chronic phases of the disease is tachycardia, labile blood pressure, muscular fatigue and shortness of breath. Because abnormalities in the ANS can contribute to each of these symptoms, herein a review of autonomic dysfunction in SARS-COV-2 infection is provided to guide diagnostic testing, patient care and research initiatives.

2262

N180

Silvia Bozzetti, Sergio Ferrari, Serena Zanzoni, Daniela Alberti, Michele Braggio, Sara Carta, Francesco Piraino, Daniele Gabbiani, Domenico Girelli, Riccardo Nocini, Salvatore Monaco, Ernesto Crisafulli & Sara Mariotto

Neurological symptoms and axonal damage in COVID-19 survivors: are there sequelae?

https://doi.org/10.1007/s12026-021-09220-5

Published

7-Aug-21

Study

https://link.springer.com/article/10.1007/s12026-021-09220-5

The persistence of neurological symptoms after SARS-CoV-2 infection, as well as the presence of late axonal damage, is still unknown. We performed extensive systemic and neurological follow-up evaluations in 107 out of 193 consecutive patients admitted to the COVID-19 medical unit, University Hospital of Verona, Italy between March and June 2020. We analysed serum neurofilament light chain (NfL) levels in all cases including a subgroup (n = 29) of patients with available onset samples. Comparisons between clinical and biomarker data were then performed. Neurological symptoms were still present in a significant number (n = 49) of patients over the follow-up. The most common reported symptoms were hyposmia (n = 11), fatigue (n = 28), myalgia (n = 14), and impaired memory (n = 11) and were more common in cases with severe acute COVID-19. Follow-up serum NfL values (15.2 pg/mL, range 2.4–62.4) were within normal range in all except 5 patients and did not differentiate patients with vs without persistent neurological symptoms. In patients with available onset and follow-up samples, a significant (p < 0.001) decrease of NfL levels was observed and was more evident in patients with a severe acute disease. Despite the common persistence of neurological symptoms, COVID-19 survivors do not show active axonal damage, which seems a peculiar feature of acute SARS-CoV-2 infection.

2263

N181

Edoardo Caronna MD, Alicia Alpuente MD, Marta Torres-Ferrus MD, PhD, Patricia Pozo-Rosich MD, PhD

Toward a better understanding of persistent headache after mild COVID-19: Three migraine-like yet distinct scenarios

https://doi.org/10.1111/head.14197

Published

7-Aug-21

Cases Report

https://headachejournal.onlinelibrary.wiley.com/doi/full/10.1111/head.14197

One year after the outbreak of coronavirus disease 2019 (COVID-19), referrals for persistent headache, often defined as “post-COVID headache,” have become increasingly common in outpatient headache clinics. However, it is important to take into consideration that this term may include a spectrum of clinically different headache types. We describe three cases of migraine-like headaches in individuals with a history of mild COVID-19 infection to demonstrate some of the different phenotypes of persistent headaches seen. These cases highlight the importance of a careful evaluation when assessing the complexities of “post-COVID headache” as well as the need to further investigate the different, underlying, pathophysiological mechanisms.

2264

N182

Ling Zhang, Li Zhou, Linlin Bao, Jiangning Liu, Hua Zhu, Qi Lv, Ruixue Liu, Wei Chen, Wei Tong, Qiang Wei, Yanfeng Xu, Wei Deng, Hong Gao, Jing Xue, Zhiqi Song, Pin Yu, Yunlin Han, Yu Zhang, Xiuping Sun, Xuan Yu & Chuan Qin

SARS-CoV-2 crosses the blood–brain barrier accompanied with basement membrane disruption without tight junctions alteration

https://doi.org/10.1038/s41392-021-00719-9

Published

6-Sep-21

Study

https://www.nature.com/articles/s41392-021-00719-9

SARS-CoV-2 has been reported to show a capacity for invading the brains of humans and model animals. However, it remains unclear whether and how SARS-CoV-2 crosses the blood–brain barrier (BBB). Herein, SARS-CoV-2 RNA was occasionally detected in the vascular wall and perivascular space, as well as in brain microvascular endothelial cells (BMECs) in the infected K18-hACE2 transgenic mice. Moreover, the permeability of the infected vessel was increased. Furthermore, disintegrity of BBB was discovered in the infected hamsters by administration of Evans blue. Interestingly, the expression of claudin5, ZO-1, occludin and the ultrastructure of tight junctions (TJs) showed unchanged, whereas, the basement membrane was disrupted in the infected animals. Using an in vitro BBB model that comprises primary BMECs with astrocytes, SARS-CoV-2 was found to infect and cross through the BMECs. Consistent with in vivo experiments, the expression of MMP9 was increased and collagen IV was decreased while the markers for TJs were not altered in the SARS-CoV-2-infected BMECs. Besides, inflammatory responses including vasculitis, glial activation, and upregulated inflammatory factors occurred after SARS-CoV-2 infection. Overall, our results provide evidence supporting that SARS-CoV-2 can cross the BBB in a transcellular pathway accompanied with basement membrane disrupted without obvious alteration of TJs.

2265

N183

Lu Wang, David Sievert, Alex E. Clark, Sangmoon Lee, Hannah Federman, Benjamin D. Gastfriend, Eric V. Shusta, Sean P. Palecek, Aaron F. Carlin & Joseph G. Gleeson

A human three-dimensional neural-perivascular ‘assembloid’ promotes astrocytic development and enables modeling of SARS-CoV-2 neuropathology

https://doi.org/10.1038/s41591-021-01443-1

Published

9-Jul-21

Study

https://www.nature.com/articles/s41591-021-01443-1

Pericytes are perivascular cells within the brain that are proposed as SARS-CoV-2 infection points. Here we show that pericyte-like cells (PLCs), when integrated into a cortical organoid, are capable of infection with authentic SARS-CoV-2. Before infection, PLCs elicited astrocytic maturation and production of basement membrane components, features attributed to pericyte functions in vivo. While traditional cortical organoids showed little evidence of infection, PLCs within cortical organoids served as viral ‘replication hubs’, with virus spreading to astrocytes and mediating inflammatory type I interferon transcriptional responses. Therefore, PLC-containing cortical organoids (PCCOs) represent a new ‘assembloid’ model that supports astrocytic maturation as well as SARS-CoV-2 entry and replication in neural tissue; thus, PCCOs serve as an experimental model for neural infection.

2266

N184

Eric Guedj,Jacques-Yves Campion,Tatiana Horowitz,Fanny Barthelemy,Serge Cammilleri,Mathieu Ceccaldi,

The impact of COVID-19 lockdown on brain metabolism

https://doi.org/10.1002/hbm.25673

Published

12-Oct-21

Study

https://onlinelibrary.wiley.com/doi/full/10.1002/hbm.25673

This study aims to evaluate the impact of French national lockdown of 55 days on brain metabolism of patients with neurological disorders. Whole-brain voxel-based PET analysis was used to correlate 18F-FDG metabolism to the number of days after March 17, 2020 (in 95 patients; mean age: 54.3 years ± 15.7; 59 men), in comparison to the same period in 2019 before the SARS-CoV-2 outbreak (in 212 patients; mean age: 59.5 years ± 15.8; 114 men), and to the first 55 days of deconfinement (in 188 patients; mean age: 57.5 years ± 16.5; 93 men). Lockdown duration was negatively correlated to the metabolism of the sensory-motor cortex with a prevailing effect on the left dominant pyramidal tract and on younger patients, also including the left amygdala, with only partial reversibility after 55 days of deconfinement. Weak overlap was found with the reported pattern of hypometabolism in long COVID (<9%). Restriction of physical activities, and possible related deconditioning, and social isolation may lead to functional disturbances of sensorimotor and emotional brain networks. Of note, this metabolic pattern seems distinct to those reported in long COVID. Further longitudinal studies with longer follow-up are needed to evaluate clinical consequences and relationships on cognitive and mental health against functional deactivation hypothesis, and to extend these findings to healthy subjects in the context of lockdown.

Une équipe de chercheurs s'est penchée sur les effets du confinement du printemps 2020 sur le métabolisme cérébral, depuis une cohorte de patients présentant des troubles neurologiques (non touchés par la covid a priori). L'objectif était de mesurer par PET-SCAN les effets délétères de la réduction d'activité physique, du déconditionnement, de l'isolement social pendant le confinement, par leurs impacts sur les réseaux cérébraux sensorimoteur et émotionnel. L'étude est faite sur 95 patients d'âge moyen de 54 ans, comparée à une cohorte témoin, et à une cohorte post-confinement. Les résultats montrent chez ces patients des altérations métaboliques du faisceau pyramidal dominant gauche et de l'amygdale cérébrale gauche, qui se résorbent partiellement dans les semaines qui suivent le déconfinement. Les auteurs insistent sur le fait que ce schéma métabolique apparaît distinct de ceux rapportés dans les covid longs, lesquels impliquent principalement les zones limbiques droites, en particulier les zones olfactives avec des hypométabolismes sévères. L'étude présente ces résultats comme des éléments confirmant l'impact négatif du confinement sur la santé mentale et cognitive, mais non superposables aux troubles neurologiques du covid long.

N014

___Neurologic___

Published study on 12-Oct-21:
"The impact of COVID-19 lockdown on brain metabolism"
Une équipe de chercheurs s'est penchée sur les effets du confinement du printemps 2020 sur le métabolisme cérébral, depuis une cohorte de patients présentant des troubles neurologiques (non touchés par la covid a priori). L'objectif était de mesurer par PET-SCAN les effets délétères de la réduction d'activité physique, du déconditionnement, de l'isolement social pendant le confinement, par leurs impacts sur les réseaux cérébraux sensorimoteur et émotionnel. L'étude est faite sur 95 patients d'âge moyen de 54 ans, comparée à une cohorte témoin, et à une cohorte post-confinement. Les résultats montrent chez ces patients des altérations métaboliques du faisceau pyramidal dominant gauche et de l'amygdale cérébrale gauche, qui se résorbent partiellement dans les semaines qui suivent le déconfinement. Les auteurs insistent sur le fait que ce schéma métabolique apparaît distinct de ceux rapportés dans les covid longs, lesquels impliquent principalement les zones limbiques droites, en particulier les zones olfactives avec des hypométabolismes sévères. L'étude présente ces résultats comme des éléments confirmant l'impact négatif du confinement sur la santé mentale et cognitive, mais non superposables aux troubles neurologiques du covid long.
Link: https://onlinelibrary.wiley.com/doi/full/10.1002/hbm.25673
Extract: "This study aims to evaluate the impact of French national lockdown of 55 days on brain metabolism of patients with neurological disorders. Whole-brain voxel-based PET analysis was used to correlate 18F-FDG metabolism to the number of days after March 17, 2020 (in 95 patients; mean age: 54.3 years ± 15.7; 59 men), in comparison to the same period in 2019 before the SARS-CoV-2 outbreak (in 212 patients; mean age: 59.5 years ± 15.8; 114 men), and to the first 55 days of deconfinement (in 188 patients; mean age: 57.5 years ± 16.5; 93 men). Lockdown duration was negatively correlated to the metabolism of the sensory-motor cortex with a prevailing effect on the left dominant pyramidal tract and on younger patients, also including the left amygdala, with only partial reversibility after 55 days of deconfinement. Weak overlap was found with the reported pattern of hypometabolism in long COVID (<9%). Restriction of physical activities, and possible related deconditioning, and social isolation may lead to functional disturbances of sensorimotor and emotional brain networks. Of note, this metabolic pattern seems distinct to those reported in long COVID. Further longitudinal studies with longer follow-up are needed to evaluate clinical consequences and relationships on cognitive and mental health against functional deactivation hypothesis, and to extend these findings to healthy subjects in the context of lockdown."

2267

N185

VP

G.FondabM.MassoncdC.LançonaeR.RichieridefE.Guedj

The neuroinflammatory pathways of post-SARS-CoV-2 psychiatric disorders

https://doi.org/10.1016/j.encep.2021.08.001

Published

30-Aug-21

Editorial

https://www.sciencedirect.com/science/article/pii/S0013700621001706

In this line, a recent review of 90 studies including neuroimaging and post-mortem analysis identified temporo-frontal areas as the most consistent cross-etiology impairment, with also microglial activation, and viral DNA detection in olfactory and orbitofrontal areas [10]. These regions have the highest concentrations of angiotensin-converting enzyme 2 (ACE2) receptor on cell surface, the receptor binding to the 1 subunit of the S protein, one of the four structural proteins of the SARS-CoV-2 virion [11]. The involvement of these limbic brain structures is well-known in emotion regulation and psychiatric disorders [12].
While individuals with severe psychiatric disorders have increased risk of mortality or ICU admission [13], [14], [15], we should not exclude that the infection itself may also more directly contribute to the degradation of mental health in infected people. This should be considered in the benefit/risk balance of non-pharmaceutical interventions taken to limit SARS-COV-2 spread, against psychological consequences of these containment measures.

_

2268

N186

Daša Viszlayová, Martin Sojka, Silvia Dobrodenková, Szabolcs Szabó, Ondrej Bilec, Mária Turzová, Juraj Ďurina, Barbara Baloghová, Zoltán Borbély, Martin Kršák

SARS-CoV-2 RNA in the Cerebrospinal Fluid of a Patient with Long COVID

https://doi.org/10.1177%2F20499361211048572

Published

7-Oct-21

Case Report

https://journals.sagepub.com/doi/10.1177/20499361211048572

We describe a long COVID patient with SARS-CoV-2 RNA in the cerebrospinal fluid, which seems important, specifically due to recent reports of gray matter volume loss in COVID-19 patients. Further studies of SARS-CoV2 RNA, markers of inflammation, and neuronal damage in the CSF of patients with long COVID would be useful and should address whether the CNS can serve as a reservoir of SARS-CoV-2, clarify the pathway by which COVID-19 contributes to CNS dysfunction, and how best to therapeutically address it.

_

2269

N187

Erin Clough, Khoo Ting Chean, Joseph Inigo, Kate E. Tubbesing, Dhyan Chandra, Lee Chaves, Jessica L. Reynolds, Ravikumar Aalinkeel, Stanley A. Schwartz, Alexander Khmaladze & Supriya D. Mahajan

Mitochondrial Dynamics in SARS-COV2 Spike Protein Treated Human Microglia: Implications for Neuro-COVID

https://doi.org/10.1007/s11481-021-10015-6

Published

2-Oct-21

Study

https://link.springer.com/article/10.1007/s11481-021-10015-6

We hypothesize that SAR-COV2 induces mitochondrial dysfunction and activation of the mitochondrial-dependent intrinsic apoptotic pathway, resulting in microglial and neuronal apoptosis. The goal of our study was to determine the effect of SARS-COV2 on mitochondrial biogenesis and to monitor cell apoptosis in human microglia non-invasively in real time using Raman spectroscopy, providing a unique spatio-temporal information on mitochondrial function in live cells. We treated human microglia with SARS-COV2 spike protein and examined the levels of cytokines and reactive oxygen species (ROS) production, determined the effect of SARS-COV2 on mitochondrial biogenesis and examined the changes in molecular composition of phospholipids. Our results show that SARS- COV2 spike protein increases the levels of pro-inflammatory cytokines and ROS production, increases apoptosis and increases the oxygen consumption rate (OCR) in microglial cells. Increases in OCR are indicative of increased ROS production and oxidative stress suggesting that SARS-COV2 induced cell death. Raman spectroscopy yielded significant differences in phospholipids such as Phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE) and phosphatidylcholine (PC), which account for ~ 80% of mitochondrial membrane lipids between SARS-COV2 treated and untreated microglial cells. These data provide important mechanistic insights into SARS-COV2 induced mitochondrial dysfunction which underlies neuropathology associated with Neuro-COVID.

2270

N188

Paola Ortelli, Davide Ferrazzoli, Luca Sebastianelli, Roberto Maestri, Sabrina Dezi, Danny Spampinato, Leopold Saltuari, Alessia Alibardi, Markus Kofler, Angelo Quartarone, Giacomo Koch, Antonio Oliviero,
Viviana Versace

Fatigue and “brain fog” in the aftermath of mild COVID-19: A neuropsychological and TMS study

https://doi.org/10.1016/j.jns.2021.119854

Published

1-Oct-21

Abstract only

https://www.jns-journal.com/article/S0022-510X(21)02550-8/fulltext#relatedArticles

Sixty-seven patients complaining of fatigue and/or “brain fog” and 22 healthy subjects (HS) were enrolled. Fatigue, perceived exertion (evaluated after motor task) and “brain fog” were evaluated. Global cognition and executive functions were assessed with Montreal Cognitive Assessment (MoCA) and Frontal Assessment Battery (FAB). Attention was measured with Sustained Attention, Stroop and Navon computerized-tasks. Transcranial magnetic stimulation (TMS) of the primary motor cortex (M1) evaluated resting motor threshold (RMT), motor evoked potential (MEP) amplitude, and cortical silent period (SP). Intracortical activity was evaluated with paired-pulse TMS protocols including short-interval intracortical inhibition (SICI), reflecting GABAA-mediated inhibition, long-interval intracortical inhibition (LICI), a marker of GABAB receptor activity, and short-latency afferent inhibition (SAI) that indexes central cholinergic transmission.
Results
Patients reported high level of perceived fatigue, exertion and “brain fog”. MOCA and FAB highlighted poorer performances in patients than HS. At computerized tasks, both, sustained and executive attention were impaired. Patients presented higher RMTs, lower MEPs amplitude and longer SPs, as compared to HS, concurring with a reduced M1 excitability. LICI and SAI were impaired, indicating altered GABAB- and cholinergic neurotransmission.
Conclusions
Overall, our results demonstrate, in long COVID-19, an important link between fatigue, “brain fog” and central nervous system dysfunctions, characterized by frontal lobe cognitive impairments and altered neurotransmission.

2271

N189

Ryan C. N. D'Arcy1,2,3*, Jagdeep K. Sandhu4,5, Shawn Marshall6 and Markus Besemann

Mitigating Long-Term COVID-19 Consequences on Brain Health

https://doi.org/10.3389/fneur.2021.630986

Published

27-Sep-21

PERSPECTIVE article

https://www.frontiersin.org/articles/10.3389/fneur.2021.630986/full

2272

N190

ES

Jan Wenzel, Josephine Lampe, Helge Müller-Fielitz, Raphael Schuster, Marietta Zille, Kristin Müller, Markus Krohn, Jakob Körbelin, Linlin Zhang, Ümit Özorhan, Christine Stadelmann, François Trottein, Ruben Nogueiras, Rolf Hilgenfeld, Markus Glatzel, Vincent Prevot & Markus Schwaninger

The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells

https://doi.org/10.1038/s41593-021-00926-1

Published

21-Oct-21

Study

https://www.nature.com/articles/s41593-021-00926-1

Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood–brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the Mpro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.

Une étude publiée dans Nature renforce la piste des dommages de la covid sur les petits vaisseaux cérébraux, pouvant expliquer les troubles neurologiques du covid long. Selon les auteurs, sont mises en évidence des preuves que les cellules endothéliales du cerveau sont infectées et qu'une protéine du SRAS-CoV-2 peut couper des liaisons de la protéine NEMO, ce qui induit la mort de cellules endothéliales et altère la barrière hémato-encéphalique. L'étude note que l'action d'un inhibiteur de la protéine RIPK (dont certains sont en essai clinique, cf https://nature.com/articles/s41573-020-0071-y -https://sciencedirect.com/science/article/abs/pii/S016561472030002X, comme le sorafénib, le ponatinib ou le pazopanib) pourrait aider à traiter la neuropathologie de la covid.

N014E

___Neurologic___

Published study on 21-Oct-21:
"The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells"
Une étude publiée dans Nature renforce la piste des dommages de la covid sur les petits vaisseaux cérébraux, pouvant expliquer les troubles neurologiques du covid long. Selon les auteurs, sont mises en évidence des preuves que les cellules endothéliales du cerveau sont infectées et qu'une protéine du SRAS-CoV-2 peut couper des liaisons de la protéine NEMO, ce qui induit la mort de cellules endothéliales et altère la barrière hémato-encéphalique. L'étude note que l'action d'un inhibiteur de la protéine RIPK (dont certains sont en essai clinique, cf https://nature.com/articles/s41573-020-0071-y -https://sciencedirect.com/science/article/abs/pii/S016561472030002X, comme le sorafénib, le ponatinib ou le pazopanib) pourrait aider à traiter la neuropathologie de la covid.
Link: https://www.nature.com/articles/s41593-021-00926-1
Extract: "Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood–brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the Mpro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19."

2273

N191

Jacqueline H. Becker, PhD1; Jenny J. Lin, MD, MPH1; Molly Doernberg, MPH1; Kimberly Stone, MPH1; Allison Navis, MD2; Joanne R. Festa, PhD2; Juan P. Wisnivesky, MD, DrPH1,3

Assessment of Cognitive Function in Patients After COVID-19 Infection

http://jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2021.30645

Published

22-Oct-21

Study

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2785388

In adjusted analyses, hospitalized patients were more likely to have impairments in attention (odds ratio [OR]: 2.8; 95% CI: 1.3-5.9), executive functioning (OR: 1.8; 95% CI: 1.0-3.4), category fluency (OR: 3.0; 95% CI: 1.7-5.2), memory encoding (OR: 2.3; 95% CI: 1.3-4.1), and memory recall (OR: 2.2; 95% CI: 1.3-3.8) than those in the outpatient group. Patients treated in the ED were more likely to have impaired category fluency (OR: 1.8; 95% CI: 1.1-3.1) and memory encoding (OR: 1.7; 95% CI: 1.0-3.0) than those treated in the outpatient setting. No significant differences in impairments in other domains were observed between groups.

2274

N192

Abhishek Goyal, Khushboo Saxena, Avishek Kar, Parneet Kaur Bhagtana, Chinta Siva Koti Rupa Sridevi, Swanzil Chaudhary & Rashida Ali

Sleep EEG Signatures in COVID-19 Survivors

https://doi.org/10.1007/s41782-021-00174-0

Published

12-Oct-21

Study

https://link.springer.com/article/10.1007/s41782-021-00174-0

Finally 81 patients (55 males, 26 females) underwent Level I PSG. Total sleep time was 345.1 ± 85.1 min. Sleep efficiency was 76.0 ± 14.2%. Mean time (%) during N1, N2, N3 and Rapid Eye movement (REM) was 16.4%, 59.2%, 7.9% and 18.4% percentage, respectively. Mean AHI was 28.7 ± 22.8 per hour and arousal index was 23.9 ± 13.3. Alpha intrusion was the most common EEG finding (78%), followed by cyclical alternating pattern (59%). REM density was significantly increased in 38% of patients. REM alpha bursts and increased spindles were also seen in 27% and 16%.
Conclusion
Abnormal EEG waves are very commonly seen in COVID-19 survivors. Presence of these abnormal PSG-EEG waves hints that COVID-19 might have similar effects as depression, insomnia on these subjects, at least in short run. Whether these changes are temporary or permanent needs to be evaluated by performing serial polysomnographies in patients with COVID-19 ARDS.

2275

N193

Contested

Andrea Dressing, Tobias Bormann, Ganna Blazhenets, Nils Schroeter, Lea I Walter, Johannes Thurow, Dietrich August, Hanna Hilger, Katarina Stete, Kathrin Gerstacker, Susan Arndt, Alexander Rau, Horst Urbach, Siegbert Rieg, Dirk Wagner, Cornelius Weiller, Philipp T Meyer and Jonas A Hosp

Neuropsychological profiles and cerebral glucose metabolism in neurocognitive Long COVID-syndrome

https://doi.org/10.2967/jnumed.121.262677

Published

14-Oct-21

Study

https://jnm.snmjournals.org/content/early/2021/10/14/jnumed.121.262677

Results: Patients self-reported impaired attention, memory, and multitasking abilities (31/31), word-finding difficulties (27/31), and fatigue (24/31). Twelve of 31 patients could not return to the previous level of independence/employment. For all cognitive domains, average group results of the neuropsychological test-battery showed no impairment, but deficits (z-score<-1.5) were present on single-patient level mainly in the domain of visual memory (in 7/31; other domains ≤2/31). Mean MoCA performance (27/30 points) was above the cutoff-value for detection of cognitive impairment (< 26 points), although 9/31 patients performed slightly below this level (23-25 points). In the subgroup of patients who underwent 18F-FDG PET, we found no significant changes of regional cerebral glucose metabolism.
Conclusion: Long COVID patients self-report uniform symptoms hampering their ability to work in a relevant fraction. However, cognitive testing showed minor impairments only on single-patient level approximately six months after the infection, whereas functional imaging revealed no distinct pathological changes. This clearly deviates from previous findings in subacute COVID-19 patients, suggesting that underlying neuronal causes are different and possibly related to the high prevalence of fatigue.

L’approche méthodologique de cette équipe a été critiquée dans une lettre publiée dans Brain (Guedj et al., doi: 10.1093/brain/awab215) associant neurologues et médecins nucléaires de Marseille et Gênes (Italie), en particulier le Pr. Eric Guedj (1er auteur des guidelines européennes en imagerie TEP, doi: 10.1007/s00259-021-05603-w), le Pr. Silvia Morbelli (dernière auteure de ces mêmes guidelines, et responsable de cette activité au sein de l’association européenne de médecine nucléaire: https://www.eanm.org/about/organs/committees/neuroimaging-2/), et par le Pr. Flavio Nobili (neurologue, 1er auteur des recommandations conjointes des sociétés européennes de neurologie et de médecine nucléaire pour l’utilisation clinique de l’imagerie TEP, doi: 10.1111/ene.13728). La critique porte sur les points suivants : la non-disponibilité publique des images analysées, la non-publication dans leurs articles des images individuelles natives avant traitement statistique (nous notons que les publications du groupe de Marseille répondent à ces 2 standards, elles ne font pas l’objet de critiques sur les plateformes de post-review, et que la seule lettre publiée en commentaire de ces travaux par des équipes françaises et brésiliennes est particulièrement positive, doi: 10.1007/s00259-021-05342-y), et enfin plus spécifiquement parce que ces auteurs proposent de normaliser la quantification des images sur l’activité métabolique de la substance blanche alors que celle-ci est décrite comme pathologique de façon consensuelle dans la littérature scientifique (doi: 10.1093/brain/awab215).

2276

N194

Min Lang, Yuh-Shin Chang, William A. Mehan Jr, Sandra P. Rincon & Karen Buch

Long-term neuroimaging follow-up of COVID-19-related leukoencephalopathy

https://doi.org/10.1007/s00234-021-02829-1

Published

18-Oct-21

Short Report

https://link.springer.com/article/10.1007/s00234-021-02829-1

More than a year after the start of the COVID-19 pandemic, long-term neurological manifestations of COVID-19 are increasingly being reported. The long-term sequelae of COVID-19-related leukoencephalopathy, however, remain unclear. Here, we present long-term neuroimaging follow-up in two cases of COVID-19-related leukoencephalopathy. The two cases demonstrate the utility of brain MRI for evaluating neurologic symptoms in critically ill patients with COVID-19, for diagnosis of underlying neural injury and prognostication of future recovery. The presence of leukoencephalopathy may result in chronic neurologic manifestations and may represent a poor prognosticator of neurologic recovery. The presence of leukoencephalomalacia on follow-up neuroimaging is potentially an indicator of irreversible white matter damage, which may be associated with more severe chronic deficits.

2277

N195

Stefano Terruzzi, Maurizia Chiusole, Donatella Ottaviani, Umberto Rozzanigo & Costanza Papagno

A case of anterograde amnesia in an MS-like demyelination after COVID-19

https://doi.org/10.1007/s10072-021-05665-6

Published

18-Oct-21

Case Report

https://link.springer.com/article/10.1007/s10072-021-05665-6

Finally, the case of MK also shows that it is likely that the SARS-CoV-2 infection has produced an inflammatory response with a CNS demyelination. Stress is a trigger for autoimmunity, including MS, and major stressful life events have been associated with an increased risk of developing MS [4]. In the very recent literature, three cases of MS-like demyelination with an atypical presentation associated with COVID-19 have been reported ([5] for review): indeed, in one case MRI lesions were round in shape and larger than typical MS plaques; in another case, lesions were located mainly in the deep white matter and subcortical areas; finally, in the remaining case, despite the presentation with optic neuritis, the associated field defect rendered the presentation atypical. To our knowledge, MK represents the first case of an MS-like demyelination with typical plaques developed after COVID-19 neutralization where an anterograde amnesia is described.

_

2278

N196

Christopher M. Bartley, MD, PhD1,2,3; Claire Johns, MD4; Thomas T. Ngo, BS2,3; Ravi Dandekar, MS2,5; Rita L. Loudermilk, BS2,5; Bonny D. Alvarenga, BA2,5; Isobel A. Hawes, BA2,5,6; Colin R. Zamecnik, PhD2,5; Kelsey C. Zorn, MHS7; Jessa R. Alexander, BA2,5; Anne E. Wapniarski, BA2,5; Joseph L. DeRisi, PhD7,8; Carla Francisco, MD2,5; Kendall B. Nash, MD2,4,5; Sharon O. Wietstock, MD2,5; Samuel J. Pleasure, MD, PhD2,5; Michael R. Wilson, MD2,5

Anti–SARS-CoV-2 and Autoantibody Profiles in the Cerebrospinal Fluid of 3 Teenaged Patients With COVID-19 and Subacute Neuropsychiatric Symptoms

https://doi.org/10.1001/jamaneurol.2021.3821

Published

25-Oct-21

Brief Report

https://jamanetwork.com/journals/jamaneurology/fullarticle/2785032

Are anti–SARS-CoV-2 or antineural antibodies present in the cerebrospinal fluid of pediatric patients with COVID-19 and neuropsychiatric symptoms?

Findings In this case series of 3 pediatric patients with subacute neuropsychiatric impairment, 2 had intrathecal anti–SARS-CoV-2 antibodies as well as intrathecal antineural antibodies. Anti–transcription factor 4 (TCF4) autoantibodies in one patient who responded to immunotherapy were validated.

Meaning A subset of pediatric patients with COVID-19 and subacute neuropsychiatric symptoms have intrathecal antineural autoantibodies, suggesting central nervous system autoimmunity in pediatric patients with COVID-19 and recent neuropsychiatric symptoms.

2279

N197

Robyn Klein, Allison Soung, Cheick Sissoko, Anna Nordvig, Peter Canoll, Madeline Mariani, Xiaoping Jiang, Traci Bricker, James Goldman, Gorazd Rosoklija, Victoria Arango, Mark Underwood, J. John Mann, Adrianus Boon, Andrew Dowrk, Maura Boldrini

COVID-19 induces neuroinflammation and loss of hippocampal neurogenesis

https://doi.org/10.21203/rs.3.rs-1031824/v1

pre-print

29-Oct-21

Study

https://www.researchsquare.com/article/rs-1031824/v1

Infection with the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is associated with onset of neurological and psychiatric symptoms during and after the acute phase of illness1-4. Acute SARS-CoV-2 disease (COVID-19) presents with deficits of memory, attention, movement coordination, and mood. The mechanisms of these central nervous system symptoms remain largely unknown.
In an established hamster model of intranasal infection with SARS-CoV-25, and patients deceased from COVID-19, we report a lack of viral neuroinvasion despite aberrant BBB permeability, microglial activation, and brain expression of interleukin (IL)-1β and IL-6, especially within the hippocampus and the inferior olivary nucleus of the medulla, when compared with non-COVID control hamsters and humans who died from other infections, cardiovascular disease, uremia or trauma. In the hippocampus dentate gyrus of both COVID-19 hamsters and humans, fewer cells expressed doublecortin, a marker of neuroblasts and immature neurons.
Despite absence of viral neurotropism, we find SARS-CoV-2-induced inflammation, and hypoxia in humans, affect brain regions essential for fine motor function, learning, memory, and emotional responses, and result in loss of adult hippocampal neurogenesis. Neuroinflammation could affect cognition and behaviour via disruption of brain vasculature integrity, neurotransmission, and neurogenesis, acute effects that may persist in COVID-19 survivors with long-COVID symptoms.

2280

N198

AnnaHeidbrederaThomasSonnweberbAmbraStefaniaAbubakerIbrahimaMatteoCesariaMelanieBergmannaElisabethBrandaueraIvanTancevskibJudithLöffler-RaggbBirgitHögla

Video-polysomnographic findings after acute COVID-19: REM sleep without atonia as sign of CNS pathology?

https://doi.org/10.1016/j.sleep.2021.01.051

Published

2-Feb-21

Study

https://www.sciencedirect.com/science/article/pii/S138994572100068X

Highlights
1.Sleep disturbances are frequent after acute COVID-19.
2.Isolated REM-sleep without atonia was present in 36% of the patients after COVID-19.
3.Follow-up investigations are needed to elucidate if RWA in the context of COVID-19 is a sign of neurodegeneration.
Eleven patients [nine men, age 52.5 (SD = 11.7) years; BMI 29 (SD = 5.2) kg/m2] were included. At 60 days follow-up after diagnosis, persisting breathing complaints were present in 7/11 (64%) patients. After v-PSG four patients (36%) were diagnosed with obstructive sleep apnea (OSA). Respiratory frequency during sleep was normal and no tachypnea, thoracoabdominal asynchrony, or periodic deep sighing were detected. Four patients (36%) showed REM sleep without atonia (RWA), and two additional patients showed an RWA index within the highest range of normality.

2281

N199

Brandon J. DeOre, Kiet A. Tran, Allison M. Andrews, Servio H. Ramirez & Peter A. Galie

SARS-CoV-2 Spike Protein Disrupts Blood–Brain Barrier Integrity via RhoA Activation

https://doi.org/10.1007/s11481-021-10029-0

Published

23-Oct-21

Brief Report

https://link.springer.com/article/10.1007/s11481-021-10029-0

The SARS-CoV-2 spike protein has been shown to disrupt blood–brain barrier (BBB) function, but its pathogenic mechanism of action is unknown. Whether angiotensin converting enzyme 2 (ACE2), the viral binding site for SARS-CoV-2, contributes to the spike protein-induced barrier disruption also remains unclear. Here, a 3D-BBB microfluidic model was used to interrogate mechanisms by which the spike protein may facilitate barrier dysfunction. The spike protein upregulated the expression of ACE2 in response to laminar shear stress. Moreover, interrogating the role of ACE2 showed that knock-down affected endothelial barrier properties. These results identify a possible role of ACE2 in barrier homeostasis. Analysis of RhoA, a key molecule in regulating endothelial cytoskeleton and tight junction complex dynamics, reveals that the spike protein triggers RhoA activation. Inhibition of RhoA with C3 transferase rescues its effect on tight junction disassembly. Overall, these results indicate a possible means by which the engagement of SARS-CoV-2 with ACE2 facilitates disruption of the BBB via RhoA activation. Understanding how SARS-CoV-2 dysregulates the BBB may lead to strategies to prevent the neurological deficits seen in COVID-19 patients.

todo

2282

N200

Mona Khan Seung-Jun Yoo Marnick Clijsters Wout Backaert Arno Vanstapel Kato Speleman Charlotte Lietaer Sumin Choi Tyler D. Hether Lukas Marcelis Andrew Nam Liuliu Pan Jason W. Reeves Pauline Van Bulck Hai Zhou Marc Bourgeois Yves Debaveye Paul De Munter Jan Gunst Mark Jorissen Katrien Lagrou Natalie Lorent Arne Neyrinck Marijke Peetermans Dietmar Rudolf Thal Christophe Vandenbriele Joost Wauters Peter Mombaerts Laura Van Gerven

Visualizing in deceased COVID-19 patients how SARS-CoV-2 attacks the respiratory and olfactory mucosae but spares the olfactory bulb

https://doi.org/10.1016/j.cell.2021.10.027

Published

2-Nov-21

Study

https://www.cell.com/cell/fulltext/S0092-8674(21)01282-4

Highlights
- Postmortem bedside surgical procedure was developed for COVID-19 and control patients
- Ciliated cells are the main target cell type for SARS-CoV-2 in respiratory mucosa
- Sustentacular cells (non-neuronal) are the main target cell type in olfactory mucosa
- No evidence for infection of olfactory sensory neurons or olfactory bulb parenchyma

2283

N201

Finja Schweitzer PhD,Yasemin Goereci MD,Christiana Franke MD,Steffi Silling PhD,Fabian Bösl MD,Franziska Maier PhD,Eva Heger PhD,Birgit Deiman PhD,Harald Prüss MD,Oezguer A. Onur MD,Florian Klein MD,Gereon Fink MD,Veronica Di Cristanziano MD,Clemens Warnke MD

CSF analysis in post-COVID-19 is not suggestive of persistent CNS infection

https://doi.org/10.1002/ana.26262

Published

1-Nov-21

Brief Communication

https://onlinelibrary.wiley.com/doi/10.1002/ana.26262

Results
Cerebrospinal fluid was assessed between day 1-30 (n=12), between day 31-90 (n=8), or later than 90 days (post-COVID-19, n=20) of COVID-19 diagnosis. SARS-CoV-2 RNA was absent in all patients, and in none of the 20 patients with post-COVID-19 syndrome intrathecally produced anti-SARS-CoV-2 antibodies were detected.
Interpretation
The absence of evidence of SARS-CoV-2 in cerebrospinal fluid argues against a persistent central nervous system infection as a cause of neurological or neuropsychiatric post-COVID-19 syndrome.

2284

N202

O. A. Gromova, I. Yu. Torshin, V. A. Semenov, M. V. Putilina & A. G. Chuchalin

Direct and Indirect Neurological Signs of COVID-19

https://doi.org/10.1007/s11055-021-01144-9

Published

4-Nov-21

Review

https://link.springer.com/article/10.1007%2Fs11055-021-01144-9

Results. A set of interactions between infection with SARS-CoV-2, metabolic impairments affecting neurotransmitters (acetylcholine, dopamine, serotonin, and GABA), enkephalins, and neurotrophins, micronutrients, chronic and acute inflammation, encephalopathy, cerebral ischemia, and neurodegeneration (including demyelination) was described. The most typical neurological manifestations of COVID-19 were anosmia/ageusia due to ischemia, neurodegeneration, and/or systematic increases in proinflammatory cytokine levels. COVID-19 provoked ischemic stroke, Guillain–Barré syndrome, polyneuropathy, encephalitis, meningitis, and parkinsonism. Coronavirus infection increased the severity of multiple sclerosis and myopathies. The possible roles of the human virome in the pathophysiology of COVID-19 are considered. A clinical case of a patient with neurological complications of COVID-19 is described. Conclusions. In the long-term perspective, COVID-19 promotes increases in neurodegenerative changes, which requires special neurological rehabilitation programs. Use of cholinergic drugs and antihypoxic agents compatible with COVID-19 therapy is advised.

2285

N203

Bernhard Prem, David T. Liu, Gerold Besser, Gunjan Sharma, Laura E. Dultinger, Sissy V. Hofer, Martina M. Matiasczyk, Bertold Renner & Christian A. Mueller

Long-lasting olfactory dysfunction in COVID-19 patients

https://doi.org/10.1007/s00405-021-07153-1

Published

10-Nov-21

Study

https://link.springer.com/article/10.1007/s00405-021-07153-1

Results
After a mean 216 days (SD 73; range 111–457) between OD onset and follow-up testing, the mean Sniffin’ Sticks (TDI) score was 27.1 points (SD 5.8; range 4.25–38.5): 4.0% were anosmic, 72.5% hyposmic, and 23.5% normosmic. At follow-up testing, 73.5% of patients reported improvement, 5.9% deterioration, and 20.6% no change in OD. Moreover, full recovery of self-perceived smell, flavor, and taste was not observed. According to questionnaires, the individual importance of smell did not change, but participants showed improvement in OD-related quality of life (p < 0.001) and had increased parosmia scores (p = 0.014) at follow-up.
Conclusion
Our results show that long-lasting OD after SARS-CoV-2 infection is a common symptom. The majority of patients had OD in the range of hyposmia, which was confirmed by comprehensive smell tests.

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2286

N204

Amish M. Khan, BS1; Dorina Kallogjeri, MD, MPH1,2; Jay F. Piccirillo

Growing Public Health Concern of COVID-19 Chronic Olfactory Dysfunction

http://jamanetwork.com/article.aspx?doi=10.1001/jamaoto.2021.3379

Published

Research Letter

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2786433

Based on intermediate estimates, the number of US individuals expected to develop COD by August 2021 was 712 268. Based on low estimates for each event, the number of US individuals who are expected to develop COD is 170 238, and based on the highest estimate, the number is 1 600 241.
Disorders estimated that, among US adults 40 years or older, measurable OD was found in up to 13.3 million adults.6 Notably, the age-specific prevalence of OD is 4.2% for individuals between age 40 to 49 years and 39.4% for individuals 80 years and older. The addition of 0.7 to 1.6 million new cases of COD represents a 5.3% to 12% relative increase. COVID-19 affects a younger demographic group than other causes of OD. Thus, the lifelong burden of OD will be much greater for the COVID-19 cohort than for patients in the older age groups. The true number of COD may be far higher than the results in this article indicate.

2287

N205

Abdul Mannan Baig

Counting the neurological cost of COVID-19

https://doi.org/10.1038/s41582-021-00593-7

Published

18-Nov-21

Article

https://www.nature.com/articles/s41582-021-00593-7

Unlike the oral cavity, the olfactory mucosa in the nose lacks lymphoid aggregates, and this feature could be exploited by SARS-CoV-2 to gain access to the CNS across the cribriform plate. En route to the CNS, SARS-CoV-2 seems to leave signatures in the form of traces of viral RNA and budding of virions from the cells in the olfactory epithelium, olfactory bulb and frontal lobe of the brain4,5,7. In addition, factors such as hypoxia, cerebral ischaemia and the cytokine storm might act together with the neurotrophic effects of SARS-CoV-2 to produce the neurological damage that is reported in COVID-19.
With the ongoing COVID-19 pandemic, clusters of patients have emerged with symptoms that continue beyond the acute phase of the disease — a condition commonly known as ‘long COVID’8. A substantial proportion of these so-called ‘long-haulers’ have neurological manifestations, and there is an urgent need to address their health issues. A global consensus is needed on diagnostic approaches, management modalities and follow-up to ensure the well-being of long-haulers in general, and to address the neurological features of COVID-19 in particular9. Topical therapy with antiviral drugs and antibodies, administered via nebulizers and nasal sprays at the portal of entry of SARS-CoV-2, is expected to reduce viral loads and minimize the incidence of neurological complications10.
In conclusion, the accumulating evidence on neurological sequelae in patients with COVID-19 is a cause for concern. Without proper care and treatment, patients with these neurological manifestations might be permanently debilitated. Moreover, the continuation of neurological symptoms in long COVID could overwhelm already fractured health-care systems. Consequently, we urgently need to understand and respond to the covert yet potentially incapacitating neurological consequences of COVID-19 in the acute and chronic phases of the disease.

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2288

N206

Luigi Angelo Vaira, MD, Giovanni Salzano, MD, Serge Le Bon, MD, Angelantonio Maglio, MD, Marzia Petrocelli, MD, Younes Steffens, MD, Enrica Ligas, MSN, Fabio Maglitto, MD, Jerome R. Lechien, MD, PhD, Sven Saussez, MD, PhD, Alessandro Vatrella, MD, Francesco Antonio Salzano, MD, Paolo Boscolo-Rizzo, MD, Claire Hopkins, FRSC (ORLHNS), DM (Oxon), Giacomo De Riu

Prevalence of Persistent Olfactory Disorders in Patients With COVID-19: A Psychophysical Case-Control Study With 1-Year Follow-up

https://doi.org/10.1177%2F01945998211061511

Published

23-Nov-21

Study

https://journals.sagepub.com/doi/abs/10.1177/01945998211061511

The purpose of this multicenter case-control study was to evaluate a group of patients at least 1 year after coronavirus disease 2019 (COVID-19) with Sniffin’ Sticks tests and to compare the results with a control population to quantify the potential bias introduced by the underlying prevalence of olfactory dysfunction (OD) in the general population. The study included 170 cases and 170 controls. In the COVID-19 group, 26.5% of cases had OD (anosmia in 4.7%, hyposmia in 21.8%) versus 3.5% in the control group (6 cases of hyposmia). The TDI score (threshold, discrimination, and identification) in the COVID-19 group was significantly lower than in the control group (32.5 [interquartile range, 29-36.5] vs 36.75 [34-39.5], P < .001). The prevalence of OD was significantly higher in the COVID-19 group, confirming that this result is not due to the underlying prevalence of OD in the general population.

_

2289

N207

SadafIftikharFCPSa1Aqeeb UrRehmanb1Muhammad ZainAmeerbAhmadNawazbMuhammadAemaz Ur RehmanMBBSaHareemFarooqMBBSaAbyazAsmarMBBSaMuhammadEbaad Ur Rehmanc

The association of posterior reversible encephalopathy syndrome with COVID-19: A systematic review

https://doi.org/10.1016/j.amsu.2021.103080

Published

20-Nov-21

Review

https://www.sciencedirect.com/science/article/pii/S204908012101030X

Highlights
•Posterior Reversible Encephalopathy Syndrome (PRES) is a neurological complication of COVID-19.
•SARS-CoV-2 disrupts the integrity of cerebral blood vessels through cytokine storm, thus driving the edema of PRES.
•COVID-19 is probably additive with hypertension, diabetes and tocilizumab in causing PRES.
•Timely diagnosis and treatment are necessary to avoid complications such as cerebral hemorrhage, epilepsy and vision loss.
•A favorable outcome is observed in most cases.
After rigorous screening as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a total of 34 articles describing 56 cases were selected as a part of this review. The mean age of the patients was 56.6 ± 15.3 years. The most common clinical presentation of PRES was altered mental status (58.9%) followed by seizures (46.4%) and visual disturbances (23.2%) while hypertension and diabetes mellitus were the most commonly reported comorbidities. 91.1% of the cases reported Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) findings suggestive of PRES in the brain. Symptomatic management was employed in most of the cases to control seizures and blood pressure, and 44 patients (78.5%) fully or partially recovered. The most likely underlying mechanism involves COVID-19 mediated cytokine storm syndrome that leads to endothelial damage and increased permeability of the cerebral vessels, thus causing the characteristic edema of PRES. High neuronal and glial cell expression of Angiotensin Converting Enzyme-2 (ACE-2) receptors also suggests the possibility of direct viral damage. Since timely diagnosis and treatment reports a good prognosis, it is vital for physicians and neurologists to be well-versed with this association.

_

2290

N208

Dandan Wan, Tingfu Du, Weiqi Hong, Li Chen, Haiying Que, Shuaiyao Lu & Xiaozhong Peng

Neurological complications and infection mechanism of SARS-COV-2

https://doi.org/10.1038/s41392-021-00818-7

Published

23-Nov-21

Review

https://www.nature.com/articles/s41392-021-00818-7

In this review, we primarily describe the clinical neurological complications associated with SARS-CoV-2 and discuss the potential mechanisms through which SARS-CoV-2 invades the brain based on the current evidence. Finally, we summarize the experimental models were used to study SARS-CoV-2 neuroinvasion. These data form the basis for studies on the significance of SARS-CoV-2 infection in the brain.

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2291

N209

Klaus J. Wirth, Carmen Scheibenbogen & Friedemann Paul

An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

https://doi.org/10.1186/s12967-021-03143-3

Published

22-Nov-21

Review

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-021-03143-3

In this paper we deduce the pathomechanisms resulting in central nervous pathology and the myriad of neurocognitive symptoms. We outline tentative mechanisms of impaired cerebral blood flow, increase in intracranial pressure and central adrenergic hyperactivity and how they can well explain the key symptoms of cognitive impairment, brain fog, headache, hypersensitivity, sleep disturbances and dysautonomia.

2292

N210

Thorsten Rudroff 1,2,* ,Craig D. Workman 1 andLaura L. Boles Ponto 3

18F-FDG-PET Imaging for Post-COVID-19 Brain and Skeletal Muscle Alterations

https://doi.org/10.3390/v13112283

Published

15-Nov-21

Review

https://www.mdpi.com/1999-4915/13/11/2283/htm

Scientific evidence concerning the subacute and long-term effects of coronavirus disease 2019 (COVID-19) is on the rise. It has been established that infection by serious acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a systemic process that involves multiple organs. The complications and long-term consequences of COVID-19 are diverse and patients need a multidisciplinary treatment approach in the acute and post-acute stages of the disease. A significant proportion of COVID-19 patients experience neurological manifestations, some enduring for several months post-recovery. However, brain and skeletal muscle changes resultant from SARS CoV-2 infection remain largely unknown. Here, we provide a brief overview of the current knowledge, and usefulness, of [18F]fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) to investigate brain and skeletal muscles changes in Post-COVID-19 patients with persistent symptoms. Furthermore, a brief discussion of future 18F-FDG-PET/CT applications that might advance the current knowledge of the pathogenesis of post-COVID-19 is also provided.

2293

N211

SadafIftikharFCPSa1Aqeeb UrRehmanb1Muhammad ZainAmeerbAhmadNawazbMuhammadAemaz Ur RehmanMBBSaHareemFarooqMBBSaAbyazAsmarMBBSaMuhammadEbaad Ur Rehmanc

The association of posterior reversible encephalopathy syndrome with COVID-19: A systematic review

https://doi.org/10.1016/j.amsu.2021.103080

Published

20-Nov-21

Review

https://www.sciencedirect.com/science/article/pii/S204908012101030X

Highlights
•Posterior Reversible Encephalopathy Syndrome (PRES) is a neurological complication of COVID-19.
•SARS-CoV-2 disrupts the integrity of cerebral blood vessels through cytokine storm, thus driving the edema of PRES.
•COVID-19 is probably additive with hypertension, diabetes and tocilizumab in causing PRES.
•Timely diagnosis and treatment are necessary to avoid complications such as cerebral hemorrhage, epilepsy and vision loss.
•A favorable outcome is observed in most cases.
The most common clinical presentation of PRES was altered mental status (58.9%) followed by seizures (46.4%) and visual disturbances (23.2%) while hypertension and diabetes mellitus were the most commonly reported comorbidities. 91.1% of the cases reported Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) findings suggestive of PRES in the brain. Symptomatic management was employed in most of the cases to control seizures and blood pressure, and 44 patients (78.5%) fully or partially recovered. The most likely underlying mechanism involves COVID-19 mediated cytokine storm syndrome that leads to endothelial damage and increased permeability of the cerebral vessels, thus causing the characteristic edema of PRES. High neuronal and glial cell expression of Angiotensin Converting Enzyme-2 (ACE-2) receptors also suggests the possibility of direct viral damage. Since timely diagnosis and treatment reports a good prognosis, it is vital for physicians and neurologists to be well-versed with this association.

_

2294

N212

Athanasia Pataka 1,* ,Seraphim Kotoulas 1 ,Elpitha Sakka 2,Paraskevi Katsaounou 3 andSofia Pappa 4,5

Sleep Dysfunction in COVID-19 Patients: Prevalence, Risk Factors, Mechanisms, and Management

https://doi.org/10.3390/jpm11111203

Published

14-Nov-21

Review

https://www.mdpi.com/2075-4426/11/11/1203/htm

Evidence to date suggests that a considerable proportion of COVID-19 patients experience significant sleep disturbances (estimated to afflict up to 50–75%) as well as psychological distress such as depression, anxiety, and traumatic stress. Duration of hospitalization, pre-existing mental health concerns, lower absolute lymphocyte count, and increased neutrophil-to-lymphocyte ratio have been all associated with a greater risk of sleep dysfunction in infected and hospitalized patients. Furthermore, in this review, we discuss the link between sleep deprivation, susceptibility to viral infections, and psychosocial wellbeing in relevance to COVID-19 and summarize the existing evidence regarding the presence and role of sleep apnea in infected individuals. Finally, we highlight the importance of suitable interventions in order to prevent and manage sleep dysfunction and avoid long-term physical and psychological implications. Future research should aim to provide high-quality information including in high risk, underserved, or difficult to reach populations and on the long-term consequences and effectiveness of applied interventions.

_

2295

N213

RayanKhaddaj-MallatacNatijaAldibabcMaximeBernardacAnne-SophiePaquetteacAymericFerreirabdSarahLecordieracArmenSaghatelyanbcLouisFlamandaeAymanElAliac

SARS-CoV-2 deregulates the vascular and immune functions of brain pericytes via Spike protein

https://doi.org/10.1016/j.nbd.2021.105561

Published

13-Nov-21

Study

https://www.sciencedirect.com/science/article/pii/S0969996121003107

Using cell-based assays, we found that ACE2 expression in human brain vascular pericytes was increased upon S protein exposure. Pericytes exposed to S protein underwent profound phenotypic changes associated with an elongated and contracted morphology accompanied with an enhanced expression of contractile and myofibrogenic proteins, such as α-smooth muscle actin (α-SMA), fibronectin, collagen I, and neurogenic locus notch homolog protein-3 (NOTCH3). On the functional level, S protein exposure promoted the acquisition of calcium (Ca2+) signature of contractile ensheathing pericytes characterized by highly regular oscillatory Ca2+ fluctuations. Furthermore, S protein induced lipid peroxidation, oxidative and nitrosative stress in pericytes as well as triggered an immune reaction translated by activation of nuclear factor-kappa-B (NF-κB) signaling pathway, which was potentiated by hypoxia, a condition associated with vascular comorbidities that exacerbate COVID-19 pathogenesis. S protein exposure combined to hypoxia enhanced the production of pro-inflammatory cytokines involved in immune cell activation and trafficking, namely macrophage migration inhibitory factor (MIF). Using transgenic mice expressing the human ACE2 that recognizes S protein, we observed that the intranasal infection with SARS-CoV-2 rapidly induced hypoxic/ischemic-like pericyte reactivity in the brain of transgenic mice, accompanied with an increased vascular expression of ACE2. Moreover, we found that SARS-CoV-2 S protein accumulated in the intranasal cavity reached the brain of mice in which the nasal mucosa is deregulated. Collectively, these findings suggest that SARS-CoV-2 S protein impairs the vascular and immune regulatory functions of brain pericytes, which may account for vascular-mediated brain damage. Our study provides a better understanding for the mechanisms underlying cerebrovascular disorders in COVID-19, paving the way to develop new therapeutic interventions.
Highlights
•SARS-CoV-2 S protein increases ACE2 expression in brain pericytes.
•ACE2+ brain pericytes adopt a contractile and myofibrogenic phenotype upon exposure to SARS-CoV-2 S protein.
•Intracellular Ca2+ dynamics are altered in brain pericytes exposed to SARS-CoV-2 S protein.
•SARS-CoV-2 S protein induces a potent inflammatory response in brain pericytes.
•Hypoxia potentiates SARS-CoV-2 S protein mediated effects on brain pericytes.
•SARS-CoV-2 infection induces an ischemic-like pericyte and vascular ACE2 reactivity in mice expressing human ACE2.

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2296

N214

FlaviaMattiolia1SimonePivabe2ChiaraStampatoria1FrancescaRighettia1IlariaMegaa1ElenaPelib2EmmaSalacCesareTomasic2Anna MariaIndelicatoe3NicolaLatronicobde24GiuseppeDe Palmae34

Neurologic and cognitive sequelae after SARS-CoV2 infection: Different impairment for ICU patients

https://doi.org/10.1016/j.jns.2021.120061

Published

26-Nov-21

Study

https://www.sciencedirect.com/science/article/abs/pii/S0022510X21027635

Highlights
•Neurological and cognitive sequelae of COVID-19 in the long term are unknown.
•Brain fog and memory deficits are frequently but not homogeneously reported by patients.
•We compared neurological deficits and cognition in mild versus severe/critical COVID-19 (ICU) cases) after four months.
•Neurological deficits and Cognitive Impairment were more frequent and severe in ICU cases.
•PNS was prominently involved and executive functions were mostly impaired.
Neurological deficits were found in 2/163 (1.2%) of non-ICU and in 7/52 (13.5%) of the ICU cases, all involving the peripheral nervous system. ICU patients performed significantly worse in all the neuropsychological tests and showed a worse age- and education-corrected cognitive impairment: Cognitive Impairment Index (CII) was higher in ICU than in non-ICU patients (median ICU 3 vs 2, p = .001).

_

2297

N215

Philip Hunter

Viral diseases and the brain
Long COVID puts the spotlight on how viral infections affect the brain

https://doi.org/10.15252/embr.202154342

Published

29-Nov-21

Study

https://www.embopress.org/doi/full/10.15252/embr.202154342

This specific research has been boosted though in light of the long-term neurological effects of SARS-CoV-2 under the banner of Long COVID. Indeed, the pandemic is providing generally fresh insights into the link between viral infections, inflammation, and neurogenerative diseases like Alzheimer’s Disease (AD) and the underlying mechanisms and causes of symptoms such as fatigue or cognitive impairment.

2298

N216

Amar D. Desai, MPH +
Brian C. Boursiquot, MD +
Catherine J. Moore, RN
Rakesh Gopinathannair, MD
Marc P. Waase, MD, PhD
Geoffrey A. Rubin, MD
Elaine Y. Wan, MD
Show less
Show footnotes

Autonomic dysfunction post-acute COVID-19 infection

https://doi.org/10.1016/j.hrcr.2021.11.019

Published

26-Nov-21

Study

https://www.heartrhythmcasereports.com/article/S2214-0271(21)00223-2/fulltext

In this small cohort of patients diagnosed with AD post-SARS-CoV-2 infection, a majority were women, and few had preexisting conditions, suggesting the unpredictability of developing AD after COVID-19 infection. Beta-blockers and vaccines both show efficacy in improving symptoms of suspected post-COVID AD. Further follow-up is necessary to assess efficacy of therapeutics, length of treatment, and time to recovery. Larger prospective studies with longer follow-up are needed to test efficacy of treatments for relief of AD symptoms following COVID-19. Lastly, as novel variants continue to arise, the impact of SARS-CoV-2 reinfection of previously infected individuals, including those with autonomic dysfunction following their first bout of the virus, should be performed to specifically evaluate the impact of reinfection on long-term sequelae like autonomic dysfunction.
Key-Points:
•AD post-SARS-CoV-2 infection affects primarily female patients without a clear history of pre-existing conditions
•AD post-SARS-CoV-2 affects patients showed of a wide age distribution
•Beta-blockers and vaccines show strong efficacy in improving symptoms of suspected post-COVID AD

2299

N217

Amish M. Khan, BS1; Dorina Kallogjeri, MD, MPH1,2; Jay F. Piccirillo, MD1,3

Growing Public Health Concern of COVID-19 Chronic Olfactory Dysfunction

https://doi.org/10.1001/jamaoto.2021.3379

Published

18-Nov-21

Study

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2786433

This analysis of new daily cases of COVID-19, acute incidence of OD, and rates of recovery suggest that more than 700 000, and possibly as many as 1.6 million, US individuals experience COD because of SARS-CoV-2. To put this number in context, before the COVID-19 pandemic, the National Institute on Deafness and Other Communication Disorders estimated that, among US adults 40 years or older, measurable OD was found in up to 13.3 million adults.6 Notably, the age-specific prevalence of OD is 4.2% for individuals between age 40 to 49 years and 39.4% for individuals 80 years and older. The addition of 0.7 to 1.6 million new cases of COD represents a 5.3% to 12% relative increase. COVID-19 affects a younger demographic group than other causes of OD. Thus, the lifelong burden of OD will be much greater for the COVID-19 cohort than for patients in the older age groups. The true number of COD may be far higher than the results in this article indicate.

2300

N218

Jamoulle, Marc mailto [Université de Liège - ULiège > Département des sciences cliniques > Département des sciences cliniques >]
Kazeneza-Mugisha, Gisele []
Zayane, Ayoub

Descriptive and narrative study of Long Covid cases in general practice and diagnostic value of brain scintigraphy

Published

Study

https://orbi.uliege.be/handle/2268/265876

In thirteen of the twenty one cases presented, brain scans (ECD Tc-99m) were able to demonstrate a severe disorder of cerebral perfusion. Two follow-up brain scans at three months showed significant improvement. In ten cases, laboratory evidence was lacking. Tissue antibody testing (B-cells) is expected. A patient who presents several months after a Covid with medically unexplained symptoms may well be a Long Covid. There is no known specific treatment. Neurocognitive revalidation and physiotherapy may help those patients who need long-term empathic support to cope with their condition.

2301

N219

Antoine Verger, Aurélie Kas, Pierre Dudouet, François Goehringer, Dominique Salmon, Eric Guedj

Visual Interpretation of Brain Hypometabolisms Related to Neurological Long COVID: A French Multicentric Experience

https://doi.org/10.21203/rs.3.rs-1159513/v1

pre-print

20-Dec-21

SHORT REPORT

https://www.researchsquare.com/article/rs-1159513/v1

This multicenter study aims to provide a qualitative and consensual description of brain 18F-FDG PET images in patients with suspected neurological long COVID, regarding the previously reported pattern involving olfactory bulbs and other limbic/paralimbic regions, as well as the brainstem and cerebellum.
Methods: From the beginning of August 2021 to the end of October 2021, brain 18F-FDG PET exams of patients referred for suspected neurological long COVID with positive reverse transcription polymerase chain reaction (RT-PCR) and/or serology for the SARS-CoV-2 infection were retrospectively reviewed in three French Nuclear Medicine departments. Experimented nuclear physicians from each department had to classify according to the same visual interpretation analysis brain 18F-FDG PET scans as being normal, mildly to moderate (incomplete or moderately hypometabolic), or severely affected within the previously reported long COVID hypometabolic pattern.
Results: On the 143 brain 18F-FDG PET performed during this period 3 months, 53% of scans were visually interpreted as normal, 31% as mildly to moderate and 16% as severely affected according to the COVID hypometabolic pattern. Importantly, this specific hypometabolic pattern is reported as identical in the three Nuclear Medicine departments. Typical illustrative examples are provided to help nuclear physicians in the interpretation of long COVID pattern.
Conclusion: The proposed PET metabolic pattern is easily identified at visual interpretation in clinical routine in part of patients with suspicion of neurological long COVID, requiring special consideration for fronto-basal paramedian regions, the brainstem and cerebellum.

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2302

N220

Katarzyna Sklinda1,Andrzej Górecki2,Małgorzata Dorobek3,Jerzy Walecki1,Aneta Modrzyńska3,Bartosz Mruk

Ischemic background of brain fog in long haul COVID-19 – a nuclear magnetic resonance spectroscopy-based metabonomic analysis. Preliminary results

https://doi.org/10.5114/pjr.2021.111100

Published

13-Dec-21

Original paper

http://www.polradiol.com/Ischemic-background-of-brain-fog-in-long-haul-COVID-19-a-nuclear-magnetic-resonance-spectroscopy-based-metabonomic-analysis-Preliminary-results,126,45699,1,1.html

A significantly higher concentration of Glx has been found in deep cerebral grey matter in patients suffering from brain fog, as shown in Figure 3, comparing to the metabolic status of a healthy volunteer, as shown in Figure 4. We extrapolate the knowledge of biochemical changes seen in stroke and recognize the metabolic features suggestive of cerebral hypoperfusion. As in stroke, the brain becomes low in energy substrates including glucose and oxygen, and resorts to anaerobic respiration. This leads to increased lactic acid, a byproduct of anaerobic glycolysis. Lactic acid has a negative impact on tissue metabolism and can potentially destroy cells [13,14]. In our case the lactic acid concentration was mildly reduced, which may be considered either as an effect of activation of mechanisms aiming on retrieval of intracellular homeostasis or as an error caused by the relatively small number of probes. The further cascade of cerebral injury is initiated when the energy production such as ATP fails, leading to failure of energy-dependent processes [13] and the release of excitatory neurotransmitters such as glutamate. It acts on receptors in neuronal cells and therefore produces an influx of calcium that activates enzymes that digest cellular proteins, lipids, and nuclear materials. Unlike in stroke, in brain fog the deterioration of cerebral function in limited. Macroscopic manifestation on neuronal disintegration of blood brain barrier was not seen in any of the cases.
Lactates are not detectable under normal circumstances; however, in pathological conditions such as neoplasm, hypoxia, or ischaemia the Lac (lactates) are often detected. Glutamate (Glu) overlaps with glutamine (Gln), and they are detected as a Glx peak. It can be elevated in MS [15], liver failure, and Raye’s syndrome [16]. In the current study, we analysed consecutive MR brain imaging scans in patients with brain fog proceeding from 2 major regional COVID-19 hospitals and found that these 11 patients had a higher concentration of Glx and mild reduction of Lac in the deep grey matter of both cerebral hemispheres compared to healthy controls not suffering from brain fog.
Brain fog remains a common long-term side effect of COVID-19 of unknown mechanism. A wide range of unspecific lingering symptoms and the impossibility to explain who will suffer from it and who will not point out the necessity of research into this matter. Taking into consideration our knowledge regarding cerebral manifestation of other viral infections, we anticipate a variety of possible scenarios. Brain fog is one of the long-covid symptoms occurring in all subpopulations of patients regardless of age, sex, severity of COVID-19, comorbidities, or vaccination status. There may be several explanations as to why MR spectroscopy did not show an increase of Glx/Cr ratio in every patient. First of all, the brain fog may linger for a non-defined period. Therefore, some patients might have undergone MRS in the recovery phase when the level of Glx was normalizing. Secondly, we performed SV MRS only and not MV MRS acquiring the signal from the voxel positioned in the basal ganglia. This may be a drawback if vascular changes would not distribute evenly showing a predilection to specific cerebral regions. Thirdly, MR spectroscopy is a very demanding imaging method, and the lack of consistent results in other patients may be caused by various reasons such as motion artifacts, lack of proper suppression of water signal, or magnetic field heterogeneity.
Conclusions
Following results along with clinical course of the brain for imply probable ischaemic background of symptoms.

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2303

N221

Matthew G.FrankaKathy H.NguyenbJayson B.BallaShelbyHopkinsbTelKelleybMichael V.BarattaaMonikaFleshnerbSteven F.Maiera

SARS-CoV-2 spike S1 subunit induces neuroinflammatory, microglial and behavioral sickness responses: Evidence of PAMP-like properties

https://doi.org/10.1016/j.bbi.2021.12.007

Published

13-Dec-21

Study

https://www.sciencedirect.com/science/article/pii/S0889159121006383

Highlights
•The SARS-CoV-2 spike S1 subunit induces sickness behavior.
•S1 induces a subacute (24 h) and chronic (7d) neuroinflammatory response.
•S1 directly induces a proinflammatory response in primary microglia.
•S1 activates TLR2 and TLR4 signaling in vitro.
•S1 might function as a pathogen-associated molecular pattern.
Here, we explore the novel hypothesis that a structural protein (S1) derived from SARS-CoV-2 functions as a pathogen-associated molecular pattern (PAMP) to induce neuroinflammatory processes independent of viral infection. Prior evidence suggests that the S1 subunit of the SARS-CoV-2 spike protein is inflammatory in vitro and signals through the pattern recognition receptor TLR4. Therefore, we examined whether the S1 subunit is sufficient to drive 1) a behavioral sickness response, 2) a neuroinflammatory response, 3) direct activation of microglia in vitro, and 4) activation of transgenic human TLR2 and TLR4 HEK293 cells. Adult male Sprague-Dawley rats were injected intra-cisterna magna (ICM) with vehicle or S1. In-cage behavioral monitoring (8 h post-ICM) demonstrated that S1 reduced several behaviors, including total activity, self-grooming, and wall-rearing. S1 also increased social avoidance in the juvenile social exploration test (24 h post-ICM). S1 increased and/or modulated neuroimmune gene expression (Iba1, Cd11b, MhcIIα, Cd200r1, Gfap, Tlr2, Tlr4, Nlrp3, Il1b, Hmgb1) and protein levels (IFNγ, IL-1β, TNF, CXCL1, IL-2, IL-10), which varied across brain regions (hypothalamus, hippocampus, and frontal cortex) and time (24 h and 7d) post-S1 treatment. Direct exposure of microglia to S1 resulted in increased gene expression (Il1b, Il6, Tnf, Nlrp3) and protein levels (IL-1β, IL-6, TNF, CXCL1, IL-10). S1 also activated TLR2 and TLR4 receptor signaling in HEK293 transgenic cells. Taken together, these findings suggest that structural proteins derived from SARS-CoV-2 might function independently as PAMPs to induce neuroinflammatory processes via pattern recognition receptor engagement.

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2304

N222

F.J.Carod-Artala1J.C.García-Moncób1

Epidemiology, pathophysiology, and classification of the neurological symptoms of post-COVID-19 syndromeEpidemiología, fisiopatología y clasificación de los síntomas neurológicos post-COVID

https://doi.org/10.1016/j.neurop.2021.07.005

Published

14-Dec-21

Review

https://www.sciencedirect.com/science/article/pii/S2667049621000612

Results
Patients with history of COVID-19 have been found to present persistent neurological symptoms, including cognitive complaints, memory and concentration problems, headache, anosmia, ageusia, vertigo, and insomnia. Post-COVID-19 syndrome is a heterogeneous disease that lacks a universally accepted definition, which may explain the great variability in the estimated prevalence (2.3%–85%) and symptom duration. The criteria differentiating post-COVID-19 syndrome from chronic fatigue syndrome or critical illness syndrome are ambiguous. Risk factors include older age, female sex, certain comorbidities, and greater number of symptoms in the acute phase. The pathophysiology of the syndrome is largely unknown, although it is probably multifactorial, including immunological mechanisms, neural network dysfunction, neurotransmitter alterations, persistent viral damage, and functional impairment.
Conclusions
Post-COVID-19 syndrome may present after mild or even asymptomatic SARS-CoV-2 infection, causing limitations in activities of daily living and in quality of life. Further research will clarify the origin and most appropriate management of these neurological alterations.

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2305

N223

Oscar H. Del Brutto,Denisse A. Rumbea,Bettsy Y. Recalde,Robertino M. Mera

Cognitive sequelae of long COVID may not be permanent. A prospective study

https://doi.org/10.1111/ene.15215

Published

16-Dec-21

Short Communication

https://onlinelibrary.wiley.com/doi/abs/10.1111/ene.15215

Cognitive performance was evaluated by means of the Montreal Cognitive Assessment (MoCA) in COVID-19 survivors and non-infected individuals. All study participants had four cognitive evaluations, two of them before the pandemic and the other two, six and 18 months after the initial SARS-CoV-2 outbreak infection in the village. Linear mixed effects models for longitudinal data were fitted to assess differences in cognitive performance across COVID-19 survivors and non-infected individuals.
Results
The study included 78 participants, 50 with history of mild COVID-19 and 28 without. There was a significant – likely age-related – decline in MoCA scores between the two pre-pandemic tests (β: -1.53; 95% C.I.: -2.14 to -0.92; p<0.001), which did not differ across individuals who later developed COVID-19 when compared to non-infected individuals. Six months after infection, only COVID-19 survivors had a significant decline in MoCA scores (β: -1.37; 95% C.I.: -2.14 to -0.61; p<0.001), which reversed after one additional year of follow-up (β: 0.66; 95% C.I.: -0.11 to 1.42; p=0.092). No differences were noticed among non-infected individuals when both post-pandemic MoCA scores were compared.
Conclusion
Study results suggest that long COVID-related cognitive decline may spontaneously improve over time.

_

2306

N224

Enric Vidal*, Carlos López-Figueroa*, Jordi Rodon, Mónica Pérez, Marco Brustolin, Guillermo Cantero, Víctor Guallar, Nuria Izquierdo-Useros, Jorge Carrillo, Julià Blanco, Bonaventura Clotet, Júlia Vergara-Alert, Joaquim Segalés

Chronological brain lesions after SARS-CoV-2 infection in hACE2-transgenic mice

https://doi.org/10.1177%2F03009858211066841

Published

27-Dec-21

Study

https://journals.sagepub.com/doi/10.1177/03009858211066841

Wild-type mice are minimally susceptible to certain SARS-CoV-2 lineages (beta and gamma variants), whereas hACE2-transgenic mice succumb to SARS-CoV-2 and develop a fatal neurological disease. In this article, we aimed to chronologically characterize SARS-CoV-2 neuroinvasion and neuropathology. Necropsies were performed at different time points, and the brain and olfactory mucosa were processed for histopathological analysis. SARS-CoV-2 virological assays including immunohistochemistry were performed along with a panel of antibodies to assess neuroinflammation. At 6 to 7 days post inoculation (dpi), brain lesions were characterized by nonsuppurative meningoencephalitis and diffuse astrogliosis and microgliosis. Vasculitis and thrombosis were also present and associated with occasional microhemorrhages and spongiosis. Moreover, there was vacuolar degeneration of virus-infected neurons. At 2 dpi, SARS-CoV-2 immunolabeling was only found in the olfactory mucosa, but at 4 dpi intraneuronal virus immunolabeling had already reached most of the brain areas. Maximal distribution of the virus was observed throughout the brain at 6 to 7 dpi except for the cerebellum, which was mostly spared. Our results suggest an early entry of the virus through the olfactory mucosa and a rapid interneuronal spread of the virus leading to acute encephalitis and neuronal damage in this mouse model.

todo

2307

N225

FeliciaCebanabSusanLingadLeanna M.W.LuiaYenaLeeacHartejGillaKayla M.TeopizaNelson B.RodriguesaMehalaSubramaniapillaiaJoshua D.Di VincenzoadBingCaoeKangguangLinfgRodrigo B.MansurahRoger C.HoijJoshua D.RosenblatadhKamilla W.MiskowiakklMajVinbergmnVladimirMaleticoRoger S.McIntyreabcdh

Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis

https://doi.org/10.1016/j.bbi.2021.12.020

Published

29-Dec-21

Study

https://www.sciencedirect.com/science/article/pii/S0889159121006516

Highlights
•Fatigue and cognitive impairment are amongst the most common and debilitating symptoms of post-COVID-19 syndrome.
•Approximately 1 in 3 individuals experienced fatigue 12 or more weeks following COVID-19 diagnosis.
•Approximately 1 in 5 individuals exhibited cognitive impairment 12 or more weeks following COVID-19 diagnosis.
•There was an elevation in proinflammatory markers and functional impairment in a subset of post-COVID individuals.
Results
The literature search yielded 10,979 studies, and 81 studies were selected for inclusion. The fatigue meta-analysis comprised 68 studies, the cognitive impairment meta-analysis comprised 43 studies, and 48 studies were included in the narrative synthesis. Meta-analysis revealed that the proportion of individuals experiencing fatigue 12 or more weeks following COVID-19 diagnosis was 0.32 (95% CI, 0.27, 0.37; p < 0.001; n = 25,268; I2 = 99.1%). The proportion of individuals exhibiting cognitive impairment was 0.22 (95% CI, 0.17, 0.28; p < 0.001; n = 13,232; I2 = 98.0). Moreover, narrative synthesis revealed elevations in proinflammatory markers and considerable functional impairment in a subset of individuals.
Conclusions & relevance
A significant proportion of individuals experience persistent fatigue and/or cognitive impairment following resolution of acute COVID-19. The frequency and debilitating nature of the foregoing symptoms provides the impetus to characterize the underlying neurobiological substrates and how to best treat these phenomena.

2308

N226

Masud Husain

COVID and the brain

https://doi.org/10.1093/brain/awab421

Published

31-Dec-21

Editorial

https://academic.oup.com/brain/article/144/12/3545/6491307

In terms of brain syndromes, it is now evident that COVID is associated with a higher risk of encephalopathy, encephalitis, stroke—ischaemic, haemorrhagic and venous—as well as a subsequent diagnosis of dementia,2,3 although the latter might well be due to be an uncovering of pre-existing cognitive decline. It is also becoming clear that these neurological consequences are much more common following SARS-CoV-2 infection than post-vaccination,3-5 which had been an initial concern particularly following descriptions of cerebral venous thrombosis cases earlier in the year. Psychiatric manifestations such as anxiety and depression are even more frequent after SARS-CoV-2 infection,6 and a particular concern that remains to be properly characterized are the symptoms of so-called ‘long COVID’.
The authors then conducted a series of investigations that led them to conclude that one of the SARS-CoV-2 proteases cleaves NEMO (nuclear factor-κΒ essential modulator), which plays a key role in cell survival and prevents apoptosis. Ablation of NEMO in brain blood vessel endothelial cells produced microvascular pathology similar to that in the brains of infected individuals. However, this could be prevented by deleting a specific protein kinase involved in regulating cell death, Ripk3. Together, these observations suggest that an important way in which SARS-CoV-2 might trigger brain changes is via an attack on the endothelium, causing microvascular injury which, in turn, might affect blood–brain barrier integrity and microvascular perfusion. The experiments on NEMO also suggest a potential way to stop such injury occurring. These mechanisms might not be brain specific; SARS-CoV-2 might also mediate injury to other organs via endothelial damage.
Clearly though we have a long way to go to understand the multitude effects of COVID on the brain, and why some people seem to be more vulnerable than others. Systemic effects including those of cytokines and other inflammatory mediators might also play a crucial role. Nevertheless, the signs are extremely encouraging that so much progress has been made in this area in such a short time.

todo

2309

N227

Ilona Merikanto,Yves Dauvilliers,Frances Chung,Brigitte Holzinger,Luigi De Gennaro,Yun Kwok Wing,Maria Korman,Markku Partinen

Disturbances in sleep, circadian rhythms and daytime functioning in relation to coronavirus infection and Long-COVID – A multinational ICOSS study

https://doi.org/10.1111/jsr.13542

Published

28-Dec-21

Study

https://onlinelibrary.wiley.com/doi/10.1111/jsr.13542

To the best of our knowledge, there is no other large-scale multinational sleep study targeting the general population regarding the role of sleep and circadian rhythms along with a variety of psychological, biological, social and economic aspects considered in relation to COVID-19 disease infection risk, severity or Long-COVID. Systematic reviews and cohort studies on the frequency and variety of persistent COVID-19 symptoms indicate that sleep problems and disorders, such as sleep difficulties and insomnia, can be high among COVID-19 patients (Lopez-Leon et al., 2021; Nalbandian, Sehgal, & Gupta, 2021). It is, however, unknown whether different sleep, circadian rhythm, daytime functioning and psychological factors have a role in COVID disease risk and prognosis, and the long-term consequences of the infection, or if there are reciprocal relationships between COVID disease prognosis and development of Long-COVID and sleep disorders.
It is plausible that the neurotropic nature of the SARS-CoV-2 infection includes similar peripheral nerve pathways to the central nervous system as Middle East respiratory syndrome (MERS-CoV) and SARS-CoV-1 (Zubair et al., 2020), which also affect sleep, dreaming and daytime functioning (Boldrini et al., 2021; Lam, Wing, & Yu, 2009; Rogers et al., 2021; Zubair et al., 2020). Furthermore, the suggested shared pathways between sleep, dreaming, daytime functioning and SARS-CoV-2 infection leading to Long-COVID can have potential neurodegenerative propensity related to, for example, RBD, parkinsonism and dementia (Brundin, Nath, & Beckham, 2020; Taquet et al., 2021). In a recent polysomnography study, REM sleep without atonia was more prevalent among COVID-19 patients than is usual in general population samples (Heidbreder, Sonnweber, & Stefani, 2021). Furthermore, olfactory impairment is common among patients with RBD (Ross et al., 2008) similarly as among COVID-19 patients (Xydakis, Albers, & Holbrook, 2021).

2310

N228

Seshagiri Veerapaneni,Mukaila Raji

COVID-19 and cognitive impairment in the elderly: A literature review

https://doi.org/10.1002/alz.055584

Published

31-Dec-21

Review

https://alz-journals.onlinelibrary.wiley.com/doi/abs/10.1002/alz.055584

Based on evidence gathered from scientific literature, this review raises a possibility of nervous system involvement in COVID-19 with progression to dementia or worsening of existing Dementia especially in the elderly patients. Longitudinal neurological assessments of patients after recovery will be crucial in understanding the natural History of COVID-19 in the CNS and monitoring for potential neurologic sequalae and long-term effects on causation and worsening of dementia. The literature review also states the need to start investigating the mechanistic link between Alzheimer's disease and COVID-19 for further follow up.

2311

N229

C. (Linda) M. C. van Campen 1,* ,Peter C. Rowe 2 andFrans C. Visser 1

Orthostatic Symptoms and Reductions in Cerebral Blood Flow in Long-Haul COVID-19 Patients: Similarities with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

https://doi.org/10.3390/medicina58010028

Published

24-Dec-21

Study

https://www.mdpi.com/1648-9144/58/1/28/htm

To investigate the overlap in these clinical phenotypes, we compared orthostatic symptoms in daily life and during head-up tilt, heart rate and blood pressure responses to tilt, and reductions in cerebral blood flow in response to orthostatic stress in long-haul COVID-19 patients, ME/CFS controls, and healthy controls. Materials and Methods: We compared 10 consecutive long-haul COVID-19 cases with 20 age- and gender-matched ME/CFS controls with postural tachycardia syndrome (POTS) during head-up tilt, 20 age- and gender-matched ME/CFS controls with a normal heart rate and blood pressure response to head-up tilt, and 10 age- and gender-matched healthy controls. Identical symptom questionnaires and tilt test procedures were used for all groups, including measurement of cerebral blood flow and cardiac index during the orthostatic stress. Results: There were no significant differences in ME/CFS symptom prevalence between the long-haul COVID-19 patients and the ME/CFS patients. All long-haul COVID-19 patients developed POTS during tilt. Cerebral blood flow and cardiac index were more significantly reduced in the three patient groups compared with the healthy controls. Cardiac index reduction was not different between the three patient groups. The cerebral blood flow reduction was larger in the long-haul COVID-19 patients compared with the ME/CFS patients with a normal heart rate and blood pressure response. Conclusions: The symptoms of long-haul COVID-19 are similar to those of ME/CFS patients, as is the response to tilt testing. Cerebral blood flow and cardiac index reductions during tilt were more severely impaired than in many patients with ME/CFS. The finding of early-onset orthostatic intolerance symptoms, and the high pre-illness physical activity level of the long-haul COVID-19 patients, makes it unlikely that POTS in this group is due to deconditioning. These data suggest that similar to SARS-CoV-1, SARS-CoV-2 infection acts as a trigger for the development of ME/CFS.

2312

N230

Natalia A. Shnayder 1,2,* ,Timur K. Sirbiladze 1,* ,Irina V. Demko 2,Marina M. Petrova 2 andRegina F. Nasyrova 1,3

Limbic Encephalitis Associated with COVID-19

https://doi.org/10.3390/encyclopedia2010003

Published

22-Dec-21

Review

https://www.mdpi.com/2673-8392/2/1/3/htm

An interesting fact is that in most patients with SARS-CoV-2, serological tests on autoimmune panels, including autoantibodies against intracellular, synaptic and surface antigens previously described in LE of a different etiology, were negative [21]. According to this fact, some authors consider the development of SARS-CoV-2-associated para-infectious LE caused by secondary hyperinflammatory syndrome with a massive release of proinflammatory cytokines and chemokines in the limbic system of the brain [21,57,58]. Taken together, these facts explain the scientific and clinical interest in studying the role of pro-inflammatory cytokines, including interleukin-1-beta (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), in the development of para-infectious LE associated with SARS-CoV-2, as overexpression of these cytokines has been described in previous studies of drug resistant para-infectious temporal lobe epilepsy [59,60,61,62,63] and also in cognitive disorders including shot-term and long-term memory [64] and Alzheimer’s type dementia [65].
However, the high tropism of SARS-CoV-2 to the structures of the limbic system of the brain, with the possibility of isolated lesions of these areas in children and adults without respiratory symptoms of COVID-19, and the high number of new cases of this infection in population worldwide indicates the importance of this interdisciplinary problem in neurology and psychiatry. In addition, the development of an autoimmune process in the CNS is also possible after the respiratory symptoms was resolved, as the long-term consequence in patients with the pulmonary form of COVID-19. In patients with a high risk of developing para-infectious LE associated with SARS-CoV-2, the diagnostic algorithm in the acute and subacute periods should include analysis of CSF, EEG monitoring and brain MRI. In patients with asymptomatic or mild COVID-19 (without respiratory symptoms) and long-term consequences of COVID-19 (long-COVID-19), the diagnostic algorithm should include neuropsychological testing, brain MRI, EEG and serological testing (evaluating the pro-inflammatory cytokines and antibodies to SARS-CoV-2 IgG). This algorithm can help in the risk assessment and early diagnosis of para-infectious LE associated with SARS-CoV-2; moreover, it gives information for consideration in treatment planning. An important but controversial issue is the acceptability of revaccination against COVID-19 in patients with high risk of developing para-infectious LE or patients with this disease.

2313

N231

Yuda Turana 1,*,† ,Michael Nathaniel 1,† ,Robert Shen 1,† ,Soegianto Ali 1 andRajender R. Aparasu 2

Citicoline and COVID-19-Related Cognitive and Other Neurologic Complications

https://doi.org/10.3390/brainsci12010059

Published

31-Dec-21

Review

https://www.mdpi.com/2076-3425/12/1/59/htm

With growing concerns about COVID-19’s hyperinflammatory condition and its potentially damaging impact on the neurovascular system, there is a need to consider potential treatment options for managing short- and long-term effects on neurological complications, especially cognitive function. While maintaining adequate structure and function of phospholipid in brain cells, citicoline, identical to the natural metabolite phospholipid phosphatidylcholine precursor, can contribute to a variety of neurological diseases and hypothetically toward post-COVID-19 cognitive effects. In this review, we comprehensively describe in detail the potential citicoline mechanisms as adjunctive therapy and prevention of COVID-19-related cognitive decline and other neurologic complications through citicoline properties of anti-inflammation, anti-viral, neuroprotection, neurorestorative, and acetylcholine neurotransmitter synthesis, and provide a recommendation for future clinical trials.

2314

N232

Anthony Fernandez-Castaneda, Peiwen Lu, Anna C Geraghty, Eric Song, Myoung-Hwa Lee, Jamie Wood, Belgin Yalcin, Kathryn R Taylor, Selena Dutton, Lehi Acosta-Alvarez, Lijun Ni, Daniel Contreras-Esquivel, Jeffrey R Gehlhausen, Jon Klein, Carolina Lucas, Tianyang Mao, Julio Silva, Mario Pena-Hernandez, Alexandra Tabachnikova, Takehiro Takahashi, Laura Tabacof, Jenna Tosto-Mancuso, Erica Breyman, Amy Kontorovich, Dayna McCarthy, Martha Quezado, Marco Hefti, Daniel Perl, Rebecca Folkerth, David Putrino, Avindra Nath, Akiko Iwasaki, Michelle Monje

Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain

https://doi.org/10.1101/2022.01.07.475453

pre-print

10-Jan-22

Study

https://www.biorxiv.org/content/10.1101/2022.01.07.475453v1

Neuroinflammation, particularly microglial reactivity and consequent dysregulation of hippocampal neurogenesis and oligodendrocyte lineage cells, is central to CRCI. We hypothesized that similar cellular mechanisms may contribute to the persistent neurological symptoms associated with even mild SARS-CoV-2 respiratory infection. Here, we explored neuroinflammation caused by mild respiratory SARS-CoV-2 infection, without neuroinvasion, and effects on hippocampal neurogenesis and the oligodendroglial lineage. Using a mouse model of mild respiratory SARS-CoV-2 infection induced by intranasal SARS-CoV-2 delivery, we found white matter-selective microglial reactivity, a pattern observed in CRCI. Human brain tissue from 9 individuals with COVID-19 or SARS-CoV-2 infection exhibits the same pattern of prominent white matter-selective microglial reactivity. In mice, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7-weeks post-infection; among the chemokines demonstrating persistent elevation is CCL11, which is associated with impairments in neurogenesis and cognitive function. Humans experiencing long-COVID with cognitive symptoms (48 subjects) similarly demonstrate elevated CCL11 levels compared to those with long-COVID who lack cognitive symptoms (15 subjects). Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss in subcortical white matter were evident at 1 week, and persisted until at least 7 weeks, following mild respiratory SARS-CoV-2 infection in mice. Taken together, the findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and after SARS-CoV-2 infection, and elucidate cellular deficits that may contribute to lasting neurological symptoms following even mild SARS-CoV-2 infection.

2315

N233

Mirren Charnley, Saba Islam, Guneet Bindra, Jeremy Engwirda, Julian Ratcliffe, Jiangtao Zhou, Raffaele Mezzenga, Mark Hulett, Kyunghoon Han, Joshua Berryman, Nicholas Reynolds

Neurotoxic Amyloidogenic Peptides in the Proteome of SARS-COV2: Potential Implications for Neurological Symptoms in COVID-19

https://doi.org/10.21203/rs.3.rs-1201481/v1

pre-print

7-Jan-22

Study

https://www.researchsquare.com/article/rs-1201481/v1

However, neurological symptoms such as memory loss, sensory confusion, cognitive and psychiatric issues, severe headaches, and even stroke are reported in as many as 30% of cases and can persist even after the infection is over (so-called ‘long COVID’). These neurological symptoms are thought to be caused by brain inflammation, caused by the virus infecting the central nervous system of COVID-19 patients, however we still don’t understand the molecular mechanisms that trigger these symptoms. The neurological effects of COVID-19 share many similarities to neurodegenerative diseases such as Alzheimer’s and Parkinson’s in which the presence of cytotoxic protein-based amyloid aggregates is a common etiological feature. Following the hypothesis that some neurological symptoms of COVID-19 may also follow an amyloid etiology we performed a bioinformatic scan of the SARS-CoV-2 proteome, detecting peptide fragments that were predicted to be highly amyloidogenic. We selected two of these peptides from the open reading frame 6 (ORF6) and open reading frame 10 (ORF10) proteins. The amyloidogenic virus-derived proteins studied in this work did not include spike (S) protein or any other proteins that have been modified to function as antigens in any current vaccines. We discovered that these ORF protein fragments rapidly self-assemble into amyloid aggregates. Furthermore, these amyloid assemblies were shown to be highly toxic to a neuronal cell line. We introduce and support the idea that cytotoxic amyloid aggregates of SARS-CoV-2 proteins are causing some of the neurological symptoms commonly found in COVID-19 and contributing to long COVID.

2316

N234

Viviana Cristillo, Andrea Pilotto, Stefano Cotti Piccinelli, Giulio Bonzi, Antonio Canale, Stefano Gipponi, Michela Bezzi, Matilde Leonardi, Alessandro Padovani & the Neuro Covid Next Study group

Premorbid vulnerability and disease severity impact on Long-COVID cognitive impairment

https://doi.org/10.1007/s40520-021-02042-3

Published

11-Jan-22

Study

https://link.springer.com/article/10.1007/s40520-021-02042-3

Results
Abnormal MoCA scores at 6 months follow-up were associated with higher pre-hospitalization National Health System (NHS) score (Duca et al. in Emerg Med Pract 22:1–2, 2020) (OR 1.27; 95% CI 1.05–1.6; p = 0.029) and more severe pulmonary disease expressed by the Brescia-COVID Respiratory Severity Scale (Duca et al. in Emerg Med Pract 22:1–2, 2020) (BCRSS > 1OR 4.73; 95% CI 1.53–14.63; p = 0.003) during the acute phase of the disease.
Discussion
This longitudinal study showed that the severity of COVID-19, indicated by BCRSS, and a complex score given by age and premorbid medical conditions, expressed by NHS, play a major role in modulating the long-term cognitive consequences of COVID-19 disease.
Conclusions
These findings indicate that the association of age and premorbid factors might identify people at risk for long-term neurological consequences of COVID-19 disease, thus deserving longer and proper follow-up.

2317

N235

Peerapon Kiatkittikul, Chetsadaporn Promteangtrong, Anchisa Kunawudhi, Dheeratama Siripongsatian, Taweegrit Siripongboonsitti, Piyanuj Ruckpanich, Supachoke Thongdonpua, Attapon Jantarato, Chaiyawat Piboonvorawong, Nirawan Fonghoi & Chanisa Chotipanich

Abnormality Pattern of F-18 FDG PET Whole Body with Functional MRI Brain in Post-Acute COVID-19

https://doi.org/10.1007/s13139-021-00730-6

Published

15-Jan-22

Study

https://link.springer.com/article/10.1007%2Fs13139-021-00730-6

We retrospectively recruited 13 patients with post-acute COVID-19. The post-acute COVID-19 symptoms and neuropsychiatric tests were performed before F-18 FDG PET/CT whole body with PET/rsfMRI brain. Qualitative and semiquantitative analyses were also conducted in both whole body and brain images.
Results
Among the 13 patients, 8 (61.5%) had myositis, followed by 8 (61.5%) with vasculitis (mainly in the thoracic aorta), and 7 (53.8%) with lung abnormalities.. Interestingly, one patient with a very high serum RBD IgG antibody demonstrated diffuse myositis throughout the body which potentially associated with immune-mediated myositis. One patient experienced psoriasis exacerbation with autoimmune-mediated after COVID-19. Most patients had multiple areas of abnormal brain connectivity involving the frontal and parieto-temporo-occipital lobes, as well as the thalamus.
Conclusion
The whole body F-18 FDG PET can be a potential tool to assess inflammatory process and support the hyperinflammatory etiology, mainly for lesions in skeletal muscle, vascular wall, and lung, as well as, multiple brain abnormalities in post-acute COVID-19. Nonetheless, further studies are recommended to confirm the results.

2318

N236

Sijia Zhao, Kengo Shibata, Peter J. Hellyer, William Trender, Sanjay Manohar, Adam Hampshire, Masud Husain

Rapid vigilance and episodic memory decrements in COVID-19 survivors

https://doi.org/10.1093/braincomms/fcab295

Published

19-Jan-22

Study

https://academic.oup.com/braincomms/article/4/1/fcab295/6511053

In the months following acute illness, many more suffer from fatigue, low motivation, disturbed mood, poor sleep and cognitive symptoms, colloquially referred to as ‘brain fog’. But what about individuals who had asymptomatic to moderate COVID-19 and reported no concerns after recovering from COVID-19? Here, we examined a wide range of cognitive functions critical for daily life (including sustained attention, memory, motor control, planning, semantic reasoning, mental rotation and spatial–visual attention) in people who had previously suffered from COVID-19 but were not significantly different from a control group on self-reported fatigue, forgetfulness, sleep abnormality, motivation, depression, anxiety and personality profile. Reassuringly, COVID-19 survivors performed well in most abilities tested, including working memory, executive function, planning and mental rotation. However, they displayed significantly worse episodic memory (up to 6 months post-infection) and greater decline in vigilance with time on task (for up to 9 months). Overall, the results show that specific chronic cognitive changes following COVID-19 are evident on objective testing even amongst those who do not report a greater symptom burden. Importantly, in the sample tested here, these were not significantly different from normal after 6–9 months, demonstrating evidence of recovery over time.

2319

N237

Leonard B. Weinstock, MD, FACG, Jill B. Brook, MA, Arthur S. Walters, MD, Ashleigh Goris, RN, BSN, MPH, CIC, FAPIC, Lawrence B. Afrin, MD, Gerhard J. Molderings, MD

Restless legs syndrome is associated with long-COVID in women

https://doi.org/10.5664/jcsm.9898

Published

25-Jan-22

Study

https://jcsm.aasm.org/doi/abs/10.5664/jcsm.9898

STUDY OBJECTIVES: Sleep disturbance is common in long-COVID (LC). Restless legs syndrome (RLS) is characterized by sleep disturbance and has been reported after viral infections. Therefore, we evaluated RLS symptoms cross-sectionally in individuals with LC at both current and pre-COVID19 timepoints.
METHODS: LC-focused Facebook adults were recruited for an online assessment of symptoms before COVID-19 infection and during their present LC state in a cross-sectional manner. The LC group documented baseline symptoms retrospectively. Questions were included about the presence/severity of RLS symptoms and assessments of fatigue, quality of life, and sleep apnea. A control group was recruited and included individuals ≥18 years of age who never had overt symptoms of COVID-19. Pregnancy was exclusion criteria for both groups.
RESULTS: There were 136 LC participants (89.7% females, age 46.9 ±12.9 years) and 136 controls (65.4% females, age 49.2 ±15.5). RLS prevalence in LC-females was 5.7% pre-COVID-19 and 14.8% post-COVID-19 (p<0.01) vs. 6.7% in control-females. Severity of RLS was moderate in both groups. Logistic regression predicting post-COVID-19 RLS among LC-females failed to find significant effects of hospitalization, sleep apnea, neuropathic pain severity or use of antihistamines and antidepressants.
CONCLUSIONS: The baseline prevalence of RLS in LC-females was similar to the general population group as well as to patients in epidemiological studies. The prevalence significantly increased in the LC state. Post-infectious immunological mechanisms may be at play in the production for RLS symptoms.

2320

N238

AthinaSamara12EricHerlenius12PatrickO’ Brien34AsmaKhalil567

Potential role of neurofilament in COVID-19 and preeclampsia

https://doi.org/10.1016/j.xcrm.2021.100490

Published

18-Jan-22

Commentary

https://www.sciencedirect.com/science/article/pii/S2666379121003670

Neurofilament light (NFL) is a promising circulating biomarker in preeclampsia and COVID-19, even without evident neurological complications. Several pathways might contribute to the elevated serum NFL levels seen in both pathologies. Future studies will determine whether NFL is a long COVID marker and delineate NFL’s role in COVID-19-associated preeclampsia.

2321

N239

Fatemeh Sadat Mirfazeli, Atiye Sarabi-Jamab, Victor Pereira-Sanchez, Alireza Kordi, Behnam Shariati, Seyed Vahid Shariat, Salar Bahrami, Shabnam Nohesara, Mostafa Almasi-Dooghaee & Seyed Hamid Reza Faiz

Chronic fatigue syndrome and cognitive deficit are associated with acute-phase neuropsychiatric manifestations of COVID-19: A 9-month follow-up study

https://doi.org/10.1007/s10072-021-05786-y

Published

21-Jan-22

Study

https://link.springer.com/article/10.1007/s10072-021-05786-y

The prevalence of long-COVID symptoms is rising but it is not still possible to predict which patients will present them, and which types of symptoms they will present. We followed up 95 patients with confirmed COVID-19 for 9 months to identify and characterize long-COVID symptoms. Easy fatigability was the most common symptom (51.04%), followed by anxiety (38.54%), dyspnea (38.54%), and new-onset headache (38.54%). There was no association between COVID-19 severity in the acute phase and the number of long-COVID symptoms (F(1,93) = 0.75, p = 0.45), and cognitive function (MoCA) scores (F(1,90) = 0.073, p = 0.787) at follow-up. Being female (F(1,92) = − 2.27, p = 0.02), having a higher number of symptoms (F(1,93) = 2.76, p = 0.0068), and experiencing constitutional neuropsychiatric symptoms (F(1,93) = 2.529, p = 0.01) in the acute phase were associated with having chronic fatigue syndrome at follow-up. Moreover, constitutional neuropsychiatric symptoms in the acute phase were associated with a lower MoCA score (F(1,93) = 10.84, p = 0.001) at follow-up. Specific clinical presentations such as constitutional neuropsychiatric symptoms in the acute phase might be predictors of debilitating long-COVID symptoms such as chronic fatigue syndrome and cognitive deficits.

2322

N240

Stéphane Kremer, Simonetta Gerevini, Ana Ramos, François Lersy, Tarek Yousry, Meike W. Vernooij, Nicoletta Anzalone & Hans Rolf Jäger

Neuroimaging in patients with COVID-19: a neuroradiology expert group consensus

https://doi.org/10.1007/s00330-021-08499-0

Published

19-Jan-22

Article

https://link.springer.com/article/10.1007/s00330-021-08499-0

Neurological and neuroradiological manifestations in patients with COVID-19 have been extensively reported. Available imaging data are, however, very heterogeneous. Hence, there is a growing need to standardise clinical indications for neuroimaging, MRI acquisition protocols, and necessity of follow-up examinations. A NeuroCovid working group with experts in the field of neuroimaging in COVID-19 has been constituted under the aegis of the Subspecialty Committee on Diagnostic Neuroradiology of the European Society of Neuroradiology (ESNR). The initial objectives of this NeuroCovid working group are to address the standardisation of the imaging in patients with neurological manifestations of COVID-19 and to give advice based on expert opinion with the aim of improving the quality of patient care and ensure high quality of any future clinical studies.
Key Points
• In patients with COVID-19 and neurological manifestations, neuroimaging should be performed in order to detect underlying causal pathology.
• The basic MRI recommended protocol includes T2-weighted, FLAIR (preferably 3D), and diffusion-weighted images, as well as haemorrhage-sensitive sequence (preferably SWI), and at least for the initial investigation pre and post-contrast T1 weighted-images.
• 3D FLAIR should be acquired after gadolinium administration in order to optimise the detection of leptomeningeal contrast enhancement.

2323

N241

Shivam Bhola, Jhillika Trisal, Vikram Thakur, Parneet Kaur, Saurabh Kulshrestha, Shashi Kant Bhatia & Pradeep Kumar

Neurological toll of COVID-19

https://doi.org/10.1007/s10072-022-05875-6

Published

16-Jan-22

Review

https://link.springer.com/article/10.1007/s10072-022-05875-6

The review is focused on the manifestation of various neurological disorders linked with both the central nervous system and peripheral nervous system. Disorders such as cytokine release syndrome, encephalitis, acute stroke, and Bell’s palsy are given specific attention and psychological manifestations are also investigated. For a clear conclusion, cognitive impairment, drug addiction disorders, mood and anxiety disorders, and post-traumatic stress disorder are all fully examined. The association of the SARS-CoV-2 with neurological disorders and pathway is yet to be clear. For better understanding, the explanation of the possible mechanism of viral infection influencing the nervous system is also attempted in the review. While several vaccines and drugs are already involved in treating the SARS-CoV-2 condition, the disease is still considered fatal and more likely to leave permanent neurological damage, which leads to an essential requirement for more research to explore the neurological toll of the COVID-19 disease.

2324

N242

LaShyra T. Nolen, Shibani S. Mukerji & Nicte I. Mejia

Post-acute neurological consequences of COVID-19: an unequal burden

https://doi.org/10.1038/s41591-021-01647-5

Published

17-Jan-22

Comment

https://www.nature.com/articles/s41591-021-01647-5

Our world has witnessed over 275 million confirmed cases of COVID-19 and over 5 million related deaths1. Marginalized communities everywhere continue to be disproportionately affected as the pandemic amplifies longstanding health and healthcare disparities. As an example, in the United States, members of the Black, Indigenous and Latino communities remain two to three times more likely to be infected with SARS-CoV-2, to be hospitalized with COVID-19 and to die from this disease2. Dismantling structural racism is necessary to improve neurological health, as greater attention is focused on understanding and addressing the post-acute neurological consequences of COVID-19, or the neurological manifestations of what is sometimes called long COVID.

2325

N243

Alexandra C. Apple,Alexis Oddi,Michael J. Peluso,Breton M. Asken,Timothy J. Henrich,J. Daniel Kelly,Samuel J. Pleasure,Steven G. Deeks,Isabel Elaine Allen,Jeffrey N. Martin,Lishomwa C. Ndhlovu,Bruce L. Miller,Melanie L. Stephens,Joanna Hellmuth … See fewer authors

Risk factors and abnormal cerebrospinal fluid associate with cognitive symptoms after mild COVID-19

https://doi.org/10.1002/acn3.51498

Published

19-Jan-22

Study

https://onlinelibrary.wiley.com/doi/full/10.1002/acn3.51498

Cognitive post-acute sequelae of SARS-CoV-2 (PASC) can occur after mild COVID-19. Detailed clinical characterizations may inform pathogenesis. We evaluated 22 adults reporting cognitive PASC and 10 not reporting cognitive symptoms after mild SARS-CoV-2 infection through structured interviews, neuropsychological testing, and optional cerebrospinal fluid (CSF) evaluations (53%). Delayed onset of cognitive PASC occurred in 43% and associated with younger age. Cognitive PASC participants had a higher number of pre-existing cognitive risk factors (2.5 vs. 0; p = 0.03) and higher proportion with abnormal CSF findings (77% vs. 0%; p = 0.01) versus controls. Cognitive risk factors and immunologic mechanisms may contribute to cognitive PASC pathogenesis.

2326

N244

Saab C, Valsamis H, Baki S, Leung J, Ghosn S, Lapin B, Chari G, Rasheed I, Park J, Punia V, Nair D, Kaniecki AM, Edhi M

SARS-CoV-2 Slows Brain Rhythms with more Severe Effects in Younger Individuals

https://doi.org/10.21203/rs.3.rs-1197196/v1

pre-print

12-Jan-22

Study

https://europepmc.org/article/ppr/ppr441883

In a previous study, we developed a computational pipeline for the automated, rapid, high-throughput and objective analysis of brain encephalography (EEG) rhythms. In this retrospective study, we used this pipeline to define the quantitative EEG changes in patients with a PCR-positive diagnosis of C19 (n=31) in the intensive care unit (ICU) of Cleveland Clinic, compared to a group of age-matched PCR-negative (n=38) control patients in the same ICU setting. Qualitative assessment of EEG by two independent teams of electroencephalographers confirmed prior reports with regards to the high prevalence of diffuse encephalopathy in C19 patients, although the diagnosis of encephalopathy was inconsistent between teams. Quantitative analysis of EEG showed distinct slowing of brain rhythms in C19 patients compared to control (enhanced delta power and attenuated alpha-beta power). Surprisingly, these C19-related changes in EEG power were more prominent in patients below age 70. Moreover, machine learning algorithms showed consistently higher accuracy in the binary classification of patients as C19 versus control using EEG power for subjects below age 70 compared to older ones, providing further evidence for the more severe impact of SARS-CoV-2 on brain rhythms in younger individuals irrespective of PCR diagnosis or symptomatology, and raising concerns over potential long-term effects of C19 on brain physiology in the adult population and the utility of EEG monitoring in C19 patients.

2327

N245

Akshamal M. Gamage, Kai Sen Tan, Wharton O. Y. Chan, Zhe Zhang Ryan Lew, Jing Liu, Chee Wah Tan, Deepa Rajagopalan, , Quy Xiao Xuan Lin, Le Min Tan, Prasanna Nori Venkatesh, Yew Kwang Ong, Mark Thong, Raymond Tzer Pin Lin, Shyam Prabhakar, De Yun Wang entwdy@nus.edu.sg, Lin-Fa Wang

Human Nasal Epithelial Cells Sustain Persistent SARS-CoV-2 Infection In Vitro, despite Eliciting a Prolonged Antiviral Response

https://doi.org/10.1128/mbio.03436-21

Published

18-Jan-22

Study

https://journals.asm.org/doi/10.1128/mbio.03436-21

In this study, the long-term dynamics of SARS-CoV-2 infection were investigated using a human well-differentiated nasal epithelial cell (NEC) model of infection. NECs were observed to release SARS-CoV-2 virus onto the apical surface for up to 28 days postinfection (dpi), further corroborated by viral antigen staining. Single-cell transcriptome sequencing (sc-seq) was utilized to explore the host response from infected NECs after short-term (3-dpi) and long-term (28-dpi) infection. We identified a unique population of cells harboring high viral loads present at both 3 and 28 dpi, characterized by expression of cell stress-related genes DDIT3 and ATF3 and enriched for genes involved in tumor necrosis factor alpha (TNF-α) signaling and apoptosis. Remarkably, this sc-seq analysis revealed an antiviral gene signature within all NEC cell types even at 28 dpi. We demonstrate increased replication of basal cells, absence of widespread cell death within the epithelial monolayer, and the ability of SARS-CoV-2 to replicate despite a continuous interferon response as factors likely contributing to SARS-CoV-2 persistence. This study provides a model system for development of therapeutics aimed at improving viral clearance in immunocompromised patients and implies a crucial role for immune cells in mediating viral clearance from infected epithelia.
IMPORTANCE Increasing medical attention has been drawn to the persistence of symptoms (long-COVID syndrome) or live virus shedding from subsets of COVID-19 patients weeks to months after the initial onset of symptoms. In vitro approaches to model viral or symptom persistence are needed to fully dissect the complex and likely varied mechanisms underlying these clinical observations. We show that in vitro differentiated human NECs are persistently infected with SARS-CoV-2 for up to 28 dpi. This viral replication occurred despite the presence of an antiviral gene signature across all NEC cell types even at 28 dpi. This indicates that epithelial cell intrinsic antiviral responses are insufficient for the clearance of SARS-CoV-2, implying an essential role for tissue-resident and infiltrating immune cells for eventual viral clearance from infected airway tissue in COVID-19 patients.

2328

N246

Yuda Turana 1,*,† ,Michael Nathaniel 1,† ,Robert Shen 1,† ,Soegianto Ali 1 andRajender R. Aparasu 2

Citicoline and COVID-19-Related Cognitive and Other Neurologic Complications

https://doi.org/10.3390/brainsci12010059

Published

31-Dec-21

Study

https://www.mdpi.com/2076-3425/12/1/59/htm

With growing concerns about COVID-19’s hyperinflammatory condition and its potentially damaging impact on the neurovascular system, there is a need to consider potential treatment options for managing short- and long-term effects on neurological complications, especially cognitive function. While maintaining adequate structure and function of phospholipid in brain cells, citicoline, identical to the natural metabolite phospholipid phosphatidylcholine precursor, can contribute to a variety of neurological diseases and hypothetically toward post-COVID-19 cognitive effects. In this review, we comprehensively describe in detail the potential citicoline mechanisms as adjunctive therapy and prevention of COVID-19-related cognitive decline and other neurologic complications through citicoline properties of anti-inflammation, anti-viral, neuroprotection, neurorestorative, and acetylcholine neurotransmitter synthesis, and provide a recommendation for future clinical trials.

2329

N247

Natalia A. Shnayder 1,2,* ,Timur K. Sirbiladze 1,* ,Irina V. Demko 2,Marina M. Petrova 2 andRegina F. Nasyrova 1,3

Limbic Encephalitis Associated with COVID-19

https://doi.org/10.3390/encyclopedia2010003

Published

22-Dec-21

Review

https://www.mdpi.com/2673-8392/2/1/3/htm

Concluding, we should mention that the number of publications dedicated to para-infectious LE associated with SARS-CoV-2 is currently limited. However, the high tropism of SARS-CoV-2 to the structures of the limbic system of the brain, with the possibility of isolated lesions of these areas in children and adults without respiratory symptoms of COVID-19, and the high number of new cases of this infection in population worldwide indicates the importance of this interdisciplinary problem in neurology and psychiatry. In addition, the development of an autoimmune process in the CNS is also possible after the respiratory symptoms was resolved, as the long-term consequence in patients with the pulmonary form of COVID-19. In patients with a high risk of developing para-infectious LE associated with SARS-CoV-2, the diagnostic algorithm in the acute and subacute periods should include analysis of CSF, EEG monitoring and brain MRI. In patients with asymptomatic or mild COVID-19 (without respiratory symptoms) and long-term consequences of COVID-19 (long-COVID-19), the diagnostic algorithm should include neuropsychological testing, brain MRI, EEG and serological testing (evaluating the pro-inflammatory cytokines and antibodies to SARS-CoV-2 IgG). This algorithm can help in the risk assessment and early diagnosis of para-infectious LE associated with SARS-CoV-2; moreover, it gives information for consideration in treatment planning. An important but controversial issue is the acceptability of revaccination against COVID-19 in patients with high risk of developing para-infectious LE or patients with this disease.

2330

N248

Arianna Di Stadio 1,*,†,Michael J. Brenner 2 ,Pietro De Luca 3 ,Maria Albanese 4 ,Luca D’Ascanio 5 ,Massimo Ralli 6 ,Dalila Roccamatisi 7,Cristina Cingolani 5,Federica Vitelli 5,Angelo Camaioni 8,Stefano Di Girolamo 9 andEvanthia Bernitsas 10,†

Olfactory Dysfunction, Headache, and Mental Clouding in Adults with Long-COVID-19: What Is the Link between Cognition and Olfaction? A Cross-Sectional Study

https://doi.org/10.3390/brainsci12020154

Published

24-Jan-22

Study

https://www.mdpi.com/2076-3425/12/2/154/htm

We investigated mental clouding, headache, and cognitive function in adult patients with persistent COVID-19 olfactory dysfunction. This multi-center cross-sectional study enrolled 152 adults with self-reported olfactory dysfunction from 3 tertiary centers specialized in COVID-19 olfactory disorders. Inclusion criteria were smell alterations after COVID-19 persisting over 6 months from infection, age >18 and < 65. Exclusion criteria included smell alterations, headache, or memory problems prior to COVID-19 infection. The patients were evaluated by olfactometry, nasal endoscopy, headache scale, cognitive assessment, Mini Mental State Examination (MMSE), and self-reported measures. Smell dysfunction was stratified and classified based on olfactory deficit severity and presence of olfactory distortion (parosmia, cacosmia). Data on smell disorder, mental clouding, MMSE, and headache were analyzed to assess correlations. Among the 152 patients studied, 50 (32.8%) presented with anosmia, 25 (16.4%) with hyposmia, 10 (6.6%) with parosmia/cacosmia, and 58 patients (38.2%) with a combination of hyposmia and parosmia; seven (4.6%) patients suffered from headache exclusively, and two (1.4%) had headache and mental clouding as their primary symptom. Headache was reported by 76 (50%) patients, and mental clouding by 71 (46.7%). The patients reporting headache, mental clouding, or both, had significantly increased risk of suffering from anosmia and/or hyposmia when compared with their counterparts without these neurological symptoms. No patients had reduced MMSE scores. In our cohort of adult patients with post-COVID-19, smell alterations persisting over 6 months, cognitive impairment and headache were associated with more severe olfactory loss, consistent with neuroinflammatory mechanisms mediating a variety of Long-COVID symptoms.

2331

N249

MariannaZazhytska1∗AlbanaKodra12∗Daisy A.Hoagland3JustinFrere314John F.Fullard456HaniShayya12Natalie G.McArthur8RasmusMoeller3SkylerUhl3Arina D.Omer7Max E.Gottesman13StuartFirestein8QizhiGong9Peter D.Canoll10James E.Goldman10PanosRoussos45611Benjamin R.tenOever314#Jonathan B.Overdevest12#StavrosLomvardas113#&

Non-cell autonomous disruption of nuclear architecture as a potential cause of COVID-19 induced anosmia

https://doi.org/10.1016/j.cell.2022.01.024

Published

2-Feb-22

Study

https://www.sciencedirect.com/science/article/pii/S0092867422001350

Highlights
•Downregulation of odor detection pathways may explain COVID-19 induced anosmia.
•SARS-CoV-2 mediated disruption of nuclear architecture may impair odor detection.
•SARS-CoV-2 mediated nuclear reorganization is non-cell autonomous.
SARS-CoV-2 infects less than 1% of cells in the human body, yet it can cause severe damage in a variety of organs. Thus, deciphering the non-cell autonomous effects of SARS-CoV-2 infection is imperative for understanding the cellular and molecular disruption it elicits. Neurological and cognitive defects are among the least understood symptoms of COVID-19 patients, with olfactory dysfunction being their most common sensory deficit. Here, we show that both in humans and hamsters SARS-CoV-2 infection causes widespread downregulation of olfactory receptors (OR) and of their signaling components. This non-cell autonomous effect is preceded by a dramatic reorganization of the neuronal nuclear architecture, which results in dissipation of genomic compartments harboring OR genes. Our data provide a potential mechanism by which SARS-CoV-2 infection alters the cellular morphology and the transcriptome of cells it cannot infect, offering insight to its systemic effects in olfaction and beyond.

Dans une étude publiée dans Cell, des chercheurs expliquent, par des modèles sur l'humain et sur le hamster, que l'infection par le SRAS-CoV-2 peut entraîner une régulation négative généralisée des récepteurs olfactifs et de leurs composants de signalisation. Ils notent que cet effet non cellulaire autonome est précédé d'une réorganisation spectaculaire de l'architecture nucléaire neuronale, entraînant la dissipation des compartiments génomiques abritant les gènes des récepteurs olfactifs. Cette présentation fournit un mécanisme potentiel par lequel l'infection du virus modifie la morphologie cellulaire et le transcriptome des cellules qu'elle ne peut pas infecter, à même d'expliquer les troubles persistants olfactifs. Selon cette équipe américaine, ces déficits à long terme de l'architecture nucléaire pourraient être applicables à d'autres d'autres populations neuronales (et donc à même d'expliquer d'autres symptômes neurologiques du covid long), puisque les neurones adultes du système nerveux central assemblent également des compartiments génomiques cis et trans à longue portée entre les gènes des récepteurs olfactifs et d'autres familles de gènes neuronaux.

2332

N250

Care

Kamini Krishnan, YuFang Lin, Kia-Rai M. Prewitt & Dawn A. Potter

Multidisciplinary Approach to Brain Fog and Related Persisting Symptoms Post COVID-19

https://doi.org/10.1007/s42843-022-00056-7

Published

2-Feb-22

Article

https://link.springer.com/article/10.1007/s42843-022-00056-7

A third of patients who developed COVID-19 experience a persisting, diverse array of symptoms including respiratory, neurological, and psychiatric complaints referred to as post-acute sequelae of COVID-19 (PASC). Symptoms can last for months after the original infection and appear unrelated to the severity of the initial illness, which suggests that even patients who did not require extensive interventions at the acute stage may experience new and/or long-term symptoms. Brain fog is a colloquial term for a common complaint among patients with PASC and generally implies cognitive impairment in domains of attention and processing speed. There are multiple hypotheses for etiologies and explanations of mechanisms contributing to brain fog in PASC. In this paper, we describe some of the mechanisms associated with brain fog post COVID-19 and provide readers with treatment recommendations that encompass cognition, mood disorders, sleep disorders, and neuroinflammation.

2333

N251

Kamen A Tsvetanov, Lennart R B Spindler, View ProfileEmmanuel A Stamatakis, Virginia FJ Newcombe, Victoria C Lupson, Doris A Chatfield, Anne E Manktelow, Joanne G Outtrim, Anne Elmer, Nathalie Kingston, John R Bradley, View ProfileEdward T Bullmore, View ProfileJames B Rowe, David K Menon

Hospitalisation for COVID-19 predicts long lasting cerebrovascular impairment: A prospective observational cohort study

https://doi.org/10.1101/2022.02.01.22270235

Published

2-Feb-22

Study

https://www.medrxiv.org/content/10.1101/2022.02.01.22270235v1.full-text

Human coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has multiple neurological consequences, but its long-term effect on brain health is still uncertain. The cerebrovascular consequences of COVID-19 may also affect brain health. Here we assess cerebrovascular health in 45 hospitalised patients using the resting state fluctuation amplitudes (RSFA) from functional magnetic resonance imaging, in relation to disease severity and in contrast with 42 controls. Widespread changes in frontoparietal RSFA were related to the severity of the acute COVID-19 episode, as indexed by COVID-19 WHO Progression Scale, inflammatory and coagulatory biomarkers. This relationship was not explained by chronic cardiorespiratory dysfunction, age, or sex. Exploratory analysis suggests that the level of cerebrovascular dysfunction is associated with cognitive, mental, and physical health at follow-up. The principal findings were consistent across univariate and multivariate approaches. The results indicate chronic cerebrovascular impairment following severe acute COVID-19, with the potential for long-term consequences on cognitive function and mental wellbeing.

2334

N252

George B Stefano 1, Pascal Büttiker 1, Simon Weissenberger 1, Radek Ptacek 1, Fuzhou Wang 2, Tobias Esch 3, Thomas V Bilfinger 4, Richard M Kream 1

Biomedical Perspectives of Acute and Chronic Neurological and Neuropsychiatric Sequelae of COVID-19

https://doi.org/10.2174/1570159x20666211223130228

Published

23-Dec-21

Review

https://pubmed.ncbi.nlm.nih.gov/34951387/

The incidence of infections from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent for coronavirus disease 2019 (COVID-19), has dramatically escalated following the initial outbreak in China in late 2019, resulting in a global pandemic with millions of deaths. Although the majority of infected patients survive, and the rapid advent and deployment of vaccines have afforded increased immunity against SARS-CoV-2, long term sequelae of SARS-CoV-2 infection have become increasingly recognized. These include, but are not limited to, chronic pulmonary disease, cardiovascular disorders, and proinflammatory-associated neurological dysfunction that may lead to psychological and neurocognitive impairment. A major component of cognitive dysfunction is operationally categorized as "brain fog" which comprises difficulty with concentration, forgetfulness, confusion, depression, and fatigue. Multiple parameters associated with long-term neuropsychiatric sequelae of SARS-CoV-2 infection have been detailed in clinical studies. Empirically elucidated mechanisms associated with the neuropsychiatric manifestations of COVID-19 are by nature complex, but broad based working models have focused on mitochondrial dysregulation leading to systemic reductions of metabolic activity and cellular bioenergetics within CNS structures. Multiple factors underlying the expression of brain fog may facilitate future pathogenic insults leading to repetitive cycles of viral and bacterial propagation. Interestingly, diverse neurocognitive sequelae associated with COVID-19 are not dissimilar from those observed in other historical pandemics, thereby providing a broad and integrative perspective on potential common mechanisms of CNS dysfunction subsequent to viral infection. Poor mental health status may be reciprocally linked to compromised immune processes and enhanced susceptibility to infection by diverse pathogens. By extrapolation, we contend that COVID-19 may potentiate the severity of neurological/neurocognitive deficits in patients afflicted by well-studied neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Accordingly, the prevention, diagnosis, and management of sustained neuropsychiatric manifestations of COVID-19 are pivotal health care directives and provide a compelling rationale for careful monitoring of infected patients, as early mitigation efforts may reduce short- and long-term complications.

2335

N253

Kamini Krishnan, Ashley K Miller, Katherine Reiter, Aaron Bonner-Jackson

Neurocognitive Profiles in Patients With Persisting Cognitive Symptoms Associated With COVID-19

https://doi.org/10.1093/arclin/acac004

Published

5-Feb-22

Study

https://academic.oup.com/acn/advance-article/doi/10.1093/arclin/acac004/6522998?login=true

A subset of individuals with coronavirus disease 2019 (COVID-19) appears to develop persisting cognitive and medical symptoms. Research in the acute stages of illness, generally utilizing cognitive screening measures or case reports, suggests presence of deficits in attention and executive function. This observational study investigated cognitive functioning among individuals with persistent cognitive complaints about 5.5 months after COVID-19 infection.
Methods
Patients with polymerase chain reaction confirmed COVID-19 and persistent cognitive complaints underwent comprehensive in-person neuropsychological evaluations. Patients with prior neurological disorders were excluded. When diagnosed, 40% required hospitalization, 15% were in an intensive care unit, 10% needed mechanical ventilation, and 10% experienced delirium.
Results
This sample was predominately women (90%), White non-Hispanic (70%), with average education of 15 years. Mild cognitive deficits were seen on tests involving attention and processing speed or executive function. Seventy percent of patients were diagnosed with a mood disorder prior to COVID-19 infection. At the time of testing, 35%–40% endorsed moderate to severe mood symptoms and 85% noted significant fatigue as measured by the Fatigue Severity Scale.
Conclusions
The pattern of cognitive deficits, although mild, is consistent with prior research at the acute stage of the illness. These findings suggest that psychological factors and other persisting symptoms (e.g., sleep, fatigue) may play a significant role in subjective cognitive complaints in patients with persisting complaints post COVID-19 who did not require intensive treatment. These patients would likely benefit from resources to manage persisting or new mood symptoms and compensatory strategies for the cognitive inefficiencies they experience.

2336

N254

JessicaHamzelou

What covid-19 does to the brain

https://doi.org/10.1016/S0262-4079(22)00130-0

Published

31-Jan-22

Review

https://www.sciencedirect.com/science/article/pii/S0262407922001300?via%3Dihub

OVER the past two years, we have learned that covid-19 can have profound consequences for the brain – in the short and long term.

Now, researchers are starting to get a clearer picture of how the coronavirus may cause symptoms that include brain fog, depression, confusion and even stroke. The latest insights suggest that the virus seldom infects brain cells directly, but instead causes harm through blood clots or by spurring a destructive immune response. Encouragingly, many of the effects caused by harmful immune changes are likely to be reversible.

2337

N255

Paola Ortelli,Davide Ferrazzoli,Luca Sebastianelli,Roberto Maestri,Sabrina Dezi,Danny Spampinato,Leopold Saltuari,Alessia Alibardi,Michael Engl,Markus Kofler,Angelo Quartarone,Giacomo Koch,Antonio Oliviero,Viviana Versace

Altered motor cortex physiology and dysexecutive syndrome in patients with fatigue and cognitive difficulties after mild COVID-19

https://doi.org/10.1111/ene.15278

Published

9-Feb-22

Study

https://onlinelibrary.wiley.com/doi/abs/10.1111/ene.15278

Methods
We enrolled 67 patients complaining of fatigue and/or cognitive difficulties after resolution of mild SARS-CoV-2 infection and 22 healthy controls (HC). Persistent clinical symptoms were investigated by means of a 16-item questionnaire. Fatigue, exertion, cognitive difficulties, mood and “well-being” were evaluated through self-administered tools. Utilizing transcranial magnetic stimulation of the primary motor cortex (M1) we evaluated resting motor threshold (RMT), motor evoked potential (MEP) amplitude, cortical silent period (SP) duration, short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), long-interval intracortical inhibition (LICI), and short-latency afferent inhibition (SAI). Global cognition and executive functions were assessed with screening tests. Attention was measured with computerized tasks.
Results
Post COVID-19 patients reported a mean of 4.9 persistent symptoms, high levels of fatigue, exertion, cognitive difficulties, low levels of well-being and depressive symptoms. Compared to HC, patients presented higher RMTs, lower MEP amplitudes and longer SPs, concurring with reduced M1 excitability. LICI and SAI were also impaired, indicating altered GABAB- and cholinergic neurotransmission. SICI and ICF were not affected. Patients also showed poorer global cognition and executive functions as compared to HC and a clear impairment in sustained and executive attention.
Conclusions
Patients with fatigue and cognitive difficulties following mild COVID-19 present altered excitability and neurotransmission within M1 and deficits in executive functions and attention.

2338

N256

Richard J Smeyne, View ProfileJeffrey Eells, View ProfileDebotri Chatterjee, View ProfileMatthew Byrne, View ProfileShaw M. Akula, View ProfileSrinivas Sriramula, View ProfileDorcas P. O’Rourke, View ProfilePeter Schmidt

COVID-19 infection enhances susceptibility to oxidative-stress induced parkinsonism

https://doi.org/10.1101/2022.02.02.478719

pre-print

3-Feb-22

Study

https://www.biorxiv.org/content/10.1101/2022.02.02.478719v1.full

Background Viral induction of neurological syndromes has been a concern since parkinsonian-like features were observed in patients diagnosed with encephalitis lethargica subsequent to the 1918 influenza pandemic. Given the similarities in the systemic responses following SARS-CoV-2 infection with those observed after pandemic influenza, there is a question if a similar syndrome of post-encephalic parkinsonism could follow COVID-19 infection.
Objectives To determine if prior infection with SARS-CoV-2 increased sensitivity to a mitochondrial toxin known to induce parkinsonism.
Methods hACE2 mice were infected with SARS-CoV-2 to induce mild to moderate disease. After 31 days recovery, mice were administered a non-lesion inducing dose of the parkinsonian toxin MPTP. Subsequent neuroinflammation and SNpc dopaminergic neuron loss was determined and compared to SARS-CoV-2 or MPTP alone.
Results hACE2 mice infected with SARS-CoV-2 or MPTP showed no SNpc DA neuron loss following MPTP. In mice infected and recovered from SARS-CoV-2 infection, MPTP induced a 23% or 19% greater loss of SNpc dopaminergic neurons than SARS-CoV-2 or MPTP, respectively (p□<□0.05).
Examination of microglial activation showed a significant increase in the number of activated microglia in the SARS-CoV-2 + MPTP group compared to SARS-CoV-2 or MPTP alone.
Conclusions Our observations have important implications for long-term public health, given the number of people that have survived SARS-CoV-2 infection as well as for future public policy regarding infection mitigation. However, it will be critical to determine if other agents known to increase risk of PD also have synergistic effects with SARS-CoV-2 and if are abrogated by vaccination.

2339

N257

Nizama Salihefendic, 1 Muharem Zildzic, 2 and Haris Huseinagic 3

Ischemic Vasculitis as a Cause of Brain Disorder’s in Patients with Long Covid: Case Report

https://dx.doi.org/10.5455%2Fmedarh.2021.75.471-474

Published

1-Dec-21

Case Report

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8810149/

Objective:
The aim of this article is to describe 2 young adults who developed neuropsychiatric symptoms in the course of Long COVID-19 syndrome. Ischemic vasculitis was proved using CT imaging.
Case report:
We collected data of two younger females who had previously recovered from the acute form of COVID-19 without respiratory complications. They developed in the next 1-2 months a clinical picture of a brain disorder. In both cases, CT and angiography scans of the brain showed signs of ischemic vasculitis. Neurological therapy has led to an improvement of the neuropsychiatric symptoms.
Conclusion:
Neuropsychiatric disorders in Long Covid syndrome are common and diverse. Two cases of young adults who developed signs of neurological disorder in the post COVID-19 period were presented, and CT scans of the brain showed signs of ischemic vasculitis.

2340

N258

ES

Steve Reiken,Leah Sittenfeld,Haikel Dridi,Yang Liu,Xiaoping Liu,Andrew R. Marks

Alzheimer's-like signaling in brains of COVID-19 patients

https://doi.org/10.1002/alz.12558

Published

3-Feb-22

Study

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12558

Methods
Brain lysates from control and COVID-19 patients were analyzed for oxidative stress and inflammatory signaling pathway markers, and measurements of Alzheimer’s disease (AD)-linked signaling biochemistry. Post-translational modifications of the ryanodine receptor/calcium (Ca2+) release channels (RyR) on the endoplasmic reticuli (ER), known to be linked to AD, were also measured by co-immunoprecipitation/immunoblotting of the brain lysates.
Results
We provide evidence linking SARS-CoV-2 infection to activation of TGF-β signaling and oxidative overload. The neuropathological pathways causing tau hyperphosphorylation typically associated with AD were also shown to be activated in COVID-19 patients. RyR2 in COVID-19 brains demonstrated a “leaky” phenotype, which can promote cognitive and behavioral defects.
Discussion
COVID-19 neuropathology includes AD-like features and leaky RyR2 channels could be a therapeutic target for amelioration of some cognitive defects associated with SARS-CoV-2 infection and long COVID.
RESEARCH-IN-CONTEXT
Systematic review: The authors reviewed the literature using PubMed. While the mechanisms that lead to cognitive impairment associated with COVID-19 are not well understood, there have been recent reports studying SARS-CoV-2 infection and brain biochemistry and neuropathology. These relevant citations are appropriately cited.
Interpretation: Our findings link the inflammatory response to SARS-CoV-2 infection with the neuropathological pathways causing tau hyperphosphorylation typically associated with Alzheimer's disease (AD). Furthermore, our data indicate a role for leaky ryanodine receptor 2 (RyR2) in the pathophysiology of SARS-CoV-2 infection.
Future directions: The article proposes that the alteration of cellular calcium dynamics due to leaky RyR2 in COVID-19 brains is associated with the activation of neuropathological pathways that are also found in the brains of AD patients. Both the cortex and cerebellum of SARS-CoV-2–infected patients exhibited a reduced expression of the Ca2+ buffering protein calbindin. Decreased calbindin could render these tissues more vulnerable to cytosolic Ca2+ overload. Ex vivo treatment of the COVID-19 brain using a Rycal drug (ARM210) that targets RyR2 channels prevented intracellular Ca2+ leak in patient samples. Future experiments will explore calcium channels as a potential therapeutic target for the neurological complications associated with COVID-19.

todo

2341

N259

Anne M.E. Baker, View ProfileNatalie J. Maffitt, Alessandro Del Vecchio, Katherine M. McKeating, View ProfileMark R. Baker, View ProfileStuart N. Baker, View ProfileDemetris S. Soteropoulos

Neural Dysregulation in Post-Covid Fatigue

https://doi.org/10.1101/2022.02.18.22271040

pre-print

21-Feb-22

Study

https://www.medrxiv.org/content/10.1101/2022.02.18.22271040v1.full-text

Fatigue is a common complaint with substantial impact on daily life, but the neural mechanisms behind post-COVID fatigue remain unclear. We recruited volunteers with self-reported fatigue after a mild COVID infection and carried out a battery of behavioural and neurophysiological tests assessing the central, peripheral and autonomic nervous systems. In comparison to age and gender matched volunteers without fatigue, we show underactivity in specific cortical circuits, dysregulation of autonomic function, and myopathic change in skeletal muscles. Cluster analysis revealed no sub-groupings, suggesting post-COVID fatigue is a single entity with individual variation, rather than a small number of distinct syndromes. These abnormalities on objective tests may indicate novel avenues for principled therapeutic intervention, and could act as fast and reliable biomarkers for diagnosing and monitoring the progression of fatigue over time.
Most people infected with SARS-CoV-2 do not require hospitalisation. However, even after a mild infection, a minority develop symptoms that linger for weeks or months (long COVID). Persistent fatigue, where everyday actions become laborious, is one of the more commonly reported after-effects1 and can have a substantial impact on the quality of life and productivity of sufferers2-4. At the time of publication ∼2% of the UK population are experiencing long COVID; >50% report fatigue as their primary symptom5.
Fatigue appears to be a multi-system pathology, with immunological, metabolic and hormonal anomalies. These presumably generate changes in neurological function6 which lead to feelings of weakness and actions being more effortful. Changes could occur at many loci – for example, reduced activation of central motor circuits or impaired muscle function could lead to weakness; upregulated sensory feedback could increase sense of effort. To date no studies have investigated deficits in specific neural circuits with post-covid fatigue (pCF).

2342

N260

Maria-Ioanna Stefanou, Lina Palaiodimou, Eleni Bakola, Nikolaos Smyrnis, Marianna Papadopoulou, George P. Paraskevas, Emmanouil Rizos, Eleni Boutati, Nikolaos Grigoriadis, Christos Krogias, Sotirios Giannopoulos, Sotirios Tsiodras, Mina Gaga, Georgios Tsivgoulis

Neurological manifestations of long-COVID syndrome: a narrative review

https://doi.org/10.1177%2F20406223221076890

Published

17-Feb-22

Review

https://journals.sagepub.com/doi/full/10.1177/20406223221076890

Accumulating evidence points toward a very high prevalence of prolonged neurological symptoms among coronavirus disease 2019 (COVID-19) survivors. To date, there are no solidified criteria for ‘long-COVID’ diagnosis. Nevertheless, ‘long-COVID’ is conceptualized as a multi-organ disorder with a wide spectrum of clinical manifestations that may be indicative of underlying pulmonary, cardiovascular, endocrine, hematologic, renal, gastrointestinal, dermatologic, immunological, psychiatric, or neurological disease. Involvement of the central or peripheral nervous system is noted in more than one-third of patients with antecedent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, while an approximately threefold higher incidence of neurological symptoms is recorded in observational studies including patient-reported data. The most frequent neurological manifestations of ‘long-COVID’ encompass fatigue; ‘brain fog’; headache; cognitive impairment; sleep, mood, smell, or taste disorders; myalgias; sensorimotor deficits; and dysautonomia. Although very limited evidence exists to date on the pathophysiological mechanisms implicated in the manifestation of ‘long-COVID’, neuroinflammatory and oxidative stress processes are thought to prevail in propagating neurological ‘long-COVID’ sequelae. In this narrative review, we sought to present a comprehensive overview of our current understanding of clinical features, risk factors, and pathophysiological processes of neurological ‘long-COVID’ sequelae. Moreover, we propose diagnostic and therapeutic algorithms that may aid in the prompt recognition and management of underlying causes of neurological symptoms that persist beyond the resolution of acute COVID-19. Furthermore, as causal treatments for ‘long-COVID’ are currently unavailable, we propose therapeutic approaches for symptom-oriented management of neurological ‘long-COVID’ symptoms. In addition, we emphasize that collaborative research initiatives are urgently needed to expedite the development of preventive and therapeutic strategies for neurological ‘long-COVID’ sequelae.

2343

N261

César Fernández-de-las-Peñas PhD, José D. Martín-Guerrero PhD, Esperanza Navarro-Pardo PhD, Ignacio Cancela-Cilleruelo PT, MSc, Paloma Moro-López-Menchero PT, MSc & Oscar J. Pellicer-Valero MSc

Exploring Trajectory Curves from Loss of Smell and Taste in Previously Hospitalized COVID-19 Survivors: the LONG-COVID-EXP-CM Multicenter Study

https://doi.org/10.1007/s11606-022-07459-8

Published

22-Feb-22

Study

https://link.springer.com/article/10.1007/s11606-022-07459-8

elf-reported loss of smell (anosmia) and taste (ageusia) have a prevalence of 19% and 23% in COVID-19 patients at the acute phase1 and a prevalence of 15% in a post-COVID phase2, 3. Altered taste and smell may lead to disruption to basic daily living activities; nevertheless, almost 80% of patients may expect spontaneous recovery after 6 months4. Most studies investigating loss of smell/taste have used cross-sectional designs assessing their presence just once. Understanding longitudinal patterns of loss of smell/taste could have significant implications for determining comprehensive plans for prevention and management of these post-COVID complications.5 This study explores the recovery trajectory of loss of smell/taste symptom in previously hospitalized COVID-19 survivors by using mosaic and exponential model bar plots for showing the long-term evolution of these symptoms.

2344

N262

Giovani Zocche Junior, Lia Fonseca Siqueira, Leonardo Bongiovani Loro, Felipe Valles Fortes, Gabriele Zanirati, Daniel Marinowic, Jaderson Costa da Costa

Neurologic and neuropsychiatric symptoms in long-COVID 19 syndrome: a systematic review

10.21203/rs.3.rs-1359143/v1

pre-print

15-Feb-22

Review

researchsquare.com/article/rs-1359143/v1

This broad concept of COVID-19 long defined as symptoms occurring after infection is very relevant for health care taken together with patient complaints related to new emerging variants and prior infections. Therefore, establishing the relationship between neurological symptoms and COVID-19 is very important. For this review, we considered only neurologic or neuropsychiatric findings after a positive SARS-CoV-2 serological test and COVID-19 long symptoms after a negative PCR test, which resulted in 42 studies after exclusions. Our results demonstrated that the most relevant and frequent neurological complaints reported was fatigue, followed by attention or memory difficulties, including brain fog and smell and taste disturbances. This systematic literature review of long COVID-19 aims to enhance the current knowledge regarding symptoms after infection and to discuss long-term COVID-19 concept, given the possibility of new or persistent symptoms.

2345

N263

Maria-Ioanna Stefanou, Lina Palaiodimou, Eleni Bakola, Nikolaos Smyrnis, Marianna Papadopoulou, George P. Paraskevas, Emmanouil Rizos, Eleni Boutati, Nikolaos Grigoriadis, Christos Krogias, Sotirios Giannopoulos, Sotirios Tsiodras, Mina Gaga, Georgios TsivgoulisFirst Published February 17, 2022 Review

Neurological manifestations of long-COVID syndrome: a narrative review

https://doi.org/10.1177%2F20406223221076890

Published

17-Feb-22

Review

https://journals.sagepub.com/doi/full/10.1177/20406223221076890

To date, there are no solidified criteria for ‘long-COVID’ diagnosis. Nevertheless, ‘long-COVID’ is conceptualized as a multi-organ disorder with a wide spectrum of clinical manifestations that may be indicative of underlying pulmonary, cardiovascular, endocrine, hematologic, renal, gastrointestinal, dermatologic, immunological, psychiatric, or neurological disease. Involvement of the central or peripheral nervous system is noted in more than one-third of patients with antecedent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, while an approximately threefold higher incidence of neurological symptoms is recorded in observational studies including patient-reported data. The most frequent neurological manifestations of ‘long-COVID’ encompass fatigue; ‘brain fog’; headache; cognitive impairment; sleep, mood, smell, or taste disorders; myalgias; sensorimotor deficits; and dysautonomia. Although very limited evidence exists to date on the pathophysiological mechanisms implicated in the manifestation of ‘long-COVID’, neuroinflammatory and oxidative stress processes are thought to prevail in propagating neurological ‘long-COVID’ sequelae. In this narrative review, we sought to present a comprehensive overview of our current understanding of clinical features, risk factors, and pathophysiological processes of neurological ‘long-COVID’ sequelae. Moreover, we propose diagnostic and therapeutic algorithms that may aid in the prompt recognition and management of underlying causes of neurological symptoms that persist beyond the resolution of acute COVID-19. Furthermore, as causal treatments for ‘long-COVID’ are currently unavailable, we propose therapeutic approaches for symptom-oriented management of neurological ‘long-COVID’ symptoms. In addition, we emphasize that collaborative research initiatives are urgently needed to expedite the development of preventive and therapeutic strategies for neurological ‘long-COVID’ sequelae.

2346

N264

Philipp T Meyer 1, Sabine Hellwig 1, Ganna Blazhenets 1, Jonas A Hosp

Molecular imaging findings on acute and long-term effects of COVID-19 on the brain: A systematic review

https://doi.org/10.2967/jnumed.121.263085

Published

17-Feb-22

Review

https://pubmed.ncbi.nlm.nih.gov/35177424/

Molecular imaging techniques like positron emission tomography (PET) and single-photon emission computed tomography (SPECT) have been used to shed light on how the Corona Virus Disease 2019 (COVID-19) affects the human brain. We provide a systematic review that summarizes the current literature according to five predominant topics: 1. Few case reports suggest reversible cortical and subcortical metabolic alterations in rare cases with concomitant, para- or post-infectious encephalitis. 2. Imaging findings in single patients with first manifestations of parkinsonism in the context of COVID-19 resemble those in neurodegenerative parkinsonism (loss of nigrostriatal integrity), but scarceness of data and a lack of follow-up preclude further etiological conclusions (e.g., unmasking/hastening of neurodegeneration vs. (para-) infectious parkinsonism). 3. Several case reports and few systematic studies addressed focal symptoms and lesions, most notably hyposmia. Results are variable, although some studies found regional hypometabolism of regions related to olfaction (e.g., orbitofrontal and mesiotemporal). 4. A case series and systematic studies in inpatients with COVID-19-related encephalopathy (acute to subacute stage) consistently found a frontoparietal-dominant neocortical dysfunction (on imaging and clinically) that proved to be grossly reversible in the majority of cases until 6 months. 5. Studies in "Post-COVID-19 syndrome" provided controversial results. In patients with a high level of self-reported complaints (e.g., fatigue, memory impairment, hyposmia, dyspnea) some authors found extensive areas of limbic and subcortical hypometabolism, while others found no metabolic alterations on PET and only minor cognitive impairments (if any) on neuropsychological assessment. Furthermore, we provide a critical appraisal of studies in regard of frequent methodological issues and current pathophysiological concepts. Finally, we devised possible applications of PET and SPECT in the clinical work-up of diagnostic questions related to COVID-19.

2347

N265

Tian Tian,1 Jinfeng Wu,2 Tao Chen,3 Jia Li,1 Su Yan,1 Yiran Zhou,1 Xiaolong Peng,1 Yuanhao Li,1 Ning Zheng,2 Aoling Cai,2 Qin Ning,3 Hongbing Xiang,4 Fuqiang Xu,2,5 Yuanyuan Qin,1 Wenzhen Zhu,1 and Jie Wang2,5

Long-term follow-up of dynamic brain changes in patients recovered from COVID-19 without neurological manifestations

https://doi.org/10.1172/jci.insight.155827

Published

22-Feb-22

Study

https://insight.jci.org/articles/view/155827

METHODS. Dynamic brain changes are crucial for a better understanding and early prevention of “long COVID.” Here, we explored the cross-sectional and longitudinal consequences of COVID-19 on the brain in 34 discharged patients without neurological manifestations. Gray matter morphology, cerebral blood flow (CBF), and volumes of white matter tracts were investigated using advanced magnetic resonance imaging techniques to explore dynamic brain changes from 3 to 10 months after discharge.
RESULTS. Overall, the differences of cortical thickness were dynamic and finally returned to the baseline. For cortical CBF, hypoperfusion in severe cases observed at 3 months tended to recover at 10 months. Subcortical nuclei and white matter differences between groups and within subjects showed various trends, including recoverable and long-term unrecovered differences. After a 10-month recovery period, a reduced volume of nuclei in severe cases was still more extensive and profound than that in mild cases.
CONCLUSION. Our study provides objective neuroimaging evidence for the coexistence of recoverable and long-term unrecovered changes in 10-month effects of COVID-19 on the brain. The remaining potential abnormalities still deserve public attention, which is critically important for a better understanding of “long COVID” and early clinical guidance toward complete recovery.

2348

N266

Marc Jamoulle

Vascular encephalopathy demonstrated by
brain single-photon emission computed
tomography (SPECT-CT scan) in Long
Covid patients

https://hdl.handle.net/2268/288290

Published

1-Mar-22

Study

https://orbi.uliege.be/bitstream/2268/288290/1/Long_Covid_Letter_JABFM_Jamoulle_20220226.pdf

Brain single-photon emission computed tomography (SPECT-CT scanning) has been used in fourteen Long Covid patients seen in family practice with severe neurocognitive problems. Vascular encephalopathy has been demonstrated in each patient and supports the hypothesis of a persistent coagulation disorder in Long Covid.
The fourteen patients for whom a brain SPECT CT scan was requested had signs of brain impairment including three or more of the following symptoms; huge tiredness, exercise intolerance, cognitive problems such as brain fog, memory loss, anomia, headache, dysphasia, anosmia, dysgeusia, dysesthesia. Their DUSOI/WONCA severity index was high or maximum and their WONCA COOP charts score was over 20, meaning severe functional loss. Unexpectedly, brain SPECT showed severe alterations in cerebral blood flow in all patients, both cortical and central. All the lesions observed by brain SPECT CT scan are similar in all cases to those shown in Fig 1. This supports the hypothesis of a vascular perfusion disorder and localized brain ischemia secondary to a unexplained process like a coagulation disorder and/or the presence of auto-antibodies4 and could guide a therapeutic approach. It should be noted that fatigue and exhaustion during exercise can result from a difficult extraction of oxygen from the lungs, probably due also to vascular flow impairment.

2349

N267

OmidMirmosayyeb12Elham MoasesGhaffary2SaraBagherieh2MahdiBarzegar12Mohammad SadeghDehghan2VahidShaygannejad12

Post COVID-19 Infection Neuromyelitis Optica Spectrum Disorder (NMOSD): A Case Report-Based Systematic Review

https://doi.org/10.1016/j.msard.2022.103697

Published

19-Feb-22

Review

https://www.sciencedirect.com/science/article/pii/S2211034822002127

Highlights
•NMOSD is a rare CNS inflammatory condition associated with optic neuritis, longitudinally extensive transverse myelitis (LETM), and involving aquaporin-4 (AQP4) in the astrocytic water channel.
•Parainfectious pathogenesis as an environmental risk factor could play a key role in triggering NMOSD.
•Our systematic review presented the case reports of patients with NMOSD following COVID-19.
Abstract
Background: One of the rare neuroinflammatory disorders is Neuromyelitis optica spectrum disorder (NMOSD) which involves the central nervous system (CNS), and develops by various etiologies. It is evident that viral infections could cause neurological disorders. In this regard, novel coronavirus (COVID-19) triggers NMOSD, based on reports. We performed this systematic review to evaluate NMOSD patients following COVID-19 infection.
Methods: We collected 345 studies from PubMed (Medline), Embase, Scopus, and Web of Science databases from inception to 20 October 2021, and our inclusion criteria were English case reports/case series. Other types of Coronaviridae virus studies, review articles, articles written in any language other than English were excluded as well.
Results: 11 case reports were selected from 345 studies and data was extracted according to inclusion criteria. In all cases, NMOSD was reported following COVID-19 infection, and various symptoms such as blurring or loss of vision, weakness, and numbness were common, and the COVID-19 infection was confirmed by different tests such as PCR test, immunoglobulin assay and chest imaging.
Conclusion: Review regarding case reports showed that NMOSD is conceivable following COVID-19.

2350

N268

Publication of N138 ES

Gwenaëlle Douaud, Soojin Lee, Fidel Alfaro-Almagro, Christoph Arthofer, Chaoyue Wang, Paul McCarthy, Frederik Lange, Jesper L. R. Andersson, Ludovica Griffanti, Eugene Duff, Saad Jbabdi, Bernd Taschler, Peter Keating, Anderson M. Winkler, Rory Collins, Paul M. Matthews, Naomi Allen, Karla L. Miller, Thomas E. Nichols & Stephen M. Smith

SARS-CoV-2 is associated with changes in brain structure in UK Biobank

https://doi.org/10.1038/s41586-022-04569-5

Published

7-Mar-22

Study

https://www.nature.com/articles/s41586-022-04569-5

There is strong evidence for brain-related abnormalities in COVID-191–13. It remains unknown however whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. Here, we investigated brain changes in 785 UK Biobank participants (aged 51–81) imaged twice, including 401 cases who tested positive for infection with SARS-CoV-2 between their two scans, with 141 days on average separating their diagnosis and second scan, and 384 controls. The availability of pre-infection imaging data reduces the likelihood of pre-existing risk factors being misinterpreted as disease effects. We identified significant longitudinal effects when comparing the two groups, including: (i) greater reduction in grey matter thickness and tissue-contrast in the orbitofrontal cortex and parahippocampal gyrus, (ii) greater changes in markers of tissue damage in regions functionally-connected to the primary olfactory cortex, and (iii) greater reduction in global brain size. The infected participants also showed on average larger cognitive decline between the two timepoints. Importantly, these imaging and cognitive longitudinal effects were still seen after excluding the 15 cases who had been hospitalised. These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease via olfactory pathways, of neuroinflammatory events, or of the loss of sensory input due to anosmia. Whether this deleterious impact can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow up.

2351

N269

ES

Randy L. Gollub

Brain changes after COVID revealed by imaging
Imaging before and after infection by the SARS-CoV-2 virus reveals substantial changes in the brain after infection. The work sets an example for the high standards required in large longitudinal neuroimaging studies.

https://doi.org/10.1038/d41586-022-00503-x

Published

8-Mar-22

Article

https://www.nature.com/articles/d41586-022-00503-x

Myriad neuropsychiatric symptoms have been attributed to infection with the SARS-CoV-2 virus1,2, from lost sense of smell and taste to headaches, memory problems and more. Knowing precisely how the brain is changed by infection would help us to understand these debilitating symptoms. Large-scale brain-imaging studies can provide quantitative measures of subtle changes — but conducting these studies presents a formidable challenge. Writing in Nature, Douaud et al.3 describe 785 sets of brain scans that mark the first step in tackling this challenge head-on.

2352

N270

Jemmyson Romáriode JesusabRodrigo MorettoGalazzicCícero AlvesLopes JúniordMarco Aurélio ZezziArrudaef

Trace element homeostasis in the neurological system after SARS-CoV-2 infection: Insight into potential biochemical mechanisms

https://doi.org/10.1016/j.jtemb.2022.126964

Published

28-Feb-22

Review

https://www.sciencedirect.com/science/article/pii/S0946672X2200044X

Highlights
•Understanding the role of trace elements in the neurovirulence of SARS-CoV-2.
•Insight into potential biochemical mechanisms.
•Trends in treatments against SARS-CoV-2 infection.
Results
The imbalance of important trace elements can accelerate SARS-CoV-2 neurovirulence and increase the neurotoxicity since many neurological processes can be associated with the homeostasis of metal and metalloproteins. Some studies involving animals and humans have suggested the synapse as a vulnerable region of the brain to neurological disorders after viral infection. Considering the combined evidence, some mechanisms have been suggested to understand the relationship between neurological disorders and imbalance of trace elements in the brain after viral infection.
Conclusion
Trace elements play important roles in viral infections, such as helping to activate immune cells, produce antibodies, and inhibit virus replication. However, the relationship between trace elements and virus infections is complex since the specific functions of several elements remain largely undefined. Therefore, there is still a lot to be explored to understand the biochemical mechanisms involved between trace elements and viral infections, especially in the brain.

2353

N271

JonathanTaieb1VictorPitron1MaximeElbaz2AlexandreRouen3CarolineGauriau3DominiqueSalmon4DamienLeger1

Évaluation polysomnographique des troubles du sommeil chez des patients COVID-long

https://doi.org/10.1016/j.msom.2022.01.125

Published

23-Feb-22

Study

https://www.sciencedirect.com/science/article/pii/S176944932200125X

De nombreux patients COVID-long décrivent des troubles du sommeil, sur la base d’études cliniques sans polysomnographie (PSG). Notre objectif a été d’évaluer ces troubles du sommeil par un enregistrement PSG.
Méthodes
Vingt-deux patients COVID-long ont été adressés pour réalisation d’une PSG au centre du sommeil et de la vigilance de l’Hôtel-Dieu. Critères inclusion : critères HAS du COVID-long et critères ICSD3 de l’insomnie chronique. Critères d’exclusion : trouble du sommeil antérieur au COVID.
Résultats
Vingt-deux patients (13 femmes, 9 hommes), âgés de 45,9 ± 12,8 ; IMC, 24,26 ± 4,61. Vingt et un patients/22 présentent les critères PSG d’insomnie. Un seul patient présente un SAS avec un IAH > 15. Cinquante pour cent ont un TST < 6 heures temps de sommeil total (TST) 352,8 ± 78,2 min ; latence d’endormissement 28,5 ± 23,7 minutes (norme : < 30 min) ; temps d’éveil intra-sommeil 77,7 min 45,3 ± 45,3 (norme : < 30 min).
Conclusion
À notre connaissance il s’agit de la première étude polysomnographique de patients COVID-long souffrant de troubles du sommeil. Nos résultats confirment la haute prévalence de troubles objectifs PSG chez ces patients.

2354

N272

Andrea Ciofalo 1,Carlo Cavaliere 1,* ,Simonetta Masieri 2,Alessandra Di Chicco 1,Irene Fatuzzo 1 ,Federica Lo Re 1 ,Silvia Baroncelli 3 ,Elona Begvarfaj 1,Andrea Adduci 1,Ivano Mezzaroma 4 ,Claudio Maria Mastroianni 5 ,Marco de Vincentiis 1,Antonio Greco 1,Loris Zamai 6,7 andMarco Artico 1

Long-Term Subjective and Objective Assessment of Smell and Taste in COVID-19

https://doi.org/10.3390/cells11050788

Published

24-Feb-22

Study

https://www.mdpi.com/2073-4409/11/5/788/htm

Among the first clinical symptoms of the SARS-CoV-2 infection is olfactory–gustatory deficit; this continues for weeks and, in some cases, can be persistent. We prospectively evaluated 162 patients affected by COVID-19 using a visual analogue scale (VAS) for nasal and olfactory–gustatory symptoms. Patients were checked after 7, 14, 21, 28, 90, and 180 days. A total of 118 patients (72.8%) reported an olfactory VAS < 7 at baseline (group B), and 44 (27.2%) reported anosmia (VAS ≥ 7) (group A) and underwent the Brief Smell Identification Test (B-SIT) and Burghart Taste Strips (BTS) to quantify the deficit objectively and repeated the tests to confirm the sense recovery. Group A patients showed B-SIT anosmia and hyposmia in 44.2% and 55.8% of cases, respectively. A total of 88.6% of group A patients reported ageusia with VAS ≥ 7, and BTS confirmed 81.8% of ageusia and 18.2% of hypogeusia. VAS smell recovery was recorded starting from 14 days, with normalization at 28 days. The 28-day B-SIT score showed normosmia in 90.6% of group A patients. The mean time for full recovery (VAS = 0) was shorter in group B (22.9 days) than in group A (31.9 days). Chemosensory deficit is frequently the first symptom in patients with COVID-19, and, in most cases, recovery occurs after four weeks.

2355

N273

Srikent Siruvella1
; Kaushik Sreeram2
; Vithi Hitendra Patel3

Anticipated Long-Term Cognitive Impairment
Following Covid-19 Recovery in Elderly Patients

Published

18-Feb-22

Review

https://meddocsonline.org/journal-of-clinical-images/anticipated-long-term-cognitive-impairment-following-covid-19-recovery-in-elderly-patients.pdf

The coronavirus disease 2019 (COVID-19) pandemic was declared by the World Health Organization on 11th March 2020. The novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causing the disease was mainly associated with pulmonary manifestations. But according to the neuroinvasive properties of prior coronaviruses and the similarity of neuropsychological conditions, it appears that patients can develop injurious long-term cognitive events post-COVID-19 infection. Although geriatric patients with underlying comorbidities are highly susceptible to severe disease, most of them survive and recover from COVID-19. The survivors experienced long-lasting cognitive dysfunction that occurred after suffering from COVID-19 neuro infections. A comprehensive review of literature on peerreviewed journals was conducted using a variety of keywords, including COVID-19, late consequences of COVID-19, cognitive impairment, neuroinvasion, and neurodegeneration. This review aimed at exploring the anticipated longterm cognitive impairment in geriatric patients following COVID-19 infection recovery, the neuroinvasive properties of prior Human Coronaviruses (HCoVs), and extensively researched disorders that share similar neurological mechanisms. Deeper insight into the full spectrum of these neurological disorders can result in improved clinical outcomes and better treatment algorithms. Consequently, this review summarizes only what is currently known about SARS-CoV2-mediated neurological injury and establishes a framework for future and larger clinical studies to shed new light on the long-term cognitive impairment after overcoming the primary COVID-19 infection.

2356

N274

Philippe Voruz, Alexandre Cionca, Isabele Jacot de Alcântara, Anthony Nuber-Champier, Gilles Allali, Lamyae Benzakour, Marine Thomasson, Patrice H. Lalive, Karl-Olof Lövblad, Olivia Braillard, Mayssam Nehme, Matteo Coen, Jacques Serratrice, Jérôme Pugin, Idris Guessous, Basile N. Landis, Dan Adler, Alessandra Griffa, Dimitri Van De Ville, Frédéric Assal, Julie A. Péron

Functional connectivity underlying cognitive and psychiatric symptoms in post-COVID-19 syndrome: is anosognosia a key determinant?

https://doi.org/10.1093/braincomms/fcac057

Published

9-Mar-22

qstudy

https://academic.oup.com/braincomms/advance-article/doi/10.1093/braincomms/fcac057/6545202?login=false

Lack of awareness of cognitive impairment (i.e., anosognosia) could be a key factor for distinguishing between neuropsychological post-COVID-19 condition phenotypes. In this context, the twofold aim of the present study was to i) establish the prevalence of anosognosia for memory impairment, according to the severity of the infection in the acute phase, and ii) determine whether anosognosic patients with post-COVID syndrome have a different cognitive and psychiatric profile from nosognosic patients, with associated differences in brain functional connectivity.
A battery of neuropsychological, psychiatric, olfactory, dyspnea, fatigue and quality-of-life tests was administered 227.07 ± 42.69 days post-SARS-CoV-2 infection to 102 patients (mean age: 56.35 years, 65 men, no history of neurological, psychiatric, neuro-oncological or neurodevelopmental disorder prior to infection) who had experienced either a mild (not hospitalized; n = 45), moderate (conventional hospitalization; n = 34) or severe (hospitalization with intensive care unit stay and mechanical ventilation; n = 23) presentation in the acute phase. Patients were first divided into two groups according to the presence or absence of anosognosia for memory deficits (26 anosognosic patients and 76 nosognosic patients). Of these, 49 patients underwent an MRI. Structural images were visually analyzed, and statistical intergroup analyses were then performed on behavioral and functional connectivity measures.
Only 15.6% of patients who presented mild disease displayed anosognosia for memory dysfunction, compared with 32.4% of patients with moderate presentation and 34.8% of patients with severe disease. Compared with nosognosic patients, those with anosognosia for memory dysfunction performed significantly more poorly on objective cognitive and olfactory measures. By contrast, they gave significantly more positive subjective assessments of their quality of life, psychiatric status, and fatigue. Interestingly, the proportion of patients exhibiting a lack of consciousness of olfactory deficits was significantly higher in the anosognosic group. Functional connectivity analyses revealed significant decrease in connectivity, in the anosognosic group as compared to the nosognosic group, within and between the following networks: the left default mode, the bilateral somatosensory motor, the right executive control, the right salient ventral attention and the bilateral dorsal attention networks, as well as the right Lobules IV and V of the cerebellum.
Lack of awareness of cognitive disorders and, to a broader extent, impairment of the self-monitoring brain system, may be a key factor for distinguishing between the clinical phenotypes of post-COVID syndrome with neuropsychological deficits.

2357

N275

Natalia M.Lyra e Silvaab1Fernanda G.Q.Barros-Aragãocd1Fernanda G.De FeliceabcdSergio T.Ferreiracde

Inflammation at the crossroads of COVID-19, cognitive deficits and depression

https://doi.org/10.1016/j.neuropharm.2022.109023

Published

4-Mar-22

Review

https://www.sciencedirect.com/science/article/pii/S002839082200082X

Highlights
•COVID-19 is frequently associated with acute or persistent neurological impacts.
•COVID-19 survivors may be at increased risk for cognitive and mood disorders.
•Dementia and neuropsychiatric disorders appear to be risk factors for COVID-19 complications.
•Inflammation links COVID-19, Alzheimer's disease and depression.
Acute neurological alterations have been associated with SARS-CoV-2 infection. Additionally, it is becoming clear that coronavirus disease 2019 (COVID-19) survivors may experience long-term neurological abnormalities, including cognitive deficits and mood alterations. The mechanisms underlying acute and long-term impacts of COVID-19 in the brain are being actively investigated. Due to the heterogeneous manifestations of neurological outcomes, it is possible that different mechanisms operate following SARS-CoV-2 infection, which may include direct brain infection by SARS-CoV-2, mechanisms resulting from hyperinflammatory systemic disease, or a combination of both. Inflammation is a core feature of COVID-19, and both central and systemic inflammation are known to lead to acute and persistent neurological alterations in other diseases. Here, we review evidence indicating that COVID-19 is associated with neuroinflammation, along with blood-brain barrier dysfunction. Similar neuroinflammatory signatures have been associated with Alzheimer's disease and major depressive disorder. Current evidence demonstrates that patients with pre-existing cognitive and neuropsychiatric deficits show worse outcomes upon infection by SARS-CoV-2 and, conversely, COVID-19 survivors may be at increased risk of developing dementia and mood disorders. Considering the high prevalence of COVID-19 patients that recovered from infection in the world and the alarming projections for the prevalence of dementia and depression, investigation of possible molecular similarities between those diseases may shed light on mechanisms leading to long-term neurological abnormalities in COVID-19 survivors.

2358

N276

Abdulrahman K. Ahmed, Reem Sayad, Islam A. Mahmoud, Aya M. Abd EL-Monem, Salma H. Badry, Islam H. Ibrahim, Mahmoud HR Hafez, Mohamed A. El-Mokhtar & Ibrahim M. Sayed

“Anosmia” the mysterious collateral damage of COVID-19

https://doi.org/10.1007/s13365-022-01060-9

Published

5-Mar-22

Review

https://link.springer.com/article/10.1007/s13365-022-01060-9

From the beginning of the COVID-19 pandemic, several otolaryngologists described many cases of a sudden loss of smell (anosmia) associated with the disease with or without additional symptoms. Anosmia is often the first and sometimes the only sign in the asymptomatic carriers of COVID-19. Still, this disorder is underestimated, and it is not life-threatening. However, it significantly decreases the quality of life. This olfactory dysfunction continues in several cases even after the nasopharyngeal swab was negative. The occurrence of anosmia can be used as a screening tool for COVID-19 patients and can be used to identify these patients to accomplish the isolation and tracking procedures. In this review, we highlighted the possible mechanisms of anosmia in COVID-19 patients, major pathologies and features of anosmia, implications of anosmia in early diagnosis of COVID-19, evaluation of the smell function during COVID-19, and management and treatment options of COVID-19 anosmia.

2359

N277

Pasquale Moretta 1,*,† ,Pasquale Ambrosino 2,*,† ,Anna Lanzillo 1,Laura Marcuccio 1,Salvatore Fuschillo 3,Antimo Papa 2,Gabriella Santangelo 4,Luigi Trojano 4,‡ andMauro Maniscalco 3,‡

Cognitive Impairment in Convalescent COVID-19 Patients Undergoing Multidisciplinary Rehabilitation: The Association with the Clinical and Functional Status

https://doi.org/10.3390/healthcare10030480

Published

4-Mar-22

Study

https://www.mdpi.com/2227-9032/10/3/480/htm

We investigated the possible association between cognitive impairment and the main clinical and functional status variables in a cohort of convalescent COVID-19 patients without premorbid diseases potentially affecting cognition. Methods. We consecutively screened for inclusion of convalescent COVID-19 patients referring to a post-acute care facility for pulmonary rehabilitation. All the enrolled patients were assessed for cognitive functions. We also investigated features of psychological distress (anxiety, depression, symptoms of posttraumatic stress disorder and quality of life) and cardiac and pulmonary functional status. Results. The 63 enrolled patients (mean age 59.82 ± 10.78, male gender = 47) showed a high frequency of depressive symptoms (76.2%) and anxiety (55.5%), and a high prevalence of symptoms of posttraumatic stress disorder (PTSD, 44.4%). About half of the total sample showed reduced cognitive efficiency (RCE, 44.4%) in the domains of spatial and verbal long-term memory and executive functions. Patients with RCE more frequently showed alteration of blood pressure (BP) circadian rhythm (p = 0.01), higher levels of D-Dimer (p = 0.03), had experienced a severe illness (p = 0.02), had longer disease duration (p = 0.04), more clinically relevant symptoms of PTSD (p = 0.02), more frequent cognitive complaints (p = 0.002), higher anxiety scores (p = 0.01) and lower quality of life (p = 0.02) than patients with normal cognitive efficiency. Conclusions. Our findings indicated a possible association between the RCE after COVID-19 and some cardiological variables, including some indirect measures of a residual autonomic disorder, such as the presence of an altered BP circadian rhythm. Future research studies with large samples are needed to provide valid conclusions.

2360

N278

Marc Jamoulle, Gisèle Kazeneza-Mugisha, Ayoub Zayane

Descriptive and Narrative Study of Long Covid Cases in General Practice and Diagnostic Value of Single Photon Emission Computed Tomography (SPECT scan)

https://www.medrxiv.org/content/10.1101/2022.03.01.22270897v1.full-text

pre-print

2-Mar-22

Study

https://www.medrxiv.org/content/10.1101/2022.03.01.22270897v1.full-text

Diagnosis is based on careful listening to the patient’s history. Previously unknown irrepressible fatigue, brain fog, working memory disorders with possible anomia, anosmia, dysgeusia or other muli-systemic symptoms occurring after an acute Covid are varying characteristics of Long Covid. Biological evidence of Covid is missing in fourteen patients as PCRs may have been not done or came back negative in the acute phase of the disease. Anti-SARS-CoV-2 antibodies are not always present or are indistinguishable from post-vaccine antibodies. In fourteen severe cases presented, Single Photon Emission Computed Tomography (SPECT scan) after intravenous administration of Technetium-99m (Tc-99m HM-PAO) were able to demonstrate a disorder of cerebral perfusion. Two follow -up brain SPECT at three months showed significant improvement. Further genetic and immunologic study is ongoing for all patient with the help of the international consortium COVID Human Genetic Effort. A patient who presents after a Covid with medically unexplained symptoms may well be a Long Covid. Despite some interesting hypothesis, there is no known specific treatment. Neurocognitive revalidation and physiotherapy may help those patients who need long -term empathic support to cope with their condition.
Key messages
□ Long Covid is a recent onset, multi-systemic, long-term condition that can be very debilitating.
□ The main symptoms are severe fatigue, exertional exhaustion, and cognitive and memory problems, among others.
□ Patients who suffer from it may not realize it, may not talk about it, or may attribute their problem to other causes.
□ Single Photon Emission Computed Tomography (SPECT CT) contributes to the hypothesis of a vascular perfusion disorder induced by SARS -coV-2 and should be validated as a diagnostic tool in neurological Long Covid.
□ Tissue immunity should be available to prove Long Covid in case of humoral seronegativity
□ There is no identified treatment that can be recommended yet. Careful listening, empathic support and cognitive and physical rehabilitation are suggested and should be organised or supported by the Belgian state.

2361

N279

Anthony Nuber-Champier, Philippe Voruz, Isabele Jacot de Alcântara, Gautier Breville, Gilles Allali, Patrice. H Lalive, Frédéric Assal, Julie Anne Péron

Monocytosis in the Acute Phase of SARS-CoV-2 Infection Predicts the Presence of Anosognosia for Cognitive Deficits in the Chronic Phase

https://doi.org/10.21203/rs.3.rs-1361211/v1

pre-print

2-Mar-22

Study

https://www.researchsquare.com/article/rs-1361211/v1

Altered awareness of neuropsychological disorders (i.e., anosognosia) is a striking symptom of post-COVID-19 syndrome. Some leukocytes markers in the acute phase might predict the presence of anosognosia in the chronic phase, but they have not been identified yet. This study aims to determine whether patients with anosognosia for their memory deficits in the chronic phase present specific leukocytes distribution in the acute phase, and if so, whether these leukocytes parameters could predict this anosognosia.
First, we compare the acute immunological data of the leukocytes distribution of 20 patients infected with SARS-Cov-2 who displayed anosognosia 69 months after SARS-Cov-2 infection (230.25 ± 46.65 days) versus 41 patients infected with SARS-Cov-2 without developing anosognosia. Second, we performed a ROC analysis to evaluate the predictive value of the leukocytes markers that emerged from this comparison.
Blood circulating monocytes (%) at the acute phase of SARS-CoV2 infection is associated with long term post-COVID-19 anosognosia. Finally, serology on admission showing a percentage rate of monocytes of 7.35% of the total number of leukocytes, seems to predict the presence of chronic anosognosia for 6–9 months after infection.

2362

N280

ES

Lisa Bauer 4
Brigitta M. Laksono 4
Femke M.S. de Vrij
Steven A. Kushner
Oliver Harschnitz
Debby van Riel

The neuroinvasiveness, neurotropism, and neurovirulence of SARS-CoV-2

https://doi.org/10.1016/j.tins.2022.02.006

Published

2-Mar-22

Review

https://www.cell.com/trends/neurosciences/fulltext/S0166-2236(22)00050-9

Highlights
Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection has been shown to be associated with a range of neurological complications during the acute and postacute phases.
The pathogenesis of SARS-CoV-2-associated CNS disease is complex and diverse, and cannot be explained by one sole mechanism.
To understand the pathogenesis of SARS-CoV-2-associated CNS disease, it is important to gain deeper insights into the neuroinvasiveness, neurotropism, and neurovirulence of SARS-CoV-2. It is also imperative to consider the kinetics, since a viral infection is not a static event.
Relevant in vivo models can be used to study the neuroinvasiveness, neurotropism, and neurovirulence of SARS-CoV-2, and in vitro human pluripotent stem cell (hPSC) models can be used to study the neurotropism of the virus and the associated cellular responses. These models may be further leveraged to study differences among SARS-CoV-2 variants and for the design of therapeutic approaches.
Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection is associated with a diverse spectrum of neurological complications during the acute and postacute stages. The pathogenesis of these complications is complex and dependent on many factors. For accurate and consistent interpretation of experimental data in this fast-growing field of research, it is essential to use terminology consistently. In this article, we outline the distinctions between neuroinvasiveness, neurotropism, and neurovirulence. Additionally, we discuss current knowledge of these distinct features underlying the pathogenesis of SARS-CoV-2-associated neurological complications. Lastly, we briefly discuss the advantages and limitations of different experimental models, and how these approaches can further be leveraged to advance the field.

2363

N281

Yu-Hui Liu, MD, PhD1; Yang Chen, MD1; Qing-Hua Wang, MD, PhD1; Ling-Ru Wang, BN1; Li Jiang, BN1; Ying Yang, BN1; Xian Chen, BN2; Ying Li, BN3; Yuan Cen, BN4; Cheng Xu, MD, PhD5; Jie Zhu, MD, PhD1; Wei Li, MD, PhD1; Ye-Ran Wang, MD1; Li-Li Zhang, MD, PhD1; Juan Liu, MD, PhD1; Zhi-Qiang Xu, MD, PhD1; Yan-Jiang Wang, MD, PhD1

One-Year Trajectory of Cognitive Changes in Older Survivors of COVID-19 in Wuhan, China
A Longitudinal Cohort Study

https://doi.org/10.1001/jamaneurol.2022.0461

Published

8-Mar-22

Study

https://jamanetwork.com/journals/jamaneurology/fullarticle/2789919

Key Points
- Question What is the dynamic trajectory of cognitive changes in the elderly population surviving COVID-19?
- Findings In this cohort study of 1438 COVID-19 survivors 60 years and older who were discharged from COVID-19–designated hospitals in Wuhan, China, the incidence of cognitive impairment was higher in COVID-19 survivors, especially those with severe cases, compared with uninfected participants during a 1-year follow-up period.
- Meaning The findings suggest that long-term cognitive decline is common after SARS-CoV-2 infection, indicating the necessity of evaluating the impact of the COVID-19 pandemic on the future dementia burden worldwide.
Results Among the 3233 COVID-19 survivors and 1317 uninfected spouses screened, 1438 participants who were treated for COVID-19 (691 male [48.05%] and 747 female [51.95%]; median [IQR] age, 69 [66-74] years) and 438 uninfected control individuals (222 male [50.68%] and 216 female [49.32%]; median [IQR] age, 67 [66-74] years) completed the 12-month follow-up. The incidence of cognitive impairment in survivors 12 months after discharge was 12.45%. Individuals with severe cases had lower Telephone Interview of Cognitive Status-40 scores than those with nonsevere cases and control individuals at 12 months (median [IQR]: severe, 22.50 [16.00-28.00]; nonsevere, 30.00 [26.00-33.00]; control, 31.00 [26.00-33.00]). Severe COVID-19 was associated with a higher risk of early-onset cognitive decline (odds ratio [OR], 4.87; 95% CI, 3.30-7.20), late-onset cognitive decline (OR, 7.58; 95% CI, 3.58-16.03), and progressive cognitive decline (OR, 19.00; 95% CI, 9.14-39.51), while nonsevere COVID-19 was associated with a higher risk of early-onset cognitive decline (OR, 1.71; 95% CI, 1.30-2.27) when adjusting for age, sex, education level, body mass index, and comorbidities.
Conclusions and Relevance In this cohort study, COVID-19 survival was associated with an increase in risk of longitudinal cognitive decline, highlighting the importance of immediate measures to deal with this challenge.

2364

N282

Barbara A. Hanson, View ProfileLavanya Visvabharathy, Sareen T. Ali, Anthony K. Kang, Tulsi R. Patel, Jeffrey R. Clark, Patrick H. Lim, View ProfileZachary S. Orban, Soyoon S. Hwang, Dawn Mattoon, View ProfileAyush Batra, View ProfileEric M. Liotta, View ProfileIgor J. Koralnik

Plasma Biomarkers of Neuropathogenesis in Hospitalized Patients With COVID-19 and Those With Postacute Sequelae of SARS-CoV-2 Infection

https://doi.org/10.1212/NXI.0000000000001151

Published

7-Mar-22

Study

https://nn.neurology.org/content/9/3/e1151.abstract

The pathogenic mechanisms of COVID-19 encephalopathy and neuro-PASC are unknown. We sought to establish biochemical evidence of CNS injury in those patients and their association with neuropsychiatric manifestations and SARS-CoV-2 antigenemia.
Results We enrolled a total of 64 study participants, including 9 hospitalized patients with COVID-19 encephalopathy (CE), 9 posthospitalization neuro-PASC (PNP) patients, 38 nonhospitalized neuro-PASC (NNP) patients, and 8 HC subjects. Patients with CE were older, had higher pNfL and pGFAP concentrations, and more frequent pN Ag detection than all neuro-PASC groups. PNP and NNP patients exhibited similar PASC symptoms, decreased quality-of-life measures, and cognitive dysfunction, and 1 of the 38 (2.6%) NNP patients had pN Ag detectable 3 weeks postsymptoms onset. Patients with neuro-PASC presenting with anxiety/depression had higher neuroglial scores, which were correlated with increased anxiety on quality-of-life measures.
Discussion pNfL, pGFAP, and pN Ag measurements indicate neuronal dysfunction and systemic involvement in hospitalized COVID-19 patients with encephalopathy. Detection of SARS-CoV-2 N Ag in blood 3 weeks after symptoms onset in a nonhospitalized patient suggests that prolonged antigenic stimulation, or possibly latent infection, may occur. Anxiety was associated with evidence of astroglial activation in patients with neuro-PASC. These data shed new light on SARS-Cov-2 neuropathogenesis and demonstrate the value of plasma biomarkers across the COVID-19 disease spectrum.

2365

N283

A.Costanzaab1A.AmeriocdA.AgugliacdG.SerafinicdM.AmorecdR.HasleraeJ.AmbrosettifG.BondolfiabgG.SampognahI.BerardelliiA.FiorillohM.PompiliiK.D.Nguyenjk

Hyper/neuroinflammation in COVID-19 and suicide etiopathogenesis: Hypothesis for a nefarious collision?

https://doi.org/10.1016/j.neubiorev.2022.104606

Published

14-Mar-22

Review

https://www.sciencedirect.com/science/article/pii/S0149763422000951

Highlights
•Hyperinflammation is a hallmark of COVID-19 disease.
•Neuroinflammation is also involved in suicide pathogenesis.
•It is possible that the two inflammation cascades share colliding points.
•Hyper/neuroinflammation could be synergic in chronic neuropsychiatric sequelae, including suicide.
•This is relevant to COVID-19 survivors as long-term impact of the disease is unknown.
Accumulating scientific and clinical evidence highlighted pathological hyperinflammation as a cardinal feature of SARS-CoV-2 infection and acute COVID-19 disease. With the emergence of long COVID-19 syndrome, several chronic health consequences, including neuropsychiatric sequelae, have gained attention from the public and medical communities. Since inflammatory mediators have also been accredited as putative biomarkers of suicidal ideations and behaviors, hyper- and neuroinflammation might share some colliding points, overlapping and being interconnected in the context of COVID-19. This review aims to provide a summary of current knowledge on the molecular and cellular mechanisms of COVID-19-associated hyper/neuroinflammation with focus on their relevance to the inflammatory hypothesis of suicide development. Subsequently, strategies to alleviate COVID-19 hyper/neuroinflammation by immunomodulatory agents (many of which at experimental stages) as well as psychopharmacologic/psychotherapeutic approaches are also mentioned. While suicide risk in COVID-19 survivors - until now little known - needs further analysis through longitudinal studies, current observations and mechanistic postulates warrant additional attention to this possibly emerging mental health concern.

2366

N284

A.Costanzaab1A.AmeriocdA.AgugliacdG.SerafinicdM.AmorecdR.HasleraeJ.AmbrosettifG.BondolfiabgG.SampognahI.BerardelliiA.FiorillohM.PompiliiK.D.Nguyenjk

Hyper/neuroinflammation in COVID-19 and suicide etiopathogenesis: Hypothesis for a nefarious collision?

https://doi.org/10.1016/j.neubiorev.2022.104606

Published

12-Mar-22

Review

https://www.sciencedirect.com/science/article/pii/S0149763422000951

Highlights
•Hyperinflammation is a hallmark of COVID-19 disease.
•Neuroinflammation is also involved in suicide pathogenesis.
•It is possible that the two inflammation cascades share colliding points.
•Hyper/neuroinflammation could be synergic in chronic neuropsychiatric sequelae, including suicide.
•This is relevant to COVID-19 survivors as long-term impact of the disease is unknown.
Abstract
Accumulating scientific and clinical evidence highlighted pathological hyperinflammation as a cardinal feature of SARS-CoV-2 infection and acute COVID-19 disease. With the emergence of long COVID-19 syndrome, several chronic health consequences, including neuropsychiatric sequelae, have gained attention from the public and medical communities. Since inflammatory mediators have also been accredited as putative biomarkers of suicidal ideations and behaviors, hyper- and neuroinflammation might share some colliding points, overlapping and being interconnected in the context of COVID-19. This review aims to provide a summary of current knowledge on the molecular and cellular mechanisms of COVID-19-associated hyper/neuroinflammation with focus on their relevance to the inflammatory hypothesis of suicide development. Subsequently, strategies to alleviate COVID-19 hyper/neuroinflammation by immunomodulatory agents (many of which at experimental stages) as well as psychopharmacologic/psychotherapeutic approaches are also mentioned. While suicide risk in COVID-19 survivors - until now little known - needs further analysis through longitudinal studies, current observations and mechanistic postulates warrant additional attention to this possibly emerging mental health concern.

2367

N285

E.Guedj1J.YCampion2T.Horowitz1F.Barthelemy1S.Cammilleri1M.Ceccaldi3

L’impact du confinement COVID-19 sur le métabolisme cérébral

https://doi.org/10.1016/j.mednuc.2022.01.011

Published

11-Mar-22

Study

https://www.sciencedirect.com/science/article/pii/S0928125822000110

Résultats
La durée du confinement était négativement corrélée au métabolisme du cortex sensori-moteur avec un effet prédominant sur le réseau pyramidal de l’hémisphère majeur et chez les patients les plus jeunes, incluant également l’amygdale gauche, avec une réversibilité seulement partielle après 55 jours de déconfinement. Un faible recouvrement était retrouvé avec le profil d’hypométabolisme décrit dans le COVID long (<9 %).
Conclusion
La restriction des activités physiques, avec son déconditionnement associé, et l’isolement social pourraient entraîner des perturbations fonctionnelles des réseaux cérébraux sensorimoteurs et émotionnels. Ce profil métabolique semble distinct de celui rapporté dans le COVID long. D’autres études longitudinales sont nécessaires, avec un suivi plus long, pour évaluer les conséquences cliniques et, en particulier, l’impact sur la santé cognitive et mentale, et pour étendre ces résultats aux sujets sains dans ce contexte de confinement.

2368

N286

Philippe Voruz, Alexandre Cionca, Isabele Jacot de Alcântara, Anthony Nuber-Champier, Gilles Allali, Lamyae Benzakour, Marine Thomasson, Patrice H. Lalive, Karl-Olof Lövblad, Olivia Braillard, Mayssam Nehme, Matteo Coen, Jacques Serratrice, Jérôme Pugin, Idris Guessous, Basile N. Landis, Dan Adler, Alessandra Griffa, Dimitri Van De Ville, Frédéric Assal, Julie A. Péron

Functional connectivity underlying cognitive and psychiatric symptoms in post-COVID-19 syndrome: is anosognosia a key determinant?

https://doi.org/10.1093/braincomms/fcac057

Published

9-Mar-22

Study

https://academic.oup.com/braincomms/advance-article/doi/10.1093/braincomms/fcac057/6545202?login=true

Lack of awareness of cognitive impairment (i.e., anosognosia) could be a key factor for distinguishing between neuropsychological post-COVID-19 condition phenotypes. In this context, the twofold aim of the present study was to i) establish the prevalence of anosognosia for memory impairment, according to the severity of the infection in the acute phase, and ii) determine whether anosognosic patients with post-COVID syndrome have a different cognitive and psychiatric profile from nosognosic patients, with associated differences in brain functional connectivity.
A battery of neuropsychological, psychiatric, olfactory, dyspnea, fatigue and quality-of-life tests was administered 227.07 ± 42.69 days post-SARS-CoV-2 infection to 102 patients (mean age: 56.35 years, 65 men, no history of neurological, psychiatric, neuro-oncological or neurodevelopmental disorder prior to infection) who had experienced either a mild (not hospitalized; n = 45), moderate (conventional hospitalization; n = 34) or severe (hospitalization with intensive care unit stay and mechanical ventilation; n = 23) presentation in the acute phase. Patients were first divided into two groups according to the presence or absence of anosognosia for memory deficits (26 anosognosic patients and 76 nosognosic patients). Of these, 49 patients underwent an MRI. Structural images were visually analyzed, and statistical intergroup analyses were then performed on behavioral and functional connectivity measures.
Only 15.6% of patients who presented mild disease displayed anosognosia for memory dysfunction, compared with 32.4% of patients with moderate presentation and 34.8% of patients with severe disease. Compared with nosognosic patients, those with anosognosia for memory dysfunction performed significantly more poorly on objective cognitive and olfactory measures. By contrast, they gave significantly more positive subjective assessments of their quality of life, psychiatric status, and fatigue. Interestingly, the proportion of patients exhibiting a lack of consciousness of olfactory deficits was significantly higher in the anosognosic group. Functional connectivity analyses revealed significant decrease in connectivity, in the anosognosic group as compared to the nosognosic group, within and between the following networks: the left default mode, the bilateral somatosensory motor, the right executive control, the right salient ventral attention and the bilateral dorsal attention networks, as well as the right Lobules IV and V of the cerebellum.
Lack of awareness of cognitive disorders and, to a broader extent, impairment of the self-monitoring brain system, may be a key factor for distinguishing between the clinical phenotypes of post-COVID syndrome with neuropsychological deficits.

2369

N287

Light S.N.

The Combined Use of Neuropsychiatric and Neuropsychological Assessment Tools to Make a Differential Dementia Diagnosis in the Presence of “Long-Haul” COVID-19

https://doi.org/10.1159/000522020

Published

15-Mar-22

Case Report

https://www.karger.com/Article/FullText/522020

The longer term neurocognitive/neuropsychiatric consequences of moderate/severe COVID-19 infection have not been explored. The case herein illustrates a complex web of differential diagnosis. The onset, clinical trajectory, treatment course/response, serial neuroimaging findings, and neuropsychological test data were taken into account when assessing a patient presenting 8 months post-COVID-19 (with premorbid attention-deficit hyperactivity disorder, diabetes mellitus, mood difficulties, and a positive family history of vascular dementia). Her acute COVID-19 infection was complicated by altered mental status associated with encephalopathy and bacterial pneumonia. After recovery from COVID-19, the patient continues to experience persisting cognitive and emotive difficulties despite an ongoing psychopharmacotherapy regimen (16 + years), psychotherapy (15 + sessions), and speech-language pathology SLP; 2 × week/for 12 weeks). The purpose of her most recent and comprehensive neuropsychological evaluation was to determine the presence/absence of neurocognitive disorder. The patient is a 62-year-old Caucasian woman. Cognitive screening was completed 3 months post-acute COVID-19 as part of an SLP evaluation, and a full neuropsychological evaluation was conducted 8 months post-COVID-19 recovery on an outpatient basis (in person). The patient had serial neuroimaging. Initial neurological evaluation during acute COVID-19 included unremarkable brain computed tomography (CT)/magnetic resonance imaging. However, follow-up CT (without contrast) revealed, in part, “asymmetric perisylvian atrophy on the left.” Full neuropsychological evaluation at 8 months post-COVID-19 recovery revealed a dysexecutive syndrome characterized by language dysfunction and affective theory-of-mind deficit, consistent with dementia. There is need for careful use of differential diagnosis in COVID-19 patients with multiple risk factors that make them more susceptible to long-term neurological complications post-COVID-19. Differential diagnosis should involve multidisciplinary assessment (e.g., neuropsychology, SLP, neurology, and psychiatry).

2370

N288

Cédric Hirzel, , Denis Grandgirard, Bernard Surial, Manon F. Wider, David Leppert, Jens Kuhle, Laura N. Walti, Joerg C. Schefold, Thibaud Spinetti, Franziska Suter-Riniker, Ronald Dijkman*, Stephen L. Leib*

Neuro-axonal injury in COVID-19: the role of systemic inflammation and SARS-CoV-2 specific immune response

https://doi.org/10.1177%2F17562864221080528

Published

12-Mar-22

Study

https://journals.sagepub.com/doi/10.1177/17562864221080528

In coronavirus disease-2019 (COVID-19) patients, there is increasing evidence of neuronal injury by the means of elevated serum neurofilament light chain (sNfL) levels. However, the role of systemic inflammation and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–specific immune response with regard to neuronal injury has not yet been investigated.
Methods:
In a prospective cohort study, we recruited patients with mild–moderate (n = 39) and severe (n = 14) COVID-19 and measured sNfL levels, cytokine concentrations, SARS-CoV-2-specific antibodies including neutralizing antibody titers, and cell-mediated immune responses at enrollment and at 28(±7) days. We explored the association of neuro-axonal injury as by the means of sNfL measurements with disease severity, cytokine levels, and virus-specific immune responses.
Results:
sNfL levels, as an indicator for neuronal injury, were higher at enrollment and increased during follow-up in severely ill patients, whereas during mild–moderate COVID-19, sNfL levels remained unchanged. Severe COVID-19 was associated with increased concentrations of cytokines assessed [interleukin (IL)-6, IL-8, interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α)], higher anti-spike IgG and anti-nucleocapsid IgG concentrations, and increased neutralizing antibody titers compared with mild–moderate disease. Patients with more severe disease had higher counts of defined SARS-CoV-2-specific T cells. Increases in sNfL concentrations from baseline to day 28(±7) positively correlated with anti-spike protein IgG antibody levels and with titers of neutralizing antibodies.
Conclusion:
Severe COVID-19 is associated with increased serum concentration of cytokines and subsequent neuronal injury as reflected by increased levels of sNfL. Patients with more severe disease developed higher neutralizing antibody titers and higher counts of SARS-CoV-2-specific T cells during the course of COVID-19 disease. Mounting a pronounced virus-specific humoral and cell-mediated immune response upon SARS-CoV-2 infection did not protect from neuro-axonal damage as by the means of sNfL levels.

2371

N289

Jacques Hugon,Mathieu Queneau,Marta Sanchez Ortiz,Eva Flore Msika,Karim Farid,Claire Paquet

Cognitive decline and brainstem hypometabolism in long COVID: A case series

https://doi.org/10.1002/brb3.2513

Published

15-Mar-22

Study

https://onlinelibrary.wiley.com/doi/10.1002/brb3.2513

Objective
To assess FDG cerebral PET in patients suffering from cognitive impairment linked to Long COVID. The COVID pandemic has affected dozens of millions of people around the world and has resulted in the deaths of more than 3 million people. Following the acute forms, it has been reported sometimes long forms of COVID, with involvements of several organs including the brain. Neurological complications can include cognitive disturbances (brain fog) that are very common and can seriously disturb the life of patients.
Methods
Fluorodeoxyglucose PETs were performed in 3 patients with cognitive decline following COVID infection.
Results
We report here 3 cases of brain fog with major hypometabolic areas of the pons revealed by the cerebral FDG PET.
Conclusion
The dysfunction of the locus coeruleus in these patients could partly explain the cognitive disorders observed. Further studies involving larger cohorts of patients suffering from cognitive dysfunction will be needed to determine if the brainstem is frequently affected in these patients.

2372

N290

Che Mohd Nasril Che Mohd Nassir 1,* ,Mohd K. I. Zolkefley 2 ,Muhammad Danial Ramli 3 ,Haziq Hazman Norman 4,Hafizah Abdul Hamid 5 andMuzaimi Mustapha

Neuroinflammation and COVID-19 Ischemic Stroke Recovery—Evolving Evidence for the Mediating Roles of the ACE2/Angiotensin-(1–7)/Mas Receptor Axis and NLRP3 Inflammasome

https://doi.org/10.3390/ijms23063085

Published

13-Mar-22

Review

https://www.mdpi.com/1422-0067/23/6/3085/htm

Cerebrovascular events, notably acute ischemic strokes (AIS), have been reported in the setting of novel coronavirus disease (COVID-19) infection. Commonly regarded as cryptogenic, to date, the etiology is thought to be multifactorial and remains obscure; it is linked either to a direct viral invasion or to an indirect virus-induced prothrombotic state, with or without the presence of conventional cerebrovascular risk factors. In addition, patients are at a greater risk of developing long-term negative sequelae, i.e., long-COVID-related neurological problems, when compared to non-COVID-19 stroke patients. Central to the underlying neurobiology of stroke recovery in the context of COVID-19 infection is reduced angiotensin-converting enzyme 2 (ACE2) expression, which is known to lead to thrombo-inflammation and ACE2/angiotensin-(1–7)/mitochondrial assembly receptor (MasR) (ACE2/Ang-(1-7)/MasR) axis inhibition. Moreover, after AIS, the activated nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome may heighten the production of numerous proinflammatory cytokines, mediating neuro-glial cell dysfunction, ultimately leading to nerve-cell death. Therefore, potential neuroprotective therapies targeting the molecular mechanisms of the aforementioned mediators may help to inform rehabilitation strategies to improve brain reorganization (i.e., neuro-gliogenesis and synaptogenesis) and secondary prevention among AIS patients with or without COVID-19. Therefore, this narrative review aims to evaluate the mediating role of the ACE2/Ang- (1-7)/MasR axis and NLRP3 inflammasome in COVID-19-mediated AIS, as well as the prospects of these neuroinflammation mediators for brain repair and in secondary prevention strategies against AIS in stroke rehabilitation.

2373

N291

Peter A.HallabGangMengbAnnaHudsonaMohammad N.SakibaSara C.HitchmancJamesMacKillopdWarren K.BickeleGeoffrey T.Fongabf

Cognitive function following SARS-CoV-2 infection in a population-representative Canadian sample

https://doi.org/10.1016/j.bbih.2022.100454

Published

25-Mar-22

Study

https://www.sciencedirect.com/science/article/pii/S2666354622000448

Background
SARS-CoV-2 infection is believed to adversely affect the brain, but the degree of impact on socially relevant cognitive functioning and decision-making is not well-studied, particularly among those less vulnerable to age-related mortality. The current study sought to determine whether infection status and COVID-19 symptom severity are associated with cognitive dysfunction among young and middled-aged adults in the general population, using self-reported lapses in executive control and a standardized decision-making task.
Method
The survey sample comprised 1958 adults with a mean age of 37 years (SD = 10.4); 60.8% were female. Participants reported SARS-CoV-2 infection history and, among those reporting a prior infection, COVID-19 symptom severity. Primary outcomes were self-reported symptoms of cognitive dysfunction assessed via an abbreviated form of the Barkley Deficits in Executive Functioning Scale (BDEFS) and performance on a validated delay-discounting task.
Results
Young and middle-aged adults with a positive SARS-CoV-2 infection history reported a significantly higher number of cognitive dysfunction symptoms (Madj = 1.89, SE = 0.08, CI: 1.74, 2.04; n = 175) than their non-infected counterparts (Madj = 1.63, SE = 0.08, CI: 1.47,1.80; n = 1599; β = 0.26, p = .001). Among those infected, there was a dose-response relationship between COVID-19 symptom severity and level of cognitive dysfunction reported, with moderate (β = 0.23, CI: 0.003–0.46) and very/extremely severe (β = 0.69, CI: 0.22–1.16) COVID-19 symptoms being associated with significantly greater cognitive dysfunction. These effects remained reliable and of similar magnitude after controlling for demographics, vaccination status, mitigation behavior frequency, and geographic region, and after removal of those who had been intubated during hospitalization. Very similar—and comparatively larger—effects were found for the delay-discounting task, and when using only PCR confirmed SARS-CoV-2 cases.
Conclusions
Positive SARS-CoV-2 infection history and moderate or higher COVID-19 symptom severity are associated with significant symptoms of cognitive dysfunction and amplified delay discounting among young and middle-aged adults with no history of medically induced coma.

2374

N292

JacquesReis1AlainBuguet2Gustavo C.Román3Peter S.Spencer4

The Covid-19 pandemic, an Environmental Neurology perspective

https://doi.org/10.1016/j.neurol.2022.02.455

Published

22-Mar-22

Review

https://www.sciencedirect.com/science/article/pii/S0035378722005495

Neurologists have a particular interest in SARS-CoV-2 because the nervous system is a major participant in Covid-19, both in its acute phase and in its persistent post-Covid phase. The global spread of SARS-CoV-2 infection has revealed most of the challenges and risk factors that humanity will face in the future. We review from an Environmental Neurology perspective some characteristics that have underpinned the pandemic. We consider the agent, SARS-CoV-2, the spread of SARS-CoV-2 influenced by environmental factors, its impact on the brain and some containment measures on brain health. Several questions remain, including the differential clinical impact of variants, the impact of SARS-CoV-2 on sleep and wakefulness, and the neurological components of Long-Covid syndrome. We touch on the role of national leaders and public health policies that have underpinned management of the Covid-19 pandemic. Increased awareness, anticipation and preparedness are needed to address comparable future challenges.

2375

N293

Stephen J.FerrandoM.D.abRheaDornbushPh.D., M.P.H.abSeanLynchM.D.abSivanShaharB.A.bLidiaKlepaczM.D.abCarol L.KarmenM.D.bcDonaldChenM.D.bcStephen A.LoboM.D.bcDaniaLermanM.S.W.

Neuropsychological, Medical, and Psychiatric Findings After Recovery From Acute COVID-19: A Cross-sectional Study

https://doi.org/10.1016/j.jaclp.2022.01.003

Published

25-Jan-22

Study

https://www.sciencedirect.com/science/article/pii/S2667296022000039

Background
Persistent cognitive, medical and psychiatric complaints have been extensively described after recovery from acute SARS-CoV-2 infection.
Objective
To describe neuropsychological, medical, psychiatric, and functional correlates of cognitive complaints experienced after recovery from acute COVID-19 infection.
Methods
Sixty participants underwent neuropsychological, psychiatric, medical, functional, and quality-of-life assessments 6–8 months after acute COVID-19. Those seeking care for cognitive complaints in a post-COVID-19 clinical program for post-acute symptoms of COVID-19 (clinical group, N = 32) were compared with those recruited from the community who were not seeking care (nonclinical, N = 28). A subset of participants underwent serological testing for proinflammatory cytokines C-reactive protein, interleukin-6, and tumor necrosis factor-α to explore correlations with neuropsychological, psychiatric, and medical variables.
Results
For the entire sample, 16 (27%) had extremely low test scores (less than second percentile on at least 1 neuropsychological test). The clinical group with cognitive complaints scored lower than age-adjusted population norms in tests of attention, processing speed, memory, and executive function and scored significantly more in the extremely low range than the nonclinical group (38% vs. 14%, P < 0.04). The clinical group also reported higher levels of depression, anxiety, fatigue, posttraumatic stress disorder, and functional difficulties and lower quality of life. In logistic regression analysis, scoring in the extremely low range was predicted by acute COVID-19 symptoms, current depression score, number of medical comorbidities, and subjective cognitive complaints in the areas of memory, language, and executive functions. Interleukin-6 correlated with acute COVID symptoms, number of medical comorbidities, fatigue, and inversely with measures of executive function. C-reactive protein correlated with current COVID symptoms and depression score but inversely with quality of life.
Conclusion
Results suggest the existence of extremely low neuropsychological test performance experienced by some individuals months after acute COVID-19 infection, affecting multiple neurocognitive domains. This extremely low neuropsychological test performance is associated with worse acute COVID-19 symptoms, depression, medical comorbidities, functional complaints, and subjective cognitive complaints. Exploratory correlations with proinflammatory cytokines support further research into inflammatory mechanisms and viable treatments.

2376

N294

Publication of N219 ES

Antoine Verger, Aurélie Kas, Pierre Dudouet, François Goehringer, Dominique Salmon, Eric Guedj

Visual Interpretation of Brain Hypometabolisms Related to Neurological Long COVID: A French Multicentric Experience

https://doi.org/10.1007/s00259-022-05753-5

Published

23-Mar-22

Short communication

https://link.springer.com/article/10.1007/s00259-022-05753-5

This multicenter study aims to provide a qualitative and consensual description of brain 18F-FDG PET images in patients with suspected neurological long COVID, regarding the previously reported pattern involving olfactory bulbs and other limbic/paralimbic regions, as well as the brainstem and cerebellum.
Methods: From the beginning of August 2021 to the end of October 2021, brain 18F-FDG PET exams of patients referred for suspected neurological long COVID with positive reverse transcription polymerase chain reaction (RT-PCR) and/or serology for the SARS-CoV-2 infection were retrospectively reviewed in three French Nuclear Medicine departments. Experimented nuclear physicians from each department had to classify according to the same visual interpretation analysis brain 18F-FDG PET scans as being normal, mildly to moderate (incomplete or moderately hypometabolic), or severely affected within the previously reported long COVID hypometabolic pattern.
Results: On the 143 brain 18F-FDG PET performed during this period 3 months, 53% of scans were visually interpreted as normal, 31% as mildly to moderate and 16% as severely affected according to the COVID hypometabolic pattern. Importantly, this specific hypometabolic pattern is reported as identical in the three Nuclear Medicine departments. Typical illustrative examples are provided to help nuclear physicians in the interpretation of long COVID pattern.
Conclusion: The proposed PET metabolic pattern is easily identified at visual interpretation in clinical routine in part of patients with suspicion of neurological long COVID, requiring special consideration for fronto-basal paramedian regions, the brainstem and cerebellum.

2377

N295

Abdulhafeez M. Khair, Rahul Nikam, Sumair Husain, Melanie Ortiz, Gurcharanjeet Kaur

Para and Post-COVID-19 CNS Acute Demyelinating Disorders in Children: A Case Series on Expanding the Spectrum of Clinical and Radiological Characteristics

https://doi.org/10.7759/cureus.23405

Published

22-Mar-22

Case Reports

https://www.cureus.com/articles/89080-para-and-post-covid-19-cns-acute-demyelinating-disorders-in-children-a-case-series-on-expanding-the-spectrum-of-clinical-and-radiological-characteristics

Viral infections can serve as a trigger for variable autoimmune, antibody-mediated demyelinating disorders. There is accumulating evidence that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, causing coronavirus disease 2019 (COVID-19) infection and responsible for the current worldwide pandemic, can lead to a cascade of immune-mediated brain and spinal cord demyelinating injuries. However, such observation in the pediatric age group was only reported in very few patients. Thus, the heterogeneous spectrum of this phenomenon in children is still unfolding. We are reporting a case series of five pediatric patients with a variety of acute central nervous system (CNS) demyelinating disorders in the context of acute or recent COVID-19 infection. A 16-year-old female with anti-myelin oligodendrocyte glycoprotein (MOG) disorder, an eight-year-old male with acute disseminated encephalomyelitis (ADEM), a 13-year-old female with neuromyelitis optica spectrum disorder (NMOSD), and two 14 and 13-year-old females with new-onset multiple sclerosis (MS) are reported, all of whom presented acutely following COVID-19 infection. We propose that para and post-infectious CNS demyelinating disorders can potentially follow acute COVID-19 infection in children. Considering SARS-CoV-2 testing as a part of diagnostic workup is possibly useful. Awareness of the presence of this phenomenon can help in the recognition and management of those patients.

2378

N296

ES

Lucia Crivelli,Katie Palmer,Ismael Calandri,Alla Guekht,Ettore Beghi,William Carroll,Jennifer Frontera,David García-Azorín,Erica Westenberg,Andrea Sylvia Winkler,Francesca Mangialasche,Ricardo F. Allegri,Miia Kivipelto

Changes in cognitive functioning after COVID-19: A systematic review and meta-analysis

https://doi.org/10.1002/alz.12644

Published

17-Mar-22

Review

https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.12644

We conducted a systematic review and meta-analysis of the cognitive effects of coronavirus disease 2019 (COVID-19) in adults with no prior history of cognitive impairment.
Methods
Searches in Medline/Web of Science/Embase from January 1, 2020, to December 13, 2021, were performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A meta-analysis of the Montreal Cognitive Assessment (MoCA) total score comparing recovered COVID-19 and healthy controls was performed.
Results
Oof 6202 articles, 27 studies with 2049 individuals were included (mean age = 56.05 years, evaluation time ranged from the acute phase to 7 months post-infection). Impairment in executive functions, attention, and memory were found in post-COVID-19 patients. The meta-analysis was performed with a subgroup of 290 individuals and showed a difference in MoCA score between post-COVID-19 patients versus controls (mean difference = −0.94, 95% confidence interval [CI] −1.59, −0.29; P = .0049).
Discussion
Patients recovered from COVID-19 have lower general cognition compared to healthy controls up to 7 months post-infection.

2379

N297

Manuel Herrero-Montes,1,2 César Fernández-de-las-Peñas ,3 Diego Ferrer-Pargada,4 Sandra Tello-Mena,4 Ignacio Cancela-Cilleruelo,3 Jorge Rodríguez-Jiménez,3 Domingo Palacios-Ceña,3 and Paula Parás-Bravo1,2

Prevalence of Neuropathic Component in Post-COVID Pain Symptoms in Previously Hospitalized COVID-19 Survivors

https://doi.org/10.1155/2022/3532917

Published

16-Mar-22

Study

https://www.hindawi.com/journals/ijclp/2022/3532917/

To investigate the prevalence of neuropathic pain symptoms and to analyze the correlation between neuropathic symptoms with pain-related, psychological, and cognitive variables in COVID-19 survivors exhibiting “de novo” post-COVID pain. Methods. Seventy-seven (n = 77) previously hospitalized COVID-19 survivors presenting with post-COVID pain completed demographic (such as age, height, and weight), pain-related (the duration and intensity of pain), psychological (depressive/anxiety levels), and cognitive (catastrophizing and kinesiophobia) variables. The Self-Report Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) questionnaire was also assessed. After conducting multivariable correlation analyses, a stepwise multiple linear regression model was performed to identify S-LANSS predictors. Results. Participants were assessed a mean of 6.0 (SD 0.8) months after hospital discharge. Nineteen (24.6%) exhibited neuropathic pain symptoms (S-LANSS score≥12 points). The S-LANSS score was positively associated with the duration of post-COVID pain (r: 0.262), anxiety levels (r: 0.275), and kinesiophobia level (r: 0.291) (all, < 0.05). The stepwise regression analysis revealed that 12.8% of the S-LANSS variance was just explained by kinesiophobia. Conclusion. This study found that almost 25% of previously hospitalized COVID-19 survivors with “de novo” post-COVID pain reported a neuropathic pain component. The presence of neuropathic pain symptomatology was associated with more anxiety and kinesiophobia, but only kinesiophobia level was significantly associated explaining 12.8% of the variance of the S-LANSS score.

2380

N298

Abdullah Egiz 1 2 , Sarvin Farajzadeh-Asl 1 2 , Bassel Alaa Abouzeid 1 2 , Radhi Al-Shaharli 1 2 , Rand Al-Assadi 1 2

The Potential Cerebrovascular Sequelae of Coronavirus Disease 19 in Alzheimer’s Disease: Coincidental or Causative?

https://doi.org/10.5152/eurasianjmed.2022.21146

Published

1-Feb-22

Article

https://www.eajm.org/en/the-potential-cerebrovascular-sequelae-of-coronavirus-disease-19-in-alzheimer-s-disease-coincidental-or-causative-133366

Since coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health
Organization on March 11, 2020, the impact of this global health crisis has resulted in numerous disruptions to clinical research.1
Coronavirus disease 2019 seems to be leaving a long-lasting
effect, reducing the quality of life of many individuals.1
The current research suggests that the
long-term sequelae of COVID-19 are likely to disproportionately affect high-risk individuals
including Alzheimer’s disease (AD) patients.1
The neuropsychiatric sequelae of COVID-19 have
gained attention given its projected weight in the global burden of disability.1
However, it seems
that a deeper look into the effect of COVID-19 on AD has overlooked the potential cerebrovascular alterations. Therefore, we would like to highlight the potential cerebrovascular sequelae
associated with COVID-19 infections in patients with AD as shown in Figure 1.
Alzheimer’s disease and dementia are an increasing global health challenge, affecting nearly
40-50 million people.2
Alzheimer’s disease is a neurodegenerative disease caused by the formation of β-amyloid plaques and neurofibrillary tangles in the cortex, manifesting clinically as a
cognitive impairment that progressively declines with age.2 Given the prevalence of the disease,
many individuals are at risk of acquiring COVID-19 infections and possibly experiencing neurological sequelae.1
A systematic review by Fraiman et al3
concluded that cerebrovascular events
are common findings in COVID-19 infections as authors’ analyses reported 275 patients experienced cerebrovascular accidents (CVAs), ischemic stroke, intracranial hemorrhage, and cerebral
venous sinus thrombosis.3,4

2381

N299

Ibolya Rutkai, Meredith G. Mayer, Linh M. Hellmers, Bo Ning, Zhen Huang, Christopher J. Monjure, Carol Coyne, Rachel Silvestri, Nadia Golden, Krystle Hensley, Kristin Chandler, Gabrielle Lehmicke, Gregory J. Bix, Nicholas J. Maness, Kasi Russell-Lodrigue, Tony Y. Hu, Chad J. Roy, Robert V. Blair, Rudolf Bohm, Lara A. Doyle-Meyers, Jay Rappaport & Tracy Fischer

Neuropathology and virus in brain of SARS-CoV-2 infected non-human primates

https://doi.org/10.1038/s41467-022-29440-z

Published

1-Apr-22

https://www.nature.com/articles/s41467-022-29440-z

Neurological manifestations are a significant complication of coronavirus disease (COVID-19), but underlying mechanisms aren’t well understood. The development of animal models that recapitulate the neuropathological findings of autopsied brain tissue from patients who died from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are critical for elucidating the neuropathogenesis of infection and disease. Here, we show neuroinflammation, microhemorrhages, brain hypoxia, and neuropathology that is consistent with hypoxic-ischemic injury in SARS-CoV-2 infected non-human primates (NHPs), including evidence of neuron degeneration and apoptosis. Importantly, this is seen among infected animals that do not develop severe respiratory disease, which may provide insight into neurological symptoms associated with “long COVID”. Sparse virus is detected in brain endothelial cells but does not associate with the severity of central nervous system (CNS) injury. We anticipate our findings will advance our current understanding of the neuropathogenesis of SARS-CoV-2 infection and demonstrate SARS-CoV-2 infected NHPs are a highly relevant animal model for investigating COVID-19 neuropathogenesis among human subjects.

2382

N300

Justin J. Frere, Randal A. Serafini, Kerri D. Pryce, Marianna Zazhytska, Kohei Oishi, Ilona Golynker, Maryline Panis, Jeffrey Zimering, Shu Horiuchi, Daisy A. Hoagland, Rasmus Møller, Anne Ruiz, Jonathan B. Overdevest, Albana Kodra, Peter D. Canoll, James E. Goldman, Alain C. Borczuk, Vasuretha Chandar, Yaron Bram, Robert Schwartz, Stavros Lomvardas, Venetia Zachariou, Benjamin R. tenOever

SARS-CoV-2 infection results in lasting and systemic perturbations post recovery

https://doi.org/10.1101/2022.01.18.476786

pre-print

20-Jan-22

Study

https://www.biorxiv.org/content/10.1101/2022.01.18.476786v1.full

SARS-CoV-2 has been found capable of inducing prolonged pathologies collectively referred to as Long-COVID. To better understand this biology, we compared the short- and long-term systemic responses in the golden hamster following either SARS-CoV-2 or influenza A virus (IAV) infection. While SARS-CoV-2 exceeded IAV in its capacity to cause injury to the lung and kidney, the most significant changes were observed in the olfactory bulb (OB) and olfactory epithelium (OE) where inflammation was visible beyond one month post SARS-CoV-2 infection. Despite a lack of detectable virus, OB/OE demonstrated microglial and T cell activation, proinflammatory cytokine production, and interferon responses that correlated with behavioral changes. These findings could be corroborated through sequencing of individuals who recovered from COVID-19, as sustained inflammation in OB/OE tissue remained evident months beyond disease resolution. These data highlight a molecular mechanism for persistent COVID-19 symptomology and characterize a small animal model to develop future therapeutics.

2383

N301

Thibaut Dondaine, Florine Ruthmann, Fanny Vuotto, Louise Carton, Patrick Gelé, Karine Faure, Dominique Deplanque & Régis Bordet

Long-term cognitive impairments following COVID-19: a possible impact of hypoxia

https://doi.org/10.1007/s00415-022-11077-z

Published

24-Mar-22

Study

https://link.springer.com/article/10.1007/s00415-022-11077-z

Background
Cognitive and emotional disorders frequently persist after recovery from the acute symptoms of COVID-19; possible explanations include pneumonia-induced hypoxia, infection of the central nervous system, and microstrokes. The objective of the present study was to characterize the impact of hypoxia on the cognitive and psychological profile following COVID-19.
Methods
Sixty-two patients with COVID-19 were enrolled in a cross-sectional study and divided into two groups based on disease severity: outpatients with no pulmonary complications vs. inpatients with hypoxemic pneumonia having received oxygen therapy. All the participants underwent a comprehensive neuropsychological evaluation that included depression, anxiety, fatigue, sleepiness, attentional, memory and executive processes, and social cognition. For the inpatients, we also collected laboratory data (blood gas, blood glucose, fibrin, fibrinogen, D-dimer, and C-reactive protein).
Results
Cognitive disorders was found in patients with COVID-19: at least 18% had an impairment of memory and 11% had attentional dysfunctions. A high level of fatigue (90% of the patients), anxiety (52%), and depression (50%) was also observed. The impairments in attentional (p < 0.001 for omission and commission in CPT 3) and memory (p < 0.003 for Index Cue Efficiency from free and cue selected reminding test) functions were greater in COVID-19 inpatients that in COVID-19 outpatients. In contrast, levels of fatigue, depression, and anxiety were similarly high in both groups.
Conclusions
These findings might help to improve the management of COVID-19 patients as a function of the disease severity in particular for patients with hypoxia.

2384

N302

FaizaAziouaz1SamahYousfi1YassineMebrouk1ChristineKora2SoumayaElarabi2SihamNasri2ImaneKamaoui2ImaneSkiker2

Aspects radiologiques du neuro-COVID: véritable lien de causalité ou simple coïncidence

https://doi.org/10.1016/j.neurad.2022.01.036

Published

25-Mar-22

Study

https://www.sciencedirect.com/science/article/pii/S0150986122000360

Introduction
Le neuro-Covid désigne l'ensemble des atteintes du système nerveux associées à l'infection par Sars-CoV-2, et regroupe des entités variées. Elles touchent 8 à 13 % des patients hospitalisés pour infection Covid. Il s'agit soit d'une atteinte directe
Objectif
L'objectif de notre étude est d'analyser le profil clinico-radiologique des patients étiqueter neuroCovid et de détailler les différents critères permettant de rattacher l'atteinte neurologique à l'infection par le Sars-Cov2.
Patients et méthodes
Il s'agit d'une étude rétrospective sur dossiers médicaux de 52 patients, colligés au sein du service de neurologie du CHU Mohammed VI d'Oujda, durant une période allant de Mars 2020 à Novembre 2021. Tous les patients ont bénéficié d'un examen clinique rigoureux, d'une IRM médullaire et / ou encéphalique, d'un bilan biologique exhaustif et d'un suivi régulier.
Résultats
L’âge moyen de nos patients était de 42 ans, avec des extrêmes d’âge, allant de 16 à 71 ans. Le sex-ratio (H/F) était de 0,7. Le raisonnement étiologique s'est basé sur le contexte clinique, l'IRM du névraxe, le bilan biologique et l’évolution sous traitement. Plusieurs aspects radiologiques ont été retrouvés : les accidents ischémiques cérébraux (38%), les encéphalopathies nécrotico-hémorragiques (35%), les atteintes neuro-inflammatoires (21%), telles que des encéphalites ou des myélites, mais également les myéloradiculites (5%).
Discussion
l'IRM est l'examen de première intention dans l'exploration d'une atteinte neurologique centrale du Sars-Cov-2. Elle permet de mettre en évidence d'une part la lésion responsable du tableau clinique et d'autre part d’éliminer plusieurs hypothèses diagnostiques. La discussion diagnostique se base sur l'exclusion des étiologies pouvant être à l'origine de l'affection neurologique, en se basant sur les données récentes de la littérature, et sur l’évolution sous traitement.
Conclusion
Le diagnostic étiologique des neuro-Covid reste difficile. La démarche diagnostique doit être rigoureuse pour ne pas lier tout symptôme à l'infection Covid.

2385

N303

JulienCoelhoabcJean-ArthurMicoulaud-FranchiabcAnne-SophieWietdDucNguyendJacquesTaillardabPierrePhilipabc

Circadian misalignment is associated with Covid-19 infection

https://doi.org/10.1016/j.sleep.2022.03.015

Published

26-Mar-22

Study

https://www.sciencedirect.com/science/article/pii/S1389945722000910

Highlights
•Circadian misalignment is frequent (20.8%) in the general population.
•Circadian misalignment is associated with Covid-19 infection (OR=2.07 [1.12-3.80]).
•Mean sleep duration was not associated with Covid-19 infection.
•Appropriate schedules could help to reduce the risk of Covid-19 infection.
Background
Circadian system contributes to the regulation of inflammatory processes, but the role of circadian misalignment as a risk factor for contracting Covid-19 has up to now been poorly studied. The aim of this study was to explore the relationship between circadian misalignment (chronic disturbance of the circadian system) and the risk of Covid-19 infection in a population of subjects suspected of contact or infection with SARS-CoV-2.
Methods
Cross-sectional single-center study conducted during a period without lockdown in winter 2021. Recruitment took place in a Covid-19 outpatient testing center. Subjects between 18 and 45 years old were included whether they were symptomatic or not, healthcare workers or not, in contact with a Covid-19 case or not. To determine social jetlag, a proxy of circadian misalignment, they were asked about their usual sleep-wake behaviors. Usual sleep duration and sleep-wake timing were explored on workdays and free days. Social jetlag was defined as at least 2 hours shift of circadian alignment (defined as the difference between mid-sleep on workdays and mid-sleep on free days, mid-sleep as the median between bedtime and rise time).
Results
One thousand fourteen subjects were included (sampling rate: 10.8%, 39% men, mean age 28± 8) with 56 subjects positive for Covid-19 (positivity rate: 5.5%). Usual mean sleep duration was equivalent in both groups (7h47 versus 7h49, p=0.733). Social jetlag greater than 2 hours comprised 33.3% of subjects in the Covid-19 group versus 20.6% in the control group (p=0.026). After adjustment on age, gender, BMI and work schedules, subjects presenting with social jetlag greater than 2 hours had a 2.07-fold higher likelihood to test positive than subjects who had identical sleep-wake timing on workdays and free days (OR=2.07, 95%CI= [1.12-3.80], p=0.024).
Conclusion
Circadian misalignment not only is present in subjects infected by Covid-19 but could also be responsible for a higher likelihood of being infected. The chronobiological impact on the immune system or a higher likelihood of being exposed to social contacts during nocturnal activities could explain our findings, which need to be confirmed in a future large cohort study. Regular sleep-wake timing could ultimately become a target for preventing Covid-19 infection.

2386

N304

Masha G.SavelieffaEva L.FeldmanabcAmro M.Stinobc

Neurological sequela and disruption of neuron-glia homeostasis in SARS-CoV-2 infection

https://doi.org/10.1016/j.nbd.2022.105715

Published

29-Mar-22

Review

https://www.sciencedirect.com/science/article/pii/S0969996122001073

The coronavirus disease 2019 (COVID-19) pandemic is responsible for 267 million infections and over 5 million deaths globally. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a single-stranded RNA beta-coronavirus, which causes a systemic inflammatory response, multi-organ damage, and respiratory failure requiring intubation in serious cases. SARS-CoV-2 can also trigger neurological conditions and syndromes, which can be long-lasting and potentially irreversible. Since COVID-19 infections continue to mount, the burden of SARS-CoV-2-induced neurologic sequalae will rise in parallel. Therefore, understanding the spectrum of neurological clinical presentations in SARS-CoV-2 is needed to manage COVID-19 patients, facilitate diagnosis, and expedite earlier treatment to improve outcomes. Furthermore, a deeper knowledge of the neurological SARS-CoV-2 pathomechanisms could uncover potential therapeutic targets to prevent or mitigate neurologic damage secondary to COVID-19 infection. Evidence indicates a multifaceted pathology involving viral neurotropism and direct neuroinvasion along with cytokine storm and neuroinflammation leading to nerve injury. Importantly, pathological processes in neural tissue are non-cell autonomous and occur through a concerted breakdown in neuron-glia homeostasis, spanning neuron axonal damage, astrogliosis, microgliosis, and impaired neuron-glia communication. A clearer mechanistic and molecular picture of neurological pathology in SARS-CoV-2 may lead to effective therapies that prevent or mitigate neural damage in patients contracting and developing severe COVID-19 infection.

2387

N305

Shwan A.AhmadaShvan H.MohammedbBerwn A.AbdullaabBestoon KhSalihaMarwan N.HassanabAbdulwahid M.SalihacFahmi H.KakamadabcHiwa O.AbdullahabHemn AliHassanabSnurOthmanbShadi HamidSidiqb

Post COVID – 19 neurological disorders; a single center experience; a case series

https://doi.org/10.1016/j.amsu.2022.103508

Published

27-Mar-22

Case Reports

https://www.sciencedirect.com/science/article/pii/S2049080122002680

Highlights
•COVID-19 survivors might be at risk of developing neurological disorders.
•The exact prevalence and risk groups are yet to be established.
•This study aims to estimate the post-COVID-19 neurological sequelae.
Introduction
Coronavirus disease 2019 (COVID-19) pandemic, is a newly conducted respiratory disease caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). The current study aims to estimate the neurological diseases which develop after COVID-19 infection.
Method
This is a single center retrospective case series conducted in seven months. the patients were collected in an out-patient clinic. Diagnosis of COVID-19 and the way of diagnosis is confirmed through either polymerase chain reaction (PCR) test for COVID-19 and/or typical findings on chest computed tomography scan (CT scan). Patients developed neurological symptoms after being infected with COVID-19. Symptoms have to be developed within less than 6 months of recovery, or developed during illness and persisted after recovery.
Result
A total number of 59 patients infected with SARS-CoV2 were included. The majority of the patients had mild symptoms 32 (54%), 12 (20%) patients developed severe symptoms. Headache was the most common presenting symptom 27(46%) followed by fatigue in 8 (13.5%). The majority of the patients 55 (91.6%) presented with no focal signs. MRI was done for 27 (46%) patients without abnormal finding in 22 cases. Nearly 22 (37.3%) cases were diagnosed as recurrent episodes of migraine or new onset of migraine. All patients were managed according to the underlying pathology, only (28, 47.5%) patients were known to be completely recovered.
Conclusion
SARS-CoV2 can invade and cause inflammation in the central and peripheral nervous systems. It is responsible for many neurological problems. More studies are necessary to analyze the long term effect of the virus on the nervous system.

2388

N306

FrançoisLERSY1CarolineBund2Izzie JacquesNamer2StéphaneKremer1

Evolution des données de neuro-imagerie chez les patients COVID-19 sévères avec atteinte neurologique initiale

https://doi.org/10.1016/j.neurad.2022.01.026

Published

25-Mar-22

Study

https://www.sciencedirect.com/science/article/pii/S0150986122000268

Introduction
Les complications cérébrales aiguës en lien avec la COVID-19 ont été largement documentées par IRM cérébrales. Le but de cette étude était de présenter l’évolution des données de neuro-imagerie (IRM et PET-TDM au 18F-FDG) chez les patients guéris de la COVID-19.
Matériels et méthodes
Durant la première vague de la pandémie de COVID-19 entre le 1er mars et le 31 mai 2021, 112 consécutifs patients COVID-19 ayant des manifestations neurologiques ont réalisées une IRM cérébrale aux Hôpitaux Universitaires de Strasbourg. Après guérison, durant le suivi, parmi ces 112 patients, 31 ont réalisé des examens d'imagerie complémentaires (au moins une IRM cérébrale). L'ensemble de ces 31 patients était initialement hospitalisé en réanimation pour une maladie sévère.
Résultats
23 hommes (74%) et 8 (26%) femmes ont été inclus avec une moyenne d’âge de 61 ans (18-79 ans). Les diagnostics retenus sur la première IRM cérébrale regroupaient: i) Prise de contraste leptoméningées; ii) Microsaignements diffus (« Critical illness-associated cerebral microbleeds »); iii) AVC ischémique; iv) Suspicion de vascularite cérébrale; v) Lésions démyélinisantes inflammatoires aiguës. Durant le suivi, l’évolution des prises de contraste leptoméningées était dissociée et les microsaignements étaient stables. Les anomalies artérielles pariétales ont régressé chez l'ensemble des sujets ayant une suspicion de vascularite cérébrale. 4 (13%) patients ont présenté de nouvelles complications durant le suivi: AVC ischémique, névrite, nette augmentation de la charge lésionnelle vasculaire chez un patient avec une suspicion initiale de vascularite cérébrale, apparition d'un rehaussement pariétal artériel évocateur d'une vascularite cérébrale. La majorité de nos patients ont démontré une normalisation, au moins partielle, de la perfusion cérébrale. Concernant la volumétrie cérébrale, nous avons observé une perte de volume de 3.2% pour la substance grise sur une période moyenne de 5 mois. Concernant les données de médecine nucléaire, les principaux résultats observés étaient des hypométabolismes temporo-insulaire et des hypermétabolismes des colliculi.
Conclusion
Lors du suivi, une minorité de nos patients inclus ont démontré de nouvelles complications en imagerie.

2389

N307

Jane K. Parker 1,* ,Lisa Methven 1 ,Robert Pellegrino 2 ,Barry C. Smith 3 ,Simon Gane 4 andChristine E. Kelly 1,5

Emerging Pattern of Post-COVID-19 Parosmia and Its Effect on Food Perception

https://doi.org/10.3390/foods11070967

Published

27-Mar-22

Study

https://www.mdpi.com/2304-8158/11/7/967/htm

Olfactory dysfunction is amongst the many symptoms of Long COVID. Whilst most people that experience smell loss post COVID-19 recover their sense of smell and taste within a few weeks, about 10% of cases experience long-term problems, and their smell recovery journey often begins a few months later when everyday items start to smell distorted. This is known as parosmia. The aim of this study was to identify the key food triggers of parosmic distortions and investigate the relationship between distortion and disgust in order to establish the impact of parosmia on diet and quality of life. In this cross-sectional study (n = 727), respondents experiencing smell distortions completed a questionnaire covering aspects of smell loss, parosmia and the associated change in valence of everyday items. There was a significant correlation between strength and disgust (p < 0.0001), and when the selected items were reported as distorted, they were described as either unpleasant or gag-inducing 84% of the time. This change in valence associated with loss of expected pleasure and the presence of strange tastes and burning sensations must certainly lead to changes in eating behaviours and serious longer-term consequences for mental health and quality of life.

2390

N308

Andrea Frosolini 1,2,*,† ,Daniela Parrino 3,† ,Cristoforo Fabbris 4,Francesco Fantin 1,2,Ingrid Inches 5,Sara Invitto 6 ,Giacomo Spinato 1,4 andCosimo De Filippis 1

Magnetic Resonance Imaging Confirmed Olfactory Bulb Reduction in Long COVID-19: Literature Review and Case Series

https://doi.org/10.3390/brainsci12040430

Published

24-Mar-22

Case Series

https://www.mdpi.com/2076-3425/12/4/430/htm

An altered sense of smell and taste was recognized as one of the most characteristic symptoms of coronavirus infection disease (COVID-19). Despite most patients experiencing a complete functional resolution, there is a 21.3% prevalence of persistent alteration at 12 months after infection. To date, magnetic resonance imaging (MRI) findings in these patients have been variable and not clearly defined. We aimed to clarify radiological alterations of olfactory pathways in patients with long COVID-19 characterized by olfactory dysfunction. A comprehensive review of the English literature was performed by analyzing relevant papers about this topic. A case series was presented: all patients underwent complete otorhinolaryngology evaluation including the Sniffin’ Sticks battery test. A previous diagnosis of SARS-CoV-2 infection was confirmed by positive swabs. The MRIs were acquired using a 3.0T MR scanner with a standardized protocol for olfactory tract analysis. Images were first analysed by a dedicated neuroradiologist and subsequently reviewed and compared with the previous available MRIs. The review of the literature retrieved 25 studies; most cases of olfactory dysfunction more than 3 months after SARS-CoV-2 infection showed olfactory bulb (OB) reduction. Patients in the personal case series had asymmetry and a reduction in the volume of the OB. This evidence was strengthened by the comparison with a previous MRI, where the OBs were normal. The results preliminarily confirmed OB reduction in cases of long COVID-19 with an altered sense of smell. Further studies are needed to clarify the epidemiology, pathophysiology and prognosis.

2391

N309

ES

Jennifer Abbasi

Even Mild COVID-19 May Change the Brain

https://doi.org/10.1001/jama.2022.4507

Published

23-Mar-22

Article

https://jamanetwork.com/journals/jama/fullarticle/2790595

What We’ve Learned
The brain scans and cognitive scores of participants who had been infected with SARS-CoV-2 showed changes between the 2 time points that differed from those seen in the control group, with greater differences among older participants. Although not everyone who became infected with SARS-CoV-2 had these differences, the prior-infection group on average had:
greater loss of gray matter thickness in the orbitofrontal cortex and parahippocampal gyrus, areas associated with the sense of smell
greater tissue damage in areas connected with the primary olfactory cortex, also linked with smell
greater decrease in whole-brain volume and increase in cerebrospinal fluid volume
greater decline in the ability to perform complex tasks, which on brain scans was associated with atrophy in crus II, an area of the cerebellum associated with cognition
Compared with the control group, volunteers with a prior SARS-CoV-2 infection had an additional 0.2% to 2% gray matter loss or tissue damage on average between their 2 sets of scans. For context, adults lose about 0.2% to 0.3% of gray matter in memory-related brain regions per year, according to Gwenaëlle Douaud, PhD, the study’s lead author and an associate professor at the NDCN.
The findings remained statistically significant when the patients hospitalized with COVID-19 were removed from the analysis.
Too few influenza cases occurred to draw comparisons, but brain differences among 11 volunteers who developed non–COVID-19 pneumonia between imaging sessions did not substantially overlap with brain regions implicated in the COVID-19 analysis. This could indicate that the study’s findings are specific to SARS-CoV-2 infection, not respiratory infection in general.
Possible Explanations
In their article, Douaud’s team offered several potential mechanisms by which SARS-CoV-2 infection might directly or indirectly alter brain structure, including
reduced sensory input related to loss of smell
neuroinflammation or immune reactions
direct viral infection of brain cells

2392

N310

ES

SERENA SPUDICH AND AVINDRA NATH

Nervous system consequences of COVID-19

https://doi.org/10.1126/science.abm2052

Published

20-Jan-22

Article

https://www.science.org/doi/10.1126/science.abm2052

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is considered a respiratory pathogen, myriad neurologic complications—including confusion, stroke, and neuromuscular disorders—manifest during acute COVID-19. Furthermore, maladies such as impaired concentration, headache, sensory disturbances, depression, and even psychosis may persist for months after infection, as part of a constellation of symptoms now called Long Covid. Even young people with mild initial disease can develop acute COVID-19 and Long Covid neuropsychiatric syndromes. The pathophysiological mechanisms are not well understood, although evidence primarily implicates immune dysfunction, including nonspecific neuroinflammation and antineural autoimmune dysregulation. It is uncertain whether unforeseen neurological consequences may develop years after initial infection. With millions of individuals affected, nervous system complications pose public health challenges for rehabilitation and recovery and for disruptions in the workforce due to loss of functional capacity. There is an urgent need to understand the pathophysiology of these disorders and develop disease-modifying therapies.

2393

N311

Aureodo Carmo FilhoaEelcovan DuinkerkenabcJulio CesarTolentinoaSergio LuisSchmidta

Attention profile of physically recovered COVID-19 inpatients on the day of discharge

https://doi.org/10.1016/j.jpsychires.2022.03.047

Published

5-Apr-22

Study

https://www.sciencedirect.com/science/article/pii/S0022395622001765

Few studies have reported specific attention deficits in post-COVID-19 patients. Attention consists of different subdomains. Disruptions to specific attention subdomains might impair a wide range of everyday tasks, including road safety. As there are millions of COVID-19 patients with different socio-economic backgrounds, screening of attentional performance less dependent on education is needed. Here, we verified if physically recovered COVID-19 inpatients showed specific attention decrements at discharge. The Continuous Visual Attention Test (CVAT) is a Go/No-go task which is independent of participants’ schooling. It detects visuomotor reaction time (RT = intrinsic alertness), variability of reaction time (VRT = sustained attention), omission (focused-attention), and commission errors (response-inhibition). Thirty physically functional COVID-19 inpatients at discharge and 30 non-infected controls underwent the CVAT. A MANCOVA was performed to examine differences between controls and patients, followed by post-hoc ANCOVAs. Then, we identified the percentile score for each patient within the distribution of the CVAT performance of 211 subjects mentally capable of driving (reference group). COVID-19 patients at discharge showed greater RT and VRT, and more omission errors than controls. Twenty-two patients (73%) had performance below the 5th percentile of the reference group in one or more subdomains. As slow visuomotor RT, deficits in focusing and difficulties in keeping visual attention are associated with traffic accidents, we concluded that most COVID-19 patients at discharge had deficits that may increase the risk of road injuries. As these deficits will probably affect other daily activities, a routine assessment with the CVAT could provide useful information on whom to send to post-COVID centers.

2394

N312

Helena Ariño, Rosie Heartshorne, Benedict D. Michael, Timothy R. Nicholson, Angela Vincent, Thomas A. Pollak & Alberto Vogrig

Neuroimmune disorders in COVID-19

https://doi.org/10.1007/s00415-022-11050-w

Published

30-Mar-22

Review

https://link.springer.com/article/10.1007/s00415-022-11050-w

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the aetiologic agent of the coronavirus disease 2019 (COVID-19), is now rapidly disseminating throughout the world with 147,443,848 cases reported so far. Around 30–80% of cases (depending on COVID-19 severity) are reported to have neurological manifestations including anosmia, stroke, and encephalopathy. In addition, some patients have recognised autoimmune neurological disorders, including both central (limbic and brainstem encephalitis, acute disseminated encephalomyelitis [ADEM], and myelitis) and peripheral diseases (Guillain–Barré and Miller Fisher syndrome). We systematically describe data from 133 reported series on the Neurology and Neuropsychiatry of COVID-19 blog (https://blogs.bmj.com/jnnp/2020/05/01/the-neurology-and-neuropsychiatry-of-covid-19/) providing a comprehensive overview concerning the diagnosis, and treatment of patients with neurological immune-mediated complications of SARS-CoV-2. In most cases the latency to neurological disorder was highly variable and the immunological or other mechanisms involved were unclear. Despite specific neuronal or ganglioside antibodies only being identified in 10, many had apparent responses to immunotherapies. Although the proportion of patients experiencing immune-mediated neurological disorders is small, the total number is likely to be underestimated. The early recognition and improvement seen with use of immunomodulatory treatment, even in those without identified autoantibodies, makes delayed or missed diagnoses risk the potential for long-term disability, including the emerging challenge of post-acute COVID-19 sequelae (PACS). Finally, potential issues regarding the use of immunotherapies in patients with pre-existent neuro-immunological disorders are also discussed.

2395

N313

Abdul Mannan Baig*

Correlating Biochemical and Structural Changes in the Brain with Clinical Features in COVID-19

https://doi.org/10.1021/acschemneuro.2c00164

Published

2-Apr-22

Article

https://pubs.acs.org/doi/full/10.1021/acschemneuro.2c00164

With emerging reports of the deleterious effects of SARS-CoV-2 reflecting as neurological deficits in COVID-19, the biochemical and morphological changes it casts on the brain are also being investigated. This is an important niche of research as it is expected to predict and relate the neurological clinical features in the acute phase and chronic syndromic forms of COVID-19. Here debated are the biochemical and structural changes that can be related to the neurological manifestations in COVID-19.

2396

N314

Paul Lingor, Antonia F. Demleitner, Andreas W. Wolff & Emily Feneberg

SARS-CoV-2 and neurodegenerative diseases: what we know and what we don’t

https://doi.org/10.1007/s00702-022-02500-w

Published

17-Apr-22

Review

https://link.springer.com/article/10.1007/s00702-022-02500-w

Infection of the CNS with the SARS-CoV-2 can occur via different routes and results in para- or post-infectious manifestations with a variety of neurological symptoms. In patients with neurodegenerative diseases, SARS-CoV-2 is often associated with a higher fatality rate, which is a relevant problem in increasingly older populations. Apart from the direct consequences of an infection in patients with neurodegenerative diseases, indirect consequences of the pandemic such as limited access to care facilities and treatment have negative effects on the course of these chronic disorders. The occurrence of long-lasting neurological symptoms after infection with SARS-CoV-2 indicates a prolonged impact on the CNS. However, while it is known that SARS-CoV-2 affects neuronal populations that are relevant in the pathogenesis of neurodegenerative diseases, it is yet unclear whether an infection with SARS-CoV-2 is sufficient to trigger neurodegeneration. Reflecting on the impact of SARS-CoV-2 on neurodegeneration, we provide a concise overview on the current knowledge of SARS-CoV-2-induced pathology in the CNS and discuss yet open questions in the field.

2397

N315

Sajal Shukla

The Role of the Blood-Brain Barrier in Stopping the Spread of SARS-CoV-2 to the Brain and Brain Tumors

-

Published

Article

https://digitalcommons.imsa.edu/sir_presentations/2022/session2/60/

The initial site for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is the upper respiratory system. In many patients, however, the virus finds a way to reach the lungs, which can result in serious infection. Coronavirus can also spread to various parts of the body causing multiorgan failure. Although over 80% of patients with severe COVID-19 demonstrate neurological symptoms, very little direct evidence exists to support the claim that the virus can cross the blood-brain barrier and actively infect the brain. Interestingly, we discovered lung cancer tissue spread to the brain of a COVID-19 patient to be positive for SARS-CoV-2 along with brain tissue adjacent to the metastatic tumor. These findings raise the possibility that metastatic tumors may bring the virus from alternative parts of the body to the brain or may break down the blood-brain barrier to allow for the virus to spread to the brain. In this project, based on extensive literature review, we discuss the role of the blood-brain barrier in limiting the spread of SARS-CoV-2 to the brain and possible mechanisms, which may allow SARS-CoV-2 to reach and infect the brain and brain tumors. We also provide detailed information about the pattern of SARS-CoV-2 detection in metastatic brain tumor and adjacent brain tissue. These findings are important for the understanding of mechanisms by which SARS-CoV-2 can cause brain disease.

2398

N316

Marcell P. Szabo, Michiyo Iba, Avindra Nath, Eliezer Masliah & Changyoun Kim

Does SARS-CoV-2 affect neurodegenerative disorders? TLR2, a potential receptor for SARS-CoV-2 in the CNS

https://doi.org/10.1038/s12276-022-00755-7

Published

8-Apr-22

Review

https://www.nature.com/articles/s12276-022-00755-7

The coronavirus (COVID-19) pandemic, caused by severe acute respiratory system coronavirus 2 (SARS-CoV-2), has created significant challenges for scientists seeking to understand the pathogenic mechanisms of SARS-CoV-2 infection and to identify the best therapies for infected patients. Although ACE2 is a known receptor for the virus and has been shown to mediate viral entry into the lungs, accumulating reports highlight the presence of neurological symptoms resulting from infection. As ACE2 expression is low in the central nervous system (CNS), these neurological symptoms are unlikely to be caused by ACE2-virus binding. In this review, we will discuss a proposed interaction between SARS-CoV-2 and Toll-like receptor 2 (TLR2) in the CNS. TLR2 is an innate immune receptor that recognizes exogenous microbial components but has also been shown to interact with multiple viral components, including the envelope (E) protein of SARS-CoV-2. In addition, TLR2 plays an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Based on these observations, we hypothesize that TLR2 may play a critical role in the response to SARS-CoV-2 infiltration in the CNS, thereby resulting in the induction or acceleration of AD and PD pathologies in patients.

2399

N317

Yahyah Aman

COVID-19-associated cognitive decline

https://doi.org/10.1038/s43587-022-00216-w

Published

4-Apr-22

Article

https://www.nature.com/articles/s43587-022-00216-w

There have been reports of negative cognitive outcomes during and after SARS-CoV-2 infection, but the long-term effect of COVID-19 on cognitive function remains unclear. In a study published in JAMA Neurology, Liu and colleagues conducted a 1-year longitudinal assessment of the trajectory of cognitive change in survivors of COVID-19 over the age of 60 (n = 1,438), and age- and sex-matched uninfected control individuals (n = 438), in Wuhan, China. Cognitive assessments were conducted at 6 months and 12 months after discharge from COVID-19-designated hospitals, via questionnaires and telephone interviews. The authors report that survivors of COVID-19 had lower cognitive scores at both time points, and that the incidence of mild cognitive impairment or dementia was higher compared to uninfected individuals. The effects were stronger for those who experienced a severe form of the disease. The incidences of dementia and mild cognitive impairment were 15.00% and 26.15%, respectively, in individuals with severe COVID-19, compared to 0.68% and 5.05%, respectively, in the uninfected control cohort. These findings suggest that, over the long term, severe COVID-19 may lead to an increase in cognitive decline and dementia in older adults, and point to the need to evaluate the effect of the COVID-19 pandemic on future dementia burden worldwide.

2400

N318

ES

José WagnerLeonel Tavares-JúnioraAna CéliaCaetano de SouzabJosé WictoPereira BorgescDanilo NunesOliveiraaJosé IbiapinaSiqueira-NetoaManoel AlvesSobreira-NetoaPedroBraga-Netoad

Covid-19 Associated Cognitive Impairment: A Systematic Review

https://doi.org/10.1016/j.cortex.2022.04.006

Published

18-Apr-22

Review

https://www.sciencedirect.com/science/article/pii/S0010945222001150

Introduction
COVID-19 has a wide range of clinical manifestations. Neurological manifestations in COVID-19 patients were demonstrated during the pandemic, including cognitive impairment. This study aimed to determine any relationship between COVID-19 and cognitive complaints, such as dementia, mild cognitive impairment (MCI), or subjective cognitive decline (SCD).
Methods
We performed a systematic review of MEDLINE via Ebsco, Cochrane EMBASE, SCOPUS, and LILACS electronic databases of observational studies with COVID-19 patients confirmed by serology or PCR who developed new cognitive impairment or deteriorated from previous cognitive impairment after infection. This review protocol was recorded on PROSPERO with registration number CRD 42021241590.
Results
A total of 3.520 articles were retrieved and read. Twenty-two studies were selected for our review. A wide range of cognitive assessment tools (n=25) was used. The most described affected domains in these studies were executive functions, attention, and episodic memory. Thirteen studies showed a pattern of cognitive impairment in processing speed, inattention, or executive dysfunction assessed through working memory.
Conclusion
This review highlights the high frequency of cognitive impairment after COVID-19 infection. However, we were unable to differentiate whether the cognitive impairment found corresponded to mild cognitive impairment or dementia through data from selected studies, and this issue serves as one objective of future studies to be addressed on this topic.

2401

N319

ChristopherKäuferaCara S.SchreiberaeAnna-SophiaHartkeaeIvoDendenaStephanieStanelle-BertrambSebastianBeckbNancy MounogouKouassibGeorgBeythiendKathrinBeckerdTomSchreinerdBerfinSchaumburgbAndreasBeinekedeWolfgangBaumgärtnerdeGülsahGabrielbcFranziskaRichterae

Microgliosis and neuronal proteinopathy in brain persist beyond viral clearance in SARS-CoV-2 hamster model

https://doi.org/10.1016/j.ebiom.2022.103999

Published

16-Apr-22

Study

https://www.sciencedirect.com/science/article/pii/S2352396422001839

Background
Neurological symptoms such as cognitive decline and depression contribute substantially to post-COVID-19 syndrome, defined as lasting symptoms several weeks after initial SARS-CoV-2 infection. The pathogenesis is still elusive, which hampers appropriate treatment. Neuroinflammatory responses and neurodegenerative processes may occur in absence of overt neuroinvasion.
Methods
Here we determined whether intranasal SARS-CoV-2 infection in male and female syrian golden hamsters results in persistent brain pathology. Brains 3 (symptomatic) or 14 days (viral clearance) post infection versus mock (n = 10 each) were immunohistochemically analyzed for viral protein, neuroinflammatory response and accumulation of tau, hyperphosphorylated tau and alpha-synuclein protein.
Findings
Viral protein in the nasal cavity led to pronounced microglia activation in the olfactory bulb beyond viral clearance. Cortical but not hippocampal neurons accumulated hyperphosphorylated tau and alpha-synuclein, in the absence of overt inflammation and neurodegeneration. Importantly, not all brain regions were affected, which is in line with selective vulnerability.
Interpretation
Thus, despite the absence of virus in brain, neurons develop signatures of proteinopathies that may contribute to progressive neuronal dysfunction. Further in depth analysis of this important mechanism is required.

2402

N320

HilalKeklicekaHalitSelçukabİlkeKurtcSezerUlukayadGülnurÖztürka

Individuals with a COVID-19 history exhibit asymmetric gait patterns despite full recovery

https://doi.org/10.1016/j.jbiomech.2022.111098

Published

20-Apr-22

Study

https://www.sciencedirect.com/science/article/pii/S0021929022001518

COVID-19 is a multisystem infectious disease affecting the body systems. Its neurologic complications include -but are not limited to headache, loss of smell, encephalitis, and cerebrovascular accidents. Even though gait analysis is an objective measure of the neuro-motor system and may provide significant information about the pathophysiology of specific diseases, no studies have investigated the gait characteristics in adults after full recovery from COVID-19. This was a cross-sectional, controlled study that included 12 individuals (mean age, 23.0 ± 4.1 years) with mild-to-moderate COVID-19 history (COVD) and 20 sedentary controls (CONT; mean age, 24.0 ± 3.6 years). Gait was evaluated using inertial sensors on a motorized treadmill. Spatial-temporal gait parameters and gait symmetry were calculated by using at least 512 consecutive steps for each participant. The effect-size analyses were utilized to interpret the impact of the results. Spatial-temporal gait characteristics were comparable between the two groups. The COVD group showed more asymmetrical gait patterns than the CONT group in the double support duration symmetry (p = 0.042), single support duration symmetry (p = 0.006), loading response duration symmetry (p = 0.042), and pre-swing duration symmetry (p = 0.018). The effect size analyses of the differences showed large effects (d = 0.68–0.831). Individuals with a history of mild-to-moderate COVID-19 showed more asymmetrical gait patterns than individuals without a disease history. Regardless of its severity, the multifaceted long-term effects of COVID-19 need to be examined and the scope of clinical follow-up should be detailed.

2403

N321

DivyanshiSinghaEktaSinghb

An overview of the neurological aspects in COVID-19 infection

https://doi.org/10.1016/j.jchemneu.2022.102101

Published

14-Apr-22

Review

https://www.sciencedirect.com/science/article/pii/S089106182200031X

HIGHLIGHTS
•The information provided focuses on COVID-19 adversities extended to the central as well as the peripheral nervous system.
•The article helps to understand neurological and neuropsychiatric complications.
•This approach can help to develop a recuperative response.
The Crown-shaped, severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) triggered the globally fatal illness of Coronavirus disease-2019 (COVID-19). This infection is known to be initially reported in bats and has been causing major respiratory challenges. The primary symptoms of COVID-19 include fever, fatigue and dry cough. As progressed the complications may lead to acute respiratory distress syndrome (ADRS), arrhythmia and shock. This review illustrates the neurological and neuropsychiatric impairments due to COVID-19 infection. The SARS-CoV-2 virus enters via the hematogenous or neural route, spreads to the Central Nervous System (CNS), causing a blood-brain barrier (BBB) dysfunction. Recent scientific articles have reported that SARS-CoV-2 causes several neurological issues such as encephalitis, seizures, acute stroke, delirium, meningoencephalitis and Guillain-Barré Syndrome (GBS). As a long-term effect of this disease certain neuropsychiatric conditions are witnessed such as depression and anxiety. Invasion into followed by degeneration takes place causing an uncontrolled immune response. Transcription factors like NF-κB (nuclear factor kappa light chain enhancer of activated B cells), which modulate genes responsible for inflammatory response gets over expressed. Nrf2 (nuclear factor erythroid 2- related factor 2) counterpoises the inflammation by antioxidant response towards COVID-19 infection. Like every other infection, the severity of this infection leads to deterioration of major organ systems and even leads to death. By the columns of this review, we elaborate on the neurological aspects of this life-threatening infection.

2404

N322

AliDehghaniaElhamZokaeibSeyyed MohammadKahaniaElahehAlavinejadcMohammadDehghanidGholam HosseinMeftahieMohammad RezaAfarineshf1

The potential impact of Covid-19 on CNS and psychiatric sequels

https://doi.org/10.1016/j.ajp.2022.103097

Published

8-Apr-22

Short communication

https://www.sciencedirect.com/science/article/pii/S1876201822000958

Highlights
•Survey answers the question of whether COVID-19 can impact psychiatric disorders, including psychosis and PTSD.
•Neuroinvasion of SARS-CoV2 may partially explain why some patients develop mental illnesses.
•We also looked at the potential capabilities of COVID-19 that might influence CNS.
Due to its high prevalence and fatality, the current Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2) virus, which first emerged in China in 2019, quickly spread around the world and immediately became a serious global health concern. Although respiratory issues were initially the most prominent symptom of coronavirus disease 2019 (COVID-19), it became obvious rapidly that COVID-19, like many other coronavirus family members, could affect the central nervous system (CNS). During the pandemic, CNS involvement expressed itself in a variety of forms, including insomnia, anosmia, headaches, encephalopathies, encephalitis, cerebrovascular accidents, cognitive and memory impairment, and increased psychiatric disorders. Almost everyone who has been infected has at least one of these neurological symptoms, demonstrating that the virus has a high ability to impact the CNS. As the coronavirus pandemic passes its second year, the manifestations it can cause in the long run, such as its psychological sequels, have not yet been thoroughly studied. Given the high importance of this issue in today’s society and due to the lack of reliable knowledge about the COVID-19 landscape on psychiatric disorders, we intend to investigate coronavirus’s possible effect on mental illnesses based on available literature. Because the majority of the psychological effects of the coronavirus can continue for a long period after the pandemic ends, our research can give insight into potential psychiatric sequels associated with COVID-19.

2405

N323

ES

Ingrid H. C. H. M. Philippens 1,†,‡ORCID,Kinga P. Böszörményi 1,‡ORCID,Jacqueline A. M. Wubben 1,Zahra C. Fagrouch 1,Nikki van Driel 1,†ORCID,Amber Q. Mayenburg 1ORCID,Diana Lozovagia 1ORCID,Eva Roos 2,Bernadette Schurink 2ORCID,Marianna Bugiani 2,Ronald E. Bontrop 1,3,Jinte Middeldorp 1ORCID,Willy M. Bogers 1ORCID,Lioe-Fee de Geus-Oei 4,5ORCID,Jan A. M. Langermans 1,6ORCID,Ernst J. Verschoor 1,*,§ORCID,Marieke A. Stammes 1,§ORCID andBabs E. Verstrepen 1,†,§ORCID

Brain Inflammation and Intracellular α-Synuclein Aggregates in Macaques after SARS-CoV-2 Infection

https://doi.org/10.3390/v14040776

Published

8-Apr-22

Study

https://www.mdpi.com/1999-4915/14/4/776/htm

SARS-CoV-2 causes acute respiratory disease, but many patients also experience neurological complications. Neuropathological changes with pronounced neuroinflammation have been described in individuals after lethal COVID-19, as well as in the CSF of hospitalized patients with neurological complications. To assess whether neuropathological changes can occur after a SARS-CoV-2 infection, leading to mild-to-moderate disease, we investigated the brains of four rhesus and four cynomolgus macaques after pulmonary disease and without overt clinical symptoms. Postmortem analysis demonstrated the infiltration of T-cells and activated microglia in the parenchyma of all infected animals, even in the absence of viral antigen or RNA. Moreover, intracellular α-synuclein aggregates were found in the brains of both macaque species. The heterogeneity of these manifestations in the brains indicates the virus’ neuropathological potential and should be considered a warning for long-term health risks, following SARS-CoV-2 infection.

2406

N324

Ahmed M. Eldokla,Aliae A. Mohamed-Hussein,Ahmed M. Fouad,Mariam G. Abdelnaser,Sara T. Ali,Nahed A. Makhlouf,Islam G. Sayed,Hoda A. Makhlouf,Jaffer Shah,Hani Aiash

Prevalence and patterns of symptoms of dysautonomia in patients with long-COVID syndrome: A cross-sectional study

https://doi.org/10.1002/acn3.51557

Published

8-Apr-22

Study

https://onlinelibrary.wiley.com/doi/10.1002/acn3.51557

Background
The association between autonomic dysfunction and long-COVID syndrome is established. However, the prevalence and patterns of symptoms of dysautonomia in long-COVID syndrome in a large population are lacking.
Objective
To evaluate the prevalence and patterns of symptoms of dysautonomia in patients with long-COVID syndrome.
Methods
We administered the Composite Autonomic Symptom Score 31 (COMPASS-31) questionnaire to a sample of post-COVID-19 patients who were referred to post-COVID clinic in Assiut University Hospitals, Egypt for symptoms concerning for long-COVID syndrome. Participants were asked to complete the COMPASS-31 questionnaire referring to the period of more than 4 weeks after acute COVID-19.
Results
We included 320 patients (35.92 ± 11.92 years, 73% females). The median COMPASS-31 score was 26.29 (0–76.73). The most affected domains of dysautonomia were gastrointestinal, secretomotor, and orthostatic intolerance with 91.6%, 76.4%, and 73.6%, respectively. There was a positive correlation between COMPASS-31 score and long-COVID duration (p < 0.001) and a positive correlation between orthostatic intolerance domain score and post-COVID duration (p < 0.001). There was a positive correlation between orthostatic intolerance domain score and age of participants (p = 0.004). Two hundred forty-seven patients (76.7%) had a high score of COMPASS-31 >16.4. Patients with COMPASS-31 >16.4 had a longer duration of long-COVID syndrome than those with score <16.4 (46.2 vs. 26.8 weeks, p < 0.001).
Conclusions
Symptoms of dysautonomia are common in long-COVID syndrome. The most common COMPASS-31 affected domains of dysautonomia are gastrointestinal, secretomotor, and orthostatic intolerance. There is a positive correlation between orthostatic intolerance domain score and patients' age.

2407

N325

Ili Margalit, Dana Yelin, Moshe Sagi, Maya Merav Rahat, Liron Sheena, Nadav Mizrahi, Yael Gordin, Hadar Agmon, Nitzan Karny Epstein, Alaa Atamna, Ori Tishler, Vered Daitch, Tanya Babich, Donna Abecasis, Yoni Yarom, Shirit Kazum, Dorit Shitenberg, Erik Baltaxe, Odelia Elkana, Irit Shapira-Lichter, Leonard Leibovici, Dafna Yahav

Risk factors and multidimensional assessment of long COVID fatigue: a nested case-control study

https://doi.org/10.1093/cid/ciac283

Published

11-Apr-22

Study

https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciac283/6566295

Background
Fatigue is the most prevalent and debilitating long COVID symptom, however risk factors and pathophysiology of this condition remain unknown.
We assessed risk factors for long COVID fatigue and explored its possible pathophysiology.
Methods
Nested case-control study in a COVID recovery clinic. Individuals with (cases) and without (controls) significant fatigue were included. We performed a multidimensional assessment evaluating various parameters, including pulmonary function tests and cardiopulmonary exercise testing, and implemented multivariable logistic regression to assess risk factors for significant long COVID fatigue.
Results
Total of 141 individuals were included. Mean age was 47 (SD 13) years; 115 (82%) were recovering from mild COVID-19. Mean time for evaluation was 8 months following COVID-19. Sixty-six (47%) individuals were classified with significant long COVID fatigue. They had significantly higher number of children, lower proportion of hypothyroidism, higher proportion of sore throat during acute illness and long COVID symptoms, and of physical limitation in daily activities.
Individuals with fatigue had poorer sleep quality and higher degree of depression. They had significantly lower heart rate [153.52 (22.64) vs 163.52 (18.53), p=0.038] and oxygen consumption per Kg [27.69 (7.52) vs 30.71 (7.52), p=0.036] at peak exercise.
The two independent risk factors for fatigue identified in multivariable analysis were peak exercise heart rate (odds ratio [OR] 0.79 per 10 beats/minute, 95% confidence interval [CI] 0.65-0.96, p=0.019); and long COVID memory impairment (OR 3.76, 95% CI 1.57-9.01, p=0.003).
Conclusions
Long COVID fatigue may be related to autonomic dysfunction, impaired cognition and decreased mood. This may suggest a limbic-vagal pathophysiology.

2408

N326

ES

Carlotta Pipolo ,Daniele Bottai ,Emanuela Fuccillo,Eleonora Aronica,Fabio Bruschi,Antonio Mario Bulfamante,Luca Castellani,Maria Paola Canevini,Davide Chiumello,Sergio Ferrari,Carla Martinelli,Stefano Muttini,Alberto Priori,Alberto Maria Saibene,Chiara Spoldi,Delfina Tosi,Gianluigi Zanusso,Gaetano Pietro Bulfamante,Giovanni Felisati

Evidence of SARS-CoV-2 in nasal brushings and olfactory mucosa biopsies of COVID-19 patients

https://doi.org/10.1371/journal.pone.0266740

Published

12-Apr-22

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0266740

The aim of the present study is to detect the presence of SARS-CoV-2 of patients affected by COVID-19 in olfactory mucosa (OM), sampled with nasal brushing (NB) and biopsy, and to assess whether a non-invasive procedure, such as NB, might be used as a large-scale procedure for demonstrating SARS-CoV-2 presence in olfactory neuroepithelium. Nasal brushings obtained from all the COVID-19 patients resulted positive to SARS-CoV-2 immunocytochemistry while controls were negative. Double immunofluorescence showed that SARS-CoV-2 positive cells included supporting cells as well as olfactory neurons and basal cells. OM biopsies showed an uneven distribution of SARS-CoV-2 positivity along the olfactory neuroepithelium, while OM from controls were negative. SARS-CoV-2 was distinctively found in sustentacular cells, olfactory neurons, and basal cells, supporting what was observed in NB. Ultrastructural analysis of OM biopsies showed SARS-CoV-2 viral particles in the cytoplasm of sustentacular cells. This study shows the presence of SARS-CoV-2 at the level of the olfactory neuroepithelium in patients affected by COVID-19. For the first time, we used NB as a rapid non-invasive tool for assessing a potential neuroinvasion by SARS-CoV-2 infection.

2409

N327

Stephanie L Grach ,1
Ravindra Ganesh ,2
Steven A Messina,3
Ryan T Hurt

Post-COVID-19 syndrome: persistent neuroimaging
changes and symptoms 9 months after
initial infection

https://doi.org/10.1136/bcr-2021-248448

Published

8-Apr-22

Case Report

https://casereports.bmj.com/content/bmjcr/15/4/e248448.full.pdf

A previously healthy and active middle-aged woman acquired COVID-19 as an occupational exposure with subsequent persistent post-COVID-19 symptoms including headache, dyspnoea on exertion, chest pressure, tachycardia, anosmia, parosmia, persistent myalgia, vertigo, cognitive decline and fatigue. She presented to a tertiary medical centre for further evaluation after 9 months of persistent symptoms and had a largely unremarkable workup with the exception of a persistently elevated monocyte chemoattractant protein 1, blunted cardiovagal response and non-specific scattered areas of low-level hypometabolism at the bilateral frontal, left precuneus, occipital and parietal regions on PET scan.

2410

N328

Mohamed S. Mohamed,Anton Johansson,Jörgen Jonsson † andHelgi B. Schiöth *,†

Dissecting the Molecular Mechanisms Surrounding Post-COVID-19 Syndrome and Neurological Features

https://doi.org/10.3390/ijms23084275

Published

12-Apr-22

Review

https://www.mdpi.com/1422-0067/23/8/4275/htm

Many of the survivors of the novel coronavirus disease (COVID-19) are suffering from persistent symptoms, causing significant morbidity and decreasing their quality of life, termed “post-COVID-19 syndrome” or “long COVID”. Understanding the mechanisms surrounding PCS is vital to developing the diagnosis, biomarkers, and possible treatments. Here, we describe the prevalence and manifestations of PCS, and similarities with previous SARS epidemics. Furthermore, we look at the molecular mechanisms behind the neurological features of PCS, where we highlight important neural mechanisms that may potentially be involved and pharmacologically targeted, such as glutamate reuptake in astrocytes, the role of NMDA receptors and transporters (EAAT2), ROS signaling, astrogliosis triggered by NF-κB signaling, KNDy neurons, and hypothalamic networks involving Kiss1 (a ligand for the G-protein-coupled receptor 54 (GPR54)), among others. We highlight the possible role of reactive gliosis following SARS-CoV-2 CNS injury, as well as the potential role of the hypothalamus network in PCS manifestations.

2411

N329

Mulazim Hussain Bukhari1*, Shumaila Liaqat2
,
Nadia Naseem

Glymphatics and brain fog - the
post-COVID-19 phenomenon

https://doi.org/10.51441.BioMedica.5-648

Published

3-Mar-22

Mini-review

https://biomedicapk.com/files/pdf/biomedica-648.pdf

Since the COVID-19 pandemic and now since the vaccination, many new signs and symptoms are being observed. Although most people with COVID-19 get better within weeks of illness, there is a wide range of new, relapsing, or ongoing health problems that many people may experience for weeks or more after being infected with the virus that causes COVID-19. Even people who did not have symptoms when they were infected can have post-COVID conditions. The most commonly reported of these symptoms are related to the neurological system, including brain fog, fatigue, anxiety, anosmia, and depression. The role of glymphatics in post-COVID brain fog is a widely studied phenomenon. This review will also explore the possible etio-pathogenesis of brain fog in post-COVID-19 patients.

2412

N330

Jeremy M. Morowitz 1,†,Kaylyn B. Pogson 2,†,Daniel A. Roque 3 andFrank C. Church 4,*ORCID

Role of SARS-CoV-2 in Modifying Neurodegenerative Processes in Parkinson’s Disease: A Narrative Review

https://doi.org/10.3390/brainsci12050536

Published

22-Apr-22

Review

https://www.mdpi.com/2076-3425/12/5/536/htm

The COVID-19 pandemic, caused by SARS-CoV-2, continues to impact global health regarding both morbidity and mortality. Although SARS-CoV-2 primarily causes acute respiratory distress syndrome (ARDS), the virus interacts with and influences other organs and tissues, including blood vessel endothelium, heart, gastrointestinal tract, and brain. We are learning much about the pathophysiology of SARS-CoV-2 infection; however, we are just beginning to study and understand the long-term and chronic health consequences. Since the pandemic’s beginning in late 2019, older adults, those with pre-existing illnesses, or both, have an increased risk of contracting COVID-19 and developing severe COVID-19. Furthermore, older adults are also more likely to develop the neurodegenerative disorder Parkinson’s disease (PD), with advanced age as the most significant risk factor. Thus, does SARS-CoV-2 potentially influence, promote, or accelerate the development of PD in older adults? Our initial focus was aimed at understanding SARS-CoV-2 pathophysiology and the connection to neurodegenerative disorders. We then completed a literature review to assess the relationship between PD and COVID-19. We described potential molecular and cellular pathways that indicate dopaminergic neurons are susceptible, both directly and indirectly, to SARS-CoV-2 infection. We concluded that under certain pathological circumstances, in vulnerable persons-with-Parkinson’s disease (PwP), SARS-CoV-2 acts as a neurodegenerative enhancer to potentially support the development or progression of PD and its related motor and non-motor symptoms.

2413

N331

Dakheelallah M. Almutairi,Abdulaziz H. AlmalkiORCID Icon,Ahmad A. MirzaORCID Icon,Mohammed J. Khalifah,Ammar A. Aljefri,Khalid A. Alsalmi,Majid S. Al-Thaqafy &Mohammed A. Algarni show less

Patterns of self-reported recovery from chemosensory dysfunction following SARS-CoV-2 infection: insights after 1 year of the pandemic

https://doi.org/10.1080/00016489.2022.2062047

Published

24-Apr-22

Study

https://www.tandfonline.com/doi/abs/10.1080/00016489.2022.2062047

Background
The coronavirus disease (COVID-19), due to the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), causes chemosensory dysfunction.
Aims/objectives
To determine the characteristics of chemosensory dysfunction and to identify factors associated with chemosensory complete recovery and time to recovery.
Materials and methods
This cross-sectional study included all patients presenting with chemosensory dysfunction and confirmed SARS-CoV-2 infection from May to August 2020 who underwent telemedicine follow-up after 1 year to assess their chemosensory recovery.
Results
A total of 372 patients were included, of which 53.8% were male. The mean age ± SD was 37.45 ± 13.44. The majority experienced combined (olfactory and gustatory) dysfunction (85.7%), and 315 patients (84.7%) had complete loss of chemosensory function. The independent predictors associated with a low likelihood of complete recovery were parosmia (aOR 0.16, p < .001), upper respiratory tract symptoms (aOR 0.28, p = .001), and dyspnoea (aOR 0.21, p < .001), whereas the factors associated with a long recovery period were parosmia (aOR 12.04, p = .002), headache (aOR 7.19, p = .007), and hypertension (aOR 7.76, p = .039).
Conclusions
A full recovery outcome was predominant. The presence of parosmia was linked to both an incomplete recovery and a long time to recovery.
Significance
Parosmia and respiratory symptoms are implicated in the incomplete recuperation of chemosensory function.

2414

N332

Karan S.Hingorani1ShivkumarBhadola1Anna M.Cervantes-Arslanian123

COVID-19 and the Brain

https://doi.org/10.1016/j.tcm.2022.04.004

Published

21-Apr-22

Review

https://www.sciencedirect.com/science/article/pii/S1050173822000640

Entering the third year into the pandemic, overwhelming evidence demonstrates that Coronavirus disease 2019 (COVID-19) infection is a systemic illness, often with involvement of the central nervous system. Multiple mechanisms may underlie the development of neurologic manifestations of illness, including hypoxia, systemic illness, hypercoagulability, endothelial dysfunction, general critical illness, inflammatory response, and neurotropism of the severe acute respiratory syndrome coronavirus 2 (SARS-Co-V2) virus. COVID-19 infection is associated with neurologic involvement in all stages; acute infection, subacute/post-infection, and growing evidence also suggests during a chronic phase, the post-acute sequalae of COVID-19 (PASC). With over 20,000 published articles on COVID and the brain at the time of writing, it is virtually impossible to present an unbiased comprehensive review of how SARS-Co-V2 impacts the nervous system. In this review, we will present an overview of common neurologic manifestations, in particular focusing on the cerebrovascular complications, and proposed pathophysiology.

2415

N333

Stéphane Kremer & H. Rolf Jäger

Brain changes after COVID-19 — how concerned should we be?

https://doi.org/10.1038/s41582-022-00661-6

Published

21-Apr-22

Article

https://www.nature.com/articles/s41582-022-00661-6

Analysis of brain images taken before and after infection with SARS-CoV-2 suggests that even mild COVID-19 is associated with brain structure alterations and cognitive impairment. However, the clinical implications for individuals are unclear and further studies are needed to assess the generalizability of the findings and whether the effects are long-lasting.
In summary, this important, large cohort study by Douaud et al.1 provides evidence of potentially deleterious effects of mild SARS-CoV-2 infection on brain tissue at the group level. However, the limitations of the study make the full clinical implications of these findings unclear. Further analysis of these data, including correlation with vaccination status, olfactory symptoms, and future development of long COVID symptoms, could provide more insight into the vulnerability of particular subgroups. Importantly, additional follow-up imaging is needed to assess the longevity and reversibility of the observed changes.

2416

N334

Ted L. Rothstein

Cortical Grey Matter Volume Loss links to Neurological Sequelae in post COVID-19 “Long Haulers”

https://doi.org/10.21203/rs.3.rs-1582065/v1

pre-print

26-Apr-22

Study

https://www.researchsquare.com/article/rs-1582065/v1

Objective
COVID-19 (SARS-CoV-2) has been associated with neurological sequelae even in those patients with mild respiratory symptoms. Patients experiencing cognitive symptoms such as “brain fog” and other neurologic sequelae for more than 4 weeks define “long haulers”. There is limited information regarding damage to grey matter structures occurring in COVID-19 “long haulers”. Detecting possible anatomic changes related to COVID-19 is important as conventional Brain MRI often fails to identify disease correlates. 3-dimensional voxel-based morphometry (3D VBM) accurately analyzes, segments and quantifies brain volumes which allows for comparisons between infected COVID-19 “long haulers” and normative data from age and sex-matched healthy controls to obtain values based on their percentage of intracranial volume.
Methods
This study involved 19 consecutive post COVID-19 surviving “long haulers” who experienced neurologic symptoms. Each patient had Brain MRI with 3D VBM at median time of 72 days following laboratory confirmation. All patients had relatively mild respiratory symptoms which did not require oxygen supplementation, hospitalization, or assisted ventilation. 3D VBM was obtained for whole brain, forebrain parenchyma, cortical grey matter, hippocampus, and thalamus.
Results
The key finding is a statistically significant loss of cortical grey matter (CGM) volume in each COVID-19 “long hauler”. The loss of CGM volume likely contributes to long term neurological sequelae resulting from COVID-19 infection.
Conclusion
This study provides evidence for selective loss of volume in CGM as documented by 3D VBM in 19 COVID-19 “long haulers”. Damage to the CGM provides linkage to neurologic symptoms which can affect their quality of life.

2417

N335

Mulazim Hussain Bukhari1*, Shumaila Liaqat2
,
Nadia Naseem

Glymphatics and brain fog - the
post-COVID-19 phenomenon

https://doi.org/10.51441/BioMedica/5-648

Published

3-Mar-22

Article

https://biomedicapk.com/files/pdf/biomedica-648.pdf

Since the COVID-19 pandemic and now since the vaccination has emerged as a success, many new signs and symptoms are being observed. Although most people with COVID-19 get better within weeks of illness, there is a wide range of new, relapsing, or ongoing health problems that many people may experience for weeks or more after being infected with the virus that causes COVID-19. Even people who did not have symptoms when they were infected can have post-COVID conditions. The most commonly reported of these symptoms are related to the neurological system, including brain fog, fatigue, anxiety, anosmia, and depression. The role of glymphatics in post-COVID brain fog is a widely studied phenomenon.
This review will also explore the possible etio-pathogenesis of brain fog in post-COVID-19 patients.
The underlying pathogenesis, after the infection with the virus ends in the brain tissue, may be as follows:
1. It may be immune system hyperactivity, microglial activation with formation of microglial nodules, and
destruction of neurons.7
2. It may be due to slow clearance of the virus after infecting the monocytes, which delays the recovery
of the patients from post-COVID-19 syndrome.8
3. Angiotensin-converting enzyme 1 and 2 imbalances leading to grave consequences.9
4. Disruption of glymphatics and failure in cleansing system of wastes and proinflammatory cytokines.1
5. Damage of blood-brain barrier due to cytokine storm.10
6. Damage by mimicry or tissue-mimicking effect of autoantibodies.11
7. This may be due to other viruses sitting around and reactivating, e.g., Epstein-Barr virus which, in turn,
can cause fatigue.12
The problem in long haulers is the disruption of this lymphatic system, and the inflammatory end products are
not washed out and start accumulating and compressing, thus resulting in a brain fog. Majority of this drainage is
near the olfactory nerves with a resultant inflammation of the olfactory nerve in COVID-19 infection, leading to altered or loss of sense of smell.18 The ongoing volume overload and inflammation blocks the lymphatics, thus hampering the drainage of fluid to the venous sinuses. As a result, the fluid and the debris start accumulating in the brain. These end products, which affect the hypothalamus, cause fever, metal confusion, loss of sensation, and disturbance of the emotional system (three main jobs of this area are control of temperature, sensation, and emotion). So, the patients develop fatigue, myalgia, and fever.1,17

2418

N336

Adam Hampshire Doris A. Chatfield Anne Manktelow MPhil Amy Jolly William Trender Peter J. Hellyer Martina Del Giovane Virginia F.J. Newcombe Joanne G. Outtrim Ben Warne Junaid Bhatti Linda Pointon Anne Elmer Nyarie Sithole John Bradley Nathalie Kingston Stephen J. Sawcer Edward T. Bullmore James B. Rowe David K. Menon

Multivariate profile and acute-phase correlates of cognitive deficits in a COVID-19 hospitalised cohort

https://doi.org/10.1016/j.eclinm.2022.101417

Published

28-Apr-22

Study

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(22)00147-X/fulltext

Background
Preliminary evidence has highlighted a possible association between severe COVID-19 and persistent cognitive deficits. Further research is required to confirm this association, determine whether cognitive deficits relate to clinical features from the acute phase or to mental health status at the point of assessment, and quantify rate of recovery.
Methods
46 individuals who received critical care for COVID-19 at Addenbrooke's hospital between 10th March 2020 and 31st July 2020 (16 mechanically ventilated) underwent detailed computerised cognitive assessment alongside scales measuring anxiety, depression and post-traumatic stress disorder under supervised conditions at a mean follow up of 6.0 (± 2.1) months following acute illness. Patient and matched control (N = 460) performances were transformed into standard deviation from expected scores, accounting for age and demographic factors using N = 66,008 normative datasets. Global accuracy and response time composites were calculated (G_SScore & G_RT). Linear modelling predicted composite score deficits from acute severity, mental-health status at assessment, and time from hospital admission. The pattern of deficits across tasks was qualitatively compared with normal age-related decline, and early-stage dementia.
Findings
COVID-19 survivors were less accurate (G_SScore=-0.53SDs) and slower (G_RT=+0.89SDs) in their responses than expected compared to their matched controls. Acute illness, but not chronic mental health, significantly predicted cognitive deviation from expected scores (G_SScore (p=0.0037) and G_RT (p = 0.0366)). The most prominent task associations with COVID-19 were for higher cognition and processing speed, which was qualitatively distinct from the profiles of normal ageing and dementia and similar in magnitude to the effects of ageing between 50 and 70 years of age. A trend towards reduced deficits with time from illness (r∼=0.15) did not reach statistical significance.
Interpretation
Cognitive deficits after severe COVID-19 relate most strongly to acute illness severity, persist long into the chronic phase, and recover slowly if at all, with a characteristic profile highlighting higher cognitive functions and processing speed.

2419

N337

AdamHampshireaDoris A.ChatfieldbAnne ManktelowMPhilbAmyJollyaWilliamTrenderaPeter J.HellyeraMartina DelGiovaneaVirginia F.J.NewcombebJoanne G.OuttrimbBenWarnebJunaidBhattidLindaPointondAnneElmereNyarieSitholebfJohnBradleybghNathalieKingstonlStephen J.SawceriEdward T.Bullmorecdj…David K.Menonbck1

Multivariate profile and acute-phase correlates of cognitive deficits in a COVID-19 hospitalised cohort

https://doi.org/10.1016/j.eclinm.2022.101417

Published

28-Apr-22

Study

https://www.sciencedirect.com/science/article/pii/S258953702200147X

Background
Preliminary evidence has highlighted a possible association between severe COVID-19 and persistent cognitive deficits. Further research is required to confirm this association, determine whether cognitive deficits relate to clinical features from the acute phase or to mental health status at the point of assessment, and quantify rate of recovery.
Methods
46 individuals who received critical care for COVID-19 at Addenbrooke's hospital between 10th March 2020 and 31st July 2020 (16 mechanically ventilated) underwent detailed computerised cognitive assessment alongside scales measuring anxiety, depression and post-traumatic stress disorder under supervised conditions at a mean follow up of 6.0 (± 2.1) months following acute illness. Patient and matched control (N = 460) performances were transformed into standard deviation from expected scores, accounting for age and demographic factors using N = 66,008 normative datasets. Global accuracy and response time composites were calculated (G_SScore & G_RT). Linear modelling predicted composite score deficits from acute severity, mental-health status at assessment, and time from hospital admission. The pattern of deficits across tasks was qualitatively compared with normal age-related decline, and early-stage dementia.
Findings
COVID-19 survivors were less accurate (G_SScore=-0.53SDs) and slower (G_RT=+0.89SDs) in their responses than expected compared to their matched controls. Acute illness, but not chronic mental health, significantly predicted cognitive deviation from expected scores (G_SScore (p=0.0037) and G_RT (p = 0.0366)). The most prominent task associations with COVID-19 were for higher cognition and processing speed, which was qualitatively distinct from the profiles of normal ageing and dementia and similar in magnitude to the effects of ageing between 50 and 70 years of age. A trend towards reduced deficits with time from illness (r∼=0.15) did not reach statistical significance.
Interpretation
Cognitive deficits after severe COVID-19 relate most strongly to acute illness severity, persist long into the chronic phase, and recover slowly if at all, with a characteristic profile highlighting higher cognitive functions and processing speed.

2420

N338

AmulyaAgrawalaAniketChauhanaManu KumarShettybGirish M.PcMohit D.GuptacAnubhaGuptaa

ECG-iCOVIDNet: Interpretable AI model to identify changes in the ECG signals of post-COVID subjects

https://doi.org/10.1016/j.compbiomed.2022.105540

Published

30-Apr-22

Study

https://www.sciencedirect.com/science/article/pii/S0010482522003328

Highlights
•Propose shallow CNNs for the classification of healthy and post-COVID using ECG data.
•Proposed ECG-iCOVIDNet works only on the raw ECG data.
•ECG-HiCOVIDNet does late fusion of HRV & CNN features extracted from the raw ECG.
•Elaborate evaluation has been done against state-of-the-art methods.
•ShAP is used to evaluate interpretability at the patient and population level.
Objective
Studies showed that many COVID-19 survivors develop sub-clinical to clinical heart damage, even if subjects did not have underlying heart disease before COVID. Since Electrocardiogram (ECG) is a reliable technique for cardiovascular disease diagnosis, this study analyzes the 12-lead ECG recordings of healthy and post-COVID (COVID-recovered) subjects to ascertain ECG changes after suffering from COVID-19.
Method
We propose a shallow 1-D convolutional neural network (CNN) deep learning architecture, namely ECG-iCOVIDNet, to distinguish ECG data of post-COVID subjects and healthy subjects. Further, we employed ShAP technique to interpret ECG segments that are highlighted by the CNN model for the classification of ECG recordings into healthy and post-COVID subjects.
Results
ECG data of 427 healthy and 105 post-COVID subjects were analyzed. Results show that the proposed ECG-iCOVIDNet model could classify the ECG recordings of healthy and post-COVID subjects better than the state-of-the-art deep learning models. The proposed model yields an F1-score of 100%.
Conclusion
So far, we have not come across any other study with an in-depth ECG signal analysis of the COVID-recovered subjects. In this study, it is shown that the shallow ECG-iCOVIDNet CNN model performed good for distinguishing ECG signals of COVID-recovered subjects from those of healthy subjects. In line with the literature, this study confirms changes in the ECG signals of COVID-recovered patients that could be captured by the proposed CNN model. Successful deployment of such systems can help the doctors identify the changes in the ECG of the post-COVID subjects on time that can save many lives.

2421

N339

Sin ManLam12XunHuang13GuanghouShui13

Neurological aspects of SARS-CoV-2 infection – Lipoproteins and exosomes as Trojan horses

https://doi.org/10.1016/j.tem.2022.04.011

Published

2-May-22

Review

https://www.sciencedirect.com/science/article/pii/S1043276022000844

Highlights
•Increasing evidence point to the neurological consequences of SARS-CoV-2 infection.
•SARS-CoV-2 may gain access into the brain by leveraging upon endogenous lipid couriers including HDLs and exosomes.
•Lipid rafts mediate SARS-CoV-2 neurotropism by partaking in the production and BBB transmigration of both HDLs and exosomes.
•Repurposing existing drugs targeting lipid metabolism provides an expedited track to alleviate the disease burden of COVID-19.
SARS-CoV-2 primarily targets lipid-producing cells for viral tropism. In this review, we connect systemic lipid couriers, particularly high-density lipoproteins (HDLs) and exosomes, with the neurological facets of SARS-CoV-2 infection. We discuss how SARS-CoV-2 preferentially targets lipid-secreting cells and usurp host cell lipid metabolism for efficient replication and systemic spreading. Besides providing natural veils for viral materials against host immunity, the inherent properties of some of these endogenous lipid particles to traverse the blood-brain barrier (BBB) also offer alternative routes for SARS-CoV-2 neurotropism. Importantly, viral-driven neurological aberrations mediated by HDLs and exosomes are fueled by lipid rafts, which are implicated in the production and transmigration of these lipid particles across the BBB. Finally, we discuss how repurposing existing drugs targeting lipid rafts and cholesterol homeostasis may be beneficial toward alleviating the global COVID-19 disease burden.

2422

N340

Marco Calabria, Carmen García-Sánchez, Nicholas Grunden, Catalina Pons, Juan Antonio Arroyo, Beatriz Gómez-Anson, Marina del Carmen Estévez García, Roberto Belvís, Noemí Morollón, Javier Vera Igual, Isabel Mur, Virginia Pomar & Pere Domingo

Post-COVID-19 fatigue: the contribution of cognitive and neuropsychiatric symptoms

https://doi.org/10.1007/s00415-022-11141-8

Published

30-Apr-22

Study

https://link.springer.com/article/10.1007/s00415-022-11141-8

Fatigue in its many forms of physical, mental, and psychosocial exhaustion is a common symptom of post-COVID-19 condition, also known as “Long COVID.” Persistent fatigue in COVID-19 patients is frequently accompanied by cognitive dysfunction and neuropsychiatric symptoms; however, less is known about the relationships between these components of post-COVID-19 condition and fatigue itself. Consequently, the present study sought to (1) distinguish the types of fatigue experienced by participants, and (2) investigate whether cognitive deficits across various domains and neuropsychiatric conditions predicted these different types of fatigue. The study included 136 COVID-19 patients referred for neuropsychological evaluation due to cognitive complaints 8 months on average after SARS-CoV-2 infection. Measures included self-reported fatigue (physical, cognitive, and psychosocial), neuropsychiatric questionnaires (assessing symptoms of depression, anxiety, apathy, and executive functioning), a comprehensive neuropsychological assessment, and self-reported quality of life and everyday functioning. Results showed that reports of clinical significant fatigue were pervasive in our sample (82.3% of participants), with physical fatigue rated highest on average relative to the subscale maximum. Elevated levels of apathy, anxiety, and executive dysfunction in neuropsychiatric measures along with executive and attentional difficulties on cognitive tests were found to be consistently important predictors among different types of fatigue. This implicates both cognitive and neuropsychiatric symptoms as predictors of fatigue in post-COVID-19 condition, and stresses the importance of a holistic approach in assessing and considering potential treatment for COVID-19 patients experiencing fatigue.

2423

N341

Barbara Tomasino, Gaia Pellitteri, Francesco Bax, Alessandro Marini, Andrea Surcinelli, Gian Luigi Gigli & Mariarosaria Valente

Multisensory mental representation in covid-19 patients and the possibility of long-lasting gustatory and olfactory dysfunction in the CNS

https://doi.org/10.1038/s41598-022-11119-6

Published

5-May-22

Study

https://www.nature.com/articles/s41598-022-11119-6

Gustatory (GD) and olfactory (OD) dysfunctions are the most frequent neurological manifestations of COVID-19. We used mental imagery as an experimental psychological paradigm to access olfactory and gustatory brain representations in 80 Italian COVID-19 adult patients (68.75% reported both OD and GD). COVID-19 patients with OD + GD have a significantly and selectively decreased vividness of odor and taste imagery, indicating that COVID-19 has an effect on their chemosensory mental representations. OD + GD length and type influenced the status of mental chemosensory representations. OD + GD were become all COVID-19 negative at the time of testing. Data suggest that patients are not explicitly aware of long-term altered chemosensory processing. However, differences emerge when their chemosensory function is implicitly assessed using self-ratings. Among patients developing OD + GD, self-ratings of chemosensory function (taste, flavor) were significantly lower as compared to those who did not. At the level of mental representation, such differences can be further detected, in terms of a reduced ability to mentally activate an odor or taste mental image. Our study shows that COVID-19 infection not only frequently causes hyposmia and dysgeusia, but that may also alter the mental representations responsible for olfactory and gustatory perception.

2424

N342

Aurelian Anghelescu 1,2ORCID,Gelu Onose 2,3,*ORCID,Cristina Popescu 2,Mihai Băilă 2,3,Simona Isabelle Stoica 1,2,Ruxandra Postoiu 2,Elena Brumă 2,Irina Raluca Petcu 4,Vlad Ciobanu 5 andConstantin Munteanu 3,6,*ORCID

Parkinson’s Disease and SARS-CoV-2 Infection: Particularities of Molecular and Cellular Mechanisms Regarding Pathogenesis and Treatment

https://doi.org/10.3390/biomedicines10051000

Published

26-Apr-22

Review

https://www.mdpi.com/2227-9059/10/5/1000/htm

Accumulating data suggest that chronic neuroinflammation-mediated neurodegeneration is a significant contributing factor for progressive neuronal and glial cell death in age-related neurodegenerative pathology. Furthermore, it could be encountered as long-term consequences in some viral infections, including post-COVID-19 Parkinsonism-related chronic sequelae. The current systematic review is focused on a recent question aroused during the pandemic’s successive waves: are there post-SARS-CoV-2 immune-mediated reactions responsible for promoting neurodegeneration? Does the host’s dysregulated immune counter-offensive contribute to the pathogenesis of neurodegenerative diseases, emerging as Parkinson’s disease, in a complex interrelation between genetic and epigenetic risk factors? A synthetic and systematic literature review was accomplished based on the ”Preferred Reporting Items for Systematic Principles Reviews and Meta-Analyses” (PRISMA) methodology, including registration on the specific online platform: International prospective register of systematic reviews—PROSPERO, no. 312183. Initially, 1894 articles were detected. After fulfilling the five steps of the selection methodology, 104 papers were selected for this synthetic review. Documentation was enhanced with a supplementary 47 bibliographic resources identified in the literature within a non-standardized search connected to the subject. As a final step of the PRISMA method, we have fulfilled a Population-Intervention-Comparison-Outcome-Time (PICOT)/Population-Intervention-Comparison-Outcome-Study type (PICOS)—based metanalysis of clinical trials identified as connected to our search, targeting the outcomes of rehabilitative kinesitherapeutic interventions compared to clinical approaches lacking such kind of treatment. Accordingly, we identified 10 clinical trials related to our article. The multi/interdisciplinary conventional therapy of Parkinson’s disease and non-conventional multitarget approach to an integrative treatment was briefly analyzed. This article synthesizes the current findings on the pathogenic interference between the dysregulated complex mechanisms involved in aging, neuroinflammation, and neurodegeneration, focusing on Parkinson’s disease and the acute and chronic repercussions of COVID-19. Time will tell whether COVID-19 neuroinflammatory events could trigger long-term neurodegenerative effects and contribute to the worsening and/or explosion of new cases of PD. The extent of the interrelated neuropathogenic phenomenon remains obscure, so further clinical observations and prospective longitudinal cohort studies are needed.

2425

N343

Adam Hampshire, Doris A. Chatfield, Anne Manktelow MPhil, Amy Jolly, William Trender, Peter J. Hellyer, Martina Del Giovane, Virginia F.J. Newcombe, Joanne G. Outtrim, Ben Warne, Junaid Bhatti, Linda Pointon, Anne Elmer, Nyarie Sithole, John Bradley, Nathalie Kingston, Stephen J. Sawcer, Edward T. Bullmore, James B. Rowe, David K. Menon 1, the Cambridge NeuroCOVID Group, the NIHR C

Multivariate profile and acute-phase correlates of cognitive deficits in a COVID-19 hospitalised cohort

https://doi.org/10.1016/j.eclinm.2022.101417

Published

28-Apr-22

Study

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(22)00147-X/fulltext

Background
Preliminary evidence has highlighted a possible association between severe COVID-19 and persistent cognitive deficits. Further research is required to confirm this association, determine whether cognitive deficits relate to clinical features from the acute phase or to mental health status at the point of assessment, and quantify rate of recovery.
Methods
46 individuals who received critical care for COVID-19 at Addenbrooke's hospital between 10th March 2020 and 31st July 2020 (16 mechanically ventilated) underwent detailed computerised cognitive assessment alongside scales measuring anxiety, depression and post-traumatic stress disorder under supervised conditions at a mean follow up of 6.0 (± 2.1) months following acute illness. Patient and matched control (N = 460) performances were transformed into standard deviation from expected scores, accounting for age and demographic factors using N = 66,008 normative datasets. Global accuracy and response time composites were calculated (G_SScore & G_RT). Linear modelling predicted composite score deficits from acute severity, mental-health status at assessment, and time from hospital admission. The pattern of deficits across tasks was qualitatively compared with normal age-related decline, and early-stage dementia.
Findings
COVID-19 survivors were less accurate (G_SScore=-0.53SDs) and slower (G_RT=+0.89SDs) in their responses than expected compared to their matched controls. Acute illness, but not chronic mental health, significantly predicted cognitive deviation from expected scores (G_SScore (p=0.0037) and G_RT (p = 0.0366)). The most prominent task associations with COVID-19 were for higher cognition and processing speed, which was qualitatively distinct from the profiles of normal ageing and dementia and similar in magnitude to the effects of ageing between 50 and 70 years of age. A trend towards reduced deficits with time from illness (r∼=0.15) did not reach statistical significance.
Interpretation
Cognitive deficits after severe COVID-19 relate most strongly to acute illness severity, persist long into the chronic phase, and recover slowly if at all, with a characteristic profile highlighting higher cognitive functions and processing speed.

2426

N344

Christopher Cantrell, Robert Wilson

COVID-Long Haulers Can Develop POTS (Postural Orthostatic Tachycardia Syndrome) with Small Fiber Neuropathy and Abnormal Autonomic Testing (P17-1.005)

Published

3-May-22

Study

https://n.neurology.org/content/98/18_Supplement/3392

Objective: A substantial number of COVID long-haulers have developed POTS, which warrants further investigation. This study is intended as a first look at a new and growing patient population that is bringing greater attention to the prevalent autonomic disease of POTS.
Background: POTS (Postural Orthostatic Tachycardia Syndrome) is a disorder of autonomic dysregulation involving overactive compensation for postural blood pressure changes. This debilitating syndrome can be associated with small fiber neuropathy and a broad spectrum of autonomic symptoms including palpitations, changes in sweating, and gastrointestinal problems like constipation. Respiratory and gastrointestinal viruses have been known to cause onset of POTS pathophysiology. In approximately 10% of COVID cases, patients experience long-term health effects after the conclusion of their COVID infection. These patients are called COVID “long-haulers.”
Design/Methods: We conducted a chart review of 25 Cleveland Clinic post-COVID POTS patients who are mostly female (84%) to learn about this patient population’s distribution of top symptoms, comorbidities, autonomic testing, and autonomic questionnaire scores. Top three symptoms were determined based on the physician’s note from the patients’ initial visit to the Cleveland Clinic Neurology Department.
Results: Our chart review revealed a high occurrence of excitatory comorbidities such as chronic migraine (44%) and irritable bowel syndrome (24%). In addition, when assessing patients’ top three POTS symptoms, we found that palpitations, fatigue, and dyspnea were affecting patients most. As with POTS in general, autonomic testing outside of tilt table testing (85.7%) shows variable results with QSART (50%), skin punch biopsy (37.5%), deep breathing (14.3%), and Valsalva testing (0%) all showing positivity rates of 50% or less for our patient sample.
Conclusions: Post-COVID POTS could be an excitatory process with hyperadrenergic signaling based on the symptoms and comorbidities. We hope that this chart review will be the launching point for future studies aimed at achieving greater understanding of the post-COVID POTS phenomenon.

2427

N345

Emma Reford, Nicki Mohammadi, Natalia Romano Spica, Jenna Tosto, LAURA ROSENBAUM TABACOF, David Putrino, Christopher Kellner

Post Covid-19 Neurological Impairment Effects on Activities of Daily Living: Patient Perspectives from a Remote Patient Monitoring Program (P4-9.002)

Published

3-May-22

Study

https://n.neurology.org/content/98/18_Supplement/1322

Objective: Here, we emphasize the debilitating effects on daily life of post covid cognitive impairment, from the patient perspective. In this, we will gain deeper insight into the post-acute illness phase of COVID-19 to formulate more compassionate, supportive, and efficacious treatment protocols.
Background: Post Covid-19 acute infection neurological impairment has been shown to be a long term effect of the disease. 18 months after the onset of the COVID-19 pandemic, with over 230 million cases worldwide, it has never been more critical to understand such long term effects.
Design/Methods: 46 Patients in a COVID-19 Remote Patient Monitoring Program (Precision Recovery: Mount Sinai Health System) were interviewed regarding their experience with COVID-19. Patients were asked about their experiences navigating COVID-19 diagnoses, the health care system, and their recovery process. Patients were not pointedly asked about cognitive impairment post covid and all mentions were unprompted. References to post-cognitive impairment were analyzed for statistical and qualitative significance.
Results: 20/46 (43%) of patients reported cognitive impairment after the acute phase of their covid illness. 8/20 of these individuals (40%) were self identified long-haul covid patients. Patients identified three patterns of impairment: (1) memory; (2) attention; and (3) mental stamina. These new cognitive deficits impacted daily life in four key ways: (1) failure to adhere to daily responsibilities; (2) necessitated decrease in employment responsibilities; (3) insecurity in social interactions; and (4) development of coping strategies.
Conclusions: Post covid cognitive impairment significantly impacted both acute and long-haul covid patients. It is therefore critical to acknowledge this potential long-term effect as an outcome for anyone who experiences Covid-19 for improved understanding of patient illness experience and development of covid-19 treatment post-acute infection.

2428

N346

Lindsay McAlpine, Adeel Zubair, Serena Spudich

Case Series: Post-COVID Small Fiber Neuropathy (P9-9.002)

Published

3-May-22

Case Series

https://n.neurology.org/content/98/18_Supplement/348.abstract

Objective: To report a case series documenting biopsy-proven small fiber neuropathy (SFN) after COVID-19.
Background: Patients recovering from COVID-19 who present with sensory as well as autonomic symptoms, including positional orthostatic tachycardia syndrome (POTS), frequently have negative electrodiagnostic testing. Skin biopsy may be required to reveal SFN.
Design/Methods: This is a retrospective case series of patients seen in the Yale Neurology COVID-19 Clinic with positive SARS-CoV-2 PCR or antibody or a clinically consistent illness. After laboratory testing and a negative nerve conduction study, all patients underwent skin biopsy to test for intraepidermal SFN.
Case 1: A 40F with pre-diabetes (HbA1c 6.2%) developed burning, numbness, and tingling in the hands and legs and POTS 6 weeks after acute COVID-19. Skin biopsy demonstrated non-length dependent SFN. Complete remission of neuropathy symptoms occurred within days of intravenous immunoglobulin (IVIG) therapy, which has been continued longitudinally.
Case 2: A 65F with non-insulin dependent diabetes (HbA1c 8.0%) developed excruciating burning pain in her feet and orthostasis within weeks of acute COVID-19. Skin biopsy demonstrated non-length dependent SFN. She experienced partial relief of symptoms after IVIG and gabapentin.
Case 3: A 43F with pre-diabetes (HbA1c 6.0%) developed orthostasis, numbness, paresthesias, and a “sunburned” feeling in her face, back, hands, and feet 2 weeks after acute COVID-19. Skin biopsy demonstrated length-dependent SFN. Symptoms improved over several months of pregabalin treatment, but have not resolved. The patient deferred immunotherapy.
Case 4: A 40M developed POTS, numbness, and paresthesias in his face and left leg up to the knee within weeks of a clinical COVID-19 illness. Skin biopsy demonstrated non-length dependent SFN. IVIG therapy has resulted in significant improvement in symptoms.
Conclusions: Sensory symptoms and POTS occur post-COVID, and SFN should be considered in the differential. Given the time of onset and response to immunotherapy, post-COVID SFN may have an underlying autoimmune etiology.

2429

N347

Pietro De Luca Arianna Di Stadio Vito Colacurcio Pasquale Marra Alfonso Scarpa Filippo Ricciardiello Claudia Cassandro Angelo Camaioni Ettore Cassandro

Long COVID, audiovestibular symptoms and persistent chemosensory dysfunction: a systematic review of the current evidence

https://doi.org/10.14639/0392-100X-suppl.1-42-2022-10

Published

26-Apr-22

Review

https://www.actaitalica.it/article/view/1886

Objective. The persistence of auditory, vestibular, olfactory, and gustatory dysfunction for an extended time after COVID-19 has been documented, which represents an emerging challenge of which ENT specialists must be aware. This systematic review aims to evaluate the prevalence of persistent audiovestibolar and olfactory/gustatory symptoms in patients with “long-COVID”.
Methods. The literature was systematically reviewed according to PRISMA guidelines; PubMed, Scopus and Google Scholar were screened by searching articles on audiovestibular symptoms and olfactory/gustatory dysfunction after SARS-CoV-2 infection. The keywords used were hearing loss, tinnitus, vertigo, smell disorders, parosmia, anosmia, hyposmia, dysgeusia combined with COVID-19 or SARS-CoV-2.
Results. 1100 articles were identified. After removal of duplicates (382), 702 articles were excluded, and 16 were included in the systematic review. All articles included identified an association between SARS-CoV-2 infection and persistent hearing or chemosensory impairment. The studies were published over a period of 2 years, between 2019 and 2021.
Conclusions. The likelihood of patients with persistent audiovestibular symptoms related to COVID-19 was different among the articles; however, olfactory and gustatory disturbances were more consistently reported. Studies with longer follow-up are required to fully evaluate the long-term impact of these conditions.

2430

N348

Herbert Renz-Polster1*, Marie-Eve Tremblay2,3,4,5,6,7, Dorothee Bienzle8 and Joachim E. Fischer1

The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure

https://doi.org/10.3389/fncel.2022.888232

Published

9-May-22

Review

https://www.frontiersin.org/articles/10.3389/fncel.2022.888232/full

Although myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has a specific and distinctive profile of clinical features, the disease remains an enigma because causal explanation of the pathobiological matrix is lacking. Several potential disease mechanisms have been identified, including immune abnormalities, inflammatory activation, mitochondrial alterations, endothelial and muscular disturbances, cardiovascular anomalies, and dysfunction of the peripheral and central nervous systems. Yet, it remains unclear whether and how these pathways may be related and orchestrated. Here we explore the hypothesis that a common denominator of the pathobiological processes in ME/CFS may be central nervous system dysfunction due to impaired or pathologically reactive neuroglia (astrocytes, microglia and oligodendrocytes). We will test this hypothesis by reviewing, in reference to the current literature, the two most salient and widely accepted features of ME/CFS, and by investigating how these might be linked to dysfunctional neuroglia. From this review we conclude that the multifaceted pathobiology of ME/CFS may be attributable in a unifying manner to neuroglial dysfunction. Because the two key features – post exertional malaise and decreased cerebral blood flow – are also recognized in a subset of patients with post-acute sequelae COVID, we suggest that our findings may also be pertinent to this entity.

2431

N349

Matan Sorek
Eran Meshorer

Can’t smell the virus: SARS-CoV-2, chromatin organization, and anosmia

https://doi.org/10.1016/j.devcel.2022.04.015

Published

9-May-22

SPOTLIGHT

https://www.cell.com/developmental-cell/fulltext/S1534-5807(22)00272-6

Anosmia, or loss of smell, is strongly associated with SARS-CoV-2 infection in humans, but the underlying mechanism remains obscure. In a recent Cell study, Zazhytska et al., 2022 report non-cell-autonomous disruption of long-range genomic interactions of olfactory receptor genes in response to SARS-CoV-2 infection, and these interactions remain disrupted long after virus clearance.
Transient anosmia, an inability to smell, is a common symptom associated with many upper respiratory viral infections, including SARS-CoV-2. Typically, upon infection, nasal congestion blocks the odorants in sensory neurons, causing loss of smell. Anosmia in SARS-CoV-2 infection, however, occurs independently from nasal symptoms, and it may last long after the infection is resolved. In addition, the SARS-CoV-2 host cell entry proteins are not expressed by olfactory sensory neurons (OSNs) (Bilinska et al., 2020), and this makes viral infection of these neurons exceedingly rare. These pathological and molecular features raise the possibility that non-cell-autonomous mechanisms may underlie the anosmia that is frequently induced by SARS-CoV-2 infection.
In a recent study published in Cell, Zazhytska et al., 2022 explored the non-cell-autonomous molecular changes that occur in response to SARS-CoV-2 infection. As a model, they used golden hamsters (M. auratus), which have a host cell receptor, ACE2, through which SARS-CoV-2 enters cells (Bilinska et al., 2020) and which is highly similar to the human ortholog. They therefore closely resemble humans in SARS-CoV-2-related pathogenicity and immunogenicity (Cleary et al., 2020; Sia et al., 2020). To explore the changes in cellular composition and gene expression following SARS-CoV-2 infection, the authors collected olfactory epithelium (OE) from sham-infected or SARS-CoV-2-infected golden hamsters 1, 3, and 10 days post-infection, and performed single-cell RNA-sequencing (scRNA-seq). They identified 13 different cell types and found, as expected, that sustentacular (SUS) cells, which express the ACE2 receptor, comprise the large majority of the infected cells. Although microglia and assorted immune cells also demonstrated substantial viral uptake, only a small fraction of the OSNs were infected. The cellular effects of direct viral infection were evinced by the fraction of SUS cells decreasing substantially (from ∼20% to ∼6%), whereas viability of OSNs remained unaffected. By day 10, the original cellular composition was restored, and the virus was no longer detected in any of the OE cells.
Zazhytska et al., 2022 then analyzed transcriptional changes in OE cells and, remarkably, found a significant reduction in genes related to olfaction, including transcription factors which regulate olfactory receptors (OR) and OR signaling genes. A notable example is adenylyl cyclase 3 (Adcy3), whose loss leads to anosmia in mice (Wong et al., 2000). But why are OR genes dysregulated following SARS-CoV-2 infection? During OSN maturation, the lamin B receptor protein (LBR) is downregulated, and suppressive heterochromatin is rearranged to form nuclear hubs, thus generating “fried-egg”-like inverted nuclei which contain both heterochromatin cores and multi-enhancer hubs (Pourmorady and Lomvardas, 2022). Active OR alleles are arranged in proximity to their corresponding enhancers to enable active mono-allelic transcription. Using Hi-C experiments in sham- and SARS-CoV-2-infected hamsters, the authors found disruption of long-range genomic interactions of OR genes happening already 1 day post-infection (Figure 1). By day 3, they detected more widespread and global chromatin rearrangements. Remarkably, OR gene rearrangements persisted at day 10 post-infection, when the virus is already completely cleared, and this potentially explains the persistent changes in expression of OR-related genes and the long-lasting anosmia that is associated with SARS-CoV-2 infection.
The low susceptibility of OSNs to viral entry, together with evident OR chromatin and transcriptional changes, suggests that anosmia is not the result of a direct viral mechanism. To test whether these effects were indeed non-cell-autonomous, the authors performed an elegant experiment. They collected serum from SARS-CoV-2-infected hamsters, whereupon UV irradiation was used to inactivate the virus prior to administration of the irradiated serum directly into the nasal cavity of virus-naïve hamsters. The irradiated serum not only caused a comparable disruption in nuclear architecture to that of SARS-CoV-2-infected hamsters, but, when examined merely 12.5 h after the nasal administration, when the effect of the released cytokines is at its peak, it resulted in faster kinetics than SARS-CoV-2 infection. Subtle reduction in OR gene expression was already detectable at this early timepoint. Taken together, these experiments demonstrate global changes in nuclear architecture related to OR genes in OSNs, caused by components, cellular or viral, that are released from other infected cells, presumably the infected SUS cells, and that operate in trans.
The authors’ next goal was to assess the relevance of these findings in humans. Working with postmortem human tissues, the authors compared changes in gene expression between SARS-CoV-2-infected individuals and controls. They found a selective reduction in the expression of OR-related genes in human autopsies, including Adcy3 and other key olfactory transcripts. Furthermore, comparing Hi-C interaction maps between OSNs from SARS-CoV-2-infected human autopsy specimens and OSNs from control autopsies, the authors found large-scale loss of long-distance interactions, many of which were specific to OR-related genes.
Overall, these results support the model that non-autonomous disruption of long-range genomic interactions of OR-related genes underlies SARS-CoV-2-induced loss of smell. Such disruptions in nuclear architecture may not be readily re-established in post-mitotic cells such as OSNs, and thus they may also explain the persistence of the anosmia phenotypes for weeks and months after infection, as well as other related phenotypes such as parosmia, a distortion in the sense of smell.
This study raises several interesting questions. Although it is clear from the experiments that the mechanism for the loss of smell is non-cell-autonomous and does not require live virus, the specific molecules that are responsible are yet to be identified. Possibilities include non-viable viral particles, molecules secreted from infected cells such as cytokines, and circulating fragments of SUS cells, as dying cells are constantly being shed into the bloodstream. It is also unclear how such a molecule would elicit the profound changes in nuclear architecture in OSNs.
Transcriptional studies of SARS-CoV-2 have revealed that the expression of many epigenetic factors correlate with an interferon response and with general activation of transposable elements (Sorek et al., 2022). Therefore, if, as the authors hypothesize, cytokines are responsible for the non-cell-autonomous anosmia, interferon activation in the OSNs may cause changes in expression of these factors, which can lead to the observed chromatin-related phenotype. Another outstanding question is, how specific is the response? Can other neurons or non-dividing cells in general be similarly affected? Can other viruses elicit similar pathologies? Are cells with unique nuclear architectures more susceptible than other cells? Such emerging questions will no doubt be the focus of follow-up investigations.

2432

N350

Ameli Gerhard, Harald Prüß & Christiana Franke

Manifestationen im Zentralnervensystem nach COVID-19

https://doi.org/10.1007/s00115-022-01294-2

Published

12-May-22

Review

https://link.springer.com/article/10.1007/s00115-022-01294-2

Numerous diseases of the central nervous system (CNS), especially in the postacute phase after an infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been described. These include neuroimmunologically mediated diseases, such as encephalopathy, encephalitis, myelitis, acute disseminated encephalomyelitis (ADEM), acute necrotizing hemorrhagic leukoencephalitis (ANHLE) and neuromyelitis optica spectrum disorder (NMOSD) as well as others, such as posterior reversible encephalopathy syndrome (PRES), opsoclonus myoclonus ataxia (OMA) and cerebrovascular diseases. A parainfectious or postinfectious association is discussed but the pathophysiological mechanisms are so far unknown. Underlying mechanisms could be a virus-triggered overactivation of the immune system with hyperinflammation and cytokine storm but possibly also the development of specific autoantibodies against CNS tissue. Direct damage due to the invasion of SARS-CoV‑2 into the brain or spinal cord does not seem to play a relevant role. An exact clinical phenotyping and initiation of additional diagnostics are recommended, also to rule out other causes. To date no medicinal treatment options for CNS manifestations of long COVID exist; however, first results regarding inflammation and autoimmunity are promising and could lead to new treatment approaches.

2433

N351

Mitchell G. Miglis, Jordan Seliger, Ruba Shaik & Christopher H. Gibbons

A case series of cutaneous phosphorylated α-synuclein in Long-COVID POTS

https://doi.org/10.1007/s10286-022-00867-0

Published

16-May-22

Letter to the Editor

https://link.springer.com/article/10.1007/s10286-022-00867-0

As case numbers of coronavirus disease 19 (COVID-19) increase, chronic symptoms, including those of autonomic dysfunction, are being reported with increasing frequency [1], leading to the diagnosis of post-acute sequelae of COVID-19 (PASC), or Long-COVID. In addition, small fiber neuropathy (SFN) has been reported after viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [2]. These associations have prompted our group to systematically perform autonomic testing and skin biopsies in a cohort of patients who have developed postural tachycardia syndrome (POTS) as a consequence of PASC (Long-COVID POTS). As part of this evaluation, all skin biopsy samples undergo immunohistochemical analysis of both intraepidermal nerve fiber density (IENFD) and phosphorylated α-synuclein (p-syn) [3], the pathological form of α-synuclein associated with the neurodegenerative diseases of Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and pure autonomic failure (PAF), as well as isolated REM sleep behavior disorder (iRBD), a prodromal manifestation of synucleinopathy for the majority of patients.
We report the presence of p-syn in five young patients with Long-COVID POTS (LC-POTS) but without prodromal features of neurodegenerative disease.
Without a comparative biopsy prior to SARS-CoV-2 infection, it is unclear if the presence of p-syn is an incidental and unrelated finding, if the infection triggered accelerated aggregation of p-syn, or if the presence of p-syn predated the infection and predisposed our patients to the development of Long-COVID and/or POTS. One potential theory is that the pre-existing presence of phosphorylated α-synuclein could predispose individuals to more prolonged complications after COVID-19 infection. This would suggest that individuals with PD or other synucleinopathies might be at greater risk of complications [9]. Comparisons with other neurodegenerative diseases with similar morbidity would be required to determine the clinical relevance of this possibility.

2434

N352

PESE

Hamidreza Zalpoor, Hooriyeh Shapourian, Abdullatif Akbari, Shaghayegh Shahveh & Leila Haghshenas

Increased neuropilin-1 expression by COVID-19: a possible cause of long-term neurological complications and progression of primary brain tumors

https://doi.org/10.1007/s13577-022-00716-2

Published

9-May-22

Letter to the Editor

https://link.springer.com/article/10.1007/s13577-022-00716-2

Here, we hypothesized that SARS-CoV-2 infection could lead to long-term neurological complications and progression in primary brain tumors by upregulating the expression of Neuropilin-1 (NRP-1), especially in those who have contracted SARS-CoV-2 several times.
NRP-1 acts as a viral entry receptor besides angiotensin-converting enzyme 2 (ACE2), Ephrin (Eph) receptor, and CD147 that can contribute to SARS-CoV-2 viral entry to host cells in CNS, as well as stimulating intracellular signaling pathways which may be associated with pathological complications related to CNS and glioblastoma [2, 3, 5,6,7].
Previous studies have discussed the neurologic impacts of long-COVID, and the implications of this potential neurotropism. It includes how viruses use complete cytokine profiles and cause pain through direct and indirect interactions with nociceptors' plasticity [5].
Recent reports also revealed different nervous system complications observed during the acute and post-infection phases of COVID-19. However, knowledge of the post-acute neurological magnitudes of COVID-19, including memory or cognitive disturbances, insomnia, post-exertional malaise or fatigue, loss of smell or taste, headache, and other sleep disturbances, remained limited. Furthermore, the neurological problems that persisted 3–9 months from their date of infection with SARS-CoV-2 included vertigo, depression, memory, taste or smell disturbances, and cognitive disturbances reported as negatively affecting the neurological health of individuals [1]. In a recent study by Gwenaëlle Douaud et al. [1], the results have shown that COVID-19 can change the brain structure. Their investigation found significant long-term effects in these cases: (a) reduction in gray matter thickness and tissue contrast in the para-hippocampal gyrus and orbitofrontal cortex, (b) changes in tissue damage markers in regions functionally connected to the primary olfactory cortex, and (c) total brain size reduction.
Studies conducted previously revealed that the occurrence of neurological symptoms associated with COVID-19, such as acute ischemic stroke (AIS), acute necrotizing encephalitis, encephalopathy, peripheral neuropathy, headaches, seizures, cerebral micro-bleeds, demyelinating diseases, meningitis, Guillain–Barré syndrome, skeletal muscular symptoms, neurodegenerative diseases, as well as multiple cancers like glioblastoma is rapidly increasing [2, 8,9,10]. According to a study by de Joode et al., overall mortality rates for cancer patients with COVID-19 in some studies are between 32.3 and 35.4% [11], and the pooled case mortality rate among patients with cancer and COVID-19 was 25.6% [12]. Also, it has been reported that patients with primary brain tumors [e.g., glioblastoma, astrocytoma, oligodendroglioma, ependymoma, primary central nervous system lymphoma (PCNSL)] are more prone to experience a severe form of COVID-19 and/or a higher rate of mortality [11].
Infection of the CNS with SARS-CoV-2 could result in neurodegenerative diseases due to entry receptors for the virus in this region. NRP-1 is one of the two homologous neuropilins that plays critical roles in physiological and pathological conditions. An essential function of NRP-1 is to act as a receptor for signaling ligands, such as vascular endothelial growth factor (VEGF) (especially VEGF-A), integrins, semaphorins, transforming growth factor-beta (TGF-β), and plexins. It plays an essential role in many processes, including tumor progression, angiogenesis, viral entry, axonal guidance in the CNS and peripheral nervous system (PNS), and immune function [2]. In a study by Cantuti-Castelvetri et al., SARS-CoV-2 was shown to bind with NRP-1 by S protein and ultimately enter neurons and then increase NRP-1 expression and two crucial factors proteases Furin and Transmembrane serine protease 11A (TMPRSS11A) in SARS-CoV-2-infected cells [13]. Since olfactory epithelial cells express high levels of NRP-1 in COVID-19 patients, and VEGF-A is a ligand for NRP-1 [14], this suggests that one cause of patients' cognitive and neurological impairment may be the vulnerability of these brain regions to SARS-CoV-2. In addition, increased expression of NRP-1 may promote viral entry, stimulate intracellular signaling pathways in CNS cells, and contribute to the development and progression of neurodegenerative diseases and primary brain tumors in susceptible individuals.
A part of NRPs involved in binding vascular endothelial growth factor A (VEGF-A) is their extracellular b1b2 domain. This receptor plays a major role in angiogenesis as co-receptors for VEGFR-1 and -2 [15]. As VEGF-A binds to NRP-1, it increases the interaction between NRP-1 and GIPC1 (a scaffold protein) and facilitates the assembly of the GAIP/RGS19-interacting protein (GIPC1) + Syx signaling molecular complex, resulting in RhoA GTP binding. RhoA is activated and this activated form leads to the tumor suppressor p27 protein degradation. Therefore, this leads to the proliferation of tumor cells [16]. In addition, angiogenesis, proliferation, and migration mediated by NRP-1/GIPC1 are likely to be regulated by PI3K/Akt/NF-κB pathway activation [15].
In conclusion, we hypothesized that upregulated expression of NRP-1 by COVID-19 may be a significant cause of long-term CNS-related pathological complications and possibly lead to progression of primary brain tumors, especially in cases infected by SARS-CoV-2 several times. Therefore, we suggest that pharmacological targeting of NRP-1 in such susceptible patients could be beneficial and a promising therapeutic approach to combat long-term neurological complications and reduce the risk of primary brain tumors' progression.

2435

N353

César Fernández-de-las-Peñas, José D. Martín-Guerrero, Ignacio Cancela-Cilleruelo, Jorge Rodríguez-Jiménez, Paloma Moro-López-Menchero & Oscar J. Pellicer-Valero

Exploring trajectory recovery curves of post-COVID cognitive symptoms in previously hospitalized COVID-19 survivors: the LONG-COVID-EXP-CM multicenter study

https://doi.org/10.1007/s00415-022-11176-x

Published

10-May-22

Letter to the Editors

https://link.springer.com/article/10.1007/s00415-022-11176-x

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, responsible of causing coronavirus disease 2019 (COVID-19), primary affects the respiratory system; however, neurological symptoms (e.g., ageusia, anosmia, headache) and also other severe complication are commonly experienced at the acute phase [1, 2]. Neurological symptoms presented at the acute COVID-19 phase such as headache [3] or anosmia [4] are likely present at a post-COVID phase; however, other neurological symptoms, e.g., cognitive disorders, are “de novo” developed in up to 22% of COVID-19 survivors [5]. A recent meta-analysis reported prevalence rates of 32%, 27% and 22% for post-COVID brain fog, memory loss, and attention/concentration problems the six months after respectively [6]. However, the presence of post-COVID cognitive symptoms are questioned by others [7].
Interestingly, the recent definition of post-COVID includes cognitive dysfunction as one of the most common symptoms, after fatigue or dyspnoea [8]. The presence of post-COVID symptoms is overall associated with worse quality of life [9]. In fact, the presence of post-COVID cognitive symptoms represents a challenge for affected individuals since these symptoms affect daily life [10]. Although the presence of post-COVID cognitive symptoms is associated with nervous system changes [11], it seems that these symptoms generally improve over time [12]. However, most studies investigating these symptoms have used cross-sectional designs. Therefore, understanding the longitudinal pattern of post-COVID cognitive symptoms may have significant implications in diagnosis, triaging, and management of post-COVID individuals.
This letter to the editor presents the trajectory recovery curves of post-COVID cognitive symptoms using an exponentially fitted bar plot model of the longitudinal evolution of the symptoms in previously hospitalized COVID-19 survivors. We also illustrate the relationships of the cognitive symptoms by means of mosaic plots.

2436

N354

Marianna Papadopoulou, Eleni Bakola, Apostolos Papapostolou, Maria-Ioanna Stefanou, Mina Gaga, Vasiliki Zouvelou, Ioannis Michopoulos & Georgios Tsivgoulis

Autonomic dysfunction in long-COVID syndrome: a neurophysiological and neurosonology study

https://doi.org/10.1007/s00415-022-11172-1

Published

10-May-22

Letter to the Editors

https://link.springer.com/article/10.1007/s00415-022-11172-1

This study provides evidence that autonomic dysfunction may contribute to LCS symptoms that persist for several months beyond the resolution of acute COVID-19. It was demonstrated that LCS patients show vagus atrophy accounting for parasympathetic implication and prolonged SSR latencies, accounting for sympathetic implication.
Dysautonomia in acute COVID-19 has been involved in the development of acute respiratory distress syndrome and is attributed to either direct neuronal injury, or to immune-induced mechanisms [5]. In LCS, postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia have been reported and are similar to previous post-viral dysautonomia syndromes [6].

2437

N355

Amber N. Edinoff 1,*ORCID,Maithreyi Chappidi 2,E. Saunders Alpaugh 3,Bailey C. Turbeville 4,Evan P. Falgoust 4,Elyse M. Cornett 5ORCID,Kevin S. Murnane 1,6,7,Adam M. Kaye 8ORCID andAlan D. Kaye 5

Neurological and Psychiatric Symptoms of COVID-19: A Narrative Review

https://doi.org/10.3390/psychiatryint3020013

Published

7-May-22

Review

https://www.mdpi.com/2673-5318/3/2/13/htm

Recently dubbed Long COVID or Long-Haul COVID, those recovering from the initial COVID-19 infection may maintain clinical signs for longer than two or more weeks following the initial onset of the infection. The virus can gain entry into the CNS through axonal transport mediated through the olfactory nerve or hematogenous spread and can also cross the blood–brain barrier to access the temporal lobe and the brainstem. The neurologic and neuropsychiatric symptoms associated with COVID-19 patients are becoming a highly studied area due to the increased frequency of reported cases. Multiple hospital case series and observational studies have found a headache to be a common symptom among patients who are symptomatic with the SARS-CoV-2 virus. The headache described by many of these patients is similar to new daily persistent headache (NDPH). NDPH potentially develops in response to pro-inflammatory cytokines during a persistent systemic or CNS inflammation, mostly due to the initial infection. The treatments investigated were high-dose steroids, tetracycline derivatives, onabotulinum toxin type A, and long-term multidrug regimens. Among the identified symptoms of post-COVID-19 viral illness, fatigue appears to be the most ubiquitous. High-dose vitamin C is currently a suggested therapy proposed for its antioxidant, anti-inflammatory, and immunomodulatory properties. The mental health consequences of this diagnosis are being identified among large portions of COVID-19 survivors. Among these consequences, cases of major depressive disorder (MDD) and anxiety are being reported and closely examined. The aim of this narrative review is to highlight the neurological and psychiatric symptoms that have been associated with Long-Haul COVID and their possible treatments.

2438

N356

Frauke Seehusen 1,Jordan J. Clark 2ORCID,Parul Sharma 2,Eleanor G. Bentley 2,Adam Kirby 2,Krishanthi Subramaniam 2,Sabina Wunderlin-Giuliani 1,Grant L. Hughes 3ORCID,Edward I. Patterson 3ORCID,Benedict D. Michael 4,5ORCID,Andrew Owen 6ORCID,Julian A. Hiscox 2,James P. Stewart 2ORCID andAnja Kipar 1,2,*

Neuroinvasion and Neurotropism by SARS-CoV-2 Variants in the K18-hACE2 Mouse

https://doi.org/10.3390/v14051020

Published

11-May-22

Study

https://www.mdpi.com/1999-4915/14/5/1020/htm

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) not only affects the respiratory tract but also causes neurological symptoms such as loss of smell and taste, headache, fatigue or severe cerebrovascular complications. Using transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2), we investigated the spatiotemporal distribution and pathomorphological features in the CNS following intranasal infection with SARS-CoV-2 variants, as well as after prior influenza A virus infection. Apart from Omicron, we found all variants to frequently spread to and within the CNS. Infection was restricted to neurons and appeared to spread from the olfactory bulb mainly in basally oriented regions in the brain and into the spinal cord, independent of ACE2 expression and without evidence of neuronal cell death, axonal damage or demyelination. However, microglial activation, microgliosis and a mild macrophage and T cell dominated inflammatory response was consistently observed, accompanied by apoptotic death of endothelial, microglial and immune cells, without their apparent infection. Microgliosis and immune cell apoptosis indicate a potential role of microglia for pathogenesis and viral effect in COVID-19 and the possible impairment of neurological functions, especially in long COVID. These data may also be informative for the selection of therapeutic candidates and broadly support the investigation of agents with adequate penetration into relevant regions of the CNS.

2439

N357

Marko Ercegovac 1,2,†,Milika Asanin 1,3,†,Ana Savic-Radojevic 1,4ORCID,Jovan Ranin 1,5,Marija Matic 1,4,Tatjana Djukic 1,4,Vesna Coric 1,4ORCID,Djurdja Jerotic 1,4,Nevena Todorovic 5,Ivana Milosevic 1,5ORCID,Goran Stevanovic 1,5,Tatjana Simic 1,4,6ORCID,Zoran Bukumiric 1,7,* andMarija Pljesa-Ercegovac 1,4,*ORCID

Antioxidant Genetic Profile Modifies Probability of Developing Neurological Sequelae in Long-COVID

https://doi.org/10.3390/antiox11050954

Published

12-May-22

Study

https://www.mdpi.com/2076-3921/11/5/954/htm

Understanding the sequelae of COVID-19 is of utmost importance. Neuroinflammation and disturbed redox homeostasis are suggested as prevailing underlying mechanisms in neurological sequelae propagation in long-COVID. We aimed to investigate whether variations in antioxidant genetic profile might be associated with neurological sequelae in long-COVID. Neurological examination and antioxidant genetic profile (SOD2, GPXs and GSTs) determination, as well as, genotype analysis of Nrf2 and ACE2, were conducted on 167 COVID-19 patients. Polymorphisms were determined by the appropriate PCR methods. Only polymorphisms in GSTP1AB and GSTO1 were independently associated with long-COVID manifestations. Indeed, individuals carrying GSTP1 Val or GSTO1 Asp allele exhibited lower odds of long-COVID myalgia development, both independently and in combination. Furthermore, the combined presence of GSTP1 Ile and GSTO1 Ala alleles exhibited cumulative risk regarding long-COVID myalgia in carriers of the combined GPX1 LeuLeu/GPX3 CC genotype. Moreover, individuals carrying combined GSTM1-null/GPX1LeuLeu genotype were more prone to developing long-COVID “brain fog”, while this probability further enlarged if the Nrf2 A allele was also present. The fact that certain genetic variants of antioxidant enzymes, independently or in combination, affect the probability of long-COVID manifestations, further emphasizes the involvement of genetic susceptibility when SARS-CoV-2 infection is initiated in the host cells, and also months after.

2440

N358

Aurelian Anghelescu 1,2ORCID,Gelu Onose 2,3,*ORCID,Cristina Popescu 2,Mihai Băilă 2,3,Simona Isabelle Stoica 1,2,Ruxandra Postoiu 2,Elena Brumă 2,Irina Raluca Petcu 4,Vlad Ciobanu 5 andConstantin Munteanu 3,6,*ORCID

Parkinson’s Disease and SARS-CoV-2 Infection: Particularities of Molecular and Cellular Mechanisms Regarding Pathogenesis and Treatment

https://doi.org/10.3390/biomedicines10051000

Published

26-Apr-22

Systematic Review

https://www.mdpi.com/2227-9059/10/5/1000/htm

Accumulating data suggest that chronic neuroinflammation-mediated neurodegeneration is a significant contributing factor for progressive neuronal and glial cell death in age-related neurodegenerative pathology. Furthermore, it could be encountered as long-term consequences in some viral infections, including post-COVID-19 Parkinsonism-related chronic sequelae. The current systematic review is focused on a recent question aroused during the pandemic’s successive waves: are there post-SARS-CoV-2 immune-mediated reactions responsible for promoting neurodegeneration? Does the host’s dysregulated immune counter-offensive contribute to the pathogenesis of neurodegenerative diseases, emerging as Parkinson’s disease, in a complex interrelation between genetic and epigenetic risk factors? A synthetic and systematic literature review was accomplished based on the ”Preferred Reporting Items for Systematic Principles Reviews and Meta-Analyses” (PRISMA) methodology, including registration on the specific online platform: International prospective register of systematic reviews—PROSPERO, no. 312183. Initially, 1894 articles were detected. After fulfilling the five steps of the selection methodology, 104 papers were selected for this synthetic review. Documentation was enhanced with a supplementary 47 bibliographic resources identified in the literature within a non-standardized search connected to the subject. As a final step of the PRISMA method, we have fulfilled a Population-Intervention-Comparison-Outcome-Time (PICOT)/Population-Intervention-Comparison-Outcome-Study type (PICOS)—based metanalysis of clinical trials identified as connected to our search, targeting the outcomes of rehabilitative kinesitherapeutic interventions compared to clinical approaches lacking such kind of treatment. Accordingly, we identified 10 clinical trials related to our article. The multi/interdisciplinary conventional therapy of Parkinson’s disease and non-conventional multitarget approach to an integrative treatment was briefly analyzed. This article synthesizes the current findings on the pathogenic interference between the dysregulated complex mechanisms involved in aging, neuroinflammation, and neurodegeneration, focusing on Parkinson’s disease and the acute and chronic repercussions of COVID-19. Time will tell whether COVID-19 neuroinflammatory events could trigger long-term neurodegenerative effects and contribute to the worsening and/or explosion of new cases of PD. The extent of the interrelated neuropathogenic phenomenon remains obscure, so further clinical observations and prospective longitudinal cohort studies are needed.

2441

N359

Arvid Edén, MD, PhD1,2; Anna Grahn, MD, PhD1,2; Daniel Bremell, MD, PhD1,2; Anahit Aghvanyan, MD3; Pradeepthi Bathala, MS3; Dietmar Fuchs, PhD4; Johanna Gostner, PhD5; Lars Hagberg, MD, PhD1,2; Nelly Kanberg, MD1,2; Sunsanee Kanjananimmanont, MS3; Magnus Lindh, MD, PhD1; Salvia Misaghian, MS3; Staffan Nilsson, PhD6; Michael Schöll, PhD7,8,9; George Sigal, PhD3; Erika Stentoft, MD1,2; Marie Studahl, MD, PhD1,2; Aylin Yilmaz, MD, PhD1,2; Mingyue Wang, MD3; Martin Stengelin, PhD3; Henrik Zetterberg, MD, PhD7,9,10,11,12; Magnus Gisslén

Viral Antigen and Inflammatory Biomarkers in Cerebrospinal Fluid in Patients With COVID-19 Infection and Neurologic Symptoms Compared With Control Participants Without Infection or Neurologic Symptoms

http://jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2022.13253

Published

23-May-22

Study

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2792536

Question:  Are cerebrospinal fluid (CSF) SARS-CoV-2 antigens associated with central nervous system inflammation in patients with COVID-19?
Findings:  Of 44 patients with COVID-19 (23 neurosymptomatic) included in this hospital-based cross-sectional study, CSF nucleocapsid antigen was detectable in 89% of patients with available data and was significantly correlated with immune activation markers (neopterin and interferon γ). Moreover, neurosymptomatic patients had a more pronounced inflammatory CSF profile compared with neuroasymptomatic patients that could not be attributed to differences in COVID-19 severity.
Meaning:  These results suggest that viral components may contribute to central nervous system immune responses without direct viral invasion and highlight the clinical importance of neurologic symptoms.

Importance:  Neurologic symptoms are common in COVID-19, but the central nervous system (CNS) pathogenesis is unclear, and viral RNA is rarely detected in cerebrospinal fluid (CSF).
Objective:  To measure viral antigen and inflammatory biomarkers in CSF in relation to neurologic symptoms and disease severity.
Design, Setting, and Participants:  This cross-sectional study was performed from March 1, 2020, to June 30, 2021, in patients 18 years or older who were admitted to Sahlgrenska University Hospital, Gothenburg, Sweden, with COVID-19. All patients had CSF samples taken because of neurologic symptoms or within a study protocol. Healthy volunteer and prepandemic control groups were included.
Exposure:  SARS-CoV-2 infection.
Main Outcomes and Measures:  Outcomes included CSF SARS-CoV-2 nucleocapsid antigen (N-Ag) using an ultrasensitive antigen capture immunoassay platform and CSF biomarkers of immune activation (neopterin, β2-microglobulin, and cytokines) and neuronal injury (neurofilament light protein [NfL]).
Results:  Forty-four patients (median [IQR] age, 57 [48-69] years; 30 [68%] male; 26 with moderate COVID-19 and 18 with severe COVID-19 based on the World Health Organization Clinical Progression Scale), 10 healthy controls (median [IQR] age, 58 [54-60] years; 5 [50%] male), and 41 patient controls (COVID negative without evidence of CNS infection) (median [IQR] age, 59 [49-70] years; 19 [46%] male) were included in the study. Twenty-one patients were neuroasymptomatic and 23 were neurosymptomatic (21 with encephalopathy). In 31 of 35 patients for whom data were available (89%), CSF N-Ag was detected; viral RNA test results were negative in all. Nucleocapsid antigen was significantly correlated with CSF neopterin (r = 0.38; P = .03) and interferon γ (r = 0.42; P = .01). No differences in CSF N-Ag concentrations were found between patient groups. Patients had markedly increased CSF neopterin, β2-microglobulin, interleukin (IL) 2, IL-6, IL-10, and tumor necrosis factor α compared with controls. Neurosymptomatic patients had significantly higher median (IQR) CSF interferon γ (86 [47-172] vs 21 [17-81] fg/mL; P = .03) and had a significantly higher inflammatory biomarker profile using principal component analysis compared with neuroasymptomatic patients (0.54; 95% CI, 0.03-1.05; P = .04). Age-adjusted median (IQR) CSF NfL concentrations were higher in patients compared with controls (960 [673-1307] vs 618 [489-786] ng/L; P = .002). No differences were seen in any CSF biomarkers in moderate compared with severe disease.
Conclusions and Relevance:  In this study of Swedish adults with COVID-19 infection and neurologic symptoms, compared with control participants, viral antigen was detectable in CSF and correlated with CNS immune activation. Patients with COVID-19 had signs of neuroaxonal injury, and neurosymptomatic patients had a more marked inflammatory profile that could not be attributed to differences in COVID-19 severity. These results highlight the clinical relevance of neurologic symptoms and suggest that viral components can contribute to CNS immune responses without direct viral invasion.

2442

N360

Irene Scala, Simone Bellavia, Marco Luigetti, Valerio Brunetti, Aldobrando Broccolini, Maurizio Gabrielli, Lorenzo Zileri Dal Verme, Paolo Calabresi, Giacomo Della Marca & Giovanni Frisullo

Autonomic dysfunction in non-critically ill COVID-19 patients during the acute phase of disease: an observational, cross-sectional study

https://doi.org/10.1007/s10072-022-06136-2

Published

24-May-22

Study

https://link.springer.com/article/10.1007/s10072-022-06136-2

Introduction
Evidence is emerging about an extra-pulmonary involvement of SARS-CoV-2, including the nervous system. Autonomic dysfunction in patients recovering from acute coronavirus disease 2019 (COVID-19) has been recently described. Dysautonomic symptoms have been reported in the acute phase of the disease, but clear evidence is lacking, especially in the non-critical forms of the infection.
Objective
The aim of this study is to assess the prevalence of dysautonomia in acute, non-critically ill COVID-19 patients.
Methods
In this observational, cross-sectional study, we compared 38 non-critically ill patients with acute COVID-19 (COVID + group) to 38 healthy volunteers (COVID − group) in order to assess the prevalence of signs and symptoms of dysautonomia through the administration of the composite autonomic symptom score 31 (COMPASS-31) and an active standing test. Comparisons between groups were performed by means of both univariate and multivariate analyses.
Results
The prevalence of orthostatic hypotension was significantly higher in the COVID + group. Higher total scores of COMPASS-31 were observed in the COVID + group than controls. Significant differences between groups emerged in the secretomotor, orthostatic intolerance, and gastrointestinal COMPASS-31 domains. All these results maintained the statistical significance after the adjustment for concomitant drugs with a known effect on the autonomic nervous system assumed by the study participants, except for the differences in the gastrointestinal domain of COMPASS-31.
Conclusion
Our results suggest that an autonomic dysfunction could be an early manifestation of COVID-19, even in the contest of mild forms of the infection.

2443

N361

Mia I. Loft, Eva M. Foged, Mai Koreska

An Unexpected Journey: The Lived Experiences of Patients with Long-Term Cognitive Sequelae After Recovering from COVID-19

https://doi.org/10.1177%2F10497323221099467

Published

21-May-22

Study

https://journals.sagepub.com/doi/abs/10.1177/10497323221099467

This current study explored the lived experiences of patients with long-term cognitive sequelae after recovering from COVID-19. A qualitative design with in-depth interviews and an analysis inspired by Ricoeur’s interpretation theory was utilised. Contracting COVID-19 and suffering long-term sequelae presented as a life-altering event with significant consequences for one’s social, psychological and vocational being in the world in the months following the infection. Patients living with long-term cognitive sequelae after COVID-19 were in an unknown life situation characterised by feelings of anxiety, uncertainty and concerns about the future, significantly disrupting their life trajectory and forcing them to change their ways of life. While awaiting studies on treatment, symptom management and recovery after persistent sequelae of COVID-19, clinicians and researchers may find inspiration in experiences of other health conditions with similar phenomenology, such as ME/chronic fatigue syndrome and chronic headaches.

2444

N362

Sareen T. Ali† , Anthony K. Kang† , Tulsi R. Patel , Jeffrey R. Clark , Gina S. Perez-Giraldo,
Zachary S. Orban, Patrick H. Lim, Millenia Jimenez, Edith L. Graham , Ayush Batra ,
Eric M. Liotta & Igor J. Koralnik

Evolution of neurologic symptoms in non-hospitalized
COVID-19 “long haulers”

https://doi.org/10.1002/acn3.51570

Published

25-Apr-22

Study

https://onlinelibrary.wiley.com/doi/pdf/10.1002/acn3.51570

Objective: We characterized the evolution of neurologic symptoms and selfperceived recovery of non-hospitalized COVID-19 “long haulers” 6–9 months after their initial Neuro-COVID-19 clinic evaluation. Methods: In this followup study on the first 100 patients, 50 SARS-CoV-2 laboratory-positive (SARS-CoV-2+), and 50 laboratory-negative (SARS-CoV-2�), evaluated at our
Neuro-COVID-19 clinic between May and November 2020, patients completed phone questionnaires on their neurologic symptoms, subjective impression of recovery and quality of life.
Results: Of 52 patients who completed the study (27 SARS-CoV-2+, 25 SARS-CoV-2�) a median 14.8 (range 11–18) months
after symptom onset, mean age was 42.8 years, 73% were female, and 77% were vaccinated for SARS-CoV-2. Overall, there was no significant change in the frequency of most neurologic symptoms between first and follow-up evaluations, including “brain fog” (81 vs. 71%), numbness/tingling (69 vs. 65%), headache (67 vs. 54%), dizziness (50 vs. 54%), blurred vision (34 vs. 44%), tinnitus (33 vs. 42%), and fatigue (87 vs. 81%). However, dysgeusia and anosmia decreased overall (63 vs. 27%, 58 vs. 21%, both p < 0.001). Conversely, heart rate and blood pressure variation (35 vs. 56%, p = 0.01) and gastrointestinal
symptoms (27 vs. 48%, p = 0.04) increased at follow-up. Patients reported improvements in their recovery, cognitive function, and fatigue, but quality of life measures remained lower than the US normative population (p < 0.001). SARS-CoV-2 vaccination did not have a positive or detrimental impact on cognitive function or fatigue. Interpretation: Non-hospitalized COVID-19 “long haulers” continue to experience neurologic symptoms, fatigue, and compromised quality of life 14.8 months after initial infection.

2445

N363

Josephine Heine1, Katia Schwichtenberg1, Sophia Rekers1, Fabian Bösl1, Christiana
Franke1, Kathrin Reetz2,3 & Carsten Finke1,4

White matter changes and cognitive impairment in Long-COVID
patients with fatigue

Published

1-May-22

Study

https://cognitive-neurology.com/wp-content/uploads/2022/05/Abstract_OHBM_2.pdf

The CAMINO study protocol included a structured neuropsychological assessment of memory, attention, executive functions, and spatial navigation, and a 3T MRI acquisition. The diffusion-weighted scan (multiband EPI, 1.5x1.5x1.5mm, 98 diffusion directions, 1.5mm slice thickness, bvalue=3000s/mm²) was analysed using the FSL FDT Diffusion Toolbox [2]. Preprocessing included correcting for eddy currents, brain extraction, and fitting of diffusion tensor models. Diffusion maps were processed using tract-based spatial statistics (TBSS)[3] and Randomise with FDR correction [4]. Additionally, we
segmented high-resolution T1-weighted scans (MPRAGE, 1x1x1mm³) using FSL FIRST [5] to obtain volume estimates and extract microstructural integrity scores for subcortical structures. The study was approved by the ethics committee of Charité–Universitätsmedizin Berlin.
Results
At a median of 8.4 (3.2-19.8) months after acute SARS-CoV-2 infection, we observed neuropsychological impairments of higher attentional functions (80%, 40/50 of the patients affected)), processing speed (64%, 32/50), executive functions (46%, 23/50), working memory (36%, 18/50), and verbal episodic memory (30%, 15/50). Severe motor (86%, 43/50) and cognitive fatigue (82%, 41/50) were the most prevalent neuropsychiatric features (FSMC: 74.5±11.2). Moreover, we observed increased levels of depressive (BDI-II: 16.6±6.1) and anxiety symptoms (BAI: 14.7±6.9). Diffusion imaging revealed significantly reduced axial diffusivity (AD) of the left amygdala (7.33*10-4 (±0.59*10-4, patients) vs. 7.67*10-4 (±0.59*10-4, controls), F(1,93)=4.37, p=.039) and right putamen (6.22*10-4 (±0.36*10-4) vs. 6.53*10-4 (±0.33*10-4), F(1,93)=6.76, p=.011). There was no evidence for damage to major white matter tracts on whole brain imaging, including the corpus callosum and association fibres such as the superior longitudinal fasciculus, uncinate, fornix, and cingulum.
Clinical scores were significantly associated with white matter and subcortical integrity in patients. Higher anxiety scores correlated with aberrant radial diffusivity (RD) of the amygdala (left: r=-.38, p=.008; right: r=-.43, p=.002) and hippocampus (left: r=-.36, p=.011; right: r=-.40, p=.004). Additionally, increased fatigue was related to altered RD of the caudate nucleus (left: r=-.44, p=.002; right: r=-.04; p=.042 (n.s. after Benjamini-Hochberg correction)) and amygdala (left: r=-.56, p<.001; right: r=-.50, p<.001). Lower attention and executive functioning were associated with integrity of the right uncinate
fasciculus (Trail Making Test B, FA: r=-.45, p=.001; Stroop test errors, RD: r=-.40, p=.005). Lastly, impaired spatial navigation performance was accompanied by lower hippocampal volumes (left: r=.49, p<.001; right: r=.38, p=.008) and decreased integrity of hippocampal white matter tracts, including fornix (FA: r=.37, p=.009) and cingulum (MD, left: r=-.42, p=.002; right: r=-.41, p=.003).
Conclusions
Impairment of higher attentional and executive functions, affective symptoms, and severe fatigue are frequent presentations of Long-COVID patients with neurological complaints. Our analyses show that, in the absence of global white matter damage, compromised microstructural integrity of subcortical hubs contributes to cognitive and neuropsychiatric symptoms in these patients. Future research will determine whether these neuronal correlates represent transient or persistent changes and shed light on their neuroimmunological mechanisms.

2446

N364

Julie Fiorentino 1,2,*ORCID,Magali Payne 1,2,Elisa Cancian 3,Alexandra Plonka 1,2,4,Louise-Émilie Dumas 2,5,David Chirio 6,Élisa Demonchy 6,Karine Risso 6,Florence Askenazy-Gittard 2,5,Nicolas Guevara 4ORCID,Laurent Castillo 4,Philippe Robert 1,2,Valeria Manera 1,2,Clair Vandersteen 2,3ORCID andAuriane Gros 1

Correlations between Persistent Olfactory and Semantic Memory Disorders after SARS-CoV-2 Infection

https://doi.org/10.3390/brainsci12060714

Published

31-May-22

Study

https://www.mdpi.com/2076-3425/12/6/714/htm

Background: One of the main symptoms of COVID-19 is hyposmia or even anosmia. Olfactory identification is most often affected. In addition, some cognitive disorders tend to appear following the infection, particularly regarding executive functions, attention, and memory. Olfaction, and especially olfactory identification, is related to semantic memory which manages general knowledge about the world. The main objective of this study was to determine whether semantic memory is impaired in case of persistent post COVID-19 olfactory disorders. Methods: 84 patients (average age of 42.8 ± 13.6 years) with post COVID-19 olfactory loss were included after consulting to the ENT department. The clinical evaluation was carried out with the Pyramid and Palm Tree Test, the word-retrieval task from the Grémots, the Sniffin’ Sticks Test and the Computerised Olfactory Test for the Diagnosis of Alzheimer’s Disease. Results: Semantic memory was impaired in 20% (n = 17) of patients, especially in the 19–39 age-group. The olfactory threshold was only significantly correlated with the semantic memory scores. Conclusions: Similar to all cognitive disorders, semantic disorders can have a negative impact on quality of life if left untreated. It is essential to carry out specific assessments of post COVID-19 patients to accurately determine their disorders and to put in place the best possible rehabilitation, such as speech and language therapy, to avoid quality-of-life impairment.

2447

N365

Michael J. Peluso MD,Steven G. Deeks MD,Maja Mustapic PhD,Dimitrios Kapogiannis MD,Timothy J. Henrich MD,Scott Lu MBBS,Sarah A. Goldberg BA,Rebecca Hoh MS,Jessica Y. Chen,Enrique O. Martinez BA,J. Daniel Kelly MD, PhD,Jeffrey N. Martin MD,Edward J. Goetzl MD

SARS-CoV-2 and Mitochondrial Proteins in Neural-Derived Exosomes of COVID-19

https://doi.org/10.1002/ana.26350

Published

13-Mar-22

Study

https://onlinelibrary.wiley.com/doi/10.1002/ana.26350

Objective
As SARS-CoV-2 is known to invade neural cell mitochondria, a plasma system for quantifying central nervous system proteins in living humans was used to investigate neuropathogenic mechanisms of long-COVID-19.
Methods
SARS-CoV-2 proteins and mitochondrial proteins (MPs) in enriched plasma neuron-derived extracellular vesicles (NDEVs) and astrocyte-derived EVs (ADEVs) were quantified in resolved acute COVID-19 without post-acute sequelae of SARS-CoV-2 (PASC), PASC without neuropsychiatric manifestations (NP), PASC with NP and healthy controls.
Results
NDEV and ADEV mean levels of SARS-CoV-2 S1 and nucleocapsid (N) proteins were higher in all PASC sub-groups than controls, but only N levels were higher in PASC with than without NP. Exosome marker CD81-normalized NDEV mean levels of subunit 6 of MP respiratory chain complex I and subunit 10 of complex III, and neuroprotective MPs Humanin and mitochondrial open-reading frame of the 12S rRNA-c (MOTS-c) all were decreased significantly in PASC with NP but not in PASC without NP relative to controls. NDEV levels of MPs voltage-dependent anion-selective channel protein 1 (VDAC1) and N-methyl-D-aspartate receptor 1 (NMDAR1) were decreased in PASC without and with NP, whereas those of calcium channel MPs mitochondrial calcium uniporter (MCU), sodium/calcium exchanger (NCLX) and leucine zipper EF-hand containing transmembrane 1 protein (LETM1) were decreased only in PASC with NP. ADEV levels of MCU and NCLX only were increased in PASC without and with NP.
Interpretation
Abnormal NDEV and ADEV levels of SARS-CoV-2 N and S1 protein and MPs correlate with NP and may be biomarkers for long-COVID prognostics and therapeutic trials.

2448

N366

Denise Visser, Sandeep S.V. Golla, Sander C.J. Verfaillie, Emma M. Coomans, Roos M. Rikken, Elsmarieke M. van de Giessen, Marijke E. den Hollander, Anouk Verveen, Maqsood Yaqub, Frederik Barkhof, Janneke Horn, Bart Koopman, Patrick Schober, Dook W. Koch, Robert C. Schuit, Albert D. Windhorst, Michael Kassiou, Ronald Boellaard, Michele van Vugt, Hans Knoop, Nelleke Tolboom, Bart N.M. van Berckel

Long COVID is associated with extensive in-vivo neuroinflammation on [18F]DPA-714 PET

https://doi.org/10.1101/2022.06.02.22275916

pre-print

4-Jun-22

Case Reports

https://www.medrxiv.org/content/10.1101/2022.06.02.22275916v1

A significant number of COVID-19 patients develop 'long COVID', a condition defined by long-lasting debilitating, often neurological, symptoms. The pathophysiology of long COVID is unknown. Here we present in-vivo evidence of widespread neuroinflammation in long COVID, using a quantitative assessment, [18F]DPA-714 PET, in two long COVID patients. We reanalyzed historical data from three matched healthy control subjects, for comparison purposes. Both patients with long COVID had widespread increases in [18F]DPA-714 binding throughout the brain. Quantitative measures of binding (BPND values) were increased on average by 121% and 76%, respectively. This implicates profound neuroinflammation in the pathophysiology of long COVID.

2449

N367

Rafi Hadad, Johad Khoury, Chen Stanger, Tali Fisher, Sonia Schneer, Rachel Ben-Hayun, Katherine Possin, Victor Valcour, Judith Aharon-Peretz & Yochai Adir

Cognitive dysfunction following COVID-19 infection

https://doi.org/10.1007/s13365-022-01079-y

Published

26-May-22

Study

https://link.springer.com/article/10.1007/s13365-022-01079-y

The long-term sequelae of COVID-19 and neurologic syndromes post COVID remain poorly understood. The present study aims to characterize cognitive performance in patients experiencing cognitive symptoms post-COVID infection. Patients evaluated at a post COVID clinic in Northern Israel who endorsed cognitive symptoms were referred for neurologic consultation. The neurologic work-up included detailed medical history, symptom inventory, neurological examination, the Montreal Cognitive Assessment (MoCA), laboratory tests and brain CT or MRI. Between December 2020 and June 2021, 46 patients were referred for neurological consultation (65% female), mean age 49.5 (19–72 years). On the MoCA test, executive functions, particularly phonemic fluency, and attention, were impaired. In contrast, the total MoCA score, and memory and orientation subscores did not differ from expected ranges. Disease severity, premorbid condition, pulmonary function tests and hypoxia did not contribute to cognitive performance. Cognitive decline may affect otherwise healthy patients post-COVID, independent of disease severity. Our examination identified abnormalities in executive function, attention, and phonemic fluency. These findings occurred despite normal laboratory tests and imaging findings.

2450

N368

Rodolfo Furlan Damiano, Deusdedit Brandão Neto, João Vitor Ribeiro Oliveira, Jonatas Magalhães Santos, Julia Vallin Rodrigues Alves, Bruno F. Guedes, Ricardo Nitrini, Adriana Ladeira de Araújo, Melaine Oliveira, André R. Brunoni, Richard Louis Voegels, Ricardo Ferreira Bento, Geraldo Busatto, Euripedes Constantino Miguel, Orestes V. Forlenza, Fabio de Rezende Pinna & HCFMUSP COVID-19 study group

Association between chemosensory impairment with neuropsychiatric morbidity in post-acute COVID-19 syndrome: results from a multidisciplinary cohort study

https://doi.org/10.1007/s00406-022-01427-3

Published

28-May-22

Study

https://link.springer.com/article/10.1007/s00406-022-01427-3

Preliminary methodologically limited studies suggested that taste and smell known as chemosensory impairments and neuropsychiatric symptoms are associated in post-COVID-19. The objective of this study is to evaluate whether chemosensory dysfunction and neuropsychiatric impairments in a well-characterized post-COVID-19 sample. This is a cohort study assessing adult patients hospitalized due to moderate or severe forms of COVID-19 between March and August 2020. Baseline information includes several clinical and hospitalization data. Further evaluations were made using several different reliable instruments designed to assess taste and smell functions, parosmia, and neuropsychiatric disorders (using standardized psychiatric and cognitive measures). Out of 1800 eligible individuals, 701 volunteers were assessed on this study. After multivariate analysis, patients reporting parosmia had a worse perception of memory performance (p < 0.001). Moderate/severe hypogeusia was significantly associated with a worse performance on the word list memory task (p = 0.012); Concomitant moderate/severe olfactory and gustatory loss during the acute phase of COVID-19 was also significantly associated with episodic memory impairment (p = 0.006). We found a positive association between reported chemosensory (taste and olfaction) abnormalities and cognition dysfunction in post-COVID-19 patients. These findings may help us identify potential mechanisms linking these two neurobiological functions, and also support the speculation on a possible route through which SARS-CoV-2 may reach the central nervous system.

2451

N369

P. Young

Schlafstörungen und Erschöpfungssyndrom bei Long-COVID-Syndrom: Fallbasierte Erfahrungen aus der neurologischen/schlafmedizinischen Rehabilitation
Sleep disorders and fatigue syndrome in long COVID syndrome: case-based experiences from neurological/sleep medicine rehabilitation

https://doi.org/10.1007/s11818-022-00353-9

Published

30-May-22

Case Series

https://link.springer.com/article/10.1007/s11818-022-00353-9

Schlafstörungen und ein klinisch signifikantes Erschöpfungssyndrom werden für das Long-COVID-Syndrom regelhaft beschrieben. Die pathophysiologischen Zusammenhänge sind weitergehend unbekannt. Die klinische Präsentation ist unterschiedlich und muss individuell betrachtet werden. Anhand von vier Fallbeispielen wird dargestellt, welche Symptome ein Long-COVID-Syndrom ausmachen und welche Therapieoptionen zur Verfügung stehen. Eine multimodale individualisierte Rehabilitation scheint geeignet, Betroffene wieder an die prämorbide Leistungsfähigkeit heranzuführen und eine erhebliche Reduktion von insomnischen Beschwerden zu erreichen.
Abstract
Sleep disturbances and clinically significant fatigue syndrome are regularly described for long COVID syndrome. The pathophysiological correlations remain unknown. The clinical presentation is variable and must be considered individually. Four case studies will be used to illustrate the symptoms that constitute long COVID syndrome and the treatment options available. Multimodal individualized rehabilitation seems to be suitable to return those affected to their premorbid performance and to achieve a considerable reduction in insomniac complaints.

2452

N370

A.MenardM.ChineL.MeddebS.CamilleriE.Guedj

Imagerie TEP au 18FDG et Covid-Long : retour d'expérience en pratique clinique

https://doi.org/10.1016/j.mmifmc.2022.03.031

Published

31-May-22

Article

https://www.sciencedirect.com/science/article/pii/S2772743222000496

Introduction
L'hypothèse d'une atteinte cérébrale associée au COVID long neurologique a été posée dès le mois de mai 2020, sur la base des premières descriptions de cas d'anosmie après infection à la COVID-19 et de travaux précédents sur les autres SARS montrant un possible passage du virus de la sphère ORL vers le cerveau, avec une progression trans-synaptique ultérieure vers les régions cérébrales connectées aux bulbes olfactifs, et en particulier les régions limbiques, le tronc cérébral et le cervelet. Ce profil d'atteinte spécifique a été authentifie chez des patients présentant un COVID long neurologique en évaluant l'hypométabolisme de ces régions en imagerie TEP au 18FDG par plusieurs équipes dans le monde.
Matériels et méthodes
Depuis mai 2020 dans notre centre un suivi standardisé (tous les 3 mois) et pluri disciplinaire est proposé aux patients ayant fait une forme sévère (post hospitalisation) ou ambulatoire mais avec symptômes persistants. Ils sont inclus dans une cohorte de suivi longitudinale avec un recueil à chaque visite des auto questionnaires (qualité de vie :SF36, fatigue :Pichot,dyspnée :MRC,Borg, cognitifs :MoCa, Stress :SSPT) un examen clinique exhaustif, des avis spécialisés avec bilan sanguin et imagerie par TEP selon l'évolution. Nous analysons ici les données des TEP dans notre cohorte à 18 mois.
Résultats
201 patients ont été inclus, 190 analysés dont 55% de femmes, d'âge médian de 55 ans, actif dans 60% des cas (24% domaine santé), 58% avec une comorbidité à risque de forme sévère. L'épisode aigue en ambulatoire pour 85 (42.2%) patients, en hospitalisation conventionnelle pour 76 (37.8%) ou en soins intensif/réanimation pour 40 (20%). Une corticothérapie et une oxygénothérapie ont été prescrite pour respectivement 78 (38.8%) et 114 (56.7%). 49 (24.4%) patients ont décompensé ou découvert (7%) une maladie chronique. En moyenne les patients ont eu 2,6 visites et 48% d'entre eux ont un suivi de plus de 12 mois. A S12 du suivi, 122 patients ont le statut de COVID Long (CL+) avec un nb moyen de symp = 3,6+/-2,2 (1-10) et 68 sont guéris (CL-). 81% des patients CL+ ont bénéficié d'une évaluation par TEP entre 6 et 12 mois post COVID et 70% des TEP cérébraux étaient anormaux (hypo métabolisme compatible avec un profil de COVID-long) contre 14% des TEP corps (hyper métabolisme médullaire, articulaire, splénique). Les patients améliorés avant 3 mois durant le suivi (CL-,n=68) ont bénéficié pour 14 d'entre eux (20%) d'un TEP cerebral qui était anormal dans 7 % des cas. L'analyse multi variée retrouve un lien statistique (<0,05) avec un profil clinique particulier du CL+ sexe féminin, un âge <65 ans une fatigue sévère (Pichot >20) une dyspnee (Borg<3 et MRc<1) et les troubles cognitifs.
Conclusion
L'expérience clinique rapportée au travers de l'analyse de notre cohorte de Covid Long objective un hypo métabolisme cérébrale dans des régions en lien avec la symptomatologie dans 70 % des TEP réalisés. L'hypothèse d'une atteinte cérébrale neuro-inflammatoire par activation microgliale a été posée par plusieurs équipes internationales apres la démonstration d'une inflammation virale de l'épithélium olfactif après infection COVID-19 et d'une activation microgliale sur les séries autopsiques de sujets décédés du COVID-19. L'intérêt du TEP cérébral comme marqueur pronostic d'une évolution chronique et complexe du Covid-Long devra être évalué dans de futures études.

2453

N371

Pablo Andrei Appelt, Angélica Taciana Sisconetto, Kelly Savana Minaré Baldo Sucupira, Eduardo de Moura Neto, Tatiane de Jesus Chagas, Rodrigo Bazan, Ariana Moura Cabral, Adriano de Oliveira Andrade, Luciane Aparecida Pascucci Sande de Souza, Gustavo José Luvizutto

Changes in Electrical Brain Activity and Cognitive Functions Following Mild to Moderate COVID-19: A one-Year Prospective Study After Acute Infection

https://doi.org/10.1177%2F15500594221103834

Published

29-May-22

Study

https://journals.sagepub.com/doi/abs/10.1177/15500594221103834

The coronavirus disease 2019 (COVID-19) can disrupt various brain functions. Over a one-year period, we aimed to assess brain activity and cognitive function in 53 COVID-19 patients and 30 individuals without COVID-19 (or asymptomatic). The Montreal Cognitive Assessment, Trail Making Test Parts A and B (TMT-A and B), and Digit Span Test were used to assess cognitive function. Cognitive variables and electroencephalography (EEG) data (activity, mobility, and complexity) were compared between the groups at rest and during cognitive demand (F3-F7, Fz-F3, Fz-F4, and F4-F8). There was a reduction in F3-F7 activity during the TMT-B in the COVID-19 group at 6-12 months compared to the controls (p = 0.01) at baseline (p = 0.03), a reduction in signal complexity at F3-F7 at rest in the COVID-19 group at baseline and 6-12 months compared to the controls (p < 0.001), and a reduction in Fz-F4 activity at rest from 6-12 months in the post-COVID group compared to baseline (p = 0.02) and 3-6 months (p = 0.04). At 6-12 months, there was a time increase in TMT-A in the COVID-19 group compared to that in the controls (p = 0.04). Some correlations were found between EEG data and cognitive test in both groups. In conclusion, there was a reduction in brain activity at rest in the Fz-F4 areas and during high cognitive demands in the F3-F7 areas. A reduction in signal complexity in F3-F7 at rest was found in the COVID-19 group at 6-12 months after acute infection. Furthermore, individuals with COVID-19 experience long-term changes in cognitive function.

2454

N372

Jonas Jardim de Paula, Rachel E. R. P. Paiva, Nathália Gualberto Souza-Silva, Daniela Valadão Rosa, Fabio Luis de Souza Duran, Roney Santos Coimbra, Danielle de Souza Costa, Pedro Robles Dutenhefner, Henrique Soares Dutra Oliveira, Sarah Teixeira Camargos, Herika Martins Mendes Vasconcelos, Nara de Oliveira Carvalho, Juliana Batista da Silva, Marina Bicalho Silveira, Carlos Malamut, Derick Matheus Oliveira, Luiz Carlos Molinari, Danilo Bretas de Oliveira, José Nélio Januário, Luciana Costa Silva, Luiz Armando De Marco, Dulciene Maria de Magalhaes Queiroz, Wagner Meira, Geraldo Busatto, Débora Marques Miranda & Marco Aurélio Romano-Silva

Selective visuoconstructional impairment following mild COVID-19 with inflammatory and neuroimaging correlation findings

https://doi.org/10.1038/s41380-022-01632-5

Published

14-Jun-22

Study

https://www.nature.com/articles/s41380-022-01632-5

People recovered from COVID-19 may still present complications including respiratory and neurological sequelae. In other viral infections, cognitive impairment occurs due to brain damage or dysfunction caused by vascular lesions and inflammatory processes. Persistent cognitive impairment compromises daily activities and psychosocial adaptation. Some level of neurological and psychiatric consequences were expected and described in severe cases of COVID-19. However, it is debatable whether neuropsychiatric complications are related to COVID-19 or to unfoldings from a severe infection. Nevertheless, the majority of cases recorded worldwide were mild to moderate self-limited illness in non-hospitalized people. Thus, it is important to understand what are the implications of mild COVID-19, which is the largest and understudied pool of COVID-19 cases. We aimed to investigate adults at least four months after recovering from mild COVID-19, which were assessed by neuropsychological, ocular and neurological tests, immune markers assay, and by structural MRI and 18FDG-PET neuroimaging to shed light on putative brain changes and clinical correlations. In approximately one-quarter of mild-COVID-19 individuals, we detected a specific visuoconstructive deficit, which was associated with changes in molecular and structural brain imaging, and correlated with upregulation of peripheral immune markers. Our findings provide evidence of neuroinflammatory burden causing cognitive deficit, in an already large and growing fraction of the world population. While living with a multitude of mild COVID-19 cases, action is required for a more comprehensive assessment and follow-up of the cognitive impairment, allowing to better understand symptom persistence and the necessity of rehabilitation of the affected individuals.

2455

N373

COA

Anthony Fernández-Castañeda ∗Peiwen Lu ∗ Anna C. Geraghty ∗Eric Song ∗Myoung-Hwa Lee Jamie Wood Michael R. O’Dea Selena Dutton Kiarash Shamardani Kamsi Nwangwu Rebecca Mancusi Belgin Yalçın Kathryn R. Taylor Lehi Acosta-Alvarez Karen Malacon Michael B. Keough Lijun Ni Pamelyn J. Woo Daniel Contreras-Esquivel Angus Martin Shaw Toland Jeff R. Gehlhausen Jon Klein Takehiro Takahashi Julio Silva Benjamin Israelow Carolina Lucas Tianyang Mao Mario A. Peña-Hernández Alexandra Tabachnikova Robert J. Homer Laura Tabacof Jenna Tosto-Mancuso Erica Breyman Amy Kontorovich Dayna McCarthy Martha Quezado Hannes Vogel Marco M. Hefti Daniel P. Perl Shane Liddelow Rebecca Folkerth David Putrino Avindra Nath Akiko Iwasaki Michelle Monje

Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation

https://doi.org/10.1016/j.cell.2022.06.008

Published

12-Jun-22

Study

https://www.cell.com/cell/fulltext/S0092-8674(22)00713-9

COVID survivors frequently experience lingering neurological symptoms that resemble cancer therapy-related cognitive impairment, a syndrome for which white-matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared to SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis and elevated CCL11 at early timepoints, but after influenza only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.

2456

N374

MargheritaBertuccelliab1LucianaCiringionea1MariaRubegaaPatriziaBisiacchibcStefanoMasieroabAlessandraDel Feliceab

Cognitive impairment in people with previous COVID-19 infection: a scoping review

https://doi.org/10.1016/j.cortex.2022.06.002

Published

11-Jun-22

Review

https://www.sciencedirect.com/science/article/pii/S0010945222001691

Highlights
•Long-term cognitive COVID-19 sequelae are a growing public-health issue.
•Memory, attention, and executive functions appeared to be the most affected domains.
•Anxiety, depression, and PTSD are observed just in the non-ICU hospitalized group.
•Larger cohorts and comprehensive neuropsychological batteries are required.
Severe acute respiratory syndrome coronavirus 2 is a worldwide public health issue. Almost 2 years into the pandemic, the persistence of symptoms after the acute phase is a well-recognized phenomenon.
We conducted a scoping review to map cognitive domain impairments, their frequency, and associated psycho-affective disorders in people with a previous COVID-19 infection. We searched PubMed/MEDLINE, Scopus, and PsycInfo to identify relevant reports published between December 1, 2019 and February 21, 2022. We followed the Preferred-Reporting-Items-for-Systematic-Reviews-and-Meta-Analyses extension for scoping review guidelines.
Three independent reviewers selected and charted 25 records out of 922. Memory, attention, and executive functions appeared to be the most affected domains. Delayed recall and learning were the most impaired domains of memory. Among the executive functions, abstraction, inhibition, set shifting, and sustained and selective attention were most commonly impaired. Language and visuo-spatial abilities were rarely affected, although this finding might be biased by the scarcity of reports. Neurological and respiratory conditions were often reported in association with cognitive deficits. Results on psycho-affective conditions were inconclusive due to the low frequency of reported data. Admission to an intensive care unit is not related to cognitive deficits.
This review highlighted a potential effect of a previous post-COVID-19 infection on a pattern of memory, attention, and executive functions impairments. These findings need to be confirmed on larger cohorts with comprehensive neuropsychological batteries and correlated to neurophysiological and neurobiological substrates.

2457

N375

Mirren Charnley, Saba Islam, Guneet K. Bindra, Jeremy Engwirda, Julian Ratcliffe, Jiangtao Zhou, Raffaele Mezzenga, Mark D. Hulett, Kyunghoon Han, Joshua T. Berryman & Nicholas P. Reynolds

Neurotoxic amyloidogenic peptides in the proteome of SARS-COV2: potential implications for neurological symptoms in COVID-19

https://doi.org/10.1038/s41467-022-30932-1

Published

13-Jun-22

Study

https://www.nature.com/articles/s41467-022-30932-1

COVID-19 is primarily known as a respiratory disease caused by SARS-CoV-2. However, neurological symptoms such as memory loss, sensory confusion, severe headaches, and even stroke are reported in up to 30% of cases and can persist even after the infection is over (long COVID). These neurological symptoms are thought to be produced by the virus infecting the central nervous system, however we don’t understand the molecular mechanisms triggering them. The neurological effects of COVID-19 share similarities to neurodegenerative diseases in which the presence of cytotoxic aggregated amyloid protein or peptides is a common feature. Following the hypothesis that some neurological symptoms of COVID-19 may also follow an amyloid etiology we identified two peptides from the SARS-CoV-2 proteome that self-assemble into amyloid assemblies. Furthermore, these amyloids were shown to be highly toxic to neuronal cells. We suggest that cytotoxic aggregates of SARS-CoV-2 proteins may trigger neurological symptoms in COVID-19.

2458

N376

MargheritaBertuccelliab1LucianaCiringionea1MariaRubegaaPatriziaBisiacchibcStefanoMasieroabAlessandraDel Feliceab

Cognitive impairment in people with previous COVID-19 infection: a scoping review

https://doi.org/10.1016/j.cortex.2022.06.002

Published

11-Jun-22

Review

https://www.sciencedirect.com/science/article/pii/S0010945222001691

Highlights
•Long-term cognitive COVID-19 sequelae are a growing public-health issue.
•Memory, attention, and executive functions appeared to be the most affected domains.
•Anxiety, depression, and PTSD are observed just in the non-ICU hospitalized group.
•Larger cohorts and comprehensive neuropsychological batteries are required.
Severe acute respiratory syndrome coronavirus 2 is a worldwide public health issue. Almost 2 years into the pandemic, the persistence of symptoms after the acute phase is a well-recognized phenomenon.
We conducted a scoping review to map cognitive domain impairments, their frequency, and associated psycho-affective disorders in people with a previous COVID-19 infection. We searched PubMed/MEDLINE, Scopus, and PsycInfo to identify relevant reports published between December 1, 2019 and February 21, 2022. We followed the Preferred-Reporting-Items-for-Systematic-Reviews-and-Meta-Analyses extension for scoping review guidelines.
Three independent reviewers selected and charted 25 records out of 922. Memory, attention, and executive functions appeared to be the most affected domains. Delayed recall and learning were the most impaired domains of memory. Among the executive functions, abstraction, inhibition, set shifting, and sustained and selective attention were most commonly impaired. Language and visuo-spatial abilities were rarely affected, although this finding might be biased by the scarcity of reports. Neurological and respiratory conditions were often reported in association with cognitive deficits. Results on psycho-affective conditions were inconclusive due to the low frequency of reported data. Admission to an intensive care unit is not related to cognitive deficits.
This review highlighted a potential effect of a previous post-COVID-19 infection on a pattern of memory, attention, and executive functions impairments. These findings need to be confirmed on larger cohorts with comprehensive neuropsychological batteries and correlated to neurophysiological and neurobiological substrates.

2459

N377

Sarah E.ConwayaBrian C.HealybJonathanZurawskiaChristopherSeversonaTamaraKaplanaLynnStazzoneaKristinGalettaaTanujaChitnisaMaria K.Houtchensa

COVID-19 severity is associated with worsened neurological outcomes in multiple sclerosis and related disorders

https://doi.org/10.1016/j.msard.2022.103946

Published

13-Jun-22

Study

https://www.sciencedirect.com/science/article/pii/S2211034822004576

Highlights
•We report on 111 patients with MS and related disorders (MSRD) with COVID-19.
•36.9% of MSRD patients had neurologic worsening after COVID-19.
•Neurologic worsening was associated with hospitalization for COVID-19.
•Neurologic worsening was not associated with age, sex, EDSS, race or disease type.
Background
Neurologic outcomes in patients with multiple sclerosis (MS) and related disorders (MSRD) following COVID-19 is not well understood. The objective of this study was to investigate neurologic outcomes in patients with MSRD post-COVID-19.
Methods
This was a retrospective medical records review study of adult patients with MSRD and COVID-19 infection at the Brigham MS Center. Neurologic worsening post-COVID-19 was defined as having a relapse, pseudorelapse, new brain MRI activity, worsening of preexisting MSRD symptoms, or development of other long-term neurologic symptoms.
Results
111 patients, 85 (76.6%) females, with a mean [SD] age of 49.3 [12.2] years and median [range] EDSS of 2.5 [0, 8.5] were identified. 41 patients (36.9%) had neurologic worsening post-COVID-19. Of those, 19 (46.3%) had pseudorelapses, 2 (4.8%) had relapses, and 24 (58.5%) patients reported worsening of preexisting MSRD symptoms, or other new long-term neurologic symptoms. Neurologic worsening was associated with hospitalized (moderate or severe) COVID-19 (p = 0.001), treatment for COVID-19 (p = 0.006), and incomplete COVID-19 recovery (p = 0.0267) but not with age, sex, MS type, race, disease duration, EDSS, vitamin D use, or disease modifying therapy use.
Conclusions
COVID-19 severity and lack of complete systemic recovery were associated with new or worsening neurologic symptoms in 36.9% of MSRD patients.

2460

N378

César Fernández-de-las-Peñas, Umut Varol, Víctor Gómez-Mayordomo, María L. Cuadrado & Juan Antonio Valera-Calero

The relevance of headache as an onset symptom in COVID-19: a network analysis of data from the LONG-COVID-EXP-CM multicentre study

https://doi.org/10.1007/s13760-022-01998-x

Published

7-Jun-22

Letter to the Editor

https://link.springer.com/article/10.1007/s13760-022-01998-x

The application of network analysis in a large population of COVID-19 survivors from five different hospitals supports the relevance of headache as an onset symptom at the acute COVID-19 phase, in agreement with previous studies. The SARS-CoV-2 virus exhibits neurotropic properties leading to an invasion of the central nervous system through potential direct mechanisms (e.g., haematogenous dissemination or neuronal retrograde dissemination) or others. These mechanisms could activate the trigeminal nerve pathways, contributing to the development of headache and anosmia. Monitoring headache at the acute phase may alert clinicians of an early potential invasion of the central nervous system or of a systemic inflammatory response caused by the SARS-CoV-2 virus. The better prognosis of patients reporting headache during the acute COVID-19 phase could be also linked to a stronger immune response against the SARS-CoV-2 virus.
Although this is the largest multicentre cohort study focusing on headache as a COVID-19-onset symptom using a network analysis, it should be considered that we only included hospitalised COVID-19 survivors, and we did not characterise the semiological features of headache as an onset symptom.
In conclusion, this multicentre study using a network analysis in a large population of COVID-19 survivors supports the relevance of headache as a key onset symptom at the acute COVID-19 phase.

2461

N379

Lise Lamoureux 1,†,Babu Sajesh 1,†,Jessy A. Slota 1,2,†ORCID,Sarah J. Medina 1,Matthew Mayor 1,Kathy L. Frost 1,Bryce Warner 3,Kathy Manguiat 1,Heidi Wood 1,Darwyn Kobasa 2,3ORCID andStephanie A. Booth 1,2,*

Non-Productive Infection of Glial Cells with SARS-CoV-2 in Hamster Organotypic Cerebellar Slice Cultures

https://doi.org/10.3390/v14061218

Published

3-Jun-22

Study

https://www.mdpi.com/1999-4915/14/6/1218/htm

The numerous neurological syndromes associated with COVID-19 implicate an effect of viral pathogenesis on neuronal function, yet reports of direct SARS-CoV-2 infection in the brain are conflicting. We used a well-established organotypic brain slice culture to determine the permissivity of hamster brain tissues to SARS-CoV-2 infection. We found levels of live virus waned after inoculation and observed no evidence of cell-to-cell spread, indicating that SARS-CoV-2 infection was non-productive. Nonetheless, we identified a small number of infected cells with glial phenotypes; however, no evidence of viral infection or replication was observed in neurons. Our data corroborate several clinical studies that have assessed patients with COVID-19 and their association with neurological involvement.
In summary, we find that a small population of glial cells in hamster cerebellar sections were permissive for SARS-CoV-2, although infection was non-productive even in the absence of a BBB. We speculate that in severe disease, a disrupted BBB could lead to localized infection of glia and may explain the findings of a small number of studies in which viral proteins and RNA have been detected in brain tissue of patients and animals. However, the paucity of SARS-CoV-2 infection observed here aligns more closely with other reports that failed to identify evidence of neuroinvasion. Evidence from experimental models remains inconclusive, and careful examination of clinical cases will undoubtedly be required to shed further light on the troubling long-term neurological manifestations associated with COVID-19.

2462

N380

Rosalia Dacosta-Aguayo 1,2,3,Noemí Lamonja-Vicente 1,4ORCID,Carla Chacón 1,4,Lucia Amalía Carrasco-Ribelles 1ORCID,Pilar Montero-Alia 1,4,5,6,Anna Costa-Garrido 1,Rosa García-Sierra 1,5,7ORCID,Victor M. López-Lifante 1,4,8ORCID,Eduard Moreno-Gabriel 1,4,5,9ORCID,Marta Massanella 10,11,12ORCID,Josep Puig 2ORCID,Jose A. Muñoz-Moreno 13,14,Lourdes Mateu 10,11,12,13,15ORCID,Anna Prats 13,Carmina Rodríguez 1,4,5,16,Maria Mataró 3ORCID,Julia G. Prado 10,11,17ORCID,Eva Martínez-Cáceres 18,19,20,Concepción Violán 1,4,17,21,* andPere Torán-Monserrat

Neurocognitive Profile of the Post-COVID Condition in Adults in Catalonia—A Mixed Method Prospective Cohort and Nested Case–Control Study: Study Protocol

https://doi.org/10.3390/vaccines10060849

Published

26-May-22

Study Protocol

https://www.mdpi.com/2076-393X/10/6/849/htm

The diagnosis of the post-COVID condition is usually achieved by excluding other diseases; however, cognitive changes are often found in the post-COVID disorder. Therefore, monitoring and treating the recovery from the post-COVID condition is necessary to establish biomarkers to guide the diagnosis of symptoms, including cognitive impairment. Our study employs a prospected cohort and nested case–control design with mixed methods, including statistical analyses, interviews, and focus groups. Our main aim is to identify biomarkers (functional and structural neural changes, inflammatory and immune status, vascular and vestibular signs and symptoms) easily applied in primary care to detect cognitive changes in post-COVID cases. The results will open up a new line of research to inform diagnostic and therapeutic decisions with special considerations for cognitive impairment in the post-COVID condition.

2463

N381

CPET

David A. HoldsworthID
1,2,3*, Rebecca Chamley2,4, Rob Barker-Davies5,6,
Oliver O’SullivanID
5, Peter Ladlow5,7, James L. Mitchell5,8, Dominic Dewson5,
Daniel Mills5, Samantha L. J. May5, Mark Cranley9, Cheng Xie3, Edward Sellon3,9,
Joseph Mulae1, Jon Naylor1, Betty Raman4, Nick P. Talbot3,10, Oliver J. Rider4, Alexander
N. Bennett5,11, Edward D. Nicol

Comprehensive clinical assessment identifies specific neurocognitive deficits in working-age patients with long-COVID

https://doi.org/10.1371/journal.pone.0267392

Published

10-Jun-22

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0267392

Introduction
There have been more than 425 million COVID-19 infections worldwide. Post-COVID illness has become a common, disabling complication of this infection. Therefore, it presents a significant challenge to global public health and economic activity.
Methods
Comprehensive clinical assessment (symptoms, WHO performance status, cognitive testing, CPET, lung function, high-resolution CT chest, CT pulmonary angiogram and cardiac MRI) of previously well, working-age adults in full-time employment was conducted to identify physical and neurocognitive deficits in those with severe or prolonged COVID-19 illness.
Results
205 consecutive patients, age 39 (IQR30.0–46.7) years, 84% male, were assessed 24 (IQR17.1–34.0) weeks after acute illness. 69% reported ≥3 ongoing symptoms. Shortness of breath (61%), fatigue (54%) and cognitive problems (47%) were the most frequent symptoms, 17% met criteria for anxiety and 24% depression. 67% remained below pre-COVID performance status at 24 weeks. One third of lung function tests were abnormal, (reduced lung volume and transfer factor, and obstructive spirometry). HRCT lung was clinically indicated in <50% of patients, with COVID-associated pathology found in 25% of these. In all but three HRCTs, changes were graded ‘mild’. There was an extremely low incidence of pulmonary thromboembolic disease or significant cardiac pathology. A specific, focal cognitive deficit was identified in those with ongoing symptoms of fatigue, poor concentration, poor memory, low mood, and anxiety. This was notably more common in patients managed in the community during their acute illness.
Conclusion
Despite low rates of residual cardiopulmonary pathology, in this cohort, with low rates of premorbid illness, there is a high burden of symptoms and failure to regain pre-COVID performance 6-months after acute illness. Cognitive assessment identified a specific deficit of the same magnitude as intoxication at the UK drink driving limit or the deterioration expected with 10 years ageing, which appears to contribute significantly to the symptomatology of long-COVID.

2464

N382

Stefano GiuseppeGrisantiaSaraGarbarinobEmanuelaBarisionecTeresitaAloècMarcoGrossocCristinaSchenoneaMatteoPardiniacEricaBiassoniaFedericoZaottinicRiccardoPicassocSilviaMorbellicCristinaCampidbGiampaolaPescecFedericoMassaaNicolaGirtleracDeniseBattaglinieCorradoCabonacMatteoBassetticAntonioUccelliacAngeloSchenoneacMichelePianadbLuanaBenedettic

Neurological long-COVID in the outpatient clinic: Two subtypes, two courses

https://doi.org/10.1016/j.jns.2022.120315

Published

3-Jun-22

Study

https://www.sciencedirect.com/science/article/pii/S0022510X22001770

Highlights
•Neurological involvement related to COVID-19 can manifest itself both in the acute phase of infection or during long-COVID.
•Neurological symptoms due to SARS-CoV-2 infection can involve both the central and the peripheral nervous system.
•Neurological symptoms during COVID-19 may be related to virus-induced injury or iatrogenic injury during hospitalization.
•Depending on the severity of SARS-CoV-2 infection, different neurological disorders may develop.
Introduction
Symptoms referable to central and peripheral nervous system involvement are often evident both during the acute phase of COVID-19 infection and during long-COVID. In this study, we evaluated a population of patients with prior COVID-19 infection who showed signs and symptoms consistent with neurological long-COVID.
Methods
We prospectively collected demographic and acute phase course data from patients with prior COVID-19 infection who showed symptoms related to neurological involvement in the long-COVID phase. Firstly, we performed a multivariate logistic linear regression analysis to investigate the impact of demographic and clinical data, the severity of the acute COVID-19 infection and hospitalization course, on the post-COVID neurological symptoms at three months follow-up. Secondly, we performed an unsupervised clustering analysis to investigate whether there was evidence of different subtypes of neurological long COVID-19.
Results
One hundred and nine patients referred to the neurological post-COVID outpatient clinic. Clustering analysis on the most common neurological symptoms returned two well-separated and well-balanced clusters: long-COVID type 1 contains the subjects with memory disturbances, psychological impairment, headache, anosmia and ageusia, while long-COVID type 2 contains all the subjects with reported symptoms related to PNS involvement. The analysis of potential risk-factors among the demographic, clinical presentation, COVID 19 severity and hospitalization course variables showed that the number of comorbidities at onset, the BMI, the number of COVID-19 symptoms, the number of non-neurological complications and a more severe course of the acute infection were all, on average, higher for the cluster of subjects with reported symptoms related to PNS involvement.
Conclusion
We analyzed the characteristics of neurological long-COVID and presented a method to identify well-defined patient groups with distinct symptoms and risk factors. The proposed method could potentially enable treatment deployment by identifying the optimal interventions and services for well-defined patient groups, so alleviating long-COVID and easing recovery.

2465

N383

Julie Fiorentino 1,2,*ORCID,Magali Payne 1,2,Elisa Cancian 3,Alexandra Plonka 1,2,4,Louise-Émilie Dumas 2,5,David Chirio 6,Élisa Demonchy 6,Karine Risso 6,Florence Askenazy-Gittard 2,5,Nicolas Guevara 4ORCID,Laurent Castillo 4,Philippe Robert 1,2,Valeria Manera 1,2,Clair Vandersteen 2,3ORCID andAuriane Gros 1,2

Correlations between Persistent Olfactory and Semantic Memory Disorders after SARS-CoV-2 Infection

https://doi.org/10.3390/brainsci12060714

Published

31-May-22

Study

https://www.mdpi.com/2076-3425/12/6/714/htm

Background: One of the main symptoms of COVID-19 is hyposmia or even anosmia. Olfactory identification is most often affected. In addition, some cognitive disorders tend to appear following the infection, particularly regarding executive functions, attention, and memory. Olfaction, and especially olfactory identification, is related to semantic memory which manages general knowledge about the world. The main objective of this study was to determine whether semantic memory is impaired in case of persistent post COVID-19 olfactory disorders. Methods: 84 patients (average age of 42.8 ± 13.6 years) with post COVID-19 olfactory loss were included after consulting to the ENT department. The clinical evaluation was carried out with the Pyramid and Palm Tree Test, the word-retrieval task from the Grémots, the Sniffin’ Sticks Test and the Computerised Olfactory Test for the Diagnosis of Alzheimer’s Disease. Results: Semantic memory was impaired in 20% (n = 17) of patients, especially in the 19–39 age-group. The olfactory threshold was only significantly correlated with the semantic memory scores. Conclusions: Similar to all cognitive disorders, semantic disorders can have a negative impact on quality of life if left untreated. It is essential to carry out specific assessments of post COVID-19 patients to accurately determine their disorders and to put in place the best possible rehabilitation, such as speech and language therapy, to avoid quality-of-life impairment.

2466

N384

Virginia Fancello 1,*,†ORCID,Giuseppe Fancello 2,†,Stavros Hatzopoulos 1ORCID,Chiara Bianchini 1,Francesco Stomeo 1,Stefano Pelucchi 1 andAndrea Ciorba 1ORCID

Sensorineural Hearing Loss Post-COVID-19 Infection: An Update

https://doi.org/10.3390/audiolres12030032

Published

1-Jun-22

Review

https://www.mdpi.com/2039-4349/12/3/32/htm

The course of COVID-19 infection may be complicated by a variety of neurological manifestations. Since the inner ear is vulnerable to viruses, sensorineural hearing loss (SNHL) has been reported to occur following the SARS-CoV-2 infection, often resulting in long-term morbidity and worsening the quality of life. The interest in how the virus affects the inner ear has gradually increased since the pandemic’s spread, but little is still known about the SNHL potentially caused by SARS-CoV-2. The aim of this paper is to evaluate the possible association between SNHL and COVID-19 infection, through a systematic literature review. Currently available data suggest that SARS-CoV-2 may hamper cochlear function; however, available reports are still limited. Large cohort and prospective studies are necessary to evaluate the long-term effects of this viral infection in the inner ear.

2467

N385

Lucette A. Cysique, View ORCID ProfileDavid Jakabek, Sophia G. Bracken, Yasmin Allen-Davidian, View ORCID ProfileBenjamin Heng, View ORCID ProfileSharron Chow, Mona Dehhaghi, Ananda Staats Pires, View ORCID ProfileDavid R. Darley, View ORCID ProfileAnthony Byrne, View ORCID ProfileChansavath Phetsouphanh, View ORCID ProfileAnthony Kelleher, View ORCID ProfileGregory J. Dore, View ORCID ProfileGail V. Matthews, View ORCID ProfileGilles J Guillemin, View ORCID ProfileBruce J. Brew

Post-acute COVID-19 cognitive impairment and decline uniquely associate with kynurenine pathway activation: a longitudinal observational study

https://doi.org/10.1101/2022.06.07.22276020

pre-print

7-Jun-22

Study

https://www.medrxiv.org/content/10.1101/2022.06.07.22276020v1.full-text

Cognitive impairment and function post-acute mild to moderate COVID-19 are poorly understood. We report findings of 128 prospectively studied SARS-CoV-2 positive patients. Cognition and olfaction were assessed at 2-, 4- and 12-months post-diagnosis. Lung function, physical and mental health were assessed at 2-month post diagnosis. Blood cytokines, neuro-biomarkers, and kynurenine pathway (KP) metabolites were measured at 2-, 4-, 8- and 12- months. Mild to moderate cognitive impairment (demographically corrected) was present in 16%, 23%, and 26%, at 2-, 4- and 12-months post diagnosis, respectively. Overall cognitive performance mildly, but significantly (p<.001) declined. Cognitive impairment was more common in those with anosmia (p=.05), but only at 2 months. KP metabolites quinolinic acid, 3-hydroxyanthranilic acid, and kynurenine were significantly (p<.001) associated with cognitive decline. The KP as a unique biomarker offers a potential therapeutic target for COVID-19-related cognitive impairment.
There is evidence that SARS CoV-2 is associated with objectively tested cognitive impairment (CI) post-acute illness1–3 (see Table S1) but the extent, trajectory, and the nature of this new condition is unclear. Acute COVID-19 disease severity with its attendant complications is a major differential factor in the nature and extent of cognitive deficits4. Severe cases (cases that require hospitalization) are at risk for both indirect and direct mechanisms of COVID-19 associated brain damage, particularly from hypoxia5, 6, stroke, as well as the immune and inflammatory response to SARS-CoV-21. Mild to moderate cases of COVID-19 (not requiring hospitalization) are still at risk of brain dysfunction, and cognitive deficits7, 8. Such cases provide a window into the potential mechanisms of brain injury without the confounding role of severe disease and its complications9–11. As most patients with SARS-CoV-2 virus do not require hospitalization, cognitive decline associated with mild to moderate COVID-19 disease would have significant implications for public health given the current global prevalence of the infection.
There are several challenges in addressing the pathogenesis of post-acute COVID-19 CI. First, there is the accurate identification and quantitation of medical co-morbidities particularly pre-morbid psychiatric conditions and illness-associated psychological distress12. Second, appropriate correction for normative demographic effects are imperative to accurately and specifically determine if cognitive deficits are present and to quantify their severity13. Many existing cognitive studies of COVID-19 that used objective testing14 (Table S1) have not appropriately controlled for demographics, mental health, and comorbid medical conditions. This lack of adjustment probably explains some of the large variance in the observed prevalence of CI. In addition, the previous literature on cognition in recovering COVID-19 patients has focused on patients who were hospitalized with severe acute COVID-19 disease (Table S1). Such patients can show extensive neuropsychological impairment (up to 87%) including focal insults due to stroke3, although improvement is detected in about half of this population at 12-months3. Furthermore, most cognitive studies are cross-sectional, and often have relatively small sample sizes (Table S1). Finally, studies have tended to consider olfaction and cognition separately and olfaction, in most instances, has been tested subjectively rather than objectively15.
To address these limitations, the current study implements a rigorous neuropsychological framework as advocated via the International Neuropsychology COVID-19 taskforce16 where consideration of disease severity, demographics, mental health, objectively tested olfaction, and co-morbidities is conducted a priori. Furthermore, a longitudinal study design is used because COVID-19 can have lasting effects and post-acute CI are, by definition, time-based processes. The definition of cognitive performance over time is optimized by including the initial visit overall cognitive performance, and practice effect17, 18. Lack of correction for these factors in cognitive studies leads to biased estimation of cognitive change17–19.
Using this robust neuropsychological basis, our aim was to elucidate the pathogenesis of COVID-19 associated CI by selecting a range of blood cytokines (Interferons (IFNs), major Interleukins, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α), peripheral biomarkers of brain injury and metabolic products. The selection of the biomarkers is founded on previous immunological findings in the same cohort, where persistently elevated IFNs (i.e., elevated expression of type I IFN (IFN-β) and type III IFN (IFN-λ1)) was associated with chest pain, and dyspnea20 up to 8-month post diagnosis. Next, we elected to test the components of the plasma kynurenine pathway (KP)21, 22 which is an IFN23, 24 stimulated myeloid cell mediated tryptophan degradation pathway important in immune tolerance, neurotoxicity, and vascular injury. The KP is dysregulated in COVID-19 infection25 including in mild cases26, although sex may have a moderating effect27. The peripheral biomarkers of brain injury have been selected because of their detectability in peripheral blood, their ability to facilitate understanding of major neurobiological mechanisms (e.g., neuro-axonal with Neurofilament Light Chain (NFL); astrogliosis with Glial fibrillary acidic protein (GFAP); blood brain barrier permeability (BBB), brain injury and astrocytosis with S100β; macrophage and granulocyte proliferation with Granulocyte macrophage colony-stimulating factor (GMCSF)), and because each is abnormally elevated in COVID-19 infection (NFL28; GFAP29; S100β30; GMCSF31).
The aims of the current study were to determine the prevalence of CI and the trajectories of overall cognitive performance (both corrected for age, education, and sex) in COVID-19 cases recovering from mostly mild-moderate acute infection across a 12-month period. This is achieved by using the widely recognized Cogstate computerized battery that is ideal for serial repeating testing. Furthermore, we aimed to elucidate the pathogenesis of the observed cognitive changes. Moreover, the clinical significance of CI was assessed against functional status. The pathogenic axes assessed included systemic disease severity (and indirectly hypoxia), lung function, objectively tested olfaction, pre-existing and illness-associated anxiety and depression, medical comorbidities, initial visit CI, blood cytokines, the KP and peripheral biomarkers of brain injury. Time-variant predictors (all biomarkers but IFN-β IFN-λ1, olfaction) were tested for their main and time association with overall cognitive performance. The KP was also tested for its trajectory and its dynamic links to other biomarkers.
Despite the exploratory angle of our study, we expected to detect a level of mild cognitive impairment, but without evidence of severe cognitive deficits or rapid deterioration based on previous studies in similar COVID-19 cases. We hypothesized that systemic disease severity, lung function, objectively tested olfaction, pre-existing and illness-associated anxiety and depression, initial visit CI, IFN-β, Quinolinic Acid as well as involvement of peripheral biomarkers of brain injury would show some level of association with cognitive decline.

2468

N386

Erika Cecon, Daniela Fernandois, Nicolas Renault, Caio Fernando Ferreira Coelho, Jan Wenzel, Corentin Bedart, Charlotte Izabelle, Sarah Gallet, Sophie Le Poder, Bernard Klonjkowski, Markus Schwaninger, Vincent Prevot, Julie Dam & Ralf Jockers

Melatonin drugs inhibit SARS-CoV-2 entry into the brain and virus-induced damage of cerebral small vessels

https://doi.org/10.1007/s00018-022-04390-3

Published

13-Jun-22

Study

https://link.springer.com/article/10.1007/s00018-022-04390-3

COVID-19 is a complex disease with short- and long-term respiratory, inflammatory and neurological symptoms that are triggered by the infection with SARS-CoV-2. Invasion of the brain by SARS-CoV-2 has been observed in humans and is postulated to be involved in post-COVID state. Brain infection is particularly pronounced in the K18-hACE2 mouse model of COVID-19. Prevention of brain infection in the acute phase of the disease might thus be of therapeutic relevance to prevent long-lasting symptoms of COVID-19. We previously showed that melatonin or two prescribed structural analogs, agomelatine and ramelteon delay the onset of severe clinical symptoms and improve survival of SARS-CoV-2-infected K18-hACE2 mice. Here, we show that treatment of K18-hACE2 mice with melatonin and two melatonin-derived marketed drugs, agomelatine and ramelteon, prevents SARS-CoV-2 entry in the brain, thereby reducing virus-induced damage of small cerebral vessels, immune cell infiltration and brain inflammation. Molecular modeling analyses complemented by experimental studies in cells showed that SARS-CoV-2 entry in endothelial cells is prevented by melatonin binding to an allosteric-binding site on human angiotensin-converting enzyme 2 (ACE2), thus interfering with ACE2 function as an entry receptor for SARS-CoV-2. Our findings open new perspectives for the repurposing of melatonergic drugs and its clinically used analogs in the prevention of brain infection by SARS-CoV-2 and COVID-19-related long-term neurological symptoms.

Selon une étude très prometteuse sur l'animal (souris avec certains gènes humanisés), la mélatonine possède un fort potentiel pour bloquer l'entrée du SARS-CoV-2 au niveau du système nerveux central. À des doses de quelques dizaines de mg par kg, la mélatonine abaisse la charge virale dans le cerveau, et prévient l'infection cérébrale dans la phase aiguë de la maladie, réduisant ainsi les dommages induits par le virus aux petits vaisseaux cérébraux, l'infiltration des cellules immunitaires et l'inflammation cérébrale. La même équipe avait déjà établi que la mélatonine retarde sur le modèle animal l'apparition de symptômes cliniques graves et améliorent la survie.
Selon les auteurs, cette découverte ouvre de nouvelles perspectives pour la réutilisation des médicaments mélatoninergiques et de ses analogues utilisés en clinique dans la prévention de l'infection cérébrale par le SRAS-CoV-2 et les symptômes neurologiques à long terme liés à la covid.

2469

N387

Fabricia L. Fontes-Dantas, Gabriel G. Fernandes, Elisa G. Gutman, Emanuelle V. De Lima, Leticia S. Antonio, Mariana B. Hammerle, Hannah P. Mota-Araujo, Lilian C. Colodeti, Suzana M. B. Araújo, Talita N. da Silva, Larissa A. Duarte, Andreza L. Salvio, Karina L. Pires, Luciane A. A. Leon, Claudia Cristina F. Vasconcelos, Luciana Romão, View ORCID ProfileLuiz Eduardo B. Savio, Jerson L. Silva, Robson da Costa, Julia R. Clarke, Andrea T. Da Poian, View ORCID ProfileSoniza V. Alves-Leon, Giselle F. Passos, Claudia P. Figueiredo

SARS-CoV-2 spike protein induces TLR-4-mediated long-term cognitive dysfunction recapitulating post-COVID syndrome

https://doi.org/10.1101/2022.06.07.495149

pre-print

10-Jun-22

Study

https://www.biorxiv.org/content/10.1101/2022.06.07.495149v2.full

Cognitive dysfunction is often reported in post-COVID patients, but its underlying mechanisms remain unknown. While some evidence indicate that SARS-CoV-2 can reach and directly impact the brain, others suggest viral neuroinvasion as a rare event. Independently of brain viral infection, the ability of SARS-CoV-2 spike (S) protein to cross the BBB and reach memory-related brain regions has already been shown. Here, we demonstrate that brain infusion of S protein in mice induces late cognitive impairment and increases serum levels of neurofilament light chain (NFL), which recapitulates post-COVID features. Neuroinflammation, hippocampal microgliosis and synapse loss are induced by S protein. Increased engulfment of hippocampal presynaptic terminals late after S protein brain infusion were found to temporally correlate with cognitive deficit in mice. Blockage of TLR4 signaling prevented S-associated detrimental effects on synapse and memory loss. In a cohort of 86 patients recovered from mild COVID-19, genotype GG TLR4 -2604G>A (rs10759931) was associated with poor cognitive outcome. Collectively, these findings indicate that S protein directly impacts the brain and suggest that TLR4 is a potential target to prevent post-COVID cognitive dysfunction.

One Sentence Summary TLR4 mediates long-term cognitive impairment in mice and its genetic variant increases the risk of poor cognitive outcome in post-COVID patients.

2470

N388

MariaRubegaaLucianaCiringioneaMargheritaBertuccelliabMatildeParamentocGiovanniSparacinocAndreaVianellodStefanoMasieroabAntoninoVallesiabEmanuelaFormaggioabAlessandraDel Feliceab

High-density EEG sleep correlates of cognitive and affective impairment at 12-month follow-up after COVID-19

https://doi.org/10.1016/j.clinph.2022.05.017

Published

25-Jun-22

Study

https://www.sciencedirect.com/science/article/pii/S1388245722002942

Highlights
•Sleep spindles may be a biomarker of psycho-affective symptoms in long COVID-19.
•Survivors perceive a decreased quality of life and post-traumatic stress symptoms .
•Post-traumatic stress symptoms may crucially contribute to cognitive impairment.
Abstract
Objective
To disentangle the pathophysiology of cognitive/affective impairment in Coronavirus Disease-2019 (COVID-19), we studied long-term cognitive and affective sequelae and sleep high-density electroencephalography (EEG) at 12-month follow-up in people with a previous hospital admission for acute COVID-19.
Methods
People discharged from an intensive care unit (ICU) and a sub-intensive ward (nonICU) between March and May 2020 were contacted between March and June 2021. Participants underwent cognitive, psychological, and sleep assessment. High-density EEG recording was acquired during a nap. Slow and fast spindles density/amplitude/frequency and source reconstruction in brain gray matter were extracted. The relationship between psychological and cognitive findings was explored with Pearson correlation.
Results
We enrolled 33 participants ( 17 nonICU) and 12 controls. We observed a lower Physical Quality of Life index, higher post-traumatic stress disorder (PTSD) score, and a worse executive function performance in nonICU participants. Higher PTSD and Beck Depression Inventory scores correlated with lower executive performance. The same group showed a reorganization of spindle cortical generators.
Conclusions
Our results show executive and psycho-affective deficits and spindle alterations in COVID-19 survivors – especially in nonICU participants – after 12 months from discharge.
Significance
These findings may be suggestive of a crucial contribution of stress experienced during hospital admission on long-term cognitive functioning.

2471

N389

Richard L.Doty

Olfactory Dysfunction in COVID-19: Pathology and Long-Term Implications for Brain Health

https://doi.org/10.1016/j.molmed.2022.06.005

Published

20-Jun-22

Review

https://www.sciencedirect.com/science/article/pii/S1471491422001605

Highlights
•COVID-19 has brought to public attention the importance of the sense of smell in everyday life, with untold numbers of patients seeking treatment for decreased ability to smell which, in many cases, may be permanent.
•The neuroepithelium that harbors the olfactory receptor cells is directly exposed to the outside environment, making it susceptible to damage from toxic agents and a host of viruses, most notably SARS-CoV-2, the cause of COVID-19.
•SARS-CoV-2 invades nearly all types of cells within the olfactory neuroepithelium, but does not appear to significantly invade olfactory receptor cells, which lack the primary entry receptor, angiotensin-converting enzyme II (ACE2). However, other entry receptors may also be involved.
•The degree to which SARS-CoV-2 impacts central olfactory processing centers or leads to later neurological disorders has yet to be determined.
ABSTRACT
Decreased smell function is related to brain health, future mortality, and quality of life. Most people inflicted with the SARS-CoV-2 virus evidence some measurable smell dysfunction during its acute phase, although many are unaware of the loss. Long-term deficits occur in up to 30% of COVID-19 cases, although total anosmia is relatively rare. This review explores what is presently known about the nature and pathophysiology of olfactory dysfunction due to the SARS-CoV-2 virus, including reversible inflammation within the olfactory cleft, downregulation of olfactory receptor proteins, and long-lasting peripheral and central damage to olfactory structures. It also addresses the question as to whether long-term smell loss might increase the likelihood of future development of cognitive and neurological deficits.

2472

N390

TomAschman1RonjaMothes1Frank L.Heppner123+HelenaRadbruch1+

What SARS-CoV-2 does to our brains

https://doi.org/10.1016/j.immuni.2022.06.013

Published

20-Jun-22

Perspective

https://www.sciencedirect.com/science/article/pii/S1074761322002862

Neurological symptoms in SARS-CoV-2-infected patients have been reported, but their cause remains unclear. In theory, the neurological symptoms observed after SARS-CoV-2 infection could be (i) directly caused by the virus infecting brain cells, (ii) indirectly by our body’s local or systemic immune response towards the virus, (iii) by co-incidental phenomena or (iv) a combination of these factors. As indisputable evidence of intact and replicating SARS-CoV-2 particles in the central nervous system (CNS) is currently lacking, we suggest focusing on the host’s immune reaction when trying to understand the neurocognitive symptoms associated with SARS-CoV-2 infection. In this Perspective, we discuss the possible immune-mediated mechanisms causing functional or structural CNS alterations during acute infection as well as in the post-infectious context. We also review the available literature on CNS affection in the context of COVID-19 infection, as well as observations from animal studies on the molecular pathways involved in sickness behavior.

2473

N391

About N373

JenniferKao12Paul W.Frankland12345

COVID fog demystified

https://doi.org/10.1016/j.cell.2022.06.020

Published

15-Jun-22

Article

https://www.sciencedirect.com/science/article/pii/S0092867422007255

Acute mild respiratory COVID-19 infection can lead to a more chronic cognitive syndrome known as "COVID fog". New findings from Fernandez-Castaneda et al reveal how glial dysregulation and consequent neural circuit dysfunction may contribute to cognitive impairments in long COVID.

2474

N392

Glenn Jennings 1,*ORCID,Ann Monaghan 1,Feng Xue 1,Eoin Duggan 1,2 andRomán Romero-Ortuño 1,2,3ORCID

Comprehensive Clinical Characterisation of Brain Fog in Adults Reporting Long COVID Symptoms

https://doi.org/10.3390/jcm11123440

Published

15-Jun-22

Study

https://www.mdpi.com/2077-0383/11/12/3440/htm

Introduction: A subset of individuals experiencing long COVID symptoms are affected by ‘brain fog’, a lay term that often refers to general cognitive dysfunction but one that is still poorly characterised. In this study, a comprehensive clinical characterisation of self-reported brain fog was conducted vis-à-vis other long COVID symptoms and parameters of mental, cognitive, and physical health. (2) Methodology: Adult participants reporting long COVID symptoms were recruited from hospital clinics and as self-referrals. Participants completed a battery of questionnaires and clinical assessments, including COVID-19 history, symptomatology, self-reported scales (Chalder Fatigue Scale [CFQ], Center for Epidemiological Studies Depression Scale, and Impact of Events Scale–Revised), computer-based cognitive assessments (simple response time and choice reaction time tasks), physical performance tests (gait velocity and muscle strength assessments), and an orthostatic active stand test. A systematic comparison between participants with and without self-reported brain fog was conducted, and a backwards binary logistic regression model was computed to identify the strongest independent associations with brain fog. This was complemented by an automatic cluster analysis to rank the importance of associations. Finally, a structural equation model was postulated with a causal model of key symptomatic indicators and functional consequences of brain fog as a latent variable. (3) Results: Of 108 participants assessed, brain fog was a self-reported symptom in 71 (65.7%) participants. Those with brain fog were at a longer point in time since COVID-19 onset and reported longer duration of low activity during the acute illness. When assessed, those with brain fog had higher frequencies of subjective memory impairment, word-finding difficulties, dizziness, myalgia, arthralgia, hyperhidrosis, cough, voice weakness, throat pain, visual and hearing problems, dysosmia, paraesthesia, chest pain, skin rashes, and hair loss; mean scores in fatigue, depression, and post-traumatic stress scales were higher; performance in both computer-based cognitive tasks was poorer; and measured gait speed and grip strength were lower. The logistic regression suggested that the best independent associations with brain fog were memory impairment, CFQ, and myalgia. The cluster analysis suggested that the most important associations with brain fog were CFQ, dizziness, myalgia, reduced gait speed, word-finding difficulties, reduced grip strength, and memory impairment. The SEM was consistent with key indicators of brain fog being CFQ, dizziness, myalgia, word-finding difficulties, and memory impairment; and reduced grip strength, gait speed, and cognitive response times its functional consequences. (4) Conclusions: The findings indicate that self-reported brain fog in long COVID is a recognisable symptom cluster primarily characterised by fatigue, dizziness, myalgia, word-finding difficulties, and memory impairment and has adverse psychological and psychomotor correlates. In long COVID, brain fog should be regarded as a wide-ranging symptom and addressed holistically with medical, psychological, and rehabilitative supports as guided by individual needs.

2475

N393

Anna Milan, Philippe Salles, Carolina Pelayo, Reinaldo Uribe-San-Martin

Acute to Chronic Electro-Clinical Manifestations of Neuro-COVID and the Long-Haul Consequences in People With Epilepsy: A Review

https://doi.org/10.7759/cureus.26020

Published

16-Jun-22

Review

https://www.cureus.com/articles/98115-acute-to-chronic-electro-clinical-manifestations-of-neuro-covid-and-the-long-haul-consequences-in-people-with-epilepsy-a-review

Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection can involve the central nervous system (CNS). Acute symptomatic seizures or epileptiform discharges have not been commonly reported in patients with altered mental status related to coronavirus disease 2019 (COVID-19) infection. However, long-term neurological symptoms have been reported after COVID-19 infection (i.e., brain fog, cognitive complaints, and confusion), suggesting chronic encephalopathy. People with epilepsy (PWE) have been specifically affected by the COVID-19 pandemic, with changes in their seizure frequency, quality of life, health care accessibility, and medication interactions. This narrative review highlights possible pathophysiological mechanisms of COVID-19 on the brain, related to short- and long-term epileptiform activity and the impact of this infection on PWE.

2476

N394

Yan Zhang,Xue Chen,Lin Jia,Yulin Zhang

Potential mechanism of SARS-CoV-2-associated central and peripheral nervous system impairment

https://doi.org/10.1111/ane.13657

Published

14-Jun-22

Review

https://onlinelibrary.wiley.com/doi/full/10.1111/ane.13657

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is more than merely a respiratory disease, as it also presents with various neurological symptoms. SARS-CoV-2 may infect the central nervous system (CNS) and thus is neurotropic. However, the pathophysiological mechanism of coronavirus disease 2019 (COVID-19)-associated neuropathy remains unclear. Many studies have reported that SARS-CoV-2 enters the CNS through the hematogenous and neuronal routes, as well as through the main host neurological immune responses and cells involved in these responses. The neurological immune responses to COVID-19 and potential mechanisms of the extensive neuroinflammation induced by SARS-CoV-2 have been investigated. Although CNS infection with SARS-CoV-2 was shown to lead to neuronal impairment, certain aspects of this mechanism remain controversial and require further analysis. In this review, we discussed the pathway and mechanisms of SARS-CoV-2 invasion in the CNS, and associated clinical manifestations, such as anosmia, headache, and hyposmia. Moreover, the mechanism of neurological damage caused by SARS-CoV-2 may provide potential treatment methods for patients presenting with SARS-CoV-2-associated neuropathy.

2477

N395

Jacqueline E. Shanley,Andrew F. Valenciano,Garrett Timmons,Annalise E. Miner,Visesha Kakarla,Torge Rempe,Jennifer H. Yang,Amanda Gooding,Marc A. Norman,Sarah J. Banks,Michelle L. Ritter,Ronald J. Ellis,Lucy Horton,Jennifer S. Graves … See fewer authors

Longitudinal evaluation of neurologic-post acute sequelae SARS-CoV-2 infection symptoms

https://doi.org/10.1002/acn3.51578

Published

15-Jun-22

Study

https://onlinelibrary.wiley.com/doi/full/10.1002/acn3.51578

Objective
To assess the initial features and evolution of neurologic Postacute Sequelae of SARS-CoV-2 infection (neuro-PASC) in patients with and without prior neurologic disease.
Methods
Participants with neurologic symptoms following acute SARS-CoV-2 infection were recruited from October 9, 2020 to October 11, 2021. Clinical data included a SARS-CoV-2 infection history, neurologic review of systems, neurologic exam, Montreal cognitive assessment (MoCA), and symptom-based self-reported surveys at baseline (conducted after acute infection) and 6-month follow-up assessments.
Results
Fifty-six participants (69% female, mean age 50 years, 29% with prior neurologic disease such as multiple sclerosis) were enrolled, of which 27 had completed the 6-month follow-up visit in this ongoing study. SARS-CoV-2 infection severity was largely described as mild (39.3%) or moderate (42.9%). At baseline, following acute infection, the most common neurologic symptoms were fatigue (89.3%) and headaches (80.4%). At the 6-month follow-up, memory impairment (68.8%) and decreased concentration (61.5%) were the most prevalent, though on average all symptoms showed a reduction in reported severity score at the follow-up. Complete symptom resolution was reported in 33.3% of participants by 6 months. From baseline to 6 months, average MoCA scores improved overall though 26.3% of participants’ scores decreased. A syndrome consisting of tremor, ataxia, and cognitive dysfunction (PASC-TAC) was observed in 7.1% of patients.
Interpretation
Early in the neuro-PASC syndrome, fatigue and headache are the most commonly reported symptoms. At 6 months, memory impairment and decreased concentration were most prominent. Only one-third of participants had completed resolution of neuro-PASC at 6 months, although persistent symptoms trended toward improvement at follow-up.

2478

N396

Andrei L. Iosifescu,Wouter S. Hoogenboom,Alexandra J. Buczek,Roman Fleysher,Tim Q. Duong

New-onset and persistent neurological and psychiatric sequelae of COVID-19 compared to influenza: A retrospective cohort study in a large New York City healthcare network

https://doi.org/10.1002/mpr.1914

Published

15-Jun-22

Study

https://onlinelibrary.wiley.com/doi/full/10.1002/mpr.1914

Objectives
Neurological and neuropsychiatric manifestations of post-acute SARS-CoV-2 infection (neuro-PASC) are common among COVID-19 survivors, but it is unknown how neuro-PASC differs from influenza-related neuro-sequelae. This study investigated the clinical characteristics of COVID-19 patients with and without new-onset neuro-PASC, and of flu patients with similar symptoms.
Methods
We retrospectively screened 18,811 COVID-19 patients and 5772 flu patients between January 2020 and June 2021 for the presence of new-onset neuro-sequelae that persisted at least 2 weeks past the date of COVID-19 or flu diagnosis.
Results
We observed 388 COVID-19 patients with neuro-PASC versus 149 flu patients with neuro-sequelae. Common neuro-PASC symptoms were anxiety (30%), depression (27%), dizziness (22%), altered mental status (17%), chronic headaches (17%), and nausea (11%). The average time to neuro-PASC onset was 138 days, with hospitalized patients reporting earlier onset than non-hospitalized patients. Neuro-PASC was associated with female sex and older age (p < 0.05), but not race, ethnicity, most comorbidities, or COVID-19 disease severity (p > 0.05). Compared to flu patients, COVID-19 patients were older, exhibited higher incidence of altered mental status, developed symptoms more quickly, and were prescribed psychiatric drugs more often (p < 0.05).
Conclusions
This study provides additional insights into neuro-PASC risk factors and differentiates between post-COVID-19 and post-flu neuro-sequelae.

2479

N397

Rizaldy TaslimPinzonabVincent OngkoWijayaaAbraham AlJodyaPatrick NallaNunsioaRanbebasa BijakBuanaa

Persistent Neurological Manifestations in Long COVID-19 syndrome: A Systematic Review and Meta-Analysis

https://doi.org/10.1016/j.jiph.2022.06.013

Published

23-Jun-22

Systematic Review and Meta-Analysis

https://www.sciencedirect.com/science/article/pii/S1876034122001575

Background
Several studies have reported prolonged symptoms especially neurological symptoms following acute infection in patients with COVID-19, known as long COVID-19. There are only few studies investigating this population and relatively less known, including nervous system involvement. A systematic review and meta-analysis of these studies are required to understanding the prevalence of persistent neurological manifestations after COVID-19.
Objective
To conduct a systematic review and meta-analysis on the persistent neurological manifestations in COVID-19 survivors.
Methods
Authors conducted a literature search through PubMed and MedRxiv from January 1st, 2020 to October 2021 according to PRISMA guideline. Furthermore, the authors added additional sources by reviewing related references. Studies presenting the neurologic features of long COVID-19 patients in their data were included. Case reports and case series also included in this review. The quality of the studies was assessed based on the Oxford Centre for Evidence-Based Medicine guidelines. Selected studies were included in the meta-analysis of proportion and heterogeneity test.
Findings
From 128 identified studies, 36 were eligible, with 9944 participants included. Most of the included studies had mean duration of follow-up after COVID-19 onset of less than 6 months. Fatigue was the most common (52.8%, 95%CI 19.9 – 84.4) symptoms of long COVID, followed by cognitive disorder (35.4%, 95%CI 2.1 – 81.7); paresthesia (33.3%, 95%CI 2.7 – 76.6); sleep disorder (32.9%, 95%CI 6.5 – 67.4); musculoskeletal pain (27.8%, 95%CI 12.7 – 46); and dizziness (26.4%, 95%CI 4.6 – 57.9).
Conclusion
Neurological manifestations are prevalent and persisting in patients with long COVID. The duration of the symptoms are vary among literatures. However, the frequency are mostly observed during the first six months after the illness onset.

2480

N398

GiuliaCattarinussiab1AlessandroMiolaab1NicolòTrevisanabSilviaValeggiacElenaTramarincCarlaMucignatdFrancescoMorracMatteoMinervacGiovanniLibrizzicAnnaBordineFrancescoCausinfGiancarloOttavianoeAngeloAntoninibgFabioSambataroabRenzoManaraf

Altered brain regional homogeneity is associated with depressive symptoms in COVID-19

https://doi.org/10.1016/j.jad.2022.06.061

Published

25-Jun-22

Study

https://www.sciencedirect.com/science/article/pii/S0165032722007224

Highlights
•COVID-19 is associated to depression, anxiety and fatigue.
•COVID-19 presents functional connectivity alterations in parieto-temporal regions.
•There alterations are associated with the severity of depressive symptoms.
Abstract
Background
COVID-19 is an infectious disease that has spread worldwide in 2020, causing a severe pandemic. In addition to respiratory symptoms, neuropsychiatric manifestations are commonly observed, including chronic fatigue, depression, and anxiety. The neural correlates of neuropsychiatric symptoms in COVID-19 are still largely unknown.
Methods
A total of 79 patients with COVID-19 (COV) and 17 healthy controls (HC) underwent 3 T functional magnetic resonance imaging at rest, as well as structural imaging. Regional homogeneity (ReHo) was calculated. We also measured depressive symptoms with the Patient Health Questionnaire (PHQ-9), anxiety using the General Anxiety Disorder 7-item scale, and fatigue with the Multidimension Fatigue Inventory.
Results
In comparison with HC, COV showed significantly higher depressive scores. Moreover, COV presented reduced ReHo in the left angular gyrus, the right superior/middle temporal gyrus and the left inferior temporal gyrus, and higher ReHo in the right hippocampus. No differences in gray matter were detected in these areas. Furthermore, we observed a negative correlation between ReHo in the left angular gyrus and PHQ-9 scores and a trend toward a positive correlation between ReHo in the right hippocampus and PHQ-9 scores.
Limitations
Heterogeneity in the clinical presentation in COV, the different timing from the first positive molecular swab test to the MRI, and the cross-sectional design of the study limit the generalizability of our findings.
Conclusions
Our results suggest that COVID-19 infection may contribute to depressive symptoms via a modulation of local functional connectivity in cortico-limbic circuits.

2481

N399

Fabio Ferreli, Francesca Gaino, Elena Russo, Matteo Di Bari, Vanessa Rossi, Armando De Virgilio, Luca Malvezzi, Giovanni Colombo, Giovanni Cristalli, Giuseppe Spriano & Giuseppe Mercante

Long-standing gustatory and olfactory dysfunction in COVID-19 patients: a prospective study

https://doi.org/10.1007/s00405-022-07428-1

Published

29-Jun-22

Study

https://link.springer.com/article/10.1007/s00405-022-07428-1

Abstract
Purpose
Our study aimed to describe recovery of gustatory dysfunction (GD) and olfactory dysfunction (OD) in COVID-19 patients, and to analyze variables associated with early or late recovery.
Methods
Telephone surveys were administered during an 18-month follow-up after COVID-19 diagnosis. One hundred and thirty-two included patients rated olfactory and gustatory function at each follow-up.
Results
One hundred and twenty-nine patients reported GD, of whom 91 (70.5%) reported severe GD, and 99 patients reported OD, of whom 84 (84.9%) reported severe OD. Seventy-two/129 (55.8%) and 52/99 (52.5%) patients reported an improvement in GD and in OD during the first 7 days from the onset, respectively. At 3-month follow-up, 110/120 patients (85.3%) recovered from GD, while 80/99 patients (80.8%) recovered from OD. At 18-month follow-up, a total of 120/129 patients (93.0%) recovered from GD and 86/99 patients (86.9%) recovered from OD; while 10 patients (7.0%) still reported GD and 13 patients (13.1%) still reported OD. Severe GD/OD at presentation were associated with late complete recovery of taste/smell (p = 0.019 and p = 0.034, respectively). Improvement over the first 7 days from onset was significantly associated with faster recovery (p < 0.001).
Conclusions
More than 80% of patients reported complete recovery of olfactory/gustatory function in the first 3 months after symptom onset. At 18-month follow-up, patients reporting complete recovery of gustatory and olfactory function were 93% and 87%, respectively. Severity of chemosensory dysfunction at the onset was negatively correlated to recovery, and improvement of taste and/or smell function within the first 7 days from symptom onset was significantly associated with early resolution.

2482

N400

PESE

Kazuki Tokumasu 1ORCID,Hiroyuki Honda 1,Naruhiko Sunada 1,Yasue Sakurada 1,Yui Matsuda 1,Koichiro Yamamoto 1ORCID,Yasuhiro Nakano 1ORCID,Toru Hasegawa 1,Yukichika Yamamoto 1,Yuki Otsuka 1ORCID,Hideharu Hagiya 1ORCID,Hitomi Kataoka 1,Keigo Ueda 1,2 andFumio Otsuka 1,2,*ORCID

Clinical Characteristics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Diagnosed in Patients with Long COVID

https://doi.org/10.3390/medicina58070850

Published

25-Jun-22

Study

https://www.mdpi.com/1648-9144/58/7/850/htm

Background and Objectives: COVID-19 can be serious not only in the acute phase but also after the acute phase and some patients develop ME/CFS. There have been few studies on patients with long COVID in whom ME/CFS was diagnosed by physicians based on standardized criteria after examinations and exclusion diagnosis and not based on only subjective symptoms. The purpose of this study was to elucidate the detailed characteristics of ME/CFS in patients with long COVID. Materials and Methods: A retrospective descriptive study was performed for patients who visited a COVID-19 aftercare clinic established in Okayama University Hospital during the period was from February 2021 to April 2022. Results: Clinical data were obtained from medical records for 281 patients, and 279 patients who met the definition of long COVID were included. The overall prevalence rate of ME/CFS diagnosed by three sets of ME/CFS criteria (Fukuda, Canadian and IOM criteria) was 16.8% (48.9% in male and 51.1% in females). The most frequent symptoms in ME/CFS patients were general fatigue and post-exertional malaise (89.4% of the patients), headache (34.0%), insomnia (23.4%), dysosmia (21.3%) and dysgeusia (19.1%). Dizziness, chest pain, insomnia and headache were characteristic symptoms related to ME/CFS. The male to female ratio in ME/CFS patients was equal in the present study, although ME/CFS was generally more common in women in previous studies. Given that patients with ME/CFS had more severe conditions in the acute phase of COVID-19, the severity of the acute infectious state might be involved in the pathophysiology of ME/CFS. Conclusions: The prevalence rate of ME/CFS and the characteristic sequelae in the long COVID condition were revealed in this study.

2483

N401

Jonas Jardim de Paula, Rachel E. R. P. Paiva, Nathália Gualberto Souza-Silva, Daniela Valadão Rosa, Fabio Luis de Souza Duran, Roney Santos Coimbra, Danielle de Souza Costa, Pedro Robles Dutenhefner, Henrique Soares Dutra Oliveira, Sarah Teixeira Camargos, Herika Martins Mendes Vasconcelos, Nara de Oliveira Carvalho, Juliana Batista da Silva, Marina Bicalho Silveira, Carlos Malamut, Derick Matheus Oliveira, Luiz Carlos Molinari, Danilo Bretas de Oliveira, José Nélio Januário, Luciana Costa Silva, Luiz Armando De Marco, Dulciene Maria de Magalhaes Queiroz, Wagner Meira, Geraldo Busatto, Débora Marques Miranda & Marco Aurélio Romano-Silva

Selective visuoconstructional impairment following mild COVID-19 with inflammatory and neuroimaging correlation findings

https://doi.org/10.1038/s41380-022-01632-5

Published

14-Jun-22

Study

https://www.nature.com/articles/s41380-022-01632-5

People recovered from COVID-19 may still present complications including respiratory and neurological sequelae. In other viral infections, cognitive impairment occurs due to brain damage or dysfunction caused by vascular lesions and inflammatory processes. Persistent cognitive impairment compromises daily activities and psychosocial adaptation. Some level of neurological and psychiatric consequences were expected and described in severe cases of COVID-19. However, it is debatable whether neuropsychiatric complications are related to COVID-19 or to unfoldings from a severe infection. Nevertheless, the majority of cases recorded worldwide were mild to moderate self-limited illness in non-hospitalized people. Thus, it is important to understand what are the implications of mild COVID-19, which is the largest and understudied pool of COVID-19 cases. We aimed to investigate adults at least four months after recovering from mild COVID-19, which were assessed by neuropsychological, ocular and neurological tests, immune markers assay, and by structural MRI and 18FDG-PET neuroimaging to shed light on putative brain changes and clinical correlations. In approximately one-quarter of mild-COVID-19 individuals, we detected a specific visuoconstructive deficit, which was associated with changes in molecular and structural brain imaging, and correlated with upregulation of peripheral immune markers. Our findings provide evidence of neuroinflammatory burden causing cognitive deficit, in an already large and growing fraction of the world population. While living with a multitude of mild COVID-19 cases, action is required for a more comprehensive assessment and follow-up of the cognitive impairment, allowing to better understand symptom persistence and the necessity of rehabilitation of the affected individuals.

2484

N402

Charlotte Arlt

Shared COVID- and chemo-fog

https://doi.org/10.1038/s41593-022-01120-7

Published

5-Jul-22

Article

https://www.nature.com/articles/s41593-022-01120-7

Even after seemingly mild infection with SARS-CoV-2, many suffer from persistent cognitive impairment, or ‘COVID brain fog’, that resembles the ‘chemo-fog’ associated with cancer therapy. Chemo-fog is known to be mediated by microglial reactivity and subsequent neural dysregulation, and a study published in Cell investigated whether COVID recruits similar pathophysiological processes. In a mouse model of mild respiratory SARS-CoV-2 infection, the authors observed elevated cytokines and chemokines in serum and cerebrospinal fluid, increased microglial reactivity specifically in white matter, a loss of oligodendrocytes and myelin, and decreased hippocampal neurogenesis. These changes persisted for many weeks after the respiratory infection had cleared, and had human counterparts: brain tissue from patients with COVID-19 also showed white-matter-specific microglial reactivity and, intriguingly, cytokine CCL11 levels were higher in the plasma of patients with long-COVID who had ‘brain-fog’ than in plasma from patients without cognitive symptoms. Systemic CCL11 injection in mice induced white-matter microglial reactivity in hippocampus, along with impaired neurogenesis. Mild respiratory influenza in mice caused similar neuroinflammation and hippocampal pathology, but only transient subcortical white-matter changes. This work starts to unravel the mechanisms that underlie persistent COVID-related cognitive impairments, opening the door for future studies on how these mechanisms may depend on COVID-19 variant, vaccination status and age.

2485

N403

Kirsty Minton

When ‘mild’ COVID-19 is not so mild

https://doi.org/10.1038/s41577-022-00755-8

Published

29-Jun-22

Article

https://www.nature.com/articles/s41577-022-00755-8

Neurological symptoms are common even after ‘mild’ COVID-19. Using a mouse model of SARS-CoV-2 infection limited to the respiratory tract, this study shows that even after viral clearance, there is prolonged microglial reactivity in subcortical and hippocampal white matter and increased levels of CCL11 in the cerebrospinal fluid. Loss of myelin-forming oligodendrocytes and reduced hippocampal neurogenesis were also observed. CCL11 administration in mice causes hippocampal microglial reactivity and impaired hippocampal neurogenesis. Increased plasma levels of CCL11 were also observed in patients with Long COVID with cognitive symptoms, and white matter microglial reactivity was observed in patients who died while infected with SARS-CoV-2 without severe COVID-19. Influenza A virus infection also resulted in neuroinflammation but without the prolonged effects on subcortical white matter.

2486

N404

Y.-W. Fu, H.-S. Xu, S.-J. Liu

COVID-19 and neurodegenerative diseases

https://doi.org/10.26355/eurrev_202206_29093

Published

Review

https://www.europeanreview.org/article/29093

OBJECTIVE: The pandemic of Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues, and SARS-CoV-2 variants continue to emerge. In addition to typical fever and respiratory symptoms, many patients with COVID-19 experience a variety of neurological complications. In this review, we analyzed and reviewed the current status and possible mechanisms between COVID-19 and several typical neurodegenerative diseases, particularly Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, hoping to propose the potential direction of further research and concern.
MATERIALS AND METHODS: Electronic literature search of the databases (Medline/PubMed, Web of Science, and Google Scholar). The keywords used were COVID-19, SARS-CoV-2, neurodegenerative disease, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. The retrieved relevant articles were reviewed and critically analyzed.
RESULTS: SARS-CoV-2 is a highly neuroinvasive neurotropic virus that invades cells through angiotensin-converting enzyme 2 (ACE2) receptor-driven pathway. SARS-CoV-2 neuroinvasion, neuroinflammation, and blood-brain barrier (BBB) dysfunction may contribute to the pathogenesis of neurodegenerative diseases.
CONCLUSIONS: Some patients with neurodegenerative diseases have already shown more susceptibility to SARS-CoV-2 infection and significantly higher mortality due to the elderly population with underlying diseases. Moreover, SARS-CoV-2 could cause damage to the central nervous system (CNS) that may substantially increase the incidence of neurodegenerative diseases and accelerate the progression of them

2487

N405

Nick R. Natale,John R. Lukens,William A. Petri Jr

The nervous system during COVID-19: Caught in the crossfire

https://doi.org/10.1111/imr.13114

Published

30-Jun-22

Review

https://onlinelibrary.wiley.com/doi/10.1111/imr.13114

SARS-CoV-2, the virus that causes coronavirus disease (COVID)-19, has become a persistent global health threat. Individuals who are symptomatic for COVID-19 frequently exhibit respiratory illness, which is often accompanied by neurological symptoms of anosmia and fatigue. Mounting clinical data also indicate that many COVID-19 patients display long-term neurological disorders postinfection such as cognitive decline, which emphasizes the need to further elucidate the effects of COVID-19 on the central nervous system. In this review article, we summarize an emerging body of literature describing the impact of SARS-CoV-2 infection on central nervous system (CNS) health and highlight important areas of future investigation.

2488

N406

Mario Mekhael 1 Chan Ho Lim 1 Abdel Hadi El Hajjar 1 Charbel Noujaim 1 Christopher Pottle 1 Noor Makan 1 Lilas Dagher 2 Yichi Zhang 1 Nour Chouman 1 Dan L Li 1 Tarek Ayoub 1 Nassir Marrouche 1 Author

Studying the Effect of Long COVID-19 Infection on Sleep Quality Using Wearable Health Devices: Observational Study

https://doi.org/10.2196/38000

Published

1-Jul-22

Study

https://www.jmir.org/2022/7/e38000/

Background:
Patients with COVID-19 have increased sleep disturbances and decreased sleep quality during and after the infection. The current published literature focuses mainly on qualitative analyses based on surveys and subjective measurements rather than quantitative data.
Objective:
In this paper, we assessed the long-term effects of COVID-19 through sleep patterns from continuous signals collected via wearable wristbands.
Methods:
Patients with a history of COVID-19 were compared to a control arm of individuals who never had COVID-19. Baseline demographics were collected for each subject. Linear correlations among the mean duration of each sleep phase and the mean daily biometrics were performed. The average duration for each subject’s total sleep time and sleep phases per night was calculated and compared between the 2 groups.
Results:
This study includes 122 patients with COVID-19 and 588 controls (N=710). Total sleep time was positively correlated with respiratory rate (RR) and oxygen saturation (SpO2). Increased awake sleep phase was correlated with increased heart rate, decreased RR, heart rate variability (HRV), and SpO2. Increased light sleep time was correlated with increased RR and SpO2 in the group with COVID-19. Deep sleep duration was correlated with decreased heart rate as well as increased RR and SpO2. When comparing different sleep phases, patients with long COVID-19 had decreased light sleep (244, SD 67 vs 258, SD 67; P=.003) and decreased deep sleep time (123, SD 66 vs 128, SD 58; P=.02).
Conclusions:
Regardless of the demographic background and symptom levels, patients with a history of COVID-19 infection demonstrated altered sleep architecture when compared to matched controls. The sleep of patients with COVID-19 was characterized by decreased total sleep and deep sleep.

2489

N407

Daniela Latorre

Autoimmunity and SARS-CoV-2 infection: Unraveling the link in neurological disorders

https://doi.org/10.1002/eji.202149475

Published

14-Jul-22

Review

https://onlinelibrary.wiley.com/doi/10.1002/eji.202149475

According to the World Health Organization, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has already infected more than 400 million people and caused over 5 million deaths globally. The infection is associated with a wide spectrum of clinical manifestations, ranging from no signs of illness to severe pathological complications that go beyond the typical respiratory symptoms. On this note, new-onset neurological and neuropsychiatric syndromes have been increasingly reported in a large fraction of COVID-19 patients, thus potentially representing a significant public health threat. Although the underlying pathophysiological mechanisms remain elusive, a growing body of evidence suggests that SARS-CoV-2 infection may trigger an autoimmune response, which could potentially contribute to the establishment and/or exacerbation of neurological disorders in COVID-19 patients. Shedding light on this aspect is urgently needed for the development of effective therapeutic intervention. This review highlights the current knowledge of the immune responses occurring in Neuro-COVID patients and discusses potential immune-mediated mechanisms by which SARS-CoV-2 infection may trigger neurological complications.

2490

N408

COA

Antoine Verger, Henryk Barthel, Nelleke Tolboom, Francesco Fraioli, Diego Cecchin, Nathalie L. Albert, Bart van Berckel, Ronald Boellaard, Matthias Brendel, Ozgul Ekmekcioglu, Franck Semah, Tatjana Traub-Weidinger, Donatienne van de Weehaeghe, Silvia Morbelli & Eric Guedj

2-[18F]-FDG PET for imaging brain involvement in patients with long COVID: perspective of the EANM Neuroimaging Committee

https://doi.org/10.1007/s00259-022-05913-7

Published

16-Jul-22

Editorial

https://link.springer.com/article/10.1007/s00259-022-05913-7

While long COVID is viewed as a multisystemic disease due to the ubiquitous distribution of ACE2 receptors as a virus entry pathway into cells, cerebral impairment has received special attention because of symptoms of possible brain origin: loss of smell and taste, cognitive complaints of brain “fog,” impairment in attentional and memory functions, sleep disturbances, pain, emotion disorders [5], and other symptoms that might be related to dysautonomia, such as breathlessness, tachycardia, and orthostatic intolerance, including orthostatic hypotension [6]. These heterogeneous long COVID symptoms, which also potentially fluctuate over time, are firstly not exclusively specific to genuine brain involvement, and may also correspond in some cases to another disease potentially unmasked by the infection. For example, extracerebral explanations might be assigned to a loss of smell in individuals with a nasal obstruction, to dyspnoea in individuals with lung sequelae, and even in individuals with cognitive complaints presenting severe asthenia. On the other hand, several hypotheses have been proposed to anticipate potential cerebral damage related to the infection [5, 6]. Indeed, acute neurological complications associated with COVID-19 [7, 8], such as stroke or encephalopathy/encephalitis, suggest a possible direct or indirect effect of SARS-CoV-2 on the brain. Moreover, other SARS viruses were similarly associated with neuropsychiatric presentations [9]. Consistent with these findings, a recent meta-analysis showed that the post-illness stage of previous infections with SARS viruses was characterized by memory impairment in 19% of patients, irritability in 13%, insomnia and anxiety in 12%, and a depressed mood in 10% of patients [9]. These associations with neuropsychiatric symptoms were even observed in patients infected with other respiratory viruses, such as the “Spanish” pandemic flu virus in adults and children [10]. Some authors consequently argued for possible direct viral brain invasion [11], while others proposed that cerebral damage might be related to an extensive inflammatory/immune response related to the infection [12]. The two hypotheses may also be linked and could suggest a possible brain pathway. A trans-ethmoidal propagation from the olfactory bulbs through the lamina cribrosa to connected cerebral regions, namely, from the nose to the brain, has been proposed, while alternative or complementary pathways might involve pulmonary innervation or the vascular compartment [13]. Notably, an impairment of olfactory brain areas and their projections to the limbic/paralimbic system, brainstem nuclei, and cerebellum might explain several symptoms of long COVID in sensorial, cognitive, motor, and autonomic dimensions, as well as potentially those in the emotion spectrum. Patients indeed also present psychological and psychiatric symptoms, which are potentially related to the stress associated with the pandemic context, carelessness, chronic evolution, and disability, but which might also be related to brain damages in emotion networks [14]. Overall, neurological and psychiatric symptoms presented by patients with long COVID could at least partially be related to the impairment of the same brain network [15]: the olfactory symptoms with the impairment of the olfactory bulbs; the memory/attention deficits with those of the hippocampus and cingulum; the psychological and psychiatric disorders such as irritability, depression, or anxiety with changes in amygdalae; tachycardia, orthostatic intolerance, or breathlessness as a dysfunction of the autonomic nervous system on brainstem nuclei (dysautonomia); and motor symptoms with the impairment of the cerebellum. Consistent with this hypothesis, the olfactory bulbs have indeed been proposed as a possible pathway in this implicated brain network, as all involved regions are anatomically linked to these olfactory structures [16].
Given the subtle clinical presentations and the heterogeneity of individual profiles, a diagnostic flow chart for a positive diagnosis of long COVID is currently difficult to define. In the future, this diagnosis might be based on a composite definition of clinical, biological, and imaging signatures. At present, biomarkers should first be considered to exclude other underlying aetiologies with respect to the current WHO definition. These biomarkers could also specify the extent of the disease, especially the possible impairment of the brain, which may correspond to both a specific prognosis and management. Nuclear medicine using brain 2-[18F]-FDG (FDG) PET imaging potentially fills these medical needs; however, the observation of cortical metabolic abnormalities and their interpretation at the single-patient level should also be carefully considered based on the patient’s clinical history and potential confounders. The EANM Neuroimaging Committee hereby aims to summarize and discuss potential applications, pitfalls, and prospects of the use of FDG PET to image brain involvement in patients with long COVID.
Using brain FDG PET, a hypometabolic profile has been observed in a relevant portion of patients with long COVID, suggesting network-based involvement. Brain FDG PET might therefore be a promising approach to objectify brain involvement in individuals with long COVID, which should correspond to distinct prognoses and management strategies. In addition, brain FDG PET potentially provides a differential diagnosis for clinical symptoms related to neurodegenerative diseases, encephalitis/encephalopathy, or psychiatric disorders. In our opinion, and as previously proposed by Meyer et al. [21], this examination should be considered in these two frameworks only after a dedicated clinical evaluation and after a significant delay (3 to 6 months) from the initial infection, or in case of worsening [19]. Clinicians should remember that cerebral symptoms of long COVID are not limited to cognitive complaints, and consequently, a broader evaluation should be considered beyond the neuropsychometric assessment for these PET indications, especially considering dysautonomia. A multicentre international collaboration among clinicians and patients is expected to improve the brain FDG PET imaging evaluation of long COVID.

2491

N409

Agnieszka Guzik, Andżelina Wolan-Nieroda, Maciej Kochman, Lidia Perenc & Mariusz Drużbicki

Impact of mild COVID-19 on balance function in young adults, a prospective observational study

https://doi.org/10.1038/s41598-022-16397-8

Published

16-Jul-22

Study

https://www.nature.com/articles/s41598-022-16397-8

Balance is of essential importance in human life. The aim of the study is to examine the incidence of balance impairments in young adults who have recovered from mild COVID-19. The study involved 100 subjects, divided into two groups: the study group (50 individuals) comprised subjects who had recovered from mild COVID-19, and the control group (50 individuals) consisted of healthy subjects matched for gender and age. Balance was assessed using a force platform and clinical tests such as: timed up and go test, 15-s step test, sit-to-stand test and 6-min walk test. The assessment on the platform showed greater balance impairments in the trials with eyes closed; more specifically, compared to the controls, in trials with double-leg support the subjects from the study group acquired significantly higher scores in X average (lateral coordinates) (p < 0.05), Path length, V average (average Centre of Foot Pressure Velocity) (p < 0.05) and Area circular (p < 0.01), with even more significant results in trials with single-leg support in X average (p < 0.001), Y average (anterior–posterior coordinates) (p < 0.001) and Path length (p = 0.004). Higher scores in the timed up and go test were found in the study group (p = 0.013). The control group had higher scores in the remaining tests. The current findings show that mild COVID-19 may lead to balance impairments in young adults. Statistically significant differences in balance were found between the subjects in the study group and the healthy controls. Further studies in this area should take into account more age groups, and patients recovered from severe COVID-19, and should investigate long-term consequences of COVID-19 reflected by balance problems.

2492

N410

Konstantinos Dimitriadis, Jan Meis, Hermann Neugebauer, Kristian Barlinn, Bernhard Neumann, Georg Gahn, Piergiorgio Lochner, Benjamin Knier, Sarah Lindemann, Kurt Wolfram Sühs, Kristina Szabo, Thomas Pfefferkorn, Ingo Schirotzek, Tobias Freilinger, Bassa Burc, Albrecht Günther, Matthias Wittstock, Patrick Schramm, Gernot Reimann, Jana Godau, Gabor Nagy, Fatima B. Koenig, Fabian Essig, Hartwig Klinker, Christian Hartmann, Moritz L. Schmidbauer, Tim Steinberg, Lora Lefterova, Christina Klose & Julian Bösel for the IGNITE study group

Neurologic manifestations of COVID-19 in critically ill patients: results of the prospective multicenter registry PANDEMIC

https://doi.org/10.1186/s13054-022-04080-3

Published

16-Jul-22

Study

https://ccforum.biomedcentral.com/articles/10.1186/s13054-022-04080-3

Background
Neurologic manifestations are increasingly reported in patients with coronavirus disease 2019 (COVID-19). Yet, data on prevalence, predictors and relevance for outcome of neurological manifestations in patients requiring intensive care are scarce. We aimed to characterize prevalence, risk factors and impact on outcome of neurologic manifestations in critically ill COVID-19 patients.
Methods
In the prospective, multicenter, observational registry study PANDEMIC (Pooled Analysis of Neurologic DisordErs Manifesting in Intensive care of COVID-19), we enrolled COVID-19 patients with neurologic manifestations admitted to 19 German intensive care units (ICU) between April 2020 and September 2021. We performed descriptive and explorative statistical analyses. Multivariable models were used to investigate factors associated with disorder categories and their underlying diagnoses as well as to identify predictors of outcome.
Results
Of the 392 patients included in the analysis, 70.7% (277/392) were male and the mean age was 65.3 (SD ± 3.1) years. During the study period, a total of 2681 patients with COVID-19 were treated at the ICUs of 15 participating centers. New neurologic disorders were identified in 350 patients, reported by these centers, suggesting a prevalence of COVID-19-associated neurologic disorders of 12.7% among COVID-19 ICU patients. Encephalopathy (46.2%; 181/392), cerebrovascular (41.0%; 161/392) and neuromuscular disorders (20.4%; 80/392) were the most frequent categories identified. Out of 35 cerebrospinal fluid analyses with reverse transcriptase PCR for SARS-COV-2, only 3 were positive. In-hospital mortality was 36.0% (140/389), and functional outcome (mRS 3 to 5) of surviving patients was poor at hospital discharge in 70.9% (161/227). Intracerebral hemorrhage (OR 6.2, 95% CI 2.5–14.9, p < 0.001) and acute ischemic stroke (OR 3.9, 95% CI 1.9–8.2, p < 0.001) were the strongest predictors of poor outcome among the included patients.
Conclusions
Based on this well-characterized COVID-19 ICU cohort, that comprised 12.7% of all severe ill COVID-19 patients, neurologic manifestations increase mortality and morbidity. Since no reliable evidence of direct viral affection of the nervous system by COVID-19 could be found, these neurologic manifestations may for a great part be indirect para- or postinfectious sequelae of the infection or severe critical illness. Neurologic ICU complications should be actively searched for and treated.

2493

N411

COA

JoyMitraaManoharKodavatiaVincent E.ProvasekagK.S.RaobSankarMitraaDale J.HamiltoncdPhilip J.HorneradFarhaan S.VahidyeGavin W.BritzadThomas A.KentfMuralidhar L.Hegdead

SARS-CoV-2 and the central nervous system: Emerging insights into hemorrhage-associated neurological consequences and therapeutic considerations

https://doi.org/10.1016/j.arr.2022.101687

Published

27-Jul-22

Review

https://www.sciencedirect.com/science/article/pii/S1568163722001295

Highlights
•Although primarily a respiratory virus, Coronavirus also infects human brain in multi-modal pathways.
•Ageing is a critical determinant in the COVID-19 onset, progression, and outcome, particularly for neurological impact.
•Microbleeds and microstructural-vascular changes are prevalent in COVID-19 infection of brain.
•Hemorrhage-mediated neurotoxicity and ageing may synergistically predispose to neurodegeneration/dementia in Covid-19 survivors.
•A potential mitigation strategy for COVID-19-associated microhemorrhagic lesions and related neurological disorders.
Abstract
Coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to impact our lives by causing widespread illness and death and poses a threat due to the possibility of emerging strains. SARS-CoV-2 targets angiotensin-converting enzyme 2 (ACE2) before entering vital organs of the body, including the brain. Studies have shown systemic inflammation, cellular senescence, and viral toxicity-mediated multi-organ failure occur during infectious periods. However, prognostic investigations suggest that both acute and long-term neurological complications, including predisposition to irreversible neurodegenerative diseases, can be a serious concern for COVID-19 survivors, especially the elderly population. As emerging studies reveal sites of SARS-CoV-2 infection in different parts of the brain, potential causes of chronic lesions including cerebral and deep-brain microbleeds and the likelihood of developing stroke-like pathologies increases, with critical long-term consequences, particularly for individuals with neuropathological and/or age-associated comorbid conditions. Our recent studies linking the blood degradation products to genome instability, leading to cellular senescence and ferroptosis, raise the possibility of similar neurovascular events as a result of SARS-CoV-2 infection. In this review, we discuss the neuropathological consequences of SARS-CoV-2 infection in COVID survivors, focusing on possible hemorrhagic damage in brain cells, its association to aging, and the future directions in developing mechanism-guided therapeutic strategies.

2494

N412

Kumar, Niraj; Goyal, Abhishek1; Hussain, Arshad2; Saini, Lokesh Kumar3; Chawla, Omna4; Arora, Pankaj5; Daga, Ritu6; Tikka, Sai Krishna7; Goyal, Sandeep Kumar8; Kanchan, Shweta9; Desai, Soaham10; Ahmed, Sohaib11; Das, Sourav12; Dubey, Vaibhav13; Gupta, Ravi14,

SARS-CoV-2 infection is associated with increased odds of insomnia, RLS and dream enactment behavior

https://doi.org/10.4103/indianjpsychiatry.indianjpsychiatry_586_21

Published

1-Jul-22

Study

https://journals.lww.com/indianjpsychiatry/Fulltext/2022/64080/SARS_CoV_2_infection_is_associated_with_increased.6.aspx

Background:
Literature suggests that the COVID-19 pandemic has resulted in poor sleep quality, especially among the infected population. However, literature regarding the effect of COVID-19 pandemic and SARS-CoV-2 infection on occurrence of insomnia, restless legs syndrome and dream enactment behavior is either scarce or unavailable.
Methods:
This study was planned to assess the effect of SARS-CoV-2 infection on the occurrence of insomnia, restless legs syndrome (RLS) and dream enactment behavior (DEB). For this cross-sectional study, a questionnaire comprising of items related to demographic details, past medical history, and information related to SARS-CoV-2 infection was distributed through social media. Insomnia was diagnosed using clinical criteria. RLS, DEB, sleep quality, depression and anxiety were assessed using a validated questionnaire. Information regarding the use of hypnotic medications was also gathered.
Results:
Of the 1596 respondents, 37.2% reported disturbed sleep while insomnia was reported by 22.6% respondents. 27.3% of respondents reported RLS and 17.4% suffered DEB. The odds of insomnia were greater among males (OR = 1.27; 95% CI: 1.03–1.58; P < 0.02) and among those who had SARS-CoV-2 infection (OR = 1.76; 95% CI = 1.42–2.19; P < 0.001). Similarly, SARS-CoV-2 infection was also associated with increased odds of RLS (OR = 2.48; 95% CI = 1.98–3.11; P < 0.001) and DEB (OR = 1.58; 95%CI = 1.21–2.06; P < 0.001). Insomnia, RLS and DEB were more frequent among respondents who required oxygen therapy, those who experienced loss of taste and/or smell, depression and anxiety. Prevalence of insomnia, DEB and RLS was higher than said prevalence among respondents with no history of SARS-CoV-2 infection, but lower than that of those with positive history of SARS-CoV-2 infection. 5.3% of respondents reported taking hypnotic medications before infection, 7% during infection and 5.3% after infection.
Conclusion:
SARS-CoV-2-infection-related factors in association with environmental factors have increased the prevalence of insomnia, DEB and RLS among subjects having infection. SARS-CoV-2-associated immunological changes, hypoxia and neurotropism may play a role in occurrence of insomnia, DEB and RLS.

2495

N413

Josef Finsterer

Letter to the Editor regarding “COVID-19-Related Burden and Risk Perception in Individuals with Chronic Inflammatory Demyelinating Polyneuropathy and Multifocal Motor Neuropathy: A Cross-Sectional Study”

https://doi.org/10.1007/s40120-022-00386-0

Published

16-Jul-22

Letter to the Editor

https://link.springer.com/article/10.1007/s40120-022-00386-0

Overall, the interesting study has some limitations that call the results and their interpretation into question. Clarifying these weaknesses would strengthen the conclusions and could improve the study. To assess the impact of diagnosis and treatment on attitudes toward COVID-19, study groups of interest should be homogenized not only in terms of demographics but also in terms of diagnosis, treatment, and comorbidities. Due to the inherent disadvantages, on-site surveys should be preferred to on-line surveys. However, attempting to use an online survey also has advantages, and is timely because investigators can access a wide range of patients, including those who are unable to go to the clinic. Examining questions about psychiatric aspects of patients suffering from immune-mediated disorders in the COVID-19 era is also important. Therefore, discussion of these concerns will deepen understanding of the limitations and benefits of online surveys and the current situation of patients with immune-mediated diseases.

2496

N414

Alex K.ChenaXiaolingWangbLynnette P.McCluskeycJohn C.MorgandJeffrey A.SwitzereRohiniMehtafMarthaTingenbShaoyongSubRyan AlanHarrisbDavid C.HesseElizabeth K.Rutkowskie

Neuropsychiatric sequelae of long COVID-19: Pilot results from the COVID-19 neurological and molecular prospective cohort study in Georgia, USA

https://doi.org/10.1016/j.bbih.2022.100491

Published

30-Jul-22

Study

https://www.sciencedirect.com/science/article/pii/S2666354622000813

Highlights
•Neuropsychiatric symptoms are often reported following COVID-19 infection.
•Self-reported symptoms may not be associated with objective dysfunction.
•Self-reported symptoms may be associated with depression and anxiety.
•Cognitive testing may overestimate clinical impairment in disadvantaged populations.
Abstract
Background
As the coronavirus disease 2019 (COVID-19) pandemic continues, there has been a growing interest in the chronic sequelae of COVID-19. Neuropsychiatric symptoms are observed in the acute phase of infection, but there is a need for accurate characterization of how these symptoms evolve over time. Additionally, African American populations have been disproportionately affected by the COVID-19 pandemic. The COVID-19 Neurological and Molecular Prospective Cohort Study in Georgia (CONGA) was established to investigate the severity and chronicity of these neurologic findings over the five-year period following infection.
Methods
The CONGA study aims to recruit COVID-19 positive adult patients in Georgia, United States from both the inpatient and outpatient setting, with 50% being African American. This paper reports our preliminary results from the baseline visits of the first 200 patients recruited who were on average 125 days since having a positive COVID-19 test. The demographics, self-reported symptoms, comorbidities, and quantitative measures of depression, anxiety, smell, taste, and cognition were analyzed. Cognitive measures were compared to demographically matched controls. Blood and mononuclear cells were drawn and stored for future analysis.
Results
Fatigue was the most reported symptom in the study cohort (68.5%). Thirty percent of participants demonstrated hyposmia and 30% of participants demonstrated hypogeusia. Self-reported neurologic dysfunction did not correlate with dysfunction on quantitative neurologic testing. Additionally, self-reported symptoms and comorbidities were associated with depression and anxiety. The study cohort performed worse on cognitive measures compared to demographically matched controls, and African American patients scored lower compared to non-Hispanic White patients on all quantitative cognitive testing.
Conclusion
Our results support the growing evidence that there are chronic neuropsychiatric symptoms following COVID-19 infection. Our results suggest that self-reported neurologic symptoms do not appear to correlate with associated quantitative dysfunction, emphasizing the importance of quantitative measurements in the complete assessment of deficits. Self-reported symptoms are associated with depression and anxiety. COVID-19 infection appears to be associated with worse performance on cognitive measures, though the disparity in score between African American patients and non-Hispanic White patients is likely largely due to psychosocial, physical health, and socioeconomic factors.

2497

N415

Christiana Franke, Peter Berlit & Harald Prüss

Neurological manifestations of post-COVID-19 syndrome S1-guideline of the German society of neurology

https://doi.org/10.1186/s42466-022-00191-y

Published

18-Jul-22

Guidelines

https://link.springer.com/article/10.1186/s42466-022-00191-y

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to COVID-19 (COrona VIrus Disease-2019). SARS-CoV-2 acute infection may be associated with an increased incidence of neurological manifestations such as encephalopathy and encephalomyelitis, ischemic stroke and intracerebral hemorrhage, anosmia and neuromuscular diseases. Neurological manifestations are commonly reported during the post-acute phase and are also present in Long-COVID (LCS) and post-COVID-19 syndrome (PCS). In October 2020, the German Society of Neurology (DGN, Deutsche Gesellschaft für Neurologie) published the first guideline on the neurological manifestations of COVID-19. In December 2021 this S1 guideline was revised and guidance for the care of patients with post-COVID-19 syndrome regarding neurological manifestations was added. This is an abbreviated version of the post-COVID-19 syndrome chapter of the guideline issued by the German Neurological society and published in the Guideline repository of the AWMF (Working Group of Scientific Medical Societies; Arbeitsgemeinschaft wissenschaftlicher Medizinischer Fachgesellschaften).

Neurological manifestations are common in patients with LCS and PCS; commonly reported are cognitive deficits, fatigue, headache, myalgia and neuropathy. A comprehensive—ideally interdisciplinary—diagnostic assessment should be initiated in patients who complain about residual or new symptoms more than 3 months after the acute infection. If immune involvement is detected, immunomodulatory therapy may be considered as an individual treatment attempt. A causal therapy does not yet exist; the symptomatic therapy is carried out according to the guidelines of the DGN. Structured neurorehabilitation programs are urgently needed. In parallel, patients should be offered concomitant psychosomatic co-treatment. Avoiding SARS-CoV-2 infection is the key most important preventive factor, and therefore vaccination against SARS-CoV-2 with one of the available vaccines is highly recommended. An interdisciplinary treatment including internal, psychosomatic, and psychiatric expertise is crucial in diagnostic and treatment of PCS patients.

2498

N416

S. Iacovides,1 E. Alzueta,2 P.B. Perrin,3 D. Yüksel,2 D. Ramos-Usuga,4,5 O. Kiss,2 M. de Zambotti,2 M. Cortes,6 L. Olabarrieta-Landa,7 J.C. Arango-Lasprilla,5,8,9 and F.C. Baker2

Effects of Long COVID on Sleep Health

https://doi.org/10.1016%2Fj.sleep.2022.05.216

Published

21-Jul-22

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9300253/

Introduction: COVID-19 has infected millions of people worldwide with growing evidence showing that those individuals may continue to show persistent post-COVID symptoms (long COVID). The aim of this study was to investigate sleep health in an international sample of individuals who reported previously testing positive for COVID-19.
Materials and Methods: 1001 individuals who reported a positive diagnosis of COVID-19, across different geographical regions, including North and South America, Sub-Saharan Africa, and Europe, completed an online survey between March 4–June 15, 2021. Self-reported sleep health was assessed using the RU-SATED scale, as recalled before a COVID-19 diagnosis and as reported currently.
Results: Individuals reported a poorer overall current sleep health, with poorer ratings across the six dimensions of sleep health (sleep regularity, satisfaction, alertness, timing, efficiency, and duration) compared to their ratings as recalled before COVID-19 infection. Greater severity of symptoms during COVID-19 infection was the strongest predictor of poor current sleep health (p < .001), independent of demographics, presence of a pre-existing condition, and time since infection. Poor current sleep health was associated with poorer current quality of life (p<.001).
Conclusions: Poor sleep health is evident in individuals with a history of COVID-19, particularly those with more severe symptoms at the time of their COVID-19 infection, and is associated with a poorer quality of life. Clinicians and researchers should assess sleep health in COVID-19 survivors and investigate long-term associations with their mental and physical health, as well as potential benefits of improving sleep in this population.

2499

N417

Nico Sollmann, Ambros J. Beer & Frank Kirchhoff

SARS-CoV-2 infection and the brain: direct evidence for brain changes in milder cases

https://doi.org/10.1038/s41392-022-01072-1

Published

11-Jul-22

Article

https://www.nature.com/articles/s41392-022-01072-1

A recent study published in Nature by Douaud and colleagues1 shows that SARS-CoV-2 infection is associated with longitudinal effects, particularly on brain structures linked to the olfactory cortex, modestly accelerated reduction in global brain volume, and enhanced cognitive decline. Thus, even mild COVID-19 can be associated with long-lasting deleterious effects on brain structure and function.

The study provides unique insights into COVID-19-associated changes in brain structure. The authors took great care in appropriately matching the case and control groups, making it unlikely that observed differences are due to confounding factors, although this possibility can never be entirely excluded. The mechanisms underlying these infection-associated changes, however, remain to be clarified. Viral neurotropism and direct infection of cells of the olfactory system, neuroinflammation and lack of sensory input have been suggested as reasons for the degenerative events in olfactory-related brain structures and neurological complications.4 These mechanisms are not mutually exclusive and may synergize in causing neurodegenerative disorders as consequence of COVID-19.
The study participants became infected between March 2020 and April 2021, before the emergence of the Omicron variant of concern (VOC) that currently dominates the COVID-19 pandemic. During that time period, the Alpha and Beta VOCs dominated in the UK and all results were obtained from individuals between 51 and 81 years of age. It will be of great interest to clarify whether Omicron, that seems to be less pathogenic than other SARS-CoV-2 variants, also causes long-term brain damage. The vaccination status of the participants was not available in the study1 and it will be important to clarify whether long-term changes in brain structure also occur in vaccinated and/or younger individuals. Other important questions are whether these structural changes are reversible or permanent and may even enhance the frequency for neurodegenerative diseases that are usually age-related, such as Alzheimer’s, Parkinson’s or Huntington’s disease. Previous findings suggest that cognitive disorders improve over time after severe COVID-19;5 yet it remains to be determined whether the described brain changes will translate into symptoms later in life such as dementia. Douaud and colleagues report that none of top 10 IDPs correlated significantly with the time interval between SARS-CoV-2 infection and the 2nd MRI acquisition, suggesting that the observed abnormalities might be very long-lasting.
Currently, many restrictions and protective measures are relaxed because Omicron is highly transmissible but usually causes mild to moderate acute disease. This raises hope that SARS-CoV-2 may evolve towards reduced pathogenicity and become similar to circulating coronaviruses causing mild respiratory infections. More work needs to be done to clarify whether the current Omicron and future variants of SARS-CoV-2 may also cause lasting brain abnormalities and whether these can be prevented by vaccination or therapy. However, the finding by Douaud and colleagues1 that SARS-CoV-2 causes structural changes in the brain that may be permanent and could relate to neurological decline is of concern and illustrates that the pathogenesis of this virus is markedly different from that of circulating human coronaviruses. Further studies, to elucidate the mechanisms underlying COVID-19-associated neurological abnormalities and how to prevent or reverse them are urgently needed.

2500

N418

Srinivas Sriramula1 Rohan Parekh1
Drew Theobald1 Shaw Akula1
Dorcas O’Rourke1 Jeffrey Eells

Long COVID in K18-hACE2 mice causes persistent brain inflammation and cognitive impairment

https://doi.org/10.21203/rs.3.rs-1818930/v1

pre-print

6-Jul-22

Study

https://www.researchsquare.com/article/rs-1818930/v1

Evidence suggests that patients with long COVID experience cognitive abnormalities. However, these clinical data are mostly associational studies complicated by confounding variables, thus the mechanisms responsible for persistent neurological symptoms are unknown. Here we establish an animal model of long COVID by eliciting mild disease in K18-hACE2 mice. Following recovery from infection with a low dose of SARS-CoV-2, K18-hACE2 mice show the characteristic lung fibrosis associated with SARS-CoV-2 infection, which correlates with increased expression of the pro-inflammatory kinin B1 receptor (B1R). These mice also have elevated expression of B1Rs and inflammatory markers in the brain and exhibit cognitive impairments such as elevated anxiety and attenuated exploratory behavior. Our data demonstrate that K18-hACE2 mice exhibit persistent effects of SARS-CoV-2 infection on brain tissue, revealing the potential of this model for investigating long COVID. The results further imply that elevated B1R expression may drive the long-lasting inflammatory response associated with SARS-CoV-2 infection.

2501

N419

Laura Pelizzari, Marta Cazzoli, Susanna Lipari, Maria Marcella Laganà, Monia Cabinio, Sara Isernia, Alice Pirastru, Mario Clerici, Francesca Baglio

Mid-term MRI evaluation reveals microstructural white matter alterations in COVID-19 fully recovered subjects with anosmia presentation

https://doi.org/10.1177%2F17562864221111995

Published

23-Jul-22

Study

https://journals.sagepub.com/doi/full/10.1177/17562864221111995

Background:
Little is still known about the mid/long-term effects of coronavirus disease 2019 (COVID-19) on the brain, especially in subjects who have never been hospitalized due to the infection. In this neuroimaging exploratory study, we analyzed the medium-term effect of COVID-19 on the brain of people who recovered from COVID-19, experienced anosmia during the acute phase of the disease, and have never been hospitalized due to SARS-Co-V-2 infection.
Methods:
Forty-three individuals who had (COV+, n = 22) or had not (COV−, n = 21) been infected with SARS-Co-V-2 were included in the study; the two groups were age- and sex-matched and were investigated using 3T magnetic resonance imaging (MRI). Gray matter (GM) volume, white matter (WM) hyperintensity volume, WM microstrutural integrity (i.e. fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity [AD], radial diffusivity [RD]) and cerebral blood flow (CBF) differences between the two groups were tested with either analysis of covariance or voxel-wise analyses. Results were family wise error (FWE) corrected.
Results:
No significant differences between COV+ and COV− groups were observed in terms of GM volume, WM hyperintensity volume, and CBF. Conversely, local WM microstructural alterations were detected in COV+ when compared with COV− with tract-based spatial statistics. Specifically, COV+ showed lower FA (pFWE-peak = 0.035) and higher RD (pFWE-peak = 0.038) than COV− in several WM regions.
Conclusion:
COVID-19 may produce mid/long-term microstructural effect on the brain, even in case of mild-to-moderate disease not requiring hospitalization. Further investigation and additional follow-ups are warranted to assess if the alterations reported in this study totally recover over time. As brain alterations could increase the risk of cognitive decline, greater knowledge of their trajectories is crucial to aid neurorehabilitation treatments.

2502

N420

Amir-Hossein Bayat, Helia Azimi, Meysam Hassani Moghaddam, Vahid Ebrahimi, Mobina Fathi, Kimia Vakili, Gholam-Reza Mahmoudiasl, Mahdi Forouzesh, Mahdi Eskandarian Boroujeni, Zahra Nariman, Hojjat-Allah Abbaszadeh, Arefeh Aryan, Abbas Aliaghaei & Mohammad-Amin Abdollahifar

COVID-19 causes neuronal degeneration and reduces neurogenesis in human hippocampus

https://doi.org/10.1007/s10495-022-01754-9

Published

25-Jul-22

Study

https://link.springer.com/article/10.1007/s10495-022-01754-9

Recent investigations of COVID-19 have largely focused on the effects of this novel virus on the vital organs in order to efficiently assist individuals who have recovered from the disease. In the present study we used hippocampal tissue samples extracted from people who died after COVID-19. Utilizing histological techniques to analyze glial and neuronal cells we illuminated a massive degeneration of neuronal cells and changes in glial cells morphology in hippocampal samples. The results showed that in hippocampus of the studied brains there were morphological changes in pyramidal cells, an increase in apoptosis, a drop in neurogenesis, and change in spatial distribution of neurons in the pyramidal and granular layer. It was also demonstrated that COVID-19 alter the morphological characteristics and distribution of astrocyte and microglia cells. While the exact mechanism(s) by which the virus causes neuronal loss and morphology in the central nervous system (CNS) remains to be determined, it is necessary to monitor the effect of SARS-CoV-2 infection on CNS compartments like the hippocampus in future investigations. As a result of what happened in the hippocampus secondary to COVID-19, memory impairment may be a long-term neurological complication which can be a predisposing factor for neurodegenerative disorders through neuroinflammation and oxidative stress mechanisms.

2503

N421

Maryame Mohammadian & Ravieh Golchoobian

Potential autonomic nervous system dysfunction in COVID-19 patients detected by heart rate variability is a sign of SARS-CoV-2 neurotropic features

https://doi.org/10.1007/s11033-022-07486-y

Published

9-Jul-22

Article

https://link.springer.com/article/10.1007/s11033-022-07486-y

Increasing evidence strongly support that the newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to the development of COVID-19-associated central nervous system (CNS) manifestations. The presence of SARS-CoV-2 viral protein in the brainstem, which includes cardiovascular control centers, has been documented previously. Given the changes in autonomic nervous system function evaluated by heart rate variability (HRV) metrics, which are observed even prior to clinical signs, the potential effect of SARS-CoV-2 on the autonomic nervous system (ANS) center is likely. The integral parts of the brain renin-angiotensin system, as ACE2 enzyme, are highly expressed in the brainstem, which may also be involved in baroreflex sensitivity, playing an important role in HRV. SARS-CoV-2 may bind to ACE2 in order to enter the host brainstem cell and change baroreflex sensitivity due to the altered ratio of the concentration of angiotensin II (Ag II) to angiotensin (1–7). In this article, we discussed the information on the possibility that the SARS-CoV-2 viral particle by disrupting the homeostasis of the brain renin-angiotensin system even without brainstem neuropathological changes, may affect the function of the ANS center in the brainstem. SARS-CoV-2 could influence ANS function before affecting the immune system. It is possible that the altered HRV parameters imply the potential neurotropic characteristics of SARS-CoV-2. Therefore, this potential feature should be taken into account in diagnostic and therapeutic approaches for COVID-19 patients.

2504

N422

Madeline G. Andrews , Tanzila Mukhtar, Ugomma C. Eze , +24 , Camille R. Simoneau, Jayden Ross, Neelroop Parikshak, Shaohui Wang, Li Zhou , Mark Koontz, Dmitry Velmeshev, Clara-Vita Siebert, Kaila M. Gemenes , Takako Tabata, Yonatan Perez, Li Wang, Mohammed A. Mostajo-Radji, Martina de Majo , Kevin C. Donohue , David Shin, Jahan Salma , Alex A. Pollen , Tomasz J. Nowakowski, Erik Ullian, G. Renuka Kumar , Ethan A. Winkler, Elizabeth E. Crouch , Melanie Ott, and Arnold R. Kriegstein

Tropism of SARS-CoV-2 for human cortical astrocytes

https://doi.org/10.1073/pnas.2122236119

Published

12-Jul-22

Study

https://www.pnas.org/doi/full/10.1073/pnas.2122236119

Significance
Neurological and neuropsychiatric symptoms occur in as many as one-third of patients with or recovering from COVID-19. To address severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neural tropism, we evaluated the vulnerability of primary developing and adult cortical tissue and stem-cell-derived cortical organoids to SARS-CoV-2 infection. We observe robust infection and viral replication in human cortical astrocytes; they become reactive, have increased growth factor signaling, and activate cellular stress. Despite infection in astroglial cells, there is minimal infection of other neural cell types, including neurons. Surprisingly, we discover that astrocyte infection is unlikely to be mediated by the predominant coronavirus receptor, ACE2, and instead observe alternative glycoproteins, CD147 and DPP4, expressed on astrocytes; they are necessary and sufficient for SARS-CoV-2 infection.
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) readily infects a variety of cell types impacting the function of vital organ systems, with particularly severe impact on respiratory function. Neurological symptoms, which range in severity, accompany as many as one-third of COVID-19 cases, indicating a potential vulnerability of neural cell types. To assess whether human cortical cells can be directly infected by SARS-CoV-2, we utilized stem-cell-derived cortical organoids as well as primary human cortical tissue, both from developmental and adult stages. We find significant and predominant infection in cortical astrocytes in both primary tissue and organoid cultures, with minimal infection of other cortical populations. Infected and bystander astrocytes have a corresponding increase in inflammatory gene expression, reactivity characteristics, increased cytokine and growth factor signaling, and cellular stress. Although human cortical cells, particularly astrocytes, have no observable ACE2 expression, we find high levels of coronavirus coreceptors in infected astrocytes, including CD147 and DPP4. Decreasing coreceptor abundance and activity reduces overall infection rate, and increasing expression is sufficient to promote infection. Thus, we find tropism of SARS-CoV-2 for human astrocytes resulting in inflammatory gliosis-type injury that is dependent on coronavirus coreceptors.

2505

N423

Bruno Biagianti1,2*, Asia Di Liberto1, Aiello Nicolò Edoardo3,4, Ilaria Lisi5, Letizia Nobilia6, Giulia Delor de Ferrabonc1, Elisa R. Zanier5, Nino Stocchetti2,7 and Paolo Brambilla1,2

Cognitive Assessment in SARS-CoV-2 Patients: A Systematic Review

https://doi.org/10.3389/fnagi.2022.909661

Published

1-Jul-22

Review

https://www.frontiersin.org/articles/10.3389/fnagi.2022.909661/full

Background: Patients with post-infective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) often show both short- and long-term cognitive deficits within the dysexecutive/inattentive spectrum. However, little is known about which cognitive alterations are commonly found in patients recovered from SARS-CoV-2, and which psychometric tools clinicians should consider when assessing cognition in this population. The present work reviewed published studies to provide a critical narrative of neuropsychological (NPs) deficits commonly observed after SARS-CoV-2 infection and the tests most suited for detecting such cognitive sequelae depending on illness severity.
Methods: This review followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and was pre-registered on Prospective Register of Systematic Reviews (PROSPERO) (CRD42021253079). Observational studies quantitatively assessing cognition in patients with post-infective SARS-CoV-2 were considered. From 711 retrieved articles, 19 studies conducted on patients with SARS-CoV-2 without medical comorbidities were included and stratified by disease severity.
Results: The majority of studies (N = 13) adopted first-level tests. The most frequently administered screeners were the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE)—with the former more likely to detect mild, and the latter moderate/severe deficits. Among second-level tests, those assessing attention and executive functions (EFs) were highly represented. Remotely-delivered tests yielded lower percentages of cognitive impairment. Overall, cognitive domains often found to be impaired were EFs, attention, and memory.
Conclusion: Cognitive sequelae in patients with post-infective SARS-CoV-2 can be detected with NPs testing. Depending on the psychometric test features, the likelihood of observing cognitive deficits can vary. Further studies on larger sample sizes are needed to investigate the clinical usefulness of second-level tools. The primary goal of preventative health services should be the early detection and intervention of emerging cognitive deficits.
Key Points
- Cognitive sequelae are prevalent in patients with SARS-CoV-2, while the likelihood of observing such sequelae varies depending on the test used.
- Among patients with SARS-CoV-2, MoCA is more likely to detect mild cognitive deficits, whereas MMSE moderate/severe deficits.
- Studies using domain-specific tests are needed, to investigate whether some specific cognitive functions are more impaired than others.
- A standardized protocol for cognitive assessment in patients with SARS-CoV-2 should be made available to clinicians.

2506

N424

Jung Woo Park1,2, Corresponding address, Xiaoyan Wang1,2, Ren-He Xu1,2

Revealing the mystery of persistent smell loss in Long COVID patients

https://doi.org/10.7150/ijbs.73485

Published

15-Jul-22

Review

https://www.ijbs.com/v18p4795.htm

COVID-19 is hopefully approaching its end in many countries as herd immunity develops and weaker strains of SARS-CoV-2 dominate. However, a new concern occurs over the long-term effects of COVID-19, collectively called “Long COVID”, as some symptoms of the nervous system last even after patients recover from COVID-19. This review focuses on studies of anosmia, i.e., impairment of smell, which is the most common sensory defect during the disease course and is caused by olfactory dysfunctions. It remains mysterious how the olfactory functions are affected since the virus can't invade olfactory receptor neurons. We describe several leading hypotheses about the mystery in hope to provide insights into the pathophysiology and treatment strategies for anosmia.

2507

N425

COA

Fernanda Crunfli 1, Victor C Carregari 1, Flavio P Veras 2, Lucas S Silva 1, Mateus Henrique Nogueira 1, André Saraiva Leão Marcelo Antunes 1, Pedro Henrique Vendramini 1, Aline Gazzola Fragnani Valença 1, Caroline Brandão-Teles 1, Giuliana da Silva Zuccoli 1, Guilherme Reis-de-Oliveira 1, Lícia C Silva-Costa 1, Verônica Monteiro Saia-Cereda 1, Bradley J Smith 1, Ana Campos Codo 1, Gabriela F de Souza 1, Stéfanie P Muraro 1, Pierina Lorencini Parise 1, Paulo Hilario Nascimento Saldiva 3, Alessandro S Farias 1, Fernando Cendes 1, Pedro Manoel M Moraes-Vieira 1, Alexandre T Fabro 2, Adriano Sebollela 2, José L Proença-Modena 1, Clarissa L Yasuda 1, Marcelo A Mori 1, Thiago M Cunha 2, Daniel Martins-de-Souza

Morphological, cellular, and molecular basis of brain infection in COVID-19 patients

https://doi.org/10.1073/pnas.2200960119

Published

11-Aug-22

Study

https://www.pnas.org/doi/full/10.1073/pnas.2200960119

Significance
Neurological symptoms are among the most prevalent of the extrapulmonary complications of COVID-19, affecting more than 30% of patients. In this study, we provide evidence that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is found in the human brain, where it infects astrocytes and to a lesser extent, neurons. We also show that astrocytes are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike–NRP1 interaction and respond to the infection by remodeling energy metabolism, which in turn, alters the levels of metabolites used to fuel neurons and support neurotransmitter synthesis. The altered secretory phenotype of infected astrocytes then impairs neuronal viability. These features could explain the damage and structural changes observed in the brains of COVID-19 patients.
Abstract
Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of “long COVID-19” syndrome) has been frequently observed after mild infection. We show the spectrum of cerebral impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal transethmoidal access) from individuals who died of COVID-19. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell–derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike–NRP1 interaction. SARS-CoV-2–infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.

2508

N426

ValentinaLetaab†IroBouraabc†Daniel J.van WamelenabdMayelaRodriguez-ViolanteeAngeloAntoninifKallol RayChaudhuriab

Covid-19 and Parkinson's disease: Acute clinical implications, long-COVID and post-COVID-19 parkinsonism

https://doi.org/10.1016/bs.irn.2022.04.004

Published

8-Aug-22

Study

https://www.sciencedirect.com/science/article/pii/S0074774222000332

The Coronavirus Disease 2019 (Covid-19), caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has led to unprecedented challenges for the delivery of healthcare and has had a clear impact on people with chronic neurological conditions such as Parkinson's disease (PD). Acute worsening of motor and non-motor symptoms and long-term sequalae have been described during and after SARS-CoV-2 infections in people with Parkinson's (PwP), which are likely to be multifactorial in their origin. On the one hand, it is likely that worsening of symptoms has been related to the viral infection itself, whereas social restrictions imposed over the course of the Covid-19 pandemic might also have had such an effect. Twenty cases of post-Covid-19 para-infectious or post-infectious parkinsonism have been described so far where a variety of pathophysiological mechanisms seem to be involved; however, a Covid-19-induced wave of post-viral parkinsonism seems rather unlikely at the moment. Here, we describe the interaction between SARS-CoV-2 and PD in the short- and long-term and summarize the clinical features of post-Covid-19 cases of parkinsonism observed so far.

2509

N427

Luciew, Joshua D. MPAS, PA-C; Erickson, Rodney A. MD; Kaufman, Tara K. MD

Post-COVID-19 neurologic syndrome
Another legacy of the pandemic

https://doi.org/10.1097/01.JAA.0000854524.40560.f3

Published

9-Aug-22

Article

https://journals.lww.com/jaapa/Fulltext/9900/Post_COVID_19_neurologic_syndrome__Another_legacy.18.aspx

COVID-19 quickly escalated to a global pandemic in 2020. As research on the topic continues, the medical community has found that this acute illness can cause a new chronic illness: postacute sequelae of SARS-CoV-2 (PASC). Some patients with PASC develop predominately neurologic sequelae (post-COVID-19 neurologic syndrome or PCNS). This article describes PASC and PCNS, their proposed pathogenicity and possible neurovirulence mechanisms, symptoms, and treatment recommendations.

2510

N428

Syed SamiAliaAfshanMumtazbMohammad AadilQamaraSameer SaleemTebhacAzmaParhindMehwishButtcMohammad YasirEssar

New-onset Parkinsonism as a Covid-19 infection sequela: A systematic review and meta-analysis

https://doi.org/10.1016/j.amsu.2022.104281

Published

8-Aug-22

Systematic Review / Meta-analysis

https://www.sciencedirect.com/science/article/pii/S204908012201041X

Highlights
•There have been well-documented reports about the occurrence of parkinsonism after viral infections.
•10 studies including 13 patients reported the development of parkinsonism in individuals who recovered from COVID-19 infection.
•The commonest symptom of parkinsonism reported in these individuals was cogwheel rigidity 84.6%.
•53.8% of individuals fully recovered and had their symptoms resolved after treatment.
Background
There remains a scarcity of literature regarding COVID-19 and its neurological sequelae. This study highlights Parkinsonism as a post-COVID-19 sequela and helps us understand a possible link between the two.
Methods
A literature search covering relevant databases was conducted for studies reporting the development of Parkinsonism in patients recovering from COVID-19 infection. A quality assessment tool developed by The Joanna Briggs Institute Critical Appraisal tools for the assessment of case reports was utilized. Fisher's exact test was used to explore the factors associated with COVID-19 and Parkinsonism as its complication.
Results
Ten studies were included in our study. The median age of patients was 60.0, with an interquartile range of 42.5–72.0. There were 8 males (61.5%) patients, and 53.8% of cases were reported to have at least one comorbidity. Cogwheel rigidity was the most common symptom of Parkinsonism in 11 patients. While the most standard treatment modality used was Levodopa in 76.9% of cases. Using the Fisher's Exact test, it was identified that 10 patients (76.9%) with bradykinesia made a full recovery.
Conclusion
Despite presumed “recovery” from COVID-19, patients still face a wide range of neurological complications. One of these complications presenting as Parkinsonism requires health care professionals to be on the lookout for the long-term effects of COVID-19. Hence, our study provides information on the possible likely hood of a link between COVID-19 and the development of Parkinsonism as post-COVID neurological sequelae.

2511

N429

P. Voruz1,2,3, I. Jacot de Alcântara1,2, A. Nuber-Champier1, A. Cionca1, G. Allali2,3,4, L. Benzakour3,5,
P.H. Lalive2,3, K.-O. Lövblad3,6, O. Braillard7, M. Nehme7, M. Coen8, J. Serratrice8, J.-L. Reny8,
J. Pugin3,9, I. Guessous3,7, R. Ptak3,10, B.N. Landis3,11, F. Assal2,3,†, J.A. Péron

Frequency of Abnormally Low Neuropsychological Scores in
Post-COVID-19 Syndrome: the Geneva COVID-COG Cohort

https://academic.oup.com/acn/advance-article/doi/10.1093/arclin/acac068/6658442

Published

20-Jul-22

Study

https://www.researchgate.net/profile/Philippe-Voruz/publication/362581698_Frequency_of_Abnormally_Low_Neuropsychological_Scores_in_Post-COVID-19_Syndrome_the_Geneva_COVID-COG_Cohort/links/62f2cb0a88b83e7320becc4a/Frequency-of-Abnormally-Low-Neuropsychological-Scores-in-Post-COVID-19-Syndrome-the-Geneva-COVID-COG-Cohort.pdf

Objective: Several studies have reported poor long-term neuropsychological performances in patients following severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but none has yet considered the effect of administering multiple
intercorrelated neuropsychological tests and assessed the frequency of cognitive deficits in a normative population. Our aim
was therefore to assess the presence of cumulative neuropsychological deficits in an actual post-coronavirus disease of 2019
(COVID-19) comparison group versus one simulated using Monte-Carlo methods.
Method: Validated neuropsychological Monte-Carlo simulation methods were applied to scores from a battery of neuropsychological tests (memory, executive, attentional, perceptual, logical reasoning, language, and ideomotor praxis) administered to 121
patients who had had mild, moderate, or severe COVID-19 (mean age: 56.70 years; 32% women), 222 ± 43 days post-infection.
The cumulative percentages of the three severity subgroups were compared with the results of a false discovery rate-corrected
probability analysis based on normative data.
Results: The cumulative percentages of deficits in memory and executive functions among the severe and moderate patients were
significantly higher than those estimated for the normative population. Moderate patients also had significantly more deficits in
perception and logical reasoning. In contrast, the mild group did not have significantly more cumulative deficits.
Conclusions: Moderate and severe forms of COVID-19 cause greater long-term neuropsychological deficits than those that
would be found in a normative population, reinforcing the hypothesis of long-term effects of SARS-CoV-2 on cognitive function,
independent of the severity of the initial infection.

2512

N430

COA

Maxime Taquet, PhD
Rebecca Sillett, BA
Lena Zhu, BS
Jacob Mendel, MMath
Isabella Camplisson, BS
Quentin Dercon, MSc
Paul J Harrison, FRCPsych

Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1 284 437 patients

https://doi.org/10.1016/S2215-0366(22)00260-7

Published

17-Aug-22

Study

https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(22)00260-7/fulltext

Background
COVID-19 is associated with increased risks of neurological and psychiatric sequelae in the weeks and months thereafter. How long these risks remain, whether they affect children and adults similarly, and whether SARS-CoV-2 variants differ in their risk profiles remains unclear.
Methods
In this analysis of 2-year retrospective cohort studies, we extracted data from the TriNetX electronic health records network, an international network of de-identified data from health-care records of approximately 89 million patients collected from hospital, primary care, and specialist providers (mostly from the USA, but also from Australia, the UK, Spain, Bulgaria, India, Malaysia, and Taiwan). A cohort of patients of any age with COVID-19 diagnosed between Jan 20, 2020, and April 13, 2022, was identified and propensity-score matched (1:1) to a contemporaneous cohort of patients with any other respiratory infection. Matching was done on the basis of demographic factors, risk factors for COVID-19 and severe COVID-19 illness, and vaccination status. Analyses were stratified by age group (age <18 years [children], 18–64 years [adults], and ≥65 years [older adults]) and date of diagnosis. We assessed the risks of 14 neurological and psychiatric diagnoses after SARS-CoV-2 infection and compared these risks with the matched comparator cohort. The 2-year risk trajectories were represented by time-varying hazard ratios (HRs) and summarised using the 6-month constant HRs (representing the risks in the earlier phase of follow-up, which have not yet been well characterised in children), the risk horizon for each outcome (ie, the time at which the HR returns to 1), and the time to equal incidence in the two cohorts. We also estimated how many people died after a neurological or psychiatric diagnosis during follow-up in each age group. Finally, we compared matched cohorts of patients diagnosed with COVID-19 directly before and after the emergence of the alpha (B.1.1.7), delta (B.1.617.2), and omicron (B.1.1.529) variants.
Findings
We identified 1 487 712 patients with a recorded diagnosis of COVID-19 during the study period, of whom 1 284 437 (185 748 children, 856 588 adults, and 242 101 older adults; overall mean age 42·5 years [SD 21·9]; 741 806 [57·8%] were female and 542 192 [42·2%] were male) were adequately matched with an equal number of patients with another respiratory infection. The risk trajectories of outcomes after SARS-CoV-2 infection in the whole cohort differed substantially. While most outcomes had HRs significantly greater than 1 after 6 months (with the exception of encephalitis; Guillain-Barré syndrome; nerve, nerve root, and plexus disorder; and parkinsonism), their risk horizons and time to equal incidence varied greatly. Risks of the common psychiatric disorders returned to baseline after 1–2 months (mood disorders at 43 days, anxiety disorders at 58 days) and subsequently reached an equal overall incidence to the matched comparison group (mood disorders at 457 days, anxiety disorders at 417 days). By contrast, risks of cognitive deficit (known as brain fog), dementia, psychotic disorders, and epilepsy or seizures were still increased at the end of the 2-year follow-up period. Post-COVID-19 risk trajectories differed in children compared with adults: in the 6 months after SARS-CoV-2 infection, children were not at an increased risk of mood (HR 1·02 [95% CI 0·94–1·10) or anxiety (1·00 [0·94–1·06]) disorders, but did have an increased risk of cognitive deficit, insomnia, intracranial haemorrhage, ischaemic stroke, nerve, nerve root, and plexus disorders, psychotic disorders, and epilepsy or seizures (HRs ranging from 1·20 [1·09–1·33] to 2·16 [1·46–3·19]). Unlike adults, cognitive deficit in children had a finite risk horizon (75 days) and a finite time to equal incidence (491 days). A sizeable proportion of older adults who received a neurological or psychiatric diagnosis, in either cohort, subsequently died, especially those diagnosed with dementia or epilepsy or seizures. Risk profiles were similar just before versus just after the emergence of the alpha variant (n=47 675 in each cohort). Just after (vs just before) the emergence of the delta variant (n=44 835 in each cohort), increased risks of ischaemic stroke, epilepsy or seizures, cognitive deficit, insomnia, and anxiety disorders were observed, compounded by an increased death rate. With omicron (n=39 845 in each cohort), there was a lower death rate than just before emergence of the variant, but the risks of neurological and psychiatric outcomes remained similar.
Interpretation
This analysis of 2-year retrospective cohort studies of individuals diagnosed with COVID-19 showed that the increased incidence of mood and anxiety disorders was transient, with no overall excess of these diagnoses compared with other respiratory infections. In contrast, the increased risk of psychotic disorder, cognitive deficit, dementia, and epilepsy or seizures persisted throughout. The differing trajectories suggest a different pathogenesis for these outcomes. Children have a more benign overall profile of psychiatric risk than do adults and older adults, but their sustained higher risk of some diagnoses is of concern. The fact that neurological and psychiatric outcomes were similar during the delta and omicron waves indicates that the burden on the health-care system might continue even with variants that are less severe in other respects. Our findings are relevant to understanding individual-level and population-level risks of neurological and psychiatric disorders after SARS-CoV-2 infection and can help inform our responses to them.

2513

N431

Meghann Ryan, Huajun Liang, Eleanor Wilson, Andrea Levine, Shyamasundaran Kottilil, Thomas Ernst and Linda Chang

Quantifying the neuropsychiatric symptoms in post-acute sequelae of COVID-19 (PASC) using the NIH Toolbox ® and PROMIS

https://doi.org/10.1515/nipt-2022-0010

Published

15-Aug-22

Study

https://www.degruyter.com/document/doi/10.1515/nipt-2022-0010/html

Objective
To quantify neuropsychiatric symptoms reported by individuals with Post-Acute Sequelae of COVID-19 (PASC) using the NIH Toolbox for Assessment of Neurological and Behavioral Function (NIHTB) and Patient-Reported Outcomes Measurement Information System (PROMIS).
Methods
30 PASC (20 women, 21–63 years) and 27 control (16 women, 25–68 years) participants completed three NIHTB batteries and selected PROMIS tests. Group differences on fully corrected T-scores were evaluated using analysis of covariance and Cohen’s d effect sizes. A linear regression model predicted the effects from time since diagnosis.
Results
PASC had poorer emotional health and motor function than controls, including poorer locomotion, endurance and dexterity, but normal cognitive function, ∼7 months post-infection. PASC participants had a steeper age-related decline on the 2-Minute Walk Endurance Test than controls. T-scores on four cognitive and three motor tests improved with longer time since diagnosis.
Conclusion
NIHTB and PROMIS captured the poorer emotional health and motor function in PASC, including the novel findings of deficits in locomotion and dexterity. The normal cognitive performance suggests subclinical effects that may be compensated by neural and cognitive reserves, and manifested subjectively by the negative psychological effects and fatigue. The persistent emotional and psychiatric symptoms necessitate mental health treatment be prioritized.

2514

N432

Michał Chudzik 1ORCID,Mateusz Babicki 2ORCID,Agnieszka Mastalerz-Migas 2ORCID andJoanna Kapusta 3,*ORCID

Persisting Smell and Taste Disorders in Patients Who Recovered from SARS-CoV-2 Virus Infection—Data from the Polish PoLoCOV-CVD Study

https://doi.org/10.3390/v14081763

Published

12-Aug-22

Study

https://www.mdpi.com/1999-4915/14/8/1763/htm

In the majority of cases, patients infected with the SARS-CoV-2 virus experience a complete resolution of symptoms within six weeks of acquiring the infection, but an increasing number of patients report persistent symptoms. This study aimed to analyse the prevalence of self-reported smell and/or taste disorders (STDs) in a group of convalescent patients after infection with the SARS-CoV-2 virus and to identify risk factors for the disease. The study included 2218 COVID-19 convalescents after both inpatient and outpatient treatment. The sample group was analysed with regard to chronic diseases, place of isolation and clinical symptoms occurring during COVID-19 along with their duration. The assessment also included the most common symptoms of COVID-19 and the severity of the disease course. A total of 98 patients reported persistent smell and taste disorders up to three months after the end of isolation (67.4% of men and 32.6% of women). The mean age of the participants was 53.8 ± 13.5 years (49.19 ± 14.68 in patients with an STD vs. 54.01 ± 13.44 in patients without an STD). The patients treated for COVID-19 at home (p < 0.001) constituted almost the entire group of patients with persistent smell and taste disorders (97%). Among the patients with persistent smell and taste disorders, 57.1% suffered from at least one chronic condition (vs. 71.4% of patients without an STD). In patients with an STD, the number of symptoms per patient was higher than in the other group at 8.87 ± 3.65 (p = 0.018), while the most common clinical symptoms during the acute phase of COVID-19 were smell and taste disorders (84%) (p < 0.001), significant weakness (70%), headache (60%), cough (55%), arthralgia (51%) (p = 0.034) and back muscle pain (51%). Based on the results obtained, the following conclusions were drawn: the risk of developing persistent smell and taste disorders after COVID-19 is greater in younger people with less comorbidities and a higher number of symptoms during the acute phase of COVID-19. The risk is associated with clinical symptoms occurring during the acute phase of COVID-19, i.e., smell and taste disorders and arthralgia. In addition, this risk is higher in patients receiving outpatient treatment for COVID-19.

2515

N433

Michael P.McWilliamsaDaniel H.CoelhoabEvan R.ReiteraRichard M.Costanzo

Recovery from Covid-19 smell loss: Two-years of follow up

https://doi.org/10.1016/j.amjoto.2022.103607

Published

18-Aug-22

Study

https://www.sciencedirect.com/science/article/pii/S0196070922002344

Objective - To report long-term patterns of recovery and non-recovery in a large nationwide cohort of subjects with COVID-19 associated smell loss.
Study design - Prospectively, longitudinal questionnaires.
Setting - Web-based national survey.
Methods - A longitudinal survey of adults with COVID-19 and/or sudden change in smell or taste since January 1, 2020 was launched April 10, 2020. Participants were queried again in late May 2022 regarding recovery. Data from respondents with >2 years since loss were analyzed and compared to recovery status of those more recently effected.
Results
1103 responded to the survey of whom 946 met inclusion criteria. Among the 267 respondents for whom at least 2 years of follow up was available, 38.2 % reported full recovery, 54.3 % partial, and 7.5 % no recovery. For the entire cohort (all with ≥3 months since smell loss), 38.7 % reported complete recovery, 51.0 % reported partial recovery (ranging from mild complaints to severe phantosmia or dysosmia), and 10.3 % reported no improvement at all. Complete recovery of smell function was significantly higher in those under 40 years old (45.6 % compared to 32.9 % in those over 40).
Conclusion
Although the vast majority of subjects who do recover do so within the first 3 months, long-term spontaneous recovery can occur. Rates of recovery do not seem to differ depending on when during the pandemic the loss first occurred.

2516

N434

Claudio Tana, Enrico Bentivegna, Soo-Jin Cho, Andrea M. Harriott, David García-Azorín, Alejandro Labastida-Ramirez, Raffaele Ornello, Bianca Raffaelli, Eloísa Rubio Beltrán, Ruth Ruscheweyh & Paolo Martelletti

Long COVID headache

https://doi.org/10.1186/s10194-022-01450-8

Published

1-Aug-22

Review

https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-022-01450-8

Headache is among the most frequent symptoms persisting or newly developing after coronavirus disease 2019 (COVID-19) as part of the so-called long COVID syndrome. The knowledge on long COVID headache is still limited, however growing evidence is defining the features of this novel condition, in particular regarding clinical characteristics, some pathophysiological mechanisms and first treatment recommendations. Long COVID headache can present in the form of worsening of a preexisting primary headache, or, more specifically, in the form of a new (intermittent or daily) headache starting during the acute infection or after a delay. It often presents together with other long COVID symptoms, most frequently with hyposmia. It can manifest with a migrainous or, more frequently, with a tension-type-like phenotype. Persistent activation of the immune system and trigeminovascular activation are thought to play a role. As there are virtually no treatment studies, treatment currently is largely guided by the existing guidelines for primary headaches with the corresponding phenotype. The present report, a collaborative work of the international group of the Junior Editorial Board of The Journal of Headache and Pain aims to summarize the most recent evidence about long COVID headache and suggests approaches to the diagnosis and treatment of this disorder.

2517

N435

COA

Michail Spanos
Sigal Shachar 3
Thadryan Sweeney 3
H. Immo Lehmann 3
Priyanka Gokulnath
Guoping Li
George B. Sigal
Rajini Nagaraj
Pradeepthi Bathala
Farhan Rana
Ravi V. Shah
David A. Routenberg
Saumya Das

Elevation of neural injury markers in patients with neurologic sequelae after hospitalization for SARS-CoV-2 infection

https://doi.org/10.1016/j.isci.2022.104833

Published

1-Aug-22

Study

https://www.cell.com/iscience/fulltext/S2589-0042(22)01105-1

Highlights
•40% of hospitalized patients with COVID-19 developed neurological sequelae after recovery
•Age, disease severity, and COVID-19 infection were associated with neurological sequelae
•GFAP and NF-L were significantly elevated in SARS-CoV-2 infection compared to controls
•GFAP and NF-L were elevated in patients with long-term neurological symptoms
Summary
Patients with SARS-CoV-2 infection (COVID-19) risk developing long-term neurologic symptoms after infection. Here, we identify biomarkers associated with neurologic sequelae one year after hospitalization for SARS-CoV-2 infection. SARS-CoV-2-positive patients were followed using post-SARS-CoV-2 online questionnaires and virtual visits. Hospitalized adults from the pre-SARS-CoV-2 era served as historical controls. 40% of hospitalized patients develop neurological sequelae in the year after recovery from acute COVID-19 infection. Age, disease severity, and COVID-19 infection itself was associated with additional risk for neurological sequelae in our cohorts. Glial fibrillary astrocytic protein (GFAP) and neurofilament light chain (NF-L) were significantly elevated in SARS-CoV-2 infection. After adjusting for age, sex, and disease severity, GFAP and NF-L remained significantly associated with longer term neurological symptoms in patients with SARS-CoV-2 infection. GFAP and NF-L warrant exploration as biomarkers for long-term neurologic complications after SARS-CoV-2 infection.

2518

N436

Tan B K J, Han R, Zhao J J, Tan N K W, Quah E S H, Tan C J et al.

Prognosis and persistence of smell and taste dysfunction in patients with covid-19: meta-analysis with parametric cure modelling of recovery curves

https://doi.org/10.1136/bmj-2021-069503

Published

27-Jul-22

Systematic review and meta-analysis

https://www.bmj.com/content/378/bmj-2021-069503

Objective To clarify in patients with covid-19 the recovery rate of smell and taste, proportion with persistent dysfunction of smell and taste, and prognostic factors associated with recovery of smell and taste.
Design - Systematic review and meta-analysis.
Data sources - PubMed, Embase, Scopus, Cochrane Library, and medRxiv from inception to 3 October 2021.
Review methods - Two blinded reviewers selected observational studies of adults (≥18 years) with covid-19 related dysfunction of smell or taste. Descriptive prognosis studies with time-to-event curves and prognostic association studies of any prognostic factor were included.
Data extraction and synthesis - Two reviewers extracted data, evaluated study bias using QUIPS, and appraised evidence quality using GRADE, following PRISMA and MOOSE reporting guidelines. Using iterative numerical algorithms, time-to-event individual patient data (IPD) were reconstructed and pooled to retrieve distribution-free summary survival curves, with recovery rates reported at 30 day intervals for participants who remained alive. To estimate the proportion with persistent smell and taste dysfunction, cure fractions from Weibull non-mixture cure models of plateaued survival curves were logit transformed and pooled in a two stage meta-analysis. Conventional aggregate data meta-analysis was performed to explore unadjusted associations of prognostic factors with recovery.
Main outcome measures - The primary outcomes were the proportions of patients remaining with smell or taste dysfunction. Secondary outcomes were the odds ratios of prognostic variables associated with recovery of smell and taste.
Results - 18 studies (3699 patients) from 4180 records were included in reconstructed IPD meta-analyses. Risk of bias was low to moderate; conclusions remained unaltered after exclusion of four high risk studies. Evidence quality was moderate to high. Based on parametric cure modelling, persistent self-reported smell and taste dysfunction could develop in an estimated 5.6% (95% confidence interval 2.7% to 11.0%, I2=70%, τ2=0.756, 95% prediction interval 0.7% to 33.5%) and 4.4% (1.2% to 14.6%, I2=67%, τ2=0.684, 95% prediction interval 0.0% to 49.0%) of patients, respectively. Sensitivity analyses suggest these could be underestimates. At 30, 60, 90, and 180 days, respectively, 74.1% (95% confidence interval 64.0% to 81.3%), 85.8% (77.6% to 90.9%), 90.0% (83.3% to 94.0%), and 95.7% (89.5% to 98.3%) of patients recovered their sense of smell (I2=0.0-77.2%, τ2=0.006-0.050) and 78.8% (70.5% to 84.7%), 87.7% (82.0% to 91.6%), 90.3% (83.5% to 94.3%), and 98.0% (92.2% to 95.5%) recovered their sense of taste (range of I2=0.0-72.1%, τ2=0.000-0.015). Women were less likely to recover their sense of smell (odds ratio 0.52, 95% confidence interval 0.37 to 0.72, seven studies, I2=20%, τ2=0.0224) and taste (0.31, 0.13 to 0.72, seven studies, I2=78%, τ2=0.5121) than men, and patients with greater initial severity of dysfunction (0.48, 0.31 to 0.73, five studies, I2=10%, τ2<0.001) or nasal congestion (0.42, 0.18 to 0.97, three studies, I2=0%, τ2<0.001) were less likely to recover their sense of smell.
Conclusions - A substantial proportion of patients with covid-19 might develop long lasting change in their sense of smell or taste. This could contribute to the growing burden of long covid.

2519

N437

Leslie M. Kay

COVID-19 and olfactory dysfunction: a looming wave of dementia?

https://doi.org/10.1152/jn.00255.2022

Published

15-Aug-22

Review

https://journals.physiology.org/doi/full/10.1152/jn.00255.2022

Olfactory dysfunction is a hallmark symptom of COVID-19 disease resulting from the SARS-CoV-2 virus. The cause of the sudden and usually temporary anosmia that most people suffer from COVID-19 is likely entirely peripheral—inflammation and other damage caused by the virus in the sensory epithelium inside the upper recesses of the nasal cavity can damage or prevent chemicals from properly activating the olfactory sensory neurons. However, persistent olfactory dysfunction from COVID-19, in the form of hyposmia and parosmia (decreased or altered smell) may affect as many as 15 million people worldwide. This epidemic of olfactory dysfunction is thus a continuing public health concern. Mounting evidence suggests that the SARS-CoV-2 virus itself or inflammation from the immune response in the nasal sensory epithelium may invade the olfactory bulb, likely via non-neuronal transmission. COVID-19-related long-term olfactory dysfunction and early damage to olfactory and limbic brain regions suggest a pattern of degeneration similar to that seen in early stages of Alzheimer’s disease, Parkinson’s disease, and Lewy body dementia. Thus, long-term olfactory dysfunction coupled with cognitive and emotional disturbance from COVID-19 may be the first signs of delayed onset dementia from neurodegeneration. Few treatments are known to be effective to prevent further degeneration, but the first line of defense against degeneration may be olfactory and environmental enrichment. There is a pressing need for more research on treatments for olfactory dysfunction and longitudinal studies including cognitive and olfactory function from patients who have recovered from even mild COVID-19.

2520

N438

Boscolo-Rizzo P, Polesel J, Vaira L A

Smell and taste dysfunction after covid-19

https://doi.org/10.1136/bmj.o1653

Published

27-Jul-22

Article

https://www.bmj.com/content/378/bmj.o1653.full

The sense of smell is an ancient and vital perception in mammals, with the olfactory receptor gene family making up 1% of the mammalian genome, and the human olfactory system being able to discriminate among thousands of airborne chemicals at concentrations below the detection limits of the most complex analytical systems.1 However, people only realise the importance of smell when it is lost. The covid-19 pandemic has put both smell and taste disturbances in the spotlight because of the functional impact and severe distress caused by the loss of these senses, their fundamental diagnostic value,2 and, more recently, the high rate of long term dysfunction.
The linked meta-analysis by Tan and colleagues (doi:10.1136/bmj-2021-069503) gives a clear picture of the challenge humans face.4 About 5% of people who report initial changes to their sense of smell or taste after covid-19 still report smell and taste dysfunction six months later and, given that an estimated 550 million cases of covid-19 have been reported worldwide as of July 2022, large numbers of patients will be seeking care for these disabling morbidities. Health systems should therefore be ready to provide support to these patients who often report feeling isolated when their symptoms are overlooked by clinicians.
More than other senses, smell and taste include emotional and affective elements of experience. These senses cannot be communicated through social networks—as with ideas, imaging, and music, sharing them requires coexistence. Loss of smell and taste adversely affects quality of life by depriving those affected of several everyday pleasures and social bonds.6 People can also experience anorexia, food aversions, malnutrition, anxiety, and depression.7 All these disturbances can be greatly amplified by the onset of qualitative alterations, in particular by parosmia. Parosmia, a fluctuant distorted smell perception, is a common sequela of the olfactory dysfunction associated with covid-19, arising on average three months after SARS-CoV-2 infection.8 For the overwhelming majority, parosmia transforms a pleasant odour into an unpleasant one, and daily activities such as smelling coffee and sensing the flavour of food can become disgusting and emotionally distressing.
In addition to the use of nasal steroids, which aim to resolve SARS-CoV-2 induced inflammation, other treatments that have shown some, albeit marginal, benefit in small clinical trials include intranasal vitamin A and supplements of alpha lipoic acid and omega 3 fatty acids.15 As olfactory neuroepithelium is located in the hidden posterior roof of the nasal cavity, specific delivery systems able to distribute drugs to the olfactory region could improve the efficacy of intranasal treatment options.

The large number of people with long lasting chemosensory dysfunction after covid-19 offers a unique opportunity to test new treatments in large multicentre trials. Health leaders, policy makers, and research funders should realise the extraordinary importance of good chemosensory function for the wellbeing of humans, allocate adequate resources to support chemosensory research, and sustain medical specialists faced with an exceptional number of patients with smell and taste dysfunction.

2521

N439

Paola Ortelli, Francesco Benso, Davide Ferrazzoli, Ilaria Scarano, Leopold Saltuari, Luca Sebastianelli, Viviana Versace & Roberto Maestri

Global slowness and increased intra-individual variability are key features of attentional deficits and cognitive fluctuations in post COVID-19 patients

https://doi.org/10.1038/s41598-022-17463-x

Published

30-Jul-22

Study

https://www.nature.com/articles/s41598-022-17463-x

Fatigue, attentional deficits and cognitive fluctuations are the most characterizing symptoms of neurological involvement in Post COVID-19 syndrome (PCS). As the intraindividual variability (IIV) in cognitive performances has been recognized as a hallmark of brain-related disorders associated with cognitive deficits, it could be an interesting measure to elucidate the mechanisms subtending both the attentive impairment and the cognitive fluctuations in these patients. By referring to IIV analysis of Reaction Times (RTs), the present study aims to define the attentive impairment and its relation to fluctuations and fatigue, in patients suffering from Post COVID-19 neurological symptoms. 74 patients were enrolled. They underwent an extensive clinical and neuropsychological assessments, as well as computerized Sustained Attention and Stroop tasks. For studying IIV, RTs distributions of performances in computerized tasks were fitted with ex-Gaussian distribution, for obtaining the τ values. Finally, the Resting Motor Threshold (RMT) was also collected to estimate cortical excitability. 29 healthy volunteers served as controls. Patients showed poorer scores in Montreal Cognitive Assessment and higher RMT, in comparison with controls. In Sustained Attention Task, Mean, µ, σ and τ values were significantly higher in PCS patients (p value = < 0.0001; 0.001; 0.018 and < 0.0001, respectively). Repeated measures ANOVA comparing the RTs mean in Stroop task within-subject and between-subjects revealed significant condition and group effect (p < 0.0001 both) and significant interaction (p = 0.005), indicating worst performances in patients. The mean of the derived interference value was significantly higher in PCS patients than in controls (p = 0.036). Patients suffering from PCS show deficits in attention, both in the sustained and executive components. Both high RTs means and high IIV subtend these deficits and could explain the often-complained cognitive fluctuations in this population.

2522

N440

Naim Mahroum 1,*ORCID andYehuda Shoenfeld 2

Autoimmune Autonomic Dysfunction Syndromes: Potential Involvement and Pathophysiology Related to Complex Regional Pain Syndrome, Fibromyalgia, Chronic Fatigue Syndrome, Silicone Breast Implant–Related Symptoms and Post-COVID Syndrome

https://doi.org/10.3390/pathophysiology29030033

Published

28-Jul-22

Review

https://www.mdpi.com/1873-149X/29/3/33/htm

The pathophysiological mechanisms involved in chronic disorders such as complex regional pain syndrome, fibromyalgia, chronic fatigue syndrome, silicone breast implant–related symptoms, and post-COVID syndrome have not been clearly defined. The course of the pain in some of the syndromes, the absence of evident tissue damage, and the predominance of alterations in the autonomic nervous system are shared similarities between them. The production of autoantibodies following a trigger in the syndromes was previously described, for instance, trauma in complex regional pain syndrome, infectious agents in fibromyalgia, chronic fatigue syndrome, and post-COVID syndrome, and the immune stimulation by silicone in women with breast implants. In fact, the autoantibodies produced were shown to be directed against the autonomic nervous system receptors, leading to the amplification of the perception of pain alongside various clinical symptoms seen during the clinical course of the syndromes. Therefore, we viewed autoantibodies targeting the autonomic nervous system resulting in autonomic dysfunction as likely the most comprehensive explanation of the pathophysiology of the disorders mentioned. Based on this, we aimed to introduce a new concept uniting complex regional pain syndrome, fibromyalgia, chronic fatigue syndrome, silicone breast implant–related symptoms, and post-COVID syndrome, namely “autoimmune autonomic dysfunction syndromes”. Due to its etiological, pathophysiological, and clinical implications, the suggested term would be more precise in classifying the syndromes under one title. The new title would doubtlessly facilitate both laboratory and clinical studies aimed to improve diagnosis and make treatment options more directed and precise.

2523

N441

NedaOmidianaPanteaMohammadibMonaSadeghalvadbHamid-RezaMohammadi-Motlaghb1

Cerebral microvascular complications associated with SARS-CoV-2 infection: How did it occur and how should it be treated?

https://doi.org/10.1016/j.biopha.2022.113534

Published

17-Aug-22

Review

https://www.sciencedirect.com/science/article/pii/S0753332222009234

Highlights
•Endothelial dysfunction in Blood-Brain Barrier injures cerebrovascular in COVID-19.
•Hypercoagulation due to cerebral endothelial damage can cause stroke in COVID-19.
•Ischemic stroke due to SARS-CoV-2 infection is mostly present in younger patients.
•Anticoagulant therapy may improve cerebrovascular diseases in COVID-19 patients.
•Vaccine-induced immune thrombotic thrombocytopenia may rarely occur in some cases.
Abstract
Cerebral microvascular disease has been reported as a central feature of the neurological disorders in patients with SARS-CoV-2 infection that may be associated with an increased risk of ischemic stroke. The main pathomechanism in the development of cerebrovascular injury due to SARS-CoV-2 infection can be a consequence of endothelial cell dysfunction as a structural part of the blood-brain barrier (BBB), which may be accompanied by increased inflammatory response and thrombocytopenia along with blood coagulation disorders. In this review, we described the properties of the BBB, the neurotropism behavior of SARS-CoV-2, and the possible mechanisms of damage to the CNS microvascular upon SARS-CoV-2 infection.

2524

N442

Kristine Lokken, Melissa J Greenfield, Jamie Hansel Robinson, Udit Vipul Shah, Ronald M Lazar, Richard Kennedy, Roy C Martin, Kristen Triebel Gerstenecker, Adam Gerstenecker, Pariya Fazeli Wheeler, Shruti P Agnihotri, David E Vance

A-159 Neurocognitive Performance in Post-Acute Sequelae of COVID-19 (PASC)

https://doi.org/10.1093/arclin/acac060.159

Published

17-Aug-22

Study

https://academic.oup.com/acn/article/37/6/1313/6669101

Objective: Describe cognitive function in patients seeking treatment for Post-Acute Sequelae of COVID-19 (PASC).
Method: Ninety-two patients underwent neuropsychological evaluation secondary to reported “brain fog” following COVID-19 infection. Patients were referred from the University of Alabama at Birmingham (UAB) Post-COVID Treatment Program. Patients were on average 49 years of age (range: 18-74), female (77%), and White/Caucasian (73%)/Black/AA (25%), with 15.49 years of education (SD = 2.43).
Results: Overall, many patients demonstrated mild impairment on a brief global cognitive screener (MoCA; M = 24.78, SD = 3.46). On specific tasks of cognitive abilities, processing speed was variable; ranging from low average (Oral TMT Part A; M = 88.31, SD = 28.78) to below average (Oral SDMT; M = 72.80, SD = 20.37). Memory for immediate recall was low average (CVLT3-Brief Form (BF) Trials 1-4, M = 88.01, SD = 17.11), while delayed recall was average (CVLT3-BF, M = 94.17, SD = 19.11). Performances on measures of attention/working memory (WAIS-IV Digit Span; M = 96.75, SD = 12.54), executive functioning (Oral TMT Part B; M = 92.71, SD = 28.48), language (COWAT; M = 92.03, SD = 14.19) and visuospatial abilities (RBANS Figure Copy M = 104.04, SD = 16.08) were intact. Performance on embedded validity measures was also intact (RDS [95% valid]; CVLT-3 FC [93% valid]).
Conclusion: Overall, patients with “brain fog” following COVID-19 infection experience difficulties in specific domains of cognitive functioning. Further investigation of neuropsychological profiles associated with PASC is warranted to inform diagnosis, neurocognitive trajectory, and treatment planning.

2525

N443

Merve Hazal Ser, Fatma Zehra Çalıkuşu, Uygur Tanrıverdi, Hikmet Abbaszade, Sena Hakyemez, İlker İnanç Balkan, Rıdvan Karaali & Ayşegül Gündüz

Autonomic and neuropathic complaints of long-COVID objectified: an investigation from electrophysiological perspective

https://doi.org/10.1007/s10072-022-06350-y

Published

22-Aug-22

Study

https://link.springer.com/article/10.1007/s10072-022-06350-y

Purpose
Here , we aimed to assess the frequency and phenomenology of autonomic and neuropathic complaints of long-COVID and to evaluate them by means of electrophysiology.
Methods
Step 1. Patients with prior COVID-19 infection were screened by COMPASS-31 and mTORONTO to create the target population for further evaluation. Step 2. Patients with high scores were invited for a detailed history of their complaints and electrophysiological analysis, which included nerve conduction studies, cutaneous silent period (CSP), and sympathetic skin response (SSR). We also constituted a control group composed of healthy subjects of similar age and sex for electrophysiological analysis.
Results
There were 106 patients, who matched the study criteria. Among them, thirty-eight patients (%35.8) had neuropathic or autonomic complaints or both. Fatigue and headache were significantly more frequent in patients with autonomic and neuropathic complaints. Detailed examination and electrophysiological evaluation were performed in 14 of 38 patients. Neuropathic complaints were patchy and proximally located in the majority. The entire CSP suppression index was higher in the patients (p = 0.002). There was no difference in palmar and plantar SSR between patients and healthy subjects. mTORONTO scores were negatively correlated with palmar and plantar SSR amplitudes, and the correlation was moderate.
Conclusion
Neuropathic or autonomic complaints were seen in more than one-third of patients with long-COVID. Neuropathic complaints were generally patchy, proximally predominant, asymmetric, or diffuse. The CSP suppression index was abnormal whereas SSRs were normal.

2526

N444

Knut Stavem ,Gunnar Einvik,Birgitte Tholin,Waleed Ghanima,Erik Hessen,Christofer Lundqvist

Cognitive function in non-hospitalized patients 8–13 months after acute COVID-19 infection: A cohort study in Norway

https://doi.org/10.1371/journal.pone.0273352

Published

22-Aug-22

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0273352

Studies have reported reduced cognitive function following COVID-19 illness, mostly from hospital settings with short follow-up times. This study recruited non-hospitalized COVID-19 patients from a general population to study prevalence of late cognitive impairment and associations with initial symptoms. We invited patients with PCR-confirmed COVID-19. A postal questionnaire addressed basic demographics, initial COVID-19 symptoms and co-morbidity about 4 months after diagnosis. About 7 months later, we conducted cognitive tests using the Cambridge Neuropsychological Test Automated Battery, comprising four tests for short-term memory, attention and executive function. We present descriptive statistics using z-scores relative to UK population norms and defined impairment as z-score <-1.5. We used multivariable logistic regression with impairment as outcome. Continuous domain scores were analysed by multiple linear regression. Of the initial 458 participants; 305 were invited, and 234 (77%) completed cognitive testing. At median 11 (range 8–13) months after PCR positivity, cognitive scores for short term memory, visuospatial processing, learning and attention were lower than norms (p≤0.001). In each domain, 4–14% were cognitively impaired; 68/232 (29%) were impaired in ≥ 1 of 4 tests. There was no association between initial symptom severity and impairment. Multivariable linear regression showed association between spatial working memory and initial symptom load (6–9 symptoms vs. 0–5, coef. 4.26, 95% CI: 0.65; 7.86). No other dimension scores were associated with symptom load. At median 11 months after out-of-hospital SARS-Cov-2 infection, minor cognitive impairment was seen with little association between COVID-19 symptom severity and outcome.

2527

N445

COA

Amy Newhouse, MD,1,3,∗ Michael D. Kritzer, MD, PhD,1 Hamdi Eryilmaz, PhD,1 Nathan Praschan, MD, MPH,1 Joan A. Camprodon, MD, MPH, PhD,1,2 Gregory Fricchione, MD,1 and Zeina Chemali, MD, MPH1,2

Neurocircuitry hypothesis and clinical experience treating neuropsychiatric symptoms of post-acute sequelae of SARS-CoV-2 (PASC)

https://doi.org/10.1016%2Fj.jaclp.2022.08.007

Published

25-Aug-22

Review

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9404079/

Persistent symptoms following COVID-19 infection have been termed post-acute sequelae of SARS-CoV-2 infection (PASC). Many of these symptoms are neuropsychiatric, such as inattention, impaired memory, and executive dysfunction; these are often colloquially termed “brain fog”. These symptoms are common and often persist long after the acute phase. The pattern of these deficits combined with laboratory, neuroimaging, electroencephalographic and neuropsychological data suggest that these symptoms may be driven by direct and indirect damage to the frontal-subcortical neural networks. Here, we review this evidence, share our clinical experience at an academic medical center, and discuss potential treatment implications. While the exact etiology remains unknown, a neurocircuit-informed understanding of PASC can help guide pharmacology, neuromodulation, physical and psychological therapeutic approaches.

2528

N446

Michael Fleischer, Fabian Szepanowski, Muriel Tovar, Klaas Herchert, Hannah Dinse, Adam Schweda, Anne K. Mausberg, Dagny Holle-Lee, Martin Köhrmann, Julia Stögbauer, Daniel Jokisch, Martha Jokisch, Cornelius Deuschl, Eva-Maria Skoda, Martin Teufel, Mark Stettner & Christoph Kleinschnitz

Post-COVID-19 Syndrome is Rarely Associated with Damage of the Nervous System: Findings from a Prospective Observational Cohort Study in 171 Patients

https://doi.org/10.1007/s40120-022-00395-z

Published

26-Aug-22

Study

https://link.springer.com/article/10.1007/s40120-022-00395-z

Introduction
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can affect multiple organs. Reports of persistent or newly emergent symptoms, including those related to the nervous system, have increased over the course of the pandemic, leading to the introduction of post-COVID-19 syndrome. However, this novel syndrome is still ill-defined and structured objectification of complaints is scarce. Therefore, we performed a prospective observational cohort study to better define and validate subjective neurological disturbances in patients with post-COVID-19 syndrome.
Methods
A total of 171 patients fulfilling the post-COVID-19 WHO Delphi consensus criteria underwent a comprehensive neurological diagnostic work-up including neurovascular, electrophysiological, and blood analysis. In addition, magnetic resonance imaging (MRI) and lumbar puncture were conducted in subgroups of patients. Furthermore, patients underwent neuropsychological, psychosomatic, and fatigue assessment.
Results
Patients were predominantly female, middle-aged, and had incurred mostly mild-to-moderate acute COVID-19. The most frequent post-COVID-19 complaints included fatigue, difficulties in concentration, and memory deficits. In most patients (85.8%), in-depth neurological assessment yielded no pathological findings. In 97.7% of the cases, either no diagnosis other than post COVID-19 syndrome, or no diagnosis likely related to preceding acute COVID-19 could be established. Sensory or motor complaints were more often associated with a neurological diagnosis other than post-COVID-19 syndrome. Previous psychiatric conditions were identified as a risk factor for developing post-COVID-19 syndrome. We found high somatization scores in our patient group that correlated with cognitive deficits and the extent of fatigue.
Conclusions
Albeit frequently reported by patients, objectifiable affection of the nervous system is rare in post-COVID-19 syndrome. Instead, elevated levels of somatization point towards a pathogenesis potentially involving psychosomatic factors. However, thorough neurological assessment is important in this patient group in order to not miss neurological diseases other than post-COVID-19.
Key Summary Points
Why carry out this study?
To validate subjective neurological complaints in patients with post-COVID-19 by applying a comprehensive neuro-psychiatric diagnostic workup.
What was learned from the study?
The nervous system is rarely affected in patients with post-COVID-19 syndrome.
Psychosomatic factors probably contribute to the pathogenesis of post-COVID-19 syndrome.
Patients presenting with post-COVID-19 should be thoroughly assessed in order to not miss other diagnoses.

2529

N447

Ayşe YağmurKanraaMeltem GüzinAltınelbFundaAlparslanc

EVALUATION OF RETINAL AND CHOROIDAL PARAMETERS AS NEURODEGENERATION BIOMARKERS IN PATIENTS WITH POST-COVID-19 SYNDROME: Evaluation of retinal and choroidal parameters as neurodegeneration biomarkers in patients with persistent post-COVID symptoms

https://doi.org/10.1016/j.pdpdt.2022.103108

Published

6-Sep-22

Study

https://www.sciencedirect.com/science/article/abs/pii/S1572100022003945

Highlights
•An overall thinning of the GCL, IPL, and IRL layers can be detected as the direct or indirect effect of SARS-CoV-2, a neurotropic virus, on these layers, rather than a long-term neurodegenerative effect in the post-COVID-19 period.
•Statistically significant change in CMT, pRNFL, and CVI parameters are not observed in the post-COVID-19 period.
•SARS-CoV-2, as a neurotropic virus, may trigger such neurodegenerative diseases in susceptible individuals in the long term.
•The most common neurologic symptom is the headache in the post-COVID-19 period.
Abstract
Background
To investigate the neurodegenerative effects of post-COVID-19 syndrome.
Methods
This comparative, cross-sectional study included patients who had post-COVID-19 prolonged neurologic symptoms. The control group was selected from volunteer participants with similar age, sex, and spherical equivalent characteristics. After detailed ophthalmic examinations, spectral-domain optic coherence tomography (SD-OCT) analysis of the macula and peripapillary retinal nerve fiber layer (m-RNFL, p-RNFL respectively) were obtained. We also evaluated the choroidal parameters with the ImageJ software. Post-COVID-19 symptoms and disease severity of the patients were also questioned.
Results
Thirty-four eyes of 20 patients, and 39 eyes of 23 healthy individuals were included in the study. Thinning was found in the inner superior quadrant of mRNFL (p<0.05). More prominent and common thinning of retinal layers was observed in the ganglion cell layer (GCL) and inner plexiform layer (IPL) segments in the patient group. There was no difference between the groups in the calculated choroidal parameters (p>0.05). In the regression models created, lung involvement was the most prominent parameter associated with thinning of the OCT layers. The other factors were male sex, and the presence of loss of taste and smell also led to deterioration in some parameters.
Conclusions
We detected an overall thinning of the GCL and IPL layers with no significant change in CMT, pRNFL, and CVI in the post-COVID-19 period, indicating the direct or indirect effect of SARS-CoV-2 on these layers, rather than a long-term neurodegenerative effect.

2530

N448

Kristin L. Bigos
Andrea M. Goldensohn

COVID-19 Infection and Risk for Neuropsychiatric Symptoms

https://doi.org/10.1016/j.biopsych.2022.06.032

Published

1-Oct-22

Commentary

https://www.biologicalpsychiatryjournal.com/article/S0006-3223(22)01402-0/fulltext

In the current issue of Biological Psychiatry, Gillespie et al. (1) show a notable association between the use of statins and cognitive markers that indicate a decreased psychological vulnerability to depression, including affective bias and reward processing. In this study, use of statins was associated with reduced recognition of angry and fearful faces, and reduced learning about stimuli associated with loss. Further, these indicators of reduced negative bias were not found in patients taking antihypertensive medications, without statins. Future prospective, controlled, randomized, clinical studies should be conducted to determine the potential use of statins as prophylactic treatment for depression. Statins are among the most commonly prescribed classes of medications, and their use has been associated with a lower risk of all-cause mortality, with an even greater effect in patients with dementia (2). These new data suggest a potential role for statins in the prevention and treatment of depression, especially in older adults, which may contribute to their effects on lifespan by promoting psychological resilience. Safe and effective use of medications for the prevention and/or treatment of mood symptoms is even more important during the COVID-19 pandemic.
In addition to the acute effects of the virus, some patients experience longer-term symptoms after COVID-19 infection, termed post-acute sequelae of SARS-CoV-2 infection (PASC), and also known as long COVID. Neuropsychological symptoms of PASC include depression, anxiety, cognitive impairment, sleep dysfunction, chronic fatigue, headache, and sensorimotor symptoms. Most studies of neuropsychiatric symptoms related to PASC have been conducted in adults, but there are case reports of children with similar neuropsychiatric manifestations. One study found that 15% of adult patients reported posttraumatic stress symptoms 1 month postdischarge from their COVID-19 hospitalization (5). Another study followed up with patients 3 months postdischarge and found that 15% of patients met the criteria for a diagnosis of depression based on their responses on the Patient Health Questionnaire-9, and 6% of patients experienced suicidality (6). In this study, the greatest predictors of the development of depression were history of a prior psychiatric disorder, female sex, and chronic pulmonary conditions (6), suggesting that those individuals should be most closely monitored for psychiatric symptoms after hospitalization for COVID-19. A separate study recruited patients with no prior psychiatric history and found that subjects who were previously diagnosed with COVID-19 had significantly higher scores of depression (Beck Depression Inventory-II), anxiety (Mood and Anxiety Symptom Questionnaire), and anhedonia (Snaith-Hamilton Pleasure Scale) than those who did not have a COVID-19 infection (7). The scores were highest during the acute phase (14–30 days postdiagnosis) and PASC phase (1–4 months postdiagnosis) compared with more than 4 months postdiagnosis (7). In addition, the subjects with a prior COVID-19 infection had a selective impairment in executive functioning, while alerting and orienting abilities remained intact (7). These case-control studies have become harder to conduct because vaccines have become less effective at preventing infection, and therefore a greater percentage of the population has become infected. However, future research could correlate infection duration and severity with acute and longer-term neuropsychiatric symptoms and structural and functional brain changes, such as task-based functional magnetic resonance imaging (MRI).
There is emerging evidence of structural, functional, and biochemical changes in the human brain after COVID-19 infection. A longitudinal study using structural MRI data from the UK Biobank (n = 755, ages 51–81 years) included 401 subjects who tested positive for infection with SARS-CoV-2 between their two MRI scans and 384 control subjects (8). Subjects who had a prior infection showed a greater cognitive decline between their first and second scans, with an average of 4.5 months between reported diagnosis and the second scan. They found structural brain changes in patients after even mild COVID-19 infection, including a greater reduction in global brain size, a greater reduction in gray matter in the orbitofrontal cortex and parahippocampal gyrus, and greater changes in markers of tissue damage in regions connected to the primary olfactory cortex (8). Concerningly, there are also reports of MRI evidence of brain inflammation in children with mild or even asymptomatic COVID-19 infection. A postmortem study found tau hyperphosphorylation in brain lysate from deceased COVID-19 patients (9), which is pathology found in patients with Alzheimer’s disease and associated with neurodegeneration and Alzheimer’s disease progression. The same postmortem study found increased glutamate carboxypeptidase II (GCPII) (9), which is known to be increased with inflammation, aging, and several neuropsychiatric disorders. GCPII is the primary regulator of N-acetylaspartyl glutamate (NAAG), the endogenous ligand for the metabotropic glutamate receptor 3, and increases in GCPII are associated with lower NAAG and cognitive deficits (10). The increased incidence of neuropsychiatric and cognitive symptoms after COVID-19 infection may be related to these signs of brain inflammation and structural damage to key brain regions and circuitries.
Consequently, there is an urgent need to identify and/or develop tools for the prevention or treatment of the neuropsychiatric and cognitive symptoms associated with COVID-19 infection. Repurposing medications could provide much-needed treatment options to promote psychological resilience. Neuropsychiatric symptoms are most likely to emerge or worsen in older adults with and without dementia and appear to be the consequence of both COVID-19 infection and prolonged social isolation. Preventive treatment options may be most important for young children, whose brains are still developing and changing at the highest rate and therefore are most vulnerable to viral and immunological insults. Further research is also required to understand the indirect effect of the pandemic on mental health in order to improve prevention, treatment, and planning for increased availability of mental health care services during COVID-19, as well as potential future pandemics.

2531

N449

BiancaBesteheraMarleneMachnikaMarieTrollaAntoniaToepfferaAniZerekidzeaToniaRocktäschelaCarinaHellerabcZoraKikinisbStefanBrodoehldKathrinFinkedPhilipp A.ReukeneNilsOpelaAndreasStallmacheChristianGaserad1MartinWaltera1

Larger gray matter volumes in neuropsychiatric long-COVID syndrome

https://doi.org/10.1016/j.psychres.2022.114836

Published

6-Sep-22

Study

https://www.sciencedirect.com/science/article/pii/S0165178122004292

Highlights
•Neuropsychiatric symptoms are common among long-COVID patients.
•Cortical and subcortical gray matter volumes are increased in these patients.
•Gray matter alterations occur in limbic and secondary olfactory system.
•Gray matter volumes are inversely associated with time since onset of COVID-19.
Abstract
Neuropsychiatric symptoms are the most common sequelae of long-COVID. As accumulating evidence suggests an impact of survived SARS-CoV-2-infection on brain physiology, it is necessary to further investigate brain structural changes in relation to course and neuropsychiatric symptom burden in long-COVID.
To this end, the present study investigated 3T-MRI scans from long-COVID patients suffering from neuropsychiatric symptoms (n = 30), and healthy controls (n = 20). Whole-brain comparison of gray matter volume (GMV) was conducted by voxel-based morphometry. To determine whether changes in GMV are predicted by neuropsychiatric symptom burden and/or initial severity of symptoms of COVID-19 and time since onset of COVID-19 stepwise linear regression analysis was performed.
Significantly enlarged GMV in long-COVID patients was present in several clusters (spanning fronto-temporal areas, insula, hippocampus, amygdala, basal ganglia, and thalamus in both hemispheres) when compared to controls. Time since onset of COVID-19 was a significant regressor in four of these clusters with an inverse relationship. No associations with clinical symptom burden were found.
GMV alterations in limbic and secondary olfactory areas are present in long-COVID patients and might be dynamic over time. Larger samples and longitudinal data in long-COVID patients are required to further clarify the mediating mechanisms between COVID-19, GMV and neuropsychiatric symptoms.

2532

N450

Christina D. Kay 1,†,Ana Sofia Costa 2,3,†ORCID,Tracy D. Vannorsdall 4,5,Paula Aduen 6,Clara Vila-Castelar 6ORCID,Sarah M. Burstein 1,Lauren Pollak 1,Daniel K. Leibel 4,Janet C. Sherman 1,Julia Bungenberg 2,Kathrin Reetz 2,3ORCID andYakeel T. Quiroz 6,*

Neuropsychological Outcomes of COVID-19: A Multicenter, Cross-Cultural Study of Patients Referred for Outpatient Assessment

https://doi.org/10.3390/covid2090092

Published

2-Sep-22

Study

https://www.mdpi.com/2673-8112/2/9/92/htm

Objective: Cognitive dysfunction is one of the most frequently reported symptoms in post-acute sequelae of COVID-19 (PASC) and has become a common reason for neuropsychological referral. While data are emerging, we aimed to address possible cross-cultural patterns of neuropsychological outcomes that remain underexplored. Methods: In this cross-sectional, retrospective study, we characterize the cognitive performance, demographic makeup, and clinical characteristics of 84 PASC patients (Mage = 57 years) referred for neuropsychological evaluation to three USA sites and one in Germany. Neuropsychological data (mean demographically adjusted z-scores and frequencies of impairment) were examined across six cognitive domains. Independent t-tests compared performances of previously hospitalized and non-hospitalized patients. Results: Patients were assessed on average seven months post-COVID-19 infection. The majority were women and non-hospitalized. Mean cognitive performance was within the normative range, but high variability existed within and between sites. Deficits were generally mild and most frequent in processing speed (range across sites: 9–57% of patients), executive functioning (range across sites: 4–43% of patients) and attention/working memory (range across sites: 0–43% of patients). Hospitalized patients showed greater cognitive impairment than those not requiring hospitalization. Mood symptoms and fatigue/sleep disturbance were more frequent than objective cognitive impairments. At the time of assessment, most patients were unable to return to work. Conclusions: Cognitive performance in clinically referred PASC patients was, overall, within the normative range. Mild deficits were most frequent in time-based attentional/executive tasks. Other factors, such as affective symptoms and fatigue, were frequent and may significantly impact functioning, perhaps more than cognition. Further work with larger samples and longitudinal measures is needed to clarify the impact of COVID-19 on cognitive function and psychiatric distress.

2533

N451

Pasquale Picone, Tiziana Sanfilippo, Rossella Guggino, Luca Scalisi, Roberto Monastero, Roberta Baschi, Valeria Mandalà, Livio San Biagio, Manfredi Rizzo, Daniela Giacomazza, Clelia Dispenza & Domenico Nuzzo

Neurological Consequences, Mental Health, Physical Care, and Appropriate Nutrition in Long-COVID-19

https://doi.org/10.1007/s10571-022-01281-w

Published

14-Sep-22

Review

https://link.springer.com/article/10.1007/s10571-022-01281-w

SARS-CoV-2 pandemic has caused a collapse of the world health systems. Now, vaccines and more effective therapies have reversed this crisis but the scenario is further aggravated by the appearance of a new pathology, occurring as SARS-CoV-2 infection consequence: the long-COVID-19. This term is commonly used to describe signs and symptoms that continue or develop after acute infection of COVID-19 up to several months. In this review, the consequences of the disease on mental health and the neurological implications due to the long-COVID are described. Furthermore, the appropriate nutritional approach and some recommendations to relieve the symptoms of the pathology are presented. Data collected indicated that in the next future the disease will affect an increasing number of individuals and that interdisciplinary action is needed to counteract it.

2534

N452

Tania LlanaORCID Icon,Candela ZorzoORCID Icon,Magdalena Mendez-LopezORCID Icon &Marta MendezORCID Icon

Memory alterations after COVID-19 infection: a systematic review

https://doi.org/10.1080/23279095.2022.2123739

Published

15-Sep-22

Review

https://www.tandfonline.com/doi/abs/10.1080/23279095.2022.2123739

SARS-CoV-2 infection has a wide range of both acute and long-term symptoms. Memory alterations have been frequently reported in studies that explore cognition. The main objective of the systematic review is to update and further analyze the existing evidence of objective memory impairments in long-COVID-19 considering sample and study design characteristics, as well as to explore associations between memory performance and their epidemiological, clinical, and pathological features. A total of 13 studies were identified by searching in PubMed, Web of Science, and PsycInfo databases up to May 6, 2022. Most studies evaluated verbal component of memory in the short-term and long-term recall up to 30 min and mainly performed a single assessment completed at 4–6 months after the infection. The samples mainly consisted of middle-aged adults that required hospitalization. Samples were not stratified by sex, age, and severity. Poor verbal learning was reported in most cases (6–58%), followed by deficits in long-term (4–58%) and short-term (4–37%) verbal memory. Visuospatial component of memory was studied less than verbal component, showing impairment of long-term retention of visual items (10–49%). COVID-19 severity in the acute stage was not systematically associated with poor memory performance. Verbal memory deficits were associated with anxiety and depression. The existing literature on objective memory assessment in long-COVID suggests further research is warranted to confirm memory dysfunction in association with epidemiological, pathological, and clinical factors, using both verbal and visuospatial tests, and exploring in deep long-term memory deficits.

2535

N453

César Fernández-de-las-Peñas Dr. Med, PhD,Maria L. Cuadrado MD, PhD,Victor Gómez-Mayordomo MD,Juan Torres-Macho MD,Oscar J. Pellicer-Valero PhD,José D. Martín-Guerrero PhD,Lars Arendt-Nielsen Dr. Med, PhD

Headache as a COVID-19 onset symptom and post-COVID-19 symptom in hospitalized COVID-19 survivors infected with the Wuhan, Alpha, or Delta SARS-CoV-2 variants

https://doi.org/10.1111/head.14398

Published

16-Sep-22

Study

https://headachejournal.onlinelibrary.wiley.com/doi/10.1111/head.14398

Objective
This study looked at differences in the presence of headache as an onset symptom of coronavirus disease 2019 (COVID-19) and as a post-COVID-19 symptom in individuals previously hospitalized owing to infection with the Wuhan, Alpha, or Delta variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Background
Headache can be present in up to 50% of individuals during the acute phase of SARS-CoV-2 infection and in 10% of subjects during the post-COVID-19 phase. There are no data on differences in the occurrence of headache in the acute- and post-COVID-19 phase according to the SARS-CoV-2 variants.
Methods
A cross-sectional cohort study was conducted. Unvaccinated subjects previously hospitalized for COVID-19 caused by the Wuhan (n = 201), Alpha (n = 211), or Delta (n = 202) SARS-CoV-2 variants were scheduled for a telephone interview 6 months after hospital discharge. Hospitalization data were collected from hospital medical records.
Results
The presence of headache as a COVID-19 onset symptom at hospitalization was higher in subjects with the Delta variant (66/202, 32.7%) than in those infected with the Wuhan (42/201, 20.9%; odds ratio [OR] 1.83, 95% confidence interval [CI] 1.17–2.88) or Alpha (25/211, 11.8%; OR 3.61, 95% CI, 2.16–6.01) variants. The prevalence of post-COVID-19 headache 6 months after hospital discharge was higher in individuals infected with the Delta variant (26/202, 12.9%) than in those infected with the Wuhan (11/201, 5.5%; OR 2.52, 95% CI 1.22–5.31) or Alpha (eight of 211, 3.8%; OR 3.74, 95% CI 1.65–8.49) variants. The presence of headache as a COVID-19 onset symptom was associated with post-COVID-19 headache in subjects infected with the Wuhan (OR 7.75, 95% CI 2.15–27.93) and Delta variants (OR 2.78, 95% CI 1.20–6.42) but not with the Alpha variant (OR 2.60, 95% CI 0.49–13.69).
Conclusion
Headache was a common symptom in both the acute- and post-COVID-19 phase in subjects infected with the Wuhan, Alpha, and Delta variants but mostly in those infected with the Delta variant.

2536

N454

Tim J.Hartungab1ChristianNeumannc1ThomasBahmerdeIrinaChaplinskaya-SobolfMatthiasEndresaghijJohannaGeritzcKarl GeorgHaeuslerkPeter U.HeuschmannlmHannaHildesheimcAndreasHinzbSinaHopffnAnnaHornlMichaelKrawczakoLilianKristpJenniferKudelkacWolfgangLiebqCorinaMaetzlercAnjaMehnert-TheuerkaufbFelipe A.MontellanolkrCarolineMorbachsSeinSchmidttStefanSchreiberuFloSteigerwaldaStefanStörkvwWalterMaetzlerc1CarstenFinkea1

Fatigue and cognitive impairment after COVID-19: A prospective multicentre study

https://doi.org/10.1016/j.eclinm.2022.101651

Published

17-Sep-22

Study

https://www.sciencedirect.com/science/article/pii/S2589537022003819

Background
Reliable estimates of frequency, severity and associated factors of both fatigue and cognitive impairment after COVID-19 are needed. Also, it is not clear whether the two are distinct sequelae of COVID-19 or part of the same syndrome.
Methods
In this prospective multicentre study, frequency of post-COVID fatigue and cognitive impairment were assessed in n = 969 patients (535 [55%] female) ≥6 months after SARS-CoV-2 infection with the FACIT-Fatigue scale (cut-off ≤30) and Montreal Cognitive Assessment (≤25 mild, ≤17 moderate impairment) between November 15, 2020 and September 29, 2021 at University Medical Center Schleswig-Holstein, Campus Kiel and University Hospital Würzburg in Germany. 969 matched non-COVID controls were drawn from a pre-pandemic, randomised, Germany-wide population survey which also included the FACIT-Fatigue scale. Associated sociodemographic, comorbid, clinical, psychosocial factors and laboratory markers were identified with univariate and multivariable linear regression models.
Findings
On average 9 months after infection, 19% of patients had clinically relevant fatigue, compared to 8% of matched non-COVID controls (p < 0.001). Factors associated with fatigue were female gender, younger age, history of depression and the number of acute COVID symptoms. Among acute COVID symptoms, altered consciousness, dizziness and myalgia were most strongly associated with long-term fatigue. Moreover, 26% of patients had mild and 1% had moderate cognitive impairment. Factors associated with cognitive impairment were older age, male gender, shorter education and a history of neuropsychiatric disease. There was no significant correlation between fatigue and cognitive impairment and only 5% of patients suffered from both conditions.
Interpretation
Fatigue and cognitive impairment are two common, but distinct sequelae of COVID-19 with potentially separate pathophysiological pathways.

2537

N455

Md Sakibuzzaman, Anid Hassan, Samira Hayee, Fariah Asha Haque, Sumaita Sadida Bushra, Maisha Maliha, Maksuda Khan Tania, Anahita Sadat, Fahima Akter, Tanusree Mazumder, Joyeta Razzaque, Progga Kapuria, Ishra Jalal, Prince Shah-Riar

Exacerbation of Pre-existing Neurological Symptoms With COVID-19 in Patients With Chronic Neurological Diseases: An Updated Systematic Review

https://doi.org/10.7759/cureus.29297

Published

18-Sep-22

Review

https://www.cureus.com/articles/113896-exacerbation-of-pre-existing-neurological-symptoms-with-covid-19-in-patients-with-chronic-neurological-diseases-an-updated-systematic-review

The neurotropism of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can potentially explain the worsening of symptoms in patients with a history of neurological conditions such as stroke, Parkinson's disease, Alzheimer's, and epilepsy. Several studies have reported that these pre-existing conditions may worsen with a higher frequency of flare-ups, thus resulting in a more significant risk of patient mortality. In this review, we sought to provide an overview of the relationship between pre-existing neurological disorders and COVID-19, focusing on whether the initial infection directly influenced the severity of symptoms. We systematically searched the electronic database PubMed (MEDLINE) and used specific keywords related to our aims from January 2020 to July 2022. All articles published on COVID-19 with keywords pertaining to pre-existing neurological diseases were retrieved and subsequently analyzed. After independent review, the data from 107 articles were selected and evaluated. After analyzing the data from selected articles reviewing the effect of COVID-19 on neurological conditions, we have documented the relationship between said pre-existing neurological diseases, showing an increased risk of hospitalization, admission length, worsening of symptoms, and even mortality in COVID-19 patients.

2538

N456

Abdul Mannan Baig*

Differential diagnosis and pathogenesis of the neurological signs and symptoms in COVID-19 and long-COVID syndrome

https://doi.org/10.1111/cns.13957

Published

19-Sep-22

EDITORIAL COMMENTARY

https://onlinelibrary.wiley.com/doi/10.1111/cns.13957

Neurological features have now been reported very frequently in the ongoing COVID-19 pandemic caused by SARS-CoV-2. The neurological deficits associated features are observed in both acute and chronic stages of COVID-19 and they appear to overlap with wide-ranging symptoms that can be attributed to being of non-neural origins, thus obscuring the definitive diagnosis of neuro-COVID. The pathogenetic factors acting in concert to cause neuronal injury are now emerging, with SARS-CoV-2 directly affecting the brain coupled with the neuroinflammatory factors have been implicated in the causation of disabilities in acute COVID-19 and patients with Long-COVID syndrome. As the differentiation between a neural origin and other organ-based causation of a particular neurological feature is of prognostic significance, it implores a course of action to this covert, yet important neurological challenge.

2539

N457

Dean Walton, Roberto Acampora, Greta Karen Wood, Elias Premi, Ingrid Andreea Ilie, Francesco Lanfranchi & Benedict Daniel Michael

Neurological Complications of COVID-19

https://doi.org/10.1007/978-3-031-08045-6_18

Published

9-Sep-22

Review

https://link.springer.com/chapter/10.1007/978-3-031-08045-6_18

The neurological complications of COVID-19 are an expansive and heterogeneous topic. This chapter discusses the neuropathophysiology of COVID-19 and the potential mechanisms through which the disease leads to neurological manifestations while also exploring historical viruses that have also led to neurological sequelae. These complications are then characterized and classified into several groups with support from contemporaneous evidence. In addition to this we examine common neurological imaging and their findings and finally discuss the greatest needs moving forward with regard to evidence and research through collaborative efforts.

2540

N458

Alna Carolina Mendes Paranhos, MSc1,2; Ápio Ricardo Nazareth Dias, PhD2; Livia Caroline Machado da Silva2; Gisele Vieira Hennemann Koury, PhD2; Emanuel de Jesus Sousa, PhD2; Antônio José Cerasi Jr, MSc3,4; Givago Silva Souza, PhD1,3; Juarez Antônio Simões Quaresma, PhD1,2; Luiz Fábio Magno Falcão, PhD2,5

Sociodemographic Characteristics and Comorbidities of Patients With Long COVID and Persistent Olfactory Dysfunction

https://doi.org/10.1001/jamanetworkopen.2022.30637

Published

8-Sep-22

Study

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2795995

Key Points
Question What are the sociodemographic and clinical characteristics of patients with long COVID and persistent olfactory dysfunction?
Findings In this cross-sectional study of 219 patients with long COVID and neurologic symptoms, 64% had olfactory dysfunction, with the highest prevalence among women, adults, and outpatients. Patients with olfactory dysfunction may develop severe olfactory loss (hyposmia or anosmia) that may persist for more than 1 year after the onset of symptoms.
Meaning This study suggests that olfactory dysfunction in patients with long COVID may become permanent.
Abstract
Importance Determining the characteristics, type, and severity of olfactory dysfunction in patients with long COVID is important for the prognosis and potential treatment of the affected population.
Objective To describe the sociodemographic and clinical features of patients with long COVID who develop persistent olfactory dysfunction.
Design, Setting, and Participants This cross-sectional study, conducted at a rehabilitation center at a public university in the Amazon region of Brazil between September 9, 2020, and October 20, 2021, comprised 219 patients with long COVID and self-reported neurologic symptoms. Of these 219 patients, 139 received a diagnosis of chronic olfactory dysfunction, as confirmed by the Connecticut Chemosensory Clinical Research Center (CCCRC) test.
Exposure Clinical diagnosis of long COVID.
Main Outcomes and Measures Electronic case report forms were prepared for the collection of sociodemographic and clinical data. Patients’ sense of smell was evaluated via a CCCRC test, and the association of olfactory dysfunction with aspects of daily life was recorded using a questionnaire.
Results Of the 219 patients included in the study, 164 (74.9%) were women, 194 (88.6%) were between 18 and 59 years of age (mean [SD] age, 43.2 [12.9] years), 206 (94.1%) had more than 9 years of education, and 115 (52.5%) had a monthly income of up to US $192.00. In the study group, 139 patients (63.5%) had some degree of olfactory dysfunction, whereas 80 patients (36.5%) had normosmia. Patients with olfactory dysfunction had a significantly longer duration of long COVID symptoms than those in the normosmia group (mean [SD], 242.7 [101.9] vs 221.0 [97.5] days; P = .01). Among patients with anosmia, there was a significant association between olfactory dysfunction and daily activities, especially in terms of impairment in hazard detection (21 of 31 patients [67.7%]), personal hygiene (21 of 31 patients [67.7%]), and food intake (21 of 31 patients [67.7%]). Univariable logistic regression analyses found that ageusia symptoms were associated with the occurrence of olfactory dysfunction (odds ratio [OR], 11.14 [95% CI, 4.76-26.07]; P < .001), whereas headache (OR, 0.41 [95% CI, 0.22-0.76]; P < .001) and sleep disorders (OR, 0.48 [95% CI, 0.26-0.92]; P = .02) showed an inverse association with the occurrence of olfactory dysfunction.
Conclusions and Relevance Olfactory dysfunction is one of the most important long-term neurologic symptoms of COVID-19, with the highest prevalence seen among women, adults, and outpatients. Patients with olfactory dysfunction may experience persistent severe hyposmia or anosmia more than 1 year from the onset of symptoms, suggesting the possibility of the condition becoming a permanent sequela.

2541

N459

AnnaBaumeisteraAnja S.GöritzdCharlesBenoybcLenaJelinekaSteffenMoritza

Long-COVID or long before? Neurocognitive deficits in people with COVID-19

https://doi.org/10.1016/j.psychres.2022.114822

Published

8-Sep-22

Study

https://www.sciencedirect.com/science/article/pii/S0165178122004152

Highlights
•The COVID group of the follow-up survey reported increased subjective neurocognitive complaints.
•These complaints were not consistent with objective test performance.
•The COVID group showed a greater depressive symptom burden compared with the non-COVID group.
•Complaints need to be put into perspective when considering pre-pandemic data, as they were present prior to infection.
Abstract
In connection with COVID-19 disease, evidence of persisting psychiatric and neurocognitive effects is accumulating. To examine long COVID symptoms, baseline data from 2015 (i.e., before the pandemic) and follow-up data from 2021 from 428 participants were compared. Participants with COVID-19 reported more subjective neurocognitive complaints in the follow-up, but this did not correspond to the test performance. Also, greater depressive symptoms compared with the no-COVID group were reported. However, these complaints must be put into perspective when considering the baseline data, since complaints were present before the COVID infection. Thus, premorbid performance as well as psychological factors should be considered when discussing long COVID.

2542

N460

AshwinKumariaaAbiodunNoahbMatthew A.Kirkmana

Does covid-19 impair endogenous neurogenesis?

https://doi.org/10.1016/j.jocn.2022.09.006

Published

13-Sep-22

Opinion

https://www.sciencedirect.com/science/article/pii/S0967586822003575

Highlights
•COVID-19 associated impairment in neural stem cell activity may contribute to cognitive impairment and hyposmia.
•Neural stem cell dysfunction may be a neuropathological link between neurodegeneration and hyposmia.
•Therapeutic upregulation of neural stem cell activity may improve symptoms of long COVID.
•SARS-CoV-2 may have a role in oncolytic virotherapy by targeting brain tumour stem cells.
Abstract
Endogenous neural stem cells are thought to continue to generate new neurons throughout life in the human brain. Endogenous neurogenesis has been proposed to contribute to physiological roles in maintaining and regenerating olfaction, as well as promoting normal cognition, learning and memory. Specific impairments in these processes in COVID-19 – impaired olfaction and cognition – may implicate the SARS-CoV-2 virus in attenuating neurogenesis. Furthermore, neurogenesis has been linked with neuroregeneration; and impaired neuroregeneration has previously been linked with neurodegenerative diseases. Emerging evidence supports an association between COVID-19 infection and accelerated neurodegeneration. Also, structural changes indicating global reduction in brain size and specific reduction in the size of limbic structures – including orbitofrontal cortex, olfactory cortex and parahippocampal gyrus – as a result of SARS-CoV-2 infection have been demonstrated.
This paper proposes the hypothesis that SARS-CoV-2 infection may impair endogenous neural stem cell activity. An attenuation of neurogenesis may contribute to reduction in brain size and/or neurodegenerative processes following SARS-CoV-2 infection. Furthermore, as neural stem cells are thought to be the cell of origin in glioma, better understanding of SARS-CoV-2 interaction with tumorigenic stem cells is indicated, with a view to informing therapeutic modulation. The subacute and chronic implications of attenuated endogenous neurogenesis are explored in the context of long COVID. Modulating endogenous neurogenesis may be a novel therapeutic strategy to address specific neurological manifestations of COVID-19 and potential applicability in tumour virotherapy.

2543

N461

Erin K. Bailey, Joel E. Kamper & Becky Gius

Anticipated Long-Term Neurobehavioral Outcomes Following COVID-19

https://doi.org/10.1007/978-3-031-08045-6_30

Published

9-Sep-22

Article

https://link.springer.com/chapter/10.1007/978-3-031-08045-6_30

First identified in December 2021, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)—the virus causing COVID-19, is responsible for significant morbidity and mortality rates. Given the worldwide impact of COVID-19, there is much interest in the anticipated long-term effects for those with history of SARS-CoV-2 infection. While initially presumed as a respiratory infection, there is now evidence of a broader array of pathophysiological mechanisms which result in a wide spectrum of reported acute and chronic symptoms in patients with confirmed COVID-19. These include including memory and other neurocognitive changes as well as psychiatric and behavioral symptoms. These nonspecific, but often debilitating, sequalaeare complex and difficult to disentangle from more common causes of neurobehavioral change. The goal of this chapter is to discuss anticipated chronic neurocognitive and psychiatric outcomes of COVID-19 survivors based on emerging peer-reviewed literature, data from prior pandemics, and outcome studies from well-characterized, clinically similar syndromes. This unpacking of long-term complications from COVID-19 will seek to set expectations and provide guidance for clinicians who will undoubtably encounter increased volumes of patients with residual post-COVID-19 neurobehavioral changes.

2544

N462

Walter J. Lukiw 1,2,3,4,*,Vivian R. Jaber 1,Aileen I. Pogue 2 andYuhai Zhao 1,5

SARS-CoV-2 Invasion and Pathological Links to Prion Disease

https://doi.org/10.3390/biom12091253

Published

7-Sep-22

Commentary

https://www.mdpi.com/2218-273X/12/9/1253/htm

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 disease, is a highly infectious and transmissible viral pathogen that continues to impact human health globally. Nearly ~600 million people have been infected with SARS-CoV-2, and about half exhibit some degree of continuing health complication, generically referred to as long COVID. Lingering and often serious neurological problems for patients in the post-COVID-19 recovery period include brain fog, behavioral changes, confusion, delirium, deficits in intellect, cognition and memory issues, loss of balance and coordination, problems with vision, visual processing and hallucinations, encephalopathy, encephalitis, neurovascular or cerebrovascular insufficiency, and/or impaired consciousness. Depending upon the patient’s age at the onset of COVID-19 and other factors, up to ~35% of all elderly COVID-19 patients develop a mild-to-severe encephalopathy due to complications arising from a SARS-CoV-2-induced cytokine storm and a surge in cytokine-mediated pro-inflammatory and immune signaling. In fact, this cytokine storm syndrome: (i) appears to predispose aged COVID-19 patients to the development of other neurological complications, especially those who have experienced a more serious grade of COVID-19 infection; (ii) lies along highly interactive and pathological pathways involving SARS-CoV-2 infection that promotes the parallel development and/or intensification of progressive and often lethal neurological conditions, and (iii) is strongly associated with the symptomology, onset, and development of human prion disease (PrD) and other insidious and incurable neurological syndromes. This commentary paper will evaluate some recent peer-reviewed studies in this intriguing area of human SARS-CoV-2-associated neuropathology and will assess how chronic, viral-mediated changes to the brain and CNS contribute to cognitive decline in PrD and other progressive, age-related neurodegenerative disorders.

2545

N463

Emma Kavanagh

Long Covid brain fog: a neuroinflammation phenomenon?

https://doi.org/10.1093/oxfimm/iqac007

Published

27-Sep-22

Article

https://academic.oup.com/ooim/advance-article/doi/10.1093/oxfimm/iqac007/6722625

Long Covid is an ongoing problem for large numbers of survivors of SARS-CoV-2 infection. One of its more significant, and as yet under explored symptoms is brain fog. Here we discuss the role of brain fog in Long Covid symptomatology, and consider the impact of this reduction in cognitive function in terms of a Long Covid patient narrative. We then consider the mechanisms likely to contribute to these effects, discussing neuroinflammation and the effects that the activation of microglia can have on cognitive processes, such as learning, memory and emotional regulation.1

Inflammatory cytokines have been found to play a significant role in reductions in LTP and LTD2, a reduction in neurogenesis3, and in dendritic sprouting4. We consider the role of these systems in the cognitive challenges posed by brain fog, and its effects on learning, memory, emotional regulation and the gender disparity noted in the diagnosis of Long Covid. It is hoped that this article will allow for greater examination of the effects of inflammatory factors on brain function, most particularly in terms of their role in chronic conditions.

2546

N464

Peter Novak, Matthew P. Giannetti, Emily Weller, Matthew J. Hamilton, Shibani S. Mukerji, Haitham S. Alabsi, David Systrom, Sadie P. Marciano, Donna Felsenstein, William J. Mullally, David M. Pilgrim & Mariana Castells

Network autonomic analysis of post-acute sequelae of COVID-19 and postural tachycardia syndrome

https://doi.org/10.1007/s10072-022-06423-y

Published

28-Sep-22

Study

https://link.springer.com/article/10.1007/s10072-022-06423-y

Background
The autonomic nervous system (ANS) is a complex network where sympathetic and parasympathetic domains interact inside and outside of the network. Correlation-based network analysis (NA) is a novel approach enabling the quantification of these interactions. The aim of this study is to assess the applicability of NA to assess relationships between autonomic, sensory, respiratory, cerebrovascular, and inflammatory markers on post-acute sequela of COVID-19 (PASC) and postural tachycardia syndrome (POTS).

Methods
In this retrospective study, datasets from PASC (n = 15), POTS (n = 15), and matched controls (n = 11) were analyzed. Networks were constructed from surveys (autonomic and sensory), autonomic tests (deep breathing, Valsalva maneuver, tilt, and sudomotor test) results using heart rate, blood pressure, cerebral blood flow velocity (CBFv), capnography, skin biopsies for assessment of small fiber neuropathy (SFN), and various inflammatory markers. Networks were characterized by clusters and centrality metrics.

Results
Standard analysis showed widespread abnormalities including reduced orthostatic CBFv in 100%/88% (PASC/POTS), SFN 77%/88%, mild-to-moderate dysautonomia 100%/100%, hypocapnia 87%/100%, and elevated inflammatory markers. NA showed different signatures for both disorders with centrality metrics of vascular and inflammatory variables playing prominent roles in differentiating PASC from POTS.

Conclusions
NA is suitable for a relationship analysis between autonomic and nonautonomic components. Our preliminary analyses indicate that NA can expand the value of autonomic testing and provide new insight into the functioning of the ANS and related systems in complex disease processes such as PASC and POTS.

2547

N465

Urvish K. Patel, Neev Mehta, Amrapali Patel, Neel Patel, Juan Fernando Ortiz, Mahika Khurana, Eseosa Urhoghide, Akshada Parulekar, Arpita Bhriguvanshi, Nidhi Patel, Anuja Mahesh Mistry, Rutul Patel, Kogulavadanan Arumaithurai, Shamik Shah

Long-Term Neurological Sequelae Among Severe COVID-19 Patients: A Systematic Review and Meta-Analysis

https://doi.org/10.7759/cureus.29694

Published

28-Sep-22

Systematic Review and Meta-Analysis

https://www.cureus.com/articles/110766-long-term-neurological-sequelae-among-severe-covid-19-patients-a-systematic-review-and-meta-analysis

Few studies have thoroughly evaluated the neuro-invasive effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which may contribute to a wide range of sequelae from mild long-term effects like headaches and fatigue to severe events like stroke and arrhythmias. Our study aimed to evaluate the long-term neurological effects of coronavirus disease 2019 (COVID-19) among patients discharged from the hospital.

In this systematic review and meta-analysis, we assessed the long-term neurocognitive effects of COVID-19. Post-COVID-19 neurological sequelae were defined as persistent symptoms of headache, fatigue, myalgia, anosmia, dysgeusia, sleep disturbance, issues with concentration, post-traumatic stress disorder (PTSD), suicidality, and depression long after the acute phase of COVID-19. Data from observational studies describing post-COVID-19 neurocognitive sequelae and severity of COVID-19 from September 1, 2019, to the present were extracted following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol with a consensus of three independent reviewers. A systematic review was performed for qualitative evaluation and a meta-analysis was performed for quantitative analysis by calculating log odds of COVID-19 neurocognitive sequelae. The odds ratio (OR) and 95% confidence interval (CI) were obtained and forest plots were created using random effects models.

We found seven studies, out of which three were used for quantitative synthesis of evidence. Of the 3,304 post-COVID-19 patients identified, 50.27% were male with a mean age of 56 years; 20.20% had post-COVID-19 symptoms more than two weeks after the acute phase of infection. Among persistence symptoms, neurocognitive symptoms like headache (27.8%), fatigue (26.7%), myalgia (23.14%), anosmia (22.8%), dysgeusia (12.1%), sleep disturbance (63.1%), confusion (32.6%), difficulty to concentrate (22%), and psychiatric symptoms like PTSD (31%), feeling depressed (20%), and suicidality (2%) had a higher prevalence. In meta-analysis, COVID-19 patients with severe symptoms had higher odds of headache (pooled OR: 4.53; 95% CI: 2.37-8.65; p<0.00001; I2: 0%) and myalgia (pooled OR: 3.36; 95% CI: 2.71-4.17; p<0.00001; I2: 0%). Anosmia, fatigue, and dysgeusia had higher but non-significant odds following COVID-19.

Although we had sufficient data for headache and fatigue to identify higher rates and associations following COVID-19, we could not establish relationships with other post-COVID-19 neurocognitive séqueles. Long-term follow-up may mitigate the neurocognitive effects among COVID-19 patients as these symptoms are also associated with a poor quality of life.

2548

N466

Waldemar Brola & Maciej Wilski

Neurological consequences of COVID-19

https://doi.org/10.1007/s43440-022-00424-6

Published

30-Sep-22

Review

https://link.springer.com/article/10.1007/s43440-022-00424-6

In December 2019, cases of pneumonia caused by infection with the previously unknown severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), leading to coronavirus disease 2019 (COVID-19), were identified. Typical manifestations of COVID-19 are fever, cough, fatigue and dyspnoea. Initially, it was thought that the mechanism of action of SARS-CoV-2 was only associated with respiratory tract invasion, but it was later revealed that the infection might involve many other organs and systems, including the central and peripheral nervous systems. Neurological complications associated with SARS-CoV-2 infection include encephalopathy, encephalitis, meningitis, acute disseminated encephalomyelitis (ADEM), ischaemic and haemorrhagic stroke and cerebral venous sinus thrombosis. In cases of peripheral nervous system involvement, smell and taste disorders, myopathy or the signs and symptoms of Guillain‒Barré syndrome are observed. The most common early neurological complications, particularly during the first year of the epidemic, were anosmia and taste disorders, which, according to some studies, occurred in over 80 percent of patients with COVID-19. The proportion of patients with serious neurological manifestations was small compared to the global number of patients, but the numbers of SARS-CoV-2 infections and critical patients increased substantially. The experience from 2 years of the pandemic has shown that approximately 13% of infected patients suffer from severe neurological complications. The relationship between SARS-CoV-2 and the nervous system is not only a cause of neurological complications in previously healthy individuals but also directly and indirectly affects the courses of many nervous system diseases.

2549

N467

Max Oliver Mackay Walker
Department of Biochemistry, School of Biomedical Science, University of Otago, Dunedin, New Zealand
Katherine H Hall
Department of General Practice and Rural Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
Katie Peppercorn
Department of Biochemistry, School of Biomedical Science, University of Otago, Dunedin, New Zealand
Warren Perry Tate

The significance of oxidative stress in the pathophysiology of Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

https://doi.org/10.18103/mra.v10i9.3050

Published

20-Sep-22

Article

https://esmed.org/MRA/mra/article/view/3050

Long COVID is now well accepted as an ongoing post-viral syndrome resulting from infection of a single virus, the pandemic SARS-CoV-2. It mirrors the post-viral fatigue syndrome, Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, a global debilitating illness arising mainly from sporadic geographically-specific viral outbreaks, and from community endemic infections, but also from other stressors. Core symptoms of both syndromes are post-exertional malaise (a worsening of symptoms following mental or physical activity), pervasive fatigue, cognitive dysfunction (brain fog), and sleep disturbance. Long COVID patients frequently also suffer from shortness of breath, relating to the lung involvement of the SARS-CoV-2 virus. There is no universally accepted pathophysiology, or recognized biomarkers yet for Long COVID or indeed for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Clinical case definitions with very similar characteristics for each have been defined. Chronic inflammation, immune dysfunction, and disrupted energy production in the peripheral system has been confirmed in Long COVID and has been well documented in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Neuroinflammation occurs in the brain in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome as shown from a small number of positron emission tomography and magnetic resonance spectroscopy studies, and has now been demonstrated for Long COVID. Oxidative stress, an increase in reactive oxygen and reactive nitrogen species, and free radicals, has long been suggested as a potential cause for many of the symptoms seen in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, resulting from both activation of the brain’s immune system and dysregulation of mitochondrial function throughout the body. The brain as a high producer of energy may be particularly susceptible to oxidative stress. It has been shown in peripheral immune cells that the balanced production of proteins involved in regulation of the reactive oxygen species in mitochondria is disturbed in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Fluctuations in the chronic low level neuroinflammation during the ongoing course of Long COVID as well as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome have been proposed to cause the characteristic severe relapses in patients. This review explores oxidative stress as a likely significant contributor to the pathophysiology of Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, and the mechanisms by which oxidative stress could cause the symptoms seen in both syndromes. Treatments that could mitigate oxidative stress and thereby lessen the debilitating symptoms to improve the life of patients are discussed.

2550

N468

Abdul Mannan Baig*, Nigel H. Greig, Joachim Gerlach, Prakash Salunke, Mark Fabrowski, Valentina Viduto, and Tazeen Ali

Underlying Causes and Treatment Modalities for Neurological Deficits in COVID-19 and Long-COVID

https://doi.org/10.1021/acschemneuro.2c00482

Published

3-Oct-22

Article

https://pubs.acs.org/doi/abs/10.1021/acschemneuro.2c00482

With reports of diverse neurological deficits in the acute phase of COVID-19, there is a surge in neurological findings in Long-COVID─a protracted phase of SARS-CoV-2 infection. Very little is known regarding the pathogenic mechanisms of Neuro-COVID in the above two settings in the current pandemic. Herein, we hint toward the possible molecular mechanism that can contribute to the signs and symptoms of patients with neurological deficits and possible treatment and prevention modalities in the acute and chronic phases of COVID-19.

2551

N469

Maria CristineCamposTatyanaNeryAna CarolinaStarkeAna Cristinade Bem AlvesAna ElisaSpeckAderbalS Aguiar

Post-viral fatigue in COVID-19: A review of symptom assessment methods, mental, cognitive, and physical impairment

https://doi.org/10.1016/j.neubiorev.2022.104902

Published

3-Oct-22

Review

https://www.sciencedirect.com/science/article/pii/S0149763422003918

Highlights
•Fatigue is the main sequela of long COVID-19 and needs follow-up.
•There are physical and mental manifestations of fatigue in long COVID-19.
•This review presents the most used instruments in assessing fatigue in long COVID-19.
•Muscle strength, walking, and functional tests assess physical fatigue in long COVID-19.
•Executive function psychological tests assess mental fatigue in long COVID-19.
Abstract
Coronavirus 2 is responsible for Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2), and the main sequela is persistent fatigue. Post-viral fatigue is common and affects patients with mild, asymptomatic coronavirus disease-2019 (COVID-19). However, the exact mechanisms involved in developing post-COVID-19 fatigue remain unclear. Furthermore, physical and cognitive impairments in these individuals have been widely described. Therefore, this review aims to summarize and propose tools from a multifaceted perspective to assess COVID-19 infection. Herein, we point out the instruments that can be used to assess fatigue in long-term COVID-19: fatigue in a subjective manner or fatigability in an objective manner. For physical and mental fatigue, structured questionnaires were used to assess perceived symptoms, and physical and cognitive performance assessment tests were used to measure fatigability using reduced performance.

2552

N470

Nikita Chhabra, Marie F. Grill & Rashmi B. Halker Singh

Post-COVID Headache: A Literature Review

https://doi.org/10.1007/s11916-022-01086-y

Published

5-Oct-22

Review

https://link.springer.com/article/10.1007/s11916-022-01086-y

Purpose of Review
Post-COVID headache may be unique in presentation and mechanism, often presenting as a new phenotype in patients with a history of a primary headache disorder or resulting in a new headache syndrome in those without history of headache. This review presents a description of the literature published focused on post-COVID headache. Additionally, we discuss potential mechanisms and considerations for treatment of post-COVID headache.
Recent Findings
Headache is one of the most common symptoms of COVID. Common characteristics are revealed when reviewing the phenotypes of headaches that have been described in patients with COVID-19, with most headache phenotypes resembling migraine and new persistent daily headache. Post-COVID headaches are often described as moderate to severe, persistent, and treatment refractory.
Summary
This review highlights the diversity of presentation of headaches that present as a complication of COVID-19. Treatment of post-COVID headache is challenging, especially in the setting of a pandemic where resources are limited.
Clinical Case
A 42-year-old woman with a history of episodic migraine without aura presents over video visit with a new headache type. Her typical headaches are predominantly left sided, throbbing in nature, and associated with photophobia and phonophobia. They are fully relieved by oral sumatriptan 2 h after treatment. She describes this new headache as a constant, pulsating, holocephalic pain with no other migrainous features that have been ongoing for 6 weeks. She notes that the headache has been persistent since that time. She has tried over-the-counter acetaminophen and ibuprofen and her typical migraine abortive therapy without relief. She is debilitated and wonders if there is anything that will take the pain away. She shares that she tested positive for COVID-19 about 2 days prior to headache onset and has associated rhinorrhea, anosmia, and ageusia.

2553

N471

COA

Samudyata, Ana O. Oliveira, Susmita Malwade, Nuno Rufino de Sousa, Sravan K. Goparaju, Jessica Gracias, Funda Orhan, Laura Steponaviciute, Martin Schalling, Steven D. Sheridan, Roy H. Perlis, Antonio G. Rothfuchs & Carl M. Sellgren

SARS-CoV-2 promotes microglial synapse elimination in human brain organoids

https://doi.org/10.1038/s41380-022-01786-2

Published

5-Oct-22

Study

https://www.nature.com/articles/s41380-022-01786-2

Neuropsychiatric manifestations are common in both the acute and post-acute phase of SARS-CoV-2 infection, but the mechanisms of these effects are unknown. In a newly established brain organoid model with innately developing microglia, we demonstrate that SARS-CoV-2 infection initiate neuronal cell death and cause a loss of post-synaptic termini. Despite limited neurotropism and a decelerating viral replication, we observe a threefold increase in microglial engulfment of postsynaptic termini after SARS-CoV-2 exposure. We define the microglial responses to SARS-CoV-2 infection by single cell transcriptomic profiling and observe an upregulation of interferon-responsive genes as well as genes promoting migration and synapse engulfment. To a large extent, SARS-CoV-2 exposed microglia adopt a transcriptomic profile overlapping with neurodegenerative disorders that display an early synapse loss as well as an increased incident risk after a SARS-CoV-2 infection. Our results reveal that brain organoids infected with SARS-CoV-2 display disruption in circuit integrity via microglia-mediated synapse elimination and identifies a potential novel mechanism contributing to cognitive impairments in patients recovering from COVID-19.

2554

N472

MichelleMonje12AkikoIwasaki34

The Neurobiology of Long COVID

https://doi.org/10.1016/j.neuron.2022.10.006

Published

7-Oct-22

Article

https://www.sciencedirect.com/science/article/pii/S0896627322009102

Persistent neurological and neuropsychiatric symptoms affect a substantial fraction of people after COVID-19 and represent a major component of the post-acute COVID syndrome, also known as long COVID. Here, we review what is understood about the pathobiology of post-acute COVID-19 impacts on the CNS and discuss possible neurobiological underpinnings of the cognitive symptoms affecting COVID-19 survivors. We propose the chief mechanisms that may contribute to this emerging neurological health crisis.

2555

N473

COA

Evan Xu, Yan Xie & Ziyad Al-Aly

Long-term neurologic outcomes of COVID-19

https://doi.org/10.1038/s41591-022-02001-z

Published

22-Sep-22

Study

https://www.nature.com/articles/s41591-022-02001-z

The neurologic manifestations of acute COVID-19 are well characterized, but a comprehensive evaluation of postacute neurologic sequelae at 1 year has not been undertaken. Here we use the national healthcare databases of the US Department of Veterans Affairs to build a cohort of 154,068 individuals with COVID-19, 5,638,795 contemporary controls and 5,859,621 historical controls; we use inverse probability weighting to balance the cohorts, and estimate risks and burdens of incident neurologic disorders at 12 months following acute SARS-CoV-2 infection. Our results show that in the postacute phase of COVID-19, there was increased risk of an array of incident neurologic sequelae including ischemic and hemorrhagic stroke, cognition and memory disorders, peripheral nervous system disorders, episodic disorders (for example, migraine and seizures), extrapyramidal and movement disorders, mental health disorders, musculoskeletal disorders, sensory disorders, Guillain–Barré syndrome, and encephalitis or encephalopathy. We estimated that the hazard ratio of any neurologic sequela was 1.42 (95% confidence intervals 1.38, 1.47) and burden 70.69 (95% confidence intervals 63.54, 78.01) per 1,000 persons at 12 months. The risks and burdens were elevated even in people who did not require hospitalization during acute COVID-19. Limitations include a cohort comprising mostly White males. Taken together, our results provide evidence of increased risk of long-term neurologic disorders in people who had COVID-19.

2556

N474

Rahmouni Nesrine, Rosa-Neto Pedro & Brunet Alain

To the editor: Response to post-infection cognitive impairments in a cohort of elderly patients with COVID-19, by Wang, Y.J. et al. (2021)

https://doi.org/10.1186/s13024-022-00567-3

Published

25-Sep-22

Letter to the Editor

https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-022-00567-3

Using spouses as a control group sounds like a good idea at first sight. However, the fact that spouses had to be in better health conditions for them not to catch COVID-19 when their partner did constitute an important bias. Over a third of the COVID-19 patients in this study had their spouses in the control group. The authors acknowledged this issue as one of their limitations and suggested that non-covid pneumonia patients would have been a better option to assess the COVID-19 specificity of the associations. We agree in principle but think that this wouldn’t be sufficient: Cheng et al. [2] reported a longer Intensive Care Unit (ICU) or hospital stay contributes significantly to the development of dementia in patients. Additionally, Katon et al. [3] reported similar results, showing that older adults who experienced acute and critical illness hospitalization had greater chances of cognitive decline compared with patients that were not hospitalized. In the present paper, the authors report that ICU admission is significantly associated with cognitive impairment and cognitive decline, and severe COVID-19 cases had higher frequency of ICU admission than non-severe COVID-19 cases and controls. For the authors to consider that the cognitive impairment and decline of patients in this study are due to their COVID-19 infection is far-fetched as it can be explained by their ICU admission [4]. A more adequate control group for this study would have been a non-COVID-19 ICU patient.

2557

N475

RyanGreen125#KarthickMayilsamy15#Andrew R.McGill125TaylorMartinez15BalaChandran1Laura J.Blair135Paula C.Bickford45Shyam S.Mohapatra25SubhraMohapatra15

SARS-CoV-2 Infection Increases the Gene Expression Profile for Alzheimer’s Disease Risk

https://doi.org/10.1016/j.omtm.2022.09.007

Published

24-Sep-22

Study

https://www.sciencedirect.com/science/article/pii/S2329050122001322

The COVID-19 pandemic has caused over 600,000,000 infections globally thus far. Up to 30 % of individuals with mild to severe disease develop long-COVID, exhibiting diverse neurologic symptoms including dementias. However, there is a paucity of knowledge of molecular brain markers, and whether these can precipitate the onset of Alzheimer’s disease (AD). Herein, we report the brain gene expression profiles of severe COVID-19 patients showing increased expression of innate immune response genes and genes implicated in AD pathogenesis. The use of a mouse-adapted strain of SARS CoV-2 (MA10) in an aged mouse model shows evidence of viral neurotropism, prolonged viral infection, increased expression of tau aggregator FKBP51, interferon-inducible gene Ifi204, and complement genes C4 and C5AR1. Brain histopathology showed AD signatures including increased tau-phosphorylation, tau-oligomerization, and α-synuclein expression in aged MA10 infected mice. The results of gene expression profiling of SARS CoV-2 infected and AD brains and studies in the MA10 aged mouse model taken together, for the first time provide evidence suggesting that SARS CoV-2 infection alters expression of genes in the brain associated with the development of AD. Future studies of common molecular markers in SARS CoV-2 infection and AD could be useful for developing novel therapies targeting AD.

2558

N476

COA

Jolanta B.ZawilskaKatarzynaKuczyńska

Psychiatric and neurological complications of long COVID

https://doi.org/10.1016/j.jpsychires.2022.10.045

Published

20-Oct-22

Review

https://www.sciencedirect.com/science/article/pii/S0022395622005982

Highlights
•Apart from respiratory tract, COVID-19 affects nervous system.
•Psychiatric and neurological symptoms of COVID-19 may persist for over 24 weeks.
•Long COVID mostly affects adults but it may be observed in children and adolescents.
•Chronic fatigue, depression, anxiety and cognitive deficits are the most common symptoms of long COVID.
•Patients with long COVID may demonstrate brain hypometabolism.
COVID-19 was primarily considered a pulmonary disease with extrapulmonary manifestations. As the pandemic spread, there has been growing evidence that the disease affects various organs/systems, including the central and peripheral nervous systems. Accumulation of clinical data demonstrates that in a large population of survivors impairments in the function of one or more organs may persist for a long time, a phenomenon commonly known as post COVID or long COVID. Fatigue and cognitive dysfunction, such as concentration problems, short-term memory deficits, general memory loss, a specific decline in attention, language and praxis abilities, encoding and verbal fluency, impairment of executive functions, and psychomotor coordination, are amongst the most common and debilitating features of neuropsychatric symptoms of post COVID syndrome. Several patients also suffer from compromised sleep, depression, anxiety and post-traumatic stress disorder. Patients with long COVID may demonstrate brain hypometabolism, hypoperfusion of the cerebral cortex and changes in the brain structure and functional connectivity. Children and adolescents represent a minority of COVID-19 cases, so not surprisingly data on the long-term sequelae after SARS-CoV-2 infections in these age groups are scarce. Although the pathogenesis, clinical characteristics, epidemiology, and risk factors of the acute phase of COVID-19 have been largely explained, these areas are yet to be explored in long COVID. This review aims to provide an update on what is currently known about long COVID effects on mental health.

2559

N477

Dr Alexander Grundmann MD,Dr Chieh-Hsi Wu PhD,Dr Marc Hardwick MD,Prof J Kenneth Baillie MD PhD,Prof Peter JM Openshaw MD PhD,Prof Malcolm G Semple MD PhD,Prof Dankmar Böhning PhD,Prof Sarah Pett MD PhD,Dr Benedict D Michael MD PhD,Dr Rhys H Thomas MD PhD,Prof Ian Galea MD PhD,

Fewer COVID-19 neurological complications with dexamethasone and remdesivir

https://doi.org/10.1002/ana.26536

Published

19-Oct-22

Study

https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.26536

Objective
To assess the impact of treatment with dexamethasone, remdesivir or both on neurological complications in acute COVID-19.
Methods
We used observational data from the International Severe Acute and emerging Respiratory Infection Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK). Hospital inpatients aged ≥18 years with laboratory-confirmed SARS-CoV-2 infection admitted between 31 January 2020 and 29 June 2021 were included. Treatment allocation was non-blinded and performed by reporting clinicians. A propensity scoring methodology was used to minimize confounding. Treatment with remdesivir, dexamethasone or both was assessed against standard of care. The primary outcome was a neurological complication occurring at the point of death, discharge, or resolution of the COVID-19 clinical episode.
Results
Out of 89,297 hospital inpatients, 64,088 had severe COVID-19 and 25,209 had non-hypoxic COVID-19. Neurological complications developed in 4.8% and 4.5% respectively. In both groups, neurological complications associated with increased mortality, ICU admission, worse self-care on discharge and time to recovery. In severe COVID-19, treatment with dexamethasone (n=21,129), remdesivir (n=1,428) and both combined (n=10,846) associated with a lower frequency of neurological complications: OR=0.76 (95% CI=0.69-0.83), OR 0.69 (95% CI=0.51-0.90) and OR=0.54, (95% CI=0.47-0.61) respectively. In non-hypoxic COVID-19, dexamethasone (n=2,580) associated with less neurological complications (OR=0.78, 95% CI 0.62-0.97), while the dexamethasone/remdesivir combination (n=460) showed a similar trend (OR=0.63, 95% CI=0.31-1.15).
Interpretation
Treatment with dexamethasone, remdesivir or both in patients hospitalised with COVID-19 associated with a lower frequency of neurological complications in an additive manner, such that the greatest benefit was observed in patients who received both drugs together.

2560

N478

María Díez-Cirarda, Miguel Yus, Natividad Gómez-Ruiz, Carmen Polidura, Lidia Gil-Martínez, Cristina Delgado-Alonso, Manuela Jorquera, Ulises Gómez-Pinedo, Jorge Matias-Guiu, Juan Arrazola, Jordi A Matias-Guiu

Multimodal neuroimaging in post-COVID syndrome and correlation with cognition

https://doi.org/10.1093/brain/awac384

Published

26-Oct-22

Study

https://academic.oup.com/brain/advance-article-abstract/doi/10.1093/brain/awac384/6775147

Brain changes have been reported in the first weeks after SARS-CoV-2 infection. However, limited literature exists about brain alterations in post-COVID syndrome, a condition increasingly associated with cognitive impairment. The present study aimed to evaluate brain functional and structural alterations in patients with post-COVID syndrome, and assess whether these brain alterations were related to cognitive dysfunction.
Eighty-six patients with post-COVID syndrome and 36 healthy controls were recruited and underwent neuroimaging acquisition and a comprehensive neuropsychological assessment. Cognitive and neuroimaging examinations were performed 11 months after the first symptoms of SARS-CoV-2. Whole-brain functional connectivity analysis was performed. Voxel-based morphometry was performed to evaluate grey matter volume, and diffusion tensor imaging was carried out to analyse white matter alterations. Correlations between cognition and brain changes were conducted and Bonferroni corrected.
Post-COVID syndrome patients presented with functional connectivity changes, characterized by hypoconnectivity between left and right parahippocampal areas, and between bilateral orbitofrontal and cerebellar areas compared to controls. These alterations were accompanied by reduced grey matter volume in cortical, limbic and cerebellar areas, and alterations in white matter axial and mean diffusivity. Grey matter volume loss showed significant associations with cognitive dysfunction. These cognitive and brain alterations were more pronounced in hospitalized patients compared to non-hospitalized patients. No associations with vaccination status were found.
The present study shows persistent structural and functional brain abnormalities 11 months after the acute infection. These changes are associated with cognitive dysfunction and contribute to a better understanding of the pathophysiology of the post-COVID syndrome.

2561

N479

Dovile Stankevice MD,Alexander Wieck Fjaeldstad MD, PhD,Jane Agergaard MD, PhD,Therese Ovesen MD, DMSc

Long-Term COVID-19 Smell and Taste Disorders Differ Significantly from Other Post-Infectious Cases

https://doi.org/10.1002/lary.30453

Published

28-Oct-22

Study

https://onlinelibrary.wiley.com/doi/10.1002/lary.30453

Introduction
COVID-19 is causing a wide range of clinical manifestations. Severe complications and long-lasting sequelae have been identified. Thus, olfactory disorders are reported in up to 86% of cases in mild and moderate COVID-19 infections. We present the first study comparing simple and complex post-COVID-19 cases with matched non-COVID-19 post-infectious smell and taste disorders.
Methods
A total of 328 patients were recruited from the University Clinic for Flavour, Balance and Sleep, Ear-nose-throat Department, Goedstrup Hospital, Denmark. A non-COVID -19 post-infectious population of 148 individuals was identified from the Redcap database, and was matched by duration of smell and taste disorders. Post-COVID-19 patients were divided into 99 patients with simple smell and taste disorders (only suffering from smell and taste disorders after COVID-19); and (81 patients with complex smell and taste disorder plus several other post-COVID-19 complaints). Besides patient-reported outcome measures (PROM) questionnaires and quality of life score (QoL), ear-nose-throat examination, Mini-Mental State Examination (MMSE), orthonasal smell test (Sniffing's sticks), retronasal quick test, and taste screening were performed.
Results
Cases with post-COVID-19-related smell and taste disorders deviated from non-COVID-19 post-infectious cases; the patients were younger, had a lower occurrence of anosmia/ageusia, and had higher overall smell test scores. In contrast, patients with post-COVID-19-related smell and taste disorders more frequently complained of distorted senses. Parosmia and phantosmia were more prevalent among patients with simple post-COVID-19 complaints than among complex cases and their QoL were more negatively affected.
Conclusion
Smell and taste function differ significantly between post-COVID-19 and other non-COVID-19 post-viral cases.

2562

N480

Marissa Alvarez†, Erick Trent†, Bruno De Souza Goncalves, Duane G. Pereira, Raghav Puri, Nicolas Anthony Frazier, Komal Sodhi and Sneha S. Pillai*

Cognitive dysfunction associated with COVID-19: Prognostic role of circulating biomarkers and microRNAs

https://doi.org/10.3389/fnagi.2022.1020092

Published

4-Oct-22

Review

https://www.frontiersin.org/articles/10.3389/fnagi.2022.1020092/full

COVID-19 is renowned as a multi-organ disease having subacute and long-term effects with a broad spectrum of clinical manifestations. The evolving scientific and clinical evidence demonstrates that the frequency of cognitive impairment after COVID-19 is high and it is crucial to explore more clinical research and implement proper diagnostic and treatment strategies. Several central nervous system complications have been reported as comorbidities of COVID-19. The changes in cognitive function associated with neurodegenerative diseases develop slowly over time and are only diagnosed at an already advanced stage of molecular pathology. Hence, understanding the common links between COVID-19 and neurodegenerative diseases will broaden our knowledge and help in strategizing prognostic and therapeutic approaches. The present review focuses on the diverse neurodegenerative changes associated with COVID-19 and will highlight the importance of major circulating biomarkers and microRNAs (miRNAs) associated with the disease progression and severity. The literature analysis showed that major proteins associated with central nervous system function, such as Glial fibrillary acidic protein, neurofilament light chain, p-tau 181, Ubiquitin C-terminal hydrolase L1, S100 calcium-binding protein B, Neuron-specific enolase and various inflammatory cytokines, were significantly altered in COVID-19 patients. Furthermore, among various miRNAs that are having pivotal roles in various neurodegenerative diseases, miR-146a, miR-155, Let-7b, miR-31, miR-16 and miR-21 have shown significant dysregulation in COVID-19 patients. Thus the review consolidates the important findings from the numerous studies to unravel the underlying mechanism of neurological sequelae in COVID-19 and the possible association of circulatory biomarkers, which may serve as prognostic predictors and therapeutic targets in future research.

2563

N481

M. AymanHaykalDaniel L.Menkes

The Clinical Neurophysiology of COVID-19- Direct Infection, Long-Term Sequelae and Para-Immunization responses: A literature review

https://doi.org/10.1016/j.cnp.2022.09.005

Published

17-Oct-22

Review

https://www.sciencedirect.com/science/article/pii/S2467981X22000397

Highlights
•Several neurophysiological techniques are useful in evaluating neurological symptoms related to SARS-CoV-2 infection but cannot affirm a causative association.
•There is no specific electrodiagnostic signature that is pathognomonic for SARS-CoV-2 infection, possible vaccination side effects against SARS-CoV-2 or “long COVID”.
•However, clinical neurophysiology modalities have a role in the evaluation of “long COVID” as they may provide objective validation of the patient's reported symptoms.
Abstract
The COVID-19 pandemic resulting from the SARS-CoV-2 virus is in its third year. There is continuously evolving information regarding its pathophysiology and its effects on the nervous system. Clinical neurophysiology techniques are commonly employed to assess for neuroanatomical localization and/or defining the spectrum of neurological illness. There is an evolving body of literature delineating the effects of the SARS-CoV-2 virus on the nervous system as well as para-immunization responses to vaccination against this virus. This review focuses on the use of neurophysiological diagnostic modalities in the evaluation of potential acute and long-term neurological complications in patients that experience direct infection with SARS-CoV-2 and analyzes those reports of para-immunization responses to vaccination against the SARS-CoV-2 virus. The neurophysiological modalities to be discussed include electroencephalography (EEG), evoked potentials (EPs), nerve conduction studies and electromyography (EMG/NCV), autonomic function tests, transcranial magnetic stimulation (TMS) and Transcranial Doppler ultrasound (TCD).

2564

N482

César Fernández-de-las-Peñas 1,2,*ORCID,Jo Nijs 3,4,5ORCID,Randy Neblett 6ORCID,Andrea Polli 3,7,8ORCID,Maarten Moens 3,9,10,11,12ORCID,Lisa Goudman 3,7,9,10,11ORCID,Madhura Shekhar Patil 8,Roger D. Knaggs 13,Gisele Pickering 14,15 andLars Arendt-Nielsen 2,16

Phenotyping Post-COVID Pain as a Nociceptive, Neuropathic, or Nociplastic Pain Condition

https://doi.org/10.3390/biomedicines10102562

Published

13-Oct-22

Review

https://www.mdpi.com/2227-9059/10/10/2562/htm

Pain after an acute Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) condition (post-COVID pain) is becoming a new healthcare emergency. Precision medicine refers to an evidence-based method of grouping patients based on their diagnostic/symptom presentation and then tailoring specific treatments accordingly. Evidence suggests that post-COVID pain can be categorized as nociceptive (i.e., pain attributable to the activation of the peripheral receptive terminals of primary afferent neurons in response to noxious chemical, mechanical, or thermal stimuli), neuropathic (i.e., pain associated with a lesion or disease of the somatosensory nervous system and limited to a “neuroanatomically plausible” distribution of the system), nociplastic (i.e., pain arising from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain), or mixed type (when two pain phenotypes co-exist). Each of these pain phenotypes may require a different treatment approach to maximize treatment effectiveness. Accordingly, the ability to classify post-COVID pain patients into one of these phenotypes would likely be critical for producing successful treatment outcomes. The 2021 International Association for the Study of Pain (IASP) clinical criteria and grading system provide a framework for classifying pain within a precision pain medicine approach. Here we present data supporting the possibility of grouping patients with post-COVID pain into pain phenotypes, using the 2021 IASP classification criteria, with a specific focus on nociplastic pain, which is probably the primary mechanism involved in post-COVID pain. Nociplastic pain, which is usually associated with comorbid symptomology (e.g., poor sleep quality, fatigue, cognitive–emotional disturbances, etc.) and is considered to be more difficult to treat than other pain types, may require a more nuanced multimodal treatment approach to achieve better treatment outcomes.

2565

N483

Marino Marcic 1,*ORCID,Ljiljana Marcic 2,3,Sanja Lovric Kojundzic 4ORCID,Maja Marinovic Guic 3,4,Barbara Marcic 5 andKresimir Caljkusic 1

Chronic Endothelial Dysfunction after COVID-19 Infection Shown by Transcranial Color-Coded Doppler: A Cross-Sectional Study

https://doi.org/10.3390/biomedicines10102550

Published

13-Oct-22

Study

https://www.mdpi.com/2227-9059/10/10/2550/htm

In addition to respiratory symptoms, COVID-19 often causes damage to many other organs, especially in severe forms of the disease. Long-term consequences after COVID-19 are common and often have neurological symptoms. Cerebral vasoreactivity may be impaired after acute COVID-19 and in our study, we wanted to show how constant and reversible are the changes in brain vasoreactivity after infection. This cross-sectional observational study included 49 patients diagnosed with COVID-19 and mild neurological symptoms 300 days after the onset of the disease. We used a transcranial color-coded Doppler (TCCD) and a breath-holding test (BHT) to examine cerebral vasoreactivity and brain endothelial function. We analyzed the parameters of the flow rate through the middle cerebral artery (MCA): peak systolic velocity (PSV), end-diastolic velocity (EDV), mean velocity (MV), resistance index (RI) and pulsatility index (PI), and we calculated the breath-holding index (BHI). Subjects after COVID-19 infection had lower measured velocity parameters through MCA at rest period and after BHT, lower relative increases of flow velocities after BHT, and lower BHI. We showed that subjects, 300 days after COVID-19, still have impaired cerebral vasoreactivity measured by TCCD and they have chronic endothelial dysfunction.

2566

N484

Concetta Mezzatesta 1,*ORCID,Sara Bazzano 2,Rosa Gesualdo 2,Simone Marchese 1,Maria Luisa Savona 1,Mario Tambone Reyes 3 andVincenzo Provenzano 2

Neurocognitive Disorders in Post and Long Covid Patients: Preliminary Data, Gender Differences and New Diabetes Diagnosis

https://doi.org/10.3390/diabetology3040039

Published

6-Oct-22

Study

https://www.mdpi.com/2673-4540/3/4/39/htm

The research is based on a clinical observation of the neurological and neuro-cognitive status of 300 patients, belonging to the Partinico Hospital and the Post-Long Covid clinic, which had contracted the SARS-CoV-2 virus in the period between April 2021 and May 2022. In this paper, we present the analysis of the first 100 patients subjected to a neurocognitive screening protocol. The procedure consists of tests that examine the mechanism of different brain domains to check for the presence of cognitive deficits that arose after the negativization of the viral infection. Through a neurocognitive protocol, the research aims to investigate different brain areas and mental functioning. This allowed us to raise the possibility that the presence of cognitive alterations may be related to the evidence of point-like brain alterations (from the cortex to the trunk) visible through neuroimaging techniques. In the article, we highlight the hypothesis that SARS-covid 2, as stated in recently published studies, can produce an alteration of executive functions such as to configure a real dysexecutive syndrome. This research evaluates the symptomatic gender variability within the sample, the presence of important differences in the affective state, and provides a first observation of the impact of SARS-CoV-2 in diabetic pathology as well.

2567

N485

Genaro Gabriel Ortiz 1ORCID,Irma E. Velázquez-Brizuela 1,Genaro E. Ortiz-Velázquez 2,María J. Ocampo-Alfaro 3,Joel Salazar-Flores 4,Daniela L. C. Delgado-Lara 1,5,*ORCID andErandis D. Torres-Sanchez 4,*ORCID

Alzheimer’s Disease and SARS-CoV-2: Pathophysiological Analysis and Social Context

https://doi.org/10.3390/brainsci12101405

Published

18-Oct-22

Review

https://www.mdpi.com/2076-3425/12/10/1405/htm

The COVID-19 pandemic has proven to be a challenge for healthcare systems, especially in terms of the care of patients with Alzheimer’s disease (AD). Age is one of the major risk factors for severe forms of COVID-19, most probably due to the presence of comorbidities and inflammations. It is known that SARS-CoV-2 invades nerve endings and olfactory nerves through the binding of the spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor. This interaction triggers an inflammatory cascade that results in cognitive impairment. In turn, the isoform of apolipoprotein-E4 (APOE-4ε) in AD is a risk factor for increased neuroinflammation through microglia activation, increased oxidative stress, and neurodegeneration. AD and SARS-CoV-2 are associated with increases in levels of inflammatory markers, as well as increases in levels of APOE-4ε, ACE2 and oxidative stress. Thus, there is a synergistic relationship between AD and SARS-CoV-2. In addition, the social isolation and other health measures resulting from the pandemic have led to a higher level of anxiety and depression among AD patients, a situation which may lead to a decline in cognitive function. Therefore, there is a need to develop strategies for keeping the patient calm but active.

2568

N486

Laura de Boni, Alexandru Odainic, Natalie Gancarczyk, Luisa Kaluza, Christian P. Strassburg, Xenia A. K. Kersting, Joseph M. Johnson, Ullrich Wüllner, Susanne V. Schmidt, Jacob Nattermann & Gabor C. Petzold

No serological evidence for neuronal damage or reactive gliosis in neuro-COVID-19 patients with long-term persistent headache

https://doi.org/10.1186/s42466-022-00217-5

Published

31-Oct-22

Study

https://neurolrespract.biomedcentral.com/articles/10.1186/s42466-022-00217-5

Recent studies have indicated that long-term neurological sequelae after COVID-19 are not accompanied by an increase of canonical biomarkers of central nervous system injury in blood, but subgroup stratifications are lacking. This is a particular concern in chronic headache, which can be a leading symptom of Post-COVID diseases associated with neuronal damage such as vasculitis or autoimmune encephalitis. We here compared patients with mild Post-COVID-19 syndrome and persistent headache (persistent Post-COVID-19 headache) lasting longer than 12 weeks after the initial serological diagnosis, to patients with mild and severe COVID-19 and COVID-19-negative controls. Levels of neurofilament light chain and glial fibrillary astrocytic protein, i.e. markers of neuronal damage and reactive astrogliosis, were lower in blood from patients with persistent Post-COVID-19 headache compared to patients with severe COVID-19. Hence, our pilot serological study indicates that long-term Post-COVID-19 headache may not be a sign of underlying neuronal damage or neuroinflammation.

2569

N487

Eduardo A. Albornoz, Alberto A. Amarilla, Naphak Modhiran, Sandra Parker, Xaria X. Li, Danushka K. Wijesundara, Julio Aguado, Adriana Pliego Zamora, Christopher L. D. McMillan, Benjamin Liang, Nias Y. G. Peng, Julian D. J. Sng, Fatema Tuj Saima, Jenny N. Fung, John D. Lee, Devina Paramitha, Rhys Parry, Michael S. Avumegah, Ariel Isaacs, Martin W. Lo, Zaray Miranda-Chacon, Daniella Bradshaw, Constanza Salinas-Rebolledo, Niwanthi W. Rajapakse, Ernst J. Wolvetang, Trent P. Munro, Alejandro Rojas-Fernandez, Paul R. Young, Katryn J. Stacey, Alexander A. Khromykh, Keith J. Chappell, Daniel Watterson & Trent M. Woodruff Show fewer authors

SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein

https://doi.org/10.1038/s41380-022-01831-0

Published

1-Nov-22

Study

https://www.nature.com/articles/s41380-022-01831-0

Coronavirus disease-2019 (COVID-19) is primarily a respiratory disease, however, an increasing number of reports indicate that SARS-CoV-2 infection can also cause severe neurological manifestations, including precipitating cases of probable Parkinson’s disease. As microglial NLRP3 inflammasome activation is a major driver of neurodegeneration, here we interrogated whether SARS-CoV-2 can promote microglial NLRP3 inflammasome activation. Using SARS-CoV-2 infection of transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) as a COVID-19 pre-clinical model, we established the presence of virus in the brain together with microglial activation and NLRP3 inflammasome upregulation in comparison to uninfected mice. Next, utilising a model of human monocyte-derived microglia, we identified that SARS-CoV-2 isolates can bind and enter human microglia in the absence of viral replication. This interaction of virus and microglia directly induced robust inflammasome activation, even in the absence of another priming signal. Mechanistically, we demonstrated that purified SARS-CoV-2 spike glycoprotein activated the NLRP3 inflammasome in LPS-primed microglia, in a ACE2-dependent manner. Spike protein also could prime the inflammasome in microglia through NF-κB signalling, allowing for activation through either ATP, nigericin or α-synuclein. Notably, SARS-CoV-2 and spike protein-mediated microglial inflammasome activation was significantly enhanced in the presence of α-synuclein fibrils and was entirely ablated by NLRP3-inhibition. Finally, we demonstrate SARS-CoV-2 infected hACE2 mice treated orally post-infection with the NLRP3 inhibitory drug MCC950, have significantly reduced microglial inflammasome activation, and increased survival in comparison with untreated SARS-CoV-2 infected mice. These results support a possible mechanism of microglial innate immune activation by SARS-CoV-2, which could explain the increased vulnerability to developing neurological symptoms akin to Parkinson’s disease in COVID-19 infected individuals, and a potential therapeutic avenue for intervention.

2570

N488

François Goehringer, Alexandra Bruyere, Matthieu Doyen, Sibylle Bevilacqua, Alexandre Charmillon, Sebastien Heyer & Antoine Verger

Brain 18F-FDG PET imaging in outpatients with post-COVID-19 conditions: findings and associations with clinical characteristics

https://doi.org/10.1007/s00259-022-06013-2

Published

2-Nov-22

Study

https://link.springer.com/article/10.1007/s00259-022-06013-2

Background
Brain 18F-FDG PET imaging has the potential to provide an objective assessment of brain involvement in post-COVID-19 conditions but previous studies of heterogeneous patient series yield inconsistent results. The current study aimed to investigate brain 18F-FDG PET findings in a homogeneous series of outpatients with post-COVID-19 conditions and to identify associations with clinical patient characteristics.
Methods
We retrospectively included 28 consecutive outpatients who presented with post-COVID-19 conditions between September 2020 and May 2022 and who satisfied the WHO definition, and had a brain 18F-FDG PET for suspected brain involvement but had not been hospitalized for COVID-19. A voxel-based group comparison with 28 age- and sex-matched healthy controls was performed (p-voxel at 0.005 uncorrected, p-cluster at 0.05 FWE corrected) and identified clusters were correlated with clinical characteristics.
Results
Outpatients with post-COVID-19 conditions exhibited diffuse hypometabolism predominantly involving right frontal and temporal lobes including the orbito-frontal cortex and internal temporal areas. Metabolism in these clusters was inversely correlated with the number of symptoms during the initial infection (r = − 0.44, p = 0.02) and with the duration of symptoms (r = − 0.39, p = 0.04). Asthenia and cardiovascular, digestive, and neurological disorders during the acute phase and asthenia and language disorders during the chronic phase (p ≤ 0.04) were associated with these hypometabolic clusters.
Conclusion
Outpatients with post-COVID-19 conditions exhibited extensive hypometabolic right fronto-temporal clusters. Patients with more numerous symptoms during the initial phase and with a longer duration of symptoms were at higher risk of persistent brain involvement.

2571

N489

Elena Rossi 1,Luciano Mutti 2,3,4ORCID,Andrea Morrione 2,*ORCID andAntonio Giordano 1,2,*ORCID

Neuro–Immune Interactions in Severe COVID-19 Infection

https://doi.org/10.3390/pathogens11111256

Published

29-Oct-22

Review

https://www.mdpi.com/2076-0817/11/11/1256/htm

SARS-CoV-2 is a new coronavirus that has affected the world since 2019. Interstitial pneumonia is the most common clinical presentation, but additional symptoms have been reported, including neurological manifestations. Severe forms of infection, especially in elderly patients, present as an excessive inflammatory response called “cytokine storm”, which can lead to acute respiratory distress syndrome (ARDS), multiorgan failure and death. Little is known about the relationship between symptoms and clinical outcomes or the characteristics of virus–host interactions. The aim of this narrative review is to highlight possible links between neurological involvement and respiratory damage mediated by pathological inflammatory pathways in SARS-CoV-2 infection. We will focus on neuro–immune interactions and age-related immunity decline and discuss some pathological mechanisms that contribute to negative outcomes in COVID-19 patients. Furthermore, we will describe available therapeutic strategies and their effects on COVID-19 neurological symptoms.

2572

N490

Harumi Jyonouchi 1,*,Lee Geng 1,Daniel A. Rossignol 2 andRichard E. Frye 3ORCID

Long COVID Syndrome Presenting as Neuropsychiatric Exacerbations in Autism Spectrum Disorder: Insights for Treatment

https://doi.org/10.3390/jpm12111815

Published

2-Nov-22

Case Report

https://www.mdpi.com/2075-4426/12/11/1815/htm

COVID-19 causes not only severe respiratory symptoms, but also long-term sequelae, even if the acute-phase symptoms are minor. Neurological and neuropsychiatric symptoms are emerging as major long-term sequalae. In patients with pre-existing behavioral symptoms, such as individuals with autism spectrum disorders (ASD), the emergence of neuropsychiatric symptoms due to long COVID can be difficult to diagnose and manage. Herein, we present three ASD cases who presented with markedly worsening neuropsychiatric symptoms following COVID-19 exposure and subsequent difficulty in managing the post-COVID neuropsychiatric symptoms. Case 1 contracted SARS-CoV-2 during the early stages of the pandemic and treatment targeting COVID-19-induced immune activation was delayed. Case 2 was asymptomatic in the acute stage of a confirmed COVID-19 exposure, but still developed significant neuropsychiatric symptoms. Case 3 demonstrated a difficult course, partly due to pre-existing immune dysregulation and prior use of multiple immunomodulating agents. In cases 1 and 3 for whom serial blood samples were obtained, notable changes in the production of inflammatory and counter-regulatory cytokines by peripheral blood monocytes were observed. The presented cases illustrate the profound effects of COVID-19 on neuropsychiatric symptoms in ASD subjects and the difficulty of managing long-COVID symptoms.

2573

N491

About N373

Varun Venkataramani, M.D., Ph.D., and Frank Winkler, M.D., Ph.D.

Microglia in Cancer Therapy-Related Cognitive Impairment

https://doi.org/10.1016/j.tins.2021.02.003

Published

2-Mar-21

Review

https://www.cell.com/trends/neurosciences/fulltext/S0166-2236(21)00035-7

Highlights
Cancer survivors frequently exhibit persistent disruptions in cognitive function, including deficits in memory, attention, speed of information processing, and mental health.
Studies in both human cancer survivors and preclinical rodent models of chemotherapy and radiation exposure indicate dysregulation of neural plasticity mechanisms underlying cancer therapy-related cognitive impairment.
Both cranial irradiation and systemic chemotherapy treatment have been shown to induce a reactive state in microglia.
Activated microglia are associated with deficits in neural precursor cell population maintenance and neurogenesis, in synaptic structure and function, and in myelin plasticity.
Millions of cancer survivors experience a persistent neurological syndrome that includes deficits in memory, attention, information processing, and mental health. Cancer therapy-related cognitive impairment can cause mild to severe disruptions to quality of life for these cancer survivors. Understanding the cellular and molecular underpinnings of this disorder will facilitate new therapeutic strategies aimed at ameliorating these long-lasting impairments. Accumulating evidence suggests that a range of cancer therapies induce persistent activation of the brain’s resident immune cells, microglia. Cancer therapy-induced microglial activation disrupts numerous mechanisms of neuroplasticity, and emerging findings suggest that this impairment in plasticity is central to cancer therapy-related cognitive impairment. This review explores reactive microglial dysregulation of neural circuit structure and function following cancer therapy.

2574

N492

Kathryn L Eschbacher, MD, Rachel A Larsen, MS, Ann M Moyer, MD, PhD, Ramanath Majumdar, PhD, MS, Robert Ross Reichard, MD

Neuropathological findings in COVID-19: an autopsy cohort

https://doi.org/10.1093/jnen/nlac101

Published

10-Nov-22

Study

https://academic.oup.com/jnen/advance-article/doi/10.1093/jnen/nlac101/6820985

The literature regarding the neuropathological findings in cases of SARS-CoV-2 infection, which causes coronavirus disease 2019 (COVID-19), is expanding. We identified 72 patients who died of COVID-19 (n = 48) or had recovered shortly before death (n = 24) and had autopsies performed at our institution (49 males, 23 females; median age at death 76.4 years, range: 0.0–95.0 years). Droplet digital polymerase chain reaction (ddPCR) for the detection of SARS-CoV-2 was performed (n = 58) in multiple brain regions. In cases the assay was successfully completed (n = 50), 98.0% were negative (n = 49) and 2% were indeterminate (n = 1). Most histologic findings were typical of the patient age demographic, such as neurodegenerative disease and arteriolosclerosis. A subset of cases demonstrated findings which may be associated with sequelae of critical illness. We identified 3 cases with destructive perivascular lesions with axonal injury, one of which also harbored perivascular demyelinating lesions. These rare cases may represent a parainfectious process versus sequelae of vascular injury. The lack of detectable SARS-CoV-2 by ddPCR or significant histologic evidence of direct infection suggests that active encephalitis is not a feature of COVID-19.

2575

N493

Biçem Demir, Elmas Beyazyüz, Murat Beyazyüz, Aliye Çelikkol & Yakup Albayrak

Long-lasting cognitive effects of COVID-19: is there a role of BDNF?

https://doi.org/10.1007/s00406-022-01514-5

Published

10-Nov-22

Study

https://link.springer.com/article/10.1007/s00406-022-01514-5

Coronavirus disease 2019 (COVID-19) affects numerous systems of the body during the illness, and there have been long-lasting effects. BDNF plays an important role in synaptic plasticity and synaptic communication. According to the inclusion and exclusion criteria, 54 patients who had COVID-19 infection participated in this study. Thirty-six age-, sex-, body mass index (BMI)-, education level- and smoking status-matched healthy controls were included in the present study. All participants were individually administered the Stroop test and Visual Aural Digit Span Test Form B (VADS-B). Serum BDNF levels were measured by ELISA. Stroop test word reading spontaneous correction number and reading time, word color saying wrong number, spontaneous correction number and reading time, box color speaking spontaneous correction number and reading time, Stroop interference and speed factor duration were significantly higher in the COVID-19 group than in the control group. All scores of the VADS-B test were found to be significantly lower in the COVID-19 group. The mean serum BDNF levels were found to be 10.9 ± 6.9 ng/ml in the COVID-19 group and 12.8 ± 6.4 ng/ml in the healthy control group. Two-way ANOVA showed that the serum mean BDNF level was significantly lower in the COVID-19 group than in the control group. Gender had a significant effect on BDNF levels (F = 12.21; p = 0.008). The present study is the first to demonstrate the association between the role of serum BDNF and cognitive decline in patients with COVID-19 infection. Additionally, there is a significant role of male gender in terms of lower BDNF level and cognitive decline.

2576

N494

G. Di Stefano,P. Falco,E. Galosi,G. Di Pietro,C. Leone,A. Truini

A systematic review and metanalysis of neuropathic pain associated with coronavirus disease 2019

https://doi.org/10.1002/ejp.2055

Published

11-Nov-22

Review

https://onlinelibrary.wiley.com/doi/abs/10.1002/ejp.2055

Background and objective
Neuropathic pain is an occasionally reported complication of coronavirus disease 2019 (COVID-19) that has received increased attention in scientific literature. In this systematic review and metanalysis, we aimed to provide information on the frequency of neuropathic pain associated with COVID-19.
Databases and data treatment
We systematically reviewed and analysed literature regarding neuropathic pain associated with COVID-19. Literature searches were conducted in PubMed, EMBASE, and Cochrane Library databases. We considered prospective and retrospective studies published up until September 2022 (limitations included English language, full-text publications, and studies including at least 10 patients). A random effects metanalysis was performed and heterogeneity and publication bias were assessed.
Results
We identified 149 studies. We included 17 studies in the systematic review, and six studies reporting the frequency of neuropathic pain in the acute/subacute phase of COVID-19 in the metanalysis. The estimated frequency of neuropathic pain ranged between 0.4 and 25%. Forest plot analysis showed that the random effect overall frequency was 10% (95% confidence interval: 5-15%), with a high level of heterogeneity (Chi2 = 104; Tau2 = 0.004; df = 5; I2 = 95%; test for overall effect: Z = 3.584; P < 0.0005). The overall risk of bias was moderate in all studies selected, particularly due to the poor description of neuropathic pain diagnostic criteria.
Conclusions
The pooled estimated frequency of neuropathic pain associated with COVID-19 should be considered with caution due to the high heterogeneity across studies and the poor description of the neuropathic pain diagnostic criteria applied.

2577

N495

RafalButowt1KatarzynaBilinska2Christopher S.von Bartheld34

Olfactory dysfunction in COVID-19: new insights into the underlying mechanisms

https://doi.org/10.1016/j.tins.2022.11.003

Published

16-Nov-22

Review

https://www.sciencedirect.com/science/article/pii/S016622362200234X

Highlights
•The underlying mechanisms of the loss of smell in COVID-19 can be narrowed down to five plausible scenarios in the olfactory epithelium that are not mutually exclusive.
•One series of mechanisms focuses on the primary target of SARS-CoV-2 in the olfactory epithelium, the support cells, which provide the mucus to dissolve odorants, and the energy required for olfactory cilia to power olfactory signal transduction, as well as a putative maintenance factor for cilia.
•A second set of scenarios emphasizes changes in gene expression in olfactory receptor neurons, which may be linked to the loss of cilia causing the neurons to become immature-like.
•Both viral and host factors modulate the prevalence of olfactory dysfunction, with the omicron variant preferring an endosomal route that enters support cells less efficiently, resulting in a relative sparing of olfaction in patients infected with this variant.
Abstract
The mechanisms of olfactory dysfunction in coronavirus disease 2019 (COVID-19) are still unclear. In this review, we examine potential mechanism that may explain why the sense of smell is lost or altered. Among the current hypotheses, the most plausible is that death of infected support cells in the olfactory epithelium causes – besides altered composition of the mucus – retraction of the cilia on olfactory receptor neurons, possibly because of lack of support-cell derived glucose in the mucus that powers olfactory signal transduction within the cilia. This mechanism is consistent with the rapid loss of smell and the rapid recovery of smell after regeneration of support cells. Host immune responses that cause downregulation of genes involved in olfactory signal transduction occur too late to trigger anosmia, but may contribute to the duration of the olfactory dysfunction.

2578

N496

Takafumi Kubota,Naoto Kuroda,Daichi Sone

Neuropsychiatric Aspects of Long COVID: A Comprehensive Review

https://doi.org/10.1111/pcn.13508

Published

16-Nov-22

Review

https://onlinelibrary.wiley.com/doi/abs/10.1111/pcn.13508

Although some patients have persistent symptoms or develop new symptoms following coronavirus disease 2019 (COVID-19) infection, neuropsychiatric aspects of long COVID are not well known. This review summarizes and provides an update on the neuropsychiatric dimensions of long COVID. Its neuropsychiatric manifestations commonly include fatigue, cognitive impairment, sleep disorders, depression, anxiety, and post-traumatic stress disorder. There are no specific tests for long COVID, but some characteristic findings such as hypometabolism on positron emission tomography have been reported. The possible mechanisms of long COVID include inflammation, ischemic effects, direct viral invasion, and social and environmental changes. Some patient characteristics and the severity and complications of acute COVID-19 infection may be associated with an increased risk of neuropsychiatric symptoms. Long COVID may resolve spontaneously or persist, depending on the type of neuropsychiatric symptoms. Although established treatments are lacking, various psychological and pharmacological treatments have been attempted. Vaccination against COVID-19 infection plays a key role in the prevention of long coronavirus disease. With differences among the SARS-CoV-2 variants, including the omicron variant, the aspects of long COVID are likely to change in the future. Further studies clarifying the aspects of long COVID to develop effective treatments are warranted.

2579

N497

Meenakshi Pardasani and Nixon M. Abraham

Neurotropic SARS-CoV-2: Causalities and Realities

10.5772/intechopen.108573

Published

Review

https://www.intechopen.com/online-first/84633

Evidences for the dysfunctions of central nervous system (CNS) caused by SARS-CoV-2 infection have accumulated since the beginning of pandemic. The clinical and experimental evidences on viral entry routes to CNS lead to several open questions. While the neurological impairments caused by the virus stay as a reality under Long COVID, dissecting the causality underlying these problems continues to be an intensely studied topic. Extensive reports of olfactory dysfunctions including anosmia, hyposmia, and parosmia due to infections during 2020–2021, led to the hypothesis of virus’ CNS invasion through the olfactory nerve. Some of the investigations using animal models of cellular factors mediating the viral entry also suggest potential neurotropism. Conversely, recent studies proved the absence of viral particles in olfactory sensory neurons and olfactory bulb, hence leading to the deliberation on viral entry route. Here, we summarize the findings on the debated neurotropic characteristics of the virus, including clinical observations and the results from animal models. Further, we emphasize on the need of tracking olfactory and cognitive fitness in the post-COVID-19 era.

2580

N498

Alves de Sousa F.a · Tarrio J.b,c · Sousa Machado A.a · Costa J.R.a · Pinto C.b · Nóbrega Pinto A.a · Moreira B.b · Meireles L.a

Olfactory Cleft Length: A Possible Risk Factor for Persistent Post-COVID-19 Olfactory Dysfunction

https://doi.org/10.1159/000527141

Published

1-Nov-22

Study

https://www.karger.com/article/FullText/527141

Introduction: To date, little is known about predisposing factors for persistent COVID-19-induced olfactory dysfunction (pCIOD). The objective was to determine whether olfactory cleft (OC) measurements associate with pCIOD risk. Material and Methods: Three subgroups were recruited: group A included patients with pCIOD, group B included patients without olfactory dysfunction following SARS-CoV-2 infection (ntCIOD), and group C consisted in controls without past history of SARS-CoV-2 infection (noCOVID-19). Olfactory perception threshold (OPT) and visual analog scale for olfactory impairment (VAS-olf) were obtained. OC measurements were obtained through computed tomography scans. Results were subsequently compared. Results: A total of 55 patients with a mean age of 39 ± 10 years were included. OPT was significantly lower in pCIOD patients (group A: 4.2 ± 2.1 vs. group B: 12.3 ± 1.8 and group C: 12.2 ± 1.5, p < 0.001). VAS-olf was significantly higher in pCIOD (group A: 6 ± 2.6 vs. group B: 1.7 ± 1.6 and group C: 1.6 ± 1.5, p < 0.001). OC length was significantly higher in group A (42.8 ± 4.6) compared to group B (39.7 ± 3.4, p = 0.047) and C (39.8 ± 4, p = 0.037). The odd of pCIOD occurring after COVID-19 infection increased by 21% (95% CI [0.981, 1.495]) for a one unit (mm) increase in OC length. The odd of pCIOD occurring was 6.9 times higher when OC length >40 mm. Conclusion: Longer OC may be a predisposing factor for pCIOD. This study is expected to encourage further research on OC morphology and its impact on olfactory disorders.

2581

N499

ElenaHerreraMaríaGonzález-Nosti

The effect of age on cognitive impairment associated with post COVID-19 syndrome

https://doi.org/10.1016/j.psychres.2022.114945

Published

9-Nov-22

Study

https://www.sciencedirect.com/science/article/pii/S0165178122005364

The results show alterations in at least one neuropsychological test in more than 85% of the patients, although no statistical differences were found between hospitalized and non-hospitalized patients, which rules out that these deficits are a consequence of the severity of the disease. On the contrary, the presence and severity of the cognitive impairments seem to be related to the age of the patients, although in a direction opposite to that expected, i.e., younger patients show impairment in some cognitive domain more frequently than older ones, and the severity of this impairment is greater in these younger patients. This result has been corroborated both by correlation analysis and by comparisons between groups of patients according to their age (young: N=29, ranged 26 to 39 years; middle age: N=97, ranged 40 to 49 years; senior: N=88, ranged 50 to 64 years). This outcome, a priori contrary to expectations, since younger age usually induces a better prognosis in virtually all disorders with cognitive deficits, seems to support one of the causal hypothesis of post COVID-19 syndrome, according to which many SARS-CoV-2-infected patients have antibodies specific for the ACE2 enzyme. Binding of SARS-CoV-2 to ACE2 results in cytokine storming and increased inflammation during SARS-CoV-2 infection (Arthur et al., 2021). Since aging affects the immune system by weakening it, the autoimmune response will also be weaker in seniors than in young patients.
Regarding the different cognitive functions, attention shows the greatest deficit, regardless of the age of the patients. It is followed by processing speed, verbal memory and verbal fluency, in which the effect of age is clearly observed, with a higher percentage of patients with altered scores and a higher percentage of scores corresponding to severe deficits in the young group. Scores in executive functions and visual and working memory also show this effect of age. The time of evolution of the disorder, as well as cognitive reserve, had a little impact on the cognitive performance of our patients.
In conclusion, the results presented here reveal that a high percentage of patients with post COVID-19 syndrome exhibit deficits in some cognitive ability, which corroborates their subjective complaints. In addition, the youngest patients were those who showed the most marked and heterogeneous cognitive impairment, while the oldest patients maintained their cognitive functions preserved to a greater extent with only a mild impairment in attention and speed processing. Precisely both functions were the cognitive processes that are most deficient and homogeneously identified across the different age subgroups.

2582

N500

Alissa Elen Formiga Moura, Danilo Nunes Oliveira, Danielle Mesquista Torres, José Wagner Leonel Tavares-Júnior, Paulo Ribeiro Nóbrega, Pedro Braga-Neto & Manoel Alves Sobreira-Neto

Central hypersomnia and chronic insomnia: expanding the spectrum of sleep disorders in long COVID syndrome - a prospective cohort study

https://doi.org/10.1186/s12883-022-02940-7

Published

9-Nov-22

Study

https://bmcneurol.biomedcentral.com/articles/10.1186/s12883-022-02940-7

Introduction
Long-onset COVID syndrome has been described in patients with COVID-19 infection with persistence of symptoms or development of sequelae beyond 4 weeks after the onset of acute symptoms, a medium- and long-term consequence of COVID-19. This syndrome can affect up to 32% of affected individuals, with symptoms of fatigue, dyspnea, chest pain, cognitive disorders, insomnia, and psychiatric disorders. The present study aimed to characterize and evaluate the prevalence of sleep symptoms in patients with long COVID syndrome.
Methodology
A total of 207 patients with post-COVID symptoms were evaluated through clinical evaluation with a neurologist and specific exams in the subgroup complaining of excessive sleepiness.
Results
Among 189 patients included in the long COVID sample, 48 (25.3%) had sleep-related symptoms. Insomnia was reported by 42 patients (22.2%), and excessive sleepiness (ES) was reported by 6 patients (3.17%). Four patients with ES were evaluated with polysomnography and test, multiple sleep latencies test, and actigraphic data. Two patients had a diagnosis of central hypersomnia, and one had narcolepsy. A history of steroid use was related to sleep complaints (insomnia and excessive sleepiness), whereas depression was related to excessive sleepiness. We observed a high prevalence of cognitive complaints in these patients.
Conclusion
Complaints related to sleep, such as insomnia and excessive sleepiness, seem to be part of the clinical post-acute syndrome (long COVID syndrome), composing part of its clinical spectrum, relating to some clinical data.

2583

N501

Franco Gemignani
Maria F. Bellanova
Elena Saccani

Long-COVID phenotypes and small fiber neuropathy

https://doi.org/10.1016/j.jns.2022.120490

Published

8-Nov-22

Correspondence

https://www.jns-journal.com/article/S0022-510X(22)00352-5/fulltext

Grisanti et al. report on the features of a cohort of patients with neurological post-COVID manifestations in a prospective study aimed at definition of phenotypes, identifying the subgroups of long-COVID type 1 (neuropsychiatric phenotype) and long-COVID type 2 (characterized by symptoms related to peripheral nervous system –PNS- involvement) [ [1] ].

2584

N502

Bianca Besteher , Tonia Rocktäschel , Marlene Machnik , Kathrin Finke , Philipp Reuken , Christian Gaser , Martin Walter

Cortical and subcortical grey matter volume alterations in neuropsychiatric long-COVID syndrome episode

https://doi.org/10.1055/s-0042-1757658

Published

8-Nov-22

Study

https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0042-1757658

Introduction Neuropsychiatric symptoms are among the most common sequelae of long-COVID-19 and highly diminish the patient’s quality of life. As accumulating evidence suggests an impact of survived SARS-CoV-2-infection on brain physiology, it appears necessary to further investigate brain structural changes in relation to clinical long-COVID symptoms. Understanding the pathogenic processes in neuropsychiatric long-COVID will be vital to identify targeted therapy and to ease the months long-lasting symptoms.
Methods The present cross-sectional study investigated 3T-MRI scans from long-COVID patients (n=30) with neuropsychiatric symptoms, and healthy controls matched for age and gender (n=20). Whole-brain comparison of grey matter volume (GMV) was conducted by voxel-based morphometry using the CAT12 software package. To determine whether changes in GMV are predicted by neuropsychiatric symptom burden and / or initial severity of symptoms of COVID-19 and time since onset of COVID-19, we performed multiple linear regression analysis.
Results Enlarged GMV in long-COVID patients was present in several clusters (p<0.05, FWE- corr–ected) spanning fronto-temporal areas, insula, hippocampus, amygdala, basal ganglia, and thalamus in both hemispheres when compared to controls. Time since onset of COVID-19 was a significant regressor in three of these clusters (anatomically located in right inferior frontal gyrus, lateral and posterior orbital gyrus, anterior parts of the insula, left superior, middle and inferior temporal gyrus and left postcentral and precentral gyrus).
Conclusion Grey matter alterations in limbic and secondary olfactory areas are present in neuropsychiatric long-COVID patients. Some GMV alterations were inversely associated with time elapsed since acute COVID-19, suggesting higher GMV with shorter time since onset of COVID-19. Detection of associations between GMV and clinical symptoms might be difficult, because of heterogenous clinical presentation. Larger samples and longitudinal data in neuropsychiatric long-COVID patients are required to further clarify the mediating mechanisms between COVID-19 and GMV.

2585

N503

Adonis Sfera 1,2,*ORCID,Carolina Osorio 3,Sabine Hazan 4,Zisis Kozlakidis 5ORCID,Jose Campo Maldonado 6,Carlos Manuel Zapata-Martín del Campo 7,Jonathan J. Anton 8,Leah Rahman 9,Christina V. Andronescu 10 andGarth L. Nicolson 11

Long COVID and the Neuroendocrinology of Microbial Translocation Outside the GI Tract: Some Treatment Strategies

https://doi.org/10.3390/endocrines3040058

Published

7-Nov-22

Review

https://www.mdpi.com/2673-396X/3/4/58

Similar to previous pandemics, COVID-19 has been succeeded by well-documented post-infectious sequelae, including chronic fatigue, cough, shortness of breath, myalgia, and concentration difficulties, which may last 5 to 12 weeks or longer after the acute phase of illness. Both the psychological stress of SARS-CoV-2 infection and being diagnosed with COVID-19 can upregulate cortisol, a stress hormone that disrupts the efferocytosis effectors, macrophages, and natural killer cells, leading to the excessive accumulation of senescent cells and disruption of biological barriers. This has been well-established in cancer patients who often experience unrelenting fatigue as well as gut and blood–brain barrier dysfunction upon treatment with senescence-inducing radiation or chemotherapy. In our previous research from 2020 and 2021, we linked COVID-19 to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) via angiotensin II upregulation, premature endothelial senescence, intestinal barrier dysfunction, and microbial translocation from the gastrointestinal tract into the systemic circulation. In 2021 and 2022, these hypotheses were validated and SARS-CoV-2-induced cellular senescence as well as microbial translocation were documented in both acute SARS-CoV-2 infection, long COVID, and ME/CFS, connecting intestinal barrier dysfunction to disabling fatigue and specific infectious events. The purpose of this narrative review is to summarize what is currently known about host immune responses to translocated gut microbes and how these responses relate to fatiguing illnesses, including long COVID. To accomplish this goal, we examine the role of intestinal and blood–brain barriers in long COVID and other illnesses typified by chronic fatigue, with a special emphasis on commensal microbes functioning as viral reservoirs. Furthermore, we discuss the role of SARS-CoV-2/Mycoplasma coinfection in dysfunctional efferocytosis, emphasizing some potential novel treatment strategies, including the use of senotherapeutic drugs, HMGB1 inhibitors, Toll-like receptor 4 (TLR4) blockers, and membrane lipid replacement.

2586

N504

César Fernández-de-las-Peñas 1,*ORCID,Bernard X. W. Liew 2,Manuel Herrero-Montes 3,4ORCID,Pablo del-Valle-Loarte 5ORCID,Rafael Rodríguez-Rosado 5,Diego Ferrer-Pargada 6,Randy Neblett 7ORCID andPaula Paras-Bravo 3,4ORCID

Data-Driven Path Analytic Modeling to Understand Underlying Mechanisms in COVID-19 Survivors Suffering from Long-Term Post-COVID Pain: A Spanish Cohort Study

https://doi.org/10.3390/pathogens11111336

Published

12-Nov-22

Study

https://www.mdpi.com/2076-0817/11/11/1336

Pain can be present in up to 50% of people with post-COVID-19 condition. Understanding the complexity of post-COVID pain can help with better phenotyping of this post-COVID symptom. The aim of this study is to describe the complex associations between sensory-related, psychological, and cognitive variables in previously hospitalized COVID-19 survivors with post-COVID pain, recruited from three hospitals in Madrid (Spain) by using data-driven path analytic modeling. Demographic (i.e., age, height, and weight), sensory-related (intensity or duration of pain, central sensitization-associated symptoms, and neuropathic pain features), psychological (anxiety and depressive levels, and sleep quality), and cognitive (catastrophizing and kinesiophobia) variables were collected in a sample of 149 subjects with post-COVID pain. A Bayesian network was used for structural learning, and the structural model was fitted using structural equation modeling (SEM). The SEM model fit was excellent: RMSEA < 0.001, CFI = 1.000, SRMR = 0.063, and NNFI = 1.008. The only significant predictor of post-COVID pain was the level of depressive symptoms (β=0.241, p = 0.001). Higher levels of anxiety were associated with greater central sensitization-associated symptoms by a magnitude of β=0.406 (p = 0.008). Males reported less severe neuropathic pain symptoms (−1.50 SD S-LANSS score, p < 0.001) than females. A higher level of depressive symptoms was associated with worse sleep quality (β=0.406, p < 0.001), and greater levels of catastrophizing (β=0.345, p < 0.001). This study presents a model for post-COVID pain where psychological factors were related to central sensitization-associated symptoms and sleep quality. Further, maladaptive cognitions, such as catastrophizing, were also associated with depression. Finally, females reported more neuropathic pain features than males. Our data-driven model could be leveraged in clinical trials investigating treatment approaches in COVID-19 survivors with post-COVID pain and can represent a first step for the development of a theoretical/conceptual framework for post-COVID pain.

2587

N505

Evgenia Kalamara 1,*ORCID,Athanasia Pataka 1ORCID,Afroditi Boutou 2ORCID,Evangelia Panagiotidou 1,Athina Georgopoulou 3,Evangelos Ballas 4ORCID,Diamantis Chloros 3,Symeon Metallidis 5,Ioannis Kioumis 1 andGeorgia Pitsiou 1ORCID

Persistent Sleep Quality Deterioration among Post-COVID-19 Patients: Results from a 6-Month Follow-Up Study

https://doi.org/10.3390/jpm12111909

Published

16-Nov-22

Study

https://www.mdpi.com/2075-4426/12/11/1909

Background: To date, evidence about sleep disturbances among post-COVID-19 patients is limited. This study aimed to evaluate sleep quality after hospitalization due to SARS-CoV-2 infection. Methods: In-person follow-up was conducted in patients with prior hospitalization due to COVID-19 1(Τ1), 3(Τ2), and 6 (Τ3) months after hospital discharge. Patients were asked to complete questionnaires concerning sleep quality: the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), the Athens Insomnia Scale (AIS), the Fatigue Severity Scale (FSS), and the Stop-BANG (S-B) questionnaire. Results: In total, 133 patients were enrolled (mean age: 56.0 ± 11.48 years, 59.4% males). The most frequently reported comorbidity was arterial hypertension (29.8% of patients), while 37.4% of patients had no comorbidities. The majority of participants exhibited poor sleep quality (global PSQI ≥ 5) at T1 (84.3%), T2 (75.7%), and T3 (77.4%). Insomnia was observed in 56.5%, 53.5%, and 39.2% of participants, respectively (AIS ≥ 6). An FSS score ≥ 4 was observed in 51.2%, 33.7%, and 29.1% of participants at T1, T2, T3, respectively. Elapsed time was found to be negatively and independently associated with the global PSQI, PSQI C5-Sleep disturbance, PSQI C7-Daytime dysfunctions, FSS, and AIS after adjustment for possible confounders. No significant difference was found between groups with good and poor sleep quality (based on the global PSQI) with respect to gender (p = 0.110), age (p = 0.528), BMI (p = 0.816), smoking status (p = 0.489), hypertension (p = 0.427), severity of disease (p = 0.224), the Charlson Comorbidity Index (p = 0.827), or the length of hospital stay (p = 0.162). Participants with excessive daytime sleepiness (EDS) and patients with severe fatigue (FSS ≥ 4) were significantly younger. Females presented a higher rate of insomnia symptoms (55.7% vs. 44.3%, p < 0.001). Conclusions: Several sleep disturbances were observed after hospital discharge for COVID-19 pneumonia at certain time points; However, the improvement over time was remarkable in most domains of the assessed questionnaires.

2588

N506

Philippe Voruz,Alexandre Cionca,Isabele Jacot de Alcântara,Anthony Nuber-Champier,Gilles Allali,Lamyae Benzakour,Patrice H. Lalive,Karl O. Lövblad,Olivia Braillard,Mayssam Nehme,Matteo Coen,Jacques Serratrice,Jean-Luc Reny,Jérôme Pugin,Idris Guessous,Radek Ptak,Basile N. Landis,Dan Adler,Alessandra Griffa,Dimitri Van De Ville,Frédéric Assal,Julie A. Péron

Brain functional connectivity alterations associated with neuropsychological performance 6–9 months following SARS-CoV-2 infection

https://doi.org/10.1002/hbm.26163

Published

2-Dec-22

Study

https://onlinelibrary.wiley.com/doi/10.1002/hbm.26163

Neuropsychological deficits and brain damage following SARS-CoV-2 infection are not well understood. Then, 116 patients, with either severe, moderate, or mild disease in the acute phase underwent neuropsychological and olfactory tests, as well as completed psychiatric and respiratory questionnaires at 223 ± 42 days postinfection. Additionally, a subgroup of 50 patients underwent functional magnetic resonance imaging. Patients in the severe group displayed poorer verbal episodic memory performances, and moderate patients had reduced mental flexibility. Neuroimaging revealed patterns of hypofunctional and hyperfunctional connectivities in severe patients, while only hyperconnectivity patterns were observed for moderate. The default mode, somatosensory, dorsal attention, subcortical, and cerebellar networks were implicated. Partial least squares correlations analysis confirmed specific association between memory, executive functions performances and brain functional connectivity. The severity of the infection in the acute phase is a predictor of neuropsychological performance 6–9 months following SARS-CoV-2 infection. SARS-CoV-2 infection causes long-term memory and executive dysfunctions, related to large-scale functional brain connectivity alterations.

2589

N507

YanyaoDua1WeiZhaoabc1SihongHuangaYijieHuangaYanjingChenaHuitingZhangdHuGuoeJunLiuabc

Two-year follow-up of brain structural changes in patients who recovered from COVID-19: A prospective study

https://doi.org/10.1016/j.psychres.2022.114969

Published

24-Nov-22

Study

https://www.sciencedirect.com/science/article/pii/S0165178122005601

Highlights
•Longitudinal MRI data to explore brain structural changes of patients recovered from COVID-19 after two years.
•After two years of follow-up, the dynamics of clinical sequelae varied.
•GMV recovered in the left frontal and temporal lobes, while persisted in the cerebellum, vermis, and right temporal lobe.
Abstract
The long-term effects of COVID-19 on brain structure remain unclear. A prospective study was conducted to explore the changes in brain structure in COVID-19 survivors at one and two years after discharge (COVID-19one, COVID-19two). The difference in gray matter volume (GMV) was analyzed using the voxel-based morphometry method, and correlation analyses were conducted. The dynamic changes in clinical sequelae varied. The GMVs in the cerebellum and vermis were reduced in COVID-19one and COVID-19two, positively correlated with lymphocyte count, and negatively correlated with neutrophil count, neutrophil/lymphocyte ratio (COVID-19one), and systemic immune-inflammation index (COVID-19two). The decreased GMVs in the left middle frontal gyrus, inferior frontal gyrus of the operculum, right middle temporal gyrus, and inferior temporal gyrus returned to normal in COVID-19two. The decreased GMV in the left frontal lobe was negatively correlated with the Athens Insomnia Scale (AIS). The GMV in the left temporal lobe was aggravated in COVID-19two and positively correlated with C-reactive protein. In conclusion, GMV recovery coexisted with injury, which was associated with AIS and inflammatory factors. This may shed some light on the dynamic changes in brain structure and the possible predictors that may be related to GMV changes in COVID-19two.

2590

N508

Haúla Faruk Haider1 and Agnieszka J. Szczepek2,3*

Editorial: Neurotological consequences of long COVID

https://doi.org/10.3389/fneur.2022.1087896

Published

21-Nov-22

Editorial

https://www.frontiersin.org/articles/10.3389/fneur.2022.1087896/full

As we write this editorial, the pandemic has been going on for almost 3 years, and although vaccines are effective in priming the immune system to fight the virus (2), and sophisticated modeling helps predict the subsequent waves of infection (3), but there is no forecast that this global problem will end soon. Neurotological symptoms are neither leading during primary SARS-CoV-2 infection nor among long-term post-COVID symptoms. Nevertheless, hearing loss, tinnitus, hyperacusis, or vertigo significantly reduce the quality of life and negatively affect interpersonal communication and social life. All these conditions were documented in our RT as the long-term consequences of COVID-19, but many questions remain open. What factors predispose to the development of post-COVID neurotological symptoms? Do vaccines protect against the neurotologic COVID sequel? Is there a link between the virus strain and the neurotological consequences of COVID-19? To answer these and many other questions, we encourage the community to continue to collect and analyze clinical data and conduct translational research that may provide some solutions in the future.

2591

N509

Ali Nouraeinejad

Brain fog as a Long-term Sequela of COVID-19

https://doi.org/10.1007/s42399-022-01352-5

Published

24-Nov-22

Review

https://link.springer.com/article/10.1007/s42399-022-01352-5

Increasing data indicate that people infected with COVID-19 are at high risk for developing long-term neurological complications, such as “brain fog” or cognitive impairment. However, little is known about the long-term outcomes of COVID-19 survivors. This also applies to the prevalence, risk factors, and pathobiological findings associated with these consequences. Although cognitive complications are anticipated in patients who require a long-lasting hospital stay or intubation, milder cases of COVID-19 with no record of hospitalization have also been shown to experience assessable cognitive challenges. Cognitive impairment can have a devastating impact on daily functioning. Understanding the long-term effect of COVID-19 on cognitive function is vital for applying specific schemes to those who wish to return to their jobs productively.

2592

N510

Alessandro Padovani & Andrea Pilotto

Looking for lights in the fog of long-term neurological COVID

https://doi.org/10.1038/s41582-022-00750-6

Published

18-Nov-22

Editorial

https://www.nature.com/articles/s41582-022-00750-6

A new study provides evidence for an association between COVID-19 and long-term neurological syndromes. The findings highlight the need for further research into the long-term neurological consequences of SARS-CoV-2 infection and the development of strategies that lessen the effects of these consequences on patient quality of life and on healthcare systems.
Refers to Xu, E. et al. Long-term neurologic outcomes of COVID-19. Nat. Med. https://doi.org/10.1038/s41591-022-02001-z (2022).

2593

N511

Yuxin Hou, Chang Li, Chaemin Yoon, On Wah Leung, Sikun You, Xiaoming Cui, Jasper Fuk-Woo Chan, Duanqing Pei, Hoi Hung Cheung & Hin Chu

Enhanced replication of SARS-CoV-2 Omicron BA.2 in human forebrain and midbrain organoids

https://doi.org/10.1038/s41392-022-01241-2

Published

20-Nov-22

Study

https://www.nature.com/articles/s41392-022-01241-2

Coronavirus Disease 2019 (COVID-19) is associated with a variety of neurological complications, including encephalopathy, encephalitis, dementia, and others.1 The pathogenic mechanism of these neurological manifestations remains incompletely understood but may be due to factors such as coagulation problem, immune-mediated response, or direct viral invasion into the central nervous system (CNS).2 We and others previously reported that ancestral SARS-CoV-2 could infect and replicate in human brain organoids.3,4 More recently, SARS-CoV-2 Omicron BA.1 emerged in late 2021 and demonstrated altered virological features including increased immunoevasion and attenuated pathogenicity comparing to SARS-CoV-2 wildtype (WT) and previous variants.5 However, the neuroinvasiveness of Omicron sublineages remain unexplored. Here, we investigated the neuroinvasion and neurotoxicity of Omicron BA.1 and BA.2, and compared the findings with those of SARS-CoV-2 WT and Delta in human forebrain and midbrain organoids. Our results demonstrated that BA.2 replicated more efficiently while triggered lower levels of type I interferon response than that of SARS-CoV-2 WT, Delta, and BA.1 in both human forebrain and midbrain organoids. In addition, BA.2 triggered substantially higher levels of apoptosis in the infected human forebrain and midbrain organoids. Together, these findings suggest that BA.2 may be different from SARS-CoV-2 WT and previous variants in its capacity in targeting and causing diseases in the human brain.
Together, our study revealed a number of interesting findings which will be important for follow-up studies. First, the reason behind the enhanced replication of BA.2 in brain organoids should be dissected. Second, the importance and mechanism behind the down-regulation of entry-related factors in SARS-CoV-2-infected brain organoids should be investigated. Third, the mechanism of why BA.2 triggered the lowest IFN response in brain organoid deserves further investigation. Forth, the cause and the physiological importance of BA.2-induced apoptosis in the brain organoids should be further dissected.

2594

N512

Andrea Mazzatenta

Physiological discrimination and correlation between olfactory and gustatory dysfunction in long-term COVID-19

https://doi.org/10.14814/phy2.15486

Published

22-Nov-22

Study

https://physoc.onlinelibrary.wiley.com/doi/10.14814/phy2.15486

The spread of the SARS-CoV-2 virus produces a new disease termed COVID-19, the underlying physiological mechanisms of which are still being understood. Characteristic of the infection is the compromising of taste and smell. There is a persistent need to discriminate the dysfunctions and correlation between taste and smell, which are probably epiphenomena of other concealed conditions. Anosmic and ageusic long-term COVID-19 patients were re-evaluated after 1 year using a Volabolomic approach with an e-nose recording system coupled with olfactometric and gustometric tests. Here a range of sensory arrangements was found, from normal taste and smell to complete losses. The following patterns of olfactory threshold (OT)-taste threshold-olfactory uni- and cross-modal perception were found anosmia-severe hypogeusia-anosmia; hyposmia-hypogeusia-severe hyposmia; normosmia-ageusia-hyposmia; severe hyposmia -normogeusia-normosmia. There is a strong correlation between OT and olfactory uni- and cross-modal perception, a moderate correlation between olfactory and taste threshold and no correlation between OT and taste threshold. In conclusion, this study provides evidence for the feasibility of testing the chemical senses to directly objectify function in order to discriminate taste from olfactory impairment. Furthermore, it allows to hypothesize a long-term effect of the virus due to neuroinvasion through, probably, the olfactory system with injury in the related multisensory areas of taste and smell.

2595

N513

Ann-Katrin Schild, Yasemin Goereci, Daniel Scharfenberg, Kim Klein, Joachim Lülling, Dix Meiberth, Finja Schweitzer, Sophie Stürmer, Philip Zeyen, Derya Sahin, Gereon R. Fink, Frank Jessen, Christiana Franke, Oezguer A. Onur, Josef Kessler, Clemens Warnke & Franziska Maier

Multidomain cognitive impairment in non-hospitalized patients with the post-COVID-19 syndrome: results from a prospective monocentric cohort

https://doi.org/10.1007/s00415-022-11444-w

Published

23-Nov-22

Study

https://link.springer.com/article/10.1007/s00415-022-11444-w

Background
A fraction of patients with asymptomatic to mild/moderate acute COVID-19 disease report cognitive deficits as part of the post-COVID-19 syndrome. This study aimed to assess the neuropsychological profile of these patients.
Methods
Assessment at baseline (three months or more following acute COVID-19) of a monocentric prospective cohort of patients with post-COVID-19 syndrome. Multidomain neuropsychological tests were performed, and questionnaires on depression, anxiety, fatigue, sleep, and general health status were administered.
Results
Of the 58 patients screened, six were excluded due to possible alternative causes of cognitive impairment (major depression, neurodegenerative disease). Of the remaining 52 individuals, only one had a below-threshold screening result on Mini-Mental State Examination, and 13 scored below the cut-off on Montreal Cognitive Assessment. Extended neuropsychological testing revealed a neurocognitive disorder (NCD) in 31 (59.6%) participants with minor NCD in the majority of cases (n = 26). In patients with NCD, the cognitive domains learning/memory and executive functions were impaired in 60.7%, complex attention in 51.6%, language in 35.5%, and perceptual-motor function in 29.0%. Cognitive profiles were associated with daytime sleepiness but not with depression, anxiety, sleep quality, total general health status, or fatigue.
Conclusion
Neurocognitive impairment can be confirmed in around 60% of individuals with self-reported deficits as part of post-COVID-19 syndrome following a mild acute COVID-19 disease course. Notably, screening tests cannot reliably detect this dysfunction. Standard psychiatric assessments showed no association with cognitive profiles. Longitudinal studies are needed to further evaluate the course of neurocognitive deficits and clarify pathophysiology.

2596

N514

Serena Scarpelli,Alessandra De Santis,Valentina Alfonsi,Maurizio Gorgoni,Charles M. Morin,Colin Espie,Ilona Merikanto,Frances Chung,Thomas Penzel,Bjørn Bjorvatn,Yves Dauvilliers,Brigitte Holzinger,Yun K. Wing,Markku Partinen,Giuseppe Plazzi,Luigi De Gennaro

The role of sleep and dreams in long-COVID

https://doi.org/10.1111/jsr.13789

Published

18-Nov-22

Study

https://onlinelibrary.wiley.com/doi/abs/10.1111/jsr.13789

Recent investigations show that many people affected by SARS-CoV2 (COVID-19) report persistent symptoms 2–3 months from the onset of the infection. Here, we report the Italian findings from the second International COVID-19 Sleep Study survey, aiming to investigate sleep and dream alterations in participants with post-acute symptoms, and identify the best determinants of these alterations among patients with long-COVID. Data from 383 participants who have had COVID-19 were collected through a web-survey (May–November 2021). Descriptive analyses were performed to outline the sociodemographic characteristics of long-COVID (N = 270, with at least two long-lasting symptoms) and short-COVID (N = 113, with none or one long-lasting symptom) participants. They were then compared concerning sleep and dream measures. We performed multiple linear regressions considering as dependent variables sleep and dream parameters discriminating the long-COVID group. Age, gender, work status, financial burden, COVID-19 severity and the level of care were significantly different between long-COVID and short-COVID subjects. The long-COVID group showed greater sleep alterations (sleep quality, daytime sleepiness, sleep inertia, naps, insomnia, sleep apnea, nightmares) compared with the short-COVID group. We also found that the number of long-COVID symptoms, psychological factors and age were the best explanatory variables of sleep and oneiric alterations. Our findings highlight that sleep alterations are part of the clinical presentation of the long-COVID syndrome. Moreover, psychological status and the number of post-acute symptoms should be considered as state-like variables modulating the sleep problems in long-COVID individuals. Finally, according to previous investigations, oneiric alterations are confirmed as a reliable mental health index.

2597

N515

N. Azcue, J. C. Gómez-Esteban, M. Acera, B. Tijero, T. Fernandez, N. Ayo-Mentxakatorre, T. Pérez-Concha, A. Murueta-Goyena, J. V. Lafuente, Á. Prada, A. López de Munain, G. Ruiz-Irastorza, L. Ribacoba, I. Gabilondo & R. Del Pino

Brain fog of post-COVID-19 condition and Chronic Fatigue Syndrome, same medical disorder?

https://doi.org/10.1186/s12967-022-03764-2

Published

6-Dec-22

Study

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03764-2

Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is characterized by persistent physical and mental fatigue. The post-COVID-19 condition patients refer physical fatigue and cognitive impairment sequelae. Given the similarity between both conditions, could it be the same pathology with a different precipitating factor?
Objective
To describe the cognitive impairment, neuropsychiatric symptoms, and general symptomatology in both groups, to find out if it is the same pathology. As well as verify if the affectation of smell is related to cognitive deterioration in patients with post-COVID-19 condition.
Methods
The sample included 42 ME/CFS and 73 post-COVID-19 condition patients. Fatigue, sleep quality, anxiety and depressive symptoms, the frequency and severity of different symptoms, olfactory function and a wide range of cognitive domains were evaluated.
Results
Both syndromes are characterized by excessive physical fatigue, sleep problems and myalgia. Sustained attention and processing speed were impaired in 83.3% and 52.4% of ME/CFS patients while in post-COVID-19 condition were impaired in 56.2% and 41.4% of patients, respectively. Statistically significant differences were found in sustained attention and visuospatial ability, being the ME/CFS group who presented the worst performance. Physical problems and mood issues were the main variables correlating with cognitive performance in post-COVID-19 patients, while in ME/CFS it was anxiety symptoms and physical fatigue.
Conclusions
The symptomatology and cognitive patterns were similar in both groups, with greater impairment in ME/CFS. This disease is characterized by greater physical and neuropsychiatric problems compared to post-COVID-19 condition. Likewise, we also propose the relevance of prolonged hyposmia as a possible marker of cognitive deterioration in patients with post-COVID-19.

2598

N516

Mariana Beiral Hammerle, Deborah Santos Sales, Patricia Gomes Pinheiro, Elisa Gutman Gouvea, Pedro Ignacio F M de Almeida, Clarissa de Araujo Davico, Rayanne S Souza, Carina Tellaroli Spedo, Denise Hack Nicaretta, Regina Maria Papais Alvarenga, Karina Lebeis Pires, Luiz Claudio Santos Thuler, Claudia Cristina Ferreira Vasconcelos

Cognitive Complaints Assessment and Neuropsychiatric Disorders After Mild COVID-19 Infection

https://doi.org/10.1093/arclin/acac093

Published

2-Dec-22

Study

https://academic.oup.com/acn/advance-article/doi/10.1093/arclin/acac093/6865028

Objectives
This study aimed to analyze cognitive impairment associated with long-term coronavirus disease 2019 (COVID-19) syndrome and its correlation with anxiety, depression, and fatigue in patients infected with severe acute respiratory syndrome coronavirus.
Methods
This was a cross-sectional study of 127 patients with COVID-19. Tests to screen for neuropsychiatric symptoms included the Fatigue Severity Scale, Mini-Mental State Exam 2 (MMSE-2), Symbol Digit Modalities Test (SDMT), and Hospital Anxiety and Depression Scale.
Results
In cognitive tests, SDMT was abnormal in 22%, being more sensitive than MMSE-2 to detect cognitive changes. Furthermore, although manifestations such as fatigue, depression, and anxiety were frequent in the post-COVID-19 phase, these 3 conditions, known to contribute to cognitive impairment, were slightly correlated with worse performance on the rapid screening tests.
Conclusions
In patients with mild COVID-19 and cognitive complaints, SDMT helped to confirm disturbances in the attention domain and processing speed.

2599

N517

LorenzoDianaabRossanaRegazzoniaMatteoSozziaStefaniaPiconicLucaBorghesicElisaLazzaronidPaolaBasilicoaAngeloAliprandiaNadiaBologninibeDaniela R.BonardifDanieleColombofAndreaSalmaggia

Monitoring cognitive and psychological alterations in COVID-19 patients: A longitudinal neuropsychological study

https://doi.org/10.1016/j.jns.2022.120511

Published

29-Nov-22

Study

https://www.sciencedirect.com/science/article/pii/S0022510X22003732

Highlights
•Longitudinal assessment of COVID-19-related cognitive symptoms was performed.
•Cognitive alterations may extend beyond 1 year after the acute phase.
•Several borderline scores in memory and executive tests were detected.
•Longitudinal improvements were observed in several cognitive tests.
Abstract
Background
SARS-COV-2 infection has been associated to long-lasting neuropsychiatric sequelae, including cognitive deficits, that persist after one year. However, longitudinal monitoring has been scarcely performed. Here, in a sample of COVID-19 patients, we monitor cognitive, psychological and quality of life-related profiles up to 22 months from resolution of respiratory disease.
Methods
Out of 657 COVID-19 patients screened at Manzoni Hospital (Lecco, Italy), 22 underwent neuropsychological testing because of subjective cognitive disturbances at 6 months, 16 months, and 22 months. Tests of memory, attention, and executive functions were administered, along with questionnaires for depressive and Post-traumatic stress disorder (PTSD) symptoms, psychological well-being and quality of life. Cross-sectional descriptives, correlational, as well as longitudinal analyses considering COVID19-severity were carried out. A preliminary comparison with a sample of obstructive sleep apneas patients was also performed.
Results
Around 50% of COVID-19 patients presented with cognitive deficits at t0. The most affected domain was verbal memory. Pathological scores diminished over time, but a high rate of borderline scores was still observable. Longitudinal analyses highlighted improvements in verbal and non-verbal long term memory, as well as attention, and executive functioning. Depression and PTSD-related symptoms were present in 30% of patients. The latter decreased over time and were associated to attentional-executive performance.
Conclusions
Cognitive dysfunctions in COVID-19 patients may extend over 1 year, yet showing a significant recovery in several cases. Cognitive alterations are accompanied by a significant psychological distress. Many patients displaying borderline scores, especially those at higher risk of dementia, deserve clinical monitoring.

2600

N518

Michael J. Strong

SARS-CoV-2, aging, and Post-COVID-19 neurodegeneration

https://doi.org/10.1111/jnc.15736

Published

2-Dec-22

Review

https://onlinelibrary.wiley.com/doi/10.1111/jnc.15736

As the world continues to experience the effects of SARS-CoV-2, there is evidence to suggest that the sequelae of viral infection (the post-COVID-19 condition; PCC) at both an individual and population level will be significant and long-lasting. The history of pandemics or epidemics in the last 100 years caused by members of the RNA virus family, of which coronaviruses are a member, provides ample evidence of the acute neurological effects. However, except for the H1N1 influenza pandemic of 1918/1919 (the Spanish flu) with its associated encephalitis lethargica, there is little information on long-term neurological sequelae. COVID-19 is the first pandemic that has occurred in a setting of an aging population, especially in several high-income countries. Its survivors are at the greatest risk for developing neurodegenerative conditions as they age, rendering the current pandemic a unique paradigm not previously witnessed. The SARS-CoV-2 virus, among the largest of the RNA viruses, is a single-stranded RNA that encodes for 29 proteins that include the spike protein that contains the key domains required for ACE2 binding, and a complex array of nonstructural proteins (NSPs) and accessory proteins that ensure the escape of the virus from the innate immune response, allowing for its efficient replication, translation, and exocytosis as a fully functional virion. Increasingly, these proteins are also recognized as potentially contributing to biochemical and molecular processes underlying neurodegeneration. In addition to directly being taken up by brain endothelium, the virus or key protein constituents can be transported to neurons, astrocytes, and microglia by extracellular vesicles and can accelerate pathological fibril formation. The SARS-CoV-2 nucleocapsid protein is intrinsically disordered and can participate in liquid condensate formation, including as pathological heteropolymers with neurodegenerative disease-associated RNA-binding proteins such as TDP-43, FUS, and hnRNP1A. As the SARS-CoV-2 virus continues to mutate under the immune pressure exerted by highly efficacious vaccines, it is evolving into a virus with greater transmissibility but less severity compared with the original strain. The potential of its lingering impact on the nervous system thus has the potential to represent an ongoing legacy of an even greater global health challenge than acute infection.

2601

N519

Zuin, Marco; Rigatelli, Gianluca; Bilato, Claudio; Porcari, Aldostefano; Merlo, Marco; Roncon, Loris; Sinagra, Gianfranco

One-Year Risk of myocarditis after COVID-19 infection: a systematic review and meta-analysis

https://doi.org/10.1038/s41467-022-35225-1

Published

Study

https://www.nature.com/articles/s41467-022-35225-1

Although ocular manifestations are reported in patients with COVID-19, consensus on ocular tropism of SARS-CoV-2 is lacking. Here, we infect K18-hACE2 transgenic mice with SARS-CoV-2 using various routes. We observe ocular manifestation and retinal inflammation with production of pro-inflammatory cytokines in the eyes of intranasally (IN)-infected mice. Intratracheal (IT) infection results in dissemination of the virus from the lungs to the brain and eyes via trigeminal and optic nerves. Ocular and neuronal invasions are confirmed using intracerebral (IC) infection. Notably, the eye-dropped (ED) virus does not cause lung infection and becomes undetectable with time. Ocular and neurotropic distribution of the virus in vivo is evident in fluorescence imaging with an infectious clone of SARS-CoV-2-mCherry. The ocular tropic and neuroinvasive characteristics of SARS-CoV-2 are confirmed in wild-type Syrian hamsters. Our data can improve the understanding regarding viral transmission and clinical characteristics of SARS-CoV-2 and help in improving COVID-19 control procedures.

2602

N520

Paolini, Marco; Palladini, Mariagrazia; Mazza, Mario Gennaro; Colombo, Federica; Vai, Benedetta; Rovere-Querini, Patrizia; Falini, Andrea; Poletti, Sara; Benedetti, Francesco

Brain correlates of subjective cognitive complaints in COVID-19 survivors: a multimodal magnetic resonance imaging study

https://doi.org/10.1016/j.euroneuro.2022.12.002

Published

Study

https://www.sciencedirect.com/science/article/pii/S0924977X22009130

Cognitive impairment represents a leading residual symptom of COVID-19 infection, which lasts for months after the virus clearance. Up-to-date scientific reports documented a wide spectrum of brain changes in COVID-19 survivors following the illness's resolution, mainly related to neurological and neuropsychiatric consequences. Preliminary insights suggest abnormal brain metabolism, microstructure, and functionality as neural under-layer of post-acute cognitive dysfunction. While previous works focused on brain correlates of impaired cognition as objectively assessed, herein we investigated long-term neural correlates of subjective cognitive decline in a sample of 58 COVID-19 survivors with a multimodal imaging approach. Diffusion Tensor Imaging (DTI) analyses revealed widespread white matter disruption in the sub-group of cognitive complainers compared to the non-complainer one, as indexed by increased axial, radial, and mean diffusivity in several commissural, projection and associative fibres. Likewise, the Multivoxel Pattern Connectivity analysis (MVPA) revealed highly discriminant patterns of functional connectivity in resting-state among the two groups in the right frontal pole and in the middle temporal gyrus, suggestive of inefficient dynamic modulation of frontal brain activity and possible metacognitive dysfunction at rest. Beyond COVID-19 actual pathophysiological brain processes, our findings point toward brain connectome disruption conceivably translating into clinical post-COVID cognitive symptomatology. Our results could pave the way for a potential brain signature of cognitive complaints experienced by COVID-19 survivors, possibly leading to identify early therapeutic targets and thus mitigating its detrimental long-term impact on quality of life in the post-COVID-19 stages.

2603

N521

Jeong, Gi Uk; Kwon, Hyung-Jun; Ng, Wern Hann; Liu, Xiang; Moon, Hyun Woo; Yoon, Gun Young; Shin, Hye Jin; Lee, In-Chul; Ling, Zheng Lung; Spiteri, Alanna G.; King, Nicholas J. C.; Taylor, Adam; Chae, Ji Soo; Kim, Chonsaeng; Ahn, Dae-Gyun; Kim, Kyun-Do; Ryu, Young Bae; Kim, Seong-Jun; Mahalingam, Suresh; Kwon, Young-Chan

Ocular tropism of SARS-CoV-2 in animal models with retinal inflammation via neuronal invasion following intranasal inoculation

https://doi.org/10.1007/s40120-022-00395-z

Published

Study

https://doi.org/10.1007/s40120-022-00395-z

Introduction
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can affect multiple organs. Reports of persistent or newly emergent symptoms, including those related to the nervous system, have increased over the course of the pandemic, leading to the introduction of post-COVID-19 syndrome. However, this novel syndrome is still ill-defined and structured objectification of complaints is scarce. Therefore, we performed a prospective observational cohort study to better define and validate subjective neurological disturbances in patients with post-COVID-19 syndrome.

Methods
A total of 171 patients fulfilling the post-COVID-19 WHO Delphi consensus criteria underwent a comprehensive neurological diagnostic work-up including neurovascular, electrophysiological, and blood analysis. In addition, magnetic resonance imaging (MRI) and lumbar puncture were conducted in subgroups of patients. Furthermore, patients underwent neuropsychological, psychosomatic, and fatigue assessment.

Results
Patients were predominantly female, middle-aged, and had incurred mostly mild-to-moderate acute COVID-19. The most frequent post-COVID-19 complaints included fatigue, difficulties in concentration, and memory deficits. In most patients (85.8%), in-depth neurological assessment yielded no pathological findings. In 97.7% of the cases, either no diagnosis other than post COVID-19 syndrome, or no diagnosis likely related to preceding acute COVID-19 could be established. Sensory or motor complaints were more often associated with a neurological diagnosis other than post-COVID-19 syndrome. Previous psychiatric conditions were identified as a risk factor for developing post-COVID-19 syndrome. We found high somatization scores in our patient group that correlated with cognitive deficits and the extent of fatigue.

Conclusions
Albeit frequently reported by patients, objectifiable affection of the nervous system is rare in post-COVID-19 syndrome. Instead, elevated levels of somatization point towards a pathogenesis potentially involving psychosomatic factors. However, thorough neurological assessment is important in this patient group in order to not miss neurological diseases other than post-COVID-19.

Key Summary Points
Why carry out this study?
To validate subjective neurological complaints in patients with post-COVID-19 by applying a comprehensive neuro-psychiatric diagnostic workup.
What was learned from the study?
The nervous system is rarely affected in patients with post-COVID-19 syndrome.
Psychosomatic factors probably contribute to the pathogenesis of post-COVID-19 syndrome.
Patients presenting with post-COVID-19 should be thoroughly assessed in order to not miss other diagnoses.

2604

N522

Santos-Rebouças, Cíntia Barros; Piergiorge, Rafael Mina; dos Santos Ferreira, Cristina; Seixas Zeitel, Raquel de; Gerber, Alexandra Lehmkuhl; Rodrigues, Marta Cristine Felix; Guimarães, Ana Paula de Campos; Silva, Rodrigo Moulin; Fonseca, Adriana Rodrigues; Souza, Rangel Celso; de Souza, Ana Tereza Antunes Monteiro; Rossi, Átila Duque; Porto, Luís Cristóvão de Moraes Sobrino; Cardoso, Cynthia Chester; de Vasconcelos, Ana Tereza Ribeiro

Host genetic susceptibility underlying SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Brazilian Children

https://doi.org/10.1007/s40120-022-00426-9

Published

Study

https://doi.org/10.1007/s40120-022-00426-9

The authors claim to have performed a comprehensive neurological assessment of patients with post-COVID-19 syndrome. However, ultrasound examination of the extra- and intracranial head and neck arteries was only performed in 76 patients, brain magnetic resonance imaging in only 41 patients and a lumbar puncture in only nine patients, even though 171 patients were enrolled in the study. The study did not include positron emission tomography (PET) or single-photon emission computerized tomography (SPECT) scans of the brain nor did it include cerebral Doppler scans to see if there was objective evidence for the cognitive problems of patients. In this context, it should be noted that the cerebral Doppler scan study of Van Campen et al., which was published in December 2021, found a reduction in cerebral blood flow in response to tilt testing in long COVID-19 patients, similar to that observed in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which was not seen in healthy controls [4].

The study also did not enquire about exertional intolerance even though many long COVID patients suffer from that. Objective evidence for exertional intolerance in long COVID-19 patients was provided by Singh et al. using invasive cardiopulmonary exercise testing [5].

2605

N523

Zinatizadeh, Mohammad Reza; Zarandi, Peyman Kheirandish; Ghiasi, Mohsen; Kooshki, Hamid; Mohammadi, Mozafar; Amani, Jafar; Rezaei, Nima

Immunosenescence and inflamm-ageing in COVID-19

https://doi.org/10.1007/s40120-022-00424-x

Published

Study

https://doi.org/10.1007/s40120-022-00424-x

The authors allege that our study would have labelled all patients with post-COVID-19 syndrome as ‘psychosomatic’ since the neurological workup was normal. Unfortunately, however, this claim is a misrepresentation of our conclusions. Rather, we suggested that psychosomatic factors should be taken into account since we were widely unable to objectify neurological impairment in our cohort. We regard this approach as state-of-the-art in modern medicine. It is best medical practice and in line with current guidelines—including post-COVID-19 guidelines [3]—to consider psychological and social factors in disease states without obvious organ damage. Even further, physicians would be acting negligently and potentially withholding patients from effective therapies, such as psychotherapy, if psychosomatic origin was not taken into account under such a constellation. The authors summarize their view as ‘absence of evidence is no evidence of absence’. This rather general statement does not add anything specific to the current debate but in fact could be directed to any scientific finding. We have not claimed causality from our data and are fully aware of the fact that it is never possible to finally ‘prove’ absence of a specific condition.

2606

N524

Campos, Catherine; Prokopich, Samantha; Loewen, Hal; Sanchez-Ramirez, Diana C.

Long-Term Effect of COVID-19 on Lung Imaging and Function, Cardiorespiratory Symptoms, Fatigue, Exercise Capacity, and Functional Capacity in Children and Adolescents: A Systematic Review and Meta-Analysis

https://doi.org/10.1016/j.arr.2022.101818

Published

Study

https://www.sciencedirect.com/science/article/pii/S1568163722002604

Highlights
•Immunosenescence and inflamm-ageing are critical characteristics of the aging immune system.
•COVID-19 mortality is higher in the elderly with one or more co-morbidities.
•In the elderly, the function of innate immune cells and the inflammatory response to SARS-CoV-2 are unregulated.
Abstract
The destructive effects of coronavirus disease 2019 (COVID-19) on the elderly and people with cardiovascular disease have been proven. New findings shed light on the role of aging pathways on life span and health age. New therapies that focus on aging-related pathways may positively impact the treatment of this acute respiratory infection. Using new therapies that boost the level of the immune system can support the elderly with co-morbidities against the acute form of COVID-19. This article discusses the effect of the aging immune system against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the pathways affecting this severity of infection.

2607

N525

Schirinzi, Tommaso; Lattanzi, Roberta; Maftei, Daniela; Grillo, Piergiorgio; Zenuni, Henri; Boffa, Laura; Albanese, Maria; Simonetta, Clara; Bovenzi, Roberta; Maurizi, Riccardo; Loccisano, Laura; Vincenzi, Martina; Greco, Antonio; Di Girolamo, Stefano; Mercuri, Nicola B.; Passali, Francesco M.; Severini, Cinzia

Substance P and Prokineticin-2 are overexpressed in olfactory neurons and play differential roles in persons with persistent post-COVID-19 olfactory dysfunction

https://doi.org/10.1016/j.bbi.2022.12.017

Published

Study

https://www.sciencedirect.com/science/article/pii/S0889159122004755

Highlights
•
Persistent post-COVID-19 OD is an unexplained condition, at risk for neurological sequelae.

•
Molecular analysis of ONs may unravel the underlying mechanisms.

•
ONs overexpress SP and PK2, the latter proportionally to residual olfaction.

•
SP and PK2 could be involved in the pathogenesis and the recovery of OD respectively.

•
SP and PK2 represent two candidate therapeutic targets for post-COVID-19 OD.

Abstract
Persistent olfactory dysfunction (OD) is one of the most complaining and worrying complications of long COVID-19 because of the potential long-term neurological consequences. While causes of OD in the acute phases of the SARS-CoV-2 infection have been figured out, reasons for persistent OD are still unclear.

Here we investigated the activity of two inflammatory pathways tightly linked with olfaction pathophysiology, namely Substance P (SP) and Prokineticin-2 (PK2), directly within the olfactory neurons (ONs) of patients to understand mechanisms of persistent post-COVID-19 OD.

ONs were collected by non-invasive brushing from ten patients with persistent post-COVID-19 OD and ten healthy controls. Gene expression levels of SP, Neurokinin receptor 1, Interleukin-1β (IL-1β), PK2, PK2 receptors type 1 and 2, and Prokineticin-2-long peptide were measured in ONs by Real Time-PCR in both the groups, and correlated with residual olfaction. Immunofluorescence staining was also performed to quantify SP and PK2 proteins.

OD patients, compared to controls, exhibited increased levels of both SP and PK2 in ONs, the latter proportional to residual olfaction.

This work provided unprecedented, preliminary evidence that both SP and PK2 pathways may have a role in persistent post-COVID-19 OD. Namely, if the sustained activation of SP, lasting months after infection’s resolution, might foster chronic inflammation and contribute to hyposmia, the PK2 expression could instead support the smell recovery.

2608

N526

He, Danmei; Yuan, Minlan; Dang, Wen; Bai, Lin; Yang, Runnan; Wang, Jingyi; Ma, Yao; Liu, Bo; Liu, Shiyu; Zhang, Simai; Liao, Xiao; Zhang, Wei

Long term neuropsychiatric consequences in COVID-19 survivors: Cognitive impairment and inflammatory underpinnings fifteen months after discharge

https://doi.org/10.1016/j.ajp.2022.103409

Published

Study

https://www.sciencedirect.com/science/article/pii/S1876201822004075

Highlights
•
COVID-19 survivors show long-term cognitive impairment in executive function, even at 15 months after discharge.

•
The interferon-inducible T cell alpha chemoattractant, Interleukin-8, and tumor necrosis factor (TNF)- α level were significantly elevated in COVID-19 group.

•
The TNF-α levels were negatively correlated with performance on the Trails.

Abstract
Background
Emerging evidence shows that cognitive dysfunction may occur following coronavirus disease 19 (COVID-19) infection which is one of the most common symptoms reported in researches of “Long COVID”. Several inflammatory markers are known to be elevated in COVID-19 survivors and the relationship between long-term inflammation changes and cognitive function remains unknown.

Methods
We assessed cognitive function and neuropsychiatric symptoms of 66 COVID-19 survivors and 79 healthy controls (HCs) matched with sex, age, and education level using a digital, gamified cognitive function evaluation tool and questionnaires at 15 months after discharge. Venous blood samples were collected to measure cytokine levels. We performed correlation analyses and multiple linear regression analysis to identify the factors potentially related to cognitive function.

Results
The COVID-19 survivors performed less well on the Trails (p = 0.047) than the HCs, but most of them did not report subjective neuropsychiatric symptoms. Intensive care unit experience (β = −2.247, p < 0.0001) and self-perceived disease severity (β = −1.522, p = 0.007) were positively correlated, whereas years of education (β = 0.098, p = 0.013) was negatively associated with the performance on the Trails. Moreover, the abnormally elevated TNF-α levels (r = −0.19, p = 0.040) were negatively correlated with performance on the Trails in COVID-19 group.

Conclusion
Our findings suggest that COVID-19 survivors show long-term cognitive impairment in executive function, even at 15 months after discharge. Serum TNF-α levels may be an underlying mechanism of long-term cognitive impairment in patients recovering from COVID-19.

2609

N527

Finlay, John B.; Brann, David H.; Abi Hachem, Ralph; Jang, David W.; Oliva, Allison D.; Ko, Tiffany; Gupta, Rupali; Wellford, Sebastian A.; Moseman, E. Ashley; Jang, Sophie S.; Yan, Carol H.; Matsunami, Hiroaki; Tsukahara, Tatsuya; Datta, Sandeep Robert; Goldstein, Bradley J.

Persistent post–COVID-19 smell loss is associated with immune cell infiltration and altered gene expression in olfactory epithelium

https://doi.org/10.1126/scitranslmed.add0484

Published

Study

https://www.science.org/doi/full/10.1126/scitranslmed.add0484

SARS-CoV-2 causes profound changes in the sense of smell, including total smell loss. Although these alterations are often transient, many patients with COVID-19 exhibit olfactory dysfunction that lasts months to years. Although animal and human autopsy studies have suggested mechanisms driving acute anosmia, it remains unclear how SARS-CoV-2 causes persistent smell loss in a subset of patients. To address this question, we analyzed olfactory epithelial samples collected from 24 biopsies, including from nine patients with objectively quantified long-term smell loss after COVID-19. This biopsy-based approach revealed a diffuse infiltrate of T cells expressing interferon-γ and a shift in myeloid cell population composition, including enrichment of CD207+ dendritic cells and depletion of anti-inflammatory M2 macrophages. Despite the absence of detectable SARS-CoV-2 RNA or protein, gene expression in the barrier supporting cells of the olfactory epithelium, termed sustentacular cells, appeared to reflect a response to ongoing inflammatory signaling, which was accompanied by a reduction in the number of olfactory sensory neurons relative to olfactory epithelial sustentacular cells. These findings indicate that T cell–mediated inflammation persists in the olfactory epithelium long after SARS-CoV-2 has been eliminated from the tissue, suggesting a mechanism for long-term post–COVID-19 smell loss.

2610

N528

Li, Qian; Dang, Chun; Wang, Li-Hua

Neuroinflammation in mild respiratory COVID-19: insights into cognitive impairment in milder cases

https://doi.org/10.1186/s40779-022-00431-x

Published

Commentary

https://doi.org/10.1186/s40779-022-00431-x

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been extensively shown to cause many neurological sequelae, and cognitive deficits (known as “brain fog”) may particularly and widely occur even in individuals with mild symptoms [1]. Peripheral hyperinflammation as well as central nervous system (CNS) local immune responses may synergistically contribute to brain autoimmune injury. In addition to the direct neuroinvasion of SARS-CoV-2 and nonimmune effects such as severe systemic hypoxemia and vascular thrombosis, the central mechanism by which SARS-CoV-2 accelerates cognitive-related symptoms may be related to immune effects [2]. However, the precise neuroinflammatory mechanisms of SARS-CoV-2 infection have not been fully established. Fernández-Castañeda et al. [3] provided direct evidence and unique insights into the potential mechanism of cognitive impairment in mild respiratory coronavirus disease 2019 (COVID-19) cases.
“Long COVID” has become another major public health crisis. The “lung-brain axis” has recently received increasing attention, and research published in Nature by Hosang et al. [4] suggested a close link between the lung microbiota and brain autoimmune responses, providing novel evidence that peripheral organs influence immune responses in the CNS. Inflammation has been considered to play a crucial pathogenic role and has been implicated in the neuropathological cascade leading to the development of cognitive dysfunction symptoms [5]. The inflammatory changes underlying SARS-CoV-2 post-infection that are associated with cognitive impairment, however, remain to be clarified. Fernández-Castañeda et al. [3] revealed that peripheral respiratory SARS-CoV-2 infection causes significant and persistent CNS inflammation. Different immune challenges may induce diverse immunological responses, COVID-19 and pandemic influenza have both common and specific immune features.
The peripheral cytokine storm initiated by SARS-CoV-2 infection may subsequently impact and trigger an inflammatory response in the nervous system [6]. Understanding the pathological mechanism of SARS-CoV-2 affecting the nervous system is critical for selecting potential therapeutic targets for patients. Microglia are sensitive to even minor changes in the microenvironment within the CNS and may trigger subsequent inflammatory cascades, leading to secondary immune injury. Fernández-Castañeda et al. [3] demonstrated that the neuroinflammation caused by the mild respiratory SARS-CoV-2 infection may be a link between mild respiratory COVID-19 and cognitive impairment. The CNS pathological mechanisms may be caused by the elevation of C-C motif chemokine ligand 11 (CCL11) associated with COVID-19, which exhibited similar neuropathology caused by cancer therapy. Neurotoxic CCL11 causes white matter selective microglial reactivity, then elevated CCL11 and active microglia lead to deleterious cascade effects on CNS multi-lineage neuronal cellular function and structure dysregulation, particularly on oligodendrocytes, myelinated axons, and hippocampal neurogenesis, which in turn causes the cognitive dysfunction symptoms in COVID-19 (Fig. 1).
Neuroinflammation is the central pathophysiology that links mild respiratory COVID-19 to cognitive impairment. Respiratory SARS-CoV-2 infection can cause an excessive peripheral inflammatory response to result in the consequent immune injury in CNS. The elevated CSF CCL11 and white matter microglial reactivity are associated with multi-lineage cellular dysregulation in the CNS, including impaired hippocampal neurogenesis, persistent loss of oligodendrocytes, and myelinated axons. SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, COVID-19 coronavirus disease 2019, CCL11 C-C motif chemokine ligand 11, CNS central nervous system, CSF cerebrospinal fluid
Full size image
Taken as a whole, Fernández-Castañeda et al. [3] demonstrated that cognitive impairment following mild respiratory COVID-19 is associated with persistent neuroinflammation, providing robust animal and human data to illustrate the pathophysiological similarities between “COVID fog” and “chemo fog” syndromes. As such, anti-inflammatory strategies targeting microglia or CCL11 signaling may hopefully prevent and correct this multicellular dysregulation. However, the underlying precise regulatory mechanism and signal transduction mediating respiratory infection-induced microglial reactivity in subcortical white matter remain to be fully elucidated. The mechanisms of cognitive impairment in the context of other causes, such as ageing and stroke, might provide further insight into the mechanisms of COVID-19-related cognitive deficits. Moreover, given that the role of microglia is very complicated and can be both neuroprotective and neurotoxic, the determination of the key regulators that can convert microglia into an anti-inflammatory phenotype or regulate the initiation of microglial activity is urgently needed, as the manipulation of these regulators may have the ability to prevent or alleviate neuropathology and improve impaired cognitive performance. Nevertheless, additional studies should be performed to investigate the immunomodulatory effects of peripheral infiltrated immune cells, other subtypes of brain immune cells such as astrocytes, and cellular neuroimmune interactions between the CNS and peripheral systems [7].
An analysis of 2-years retrospective cohort study indicated that the increased cognitive deficit after COVID-19 persisted throughout the follow-up [8]. Important questions remain that whether this pathology is reversible or permanent. Furthermore, it requires to be fully determined whether neuroimmune injury follows COVID-19 caused by novel SARS-CoV-2 variants, such as Omicron variants, or breakthrough infections in vaccinated individuals, as well as whether infection with the SARS-CoV-2 Omicron variant in children could cause unique neuropathology. Therefore, studies and comparisons of patients in various mentioned situations with long-term clinical outcomes will be highly valuable.

2611

N529

Jammoul, Maya; Naddour, Judith; Madi, Amir; Reslan, Mohammad Amine; Hatoum, Firas; Zeineddine, Jana; Abou-Kheir, Wassim; Lawand, Nada

Investigating the possible mechanisms of autonomic dysfunction post-COVID-19

https://doi.org/10.1016/j.autneu.2022.103071

Published

Review

https://www.sciencedirect.com/science/article/pii/S1566070222001308

Patients with long COVID suffer from many neurological manifestations that persist for 3 months following infection by SARS-CoV-2. Autonomic dysfunction (AD) or dysautonomia is one complication of long COVID that causes patients to experience fatigue, dizziness, syncope, dyspnea, orthostatic intolerance, nausea, vomiting, and heart palpitations. The pathophysiology behind AD onset post-COVID is largely unknown. As such, this review aims to highlight the potential mechanisms by which AD occurs in patients with long COVID. The first proposed mechanism includes the direct invasion of the hypothalamus or the medulla by SARS-CoV-2. Entry to these autonomic centers may occur through the neuronal or hematogenous routes. However, evidence so far indicates that neurological manifestations such as AD are caused indirectly. Another mechanism is autoimmunity whereby autoantibodies against different receptors and glycoproteins expressed on cellular membranes are produced. Additionally, persistent inflammation and hypoxia can work separately or together to promote sympathetic overactivation in a bidirectional interaction. Renin-angiotensin system imbalance can also drive AD in long COVID through the downregulation of relevant receptors and formation of autoantibodies. Understanding the pathophysiology of AD post-COVID-19 may help provide early diagnosis and better therapy for patients.

2612

N530

Jason, Leonard A.; Dorri, Joseph A.

ME/CFS and Post-Exertional Malaise among Patients with Long COVID

https://doi.org/10.3390/neurolint15010001

Published

Study

https://www.mdpi.com/2035-8377/15/1/1

This study sought to ascertain the prevalence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) among a sample of 465 patients with Long COVID. The participants completed three questionnaires: (1) a new questionnaire measuring both the frequency and severity of 38 common symptoms of COVID and Long COVID, (2) a validated short form questionnaire assessing ME/CFS, and (3) a validated questionnaire measuring post-exertional malaise. The population was predominantly white, female, and living in North America. The mean duration since the onset of COVID-19 symptoms was 70.5 weeks. Among the 465 participants, 58% met a ME/CFS case definition. Of respondents who reported that they had ME/CFS only 71% met criteria for ME/CFS and of those who did not report they had ME/CFS, 40% nevertheless did meet criteria for the disease: both over-diagnosis and under-diagnosis were evident on self-report. This study supports prior findings that ME/CFS occurs with high prevalence among those who have persistent COVID-19 symptoms.

2613

N531

Chung, Tae Hwan; Azar, Antoine

Autonomic Nerve Involvement in Post-Acute Sequelae of SARS-CoV-2 Syndrome (PASC)

https://doi.org/10.3390/jcm12010073

Published

Study

https://www.mdpi.com/2077-0383/12/1/73

The novel SARS-CoV-2 virus and resulting COVID-19 global pandemic emerged in 2019 and continues into 2022. While mortality from COVID-19 is slowly declining, a subset of patients have developed chronic, debilitating symptoms following complete recovery from acute infection with COVID-19. Termed as post-acute sequelae of SARS-CoV-2 syndrome (PASC), the underlying pathophysiology of PASC is still not well understood. Given the similarity between the clinical phenotypes of PASC and postural orthostatic tachycardia syndrome (POTS), it has been postulated that dysautonomia may play a role in the pathophysiology of PASC. However, there have been only a few studies that have examined autonomic function in PASC. In this retrospective study, we performed an analysis of autonomic nerve function testing in PASC patients and compared the results with those of POTS patients and healthy controls. Our results suggest that a significant number of PASC patients have abnormal autonomic function tests, and their clinical features are indistinguishable from POTS.

2614

N532

Meglio, Marco

COVID-19 and the Brain: Understanding the Neurological Effects of the Virus as the Pandemic Evolves

https://doi.org/

Published

Study

https://www.hcplive.com/view/covid-19-and-the-brain-understanding-neurological-effects-virus-pandemic-evolves

Almost 4 years since the beginning of the pandemic, continuous research efforts have begun to paint a better picture of the impact the virus has on the brain and the central nervous system.
When the COVID-19 pandemic was formally declared by the Centers for Disease Control in March 2020, countless questions swirled around what sort of short- and long-term effects the virus could have on an individual and their brain.
Vaccines aside, the symptoms of the COVID-19 have been well documented, even in the early stages of the pandemic. Infected patients can experience a range of symptoms—from mild to severe—that include fever or chills, cough, shortness of breath, fatigue, muscle or body aches, headache, loss of taste or smell, sort throat, congestion, nausea or vomiting, and diarrhea that can last from anywhere between 2-14 days.
As evidence began to pile up, it became clear that individuals who are immunocompromised may be more prone to a severe case of COVID-19, which could lead to hospitalization, intensive care, ventilator use, and death. Older adults have been proven to be at the highest risk for severe COVID-19. In fact, more than 81% of COVID-19 deaths occur in people over 65, and the number of deaths among people over that age is 97-times higher than the number of deaths in those between the ages of 18 and 29 years.1
COVID-19 and the Brain: Understanding the Neurological Effects of the Virus as the Pandemic Evolves
Post-acute Sequelae of COVID-19
After closely following people who contracted the virus, the clinical community started to gain a better understand of potential post-acute sequelae (PASC). PASC of COVID-19 has had a wide prevalence range reported, mainly due the heterogenous definitions of the condition, differences in populations being assessed, and types of symptoms or signs included in rate estimates. Some patients have had ≥20 different symptoms, indicating that COVID-19 is a multisystem disease.2
Men and women can both be affected by PASC. A recent meta-narrative review showed that men are at a greater risk for increased symptom severity and death; however, PASC is more common in women, and women are more likely to have persistent fatigue, anxiety, and depression and at a 6-month follow-up.3 Additionally, individuals with underlying pulmonary conditions, obesity, and older age are at increased risk for developing PASC.
For the management of PASC, clinicians have generally recommended controlling comorbid conditions, such as diabetes, hypertension, kidney disease, respiratory diseases, and ischemic heart disease, and treating specific complications when necessary. Anosmia and ageusia, otherwise known as the loss of sense of smell and taste, have been other PASC symptoms that had shown persistence even after recovery from COVID-19; although, it’s uncertain whether these symptoms are permanent or transient
Over time, the FDA began to authorize certain medications for emergency use to treat COVID-19 and thus, the subsequent issues that follow. Nirmatrelvir (Paxlovid), an oral protease inhibitor that is active against MPRO, is packaged with ritonavir, a strong cytochrome P450 3A4 inhibitor that has been used to boost HIV protease inhibitors, was among those to receive authorization.5 A recently published large-scale trial included those treated with oral nirmatrelvir within 5 days after a positive test (n = 9217) and those who received no COVID-19 antiviral or antibody treatment during the acute phase of their infection (n = 47,123).

The findings were a success, as nirmatrelvir-treated patients showed a reduced risk of PASC (HR, 0.74; 95% CI, 0.69-0.81) including a reduced risk of 10 of 12 post-acute sequelae in the cardiovascular system, coagulation and hematologic disorders, fatigue, liver disease, acute kidney disease, muscle pain, neurocognitive impairment, and shortness of breath. Additionally, mirmatrlevir was associated with a decreased risk of post-acute death (HR, 0.52) and post-acute hospitalization (HR, 0.70). These associations remained true in unvaccinated, vaccinated, and boosted individuals, and in those with primary SARS-CoV-2 infection and reinfection.6
Hyper Inflammation and Truths Behind Alzheimer Risk
At first, researchers believed that SARS-CoV-2 infection primarily affected the pulmonary system, but accumulating evidence suggested that it also affects the panvasculature in the extrapulmonary systems by directly or indirectly causing endothelial dysfunction and multi-organ injury. The consequential endotheliitis/endotheliopathy can incite multiple instances of endothelial dysfunction, including altered vascular tone, oxidative stress, inflammation/leukocyte adhesion, endothelial mesenchymal transition, mitochondria dysfunction, virus-induced senescence, cytokine storm, and coagulopathy.7
“It can also ramp up amyloid deposition or decrease breakdown of amyloid, and potentially also tau tangle formulation,” said Jennifer Frontera, MD. “That’s the whole kind of viral or inflammatory hypothesis of Alzheimer [disease]. It’s led to people doing studies with valacyclovir for patients with HSE (herpes simplex encephalitis) and mild cognitive impairment. Just to see if treating the chronic infection or the reactivation of that infection will ameliorate some of the pathological changes.”
Frontera, a neuro-critical care specialist at NYU Langone, has experience on all levels of the pandemic, serving both on the front lines during some of the earliest days, to being a leader in the research field, where she’s conducted multiple trials exploring the effects of the virus on the brain and body. She believes the general concept of increased microglial activation from inflammatory states could be “in-play” when it comes to post-COVID cognitive disorders.
“The more we understand about what’s happening in COVID-19, or hypoxia, for example, may help us understand other Alzheimer-type pathologies and what interventions might be useful in people with sporadic Alzheimer [disease], for example,” Frontera added. “Hopefully there will be more evolution in terms of our understanding of cognitive processes in general, even as they relate to post-ICU patients.”
The link between COVID-19 and Alzheimer disease is still being understood, with some studies signaling a connection and others pumping the breaks. A retrospective study published in September 2022 suggested that individuals at least 65 years infected with the virus are at an increased risk for the neurodegenerative disorder. That trial, which included 6,245,282 older adults, also showed an elevated risk when stratified by age groups (65-74, 75-84, ≥85 years), race or ethnicity (Black, White, Hispanic, with the highest risk in those above 85 years old (HR, 1.89; 95% CI, 1.73-2.07), and in women (HR, 1.82; 95% CI, 1.69-1.97).8
Some of the fears of long-term development of Alzheimer disease stem from “brain fog,” a term commonly used to describe the sluggish, fuzzy feelings patients experience weeks, and sometimes months after infection. Headed by the National Institutes of Health, a mouse study showed that even a mild case of COVID-19 could cause long-term changes to the immune system and neurons. Weeks after being infected, the microglia in the mice stayed reactive. Investigators concluded that this reactivation caused trouble with completing tasks, such as making new neurons in the hippocampus, a region of the brain that plays an important role in learning and memory.9
Debunked Myths of COVID-19
Although the pathological mechanisms of COVID-19 still remain a question, research has debunked, or at least cleared up, some of the initial thoughts, the biggest being the virus’s role in central nervous system (CNS) invasion, according to Frontera. “We really don’t think that’s a major player here, or a pathological driver. Encephalitis, meningitis, that are related to direct SARS-CoV-2 is really not a thing,” she said.
A 2021 paper by Conor McQuaid et al reviewed SARS-CoV-2/COVID-19, ACE2 distribution and beneficial effects, the CNS vascular barriers, possible mechanisms by which the virus enters the brain, outlined prior health conditions, neurological COVID-19 manifestation, and the aging cerebrovascularture.10 After sifting through the literature, the authors concluded that there is no sound evidence of SARS-CoV-2 flux into brain to significantly contribute to the overall outcomes once the respiratory system is invaded by the virus.
The paper highlighted that although unknown, the normal route of infection and presence of SARS-CoV-2 in severely infected patients could be from the olfactory mucosa, an idea that has been brought up previously before. “It is possible that the neurological manifestations of COVID-19 are a consequence of mainly cardio-respiratory distress and multiorgan failure,” McQuaid et al wrote. “Understanding potential SARS-CoV-2 neuroinvasion pathways could help to better define the non-respiratory neurological manifestation of COVID-19.”
Throughout the pandemic, it has been widely understood that the severity of COVID-19 is one of, if not the, greatest predictors of long-term prognosis. In December 2020, the FDA issued the first emergency use authorization for a vaccine for the prevention of COVID-19 in individuals aged 16 years and older, with the goal to lower hospitalization rates, ventilation rates, and ultimately, death.11
In fact, it worked. A 2022 retrospective study of nearly 200,000 hospitalizations showed that COVID-19-associated hospitalization rates ranged from 3.5 times to 17.7 times higher in unvaccinated persons than vaccinated persons regardless of booster dose status. Among sampled cases, vaccinated hospitalized patients with the virus were older than those who were vaccinated (mean age, 70 years vs 58 years; P <.001) were more likely to have 3 or more underlying medical conditions (77.8% vs 51.6; P <.001).12
As more vaccines were authorized over time, some were curious whether they could have a positive impact on the symptoms of long COVID in those already infected. “Vaccines are lowering the severity of COVID-19 if you do get it, and therefore you’re less likely to have long COVID, but I don’t think that if you already had long COVID and get vaccinated that it’s necessarily improving anything,” Frontera added.

“Theoretically, it could still, but I think the interest in that area kind of fell off as people weren’t seeing an association between post COVID vaccination and long-term outcomes. I don’t know if it’s a myth, but we probably underestimate the impact of pandemic-related stressors on outcomes and how people are doing. Are there comorbidities like mood disorders, anxiety, depression, and so forth, that exacerbate symptoms or are even sometimes, the progenitor of symptoms. For example, untreated depression can present as brain fog. That doesn’t mean everyone with brain fog has depression, and that’s the reason there are comorbidities that should be looked at and addressed.”
While severe COVID-19 cases continued to cause concern, researchers started to uncover that even those with a mild case or no symptoms can develop long COVID. In a 2022 study that featured 486,149 non-hospitalized adults with confirmed SARS-CoV-2 infection and 1,944,580 propensity score-matched adults with no evidence of infection, a total of 62 symptoms were significantly associated with SARS-CoV-2 infection after 12 weeks.13
The trial, led by Anuradhaa Subramanian, MSc, a research fellow at the University of Birmingham, also showed that the risk of developing long COVID increased along a gradient of decreasing age. The largest adjusted HRs for symptoms of long COVID included anosmia (6.49; 95% CI, 5.02-8.39), hair loss (3.99; 95% CI, 3.63-4.39), sneezing (2.77; 95% CI, 1.40-5.50), ejaculation difficulty (2.63; 95% CI, 1.61-4.28) and reduced libido (2.36; 95% CI, 1.61-3.47). In a post-hoc subgroup analysis of patients infected during the first and second stages of the pandemic in the United Kingdom, the association between SARS-CoV-2 infection and the reported symptoms was more pronounced among those infected during the second wave of the pandemic.
There are several aspects of COVID-19 that are still not fully understood and will continue to be researched in the coming years. “There’s been a lot of press related to the neurological aspect, and at the end of the day, the shortness of breath and pulmonary recovery is probably the main issue people are facing,” Frontera added. “The neurological components are probably a factor for some percentage of people. How much of them are directly related to COVID? It’s hard to know.”

2615

N533

Dağ Şeker, Esra; Erbahçeci Timur, İnci Elif

Assessment of early and long-COVID related retinal neurodegeneration with optical coherence tomography

https://doi.org/10.1007/s10792-022-02607-9

Published

Study

https://doi.org/10.1007/s10792-022-02607-9

Abstract
Purpose
The aim of this study is to investigate short-term and long-term effects of coronovirus 19 disease (COVID-19) at inner and outer retinal layers of patients recovered from COVID-19 with Spectral Domain Optical Coherence Tomography (SD-OCT) and compare these to healthy subjects.

Methods
Twenty-seven patients recovered from COVID-19, and age- and gender-matched 27 healthy controls were included in this study. Macular and peripapillary retinal nerve fiber layer (RNFL), ganglion cell-inner plexiform layer (GCIPL), inner nuclear layer (INL), outer plexiform layer (OPL) and outer nuclear layer (ONL) were analyzed with SD-OCT 1 month (V1 visit) and 12 months (V2 visit) after negative result of reverse transcriptase-polymerase chain reaction test.

Results
Macular RNFL thickness in outer ring was thinner at V1 and V2 visits than healthy control (p = 0.049 and p = 0.005). Central and inferonasal quadrants of peripapillary RNFL thicknesses were reduced at V1 and V2 visits compared to controls (p = 0.001 and p = 0.024 for V1 visit; p = 0.001 and p = 0.006 for V2 visit). Thinning in ONL thickness in inner ring was observed at V1 and V2 visits than healthy subjects (p = 0.006 and p = 0.001).

Conclusion
Subclinical localized changes in macular and peripapillary RNFL and outer nuclear layer were demonstrated in early and 12-months follow-up after COVID-19 recovery.

2616

N534

Liao, Bo; Deng, Yi-Ke; Zeng, Ming; Liu, Zheng

Long-term Consequences of COVID-19: Chemosensory Disorders

https://doi.org/10.1007/s11882-022-01062-x

Published

Review

https://doi.org/10.1007/s11882-022-01062-x

Purpose of Review
A number of sequelae after acute coronavirus disease 2019 (COVID-19) significantly affect the quality of life of patients. The chemosensory disorders including olfactory dysfunction (OD) and gustatory dysfunction (GD) are two of the commonest symptoms complained by patients with COVID-19. Although chemosensory function has been reported improved in over 60% of COVID-19 patients in a short time after acute infection, it may last as a major symptom for patients with long COVID-19. This narrative review discussed current literatures on OD and GD in long COVID-19 including the prevalence, risk factors, possible mechanisms, and potential therapies.

Recent Findings
Although the prevalence of OD and GD has declined continuously after acute COVID-19, a considerable number of patients had persistent chemosensory disorders 3 months to 2 years after symptom onset. Female gender, initial severity of dysfunction, nasal congestion, emotional distress and depression, and SARS-CoV-2 variants have been identified as risk factors for persistent OD and GD in long COVID-19. The pathogenesis of OD and GD in long COVID-19 remains unknown, but may be analogous to the persistent OD and GD post common respiratory viral infection. Corticosteroids and olfactory training might be a potential choice regarding the treatment of lasting OD and GD after SARS-CoV-2 infection; however, more studies are needed to prove it.

Summary
OD and GD are common long-term consequences of COVID-19 and influenced by gender, initial severity of dysfunction, emotional distress and depression, and SARS-CoV-2 variants. More studies are needed to illustrate their pathogenesis and to establish therapeutic strategies.

2617

N535

Sia, Alexandrea; Ee, Neo Jean; Tan, Brendan Jen-Wei; Tan, Eng-King

“Brain fog” and COVID-19

https://doi.org/10.1016/j.amjms.2023.01.003

Published

9-Jan-23

Review

https://www.amjmedsci.com/article/S0002-9629(23)00004-6/fulltext

publisher: Elsevier
PMID: 36632867
Here, we review current available scientific evidence in published literature that studied patients with “brain fog” symptoms, highlight the biological evidence that might explain this phenomenon, and draw attention to limitations of current studies and challenges for future investigations.
We searched the key words “brain fog”, “COVID-19”, in PubMed and Embase from 1st May 2020 to 30th June 2022 and identified 3 clinical studies (with sample size of >50 subjects and with age >18 years old)1, 2, 3 and 2 biological studies4, 5 that examined the association of post COVID-19 infections and “brain fog”.
The key findings of the 3 clinical studies are summarized in Table 1. In general, the studies suggest that COVID-19 infection is associated with inattention, worsened memory, and slower processing speed with improvement in neurological deficits a few months from initial infection. There appears to be a correlation between symptom severity and the degree of neurological deficits. One study found that chronic post-COVID “brain fog” was significantly associated with the severity of respiratory symptoms at onset and with intensive care unit admission,1 and another identified fatigue and dermatological symptoms during the initial 3 weeks of illness to be linked with memory performances and slower reaction times on the executive function performance.3
Based on current literature and evidence, we do not suggest using “brain fog” as a disease entity for clinical studies as this may add to confusion in the inclusion and exclusion criteria making comparisons difficult. In a recent meta-analysis, Ceban and colleagues5 specifically included studies that reported on fatigue, cognitive impairment and inflammatory parameters. They found a significant proportion of them having persistent fatigue and/or cognitive symptoms 12 weeks or more after COVID-19 infection.5 These findings corroborate to some extent the observations in our included studies identified using “brain fog” as a search term.
It is currently unclear if “brain fog” is a separate entity or subset of long COVID syndrome or if there is an overlap in the pathogenesis with cognitive impairment and other non-specific systemic complaints. To address neurological sequalae post COVID-19 regardless of “brain fog” symptoms, there is a need for long-term large multi-center prospective studies to evaluate quantitatively the different “brain fog” symptoms, and also to assess a spectrum of neuropsychological domains (such as attention, processing speed, learning and memory, executive functions, visuospatial skills, mood and personality). In addition, comprehensive and standardized validated assessments tools are required, and the results should be compared with appropriate age and gender matched healthy controls. Advanced structural and functional imaging (such as diffusion tensor magnetic resonance imaging, positron emission tomography, etc.) and biochemical measurements of amyloid and tau proteins in the blood and cerebrospinal fluid should be performed and the data correlated with the cognitive tests and clinical parameters. This will provide more robust evidence on the cause and effect association between COVID-19 and brain functions. In the laboratory, using mouse models to investigate the neuroinflammatory nature of the COVID infection may not be ideal as mice lack the ACE receptor that COVID virus use to invade human cells. In this context, certain non-human primate models which share similar ACE-2 receptor at positions critical for the interaction with SARS-CoV-2 spike may be better suited to study the long term neurological effects of COVID.

2618

N536

Villadiego, Javier; García-Arriaza, Juan; Ramírez-Lorca, Reposo; García-Swinburn, Roberto; Cabello-Rivera, Daniel; Rosales-Nieves, Alicia E.; Álvarez-Vergara, María I.; Cala-Fernández, Fernando; García-Roldán, Ernesto; López-Ogáyar, Juan L.; Zamora, Carmen; Astorgano, David; Albericio, Guillermo; Pérez, Patricia; Muñoz-Cabello, Ana M.; Pascual, Alberto; Esteban, Mariano; López-Barneo, José; Toledo-Aral, Juan José

Full protection from SARS-CoV-2 brain infection and damage in susceptible transgenic mice conferred by MVA-CoV2-S vaccine candidate

https://doi.org/10.1038/s41593-022-01242-y

Published

9-Jan-23

Study

https://www.nature.com/articles/s41593-022-01242-y

Vaccines against SARS-CoV-2 have been shown to be safe and effective but their protective efficacy against infection in the brain is yet unclear. Here, in the susceptible transgenic K18-hACE2 mouse model of severe coronavirus disease 2019 (COVID-19), we report a spatiotemporal description of SARS-CoV-2 infection and replication through the brain. SARS-CoV-2 brain replication occurs primarily in neurons, leading to neuronal loss, signs of glial activation and vascular damage in mice infected with SARS-CoV-2. One or two doses of a modified vaccinia virus Ankara (MVA) vector expressing the SARS-CoV-2 spike (S) protein (MVA-CoV2-S) conferred full protection against SARS-CoV-2 cerebral infection, preventing virus replication in all areas of the brain and its associated damage. This protection was maintained even after SARS-CoV-2 reinfection. These findings further support the use of MVA-CoV2-S as a promising vaccine candidate against SARS-CoV-2/COVID-19.

2619

N537

Lake, Camille M.; Breen, Joseph J.

Sequence similarity between SARS-CoV-2 nucleocapsid and multiple sclerosis-associated proteins provides insight into viral neuropathogenesis following infection

https://doi.org/10.1038/s41598-022-27348-8

Published

8-Jan-23

Article

https://www.nature.com/articles/s41598-022-27348-8

The novel coronavirus SARS-CoV-2 continues to cause death and disease throughout the world, underscoring the necessity of understanding the virus and host immune response. From the start of the pandemic, a prominent pattern of central nervous system (CNS) pathologies, including demyelination, has emerged, suggesting an underlying mechanism of viral mimicry to CNS proteins. We hypothesized that immunodominant epitopes of SARS-CoV-2 share homology with proteins associated with multiple sclerosis (MS). Using PEPMatch, a newly developed bioinformatics package which predicts peptide similarity within specific amino acid mismatching parameters consistent with published MHC binding capacity, we discovered that nucleocapsid protein shares significant overlap with 22 MS-associated proteins, including myelin proteolipid protein (PLP). Further computational evaluation demonstrated that this overlap may have critical implications for T cell responses in MS patients and is likely unique to SARS-CoV-2 among the major human coronaviruses. Our findings substantiate the hypothesis of viral molecular mimicry in the pathogenesis of MS and warrant further experimental exploration.

2620

N538

Francis, Gregory; Thunell, Evelina

COVID-19 infection does not seem to affect cognition in college students

https://doi.org/10.1016/j.concog.2023.103464

Published

10-Jan-23

Study

https://www.sciencedirect.com/science/article/pii/S1053810023000016

Emerging evidence indicates that COVID-19 damages the central nervous system and thereby might engender long-term cognitive impairment. Self-reports and some measures of cognitive ability suggest that long COVID can lead to substantial and frightening detriments in cognition. To further explore this issue, we used data from university courses on cognitive psychology where students participated in classic experiments that measure various aspects of cognition. Across 24 experiments we compared cognitive performance of students who had contracted COVID-19 against those who were uninfected. Using Bayes Factor analyses, we assessed both differences and invariances in performance as a function of infection status. Our findings suggest that COVID-19 infection has hardly any impact on cognition for university students.

2621

N539

Eschbacher, Kathryn L; Larsen, Rachel A; Reichard, R Ross

Authors’ reply to: “Neuropathologic findings in COVID-19 patients should be correlated with clinical neurologic abnormalities”

https://doi.org/10.1093/jnen/nlac129

Published

10-Jan-23

Study

https://doi.org/10.1093/jnen/nlac129

We appreciate the insightful comments made by our colleague regarding the article “Neuropathological findings in COVID-19: an autopsy cohort” (1), and the opportunity to respond to his concerns.

Regarding neurologic symptoms, 22 patients (30.6%) demonstrated neurologic symptoms during the disease course, the majority of which were generalized, including delirium or agitation (n = 5), encephalopathy (n = 9), decreased level of consciousness or altered mental status (n = 3), or confusion (n = 2). Rare patients presented with symptoms of acute stroke (n = 1), symptoms of increased intracranial pressure due to an acute subdural hemorrhage (n = 1), or seizure (n = 1). Of note, 24 patients had a previous diagnosis of dementia or mild cognitive impairment (33.3%), and 25 were sedated due to intubation (34.7%), so neurologic symptoms could not be accurately assessed in that subset. No patients presented with Guillain-Barré Syndrome. Only a portion of our cohort was hospitalized (n = 54; 75%); and CSF analysis was not routinely performed as a part of their care. In 2 patients, CSF was collected to evaluate for concern of Creutzfeldt-Jakob disease and both demonstrated elevated neuro-specific enolase.
Of note, in the 3 cases harboring microscopic destructive hemorrhagic white matter lesions, there was no clinical suspicion of acute disseminated encephalomyelitis (ADEM) or acute hemorrhagic leukoencephalitis (AHLE)/acute hemorrhagic necrotizing encephalitis. All were sedated and intubated during their disease course, so neurologic assessment was limited. Imaging was performed in a single case, which demonstrated subarachnoid hemorrhage and possible right parietal subcortical white matter hyperdensities. ADEM-like lesions with associated demyelination were identified in 1 case, as previously reported (3). Although the hemorrhagic destructive lesions were reminiscent of AHLE, distinct differences from the classic histologic descriptions of this entity were identified. Notably, the lesions were not limited to a perivascular location, and there was no evidence of vascular damage (4). Additionally, no significant inflammation was identified in these cases (4). However, given the similarities the findings in ADEM and AHLE, these cases raised the possibility of a rare parainfectious phenomenon that may occur in the context of SARS-CoV-2 infection.

Although the potential long-term neuropathologic sequelae of SARS-CoV-2 remain to be determined, the development of post-acute sequelae of SARS-CoV-2 infection (PASC) is becoming increasingly recognized (5). It is therefore important to include survivors of SARS-CoV-2 infection in cohorts in attempts to identify neuropathologic correlates to PASC and further understand the long-term effects of infection.

Ultimately, our findings suggest that active encephalitis is not a common feature of SARS-CoV-2 infection. Evaluation of large cohorts with appropriate age-matched controls, imaging, and neurologic examination findings are needed to further understand the immediate and long-term neuropathologic sequelae of SARS-CoV-2 infection.

2622

N540

Stępień, Tomasz; Tarka, Sylwia; Chmura, Natalia; Grzegorczyk, Michał; Acewicz, Albert; Felczak, Paulina; Wierzba-Bobrowicz, Teresa

Influence of SARS-CoV-2 on Adult Human Neurogenesis

https://doi.org/10.3390/cells12020244

Published

1-Jan-23

Study

https://www.mdpi.com/2073-4409/12/2/244

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with the onset of neurological and psychiatric symptoms during and after the acute phase of illness. Inflammation and hypoxia induced by SARS-CoV-2 affect brain regions essential for fine motor function, learning, memory, and emotional responses. The mechanisms of these central nervous system symptoms remain largely unknown. While looking for the causes of neurological deficits, we conducted a study on how SARS-CoV-2 affects neurogenesis. In this study, we compared a control group with a group of patients diagnosed with COVID-19. Analysis of the expression of neurogenesis markers showed a decrease in the density of neuronal progenitor cells and newborn neurons in the SARS-CoV-2 group. Analysis of COVID-19 patients revealed increased microglial activation compared with the control group. The unfavorable effect of the inflammatory process in the brain associated with COVID-19 disease increases the concentration of cytokines that negatively affect adult human neurogenesis.

2623

N541

Kazantseva, Anastasiya; Enikeeva, Renata; Takhirova, Zalina; Davydova, Yuliya; Mustafin, Rustam; Malykh, Sergey; Karunas, Alexandra; Kanapin, Alexander; Khusnutdinova, Elza

Host Genetic Variants Linked to COVID-19 Neurological Complications and Susceptibility in Young Adults—A Preliminary Analysis

https://doi.org/10.3390/jpm13010123

Published

1-Jan-23

Study

https://www.mdpi.com/2075-4426/13/1/123

To date, multiple efforts have been made to use genome-wide association studies (GWAS) to untangle the genetic basis for SARS-CoV-2 infection susceptibility and severe COVID-19. However, data on the genetic-related effects of SARS-CoV-2 infection on the presence of accompanying and long-term post-COVID-19 neurological symptoms in younger individuals remain absent. We aimed to examine the possible association between SNPs found in a GWAS of COVID-19 outcomes and three phenotypes: SARS-CoV-2 infection, neurological complications during disease progression, and long-term neurological complications in young adults with a mild-to-moderate disease course. University students (N = 336, age 18–25 years, European ancestry) with or without COVID-19 and neurological symptoms in anamnesis comprised the study sample. Logistic regression was performed with COVID-19-related phenotypes as outcomes, and the top 25 SNPs from GWAS meta-analyses and an MR study linking COVID-19 and cognitive deficits were found. We replicated previously reported associations of the FURIN and SLC6A20 gene variants (OR = 2.36, 95% CI 1.31–4.24) and OR = 1.94, 95% CI 1.08–3.49, respectively) and remaining neurological complications (OR = 2.12, 95% CI 1.10–4.35 for SLC6A20), while NR1H2 (OR = 2.99, 95% CI 1.39–6.69) and TMPRSS2 (OR = 2.03, 95% CI 1.19–3.50) SNPs were associated with neurological symptoms accompanying COVID-19. Our findings indicate that genetic variants related to a severe COVID-19 course in adults may contribute to the occurrence of neurological repercussions in individuals at a young age.

2624

N542

Amruta, Narayanappa; Ismael, Saifudeen; Leist, Sarah R.; Gressett, Timothy E.; Srivastava, Akhilesh; Dinnon, Kenneth H.; Engler-Chiurazzi, Elizabeth B.; Maness, Nicholas J.; Qin, Xuebin; Kolls, Jay K.; Baric, Ralph S.; Bix, Gregory

Mouse Adapted SARS-CoV-2 (MA10) Viral Infection Induces Neuroinflammation in Standard Laboratory Mice

https://doi.org/10.3390/v15010114

Published

1-Jan-23

Study

https://www.mdpi.com/1999-4915/15/1/114

Increasing evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection impacts neurological function both acutely and chronically, even in the absence of pronounced respiratory distress. Developing clinically relevant laboratory mouse models of the neuropathogenesis of SARS-CoV-2 infection is an important step toward elucidating the underlying mechanisms of SARS-CoV-2-induced neurological dysfunction. Although various transgenic models and viral delivery methods have been used to study the infection potential of SARS-CoV-2 in mice, the use of commonly available laboratory mice would facilitate the study of SARS-CoV-2 neuropathology. Herein we show neuroinflammatory profiles of immunologically intact mice, C57BL/6J and BALB/c, as well as immunodeficient (Rag2−/−) mice, to a mouse-adapted strain of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2 (MA10)). Our findings indicate that brain IL-6 levels are significantly higher in BALB/c male mice infected with SARS-CoV-2 MA10. Additionally, blood-brain barrier integrity, as measured by the vascular tight junction protein claudin-5, was reduced by SARS-CoV-2 MA10 infection in all three strains. Brain glial fibrillary acidic protein (GFAP) mRNA was also elevated in male C57BL/6J infected mice compared with the mock group. Lastly, immune-vascular effects of SARS-CoV-2 (MA10), as measured by H&E scores, demonstrate an increase in perivascular lymphocyte cuffing (PLC) at 30 days post-infection among infected female BALB/c mice with a significant increase in PLC over time only in SARS-CoV-2 MA10) infected mice. Our study is the first to demonstrate that SARS-CoV-2 (MA10) infection induces neuroinflammation in laboratory mice and could be used as a novel model to study SARS-CoV-2-mediated cerebrovascular pathology.

2625

N543

Liviero, Filippo; Scapellato, Maria Luisa; Folino, Franco; Moretto, Angelo; Mason, Paola; Pavanello, Sofia

Persistent Increase of Sympathetic Activity in Post-Acute COVID-19 of Paucisymptomatic Healthcare Workers

https://doi.org/10.3390/ijerph20010830

Published

1-Jan-23

Study

https://www.mdpi.com/1660-4601/20/1/830

Healthcare workers (HCWs) represent a population with a significant burden of paucisymptomatic COVID-19, as the general population. We evaluated autonomic nervous system activity by means of heart rate variability (HRV) in HCWs during health surveillance visits. Short-term electrocardiogram (ECG) recordings were obtained 30 days (IQR 5.25–55.75) after a negative naso-pharyngeal swab for SARS-CoV-2 in 44 cases and compared with ECGs of 44 controls with similar age and sex distribution. Time and frequency domain HRV were evaluated. HCWs who used drugs, had comorbidities that affected HRV, or were hospitalized with severe COVID-19 were excluded. Frequency domain HRV analysis showed a significantly higher low/high-frequency power ratio (LF/HF) in the case study compared with controls (t = 2.84, p = 0.006). In time domain HRV analysis, mean standard deviation of normal-to-normal intervals (SDNN) and root mean square of successive RR interval differences (RMSSD) were significantly lower for cases compared with controls (t = −2.64, p = 0.01 and t = −3.27, p = 0.002, respectively). In the post-acute phase of infection, SARS-CoV-2 produces an autonomic imbalance mirrored by a reduction in HRV. These results are consistent with epidemiological data that suggest a higher risk of acute cardiovascular complications in the first 30 days after COVID-19 infection.

2626

N544

Gamberini, Giulia; Masuccio, Fabio Giuseppe; Cerrato, Marta; Strazzacappa, Mara; Ferraro, Diana; Solaro, Claudio

Previously independent patients with mild-symptomatic COVID-19 are at high risk of developing cognitive impairment but not depression or anxiety

https://doi.org/10.1016/j.jad.2022.12.100

Published

1-Mar-23

Study

https://www.sciencedirect.com/science/article/pii/S0165032722014616

Highlights
•High rate of cognitive impairment in previously independent mild COVID-19 patients.
•Cognitive impairment is a potential threat for the independence of these patients in everyday life activities and work.
•These subjects should be monitored to better understand the progression and consequences of the so-called “Long COVID”.
Abstract
Objectives
The aim of the study was to explore the cognitive functions of a large sample of hospitalised subjects with mild symptomatic Coronavirus Disease (COVID-19) who were previously independent at home and without neurological diseases.

Methods
Patients admitted in a COVID-19 Unit for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection between November 2020 and March 2021 were recruited. Inclusion criteria were: being independent at home before the infection, radiologically confirmed COVID-19 pneumonia, positive reverse transcriptase-polymerase chain reaction nasopharyngeal swab and no oxygen supplementation at the time of evaluation. Exclusion criteria: cognitive impairment or neurological diseases previous to the infection, delirium episodes, and history of any mechanical ventilation use. They were evaluated with Montreal Cognitive Assessment (MoCA), Hamilton Depression Rating Scale (HAM-D) and Hamilton Anxiety Rating Scale (HAM-A).

Results
Out of 522 subjects admitted in the COVID-19 Unit, 90 were enrolled [mean age = 68.32(11.99); 46M/44F]. An impaired MoCA (cut-off < 23) was found in 60 subjects (66.66 %). Pathological scores were obtained by 36.7 % of the subjects with <65 years and 78.3 % of those older than 65 years. A high prevalence of executive function and memory impairment was detected.

Conclusions
The results underline a high rate of cognitive impairment in previously independent mild COVID-19 patients. This might represent a potential threat for the everyday independence of these patients due to the consequences on everyday life activities and work following discharge from hospital. These subjects should, therefore, be monitored in order to allow a better understanding of the progression and consequences of the so-called “Long COVID”.

2627

N545

Dunn, Eric; Ibrahim, Faisal; Neme-Mercante, Silvia; Nair, Dileep; Morris, Spencer; Wang, Irene; Punia, Vineet

Possible post-COVID epilepsy: A review of epilepsy monitoring unit admissions during the two years of COVID-19 pandemic

https://doi.org/10.1016/j.ebr.2023.100584

Published

1-Jan-23

Case Report

https://www.sciencedirect.com/science/article/pii/S2589986423000023

Highlights
•We report three cases of confirmed new-onset temporal epilepsy after mild COVID-19.
•The three patients developed seizures within three months of COVID-19 diagnosis.
•All three had bilateral enlarged perivascular space on MRI of unclear significance.
•Small number of patients with new-onset spells post-COVID may have focal epilepsy.
Abstract
Large scale healthcare data shows that new-onset epilepsy is noted in 0.3 % patients within 6 months of COVID-19 infection. We analyzed diagnostic epilepsy monitoring unit (EMU) evaluations to identify and report such cases. We thoroughly reviewed our EMU database and identified patients having “COVID” or “Corona” virus mention in their medical record from 03/15/2020 to 02/28/2022. Patients with epilepsy prior to COVID infection were excluded. Among 62 patients without prior epilepsy evaluated in the EMU for new-onset spells after confirmed COVID-19 infection, three patients were diagnosed with focal epilepsy. These three women without epilepsy risk factors had seizure onset at the time of, or within one to three months of, COVID-19 diagnosis. Their 3 T MRI imaging was non-lesional but revealed bilateral enlarged perivascular spaces. The video EEG monitoring was consistent with temporal or fronto-temporal lobe epilepsy in all three patients. Two of them developed drug-resistant epilepsy within six months of seizure onset. Our thorough analysis of diagnostic EMU evaluations during the two years of pandemic reveals three cases of post-COVID-19 epilepsy after non-symptomatic to mild disease. Although coincidental epilepsy onset cannot be ruled out, larger multicenter or national database investigations are needed to further analyze the possibility of post-COVID epilepsy.

2628

N546

Alqahtani, Mohammed S.; Abbas, Mohamed; Alshahrani, Mohammad Y.; Alabdullh, Khulud; Alqarni, Amjad; Alqahtani, Fawaz F.; Jambi, Layal K.; Alkhayat, Adnan

Effects of COVID-19 on Synaptic and Neuronal Degeneration

https://doi.org/10.3390/brainsci13010131

Published

1-Jan-23

Review

https://www.mdpi.com/2076-3425/13/1/131

Neurons are the basic building blocks of the human body’s neurological system. Atrophy is defined by the disintegration of the connections between cells that enable them to communicate. Peripheral neuropathy and demyelinating disorders, as well as cerebrovascular illnesses and central nervous system (CNS) inflammatory diseases, have all been linked to brain damage, including Parkinson’s disease (PD). It turns out that these diseases have a direct impact on brain atrophy. However, it may take some time after the onset of one of these diseases for this atrophy to be clearly diagnosed. With the emergence of the Coronavirus disease 2019 (COVID-19) pandemic, there were several clinical observations of COVID-19 patients. Among those observations is that the virus can cause any of the diseases that can lead to brain atrophy. Here we shed light on the research that tracked the relationship of these diseases to the COVID-19 virus. The importance of this review is that it is the first to link the relationship between the Coronavirus and diseases that cause brain atrophy. It also indicates the indirect role of the virus in dystrophy.

2629

N547

Franke, Christiana; Boesl, Fabian; Goereci, Yasemin; Gerhard, Ameli; Schweitzer, Finja; Schroeder, Maria; Foverskov-Rasmussen, Helle; Heine, Josephine; Quitschau, Anneke; Kandil, Farid I.; Schild, Ann-Katrin; Finke, Carsten; Audebert, Heinrich J.; Endres, Matthias; Warnke, Clemens; Prüss, Harald

Association of cerebrospinal fluid brain-binding autoantibodies with cognitive impairment in post-COVID-19 syndrome

https://doi.org/10.1016/j.bbi.2023.01.006

Published

1-Mar-23

Study

https://www.sciencedirect.com/science/article/pii/S0889159123000065

Highlights
•Cognitive deficits are frequently reported as one of the major symptoms of post-COVID-19 syndrome.
•Humoral autoimmunity may contribute to cognitive impairment in post-COVID-19 syndrome.
•Further data on autoimmunological mechanisms in post-COVID-19 syndrome are needed to identify eligible patients for immunotherapy.
Abstract
Background
Neurological symptoms, in particular cognitive deficits, are common in post-COVID-19 syndrome (PCS). There is no approved therapy available, and the underlying disease mechanisms are largely unknown. Besides others, autoimmune processes may play a key role.

Design
We here present data of a prospective study conducted between September 2020 and December 2021 and performed at two German University hospitals with specialized Neurology outpatient clinics. Fifty patients with self-reported cognitive deficits as main complaint of PCS and available serum and CSF samples were included. Cell-based assays and indirect immunofluorescence on murine brain sections were used to detect autoantibodies against intracellular and surface antigens in serum and CSF and analyzed for associations with cognitive screening assessment.

Results
Clearly abnormal cognitive status (MoCA ≤ 25/30 points) was only seen in 18/50 patients with self-reported cognitive deficits. Most patients (46/50) had normal routine CSF parameters. anti-neuronal autoantibodies were found in 52 % of all patients: n = 9 in serum only, n = 3 in CSF only and n = 14 in both, including those against myelin, Yo, Ma2/Ta, GAD65 and NMDA receptor, but also a variety of undetermined epitopes on brain sections. These included cerebral vessel endothelium, Purkinje neurons, granule cells, axon initial segments, astrocytic proteins and neuropil of basal ganglia or hippocampus as well as a formerly unknown perinuclear rim pattern. Pathological MoCA results were associated with the presence of anti-neuronal antibodies in CSF (p = 0.0004).

Conclusions
Autoantibodies targeting brain epitopes are common in PCS patients and strongly associate with pathological cognitive screening tests, in particular when found in CSF. Several underlying autoantigens still await experimental identification. Further research is needed to inform on the clinical relevance of these autoantibodies, including controlled studies that explore the potential efficacy of antibody-depleting immunotherapy in PCS.

2630

N548

Maiorana, Natale Vincenzo; Aiello, Edoardo Nicolò; Poletti, Barbara; Carusi, Fabrizio; De Sandi, Angelica; Guidetti, Matteo; Prandin, Roberto; Marceglia, Sara; Ticozzi, Nicola; Silani, Vincenzo; Priori, Alberto; Ferrucci, Roberta

Relationship between Reaction Times and Post-COVID-19 Symptoms Assessed by a Web-Based Visual Detection Task

https://doi.org/10.3390/healthcare11030284

Published

1-Jan-23

Study

https://www.mdpi.com/2227-9032/11/3/284

Long-COVID is a clinical condition in which patients affected by SARS-CoV-2 usually report a wide range of physical and cognitive symptoms from 3 to 6 months after the infection recovery. The aim of the current study was to assess the link between self-reported long-COVID symptoms and reaction times (RTs) in a self-administered Visual Detection Task (VDT) in order to identify the predictor symptoms of the slowing in reaction times to determine attention impairment. In total, 362 participants (age (mean ± S.D.: 38.56 ± 13.14); sex (female–male: 73.76–26.24%)) responded to a web-based self-report questionnaire consisting of four sections: demographics, disease-related characteristics, and medical history questions. The final section consisted of a 23 item 5-point Likert-scale questionnaire related to long-term COVID-19 symptoms. After completing the questionnaire, subjects performed a VDT on a tablet screen to assess reaction times (RTs). An exploratory factorial analysis (EFA) was performed on the 23 long-COVID symptom questions, identifying 4 factors (cognition, behavior, physical condition, presence of anosmia and/or ageusia). The most important predictors of RTs were cognition and physical factors. By dissecting the cognitive and physical factors, learning, visual impairment, and headache were the top predictors of subjects’ performance in the VDT. Long-COVID subjects showed higher RTs in the VDT after a considerable time post-disease, suggesting the presence of an attention deficit disorder. Attention impairment due to COVID-19 can be due to the presence of headaches, visual impairments, and the presence of cognitive problems related to the difficulty in learning new activities. The link between the slowing of reaction times and physical and cognitive symptoms post-COVID-19 suggests that attention deficit disorder is caused by a complex interaction between physical and cognitive symptoms. In addition, the study provides evidence that RTs in a VDT represent a reliable measure to detect the presence of long-COVID neurological sequelae.

2631

N549

Rothstein, Ted L.

Cortical Grey matter volume depletion links to neurological sequelae in post COVID-19 “long haulers”

https://doi.org/10.1186/s12883-023-03049-1

Published

17-Jan-23

Study

https://doi.org/10.1186/s12883-023-03049-1

Objective
COVID-19 (SARS-CoV-2) has been associated with neurological sequelae even in those patients with mild respiratory symptoms. Patients experiencing cognitive symptoms such as “brain fog” and other neurologic sequelae for 8 or more weeks define “long haulers”. There is limited information regarding damage to grey matter (GM) structures occurring in COVID-19 “long haulers”. Advanced imaging techniques can quantify brain volume depletions related to COVID-19 infection which is important as conventional Brain MRI often fails to identify disease correlates. 3-dimensional voxel-based morphometry (3D VBM) analyzes, segments and quantifies key brain volumes allowing comparisons between COVID-19 “long haulers” and normative data drawn from healthy controls, with values based on percentages of intracranial volume.

Methods
This is a retrospective single center study which analyzed 24 consecutive COVID-19 infected patients with long term neurologic symptoms. Each patient underwent Brain MRI with 3D VBM at median time of 85 days following laboratory confirmation. All patients had relatively mild respiratory symptoms not requiring oxygen supplementation, hospitalization, or assisted ventilation. 3D VBM was obtained for whole brain and forebrain parenchyma, cortical grey matter (CGM), hippocampus, and thalamus.

Results
The results demonstrate a statistically significant depletion of CGM volume in 24 COVID-19 infected patients. Reduced CGM volume likely influences their long term neurological sequelae and may impair post COVID-19 patient’s quality of life and productivity.

Conclusion
This study contributes to understanding effects of COVID-19 infection on patient’s neurocognitive and neurological function, with potential for producing serious long term personal and economic consequences, and ongoing challenges to public health systems.

2632

N550

Kong, Dasom; Park, Ki Hoon; Kim, Da-Hyun; Kim, Nam Gyo; Lee, Seung-Eun; Shin, Nari; Kook, Myung Geun; Kim, Young Bong; Kang, Kyung-Sun

Cortical-blood vessel assembloids exhibit Alzheimer’s disease phenotypes by activating glia after SARS-CoV-2 infection

https://doi.org/10.1038/s41420-022-01288-8

Published

25-Jan-23

Study

https://www.nature.com/articles/s41420-022-01288-8

A correlation between COVID-19 and Alzheimer’s disease (AD) has been proposed recently. Although the number of case reports on neuroinflammation in COVID-19 patients has increased, studies of SARS-CoV-2 neurotrophic pathology using brain organoids have restricted recapitulation of those phenotypes due to insufficiency of immune cells and absence of vasculature. Cerebral pericytes and endothelial cells, the major components of blood-brain barrier, express viral entry receptors for SARS-CoV-2 and response to systemic inflammation including direct cell death. To overcome the limitations, we developed cortical-blood vessel assembloids by fusing cortical organoid with blood vessel organoid to provide vasculature to brain organoids a nd obtained the characteristics of increased expression of microglia and astrocytes in brain organoids. Furthermore, we observed AD pathologies, including β-amyloid plaques, which were affected by the inflammatory response from SARS-CoV-2 infection. These findings provide an advanced platform to investigate human neurotrophic diseases, including COVID-19, and suggest that neuroinflammation caused by viral infection facilitates AD pathology.

2633

N551

Caroli, Anna; Capelli, Serena; Napolitano, Angela; Cabrini, Giulia; Arrigoni, Alberto; Pezzetti, Giulio; Previtali, Mattia; Longhi, Luca Giovanni; Zangari, Rosalia; Lorini, Ferdinando Luca; Sessa, Maria; Remuzzi, Andrea; Gerevini, Simonetta

Brain diffusion alterations in patients with COVID-19 pathology and neurological manifestations

https://doi.org/10.1016/j.nicl.2023.103338

Published

1-Jan-23

Study

https://www.sciencedirect.com/science/article/pii/S221315822300027X

Highlights
•Brain diffusivity is increased in COVID-19 patients, mainly in white matter.
•Hospitalized patients show higher diffusivity than non-hospitalized patients.
•Brain diffusivity is significantly correlated with the time from COVID-19 onset.
Abstract
Background and objective
COVID-19 neurological manifestations have been progressively recognized. Among available MRI techniques, diffusion weighted imaging (DWI) shows promise to study microstructure, inflammation, and edema. Previous DWI studies reported alterations in brain diffusivity in COVID-19 patients, as assessed by morphologic evaluation of brain DWI scans only. The aim of this study was to assess and quantify brain diffusion alterations in COVID-19 patients with neurological manifestations.
Methods
215 COVID-19 patients with neurological manifestations (olfactory and/or other neurological disorders) and 36 normal controls were compared and studied with DWI and T1-weighted MRI scans. MRI scans were processed by a semi-automatic processing procedure specifically developed for the purpose of this study, and the Apparent Diffusion Coefficient (ADC) was quantified in different brain tissues and individual white matter (WM) and gray matter (GM) regions. Differences in ADC values were assessed between COVID-19 patients and normal controls, as well as in the COVID-19 patient population grouped by hospitalization and neurological symptoms.
Results
Among COVID-19 patients (median [IQR] = 52 [42 – 60] years of age, 58 % females), 91 were hospitalized and 26 needed intensive care. 84 patients had hyposmia/ageusia only, while 131 ones showed other neurological disorders. COVID-19 patients showed significantly increased ADC values in the WM and in several GM regions (p < 0.001). ADC values were significantly correlated with MRI time from disease onset (p < 0.05).
Hospitalized patients showed significantly higher ADC alteration than non-hospitalized patients in all brain tissues; similarly, COVID-19 patients with neurological disorders showed significantly higher ADC values than those with olfactory loss only. ADC alteration was highest in patients with cognitive or memory disorder and in those with encephalitis or meningitis. ADC values were neither associated with the duration of hospitalization nor with the need for intensive care.
Conclusion
Current findings suggest DWI potential as a non-invasive marker of neuroinflammation in COVID-19, and the transient nature of the same. Future longitudinal studies are needed to confirm our findings.

2634

N552

Tassignon, B.; Radwan, A.; Blommaert, J.; Stas, L.; Allard, S. D.; De Ridder, F.; De Waele, E.; Bulnes, L. C.; Hoornaert, N.; Lacor, P.; Lathouwers, E.; Mertens, R.; Naeyaert, M.; Raeymaekers, H.; Seyler, L.; Van Binst, A. M.; Van Imschoot, L.; Van Liedekerke, L.; Van Schependom, J.; Van Schuerbeek, P.; Vandekerckhove, M.; Meeusen, R.; Sunaert, S.; Nagels, G.; De Mey, J.; De Pauw, K.

Longitudinal changes in global structural brain connectivity and cognitive performance in former hospitalized COVID-19 survivors: an exploratory study

https://doi.org/10.1007/s00221-023-06545-5

Published

28-Jan-23

Study

https://doi.org/10.1007/s00221-023-06545-5

Background
Long-term sequelae of COVID-19 can result in reduced functionality of the central nervous system and substandard quality of life. Gaining insight into the recovery trajectory of admitted COVID-19 patients on their cognitive performance and global structural brain connectivity may allow a better understanding of the diseases' relevance.
Objectives
To assess whole-brain structural connectivity in former non-intensive-care unit (ICU)- and ICU-admitted COVID-19 survivors over 2 months following hospital discharge and correlate structural connectivity measures to cognitive performance.
Methods
Participants underwent Magnetic Resonance Imaging brain scans and a cognitive test battery after hospital discharge to evaluate structural connectivity and cognitive performance. Multilevel models were constructed for each graph measure and cognitive test, assessing the groups' influence, time since discharge, and interactions. Linear regression models estimated whether the graph measurements affected cognitive measures and whether they differed between ICU and non-ICU patients.
Results
Six former ICU and six non-ICU patients completed the study. Across the various graph measures, the characteristic path length decreased over time (β = 0.97, p = 0.006). We detected no group-level effects (β = 1.07, p = 0.442) nor interaction effects (β = 1.02, p = 0.220). Cognitive performance improved for both non-ICU and ICU COVID-19 survivors on four out of seven cognitive tests 2 months later (p < 0.05).
Conclusion
Adverse effects of COVID-19 on brain functioning and structure abate over time. These results should be supported by future research including larger sample sizes, matched control groups of healthy non-infected individuals, and more extended follow-up periods.

2635

N553

Li, Jason; Bohn, Camden; Todd, Noah; Pater, Jessica; Carroll, Jeanne; Henriksen, Brian

Peripheral Neuropathy in Long-COVID Patients: Demographic Distribution and Medical Risk Factors

https://doi.org/10.18060/26906

Published

14-Jul-05

Study

https://journals.iupui.edu/index.php/IMPRS/article/view/26906

Objective: A retrospective study was conducted to examine the relationship between long-COVID peripheral neuropathy and patient demographics and comorbid medical conditions.
Methods: Electronic health records of 543 patients from the Parkview Post-COVID Clinic were reviewed for their demographic information, past medical histories, and post-COVID clinic visit summaries. Based on whether patients had peripheral neuropathy as a post-COVID clinical visit diagnosis and whether they had had a history of neuropathy prior to COVID infection, the patients were assigned into the new-onset neuropathy group, progressing and non-progressing neuropathy groups, and non-neuropathy group. Age and BMI were compared among the four groups using two-sampled t test. Sex, prior COVID hospitalization status, and chronic comorbidities including hypertension, diabetes, and anemia were compared using chi-squared test.
Results: 19 of 543 (3.5%) patients had new-onset neuropathy and 18 (3.3%) were found to have progressing neuropathy. The study’s incidence of new-onset peripheral neuropathy (3.5% over two years) in long-COVID patients is higher than the incidence of non-COVID-related neuropathy indicated in literature (0.76% each year, p = 0.025). Compared with patients with no neuropathy, patients with new-onset neuropathy were of older age (p = 0.042), more male (p = 0.022), and more frequently hospitalized for COVID (p = 0.003). Compared to patients with no neuropathy, patients with progressing neuropathy were of older age (p < 0.001), had more COVID hospitalization (p = 0.033), diabetes (0.014), hypertension (p < 0.001), and anemia (p = 0.02).
Conclusion: Age and COVID hospitalization were found to be risk factors for both new-onset and progressing neuropathy. Being male was a risk factor for new-onset neuropathy only. Diabetes, anemia, and hypertensionwere risk factors for both progressing and non-progressing neuropathy but not for new-onset neuropathy. The results can prompt clinicians to assess peripheral neuropathy in long-COVID patients that have high demographic and medical risk factors.

2636

N554

Silva, Ryan C.; da Rosa, Michelle M.; Leão, Heloísa I.; Silva, Eduardo D. L.; Ferreira, Nathália T.; Albuquerque, Amanda P. B.; Duarte, Gisele S.; Siqueira, André M.; Pereira, Michelly C.; Rêgo, Moacyr J. B. M.; Pitta, Maira G. R.

Brain damage serum biomarkers induced by COVID-19 in patients from northeast Brazil

https://doi.org/10.1007/s13365-023-01119-1

Published

31-Jan-23

Study

https://doi.org/10.1007/s13365-023-01119-1

Neurological symptoms have been often reported in COVID-19 disease. In the present study, we evaluated brain damage associated with the increase of serum levels of neurological biomarkers S100B and neuron-specific enolase (NSE) induced by SARS-CoV-2 infection, in a population from Northeastern Brazil. Thirty-six healthy control (G1) individuals and 141 patients with confirmed COVID-19 were enrolled in this study. Positive-COVID-19 patients were divided into two groups according to the severity of illness by the National Institute of Health (NIH) criteria, 76 patients with mild symptoms for COVID-19 and (G2) and 65 with acute respiratory conditions requiring supplemental oxygenation via intensive care unit (ICU) admission (G3). A follow-up study was conducted with 23 patients from G2 14 (D14) and 21 (D21) days after the onset of symptoms. Serum levels of NSE and S100B were measured using the enzyme-linked immunoassay method (ELISA). Results revealed a significant positive association between G3 patients and S100B serum expression (p = 0.0403). The serum levels of NSE were also significantly enhanced in the G3 group compared to the control (p < 0.0001) and G2 group (p < 0.0001). In addition, clinical features such as symptoms and oxygenation status were not correlated with NSE or S100B serum expression. The follow-up study demonstrated a decrease over time (21 days) in NSE serum expression (p < 0.0001). These results suggest that brain damage is followed by acute virus exposure, with no long-term effects. Future work examining COVID-19 recovery will shed light on chronic neurological damage of SARS-CoV-2 infection.

2637

N555

Al-kuraishy, Hayder M.; Al-Gareeb, Ali I.; Kaushik, Ajeet; Kujawska, Małgorzata; Ahmed, Eman A.; Batiha, Gaber El-Saber

SARS-COV-2 infection and Parkinson's disease: Possible links and perspectives

https://doi.org/10.1002/jnr.25171

Published

30-Jan-23

Review

https://onlinelibrary.wiley.com/doi/abs/10.1002/jnr.25171

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. The hallmarks are the presence of Lewy bodies composed mainly of aggregated α-synuclein and immune activation and inflammation in the brain. The neurotropism of SARS-CoV-2 with induction of cytokine storm and neuroinflammation can contribute to the development of PD. Interestingly, overexpression of α-synuclein in PD patients may limit SARS-CoV-2 neuroinvasion and degeneration of dopaminergic neurons; however, on the other hand, this virus can speed up the α-synuclein aggregation. The review aims to discuss the potential link between COVID-19 and the risk of PD, highlighting the need for further studies to authenticate the potential association. We have also overviewed the influence of SARS-CoV-2 infection on the PD course and management. In this context, we presented the prospects for controlling the COVID-19 pandemic and related PD cases that, beyond global vaccination and novel anti-SARS-CoV-2 agents, may include the development of graphene-based nanoscale platforms offering antiviral and anti-amyloid strategies against PD.

2638

N556

Teodoro, Tiago; Chen, Jiaying; Gelauff, Jeannette; Edwards, Mark J.

Functional Neurological Disorder in people with Long-Covid: A Systematic Review

https://doi.org/10.1111/ene.15721

Published

31-Jan-23

Review

https://onlinelibrary.wiley.com/doi/abs/10.1111/ene.15721

Background Acute health events, including infections, can trigger the onset of functional neurological disorder (FND). We hypothesised that a proportion of people with long-COVID might be experiencing functional symptoms. Methods We performed a systematic review of studies containing original data on long-COVID. We reviewed the frequency and characteristics of neurological symptoms, looking for positive evidence suggesting an underlying functional disorder, and the hypothesised causes of long-COVID. Results We included 102 studies in our narrative synthesis. The most consistently reported neurological symptoms were cognitive difficulties, headaches, pain, dizziness, fatigue, sleep-related symptoms, and ageusia/anosmia. Overall, we found no evidence that any authors had systematically looked for positive features of FND. An exception were three studies describing temporal inconsistency. In general, the neurological symptoms were insufficiently characterised in order to support or refute a diagnosis of FND. Moreover, only 13 studies specifically focussed on long-COVID after mild infection, where the impact of confounders from the general effects of severe illness would be mitigated. Only one study hypothesised that some people with long-COVID might have a functional disorder, and another 8 studies a chronic fatigue syndrome-like response. Discussion Neurological symptoms are prevalent in long-COVID, but poorly characterised. We are struck by the similarities between some manifestations of long-COVID and functional disorders triggered by acute illnesses. Unfortunately, the current literature is plagued by confounders, including the mixing of patients with initial mild infection with those with severe acute medical complications. The hypothesis that long-COVID might in part correspond to a functional disorder remains untested.

2639

N557

Ong, Ian Z.; Kolson, Dennis L.; Schindler, Matthew K.

Mechanisms, Effects, and Management of Neurological Complications of Post-Acute Sequelae of COVID-19 (NC-PASC)

https://doi.org/10.3390/biomedicines11020377

Published

1-Feb-23

Review

https://www.mdpi.com/2227-9059/11/2/377

With a growing number of patients entering the recovery phase following infection with SARS-CoV-2, understanding the long-term neurological consequences of the disease is important to their care. The neurological complications of post-acute sequelae of SARS-CoV-2 infection (NC-PASC) represent a myriad of symptoms including headaches, brain fog, numbness/tingling, and other neurological symptoms that many people report long after their acute infection has resolved. Emerging reports are being published concerning COVID-19 and its chronic effects, yet limited knowledge of disease mechanisms has challenged therapeutic efforts. To address these issues, we review broadly the literature spanning 2020–2022 concerning the proposed mechanisms underlying NC-PASC, outline the long-term neurological sequelae associated with COVID-19, and discuss potential clinical interventions.

2640

N558

Reinhold, Dirk; Farztdinov, Vadim; Yan, Yan; Meisel, Christian; Sadlowski, Henrik; Kühn, Joachim; Perschel, Frank H.; Endres, Matthias; Düzel, Emrah; Vielhaber, Stefan; Guttek, Karina; Goihl, Alexander; Venø, Morten; Teegen, Bianca; Stöcker, Winfried; Stubbemann, Paula; Kurth, Florian; Sander, Leif E.; Ralser, Markus; Otto, Carolin; Streit, Simon; Jarius, Sven; Ruprecht, Klemens; Radbruch, Helena; Kjems, Jørgen; Mülleder, Michael; Heppner, Frank; Körtvelyessy, Peter

The brain reacting to COVID-19: analysis of the cerebrospinal fluid proteome, RNA and inflammation

https://doi.org/10.1186/s12974-023-02711-2

Published

9-Feb-23

Study

https://doi.org/10.1186/s12974-023-02711-2

Patients with COVID-19 can have a variety of neurological symptoms, but the active involvement of central nervous system (CNS) in COVID-19 remains unclear. While routine cerebrospinal fluid (CSF) analyses in patients with neurological manifestations of COVID-19 generally show no or only mild inflammation, more detailed data on inflammatory mediators in the CSF of patients with COVID-19 are scarce. We studied the inflammatory response in paired CSF and serum samples of patients with COVID-19 (n = 38). Patients with herpes simplex virus encephalitis (HSVE, n = 10) and patients with non-inflammatory, non-neurodegenerative neurological diseases (n = 28) served as controls. We used proteomics, enzyme-linked immunoassays, and semiquantitative cytokine arrays to characterize inflammatory proteins. Autoantibody screening was performed with cell-based assays and native tissue staining. RNA sequencing of long-non-coding RNA and circular RNA was done to study the transcriptome. Proteomics on single protein level and subsequent pathway analysis showed similar yet strongly attenuated inflammatory changes in the CSF of COVID-19 patients compared to HSVE patients with, e.g., downregulation of the apolipoproteins and extracellular matrix proteins. Protein upregulation of the complement system, the serpin proteins pathways, and other proteins including glycoproteins alpha-2 and alpha-1 acid. Importantly, calculation of interleukin-6, interleukin-16, and CXCL10 CSF/serum indices suggest that these inflammatory mediators reach the CSF from the systemic circulation, rather than being produced within the CNS. Antibody screening revealed no pathological levels of known neuronal autoantibodies. When stratifying COVID-19 patients into those with and without bacterial superinfection as indicated by elevated procalcitonin levels, inflammatory markers were significantly (p < 0.01) higher in those with bacterial superinfection. RNA sequencing in the CSF revealed 101 linear RNAs comprising messenger RNAs, and two circRNAs being significantly differentially expressed in COVID-19 than in non-neuroinflammatory controls and neurodegenerative patients. Our findings may explain the absence of signs of intrathecal inflammation upon routine CSF testing despite the presence of SARS-CoV2 infection-associated neurological symptoms. The relevance of blood-derived mediators of inflammation in the CSF for neurological COVID-19 and post-COVID-19 symptoms deserves further investigation.

2641

N559

Emmi, Aron; Rizzo, Stefania; Barzon, Luisa; Sandre, Michele; Carturan, Elisa; Sinigaglia, Alessandro; Riccetti, Silvia; Della Barbera, Mila; Boscolo-Berto, Rafael; Cocco, Patrizia; Macchi, Veronica; Antonini, Angelo; De Gaspari, Monica; Basso, Cristina; De Caro, Raffaele; Porzionato, Andrea

Detection of SARS-CoV-2 viral proteins and genomic sequences in human brainstem nuclei

https://doi.org/10.1038/s41531-023-00467-3

Published

13-Feb-23

Study

https://www.nature.com/articles/s41531-023-00467-3

Neurological manifestations are common in COVID-19, the disease caused by SARS-CoV-2. Despite reports of SARS-CoV-2 detection in the brain and cerebrospinal fluid of COVID-19 patients, it is still unclear whether the virus can infect the central nervous system, and which neuropathological alterations can be ascribed to viral tropism, rather than immune-mediated mechanisms. Here, we assess neuropathological alterations in 24 COVID-19 patients and 18 matched controls who died due to pneumonia/respiratory failure. Aside from a wide spectrum of neuropathological alterations, SARS-CoV-2-immunoreactive neurons were detected in the dorsal medulla and in the substantia nigra of five COVID-19 subjects. Viral RNA was also detected by real-time RT-PCR. Quantification of reactive microglia revealed an anatomically segregated pattern of inflammation within affected brainstem regions, and was higher when compared to controls. While the results of this study support the neuroinvasive potential of SARS-CoV-2 and characterize the role of brainstem inflammation in COVID-19, its potential implications for neurodegeneration, especially in Parkinson’s disease, require further investigations.

2642

N560

Lukiw, Walter J.; Pogue, Aileen I.

Endogenous miRNA-Based Innate-Immunity against SARS-CoV-2 Invasion of the Brain

https://doi.org/10.3390/ijms24043363

Published

1-Jan-23

Review

https://www.mdpi.com/1422-0067/24/4/3363

The severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, possesses an unusually large positive-sense, single-stranded viral RNA (ssvRNA) genome of about ~29,903 nucleotides (nt). In many respects, this ssvRNA resembles a very large, polycistronic messenger RNA (mRNA) possessing a 5′-methyl cap (m7GpppN), a 3′- and 5′-untranslated region (3′-UTR, 5′-UTR), and a poly-adenylated (poly-A+) tail. As such, the SARS-CoV-2 ssvRNA is susceptible to targeting by small non-coding RNA (sncRNA) and/or microRNA (miRNA), as well as neutralization and/or inhibition of its infectivity via the human body’s natural complement of about ~2650 miRNA species. Depending on host cell and tissue type, in silico analysis, RNA sequencing, and molecular-genetic investigations indicate that, remarkably, almost every single human miRNA has the potential to interact with the primary sequence of SARS-CoV-2 ssvRNA. Individual human variation in host miRNA abundance, speciation, and complexity among different human populations and additional variability in the cell and tissue distribution of the SARS-CoV-2 angiotensin converting enzyme-2 (ACE2) receptor (ACE2R) appear to further contribute to the molecular-genetic basis for the wide variation in individual host cell and tissue susceptibility to COVID-19 infection. In this paper, we review recently described aspects of the miRNA and ssvRNA ribonucleotide sequence structure in this highly evolved miRNA–ssvRNA recognition and signaling system and, for the first time, report the most abundant miRNAs in the control superior temporal lobe neocortex (STLN), an anatomical area involved in cognition and targeted by both SARS-CoV-2 invasion and Alzheimer’s disease (AD). We further evaluate important factors involving the neurotropic nature of SARS-CoV-2 and miRNAs and ACE2R distribution in the STLN that modulate significant functional deficits in the brain and CNS associated with SARS-CoV-2 infection and COVID-19’s long-term neurological effects.

2643

N561

Zehra, Azme; Gautam, Harendra Kumar; Kanaujia, S. K.; Srivastava, Amrita; Kumar, Arvind; Kumar, Awadhesh; Singh, Chandra Shekhar; Singh, Shiroman; Purwar, A. K.

Irreversible Sensorineural Hearing Loss in Post Covid-19 Patients—An Institutional Prospective Study

https://doi.org/10.1007/s12070-023-03540-8

Published

6-Feb-23

Study

https://doi.org/10.1007/s12070-023-03540-8

SARS-CoV-2 virus could damage the hearing by several mechanisms, it could damage the auditory centre in the temporal lobe and direct peripheral injury to the sensory cells of the cochlear due to neurotropism of the virus. A Prospective hospital-based observational study was carried out at a tertiary care centre for a period of 22 months from January 2021 to October 2022. A total of 100 patients were selected according to inclusion criteria and exclusion criteria. Pure-tone audiometry (PTA) was done as a screening test; patients were followed up till 6 months. Among those patients who had hearing loss, repeat audiological profile (PTA) was done after 1 month, 13(65%) patients were found to have normal hearing. After 3 months, repeat PTA was done, 18 patients (90%) found to have normal hearing and the remaining 2 patients followed up till 6 months and again PTA was done where only 1 patient continued to have sensorineural hearing loss.

2644

N562

Barroso, Erika; Tuta-Quintero, Eduardo; Olivella, Juan; Aragón, Camila; Vásquez, Lorena; Acosta, Lina; Pinzón, Oscar; Pantoja, Carlos A.; Collazos, Estefanía; Ascanio, Yesica P.; Morales, Violett del Carmen Del Río; Kuan, Juan C.; Velásquez, Liley A.; Díaz, Yeimy N.; Pimentel, Juan

Guillain Barré syndrome in the paediatric population. Consequence of active infection or long Covid?

https://doi.org/10.1016/j.rcreue.2023.01.001

Published

3-Feb-23

Review

https://www.sciencedirect.com/science/article/pii/S2444440523000018

Background
Guillain-Barré syndrome is a polyradiculoneuropathy that has been associated with infectious diseases as triggers. There is currently little medical evidence exploring the relationship between the development of Guillain-Barré syndrome caused by SARS-CoV-2 infection and long Covid.
Objective
To synthesize the medical evidence that describes the relationship between post Covid syndrome and Guillain-Barré syndrome in the paediatric population.
Methodology
A scoping review was developed using Scopus and PubMed databases, including analytical and/or descriptive experimental and observational studies.
Results
The main clinical manifestations presented by paediatric patients were distal and ascending weakness in the lower limbs and myalgia. The diagnostic approach was based on clinical findings, imaging findings on spinal magnetic resonance and electromyography. The therapeutic strategy is based on the use of intravenous human immunoglobulins.
Conclusion
Guillain-Barré syndrome is a frequent disease in the paediatric population with active SARS-CoV-2 infection or in survivors, however, it is necessary to encourage further clinical studies that increase the medical literature that describes this association.
Resumen
Introducción
El síndrome de Guillain-Barré es una polirradiculoneuropatía que se ha asociado con enfermedades infecciosas como desencadenantes. En la actualidad es escasa la evidencia médica que explore la relación entre el desarrollo del síndrome de Guillain-Barré causado por la infección por SARS-CoV-2 y la COVID prolongada.
Objetivo
Sintetizar la evidencia médica que describe la relación entre el síndrome pos-COVID y el síndrome de Guillain-Barré en la población pediátrica.
Metodología
Se realizó una revisión exploratoria utilizando las bases de datos de Scopus y PubMed, incluyendo estudios experimentales y observacionales analíticos o descriptivos.
Resultados
Las principales manifestaciones clínicas presentadas por los pacientes fueron debilidad distal y ascendente en miembros inferiores y mialgias. El enfoque diagnóstico se apoyó en los hallazgos clínicos, hallazgos imagenológicos por resonancia magnética de columna y electromiografía. La estrategia terapéutica se basó en el uso de inmunoglobulinas humanas intravenosas.
Conclusión
El síndrome de Guillain-Barré es una enfermedad frecuente en la población pediátrica con infección activa por SARS-CoV-2 o en sobrevivientes, sin embargo, es necesario incentivar el desarrollo de estudios clínicos que incrementen la literatura médica que describe esta asociación.

2645

N563

Chatterjee, Swapan Kumar; Saha, Snigdha; T.k, Shahin Muhammed; Chatterjee, Swapan Kumar; Saha, Snigdha; T.k, Shahin Muhammed

COVID-19 and Its Impact on Onset and Progression of Parkinson’s and Cognitive Dysfunction

https://doi.org/10.5772/intechopen.105667

Published

2-Feb-23

Article

https://www.intechopen.com/online-first/82534

In the COVID-19 pandemic, neurological complications have emerged as a significant cause of morbidity and mortality. A wide range of neurological manifestations ranging from cognitive or memory disturbances, headache, loss of smell or taste, confusion, and disabling strokes have been reported during and post COVID conditions. The COVID-19 virus can utilize two possible pathways for invasion into the brain, either through retrograde axonal transport (olfactory route) or by crossing the blood-brain barrier (BBB). Furthermore, the production of SARS-CoV-2-associated cytokines, such as interleukin (IL)-6, IL-17, IL-1b, and tumor necrosis factor (TNF), is able to disrupt the BBB. The neuroinvasive nature of SARS-CoV-2 has a more severe impact on patients with preexisting neurological manifestations such as Parkinson’s disease (PD). Pathological features of PD include selective loss of dopaminergic neurons in the substantia nigra pars compacta and aggregation of α-syn proteins present in neurons. Interaction between SARS-COV-2 infection and α-synuclein might have long-term implications on the onset of Parkinsonism by the formation of toxic protein clumps called amyloid fibrils—a hallmark of Parkinson’s. Molecular modeling is an emerging tool to predict potential inhibitors against the enzyme α-synuclein in neurodegenerative diseases by using plant bioactive molecules.

2646

N564

El-Fadeal, Noha M. Abd; Anber, Sara A.; Elkot, Hoda A.; Maged, Ghada; Saeed, Iman A.; Negm, Marwa M.; Abdelsamad, Menna Allah; El-bakri, Asmaa; Mohamed, Wael

COVID-19 and the central nervous system: What is the interplay?

https://doi.org/10.31117/neuroscirn.v5i4.155

Published

31-Dec-22

Review

https://neuroscirn.org/ojs/index.php/nrnotes/article/view/155

Since the outbreak of COVID-19 in 2019-2020, the highly contiguous disease caused by coronavirus 2 (SARS-CoV-2) spread worldwide in a short life span causing a disastrous effect and nearly 5.8 million deaths until February 2022. This global health crisis caused concerns about the disease's aetiology, epidemiology, and management. Understanding the virus's long- and short-term consequences on diverse human body organs and systems was one of the scientist's concerns despite the virus' respiratory system principal effect. Thus, after reporting neurological symptoms in approximately one-third of hospitalised patients with COVID-19, demonstrating how COVID-19 infects the central nervous system (CNS), causing neurodegenerative diseases in various patients and how the virus affects CNS function became quintessential. There are various mechanisms for COVID-19 pathophysiology, some implicating the potential virus invasion of the blood-brain barrier (BBB). Trans-synaptic and hematogenous routes are the main routes for the virus to pass through the barrier. Binding to the BBB endothelial cells is causing significant alterations in the permeability and integrity properties of the barrier, which cause an elevation of the incidence rate of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis among COVI-19 patients. COVID-19 patients developed neurological manifestations ranging from mild symptoms to severe diseases such as headache and loss of smell, encephalitis and CNS-mediated respiratory distress. However, encephalitis is not a common complication, and it has a significant mortality rate in severely ill patients due to the hyperactivation of the host immune response. Although more investigations are needed, severe COVID- 19 patients are considered at a high risk of neurodegenerative disorder as a long-term consequence of SARS-CoV-2 infection.

2647

N565

Telser, Julia; Grossmann, Kirsten; Weideli, Ornella C.; Hillmann, Dorothea; Aeschbacher, Stefanie; Wohlwend, Niklas; Velez, Laura; Kuhle, Jens; Maleska, Aleksandra; Benkert, Pascal; Risch, Corina; Conen, David; Risch, Martin; Risch, Lorenz

The role of serum brain injury biomarkers in individuals with a mild-to-moderate COVID infection and Long-COVID - results from the prospective population-based COVI-GAPP study

https://doi.org/10.1101/2023.02.15.23285972

Published

16-Feb-23

Study

https://www.medrxiv.org/content/10.1101/2023.02.15.23285972v1

Background During and after mild (no hospitalization) or moderate (hospitalization without ICU) SARS-CoV-2 infections, a wide range of symptoms, including neurological disorders have been reported. It is, however, unknown if these neurological symptoms are associated with brain injury and whether brain injury and related symptoms also emerge in patients suffering from Long-COVID. Neuronal biomarkers such as serum neurofilament light chain and glial fibrillary acidic protein can be used to elucidate neuro-axonal and astroglial injuries. We therefore investigated whether these biomarkers are associated with the COVID-19 infection status (mild-to-moderate), the associated symptoms and Long-COVID.
Methods From 146 individuals of the general population with a post-acute, mild-to-moderate SARS-CoV-2 infection, serum neurofilament light chain (sNfL; marker of intra-axonal neuronal injury) and serum glial fibrillary acidic protein (sGFAP; marker of astrocytic activation/injury) were measured. Samples were taken before, during and after (five and ten months) a SARS-CoV-2 infection. Individual symptoms and Long-COVID status were assessed using questionnaires.
Results Neurological symptoms were described for individuals after a mild and moderate COVID-19 infection, however, serum markers of brain injury (sNfL/sGFAP) did not change after an infection (sNfL: P = 0.74; sGFAP: P = 0.24) and were not associated with headache (P = 0.51), fatigue (P = 0.93), anosmia (P = 0.77) and ageusia (P = 0.47). In participants with Long-COVID, sGFAP (P = 0.038), but not sNfL (P = 0.58) significantly increased but was not associated with neurological symptoms.
Conclusion Neurological symptoms in individuals after a mild-to-moderate SARS-CoV-2 infection with and without Long-COVID were not associated with brain injury, although there was some astroglial injury observed in Long-COVID patients.
Funding The COVI-GAPP study received grants from the Innovative Medicines Initiative (IMI grant agreement number 101005177), the Princely House of Liechtenstein, the government of the Principality of Liechtenstein, and the Hanela Foundation (Switzerland). None of the funders played a role in the study design, data collection, data analysis, data interpretation, writing of the report, or decision to publish.
Background During and after mild (no hospitalization) or moderate (hospitalization without ICU) SARS-CoV-2 infections, a wide range of symptoms, including neurological disorders have been reported. It is, however, unknown if these neurological symptoms are associated with brain injury and whether brain injury and related symptoms also emerge in patients suffering from Long-COVID. Neuronal biomarkers such as serum neurofilament light chain and glial fibrillary acidic protein can be used to elucidate neuro-axonal and astroglial injuries. We therefore investigated whether these biomarkers are associated with the COVID-19 infection status (mild-to-moderate), the associated symptoms and Long-COVID.
Methods From 146 individuals of the general population with a post-acute, mild-to-moderate SARS-CoV-2 infection, serum neurofilament light chain (sNfL; marker of intra-axonal neuronal injury) and serum glial fibrillary acidic protein (sGFAP; marker of astrocytic activation/injury) were measured. Samples were taken before, during and after (five and ten months) a SARS-CoV-2 infection. Individual symptoms and Long-COVID status were assessed using questionnaires.
Results Neurological symptoms were described for individuals after a mild and moderate COVID-19 infection, however, serum markers of brain injury (sNfL/sGFAP) did not change after an infection (sNfL: P = 0.74; sGFAP: P = 0.24) and were not associated with headache (P = 0.51), fatigue (P = 0.93), anosmia (P = 0.77) and ageusia (P = 0.47). In participants with Long-COVID, sGFAP (P = 0.038), but not sNfL (P = 0.58) significantly increased but was not associated with neurological symptoms.
Conclusion Neurological symptoms in individuals after a mild-to-moderate SARS-CoV-2 infection with and without Long-COVID were not associated with brain injury, although there was some astroglial injury observed in Long-COVID patients.
Funding The COVI-GAPP study received grants from the Innovative Medicines Initiative (IMI grant agreement number 101005177), the Princely House of Liechtenstein, the government of the Principality of Liechtenstein, and the Hanela Foundation (Switzerland). None of the funders played a role in the study design, data collection, data analysis, data interpretation, writing of the report, or decision to publish.

2648

N566

Jileaeva, Ilona; Bakre, Sulaimon; Huff, Laura; Ratnakaran, Badr

The Same Day on Repeat: A Unique Case of Persistent DÉjÀ Vu Phenomenon as a Long COVID Symptom in an Older Adult

https://doi.org/10.1016/j.jagp.2022.12.250

Published

1-Mar-23

Case Report

https://www.sciencedirect.com/science/article/pii/S1064748123000751

Introduction
From anosmia to encephalopathy, ongoing neuropsychiatric manifestations after infection with COVID-19 are common and persistent. Déjà vu is a condition characterized by the experience of recognizing a current situation as familiar with the awareness that the recognition is inappropriate.1 This phenomenon has been well described in temporal lobe epilepsy and is thought to be caused by abnormal synchronization in the corticolimbic network. While the etiology of neuropsychiatric symptoms in long COVID is still not well demarcated, studies have found that the virus attacks the temporal lobe and limbic system, therefore, we suggest that the ongoing symptoms of déjà vu in this case may be a manifestation of long COVID.
Methods
The patient is a 79-year-old female with a pertinent past medical history of generalized anxiety disorder, major depressive disorder, and prior hospitalization for delirium who presented with a chief complaint of being tired of living the same day over and over again. The patient was hospitalized eight months prior for a severe COVID-19 infection that now requires continuous oxygen therapy. Since leaving the hospital, the patient began to develop episodic confusion, agitation and memory impairment which has gradually improved. However, the patient developed severe distress due to a feeling of déjà vu characterized by a sense of familiarity with events in her daily life. There was no history of loss of consciousness, abnormal involuntary movements, or other semiology related to seizures. Due to the distress caused by the déjà vu symptoms, the patient also endorsed depression, anxiety, and insomnia due to deterioration of quality of life. She described the déjà vu experience as similar to being “stuck in a loop” of the same day. She also endorsed several months of hearing ringing and flowing of water in her ears.
Results
Patient MRI showed mild volume loss and multifocal regions, including bilateral temporal lobes, of subcortical and periventricular high T2/FLAIR signal abnormality consistent with chronic white matter microangiopathy. Her MOCA score was 24/30, and her dissociative experience scale was 15.36/100. An electroencephalogram and neuropsychological evaluation are being scheduled for further evaluation and to rule out temporal lobe pathology. The patient continues to be treated for her depression, insomnia, and severe anxiety with oral escitalopram 10mg daily and oral mirtazapine 7.5mg at night.
Conclusions
Studies show that COVID-19 may be neurotropic, with an incidence of neurological symptoms in more than 80% of severe cases.2 These symptoms frequently occur in elderly patients and individuals with multiple comorbidities. In this case, the patient's age, psychiatric history, and severity of infection likely predisposed her to her current presentation. Current MRI findings in patients with neuropsychiatric symptoms after severe COVID-19 include ischemic infarction, signal abnormalities in the medial temporal lobe, non-confluent multifocal white matter hyperintense lesions, and extensive and isolated white matter microhemorrhages.3 While the experiences of déjà vu are rare and difficult to classify, they have been consistently shown to occur in temporal lobe epilepsy. Interestingly, déjà vu is also seen in schizophrenia and depersonalization disorders, which also affect the limbic-temporal lobe networks.1 Given that MRI findings in COVID-19 patients have shown changes in these same networks, it may be that the déjà vu and cognitive and memory impairments in this case are occurring as a consequence of COVID-19 virus infecting the temporal lobe. Given the large and often distressing disease burden, especially in this case, of neuropsychiatric symptoms in long COVID, it is important that further studies are done to elucidate the mechanism of how COVID-19 affects the brain. (1) Bošnjak Pašić, M., Horvat Velić, E., Fotak, L., et al: Many Faces of Déjà Vu: a Narrative Review. Psychiatria Danubina, 2018, 30(1), 21–25. (2) Douaud, G., Lee, S., Alfaro-Almagro, F., et al: SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature, 2022, 604 (7907), 697–707. (3) Han, Y., Yuan, K., Wang, Z., et al: Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions. Translational psychiatry, 2021, 11(1), 499.
This research was funded by
None.

2649

N567

Calculli, Alessandra; Bocci, Tommaso; Porcino, Mattia; Avenali, Micol; Casellato, Chiara; Arceri, Sebastiano; Regalbuto, Simone; Priori, Alberto; Pisani, Antonio

Parkinson's disease following COVID-19: six cases report

https://doi.org/10.1111/ene.15732

Published

18-Feb-23

Study

https://onlinelibrary.wiley.com/doi/abs/10.1111/ene.15732

Background Core clinical manifestation of COVID-19 include flu-like and respiratory symptoms. However, it is now evident that neurological involvement may occur during SARS-CoV-2 infection, covering an extensive spectrum of phenotypical manifestations. A major challenge arising from this pandemic is represented by detecting emerging neurological complications following recovery from SARS-CoV-2 infection. To date, few post-COVID-19 infected subjects diagnosed with Parkinson's Disease (PD) were described, raising the possibility of a connection between the infection and neurodegenerative process. Here, we describe a cases series of six subjects, who developed PD after COVID-19. Methods Patients were observed at IRCCS Mondino Foundation Hospital, Pavia (Italy), and San Paolo University Hospital of Milan (Italy) between March 2021 and June 2022. In all subjects, SARS-CoV-2 infection was confirmed by means of a RT-PCR from a nasopharyngeal swab. Subjects underwent an accurate neurological evaluation, and neuroimaging studies were performed. Results We describe six subjects, who developed PD with an average time window after SARS-CoV-2 infection of 4-7 weeks. Apparently, no relationship with COVID-19 severity emerged, and no overt structural brain abnormalities were found. All subjects experienced unilateral resting tremor at onset and showed a satisfactory response to dopaminergic treatment. Conclusions Immune responses to SARS-CoV-2 infection have been shown to shape the individual susceptibility to develop long-term consequences. We hypothesize that, in these subjects, COVID-19 has unmasked a latent neurodegenerative process. Characterization of the neuroinflammatory signatures in larger cohorts is warranted, which might provide novel insights in the pathogenesis of PD.

2650

N568

Valsamis, Helen; Baki, Samah Abdul; Leung, Jason; Ghosn, Samer; Lapin, Brittany; Chari, Geetha; Rasheed, Izad-Yar; Park, Jaehan; Punia, Vineet; Masri, Ghinwa; Nair, Dileep; Kaniecki, Ann Marie; Edhi, Muhammad; Saab, Carl Y.

SARS-CoV-2 alters neural synchronies in the brain with more severe effects in younger individuals

https://doi.org/10.1038/s41598-023-29856-7

Published

20-Feb-23

Study

https://www.nature.com/articles/s41598-023-29856-7

Coronavirus disease secondary to infection by SARS-CoV-2 (COVID19 or C19) causes respiratory illness, as well as severe neurological symptoms that have not been fully characterized. In a previous study, we developed a computational pipeline for the automated, rapid, high-throughput and objective analysis of electroencephalography (EEG) rhythms. In this retrospective study, we used this pipeline to define the quantitative EEG changes in patients with a PCR-positive diagnosis of C19 (n = 31) in the intensive care unit (ICU) of Cleveland Clinic, compared to a group of age-matched PCR-negative (n = 38) control patients in the same ICU setting. Qualitative assessment of EEG by two independent teams of electroencephalographers confirmed prior reports with regards to the high prevalence of diffuse encephalopathy in C19 patients, although the diagnosis of encephalopathy was inconsistent between teams. Quantitative analysis of EEG showed distinct slowing of brain rhythms in C19 patients compared to control (enhanced delta power and attenuated alpha–beta power). Surprisingly, these C19-related changes in EEG power were more prominent in patients below age 70. Moreover, machine learning algorithms showed consistently higher accuracy in the binary classification of patients as C19 versus control using EEG power for subjects below age 70 compared to older ones, providing further evidence for the more severe impact of SARS-CoV-2 on brain rhythms in younger individuals irrespective of PCR diagnosis or symptomatology, and raising concerns over potential long-term effects of C19 on brain physiology in the adult population and the utility of EEG monitoring in C19 patients.

2651

N569

Williams, Laura Dawn; Zis, Panagiotis

COVID-19-Related Neuropathic Pain: A Systematic Review and Meta-Analysis

https://doi.org/10.3390/jcm12041672

Published

1-Jan-23

Systematic review and meta-analysis

https://www.mdpi.com/2077-0383/12/4/1672

Introduction: SARS-CoV-2, responsible for the coronavirus disease (COVID-19) pandemic, may impact other systems apart from the respiratory system, including the nervous system. In this systematic review, we aimed to establish the prevalence and determinants of neuropathic pain amongst COVID-19-infected individuals. Methodology: A literature search in the PubMed database was performed and 11 papers were eligible for inclusion in this systematic review and meta-analysis. Results: The pooled prevalence of COVID-19-related neuropathic pain was 6.7% (95% CI: 4.7–9.5%) for hospitalised patients during the acute phase and 34.3% (95% CI: 14.3–62%) for long COVID patients. The identified risk factors for COVID-19-related neuropathic pain development included depression, COVID-19 severity and azithromycin use. Conclusions: Neuropathic pain is a very common symptom in long COVID, indicating the urgency for further research in this direction.

2652

N570

Heine, Josephine; Schwichtenberg, Katia; Hartung, Tim J.; Rekers, Sophia; Chien, Claudia; Boesl, Fabian; Rust, Rebekka; Hohenfeld, Christian; Bungenberg, Julia; Costa, Ana S.; Scheibenbogen, Carmen; Bellmann-Strobl, Judith; Paul, Friedemann; Franke, Christiana; Reetz, Kathrin; Finke, Carsten

Structural brain changes in patients with post-COVID fatigue: a prospective observational study

https://doi.org/10.1016/j.eclinm.2023.101874

Published

1-Apr-23

Study

https://www.sciencedirect.com/science/article/pii/S2589537023000512

Background
Post-COVID syndrome is a severe long-term complication of COVID-19. Although fatigue and cognitive complaints are the most prominent symptoms, it is unclear whether they have structural correlates in the brain. We therefore explored the clinical characteristics of post-COVID fatigue, describe associated structural imaging changes, and determine what influences fatigue severity.
Methods
We prospectively recruited 50 patients from neurological post-COVID outpatient clinics (age 18–69 years, 39f/8m) and matched non-COVID healthy controls between April 15 and December 31, 2021. Assessments included diffusion and volumetric MR imaging, neuropsychiatric, and cognitive testing. At 7.5 months (median, IQR 6.5–9.2) after the acute SARS-CoV-2 infection, moderate or severe fatigue was identified in 47/50 patients with post-COVID syndrome who were included in the analyses. As a clinical control group, we included 47 matched multiple sclerosis patients with fatigue.
Findings
Our diffusion imaging analyses revealed aberrant fractional anisotropy of the thalamus. Diffusion markers correlated with fatigue severity, such as physical fatigue, fatigue-related impairment in everyday life (Bell score) and daytime sleepiness. Moreover, we observed shape deformations and decreased volumes of the left thalamus, putamen, and pallidum. These overlapped with the more extensive subcortical changes in MS and were associated with impaired short-term memory. While fatigue severity was not related to COVID-19 disease courses (6/47 hospitalised, 2/47 with ICU treatment), post-acute sleep quality and depressiveness emerged as associated factors and were accompanied by increased levels of anxiety and daytime sleepiness.
Interpretation
Characteristic structural imaging changes of the thalamus and basal ganglia underlie the persistent fatigue experienced by patients with post-COVID syndrome. Evidence for pathological changes to these subcortical motor and cognitive hubs provides a key to the understanding of post-COVID fatigue and related neuropsychiatric complications.
Funding
Deutsche Forschungsgemeinschaft (DFG) and German Ministry of Education and Research (BMBF).

2653

N571

Normandin, Erica; Valizadeh, Navid; Rudmann, Emily A; Uddin, Rockib; Dobbins, Sabrina T; MacInnis, Bronwyn L; Padera, Robert F, Jr; Siddle, Katherine J; Lemieux, Jacob E; Sabeti, Pardis C; Mukerji, Shibani S; Solomon, Isaac H

Neuropathological features of SARS-CoV-2 delta and omicron variants

https://doi.org/10.1093/jnen/nlad015

Published

27-Feb-23

Study

https://doi.org/10.1093/jnen/nlad015

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continually evolving resulting in variants with increased transmissibility, more severe disease, reduced effectiveness of treatments or vaccines, or diagnostic detection failure. The SARS-CoV-2 Delta variant (B.1.617.2 and AY lineages) was the dominant circulating strain in the United States from July to mid-December 2021, followed by the Omicron variant (B.1.1.529 and BA lineages). Coronavirus disease 2019 (COVID-19) has been associated with neurological sequelae including loss of taste/smell, headache, encephalopathy, and stroke, yet little is known about the impact of viral strain on neuropathogenesis. Detailed postmortem brain evaluations were performed for 22 patients from Massachusetts, including 12 who died following infection with Delta variant and 5 with Omicron variant, compared to 5 patients who died earlier in the pandemic. Diffuse hypoxic injury, occasional microinfarcts and hemorrhage, perivascular fibrinogen, and rare lymphocytes were observed across the 3 groups. SARS-CoV-2 protein and RNA were not detected in any brain samples by immunohistochemistry, in situ hybridization, or real-time quantitative PCR. These results, although preliminary, demonstrate that, among a subset of severely ill patients, similar neuropathological features are present in Delta, Omicron, and non-Delta/non-Omicron variant patients, suggesting that SARS-CoV-2 variants are likely to affect the brain by common neuropathogenic mechanisms.

2654

N572

Fernández-de-Las-Peñas, César; Cuadrado, Maria L; Gómez-Mayordomo, Victor; García-Azorín, David; Arendt-Nielsen, Lars

Headache as a COVID-19 onset symptom or Post-COVID symptom according to the SARS-CoV-2 Variant

https://doi.org/10.1080/14737175.2023.2185138

Published

1-Feb-23

Review

https://doi.org/10.1080/14737175.2023.2185138

Introduction COVID19 associated headaches are highly common and there is currently an unmet need to better understand their association with SARSCoV2 variants. Headaches are a prevalent symptom in the acute phase of COVID19 and are associated with a better prognosis and better immune response. They are also a relevant post-COVID symptom.Areas covered This article analyses the differences in the prevalence of headache as an onset symptom and in post-COVID headache among the different SARS-CoV-2 variants: the historical strain, Alpha, Delta and Omicron. The different pathophysiological mechanisms by which SARS-CoV-2 infection may cause headache are also discussed.Expert opinion The presence of headache at the acute phase is a risk factor for post-COVID headache, whereas a history of primary headache does not appear to be associated with post-COVID headache. The prevalence of headache as an onset symptom appears to be variable for the different SARS-CoV-2 variants, but current data are inconclusive. However, the current evidence also suggests that headache represents a prevalent symptom in the acute and post-infection COVID-19 phase, regardless of SARS-CoV-2 variant.

2655

N573

Oka, Takakazu

A patient who recovered from post-COVID myalgic encephalomyelitis/chronic fatigue syndrome: a case report

https://doi.org/10.1186/s13030-022-00260-3

Published

28-Feb-23

Case Report

https://doi.org/10.1186/s13030-022-00260-3

Background
Some patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) complain of persistent fatigue, dyspnea, pain, and cognitive dysfunction. These symptoms are often described as “long COVID”. Whether a patient with long COVID might develop myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is of interest, as is the treatment and management of ME/CFS in a post-COVID patient. Here I report a patient, who, after an infection with SARS-CoV-2, developed ME/CFS and recovered after treatment.

Case presentation
The patient was a previously healthy 55-year-old woman who worked as a nurse and became ill with COVID-19 pneumonia. She then presented with severe fatigue, post-exertional malaise, dyspnea, pain, cognitive dysfunction, tachycardia, and exacerbation of fatigue on physical exertion, which persisted for more than 6 months after her recovery from COVID-19 pneumonia. She was bedridden for more than half of each day. The patient was treated from multiple perspectives, which included (1) instructions on eating habits and supplements; (2) cognitive and behavioral modifications for coping with physical, emotional, and cognitive fatigue; (3) instructions on conditioning exercises to improve deconditioning due to fatigue and dyspnea; and (4) pharmacotherapy with amitriptyline and hochuekkito, a Japanese herbal (Kampo) medicine. The patient made a complete recovery after completing the prescribed regimen and was able to return to work as a nurse.

Conclusions
To the best of my knowledge, this is the first detailed report on a patient infected with SARS-CoV-2 followed by long COVID with the signs/symptoms of ME/CFS who recovered after treatment. I hope this case report will be helpful to health care practitioners by its presentation of some of the therapeutic options for alleviating disabling signs/symptoms in patients with post-COVID ME/CFS.

2656

N574

Stefanou, Εleni; Karvelas, Nikolaos; Bennett, Samuel; Kole, Christo

Cerebrovascular Manifestations of SARS-CoV-2: A Comprehensive Review

https://doi.org/10.1007/s11940-023-00747-6

Published

4-Mar-23

Review

https://doi.org/10.1007/s11940-023-00747-6

Purpose of review
The risks of cerebrovascular manifestations due to SARS-CoV-2 infection are significantly increased within the first 6 months of the infection. Our work aims to give an update on current clinical aspects of diagnosis and treatment of cerebrovascular manifestations during acute and long-term SARS-CoV-2 infection.

Recent findings
The incidence of acute ischemic stroke and haemorrhagic stroke during acute SARS-CoV-2 patients is estimated at 0.9 to 4.6% and 0.5–0.9%, respectively, and were associated with increased mortality. The majority presented with hemiparesis, dysarthria, sensory deficits, and a NIHSS score within 5–15. In addition, beyond the first 30 days of infection people with COVID-19 exhibited increased risk of stroke. During acute phase, age, hypertension, diabetes, and medical history of vascular disease were increased in patients with COVID-19 with new onset of cerebrovascular manifestations, while during long-COVID-19, the risk of cerebrovascular manifestations were found increased regardless of these factors. The management of patients with large-vessel ischemic stroke fulfilling the intravenous thrombolysis criteria are successfully treated according to the guidelines, while hyperosmolar therapy is typically administered in 4- to 6-h intervals. In addition, prophylaxis of anticoagulation therapy is associated with a better prognosis and low mortality during acute and post hospital discharge of patients with COVID-19.

Summary
In this work, we provide a comprehensive review of the current literature on acute and post-acute COVID-19 cerebrovascular sequelae, symptomatology, and its pathophysiology mechanisms. Moreover, we discuss therapeutic strategies for these patients during acute and long-term care and point populations at risk. Our findings suggest that older patients with risk factors such as hypertension, diabetes, and medical history of vascular disease are more likely to develop cerebrovascular complications.

2657

N575

Wingrove, Jed; Makaronidis, Janine; Prados, Ferran; Kanber, Baris; Yiannakas, Marios C.; Magee, Cormac; Castellazzi, Gloria; Grandjean, Louis; Golay, Xavier; Tur, Carmen; Ciccarelli, Olga; D'Angelo, Egidio; Wheeler-Kingshott, Claudia A. M. Gandini; Batterham, Rachel L.

Aberrant olfactory network functional connectivity in people with olfactory dysfunction following COVID-19 infection: an exploratory, observational study

https://doi.org/10.1016/j.eclinm.2023.101883

Published

1-Apr-23

Study

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00060-3/fulltext

Background
Olfactory impairments and anosmia from COVID-19 infection typically resolve within 2–4 weeks, although in some cases, symptoms persist longer. COVID-19-related anosmia is associated with olfactory bulb atrophy, however, the impact on cortical structures is relatively unknown, particularly in those with long-term symptoms.
Methods
In this exploratory, observational study, we studied individuals who experienced COVID-19-related anosmia, with or without recovered sense of smell, and compared against individuals with no prior COVID-19 infection (confirmed by antibody testing, all vaccine naïve). MRI Imaging was carried out between the 15th July and 17th November 2020 at the Queen Square House Clinical Scanning Facility, UCL, United Kingdom. Using functional magnetic resonance imaging (fMRI) and structural imaging, we assessed differences in functional connectivity (FC) between olfactory regions, whole brain grey matter (GM) cerebral blood flow (CBF) and GM density.
Findings
Individuals with anosmia showed increased FC between the left orbitofrontal cortex (OFC), visual association cortex and cerebellum and FC reductions between the right OFC and dorsal anterior cingulate cortex compared to those with no prior COVID-19 infection (p < 0.05, from whole brain statistical parametric map analysis). Individuals with anosmia also showed greater CBF in the left insula, hippocampus and ventral posterior cingulate when compared to those with resolved anosmia (p < 0.05, from whole brain statistical parametric map analysis).
Interpretation
This work describes, for the first time to our knowledge, functional differences within olfactory areas and regions involved in sensory processing and cognitive functioning. This work identifies key areas for further research and potential target sites for therapeutic strategies.
Funding
This study was funded by the National Institute for Health and Care Research and supported by the Queen Square Scanner business case.Publisher: Elsevier
PMID: 36883140

2658

N576

Calvache-Mateo, Andrés; López-López, Laura; Martín-Núñez, Javier; Heredia-Ciuró, Alejandro; Granados-Santiago, María; Ortiz-Rubio, Araceli; Valenza, Marie Carmen

Pain and Clinical Presentation: A Cross-Sectional Study of Patients with New-Onset Chronic Pain in Long-COVID-19 Syndrome

https://doi.org/10.3390/ijerph20054049

Published

1-Jan-23

Study

https://www.mdpi.com/1660-4601/20/5/4049

The aim of this study was to evaluate the characteristics of pain (i.e., pain intensity, pain interference, clinical presentation) in Long-COVID-19 patients and compare the location of pain between successfully recovered COVID-19 patients and healthy matched controls. A cross-sectional case-control study was carried out. Long-COVID-19 patients, age- and sex-matched patients with a history of COVID-19 who had successfully recovered, and healthy controls were included. Outcomes included were pain characteristics (Brief Pain Inventory and Short-Form McGill Pain Questionnaire) and clinical presentation (Widespread Pain Index and Euroqol-5 Dimensions 5 Levels Visual Analogue Scale). Sixty-nine patients with Long-COVID-19 syndrome, sixty-six successfully recovered COVID-19 patients, and sixty-seven healthy controls were evaluated. Patients with Long-COVID-19 syndrome showed greater pain intensity and interference. In addition, they showed worse quality of life and greater widespread pain, with the most frequent locations of pain being the neck, legs, and head. In conclusion, patients with Long-COVID-19 syndrome show a high prevalence of pain, characterized by widespread pain of moderate intensity and interference, with the most frequent locations being the neck, legs, and head, significantly affecting the quality of life of these patients.

2659

N577

Mancini, Maria; Natoli, Silvia; Gardoni, Fabrizio; Di Luca, Monica; Pisani, Antonio

Dopamine Transmission Imbalance in Neuroinflammation: Perspectives on Long-Term COVID-19

https://doi.org/10.3390/ijms24065618

Published

1-Jan-23

Review

https://www.mdpi.com/1422-0067/24/6/5618

Dopamine (DA) is a key neurotransmitter in the basal ganglia, implicated in the control of movement and motivation. Alteration of DA levels is central in Parkinson’s disease (PD), a common neurodegenerative disorder characterized by motor and non-motor manifestations and deposition of alpha-synuclein (α-syn) aggregates. Previous studies have hypothesized a link between PD and viral infections. Indeed, different cases of parkinsonism have been reported following COVID-19. However, whether SARS-CoV-2 may trigger a neurodegenerative process is still a matter of debate. Interestingly, evidence of brain inflammation has been described in postmortem samples of patients infected by SARS-CoV-2, which suggests immune-mediated mechanisms triggering the neurological sequelae. In this review, we discuss the role of proinflammatory molecules such as cytokines, chemokines, and oxygen reactive species in modulating DA homeostasis. Moreover, we review the existing literature on the possible mechanistic interplay between SARS-CoV-2-mediated neuroinflammation and nigrostriatal DAergic impairment, and the cross-talk with aberrant α-syn metabolism.

2660

N578

Van der Feltz-Cornelis, Christina M.; Moriarty, Andrew S.; Strain, William David

Neurological Dysfunction in Long COVID Should Not Be Labelled as Functional Neurological Disorder

https://doi.org/10.3390/v15030783

Published

1-Mar-23

Article

https://www.mdpi.com/1999-4915/15/3/783

There have been suggestions that Long COVID might be purely functional (meaning psychological) in origin. Labelling patients with neurological dysfunction in Long COVID as having functional neurological disorder (FND) in the absence of proper testing may be symptomatic of that line of thought. This practice is problematic for Long COVID patients, as motor and balance symptoms have been reported to occur in Long COVID frequently. FND is characterized by the presentation of symptoms that seem neurological but lack compatibility of the symptom with a neurological substrate. Although diagnostic classification according to the ICD-11 and DSM-5-TR is dependent predominantly on the exclusion of any other medical condition that could account for the symptoms, current neurological practice of FND classification allows for such comorbidity. As a consequence, Long COVID patients with motor and balance symptoms mislabeled as FND have no longer access to Long COVID care, whereas treatment for FND is seldom provided and is ineffective. Research into underlying mechanisms and diagnostic methods should explore how to determine whether motor and balance symptoms currently diagnosed as FND should be considered one part of Long COVID symptoms, in other words, one component of symptomatology, and in which cases they correctly represent FND. Research into rehabilitation models, treatment and integrated care are needed, which should take into account biological underpinnings as well as possible psychological mechanisms and the patient perspective.

2661

N579

Ariza, Mar; Cano, Neus; Segura, Bàrbara; Adan, Ana; Bargalló, Núria; Caldú, Xavier; Campabadal, Anna; Jurado, Maria Angeles; Mataró, Maria; Pueyo, Roser; Sala-Llonch, Roser; Barrué, Cristian; Bejar, Javier; Cortés, Claudio Ulises; Bernia, Jose A.; Arauzo, Vanesa; Balague-Marmaña, Marta; Valles-Pauls, Berta; Caballero, Jesús; Carnes-Vendrell, Anna; Piñol-Ripoll, Gerard; Gonzalez-Aguado, Ester; Tayó-Juli, Carme; Forcadell-Ferreres, Eva; Reverte-Vilarroya, Silvia; Forné, Susanna; Muñoz-Padros, Jordina; Bartes-Plan, Anna; Muñoz-Moreno, Jose A.; Prats-Paris, Anna; Rico, Inmaculada; Sabé, Nuria; Casas, Laura; Almeria, Marta; Ciudad, Maria José; Ferré, Anna; Lozano, Manuela; Garzon, Tamar; Cullell, Marta; Vega, Sonia; Alsina, Sílvia; Maldonado-Belmonte, Maria J.; Vazquez-Rivera, Susana; Navarro, Sandra; Baillès, Eva; Garolera, Maite; Junqué, Carme; NAUTILUS Project Collaborative Group

COVID-19 severity is related to poor executive function in people with post-COVID conditions

https://doi.org/10.1007/s00415-023-11587-4

Published

20-Mar-23

Study

https://doi.org/10.1007/s00415-023-11587-4

Patients with post-coronavirus disease 2019 (COVID-19) conditions typically experience cognitive problems. Some studies have linked COVID-19 severity with long-term cognitive damage, while others did not observe such associations. This discrepancy can be attributed to methodological and sample variations. We aimed to clarify the relationship between COVID-19 severity and long-term cognitive outcomes and determine whether the initial symptomatology can predict long-term cognitive problems. Cognitive evaluations were performed on 109 healthy controls and 319 post-COVID individuals categorized into three groups according to the WHO clinical progression scale: severe-critical (n = 77), moderate-hospitalized (n = 73), and outpatients (n = 169). Principal component analysis was used to identify factors associated with symptoms in the acute-phase and cognitive domains. Analyses of variance and regression linear models were used to study intergroup differences and the relationship between initial symptomatology and long-term cognitive problems. The severe-critical group performed significantly worse than the control group in general cognition (Montreal Cognitive Assessment), executive function (Digit symbol, Trail Making Test B, phonetic fluency), and social cognition (Reading the Mind in the Eyes test). Five components of symptoms emerged from the principal component analysis: the “Neurologic/Pain/Dermatologic” “Digestive/Headache”, “Respiratory/Fever/Fatigue/Psychiatric” and “Smell/ Taste” components were predictors of Montreal Cognitive Assessment scores; the “Neurologic/Pain/Dermatologic” component predicted attention and working memory; the “Neurologic/Pain/Dermatologic” and “Respiratory/Fever/Fatigue/Psychiatric” components predicted verbal memory, and the “Respiratory/Fever/Fatigue/Psychiatric,” “Neurologic/Pain/Dermatologic,” and “Digestive/Headache” components predicted executive function. Patients with severe COVID-19 exhibited persistent deficits in executive function. Several initial symptoms were predictors of long-term sequelae, indicating the role of systemic inflammation and neuroinflammation in the acute-phase symptoms of COVID-19.” Study Registration: www.ClinicalTrials.gov, identifier NCT05307549 and NCT05307575.

2662

N580

Yang, Jiaxin; Li, Yan; Wang, Shijin; Li, Huili; Zhang, Lili; Zhang, Haichen; Wang, Pei-Hui; Zheng, Xiangyu; Yu, Xiao-Fang; Wei, Wei

The SARS-CoV-2 main protease induces neurotoxic TDP-43 cleavage and aggregates

https://doi.org/10.1038/s41392-023-01386-8

Published

9-Mar-23

Study

https://www.nature.com/articles/s41392-023-01386-8

Our findings led us to investigate the cytotoxic effects of Nsp5 cleavage of TDP-43 in neural cells. In SH-SY5Y human neuroblastoma cells, TDP-43 expression resulted in higher cytotoxicity with increased LDH release in the presence of Nsp5 in a dose-dependent manner (Fig. 1n). We used the Nsp5-resistant mutant TDP-43-Q331A as a negative control, which had no influence on TDP-43 cytotoxicity, with or without Nsp5 expression (Fig. 1n). Similar results were also observed in T98G human glioblastoma cells (Supplementary Fig. 7). We also found that ectopic expression of TDP-43 Q331A relieved Nsp5-triggered neurotoxicity (Supplementary Fig. 8), further supporting the ability of Nsp5 to cause neural damage Nsp5 via cleavage of TDP-43.

The observed dependence of 3CLpro activity on Nsp5-mediated TDP-43 cleavage led us to measure the effects of the small-molecule inhibitor GC376 on Nsp5 neurotoxicity. As expected, GC376 alleviated the inhibition of LDH release and neural cell proliferation triggered by Nsp5 expression without cytotoxicity (Fig. 1o, p and Supplementary Fig. 9). Thus, Nsp5 is a viral neurotoxic factor, and its 3CLpro activity is a druggable target for relieving neural damage.

SARS-CoV-2 infection results in multilineage neural cell dysregulation, decreased new neuron generation, and a reduction in overall brain size in patients, even those with mild respiratory COVID-19.2 The infectivity of SARS-CoV-2 in neural cells has been confirmed in human neural progenitor cells, brain organoids and nonhuman primates.3,9,10 Overall, there is a critical need to determine which viral factors contribute to central nervous system (CNS) disorders. Hence, our identification of Nsp5 as cytotoxic towards neuroblasts and glial cells demonstrates a direct killing effect of SARS-CoV-2 infection on neuronal cells through TDP-43 cleavage, which may lead to further CNS dysfunction, including neuroinflammation. Nevertheless, the effects of TDP-43 cleavage by the viral protease Nsp5 on host neural damage still need to be further confirmed in organoids, animal models, and infected patients.

The number of COVID-19 cases continues to rise and now exceeds 625 million worldwide, and long COVID has emerged and cannot be ignored. Considering that TDP-43 dysfunction has been well defined as a hallmark associated with several neurodegenerative diseases,4 including ALS, FTLD and Alzheimer’s disease, whether the devastating effect of Nsp5-mediated TDP-43 cleavage can be reversed after infection and the relationship between SARS-CoV-2 infection and a high risk of neurodegenerative-like diseases urgently need to be investigated with additional research.
number: 1
publisher: Nature Publishing Group

2663

N581

Kieseler, Marie-Luise; Duchaine, Brad

Persistent prosopagnosia following COVID-19

https://doi.org/10.1016/j.cortex.2023.01.012

Published

1-May-23

Case Report

https://www.sciencedirect.com/science/article/pii/S0010945223000448

COVID-19 can cause psychological problems including loss of smell and taste, long-lasting memory, speech, and language impairments, and psychosis. Here, we provide the first report of prosopagnosia following symptoms consistent with COVID-19. Annie is a 28-year-old woman who had normal face recognition prior to contracting COVID-19 in March 2020. Two months later, she noticed face recognition difficulties while experiencing symptom relapses and her deficits with faces have persisted. On two tests of familiar face recognition and two tests of unfamiliar face recognition, Annie showed clear impairments. In contrast, she scored normally on tests assessing face detection, face identity perception, object recognition, scene recognition, and non-visual memory. Navigational deficits frequently co-occur with prosopagnosia, and Annie reports that her navigational abilities are substantially worse than before she became ill. Self-report survey data from 54 respondents with long COVID showed that a majority reported reductions in visual recognition and navigation abilities. In summary, Annie's results indicate that COVID-19 can produce severe and selective neuropsychological impairments similar to deficits seen following brain damage, and it appears that high-level visual impairments are not uncommon in people with long COVID.

2664

N582

Oner, Pinar; Yilmaz, Seda; Doğan, Serpil

High Homocysteine Levels Are Associated with Cognitive Impairment in Patients Who Recovered from COVID-19 in the Long Term

https://doi.org/10.3390/jpm13030503

Published

1-Mar-23

Study

https://www.mdpi.com/2075-4426/13/3/503

In this study, we measured the levels of depression and cognition in people recovering from COVID-19. Moreover, we aimed to investigate the relationship between depression and cognition levels by measuring homocysteine concentrations. It included 62 people recovering from COVID-19 (at least 3 months after positive RT-PCR) and 64 people without COVID-19 (control group). At first, the homocysteine levels of participants were measured. Beck Depression Inventory (BDI) and Montreal Cognitive Assessment (MoCA) were performed to collect data. Homocysteine levels of the group recovering from COVID-19 (x− = 19.065 µmol/L) were higher than the control group (x− = 11.313 µmol/L). There was no significant difference between the groups for BDI scores. The MoCA scores of the group recovering from COVID-19 (x− = 20.774) were lower than the control group (x− = 24.297). There was a negative high (r = –0.705, p < 0.001) correlation between homocysteine levels and MoCA scores. Linear regression analysis is shown to be significant, and the MoCA explanatory value of the variables in the model is 58.6% (p < 0.0001). A 1 µmol/L observed increase in homocysteine level constituted a risk for a 0.765-point decrease in MOCA scores. In patients recovering from COVID-19, early interventions to high homocysteine levels may prevent cognitive impairments that may persist in the long term.

2665

N583

Invitto, Sara; Boscolo-Rizzo, Paolo; Fantin, Francesco; Bonifati, Domenico Marco; de Filippis, Cosimo; Emanuelli, Enzo; Frezza, Daniele; Giopato, Federico; Caggiula, Marcella; Schito, Andrea; Ciccarese, Vincenzo; Spinato, Giacomo

Exploratory Study on Chemosensory Event-Related Potentials in Long COVID-19 and Mild Cognitive Impairment: A Common Pathway?

https://doi.org/10.3390/bioengineering10030376

Published

1-Mar-23

Study

https://www.mdpi.com/2306-5354/10/3/376

People affected by the Long COVID-19 (LC) syndrome often show clinical manifestations that are similar to those observed in patients with mild cognitive impairments (MCI), such as olfactory dysfunction (OD), brain fog, and cognitive and attentional diseases. This study aimed to investigate the chemosensory-evoked related potentials (CSERP) in LC and MCI to understand if there is a common pathway for the similarity of symptoms associated with these disorders. Eighteen LC patients (mean age 53; s.d. = 7), 12 patients diagnosed with MCI (mean age 67; s.d. = 6), and 10 healthy control subjects (mean age 66; s.d. = 5, 7) were recruited for this exploratory study. All of them performed a chemosensory event-related potentials (CSERP) task with the administration of trigeminal stimulations (e.g., the odorants cinnamaldehyde and eucalyptus). Study results highlighted that MCI and LC showed reduced N1 amplitude, particularly in the left frontoparietal network, involved in working memory and attentional deficits, and a reduction of P3 latency in LC. This study lays the foundations for evaluating aspects of LC as a process that could trigger long-term functional alterations, and CSERPs could be considered valid biomarkers for assessing the progress of OD and an indicator of other impairments (e.g., attentional and cognitive impairments), as they occur in MCI.

2666

N584

Leng, Albert; Shah, Manuj; Ahmad, Syed Ameen; Premraj, Lavienraj; Wildi, Karin; Li Bassi, Gianluigi; Pardo, Carlos A.; Choi, Alex; Cho, Sung-Min

Pathogenesis Underlying Neurological Manifestations of Long COVID Syndrome and Potential Therapeutics

https://doi.org/10.3390/cells12050816

Published

1-Jan-23

Review

https://www.mdpi.com/2073-4409/12/5/816

The development of long-term symptoms of coronavirus disease 2019 (COVID-19) more than four weeks after primary infection, termed “long COVID” or post-acute sequela of COVID-19 (PASC), can implicate persistent neurological complications in up to one third of patients and present as fatigue, “brain fog”, headaches, cognitive impairment, dysautonomia, neuropsychiatric symptoms, anosmia, hypogeusia, and peripheral neuropathy. Pathogenic mechanisms of these symptoms of long COVID remain largely unclear; however, several hypotheses implicate both nervous system and systemic pathogenic mechanisms such as SARS-CoV2 viral persistence and neuroinvasion, abnormal immunological response, autoimmunity, coagulopathies, and endotheliopathy. Outside of the CNS, SARS-CoV-2 can invade the support and stem cells of the olfactory epithelium leading to persistent alterations to olfactory function. SARS-CoV-2 infection may induce abnormalities in innate and adaptive immunity including monocyte expansion, T-cell exhaustion, and prolonged cytokine release, which may cause neuroinflammatory responses and microglia activation, white matter abnormalities, and microvascular changes. Additionally, microvascular clot formation can occlude capillaries and endotheliopathy, due to SARS-CoV-2 protease activity and complement activation, can contribute to hypoxic neuronal injury and blood–brain barrier dysfunction, respectively. Current therapeutics target pathological mechanisms by employing antivirals, decreasing inflammation, and promoting olfactory epithelium regeneration. Thus, from laboratory evidence and clinical trials in the literature, we sought to synthesize the pathophysiological pathways underlying neurological symptoms of long COVID and potential therapeutics.

2667

N585

Kamasak, Burcu; Ulcay, Tufan; Nisari, Mehtap; Gorgulu, Ozkan; Akca, Veysel; Alpaslan, Muhammet; Yetis, Aysu; Hizmali, Lokman; Karahocagil, Mustafa Kasim; Aycan, Kenan

Effects of COVID-19 on brain and cerebellum: a voxel based morphometrical analysis

https://doi.org/10.4149/bll_2023_068

Published

1-Feb-23

Study

https://doi.org/10.4149/BLL_2023_068

ObjectiveCOVID-19 is caused by SARS-CoV-2 virus and turned into a pandemic in a short time, affects many organs and systems, especially the nervous system. In the present study, it was aimed to determine the morphological and volumetric changes in cortical and subcortical structures in recovered COVID-19 patients.BackgroundWe think that COVID-19 has a long-term effect on cortical and subcortical structures.MethodsIn our study, 50 post-COVID-19 patients and 50 healthy volunteers participated. In both groups, brain parcellations were made with Voxel-Based Morphometry (VBM) and regions showing density changes in the brain and cerebellum were determined. Gray matter (GM), white matter, cerebrospinal fluid and total intracranial volume were calculated.ResultsNeurological symptoms developed in 80% of COVID-19 patients. In post-COVID-19 patients, a decrease in GM density was detected in pons, gyrus frontalis inferior, gyri orbitales, gyrus rectus, gyrus cinguli, lobus parietalis, gyrus supramarginalis, gyrus angularis, hippocampus, lobulus semilunaris superior of cerebellum, declive, and Brodmann area 7-11-39-40. There was a significant decrease in GM density in these regions and an increase in GM density in amygdala (pConclusionsAs a result, it was seen that COVID-19 negatively affected many structures related to the nervous system. This study is a pioneering study to determine the consequences of COVID-19, especially in the nervous system, and to determine the etiology of these possible problems (Tab. 4, Fig. 5, Ref. 25). Text in PDF www.elis.sk Keywords: COVID-19, pandemic, Voxel-based morphometry (VBM), brain, magnetic resonance imaging (MRI).

2668

N586

Perez Giraldo, Gina S.; Ali, Sareen T.; Kang, Anthony K.; Patel, Tulsi R.; Budhiraja, Shreya; Gaelen, Jordan I.; Lank, Grace K.; Clark, Jeffrey R.; Mukherjee, Shreya; Singer, Tracey; Venkatesh, Aditi; Orban, Zachary S.; Lim, Patrick H.; Jimenez, Millenia; Miller, Janet; Taylor, Carolyn; Szymanski, April L; Scarpelli, Jessica; Graham, Edith L.; Balabanov, Roumen D.; Barcelo, Bianca E.; Cahan, Joshua G.; Ruckman, Kaitlyn; Shepard, Alan G.; Slutzky, Marc W.; LaFaver, Kathrin; Kumthekar, Priya U.; Shetty, Neil K.; Carroll, Katherine S.; Ho, Sam U.; Lukas, Rimas V.; Batra, Ayush; Liotta, Eric M.; Koralnik, Igor J.

Neurologic manifestations of long COVID differ based on acute COVID-19 severity

https://doi.org/10.1002/ana.26649

Published

Study

https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.26649

Objective To characterize neurologic manifestations in post-hospitalization Neuro-PASC (PNP) and non-hospitalized Neuro-PASC (NNP) patients. Methods Prospective study of the first 100 consecutive PNP and 500 NNP patients evaluated at a Neuro-COVID-19 clinic between 5/2020 and 8/2021. Results PNP were older than NNP patients (mean 53.9 vs 44.9 y; p < 0.0001) with a higher prevalence of pre-existing comorbidities. An average 6.8 months from onset, the main neurologic symptoms were “brain fog” (81.2%), headache (70.3%), and dizziness (49.5%) with only anosmia, dysgeusia and myalgias being more frequent in the NNP compared to the PNP group (59 vs 39%, 57.6 vs 39% and 50.4 vs 33%, all p < 0.003). Moreover, 85.8% of patients experienced fatigue. PNP more frequently had an abnormal neurologic exam than NNP patients (62.2 vs 37%, p < 0.0001). Both groups had impaired quality of life in cognitive, fatigue, sleep, anxiety, and depression domains. PNP patients performed worse on processing speed, attention, and working memory tasks than NNP patients (T-score 41.5 vs 55, 42.5 vs 47 and 45.5 vs 49, all p < 0.001) and a US normative population. NNP patients had lower results in attention task only. Subjective impression of cognitive ability correlated with cognitive test results in NNP but not in PNP patients. Interpretation PNP and NNP patients both experience persistent neurologic symptoms affecting their quality of life. However, they harbor significant differences in demographics, comorbidities, neurologic symptoms and findings, as well as pattern of cognitive dysfunction. Such differences suggest distinct etiologies of Neuro-PASC in these populations warranting targeted interventions. This article is protected by copyright. All rights reserved.

2669

N587

Peron, J. P. S.

Direct and indirect impact of SARS-CoV-2 on the brain

https://doi.org/10.1007/s00439-023-02549-x

Published

1-Apr-23

Review

https://doi.org/10.1007/s00439-023-02549-x

Although COVID-19 is mostly a pulmonary disease, it is now well accepted that it can cause a much broader spectrum of signs and symptoms and affect many other organs and tissue. From mild anosmia to severe ischemic stroke, the impact of SARS-CoV-2 on the central nervous system is still a great challenge to scientists and health care practitioners. Besides the acute and severe neurological problems described, as encephalopathies, leptomeningitis, and stroke, after 2 years of pandemic, the chronic impact observed during long-COVID or the post-acute sequelae of COVID-19 (PASC) greatly intrigues scientists worldwide. Strikingly, even asymptomatic, and mild diseased patients may evolve with important neurological and psychiatric symptoms, as confusion, memory loss, cognitive decline, chronic fatigue, associated or not with anxiety and depression. Thus, the knowledge on the correlation between COVID-19 and the central nervous system is of great relevance. In this sense, here we discuss some important mechanisms obtained from in vitro and in vivo investigation regarding how SARS-CoV-2 impacts the brain and its cells and function.

2670

N588

Besteher, Bianca; Kantola, Jussi; Li, Meng; Bernal, Jose; Machnik, Marlene; Reuken, Philipp; Finke, Kathrin; Opel, Nils; Kiviniemi, Vesa; Mattern, Hendrik; Walter, Martin

From inflammation to degeneration – Enlarged perivascular spaces and glymphatic clearance in neuropsychiatric long-COVID syndrome

https://doi.org/10.1016/j.jadr.2023.100522

Published

1-Apr-23

Study

https://www.sciencedirect.com/science/article/pii/S2666915323000616

Neuropsychiatric symptoms, such as executive dysfunction, fatigue and depression, are highly prevalent and severely incapacitating among Long- and Post-COVID patients (Schou et al., 2021), to the point where some are unable to resume their jobs and even their daily lives. While the prognosis of these patients remains elusive, cognition worsens over time in many of them (Lu et al., 2020). Perivascular inflammation in the brain, as a consequence of the blood-brain barrier damage caused by SARS-CoV-2 (Yang et al., 2020), is one of the mechanisms of ongoing systemic and intracerebral inflammation proposed to contribute to these long-lasting symptoms. We thus investigated two surrogate measurements of glymphatics, enlarged perivascular spaces in T1-w magnetic resonance imaging and three-dimensional propagation of cardiorespiratory pulsations in ultrafast magnetic resonance encephalography (Barghoorn et al., 2021), in 60 neuropsychiatric long-COVID patients, 30 healthy COVID-19 survivors and 30 never-infected healthy controls. We provide evidence of EPVS burden being associated with cognitive impairment and cardiorespiratory pulsations slightly varying among these groups. We hypothesize glymphatic clearance dysfunction might be a way for post-COVID to transition into a neurodegenerative disorder.

2671

N589

Stefano, George B.; Büttiker, Pascal; Weissenberger, Simon; Anders, Martin; Raboch, Jiri; Ptacek, Radek; Kream, Richard M.

Potential Prion Involvement in Long COVID-19 Neuropathology, Including Behavior

https://doi.org/10.1007/s10571-023-01342-8

Published

28-Mar-23

Review

https://doi.org/10.1007/s10571-023-01342-8

Prion’ is a term used to describe a protein infectious particle responsible for several neurodegenerative diseases in mammals, e.g., Creutzfeldt-Jakob disease. The novelty is that it is protein based infectious agent not involving a nucleic acid genome as found in viruses and bacteria. Prion disorders exhibit, in part, incubation periods, neuronal loss, and induce abnormal folding of specific normal cellular proteins due to enhancing reactive oxygen species associated with mitochondria energy metabolism. These agents may also induce memory, personality and movement abnormalities as well as depression, confusion and disorientation. Interestingly, some of these behavioral changes also occur in COVID-19 and mechanistically include mitochondrial damage caused by SARS-CoV-2 and subsequenct production of reactive oxygen species. Taken together, we surmise, in part, long COVID may involve the induction of spontaneous prion emergence, especially in individuals susceptible to its origin may thus explain some of its manesfestions post-acute viral infection.

2672

N590

Hammarström, Per; Nyström, Sofie

Viruses and amyloids - a vicious liaison

https://doi.org/10.1080/19336896.2023.2194212

Published

31-Dec-23

Article

https://doi.org/10.1080/19336896.2023.2194212

The crosstalk between viral infections, amyloid formation and neurodegeneration has been discussed with varying intensity since the last century. Several viral proteins are known to be amyloidogenic. Post-acute sequalae (PAS) of viral infections is known for several viruses. SARS-CoV-2 and COVID-19 implicate connections between amyloid formation and severe outcomes in the acute infection, PAS and neurodegenerative diseases. Is the amyloid connection causation or just correlation? In this review we highlight several aspects where amyloids and viruses meet. The evolutionary driving forces that dictate protein amyloid formation propensity are different for viruses compared to prokaryotes and eukaryotes, while posttranslational endoproteolysis appears to be a common mechanism leading up to amyloid formation for both viral and human proteins. Not only do human and viral proteins form amyloid irrespective of each other but there are also several examples of co-operativity between amyloids, viruses and the inter-, and intra-host spread of the respective entity. Abnormal blood clotting in severe and long COVID and as a side effect in some vaccine recipients has been connected to amyloid formation of both the human fibrin and the viral Spike-protein. We conclude that there are many intersects between viruses and amyloids and, consequently, amyloid and virus research need to join forces here. We emphasize the need to accelerate development and implementation in clinical practice of antiviral drugs to preclude PAS and downstream neurological damage. There is also an ample need for retake on suitable antigen targets for the further development of next generation of vaccines against the current and coming pandemics.

2673

N591

Hugon J, Farid K, Queneau M, Vrillon A, Msika EF, Fayel A, Ortiz MS, Indart S, Paquet C

Long COVID: Cognitive and FDG PET evolutions in six patients

https://doi.org/10.21203/rs.3.rs-2703691/v1

Published

3-Apr-23

Study

https://europepmc.org/article/PPR/PPR639891

Long COVID is often characterized by cognitive complaints and deficits occurring immediately or several weeks after the infectious disease. Neuropsychological tests can revealed attention and executive function anomalies and FDG PET can display hypometabolic areas affecting various regions inc...

2674

N592

Otani, Kyohei; Fukushima, Haruko; Matsuishi, Kunitaka

COVID-19 delirium and encephalopathy: Pathophysiology assumed in the first 3 years of the ongoing pandemic

https://doi.org/10.1016/j.dscb.2023.100074

Published

1-Jun-23

Review

https://www.sciencedirect.com/science/article/pii/S2666459323000112

Highlights
•Among COVID-19 patients, delirium and encephalopathy have been observed.
•Cytokine storms and CNS damage result from viral induced hyperinflammation.
•BBB failure and elevated microglia activation may be signs of COVID encephalopathy.
•COVID-19 can result in cognitive impairment, starting with delirium.
Abstract
Background
The coronavirus disease (COVID-19) continues to spread worldwide. It has a high rate of delirium, even in young patients without comorbidities. Infected patients required isolation because of the high infectivity and virulence of COVID-19. The high prevalence of delirium in COVID-19 primarily results from encephalopathy and neuroinflammation caused by acute respiratory distress syndrome (ARDS)-associated cytokine storm. Acute respiratory distress syndrome has been linked to delirium and psychotic symptoms in the subacute phase (4 to 12 weeks), termed post-acute COVID-19 syndrome (PACS), and to brain fog, cognitive dysfunction, and fatigue, termed “long COVID,” which persists beyond 12 weeks. However, no review article that mentions “COVID-19 delirium” have never been reported.

Basic Procedures
This narrative review summarizes data on delirium associated with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and related neurological symptoms of persistent post-infection illness (PACS or long COVID) after persistence of cognitive dysfunction. Thus, we describe the pathophysiological hypothesis of COVID-19 delirium and its continuation as long COVID. This review also describes the treatment of delirium complicated by COVID-19 pneumonia.

Main Findings
SARS-CoV-2 infection is associated with encephalopathy and delirium. An association between COVID-19 infection and Alzheimer's disease has been suggested, and studies are being conducted from multiple facets including genetics, cytology, and postmortem study.

Principal Conclusions
This review suggests that COVID-19 has important short and long-term neuropsychiatric effects. Several hypotheses have been proposed that highlight potential neurobiological mechanisms as causal factors, including neuronal-inflammatory pathways by cytokine storm and cellular senescence, and chronic inflammation.

2675

N593

Fontes-Dantas, Fabricia L.; Fernandes, Gabriel G.; Gutman, Elisa G.; Lima, Emanuelle V. De; Antonio, Leticia S.; Hammerle, Mariana B.; Mota-Araujo, Hannah P.; Colodeti, Lilian C.; Araújo, Suzana M. B.; Froz, Gabrielle M.; Silva, Talita N. da; Duarte, Larissa A.; Salvio, Andreza L.; Pires, Karina L.; Leon, Luciane A. A.; Vasconcelos, Claudia Cristina F.; Romão, Luciana; Savio, Luiz Eduardo B.; Silva, Jerson L.; Costa, Robson da; Clarke, Julia R.; Poian, Andrea T. Da; Alves-Leon, Soniza V.; Passos, Giselle F.; Figueiredo, Claudia P.

SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in mice

https://doi.org/10.1016/j.celrep.2023.112189

Published

28-Mar-23

Study

https://www.cell.com/cell-reports/abstract/S2211-1247(23)00200-0

Highlights
•Spike protein infusion into mouse brain induces late cognitive dysfunction
•Spike protein induces late hippocampal microgliosis and synapse loss
•Blockage of TLR4 renders mice resistant to Spike-induced cognitive dysfunction
•TLR4-2604G>A GG genotype was related to poor cognitive outcome in COVID-19 patients
Summary
Cognitive dysfunction is often reported in patients with post-coronavirus disease 2019 (COVID-19) syndrome, but its underlying mechanisms are not completely understood. Evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein or its fragments are released from cells during infection, reaching different tissues, including the CNS, irrespective of the presence of the viral RNA. Here, we demonstrate that brain infusion of Spike protein in mice has a late impact on cognitive function, recapitulating post-COVID-19 syndrome. We also show that neuroinflammation and hippocampal microgliosis mediate Spike-induced memory dysfunction via complement-dependent engulfment of synapses. Genetic or pharmacological blockage of Toll-like receptor 4 (TLR4) signaling protects animals against synapse elimination and memory dysfunction induced by Spike brain infusion. Accordingly, in a cohort of 86 patients who recovered from mild COVID-19, the genotype GG TLR4-2604G>A (rs10759931) is associated with poor cognitive outcome. These results identify TLR4 as a key target to investigate the long-term cognitive dysfunction after COVID-19 infection in humans and rodents.
publisher: Elsevier
PMID: 36857178

2676

N594

Li, Carol; Verduzco-Gutierrez, Monica

Neurological and Neuromuscular Sequelae of COVID-19

https://doi.org/10.1016/j.pmr.2023.04.002

Published

6-Apr-23

Review

https://www.pmr.theclinics.com/article/S1047-9651(23)00025-6/fulltext

Key Points:
•Exact pathophysiology for neurotropic features of SARS-CoV-2 is still unclear; direct neuroinvasion is becoming less probable, but more theories involving cytokine storm and activation of pro-inflammatory cascade leading to endothelial and blood-brain-barrier disruption are more likely.
•Older patients with vascular comorbidities such as cardiovascular disease and diabetes are at a higher risk of cerebral microangiopathy, thromboembolism and subsequent brain atrophy.
•Generalized muscle weakness, muscle injury and myalgias are the most common neurological and neuromuscular sequelae; second most common symptom is headache.
•Encephalopathy, cerebrovascular disease, Guillain Barre syndrome, critical illness myopathy are generally associated with higher mortality and poorer prognosis; depending on severity and medical stability, early rehabilitation intervention may be key to recovery though long term sequelae may still be possible.
•Pharmacologic options for specific neurological symptoms may be limited to supportive management and dependent on existing guidelines for respective diagnoses, though novel interventions and related research are underway.
publisher: Elsevier

2677

N595

Sarkar, Sibani; Karmakar, Subhajit; Basu, Malini; Ghosh, Pratyasha; Ghosh, Mrinal K

Neurological damages in COVID-19 patients: Mechanisms and preventive interventions

https://doi.org/10.1002/mco2.247

Published

6-Apr-23

Review

https://onlinelibrary.wiley.com/doi/abs/10.1002/mco2.247

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, causes coronavirus disease 2019 (COVID-19) which led to neurological damage and increased mortality worldwide in its second and third waves. It is associated with systemic inflammation, myocardial infarction, neurological illness including ischemic strokes (e.g., cardiac and cerebral ischemia), and even death through multi-organ failure. At the early stage, the virus infects the lung epithelial cells and is slowly transmitted to the other organs including the gastrointestinal tract, blood vessels, kidneys, heart, and brain. The neurological effect of the virus is mainly due to hypoxia-driven reactive oxygen species (ROS) and generated cytokine storm. Internalization of SARS-CoV-2 triggers ROS production and modulation of the immunological cascade which ultimately initiates the hypercoagulable state and vascular thrombosis. Suppression of immunological machinery and inhibition of ROS play an important role in neurological disturbances. So, COVID-19 associated damage to the central nervous system, patients need special care to prevent multi-organ failure at later stages of disease progression. Here in this review, we are selectively discussing these issues and possible antioxidant-based prevention therapies for COVID-19-associated neurological damage that leads to multi-organ failure.

2678

N596

Martins-de-Souza, Daniel

1. Morphological, Cellular, and Molecular Basis of Brain Infection in COVID-19 Patients and Its Association to Psychiatric Symptoms

https://doi.org/10.1016/j.biopsych.2023.02.184

Published

1-May-23

Study

https://www.biologicalpsychiatryjournal.com/article/S0006-3223(23)00258-5/fulltext

Background
Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of “long COVID-19” syndrome) has been frequently observed after mild infection.
Methods
We performed a broad translational investigation, employing brain imaging and cognitive tests in 81 living COVID-19 patients (mildly infected individuals) as well as flow cytometry, respirometry, microscopy, proteomics, and metabolomics in postmortem brain samples, and in preclinical in vitro and ex vivo models.
Results
We observed orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms in living individuals. Postmortem brain tissue from 26 individuals who died of COVID-19 revealed histopathological signs of brain damage. Five individuals out of the 26 exhibited foci of SARS- CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell–derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a non-canonical mechanism that involves spike–NRP1 interaction. SARS-CoV-2–infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that significantly reduces neuronal viability.
Conclusions
Our data support the model in which COVID-19 alter cortical thickness, promoting psychiatric symptoms. In addition, SARS-CoV-2 is able to reach the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.
publisher: Elsevier

2679

N597

Rousseau, Beth A.; Bhaduri-McIntosh, Sumita

Inflammation and Epstein–Barr Virus at the Crossroads of Multiple Sclerosis and Post-Acute Sequelae of COVID-19 Infection

https://doi.org/10.3390/v15040949

Published

1-Apr-23

Review

https://www.mdpi.com/1999-4915/15/4/949

Recent studies have strengthened the evidence for Epstein–Barr Virus (EBV) as an important contributing factor in the development of multiple sclerosis (MS). Chronic inflammation is a key feature of MS. EBV+ B cells can express cytokines and exosomes that promote inflammation, and EBV is known to be reactivated through the upregulation of cellular inflammasomes. Inflammation is a possible cause of the breakdown of the blood–brain barrier (BBB), which allows the infiltration of lymphocytes into the central nervous system. Once resident, EBV+ or EBV-specific B cells could both plausibly exacerbate MS plaques through continued inflammatory processes, EBV reactivation, T cell exhaustion, and/or molecular mimicry. Another virus, SARS-CoV-2, the cause of COVID-19, is known to elicit a strong inflammatory response in infected and immune cells. COVID-19 is also associated with EBV reactivation, particularly in severely ill patients. Following viral clearance, continued inflammation may be a contributor to post-acute sequelae of COVID-19 infection (PASC). Evidence of aberrant cytokine activation in patients with PASC supports this hypothesis. If unaddressed, long-term inflammation could put patients at risk for reactivation of EBV. Determining mechanisms by which viruses can cause inflammation and finding treatments for reducing that inflammation may help reduce the disease burden for patients suffering from PASC, MS, and EBV diseases.

2680

N598

Ajčević, Miloš; Iscra, Katerina; Furlanis, Giovanni; Michelutti, Marco; Miladinović, Aleksandar; Buoite Stella, Alex; Ukmar, Maja; Cova, Maria Assunta; Accardo, Agostino; Manganotti, Paolo

Cerebral hypoperfusion in post-COVID-19 cognitively impaired subjects revealed by arterial spin labeling MRI

https://doi.org/10.1038/s41598-023-32275-3

Published

10-Apr-23

Study

https://www.nature.com/articles/s41598-023-32275-3

Cognitive impairment is one of the most prevalent symptoms of post Severe Acute Respiratory Syndrome COronaVirus 2 (SARS-CoV-2) state, which is known as Long COVID. Advanced neuroimaging techniques may contribute to a better understanding of the pathophysiological brain changes and the underlying mechanisms in post-COVID-19 subjects. We aimed at investigating regional cerebral perfusion alterations in post-COVID-19 subjects who reported a subjective cognitive impairment after a mild SARS-CoV-2 infection, using a non-invasive Arterial Spin Labeling (ASL) MRI technique and analysis. Using MRI-ASL image processing, we investigated the brain perfusion alterations in 24 patients (53.0 ± 14.5 years, 15F/9M) with persistent cognitive complaints in the post COVID-19 period. Voxelwise and region-of-interest analyses were performed to identify statistically significant differences in cerebral blood flow (CBF) maps between post-COVID-19 patients, and age and sex matched healthy controls (54.8 ± 9.1 years, 13F/9M). The results showed a significant hypoperfusion in a widespread cerebral network in the post-COVID-19 group, predominantly affecting the frontal cortex, as well as the parietal and temporal cortex, as identified by a non-parametric permutation testing (p < 0.05, FWE-corrected with TFCE). The hypoperfusion areas identified in the right hemisphere regions were more extensive. These findings support the hypothesis of a large network dysfunction in post-COVID subjects with cognitive complaints. The non-invasive nature of the ASL-MRI method may play an important role in the monitoring and prognosis of post-COVID-19 subjects.

2681

N599

Mehraeen, Esmaeil; Afzalian, Arian; Afsahi, Amir Masoud; Shahidi, Ramin; Fakhfouri, Amirata; Karimi, Kiana; Varshochi, Sanaz; Habibi, Mohammad Amin; Molla, Ayoob; Dadjou, Ali; Tajabadi, Zohreh; Nasiri, Khadijeh; Seyed Alinaghi, Seyed Ahmad; Hackett, Daniel

Hearing loss and COVID-19: an umbrella review

https://doi.org/10.1007/s00405-023-07982-2

Published

24-Apr-23

Review

https://doi.org/10.1007/s00405-023-07982-2

Introduction
COVID-19 can result in an extensive range of extrapulmonary, and neurological signs and symptoms such as olfactory and/or taste dysfunction, and otologic symptoms. The aim of this study was to investigate the hearing loss manifestation from COVID-19.

Methods
The goal of this umbrella review was to examine hearing loss associated with COVID-19 disease. English literature published until October 15, 2022 in online databases including PubMed, Scopus, Web of Science, and Embase was considered for this purpose. Eligibility of the articles for subsequent data extraction was evaluated in a two-step selection process with consideration to an inclusion/exclusion criterion. This review followed the PRISMA protocol and the Amstar-2 checklist for quality assessment.

Results
A total of four treatment strategies were used by different studies which included oral corticosteroids, intratympanic corticosteroids, combined oral and intratympanic corticosteroids, and hyperbaric oxygen therapy. Five studies investigated corticosteroid use in the forms of oral or intratympanic injection; four studies reported (complete or partial) hearing improvements after steroid treatment, while one study stated no significant improvement in hearing function. One study reported that oral corticosteroid monotherapy alone was not effective, while vestibular symptoms were ameliorated by a combination of oral prednisone, intratympanic dexamethasone injection, and hydroxychloroquine.

Conclusion
The findings suggest that despite being one of the rare complications of COVID-19, hearing loss can impact a patient's quality of life. The most common type reported was sensorineural hearing loss, which can be diagnosed with variable techniques.

2682

N600

Tana, Claudio; Giamberardino, Maria Adele; Martelletti, Paolo

Long COVID and especially headache syndromes

https://doi.org/10.1097/wco.0000000000001153

Published

1-Jun-23

Review

https://doi.org/10.1097/WCO.0000000000001153

Purpose of review
This is an expert overview on recent literature about the complex relationship between coronavirus disease 2019 (COVID-19) and headache.
Recent findings
Long COVID is a clinical syndrome characterized by the presence of persistent symptoms following the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Headache is one of the most common symptoms and is described most often as throbbing pain, associated with photo and phonofobia and worsening with physical exercise. In acute COVID-19, headache is usually described as moderate or severe, diffuse and oppressive although sometimes it has been described with a migraine-like phenotype, especially in patients with a previous history of migraine. Headache intensity during acute phase seems to be the most important predictor of duration of headache over time. Some COVID-19 cases can be associated with cerebrovascular complications, and red flags of secondary headaches (e.g. new worsening or unresponsive headache, or new onset of neurological focal signs) should be urgently investigated with imaging. Treatment goals are the reduction of number and intensity of headache crises, and the prevention of chronic forms.
Summary
This review can help clinicians to approach patients with headache and infection from SARS-CoV-2, with particular attention to persistent headache in long COVID.

2683

N601

Nouraeinejad, Ali

Memory loss in patients with long COVID can be due to reduced hippocampal neurogenesis

https://doi.org/10.1007/s00406-023-01610-0

Published

18-Apr-23

Article

https://doi.org/10.1007/s00406-023-01610-0

The post-coronavirus disease 2019 (COVID-19) condition, commonly known as “long COVID,” is defined by the World Health Organization (WHO) as the continuation or development of new symptoms 3 months after the initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, with these symptoms lasting for at least 2 months with no other explanation [1, 2].

Studies have widely clarified that “long COVID” after discharge from hospital include a mixture of neuropsychiatric complaints, such as defective instant verbal memory and learning, deferred verbal memory difficulties, verbal fluency problems, working memory issues, anxiety, depression, and post-traumatic stress disorder (PTSD) [1, 2]. These complaints can persist for at least 1 year [2]. In some COVID-19 patients, cognitive impairments can even deteriorate over time [2]. Although several pathological mechanisms have been proposed by the author [1], the pathological basis of these symptoms remains unknown.

The hippocampus has imperative functions in spatial and episodic memory [3] as well as learning [4]. In addition, the hippocampus plays an accompanying imperative role in neurogenesis [5] by self-reproducing multipotent adult neural stem cells (NSCs) located in the subgranular zone (SGZ) of the dentate gyrus (DG) [5, 6]. However, the hippocampus, as a vulnerable configuration, can be upset by various neurological and psychiatric disorders [4]. Since the hippocampus is predominantly susceptible to injuries caused by COVID-19 [1], there is increasing evidence indicating the possibility of post-infection memory loss [2, 7].

To explore the etiology of post-infection memory loss in “long COVID,” the role of activated microglial cells has already been highlighted by the author [1, 2]. In this regard, COVID-19 can activate microglia in the hippocampus and induce a central nervous system (CNS) cytokine storm, leading to loss of hippocampal neurogenesis [1, 2]. The activation of microglia in the hippocampus of deceased patients with “long COVID” and cognitive impairments as well as mild COVID-19 animal model was shown to be due to elevated levels of C–C motif chemokine ligand 11 (CCL11), leading to inhibited neurogenesis [8]. Activated pro-inflammatory microglia through inflammatory mediators, such as tumor necrosis factor alpha (TNF-α), interleukin-1 alpha (IL-1α), complement component 1q, and IL-1β, can then activate pro-inflammatory astrocytes and fuel a secondary inflammatory response [1, 2]. Consequently, this disturbs hippocampal neuronal cells, leading to memory difficulties and neuronal apoptosis. These pathological pathways can explain the potential damaging consequences of SARS-CoV-2-linked glial activation, neuroinflammation, and apoptosis [1, 2]. This can eventually disturb hippocampal neuronal cells, leading to memory difficulties and neuronal apoptosis [1, 2].

Therefore, the reduced neurogenesis, which was shown in the COVID-19 group [9], could be due to microglial activation and the subsequent production of inflammatory cytokines, such as TNF-α, IL-6, and IL-1β, causing neuroinflammation and the resultant impaired neurogenesis [1, 2, 9]. This eventually results in cognitive decline due to the destruction of spatial memory and learning [1, 2, 9]. These implications on the hippocampus, especially the loss of hippocampal neurogenesis in the brains of COVID-19 patients, elucidate learning, memory, and executive impairments in COVID-19 patients compared with uninfected healthy controls [10].

As a result, memory loss in patients with “long COVID” can be due to reduced hippocampal neurogenesis. This negative consequence is mediated by inflammatory mediators secreted by activated microglia in the hippocampus, which can induce a cytokine storm in the CNS. This highlights the specific susceptibility of the hippocampus to neuroinflammation. A better perspective of the cellular features of COVID-19 brain injury could assist in interventions to ease long-term neuropsychiatric complaints. In addition, the neuropathology of COVID-19 may provide a replica for decoding the neurodegenerative mechanisms related to neuroinflammation in other brain diseases and for developing new therapeutic strategies.

2684

N602

Herrera, Elena; Pérez-Sánchez, María del Carmen; San Miguel-Abella, Romina; Barrenechea, Arrate; Blanco, Claudia; Solares, Lucía; González, Lucía; Iza, Clara; Castro, Isabel; Nicolás, Elena; Sierra, Damián; Suárez, Paula; González-Nosti, María

Cognitive impairment in young adults with post COVID-19 syndrome

https://doi.org/10.1038/s41598-023-32939-0

Published

19-Apr-23

Study

https://www.nature.com/articles/s41598-023-32939-0

In this study, we aimed to examine different cognitive domains in a large sample of patients with post COVID-19 syndrome. Two hundred and fourteen patients, 85.04% women, ranged 26 to 64 years (mean = 47.48 years) took part in this investigation. Patients’ processing speed, attention, executive functions and various language modalities were examined online using a comprehensive task protocol designed for this research. Alteration in some of the tasks was observed in 85% of the participants, being the attention and executive functions tests the ones that show the highest percentage of patients with severe impairment. Positive correlations were observed between the age of the participants in almost all the tasks assessed, implying better performance and milder impairment with increasing age. In the comparisons of patients according to age, the oldest patients were found to maintain their cognitive functions relatively preserved, with only a mild impairment in attention and speed processing, while the youngest showed the most marked and heterogeneous cognitive impairment. These results confirm the subjective complaints in patients with post COVID-19 syndrome and, thanks to the large sample size, allow us to observe the effect of patient age on performance, an effect never reported before in patients with these characteristics.

2685

N603

Deters, Justin R.; Fietsam, Alexandra C.; Gander, Phillip E.; Boles Ponto, Laura L.; Rudroff, Thorsten

Effect of Post-COVID-19 on Brain Volume and Glucose Metabolism: Influence of Time Since Infection and Fatigue Status

https://doi.org/10.3390/brainsci13040675

Published

1-Apr-23

Study

https://www.mdpi.com/2076-3425/13/4/675

Post-COVID-19 syndrome (PCS) fatigue is typically most severe <6 months post-infection. Combining magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging with the glucose analog [18F]-Fluorodeoxyglucose (FDG) provides a comprehensive overview of the effects of PCS on regional brain volumes and metabolism, respectively. The primary purpose of this exploratory study was to investigate differences in MRI/PET outcomes between people < 6 months (N = 18, 11 female) and > 6 months (N = 15, 6 female) after COVID-19. The secondary purpose was to assess if any differences in MRI/PET outcomes were associated with fatigue symptoms. Subjects > 6 months showed smaller volumes in the putamen, pallidum, and thalamus compared to subjects < 6 months. In subjects > 6 months, fatigued subjects had smaller volumes in frontal areas compared to non-fatigued subjects. Moreover, worse fatigue was associated with smaller volumes in several frontal areas in subjects > 6 months. The results revealed no brain metabolism differences between subjects > 6 and < 6 months. However, both groups exhibited both regional hypo- and hypermetabolism compared to a normative database. These results suggest that PCS may alter regional brain volumes but not metabolism in people > 6 months, particularly those experiencing fatigue symptoms.

2686

N604

Alabsi, Haitham; Emerson, Kristi; Lin, David J.

Neurorecovery after Critical COVID-19 Illness

https://doi.org/10.1055/s-0043-1768714

Published

11-May-23

Review

http://www.thieme-connect.de/DOI/DOI?10.1055/s-0043-1768714

With the hundreds of millions of people worldwide who have been, and continue to be, affected by pandemic coronavirus disease (COVID-19) and its chronic sequelae, strategies to improve recovery and rehabilitation from COVID-19 are critical global public health priorities. Neurologic complications have been associated with acute COVID-19 infection, usually in the setting of critical COVID-19 illness. Neurologic complications are also a core feature of the symptom constellation of long COVID and portend poor outcomes. In this article, we review neurologic complications and their mechanisms in critical COVID-19 illness and long COVID. We focus on parallels with neurologic disease associated with non-COVID critical systemic illness. We conclude with a discussion of how recent findings can guide both neurologists working in post-acute neurologic rehabilitation facilities and policy makers who influence neurologic resource allocation.

2687

N605

El-Agnaf, Omar; Bensmail, Ilham; Al-Nesf, Maryam A. Y.; Flynn, James; Taylor, Mark; Majbour, Nour K.; Abdi, Ilham Y.; Vaikath, Nishant N.; Farooq, Abdulaziz; Vemulapalli, Praveen B.; Schmidt, Frank; Ouararhni, Khalid; Al-Siddiqi, Heba H.; Arredouani, Abdelilah; Wijten, Patrick; Al-Maadheed, Mohammed; Mohamed-Ali, Vidya; Decock, Julie; Abdesselem, Houari B.

Uncovering a neurological protein signature for severe COVID-19

https://doi.org/10.1016/j.nbd.2023.106147

Published

15-Jun-23

Study

https://www.sciencedirect.com/science/article/pii/S0969996123001614

Highlights
•Neurological protein signature of severe COVID-19.
•Validation of Qatar severe COVID-19 neurological protein signature in independent cohorts at protein and RNA levels.
•Neurological proteins signature of severe COVID-19 corelates with Neurological diseases such as Nerve Injury, Parkinson's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, and Schizophrenia.
•Neurological proteins signature of severe COVID-19 corelates with pharmacological drugs such as risperidone.
•The risk of developing chronic neurological diseases in post-severe COVID-19 patients.
Abstract
Coronavirus disease of 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has sparked a global pandemic with severe complications and high morbidity rate. Neurological symptoms in COVID-19 patients, and neurological sequelae post COVID-19 recovery have been extensively reported. Yet, neurological molecular signature and signaling pathways that are affected in the central nervous system (CNS) of COVID-19 severe patients remain still unknown and need to be identified. Plasma samples from 49 severe COVID-19 patients, 50 mild COVID-19 patients, and 40 healthy controls were subjected to Olink proteomics analysis of 184 CNS-enriched proteins. By using a multi-approach bioinformatics analysis, we identified a 34-neurological protein signature for COVID-19 severity and unveiled dysregulated neurological pathways in severe cases. Here, we identified a new neurological protein signature for severe COVID-19 that was validated in different independent cohorts using blood and postmortem brain samples and shown to correlate with neurological diseases and pharmacological drugs. This protein signature could potentially aid the development of prognostic and diagnostic tools for neurological complications in post-COVID-19 convalescent patients with long term neurological sequelae.

2688

N606

Manganotti, Paolo; Michelutti, Marco; Furlanis, Giovanni; Deodato, Manuela; Buoite Stella, Alex

Deficient GABABergic and glutamatergic excitability in the motor cortex of patients with long-COVID and cognitive impairment

https://doi.org/10.1016/j.clinph.2023.04.010

Published

1-Jul-23

Study

https://www.sciencedirect.com/science/article/pii/S1388245723006156

Highlights
•Clinical manifestations of the long COVID syndrome include cognitive impairments, named “brain fog”.
•Previous literature suggest possible mechanisms that might result in altered cortical excitability.
•This study confirms impaired glutamate and GABAb regulatory pathways in long COVID “brain fog”.
Abstract
Objective
Attention, working memory and executive processing have been reported to be consistently impaired in Neuro-Long coronavirus disease (COVID). On the hypothesis of abnormal cortical excitability, we investigated the functional state of inhibitory and excitatory cortical regulatory circuits by single “paired-pulse” transcranial magnetic stimulation (ppTMS) and Short-latency Afferent Inhibition (SAI).

Methods
We compared clinical and neurophysiological data of 18 Long COVID patients complaining of persistent cognitive impairment with 16 Healthy control (HC) subjects. Cognitive status was evaluated by means of the Montreal Cognitive Assessment (MoCA) and a neuropsychological evaluation of the executive function domain; fatigue was scored by the Fatigue Severity Scale (FSS). Resting motor threshold (RMT), the amplitude of the motor evoked potential (MEP), Short Intra-cortical Inhibition (SICI), Intra-cortical Facilitation (ICF), Long-interval Intracortical Inhibition (LICI) and Short-afferent inhibition (SAI) were investigated over the motor (M1) cortex.

Results
MoCA corrected scores were significantly different between the two groups (p = 0.023). The majority of the patients’ performed sub-optimally in the neuropsychological assessment of the executive functions. The majority (77.80%) of the patients reported high levels of perceived fatigue in the FSS. RMT, MEPs, SICI and SAI were not significantly different between the two groups. On the other hand, Long COVID patients showed a reduced amount of inhibition in LICI (p = 0.003) and a significant reduction in ICF (p < 0.001).

Conclusions
Neuro-Long COVID patients performing sub-optimally in the executive functions showed a reduction of LICI related to GABAb inhibition and a reduction of ICF related to glutamatergic regulation. No alteration in cholinergic circuits was found.

2689

N607

Daker, Lamiaa I.; Elshafei, Reham R.; Bahi, Mohammad; Mohammed, Asmaa; Erfan, Randa; Gomaa, Mohammed

Could vertigo be a post-COVID-19 sequela or presenting symptom?

https://doi.org/10.1186/s41983-023-00659-x

Published

11-May-23

Study

https://doi.org/10.1186/s41983-023-00659-x

Background
It has been postulated that COVID-19 has a substantial neuro-otological impact such as vertigo or dizziness that is rarely evaluated. The purpose of this research is to study the occurrence of vertigo (whether as presenting symptom or a sequela) and its etiological characteristics in patients with covid 19 infection and close contact. It is a cross-sectional study (convenient sample) conducted on patients that had a previous history of covid 19 infection and another group of contact individuals who presented with the sensation of vertigo. All the included participants underwent full neurological and otological examination, nasopharyngeal swab PCR to confirm COVID-19 infection and video nystgmograghy (VNG).

Results
it was included 44 participants, where 7 (15.9%) of the participants were post-COVID-19 patients and 37 (84.1%) were close contacts of COVID patients. It was found that 6(85.7%) of post-COVID-19 patients had vestibular neuritis (VN), and 1(14.3%) patient had Benign Paroxysmal Positional Vertigo (BPPV). 9(23%) of those in close contact had positive PCR for COVID infection, 6(66.7%) of them had VN, and the other 3 (33.3%) had BPPV.

Conclusion
Vertigo could be a possible complication or a presenting symptom in patients with COVID patients that is mainly attributed to peripheral vestibular dysfunction.

2690

N608

Mandel, Hannah L; Colleen, Gunnar; Abedian, Sajjad; Ammar, Nariman; Bailey, L Charles; Bennett, Tellen D; Brannock, M Daniel; Brosnahan, Shari B; Chen, Yu; Chute, Christopher G; Divers, Jasmin; Evans, Michael D; Haendel, Melissa; Hall, Margaret A; Hirabayashi, Kathryn; Hornig, Mady; Katz, Stuart D; Krieger, Ana C; Loomba, Johanna; Lorman, Vitaly; Mazzotti, Diego R; McMurry, Julie; Moffitt, Richard A; Pajor, Nathan M; Pfaff, Emily; Radwell, Jeff; Razzaghi, Hanieh; Redline, Susan; Seibert, Elle; Sekar, Anisha; Sharma, Suchetha; Thaweethai, Tanayott; Weiner, Mark G; Yoo, Yun Jae; Zhou, Andrea; Thorpe, Lorna E; on behalf of the RECOVER Consortium

Risk of post-acute sequelae of SARS-CoV-2 infection associated with pre-coronavirus disease obstructive sleep apnea diagnoses: an electronic health record-based analysis from the RECOVER initiative

https://doi.org/10.1093/sleep/zsad126

Published

11-May-23

Study

https://doi.org/10.1093/sleep/zsad126

Statement of Significance
Recent studies have identified a positive association between obstructive sleep apnea (OSA) and acute coronavirus disease-2019 (COVID-19) outcomes, but few studies have examined outcomes beyond acute illness. This is the first large-scale, multi-cohort collaboration to examine the role of preexisting OSA on risk for Post-Acute Sequelae of SARS-CoV-2 (often referred to as Long COVID). Notably, our analysis was conducted across multiple data sources, employed different approaches for identifying COVID-19-positive patients, and used multiple definitions of Long COVID. While we found consistent evidence of elevated risk for Long COVID among adults with preexisting OSA, additional research is needed to elucidate the role of severity, and treatment.
Study Objectives
Obstructive sleep apnea (OSA) has been associated with more severe acute coronavirus disease-2019 (COVID-19) outcomes. We assessed OSA as a potential risk factor for Post-Acute Sequelae of SARS-CoV-2 (PASC).

Methods
We assessed the impact of preexisting OSA on the risk for probable PASC in adults and children using electronic health record data from multiple research networks. Three research networks within the REsearching COVID to Enhance Recovery initiative (PCORnet Adult, PCORnet Pediatric, and the National COVID Cohort Collaborative [N3C]) employed a harmonized analytic approach to examine the risk of probable PASC in COVID-19-positive patients with and without a diagnosis of OSA prior to pandemic onset. Unadjusted odds ratios (ORs) were calculated as well as ORs adjusted for age group, sex, race/ethnicity, hospitalization status, obesity, and preexisting comorbidities.

Results
Across networks, the unadjusted OR for probable PASC associated with a preexisting OSA diagnosis in adults and children ranged from 1.41 to 3.93. Adjusted analyses found an attenuated association that remained significant among adults only. Multiple sensitivity analyses with expanded inclusion criteria and covariates yielded results consistent with the primary analysis.

Conclusions
Adults with preexisting OSA were found to have significantly elevated odds of probable PASC. This finding was consistent across data sources, approaches for identifying COVID-19-positive patients, and definitions of PASC. Patients with OSA may be at elevated risk for PASC after SARS-CoV-2 infection and should be monitored for post-acute sequelae.

2691

N609

Mahali, Madhumita; Coolidge, Frederick L.

On the relationship between neurocognitive measures and olfactory dysfunction in COVID-19 patients with and without anosmia

https://doi.org/10.1016/j.bbih.2023.100632

Published

1-Jul-23

Study

https://www.sciencedirect.com/science/article/pii/S2666354623000467

Highlights
•There was a high degree of neurocognitive dsyfunction associated with olfactory dysfunction in recovered COVID-19 patients.
•Self-reported olfactory dysfunction in recovered COVID-19 patients was invalid.
•Any studies assessing olfactory dysfunction must include objective testing.
Abstract
One of the predominant symptoms of the COVID-19 virus is the complete (anosmia) or partial (hyposmia) loss of smell. Anosmia may be a critical neurocognitive symptom because there is an empirically demonstrated association of anosmia with neurodegenerative diseases like Parkinson's disease, Alzheimer's disease, etc. The present study assessed the neurocognitive disorder patterns in recovered COVID-19 patients who either self-reported anosmia or its absence. Of the 60 adult participants (n = 32 males, n = 28 females; Mage = 20.78 years, range = 18–31 years), 15 reported COVID-19 induced anosmia, 15 reported COVID-19 without anosmia, and 30 reported not having contracted COVID-19. The participants were first administered a 10-item smell test, and analysis of variance revealed significantly better scores for the control group than the other two groups. Further, there was no significant difference in smell scores between the patients who self-reported anosmia or denied it. This statistical pattern was consistent across all neuropsychological tests: short- and long-term verbal memory, digit span, Trail Making, and a self-report 46-item neurocognitive scale. Regardless of the self-report of anosmia or denial, all thirty COVID-19 patients scored significantly poorer than the control group on all of the tests and neurocognitive scale. In summary, the self-report of anosmia appears to be unreliable, and the COVID-19 patients who were found to be anosmic on the initial objective smell test demonstrated poorer neuropsychological performance than controls.

2692

N610

Hassan, Rania Mostafa; Almalki, Yassir Edrees; Basha, Mohammad Abd Alkhalik; Gobran, Mai Ahmed; Alqahtani, Saad Misfer; Assiri, Abdullah M.; Alqahtani, Saeed; Alduraibi, Sharifa Khalid; Aboualkheir, Mervat; Almushayti, Ziyad A.; Aldhilan, Asim S.; Aly, Sameh Abdelaziz; Alshamy, Asmaa A.

Magnetic Resonance Imaging Features of Rhino-Orbito-Cerebral Mucormycosis in Post-COVID-19 Patients: Radio-Pathological Correlation

https://doi.org/10.3390/diagnostics13091546

Published

1-Jan-23

Study

https://www.mdpi.com/2075-4418/13/9/1546

There has been a notable increase in rhino-orbito-cerebral mucormycosis (ROCM) post-coronavirus disease 2019 (COVID-19), which is an invasive fungal infection with a fatal outcome. Magnetic resonance imaging (MRI) is a valuable tool for early diagnosis of ROCM and assists in the proper management of these cases. This study aimed to describe the characteristic MRI findings of ROCM in post-COVID-19 patients to help in the early diagnosis and management of these patients. This retrospective descriptive study was conducted at a single hospital and included 52 patients with COVID-19 and a histopathologically proven ROCM infection who were referred for an MRI of the paranasal sinuses (PNS) due to sino-orbital manifestations. Two radiologists reviewed all the MR images in consensus. The diagnosis was confirmed by histopathological examination. The maxillary sinus was the most commonly affected PNS (96.2%). In most patients (57.7%), multiple sinuses were involved with the black turbinate sign on postcontrast images. Extrasinus was evident in 43 patients with orbital involvement. The pterygopalatine fossa was involved in four patients. Three patients had cavernous sinus extension, two had pachymeningeal enhancement, and one had epidural collection. The alveolar margin was affected in two patients, and five patients had an extension to the cheek. The awareness of radiologists by the characteristic MRI features of ROCM in post-COVID-19 patients helps in early detection, early proper management, and prevention of morbid complications.

2693

N611

Lebrun, Laetitia; Absil, Lara; Remmelink, Myriam; De Mendonça, Ricardo; D’Haene, Nicky; Gaspard, Nicolas; Rusu, Stefan; Racu, Marie-Lucie; Collin, Amandine; Allard, Justine; Zindy, Egor; Schiavo, Andrea Alex; De Clercq, Sarah; De Witte, Olivier; Decaestecker, Christine; Lopes, Maria-Beatriz; Salmon, Isabelle

SARS-Cov-2 infection and neuropathological findings: a report of 18 cases and review of the literature

https://doi.org/10.1186/s40478-023-01566-1

Published

10-May-23

Study

https://doi.org/10.1186/s40478-023-01566-1

Introduction
COVID-19-infected patients harbour neurological symptoms such as stroke and anosmia, leading to the hypothesis that there is direct invasion of the central nervous system (CNS) by SARS-CoV-2. Several studies have reported the neuropathological examination of brain samples from patients who died from COVID-19. However, there is still sparse evidence of virus replication in the human brain, suggesting that neurologic symptoms could be related to mechanisms other than CNS infection by the virus. Our objective was to provide an extensive review of the literature on the neuropathological findings of postmortem brain samples from patients who died from COVID-19 and to report our own experience with 18 postmortem brain samples.

Material and methods
We used microscopic examination, immunohistochemistry (using two different antibodies) and PCR-based techniques to describe the neuropathological findings and the presence of SARS-CoV-2 virus in postmortem brain samples. For comparison, similar techniques (IHC and PCR) were applied to the lung tissue samples for each patient from our cohort. The systematic literature review was conducted from the beginning of the pandemic in 2019 until June 1st, 2022.

Results
In our cohort, the most common neuropathological findings were perivascular haemosiderin-laden macrophages and hypoxic-ischaemic changes in neurons, which were found in all cases (n = 18). Only one brain tissue sample harboured SARS-CoV-2 viral spike and nucleocapsid protein expression, while all brain cases harboured SARS-CoV-2 RNA positivity by PCR. A colocalization immunohistochemistry study revealed that SARS-CoV-2 antigens could be located in brain perivascular macrophages.

The literature review highlighted that the most frequent neuropathological findings were ischaemic and haemorrhagic lesions, including hypoxic/ischaemic alterations. However, few studies have confirmed the presence of SARS-CoV-2 antigens in brain tissue samples.

Conclusion
This study highlighted the lack of specific neuropathological alterations in COVID-19-infected patients. There is still no evidence of neurotropism for SARS-CoV-2 in our cohort or in the literature.

2694

N612

Zhong, Yue; Ji, Qiang; Zhou, Li

Sleep disorders of post-COVID-19 conditions

https://doi.org/10.1007/s11325-023-02848-7

Published

10-May-23

Article

https://doi.org/10.1007/s11325-023-02848-7

Some research has focused on the treatment of PCC sleep disorders, but there are few reports in the literature. Two randomized controlled trials have shown that hyperbaric oxygen therapy (HBOT) may induce neuroplasticity and improve cognitive, mental, fatigue, sleep, and pain symptoms in patients with PCC. The beneficial effects of HBOT may be attributed to altered functional connectivity of neural pathways in areas associated with cognitive and emotional roles [4, 5]. Probiotics have been recommended to regulate the gut microbiome and correct the microbiome-intestine-brain axis to improve neuropsychiatric complications in patients with PCC.

Prior to the COVID-19 epidemic, the worldwide prevalence of sleep disorders was substantial. Given the large global population infected with COVID-19, the prevalence of sleep disorders is very likely to increase. Therefore, it is justifiable to direct more resources to investigate epidemiological factors, pathophysiologic mechanisms, and interventional strategies for sleep disorders associated with PCC.

2695

N613

Dutta, Debashis; Liu, Jianuo; Xiong, Huangui

The Impact of COVID-19 on People Living with HIV-1 and HIV-1-Associated Neurological Complications

https://doi.org/10.3390/v15051117

Published

1-May-23

Review

https://www.mdpi.com/1999-4915/15/5/1117

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative pathogen of the coronavirus disease 2019 (COVID-19) pandemic, a fatal respiratory illness. The associated risk factors for COVID-19 are old age and medical comorbidities. In the current combined antiretroviral therapy (cART) era, a significant portion of people living with HIV-1 (PLWH) with controlled viremia is older and with comorbidities, making these people vulnerable to SARS-CoV-2 infection and COVID-19-associated severe outcomes. Additionally, SARS-CoV-2 is neurotropic and causes neurological complications, resulting in a health burden and an adverse impact on PLWH and exacerbating HIV-1-associated neurocognitive disorder (HAND). The impact of SARS-CoV-2 infection and COVID-19 severity on neuroinflammation, the development of HAND and preexisting HAND is poorly explored. In the present review, we compiled the current knowledge of differences and similarities between SARS-CoV-2 and HIV-1, the conditions of the SARS-CoV-2/COVID-19 and HIV-1/AIDS syndemic and their impact on the central nervous system (CNS). Risk factors of COVID-19 on PLWH and neurological manifestations, inflammatory mechanisms leading to the neurological syndrome, the development of HAND, and its influence on preexisting HAND are also discussed. Finally, we have reviewed the challenges of the present syndemic on the world population, with a particular emphasis on PLWH.

2696

N614

Owens, Cameron D.; Pinto, Camila Bonin; Detwiler, Sam; Mukli, Peter; Peterfi, Anna; Szarvas, Zsofia; Hoffmeister, Jordan R.; Galindo, Juliette; Noori, Jila; Kirkpatrick, Angelia C.; Dasari, Tarun W.; James, Judith; Tarantini, Stefano; Csiszar, Anna; Ungvari, Zoltan; Prodan, Calin I.; Yabluchanskiy, Andriy

Cerebral small vessel disease pathology in COVID-19 patients: A systematic review

https://doi.org/10.1016/j.arr.2023.101962

Published

1-Jul-23

Review

https://www.sciencedirect.com/science/article/pii/S1568163723001216

Highlights
•COVID-19 induced CSVD pathology is differentiated from other known causes.
•CSVD in COVID-19 patients have a predilection for white matter of the cerebrum.
•Microbleeds and ischemic lesions both should be assessed as COVID-19 CSVD markers.
•Cognition is commonly impaired in recovered COVID-19 patients.
•NVC should be assessed as a mechanism for recovered COVID-19 cognitive impairment.
Abstract
Cerebral small vessel disease (CSVD) is the leading cause of vascular cognitive impairment and is associated with COVID-19. However, contributing factors that often accompany CSVD pathology in COVID-19 patients may influence the incidence of cerebrovascular complications. Thus, a mechanism linking COVID-19 and CSVD has yet to be uncovered and differentiated from age-related comorbidities (i.e., hypertension), and medical interventions during acute infection. We aimed to evaluate CSVD in acute and recovered COVID-19 patients and to differentiate COVID-19-related cerebrovascular pathology from the above-mentioned contributing factors by assessing the localization of microbleeds and ischemic lesions/infarctions in the cerebrum, cerebellum, and brainstem. A systematic search was performed in December 2022 on PubMed, Web of Science, and Embase using a pre-established search criterion related to history of, or active COVID-19 with CSVD pathology in adults. From a pool of 161 studies, 59 met eligibility criteria and were included. Microbleeds and ischemic lesions had a strong predilection for the corpus callosum and subcortical/deep white matter in COVID-19 patients, suggesting a distinct CSVD pathology. These findings have important implications for clinical practice and biomedical research as COVID-19 may independently, and through exacerbation of age-related mechanisms, contribute to increased incidence of CSVD.

2697

N615

Zanin, Adrien; Amah, Guy; Chakroun, Sahar; Testard, Pauline; Faucher, Alice; Le, Thi Yen Vy; Slama, Dorsaf; Le Baut, Valérie; Lozeron, Pierre; Salmon, Dominique; Kubis, Nathalie

Parasympathetic autonomic dysfunction is more often evidenced than sympathetic autonomic dysfunction in fluctuating and polymorphic symptoms of

https://doi.org/10.1038/s41598-023-35086-8

Published

22-May-23

Study

https://www.nature.com/articles/s41598-023-35086-8

Several disabling symptoms potentially related to dysautonomia have been reported in “long-COVID” patients. Unfortunately, these symptoms are often nonspecific, and autonomic nervous system explorations are rarely performed in these patients. This study aimed to evaluate prospectively a cohort of long-COVID patients presenting severe disabling and non-relapsing symptoms of potential dysautonomia and to identify sensitive tests. Autonomic function was assessed by clinical examination, the Schirmer test; sudomotor evaluation, orthostatic blood pressure (BP) variation, 24-h ambulatory BP monitoring for sympathetic evaluation, and heart rate variation during orthostatism, deep breathing and Valsalva maneuvers for parasympathetic evaluation. Test results were considered abnormal if they reached the lower thresholds defined in publications and in our department. We also compared mean values for autonomic function tests between patients and age-matched controls. Sixteen patients (median age 37 years [31–43 years], 15 women) were included in this study and referred 14.5 months (median) [12.0–16.5 months] after initial infection. Nine had at least one positive SARS-CoV-2 RT-PCR or serology result. Symptoms after SARS-CoV-2 infection were severe, fluctuating and disabling with effort intolerance. Six patients (37.5%) had one or several abnormal test results, affecting the parasympathetic cardiac function in five of them (31%). Mean Valsalva score was significantly lower in patients than in controls. In this cohort of severely disabled long-COVID patients, 37.5% of them had at least one abnormal test result showing a possible contribution of dysautonomia to these nonspecific symptoms. Interestingly, mean values of the Valsalva test were significantly lower in patients than in control subjects, suggesting that normal values thresholds might not be appropriate in this population.

2698

N616

Nuber-Champier, Anthony; Voruz, Philippe; Cionca, Alexandre; Jacot De Alcântara, Isabele; Anne Péron, Julie; Assal, Frédéric

Covid long : aspects neurologiques

Published

17-May-23

Review

https://www.revmed.ch/revue-medicale-suisse/2023/revue-medicale-suisse-827/covid-long-aspects-neurologiques

The study of post-COVID-19 symptomatology revealed a first wave of post-acute (persistence of symptoms less than 3 months) neurocognitive symptoms. However, some of these symptoms worsened, while others improved. To our knowledge, these symptoms may persist for up to 1 to 2 years after infection. The intensity, variability and persistence of neurocognitive symptoms may rise the hypotheses of accelerated neurodegenerative processes, as well as neuropsychiatric and/or genetic vulnerabilities that are still poorly understood. Moreover, the multi-organ manifestations of post-COVID-19 symptoms remind us of the importance of promoting an interdisciplinary perspective at both clinical and fundamental levels. Finally, many social and economic issues parallel to the neuropathological consequences remain to be investigated.
L’étude de la symptomatologie post-Covid-19 a permis de mettre en évidence une première vague de symptômes neurocognitifs postaigus (persistance des symptômes inférieurs à 3 mois). Certains se sont aggravés, tandis que d’autres se sont améliorés. Ils peuvent perdurer jusqu’à 1 à 2 ans après l’infection. L’intensité, la variabilité et la persistance des symptômes neurocognitifs pourraient suggérer des hypothèses d’accélération de processus neurodégénératifs et des vulnérabilités neuropsychiatriques et/ou génétiques encore mal comprises. De plus, les manifestations multi-organiques des symptômes post-Covid-19 nous rappellent l’importance de promouvoir une perspective multidisciplinaire sur les plans clinique et fondamental. Finalement, de nombreuses questions sociales et économiques parallèles aux conséquences neuropathologiques restent à investiguer.

2699

N617

Malekpour, Mahdi; Khanmohammadi, Shaghayegh; Meybodi, Mohammad Javad Entezari; Shekouh, Dorsa; Rahmanian, Mohammad Reza; Kardeh, Sina; Azarpira, Negar

COVID‐19 as a trigger of Guillain‐Barré syndrome: A review of the molecular mechanism

https://doi.org/10.1002/iid3.875

Published

16-May-23

Review

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10187022/

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) caused a pandemic with serious complications. After coronavirus disease 2019 (COVID‐19), several post‐acute COVID‐19 syndromes (PACSs) and long‐COVID sequels were reported. PACSs involve many organs, including the nervous, gustatory, and immune systems. One of the PACSs after SARS‐CoV‐2 infection and vaccination is Guillain‐Barré syndrome (GBS). The incidence rate of GBS after SARS‐CoV‐2 infection or vaccination is low. However, the high prevalence of COVID‐19 and severe complications of GBS, for example, autonomic dysfunction and respiratory failure, highlight the importance of post‐COVID‐19 GBS. It is while patients with simultaneous COVID‐19 and GBS seem to have higher admission rates to the intensive care unit, and demyelination is more aggressive in post‐COVID‐19 GBS patients. SARS‐CoV‐2 can trigger GBS via several pathways like direct neurotropism and neurovirulence, microvascular dysfunction and oxidative stress, immune system disruption, molecular mimicry, and autoantibody production. Although there are few molecular studies on the molecular and cellular mechanisms of GBS occurrence after SARS‐CoV‐2 infection and vaccination, we aimed to discuss the possible pathomechanism of post‐COVID‐19 GBS by gathering the most recent molecular evidence., Due to the importance of Guillain−Barre syndrome as a long‐COVID disease, this review performs information about the molecular mechanism of post‐acute severe acute respiratory syndrome coronavirus 2.

2700

N618

Chatton, Pauline; Martins, Marta; Carlier, Sabrina; Bieler-Aeschlimann, Mélanie

[Long COVID : which neuropsychological intervention ? The example applied at the Leenaards Memory Centre]

https://doi.org/10.53738/REVMED.2023.19.827.979

Published

17-May-23

Article

https://pubmed.ncbi.nlm.nih.gov/37195114/

A "Long COVID" care management was created at the Leenaards Memory Centre (Lausanne University Hospital) to meet the high demand for neuropsychological examinations in the patients which have persistent symptoms for several months. A multidisciplinary evaluation specifically addressing aspects of fatigue and sleep as well as cognition has been developed to receive these patients. Depending on the severity of their symptoms, they are then oriented towards a holistic group treatment, integrating cognitive remediation including psycho-education, restorative and compensatory methods to cope with their cognitive difficulties, and tools to manage the various symptoms of COVID-long (fatigue, insomnia, stress, depression and reduced quality of life).

2701

N619

Braga, Joeffre; Lepra, Mariel; Kish, Stephen J.; Rusjan, Pablo. M.; Nasser, Zahra; Verhoeff, Natasha; Vasdev, Neil; Bagby, Michael; Boileau, Isabelle; Husain, M. Ishrat; Kolla, Nathan; Garcia, Armando; Chao, Thomas; Mizrahi, Romina; Faiz, Khunsa; Vieira, Erica L.; Meyer, Jeffrey H.

Neuroinflammation After COVID-19 With Persistent Depressive and Cognitive Symptoms

https://doi.org/10.1001/jamapsychiatry.2023.1321

Published

31-May-23

Study

https://doi.org/10.1001/jamapsychiatry.2023.1321

Key Points
Question Is translocator protein distribution volume (TSPO VT), an index of gliosis (an inflammatory change), measured by positron emission tomography, elevated in the brain after acute COVID-19 infection with sequelae of depressive and cognitive symptoms?

Findings In this case-control study, TSPO VT was elevated in 20 participants with persistent depressive and cognitive symptoms after initially mild to moderate COVID-19 infection when compared with 20 healthy controls, more prominently in the ventral striatum and dorsal putamen. The TSPO VT in the dorsal putamen of COVID-19 cases negatively correlated with motor speed.

Meaning These findings suggest that gliosis, especially in the ventral striatum and dorsal putamen, may reflect injury, ongoing inflammation, or both and provide directions for further therapeutic development.

Abstract
Importance Persistent depressive symptoms, often accompanied by cognitive symptoms, commonly occur after COVID-19 illness (hereinafter termed COVID-DC, DC for depressive and/or cognitive symptoms). In patients with COVID-DC, gliosis, an inflammatory change, was suspected, but measurements of gliosis had not been studied in the brain for this condition.

Objective To determine whether translocator protein total distribution volume (TSPO VT), a marker of gliosis that is quantifiable with positron emission tomography (PET), is elevated in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus of persons with COVID-DC.

Design, Setting, and Participants This case-control study conducted at a tertiary care psychiatric hospital in Canada from April 1, 2021, to June 30, 2022, compared TSPO VT of specific brain regions in 20 participants with COVID-DC with that in 20 healthy controls. The TSPO VT was measured with fluorine F 18–labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([18F]FEPPA) PET.

Main Outcomes and Measures The TSPO VT was measured in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus. Symptoms were measured with neuropsychological and psychological tests, prioritizing outcomes related to striatal function.

Results The study population included 40 participants (mean [SD] age, 32.9 [12.3] years). The TSPO VT across the regions of interest was greater in persons with COVID-DC (mean [SD] age, 32.7 [11.4] years; 12 [60%] women) compared with healthy control participants (mean [SD] age, 33.3 [13.9] years; 11 [55%] women): mean (SD) difference, 1.51 (4.47); 95% CI, 0.04-2.98; 1.51 divided by 9.20 (17%). The difference was most prominent in the ventral striatum (mean [SD] difference, 1.97 [4.88]; 95% CI, 0.36-3.58; 1.97 divided by 8.87 [22%]) and dorsal putamen (mean difference, 1.70 [4.25]; 95% CI, 0.34-3.06; 1.70 divided by 8.37 [20%]). Motor speed on the finger-tapping test negatively correlated with dorsal putamen TSPO VT (r, −0.53; 95% CI, −0.79 to −0.09), and the 10 persons with the slowest speed among those with COVID-DC had higher dorsal putamen TSPO VT than healthy persons by 2.3 (2.30 divided by 8.37 [27%]; SD, 2.46; 95% CI, 0.92-3.68).

Conclusions and Relevance In this case-control study, TSPO VT was higher in patients with COVID-DC. Greater TSPO VT is evidence for an inflammatory change of elevated gliosis in the brain of an individual with COVID-DC. Gliosis may be consequent to inflammation, injury, or both, particularly in the ventral striatum and dorsal putamen, which may explain some persistent depressive and cognitive symptoms, including slowed motor speed, low motivation or energy, and anhedonia, after initially mild to moderate COVID-19 illness.

2702

N620

Gerhard, Alexander

Does Microglial Activation Lead to Cognitive Changes After COVID-19 Infection?

https://doi.org/10.1001/jamapsychiatry.2023.0664

Published

31-May-23

Editorial

https://doi.org/10.1001/jamapsychiatry.2023.0664

One of the many issues we have yet to understand in relation to the COVID-19 pandemic is the mechanism by which the infection can cause long-lasting neuropsychiatric symptoms, particularly cognitive symptoms and depression as part of the postacute period, referred to as post–COVID-19 condition (also known as long COVID). Since as many as 20% of individuals might experience cognitive impairment 12 or more weeks following COVID-19 diagnosis,1 it is paramount to understand the underlying pathophysiology in order to develop potential therapeutic avenues. Microglial activation as part of the neuroinflammatory response of the brain can occur as an answer to a direct insult to the brain (this includes viral infection) but can also occur following respiratory inflammation and might play an important role in the development of cognitive problems after COVID-19 infection.2

Braga et al3 present elegant work on this matter. They have examined the in vivo neuroinflammatory changes in patients with persistent depressive and cognitive symptoms after COVID-19 infection using positron emission tomography (PET) and the ligand [18F]FEPPA for the translocator protein 18 kDa (TSPO), which is expressed by activated microglia as part of the neuroinflammatory response of the brain.

They found an increased expression of TSPO in patients with persistent neurocognitive symptoms after COVID-19 infection compared to healthy control individuals, especially in the ventral striatum and dorsal putamen. TSPO binding in the dorsal putamen of individuals with post–COVID-19 conditions negatively correlated with speed in motor tasks.

These findings indicate that microglial activation was associated with the development of neurocognitive symptoms after COVID-19 infection and the imaging technique the authors used has the advantage that it allows the imaging of this part of the neuroinflammatory process in vivo. The authors conclude that increased microglial activation in the ventral striatal and dorsal putamen reflects a possible mechanism to explain persistent depressive cognitive symptoms after COVID-19 infection.

The work by Braga et al3 has important pilot character, as it elucidates a possible mechanism behind neurocognitive symptoms after COVID-19 infection. One could speculate that suppression of microglial activation might lead to improvement of these symptoms. While this is an important piece in the jigsaw puzzle of neuroinflammation in chronic neurological disease, it is important to keep in mind that we still lack understanding of the complex picture for several reasons.

Although the PET technique Braga and colleagues3 applied has been used with their own and other TSPO tracers for more than 25 years, particularly in the investigation of neurodegenerative disorders and their association with neuroinflammatory changes, it has a number of limitations—mainly the fact that the PET signal is particularly noisy and is not restricted to microglial cells.4,5

TSPO expression is only one part of the complex neuroinflammatory response of the brain (however, it is the only one we can currently relatively reliably image in vivo in patients). Our PET techniques do not currently allow us to distinguish between different states of microglial activation.

To target neuroinflammatory changes therapeutically, we will need a much more detailed understanding of microglial activation at different time points of neurological disorders. Not surprisingly, relatively simplistic attempts to suppress microglial activation have so far not resulted in clinical meaningful results.6

Future work aiming to understand the potential neuroinflammatory basis of cognitive symptoms and mood changes after COVID-19 infection will therefore need to concentrate on additional targets other than TSPO. Furthermore, longitudinal imaging (PET) studies should be carried out, allowing us to establish the correlation between the time course of central inflammatory changes and clinical parameters and, in turn, with peripheral inflammatory changes. Combining these lines of investigation might ultimately allow us to modulate neuroinflammatory changes after COVID-19 and other neuropsychiatric disorders in a way that is beneficial to patients.

2703

N621

Morgan, Larry; Hollist, Mary; Au, Katherine; Ayari, Lena; Betts, Colton; Kirmani, Batool F

Neuromuscular Disorders Associated With COVID-19

https://doi.org/10.1177/26331055231176251

Published

1-Jan-23

Review

https://doi.org/10.1177/26331055231176251

The coronavirus disease 2019 (COVID-19) pandemic has had an enormous impact on practically every aspect of daily life, and those with neuromuscular disorders have certainly not been spared. The effects of COVID-19 infection are far-reaching, going well beyond respiratory symptoms alone. From simple myalgias to debilitating critical illness neuromyopathies, we continue to learn and catalog the diverse pathologies presented by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as it relates to the neuromuscular system. Complications have been documented both as a direct result of primary infection but also in those with pre-existing neuromuscular disorders from myasthenia gravis to devastating critical illness neuromyopathies. In this review, we will discuss the relationship between COVID-19 infection and critical illness neuromyopathy, peripheral nerve palsies, myalgias, positional compressive neuropathy, myasthenia gravis, and Guillain-Barré syndrome.

2704

N622

Kang, Zijian; Wang, Jing; Meng, Tong; Zhang, Hao; Xu, Da; Gong, Haiyi; Chang, Zhenyan; Li, Zifu; Cui, Xingang; Xiao, Jianru; Qureshi, Adnan I.; Zhou, Wang; Liu, Jianmin; Xu, Huji

Pericytes may facilitate SARS-CoV-2 entry into the nervous system

https://doi.org/10.1097/JBR.0000000000000137

Published

30-Mar-23

Study

https://mednexus.org/doi/full/10.1097/JBR.0000000000000137

Objective:
Although the neurological and olfactory symptoms of coronavirus disease 2019 have been identified, the neurotropic properties of the causative virus, severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2), remain unknown. We sought to identify the susceptible cell types and potential routes of SARS-CoV-2 entry into the central nervous system, olfactory system, and respiratory system.
Methods:
We collected single-cell RNA data from normal brain and nasal epithelium specimens, along with bronchial, tracheal, and lung specimens in public datasets. The susceptible cell types that express SARS-CoV-2 entry genes were identified using single-cell RNA sequencing and the expression of the key genes at protein levels was verified by immunohistochemistry. We compared the coexpression patterns of the entry receptor angiotensin-converting enzyme 2 (ACE2) and the spike protein priming enzyme transmembrane serine protease (TMPRSS)/cathepsin L among the specimens.
Results:
The SARS-CoV-2 entry receptor ACE2 and the spike protein priming enzyme TMPRSS/cathepsin L were coexpressed by pericytes in brain tissue; this coexpression was confirmed by immunohistochemistry. In the nasal epithelium, ciliated cells and sustentacular cells exhibited strong coexpression of ACE2 and TMPRSS. Neurons and glia in the brain and nasal epithelium did not exhibit coexpression of ACE2 and TMPRSS. However, coexpression was present in ciliated cells, vascular smooth muscle cells, and fibroblasts in tracheal tissue; ciliated cells and goblet cells in bronchial tissue; and alveolar epithelium type 1 cells, AT2 cells, and ciliated cells in lung tissue.
Conclusion:
Neurological symptoms in patients with coronavirus disease 2019 could be associated with SARS-CoV-2 invasion across the blood-brain barrier via pericytes. Additionally, SARS-CoV-2-induced olfactory disorders could be the result of localized cell damage in the nasal epithelium.

2705

N623

Owens, Cameron; Mukli, Peter; Bonin Pinto, Camila; Detwiler, Sam; Tarantini, Stefano; Hoffmeister, Jordan; Csiszar, Anna; Ungvari, Zoltan; Kirkpatrick, Angelia; Prodan, Calin; Yabluchanskiy, Andriy

Long-term effects of COVID-19 on cerebrovascular function in patients with mild cognitive impairment

https://doi.org/10.1152/physiol.2023.38.S1.5731169

Published

1-May-23

Study

https://journals.physiology.org/doi/abs/10.1152/physiol.2023.38.S1.5731169

Background: Dementia is the sixth leading cause of death in United States and causes significant disability in the aging population. Therefore, conversion of mild cognitive impairment (MCI) to dementia, and conditions affecting conversion (e.g., hypertension), is of the utmost public health concerns. COVID-19 has had a profound effect on the aging population with increased risk of cognitive dysfunction and cerebrovascular complications following recovery of infection. We have strong preliminary data that suggest COVID-19 increases progression rate from MCI to dementia compared to MCI patients with no COVID-19 history (56% vs 23%, respectively, p=0.011). However, mechanisms contributing to these findings have yet to be elucidated. Normal brain function is reliant on endothelium dependent cerebromicrovascular dilation to provide sufficient oxygen and nutrients to active neurons (neurovascular coupling [NVC]). Thus, due to COVID-19’s deleterious effects on the cerebrovasculature and association with cognitive impairment, it is necessary to investigate vascular mechanisms that may contribute to COVID-19 induced cognitive dysfunction. Our central hypothesis is that COVID-19 induces systemic endothelial dysfunction, impairing NVC responses and contributing to increased progression of MCI to dementia. Methods: We are addressing the central hypothesis through prospective follow-up design, assessing systemic and cerebrovascular function at baseline and 18-month follow-up in MCI patients with and without history of COVID-19 infection. We will collect 200 participants over the course of 3 years and progression to dementia data will be measured by semiannual evaluation in the Department of Neurology at the University of Oklahoma Health Sciences Center. Assessment of endothelial function was measured by laser speckle contrast imaging and flow mediated dilation studies. NVC responses were measured with functional near-infrared spectroscopy during cognitive stimulation with n-back test.Preliminary results: Our preliminary results were collected at baseline from 3 MCI patients with no history of cerebrovascular complications (1 COVID+ patient [77 years old, male]; 2 COVID- patients [55 and 65 years old, female]). COVID+ patient showed significant attenuation of NVC responses and peripheral macro- and microvascular endothelial function compared to COVID- patients. Conclusion: Preliminary data suggest that NVC and peripheral macro- and microvascular endothelium may be impaired in MCI patients with history of COVID-19 diagnosis. Further investigation into the role that COVID-19 has on cerebrovascular function and conversion to dementia will enhance the understanding of predisposing factors that influence progression to dementia. These findings may uncover a mechanism for how COVID-19 affects cognitive function, paving the way for future therapeutic interventions targeting neurovascular uncoupling as a prominent feature in the conversion to dementia.

American Heart Association (AHA834339), the National Institute on Aging of National Institutes of Health (R01AG075834), and the NIA-supported Geroscience Training Program in Oklahoma (T32AG052363)

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

2706

N624

Nouraeinejad, Ali

The functional and structural changes in the hippocampus of COVID-19 patients

https://doi.org/10.1007/s13760-023-02291-1

Published

25-May-23

Review

https://doi.org/10.1007/s13760-023-02291-1

Since the hippocampus is predominantly susceptible to injuries caused by COVID-19, there are increasing data indicating the likelihood of post-infection memory loss and quickening neurodegenerative disorders, such as Alzheimer’s disease. This is due to the fact that the hippocampus has imperative functions in spatial and episodic memory as well as learning. COVID-19 activates microglia in the hippocampus and induces a CNS cytokine storm, leading to loss of hippocampal neurogenesis. The functional and structural changes in the hippocampus of COVID-19 patients can explain neuronal degeneration and reduced neurogenesis in the human hippocampus. This will open a window to explain memory and cognitive dysfunctions in “long COVID” through the resultant loss of hippocampal neurogenesis.

2707

N625

Adingupu, Damilola D.; Soroush, Ateyeh; Hansen, Ayden; Twomey, Rosie; Dunn, Jeff F.

Brain hypoxia, neurocognitive impairment, and quality of life in people post-COVID-19

https://doi.org/10.1007/s00415-023-11767-2

Published

21-May-23

Study

https://doi.org/10.1007/s00415-023-11767-2

Objective
Systemic hypoxia occurs in COVID-19 infection; however, it is unknown if cerebral hypoxia occurs in convalescent individuals. We have evidence from other conditions associated with central nervous system inflammation that hypoxia may occur in the brain. If so, hypoxia could reduce the quality of life and brain function. This study was undertaken to assess if brain hypoxia occurs in individuals after recovery from acute COVID-19 infection and if this hypoxia is associated with neurocognitive impairment and reduced quality of life.

Methods
Using frequency-domain near-infrared spectroscopy (fdNIRS), we measured cerebral tissue oxygen saturation (StO2) (a measure of hypoxia) in participants who had contracted COVID-19 at least 8 weeks prior to the study visit and healthy controls. We also conducted neuropsychological assessments and health-related quality of life assessments, fatigue, and depression.

Results
Fifty-six percent of the post-COVID-19 participants self-reported having persistent symptoms (from a list of 18), with the most reported symptom being fatigue and brain fog. There was a gradation in the decrease of oxyhemoglobin between controls, and normoxic and hypoxic post-COVID-19 groups (31.7 ± 8.3 μM, 27.8 ± 7.0 μM and 21.1 ± 7.2 μM, respectively, p = 0.028, p = 0.005, and p = 0.081). We detected that 24% of convalescent individuals’ post-COVID-19 infection had reduced StO2 in the brain and that this relates to reduced neurological function and quality of life.

Interpretation
We believe that the hypoxia reported here will have health consequences for these individuals, and this is reflected in the correlation of hypoxia with greater symptomology. With the fdNIRS technology, combined with neuropsychological assessment, we may be able to identify individuals at risk of hypoxia-related symptomology and target individuals that are likely to respond to treatments aimed at improving cerebral oxygenation.

2708

N626

Schild, Ann-Katrin; Scharfenberg, Daniel; Kirchner, Lukas; Klein, Kim; Regorius, Anton; Goereci, Yasemin; Meiberth, Dix; Sannemann, Lena; Lülling, Joachim; Schweitzer, Finja; Fink, Gereon R.; Jessen, Frank; Franke, Christiana; Onur, Özgür; Jost, Stefanie; Warnke, Clemens; Maier, Franziska

Subjective and Objective Cognitive Deficits in Patients with Post-COVID Syndrome

https://doi.org/10.1024/1016-264X/a000374

Published

1-Jun-23

Study

https://econtent.hogrefe.com/doi/full/10.1024/1016-264X/a000374

: Cognitive impairment is a prominent symptom of the post-COVID syndrome (PCS). However, the correspondence between subjective cognitive complaints (SCC) and objective results is inconsistent. Here, we investigated this discrepancy. This longitudinal study included N = 42 individuals who reported SCC as PCS after mild infection at inclusion. Data collection comprised questionnaires and neuropsychological assessment at baseline and follow-up (FU). At FU – on average 15 months after acute COVID-19 – 88 % of patients reported persisting SCC. There was an approx. 40 % discrepancy between subjective report and test results at both visits. Patients with SCC and objective impairment indicated elevated fatigue and reduced quality of life compared to patients without SCC at FU. A growing number of patients is anticipated to request neuropsychological assessments even after mild infections.

2709

P01

Mario Gennaro Mazzaab Rebecca De Lorenzo bc CaterinaConte bc Sara Polettia b Benedetta VaiabIrene Bollettinia

Anxiety and depression in COVID-19 survivors: Role of inflammatory and clinical predictors

https://doi.org/10.1016/j.bbi.2020.07.037

Published

1-Oct-20

Study

https://www.sciencedirect.com/science/article/pii/S0889159120316068

Anxiety - insomnia - depression - post-traumatic stress disorder - OCD:
symptoms common in covid survivors one month after hospitalization, according to an Italian survey of 402 patients.

Anxiété - insomnies - dépression - trouble de stress post-traumatique - TOC :
des symptômes fréquents chez les survivants de la covid un mois après hospitalisation, selon une étude italienne sur 402 patients.

2710

P02

Maxime Taquet, PhD
Sierra Luciano, BA
Prof John R Geddes, FRCPsych
Prof Paul J Harrison, FRCPsych

Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA

https://doi.org/10.1016/S2215-0366(20)30462-4

Published

9-Nov-20

Study

https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(20)30462-4/fulltext

A large Lancet study notes that one in 5 patients with covid suffers from anxiety, depression or insomnia for at least 3 months following infection. The pre-existence of psychiatric disorders is also correlated with the risk of being infected. The study also notes that covid increases the risk of a range of psychiatric disorders, including dementia, including in patients for whom these disorders were not pre-existing.

Une large étude du Lancet note qu'un malade de la covid sur 5 souffre d'anxiété, dépression ou insomnie sur les 3 mois a minima qui suivent sa contamination. La préexistence de troubles psychiatriques est aussi corrélée avec le risque d'être contaminé. L'étude remarque également que la covid majore le risque d'un ensemble de troubles psychiatriques, dont la démence, y compris chez les patients pour qui ces troubles n'étaient pas préexistants.

2711

P03

Ipsit V. Vahia, MD1,2; Dilip V. Jeste, MD3; Charles F. Reynolds III, MD4

Older Adults and the Mental Health Effects of COVID-19

https://doi.org/10.1001/jama.2020.21753

Published

20-Nov-20

Viewpoint

https://jamanetwork.com/journals/jama/fullarticle/2773479

An article in JAMA draws a state of knowledge on anxiety disorders, depression and mental health in general in the elderly parts of the population as a consequence of a covid, and emphasizes the importance of nonpharmacological approaches.

Un article dans JAMA dessine un état des connaissances sur les troubles d'anxiété, dépression et santé mentale en général chez les tranches âgées de la population en répercussion d'une covid, et insiste sur l'importance des approches non médicamenteuses.

2712

P04

Liam Townsend ,Adam H. Dyer ,Karen Jones,Jean Dunne,Aoife Mooney,Fiona Gaffney,Laura O'Connor,

Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection

https://doi.org/10.1371/journal.pone.0240784

Published

9-Nov-20

RESEARCH ARTICLE

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240784

A study of 128 cases with persistent symptoms, avg. 49.5 ±15 years, 54% of women, indicates that post-viral fatigue does not appear to be associated with the severity of the acute phase, nor with markers of inflammation or immune disorders. Chronic fatigue at 2.5 months is present in 67 patients, or 52%. Of these 67, nine had a history of anxiety or depression, or 13%. Conversely, 9 of the 10 patients who had a history of anxiety/depression experienced persistent fatigue. 55% of patients were hospitalized. Persistent fatigue concerns 67% of women. The study makes a link with the effects of chronic fatigue observed during the SARS and MERS epidemics, and questions the possibility of developing chronic fatigue syndrome (CFS).

Une étude de 128 cas avec des symptômes persistants, d'âge moy. 49,5 ±15 ans, 54% de femmes, indique que la fatigue post-virale n'apparaît pas associée à la sévérité de la phase aiguë, ni aux marqueurs d'inflammation ou de dérèglements immunitaires. La fatigue persistante à 2,5 mois est présente chez 67 patients, soit 52%. Sur ces 67, neuf avait un historique d'anxiété ou de dépression, soit 13%. À l'inverse, 9 patient(e)s sur les 10 qui avaient des antécédents d'anxiété/dépression ont présenté une fatigue persistante. 55% des patients ont été hospitalisés. La fatigue persistante concerne pour 67% des femmes. L'étude fait un lien avec les effets de fatigue chronique relevés lors des épidémies de SARS et MERS, et s'interroge sur la possibilité de développer un syndrome de fatigue chronique. <Stats> La "valeur p" pour le sexe est dans l'étude à 0,2%.
Traduction : Si hommes et femmes avaient le même risque de développer une fatigue persistante post-infection covid, il n'y aurait eu que 0,2% de chances d'avoir de telles données (si étude correctement menée). De même, si les antécédents anxiété/dépression n'étaient pas corrélés à un risque plus fort d'être en fatigue persistance post-infection covid, il n'y aurait eu que 2% de chances d'avoir un tel écart dans les données (si l'étude est correctement menée). Et si un taux fort de protéine C réactive (CRP, indicateur d'inflammation) n'était pas corrélé à un risque plus fort d'être en fatigue persistante après infection covid, il n'y aurait eu que 6% de chances d'avoir un tel écart dans les données (si étude correctement menée).

2713

P05

Anna Valenzano 1,,Alessia Scarinci 2,,Vincenzo Monda 3 ,

The Social Brain and Emotional Contagion: COVID-19 Effects

https://doi.org/10.3390/medicina56120640

Published

25-Nov-20

Review

https://pubmed.ncbi.nlm.nih.gov/33255569/

Une étude italienne analyse la crise sanitaire en tant qu'épidémie émotionnelle, et ses impacts mondiaux sur la santé mentale, par les dépressions et l'anxiété. Elle préconise de s'inspirer des épidémies passées pour la prise en charge thérapeutique.

2714

P06

Humanitarian
Disaster Institute

COVID-19 MENTAL HEALTH HANDBOOK
Evidence-Informed Approaches to Mental Wellbeing During a Pandemic

Published

1-Dec-20

Handbook

https://www.chihealth.com/content/dam/chi-health/website/documents/MentalHealth_Handbook_FINAL.pdf

Un rapport américain de 200 pages, écrits par un panel de médecins, qui traite de la covid et la santé mentale.

N002

2715

P07

Syed Z. Iqbal, MD; Benjamin Li, MD; Edore Onigu-Otito, MD; Mohammad Faraz Naqvi, MD; Asim A. Shah, MD

The Long-Term Mental Health Effects of COVID-19

https://doi.org/10.3928/00485713-20201103-01

Published

10-Dec-20

Article

https://www.healio.com/psychiatry/journals/psycann/2020-12-50-12/%7Bbf43fdf5-3a35-4821-8cec-fd332dc442b8%7D/the-long-term-mental-health-effects-of-covid-19

Un article qui décrit les impacts neuropsychiatriques indirectes de la crise sanitaire et des mesures qui y sont liées comme les confinements. Les troubles d'anxiété, les phobies les comportements d'évitement, sont évalués.

2716

P08

Ashley Clarke

The Impact of Sustained Psychological Distress and Elevated Anxiety Symptoms on Long-Term Mental and Physical Wellbeing of COVID-19 Healthcare Providers

Published

1-Dec-20

Article

https://www.ceeol.com/search/article-detail?id=913406

Un article académique s'intéresse aux impacts sur la santé mentale et la détérioration des capacités physiques du personnel de santé au front de la crise sanitaire de la covid.

2717

P09

Sanjay Kumar1
, Alfred Veldhuis1
, Tina Malhotra2

Neuropsychiatric and Cognitive Sequelae of COVID-19

http://dx.doi.org/10.3389/fpsyg.2021.577529

Published

1-Feb-21

Review

https://www.researchgate.net/publication/349140814_Neuropsychiatric_and_Cognitive_Sequelae_of_COVID-19

In this paper, we will briefly outline how COVID-19 can affect the CNS, review emerging evidence of effects on CNS and explore the possible neuropsychiatric sequelae of the COVID-19 infection.

Une revue d'études britannique répertorie les possibles séquelles neuro-psychiatriques d'une infection de covid. Les auteurs s'interrogent sur les conséquences à long terme pour la rééducation et la réadaptation des malades.

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2718

P10

Klaus W.Lange

COVID-19 and global mental health

https://doi.org/10.1016/j.glohj.2021.02.004

Published

13-Feb-21

Review Article

https://www.sciencedirect.com/science/article/pii/S241464472100004X

"A focus on the long-term mental health consequences may be at least as important as the measures currently seeking to mitigate the short-term effects of COVID-19 and to save lives."

Cette étude balaie les impacts psychiatriques de la covid via les dommages neurologiques possibles, mais essaie d'évaluer également les impacts psychiatriques indirects de la pandémie.

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P11

Genoveva Uzunova,Stefano Pallanti &Eric Hollander

Presentation and management of anxiety in individuals with acute symptomatic or asymptomatic COVID-19 infection, and in the post-COVID-19 recovery phase

https://doi.org/10.1080/13651501.2021.1887264

Published

26-Feb-21

Review Article

https://www.tandfonline.com/doi/full/10.1080/13651501.2021.1887264

Key points
Patients with COVID-19 (symptomatic or asymptomatic) exhibit a high frequency of neuropsychiatric complications with highest percentage attributed to anxiety.

Multiple biological and psychosocial risk factors for anxiety exist in COVID-19-ill individuals. Biological risk factors include stress, resilience, genetics, gender, age, immune system, direct infection of the central nervous system (CNS) with SARS-CoV-2, comorbid psychiatric and general medical illnesses, ARDS and ICU stay. Anosmia and hypogeusia are COVID-19-specific anxiety risk factors. Knowledge of the anxiety risk factors is essential to focus on timely interventions, because anxiety may be a complication of and exacerbate the COVID-19 course. An inverse correlation exists between resilience and anxiety because of COVID-19, and therefore efforts should be made to increase resilience in COVID-19 patients.
In COVID-19, important anxiety mechanism is neuroinflammation resulting from activation of the immune system and an ensuing cytokine storm.
The general approach to management of anxiety in COVID-19 should be compassionate, similar to that during trauma or disaster, with efforts focussed on instilling a sense of hope and resilience.
In selecting pharmacological treatment of anxiety, the stress response and immune system effects should be key. Medications with cardio-respiratory adverse effects should be avoided in patients with respiratory problems.
Anxiety is a disorder that will require for long-term follow up at least one month after COVID-19.

Une revue d'études menée en octobre 2020 dans International Journal of Psychiatry in Clinical Practice considère l'anxiété comme jouant un rôle prépondérant dans l'évolution clinique chez les malades de la covid. L'étude présente l'infection et l'anxiété comme s'influençant mutuellement de façon directe ou indirecte, notamment par des perturbations du système immunitaire. Elle liste aussi des traitements pour soigner ces conséquences, et insiste sur l'objectif de résilience pour la guérison.

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2720

P12

Soon Tjin Lim, MRCP, PhD, Benjamin Janaway, MBChB, BMedSci, Harry Costello, MSc MRCPsych, Anand Trip, PhD FRCP,* and Gary Price

Persistent psychotic symptoms following COVID-19 infection

https://doi.org/10.1192%2Fbjo.2020.76

Published

22-Jul-20

Case Report

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477483/

We report on a female patient who, post-COVID-19 infection, developed an initial delirium followed by persistent and florid psychotic symptoms consisting of persecutory delusion, complex visual and auditory hallucinations and Capgras phenomenon in the absence of hypoxia but elevated tumour necrosis factor (TNF)-α. The psychotic symptoms persisted for about 40 days. Her magnetic resonance imaging brain scan, electroencephalogram, cerebrospinal fluid examination and extensive autoimmune panel did not show any abnormalities. The cause of the psychotic symptoms in this patient were not ascertained but we propose either an inflammatory state, characterised by the patient's elevated TNF-alpha levels as a possible contributing mechanism for her psychosis in line with the proinflammatory changes observed in some cases of psychosis. Or, an alternative, but unproven, hypothesis is one of an antibody-mediated encephalitic event induced by viral infection.

Des cas d'événements psychotiques ont été attribués à la covid. Ils auraient pour origine possible une inflammation caractérisée par des taux élevés de TNF α, ou éventuellement une neuro-invasion qui causerait un événement encéphalitique dont les médiateurs seraient des anticorps.

2721

P13

Rachel Noone, Johanna A. Cabassa, Laura Gardner, Bruce Schwartz, and Jonathan E. Alpert Vilma Gabbay

Letter to the Editor: New onset psychosis and mania following COVID-19 infection

https://doi.org/10.1016%2Fj.jpsychires.2020.07.042

Published

8-Aug-20

Cases Report

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414775/

Here we present two case reports of adult patients with COVID-19 infections who presented with severe psychosis and mania with no prior psychiatric history and in the absence of significant medical or pulmonary symptoms and an unremarkable neurological work-up.

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2722

P14

A.ParraaA.JuanesaC.P.LosadaabcS.Álvarez-SesmeroaV.D.SantanaaI.MartíaJ.UrricelquiaD.Rentero

Psychotic symptoms in COVID-19 patients. A retrospective descriptive study

https://doi.org/10.1016/j.psychres.2020.113254

Published

1-Sep-20

Short communication

https://www.sciencedirect.com/science/article/abs/pii/S0165178120315092

Highlights
•Psychotic symptoms have been observed in patients infected by SARS-CoV-2 with no previous psychiatric history.
•Psychotic episodes in COVID-19 patients present with confusional symptoms, instaure rapidly and resolve with low doses of antipsychotics.
•Psychotic symptoms related to SARS-CoV-2 are more frequent in patients discharged from intensive care units.
•Pharmacological treatments utilized against COVID-19 can be related with the new-onset psychotic manifestations.

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2723

P15

Aravinthan Varatharaj, MRCP,a,b Naomi Thomas, MRCPCH,c,d Mark A Ellul, MRCP,e,f,g Nicholas W S Davies, PhD,h Thomas A Pollak, MRCP,i Elizabeth L Tenorio, PhD,k,l Mustafa Sultan,c Ava Easton, PhD,f,m Gerome Breen, Prof, PhD,j Michael Zandi, PhD,n Jonathan P Coles, Prof, PhD, Sarah L Pett, Prof, PhD,o,p Ian Galea, PhD,a,b,* Rhys H Thomas, PhD,c,v,* Benedict D Michael

Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study

https://doi.org/10.1016%2FS2215-0366(20)30287-X

Published

25-Jun-20

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316461/

Median patient age was 71 years (range 23–94; IQR 58–79). Complete clinical datasets were available for 125 (82%) of 153 patients. 77 (62%) of 125 patients presented with a cerebrovascular event, of whom 57 (74%) had an ischaemic stroke, nine (12%) an intracerebral haemorrhage, and one (1%) CNS vasculitis. 39 (31%) of 125 patients presented with altered mental status, comprising nine (23%) patients with unspecified encephalopathy and seven (18%) patients with encephalitis. The remaining 23 (59%) patients with altered mental status fulfilled the clinical case definitions for psychiatric diagnoses as classified by the notifying psychiatrist or neuropsychiatrist, and 21 (92%) of these were new diagnoses. Ten (43%) of 23 patients with neuropsychiatric disorders had new-onset psychosis, six (26%) had a neurocognitive (dementia-like) syndrome, and four (17%) had an affective disorder. 18 (49%) of 37 patients with altered mental status were younger than 60 years and 19 (51%) were older than 60 years, whereas 13 (18%) of 74 patients with cerebrovascular events were younger than 60 years versus 61 (82%) patients older than 60 years.

First nationwide, cross-specialty surveillance study of acute neurological and psychiatric complications of COVID-19. Altered mental status was the second most common presentation, comprising encephalopathy or encephalitis and primary psychiatric diagnoses, often occurring in younger patients.

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P16

Kevin Gournay

Post COVID-19 mental health: please do not forget severe mental health problems

https://doi.org/10.12968/bjmh.2021.0008

Published

13-Mar-21

Article

https://www.magonlinelibrary.com/doi/full/10.12968/bjmh.2021.0008

Kevin Gournay discusses the impact of COVID-19 and those living with severe mental health problems.

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2725

P17

Zev M. Nakamura, Rebekah P. Nash, Sarah L. Laughon & Donald L. Rosenstein

Neuropsychiatric Complications of COVID-19

https://doi.org/10.1007/s11920-021-01237-9

Published

16-Mar-21

Review

https://link.springer.com/article/10.1007/s11920-021-01237-9

Over 30% of patients hospitalized with COVID-19 may exhibit cognitive impairment, depression, and anxiety that persist for months after discharge. These symptoms are even more common in patients who required intensive care for severe effects of the virus. In addition to the pandemic-related psychological stress, multiple biological mechanisms have been proposed to understand the neuropsychiatric symptoms observed with COVID-19. Given limited research regarding effective interventions, we recommend pharmacologic and behavioral strategies with established evidence in other medically-ill populations.

Les conséquences psychiatriques sont fréquentes chez les malades hospitalisés de la covid selon cette étude. Elle peuvent parfois être induites par un traitement inapproprié, comme l'hydroxychloroquine ou les combinaisons lopinavir/ritonavir.

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2726

P18

María José Valdés-Florido, Álvaro López-Díaz, Fernanda Jazmín Palermo-Zeballos, Nathalia Garrido-Torres, Paula Álvarez-Gil, Iván Martínez-Molina, Victoria Eugenia Martín-Gil, Elena Ruiz-Ruiz, Macarena Mota-Molina, María Paz Algarín-Moriana, Antonio Hipólito Guzmán-del Castillo, Ángela Ruiz-Arcos, Rafael Gómez-Coronado, Sara Galiano-Rus, Alfonso Rosa-Ruiz, Juan Luis Prados-Ojeda, Luis Gutierrez-Rojas, Benedicto Crespo-Facorro & Miguel Ruiz-Veguilla

Clinical characterization of brief psychotic disorders triggered by the COVID-19 pandemic: a multicenter observational study

https://doi.org/10.1007/s00406-021-01256-w

Published

3-Apr-21

Study

https://link.springer.com/article/10.1007/s00406-021-01256-w

Psychotic disorders triggered by the COVID-19 pandemic

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2727

P19

V. E. Medvedev

Anxiety and depression in COVID-19: treatment options

https://doi.org/10.14412/2074-2711-2021-2-111-116

Published

Review

https://nnp.ima-press.net/nnp/article/view/1549

During the examination of post-COVID patients, a direct and indirect negative effect of COVID-19 on the nervous system is found. Among the mediated subjectively significant stress factors of the pandemic, a potential long-term threat to life, prolonged quarantine measures with selfisolation, lack of stable immunity, restriction of access to medical services, etc. are of particular importance.
An increased frequency of depression (up to 53.5%), anxiety (up to 50.9%), and mixed anxiety/depressive disorders were reported during the pandemic.
Psychopharmacotherapy in patients with COVID-19 should include drugs not only with minimally expressed undesirable effects and adverse drug interactions but also with the presence of additional therapeutic procognitive and somatotropic properties, similar to those identified in the antidepressant fluvoxamine.

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2728

P20

Yuan Yang, PhD,1,2,3,# Wen Li, MD, PhD,1,2,3,# Qinge Zhang, MD, PhD,4,# Ling Zhang, MD, PhD,4,# Teris Cheung, PhD,5 Chee H Ng, MBBS, MD,6, and Yu-Tao Xiang, MD, PhD1,2,3,

Should people with severe mental illness be prioritized for the COVID-19 vaccination?

https://dx.doi.org/10.7150%2Fijbs.57750

Published

10-Apr-21

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071759/

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2729

P21

Osman Sinanović

LONG-TERM NEUROPSYCHIATRIC
CONSEQUENCES OF SARS-COV INFECTIONS

Published

1-May-21

Review

https://pubmed.ncbi.nlm.nih.gov/34010256/

The review of the so far published papers shows that although more and more papers are reporting neuro-logical and psyhiatric manifestations associated with COVID-19, many items remain unclear. The long-term psychological implications of this infectious diseases should not be ignored. In this paper, we aim to present a some of psychological consequences and neurological disorders associat-ed with the SARS-CoV-2 infection, and to emphasize the need a global action that requires close coordination and open-data sharing between hospitals, academic and public health institutions and the fast establishment of harmonised research priorities to face acut and long-term the neurological and psychological consequences.

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2730

P22

Daniella Winter Yoram Braw

COVID-19: Impact of Diagnosis Threat and Suggestibility on Subjective Cognitive Complaints

https://doi.org/10.1016/j.ijchp.2021.100253

Published

24-May-21

https://www.sciencedirect.com/science/article/pii/S169726002100034X

Background/Objective
A subset of recovered COVID-19 patients report persistent neurological symptoms. These include non-specific symptoms (e.g., headaches and fatigue) which were found to be affected by psychological processes in other disorders (e.g., post-concussion syndrome, PCS, after mild traumatic brain injury). The current study assessed the impact of diagnosis threat (i.e., information regarding the long-term neurological impact of COVID-19) and suggestibility on endorsed symptoms of both recovered patients and healthy controls.
Method
Recovered patients (n = 90) and healthy controls (n = 210) described their cognitive functioning after being randomly assigned to: (a) Experimental group: These participants read an article that explored long-term neurological symptoms among COVID-19 survivors. (b) Control group: These participants read an article providing general information regarding the disease.
Results
Recovered patients, but not healthy controls, endorsed more symptoms in the experimental condition compared to the control condition. Moreover, suggestibility was correlated with endorsement of symptoms.
Conclusions
Post COVID-19 neurological symptoms may, at least partially, be affected by non-neurological factors such as diagnosis threat. Information regarding long-term effects of COVID-19 may skew reported symptoms with highly suggestible individuals particularly susceptible to these effects. Further research, however, is needed to validate and elaborate upon these initial findings.

Selon une étude randomisée en aveugle, les symptômes neurologiques prolongés de la covid peuvent partiellement être affectés par des facteurs non neurologiques, comme l'annonce d'un diagnostic inquiétant, notamment chez les personnes très suggestibles.

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2731

P23

H. Dreßing & A. Meyer-Lindenberg

Künftige Aufgaben der psychiatrischen Begutachtung bei „Long-COVID“

https://doi.org/10.1007/s00115-021-01142-9

7-Jun-21

https://link.springer.com/article/10.1007/s00115-021-01142-9

Fazit für die Praxis
Mit zunehmender Dauer der COVID-19-Pandemie rücken auch mögliche neuropsychiatrische Langzeitfolgen in den Fokus.
Im Rahmen einer Infektion kann das Virus das zentrale Nervensystem befallen und neuropsychiatrische Symptome verursachen.
Die Spätfolgen einer durchgemachten COVID-19-Infektion sind zum Teil unspezifisch und im Hinblick auf bleibende Schäden derzeit noch nicht hinreichend zu beurteilen.
In der sozialmedizinischen Begutachtungspraxis werden sich in unterschiedlichen Versicherungssystemen sowohl finale als auch kausale gutachtliche Fragestellungen ergeben.
Zumindest nach gegenwärtigem Kenntnisstand kann bei der gutachtlichen Einschätzung einer „Long-COVID-Symptomatik“ auf das auch in anderen Kontexten bewährte Vorgehen zurückgegriffen werden.

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2732

P24

B. Ranque

Appeler un chat un chat To call a spade a spade

https://doi.org/10.1016/j.revmed.2021.06.001

Published

18-Jun-21

Éditorial

https://www.sciencedirect.com/science/article/abs/pii/S0248866321005208

Pour conclure, il me semble que notre objectif doit être avant
tout de rendre au patient son bien-être antérieur et qu’il est
bien plus important de faire disparaître les symptômes que d’en
avoir une explication physiopathologique parfaitement exacte.
Cela nécessite d’évoquer explicitement avec le patient la possibilité de mécanismes cognitifs et comportementaux sous-tendant
les symptômes inexpliqués persistant après une COVID-19, c’est-à-dire d’appeler un chat un chat, sans hypocrisie ni mépris des liens
complexes qui unissent le corps et l’esprit de tout être humain.

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2733

P25

Yiheng Tu, Yuqi Zhang, Yu Li, Qing Zhao, Yanzhi Bi, Xuejing Lu, Yazhuo Kong, Li Wang, Zhijie Lu & Li Hu

Post-traumatic stress symptoms in COVID-19 survivors: a self-report and brain imaging follow-up study

https://doi.org/10.1038/s41380-021-01223-w

Published

20-Jul-21

Study

https://www.nature.com/articles/s41380-021-01223-w

We conducted a two-session study to record PTSS in the COVID-19 survivors discharged from hospitals for a short (i.e., about 3 months, Session 1) to a medium period (i.e., about 6 months, Session 2), as well as brain imaging data in Session 2. The control groups were non-COVID-19 locals. Session 1 was completed for 126 COVID-19 survivors and 126 controls. Session 2 was completed for 47 COVID-19 survivors and 43 controls. The total score of post-traumatic stress disorder (PTSD) checklist for DSM-5 (PCL-5) score was significantly higher in COVID-19 survivors compared with controls in both sessions. The PCL-5 score in COVID-19 survivors was positively correlated with the duration after discharge (r = 0.27, p = 0.003 for Session 1), and increased by 20% from Session 1 to Session 2 for the survivors who participated both sessions. The increase was positively correlated with individual’s test-retest duration (r = 0.46, p = 0.03). Brain structural volume and functional activity in bilateral hippocampus and amygdala were significantly larger in COVID-19 survivors compared with controls. However, the volumes of the left hippocampus and amygdala were negatively correlated with the PCL-5 score for the COVID-19 survivors. Our study suggests that COVID-19 survivors might face possible PTSS deteriorations, and highlights the importance of monitoring mental wellness of COVID-19 survivors.

2734

P26

ThorMertz SchouaSamiaJocabGregersWegeneraCecilieBay-Richtera

Psychiatric and neuropsychiatric sequelae of COVID-19 – a systematic review

https://doi.org/10.1016/j.bbi.2021.07.018

Published

30-Jul-21

Review

https://www.sciencedirect.com/science/article/pii/S0889159121002816

Highlights
•66 studies examined psychiatric or neuropsychiatric sequelae following COVID-19.
•Fatigue, anxiety/depression, PTSD, cognitive deficits, and sleep disturbances were most commonly reported.
•COVID-19 survivors were at risk of psychiatric sequelae but symptoms generally improve over time.

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P27

Evan J.KyzarMD PhD1Lawrence J.PurpuraMD23JayeshShah2AnyelinaCantos2Anna S.NordvigMD4Michael T.YinMD2

Anxiety, depression, insomnia, and trauma-related symptoms following COVID-19 infection at long-term follow-up

https://doi.org/10.1016/j.bbih.2021.100315

Published

30-Jul-21

Study

https://www.sciencedirect.com/science/article/pii/S2666354621001186

Here, we report findings from a cohort study of 52 participants recruited from the greater New York City area following acute COVID-19 infection. Participants completed the Patient Health Questionnaire-9 (PHQ-9) for depressive symptoms, the Generalized Anxiety Disorder-7 (GAD-7) for anxiety-related symptoms, the Insomnia Severity Scale (ISS) from sleep-related symptoms, and the PTSD Checklist-Civilian version (PCL-C) for trauma-related symptoms both at baseline and at long-term (24 to 60 weeks post-infection) follow-up. We found a high degree of correlation between psychiatric symptom scales within participants. More participants met established cutoffs for clinically significant insomnia and post-traumatic stress at follow-up compared to baseline. Symptom scales for depression, insomnia, and PTSD were increased at long-term follow-up, with only increased PCL-C scores surviving correction for multiple comparisons (Z=2.92, W=434, p=0.004). Our results present evidence from a small cohort that neuropsychiatric symptoms, particularly those related to PTSD, may worsen over time in COVID-19 survivors.

2736

P28

Laura Dellazizzo 1,2 ,Nayla Léveillé 1,2,Clara Landry 1,2 andAlexandre Dumais

Systematic Review on the Mental Health and Treatment Impacts of COVID-19 on Neurocognitive Disorders

https://doi.org/10.3390/jpm11080746

Published

29-Jul-21

Review

https://www.mdpi.com/2075-4426/11/8/746/htm

First, the pandemic and resulting self-isolation led to many detrimental effects on psychological well-being. Exacerbation and relapses of neurocognitive and behavioral symptoms were observed, as well as emergences of new psychological symptoms (i.e., depression, anxiety). Second, therapeutic and community services for individuals suffering from NCD, such as social support services and outpatient clinics, were disrupted or reduced leading to postponed appointments and evaluations, as well as reduced access to medications. These issues were somewhat palliated with the growth of telemedicine. Conclusions. This systematic review highlights the extent of the effects of the pandemic, and the topics addressed should be taken into consideration by healthcare practitioners, institutions, and policymakers to ensure that proper measures are employed to protect this population from additional harm.

2737

P29

Steven J.LamontagneabMakaila F.WintersaDiego A.PizzagallibcMary C.Olmsteadad

Post-acute sequelae of COVID-19: Evidence of mood & cognitive impairment

https://doi.org/10.1016/j.bbih.2021.100347

Published

14-Sep-21

Study

https://www.sciencedirect.com/science/article/pii/S2666354621001502

Depressive symptoms were found in the post-acute sequelae of COVID-19 (PASC) sample.
•Reward processing and cognitive functioning were impaired in the PASC phase.
•PASC was associated with impaired executive function, but not orienting or alerting.
•Stress did not moderate PASC effects; between-group pandemic experience was similar.
•Protracted inflammatory responses may contribute to post-acute psychiatric sequelae.

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P30

Mario GennaroMazzaabRaffaellaZanardiacMariagraziaPalladinibPatriziaRovere-QueriniadFrancescoBenedettiab

Rapid response to selective serotonin reuptake inhibitors in post-COVID depression

https://doi.org/10.1016/j.euroneuro.2021.09.009

Published

9-Oct-21

Review

https://www.sciencedirect.com/science/article/pii/S0924977X21007616

We included 60 patients affected by a major depressive episode and treated with SSRI in the six months following recovery from COVID. The severity of depression was rated at baseline and after four weeks on the Hamilton Depression Rating Scale (HDRS). Response to treatment was considered when the patients achieved a 50% HDRS reduction. To investigate changes of depressive symptomatology over time, repeated measures ANOVAs according to clinical variables were performed.
We found that 55 (92%) patients showed a clinical response to antidepressant. Patients showed a significant decrease over time of HDRS score (baseline HDRS = 23.37 ± 3.94, post-treatment HDRS = 6.71±4.41, F = 618.90, p < 0.001), irrespectively of sex, previous psychiatric history, previous history of mood disorder, and SSRI type.
This is the first study to explore the SSRI efficacy in post-COVID depression, suggesting rapid antidepressant effects in most patients. SSRIs treatment could contribute to the rapid antidepressant response by directly targeting the neuroinflammation triggered by SARS-CoV-2. We suggest screening psychopathology of COVID-19 survivors to diagnose emergent depression and pharmacologically treat it to reduce the disease burden and related years of life lived with disability.

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2739

P31

Eliza Dąbrowska * ,Beata Galińska-Skok andNapoleon Waszkiewicz

Depressive and Neurocognitive Disorders in the Context of the Inflammatory Background of COVID-19

https://doi.org/10.3390/life11101056

Published

8-Oct-21

Review

https://www.mdpi.com/2075-1729/11/10/1056

It is suggested that neuroinflammation and associated central nervous system changes may significantly contribute to the etiopathogenesis of depressive disorders. In addition, symptoms after a COVID-19 infection may persist for up to several weeks after an acute infection as a post-COVID-19 syndrome. Moreover, previous knowledge indicates that among SSRI (selective serotonin reuptake inhibitor) group antidepressants, fluoxetine is a promising drug against COVID-19. In conclusion, further research, observation and broadening of the knowledge of the pathomechanism of a SARS-CoV-2 infection and the impact on potential complications are necessary. It is essential to continue research in order to assess the long-term neuropsychiatric effects in COVID-19 patients and to find new therapeutic strategies.It is suggested that neuroinflammation and associated central nervous system changes may significantly contribute to the etiopathogenesis of depressive disorders. In addition, symptoms after a COVID-19 infection may persist for up to several weeks after an acute infection as a post-COVID-19 syndrome. Moreover, previous knowledge indicates that among SSRI (selective serotonin reuptake inhibitor) group antidepressants, fluoxetine is a promising drug against COVID-19. In conclusion, further research, observation and broadening of the knowledge of the pathomechanism of a SARS-CoV-2 infection and the impact on potential complications are necessary. It is essential to continue research in order to assess the long-term neuropsychiatric effects in COVID-19 patients and to find new therapeutic strategies.

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2740

P32

Mark Shevlin,Emma Nolan,Marcin Owczarek,Orla McBride,Jamie Murphy,Jilly Gibson Miller,Todd K. Hartman,Liat Levita,Liam Mason,Anton P. Martinez,Ryan McKay,Thomas V. A. Stocks,Kate M. Bennett,Philip Hyland,Richard P. Bental

COVID-19-related anxiety predicts somatic symptoms in the UK population

https://doi.org/10.1111/bjhp.12430

Published

27-May-20

Study

https://bpspsychub.onlinelibrary.wiley.com/doi/full/10.1111/bjhp.12430

During the current COVID-19 pandemic in the United Kingdom, there may be increased levels of generalized anxiety in the general population, but there may also be anxiety specifically associated with COVID-19. This study is the first to show that there is a positive association between both generalized anxiety and COVID-19 specific anxiety and the reporting of somatic symptoms. Indeed, COVID-19 specific anxiety explained unique variance in somatic symptoms after controlling for generalized anxiety and other potential confounding variables.

2741

P33

LiuyiRana1WoWanga1MingAibYitingKongbJianmeiChenbLiKuang

Psychological resilience, depression, anxiety, and somatization symptoms in response to COVID-19: A study of the general population in China at the peak of its epidemic

https://doi.org/10.1016/j.socscimed.2020.113261

Published

29-Jul-20

Study

https://www.sciencedirect.com/science/article/abs/pii/S0277953620304809

Results
The prevalence of depression, anxiety, somatization symptoms was found to be 47.1%, 31.9%, 45.9%, respectively, among all participants. From them, 18.2% showed moderate to severe symptoms of depression, 8.8% showed moderate to severe symptoms of anxiety, and 16.6% showed moderate to severe symptoms of somatization. Psychological resilience was negatively correlated with depression (standardized β = −0.490, P < 0.001), anxiety (standardized β = −0.443, P < 0.001), and somatization symptom scores (standardized β = −0.358, P < 0.001), while controlling for confounding factors. Analysis of the three-factor resilience structure showed that strength and tenacity were correlated with depression (standardized β = −0.256, P < 0.001; standardized β = −0.217, P < 0.001), anxiety (standardized β = −0.268, P < 0.001; standardized β = −0.147, P < 0.001), and somatization symptoms (standardized β = −0.236, P < 0.001; standardized β = −0.126, P < 0.01).

Conclusions
Our results suggest that there is a high prevalence of psychological distresses among the general population at the peak of the COVID-19 epidemic in China, which is negatively correlated with resilience. Psychological resilience represents an essential target for psychological intervention in a public health emergency.

Highlights
•Investigated mental health and resilience in response to COVID-19.
•The study took place at the peak of the COVID-19 epidemic in China.
•In total, 18.2% had depression, 8.8% had anxiety, and 16.6% had somatic symptoms.
•Resilience negatively correlated with depression, anxiety, and somatic symptoms.
•Resilience represents an essential target for psychological interventions.

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BarisSancakM.D.UrunOzer AgirbasM.D.CenkKilicM.D.

Long COVID and Its Psychiatric Aspects

https://dx.doi.org/10.1016%2Fj.jaclp.2021.03.003

Published

29-Mar-21

Letter to the Editor

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005382/

While research on long COVID continues, psychiatrists should be involved in this process. We often see that people with symptoms such as fatigue, insomnia, shortness of breath, or palpitations are referred to psychiatry because no underlying cause can be found. Referral of these patients who experience repetitive physical symptoms to psychiatry often leads them to feel that they are not believed or are inventing symptoms. Interestingly, in the psychiatric outpatient setting, it is not uncommon to discover that the symptoms of patients with similar thoughts are due to overlooked organic causes. In this respect, it is necessary to be curious and open-minded about the chronic effects of a disease such as COVID-19 that can only be fully understood with time.

We think that psychiatrists have 2 critical duties here. First, because we are facing a disease whose etiology and long-term symptomatology are not yet fully defined, prematurely diagnosing potential long COVID symptoms as psychiatric disorders may harm the patient by delaying the appropriate treatment. For example, frequent complaints such as shortness of breath, palpitations, and fatigue should not be immediately considered to reflect “anxiety”.2 This attitude may cause an inaccurate diagnosis overlooking the underlying disease, affecting the treatment and the patient's compliance. Therefore a very detailed psychiatric history and examination, inclusive of premorbid characteristics and generating a careful differential diagnosis is essential.

Second, it should not be forgotten that psychiatric symptoms may accompany long COVID. Health anxiety and depressive complaints associated with the feeling of hopelessness can be seen. Insomnia and concentration problems are also common psychiatric findings. Long COVID is a condition that may seriously affect the functioning of patients. Diagnosis and treatment of psychiatric symptoms can significantly improve patients' quality of life. Thus, a careful psychiatric examination and effective treatment of psychiatric comorbidities are crucial in patients with COVID-19. There is no information in the literature that psychotropic medicines that are routinely used in the treatment of the previously mentioned psychiatric conditions cause worsening of physical symptoms. Psychotherapy options should be evaluated in cases where there is hesitation about psychopharmacology. In particular, cognitive behavioral therapy is considered to be effective on postviral fatigue and may be useful in long COVID.6

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Mathilde Horn,a,⁎ Thomas Fovet,a,b Guillaume Vaiva,a,b Fabien D'Hondt,a,b and Ali Amad

Somatic symptom disorders and long COVID: A critical but overlooked topic

https://dx.doi.org/10.1016%2Fj.genhosppsych.2021.06.007

Published

25-Jun-21

Letter to the Editor

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233051/

As psychiatric symptoms often accompany long COVID, several authors point out the need to discriminate psychiatric from physical symptoms, suggesting that wrongly considering symptoms such as fatigue, insomnia, shortness of breath, as psychiatric symptoms may overlook the underlying disease and delay the appropriate treatment [2]. We agree that people with mental health problems have poorer physical health than the general population and that they face additional obstacles to access appropriate care. Nevertheless, we also think that the reverse is true. The diagnoses of SSD or related disorders are often delayed, after patients have received inappropriate and excessive “diagnosis” testing, dangerous or ineffective therapies, and multiple, often unnecessary, referrals. Considering the risk of SSD following hospitalization related to COVID-19 infection, its potentially detrimental effects on the patient's quality of life, and consequent cost for the health care systems, early detection and optimal management of SSD is essential. For this purpose, Toussaint et al. have recently developed the SSD scale (SSD-12), a self-rating questionnaire composed of 12 items, designed to assess patients' perceptions of their symptom-related thoughts, feelings, and behaviors using questions directly based on the DSM-5 criteria. SSD-12 appears as an easy tool that should assist clinicians in the diagnosis and assessment of SSD [3]. Patients with a diagnosis of SSD should then benefit from multidisciplinary care based on the biopsychosocial model [4]. The main objective of this approach is to help the patients to realize that persistent symptoms arise from the interaction of physiological, cognitive, behavioral, emotional and social factors, which need to be addressed concurrently.

Finally, recent literature has highlighted the importance of consultation-liaison psychiatrists (CLPs) in the evaluation of hospitalized patients with COVID-19 [2,5,6]. Indeed, as CLPs use to work with other specialist clinicians, they are particularly well-positioned to manage COVID-19 patients with, or at risk for, SSD who are hospitalized [6]. We believe that a multidisciplinary health care approach of SSD in the context of COVID-19 is an important measure to reduce the psychological impact of the COVID-19 pandemic.

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S.N. Mosolov

Long-Term Psychiatric Sequelae of SARS-CoV-2 Infection

10.21265/PSYPH.2021.31.25.001

Published

13-Jul-05

Review

https://www.researchgate.net/profile/Sergey-Mosolov/publication/355118551_Dlitelnye_psihiceskie_narusenia_posle_perenesennoj_ostroj_koronavirusnoj_infekcii_SARS-CoV-2_Long-Term_Psychiatric_Sequelae_of_SARS-CoV-2_Infection/links/615ec49efbd5153f47eac566/Dlitelnye-psihiceskie-narusenia-posle-perenesennoj-ostroj-koronavirusnoj-infekcii-SARS-CoV-2-Long-Term-Psychiatric-Sequelae-of-SARS-CoV-2-Infection.pdf

This psychopathological symptom complex occurs twice as often in patients with COVID-19 as in patients with other acute respiratory viral infections, and is detected in almost one third of all cases and in two thirds of patients with severe coronavirus infection that required hospital admission. Despite the lack of a clear understanding of the pathogenesis, risk factors, prognosis and outcomes of psychopathological symptoms of PCS, it should be regarded as COVID-19 complication that is associated with direct viral damage of the central nervous system (CNS), negative effects of other organ systems damage (primarily cardiovascular and respiratory), and stress response. Considering that the majority of mental health complications, such as asthenia and cognitive deficit, are often accompanied by neurological symptoms, are closely adhered to them and indicate damage of the CNS, it is proposed to define neuropsychiatric PCS as “Brain Long COVID”.

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Gellan K.AhmedabEman M.KhedraDina A.HamadcTaghreed S.MeshrefcMustafa M.HashemaMai M.Alyd

Long term impact of Covid-19 infection on sleep and mental health: A cross-sectional study

https://doi.org/10.1016/j.psychres.2021.114243

Published

12-Oct-21

Study

https://www.sciencedirect.com/science/article/pii/S0165178121005382

Only 8.8% had no psychiatric symptoms while 91.2% had psychiatric symptoms as follow (poor sleep (64.8%), PTSD (28.6%), somatization (41.8%), obsessive-compulsive (OCD) (19.8%), depression (11.5%), anxiety (28%), phobic-anxiety (24.2%), psychoticism (17.6%)). Diabetes, oxygen support or mechanically ventilated were a risk for sleep impairment, while high Neutrophil/lymphocyte ratio(NLR) was the only risk factor for PTSD. Other psychiatric illnesses had several risk factors: being female, diabetes, oxygen support or mechanically ventilated. Abnormal sleep, somatization and anxiety are the most common mental illnesses in Post-Covid19. The critical group is common associated with PTSD, anxiety, and psychosis. Being female, diabetic, having oxygen support or mechanically ventilated, and high NLR level are more vulnerable for mental illness in post COVID19.
•The long-term impact of the COVID-19 pandemic on mental health in people is unclear.
•Abnormal sleep, somatization, and anxiety are the most common mental illnesses in Post-Covid19.
•The critical group is common associated with PTSD, anxiety, and psychosis.
•Being female, diabetic, having oxygen support or mechanically ventilated, and high NLR level are more vulnerable for mental illness in post COVID19.

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Rafael A. Rivas-Vazquez, PsyDa,*; Mark A. Blais, PsyDb; and Enrique Carrazana, MDc

Does Anxiety Sensitivity Complicate Recovery From COVID-19 Infection?

https://doi.org/10.4088/PCC.21br03145

Published

18-Nov-21

Case Reports

https://www.psychiatrist.com/pcc/covid-19/anxiety-sensitivity-recovery-covid-19-infection/

We recently assessed 3 individuals recovering from mild COVID-19, none requiring hospitalization or respiratory support, but who were now presenting with panic attacks. Their ages ranged from 29 to 42 years, and all were in good premorbid health. None had cardiovascular or pulmonary disease or other medical comorbidities. Two had no past psychiatric history; one reported a remote history of treatment for anxiety. As a group, they described fatigue, mental dullness, shortness of breath (particularly upon exertion), and difficulty returning to exercise or their normal activity levels. In obtaining detailed history, these patients appeared to demonstrate anxiety sensitivity.
Our patients all described heightened vigilance to the somatic sensations that are typically being reported by long haulers (particularly, shortness of breath, chest tightness, fatigue upon exertion) and fear that these sensations meant compromised health status and inability to resume or maintain their premorbid psychosocial functioning. We were struck by how these cognitions triggered rapid escalation of nervousness, anxiety, and panic symptoms. All 3 patients reported reluctance to engage in activities that may elicit physical or somatic symptoms that could mimic or induce panic-like sensations. In addition to appropriate pharmacologic treatment, recommendations included educational and cognitive-behavioral interventions targeting this hypervigilance and misinterpretation of somatic symptoms. We recommend that practitioners be attentive to the possibility of anxiety sensitivity when assessing patients presenting post–COVID-19 infection, as this may complicate recovery and return to premorbid functioning.

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Mario GennaroMazzaabMariagraziaPalladiniaRebeccaDe LorenzobcBeatriceBraviaSaraPolettiabRobertoFurlanbdFabioCiceribc

One-year mental health outcomes in a cohort of COVID-19 survivors

https://doi.org/10.1016/j.jpsychires.2021.11.031

Published

Study

https://www.sciencedirect.com/science/article/pii/S0022395621006804

We evaluated 402, 216, and 192 COVID-19 survivors respectively at one, six, and 12 months. A subgroup of 95 patients was evaluated longitudinally both at one, six, and 12 months. Validated self-report questionnaires were administered to assess depression, fatigue, anxiety, and post-traumatic distress. Socio-demographics and setting of care information were gathered for each participant.
At six and twelve months, respectively 94 (44%) and 86 (45%) patients self-rated in the clinical range in at least one psychopathological dimension. Pathological fatigue at twelve months was detected in 63 patients (33%). Considering the longitudinal cohort an interaction effect of sex and time was observed for depression (F = 8.63, p < 0.001) and anxiety (F = 5.42, p = 0.005) with males showing a significant increasing trend of symptoms, whereas an opposite course was observed in females.

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Nicole WallbridgeBourmistrova1$TomasSolomon1$PhilipBraude2RebeccaStrawbridge34#BenCarter

Long-term effects of COVID-19 on mental health: A systematic review

https://doi.org/10.1016/j.jad.2021.11.031

Published

16-Nov-21

Review

https://www.sciencedirect.com/science/article/pii/S0165032721012532

Highlights
•This is the first systematic review to assess longer term psychiatric disorders symptom for COVID-19 survivors.
•33 studies were included involving 6,743 participants, with outcomes assessed between one to three months after diagnosis
•From the included studies there was no evidence that survivors experienced worse anxiety, or depression than would be expected to the general population levels

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VeraNezgovorovaaCasara JeanFerrettiaStefanoPallantiabEricHollandera

Modulating neuroinflammation in COVID-19 patients with obsessive-compulsive disorder

https://doi.org/10.1016/j.jpsychires.2021.11.025

Published

17-Nov-21

Review

https://www.sciencedirect.com/science/article/pii/S0022395621006749

Exacerbation of symptoms of obsessive-compulsive disorder (OCD) during COVID-19 or new onset of the OCD symptoms resulting from COVID-19 infection is an understudied area of research. It is possible that increased proinflammatory immune status is associated with the onset of obsessive-compulsive symptoms in patients with COVID-19 and that targeted anti-inflammatory treatments for COVID-19 infection can mitigate the new onset of Obsessive-Compulsive (OC) spectrum symptoms. In this review, we cover OCD pathogenesis as related to COVID-19, summarize the impact of cytokines on behavior, and suggest that anti-cytokine treatments can help mitigate post-COVID-19 and new onset of the OC symptoms.

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A.Kachaner1L.Cedric2D.Julie3D.Salmon4B.Ranque5T.De Broucker6M.Elodie3

Diagnostic de trouble fonctionnel somatique chez des patients atteints de symptômes neurologiques inexpliqués post-COVID-19 : l’étude SOMATiC (Somatic Symptom Disorder Triggered by COVID-19)

https://doi.org/10.1016/j.revmed.2021.10.293

Published

24-Nov-21

Study

https://www.sciencedirect.com/science/article/pii/S0248866321010171

La plupart des patients ayant des symptômes neurologiques persistants médicalement inexpliqués après un COVID-19 non sévère remplissent les critères diagnostiques d’un trouble fonctionnel somatique selon le DSM-5. Une prise en charge spécifique du trouble fonctionnel dans le COVID long pourrait ainsi permettre d’envisager une amélioration clinique de ces patients.

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Angel Yun-Kuan Thye 1,Jodi Woan-Fei Law 1 ,Loh Teng-Hern Tan 1,2 ,Priyia Pusparajah 1,Hooi-Leng Ser 1 ,Sivakumar Thurairajasingam 2,*,Vengadesh Letchumanan 1,* andLearn-Han Lee 1,*

Psychological Symptoms in COVID-19 Patients: Insights into Pathophysiology and Risk Factors of Long COVID-19

https://doi.org/10.3390/biology11010061

Published

2-Jan-22

Review

https://www.mdpi.com/2079-7737/11/1/61/htm

The neuro-invasive potential of certain coronaviruses has been observed in the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). Based on past outbreaks, including SARS, MERS, and current reports of neuropsychiatric complications following COVID-19, many survivors may be at risk of a number of neuropsychiatric sequelae. Mounting evidence has shown the presence of mental health implications in COVID-19 survivors. This review shows that psychological symptoms including anxiety, depression, and post-traumatic stress disorder (PTSD) have an association with post-COVID-19 infection. The exact cause of these psychiatric sequelae is yet to be determined, but it seems to involve environmental, psychological, and biological factors. Although there are variations in terms of risk factors and the prevalence rate of these psychological symptoms, risk factors including the female gender and having a history of psychiatric disorders appears to be consistent a across few studies, and there are studies showing a higher prevalence rate among post-COVID-19 survivors than among the general population. A therapeutic intervention commonly used to alleviate these psychological symptoms are psychotropic medications, but probiotics could be a safe adjunctive treatment to improve these symptoms.
There is growing evidence of studies associating COVID-19 survivors with increased mental health consequences. Mental health implications related to a COVID-19 infection include both acute and long-term consequences. Here we discuss COVID-19-associated psychiatric sequelae, particularly anxiety, depression, and post-traumatic stress disorder (PTSD), drawing parallels to past coronavirus outbreaks. A literature search was completed across three databases, using keywords to search for relevant articles. The cause may directly correlate to the infection through both direct and indirect mechanisms, but the underlying etiology appears more complex and multifactorial, involving environmental, psychological, and biological factors. Although most risk factors and prevalence rates vary across various studies, being of the female gender and having a history of psychiatric disorders seem consistent. Several studies will be presented, demonstrating COVID-19 survivors presenting higher rates of mental health consequences than the general population. The possible mechanisms by which the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the brain, affecting the central nervous system (CNS) and causing these psychiatric sequelae, will be discussed, particularly concerning the SARS-CoV-2 entry via the angiotensin-converting enzyme 2 (ACE-2) receptors and the implications of the immune inflammatory signaling on neuropsychiatric disorders. Some possible therapeutic options will also be considered.

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Rodolfo FurlanDamianoaMaria Julia GuimarãesCarusoaAlissom VittiCincotoaCristiana Castanhode Almeida RoccaaAntoniode Pádua SerafimaPedroBacchiaBruno F.GuedesbAndré R.BrunonicdefPedro MarioPangRicardoNitrinibScottBeachhiGregoryFricchionehiGeraldoBusattoaEuripedes ConstantinoMiguelaOrestes V.ForlenzaaHCFMUSP COVID-19 Study Group1

Post-COVID-19 psychiatric and cognitive morbidity: Preliminary findings from a Brazilian cohort study

https://doi.org/10.1016/j.genhosppsych.2022.01.002

Published

6-Jan-22

Study

https://www.sciencedirect.com/science/article/pii/S0163834322000020

Highlights
•This is the first study to capture psychiatric diagnosis in a large cohort of post-COVID-patients using structured clinical interview.
•We found a high prevalence of psychiatric diagnosis, such as generalized anxiety disorder, depression, and post-traumatic stress disorder as well cognitive issues 6 months post-COVID-19.
•Our findings do not point out to a relationship between disease severity at baseline and the degree of mental and cognitive impairment.
Diagnoses of ‘depression’, ‘generalized anxiety disorder’ and ‘post-traumatic stress disorder’ were established respectively in 8%, 15.5% and 13.6% of the sample. After pandemic onset (i.e., within the previous year), the prevalence of ‘depression’ and ‘generalized anxiety disorder’ were 2.56% and 8.14%, respectively. Memory decline was subjectively reported by 51.1% of the patients. Psychiatric or cognitive outcomes were not associated with any clinical variables related to the severity of acute-phase disease, nor by disease-related psychosocial stressors.
Conclusions
This is the first study to access rates of psychiatric and cognitive morbidity in the long-term outcome after moderate or severe forms of COVID-19 using standardized measures. As a key finding, there was no significant association between clinical severity in the acute-phase of SARS-CoV-2 infection and the neuropsychiatric impairment 6 to 9 months thereafter.

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César Fernández-de-las-Peñas Open the record for César Fernández-de-las-Peñas , José D. Martín-Guerrero , Ignacio Cancela-Cilleruelo , Paloma Moro-López-Menchero , Jorge Rodríguez-Jiménez and Oscar J. Pellicer-Valero

Trajectory curves of post-COVID anxiety/depressive symptoms and sleep quality in previously hospitalized COVID-19 survivors: the LONG-COVID-EXP-CM multicenter study

https://doi.org/10.1017/S003329172200006X

Published

10-Jan-22

Study

https://www.cambridge.org/core/journals/psychological-medicine/article/trajectory-curves-of-postcovid-anxietydepressive-symptoms-and-sleep-quality-in-previously-hospitalized-covid19-survivors-the-longcovidexpcm-multicenter-study/A036B60A0F9CE23EE03E1577E64D30B8

No previous study has investigated the trajectory curve of anxiety/depressive symptoms as post-COVID sequelae. We present here a study investigating the trajectory curves of post-COVID anxiety/depressive symptoms as well as sleep quality, fitted with an exponential trajectory model, in previously hospitalized COVID-19 survivors.

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Ricardo Titze-de-Almeida, Thaylise Ramalho da Cunha, Letícia Dias dos Santos Silva, Clarisse Santos Ferreira, Caroline Pena Silva, Adriana Pinheiro Ribeiro, Agenor de Castro Moreira Santos Júnior, Pedro Renato de Paula Brandão, Andrezza Paula Brito Silva, Márcia Cristina Oliveira da Rocha, Mary-Ann Elvina Xavier, Simoneide Souza Titze-de-Almeida, Helena Eri Shimizu & Raimundo Nonato Delgado-Rodrigues

Persistent, new-onset symptoms and mental health complaints in Long COVID in a Brazilian cohort of non-hospitalized patients

https://doi.org/10.1186/s12879-022-07065-3

Published

8-Feb-22

Study

https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-022-07065-3

Background
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections lead to acute- and chronic Long COVID (LC) symptoms. However, few studies have addressed LC sequelae on brain functions. This study was aimed to examine if acute symptoms of coronavirus disease 2019 (COVID-19) would persist during LC, and if memory problems would be correlated with sleep, depressive mood, or anxious complaints.
Methods
Our work followed a cohort of 236 patients from two public hospitals of the Federal District in mid-western Brazil. Patients’ interviews checked for clinical symptoms during acute and LC (5–8 months after real-time reverse transcription polymerase chain reaction, RT-qPCR).
Results
Most cases were non-hospitalized individuals (86.3%) with a median age of 41.2 years. While myalgia (50%), hyposmia (48.3%), and dysgeusia (45.8%) were prevalent symptoms in acute phase, fatigue (21.6%) followed by headache (19.1%) and myalgia (16.1%) commonly occurred during LC. In LC, 39.8% of individuals reported memory complaints, 36.9% felt anxious, 44.9% felt depressed, and 45.8% had sleep problems. Furthermore, memory complaints were associated with sleep problems (adjusted OR 3.206; 95% CI 1.723–6.030) and depressive feelings (adjusted OR 3.981; 95% CI 2.068–7.815).
Conclusions
The SARS-CoV-2 infection leads to persistent symptoms during LC, in which memory problems may be associated with sleep and depressive complaints.

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Milena NogueiraAzevedoab#Elisângela da SilvaRodriguesdh#Emília Augusta Franz VieiraPassosaeMárcio Andrade BarretoFilhoacAna Paula AndradeBarretoacMarcelo Chalhoub CoelhoLimaafMauricio LimaBarretodLuis Fernando SilvaCastro-de-Araujodg

Multimorbidity associated with anxiety symptomatology in post-COVID patients

https://doi.org/10.1016/j.psychres.2022.114427

Published

3-Feb-22

Study

https://www.sciencedirect.com/science/article/pii/S0165178122000415

Highlights
•Few studies have described post-covid conditions in a population, mainly de low/middle-income country.
•Multimorbidity was significantly associated with anxiety symptomatology.
•Being male and aging reduced the anxiety and depression score.
Abstract
The COVID-19 pandemic hit individuals with chronic conditions the hardest. It is known that anxiety symptoms are frequent in post-COVID conditions. We want to examine whether multimorbidity is associated with anxiety in post-COVID patients. We reported descriptive statistics from 389 post-COVID patients and perform a linear regression with anxiety symptoms measured using the Hospital Anxiety and Depression (HAD) scale. For each extra chronic condition, there was a mean increase of 0.11 in the HAD-anxiety score. However, there was a reduction for age and being male. These findings can potentially help policy-makers better organize post-COVID health services and improve patients care.

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Lamyae Benzakour Frédéric Assal Julie Anne Péron

Covid long neuropsychologique : origine neurologique ou psychiatrique ?

Published

Article

https://www.revmed.ch/revue-medicale-suisse/2021/revue-medicale-suisse-736/covid-long-neuropsychologique-origine-neurologique-ou-psychiatrique

Résumé
Parmi les symptômes de Covid long, les séquelles neuropsychologiques sont fréquentes dans les suites d’une infection par le SARS-CoV-2, et ce quel que soit le degré de sévérité de l’atteinte respiratoire en phase aiguë. Ces déficits semblent résulter d’une atteinte neurologique, mais aussi de l’installation de troubles psychiatriques. En plus de l’inflammation, qui joue un rôle majeur dans la genèse des séquelles neuropsychologiques, les hypothèses de lésions endothéliales systémiques, de l’existence d’un neurotropisme du SARS-CoV-2, de même que de celles de l’effet du stress et de la mise en jeu de l’axe hypothalamo-hypophysaire-surrénalien, sont proposées. Les complications psychiatriques de l’infection par le SARS-CoV-2 semblent, quant à elles, n’expliquer qu’une partie des séquelles neuropsychologiques.
Implications pratiques
• Les séquelles neuropsychologiques dans les suites de l’infection par le SARS-CoV-2 sont fréquentes
• Le risque de séquelles neuropsychologiques ne dépend pas du niveau de sévérité de l’atteinte respiratoire de l’infection par le SARS-CoV-2 en phase aiguë
• Les troubles psychiatriques expliquent une partie des séquelles neuropsychologiques et doivent être recherchés mais des causes neurologiques peuvent également être incriminées
• La recherche sur le Covid long doit ouvrir des pistes thérapeutiques, en permettant de mieux caractériser les mécanismes sous-tendant les séquelles neuropsychologiques afin d’optimiser la prise en charge

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Cristina Delgado-Alonso 1,María Valles-Salgado 1,Alfonso Delgado-Álvarez 1,Natividad Gómez-Ruiz 2 ,Miguel Yus 2 ,Carmen Polidura 2,Carlos Pérez-Izquierdo 3,Alberto Marcos 1,María José Gil 1 ,Jorge Matías-Guiu 1 andJordi A. Matias-Guiu 1,*

Examining Association of Personality Characteristics and Neuropsychiatric Symptoms in Post-COVID Syndrome

https://doi.org/10.3390/brainsci12020265

Published

14-Feb-22

Article

https://www.mdpi.com/2076-3425/12/2/265/htm

Highlights
•Few studies have described post-covid conditions in a population, mainly de low/middle-income country.
•Multimorbidity was significantly associated with anxiety symptomatology.
•Being male and aging reduced the anxiety and depression score.
Abstract
The COVID-19 pandemic hit individuals with chronic conditions the hardest. It is known that anxiety symptoms are frequent in post-COVID conditions. We want to examine whether multimorbidity is associated with anxiety in post-COVID patients. We reported descriptive statistics from 389 post-COVID patients and perform a linear regression with anxiety symptoms measured using the Hospital Anxiety and Depression (HAD) scale. For each extra chronic condition, there was a mean increase of 0.11 in the HAD-anxiety score. However, there was a reduction for age and being male. These findings can potentially help policy-makers better organize post-COVID health services and improve patients care.

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Alicia W. Villanueva Van Den Hurk, Cady Ujvari, View ProfileNoah Greenspan, View ProfileDolores Malaspina, Xavier F. Jimenez, View ProfileJulie Walsh-Messinger

Childhood Trauma Exposure Increases Long COVID Risk

https://doi.org/10.1101/2022.02.18.22271191

pre-print

22-Feb-22

Study

https://www.medrxiv.org/content/10.1101/2022.02.18.22271191v1.full-text

Methods Participants (N=338) completed online measures of premorbid health, COVID-19 positivity, symptoms, recovery, depression, anxiety, and post-traumatic stress disorder (PTSD). Questionnaires about childhood and recent traumatic experiences were completed by half of the sample (N=162).
Results Fifty-three percent of participants developed long COVID, of whom over 60% endorsed exercise intolerance and protracted myalgias, headaches, brain fog, and shortness of breath. Participants who experienced at least one childhood traumatic event were 3-fold more likely to develop the syndrome (OR=3.11, 95% CI, 1.49 to 6.48), while risk was nearly 6-fold increased for two or more events (OR=5.67, CI, 2.44 to 13.13). Regression models showed childhood trauma (OR=5.32, CI, 1.44 to 19.68), older age (OR=1.11, CI, 1.06 to 1.16), female sex (OR=4.02, CI, 1.34 to 12.12), along with chest pain (OR=8.77, CI, 2.80 to 27.43), brain fog (OR=3.33, CI, 1.16 to 9.57) and phantosmia (OR=5.90, CI, 1.40 to 24.86) during acute illness accurately classified long COVID status in 87% of participants.
Interpretations Early adversity is a risk-factor for long COVID, likely due to altered immune response, central sensitization, and peripheral dysfunction. Childhood trauma, a crucial social determinant of health, should be routinely assessed in COVID-19 survivors and may aid in determining prognosis.

todo

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Ziyad Al-Aly

Mental health in people with covid-19

https://doi.org/10.1136/bmj.o415

Published

17-Feb-22

Opinion

https://www.bmj.com/content/376/bmj.o415

In April 2021, we published a large-scale systematic characterisation of the clinical manifestations of long covid—the post-acute sequelae that result from an infection with SARS-CoV-2.1 We followed people for six months and showed that covid-19 can lead to post-acute sequelae in nearly every organ system, including increased risk of mental health disorders.
The research prompted calls from patients and healthcare practitioners to do a detailed analysis with longer follow-up to better understand the risks of the mental health outcomes experienced by people with covid-19.
In our recent study, published in The BMJ, we perform a comprehensive in-depth evaluation of the risks of mental health disorders in people with covid-19 at one year.2 The results show that even when compared to contemporaneous controls of people who did not have covid-19, but were exposed to the same adverse forces of the pandemic—including economic, social, and other stressors—those with covid-19 exhibited increased risk of mental health outcomes. This was consistent in analyses versus a historical control group from a pre-pandemic era.
Our research catalogues the breadth of post-acute mental health outcomes experienced by people with covid-19 including depression, anxiety, and stress and adjustment disorders. There was also evidence of increased risk of substance use disorders, neurocognitive decline, and sleep problems. These risks were evident even among those people whose disease was mild and did not require hospital admission for covid-19.
Altogether, the findings suggest that people with covid-19 are experiencing increased rates of mental health outcomes, which could have far-reaching consequences. The increased risk of opioid use is of particular concern, especially considering the high rates of opioid use disorders pre-pandemic. The increased risks of mental health outcomes in people with covid-19 demands greater attention now to mitigate much more serious downstream consequences in the future.
Some may use our findings to gaslight or dismiss long covid as a psychosomatic condition or explain the myriad manifestations of long covid as the result of mental illness. This dismissal is contrary to scientific evidence and is harmful to patients and communities. Mental health disorders represent one part of the multifaceted nature of long covid which can affect nearly every organ system (including the brain, heart, and kidneys). Our results should be used to promote awareness of this risk among people with covid-19 and to guide efforts for the early identification and treatment of affected individuals.
The body of evidence on long covid—from our work and others—suggests the need to reframe our thinking about SARS-CoV-2. It is not only a respiratory virus; it is a systemic virus that may provoke damage and clinical consequences in nearly every organ system—including mental health disorders and neurocognitive decline.
Long covid demands greater attention now to better understand it, prevent it, and treat affected individuals. International bodies, governments, and other stakeholders must pay attention. Failure to attend to the risks of long covid risks amplifying the profound losses we have experienced in this global pandemic.

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Scott Weich

Mental health after covid-19

https://doi.org/10.1136/bmj.o326

Published

16-Feb-22

Editorial

https://www.bmj.com/content/376/bmj.o326

What do these studies tell us? Both report significant and consistent but modest associations between SARS-CoV-2 infection and increased rates of psychiatric disorders. Although between group differences persist for at least 12 months,7 the absolute risk of experiencing a psychiatric disorder decreases sharply after the first month.9 Both studies were susceptible to residual confounding and potential misclassification of recurrent versus first onset infections, limiting causal inference and interpretation. Importantly, mental healthcare might have been more accessible to those known to have had covid-19 than contemporaries without this condition or among historical cohorts, further biasing estimates away from the null.10
What have we learnt? Time, money, and scarce research expertise have been devoted to showing, again and on a societal scale, that threat makes people anxious but diminishes for most people when the danger passes.1 Further confirmation has shown that those who are most disadvantaged experience the worst (mental) health outcomes, particularly after the harms caused by a decade of austerity in the UK and many other countries.1112 Health inequalities have widened, particularly for people with serious mental illness who have experienced even more exclusion and premature mortality during the pandemic.1213
The worst of the pandemic might be behind us in terms of mortality and social restrictions. Taking stock, it could be argued that much of the research concerned with the mental health impacts of covid-19 represents more hindsight than insight. Looking back at what happened is arguably less important than reflecting on what we have learnt, what we need to do next, and what we still do not know. Our attachment to syndromal phenotypes14 means that we have learnt remarkably little about the causes of mental ill health—in this case psychopathology associated with a viral pandemic. We continue to generate more heat than light as we reflect on the usual biopsychosocial suspects10 without cutting through to conclusive insights or effective interventions.
We do not yet know the true incidence and consequences of long covid,15 and we are still witnessing the unfolding toll of the pandemic on healthcare staff.16 Also, we do not have an effective response to the devastating disruption to health, social care, and voluntary sector services on the lives of people with serious mental illness.17 And while epidemiological research has flourished—at least in terms of scientific publications—we are guilty of failing to prioritise evaluations of mental healthcare interventions, including clinical trials, just when these are most needed.

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Yan Xie, Evan Xu, Ziyad Al-Aly

Risks of mental health outcomes in people with covid-19: cohort study

https://doi.org/10.1136/bmj-2021-068993

Published

16-Feb-22

Study

https://www.bmj.com/content/376/bmj-2021-068993

Results The covid-19 group showed an increased risk of incident anxiety disorders (hazard ratio 1.35 (95% confidence interval 1.30 to 1.39); risk difference 11.06 (95% confidence interval 9.64 to 12.53) per 1000 people at one year), depressive disorders (1.39 (1.34 to 1.43); 15.12 (13.38 to 16.91) per 1000 people at one year), stress and adjustment disorders (1.38 (1.34 to 1.43); 13.29 (11.71 to 14.92) per 1000 people at one year), and use of antidepressants (1.55 (1.50 to 1.60); 21.59 (19.63 to 23.60) per 1000 people at one year) and benzodiazepines (1.65 (1.58 to 1.72); 10.46 (9.37 to 11.61) per 1000 people at one year). The risk of incident opioid prescriptions also increased (1.76 (1.71 to 1.81); 35.90 (33.61 to 38.25) per 1000 people at one year), opioid use disorders (1.34 (1.21 to 1.48); 0.96 (0.59 to 1.37) per 1000 people at one year), and other (non-opioid) substance use disorders (1.20 (1.15 to 1.26); 4.34 (3.22 to 5.51) per 1000 people at one year). The covid-19 group also showed an increased risk of incident neurocognitive decline (1.80 (1.72 to 1.89); 10.75 (9.65 to 11.91) per 1000 people at one year) and sleep disorders (1.41 (1.38 to 1.45); 23.80 (21.65 to 26.00) per 1000 people at one year). The risk of any incident mental health diagnosis or prescription was increased (1.60 (1.55 to 1.66); 64.38 (58.90 to 70.01) per 1000 people at one year). The risks of examined outcomes were increased even among people who were not admitted to hospital and were highest among those who were admitted to hospital during the acute phase of covid-19. Results were consistent with those in the historical control group. The risk of incident mental health disorders was consistently higher in the covid-19 group in comparisons of people with covid-19 not admitted to hospital versus those not admitted to hospital for seasonal influenza, admitted to hospital with covid-19 versus admitted to hospital with seasonal influenza, and admitted to hospital with covid-19 versus admitted to hospital for any other cause.
Conclusions The findings suggest that people who survive the acute phase of covid-19 are at increased risk of an array of incident mental health disorders. Tackling mental health disorders among survivors of covid-19 should be a priority.

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Sarah Houben-Wilke 1 Author Image ; Yvonne MJ Goërtz 1, 2, 3 Author Image ; Jeannet M Delbressine 1 Author Image ; Anouk W Vaes 1 Author Image ; Roy Meys 1, 2, 3 Author Image ; Felipe VC Machado 1, 2, 3 Author Image ; Maarten van Herck 1, 2, 3, 4 Author Image ; Chris Burtin 4 Author Image ; Rein Posthuma 1, 2, 3 Author Image ; Frits ME Franssen 1, 2, 3 Author Image ; Herman Vijlbrief 5 Author Image ; Yvonne Spies 5 Author Image ; Alex J van 't Hul 6 Author Image ; Martijn A Spruit 1, 2, 3 Author Image ; Daisy JA Janssen 1, 7 Author Image

The Impact of Long COVID-19 on Mental Health: Observational 6-Month Follow-Up Study

https://doi.org/10.2196/33704

Published

Study

https://mental.jmir.org/2022/2/e33704/

Objective:
In this longitudinal, observational study, we aimed to reveal symptoms of posttraumatic stress disorder (PTSD) and symptoms of anxiety and depression up to 6 months after the onset of COVID-19–related symptoms in patients with confirmed COVID-19 and persistent complaints. To demonstrate the impact in nonhospitalized patients, we further aimed to compare these outcomes between nonhospitalized and hospitalized patients.
Methods:
Demographics, symptoms of PTSD (Trauma Screening Questionnaire [TSQ] ≥6 points) and symptoms of anxiety and depression (Hospital Anxiety and Depression Scale [HADS] ≥8 points) were assessed at 3 and 6 months after the onset of COVID-19–related symptoms in members of online long COVID-19 peer support groups.
Results:
Data from 239 patients with confirmed COVID-19 (198/239, 82.8% female; median age: 50 [IQR 39-56] years) were analyzed. At the 3-month follow-up, 37.2% (89/239) of the patients had symptoms of PTSD, 35.6% (85/239) had symptoms of anxiety, and 46.9% (112/239) had symptoms of depression, which remained high at the 6-month follow-up (64/239, 26.8%, P=.001; 83/239, 34.7%, P=.90; 97/239, 40.6%, P=.08, respectively; versus the 3-month follow-up). TSQ scores and HADS anxiety and depression scores were strongly correlated at the 3- and 6-month follow-ups (r=0.63-0.71, P<.001). Symptoms of PTSD, anxiety, and depression were comparable between hospitalized (n=62) and nonhospitalized (n=177) patients.
Conclusions:
A substantial percentage of patients with confirmed COVID-19 and persistent complaints reported symptoms of PTSD, anxiety, or depression 3 and 6 months after the onset of COVID-19–related symptoms. The prevalence rates of symptoms of PTSD, anxiety, and depression were comparable between hospitalized and nonhospitalized patients and merely improved over time. Health care professionals need to be aware of these psychological complications and intervene on time in post-COVID-19 patients with persistent complaints.

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Nadia A.Liyanage-DonabMelodie R.WinawercMarla J.HambergercSachinAgarwalcAlison R.TrainoraKristal A.QuispeaIan M.Kronishab

Association of depression and COVID-induced PTSD with cognitive symptoms after COVID-19 illness

https://doi.org/10.1016/j.genhosppsych.2022.02.006

Published

2-Mar-22

Study

https://www.sciencedirect.com/science/article/pii/S016383432200024X

Results
Among 153 participants, 44.4% reported at least one cognitive symptom, 18.3% were depressed, and 23.5% had COVID-induced PTSD. Adjusting for covariates, depression (OR 5.15, 95% CI 1.30–20.35, p = 0.02) and COVID-induced PTSD (OR 3.67, 95% CI 1.13–11.89, p = 0.03) were significantly associated with cognitive symptoms; self-reported history of mental illness was also associated (OR 4.90, 95% CI 1.24–19.41, p = 0.02).
Conclusions
Depression, COVID-induced PTSD, and prior mental illness were strongly associated with cognitive symptoms three months after acute COVID-19 illness.

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Jean-LucMommaertsMD, MSc, PhD

Where is the mind in COVID-19 causality?

https://doi.org/10.1016/j.bbih.2022.100434

Published

9-Mar-22

Article

https://www.sciencedirect.com/science/article/pii/S2666354622000242

Two years into the pandemic, hardly any studies have been done regarding the influence of the mind on COVID-19. However, there is much circumstantial evidence. The mind influences the body in ways relevant to COVID-19. Unfortunately, of the scientifically proven mental factors influencing immunology, many have been intensified by lockdowns. Relevant research might help us see COVID-19 not as a disease straightforwardly caused by a virus but by a whirlpool of factors in which the virus and mind play essential roles. Social nocebo (mass psychogenic illness) may be a significant mind-related factor in the whirlpool through heightening the suggestive idea that worse will come. This insight might bring a more profound view of the human social condition, transcending the present disaster. Meanwhile, the whirlpool metaphor may help acute COVID-19 patients and long-haulers, letting them understand that their mind is one element in the whole, no more and no less.

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Virginie FreytagNathalie SchicktanzDavid CoynelThomas SchlittEhssan AminiAndreas PapassotiropoulosDominique de Quervain

The Swiss Corona Stress Study: Long Covid symptoms in relation to stress and depressive symptoms

https://doi.org/10.31219/osf.io/2x4pg

pre-print

22-Mar-22

Study

https://osf.io/2x4pg/

Background: An infection with SARS-CoV-2 can lead to long-term health problems known as Long Covid or Post Covid-19 condition. Whereas Long Covid symptoms may induce stress and depressive symptoms, it is also possible that stress and depressive symptoms can contribute to some of the symptoms. Importantly, stress levels and depressive symptoms have been found to be increased during the pandemic and may be also increased after infection. When investigating the prevalence of Long Covid symptoms it seems therefore important to use well-matched controls and to take stress levels and depressive symptoms into account.
Methods: We conducted a survey study in over 11’000 subjects in the framework of the Swiss Corona Stress Study (4th survey, November 2021) and assessed stress levels and depressive symptoms (PHQ-9) along with physical and neurological symptoms of the past two weeks. From the 1’428 participants reporting at least one SARS-CoV-2 positive PCR test (98% non-hospitalized), we created 3 non-overlapping groups based on the date of the last reported positive test: at least 9 months before the study (n=774); between 9 and 3 months before the study (n=238); within 3 months before the study (n=416). For each group, we selected an equally sized subset of matched participants from the study pool of 9’651 subjects who didn’t report any SARS-CoV-2 positive test.
Results: We found that the prevalence of several physical/neurological symptoms was significantly higher in SARS-CoV-2 positives as compared to the negative controls at all 3 time points. For participants who report having been tested positive at least 9 months ago, the top 3 symptoms as compared to negative controls were loss of smell/taste (prevalence positives: 20%, prevalence negatives: 1%, p=4.0E-20), rapid physical exhaustion (prevalence positives: 29%, prevalence negatives: 15%, p=2.3E-10) and fever (prevalence positives: 10%, prevalence negatives: 3%, p=1.9E-8). Stress levels and depressive symptoms were significantly associated with increased prevalence for most of the symptoms in both SARS-CoV-2 positives and negative controls. However, a history of SARS-CoV-2 infection was not significantly associated with heightened levels of stress or depressive symptoms at any of the investigated time intervals, and a higher prevalence of symptoms in these participants was also observed under adjustment for psychological state measures.
Conclusion: The present results indicate that SARS-CoV-2 positivity is associated with higher prevalence of physical or neurological symptoms independently from stress levels or depressive symptoms.

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Sy Atezaz Saeed MD, MS, Irene S. Pastis MD & Melody Grace Santos MD

COVID-19 and its impact on the brain and Mind- A conceptual model and supporting evidence

https://doi.org/10.1007/s11126-022-09980-9

Published

18-Mar-22

Review

https://link.springer.com/article/10.1007/s11126-022-09980-9

Although the reported symptoms of COVID-19 are primarily respiratory with acute respiratory distress syndrome, SARS-CoV-2 has also been shown to affect other organs, including brain, and there are growing reports of neuropsychiatric symptoms due to COVID-19. There are two suggested pathways for how COVID-19 can affect the brain and mind: the direct impact on the brain and impact mediated via stress. Direct impact on the brain is manifested as encephalitis/encephalopathy with altered mental status (AMS) and delirium. In this paper, we summarize evidence from studies of previous outbreaks and current data from the COVID-19 pandemic that describe how COVID-19 is associated with an increased prevalence of anxiety, stress, poor sleep quality, obsessive-compulsive symptoms, and depression among the general population during the pandemic. In addition, we summarize the current evidence that supports how COVID-19 can also impact the CNS directly and result in delirium, cerebrovascular events, encephalitis, unspecified encephalopathy, AMS, or peripheral neurologic disorders.

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Alexandra Burton 1, Henry Aughterson 1, Daisy Fancourt 1, Keir E J Philip 2

Factors shaping the mental health and well-being of people experiencing persistent COVID-19 symptoms or 'long COVID': qualitative study

https://doi.org/10.1192/bjo.2022.38

Published

21-Mar-22

Study

https://pubmed.ncbi.nlm.nih.gov/35307048/

Background: Around one in ten people who contract COVID-19 report persistent symptoms or 'long COVID'. Impaired mental health and well-being is commonly reported, including anxiety, depression and reduced quality of life. However, there is limited in-depth research exploring why mental health and well-being are affected in people experiencing long COVID.
Aims: To explore factors affecting mental health and well-being from the perspective of people with long COVID.
Method: Semi-structured qualitative interviews were audio-recorded and transcribed. Data were analysed using reflexive thematic analysis. Twenty-one people with long COVID participated in the study. Participants were eligible if they self-reported a positive swab test/antibody test or one or more commonly reported COVID-19 symptoms at illness onset. and experiences of one or more long COVID symptoms ≥3 weeks following illness onset.
Results: Five themes were identified across participant accounts regarding factors affecting mental health and well-being, including symptoms causing severe disruption to daily life, lack of service and treatment options, uncertainty of illness trajectories, experiences of care and understanding from others and changes to identity.
Conclusions: People with long COVID experience a range of factors that negatively affect their mental health and well-being. Providing patient-centred health services that integrate rapidly evolving research in this area is important, as are peer support groups and supported approaches to self-management.

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Zheng-An Lu 1,†,Le Shi 1,†,Jian-Yu Que 1,Yong-Bo Zheng 1,2,Qian-Wen Wang 1,Wei-Jian Liu 1,Yue-Tong Huang 1,Xiao-Xing Liu 1,Kai Yuan 1,Wei Yan 1,Jie Shi 3,Yan-Ping Bao 3,* andLin Lu 1,2,3,*

Accessibility to Digital Mental Health Services among the General Public throughout COVID-19: Trajectories, Influencing Factors and Association with Long-Term Mental Health Symptoms

https://doi.org/10.3390/ijerph19063593

Published

17-Mar-22

Study

https://www.mdpi.com/1660-4601/19/6/3593/htm

Digital mental health services (DMHSs) have great potential for mitigating the mental health burden related to COVID-19, but public accessibility (ease of acquiring services when needed) to DMHSs during the pandemic is largely unknown. Accessibility to DMHSs was tracked longitudinally among a nationwide sample of 18,804 adults in China from before to one year after COVID-19 outbreak. Unconditional and conditional latent growth curve models and latent growth mixture models were fitted to explore the overall growth trend, influencing factors, and latent trajectory classes of accessibility to DMHSs throughout COVID-19. Generalized estimating equation models and generalized linear mixed models were employed to explore the association between accessibility to DMHSs and long-term mental health symptoms. We found that people generally reported increased difficulty in accessing DMHSs from before to one year after COVID-19 outbreak. Males, youngsters, individuals with low socioeconomic status, and individuals greatly affected by COVID-19 reported greater difficulty in accessing DMHSs. Four DMHS accessibility trajectory classes were identified: “lowest–great increase” (6.3%), “moderate low–slight increase” (44.4%), “moderate high–slight decrease” (18.1%) and “highest–great decrease” (31.2%). Trajectory classes reporting greater difficulty in accessing DMHSs were at higher risk for long-term mental symptoms. In conclusion, an overall increase in difficulty in accessing DMHSs is observed throughout COVID-19, and heterogeneity exists in DMHS accessibility trajectories. Our results suggest that easy access to DMHSs should be consistently facilitated. Moreover, access gaps should be reduced across demographic groups, and target populations for service allocation should alter as the pandemic evolves.

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Tony Kirby

Paul Harrison—investigating the psychiatric sequelae of COVID-19

https://doi.org/10.1016/S2215-0366(22)00116-X

Published

1-Apr-22

Article

https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(22)00116-X/fulltext

The first analysis (published in The Lancet Psychiatry) of more than 60 000 survivors of COVID-19, mostly in the USA, showed that a diagnosis of COVID-19 was associated with an increased incidence of a first or a recurrent psychiatric diagnosis in the following 14 to 90 days compared with six other health events, including influenza, respiratory tract infections, and bone fractures. The greatest increased incidence was found for anxiety disorders. The study also showed that having an existing psychiatric diagnosis was linked to an increased risk of COVID-19. The second study (also published in The Lancet Psychiatry) of more than 230 000 survivors of COVID-19 provided further evidence for substantial psychiatric, and neurological, morbidity in the 6 months after COVID-19 infection. “One in three patients was diagnosed with a psychiatric or neurological condition, and one in eight received their first such diagnosis of this kind”, explains Harrison. “The risks were greatest in, but not limited to, patients who had experienced severe COVID-19.”
The third study, published in PLOS Medicine, studied more than 270 000 patients and found that over one in three had one or more features of long-COVID (such as fatigue, pain, or brain fog) recorded between 3 and 6 months after a diagnosis of COVID-19. This was significantly higher than after influenza. The risk of long-COVID features was higher in patients who had more severe COVID-19 illness, and slightly higher among females. White and non-White patients were equally affected. “We plan to extend our work to look at longer-term follow up, as well as to see whether the effects of the virus are evolving over time, in relation to change in dominance of differing variants”, explains Harrison.
Other studies that his team has carried out include one showing a marked increase in eating disorders since the pandemic began. He has also just begun a detailed study into brain fog, which will conduct a battery of tests on volunteers with the condition to try to identify the causes and potential treatments. “Early clues are that this could be related to persistent inflammation, or small blood clots in the blood vessels of the brain”, he says.

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Lily A.BrownaEmilyBallentineaYiqinZhuaEmily L.McGinleybLilianaPezzincBenjaminAbramoffd

The unique contribution of depression to cognitive impairment in Post-Acute Sequelae of SARS-CoV-2 infection

https://doi.org/10.1016/j.bbih.2022.100460

Published

12-Apr-22

Study

https://www.sciencedirect.com/science/article/pii/S2666354622000503

Highlights
•Depression was positively associated with cognitive impairment post-COVID-19 infection.
•Depression was associated with lower performance on verbal fluency, attention, and delayed recall.
•Perceived sleep concerns predicted self-reported memory disturbances.
•Neither PTSD nor anxiety predicted cognitive impairment memory.
Background
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with significant cognitive impairment and increased risk for mental health comorbidities. This study aimed to identify specific associations between cognitive impairment, self-reported disruptions in memory, and psychiatric symptoms including depression, anxiety, posttraumatic stress disorder (PTSD), and perceived sleep concerns.
Methods
Data collected from all consecutive patients with Post-Acute Sequelae of SARS-CoV-2 infection (PASC) who presented to a dedicated Post-COVID Clinic were used to evaluate whether certain psychiatric symptoms were more strongly associated with cognitive impairment and self-reported memory disturbances.
Results
Univariate and multivariable analyses revealed that depression symptom severity was significantly associated with the severity of cognitive impairment among patients with PASC. This association was driven primarily by lower performance on verbal fluency, attention, and delayed recall tasks among patients with higher depression symptoms severity. Perceived sleep concerns were an important predictor of self-reported memory disturbances. Conversely, neither PTSD symptom severity nor anxiety symptom severity were significant predictors of cognitive impairment or self-reported memory disturbances.
Conclusions
These findings have important clinical implications for justifying the need for screening patients with PASC for both depression and cognitive impairment.

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Michele Fabrazzo1*, Antonio Russo2, Mario Luciano1, Alessio Camerlengo1, Pierluigi Catapano1, Bianca Amoroso1, Francesco Catapano1 and Nicola Coppola2

Delirium and Psychiatric Sequelae Associated to SARS-CoV-2 in Asymptomatic Patients With Psychiatric History and Mild Cognitive Impairment as Risk Factors: Three Case Reports

https://doi.org/10.3389/fpsyt.2022.868286

Published

7-Apr-22

Study

https://www.frontiersin.org/articles/10.3389/fpsyt.2022.868286/full

Human coronaviruses have neuroinvasive and neurotropic abilities that might explain psychiatric outcomes in affected patients. We hypothesized that delirium might be the sole clinical manifestation or even the prodrome of a psychiatric episode consistent with the mental history of a few infected patients with a preexisting diagnosed cognitive impairment. We examined three patients with preexisting mild cognitive impairment and delirium at admission for suspected SARS-CoV-2 infection. We diagnosed delirium using DSM-5 and Confusion Assessment Method (CAM) and measured consciousness level by the Glasgow Coma Scale. All the patients had no history of fever, respiratory complications, anosmia or ageusia, meningitis, and negative cerebrospinal fluid analysis for SARS-CoV-2. Our first patient had no psychiatric history, the second reported only a depressive episode, and the third had a history of bipolar disorder dated back to 40 years before. In the first patient, delirium resolved 2 days following the admission. The other two patients recovered in 4 and 14 days, and delirium appeared as the prodrome of a new psychiatric episode resembling past events. Clinicians should monitor the possibility that SARS-CoV-2 presence in the brain might clinically manifest in the form of delirium and acute psychiatric sequelae, even without other systemic symptoms. Psychiatric history and preexisting mild cognitive impairment are to be considered as predisposing factors for COVID-19 sequelae in delirium patients.

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Sara Nowakowski 1,2,3,*ORCID,Manasa Kokonda 1,2,Rizwana Sultana 4,Brittany B. Duong 4,Sarah E. Nagy 4,Mohammed F. Zaidan 4,Mirza M. Baig 4,Bryan V. Grigg 5,Justin Seashore 4 andRachel R. Deer 6,7ORCID

Association between Sleep Quality and Mental Health among Patients at a Post-COVID-19 Recovery Clinic

https://doi.org/10.3390/brainsci12050586

Published

30-Apr-22

Study

https://www.mdpi.com/2076-3425/12/5/586/htm

A growing body of research documents the persistence of physical and neuropsychiatric symptoms following the resolution of acute COVID-19 infection. To the best of our knowledge, no published study has examined the interaction between insomnia and mental health. Accordingly, we proposed to examine new diagnoses of insomnia, and referrals to pulmonary and sleep medicine clinics for treatment of sleep disorders, in patients presenting to one post-acute COVID-19 recovery clinic. Additionally, we aimed to examine the relationship between poor sleep quality, depression, anxiety, and post-traumatic stress. Patients presented to the clinic on average 2 months following COVID-19 infection; 51.9% (n = 41) were hospitalized, 11.4% (n = 9) were in the intensive care unit, 2.5% (n = 2) were on a mechanical ventilator, and 38.0% (n = 30) were discharged on oxygen. The most commonly reported symptom was fatigue (88%, n = 70), with worse sleep following a COVID-19 infection reported in 50.6% (n = 40). The mean PSQI score was 9.7 (82.3%, n = 65 with poor sleep quality). The mean GAD-7 score was 8.3 (22.8%, n = 14 with severe depression). The mean PHQ-9 was 10.1 (17.8%, n = 18 with severe anxiety). The mean IES-6 was 2.1 (54.4%, n = 43 with post-traumatic stress). Poor sleep quality was significantly associated with increased severity of depression, anxiety, and post-traumatic stress. Future work should follow patients longitudinally to examine if sleep, fatigue, and mental health symptoms improve over time.

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Daniel Richter, Hannah Schulze, Jeyanthan Charles James, Nadine Siems, Nadine Trampe, Ralf Gold, Christos Krogias & Simon Faissner

Hypoechogenicity of brainstem raphe in long-COVID syndrome–less common but independently associated with depressive symptoms: a cross-sectional study

https://doi.org/10.1007/s00415-022-11154-3

Published

12-May-22

Study

https://link.springer.com/article/10.1007/s00415-022-11154-3

Objective
Long coronavirus disease (Long-COVID) syndrome is a hitherto poorly understood phenomenon with a broad spectrum of symptoms, including depression and anxiety. Depressive symptoms have been associated with brainstem raphe (BR) alterations in transcranial sonography (TCS) that might reflect dysfunction of the serotonergic system. The primary aim was to investigate the connection of BR alterations with depressive and anxiety symptoms in patients with Long-COVID syndrome.
Methods
In a cross-sectional study design, we included outpatients fulfilling the criteria of Long-COVID syndrome. All patients were examined by TCS in the axial plane with focus on BR signal alterations. The Hospital Anxiety and Depression Scale (HADS) was used to test for symptoms of anxiety and depression.
Results
We included n = 70 patients with Long-COVID syndrome, of which 28.6% (n = 20) exhibited a reduced echogenicity of BR in the TCS examination. Patients with hypoechogenic BR had higher subscores for anxiety and depression compared to normoechogenic patients (HADS depression: median 8 versus 5.5, p = 0.006; HADS anxiety: median 9 versus 6.5, p = 0.006). After adjustment for reasonable confounders, only the odds ratio (OR) for relevant depressive symptoms was higher among Long-COVID patients with hypoechogenic raphe (adjusted OR 3.884, 95% CI 1.244–12.123).
Discussion
Hypoechogenic BR alterations are independently associated with depressive symptoms in Long-COVID patients but are not highly frequent. Future studies should investigate whether the hypoechogenicity of the BR is a direct consequence or whether it reflects a priori a higher susceptibility to depressive symptoms after COVID-19, thus enabling to identify COVID-19 patients at higher risk of developing Long-COVID depressive symptoms.

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Candi M. C. Leung, Margaret K. Ho, Alina A. Bharwani, Hugo Cogo-Moreira, Yishan Wang, Mathew S. C. Chow, Xiaoyan Fan, Sandro Galea, Gabriel M. Leung & Michael Y. Ni

Mental disorders following COVID-19 and other epidemics: a systematic review and meta-analysis

https://doi.org/10.1038/s41398-022-01946-6

Published

17-May-22

Systematic Review

https://www.nature.com/articles/s41398-022-01946-6

COVID-19 has imposed a very substantial direct threat to the physical health of those infected, although the corollary impact on mental health may be even more burdensome. Here we focus on assessing the mental health impact of COVID-19 and of other epidemics in the community. We searched five electronic databases until December 9, 2020, for all peer-reviewed original studies reporting any prevalence or correlates of mental disorders in the general population following novel epidemics in English, Chinese or Portuguese. We synthesised prevalence estimates from probability samples during COVID-19 and past epidemics. The meta-analytical effect size was the prevalence of relevant outcomes, estimated via random-effects model. I2 statistics, Doi plots and the LFK index were used to examine heterogeneity and publication bias. This study is pre-registered with PROSPERO, CRD42020179105. We identified 255 eligible studies from 50 countries on: COVID-19 (n = 247 studies), severe acute respiratory syndrome (SARS; n = 5), Ebola virus disease (n = 2), and 1918 influenza (n = 1). During COVID-19, we estimated the point prevalence for probable anxiety (20.7%, 95% CI 12.9–29.7), probable depression (18.1%, 13.0–23.9), and psychological distress (13.0%, 0–34.1). Correlates for poorer mental health include female sex, lower income, pre-existing medical conditions, perceived risk of infection, exhibiting COVID-19-like symptoms, social media use, financial stress, and loneliness. Public trust in authorities, availability of accurate information, adoption of preventive measures and social support were associated with less morbidity. The mental health consequences of COVID-19 and other epidemics could be comparable to major disasters and armed conflicts. The considerable heterogeneity in our analysis indicates that more random samples are needed. Health-care professionals should be vigilant of the psychological toll of epidemics, including among those who have not been infected.

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Zsófia Ocsovszky1, József Otohal1, Blanka Berényi2, Vencel Juhász1, Réka Skoda1, Laura Bokor1, Zsófia Dohy1, Liliána Szabó1, György Nagy3,4, Dávid Becker1, Béla Merkely1,5, and Hajnalka Vágóvagoha@gmail.com1,5

The associations of long-COVID symptoms, clinical characteristics and affective psychological constructs in a non-hospitalized cohort

https://doi.org/10.1556/2060.2022.00030

Published

16-May-22

Study

https://akjournals.com/view/journals/2060/aop/article-10.1556-2060.2022.00030/article-10.1556-2060.2022.00030.xml

Objective
The effects of COVID-19, especially long-COVID, on the psychological health is incompletely understood. We aimed to evaluate the mid-term associations of the long-COVID symptoms and affective factors in a cohort of non-hospitalized patients.
Method
A total of 166 patients were enrolled in this study, including 119 sedentary/non-athlete and 47 athlete subjects at the Post-COVID Outpatient Clinic of Semmelweis University. Clinical data regarding acute and long-term symptoms were obtained and detailed laboratory testing was carried out. Demographic data and psychological tests were collected.
Results
We found a positive association between the level of depressive symptoms and anxiety and long-COVID symptom count, while life satisfaction and social support correlated negatively with the long-COVID symptom count. Higher haemoglobin levels and lower LDL-cholesterol were also shown to be moderating factors. A regression model showed that symptoms during acute infection, depression, age, and life satisfaction are predictors of the long-COVID symptom count. The presence of pre-existing affective or anxiety problems was also associated with higher reported long-COVID symptom count. Furthermore, we found significant association between pre-existing mental health problems and the investigated psychological constructs.
Conclusion
It appears that long COVID-19 is associated with acute symptoms and mental factors. Depression and anxiety have been shown to have a negative effect on symptom perception, and also contribute to a higher number of symptoms in a non-hospitalized sample. Our study suggests bi-directional interconnection between clinical and psychological factors.

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Dirk Schmoll

Long-COVID: Worauf kann sich der psychiatrische Gutachter stützen?
Long COVID: what can the psychiatric expert use for support?

https://doi.org/10.1007/s00115-022-01317-y

Published

24-May-22

Opinion

https://link.springer.com/article/10.1007/s00115-022-01317-y

Vor dem Hintergrund, dass als pathophysiologisches Korrelat eine Viruspersistenz, ein autoinflammatorischer/autoimmunologischer Prozess und eine Hyperkoagulabilität mit Endotheldysfunktion im Gehirn diskutiert werden, stellt sich die Frage, ob sich nicht doch somatische Befunde erheben lassen, die die Sicherheit einer Kausalitätsbeurteilung erhöhen können? Dabei wäre daran zu denken, einen Antikörpernachweis im Serum und Liquor und vielleicht sogar einen Antigennachweis zu fordern, ggf. auch ein cMRT. Ist dies nicht sogar geboten angesichts einer kürzlich in JAMA Internal Medicine publizierten Studie, in der sich zeigte, dass Menschen ohne Antikörper mehr Krankheitssymptome angaben als diejenigen mit einer nachweisbaren COVID-Erkrankung [1]? Ist das nicht ein Hinweis darauf, dass die Erwartungshaltung neben anderen psychogenen Faktoren die Ausprägung kognitiver oder somatoformer Störungen wesentlich prägt?

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Sabine Hellwig & Katharina Domschke

Post-COVID-Syndrom – Fokus Fatigue
Post-COVID syndrome—Focus fatigue

https://doi.org/10.1007/s00115-022-01306-1

Published

23-May-22

Article

https://link.springer.com/article/10.1007/s00115-022-01306-1

The World Health Organization (WHO) defines post-coronavirus disease 2019 (COVID-19) as a condition which occurs in individuals with a history of probable or confirmed severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection 3 months after the onset of COVID-19 symptoms, lasts for at least 2 months and cannot be explained by an alternative diagnosis. Core symptoms of post-COVID syndrome are fatigue, dyspnea and cognitive dysfunction, which have an impact on everyday functional level. Neuropsychiatric late sequelae are common in COVID-19 patients, with incidence rates over 30%. Beside the abovementioned core symptoms, sleep disorders, depression and anxiety show increased incidences. According to current opinion, associated neuropsychiatric symptoms are subsumed under the term post-COVID syndrome but are also interpreted as comorbidities, which can promote the manifestation of a post-COVID syndrome. The key symptom fatigue shows symptom overlapping and comorbidity with psychiatric disorders. Imaging studies indicate an organic correlate of fatigue in post-COVID patients. Furthermore, psychosocial aspects and psychiatric comorbidities, such as depression and anxiety disorders as modulating and therefore potentially treatable factors were identified. Treatment of fatigue consists of pharmacological management with stimulants and antidepressants as well as nonpharmacological strategies, most notably cognitive behavioral therapy and exercise-focused interventions. The evidence for this comes from meta-analyses of tumor-associated or post-viral fatigue.

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Carmen Cecilia Caballero-Domínguez,John Carlos Pedrozo-PupoORCID Icon &Adalberto Campo-AriasORCID Icon

Depression among COVID-19 survivors in Colombia

https://doi.org/10.1080/13548506.2022.2085879

Published

6-Jun-22

Study

https://www.tandfonline.com/doi/abs/10.1080/13548506.2022.2085879

The COVID-19 survivors are at high risk of meeting the criteria for depression. However, few studies have explored its prevalence and associated factors. The study aimed to know the frequency and variables associated with depression among COVID-19 survivors in Santa Marta, Colombia. A sample of COVID-19 survivors was included. Depression was quantified with the Patient Health Questionnaire (PHQ-9, α = 0.85). Three hundred and thirty survivors participated in the research. They were aged between 18 and 89 years, 61.5% were women, and 49.7% of participants scored above the cut-off point for depression. Depression was associated with female gender, younger age, COVID moderate or severe, and having presented symptoms for more than three weeks. In conclusion, depression occurs in half of the COVID-19 survivors and is higher in younger, women and who report more severe symptoms. Longitudinal studies can provide further information on the long-term impact on the mental health of COVID-19 survivors.

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Mario Gennaro Mazza, Mariagrazia Palladini, Sara Poletti & Francesco Benedetti

Post-COVID-19 Depressive Symptoms: Epidemiology, Pathophysiology, and Pharmacological Treatment

https://doi.org/10.1007/s40263-022-00931-3

Published

21-Jun-22

Review

https://link.springer.com/article/10.1007/s40263-022-00931-3

The Coronavirus Disease 2019 (COVID-19) pandemic is still spreading worldwide over 2 years since its outbreak. The psychopathological implications in COVID-19 survivors such as depression, anxiety, and cognitive impairments are now recognized as primary symptoms of the “post-acute COVID-19 syndrome.” Depressive psychopathology was reported in around 35% of patients at short, medium, and long-term follow-up after the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection. Post-COVID-19 depressive symptoms are known to increase fatigue and affect neurocognitive functioning, sleep, quality of life, and global functioning in COVID-19 survivors. The psychopathological mechanisms underlying post-COVID-19 depressive symptoms are mainly related to the inflammation triggered by the peripheral immune-inflammatory response to the viral infection and to the persistent psychological burden during and after infection. The large number of SARS-CoV-2-infected patients and the high prevalence of post-COVID-19 depressive symptoms may significantly increase the pool of people suffering from depressive disorders. Therefore, it is essential to screen, diagnose, treat, and monitor COVID-19 survivors’ psychopathology to counteract the depression disease burden and related years of life lived with disability. This paper reviews the current literature in order to synthesize the available evidence regarding epidemiology, clinical features, neurobiological underpinning, and pharmacological treatment of post-COVID-19 depressive symptoms.
Key Points
Post-COVID-19 depressive symptoms have been reported in around 35% of patients at short, medium, and long-term follow-up after infection.
The psychopathological mechanisms of post-COVID-19 depressive symptoms are mainly related to the peripheral immune-inflammatory response triggered by the viral infection.
Conventional antidepressants have proved to be effective in treating post-COVID-19 depression.

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P72

E.Meppiel

Le « COVID-Long », entre somatique et psychisme : pour une approche intégrativeCovid “long-gauler”: Between somatic and psyche: For an integrative approach

https://doi.org/10.1016/j.praneu.2022.04.010

Published

19-Jun-22

Editorial

https://www.sciencedirect.com/science/article/pii/S187877622200036X

La place du neurologue dans la prise en charge des patients COVID-Long est le plus souvent ponctuelle, dans le but d’assurer au correspondant adressant le patient l’absence de pathologie neurologique évolutive. Il est cependant utile de bien garder en tête ce contexte global et complexe, en évaluant objectivement et individuellement les symptômes neurologiques dont font état les patients, et en pondérant l’indication des examens complémentaires à effectuer. Une IRM cérébrale et une évaluation cognitive seront souvent nécessaires, alors que le PET-scan cérébral reste à ce jour du domaine de la recherche, en dehors d’une indication spécifique non liée au COVID-19. Il est également utile de préciser qu’à ce jour, l’état des connaissances sur le SARS-CoV-2 nous indique qu’il n’y a pas de pathogénicité directe sur le parenchyme cérébral [4], et que les voies olfactives ne sont pas une voie d’entrée du virus vers le système nerveux central [5] contrairement aux hypothèses qui ont pu être émises ces deux dernières années.

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Sergio Machado1,2,4
Eric Murillo-Rodriguez3,4
Claudio Imperatori4,5
Alberto Souza de Sá Filho6

Neuropsychiatric Consequences of COVID-19:
What Do We Know So Far?

https://doi.org/2022;23(4):155-156

Published

1-Jun-22

Review

https://alpha-psychiatry.com/Content/files/sayilar/177/AP_July_2022-155-156.pdf

Studies indicate that COVID-19 causes long-term mental health sequelae in individuals who have recovered from the disease1
. For this reason, a global movement towards recognition and planning of how to deal with mental health problems for all those impacted by the global pandemic is being carried out, whether patients or healthcare professionals. In addition, a better understanding of the role of the virus in the pathophysiology of mental health disorders and long-term mental health sequelae is needed.
According to the existing literature, the neuropsychiatric consequences of COVID-19 appear to be due to several factors, such as the direct effect of the infection, the body's responses against the infection, or the psychological sequelae of social isolation, unemployment, and fear for health and well-being. Subsistence3
. Pandi-Perumal et al.4 showed evidence that COVID-19 virus affects the central nervous system (CNS), and that people who recover from COVID-19 develop neurological symptoms such as headache, paresthesia, and changes in levels of consciousness, cerebral edema and neurodegeneration, as well as several acute and long-term neuropsychiatric symptoms. Another important point discussed by authors is that brain pathologies associated with COVID-19 can also impact long-term cognitive status after COVID-19 recovery.
According to the studies, the greater the severity of COVID-19, the greater the likelihood of CNS complications, such as symptoms similar to chronic fatigue, neurocognitive deficits, which persist even after recovery from COVID-192
. An increase in symptoms of depression, anxiety and trauma-related stress has also been observed due to the economic crisis and isolation from friends and family. But we cannot forget that the pandemic has had consequences not only for adults, but also for children who have started to study remotely and stay away from friends, as well as changing their routines lead to adaptation disorders, acute stress and other conditions.
Corroborating Pandi-Perumal et al.4, Nakamura et al.5 showed that more than 30% of hospitalized patients with COVID-19 had symptoms of cognitive impairment, depression and anxiety that lasted for months after recovery from COVID-19, more common and more severe in patients who required intensive care for severe effects of COVID-19. It was also discussed that in addition to the psychological stress related to the pandemic, several biological mechanisms were thought to be responsible for post-COVID-19 neuropsychiatric symptoms.
Therefore, there is no consensus on whether the manifestations of psychiatric disorders result ffrom social causes or whether CNS complications may be responsible, but literature indicates a particularly high prevalence of insomnia, fatigue, cognitive impairment, and anxiety disorders in the first 6 months post-COVID-19.

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Jennifer A. Frontera, MD1; Naomi M. Simon, MD, MSc2

Bridging Knowledge Gaps in the Diagnosis and Management of Neuropsychiatric Sequelae of COVID-19

https://doi.org/10.1001/jamapsychiatry.2022.1616

Published

29-Jun-22

Special Communication

https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2793903

Importance Neuropsychiatric symptoms have been reported as a prominent feature of postacute sequelae of COVID-19 (PASC), with common symptoms that include cognitive impairment, sleep difficulties, depression, posttraumatic stress, and substance use disorders. A primary challenge of parsing PASC epidemiology and pathophysiology is the lack of a standard definition of the syndrome, and little is known regarding mechanisms of neuropsychiatric PASC.
Observations Rates of symptom prevalence vary, but at least 1 PASC neuropsychiatric symptom has been reported in as many as 90% of patients 6 months after COVID-19 hospitalization and in approximately 25% of nonhospitalized adults with COVID-19. Mechanisms of neuropsychiatric sequelae of COVID-19 are still being elucidated. They may include static brain injury accrued during acute COVID-19, neurodegeneration triggered by secondary effects of acute COVID-19, autoimmune mechanisms with chronic inflammation, viral persistence in tissue reservoirs, or reactivation of other latent viruses. Despite rapidly emerging data, many gaps in knowledge persist related to the variable definitions of PASC, lack of standardized phenotyping or biomarkers, variability in virus genotypes, ascertainment biases, and limited accounting for social determinants of health and pandemic-related stressors.
Conclusions and Relevance Growing data support a high prevalence of PASC neuropsychiatric symptoms, but the current literature is heterogeneous with variable assessments of critical epidemiological factors. By enrolling large patient samples and conducting state-of-the-art assessments, the Researching COVID to Enhance Recovery (RECOVER), a multicenter research initiative funded by the National Institutes of Health, will help clarify PASC epidemiology, pathophysiology, and mechanisms of injury, as well as identify targets for therapeutic intervention.

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Rozenkrantz, Liron Kube, Tobias Bernstein, Michael H. Gabrieli, John D. E.

How beliefs about coronavirus disease (COVID) influence COVID-like symptoms? – A longitudinal study.

https://psycnet.apa.org/doi/10.1037/hea0001219

Published

1-Aug-22

Study

https://psycnet.apa.org/record/2022-83016-001

Objective: Evidence from psychosomatic and nocebo research has indicated that believing one will develop symptoms makes the experience of such symptoms more likely. We applied this idea in the context of coronavirus disease 2019 (COVID-19). Specifically, we assessed whether beliefs regarding COVID-19 predict COVID-like symptoms 3–4 weeks later, and what specific belief has the greatest influence on symptom experience. Method: We conducted two studies with over 300 participants, approached at two successive timepoints, 3–4 weeks apart. Participants reported their experienced symptoms, COVID-19-related beliefs, demographics, and state anxiety. To target COVID-like symptoms, participants who reported having contracted COVID-19 or attributed their symptoms to another known cause were excluded. Regression analyses were conducted to test the predictive value of beliefs regarding COVID-19 on experienced symptoms. Results: A particular belief regarding one’s estimated symptom severity if infected with coronavirus predicted the experience of symptoms 3–4 weeks later (β = .17, p = .011). This result persisted after controlling for potential confounds, including state anxiety (β = .22, p = .002). Findings were preregistered and replicated in a separate cohort. A novel scale for perception of the body’s ability to fight diseases contributed to mediating the effect of estimated symptom severity on later experienced symptoms. Conclusions: A particular belief about estimated symptom severity if infected with COVID predicted the experience of COVID-like physical symptoms several weeks later. These findings contribute to the understanding of the development of unexplained physical symptoms. Furthermore, identification of a particular belief that increases the likelihood of symptoms informs intervention that may mitigate its effects

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Lakshmi Chennapragada,a,⁎ Sarah R. Sullivan,a,b,c Kyra K. Hamerling-Potts,a Hannah Tran,a Jake Szeszko,a Joseph Wrobleski,a Emily L. Mitchell,a Samantha Walsh,d and Marianne Goodmana,b

International PRISMA Scoping Review to Understand Mental Health Interventions for Depression in COVID-19 Patients

https://doi.org/10.1016%2Fj.psychres.2022.114748

Published

25-Jul-22

Review

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9313534/

Preliminary research indicates that the COVID-19 illness affects the mental well-being of patients. This scoping review, thus, aims to examine the current state of research into mental health treatments for depression symptoms in COVID-19 patients. Select databases were searched on 7/1/2021. Full-text articles involved 1) mental health treatment 2) suicide and/or depression outcomes, 3) a quasi-experimental research trial, and 4) a primary analysis. 11 articles were included in this review. The studies spanned 5 countries, and demonstrated immediate positive effects of mental health treatments and tele-health as a treatment modality for depression in COVID-19 patients. 6 studies were randomized controlled trials. Various treatments were administered, including cognitive behavior therapy, mindfulness, and muscle relaxation. Most interventions were conducted in in-patient units and focused on acute symptoms. There were limitations in the design and description of methodology in many studies, which affects the generalizability and replicability of positive findings. Only two studies included a post-intervention follow-up and one study assessed suicide risk. Thus, this review found there is a pressing need for more research in the area, with greater rigor in study methodology, and for treatments targeting long-term symptoms and suicidality, and outpatient services.

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Matthieu Gasnier1,2, Walid Choucha1,2, Francois Radiguer3, Theo Faulet1,2, Kenneth Chappell1,2, Aurore Bougarel1, Christian Kondarjian1, Paul Thorey1, Antoine Baldacci1, Maryne Ballerini1, Abd El Kader Ait Tayeb1,2, Hugo Herrero1,2, Isabelle Hardy-Leger4, Olivier Meyrignac5, Luc Morin6, Anne-Lise Lecoq7, Tài Pham8, Nicolas Noel4, Fabrice Jollant1,2, David Montani9, Xavier Monnet9, Laurent Becquemont2,7, Emmanuelle Corruble

Comorbidity of long COVID and psychiatric disorders after a hospitalisation for COVID-19: a cross-sectional study

http://dx.doi.org/10.1136/jnnp-2021-328516

Published

11-Aug-22

Study

https://jnnp.bmj.com/content/early/2022/08/10/jnnp-2021-328516.abstract

Objectives - Long COVID is a major public health issue. Whether long COVID is comorbid with psychiatric disorders remains unclear. Here, we investigate the association between long COVID, psychiatric symptoms and psychiatric disorders.
Design - Cross-sectional.
Settings - Bicêtre Hospital, France, secondary care.
Participants One hundred seventy-seven patients admitted in intensive care unit during acute phase and/or reporting long COVID complaints were assessed 4 months after hospitalisation for an acute COVID.
Main outcome measures - Eight long COVID complaints were investigated: fatigue, respiratory and cognitive complaints, muscle weakness, pain, headache, paraesthesia and anosmia. The number of complaints, the presence/absence of each COVID-19 complaint as well as lung CT scan abnormalities and objective cognitive impairment) were considered. Self-reported psychiatric symptoms were assessed with questionnaires. Experienced psychiatrists assessed Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition-based diagnoses of psychiatric disorders.
Results - One hundred and fifteen (65%) patients had at least one long COVID complaint. The number of long COVID complaints was associated with psychiatric symptoms. The number of long COVID complaints was higher in patients with psychiatric disorders (mean (m) (SD)=2.47 (1.30), p<0.05), new-onset psychiatric disorders (m (SD)=2.41 (1.32), p<0.05) and significant suicide risk (m (SD)=2.67 (1.32), p<0.05) than in patients without any psychiatric disorder (m (SD)=1.43 (1.48)). Respiratory complaints were associated with a higher risk of psychiatric disorder and new-onset psychiatric disorder, and cognitive complaints were associated with a higher risk of psychiatric disorder.
Conclusions - Long COVID is associated with psychiatric disorders, new-onset psychiatric disorders and suicide risk. Psychiatric disorders and suicide risk should be systematically assessed in patients with long COVID.

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JasminaMalletabcCélieMassinidJulienDubreucqeRomainPadovanifGuillaumeFondcgSélim BenjaminGuessoumh

Santé mentale et Covid : toutes et tous concernés. Une revue narrativeMental health during the Covid pandemic, a narrative review

https://doi.org/10.1016/j.amp.2022.07.019

Published

6-Aug-22

Review

https://www.sciencedirect.com/science/article/pii/S0003448722002219

Résumé - La pandémie de COVID-19 (due au coronavirus SARS-CoV-2) a apporté des défis sans précédent en termes de santé publique, système de soins et vie quotidienne (incluant le travail et l’éducation), particulièrement lors de la première vague pandémique au début de l’année 2020. Afin de limiter la propagation du virus, de nombreux pays ont imposé des mesures restrictives pour favoriser la distanciation sociale, allant des couvre-feux et fermetures d’écoles à un confinement généralisé. Début 2022, on recense 135 000 décès dus au virus SARS-CoV-2 en France et près de 6 millions dans le monde. Au-delà de l’impact possible du SARS-CoV-2 sur le cerveau, la pandémie a été à l’origine de difficultés humaines complexes, avec un retentissement possible sur la santé mentale des populations. Dans cette revue narrative, nous résumons les données actuelles concernant l’impact de la pandémie sur la santé mentale en s’intéressant aux troubles psychiatriques en population générale et parmi les groupes vulnérables. L’objectif est de promouvoir une prévention ciblée sur ces populations. Notre revue a identifié plusieurs sous-groupes de sujets plus à risque de troubles psychiques dans le contexte de la pandémie de COVID-19 : les endeuillés par la COVID-19, les adolescents, les étudiants, les personnes atteintes par le virus (avec une atteinte potentiellement directe sur le cerveau) et enfin, le personnel de santé. Les disparités de genre ont également été accentuées, en défaveur des femmes. Des mesures de dépistage et de prévention doivent être prises pour limiter l’impact de cette pandémie sur la santé mentale. D’une façon plus générale, l’approche « une santé/one health » qui place la santé humaine (et donc mentale) à l’interface de la santé environnementale et animale semble indispensable pour éviter la survenue de ce type de pandémie et ses conséquences à l’avenir.
Abstract - The COVID-19 pandemic (caused by the Sars-CoV-2 coronavirus) led to unprecedented challenges to public health, the healthcare system, and our daily lives (including work and education), particularly during the first wave in early 2020. In order to control infection of the virus, many countries have imposed restrictive measures to promote social distancing, ranging from curfews and school closures to widespread lockdown. At the beginning of 2022, there were 135,000 deaths from Sars-CoV-2 in France (nearly 6 million worldwide). Beyond the possible impact of Sars-CoV-2 on the brain, the pandemic has created complex human situations, with a possible impact on the mental health of populations. In this narrative review, we summarize current data on the impact of the pandemic on mental health in the general population and identify the most vulnerable groups. The goal is to provide more targeted prevention for these populations. Our review has identified several subgroups of subjects at higher risk of disorder in the context of the COVID-19 pandemic: those bereaved by COVID-19, adolescents, students, people with COVID (with potentially direct brain damages), and finally, health care workers. Gender disparities were accentuated, leading to more mental disorders in women. Longitudinal follow-up studies are needed to better identify the effects of the pandemic on the mental health of different populations, and also to define personalized prevention strategies. Screening and prevention measures must be taken to limit the impact of this pandemic on mental health. More generally, the “one health” approach, which places human health at the interface of environmental and animal health, seems essential to avoid the occurrence of this type of pandemic and its consequences in the future.

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W. BierbauerORCID Icon,J. LüscherORCID Icon &U. ScholzORCID Icon |Daryl O’Connor (Reviewing editor:)

Illness perceptions in long-COVID: A cross-sectional analysis in adults

https://doi.org/10.1080/23311908.2022.2105007

Published

27-Jul-22

Study

https://www.tandfonline.com/doi/full/10.1080/23311908.2022.2105007

Symptoms may persist after an acute COVID-19 infection, a phenomenon termed long-COVID. Increasing attention is now directed toward these long-term effects, as many seem to be affected. So far, long-COVID was primarily discussed from a medical perspective, leaving psychological factors on health-related outcomes understudied. Thus, the present study contributes to the current literature by examining Leventhal’s common-sense model of self-regulation, investigating patients’ cognitive and emotional illness perceptions and their association with different health-related outcomes in the context of long-COVID. We examined 246 long-COVID patients (89.0% female, Mage = 45.29 ± 12.12 years), assessing illness perceptions, fatigue, depressive symptoms, anxiety, and quality of life in a cross-sectional survey study. Linear regression analyses were applied to model the unique effects of the illness perception dimension on health-related outcomes. More than half of the sample had elevated levels of depressive symptoms, anxiety, and fatigue. Illness perception dimensions explained between 28% and 37% of the variance across the analyzed health-related outcomes. More symptoms, higher perceived consequences, and higher emotional representation were related to worse health-related outcomes. In general, long-COVID was poorly understood (i.e., low coherence) and perceived as difficult to control (i.e., personal & treatment control). Health professionals involved in counseling should pay close attention to both cognitive and emotional illness perceptions to address possible ways of coping with long-COVID.

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Sverre UrnesJohnson12Ole MyklebustAmundsen4Miriam SinkerudJohnson3AsleHoffart12ØyvindHalsøy1NoraSkjerdingstad1SaraEbling4Omid V.Ebrahimi12

Psychiatric Symptoms in COVID-19-positive Individuals in the General Population: Trajectories of Depression, Anxiety, and Insomnia

https://doi.org/10.1016/j.psychres.2022.114806

Published

21-Aug-22

Study

https://www.sciencedirect.com/science/article/pii/S0165178122003997

Highlights
•Those tested positive for COVID-19 experience higher levels of depression after restrictions are lifted.
•Psychiatric symptoms of SARS-CoV-2-positive individuals decreased over time
•Age and amount of physical activity did not predict the trajectories of anxiety and depression
•There were no significant differences in trajectory when compared to matched controls.
Abstract
The present study investigates differences in the trajectories of anxiety, depression, and sleep problems among infected versus non-infected case-controlled individuals. Patients who tested positive for COVID-19 were selected from a representative sample in Norway (N > 10,000). In total, 126 of these individuals were infected during the project period, and this group was analyzed at T5 (May 2021). Of these positive cases, those who had completed both PHQ-9 and GAD-7 at all three measurement points were selected for longitudinal analysis using multilevel modeling. There was a significant difference at T5 between those who had tested positive for COVID-19 and matched controls. Anxiety and depression were reduced among those who tested positive, but there were no differences in trajectory when compared to matched controls. Limitations include the use of self-report measures and the assessment of symptoms at a time when strict virus mitigation protocols were in place. The present findings indicate that individuals who test positive for COVID-19 exhibit higher levels of depressive symptoms after restrictions are lifted. However, comparison of anxiety and depression symptom trajectories with matched controls reveals that both groups exhibited stable or slightly decreased symptoms.

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Emily A.TroyeraJordan N.KohnaSuziHongab

Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms

https://doi.org/10.1016/j.bbi.2020.04.027

Published

13-Apr-20

Review

https://www.sciencedirect.com/science/article/pii/S088915912030489X

Highlights
•The COVID-19 pandemic is a significant source of psychological distress globally.
•The novel coronavirus and host immunologic response may also directly affect brain and behavior.
•Acute and delayed neuropsychiatric sequelae have been associated with past viral pandemics.
•Prospective monitoring of COVID-19 patients is needed to determine neuropsychiatric outcomes.
•A psychoneuroimmunology perspective will aid in promoting post-pandemic public mental health.
The coronavirus disease 19 (COVID-19) pandemic is a significant psychological stressor in addition to its tremendous impact on every facet of individuals’ lives and organizations in virtually all social and economic sectors worldwide. Fear of illness and uncertainty about the future precipitate anxiety- and stress-related disorders, and several groups have rightfully called for the creation and dissemination of robust mental health screening and treatment programs for the general public and front-line healthcare workers. However, in addition to pandemic-associated psychological distress, the direct effects of the virus itself (several acute respiratory syndrome coronavirus; SARS-CoV-2), and the subsequent host immunologic response, on the human central nervous system (CNS) and related outcomes are unknown. We discuss currently available evidence of COVID-19 related neuropsychiatric sequelae while drawing parallels to past viral pandemic-related outcomes. Past pandemics have demonstrated that diverse types of neuropsychiatric symptoms, such as encephalopathy, mood changes, psychosis, neuromuscular dysfunction, or demyelinating processes, may accompany acute viral infection, or may follow infection by weeks, months, or longer in recovered patients. The potential mechanisms are also discussed, including viral and immunological underpinnings. Therefore, prospective neuropsychiatric monitoring of individuals exposed to SARS-CoV-2 at various points in the life course, as well as their neuroimmune status, are needed to fully understand the long-term impact of COVID-19, and to establish a framework for integrating psychoneuroimmunology into epidemiologic studies of pandemics.

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Maria SimonettaSpadaaAve MariaBiffiaLucaBelottiaLauraCremaschibClaudiaPalumbocClaraLocatellicBruno MarioCesanadEmiBondic

Psychological impact of COVID-19 after hospital discharge: A follow-up study on Italian recovered patients

https://doi.org/10.1016/j.jad.2022.08.086

Published

24-Aug-22

Study

https://www.sciencedirect.com/science/article/pii/S0165032722009417

Highlights
•Few data are available regarding the consequences of COVID-19 on survivors’ mental health over the long-term.
•Authors investigated the psychological impact in 1457 recovered patients during the post-acute phase.
•Almost one third of the sample reported post-traumatic symptoms at follow-up; anxiety was more represented than depression.
•Hospitalization, regardless of the care setting, and promptness in follow-up evaluation play a protective role on recovery.
Background
Since COVID-19 outbreak, clinical experience on its management during the acute phase has rapidly grown, including potential effects on the psychopathological dimension. However, still few data are available regarding the impact on survivors' mental health over the long-term.
Methods
A sample of 1457 COVID-19 patients underwent a multidisciplinary follow-up protocol, approximately 3 months after hospital discharge, including a psychological evaluation. The primary outcomes were anxiety, depression, resilience, post-traumatic symptoms, and health-related quality of life. Furthermore, we examined the potential role of hospitalization and delay in the follow-up assessment on the increased burden of illness.
Results
Although a general high level of resilience emerged, suggesting most patients relied on their individual and interpersonal resources to face difficulties related to the pandemic, almost one third of the sample reported signs of psychological distress over time, especially post-traumatic symptoms, with anxiety being more represented than depression. Furthermore, hospitalization – regardless of the setting of care – and promptness in follow-up evaluation were found to play a protective role on patients' recovery and mental wellbeing.
Limitations
Selection bias of patients exclusively admitted to the hospital; absence of a control group; psychological assessment relying on self-reported instruments.
Conclusions
The current crisis demands resilience and adjustment resources, either in the acute and post-acute phase. Thus, the clinical effort should aim at relieving the traumatic impact of such condition through timely interventions. Further investigation may address potential predictors of developing a traumatic stress response, in order to identify and promptly treat at-risk subpopulations.

2791

P83

Claudio L. A. Bassetti, Raimund Helbok Open the ORCID record for Raimund Helbok[Opens in a new window]
, Kristina Adorjan Open the ORCID record for Kristina Adorjan[Opens in a new window] and Peter Falkai

European Psychiatric Association–European Academy of Neurology statement on post-COVID syndrome

https://doi.org/10.1192/j.eurpsy.2022.2317

Published

8-Sep-22

Statement

https://www.cambridge.org/core/journals/european-psychiatry/article/epaean-statement-on-postcovid-syndrome/54EFFC48E3B0A85654B04C94A08E680F

Proposed mechanisms of persistent and new onset postinfectious disorders include immune dysregulation with persistent low-grade (neuro-)inflammation, immune dysregulation, autoimmunity, and viral persistence in various tissues [Reference Balcom, Nath and Power13]. Each of these hypotheses needs confirmation in larger scale studies and builds upon direct and indirect neuropathogenic effects of SARS-CoV-2 in the acute phase [Reference Spudich and Nath14].
Long-term neurologic manifestations include fatigue, neurocognitive symptoms, sleep–wake disorders, dysautonomia, hyposmia, hypogeusia, and pain syndromes among others [Reference Balcom, Nath and Power13].
Fatigue was shown in a recent meta-analysis including 36 studies and a total of 9,944 participants to be the most common symptom (mean 52.8%; 95% Confidence Interval 19.9–84.4) [Reference Pinzon, Wijaya, Jody, Nunsio and Buana15]. The large 95% confidence intervals highlight the need for a more strict and homogenous definition of the post-COVID syndrome and its symptoms. The authors also suggest a better analysis in future studies of the longitudinal course of symtpoms, which appear to strongly fluctuate within the first year post-SARS-CoV-2 infection and even during the day.
Neurocognitive symptoms are commonly associated with impaired performance in neuropsychological testing and are expected sequelae among ICU survivors including those with COVID-19. Of note, early reports of frontotemporal FDG-PET hypometabolism [Reference Helms, Kremer, Merdji, Clere-Jehl, Schenck and Kummerlen16] during acute COVID-19 have now been replicated in the subacute phase and associated with memory deficits and executive dysfunction [Reference Hosp, Dressing, Blazhenets, Bormann, Rau and Schwabenland17]. Despite longitudinal recovery from cognitive deficits [Reference Blazhenets, Schroeter, Bormann, Thurow, Wagner and Frings18], the increased risk for neurological and psychiatric diagnoses in the 6 months after infection deserves attention [Reference Taquet, Dercon, Luciano, Geddes, Husain and Harrison19]. These data derive from a large retrospective cohort of more than 250,000 survivors of COVID-19 reporting even a higher risk compared to propensity score-matched cohorts of influenza patients and those with other respiratory infections [Reference Taquet, Dercon, Luciano, Geddes, Husain and Harrison19]. Interestingly, even patients with mild and moderate COVID-19 report poor concentration, lack of intellectual clarity and mental fatigue which is referred to as “brain fog” and is poorly captured by conventional testing including the MOCA test [Reference Graham, Clark, Orban, Lim, Szymanski and Taylor20]. This and other consequences of COVID-19 lack of specificity and need a more precise definition. In general, neurological manifestations improve over time [Reference Beghi, Helbok, Ozturk, Karadas, Lisnic and Grosu6, Reference Rass, Beer, Schiefecker, Lindner, Kofler and Ianosi21]; however, long-term effects and new onset neurological diseases including autoimmune diseases and neurodegenerative diseases need close surveillance through national and international registries.

2792

P84

AXD

Siwen Wang, MD1; Luwei Quan, BA2; Jorge E. Chavarro, ScD1,3,4; Natalie Slopen, ScD5; Laura D. Kubzansky, PhD5; Karestan C. Koenen, PhD3,5,6; Jae Hee Kang, ScD4; Marc G. Weisskopf, PhD2; Westyn Branch-Elliman, MD7,8; Andrea L. Roberts, PhD2

Associations of Depression, Anxiety, Worry, Perceived Stress, and Loneliness Prior to Infection With Risk of Post–COVID-19 Conditions

https://doi.org/10.1001/jamapsychiatry.2022.2640

Published

7-Sep-22

Study

https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2796097

Key Points
Question Is psychological distress before SARS-CoV-2 infection associated with risk of COVID-19–related symptoms lasting 4 weeks or longer, known as post–COVID-19 conditions?
Findings This cohort study found that among participants who did not report SARS-CoV-2 infection at baseline (April 2020) and reported a positive SARS-CoV-2 test result over 1 year of follow-up (N = 3193), depression, anxiety, perceived stress, loneliness, and worry about COVID-19 were prospectively associated with a 1.3- to 1.5-fold increased risk of self-reported post–COVID-19 conditions, as well as increased risk of daily life impairment related to post–COVID-19 conditions.
Meaning In this study, preinfection psychological distress was associated with risk of post–COVID-19 conditions and daily life impairment in those with post–COVID-19 conditions.
Abstract
Importance Few risk factors for long-lasting (≥4 weeks) COVID-19 symptoms have been identified.
Objective To determine whether high levels of psychological distress before SARS-CoV-2 infection, characterized by depression, anxiety, worry, perceived stress, and loneliness, are prospectively associated with increased risk of developing post–COVID-19 conditions (sometimes called long COVID).
Design, Setting, and Participants This prospective cohort study used data from 3 large ongoing, predominantly female cohorts: Nurses’ Health Study II, Nurses’ Health Study 3, and the Growing Up Today Study. Between April 2020 and November 2021, participants were followed up with periodic surveys. Participants were included if they reported no current or prior SARS-CoV-2 infection at the April 2020 baseline survey when distress was assessed and returned 1 or more follow-up questionnaires.
Exposures Depression, anxiety, worry about COVID-19, perceived stress, and loneliness were measured at study baseline early in the pandemic, before SARS-CoV-2 infection, using validated questionnaires.
Main Outcomes and Measures SARS-CoV-2 infection was self-reported during each of 6 monthly and then quarterly follow-up questionnaires. COVID-19–related symptoms lasting 4 weeks or longer and daily life impairment due to these symptoms were self-reported on the final questionnaire, 1 year after baseline.
Results Of 54 960 participants, 38.0% (n = 20 902) were active health care workers, and 96.6% (n = 53 107) were female; the mean (SD) age was 57.5 (13.8) years. Six percent (3193 participants) reported a positive SARS-CoV-2 test result during follow-up (1-47 weeks after baseline). Among these, probable depression (risk ratio [RR], 1.32; 95% CI = 1.12-1.55), probable anxiety (RR = 1.42; 95% CI, 1.23-1.65), worry about COVID-19 (RR, 1.37; 95% CI, 1.17-1.61), perceived stress (highest vs lowest quartile: RR, 1.46; 95% CI, 1.18-1.81), and loneliness (RR, 1.32; 95% CI, 1.08-1.61) were each associated with post–COVID-19 conditions (1403 cases) in generalized estimating equation models adjusted for sociodemographic factors, health behaviors, and comorbidities. Participants with 2 or more types of distress prior to infection were at nearly 50% increased risk for post–COVID-19 conditions (RR, 1.49; 95% CI, 1.23-1.80). All types of distress were associated with increased risk of daily life impairment (783 cases) among individuals with post–COVID-19 conditions (RR range, 1.15-1.51).
Conclusions and Relevance The findings of this study suggest that preinfection psychological distress may be a risk factor for post–COVID-19 conditions in individuals with SARS-CoV-2 infection. Future work should examine the biobehavioral mechanism linking psychological distress with persistent postinfection symptoms.

2793

P85

Asmaa Azizi
Doha Achak
Elmadani Saad
Abderraouf Hilali
Ibtissam Youlyouz-Marfak
Abdelghafour Marfak

Post-COVID-19 mental health and its associated factors at 3-months after discharge: A case-control study

https://doi.org/10.1016/j.cegh.2022.101141

Published

10-Sep-22

Study

https://www.ceghonline.com/article/S2213-3984(22)00183-X/fulltext

Background
Mental health disorders are among the most significant sequelae of the COVID-19 pandemic. Therefore, the aim of this study is to investigate the mental health status and associated risk factors of Moroccan COVID-19 survivors 3 months after hospital discharge.
Methods
A case-control study was conducted from September 2021 to February 2022 on 824 participants. 213 were COVID-19 survivors and 611 were control group. Data were collected ether through an online anonymous survey. Anxiety and depression disorders were assessed using Hospital Anxiety and Depression Scale (HADS).
Results
The average age of all participants was 55.17 ± 16.44. Our findings highlighted higher prevalence of mental health disorders including anxiety and depression in COVID-19 survivors at 3 months after hospital discharge (HADS-A = 12.84; HADS-D = 10.91) compared to control group (HADS-A = 9.90; HADS-D = 8.27) (p < 0.001). Older patients, suffering from type 2 diabetes and kidney diseases, admitted to ICU, who stayed a long duration in the hospital, who had severe and longer duration of symptoms and who used Chloroquine, had higher levels of anxiety and depression after discharge.
Conclusions
The present investigation highlights the need to develop a post-COVID-19 rehabilitation programs that can better manage the post COVID-19 impact and restore a good mental health for COVID-19 survivors. Also, to create preventative strategies to limit mental health disorders in COVID-19 survivors.

2794

P86

AXD

John W. Blackett
Milton Wainberg
Mitchell S.V. Elkind
Daniel E. Freedberg

Potential Long Coronavirus Disease 2019 Gastrointestinal Symptoms 6 Months After Coronavirus Infection Are Associated With Mental Health Symptoms

https://doi.org/10.1053/j.gastro.2021.10.040

Published

30-Oct-21

Study

https://www.gastrojournal.org/article/S0016-5085(21)03712-4/fulltext

Over 200 million people globally have been infected with the severe acute respiratory syndrome coronavirus 2, also known as coronavirus disease 2019 (COVID-19).1 Some COVID-19 survivors recover from acute infection yet suffer from persistent symptoms including fatigue, anxiety, and depression.2 New, chronic gastrointestinal (GI) symptoms are also commonly reported after COVID-19.3, 4, 5, 6, 7 There is an established association between mental health symptoms and chronic GI symptoms, especially irritable bowel syndrome (IBS).8,9 However, the association between mental health symptoms and chronic GI symptoms after COVID-19 has not been fully explored.
The Columbia University Institutional Review Board approved this study. This survey study, nested within a prospective cohort of COVID-19 survivors with a minimum of 6 months of follow-up, assessed the hypothesis that mental health symptoms both before and after COVID-19 infection would be associated with post–COVID-19 chronic GI symptoms (see Supplementary Methods for full study details). Of 1783 patients surveyed, 749 (42%) responded (67% women; median age, 43 years). The cohort comprised 61% white, 9.6% black, and 20% other races (with 9.6% choosing not to answer) and 28% Hispanic and 70% non-Hispanic (with 2% choosing not to answer). The survey was completed in English by 93% of respondents and in Spanish by 6.8%. Fifteen percent of patients had been hospitalized for COVID-19, with 1.7% requiring mechanical ventilation.
Six months after COVID-19 diagnosis, 220 patients (29%) reported GI symptoms self-perceived to be related to COVID-19. These included 72 (9.6%) with diarrhea, 83 (11%) with constipation, 70 (9.4%) with abdominal pain, 53 (7.1%) with nausea/vomiting, and 122 (16%) with heartburn (Table 1). A GI symptom was the most bothersome current symptom in 83 patients (11%).

Overall, these results highlight the potential bidirectionality of mental health and chronic GI symptoms after COVID-19, as has previously been observed in non–COVID-19 studies. Anxiety or sadness may exacerbate functional GI symptoms, and functional GI symptoms may lead to anxiety or sadness.10 Alternatively, a common underlying mechanism could explain both GI and mental health symptoms. This study, which involved an assessment made at a single time point, cannot fully determine the temporality between mental health and GI symptoms after COVID-19. This may be a fruitful area for future studies that can use longitudinal assessment strategies to tease apart the causal chain of events and evaluate strategies to improve long-term GI outcomes after COVID-19. Although all patients with chronic GI symptoms should receive screening for comorbid mental health symptoms, this study provides specific evidence that screening COVID-19 survivors will be high yield.
The study has some limitations. The response rate was 42%, raising the possibility of response bias, but, reassuringly, the estimate of prevalence for new GI symptoms after COVID-19 (29%) fell squarely in the middle of the range of 16%–40% from a retrospective study.7 Although post–COVID-19 symptoms were assessed prospectively, reporting of mental health symptoms before COVID-19 was assessed retrospectively and may have been under-reported because of recall bias related to the stigma of such symptoms. Because the survey instrument from which these data were generated was focused primarily on new physical symptoms after COVID-19, there was limited detail on the characteristics of current mental health symptoms. Importantly, the association found between mental health symptoms and GI symptoms after COVID-19 is not necessarily causal. It is possible that post–COVID-19 GI symptoms may be partially due to heightened stress and anxiety arising from pandemic-related lifestyle changes rather than the direct consequence of severe acute respiratory syndrome coronavirus 2 infection. In future studies, a control group assessing the incidence of new GI symptoms in patients who tested negative for COVID would help to clarify this question.
In summary, we observed very strong associations between mental health symptoms and post–COVID-19 GI symptoms. Nearly one-third of patients (29%) reported at least 1 new GI symptom after COVID-19. These were not trivial, because over 10% of the cohort reported a GI symptom as their most bothersome COVID-19–related condition.

to Zotero

2795

P87

AXD

Julia Lier1*, Kristin Stoll1, Hellmuth Obrig2, Paul Baum3, Lea Deterding4, Nora Bernsdorff1, Franz Hermsdorf1, Ines Kunis1, Andrea Bräsecke1, Sabine Herzig2, Matthias L. Schroeter2, Angelika Thöne-Otto2, Steffi G. Riedel-Heller5, Ulrich Laufs3, Hubert Wirtz4, Joseph Classen1 and Dorothee Saur1

Neuropsychiatric phenotype of post COVID-19 syndrome in non-hospitalized patients

https://doi.org/10.3389/fneur.2022.988359

Published

27-Sep-22

Study

https://www.frontiersin.org/articles/10.3389/fneur.2022.988359/full

The post COVID-19 syndrome (PCS) is an emerging phenomenon worldwide with enormous socioeconomic impact. While many patients describe neuropsychiatric deficits, the symptoms are yet to be assessed and defined systematically. In this prospective cohort study, we report on the results of a neuropsychiatric consultation implemented in May 2021. A cohort of 105 consecutive patients with merely mild acute course of disease was identified by its high symptom load 6 months post infection using a standardized neurocognitive and psychiatric-psychosomatic assessment. In this cohort, we found a strong correlation between higher scores in questionnaires for fatigue (MFI-20), somatization (PHQ15) and depression (PHQ9) and worse functional outcome as measured by the post COVID functional scale (PCFS). In contrast, neurocognitive scales correlated with age, but not with PCFS. Standard laboratory and cardiopulmonary biomarkers did not differ between the group of patients with predominant neuropsychiatric symptoms and a control group of neuropsychiatrically unaffected PCS patients. Our study delineates a phenotype of PCS dominated by symptoms of fatigue, somatisation and depression. The strong association of psychiatric and psychosomatic symptoms with the PCFS warrants a systematic evaluation of psychosocial side effects of the pandemic itself and psychiatric comorbidities on the long-term outcome of patients with SARS-CoV-2 infection.

to Zotero

2796

P88

Brenda W. J. H. Penninx, Michael E. Benros, Robyn S. Klein & Christiaan H. Vinkers

How COVID-19 shaped mental health: from infection to pandemic effects

https://doi.org/10.1038/s41591-022-02028-2

Published

3-Oct-22

Review

https://www.nature.com/articles/s41591-022-02028-2

The Coronavirus Disease 2019 (COVID-19) pandemic has threatened global mental health, both indirectly via disruptive societal changes and directly via neuropsychiatric sequelae after SARS-CoV-2 infection. Despite a small increase in self-reported mental health problems, this has (so far) not translated into objectively measurable increased rates of mental disorders, self-harm or suicide rates at the population level. This could suggest effective resilience and adaptation, but there is substantial heterogeneity among subgroups, and time-lag effects may also exist. With regard to COVID-19 itself, both acute and post-acute neuropsychiatric sequelae have become apparent, with high prevalence of fatigue, cognitive impairments and anxiety and depressive symptoms, even months after infection. To understand how COVID-19 continues to shape mental health in the longer term, fine-grained, well-controlled longitudinal data at the (neuro)biological, individual and societal levels remain essential. For future pandemics, policymakers and clinicians should prioritize mental health from the outset to identify and protect those at risk and promote long-term resilience.

2797

P89

Marc Scherlinger, Cédric Lemogne, Renaud Felten & Jean Sibilia

Excess of Post-Acute Sequelae of COVID-19 After the First Wave of the Pandemic

Published

26-Sep-22

Study

https://link.springer.com/article/10.1007/s40121-022-00698-6

Introduction
To compare the time distribution of initial COVID-19 among patients with self-reported post-acute sequelae of COVID-19 (PASC).
Methods
We compared the distribution of the date of the reported initial COVID-19 among patients with self-reported PASC and the COVID-19 cases in France between the first wave (January 1–May 11, 2020) and the later period (May 12, 2020–June 30, 2021) using the chi-squared test. COVID-19 cases in France were assessed using previous modeling of COVID-19 burden in France for the first time period, and positive RT-PCR testing for the second time period.
Results
The study included 567 individuals with PASC (median age 44, [IQR 37–50]; 83.4% women). A total of 293 (51.7%) patients reported an initial COVID-19 infection during the first period while 272 (48%) reported it during the later period (missing data, n = 2; 0.3%). Patients with PASC were 82% more likely to report initial COVID-19 during the first pandemic wave than afterward (OR 1.82, 95% CI [1.55–2.15]; p < 0.0001).
Conclusions
The incidence of self-reported PASC wave was significantly higher when initial COVID-19 happened during the first pandemic wave than afterward, suggesting the importance of non-viral factors in PASC development.
Key Summary Points
In France, patients with post-acute sequelae of COVID-19 (PASC) were 82% more likely to report an initial infection during the first pandemic wave, and aggregated around the lockdown announcement.
Viral factors (i.e. variants) or prior vaccination were unlikely to explain the observed differences in PASC incidence considering the study period.
We hypothesize that the stress induced by the first wave of the pandemic may have fostered the onset or chronicization of symptoms in a subset of patients with PASC.

2798

P90

SashaRudenstineaTaliaSchulderaKrish J.BhattbKatMcNealaCatherine K.EttmancSandroGaleac

Long-COVID and comorbid depression and anxiety two years into the COVID-19 pandemic

https://doi.org/10.1016/j.psychres.2022.114924

Published

25-Oct-22

Study

https://www.sciencedirect.com/science/article/pii/S0165178122005157

Highlights
•The present study investigated demographics, stressors, and long-COVID in relation to depression, anxiety, and comorbid depression and anxiety outcomes.
•Results showed that gender was a significant correlate for probable depression, stressors were a significant correlate for probable anxiety, and gender, socioeconomic status, stressors, and long-COVID were all significant correlates for comorbid outcomes.
•Findings highlight the importance of social location, stress, and long-COVID, in tandem, as correlates of psychological health during the shifting pandemic.
Abstract
Long-COVID, or the persistence of COVID-19 symptoms for months after initial infection, has been shown to impact the lives of those affected. The current study sought to investigate the relationships between long-COVID, COVID-19 related stress, depression, anxiety, and comorbid depression and anxiety outcomes. Data were collected in Winter 2021-2022 from a population of adults enrolled in at least one course across multiple City University of New York (CUNY) campuses. Frequencies and chi-square tests were computed to assess for demographics and relationships to probable diagnoses of depression and anxiety, and binary logistic regressions were computed to assess for the odds of probable comorbid depression and anxiety based on demographics, stressors, and long-COVID. Women participants reported higher odds of probable depression outcomes, and stressor levels were significant correlates of probable anxiety outcomes. Women participants, 3.2 [1.5-6.9], as compared to men, lower-SES participants, 2.16 [1.1-4.2], as compared to higher-SES participants, participants with higher COVID-19 related stress levels, 4.8 [2.0-12.0], as compared to those with low levels, and participants with long-COVID, 3.7 [1.9-7.0], as compared to those without, all had higher odds of probable comorbid depression and anxiety. Findings highlight the importance of social location, stress, and long-COVID, in tandem, as correlates of psychological health during the shifting pandemic.

2799

P91

Xutong Zheng RN, MSN Student,Min Qian RN, MSN,Xinxin Ye PhD,Man Zhang RN, MSN Student,Chenju Zhan RN,Hui Li RN, MSN Student,Tiantian Luo RN, MSN Student

Implications for long COVID: A systematic review and meta-aggregation of experience of patients diagnosed with COVID-19

https://doi.org/10.1111/jocn.16537

Published

17-Oct-22

Review

https://onlinelibrary.wiley.com/doi/abs/10.1111/jocn.16537

Aims and Objectives
This review aims to synthesize the available evidence of what patients experience when infected with COVID-19, both in hospital and post-discharge settings.
Design
This review was conducted using the Joanna Briggs Institute (JBI) methodology for qualitative systematic reviews and evidence synthesis. Reporting of results was presented according to the Enhancing Transparency in Reporting the Synthesis of Qualitative Research (ENTREQ) checklist.
Background
Coronavirus disease 2019 (COVID-19) continues to be a public health crisis worldwide. Many patients diagnosed with COVID-19 have varied levels of persisting mental disorders. Previous studies have reported the degree, prevalence and outcome of psychological problems. Minimal research explored the experience of patients with long COVID. The real-life experience of patients with COVID-19 from diagnosis to post-discharge can deepen the understanding of nurses, physicians and policymakers.
Methods
All studies describing the experience of patients were included. Two authors independently appraised the methodological quality of the included studies using the JBI Critical Appraisal Checklist for Qualitative Research 2020.
Results
This systematic review aggregated patients’ experience of being diagnosed with COVID-19 in both hospitalized and post-discharge settings. Finally, 17 studies met inclusion criteria and quality appraisal guidelines. The selected studies in the meta-synthesis resulted in 12 categories, and further were concluded as five synthesized findings: physical symptoms caused by the virus, positive and negative emotional responses to the virus, positive coping strategies as facilitators of epidemic prevention and control, negative coping strategies as obstacles of epidemic prevention and control, and unmet needs for medical resource.
Conclusions
The psychological burden of patients diagnosed with COVID-19 is heavy and persistent. Social support is essential in the control and prevention of the epidemic. Nurses and other staff should pay more attention to the mental health of the infected patients both in and after hospitalization.

2800

P92

Peter W Ward

Long covid update for primary care should acknowledge functional symptoms

https://doi.org/10.1136/bmj.o2501

Published

19-Oct-22

Opinion

https://www.bmj.com/content/379/bmj.o2501.full

It must be a fraught task, writing about long covid. The list of symptoms is huge and we don’t really know how it arises. I often feel inadequate faced with patients distressed by their long covid symptoms.
I was bothered by the lack of any mention by Greenhalgh and colleagues of a functional element to long covid.1 It seemed a huge omission to me. Many of the complaints we see in primary care are of a functional nature and there is often a large functional component to physical illnesses like chronic obstructive pulmonary disease, asthma, heart disease, and musculoskeletal pains. How can we start to help people who suffer functional symptoms if there is a taboo about mentioning it?
People with functional symptoms are suffering in the same way as those with physical symptoms and if we are to destigmatise this area of medicine then authors as important and respected as Greenhalgh and colleagues should acknowledge their existence. It would be extraordinary if many people suffering long covid did not have a functional element to their presentations. Concentrating on physical tests and bodily mechanisms wholly risks missing this component.

2801

P93

Amanda Sacks-Zimmerman, Ph.D.
Thomas F. Bergquist, Ph.D.
Ellen M. Farr, M.D.
Melinda A. Cornwell, Ph.D.
Dora Kanellopoulos, Ph.D.

Rehabilitation of Neuropsychiatric Symptoms in Patients with Long-COVID: Position Statement

https://doi.org/10.1016/j.apmr.2022.10.001

Published

19-Oct-22

Article

https://www.archives-pmr.org/article/S0003-9993(22)01658-6/fulltext

Long-COVID, a term used to describe ongoing symptoms following SARS-CoV-2 (COVID-19) infection, parallels the course of other post-viral syndromes. Neuropsychiatric symptoms of Long-COVID can be persistent and interfere with quality of life and functioning. Within the biopsychosocial framework of chronic illness, rehabilitation professionals can address the neuropsychiatric sequelae of Long-COVID. However, current practice models are not designed to address concurrent psychiatric and cognitive symptoms in adults living with Long-COVID. Thus, we present a biopsychosocial framework for Long-COVID and provide treatment strategies based on evidence from current literature of post-viral chronic illness. These recommendations will guide rehabilitation professionals in 1) identifying common neuropsychiatric symptoms in Long-COVID that can be targeted for intervention and 2) addressing these symptoms via integrative interventions taking into account the biopsychosocial presentation of Long-COVID symptoms.

2802

P94

KeerthanaSankarMDaMichael K.GouldMDbHallie C.PrescottMDc

Psychological Morbidity After COVID-19 Critical Illness

https://doi.org/10.1016/j.chest.2022.09.035

Published

3-Oct-22

Review

https://www.sciencedirect.com/science/article/pii/S0012369222039058

Survivors of ICU hospitalizations often experience severe and debilitating symptoms long after critical illness has resolved. Many patients experience notable psychiatric sequelae such as depression, anxiety, and posttraumatic stress disorder (PTSD) that may persist for months to years after discharge. The COVID-19 pandemic has produced large numbers of critical illness survivors, warranting deeper understanding of psychological morbidity after COVID-19 critical illness. Many patients with critical illness caused by COVID-19 experience substantial post-ICU psychological sequelae mediated by specific pathophysiologic, iatrogenic, and situational risk factors. Existing and novel interventions focused on minimizing psychiatric morbidity need to be further investigated to improve critical care survivorship after COVID-19 illness. This review proposes a framework to conceptualize three domains of risk factors (pathophysiologic, iatrogenic, and situational) associated with psychological morbidity caused by COVID-19 critical illness: (1) direct and indirect effects of the COVID-19 virus in the brain; (2) iatrogenic complications of ICU care that may disproportionately affect patients with COVID-19; and (3) social isolation that may worsen psychological morbidity. In addition, we review current interventions to minimize psychological complications after critical illness.

2803

P95

Gaia Sampogna *,Matteo Di Vincenzo,Vincenzo Giallonardo,Francesco Perris,Antonio Volpicelli,Valeria Del Vecchio,Mario LucianoORCID andAndrea Fiorillo

The Psychiatric Consequences of Long-COVID: A Scoping Review

https://doi.org/10.3390/jpm12111767

Published

26-Oct-22

Review

https://www.mdpi.com/2075-4426/12/11/1767/htm

The COVID-19 pandemic has represented a new form of traumatic event, affecting the general population worldwide and causing severe disruption of daily routine. A new urgent concern is related to the burden associated with COVID-19 symptoms that persist beyond the onset of infection, the so-called long-COVID syndrome. The present paper aims to: (1) describe the most frequent psychiatric symptoms reported by patients affected by long-COVID syndrome; (2) evaluate methodological discrepancies among the available studies; (3) inform clinicians and policy-makers on the possible strategies to be promoted in order to manage the psychiatric consequences of long-COVID syndrome. Twenty-one papers have been included in the present review, mostly with a cross-sectional or cohort design. Significant heterogeneity of long-COVID syndrome definitions was found. The presence of psychiatric symptoms was evaluated with very different assessment tools. The most common psychiatric symptoms of the long-COVID syndrome included fatigue, cognitive disturbances/impairment, depression, and anxiety symptoms. The rate of fatigue varied from 93.2–82.3% to 11.5%, cognitive impairment/cognitive dysfunction from 61.4% to 23.5% and depressive-anxiety symptoms from 23.5%to 9.5%.

2804

P96

Lilly Lerer,1 Michael Marcangelo,2 Leora R. Cherney,3 and Elliot J. Roth3

(30) Characterizing Mood Symptoms in Long Covid: A Qualitative Perspective

https://doi.org/10.1016%2Fj.jaclp.2022.10.033

Published

10-Nov-22

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9646369/

Abstract: Background
Mood symptoms are commonly experienced by individuals with Post-Acute Covid-19 Syndrome (PACS, or “Long Covid”), especially anxiety and depression (1). This qualitative study was performed to investigate experiences of PACS, in order to characterize the nature of self-reported mood symptoms associated with PACS.
Methods
Semi-structured interviews were conducted with 8 English-speaking adults who met WHO Criteria for PACS, recruited from a general rehabilitation clinic and by word-of-mouth in Chicago between November 2021-March 2022 (2). The interview guide consisted of a modified version of the McGill Illness Narratives Interview (MINI) to elicit descriptions of the nature and impact of the symptoms of PACS. Interviews were de-identified, transcribed, coded using grounded theory methodology, and analyzed for themes.
Results
Individuals evidenced four distinct trajectories of self-reported mood symptoms during PACS, compared to their pre-PACS baselines: persistence or worsening of pre-PACS mood symptoms, development of mood symptoms not present before PACS, relief of pre-PACS mood symptoms during PACS, or no mood symptoms before or during PACS. Five individuals reported histories of depression and anxiety before PACS occurred, including four individuals receiving ongoing psychiatric treatment. Among these, PACS was associated with worsening of symptoms for four individuals, and did not influence the symptoms of one individual. Three individuals reported no history of anxiety or depression before PACS. Among these, one reported the development of significant mood symptoms during PACS, while two did not. Several themes emerged regarding the contextual factors associated with mood symptoms. Participants described depression, anxiety, insomnia, hopelessness, apathy, and irritability as resulting from multiple sources, including the debilitating nature of symptoms, uncertainty about their ability to work, exposure to distressing news stories, lack of support from family members, financial impact, poor treatment from employers, hopelessness about living with symptoms indefinitely, negative impact on self-image, and the harmful impact of symptoms on marriage, dating life, sexual function, and future childbearing ability.
Discussion
While epidemiological data has established the prevalence of neuropsychiatric symptoms of PACS, debate exists over their mechanistic etiology, which if known could help refine treatment approaches or identify predictive factors. Themes from this dataset support the hypothesis that circumstantial stressors of PACS are associated with self-reported mood symptoms. However, this relationship was not universal, and supports the practice of a highly individualized treatment approach for individuals with PACS. Finally, while circumstances caused by PACS may influence mood symptoms, research must be conducted to understand primary mechanistic explanations for neuropsychiatric symptoms of PACS.

2805

P97

Luigi De Gennaro 1,2,*ORCID,Serena Scarpelli 1ORCID andMaurizio Gorgoni 1,2ORCID

The Effect of COVID-19 on Sleep Quality and Mental Health: Adolescents Are More at Risk Than the Elderly

https://doi.org/10.3390/brainsci12111543

Published

14-Nov-22

Editorial

https://www.mdpi.com/2076-3425/12/11/1543/htm

After the appearance of a novel coronavirus (2019-nCoV) during 2019, the virus has spread with alarming speed and a pandemic quickly developed. The complex consequences of the pandemic phenomenon, i.e., the consequences of the pandemic per se and the countermeasures adopted to control infections and deaths, were associated with a negative impact on sleep quality [1] and, in general, mental health [2]. With a global prevalence of sleep disturbances of approximately 30–40%, as suggested by meta-analytical studies [3,4], a stable association with psychological distress has been repeatedly reported [5].
In Europe, Italy was the first country to report high rates of infection and deaths, and, as a consequence, the Italian Government declared unprecedented restrictive measures with a total lockdown on 9 March 2020. Not surprisingly, many studies on the effects of the lockdown and/or the pandemic were conducted in Italy (e.g., [6,7,8,9]), reporting an increase in sleep difficulties associated with the pandemic, particularly during the lockdown periods. Along this vein, the Italian study by Amicucci et al. [10] also investigated the impact of the COVID-19 lockdown during Spring 2020 on sleep quality and mental health. The main merit of this study is a specific focus on two at-risk groups: late adolescents (18–20 years) and the elderly (65–75 years).
The authors used a web-based survey and validated questionnaires to assess sleep quality, insomnia, stress, depression, and anxiety. The adolescents reported more insomnia symptoms, worse sleep quality, longer sleep latency, higher daytime dysfunction, a more prevalent disruption of sleep habits (bedtime, get-up time, and nap), and a more negative impact on mental health (higher levels of depression and perceived stress than the elderly). Older participants showed shorter sleep durations, lower habitual sleep efficiency, and greater use of sleep medications. These findings in the elderly are mostly common characteristics of sleep in this age range [11], and they can be considered to have been pre-existing prior to the pandemic. On the other hand, the results from the late adolescents point to pervasive consequences for sleep and mental health in this group.
The apparent paradox is represented by the elderly population having the highest risk of morbidity and mortality due to the pandemic, whereas adolescents show the strongest impact in terms of sleep quality and mental health. This finding should be considered in light of previous observations that point to greater resilience in older adults during difficult times [12], which is likely associated with better emotional regulation and coping strategies [13,14] developed over one’s lifetime. Although this study does not allow for the disentanglement of the consequences of the pandemic per se and the consequences of home confinement (i.e., the COVID-19 lockdown), the interpretation in terms of a greater suffering due to the restrictive measures experienced by adolescents seems more tenable, since about sixty percent of adolescents reported the restraining measures having a negative impact on sleep as compared to about forty percent of the elderly. However, a note of caution with regard to the interpretation of these findings is needed, since several pieces of information about the composition of the sample (e.g., job, family composition, social environment, physical activity, and lockdown- or pandemic-related changes in daily habits) are not available and may have affected the results. Longitudinal observations and a greater focus on the possible intervening variables are needed.
Another point highlighted by the present study appears relevant from a methodological standpoint for future evaluations of subjective sleep quality during the pandemic. Indeed, in spite of a significant difference in insomnia levels between late adolescents and the elderly, the authors did not find differences in the overall subjective sleep quality expressed by the Pittsburg Sleep Quality Index (PSQI) [15] global score. However, this finding is due to a dissociation in the direction of the differences between groups in specific sleep domains that clearly emerged when assessing the PSQI subscales. Consistent with previous observations [16], this result highlights the complex nature of the pandemic’s influence on sleep, and the exclusive assessment of global sleep quality measures may possibly prevent findings from reflecting this multifaced effect.
Overall, the results from Amicucci and coworkers [10] confirm the emerging evidence of late adolescents/young adults having a high vulnerability to pandemic-related sleep and mental health problems (e.g., [8,17,18,19]). In this view, it is crucial to monitor this population over time to detect possible long-term consequences of the pandemic on sleep and psychological wellbeing, determine specific protective and risk factors, and develop timely preventive and interventional strategies.

2806

P98

Yunyu Xiao, Mohit M. Sharma, Rohith K. Thiruvalluru, Catherine Gimbrone, Myrna M. Weissman, Mark Olfson, Katherine M. Keyes & Jyotishman Pathak

Trends in psychiatric diagnoses by COVID-19 infection and hospitalization among patients with and without recent clinical psychiatric diagnoses in New York city from March 2020 to August 2021

https://doi.org/10.1038/s41398-022-02255-8

Published

21-Nov-22

Study

https://www.nature.com/articles/s41398-022-02255-8

Determining emerging trends of clinical psychiatric diagnoses among patients infected with the SARS-CoV-2 virus is important to understand post-acute sequelae of SARS-CoV-2 infection or long COVID. However, published reports accounting for pre-COVID psychiatric diagnoses have usually relied on self-report rather than clinical diagnoses. Using electronic health records (EHRs) among 2,358,318 patients from the New York City (NYC) metropolitan region, this time series study examined changes in clinical psychiatric diagnoses between March 2020 and August 2021 with month as the unit of analysis. We compared trends in patients with and without recent pre-COVID clinical psychiatric diagnoses noted in the EHRs up to 3 years before the first COVID-19 test. Patients with recent clinical psychiatric diagnoses, as compared to those without, had more subsequent anxiety disorders, mood disorders, and psychosis throughout the study period. Substance use disorders were greater between March and August 2020 among patients without any recent clinical psychiatric diagnoses than those with. COVID-19 positive patients (both hospitalized and non-hospitalized) had greater post-COVID psychiatric diagnoses than COVID-19 negative patients. Among patients with recent clinical psychiatric diagnoses, psychiatric diagnoses have decreased since January 2021, regardless of COVID-19 infection/hospitalization. However, among patients without recent clinical psychiatric diagnoses, new anxiety disorders, mood disorders, and psychosis diagnoses increased between February and August 2021 among all patients (COVID-19 positive and negative). The greatest increases were anxiety disorders (378.7%) and mood disorders (269.0%) among COVID-19 positive non-hospitalized patients. New clinical psychosis diagnoses increased by 242.5% among COVID-19 negative patients. This study is the first to delineate the impact of COVID-19 on different clinical psychiatric diagnoses by pre-COVID psychiatric diagnoses and COVID-19 infections and hospitalizations across NYC, one of the hardest-hit US cities in the early pandemic. Our findings suggest the need for tailoring treatment and policies to meet the needs of individuals with pre-COVID psychiatric diagnoses.

2807

P99

Kristen Nishimi, Thomas C. Neylan, Daniel Bertenthal, Emily A. Dolsen, Karen H. Seal & Aoife O’Donovan

Post-traumatic stress disorder and risk for hospitalization and death following COVID-19 infection

https://doi.org/10.1038/s41398-022-02156-w

Published

22-Nov-22

Study

https://www.nature.com/articles/s41398-022-02156-w

Post-traumatic stress disorder (PTSD) is associated with an increased risk for physical illnesses and early mortality. However, we do not know if it also increases the risk for adverse outcomes of coronavirus disease 2019 (COVID-19). In this retrospective cohort study, we examined associations of PTSD and other psychiatric disorders with risk for hospitalization and death in the 60 days following a COVID-19 infection in 228,367 U.S. Department of Veteran Affairs (VA) patients who tested positive for COVID-19 between February 2020 and August 2021 (age m = 60.6, 89.5% male). Generalized linear models estimated associations of PTSD and other psychiatric disorders with outcomes following a positive SARS-CoV-2 test, adjusting for socio-demographic, medical, and behavioral factors. Among 228,367 VA patients, 25.6% had PTSD, and 28.2% had a psychiatric disorder other than PTSD. In the 60 days following a positive COVID-19 test, 15% of patients were hospitalized, and 6% died. Patients with PTSD had an increased risk for both hospitalization (adjusted relative risk, ARR = 1.18, 95% CI 1.15–1.21) and death (ARR = 1.13, 95% CI 1.08–1.19) relative to those with no psychiatric disorders, adjusting for socio-demographics. Estimates remained significant when models were additionally adjusted for medical comorbidities and smoking. Patients with other psychiatric disorders also had an increased risk of adverse COVID-19 outcomes, with larger effect sizes than PTSD in older (≥65 years) but not younger patients. In this large-scale study of VA patients, individuals with PTSD, and other psychiatric disorders, had heightened vulnerability to severe adverse outcomes of COVID-19; thus, individuals with PTSD should also be considered at higher risk for severe COVID-19 outcomes, and potentially prioritized for vaccination, screening, and early treatment intervention for COVID-19.

2808

P100

Delfina Janiri 1,2,3,*,Matteo Tosato 4ORCID,Alessio Simonetti 1,3ORCID,Silvia Montanari 1,Beatrice Terenzi 1,Antonello Catinari 1,Lorenzo De Mori 1,Gaspare Filippo Ferrajoli 1,Georgios D. Kotzalidis 5ORCID,Francesco Landi 4,Roberto Bernabei 4 andGabriele Sani 1,3ORCID

Post-COVID-19 Psychiatric Symptoms in the Elderly: The Role of Gender and Resilience

https://doi.org/10.3390/jpm12122016

Published

6-Dec-22

Study

https://www.mdpi.com/2075-4426/12/12/2016

COVID-19 represents an overwhelming stressor to mental health. Elderly individuals are particularly at risk, but it is still unclear whether the risk is equally distributed among men and women. The aim of this study was to define gender differences in persistent psychiatric symptoms after COVID-19 illness and to test their association with resilience factors. Methods: We assessed 348 individuals aged >65 years at a multidisciplinary post-COVID-19 service. Mood and anxiety symptoms were investigated, as well as psychological distress and resilience, as assessed with the Kessler-10 (K10) Scale and the Connor-Davidson Resilience Scale (CD-RISC), respectively. Multivariate and linear regression analyses were used to test the distribution patterns of psychiatric symptoms and resilience factors. Results: In the total sample, 214 (61.5%) were men (a mean age of 73.25 years ±6.04) and 134 (38.5%) were women (a mean age of 72.69 years ±6.43; p = 0.407). Men and women significantly differed in marital status (χ2 = 25.17; p < 0.001, more men were married), living alone (χ2 = 11.62; p < 0.01, fewer men were living alone), hospitalization during COVID-19 illness (χ2 = 12.35; p < 0.001, more men were hospitalized during COVID-19), and subjective health status before COVID-19 infection (χ2 = 4.32; p < 0.001, men reporting better subjective health than women). Women reported more psychiatric symptoms and fewer resilience factors than men. Low resilience levels significantly predicted psychological distress in both men and women. Conclusions: The female elderly population affected by COVID-19 showed a greater vulnerability to psychiatric symptoms. Our data point to the need to strengthen resilience resources, especially in women.

2809

P101

Alessio Simonetti 1,2,*,†,Evelina Bernardi 2,†,Delfina Janiri 1,3,Marianna Mazza 2ORCID,Silvia Montanari 2,Antonello Catinari 2,Beatrice Terenzi 2,Matteo Tosato 4,5ORCID,Vincenzo Galluzzo 5ORCID,Francesca Ciciarello 5,Francesco Landi 4,5 andGabriele Sani 2,6ORCID

Suicide Risk in Post-COVID-19 Syndrome

https://doi.org/10.3390/jpm12122019

Published

7-Dec-22

Study

https://www.mdpi.com/2075-4426/12/12/2019

Post-acute sequelae of COVID-19 include several neuropsychiatric disorders. Little is known about the relationship between post-COVID-19 syndrome and suicidality. The aim of the study was to investigate the risk of suicide in subjects with persistent post-COVID-19 syndrome. One-thousand five-hundred eighty-eight subjects were assessed in the Post-Acute Care Service at the Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS of Rome. Assessment included: (a) sociodemographic characteristics; (b) symptoms during and after COVID-19; (c) psychopathological evaluation. Participants were divided in those with (SUI) or without (NON SUI) suicide risk according to the Mini International Neuropsychiatric Interview. Additionally, subjects with SUI were split into those with high (HIGH SUI) and low (LOW SUI) suicide risk. Between-group comparisons were made with t-tests for continuous variables and χ2 tests for categorical variables. SUI showed greater percentages of physical complaints during and after COVID-19, greater percentages of psychiatric history and presence of psychiatric history in relatives, greater percentages of subjects previously undergoing psychopharmacotherapy, and greater levels of anxiety, mixed depressive symptoms, general psychopathology than NON SUI. HIGH SUI showed greater number of symptoms during and after COVID-19 and higher levels of mixed depressive symptoms than LOW SUI. Percentages of subjects undergoing psychotherapy was higher in LOW SUI than HIGH SUI. Greater levels of physical complaints and psychopathology during post-COVID-syndrome might enhance the risk of committing suicide. Treatment of physical complaints and psychotherapy might reduce suicide risk.

2810

P102

Mohammad Pourfridoni,Hedyeh Askarpour

COVID-19 and the increase in schizophrenia incidence in the future: A hypothesis and a serious warning

https://doi.org/10.1002/hsr2.978

Published

5-Dec-22

Article

https://onlinelibrary.wiley.com/doi/10.1002/hsr2.978

Background and Aims
The coronavirus disease 2019 (COVID-19), which has caused a global pandemic, is brought on by the Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). Since the COVID-19 pandemic started so recently, dealing with complications that emerge years later and have the potential to cause several crises for humanity is one of the issues we face in the post-COVID-19 age. Therefore, we wish to discuss a theory and potential dangers surrounding the probability of schizophrenia following COVID-19 infection in this study.
Methods
The literature search for this article has been entirely internet-based. Information was gathered using the Web of Science, PubMed, Scopus, and Google Scholar databases.
Results
The results showed that multiple immune system changes brought on by COVID-19 have been identified as potential causes of schizophrenia.
Conclusion
It is predicted that one of the long-term effects of COVID-19 is an increase in the risk of schizophrenia incidence based on the results of this study, which looked at the pathophysiology and etiology of schizophrenia as well as the pathogenic mechanisms of the SARS-CoV-2. Therefore, healthcare staff should be prepared to handle any potential risks in future.

2811

P103

Daisy Fancourt
Andrew Steptoe
and Feifei Bu

Psychological consequences of long COVID: comparing trajectories of depressive and anxiety symptoms before and after contracting SARS-CoV-2 between matched long- and short-COVID groups

https://doi.org/10.1192/bjp.2022.155

Published

2-Dec-22

Study

https://www.cambridge.org/core/journals/the-british-journal-of-psychiatry/article/psychological-consequences-of-long-covid-comparing-trajectories-of-depressive-and-anxiety-symptoms-before-and-after-contracting-sarscov2-between-matched-long-and-shortcovid-groups/923140B3F95F1158C0CDC188002531AE

Background
There is a growing global awareness of the psychological consequences of long COVID, supported by emerging empirical evidence. However, the emergence and long-term trajectories of psychological symptoms following the infection are still unclear.
Aims
To examine when psychological symptoms first emerge following infection with SARS-CoV-2 and the long-term trajectories of psychological symptoms comparing long- and short-COVID groups.
Method
We analysed longitudinal data from the UCL COVID-19 Social Study (March 2020 to November 2021). We included data from adults living in England who reported contracting SARS-CoV-2 by November 2021 (n = 3115). Of these, 15.9% reported having had long COVID (n = 495). They were matched to participants who had short COVID using propensity score matching on a variety of demographic, socioeconomic and health covariates (n = 962 individuals with 13 325 observations) and data were further analysed using growth curve modelling.
Results
Depressive and anxiety symptoms increased immediately following the onset of infection in both long- and short-COVID groups. But the long-COVID group had substantially greater initial increases in depressive symptoms and heightened levels over 22 months follow-up. Initial increases in anxiety were not significantly different between groups, but only the short-COVID group experienced an improvement in anxiety over follow-up, leading to widening differences between groups.
Conclusions
The findings support work on the psychobiological pathways involved in the development of psychological symptoms relating to long COVID. The results highlight the need for monitoring of mental health and provision of adequate support to be interwoven with diagnosis and treatment of the physical consequences of long COVID.

2812

P104

Fenton, Caroline; Lee, Arnold

Antidepressants with anti-inflammatory properties may be useful in long COVID depression

https://doi.org/10.1007/s40267-022-00975-x

Published

Study

https://doi.org/10.1007/s40267-022-00975-x

Long COVID, which is characterised by the presence of persistent symptoms following a COVID infection, may also cause long COVID depression (LCD). Although the risk factors for LCD are not directly characterised, prior mental health visits were associated with an increased risk for long COVID, whereas antidepressant use was not. Current evidence suggests that pro-inflammatory factors in the brain are linked to LCD, thus anti-inflammatory agents may be useful in mitigating LCD. Limited evidence suggests that selective serotonin reuptake inhibitors may also be effective in the treatment of LCD.

2813

P105

Benzakour, L.; Voruz, P.; Lador, F.; Guerreiro, I.; Kharat, A.; Assal, F.; Péron, J. A.

Posttraumatic Stress Disorder and Hyperventilation in Post-COVID-19 Syndrome: An Underestimated Association

https://doi.org/10.1016/j.jaclp.2022.08.006

Published

Case Report

https://www.sciencedirect.com/science/article/pii/S2667296022003147

Hyperventilation syndrome (HVS) is a dysfunctional breathing syndrome in which minute ventilation exceeds metabolic demands, resulting in hemodynamic and chemical changes. Recent data suggest that HVS incidence is high in the post-COVID-19 condition,1 and its management may involve consultation-liaison (CL) psychiatry considering the presence of functional symptoms. In our clinical practice, we observed an association between posttraumatic stress disorder (PTSD), which is also prevalent in the post-COVID-19 condition,2 and HVS that could be explained by a traumatic experience during the acute phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. These 2 phenomena have so far only been studied separately in the post-COVID-19 condition despite the evidence of their interaction in other pathologies. In the present letter case, we would like to highlight the possible interaction between HVS and PTSD in post-COVID-19 condition.

2814

P106

Pick, Anton

Is Long Covid a Functional Disorder?

https://doi.org/10.1177/11795727221141193

Published

1-Jan-23

Article

https://doi.org/10.1177/11795727221141193

publisher: SAGE Publications
‘Functional disorders’ are described as resulting from pathological changes in bodily ‘function’ rather than ‘structure’. This conceptualisation is thought to offer an explanation as to why standard medical investigations are commonly unremarkable. Other conditions that fall under the umbrella of ‘functional disorder’ include Fibromyalgia, ME/CFS, Chronic Pelvic Pain, Functional Dyspepsia, Functional Neurological Disorder and Overactive Bladder Syndrome. Some clinicians, researchers and patient advocacy groups are supportive of the term as it can be used to validate the patient’s experience in lieu of a clear biological explanation. I suggest, however, the label of ‘functional disorder’ might in other ways be unhelpful. In its most clumsy usage, the term ‘functional’ suggests a fundamental difference between those conditions that are easily explained biomedically and those that aren’t. This distinction is not reflective of real life clinical practice. Diseases thought to be well understood biomedically continue to confound. Firstly, the degree of disability of two patients with the same disease, with the same objective ‘severity’ can diverge massively in terms of their level of disability. For example, in chronic obstructive pulmonary disease (COPD) it is common for different patients with similar imaging and lung function testing results to present entirely differently.4 Secondly, the relationship between proposed biomedical mechanisms and disease outcomes is not straightforward. For example, behavioural factors, such as stress and bereavement, independently increase the risk of adverse cardiac outcomes. Put simply, no two disease presentations are alike, regardless of the results of investigations. Categorising diseases as ‘functional’ or not risks limiting our curiosity about such complexity.
The term ‘functional’ evolved from now outdated terms such as ‘psychosomatic’ or ‘hysterical’. Unfortunataly, however, the insidious and stigmatising question of whether a condition is ‘in your head’ or not continues to rear its head. Simply replacing ‘psychosomatic’ with ‘functional’ can seem, at its worst, somewhat cloak and dagger. Its use in this way risks furthering an unhelpful and inaccurate distinction between mind and body. Yet another critique of Descartes’ Cartesian dualism is not required – this has been widely written about elsewhere.5 Any disease or injury, be it Long Covid or a broken arm is experienced in the mind. Designating Long Covid a ‘functional disorder’ may perpetuate stigma and impede scientific curiosity.

2815

P107

Kataoka, Mayumi; Hazumi, Megumi; Usuda, Kentaro; Okazaki, Emi; Nishi, Daisuke

Association of preexisting psychiatric disorders with post-COVID-19 prevalence: a cross-sectional study

https://doi.org/10.1038/s41598-023-27405-w

Published

7-Jan-23

Study

https://www.nature.com/articles/s41598-023-27405-w

Evidence demonstrating the association of preexisting psychiatric disorders with post-COVID-19 is limited. We aim to investigate the association using larger sample sizes and more extended postinfection periods than previous studies. A total of 6015 (response rate = 77.5%) COVID-19 survivors were surveyed using a self-administered questionnaire from July to September 2021. Poisson regression analysis with robust error variance was performed to estimate post-COVID-19 prevalence ratios (PRs) with or without preexisting psychiatric disorders. Participants with preexisting psychiatric disorders numbered 1067 (17.7%), and with post-COVID-19 were 2149 (35.7%). Post-COVID-19 PR with preexisting psychiatric disorders was 1.09 (95% CI 1.02–1.18, p = 0.013). The interaction between preexisting psychiatric disorders and postinfection periods was significant (p for interaction < 0.001). The subgroup analysis showed that those with preexisting psychiatric disorders might be at greater prolonged risk of post-COVID-19 than those without the disorders. These findings suggested that preexisting psychiatric disorders were associated with an increased post-COVID-19 risk, and post-COVID-19 with preexisting psychiatric disorders might prolong even if time passes.

2816

P108

Craparo, Giuseppe; La Rosa, Valentina Lucia; Commodari, Elena; Marino, Graziella; Vezzoli, Michela; Faraci, Palmira; Vicario, Carmelo Mario; Cinà, Gabriella Serena; Colombi, Morena; Arcoleo, Giuseppe; Severino, Maria; Costanzo, Giulia; Gori, Alessio; Mangiapane, Ernesto

What Is the Role of Psychological Factors in Long COVID Syndrome? Latent Class Analysis in a Sample of Patients Recovered from COVID-19

https://doi.org/10.3390/ijerph20010494

Published

1-Jan-23

Study

https://www.mdpi.com/1660-4601/20/1/494

Background: This study aimed to identify clusters of long COVID-19 symptoms using latent class analysis and investigate the psychological factors involved in the onset of this syndrome. Method: Five hundred and six subjects recovering from COVID-19 completed a series of standardized questionnaires to evaluate the personality traits, alexithymia, and post-traumatic stress. Results: Five classes were identified: Brain fog (31.82%), No symptoms (20.95%), Sensory disorders (18.77%), Breath impairment (17.59%), and Multiple disorders (10.87%). Women reported post-COVID-19 respiratory symptoms and multiple disorders to a greater extent than men. Hospitalized subjects were more likely to report persistent symptoms after COVID-19 than asymptomatic or home-treated subjects. Antagonism, hyperarousal, and difficulty identifying emotions significantly predicted post COVID-19 symptoms. Conclusions: These findings open new questions for research on long COVID-19 and how states of emotional dysregulation can alter the physiological processes of the body and contribute to the onset of organic pathologies.

2817

P109

Sakka, Elpitha; Kalniunas, Arturas; Vitkauskaite, Elzbieta; Salman, Wala; Chaudhri, Subhana; Pappa, Sofia

Psychological Effects and Neuropsychiatric Sequelae in COVID-19 Patients

https://doi.org/10.1002/9781119789741.ch25

Published

1-Jan-23

Review

https://onlinelibrary.wiley.com/doi/abs/10.1002/9781119789741.ch25

With the continuity of the COVID-19 global health crisis, the need to establish the short- and long-term health implications of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) virus on infected patients is of critical importance. In this chapter, we summarize information concerning the prevalence of associated mental health effects and neuropsychiatric sequelae in addition to predictive and preventative factors in patients with COVID-19. Evidence to date suggests a significant proportion of infected and hospitalized patients experience a variety of adverse psychological effects, reporting symptoms of depression, anxiety, posttraumatic stress disorder, cognitive impairment, and sleep abnormalities. Severity of COVID-19 infection, duration of hospitalization, admission to the intensive care unit, and preexisting mental health issues have all been associated with a greater risk of developing various psychiatric complications in patients. Identification of relevant factors will hopefully lead to the effective diagnosis and management of symptoms of psychological distress that may arise during or after recovery of COVID-19 more effectively. Finally, we discuss appropriate management strategies and interventions to prevent the immediate and enduring psychological complications in patients with COVID-19, including those of the post-COVID-19 syndrome.

2818

P110

Todd, Noah; Pater, Jessica; Li, Jason; Bohn, Camden; Henriksen, Brian; Carroll, Jeanne; Chang, Fen-Lei

Associations Between Psychiatric Symptoms and Cognitive Impairment in Post-Acute Sequelae of COVID

https://doi.org/10.18060/26789

Published

14-Jul-05

Study

https://journals.iupui.edu/index.php/IMPRS/article/view/26789

Introduction: Post-acute sequelae of COVID (PASC) is an emerging postviral syndrome affecting patients who have recovered from acute COVID infection. Symptoms can affect many different organ systems, including the CNS. Neuropsychiatric complications are common in PASC, affecting roughly 1 in 3 patients who recover from COVID. The present study aims to investigate relationships between depressive, anxious, somatic, and general psychiatric symptom burden and cognitive impairment in PASC.
Methods: Patients were recruited from the Parkview Post-COVID Clinic (PPCC) from April 2021 to March 2022. Patients were deemed eligible if data were available for both Brief Symptomatic Inventory (BSI) and BrainCheck scores. Eligible patients were divided into low or normal cognitive function based on BrainCheck guidelines, and differences in psychiatric symptom severity were assessed via Mann-Whitney U testing. Strength and direction of associations were determined using Pearson’s correlation coefficient. A smaller subset of patients was analyzed for differences in PASC symptom severity based on Omicron or Delta infection.
Results: Generalized cognitive and mental flexibility complaints were associated with more severe psychiatric symptom burden in all domains measured by BSI (p = 0.003 and p = 0.01, respectively). Impaired attention was not related to any psychiatric symptom domain (p > 0.05). Impaired memory was related to more severe symptom burden in all psychiatric domains except depression (immediate recall p = 0.015; delayed recall p = 0.015).
Conclusion: General cognitive and mental flexibility complaints can be used to prompt clinical suspicion of concurrent psychiatric symptoms. Complaints regarding attention are not linked to any psychiatric symptom domain. Complaints regarding memory can also provide impetus for investigating concurrent psychiatric symptoms, excluding depression. These associations can be used to facilitate earlier diagnosis and treatment of cognitive impairment and psychiatric illness in the context of PASC.

2819

P111

Effiong, Andem

Postacute Sequelae of COVID-19 and Adverse Psychiatric Outcomes: Protocol for an Etiology and Risk Systematic Review

https://doi.org/10.2196/43880

Published

14-Mar-23

Review

https://xmed.jmir.org/2023/1/e43880

Background: The postacute sequelae of COVID-19 (PASC) is a syndrome characterized by persistent COVID-19 symptoms or the onset of new symptoms following recovery from the initial or acute phase of the illness. Such symptoms often occur 4 or more weeks after being diagnosed with COVID-19. Although a lot of work has gone into understanding the long-term mental health effects of PASC, many questions related to the etiology and risk of this condition remain.
Objective: This protocol is for a systematic review assessing the association between PASC and adverse psychiatric outcomes and whether people with PASC are at greater risk of developing an adverse psychiatric outcome than those without PASC.
Methods: Various medical literature databases (eg, PubMed and EMBASE) will be searched for eligible articles, using predefined search criteria. Gray literature will also be explored. Epidemiological observational studies and secondary analyses of randomized controlled trials that report a quantitative relationship between PASC and at least one adverse psychiatric outcome will be included. The Population, Exposure of interest, Comparator, and Outcome framework will be used as a standardized framework for the inclusion criteria. The Joanna Briggs Institute critical appraisal tools will be used to assess methodological quality and critically appraise the risk of bias in included studies. A random-effects meta-analysis will be conducted if possible. A formal narrative synthesis will be performed if a meta-analysis is impossible due to substantial heterogeneity across studies. The Grading of Recommendations Assessment, Development and Evaluation approach will be used to rate the cumulative certainty of the evidence for all outcomes. Ethical approval is not required. The study results will be published in a peer-reviewed journal.
Results: This study documents and addresses etiology, risk factors, and long-term symptoms of COVID-19 among people with PASC. It focuses on a key priority area for new evidence syntheses on the clinical management of COVID-19 and pandemic-related conditions. It will include evidence on nonhospitalized and hospitalized patients with a history of PASC.
Conclusions: Substantial heterogeneity across studies may limit the ability to perform a meta-analysis. Findings will inform disease prevention, decision-making, health care policy, and clinical research (Reviewed by the Plan P #PeerRef Community).
Trial Registration: PROSPERO CRD42022308737; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=308737

2820

P112

Sun, Luna; Shang, Zhilei; Wu, Lili; Pan, Xiao; Sun, LiangLiang; Ouyang, Hui; Huang, Hai; Zhan, Jingye; Jia, Yanpu; Zhou, Yaoguang; Bai, Yonghai; Xie, Weifen; Liu, Weizhi

One-quarter of COVID-19 patients developed PTSD symptoms: A one-year longitudinal study

https://doi.org/10.1016/j.psychres.2023.115161

Published

1-May-23

Study

https://www.sciencedirect.com/science/article/pii/S0165178123001129

Highlights
•The cumulative occurrence of probable PTSD was 26.7% in COVID-19 patients over 12 months after hospital discharge.
•PTSD symptoms of non-severe patients recovered better compared with severe patients.
•Patients who were females and had sequelae of cough or dyspnea require special attention during long-term convalescence.
Abstract
This study investigated the longitudinal development of PTSD symptoms and respiratory sequelae among COVID-19 patients one year after hospital discharge. The cumulative occurrence of probable PTSD in COVID-19 survivors (n = 329) was 26.7%, which significantly decreased over the 12-month period (23.1% to 4.3%). Non-severe patients showed marked improvement in all four clusters of PTSD symptoms at 12 months compared to 3 months, while severe patients only showed improvements in re-experiencing and numbing symptoms. Moreover, being female and having respiratory sequelae increased the risk for chronic PTSD. Psychological interventions are required for COVID-19 patients during long-term convalescence.

2821

P113

Chow, Clifton M.; Schleyer, Will; DeLisi, Lynn E

The prevalence of psychiatric symptoms and their correlates as part of the long-COVID syndrome

https://doi.org/10.1016/j.psychres.2023.115166

Published

1-May-23

Review

https://www.sciencedirect.com/science/article/pii/S0165178123001178

The Long COVID syndrome has now been documented clearly in the literature, but whether or not psychiatric symptoms are prominent is unclear. We performed a retrospective chart review of all patients receiving medical care during the pandemic in an outpatient Long-COVID specialty clinic that serves a large racial and ethnic minority population. As many as 44% of patients had symptoms that necessitated referrals to psychiatrists, predominantly depression or anxiety. Spanish speaking patients had greater COVID severity (48%) than did predominantly English speakers (15%). We conclude that the long COVID syndrome is predominantly a cluster of physical symptoms that are sequelae of the viral infection.

2822

P114

Benedetti, Francesco

Immunopsychiatry after COVID-19

https://doi.org/10.1016/j.jadr.2023.100521

Published

1-Apr-23

Article

https://www.sciencedirect.com/science/article/pii/S2666915323000604

Immunopsychiatry can be defined as the study of immune-inflammatory pathways in order to identify pathogenetic mechanisms, and targets for treatment, in psychiatric conditions: under the premises that interactions between the immune system and the central nervous system are crucial for brain homeostasis and function, and their disruption has major consequences on mental health. With its terrible burden of disease inflicted on mankind, the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection provided a natural experiment, to provocatively test the relationship between inflammation and mood disorders. Consistent systematic reviews and meta-analyses now affirm that COVID-19 survivors show persistent psychopathology and neurocognitive impairment, with clinically significant depressive psychopathology being reported in around 35% of patients. The cluster of Post-Acute Sequelae of COVID-19 (PASC) symptoms typically emerge after the acute phase of illness, when patients are no longer positive to SARS-CoV-2, including dyspnoea, hypoxia, joint and muscle pain, paraesthesia, dysgeusia, anosmia, fatigue; and, unrelated to the above, neuropsychiatric and neurocognitive symptoms with depression, anxiety, insomnia, difficulties in sustained attention and memory, which worsen over the months. Psychopathological features are the same observed in Major Depressive Disorder, distributing along the same gradient of severity, and including a typically melancholic cognitive vulnerability with self-reproach and depressive cognitive style in evaluating events. Neurocognitive impairment could possibly separate from depression in the long term, but not in the first 6 months after infection, and it is largely overlapping with persistent cognitive deficits described in severe mood disorders. Brain correlates are the same observed in Major Depressive Disorder and in Bipolar Disorder, involving spread disruption of white matter microstructure, reduced grey matter volumes in anterior cingulate cortex, and abnormal functional connectivity in the cortico-limbic circuitries: all the above, being proportional to the degree of persistent systemic inflammation, and not to the severity of the acute illness and of the breadth of exposure to stressful events during the pandemic. We suggest that post-COVID depression provides an invaluable model illness for the study of immune-inflammatory mechanisms involved in the pathogenesis of mood disorders, to identify new targets for treatment, with the aim of restoring mental health and brain homeostasis.

2823

P115

Zakia, Halwa; Pradana, Kent; Iskandar, Shelly

Risk factors for psychiatric symptoms in patients with long COVID: A systematic review

https://doi.org/10.1371/journal.pone.0284075

Published

7-Apr-23

Review

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0284075

Prolonged symptoms of COVID-19 have been found in many patients, often known as Long COVID. Psychiatric symptoms are commonly seen in Long COVID patients and could last for weeks, even months, after recovery. However, the symptoms and risk factors associated with it remain unclear. In the current systematic review, we provide an overview of psychiatric symptoms in Long COVID patients and risk factors associated with the development of those symptoms. Articles were systematically searched on SCOPUS, PubMed, and EMBASE up to October 2021. Studies involving adults and geriatric participants with a confirmed previous COVID-19 diagnosis and reported psychiatric symptoms that persist for more than four weeks after the initial infection were included. The risk of bias was assessed using the Newcastle-Ottawa Scale (NOS) for observational studies. Prevalence rates and risk factors associated with psychiatric symptoms were collected. This present study was registered at PROSPERO (CRD42021240776). In total, 23 studies were included. Several limitations in this review were the heterogeneity of studies’ outcomes and designs, studies limited to articles published in English, and the psychiatric symptoms mainly were assessed using self-report questionnaires. The most prevalent reported psychiatric symptoms, from the most to the least reported, were anxiety, depression, post-traumatic stress disorder (PTSD), poor sleep qualities, somatic symptoms, and cognitive deficits. Being female and having previous psychiatric diagnoses were risk factors for the development of the reported symptoms.

2824

P116

Gasnier, Matthieu; David, Denis; Becquemont, Laurent; Corruble, Emmanuelle; Colle, Romain

128. Long Covid and Psychiatric Disorders 4 Months After a Hospitalization for COVID-19: A Cross Sectional Study

https://doi.org/10.1016/j.biopsych.2023.02.368

Published

1-May-23

Study

https://www.biologicalpsychiatryjournal.com/article/S0006-3223(23)00442-0/fulltext

Background
Long COVID is a major public health issue. Whether long COVID is comorbid with psychiatric disorders remains unclear. Here, we investigate the association between long COVID, psychiatric symptoms and psychiatric disorders.
Methods
One hundred seventy-seven patients admitted in ICU during acute phase and/or reporting long COVID complaints were assessed four months after hospitalization for an acute COVID-19. Eight long COVID complaints were investigated: fatigue, respiratory and cognitive complaints, muscle weakness, pain, headache, paraesthesia, and anosmia. The number of complaints, the presence/absence of each COVID complaint as well as lung CT-scan abnormalities and objective cognitive impairment) were considered. Self-reported psychiatric symptoms were assessed with questionnaires. Experienced psychiatrists assessed DSM-5-based diagnoses of psychiatric disorders.
Results
One hundred and fifteen (65%) patients had at least one long COVID complaint. The number of long COVID complaints was associated with psychiatric symptoms. The number of long COVID complaints was higher in patients with psychiatric disorders (m(sd)=2.47(1.30), p<0.05), new onset psychiatric disorders (m(sd)=2.41(1.32), p<0.05), and significant suicide risk (m(sd)=2.67(1.32), p<0.05) than in patients without any psychiatric disorder (m(sd)=1.43 (1.48)). ROC analyses showed that the threshold of one long COVID complaint had a good sensitivity (83.3%) to detect psychiatric disorders. Respiratory complaints were associated with a higher risk of psychiatric disorder and new-onset psychiatric disorder, and cognitive complaints were associated with a higher risk of psychiatric disorder.
Conclusions
Long COVID is associated with psychiatric disorders, new-onset psychiatric disorders, and suicide risk. Psychiatric disorders and suicide risk should be systematically assessed in patients with long COVID.
publisher: Elsevier

2825

P117

Nishimi, Kristen; Tan, Jeri; Scoglio, Arielle; Choi, Karmel; Kelley, D. Parker; Neylan, Thomas; O'Donovan, Aoife

37. Associations of Psychological Resilience to Trauma With Somatic Symptoms and COVID-19 Infection Over Two Years

https://doi.org/10.1016/j.biopsych.2023.02.277

Published

1-May-23

Study

https://www.biologicalpsychiatryjournal.com/article/S0006-3223(23)00351-7/fulltext

Background
Experiences of trauma may increase risk for physical health consequences, such as somatic symptoms, chronic conditions, and even infections, due in part to post-traumatic psychological sequelae. However, various internal and external factors cause many individuals to show psychological resilience to trauma, or positive psychological adaptation despite exposure. Thus, showing psychological resilience to prior trauma may be associated with better physical health outcomes, particularly in the face of subsequent stressors such as the COVID-19 pandemic.
Methods
Among 528 US adults in a longitudinal cohort, we examined psychological resilience to trauma early in the pandemic and levels of somatic symptoms and COVID-19 risk over two years of follow-up. Resilience was defined as one's relative level of psychological health (i.e., low distress and positive functioning) to lifetime trauma burden (i.e., count of traumatic events) in August 2020. Outcomes included somatic symptoms, COVID-19 infection, COVID-19 symptom severity, and long COVID risk assessed every six months. Covariate-adjusted regressions examined associations between resilience and outcomes.
Results
Higher resilience was associated with lower levels of somatic symptoms across follow-up, adjusting for sociodemographics, COVID-19 infection, and long COVID. One standard deviation higher resilience was associated with 31% lower likelihood of COVID-19 infection across time (Relative Risk=0.69, 95%CI 0.49-0.99), adjusting for sociodemographics and COVID-19 vaccination. In contrast, resilience was not associated with COVID-19 symptom severity or long COVID risk.
Conclusions
Psychological resilience to trauma may protect against somatic symptom experience and COVID-19 infection risk. Supporting recovery from trauma, both reducing distress and bolstering positive capacities, may benefit later mental and physical health.
publisher: Elsevier

2826

P118

Simonetti, Alessio; Bernardi, Evelina; Margoni, Stella; Catinari, Antonello; Restaino, Antonio; Ieritano, Valentina; Palazzetti, Marta; Mastrantonio, Federico; Janiri, Delfina; Tosato, Matteo; Landi, Francesco; Sani, Gabriele

Mixed Depression in the Post-COVID-19 Syndrome: Correlation between Excitatory Symptoms in Depression and Physical Burden after COVID-19

https://doi.org/10.3390/brainsci13040688

Published

1-Apr-23

Study

https://www.mdpi.com/2076-3425/13/4/688

The relationship between depression and post-COVID-19 disease syndrome (post-COVID-19 syndrome) is established. Nevertheless, few studies have investigated the association between post-COVID-19 syndrome and mixed depression, i.e., a specific sub-form of depression characterized by high level of excitatory symptoms. Aims of the present study are: (a) to compare the post-COVID-19 syndrome’s burden in depressed and non-depressed patients, and (b) to investigate the correlation between post-COVID-19 syndrome’s burden and the severity of mixed depression. One thousand and forty six (n = 1460) subjects with post-COVID-19 syndrome were assessed. Subjects were divided into those with (DEP) or without (CONT) depression. Sociodemographically, post-COVID-19 syndrome’s symptoms number and type were compared. In DEP, association between levels of excitatory symptoms and the presence of post-COVID-19 syndrome’s symptoms were additionally assessed. DEP showed greater percentages of family history of psychiatric disorders than CONT. DEP showed higher percentages of post-COVID-19 symptoms than CONT. A greater level of excitatory symptoms were associated to higher frequencies of post-COVID-19 syndrome’ symptoms. Higher levels of post-COVID-19 syndrome’s symptoms in DEP corroborate the evidence of a common pathway between these two syndromes. Presence of excitatory symptoms seem to additionally add a greater illness burden. Such findings might help clinicians choose the appropriate treatment for such states. More specifically, therapies aimed to treat excitatory symptoms, such as antipsychotics and mood stabilizers, might help reduce the illness burden in post-COVID-19 patients with mixed depression.

2827

P119

Schultebraucks, Katharina; Blekic, Wivine; Basaraba, Cale; Corbeil, Tom; Khan, Zain; Henry, Brandy F.; Krawczyk, Noa; Rivera, Bianca D.; Allen, Bennett; Arout, Caroline; Pincus, Harold Alan; Martinez, Diana M.; Levin, Frances R.

The impact of preexisting psychiatric disorders and antidepressant use on COVID-19 related outcomes: a multicenter study

https://doi.org/10.1038/s41380-023-02049-4

Published

17-Apr-23

Study

https://www.nature.com/articles/s41380-023-02049-4

Pre-existing mental disorders are linked to COVID-19-related outcomes. However, the findings are inconsistent and a thorough analysis of a broader spectrum of outcomes such as COVID-19 infection severity, morbidity, and mortality is required. We investigated whether the presence of psychiatric diagnoses and/or the use of antidepressants influenced the severity of the outcome of COVID-19. This retrospective cohort study evaluated electronic health records from the INSIGHT Clinical Research Network in 116,498 individuals who were diagnosed with COVID-19 between March 1, 2020, and February 23, 2021. We examined hospitalization, intubation/mechanical ventilation, acute kidney failure, severe sepsis, and death as COVID-19-related outcomes. After using propensity score matching to control for demographics and medical comorbidities, we used contingency tables to assess whether patients with (1) a history of psychiatric disorders were at higher risk of more severe COVID-19-related outcomes and (2) if use of antidepressants decreased the risk of more severe COVID-19 infection. Pre-existing psychiatric disorders were associated with an increased risk for hospitalization, and subsequent outcomes such as acute kidney failure and severe sepsis, including an increased risk of death in patients with schizophrenia spectrum disorders or bipolar disorders. The use of antidepressants was associated with significantly reduced risk of sepsis (p = 0.033), death (p = 0.026). Psychiatric disorder diagnosis prior to a COVID-19-related healthcare encounter increased the risk of more severe COVID-19-related outcomes as well as subsequent health complications. However, there are indications that the use of antidepressants might decrease this risk. This may have significant implications for the treatment and prognosis of patients with COVID-19.

2828

P120

Rouquette, Alexandra; Descarpentry, Arthur; Dione, Fallou; Falissard, Bruno; Legleye, Stéphane; Vuillermoz, Cécile; Pastorello, Anne; Meyer, Laurence; Warszawski, Josiane; Davisse-Paturet, Camille; Melchior, Maria; EpiCoV Study Group

Comparison of Depression and Anxiety Following Self-reported COVID-19–Like Symptoms vs SARS-CoV-2 Seropositivity in France

https://doi.org/10.1001/jamanetworkopen.2023.12892

Published

11-May-23

Study

https://doi.org/10.1001/jamanetworkopen.2023.12892

Key Points
Question Is SARS-CoV-2 infection associated with subsequent long-term depression or anxiety?

Findings In this propensity score–matched, population-based cohort study of 45 260 participants, COVID-19–like symptoms, but not SARS-CoV-2 infection, during the first months of the pandemic were associated with an increased occurrence of subsequent depression and anxiety 8 months or more after the occurrence of COVID-19–like symptoms, even when SARS-CoV-2 serologic test results were negative.

Meaning These findings suggest that SARS-CoV-2 infection is not a risk factor for long-term mental health issues; however, further research is needed to identify factors other than SARS-CoV-2 infection implied in the association between COVID-19–like symptoms and poor mental health outcomes.

Abstract
Importance The long-term consequences of COVID-19 on mental health are a critical issue given the number of people infected with SARS-CoV-2 worldwide since the beginning of the pandemic.

Objective To investigate the associations between self-reported COVID-19–like symptoms or SARS-CoV-2 seropositivity and subsequent depression or anxiety.

Design, Setting, and Participants This propensity score–matched cohort study began in May 2020, with follow-ups in November 2020 and July 2021. The study used data from a large, randomly selected, national population–based cohort from France, the EpiCoV (Epidémiologie et Conditions de Vie) study. Of 85 074 individuals 15 years or older who completed the questionnaires at the 3 collection times, 28 568 were excluded because they did not return a blood sample for serologic testing, 1994 because of missing data on outcomes or exposures, and 9252 to respect the temporal sequence (exposure must precede the outcome).

Exposures Propensity scores based on various socioeconomic, lifestyle, and health variables were computed to match participants who experienced COVID-19–like symptoms between February and November 2020 or showed SARS-CoV-2 seropositivity in November 2020.

Main Outcomes and Measures Logistic regression models were used to estimate associations between these occurrences and depression or anxiety assessed in July 2021 using the Patient Health Questionnaire 9-item and Generalized Anxiety Disorder 7-item scales, respectively.

Results Among the 45 260 included participants (mean [SD] age, 51.1 [18.9] years; 52.4% women; 8.0% with depression and 5.3% with anxiety in July 2021), COVID-19–like symptoms were associated with subsequent depression (adjusted odds ratio, 1.70; 95% CI, 1.45-1.99) and anxiety (adjusted OR, 1.57; 95% CI, 1.29-1.92), whereas SARS-CoV-2 seropositivity was not. Furthermore, COVID-19–like symptoms, but not anosmia or dysgeusia alone, were associated with subsequent depression and anxiety in both the seropositive and seronegative subgroups.

Conclusions and Relevance In this cohort study of more than 45 000 individuals drawn from the French general population, SARS-CoV-2 infection was not found as a risk factor of subsequent depression or anxiety. Moreover, self-reported COVID-19–like symptoms were associated with depression and anxiety assessed at least 8 months later in both seropositive and seronegative subgroups, suggesting that factors other than SARS-CoV-2 infection are implied in this association.

2829

P121

Re’em, Yochai; Stelson, Elisabeth A.; Davis, Hannah E.; McCorkell, Lisa; Wei, Hannah; Assaf, Gina; Akrami, Athena

Factors associated with psychiatric outcomes and coping in Long COVID

https://doi.org/10.1038/s44220-023-00064-6

Published

1-May-23

Study

https://www.nature.com/articles/s44220-023-00064-6

The relationship between Long COVID (LC) and psychiatric outcomes, as well as factors associated with presence and absence of these, has so far been insufficiently studied. Here we evaluated psychiatric symptoms and coping among patients with LC and patients recovered from COVID-19 who participated in a large international survey. Given increased rates of psychiatric illness with chronic medical conditions and known immune-inflammatory contributors to psychiatric disease, we hypothesized that a subset, but not the entirety, of LC respondents may have comorbid psychopathology. A substantial minority of both groups experienced suicidality, depression and anxiety symptoms, with these symptoms being more common in the LC group. LC respondents used more adaptive coping styles. Psychiatric outcomes in LC were associated with younger age, greater reductions in overall health, higher symptom severity, limitations to physical capability, lower income, financial hardship, psychiatric history, employment impact, male sex, men and non-binary gender, and negative experiences with medical professionals, family, friends, partners and employers.

2830

P122

Liu, Teresa C.; Yoo, Sun M.; Sim, Myung S.; Motwani, Yash; Viswanathan, Nisha; Wenger, Neil S.

Perceived Cognitive Deficits in Patients With Symptomatic SARS-CoV-2 and Their Association With Post–COVID-19 Condition:

https://doi.org/10.1001/jamanetworkopen.2023.11974

Published

5-May-23

Study

https://doi.org/10.1001/jamanetworkopen.2023.11974

Neuropsychiatric symptoms are common in acute SARS-CoV-2 infection and in post–COVID-19 condition (PCC; colloquially known as long COVID), but the association between early presenting neuropsychiatric symptoms and PCC is unknown.To describe the characteristics of patients with perceived cognitive deficits within the first 4 weeks of SARS-CoV-2 infection and the association of those deficits with PCC symptoms.This prospective cohort study was conducted from April 2020 to February 2021, with follow-up of 60 to 90 days. The cohort consisted of adults enrolled in the University of California, Los Angeles, SARS-CoV-2 Ambulatory Program who had a laboratory-confirmed symptomatic SARS-CoV-2 infection and were either hospitalized in a University of California, Los Angeles, hospital or one of 20 local health care facilities, or were outpatients referred by a primary care clinician. Data analysis was performed from March 2022 to February 2023.Laboratory-confirmed SARS-CoV-2 infection.Patients responded to surveys that included questions about perceived cognitive deficits modified from the Perceived Deficits Questionnaire, Fifth Edition, (ie, trouble being organized, trouble concentrating, and forgetfulness) and symptoms of PCC at 30, 60, and 90 days after hospital discharge or initial laboratory-confirmed infection of SARS-CoV-2. Perceived cognitive deficits were scored on a scale from 0 to 4. Development of PCC was determined by patient self-report of persistent symptoms 60 or 90 days after initial SARS-CoV-2 infection or hospital discharge.Of 1296 patients enrolled in the program, 766 (59.1%) (mean [SD] age, 60.0 [16.7] years; 399 men [52.1%]; 317 Hispanic/Latinx patients [41.4%]) completed the perceived cognitive deficit items at 30 days after hospital discharge or outpatient diagnosis. Of the 766 patients, 276 (36.1%) perceived a cognitive deficit, with 164 (21.4%) having a mean score of greater than 0 to 1.5 and 112 patients (14.6 %) having a mean score greater than 1.5. Prior cognitive difficulties (odds ratio [OR], 1.46; 95% CI, 1.16-1.83) and diagnosis of depressive disorder (OR, 1.51; 95% CI, 1.23-1.86) were associated with report of a perceived cognitive deficit. Patients reporting perceived cognitive deficits in the first 4 weeks of SARS-CoV-2 infection were more likely to report symptoms of PCC than those without perceived cognitive deficits (118 of 276 patients [42.8%] vs 105 of 490 patients [21.4%]; χ21, 38.9; P < .001). Adjusting for demographic and clinical factors, perceived cognitive deficits in the first 4 weeks of SARS-CoV-2 were associated with PCC symptoms (patients with a cognitive deficit score of >0 to 1.5: OR, 2.42; 95% CI, 1.62-3.60; patients with cognitive deficit score >1.5: OR, 2.97; 95% CI, 1.86-4.75) compared to patients who reported no perceived cognitive deficits.These findings suggest that patient-reported perceived cognitive deficits in the first 4 weeks of SARS-CoV-2 infection are associated with PCC symptoms and that there may be an affective component to PCC in some patients. The underlying reasons for PCC merit additional exploration.

2831

P123

Loftis, Jennifer M.; Firsick, Evan; Shirley, Kate; Adkins, James L.; Le-Cook, Anh; Sano, Emily; Hudson, Rebekah; Moorman, Jonathan

Inflammatory and mental health sequelae of COVID-19

https://doi.org/10.1016/j.cpnec.2023.100186

Published

1-Aug-23

Study

https://www.sciencedirect.com/science/article/pii/S2666497623000206

Highlights
•Severity of anxiety symptoms reduced over time in adults who tested negative for COVID-19.
•In adults negative for COVID-19, less anxiety was accompanied by decreases in inflammatory factors.
•Adults with neuro-PASC had depression scores in the moderate-severe range.
•Adults with more severe COVID-19 reported significantly greater depression.
•Adults with more severe COVID-19 had higher plasma levels of monokine induced by interferon gamma.
Abstract
The COVID-19 pandemic has caused significant negative consequences to mental health. Increased inflammatory factors and neuropsychiatric symptoms, such as cognitive impairment (“brain fog”), depression, and anxiety are associated with long COVID [post-acute sequelae of SARS-CoV-2 infection (PASC), termed neuro-PASC]. The present study sought to examine the role of inflammatory factors as predictors of neuropsychiatric symptom severity in the context of COVID-19. Adults (n = 52) who tested negative or positive for COVID-19 were asked to complete self-report questionnaires and to provide blood samples for multiplex immunoassays. Participants who tested negative for COVID-19 were assessed at baseline and at a follow-up study visit (∼4 weeks later). Individuals without COVID-19 reported significantly lower PHQ-4 scores at the follow-up visit, as compared to baseline (p = 0.03; 95% CI-1.67 to −0.084). Individuals who tested positive for COVID-19 and experienced neuro-PASC had PHQ-4 scores in the moderate range. The majority of people with neuro-PASC reported experiencing brain fog (70% vs. 30%). Those with more severe COVID-19 had significantly higher PHQ-4 scores, as compared to those with mild disease (p = 0.008; 95% CI 1.32 to 7.97). Changes in neuropsychiatric symptom severity were accompanied by alterations in immune factors, particularly monokine induced by gamma interferon (IFN-γ) (MIG, a. k.a. CXCL9). These findings add to the growing evidence supporting the usefulness of circulating MIG levels as a biomarker reflecting IFN-γ production, which is important because individuals with neuro-PASC have elevated IFN-γ responses to internal SARS-CoV-2 proteins.

2832

P124

Ranieri, Jessica; Capuani, Anika; Di Giacomo, Dina; Guerra, Federica; Cilli, Eleonora; Martelli, Alessandra

Psychological Distress and Negative Emotions in Post-COVID Infection: A Comparative Study of the COVID and NO-COVID Young Patients

https://doi.org/10.1177/00332941231177244

Published

25-May-23

Study

https://doi.org/10.1177/00332941231177244

According to the literature, mental health assumed urgent relevance, and several scholars are debating on the enduring of the neurological and psychiatric symptoms in post COVID patients. Our study aimed to investigate the emotional dimensions in young population to the COVID exposition: primary endpoint was to detect the psychological distress up to 3 months in post-COVID-19. A comparative study was conducted among young adults in Italy. We also assessed dysphoria, depression, anxiety, stress symptoms, pessimism, and positive personality traits. The participants were 140 Italian young aged 18–30 years (mean = 22.1, SD ± 2.65; 65.0% female). The sample was distinguished in two groups: COVID and NO-COVID groups. The results revealed that young who have been exposed to COVID-19 infection evidenced emotional vulnerability by higher psychological distress (depression, anxiety, stress), dysphoria signs (irritability, discontent, interpersonal resentment, and feelings of renunciation/surrender) then No COVID-19 infection young. Furthermore, COVID patients showed higher negative emotions about the expected life, uncertain for future, and loss of motivation (characterized no desires) than NO-COVID infection. In conclusion, the vulnerability of young exposed to COVID infection even in mild severity should be considered as emerging unmet need of mental health recovering: urgent health policy actions to boost the psychological, biological and social strategic pillar for young generation.

2833

R01

Molly Fisher, Joel Neugarten, Eran Bellin, Milagros Yunes, Lindsay Stahl, Tanya S. Johns

AKI in Hospitalized Patients with and without COVID-19: A Comparison Study

https://doi.org/10.1681/ASN.2020040509

Published

1-Sep-20

Clinical Research

https://jasn.asnjournals.org/content/31/9/2145.abstract

The frequency of acute renal failure during or after severe covid suggests a high prevalence of post-covid kidney disease, according to an American study.

La fréquence des insuffisances rénales aiguës pendant ou après un covid sévère laisse craindre une forte prévalence de malades des reins post-covid, selon une étude américaine.

2834

R02

Girish N. Nadkarni

Considering COVID-19 kidney injury

https://doi.org/10.1126/scitranslmed.abd4935

19-Aug-20

EDITORS' CHOICE

https://stm.sciencemag.org/content/12/557/eabd4935

Does SARS-CoV-2 infection have long-term effects on the kidney?

2835

R03

Erpicum P, Grosch S, Bouquegneau A, Huart J, Résimont G, Bovy C, Habran L

Atteintes rénales de la COVID-19

https://doi.org/10.1016%2Fj.nephro.2021.06.002

Published

Article Revue médicale Liège

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221000/

Dans la revue médicale de Liège, un article sur les atteintes rénales attribuées à la covid : nécrose tubulaire aiguë de sévérité variable, et congestion des capillaires glomérulaires et péri-tubulaires. Plus rarement, une endothélite.

2836

R04

S. Boeger, J. Petrovic, E. Busink, C. Apel, F. Kircelli, R. Pohlmeier

PUK14 ACUTE Renal Failure during COVID-19 and Its LONG-TERM IMPACT on Health System

https://doi.org/10.1016/j.jval.2020.08.2057

Published

1-Dec-20

https://www.valueinhealthjournal.com/article/S1098-3015(20)34313-8/fulltext

Une méta-analyse montre que sur 12000 malades critiques de la covid en Europe, 3126 ont nécessité un support de la fonction rénale. 62% d'entre eux en sont morts, et parmi les survivants 19% devront vivre sous dialyse.

2837

R05

Shrikant B Deshmukh, Kavita M Upadhyay, Advait Kulkarni, Sudhir Deshpande, Rajshri Purohit, Milind Kulkarni

Renal Artery Thrombosis: A Post COVID-19
Sequel

https://doi.org/10.24321/2349.7181.202009

Published

5-Dec-20

Case Report

https://medical.advancedresearchpublications.com/index.php/MedicineJournal/article/view/458

Un cas rapporté de thrombose de l'artère rénale décrit comme lié à une infection à la covid, dans une étude qui rappelle le risque de thromboses vasculaires aussi bien chez les patients symptomatiques qu'asymptomatiques.

2838

R06

Paul M. Palevsky

COVID-19 and AKI: Where Do We Stand?

https://doi.org/10.1681/ASN.2020121768

Published

1-Feb-21

Review

https://jasn.asnjournals.org/content/early/2021/02/25/ASN.2020121768

Finally, it is still too early to understand the effect of the large number of patients with COVID-19–associated AKI on the future epidemiology of kidney disease. It is easy to speculate that unresolved and incompletely resolved AKI will increase the burden of CKD and ESKD and that superimposition of AKI on CKD will accelerate progression to kidney failure.

Un article dresse un état des lieux de la littérature sur les insuffisances rénales aiguës liées à la covid.

N004R

2839

R07

Yi-FuFenga1Kun-PengWanga1Jing-GangMoaYing-HeXubLie-ZhiWangaChongJinaXiangChencBinYi

The spatiotemporal trend of renal involvement in COVID-19: a pooled analysis of 17,134 patients

https://doi.org/10.1016/j.ijid.2021.03.082

Published

3-Apr-21

Study

https://www.sciencedirect.com/science/article/pii/S1201971221003003

Highlights
•Renal involvement in COVID-19 becomes an increasingly serious problem over time.
•Spatial differences are significant in renal involvement superimposed COVID-19.
•Renal involvement may increase the risk of severity and mortality of COVID-19 patients.

_

2840

R08

Pierre Delanaye
Justine Huart
Antoine Bouquegneau
François Jouret

Long-term effects of COVID-19 on kidney function

https://doi.org/10.1016/S0140-6736(21)00881-3

Published

15-May-21

Correspondance

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00881-3/fulltext

Chaolin Huang and colleagues1 have highlighted the putative renal consequences of COVID-19 at 6 months from discharge. A decreased estimated glomerular filtration rate (eGFR) was defined as less than 90 mL/min per 1·73 m2 and was observed in 35% of participants during follow-up. The pathological relevance of an eGFR between 60 and 90 mL/min per 1·73 m2 is questionable in the absence of proteinuria.2 Proteinuria has been frequently described in patients with COVID-19. Our follow-up observations suggest a spontaneous remission within a few weeks after discharge.5 The available data of Huang and colleagues do not support their alarming conclusions about the poor renal prognosis at 6 months after COVID-19.

_

2841

R09

Lixue Huang
Xiaoying Gu
Yeming Wang
Chaolin Huang
Bin Cao

Long-term effects of COVID-19 on kidney function – Authors' reply

https://doi.org/10.1016/S0140-6736(21)00875-8

Published

15-May-21

Correspondance

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00875-8/fulltext

We agree that the criteria of an eGFR less than 90 mL/min per 1·73 m2 cannot define chronic kidney disease, especially for those with an eGFR between 60 and 90 mL/min per 1·73 m2 in the absence of proteinuria; although, we do not want to ignore patients with preclinical manifestation of kidney damage as proteinuria was not measured then. We hope these important questions can be further answered in future studies.

_

2842

R10

Rhian MTouyzMBBCh, PhDMarcus OEBoydTomaszGuzikMD, PhDSandoshPadmanabhanMD, PhDLinsayMcCallumMBChBChristianDellesMDPatrick BMarkMBChB, PhDJohn RPetrieMBChB, PhDFranciscoRiosPhDAugusto CMontezanoPhDRobertSykesMBChB, BMedSciColinBerryMBChB, PhD

Cardiovascular and renal risk factors and complications associated with COVID-19

https://doi.org/10.1016/j.cjco.2021.05.020

Published

16-Jun-21

Review

https://www.sciencedirect.com/science/article/pii/S2589790X21001554

Here we discuss cardiovascular and kidney disease in the context of COVID-19 and provide recent advances on putative pathophysiological mechanisms linking cardiovascular disease and COVID-19, focusing on the RAS and ACE2 as well as the immune system and inflammation. We provide up-to-date information on the relationship between hypertension, diabetes, and COVID-19 and emphasize the major cardiovascular diseases associated with COVID-19. We also briefly discuss emerging cardiovascular complications associated with long COVID-19, notably postural tachycardia syndrome (POTS).

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2843

R11

Stéphane Burtey a b Marion Sallée a b

Les atteintes rénales de la COVID-19 - Kidney damage in COVID-19

https://doi.org/10.1016/j.nephro.2021.06.002

Published

23-Jun-21

Article

https://www.sciencedirect.com/science/article/pii/S1769725521001383

Il existe une atteinte rénale qui se caractérise par trois atteintes principales, une nécrose tubulaire aiguë survenant dans les cas les plus sévères, une tubulopathie proximale, qui est un marqueur pronostique de la maladie, et une hyalinose segmentaire et focale survenant sur un terrain génétiquement prédisposé. La physiopathologie de l’atteinte rénale du SARS-CoV-2 n’est pas encore définie. Le rôle direct du virus est discuté alors que la tempête cytokinique et les complications hypoxiques et thrombotiques semblent plus importantes. Le devenir à long terme des atteintes rénales paraît plutôt bon. Un suivi à long terme permettra de dire si l’atteinte rénale fait partie du COVID long.

2844

R12

Gabriel Cavalcante Lima ChagasAmanda Ribeiro RangelLuisa Macambira NoronhaGeraldo Bezerra da Silva Jr.Gdayllon Cavalcante MenesesAlice Maria Costa MartinsElizabeth De Francesco Daher

COVID-19 and Kidney: a narrative review

https://doi.org/10.1590/1806-9304202100S200003

Published

1-May-21

Review

https://www.scielo.br/j/rbsmi/a/twcS7TwJggTThZXKYzjdWnH/?lang=en

In this study, we aimed to present a narrative review on kidney involvement in COVID-19. Kidney involvement could be derived from direct cytopathic effects, immunological mechanisms, indirect effects on renal tissue through other mediators, and dysfunction or injury of other organs.

2845

R13

Matthieu Legrand, Samira Bell, Lui Forni, Michael Joannidis, Jay L. Koyner, Kathleen Liu & Vincenzo Cantaluppi

Pathophysiology of COVID-19-associated acute kidney injury

https://doi.org/10.1038/s41581-021-00452-0

Published

5-Jul-21

Article

https://www.nature.com/articles/s41581-021-00452-0

Key points
Over a quarter of patients hospitalized with coronavirus disease 2019 (COVID-19) have been reported to develop acute kidney injury (AKI).
Low molecular weight proteinuria, Fanconi syndrome and histological findings point towards tubular injury.
Analyses of kidney biopsy samples from patients with COVID-19 and AKI have inconsistently reported viral infection of kidney cells.
Collapsing glomerulopathy has been identified in patients with high-risk APOL1 genotypes, mostly in those without severe respiratory symptoms.
Regional inflammation, endothelial injury and renal microthrombi have been reported but their implication in the pathogenesis of COVID-associated AKI remains uncertain.
Anti-inflammatory drugs (for example, steroids and IL-6 receptor blockers) seem to limit the development of severe AKI in patients with COVID-19.

2846

R14

Burtey S1, Sallée M

Kidney damage in COVID-19

https://doi.org/10.1016/j.nephro.2021.06.002

Published

23-Jun-21

Review

https://europepmc.org/article/med/34266783

There is renal involvement which is characterised by three main types of damage, acute tubular necrosis occurring in the most severe cases, proximal tubulopathy which is a prognostic marker of the disease and segmental and focal hyalinosis occurring in a genetically predisposed terrain. The pathophysiology of SARS-CoV-2 renal involvement is not yet defined. The direct role of the virus is debated, whereas the cytokine storm and the hypoxic and thrombotic complications seem more important. The long-term outcome of the renal damage appears to be quite good. Long-term follow-up will allow us to say whether the renal damage is part of the long COVID.

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2847

R15

Ian A.Strohbehn1SophiaZhao1HarishSeethapathy1MeghanLee1NifashaRusibamayila1Andrew S.Allegretti1Xavier VelaParada1Meghan E.Sise

Acute kidney injury incidence, recovery, and long-term kidney outcomes among hospitalized patients with COVID-19 and influenza

https://doi.org/10.1016/j.ekir.2021.07.008

Published

15-Jul-21

Study

https://www.sciencedirect.com/science/article/pii/S2468024921013024

A total of 2425 patients were included; 1091 (45%) had COVID-19 and 1334 (55%) had influenza. Overall AKI rate was 23% and 13% in patients with COVID-19 and influenza, respectively. Compared to influenza, hospitalized patients with COVID-19 had an increased risk of developing AKI (adjusted hazard ratio, aHR 1.58, 95% CI 1.29–1.94). Patients with AKI were more likely to die during hospital when infected with COVID-19 vs. influenza (aHR 3.55, 95% CI 2.11–5.97). Among patients surviving to hospital discharge, the rate of AKI recovery was lower in patients with COVID-19 (aHR 0.47, 95% CI 0.36–0.62); however, among patients followed for ≥ 90 days, new-onset CKD (aHR 1.24, 95% CI 0.86–1.78) and ≥ 25% eGFR decline at last follow-up (aHR 1.36, 95% CI 0.97–1.90) were not significantly different between the cohorts.

Conclusion
AKI and mortality rates are significantly higher in COVID-19 than influenza; however, kidney recovery among long-term survivors appears to be similar.

La covid provoque 60% de plus d'insuffisances rénales aiguës que la grippe, avec un taux de rémission deux fois inférieur, selon une étude américaine. Au delà de la rémission, les suivis post-accident rénaux entre covid et grippe sont comparables.

N014E

2848

R16

Benjamin Bowe, Yan Xie, Evan Xu and Ziyad Al-Aly

Kidney Outcomes in Long COVID

https://doi.org/10.1681/ASN.2021060734

Published

1-Sep-21

Study

https://jasn.asnjournals.org/content/early/2021/08/25/ASN.2021060734

Methods: We built a cohort of 1,726,683 US Veterans identified from March 01, 2020 to March 15, 2021 including 89,216 30-day COVID-19 survivors and 1,637,467 non-infected controls. We examined risks of AKI, eGFR decline, ESKD, and major adverse kidney events (MAKE) defined as eGFR decline ≥50%, ESKD, or all-cause mortality using inverse probability weighted survival regressions, adjusting for predefined demographic and health characteristics, and algorithmically selected high-dimensional covariates including diagnoses, medications, and laboratory tests. Linear mixed models characterized intra-individual eGFR trajectory.

Results: Beyond the acute illness, 30-day survivors of COVID-19 exhibited a higher risk of AKI (aHR=1.94 (95%CI: 1.86,2.04)), eGFR decline ≥30% (1.25 (1.14,1.37)), eGFR decline ≥40% (1.44 (1.37,1.51)), eGFR decline ≥50% (1.62 (1.51,1.74)), ESKD (2.96 (2.49-3.51)), and MAKE (1.66 (1.58,1.74)). There was a graded increase in risks of post-acute kidney outcomes according to the severity of the acute infection (whether patients were non-hospitalized, hospitalized, or admitted to intensive care). Compared to non-infected controls, 30-day COVID-19 survivors exhibited excess eGFR decline of -3.26 (-3.58, -2.94), -5.20 (-6.24, -4.16), and -7.69 (-8.27, -7.12) mL/min/1.73m2/year in non-hospitalized, hospitalized, and those admitted to intensive care during the acute phase of COVID-19 infection.

2849

R17

S Svetitsky,1,2 R Shuaib,2 S McAdoo,1,2 and D C Thomas1,

Long-term effects of Covid-19 on the kidney

https://dx.doi.org/10.1093%2Fqjmed%2Fhcab061

Published

17-Sep-21

FReview

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500011/

Acute kidney injury (AKI) is a common complication of Covid-19 and one associated with increased mortality, especially when requiring renal replacement therapy.1,2 AKI affects over 20% of hospitalized patients and over 50% of patients in the ICU.3 Varying rates of recovery of renal function on discharge are described. Unsurprisingly, pre-existing CKD is a risk factor for dialysis dependence on discharge.4 Previous studies have found that AKI, regardless of cause, results in pre-disposition to progressive CKD and the risk increases with the severity of AKI;5 this will likely be the case with Covid-19 infection as well. Understanding the long-term impact of Covid-19 on the kidney is vital for planning and resource allocation for nephrology services.

2850

R18

Joshua D.Long1IanStrohbehn1RaniSawtell1RobyBhattacharyya2Meghan E.Sise1

COVID-19 Survival and its Impact on Chronic Kidney Disease

https://doi.org/10.1016/j.trsl.2021.11.003

Published

10-Nov-21

Review

https://www.sciencedirect.com/science/article/pii/S1931524421002668

In this review, we highlight the current understanding of the pathophysiology of COVID-19-associated kidney injury and the impact COVID-19 may have on long-term kidney function. COVID-19-induced acute kidney injury may lead to tubular injury, endothelial injury, and glomerular injury. We highlight histopathologic correlates from large kidney biopsy and autopsy series. By conducting a comprehensive review of published literature to date, we summarize the rates of recovery from COVID-19-associated-AKI. Finally, we discuss how certain genetic differences, including APOL1 risk alleles (a risk factor for collapsing glomerulopathy), coupled with systemic healthcare disparities, may lead to a disproportionate burden of post-COVID-19-kidney function decline among racial and ethnic minority groups. We highlight the need for prospective studies to determine the true incidence of chronic kidney disease burden after COVID-19.

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2851

R19

Wissam H. Faour, Ali Choaib, Elio Issa, Francesca El Choueiry, Khodor Shbaklo, Maryline Alhajj, Ramy Touma Sawaya, Zeina Harhous, Eman Alefishat & Moni Nader

Mechanisms of COVID-19-induced kidney injury and current pharmacotherapies

https://doi.org/10.1007/s00011-021-01520-8

Published

21-Nov-21

Review

https://link.springer.com/article/10.1007/s00011-021-01520-8

While significant evidence is currently available online and targets various aspects of the disease, both inflammatory and noninflammatory kidney manifestations secondary to COVID-19 infection are still largely underrepresented. In this review, we summarized current knowledge about COVID-19-related kidney manifestations, their pathologic mechanisms as well as various pharmacotherapies used to treat patients with COVID-19. We also shed light on the effect of these medications on kidney functions that can further enhance renal damage secondary to the illness.

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2852

R20

Togay Evrin, Burak Katipoglu

COVID-19 are dangerous to the kidneys in any situation, not
only in a pandemic: LONG-COVID-19 and kidney disease

https://doi.org/10.5603/CJ.a2021.0163

pre-print

7-Dec-21

Article

https://journals.viamedica.pl/cardiology_journal/article/view/CJ.a2021.0163

Clinicians who must pay close attention to kidney function evaluation will play a critical
role, not only in the group of hospitalized patients, but also in the group of seemingly
asymptomatic patients, and notably in the group of patients with LONG-COVID-19.
Vaccinations also play an important role in reducing the risk of serious illness, hospitalization,
and complications such as LONG-COVID-19.

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2853

R21

Jochen Reiser
Ryan Spear
Shengyuan Luo

SARS-CoV-2 pirates the kidneys: A scar(y) story

https://doi.org/10.1016/j.cmet.2022.02.005

Published

1-Mar-22

Article

https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00049-3

As the coronavirus disease 2019 (COVID-19) global pandemic continues for a third year, more has been unveiled about its culprit, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Aside from triggering a possibly dire innate immune response, it also causes severe respiratory illness and a myriad of acute and chronic multi-organ damage, with the kidneys being one of the most frequently targeted organs outside the lungs. Accumulating evidence suggests the presence of SARS-CoV-2 in some but not all kidneys from COVID-19 cases, yet at higher concentrations compared to other organs (Puelles et al., 2020). Renal manifestations of COVID-19 can range from acute kidney injury (AKI), hematuria, proteinuria, podocytopathy, and tubulointerstitial fibrosis (Diao et al., 2021). Importantly, a substantial number of individuals with COVID-19 experience post-acute sequelae, a syndrome now referred to as “long COVID,” many of whom suffered worse outcomes of AKI such as rapid kidney function decline and chronic kidney disease (CKD) (Bowe et al., 2021). One key to understanding these phenomena is to determine if the virus infects kidney cells directly and, if so, if this leads to short- and/or long-term renal damage.
In the latest issue of Cell Stem Cell, Jansen et al. comprehensively investigated whether direct infection of the kidneys by SARS-CoV-2 introduces a pro-fibrotic phenotype (Jansen et al., 2022). The authors compared kidneys of individuals with COVID-19 compared to matched controls. With data derived from 61 human autopsies and single-RNA nucleus sequencing, the study associated increased interstitial fibrosis with the presence of higher activity in proinflammatory and fibrosis-driving pathways (notably, tumor necrosis factor alpha [TNFα], transforming growth factor beta, nuclear factor kB, and JAK-STAT). Taking this to the next level, the study utilized human induced pluripotent stem cell (hiPSC)-derived kidney organoids to fine map cellular locations of SARS-CoV-2 infection and accompanying signaling changes. In addition to verifying upregulated activity of pro-fibrotic pathways found in SARS-CoV-2-infected autopsied kidneys, the team identified evidence of a molecular crosstalk between proximal tubular cells and PDGFRa/b+ mesenchymal cells (a key source of myofibroblasts) that further contributed to fibrosis.
The findings by Jansen and colleagues are exciting and supported by both human tissues and hiPSC-derived organoids. They can serve as strong evidence to support the notion that SARS-CoV-2 can directly drive renal fibrosis, a CKD hallmark, suggesting a likely impact on the worse AKI outcomes during COVID-19 that are often observed. These findings also bridged a knowledge gap, linking acute viral illness to kidney disease during long-COVID. hiPSC-derived organoids have the advantage of being able to assess intercellular interactions, which possibly explains the greater extent of cytopathic changes seen in organoids compared to other studies using SARS-CoV-2-infected ex vivo models comprised solely of tubular epithelial cells and that lacked cytopathic changes (Omer et al., 2021). Jansen et al. provided the first hints that SARS-CoV-2 infection in kidney organoids is amenable to a treatment with a protease inhibitor, providing a glimpse into potential future treatments for COVID-19-related kidney injury. The findings also stimulate further clinical and translational investigations for testing SARS-CoV-2 tropism in the kidneys of infected individuals to identify potential virus-free kidneys for transplantation procured from individuals who died of fulminant COVID-19 (Lee et al., 2022).
The use of hiPSC-kidney organoids is not without caveats, however. As the authors pointed out, the protocols to differentiate hiPSCs to model the adult kidney in its entirety are still suboptimal. While excluding extra-renal factors, such as intensive care treatment, the model also isolates kidney cells from the involvement of immune cells. For example, the recruitment of CD68+ macrophages, CD56+ natural killer cells, and CD8+ T cells, alongside strong C5b-9 deposition, was found with tubular necrosis in the kidneys of patients with COVID-19 (Diao et al., 2021). Jansen et al. also observed an interaction between podocytes and the mesenchymal endothelial progenitor population. The cytologic consequences were beyond the study’s scope and therefore not described, but one must recognize podocytopathy, glomerular collapsing, and sclerosis as indispensable parts of the COVID-19-related kidney disease spectrum, in which innate immunity likely plays an essential role. The massive release of immune mediators such as soluble urokinase plasminogen activator receptor (suPAR), TNFα, and interferon gamma, i.e., a cytokine storm, signifies severe COVID-19 and confers substantial risk for AKI (Azam et al., 2020; Karki et al., 2021). Biomarkers predictive of outcomes that are elevated early during disease progression, such as suPAR, have been successfully applied in clinical practice to guide immunomodulative treatment and improve prognosis (Kyriazopoulou et al., 2021). Future studies aiming to examine viral triggers, innate immune mediators, and kidney cell reactivity in concert will need to be performed. In the meantime, Jansen et al. allow us to draw the conclusion that the renal presence of SARS-CoV-2 can bring about pro-inflammatory and pro-fibrotic molecular changes that may prime the kidneys for further damage (including hits from circulating mediators such as suPAR and TNFα), ultimately leading to lasting kidney disease in long COVID.
The study by Jansen et al. provides additional insights to allow for a comparison of kidneys infected by SARS-CoV-2 and other viral infections, especially human immunodeficiency virus (HIV) infection (Figure 1). Both SARS-CoV-2 and HIV directly infect podocytes and tubular epithelial cells. Collapsing glomerulopathy, tubulointerstitial fibrosis, and mesangial injury can be seen in both COVID-19 and HIV infection and are perhaps dependent on the amount of the innate immune activation that is mounted as an anti-infection response. Lessons learned from our experience with HIV infection may offer insight into the study of COVID-19-related kidney disease. Is there a set of COVID-19 gene products that converges pro-fibrotic and other pathways in diverse kidney cells and structures? African Americans develop COVID-19 associated with stronger AKI more often than other racial and ethnic groups (Hung et al., 2022). Are socioeconomic factors the sole drivers of these disparities, or is there a role for other genetic factors and environmental factors? It is noteworthy that untreated HIV infection caused glomerulopathy in 50% of African Americans with two APOL1 risk alleles. Data from patients with COVID-19 also suggested AKI, proteinuria, and podocytopathy were more prevalent among those with the high-risk APOL1 genotype. Will there be a need for screening and early detection of CKD in long COVID? Which antivirals and what duration of treatment will ensure clearance of SARS-CoV-2 in the kidneys? A stage is now set for these topics to be addressed.

2854

R22

Jitske Jansen 22 Katharina C. Reimer 22 James S. Nagai 22 Finny S. Varghese 23 Gijs J. Overheul Marit de Beer Rona Roverts Deniz Daviran Liline A.S. Fermin Brigith Willemsen Marcel Beukenboom Sonja Djudjaj Saskia von Stillfried Larissa E. van Eijk Mirjam Mastik Marian Bulthuis Wilfred den Dunnen Harry van Goor Jan-Luuk Hillebrands Anat Akiva Peter Boor Victor G. Puelles Jürgen Floege Tobias B. Huber Ronald P. van Rij Ivan G. Costa 21 Rebekka K. Schneider 21 Bart Smeets 21 Rafael Kramann 21

SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids

https://doi.org/10.1016/j.stem.2021.12.010

Published

3-Feb-22

Study

https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00520-8

Kidney failure is frequently observed during and after COVID-19, but it remains elusive whether this is a direct effect of the virus. Here, we report that SARS-CoV-2 directly infects kidney cells and is associated with increased tubule-interstitial kidney fibrosis in patient autopsy samples. To study direct effects of the virus on the kidney independent of systemic effects of COVID-19, we infected human-induced pluripotent stem-cell-derived kidney organoids with SARS-CoV-2. Single-cell RNA sequencing indicated injury and dedifferentiation of infected cells with activation of profibrotic signaling pathways. Importantly, SARS-CoV-2 infection also led to increased collagen 1 protein expression in organoids. A SARS-CoV-2 protease inhibitor was able to ameliorate the infection of kidney cells by SARS-CoV-2. Our results suggest that SARS-CoV-2 can directly infect kidney cells and induce cell injury with subsequent fibrosis. These data could explain both acute kidney injury in COVID-19 patients and the development of chronic kidney disease in long COVID.

2855

R23

Juan León-Román, Irene Agraz, Ander Vergara, Natalia Ramos, Nestor Toapanta, Clara García-Carro, Alejandra Gabaldón, Roxana Bury, Sheila Bermejo, Oriol Bestard, María José Soler

COVID-19 infection and renal injury: where is the place for acute interstitial nephritis disease?

https://doi.org/10.1093/ckj/sfac079

Published

14-Mar-22

Study

https://academic.oup.com/ckj/advance-article/doi/10.1093/ckj/sfac079/6548197

Novel coronavirus disease infection (COVID-19) was declared a global pandemic in March 2020 and since then has become a major public health problem. The prevalence of COVID-19 infection and acute kidney injury (AKI) is variable depending on several factors such as race/ethnicity, and severity of illness. The pathophysiology of renal involvement in COVID-19 infection is not entirely clear but it could be in part explained by the viral tropism in the kidney parenchyma. AKI in COVID-19 infection can be either by direct invasion of the virus, or as a consequence of immunologic response. Diverse studies have focused on the effect of COVID-19 on glomerulonephritis (GN) patients or the “novo” GN; however, the effect of COVID-19 in acute tubulointerstitial nephritis (ATIN) has been scarcely studied. In this article, we present five cases with different spectrums of COVID-19 infection and ATIN that may suggest that recent diagnosis of ATIN is accompanied with a worse clinical prognosis in comparison with long-term diagnosed ATIN.

2856

R24

Sidar Copur, Metehan Berkkan, Carlo Basile, Katherine Tuttle & Mehmet Kanbay

Post-acute COVID-19 syndrome and kidney diseases: what do we know?

https://doi.org/10.1007/s40620-022-01296-y

Published

16-Mar-22

Review

https://link.springer.com/article/10.1007/s40620-022-01296-y

COVID-19 presents various respiratory, cardiovascular, neuropsychiatric, musculoskeletal and kidney features during the acute phase; nevertheless, renal involvement in the post-infection period has recently been emphasized. The present review aims to evaluate the growing literature on kidney involvement in the SARS-CoV-2 infection along with clinical features reported both in the acute phase of the infection and in the post-acute COVID-19 period by assessing potential pathophysiological frameworks explaining such conditions. Chronic kidney disease and development of acute kidney injury (AKI) in the course of initial hospitalization are associated with high mortality and morbidity rates. Moreover, growing evidence suggests a decline in renal function in the 6-to-12-month follow-up period even in patients without any signs of AKI during the acute phase. Despite such concerns there are no guidelines regulating the follow-up period or therapeutic alternatives for such patient population. In conclusion, the burden of COVID-19 on the kidney is yet to be determined. Future prospective large scale studies are needed with long follow-up periods assessing kidney involvement via multiple parameters such as biopsy studies, urinalysis, measurement of serum creatinine and cystatin C, directly measured glomerular filtration rate, and assessment of tubular function via urinary β2-microglobulin measurements.

2857

R25

Hadadi A. · Farrokhpour H. · Rashedi S. · Kafan S. · Sotoudehnia M. · Rahimzadeh H. · Tabatabaei S. · Razeghi E. · Aghsaeifard Z.

Long term impact of the COVID-19 associated AKI: the relationship between kidney recovery and mortality in a 10-month follow-up cohort study

https://doi.org/10.1159/000524451

Published

4-Apr-22

Study

https://www.karger.com/Article/Abstract/524451

Abstract Introduction: Corona Virus-2019 (COVID-19) associated acute kidney injury (AKI) and its short and mid-term effect on kidney has been well established in the previous literature, indicating a high number of AKI in hospitalized patients associated with high rates of mortality, followed by high rates of unresolved kidney injury at the time of discharge. However, the long-term impact of AKI and its resulting lack of recovery at discharge has not been investigated. Herein, we sought to explore the possible relationship between AKI and unresolved kidney injury and post-discharge mortality. Method: In this cohort study, patients hospitalized with COVID-19 who survived to the discharge were followed for a median of 9.6 months. AKI during hospitalization based on the staging according to KDIGO criteria and Kidney injury status at the time of discharge and other comorbidities and mortality during the follow-up period, were recorded. Using Cox proportional hazards regression, the desired association was investigated after adjustment for potential confounders. Result: Among 1017 discharged patients, 298 patients (29.3%) experienced AKI during hospitalization according to KDIGO criteria, of whom 178 patients (59.7%) were diagnosed with unresolved kidney injury at the time of discharge. After adjusting for potential confounders, Cox regression indicated that AKI stage 3 (HR: 4.56, 95% CI: 1.89-10.99, p=0.001) and unresolved kidney injury at the time of discharge (HR: 2.09, 95% CI: 1.18-3.73, p=0.011) were significantly associated with mortality during the post-discharge period. Additionally, Kaplan-Meier curves for overall survival indicated an increased risk of mortality in patients with stage 2, stage 3 AKI, and unresolved kidney injury at the time of discharge. ( P<0.001) Conclusion: Overall, it was shown that patients with COVID-19 who develop AKI, mainly stage 2 and 3, and patients with unresolved kidney injury at the time of discharge, were at increased risk of mortality, even after hospitalization for an extended time

2858

R26

M.Zaidan1F.Gaillard2A.Barnoud3Y.Darhi3P.Samb4L.Grimaldi5

Conséquences à long terme de l’insuffisance rénale aiguë au cours de la COVID-19 : données de l’entrepôt de données de santé de l’AP–HP

https://doi.org/10.1016/j.nephro.2022.07.253

Published

5-Sep-22

Study

https://www.sciencedirect.com/science/article/pii/S1769725522003820

Introduction
L’insuffisance rénale aiguë (IRA) est une complication fréquente et sévère chez les patients hospitalisés pour COVID-19. Les conséquences rénales à long terme restent à déterminer.
Description/Méthodes
Il s’agit d’une cohorte de patients adultes hospitalisés à l’AP–HP pendant plus de 24 h pour COVID-19 entre le 01/02/2020 et le 31/05/2020, constituée à partir de l’Entrepôt de Données de Santé de l’AP–HP. Les patients au statut rénal (de base et/ou à distance) indéterminé ont été exclus ou n’ont pas été inclus dans l’analyse par régression logistique des facteurs de risque d’insuffisance rénale chronique (IRC) post-COVID-19.
Résultats
Au total, 8492 patients ont été admis pour COVID-19 à l’AP–HP sur la période d’étude, incluant 5718 patients sans IRC préalable et dont le statut rénal pouvait être étudié. Sur les 2151 (37,6 %) patients ayant développé une IRA, 481 (22,4 %) sont décédés durant leur séjour, 1195 (55,6 %) ont récupéré une fonction rénale normale et 475 (22,1 %) avaient une altération persistante de la fonction rénale à la sortie d’hospitalisation. Par la suite, 46 patients sont décédés et 628 ont été perdus de vue. Sur les 996 patients survivants et pour lesquels le statut rénal à long terme était disponible, 565 ont récupéré une fonction rénale normale et 431 ont développé une IRC. En analyse multivariée, les facteurs associés au risque d’IRC étaient : l’âge, le sexe masculin, l’hypertension, le diabète, les maladies cardiaques, les transplantations d’organes, le taux d’hémoglobine à l’entrée, la sévérité de l’IRA durant l’hospitalisation, l’oxygénothérapie et le passage en réanimation.
Conclusion
Notre étude montre un risque important d’IRC chez les patients hospitalisés pour COVID-19 et qui développent une IRA, y compris chez ceux ayant récupéré une fonction « normale » à la sortie d’hospitalisation, soulignant l’intérêt d’une évaluation rénale à distance de la COVID-19.

2859

R27

Maureen Brogan1 and Michael J. Ross

COVID-19 and Kidney Disease

https://doi.org/10.1146/annurev-med-042420-104753

Published

15-Sep-22

Review

https://www.annualreviews.org/doi/abs/10.1146/annurev-med-042420-104753

COVID-19 can cause acute kidney injury and may cause or exacerbate chronic kidney diseases, including glomerular diseases. SARS-CoV-2 infection of kidney cells has been reported, but it remains unclear if viral infection of kidney cells causes disease. The most important causes of kidney injury in patients with COVID-19 include impaired renal perfusion and immune dysregulation. Chronic kidney disease, especially kidney failure with kidney replacement therapy and kidney transplant, is associated with markedly increased COVID-19 mortality. Persons with severe kidney disease have been excluded from most clinical trials of COVID-19 therapies, so therapeutic approaches must be extrapolated from studies of patients without kidney disease. Some medications used to treat COVID-19 should be avoided or used at reduced dosages in patients with severe kidney disease and in kidney transplant recipients. Additional research is needed to determine the optimal strategies to prevent and treat COVID-19 in patients with kidney disease.

2860

R28

Ivan Cancarevic, Mahmoud Nassar, Luis Medina, Angelica Sanchez, Avish Parikh, Asma Hosna, Bhavana Devanabanda, Mallorie Vest, Fatima Ayotunde, Muhammad Ghallab, Ismail Omran

Nephrotic Syndrome in Adult Patients With COVID-19 Infection or Post COVID-19 Vaccine: A Systematic Review

https://doi.org/10.7759/cureus.29613

Published

26-Sep-22

Study

https://www.cureus.com/articles/110827-nephrotic-syndrome-in-adult-patients-with-covid-19-infection-or-post-covid-19-vaccine-a-systematic-review

Nephrotic syndrome is a condition characterized by damage to podocytes that results in significant proteinuria, edema, hyperlipidemia, and hypercoagulability. Infections and malignancies are frequently associated with nephrotic syndrome. The COVID-19 virus has been associated with several atypical presentations of upper respiratory infections and acute kidney injury. Considering that COVID-19 causes systemic inflammatory changes, it seems plausible that it may also lead to nephrotic syndrome. This study aimed to investigate if an association between COVID-19 and the different types of nephrotic syndromes exists. Data were extracted into a spreadsheet. Statistical analysis was performed using Statistical Package for Social Sciences (SPSS, IBM Corp., Armonk, NY, USA).

We performed a systematic search of PubMed/Medline and Embase databases using both medical subject headings (MeSH) and regular keywords associated with COVID-19 and nephrotic syndrome, including different types of nephrotic syndromes. The search was performed on 17th December 2021. We included case reports and case series about adult patients who developed findings suggestive of nephrotic syndrome shortly after infection or vaccination. We excluded cases involving children, pregnant women, articles written in languages other than English, and those that were not retrievable. The relevance and quality of identified articles were assessed.

We included 32 articles in the study, primarily case reports and case series. In our study, COVID-19 and the COVID-19 vaccine have been associated with the development of nephrotic syndrome, primarily a collapsing form of focal segmental glomerulosclerosis, although other forms have been observed as well. There was little consistency in patient histories, clinical presentations, clinical courses, or treatment regimens, although it appeared that most cases eventually resolved. More cases need to be reported and analyzed before more definitive conclusions can be reached.

In conclusion, nephrotic syndrome is a possible complication of both COVID-19 infection and the COVD-19 vaccine and should be considered in patients exhibiting sudden onset edemas or deterioration in kidney function. While the majority of cases respond to standard treatment, clearer guidelines will need to be developed once more data is available.

2861

R29

Amorim, Carlos Eduardo Neves MD, PhD1; Gomes, Vinicius Lafico Teixeira2; Cristelli, Marina Pontello MD, PhD2; Viana, Laila Almeida MD2; de Luca Correa, Hugo MD3; Lima, Gierisson Brenno Borges MSc1; de Sousa Silva, Flaviana Santos MSc1; de Castro Lima, Gabriel Santos MSc1; Rosa, Thiago dos Santos PhD3; Nakamura, Monica Rika MSc2; Quintino, Priscilla Monteiro MSc2; Tedesco-Silva, Helio MD, PhD2; Medina-Pestana, José MD, PhD2

High Prevalence of Long-COVID Among Kidney Transplant Recipients: A Longitudinal Cohort Study

https://doi.org/10.1097/TP.0000000000004359

Published

13-Oct-22

Study

https://journals.lww.com/transplantjournal/Fulltext/9900/High_Prevalence_of_Long_COVID_Among_Kidney.193.aspx

Background.
Kidney transplant recipients are at a higher risk to develop more severe clinical forms of coronavirus disease 2019 (COVID-19), perhaps increasing the risk of presenting its long-term clinical complications, labeled as Long-COVID.
Methods.
This single-center, observational, prospective study included adult kidney transplant recipients with COVID-19 confirmed by reverse transcription polymerase chain reaction between March 20, 2020, and May 31, 2021, who were alive and with functioning graft 3 mo after the onset of symptoms. The prevalence of Long-COVID was investigated by a phone survey using a structured questionnaire of organic symptoms. Adjusted multivariable logistic regression models were used to investigate independent risk factors.
Results.
Of 1741 patients who developed COVID-19, 465 died, and 37 returned to dialysis. Of the 1239 eligible patients, 780 (63%) answered the survey during the window period. The mean age was 48 ± 12 y, 41% were women, and the mean time from transplantation was 8 ± 6 y. During acute illness, 45% needed hospitalization. Long-COVID was identified in 214 (27%) of the subjects, with body aches being the most prevalent symptom (44%). Of 233 who provided working status, 17% did not return to work within 3 mo. No baseline characteristics or infection-related variables predicted Long-COVID; actually, the number of symptoms in the acute illness was the only independent risk factor identified (hazard ratio, 1.12; 95% confidence interval, 1.02-1.22).
Conclusion.
In this cohort of kidney transplant recipients, Long-COVID was prevalent and associated with a reduced return to work. The burden of acute phase symptoms was the only risk factor associated with Long-COVID.

2862

R30

Byorn W.L. Tan aa
Bryce W.Q. Tan aa
Amelia L.M. Tan
Emily R. Schriver
Alba Gutiérrez-Sacristán
Priyam Das
William Yuan
Meghan R. Hutch
Noelia García Barrio
Miguel Pedrera Jimenez
Griffin M. Weber
Isaac S. Kohane
Tianxi Cai
Gilbert S. Omenn
John H. Holmes
Kee Yuan Ngiam

Long-term kidney function recovery and mortality after COVID-19-associated acute kidney injury: An international multi-centre observational cohort study

https://doi.org/10.1016/j.eclinm.2022.101724

Published

7-Nov-22

Study

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(22)00454-0/fulltext

Background
While acute kidney injury (AKI) is a common complication in COVID-19, data on post-AKI kidney function recovery and the clinical factors associated with poor kidney function recovery is lacking.
Methods
A retrospective multi-centre observational cohort study comprising 12,891 hospitalized patients aged 18 years or older with a diagnosis of SARS-CoV-2 infection confirmed by polymerase chain reaction from 1 January 2020 to 10 September 2020, and with at least one serum creatinine value 1–365 days prior to admission. Mortality and serum creatinine values were obtained up to 10 September 2021.
Findings
Advanced age (HR 2.77, 95%CI 2.53–3.04, p < 0.0001), severe COVID-19 (HR 2.91, 95%CI 2.03–4.17, p < 0.0001), severe AKI (KDIGO stage 3: HR 4.22, 95%CI 3.55–5.00, p < 0.0001), and ischemic heart disease (HR 1.26, 95%CI 1.14–1.39, p < 0.0001) were associated with worse mortality outcomes. AKI severity (KDIGO stage 3: HR 0.41, 95%CI 0.37–0.46, p < 0.0001) was associated with worse kidney function recovery, whereas remdesivir use (HR 1.34, 95%CI 1.17–1.54, p < 0.0001) was associated with better kidney function recovery. In a subset of patients without chronic kidney disease, advanced age (HR 1.38, 95%CI 1.20–1.58, p < 0.0001), male sex (HR 1.67, 95%CI 1.45–1.93, p < 0.0001), severe AKI (KDIGO stage 3: HR 11.68, 95%CI 9.80–13.91, p < 0.0001), and hypertension (HR 1.22, 95%CI 1.10–1.36, p = 0.0002) were associated with post-AKI kidney function impairment. Furthermore, patients with COVID-19-associated AKI had significant and persistent elevations of baseline serum creatinine 125% or more at 180 days (RR 1.49, 95%CI 1.32–1.67) and 365 days (RR 1.54, 95%CI 1.21–1.96) compared to COVID-19 patients with no AKI.
Interpretation
COVID-19-associated AKI was associated with higher mortality, and severe COVID-19-associated AKI was associated with worse long-term post-AKI kidney function recovery.

2863

R31

Lirong Lin,Junhui Deng,Jie Li,Luquan Zheng,Zhifeng Wu,Wei Tan,Jurong Yang

Pathogenesis and histological changes of nephropathy associated with COVID-19

https://doi.org/10.1002/jmv.28311

Published

15-Nov-22

Review

https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.28311

Coronavirus disease 2019 (COVID-19) can cause damage to multiple organ, not only to the lungs, but also to the kidneys. Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) can cause acute and chronic kidney disease through direct viral infection, indirect injury, and vaccination-related injury. Like lung injury, kidney injury is also an important aspect affecting the severity and prognosis of SARS-CoV-2. This article summarizes the pathogenesis, pathological manifestations, and clinical features of SARS-CoV-2 direct or indirect renal injury. Including direct injury, indirect injury, special comorbidities (receiving kidney transplantation and CKD), and vaccine-related renal injury, and exploring the possible therapeutic effect of anti-SARS-CoV-2 therapy on renal injury. The purpose is to provide reference for understanding COVID-19-related renal injury, guiding clinical and pathological diagnosis and treatment, and evaluating prognosis.

2864

R32

Schiffl, Helmut; Lang, Susanne M.

Long-term interplay between COVID-19 and chronic kidney disease

https://doi.org/10.1007/s11255-023-03528-x

Published

24-Feb-23

Review

https://doi.org/10.1007/s11255-023-03528-x

Purpose
The COVID-19 pandemic may have an impact on the long-term kidney function of survivors. The clinical relevance is not clear.

Methods
This review summarises the currently published data.

Results
There is a bidirectional relationship between chronic kidney disease and COVID-19 disease. Chronic kidney diseases due to primary kidney disease or chronic conditions affecting kidneys increase the susceptibility to COVID-19 infection, the risks for progression and critical COVID-19 disease (with acute or acute-on-chronic kidney damage), and death. Patients who have survived COVID-19 face an increased risk of worse kidney outcomes in the post-acute phase of the disease. Of clinical significance, COVID-19 may predispose surviving patients to chronic kidney disease, independently of clinically apparent acute kidney injury (AKI). The increased risk of post-acute renal dysfunction of COVID-19 patients can be graded according to the severity of the acute infection (non-hospitalised, hospitalised or ICU patients). The burden of chronic kidney disease developing after COVID-19 is currently unknown.

Conclusion
Post-acute COVID-19 care should include close attention to kidney function. Future prospective large-scale studies are needed with long and complete follow-up periods, assessing kidney function using novel markers of kidney function/damage, urinalysis and biopsy studies.

2865

R33

Kroll, Marie-Kristin; Schloer, Sebastian; Candan, Peynaz; Korthals, Nadia; Wenzel, Christoph; Ihle, Hannah; Gilhaus, Kevin; Liedtke, Kim Rouven; Schöfbänker, Michael; Surmann, Beate; Schröter, Rita; Neugebauer, Ute; Mall, Gita; Oswald, Stefan; Ludwig, Stephan; Rescher, Ursula; Vollenbröker, Beate; Ciarimboli, Giuliano

Importance of ACE2 for SARS-CoV-2 Infection of Kidney Cells

https://doi.org/10.3390/biom13030472

Published

1-Mar-23

Study

https://www.mdpi.com/2218-273X/13/3/472

In late 2019, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as the causative agent of coronavirus disease 2019 (COVID-19) emerged in China and spread rapidly around the world, causing an ongoing pandemic of global concern. COVID-19 proceeds with moderate symptoms in most patients, whereas others experience serious respiratory illness that requires intensive care treatment and may end in death. The severity of COVID-19 is linked to several risk factors including male sex, comorbidities, and advanced age. Apart from respiratory complications, further impairments by COVID-19 affecting other tissues of the human body are observed. In this respect, the human kidney is one of the most frequently affected extrapulmonary organs and acute kidney injury (AKI) is known as a direct or indirect complication of SARS-CoV-2 infection. The aim of this work was to investigate the importance of the protein angiotensin-converting enzyme 2 (ACE2) for a possible cell entry of SARS-CoV-2 into human kidney cells. First, the expression of the cellular receptor ACE2 was demonstrated to be decisive for viral SARS-CoV-2 cell entry in human AB8 podocytes, whereas the presence of the transmembrane protease serine 2 (TMPRSS2) was dispensable. Moreover, the ACE2 protein amount was well detectable by mass spectrometry analysis in human kidneys, while TMPRSS2 could be detected only in a few samples. Additionally, a negative correlation of the ACE2 protein abundance to male sex and elderly aged females in human kidney tissues was demonstrated in this work. Last, the possibility of a direct infection of kidney tubular renal structures by SARS-CoV-2 was demonstrated.

2866

Ch01

Prateek Kumar Panda, MD, DM, Indar Kumar Sharawat, MD, DM, Pragnya Panda, MD, Vivekanand Natarajan,

Neurological Complications of SARS-CoV-2 Infection in Children: A Systematic Review and Meta-Analysis

https://doi.org/10.1093/tropej/fmaa070

Published

10-Sep-20

Systematic Review and Meta-Analysis

https://academic.oup.com/tropej/advance-article/doi/10.1093/tropej/fmaa070/5903829

Children affected by neurological complications

Les enfants peu touchés par des complications neurologiques

2867

Ch02

MIS-C

Jayakanthan Kabeerdoss, Rakesh Kumar Pilania, Reena Karkhele, T. Sathish Kumar, Debashish Danda &

Severe COVID-19, multisystem inflammatory syndrome in children, and Kawasaki disease: immunological mechanisms, clinical manifestations and management

https://doi.org/10.1007/s00296-020-04749-4

Published

21-Nov-20

Review

https://link.springer.com/article/10.1007/s00296-020-04749-4

An Indian study is investigating the triggering mechanisms of multisystem inflammatory syndrome in children (MIS-C) with covid, whose symptoms resemble those of Kawasaki disease.

Une étude indienne s'intéresse aux mécanismes de déclenchement du syndrome inflammatoire multisystémique chez les enfants (multisystem inflammatory syndrome, MIS-C) atteints de la covid, dont les symptômes évoquent ceux de la maladie de Kawasaki.

2868

Ch03

Jonas F Ludvigsson

Case report and systematic review suggest that children may experience similar long‐term effects to adults after clinical COVID‐19

https://doi.org/10.1111/apa.15673

Published

17-Nov-20

Cases report and review

https://onlinelibrary.wiley.com/doi/10.1111/apa.15673

According to this case study (9 to 15 years old) accompanied by a review of the literature, long covid is possible in children and mainly affects girls. Out of 5 cases reported in Sweden, 4 had no pre-existing co-morbidities. The study has been critisized in the same journal for its méthodology (Ch11).

Selon cette étude de cas (9 à 15 ans) accompagnée d'une revue de la littérature, le covid long est possible chez les enfants et toucherait surtout les filles. Sur 5 cas rapportés en Suède, 4 n'avaient pas de comorbidités préexistantes. L'étude a été critiquée dans la même publication par 2 médecins pour ses lacunes méthodologiques. (Ch11).

2869

Ch04

MIS-C

Anjali Ramaswamy, Nina N. Brodsky, Tomokazu S. Sumida, Michela Comi

Post-infectious inflammatory disease in MIS-C features elevated cytotoxicity signatures and autoreactivity that correlates with severity

https://doi.org/10.1101/2020.12.01.20241364

pre-print

4-Dec-20

https://www.medrxiv.org/content/10.1101/2020.12.01.20241364v1

Un pre-print identifie des autoanticorps dirigés contre les cellules endothéliales du cœur, dans le cadre du syndrome inflammatoire multisystémique chez les enfants post-covid.
Également détaillé dans ce thread d'une des auteurs : https://twitter.com/lucasite_lab/status/1334932293366976512?s=19

2870

Ch05

MadhuSharmaMDaSamuelGorsteinMDbMargaret L.Aldrich

Reversible Myocardial Injury Associated With SARS-CoV-2 in an Infant

https://doi.org/10.1016/j.jaccas.2020.09.031

Published

12-Oct-20

Case Report

https://www.sciencedirect.com/science/article/pii/S2666084920311827

Un cas rapporté de lésion cardiaque (heureusement réversible), accompagnée d'une insuffisance cardiaque en décompensation aiguë, chez un bébé de 2 mois infecté par le SARS-CoV-2.

2871

Ch06

MIS-C

Julie Toubiana1,2, Corinne Levy3,4,5,6,7 , Slimane Allali1

Association between SARS-CoV-2 infection and Kawasaki-like multisystem inflammatory syndrome: a retrospective matched case–control study, Paris, France, April to May 2020

https://doi.org/10.2807/1560-7917.es.2020.25.48.2001813

Published

3-Dec-20

Rapid communication

https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.48.2001813

Etude française sur les cas de syndrome inflammatoire multisystémique chez les enfants, de type maladie de Kawasaki, en région parisienne.

2872

Ch07

Caroline Diorio, Kevin O. McNerney, Michele Lambert, Michele Paessler, Elizabeth M. Anderson, Sarah E. Henrickson, Julie Chase, Emily J. Liebling,

Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations

https://doi.org/10.1182/bloodadvances.2020003471

Published

8-Dec-20

https://ashpublications.org/bloodadvances/article/4/23/6051/474421/Evidence-of-thrombotic-microangiopathy-in-children

sC5b9 plasma levels are elevated in children with SARS-CoV-2 infection, even if they have minimal symptoms of COVID-19. A high proportion of children with SARS-CoV-2 infection met clinical criteria for TMA (thrombotic microangiopathy). Study of a biomarker of blood clots in small blood vessels in 50 children with mild (n=21) & severe (n=11) #COVID19, and MIS-C (n=18). -> Biomarker elevated in all groups. -> Evidence of kidney injury in 10% of mild cases (36% severe, 28% MIS-C). The children with mild illness included hospital patients in which #SARSCoV2 had been identified in routine testing before admission (unrelated to #COVID19). As such, it is possible they may not be representative of mild cases generally. It is unclear what the long-term implications of this study are. It is possible these findings are fully reversible. However, there is also the possibility that children who had evidence of blood clots in small blood vessels (TMA) may be at increased risk of developing chronic disease, including cardiovascular and kidney disease in later life. More research with larger samples of children, particularly those from the general community rather than hospital settings, is required to understand whether this is common. Follow-up of affected children is needed to determine whether there are any long-term consequences.

_

2873

Ch08

Camilla E Lindan, MD, Kshitij Mankad, FRCR, Dipak Ram, FRCPCH, Larry K Kociolek, MD, V Michelle Silvera, MD, Prof Nathalie Boddaert, MD, Prof Stavros Michael Stivaros, PhD *, Susan Palasis, MD

Neuroimaging manifestations in children with SARS-CoV-2 infection: a multinational, multicentre collaborative study

https://doi.org/10.1016/S2352-4642(20)30362-X

Published

15-Dec-20

https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(20)30362-X/fulltext

Cette étude indique que les complications neurologiques de la covid chez l'enfant sont rares, en contraste avec les adultes. L'analyse de 38 cas montre une variété d'atteintes, parfois graves, chez des sujets sans comorbidités.

2874

Ch09

Ebtsam Salah Yonis Mahrous

Impact of COVID-19 on Children

Published

2-Jan-21

Review

https://journals.ekb.eg/article_134865_0.html

Un article évoque les conséquences directes mais surtout indirectes de la pandémie de covid sur les enfants.

2875

Ch10

Dr. Ardhanaari M Dr.Anita Harry

A SYSTAMATIC REVIEW ON EFFECT OF COVID ON CHILDREN

Published

12-Jul-05

Review

https://ejmcm.com/article_5865.html

Une autre courte revue d'études sur les effets directs et indirects de la pandémie de covid sur les enfants.

2876

Ch11

Viktor Peny Anders Valind

Re: Case Reports and systematic review suggest that children may experience similar long‐term effects to adults after clinical COVID‐19

https://doi.org/10.1111/apa.15764

Published

18-Jan-21

LETTER

https://onlinelibrary.wiley.com/doi/abs/10.1111/apa.15764

Dans le Acta Pediatrica qui avait publié une étude de 5 cas d'enfant suédois suspectés d'être atteints d'un covid long (J. Ludvigsson & al.), paraît une lettre de deux médecins qui critiquent la méthodologie de l'étude, jugée inadaptée et insuffisante.

2877

Ch12

danilo buonsenso, Daniel Munblit, Cristina De Rose, Dario Sinatti, Antonia Ricchiuto, Angelo Carfi, Piero Valentini

Preliminary Evidence on Long COVID in children

https://doi.org/10.1111/apa.15870

Published

9-Apr-21

Study

https://onlinelibrary.wiley.com/doi/10.1111/apa.15870

ex pre-print in anuary https://www.medrxiv.org/content/10.1101/2021.01.23.21250375v1
We assessed persistent symptoms in pediatric patients previously diagnosed with COVID-19. More than a half reported at least one persisting symptom even after 120 days since COVID-19, with 42.6% being impaired by these symptoms during daily activities. Symptoms like fatigue, muscle and joint pain, headache, insomnia, respiratory problems and palpitations were particularly frequent, as also described in adults.

En Italie, une étude indique que sur 129 enfants suivis (<18 ans, diagnostiqués covid par test PCR, les 3/4 ayant une covid symptomatique, mais seulement 5% hospitalisés), une récupération complète au bout de 4 mois n'est observée que pour 47% d'entre eux. Les symptômes reportés sont principalement l'insomnie, la congestion nasale, la fatigue, les maux de tête, le manque de concentration et les douleurs musculaires.

N001

2878

Ch13

Timothy G. Singer
Karen Evankovich
Kristen Fisher
Gail Demmler Harrison
Sarah R. Risen

Coronavirus infections in the nervous system of children: a scoping review making the case for long-term neurodevelopmental surveillance

https://doi.org/10.1016/j.pediatrneurol.2021.01.007

Published

28-Jan-21

Scoping Review

https://www.pedneur.com/article/S0887-8994(21)00008-4/fulltext

Une revue d'études sur les effets de 6 coronavirus sur les enfants soutient que ces infections peuvent causer des maladies neurologiques graves chez les enfants, ce qui constitue une menace pour le développement neurologique à long terme.

N001

2879

Ch14

MIS-C

Mubbasheer Ahmed, Shailesh Advani, Axel Moreira, Sarah Zoretic, John Martinez, Kevin Chorath, Sebastian Acosta, Rija Naqvi, Finn Burmeister-Morton, Fiona Burmeister, Aina Tarriela, Matthew Petershack, Mary Evans, Ansel Hoang, Karthik Rajasekaran, Sunil Ahuja, Alvaro Moreira

Multisystem inflammatory syndrome in children: A systematic review

https://doi.org/10.1016/j.eclinm.2020.100527

Published

4-Sep-20

Systematic Review

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(20)30271-6/fulltext

While 71·0% of children (n = 470) were admitted to the intensive care unit, only 11 deaths (1·7%) were reported. Average length of hospital stay was 7·9 ± 0·6 days. Fever (100%, n = 662), abdominal pain or diarrhea (73·7%, n = 488), and vomiting (68·3%, n = 452) were the most common clinical presentation. Serum inflammatory, coagulative, and cardiac markers were considerably abnormal. Mechanical ventilation and extracorporeal membrane oxygenation were necessary in 22·2% (n = 147) and 4·4% (n = 29) of patients, respectively. An abnormal echocardiograph was observed in 314 of 581 individuals (54·0%) with depressed ejection fraction (45·1%, n = 262 of 581) comprising the most common aberrancy. Multisystem inflammatory syndrome is a new pediatric disease associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is dangerous and potentially lethal. With prompt recognition and medical attention, most children will survive but the long-term outcomes from this condition are presently unknown.

_

2880

Ch15

Donavyn Coffey

Long-COVID in Children: It's a Thing

Published

19-Feb-21

Article

https://www.medscape.com/viewarticle/946161

"The current data are important and make it clear that long-COVID is occurring in children."
"we really need to understand what the true penetration of symptoms is," Danziger-Isakov said, and that requires studying more than 129 patients.

Une analyse revient sur l'étude italienne (qui était alors en pre-print paru le 26/01) sur le covid long chez les enfants. Elle note que les résultats de l'étude sont encore débattus par les spécialistes qui appellent à la prudence sur la prévalence, à cause de biais possibles.

2881

Ch16

MIS-C

Peart Akindele, clinical and, research pediatric infectious disease fellow1, Megan M Tschudy, assistant professor of pediatrics2, Anna C Sick-Samuels, assistant professor of pediatrics1

Acute covid-19 and multisystem inflammatory syndrome in children

https://doi.org/10.1136/bmj.n385

Published

1-Mar-21

Article

https://www.bmj.com/content/372/bmj.n385

Children with acute covid-19 can present with non-specific symptoms. Exclude covid-19 in children with fever and respiratory tract symptoms or loss of taste or smell, especially if there is possible exposure to others with the virus
Consider multisystem inflammatory syndrome (MIS-C) in children presenting with fever and abdominal symptoms—particularly if they develop conjunctivitis or rash—and refer to a paediatric emergency department for evaluation
MIS-C can have overlapping symptomatology with disease processes that require prompt treatment, such as sepsis, toxic shock syndrome, myocarditis, and meningitis. Therefore, consider initiation of empiric antibiotics and necessary evaluations if the patient develops cardiovascular or respiratory compromise, evidence of acute abdomen, or meningismus

Un article dans BMJ répond à plusieurs questions concernant la covid et le syndrome inflammatoire multisystémique qui peut lui être consécutif chez l'enfant : les risques d'infection à l'école, les tests, la prévention.

N003A

2882

Ch17

Helen Thomson

Children with long covid

https://doi.org/10.1016%2FS0262-4079(21)00303-1

Published

3-Mar-21

Article

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927578/

Children seem to be fairly well-protected from the most severe symptoms of covid-19. According to the European Centre for Disease Prevention and Control, the majority of children don't develop symptoms when infected with the coronavirus, or their symptoms are very mild.

However, it is becoming increasingly apparent that a large number of children with symptomatic and asymptomatic covid-19 are experiencing long-term effects, many months after the initial infection.

Un article d'opinion s'intéresse aux données sur les cas de covid long chez les enfants.

2883

Ch18

Danilo Buonsenso * , Ferran Espuny Pujol , Daniel Munblit logo , Sammie Mcfarland , Frances Simpson

Clinical Characteristics, Activity Levels and Mental Health Problems in Children with Long COVID: A Survey of 510 Children

https://doi.org/10.20944/preprints202103.0271.v1

pre-print

9-Mar-21

Survey

https://www.preprints.org/manuscript/202103.0271/v1

Our study provides further evidence on Long COVID in children. Symptoms like fatigue, headache, muscle and joint pain, rashes and heart palpitations, and mental health issues like lack of concentration and short memory problems, were particularly frequent and confirm previous observations, suggesting that they may characterize this condition. A better comprehension of Long COVID is urgently needed.

Dans une étude non encore relue ni publiée, sur 510 enfants avec un covid long, les symptômes les plus fréquents sont : l'asthénie, les maux de tête, les douleurs abdominales, musculaires et articulaires, le malaise post-effort et les éruptions cutanées.

2884

Ch19

MIS-C

Kerri L. LaRovere, MD1; Becky J. Riggs, MD2; Tina Y. Poussaint, MD3; Cameron C. Young4; Margaret M. Newhams, Heidi R. Flori, MD45; Manish M. Patel, MD24,25; Adrienne G. Randolph, MD4,46; for the Overcoming COVID-19 Investigators

Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome

https://doi.org/10.1001/jamaneurol.2021.0504

Published

5-Mar-21

Original Investigation

https://jamanetwork.com/journals/jamaneurology/fullarticle/2777392

Findings In this study of 1695 patients 21 years or younger hospitalized for acute COVID-19 or multisystem inflammatory syndrome, 365 (22%) had neurologic involvement. Forty-three patients (12%) developed COVID-19–related life-threatening neurologic disorders, 11 (26%) died, and 17 (40%) survived with new neurologic sequelae.

Dans une étude américaine (JAMA Neurology) sur 1695 patients de moins de 21 ans qui ont été hospitalisés pour la covid :
365 patients ont eu une atteinte neurologique pendant l'hospitalisation, dont 43 qui ont développé des troubles neurologiques potentiellement mortels liés au COVID-19.
Parmi eux, 11 patients sont décédés et 17 ont survécu avec de nouvelles séquelles neurologiques.

N004

2885

Ch20

MIS-C

J.-C. Mercier,a,⁎ A. Maroni,b M. Levy,b I. Melki,c,d U. Meinzer,c,e J. Gaschignard,c,f C. Beyler,g et A. Santos

COVID-19 chez l’enfant : syndrome inflammatoire multi-systémique lié à SARS-CoV-2 mimant un syndrome de Kawasaki

https://dx.doi.org/10.1016%2Fj.banm.2020.11.018

Published

18-Mar-21

Review

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969823/

S’il est manifeste que les enfants sont moins susceptibles que les adultes au SARS-CoV-2 (COVID-19) et qu’ils développent des formes cliniques moins sévères, un petit nombre, peut-être du fait de comorbidités associées (malformations congénitales, obésité, hypertension artérielle) ou d’une dysrégulation cytokinique inflammatoire, peut présenter une dysfonction ventriculaire gauche et/ou un syndrome de Kawasaki régressant rapidement après un traitement par immunoglobulines intraveineuses et/ou une corticothérapie associée.

_

2886

Ch21

MIS-C

Takuya Hara, MD1; Kenji Furuno, MD, PhD1; Kenichiro Yamamura, MD, PhD2; Junji Kishimoto, PhD3; Yumi Mizuno, Mayumi Yashiro, BA9; Yoshikazu Nakamura, MD, PhD9; Toshiro Hara, MD, PhD1

Assessment of Pediatric Admissions for Kawasaki Disease or Infectious Disease During the COVID-19 State of Emergency in Japan

https://doi.org/10.1001/jamanetworkopen.2021.4475

Published

6-Apr-21

Study

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2778178

The development of Kawasaki disease (KD) has been suggested to be associated with droplet- or contact-transmitted infection; however, its triggers and transmission modes remain to be determined. Under an epidemic of SARS-CoV-2, the COVID-19 state of emergency in Japan served as a nationwide social experiment to investigate the impact of quarantine or isolation on the incidence of KD.
These findings suggest that contact or droplet transmission is not a major route for KD development and that KD may be associated with airborne disease.

_

2887

Ch22

MIS-C

AnjaliRamaswamy1Nina N.Brodsky12Tomokazu S.Sumida13MichelaComi13HiromitsuAsashima13Kenneth B.Hoehn4NingshanLi5YunqingLiu5AagamShah67Neal G.Ravindra67JasonBishai67AlamzebKhan2WilliamLau89BrianSellers8NehaBansal89PamelaGuerrerio10AvrahamUnterman11VictoriaHabet2…Carrie L.Lucas

Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children

https://doi.org/10.1016/j.immuni.2021.04.003

Published

13-Apr-21

Study

https://www.sciencedirect.com/science/article/pii/S1074761321001655

Highlights
•scRNA-seq of PBMCs from MIS-C patients reveals immunopathology signatures
•MIS-C patients display elevated alarmins and NK/CD8+ T-cell cytotoxicity effectors
•TRBV11-2-expressing CD4+ and CD8+ memory T cells are expanded in severe MIS-C
•Increased plasmablasts and endothelium-reactive IgG are features of severe MIS-C

Une étude sur le PIMS-Covid (syndrome inflammatoire multisystémique pédiatrique) identifie les taux d'alarmine, la cytotoxicité, les récepteurs des cellules T et les signatures plasmablastiques comme biomarqueurs permettant de diagnostiquer la gravité de la maladie.

N011

2888

Ch23

MIS-C

Theodore Kouo1 and Worarat Chaisawangwong

SARS-CoV-2 as a superantigen in multisystem inflammatory syndrome in children (MIS-C)

https://doi.org/10.1172/JCI149327

Published

12-Apr-21

Commentary

https://www.jci.org/articles/view/149327

Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare but deadly new disease in children that rapidly progresses to hyperinflammation, shock, and can lead to multiple organ failure if unrecognized. It has been found to be temporally associated with the COVID-19 pandemic and is often associated with SARS-CoV-2 exposure in children. In this issue of the JCI, Porritt, Paschold, and Rivas et al. identify restricted T cell receptor (TCR) β-chain variable domain (Vβ) usage in patients with severe MIS-C indicating a potential role for SARS-CoV-2 as a superantigen. These findings suggest that a blood test that determines the presence of specific TCR beta variable gene segments (TRBV) may identify patients at risk for severe MIS-C.

_

2889

Ch24

MIS-C

Vanessa Sancho-Shimizu , Petter Brodin, Aurélie Cobat, Catherine M. Biggs, Julie Toubiana, Carrie L. Lucas, Sarah E. Henrickso, Alexandre Belot, MIS-C@CHGE , Stuart G. Tangye, Joshua D. Milner, Michael Lev, Laurent Abel, Dusan Bogunovic, Jean-Laurent Casanova, Shen-Ying Zhang

SARS-CoV-2–related MIS-C: A key to the viral and genetic causes of Kawasaki disease?

https://doi.org/10.1084/jem.20210446

Published

27-Apr-21

Article

https://rupress.org/jem/article/218/6/e20210446/212029/SARS-CoV-2-related-MIS-C-A-key-to-the-viral-and

Multisystem inflammatory syndrome in children (MIS-C) emerged in April 2020 in communities with high COVID-19 rates. This new condition is heterogenous but resembles Kawasaki disease (KD), a well-known but poorly understood and clinically heterogenous pediatric inflammatory condition for which weak associations have been found with a myriad of viral illnesses. Epidemiological data clearly indicate that SARS-CoV-2 is the trigger for MIS-C, which typically occurs about 1 mo after infection. These findings support the hypothesis of viral triggers for the various forms of classic KD. We further suggest that rare inborn errors of immunity (IEIs) altering the immune response to SARS-CoV-2 may underlie the pathogenesis of MIS-C in some children. The discovery of monogenic IEIs underlying MIS-C would shed light on its pathogenesis, paving the way for a new genetic approach to classic KD, revisited as a heterogeneous collection of IEIs to viruses.

_

2890

Ch25

PESE

Gabriele Di Sante, Danilo Buonsenso, Cristina De Rose, Piero Valentini, Francesco Ria, Maurizio Sanguinetti, Michela Sali

Immune profile of children with post-acute sequelae of SARS-CoV-2 infection (Long Covid)

https://doi.org/10.1101/2021.05.07.21256539

Pre-print

10-May-21

Study

https://www.medrxiv.org/content/10.1101/2021.05.07.21256539v1.full-text

In this study, we documented significant immunologic differences between children that completely recovered from acute infection and those with PASC, providing the first objective laboratory sign of the existence of PASC in children. Healed children restored B-cell homeostasis, by reconstituting the naïve/unswitched B-cell compartment. In PASC children, the consistent amounts of plasmablasts, switched and memory B lymphocytes revealed the involvement of those subsets in the immunopathogenesis of chronic symptoms. Moreover, the persisting high levels of IL6 and IL1β suggest that innate immune response played a pivotal role in children with PASC. Considering their role as mediators of inflammatory responses and auto-immune processes, these findings could explain systemic persisting symptoms such as fatigue and post-exertional malaise, headache, muscle and joint pain, and tachycardia.

Our findings provide further evidence that a chronic inflammatory process and immune dysfunction may explain why some children develop PASC, highlighting the importance of further studies aimed to better characterize this new condition. A better understating of PASC will also provide indirect benefits for other post-infectious conditions.

Limitations of our study are the low number of children included and the lack of ex-vivo immunologic studies performed after in-vitro stimulation with SARS-CoV-2, which we plan as a future study.

Une étude en pre-print (non relue ni publiée) documente les différences immunologiques significatives entre les enfants qui ont complètement récupéré d'une infection aiguë, et ceux avec un covid long, dans le but d'objectiver le covid long pédiatrique. Les quantités de plasmablastes, de lymphocytes B commutés et mémoires pourraient révéler leur implication dans l'immunopathogenèse des symptômes. De plus, les niveaux élevés persistants d'IL6 et d'IL1β suggèrent que la réponse immunitaire innée a joué un rôle central.

N011?

2891

Ch26

VP

Araújo, Naiana Mota; Ferreira, Lis Campos MD; Dantas, Débora Paraíso; Silva, Denison Santos MD dos Santos, Cliomar Alves; Cipolotti, Rosana, Martins-Filho, Paulo Ricardo

First Report of SARS-CoV-2 Detection in Cerebrospinal Fluid in a Child With Guillain-Barré Syndrome

https://doi.org/10.1097/INF.0000000000003146

Published

7-May-21

Case Report

https://journals.lww.com/pidj/Abstract/9000/First_Report_of_SARS_CoV_2_Detection_in.95815.aspx

Underlying mechanisms on the association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and neurological complications are still poorly understood. Cases of Guillain-Barré Syndrome (GBS) have been linked to the SARS-CoV-2 infection as the result of dysregulated immune response with damage in neuronal tissues. In the current report, we present the first pediatric case of GBS with detection of SARS-CoV-2 in the cerebrospinal fluid (CFS). This unique case of COVID-19-associated GBS with detection of SARS-CoV-2 RNA in the CSF indicates direct viral involvement inducing peripheral nerve inflammation.

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2892

Ch27

Erika Molteni, Carole H. Sudre, Liane S. Canas, Sunil S. Bhopal, Robert C. Hughes, Michela Antonelli, Benjamin Murray, Kerstin Kläser, Eric Kerfoot, Liyuan Chen, Jie Deng, Christina Hu, Somesh Selvachandran, Kenneth Read, Joan Capdevila Pujol, Alexander Hammers, Tim D. Spector, Sebastien Ourselin, Claire J. Steves, Marc Modat, Michael Absoud, Emma L. Duncan

Illness duration and symptom profile in a large cohort of symptomatic UK school-aged children tested for SARS-CoV-2

https://doi.org/10.1101/2021.05.05.21256649

pre-print

13-May-21

Study

https://www.medrxiv.org/content/10.1101/2021.05.05.21256649v2

Methods Data from 258,790 children aged 5-17 years were reported by an adult proxy between 24 March 2020 and 22 February 2021. Illness duration and symptom profiles were analysed for all children testing positive for SARS-CoV-2 for whom illness duration could be determined, considered overall and within younger (5-11 years) and older (12-17 years) groups. Data from symptomatic children testing negative for SARS-CoV-2, matched 1:1 for age, gender, and week of testing, were also assessed.
Findings 1,734 children (588 younger, 1,146 older children) had a positive SARS-CoV-2 test result and calculable illness duration within the study time frame. The commonest symptoms were headache (62.2%) and fatigue (55.0%). Median illness duration was six days (vs. three days in children testing negative), and was positively associated with age (rs 0.19, p<1.e-4) with median duration of seven days in older vs. five days in younger children.
Seventy-seven (4.4%) children had illness duration ≥28 days (LC28), more commonly experienced by older vs. younger children (59 (5.1%) vs. 18 (3.1%), p=0.046). The commonest symptoms experienced by these children were fatigue (84%), headache (80%) and anosmia (80%); however, by day 28 the symptom burden was low (median, two). Only 25 (1.8%) of 1,379 children experienced symptoms for ≥56 days. Few children (15 children, 0.9%) in the negatively-tested cohort experienced prolonged symptom duration; however, these children experienced greater symptom burden (both throughout their illness and at day 28) than children positive for SARS-CoV-2.
Interpretation Some children with COVID-19 experience prolonged illness duration. Reassuringly, symptom burden in these children did not increase with time, and most recovered by day 56. Some children who tested negative for SARS-CoV-2 also had persistent and burdensome illness. A holistic approach for all children with persistent illness during the pandemic is appropriate.

Une étude britannique en preprint (ni relue ni publiée) a suivi 1734 enfants (588 de 5-11 ans et 1146 de 12-17 ans) testés positifs à la covid.
77 enfants (4,4 %) ont eu des symptômes dépassant 28 j, et 25 (1,8 %) parmi 1379 enfants ont présenté des symptômes pendant plus de 55 jours.
Les symptômes les plus courants étaient la fatigue (84 %), les maux de tête (80 %) et l'anosmie (80 %).
La durée médiane des symptômes était de 6 jours.

N011

2893

Ch28

MIS-C - VP

Lael M. Yonker,1 Tal Gilboa,2 Alana F. Ogata,2 Yasmeen Senussi,2 Roey Lazarovits,2 Brittany P. Boribong,1 Yannic C. Bartsch,3 Maggie Loiselle,1 Magali Noval Rivas, Moshe Arditi,4 Galit Alter,10 David R. Walt,11 and Alessio Fasano

Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier

https://doi.org/10.1172/JCI149633

Published

25-May-21

Study

https://www.jci.org/articles/view/149633

Methods: Here, we analyzed biospecimens from 100 children: 19 children with MIS-C, 26 with acute COVID-19, and 55 controls. Stool was assessed for SARS-CoV-2 by RT-PCR and plasma was assessed for markers of breakdown of mucosal barrier integrity, including zonulin. Ultrasensitive antigen detection was used to probe for SARS-CoV-2 antigenemia in plasma, and immune responses were characterized. As proof of concept, we treated a MIS-C patient with larazotide, a zonulin antagonist, and monitored impact on antigenemia and clinical response.
Results: We showed that in MIS-C, prolonged presence of SARS-CoV-2 in the GI tract leads to release of zonulin, a biomarker of intestinal permeability, with subsequent trafficking of SARSCoV-2 antigens into the bloodstream, leading to hyperinflammation. The MIS-C patient treated with larazotide displayed a coinciding decrease in plasma SARS-CoV-2 Spike antigen levels, inflammatory markers, and a resultant clinical improvement above that achieved with currently available treatments.
Conclusion: These mechanistic data of MIS-C pathogenesis provide insight into targets for diagnosing, treating, and preventing MIS-C, which are urgently needed for this increasingly common severe COVID-19-related disease in children.

Selon une étude, le syndrome inflammatoire multisystémique chez les enfants (PIMS-Covid) est provoqué par une libération de zonuline (un biomarqueur de la perméabilité intestinale), affectant la barrière muqueuse colique, et conduisant à une hyperinflammation.
Le traitement au larazotide permettrait selon l'étude d'obtenir une diminution des taux plasmatiques d'antigènes du virus et une amélioration clinique supérieure aux traitements standards.

N011

2894

Ch29

LC

Daniel Munblit 1,2, Frances Simpson 3, Jeremy Mabbitt 4, Audrey Dunn-Galvin 2,5, Calum Semple, John O Warner

Legacy of COVID-19 infection in children: long-COVID will have a lifelong health/economic impact

http://dx.doi.org/10.1136/archdischild-2021-321882

Published

27-May-21

Opinion

https://adc.bmj.com/content/early/2021/05/27/archdischild-2021-321882.full

There is an urgent need to study the impacts of the pandemic on all children as well as those who have had acute infection followed by long-COVID. Such research will help to elaborate on clinical features, mechanisms and strategies to mitigate adverse outcomes. The direct effects must be distinguished from those induced by lockdowns, school closures, parental loss of income, quarantine and other illnesses. This will provide the evidence to influence government action and design of appropriate service provision to protect children and young people from the potentially lifelong adverse effects of the pandemic. Thankfully, a large UK investigation of 3000 infected and 3000 uninfected children has now been funded, ‘The CLoCk Study’. The next step will be trials of interventions to mitigate the potentially lifelong adverse effects of this devastating pandemic.

Un article d'opinion dans le BMJ invite à mener des recherches sur les séquelles neuropsychiatriques de la covid chez l'enfant.
Il se félicite que "The CLoCk Study", une grande enquête britannique portant sur 3000 enfants infectés et 3000 enfants non infectés, soit désormais financée.

N011

2895

Ch30

LC

L. Siracusa, A. Cascio, S. Giordano, A. A. Medaglia, G. A. Restivo, I. Pirrone, G. F. Saia, F. Collura & C. Colomba

Neurological complications in pediatric patients with SARS-CoV-2 infection: a systematic review of the literature

https://doi.org/10.1186/s13052-021-01066-9

Published

2-Jun-21

Review

https://link.springer.com/article/10.1186/s13052-021-01066-9

Forty-four articles reporting 59 cases of neurological manifestations in pediatric patients were included in our review. Most (32/59) cases occurred in the course of a multisystem inflammatory syndrome in children (MIS-C). Neurological disorders secondary to cerebrovascular involvement were reported in 10 cases: 4 children with an ischemic stroke, 3 with intracerebral hemorrhage, 1 with a cerebral sinus venous thrombosis, 1 with a subarachnoid hemorrhage, 1 with multiple diffuse microhemorrhages. Reversible splenial lesions were recognized in 9 cases, benign intracranial hypertension in 4 patients, meningoencephalitis in 4 cases, autoimmune encephalitis in 1 girl, cranial nerves impairment in 2 patients and transverse myelitis in 1 case. Five cases had Guillain-Barré syndrome (GBS) and two, including ours, had ADEM. Radiological investigations were performed in almost all cases (45/60): the most recurrent radiological finding was a signal change in the splenium of the corpus callosum. The presence of SARS-CoV-2 viral nucleic acid in the cerebrospinal fluid was proved only in 2 cases. The outcome was favorable in almost all, except in 5 cases.

Un article italien présente une revue d'études des manifestations neurologiques liées à la covid chez l'enfant.
59 cas sont ici répertoriés, 32 d'entre eux étant consécutifs à un PIMS-Covid (syndrome inflammatoire multisystémique).

N011

2896

Ch31

LC

Carmelina Calitri1, Francesca Fantone1, Stefania Benetti1, Maria Maddalena Lupica1,Maria Giovanna Ignaccolo1, Elena Banino1, Alice Viano1, Mariella Pace1, Annalisa Castella2,Flavio Gaido3, Franco Garofalo1, and the ASLTO3 Study Group on Paediatric COVID-19

Long-term clinical and serological follow-up of paediatric patients infected by SARS-CoV-2

Published

1-Jun-21

Case Report

https://www.infezmed.it/media/journal/Vol_29_2_2021_6.pdf

We aimed to describe the course of the Coronavirus Disease 2019 (COVID-19) in a population of children enrolled by place of residence, from diagnosis to recovery, with a long-term clinical and serological follow-up. We identified patients aged <14 years old living in the Turin Health District 3 who had SARS-CoV-2 detected in at least one nasopharyngeal swab from 1st March to 1st June 2020. Epidemiological and clinical features of SARSCoV-2 infection were collected by way of a telephone inquiry. Enrolled patients were tested for SARS-CoV-2
serology in order to provide evidence of seroconversion and persistence of specific antibodies some time after the infection. A total of 46 patients with SARSSUMMARY CoV-2 infection/COVID-19 were identified. The main pattern of viral transmission was intra-family. Eleven
children were totally asymptomatic. If symptoms appeared, the disease had a mild course. A single case of COVID-19-related respiratory insufficiency was registered. Among children who underwent serological evaluation, 84% had seroconversion. No significant differences in antibody development were found according to the age and the burden of the disease. Children tested farther from the primary infection
had lower antibody index titer values than the others. In conclusion, COVID-19 has a good prognosis in paediatric age. Children are able to develop a valid immune response, although their index titers seem to decrease a long time after the disease.

_

2897

Ch32

MIS-C

Fatih Haslak, Kenan Barut, Cansu Durak, Ayten Aliyeva, Mehmet Yildiz, Vafa Guliyeva, Sevki Erdem Varol, Sinem Oral Cebeci, Fatih Aygun, Yusuf Ziya Varli, Abdulrahman Ozel, Sertac Hanedan Onan, Ulkem Kocoglu, Meltem Erol, Fatih Karagozlu, Nujin Ulug, Reyhan Dedeoglu, Sezgin Sahin, Amra Adrovic, Funda Oztunc & Ozgur Kasapcopur

Clinical features and outcomes of 76 patients with COVID-19-related multi-system inflammatory syndrome in children

https://doi.org/10.1007/s10067-021-05780-x

Published

5-Jun-21

Study

https://link.springer.com/article/10.1007/s10067-021-05780-x

Overall, 76 subjects (24 females) with a mean age of 8.17 ± 4.42 years were enrolled. Twenty-seven (35.5%) patients were admitted to the PICUs. The two most common systemic involvement patterns were cardiac and gastrointestinal. There was only one lethal outcome in a patient with underlying acute lymphoblastic leukemia. Those with higher procalcitonin levels at admission were found to stay longer in the hospital (r = 0.254, p = 0.027). The risk of PICU admission increased with age (aOR: 1.277; 95% CI: 1.089–1.498; p = 0.003) and with decreased initial serum albumin levels (aOR: 0.105; 95% CI: 0.029–0.378; p = 0.001).

Conclusion
Although there is a wide clinical variability among the patients with MIS-C, we suggest that those with older age and lower initial serum albumin levels merit close monitoring due to their higher risk for PICU admission.

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2898

Ch33

Caroline L. H. Brackel MD, Coen R. Lap BSc, Emilie P. Buddingh MD, PhD, Marlies A. van Houten MD, PhD, PhD, Simone Hashimoto MD, PhD, Suzanne W. J. Terheggen-Lagro MD, PhD

Pediatric long-COVID: An overlooked phenomenon?

https://doi.org/10.1002/ppul.25521

Published

8-Jun-21

https://onlinelibrary.wiley.com/doi/10.1002/ppul.25521

With a response rate of 78% of Dutch pediatric departments, we identified 89 children, aged 2–18 years, suspected of long-COVID with various complaints. Of these children, 36% experienced severe limitations in daily function. The most common complaints were fatigue, dyspnea, and concentration difficulties with 87%, 55%, and 45% respectively. Our case series emphasizes the nonspecific and broad clinical manifestations seen in post-COVID complaints.

Une étude danoise a répertorié au niveau national 89 cas de mineurs présentant une suspicion de covid long. Parmi ceux-ci, 36% ont présenté de graves limitations dans leurs fonctions quotidiennes.

N011

2899

Ch34

MIS-C

Jackeline J Rodriguez-Smith, MD
Emely L Verweyen, PhD
Gwendolyn M Clay, PhD
Ysabella M Esteban, MD
Sarah R de Loizaga, MD
Elizabeth Joy Baker
Thuy Do, BS
Sanjeev Dhakal, MS
Sean M Lang, MD
Prof Alexei A Grom, MD
David Grier, MD
Grant S Schulert

Inflammatory biomarkers in COVID-19-associated multisystem inflammatory syndrome in children, Kawasaki disease, and macrophage activation syndrome: a cohort study

https://doi.org/10.1016/S2665-9913(21)00139-9

Published

8-Jun-21

Study

https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(21)00139-9/fulltext

Between April 30, 2019, and Dec 14, 2020, we enrolled 19 patients with MIS-C (median age 9·0 years [IQR 4·5–15·0]; eight [42%] girls and 11 [58%] boys) and nine patients with Kawasaki disease (median age 2·0 years [2·0–4·0]); seven [78%] girls and two [22%] boys). Patients with MIS-C and Kawasaki disease had similar S100 proteins and IL-18 concentrations but patients with MIS-C were distinguished by significantly higher median concentrations of the IFNγ-induced CXCL9 (1730 pg/mL [IQR 604–6300] vs 278 pg/mL [54–477]; p=0·038). Stratifying patients with MIS-C by CXCL9 concentrations (high vs low) revealed differential severity of clinical and laboratory presentation. Compared with patients with MIS-C and low CXCL9 concentrations, more patients with high CXCL9 concentrations had acute kidney injury (six [60%] of ten vs none [0%] of five), altered mental status (four [40%] of ten vs none [0%] of five), shock (nine [90%] of ten vs two [40%] of five), and myocardial dysfunction (five [50%] of ten vs one [20%] of five); these patients also had higher concentrations of systemic inflammatory markers and increased severity of cytopenia and coagulopathy. By contrast, patients with MIS-C and low CXCL9 concentrations resembled patients with Kawasaki disease, including the frequency of coronary involvement. Elevated concentrations of S100A8/A9, S100A12, and IL-18 were also useful in distinguishing systemic JIA from Kawasaki disease with high sensitivity and specificity.
Interpretation
Our findings show MIS-C is distinguishable from Kawasaki disease primarily by elevated CXCL9 concentrations. The stratification of patients with MIS-C by high or low CXCL9 concentrations provides support for MAS-like pathophysiology in patients with severe MIS-C, suggesting new approaches for diagnosis and management.

_

2900

Ch35

MIS-C

Margaret W. Bultas, PhD, RN, CNE, CNL, CPNP-PC, Kelli Fuller

Multisystem Inflammatory Syndrome in Children and COVID-19 Infections

https://doi.org/10.1177%2F1942602X211021136

Published

8-Jun-21

Review

https://journals.sagepub.com/doi/full/10.1177/1942602X211021136

Information regarding the long-term implications of COVID-19 infections in children, as well as MIS-C, is scarce and is emerging on an almost daily basis. The purpose of this article is to provide an overview of the recent literature regarding COVID-19 and MIS-C, a Kawasaki-like inflammatory syndrome that developed in children around the same time the COVID-19 pandemic began. Because the school nurse monitors children across a variety of developmental domains, they are in a unique position to identify changes and notice long-term trends related to the health and development of children who contract both COVID-19 and MIS-C.

2901

Ch36

MIS-C

MichaelGottliebMDaRachelBridwellMDbJosephRaveraMDcBritLongMDb

Multisystem inflammatory syndrome in children with COVID-19

https://doi.org/10.1016/j.ajem.2021.05.076

Published

1-Jun-21

Review

https://www.sciencedirect.com/science/article/pii/S0735675721004605

MIS-C is an inflammatory syndrome which can affect nearly any organ system. The most common symptoms are fever and gastrointestinal symptoms, though neurologic and dermatologic findings are also well-described. The diagnosis includes a combination of clinical and laboratory testing. Patients with MIS-C will often have elevated inflammatory markers and may have an abnormal electrocardiogram or echocardiogram. Initial treatment involves resuscitation with careful assessment for cardiac versus vasodilatory shock using point-of-care ultrasound. Treatment should include intravenous immunoglobulin, anticoagulation, and consideration of corticosteroids. Interleukin-1 and/or interleukin-6 blockade may be considered for refractory cases. Aspirin is recommended if there is thrombocytosis or Kawasaki disease-like features on echocardiogram. Patients will generally require admission to an intensive care unit.

Revue d'études sur la physiopathologie, le diagnostic et le traitement du PIMS-Covid (syndrome inflammatoire multisystémique chez les enfants, déclenché par la covid).

N011

2902

Ch37

Prof Eduardo A Oliveira, PhD
Enrico A Colosimo, PhD
Ana Cristina Simões e Silva, PhD
Robert H Mak, PhD
Daniella B Martelli, PhD
Ludmila R Silva, MSc
Hercílio Martelli-Júnior, PhD
Maria Christina L Oliveira

Clinical characteristics and risk factors for death among hospitalised children and adolescents with COVID-19 in Brazil: an analysis of a nationwide database

https://doi.org/10.1016/S2352-4642(21)00134-6

Published

10-Jun-21

Study

https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00134-6/fulltext

Of the 82 055 patients younger than 20 years reported to SIVEP-Gripe during the study period, 11 613 (14·2%) had available data showing laboratory-confirmed SARS-CoV-2 infection and were included in the sample. Among these patients, 886 (7·6%) died in hospital (at a median 6 days [IQR 3–15] after hospital admission), 10 041 (86·5%) patients were discharged from the hospital, 369 (3·2%) were in hospital at the time of analysis, and 317 (2·7%) were missing information on outcome. The estimated probability of death was 4·8% during the first 10 days after hospital admission, 6·7% during the first 20 days, and 8·1% at the end of follow-up. Probability of discharge was 54·1% during the first 10 days, 78·4% during the first 20 days, and 92·0% at the end of follow-up. Our competing risks multivariate survival analysis showed that risk of death was increased in infants younger than 2 years (hazard ratio 2·36 [95% CI 1·94–2·88]) or adolescents aged 12–19 years (2·23 [1·84–2·71]) relative to children aged 2–11 years; those of Indigenous ethnicity (3·36 [2·15–5·24]) relative to those of White ethnicity; those living in the Northeast region (2·06 [1·68–2·52]) or North region (1·55 [1·22–1·98]) relative to those in the Southeast region; and those with one (2·96 [2·52–3·47]), two (4·96 [3·80–6·48]), or three or more (7·28 [4·56–11·6]) pre-existing medical conditions relative to those with none.

_

2903

Ch38

Joseph R. Hageman, MD

Long COVID-19 or Post-Acute Sequelae of SARS-CoV-2 Infection in Children, Adolescents, and Young Adults

https://doi.org/10.3928/19382359-20210519-02

Published

1-Jun-21

Editorial

https://journals.healio.com/doi/full/10.3928/19382359-20210519-02

Now we need to gather more clinical information about “long COVID-19” or post-acute sequelae of SARS-CoV-2 infection (PASC).

_

2904

Ch39

Saba Ahmad, MD

Neurological Complications of COVID-19 in Children

https://doi.org/10.3928/19382359-20210517-01

Published

1-Jun-21

Article

https://journals.healio.com/doi/abs/10.3928/19382359-20210517-01

Neurological complications of coronavirus disease 2019 (COVID-19) are highly variable and can be quite severe, but they are rare in children. A careful understanding of the variety of presentations of neurological symptoms related to COVID-19 is critical for the effective management of these patients. Given the smaller numbers of children with these complications, a comprehensive review of neurological presentations in adults with COVID-19 may help facilitate the understanding of those complications that may present in children and how these presentations may be similar.

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2905

Ch40

Faith Miller, Vincent Nguyen, Annalan MD Navaratnam, Madhumita Shrotri, Jana Kovar, Andrew C Hayward, Ellen Fragaszy, Robert W Aldridge, Pia Hardelid

Prevalence of persistent symptoms in children during the COVID-19 pandemic: evidence from a household cohort study in England and Wales

https://doi.org/10.1101/2021.05.28.21257602

pre-print

2-Jun-21

Study

https://www.medrxiv.org/content/10.1101/2021.05.28.21257602v1.full-text

Using data from 4678 children participating in VirusWatch, a household cohort study, we estimated the prevalence of persistent symptoms lasting ≥4 weeks as 1.7%, and 4.6% in children with a history of SARS-CoV-2 infection. Persistent symptom prevalence was higher in girls, teenagers and children with long-term conditions.

2906

Ch41

Hirt

Ellinor Sterky,Selma Olsson-Åkefeldt,Olof Hertting,Eric Herlenius,Tobias Alfven,Malin Ryd Rinder,Samuel Rhedin,Helena Hildenwall

Persistent symptoms in Swedish children after hospitalisation due to COVID-19

https://doi.org/10.1111/apa.15999

Published

22-Jun-21

BRIEF REPORT

https://onlinelibrary.wiley.com/doi/10.1111/apa.15999

2907

Ch42

Defne Saatci, MD1; Tom A. Ranger, PhD1; Cesar Garriga, PhD1; Ash Kieran Clift, MD1,2; Francesco Zaccardi, PhD3; Pui San Tan, PhD1; Martina Patone, PhD1; Carol Coupland, PhD4; Anthony Harnden, MD1; Simon J. Griffin, MD5,6; Kamlesh Khunti, PhD3; Hajira Dambha-Miller, MD7; Julia Hippisley-Cox, MD1

Association Between Race and COVID-19 Outcomes Among 2.6 Million Children in England

https://doi.org/10.1001/jamapediatrics.2021.1685

Published

21-Jun-21

Study

https://jamanetwork.com/journals/jamapediatrics/fullarticle/2780966

Question Is race associated with COVID-19 testing and hospital outcomes in children in England?
Findings In this cohort study of 2 576 353 children (0-18 years of age) in England with COVID-19 disease, children who were Black, Asian, or of mixed race had lower proportions of SARS-CoV-2 tests and had higher positive results and COVID-19 hospitalizations compared with White children. These results held after key demographic factors and selected comorbidities were accounted for.
Meaning These findings suggest that race may play an important role in childhood COVID-19 outcomes, which reinforces the continued need for a race-tailored focus on health system performance and targeted public health interventions.

2908

Ch43

Lindsay A. Thompson, MD, MS1,2; Maria N. Kelly, MD1

Return to Play After COVID-19 Infection in Children

http://jamanetwork.com/article.aspx?doi=10.1001/jamapediatrics.2021.1485

Published

28-Jun-21

Article

https://jamanetwork.com/journals/jamapediatrics/fullarticle/2781110

As the pandemic continues, children may experience long-term effects from COVID-19 infections.
Because children may become “long haulers” or develop multisystem inflammatory syndrome in children (MIS-C), close monitoring after a COVID-19 diagnosis is important. In addition, children who are athletes require a separate return-to-play evaluation before they return to competitive sports or physical activities.

2909

Ch44

Michelle Elena Schober, Courtney Leigh Robertson, Mark Stephen Wainwright, Juan David Roa & Ericka Linn Fink

COVID-19 and the Pediatric Nervous System: Global Collaboration to Meet a Global Need

https://doi.org/10.1007/s12028-021-01269-2

Published

28-Jun-21

Viewpoint

https://link.springer.com/article/10.1007/s12028-021-01269-2

Emerging data suggest a cohort of patients with COVID-19 will have longitudinal illness affecting their cognitive, physical, and emotional health, but little is known about the long-term impact on affected children and their families. Pediatric collaboratives have begun to provide important initial information on neuroimaging manifestations and the incidence of ischemic stroke in children with COVID 19. The Global Consortium Study of Neurologic Dysfunction in COVID-19-Pediatrics, a multinational collaborative, is working to improve understanding of the epidemiology, mechanisms of neurological manifestations, and the long-term implications of COVID-19 in children and their families.

2910

Ch45

Maria Rosaria Scala, Pietro Spennato, Domenico Cicala, Veronica Piccolo, Antonio Varone & Giuseppe Cinalli

Malignant cerebral infarction associated with COVID-19 in a child

https://doi.org/10.1007/s00381-021-05273-x

Published

26-Jun-21

Case Report

https://link.springer.com/article/10.1007/s00381-021-05273-x

We present a case of a child with serological evidence of SARS-CoV-2 infection whose onset was a massive right cerebral artery ischemia that led to a malignant cerebral infarction. The patient underwent a life-saving decompressive hemicraniectomy, with good functional recovery, except for residual hemiplegia. During rehabilitation, the patient also developed a lower extremity peripheral nerve neuropathy, likely related to a long-Covid syndrome.

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2911

Ch46

MIS-C

Ravindra Pawar 1,* ,Vijay Gavade 2,Nivedita Patil 1,Vijay Mali 1,3 ,Amol Girwalkar 4,5,Vyankatesh Tarkasband 5,Sanjog Loya 2,Amit Chavan 2,Narendra Nanivadekar 6,Rahul Shinde 7,Uday Patil 2 andSatyan Lakshminrusimha 8

Neonatal Multisystem Inflammatory Syndrome (MIS-N) Associated with Prenatal Maternal SARS-CoV-2: A Case Series

https://doi.org/10.3390/children8070572

Published

2-Jul-21

Study

https://www.mdpi.com/2227-9067/8/7/572/htm

We reviewed the perinatal history, clinical features, and outcomes of 20 neonates with features consistent with MIS-C related to maternal SARS-CoV-2 in Kolhapur, India, from 1 September 2020 to 30 April 2021. Anti-SARS-CoV-2 IgG and IgM antibodies were tested in all neonates. Fifteen singletons and five twins born to eighteen mothers with a history of COVID-19 disease or exposure during pregnancy presented with features consistent with MIS-C during the first 5 days after birth. Nineteen were positive for anti-SARS-CoV-2 IgG and all were negative for IgM antibodies. All mothers were asymptomatic and therefore not tested by RTPCR-SARS-CoV-2 at delivery. Eighteen neonates (90%) had cardiac involvement with prolonged QTc, 2:1 AV block, cardiogenic shock, or coronary dilatation. Other findings included respiratory failure (40%), fever (10%), feeding intolerance (30%), melena (10%), and renal failure (5%). All infants had elevated inflammatory biomarkers and received steroids and IVIG. Two infants died. We speculate that maternal SARS-CoV-2 and transplacental antibodies cause multisystem inflammatory syndrome in neonates (MIS-N). Immunomodulation may be beneficial in some cases, but further studies are needed.

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2912

Ch47

MIS-C

Öcal Demir, Sevliya; Tosun, Öykü; Öztürk, Kübra; Duyu, Muhterem; Bucak, Abdülmelik; Akkus, Gökhan; Bayraktar, Ali C; Demirel, Hande N; Arslanoglu, Sertaç; Ovali, Fahri.

SARS-CoV-2 associated multisystem inflammatory syndrome in children (MIS-C). A single center's experience

Published

23-Apr-21

Study

https://pesquisa.bvsalud.org/global-literature-on-novel-coronavirus-2019-ncov/resource/pt/covidwho-1200473

The median age of 20 children with MIS-C was 80.5 months, 11 of them were male. The most common symptoms at admission were fever (100%), abdominal pain (70%), myalgia (50%), and rash (50%). Lymphopenia, elevated inflammatory markers and cardiac enzymes were their main laboratory findings. Cardiac involvement (90%) consisted of myopericarditis, valvulitis, left ventricular dysfunction, and coronary arteritis. Symptoms mimicking acute appendicitis and ileus were due to gastrointestinal involvement (50%). Macular rash on the trunk, erythema on upper eyelids were striking. Empiric antibiotics and intravenous immunoglobulin were used in all patients, glucocorticoids (90%), anti-thrombotic (65%) and vasoactive (45%) agents were used according to severity of disease. Response to IVIG treatment was poor, whereas glucocorticoids have dramatic affect. Seven patients (35%) were monitored in intensive care unit, none of them required intubation, mechanic ventilation or ECMO. The median recovery time, that is, the period when fever subside and inflammatory markers returned to normal was 9.5 days.

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2913

Ch48

Shoshana Leftin Dobkin,Joseph Collaco,Sharon McGrath-Morrow

Protracted Respiratory Findings in Children Post-COVID-19 Infection

https://doi.org/10.22541/au.162513383.35044135/v1

pre-print

1-Jul-21

Study

https://www.authorea.com/users/423023/articles/528597-protracted-respiratory-findings-in-children-post-covid-19-infection

The mean age at presentation to clinic was 13.1 years (range: 4-19 years). Patients had persistent respiratory symptoms ranging from 1.3 to 6.7 months post-acute infection. Persistent dyspnea and/or exertional dyspnea were present in nearly all (96.6%) of the patients at the time of clinic presentation. Other reported chronic symptoms included cough (51.7%) and exercise intolerance (48.3%). Fatigue was reported in 13.7% of subjects. Many subjects were overweight or obese (62.1%) and eleven subjects had a prior history of asthma. Lung function was normal in most patients. The six-minute walk test (6MWT) revealed exercise intolerance and significant tachycardia in two-thirds of children tested. Conclusion: Exertional dyspnea, cough and exercise intolerance were the most common respiratory symptoms in children with post-acute COVID-19 respiratory symptoms seen in an outpatient pulmonary clinic. Lung function, however, was mostly normal, and exertional intolerance was frequently demonstrated using the 6MWT.

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2914

Ch49

MIS-C

Goodwin, Peter M.

New Data on COVID-19 Related Pediatric Inflammatory Syndrome

https://doi.org/10.1097/01.COT.0000765076.71129.43

Published

5-Jul-21

Article

https://journals.lww.com/oncology-times/Fulltext/2021/07050/New_Data_on_COVID_19_Related_Pediatric.17.aspx?context=LatestArticles

“As PIMS-TS is a very rare complication of COVID-19 in children, our study included a small number of children from one hospital. Nevertheless, these findings can hopefully signal cautious optimism that many of the most severe effects of PIMS appear to resolve within 6 months. However, the persisting fatigue, difficulty exercising, and mental health effects we saw in some children, which can interfere with daily lives, must be closely monitored, and patients should continue to be supported by medical teams with a range of specialisms.”

2915

Ch50

Georgia B.NikolopoulouaHelena C.Maltezoub

COVID-19 in children: where do we stand?

https://doi.org/10.1016/j.arcmed.2021.07.002

Published

6-Jul-21

Review

https://www.sciencedirect.com/science/article/pii/S018844092100148X

Highlights
•Children with SARS-CoV-2 infection are mostly asymptomatic or mildly symptomatic.
•The true prevalence of SARS-CoV-2 infection in childhood is most likely underestimated, as asymptomatic children are less frequently tested.
•School closures have a limited impact on SARS-CoV-2 transmission, much less than other social distancing measures.
•Preliminary results from COVID-19 vaccine trials indicate very good efficacy and tolerability in children.
•Vaccination of children 12 years or older is recommended to protect them but mostly to contribute to the achievement of herd immunity.

2916

Ch51

Dyani Lewis

Long COVID and kids: scientists race to find answers

https://doi.org/10.1038/d41586-021-01935-7

Published

14-Jul-21

Article

https://www.nature.com/articles/d41586-021-01935-7

As COVID-19 has ripped through communities, children have often been spared the worst of the disease’s impacts. But the spectre of long COVID developing in children is forcing researchers to reconsider the cost of the pandemic for younger people.
The question is particularly relevant as the proportion of infections that are in young people rises in countries where many adults are now vaccinated — and as debates about the benefits of vaccinating children intensify.
Most people who survive COVID-19 recover completely. But for some, the poorly understood condition that’s become known as long COVID can last for months — maybe even years. Nobody yet knows.
The condition was first described in adults. But several studies have now reported a similar phenomenon, including symptoms such as headache, fatigue and heart palpitations, in children, even though they rarely experience severe initial symptoms of COVID-19.

Un article dans Nature passe en revue les questionnements des chercheurs sur la prévalence du covid long chez les enfants. Les données manquent encore pour savoir quel pourcentage garderont des séquelles au delà de 6 mois, et à quelle sévérité.

2917

Ch52

David S. Younger

Post-acute sequelae of SARS-CoV-2 infection (PASC): peripheral, autonomic, and central nervous system features in a child

https://doi.org/10.1007/s10072-021-05345-5

Published

11-Jul-21

Case Report

https://link.springer.com/article/10.1007/s10072-021-05345-5

This paper describes the detailed evaluation and treatment of an adolescent with PASC manifesting progressive post-infectious central, peripheral, and autonomic nervous system (CNS, PNS, and ANS).

2918

Ch53

Afreen Khan, MD, Aparna Chakravarty, MD, Abhinav Jain, MD, Rekha Harish, MD, Rizwan Naqishbandi, Twisha Ishani

Clinical spectrum of neurological manifestations in pediatric Covid-19 illness: a case series

https://doi.org/10.1093/tropej/fmab059

Published

10-Jul-21

Case Series

https://academic.oup.com/tropej/advance-article/doi/10.1093/tropej/fmab059/6319043

We describe a cohort of three patients with variable neurological presentations by SARS COV-2 infection. It includes one case each of Acute Cerebellitis, Acute encephalomyelitis and Arterial Ischemic Stroke. To the best of our knowledge we report the first pediatric case of acute cerebellitis due to SARS CoV-2 infection.

All critically ill patients were treated with methylprednisolone pulse therapy and dexamethasone. Patient with acute cerebellitis in addition required Intravenous Immunoglobulin infusion. All the patients responded to the treatment with complete neurological recovery.

2919

Ch54

Hirt

Daniela Say
Nigel Crawford
Sarah McNab
Danielle Wurzel
Andrew Steer
Shidan Tosif

Post-acute COVID-19 outcomes in children with mild and asymptomatic disease

https://doi.org/10.1016/S2352-4642(21)00124-3

Published

20-Apr-21

CORRESPONDENCE

https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00124-3/fulltext

Follow-up data at 3–6 months were available for 151 (88%) of 171 children, of whom 54 (36%) were asymptomatic and 97 (64%) were symptomatic (ie, with mild, moderate, or severe disease) with acute COVID-19. 12 (8%) children had post-acute COVID-19 symptoms, all of whom were symptomatic with acute COVID-19 (table). The most common post-acute COVID-19 symptoms were mild post-viral cough (six [4%] of 151 children), fatigue (three [2%] children) or both post-viral cough and fatigue (one [1%] child). The duration of post-viral cough ranged from 3 weeks to 8 weeks and of post-viral fatigue ranged from 6 weeks to 8 weeks from the time of symptom onset. At the most recent review in March, 2021, all 151 children had returned to their baseline health status and post-acute COVID-19 symptoms had resolved. Follow-up data for 20 children were not available; seven (35%) of these children had asymptomatic COVID-19.

2920

Ch55

Dusan Bogunovic 123456 Miriam Merad

Children and SARS-CoV-2

https://doi.org/10.1016/j.chom.2021.06.015

Published

14-Jul-21

Article

https://www.sciencedirect.com/science/article/pii/S1931312821002973

Herein, we discuss known clinical and biological features of SARS-CoV-2 in children and reflect on currently identified immune features and discuss what remains unknown.

2921

Ch56

Stephen T JRayMPhilabcdxOmarAbdel-MannanBMBChefMarioSaMDhCharlotteFullerMBChBcdiGreta KWoodMResabKarenPysdenMBChBiMichaelYoongPhDjHelenMcCullaghMBChBiDavidScottMSclMartinMcMahon Michael JGriffithsDPhilabx*Benedict DMichaelPhDabaa*RachelKneen

Neurological manifestations of SARS-CoV-2 infection in hospitalised children and adolescents in the UK: a prospective national cohort study

https://doi.org/10.1016/S2352-4642(21)00193-0

Published

15-Jul-21

Study

https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00193-0/fulltext

Between April 2, 2020, and Feb 1, 2021, 52 cases were identified; in England, there were 51 cases among 1334 children and adolescents hospitalised with COVID-19, giving an estimated prevalence of 3·8 (95% CI 2·9–5·0) cases per 100 paediatric patients. 22 (42%) patients were female and 30 (58%) were male; the median age was 9 years (range 1–17). 36 (69%) patients were Black or Asian, 16 (31%) were White. 27 (52%) of 52 patients were classified into the COVID-19 neurology group and 25 (48%) were classified into the PIMS-TS neurology group. In the COVID-19 neurology group, diagnoses included status epilepticus (n=7), encephalitis (n=5), Guillain-Barré syndrome (n=5), acute demyelinating syndrome (n=3), chorea (n=2), psychosis (n=2), isolated encephalopathy (n=2), and transient ischaemic attack (n=1). The PIMS-TS neurology group more often had multiple features, which included encephalopathy (n=22 [88%]), peripheral nervous system involvement (n=10 [40%]), behavioural change (n=9 [36%]), and hallucinations at presentation (n=6 [24%]). Recognised neuroimmune disorders were more common in the COVID-19 neurology group than in the PIMS-TS neurology group (13 [48%] of 27 patients vs 1 [<1%] of 25 patients, p=0·0003). Compared with the COVID-19 neurology group, more patients in the PIMS-TS neurology group were admitted to intensive care (20 [80%] of 25 patients vs six [22%] of 27 patients, p=0·0001) and received immunomodulatory treatment (22 [88%] patients vs 12 [44%] patients, p=0·045). 17 (33%) patients (10 [37%] in the COVID-19 neurology group and 7 [28%] in the PIMS-TS neurology group) were discharged with disability; one (2%) died (who had stroke, in the PIMS-TS neurology group).

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2922

Ch57

Aurelie MORAND, Jacques-Yves CAMPION, Anne LEPINE, Emmanuelle BOSDURE, Léa LUCCIANI, Serge CAMMILLERI, Brigitte CHABROL, Eric Guedj

Similar patterns of 18F-FDG brain PET hypometabolism in paediatric and adult patients with long COVID: a paediatric case series

https://doi.org/10.1007/s00259-021-05528-4

Published

19-Aug-21

Case Series

https://link.springer.com/article/10.1007/s00259-021-05528-4

Paediatric patients demonstrated a similair brain hypometabolic pattern as that found in adult long COVID patients, involving bilateral medial temporal lobes, brainstem and cerebellum (p-voxel < 0.001, p-cluster < 0.05 FWE-corrected), and also the right olfactory gyrus after small volume correction (p-voxel = 0.010 FWE-corrected), with partial recovery in two children at follow-up.
Conclusion. These results provide arguments in favour of possible long COVID in children, with a similar functional brain involvement to those found in adults.

Une équipe du CHU Timone constate des profils d'hypométabolisme cérébral, similaires à ceux observés chez l'adulte, sur les 7 enfants de la cohorte présentant des symptômes de covid long. Font apparaître notamment des hypométabolismes : l'amygdale cérébrale, le gyrus parahippocampique, le tronc cérébral, le cervelet, ainsi que les gyrus olfactifs.

N012

2923

Ch58

BinhNgoab1Stacey A.Lappcd1BenjaminSiegelceVikashPatelcdLailaHussainicdSonaliBoraabBryanPhilbrookcehKristinWeinschenkabLauraWrightfEvan J.AndersoncdgChristina A.Rostadcd1Grace Y.Gombolayeh1

Cerebrospinal fluid cytokine, chemokine, and SARS-CoV-2 antibody profiles in children with neuropsychiatric symptoms associated with COVID-19

https://doi.org/10.1016/j.msard.2021.103169

Published

1-Jul-21

Study

https://www.sciencedirect.com/science/article/pii/S2211034821004363

Highlights
•CSF cytokines/chemokines are unknown in pediatric COVID-19.
•We discuss neurological and psychiatric symptoms in five children with COVID-19.
•CSF chemokines and SARS-CoV-2 antibodies are elevated.
•SARS-CoV-2 antibodies strongly correlate with pro-inflammatory CSF cytokines.
Results
Three of five NP-COVID-19 patients had psychiatric symptoms, and two patients had encephalopathy and seizures. All patients had full or near resolution of neuropsychiatric symptoms by discharge. One patient received intravenous steroids for treatment for psychiatric symptoms; 3/5 other patients received immunotherapy for MIS-C, including IVIG, high-dose steroids, anakinra, and tocilizumab. Pro-inflammatory chemokines, including MIG, MPC, MIP-1β, and TARC were significantly elevated in NP-COVID-19 patients compared to controls. Two of five patients had elevated CSF neurofilament light chain. CSF SARS-CoV-2 antibody titers to the full-length spike, receptor binding domain and N-terminal domain were significantly elevated. SARS-CoV-2 antibody titers strongly correlated with pro-inflammatory chemokines/cytokines, including IL-1β, IL-2, IL-8, TNF-α, and IFN-γ (P≤0.05 for all).
Conclusions
A spectrum of neuropsychiatric clinical manifestations can occur in children with SARS-CoV-2 infection. CSF pro-inflammatory chemokines and SARS-CoV-2 antibodies may serve as biomarkers of SARS-CoV-2 mediated NP-COVID-19. Additional study is required to understand the pathophysiologic mechanisms of neuroinflammation in children with COVID-19 and MIS-C.

2924

Ch59

CPET

Danilo Buonsenso, MD *
Daniela Di Giuda, MD *
Louise Sigfrid, MD
Daniele Antonio Pizzuto, MD
Gabriele Di Sante, PhD
Cristina De Rose, MD
Ilaria Lazzareschi, MD
Michela Sali, PhD
Fabiana Baldi, MD
Daniela Pia Rosaria Chieffo, MD
Prof Daniel Munblit, PhD †
Piero Valentini

Evidence of lung perfusion defects and ongoing inflammation in an adolescent with post-acute sequelae of SARS-CoV-2 infection

https://doi.org/10.1016/S2352-4642(21)00196-6

Published

30-Jul-21

Case Report

https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00196-6/fulltext

In conclusion, in this report we present the first detailed evaluation of PASC in an adolescent, providing evidence of pulmonary circulation dysfunction with possible lung microvascular or endothelial damage as detected by CPET and chest SPECT/CT. Currently, most attention has been focused on long COVID in adults, with few studies including children, resulting in a lack of case definitions and management guidelines for this population. This report supports the emerging evidence on long COVID in children and highlights that, although children generally present with mild, acute COVID-19, they are at risk of prolonged organ damage, similar to what has been identified in adults. This report highlights the importance of doing a robust assessment of children presenting with PASC. SPECT/CT is useful to detect microvascular damage in patients with more severe and persisting symptoms. We urge clinicians and policy makers to not underestimate the risk of and consequences of long-term COVID-19 sequelae in children.

Dans un compte-rendu de cas publié dans The Lancet, une équipe a poussé les investigations sur une adolescente de 14 ans active, sans comorbidités, qui avait eu une phase bégnine de covid en octobre 2020 (37,3°C, rhinite, anosmie), mais qui développe le mois d'après des symptômes persistants : maux de tête, douleurs de poitrine, asthénie et tachycardie.
Aucun examen biologique (électrocardiogramme, marqueurs de lésions cardiaques, coagulation, marqueurs inflammatoires, échocardiographie, spirométrie pulmonaire, scan pulmonaire sans contraste) ne présente alors d'anomalie.

En mai 2021, les symptômes sont toujours présents et la patiente est admise à l'hôpital, à Rome. L'IRM cardiaque est normale, ainsi que les tests psychologiques, neurologiques, et un examen sanguin de routine.
L'analyse plus poussée révèle cependant, malgré des taux élevés d'anticorps igG/IgA au SARS-CoV-2, des concentrations hautes d'IL-6 (633 pg/mL), IL-1 (8,55 pg/mL) et TNFα (32,7 pg/mL). Les titrages de lymphocytes T et B sont également inhabituels et suggèrent un fond pro-inflammatoire.
Un test de capacité cardio-pulmonaire fait apparaître une réduction légère à modérée de la capacité fonctionnelle (le pic de VO2 était de 24,4 ml/kg/min, ce qui correspond à 68 % du VO2 max prédit), secondaire à une efficacité cardiovasculaire réduite, avec des signes indirects initiaux d'augmentation de la résistance vasculaire pulmonaire (pente VE/VCO2 de 36), et une pression partielle réduite du CO2 de fin d'expiration, suggérant une hypertension pulmonaire.
Les tests confirment la présence d'une tachycardie sinusale (fréquence cardiaque maximale de 180 battements par minute), mais pas de modifications sur l'ECG ni signes de limitation ventilatoire (saturation en oxyhémoglobine au pic d'effort à 99%).
Étudiant la littérature qui évoque chez l'adulte la possibilité de séquelles vasculaires pulmonaires de covid avec charge résiduelle de caillots sanguins, les auteurs de l'étude pratiquent une tomographie/tomoscintigraphie par émission monophotonique (TEMP) avec ventilation-perfusion (SPECT V/Q en anglais, Single photon emission computed tomography), examen standard pour les troubles thromboemboliques chroniques.
Les chercheurs font précéder la TEMP par une scintigraphie pulmonaire planaire avec de l'albumine macroagrégée 99mTc.
Alors que la scintigraphie planaire n'a pas montré de zones de diminution de la captation radiopharmaceutique dans les deux poumons, un défaut de perfusion significatif a été observé sur les images de la TEMP dans le segment apical du lobe supérieur droit, qui ne correspondait pas à des altérations parenchymateuses sur les coupes au scanner. Pour les auteurs de l'article, ces résultats pourraient suggérer une implication au niveau microvasculaire, très probablement associée à des dommages endothéliaux, comme le supposent d'autres études chez l'adulte.

La TEMP détecte des signes précurseurs d'hypertension pulmonaire avec une surcharge minimale du ventricule droit, ce qui pourrait expliquer la tachycardie compensatrice ressentie lors de l'effort sous-maximal. Les chercheurs concluent à un dysfonctionnement de la circulation pulmonaire avec des dommages microvasculaires et endothéliaux périphériques possibles.
De plus, les résultats de la tomodensitométrie et des tests de la fonction respiratoire ont exclu une altération associée à la ventilation.
Il s'agit sans doute ici de la première preuve rapportée de dysfonctionnement et de dommages objectivés d'un organe chez un adolescent atteint de covid long (ou PASC).
La patiente est depuis traitée avec des stéroïdes oraux (méthylprédnisolone 2g/kg une fois par jour pendant 2 semaines, puis diminution au cours des 4 semaines suivantes, avec un inhibiteur de la pompe à protons) et de l'héparine de bas poids moléculaire (énoxaparine 6000 unités deux fois par jour, avec un plan de passage aux anticoagulants oraux et la poursuite du traitement pendant 6 à 9 mois au total).

N012

2925

Ch60

Bibhuti B. Das, MD; S. Kristen Sexon Tejtel, MD; Shriprasad Deshpande, MD; Lara S. Shekerdemian, MD, MHA

A Review of the Cardiac and Cardiovascular Effects of COVID-19 in Adults and Children

https://doi.org/10.14503/THIJ-20-7395

Published

2-Aug-21

Review

https://meridian.allenpress.com/thij/article/48/3/e207395/468681/A-Review-of-the-Cardiac-and-Cardiovascular-Effects

Myocardial injury is an essential pathogenic feature of COVID-19, but its mechanisms are not clear. Elevated levels of cardiac biomarkers, chiefly cardiac Tn, indicate acute cardiac injury and are associated with poor outcomes. Continuous inflammation may cause new-onset heart failure and other CV complications, as in other types of viral myocarditis. Endomyocardial biopsy samples may help to differentiate primary viral myocarditis from secondary myocardial dysfunction; however, EMB samples may not confirm myocarditis, so uniform CMR criteria for the diagnosis of SARS-CoV-2 myocarditis are needed. Autopsy findings may eventually enable a better understanding of the pathophysiology of COVID-19 disease and its long-term effects on the heart, thus informing future management.

2926

Ch61

Cf Ch27

Erika Molteni, PhD †
Carole H Sudre, PhD †
Liane S Canas, PhD
Sunil S Bhopal, PhD
Robert C Hughes, MPH
Michela Antonelli, PhD
Benjamin Murray, MSc
Kerstin Kläser, MSc
Eric Kerfoot, PhD
Liyuan Chen, MSc
Jie Deng, PhD
Christina Hu, BA
Somesh Selvachandran, MEng
Kenneth Read, BSc
Joan Capdevila Pujol, PhD
Prof Alexander Hammers, PhD
Prof Tim D Spector, PhD
Prof Sebastien Ourselin, PhD
Claire J Steves, PhD
Marc Modat, PhD
Michael Absoud, PhD
Prof Emma L Duncan

Illness duration and symptom profile in symptomatic UK school-aged children tested for SARS-CoV-2

https://doi.org/10.1016/S2352-4642(21)00198-X

Published

3-Aug-21

Study

https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00198-X/fulltext

PUBLICATION of #Ch27

The most common symptoms were headache (1079 [62·2%] of 1734 children), and fatigue (954 [55·0%] of 1734 children). Median illness duration was 6 days (IQR 3–11) versus 3 days (2–7) in children testing negative, and was positively associated with age (Spearman's rank-order rs 0·19, p<0·0001). Median illness duration was longer for older children (7 days, IQR 3–12) than younger children (5 days, 2–9). 77 (4·4%) of 1734 children had illness duration of at least 28 days, more commonly in older than younger children (59 [5·1%] of 1146 older children vs 18 [3·1%] of 588 younger children; p=0·046). The commonest symptoms experienced by these children during the first 4 weeks of illness were fatigue (65 [84·4%] of 77), headache (60 [77·9%] of 77), and anosmia (60 [77·9%] of 77); however, after day 28 the symptom burden was low (median 2 symptoms, IQR 1–4) compared with the first week of illness (median 6 symptoms, 4–8). Only 25 (1·8%) of 1379 children experienced symptoms for at least 56 days. Few children (15 children, 0·9%) in the negatively tested cohort had symptoms for at least 28 days; however, these children experienced greater symptom burden throughout their illness (9 symptoms, IQR 7·7–11·0 vs 8, 6–9) and after day 28 (5 symptoms, IQR 1·5–6·5 vs 2, 1–4) than did children who tested positive for SARS-CoV-2.

Une étude britannique relève que les symptômes prolongés de la covid chez l'enfant (5-17 ans) sont d'autant moins fréquents que les enfants sont jeunes. 4,4% des enfants ont des symptômes au delà d'un mois dans la cohorte étudiée, 1 à 2% au delà de 2 mois.

N014E

2927

Ch62

Daniel Munblit, MD, PhD1,2; Louise Sigfrid, MD, PhD3; John O. Warner

Setting Priorities to Address Research Gaps in Long-term COVID-19 Outcomes in Children

http://jamanetwork.com/article.aspx?doi=10.1001/jamapediatrics.2021.2281

Published

2-Aug-21

Viewpoint

https://jamanetwork.com/journals/jamapediatrics/fullarticle/2782612

Large, harmonized longitudinal studies assessing aspects of SARS-CoV-2 infection sequelae in children and adolescents are needed. Although few studies have focused on children,5,6 patient support groups have noted that many children experience long-term COVID-19 consequences. To generate high-quality evidence, studies with controls matched for the same social restrictions are urgently required. Robust case-control studies can facilitate identification of the cause of and risk factors for different long COVID syndromes in children, including well-defined characterization of symptoms, signs, psychological features, and protective factors in children in different settings. Estimation of the impact of long COVID vs the impact of wider pandemic restrictions may provide important information for policy makers to guide clinical and public health management.

2928

Ch63

Jacqui Wise

Long covid: One in seven children may still have symptoms 15 weeks after infection, data show

https://doi.org/10.1136/bmj.n2157

Published

1-Sep-21

News

https://www.bmj.com/content/374/bmj.n2157

A large study of children and young people who caught SARS-CoV-2 has found that as many as one in seven (14%) may still have symptoms 15 weeks later.1 However, this figure is lower than in some studies that have reported a prevalence of long covid as high as 51% in children and young people.

2929

Ch64

Hirt

Terence Stephenson, Terence Stephenson, Snehal Pinto Pereira, Roz Shafran, Bianca De Stavola, Natalia Rojas, Kelsey McOwat, Ruth Simmons, Maria Zavala, Lauren O’Mahoney, Trudie Chalder, Esther Crawley, Tamsin Ford, Anthony Harnden, Isobel Heyman, Olivia Swann, Liz Whittaker, CLoCk Consortium CLoCk Consortium, Shamez Ladhani

Long COVID - the physical and mental health of children and non-hospitalised young people 3 months after SARS-CoV-2 infection; a national matched cohort study (The CLoCk) Study.

https://doi.org/10.21203/rs.3.rs-798316/v1

pre-print

10-Aug-21

Study

https://www.researchsquare.com/article/rs-798316/v1

Introduction: We describe post-COVID symptomatology in a national sample of 11-17-year-old children and young people (CYP) with PCR-confirmed SARS-CoV-2 infection compared to test-negative controls.

Methods and analysis: A cohort study of test-positive (n=3,065) and age-, sex- and geographically-matched test-negative CYP (n=3,739) completed detailed questionnaires 3 months post-test.

Results: At PCR-testing, 35.4% of test-positives and 8.3% of test-negatives had any symptoms whilst 30.6% and 6.2%, respectively, had 3+ symptoms. At 3 months post-testing, 66.5% of test-positives and 53.3% of test-negatives had any symptoms, whilst 30.3% and 16.2%, respectively, had 3+ symptoms. Latent class analysis identified two classes, characterised by “few” or “multiple” symptoms. This latter class was more frequent among test-positives, females, older CYP and those with worse pre-test physical and mental health.

Discussion: Test-positive CYP had a similar symptom profile to test-negative CYP but with higher prevalence of single and, particularly, multiple symptoms at PCR-testing and 3 months later.

2930

Ch65

Liene Smane, Ieva Roge, Zanda Pucuka & Jana Pavare

Clinical features of pediatric post-acute COVID-19: a descriptive retrospective follow-up study

https://doi.org/10.1186/s13052-021-01127-z

Published

26-Aug-21

Study

https://ijponline.biomedcentral.com/articles/10.1186/s13052-021-01127-z

To date, information on COVID-19 long-term post-recovery sequelae in children and adolescents remains scarce. A retrospective descriptive cohort study was performed by collecting data on 92 patients (age ≤ 18 years). All were evaluated during a face-to-face visit following a specially designed post-COVID-19 symptom assessment protocol at the following stage: 1–3 months after COVID-19 onset. Among the 92 children, 45 (49%) were completely free of any COVID-19-related symptoms, while 47 (51%) reported persistence of at least one symptom, in particular tiredness, loss of taste and/or smell and headaches. The most common post-acute COVID-19 clinical features were noted in children aged between 10 and 18 years. A detailed multidisciplinary follow-up of patients with COVID-19 seems relevant, whatever the severity of the symptoms.

2931

Ch66

Miranda J. Delahoy, PhD1,2; Dawud Ujamaa, MS1,3; Michael Whitaker, MPH1; Alissa O’Halloran, MSPH1; Onika Anglin, MPH1,3; Erin Burns1; Charisse Cummings, MPH1; Rachel Holstein, MPH1; Anita K. Kambhampati, MPH1; Jennifer Milucky, MSPH1; Kadam Patel, MPH1,3; Huong Pham, MPH1; Christopher A. Taylor, PhD1; Aron J. Hall, DVM1; Alicia M. Fry, MD1; Meredith McMorrow, MD1; Carrie Reed, DSc1; Shikha Garg, MD1*; Fiona P. Havers

Hospitalizations Associated with COVID-19 Among Children and Adolescents —
COVID-NET, 14 States, March 1, 2020–August 14, 2021

http://dx.doi.org/10.15585/mmwr.mm7036e2

Published

3-Sep-21

Study

https://www.cdc.gov/mmwr/volumes/70/wr/mm7036e2.htm

What is already known about this topic?

COVID-19 can cause severe illness in children and adolescents.

What is added by this report?

Weekly COVID-19–associated hospitalization rates among children and adolescents rose nearly five-fold during late June–mid-August 2021, coinciding with increased circulation of the highly transmissible SARS-CoV-2 Delta variant. The proportions of hospitalized children and adolescents with severe disease were similar before and during the period of Delta predominance. Hospitalization rates were 10 times higher among unvaccinated than among fully vaccinated adolescents.

What are the implications for public health practice?

Preventive measures to reduce transmission and severe outcomes in children and adolescents are critical, including vaccination, universal masking in schools, and masking by persons aged ≥2 years in other indoor public spaces and child care centers.

2932

Ch67

Hirt

Ali A. Asadi-Pooya, Hamid Nemati, Mina Shahisavandi, Ali Akbari, Amir Emami, Mehrzad Lotfi, Mahtab Rostamihosseinkhani, Zohreh Barzegar, Maryam Kabiri, Zahra Zeraatpisheh, Mohsen Farjoud-Kouhanjani, Anahita Jafari, Fateme Sasannia, Shayan Ashrafi, Masoume Nazeri & Sara Nasiri

Long COVID in children and adolescents

https://doi.org/10.1007/s12519-021-00457-6

Published

3-Sep-21

Study

https://link.springer.com/article/10.1007/s12519-021-00457-6

All consecutive children and adolescents who were referred to the hospitals anywhere in Fars province, Iran, from 19 February 2020 until 20 November 2020 were included. All patients had a confirmed diagnosis of COVID-19. In a phone call to patients/parents, at least 3 months after their discharge from the hospital, we obtained their current status and information if their parents agreed to participate.

Results
In total, 58 children and adolescents fulfilled the inclusion criteria. Twenty-six (44·8%) children/adolescents reported symptoms/complaints of long COVID. These symptoms included fatigue in 12 (21%), shortness of breath in 7 (12%), exercise intolerance in 7 (12%), weakness in 6 (10%), and walking intolerance in 5 (9%) individuals. Older age, muscle pain on admission, and intensive care unit admission were significantly associated with long COVID.

2933

Ch68

Giuseppe Fabio Parisi 1 ,Lucia Diaferio 2,Giulia Brindisi 3 ,Cristiana Indolfi 4,Giuseppina Rosaria Umano 4 ,Angela Klain 4,Giuseppe Marchese 5,Daniele Giovanni Ghiglioni 6,Anna Maria Zicari 3,Gian Luigi Marseglia 7 andMichele Miraglia del Giudice 4,

Cross-Sectional Survey on Long Term Sequelae of Pediatric COVID-19 among Italian Pediatricians

https://doi.org/10.3390/children8090769

Published

31-Aug-21

Study

https://www.mdpi.com/2227-9067/8/9/769/htm

The survey was emailed once in March 2021 to a sample of Italian pediatricians. A total 267 Italian pediatricians participated in our survey. According to most pediatricians (97.3%), the persistence of symptoms is found in less than 20% of children. Specifically, with regard to the symptoms that persist even after swab negativization, fatigue was the most mentioned one (75.6%). Long-COVID would seem to be a phenomenon of limited occurrence in pediatric ages, affecting less than 20% of children. Among all of the symptoms, the one that was most prevalent was fatigue, a pathological entity that is associated with many viral diseases.

2934

Ch69

Nurdan Erol
Abdullah Alpinar
Cigdem Erol,
Erdal Sari and Kubra Alkan

Intriguing New Faces Of Covid-19: Persisting Clinical Symptoms And Cardiac Effects in Children

https://doi.org/10.1017/S1047951121003693

Published

19-Aug-21

Study

https://www.cambridge.org/core/journals/cardiology-in-the-young/article/intriguing-new-faces-of-covid19-persisting-clinical-symptoms-and-cardiac-effects-in-children/662BF31CEF4C7D4549C2869B08FEAF5C#

In this study, 121 children between the ages of 0-18 with Covid-19 were evaluated based on their history, blood pressure values, and electrocardiography and echocardiography results. These findings were compared with the findings of the control group which consisted of 95 healthy cases who were in the same age range as the study group and did not have Covid-19. The results were evaluated using the statistics program, SPSS 21.

Results:
There was no significant difference between the study group and the control group in terms of age, weight, and body mass index. The clinical symptoms (chest and back pain, dizziness, headache, palpitation, fatigue, shortness of breath, loss of balance, coughing) of 37.2% of the cases persisted at least 1 month after Covid-19 recovery. Statistically significant differences were found in systolic blood pressure, left ventricular ejection fraction, relative wall thickness, and tricuspid annular plane systolic excursion.

2935

Ch70

Nicola Principi & Susanna Esposito

Are we sure that the neurological impact of COVID 19 in childhood has not been underestimated?

https://doi.org/10.1186/s13052-021-01144-y

Published

18-Sep-21

https://link.springer.com/article/10.1186/s13052-021-01144-y

Fortunately, in most of the cases, neurological manifestations, mainly represented by headache and anosmia, are mild and transient and do not significantly complicate the COVID-19 course. However, in some cases, very severe clinical problems associated with relevant alterations of neuroimaging, electroencephalography, nerve conduction studies and electromyography findings can develop. Generally, almost all the children with COVID-19 and neurological manifestations till now described have made a complete recovery, although in some cases this has occurred after several weeks of treatment. Moreover, COVID-19 infection during pregnancy has been found associated with an increased risk of obstetric complications that can lead to neurological acute and long-term manifestations in neonates.
Conclusions
Based on data showing the neurologic impact of COVID-19 in pediatric age, we suggest monitoring neurological development a few months after healing in pediatric patients who have presented MIS-C, seizures or other neurological manifestations and in children of pregnant women with COVID-19 in order to detect overt and subtle deficits.

_

2936

Ch71

Zimmermann, Petra MD, PhD*,†,‡,§; Pittet, Laure F. MD-PhD‡,§,¶; Curtis, Nigel

How Common Is Long COVID in Children and Adolescents?

https://doi.org/10.1097/INF.0000000000003328

Published

16-Sep-21

Review

https://journals.lww.com/pidj/Abstract/9000/How_Common_Is_Long_COVID_in_Children_and.95677.aspx

In children, the risk of coronavirus disease (COVID) being severe is low. However, the risk of persistent symptoms following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is uncertain in this age group, and the features of “long COVID” are poorly characterized. We reviewed the 14 studies to date that have reported persistent symptoms following COVID in children and adolescents. Almost all the studies have major limitations, including the lack of a clear case definition, variable follow-up times, inclusion of children without confirmation of SARS-CoV-2 infection, reliance on self- or parent-reported symptoms without clinical assessment, nonresponse and other biases, and the absence of a control group. Of the 5 studies which included children and adolescents without SARS-CoV-2 infection as controls, 2 did not find persistent symptoms to be more prevalent in children and adolescents with evidence of SARS-CoV-2 infection. This highlights that long-term SARS-CoV-2 infection–associated symptoms are difficult to distinguish from pandemic-associated symptoms.

_

2937

Ch72

NeslihanZENGİN1Yusuf ZiyaGÜVEN

Retinal Microvascular and Perfusional Disruption in Paediatric COVID-19: A Case-Control Optical Coherence Tomography Angiography Study

https://doi.org/10.1016/j.pdpdt.2021.102577

Published

11-Oct-21

Study

https://www.sciencedirect.com/science/article/pii/S1572100021003835

Significant differences were observed between the two groups in terms of inner, outer, and full VD, as well as inner and full PD. No significant differences in centre VD and PD were observed between groups. Although it was not evident in analysis of choroidal values, inflammatory sites were thickened. FAZ area significantly differed between groups (p < 0.05). NB : vessel density (VD), perfusion density (PD), and foveal avascular zone (FAZ)

Une étude rapporte chez des enfants ayant été malades de la covid, puis rétablis, des dommages subcliniques au niveau de la vascularisation rétinienne. L'étude note que la zone avasculaire fovéale peut s'étendre pendant la phase aiguë de la maladie, sous l'effet de microthromboses et d'ischémies temporaires, par rapport à un cas contrôle.
Les auteurs estiment que les patients pédiatriques de la covid devraient être suivis par un examen d'angiographie par tomographie par cohérence optique pour détecter d'éventuels changements rétiniens infracliniques, et que des études à long terme sont nécessaires pour valider ces observations.

N014E

2938

Ch73

Mary G Hornick, PhD, Margaret E Olson, PhD, Arun L Jadhav, PhD

SARS-CoV-2 Psychiatric Sequelae: A Review of Neuroendocrine Mechanisms and Therapeutic Strategies

https://doi.org/10.1093/ijnp/pyab069

Published

14-Oct-21

Study

https://academic.oup.com/ijnp/advance-article/doi/10.1093/ijnp/pyab069/6396958

We then examine the hypothesis that COVID-19-induced psychiatric disorders result from challenges to the neuroendocrine system, in particular the hypothalamic-pituitary-adrenal (HPA) stress axis and monoamine synthesis, physiological mechanisms that are only further enhanced by the pandemic-induced social environment of fear, isolation, and socioeconomic pressure. Finally, we evaluate several FDA-approved therapeutics in the context of COVID-19-induced psychoneuroendocrine disorders.

2939

Ch74

Eleni Gavriilaki, Ioannis Eftychidis and Ioannis Papassotiriou

Update on endothelial dysfunction in COVID-19: severe disease, long COVID-19 and pediatric characteristics

https://doi.org/10.1515/labmed-2021-0134

Published

15-Oct-21

Review

https://www.degruyter.com/document/doi/10.1515/labmed-2021-0134/html

Objectives
To review current literature on the role of endothelial dysfunction in coronavirus disease-2019 (COVID-19) infection in terms of pathophysiology, laboratory features and markers, clinical phenotype in adults and children, as well as long COVID-19.

_

2940

Ch75

Nooralam Rai MD,Joseph A Cornett BS,Philip Zachariah MD MS MA,Lynne Quittell MD,Stephanie Lovinsky-Desir MD MS

Severe respiratory viral infections in children with history of asymptomatic or mild COVID-19

https://doi.org/10.1002/ppul.25752

Published

6-Nov-21

Case series

https://onlinelibrary.wiley.com/doi/10.1002/ppul.25752

Participants
Children with prior mild or asymptomatic COVID-19 and no known risk factors for severe respiratory disease, who were hospitalized at our center for acute respiratory illness from October 2020 to May 2021, were reviewed.
Main outcomes and measures
Co-morbidities, history of prior COVID-19 symptoms, respiratory viral panel findings, acuity of illness, degree of respiratory decompensation based on support and interventions required, duration of hospitalization, and overall clinical course were assessed from the medical record.
Results
This study included 5 patients (median age, 4 years; age range, 0.8-9 years; 4 [80%] male). All had positive COVID-19 serology, 1 (20%) had mild symptoms, while the others had no symptoms of prior Sars-CoV-2 infection. 3 (60%) had asthma, and the remaining had no co-morbidities. All were admitted between April and May 2021. Two were re-admitted for respiratory symptoms in the subsequent three months.
Conclusions and Relevance
This case series describes a possible association between severe lower respiratory tract infection and prior mild COVID-19 in children. Larger cohort studies describing the respiratory effects of prior COVID-19 in children are needed.

2941

Ch76

Nooralam Rai MD,Joseph A Cornett BS,Philip Zachariah MD MS MA,Lynne Quittell MD,Stephanie Lovinsky-Desir MD MS

Severe respiratory viral infections in children with history of asymptomatic or mild COVID-19

https://doi.org/10.1002/ppul.25752

Published

6-Nov-21

Case Reports

https://onlinelibrary.wiley.com/doi/abs/10.1002/ppul.25752

Results
This study included 5 patients (median age, 4 years; age range, 0.8-9 years; 4 [80%] male). All had positive COVID-19 serology, 1 (20%) had mild symptoms, while the others had no symptoms of prior Sars-CoV-2 infection. 3 (60%) had asthma, and the remaining had no co-morbidities. All were admitted between April and May 2021. Two were re-admitted for respiratory symptoms in the subsequent three months.
Conclusions and Relevance
This case series describes a possible association between severe lower respiratory tract infection and prior mild COVID-19 in children. Larger cohort studies describing the respiratory effects of prior COVID-19 in children are needed.

_

2942

Ch77

Ieva Roge1*†, Liene Smane2†, Anda Kivite-Urtane3†, Zanda Pucuka2, Iveta Racko1, Lizete Klavina1 and Jana Pavare2†

Comparison of Persistent Symptoms After COVID-19 and Other Non-SARS-CoV-2 Infections in Children

https://doi.org/10.3389/fped.2021.752385

Published

29-Oct-21

Study

https://www.frontiersin.org/articles/10.3389/fped.2021.752385/full

Results: In total, 236 pediatric COVID-19 patients were enrolled in the study. Additionally, 142 comparison group patients were also enrolled. Median follow-up time from acute symptom onset was 73.5 days (IQR; 43–110 days) in the COVID-19 patient group and 69 days (IQR, 58–84 days) in the comparison group. Most pediatric COVID-19 survivors (70%, N = 152) reported at least one persistent symptom, but more than half of the patients (53%, N = 117) noted two or more long-lasting symptoms. The most commonly reported complaints among COVID-19 patients included persistent fatigue (25.2%), cognitive sequelae, such as irritability (24.3%), and mood changes (23.3%), as well as headaches (16.9%), rhinorrhea (16.1%), coughing (14.4%), and anosmia/dysgeusia (12.3%). In addition, 105 (44.5%) COVID patients had persistent symptoms after the 12-week cut-off point, with irritability (27.6%, N = 29), mood changes (26.7%, N = 28), and fatigue (19.2%, N = 20) being the most commonly reported ones. Differences in symptom spectrum among the various age groups were seen. Logistic regression analysis showed that long-term persistent symptoms as fever, fatigue, rhinorrhea, loss of taste and/or smell, headaches, cognitive sequelae, and nocturnal sweating were significantly associated with the COVID-19 experience when compared with the controls.
Conclusions: We found that at the time of interview almost three-quarters of children reported at least one persistent symptom, but the majority of patients (53%) had two or more concurrent symptoms. The comparison group's inclusion in the study allowed us to identify that symptom persistence is more apparent with COVID-19 than any other non-SARS-CoV-2 infection. More research is needed to distinguish the symptoms of long COVID from pandemic-associated complaints. Each persistent symptom is important in terms of child well-being during COVID-19 recovery.

2943

Ch78

Amit Nahum amitna@clalit.org.il and Keren Rochwerger-Biham

Unique presentations of the post COVID-19 infection, multisystem inflammatory syndrome in children.

https://doi.org/10.14785/lymphosign-2021-0027

Published

10-Nov-21

Case Reports

https://lymphosign.com/doi/abs/10.14785/lymphosign-2021-0027

We present two patients with unusual manifestations of MIS-C, related to post COVID-19 infection, an infant born to a mother who was severely ill at the very end of pregnancy, presenting with prolonged fever, rash, pericardial effusion, and evidence of coronary arteries wall thickening as a result of inflammation, and, a teenage girl with severe cardiac tamponade without the more common cardiac manifestations of myocardial involvement.Discussion: Post COVID-19 MIS-C can present in a wide variety of manifestations.

_

2944

Ch79

Thais T. Fink, Heloisa H.S. Marques, Bruno Gualano, Livia Lindoso, Vera Bain, Camilla Astley, Carlos A. Buchpiguel, Ana Claudia L. Xavier, Marilia Seelaender, Clovis Artur Silva,#* Maria Fernanda B. Pereira

Persistent symptoms and decreased health-related quality of life after symptomatic pediatric COVID-19: A prospective study in a Latin American tertiary hospital

https://dx.doi.org/10.6061%2Fclinics%2F2021%2Fe3511

Published

17-Nov-21

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8595593/

The median duration between COVID-19 diagnosis (n=53) and follow-up was 4.4 months (0.8-10.7). Twenty-three of 53 (43%) patients reported at least one persistent symptom at the longitudinal follow-up visit and 12/53 (23%) had long COVID-19, with at least one symptom lasting for >12 weeks. The most frequently reported symptoms at the longitudinal follow-up visit were headache (19%), severe recurrent headache (9%), tiredness (9%), dyspnea (8%), and concentration difficulty (4%). At the longitudinal follow-up visit, the frequencies of anemia (11% versus 0%, p=0.030), lymphopenia (42% versus 18%, p=0.020), C-reactive protein level of >30 mg/L (35% versus 0%, p=0.0001), and D-dimer level of >1000 ng/mL (43% versus 6%, p=0.0004) significantly reduced compared with baseline values. Chest X-ray abnormalities (11% versus 2%, p=0.178) and cardiac alterations on echocardiogram (33% versus 22%, p=0.462) were similar at both visits. Comparison of characteristic data between patients with COVID-19 at the longitudinal follow-up visit and controls showed similar age (p=0.962), proportion of male sex (p=0.907), ethnicity (p=0.566), family minimum monthly wage (p=0.664), body mass index (p=0.601), and pediatric pre-existing chronic conditions (p=1.000). The Pediatric Quality of Live Inventory 4.0 scores, median physical score (69 [0-100] versus 81 [34-100], p=0.012), and school score (60 [15-100] versus 70 [15-95], p=0.028) were significantly lower in pediatric patients with COVID-19 at the longitudinal follow-up visit than in controls.
CONCLUSIONS: Pediatric patients with COVID-19 showed a longitudinal impact on HRQoL parameters, particularly in physical/school domains, reinforcing the need for a prospective multidisciplinary approach for these patients. These data highlight the importance of closer monitoring of children and adolescents by the clinical team after COVID-19.

2945

Ch80

Arostegui, Dalia MD; Castro, Kenny MD; Schwarz, Steven MD; Vaidy, Katherine MD; Rabinowitz, Simon MD; Wallach, Thomas MD

Persistent SARS-CoV-2 Nucleocapsid Protein Presence in the Intestinal Epithelium of a Pediatric Patient 3 Months After Acute Infection

https://doi.org/10.1097/PG9.0000000000000152

Published

1-Nov-21

Case Report

https://journals.lww.com/jpgnr/Fulltext/2022/02000/Persistent_SARS_CoV_2_Nucleocapsid_Protein.9.aspx

In addition to the severe impact of acute respiratory disease during the SARS-CoV-2 pandemic, the issue of “Long COVID” illness has impacted large numbers of patients following the initial infection. Wide ranges of Long Covid incidence have been reported, ranging from 30 to 87%. Long COVID has a variety of clinical manifestations, including gastrointestinal symptoms. Here, we report a case of persistent abdominal pain, 3 months following a SARS-CoV-2 diagnosis, associated with chronic colonic inflammation and the presence of mucosal SARS-CoV-2 virions.

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2946

Ch81

S A Behnood 1, R Shafran 2, S D Bennett 2, Axd Zhang 2, L L O'Mahoney 3, T J Stephenson 2, S N Ladhani 4, B L DeStavola 2, R M Viner 2, O V Swann 5

Persistent symptoms following SARS-CoV-2 infection among children and young people: a meta-analysis of controlled and uncontrolled studies

https://doi.org/10.1016/j.jinf.2021.11.011

Published

20-Nov-21

Meta Analysis

https://pubmed.ncbi.nlm.nih.gov/34813820/

Twenty two of 3357 unique studies were eligible, including 23,141 CYP. Median duration of follow-up was 125 days (IQR 99-231). Pooled risk difference in post-COVID cases compared to controls (5 studies) were significantly higher for cognitive difficulties (3% (95% CI 1, 4)), headache (5% (1, 8)), loss of smell (8%, (2, 15)), sore throat (2% (1, 2)) and sore eyes (2% (1, 3)) but not abdominal pain, cough, fatigue, myalgia, insomnia, diarrhoea, fever, dizziness or dyspnoea. Pooled prevalence of symptoms in post-COVID participants in 17 studies ranged from 15% (diarrhoea) to 47% (fatigue). Age was associated with higher prevalence of all symptoms except cough. Higher study quality was associated with lower prevalence of all symptoms, except loss of smell and cognitive symptoms.

Interpretation: The frequency of the majority of reported persistent symptoms was similar in SARS-CoV-2 positive cases and controls. This systematic review and meta-analysis highlights the critical importance of a control group in studi7777es on CYP post SARS-CoV-2 infection.

2947

Ch82

Ashkenazi-Hoffnung, Liat MD*,†; Shmueli, Einat MD*,†; Ehrlich, Shay MD*,†; Ziv, Adi MD*,†; Bar-On, Ophir MD*,†; Birk, Einat MD*,†; Lowenthal, Alexander MD*,†; Prais, Dario MD*,†

Long COVID in Children
Observations From a Designated Pediatric Clinic

https://doi.org/10.1097/INF.0000000000003285

Published

1-Dec-21

Study

https://journals.lww.com/pidj/Fulltext/2021/12000/Long_COVID_in_Children__Observations_From_a.32.aspx

In nearly 60%, symptoms were associated with functional impairment at 1–7 months after the onset of infection. A comprehensive structured evaluation revealed mild abnormal findings in approximately half the patients, mainly in the respiratory aspect

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2948

Ch83

Sammie Mcfarland, Sara Citrenbaum, Ondine Sherwood, Vicky van der Togt, Jeremy S Rossman

Long COVID in children

https://doi.org/10.1016/S2352-4642(21)00338-2

Published

1-Jan-22

CORRESPONDENCE

https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00338-2/fulltext

According to the Methods section, the study appears to only assess children with a defined illness duration (onset and recovery). Recovery was defined as a return to asymptomatic condition or the cessation of symptom logging. As such, this would exclude all children with on-going disease and classify children that stop recording as recovered, even if they might still be experiencing symptoms. The authors tested their assumption that cessation of recording indicated recovery by removing those patients from their calculation and found no significant difference in long COVID prevalence or average symptom duration. However, if patients that ceased recording continued to experience symptoms, these longer duration symptoms would not be identified by the study and their effect would not be accounted for in the existing assumption test.
Additionally, the study excludes any children that either had a gap in recording or reported being asymptomatic for more than 1 week before symptoms returned. Patients with long COVID experience a wide range of changing symptoms, including asymptomatic periods. Many long COVID symptoms were added to the Zoe app in November, 2020, but were not included in the existing analysis. With only 77 (4·4%) of 1734 patients showing an illness duration of longer than 28 days, even small changes in patient numbers could result in substantial changes in prevalence. Due to the methods used, the study probably underestimates the actual prevalence of the disease in children.

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Deepti Gurdasani, Athena Akrami, Valerie C Bradley, Anthony Costello, Trisha Greenhalgh, Seth Flaxman, Martin McKee, Susan Michie, Christina Pagel, Sarah Rasmussen, Gabriel Scally, Christian Yates, Hisham Ziauddeen

Long COVID in children

https://doi.org/10.1016/S2352-4642(21)00342-4

Published

1-Jan-22

CORRESPONDENCE

https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00342-4/fulltext

First, only a limited number of symptoms reported in long COVID were assessed,1 with other symptoms only captured if parents entered them as free text. Given that logging of symptoms regularly is laborious, this is likely to underestimate persisting symptoms for longer periods of time. Some important symptoms, such as brain fog and low mood, were added to the list only later in the study, and not included in the main illness profile analysis, despite brain fog being reported in 11·3% (105 of 932) and low mood being reported in 15·6% (145 of 932) of older children (age 12 –17 years).1
• View related content for this article

Second, the study did not adequately account for the well-known relapsing and remitting nature of long COVID.3 Children with any gap in symptoms longer than 1 week were excluded,1 so children whose symptoms temporarily resolved for more than a week and then recurred, were not counted.1
Third, the duration estimates for long COVID are based on parents either reporting their child as asymptomatic with no symptoms for a week, or the last symptomatic report if parents stopped using the app.1 Use of cessation of proxy-logged symptom data to signal resolution is unlikely to be valid. The drop off in reporting for many parents could instead be related to ongoing illness in children and the demands of managing the needs of the child. Incomplete reporting was higher for children with confirmed infection (10·6%) than in children who had tested negative (3·5%).1 A much higher proportion ceased logging symptoms while still having ongoing symptoms (28·6% among those reporting symptoms for ≥28 days compared with 9·7% for those reporting symptoms for <28 days). This assumption of cessation of logging affects both the duration and prevalence estimates of long COVID. Given these data are probably missing not at random, excluding them (as in the authors’ sensitivity analysis) is also biased, underestimating the symptom duration.
Collectively, these factors all introduce bias in a single direction, namely, to underestimate the incidence and duration of long COVID. Given all factors, this underestimation might be substantial, which could partly explain why Molteni and colleagues’ estimates are at least 7 times lower than those of a recently published prospective large-scale study that allowed for remitting and relapsing symptoms, with follow-up at 3 months, 4 but similar to other studies that were limited in systematic assessment of common symptoms of long COVID (appendix).

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Erika Molteni, Sunil S Bhopal, Robert C Hughes, Michael Absoud, Emma L Duncan

Long COVID in children – Authors' reply

https://doi.org/10.1016/S2352-4642(21)00344-8

Published

1-Jan-22

CORRESPONDENCE

https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00344-8/fulltext

We disagree that proxy-logging via smartphone is laborious, noting here the high assiduousness (mostly daily) and persistence (>90%) of proxy-reporting. We share concern that proxy-logging cessation before a healthy report might affect results, hence our sensitivity analyses, which included counting all children who had symptoms for at least 4 weeks (LC28) even if logging subsequently ceased, and estimates remained within confidence intervals. When discontinuation occurred, it was mostly at a time concomitant with median illness duration. If all 161 early-cessation children ultimately had LC28, our estimates would increase. However, if LC28 rates were proportionate to the more than 90% of children logged until healthy, seven extra LC28 cases would result, giving LC28 rates of 84 (4·8%) of 1734 children, which is still within our confidence intervals.
We allowed for up to a week of logging as asymptomatic (or healthy) within a child's total illness duration, a choice which was informed by the following: (1) this threshold was as previously published;7 (2) the median duration of illness in children with COVID-19 is less than 7 days; and (3) as wellness periods lengthen between illness episodes it becomes increasingly difficult to attribute with clinical confidence later episodes of illness to initial infection. Here, standardising post-COVID syndromes definitions in children will help future research.
We disagree with Gurdasani and colleagues that our estimates are seven-fold lower than the CLOCK study. The CLOCK study4 reported 66·5% positively tested and 53·4% negatively tested children had at least one symptom for 3 months post-infection, a risk ratio of 1·25, an extremely modest risk. If we use the same criteria, at 4 weeks our risk ratio was 5·1. Importantly, both CLOCK4 and the ONS1 showed high symptom prevalence in children testing negative, presumably capturing both effects of other illnesses and the pandemic.
We reiterate our conclusion that “a holistic approach for all children with persistent illness during the pandemic is appropriate”, irrespective of whether the illness is caused by SARS-CoV-2.3

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María Bergia, Elena Sanchez-Marcos, Blanca Gonzalez-Haba, Ana Isabel Hernaiz, María de Ceano-Vivas, Milagros García López-Hortelano, María Luz García García, Raquel Jimenez-García, Cristina Calvo

Study of Prevalence and Characteristics of Long Covid in Spanish Children

https://doi.org/10.21203/rs.3.rs-1068678/v1

pre-print

14-Dec-21

RESEARCH ARTICLE

https://www.researchsquare.com/article/rs-1068678/v1

Results
451 children met criteria and agreed to participate; 370/451 (82%) presented mild outpatient infection, and 23 required admission in PICU (5.1%). The mean age was 5.9 years old (SD 5.3). A control group of 98 children was included.
In 66 cases (14.6%) at least one symptom lasted longer than 12 weeks. Insomnia, concentration problems, apathy or sadness and anxiety were the longest (median >90 days). Age above 5 years (48/66; 72.7%, OR: 3, CI 95% (1.8-5)); admission (OR 3.9 CI 95% (2.2-6.8)), the need for PICU (OR 4.3 CI 95% (1.8-10.4)), and to have a relative with prolonged symptoms (OR 2.8 CI 95% (1.5-5.2)) were significantly associated with Long-COVID. When comparing with controls age above 5 years old, myalgia, asthenia, and loss of appetite were significantly associated with Long-COVID.

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Andrea Lo Vecchio, MD, PhD1; Silvia Garazzino, MD2; Andrea Smarrazzo, MD3; Elisabetta Venturini, MD4; Marco Poeta, MD1; Paola Berlese, MD5; Marco Denina, MD2; Antonella Meini, MD6; Raffaele Badolato, MD6; Alberto Villani, MD3; Alfredo Guarino, MD1; Guido Castelli Gattinara, MD3;

Factors Associated With Severe Gastrointestinal Diagnoses in Children With SARS-CoV-2 Infection or Multisystem Inflammatory Syndrome

https://doi.org/10.1001/jamanetworkopen.2021.39974

Published

20-Dec-21

Study

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2787258

Findings In this multicenter cohort study of 685 Italian children with COVID-19, 10% showed severe gastrointestinal involvement characterized by diffuse adeno-mesenteritis, appendicitis, abdominal fluid collection, ileal intussusception, or pancreatitis. Children older than 5 years and those presenting with abdominal pain, leukopenia, or receiving a diagnosis of multisystem inflammatory syndrome were more likely to have severe gastrointestinal manifestations.
Meaning Severe gastrointestinal involvement is not uncommon in children with COVID-19, and awareness about its frequency and presentation may help practitioners to appropriately manage children at risk of severe outcomes.

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Amal El Ouarradi,1,& Ilham Bensahi,1 Insaf Alaammari,2 Amal Haoudar,3 Nezha Dini,4 et Mohamed Sabry1

Les complications thromboemboliques chez les enfants au cours de COVID-19
Thromboembolic complications in children during COVID-19

https://dx.doi.org/10.11604%2Fpamj.2021.40.137.31979

Published

4-Nov-21

Case Report

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8641641/

Les complications thromboemboliques chez les enfants émergent dans l´ère de COVID-19, on rapporte cette lettre pour attirer l´attention sur ces complications, leurs incidences, le diagnostic et la prise en charge et surtout l´intérêt de l´anticoagulation préventive chez cette population fragile. Il existe de nombreuses différences entre les enfants et les adultes en ce qui concerne la prévalence, la gravité et les complications de l´infection COVID-19. Le pourcentage d'enfants touchés par la COVID-19 est beaucoup plus faible que celui des adultes et ils ont tendance à présenter des symptômes plus légers et une morbidité et une mortalité significativement plus faibles [1,2]. Bien que l'on ait beaucoup appris sur les taux et les risques de complications thromboemboliques (TE) chez les adultes, on en sait relativement peu sur ce problème dans la population pédiatrique. L'incidence globale de la COVID-19 et de la thrombose est nettement inférieure chez les enfants, ce qui a ajouté des défis à l'étude de cette condition dans ce groupe d'âge [3].

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Kendall Howard 1,2,Taylor Williams 2,Elizabeth Fitch 2,Heather Ots 2,Esther Pototskiy 1 ,Jay Hawkshead 3,Zelda Ghersin 4 andAlberto E. Musto 1

Neurologic Complications in Adult and Pediatric Patients with SARS-CoV-2 Infection

https://doi.org/10.3390/ctn6010001

Published

23-Dec-21

Review

https://www.mdpi.com/2514-183X/6/1/1/htm

Although the mechanism is still unclear, SARS-CoV-2 has been associated with the pathogenesis of intravascular coagulation and angiotensin-converting enzyme-I, both exacerbating systemic inflammation and contributing to hypercoagulation or blood–brain barrier leakage, resulting in ischemic or hemorrhagic stroke. On the other hand, the SARS-CoV-2 spike protein in neural tissue and within the cerebrospinal fluid may induce neural dysfunction, resulting in neuroinflammation, which is exacerbated by peripheral and neural hypercytokinemia that can lead to neuronal damage and subsequent neuroinflammation. A deeper understanding of the fundamental biological mechanisms of neurologic manifestations in SARS-CoV-2 infection can pave the way to identifying a single biomarker or network of biomarkers to help target neuroprotective therapy in patients at risk for developing neurological complications.

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Howard J. Heching Anmol Goyal, Brian Harvey, Lindsey Malloy-Walton,
Christopher Follansbee, Amanda Mcintosh and Daniel Forsha

Electrocardiographic changes in non-hospitalised children with COVID-19

https://doi.org/10.1017/S1047951121005138

Published

6-Jan-22

Study

https://www.cambridge.org/core/journals/cardiology-in-the-young/article/abs/electrocardiographic-changes-in-nonhospitalised-children-with-covid19/76AD6BD372C45F70BEB6963BAB07A468

Of the 82 children meeting inclusion criteria (14.4 years, range 1–18 years, 57% male), 17 patients (21%) demonstrated electrocardiographic changes. Ten patients (12%) had electrocardiogram of borderline significance, which included isolated mild PR prolongation or mild repolarisation abnormalities. The other seven patients (9%) had concerning electrocardiographic findings consisting of more significant repolarisation abnormalities. None of the patients with an abnormal electrocardiogram revealed any echocardiographic abnormality. All abnormal electrocardiograms normalised over time except in two cases. Across the entire cohort, greater COVID-19 disease severity and long COVID were not associated with electrocardiographic abnormalities.

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Rupesh Raina,Sidharth Kumar Sethi,Ronith Chakraborty,Siddhartha Singh,Sharon Teo,Amrit Khooblall,Giovanni Montini,Timothy Bunchman,Rezan Topaloglu,Hui Kim Yap

Blood Filters in Children with COVID-19 and AKI: A Review

https://doi.org/10.1111/1744-9987.13793

Published

8-Jan-22

Review

https://onlinelibrary.wiley.com/doi/abs/10.1111/1744-9987.13793

Although pediatric patients only comprise 1-2% of diagnosed cases, their incidence of acute kidney injury ranges from 8.2% to 18.2% compared to 49% in adults. Severe infection, initiated by dysregulated host response, can lead to multiorgan failure. In this review, we focus on the use of various blood filters approved for use in pediatric kidney replacement therapy to mitigate adverse effects of severe illness. Therapeutic effects of these blood filters range from cytokine removal (CytoSorb, HA330, HCO/MCO), endotoxin removal (Toraymyxin, CPFA), both cytokine and endotoxin removal (oXiris), and non-specific removal of proteins (PMMA) that have already been established and can be used to mitigate the various effects of the cytokine storm syndrome in COVID-19.

2957

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Luise Borch, Mette Holm, Maria Knudsen, Svend Ellermann-Eriksen & Soeren Hagstroem

Long COVID symptoms and duration in SARS-CoV-2 positive children — a nationwide cohort study

https://doi.org/10.1007/s00431-021-04345-z

Published

9-Jan-22

Study

https://link.springer.com/article/10.1007/s00431-021-04345-z

Most children have a mild course of acute COVID-19. Only few mainly non-controlled studies with small sample size have evaluated long-term recovery from SARS-CoV-2 infection in children. The aim of this study was to evaluate symptoms and duration of ‘long COVID’ in children. A nationwide cohort study of 37,522 children aged 0–17 years with RT-PCR verified SARS-CoV-2 infection (response rate 44.9%) and a control group of 78,037 children (response rate 21.3%). An electronic questionnaire was sent to all children from March 24th until May 9th, 2021. Symptoms lasting > 4 weeks were common among both SARS-CoV-2 children and controls. However, SARS-CoV-2 children aged 6–17 years reported symptoms more frequently than the control group (percent difference 0.8%). The most reported symptoms among pre-school children were fatigue Risk Difference (RD) 0.05 (CI 0.04–0.06), loss of smell RD 0.01 (CI 0.01–0.01), loss of taste RD 0.01 (CI 0.01–0.02) and muscle weakness RD 0.01 (CI 0.00–0.01). Among school children the most significant symptoms were loss of smell RD 0.12 (CI 0.12–0.13), loss of taste RD 0.10 (CI 0.09–0.10), fatigue RD 0.05 (CI 0.05–0.06), respiratory problems RD 0.03 (CI 0.03–0.04), dizziness RD 0.02 (CI 0.02–0.03), muscle weakness RD 0.02 (CI 0.01–0.02) and chest pain RD 0.01 (CI 0.01–0.01). Children in the control group experienced significantly more concentration difficulties, headache, muscle and joint pain, cough, nausea, diarrhea and fever than SARS-CoV-2 infected. In most children ‘long COVID’ symptoms resolved within 1–5 months.
Conclusions: Long COVID in children is rare and mainly of short duration.

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Nicola Principi & Susanna Esposito

Reasons in favour of universal vaccination campaign against COVID-19 in the pediatric population

https://doi.org/10.1186/s13052-021-01192-4

Published

10-Jan-22

Debate

https://ijponline.biomedcentral.com/articles/10.1186/s13052-021-01192-4

The aim of this manuscript is to explain the reasons for overcoming hesitancy towards COVID-19 vaccination in children and adolescents and to highlight the importance of universal COVID-19 vaccination in the pediatric population.
Main findings
Recent epidemiological data suggest that the risk that a child with COVID-19 is hospitalized or admitted to the pediatric intensive care unit is greater than initially thought. Children may also suffer from long COVID and school closure because of COVID-19 can cause relevant mental health problems in the pediatric population. Placebo-controlled, observer-blinded, clinical trials showed appropriate efficacy, safety and tolerability of authorized mRNA COVID-19 vaccines in children and adolescents 12–17 years old. Vaccination in children younger than 12 years of age will allow further benefits .
Conclusions
COVID-19 vaccine administration seems mandatory in all the children and adolescents because of COVID-19 related complications as well as the efficacy, safety and tolerability of COVID-19 vaccines in this population. Due to the recent approval of COVID-9 vaccines for children 5–10 years old, it is desirable that vaccine opponents can understand how important is the universal immunization against COVID-19 for the pediatric subjects.

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Stephanie Enner, MD*, Yash D. Shah, MD MPH*, Aaqil Ali, BS, Jane E. Cerise, PhD, Justin Esposito, Lorry Rubin, MD, Anupama Subramony, MD, MBA, Sanjeev Kothare, MD, FAAN

Patients Diagnosed with Multisystem Inflammatory Syndrome in Children Have Persistent Neurologic, Sleep, and Psychiatric Symptoms After Hospitalization

https://doi.org/10.1177%2F08830738221075924

Published

24-Jan-22

Study

https://journals.sagepub.com/doi/abs/10.1177/08830738221075924

Methods: We conducted a single-center retrospective chart review and cross-sectional survey of patients diagnosed with MIS-C. Patients and parents were surveyed on symptoms before the COVID-19 pandemic, upon admission, and 23 weeks (interquartile range 20-26 weeks) after discharge. Age and gender-matched patients requiring intensive care unit (ICU) care for status asthmaticus were surveyed as a control group. Results: In this cohort of 47 patients, 77% reported neurological, 60% psychiatric, and 77% sleep symptoms during hospitalization. Prior to hospitalization, 15% reported neurological, 0% psychiatric, and 7% sleep symptoms. Eighteen (50%) of the 36 patients who had neurological symptoms during hospitalization continued to have symptoms on follow-up (odds ratio [OR] = ∞, p = .003]). Similarly, 16 (57%) of 28 patients with psychiatric symptoms reported persistence at follow-up (OR = 5.00; p = .02). Fifteen (42%) of the 18 patients reporting sleep disturbance during hospitalization had persistence on follow-up (OR = 1.9; p = .49). The aggregate of neurological, psychiatric, and sleep symptoms during admission and at follow-up was significantly higher for MIS-C patients requiring ICU care when compared to the control group (p = .01). Conclusions: In this cohort of patients with MIS-C, a majority of patients reported new-onset neuropsychiatric and sleep symptoms. Almost half of these patients had persistent symptoms on a follow-up survey.

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Petra Zimmermann, Laure F Pittet

Long covid in children and adolescents

https://doi.org/10.1136/bmj.o143

Published

20-Jan-22

Editorial

https://www.bmj.com/content/376/bmj.o143

Risk appears low, but many questions remain
Symptoms involving almost every organ system have been reported after SARS-CoV-2 infection.123 Estimates of the prevalence of long covid (also called post-covid-19 condition, post-acute sequelae of covid-19, or chronic covid syndrome) vary considerably, partly because of confusion around the definition. The term long covid encompasses a broad range of symptoms, including objective complications of covid-19 (pulmonary fibrosis, myocardial dysfunction), mental health conditions, and more subjective, non-specific symptoms resembling those seen in post-viral chronic fatigue syndrome (myalgic encephalomyelitis). Most studies to date have substantial limitations, including small cohorts, absence of control groups, non-standardised capture of symptoms, lack of correction for pre-existing medical conditions, participant reported infection, and variation in follow-up, as well as selection, non-response, misclassification, and recall biases.4
In children and adolescents, acute covid-19 is less severe than in adults.56 Concern among many parents has therefore focused more on the potential long term effects of SARS-CoV-2 infection. Unfortunately, fewer data are available on long covid in young people compared with adults.7 The widely quoted one in seven frequency in children is based on a study with a 13% response rate.78
The linked study by Magnusson and colleagues (doi:10.1136/bmj-2021-066809) used nationwide register data from Norway to estimate the impact of covid-19 on long term healthcare use among 1.3 million children and adolescents.9 The authors identified a short term increase in primary (but not specialist) care use after covid-19 in all the studied age groups. This increase was related to respiratory and general or non-specific conditions, mostly in the four weeks after infection. The increase in primary care use persisted for up to six months among children aged 1-5 years. Notably, covid-19 in children had limited overall impact on healthcare services.
The linked study by Magnusson and colleagues (doi:10.1136/bmj-2021-066809) used nationwide register data from Norway to estimate the impact of covid-19 on long term healthcare use among 1.3 million children and adolescents.9 The authors identified a short term increase in primary (but not specialist) care use after covid-19 in all the studied age groups. This increase was related to respiratory and general or non-specific conditions, mostly in the four weeks after infection. The increase in primary care use persisted for up to six months among children aged 1-5 years. Notably, covid-19 in children had limited overall impact on healthcare services.
The study’s strengths include its population based design, the inclusion of SARS-CoV-2 negative and non-tested control groups, and comparison with pre-pandemic healthcare use. An unavoidable limitation is that asymptomatic children or those with mild symptoms might not have been tested. Also, changes in testing patterns could have occurred in different age groups and over time, and children testing positive for SARS-CoV-2 might also have had greater exposure to other respiratory viruses. Finally, the anxiety surrounding this previously unknown infection in children might have caused primary care providers and parents to schedule unnecessary follow-up visits after a positive test result.
Magnusson and colleagues’ study highlights the difficulty of accurately determining risk of long covid in children and adolescents, and the urgent need for further rigorous studies. Reports suggest that more than half of children who did not have covid-19 experienced symptoms such as headaches, fatigue, sleep disturbance, and concentration difficulties during the pandemic.7 Distinguishing long term symptoms caused by SARS-CoV-2 infection from pandemic related symptoms remains a challenge. One large study in the UK found that nearly all symptoms reported by children who tested positive for SARS-CoV-2 were also reported by those who tested negative.7 Moreover, no difference was reported between the two groups in mental health, overall wellbeing, or impairment of activities. Other studies with control groups have also reported minimal differences in persisting symptoms between children with SARS-CoV-2 infection and those without.4 This underlines the importance of appropriate control groups, including children with other infections and those admitted to hospital for other reasons.

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Hirt

Prof Sir Terence Stephenson, DM
Snehal M Pinto Pereira, PhD
Prof Roz Shafran, PhD
Prof Bianca L de Stavola, PhD
Natalia Rojas
Kelsey McOwat, MSc
Ruth Simmons, PhD
Maria Zavala, MPH
Lauren O'Mahoney, PhD
Prof Trudie Chalder, PhD
Prof Esther Crawley, PhD
Prof Tamsin J Ford, PhD
Prof Anthony Harnden, FRCGP
Prof Isobel Heyman, PhD
Olivia Swann, PhD
Elizabeth Whittaker, PhD
CLoCk Consortium
Prof Shamez N Ladhani, PhD

Physical and mental health 3 months after SARS-CoV-2 infection (long COVID) among adolescents in England (CLoCk): a national matched cohort study

https://doi.org/10.1016/S2352-4642(22)00022-0

Published

7-Feb-22

Study

https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(22)00022-0/fulltext

23 048 adolescents who tested positive and 27 798 adolescents who tested negative between Jan 1, 2021, and March 31, 2021, were contacted, and 6804 adolescents (3065 who tested positive and 3739 who tested negative) completed the questionnaire (response rate 13·4%). At PCR testing, 1084 (35·4%) who tested positive and 309 (8·3%) who tested negative were symptomatic and 936 (30·5%) from the test-positive group and 231 (6·2%) from the test-negative group had three or more symptoms. 3 months after testing, 2038 (66·5%) who tested positive and 1993 (53·3%) who tested negative had any symptoms, and 928 (30·3%) from the test-positive group and 603 (16·2%) from the test-negative group had three or more symptoms. At 3 months after testing, the most common symptoms among the test-positive group were tiredness (1196 [39·0%]), headache (710 [23·2%]), and shortness of breath (717 [23·4%]), and among the test-negative group were tiredness (911 [24·4%]), headache (530 [14·2%]), and other (unspecified; 590 [15·8%]). Latent class analysis identified two classes, characterised by few or multiple symptoms. The estimated probability of being in the multiple symptom class was 29·6% (95% CI 27·4–31·7) for the test-positive group and 19·3% (17·7–21·0) for the test-negative group (risk ratio 1·53; 95% CI 1·35–1·70). The multiple symptoms class was more frequent among those with positive PCR results than negative results, in girls than boys, in adolescents aged 15–17 years than those aged 11–14 years, and in those with lower pretest physical and mental health.
Interpretation
Adolescents who tested positive for SARS-CoV-2 had similar symptoms to those who tested negative, but had a higher prevalence of single and, particularly, multiple symptoms at the time of PCR testing and 3 months later. Clinicians should consider multiple symptoms that affect functioning and recognise different clusters of symptoms. The multiple and varied symptoms show that a multicomponent intervention will be required, and that mental and physical health symptoms occur concurrently, reflecting their close relationship.

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Ilaria Viganò*, Chiara Vannicola*, Maria Paola Canevini

Neurology of COVID-19 - Neuro-Covid in Children

https://doi.org/10.54103/milanoup.57

Published

1-Feb-22

Review

https://air.unimi.it/retrieve/handle/2434/897181/1962512/57-Capitolo%20di%20volume-581-1-10-20211117.pdf

Neurological manifestations in children with HCoV are relatively rare, therefore there is little information about neurodevelopmental sequelae. However, cases of neurological disease associated with SARS-CoV-2 infections in children are rapidly emerging, suggesting a possible greater neurological involrement in the pediatric population affected by this virus than in other HCoVs. Only à small fraction of children affected by SARS-CoV-2 showed neurological manifestations such as seizures, encephalitis, stroke or neuropathies!, In most cases, severe neurological manifes-
tations in the pediatric population appeared to be associated with the presence of Mültisystem Inflammatory Syndrome (MIS-C). À review conducted by Chen in 2020 considering 187 children from the six latest reports of MIS-C cases showed that 34% suffered from neurological manifestations!##. Of the 187 children studied, 64 had different neurological symptoms, most of which were headaches, positive meningeal signs (meningism), and altered mental status; taken together, most manifestations represent a central, rather than a peripheral involvement.
Neurological symptoms are thought to be secondary to a combination of different mechanisms, including the direct viral effect on the nervous system, the para- and post-infectious inflammation, and the neurological complications of the systemic effects of COVID-19.

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Siberry, Vikram G. R. MS*,†; Rowe, Peter C. MD*,†

Pediatric Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Overlaps and Opportunities

https://doi.org/10.1097/INF.0000000000003477

Published

4-Feb-22

Article

https://journals.lww.com/pidj/Citation/9000/Pediatric_Long_COVID_and_Myalgic.95546.aspx

The absence of an organized and robust clinical infrastructure for managing pediatric and adult ME/CFS has adversely affected the care of those with ME/CFS in the United States and elsewhere. Patients with ME/CFS at all ages have reported difficulty obtaining direct care. Unlike the situation in HIV and pediatric cancer, there is no coordinated network of centers that could participate in ME/CFS clinical trials. A corollary of this underdevelopment has meant that resources for managing the many people who have developed long COVID were scarce from the start of the pandemic. While post-COVID clinics are starting to emerge, it will be an important part of managing this and planning for future pandemics that we ensure these clinical efforts succeed. It would only be just and equitable to ensure that those with nonpandemic ME/CFS have similar access to care.

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Keerthi Thallapureddy, Khyathi Thallapureddy, Erika Zerda, Neeraj Suresh, Deepak Kamat, Karthik Rajasekaran & Alvaro Moreira

Long-Term Complications of COVID-19 Infection in Adolescents and Children

https://doi.org/10.1007/s40124-021-00260-x

Published

1-Feb-22

Review

https://link.springer.com/article/10.1007/s40124-021-00260-x

Recent Findings
Children were less likely to develop long COVID when compared to adults. Older children (e.g., adolescents) and those who had symptomatic COVID-19 had a higher probability for long COVID.
Summary
Families and health care providers need to be aware of a new constellation of long COVID symptoms in the pediatric population. More evidence and time are needed to better understand the potential effects of long COVID-19 in children and adolescents. In comparison to adults, children are less likely to have persistent COVID-19 symptoms.

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ProfSelinaKikkenborg BergPhDadProfSusanneDam NielsenDMScbdUlrikkaNygaardPhDcdProfHenningBundgaardDMScadPernillePalmPhDaCamillaRotvigMScaAnneVinggaard ChristensenPhDa

Long COVID symptoms in SARS-CoV-2-positive adolescents and matched controls (LongCOVIDKidsDK): a national, cross-sectional study

https://doi.org/10.1016/S2352-4642(22)00004-9

Published

8-Feb-22

Study

https://www.sciencedirect.com/science/article/pii/S2352464222000049

Findings
24 315 adolescents with a positive SARS-CoV-2 test (case group) and 97 257 matched controls were invited to participate. 3013 matched controls were excluded because of suspected SARS-CoV-2 infection. 6630 (27·3%) responded in the case group and 21 640 (22·3%) responded and were eligible to participate in the control group. Across both groups, median age was 17·6 years (IQR 16·4–18·5), 16 277 (57·6%) of 28 270 responders were female, and 11 993 (42·4%) were male. Participants in the case group had greater odds of having at least one long COVID symptom lasting at least 2 months compared with the control group (3159 [61·9%] vs 12 340 [57·0%], odds ratio 1·22 [95% CI 1·15–1·30]; p<0·0001). Participants in the case group reported significantly lower symptom scores (ie, less somatic distress) on the CSSI-24 than in the control group: mean 10·7 (SD 11·4, median 7·0 [IQR 2·0–15·0]) versus 11·9 (10·6, 9·0 [4·0–17·0]; p<0·0001). Participants in the case group had better quality of life scores on the PedsQL than in the control group: physical functioning mean score 88·7 (SD 13·9, median 93·8 [IQR 84·4–100·0]) versus 86·5 (14·3, 90·6 [81·3–96·9]; p<0·0001); emotional functioning 77·1 (20·3, 80·0 [65·0–95·0]) versus 71·7 (21·4, 75·0 [60·0–90·0]; p<0·0001); social functioning 93·1 (12·5, 100·0 [90·0–100·0]) versus 88·4 (16·2, 95·0 [80·0–100·0]; p<0·0001); and school functioning 66·9 (22·5, 65·0 [60·0–85·0]) versus 62·9 (22·1, 65·0 [50·0–80·0]; p<0·0001). More participants in the case group than in the control group reported 16 or more sick days (1205 [18·2%] vs 2518 [11·6%]; p<0·0001) and 16 or more days of school absence (695 [10·5%] vs 1777 [8·2%]; p<0·0001).
Interpretation
Participants with SARS-CoV-2-positive tests had more long-lasting symptoms and sick leave, whereas participants in the control group had more short-lasting symptoms and worse quality of life. Knowledge of long COVID in adolescents is important to guide clinical recognition and management of this condition.

2966

Ch101

Hirt (publication of Ch96 and Ch64)

Prof SirTerenceStephensonDMaSnehal MPinto PereiraPhDbProfRozShafranPhDaProfBianca Lde StavolaPhDaNataliaRojasaKelseyMcOwatMSccRuthSimmonsPhDcMariaZavalaMPHcLaurenO'MahoneyPhDdProfTrudieChalderPhDeProfEstherCrawleyPhDfProfTamsin JFordPhDgProfAnthonyHarndenFRCGPhProfIsobelHeymanPhDaOliviaSwannPhDiElizabethWhittakerPhDj

Physical and mental health 3 months after SARS-CoV-2 infection (long COVID) among adolescents in England (CLoCk): a national matched cohort study

https://doi.org/10.1016/S2352-4642(22)00022-0

Published

8-Feb-22

Study

https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(22)00022-0/fulltext

23 048 adolescents who tested positive and 27 798 adolescents who tested negative between Jan 1, 2021, and March 31, 2021, were contacted, and 6804 adolescents (3065 who tested positive and 3739 who tested negative) completed the questionnaire (response rate 13·4%). At PCR testing, 1084 (35·4%) who tested positive and 309 (8·3%) who tested negative were symptomatic and 936 (30·5%) from the test-positive group and 231 (6·2%) from the test-negative group had three or more symptoms. 3 months after testing, 2038 (66·5%) who tested positive and 1993 (53·3%) who tested negative had any symptoms, and 928 (30·3%) from the test-positive group and 603 (16·2%) from the test-negative group had three or more symptoms. At 3 months after testing, the most common symptoms among the test-positive group were tiredness (1196 [39·0%]), headache (710 [23·2%]), and shortness of breath (717 [23·4%]), and among the test-negative group were tiredness (911 [24·4%]), headache (530 [14·2%]), and other (unspecified; 590 [15·8%]). Latent class analysis identified two classes, characterised by few or multiple symptoms. The estimated probability of being in the multiple symptom class was 29·6% (95% CI 27·4–31·7) for the test-positive group and 19·3% (17·7–21·0) for the test-negative group (risk ratio 1·53; 95% CI 1·35–1·70). The multiple symptoms class was more frequent among those with positive PCR results than negative results, in girls than boys, in adolescents aged 15–17 years than those aged 11–14 years, and in those with lower pretest physical and mental health.
Interpretation
Adolescents who tested positive for SARS-CoV-2 had similar symptoms to those who tested negative, but had a higher prevalence of single and, particularly, multiple symptoms at the time of PCR testing and 3 months later. Clinicians should consider multiple symptoms that affect functioning and recognise different clusters of symptoms. The multiple and varied symptoms show that a multicomponent intervention will be required, and that mental and physical health symptoms occur concurrently, reflecting their close relationship.

2967

Ch102

MIS-C

A Spanaki, O Miller, J Wong, K Pushparajah, P Theocharis

Long term non-invasive endothelial function assessment in patients with paediatric inflammatory multisystem syndrome temporarily associated with Covid 19 (PIMS TS)

https://doi.org/10.1093/ehjci/jeab289.314

Published

4-Feb-22

Study

https://academic.oup.com/ehjcimaging/article/23/Supplement_1/jeab289.314/6522472?login=true

Introduction
Patients with PIMS-TS present with features of vasculitis (bright coronary arteries and diffuse coronary ectasia on transthoracic echocardiography) and prothrombotic features (e.g. elevated D Dimers) indicating involvement of the endothelial layer in the inflammatory process. Impairment in endothelial function may contribute to the acute but also to possible long-term consequences in patients with PIMS-TS. The aim of this pilot study is to assess non-invasively the endothelial (dys)function using reactive hyperemic peripheral arterial tonometry (RH-PAT) 6 months after the acute inflammatory phase.
Methods
Ten patients with previous diagnosis of PIMS-TS were compared to age-matched controls. The endothelial function was assessed using the EndoPAT device which provides the reactive hyperemic index (RHI) of endothelial function in a 15-min test. Cardiac function indices by means of LV fractional shortening (FS) was also assessed.
Results
There were no significant differences regarding age (11.2 ± 3.0 vs 13.6 ± 2.4, p = 0.063), height, weight and body surface area, (BSA: 1.49 ± 0.36 vs 1.52 ± 0.25, p = 0.856) in patients with previous diagnosis of PIMS-TS and controls respectively. The two groups also had similar LV systolic function assessed by FS (36.3 ± 9.1% vs 36.7 ± 7.1%, p = 0.922). The RHI in the PIMS TS group was similar to the control group (1.65 ± 0.43 vs 1.81 ± 0.60, p = 0.533 respectively).
Conclusions. Patients with PIMS-TS who may present with features of vasculitis during the acute phase, do not show evidence of endothelial dysfunction during the long term follow-up, suggesting resolution. Further studies are required to accurately determine the endothelial (dys)function during the acute phase of the inflammatory syndrome and course.

2968

Ch103

Siberry, Vikram G. R. MS*,†; Rowe, Peter C. MD*,†

Pediatric Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Overlaps and Opportunities

https://doi.org/10.1097/INF.0000000000003477

Published

4-Feb-22

Article

https://journals.lww.com/pidj/Citation/9000/Pediatric_Long_COVID_and_Myalgic.95546.aspx

David Spodick once wrote: “We must view published material critically (if not biblically), for too often the ‘Conclusions’ giveth, but the ‘Materials and Methods’ taketh away.” In the December 2021 issue of the Pediatric Infectious Diseases Journal, Zimmermann et al1 provide a masterful application of Spodick’s
exhortation. Their review of the existing evidence regarding long COVID in children enumerates important methodologic challenges in interpreting this literature, including the heterogeneity of available case definitions for long COVID, differences in the time intervals in which symptoms are ascertained, variability regarding which symptoms are included under the rubric of long COVID, and whether laboratory confirmation of the initial COVID infection is required. Additionally, the authors emphasize that without control groups in many of these studies, and in light of the overlap of some long COVID symptoms with symptoms of prolonged social isolation, it is difficult to discern which symptoms are attributable to the general pandemic circumstances rather than the COVID-19 infection itself. Despite such limitations, it is clear that pediatric patients are at risk for prolonged symptoms following acute SARS-CoV-2 infection. Although many persistent symptoms, such as anosmia, dysgeusia and shortness of breath are unique to the post-COVID state, many other symptoms such as fatigue, cognitive dysfunction, lightheadedness and postexertional malaise overlap with symptoms found in myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). In this commentary, we review case definitions for long COVID and ME/CFS, emphasize recent research findings on the biologic basis of ME/CFS, discuss the overlap with long COVID, and consider opportunities posed by the pandemic to improve the understanding of both conditions.

2969

Ch104

Michela Gatta, Alessia Raffagnato, Federica Mason, Rachele Fasolato, Annalisa Traverso, Silvia Zanato & Marina Miscioscia

Sociodemographic and clinical characteristics of paediatric patients admitted to a neuropsychiatric care hospital in the COVID-19 era

https://doi.org/10.1186/s13052-022-01213-w

Published

5-Feb-22

Study

https://link.springer.com/article/10.1186/s13052-022-01213-w

Results
Risk factors associated with mental health disorders were similar between the two years. The hospitalisation modality showed a decrease in scheduled hospitalisations compared to urgent ones, and among the reasons that led patients to hospitalisation there was a conspicuous increase in eating disorders. More suicidal and self-harming behaviours occurred in the COVID-19 group too, compared to the previous year. The methods used to attempt suicide were changed considerably, with a prevalence of that attempted within the home. Changes in pharmacological therapies also occurred, necessary for more than 80% of inpatients during the COVID year, with a greater use of neuroleptics. There were alarming data about hospitalisation relapses, which increased from 12.2% in the pre-COVID year to 35.0% in the COVID year.
Conclusion
Data shed light on clinical and policy issues in mental health care during the developmental age. Since the COVID-19 health emergency is not yet over, and its effects, especially on mental health, will be long-term, it is necessary to implement services and activities dedicated to both primary and secondary prevention of neuropsychiatric diseases especially during adolescent ages.

2970

Ch105

Janet Chou, Paul G. Thomas & Adrienne G. Randolph

Immunology of SARS-CoV-2 infection in children

https://doi.org/10.1038/s41590-021-01123-9

Published

1-Feb-22

Review

https://www.nature.com/articles/s41590-021-01123-9

Children and adolescents exhibit a broad range of clinical outcomes from SARS-CoV-2 infection, with the majority having minimal to mild symptoms. Additionally, some succumb to a severe hyperinflammatory post-infectious complication called multisystem inflammatory syndrome in children (MIS-C), predominantly affecting previously healthy individuals. Studies characterizing the immunological differences associated with these clinical outcomes have identified pathways important for host immunity to SARS-CoV-2 and innate modulators of disease severity. In this Review, we delineate the immunological mechanisms underlying the spectrum of pediatric immune response to SARS-CoV-2 infection in comparison with that of adults.

2971

Ch106

Rafael Heiss, Alexandra L Wagner, Lina Tan, Sandy Schmidt, Adrian P. Regensburger, Franziska Ewert, Dilbar Mammadova, Adrian Buehler, Jens Vogel-Claussen, Andreas Voskrebenzev, Oliver Rompel, Armin M. Nagel, Simon Levy, Sebastian Bickelhaupt, Matthias S. May, Michael Uder, Markus Metzler, Regina Trollmann, Joachim Woelfle, View ProfileFerdinand Knieling

Persisting pulmonary dysfunction in pediatric post-acute Covid-19

https://doi.org/10.1101/2022.02.21.22270909

pre-print

22-Feb-22

Study

https://www.medrxiv.org/content/10.1101/2022.02.21.22270909v1

In this cross-sectional clinical trial, we used non-invasive, label-free morphologic and free-breathing phase-resolved functional low-field magnetic resonance imaging (LF-MRI) to identify pulmonary changes in children and adolescents from 5 to <18 years after previously PCR-confirmed SARS-CoV-2 infection. While morphological pathologies were less frequent in children, functional LF-MRI visualized widespread ventilation, perfusion and combined ventilation/perfusion defects compared to healthy controls. The loss of functional lung parenchyma was more pronounced in long Covid than recovered patients. While pulmonary dysfunction was persistent even month after primary infection, LF-MRI demonstrated high capability to visualize and detect these changes in children and adolescents.

2972

Ch107

Jeané Cloete,Annelet Kruger,Maureen Masha,Nicolette M du Plessis,Dini Mawela,Mphailele Tshukudu,Tabea Manyane,Lekwetji Komane,Marietjie Venter,Waasila Jassat,Ameena Goga,Ute Feucht

Paediatric hospitalisations due to COVID-19 during the first SARS-CoV-2 omicron (B.1.1.529) variant wave in South Africa: a multicentre observational study

https://doi.org/10.1016/S2352-4642(22)00027-X

Published

18-Feb-22

Study

https://www.sciencedirect.com/science/article/abs/pii/S235246422200027X

Between Oct 31 and Dec 11, 2021, 6287 children and adolescents in Tshwane District were recorded as having COVID-19. During this period, 2550 people with COVID-19 were hospitalised, of whom 462 (18%) were aged 19 years or younger. The number of paediatric cases was higher than in the three previous SARS-CoV-2 waves, uncharacteristically increasing ahead of adult hospitalisations. 75 viral samples from adults and children in the district were sequenced, of which 74 (99%) were of the omicron variant. Detailed clinical notes were available for 138 (75%) of 183 children aged ≤13 years with COVID-19 who were hospitalised. 87 (63%) of 138 children were aged 0–4 years. In 61 (44%) of 138 cases COVID-19 was the primary diagnosis, among whom symptoms included fever (37 [61%] of 61), cough (35 [57%]), shortness of breath (19 [31%]), seizures (19 [31%]), vomiting (16 [26%]), and diarrhoea (15 [25%]). Median length of hospital stay was 2 days [IQR 1–3]). 122 (88%) of 138 children with available data needed standard ward care and 27 (20%) needed oxygen therapy. Seven (5%) of 138 children were ventilated and four (3%) died during the study period, all related to complex underlying copathologies. All children and 77 (92%) of 84 parents or guardians with available data were unvaccinated to COVID-19.

2973

Ch108

Fainardi, V.; Meoli, A.; Chiopris, G.; Motta, M.; Skenderaj, K.; Grandinetti, R.; Bergomi, A.; Antodaro, F.; Zona, S.; Esposito, S.

Long COVID in Children and Adolescents

https://doi.org/10.3390/life12020285

Published

14-Feb-22

Review

https://www.mdpi.com/2075-1729/12/2/285

Nevertheless, there are two long-term consequences of SARS-CoV-2 infection in children that raise concern: multisystem inflammatory syndrome in children (MIS-C) and long COVID. While the understanding and the experience regarding the acute phase of SARS-CoV-2 infection have remarkably increased over time, scientific and clinical research is still exploring the long-term effects of COVID-19. In children, data on long COVID are scant. Reports are conflicting regarding its prevalence, duration and impact on daily life. This narrative review explored the latest literature regarding long COVID-19 in the pediatric population. We showed that long COVID in children might be a relevant clinical problem. In most cases, the prognosis is good, but some children may develop long-term symptoms with a significant impact on their daily life. The paucity of studies on long COVID, including a control group of children not infected by SARS-CoV-2, prevents us from drawing firm conclusions. Whether the neuropsychiatric symptoms widely observed in children and adolescents with long COVID are the consequence of SARS-CoV-2 infection or are due to the tremendous stress resulting from the restrictions and the pandemics is still not clear. In both cases, psychological support can play a fundamental role in managing COVID pandemics in children. More knowledge is needed to share a standardized definition of the syndrome and improve its management and treatment.

2974

Ch109

Keith Sacco, Riccardo Castagnoli, Svetlana Vakkilainen, Can Liu, Ottavia M. Delmonte, Cihan Oguz, Ian M. Kaplan, Sara Alehashemi, Peter D. Burbelo, Farzana Bhuyan, Adriana A. de Jesus, Douglas B. Kuhns, Michail S. Lionakis, Thomas M. Snyder, Steven M. Holland, Raphaela Goldbach-Mansky, John S. Tsang & Luigi D. Notarangelo

Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19

https://doi.org/10.1038/s41591-022-01724-3

Published

17-Feb-22

Study

https://www.nature.com/articles/s41591-022-01724-3

Pediatric Coronavirus Disease 2019 (pCOVID-19) is rarely severe; however, a minority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might develop multisystem inflammatory syndrome in children (MIS-C), with substantial morbidity. In this longitudinal multi-institutional study, we applied multi-omics (analysis of soluble biomarkers, proteomics, single-cell gene expression and immune repertoire analysis) to profile children with COVID-19 (n = 110) and MIS-C (n = 76), along with pediatric healthy controls (pHCs; n = 76). pCOVID-19 was characterized by robust type I interferon (IFN) responses, whereas prominent type II IFN-dependent and NF-κB-dependent signatures, matrisome activation and increased levels of circulating spike protein were detected in MIS-C, with no correlation with SARS-CoV-2 PCR status around the time of admission. Transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation. The association of MIS-C with the combination of HLA A*02, B*35 and C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load than pCOVID-19 and pHC. These results identify distinct immunopathological signatures in pCOVID-19 and MIS-C that might help better define the pathophysiology of these disorders and guide therapy.

2975

Ch110

Tyler A. Fick, Clifford L. Cua & Simon Lee

Imaging Findings in Pediatric COVID-19: A Review of Current Literature

https://doi.org/10.1007/s40119-022-00256-8

Published

2-Mar-22

Review

https://link.springer.com/article/10.1007/s40119-022-00256-8

The recent COVID-19 pandemic has afflicted over 200 million individuals to date, with many different organ systems involved. The pediatric involvement has been variable, but of note is the risk of cardiac disease in pediatric COVID-19 patients. We review here the cardiac involvement in pediatric patients with COVID-19. Several studies highlight a possible cardiotropic nature of SARS-CoV-2, and describe the disease severity in myocarditis, both symptomatic and occult, as well as MIS-C. We describe the expected clinical course of these patients and note the lack of long-term follow-up data and the concerning prevalence of continued abnormal findings on follow-up imaging. With this paucity of long-term cardiac data, we recommend consideration of advanced imaging for pediatric patients with cardiac symptoms and/or elevation of cardiac serum biomarkers.
Key Summary Points
Several studies have described direct SARS-CoV-2 myocardial infection, raising the possibility of direct cardiotropic nature of COVID-19 in some patients.
Abnormal CMR findings have been reported in up to 33% of pediatric MIS-C patients.
Up to 14% of pediatric patients continue to have abnormal CMR at follow-up.
The clinical implications of these residual abnormal features is yet unknown, highlighting the importance of continued long-term follow-up.

2976

Ch111

Guy Hazan,Mehr Zahra Shah,Steven Brennan

Markers for Severe Disease and Long-Term Sequelae in Pediatric Patients with SARS-CoV-2 infection

https://doi.org/10.1111/ped.15177

Published

24-Feb-22

Review

https://onlinelibrary.wiley.com/doi/abs/10.1111/ped.15177

Results
Review of 101 patients with positive SARS-CoV2 testing found 67 presentations consistent with acute symptomatic infection. Age distribution was bimodal, with predominance in infancy and adolescence. Most (75%) had an extra-pulmonary comorbidity, and fewer patients (33%) had pre-existing lung disease. History of pulmonary comorbidity and obesity were significantly associated with markers for severe disease. Long-term chronic complications were associated with history of underlying lung disease and acute severe COVID-19.
Conclusions
Demographic and clinical markers were associated with severe COVID-19 in children. Moreover, both the presence of pulmonary comorbidity and severe acute COVID-19 are associated with long-term sequelae.

2977

Ch112

Susanna Esposito, Nicola Principi, Chiara Azzari, Fabio Cardinale, Giuseppe Di Mauro, Luisa Galli, Guido Castelli Gattinara, Valentina Fainardi, Alfredo Guarino, Laura Lancella, Amelia Licari, Enrica Mancino, Gian Luigi Marseglia, Salvatore Leonardi, Raffaella Nenna, Stefania Zampogna, Stefano Zona, Annamaria Staiano & Fabio Midulla

Italian intersociety consensus on management of long covid in children

https://doi.org/10.1186/s13052-022-01233-6

Published

9-Mar-22

Review

https://ijponline.biomedcentral.com/articles/10.1186/s13052-022-01233-6

Background
Two sequelae of pediatric COVID-19 have been identified, the multisystem inflammatory syndrome in children (MIS-C) and the long COVID. Long COVID is much less precisely defined and includes all the persistent or new clinical manifestations evidenced in subjects previously infected by SARS-CoV-2 beyond the period of the acute infection and that cannot be explained by an alternative diagnosis. In this Intersociety Consensus, present knowledge on pediatric long COVID as well as how to identify and manage children with long COVID are discussed.
Main findings
Although the true prevalence of long COVID in pediatrics is not exactly determined, it seems appropriate to recommend evaluating the presence of symptoms suggestive of long COVID near the end of the acute phase of the disease, between 4 and 12 weeks from this. Long COVID in children and adolescents should be suspected in presence of persistent headache and fatigue, sleep disturbance, difficulty in concentrating, abdominal pain, myalgia or arthralgia. Persistent chest pain, stomach pain, diarrhea, heart palpitations, and skin lesions should be considered as possible symptoms of long COVID. It is recommended that the primary care pediatrician visits all subjects with a suspected or a proven diagnosis of SARS-CoV-2 infection after 4 weeks to check for the presence of symptoms of previously unknown disease. In any case, a further check-up by the primary care pediatrician should be scheduled 3 months after the diagnosis of SARS-CoV-2 infection to confirm normality or to address emerging problems. The subjects who present symptoms of any organic problem must undergo a thorough evaluation of the same, with a possible request for clinical, laboratory and / or radiological in-depth analysis in case of need. Children and adolescents with clear symptoms of mental stress will need to be followed up by existing local services for problems of this type.
Conclusions
Pediatric long COVID is a relevant problem that involve a considerable proportion of children and adolescents. Prognosis of these cases is generally good as in most of them symptoms disappear spontaneously. The few children with significant medical problems should be early identified after the acute phase of the infection and adequately managed to assure complete resolution. A relevant psychological support for all the children during COVID-19 pandemic must be organized by health authorities and government that have to treat this as a public health issue.

2978

Ch113

Carl E. Stafstrom

Neurological effects of COVID-19 in infants and children

https://doi.org/10.1111/dmcn.15185

Published

3-Mar-22

Review

https://onlinelibrary.wiley.com/doi/full/10.1111/dmcn.15185

Neurological manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children are becoming increasingly apparent as the coronavirus disease (COVID-19) pandemic continues. While children manifest relatively milder features of the disease, accumulating evidence warrants concern that COVID-19 exacts both acute- and long-term effects on the developing central and peripheral nervous systems. This review focuses on the relatively underinvestigated topic of the effects of SARS-CoV-2 on the brain in infancy and childhood, concluding that clinicians should be attentive to both the acute effects and long-term consequences of COVID-19 from a neurological perspective.
What this paper adds
- Vertical transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from mother to fetus is extremely rare.
- Similar but milder neurological dysfunction occurs in infants and children compared with adults.
- There is no definitive evidence that SARS-CoV-2 invades the central nervous system.
- Long-term neurological and psychiatric effects of coronavirus disease are emerging.
- No data are yet available on variant-specific neurological effects of SARS-CoV-2.

2979

Ch114

MIS-C

Eviç Zeynep Başar 1,*,Hafize Emine Sönmez 2,Hüseyin Uzuner 3,4,Aynur Karadenizli 4,5,Hüseyin Salih Güngör 1,Gökmen Akgün 6,Ayşe Filiz Yetimakman 7 ,Selim Öncel 8 andKadir Babaoğlu 1

CXCL10/IP10 as a Biomarker Linking Multisystem Inflammatory Syndrome and Left Ventricular Dysfunction in Children with SARS-CoV-2

https://doi.org/10.3390/jcm11051416

Published

4-Mar-22

Study

https://www.mdpi.com/2077-0383/11/5/1416/htm

Background: To investigate the diagnostic accuracy of CXCL10/IP10 for left ventricular (LV) dysfunction in multisystemic inflammatory syndrome (MIS-C). Methods: This cross-sectional, longitudinal study included 36 patients with MIS-C. Patients were classified as follows: (1) patients presenting with Kawasaki-like features (group I = 11); (2) patients presenting with LV systolic dysfunction (group II = 9); and (3) other presentations (group III = 3). CXCL10/IP10 levels were measured upon admission and on days 3 and 7 of treatment. Results: Twenty patients were male and 16 were female. The median age of patients at diagnosis was 7.5 (1.5–17) years. All patients had a fever lasting for a median of 4 (2–7) days. Ten patients had LV systolic dysfunction. The duration of hospitalization was longer in group II. Lymphocyte and platelet counts were lower, whereas NT-pro-BNP, troponin-I, D-dimer, and CXCL10/IP10 levels were higher in group II. Baseline levels of CXCL10/IP10 were weakly negatively correlated with ejection fraction (r = −0.387, p = 0.022). Receiver operator characteristic curve analysis yielded a cutoff value of CXCL10/IP10 to discriminate patients with LV dysfunction was 1839 pg/mL with sensitivity 88% and specificity 68% (Area under curve (AUC) = 0.827, 95% CI 0.682–0.972, p = 0.003). Conclusion: Having a good correlation with cardiac function, CXCL10/IP10 is a potential biomarker to predict LV dysfunction in MIS-C patients.

2980

Ch115

Hirt

Thomas Radtke, View ProfileAgne Ulyte, View ProfileMilo A Puhan, View ProfileSusi Kriemler

Long-term symptoms after SARS-CoV-2 infection in school children: population-based cohort with 6-months follow-up

https://doi.org/10.1101/2021.05.16.21257255

pre-print

21-May-21

Study

https://www.medrxiv.org/content/10.1101/2021.05.16.21257255v2.full-text

Although long COVID in children exists, it is still unclear to what extent children are affected. The Ciao Corona study is a longitudinal cohort investigating SARS-CoV-2 seroprevalence and clustering of cases among around 2500 children and adolescents (hereafter referred to as children) from 55 randomly selected primary and secondary schools in the canton of Zurich in Switzerland. Between June 2020 and April 2021, we completed three testing phases where we collected venous blood for serological analysis and asked about symptoms with online questionnaires. We compared children who tested positive for SARS-CoV-2 antibodies in October/November 2020 with those who tested negative. Children who were seronegative in October/November 2020 and seroconverted or were not retested in March/April 2021 were excluded from the analysis (n=256). In March-May 2021 we assessed the presence of symptoms occurring since October 2020, lasting for at least 4 weeks, and persisting for either >4 weeks or >12 weeks. Overall, 1355 of 2503 children with a serology result in October/November 2020 and follow up questionnaire in March-May 2021 were included. Among seropositive and seronegative 6-to 16-year-old children, 9% versus 10% reported at least one symptom beyond 4 weeks, and 4% versus 2% at least one symptom beyond 12 weeks. None of the seropositive children reported hospitalization after October 2020. This study suggests a low prevalence of symptoms compatible with long COVID in a randomly selected population-based cohort of children followed over 6 months after serological testing.

2981

Ch116

PESE

Amanda K. Morrow, Laura A. Malone, Christina Kokorelis, Lindsay S. Petracek, Ella F. Eastin, Katie L. Lobner, Luise Neuendorff & Peter C. Rowe

Long-Term COVID 19 Sequelae in Adolescents: the Overlap with Orthostatic Intolerance and ME/CFS

https://doi.org/10.1007/s40124-022-00261-4

Published

9-Mar-22

Review

https://link.springer.com/article/10.1007/s40124-022-00261-4

Purpose of Review
To discuss emerging understandings of adolescent long COVID or post-COVID-19 conditions, including proposed clinical definitions, common symptoms, epidemiology, overlaps with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and orthostatic intolerance, and preliminary guidance on management.
Recent Findings
The recent World Health Organization clinical case definition of post-COVID-19 condition requires a history of probable or confirmed SARS-CoV-2 infection, with symptoms starting within 3 months of the onset of COVID-19. Symptoms must last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms of the post-COVID-19 condition include, but are not limited to, fatigue, shortness of breath, and cognitive dysfunction. These symptoms generally have an impact on everyday functioning. The incidence of prolonged symptoms following SARS-CoV-2 infection has proven challenging to define, but it is now clear that those with relatively mild initial infections, without severe initial respiratory disease or end-organ injury, can still develop chronic impairments, with symptoms that overlap with conditions like ME/CFS (profound fatigue, unrefreshing sleep, post-exertional malaise, cognitive dysfunction, and orthostatic intolerance).
Summary
We do not yet have a clear understanding of the mechanisms by which individuals develop post-COVID-19 conditions. There may be several distinct types of long COVID that require different treatments. At this point, there is no single pharmacologic agent to effectively treat all symptoms. Because some presentations of post-COVID-19 conditions mimic disorders such as ME/CFS, treatment guidelines for this and related conditions can be helpful for managing post-COVID-19 symptoms.

2982

Ch117

ES

Susanna Esposito, Nicola Principi, Chiara Azzari, Fabio Cardinale, Giuseppe Di Mauro, Luisa Galli, Guido Castelli Gattinara, Valentina Fainardi, Alfredo Guarino, Laura Lancella, Amelia Licari, Enrica Mancino, Gian Luigi Marseglia, Salvatore Leonardi, Raffaella Nenna, Stefania Zampogna, Stefano Zona, Annamaria Staiano & Fabio Midulla

Italian intersociety consensus on management of long covid in children

https://doi.org/10.1186/s13052-022-01233-6

Published

9-Mar-22

Review

https://ijponline.biomedcentral.com/articles/10.1186/s13052-022-01233-6

Background
Two sequelae of pediatric COVID-19 have been identified, the multisystem inflammatory syndrome in children (MIS-C) and the long COVID. Long COVID is much less precisely defined and includes all the persistent or new clinical manifestations evidenced in subjects previously infected by SARS-CoV-2 beyond the period of the acute infection and that cannot be explained by an alternative diagnosis. In this Intersociety Consensus, present knowledge on pediatric long COVID as well as how to identify and manage children with long COVID are discussed.
Main findings
Although the true prevalence of long COVID in pediatrics is not exactly determined, it seems appropriate to recommend evaluating the presence of symptoms suggestive of long COVID near the end of the acute phase of the disease, between 4 and 12 weeks from this. Long COVID in children and adolescents should be suspected in presence of persistent headache and fatigue, sleep disturbance, difficulty in concentrating, abdominal pain, myalgia or arthralgia. Persistent chest pain, stomach pain, diarrhea, heart palpitations, and skin lesions should be considered as possible symptoms of long COVID. It is recommended that the primary care pediatrician visits all subjects with a suspected or a proven diagnosis of SARS-CoV-2 infection after 4 weeks to check for the presence of symptoms of previously unknown disease. In any case, a further check-up by the primary care pediatrician should be scheduled 3 months after the diagnosis of SARS-CoV-2 infection to confirm normality or to address emerging problems. The subjects who present symptoms of any organic problem must undergo a thorough evaluation of the same, with a possible request for clinical, laboratory and / or radiological in-depth analysis in case of need. Children and adolescents with clear symptoms of mental stress will need to be followed up by existing local services for problems of this type.
Conclusions
Pediatric long COVID is a relevant problem that involve a considerable proportion of children and adolescents. Prognosis of these cases is generally good as in most of them symptoms disappear spontaneously. The few children with significant medical problems should be early identified after the acute phase of the infection and adequately managed to assure complete resolution. A relevant psychological support for all the children during COVID-19 pandemic must be organized by health authorities and government that have to treat this as a public health issue.

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Hossein Esmaeilzadeh, Anahita Sanaei Dashti, Negar Mortazavi, Hossein Fatemian & Mohebat Vali

Persistent cough and asthma-like symptoms post COVID-19 hospitalization in children

https://doi.org/10.1186/s12879-022-07252-2

Published

12-Mar-22

Study

https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-022-07252-2

Objectives
Present study aimed to determine the risk of developing Persistent cough and asthma-like symptoms in hospitalized children due to COVID-19.
Methods
This prospective study was carried out in a tertiary referral center. During the COVID-19 pandemic, 69 hospitalized pediatric patients admitted with COVID-19 were observed from February 2020 to January 2021. Clinical and laboratory data were recorded, and after discharge, patients were followed and visited for cough and asthma evaluation one, 2 and 6 months later. Patients with asthma-like diagnoses in follow up defined as asthma-like groups, and patients without any sign of asthma were categorized as the non-asthma group. Asthma-like co-morbids and risk factors were evaluated and compared between the two groups.
Results
In follow-up, most of the COVID-19 hospitalized patients (N = 42) (58.5%) were not affected by asthma-like symptoms. 60.9% of the COVID-19 patients were male. The asthma-like group cases had a significantly familial history of asthma (63.0%), past medical history of asthma (33.3%), and Allergic rhinitis (85.2%). Rates of signs and symptoms during hospitalization were significantly higher in patients with COVID-19 and past medical history of asthma.
Conclusions
We found an asthma-like prevalence of 41.5% in the cohort of COVID-19 hospitalized children. Family history of asthma and previous history of asthma and allergic rhinitis are risk factors for asthma-like after COVID-19 hospitalization. COVID-19 presentations are more severe in the asthma-like group.

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Ch119

Danilo Buonsenso‡ , Leonardo Di Gennaro‡, Cristina De Rose, Rosa Morello, Federico D'Ilario, Giuseppe Zampino, Michele Piazza, Attilio L Boner, Cecilia Iraci, Sarah O'Connell, Valentina B Cohen, Susanna Esposito, Daniel Munblit, Joseph Reena, Louise Sigfrid§ & Piero Valentini§

Long-term outcomes of pediatric infections: from traditional infectious diseases to long Covid

https://doi.org/10.2217/fmb-2022-0031

Published

10-Mar-22

Review

https://www.futuremedicine.com/doi/10.2217/fmb-2022-0031

There is limited evidence available on the long-term impact of SARS-CoV-2 infection in children. In this article, the authors analyze the recent evidence on pediatric long Covid and lessons learnt from a pediatric post-Covid unit in Rome, Italy. To gain a better understanding of the concerns raised by parents and physicians in relation to the potential long-term consequences of this novel infection, it is important to recognize that long-term effect of a post-infectious disease is not a new phenomenon.

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Ch120

Lynne Peeples

Understanding Kids and COVID
As researchers learn more about why COVID-19 tends to be much less severe in children, they’re finding strategies that could help protect all age groups.

https://doi.org/10.1073/pnas.2203753119

Published

22-Mar-22

Article

https://www.pnas.org/doi/full/10.1073/pnas.2203753119

Since the start of the pandemic, even as the circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus shifted from Alpha to Beta to Delta variants, it was clear that most infected children got far less sick than infected adults. We counted our blessings. “The one thing that has allowed us to tolerate this pandemic better than we otherwise would have,” former US Food and Drug Administration (FDA) Commissioner Scott Gottlieb said in a December interview with USA Today, “is that kids weren't getting very sick. If kids were excessively vulnerable to this the way older people were, I think it would have changed how society grappled with this.”

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MIS-C

Sibel Lacinel Gurlevik, Yasemin Ozsurekci, Erdal Sağ, P. Derin Oygar, Selman Kesici, Ümmüşen Kaya Akca, Muserref Kasap Cuceoglu, Ozge Basaran, Sultan Göncü, Jale Karakaya, Ali Bülent Cengiz & Seza Özen

The difference of the inflammatory milieu in MIS-C and severe COVID-19

https://doi.org/10.1038/s41390-022-02029-4

Published

29-Mar-22

Study

https://www.nature.com/articles/s41390-022-02029-4

Background
Coronavirus disease 19 (COVID-19) may have a severe course in children. Multisystem inflammatory syndrome in children (MIS-C) is the post-COVID complication characterized by an exaggerated inflammation, observed in children. However, data on the underlying pathophysiology are sparse. We therefore aimed to assess the cytokine and chemokine profiles of children with MIS-C and compare these to life-threatening severe SARS-CoV-2 and healthy controls (HCs) to shed light on disease pathophysiology.
Methods
Samples of 31 children with MIS-C, 10 with severe/critical COVID-19 and 11 HCs were included. Cytokine and chemokine profiles were studied and compared in between groups.
Results
Most cytokines and chemokines related to IL-1 family and IFN-γ pathway (including IL-18 and MIG/CXCL9) and IL-17A were significantly higher in the MIS-C group when compared to the severe/critical COVID-19 group and HCs. IP-10/CXCL10 and IL-10 were higher in both MIS-C patients and severe/critical COVID-19 compared to HCs.
Conclusion
Our results suggest that IL-1 and IFN-γ pathways play an important role in the pathophysiology of MIS-C.
Impact
This study defines a pattern of distinctive immune responses in children with MIS-C and in patients with severe/critical COVID-19.
As the COVID-19 pandemic continues, biomarkers to identify MIS-C risk are needed to guide our management that study results may shed light on it.

2987

Ch122

MIS-C

Domenico Umberto De Rose 1,2 ,Flaminia Pugnaloni 1,Monica Calì 1,Sara Ronci 1,3,Stefano Caoci 1,Chiara Maddaloni 1,Ludovica Martini 1,Alessandra Santisi 1,Andrea Dotta 1 andCinzia Auriti 1,*

Multisystem Inflammatory Syndrome in Neonates Born to Mothers with SARS-CoV-2 Infection (MIS-N) and in Neonates and Infants Younger Than 6 Months with Acquired COVID-19 (MIS-C): A Systematic Review

https://doi.org/10.3390/v14040750

Published

2-Apr-22

Review

https://www.mdpi.com/1999-4915/14/4/750/htm

Introduction: There is an increasing literature describing neonates born to mothers with SARS-CoV-2 infection (MIS-N) and infants infected with SARS-CoV-2 who presented with a severe disease (MIS-C). (2) Methods: To investigate clinical features of multisystem inflammatory syndrome in neonates and infants under six months of age, we used a systematic search to retrieve all relevant publications in the field. We screened in PubMed, EMBASE and Scopus for data published until 10 October 2021. (3) Results: Forty-eight articles were considered, including 29 case reports, six case series and 13 cohort studies. Regarding clinical features, only 18.2% of MIS-N neonates presented with fever; differently from older children with MIS-C, in which gastrointestinal symptoms were the most common manifestation, we displayed that cardiovascular dysfunction and respiratory distress are the prevalent findings both in neonates with MIS-N and in neonates/infants with MIS-C. (4) Conclusions: We suggest that all infants with suspected inflammatory disease should undergo echocardiography, due to the possibility of myocardial dysfunction and damage to the coronary arteries observed both in neonates with MIS-N and in neonates/infants with MIS-C. Moreover, we also summarize how they were treated and provide a therapeutic algorithm to suggest best management of these fragile infants.

2988

Ch123

Ran D. Goldman

Long COVID in children

https://doi.org/10.46747/cfp.6804263

Published

13-Apr-22

Article

https://www.cfp.ca/content/68/4/263.full

Question - Several physicians in our family medicine clinic noted a recent increase in the number of children with nonspecific symptoms after having had COVID-19. Based on the assumption that these children may have long COVID syndrome, what is the recommended treatment?
Answer - Lockdowns and isolation during the COVID-19 pandemic have affected the physical and mental health of children and adolescents. A recognized complication of COVID-19 is a post–COVID-19 syndrome (long COVID) that was initially reported in adults with an estimated prevalence of 10%. More recent reports on long COVID in children suggest a prevalence of 8% to 10%, but small cohorts, a range of symptoms, and challenges in defining the syndrome make accurately estimating the prevalence difficult. Furthermore, providers may find it challenging to differentiate between neuropsychiatric symptoms that are consequences of COVID-19 infection versus those that are a result of stress, anxiety, or changes in behaviour owing to restrictions associated with the pandemic. Until more evidence is available, management includes obtaining a detailed history, performing a comprehensive physical examination, and aiming to relieve symptoms while following up every 2 to 4 months.
Since the start of the COVID-19 pandemic, illness among children was considered mild.1,2 Even during the surge in prevalence of the highly transmissible Omicron variant of COVID-19 in late 2021, while many more children became symptomatic, their illness remained mild, and complications resulting in admission to hospital were few and far between.3,4
Nevertheless, lockdowns, supply chain complications, and isolation have had an impact on children. School closures and regional lockdowns were detrimental to children and adolescents’ physical activity owing to more time on screen and longer periods of sleep,5 and increases in housing and food insecurity were well documented, with concerns about the long-term health of children.6 Furthermore, reliable reports in the early stages of the pandemic described an increased prevalence of depression, anxiety, and behaviour problems in children,7 as well as delays in seeking emergency care.8
A recognized complication of COVID-19 has been termed post–COVID-19 syndrome, or long COVID. The United Kingdom’s National Institute for Health and Care Excellence definition of long COVID includes acute COVID-19, defined by signs and symptoms lasting up to 4 weeks; postacute or ongoing symptomatic COVID-19, when symptoms persist from 4 to 12 weeks; and post– COVID-19 syndrome, defined by signs and symptoms that continue for more than 12 weeks after the onset of acute symptoms. Long COVID includes both postacute COVID-19 and post–COVID-19 syndrome.9 Long COVID was initially reported in adults and included cardio-respiratory conditions, symptoms of fatigue, headache, dyspnea, and anosmia, and it was more likely to occur with older age, with higher body mass index, and among women.10 It has been estimated that up to 10% of adults who test positive for COVID-19 may experience long COVID.11 The list of postviral symptomatology among people who contracted COVID-19 is long and includes nonspecific conditions that are highly prevalent, such as sleep changes, difficulty concentrating, and anxiety.

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Ch124

Bernice D. Mowery

Long COVID and COVID-19 Omicron
Variant in Children

-

Published

1-Apr-22

Review

https://www.proquest.com/openview/63455d3a1b93e30d8efa554132f1b6ca/1?pq-origsite=gscholar&cbl=47659

Long COVID, also called post-COVID-19 syndrome or post-acute sequelae of SARS-CoV-2 (PASC), has recently been recognized but not yet defined in children (Zimmermann et al., 2021). The first large study of children with long COVID, which includes a comparison group, is a Denmark nationwide cohort study that
included 37,522 children aged 0 to 17 years with RT-PCR verified SARS-CoV-2 infection (response rate 44.9%) and a control group of 78,037 children (response rate 21.3%). None of the children had been vaccinated
because data were collected between January 27, 2020, and March 19, 2021 (Borch et al., 2022).
Of the children infected with SARS-CoV-2, 7% were asymptomatic during original infections. Symptoms
increased with age, 14.8% in age 0 to 5 years versus 28% in age 6 to 17 years (p = 0.000). More children in the SARS-CoV-2 than in the control group had symptoms lasting greater than four weeks (p < 0.0001), and children testing positive for SARS-CoV-2 reported a higher burden of illness, with 36.6% reporting three or more symptoms. Pre-school children in the COVID-19 group experienced statistically more fatigue, loss of smell and taste, and muscle weakness. School-aged children’s most predominant symptoms were loss of smell and taste, fatigue, respiratory problems, dizziness, muscle weakness, and chest pain. Children in the control group experienced significantly more concentration difficulties, headache, muscle and joint pain, cough, nausea, diarrhea, and fever. Long COVID symptoms resolved in one to five months for 54% to 75% of children. The investigators postulate that concentration difficulties (such as headache), muscle and joint pain, and nausea the control group may reflect the negative social consequences of the pandemic on children. The COVID-19 group reported higher scores on the World Health Organization-Five Well-Being Index (WHO-5) than the control group, which supports this hypothesis. Potential study limitations include those typical of observational studies, which do not include objective evaluations and diffusion risk because the control group may have included children with asymptomatic COVID-19. Further study is needed to clarify long COVID-19 and determine the effects of vaccination on long COVID-19 in the pediatric population.

2990

Ch125

Nadine Peart Akindele, Lisa Pieterse, San Suwanmanee, Diane E Griffin

B cell responses in hospitalized SARS-CoV-2-infected children with and without Multisystem Inflammatory Syndrome

https://doi.org/10.1093/infdis/jiac119

Published

18-Apr-22

Study

https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiac119/6569992?login=true

Multisystem inflammatory syndrome in children (MIS-C) can complicate infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but differences in the immune responses during MIS-C compared to coronavirus disease 2019 (COVID-19) are poorly understood. We longitudinally compared the amounts and avidity of plasma anti-nucleocapsid (N) and spike (S) antibodies, phenotypes of B cells and numbers of virus-specific antibody-secreting cells in circulation of children hospitalized with COVID-19 (N=10) and with MIS-C (N=12). N-specific IgG was higher early after presentation for MIS-C than COVID-19 patients and avidity of N- and S-specific IgG at presentation did not mature further during follow up as it did for COVID-19. Both groups had waning proportions of B cells in circulation and decreasing but sustained production of virus-specific antibody-secreting cells for months. Overall, B cell responses were similar, but those with MIS-C demonstrated a more mature antibody response at presentation, suggesting a postinfectious entity compared to COVID-19.

2991

Ch126

F. A. Khaydarova, N. U. Alimova, A. V. Alieva, A. S. Sadykova, M. D. Aripova

Impact of COVID-19 infection on the development of type 1 diabetes mellitus in children and adolescents

https://doi.org/10.14341/DM12785

Published

1-Apr-22

Study

https://www.dia-endojournals.ru/jour/article/view/12785?locale=en_US

Children did not escape the COVID-19 pandemic. Although, in general, the course of viral infection in children is mild, the question of the long-term effects of COVID-19 on a child and adolescent, in particular, on pancreatic beta cells, remains unclear.
Аim: Тo study the characteristics of children with diabetes mellitus identified after COVID-19 infection.
Materials and methods: This article presents the preliminary results obtained from children and adolescents hospitalized at the RSSPMCE clinic with the newly diagnosed diabetes mellitus after COVID infection, as well as a systematic review of 61 clinical cases (case series study).
Results: Of the 120 children hospitalized at the RSSPMCE clinic with newly diagnosed diabetes, 15 were diagnosed with diabetes after COVID-19 infection, all in a state of diabetic ketoacidosis. Only 20% of children knew about the previous COVID-19 infection, the course of the disease was mild, in 80% of children the infection was asymptomatic. At the time of diabetes onset, all children had a high level of HbA1c - above 10%, a low level of vitamin D, high levels of antibodies to SARS-CoV-2 (IgG), and the need for insulin was above the average.
Conclusion: The SARS CoV-2 virus could be the direct cause of the development of diabetes mellitus in children, even with the asymptomatic course of the viral infection. However, the question remains about the exact classification of diabetes after COVID-19 in children. It is necessary to inform the population about the first signs and symptoms of diabetes mellitus in order to timely consult a doctor for the diagnosis of diabetes mellitus.

2992

Ch127

Frank Zhu & Jocelyn Y. Ang

COVID-19 Infection in Children: Diagnosis and Management

https://doi.org/10.1007/s11908-022-00779-0

Published

11-Apr-22

Review

https://link.springer.com/article/10.1007/s11908-022-00779-0

Purpose of Review
Due to the rapidly changing landscape of COVID-19, the purpose of this review is to provide a concise and updated summary of pediatric COVID-19 diagnosis and management.
Recent Findings
The relative proportion of pediatric cases have significantly increased following the emergence of the Omicron variant (from < 2% in the early pandemic to 25% from 1/27 to 2/3/22). While children present with milder symptoms than adults, severe disease can still occur, particularly in children with comorbidities. There is a relative paucity of pediatric data in the management of COVID-19 and the majority of recommendations remain based on adult data.
Summary
Fever and cough remain the most common clinical presentations, although atypical presentations such as “COVID toes,” anosmia, and croup may be present. Children are at risk for post-infectious complications such as MIS-C and long COVID. Nucleic acid amplification tests through respiratory PCR remain the mainstay of diagnosis. The mainstay of management remains supportive care and prevention through vaccination is highly recommended. In patients at increased risk of progression, interventions such as monoclonal antibody therapy, PO Paxlovid, or IV remdesivir × 3 days should be considered. In patients with severe disease, the use of remdesivir, dexamethasone, and immunomodulatory agents (tocilizumab, baricitinib) is recommended. Children can be at risk for thrombosis from COVID-19 and anticoagulation is recommended in children with markedly elevated D-dimer levels or superimposed clinical risk factors for hospital associated venous thromboembolism.

2993

Ch128

Rosa Savino 1,*ORCID,Anna N. Polito 1,Giulia Arcidiacono 1,Mariacristina Poliseno 2ORCID andSergio Lo Caputo 2ORCID

Neuropsychiatric Disorders in Pediatric Long COVID-19: A Case Series

https://doi.org/10.3390/brainsci12050514

Published

19-Apr-22

Case Report

https://www.mdpi.com/2076-3425/12/5/514/htm

Few data are available regarding the incidence and the evolution of neuropsychiatric manifestations in children with a history of COVID-19. We herein report five consequent cases of pediatric patients with psychiatric and neurological symptoms of long COVID-19. All patients, mainly males, reported asymptomatic-to-mild COVID-19 and underwent home self-isolation. Abnormal movements, anxiety, and emotional dysregulation were the most recurrent symptoms observed from a few weeks to months after the resolution of the acute infection. A later onset was observed in younger patients. Blood tests and brain imaging resulted in negative results in all subjects; pharmacological and cognitive behavioral therapy was set. A multifactorial etiology could be hypothesized in these cases, as a result of a complex interplay between systemic and brain inflammation and environmental stress in vulnerable individuals. Longer follow-up is required to observe the evolution of neuropsychiatric manifestation in the present cohort and other young patients with previous SARS-CoV-2 infection.

2994

Ch129

Michele Piazza 1ORCID,Maria Di Cicco 2ORCID,Luca Pecoraro 1ORCID,Michele Ghezzi 3ORCID,Diego Peroni 2,*ORCID andPasquale Comberiati 2ORCID

Long COVID-19 in Children: From the Pathogenesis to the Biologically Plausible Roots of the Syndrome

https://doi.org/10.3390/biom12040556

Published

8-Apr-22

Review

https://www.mdpi.com/2218-273X/12/4/556/htm

Long Coronavirus disease-19 (COVID-19) refers to the persistence of symptoms related to the infection with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). This condition is described as persistent and can manifest in various combinations of signs and symptoms, such as fatigue, headache, dyspnea, depression, cognitive impairment, and altered perception of smells and tastes. Long COVID-19 may be due to long-term damage to different organs—such as lung, brain, kidney, and heart—caused by persisting viral-induced inflammation, immune dysregulation, autoimmunity, diffuse endothelial damage, and micro thrombosis. In this review, we discuss the potential and biologically plausible role of some vitamins, essential elements, and functional foods based on the hypothesis that an individual’s dietary status may play an important adjunctive role in protective immunity against COVID-19 and possibly against its long-term consequences.

2995

Ch130

Berfin Uysal, Tuğberk Akça, Okan Akacı, Fahrettin Uysal

The Prevalence of Post-COVID-19 Hypertension in Children

https://doi.org/10.1177%2F00099228221085346

Published

24-Apr-22

Study

https://journals.sagepub.com/doi/abs/10.1177/00099228221085346

Coronavirus disease 2019 (COVID-19) is the greatest pandemic in a century. In this study, children with mild COVID-19 infections were evaluated at least 8 weeks after the polymerase chain reaction (PCR) test positivity, and the frequency of hypertension (HT) in these children was investigated. These results were compared to those of the control group, which consisted of 32 healthy children in the same age range as the trial group but who did not have COVID-19. This prospective multicenter study was conducted including children aged 10 to 18 years. There were 16 patients (16%) who had elevated systolic blood pressure, while 11 patients (11%) had stage-1 HT and 1 patient (1%) had stage-2 HT. It was revealed that children with COVID-19 had significantly higher systolic and diastolic blood pressures than normal healthy children. The findings of this study contribute toward increasing the understanding of the sequelae of mild COVID-19 in pediatric patients.

2996

Ch131

Mayank Gupta, MDa,*; Nihit Gupta, MDb; and Michael Esang, MDa

Long COVID in Children and Adolescents

https://doi.org/10.4088/PCC.21r03218

Published

26-Apr-22

Review

https://www.psychiatrist.com/pcc/covid-19/long-covid-children-adolescents/

Objective: To review the empirical evidence regarding neuropsychiatric illness (long coronavirus disease [COVID]) in children and adolescents post–severe acute respiratory coronavirus disease 2 (SARS-CoV-2) infection.
Data Sources: A search of PubMed, PsycINFO, Cochrane Library, and Google Scholar was conducted from the date of inception until February 2022 using the keywords corona*, COVID-19, SARS-CoV-2, mental health, depression, anxiety, neurological, psychiatric, long COVID, and post-COVID outcomes. Age filters were used to include children and adolescents aged ≤ 18 years.
Study Selection: The search resulted in the identification of 526 articles; 48 articles met the inclusion criteria.
Data Extraction: Results are presented using a narrative review format. Data regarding long COVID in children and adolescents post–SARS-CoV-2 infection were extracted to understand epidemiologic trends, preventive measures, and treatment options.
Results: Studies during the initial phase of the pandemic reported a mixed range of symptoms from case reports or case series. However, multisystem inflammatory syndrome in children (MIS‐C) was widely reported. During the subsequent phases, the emergence of new variants led to a surge of SARS-CoV-2 infections in pediatric populations. There were highly variable, mixed symptom clusters within 60 days post-infection, which resolved in many patients within 6 months. There were prolonged illnesses and impairments in some children and adolescents with long COVID, and many had similar symptoms even though they tested negative for COVID-19.
Conclusions: Long COVID symptoms are both physical and mental in nature among children and adolescents. The impairments have the potential to affect long-term functioning and increase the overall burden on health care delivery. Despite current studies having methodological issues, there is a consensus to provide multidisciplinary and holistic care to those in need.

Long COVID in children and adolescents is a distinct clinical condition that presents in relapsing and remitting patterns and is recognized cross-culturally with a mixed range of highly variable symptoms within 60 days of SARS-CoV-2 infection. Many who tested negative for COVID-19 also had long COVID symptoms with impairments similar to those who tested positive. Epidemiology, risk factors, and mechanisms are largely unknown, and although most children and adolescents recover from long COVID within 6 months, many suffer from persistent illness and impairments. Vaccinations may play a role in prevention of long COVID in children and adolescents, and multidisciplinary specialized COVID rehabilitation clinics are a step in the right direction.

2997

Ch132

Gökçen Kartal Öztürk, Burçin Beken, Sümeyra Doğan & Himmet Haluk Akar

Pulmonary function tests in the follow-up of children with COVID-19

https://doi.org/10.1007/s00431-022-04493-w

Published

6-May-22

Study

https://link.springer.com/article/10.1007/s00431-022-04493-w

The SARS-CoV-2 virus has infected more than 235 million people since it was accepted as a pandemic in March 2020. Although a milder disease is seen in the pediatric age group, the extent of lung damage and its long-term effects are still unknown. In this study, persistent respiratory symptoms and pulmonary function tests were investigated in children with COVID-19. Fifty children with a confirmed diagnosis of COVID-19 were included in the study. Patients were evaluated for ongoing respiratory symptoms and pulmonary function tests 3 months after infection. Patients with and without persistent symptoms were compared in terms of demographic, clinical, laboratory, and radiological characteristics and also disease severity. Three months after infection, persistent respiratory symptoms were found to be present in 28% of patients; cough, chest pain and tightness, dyspnea, and exertional dyspnea were the most common symptoms. Three patients had an obstructive deficit, and one had a restrictive deficit. Four patients had impaired diffusing capacity of the lungs for carbon monoxide (DLCO). A significant decrease in FEV1/FVC and an increase in lung clearance index were found in the patients with persistent respiratory symptoms. Persistent respiratory symptoms were present in 50% of patients who had severe disease and 12.5% with non-severe disease. DLCO was also significantly lower in the severe disease group.
Conclusions: Our study suggests that the persistence of respiratory symptoms is not related to the severity of acute COVID-19 in children. The inflammatory process due to COVID-19 may continue regardless of its severity, and consequently, peripheral airways may be affected.

2998

Ch133

MIS-C

Conor McCafferty, Tengyi Cai, Delphine Borgel, Dominique Lasne, Sylvain Renolleau, Meryl Vedrenne-Cloquet, Damien Bonnet, Jemma Wu, Thiri Zaw, Atul Bhatnagar, Xiaomin Song, Suelyn Van Den Helm, Natasha Letunica, Chantal Attard, Vasiliki Karlaftis, Slavica Praporski, Vera Ignjatovic & Paul Monagle

Pathophysiological pathway differences in children who present with COVID-19 ARDS compared to COVID -19 induced MIS-C

https://doi.org/10.1038/s41467-022-29951-9

Published

2-May-22

Article

https://www.nature.com/articles/s41467-022-29951-9

COVID-19 has infected more than 275 million worldwide (at the beginning of 2022). Children appear less susceptible to COVID-19 and present with milder symptoms. Cases of children with COVID-19 developing clinical features of Kawasaki-disease have been described. Here we utilise Mass Spectrometry proteomics to determine the plasma proteins expressed in healthy children pre-pandemic, children with multisystem inflammatory syndrome (MIS-C) and children with COVID-19 induced ARDS. Pathway analyses were performed to determine the affected pathways. 76 proteins are differentially expressed across the groups, with 85 and 52 proteins specific to MIS-C and COVID-19 ARDS, respectively. Complement and coagulation activation are implicated in these clinical phenotypes, however there was significant contribution of FcGR and BCR activation in MIS-C and scavenging of haem and retinoid metabolism in COVID-19 ARDS. We show global proteomic differences in MIS-C and COVID-ARDS, although both show complement and coagulation dysregulation. The results contribute to our understanding of MIS-C and COVID-19 ARDS in children.

2999

Ch134

Karel Kostev, Lee Smith, Ai Koyanagi, Marcel Konrad & Louis Jacob

Post-COVID-19 conditions in children and adolescents diagnosed with COVID-19

https://doi.org/10.1038/s41390-022-02111-x

Published

14-May-22

Study

https://www.nature.com/articles/s41390-022-02111-x

Background
This study aimed to investigate the prevalence of and the factors associated with post-COVID-2019 condition in COVID-19 children and adolescents in Germany.
Methods
The present retrospective cohort study used data from the Disease Analyzer database (IQVIA), and included patients aged <18 years who were diagnosed with COVID-19 in one of 524 general and 81 pediatric practices in Germany between October 2020 and August 2021 (index date: first COVID-19 diagnosis). Post-COVID-19 condition was assessed between the index date and November 2021. Covariates included age, sex, type of practice, and chronic conditions documented in at least 1% of the population.
Results
There were 6568 children and adolescents included in this study (mean [SD] age 10.1 [4.9] years; 49.2% girls). The prevalence of post-COVID-19 condition was 1.7% in the population. Patients aged 13–17 years were more likely to be diagnosed with post-COVID-19 condition compared with those being aged ≤5 years (RR = 3.14). Anxiety disorders (RR = 2.53), somatoform disorders (RR = 2.11), and allergic rhinitis (RR = 2.02) were also significantly associated with post-COVID-19 condition.
Conclusion
Post-COVID-19 condition was rare in COVID-19 children and adolescents in Germany. Data from other settings are warranted to confirm these findings.
Impact
The prevalence of post-COVID-19 condition was 1.7% in this population of children and adolescents.
Older children and adolescents were more likely to be diagnosed with post-COVID-19 condition than their younger counterparts.
Anxiety disorders, somatoform disorders, and allergic rhinitis were significantly associated with post-COVID-19 condition.
More data from other settings and countries are warranted to corroborate or refute these findings.

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Carla Petrella 1,†ORCID,Raffaella Nenna 2,†ORCID,Laura Petrarca 2,Francesca Tarani 2,Roberto Paparella 2ORCID,Enrica Mancino 2,Greta Di Mattia 2,Maria Giulia Conti 2,Luigi Matera 2,Enea Bonci 3ORCID,Flavio Maria Ceci 3ORCID,Giampiero Ferraguti 3ORCID,Francesca Gabanella 1,Christian Barbato 1ORCID,Maria Grazia Di Certo 1,Luca Cavalcanti 4ORCID,Antonio Minni 4,Fabio Midulla 2,Luigi Tarani 2,‡ORCID andMarco Fiore 1,*,‡ORCID

Serum NGF and BDNF in Long-COVID-19 Adolescents: A Pilot Study

https://doi.org/10.3390/diagnostics12051162

Published

7-May-22

Study

https://www.mdpi.com/2075-4418/12/5/1162/htm

COVID-19 (COronaVIrus Disease 19) is an infectious disease also known as an acute respiratory syndrome caused by the SARS-CoV-2. Although in children and adolescents SARS-CoV-2 infection produces mostly mild or moderate symptoms, in a certain percentage of recovered young people a condition of malaise, defined as long-COVID-19, remains. To date, the risk factors for the development of long-COVID-19 are not completely elucidated. Neurotrophins such as NGF (Nerve Growth Factor) and BDNF (Brain-Derived Neurotrophic Factor) are known to regulate not only neuronal growth, survival and plasticity, but also to influence cardiovascular, immune, and endocrine systems in physiological and/or pathological conditions; to date only a few papers have discussed their potential role in COVID-19. In the present pilot study, we aimed to identify NGF and BDNF changes in the serum of a small cohort of male and female adolescents that contracted the infection during the second wave of the pandemic (between September and October 2020), notably in the absence of available vaccines. Blood withdrawal was carried out when the recruited adolescents tested negative for the SARS-CoV-2 (“post-infected COVID-19”), 30 to 35 days after the last molecular test. According to their COVID-19 related outcomes, the recruited individuals were divided into three groups: asymptomatics, acute symptomatics and symptomatics that over time developed long-COVID-19 symptoms (“future long-COVID-19”). As a control group, we analyzed the serum of age-matched healthy controls that did not contract the infection. Inflammatory biomarkers (TNF-α, TGF-β), MCP-1, IL-1α, IL-2, IL-6, IL-10, IL-12) were also analyzed with the free oxygen radicals’ presence as an oxidative stress index. We showed that NGF serum content was lower in post-infected-COVID-19 individuals when compared to healthy controls; BDNF levels were found to be higher compared to healthy individuals only in post-infected-COVID-19 symptomatic and future long-COVID-19 girls, leaving the BDNF levels unchanged in asymptomatic individuals if compared to controls. Oxidative stress and inflammatory biomarkers were unchanged in male and female adolescents, except for TGF-β that, similarly to BDNF, was higher in post-infected-COVID-19 symptomatic and future long-COVID-19 girls. We predicted that NGF and/or BDNF could be used as early biomarkers of COVID-19 morbidity in adolescents.

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Silvia Bloise, Sara Isoldi, Alessia Marcellino, Enrica De Luca, Anna Dilillo, Saverio Mallardo, Vanessa Martucci, Mariateresa Sanseviero, Emanuela Del Giudice, Donatella Iorfida, Rita Leone, Alessia Testa, Beatrice Frasacco, Pietro Gizzone, Claudia Proietti Ciolli, Alessandro Sinceri, Francesca Zuliani, Elena Zanardi, Anna Gambarotto, Anna Lisa Grandinetti, Flavia Ventriglia & Riccardo Lubrano

Clinical picture and long-term symptoms of SARS-CoV-2 infection in an Italian pediatric population

https://doi.org/10.1186/s13052-022-01270-1

Published

21-May-22

Study

https://ijponline.biomedcentral.com/articles/10.1186/s13052-022-01270-1

Background
SARS-CoV-2 infection in the pediatric age group has a milder course than in adults, but in some cases even children may present with severe forms or develop long-term consequences. The aim of this study was to analyze the clinical features, long-term effects, lifestyle changes and psychological effects of SARS-CoV-2 infection in a pediatric sample of the Italian population.
Methods
We conducted a telephone survey among 3075 children infected with SARS-CoV-2 in the Latina Local Health Authority. Outcomes included: clinical features of infection, long-term symptoms, lifestyle changes and emotional symptoms during the illness. The information obtained was automatically linked to a spreadsheet and analyzed.
Results
One thousand four hundred thirteen children agreed to participate in the study; the mean age was 112.8 ± 21.9 months. Children were infected mainly inside familial clusters (59.6%; n = 842); 99% (n = 1399) of children were asymptomatic or exhibited mild symptoms. 20% (n = 259) of children experienced long-term symptoms; risk factors were: older age, higher body mass index and longer duration of infection.
Throughout the period of infection, children spent most of the time on devices like tv-video, social media and mobile phone for non-educational activities. 58.8% (n = 620) of parents expressed a negative opinion about distance learning. Finally, we observed that 49,6% (n = 532) of children experienced psychological symptoms during quarantine period.
Conclusion
Despite a lower susceptibility to COVID-19 in children, it is important to keep the focus high in children, both because of the possible long symptoms after infection and the impact on a children’s mental and physical health due to pandemic. We believe that the return to school or other extracurricular activities are important to correct some of the risk factors for the long COVID syndrome, as obesity, and to limit the cultural damage generated by distance learning and psychological effects related to restrictive measures.

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Diana Drogalis-Kim, DO; Collin Kramer, MD; Silvestre Duran

Ongoing Dizziness Following Acute COVID-19 Infection: A Single Center Pediatric Case Series

https://doi.org/10.1542/peds.2022-056860

Published

1-Jun-22

Case Series

https://publications.aap.org/pediatrics/article/doi/10.1542/peds.2022-056860/188138/Ongoing-Dizziness-Following-Acute-COVID-19

Dizziness is a common concern discussed at adolescent medical visits. In this series, we describe 9 pediatric patients with Post-Acute Sequelae of SARS-CoV-2 (PASC) who presented with persistent, debilitating dizziness for weeks to months after their acute infection. Among the 9 patients, median age was 14 years (range: 11-17), 6 were female, and 8 had not received any SARS-CoV-2 vaccines. Five patients met diagnostic criteria for postural orthostatic tachycardia syndrome (POTS) by active standing testing and benefited from a combination of non-pharmacologic therapy (NPT) and medication. NPT alone did not improve symptoms in any patients. Patients who did not meet conventional criteria for POTS, but continued to have symptoms despite NPT compliance, also demonstrated subjective improvement in dizziness when medications were initiated. The majority of patients experienced improvement in dizziness and quality of life, including returning to sports teams and a regular school schedule. A review of the PACS literature demonstrates increasing recognition of a subset of patients who develop autonomic dysfunction, including POTS, although the etiology and prognosis are not completely understood. Our case series aims to highlight the phenomenon of dysautonomia after acute SARS-CoV-2 infection and its response to therapy.

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PESE

Nicole Töpfner, Martin Alberer, Tobias Ankermann, Stephan Bender, Reinhard Berner, Jan de Laffolie, Jens Dingemann, Dirk Heinicke, Johannes Peter Haas, Markus Hufnagel, Thomas Hummel, Hans-Iko Huppertz, Markus Knuf, Robin Kobbe, Thomas Lücke, Joachim Riedel, Josef Rosenecker, Joachim Wölfle, Barbara Schneider, Dominik Schneider, Valentin Schriever, Anne Schroeder, Silvia Stojanov, Tobias Tenenbaum, Stefan Trapp, Daniel Vilser, Folke Brinkmann, Uta Behrends

Einheitliche Basisversorgung von Kindern und Jugendlichen mit Long COVID
Stellungnahme einer multidisziplinären Arbeitsgruppe der DGKJ-Konvent-Gesellschaften (Stand: Februar 2022)

Recommendation for standardized medical care for children and adolescents with long COVID

Statement of a multidisciplinary pediatric expert group of the DGKJ convent societies (status: February 2022)

https://doi.org/10.1007/s00112-021-01408-1

Published

25-May-22

Review

https://link.springer.com/article/10.1007/s00112-021-01408-1

Das vorliegende Konsensuspapier bietet in Ergänzung zur AWMF-S1-Leitlinie eine Übersicht über die verschiedenen klinischen Aspekte von Long COVID im Kindes- und Jugendalter. Es wurde von Vertreter:innen aus 19 Fachgesellschaften des DGKJ-Konvents und kooperierenden Fachgesellschaften erstellt und bietet Expertenempfehlungen für die Praxis auf Grundlage der bisherigen, noch geringen studienbasierten Evidenz zu Long COVID im Kindes- und Jugendalter. Es enthält Screeningfragen zu Long COVID sowie einen Vorschlag zur strukturierten, standardisierten pädiatrischen Anamnese und zur diagnostischen Evaluation bei V. a. Long COVID. Dazu werden ein zeit- und ressourcensparender Erfassungsbogen, der die Komplexität des Krankheitsbildes berücksichtigt, über die Internetseiten der DGKJ und DGPI zur Verfügung gestellt und weitere Fragebögen zur Abklärung von spezifischen neurokognitiven und/oder psychischen Störungen sowie post-exertioneller Malaise (PEM) und myalgischer Enzephalomyelitis/chronischem Fatigue-Syndrom (ME/CFS) benannt. Anhand der jeweiligen anamnestisch und klinisch ermittelten Hauptsymptome werden ein gestuftes, diagnostisches Vorgehen und eine multidisziplinäre Betreuung empfohlen.
Abstract
This current consensus paper for long COVID complements the existing AWMF S1 guidelines for long COVID with a detailed overview on the various clinical aspects of long COVID in children and adolescents. Members of 19 different pediatric societies of the DGKJ convent and collaborating societies together provide expert-based recommendations for the clinical management of long COVID based on the currently available but limited academic evidence for long COVID in children and adolescents. It contains screening questions for long COVID and suggestions for a structured, standardized pediatric medical history and diagnostic evaluation for patients with suspected long COVID. A time and resource-saving questionnaire, which takes the clinical complexity of long COVID into account, is offered via the DGKJ and DGPI websites as well as additional questionnaires suggested for an advanced screening of specific neurocognitive and/or psychiatric symptoms including post-exertional malaise (PEM) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). According to the individual medical history as well as clinical signs and symptoms a step by step diagnostic procedure and a multidisciplinary therapeutic approach are recommended.

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M.GlaiR.GuedriZ.FitouriS.Ben Becher

Etude comparative des formes d'atteinte COVID-19 pédiatrique

https://doi.org/10.1016/j.mmifmc.2022.03.123

Published

31-May-22

Study

https://www.sciencedirect.com/science/article/pii/S2772743222001416

L'atteinte COVID-19 pédiatrique est rare et bénigne selon les données mondiales. Deux formes cliniques ont été essentiellement décrites chez l'enfant. Il s'agit de la forme aigüe active et du syndrome inflammatoire multi systémique (MIS-C syndrome). L'objectif de ce travail était de comparer les aspects épidémio-cliniques, diagnostiques, thérapeutiques et évolutifs des deux formes d'atteinte COVID-19 pédiatrique.
Matériels et méthodes
Il s'agissait d'une étude rétrospective menée sur une année (mars 2020-mars 2021) dans une unité d'isolement COVID-19.L'infection à SARS-CoV-2 a été confirmée par RT-PCR sur prélèvement nasopharyngé. Les cas de MIS-C syndrome répondaient à la définition de l'organisation mondiale de la santé (OMS).
Résultats
Nous avons colligé 99 patients répartis en 67 formes aigües (67,7 %) et 32 cas de MIS-C syndrome (32,3 %). En comparaison avec l'infection active, les patients du groupe MIS-C étaient plus âgés (7,5 ans contre 3,8 ans ;p<0.05). Ainsi, les signes les plus retrouvés étaient la fièvre [100 % (n=32) contre 79,1 % (n=53) ;p<0.05], les signes cutanéo-muqueux [90,6 % (n=29) contre 7,5 % (n=5) ;p<0,05], les manifestations cardiaques [68,8 % (n=22) contre 3 % (n=2) ;p<0,05] et les signes digestifs [56,3 % (n=18) contre 19,4 % (n=13) ;p<0,05]. Cependant, l'atteinte respiratoire était plus rarement rapportée [6,3 % (n=2) contre 56,7 % (n=38) ;p<0,05]. La myocardite (40,6 % ; n=13) et l'état de choc cardiogénique (18,75 % ; n=6) étaient les complications cardiaques les plus redoutées. Les anomalies biologiques les plus retrouvées au cours du MIS-C étaient le syndrome inflammatoire [87,5 % (n=25) contre 39,5 % (n=17) ;p<0,05], l'anémie [62,5 % (n=20) contre 35,8 % (n=24) ;p<0,05], la lymphopénie [75 % (n=24) contre 32,8 % (n=22) ;p<0.05], l'ascension des D-dimères (65,6 % ; n=21) et l'élévation des troponines (40,6 % ; n=13). Le traitement était symptomatique dans l'infection active. Le recours à l'oxygène était indiqué dans 22 % des cas. Pour la forme inflammatoire systémique, le traitement était basé sur les immunoglobulines dans 100 % des cas et sur la corticothérapie dans 75 % des cas. Trois décès sur des terrains fragilisés ont été déplorés pour la forme aigüe. Aucun décès n'était survenu dans le groupe MIS-C.
Conclusion
Le MIS-C syndrome est une forme retardée de l'infection COVID-19. Les facteurs susceptibles de déclencher la cascade inflammatoire post exposition au virus restent en cours de recherche.

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Juanjie Tang, Tanya Novak, Julian Hecker, Gabrielle Grubbs, Fatema Tuz Zahra, Lorenza Bellusci, Sara Pourhashemi, Janet Chou, Kristin Moffitt, Natasha B. Halasa, Stephanie P. Schwartz, Tracie C. Walker, Keiko M. Tarquinio, Matt S. Zinter, Mary A. Staat, Shira J. Gertz, Natalie Z. Cvijanovich, Jennifer E. Schuster, Laura L. Loftis, Bria M. Coates, Elizabeth H. Mack, Katherine Irby, Julie C. Fitzgerald, Courtney M. Rowan, Michele Kong, Heidi R. Flori, Aline B. Maddux, Steven L. Shein, Hillary Crandall, Janet R. Hume, Charlotte V. Hobbs, Adriana H. Tremoulet, Chisato Shimizu, Jane C. Burns, Sabrina R. Chen, Hye Kyung Moon, Christoph Lange, Adrienne G. Randolph & Surender Khurana

Cross-reactive immunity against the SARS-CoV-2 Omicron variant is low in pediatric patients with prior COVID-19 or MIS-C

https://doi.org/10.1038/s41467-022-30649-1

Published

27-May-22

Study

https://www.nature.com/articles/s41467-022-30649-1

Neutralization capacity of antibodies against Omicron after a prior SARS-CoV-2 infection in children and adolescents is not well studied. Therefore, we evaluated virus-neutralizing capacity against SARS-CoV-2 Alpha, Beta, Gamma, Delta and Omicron variants by age-stratified analyses (<5, 5–11, 12–21 years) in 177 pediatric patients hospitalized with severe acute COVID-19, acute MIS-C, and in convalescent samples of outpatients with mild COVID-19 during 2020 and early 2021. Across all patients, less than 10% show neutralizing antibody titers against Omicron. Children <5 years of age hospitalized with severe acute COVID-19 have lower neutralizing antibodies to SARS-CoV-2 variants compared with patients >5 years of age. As expected, convalescent pediatric COVID-19 and MIS-C cohorts demonstrate higher neutralization titers than hospitalized acute COVID-19 patients. Overall, children and adolescents show some loss of cross-neutralization against all variants, with the most pronounced loss against Omicron. In contrast to SARS-CoV-2 infection, children vaccinated twice demonstrated higher titers against Alpha, Beta, Gamma, Delta and Omicron. These findings can influence transmission, re-infection and the clinical disease outcome from emerging SARS-CoV-2 variants and supports the need for vaccination in children.

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Sepideh Benvari, Shima Mahmoudi & Mohsen Mohammadi

Gastrointestinal viral shedding in children with SARS-CoV-2: a systematic review and meta-analysis

https://doi.org/10.1007/s12519-022-00553-1

Published

4-Jun-22

Review

https://link.springer.com/article/10.1007/s12519-022-00553-1

Background
Coronavirus disease 2019 (COVID-19) has different manifestations in pediatric cases. It is assumed that they might present more gastrointestinal symptoms with a different viral shedding pattern in gastrointestinal samples. In this systematic review and meta-analysis, we aimed to evaluate the viral shedding pattern in gastrointestinal specimens of children with COVID-19.
Methods
We searched all published studies in English language in PubMed, Web of Science, and Scopus, up to date as of October 2021. Our search included the term "severe acute respiratory syndrome coronavirus 2, COVID-19, SARS-CoV-2, novel coronavirus, or coronavirus; and shed, excrete, secret, or carriage; and stool or rectal; and children or pediatrics". We included studies evaluating SARS-CoV-2 shedding in gastrointestinal specimens, including rectal swabs and stool samples of children with COVID-19 infection. We excluded duplicated data, case reports, and studies without original data.
Results
Twelve studies met the eligibility criteria for the qualitative synthesis, 10 of which were included in the meta-analysis. The pooled prevalence of gastrointestinal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in children with COVID-19 was 86% (95% confidence interval 73%–96%, I2 = 62.28%). After respiratory specimen had become negative, 72% (43/60) had persistent shedding in gastrointestinal specimens. The gastrointestinal RNA had a positive test result for more than 70 days after symptoms onset.
Conclusions
Gastrointestinal shedding of SARS-CoV-2 might occur in a substantial portion of children and might persist long after negative respiratory testing. Further research is recommended to find the role of SARS-CoV-2 gastrointestinal shedding in transmission in children.

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Ruting Wang, Zifeng Wu, Chaoli Huang, Kenji Hashimoto, Ling Yang & Chun Yang

Deleterious effects of nervous system in the offspring following maternal SARS-CoV-2 infection during the COVID-19 pandemic

https://doi.org/10.1038/s41398-022-01985-z

Published

6-Jun-22

Review

https://www.nature.com/articles/s41398-022-01985-z

During the Coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is universally susceptible to all types of populations. In addition to the elderly and children becoming the groups of great concern, pregnant women carrying new lives need to be even more alert to SARS-CoV-2 infection. Studies have shown that pregnant women infected with SARS-CoV-2 can lead to brain damage and post-birth psychiatric disorders in offspring. It has been widely recognized that SARS-CoV-2 can affect the development of the fetal nervous system directly or indirectly. Pregnant women are recommended to mitigate the effects of COVID-19 on the fetus through vaccination, nutritional supplements, and psychological support. This review summarizes the possible mechanisms of the nervous system effects of SARS-CoV-2 infection on their offspring during the pregnancy and analyzes the available prophylactic and treatment strategies to improve the prognosis of fetal-related neuropsychiatric diseases after birth.

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Cooper, Shiri MD†,⁑; Tobar, Ana MD*,⁑; Konen, Osnat MD‡,⁑; Orenshtein, Naama MD§,⁑; Kropach, Nesia MD§,⁑; Landau, Yuval MD PhD¶,⁑; Mozer-Glassberg, Yael MD†,⁑; Bar-Lev, Michal Rosenfeld MD†,⁑; Shaoul, Ron MD**; Shamir, Raanan MD†,⁑; Waisbourd-Zinman, Orith MD†,⁑

Long COVID-19 Liver Manifestation in Children

https://doi.org/10.1097/MPG.0000000000003521

Published

10-Jun-22

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0267392

Objectives:
SARS CoV-2, the novel coronavirus responsible for coronavirus disease (COVID-19), has been a major cause of morbidity and mortality worldwide. Gastrointestinal and hepatic manifestations during acute disease have been reported extensively in the literature. Post-COVID-19 cholangiopathy has been increasingly reported in adults. In children, data are sparse. Our aim was to describe pediatric patients who recovered from COVID-19 and later presented with liver injury.
Methods:
This is a retrospective case-series study of pediatric patients with post-COVID-19 liver manifestations. We collected data on demographics, medical history, clinical presentation, laboratory results, imaging, histology, treatment, and outcome.
Results:
We report five pediatric patients who recovered from COVID-19 and later presented with liver injury. Two types of clinical presentation were distinguishable. Two infants aged 3 and 5 months, previously healthy, presented with acute liver failure that rapidly progressed to liver transplantation. Their liver explant showed massive necrosis with cholangiolar proliferation and lymphocytic infiltrate. Three children, two aged 8 years and one aged 13 years, presented with hepatitis with cholestasis. Two children had a liver biopsy significant for lymphocytic portal and parenchyma inflammation, along with bile duct proliferations. All three were started on steroid treatment; liver enzymes improved, and they were weaned successfully from treatment. For all five patients, extensive etiology workup for infectious and metabolic etiologies were negative.
Conclusions:
We report two distinct patterns of potentially long COVID-19 liver manifestations in children with common clinical, radiological, and histopathological characteristics after a thorough workup excluded other known etiologies.

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Andrea G. Edlow, MD, MSc1; Victor M. Castro, MS2,3; Lydia L. Shook, MD1; Anjali J. Kaimal, MD, MAS1; Roy H. Perlis, MD, MSc2

Neurodevelopmental Outcomes at 1 Year in Infants of Mothers Who Tested Positive for SARS-CoV-2 During Pregnancy

http://jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2022.15787

Published

9-Jun-22

Study

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2793178

Key Points
Question Is COVID-19 exposure in utero associated with increased risk for neurodevelopmental disorders in the first year of life?
Findings In this cohort study of 7772 infants delivered during the COVID-19 pandemic, those born to the 222 mothers with a positive SARS-CoV-2 polymerase chain reaction test during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first 12 months after delivery, even after accounting for preterm delivery.
Meaning These preliminary findings suggest that COVID-19 exposure may be associated with neurodevelopmental changes and highlight the need for prospective investigation of outcomes in children exposed to COVID-19 in utero.
Abstract
Importance Epidemiologic studies suggest maternal immune activation during pregnancy may be associated with neurodevelopmental effects in offspring.
Objective To evaluate whether in utero exposure to SARS-CoV-2 is associated with risk for neurodevelopmental disorders in the first 12 months after birth.
Design, Setting, and Participants This retrospective cohort study examined live offspring of all mothers who delivered between March and September 2020 at any of 6 Massachusetts hospitals across 2 health systems. Statistical analysis was performed from October to December 2021.
Exposures Maternal SARS-CoV-2 infection confirmed by a polymerase chain reaction test during pregnancy.
Main Outcomes and Measures Neurodevelopmental disorders determined from International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic codes over the first 12 months of life; sociodemographic and clinical features of mothers and offspring; all drawn from the electronic health record.
Results The cohort included 7772 live births (7466 pregnancies, 96% singleton, 222 births to SARS-CoV-2 positive mothers), with mean (SD) maternal age of 32.9 (5.0) years; offspring were 9.9% Asian (772), 8.4% Black (656), and 69.0% White (5363); 15.1% (1134) were of Hispanic ethnicity. Preterm delivery was more likely among exposed mothers: 14.4% (32) vs 8.7% (654) (P = .003). Maternal SARS-CoV-2 positivity during pregnancy was associated with greater rate of neurodevelopmental diagnoses in unadjusted models (odds ratio [OR], 2.17 [95% CI, 1.24-3.79]; P = .006) as well as those adjusted for race, ethnicity, insurance status, offspring sex, maternal age, and preterm status (adjusted OR, 1.86 [95% CI, 1.03-3.36]; P = .04). Third-trimester infection was associated with effects of larger magnitude (adjusted OR, 2.34 [95% CI, 1.23-4.44]; P = .01).
Conclusions and Relevance This cohort study of SARS-CoV-2 exposure in utero found preliminary evidence that maternal SARS-CoV-2 may be associated with neurodevelopmental sequelae in some offspring. Prospective studies with longer follow-up duration will be required to exclude confounding and confirm these associations.

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XiangmingMengaKangxuZhuaJingWangbPanLiuc

Can SARS-CoV-2 positive pregnant women affect the hearing of their newborns: A systematic review

https://doi.org/10.1016/j.amjoto.2022.103523

Published

2-Jun-22

Review

https://www.sciencedirect.com/science/article/pii/S0196070922001508

The 2019 coronavirus disease (COVID-19) pandemic has caused over 500 million confirmed cases (including pregnant women) worldwide. Recently, hearing status in newborns born to mothers with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has received attention. This systematic review outlines the current knowledge regarding the effects of maternal SARS-CoV-2 infection during pregnancy on newborn hearing. Intrauterine SARS-CoV-2 infection has the potential to affect the auditory system of the newborn due to intrauterine hypoxia and vertical transmission. SARS-CoV-2 might have a greater influence on hearing loss (HL) in newborns during the second and third trimesters of pregnancy. Therefore, all newborns whose mothers had COVID-19 during pregnancy should be evaluated for cochlear function, regardless of whether their mothers were symptomatic at the time of the disease. However, the understanding of this issue is not consistent and remains controversial. Since early identification and intervention of congenital HL are crucial to the language development of newborns, newborns should be provided with audiological evaluation by various approaches, including Tele-audiology, in the COVID-19 era.

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Gianfranco Trapani, Giuseppe Verlato, Enrico Bertino, Giulia Maiocco, Roberta Vesentini, Alessia Spadavecchia, Angelica Dessì & Vassilios Fanos

Long COVID-19 in children: an Italian cohort study

https://doi.org/10.1186/s13052-022-01282-x

Published

3-Jun-22

Study

https://link.springer.com/article/10.1186/s13052-022-01282-x

Background
Long COVID-19 syndrome is a complex of symptoms that occurs after the acute SARS-CoV-2 infection, in the absence of other possible diagnoses. Studies on Long COVID-19 in pediatric population are scanty and heterogeneous in design, inclusion criteria, outcomes, and follow-up time. The objective of the present study is to assess the prevalence of Long COVID-19 syndrome in a cohort of Italian pediatric primary care patients, observed for a period of time of 8 to 36 weeks from healing. Prevalence was also assessed in a cohort of pediatric patients hospitalized during acute infection.
Methods
Data concerning 629 primary care patients with previous acute SARS-CoV-2 infection were collected by a questionnaire filled in by Primary Care Pediatrician (PCP). The questionnaire was administrated to patients by 18 PCPs based in 8 different Italian regions from June to August 2021. Data concerning 60 hospitalized patients were also collected by consultation of clinical documents.
Results
Cumulative incidence of Long COVID-19 resulted to be 24.3% in primary care patients and 58% in hospitalized patients. The most frequently reported symptoms were abnormal fatigue (7%), neurological (6.8%), and respiratory disorders (6%) for the primary care cohort. Hospitalized patients displayed more frequently psychological symptoms (36.7%), cardiac involvement (23.3%), and respiratory disorders (18.3%). No difference was observed in cumulative incidence in males and females in both cohorts. Previous diseases did not influence the probability to develop Long COVID-19. The prevalence of Long COVID-19 was 46.5% in children who were symptomatic during acute infection and 11.5% in asymptomatic ones. Children aged 0 to 5 years had a greater risk to develop respiratory symptoms, while adolescents (aged 11–16 years) had a greater risk to develop neurological and psychological Long COVID-19 symptoms.
Conclusions
Our study demonstrates that Long COVID-19 is a reality in pediatric age and could involve even patients with mild or no acute symptoms. The results stress the importance of monitoring primary care pediatric patients after acute COVID-19 infection and the relevance of vaccination programs in pediatric population, also in order to avoid the consequences of Long COVID-19 syndrome.

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N.ElengaabdM.-J.WandjicdJ.SibanabcdefM.NacherdeM.Demarbdf

Neonatal outcomes related to maternal SARS-CoV-2 infection in French Guiana: A case-control study

https://doi.org/10.1016/j.jiph.2022.06.003

Published

14-Jun-22

Study

https://www.sciencedirect.com/science/article/pii/S1876034122001472

Background
This study aims to assess the neonatal outcomes related to maternal SARS-COV-2 infection.
Methods
In this study, we identified newborns born between May 14 and August 31, 2020, to mothers who were PCR-SRAS-CoV-2 positive at the time of delivery. From the cohort of 974 infants, we performed a nested case-control study.
Results
During the study period, 133 (13.7%) mothers were positive for SARS‐CoV‐2. Among the 35 pregnant women with COVID-19 symptoms (26.3%), cough was the most common symptom, present in half of the cases. Four of them have progressed to critical pneumonia requiring transfer to intensive care unit. The neonates from mothers with positive SARS-CoV-2-RT-PCR, were routinely tested for COVID-19 within the first 24 h after labor, and 3 other newborns tested in the presence of symptoms. There was no significant difference between the two groups with respect to preterm birth, meconium-stained amniotic fluid distress, and neonatal asphyxia. Most infants were breastfed at birth, regardless of their mothers' COVID-19 status. In COVID-19-positive pregnant women admitted to intensive care unit, the proportion of preterm births (OR=12.5 [1.7–90.5]), fetal death in utero (OR=25.9 [2.2–305]) and admission in neonatal intensive care unit admission (OR=13.4 [3.0–60]), appeared higher than the controls. No maternal deaths were recorded.
Conclusions
Our data suggest little neonatal morbidity associated with maternal COVID-19, except for those born to mothers admitted to intensive care unit. However, under breastfeeding conditions with rigorous hygiene precautions and parental education, the risk of transmission of SARS-COV-2 virus to the newborn was very low.

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Jennifer A. Burney, PhD1; Samantha C. Roberts, MPH2,3; Laurel L. DeHaan, PhD4; Chisato Shimizu, MD2,3; Emelia V. Bainto, BS2,3; Jane W. Newburger, MD5,6; Samuel Dominguez, MD, PhD7; Pei-Ni Jone, MD7; Preeti Jaggi, MD8; Jacqueline R. Szmuszkovicz, MD9; Anne H. Rowley, MD10; Nichole Samuy, MD11; Paul Scalici, MD11; Adriana H. Tremoulet, MD2,3; Daniel R. Cayan, PhD4; Jane C. Burns, MD2,3; and the KIDCARE Study Investigators

Epidemiological and Clinical Features of Kawasaki Disease During the COVID-19 Pandemic in the United States

https://doi.org/10.1001/jamanetworkopen.2022.17436

Published

17-Jun-22

Study

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2793496

Key Points
Question How did the incidence and nature of Kawasaki disease (KD) in the United States change during the COVID-19 pandemic?
Findings In this cohort study of 3922 children with KD, cases of KD across the United States fell by 28% and remained low during periods of COVID-19–related masking and school closure. In the San Diego region, there was a disproportionate decline in KD cases in children aged 1 to 5 years, male children, and Asian children, and clinical features including strawberry tongue, enlarged cervical lymph node, and subacute periungual desquamation were rare.
Meaning These findings suggest that social behavior is associated with exposure to the agent(s) that trigger KD and are consistent with a respiratory portal of entry for the agent(s).
Abstract
Importance Public health measures implemented during the COVID-19 pandemic had widespread effects on population behaviors, transmission of infectious diseases, and exposures to environmental pollutants. This provided an opportunity to study how these factors potentially influenced the incidence of Kawasaki disease (KD), a self-limited pediatric vasculitis of unknown etiology.
Objectives To examine the change in KD incidence across the United States and evaluate whether public health measures affected the prevalence of KD.
Design, Setting, and Participants This multicenter cohort study included consecutive, unselected patients with KD who were diagnosed between January 1, 2018, and December 31, 2020 (multicenter cohort with 28 pediatric centers), and a detailed analysis of patients with KD who were diagnosed between January 1, 2002, and November 15, 2021 (Rady Children’s Hospital San Diego [RCHSD]).
Main Outcomes and Measures For the multicenter cohort, the date of fever onset for each patient with KD was collected. For RCHSD, detailed demographic and clinical data as well as publicly available, anonymized mobile phone data and median household income by census block group were collected. The study hypothesis was that public health measures undertaken during the pandemic would reduce exposure to the airborne trigger(s) of KD and that communities with high shelter-in-place compliance would experience the greatest decrease in KD incidence.
Results A total of 2461 KD cases were included in the multicenter study (2018: 894; 2019: 905; 2020: 646), and 1461 cases (median [IQR] age, 2.8 years [1.4-4.9 years]; 900 [61.6%] males; 220 [15.1%] Asian, 512 [35.0%] Hispanic, and 338 [23.1%] White children) from RCHSD between 2002 and 2021 were also included. The 28.2% decline in KD cases nationally during 2020 (646 cases) compared with 2018 (894 cases) and 2019 (905 cases) was uneven across the United States. For RCHSD, there was a disproportionate decline in KD cases in 2020 to 2021 compared with the mean (SD) number of cases in earlier years for children aged 1 to 5 years (22 vs 44.9 [9.9]; P = .02), male children (21 vs 47.6 [10.0]; P = .01), and Asian children (4 vs 11.8 [4.4]; P = .046). Mobility data did not suggest that shelter-in-place measures were associated with the number of KD cases. Clinical features including strawberry tongue, enlarged cervical lymph node, and subacute periungual desquamation were decreased during 2020 compared with the baseline period (strawberry tongue: 39% vs 63%; P = .04; enlarged lymph node: 21% vs 32%; P = .09; periungual desquamation: 47% vs 58%; P = .16). School closures, masking mandates, decreased ambient pollution, and decreased circulation of respiratory viruses all overlapped to different extents with the period of decreased KD cases. KD in San Diego rebounded in the spring of 2021, coincident with lifting of mask mandates.
Conclusions and Relevance In this study of epidemiological and clinical features of KD during the COVID-19 pandemic in the United States, KD cases fell and remained low during the period of masking and school closure. Mobility data indicated that differential intensity of sheltering in place was not associated with KD incidence. These findings suggest that social behavior is associated with exposure to the agent(s) that trigger KD and are consistent with a respiratory portal of entry for the agent(s).

3014

Ch149

Prof Selina Kikkenborg Berg, PhD
Pernille Palm, PhD
Ulrikka Nygaard, PhD
Prof Henning Bundgaard, DMSc
Maria Nivi Schmidt Petersen, MSc
Siri Rosenkilde, MSc
Anne Bonde Thorsted, MSc
Prof Annette Kjær Ersbøll, PhD
Prof Lau Casper Thygesen, PhD
Prof Susanne Dam Nielsen, DMSc
Anne Vinggaard Christensen, PhD

Long COVID symptoms in SARS-CoV-2-positive children aged 0–14 years and matched controls in Denmark (LongCOVIDKidsDK): a national, cross-sectional study

https://doi.org/10.1016/S2352-4642(22)00154-7

Published

22-Jun-22

Study

https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(22)00154-7/fulltext

Background
After the acute phase of SARS-CoV-2 infection, children can develop long COVID symptoms. We aimed to investigate the prevalence of long-lasting symptoms, the duration and intensity of symptoms, quality of life, number of sick days and absences from daycare or school, and psychological and social outcomes in children aged 0–14 years who had been infected with SARS-CoV-2 relative to controls with no history of SARS-CoV-2 infection.
Methods
A nationwide cross-sectional study was conducted including children with a confirmed SARS-CoV-2-positive PCR test (cases) and matched controls from Danish national registers. A survey was sent to mothers (proxy reporting) of children aged 0–14 years who had had a positive SARS-CoV-2 test between Jan 1, 2020, and July 12, 2021, and a control group matched (1:4) by age and sex. The survey included the Pediatric Quality of Life Inventory (PedsQL) and the Children's Somatic Symptoms Inventory-24 (CSSI-24) to capture current overall health and wellbeing, and ancillary questions about the 23 most common long COVID symptoms. Descriptive statistics and logistic regression analysis were used. Clinically relevant differences were defined as those with a Hedges' g score greater than 0·2. This study is registered at ClinicalTrials.gov (NCT04786353).
Findings
Responses to the survey were received from 10 997 (28·8%) of 38 152 cases and 33 016 (22·4%) of 147 212 controls between July 20, 2021, and Sept 15, 2021. Median age was 10·2 years (IQR 6·6–12·8) in cases and 10·6 years (6·9–12·9) in controls. 5267 (48·2%) cases and 15 777 (48·3%) controls were female, and 5658 (51·8%) cases and 16 870 (51·7%) controls were male. Cases had higher odds of reporting at least one symptom lasting more than 2 months than did controls in the 0–3 years age group (478 [40·0%] of 1194 vs 1049 [27·2%] of 3855; OR 1·78 [95% CI 1·55–2·04], p<0·0001), 4–11 years age group (1912 [38·1%] of 5023 vs 6189 [33·7%] of 18 372; 1·23 [1·15–1·31], p<0·0001), and 12–14 years age group (1313 [46·0%] of 2857 vs 4454 [41·3%] of 10 789; 1·21 [1·11–1·32], p<0·0001). Differences in CSSI-24 symptom scores between cases and controls were statistically significant but not clinically relevant. Small clinically relevant differences in PedsQL quality-of-life scores related to emotional functioning were found in favour of cases in the children aged 4–11 years (median score 80·0 [IQR 65·0–95·0]) in cases vs 75·0 [60·0–85·0] in controls; p<0·0001) and 12–14 years (90·0 [70·0–100·0] vs (85·0 [65·0–95·0], p<0·0001). PedsQL social functioning scores were also higher in cases (100·0 [90·0–100·0] than controls (95·0 [80·0–100·0]) in the 12–14 years age group (p<0·0001; Hedges g>0·2).
Interpretation
Compared with controls, children aged 0–14 years who had a SARS-CoV-2 infection had more prevalent long-lasting symptoms. There was a tendency towards better quality-of-life scores related to emotional and social functioning in cases than in controls in older children. The burden of symptoms among children in the control group requires attention. Long COVID must be recognised and multi-disciplinary long COVID clinics for children might be beneficial.

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Costanza Di Chiara 1,*ORCID,Silvia Carraro 2ORCID,Stefania Zanconato 2,Sandra Cozzani 1,Eugenio Baraldi 3,Carlo Giaquinto 1,Valentina Agnese Ferraro 2,†ORCID andDaniele Donà 1,†

Preliminary Evidence on Pulmonary Function after Asymptomatic and Mild COVID-19 in Children

https://doi.org/10.3390/children9070952

Published

25-Jun-22

Study

https://www.mdpi.com/2227-9067/9/7/952/htm

Background: While it has been described that adults can develop long-lasting deterioration in pulmonary function (PF) after coronavirus disease 19 (COVID-19), regardless of disease severity, data on the long-term pneumological impact of SARS-CoV-2 infection in children are lacking. Methods: Performing a single-center, prospective, observational study on children aged 6–18 years with a previous diagnosis of asymptomatic/mild COVID-19, we evaluated the long-term impact of mild severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children. Results: A total of 61 subjects underwent spirometry after a mean time of 10 ± 4 months from asymptomatic or mild infection. None of the children reported any respiratory symptoms, needed any inhaled therapy, or had abnormal lung function. Conclusions: In our study, we observed that children and adolescents did not develop chronic respiratory symptoms and did not present lung function impairment after asymptomatic or mild SARS-CoV-2 infection.
In our study, one of the largest Italian pediatric cohorts, we evaluated the long-term impact of mild SARS-CoV-2 infection in children, finding no effect on respiratory symptoms and lung function. Long-term loss of PF, due to an abnormal inflammatory response, was previously observed in children after respiratory viral infections, especially given by RSV and Rhinovirus [8,9,10]. In addition, preliminary results on long-covid in children showed that more than 40% presented at least one symptom >60 days after acute infection, and some of them developed respiratory symptoms after COVID-19 [2]. Therefore, we investigated PF in children after COVID-19, in order to assess whether asymptomatic or mild SARS-CoV-2 infection could sub-clinically impair respiratory parameters. In our population of children with a history of asymptomatic or mildly symptomatic SARS-CoV-2 infection, we found, indeed, no persistent respiratory symptoms (either at rest or on exertion) and normal lung function. Our results are in keeping with two previous pediatric studies [3,4] that found no effect on lung function in the first 6 months after asymptomatic or mild SARS-CoV-2 infection. On the other hand, focusing on a sub-group of children affected by a more severe SARS-CoV-2 infection, Knoke et al. observed a significant reduction in some spirometric parameters (i.e., FVC and MEF75) and impaired DLCO [4]. Our study has several limitations. First, including only children with mild or asymptomatic SARS-CoV-2 infection, we cannot provide any information on the possible detrimental effect of more severe cases (which are indeed very rare during childhood). Secondly, we performed only spirometry and did not examine the pulmonary gas exchange capacity.
5. Conclusions
In conclusion, we observed that children and adolescents did not develop chronic respiratory symptoms and did not present lung function impairment after asymptomatic or mild SARS-CoV-2 infection. Further studies are needed to confirm our findings and to investigate the possible long-term effects of COVID-19 on lung function in children with moderate/severe infection.

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Ch151

Maren Johanne Heilskov Rytter

Difficult questions about long COVID in children

https://doi.org/10.1016/S2352-4642(22)00167-5

Published

22-Jun-22

Comment

https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(22)00167-5/fulltext

Research in COVID-19 is like trying to hit a moving target. The present study is already somewhat historical because the children surveyed were infected with a different strain of SARS-CoV-2 than is currently dominant, and more recent strains appear to cause less severe symptoms. Additionally, since the majority of children in Denmark have immunity from previous infection, they might have milder symptoms if infected with SARS-CoV-2 again, limiting the future generalisability of the findings.
The differences found in Kikkenborg Berg and colleagues' study8 are small and probably of limited clinical relevance. Because most symptoms were mild, and the small excess of non-specific symptoms was accompanied by a paradoxical higher quality of life in children who have had COVID-19, the study findings can be considered reassuring. On a population level, the overall impact on children of having had COVID-19 is probably small, and less than the indirect effects of the pandemic. For most children with non-specific symptoms following COVID-19, the symptoms are more likely to be caused by something other than COVID-19 and, if they are related to COVID-19, they are likely to pass with time.

3017

Ch152

Dustin D. Flannery, Alvaro Zevallos Barboza, Madeline R. Pfeifer, Mark L. Hudak, Kimberly Barnette, Trace R. Getzlaff, Sascha R. Ellington, Kate R. Woodworth, Miren B. Dhudasia, Sagori Mukhopadhyay, Danielle D. Weinberg, Elizabeth E. Foglia & Karen M. Puopolo

Perinatal COVID-19 maternal and neonatal outcomes at two academic birth hospitals

https://doi.org/10.1038/s41372-022-01446-x

Published

1-Jul-22

Study

https://www.nature.com/articles/s41372-022-01446-x

Objective
Describe 1-month outcomes among newborns of persons with perinatal COVID-19.
Study design
Prospective observational study of pregnant persons who tested positive for SARS-CoV-2 between 14 days before and 3 days after delivery and their newborns, from 3/2020 to 3/2021 at two urban high-risk academic hospitals. Phone interviews were conducted to determine 1-month newborn outcomes.
Results
Among 9748 pregnant persons, 209 (2.1%) tested positive for perinatal SARS-CoV-2. Symptomatically infected persons were more likely to have a preterm delivery due to worsening maternal condition and their newborns were more likely to test positive for SARS-CoV-2 compared with asymptomatic persons. Six of 191 (3.1%) infants tested were positive for SARS-CoV-2; none had attributable illness before discharge. Of 169 eligible families, 132 (78.1%) participated in post-discharge interviews; none reported their newborn tested positive for SARS-CoV-2 by 1 month of age.
Conclusion
Symptomatic perinatal COVID-19 had a substantial effect on maternal health but no apparent short-term effect on newborns.

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Ch153

Sandra Lopez-Leon, Talia Wegman-Ostrosky, Norma Cipatli Ayuzo del Valle, Carol Perelman, Rosalinda Sepulveda, Paulina A. Rebolledo, Angelica Cuapio & Sonia Villapol

Long-COVID in children and adolescents: a systematic review and meta-analyses

https://doi.org/10.1038/s41598-022-13495-5

Published

23-Jun-22

Systematic review and meta-analysis

https://www.nature.com/articles/s41598-022-13495-5

The objective of this systematic review and meta-analyses is to estimate the prevalence of long-COVID in children and adolescents and to present the full spectrum of symptoms present after acute COVID-19. We have used PubMed and Embase to identify observational studies published before February 10th, 2022 that included a minimum of 30 patients with ages ranging from 0 to 18 years that met the National Institute for Healthcare Excellence (NICE) definition of long-COVID, which consists of both ongoing (4 to 12 weeks) and post-COVID-19 (≥ 12 weeks) symptoms. Random-effects meta-analyses were performed using the MetaXL software to estimate the pooled prevalence with a 95% confidence interval (CI). Heterogeneity was assessed using I2 statistics. The Preferred Reporting Items for Systematic Reviewers and Meta-analysis (PRISMA) reporting guideline was followed (registration PROSPERO CRD42021275408). The literature search yielded 8373 publications, of which 21 studies met the inclusion criteria, and a total of 80,071 children and adolescents were included. The prevalence of long-COVID was 25.24%, and the most prevalent clinical manifestations were mood symptoms (16.50%), fatigue (9.66%), and sleep disorders (8.42%). Children infected by SARS-CoV-2 had a higher risk of persistent dyspnea, anosmia/ageusia, and/or fever compared to controls. Limitations of the studies analyzed include lack of standardized definitions, recall, selection, misclassification, nonresponse and/or loss of follow-up, and a high level of heterogeneity.

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Ch154

Lokesh Saini ∗
Deepthi Krishna ∗
Sarbesh Tiwari
Jagdish Prasad Goyal
Prawin Kumar
Daisy Khera
Bharat Choudhary
Siyaram Didel
Ravisekhar Gadepalli
Kuldeep Singh

Post COVID-19 immune mediated neurological complications in children – A Ambispective study

https://doi.org/10.1016/j.pediatrneurol.2022.06.010

Published

5-Jul-22

Study

https://www.pedneur.com/article/S0887-8994(22)00115-1/fulltext

Background
The neurological manifestation following a SARS-CoV2 infection is varied, and till now, only a few studies have reported the same. Our study aimed to identify the varied spectrum of neurological manifestation following SARS-CoV2 infection.
Methods
We used retrospective data from May 2021 to July 2021 and prospective study data from August to September 2021, including that from children aged between one month and 18 years of age who presented to a tertiary care referral center with the neurological manifestation and had a history of COVID-19 infection or exposure and positive SARS-CoV-2 serology. The neuro-radiological manifestations were further categorized as in a predesigned proforma.
Results
Case records of the 18 children who fulfilled the criteria were included in the study; among them, seven (38.8%) were male, and 11 (61.1%) were female. Predominant presentation in our study group was status epilepticus (6/18) and Guillain-Barré Syndrome (5/18). Other manifestations included stroke (2/18), demyelinating syndromes (3/18), autoimmune encephalitis (2/18). Most of the children had favorable outcomes except for one mortality in our cohort.
Interpretation
Delayed complications following SARS-CoV2 infection with varied manifestations are seen in children. A temporal correlation was noted between the COVID-19 infection and the increasing number of neurological cases after the second wave. Steroids could be beneficial while treating such patients, especially in the presence of high inflammatory markers. Testing for SARS-CoV2 serology during the pandemic can give a clue to the underlying etiology. Further multicentric studies are required to understand the varied neurological manifestations following SARS-CoV2 infection in children.

3020

Ch155

Rhishikesh Thakre, Sandeep Kadam, Nandkishor Shrikishanji Kabra

Clinical Characteristics and Outcomes of Neonatal SARS-CoV-2 Infection in India: A Systematic Review

Published

1-Jun-22

Review

https://www.perinatology.in/clinical-characteristics-and-outcomes-of-neonatal-sarscov2-infection-in-india-a-systematic-review

Aim: To perform a systematic review to gather information on the clinical characteristics and outcomes of neonates infected with SARS-CoV-2 in India
Materials and Methods: A comprehensive search of literature published between January 1, 2020, and June 30, 2021, was performed. Studies that included neonates < 29 days old, born in India, and diagnosed with SARS-CoV-2 infection and provided data regarding the clinical manifestations, and/or laboratory tests, or radiological examinations were considered. All the included studies were evaluated for methodological quality, and the necessary data were collated.
Results: A total of 22 observational studies met the inclusion criteria. We identified 335 infected neonates. The diagnosis of SARS-CoV-2 infection was made within 48 hours of birth in 44.1% of the cases. Most of these neonates were born to SARS-CoV-2–positive mothers (97.8%). Among the infected neonates, 21.7% were preterm, and 48.6% were low birth weight. Most of the neonates were asymptomatic (66.8%). The most common clinical features were cough, respiratory distress, and hypoxia (67%), and severe illness occurred in 2.9% of the neonates. The reported mortality was 2%.
Conclusions: The available evidence (limited and of low quality) suggests that the risk of SARS-CoV-2 infection in neonates was low in India. The source of infection was the mother. Most of the neonates were asymptomatic, and respiratory symptoms were the most common clinical presentation. Most neonates stabilized upon receiving supportive care, and the overall prognosis was good.

3021

Ch156

Cocciolillo, Fabrizio MD*; Di Giuda, Daniela MD*,†; Morello, Rosa MD‡; De Rose, Cristina MD‡; Valentini, Piero MD‡; Buonsenso, Danilo MD, PhD‡,§

Orbito-Frontal Cortex Hypometabolism in Children With Post-COVID Condition (Long COVID): A Preliminary Experience

https://doi.org/10.1097/INF.0000000000003578

Published

13-Jul-22

Case Reports

https://journals.lww.com/pidj/Abstract/2022/08000/Orbito_Frontal_Cortex_Hypometabolism_in_Children.12.aspx

We describe 3 children with new-onset neurocognitive problems after coronavirus disease 2019 (COVID-19), that showed, at the brain [18F]-fluorodeoxyglucose positron emission tomography/computed tomography, hypometabolism in the left orbito-frontal region. The voxel-wise analysis confirmed a cluster of hypometabolic voxels in this region with a peak at −18/46/−4mm (179 voxels, T-Score 8.1). These findings may explain neurocognitive symptoms that some children develop after COVID-19 and require further investigations.

3022

Ch157

Ali A Asadi-Pooya,Meshkat Nemati,Hamid Nemati

‘Long COVID’: Symptom persistence in children hospitalised for COVID-19

https://doi.org/10.1111/jpc.16120

Published

19-Jul-22

Study

https://onlinelibrary.wiley.com/doi/full/10.1111/jpc.16120

Aim
We aimed to describe the long-term outcome with respect to symptom persistence amongst children hospitalised for COVID-19.
Methods
This was a follow-up study of 58 children and adolescents hospitalised with COVID-19. For all patients, the data were collected in a phone call to the family in December 2021 (9 months after the initial study and more than 13 months after their admission to hospital). We inquired about their current health status and obtained information, if the responding parent consented orally to participate and answer the questions.
Results
Fifty-one children and adolescents were studied. Only five patients (10%) had persistent symptoms compatible with long-COVID; the reported symptoms include fatigue in four (8%), weakness in three (6%), exercise intolerance in two (4%) and shortness of breath in two (4%) patients. Four patients (7.8%), who did not have any symptoms of long-COVID in phase 1 of the study, reported new-onset symptoms or complaints that are potentially compatible with the diagnosis of long-COVID (weakness, myalgia, excess sputum, cough, fatigue) in the current phase.
Conclusions
Symptom persistence of long-COVID is infrequent amongst children hospitalised for COVID-19. Most of the symptoms of long-COVID will resolve with the passage of time and the residual symptoms are often mild and tolerable. The scientific community should carefully and clearly define long-COVID and its natural course in order to facilitate and harmonise future studies.
What is already known on this topic
In a previous study, we observed that 45% of children and adolescents, who were hospitalized with COVID-19, reported symptoms of long-COVID
These symptoms included fatigue, shortness of breath, exercise intolerance, weakness, and walking intolerance.
What this paper adds
Most symptoms of long-COVID in children and adolescents will resolve with the passage of time.
Symptom persistence of long-COVID is not a common condition in children and adolescents.
Scientific community should carefully and clearly define long-COVID.

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Ch158

Iris Shachar-Lavie1 Maayan Shorer2
Hila Segal1 Silvana Fennig1 Liat Ashkenazi-Hoffnung

Mental Health among Children with Long COVID during the COVID- 19 Pandemic

https://doi.org/10.21203/rs.3.rs-1797505/v1

pre-print

22-Jul-22

Study

https://www.researchsquare.com/article/rs-1797505/v1

Purpose
A growing number of studies report that persons of all ages, infected with SARS-CoV-2, may experience long-term persistent symptoms, known as Long-COVID (LC) or post COVID-19 condition. This is one of the first studies examining the consequences of LC on children’s mental health.
Method
In this case control study, we compared select mental health aspects of 103 children diagnosed with LC to a control group of 113 children uninfected with SARS-COV-2; all 4–18 years old. Both groups were assessed via parents’ questionnaires.
Results
In comparison to the control group, children with LC exhibited more memory difficulties. However, no group differences emerged in other functional aspects (connection with friends and engagement in physical activities), problems with concentration, or levels of emotional-behavioral problems (externalizing, internalizing, ADHD, and PTSD symptoms). We also found that children with LC had greater exposure to COVID 19 related stressors. Higher levels of parental worries regarding their children’s functioning and economic difficulties at home significantly predicted higher levels of children’s emotional-behavioral problems and were better predictors than the child’s age, social functioning, or LC diagnosis.
Conclusions
LC was associated with impairments in some aspects of children’s memory which may relate to academic functioning, but not with higher rates of emotional-behavioral problems, thus warranting interventional programs addressing school functioning and cognitive abilities in this population. Additionally, parents' economic stress and worries regarding their child’s emotional adjustment during the pandemic, are important factors affecting pandemic-related emotional-behavioral problems among children, regardless of COVID-19 infection, that should be addressed.

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Ch159

Anna L. Funk, PhD, MSc1; Nathan Kuppermann, MD, MPH2,3; Todd A. Florin, MD, MSCE4,5; Daniel J. Tancredi, PhD3; Jianling Xie, MD, MPH1; Kelly Kim, BSc1; Yaron Finkelstein, MD6,7; Mark I. Neuman, MD, MPH8,9; Marina I. Salvadori, MD10; Adriana Yock-Corrales, MD11; MBChB, PhD42,43,44; Daniel C. Payne, PhD45; Richard Malley, MD46; Meredith L. Borland, MD47,48,49; Andrea K. Morrison, MD, MS50; Maala Bhatt, MD51; Pedro B. Rino, MD52; Isabel Beneyto Ferre, MD53; Michelle Eckerle, MD54,55; April J. Kam, MD56; Shu-Ling Chong, MPH57; Laura Palumbo, MD58; Maria Y. Kwok, MD, MPH59; Jonathan C. Cherry, MD60; Naveen Poonai, MD61; Muhammad Wassem, MD62; Norma-Jean Simon, MPH5,63; Stephen B. Freedman, MDCM, MSc64,65,66; for the Pediatric Emergency Research Network–COVID-19 Study Team

Post–COVID-19 Conditions Among Children 90 Days After SARS-CoV-2 Infection

https://doi.org/10.1001/jamanetworkopen.2022.23253

Published

22-Jul-22

Study

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2794484

Key Points
Question What proportion of children infected with SARS-CoV-2 who were tested in emergency departments (EDs) reported post–COVID-19 conditions (PCCs) 90 days after their ED visits?
Findings In this cohort study of 1884 SARS-CoV-2–positive children with 90-day follow-up, 5.8% of patients, including 9.8% of hospitalized children and 4.6% of discharged children, reported PCCs. Characteristics associated with PCCs included being hospitalized 48 hours or more, having 4 or more symptoms reported at the index ED visit, and being 14 years of age or older.
Meaning This study suggests that, given the prevalence of PCCs, appropriate guidance and follow-up are required for children testing positive for SARS-CoV-2.
Abstract
Importance Little is known about the risk factors for, and the risk of, developing post–COVID-19 conditions (PCCs) among children.
Objectives To estimate the proportion of SARS-CoV-2–positive children with PCCs 90 days after a positive test result, to compare this proportion with SARS-CoV-2–negative children, and to assess factors associated with PCCs.
Design, Setting, and Participants This prospective cohort study, conducted in 36 emergency departments (EDs) in 8 countries between March 7, 2020, and January 20, 2021, included 1884 SARS-CoV-2–positive children who completed 90-day follow-up; 1686 of these children were frequency matched by hospitalization status, country, and recruitment date with 1701 SARS-CoV-2–negative controls.
Exposure SARS-CoV-2 detected via nucleic acid testing.
Main Outcomes and Measures Post–COVID-19 conditions, defined as any persistent, new, or recurrent health problems reported in the 90-day follow-up survey.
Results Of 8642 enrolled children, 2368 (27.4%) were SARS-CoV-2 positive, among whom 2365 (99.9%) had index ED visit disposition data available; among the 1884 children (79.7%) who completed follow-up, the median age was 3 years (IQR, 0-10 years) and 994 (52.8%) were boys. A total of 110 SARS-CoV-2–positive children (5.8%; 95% CI, 4.8%-7.0%) reported PCCs, including 44 of 447 children (9.8%; 95% CI, 7.4%-13.0%) hospitalized during the acute illness and 66 of 1437 children (4.6%; 95% CI, 3.6%-5.8%) not hospitalized during the acute illness (difference, 5.3%; 95% CI, 2.5%-8.5%). Among SARS-CoV-2–positive children, the most common symptom was fatigue or weakness (21 [1.1%]). Characteristics associated with reporting at least 1 PCC at 90 days included being hospitalized 48 hours or more compared with no hospitalization (adjusted odds ratio [aOR], 2.67 [95% CI, 1.63-4.38]); having 4 or more symptoms reported at the index ED visit compared with 1 to 3 symptoms (4-6 symptoms: aOR, 2.35 [95% CI, 1.28-4.31]; ≥7 symptoms: aOR, 4.59 [95% CI, 2.50-8.44]); and being 14 years of age or older compared with younger than 1 year (aOR, 2.67 [95% CI, 1.43-4.99]). SARS-CoV-2–positive children were more likely to report PCCs at 90 days compared with those who tested negative, both among those who were not hospitalized (55 of 1295 [4.2%; 95% CI, 3.2%-5.5%] vs 35 of 1321 [2.7%; 95% CI, 1.9%-3.7%]; difference, 1.6% [95% CI, 0.2%-3.0%]) and those who were hospitalized (40 of 391 [10.2%; 95% CI, 7.4%-13.7%] vs 19 of 380 [5.0%; 95% CI, 3.0%-7.7%]; difference, 5.2% [95% CI, 1.5%-9.1%]). In addition, SARS-CoV-2 positivity was associated with reporting PCCs 90 days after the index ED visit (aOR, 1.63 [95% CI, 1.14-2.35]), specifically systemic health problems (eg, fatigue, weakness, fever; aOR, 2.44 [95% CI, 1.19-5.00]).
Conclusions and Relevance In this cohort study, SARS-CoV-2 infection was associated with reporting PCCs at 90 days in children. Guidance and follow-up are particularly necessary for hospitalized children who have numerous acute symptoms and are older.

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Samuela Tarantino 1,*,Sonia Graziano 1,Chiara Carducci 1,Rosaria Giampaolo 2 andTeresa Grimaldi Capitello 1ORCID

Cognitive Difficulties, Psychological Symptoms, and Long Lasting Somatic Complaints in Adolescents with Previous SARS-CoV-2 Infection: A Telehealth Cross-Sectional Pilot Study

https://doi.org/10.3390/brainsci12080969

Published

23-Jul-22

Study

https://www.mdpi.com/2076-3425/12/8/969/htm

Background. Few studies have evaluated cognitive functioning and mental health in children and adolescents who contracted the SARS-CoV-2 infection. We investigated the prevalence and association of neuropsychological difficulties, psychological symptoms, and self-reported long-COVID complaints in a sample of adolescents. Methods. Thirty-one adolescents infected by COVID-19 within 3–6 months prior to the assessment were included. Neuropsychological difficulties, psychological symptoms, and self-reported long-COVID complaints were evaluated using a checklist and a battery of multiple standardized measures, using a telehealth procedure. Symptoms during the infection were also detected. Results. We included 31 adolescents (23 girls, 8 boys; mean age 14.1, SD = 2). We found borderline scores in 32.3% and 45.2% of our sample for phonemic and category fluency, respectively. A high percentage of participants showed symptoms of depression (80.6%) and anxiety (61.3%). Fifty-eight percent reported at least one long-COVID symptom. The most common symptoms were headache and attention problems (58%). Subjects presenting numbness/weakness, fatigue, brain fog, or attention problems had higher scores in depression, anxiety, and post-traumatic stress symptoms (p ≤ 0.05). Conclusion. This is a pilot study limited by the lack of control group. However, we found that cognitive, psychological, and physical symptoms were very common among adolescents recovered from COVID-19.

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Lyudmyla Kompaniyets, PhD1; Lara Bull-Otterson, PhD1; Tegan K. Boehmer, PhD1; Sarah Baca1,2; Pablo Alvarez, MPH1,2; Kai Hong, PhD1; Joy Hsu, MD1; Aaron M. Harris, MD1; Adi V. Gundlapalli, MD, PhD1; Sharon Saydah

Post–COVID-19 Symptoms and Conditions Among Children and Adolescents — United States, March 1, 2020–January 31, 2022

Published

5-Aug-22

Study

https://www.cdc.gov/mmwr/volumes/71/wr/mm7131a3.htm

Summary
What is already known about this topic?
Children and adolescents might be at risk for certain post-COVID symptoms and conditions.
What is added by this report?
Compared with patients aged 0–17 years without previous COVID-19, those with previous COVID-19 had higher rates of acute pulmonary embolism (adjusted hazard ratio = 2.01), myocarditis and cardiomyopathy (1.99), venous thromboembolic event (1.87), acute and unspecified renal failure (1.32), and type 1 diabetes (1.23), all of which were rare or uncommon in this study population.
What are the implications for public health practice?
COVID-19 prevention strategies, including vaccination for all eligible persons aged ≥6 months, are critical to preventing SARS-CoV-2 infection and subsequent illness, and reducing the public health impact of post-COVID symptoms and conditions among persons aged 0–17 years.

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Dicle Sener Okur

Neurological symptoms and signs associated with COVID-19 in pediatric patients: a single-center experience

https://doi.org/10.1097%2FMD.0000000000029920

Published

5-Aug-22

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9351517/

There is insufficient evidence on SARS-CoV-2 induced neurological effects. Studies on CNS involvement during COVID-19 in children are limited. This study aims to identify and manage the neurological signs and symptoms in COVID-19-infected pediatric patients during follow up and plan future follow-ups.
Children diagnosed COVID-19 and hospitalized in the pediatric pandemic services, between March 18, 2020, and June 18, 2021, were included in the study. Children with underlying neurological disease were excluded from the study. Patient data retrieved from hospital files and medical records. Children divided into 2 groups, 1 and 2, based on the presence or absence of neurological findings.
A total of 243 children received follow-ups in the pandemic wards, 35 (14.4%) of these patients had neurological findings. Major neurological manifestations were headache (n:17, 7%), seizure (n:4, 1.6%), and anosmia/hyposmia (n:17, 7%). The number of boys (n:13, 37.1%) was smaller than the number of girls (n:22, 62.9%) in Group 1. Group 1 showed higher blood leukocyte, lymphocyte, thrombocyte, AST, LDH, d-dimer values. Anosmia/hyposmia occurred more often in girls, anosmia and headache occurred more often over 9 years of age. Pulmonary and hematologic involvement was more common in children with anosmia and headache.
Our study is one of the few studies on neurological involvement in COVID-19 in children. To the best of our knowledge, there is limited data on these subjects in the literature.

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Dinah V. Parums

Editorial: Long-Term Effects of Symptomatic and Asymptomatic SARS-CoV-2 Infection in Children and the Changing Pathogenesis of Common Childhood Viruses Driven by the COVID-19 Pandemic

https://doi.org/10.12659/MSM.937927

Published

1-Aug-22

Editorial

https://medscimonit.com/abstract/full/idArt/937927

The range of long-term clinical conditions following SARS-CoV-2 infection in adults is now recognized. However, the prevalence, presentation, and risk factors for long COVID, or post-COVID-19, in children are less well understood because there have been few follow-up studies or long-term clinical trials in children with COVID-19. However, recent studies have shown that children with mild or asymptomatic COVID-19 may develop long-term sequelae that include cough, fatigue, and lethargy. The incidence and severity of common childhood respiratory viruses have changed in the past year, including respiratory syncytial virus (RSV). Hepatitis of unknown cause in children with SARS-CoV-2 infection is increasingly reported. Although both a viral cause and an autoimmune cause have been proposed, adenovirus type 41 infection is of current interest. These findings support immunization programs for SARS-CoV-2 in children, and infection surveillance and monitoring of the changing patterns and severity of other pediatric viral infections, including adenovirus type 41 and RSV, to develop and administer effective vaccines. This Editorial aims to highlight what is currently known of the long-term effects of symptomatic and asymptomatic SARS-CoV-2 infection in children and the changing epidemiology and pathogenesis of previously common childhood viral infections now driven by the COVID-19 pandemic.

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Rowena Ng, Gray Vargas, Dasal Tenzin Jashar, Amanda Morrow, Laura A Malone

Neurocognitive and Psychosocial Characteristics of Pediatric Patients With Post-Acute/Long-COVID: A Retrospective Clinical Case Series

https://doi.org/10.1093/arclin/acac056

Published

29-Jul-22

Study

https://academic.oup.com/acn/advance-article/doi/10.1093/arclin/acac056/6651311

Objective
Studies suggest a large number of patients have persistent symptoms following COVID-19 infection—a condition termed “long COVID.” Although children and parents often report cognitive difficulties after COVID, very few if any studies have been published including neuropsychological testing.
Methods
A retrospective chart review was completed for the first 18 patients referred for a neuropsychological evaluation from a multidisciplinary pediatric post-COVID clinic. The neuropsychological screening battery assessed verbal fluency and category switching, attention, working memory, processing speed, and verbal learning and memory. Patients’ caregivers also completed standardized questionnaires regarding day-to-day mood and behavior.
Results
At intake, the most common neurologic symptoms reported by caregivers were attention problems (83.3%), fatigue/lethargy (77.7%), sleep disturbance (77.7%), dizziness/vertigo (72.2%), and headaches (72.2%). On rating scales, most caregivers endorsed concerns for depressed mood and anxiety (14/15 and 12/15). A large proportion of patients had difficulties with attention (9/18) and depressed mood/anxiety (13/18) before COVID. On cognitive testing, the majority of the patients performed within or above broad average range (≥16th percentile) across most domains. However, a little over half of the patients performed below average on auditory attention measures.
Conclusions
Within our clinically referred sample, children who reported lingering cognitive symptoms after COVID-19 often had a preexisting history of attention and/or mood and anxiety concerns. Many of these patients performed below average in attention testing, but it remains to be seen whether this was due to direct effects of COVID, physical symptoms, and/or preexisting difficulties with attention or mood/anxiety.

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Suchitra Rao, MBBS, MSCS1; Grace M. Lee, MD, MPH2; Hanieh Razzaghi, MPH3; Vitaly Lorman, PhD3; Asuncion Mejias, MD, PhD4; Nathan M. Pajor, MD5; Deepika Thacker, MD6; Ryan Webb, MS3; Kimberley Dickinson, BS3; L. Charles Bailey, MD, PhD3; Ravi Jhaveri, MD7; Dimitri A. Christakis, MD, MPH8,9; Tellen D. Bennett, MD, MS1; Yong Chen, PhD10; Christopher B. Forrest, MD, PhD3

Clinical Features and Burden of Postacute Sequelae of SARS-CoV-2 Infection in Children and Adolescents

https://doi.org/10.1001/jamapediatrics.2022.2800

Published

22-Aug-22

Study

https://jamanetwork.com/journals/jamapediatrics/fullarticle/2795569

Key Points
Question - What are the incidence and clinical features of postacute sequelae of SARS-CoV-2 infection (PASC) in children?
Findings - In this cohort study including 659 286 children tested for SARS-CoV-2 by antigen or polymerase chain reaction, the symptom, condition, and medication with the strongest associations with SARS-CoV-2 infection were loss of taste/smell, myocarditis, and cough and cold preparations, respectively. The incidence proportion of non–multisystem inflammatory syndrome in children–related PASC in the viral test–positive group exceeded the incidence proportion in the viral test–negative group by 3.7%, with increased rates associated with acute illness severity, young age, and medical complexity.
Meaning - PASC in children appears to be uncommon, with features that differ from adults.
Abstract
Importance - The postacute sequelae of SARS-CoV-2 infection (PASC) has emerged as a long-term complication in adults, but current understanding of the clinical presentation of PASC in children is limited.
Objective - To identify diagnosed symptoms, diagnosed health conditions, and medications associated with PASC in children.
Design, Setting and Participants - This retrospective cohort study used electronic health records from 9 US children’s hospitals for individuals younger than 21 years who underwent antigen or reverse transcriptase–polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 between March 1, 2020, and October 31, 2021, and had at least 1 encounter in the 3 years before testing.
Exposures - SARS-CoV-2 positivity by viral test (antigen or RT-PCR).
Main Outcomes and Measures - Syndromic (symptoms), systemic (conditions), and medication PASC features were identified in the 28 to 179 days following the initial test date. Adjusted hazard ratios (aHRs) were obtained for 151 clinically predicted PASC features by contrasting viral test–positive groups with viral test–negative groups using proportional hazards models, adjusting for site, age, sex, testing location, race and ethnicity, and time period of cohort entrance. The incidence proportion for any syndromic, systemic, or medication PASC feature was estimated in the 2 groups to obtain a burden of PASC estimate.
Results - Among 659 286 children in the study sample, 348 091 (52.8%) were male, and the mean (SD) age was 8.1 (5.7) years. A total of 59 893 (9.1%) tested positive by viral test for SARS-CoV-2, and 599 393 (90.9%) tested negative. Most were tested in outpatient testing facility settings (322 813 [50.3%]) or office settings (162 138 [24.6%]). The most common syndromic, systemic, and medication features were loss of taste or smell (aHR, 1.96; 95% CI, 1.16-3.32), myocarditis (aHR, 3.10; 95% CI, 1.94-4.96), and cough and cold preparations (aHR, 1.52; 95% CI, 1.18-1.96), respectively. The incidence of at least 1 systemic, syndromic, or medication feature of PASC was 41.9% (95% CI, 41.4-42.4) among viral test–positive children vs 38.2% (95% CI, 38.1-38.4) among viral test–negative children, with an incidence proportion difference of 3.7% (95% CI, 3.2-4.2). A higher strength of association for PASC was identified in those cared for in the intensive care unit during the acute illness phase, children younger than 5 years, and individuals with complex chronic conditions.
Conclusions and Relevance - In this large-scale, exploratory study, the burden of pediatric PASC that presented to health systems was low. Myocarditis was the most commonly diagnosed PASC-associated condition. Acute illness severity, young age, and comorbid complex chronic disease increased the risk of PASC.

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Ki PuiLamaMarcosChiñasabAmélie M.JuléacMariaTayloraMarinaOhashidMehdiBenamaraElenaCrestaniaMary Beth F.SonaJanetChouaCatherineGebhartdTalalChatilaaJaneNewburgereAdrienneRandolphfMariaGutierrez-ArcelusabLauren A.Hendersona

SARS-CoV-2-specific T cell responses in patients with multisystem inflammatory syndrome in children

https://doi.org/10.1016/j.clim.2022.109106

Published

30-Aug-22

Study

https://www.sciencedirect.com/science/article/pii/S1521661622001875

Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infections that occurs in the pediatric population. We sought to characterize T cell responses in MIS-C compared to COVID-19 and pediatric hyperinflammatory syndromes.
MIS-C was distinct from COVID-19 and hyperinflammatory syndromes due to an expansion of T cells expressing TRBV11–2 that was not associated with HLA genotype. Children diagnosed with MIS-C, but who were negative for SARS-CoV-2 by PCR and serology, did not display Vβ skewing. There was no difference in the proportion of T cells that became activated after stimulation with SARS-CoV-2 peptides in children with MIS-C compared to convalescent COVID-19. The frequency of SARS-CoV-2-specific TCRs and the antigens recognized by these TCRs were comparable in MIS-C and COVID-19.
Expansion of Vβ11–2+ T cells was a specific biomarker of MIS-C patients with laboratory confirmed SARS-CoV-2 infections. Children with MIS-C had robust antigen-specific T cell responses to SARS-CoV-2.

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Roberta Pellegrino, Elena Chiappini, Amelia Licari, Luisa Galli & Gian Luigi Marseglia

Prevalence and clinical presentation of long COVID in children: a systematic review

https://doi.org/10.1007/s00431-022-04600-x

Published

15-Sep-22

Review

https://link.springer.com/article/10.1007/s00431-022-04600-x

A systematic literature review was conducted up to 15th February 2022 to summarize long COVID evidence and to assess prevalence and clinical presentation in children and adolescents. Articles reporting long COVID prevalence and symptoms based on original data in the paediatric population were included. Case series quality was assessed through the JBI Critical Appraisal Checklist. For observational studies, adherence to STROBE checklist was evaluated. Twenty-two articles were included: 19 observational studies (12 cohort/7 cross-sectional) and 3 case series. Nine studies provided a control group. We found a high variability in terms of prevalence (1.6–70%). The most frequently reported symptoms were fatigue (2–87%), headache (3.5–80%), arthro-myalgias (5.4–66%), chest tightness or pain (1.4–51%), and dyspnoea (2–57.1%). Five studies reported limitations in daily function due to long COVID. Alterations at brain imaging were described in one study, transient electrocardiographic abnormalities were described in a minority of children, while most authors did not evidence long-term pulmonary sequelae. Older age, female sex, and previous long-term pathological conditions were more frequently associated with persistent symptoms.
Conclusion: Long COVID evidence in children is limited, heterogeneous, and based on low-quality studies. The lockdown consequences are difficult to distinguish from long COVID symptoms. High-quality studies are required: WHO definition of long COVID should be used, controlled clinical studies should be encouraged, and the impact of new variants on long COVID prevalence should be investigated to ensure an objective analysis of long COVID characteristics in children and a proper allocation of healthcare system resources.
What is Known:
• Children rarely develop a severe respiratory disease in the acute phase of COVID-19.
• A limited number of patients develop a multisystem inflammatory condition that can lead to multiorgan failure and shock.
What is New:
• Persistent symptoms after SARS-CoV-2 infection are reported in children and limitations in daily function due to long COVID symptoms affect school attendance.
• Functional complaints of post-acute COVID are difficult to be distinguished from those due to social restrictions.

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CARL A. PIERCEKEVAN C. HEROLD BETSY C. HEROLD JANET CHOU ADRIENNE RANDOLPHBINITA KANE SAMMIE MCFARLANDDEEPTI GURDASANI CHRISTINA PAGEL PETER HOTEZ SARAH COBEY AND SCOTT E. HENSLEY

COVID-19 and children

https://doi.org/10.1126/science.ade1675

Published

8-Sep-22

Article

https://www.science.org/doi/full/10.1126/science.ade1675

There has been substantial research on adult COVID-19 and how to treat it. But how do severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections afflict children? The COVID-19 pandemic has yielded many surprises, not least that children generally develop less severe disease than older adults, which is unusual for a respiratory disease. However, some children can develop serious complications from COVID-19, such as multisystem inflammatory syndrome in children (MIS-C) and Long Covid, even after mild or asymptomatic COVID-19. Why this occurs in some and not others is an important question. Moreover, when children do contract COVID-19, understanding their role in transmission, especially in schools and at home, is crucial to ensuring effective mitigation measures. Therefore, in addition to nonpharmaceutical interventions, such as improved ventilation, there is a strong case to vaccinate children so as to reduce possible long-term effects from infection and to decrease transmission. But questions remain about whether vaccination might skew immune responses to variants in the long term. As the experts discuss below, more is being learned about these important issues, but much more research is needed to understand the long-term effects of COVID-19 in children

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Ellen K. Kendall, BA1; Veronica R. Olaker, BS1; David C. Kaelber, MD, PhD2; Rong Xu, PhD1; Pamela B. Davis, MD, PhD3Ellen K. Kendall, BA1; Veronica R. Olaker, BS1; David C. Kaelber, MD, PhD2; Rong Xu, PhD1; Pamela B. Davis, MD, PhD3

Association of SARS-CoV-2 Infection With New-Onset Type 1 Diabetes Among Pediatric Patients From 2020 to 2021

https://doi.org/10.1001/jamanetworkopen.2022.33014

Published

23-Sep-22

Study

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2796649

Introduction
Incidence of new-onset type 1 diabetes (T1D) increased during the COVID-19 pandemic,1 and this increase has been associated with SARS-CoV-2 infection.2 The US Centers for Disease Control and Prevention reported that pediatric patients with COVID-19 were more likely to be diagnosed with diabetes after infection, although types 1 and 2 were not separated.3 Therefore, whether COVID-19 was associated with new-onset T1D among youths remains unclear. This cohort study assessed whether there was an increase in new diagnoses of T1D among pediatric patients after COVID-19.
Methods
Data were obtained using TriNetX Analytics Platform, a web-based database of deidentified electronic health records of more than 90 million patients, from the Global Collaborative Network, which includes 74 large health care organizations across 50 US states and 14 countries with diverse representation of geographic regions, self-reported race, age, income, and insurance types.4 The MetroHealth System institutional review board deemed the study exempt because it was determined to be non–human participant research. The study followed the STROBE reporting guideline.
The study population comprised pediatric patients in 2 cohorts: (1) patients aged 18 years or younger with SARS-CoV-2 infection between March 2020 and December 2021 and (2) patients aged 18 years or younger without SARS-CoV-2 infection but with non–SARS-CoV-2 respiratory infection during the same period. SARS-CoV-2 infection was defined as described in prior studies.5 These cohorts were subdivided into groups aged 0 to 9 years and 10 to 18 years.
Cohorts were propensity score matched (1:1 using nearest-neighbor greedy matching) for demographics and family history of diabetes (Table). Risk of new diagnosis of T1D within 1, 3, and 6 months after infection were compared between matched cohorts using hazard ratios (HRs) and 95% CIs. Statistical analyses were conducted in the TriNetX Analytics Platform. Further details and analyses from the TriNetX database are given in the eMethods in the Supplement.
Results
The Table shows population characteristics before and after matching. The study population included 1 091 494 pediatric patients: 314 917 with COVID-19 and 776 577 with non–COVID-19 respiratory infections. The matched cohort included 571 256 pediatric patients: 285 628 with COVID-19 and 285 628 with non–COVID-19 respiratory infections. By 6 months after COVID-19, 123 patients (0.043%) had received a new diagnosis of T1D, but only 72 (0.025%) were diagnosed with T1D within 6 months after non–COVID-19 respiratory infection. At 1, 3, and 6 months after infection, risk of diagnosis of T1D was greater among those infected with SARS-CoV-2 compared with those with non–COVID-19 respiratory infection (1 month: HR, 1.96 [95%CI, 1.26-3.06]; 3 months: HR, 2.10 [95% CI, 1.48-3.00]; 6 months: HR, 1.83 [95% CI, 1.36-2.44]) and in subgroups of patients aged 0 to 9 years, a group unlikely to develop type 2 diabetes, and 10 to 18 years (Figure). Similar increased risks were observed among children infected with SARS-CoV-2 compared with other control cohorts at 6 months (fractures: HR, 2.09 [95% CI, 1.41- 3.10]; well child visits: HR, 2.10 [95% CI, 1.61- 2.73]).
Discussion
In this study, new T1D diagnoses were more likely to occur among pediatric patients with prior COVID-19 than among those with other respiratory infections (or with other encounters with health systems). Respiratory infections have previously been associated with onset of T1D,6 but this risk was even higher among those with COVID-19 in our study, raising concern for long-term, post–COVID-19 autoimmune complications among youths. Study limitations include potential biases owing to the observational and retrospective design of the electronic health record analysis, including the possibility of misclassification of diabetes as type 1 vs type 2, and the possibility that additional unidentified factors accounted for the association. Results should be confirmed in other populations. The increased risk of new-onset T1D after COVID-19 adds an important consideration for risk-benefit discussions for prevention and treatment of SARS-CoV-2 infection in pediatric populations.

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Marco Roversi, Luana Coltella, Livia Piccioni, Umberto Raucci, Antonio Torelli, Laura Papini, Carla Olita, Antonino Reale, Carlo Federico Perno, Alberto Villani & Cristina Russo

Relationship between viral load and symptoms in children infected with SARS-CoV-2

https://doi.org/10.1038/s41390-022-02293-4

Published

7-Sep-22

Study

https://www.nature.com/articles/s41390-022-02293-4

Background
The purpose of this study is to evaluate the association between SARS-CoV-2 viral load in respiratory secretions of infected children and signs/symptoms of COVID-19.
Methods
We reported the clinical characteristics of SARS-CoV-2-infected children during the study period. We compared viral load for several clinical variables, performed a predictive linear regression analysis to identify signs and symptoms significantly associated with viral load, and searched for discriminant viral load thresholds for symptomatic versus asymptomatic infections based on receiver-operating characteristics.
Results
A total of 570 patients were included. The median age was 4.75 years. Comparison of CT values by dichotomous variable showed higher viral loads in children with fever, respiratory symptoms, and previous exposure to SARS-CoV-2. The linear regression analysis confirmed a significant relationship between the CT value with these variables and with age, other symptoms, and asymptomaticity. In particular, infants with fever and SARS-CoV-2 exposure had higher viral loads. No viral load cut-offs were found to distinguish symptomatic from asymptomatic patients.
Conclusion
Our study shows that fever, SARS-CoV-2 exposure, and respiratory symptoms are associated with higher viral load in children, especially infants, while age, presence of nonrespiratory symptoms, or absence of any symptoms are associated with lower viral load.
Impact
Key message: the clinical variables that best predict viral load in infected children are history of previous exposure to a SARS-CoV-2-infected person and presence of fever and respiratory symptoms (higher viral load).
Added value to the current literature: this is the first article to prove this point.
Impact: SARS-CoV-2 viral load should not be used as a measure of clinical severity of COVID-19 in the pediatric population; however, lower viral load appears to be associated with asymptomatic COVID-19 in older children.

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Millicent Aarah-Bapuah,Stella Sarpomaa Oppong,Anita Ohenewaa Yawson,Gladys Dzansi &Samuel Adjorlolo

Covid-19 and mental health of children and adolescents: A systematic review

https://doi.org/10.1080/23311908.2022.2111849

Published

9-Sep-22

Systematic review

https://www.tandfonline.com/doi/full/10.1080/23311908.2022.2111849

The outbreak of the COVID-19 pandemic had imposed considerable risk on public health, and had generated unprecedented levels of panic. There are increasing concerns over the possible negative impact of COVID-19 on the mental health of children/adolescents. This review was conducted to describe the impact of COVID-19 on the mental health of children and adolescents. An electronic search was conducted in PubMed, CINAHL, MEDLINE, and the WHO Global Health database on COVID-19. The 2020 updated Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guideline and an adapted Joanna Briggs aetiology review methodology were followed in conducting this review. A total of 21 studies from 8 different countries located on 4 continents (Asia, Europe, North America & South America), reporting on sample size of 56,368 met the inclusion criteria. Using the JBI critical appraisal tool for studies reporting on prevalence data, the quality of most of the studies was assessed to be moderate. Prevalence of depression, anxiety and stress was estimated to range from 7.2% to 78%; of anxiety, from 15% to 78%, depression, from 7.2% to 43.7% and stress, at 17.3%. Correlates for COVID −19 related mental health outcomes were identified as female gender and social isolation among others. The COVID-19 pandemic has negatively affected the mental health of children and adolescents. It is recommended that governments and health agencies prioritize mental health, especially for children and adolescents to prevent long-term effects on them.

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Sung Min Cho, Nicole White, Lavienraj Premraj, Denise Battaglini, Jonathon Fanning, Jacky Suen, Gianluigi Li Bassi, John Fraser, Chiara Robba, Matthew Griffee, Bhagteshwar Singh, Barbara Wanjiru Citarella, Laura Merson, Tom Solomon, David Thomson

Neurological manifestations of COVID-19 in adults and children

https://doi.org/10.1093/brain/awac332

Published

10-Sep-22

Study

https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awac332/6695387

Different neurological manifestations of COVID-19 in adults and children and their impact have not been well characterized. We aimed to determine the prevalence of neurological manifestations and in-hospital complications among hospitalized COVID-19 patients and ascertain differences between adults and children. We conducted a prospective multicenter observational study using the International Severe Acute Respiratory and emerging Infection Consortium cohort across 1507 sites worldwide from January/30th/2020 to May/25th/2021. Analyses of neurological manifestations and neurological complications considered unadjusted prevalence estimates for predefined patient subgroups, and adjusted estimates as a function of patient age and time of hospitalization using generalized linear models.
Overall, 161,239 patients (158,267 adults; 2,972 children) hospitalized with COVID-19 and assessed for neurological manifestations and complications were included. In adults and children, the most frequent neurological manifestations at admission were fatigue (adults: 37.4%; children: 20.4%), altered consciousness (20.9%; 6.8%), myalgia (16.9%; 7.6%), dysgeusia (7.4%; 1.9%), anosmia (6.0%; 2.2%), and seizure (1.1%; 5.2%). In adults, the most frequent in-hospital neurological complications were stroke (1.5%), seizure (1%), and central nervous system (CNS) infection (0.2%). Each occurred more frequently in ICU than in non-ICU patients. In children, seizure was the only neurological complication to occur more frequently in ICU vs. non-ICU (7.1% vs. 2.3%, P < .001).
Stroke prevalence increased with increasing age, while CNS infection and seizure steadily decreased with age. There was a dramatic decrease in stroke over time during the pandemic. Hypertension, chronic neurological disease, and the use of extracorporeal membrane oxygenation were associated with increased risk of stroke. Altered consciousness was associated with CNS infection, seizure, and stroke. All in-hospital neurological complications were associated with increased odds of death. The likelihood of death rose with increasing age, especially after 25 years of age.
In conclusion, adults and children have different neurological manifestations and in-hospital complications associated with COVID-19. Stroke risk increased with increasing age, while CNS infection and seizure risk decreased with age.

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Stephenson, Terencea; Shafran, Roza; Ladhani, Shamez N.b

Long COVID in children and adolescents

https://doi.org/10.1097/QCO.0000000000000854

Published

3-Aug-22

Review

https://journals.lww.com/co-infectiousdiseases/Fulltext/2022/10000/Long_COVID_in_children_and_adolescents.14.aspx

Purpose of review
Although acute COVID-19 has been milder in children and young people compared with adults, there is a concern that they may suffer persistent symptoms. There is a need to define the clinical phenotype, determine those most at risk, the natural course of the condition and evaluate preventive and therapeutic strategies for both mental health and physical symptoms.
Recent findings
More recent studies with control groups reported a lower prevalence of persistent symptoms in children and young people exposed to SARS-CoV-2. A systematic review and meta-analysis found that the frequency of the majority of reported persistent symptoms is similar in SARS-CoV-2 positive cases and controls. Children and young people infected with SARS-COV-2 had small but significant increases in persisting cognitive difficulties, headache and loss of smell. Factors associated with persisting, impairing symptoms include increased number of symptoms at the time of testing, female sex, older age, worse self-rated physical and mental health, and feelings of loneliness preinfection.
Summary
This review highlights the importance of a control group in studies following SARS-CoV-2 infection, the need for case definitions and research to understand the outcomes of long COVID in children and young people.

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Domenico Paolo La Regina 1,Daniela Pepino 2,Raffaella Nenna 1ORCID,Elio Iovine 1,Enrica Mancino 1,Gianmarco Andreoli 2,Anna Maria Zicari 1,Alberto Spalice 1,Fabio Midulla

Pediatric COVID-19 Follow-Up with Lung Ultrasound: A Prospective Cohort Study

https://doi.org/10.3390/diagnostics12092202

Published

11-Sep-22

Study

https://www.mdpi.com/2075-4418/12/9/2202/htm

During the COVID-19 pandemic, lung ultrasound (LUS) was widely used to assess SARS-CoV-2 infection. To date, there are patients with persistence of symptoms after acute infection. Therefore, it may be useful to have an objective tool to follow these patients. The aim of our study was to evaluate the presence of LUS artifacts after SARS-CoV-2 infection in children and to analyze the associations between time elapsed since infection and symptomatology during acute infection. We conducted an observational study, enrolling 607 children infected with SARS-CoV-2 in the previous twelve months. All patients performed a LUS and medical history of demographic and clinical data. We observed irregular pleural lines in 27.5%, B-lines in 16.9%, and subpleural consolidations in 8.6% of the cases. These artifacts were more frequently observed in the lower lobe projections. We have observed that the frequency of artifacts decreases with increasing time since infection. In symptomatic patients during COVID infection, B-lines (p = 0.02) were more frequently found. In our sample, some children, even after months of acute infection, have ultrasound artifacts and showed an improvement with the passage of time from the acute episode. Our study provides additional evidence about LUS in children with previous COVID-19 as a support to follow these patients in the months following the infection.

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ME

Anna-Lisa Sorg, MSc1,2; Selina Becht, MSc1; Marietta Jank, MD3; Jakob Armann, MD4; Ulrich von Both, MD5; Markus Hufnagel, MD6; Fabian Lander, MD7; Johannes G. Liese, MD8; Tim Niehues, MD9; Eva Verjans, MD10; Martin Wetzke, MD11; Silvia Stojanov, MD12; Uta Behrends, MD12; Christian Drosten, MD13; Horst Schroten, MD3; Rüdiger von Kries, MD1

Association of SARS-CoV-2 Seropositivity With Myalgic Encephalomyelitis and/or Chronic Fatigue Syndrome Among Children and Adolescents in Germany

https://doi.org/10.1001/jamanetworkopen.2022.33454

Published

27-Sep-22

Study

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2796733

Key Points
Question Is SARS-CoV-2 seropositivity associated with symptoms of myalgic encephalomyelitis and/or chronic fatigue syndrome (ME/CFS) in children and adolescents?
Findings This cross-sectional study of hospital-based SARS-CoV-2 seroprevalence surveys in Germany compared seropositive and seronegative children and adolescents and identified an excess of possible ME/CFS symptoms with serological evidence of preceding SARS-CoV-2 infection. This association almost disappeared with adjustment for confounders and restriction to children and adolescents unaware of preceding infection.
Meaning These findings suggest that the risk of ME/CFS after SARS-CoV-2 infection in children and adolescents may be small and that recall bias may contribute to risk estimates.
Abstract
Importance During the COVID-19 pandemic, a reduction in quality of life and physical and mental health among children and adolescents has been reported that may be associated with SARS-CoV-2 infection and/or containment measures.
Objective To assess the association of SARS-CoV-2 seropositivity with symptoms that may be related to myalgic encephalomyelitis and/or chronic fatigue syndrome (ME/CFS) among children and adolescents.
Design, Setting, and Participants This substudy of the cross-sectional SARS-CoV-2 seroprevalence surveys in Germany (SARS-CoV-2 KIDS) was performed in 9 pediatric hospitals from May 1 to October 31, 2021. Pediatric patients were recruited during an inpatient or outpatient visit regardless of the purpose of the visit. Parental questionnaires and serum samples were collected during clinically indicated blood draws. The parental questionnaire on demographic and clinical information was extended by items according to the DePaul Symptom Questionnaire, a pediatric screening tool for ME/CFS in epidemiological studies in patients aged 5 to 17 years.
Exposures Seropositivity was determined by SARS-CoV-2 IgG antibodies in serum samples using enzyme-linked immunosorbent assays.
Main Outcomes and Measures Key symptoms of ME/CFS were evaluated separately or as clustered ME/CFS symptoms according to the DePaul Symptom Questionnaire, including fatigue.
Results Among 634 participants (294 male [46.4%] and 340 female [53.6%]; median age, 11.5 [IQR, 8-14] years), 198 (31.2%) reported clustered ME/CFS symptoms, including 40 of 100 SARS-CoV-2–seropositive (40.0%) and 158 of 534 SARS-CoV-2–seronegative (29.6%) children and adolescents. After adjustment for sex, age group, and preexisting disease, the risk ratio for reporting clustered ME/CFS symptoms decreased from 1.35 (95% CI, 1.03-1.78) to 1.18 (95% CI, 0.90-1.53) and for substantial fatigue from 2.45 (95% CI, 1.24-4.84) to 2.08 (95% CI, 1.05-4.13). Confinement to children and adolescents with unknown previous SARS-CoV-2 infection status (n = 610) yielded lower adjusted risks for all symptoms except joint pain ME/CFS–related symptoms. The adjusted risk ratio was 1.08 (95% CI, 0.80-1.46) for reporting clustered ME/CFS symptoms and 1.43 (95% CI, 0.63-3.23) for fatigue.
Conclusions and Relevance These findings suggest that the risk of ME/CFS in children and adolescents owing to SARS-CoV-2 infection may be very small. Recall bias may contribute to risk estimates of long COVID-19 symptoms in children. Extensive lockdowns must be considered as an alternative explanation for complex unspecific symptoms during the COVID-19 pandemic.

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Ch176

Anita Slomski

Long COVID in Children

https://doi.org/10.1001/jama.2022.15439

Published

4-Oct-22

Editorial

https://jamanetwork.com/journals/jama/article-abstract/2796961

Postacute sequelae of SARS-CoV-2 infection (PASC) appears to be uncommon in children and presents with features different from long COVID in adults, according to a cohort study published in JAMA Pediatrics that included 659 286 children.

Investigators used electronic health records from 9 US children’s hospitals to collect data on children and adolescents who had an antigen or reverse transcriptase–polymerase chain reaction (RT-PCR) test for SARS-CoV-2. The average age of the children in the study was 8.1 years. In the study sample, 9.1% tested positive for SARS-CoV-2.

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Ch177

Sara Prosperi, Francesco Chiarelli

COVID-19 and diabetes in children

https://doi.org/10.6065/apem.2244150.075

Published

30-Sep-22

Review

https://e-apem.org/journal/view.php?number=955

This review describes the impact of coronavirus disease 2019 (COVID-19) in children and adolescents, investigating changes in diabetes presentation during the COVID-19 pandemic, possible links between severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection and diabetes, and mechanisms of pancreatic β-cell destruction. Although glycemic control in individuals with already known diabetes mellitus did not worsen during the pandemic, there was a worrying increase in diabetic ketoacidosis in children with new-onset diabetes, probably due to containment measures and delayed access to emergency departments. Moreover, new evidence suggests that SARS-CoV-2 has the capacity to directly and indirectly induce pancreatic β-cell destruction, and the risk of newly diagnosed diabetes after COVID-19 increased in both children and adults. While long-term studies continue to follow children with SARS-CoV-2 infection, this review discusses available findings on the relationship between COVID-19 and diabetes. It is important to emphasize the need to maintain close links between families of children with chronic conditions and their pediatricians, as well as to promote early access to healthcare services, in order to reduce dangerous delays in diabetes diagnosis and prevent diabetic ketoacidosis.

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Corey Diamond, PharmD

Study gives clinicians snapshot into long COVID for children

https://doi.org/10.1016/j.ptdy.2022.10.018

Published

1-Oct-22

https://www.pharmacytoday.org/article/S1042-0991(22)00801-5/fulltext

Their regression model found that children who tested positive for COVID-19 hospitalized for more than 48 hours had an over 2.5-fold stronger association with post–COVID-19 conditions compared to nonhospitalized children. These conditions were also strongly associated with symptom quantity at the index ED visit. Compared to children with 3 or fewer symptoms on ED presentation, children who tested positive for COVID-19 with 7 or more symptoms and 4 or more symptoms had about a 4.5-fold and 2.5-fold stronger association with post–COVID-19 conditions at 90 days, respectively.
The final risk factor they reported was age: Children who tested positive for COVID-19 who were 14 years or older had about a 2.5-fold stronger association with post–COVID-19 conditions at 90 days compared to children younger than one year.
Strength of the design
As a result of limitations in study methodology early in the pandemic, the literature has presented conflicting evidence of whether children were at risk of manifesting long COVID after acute COVID-19 infection. Early reports from 2020 and 2021 estimated that post–COVID-19 conditions occurred in up to 58% of pediatric patients with COVID-19, while other reports describe no disparity.
Funk and colleagues’ study now provides important insights into the characterization of COVID-19 in children as it is the first large prospective cohort study to investigate long COVID in children seeking ED care with advanced methodology that significantly mitigates bias.
“Our PCC [post-COVID-19 conditions] assessment approach, which clarifies the presence of the reported symptoms prior to the index ED visit, represents a methodological advance compared with prior assessments that focused on the presence or absence of symptoms in the preceding 7 days,” stated the authors.
They go on to say that by including children with repeat COVID-19 test results within 14 days of the index ED visit, the researchers were able to eliminate the risk of false-negative tests results. “Thus, our evaluation provides a realistic estimate of PCC prevalence along with a comparator group.”

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Kamran Hessami, MD1; Amir Hossein Norooznezhad, MD2; Sonia Monteiro, MD3; Enrico R. Barrozo, PhD4; Abolfazl Shirdel Abdolmaleki, MD, MPH5; Sara E. Arian, MD6; Nikan Zargarzadeh, MD7; Lara S. Shekerdemian, MD8; Kjersti M. Aagaard, MD, PhD4; Alireza A. Shamshirsaz, MD1

COVID-19 Pandemic and Infant Neurodevelopmental Impairment
A Systematic Review and Meta-analysis

https://doi.org/10.1001/jamanetworkopen.2022.38941

Published

28-Oct-22

Systematic Review and Meta-analysis

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2797911

Key Points
Question Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?
Findings This meta-analysis of 8 studies including 21 419 infants found that 7% of infants who had neurodevelopmental screening during the COVID-19 pandemic were at risk of neurodevelopmental impairment, and 12% of those with gestational exposure to SARS-CoV-2 were at risk for neurodevelopmental impairment. Communication impairment was the sole neurodevelopmental domain of significantly increased risk of occurrence during the COVID-19 pandemic.
Meaning These findings suggest that overall neurodevelopment was not changed by the COVID-19 pandemic, but birth or being raised during the SARS-CoV-2 pandemic, regardless of gestational exposure, was associated with a significant risk of communication impairment among the infants.
Abstract
Importance - Primary studies proposed that aberrant maternal antiviral immunity and/or giving birth in quarantine, such as during the ongoing COVID-19 pandemic, may be associated with the risk of neurodevelopmental impairment (NDI) in offspring.
Objectives - To evaluate the associations of birth and being raised during the COVID-19 pandemic with risk of NDI among infants and to assess the association of gestational exposure to SARS-CoV-2 with risk of NDI.
Data Sources - PubMed, Web of Science, Scopus, Embase, and preprint servers were systematically searched from inception to March 25, 2022.
Study Selection - Studies evaluating the neurodevelopment of infants born during the SARS-CoV-2 pandemic were included in this systematic review and meta-analysis. Studies using Ages and Stages Questionnaires, Third Edition (ASQ-3), were used for quantitative meta-analysis.
Data Extraction and Synthesis - Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses, a random-effects model meta-analysis was used to pool the proportion and odds ratios (ORs) of overall NDI, as well as each developmental domain on ASQ-3 with the corresponding 95% CI.
Main Outcomes and Measures - The primary outcome was the risk of overall NDI among infants screened during the pandemic vs prepandemic. The secondary outcome was the comparison of NDI by ASQ-3 domain among infants born to women with known gestational exposure to SARS-CoV-2 vs no exposure.
Results - A total of 8 studies were included, including 21 419 infants (11 438 screened in pandemic and 9981 in prepandemic period). NDI was present in 330 of 8992 infants (7%; 95% CI, 4%-10%) screened during the COVID-19 pandemic from January 2020 to January 2021. Among the pandemic cohort, the prevalence of NDI among infants with gestational exposure to SARS-CoV-2 was 77 of 691 (12%; 95% CI, 6%-18%). Compared with the prepandemic cohort (2015-2019), the pandemic cohort was more likely to have communication impairment (OR, 1.70; 95% CI, 1.37-2.11; P < .001), without significant differences in other ASQ-3 domains (eg, gross motor, fine motor, personal-social, and problem-solving). In contrast, maternal SARS-CoV-2 infection was not associated with significant differences in any neurodevelopment domain in offspring, except for increasing the odds of fine motor impairment (OR, 3.46; 95% CI, 1.43-8.38; P < .001).
Conclusions and Relevance In this systematic review and meta-analysis examining the association between COVID-19 pandemic and the risk of NDI, findings suggest that overall neurodevelopment in the first year of life was not changed by either being born or raised during the SARS-CoV-2 pandemic or by gestational exposure to SARS-CoV-2. Interestingly, the first year of life during the COVID-19 pandemic, regardless of maternal infection, was significantly associated with the risk of communication delay among the offspring.

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by Alba Gonzalez-Aumatell 1,2,*,†ORCID,Maria Victoria Bovo 1,†,Clara Carreras-Abad 1ORCID,Sara Cuso-Perez 1,Èlia Domènech Marsal 1,Roser Coll-Fernández 3,Aroia Goicoechea Calvo 3,Maria Giralt-López 4,5ORCID,Antonia Enseñat Cantallops 6,Sara Moron-Lopez 7,8ORCID,Javier Martinez-Picado 7,8,9,10ORCID,Paula Sol Ventura 11ORCID,Carlos Rodrigo 1,2ORCID andMaria Méndez Hernández 1,2ORCID

Social, Academic, and Health Status Impact of Long COVID on Children and Young People: An Observational, Descriptive, and Longitudinal Cohort Study

https://doi.org/10.3390/children9111677

Published

31-Oct-22

Study

https://www.mdpi.com/2227-9067/9/11/1677

There is a lack of evidence of the health impacts due to long COVID among children and young people (CYP). The objective of this study is to determine the main clinical characteristics of long COVID in CYP and to investigate the academic, social, and health status impacts of long COVID in this population. An observational, descriptive, and longitudinal study on CYP who presented COVID-19 symptoms for more than twelve weeks after SARS-CoV-2 infection was performed between December 2020 and May 2021. Fifty CYP were included, with a median age of 14.1 years, 33 (66%) were female, and 17 (34%) had a relative diagnosed with long COVID. Since the initial infection and up to the first visit, CYP had persisting symptoms for a median of 4.1 months, and for 18 (36%) CYP these symptoms persisted for more than 6 months. Fatigue (100%), neurocognitive disorders (74%), muscular weakness (74%), and headache (72%) were the most reported symptoms. A total of 9 (18%) CYP could not attend school, 17 (34%) had a reduced schedule, 33 (66%) showed a decreased school performance, and 68% had stopped extracurricular activities. This preliminary study shows the impact that long COVID has on the health, academic, and social life of CYP.

3046

Ch181

Leonardo Di Gennaro, Piero Valentini, Silvia Sorrentino, Maria Antonietta Ferretti, Erica De Candia, Maria Basso, Stefano Lancellotti, Raimondo De Cristofaro, Cristina De Rose, Francesco Mariani, Rosa Morello, Ilaria Lazzareschi, Louise Sigfrid, Daniel Munblit & Danilo Buonsenso

Extended coagulation profile of children with Long Covid: a prospective study

https://doi.org/10.1038/s41598-022-23168-y

Published

1-Nov-22

Study

https://www.nature.com/articles/s41598-022-23168-y

Emerging data suggests that endotheliopathy changes can be associated with post covid condition (PCC) in adults. Research on the matter in children is lacking. We analyzed an extended coagulation profile including biomarkers of endothelial damage in children with PCC and compared it with a control group of children that fully recovered post- SARS-CoV-2 infection. A case-control study enrolling children below 18 years of age with previous microbiologically confirmed SARS-CoV-2 infection in a pediatric post-covid unit in Italy ≥ 8 weeks after the initial infection. Samples were taken at 8 and 12 weeks after the SARS-CoV-2 diagnosis and analyzed for coagulation profiling (fibrinogen, prothrombin time, international normalized ratio, activated partial thromboplastin time, d-dimers, factor VIII coagulant activity, plasma von Willebrand factor (VWF) antigen and VWF ristocetin cofactor (RC)). We compared coagulation profiles in samples from children identified with PCC (at least one, or three or more symptoms, which could not be explained by an alternative diagnosis, at the 8- and 12-week follow-up assessment using the pediatric Long Covid International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) survey. Seventy-five children were enrolled, 49.3% were females, the median age was 10.2 (IQR 4.9) years. Forty-six (61%) of the children had at least one persisting symptom at the eight weeks post-onset, (PCC8); 39/75 (52%) had persistent symptoms for more than 12 weeks (PCC12) and 15/75(32%) had at least three persisting symptoms (PCC ≥ 3) at 12 weeks. Children with PCC presented more frequently with abnormal D-Dimer levels above the reference range compared to children that had fully recovered at the 8–12 weeks (39.1% vs. 17.2%, p = 0.04), and 12 week follow up or more (41% vs. 17.2%, p = 0.05), and in children with three or more symptoms at 12 weeks follow up compared to those that had recovered (64.3% vs. 22.2%, p = 0.002). For the other coagulation profiles, there were abnormal values detected for VWF, FVIII, RC and Fibrinogen but no significant differences between children with PCC compared to controls. Although the majority of children in our cohort showed coagulation profile within or close to normal ranges, we found that a higher proportion of children with PCC, and specifically those with a more severe spectrum characterized with three or more persisting symptoms, had abnormal D-dimer levels compared to other children that fully recovered from an acute SARS-CoV-2 infection.

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Ch182

Martin Roessler ,Falko Tesch,Manuel Batram,Josephine Jacob,Friedrich Loser,Oliver Weidinger,Danny Wende,Annika Vivirito,Nicole Toepfner,Franz Ehm,Martin Seifert,Oliver Nagel,Christina König,Roland Jucknewitz,Jakob Peter Armann,Reinhard Berner,Marina Treskova-Schwarzbach,Dagmar Hertle,Stefan Scholz,Stefan Stern,Pedro Ballesteros,Stefan Baßler,Barbara Bertele,Uwe Repschläger,Nico Richter,Cordula Riederer,Franziska Sobik,Anja Schramm,Claudia Schulte,Lothar Wieler,Jochen Walker,Christa Scheidt-Nave,Jochen Schmitt

Post-COVID-19-associated morbidity in children, adolescents, and adults: A matched cohort study including more than 157,000 individuals with COVID-19 in Germany

https://doi.org/10.1371/journal.pmed.1004122

Published

10-Nov-22

Study

https://journals.plos.org/PLoSmedicine/article?id=10.1371/journal.pmed.1004122

Background
Long-term health sequelae of the Coronavirus Disease 2019 (COVID-19) are a major public health concern. However, evidence on post-acute COVID-19 syndrome (post-COVID-19) is still limited, particularly for children and adolescents. Utilizing comprehensive healthcare data on approximately 46% of the German population, we investigated post-COVID-19-associated morbidity in children/adolescents and adults.
Methods and findings
We used routine data from German statutory health insurance organizations covering the period between January 1, 2019 and December 31, 2020. The base population included all individuals insured for at least 1 day in 2020. Based on documented diagnoses, we identified individuals with polymerase chain reaction (PCR)-confirmed COVID-19 through June 30, 2020. A control cohort was assigned using 1:5 exact matching on age and sex, and propensity score matching on preexisting medical conditions. The date of COVID-19 diagnosis was used as index date for both cohorts, which were followed for incident morbidity outcomes documented in the second quarter after index date or later.Overall, 96 prespecified outcomes were aggregated into 13 diagnosis/symptom complexes and 3 domains (physical health, mental health, and physical/mental overlap domain). We used Poisson regression to estimate incidence rate ratios (IRRs) with 95% confidence intervals (95% CIs). The study population included 11,950 children/adolescents (48.1% female, 67.2% aged between 0 and 11 years) and 145,184 adults (60.2% female, 51.1% aged between 18 and 49 years). The mean follow-up time was 236 days (standard deviation (SD) = 44 days, range = 121 to 339 days) in children/adolescents and 254 days (SD = 36 days, range = 93 to 340 days) in adults. COVID-19 and control cohort were well balanced regarding covariates. The specific outcomes with the highest IRR and an incidence rate (IR) of at least 1/100 person-years in the COVID-19 cohort in children and adolescents were malaise/fatigue/exhaustion (IRR: 2.28, 95% CI: 1.71 to 3.06, p < 0.01, IR COVID-19: 12.58, IR Control: 5.51), cough (IRR: 1.74, 95% CI: 1.48 to 2.04, p < 0.01, IR COVID-19: 36.56, IR Control: 21.06), and throat/chest pain (IRR: 1.72, 95% CI: 1.39 to 2.12, p < 0.01, IR COVID-19: 20.01, IR Control: 11.66). In adults, these included disturbances of smell and taste (IRR: 6.69, 95% CI: 5.88 to 7.60, p < 0.01, IR COVID-19: 12.42, IR Control: 1.86), fever (IRR: 3.33, 95% CI: 3.01 to 3.68, p < 0.01, IR COVID-19: 11.53, IR Control: 3.46), and dyspnea (IRR: 2.88, 95% CI: 2.74 to 3.02, p < 0.01, IR COVID-19: 43.91, IR Control: 15.27). For all health outcomes combined, IRs per 1,000 person-years in the COVID-19 cohort were significantly higher than those in the control cohort in both children/adolescents (IRR: 1.30, 95% CI: 1.25 to 1.35, p < 0.01, IR COVID-19: 436.91, IR Control: 335.98) and adults (IRR: 1.33, 95% CI: 1.31 to 1.34, p < 0.01, IR COVID-19: 615.82, IR Control: 464.15). The relative magnitude of increased documented morbidity was similar for the physical, mental, and physical/mental overlap domain. In the COVID-19 cohort, IRs were significantly higher in all 13 diagnosis/symptom complexes in adults and in 10 diagnosis/symptom complexes in children/adolescents. IRR estimates were similar for age groups 0 to 11 and 12 to 17. IRs in children/adolescents were consistently lower than those in adults. Limitations of our study include potentially unmeasured confounding and detection bias.
Conclusions
In this retrospective matched cohort study, we observed significant new onset morbidity in children, adolescents, and adults across 13 prespecified diagnosis/symptom complexes, following COVID-19 infection. These findings expand the existing available evidence on post-COVID-19 conditions in younger age groups and confirm previous findings in adults.

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Ch183

RJ Langley, PD Burns, PL Davies, C Presslie

P230 Assessment of Cardio-pulmonary function in children and adolescents with suspected long COVID

http://dx.doi.org/10.1136/thorax-2022-BTSabstracts.362

Published

11-Nov-22

Study

https://thorax.bmj.com/content/77/Suppl_1/A207.abstract

Introduction Persistent respiratory symptoms and exercise intolerance following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents is common.1 Our aim was to review the clinical data on patients who had been referred with suspected long COVID (LC). Unfortunately, there is a lack of an agreed definition for LC. The patient cohort were referred with persistent respiratory symptoms/signs (cough, exertional dyspnoea or wheeze) for at least 3 months following confirmed (PCR or antigen test positive) mild SARS-CoV-2 infection that did not require hospitalisation.
Methods This was a retrospective analysis of clinical data obtained during clinical assessment. Patients had undergone pulmonary function tests (PFTs) including; spirometry, Single breath transfer factor (T LCO) and static lung volume measurements (Vyntus Body – VyaireTM Medical) followed by an incremental maximal ramp cardiopulmonary exercise testing (CPET) performed on a cycle ergometer (Jaeger CPX & Vyntus ONE – VyaireTM Medical).
Results Seven patients (four male) with suspected LC had undergone PFTs and CPET. Demographics and summary data are presented (table 1). Five had normal PFT results. Of the two that had abnormal PFTs both had co-existing morbidities. One had mild airflow obstruction (previous pneumothorax) and the other had a restrictive defect (Di-George syndrome and obesity). Three patients had a reduced peak Oxygen uptake (VO2peak < 85% predicted). The cardiovascular and gas exchange response to incremental exercise were normal and there was no evidence of ventilatory limitation or dysfunctional breathing in any of the patients.
Conclusions Although only a small cohort was examined, this study suggests that SARS-CoV-2 infection does not seem to be causing any longstanding cardiopulmonary function impairment in children and adolescents. Whilst there may be pathophysiological changes following SARS-CoV-2 infection, as previously reported in adults,2 a reduced aerobic capacity is seen in some of these patients and this may due to physical de-conditioning rather than any physiological impairment caused by SARS-CoV-2 infection.

3049

Ch184

CamilleBréhin

Diagnostic d’un syndrome inflammatoire multi-systémique pédiatrique associé à la COVID-19Diagnosis of a Pediatric Inflammatory multisystemic Syndrome associated with COVID-19

https://doi.org/10.1016/j.jpp.2022.11.001

Published

15-Nov-22

Article

https://www.sciencedirect.com/science/article/pii/S0987798322001360

Résumé
Suite à la propagation de la pandémie de coronavirus 2019 (COVID-19), une nouvelle entité pathologique est apparue, définie comme le syndrome inflammatoire multi-systémique pédiatrique associé à la COVID-19 (PIMS-TS), ou le syndrome inflammatoire multisystémique chez l’enfant (MIS-C).
Cet article a pour but de détailler la démarche pour établir le diagnostic de syndrome inflammatoire multi-systémique pédiatrique (PIMS).
Le PIMS est une affection rare et grave. Cette affection nécessite d’être détectée précocement pour enclencher une prise en charge hospitalière en urgence. Il faut évoquer un PIMS chez un enfant présentant les signes d’appel suivants : fièvre élevée avec altération marquée de l’état général et présentant des signes digestifs. Ce syndrome doit être envisagé chez les enfants présentant des caractéristiques de la maladie de Kawasaki (typique ou atypique) ou du syndrome de choc toxique ou en cas de tableau d'insuffisance cardiaque aigue/myocardite aigue.
Comme ce domaine évolue rapidement, des modifications dans les mois à venir sont possibles, au fur et à mesure de l’évolution de la pandémie.
Abstract
Following the spread of the 2019 coronavirus (COVID-19) pandemic, a new disease entity has emerged, defined as Pediatric Inflammatory Multisystemic Syndrome temporally associated with COVID-19 (PIMS-TS), or Multisystem Inflammatory Syndrome in Children (MIS-C).
The purpose of this article is to detail the approach to establishing the diagnosis of pediatric multisystemic inflammatory syndrome (PIMS).
PIMS is a rare and serious condition. This condition needs to be detected early to initiate emergency hospital management. PIMS should be considered in a child presenting with the following warning signs: high fever with marked deterioration in general condition and digestive signs. This syndrome should be considered in children with features of Kawasaki disease (typical or atypical) or toxic shock syndrome or in cases of acute heart failure/acute myocarditis.
As this area is rapidly evolving, changes in the coming months are possible; as the pandemic progresses.

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Alexandra Brugler Yonts, MD, Justin Burton, MD, and Linda Jones Herbert, PhD

A Review of Current Evaluation and Management Strategies in Pediatric Postacute Sequelae of COVID-19

https://doi.org/10.3928/19382359-20220913-08

Published

1-Nov-22

Review

https://journals.healio.com/doi/abs/10.3928/19382359-20220913-08

Pediatric postacute sequelae of COVID-19 (pPASC), or long COVID, is a complex, heterogeneous, multisystem syndrome that leads to disruption in the lives of children and adolescents for months, and possibly years, after recovery from acute SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection. While the underlying pathophysiologic mechanisms of PASC are still under investigation, clinicians are facing the immediate challenges of treating these patients. In this article, we provide an overview of the current multidisciplinary evaluation of patients with pPASC. We also offer guidance on the medical, psychological, and rehabilitative management strategies based on experience with both pPASC and patients with other postviral syndromes

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Alexandra Brugler Yonts, MD, Justin Burton, MD, and Linda Jones Herbert, PhD

Pediatric Long-COVID: A Review of the Definition, Epidemiology, Presentation, and Pathophysiology

https://doi.org/10.3928/19382359-20220913-06

Published

1-Nov-22

Review

https://journals.healio.com/doi/abs/10.3928/19382359-20220913-06

Although children have been largely spared the most severe consequences of acute infection with SARS-CoV-2 virus, it is estimated that up to one-quarter of the more than 14 million children diagnosed as having coronavirus disease 2019 (COVID-19) have developed persistent symptoms of fatigue, postexertional malaise, neurologic and cognitive symptoms, and other symptoms that interfere with activities of daily living for months after their initial illness. Pediatric postacute sequelae of COVID-19 (pPASC), or long-COVID, is a complex, heterogeneous, postviral condition involving multiple body systems and is likely attributable to several concurrent underlying physiologic processes, including damage from direct viral invasion, endovascular dysfunction and microthrombosis, viral persistence, and the development of autoimmunity. In this review, we explore the current state of the literature regarding definition, epidemiology, clinical presentation, and proposed pathophysiologic mechanisms of pPASC.

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Alpana Waghmare, MD
Diego R. Hijano, MD MSc

SARS-CoV-2 infection and COVID-19 in children

https://doi.org/10.1016/j.ccm.2022.11.014

Published

21-Nov-22

Review

https://www.chestmed.theclinics.com/article/S0272-5231(22)00130-7/fulltext

Key points
•SARS-CoV-2 prevalence is high in pediatric populations, especially during the Omicron variant and subvariant waves.
•Clinical manifestations of COVID-19 are generally less severe than in adults, though severe disease can occur in high-risk individuals.
•Multisystem inflammatory syndrome in children is a unique post-COVID phenomenon that occurs rarely, mostly in children approximately one month after acute SARS-CoV-2 infection.
•SARS-CoV-2 vaccination remains crucial to prevent severe disease in children.
•Treatment considerations generally follow recommendations for adults and older adolescents should be managed similarly to adults.
Epidemiology
Several databases are available to determine the burden of SARS-CoV-2 infection and COVID-19 in pediatric populations. The COVerAGE database (COVerAGE-DB), an open-access database from over 103 countries, recorded 56.9 million COVID-19 cases children and adolescents under 20 years of age with a prevalence range from 0–37% of the national caseload across countries1. Of these, 63% occurred among adolescents ages 10–19, and 37% among children ages 0–9. The Pediatric COVID-19 case registry, the largest registry in the US, collected information from 12,917 children with COVID-19 during the first year of the pandemic2. Infections were most common among those 12-18 years of age (31%), followed by 5-11 years of age (24%) with no significant difference in gender. Most cases were in White Caucasians followed by in Blacks. One in four cases were in Hispanic/Latinos. Reported COVID-19 cases in children increased significantly in 2022 during the Omicron surge. In the US alone, more than 5 million of a total 13 million cases were diagnosed between January 1st and May 12th, 2022 and the percent of total cases occurring in children increased from 10% to 30%3, 4, 5. As of February 2022, almost 75% of children and adolescents had serologic evidence of previous infection with SARS-CoV-2, with approximately one third becoming newly seropositive since December 2021 with the highest in the age group with lowest vaccination rates (5–11 years, 28%)6.
Most children appear to have asymptomatic, mild, or moderate disease and recover within one to two weeks of disease onset7, 8, 9. However, children with COVID-19 may develop severe complications, such as respiratory distress syndrome, myocarditis, acute renal failure, and multisystem organ failure10, 11, 12, 13, 14. Around 0.1-1.5% of pediatric COVID-19 patients require hospitalization, representing close to 5% of all pediatric hospitalizations in the US3. Age, race, and ethnicity have been described as risk factors for hospitalization with the highest rates seen in those <12 months of age, Hispanics, and Non-Hispanic Black children15, 16, 17, 18, 19, 20. The annual COVID-19-associated hospitalization rate by age is shown in Table 1. Among children hospitalized with COVID-19 in the US, between 28% to 40% required ICU, 6% to 18% needed invasive mechanical ventilation, and up to 3% died21,22.

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Réka Garai, Péter Krivácsy, Vivien Herczeg, Fanni Kovács, Bálint Tél, Judit Kelemen, Anna Máthé, Eszter Zsáry, Johanna Takács, Dániel Sándor Veres & Attila J. Szabó

Clinical assessment of children with long COVID syndrome

https://doi.org/10.1038/s41390-022-02378-0

Published

7-Dec-22

Study

https://www.nature.com/articles/s41390-022-02378-0

Background
There is a need for further understanding pediatric long COVID syndrome (LCS) to be able to create specific case definitions and guidelines for providing good clinical care.
Methods
Medical records of all LCS patients who presented at our designated LC clinic were collected. We carried out descriptive analyses summarizing the history, clinical presentation, and findings of children, while doing a diagnosis of exclusion with multi-disciplinary medical examinations (physical, laboratory, and radiological examinations, specialist consultations, etc.) without a control group.
Results
Most children reported at least minor impairment to their quality of life, of which 17 (23%) had moderate or severe difficulties. Findings that could be directly connected to the linked complaint category were observed in an average of 18%, respiratory symptoms with objective alterations being the most frequent (37%). Despite our detecting mostly non-specific conditions, in a smaller number we identified well-described causes such as autoimmune thyroiditis (7%).
Conclusions
The majority of children stated an impairment in their quality of life, while symptom-related conditions were detected only in a minority. Controlled studies are needed to separate the effect of the pandemic era from the infection itself. Evidence-based pediatric guidelines could aid to rationalize the list of recommended examinations.
Impact
Long COVID syndrome is a complex entity with a great impact on children’s everyday lives. Still, there is no clear guidance for pediatric clinical management. Systematic, detailed studies with medical assessment findings could aid the process of creating evidence-based guidelines.
We present validated systematic information collected during in-person medical assessments with detailed medical findings and quality of life changes.
While making a diagnosis of exclusion, we could confirm symptom-related conditions only in a minority of children; however, the majority reported at least minor impairment to their quality of life.

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Roxane Dumont, Viviane Richard, Elsa Lorthe, Andrea Loizeau, Francesco Pennacchio, María-Eugenia Zaballa, Hélène Baysson, Mayssam Nehme, Anne Perrin, Arnaud G. L’Huillier, Laurent Kaiser, Rémy P. Barbe, Klara M. Posfay-Barbe, Silvia Stringhini, SEROCoV-KIDS study group & Idris Guessous

A population-based serological study of post-COVID syndrome prevalence and risk factors in children and adolescents

https://doi.org/10.1038/s41467-022-34616-8

Published

29-Nov-22

Study

https://www.nature.com/articles/s41467-022-34616-8

Post-COVID syndrome remains poorly studied in children and adolescents. Here, we aimed to investigate the prevalence and risk factors of pediatric post-COVID in a population-based sample, stratifying by serological status. Children from the SEROCoV-KIDS cohort study (State of Geneva, Switzerland), aged 6 months to 17 years, were tested for anti-SARS-CoV-2 N antibodies (December 2021-February 2022) and parents filled in a questionnaire on persistent symptoms in their children (lasting over 12 weeks) compatible with post-COVID. Of 1034 children tested, 570 (55.1%) were seropositive. The sex- and age-adjusted prevalence of persistent symptoms among seropositive children was 9.1% (95%CI: 6.7;11.8) and 5.0% (95%CI: 3.0;7.1) among seronegatives, with an adjusted prevalence difference (ΔaPrev) of 4.1% (95%CI: 1.1;7.3). Stratifying per age group, only adolescents displayed a substantial risk of having post-COVID symptoms (ΔaPrev = 8.3%, 95%CI: 3.5;13.5). Identified risk factors for post-COVID syndrome were older age, having a lower socioeconomic status and suffering from chronic health conditions, especially asthma. Our findings show that a significant proportion of seropositive children, particularly adolescents, experienced persistent COVID symptoms. While there is a need for further investigations, growing evidence of pediatric post-COVID urges early screening and primary care management.

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Manjula D. Nugawela, Terence Stephenson, Roz Shafran, Bianca L. De Stavola, Shamez N. Ladhani, Ruth Simmons, Kelsey McOwat, Natalia Rojas, Emma Dalrymple, Emily Y. Cheung, Tamsin Ford, Isobel Heyman, Esther Crawley & Snehal M. Pinto Pereira

Predictive model for long COVID in children 3 months after a SARS-CoV-2 PCR test

https://doi.org/10.1186/s12916-022-02664-y

Published

30-Nov-22

Study

https://link.springer.com/article/10.1186/s12916-022-02664-y

Background
To update and internally validate a model to predict children and young people (CYP) most likely to experience long COVID (i.e. at least one impairing symptom) 3 months after SARS-CoV-2 PCR testing and to determine whether the impact of predictors differed by SARS-CoV-2 status.
Methods
Data from a nationally matched cohort of SARS-CoV-2 test-positive and test-negative CYP aged 11–17 years was used. The main outcome measure, long COVID, was defined as one or more impairing symptoms 3 months after PCR testing. Potential pre-specified predictors included SARS-CoV-2 status, sex, age, ethnicity, deprivation, quality of life/functioning (five EQ-5D-Y items), physical and mental health and loneliness (prior to testing) and number of symptoms at testing. The model was developed using logistic regression; performance was assessed using calibration and discrimination measures; internal validation was performed via bootstrapping and the final model was adjusted for overfitting.
Results
A total of 7139 (3246 test-positives, 3893 test-negatives) completing a questionnaire 3 months post-test were included. 25.2% (817/3246) of SARS-CoV-2 PCR-positives and 18.5% (719/3893) of SARS-CoV-2 PCR-negatives had one or more impairing symptoms 3 months post-test. The final model contained SARS-CoV-2 status, number of symptoms at testing, sex, age, ethnicity, physical and mental health, loneliness and four EQ-5D-Y items before testing. Internal validation showed minimal overfitting with excellent calibration and discrimination measures (optimism-adjusted calibration slope: 0.96575; C-statistic: 0.83130).
Conclusions
We updated a risk prediction equation to identify those most at risk of long COVID 3 months after a SARS-CoV-2 PCR test which could serve as a useful triage and management tool for CYP during the ongoing pandemic. External validation is required before large-scale implementation.

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Ch191

G. Biesbroek ,B. Kapitein ,I. M. Kuipers ,M. P. Gruppen,D. van Stijn,T. E. Peros,M. van Veenendaal,M. H. A. Jansen,C. W. van der Zee,M. van der Kuip,E. G. J. von Asmuth,M. G. Mooij,M. E. J. den Boer,G. W. Landman,M. A. van Houten,D. Schonenberg-Meinema,A. M. Tutu van Furth,M. Boele van Hensbroek,H. Scherpbier,K. E. van Meijgaarden,T. H. M. Ottenhoff,S. A. Joosten,N. Ketharanathan,M. Blink,C. L. H. Brackel,H. L. Zaaijer,P. Hombrink,J. M. van den Berg,E. P. Buddingh ,T. W. Kuijpers

Inflammatory responses in SARS-CoV-2 associated Multisystem Inflammatory Syndrome and Kawasaki Disease in children: An observational study

https://doi.org/10.1371/journal.pone.0266336

Published

30-Nov-22

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0266336

Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe inflammatory disease in children related to SARS-CoV-2 with multisystem involvement including marked cardiac dysfunction and clinical symptoms that can resemble Kawasaki Disease (KD). We hypothesized that MIS-C and KD might have commonalities as well as unique inflammatory responses and studied these responses in both diseases. In total, fourteen children with MIS-C (n=8) and KD (n=6) were included in the period of March-June 2020. Clinical and routine blood parameters, cardiac follow-up, SARS-CoV-2-specific antibodies and CD4+ T-cell responses, and cytokine-profiles were determined in both groups. In contrast to KD patients, all MIS-C patients had positive Spike protein-specific CD3+CD4+ T-cell responses. MIS-C and KD patients displayed marked hyper-inflammation with high expression of serum cytokines, including the drug-targetable interleukin (IL)-6 and IFN-γ associated chemokines CXCL9, 10 and 11, which decreased at follow-up. No statistical differences were observed between groups. Clinical outcomes were all favourable without cardiac sequelae at 6 months follow-up. In conclusion, MIS-C and KD-patients both displayed cytokine-associated hyper-inflammation with several high levels of drug-targetable cytokines.

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Ch192

Fauveau, Valentin; Jacobi, Adam; Bernheim, Adam; Chung, Michael; Benkert, Thomas; Fayad, Zahi A.; Feng, Li

Performance of spiral UTE-MRI of the lung in post-COVID patients

https://doi.org/10.1016/j.ijporl.2022.111406

Published

Study

https://www.sciencedirect.com/science/article/pii/S0165587622003676

Objectives
The audio-vestibular equivalent of neurological symptoms secondary to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been discussed; however, it has not been fully clarified. Although it has been reported that the vestibulocochlear system is affected in adult coronavirus disease-2019 (COVID-19) patients, there is no study in the literature in which the pediatric patient group with COVID-19 was evaluated comprehensively with auditory and vestibular tests. In this study, the short-term damage caused by SARS-CoV-2 in the vestibulocochlear system in pediatric patients was examined.
Methods
This study aimed to evaluate the vestibulocochlear system of pediatric patients (aged 9–15 years) with a recent history of COVID-19. The study included 35 individuals with a recent history of COVID-19 and 35 age-gender-matched healthy individuals (control group). Pure tone audiometry, suppressed otoacoustic emission (OAE), video head impulse test (VHIT), and cervical and ocular vestibular evoked myogenic potentials (c/o-VEMP) tests were administered to all participants following their otoscopic examinations, and the obtained data were compared between the two groups.
Results
When the data obtained with pure tone audiometry were compared, statistically significant differences were found between the groups at four different frequencies (1000, 2000, 4000, and 8000 Hz) in favor of the control group. There was a statistically significant difference between the groups in the signal-to-noise ratio (SNR) values obtained before noise at 2800 Hz and before and after noise at 4000 Hz. VHIT lateral gain, LARP gain, and RALP gain were statistically significantly lower in the COVID-19 group than in the control group (p < 0.05). VHIT lateral asymmetry parameter was measured higher in the COVID-19 group than in the control group, and this difference was statistically significant (p < 0.05). In the VHIT test, the asymmetry parameter was significantly higher in the COVID-19 group (p < 0.05). In the o-VEMP test, n10 latency, p15 latency, n10-p15 interlatency, n10-p15 interpeak amplitude, and asymmetry parameters were measured, and no statistically significant difference was found between the COVID-19 group and the control group (p > 0.05).
Conclusion
Evidence was obtained that the cochleovestibular system was damaged in pediatric patients in the early post-COVID-19 period.

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Melgar, Michael

Council of State and Territorial Epidemiologists/CDC Surveillance Case Definition for Multisystem Inflammatory Syndrome in Children Associated with SARS-CoV-2 Infection — United States

https://doi.org/10.15585/mmwr.rr7104a1

Published

Recommendations and Reports

https://www.cdc.gov/mmwr/volumes/71/rr/rr7104a1.htm

Since May 14, 2020, CDC has conducted national surveillance for multisystem inflammatory syndrome in children (MIS-C) associated with infection with SARS-CoV-2, the virus that causes COVID-19, among persons aged <21 years using a CDC case definition based on public health need and data from early reports of patients with this condition. Recent analyses of accumulated data indicated that certain criteria from the 2020 CDC MIS-C case definition performed better than others in distinguishing MIS-C from other illnesses and that certain other criteria likely contributed to misclassification. To incorporate lessons learned from MIS-C surveillance and public health investigations and to improve feasibility of implementation by surveillance staff at state, local, territorial, and tribal health departments, the Council of State and Territorial Epidemiologists (CSTE) and CDC developed a CSTE/CDC position statement (approved by CSTE in 2022) that includes an MIS-C surveillance case definition for voluntary reporting to CDC (effective January 1, 2023).

This report summarizes the evidence and rationale supporting the components of the CSTE/CDC MIS-C surveillance case definition and describes the methods used to develop the definition. These methods included convening MIS-C clinical experts (i.e., consultants) regarding identification of MIS-C and its distinction from other pediatric conditions, a review of available literature comparing MIS-C phenotype with that of pediatric COVID-19 and other hyperinflammatory syndromes, and retrospective application of different criteria to data from MIS-C cases previously reported to CDC.

The CSTE/CDC surveillance case definition for MIS-C includes four important changes, in comparison with the 2020 CDC MIS-C case definition. These changes are 1) no required duration of subjective or measured fever; 2) requirement of C-reactive protein ≥3.0 mg/dL to indicate systemic inflammation; 3) adjustments to criteria of organ system involvement to include addition of shock as a separate category and elimination of respiratory, neurologic, and renal criteria; and 4) new requirements on timing of positive SARS-CoV-2 laboratory testing relative to the MIS-C illness. Although MIS-C is not a nationally notifiable condition and reporting is voluntary, CSTE and CDC recommend that all states and territories report all cases meeting confirmed, probable, or suspect criteria of the CSTE/CDC MIS-C surveillance case definition beginning January 1, 2023, for cases with MIS-C illness onset on or after that date.

3059

Ch194

Khoo, Weng Hua; Jackson, Katherine; Phetsouphanh, Chansavath; Zaunders, John J.; Alquicira-Hernandez, José; Yazar, Seyhan; Ruiz-Diaz, Stephanie; Singh, Mandeep; Dhenni, Rama; Kyaw, Wunna; Tea, Fiona; Merheb, Vera; Lee, Fiona X. Z.; Burrell, Rebecca; Howard-Jones, Annaleise; Koirala, Archana; Zhou, Li; Yuksel, Aysen; Catchpoole, Daniel R.; Lai, Catherine L.; Vitagliano, Tennille L.; Rouet, Romain; Christ, Daniel; Tang, Benjamin; West, Nicholas P.; George, Shane; Gerrard, John; Croucher, Peter I.; Kelleher, Anthony D.; Goodnow, Christopher G.; Sprent, Jonathan D.; Powell, Joseph E.; Brilot, Fabienne; Nanan, Ralph; Hsu, Peter S.; Deenick, Elissa K.; Britton, Philip N.; Phan, Tri Giang

Tracking the clonal dynamics of SARS-CoV-2-specific T cells in children and adults with mild/asymptomatic COVID-19

https://doi.org/10.1016/j.clim.2022.109209

Published

Study

https://www.sciencedirect.com/science/article/pii/S152166162200290X

Highlights
•
Children have diverse polyclonal SARS-CoV-2-specific naïve T cells.

•
Adults have clonally expanded exhausted SARS-CoV-2-specific memory T cells.

•
Interferon-activated naïve T cells differentiate into memory T cells in adults but not children.

•
Adults but not children develop robust memory T cell responses to SARS-CoV-2.

Abstract
Children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop less severe coronavirus disease 2019 (COVID-19) than adults. The mechanisms for the age-specific differences and the implications for infection-induced immunity are beginning to be uncovered. We show by longitudinal multimodal analysis that SARS-CoV-2 leaves a small footprint in the circulating T cell compartment in children with mild/asymptomatic COVID-19 compared to adult household contacts with the same disease severity who had more evidence of systemic T cell interferon activation, cytotoxicity and exhaustion. Children harbored diverse polyclonal SARS-CoV-2-specific naïve T cells whereas adults harbored clonally expanded SARS-CoV-2-specific memory T cells. A novel population of naïve interferon-activated T cells is expanded in acute COVID-19 and is recruited into the memory compartment during convalescence in adults but not children. This was associated with the development of robust CD4+ memory T cell responses in adults but not children. These data suggest that rapid clearance of SARS-CoV-2 in children may compromise their cellular immunity and ability to resist reinfection.

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Lee, Danyel; Le Pen, Jérémie; Yatim, Ahmad; Dong, Beihua; Aquino, Yann; Ogishi, Masato; Pescarmona, Rémi; Talouarn, Estelle; Rinchai, Darawan; Zhang, Peng; Perret, Magali; Liu, Zhiyong; Jordan, Iolanda; Elmas Bozdemir, Sefika; Bayhan, Gulsum Iclal; Beaufils, Camille; Bizien, Lucy; Bisiaux, Aurelie; Lei, Weite; Hasan, Milena; Chen, Jie; Gaughan, Christina; Asthana, Abhishek; Libri, Valentina; Luna, Joseph M.; Jaffré, Fabrice; Hoffmann, H.-Heinrich; Michailidis, Eleftherios; Moreews, Marion; Seeleuthner, Yoann; Bilguvar, Kaya; Mane, Shrikant; Flores, Carlos; Zhang, Yu; Arias, Andrés A.; Bailey, Rasheed; Schlüter, Agatha; Milisavljevic, Baptiste; Bigio, Benedetta; Le Voyer, Tom; Materna, Marie; Gervais, Adrian; Moncada-Velez, Marcela; Pala, Francesca; Lazarov, Tomi; Levy, Romain; Neehus, Anna-Lena; Rosain, Jérémie; Peel, Jessica; Chan, Yi-Hao; Morin, Marie-Paule; Pino-Ramirez, Rosa Maria; Belkaya, Serkan; Lorenzo, Lazaro; Anton, Jordi; Delafontaine, Selket; Toubiana, Julie; Bajolle, Fanny; Fumadó, Victoria; DeDiego, Marta L.; Fidouh, Nadhira; Rozenberg, Flore; Pérez-Tur, Jordi; Chen, Shuibing; Evans, Todd; Geissmann, Frédéric; Lebon, Pierre; Weiss, Susan R.; Bonnet, Damien; Duval, Xavier; CoV-Contact Cohort; COVID, Human Genetic Effort; Pan-Hammarström, Qiang; Planas, Anna M.; Meyts, Isabelle; Haerynck, Filomeen; Pujol, Aurora; Sancho-Shimizu, Vanessa; Dalgard, Clifford; Bustamante, Jacinta; Puel, Anne; Boisson-Dupuis, Stéphanie; Boisson, Bertrand; Maniatis, Tom; Zhang, Qian; Bastard, Paul; Notarangelo, Luigi; Béziat, Vivien; Perez de Diego, Rebeca; Rodriguez-Gallego, Carlos; Su, Helen C.; Lifton, Richard P.; Jouanguy, Emmanuelle; Cobat, Aurélie; Alsina, Laia; Keles, Sevgi; Haddad, Elie; Abel, Laurent; Belot, Alexandre; Quintana-Murci, Lluis; Rice, Charles M.; Silverman, Robert H.; Zhang, Shen-Ying; Casanova, Jean-Laurent

Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children

https://doi.org/10.1126/science.abo3627

Published

Study

https://www.science.org/doi/full/10.1126/science.abo3627

Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic dsRNA-sensing OAS1 and OAS2 generate 2′-5′-linked oligoadenylates (2-5A) that activate the ssRNA-degrading RNase L. Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNASEL deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or SARS-CoV-2 stimulation. Exogenous 2-5A suppresses cytokine production in OAS1- but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by MAVS deficiency. Recessive OAS–RNase L deficiencies in these patients unleash the production of SARS-CoV-2–triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.

3061

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Sabatino, Jolanda; Di Chiara, Costanza; Di Candia, Angela; Sirico, Domenico; Donà, Daniele; Fumanelli, Jennifer; Basso, Alessia; Pogacnik, Pietro; Cuppini, Elena; Romano, Letizia Rosa; Castaldi, Biagio; Reffo, Elena; Cerutti, Alessia; Biffanti, Roberta; Cozzani, Sandra; Giaquinto, Carlo; Di Salvo, Giovanni

Mid- and Long-Term Atrio-Ventricular Functional Changes in Children after Recovery from COVID-19

https://doi.org/10.3390/jcm12010186

Published

Study

https://www.mdpi.com/2077-0383/12/1/186

Background: Although most children may experience mild to moderate symptoms and do not require hospitalization, there are little data on cardiac involvement in COVID-19. However, cardiac involvement is accurately demonstrated in children with MISC. The objective of this study was to evaluate cardiac mechanics in previously healthy children who recovered from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in a long-term follow-up by means of two-dimensional speckle-tracking echocardiography (STE). Methods: We analyzed a cohort of 157 paediatric patients, mean age 7.7 ± 4.5 years (age range 0.3–18 years), who had a laboratory-confirmed diagnosis of SARS-CoV-2 infection and were asymptomatic or mildly symptomatic for COVID-19. Patients underwent a standard transthoracic echocardiogram and STE at an average time of 148 ± 68 days after diagnosis and were divided in three follow-up groups (<180 days, 180–240 days, >240 days). Patients were compared with 107 (41 females—38%) age- and BSA-comparable healthy controls (CTRL). Results: Left ventricular (LV) global longitudinal strain (post-COVID-19: −20.5 ± 2.9%; CTRL: −21.8 ± 1.7%; p < 0.001) was significantly reduced in cases compared with CTRLs. No significant differences were seen among the three follow-up groups (p = NS). Moreover, regional longitudinal strain was significantly reduced in LV apical-wall segments of children with disease onset during the second wave of the COVID-19 pandemic compared to the first wave (second wave: −20.2 ± 2.6%; first wave: −21.2 ± 3.4%; p = 0.048). Finally, peak left atrial systolic strain was within the normal range in the post-COVID-19 group with no significant differences compared to CTRLs. Conclusions: Our study demonstrated for the first time the persistence of LV myocardial deformation abnormalities in previously healthy children with an asymptomatic or mildly symptomatic (WHO stages 0 or 1) COVID-19 course after an average follow-up of 148 ± 68 days. A more significant involvement was found in children affected during the second wave. These findings imply that subclinical LV dysfunction may also be a typical characteristic of COVID-19 infection in children and are concerning given the predictive value of LV longitudinal strain in the general population.

3062

Ch197

Vasichkina, Elena; Alekseeva, Daria; Kudryavtsev, Igor; Glushkova, Anzhela; Starshinova, Anastasia Y.; Malkova, Anna; Kudlay, Dmitry; Starshinova, Anna

COVID-19 Heart Lesions in Children: Clinical, Diagnostic and Immunological Changes

https://doi.org/10.3390/ijms24021147

Published

1-Jan-23

Review

https://www.mdpi.com/1422-0067/24/2/1147

In the beginning of COVID-19, the proportion of confirmed cases in the pediatric population was relatively small and there was an opinion that children often had a mild or asymptomatic course of infection. Our understanding of the immune response, diagnosis and treatment of COVID-19 is highly oriented towards the adult population. At the same time, despite the fact that COVID-19 in children usually occurs in a mild form, there is an incomplete understanding of the course as an acute infection and its subsequent manifestations such as Long-COVID-19 or Post-COVID-19, PASC in the pediatric population, correlations with comorbidities and immunological changes. In mild COVID-19 in childhood, some authors explain the absence of population decreasing T and B lymphocytes. Regardless of the patient’s condition, they can have the second phase, related to the exacerbation of inflammation in the heart tissue even if the viral infection was completely eliminated—post infectious myocarditis. Mechanism of myocardial dysfunction development in MIS-C are not fully understood. It is known that various immunocompetent cells, including both resident inflammatory cells of peripheral tissues (for example macrophages, dendritic cells, resident memory T-lymphocytes and so on) and also circulating in the peripheral blood immune cells play an important role in the immunopathogenesis of myocarditis. It is expected that hyperproduction of interferons and the enhanced cytokine response of T cells 1 and 2 types contribute to dysfunction of the myocardium. However, the role of Th1 in the pathogenesis of myocarditis remains highly controversial. At the same time, the clinical manifestations and mechanisms of damage, including the heart, both against the background and after COVID-19, in children differ from adults. Further studies are needed to evaluate whether transient or persistent cardiac complications are associated with long-term adverse cardiac events.

3063

Ch198

Baptista de Lima, Joana; Salazar, Luís; Fernandes, Alexandre; Teixeira, Carla; Marques, Laura; Afonso, Caldas

Long COVID in Children and Adolescents: A Retrospective Study in a Pediatric Cohort

https://doi.org/10.1097/INF.0000000000003829

Published

4-Jan-23

Study

https://journals.lww.com/pidj/Fulltext/9900/Long_COVID_in_Children_and_Adolescents__A.311.aspx

Abstract
Studies on long coronavirus disease (COVID) in children are scarce. We aimed to describe persistent symptoms and identify risk factors for its development. In our study population, 17.6% presented with long COVID, with respiratory symptoms more frequent in the first weeks and neuropsychiatric symptoms over time. Chronic conditions and obesity were risk factors, and adolescents were at a greater risk for long COVID.

Children infected with Severe acute respiratory syndrome coronavirus 2 are usually asymptomatic or with a mild form of coronavirus disease (COVID).1 While the acute symptoms are well defined, the long-term symptoms are not. Most COVID-19 patients achieve full recovery within 3–4 weeks after infection; however, in some cases, persistent symptoms can be seen weeks or months after recovery.2 According to National Institute for Health and Care Excellence guidelines, symptoms from onset to 4 weeks after diagnosis are considered acute COVID-19.3 The persistence of symptoms from 4 to 12 weeks is defined as ongoing symptomatic COVID-19, whereas symptoms that continue 12 weeks after diagnosis are considered post-COVID-19. Either ongoing symptomatic COVID-19 or post-COVID-19 is considered long COVID.3 In children, information on COVID-19 persistent symptoms remains scarce. Recent studies have shown that common persistent symptoms include fatigue, headache, postviral cough, anosmia, dyspnea and chest pain.4–6 In this study, we aimed to identify the prevalence of COVID-19 persistent symptoms in patients presenting to a tertiary hospital and to investigate possible risk factors for the development of long-term COVID.

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Ch199

Jason, Leonard A.; Johnson, Madeline; Torres, Chelsea

Pediatric Post-Acute Sequelae of SARS-CoV-2 infection

https://doi.org/10.1080/21641846.2022.2162764

Published

1-Jan-23

Study

https://doi.org/10.1080/21641846.2022.2162764

Aim Youth who have not recovered from COVID-19 have been referred to as having Post-Acute Sequelae of SARS-CoV-2 Infection (PASC). The goal of this study was to better understand which symptoms persisted since onset of infection and how these symptoms compare to symptoms experienced by those with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).Method A sample of 19 parents who had a child with PASC were recruited using social media to fill out a questionnaire detailing symptoms at two time points. The first time point included their child’s current symptoms and the second captured symptoms at initial infection. These participants were compared to a sample of 19 youth with ME/CFS.Results Findings indicated significant decreases among several immune, neuroendocrine, pain, post-exertional malaise (PEM), and COVID-19 Centers for Disease Control and Prevention (CDC) domain symptoms from time of acute infection to time of current reporting. Fatigue remained at a high level as did several symptoms within the sleep and PEM domains. Participants with ME/CFS had overall worse symptomatology when compared to participants with PASC, especially in the neurocognitive domain.Conclusion Most symptoms of those with PASC decline over time, but several remain at high levels, including fatigue. These findings are helpful in better understanding common symptom presentation profiles for youth with PASC and can be used to more adequately tailor diagnostic criteria and treatment strategies for youth.

3065

Ch200

Buonsenso, Danilo

Further evidence from a large US electronic health record-based study that some children and adolescents can develop postacute sequelae of SARS-CoV-2 infection

https://doi.org/10.1136/ebnurs-2022-103632

Published

4-Jan-23

Study

https://ebn.bmj.com/content/early/2023/01/03/ebnurs-2022-103632

publisher: Royal College of Nursing
section: Commentary
PMID: 36599668
Implications for practice and research
This study provides further evidence that a subgroup of children (about 3%) and adolescents develop postacute sequelae (PASC) other than multitystem inflammatory syndrome in children (MIS-C) after SARS-CoV-2 infection.

There is urgent need to implement to identify diagnostics, biomarkers and potential therapeutics of PASC.

Context
There is a growing body of evidence that a subgroup of children and adolescents do not fully recover from acute SARS-CoV-2 infection, but can develop a cohort of persisting signs and symptoms otherwise unexplained by routine diagnostics.1 This condition is known as PASC, or postcovid condition or Long Covid. However, available studies were mostly limited by either lack of control groups, small …

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Petrella, Carla; Nenna, Raffaella; Petrarca, Laura; Tarani, Francesca; Paparella, Roberto; Mancino, Enrica; Di Mattia, Greta; Conti, Maria Giulia; Matera, Luigi; Bonci, Enea; Ceci, Flavio Maria; Ferraguti, Giampiero; Gabanella, Francesca; Barbato, Christian; Di Certo, Maria Grazia; Cavalcanti, Luca; Minni, Antonio; Midulla, Fabio; Tarani, Luigi; Fiore, Marco

Serum NGF and BDNF in Long-COVID-19 Adolescents: A Pilot Study

https://doi.org/10.3390/diagnostics12051162

Published

1-May-22

Study

https://www.mdpi.com/2075-4418/12/5/1162

COVID-19 (COronaVIrus Disease 19) is an infectious disease also known as an acute respiratory syndrome caused by the SARS-CoV-2. Although in children and adolescents SARS-CoV-2 infection produces mostly mild or moderate symptoms, in a certain percentage of recovered young people a condition of malaise, defined as long-COVID-19, remains. To date, the risk factors for the development of long-COVID-19 are not completely elucidated. Neurotrophins such as NGF (Nerve Growth Factor) and BDNF (Brain-Derived Neurotrophic Factor) are known to regulate not only neuronal growth, survival and plasticity, but also to influence cardiovascular, immune, and endocrine systems in physiological and/or pathological conditions; to date only a few papers have discussed their potential role in COVID-19. In the present pilot study, we aimed to identify NGF and BDNF changes in the serum of a small cohort of male and female adolescents that contracted the infection during the second wave of the pandemic (between September and October 2020), notably in the absence of available vaccines. Blood withdrawal was carried out when the recruited adolescents tested negative for the SARS-CoV-2 (“post-infected COVID-19”), 30 to 35 days after the last molecular test. According to their COVID-19 related outcomes, the recruited individuals were divided into three groups: asymptomatics, acute symptomatics and symptomatics that over time developed long-COVID-19 symptoms (“future long-COVID-19”). As a control group, we analyzed the serum of age-matched healthy controls that did not contract the infection. Inflammatory biomarkers (TNF-α, TGF-β), MCP-1, IL-1α, IL-2, IL-6, IL-10, IL-12) were also analyzed with the free oxygen radicals’ presence as an oxidative stress index. We showed that NGF serum content was lower in post-infected-COVID-19 individuals when compared to healthy controls; BDNF levels were found to be higher compared to healthy individuals only in post-infected-COVID-19 symptomatic and future long-COVID-19 girls, leaving the BDNF levels unchanged in asymptomatic individuals if compared to controls. Oxidative stress and inflammatory biomarkers were unchanged in male and female adolescents, except for TGF-β that, similarly to BDNF, was higher in post-infected-COVID-19 symptomatic and future long-COVID-19 girls. We predicted that NGF and/or BDNF could be used as early biomarkers of COVID-19 morbidity in adolescents.

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Pereira, Snehal M. Pinto; Nugawela, Manjula D.; Rojas, Natalia K.; Shafran, Roz; McOwat, Kelsey; Simmons, Ruth; Ford, Tamsin; Heyman, Isobel; Ladhani, Shamez N.; Cheung, Emily Y.; Fox-Smith, Lana; Dalrymple, Emma; Stephenson, Terence

Post-COVID-19 condition at 6 months and COVID-19 vaccination in non-hospitalised children and young people

https://doi.org/10.1136/archdischild-2022-324656

Published

4-Jan-23

Study

https://adc.bmj.com/content/early/2023/01/04/archdischild-2022-324656

Objectives To describe the physical and mental health of children and young people (CYP) 6 months after infection with SARS-CoV-2 and explore whether this varies by COVID-19 vaccination.
Design A non-hospitalised, national cohort of people aged 11–17 years old with PCR-confirmed SARS-CoV-2 infection and PCR negatives matched at study invitation, by age, sex, region and date of testing who completed questionnaires 6 months after PCR testing. The questionnaire included 21 symptoms and standardised scales (eg, EQ-5D-Y and Chalder Fatigue Scale).
Results 6407 test-positive and 6542 test-negative CYP completed the 6-month questionnaire: 60.9% of test-positive vs 43.2% of test-negative CYP reported at least one symptom 6 months post-test; 27.6% of test-positive vs 15.9% of test-negative CYP reported 3+ symptoms. Common symptoms at 6 months were tiredness and shortness of breath among both test-positive and test-negative CYP; however, the prevalence of both was higher in test-positive (38.4% and 22.8%, respectively) compared with test-negative CYP (26.7% and 10.9%, respectively). 24.5% test-positive vs 17.8% test-negative CYP met the Delphi research definition of long COVID. Mental health, well-being, fatigue and health-related quality of life scores were similar among test-positive and test-negative CYP 6 months post-test. Similarly, symptomatology was similar among COVID-19-vaccinated and COVID-19-unvaccinated test-positive and test-negative CYP.
Conclusions Six-months post-PCR testing, CYP who tested positive for SARS-CoV-2 had similar symptoms to those who tested negative, but test-positive CYP had higher symptom prevalence. Mental health, well-being, fatigue and health-related quality of life were similar among test-positive and test-negative CYP, and symptoms at 6 months were similar in COVID-19 vaccinated and unvaccinated.
Trial registration number ISRCTN 34804192.

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Marina Avramescu, View ORCID ProfilePierre Isnard, Sarah Temmam, Agnes Chevalier, Paul Bastard, Mikael Attia, Romain Berthaud, Marc Fila, Claire Dossier, Julien Hogan, Tim Ulinski, Damia Leguevaques, Ferielle Louillet, Edouard Martinez Casado, Jean-Michel Halimi, Sylvie Cloarec, Ariane Zaloszyc, Camille Faudeux, Caroline Rousset-Rouviere, Stephanie Clave, Jerome Harambat, Edouard Rollot, Thomas Simon, Megan Nallet-Amate, Bruno Ranchin, Justine Bacchetta, Florence Porcheret, Josselin Bernard, Amelie Ryckewaert, Anne Jamet, Jacques Fourgeaud, Nicolas Da Rocha, Philippe Perot, Nicolas Kuperwasser, Naim Bouazza, Marion Rabant, Jean-Paul Duong Van Huyen, Matthieu P Robert, Julien Zuber, Jean-Laurent Casanova, marc eloit, Isabelle Sermet-Gaudelus, Olivia Boyer

Acute tubulointerstitial nephritis with or without uveitis: a novel form of post-acute COVID-19 syndrome in children

https://doi.org/10.1101/2023.01.23.23284848

pre-print

26-Jan-23

Study

https://www.medrxiv.org/content/10.1101/2023.01.23.23284848v1

Background COVID-19 is a complex multisystem disease, frequently associated with kidney injury. Since the beginning of the COVID-19 pandemic, we observed a striking increase in the incidence of acute tubulointerstitial nephritis (aTIN) without or with uveitis (TINUs) among children. This prompted us to examine whether SARS-CoV-2 might be the underlying trigger. Methods We conducted a French nationwide retrospective cohort study. We included all consecutive children diagnosed with aTIN or TINUs of undetermined cause between April-2020 and March-2021. SARS-CoV-2 antibody responses were tested by a luciferase immunoprecipitation system and compared to age-matched controls. Immunohistochemistry, immunofluorescence and molecular microbiology analyses were performed on kidney biopsies. Results Forty-eight children were included with a median age at diagnosis of 14.7 years (9.4-17.6). aTIN and TINUs incidence rates increased 3-fold and 12-fold, respectively, compared to pre-pandemic years. All patients had impaired kidney function with a median eGFR of 31.9 ml/min/1.73m2 at diagnosis. Kidney biopsies showed lesions of acute tubulointerstitial nephritis and 25% of patients had fibrosis. No patient had concomitant acute COVID-19. All 16 children tested had high anti-N IgG titers and one had anti-S IgGs. Next-generation sequencing failed to detect any infectious agents in kidney biopsies. However, SARS-CoV-2 RNA was detected by PCR in two kidney samples supporting a potential direct link between SARS-CoV-2 and aTIN/TINUs. Conclusions We describe a novel form of post-acute COVID-19 syndrome in children, unique in its exclusive kidney and eye involvement, and its distinctive anti-SARS-CoV-2 N+/S- serological profile. Our results support a causal association linking SARS-CoV-2 infection to this newly-reported burst of renal/eye inflammation.

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Ping-Ing Lee a, Po-Ren Hsueh

Multisystem inflammatory syndrome in children: A dysregulated autoimmune disorder following COVID-19

https://doi.org/10.1016/j.jmii.2023.01.001

Published

16-Jan-23

Review

https://www.sciencedirect.com/science/article/pii/S1684118223000014

Multisystem inflammatory syndrome in children (MIS-C) is a dysregulated autoimmune-mediated illness in genetically susceptible patients following COVID-19 with an interval of 2–6 weeks. The median age of patients with MIS-C is 6–11 years. Most common manifestations are involvement of gastrointestinal tract, cardiovascular system, hematological system, and mucocutaneous system. Respiratory tract, neurological system, musculoskeletal system, and kidney are less frequently affected. Mucocutaneous manifestations and coronary artery abnormalities characteristic for Kawasaki disease (KD) may be observed in a significant proportion of MIS-C patients that may make the differential diagnosis be difficult for some patients, especially in the post-pandemic era. The mortality rate is 1–3%. Management and prognosis of MIS-C are similar to that of KD. MIS-C and KD may share a common pathogenic process. Based on the observation of MIS-C-like illness in uninfected neonates, i.e. multisystem inflammatory syndrome in neonates, both MIS-C and KD may be a consequence of dysregulated, over-exaggerated humoral immune responses triggered by a specific infectious agent.
publisher: Elsevier

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Garazzino, Silvia; Denina, Marco; Pruccoli, Giulia; Funiciello, Elisa; Ramenghi, Ugo; Fagioli, Franca

Long COVID-19/post-COVID condition in children: do we all speak the same language?

https://doi.org/10.1186/s13052-023-01417-8

Published

20-Jan-23

Article

https://doi.org/10.1186/s13052-023-01417-8

Post-COVID condition is a new and highly debated entity that is still to be outlined in its complexity, especially in the pediatric population. In response to the article by Trapani and colleagues, we report the results of a long-term follow-up conducted in the outpatient clinic of the Pediatric Infectious Diseases Unit on children admitted to our hospital with SARS-CoV-2 infection.

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Morello, Rosa; Martino, Laura; Buonsenso, Danilo

Diagnosis and management of post-COVID (Long COVID) in children: a moving target

https://doi.org/10.1097/MOP.0000000000001221

Published

24-Jan-23

Review

https://journals.lww.com/co-pediatrics/Fulltext/9900/Diagnosis_and_management_of_post_COVID__Long.63.aspx

Purpose of review
This review describes recent findings about post-COVID condition (PCC, or Long COVID) in children, including current knowledge about its epidemiology, clinical presentation, pathogenesis and care.
Recent findings
There is no internationally agreed definition of PCC, although now most researchers agree that it is a complex clinical symptomatology persisting for at least 3 months after COVID-19, without an alternative diagnosis. There are several uncertainties about paediatric PCC. So far, available literature suggest that 1–3% of recognized children with Severe Acute Respiratory Syndrome COronaVirus 2 (SARS-CoV-2) infection may develop PCC. Its pathogenesis is unknown, although there is increasing evidence about possible abnormalities in the immune responses, cellular metabolism and intestinal microbiota, along with chronic endothelitis.
Summary
Management of PCC in children is complex and require a multidisciplinary approach, with the goal of offering the best care possible to support diagnostics, research, mental health and access to research projects.

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Garazzino, Silvia; Denina, Marco; Pruccoli, Giulia; Funiciello, Elisa; Ramenghi, Ugo; Fagioli, Franca

Long COVID-19/post-COVID condition in children: do we all speak the same language?

https://doi.org/10.1186/s13052-023-01417-8

Published

20-Jan-23

Article

https://doi.org/10.1186/s13052-023-01417-8

Self-completed questionnaires administered to families and not associated with targeted assessments (especially from a neurologic or psychiatric perspective) and not supported by a medical examination risk to overestimate PCC. Indeed, many reported symptoms in older children and adolescents (such as fatigue and psychological symptoms) may be related to the complex social situation that occurred during the Pandemic as a consequence of school closure, suspension of recreational activities and social isolation. In our opinion, children identified by an indirect approach (phone call, parental questionnaires) as suffering from PCC should be clinically assessed by a multidisciplinary team to confirm or rule out the diagnosis and schedule an appropriate follow-up.

In a nationwide cohort study, Boch et al. demonstrated that symptoms lasting > 4 weeks reported through an electronic questionnaire were common also in control children, with an estimated PCC prevalence of 0.8% in the SARS-CoV-2 positive group. Authors concluded that concentration difficulties, headache, muscle and joint pain as well as nausea should not be considered symptoms of PCC as they were frequently reported also in the control group. On the contrary, fatigue, loss of smell and taste, dizziness, muscle weakness, chest pain and respiratory problems were more frequently found in SARS-CoV-2 children, especially in those aging 6-17 years and were thus not attributed to psychological sequelae of social restrictions [9].

In our cohort of hospitalized children, with a minimum 6 month-follow-up, PCC was rare, also considering that many patients had pre-existing concomitant diseases. Only symptoms occurring or persisting within 12 weeks from SARS-CoV-2 infection were deemed consistent with sequelae of COVID-19, according to temporal criteria established by WHO in adults [10]. Furthermore, a long recovery is relatively common in other viral diseases, such as EBV, CMV or enteric viruses infections and a short follow-up of SARS-CoV-2 infected children could be misleading.

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Sakurada, Yasue; Otsuka, Yuki; Tokumasu, Kazuki; Sunada, Naruhiko; Honda, Hiroyuki; Nakano, Yasuhiro; Matsuda, Yui; Hasegawa, Toru; Ochi, Kanako; Hagiya, Hideharu; Ueda, Keigo; Kataoka, Hitomi; Otsuka, Fumio

Trends in Long COVID Symptoms in Japanese Teenage Patients

https://doi.org/10.3390/medicina59020261

Published

1-Feb-23

Study

https://www.mdpi.com/1648-9144/59/2/261

Background: Since the start of the global pandemic of coronavirus disease 2019 (COVID-19), not only adults but also many children have suffered from it. However, the clinical characteristics of long COVID in children remain unclear. Methods: In this retrospective observational study conducted in a single facility, we reviewed the medical records of all long COVID patients who visited Okayama University Hospital from February 2021 to October 2022, and we compared the clinical characteristics of long COVID in teenagers (11 to 18 years of age) with those in adults. Results: Data for 452 long COVID patients including 54 teenagers (11.9%) were analyzed. Fatigue was the most frequent symptom in teenagers (55.6% of the patients) and also in adults. On the other hand, the percentage of teenagers who complained of headache, which was the second most frequent complaint, was significantly higher than the percentage of adults (35.2% vs. 21.9%, p < 0.05). A comparison of the frequencies of symptoms depending on the viral variant showed that fatigue and headache were predominant symptoms in the Omicron variant phase. Of the 50 teenagers who were enrolled in schools, 28 (56.0%) could not attend school due to long COVID symptoms. The most common symptoms as reasons for absence from school were fatigue (85.7% of the patients), headache (42.9%), and insomnia (32.1%). Conclusions: Attention should be paid to the symptoms of fatigue and headache in teenagers with long COVID.

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WHO

A clinical case definition for post COVID-19 condition in children and adolescents by expert consensus, 16 February 2023

Published

16-Feb-23

Study

https://www.who.int/publications-detail-redirect/WHO-2019-nCoV-Post-COVID-19-condition-CA-Clinical-case-definition-2023-1

Overview
The WHO definition of post Covid-19 condition for adults was published in October 2021. This enables a shared understanding of this important problem between people affected by post Covid-19 condition, healthcare workers, researchers and other stakeholders.

A separate clinical case definition for children and adolescents has been formed, through a process of expert consensus, which recognizes the unique health needs and challenges of this group of people.

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Jamaica Balderas, Lourdes María del Carmen; Navarro Fernández, Amairani; Dragustinovis Garza, Susana Azeneth; Orellana Jerves, María Isabel; Solís Figueroa, Walter Ernesto; Koretzky, Solange Gabriela; Márquez González, Horacio; Klünder Klünder, Miguel; Espinosa, Juan Garduño; Nieto Zermeño, Jaime; Villa Guillén, Mónica; Rosales Uribe, Rómulo Erick; Olivar López, Victor

Long COVID in children and adolescents: COVID-19 follow-up results in third-level pediatric hospital

https://doi.org/10.3389/fped.2023.1016394

Published

30-Jan-23

Study

https://www.frontiersin.org/articles/10.3389/fped.2023.1016394

IntroductionIn children, the manifestations of coronavirus disease 2019 (COVID-19) in the acute phase are considered mild compared with those in adults; however, some children experience a severe disease that requires hospitalization. This study was designed to present the operation and follow-up results of the Post-COVID-19 Detection and Monitoring Sequels Clinic of Hospital Infantil de Mexico Federico Gómez in managing children with a history of SARS-CoV-2 infection.MethodsThis was a prospective study conducted from July 2020 to December 2021, which included 215 children aged 0–18 years who tested positive for SARS-CoV-2 on polymerase chain reaction and/or immunoglobulin G test. The follow-up was conducted in the pulmonology medical consultation; ambulatory and hospitalized patients were assessed at 2, 4, 6, and 12 months.ResultsThe median age of the patients was 9.02 years, and neurological, endocrinological, pulmonary, oncological, and cardiological comorbidities were the most commonly observed among the patients. Moreover, 32.6% of the children had persistent symptoms at 2 months, 9.3% at 4 months, and 2.3% at 6 months, including dyspnea, dry cough, fatigue, and runny nose; the main acute complications were severe pneumonia, coagulopathy, nosocomial infections, acute renal injury, cardiac dysfunction, and pulmonary fibrosis. The more representative sequelae were alopecia, radiculopathy, perniosis, psoriasis, anxiety, and depression.ConclusionsThis study showed that children experience persistent symptoms, such as dyspnea, dry cough, fatigue, and runny nose, although to a lesser extent than adults, with significant clinical improvement 6 months after the acute infection. These results indicate the importance of monitoring children with COVID-19 through face-to-face consultations or telemedicine, with the objective of offering multidisciplinary and individualized care to preserve the health and quality of life of these children.

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Faux-Nightingale, Alice; Burton, Claire; Twohig, Helen; Blagojevic-Bucknall, Milica; Carroll, Will; Chew-Graham, Carolyn A.; Dunn, Kate; Gilchrist, Francis; Helliwell, Toby; Lawton, Oliver; Lawton, Sarah; Mallen, Christian; Saunders, Benjamin; Windt, Danielle van der; Welsh, Victoria

Symptom patterns and life with post-acute COVID-19 in children aged 8-17: a mixed methods studyprotocol

https://doi.org/10.3399/BJGPO.2022.0149

Published

9-Feb-23

Study

https://bjgpopen.org/content/early/2023/02/08/BJGPO.2022.0149

Background While there is a substantial body of knowledge about acute COVID-19, less is known about long-COVID, where symptoms continue beyond four weeks.
Aim This study aims to describe longer-term effects of COVID-19 infection in children and young people (CYP) and identify their needs in relation to long-COVID.
Design & setting This study comprises an observational prospective cohort study and a linked qualitative study, identifying participants aged 8–17 years in the West Midlands of England.
Method CYP will be invited to complete online questionnairesto monitor incidences and symptoms of Covid-19 over a 12-month period. CYP who have experienced long-term effects of COVID will be invited to interview, and those currently experiencing symptoms will be asked to document their experiences in a diary. Professionals who work with CYP will be invited to explore the impact of long-COVID on the wider experiences of CYP, in a focus group. Descriptive statistics will be used to describe the incidence and rates of resolution of symptoms, and comparisons made between exposed and non-exposed groups. Logistic regression models will be used to estimate associations between candidate predictors and the development of long-COVID, and linear regression will be used to estimate associations between candidate predictors. Qualitative data will be analysed thematically using the constant comparison method.
Conclusion This study will describe features and symptoms of long-COVID and explore the impact of long-COVID within the lives of CYP and their families, to provide better understanding of long-COVID and inform clinical practice.

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Hicks, Steven D.

Comparison of Symptom Duration Between Children With SARS-CoV-2 and Peers With Other Viral Illnesses During the COVID-19 Pandemic

https://doi.org/10.1177/00099228231152840

Published

7-Feb-23

Study

https://doi.org/10.1177/00099228231152840

Some children and young people (CYP) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) experience persistent symptoms, commonly called ?long COVID.? It remains unclear whether symptoms of SARS-CoV-2 persist longer than those of other respiratory viruses, particularly in young children. This cross-sectional study involved 372 CYP (0-15 years) tested for SARS-CoV-2. Character and duration of symptoms (cough, runny nose, sore throat, rash, diarrhea, vomiting, sore muscles, fatigue, fever, loss of smell) were compared between CYP with a positive test (n = 100) and those with a negative test (n = 272), while controlling for medical/demographic covariates. The average duration of symptoms for CYP with a positive SARS-CoV-2 test (8.5 ± 10 days) did not differ from that of CYP with a negative test (7.2 ± 5 days, P = .71, d = 0.046). A positive SARS-CoV-2 test did not increase the risk (36/372, 10%) of symptoms persisting for ≥3 weeks (odds ratio = 0.96, 95% confidence interval = 0.45-2.0). These results suggest CYP with non-SARS-CoV-2 infections experience a similar duration of symptoms as peers with SARS-CoV-2 infection.

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Tonyali, Aysegul; Karacetin, Gul; Yesilkaya, Celal; Arik, Feyza Nur Tas; Kayan Ocakoglu, Binay

Appearance of extrapyramidal symptoms in adolescent psychiatry patients during COVID-19 infection

https://doi.org/10.1002/jmv.28556

Published

4-Feb-23

Study

https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.28556

Since the start of the pandemic, there has been an increase in the incidence of psychiatric morbidity among those infected with coronavirus disease 2019 (COVID-19) and those indirectly affected by COVID-19. There has been a considerable increase in the number of individuals with such psychiatric conditions as depression, acute stress disorders, anxiety, and posttraumatic stress disorder (PTSD). About one-third of patients with COVID-19 are reported to have developed short and long-term neuropsychiatric conditions such as delirium, agitation, altered consciousness, hypoxic encephalopathy encephalitis, dysexecutive syndrome, cerebrovascular complications (e.g., stroke), hypoxic encephalopathy, convulsions, neuromuscular dysfunction, demyelinating processes, or parkinsonism through several pathophysiological mechanisms. Nevertheless, as the pandemic progressed, data on neuropsychiatric manifestations implied that the pathologic capacity of COVID-19 and its association with the onset and/or exacerbation of psychiatric morbidity indicate that COVID-19 is potentially related to neuropsychiatric involvement. Patients with existing mental disorders under psychotropic treatment exposed to the COVID-19 infection have been represented by an increased risk of worsened psychiatric symptoms and expanded drug side effects. The present study aimed to describe five pediatric patients with various psychiatric illness that experienced COVID-19 infection and had potentially associated neuropsychiatric involvement, such as exacerbation of underlying psychiatric symptoms and extrapyramidal side effects. To the best of our knowledge, the present study is the first to describe adolescents with COVID-19 infection that presented with a series of manifestations in the form of an increase in extrapyramidal symptoms (EPS) during exacerbation of underlying psychiatric disease.

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Baptista de Lima, Joana; Salazar, Luís; Fernandes, Alexandre; Teixeira, Carla; Marques, Laura; Afonso, Caldas

Long COVID in Children and Adolescents: A Retrospective Study in a Pediatric Cohort

https://doi.org/10.1097/INF.0000000000003829

Published

Study

https://journals.lww.com/pidj/Fulltext/9900/Long_COVID_in_Children_and_Adolescents__A.311.aspx

Studies on long coronavirus disease (COVID) in children are scarce. We aimed to describe persistent symptoms and identify risk factors for its development. In our study population, 17.6% presented with long COVID, with respiratory symptoms more frequent in the first weeks and neuropsychiatric symptoms over time. Chronic conditions and obesity were risk factors, and adolescents were at a greater risk for long COVID.

Children infected with Severe acute respiratory syndrome coronavirus 2 are usually asymptomatic or with a mild form of coronavirus disease (COVID).1 While the acute symptoms are well defined, the long-term symptoms are not. Most COVID-19 patients achieve full recovery within 3–4 weeks after infection; however, in some cases, persistent symptoms can be seen weeks or months after recovery.2 According to National Institute for Health and Care Excellence guidelines, symptoms from onset to 4 weeks after diagnosis are considered acute COVID-19.3 The persistence of symptoms from 4 to 12 weeks is defined as ongoing symptomatic COVID-19, whereas symptoms that continue 12 weeks after diagnosis are considered post-COVID-19. Either ongoing symptomatic COVID-19 or post-COVID-19 is considered long COVID.3 In children, information on COVID-19 persistent symptoms remains scarce. Recent studies have shown that common persistent symptoms include fatigue, headache, postviral cough, anosmia, dyspnea and chest pain.4–6 In this study, we aimed to identify the prevalence of COVID-19 persistent symptoms in patients presenting to a tertiary hospital and to investigate possible risk factors for the development of long-term COVID.

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Ahn, Bin; Choi, Sung Hwan; Yun, Ki Wook

Non-neuropsychiatric Long COVID Symptoms in Children Visiting a Pediatric Infectious Disease Clinic After an Omicron Surge

https://doi.org/10.1097/INF.0000000000003862

Published

24-Feb-23

Study

https://journals.lww.com/pidj/Fulltext/9900/Non_neuropsychiatric_Long_COVID_Symptoms_in.353.aspx

Although much interest has emerged regarding post-COVID conditions, data on children and adolescents are limited. The prevalence of long COVID and common symptoms were analyzed in this case-control study of 274 children. Prolonged non-neuropsychiatric symptoms were more frequent in the case group (17.0% and 4.8%, P = 0.004). Abdominal pain (6.6%) was the most common long COVID symptom.

There has been much interest in the aftereffects of coronavirus disease 2019 (COVID-19) because the beginning of the epidemic. However, interest in the long-term outcomes of COVID-19 has emerged, as a large part of the world’s population was infected with the Omicron variant BA2 in early 2022 and fatigue causing prolonged limitation of social activity has been increasingly reported.1 A proportion of persons with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection experience long-term symptoms. Over the course of the pandemic, various terms, including “long COVID,” “long-haul COVID” and “post COVID-19 condition” have been proposed. The World Health Organization (WHO) defines long COVID as symptoms that develop usually 3 months after COVID-19 onset, persist for more than 2 months and cannot be explained by any other etiology.2 However, it has been suggested that these diagnostic criteria cannot be applied uniformly in children and adolescents because this population experiences many viral infections and somatic symptoms. Supporting this limitation, relevant data in children and adolescents are controversial. Moreover, distinguishing neuropsychiatric long COVID symptoms from pandemic-related symptoms is difficult, particularly in adolesents.3 Therefore, in this study, we analyzed the prevalence of non-neuropsychiatric long COVID symptoms among Korean children and adolescents who were laboratory confirmed to have SARS-CoV-2 infections in February–April.

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Goretzki, Sarah C.; Brasseler, Maire; Dogan, Burcin; Hühne, Tom; Bernard, Daniel; Schönecker, Anne; Steindor, Mathis; Gangfuß, Andrea; Della Marina, Adela; Felderhoff-Müser, Ursula; Dohna-Schwake, Christian; Bruns, Nora

High Prevalence of Alternative Diagnoses in Children and Adolescents with Suspected Long COVID—A Single Center Cohort Study

https://doi.org/10.3390/v15020579

Published

1-Feb-23

Study

https://www.mdpi.com/1999-4915/15/2/579

Background: Long COVID (LC) is a diagnosis that requires exclusion of alternative somatic and mental diseases. The aim of this study was to examine the prevalence of differential diagnoses in suspected pediatric LC patients and assess whether adult LC symptom clusters are applicable to pediatric patients. Materials and Methods: Pediatric presentations at the Pediatric Infectious Diseases Department of the University Hospital Essen (Germany) were assessed retrospectively. The correlation of initial symptoms and final diagnoses (LC versus other diseases or unclarified) was assessed. The sensitivity, specificity, negative and positive predictive values of adult LC symptom clusters were calculated. Results: Of 110 patients, 32 (29%) suffered from LC, 52 (47%) were diagnosed with alternative somatic/mental diseases, and 26 (23%) remained unclarified. Combined neurological and respiratory clusters displayed a sensitivity of 0.97 (95% CI 0.91–1.00) and a negative predictive value of 0.97 (0.92–1.00) for LC. Discussion/Conclusions: The prevalence of alternative somatic and mental diseases in pediatric patients with suspected LC is high. The range of underlying diseases is wide, including chronic and potentially life-threatening conditions. Neurological and respiratory symptom clusters may help to identify patients that are unlikely to be suffering from LC.

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Avittan, Hadar; Kustovs, Dmitrijs

Cognition and Mental Health in Pediatric Patients Following COVID-19

https://doi.org/10.3390/ijerph20065061

Published

1-Jan-23

Review

https://www.mdpi.com/1660-4601/20/6/5061

The global coronavirus pandemic has significantly impacted public health and has been a research subject since its emergence in 2019. The acute phase of the disease leads to pulmonary and non-pulmonary manifestations, which in some individuals may progress to long-lasting symptoms. In this article, we conducted a narrative review of the current literature to summarize current knowledge regarding long COVID syndrome in children, focusing on cognitive symptoms. The review included a search of three databases (PubMed, Embase, and Web of Science) using the key phrases “post COVID-19 cognitive pediatric”, “long COVID pediatric”, “mental health long COVID children”, and “COVID-19 cognitive symptoms”. A total of 102 studies were included. The review revealed that the main long-term cognitive symptoms following COVID-19 were memory and concentration deficits, sleep disturbances, and psychiatric states such as anxiety and stress. In addition to the direct physiological effects of a viral infection, there are psychological, behavioral, and social factors contributing to cognitive impairment, which should be addressed regarding the pediatric population. The high prevalence of neurocognitive symptoms in children following COVID-19 emphasizes the importance of understanding the mechanisms of nervous system involvement.

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Budziło, Oskar; Irga-Jaworska, Ninela; Myszyńska, Marcelina; Malanowska, Magdalena; Niedźwiecki, Maciej

The Impact of Past COVID-19 Infection on Selected Lymphocyte Subsets in Pediatric Patients

https://doi.org/10.3390/vaccines11030659

Published

1-Mar-23

Study

https://www.mdpi.com/2076-393X/11/3/659

The impact of past COVID-19 infection on the immune system remains unidentified. So far, several papers have revealed the dependence between the count of lymphocytes and their subsets and the outcome of an acute disease. However, still there is little information about long-term consequences, particularly in the pediatric population. We attempted to verify whether a dysregulation of the immune system may be the reason for observed complications after past COVID-19 infection. Hence, we tried to prove that abnormalities in lymphocyte subpopulations are found in patients a certain time after the COVID-19 infection. In our paper, we enrolled 466 patients after SARS-CoV-2 infection, and evaluated their subsets of lymphocytes within 2–12 months after infection and compared them to the control group assessed several years before the pandemic. It occurred that main differences are observed in CD19+ lymphocytes and the index CD4+/CD8+ lymphocytes. We believe that this is only the introduction to further investigation of the immune system of pediatric patients post-COVID-19 infection.

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Filippatos, Filippos; Tatsi, Elizabeth-Barbara; Michos, Athanasios

Immunology of Multisystem Inflammatory Syndrome after COVID-19 in Children: A Review of the Current Evidence

https://doi.org/10.3390/ijms24065711

Published

1-Jan-23

Review

https://www.mdpi.com/1422-0067/24/6/5711

Immune responses following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children are still under investigation. Even though coronavirus disease 2019 (COVID-19) is usually mild in the pediatric population, some children exhibit severe clinical manifestations, require hospitalization, or develop the most severe condition: a multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 infection. The activated innate, humoral and T-cell-mediated immunological pathways that lead certain pediatric populations to present with MIS-C or remain asymptomatic after SARS-CoV-2 infection are yet to be established. This review focuses on the immunological aspects of MIS-C with respect to innate, humoral, and cellular immunity. In addition, presents the role of the SARS-CoV-2 Spike protein as a superantigen in the pathophysiological mechanisms, discusses the great heterogeneity among the immunological studies in the pediatric population, and highlights possible reasons why some children with a certain genetic background present with MIS-C.

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Kumar, Prawin; Jat, Kana Ram

Post-COVID-19 Sequelae in Children

https://doi.org/10.1007/s12098-023-04473-4

Published

8-Mar-23

Review

https://doi.org/10.1007/s12098-023-04473-4

Coronavirus disease 19 (COVID-19), caused by the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), has been implicated in having post-COVID-19 sequelae in both adults and children. There is a lack of good data on the prevalence and risk factors for post-COVID-19 sequelae in children. The authors aimed to review the current literature on post-COVID sequelae. The prevalence of post-COVID sequelae in children is highly variable among studies, with an average of 25%. The sequelae may affect many organ systems, though mood symptoms, fatigue, cough, dyspnea, and sleep problems are common. In many studies, it is difficult to establish a causal association due to the lack of a control group. Furthermore, it is difficult to differentiate whether the neuropsychiatric symptoms in children after COVID-19 are due to infection or a result of lockdowns and social restrictions imposed by the pandemic. Children with COVID-19 should be followed by a multidisciplinary team and screened for symptoms, followed by focused laboratory evaluations as needed. There is no specific treatment for the sequelae. Only symptomatic and supportive treatment is required in most cases. More research is necessary to standardize the definitions of sequelae, establish a causal association, assess various treatment options, and the effects of different virus variants, and finally, see the impact of vaccination on the sequelae.

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Burki, Talha

Clinical case definition of post-COVID-19 condition in children: a good start, but improvements are needed

https://doi.org/10.1016/S2213-2600(23)00081-4

Published

7-Mar-23

Article

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00081-4/fulltext

WHO outlined several research priorities for post-COVID-19 condition in children and adolescents. These included confirming whether certain symptoms tend to cluster together and whether a minimum number of symptoms are necessary to make a diagnosis. Ascertaining prevalence might prove impossible. Some children are too young to communicate their symptoms and others will not present to health care. “Future research will have to tease out which of the more non-specific symptoms are linked to COVID-19”, Freedman told The Lancet Respiratory Medicine.“
Research into long COVID is a complicated prospect”, added Martin Hibberd, Professor of Emerging Infectious Diseases at London School of Hygiene & Tropical Medicine (London, UK). “You have to compare cases to controls, and we are talking about a lot of non-specific or mild symptoms that are common in the general population.”
Moreover, SARS-CoV-2 is likely to have now infected billions of people around the world. Countries have mostly discontinued testing for the virus and a lot of cases are asymptomatic anyway. Identifying control populations will be tricky. It is possible that widespread exposure to SARS-CoV-2 alongside the rollout of the vaccines will drive down prevalence of post-COVID-19 condition. Alternatively, the emergence of a new variant might cause its prevalence to rise. But proving either eventuality will be difficult without controls.
Hibberd stressed that one would expect to see lingering symptoms in a minority of individuals who have contracted a viral infection. “If we can get an idea of the proportion of children and adults who have long COVID, based on the definitions WHO has provided, we can at least identify whether COVID-19 is more or less likely to result in long-term consequences than other respiratory infections”, he said. Freedman would like to see future research directed towards establishing biomarkers for long COVID, with the aim of preventing the condition from happening in the first place. He cautioned that some questions might prove irresolvable. “This is not the first illness for which we have struggled with the diagnostic criteria”, said Freedman. “It has happened with chronic fatigue syndrome, for example. Maybe we will not be able to get all the answers.”
publisher: Elsevier
PMID: 36898399

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Zheng, Yong-Bo; Zeng, Na; Yuan, Kai; Tian, Shan-Shan; Yang, Ying-Bo; Gao, Nan; Chen, Xuan; Zhang, An-Yi; Kondratiuk, Alexandra L.; Shi, Pei-Pei; Zhang, Fang; Sun, Jie; Yue, Jing-Li; Lin, Xiao; Shi, Le; Lalvani, Ajit; Shi, Jie; Bao, Yan-Ping; Lu, Lin

Prevalence and risk factor for long COVID in children and adolescents: A meta-analysis and systematic review

https://doi.org/10.1016/j.jiph.2023.03.005

Published

1-May-23

Study

https://www.sciencedirect.com/science/article/pii/S1876034123000710

Background
Millions of COVID-19 pediatric survivors are facing the risk of long COVID after recovery from acute COVID-19. The primary objective of this study was to systematically review the available literature and determine the pooled prevalence of, and risk factors for long COVID among the pediatric survivors.
Methods
Studies that assessed the prevalence of, or risk factors associated with long COVID among pediatric COVID-19 survivors were systematically searched in PubMed, Embase, and Cochrane Library up to December 11th, 2022. Random effects model was performed to estimate the pooled prevalence of long COVID among pediatric COVID-19 patients. Subgroup analyses and meta-regression on the estimated prevalence of long COVID were performed by stratification with follow-up duration, mean age, sex ratio, percentage of multisystem inflammatory syndrome, hospitalization rate at baseline, and percentage of severe illness.
Results
Based on 40 studies with 12,424 individuals, the pooled prevalence of any long COVID was 23.36 % ([95 % CI 15.27–32.53]). The generalized symptom (19.57 %, [95 % CI 9.85–31.52]) was reported most commonly, followed by respiratory (14.76 %, [95 % CI 7.22–24.27]), neurologic (13.51 %, [95 % CI 6.52–22.40]), and psychiatric (12.30 %, [95% CI 5.38–21.37]). Dyspnea (22.75 %, [95% CI 9.38–39.54]), fatigue (20.22 %, [95% CI 9.19–34.09]), and headache (15.88 %, [95 % CI 6.85–27.57]) were most widely reported specific symptoms. The prevalence of any symptom during 3–6, 6–12, and> 12 months were 26.41 % ([95 % CI 14.33–40.59]), 20.64 % ([95 % CI 17.06–24.46]), and 14.89 % ([95 % CI 6.09–26.51]), respectively. Individuals with aged over ten years, multisystem inflammatory syndrome, or had severe clinical symptoms exhibited higher prevalence of long COVID in multi-systems. Factors such as older age, female, poor physical or mental health, or had severe infection or more symptoms were more likely to have long COVID in pediatric survivors.
Conclusions
Nearly one quarter of pediatric survivors suffered multisystem long COVID, even at 1 year after infection. Ongoing monitoring, comprehensive prevention and intervention is warranted for pediatric survivors, especially for individuals with high risk factors.

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Brum, Andrea C.; Vain, Nestor E.

Impact of perinatal COVID on fetal and neonatal brain and neurodevelopmental outcomes

https://doi.org/10.1016/j.siny.2023.101427

Published

8-Mar-23

Review

https://www.sciencedirect.com/science/article/pii/S1744165X23000033

After three years of the COVID-19 pandemic, we have learned many aspects of the disease and the virus: its molecular structure, how it infects human cells, the clinical picture at different ages, potential therapies, and the effectiveness of prophylaxis. Research is currently focused on the short- and long-term consequences of COVID-19. We review the available information on the neurodevelopmental outcome of infants born during the pandemic from infected and non-infected mothers, as well as the neurological impact of neonatal SARS-CoV-2 infection. We also discuss the mechanisms that could potentially affect the fetal or neonatal brain including direct impact after vertical transmission, maternal immune activation with a proinflammatory cytokine storm, and finally the consequences of complications of pregnancy secondary to maternal infection that could affect the fetus. Several follow-up studies have noted a variety of neurodevelopmental sequelae among infants born during the pandemic. There is controversy as to the exact etiopathogenesis of these neurodevelopmental effects: from the infection itself or as a result of parental emotional stress during that period. We summarize case reports of acute neonatal SARS-CoV-2 infections associated with neurological signs and neuroimaging changes. Many infants born during previous pandemics caused by other respiratory viruses demonstrated serious neurodevelopmental and psychological sequelae that were only recognized after several years of follow-up. It is essential to warn health authorities about the need for very long-term continuous follow up of infants born during the SARS-CoV-2 pandemic for early detection and treatment that could help mitigate the neurodevelopmental consequences of perinatal COVID-19.

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Rotulo, Gioacchino Andrea; Palma, Paolo

Understanding COVID-19 in children: immune determinants and post-infection conditions

https://doi.org/10.1038/s41390-023-02549-7

Published

6-Mar-23

Review

https://www.nature.com/articles/s41390-023-02549-7

Abstract
Coronavirus disease 2019 in children presents with milder clinical manifestations than in adults. On the other hand, the presence of a wide range of inflammatory manifestations, including multisystem inflammatory syndrome in children (MIS-C), in the period after infection suggests a particular susceptibility of some children toward severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Both protective factors that prevent evolution to severe forms and risk factors for post-infectious conditions are likely to be found in age-related differences in the immune system. The prompt innate response with type I IFN production and the generation of neutralizing antibodies play a crucial role in containing the infection. The greater number of naive and regulatory cells in children helps to avoid the cytokine storm while the causes of the intense inflammatory response in MIS-C need to be elucidated. This review aims to analyze the main results of the recent literature assessing immune response to SARS-CoV-2 over the pediatric age group. We summarized such observations by dividing them into innate and acquired immunity, then reporting how altered immune responses can determine post-infectious conditions.
Impact
The main immune markers of acute SARS-CoV-2 infection in children are summarized in this review.
This paper reports a broad overview of age-related differences in the immune response to SARS-CoV-2 and emerging post-infection conditions.
A summary of currently available therapies for the pediatric age group is provided.
publisher: Nature Publishing Group

3090

Ch225

Edlow, Andrea G.; Castro, Victor M.; Shook, Lydia L.; Haneuse, Sebastien; Kaimal, Anjali J.; Perlis, Roy H.

Sex-Specific Neurodevelopmental Outcomes Among Offspring of Mothers With SARS-CoV-2 Infection During Pregnancy

https://doi.org/10.1001/jamanetworkopen.2023.4415

Published

23-Mar-23

Study

https://doi.org/10.1001/jamanetworkopen.2023.4415

Key Points
Question Is in utero exposure to maternal SARS-CoV-2 infection associated with greater rates of neurodevelopmental disorder diagnoses in male or female offspring, compared with controls with no such exposure?

Findings This cohort study of 18 355 infants delivered after February 2020 found that male but not female offspring born to mothers with a positive SARS-CoV-2 polymerase chain reaction test result during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first 12 months after delivery, even after accounting for preterm delivery.

Meaning These findings suggest that male offspring exposed to SARS-CoV-2 in utero may be at increased risk for neurodevelopmental disorders.

Abstract
Importance Prior studies using large registries have suggested a modest increase in risk for neurodevelopmental diagnoses among children of mothers with immune activation during pregnancy, and such risk may be sex-specific.

Objective To determine whether in utero exposure to SARS-CoV-2 is associated with sex-specific risk for neurodevelopmental disorders up to 18 months after birth, compared with unexposed offspring born during or prior to the COVID-19 pandemic period.

Design, Setting, and Participants This retrospective cohort study included the live offspring of all mothers who delivered between January 1 and December 31, 2018 (born and followed up before the COVID-19 pandemic), between March 1 and December 31, 2019 (born before and followed up during the COVID-19 pandemic), and between March 1, 2020, and May 31, 2021 (born and followed up during the COVID-19 pandemic). Offspring were born at any of 8 hospitals across 2 health systems in Massachusetts.

Exposures Polymerase chain reaction evidence of maternal SARS-CoV-2 infection during pregnancy.

Main Outcomes and Measures Electronic health record documentation of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnostic codes corresponding to neurodevelopmental disorders.

Results The COVID-19 pandemic cohort included 18 355 live births (9399 boys [51.2%]), including 883 (4.8%) with maternal SARS-CoV-2 positivity during pregnancy. The cohort included 1809 Asian individuals (9.9%), 1635 Black individuals (8.9%), 12 718 White individuals (69.3%), and 1714 individuals (9.3%) who were of other race (American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, more than 1 race); 2617 individuals (14.3%) were of Hispanic ethnicity. Mean maternal age was 33.0 (IQR, 30.0-36.0) years. In adjusted regression models accounting for race, ethnicity, insurance status, hospital type (academic center vs community), maternal age, and preterm status, maternal SARS-CoV-2 positivity was associated with a statistically significant elevation in risk for neurodevelopmental diagnoses at 12 months among male offspring (adjusted OR, 1.94 [95% CI 1.12-3.17]; P = .01) but not female offspring (adjusted OR, 0.89 [95% CI, 0.39-1.76]; P = .77). Similar effects were identified using matched analyses in lieu of regression. At 18 months, more modest effects were observed in male offspring (adjusted OR, 1.42 [95% CI, 0.92-2.11]; P = .10).

Conclusions and Relevance In this cohort study of offspring with SARS-CoV-2 exposure in utero, such exposure was associated with greater magnitude of risk for neurodevelopmental diagnoses among male offspring at 12 months following birth. As with prior studies of maternal infection, substantially larger cohorts and longer follow-up will be required to reliably estimate or refute risk.

3091

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Rajamanickam, Anuradha; Nathella, Pavan Kumar; Venkataraman, Aishwarya; Dasan, Bindu; Putlibai, Sulochana; Ahamed, Shaik Fayaz; Selvaraj, Nandhini; Sadasivam, Kalaimaran; Sundaram, Balasubramanian; Nutman, Thomas B.; Babu, Subash

Levels of Complement Components in Children With Acute COVID-19 or Multisystem Inflammatory Syndrome

https://doi.org/10.1001/jamanetworkopen.2023.1713

Published

24-Mar-23

Study

https://doi.org/10.1001/jamanetworkopen.2023.1713

Key Points
Question Are multisystem inflammatory syndrome in children (MIS-C) and COVID-19 in children associated with alterations in complement expression and function?

Findings In this cross-sectional study with 145 participants, MIS-C and COVID-19 were associated with higher levels of complement components, activation products, and regulators. Additionally, complement levels pretreatment were found to be potential biomarkers of disease severity in MIS-C and COVID-19.

Meaning The findings of this study suggest that complement activation was associated with the pathogenesis of MIS-C and acute COVID-19 and is a potential biomarker of disease severity.

Abstract
Importance Multisystem inflammatory syndrome in children (MIS-C) is a severe and unrestrained inflammatory response with multiorgan involvement, which occurs within a few weeks following the resolution of acute SARS-CoV-2 infection. The complement system is a vital part of the innate immune system and plays a role in COVID-19 pathogenesis.

Objective To examine and compare the levels of complement components and regulators along with complement activation products in the different clinical spectrum of children with SARS-CoV-2 and a control group.

Design, Setting, and Participants This cross-sectional study analyzed children with MIS-C admitted to a single hospital in India from June through September 2020. Eligible participants were children who were hospitalized of either sex, aged 1 to 18 years. Data were analyzed August 2022.

Measures Levels of complement components and regulators along with complement activation products in all the groups of children. Mann-Whitney U test and Kruskal-Wallis analysis were used to compare the complement component levels, and Spearman rank correlation analysis was used to describe the association between complement components and laboratory and biochemical parameters.

Results A total 145 children were included (median age, 5 years [range, 1 month-17 years); 84 [58%] male): 44 children with MIS-C, 33 with acute COVID-19 (reverse transcriptase–polymerase chain reaction [RT-PCR] positive), 47 with convalescent COVID-19 (immunoglobulin G–positive non-MIS-C) and 21 children for a control group (both serology and RT-PCR negative). Children with MIS-C and COVID-19 had higher levels of C1q (geometric mean [SD]: MIS-C, 61.5 [18.5] ng/mL; acute COVID-19, 56.9 [18.6] ng/mL; controls, 24.1 [3.3] ng/mL), C2 (MIS-C, 605.8 [219.7] ng/mL; acute COVID-19, 606.4 [167.7] ng/mL; controls, 255.9 [73.3] ng/mL), C3 (MIS-C, 318.2 [70.7] ng/mL; acute COVID-19, 237.7 [61.8] ng/mL; controls, 123.4 [15.7] ng/mL), C4b (MIS-C, 712.4 ng/mL; acute COVID-19, 640.7 ng/mL; controls, 351.5 ng/mL), C5 (MIS-C, 1487 ng/mL; acute COVID-19, 1364 ng/mL; controls, 561.9 ng/mL), C5a, (MIS-C, 2614.0 [336.2] ng/mL; acute COVID-19, 1826.0 [541.0] ng/mL; controls, 462.5 [132.4] ng/mL), C3b/iC3b (MIS-C, 3971.0 [635.1] ng/mL; acute COVID-19, 3702.0 [653.9] ng/mL; controls, 2039.0 [344.5] ng/mL), and factor B (MIS-C, 47.6 [7.8] ng/mL; acute COVID-19, 44.6 [6.3] ng/mL; controls, 27.5 [5.0] ng/mL), factor D (MIS-C, 44.0 [17.2] ng/mL; acute COVID-19, 33.8 [18.4] ng/mL; controls, 21.3 [6.1] ng/mL), and factor H (MIS-C, 53.1 [4.0] ng/mL; acute COVID-19, 50.8 [5.7] ng/mL; controls, 43.6 [3.8] ng/mL) in comparison with convalescent and control children. In addition, children with MIS-C had significantly elevated levels of C3 (318.2 [70.7] ng/mL vs 237.7 [61.8] ng/mL), C5a (2614 [336.2] ng/mL vs 1826 [541.0] ng/mL), and mannose-binding lectin (79.4 [12.4] ng/mL vs 69.6 [14.7] ng/mL) in comparison to children with acute COVID-19. Levels of some of these analytes at admission (ie, pretreatment) were more elevated in children with MIS-C who needed pediatric intensive care unit (PICU) support as compared with those who did not require PICU support, and in children with COVID-19 who developed moderate to severe disease compared with those who developed mild disease. Overall, MIS-C and acute COVID-19 were associated with the hyperactivation of complement components and complement regulators.

Conclusions and Relevance In this cross-sectional study, the complement system was associated with the pathogenesis of MIS-C and COVID-19 in children; complement inhibition could be further explored as a potential treatment option.

3092

Ch227

Mariani, Francesco; Morello, Rosa; Traini, Daniele Omar; La Rocca, Anna; De Rose, Cristina; Valentini, Piero; Buonsenso, Danilo

Risk Factors for Persistent Anosmia and Dysgeusia in Children with SARS-CoV-2 Infection: A Retrospective Study

https://doi.org/10.3390/children10030597

Published

1-Mar-23

Study

https://www.mdpi.com/2227-9067/10/3/597

Background: Olfactory and gustative dysfunctions are two of the most common post-acute sequelae of SARS-CoV-2 infection in children, which can have a negative impact on the routines of children and families. As several children have had COVID-19 since the Omicron variant, it is important to investigate if this increase in infections is reflected in higher olfactory/taste disfunctions. The primary aim of this study was to characterize the presence of olfactory/gustative problems in a cohort of children, its evolution, and its association with risk factors such as COVID-19 variant, hospitalization, presence of olfactory/gustative dysfunction during the acute phase, and vaccination. Methods: This was a retrospective analysis of children with microbiologically confirmed SARS-CoV-2 infection evaluated in person at a referral pediatric post-COVID-19 clinic in Rome, Italy. We included children younger than 19 years old, evaluated from the beginning of the pandemic up to October 2022. At specific timepoints, we investigated the presence of olfactory/taste disfunctions and evaluated them according to the SARS-CoV-2 variants circulating at the time of infection. Results: A total of 1250 children (650 females; 52.0%) with a mean age of 6.77 (±4.12) years were included in the study. At 3, 6, 12, and 18 months, 12 (9.6%), 7 (5.6%), 2 (1.6%), and 1 (0.8%) of the children reported anosmia and dysgeusia post-COVID-19 infection, respectively. The presence of anosmia and dysgeusia during the acute phase of infection and being infected with a pre-Omicron variant were found to be significant risk factors for persistent olfactory and gustatory dysfunction during all follow-up periods. Conclusions: anosmia and dysgeusia symptoms tended to decrease gradually over time, but not all children recovered quickly.

3093

Ch228

McCrindle, Brian W.; Harahsheh, Ashraf S.; Handoko, Ryan; Raghuveer, Geetha; Portman, Michael A.; Khoury, Michael; Newburger, Jane W.; Lee, Simon; Jain, Supriya S.; Khare, Manaswitha; Dahdah, Nagib; Manlhiot, Cedric

SARS-CoV-2 Variants and Multisystem Inflammatory Syndrome in Children

https://doi.org/10.1056/NEJMc2215074

Published

22-Mar-23

Study

https://doi.org/10.1056/NEJMc2215074

A total of 2017 patients were enrolled in the study. The demographic characteristics of the patients (Table S1 in the Supplementary Appendix, available with the full text of the letter at NEJM.org) were similar to those of the broader population of children with MIS-C. Patients during the delta (B.1.617.2) and omicron (B.1.1.529) periods were younger, showed greater phenotypic similarity to patients with Kawasaki’s disease, and had a lower incidence of respiratory dysfunction and coronary-artery dilatation than patients during the ancestral and alpha+ (B.1.1.7 plus other circulating minor variants) periods (Table 1). After the ancestral period, immunomodulatory management evolved to include greater use of glucocorticoids. Concurrently, the risks of serious complications (arrhythmia, cardiac arrest, renal complications, coagulopathy, and thrombosis), admission to an intensive care unit, and death decreased, with the most pronounced decrease occurring during the omicron period. Across all the variant periods, the risk of ventricular dysfunction was highest among the patients hospitalized during the alpha+ period as compared with those during the ancestral period (35% vs. 28%, relative risk, 1.19; 95% confidence interval, 1.04 to 1.35). Although the clinical phenotype became milder over time, severe disease was still prevalent, with 23% of the patients during the omicron period presenting with shock and with 37% being admitted to an intensive care unit.

The features of MIS-C at presentation were more often similar to the features of Kawasaki’s disease among patients hospitalized with SARS-CoV-2 infection during the more recent variant periods than among those during the earlier periods; however, without a definitive diagnostic test for either condition, it remains to be determined whether this represents a true change in phenotype or an increase in the number of patients with Kawasaki’s disease who meet the criteria for MIS-C through concurrent but unrelated SARS-CoV-2 infection. Although we acknowledge the limitations of the ecologic study design and the inherent risk of misclassification of variant at the patient level, our data support observations that the severity of MIS-C has decreased with each subsequent SARS-CoV-2 variant. Nevertheless, critical illness in patients hospitalized with MIS-C remains prevalent.
publisher: Massachusetts Medical Society
_eprint: https://doi.org/10.1056/NEJMc2215074

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Bentes, Aline Almeida; dos Santos Junior, Walter Rebuite; Pessoa, Natalia Lima; Costa, Thais Alkifeles; Oliveira, Gabriela Fernanda Garcia; Diniz, Lilian Martins Oliveira; Torres, Bruna Ribeiro; Teixeira, Daniela Caldas; Mendes, Renata Barandas; Avelar, Ana Beatriz Alvim; Campos, Marco Antônio; Kroon, Erna Geessien; Drumond, Betania Paiva

Neuro-COVID-19 With or Without the Multisystem Inflammatory Syndrome (MIS-C): A Single-Center Study

https://doi.org/10.1007/s12031-023-02109-y

Published

28-Mar-23

Study

https://doi.org/10.1007/s12031-023-02109-y

This study evaluates the range of neurological manifestation in children with COVID-19 (neuro-COVID-19) both with and without the multisystem inflammatory syndrome (MIS-C) and the persistence of symptoms after hospital discharge. The study was conducted as a prospective study of children and adolescents under 18 years of age who were admitted to a children’s hospital for infectious diseases from January 2021 to January 2022. The children had no previous neurological or psychiatric disorders. Out of the 3021 patients evaluated, 232 were confirmed to have COVID-19 and 21 of these patients (9%) showed neurological manifestations associated with the virus. Of these 21 patients, 14 developed MIS-C, and 7 had neurological manifestations unrelated to MIS-C. There was no statistical difference regarding the neurological manifestations during hospitalization and outcomes between patients with neuro-COVID-19 who had or did not have MIS-C, except for seizures that occurred more frequently in patients with neuro-COVID-19 without MIS-C (p-value = 0.0263). One patient died, and 5 patients still had neurological or psychiatric manifestations at discharge, which persisted for up to 7 months. The study highlights that SARS-CoV-2 infection can affect the central and peripheral nervous system, particularly in children and adolescents with MIS-C, and that it is crucial to be vigilant for long-term adverse outcomes, as the neurological and psychiatric effects of COVID-19 in children are emerging during an important stage of brain development.

3095

Ch230

Selvakumar, Joel; Havdal, Lise Beier; Drevvatne, Martin; Brodwall, Elias Myrstad; Lund Berven, Lise; Stiansen-Sonerud, Tonje; Einvik, Gunnar; Leegaard, Truls Michael; Tjade, Trygve; Michelsen, Annika E.; Mollnes, Tom Eirik; Lund-Johansen, Fridtjof; Holmøy, Trygve; Zetterberg, Henrik; Blennow, Kaj; Sandler, Carolina X.; Cvejic, Erin; Lloyd, Andrew R.; Wyller, Vegard Bruun Bratholm

Prevalence and Characteristics Associated With Post–COVID-19 Condition Among Nonhospitalized Adolescents and Young Adults

https://doi.org/10.1001/jamanetworkopen.2023.5763

Published

30-Mar-23

Study

https://doi.org/10.1001/jamanetworkopen.2023.5763

Key Points
Question What are the prevalence and associated risk factors of post–COVID-19 condition (PCC) in young people after mild acute infection?

Findings This cohort study included 382 SARS-CoV-2–positive individuals and a control group of 85 SARS-CoV-2–negative individuals aged 12 to 25 years who were assessed at the early convalescent stage and at 6-month follow-up. When applying the World Health Organization case definition of PCC, prevalence at 6 months was 49%, but was also comparably high (47%) in the control group. PCC was not associated with biological markers specific to viral infection, but with initial symptom severity and psychosocial factors.

Meaning These findings suggest that persistent symptoms in this age group are related to factors other than SARS-CoV-2 infection, and therefore question the usefulness of the WHO case definition of PCC.

Abstract
Importance The prevalence and baseline risk factors of post–COVID-19 condition (PCC) remain unresolved among the large number of young people who experienced mild COVID-19.

Objectives To determine the point prevalence of PCC 6 months after the acute infection, to determine the risk of development of PCC adjusted for possible confounders, and to explore a broad range of potential risk factors.

Design, Setting, and Participants This cohort study included nonhospitalized individuals from 2 counties in Norway between ages 12 and 25 years who underwent reverse transcription–polymerase chain reaction (RT-PCR) testing. At the early convalescent stage and at 6-month follow-up, participants underwent a clinical examination; pulmonary, cardiac, and cognitive functional testing; immunological and organ injury biomarker analyses; and completion of a questionnaire. Participants were classified according to the World Health Organization case definition of PCC at follow-up. Association analyses of 78 potential risk factors were performed.

Exposures SARS-CoV-2 infection.

Main Outcomes and Measures The point prevalence of PCC 6 months after RT-PCR testing in the SARS-CoV-2–positive and SARS-CoV-2–negative groups, and the risk difference with corresponding 95% CIs.

Results A total of 404 individuals testing positive for SARS-CoV-2 and 105 individuals testing negative were enrolled (194 male [38.1%]; 102 non-European [20.0%] ethnicity). A total of 22 of the SARS-CoV-2–positive and 4 of the SARS-CoV-2–negative individuals were lost to follow-up, and 16 SARS-CoV-2–negative individuals were excluded due to SARS-CoV-2 infection in the observational period. Hence, 382 SARS-CoV-2–positive participants (mean [SD] age, 18.0 [3.7] years; 152 male [39.8%]) and 85 SARS-CoV-2–negative participants (mean [SD] age, 17.7 [3.2] years; 31 male [36.5%]) could be evaluated. The point prevalence of PCC at 6 months was 48.5% in the SARS-CoV-2–positive group and 47.1% in the control group (risk difference, 1.5%; 95% CI, −10.2% to 13.1%). SARS-CoV-2 positivity was not associated with the development of PCC (relative risk [RR], 1.06; 95% CI, 0.83 to 1.37; final multivariable model utilizing modified Poisson regression). The main risk factor for PCC was symptom severity at baseline (RR, 1.41; 95% CI, 1.27-1.56). Low physical activity (RR, 0.96; 95% CI, 0.92-1.00) and loneliness (RR, 1.01; 95% CI, 1.00-1.02) were also associated, while biological markers were not. Symptom severity correlated with personality traits.

Conclusions and Relevance The persistent symptoms and disability that characterize PCC are associated with factors other than SARS-CoV-2 infection, including psychosocial factors. This finding raises questions about the utility of the World Health Organization case definition and has implications for the planning of health care services as well as for further research on PCC.

3096

Ch231

Chen, Erin Y.; Burton, Justin M.; Johnston, Alicia; Morrow, Amanda K.; Yonts, Alexandra B.; Malone, Laura A.

Considerations in Children and Adolescents related to COVID-19

https://doi.org/10.1016/j.pmr.2023.03.004

Published

30-Mar-23

Review

https://www.pmr.theclinics.com/article/S1047-9651(23)00020-7/fulltext

Key Points:
-PCPs should screen for PASC in children with a history of SARS-CoV-2 infection.
-PASC is a complex, multisystemic disease that benefits from a multifaceted treatment approach.
-Lifestyle interventions, physical rehabilitation, and mental health management are important in improving pediatric PASC patients’ quality of life.
publisher: Elsevier

3097

Ch232

Ramaswamy, Viraraghavan Vadakkencherry; Abiramalatha, Thangaraj; Pullattayil S, Abdul Kareem; Trevisanuto, Daniele

Multisystem inflammatory disease in neonates (MIS-N) due to maternal COVID-19

https://doi.org/10.1016/j.siny.2023.101431

Published

30-Mar-23

Review

https://www.sciencedirect.com/science/article/pii/S1744165X23000070

Multisystem inflammatory disease in neonates (MIS-N) is a disease of immune dysregulation presenting in the newborn period. Thouvgh its etiopathogenesis is proposed to be similar to multisystem inflammatory disease in Children (MIS-C), the exact pathophysiology is largely unknown as of present. The definition of MIS-N is contentious. The evidence for its incidence, the clinical features, profile of raised inflammatory markers, treatment strategies and outcomes stem from case reports, case series and cohort studies with small sample sizes. Though the incidence of MIS-N in severe acute respiratory syndrome caused by the coronavirus CoVID-2 (SARS-CoV-2) infected asymptomatic neonates is low, its incidence in symptomatic neonates is relatively higher. Further, amongst the neonates who are treated as MIS-N, the mortality rate is high. The review also evaluates the various other unresolved aspects of MIS-N from limited published literature and identifies knowledge gaps which could be areas of future research.

3098

Ch233

Druzak, Samuel; Iffrig, Elizabeth; Roberts, Blaine R.; Zhang, Tiantian; Fibben, Kirby S.; Sakurai, Yumiko; Verkerke, Hans P.; Rostad, Christina A.; Chahroudi, Ann; Schneider, Frank; Wong, Andrew Kam Ho; Roberts, Anne M.; Chandler, Joshua D.; Kim, Susan O.; Mosunjac, Mario; Mosunjac, Marina; Geller, Rachel; Albizua, Igor; Stowell, Sean R.; Arthur, Connie M.; Anderson, Evan J.; Ivanova, Anna A.; Ahn, Jun; Liu, Xueyun; Maner-Smith, Kristal; Bowen, Thomas; Paiardini, Mirko; Bosinger, Steve E.; Roback, John D.; Kulpa, Deanna A.; Silvestri, Guido; Lam, Wilbur A.; Ortlund, Eric A.; Maier, Cheryl L.

Multiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19

https://doi.org/10.1038/s41467-023-37269-3

Published

4-Apr-23

Study

https://www.nature.com/articles/s41467-023-37269-3

The pathogenesis of multi-organ dysfunction associated with severe acute SARS-CoV-2 infection remains poorly understood. Endothelial damage and microvascular thrombosis have been identified as drivers of COVID-19 severity, yet the mechanisms underlying these processes remain elusive. Here we show alterations in fluid shear stress-responsive pathways in critically ill COVID-19 adults as compared to non-COVID critically ill adults using a multiomics approach. Mechanistic in-vitro studies, using microvasculature-on-chip devices, reveal that plasma from critically ill COVID-19 adults induces fibrinogen-dependent red blood cell aggregation that mechanically damages the microvascular glycocalyx. This mechanism appears unique to COVID-19, as plasma from non-COVID sepsis patients demonstrates greater red blood cell membrane stiffness but induces less significant alterations in overall blood rheology. Multiomics analyses in pediatric patients with acute COVID-19 or the post-infectious multi-inflammatory syndrome in children (MIS-C) demonstrate little overlap in plasma cytokine and metabolite changes compared to adult COVID-19 patients. Instead, pediatric acute COVID-19 and MIS-C patients show alterations strongly associated with cytokine upregulation. These findings link high fibrinogen and red blood cell aggregation with endotheliopathy in adult COVID-19 patients and highlight differences in the key mediators of pathogenesis between adult and pediatric populations.

3099

Ch234

Abdulaziz Alsufyani, Amal

Post-COVID-19 effect on biochemical parameters in children: Should we take heed?

https://doi.org/10.1016/j.sjbs.2023.103649

Published

1-May-23

Study

https://www.sciencedirect.com/science/article/pii/S1319562X23000943

The aim of this research is to analyze the potential impact of the COVID-19 infection on the serum biochemical concentration of children 6 months after recovery from the infection. The study included 72 children with a median age of 11 years. The case group consisted of 37 children who had contracted COVID-19 6 months prior to the analysis. They reported no other pre- or post-covid chronic or systemic diseases. The control group consisted of 35 children who had no prior record of COVID-19 infection. The analysis showed a substantial variation (P = 0.026) in the mean urea values (mmol/L) between the case group (4.513 ± 0.839) and the control group (5.425 ± 1.173). However, both groups' urea levels were within the normal range of their age group. No statistical differences were found analyzing the variations between the two groups in the levels of LDH, AST, ALT, BiliT, GGT, AlbBCG2, CRP, CK, AlKP, UA, Phos, Crea2, Gluc, Ca, Na, K, Cl, TP, TC, TG, and HDL (P > 0.05). The DMFT score was substantially greater (P < 0.002) in the infected team (5.38 ± 2.841) in comparison to the non-infected group (2.6 ± 2.257). The study indicates that COVID-19 infection does not leave biochemical alterations among children who did not have pre-existing conditions. The biochemical analysis suggests that children recover better than adults from COVID-19. Furthermore, it calls for investigating non-lethal COVID-19 infection as a tool to discover underlying conditions. The DMFT score shows a correlation between COVID-19 infection and caries. However, the nature of the correlation is yet to be investigated.

3100

Ch235

Mungmunpuntipantip, Rujittika; Wiwanitkit, Viroj

Long COVID in Children up to 12 y of Age – A Retrospective Telephonic Survey: Correspondence

https://doi.org/10.1007/s12098-023-04619-4

Published

21-Apr-23

Letter to editor

https://doi.org/10.1007/s12098-023-04619-4

To the Editor: We would like to share ideas on the publication “Long COVID in children up to 12 y of age - A retrospective telephonic survey published in IJP [1].” Sah et al. conducted a telephonic survey to investigate the outcome of children hospitalized with COVID-19 infection in a tertiary care hospital in North India in terms of persistent symptoms [1]. In comparison to earlier research, Sah et al. discovered that the incidence of long-COVID was low in this telephone survey [1]. According to Sah et al., long-COVID data can impact vaccine policy for children and transform the perception of COVID-19 in children from a benign condition to one with the potential to create long-term chronic severe health consequences [1].

Long-COVID-19 has an issue that requires immediate action. Other critical difficulties must also be addressed. An important issue is that this study by Sah et al. validated the patients’ prior apparent clinical diagnosis, however, the patient could still have undetected co-morbid illnesses. Also the patients may have been given the second COVID-19 vaccine [2]. Earlier immunizations must be discussed as well. There must be sufficient evidence to reach a conclusion about how the illness affects health issues. One might believe that protracted COVID, also known as extended COVID-19, is not the major source of all symptoms experienced by a patient with the illness.

3101

Ch236

Morello, Rosa; Mariani, Francesco; Mastrantoni, Luca; Rose, Cristina De; Zampino, Giuseppe; Munblit, Daniel; Sigfrid, Louise; Valentini, Piero; Buonsenso, Danilo

Risk factors for post-COVID-19 condition (Long Covid) in children: a prospective cohort study

https://doi.org/10.1016/j.eclinm.2023.101961

Published

1-May-23

Study

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00138-4/fulltext

Background
Adults and children can develop post-Covid-19 condition (PCC) (also referred to as Long Covid). However, existing evidence is scarce, partly due to a lack of a standardised case definition, short follow up duration, and heterogenous study designs, resulting in wide variation of reported outcomes. The primary aim of this study was to characterise risk factors for PCC and longitudinal rates of recovery in a cohort of children and young people using a standardised protocol.
Methods
We performed a prospective “disease-based” cohort study between 01/02/2020 to 31/10/2022 including children aged 0–18 years old, with a previous diagnosis of Covid-19. Children with microbiologically confirmed SARS-CoV-2 infection, were invited for an in-clinic follow-up assessment at a paediatric post-covid clinic in Rome, Italy, at serial intervals (3-, 6-, 12- and 18-months post-onset). PCC was defined as persistence of otherwise unexplained symptoms for at least three months after initial infection. The statistical association between categorical variables was obtained by Chi-squared tests or Fisher's exact tests. Multivariable logistic regressions are presented using odds ratios (OR) and 95% confidence interval (CI). Survival analysis was conducted using the Kaplan–Meier method.
Findings
1243 children were included, median age: 7.5 (4–10.3) years old; 575 (46.3%) were females. Of these, 23% (294/1243) were diagnosed with PCC at three months post-onset. Among the study population, 143 patients remained symptomatic at six months, 38 at 12 months, and 15 at 18 months follow up evaluation. The following risk factors were associated with PCC: >10 years of age (OR 1.23; 95% CI 1.18–1.28), comorbidities (OR 1.68; 95% CI 1.14–2.50), and hospitalisation during the acute phase (OR 4.80; 95%CI 1.91–12.1). Using multivariable logistic regression, compared to the Omicron variant, all other variants were significantly associated with PCC at 3 and 6 months. At least one dose of vaccine was associated with a reduced, but not statistically significant risk of developing PCC.
Interpretation
In our study, acute-phase hospitalisation, pre-existing comorbidity, being infected with pre-Omicron variants and older age were associated with a higher risk of developing PCC. Most children recovered over time, but one-in-twenty of those with PCC at three months reported persistent symptoms 18 months post-Sars-CoV-2 infection. Omicron infection was associated with shorter recovery times. We did not find a strong protective effect of vaccination on PCC development. Although our cohort cannot be translated to all Italian children with PCC as more nationwide studies are needed, our findings highlight the need of new strategies to prevent and treat pediatric PCC are needed.
publisher: Elsevier
PMID: 37073325

3102

Ch237

Burns, Madeleine D.; Bartsch, Yannic C.; Davis, Jameson P.; Boribong, Brittany P.; Loiselle, Maggie; Kang, Jaewon; Kane, Abigail S.; Edlow, Andrea G.; Fasano, Alessio; Alter, Galit; Yonker, Lael M.

Long-term humoral signatures following acute pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children

https://doi.org/10.1038/s41390-023-02627-w

Published

12-May-23

Study

https://www.nature.com/articles/s41390-023-02627-w

Background
Although most children experience mild symptoms during acute SARS-CoV-2 infection, some develop the severe post-COVID-19 complication, Multisystem Inflammatory Syndrome in Children (MIS-C). While acute presentations of COVID-19 and MIS-C have been well immunophenotyped, little is known about the lasting immune profile in children after acute illness.

Methods
Children 2 months–20 years of age presenting with either acute COVID-19 (n = 9) or MIS-C (n = 12) were enrolled in a Pediatric COVID-19 Biorepository at a single medical center. We deeply profiled humoral immune responses and circulating cytokines following pediatric COVID-19 and MIS-C.

Results
Twenty-one children and young adults provided blood samples at both acute presentation and 6-month follow-up (mean: 6.5 months; standard deviation: 1.77 months). Pro-inflammatory cytokine elevations resolved after both acute COVID-19 and MIS-C. Humoral profiles continue to mature after acute COVID-19, displaying decreasing IgM and increasing IgG over time, as well as stronger effector functions, including antibody-dependent monocyte activation. In contrast, MIS-C immune signatures, especially anti-Spike IgG1, diminished over time.

Conclusions
Here, we show the mature immune signature after pediatric COVID-19 and MIS-C, displaying resolving inflammation with recalibration of the humoral responses. These humoral profiles highlight immune activation and vulnerabilities over time in these pediatric post-infectious cohorts.

Impact
The pediatric immune profile matures after both COVID-19 and MIS-C, suggesting a diversified anti-SARS-CoV-2 antibody response after resolution of acute illness.

While pro-inflammatory cytokine responses resolve in the months following acute infection in both conditions, antibody-activated responses remain relatively heightened in convalescent COVID-19.

These data may inform long-term immunoprotection from reinfection in children with past SARS-CoV-2 infections or MIS-C.

3103

Ch238

Pinto Pereira, Snehal M.; Mensah, Anna; Nugawela, Manjula D.; Stephenson, Terence; Ladhani, Shamez N.; Dalrymple, Emma; Dudley, Jake; McOwat, Kelsey; Simmons, Ruth; Heyman, Isobel; Segal, Terry; Semple, Malcolm G.; Xu, Laila; Shafran, Roz; Buszewicz, Marta; Chalder, Trudie; Crawley, Esther; De Stavola, Bianca; Ford, Tamsin; Garg, Shruti; Harnden, Anthony; Hargreaves, Dougal; Levin, Michael; Poustie, Vanessa; Semple, Calum; Sharma, Kishan; Swann, Olivia; Whittaker, Elizabeth

Long COVID in Children and Youth After Infection or Reinfection with the Omicron Variant: A Prospective Observational Study

https://doi.org/10.1016/j.jpeds.2023.113463

Published

11-May-23

Study

https://www.sciencedirect.com/science/article/pii/S0022347623003116

To describe the prevalence of long COVID in children infected for the first time (n=332) or reinfected (n=243) with Omicron variant SARS-CoV-2, compared with test-negative children (n=311). 12-16% infected with Omicron met the research definition of long COVID at 3 and 6 months after infection, with no evidence of difference between cases of first-positive and reinfection (pchi-square=0.17).

3104

Ch239

Rybkina, Ksenia; Bell, Joseph N.; Bradley, Marissa C.; Wohlbold, Teddy; Scafuro, Marika; Meng, Wenzhao; Korenberg, Rebecca C.; Davis-Porada, Julia; Anderson, Brett R.; Weller, Rachel J.; Milner, Joshua D.; Moscona, Anne; Porotto, Matteo; Luning Prak, Eline T.; Pethe, Kalpana; Connors, Thomas J.; Farber, Donna L.

SARS-CoV-2 infection and recovery in children: Distinct T cell responses in MIS-C compared to COVID-19

https://doi.org/10.1084/jem.20221518

Published

3-May-23

Study

https://doi.org/10.1084/jem.20221518

SARS-CoV-2 infection for most children results in mild or minimal symptoms, though in rare cases severe disease can develop, including a multisystem inflammatory syndrome (MIS-C) with myocarditis. Here, we present longitudinal profiling of immune responses during acute disease and following recovery in children who developed MIS-C, relative to children who experienced more typical symptoms of COVID-19. T cells in acute MIS-C exhibited transient signatures of activation, inflammation, and tissue residency which correlated with cardiac disease severity, while T cells in acute COVID-19 upregulated markers of follicular helper T cells for promoting antibody production. The resultant memory immune response in recovery showed increased frequencies of virus-specific memory T cells with pro-inflammatory functions in children with prior MIS-C compared to COVID-19 while both cohorts generated comparable antibody responses. Together our results reveal distinct effector and memory T cell responses in pediatric SARS-CoV-2 infection delineated by clinical syndrome, and a potential role for tissue-derived T cells in the immune pathology of systemic disease.

3105

Ch240

Dash, Nabaneeta; Verma, Sanjay

Long COVID in Children up to 12 y of Age – A Retrospective Telephonic Survey: Author’s Reply

https://doi.org/10.1007/s12098-023-04620-x

Published

2-May-23

Letter to editor

https://doi.org/10.1007/s12098-023-04620-x

To the Editor: We thank Mungmunpuntipantip and Wiwanikit for their comments and reflections on our paper [1, 2]. We understand that they are concerned regarding the lower incidence of long-COVID in our study subjects and the effect of underlying disease on diagnosis of long-COVID.

We agree with them that the incidence in our survey was lower as compared to other studies done mostly from developed countries [3]. We have already mentioned in our paper the various factors which might be responsible for the lower incidence like exclusion of older children, difference in methodology of study, cultural factors, and duration of follow-up. This study was only a telephonic survey and was done to sensitize treating physicians that long-COVID can be seen in Indian children too, and population-based surveys would be required to determine actual incidence and prevalence of this entity in our population.

We agree with the authors that underlying co-morbidities can influence the symptoms of long- COVID. But in our cohort, the 3 children who had persistent symptoms following diagnosis of acute COVID-19 illness did not have any underlying co-morbidities.

Hence we feel that larger prospective surveys are required to provide a more definitive answer to the pertinent questions on incidence and prevalence of long-COVID in pediatric age group, especially in developing country like ours.

3106

Ch241

Saniasiaya, Jeyasakthy

Vestibular migraine: a manifestation of long COVID syndrome in children

https://doi.org/10.1136/bcr-2023-255734

Published

1-May-23

Case Report

https://casereports.bmj.com/content/16/5/e255734

Long COVID-19 syndrome has been reported among children and adolescents following COVID-19 recovery. Among them, notable symptoms include myalgia, insomnia, loss of smell and headache. Yet, novel manifestations are being discovered daily. Herein, we report two cases of vestibular migraine post-COVID-19 involving two children who presented with vestibular migraine symptoms following COVID-19 infection and their management. Children post-COVID-19 should be thoroughly evaluated for vestibular migraine symptoms so they can be managed promptly. This is the first article to report vestibular migraine as a manifestation of long COVID-19 syndrome.

3107

Ch242

Hassan, Nurulhuda Mat; Salim, Hani Syahida; Amaran, Safiya; Yunus, Nurul Izza; Yusof, Nurul Azreen; Daud, Norwati; Fry, Deborah

Prevalence of mental health problems among children with long COVID: A systematic review and meta-analysis

https://doi.org/10.1371/journal.pone.0282538

Published

17-May-23

Systematic review and meta-analysis

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0282538

Introduction The number of children with mental health problems has more than doubled since the COVID-19 pandemic. However, the effect of long Covid on children’s mental health is still debatable. Recognising long Covid as a risk factor for mental health problems in children will increase awareness and screening for mental health problems following COVID-19 infection, resulting in earlier intervention and lower morbidity. Therefore, this study aimed to determine the proportion of mental health problems post-COVID-19 infection in children and adolescents, and to compare them with the population with no previous COVID-19 infection. Methodology A systematic search was done in seven databases using pre-defined search terms. Cross-sectional, cohort and interventional studies reporting the proportion of mental health problems among children with long COVID in the English language from 2019 to May 2022 were included. Selection of papers, extraction of data and quality assessment were done independently by two reviewers. Studies with satisfactory quality were included in meta-analysis using R and Revman software programmes. Results The initial search retrieved 1848 studies. After screening, 13 studies were included in the quality assessments. Meta-analysis showed children who had previous COVID-19 infection had more than two times higher odds of having anxiety or depression, and 14% higher odds of having appetite problems, compared to children with no previous infection. The pooled prevalence of mental health problems among the population were as follows; anxiety: 9%(95% CI:1, 23), depression: 15%(95% CI:0.4, 47), concentration problems: 6%(95% CI: 3, 11), sleep problems: 9%(95% CI:5, 13), mood swings: 13% (95%CI:5, 23) and appetite loss: 5%(95% CI:1, 13). However, studies were heterogenous and lack data from low- and middle-income countries. Conclusion Anxiety, depression and appetite problems were significantly increased among post-COVID-19 infected children, compared to those without a previous infection, which may be attributed to long COVID. The findings underscore the importance of screening and early intervention of children post-COVID-19 infection at one month and between three to four months.

3108

Ch243

AbdelMassih, Antoine; Hanafy, Maram; Elahmady, Maryam; Kozman, Sylvia; Diab, Nourine; Husseiny, Reem; Deyab, Ashrakat; Mady, Aalaa; Yasser, Alia; R.AbdelHalim, Amira; Mohyeldin, Aya; Abdelgadir, Ayat; Abdelaziz, Eslam; Elghamry, Farida; Shehata, Hana; Milad, Karim; Fouda, Lamya; Hesham, Mawada; Adly, Mina; Omar, Yasmin

Non-Multisystem Inflammatory Syndrome in Children—Postacute Sequelae of Paediatric COVID-19: Autoimmune or Autoinflammatory? A Systematic Review of the Reported Cases

https://doi.org/10.3390/rheumato3020011

Published

30-May-23

Review

https://www.mdpi.com/2674-0621/3/2/11

Three years after its emergence, coronavirus disease 2019 (COVID-19) continues to be a leading cause of worldwide morbidity and mortality. This systematic review comprises relevant case reports that discuss non-multisystem inflammatory syndrome in children (non-MIS-C) and postacute sequalae of COVID-19 (PASC) in the paediatric population, also known as long COVID syndrome. The study aims to highlight the prevalent time interval between COVID-19 and the development of non-MIS-C post-infectious sequalae (PIS). Databases were searched for studies that met our inclusion and exclusion criteria. The final screening revealed an equal sex distribution where the commonest age intervals were school-age and adolescence, with 38% of the patients being older than six years. Interestingly, hospital admission during the course of COVID-19 was not a predictor of the subsequent PASC; forty-nine patients (44.9%) were hospitalized while sixty patients (55.1%) were not hospitalized. Moreover, the most predominant time interval between COVID-19 and the developing PASC was within 14 days from the start of COVID-19 infection (61%). These findings suggest a crucial link between COVID-19 and immune PIS in the paediatric population, especially those older than six years. Accordingly, follow-up and management are encouraged in case of unusual symptoms and signs following COVID-19 infection, regardless of the COVID-19 infection severity.

3109

OO01

Rachel E. Bridwell, MD Daniel R. Merrill, MD Sean A. Griffith, DO

A coronavirus disease 2019 (COVID-19) patient with bilateral orchitis: A case report

https://doi.org/10.1016/j.ajem.2020.08.068

published

26-Aug-20

Case report

https://www.ajemjournal.com/article/S0735-6757(20)30761-0/abstract

Another (very rare) pathology linked to covid: infection of the testicles. It could cause an impairment of the subject's fertility, but transmission through sexual contact is currently excluded.

Autre pathologie (exceptionnelle) liée à la covid : infection des testicules. Elle pourrait provoquer une altération de la fertilité du sujet, mais les transmissions par contacts sexuels sont exclues à ce jour.

Testicles

3110

OO02

Alfonso Savastano 1,2, ,Emanuele Crincoli

Peripapillary Retinal Vascular Involvement in Early Post-COVID-19 Patients

https://doi.org/10.3390/jcm9092895

published

8-Sep-20

Article

https://www.mdpi.com/2077-0383/9/9/2895

The possible repercussions on the vascularization of the retina following #covid_19.

Les possibles répercussions sur la vascularisation de la rétine suite à la #covid_19.

Eyes

3111

OO03

Lin Fu#,1,2, Jun Fei#,1, Shen Xu#,1, Hui-Xian Xiang1, Ying Xiang1

Liver Dysfunction and Its Association with the Risk of Death in COVID-19 Patients: A Prospective Cohort Study

https://dx.doi.org/10.14218/JCTH.2020.00043

published

20-Aug-20

ORIGINAL ARTICLE

https://www.xiahepublishing.com/2310-8819/ArticleFullText.aspx?sid=2&id=10.14218%2FJCTH.2020.00043

Possible effects on the liver

Effets possibles sur le foie

Liver

3112

OO04

Yes

Michelle D Lundholm, Caroline Poku, Nicholas Emanuele

SARS-CoV-2 (COVID-19) and the Endocrine System

https://doi.org/10.1210/jendso/bvaa144

published

1-Oct-20

Article

https://academic.oup.com/jes/article/4/11/bvaa144/5916481

Review of the literature on covid pathologies with regard to the endocrine system, diabetes, and other areas of analysis: pituitary gland, adrenal, thyroid, bone and gonadal function.

Revue de la littérature sur les pathologies de la covid au regard du système endocrinien, diabète(s), et autres axes d'analyse : hypophyse, fonction surrénalienne, thyroïdienne, osseuse et gonadique.

Endocrine system

3113

OO05

Yes - VP

Christian Gaebler, Zijun Wang, Julio C. C. Lorenzi, Frauke Muecksch, Shlomo Finkin

Evolution of Antibody Immunity to SARS-CoV-2

https://doi.org/10.1038/s41586-021-03207-w

Published

5-Nov-20

New Results

https://www.nature.com/articles/s41586-021-03207-w

A previously preprint study (not reviewed or published) reveals possibly intact virions of SARS-CoV-2 in the intestines of some patients 3-4 months after infection. American cardiologist @EricTopol sees it as a possible link with #LongCovid.
Peviously a pre-print : https://www.biorxiv.org/content/10.1101/2020.11.03.367391v1
Now published.

Une étude met en évidence des virions, possiblement intacts, de SARS-CoV-2 dans l'intestin de certains patients 3-4 mois après une infection. Le cardiologue américain @EricTopol y voit un lien éventuel avec le #LongCovid. L'étude est détaillée par l'un des co-auteurs dans ce thread : https://twitter.com/c_gaebler/status/1324444409337942016?s=20. L'étude suggère que les lymphocytes B après une infection au SARS-CoV-2 protègeraient durablement d'une réinfection.

Intestines

3114

OO06

Yes

Lorenzo Scappaticcio, Fabián Pitoia, Katherine Esposito

Impact of COVID-19 on the thyroid gland: an update

https://doi.org/10.1007/s11154-020-09615-z

published

25-Nov-20

Article

https://link.springer.com/article/10.1007/s11154-020-09615-z

Une étude italienne étudie de quelle façon le virus SARS-CoV-2 pourrait dans certains cas prendre pour cible, directement ou indirectement, la glande thyroïde et/ou l'ensemble de l'axe hypothalamo-hypophyso-thyroïde.

Thyroid gland

3115

OO07

Heckroth, Matthew A. MD1; Eiswerth, Michael DO1; Reynolds

Liver Function as an Assessment of Disease Progression in COVID-19: A Case Series

https://doi.org/10.14309/01.ajg.0000716192.54074.60

published

1-Oct-20

Case Reports

https://journals.lww.com/ajg/Fulltext/2020/10001/S3536_Liver_Function_as_an_Assessment_of_Disease.3534.aspx

Une étude de cas de détériorations hépatiques attribuées à la covid sur des patients (37 et 78 ans) hospitalisés. Une corrélation est supposée entre une fonction hépatique anormale et/ou lésions au foie et une aggravation de la pneumopathie progressive.

Liver

3116

OO08

Claire E. Fernandez, Colin K. Franz, Jason H. Ko, James M. Walter, Igor J. Koralnik,

Imaging Review of Peripheral Nerve Injuries in Patients with COVID-19

https://doi.org/10.1148/radiol.2020203116

published

1-Dec-20

Review

https://pubs.rsna.org/doi/full/10.1148/radiol.2020203116

Selon cette étude, le diagnostic différentiel de la lésion nerveuse périphérique dans le cadre de la covid inclut la neuropathie inflammatoire post-infectieuse, la lésion par étirement/compression liée au positionnement couché, la neuropathie systémique et les nerfs coincés secondaires à un hématome. L'étude interroge l'hypothèse du SRAS-CoV-2 comme neuropathogène et détaille diverses approches d'imagerie.

Peripheral Nerve

3117

OO09

Martina Burlando Roberto Russo Emanuele Cozzani Aurora Parodi

Six months into the pandemic. A review of skin manifestations in SARS‐CoV‐2 infection

https://doi.org/10.1111/dth.14641

published

5-Dec-20

Review Article

https://onlinelibrary.wiley.com/doi/abs/10.1111/dth.14641

Une revue d'études détaille les manifestations dermatologiques possibles de la covid : lésions vasculaires et cutanées, érythème polymorphe, éruption vésiculeuse, urticaire, lésions purpuriques, livedo réticulaire.

Skin

3118

OO10

Claudio Conforti 1, Caterina Dianzani 2, Marina Agozzino 1, Roberta Giuffrida 3, Giovanni Francesco Marangi 4, Nicola di Meo 1, Silviu-Horia Morariu 5, Paolo Persichetti 4, Francesco Segreto 4, Iris Zalaudek 1, Nicoleta Neagu 5

Cutaneous Manifestations in Confirmed COVID-19 Patients: A Systematic Review

https://doi.org/10.3390/biology9120449

published

5-Dec-20

Systematic Review

https://pubmed.ncbi.nlm.nih.gov/33291502/

A total
of 655 patients were selected, with different types of skin rashes: Erythematous maculopapular
(n = 250), vascular (n = 146), vesicular (n = 99), urticarial (n = 98), erythema multiforme/generalized
pustular figurate erythema/Stevens-Johnson syndrome (n = 22), ocular/periocular (n = 14),
polymorphic pattern (n = 9), generalized pruritus (n = 8), Kawasaki disease (n = 5), atypical erythema
nodosum (n = 3), and atypical Sweet syndrome (n = 1). Chilblain-like lesions were more frequent
in the younger population and were linked to a milder disease course, while fixed livedo racemosa
and retiform purpura appeared in older patients and seemed to predict a more severe prognosis.
For vesicular rashes, PCR determined the presence of herpesviruses in the vesicle fluid, which raised the
possibility of herpesvirus co-infections. The erythema-multiforme-like pattern, generalized pustular
figurate erythema and Stevens-Johnson syndrome were most frequently linked to hydroxychloroquine
intake. A positive PCR determination of SARS-COV-2 from conjunctival swabs suggest that eye, discharge can also be contagious. These cutaneous manifestations may aid in identifying otherwise
asymptomatic COVID-19 carriers in some cases or predict a more severe evolution in others.

_

Skin

3119

OO11

NaderBakheetaRababFouadaAbdel MeguidKassemaWessamHussinbMostafaEl-Shazlyc

Persistent hiccup: A rare presentation of COVID-19

https://doi.org/10.1016/j.resinv.2020.11.003

published

30-Nov-20

Case Report

https://www.sciencedirect.com/science/article/pii/S2212534520301647

Des crises de hoquet prolongées, attribuées à la covid, sont rapportées dans une étude de cas, mais présentent un caractère rarissime.

Diaphragmatic muscle

3120

OO12

VP

Jody E Hooper, MD, Meral Uner, MD, David S Priemer, MD, Avi Rosenberg, MD, PhD, Liam Chen, MD, PhD

Muscle Biopsy Findings in a Case of SARS-CoV-2-Associated Muscle Injury

https://doi.org/10.1093/jnen/nlaa155

published

22-Dec-20

Case - Letter to the Editor

https://academic.oup.com/jnen/advance-article/doi/10.1093/jnen/nlaa155/6045056

La présence suspectées par biopsie de virions de SARS-CoV-2 dans le muscle d'une patiente décédée de la covid semble accréditer une atteinte par lésions endothéliales et vasculaires, plutôt qu'une infection directe des fibres musculaires.

Muscles

3121

OO13

Maria Rita De Giorgio 1,2, Stefania Di Noia 2,3, Cinzia Morciano 1,2, Diana Conte

The impact of SARS-CoV-2
on skeletal muscles

https://www.doi.org/10.36185/2532-1900-034

published

6-Oct-20

Brief review

https://www.actamyologica.it/article/the-impact-of-sars-cov-2-on-skeletal-muscles/

Main current findings about muscular and neuromuscular damages that may be triggered by the virus or by the drugs used to treat COVID-19
https://www.actamyologica.it/wp-content/uploads/2020/12/18_De-Giorgio-1.pdf

_

Muscles

3122

OO14

Seeun Ha, Byungchang Jin, Brooke Clemmensen, Paul Park, Sumaiya Mahboob,
Vadim Gladwill, Subhash Verma, Seungil Ro

Serotonin is elevated in COVID-19-associated diarrhoea

http://dx.doi.org/10.1136/gutjnl-2020-323542

published

5-Jan-21

Letter

https://gut.bmj.com/content/early/2021/01/04/gutjnl-2020-323542

Une lettre parue dans le BMJ note une forte corrélation entre des taux élevés de sérotonine plasmatique, de son métabolite et d'interleukine 6, avec la sévérité du covid, en particulier avec la diarrhée comme symptôme gastro-intestinal.

Gastro-intestinal

3123

OO15

Xixiang Ma, Chuhuai Guan, Rong Chen, Yunyun Wang, Shenglei Feng, Rongshuai Wang, Guoqiang Qu, Sijia Zhao, Fengli Wang, Xiaoli Wang, Dingyu Zhang, Liang Liu, Aihua Liao, Shuiqiao Yuan

Pathological and molecular examinations of postmortem testis biopsies reveal SARS-CoV-2 infection in the testis and spermatogenesis damage in COVID-19 patients

https://doi.org/10.1038/s41423-020-00604-5

published

14-Dec-20

Correspondence

https://www.nature.com/articles/s41423-020-00604-5

Quote from https://twitter.com/yaneerbaryam/status/1348338360373358592?s=20 / "Update: LongCovid and male infertility Several articles have shown potential COVID harm to male fertility. A new article is much more explicit. Massive damage to germ cells (cells that become sperm) indicates potential loss of male fertility.This autopsy study doesn’t show effect of mild cases. However, studies of mild and asymptomatic cases indicate the virus can reach multiple organs. The ACE2 receptor is highly expressed in testes. 2/Title: Pathological and molecular examinations of postmortem testis biopsies reveal SARS-CoV-2 infection in the testis and spermatogenesis damage in COVID-19 patients https://nature.com/articles/s41423-020-00604-5… 3/.”.we evaluated the effects of SARS-CoV-2 infection on spermatogenesis by examining the pathophysiology and molecular features of testes obtained from five male COVID-19 patients at autopsy. The COVID-19 patients were aged 51, 62, 70, 78, and 83 years 4/In all five COVID-19 patients, numerous degenerated germ cells (GCs) had sloughed into the lumen of seminiferous tubules (Fig. 1a). In contrast, in the age-matched control tissues, GCs at various stages were well aligned around the whole seminiferous tubules (Fig. 1a). 5/Strikingly, in four of the five cases, GC loss was massive, with only a few GCs left attached to the seminiferous tubules. In particular, many seminiferous tubules in the testes of patients 4 and 5 showed almost no intact GCs, 6/similar to Sertoli cell-only syndrome. [note: Sertoli cell only syndrome is a disorder characterized by male sterility] 7/Consistent with this morphological observation, the number of DDX4 (a germ cell marker)-positive cells was dramatically reduced in all testicular specimens from the COVID-19 group 8/These morphological changes in the testes of COVID-19 patients indicate that SARS-CoV-2 infection may impair male GC development and eventually lead to GC loss. 9/Collectively, our findings provide direct evidence that SARS-CoV-2 can infect the testis and GCs, indicating the potential impact of the COVID-19 pandemic on spermatogenesis and male fertility. 10/Note: Everything from 4/ to 10/ are quotes from the paper."

Une étude parue dans Nature, faite depuis des autopsies de victimes de la covid, montre que le virus peut endommager, parfois drastiquement, la fertilité masculine.

Testicles

3124

OO16

Wenjie Chen, MD, Yuang Tian, MD, Zhihui Li, MD, Jingqiang Zhu, PHD, Tao Wei, MD, Jianyong Lei

Potential interaction between SARS-CoV-2 and thyroid: a review

https://doi.org/10.1210/endocr/bqab004

published

11-Jan-21

Mini-review

https://academic.oup.com/endo/advance-article/doi/10.1210/endocr/bqab004/6082366?login=true

"However, subacute thyroiditis (SAT) caused by SARS-CoV-2 has been reported for the first time."

Cette étude associe un cas de thyroïdite subaiguë à une infection au SARS-CoV-2, et rappelle que les dérèglements thyroïdiens sont communs chez les malades de la covid.

Thyroid gland

3125

OO17

Devon E McMahon, Antonia E Gallman, George J Hruza, Misha Rosenbach, Jules B Lipoff, Seemal R Desai, Lars E French, Henry Lim, Jason G Cyster, Lindy P Fox, Marlys S Fassett, Esther E Freeman

Long COVID in the skin: a registry analysis of COVID-19 dermatological duration

https://doi.org/10.1016/S1473-3099(20)30986-5

published

15-Jan-21

Registry Analysis

https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30986-5/fulltext

@EricTopol "When #LongCovid is in the skin, results from an international registry, "raising questions about persistent inflammation even in patients who initially experienced relatively mild covid-19"

A partir d'un registre international , une équipe qui publie dans The Lancet répertorie et qualifie la durée des symptômes dermatologiques de la covid, qui peuvent se présenter dans les premières semaines après l'infection.

Skin

3126

OO18

Yin Ping Wong, Teck Yee Khong, Geok Chin Tan

The Effects of COVID-19 on Placenta and Pregnancy: What Do We Know So Far?

https://doi.org/10.3390/diagnostics11010094

published

8-Jan-21

Review

https://www.mdpi.com/2075-4418/11/1/94

Une revue d'études s'intéresse aux manifestations possibles du SARS-CoV-2 sur le placenta, et aux voies potentielles associées à la transmission virale transplacentaire et aux issues défavorables de la grossesse (rarement observés).

Placenta

3127

OO19

Shubhadeep Roychoudhury, Anandan Das, Niraj Kumar Jha, Dhruv Kumar and Petr Slama

Viral pathogenesis of SARS-CoV-2 infection and male reproductive health

https://doi.org/10.1098/rsob.200347

published

20-Jan-21

Review

https://royalsocietypublishing.org/doi/10.1098/rsob.200347

Une revue d'études sur les séquelles de la covid sur l'appareil reproducteur masculin estime que des effets à long terme sur la fertilité sont une possibilité à envisager. Parallèlement, la transmission sexuelle de la covid n'est pas écartée.

Testicles

3128

OO20

Robert A. Schwartz, MD, MPH, DSc (Hon), FRCP Edin, W. Clark Lambert

COVID-19 Specific skin changes related to SARS-CoV-2 Visualizing a Monumental Public Health Challenge

https://doi.org/10.1016/j.clindermatol.2021.01.009

Published

1-Feb-21

Article

https://www.cidjournal.com/article/S0738-081X(21)00010-9/fulltext

Skin lesions linked with COVID-19 have been grouped into 6 categories with three distinct indicative patterns: vesicular (varicella-like), vasculopathic, and chilblains-like (including “COVID toes” and “COVID fingers”) plus three less suggestive ones: dermatitic, maculopapular, and urticarial morphologies. Vasculopathic changes are the most concerning, in some patients reflecting a devastating blood clotting dysfunction. Ways to detect, prevent, and treat COVID-19 will be discussed keeping in mind the context of possible cutaneous markers of COVID-19 to enhance detection.

Une étude classe les atteintes dermatologiques de la covid en 6 types : 3 peu suggestifs, et les 3 autres plus spécifiques : vésiculaires, de types "engelure", et celles liées à une vasculopathie qui inquiètent le plus les auteurs.

Skin

3129

OO21

Janis A. Müller, Rüdiger Groß, […]Alexander Kleger

SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas

https://doi.org/10.1038/s42255-021-00347-1

Published

3-Feb-21

Study

https://www.nature.com/articles/s42255-021-00347-1

In the present study, we show that SARS-CoV-2 infects cells of the human exocrine and endocrine pancreas ex vivo and in vivo. We demonstrate that human β-cells express viral entry proteins, and SARS-CoV-2 infects and replicates in cultured human islets. Infection is associated with morphological, transcriptional and functional changes, including reduced numbers of insulin-secretory granules in β-cells and impaired glucose-stimulated insulin secretion. In COVID-19 full-body postmortem examinations, we detected SARS-CoV-2 nucleocapsid protein in pancreatic exocrine cells, and in cells that stain positive for the β-cell marker NKX6.1 and are in close proximity to the islets of Langerhans in all four patients investigated. Our data identify the human pancreas as a target of SARS-CoV-2 infection and suggest that β-cell infection could contribute to the metabolic dysregulation observed in patients with COVID-19.

Une étude très qualitative entend démontrer la cohérence d'un mécanisme de destruction par le SARS-CoV-2 dans le pancréas de cellules bêta d'îlots de Langerhans (qui libèrent de manière endocrine l'insuline). La covid altèrerait ainsi l'homéostasie du glucose et un ensemble de fonctions exocrines et endocrines du pancréas. Les auteurs constatent la réplication du virus dans des îlots du pancréas et attribuent à un traitement au Remdesivir un rôle inhibiteur de cette réplication. Le diabète est décrit par l'étude comme comorbidité établie, mais aussi conséquence (apparition ou aggravation) de l'infection. La publication note également que les pancréatites aiguës se retrouvent chez plus de 10% des patients hospitalisés et un tiers des malades critiques.

Pancreas

3130

OO22

Cordero, Pedro Méndez; Crespo, Diego Ochoa; Cáceres, William Salazar; Choez, Karen Moreno; Nauñay, Darío Cocha; et al..

Lesión pancreática causada por Covid-19: ¿es la diabetes una secuela de la infección?
Alternate title: Covid-19-related pancreatic injury: Is diabetes a sequel of the infection?

https://doi.org/10.5281/zenodo.4381011

Published

20-Dec-20

Study

https://zenodo.org/record/4381011#.YCMe9JTftG8

It may be difficult to determine whether the presence of pancreatitis is due to direct local damage by the SARS-CoV-2, or if it is the result of the dysregulated inflammatory response seen in the disease. Independently of the cause, pancreatic injury is an important risk factor for the development of DM and prediabetes, and hinders the correct treatment of patients with pre-established DM.

Une revue d'études s'attèle à évaluer les mécanismes moléculaires qui prennent place derrière les dommages au pancréas après une infection au SARS-CoV-2. La covid apparaît comme pouvant aggraver un diabète.

Pancreas

3131

OO23

Sumina Mannur, MBBS, MS, DNB, Talha Jabeen, PharmD, Mohd Abdul Khader, PharmD, Lendale Sai Shakti Rao

POST-COVID-19 ASSOCIATED DECLINE IN LONG-TERM MALE FERTILITY AND EMBRYO QUALITY DURING ASSISTED REPRODUCTIVE TECHNOLOGY

https://doi.org/10.1093/qjmed/hcab019

Published

28-Jan-21

Case Report

https://academic.oup.com/qjmed/advance-article/doi/10.1093/qjmed/hcab019/6122743

"In the present case, we saw even a mild infection can results in long-term alterations in sperm morphology and sperm DNA integrity of men and can take a much longer time (>4months) than what has been previously thought (70-90 days) for returning to the basal state of sperm parameters (5) or might ultimately induce male infertility."
Also:
https://pubmed.ncbi.nlm.nih.gov/33561263/
"fever, even of limited duration, can, on its own, induce sperm parameters major alteration, sperm DNA damage, sperm apoptosis and germ cell death as previously described"

Débat dans la publication médicale QJM sur l'éventuelle action du SARS-CoV-2 sur la fertilité masculine. Un cas rapporté en janvier faisait état d'une altération de l'ARN des spermatozoïdes directement consécutive à une infection covid. Cependant, une réponse d'un chercheur remet en question les conclusions de l'étude en pointant le fait que les fortes fièvres, fréquentes lors de la covid, altèrent de façon générale les spermatozoïdes pour plusieurs mois.

Testicles

N002

3132

OO24

Malik, Asmara Malik, Muhammad Javaid, Tayyaba Zahid, Uzma Ishaq, Muhammad Shoaib

Thyroid Function Analysis in COVID-19: A Retrospective Study from a Single Center

https://doi.org/10.1101/2021.02.09.21251435

pre-print

12-Feb-21

Retrospective Study

https://www.medrxiv.org/content/10.1101/2021.02.09.21251435v2

Seventy-five percent of patients with COVID-19 had thyroid abnormalities and higher IL-6 levels (76.10 ± 82.35 vs. 6.99 ± 3.99, 95% CI 52.18-100.01, P-value <0.01). Logistic regression analysis suggested TT3 (P-value 0.01), IL-6 (P-value <0.01), and Procalcitonin (P-value 0.03) as independent risk factors for COVID-19. ROC curve demonstrated IL-6 as the most sensitive marker (P-value <0.01), and TT3, and Procalcitonin as the predictor for COVID-19 disease.

Dans une étude en pre-print (non relue ni publiée), une équipe rapporte des anomalies thyroïdiennes sur 3/4 des patients hospitalisés pour une covid, y compris 3 mois après le début du suivi. Les taux d'interleukines 6 sont notamment anormalement élevés.

Thyroid gland

N003R

3133

OO26

Santhoshini Leela Ramani, Jonathan Samet, Colin K. Franz, Christine Hsieh, Cuong V. Nguyen, Craig Horbinski & Swati Deshmukh

Musculoskeletal involvement of COVID-19: review of imaging

https://doi.org/10.1007/s00256-021-03734-7

Published

18-Feb-21

Review Article

https://link.springer.com/article/10.1007/s00256-021-03734-7

Multimodality imaging supports diagnosis and evaluation of musculoskeletal disorders in COVID-19 patients. This article aims to provide a first comprehensive summary of musculoskeletal manifestations of COVID-19 with review of imaging.

En faisant une revue d'études de l'imagerie médicale des séquelles musculaires et articulaires de la covid, cette publication définit de possibles diagnostics des troubles consécutifs à l'infection de SARS-CoV-2.

Muscles

N004R

3134

OO27

Ashish Chaudhry, Jeannie McGinnis, Amali Lokugamage

We need to do more to understand chronic vocal symptoms of covid-19

Blog

19-Feb-21

https://blogs.bmj.com/bmj/2021/02/19/we-need-to-do-more-to-understand-chronic-vocal-symptoms-of-covid-19/

"Our spectrum of symptoms has varied from intermittent to persistent hoarseness, discomfort or pain, and dyspnoea."

Des professionnels de santé alertent dans un blog de la revue médicale BMJ sur les dommages aux organes vocaux de la covid. Elle pourrait être cause de dysphonies et compromettre l'avenir professionnel de personnes utilisant le chant ou l'art oratoire.

Vocal organs

3135

OO28

Augustin Lecler , François Cotton, François Lersy, Stéphane Kremer, Françoise Héran, on behalf of the SFNR’s COVID Study Group

Ocular MRI Findings in Patients with Severe COVID-19: A Retrospective Multicenter Observational Study

https://doi.org/10.1148/radiol.2021204394

Published

16-Feb-21

Original Research

https://pubs.rsna.org/doi/10.1148/radiol.2021204394

This paper reports 9 patients (1/9 [11%] woman and 8/9 [89%] men, mean age 56 ± 13 years) with globe MRI abnormalities obtained from a multicenter cohort of 129 patients presenting with severe COVID-19 from March 4th to May 1st, 2020. 9/129 (7%) patients had one or several FLAIR-WI hyperintense nodules of the posterior pole of the globe. All patients had nodules in the macular region, 8/9 (89%) had bilateral nodules, 2/9 (22%) had nodules outside the macular region. Screening of these patients might improve the management of potentially severe ophthalmological manifestations of the virus.

Une étude rapporte des cas d'anomalies de la région orbitale vues par IRM, notamment des nodules du pôle postérieur (partie de l'œil comprenant la papille et la tête du nerf optique), consécutifs à des formes sévères de covid.

Eyes

N003

3136

OO29

Sasan Andalib, José Biller, Mario Di Napoli, Narges Moghimi, Louise D McCullough, Clio A. Rubinos, Michel Torbey & Afshin A. Divani

Peripheral Nervous System Manifestations Associated with COVID-19

https://doi.org/10.1007/s11910-021-01102-5

Published

14-Feb-21

Review

https://link.springer.com/article/10.1007/s11910-021-01102-5

Nerve pain and skeletal muscle injury, Guillain-Barré syndrome, cranial polyneuritis, neuromuscular junction disorders, neuro-ophthalmological disorders, neurosensory hearing loss, and dysautonomia have been reported as PNS manifestations in patients with COVID-19.

Une revue d'articles fait le tour des atteintes possibles au système nerveux périphérique liées à une infection de covid : syndrome de Guillain-Barré, polynévrite crânienne, troubles de la jonction neuromusculaire, troubles neuro-ophtalmologiques, surdité neurosensorielle et dysautonomie.

Peripheral Nerve

N003

3137

OO30

R. U. Chowdhury, Sahedul I. Bhuiyan, Bimal C. Das, Ashim K. Saha

Acute parotitis associated with COVID-19 - an unusual presentation: a report from Bangladesh perspective

https://dx.doi.org/10.18203/2394-6040.ijcmph20210853

Published

1-Mar-21

Case Report

https://www.ijcmph.com/index.php/ijcmph/article/view/7563

We report a case of a 62 years old male presented in the outpatient department with COVID-19 associated acute parotitis, later developed bilateral pneumonia.

La parotidite, une inflammation de glandes salivaires, une conséquence rare d'une infection de covid. Un cas rapporté dans une étude au Bangladesh.

Salivary glands

3138

OO31

Puja Mehta
Christopher B Bunker
Coziana Ciurtin
Joanna C Porter
Rachel C Chambers
Charalampia Papdopoulou
Helen Garthwaite
Toby Hillman
Melissa Heightman
Kevin J Howell
Despina Eleftheriou
Christopher P Denton

Chilblain-like acral lesions in long COVID-19: management and implications for understanding microangiopathy

https://doi.org/10.1016/S1473-3099(21)00133-X

Published

8-Mar-21

Study

https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00133-X/fulltext

We agree that most acral chilblain-like or pernio-like lesions (commonly referred to as COVID toes) occur in young, previously healthy patients with relatively mild COVID-19 and frequently negative tests for SARSCoV-2. Most resolve spontaneously without any treatment approximately 2 weeks from onset, particularly in children and adolescent patients. However, in our multidisciplinary post-COVID-19 follow-up clinic of adult patients and specialist tertiary referral centre for paediatric and adolescent rheumatology, we have observed a subgroup of patients with persistent chilblain
lesions, similar to McMahon and colleagues’ report. Clinically these chilblain-like lesions resemble the digital vasculopathy of connective tissue disease.

Une étude sur les lésions aux extrémités de type engelure provoquées par la covid, et leurs liens avec la microangiopathie (affection des vaisseaux sanguins). Les options thérapeutiques y sont décrites.

Skin

N003A

3139

OO32

Thomas Marjot, Gwilym J. Webb, Alfred S. Barritt IV, Andrew M. Moon, Zania Stamataki, Vincent W. Wong & Eleanor Barnes

COVID-19 and liver disease: mechanistic and clinical perspectives

https://doi.org/10.1038/s41575-021-00426-4

Published

10-Mar-21

Review Article

https://www.nature.com/articles/s41575-021-00426-4

In this Review, we discuss the hepatotropism of SARS-CoV-2, including the differential expression of viral receptors on liver cell types, and we describe the liver histology features present in patients with COVID-19. We also provide an overview of the pattern and relevance of abnormal liver biochemistry during COVID-19 and present the possible underlying direct and indirect mechanisms for liver injury.

Key points
. Patients with cirrhosis have high rates of hepatic decompensation, acute-on-chronic liver failure and death from respiratory failure following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and should be prioritized for coronavirus disease 2019 (COVID-19) vaccination.
. The possible pathogenic mechanisms linking cirrhosis with severe COVID-19 lung disease include increased systemic inflammation, cirrhosis-associated immune dysfunction, coagulopathy and intestinal dysbiosis.
. Abnormal liver biochemistry values are common in patients with COVID-19; both the prognostic significance of these derangements and whether they are directly attributable to hepatic SARS-CoV-2 infection remain uncertain.
. Expression profiles of SARS-CoV-2 entry receptors vary across different in vitro and in vivo liver models; however, evidence of specific viral hepatotropism is limited.
. Liver transplant recipients do not appear to have an increased risk of mortality following SARS-CoV-2 infection compared with the matched general population.
. The pandemic has been associated with increased alcohol consumption, unhealthy eating habits, and interruptions to hepatology services, which might lead to an upward trend in liver disease incidence and severity.

_

Liver

3140

OO33

Yan Jing, Li Run-Qian, Wang Hao-Ran, Chen Hao-Ran, Liu Ya-Bin, Gao Yang, Chen Fei

Potential influence of COVID-19/ACE2 on the female reproductive system

https://doi.org/10.1093/molehr/gaaa030

Published

4-May-20

https://academic.oup.com/molehr/article/26/6/367/5828941?login=true

The available evidence suggests that ACE2 is widely expressed in the ovary, uterus, vagina and placenta. Therefore, we believe that apart from droplets and contact transmission, the possibility of mother-to-child and sexual transmission also exists. Ang II, ACE2 and Ang-(1-7) regulate follicle development and ovulation, modulate luteal angiogenesis and degeneration, and also influence the regular changes in endometrial tissue and embryo development. Taking these functions into account, 2019-nCoV may disturb the female reproductive functions through regulating ACE2.

_

Female reproductive system

3141

OO34

Andrea Sansone Daniele Mollaioli Giacomo Ciocca Elena Colonnello Erika Limoncin Giancarlo Balercia Emmanuele A. Jannini

“Mask up to keep it up”: preliminary evidence of the association between erectile dysfunction and COVID‐19

https://doi.org/10.1111/andr.13003

Published

20-Mar-21

Survey

https://onlinelibrary.wiley.com/doi/abs/10.1111/andr.13003

100 subjects were included in the analysis (25 COVID positive; 75 COVID negative). Prevalence of erectile dysfunction (ED,) measured with the Sexual Health Inventory for Men, was significantly higher in the COVID+ group (28% vs 9.33%; p = 0.027). Logistic regression models confirmed a significant effect of COVID‐19 on the development of ED, independently of other variables affecting erectile function, such as psychological status, age and BMI [OR 5.66 ,95% CI: 1.50 – 24.01]. Likewise, subjects with ED were more likely to have COVID‐19, once corrected for age and BMI [OR 5.27, 95% CI: 1.49 – 20.09]. Erectile dysfunction (ED)

Cette étude note que les troubles érectiles sont statistiquement plus fréquents chez les personnes infectées par la covid. Le virus pourrait jouer un rôle direct et diverses hypothèses physiopathologiques sont évoquées par les auteurs.

Penis

3142

OO35

Ibrahim Almufarrij &Kevin J. Munro

One year on: an updated systematic review of SARS-CoV-2, COVID-19 and audio-vestibular symptoms

https://doi.org/10.1080/14992027.2021.1896793

Published

22-Mar-21

Review

https://www.tandfonline.com/doi/full/10.1080/14992027.2021.1896793

There are multiple reports of hearing loss (e.g. sudden sensorineural), tinnitus and rotatory vertigo in adults having a wide range of COVID-19 symptom severity. The pooled estimate of prevalence based primarily on retrospective recall of symptoms, was 7.6% (CI: 2.5–15.1), 14.8% (CI: 6.3–26.1) and 7.2% (CI: 0.01–26.4), for hearing loss, tinnitus and rotatory vertigo, respectively. However, these could be an over-estimate because it was not always clear that studies report a change in symptom.

Une revue d'étude fait le point sur les symptômes audio-vestibulaires déclenchés par la covid : pertes auditives, acouphènes et vertiges.

Ears

3143

OO36

Mathieu Vinken

COVID-19 and the liver: an adverse outcome pathway perspective

https://doi.org/10.1016/j.tox.2021.152765

Published

23-Mar-21

Article

https://www.sciencedirect.com/science/article/pii/S0300483X21000883

The present paper introduces an adverse outcome pathway construct that mechanistically describes the pathways induced by SARS-CoV-2 leading to liver injury. This can be caused by direct binding of the virus and local actions in cholangiocytes, but may also indirectly result from the general state of hypoxia and systemic inflammation in COVID-19 patients.

_

Liver

3144

OO37

Philippe Caron

Thyroiditis and SARS-CoV-2 pandemic: a review

https://doi.org/10.1007/s12020-021-02689-y

Published

27-Mar-21

Mini Review

https://link.springer.com/article/10.1007/s12020-021-02689-y

Thyroiditis form part of the spectrum of visceral involvement linked to SARS-CoV-2. In this review, we will describe the various documented clinical forms of thyroiditis (inflammatory thyroiditis, subacute or de Quervain’s thyroiditis, chronic lymphocytic thyroiditis or Hashimoto’s disease, painless (silent) postpartum thyroiditis) to facilitate their diagnosis in more or less symptomatic Covid-19 patients and to provide guidance for patient treatment.

Une courte revue d'études des possibles inflammations de la glande thyroïde provoquées par une covid. L'article vise sur ces affections à aider au diagnostic et aux soins.

Thyroid gland

N010

3145

OO38

Lehmann HC1, Schoser B2, Wunderlich G1, Berlit P3, Fink GR1

Neuromuscular complications of SARS-CoV-2 infections-Part 1: peripheral nerves

https://doi.org/10.1007/s00115-021-01094-0

Published

26-Mar-21

Review

https://europepmc.org/article/med/33770191

In the first part of our review the current knowledge about a potential association of a SARS-CoV‑2 infection with dysfunction and diseases of cranial and peripheral nerves is discussed. Anosmia, ageusia, motor cranial nerve involvement and Guillain-Barré syndrome (GBS) were described in a temporal association with a SARS-CoV‑2 infection. Several studies could show that anosmia and ageusia were frequent symptoms of a SARS-CoV‑2 infection. In contrast the failure of other cranial nerves has so far only been sporadically described. A number of case reports and case series indicate a causal association between a SARS-CoV‑2 infection and GBS but epidemiological evidence is still lacking.

Revue d'études (en allemand) des possibles atteintes au système nerveux périphérique provoquées par la covid, qui évoque notamment le syndrome de Guillain-Barré.

Peripheral Nerve

N010

3146

OO39

Koji Kitazawa 1,2,* ,Stefanie Deinhardt-Emmer 2,3,*,Takenori Inomata 4,5,6,7 ,Sharvari Deshpande 2 andChie Sotozono

The Transmission of SARS-CoV-2 Infection on the Ocular Surface and Prevention Strategies

https://doi.org/10.3390/cells10040796

Published

2-Apr-21

Review

https://www.mdpi.com/2073-4409/10/4/796

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global health problem. Although the respiratory system is the main impaired organ, conjunctivitis is one of its common findings. However, it is not yet understood if SARS-CoV-2 can infect the eye and if the ocular surface can be a potential route of SARS-CoV-2 transmissions. Our review focuses on the viral entry mechanisms to give a better understanding of the interaction between SARS-CoV-2 and the eye. We highlighted findings that give evidence for multiple potential receptors of SARS-CoV-2 on the ocular surface. Additionally, we focused on data concerning the detection of viral RNA and its spike protein in the various ocular tissues from patients. However, the expression level seemed to be relatively low compared to the respiratory tissues as a result of a unique environment surrounding the ocular surface and the innate immune response of SARS-CoV-2. Nevertheless, our review suggests the ocular surface as a potential route for SARS-CoV-2 transmission, and as a result of this study we strongly recommend the protection of the eyes for ophthalmologists and patients at risk.

Étudiant les potentiels récepteurs du SARS-CoV-2 à la surface oculaire, une revue d'analyses insiste sur le fait que les yeux sont une voie possible de transmission de la covid.

Eyes

N007

3147

OO40

M Bendayan, F Boitrelle

COVID-19: semen impairment may not be related to the virus

https://doi.org/10.1093/humrep/deab082

Published

1-Apr-21

Letter to the Editor

https://academic.oup.com/humrep/advance-article/doi/10.1093/humrep/deab082/6208127

In conclusion, fever, medication, long sexual abstinence may explain the alteration of semen parameters. These effects could be reversible and are not specific to the COVID-19. It is for this reason that it was recommended, from the beginning of the pandemic, to delay ART activities to 3 months post-infection with SARS-CoV-2, especially in case of fever. In the absence of fever, the effects of the new coronavirus on semen remain unknown.

_

Testicles

3148

OO41

Amira Mohammed Ali 1,2,* andHiroshi Kunugi

Skeletal Muscle Damage in COVID-19: A Call for Action

https://doi.org/10.3390/medicina57040372

Published

12-Apr-21

Review

https://www.mdpi.com/1648-9144/57/4/372

The current review briefly summarizes the literature for mechanisms, assessment measures, and interventions relevant to skeletal muscle insult in COVID-19 patients. Muscle injury is likely to be attributed to the cytokine storm, disease severity, malnutrition, prolonged physical inactivity during intensive care unit (ICU) stays, mechanical ventilation, and myotoxic drugs (e.g., dexamethasone). It has been assessed by imaging and non-imaging techniques (e.g., CT and electromyography), physical performance tests (e.g., six-minute walk test), anthropometric measures (e.g., calf circumference), and biomarkers of muscle dystrophy (e.g., creatine kinase). Interventions directed toward minimizing muscle loss among COVID-19 patients are lacking. However, limited evidence shows that respiratory rehabilitation improves respiratory function, muscle strength, quality of life, and anxiety symptoms in recovering older COVID-19 patients. Neuromuscular electrical stimulation may restore muscle condition in ICU-admitted patients, albeit empirical evidence is needed. Given the contribution of malnutrition to disease severity and muscle damage, providing proper nutritional management for emaciated patients may be one of the key issues to achieve a better prognosis and prevent the after-effects of the disease. Considerable attention to longer-term consequences of muscle injury in recovering COVID-19 patients is necessary.

_

Muscles

3149

OO42

Pierpaolo Trimboli, Chiara Camponovo, Lorenzo Scappaticcio, Giuseppe Bellastella, Arnoldo Piccardo & Mario Rotondi

Thyroid sequelae of COVID-19: a systematic review of reviews

https://doi.org/10.1007/s11154-021-09653-1

Published

11-Apr-21

Review

https://link.springer.com/article/10.1007/s11154-021-09653-1

The reviews identified several potential thyroid consequences in COVID-19 patients, such as thyrotoxicosis, low-T3 syndrome and subacute thyroiditis, while no relevant data were found regarding the potential impact of COVID-19 on the management of patients on thyroid treatment. The present systematic review of reviews found that: 1) patients diagnosed with COVID-19 can develop thyroid dysfunction, frequently non-thyroidal illness syndrome when hospitalized in intensive care unit, 2) having a thyroid disease does not increase the risk for SARS-CoV-2 infection, 3) thyroid patients do not need a COVID-19-adapted follow-up. Anyway, several factors, such as critical illness and medications, could affect thyroid laboratory tests.

_

Thyroid gland

3150

OO43

Nora Majtanova 1 2, Petra Kriskova 1, Petra Keri 1, Zlatica Fellner 1, Juraj Majtan 3, Petr Kolar 1 2

Herpes Simplex Keratitis in Patients with SARS-CoV-2 Infection: A Series of Five Cases

https://doi.org/10.3390/medicina57050412

Published

24-Apr-21

Case Report

https://pubmed.ncbi.nlm.nih.gov/33923158/

Herpes simplex virus type 1 (HSV-1) is a leading cause of infectious blindness worldwide. Most of the initial infection cases manifest as acute epithelial keratitis. Reactivation of herpesviruses is common in critically ill patients, including patients with severe Coronavirus disease (COVID-19). However, the data on COVID-19-related ocular infections is sparse, despite recent observations that more than 30% of COVID-19-infected patients had ocular manifestations. We report five cases of HSV-1 keratitis in COVID-19 patients. In total, five COVID-19 patients underwent ophthalmic examination, showing similar symptoms, including photophobia, tearing, decreased vision, eye redness, and pain. After initial assessment, tests of visual acuity and corneal sensitivity, a fluorescein staining test, and complete anterior and posterior segment examinations were performed. A diagnosis of HSV-1 keratitis was confirmed in all cases. Therapy was initiated using a local and systemic antiviral approach together with local antibiotic and mydriatic therapy. The complete reduction of keratitis symptoms and a clear cornea was achieved in all patients within 2 weeks. SARS-CoV-2 infection may be a risk factor for developing HSV-1 keratitis, or it may act as a potential activator of this ocular disease.

_

Eyes

3151

OO44

Saini G1, Aneja R

Cancer as a prospective sequela of long COVID-19.

https://doi.org/10.1002/bies.202000331

Published

29-Apr-21

Article

https://europepmc.org/article/med/33914346

Nevertheless, whether long COVID-19 increases the risk of cancer in those with no prior malignancies, remains unclear. Given, the disproportionate impact of the disease on the African American community, yet another unanswered question is whether racial disparities are to be expected in COVID-19 sequelae. Herein, we propose that long COVID-19 may predispose recovered patients to cancer development and accelerate cancer progression. This hypothesis is based on growing evidence of the ability of SARS-CoV-2 to modulate oncogenic pathways, promote chronic low-grade inflammation, and cause tissue damage. Comprehensive studies are urgently required to elucidate the effects of long COVID-19 on cancer susceptibility.

Un article de chercheurs estime que le covid long pourrait être un terrain favorisant les risques de cancer et les risques d'aggravation de cancer.

Oncogenic pathways

N009

3152

OO45

Julie Byler 1, Rebecca Harrison 2, Lindsey L Fell

Rhabdomyolysis Following Recovery from Severe COVID-19: A Case Report

https://doi.org/10.12659/ajcr.931616

Published

8-May-21

Case Report

https://pubmed.ncbi.nlm.nih.gov/33963170/

This case highlights the wide differential diagnosis of rhabdomyolysis in the setting of recent COVID-19 and prolonged hospitalization. It demonstrates the possibility that muscle injury and resultant rhabdomyolysis may be a late complication of COVID-19 that is not yet fully described in the literature.

_

Muscles

3153

OO46

VP

Eliyahu Kresch1 , Justin Achua1 , Russell Saltzman2 , Kajal Khodamoradi1 , Himanshu Arora1 ,
Emad Ibrahim1 , Oleksandr N. Kryvenko1,3,6 , Vania Wolff Almeida4 , Fakiha Firdaus1 ,
Joshua M. Hare2,5 , Ranjith Ramasamy

COVID-19 Endothelial Dysfunction Can Cause
Erectile Dysfunction: Histopathological,
Immunohistochemical, and Ultrastructural Study
of the Human Penis

https://doi.org/10.5534/wjmh.210055

Published

7-May-21

Study

https://wjmh.org/DOIx.php?id=10.5534/wjmh.210055

Purpose: A pilot study to describe histopathological features of penile tissue of patients who recovered from symptomatic COVID-19 infection and subsequently developed severe erectile dysfunction (ED).
Materials and Methods: Penile tissue was collected from patients undergoing surgery for penile prosthesis for severe ED. Specimens were obtained from two men with a history of COVID-19 infection and two men with no history of infection. Specimens were imaged with TEM and H&E staining. RT-PCR was performed from corpus cavernosum biopsies. The tissues collected were analyzed for endothelial Nitric Oxide Synthase (eNOS, a marker of endothelial function) and COVID-19 spike-protein expression. Endothelial progenitor cell (EPC) function was assessed from blood samples collected from COVID-19 (+) and COVID-19 (-) men.
Results: TEM showed extracellular viral particles ~100 nm in diameter with peplomers (spikes) near penile vascular endothelial cells of the COVID-19 (+) patients and absence of viral particles in controls. PCR showed presence of viral RNA in COVID-19 (+) specimens. eNOS expression in the corpus cavernosum of COVID-19 (+) men was decreased compared to COVID-19 (-) men. Mean EPC levels from the COVID-19 (+) patients were substantially lower compared to mean EPCs from men with severe ED and no history of COVID-19.
Conclusions: Our study is the first to demonstrate the presence of the COVID-19 virus in the penis long after the initial infection in humans. Our results also suggest that widespread endothelial cell dysfunction from COVID-19 infection can contribute to ED. Future studies will evaluate novel molecular mechanisms of how COVID-19 infection leads to ED.

En utilisant la microscopie électronique à transmission, une étude américaine remarque que le virus de la covid peut rester longtemps dans le pénis, et peut être à l'origine de dysfonctions érectiles majeures.

Penis

N014E

3154

OO47

Ricardo de León Durango1, Alba Hernández Lázaro1, Paula Maria Fernandez-Trujillo-Comenge1, Agnieszka Kuzior2, Manuel Esteban Nivelo-Rivadeneira1, Ana Delia Santana-Suarez1, Carmen Acosta-Calero3, Claudia Arnas-Leon4, Paula Gonzalez-Diaz5 & Francisco Javier Martinez-Martin

Severe postprandial hypoglycemia as a possible sequel of COVID-19

https://doi.org/10.1530/endoabs.73.AEP174

Published

22-May-21

Case Report

https://www.endocrine-abstracts.org/ea/0073/ea0073aep174

Although postprandial hypoglycemia is frequent after gastric surgery, including fundoplication, there was a clear-cut temporal coincidence in our patient between the COVID-19 disease and the triggering of the hypoglycemic episodes, suggesting a causative or unmasking relationship.

_

Pancreas

3155

OO48

Huma Farid, Madiha Khah, Shizrah Jamal, Robia Ghafoor

Oral manifestations of Covid-19-A literature review

https://doi.org/10.1002/rmv.2248

Published

24-May-21

Review

https://onlinelibrary.wiley.com/doi/full/10.1002/rmv.2248

This review discusses various oral manifestations of Covid-19 reported in the literature along with possible underlying mechanisms. The reported manifestations include taste impairment, oral mucosal changes (petechiae, ulcers, plaque-like lesions, reactivation of herpes simplex virus 1(HSV1), geographical tongue and desquamative gingivitis) and dry mouth. The prominent location for mucosal lesions are tongue, palate and labial mucosa. The exact pathogenesis of these oral symptoms is not known. Angiotensin-converting enzyme 2 (ACE2) cell receptors are expressed in abundance on oral mucosa allowing severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) to infect them. Gustatory impairment along with olfactory changes is now listed as a symptom of Covid-19 by the World Health Organization, but further research is needed to confirm a link between reported additional oral symptoms and Covid-19. Dental professionals may encounter individuals with Covid-19 and be called upon to identify various oral manifestations of this disease.

_

Mouth

3156

OO49

Laura Montefusco, Moufida Ben Nasr, Francesca D’Addio, Cristian Loretelli, Antonio Rossi, Ida Pastore, Franco Folli, Gian Vincenzo Zuccotti, Massimo Galli & Paolo Fiorina

Acute and long-term disruption of glycometabolic control after SARS-CoV-2 infection

https://doi.org/10.1038/s42255-021-00407-6

Published

25-May-21

Study

https://www.nature.com/articles/s42255-021-00407-6

Here we describe abnormalities in glycometabolic control, insulin resistance and beta cell function in patients with COVID-19 without any pre-existing history or diagnosis of diabetes, and document glycaemic abnormalities in recovered patients 2 months after onset of disease. In a cohort of 551 patients hospitalized for COVID-19 in Italy, we found that 46% of patients were hyperglycaemic, whereas 27% were normoglycaemic. Using clinical assays and continuous glucose monitoring in a subset of patients, we detected altered glycometabolic control, with insulin resistance and an abnormal cytokine profile, even in normoglycaemic patients. Glycaemic abnormalities can be detected for at least 2 months in patients who recovered from COVID-19. Our data demonstrate that COVID-19 is associated with aberrant glycometabolic control, which can persist even after recovery, suggesting that further investigation of metabolic abnormalities in the context of long COVID is warranted.

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Pancreas

3157

OO50

Chien-TingWu113Peter V.Lidsky213YinghongXiao213Ivan T.Lee34513RanCheng1613TsuguhisaNakayama5713SizunJiang313JanosDemeter1Romina J.Bevacqua8Charles A.Chang891011Robert L.Whitener8Anna K.Stalder12BokaiZhu3HanChen3YuryGoltsev3AlexandarTzankov12Jayakar V.Nayak5Garry P.Nolan3 Matthias S. Matter 12RaulAndino2Peter K.Jackson

SARS-CoV-2 infects human pancreatic β cells and elicits β cell impairment

https://doi.org/10.1016/j.cmet.2021.05.013

Published

18-May-21

Study

https://www.sciencedirect.com/science/article/pii/S1550413121002308

Highlights
•SARS-CoV-2 infects β cells in COVID-19 patients and human islets in vitro
•SARS-CoV-2 infection causes β cell death and reduced GSIS in vitro
•Phosphoproteomics shows SARS-CoV-2 spike protein and virus induce apoptotic kinases
•High neuropilin-1 levels support β cell selectivity, and inhibitors block infection

Des travaux publiés dans Cell Metabolism confirment que le virus de la covid peut aggraver ou provoquer un diabète en endommageant les cellules sécrétrices d'insuline. L'article décrit les mécanismes d'infection du virus sur les fonctions pancréatiques.

Pancreas

N011

3158

OO51

Divit Shah, Dhruv Talwar, Sunil Kumar, , Sourya Acharya, Ayush Dubey

Mucormycosis as a
complication of LONG COVID:
A case series

Published

1-Jun-21

Case Report

https://www.researchgate.net/publication/352090552_Mucormycosis_as_a_complication_of_LONG_COVID_A_case_series

While aspergillosis associated with COVID-19 is a well documented association we report a case series of COVID-19 induced Mucormycosis in patients who had COVID-19 more than 3 months ago. The term used for increased inflammation for more than 3 months after COVID-19 is known as "LONG COVID" and is emerging as a entity of great concern in the recent times due to recognition of increased number of complications in patients who had earlier recovered from COVID-19. It is important to note that Diabetes Mellitus has been recognized as an important co-factor with COVID-19 in inducing mucormycosis infections. Concurrent use of glucocorticoid not only hampers the sugar control but also has immunosuppressant effect leading to predisposition to mucormycosis as an important post covid sequalae. High level of vigilance with immediate management is required to prevent adverse outcome of this serious long covid complication.

Skin

3159

OO52

Sparsh Madaan1, Arpita Jaiswal2, Sunil Kumar3, Dhruv Talwar4, Dhruva Halani1

Premature ovarian failure - A long COVID sequelae

Published

1-Jun-21

Case Report

https://www.discoveryjournals.org/medicalscience/current_issue/v25/n112/A7.htm

We Report a case a 34-year-old female who was infected with COVID-19 12 months back and presented with infertility as a post COVID sequelae. This is the first case report linking Ovarian Failure with COVID-19 in our knowledge.

_

Ovaries

3160

OO53

Charlotte Steenblock, Stefanie Richter, Ilona Berger, Marko Barovic, Janine Schmid, Undine Schubert, Natalia Jarzebska, Anne von Mässenhausen, Michele Solimena, Barbara Ludwig & Stefan R. Bornstein

Viral infiltration of pancreatic islets in patients with COVID-19

https://doi.org/10.1038/s41467-021-23886-3

Published

10-Jun-21

Study

https://www.nature.com/articles/s41467-021-23886-3

In eleven COVID-19 patients, we examined the expression of ACE2, TMPRSS and other receptors and factors, such as DPP4, HMBG1 and NRP1, that might facilitate virus entry. Whereas 70% of the COVID-19 patients expressed ACE2 in the vasculature, only 30% displayed ACE2-expression in beta-cells. Even in the absence of manifest new-onset diabetes, necroptotic cell death, immune cell infiltration and SARS-CoV-2 viral infection of pancreatic beta-cells may contribute to varying degrees of metabolic dysregulation in patients with COVID-19.

_

Pancreas

3161

OO54

Raymond Pranata
Joshua Henrina
Wilson Matthew Raffaello
Sherly Lawrensia
Ian Huang

Diabetes and COVID-19: The past, the present, and the future

https://doi.org/10.1016/j.metabol.2021.154814

Published

10-Jun-21

Study

https://www.metabolismjournal.com/article/S0026-0495(21)00114-1/fulltext

Highlights
•Diabetes mellitus (DM) is associated with morbidity and mortality in patients with COVID-19.
•Patients with both type 1 and type 2 DM should be prioritized for vaccination.
•Blood glucose control is of paramount importance and appropriate medications should be used.
•Integration of new technologies is set to change the landscape of diabetes care.
•The prevalence of non-communicable diseases is expected to rise in the future.

_

Pancreas

3162

OO55

Jacopo Ciaffi, Riccardo Meliconi, Piero Ruscitti, Annamaria Iagnocco, Clodoveo Ferri, Roberto Giacomelli & Francesco Ursini

Isolated “puffy hands” following COVID-19: clue to a long-term capillary leakage syndrome?

https://doi.org/10.1007/s10067-021-05835-z

Published

25-Jun-21

Cases Report

https://link.springer.com/article/10.1007/s10067-021-05835-z

Here we share the cases of two female patients aged, respectively, 28 and 33 years, attending our rheumatology clinic between March and April 2021 with a history of recent-onset, painful, bilateral swelling of the hands. At the time of the first evaluation, the patients reported no other medical conditions and in particular no history of symptoms consistent with Raynaud’s phenomenon, were not taking any medication and had no known allergies.

Skin

3163

OO56

Maria Raffaella Marchese, Carolina Ausili Cefaro, Mari Giorgia, Proietti Ilaria, Carfì Angelo, Tosato Matteo, Longobardi Ylenia, D’Alatri Lucia

Oropharyngeal Dysphagia After Hospitalization for COVID-19 Disease: Our Screening Results

https://doi.org/10.1007/s00455-021-10325-0

Published

24-Jun-21

Study

https://link.springer.com/article/10.1007/s00455-021-10325-0

As the pathophysiology of COVID-19 emerges, the aim of our study was to describe the prevalence of oropharyngeal dysphagia after COVID-19 disease. From March to July 2020 we enrolled patients recovered from SARS-CoV-2 infection who had been previously hospitalized for the disease. They were screened for dysphagia by mean of the Eating Assessment Tool-10 (EAT-10). The cases with EAT-10 score > 3 were graded for the aspiration risk by applying the Gugging Swallowing Screen (GUSS) and were submitted to the Swal-QoL questionnaire. The cases with a GUSS score > 19 were subjected to FEES. 8/117 (7%) patients had positive screening result. 4/8 (50%) revealed an abnormal health related quality of life in oropharyngeal dysphagia with a mean Swal-QoL score of 69.73. The most affected domain was the “time of meals” (mean score 65) following by the “sleep” (mean score 66) and “eating desire” (mean score 72). 1/8 cases showed increased risk for aspiration and did not showed endoscopic signs of oropharyngeal dysphagia. Our results showed that the prevalence of upper dysphagia after hospitalization for SARS-CoV-2 is not anecdotal and that probably this long-lasting sequela has a psychogenic etiology.

Oropharyngeal organ

3164

OO57

Sameer Acharya, Melissa Thibault, Janette Lee, Omar Taha, Andrew J. Morpurgo, Binay K. Kshetree, Kushal Regmi

COVID-19-Induced Left Sciatic Neuropathy Requiring Prolonged Physical Medicine and Rehabilitation

https://doi.org/10.7759/cureus.15803

Published

21-Jun-21

Case Report

https://www.cureus.com/articles/62426-covid-19-induced-left-sciatic-neuropathy-requiring-prolonged-physical-medicine-and-rehabilitation

However, peripheral neuropathy associated with COVID-19 disease has been uncommonly reported. Here, we describe a young patient with a COVID-19 infection who developed unilateral sciatic neuropathy during the course of treatment requiring prolonged physical medicine and rehabilitation stay. She was treated in the intensive care unit (ICU) for hypoxic respiratory failure for 22 days total, during which she was intubated, sedated, and paralyzed for 14 days.

_

Peripheral Nerve

3165

OO58

Oscar Moreno-Perez MD, Esperanza Merino, Rocio Alfayate, Maria Eugenia Torregrosa, Mariano Andres MD, PhD, Jose-Manuel Leon-Ramirez MD, Vicente Boix MD, PhD, Joan Gil MD, PhD, Antonio Pico

Male Pituitary-Gonadal axis dysfunction in Post-acute COVID-19 Syndrome. Prevalence and associated factors: A Mediterranean Case Series

https://doi.org/10.1111/cen.14537

Published

23-Jun-21

Case Series

https://onlinelibrary.wiley.com/doi/abs/10.1111/cen.14537

One hundred and forty-three patients were evaluated a median (IQR) of 77 days (72-83) after disease onset, 72% of them recovered from severe pneumonia. LT was detected in 41 patients (28.7%; 95%CI 21.8-36.5). Low levels of Inhibin-B were detected in 25 patients (18.1%; 95%CI 12.5-25.3). After multivariate adjustment, obesity and hypokalemia were associated with LT, whereas age >65 was an independent predictor of Sertoli cell dysfunction. LT or Sertoli cell dysfunction were not associated with PCS. Patients with LT had lower score in 4 domains of QOL.

_

Male Pituitary-Gonadal axis

3166

OO59

R. A. Misgar, A. Rasool, A. I. Wani & M. I. Bashir

Central diabetes insipidus (Infundibuloneuro hypophysitis): A late complication of COVID-19 infection

https://doi.org/10.1007/s40618-021-01627-z

Published

3-Jul-21

Letter to the Editor

https://link.springer.com/article/10.1007/s40618-021-01627-z

The possibility of inflammation–mediated reversible hypophysitis or a direct hypothalamic damage are the two possible mechanisms for the hypothalamo-pituitary dysfunction [5]. SARS-CoV-2 can directly target the hypothalamic and pituitary tissues because of a high expression of ACE-2 receptors [6]. In fact, autopsy studies have reported SARS genome-mediated edema and neuronal degeneration in the hypothalamus [2].
We conclude and emphasize that isolated pituitary abnormality in the form of CDI can be a late complication of COVID-19 infection.

Hypothalamic–pituitary–adrenal axis

3167

OO60

David Tak WaiLuiMBBS1Chi HoLeeMBBS1Wing SunChowMBBS1Alan Chun HongLeeMBBS1Anthony RaymondTamMBBS1PollyPangBNurs1Tip Ivan Fan NgaiHungMD1Karen Siu LingLamMD1

Long COVID in Patients with Mild to Moderate Disease: Do Thyroid Function and Autoimmunity Play a Role?

https://doi.org/10.1016/j.eprac.2021.06.016

Published

6-Jul-21

Study

https://www.sciencedirect.com/science/article/pii/S1530891X21011113

Highlights
●20% had long COVID at 3 months after recovery from non-severe acute illness
●Female and higher SARS-CoV-2 viral load on presentation predicted long COVID
●Incident thyroid dysfunction was rare, but incident anti-TPO positivity was noted
●Symptom resolution was more likely in those with positive anti-TPO upon follow-up

Thyroid gland

3168

OO61

MustafaHepokurMD, FEBO1MedineGunesMD12EbubekirDurmusMD12VeyselAykutMD12FehimEsenMD, FEBO12HalitOguzMD12

Long-term follow up of choroidal changes following COVID-19 infection: analysis of choroidal thickness and choroidal vascularity index

https://doi.org/10.1016/j.jcjo.2021.06.020

Published

5-Jul-21

Study

https://www.sciencedirect.com/science/article/pii/S0008418221002465

Subfoveal choroidal thickness (SFCT) significantly decreased at the early postinfectious period compared to healthy controls (p=0.045). SFCT significantly increased at the late postinfectious period compared to early (p=0.002) and the difference between the patients and controls became statistically insignificant (p=0.362). There was a similar trend for the peripapillary choroidal thickness measurements. CVI remained unchanged (p=0.721) despite the significant decrease in SFCT and total choroidal area (TCA, p=0.042), indicating that this decrease occurred both in choroidal stroma and blood vessels. CVI remained unchanged in the late postinfectious period (p=0.575) compared to the early period, indicating that recovery occurred in the entire choroidal tissue.
Conclusion
This study demonstrated that choroidal thickness was reduced in all measured areas and this decrease affected all choroidal layers. This choroidopathy was reversible and recovered at the 9th postinfectious month.

Eyes

3169

OO62

Е. А. Лялюкова, И. В. Долгалёв, Е. Н. Чернышева, И. В. Друк, Г. М. Коновалова, А. В. Лялюков

Поражения печени при Covid-19: патогенез и лечение - Liver damage while Covid-19: Problems of pathogenesis and treatment

https://doi.org/10.31146/1682-8658-ecg-187-3-178-185

Published

1-Jul-21

Study

https://www.nogr.org/jour/article/view/1615/1506

The purpose of the review is to present an analysis of the current literature data on the pathogenesis and therapy of liver damage in Covid-19. Liver damage in COVID-19 patients can be caused by the direct cytopathogenic effect of SARS-CoV-2, an uncontrolled immune response, sepsis, severe hypoxia, or drug damage. In addition, COVID-19 can exacerbate and decompensate previously formed chronic liver diseases with the development of acute liver failure. Physicians should carefully assess the initial state of the liver, and after prescribing therapy, intensify monitoring of its functional state, especially in patients with severe COVID-19. In each clinical case, the doctor needs to establish the possible mechanisms of organ damage in order to select the most optimal patient management tactics, which would take into account all aspects of the COVID-19 course and liver damage.

Liver

3170

OO63

Ahmad Saud, R Naveen, Rohit Aggarwal & Latika Gupta

COVID-19 and Myositis: What We Know So Far

https://doi.org/10.1007/s11926-021-01023-9

Published

3-Jul-21

Review

https://link.springer.com/article/10.1007/s11926-021-01023-9

This review examines the current literature on COVID-19-induced myositis focusing on etiopathogenesis, clinical presentations, diagnostic practices, and therapeutic challenges with immunosuppression, and the difficulties experienced by rheumatologists in established myositis in the COVID-19 era.

Muscles

3171

OO64

Nicolas Barizien, Morgan Le Guen, Stéphanie Russel, Pauline Touche, Florent Huang & Alexandre Vallée

Clinical characterization of dysautonomia in long COVID-19 patients

https://doi.org/10.1038/s41598-021-93546-5

Published

7-Jul-21

Study

https://www.nature.com/articles/s41598-021-93546-5

Here, we hypothesize that dysautonomia could occur in secondary COVID-19 infection, also called “long COVID” infection. We aim to demonstrate this phenomenon by illustrating HRV dysregulation, reflected through the NOL index showing the sympathetic/parasympathetic balance, in long COVID-19 participants. We propose that the symptoms secondary to COVID-19 could be directly related to this virus or its immune-related dysregulation to the ANS, leading to transient or long-term dysautonomia.

Autonomic system

3172

OO65

ClemenceCollaMurielTessieraChristopheVandendriesbcPaulSerorde

Névralgie amyotrophiante et infection à Covid 19: deux cas de paralysie du nerf spinal accessoire

https://doi.org/10.1016/j.rhum.2021.07.003

Published

7-Jul-21

Case Report

https://www.sciencedirect.com/science/article/pii/S116983302100209X

La névralgie amyotrophiante de Parsonage et Turner (NAPT) ne concernait que le nerf spinal accessoire dans les deux cas rapportés. L’ENMG a mis en évidence des lésions axonales récentes caractéristiques de la NAPT.Les IRM des deux patients ont révélé un hypersignal T2 de dénervation dans les muscles atteints. Aucun signe de masse, kyste, lésion, bride ou déchirure n’a été retrouvé le long du NSA.
Conclusion: Comme d’autres viroses, la Covid-19 pourrait être le facteur déclenchant de la NAPT, comme elle semble aussi être un facteur déclenchant possible du syndrome de Guillain Barré.

Nervous sytem

3173

OO66

Mirza Muhammad Fahd Qadir 1, Manika Bhondeley 1, Wandy Beatty 2, Dina D Gaupp 3, Lara A Doyle-Meyers 4, Tracy Fischer 4, Ishitri Bandyopadhyay 1, Robert V Blair 4, Rudolf Bohm 4, Jay Rappaport 4, Eric Lazartigues 5, Richard S Vander Heide 6, Jay K Kolls 7, Xuebin Qin 4, Franck Mauvais-Jarvis

SARS-CoV-2 infection of the pancreas promotes thrombo-fibrosis and is associated with new-onset diabetes

https://doi.org/10.1172/jci.insight.151551

Published

9-Jul-21

Study

https://pubmed.ncbi.nlm.nih.gov/34241597/

Evidence suggests an association between severe acute respiratory syndrome-cornavirus-2 (SARS-CoV-2) infection and the occurrence of new-onset diabetes. We examined pancreatic expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), the cell entry factors for SARS-CoV-2, using public single cell RNA sequencing datasets, and pancreas tissue from control male and female non-human primates (NHPs) and humans. We also examined SARS-CoV-2 immunolocalization in pancreas cells of SARS-CoV-2-infected NHPs, and patients deceased from coronavirus disease 2019 (COVID-19). We report expression of ACE2 in pancreatic islet, ductal, and endothelial cells in NHPs and humans. In pancreata from SARS-CoV-2-infected NHPs and COVID-19 patients, SARS-CoV-2 infected ductal, endothelial and islet cells. These pancreata also exhibited generalized fibrosis associated with multiple vascular thrombi. Two out of eight NHPs developed new onset diabetes following SARS-CoV-2 infection. Two out of five COVID-19 patients exhibited new onset diabetes at admission. These results suggest that SARS-CoV-2 infection of the pancreas may promote acute and especially chronic pancreatic dysfunction that could potentially lead to new-onset diabetes.

Pancreas

3174

OO67

Ulrike Frank & Katrin Frank

COVID-19 – neue Herausforderungen in der Dysphagie- und Atemtherapie
COVID-19—New challenges in dysphagia and respiratory therapy

https://doi.org/10.1007/s00115-021-01162-5

Published

9-Jul-21

Review

https://link.springer.com/article/10.1007/s00115-021-01162-5

Swallowing disorders (dysphagia) in this patient group can result from primary damage to the central and peripheral neuronal swallowing network but also from the frequently prolonged intensive care treatment and mechanical ventilation. Clinical observations indicate persistence of dysphagia in post-acute COVID-19 syndrome (long COVID), so that these patients probably also need long-term interventions for rehabilitation of safe and sufficient oral feeding. Therefore, structured disease-specific monitoring of dysphagia symptoms should be integrated into the treatment of COVID-19 patients and respiratory therapy should be an essential part of dysphagia management to re-establish cough effectiveness and breathing-swallowing coordination.

Pharynx

3175

OO68

Federico Montini, Vittorio Martinelli, Francesca Sangalli, Marcella Callea, Nicoletta Anzalone & Massimo Filippi

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) after SARS-CoV-2 pneumonia

https://doi.org/10.1007/s10072-021-05472-z

Published

17-Jul-21

Letter to the Editor

https://link.springer.com/article/10.1007/s10072-021-05472-z

In reaction to SARS-CoV-2 infection, the immune system can produce high cytokine levels [4], leading to a hyperinflammatory response and T-cell activation [4]. Such an inflammatory response can cause blood-brain barrier damage as well. CSF analysis of COVID-19 patients [5] showed differentiated monocytes and exhausted T-cells with consequent broad clonal T-cell expansion.

CLIPPERS is a T-cell-mediated disorder with an infiltrate characterized by an abundance of CD4+ T-cell infiltration with less CD8+ and CD20+ cells, without demyelination [6, 7] with relative widespread perivascular inflammation and postinflammatory axonal injury [7]. T-cell broad clonal expansion is present in CLIPPERS disease.

_

3176

OO222

Gulfidan Bitirgen1, Celalettin Korkmaz2, Adil Zamani2, Ahmet Ozkagnici1, Nazmi Zengin1, Georgios Ponirakis3, http:// .org/0000-0002-7188-8903Rayaz A Malik

Corneal confocal microscopy identifies corneal nerve fibre loss and increased dendritic cells in patients with long COVID

http:// .org/0000-0002-7188-8903

Published

26-Jul-21

Study

https://bjo.bmj.com/content/early/2021/07/08/bjophthalmol-2021-319450

This study has quantified corneal sub-basal nerve plexus morphology and dendritic cell (DC) density in patients with and without long COVID.
Methods Forty subjects who had recovered from COVID-19 and 30 control participants were included in this cross-sectional comparative study undertaken at a university hospital. All patients underwent assessment with the National Institute for Health and Care Excellence (NICE) long COVID, Douleur Neuropathique 4 (DN4) and Fibromyalgia questionnaires, and corneal confocal microscopy (CCM) to quantify corneal nerve fibre density (CNFD), corneal nerve branch density (CNBD), corneal nerve fibre length (CNFL), and total, mature and immature DC density.
Results The mean time after the diagnosis of COVID-19 was 3.7±1.5 months. Patients with neurological symptoms 4 weeks after acute COVID-19 had a lower CNFD (p=0.032), CNBD (p=0.020), and CNFL (p=0.012), and increased DC density (p=0.046) compared with controls, while patients without neurological symptoms had comparable corneal nerve parameters, but increased DC density (p=0.003). There were significant correlations between the total score on the NICE long COVID questionnaire at 4 and 12 weeks with CNFD (ρ=−0.436; p=0.005, ρ=−0.387; p=0.038, respectively) and CNFL (ρ=−0.404; p=0.010, ρ=−0.412; p=0.026, respectively).
Conclusion Corneal confocal microscopy identifies corneal small nerve fibre loss and increased DCs in patients with long COVID, especially those with neurological symptoms. CCM could be used to objectively identify patients with long COVID.

En utilisant la microscopie confocale cornéenne (technique en temps réel et non invasive), une étude note que les malades du covid long présentent une densité de cellules dendritiques au niveau de la cornée supérieure à la normale. Parmi ceux-ci, ceux avec des symptômes neurologiques ont également une densité de fibres et branches nerveuses (CNFD/CNBD) et une longueur de fibres nerveuses (CNFL), inférieure à la normale. Pour les auteurs, cette technique pourrait être utilisée pour diagnostiquer et objectiver le covid long.

Eyes

N012

3177

OO223

Myriem Otmani Idrissi 1,2,† ,Jean-Pierre Baudoin 1,2,†,Anne-Line Chateau 3,Sarah Aherfi 1,2,Marielle Bedotto-Buffet 1,2,Alain Latil 4,Hubert Lepidi 1,2,Jacques Chiaroni 3,5,Christophe Picard 3,5,Jean-Louis Mege 1,2,4,Bernard La Scola 1,2,* andSoraya Mezouar 1,2,*

Presence of SARS-CoV-2 in a Cornea Transplant

https://doi.org/10.3390/pathogens10080934

Published

24-Jul-21

Brief Report

https://www.mdpi.com/2076-0817/10/8/934/htm

Here, we investigated infection of a cornea graft from a COVID-19-positive donor. Methods: In order to evaluate the presence of SARS-CoV-2 in the cornea graft we first carried out a qRT-PCR and then we investigated the presence of SARS-CoV-2 by fluorescence and electron microscopy. Conclusions: Although the cornea graft was found to be negative by qRT-PCR, we were able to show the presence of SARS-CoV-2 in corneal cells expressing the SARS-CoV-2 receptor, ACE2. Taken together, our findings may have important implications for the use of corneal tissue in graft indications and open the debate on SARS-CoV-2 transmissibility.

_

Eyes

3178

OO71

Annamaria Bellomo, Erica Campanella, Maria Rita Del Zompo, Serena Calabrese, Annamaria
Cimmino, Pina Frau, Carla Ingelido, Fabio Lombardo, Chiara Lucchesi, Simona Niccolai,
Ermelinda Zeccardo, Giuliana Pisanu, Franco Fussi

Covid-19 impact on vocal and laryngeal
sequelae: a literature review

http://dx.doi.org/10.14658/pupj-ijap-2021-1-7

Published

1-Jul-21

Review

http://audiologiaefoniatria.padovauniversitypress.it/system/files/papers/IJAP-2021-06b.pdf
http://audiologiaefoniatria.padovauniversitypress.it/2021/1/7

Many researchers have focused not only on lung damage but also on the laryngeal sequelae of the Covid-19 infection. To collate this information, this review analysed the literature published between March 2020 and May 2021. The findings seem to positively correlate Covid-19 and infection-related dysphonia, post- viral vagal neuropathy, inflammation and laryngeal oedema caused by cough and vomiting, and lesions of the vocal cords due to endotracheal intubation and tracheotomy. From analysis of the data, it is clear that ENT specialists and speech and language pathologists (SLP) will play a crucial role in the detection of dysphonia onset in patients reporting a previous Covid-19 infection. Further studies to assess the incidence and characteristics of dysphonia resulting from this disease are essential.

_

Oropharyngeal organ

3179

OO72

Gaurav Gupta1
, D. K. Gupta2
, Priyanka Gupta3
, Neeraj Chandra4
, Neelja Gupta

An eye opener COVID-19 complication in oro-maxillofacial
region: Case report

https://doi.org/10.15713/ins.jcri.329

Published

14-Jun-21

Case Report

http://jcri.net/eJournals/_eJournals/329_CASE%20REPORT.pdf

The aim of this report is to discuss an eye-opening case about the complication in oromaxillofacial region in COVID-19 recovered youth. The aftermath of COVID infection
lead to various complexities in multiple organs. Recurrent follow ups of such recovered
patients are necessary to identify early dreadful effects and combat them in time. Hence,
present study throws a light on one such post-COVID complication occurring in oromaxillofacial region, its pathophysiology and treatment to overcome its worsening
upshot. To the best of our knowledge, this is the rare reported case of
complication in oro-maxillofacial region in COVID-19 recovered
patients. Awareness of such oral complication is important
because the lesions may worsen leading to more serious clinical
scenario.

_

Oro-maxillofacial
region

3180

OO224

VP

Carlla A. Araujo-Silva, MSc1,2,3; Alléxya A. A. Marcos, MD4,5; Paula M. Marinho, MD4,5,6; Ana M. C. Branco, MD4; Alexandre Roque, MD6; André C. Romano, MD4,5; Mateus L. Matuoka, MD6; Michel Farah, MD, PhD4,5; Miguel Burnier, MD, PhD7; Nara F. Moraes, MD6; Paulo F. G. M. M. Tierno, MD6; Paulo Schor, MD, PhD4,5; Victoria Sakamoto, MD4; Heloisa Nascimento, MD, PhD4,5,6; Wanderley de Sousa, MD, PhD1,2,3; Rubens Belfort Jr, MD, PhD4,5

Presumed SARS-CoV-2 Viral Particles in the Human Retina of Patients With COVID-19

http://jamanetwork.com/article.aspx?doi=10.1001/jamaophthalmol.2021.2795

Published

29-Jul-21

Study Original Investigation

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2782445

Three patients who died of COVID-19 were analyzed. Two patients were men, and 1 was a woman. The age at death ranged from 69 to 78 years. Presumed S and N COVID-19 proteins were seen by immunofluorescence microscopy within endothelial cells close to the capillary flame and cells of the inner and the outer nuclear layers. At the perinuclear region of these cells, it was possible to observe by transmission electron microscopy double-membrane vacuoles that are consistent with the virus, presumably containing COVID-19 viral particles.

Conclusions and Relevance The present observations show presumed SARS-CoV-2 viral particles in various layers of the human retina, suggesting that they may be involved in some of the infection’s ocular clinical manifestations.

JAMA Ophtalmology : une équipe présente des prélèvement post-mortem de victimes de la covid à phase respiratoire sévère, et fait part de l'observation au microscope électronique en transmission de particules virales de SARS-CoV-2 dans la rétine des sujets.

Eyes

3181

OO74

Nadia K. Qureshi 1 and Sanjay K. Bansal

Autoimmune Thyroid Disease and Psoriasis Vulgaris after COVID-19 in a Male Teenager

https://doi.org/10.1155/2021/7584729

Published

Case Report

https://www.hindawi.com/journals/cripe/2021/7584729/

COVID-19 is implicated in triggering autoimmune, dermatologic, and thyroid diseases. We present a first known case of development of Graves’ disease and psoriasis vulgaris in a previously healthy male teenager without any family history, diagnosed after COVID-19 infection. Evaluation of “long COVID syndrome” should include thorough history and thyroid evaluation.

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Skin

3182

OO75

A.V. Raveendrana and Anoop Misrab,c,d,∗

Post COVID Syndrome (“Long COVID”) and Diabetes: Challenges in Diagnosis and Management

https://dx.doi.org/10.1016%2Fj.dsx.2021.102235

Published

28-Jul-21

Review

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317446/

Presence of diabetes also influences PCS via various pathophysiological mechanisms. COVID-19 can add to or exacerbate postural hypotension with tachycardia, sarcopenia (and muscle fatigue), and microvascular dysfunction in patients with diabetes. Strict control of diabetes and other co-morbidities, supervised rehabilitation and physical exercise, and optimal nutrition could help in reducing and managing PCS.

Patients may suffer from several debilitating symptoms/signs that develop during or after an infection consistent with COVID-19, continue for more than 12 weeks after infection, and are not explained by an alternative diagnosis [1]. Common symptoms include fatigue, breathlessness, myalgia, weakness, headache, cognitive blunting etc. This conglomeration of symptoms is called “Long COVID” or more appropriately as “Post COVID-19 Syndrome (PCS)” [2]. The aim of the brief review is to summarise current knowledge of health events occurring after COVID-19 in brief and relate them for patients with diabetes.

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Pancreas

3183

OO76

J. Amorim dos Santos1, A.G.C. Normando1, 2, R.L. Carvalho da Silva1, A.C. Acevedo1, G. De Luca Canto3, N. Sugaya4, A.R. Santos-Silva2, E.N.S. Guerra1

Oral Manifestations in Patients with COVID-19: A 6-Month Update

https://doi.org/10.1177%2F00220345211029637

Published

29-Jul-21

Review

https://journals.sagepub.com/doi/10.1177/00220345211029637

The overall prevalence of taste disorders was 38% (95% CI = 22% to 56%, I2 = 98%). Hypogeusia, dysgeusia, and ageusia were also evaluated by a meta-analysis, and the pooled prevalence was 34% for hypogeusia, 33% for dysgeusia, and 26% for ageusia. Taste disorders were associated with a positive COVID-19 test (odds ratio [OR] = 7.54, 95% CI = 5.24 to 10.86, I2 = 93%, P < 0.00001), showing high certainty of evidence. However, the association between taste disorders and mild/moderate severity of COVID-19 (OR = 1.63, 95% CI = 1.33 to 1.99, I2 = 69%, P < 0.0001) and female patients with COVID-19 (OR = 1.77, 95% CI = 1.26 to 2.48, I2 = 79%, P = 0.001) presented low certainty of evidence. Xerostomia was a new feature of this update, and the pooled data demonstrated a prevalence of 43% (95% CI = 36% to 50%, I2 = 71%) in patients with COVID-19. Regarding oral mucosal lesions, the most common clinical pattern was aphthous like, followed by herpes-like lesions, candidiasis, glossitis/depapillation/geographic tongue, parotitis, and angular cheilitis. Oral lesions were more frequent in the tongue, lips, and palate, presenting miscellaneous clinical aspects that are more likely to represent coinfections. Therefore, the reanalysis of current evidence suggests the triad xerostomia, taste dysfunction, and oral mucosal lesions as common manifestations in patients with COVID-19. However, these outcomes are under discussion, and more studies will be necessary to confirm their association with direct SARS-CoV-2 infection in the oral cavity.

Oral cavity

3184

OO77

Giulia Concas, Michele Barone, Ruggiero Francavilla, Fernanda Cristofori, Vanessa Nadia Dargenio, Rossella Giorgio, Costantino Dargenio, Vassilios Fanos & Maria Antonietta Marcialis

Twelve Months with COVID-19: What Gastroenterologists Need to Know

https://doi.org/10.1007/s10620-021-07158-0

Published

31-Jul-21

Review

https://link.springer.com/article/10.1007/s10620-021-07158-0

Given the high percentage of COVID-19 patients that present with gastrointestinal symptoms (GIS), in this review, we report a practical up-to-date reference for the physician in their clinical practice with patients affected by chronic gastrointestinal (GI) diseases (inflammatory bowel disease, coeliac disease, chronic liver disease) at the time of COVID-19. First, we summarised data on the origin and pathogenetic mechanism of SARS-CoV-2. Then, we performed a literature search up to December 2020 examining clinical manifestations of GI involvement. Next, we illustrated and summarised the most recent guidelines on how to adhere to GI procedures (endoscopy, liver biopsy, faecal transplantation), maintaining social distance and how to deal with immunosuppressive treatment. Finally, we focussed on some special conditions such as faecal–oral transmission and gut microbiota. The rapid accumulation of information relating to this condition makes it particularly essential to revise the literature to take account of the most recent publications for medical consultation and patient care.

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Gastro-intestinal

3185

OO78

Dina Sweed, Eman Abdelsameea, Esraa A. Khalifa, Heba Abdallah, Heba Moaz, Inas Moaz, Shimaa Abdelsattar, Nadine Abdel-Rahman, Asmaa Mosbeh, Hussein A. Elmahdy & Eman Sweed

SARS-CoV-2-associated gastrointestinal and liver diseases: what is known and what is needed to explore

https://doi.org/10.1186/s43066-021-00123-6

Published

31-Jul-21

Review

https://eglj.springeropen.com/articles/10.1186/s43066-021-00123-6

In addition to respiratory droplets, SARS-CoV-2 may reach the GI system through the fecal-oral route, saliva, and swallowing of nasopharyngeal fluids, while breastmilk and blood transmission were not implicated. Moreover, GI infection may act as a septic focus for viral persistence and transmission to the liver, appendix, and brain. In addition to the direct viral cytopathic effect, the mechanism of injury is multifactorial and is related to genetic and demographic variations. The most frequently reported GI symptoms are diarrhea, nausea, vomiting, abdominal pain, and bleeding. However, liver infection is generally discovered during laboratory testing or a post-mortem. Radiological imaging is the gold standard in diagnosing COVID-19 patients and contributes to understanding the mechanism of extra-thoracic involvement. Medications should be prescribed with caution, especially in chronic GI and liver patients.

Conclusion
GI manifestations are common in COVID-19 patients. Special care should be paid for high-risk patients, older males, and those with background liver disease.

_

Gastro-intestinal

3186

OO79

H.Mascitti12P.Jourdain12A.Bleibtreu2L.Jaulmes2A.Dechartres34X.Lescure2Y.Yordanov2A.Dinh

Les engelures : un facteur pronostique associé à moins d’hospitalisations pour COVID-19

https://doi.org/10.1016/j.idnow.2021.06.147

Published

Study

https://www.sciencedirect.com/science/article/pii/S2666991921002633

La prévalence du rash et des engelures était respectivement de 9,5 % (2756/28 957) et 3,7 % (1082/28 957).
En analyse multivariée, la présence d’un rash survenait préférentiellement chez les asthmatiques ([OR] = 1,14 ; IC95 % = 1,02–1,28), et était significativement associée à l’asthénie, frissons et myalgies ([OR] = 2,01 ; IC95 % = 1,59–2,53), aux symptômes respiratoires (dyspnée [OR] = 1,18 ; IC95 % = 1,07–1,29, toux [OR] = 1,15 ; IC95 % = 1,05–1,26, douleurs thoraciques [OR] = 1,22 ; IC95 % = 1,11–1,33, oppressions thoraciques [OR] = 1,33 ; IC95 % = 1,21–1,46), aux symptômes gastro-intestinaux (anorexie [OR] = 1,36 ; IC95 % = 1,24–1,49, nausées/vomissements [OR] = 1,36 ; IC95 % = 1,24–1,49, diarrhées [OR] = 1,54 ; IC95 % = 1,42–1,68), et à l’anosmie/agueusie ([OR] = 1,23 ; IC95 % = 1,13–1,34).
La présence d’engelures était significativement associée aux douleurs thoraciques ([OR] = 1,33 ; IC95 % = 1,15–1,53), oppressions thoraciques ([OR] = 1,24 ; IC95 % = 1,07–1,43), nausées/vomissements ([OR] = 1,35 ; IC95 % = 1,16–1,57), et anosmie/agueusie ([OR] = 1,87 ; IC95 % = 1,64–2,14).
Une évolution défavorable (hospitalisation ou décès) est survenue chez 1119 patients (3,9 %).
Les patients ayant présenté des engelures étaient significativement moins sujets à avoir une évolution défavorable ([OR] = 0,64 ; IC95 % = 0,43–0,97).
Conclusion
Les patients COVID-19 ambulatoires ayant un rash et/ou une engelure étaient le plus souvent des femmes.
La présence d’engelures était associée significativement à moins d’hospitalisations.

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Skin

3187

OO80

Ö Gedik 1, H Hüsam 1, M Başöz 1, N Tas 2, F Aksoy

The effect of coronavirus disease 2019 on the hearing system

https://doi.org/10.1017/s0022215121001961

Published

4-Aug-21

Study

https://pubmed.ncbi.nlm.nih.gov/34344488/

The pure tone audiometry and extended high-frequency mean threshold values were higher in the coronavirus disease 2019 group. The transient evoked otoacoustic emissions signal-to-noise ratios were bilaterally lower at 4 kHz in individuals with a coronavirus disease 2019 history. In the auditory brainstem response test, only the interpeak latencies of waves III-V were significantly different between groups.

Conclusion: Coronavirus disease 2019 may cause damage to the hearing system. Patients should be followed up in the long term with advanced audiological evaluation methods in order to determine the extent and level of damage.

Une étude montre que la covid peut endommager le système auditif.

Ears

N014E

3188

OO81

Ojas Mahajan1
, Dhruv Talwar1, Sunil Kumar2
, Arpita
Jaiswal3
, Sparsh Madaan4
, Shivam Khanna1
, Divit Shah1

Fatal HELLP syndrome in
pregnancy: A sequelae of Long
COVID?

Published

1-Aug-21

Case Report

https://www.researchgate.net/publication/353543619_Fatal_HELLP_syndrome_in_pregnancy_A_sequelae_of_Long_COVID

ABSTRACT
The coronavirus disease resulted by infection with severe acute respiratory
syndrome-Coronavirus 2 (SARS-CoV-2) was initiated in China in during the
end of 2019 and spread exponentially as a global health Pandemic. The current
pandemic (COVID-19) caused by SARS-CoV-2 novel coronavirus lead to high
mortality and morbidity in terminally ill patients. We present a link between
maternal severe acute respiratory syndrome-Coronavirus 2 (SARS-CoV-2)
infections in the peripartum period and rapid maternal deterioration with
coagulopathy. Also, we wish to draw attention towards the overlap which is
significant between the clinical findings of COVID19 and HELLP Syndrome
along with importance of persistence of inflammation over 3 months after
COVID19 known as “Long COVID”.

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Placenta

3189

OO82

Amgad MRabie

COVID-19 and Sexual Dysfunction in Men: SARS-CoV-2 in the TestesCOVID-19 et Dysfonctionnement Sexuel chez les Hommes: SARS-CoV-2 dans les Testicules)

https://doi.org/10.1016/j.sexol.2021.07.004

Published

7-Aug-21

Study

https://www.sciencedirect.com/science/article/pii/S1158136021000621

We mainly deduced, for the first time, that SARS-CoV-2 invasion of the male's reproductive system may directly cause sudden temporary sexual dysfunction problems ranged from unobserved moderate to irritatingly severe and complete in their pathologic outcomes, hence sex should be avoided during the pandemic.

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Penis

3190

OO83

Vinod Nikhra

Involvement of Gastrointestinal and Hepato-Biliary System in
COVID-19 and Long Covid

http://dx.doi.org/10.13140/RG.2.2.29491.55849

pre-print

1-Aug-21

Review

https://www.researchgate.net/profile/Vinod-Nikhra/publication/353828118_Involvement_of_Gastrointestinal_and_Hepato-Biliary_System_in_COVID-19_and_Long_Covid/links/6113ec091ca20f6f8616d783/Involvement-of-Gastrointestinal-and-Hepato-Biliary-System-in-COVID-19-and-Long-Covid.pdf

CONCLUSION – DEALING WITH GI MANIFESTATIONS: The GI manifestations are associated with elevated liver enzymes,
increased prothrombin time and decreased serum albumin levels. The abdominopelvic CT scans in symptomatic COVIDpositive patients may show intestinal mural thickening, abnormalities in the gallbladder and biliary system. The abdominal
ultrasound may show similar findings. There being no specific treatment antacids, anti-emetics, and anti-diarrhoeal agents
may provide symptomatic improvement, and nutritious diet, regular exercise and a stress-free lifestyle may be helpful.

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Gastro-intestinal

3191

OO84

Sophie A Clarke, Ali Abbara, Waljit S Dhillo

Impact of COVID-19 on the Endocrine System – a mini-review

https://doi.org/10.1210/endocr/bqab203

20-Sep-21

https://academic.oup.com/endo/advance-article/doi/10.1210/endocr/bqab203/6372868

The coronavirus responsible for COVID-19, SARS-CoV-2, obtains cellular access through the angiotensin converting enzyme 2 (ACE2) receptor in a process requiring the transmembrane serine protease 2 (TMPRSS2) protein. Both ACE2 and TMPRSS2 are widely expressed in many endocrine glands. This, along with several case reports of thyroid and pituitary disruption in patients with COVID-19, has resulted in significant interest in its impact on the endocrine system. Indeed, as mortality is abated by the increasing availability of effective vaccines, there is increasing focus on the long-term effects on health in COVID-19 survivors. This review summarises data investigating the effects of COVID-19 on each of the endocrine axes to guide appropriate investigations and optimal management.

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Endocrine system

3192

OO85

César Fernández-de-las-Peñas, Carlos Guijarro, Juan Torres-Macho, María Velasco-Arribas, Plaza-Canteli Susana, Valentín Hernández-Barrera, José A. Arias-Navalón

Diabetes and the Risk of Long-Term Post-COVID Symptoms

https://doi.org/10.2337/db21-0329

Published

27-Sep-21

Study

https://diabetes.diabetesjournals.org/content/early/2021/09/30/db21-0329?rss=1

Overall, 145 patients with diabetes and 144 non-diabetic controls who had recovered from
COVID-19 were assessed at 7.2 months (SD 0.6) after hospital discharge. The number of
post-COVID symptoms was similar between groups (IRR1.06, 95%CI 0.92-1.24,
P=0.372). The most prevalent post-COVID symptoms were fatigue, dyspnea on exertion,
and pain. No between-groups differences in any post-COVID symptom were observed.
Similarly, no differences in limitations with daily living activities were either found
between patients with/without diabetes. Diabetes was not a risk factor for suffering long-
term post-COVID symptoms.

Pancreas

3193

OO225

SnehaSinghaGustavoGarciabRuchiShahcAndrei A.KramerovcRobert EmeryWrightIIIaTanya M.Spektorc1Alexander V.LjubimovcdVaithilingarajaArumugaswamibAshokKumara

SARS-CoV-2 and its beta variant of concern infect human conjunctival epithelial cells and induce differential antiviral innate immune response

https://doi.org/10.1016/j.jtos.2021.09.007

Published

25-Sep-21

Study

https://www.sciencedirect.com/science/article/pii/S1542012421001063

Highlights
•SARS-CoV-2 viral proteins detected in conjunctival tissue of COVID-19 donors.
•Human conjunctiva expresses five major SARS-CoV-2 entry receptors.
•SARS-CoV-2 infected cells elicit innate antiviral and inflammatory response.
•Beta variant of SARS-CoV-2 is more infectious than the parental strain.
Spike and envelope proteins were found in conjunctiva from COVID-19 patients. SARS-CoV-2 infected hCECs showed high viral copy numbers at 24–72h post-infection; spike protein levels were the highest at 24hpi. Viral entry receptors ACE2, TMPRSS2, CD147, Axl, and NRP1 were detected in conjunctival tissue and hCECs. SARS-CoV-2 infection-induced receptor gene expression peaked at early time points post-infection, but gene expression of most TLRs peaked at 48 or 72hpi. SARS-CoV-2 infected hCECs showed higher expression of genes regulating antiviral response, RIG-I, interferons (α, β, & λ), ISG15 & OAS2, cytokines (IL6, IL1β, TNFα), and chemokines (CXCL10, CCL5). Compared to the parental strain, beta VOC induced increased viral copy number and innate response in hCECs

Eyes

3194

OO87

Francesco Ursini1,2, Jacopo Ciaffi1, Luana Mancarella1, Lucia Lisi1, Veronica Brusi1, Carlotta Cavallari1, Martina D’Onghia1, Anna Mari1, Elena Borlandelli3, Jacopo Faranda Cordella4, Micaela La Regina5, Pasquale Viola6, Piero Ruscitti7, Marco Miceli8, Roberto De Giorgio9, Nicola Baldini10, Claudio Borghi11, Alessandro Gasbarrini12, Annamaria Iagnocco13, Roberto Giacomelli14, Cesare Faldini15, Maria Paola Landini16 and http:// .org/0000-0001-5216-5219Riccardo Meliconi1

Fibromyalgia: a new facet of the post-COVID-19 syndrome spectrum? Results from a web-based survey

http://dx.doi.org/10.1136/rmdopen-2021-001735

Published

23-Aug-21

Study

https://rmdopen.bmj.com/content/7/3/e001735

A final sample of 616 individuals (77.4% women) filled the form 6±3 months after the COVID-19 diagnosis. Of these, 189 (30.7%) satisfied the ACR survey criteria for FM (56.6% women). A multivariate logistic regression model including demographic and clinical factors showed that male gender (OR: 9.95, 95% CI 6.02 to 16.43, p<0.0001) and obesity (OR: 41.20, 95% CI 18.00 to 98.88, p<0.0001) were the strongest predictors of being classified as having post-COVID-19 FM. Hospital admission rate was significantly higher in men (15.8% vs 9.2%, p=0.001) and obese (19.2 vs 10.8%, p=0.016) respondents.

Conclusion Our data suggest that clinical features of FM are common in patients who recovered from COVID-19 and that obesity and male gender affect the risk of developing post-COVID-19 FM.

Muscles

3195

OO88

Mustafa Soytas,Yavuz Onur Danacioglu,Mustafa Yucel Boz,Rahim Horuz,Selami Albayrak,

COVID-19 and urology: A bibliometric analysis of the literature

https://doi.org/10.1111/ijcp.14965

Published

8-Oct-21

Review

https://onlinelibrary.wiley.com/doi/full/10.1111/ijcp.14965

The most worrying issues in the articles are the negative impact of COVID-19 on resident training and permanent damage to urological organs.

Une revue de la littérature sur les impacts urologiques de la covid.

Urological organs

3196

OO89

Ciro Salzano 1 ,Giovanna Saracino 2 andGiuseppe Cardillo 2,*

Possible Adrenal Involvement in Long COVID Syndrome

https://doi.org/10.3390/medicina57101087

Published

11-Oct-21

Case Report

https://www.mdpi.com/1648-9144/57/10/1087

We describe a patient suffering from Long COVID in whom adrenal involvement was highlighted. Methods: The patient described Long COVID symptoms that persist 3 months after the negativization of the molecular swab test. The main symptoms were weakness, brain fog, dizziness, and muscular and joint pain. All routine lab panels for inflammation, anemia, and thyroid and liver function were conducted. Moreover, salivary cortisol and DHEA-S determinations were used to compute the adrenal stress index (ASI). Results: All tests were negative, except the ASI that showed very low levels of free cortisol. The patient started hydrocortisone acetate supplementation. Conclusion: Long COVID symptoms could be explained by an adrenal involvement, due to a COVID-19 action on adrenal glands and by a iatrogenic side effect of high glucocorticoid therapy during the COVID-19 infection. Salivary cortisol determination is effective for establishing a correct recovery plan.

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Adrenal glands

3197

OO90

Aleksandar Botushanov1
, Nikolay Botushanov2

Subacute thyroiditis after asymptomatic SARS-CoV-2 infection

Case Report

https://www.researchgate.net/profile/Velizar-Hadzhiminev/publication/355173719_Pneumothorax_associated_with_COVID-19_-_the_first_three_cases/links/61642183e7993f536cbf3b09/Pneumothorax-associated-with-COVID-19-the-first-three-cases.pdf#page=108

We report a patient with subacute thyroiditis after asymptomatic COVID-19. Objectives: Subacute thyroiditis (SAT) is a viral inflammatory disorder of the thyroid that causes destructive thyrotoxicosis. The objective is to report a case of SAT related to asymptomatic SARS-CoV-2 infection. Methods: We present the clinical findings, ultrasound features, thyroid function and antibodies tests of a woman with no history of thyroid disorder who presented with clinical features of thyroiditis after asymptomatic COVID-19 infection. Case presentation: A 36-year-old woman with neck pain, odynophagia, palpitations, without fever or respiratory symptoms treated with ibuprofen with satisfactory effect. Thyroid function tests showed destructive thyrotoxicosis with negative thyroid antibodies, elevated inflammatory markers and leukocytosis. The neck ultrasound concluded subacute thyroiditis with involvement of the left thyroid lobe. After a gradual resolution, the symptoms worsened and further immunological testing suggested a past asymptomatic COVID-19. Follow up tests revealed worsening of the thyrotoxicosis with bilateral thyroid involvement. After prednisolone treatment symptoms resolved within 1 week with restoration of normal thyroid volume and hypothyroid phase registered after 45 days. Conclusions: A relevant target of damage by SARS-CoV-2 could be the thyroid gland in the form of subacute thyroiditis (SAT).

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Thyroid gland

3198

OO91

César Fernández-de-las-Peñas, José Martín-Guerrero, Esperanza Navarro-Pardo, Juan Torres-Macho, Mª Gabriela Canto-Diez & Oscar Pellicer-Valero

Gastrointestinal symptoms at the acute COVID-19 phase are risk factors for developing gastrointestinal post-COVID symptoms: a multicenter study

https://doi.org/10.1007/s11739-021-02850-5

Published

12-Oct-21

Study

https://link.springer.com/article/10.1007/s11739-021-02850-5

In conclusion, the presence of gastrointestinal symptoms during the acute phase of the infection is associated with a higher risk of suffering from gastrointestinal post-COVID symptoms at long-term.

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Gastro-intestinal

3199

OO226

Bettina Hohberger1*†, Marion Ganslmayer2†, Marianna Lucio3, Friedrich Kruse1, Jakob Hoffmanns1, Michael Moritz1, Lennart Rogge1, Felix Heltmann1, Charlotte Szewczykowski1, Julia Fürst2, Maximilian Raftis1, Antonio Bergua1, Matthias Zenkel1, Andreas Gießl1, Ursula Schlötzer-Schrehardt1, Paul Lehmann1, Richard Strauß2‡, Christian Mardin1‡ and Martin Herrmann4‡

Retinal Microcirculation as a Correlate of a Systemic Capillary Impairment After Severe Acute Respiratory Syndrome Coronavirus 2 Infection

https://doi.org/10.3389/fmed.2021.676554

Published

9-Jul-21

Study

https://www.frontiersin.org/articles/10.3389/fmed.2021.676554/full

The aim of the study was to investigate retinal microcirculation by OCT-A after COVID-19 infection in three subdivided layers (I). In addition, short-term retinal affections were monitored during COVID-19 disease (II). Considering (I), a prospective study (33 patientspost−COVID and 28 controls) was done. Macula and peripapillary vessel density (VD) were scanned with the Spectralis II. Macula VD was measured in three layers: superficial vascular plexus (SVP), intermediate capillary plexus (ICP), and deep capillary plexus (DCP). Analysis was done by the EA-Tool, including an Anatomical Positioning System and an analysis of peripapillary VD by implementing Bruch's membrane opening (BMO) landmarks. Overall, circular (c1, c2, and c3) and sectorial VD (s1-s12) was analyzed. Considering (II), in a retrospective study, 29 patients with severe complications of COVID-19 infection, hospitalized at the intensive care unit, were monitored for retinal findings at bedside during hospitalization. (I) Overall (p = 0.0133) and circular (c1, p = 0.00257; c2, p = 0.0067; and c3, p = 0.0345). VD of the ICP was significantly reduced between patientspost−COVID and controls, respectively. Overall (p = 0.0179) and circular (c1, p = 0.0189) peripapillary VD was significantly reduced between both groups. Subgroup analysis of hospitalized vs. non-hospitalized patientspost−COVID yielded a significantly reduced VD of adjacent layers (DCP and SVP) with increased severity of COVID-19 disease. Clinical severity parameters showed a negative correlation with VD (ICP) and peripapillary VD. (II) Funduscopy yielded retinal hemorrhages and cotton wool spots in 17% of patients during SARS-CoV-2 infection. As VD of the ICP and peripapillary regions was significantly reduced after COVID-19 disease and showed a link to clinical severity markers, we assume that the severity of capillary impairment after COVID-19 infection is mapped on retinal microcirculation, visualized by non-invasive OCT-A.

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Eyes

3200

OO93

Louise Newson
Rebecca Lewis
Margaret O'Hara

Long Covid and menopause - the important role of hormones in Long Covid must be considered

https://doi.org/10.1016/j.maturitas.2021.08.026

Published

1-Oct-21

Study

https://www.maturitas.org/article/S0378-5122(21)00174-2/fulltext

A total of 460 women responded. 48% of women had been experiencing symptoms for more than 6 months. 50% of women reported that their periods had stopped or changed since their infection and 80% stated that their periods had not returned to how they were before their Covid infection.
Interestingly, 62% of responders reported that their symptoms of Long Covid were worse on the days before their periods which is when hormone levels are usually at their lowest. The vast majority of women, 70%, had thought that some of their Long Covid symptoms could be a result of either their perimenopause or menopause. However, 84% of women had never been asked by a healthcare professional about whether or not they could be perimenopausal or menopausal. They were given no advise about treatment of their perimenopause or menopause.
Conclusion: The symptoms of Long Covid may partly be due to the disturbance of physiological ovarian steroid hormone production and/or an altered chronic inflammatory response due to sex-based immunomodulation. Also, many perimenopausal and menopausal women may be misdiagnosed with Long Covid.
This study has also highlighted the importance of women with Long Covid being asked about possible perimenopause or menopause, given adequate information and then managed appropriately with HRT. This study emphasises the need for more healthcare professionals working in Long Covid clinics to be asking women about potential perimenopause or menopause either contributing or causing their patients' symptoms.

Female reproductive system

3201

OO94

Stuart Stewart
Louise Newson
Tracy A Briggs
Dimitris Grammatopoulos
Lawrence Young
Paramjit Gill

Long COVID risk - a signal to address sex hormones and women's health

https://doi.org/10.1016/j.lanepe.2021.100242

Published

COMMENTARY

https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(21)00228-3/fulltext

Clinicians working in Long COVID clinics should receive training in menopause care so perimenopausal and menopausal women can be promptly diagnosed and offered appropriate management. Screening for and diagnosis of perimenopause and menopause is simple and quick, does not usually involve serum sex hormone analysis [[6]], and should be routinely performed in all women in Long COVID clinics. Changes in menstruation are often early signs of perimenopause [[6]]; other common symptoms of perimenopause and menopause include hot flushes, memory problems, brain fog, reduced stamina, fatigue, anxiety, low mood, joint pains and headaches [[6]]. Clinicians should actively enquire about all of these symptoms. Where appropriate, a trial of HRT is a safe and useful treatment option [[6]] for women and clinicians to consider, as an improvement in symptoms supports a diagnosis of hormone deficiency.

Female reproductive system

3202

OO227

YueyangZhong1KaiWang1YananZhuDanniLyuYinhuiYuSuLiKeYao

Ocular manifestations in COVID-19 patients: A systematic review and meta-analysis

https://doi.org/10.1016/j.tmaid.2021.102191

Published

1-Nov-21

Review

https://www.sciencedirect.com/science/article/pii/S1477893921002325

A total of 30 studies involving 5,717 patients were identified. Ocular manifestations including conjunctival hyperemia (7.6%, 95% confidence interval [CI] 1.8–8.9%), conjunctival discharge (4.8%, 95% CI 1.8–8.9%), epiphora (6.9%, 95% CI 2.8–12.8%), and foreign body sensation (6.9%, 95% CI 2.4–13.0%) were observed. The positive rate of conjunctival swab tests was 3.9% (95% CI 0.2–6.4%). Severe cases of COVID-19 were associated with an increased risk of developing ocular complications (odds ratio [OR] = 2.77, 95% CI 1.75–4.40).
Despite their relatively low incidence rate in COVID-19 patients, ocular manifestations may be non-specific and present as the initial symptoms of infection. The presence of SARS-CoV-2 in the conjunctival swabs implicates the eye as a potential source of infection. Early diagnosis and proper eye protection would help prevent viral transmission.
Highlights
•Ocular manifestations may be the initial symptoms of COVID-19 for early diagnosis.
•Ocular manifestations of COVID-19 are non-specific with possible nerve and artery involvements.
•The presence of SARS-CoV-2 in conjunctival sac represents a source of spread.
•Severe COVID-19 patients are three times more likely to have ocular manifestations.

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Eyes

3203

OO96

Hany Mohammed Saad,Sameh Fayek GamalEl Din,Osama Mohamed Elbokl,Ahmed Adel

Predictive factors of erectile dysfunction in Egyptian individuals after contracting COVID-19: A prospective case–control study

https://doi.org/10.1111/and.14308

Published

13-Nov-21

Study

https://onlinelibrary.wiley.com/doi/full/10.1111/and.14308

This study aimed to screen healthy individuals who contracted COVID-19 for erectile dysfunction (ED) and to determine the potential risk factors that can predict ED in these individuals. One hundred and seven cases versus 90 controls agreed to participate in the study. Two structured interviews with 1 month interval were conducted. All participants were evaluated by the validated Arabic version of the international index of erectile function (IIEF-5) and assessment of the psychological state by Hamilton depression rating scale (HDRS). Interestingly, the study had demonstrated a significant difference in mean testosterone level between cases and controls (3.91 ± 2.31, 5.04 ± 2.22, p < 0.001 respectively). Additionally, the study had demonstrated a significant difference in mean IIEF-5 score between cases and controls (22.63 ± 2.79, 23.54 ± 1.26, p < 0.041 respectively). Moreover, there were significant differences in mean anxiety and stress scores of the cases before and after COVID-19 (4.95 ± 4.03, 6.19 ± 3.55, p = 0.022, 12.75 ± 9.98, 15.30 ± 7.42, p = 0.024 respectively). A multiple logistic regression model for predicting ED occurrence post-COVID-19 had revealed that smoking, baseline IIEF-5 score and COVID-19 severity (p = 0.022, p = 0.017, p = 0.021, p = 0.009, p = 0.008 respectively) were the only significant independent variables.

Penis

3204

OO97

Waldemar Kanczkowski, Katja Evert, Marlena Stadtmüller, Martina Haberecker, Laura Laks, Lan-Sun Chen, Karl Frontzek, Jessica Pablik, Constanze Hantel, Felix Beuschlein, Thomas Kurth, Sven Gruber, Adriano Aguzzi, Zsuzsanna Varga, Stefan R Bornstein

COVID-19 targets human adrenal glands

https://doi.org/10.1016/S2213-8587(21)00291-6

Published

18-Nov-21

Study

https://www.thelancet.com/journals/landia/article/PIIS2213-8587(21)00291-6/fulltext

In summary, in our study of 40 patients who died from COVID-19, we did not observe widespread degradation of human adrenals that might lead to manifestation of the adrenal crisis. However, our study shows that the adrenal gland is a prominent target for the viral infection and ensuing cellular damage, which could trigger a predisposition for adrenal dysfunction. Whether those changes directly contribute to adrenal insufficiency seen in some patients with COVID-19 or lead to its complications (such as long COVID) remains unclear. Large multicentre clinical studies should address this question.

Adrenal glands

3205

OO98

Andrea Sansone, MD, PhD
Daniele Mollaioli, Psy D, PhD
Erika Limoncin, PsyD, PhD
Giacomo Ciocca, Psy D, PhD
Nguyễn Hoài Bắc, MD, PhD
Thắng Nguyễn Cao, MD
Guangdong Hou, MD
Jianlin Yuan, MD
Michael Zitzmann, MD, PhD
Annamaria Giraldi, MD, PhD
Emmanuele A. Jannini, MD

The Sexual Long COVID (SLC): erectile dysfunction as a biomarker of systemic complications for COVID-19 long haulers

https://doi.org/10.1016/j.sxmr.2021.11.001

Published

19-Nov-21

Review

https://www.smr.jsexmed.org/article/S2050-0521(21)00085-8/fulltext

In fact, the clinical impact of the COVID -19 is largely based on the age and on the presence of comorbidities with chronic, noncommunicable diseases (NDCs), which are also largely dependent on lifestyles. Finally, the seriousness of the long COVID itself is very frequently, but not always, proportional to the presence and to the severity of NCDs. These findings are highly relevant in the context of sexual medicine, owing to the shared risk factors for sexual dysfunctions (particularly concerning ED) and COVID-19: several factors could contribute to the onset of sexual health issues in COVID patients, including endothelial dysfunction, prolonged hypoxia due to respiratory impairment, anxiety and depression, and endocrine disorders.
Taken together, all these aspects could be featured in a sexual long COVID (SLC) syndrome, which may not only have a pathophysiological and taxonomic value but could also act as a biomarker of the clinical impact of the “general” long COVID. As ED is a widely accepted clinical biomarker of cardiovascular and general health183, 184, 185, it makes sense to hypothesize SLC as a clinical biomarker of long COVID, once again highlighting the relevance of sexual function outside the boundaries of sexual medicine. Plenty of evidence, in fact, clarifies how sexual health is lost at the earliest stages of chronic diseases and belatedly recovered in the process of complete healing. In this light, SLC might become the clinical biomarker of all systemic underlying factors featured in long COVID (figure 1): patients who develop symptoms of the SLC might indeed have worse risk profiles concerning all other complications of long COVID compared to those who maintain a good erectile function. Erectile disorders might therefore be a clinically tangible warning of the complex web of underlying vascular, endothelial, metabolic, neuropsychiatric and pulmonary risk factors186. This is also supported by the bidirectional relationship existing between COVID-19 and ED, suggesting not only that COVID-19 patients are more likely to develop ED, but also that, owing to the shared risk factors, odds ratio for developing COVID-19 is much higher in men having worse erectile function186,187.
Another possible merit of the taxonomic introduction of the SLC could be educational. It is well known that arguments related to sexual health may have a much higher psychological impact on shifting from wrong behavioral habits to healthy lifestyles. This is particularly true for young people, a group peculiarly interested in sexual health and, unfortunately, still reluctant to vaccinate187,188. The ghost of SLC may help in the double effort to educate to get vaccinated and to improve healthy behaviors. “No vax, no sex” could became, on this light, a tremendously powerful motivational claim.

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Penis

3206

OO99

FlorencePoizeau1SébastienBarbarot2YannickLe Corre3MahtabSamimi4EmilieBrenaut5HélèneAubert2AlexisToubel1EstelChambrelan1CatherineDroitcourt1ValérieGissot6ChristopherHeslan7ClaireLaurent1LudovicMartin3LaurentMisery5PierreTattevin8VincentThibault7EmmanuelOger9AlainDupuy

Les engelures apparues pendant le confinement sont associées à une exposition au SARS-CoV-2

https://doi.org/10.1016/j.fander.2021.09.202

Published

19-Nov-21

Study

https://www.sciencedirect.com/science/article/pii/S2667062321004797

De nombreux cas d’engelures ont été rapportés depuis le début de la pandémie de Covid-19. Cependant, la RT-PCR et la sérologie ne mettaient pas en évidence d’infection à SARS-CoV-2 chez la majorité des patients. L’hypothèse d’une réponse interféron-médiée au SARS-CoV-2, permettant une clairance rapide du virus qui ne pourrait alors pas activer l’immunité humorale, a été soulevée et pourrait expliquer la séronégativité. Notre objectif était de rechercher une association entre les engelures survenues pendant le premier confinement en France et l’exposition au SARS-CoV-2 au sein des foyers.

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Skin

3207

OO100

FlorencePoizeau1SébastienBarbarot2YannickLe Corre3EmilieBrenaut4MahtabSamimi5HélèneAubert2AlexisToubel1AlainDupuy1

Le devenir à long terme des engelures induites par une exposition au SARS-CoV-2

https://doi.org/10.1016/j.fander.2021.09.222

Published

19-Nov-21

Study

https://www.sciencedirect.com/science/article/pii/S2667062321004992

Résultats
Parmi les 82 patients ayant présenté des engelures, 27 (33 %) ont guéri sans récidive, et 33 (40 %) ont récidivé après la résolution des engelures du printemps 2020. Vingt-deux (27 %) ont développé des manifestations acrales persistantes, de type acrocyanose principalement, suivies ou non de récidives d’engelures. La plupart des récidives d’engelures a eu lieu pendant l’automne ou l’hiver. Vingt pour cent des patients avaient des antécédents d’engelures, ce qui n’était pas associé au fait de récidiver ou de conserver des manifestations acrales : odds ratio (OR) = 1,02 ; intervalle de confiance à 95 % (IC95 %) [0,79 ; 1,32]). En revanche, les femmes avaient significativement plus de risque de présenter des manifestations acrales persistantes ou récidivantes (OR = 1,30 ; IC95 % [1,06 ; 1,59]). L’âge, les symptômes systémiques de COVID-19, la localisation et la durée de l’épisode initial n’étaient pas associées au fait de guérir ou de présenter des manifestations persistantes ou récidivantes. Par ailleurs, 2 patients rapportaient des arthralgies inflammatoires simultanées aux récidives d’engelures, et 4 gardaient un syndrome sec depuis les engelures.
Discussion
Dix mois après avoir rapporté des engelures associées au SARS-CoV-2, deux tiers des patients ont fait l’expérience de récidives d’engelures ou de manifestations acrales persistantes. Le regroupement des récidives sur l’automne et l’hiver, période de seconde vague de Covid-19, mais aussi de temps froid et humide, peut faire évoquer 2 types de déclencheurs : une réexposition au SARS-CoV-2 ou bien des conditions climatiques favorables aux engelures. Il a été supposé que les engelures du printemps 2020 aient été secondaires à une réponse interféron anti-SARS-CoV-2. La réponse immunologique pourrait être de longue durée, et entraîner localement des manifestations acrales persistantes ou récidivantes, et même au niveau systémique des symptômes de dysimmunité.

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Skin

3208

OO101

SimarBerro1AlbaneCalas1PierreSohier2DelphineDarbord1SelimAractingi1NicolasDupin1

Syndrome de Sweet secondaire à une infection sévère à SARS-CoV-2

https://doi.org/10.1016/j.fander.2021.09.279

Published

19-Nov-21

Case Report

https://www.sciencedirect.com/science/article/pii/S2667062321005560

De nombreuses manifestations cutanées associées au COVID-19 ont été décrites parmi lesquelles les engelures et les exanthèmes sont les plus fréquentes. Nous rapportons ici le cas d’un syndrome de Sweet survenant 3 semaines après le début d’infection sévère à SARS-CoV-2.

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Skin

3209

OO102

Raphaël André Aurélie Hsieh Laurence Toutous-Trellu

Lésions acrales chroniques (« orteils COVID ») : un syndrome post-COVID long ?

https://doi.org/10.1016/j.fander.2021.09.195

Published

19-Nov-21

Case Reports

https://www.sciencedirect.com/science/article/pii/S2667062321004724

Notre petite série de cas montre une durée d’évolution des engelures de 3 à 10 mois. La symptomatologie varie de l’absence de douleur à l’incapacité fonctionnelle, avec parfois une évolution nécrotique. Nos données montrent une longue durée de ces symptômes. À ce jour, les « orteils COVID » n’ont pas été intégrés dans le concept de « long COVID » représentant les complications persistantes de la COVID-19 ; et aucun syndrome acral aigu pédiatrique n’a eu cette durée d’évolution. Nous suggérons de définir les orteils chroniques de la COVID-19 comme une entité distincte des formes aiguës survenant au cours de l’infection.

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Skin

3210

OO103

ParnaMoghadam1LaureFrumholtz1LéaJaume1AdèleDe Masson1MarieJachiet1EdouardBegon2LucSulimovic1AntoinePetit1HervéBachelez1MartineBagot1Jean DavidBouaziz1CharlesCassius

Fréquence des rechutes et signes cutanés persistants après un premier épisode de pseudo engelure durant la pandémie COVID-19

https://doi.org/10.1016/j.fander.2021.09.199

Published

19-Nov-21

Study

https://www.sciencedirect.com/science/article/pii/S2667062321004761

Dans l’hypothèse d’un lien de causalité avec le SarS-CoV-2, nous avons montré une forte prévalence de symptômes persistants, les classant en « COVID long cutanés » et « COVID longs extra cutanés ». Plus de la moitié des patients adressés pour PE durant la première vague de Covid19 ont eu au moins une récidive. La majorité des récidives a eu lieu lors de la seconde vague épidémique. Une nouvelle exposition virale ne peut être exclue bien que les examens aient été le plus souvent négatifs. Le deuxième confinement ayant été moins strict que le premier, le rôle de la sédentarité nous semble peu probable. En revanche, la seconde vague s’étant déroulée en automne, le rôle du climat est à envisager. Une hypothèse physiopathologique serait que les dommages vasculaires rapportés au cours du COVID soient exacerbés par des facteurs externes comme la baisse de la température, expliquant les récidives de PE et les symptômes cutanés persistants.

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Skin

3211

OO104

Laura E. Lamb, Ryan Timar, Melissa Wills, Sorabh Dhar, Steve M. Lucas, Dragana Komnenov, Michael B. Chancellor & Nivedita Dhar

Long COVID and COVID-19-associated cystitis (CAC)

https://doi.org/10.1007/s11255-021-03030-2

Published

17-Nov-21

Study

https://link.springer.com/article/10.1007/s11255-021-03030-2

There is scarce literature regarding genitourinary symptoms in COVID-19, especially post-acute disease otherwise known as Long COVID. We identified recovered COVID-19 patients presenting with new or worsening overactive bladder symptoms, known as COVID-19-associated cystitis (CAC).
We identified 350 patients with de novo or worsening OAB symptoms 10–14 weeks after hospitalization with COVID-19. The median total OAB symptom score in both men and women was 18. The median total QoL score for both men and women was 19. Patients with worsening OAB symptoms had a median pre-COVID-19 symptom score of 8 (4–10) compared to post-COVID-19 median symptom score of 19 (17–21). Median age was 64.5 (range 47–82). Median hospital length-of-stay was 10 days (range 5–30).
We used the American Urological Association Urology Care Foundation Overactive Bladder (OAB) Assessment Tool to screen COVID-19 recovered patients presenting with urological complaints at our urban-located institution.
We report survey-based results of patients suffering from new or worsening OAB symptoms months after their hospitalization from COVID-19. Future studies with larger sample sizes and more extensive testing will hopefully elucidate the specific pathophysiology of OAB symptoms in the context of long COVID so urologists can timely and appropriately treat their patients.

_

Bladder

3212

OO105

JulienneSánchezMDaMelissaCohenMDbJoseph L.ZapaterMD PhDbYuvalEisenberg

Primary Adrenal Insufficiency After COVID-19 Infection

https://doi.org/10.1016/j.aace.2021.11.001

Published

14-Nov-21

Case Report

https://www.sciencedirect.com/science/article/pii/S237606052100119X

Highlights
•SARS-CoV-2 affects multiple organs outside of the pulmonary system.
•The precise short- and long-term effects of COVID-19 infection on the adrenal glands is not fully elucidated, but the development of adrenal insufficiency by way of adrenal infarction or hemorrhage has been reported.
•The patient presented here developed symptoms of clinically significant adrenal insufficiency after COVID-19 infection, however imaging of her adrenals did not identify acute or subacute adrenal pathology.
•The patient was found to be positive for 21-hydroxylase antibodies and developed autoimmune primary adrenal insufficiency
•This case suggests the development of and/or progression to clinically significant Addison’s disease via autoimmunity following COVID-19 infection.
The development of autoimmune Addison’s disease in the patient may be related to a prior COVID-19 infection.

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Adrenal glands

3213

OO106

A.Marty-Ane1M.Sarfati2T.Thomas3F.Berenbaum4H.Marotte5V.Jachiet6C.Guillot7I.Al Sabty8A.M.Moldovan9B.Grardel10A.Giraud-Morelet(Rhumatologue)11A.Basch12R.M.Flipo7M.H.Vieillard13

L’infection a SARS-CoV-2 pourrait-elle induire des rhumatismes inflammatoires chroniques ? Une enquête nationale française

https://doi.org/10.1016/j.rhum.2021.10.066

Published

26-Nov-21

Study

https://www.sciencedirect.com/science/article/abs/pii/S1169833021003252

Notre étude rapporte plusieurs cas de manifestations rhumatologiques inflammatoires, non érosives, après une infection à SARS-CoV-2, après un suivi moyen de 15 mois. Elles restent exceptionnelles. L’hypothèse d’une arthrite de type réactionnelle ne peut être écartée.

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Joints

3214

OO107

Matthew D.EttlesonM.D.1AvaRaine2AliceBatistuzzo3Samuel P.Batista3ElizabethMcAninchM.D.4Maria Cristina T.V.TeixeiraPh.D.3JacquieJonklaasM.D.5NedaLaiteerapongM.D.6Miriam O.RibeiroPh.D.3Antonio C.BiancoM.D., Ph.D.1

Brain Fog in Hypothyroidism: Understanding the Patient’s Perspective

https://doi.org/10.1016/j.eprac.2021.12.003

Published

8-Dec-21

Study

https://www.sciencedirect.com/science/article/abs/pii/S1530891X21014087

Highlights
Teaching Points
•Brain fog in hypothyroidism is characterized primarily by fatigue and forgetfulness
•Both rest and exercise were commonly reported lifestyle changes to alleviate brain fog symptoms
•Additional areas of concern related to brain fog included problems with language and the patient-doctor relationship
•Approaches involving lifestyle changes and cultivation of a therapeutic relationship between doctor and patient may help patients with brain fog better manage symptoms

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Thyroid gland

3215

OO108

RashikaBansalaSriramGubbiaChristian A.Kochbc

COVID-19 and Chronic Fatigue Syndrome: An Endocrine Perspective

https://doi.org/10.1016/j.jcte.2021.100284

Published

3-Dec-21

Review

https://www.sciencedirect.com/science/article/pii/S2214623721000363

Patients recovering from COVID-19 may have persistent debilitating symptoms requiring long term support through individually tailored cardiopulmonary and psychological rehabilitation programs. Clinicians need to be aware about the likely long-term complications and their diagnostic assessments to help identify any occult problems requiring additional help. Endocrinological evaluations should be considered as part of the armamentarium in the management of such individuals with diligent cognizance about the involvement of the hypothalamo-pituitary-adrenal (HPA) axis, adrenals, and thyroid.

_

Thyroid gland

3216

OO109

Barbara Rafałowicz , Leopold Wagner , Juliusz Rafałowicz

Long COVID Oral Cavity Symptoms Based on Selected Clinical Cases

https://doi.org/10.1055/s-0041-1739445

Published

17-Dec-21

Case Reports

https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0041-1739445

Among the 1,256 studied patients, 32% of them had discoloration, ulceration, and hemorrhagic changes on the oral mucosa, 29.69% had mycosis located on the tongue, 25.79% of patients had aphthous-like lesions on the hard palate, and in 12.5% atrophic cheilitis was observed. During the anamnesis, approximately 60% of patients reported salivary secretory disorders in the initial period of infection, which is 6.68% prolonged up to 4 months after systemic symptoms disappeared. In an extreme case, an aphthous-like lesion was located on the hard palate, which persisted for 6 months. Approximately 36% of patients did not agree to the proposed treatment. As a result, they only received recommendations on the use of oral hygiene products and received weekly check-ups. In this group of patients, most pathological changes spontaneously cleared after 3 weeks. The elderly with coexisting diseases, persons with a more severe SARS-CoV-2, and hospitalized patients had more extensive and severe lesions in the oral cavity that persisted for a long time after infection.
In patients after the SARS-CoV-2 infection and suspected of this infection, a detailed intraoral examination should be performed, and the patient must be obligatorily monitored for a minimum period of 6 months.

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Oral cavity

3217

OO228

Alessandro Invernizzi

The impact of COVID-19 on the retina: clinical features and management considerations

https://doi.org/10.1080/17469899.2022.2021877

Published

21-Dec-21

Review

https://www.tandfonline.com/doi/abs/10.1080/17469899.2022.2021877

Article highlights
- The retina is not the primary target of SARS-CoV-2. However, signs of capillary dropout and microangiopathy are common, even in patients with mild COVID-19 disease
- Major retinal vessels can show acute and long-lasting diameter increase in COVID-19 and retinal vascular occlusion can result from the transitory hypercoagulative status of patients during the acute phase of the disease
- The pandemic has temporarily re-directed the healthcare system resources to allow for the management of COVID-19 patients with a negative impact on the follow-up and treatment of chronic retinal diseases like age related macular degeneration and diabetic retinopathy
- New treatment strategies for retinal diseases have been developed in order to comply with pandemic social restrictions and healthcare facilities re-organization while still guaranteeing proper disease management and good outcomes
- Few cases of retinal side effects have been reported after COVID-19 vaccination but further studies are needed to confirm this association
- COVID-19 related subclinical damage to retinal vessels could have long term effects on the retina but further studies are need to establish to which extent

_

Eyes

3218

OO111

Gilbert G.G.DondersM.D., Ph.D.abcEugeneBosmansPharm.D.deJenteReumersM.Sc, R.N.bFrancescaDondersM.D.bJefJonckheerePharm.D.dfGeertSalembierPharm.D.dfNoraSternM.D.gYvesJacquemynM.D., Ph.D.aWillemOmbeletM.D., Ph.D.hChristophe E.DepuydtM.Sc., Ph.D.de

Sperm quality and absence of SARS-CoV-2 RNA in semen after COVID-19 infection: a prospective, observational study and validation of the SpermCOVID test

https://doi.org/10.1016/j.fertnstert.2021.10.022

Published

20-Dec-21

Study

https://www.sciencedirect.com/science/article/pii/S0015028221021567

Result(s)
SARS-CoV-2 RNA was not detected in semen during the period shortly after infection nor at a later time. Mean progressive motility was reduced in 60% of men tested shortly (<1 month) after COVID-19 infection, 37% of men tested 1 to 2 months after COVID-19 infection, and 28% of men tested >2 months after COVID-19 infection. Mean sperm count was reduced in 37% of men tested shortly (<1 month) after COVID-19 infection, 29% of men tested 1 to 2 months after COVID-19 infection, and 6% of men tested >2 months after COVID-19 infection. The severity of COVID-19 infection and the presence of fever were not correlated with sperm characteristics, but there were strong correlations between sperm abnormalities and the titers of SARS-CoV-2 IgG antibody against spike 1 and the receptor- binding domain of spike 1, but not against nucleotide, in serum. High levels of antisperm antibodies developed in three men (2.5%).
Conclusion(s)
Semen is not infectious with SARS-CoV-2 at 1 week or more after COVID-19 infection (mean, 53 days). However, couples with a desire for pregnancy should be warned that sperm quality after COVID-19 infection can be suboptimal. The estimated recovery time is 3 months, but further follow-up studies are under way to confirm this and to determine if permanent damage occurred in a minority of men.

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Male reproductive system

3219

OO112

Melvin R. Hayden 1,* andSuresh C. Tyagi 2

Impaired Folate-Mediated One-Carbon Metabolism in Type 2 Diabetes, Late-Onset Alzheimer’s Disease and Long COVID

https://doi.org/10.3390/medicina58010016

Published

23-Dec-21

Review

https://www.mdpi.com/1648-9144/58/1/16/htm

Impaired folate-mediated one-carbon metabolism (FOCM) is associated with many pathologies and developmental abnormalities. FOCM is a metabolic network of interdependent biosynthetic pathways that is known to be compartmentalized in the cytoplasm, mitochondria and nucleus. Currently, the biochemical mechanisms and causal metabolic pathways responsible for the initiation and/or progression of folate-associated pathologies have yet to be fully established. This review specifically examines the role of impaired FOCM in type 2 diabetes mellitus, Alzheimer’s disease and the emerging Long COVID/post-acute sequelae of SARS-CoV-2 (PASC). Importantly, elevated homocysteine may be considered a biomarker for impaired FOCM, which is known to result in increased oxidative–redox stress. Therefore, the incorporation of hyperhomocysteinemia will be discussed in relation to impaired FOCM in each of the previously listed clinical diseases. This review is intended to fill gaps in knowledge associated with these clinical diseases and impaired FOCM. Additionally, some of the therapeutics will be discussed at this early time point in studying impaired FOCM in each of the above clinical disease states. It is hoped that this review will allow the reader to better understand the role of FOCM in the development and treatment of clinical disease states that may be associated with impaired FOCM and how to restore a more normal functional role for FOCM through improved nutrition and/or restoring the essential water-soluble B vitamins through oral supplementation

_

Pancreas

3220

OO113

VP

Alexander B.Collins*1LeiZhao⁎⁎1ZiwenZhu†Nathan T.Givens*QianBai†Mark R.Wakefield†YujiangFang*†

Impact of COVID-19 on male fertility

https://doi.org/10.1016/j.urology.2021.12.025

Published

8-Jan-22

Review

https://www.sciencedirect.com/science/article/pii/S0090429522000097

COVID-19, the clinical condition caused by the SARS-CoV-2 virus, has been associated with massive cytokine storm and damage to multiple organ systems. Although evidence for the detection of SARS-CoV-2 virus in the testis remains scarce, testicular damage and dysregulation of gonadotropins associated with inflammation has been reported. Additionally, as a result of the rapidly evolving pandemic, frequently updated medical interventions and public policies leading to delays of care can play a role in fertility. This narrative review aims to summarize the current literature on how COVID-19 may influence male fertility.

Male reproductive system

3221

OO114

by Andreea Carp-Veliscu 1,2,Claudia Mehedintu 1,3,*,Francesca Frincu 1,3 ,Elvira Bratila 1,2,Simona Rasu 2,Ioana Iordache 1,2,Alina Bordea 1,2 andMihaela Braga 2

The Effects of SARS-CoV-2 Infection on Female Fertility: A Review of the Literature

https://doi.org/10.3390/ijerph19020984

Published

16-Jan-22

Review

https://www.mdpi.com/1660-4601/19/2/984/htm

The purpose of this paper is to bring light upon the possible link between COVID-19 and women’s reproductive health. This review emphasizes the effect of SARS-CoV-2 on the hormones, endometrium and menstrual cycle, ovarian reserve, follicular fluid, oocytes, and embryos. The results showed that endometrial samples did not express SARS-CoV-2 RNA. Regarding the menstrual cycle, there is a large range of alterations, but they were all reversible within the following months. The ovarian reserve was not significantly affected in patients recovering from both mild and severe infection in most cases, except one, where the levels of AMH were significantly lower and basal follicle-stimulating hormone (FSH) levels were increased. All COVID-19 recovered patients had positive levels of SARS-CoV-2 IgG in the follicular fluid. The amount of retrieved and mature oocytes and the fertilization rate were unharmed in three studies, except for one study, where the quantity of retrieved and mature oocytes was reduced in patients with higher levels of SARS-CoV-2 antibodies. The numbers of blastocysts, top-quality embryos, and euploid embryos were affected in most of the studies reviewed.

Female reproductive system

3222

OO115

Delli Muti N1, Finocchi F1, Tossetta G2, Salvio G1, Cutini M1, Marzioni D2, Balercia G1

Could SARS-CoV-2 infection affect male fertility and sexuality?

https://doi.org/10.1111/apm.13210

Published

3-Feb-22

Review

https://europepmc.org/article/med/35114008

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus infectious disease (COVID-19) and has rapidly spread worldwide, causing serious problems to the health care systems of many countries and hundreds of thousand deaths. In this review we discuss data from the literature to understand whether the various districts of the male reproductive system may represent another vulnerable target for SARS-CoV-2. Studies were searched from electronic databases such as Google Scholar, PubMed, Scopus and COVID-19 specific databases such as LitCovid, until July 31, 2021. It appears that SARS-CoV-2 virus infection not only causes damage to the respiratory system, but could have a serious impact on the reproductive system of male patients modulating many physiological processes. Like some other infections, SARS-CoV-2 also leads to a worsening of semen quality and an increase in oxidative stress (OS) levels. However, due to the limited number of studies, it is unclear whether this deterioration in semen parameters is temporary or lasts over time. It is certainly important that patients' reproductive function is monitored after coronavirus infection to avoid problems in reproductive health in the future.

Male reproductive system

3223

OO116

Sara Ibrahim Taha 1 *
Sara Farid Samaan 2
Rehab Ali Ibrahim 3
Eman Mousa El-Sehsah 4
Mariam Karam Youssef 5

Post-COVID-19 arthritis: is it hyperinflammation or autoimmunity?

https://www.jle.com/10.1684/ecn.2021.0471

Published

4-Dec-21

Study

https://www.jle.com/en/revues/ecn/e-docs/post_covid_19_arthritis_is_it_hyperinflammation_or_autoimmunity__321899/article.phtml

Background: Various musculoskeletal and autoimmune manifestations have been described in patients with coronavirus disease 2019 (COVID-19). Objectives: This study aims to investigate the prevalence and etiology of arthritis in post-COVID Egyptian patients. Methods: We included 100 post-COVID Egyptian patients who recovered 6 months ago and assessed several inflammatory and autoimmune markers. Results: The prevalence of post-COVID arthritis was 37%. Ankle, knee, and wrist were the most commonly affected joints. Old age (P = 0.010), smoking (P = 0.001), and arthralgia (P = 0.049) were all linked with post-COVID arthritis. Levels of pretreatment (baseline) interleukin (IL)-6 (46.41 ± 3.67 vs. 24.03 ± 2.46; P = 0.001), as well as 6-month post-COVID C-reactive protein (CRP; 98.49 ± 67.55 vs. 54.32 ± 65.73; P = 0.002), and erythrocyte sedimentation rate (ESR; 109.08 ± 174.91 vs. 58.35 ± 37.87; P = 0.029) were significantly higher in patients with arthritis compared to those without. On the other hand, complement C3 (P = 0.558) and C4 (P = 0.192), anti-nuclear antibodies (P = 0.709), and anti-cyclic citrullinated peptides (anti-CCP; P = 0.855) did not show significant differences. Only pretreatment IL-6 level was the significant single predictor of post-COVID arthritis with an odds ratio (95% confidence interval) of 3.988 (1.460–10.892) and a P-value of 0.007. Conclusion: The strong association observed with inflammatory markers (ESR and CRP) and the insignificant association with serologic markers of autoimmunity (ANA and anti-CCP) in our study support the notion that the underlying mechanism of post-COVID-19 arthritis is primarily due to the hyperinflammatory process associated with COVID-19 infection, and not the result of an autoimmune reaction. IL-6 levels before therapy can predict post-COVID arthritis allowing for early management.

Joints

3224

OO117

Nidhi Popat Swarali Kale
Dhruv Talwar Vinay Verma
Sunil Kumar Samarth Shukla
Sunita Vagha

Necrotizing Fasciitis of the Breast and Leukemoid Reaction in an Immunocompetent Female: An Unforeseen Misadventure of LONG COVID Syndrome?

http://dx.doi.org/10.9734/JPRI/2021/v33i62B35189

Published

1-Feb-22

Case Report

https://www.researchgate.net/publication/358305800_Necrotizing_Fasciitis_of_the_Breast_and_Leukemoid_Reaction_in_an_Immunocompetent_Female_An_Unforeseen_Misadventure_of_LONG_COVID_Syndrome

Necrotizing fasciitis is infrequently encountered but highly fatal group of infections. It is a infection
of any of the three layers of soft tissue compartments which includes the dermis, subcutaneous
tissue, superficial fascia,deep fascia or the muscle along with necrotising changes. During the initial
stages it might be tricky to differentiate cellulitis and other infections of the superficial skin from
necrotising fasciitis leading to an delay in the diagnosis. Prompt diagnosis and management can
reduce mortality .This case report highlights a previously unreported presentation of necrotising
fasciitis of breast in the form of leukemoid reaction encountered in the rural central India following
COVID-19 infection.

Skin

3225

OO118

Sara J.CromerabCaitlinCollingabDariaSchatoffabMichaelLearycMaria I.StamouabDaryl J.SelenabMelissa S.PutmanabdDeborah J.Wexlerab

Newly diagnosed diabetes vs. pre-existing diabetes upon admission for COVID-19: Associated factors, short-term outcomes, and long-term glycemic phenotypes

https://doi.org/10.1016/j.jdiacomp.2022.108145

Published

4-Feb-22

Study

https://www.sciencedirect.com/science/article/pii/S1056872722000253

Highlights
•Patients with newly diagnosed vs. pre-existing diabetes at COVID-19 admission had lower glucose but more severe COVID-19.
•After discharge, half of patients with COVID-19 and newly diagnosed diabetes regress to normoglycemia or prediabetes.
•Stress hyperglycemia, not β cell destruction, may be the major mechanism for COVID-19-associated newly diagnosed diabetes.
Results
Of 1902 individuals admitted with COVID-19, 594 (31.2%) had DM; 77 (13.0%) of these had NDDM. Compared to pre-existing DM, NDDM was more common in younger patients and less common in those of non-Hispanic White race/ethnicity. Glycemic parameters were lower and inflammatory markers higher in patients with NDDM. In adjusted models, NDDM was associated with lower insulin requirements, longer length of stay, and intensive care unit admission but not death. Of 64 survivors with NDDM, 36 (56.3%) continued to have DM, 26 (40.6%) regressed to normoglycemia or pre-diabetes, and 2 were unable to be classified at a median follow-up of 323 days.
Conclusions
Diabetes diagnosed at COVID-19 presentation is associated with lower glucose but higher inflammatory markers and ICU admission, suggesting stress hyperglycemia as a major physiologic mechanism. Approximately half of such individuals experience regression of DM.

Pancreas

3226

OO119

Mehmet Kaynar, Ana Luísa Quinta Gomes, Ioannis Sokolakis & Murat Gül

Tip of the iceberg: erectile dysfunction and COVID-19

https://doi.org/10.1038/s41443-022-00540-0

Published

12-Feb-22

Review

https://www.nature.com/articles/s41443-022-00540-0

Androgens may be responsible for the underlying reason of more severe disease, as androgen receptors have been implicated to mediate viral cell entry and infection. Besides, male reproductive organs have been reported to be affected by the especially severe disease, resulting in erectile dysfunction (ED). In this narrative review, we aimed to gather possible mechanisms of the development of ED led by COVID-19. Current evidence illuminates endothelial dysfunction, direct testicular damage, and the psychological burden of COVID-19 that are of the pathways of ED. Although the proposed underlying mechanisms partly fail to answer the questions by which COVID-19 leads to ED, it is important to monitor men who recovered from COVID-19 regarding the sexual dysfunction sequelae of infection and address the long‐term consequences.

Male reproductive system

3227

OO120

G. Yorulmaz & M. Sahin Tekin

SARS-CoV-2 vaccine-associated subacute thyroiditis

https://doi.org/10.1007/s40618-022-01767-w

Published

19-Feb-22

Study

https://link.springer.com/article/10.1007/s40618-022-01767-w

Purpose - With coronavirus disease 2019 (COVID-19), subacute thyroiditis (SAT) cases are on the rise all over the world. COVID-19 vaccine-associated SAT cases have also been reported. In this article, we present our data on 11 vaccine-associated SAT cases.
Methods - Eleven patients were included in the study. Type of the vaccines patients received, time to the occurrence of SAT after vaccination, symptoms and laboratory findings, treatment given, and response to treatment were evaluated.
Results - The age of patients ranged from 26 to 73. Four of the patients were males, and seven were females. Symptoms of six patients were seen after BNT162b2 Pfizer/BioNTech COVID-19 mRNA vaccine®, and four of them after Coronavac inactivated SARS-CoV-2 vaccine®. In one patient, SAT developed after the first dose of BNT162b2, administered after two doses of Coronavac. The average time to the onset of symptoms was 22 days (15–37) after vaccination.
Conclusions - The fact that both whole virus containing and genetic material containing vaccines cause SAT suggests that the trigger may be viral proteins rather than the whole viral particle. Although corticosteroids are commonly preferred in published vaccine-associated SAT cases, we preferred nonsteroidal anti-inflammatory therapy in our patients for sufficient vaccine antibody response. There is not enough information about whether patients who develop SAT can be revaccinated safely considering the ongoing pandemic. Further research is needed for a conclusion in the treatment and revaccination of these patients.

Thyroid gland

3228

OO121

T. T. Nguyen, J. Hulme, H. D. Tran, T. K. Vo & G. V. Vo

The potential impact of COVID-19 on male reproductive health

https://doi.org/10.1007/s40618-022-01764-z

Published

18-Feb-22

Review

https://link.springer.com/article/10.1007/s40618-022-01764-z

Invasion or damage to the male reproductive system is one of the documented outcomes of viral infection. Existing studies have reported that SARS-CoV-2 may contribute to this loss in relation to inflammatory responses and the formation of cytokine storms in COVID-19 patients. Although direct infection of the testes and entry of SARS-CoV-2 into semen as well as subsequent consequences on the male reproductive system need to be studied more systematically, warnings from two organising ASRM and SART for prospective parents when infected with SARS-CoV-2 should be considered. In the context of an increasingly complex pandemic, this review provides preliminary examples of the potential impact of COVID-19 on male reproductive health and guidance for prospective parents currently infected with or recovering from SARS-CoV-2.

Male reproductive system

3229

OO229

Maria Cristina Savastano, Anna Rita Larici, Emanuele Crincoli, Alessandro De Filippis, Giuseppe Cicchetti, Gloria Gambini, Alfonso Savastano, Riccardo Marano, Luigi Natale, Stanislao Rizzo

Retinal vascular impairment matched to the pulmonary damage in early post-COVID 19 patients

https://doi.org/10.1177%2F11206721221079153

Published

17-Feb-22

Study

https://journals.sagepub.com/doi/abs/10.1177/11206721221079153

Endothelium damage is a crucial element in the pathogenesis of SARS-Cov-2 infection. Most casualties in critical COVID-19 cases are due to ARDS, diffuse coagulopathy and cytokine storm. ARDS itself is a consequence of pulmonary endothelial cells damage. Damage to retinal capillary microcirculation in post-infective period has been investigated through Optical Coherence Tomography Angiography (OCTA). The aim of the present study is to find a correlation between signs of retinal vascular damage and pulmonary impairment.
Methods
Patients admitted to hospital and subsequently recovered from COVID-19 infection were summoned 1 month later to undergo coherence tomography (CT) scan and OCTA examination.
Results
The study population included 87 COVID-19 patients with a mean age of 54.28 ± 14.44 years. Oxygen therapy, non-invasive and invasive mechanical ventilation were necessary in 33, 11 and 4 patients respectively to provide respiratory support during the acute course of the disease. Pulmonary involvement interested 54 patients (62.1%). Peripheral (27.6%) or diffuse (29.9%) involvement and ground glass (GG) opacities (47.1%) represented the prevalent radiological finding. A reduced RCPI FI was independently correlated with the presence of reticulation pattern in CT scan (p = .019). Also, RNFL and GCC were thinner in patients who displayed reticulation pattern (respectively p = .025 and p = .015).
Conclusions
A reduction in RPCP-FI and RNFL and GCC thickness were independently correlated to the presence of CT reticulation pattern. This association can reflect cytokine induced remodeling in both organs as a consequence of systemic endothelial damage and inflammation.

Eyes

3230

OO123

Arad Dotan,Paula David,Dana Arnheim,Yehuda Shoenfeld

The autonomic aspects of the post-COVID19 syndrome

https://doi.org/10.1016/j.autrev.2022.103071

Published

16-Feb-22

Review

https://www.sciencedirect.com/science/article/pii/S1568997222000416

Highlights
•Close to 20 distinct autoantibodies which target GPCR of the nervous system and renin-angiotensin system-related molecules were found significantly associated with the clinical severity of COVID-19
•Numerous clinical and laboratory similarities exist between post-COVID19 syndrome, fibromyalgia, and chronic fatigue syndrome
•Autoimmune-mediated autonomic nervous system dysfunction may play a significant role in the pathogenesis of post-COVID19 syndrome, similarly to fibromyalgia and chronic fatigue syndrome
•Therapeutic options such as immunomodulatory and immunosuppressive therapy could be favorable for some post-COVID19 patients, while plasmapheresis and IVIG could be considered in severe cases
•Physical exercise has been found to stabilize the autonomic nervous system; thus, exercise therapy might be a safer and more effective remedy for the post-COVID19 syndrome in comparison to other therapeutic options
- Close to 20 distinct autoantibodies which target GPCR of the nervous system and renin-angiotensin system-related molecules were found significantly associated with the clinical severity of COVID-19. The new on-set of more than 10 various autoimmune disorders were documented as well. Additionally, clinical presentations of persisted symptoms were triggered in numerous recently recovered COVID-19 patients, which led to the formulation of the novel term “post-COVID19 syndrome”. Manifestations related to post-COVID-19 syndrome exist among approximately 50–80% of symptomatic COVID-19 patients who recovered, and among patients reported more than 50 different long-term effects of the SARS-CoV-2 infection. Many of the common symptoms of the post-COVID19 syndrome are not explained by the virus-related injury alone. Similarly to chronic fatigue syndrome and fibromyalgia, autoimmune-mediated autonomic nervous system dysfunction may play a significant part in the pathogenesis of such symptoms, including chronic fatigue, cognitive impairment, mood related disorders, and numerous more. Importantly, therapeutic options such as immunomodulatory and immunosuppressive therapy may favor some post-COVID19 patients, while plasmapheresis and IVIG could be considered in severe cases. Nevertheless, as physical exercise has been found to stabilize the autonomic nervous system, exercise therapy might be a safer and more effective remedy for the post-COVID19 syndrome.

Autonomic system

3231

OO124

G.Abuova1A.Ayazbekov2R.Nurkhasimova2G.Shaimardenova1S.Kulbaeva1S.Nurmagambet1

Asymptomatic forms of COVID-19 in pregnant women: long-term consequences

https://doi.org/10.1016/j.ijid.2021.12.110

Published

28-Feb-22

Study

https://www.sciencedirect.com/science/article/pii/S120197122101002X

Often asymptomatic forms remain undiagnosed and unaccounted for. We have studied cases of visits to a doctor by pregnant women for various reasons: stopping fetal movement, reducing the size of the abdomen and other complications of pregnancy. When examining them by ultrasound, oligohydroamnion was detected in 85% of cases, premature aging of the placenta, placental cysts in 27.5%, and impaired blood flow in the utero-fetal-placental circulation in 12.5%. Subsequently, 51.4% of women gave birth at full term, 48.5% gave birth prematurely, that is every second woman in the study group gave birth prematurely. In a detailed retrospective laboratory examination of women with the above pathology, IgG SARS-Cov-2 was detected in 92.5% of cases, indicating an asymptomatic coronavirus infection. The development of obstetric complications required from the medical staff reinforced observation and additional assessment, more frequent reclassification of the condition of the mother and fetus, and in some cases induction of labor. This tactic was applied in 12 cases (34.2% of the total number of women who gave birth), when prolongation of pregnancy was associated with a high risk to the health of the mother and fetus.

Male reproductive system

3232

OO230

Ganesh, Sudha K,; Mohanan-Earatt, Amanda

An analysis of the clinical profile of patients with uveitis following COVID-19 infection

https://doi.org/10.4103/ijo.IJO_2735_21

Published

1-Mar-22

Study

https://journals.lww.com/ijo/Fulltext/2022/03000/An_analysis_of_the_clinical_profile_of_patients.63.aspx

Twenty-one eyes of 13 patients were included in this hospital-based retrospective observational study. The study included six male and seven female patients. The mean age was 38 ± 16.8 years. Eight patients had bilateral involvement. Seven patients were diagnosed with anterior uveitis, three with intermediate uveitis, one with posterior uveitis, and two with panuveitis. All patients responded well to treatment and were doing well at their last visit. Two patients had complications that necessitated surgical treatment, following which they recovered good visual outcomes.
Conclusion:
With prompt diagnosis and appropriate management, all the patients with uveitis post-COVID-19 infection recovered with good visual outcomes. Thus, ophthalmologists must be aware of the possible uveitic manifestations following even uneventful COVID-19 infection.

Eyes

3233

OO126

Anne Louise Oaklander, Alexander J. Mills, Mary Kelley, Lisa S. Toran, Bryan Smith, Marinos C. Dalakas, Avindra Nath

Peripheral Neuropathy Evaluations of Patients With Prolonged Long COVID

https://doi.org/10.1212/NXI.0000000000001146

Published

1-Mar-22

Study

https://nn.neurology.org/content/9/3/e1146.abstract

Background and Objectives - Recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection appears exponential, leaving a tail of patients reporting various long COVID symptoms including unexplained fatigue/exertional intolerance and dysautonomic and sensory concerns. Indirect evidence links long COVID to incident polyneuropathy affecting the small-fiber (sensory/autonomic) axons.
Methods We analyzed cross-sectional and longitudinal data from patients with World Health Organization (WHO)-defined long COVID without prior neuropathy history or risks who were referred for peripheral neuropathy evaluations. We captured standardized symptoms, examinations, objective neurodiagnostic test results, and outcomes, tracking participants for 1.4 years on average.
Results - Among 17 patients (mean age 43.3 years, 69% female, 94% Caucasian, and 19% Latino), 59% had ≥1 test interpretation confirming neuropathy. These included 63% (10/16) of skin biopsies, 17% (2/12) of electrodiagnostic tests and 50% (4/8) of autonomic function tests. One patient was diagnosed with critical illness axonal neuropathy and another with multifocal demyelinating neuropathy 3 weeks after mild COVID, and ≥10 received small-fiber neuropathy diagnoses. Longitudinal improvement averaged 52%, although none reported complete resolution. For treatment, 65% (11/17) received immunotherapies (corticosteroids and/or IV immunoglobulins).
Discussion - Among evaluated patients with long COVID, prolonged, often disabling, small-fiber neuropathy after mild SARS-CoV-2 was most common, beginning within 1 month of COVID-19 onset. Various evidence suggested infection-triggered immune dysregulation as a common mechanism.

Peripheral Nerve

3234

OO127

Jeff R. Gehlhausen, Alicia J. Little, Christine J. Ko, +24 , Marc Emmenegger, Carolina Lucas, Patrick Wong, Jon Klein, Peiwen Lu, Tianyang Mao, Jillian Jaycox, Eric Wang, Yale IMPACT Team, Nelson Ugwu, Cate Muenker, Dilgash Mekael, Rhonda Q. Klein, Robert Patrignelli, Richard Antaya, Jennifer McNiff, William Damsky, Kathy Kamath , John Shon, Aaron M. Ring , Inci Yildirim, Saad Omer , Albert I. Ko, Adriano Aguzzi , and Akiko Iwasaki

Lack of association between pandemic chilblains and SARS-CoV-2 infection

https://doi.org/10.1073/pnas.2122090119

Published

25-Feb-22

Study

https://www.pnas.org/doi/full/10.1073/pnas.2122090119

Chilblain diagnoses have increased during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and have been attributed to viral infection and a subsequent robust antiviral immune response. As a result, providers have managed these cases differently than idiopathic chilblains, which are associated with cold exposure. The relationship between pandemic chilblains and SARS-CoV-2 infection, however, remains unclear as most patients do not test positive for SARS-CoV-2–specific PCR or antibodies. To better understand this disconnect, we enrolled cases of pandemic chilblains in a study and performed detailed immune profiling of antibody and T cell responses. Additionally, we compared immunohistochemical staining of pandemic chilblains with prepandemic tissues. Our results do not support SARS-CoV-2 as the cause of the increased chilblain incidence.
Abstract
An increased incidence of chilblains has been observed during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and attributed to viral infection. Direct evidence of this relationship has been limited, however, as most cases do not have molecular evidence of prior SARS-CoV-2 infection with PCR or antibodies. We enrolled a cohort of 23 patients who were diagnosed and managed as having SARS-CoV-2–associated skin eruptions (including 21 pandemic chilblains [PC]) during the first wave of the pandemic in Connecticut. Antibody responses were determined through endpoint titration enzyme-linked immunosorbent assay and serum epitope repertoire analysis. T cell responses to SARS-CoV-2 were assessed by T cell receptor sequencing and in vitro SARS-CoV-2 antigen-specific peptide stimulation assays. Immunohistochemical and PCR studies of PC biopsies and tissue microarrays for evidence of SARS-CoV-2 were performed. Among patients diagnosed and managed as “covid toes” during the pandemic, we find a percentage of prior SARS-CoV-2 infection (9.5%) that approximates background seroprevalence (8.5%) at the time. Immunohistochemistry studies suggest that SARS-CoV-2 staining in PC biopsies may not be from SARS-CoV-2. Our results do not support SARS-CoV-2 as the causative agent of pandemic chilblains; however, our study does not exclude the possibility of SARS-CoV-2 seronegative abortive infections.

Skin

3235

OO128

Annie E. Allisan-Arrighi BA,Sarah K. Rapoport MD,Benjamin M. Laitman MD, PhD,Rohini Bahethi BS,Matthew Mori MD,Peak Woo MD,Eric Genden MD, MBA,Mark Courey MD,Diana N. Kirke MD, MPhil

Long-term upper aerodigestive sequelae as a result of infection with COVID-19

https://doi.org/10.1002/lio2.763

Published

9-Mar-22

Study

https://onlinelibrary.wiley.com/doi/full/10.1002/lio2.763

Objectives
Respiratory, voice, and swallowing difficulties after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may result secondary to upper airway disease from prolonged intubation or mechanisms related to the virus itself. We examined a cohort who presented with new laryngeal complaints following documented SARS-CoV-2 infection. We characterized their voice, airway, and/or swallowing symptoms and reviewed the clinical course of their complaints to understand how the natural history of these symptoms relates to COVID-19 infections.
Methods
Retrospective review of patients who presented to our department with upper aerodigestive complaints as sequelae of prior infection with, and management of, SARS-CoV-2.
Results
Eighty-one patients met the inclusion criteria. Median age was 54.23 years (±17.36). Most common presenting symptoms were dysphonia (n = 58, 71.6%), dysphagia/odynophagia (n = 16, 19.75%), and sore throat (n = 9, 11.11%). Thirty-one patients (38.27%) presented after intubation. Mean length of intubation was 16.85 days (range 1–35). Eighteen patients underwent tracheostomy and were decannulated after an average of 70.69 days (range 23–160). Patients with history of intubation were significantly more likely than nonintubated patients to be diagnosed with a granuloma (8 vs. 0, respectively, p < .01). Fifty patients (61.73%) were treated for SARS-CoV-2 without requiring intubation and were significantly more likely to be diagnosed with muscle tension dysphonia (19 vs. 1, p < .01) and laryngopharyngeal reflux (18 vs. 1, p < .01).
Conclusion
In patients with persistent dyspnea, dysphonia, or dysphagia after recovering from SARS-CoV-2, early otolaryngology consultation should be considered. Accurate diagnosis and prompt management of these common underlying etiologies may improve long-term patient outcomes.

Oropharyngeal organ

3236

OO129

Emre Urhan, Zuleyha Karaca, Canan Sehit Kara, Zeynep Ture Yuce & Kursad Unluhizarci

The potential impact of COVID-19 on thyroid gland volumes among COVID-19 survivors

https://doi.org/10.1007/s12020-022-03019-6

Published

3-Mar-22

Study

https://link.springer.com/article/10.1007/s12020-022-03019-6

Purpose
Data about the effects of COVID-19 on the endocrine system are increasing over time. In the present study, we investigated the effects of COVID-19 on the thyroid gland among COVID-19 survivors by comparing them with healthy subjects.
Methods
Adult COVID-19 survivors who were managed and followed up in the Infectious Disease clinic were asked to participate in this study. COVID-19 survivors were recruited via a convenience sampling and those who agreed to participate in this study were seen by endocrinologists for assessments. The blood tests were obtained for thyroid antibodies and thyroid function tests. Thyroid ultrasonography (USG) was done by the same physician. The ellipsoid formula was used for the calculation of thyroid gland volume.
Results
64 adult COVID-19 survivors and 70 control subjects were enrolled in the study. The COVID-19 survivors were evaluated at median 5.7 months (IQR: 4–6.5) (range: 2–7 months) after acute infection. The mean thyroid gland volume was significantly lower in COVID-19 survivors (10.3 ± 3.4 mL) than in the controls (14 ± 5.3 mL) (p = 0.001). There was no significant difference in free triiodothyronine (fT3), free thyroxine (fT4) and thyroid-stimulating hormone (TSH) levels between the groups. Among the twelve patients who had thyroid function evaluated in acute COVID-19, fT3 values were lower in acute COVID-19 than at the time of USG evaluation (3.04 ± 0.41 vs 3.47 ± 0.31 pg/mL), (p = 0.02). Among COVID-19 survivors, mild TSH elevation was detected in 4 (6.2%) patients and all of the other COVID-19 survivors (93.7%) were euthyroid.
Conclusions
At 6 months after acute COVID, COVID-19 survivors had smaller thyroid gland volume than healthy controls, and only a few of the COVID-19 survivors had abnormal thyroid function.

Thyroid gland

3237

OO130

Ying Wang,
a Guojun Wu,
a,b Liping Zhao,
a,b Weizheng Wang

Nutritional Modulation of Gut Microbiota Alleviates Severe
Gastrointestinal Symptoms in a Patient with Post-Acute
COVID-19 Syndrome

Published

31-Jan-22

Case Report

https://journals.asm.org/doi/pdf/10.1128/mbio.03801-21

ABSTRACT With the increase in total coronavirus disease 2019 (COVID-19) infection cases, post-acute COVID-19 syndrome, defined as experiencing ongoing health problems 4 or more weeks after the first severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) infection, has become a new arising public health concern. As part of post-acute COVID-19 syndrome, gastrointestinal symptoms might be associated with dysbiosis of the gut microbiota, which has the potential to become a target for intervention. In this study, a patient with post-acute COVID-19 syndrome with long-lasting severe gastrointestinal symptoms was provided 2-month expanded access to a high-fiber formula with investigational new drug (IND) status developed to alleviate COVID-19-related symptoms by modulating the gut microbiota. Symptoms including severe “loss of appetite,” palpitation, and anxiety were significantly alleviated by the end of the intervention. The medication dosage for controlling nausea decreased during the intervention. The serum lipid profile, insulin level, and leptin level were improved compared to the baseline values. Significant structural changes of the patient’s gut microbiota and reduced microbial fermentation activity in the small intestine were found during the intervention. Eighteen amplicon sequence variants (ASVs) of the V4 region of the 16S rRNA gene significantly responded to this nutritional intervention. Six out of the 18 ASVs were also found to be negatively correlated with symptom severity/medication dosage. Five of the six ASVs (ASV0AKS_Oscillibacter, ASV009F_Anaerofustis, ASV02YT_Blautia, ASV07LA_Blautia, and ASV0AM6_Eubacterium hallii) were potential short-chain fatty acid (SCFA)-producing bacteria, which might be associated with the alleviation of symptoms. Our study indicates the feasibility of alleviating gastrointestinal symptoms in patients with post-acute COVID-19 syndrome by way of nutritional modulation of their gut microbiota. IMPORTANCE It has become evident that the care of patients with COVID-19 does not end at the time of negative SARS-CoV-2 detection, as the number of patients with post-acute COVID-19 syndrome increases with an ever-increasing total infected patient population. This case report shows the possibility of alleviating the gastrointestinal symptoms of post-acute COVID-19 syndrome via microbiota-targeted nutritional intervention. As a promising strategy, it might not only improve the quality of life of patients but also reduce the burden to the public health system when the end of the COVID-19 pandemic is not in sight.

Gut

3238

OO131

Joshua Rui Yen Wong, Luke Zhu, Sachi Shah, Srinivas Gadikoppula

A Case of Axial Spondyloarthritis Triggered by SARS-CoV-2 Infection

https://doi.org/10.7759/cureus.22860

Published

5-Mar-22

Case Report

https://www.cureus.com/articles/85668-a-case-of-axial-spondyloarthritis-triggered-by-sars-cov-2-infection

Ever since the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there has been a noticeable change in atypical presentations of several rheumatological diseases following COVID-19 infections. In this case report, we present a case of SARS-CoV-2-induced axial and peripheral spondyloarthritis. This case highlights the possibility of SARS-CoV-2 infection accelerating the onset of autoimmune diseases such as axial spondyloarthritis. Although uncommon, these cases warrant a referral to the rheumatologist for appropriate diagnosis and management. This case also highlights the need for further research on the mechanisms behind the viral interaction of SARS-CoV-2 infections with the host immune system, especially about accelerating the onset of autoimmune diseases.

Joints

3239

OO132

Patrick J. Madden, Yanique Thomas, Robert V. Blair, Sadia Samer, Mark Doyle, Cecily C. Midkiff, Mark E. Becker, Muhammad S. Arif, Michael D. McRaven, Lacy M. Simons, Ann M. Carias, Elena Martinelli, Ramon Lorenzo-Redondo, Judd F Hultquist, Francois J. Villinger, Ronald S. Veazey, View ProfileThomas J. Hope

An immunoPET probe to SARS-CoV-2 reveals early infection of the male genital tract in rhesus macaques

https://doi.org/10.1101/2022.02.25.481974

pre-print

28-Feb-22

Study

https://www.biorxiv.org/content/10.1101/2022.02.25.481974v1.full

Because of the recognized systemic nature of SARS-CoV-2 infection, a non-invasive and unbiased method is needed to clarify its spatiotemporal dynamics in vivo after transmission. We recently developed a probe based on the anti-SARS-CoV-2 spike antibody CR3022 to study SARS-CoV-2 pathogenesis in vivo. Herein, we describe its use in immunoPET to investigate SARS-CoV-2 infection of rhesus macaques. Using PET/CT imaging of macaques at different times post-SARS-CoV-2 inoculation, we demonstrate that the 64Cu-labelled CR3022-F(ab’)2 probe targeting the spike protein of SARS-CoV-2 can be used to study the dynamics of infection within the respiratory tract and uncover novel sites of infection. Differences in lung pathology between infection with the WA1 isolate and the delta variant were readily observed using immunoPET and corroborated CT lung pathology. The ability of the probe to illuminate lung- associated pathology demonstrates its specificity and function to detect infection in PET scan. The 64Cu-CR3022-probe also demonstrated dynamic changes occurring between 1- and 2-weeks post-infection. Remarkably, a robust signal was seen in the male genital tract (MGT) of all three animals studied. Infection of the MGT was validated by immunofluorescence imaging of infected cells in the testicular and penile tissue and severe pathology was observed in the testes of one animal at 2-weeks post-infection. The results presented here underscore the utility of using immunoPET to study the dynamics of SARS-CoV-2 infection to understand its pathogenicity and discover new anatomical sites of viral replication. We provide direct evidence for SARS-CoV-2 infection of the MGT in rhesus macaques revealing the possible pathologic outcomes of viral replication at these sites.

Male reproductive system

3240

OO133

Bintao Hu,# 1 , 2 , # Kang Liu,# 1 , 2 , # Yajun Ruan, 1 , 2 Xian Wei, 1 , 2 Yue Wu, 1 , 2 Huan Feng, 1 , 2 Zhiyao Deng, 1 , 2 Jihong Liu, 1 , 2 and Tao Wangcorresponding author 1 , 2

Evaluation of mid- and long-term impact of COVID-19 on male fertility through evaluating semen parameters

https://dx.doi.org/10.21037%2Ftau-21-922

Published

1-Feb-22

Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8899150/

The distribution of angiotensin converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) from bioinformatics evidence, the autopsy report for COVID-19 and the published study on sperm quality indicated COVID-19 could have a negative impact on male fertility. However, whether the negative impact of COVID-19 on male fertility is persistent remains unknown, which requires long-term follow-up investigation.
Methods
Semen samples were collected from 36 male COVID-19 patients with a median recovery time of 177.5 days and 45 control subjects. Then, analysis of sperm quality and alterations of total sperm number with recovery time were performed.
Results
There was no significant difference in semen parameters between male recovered patients and control subjects. And the comparisons of semen parameters between first follow-up and second follow-up revealed no significant difference. In addition, we explored the alterations of sperm count with recovery time. It showed that the group with recovery time of ≥120 and <150 days had a significantly lower total sperm number than controls while the other two groups with recovery time of ≥150 days displayed no significance with controls, and total sperm number showed a significant decline after a recovery time of 90 days and an improving trend after a recovery time of about 150 days.
Conclusions
The sperm quality of COVID-19 recovered patients improved after a recovery time of nearly half a year, while the total sperm number showed an improvement after a recovery time of about 150 days. COVID-19 patients should pay close attention to the quality of semen, and might be considered to be given medical interventions if necessary within about two months after recovery, in order to improve the fertility of male patients as soon as possible.

Male reproductive system

3241

OO134

Samir Ahmed Mirza 1,Abdul Ahad Ehsan Sheikh 2,Michaela Barbera 3,Zainab Ijaz 4 ,Muhammad Ali Javaid 1,Rahul Shekhar 3,Suman Pal 3 andAbu Baker Sheikh

COVID-19 and the Endocrine System: A Review of the Current Information and Misinformation

https://doi.org/10.3390/idr14020023

Published

11-Mar-22

Review

https://www.mdpi.com/2036-7449/14/2/23/htm

Coronavirus disease 2019 (COVID-19) infection primarily involves the respiratory system but has many noteworthy extra pulmonary manifestations as well. We write this review to highlight the basis of some pathophysiological mechanisms of COVID-19 infection-induced endocrine dysfunction. Different scientific databases and institutional websites were searched to collect and consolidate the most up-to-date data relating to COVID-19 infection and endocrine systems. Hypopituitarism, central diabetes insipidus, SIADH, thyroid abnormalities, hyperglycemia, adrenal insufficiency, orchitis and alteration in sperm morphology have been reported in case reports of patients with COVID-19 infection. Data focusing on COVID-19 vaccination was also searched to summarize the effect, if any, on the endocrine system. Endocrinopathies noted post COVID-19 vaccination, including cases of adrenal hemorrhage, new onset Type II Diabetes Mellitus and subacute thyroiditis, are also discussed in this review. This review calls attention to the misinformation relating to COVID-19 vaccination with supposed endocrine effects such as infertility and problems with pregnancy. Rebutting these misconceptions can help increase compliance and maximize COVID-19 vaccination to the public.

Endocrine system

3242

OO135

YanXieMPHacdZiyadAl-AlyMDabdef

Risks and burdens of incident diabetes in long COVID: a cohort study

https://doi.org/10.1016/S2213-8587(22)00044-4

Published

21-Mar-22

Study

https://www.thelancet.com/journals/landia/article/PIIS2213-8587(22)00044-4/fulltext

Background
There is growing evidence suggesting that beyond the acute phase of SARS-CoV-2 infection, people with COVID-19 could experience a wide range of post-acute sequelae, including diabetes. However, the risks and burdens of diabetes in the post-acute phase of the disease have not yet been comprehensively characterised. To address this knowledge gap, we aimed to examine the post-acute risk and burden of incident diabetes in people who survived the first 30 days of SARS-CoV-2 infection.
Methods
In this cohort study, we used the national databases of the US Department of Veterans Affairs to build a cohort of 181 280 participants who had a positive COVID-19 test between March 1, 2020, and Sept 30, 2021, and survived the first 30 days of COVID-19; a contemporary control (n=4 118 441) that enrolled participants between March 1, 2020, and Sept 30, 2021; and a historical control (n=4 286 911) that enrolled participants between March 1, 2018, and Sept 30, 2019. Both control groups had no evidence of SARS-CoV-2 infection. Participants in all three comparison groups were free of diabetes before cohort entry and were followed up for a median of 352 days (IQR 245–406). We used inverse probability weighted survival analyses, including predefined and algorithmically selected high dimensional variables, to estimate post-acute COVID-19 risks of incident diabetes, antihyperglycaemic use, and a composite of the two outcomes. We reported two measures of risk: hazard ratio (HR) and burden per 1000 people at 12 months.
Findings
In the post-acute phase of the disease, compared with the contemporary control group, people with COVID-19 exhibited an increased risk (HR 1·40, 95% CI 1·36–1·44) and excess burden (13·46, 95% CI 12·11–14·84, per 1000 people at 12 months) of incident diabetes; and an increased risk (1·85, 1·78–1·92) and excess burden (12·35, 11·36–13·38) of incident antihyperglycaemic use. Additionally, analyses to estimate the risk of a composite endpoint of incident diabetes or antihyperglycaemic use yielded a HR of 1·46 (95% CI 1·43–1·50) and an excess burden of 18·03 (95% CI 16·59–19·51) per 1000 people at 12 months. Risks and burdens of post-acute outcomes increased in a graded fashion according to the severity of the acute phase of COVID-19 (whether patients were non-hospitalised, hospitalised, or admitted to intensive care). All the results were consistent in analyses using the historical control as the reference category.

Interpretation
In the post-acute phase, we report increased risks and 12-month burdens of incident diabetes and antihyperglycaemic use in people with COVID-19 compared with a contemporary control group of people who were enrolled during the same period and had not contracted SARS-CoV-2, and a historical control group from a pre-pandemic era. Post-acute COVID-19 care should involve identification and management of diabetes.

Pancreas

3243

OO136

Montes-Ibarra M1, Oliveira C2, Orsso C3, Landi F4, Marzetti E5, Prado C6

The Impact of Long COVID-19 on Muscle Health

https://dx.doi.org/10.1016%2Fj.cger.2022.03.004

Published

21-Mar-22

Review

https://europepmc.org/article/pmc/pmc8934728

Coronavirus disease 2019 (COVID-19) negatively impacts several organs and systems weeks or months after initial diagnosis, a condition defined as post-acute sequelae of COVID-19 or long COVID. Skeletal muscle can be affected, leading to fatigue, lower mobility, weakness, and poor physical performance. Older adults are at increased risk of developing musculoskeletal symptoms during long COVID. Systemic inflammation, physical inactivity, and poor nutritional status are some of the mechanisms leading to muscle dysfunction in individuals with long COVID. Current evidence suggests that long COVID negatively impacts body composition, muscle function, and quality of life. Muscle mass and function assessments can contribute towards the identification, diagnosis, and management of poor muscle health resulting from long COVID.

Muscles

3244

OO137

K M Venkat Narayan
Lisa R Staimez

Rising diabetes diagnosis in long COVID

https://doi.org/10.1016/S2213-8587(22)00078-X

Published

21-Mar-22

COMMENT

https://www.thelancet.com/journals/landia/article/PIIS2213-8587(22)00078-X/fulltext

A few reports have raised the possibility that COVID-19 could increase the risk of type 2 diabetes.1, 2 In The Lancet Diabetes & Endocrinology, Xie and Al-Aly3 offer further evidence for the increased risk of diabetes beyond the first 30 days of infection (post-acute phase) by analysing the US Department of Veterans Affairs national health-care records of those who survived the first 30 days after a positive COVID-19 test. These data raise important questions about the relationship between COVID-19 and diabetes concerning causality, biological mechanisms, and implications for clinical care and public health.
Incidence of diabetes and antihyperglycaemic medication use was compared between 181 280 COVID-19 survivors, 4 118 441 contemporary controls without COVID-19 infection from the same year, and 4 286 911 historical controls from 2017. Diabetes was defined by International Classification of Diseases-10 diagnosis codes or an HbA1c of more than 6·4% (46 mmol/mol). The authors used inverse probability weighted survival analyses, including predefined and algorithmically selected high dimensional variables and reported two measures of risk; hazard ratio (HR) and burden per 1000 people at 12 months.

Pancreas

3245

OO231

Enver Mirza, Selman Belviranli, Ali Osman Gundogan, Mehmet Adam & Refik Oltulu

Quantitative assessment of the effect of SARS-CoV-2 on the corneal sub-basal nerve plexus of post-COVID-19 patients using in vivo confocal microscopy

https://doi.org/10.1038/s41433-022-02018-1

Published

23-Mar-22

Study

https://www.nature.com/articles/s41433-022-02018-1

Objectives
To investigate whether SARS-CoV-2 causes morphological changes in the corneal sub-basal nerve plexus (CSNP) of post-COVID-19 patients using in vivo confocal microscopy (IVCM).
Methods
A total of 70 participants were included in the study and were divided into three groups. Post-COVID-19 patients with neurological manifestations were considered Group 1 (n = 24), and post-COVID-19 patients without neurological manifestations were considered Group 2 (n = 24). Healthy control participants were considered Group 3 (n = 22). The parameters of the CSNP, including nerve fibre density (NFD), nerve branch density (NBD), and nerve fibre length (NFL), were investigated in all participants using IVCM. Additionally, corneal sensitivity was tested by corneal esthesiometry.
Results
The mean NFD, NBD, and NFL values of Group 1 (16.12 ± 4.84 fibre/mm2, 27.97 ± 9.62 branch/mm2, and 11.60 ± 2.89 mm/mm2) were significantly lower than those of Group 2 (19.55 ± 3.01 fibre/mm2, 40.44 ± 7.16 branch/mm2, and 15.92 ± 2.08 mm/mm2) and Group 3 (25.24 ± 3.75 fibre/mm2, 44.61 ± 11.80 branch/mm2, and 17.76 ± 3.32 mm/mm2) (p < 0.05 for all). Except the mean NFD value (p < 0.001), there were no significant differences in terms of the mean NBD and NFL values between Group 2 and Group 3 (p = 0.445, p = 0.085). The value of the mean corneal sensitivity was significantly higher in Group 3 (59.09 ± 1.97 mm) compared to Group 1 (55.21 ± 1.02 mm) and Group 2 (55.28 ± 1.18 mm) (p < 0.001, p < 0.001) but there was no significant difference between Group 1 and Group 2 (p = 1.000).
Conclusion
In post-COVID-19 patients, the mean parameters of CSNP were lower than in the control group. These differences were more pronounced in patients who had neurological manifestations of COVID-19.

Eyes

3246

OO139

Tanja Paul, Stephan Ledderose, Harald Bartsch, Na Sun, Sarah Soliman, Bruno Märkl, Viktoria Ruf, Jochen Herms, Marcel Stern, Oliver T. Keppler, Claire Delbridge, Susanna Müller, Guido Piontek, Yuki Schneider Kimoto, Franziska Schreiber, Tracy Ann Williams, Jens Neumann, Thomas Knösel, Heiko Schulz, Ria Spallek, Matthias Graw, Thomas Kirchner, Axel Walch & Martina Rudelius

Adrenal tropism of SARS-CoV-2 and adrenal findings in a post-mortem case series of patients with severe fatal COVID-19

https://doi.org/10.1038/s41467-022-29145-3

Published

24-Mar-22

Study

https://www.nature.com/articles/s41467-022-29145-3

Progressive respiratory failure and hyperinflammatory response is the primary cause of death in the coronavirus disease 2019 (COVID-19) pandemic. Despite mounting evidence of disruption of the hypothalamus-pituitary-adrenal axis in COVID-19, relatively little is known about the tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to adrenal glands and associated changes. Here we demonstrate adrenal viral tropism and replication in COVID-19 patients. Adrenal glands showed inflammation accompanied by inflammatory cell death. Histopathologic analysis revealed widespread microthrombosis and severe adrenal injury. In addition, activation of the glycerophospholipid metabolism and reduction of cortisone intensities were characteristic for COVID-19 specimens. In conclusion, our autopsy series suggests that SARS-CoV-2 facilitates the induction of adrenalitis. Given the central role of adrenal glands in immunoregulation and taking into account the significant adrenal injury observed, monitoring of developing adrenal insufficiency might be essential in acute SARS-CoV-2 infection and during recovery.

Adrenal glands

3247

OO232

Mojtaba Abrishami ,1 Kiana Hassanpour ,2 SeyedehMaryam Hosseini ,1 Nasser Shoeibi,1 Mohammad Reza Ansari-Astaneh ,1 Zahra Emamverdian,1 Bahareh Gharib,1 Nasibeh Amini,1 and Majid Abrishami1

Peripapillary Nerve Fiber Layer Thickness and Optic Nerve Head Parameters in Patients Recovered from COVID-19: A Longitudinal Study

https://doi.org/10.1155/2022/4643973

Published

29-Mar-22

Study

https://www.hindawi.com/journals/joph/2022/4643973/

To quantify the longitudinal changes of the optic nerve head (ONH) parameters and peripapillary retinal nerve fiber layer (pRNFL) thickness in patients recovered from coronavirus disease 2019 (COVID-19) using spectral-domain optical coherence tomography (OCT) analysis. Materials and Methods. In an observational longitudinal study, in patients recovered from COVID-19, ONH OCT images were recorded at least two weeks after recovery from the systemic disease as the baseline and after one and three-month follow-up. Ganglion cell complex (GCC) analysis, ONH parameters, and pRNFL thickness changes were measured. Results. A total of 36 eyes from 18 recovered COVID-19 patients including eleven (61.2%) females were studied. The average age was 35.5 ± 7.5 years. The pRNFL thickness in the nasal lower sector significantly decreased from 77 ± 18 μm in the first post-COVID-19 month to 74 ± 10 μm in the third month (). The average, superior, and inferior pRNFL thickness remained unchanged. The average cup volume significantly decreased from 0.27 ± 0.15 mm3 at baseline to 0.19 ± 0.15 mm3 in the third post-COVID-19 visit (). In terms of ONH morphologies including rim, disc and cup to disc area, and the vertical and horizontal ratio, the changes were not significant over the 3-month study period. Focal loss volume and global loss volume values were not changed significantly. Conclusion. Localized defect in the nasal lower sector of pRNFL is observed in 3-month post-recovery from COVID-19. Larger studies with longer follow-ups are required to reveal the exact changes in ONH parameters.

Eyes

3248

OO141

Hadar Meringer & Saurabh Mehandru

Gastrointestinal post-acute COVID-19 syndrome

https://doi.org/10.1038/s41575-022-00611-z

Published

5-Apr-22

Article

https://www.nature.com/articles/s41575-022-00611-z

The definition of gastrointestinal involvement in post-acute COVID-19 syndrome, its frequency and its pathophysiology are still not completely understood. Here, we discuss the emerging evidence supporting immunological signatures and the unique nature of the gastrointestinal tract in this syndrome.

Intestines

3249

OO142

QiuyiTangBS1*LinGaoPhD2*ZhihuiTongMD2WeiqinLiMD12

Hyperlipidemia, COVID-19 and acute pancreatitis: a tale of three entities

https://doi.org/10.1016/j.amjms.2022.03.007

Published

4-Apr-22

Review

https://www.sciencedirect.com/science/article/pii/S000296292200132X

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the ongoing pandemic of coronavirus disease 2019 (COVID-19), which presented as not only respiratory symptoms, but various digestive manifestations have also been recognized, including pancreatic injury and acute pancreatitis (AP). The underlying mechanism is still unclear. Hypertriglyceridemia has become one of the leading causes of AP in recent years and hyperlipidemia is highly reported in COVID-19 cases. The current narrative review aimed to explore the associations between AP, COVID-19 and hyperlipidemia. Substantial cases of COVID-19 patients complicated with AP were reported, while the incidence of AP in the COVID-19 population was relatively low. Hyperlipidemia was common in COVID-19 patients with a pooled incidence of 32.98%. Hyperlipidemia could be a mediating factor in the pathogenesis of AP in COVID-19 patients. Further studies are warranted to clarify the relationship among AP, lipid metabolism disorders and COVID-19.

Pancreas

3250

OO143

Yukichika Yamamoto,Yuki Otsuka ,Naruhiko Sunada,Kazuki Tokumasu,Yasuhiro Nakano ,Hiroyuki Honda,Yasue Sakurada,Hideharu Hagiya ,Yoshihisa Hanayama andFumio Otsuka *

Detection of Male Hypogonadism in Patients with Post COVID-19 Condition

https://doi.org/10.3390/jcm11071955

Published

31-Mar-22

Study

https://www.mdpi.com/2077-0383/11/7/1955/htm

The pathogenesis and prognosis of post COVID-19 condition have remained unclear. We set up an outpatient clinic specializing in long COVID in February 2021 and we have been investigating post COVID-19 condition. Based on the results of our earlier study showing that “general fatigue” mimicking myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is the most common symptom in long COVID patients, a retrospective analysis was performed for 39 male patients in whom serum free testosterone (FT) levels were measured out of 61 male patients who visited our clinic. We analyzed the medical records of the patients’ backgrounds, symptoms and laboratory results. Among the 39 patients, 19 patients (48.7%) met the criteria for late-onset hypogonadism (LOH; FT < 8.5 pg/mL: LOH group) and 14 patients were under 50 years of age. A weak negative correlation was found between age and serum FT level (r = −0.301, p = 0.0624). Symptoms including general fatigue, anxiety, cough and hair loss were more frequent in the LOH group than in the non-LOH group (FT ≥ 8.5 pg/mL). Among various laboratory parameters, blood hemoglobin level was slightly, but significantly, lower in the LOH group. Serum level of FT was positively correlated with the levels of blood hemoglobin and serum total protein and albumin in the total population, whereas these interrelationships were blurred in the LOH group. Collectively, the results indicate that the incidence of LOH is relatively high in male patients, even young male patients, with post COVID-19 and that serum FT measurement is useful for revealing occult LOH status in patients with long COVID.

Testicles

3251

OO233

K. Thiran Jayasundera, MD, MS1; Rebhi O. Abuzaitoun, MD1; David C. Musch, PhD, MPH1,2

COVID-19 Diagnosis and Incidence of Retinal Thromboembolism

http://jamanetwork.com/article.aspx?doi=10.1001/jamaophthalmol.2022.0666

Published

14-Apr-22

Invited commentary

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2790986

Modjtahedi and colleagues’ access to the large Kaiser Permanente database has revealed an interesting and potentially causal association between COVID-19 infection and the subsequent incidence of retinal vascular occlusions.1 COVID-19 can cause a wide array of systemic complications (arrhythmias, secondary infections, coagulopathies)2 and ocular manifestations (cranial nerve palsies, conjunctivitis, retinal microvascular changes).3 Vascular damage underlies the damage caused by COVID-19 to multiple organs via 2 main mechanisms: disseminated intravascular coagulation–like reaction leading to hypercoagulability and direct viral infection of the endothelial cells leading to a vasculitis-like picture.4 Furthermore, patients with COVID-19 are predisposed to embolism formation due to intravascular coagulation and hypoxia.5 The combination of COVID-19’s vascular damage and higher embolism formation tendencies can hypothetically increase the risk of retinal vascular occlusion. Previous publications reporting retinal vascular occlusion (artery6 or vein7) secondary to COVID-19 infection have been case reports, which lack a study design (eg, case-control or cohort studies) wherein hypothesis testing is used to evaluate this association in a group of individuals.
In order to test for a causal association between exposure (COVID-19) and disease (retinal vascular occlusion), the following 9 aspects (known as the Bradford Hill criteria) should be taken into account: strength of association, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy.
In the study by Modjtahedi et al,1 the retrospective cohort study design does assess temporality, as all patients who were diagnosed with COVID-19 were followed up for 6 months to detect the incidence rate of retinal vascular occlusion postinfection. Furthermore, there is support from case studies reporting occurrence of retinal vascular occlusion after infection with COVID-19.6,7
The strength of association was assessed by the incidence rate ratio, which measures the increment of retinal vascular occlusion incidence from pre– to post–COVID-19 infection. None of the previous publications focusing on retinal vascular occlusion secondary to COVID-19 involved a group of individuals; therefore, none had a measure for strength of association.
Biological plausibility exists between the cause and effect. COVID-19 leads to vascular damage through disseminated intravascular coagulation and a vasculitis-like reaction. COVID-19 also leads to a higher tendency of thrombus formation through intravascular coagulation and hypoxia. Vascular damage and thrombus formation are risk factors that can lead to retinal vascular occlusion.
There is consistency in reporting of this association as findings of this retrospective cohort study are consistent with previous published case reports of retinal vascular occlusion attributed to COVID-19.
Experimental evidence is lacking and would require the study of COVID-19 infection in large animal models.
The dose-response association between exposure and disease has not been thoroughly examined. One would expect that a severe COVID-19 infection would lead to more vascular occlusions; however, this may be negated by the anticoagulation regimens initiated in hospitalized patients with severe COVID-19.
In conclusion, the retrospective cohort study by Modjtahedi et al further strengthens the association between COVID-19 and retinal vascular occlusion. However, the strength and consistency of this association would be enhanced by further evaluation including studies that access other large databases now available, to provide a robust basis for causality and help determine recommended strategies for prevention and surveillance.

Eyes

3252

OO234

Emilio Pedrotti, MD1; Erika Bonacci, MD1; Marco Ligozzi, MD2; Jacopo Bonetto, MD3; Raphael Kilian, MD1; Davide Gibellini, MD2; Giorgio Marchini, MD1

Prevalence of and Short-term Changes in Conjunctival Manifestations Among Patients With SARS-CoV-2 Infection

https://doi.org/10.1001/jamanetworkopen.2022.7734

Published

19-Apr-22

Study

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2791299

Introduction
Studies suggest that SARS-CoV-2 can infect the conjunctival mucosa.1-4 Signs of ocular involvement have been reported in 11% to 32% of SARS-CoV-2 cases, with a rate of conjunctival swab (CS) positivity from 0% to 57%. Previous studies lacked a predetermined sample size, relied on questionnaires and/or interviews, or analyzed nonhospitalized and hospitalized patients receiving anti-inflammatory agents. In this study, we assessed the prevalence of SARS-CoV-2–related conjunctival manifestations and CS positivity on hospital admission (T1) and 3 days thereafter (T2) for a predetermined sample of patients not receiving anti-inflammatory treatment.
Methods
This cohort study was approved by the ethics committees of 3 tertiary hospitals (Hospital of Verona, Hospital of Meran, and Hospital of Bozen). Participants provided written informed consent. The study followed the STROBE reporting guideline.
We enrolled hospitalized patients with SARS-CoV-2 infection who (1) had not received previous or concomitant antiviral or corticosteroid treatment or any topical ocular treatment, (2) had no eyelid pathologies, and (3) were not receiving continuous positive-airway pressure treatment. At T1 and T2, 2 ophthalmologists performed an ocular surface examination (OSE) and CS sampling of both eyes separately. Conjunctival redness (CR) was graded with the Efron scale; other conjunctival signs and symptoms (OCSSs) were considered together. Real-time polymerase chain reaction was used to confirm SARS-CoV-2 infection and exclude other conjunctival pathogens.
fter T1, all patients received hyaluronic acid artificial tears (ATs) twice daily in the clinically worse eye. Non preservative-free (NPF) ATs with povidone iodine (Medivis) were administered at 1 hospital and preservative-free (PF) ATs (SIFI) were administered at 2 hospitals. We used the McNemar-Bowker test to compare CR and OCSSs between T1 and T2 and between AT-treated and nontreated eyes. We used a Fisher exact test to compare CS positivity and OSE for the NPF- and PF-AT formulations. Multivariate analysis was performed using ordinal logistic regression. P < .05 was considered significant.
Results
Of the 144 patients enrolled, 2 had a positive CS result only for bocavirus and parainfluenza at T1 and were excluded. Of the 142 patients evaluated, 92 (64.8%) were men and 50 (35.2%) were women (mean [SD] age, 71 [18.2] years).
Eighteen patients (12.7%) had a positive CS result; 64 (45.1%) had at least 1 clinical finding (eg, CR, most commonly grade 2) (Table 1). The CR grade was significantly higher in eyes with CS positivity (P < .001).
At T2, 12 patients (8.5%) had a positive CS result (Table 2). There were 5 additional patients in the non-AT group (P = .10) and 14 fewer patients in the AT group (P = .001). Redness worsened among nontreated eyes (P = .001), whereas both CR and OCSSs improved among AT-treated eyes (both P < .001). Compared with PF-ATs, these results suggest that NPF-ATs were 1.13 times more effective at improving CR and were the only formulation in this study able to reduce OCSS and CS positivity.
Discussion
The variability of prevalence data in the literature might be due to a lack of predetermined samples and wide inclusion criteria. We applied strict inclusion criteria and assessed the sample size and found that the prevalence of conjunctival manifestations and CS positivity among patients with SARS-CoV-2 was 45.1% and 12.7%, respectively. This discrepancy could be associated with the inflammatory response related to systemic viral infections. The most frequent conjunctival manifestation was CR, a key sign of viral conjunctivitis. However, because OSE was performed at the patient bedside and other typical findings (eg, conjunctival membranes or pseudomembranes and follicles) were not assessed, a definitive diagnosis of viral conjunctivitis could not be made. Study limitations include restricted follow-up and a lack of definitive diagnoses.
These results suggest a concordance between CR grade and CS positivity. Although the difference in prevalence between the AT-treated groups could have affected the statistical analysis, our findings suggest that the virucidal activity of povidone iodine within NPF-ATs may be associated with conjunctival manifestation improvement and CS negativity among patients with SARS-CoV-2 infection.5,6

Eyes

3253

OO146

Francesco Paneni, Carlo Patrono

Increased risk of incident diabetes in patients with long COVID

https://doi.org/10.1093/eurheartj/ehac196

Published

13-Apr-22

Study

https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehac196/6568142?login=true

Key Points
Mounting evidence indicates that long COVID may lead to a wide range of post-acute outcomes, including diabetes. The present study1 examined the post-acute risk and burden of incident diabetes in people who survived the first 30 days of SARS-CoV-2 infection.
The national healthcare databases from the United States Veterans Health Administration (VHA) system were employed to build a cohort of 181 280 participants who had a positive COVID-19 test between March 2020 and September 2021. Two controls groups with no evidence of SARS-CoV-2 infection were included in the study: a contemporary control (n = 4 118 441) that enrolled participants between March 2020 and September 2021; and a historical control (n = 4 286 911) that enrolled participants between March 2018 and September 2019. All participants were free of diabetes before cohort entry and were followed up for a median of 352 days. The association of COVID-19 with new-onset diabetes was expressed by two measures of risk: hazard ratio (HR) and burden per 1000 people at 12 months.
Compared with the contemporary control group, people with COVID-19 had an increased risk [HR, 1.40; 95% confidence interval (CI), 1.36–1.44] and excess burden (13.5; 95% CI, 12.1–14.8 per 1000 people at 12 months) of incident diabetes; and an increased risk (1.85; 1.78–1.92) and excess burden (12.4; 11.4–13.4) of incident antihyperglycaemic medication use. The risk of a composite endpoint of incident diabetes or antihyperglycaemic use was also increased in COVID-19 patients (HR 1.46; 95% CI, 1.43–1.50; excess burden, 18.0; 16.6–19.5 per 1000 people at 12 months).
Based on subgroup analyses, COVID-19 was associated with a higher risk of diabetes in patients older than 65 vs. ≤65 years, in black vs. white, males vs. females, as well as in obese (BMI > 30 kg/m²) vs. lean subjects. The authors also tested the performance of a diabetes risk score [including age, race, sex, BMI, HbA1c, cardiovascular disease (CVD), hypertension, and hyperlipidaemia] which was built within the control group. Logistic regression analyses showed that COVID-19 was associated with diabetes across all risk score quartiles, including the lowest quartile. Moreover, the risk of incident diabetes and antihyperglycaemic use, as well as the composite outcome increased according to the severity of the acute infection, with the highest risk for intensive care and hospitalized patients vs. non-hospitalized subjects.

Pancreas

3254

OO235

Gulfidan Bitirgen, Celalettin Korkmaz, Adil Zamani, Mehmet Sinan Iyisoy, Hurkan Kerimoglu & Rayaz A. Malik

Abnormal quantitative pupillary light responses following COVID-19

https://doi.org/10.1007/s10792-022-02275-9

Published

5-Apr-22

Study

https://link.springer.com/article/10.1007/s10792-022-02275-9

Purpose
To characterize alterations in pupillary light reflex responses in subjects following coronavirus disease 2019 (COVID-19), especially those with long-COVID.
Methods
Thirty-five subjects with previous COVID-19 and 30 healthy control participants were enrolled in this cross-sectional comparative study. An infrared dynamic pupillometry system (MonPack One; Metrovision, France) was used to quantify pupillary light responses. The National Institute for Health and Care Excellence (NICE) long-COVID questionnaire was used to identify persisting symptoms at least 4 weeks after acute COVID-19.
Results
The median time after the diagnosis of acute COVID-19 was 4.0 (2.0–5.0) months. There was an increase in the latency of pupil contraction (P = 0.001) and a reduction in the duration of pupil contraction (P = 0.039) in post-COVID-19 subjects compared to healthy controls. No significant differences were observed in the initial pupil diameter, amplitude and velocity of pupil contraction or latency, velocity and duration of pupil dilation. Long-COVID was present in 25/35 (71%) subjects and their duration of pupil contraction was reduced compared to subjects without long-COVID (P = 0.009). The NICE long-COVID questionnaire total score (ρ = − 0.507; P = 0.002) and neurological score (ρ = − 0.412; P = 0.014) correlated with the duration of pupil contraction and the total score correlated with the latency of dilation (ρ = − 0.352; P = 0.038).
Conclusion
Dynamic pupillometry reveals significant alterations in contractile pupillary light responses, indicative of parasympathetic dysfunction after COVID-19.

Eyes

3255

OO148

Hadar Meringer & Saurabh Mehandru

Gastrointestinal post-acute COVID-19 syndrome

https://doi.org/10.1038/s41575-022-00611-z

Published

5-Apr-22

Comment

https://www.nature.com/articles/s41575-022-00611-z

The definition of gastrointestinal involvement in post-acute COVID-19 syndrome, its frequency and its pathophysiology are still not completely understood. Here, we discuss the emerging evidence supporting immunological signatures and the unique nature of the gastrointestinal tract in this syndrome.

Gastro-intestinal

3256

OO236

Apoorva Ayachit , FVRSORCID Icon,Madan Joshi , MS,Guruprasad Ayachit , FVRS,Shrinivas Joshi , FVRS &Priya Shah , DOMS

Presumed Post COVID- Infection Retinitis – Clinical and Tomographic Features of Retinitis as a Post-COVID Syndrome

https://doi.org/10.1080/09273948.2022.2060264

Published

11-Apr-22

Study

https://www.tandfonline.com/doi/abs/10.1080/09273948.2022.2060264

Purpose
To study clinical and imaging features of presumed post-COVID infection retinitis.
Method
Retrospective case series of patients presenting with retinitis lesions with evidence of recent COVID infection. Retinal findings and optical coherence tomography (OCT) features were studied at baseline and follow-ups.
Results
Twenty-four eyes of 17 patients were included. Mean age was 36.57 ± 11.78 years. Baseline visual acuity (VA) was log MAR 0.97 ± 0.43. Fundus findings included retinitis patches (n = 24),hard exudates (n = 8), and superficial hemorrhages (n = 16). OCT features included neurosensory detachment (NSD, n = 20), hyperreflective inner layers (n = 24), acute macular neuroretinopathy (AMN, n = 8), hyperreflective foci (n = 20). At final follow-up, VA was logMAR 0.43 ± 0.27. Retinitis patches persisted in four eyes, AMN in three eyes, and NSD in five eyes. Conclusion- Post- COVID infection retinitis adds to existing literature on post COVID syndromes.

Eyes

3257

OO237

Bobeck S. Modjtahedi, MD1,2,3; Duy Do, PhD1; Tiffany Q. Luong, MPH1; Jeremy Shaw, MD3,4

Changes in the Incidence of Retinal Vascular Occlusions After COVID-19 Diagnosis

https://doi.org/10.1001/jamaophthalmol.2022.0632

Published

14-Apr-22

Study

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2790988

Key Points
Question Does the incidence of retinal vascular occlusions change after COVID-19 infection?
Findings This cohort study of 432 515 patients diagnosed with COVID-19 found that the incidence of retinal vein occlusions, but not retinal artery occlusions, appeared to increase in the 6 months after COVID-19 diagnosis.
Meaning Patients with COVID-19 infection may have an increased risk of retinal vein occlusion in the 6 months after infection, similar to the increased risk of systemic vascular damage associated with COVID-19, and clinicians need to consider this factor when evaluating these patients.
Abstract
Importance COVID-19 is associated with systemic vascular damage; however, the risk posed to the retinal vasculature remains incompletely understood.
Objective To assess if there is a change in the incidence of retinal vascular occlusions after COVID-19 infection.
Design, Setting, and Participants This cohort study at an integrated health care organization (Kaiser Permanente Southern California) included patients without a history of retinal vascular occlusion who were diagnosed with COVID-19 infection between January 20, 2020, and May 31, 2021. Patients were excluded if they had a history of retinal artery occlusions (RAOs) or retinal vein occlusions (RVOs) more than 6 months before their COVID-19 diagnosis or if they were enrolled in Kaiser Permanente Southern California for less than 6 months before COVID-19 diagnosis.
Exposures COVID-19 infection.
Main Outcomes and Measures The change in the average biweekly incidence of new RAOs and RVOs after COVID-19 diagnosis. Adjusted incidence rate ratios (IRRs) were calculated to compare the incidence of retinal vascular occlusions before and after COVID-19 diagnosis after accounting for baseline demographic characteristics, medical history, and hospitalization.
Results A total of 432 515 patients diagnosed with COVID-19 infection were included in this study. The mean (SD) age was 40.9 (19.2) years, and 231 767 patients (53.6%) were women. Sixteen patients had an RAO (crude incidence rate, 3.00 per 1 000 000 patients), and 65 had an RVO (crude incidence rate, 12.20 per 1 000 000 patients) in the 6 months after COVID-19 diagnosis. The incidence of new RVOs was higher in the 6 months after COVID-19 infection compared with the 6 months before infection after adjusting for age; sex; self-reported race and ethnicity; body mass index; history of diabetes, hypertension, or hyperlipidemia; and hospitalization (adjusted IRR, 1.54; 95% CI, 1.05-2.26; P = .03). There was a smaller increase in the incidence of RAOs after COVID-19 diagnosis (IRR, 1.35; 95% CI, 0.64-2.85; P = .44). The peak incidence of RAOs and RVOs occurred 10 to 12 weeks and 6 to 8 weeks after COVID-19 diagnosis, respectively.
Conclusions and Relevance The findings of this study suggest that there was an increase in the incidence of RVOs after COVID-19 infection; however, these events remain rare, and in the absence of randomized controls, a cause-and-effect relationship cannot be established. Further large, epidemiologic studies are warranted to better define the association between retinal thromboembolic events and COVID-19 infection.

Eyes

3258

OO238

Mashael Al-Namaeh

Ocular manifestations of COVID-19

https://doi.org/10.1177%2F25158414221083374

Published

12-Apr-22

Review

https://journals.sagepub.com/doi/10.1177/25158414221083374

COVID-19 is a disease caused by a SARS-CoV-2 viral infection, a disease that was first detected in December 2019 in Wuhan, Hubei Province, China. COVID-19, formerly known as 2019 Novel Coronavirus (2019-nCoV) respiratory disease, was officially named COVID-19 by the World Health Organization (WHO) in February 2020. By 25 May 2021, there were 33,579,116 confirmed cases with 599,109 COVID-19 deaths worldwide. The purpose of this review article is to provide an update on what is currently known about COVID-19 ocular symptoms in adults, the elderly, and children in the literature. Finally, this article will review the eye protection precautions that should be implemented in our clinics. To assess the current literature, PubMed was searched from December 2019 to 25 May 2021. Randomized trials, observational studies, case series or case reports, letters of research, and letters to editors were selected for confirmed cases of COVID-19. According to current scientific literature since the outbreak in December 2019, 205 articles have been published. Conjunctivitis, conjunctival hyperemia, and chemosis have been reported in adults with COVID-19. There have been few studies on children and elderly patients, and further research in these age groups is needed. Finally, wearing eye protection when seeing patients on a daily basis during the pandemic is essential.

Eyes

3259

OO152

Ramin Ebrahim Nakhli,Aaron Shanker,Irene Sarosiek,Jeffrey Boschman,Karina Espino,Solmaz Sigaroodi,Ihsan Al Bayati,Sherif Elhanafi,Amin Sadeghi,Jerzy Sarosiek,Marc J. Zuckerman,Ali Rezaie,Richard W. McCallum,Max J. Schmulson,Ali Bashashati,Mohammad Bashashati

Gastrointestinal symptoms and the severity of COVID-19: Disorders of gut–brain interaction are an outcome

https://doi.org/10.1111/nmo.14368

Published

5-Apr-22

Study

https://onlinelibrary.wiley.com/doi/full/10.1111/nmo.14368

Key points
COVID-19 may manifest with gastrointestinal (GI) symptoms. Whether these symptoms are associated with a severe outcome has been mostly studied in hospitalized patients. Furthermore, it has been posited that Disorders of Gut–Brain Interaction (DGBI) are a sequela of COVID-19.
This work proposes an unsupervised clustering of COVID-19 patients based on the appearance of symptoms. GI symptoms, loss of smell, and chest pain are the most discriminative findings. During the acute phase, GI symptoms were associated with a more severe COVID-19.
The results of this study reconfirm the occurrence of post-COVID-19 DGBI among COVID-19 long haulers. It also reveals that these post-COVID-19 disorders may or may not be associated with the presence of GI symptoms during the acute phase.
Background
Many of the studies on COVID-19 severity and its associated symptoms focus on hospitalized patients. The aim of this study was to investigate the relationship between acute GI symptoms and COVID-19 severity in a clustering-based approach and to determine the risks and epidemiological features of post-COVID-19 Disorders of Gut–Brain Interaction (DGBI) by including both hospitalized and ambulatory patients.
Methods
The study utilized a two-phase Internet-based survey on: (1) COVID-19 patients’ demographics, comorbidities, symptoms, complications, and hospitalizations and (2) post-COVID-19 DGBI diagnosed according to Rome IV criteria in association with anxiety (GAD-7) and depression (PHQ-9). Statistical analyses included univariate and multivariate tests.
Results
Five distinct clusters of symptomatic subjects were identified based on the presence of GI symptoms, loss of smell, and chest pain, among 1114 participants who tested positive for SARS-CoV-2. GI symptoms were found to be independent risk factors for severe COVID-19; however, they did not always coincide with other severity-related factors such as age >65 years, diabetes mellitus, and Vitamin D deficiency. Of the 164 subjects with a positive test who participated in Phase-2, 108 (66%) fulfilled the criteria for at least one DGBI. The majority (n = 81; 75%) were new-onset DGBI post-COVID-19. Overall, 86% of subjects with one or more post-COVID-19 DGBI had at least one GI symptom during the acute phase of COVID-19, while 14% did not. Depression (65%), but not anxiety (48%), was significantly more common in those with post-COVID-19 DGBI.
Conclusion
GI symptoms are associated with a severe COVID-19 among survivors. Long-haulers may develop post-COVID-19 DGBI. Psychiatric disorders are common in post-COVID-19 DGBI.

Gastro-intestinal

3260

OO153

S Nackeeran
K Chu
T Masterson
R Ramasamy

COVID-19 is Associated with New Onset Erectile Dysfunction: Insights From a Multinational Registry

https://doi.org/10.1016/j.jsxm.2022.01.404

Published

1-Apr-22

Study

https://www.jsm.jsexmed.org/article/S1743-6095(22)00437-4/fulltext

Introduction
As the COVID-19 pandemic has been ongoing since 2019, we are just beginning to see some of the short and long-term effects of infection. Vascular integrity is necessary for erectile function, and endothelial damage associated with COVID-19 is likely to affect the penile vasculature. Recent studies have showed evidence of COVID-19 virus within penile tissue through electron microscopy. We hypothesized that the COVID-19 infection may be a contributing factor to subsequent development of erectile dysfunction (ED).
Objective
To determine if men with recent COVID-19 infection was associated with subsequent increased risk for development of erectile dysfunction.
Methods
We assessed the risk of ED in men with COVID-19 in the United States (US) using the TriNetX Research Network, a federated EMR network of over 42 healthcare organizations and 66 million patients from the US, from 2009-2020. We identified adult men (≥18 years) with a recorded COVID-19 infection (ICD-10-CM B34.2, U07.1, U07.2, J12.81, J12.82, B97.29) since January 1, 2020 and compared them to an equivalent number of adult men who had COVID-19. Men with prior history or diagnosis of ED were excluded. We accounted for confounding variables through propensity score matching for age, race, body mass index (BMI), and history of the following comorbid medical conditions: diabetes mellitus (ICD-10-CM E11), hypertension (ICD-10-CM I10), or hyperlipidemia (ICD-10-CM E78). We assessed the association between COVID-19 and ED (ICD-10-CM N52) as a primary outcome through regression analysis with statistical significance assessed at p<.05.
Results
Prior to propensity score matching, men with COVID-19 had an average age of 47.1 + 21.4 years, 13% had diabetes mellitus, and 27% had hypertension, while in men without COVID-19, average age was 42.4 + 24.3 years, 7% had diabetes, and 22% had hypertension. After propensity score matching, we compared 230, 517 men with COVID-19 to 232,645 men without COVID-19 and found that COVID-19 diagnosis was significantly associated with ED (OR 1.120, 95% CI 1.004-1.248, p=0.0416). Strengths include large sample size and adjustment for confounding variables. Limitations include lack of data regarding ED (mild vs moderate vs severe) or COVID-19 infection severity.
Conclusions
Our study showed that there is an increased risk of developing ED post-COVID infection, suggesting possible long-term effects due underlying endothelial dysfunction. The exact mechanism of how COVID-19 virus leads to erectile dysfunction remains to be elucidated.

Penis

3261

OO154

Nicola Wanner, Geoffroy Andrieux, Pau Badia-i-Mompel, Carolin Edler, Susanne Pfefferle, Maja T. Lindenmeyer, Christian Schmidt-Lauber, Jan Czogalla, Milagros N. Wong, Yusuke Okabayashi, Fabian Braun, Marc Lütgehetmann, Elisabeth Meister, Shun Lu, Maria L. M. Noriega, Thomas Günther, Adam Grundhoff, Nicole Fischer, Hanna Bräuninger, Diana Lindner, Dirk Westermann, Fabian Haas, Kevin Roedl, Stefan Kluge, Marylyn M. Addo, Samuel Huber, Ansgar W. Lohse, Jochen Reiser, Benjamin Ondruschka, Jan P. Sperhake, Julio Saez-Rodriguez, Melanie Boerries, Salim S. Hayek, Martin Aepfelbacher, Pietro Scaturro, Victor G. Puelles &
Tobias B. Huber

Molecular consequences of SARS-CoV-2 liver tropism

https://doi.org/10.1038/s42255-022-00552-6

Published

28-Mar-22

Article

https://www.nature.com/articles/s42255-022-00552-6

Extrapulmonary manifestations of COVID-19 have gained attention due to their links to clinical outcomes and their potential long-term sequelae1. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) displays tropism towards several organs, including the heart and kidney. Whether it also directly affects the liver has been debated2,3. Here we provide clinical, histopathological, molecular and bioinformatic evidence for the hepatic tropism of SARS-CoV-2. We find that liver injury, indicated by a high frequency of abnormal liver function tests, is a common clinical feature of COVID-19 in two independent cohorts of patients with COVID-19 requiring hospitalization. Using autopsy samples obtained from a third patient cohort, we provide multiple levels of evidence for SARS-CoV-2 liver tropism, including viral RNA detection in 69% of autopsy liver specimens, and successful isolation of infectious SARS-CoV-2 from liver tissue postmortem. Furthermore, we identify transcription-, proteomic- and transcription factor-based activity profiles in hepatic autopsy samples, revealing similarities to the signatures associated with multiple other viral infections of the human liver. Together, we provide a comprehensive multimodal analysis of SARS-CoV-2 liver tropism, which increases our understanding of the molecular consequences of severe COVID-19 and could be useful for the identification of organ-specific pharmacological targets.

Liver

3262

OO155

Lukasz Szarpak
Michal Pruc
Fiza Najeeb
Milosz J. Jaguszewski

POST-COVID-19 and the pancreas

https://doi.org/10.1016/j.ajem.2022.04.023

Published

24-Apr-22

Study

https://www.ajemjournal.com/article/S0735-6757(22)00253-4/fulltext

The COVID-19 pandemic has turned out to be a huge challenge and a burden for medical services struggling with a huge number of patients and their ailments [[1]]. Currently in addition to the ever-growing number of COVID-19 cases related to the next wave, our attention should also be paid to patients who will struggle with a number of POST-COVID-19 complications. The implications of COVID-19 infection are continually being studied, both in terms of the frequency with which they occur and the mechanism by which they occur. People with LONG-COVID-19 and POST-COVID-19 syndromes may be unable to do activities as well as employment. COVID-19, on the other hand, may raise the risk of chronic illness. In the context of the emergency department, we should pay particular attention to the possible increase in the percentage of patients due to pancreatic disorders. The SARS-CoV-2 virus can assault the pancreas and induce pancreatic injury and acute pancreatitis, according to research. The mechanism behind it is yet unknown. In recent years, hypertriglyceridemia has become one of the primary causes of acute pancreatitis, and hyperlipidemia is common in COVID-19 patients. COVID-19 individuals had a high rate of hyperlipidemia, with a total incidence of 32.98%. Hyperlipidemia may have a role in the development of acute pancreatitis in COVID-19 and POST-COVID-19 patients [[2]]. In addition, although we already know about the adverse impact of diabetes on the course of COVID-19, newer and newer reports about it are appearing [[3]]. Researchers discovered reduced granularity in beta-cell insulin production after infection with COVID-19, as well as decreased glucose-stimulated secretion. Even though they had no prior history of diabetes, some COVID-19 individuals acquired insulin resistance and raised blood glucose levels. The immune system can stay active for months after a COVID-19 infection, lowering the efficacy of insulin in the liver, muscles, and fat cells. In a large cohort study, the population following COVID-19 was compared to acute upper respiratory infections (AURI). Age, gender, health insurance, COVID-19 / AURI index month, and comorbidities including obesity, hypertension, hyperlipidemia, myocardial infarction, and stroke were used to match patients. COVID-19 infected individuals had a greater risk of type 2 diabetes than AURI infected people. COVID-19 patients acquired diabetes at a rate of 15.8 per 1000 individuals per year, compared to 12.3 for AURI patients. The adjusted IRR for type 2 diabetes was 1.28 when marginal models were used. Overall, the COVID-19 group had a 28% higher relative risk of acquiring diabetes than the AURI group [[4]]. Due to the induction of diabetes and acute pancreatitis in the POST-COVID-19 condition, the pancreas should definitely be a focus of our attention. Patients with new undiagnosed diabetes, as well as acute pancreatitis that is most likely connected to cholesterol levels, should be given extra care. Studies have shown that persons with high levels of high-density lipoproteins in their blood are less prone to severe COVID-19 infection, which is another important factor to consider among COVID-19 patients [[5]]. During our work, we must be ready for the increased number of patients suffering from previously undiagnosed diabetes acquired as the POST-COVID-19 syndrome, as well as those who, due to the pandemic, were unable to obtain this diagnosis, which may overlap. COVID-19 itself affects the lipid metabolism, but additionally the overlapping mode of isolation that took place may mean that we will have to deal with a significantly increased percentage of patients with acute pancreatitis. More research is needed to explain the effects of COVID-19 and the LONG-COVID-19 syndrome on the pancreas.

Pancreas

3263

OO156

ShigeruYamadaaTakamasaNodabcdeKaoriOkabebShotaYanagidaaMotohiroNishidafgYasunariKandaa

SARS-CoV-2 induces barrier damage and inflammatory responses in the human iPSC-derived intestinal epithelium

https://doi.org/10.1016/j.jphs.2022.04.010

Published

2-May-22

Study

https://www.sciencedirect.com/science/article/pii/S1347861322000378

COVID-19 causes well-known respiratory failure and gastrointestinal symptoms, such as diarrhea, nausea, and vomiting. Thus, human gastrointestinal cell models are urgently needed for COVID-19 research; however, it is difficult to obtain primary human intestinal cells. In this study, we examined whether human induced pluripotent stem cell (iPSC)-derived small intestinal epithelial cells (iPSC-SIECs) could be used as a SARS-CoV-2 infection model. We observed that iPSC-SIECs, such as absorptive and Paneth cells, were infected with SARS-CoV-2, and remdesivir treatment decreased intracellular SARS-CoV-2 replication in iPSC-SIECs. SARS-CoV-2 infection decreased expression levels of tight junction markers, ZO-3 and CLDN1, and transepithelial electrical resistance (TEER), which evaluates the integrity of tight junction dynamics. In addition, SARS-CoV-2 infection increased expression levels of proinflammatory genes, which are elevated in patients with COVID-19. These findings suggest iPSC-SIECs as a useful in vitro model for elucidating COVID-19 pathology and drug development.

Gastro-intestinal

3264

OO239

Dipu, Taw; Goel, Ruchi,; Arora, Ritu; Thakar, Meenakshi; Gautam, Akanksha; Shah, Shalin; Gupta, Yashi; Chhabra, Mohit; Kumar, Sumit; Singh, Kirti; Kumar, Suresh1; Garg, Sandeep1; Singh, Harpreet1; Pant, Rashmi2

Ocular sequelae in severe COVID-19 recovered patients of second wave

https://doi.org/10.4103/ijo.IJO_2882_21

Published

28-Apr-22

Study

https://journals.lww.com/ijo/Fulltext/2022/05000/Ocular_sequelae_in_severe_COVID_19_recovered.70.aspx

Purpose:
To evaluate the retinal microvascular changes in patients, recovered from severe COVID-19 during the second wave of the pandemic in North India.
Methods:
In this observational cross-sectional study, 70 eyes of 35 patients who recovered from severe COVID-19 during the second wave underwent detailed ophthalmic evaluation 4–6 weeks after discharge. Twelve controls were also enrolled, and the difference in the findings between the case and control groups on optical coherence tomography (OCTA) were studied.
Result:
The ages of study participants ranged from 27 to 60 years with the male:female ratio being 1.05:1. The fundus changes suggestive of ischemia in the form of cotton wool spots and vascular tortuosity were seen in 25 eyes (35.71%). Increased venous tortuosity was the most common finding seen in 23 eyes (32.85%), of which 10 eyes (28.57%) had concurrent hypertensive retinopathy (HTR) changes. There was a significant reduction in the mean vascular density (VD) and perfusion density (PD) for both the superficial capillary plexus (SCP) and deep capillary plexus (DCP) at inner, outer ring, and whole (P < 0.05). Foveal avascular zone was significantly enlarged in both the SCP (P = 0.01) and the DCP (P = 0.03). The mean ganglion cell-inner plexiform layer (GC-IPL) was significantly reduced in comparison to controls (P < 0.001).
Conclusion:
Severe COVID-19 can result in microvascular changes at the macula in the form of reduction in vascular and perfusion density, which can be evaluated using OCTA. As structural changes precede functional changes, a close watch is recommended in patients showing compromise in retinal microvasculature.

Eyes

3265

OO240

Maria Lukashenko1 ID
, Lidiia Soprun1,2 ID , Anna Bregovskaya3 ID , Natalia Gavrilova1,2,4* ID , Vladimir I. Utekhin

The confocal microscopy of the cornea in postCOVID syndrome; the clinical observation

https://doi.org/10.34172/ipp.2022.31338

Published

17-Apr-22

Study

https://immunopathol.com/Files/Inpress/ipp-31338.pdf

One of the most important complications of the post-COVID-19 syndrome may be a small fiber neuropathy, which cannot be evaluated by a routine electroneuromyography. Confocal microscopy of the cornea (CCM) may be a promising method for early neuropathy verification. To study the possibility of the small fiber neuropathy evaluation using the CCM in a patient with the post-COVID-19 condition. The patient is a female of 61 years old, which suffered from a COVID-19 infection in October 2020. After a month, she noted the presence of myalgia and polyneuropathy. A year after the onset of the disease, in addition to myalgia, headaches, neuropathy pain, the patient also experienced bowel disorders and stomach aches, which cannot be explained with an alternative diagnosis. The patient underwent CCM to assess the structure of nerve fibers to prove the presence of the small fiber neuropathy as a complication of the COVID-19 infection. The presence of the small fiber neuropathy was evaluated in the patient as well as enlarged Langerhans cells in the cornea. Considering the pivotal role of these cells in the immunological processes, the “activated” dendritic cells in post-COVID-19 patients may serve as another evidence of the autoimmune nature of this complication and possibly, a method for the monitoring treatment effectiveness of this disease. In this clinical case of a 61-year-old patient with the post-COVID-19 syndrome, the possibility of application of the confocal microscopy of the cornea for the diagnosis of neuropathy of small fibers and monitoring of the patient›s condition is shown.
Key point
Post-COVID-19 syndrome may manifest with multiple autoimmune complications; one of the most important is small fiber neuropathy with pain syndrome and dysautonomia. Confocal microscopy of the cornea may be a promising method for the diagnostic of such disease.

Eyes

3266

OO159

Arturo Lorenzo, María Martínez Manrique, Paula Ardura, Isabel Acosta-Ochoa, Ana Lucía Valencia, Alicia Mendiluce, Veronica Fidalgo, Jimmy Reinaldo Sanchez Gil, Armando Coca

MO442: COVID-19 Disease Severity and Risk of 12-Month CKD Progression

https://doi.org/10.1093/ndt/gfac070.056

Published

3-May-22

Study

https://academic.oup.com/ndt/article/37/Supplement_3/gfac070.056/6578274?login=true

BACKGROUND AND AIMS
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been in our daily practice for almost 2 years now. Since the beginning of the pandemic, we have aimed to study its most immediate effects on patients to find the best line of treatment or, at least, mitigate its worst outcomes. Nevertheless, we also know some long-term health consequences such as fatigue, sleep difficulties, headache, among others, but its long-term kidney effects are not entirely clear yet. The aim of this study was to describe if coronavirus disease's (COVID-19) severity increases the risk of chronic kidney disease (CKD) progression after a previous hospitalization and observe if there are any additional risk factors that could help us predict this outcome.
METHOD
In this study, a sample of consecutive patients who required admission due to COVID-19 during the first wave of the pandemic (from March to May of 2020) was recruited. Patients were followed for 12 months since initial admission. The composite outcome of the study included either death or CKD progression. CKD progression was defined as incremental progression to a higher KDIGO CKD stage compared to baseline pre COVID-19 renal function [(in mL/min/1.73 m2): estimated glomerular filtration rate (eGFR) ≥60; stage 3a: 45–59; stage 3b: 30–44; stage 4: 15–29; stage 5: <15], or dialysis initiation. Cardiovascular disease was defined as a history of myocardial infarction, stroke, or peripheral vascular disease. Chronic lung diseases included asthma, chronic obstructive pulmonary disease and chronic bronchitis.
RESULTS
The sample was composed of 93 patients, of which 14 (15.1%) died during follow-up. Of those alive 12 months after initial admission, 17 (21.5%) suffered CKD progression. No patient required renal replacement therapy. Patients that suffered the composite outcome presented a higher prevalence of cancer, tended to be slightly older and suffered from additional comorbidities more frequently (Table). In multivariate logistic regression analysis, previous history of CKD [odds ratio (OR): 1.066 (0.433–2.624); P = 0.889], severe or critical COVID-19 on admission [OR: 0.657 (0.24–1.8); P =0.414] or ICU admission [OR: 0.986 (0.082–11.898); P = 0.991] failed to predict the composite outcome.
CONCLUSION
Our main hypothesis was that COVID-19 sequelae should be due to an exaggerated activation of the immune system against the virus. Thus, patients that suffered severe COVID-19 should be expected to develop more long-term health consequences of the infection when compared with those with milder disease. However, we failed to prove any link between COVID-19 severity and long-term CKD progression. History of CKD or ICU admission was also unable to predict the composite outcome.
Previous studies have described a relationship between COVID-19 severity and adverse renal outcomes, a relationship that we failed to observe. These discrepancies could be due to the small sample size of our study and the different definition of CKD progression applied. In addition, age could act as a potential modifier of CKD progression after admission due to COVID. More studies are required to further clarify the mechanisms and long-term renal consequences of COVID-19 and define potential lines of treatment.

Kidney

3267

OO160

Bubnov Rostyslav

MO110: Ultrasound Evaluation of Post-COVID Kidney Disease

https://doi.org/10.1093/ndt/gfac066.013

Published

3-May-22

Study

https://academic.oup.com/ndt/article/37/Supplement_3/gfac066.013/6578560?login=true

BACKGROUND AND AIMS
COVID can affect many organs including kidneys involving various possible pathophysiological mechanisms [1]. Post-COVID conditions require focused approach for diagnosis, personalized treatments and rehabilitation. Ultrasonography (US) can provide accurate information for detecting kidney disease [2]. Shear wave elastography (SWE) is a recognized ultrasound method, still having a limited use in nephrology, yet can be used for early detections of kidney abnormalities.
The aim of this study was to evaluate semiotics and the added diagnostic value of US for post-COVID kidney disease.
METHOD
We included 20 cases to the study (23–68 years; 8 women) who underwent COVID-19 during last 3 months with signs of kidney disease (proteinuria, increased levels of creatinine, uric acid in blood, hypertension) and other clinical, laboratory symptoms of nephropathy after COVID-19 without specific data of previous history of kidney disease. The control group included 20 healthy individuals (9 women), with mean age 37 ± 7 years without clinical, laboratory signs of nephropathy according to disease history. All patients underwent general clinical, lab tests; abdominal US including precise multiparameter US of kidneys as in [2] measuring renal resistive index (RI), did SWE, and sensitive Doppler (B-flow and similar) in parenchyma and vessels using curved abdominal transducer of US systems: LOGIQ 9 (GE Healthcare), Toshiba Aplio and Hitachi Arietta.
RESULTS
We detected US changes in all age groups, both in females and males. Severe kidney disease signs included thinning, increasing echogenicity of kidney parenchyma (P < .05), detection of fibrotic changes and small hyperechoic inclusions, hilly margins, anaechoic strips under the capsule, RI increasing in segmental arteries over 0.75, and decreasing velocities under 25 cm/s. SWE showed increased parenchyma stiffness to 10 ± 1.7 kPa (6–13 kPa) versus 4.2 ± 1.2 kPa (P < .05).
Moderate changes included mild decrease of kidney medullary differentiation, RI increasing in segmental arteries over 0.7; parenchyma stiffness increased to 7.2 ± 1.5 kPa (5–10 kPa), P < .05.
In 16 patients we diagnosed hypertension; all patients had increased RI over 0.75; pyelonephritis was in 2 patients.
Three patients had the following abnormalities: amyloid kidney after COVID-19 was in two patients (male 62 years and female 58 years) manifesting on US with increased echogenicity small kidney, decreased blood flow and increasing RI (Figure 1).
One patient had collapsing glomerulopathy [3] manifesting with proteinuria; kidney biopsy with immunohistochemistry performed 1 month after beginning of COVID-19 showed collapsing focal segmental glomerulosclerosis; US symptoms were unspecific (Figure 2).
CONCLUSION
Multiparameter ultrasound is an effective method for early detection of various types of kidney disease in patients after coronavirus disease, potentially effective to distinguish signs of nephropathy associated to COVID-19. Evaluation of renal RI and increased stiffness of kidney parenchyma are reliable markers.

Kidney

3268

OO161

Madhurima Sachan Kamlesh Chaudhari Sparsh Madaan
Saunitra A Inamdar Priti Varma

Fallopian tube block induced secondary infertility in a case of unicornuate uterus treated successfully: A long covid sequalae?

Published

27-Apr-22

Case Report

https://www.researchgate.net/publication/360270273_Fallopian_tube_block_induced_secondary_infertility_in_a_case_of_unicornuate_uterus_treated_successfully_A_long_covid_sequalae

Infertility arising from infections is alarming cause of secondary infertility which is growing in number by the day. Mullerian anomalies can result in female infertility. A unicornuate uterus with a rudimentary horn is an abnormality induced by a faulty mullerian duct fusion. On Hysterosalpingogram, the uterine cavity has a spindle-shaped that tapers at the tip and drains in to a single oviduct. A 30 years old female with secondary infertility post COVID 19 infection, which upon investigated turned out to be unicornuate uterus with single fallopian tube on left side cornual block visualized in fallopian tube. All the causes of fallopian tube block including pelvic inflammatory disesase, tuberculosis, trauma and bacterial infections were ruled out yielding COVID19 as the probable cause of infertility. Fallopian tube cannulation was done following which she conceived spontaneously. Elective encirclage done at 12 weeks and she was asked to report at 37 completed weeks for cervical stitch removal. After that emergency LSCS done. She delivered baby boy of 2.7kg with APGAR score 9/10. We concluded that angiotensin convertase enzyme 2 receptor were present on the fallopian tube might be responsible for post COVID fallopian tube blockage which is a topic for further studies. Prompt detection and management of long COVID sequelae in the form of infertility, particularly in predisposed people who are more likely to develop such difficulties, is thus critical to preserve infertility.

Female reproductive system

3269

OO162

R Rangu, Medicine, VA Puget Sound Health Care System, Seattle, United States | 2 P Wander, Medicine, VA Puget Sound Health Care System, Seattle, United States | 3 B Barrow, Medicine, VA Puget Sound Health Care System, Seattle, United States | 4 S Zraika, Medicine

Going viral in the islet: mediators of SARS-CoV-2 entry beyond ACE2

https://doi.org/10.1530/JME-21-0282

Published

1-May-22

Review

https://jme.bioscientifica.com/view/journals/jme/aop/jme-21-0282/jme-21-0282.xml

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Following initial infection of airway epithelia, SARS-CoV-2 invades a wide range of cells in multiple organs, including pancreatic islet cells. Diabetes is now recognized as a risk factor for severe COVID-19 outcomes, including hospitalisation and death. Additionally, COVID-19 is associated with higher risk of new-onset diabetes and metabolic complications of diabetes. One mechanism by which these deleterious outcomes may occur is via destruction of insulin-producing islet β cells, either directly by SARS-CoV-2 entry into β cells or indirectly due to inflammation and fibrosis in the surrounding microenvironment. While the canonical pathway of viral entry via angiotensin converting enzyme 2 (ACE2) has been established as a major route of SARS-CoV-2 infection in the lung, it may not be solely responsible for viral entry into the endocrine pancreas. This is likely due to divergent expression of viral entry factors amongst different tissues. For example, expression of ACE2 has not been unequivocally demonstrated in β cells. Thus, it is important to understand how other proteins known to be highly expressed in pancreatic endocrine cells may be involved in SARS-CoV-2 entry, with the view that these could be targeted to prevent demise of the β cell in COVID-19. To that end, this review discusses alternate receptors of SARS-CoV-2 (CD147 and GRP78), as well as mediators (furin, TMPRSS2, cathepsin L, ADAM17, neuropilin-1 and heparan sulphate) that may facilitate SARS-CoV-2 entry into pancreatic islets independent of or in conjunction with ACE2.

Pancreas

3270

OO163

Naruhiko Sunada, Hiroyuki Honda, Yasuhiro Nakano, Koichiro Yamamoto, Kazuki Tokumasu, Yasue Sakurada, Yui Matsuda, Toru Hasegawa, Yuki Otsuka, Mikako Obika, Yoshihisa Hanayama, Hideharu Hagiya, Keigo Ueda, Hitomi Kataoka, Fumio Otsuka

Hormonal trends in patients suffering from long COVID symptoms

https://doi.org/10.1507/endocrj.EJ22-0093

Published

28-Apr-22

Study

https://www.jstage.jst.go.jp/article/endocrj/advpub/0/advpub_EJ22-0093/_article

Symptoms of long COVID are complex and long-lasting, and endocrine dysfunction might be involved in the underlying mechanisms. In this study, to clarify the hormonal characteristics of long COVID patients, laboratory data for patients who visited the outpatient clinic for long COVID were evaluated. A retrospective analysis was performed for patients who visited Okayama University Hospital during the period from Feb 2021 to Dec 2021 with focus on the interrelationships between major symptoms and endocrine data. Information and laboratory data were obtained from medical records for 186 patients. The patients had various symptoms, and the most frequent symptoms were general malaise, dysosmia/dysgeusia, hair loss, headache, dyspnea, and sleeplessness. Patients who were suffering from fatigue and dysosmia/dysgeusia were younger, while hair loss was more frequent in older and female patients. As for the characteristics of patients suffering from general fatigue, the scores of depression and fatigue were positively correlated with serum levels of cortisol and free thyroxin (FT4), respectively. Also, patients suffering from general fatigue had lower levels of serum growth hormone and higher levels of serum FT4, while patients with dysosmia/dysgeusia had a significantly lower level of serum cortisol. Serum thyrotropin (TSH) levels were higher and the ratios of FT4/TSH were lower in the initially severe cases, suggesting occult hypothyroidism. In addition, the ratios of plasma adrenocorticotropin to serum cortisol were decreased in patients with relatively high titers of serum SARS-CoV-2 antibody. Thus, hormonal changes seem to be, at least in part, involved in the persistent symptoms of long COVID.

Endocrine system

3271

OO164

Jan K. Hennigs, Marie Huwe, Annette Hennigs, Tim Oqueka, Marcel Simon, Lars Harbaum, Jakob Körbelin, Stefan Schmiedel, Julian Schulze zur Wiesch, Marylyn M. Addo, Stefan Kluge & Hans Klose

Respiratory muscle dysfunction in long-COVID patients

https://doi.org/10.1007/s15010-022-01840-9

Published

16-May-22

Study

https://link.springer.com/article/10.1007/s15010-022-01840-9

Purpose
Symptoms often persistent for more than 4 weeks after COVID-19—now commonly referred to as ‘Long COVID’. Independent of initial disease severity or pathological pulmonary functions tests, fatigue, exertional intolerance and dyspnea are among the most common COVID-19 sequelae. We hypothesized that respiratory muscle dysfunction might be prevalent in persistently symptomatic patients after COVID-19 with self-reported exercise intolerance.
Methods
In a small cross-sectional pilot study (n = 67) of mild-to-moderate (nonhospitalized) and moderate-to-critical convalescent (formerly hospitalized) patients presenting to our outpatient clinic approx. 5 months after acute infection, we measured neuroventilatory activity P0.1, inspiratory muscle strength (PImax) and total respiratory muscle strain (P0.1/PImax) in addition to standard pulmonary functions tests, capillary blood gas analysis, 6 min walking tests and functional questionnaires.
Results
Pathological P0.1/PImax was found in 88% of symptomatic patients. Mean PImax was reduced in hospitalized patients, but reduced PImax was also found in 65% of nonhospitalized patients. Mean P0.1 was pathologically increased in both groups. Increased P0.1 was associated with exercise-induced deoxygenation, impaired exercise tolerance, decreased activity and productivity and worse Post-COVID-19 functional status scale. Pathological changes in P0.1, PImax or P0.1/PImax were not associated with pre-existing conditions.
Conclusions
Our findings point towards respiratory muscle dysfunction as a novel aspect of COVID-19 sequelae. Thus, we strongly advocate for systematic respiratory muscle testing during the diagnostic workup of persistently symptomatic, convalescent COVID-19 patients.

Muscles

3272

OO165

G. Corona, W. Vena, A. Pizzocaro, F. Pallotti, D. Paoli, G. Rastrelli, E. Baldi, N. Cilloni, M. Gacci, F. Semeraro, A. Salonia, S. Minhas, R. Pivonello, A. Sforza, L. Vignozzi, A. M. Isidori, A. Lenzi, M. Maggi & F. Lombardo

Andrological effects of SARS-Cov-2 infection: a systematic review and meta-analysis

https://doi.org/10.1007/s40618-022-01801-x

Published

9-May-22

Systematic review

https://link.springer.com/article/10.1007/s40618-022-01801-x

Purpose
The short- and long-term andrological effects of coronavirus disease 2019 (COVID-19) have not been clarified. Our aim is to evaluate the available evidence regarding possible andrological consequences of COVID-19 either on seminal or hormonal parameters. The safety of the COVID-19 vaccines in terms of sperm quality was also investigated.
Methods
All prospective and retrospective observational studies reporting information on severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) mRNA semen and male genitalia tract detection (n = 19), as well as those reporting data on semen analysis (n = 5) and hormonal parameters (n = 11) in infected/recovered patients without any arbitrary restriction were included.
Results
Out of 204 retrieved articles, 35 were considered, including 2092 patients and 1138 controls with a mean age of 44.1 ± 12.6 years, and mean follow-up 24.3 ± 18.9 days. SARS-CoV-2 mRNA can be localized in male genitalia tracts during the acute phase of the disease. COVID-19 can result in short-term impaired sperm and T production. Available data cannot clarify long-term andrological effects. Low T observed in the acute phase of the disease is associated with an increased risk of being admitted to the Intensive Care Unit or death. The two available studies showed that the use of mRNA COVID-19 vaccines does not affect sperm quality.
Conclusions
The results of our analysis clearly suggest that each patient recovering from COVID-19 should be monitored to rule out sperm and T abnormalities. The specific contribution of reduced T levels during the acute phase of the infection needs to be better clarified.

Male reproductive system

3273

OO166

Anello Marcello Poma, PhD, Agnese Proietti, MD, PhD, Elisabetta Macerola, PhD, Diana Bonuccelli, MD, Marco Conti, MD, Alessandra Salvetti, PhD, Vincenza Dolo, MD, PhD, Andrea Chillà, Alessio Basolo, MD, PhD, Ferruccio Santini, MD, PhD, Antonio Toniolo, MD, PhD, Fulvio Basolo, MD, PhD

Suppression of pituitary hormone genes in subjects who died from COVID-19 independently of virus detection in the gland

https://doi.org/10.1210/clinem/dgac312

Published

14-May-22

Study

https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgac312/6585915

Context
Involvement of the pituitary gland in SARS-CoV-2 infection has been clinically suggested by pituitary hormone deficiency in severe COVID-19 cases, by altered serum ACTH levels in hospitalized patients, and by cases of pituitary apoplexy. However, the direct viral infection of the gland has not been investigated.
Objectives
To evaluate whether the SARS-CoV-2 genome and antigens could be present in pituitary glands of lethal cases of COVID-19, and to assess possible changes in the expression of immune-related and pituitary-specific genes.
Methods
SARS-CoV-2 genome and antigens were searched in the pituitary gland of 23 patients who died from COVID-19 and, as controls, in 12 subjects who died from trauma or sudden cardiac death. Real-time RT-PCR, in situ hybridization, immunohistochemistry and transmission electron microscopy were utilized. Levels of mRNA transcripts of immune-related and pituitary-specific genes were measured by the nCounter assay.
Results
The SARS-CoV-2 genome and antigens were detected in 14/23 (61%) pituitary glands of the COVID-19 group, not in controls. In SARS-CoV-2 positive pituitaries, the viral genome was consistently detected by PCR in the adeno- and the neurohypophysis. Immunohistochemistry, in situ hybridization and transmission electron microscopy confirmed the presence of SARS-CoV-2 in the pituitary. Activation of type I interferon signaling and enhanced levels of neutrophil and cytotoxic cell scores were found in virus-positive glands. mRNA transcripts of pituitary hormones and pituitary developmental/regulatory genes were suppressed in all COVID-19 cases irrespective of virus-positivity.
Conclusion
Our study supports the tropism of SARS-CoV-2 for human pituitary and encourage to explore pituitary dysfunction post-COVID-19.

Pituitary gland

3274

OO167

Domenico Acanfora 1,*,Maria Nolano 2,3,Chiara Acanfora 1,4ORCID,Camillo Colella 1,Vincenzo Provitera 3,Giuseppe Caporaso 3,Gabriele Rosario Rodolico 5,Alessandro Santo Bortone 6,Gennaro Galasso 7ORCID andGerardo Casucci 1,*

Impaired Vagal Activity in Long-COVID-19 Patients

https://doi.org/10.3390/v14051035

Published

13-May-22

Study

https://www.mdpi.com/1999-4915/14/5/1035/htm

Long-COVID-19 refers to the signs and symptoms that continue or develop after the “acute COVID-19” phase. These patients have an increased risk of multiorgan dysfunction, readmission, and mortality. In Long-COVID-19 patients, it is possible to detect a persistent increase in D-Dimer, NT-ProBNP, and autonomic nervous system dysfunction. To verify the dysautonomia hypothesis in Long-COVID-19 patients, we studied heart rate variability using 12-lead 24-h ECG monitoring in 30 Long-COVID-19 patients and 20 No-COVID patients. Power spectral analysis of heart rate variability was lower in Long-COVID-19 patients both for total power (7.46 ± 0.5 vs. 8.08 ± 0.6; p < 0.0001; Cohens-d = 1.12) and for the VLF (6.84 ± 0.8 vs. 7.66 ± 0.6; p < 0.0001; Cohens-d = 1.16) and HF (4.65 ± 0.9 vs. 5.33 ± 0.9; p = 0.015; Cohens-d = 0.76) components. The LF/HF ratio was significantly higher in Long-COVID-19 patients (1.46 ± 0.27 vs. 1.23 ± 0.13; p = 0.001; Cohens-d = 1.09). On multivariable analysis, Long-COVID-19 is significantly correlated with D-dimer (standardized β-coefficient = 0.259), NT-ProBNP (standardized β-coefficient = 0.281), HF component of spectral analysis (standardized β-coefficient = 0.696), and LF/HF ratio (standardized β-coefficient = 0.820). Dysautonomia may explain the persistent symptoms in Long COVID-19 patients. The persistence of a procoagulative state and an elevated myocardial strain could explain vagal impairment in these patients. In Long-COVID-19 patients, impaired vagal activity, persistent increases of NT-ProBNP, and a prothrombotic state require careful monitoring and appropriate intervention.

Vagal nerve

3275

OO241

Suzhen Wang,Jie Wang,Jianbin Hu,Ningli Wang

Retinal microvascular impairment in COVID-19 patients: A meta-analysis

https://doi.org/10.1002/iid3.619

Published

11-May-22

Meta-Analysis

https://onlinelibrary.wiley.com/doi/full/10.1002/iid3.619

Background
The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a global pandemic in an unprecedented time frame. Systemic vascular involvement in COVID-19 has been identified, and SARS-CoV-2 has also been found to cause multiple organ ischemia and posterior ocular segment disease in mammals, raising concerns about the human retinal microvascular involvement in SARS-CoV-2.
Objective
To objectively assess the presence of retinal microvascular impairment in COVID-19 patients by optical coherence tomography angiography (OCTA), so as to facilitate the clinical system management of COVID-19 patients.
Methods
We searched PubMed, Cochrane Library, EMBASE, Ovid, CBM to collect eligible studies. The main outcomes included the vessel density (VD), area or perimeter of foveal avascular zone (FAZ), central foveal thickness (CFT), subfoveal choroidal thickness (SCT) in our meta-analysis.
Results
We eventually included five studies with a total of 401 participants. Our meta-analysis showed that nonacute infectious COVID-19 or post-COVID-19 patients presented significantly lower foveal VD of deep capillary plexus (WMD = −4.22, 95% CI [−8.00, −0.43]) and thinner SCT (WMD = −10.33, 95% CI [−19.08, −1.57]) than healthy controls. The foveal VD and parafoveal VD of superficial capillary plexus, parafoveal VD of deep capillary plexus, CFT, area, and perimeter of FAZ showed no significant differences between the groups.
Conclusion
The patients of nonacute infectious COVID-19 or post-COVID-19 displayed alterations in the retinal microvasculature and choroidal vessels, including a significantly lower foveal VD in deep capillary plexus and thinner SCT. The impairment may be a medium to long-term process. Close ophthalmic surveillance is necessary for COVID-19 patients or post-COVID-19 patients.

Eyes

3276

OO169

Nasir Saleem
Betty H. Li
Raj Vuppalanchi
Samer Gawrieh
Mark A. Gromski

Critical Illness Cholangiopathy in COVID-19 Long-Haulers

https://doi.org/10.1016/j.tige.2022.05.006

Published

21-May-22

Study

https://www.tigejournal.org/article/S2590-0307(22)00048-4/fulltext

On March 11, 2020, the World Health Organization declared COVID-19 a pandemic, and as of May 11, 2022, there were over 516 million confirmed cases of COVID-19 and more than 6.2 million deaths. [[1.]] COVID-19 has affected all age groups, and risk factors for severe illness or death include older age, comorbid chronic illnesses such as respiratory illnesses, diabetes, obesity, and hypertension. [[2.]] Although, respiratory illness and pneumonia are a defining feature and determinant of morbidity and mortality in COVID-19 patients, the virus has the capability to affect multiple organ systems, including the gastrointestinal tract. COVID-19 is frequently associated with abnormal liver tests, with no disease-specific features on biopsy. [[3.]] The incidence of abnormal serum liver biochemistries in hospitalized patients have been reported to range from 14%-58%. [[4.]] There have been increasing reports of long-term sequalae of COVID-19 and the term “long-haulers” has been used for patients who have recovered from the acute phase of illness but have persistent symptoms, including chronic respiratory, neurologic and psychiatric effects. [[5.], [6.]] Faruqui et al. described a syndrome in patients recovering from severe COVID-19 infection, characterized by abnormal liver tests, with marked elevation in serum alkaline phosphatase and abnormal appearance of the biliary tract on imaging, frequently with strictures similar to secondary sclerosing cholangitis seen in critically ill patients. [[3.], [7.]] The mean time to recognition of this syndrome was over 3 months after admission and all patients had been critically ill and required intensive care. This syndrome has also been reported by other authors and appears to have important consequences for long-term morbidity, patient recovery, need for liver transplantation and mortality after recovery from other manifestations of COVID-19. [8., 9., 10.]
Biliary cast formation is a complication reported in 2.1%–3.6% of patients after liver transplantation (LT). [[11.]] It has been defined as hardened material molded to the bile ducts and contains fragments of biliary epithelium, leading to obstructive jaundice and cholangitis. [[12.], [13.]] It has been hypothesized that biliary cast formation is caused by ischemic biliary injury. Therapeutic options include cast removal during endoscopic retrograde cholangiopancreatography and stent placement. [[11.]] In both cases presented, the clinical picture was consistent with biliary cast syndrome with secondary sclerosing cholangitis, related to severe COVID infection leading to critical illness. It is plausible that COVID-associated cast-forming cholangiopathy is a manifestation of critical illness cholangiopathy, which has previously been described. [[7.]] Purported pathogenetic mechanisms may include bile duct ischemia related to COVID-19–associated thrombosis or direct biliary epithelial viral infection. [[3.], [7.]] It is plausible that the resultant hypoxic injury to biliary epithelium leads to biliary cast formation and biliary strictures. Little is known about the natural history of such patients, but in our case, we believed that endoscopically clearing large casts with ERCP may help to prevent further ongoing worsening of secondary sclerosing cholangitis. The ultimate optimal management for such patients is not known. In conclusion, cholangiopathy with biliary cast formation is an important late complication of COVID-19 infection that requires further study to elucidate the underlying pathogenesis, natural history, therapeutic options and long-term outcomes.

Liver

3277

OO170

Waldemar Kanczkowski, Felix Beuschlein & Stefan R. Bornstein

Is there a role for the adrenal glands in long COVID?

https://doi.org/10.1038/s41574-022-00700-8

Published

30-May-22

Article

https://www.nature.com/articles/s41574-022-00700-8

The symptoms of long COVID and chronic adrenal insufficiency have striking similarities. Therefore, we aim to raise awareness of assessing adrenal function in patients with long COVID.
After the acute phase of SARS-CoV-2 infection, roughly 20% of patients report one or more complications, which are particularly apparent during mental or physical stress. These complications include extreme chronic fatigue, shortness of breath, sleep abnormalities, headache, brain fog, joint pains, nausea, cough and abdominal pain. When symptoms persist for more than four weeks after initial infection and cannot be attributed to other known diseases, they are described as long COVID1. When comparing the clinical presentation of long COVID and chronic adrenal insufficiency, overlap between the conditions can be seen, suggesting that long COVID might be related to some form of adrenal dysfunction2. Here we discuss the role of the adrenal glands in long COVID.

Taken together, adrenal gland insufficiency in patients with COVID-19 might be induced through different mechanisms, including vascular damage, viral replication, inflammatory factors and improper tapering off of long-term steroid replacement. Further studies are needed to define the role of the adrenal gland in long COVID and the potential benefit of low dose glucocorticoid replacement.
In conclusion, SARS-CoV-2 targets the adrenal gland and can cause adrenal insufficiency in some patients. Furthermore, numerous patients with COVID-19 have received glucocorticoid treatment over an extended period of time, therefore we believe that adrenal gland insufficiency needs to be considered and carefully ruled out in all patients with COVID-19 and long COVID.

Adrenal glands

3278

OO171

MainakBanerjeea1RimeshPalb1SulagnaDuttac

Risk of incident diabetes post-COVID-19: A systematic review and meta-analysis

https://doi.org/10.1016/j.pcd.2022.05.009

Published

30-May-22

Systematic review and meta-analysis

https://www.sciencedirect.com/science/article/pii/S1751991822001000

Highlights
•Pooled analysis showed higher risk of incident diabetes following hospital discharge or at least 28 days after the COVID-19 diagnosis.
•Evidence suggests sole contribution of type 2 diabetes on burden of incident diabetes post-acute COVID-19.
•Screening is essential during post-acute COVID-19 phase regardless of the disease severity or history of steroid use.
•Given the high risk of DM even in pediatric population, we emphasize on vaccinating all persons irrespective of age.
It remains undetermined whether burden of diabetes newly detected during acute COVID-19 persist in post-acute COVID phase. This meta-analysis was conducted to summarize the available literature and provide a pooled estimate of the risk of developing incident diabetes following hospital discharge or at least 28 days after the COVID-19 diagnosis compared to matched controls or severity matched influenza/ non-COVID-19 acute upper respiratory tract infections (AURI). Pooled analysis of 5787,027 subjects from four observational studies showed 59 % higher risk of developing incident diabetes in post-acute COVID-19 phase versus healthy controls (HR:1.59; 95 % CI:1.40–1.81, p < 0.001, I2=94 %, random-effects model). The high degree of heterogeneity in pooled estimate can be attributed to difference in demographic characteristics, hospitalization rates or disease severity between study subjects. Pooling data from three studies, higher risk of incident diabetes was also observed following COVID-19 versus severity matched non-COVID-19 respiratory tract infections (moderate-severe/hospitalized cases, HR 1.52; 95 % CI: 1.36–1.70, p < 0.01, I2=0 %, fixed-effects model; mild cases, HR 1.22; 95 % CI: 1.14–1.31, p < 0.001; I2=0 %, fixed-effects model). Majority of studies had median follow-up period of around 4 months. In view of several limitations due to retrospective design of these studies, prospective studies with long term follow-up are warranted.

Pancreas

3279

OO172

Tsung-Hsien Chen 1,†ORCID,Ming-Tse Hsu 2,†,Ming-Yang Lee 1,3,4,* andChu-Kuang Chou 2,5,6,*ORCID

Gastrointestinal Involvement in SARS-CoV-2 Infection

https://doi.org/10.3390/v14061188

Published

30-May-22

Review

https://www.mdpi.com/1999-4915/14/6/1188/htm

SARS-CoV-2 has evolved into a virus that primarily results in mild or asymptomatic disease, making its transmission more challenging to control. In addition to the respiratory tract, SARS-CoV-2 also infects the digestive tract. Some gastrointestinal symptoms occur with or before respiratory symptoms in patients with COVID-19. Respiratory infections are known to cause intestinal immune impairment and gastrointestinal symptoms. When the intestine is inflamed, cytokines affect the lung immune response and inflammation through blood circulation. The gastrointestinal microbiome may be a modifiable factor in determining the risk of SARS-CoV-2 infection and disease severity. The development of oral SARS-CoV-2 vaccine candidates and the maintenance of gut microbiota profiles may contribute to the early control of COVID-19 outbreaks. To this end, this review summarizes information on the gastrointestinal complications caused by SARS-CoV-2, SARS-CoV-2 infection, the gastrointestinal–lung axis immune response, potential control strategies for oral vaccine candidates and maintaining intestinal microbiota homeostasis.

Gastro-intestinal

3280

OO173

Allyah Abbas-Hanif, honorary clinical senior lecturer12, Neena Modi, professor of neonatal medicine3, Azeem Majeed, professor of primary care and public health1

Long term implications of covid-19 in pregnancy

https://doi.org/10.1136/bmj-2022-071296

Published

31-May-22

Editorial

https://www.bmj.com/content/377/bmj-2022-071296

We must characterise the risks and take urgent steps to reduce harm
Complications in pregnancy, including maternal and perinatal deaths, increased with each wave of the covid-19 pandemic. By contrast, serious illness fell in other high risk groups because of vaccines and approved treatments.1 More than a year after the UK’s Joint Committee on Vaccination and Immunisation (JVCI) opened up covid-19 vaccination to pregnant women, 40% of women giving birth have still not received a first dose.2 This is despite a positive benefit-risk profile, endorsement in guidelines, and public health campaigns. Worryingly, 69.5% of black women giving birth have not received any covid-19 vaccine.2
Meanwhile the JCVI has chosen not to include pregnant women in its interim autumn booster plans.3 Strategies for treating covid-19 in pregnancy and potential long term complications are also underused.1 A large portion of the diffidence for both vaccination and treatment in pregnancy stems from the continued exclusion of pregnant women from much of the pre-approval drug development process. This results in delayed or even absent data on benefit-risk profiles and a dangerous spiral of indecision.4
The public health implications for postpartum women are unclear, but some key considerations are increased cardiovascular risk, including in future pregnancies; the impact of long covid; and the effect of ethnic and socioeconomic inequalities that widened during the pandemic.4 The downstream amplification of cardiovascular risk for women who have covid-19 in pregnancy must not be overlooked. Covid-19 during pregnancy substantially increases the risk of pre-eclampsia,5 which could increase cardiovascular disease later in life.6 In addition, acute covid-19 significantly increases the risks and one year burden of cardiovascular disease in the general population.7

Reproductive System

3281

OO174

Eva K. Hejbøl,Thomas Harbo,Jane Agergaard,Line B. Madsen,Thomas H. Pedersen,Lars J. Østergaard,Henning Andersen,Henrik D. Schrøder,Hatice Tankisi

Myopathy as a cause of fatigue in long-term post-COVID-19 symptoms: Evidence of skeletal muscle histopathology

https://doi.org/10.1111/ene.15435

Published

6-Jun-22

Study

https://onlinelibrary.wiley.com/doi/10.1111/ene.15435

Background
Among post-COVID-19 symptoms, fatigue is reported as one of the most common, even after mild acute infection, and as the cause of fatigue, myopathy diagnosed by electromyography has been proposed in previous reports. This study aimed to explore the histopathological changes in patients with post-COVID-19 fatigue.
Methods
Sixteen patients (mean age:46 years) with post-COVID-19 complaints of fatigue, myalgia or weakness persisting for up to 14 months were included. In all patients, quantitative electromyography and muscle biopsies analysed with light and electron microscopy were taken.
Results
Muscle weakness was present in 50%, myopathic electromyography in 75% while in all patients, there were histological changes. Muscle fiber atrophy was found in 38%, and 56% showed indications of fiber regeneration. Mitochondrial changes, comprising loss of COX activity, subsarcollemmal accumulation and/or abnormal cristae, were present in 62%. Inflammation was found in 62%, seen as T-lymphocytes and/or muscle fiber HLA-ABC expression. In 75%, capillaries were affected involving basal lamina and cells. In two patients, uncommon amounts of basal lamina were found, not only surrounding muscle fibers but also around nerves and capillaries.
Conclusions
The wide variety of histological changes in this study suggest that skeletal muscles may be a major target of SARS-CoV-2 causing muscular post-COVID-19 symptoms. The mitochondrial changes, inflammation and capillary injury in muscle biopsies can cause fatigue in part due to reduced energy supply. Since most patients had mild-moderate acute affection, the new variants that might cause less severe acute disease could still have the ability to cause long-term myopathy.

Muscles

3282

OO175

Pires, Robinson E. MD, PhD1,2,3; Reis, Igor G.N. MD1,a; Waldolato, Gustavo S. MD2,3; Pires, Diego D. MD4; Bidolegui, Fernando MD5; Giordano, Vincenzo MD, PhD6

What Do We Need to Know About Musculoskeletal Manifestations of COVID-19?
A Systematic Review

https://doi.org/JBJS.RVW.22.00013

Published

1-Jun-22

Review

https://journals.lww.com/jbjsreviews/Abstract/2022/06000/What_Do_We_Need_to_Know_About_Musculoskeletal.1.aspx

» COVID-19 is a disease that is challenging science, health-care systems, and humanity. An astonishingly wide spectrum of manifestations of multi-organ damage, including musculoskeletal, can be associated with SARS-CoV-2.
» In the acute phase of COVID-19, fatigue, myalgia, and arthralgia are the most common musculoskeletal symptoms.
» Post-COVID-19 syndrome is a group of signs and symptoms that are present for >12 weeks. The associated musculoskeletal manifestations are fatigue, arthralgia, myalgia, new-onset back pain, muscle weakness, and poor physical performance.
» Data on COVID-19 complications are growing due to large absolute numbers of cases and survivors in these 2 years of the pandemic. Additional musculoskeletal manifestations encountered are falls by the elderly, increased mortality after hip fracture, reduced bone mineral density and osteoporosis, acute sarcopenia, rhabdomyolysis, Guillain-Barré syndrome, muscle denervation atrophy, fibromyalgia, rheumatological disease triggering, septic arthritis, adhesive capsulitis, myositis, critical illness myopathy, onset of latent muscular dystrophy, osteonecrosis, soft-tissue abscess, urticarial vasculitis with musculoskeletal manifestations, and necrotizing autoimmune myositis.
» A wide range of signs and symptoms involving the musculoskeletal system that affect quality of life and can result in a decrease in disability-adjusted life years. This powerful and unpredictable disease highlights the importance of multimodality imaging, continuing education, and multidisciplinary team care to support preventive measures, diagnosis, and treatment.

Muscles

3283

OO176

Dulce González-Islas, Carlos Sánchez-Moreno, Arturo Orea-Tejeda, Samantha Hernández-López, Fernanda Salgado-Fernández, Candace Keirns-Davis, Susana Galicia-Amor, Esperanza Trejo-Mellado, Laura Gochicoa-Rangel & Armando Castorena-Maldonado

Body composition and risk factors associated with sarcopenia in post-COVID patients after moderate or severe COVID-19 infections

https://doi.org/10.1186/s12890-022-02014-x

Published

8-Jun-22

Study

https://bmcpulmmed.biomedcentral.com/articles/10.1186/s12890-022-02014-x

Background
Post-COVID-19 syndrome is characterized by diverse symptoms and abnormalities that persist beyond 12 weeks from the onset of acute COVID-19. Severity disease has been associated with more musculoskeletal alterations such as muscle weakness, dyspnea, and distance walking. The aim was to evaluate the impact of invasive mechanical ventilation (IMV) on body composition and investigate risk factors associated with sarcopenia in post-COVID-19 patients three months after moderate or severe COVID-19 infections.
Methods
Cross-sectional study. 530 patients with PCR-confirmed diagnoses of moderate to severe COVID-19, > 18 years old, oxygen saturation ≤ 93%, PaO2/FiO2 ratio < 300, who required hospitalization and were discharged were included. We excluded those who died before the follow-up visit, declined to participate, or could not be contacted.
Results
The mean age was 53.79 ± 12.90 years. IMV subjects had lower phase angle and handgrip strength and higher impedance index, frequency of low muscle mass, and low muscle strength than those without IMV. The risk factors of sarcopenia were > 60 years of age, diabetes, obesity, IMV, and prolonged hospital stay. The multivariate model showed that age > 60 years (OR: 4.91, 95% CI: 2.26–10.63), obesity (OR: 3.73, 95% CI: 1.21–11.54), and interaction between prolonged length of hospital stay and IMV (OR: 2.92; 95% CI: 1.21–7.02) were related to a higher risk of sarcopenia.
Conclusion
Obesity and the interaction between prolonged length of hospital stay and IMV are associated with a higher risk of sarcopenia at 3 months after severe or moderate COVID-19 infection.

Muscles

3284

OO177

R. Jain
V. Seshiah
N. Bhavatharini
R. Shoghli
R. Jain
S. Davey
N. Bhavatharini
T. Mohammadabadi

IDF21-0353 Covid19 toe, a late manifestation of mild SARS-CoV-2 with Diabetes

https://doi.org/10.1016/j.diabres.2022.109342

Published

1-Apr-22

Study

https://www.diabetesresearchclinicalpractice.com/article/S0168-8227(22)00154-1/fulltext

Background: SARS-CoV-2 may present with symptoms, coughing, fever, weakness, and breathlessness. Other common symptoms are discoloring skin, rashes or toes color changes, swelling, present with pain, and some individuals without pain.
Some researchers think that these rashes are due to respiratory tract infection, which invades the peripheral skin. It has no relation with the Raynaud phenomena because of the periphery's coldness, stress, or ischemia and low blood supply to a region affected.
Aim: No all the Patients with Covid-19 toes are favorable for the Covid-19 testing, and some develop covid-19 toes after the symptoms of covid-19 have subsided; therefore, it grows in the different stages of covid-19 infection and not necessarily reflected inactive phases of the covid-19 disease.
On the other hand, many patients with Covid-19 toes do not have severe symptoms but mild congestion and fever at a younger age, leading to kolviras et al. to propose a mechanism for antiviral response mediated by more immature immune cells.
Method: The Covid-19 toe primarily presents moderate to severe levels in half of the cases, which show damage to vessels and leaking of blood, which directly links to inflammation. However, even when inflammation was mild, there was evidence of damage to the vasculature and leaking.
We do not know much about the cause of Covid-19 toe. Still, some researchers suggested coagulation pathways and various interferons might be responsible. Others say viral particles may lead to immune cells proliferating and cause the bursting of covid-19 toes. The findings of SARS-CoV-2 on endothelial cells of a skin lesion by immunohistochemistry show the pathophysiology of COVID-19.
Results: Patient-reported on 20 July 2020 developed mild symptoms of Covid-19 with mild fever, dry cough, smell loss nearly wholly, and headache for four days; RTPCR for SARS-CoV-2%25 were positive. The patient had a history of diabetes for 10 years, without hypertension, or any chronic disease. Pt received Vavipiravir 3.6 gm in 14 days, Ivermectin 12 mg once a day for five days, along with VitD3 60,000 IU, Doxycycline for seven days. After three days of starting antiviral drugs favipiravir, the symptoms were relieved, and fever subsided after five days. Patients developed reddish discoloration of great right toes after one month of symptoms with involvement of almost two-thirds of the toe with no pain or any pus formation (fig 1). It took eleven months to grow a new nail and replace most dark red discoloration, still, a broken nail at the upper margin.
Discussion: It's not a common manifestation of covid-19 infection. It may last from weeks to months, and some may not require treatment except for some with topical steroids. In this patient involvement of a single toe started after one month of infection and partial recovery of new growth of nail took 11 months which shows even in mild covid19 infection peripheral vascular complication may manifest after the infection subsided and may continue even after one year of post covid19. Therefore we need to keep watch and screen all the post covid19 patients.

Skin

3285

OO178

Rajiv K Saxena, Monica Basavaraju, T Meghana

Effect of COVID-19 Infection on Menstruation: A Retrospective Study

https://doi.org/10.5005/jp-journals-10006-2025

Published

6-Mar-22

Study

https://www.jsafog.com/abstractArticleContentBrowse/JSAFOG/6/14/2/28196/abstractArticle/Article

Background: The global coronavirus disease-2019 (COVID-19) pandemic has infected a large subset of women in the reproductive age-group, but the effect of COVID-19 infection on menstruation is still unclear. This study outlines the influence of COVID-19 infection on the menstrual cycle.
Methods: Women in the reproductive age-group, admitted with COVID-19 infection were followed up with a structured telephonic interview. Women with previously regular menstrual cycles were included in the study. The questions included severity of COVID-19 infection, details of menstrual cycle before and after the infection, and COVID-related stress recorded by Perceived Stress Scale-10.
Results: Data from 350 women with COVID-19 infection were presented. Moreover, 59.1% (n = 207) of women reported a change in their menstrual cycles. About 43.7% (n = 153) noted changes in the volume of flow with 78.4% (n = 120/153) experiencing less flow. Irregular menstrual cycles were reported by 37.1% (n = 130) women, 50.8% (n = 66/130), experienced infrequent menstruation, with delay varying from 45 to 90 days, and 13.8% (n = 18/130) of these women also experienced intermenstrual spotting. Most of these women recovered, and only 17.1% continue to have irregular menstrual cycles even after 1 year of COVID infection. Moreover, 34.28% (n = 120) reported worsening of premenstrual symptoms, and 22.44% (n = 55) reported worsening of dysmenorrhea after the COVID-19 infection. The stress score was not significantly associated with the severity of COVID-19 infection (p >0.05). Social factors like concern about health of other family members, quarantine, and isolation were the biggest contributors to stress.
Conclusion: COVID-19 infection and associated stress can influence normal menstruation.
Clinical significance: The findings of this study outline the short- and long-term effects of COVID-19 infection on menstruation. This information can be used to reassure the patients and will be helpful in counseling to allay their fears related to altered menstrual cycles after the COVID-19 infection.

Female reproductive system

3286

OO179

Yuanzhi Xie, Mina Mirzaei, Mohammad Saeed Kahrizi, Alireza Mohammadzade Shabestari, Seyed Mohammad Riahi, Marziye Farsimadan & Giandomenico Roviello

SARS-CoV-2 effects on sperm parameters: a meta-analysis study

https://doi.org/10.1007/s10815-022-02540-x

Published

18-Jun-22

Meta-analysis

https://link.springer.com/article/10.1007/s10815-022-02540-x

Aim
The rapid outbreak of the coronavirus disease 2019 (COVID-19) pandemic posed challenges across different medical fields, especially reproductive health, and gave rise to concerns regarding the effects of SARS-CoV-2 on male infertility, owing to the fact that the male reproductive system indicated to be extremely vulnerable to SARS-CoV-2 infection. Only a small number of studies have investigated the effects of SARS-CoV-2 on male reproduction, but the results are not consistent. So, we performed this meta-analysis to draw a clearer picture and evaluate the impacts of COVID-19 on male reproductive system.
Method
We searched Embase, Web of Science, PubMed, and Google Scholar databases to identify the potentially relevant studies. Standardized mean difference (SMD) with 95% confidence interval (CI) was applied to assess the relationship. Heterogeneity testing, sensitivity analysis, and publication bias testing were also performed.
Results
A total of twelve studies including 7 case control investigations and 5 retrospective cohort studies were found relevant and chosen for our research. Our result showed that different sperm parameters including semen volume [SMD = − 0.27 (− 0.46, − 1.48) (p = 0.00)], sperm concentration [SMD = − 0.41 (− 0.67, − 0.15) (p = 0.002)], sperm count [SMD = − 0.30 (− 0.44, − 0.17) (p = 0.00)], sperm motility [SMD = − 0.66 (− 0.98, − 0.33) (p = 0.00)], and progressive motility [SMD = − 0.35 (− 0.61, − 0.08) (p = 0.01)] were negatively influenced by SARS-CoV-2 infection. However, sperm concentration (p = 0.07) and progressive motility (p = 0.61) were not found to be significantly associated with SARS-CoV-2 infection in case control studies. No publication bias was detected.
Conclusion
The present study revealed the vulnerability of semen quality to SARS-CoV-2 infection. Our data showed a strong association of different sperm parameters with SARS-CoV-2 infection. The results suggested that SARS-CoV-2 infection in patients may negatively influence their fertility potential in a short-term period, but more studies are needed to decide about the long-term effects.

Male reproductive system

3287

OO180

Olatundun D. Awosanya, Ushashi C. Dadwal, Erik A. Imel, Qigui Yu & Melissa A. Kacena

The Impacts of COVID-19 on Musculoskeletal Health

https://doi.org/10.1007/s11914-022-00734-x

Published

20-Jun-22

Review

https://link.springer.com/article/10.1007/s11914-022-00734-x

Purpose of Review
Although COVID-19 was originally characterized as a respiratory disease, recent findings have shown lingering side effects in those who have recovered, and much is still unknown about the long-term consequences of the illness. Thus, the potential of unearthing multi-system dysfunction is high, with current data revealing significant impacts on musculoskeletal health.
Recent Findings
Multiple animal models of COVID-19 infection have revealed significant post-infection bone loss at several different skeletal sites. While how this loss occurred is unknown, this current review discusses the primary bone loss studies, and examines the possible mechanisms of action including: direct infection of bone marrow macrophages or hematopoietic progenitors, a proinflammatory response as a result of the COVID-19 induced cytokine storm, and/or a result of hypoxia and oxidative stress. This review will further examine how therapeutics used to treat COVID-19 affect the skeletal system. Finally, this review will examine the possible consequence that delayed care and limited healthcare accessibility has on musculoskeletal-related patient outcomes.
Summary
It is important to investigate the potential impact COVID-19 infection has on musculoskeletal health.

Muscles

3288

OO181

Khoja O , Silva Passadouro B, Mulvey M , Delis I, Astill S , Tan AL , Sivan M

Clinical Characteristics and Mechanisms of Musculoskeletal Pain in Long COVID

https://doi.org/10.2147/JPR.S365026

Published

17-Jun-22

Review

https://www.dovepress.com/clinical-characteristics-and-mechanisms-of-musculoskeletal-pain-in-lon-peer-reviewed-fulltext-article-JPR

Objective: Musculoskeletal (MSK) pain is being increasingly reported by patients as one of the most common persistent symptoms in post-COVID-19 syndrome or Long COVID. However, there is a lack of understanding of its prevalence, characteristics, and underlying pathophysiological mechanisms. The objective of this review is to identify and describe the features and characteristics of MSK pain in Long COVID patients.
Methods: The narrative review involved a literature search of the following online databases: MEDLINE (OVID), EMBASE (OVID), CINAHL, PsyclNFO, and Web of Science (December 2019 to February 2022). We included observational studies that investigated the prevalence, characteristics, risk factors and mechanisms of MSK pain in Long COVID. After screening and reviewing the initial literature search results, a total of 35 studies were included in this review.
Results: The overall reported prevalence of MSK pain in Long COVID ranged widely from 0.3% to 65.2%. The pain has been reported to be localized to a particular region or generalized and widespread. No consistent pattern of progression of MSK pain symptoms over time was identified. Female gender and higher BMI could be potential risk factors for Long COVID MSK pain, but no clear association has been found with age and ethnicity. Different pathophysiological mechanisms have been hypothesized to contribute to MSK pain in Long COVID including increased production of proinflammatory cytokines, immune cell hyperactivation, direct viral entry of neurological and MSK system cells, and psychological factors.
Conclusion: MSK pain is one of the most common symptoms in Long COVID. Most of the current literature on Long COVID focuses on reporting the prevalence of persistent MSK pain. Studies describing the pain characteristics are scarce. The precise mechanism of MSK pain in Long COVID is yet to be investigated. Future research must explore the characteristics, risk factors, natural progression, and underlying mechanisms of MSK pain in Long COVID.

Muscles

3289

OO182

Fernández-de-las-Peñas, César Med1,2,*; Cancela-Cilleruelo, Ignacio PT, MSc1; Moro-López-Menchero, Paloma PT, MSc1; Rodríguez-Jiménez, Jorge PT, MSc1; Pellicer-Valero, Oscar J.3; Martín-Guerrero, José D.3; Arendt-Nielsen, Lars Med2,4

Exploring the trajectory curve of long-term musculoskeletal post-COVID pain symptoms in hospitalized COVID-19 survivors: a multicenter study

https://doi.org/10.1097/j.pain.0000000000002718

Published

13-Jun-22

Study

https://journals.lww.com/pain/Abstract/9900/Exploring_the_trajectory_curve_of_long_term.117.aspx

This multicenter cohort study investigated the prevalence of musculoskeletal post-COVID pain during the first year after the infection with mosaic plots and an exponential bar plot model, and its associated risk factors. Patients hospitalised due to COVID-19 in five hospitals of Madrid (Spain) were scheduled for a telephone interview at two follow-up periods after hospitalization for collecting data about musculoskeletal post-COVID pain. Hospitalisation and clinical data were collected from hospital medical records. From 2,000 patients initially recruited, 1,593 (44.6% women, age: 61±15 years) were assessed at T0 (hospital admission), T1 (mean: 8.0±1.5 months after discharge) and T2 (mean: 13.2±1.5 months after discharge). The prevalence of musculoskeletal pain (myalgia) was 30.3% (n=483) at T0, increased to 43.4% (n=692) at T1 and decreased to 37.8% (n=603) at T2. The trajectory curve revealed a decreasing prevalence trend of musculoskeletal post-COVID pain the following years after hospitalization. According to the presence of pre-existing pain symptoms, the prevalence of new-onset post-COVID pain was 75.9%. Female sex (OR1.593, 95%CI 1.148-2.211), history of musculoskeletal pain (OR1.591, 95%CI 1.211-2.07), the presence of myalgia (OR1.371, 95%CI 1.032-1.821) or headache (OR2.278, 95%CI 1.622-3.199) at hospitalization, the days of hospitalization (OR1.013, 95%CI 1.000-1.025), and the presence of post-COVID pain at T1 (OR11.02, 95%CI 8.493-14.305) were factors associated with musculoskeletal post-COVID pain one-year after hospitalization. In conclusion, musculoskeletal post-COVID pain remains highly prevalent one-year after hospitalization. Female sex, previous history of pain symptoms, pain symptoms at onset, and days at hospital were factors associated with musculoskeletal post-COVID pain one-year after hospitalization.

Muscles

3290

OO183

F.Retornaz1S.Rebaudet2C.Stavris3Y.Jammes4

Conséquences neuromusculaires à long terme de la COVID-19 : analogies avec l’encéphalomyélite myalgique/syndrome de fatigue chronique

https://doi.org/10.1016/j.revmed.2022.03.308

Published

15-Jun-22

Study

https://www.sciencedirect.com/science/article/pii/S0248866322003927

Introduction
De nombreux patients infectés par SARS-CoV-2 présentent dans les mois qui suivent l’infection des symptômes non spécifiques de type fatigue non résolutive, myalgies, céphalées, troubles cognitifs, faiblesse musculaire…[1]. On appelle la persistance de ces symptômes « syndrome post-COVID » ou « COVID long ». Une métanalyse de Wong et Weitzer [2] portant sur des patients souffrant de syndrome post-COVID suggère des analogies cliniques avec l’encéphalomyélite myalgique/syndrome de fatigue chronique (EM/SFC), qui fait suite dans plus de 50 % des cas à une infection bactérienne ou virale. Une majorité de patients souffrant de EM/SFC présentent des désordres neuromusculaires caractérisés par une altération des myopotentiels (onde M) déclenchée par l’exercice et persistant en récupération.
L’objectif de ce travail était de comparer l’existence d’altérations des ondes M chez des patients souffrants de syndrome post-COVID et d’EM/SFC post infectieuse datant de moins de 2 ans.
Patients et méthodes
Cette étude rétrospective a inclu 55 patients souffrant de syndrome post-COVID ainsi que 62 patients souffrant de EM/SFC (explorés sur la même période et relatant un ou plusieurs épisodes d’infection sévère ayant précédé dans les 2 ans la survenue de la fatigue chronique). Le protocole d’exploration de la fatigue chronique consistait en un interrogatoire sur la symptomatologie neuromusculaire associée et un test d’effort sur ergocycle atteignant au moins 80 % de la puissance maximale théorique. Avant, pendant et après l’exercice un électromyogramme de surface du muscle Rectus femoris avec mesure de l’onde M déclenchée par neurostimulation directe de ce muscle (mesure d’amplitude et de durée) a été réalisé.
Résultats
La moyenne d’âge était respectivement de 46 ans (±2) pour le groupe post-COVID et 44 ans (± 3) pour le groupe EM/SFC, avec une nette prédominance féminine (71 % pour le groupe EM/SFC et 74 % pour le groupe post-COVID). La fréquence des symptômes neuromusculaires (myalgies, dégradation du sommeil, troubles cognitifs, et malaise post-exercice) était identique dans les deux groupes post-COVID et EM/SFC (respectivement : 78 % versus 84 %, 82 % versus 76 %, 82 % versus 86 %, 73 % versus 73 %). La fréquence des altérations des ondes M était similaire dans les groupes post-covid et EM/SFC (respectivement 48 % et 41 %). Le pourcentage de réduction d’amplitude et d’allongement de durée étaient identiques dans les 2 groupes (respectivement −43 ± 4 % et + 16 ±4 %).
Conclusion
Cette étude suggère que certains patients souffrant de syndrome post-COVID présentent de façon précoce des anomalies neuromusculaires fréquemment retrouvées dans l’EM/SFC. Des études longitudinales pourront permettre de déterminer si ces troubles persistent et s’autonomisent dans le temps.

Muscles

3291

OO184

Haytham Al-Mahalawy, Yehia El-Mahallawy, Noha Y. Dessoky, Sally Ibrahim, Hatem Amer, Haytham Mohamed Ayad, Hagar Mahmoud El Sherif & Alshaimaa Ahmed Shabaan

Post-COVID-19 related osteonecrosis of the jaw (PC-RONJ): an alarming morbidity in COVID-19 surviving patients

https://doi.org/10.1186/s12879-022-07518-9

Published

14-Jun-22

Case Series

https://link.springer.com/article/10.1186/s12879-022-07518-9

Purpose
The recent coronavirus disease (COVID-19) pandemic mainly affects the respiratory system; however, several oral and maxillofacial post-COVID-19 complications have also been observed. This series reports the growing number of osteonecrosis cases associated with post-COVID-19 patients.
Materials and methods
This is a retrospective, multi-center case series that reports cases with maxillary osteonecrosis after various periods of SARS-CoV-2 infection in the period between January and August 2021 based on the PROCESS guidelines.
Results
Twelve cases were reported with post-COVID-19 manifestation of spontaneous osteonecrosis of the maxillary jaw. Five patients were hospitalized during COVID-19 management and all of the twelve cases had at least one systematic Co-morbidity, and undertake corticosteroids prescription based on the COVID-19 disease treatment protocol. The mean onset of osteonecrosis symptoms appearance was 5.5 ± 2.43 weeks calculated from the day of the negative PCR test. The management was successfully done through surgical debridement and pre and post-operative antibiotics. No anti-fungal medications were prescribed as the fungal culture and the histopathological report were negative.
Conclusion
Post-COVID-related osteonecrosis of the jaw (PC-RONJ) could be now considered as one of the potential post-COVID-19 oral and maxillofacial complications that occurs unprovokedly and mainly in the maxilla.

Jaw

3292

OO185

Anna Maria Martone,Matteo Tosato,Francesca Ciciarello,Vincenzo Galluzzo,Maria Beatrice Zazzara,Cristina Pais,Giulia Savera,Riccardo Calvani,Emanuele Marzetti,Maria Camprubi Robles,Maria Ramirez,Francesco Landi,Gemelli Against COVID-19 Post-Acute Care Team … See fewer authors

Sarcopenia as potential biological substrate of long COVID-19 syndrome: prevalence, clinical features, and risk factors

https://doi.org/10.1002/jcsm.12931

Published

14-Jun-22

Study

https://onlinelibrary.wiley.com/doi/10.1002/jcsm.12931

Background
Severe clinical pictures and sequelae of COVID-19 disease are immune mediated and characterized by a ‘cytokine storm’. Skeletal muscle has emerged as a potent regulator of immune system function. The aim of the present study is to define the prevalence of sarcopenia among COVID-19 survivors and the negative impact of sarcopenia on the post-acute COVID-19 syndrome and its related risk factors.
Methods
A total of 541 subjects recovered from COVID-19 disease were enrolled in the Gemelli Against COVID-19 Post-Acute Care between April 2020 and February 2021. They underwent a multidisciplinary clinical evaluation and muscle strength and physical performance assessment.
Results
Mean age was 53.1 years (SD 15.2, range from 18 to 86 years), and 274 (51%) were women. The prevalence of sarcopenia was 19.5%, and it was higher in patients with a longer hospital stay and lower in patients who were more physically active and had higher levels of serum albumin. Patients with sarcopenia had a higher number of persistent symptoms than non-sarcopenic patients (3.8 ± 2.9 vs. 3.2 ± 2.8, respectively; P = 0.06), in particular fatigue, dyspnoea, and joint pain.
Conclusions
Sarcopenia identified according to the EWGSOP2 criteria is high in patients recovered from COVID-19 acute illness, particularly in those who had experienced the worst clinical picture reporting the persistence of fatigue and dyspnoea. Our data suggest that sarcopenia, through the persistence of inflammation, could be the biological substrate of long COVID-19 syndrome. Physical activity, especially if associated with adequate nutrition, seems to be an important protective factor.

Muscles

3293

OO186

Mingjia Luo, Maria Pilar Ballester, Ugo Soffientini, Rajiv Jalan & Gautam Mehta

SARS-CoV-2 infection and liver involvement

https://doi.org/10.1007/s12072-022-10364-1

Published

29-Jun-22

Review

https://link.springer.com/article/10.1007/s12072-022-10364-1

The COVID-19 pandemic is the largest public health challenge in living memory. Patients with underlying liver disease have been disproportionately affected, experiencing high morbidity and mortality. In addition, elevated liver enzymes appear to be a risk factor for disease progression, even in the absence of underlying liver disease. Nevertheless, the mechanism of liver injury in SARS-CoV-2 infection remains largely unknown. This review aims to provide an overview of the mechanisms by which SARS-CoV-2 induces liver injury, and the impact of COVID-19 on cirrhosis, alcohol-related liver disease, autoimmune liver disease, non-alcoholic fatty liver disease, hepatitis B and C virus infection, liver-transplant recipients and patients with hepatocellular carcinoma. Finally, emerging data on vaccination in liver diseases is discussed, to help inform public health policy.

Liver

3294

OO187

Cristina Tudoran 1,2,3,4ORCID,Mariana Tudoran 1,2,3,*,Talida Georgiana Cut 4,5,6,7,*ORCID,Voichita Elena Lazureanu 5,Felix Bende 1,3,8ORCID,Renata Fofiu 3,7,8,Alexandra Enache 6,9,Silvius Alexandru Pescariu 4,10ORCID andDorin Novacescu 3,4,7ORCID

The Impact of Metabolic Syndrome and Obesity on the Evolution of Diastolic Dysfunction in Apparently Healthy Patients Suffering from Post-COVID-19 Syndrome

https://doi.org/10.3390/biomedicines10071519

Published

27-Jun-22

Study

https://www.mdpi.com/2227-9059/10/7/1519/htm

Background: Coronavirus disease 2019 (COVID-19) has a worse prognosis in individuals with obesity and metabolic syndrome (MS), who often develop cardiovascular complications that last throughout recovery. (2) Methods: This study aimed to analyze the evolution of diastolic dysfunction (DD), assessed by transthoracic echocardiography (TTE), in 203 individuals with and without obesity and/or MS diagnosed with post-COVID-19 syndrome. (3) Results: DD was frequently diagnosed in patients with MS and obesity, but also in those without obesity (62.71% and 56.6%, respectively), in comparison to 21.97% of subjects without MS (p ˂ 0.001). Almost half of the patients with obesity and MS had more severe DD (types 2 and 3). As for evolution, the prevalence and severity of DD, particularly types 1 and 2, decreased gradually, in parallel with the improvement of symptoms, progress being more evident in subjects without MS. DD of type 3 did not show a significant reduction (p = 0.47), suggesting irreversible myocardial damages. Multivariate regression analysis indicated that the number of MS factors, the severity of initial pulmonary injury, and protein C levels could explain DD evolution. (4) Conclusions: DD was commonly diagnosed in individuals with post-COVID-19 syndrome, particularly in those with MS and obesity. After 6 months, DD evolution, excepting that of type 3, showed a significant improvement, mostly in patients without MS.

Metabolic system

3295

OO188

Tatiana Romero Arias
Moisés Betancort Montesinos

Voice sequelae following recovery from COVID-19 Biomechanical correlates of voice post COVID-19

https://doi.org/10.1016/j.jvoice.2022.06.033

Published

3-Jul-22

Study

https://www.jvoice.org/article/S0892-1997(22)00196-5/fulltext

Introduction
. Covid-19 is an infectious disease with a different symptomatic implication depending on each person. There are sequelae in the nervous, cardiovascular and / or digestive system that involve the approach and multidisciplinary work of different health professionals where the speech therapist is included. In this way, we can speak of a direct relationship between speech therapy and Covid-19; especially in those patients with serious sequelae such as the inability to eat and / or speak and the loss of voice. The damage caused to the laryngeal mucosa triggers the loss of some of the qualities of the voice, limiting oral communication. That is why we can find dysphonias caused by a great weakness, by a continuous overexertion or because of a paralysis of the vocal cords.
Objectives/Hypothesis
. The objective of this study was to identify the patterns of behavior in the biomechanical correlates of people who passed Covid-19 symptomatically with sequelae in voice.
Methods
. An experimental study with a total of 21 participants (11 women and 10 men) with sequelae in voice post Covid-19 is presented. Voice samples were collected and biomechanical correlates were analyzed through the Voice Clinical Systems program.
Results and Conclusions
. The results show different altered biomechanical patterns between men and women that correlate with other infectious diseases.

Vocal organs

3296

OO189

http://orcid.org/0000-0001-9196-1437Rithvik Golla, Sudheer Kumar Vuyyuru, Bhaskar Kante, Saurabh Kedia, http://orcid.org/0000-0002-1577-0118Vineet Ahuja

Disorders of gut-brain interaction in post-acute COVID-19 syndrome

http://dx.doi.org/10.1136/pmj-2022-141749

Published

1-Jul-22

Review

https://pmj.bmj.com/content/early/2022/07/01/pmj-2022-141749

The novel coronavirus SARS-CoV-2 is responsible for the devastating pandemic which has caused more than 5 million deaths across the world until today. Apart from causing acute respiratory illness and multiorgan dysfunction, there can be long-term multiorgan sequalae after recovery, which is termed ‘long COVID-19’ or ‘post-acute COVID-19 syndrome’. Little is known about long-term gastrointestinal (GI) consequences, occurrence of post-infection functional gastrointestinal disorders and impact the virus may have on overall intestinal health. In this review, we put forth the various mechanisms which may lead to this entity and possible ways to diagnose and manage this disorder. Hence, making physicians aware of this spectrum of disease is of utmost importance in the present pandemic and this review will help clinicians understand and suspect the occurrence of functional GI disease post recovery from COVID-19 and manage it accordingly, avoiding unnecessary misconceptions and delay in treatment.

Gastro-intestinal

3297

OO190

Maroua Slouma, Maissa Abbes, Lobna Kharrat & Imen Gharsallah

Post-COVID-19 reactive arthritis

https://doi.org/10.1007/s10067-022-06241-9

Published

5-Jul-22

Letter to Editor

https://link.springer.com/article/10.1007/s10067-022-06241-9

In this review, the authors did not specify the delay between the COVID-19 infection diagnosis and articular manifestations onset [1].
Besides, the authors did not describe the treatments received during the COVID-19 infection [1]. Indeed, articular manifestations can be triggered by several drugs prescribed during COVID-19 infection. Favipiravir may induce hyperuricemia and even acute gouty arthritis [7]. Likewise, interferon β1 treatment may be responsible for inflammatory rheumatic disease occurrence [8, 9].
There is no agreement on the ReA criteria. Therefore, we believe that ruling out differential diagnoses such as viral arthritis related to COVID-19, drug-induced arthritis, crystal-induced flares, or a recent onset of another inflammatory rheumatic disease is necessary before making the ReA diagnosis [10].
The authors included seven cases of ReA after COVID-19 vaccination with corona VAC, Sinovac, and SPUTNIK-V.
While some authors consider joint manifestations induced by anti-COVID vaccination a form of ReA, others consider it an autoimmune or inflammatory syndrome induced by adjuvants. Adjuvants are components added to subunit and inactivated vaccines to stimulate innate and adaptive immune responses. This stimulation increases the effectiveness of subunit and inactivated vaccines, but it can be responsible for autoimmune/inflammatory syndrome induced by adjuvant (ASIA) [11]. Diagnosis criteria have been suggested for ASIA. The first major criterion is exposure to external stimuli such as a vaccine, and the second is the appearance of typical clinical manifestations such as arthritis [11]. These manifestations typically occur 2 to 5 days after COVID-19 vaccination [12]. The detection of autoantibodies or anti-adjuvant antibodies is possible and considered a minor diagnosis criterion [12]. It is not clear whether articular manifestations occurring after COVID-19 vaccination correspond to ReA or ASIA [11].
ReA post-COVID-19 infection or post-COVID-19-vaccination is a matter of concern that must support increased research into the pathophysiology of ReA.

Joints

3298

OO191

Chandrakala Aluganti Narasimhulu and Dinender K Singla*

Mechanisms of COVID-19 Pathogenesis in Diabetes

https://doi.org/10.1152/ajpheart.00204.2022

Published

1-Jul-22

Review

https://journals.physiology.org/doi/abs/10.1152/ajpheart.00204.2022

Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) virus, is a global pandemic impacting 254 million people in 190 countries. Comorbidities, particularly cardiovascular disease, diabetes, and hypertension, in-crease the risk of infection and poor outcomes. SARS-CoV-2 enters host cells through the angio-tensin converting enzyme 2 (ACE2) receptor, generating inflammation and cytokine storm, often resulting in multi-organ failure. The mechanisms and effects of COVID-19 on high-risk diabetic patients is not yet completely understood. In this review, we discuss the variety of coronaviruses, structure of SARS-CoV-2, mutations in SARS-CoV-2 spike proteins, receptors associated with viral host entry, and disease progression. Further, we focus on possible mechanisms of SARS-CoV-2 in diabetes, leading to inflammation and heart failure. Finally, we discuss existing therapeutic approaches, unanswered questions, and future directions.

Pancreas

3299

OO192

Mohammad A. A. Al-Najjar,Ruaa R. Al-alwany,Firas M. Al-Rshoud,Rana K. Abu-Farha,Mohammed Zawiah

Menstrual changes following COVID-19 infection: A cross-sectional study from Jordan and Iraq

https://doi.org/10.1371/journal.pone.0270537

Published

29-Jun-22

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0270537

Purpose
COVID-19 infection is normally followed by several post-COVID effects. This study aimed to investigate to evaluate menstrual changes in females following COVID-19 infection, and to evaluate female perception about the effect of COVID-19 on their menstrual cycles.
Methods
During this cross-sectional survey-based study, a convenience sample of 483 women from Jordan and from Iraq, who had infected with COVID-19 were invited to fill-out the study questionnaire.
Results
The study was conducted on the females, with a median age 31 years old. Results showed that 47.2% of them (n = 228) suffered from a change in the number of days between two consecutive periods, as well as from a change in the amount of blood loss. Also, more than 50% of them believed that COVID-19 infection may cause changes in the amount of blood loss during the cycle (n = 375, 56.9%), and changes in the number of days between the two consecutive periods (n = 362, 54.2%).
Regression analysis showed that participants with higher educational level (bachelor or higher) (Beta = -0.114, P = 0.011), and those living in Iraq (Beta = -0.166, P<0.001) believed that COVID-19 has lower tendency to cause menstrual changes. In addition, non-married females (Beta = 0.109, P = 0.017), and those who are current smokers (Beta = 0.091, P = 0.048) believed that COVID-19 has higher tendency to cause menstrual changes.
Conclusion
his study revealed that COVID-19 infection could affect the menstrual cycle for the females. Further prospective studies should be done to confirm these findings and evaluate how long these menstrual irregularities lasted.

Female reproductive system

3300

OO193

G. Baima, C. Marruganti, M. Sanz, M. Aimetti, M. Romandini

Periodontitis and COVID-19: Biological Mechanisms and Meta-analyses of Epidemiological Evidence

https://doi.org/10.1177%2F00220345221104725

Published

30-Jun-22

Meta-analyses

https://journals.sagepub.com/doi/abs/10.1177/00220345221104725

Since the beginning of 2020, the entire global health care system has been severely challenged by the outbreak of coronavirus 2019 disease (COVID-19). Robust evidence has demonstrated a more severe course of COVID-19 in the presence of several comorbidities, such as cardiovascular diseases, diabetes mellitus, and obesity. Here, we critically appraise the recent research discoveries linking periodontitis to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and to severe COVID-19, with a special focus on the associated biological mechanisms and the available epidemiological evidence. SARS-CoV-2 main receptors and coreceptors (ACE2, TMPRSS2, furin, CD147) are overexpressed in periodontal tissues of periodontitis patients, with inflammation, periodontal pathogens, and damage-induced pyroptosis triggering a positive feedback loop. However, meta-analyses of epidemiological studies only indicated a nonstatistically significant tendency for an increased risk of SARS-CoV-2 infection in subjects with periodontitis (odds ratio [OR] = 1.69; 95% CI, 0.91–3.13, P = 0.09). Furthermore, periodontitis may worsen clinical COVID-19 courses through multiple direct and indirect pathways, including damage to lower airways due to aspiration of periodontal pathogens, exacerbation of the cytokine storm via the low-grade chronic systemic inflammation, and SARS-CoV-2 dissemination through the ulcerated gingival epithelium with consequent induced pulmonary vessels vasculopathy. Indeed, meta-analyses of epidemiological studies indicated that periodontitis subjects are more likely to experience a more severe course of COVID-19. Specifically, periodontitis was associated with a 4-fold increased odds of hospitalization (OR = 4.72; 95% CI, 1.11–20.03, P = 0.04), 6-fold of requiring assisted ventilation (OR = 6.24; 95% CI, 2.78–14.02, P = 0.00), and more than 7-fold of death due to COVID-19 complications (OR = 7.51; 95% CI, 2.16–26.10, P = 0.00). The breakthrough analyzed here emphasizes the relevance of the mouth-systemic connection as a target to mitigate the current COVID-19 emergency and the future predicted coronavirus pandemics.

Mouth

3301

OO194

Helmar C. Lehmann

Neuromuskuläre Manifestationen beim Long-COVID-Syndrom
Neuromuscular manifestations in long-COVID syndrome

https://doi.org/10.1007/s00115-022-01321-2

Published

19-Jul-22

Review

https://link.springer.com/article/10.1007/s00115-022-01321-2

Unter dem Long-COVID(„coronavirus disease“)-Syndrom werden Beschwerden zusammengefasst, die nach einer akuten SARS-CoV-2(„severe acute respiratory syndrome coronavirus type 2“)-Infektion auftreten, über einen Zeitraum von mehreren Wochen anhalten und nicht durch eine andere Diagnose erklärt werden können. Long-COVID wird als Multiorganmanifestation aufgefasst. In diesem Übersichtsartikel wird die Datenlage hinsichtlich neuromuskulärer Manifestationen des Long-COVID-Syndroms summiert und anhand von Kriterien wie Effektstärke, Plausibilität, Kohärenz und experimentelle Evidenz bewertet. Bisher sind vor allem Myalgien und eine autonome Dysfunktion (u. a. das posturale Tachykardiesyndrom) als neuromuskuläre Symptome von Long-COVID beschrieben worden. Die bisherige Evidenz ist allerdings gering: Neben einer sehr heterogenen Methodik und unterschiedlichen Definitionen in den klinischen Long-COVID-Studien fehlen schlüssige experimentelle Daten, die die beschriebenen Symptome als spezifische Langzeitfolge von COVID-19 belegen.
Abstract
The term long-COVID syndrome encompasses symptoms that occur after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, persisting over a period of several weeks, and which cannot be explained by another diagnosis. Long-COVID is considered to be a multiorgan condition. In this review article, the data regarding neuromuscular manifestations of long-COVID syndrome are summarized and evaluated based on criteria, such as effect size, plausibility, coherence, and experimental evidence. So far, myalgia and autonomic dysfunction (especially postural tachycardia syndrome) have been postulated as neuromuscular symptoms of long-COVID; however, the evidence to date is limited. In addition to very heterogeneous methodologies and different definitions of long-COVID in the clinical studies, conclusive experimental data supporting the described symptoms as a specific long-term consequence of COVID-19 are lacking.

Muscles

3302

OO195

Nicole Bechmann , Umberto Maccio , Reham Kotb , Rania Al Dweik , Michele Cherfane , Holger Moch , Stefan R. Bornstein , Zsuzsanna Varga

COVID-19 Infections in Gonads: Consequences on Fertility?

https://doi.org/10.1055/a-1891-6621

Published

19-Jul-22

Review

https://www.thieme-connect.com/products/ejournals/html/10.1055/a-1891-6621

COVID-19 may influence human fertility and sexuality in several ways. Different cell types in gonads show a constitutive expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine subtype 2 (TMPRSS2), which provide potential entry pathways for SARS-CoV-2. In addition to the biological effects of a COVID-19 infection on the gonads, the impact of the ongoing COVID-19 pandemic on mental health issues and sexual behavior may affect reproduction. This review summarizes the current knowledge on the influence of COVID-19 on the gonads and discusses possible consequences on human fertility. In this context, the close interaction between the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-gonadal axis in response to COVID-19-related stress is discussed. Some women noticed changes in their menstrual cycle during the COVID-19 pandemic, which could be due to psychological stress, for example. In addition, occasional cases of reduced oocyte quality and ovarian function are described after COVID-19 infection. In men, COVID-19 may cause a short-term decrease in fertility by damaging testicular tissue and/or impairing spermatogenesis. Moreover, decreased ratio testosterone/LH and FSH/LH in COVID-19 compared to aged-matched healthy men has been reported. Available data do not suggest any effect of the available SARS-CoV-2 vaccines on fertility. The effects of long COVID on human fertility have been reported and include cases with premature ovarian failure and oligomenorrhoea in women and erectile dysfunction in men. Despite the increasing knowledge about the effects of COVID-19 infections on human gonads and fertility, the long-term consequences of the COVID-19 pandemic cannot yet be assessed in this context.

Male reproductive system

3303

OO196

KutayKucukyildizaDidemYilmaz-OralbDamlaTurkcanaCetin VolkanOztekincSerapGura

Impact of COVID-19 on male urogenital health: Success of vaccines

https://doi.org/10.1016/j.drudis.2022.07.012

Published

26-Jul-22

Review

https://www.sciencedirect.com/science/article/pii/S1359644622002975?via%3Dihub

Highlights
•COVID-19 can have adverse effects on sexual, bladder and reproductive functions in men.
•COVID-19 can affect the reproduction system via hormones, gametes, testis integrity and spermatogenesis.
•COVID-19 can increase ED risk, and angiotensin-(1–7) appears as a novel therapeutic target for ED in COVID-19.
•Clinical research is needed to investigate the impact of COVID-19 and the toxicity of drugs on male urogenital health, particularly in the long term.
Throughout 2021, the scientific and medical communities were concentrated on dealing with the acute morbidity and mortality induced by the COVID-19 pandemic due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We reviewed the present data for adverse effects of COVID-19 on the different parts of the male urogenital system during the dynamic situation of the COVID-19 pandemic. With the approval of COVID-19 vaccinations, there is a ray of hope at the end of this dark tunnel and a chance to look ahead for the management of long-term consequences in males with urogenital illnesses. A multidisciplinary investigation of these cases could provide information for establishing and optimizing treatment protocols.

Male reproductive system

3304

OO197

Hadeel Zaghloul, Rayaz A. Malik

COVID-19 and the hidden threat of diabetic microvascular complications

https://doi.org/10.1177%2F20420188221110708

Published

11-Jul-22

Review

https://journals.sagepub.com/doi/10.1177/20420188221110708

The coronavirus disease 2019 (COVID-19) pandemic affected at least 200 million individuals worldwide and resulted in nearly 5 million deaths as of October 2021. According to the latest data from the International Diabetes Federation (IDF) in 2021, the diabetes pandemic has affected 537 million people and is associated with 6.7 million deaths. Given the high prevalence of both diabetes and COVID-19 and common pathological outcomes, a bidirectional relationship could have a catastrophic outcome. The increased risk of COVID-19 in those with obesity and diabetes and higher morbidity and mortality has received considerable attention. However, little attention has been given to the relationship between COVID-19 and microvascular complications. Indeed, microvascular complications are associated with an increased risk of cardiovascular disease (CVD) and mortality in diabetes. This review assesses the evidence for an association between diabetic microvascular complications (neuropathy, nephropathy, and retinopathy) and COVID-19. It draws parallels between the pathological changes occurring in the microvasculature in both diseases and assesses whether microvascular disease is a prognostic factor for COVID-19 outcomes in diabetes.

Pancreas

3305

OO198

Peter Liptak 1ORCID,Eva Baranovicova 2,Robert Rosolanka 3,*ORCID,Katarina Simekova 3,Anna Bobcakova 4,Robert Vysehradsky 4,Martin Duricek 1ORCID,Zuzana Dankova 2ORCID,Andrea Kapinova 2,Dana Dvorska 2,Erika Halasova 2 andPeter Banovcin 1

Persistence of Metabolomic Changes in Patients during Post-COVID Phase: A Prospective, Observational Study

https://doi.org/10.3390/metabo12070641

Published

13-Jul-22

Study

https://www.mdpi.com/2218-1989/12/7/641/htm

Several relatively recently published studies have shown changes in plasma metabolites in various viral diseases such as Zika, Dengue, RSV or SARS-CoV-1. The aim of this study was to analyze the metabolome profile of patients during acute COVID-19 approximately one month after the acute infection and to compare these results with healthy (SARS-CoV-2-negative) controls. The metabolome analysis was performed by NMR spectroscopy from the peripheral blood of patients and controls. The blood samples were collected on 3 different occasions (at admission, during hospitalization and on control visit after discharge from the hospital). When comparing sample groups (based on the date of acquisition) to controls, there is an indicative shift in metabolomics features based on the time passed after the first sample was taken towards controls. Based on the random forest algorithm, there is a strong discriminatory predictive value between controls and different sample groups (AUC equals 1 for controls versus samples taken at admission, Mathew correlation coefficient equals 1). Significant metabolomic changes persist in patients more than a month after acute SARS-CoV-2 infection. The random forest algorithm shows very strong discrimination (almost ideal) when comparing metabolite levels of patients in two various stages of disease and during the recovery period compared to SARS-CoV-2-negative controls.

Metabolic system

3306

OO199

Mohaddeseh Azadvari
Afarin Haghparast
Amin Nakhostin-Ansari
Seyede Zahra Emami Razavi
Maryam Hosseini

Musculoskeletal symptoms in patients with Long COVID: A cross-sectional study on Iranian patients

https://doi.org/10.1016/j.heliyon.2022.e10148

Published

11-Aug-22

Study

https://www.cell.com/heliyon/fulltext/S2405-8440(22)01436-0

Background and objectives
Latest studies have revealed that an increasing number of Corona Virus Disease of 2019 (COVID-19) patients may continue to feel symptoms after the acute phase. This study aimed to evaluate the prevalence of musculoskeletal symptoms after the acute phase of COVID-19 and its associated factors.
Methods
We designed a cross-sectional study from January 2021 to April 2021. An online questionnaire was designed and sent to patients who had recovered from COVID-19. The questionnaire contained questions on participants’ demographic characteristics, COVID-19 course at its acute phase, and musculoskeletal symptoms after recovering from COVID-19. Musculoskeletal symptoms associations with patients’ characteristic and COVID-19 course was evaluated.
Result
239 patients, including 72 (30.1%) males and 167 (69.9%) females with a mean age of 37.96 years (SD=11.19), were included in the study. 98.74% of our patients had experienced at least one musculoskeletal symptom after recovering from COVID-19, and the most common symptom was fatigue, as 91.2% of participants experienced this symptom, followed by myalgia, headache, and low back pain. High BMI, hospitalization, and ICU admission were associated with a higher risk of musculoskeletal symptoms.
Conclusion
This study indicated a high prevalence of persistent musculoskeletal symptoms among patients who recovered from COVID-19. Modifiable factors, such as BMI, can be targeted to reduce the prevalence of musculoskeletal symptoms in COVID-19 survivors and reduce its burden.

Muscles

3307

OO200

Waldemar Kanczkowski , Waqar Haider Gaba , Nils Krone , Zsuzsanna Varga , Felix Beuschlein , Constanze Hantel , Cynthia Andoniadou , Stefan R. Bornstein

Adrenal Gland Function and Dysfunction During COVID-19

https://doi.org/10.1055/a-1873-2150

Published

9-Aug-22

Review

https://www.thieme-connect.com/products/ejournals/abstract/10.1055/a-1873-2150

The coronavirus disease 2019 (COVID-19) pandemic is currently one of the major health concerns worldwide accounting for many deaths and posing a great social and economic burden. Early activation of adrenal hormone secretion is pivotal to surviving systemic microbial infections. In addition, clinical studies demonstrated that glucocorticoids might also be beneficial in reducing disease progression and life deterioration in certain patients with COVID-19. Recent studies demonstrated that SARS-CoV-2 might target the adrenal glands, raising the possibility that at least some COVID-19 complications may be associated with adrenal dysfunction. Whether SARS-CoV-2 infection might cause adrenal dysfunction remains unknown. Histopathological examinations provided evidence that SARS-CoV-2 infection might indeed cause certain structural damage to the adrenal glands, especially concerning its vascular system. However, since no widespread cellular damage to cortical cells was observed, it is less likely that those changes could lead to an immediate adrenal crisis. This assumption is supported by the limited number of studies reporting rather adequate cortisol levels in patients with acute COVID-19. Those studies, however, could not exclude a potential late-onset or milder form of adrenal insufficiency. Although structural damage to adrenal glands is a rarely reported complication of COVID-19, some patients might develop a critical illness-related corticosteroid insufficiency (CIRCI), or iatrogenic adrenal insufficiency resulting from prolonged treatment with synthetic glucocorticoids. In this mini-review article, we aimed at describing and discussing factors involved in the adrenal gland function and possible dysfunction during COVID-19.

Adrenal glands

3308

OO201

D. Paoli, F. Pallotti, A. Anzuini, S. Bianchini, L. Caponecchia, A. Carraro, M. R. Ciardi, F. Faja, C. Fiori, D. Gianfrilli, A. Lenzi, M. Lichtner, I. Marcucci, C. M. Mastroianni, G. Nigro, P. Pasculli, C. Pozza, F. Rizzo, P. Salacone, A. Sebastianelli & F. Lombardo

Male reproductive health after 3 months from SARS-CoV-2 infection: a multicentric study

https://doi.org/10.1007/s40618-022-01887-3

Published

9-Aug-22

Study

https://link.springer.com/article/10.1007/s40618-022-01887-3

Purpose
While SARS-CoV-2 infection appears not to be clinically evident in the testes, indirect inflammatory effects and fever may impair testicular function. To date, few long-term data of semen parameters impairment after recovery and comprehensive andrological evaluation of recovered patients has been published. The purpose of this study was to investigate whether SARS-CoV-2 infection affect male reproductive health.
Methods
Eighty patients were recruited three months after COVID-19 recovery. They performed physical examination, testicular ultrasound, semen analysis, sperm DNA integrity evaluation (TUNEL), anti-sperm antibodies (ASA) testing, sex hormone profile evaluation (Total testosterone, LH, FSH). In addition, all patients were administered International Index of Erectile Function questionnaire (IIEF-15). Sperm parameters were compared with two age-matched healthy pre-COVID-19 control groups of normozoospermic (CTR1) and primary infertile (CTR2) subjects.
Results
Median values of semen parameters from recovered SARS-CoV-2 subjects were within WHO 2010 fifth percentile. Mean percentage of sperm DNA fragmentation (%SDF) was 14.1 ± 7.0%. Gelatin Agglutination Test (GAT) was positive in 3.9% of blood serum samples, but no positive semen plasma sample was found. Only five subjects (6.2%) had total testosterone levels below the laboratory reference range. Mean bilateral testicular volume was 31.5 ± 9.6 ml. Erectile dysfunction was detected in 30% of subjects.
Conclusion
Our data remark that COVID-19 does not seem to cause direct damage to the testicular function, while indirect damage appears to be transient. It is possible to counsel infertile couples to postpone the research of parenthood or ART procedures around three months after recovery from the infection.

Male reproductive system

3309

OO202

Ali Mohamed Ali Ismail

Erectile dysfunction: the non-utilized role of exercise rehabilitation for the most embarrassing forgotten post-COVID complication in men

https://doi.org/10.1080/13685538.2022.2108013

Published

10-Aug-22

Letter to the Editor

https://www.tandfonline.com/doi/full/10.1080/13685538.2022.2108013

Dear Editor,
For good subjective wellbeing and quality of life (QoL), a good penile erection is an important cornerstone for normal sexual activity in men [1]. Erectile dysfunction (ED), the inability to achieve and/or maintain a penile erection sufficient for successful vaginal intercourse for satisfactory sexual performance or penetration [2], develops psychological disorders that decreases the man’s confidence and his QoL [1].
Recently, according to published literature, many body organs/structures express their post-COVID dysfunctions. ED is one of the most silent/embarrassing residual post-COVID complications in men [3]. At the same time that patients with COVID-19 were 3.3 times more likely to have ED [4], great attention and research are directed toward other post-COVID complications such as dyspnea, limited physical capacity, fatigue, poor sleepiness, etc.
The majority of evidence points to COVID-19's participation in the ED, however, the exact pathophysiology has yet to be thoroughly understood. COVID-19 infection may disrupt male sexual function by causing endothelium damage in erectile tissue, testicular injury, psychological changes [5]. In this domain, the concept of sexual long COVID may raise. Symptoms/complications of long COVID that affect many systems including the respiratory system (dyspnea and pulmonary fibrosis), cardiovascular system (myocarditis and endothelial dysfunction), and endocrine system (thyroid dysfunctions, diabetes, or hypogonadism) may impair erectile function in COVID-19 long haulers [6]. SARS-CoV-2 viral particles have been found in penile and testicular tissue, both in living COVID-19 patients who recovered and in males who died from the COVID condition. SARS-CoV-2 can directly damage cavernosal endothelium, resulting in male sexual dysfunction, as evidenced by the virus's persistence in penile tissue up to 7 months after infection [7].
At the end of this topic, and in light of the growing interest in the role of exercise in fixing/treating the post-COVID complications across all parts of the body, I do not fail to remind all researchers in sexual rehabilitation to work to find an answer to this forgotten question in their future research: Is there an effect of exercise rehabilitation programs on COVID-induced ED?.

Male reproductive system

3310

OO203

AnnaMoltoMD PhDPierrePinsonNathanaelBeekerChristianRoux

Evaluation of the prevalence of new-onset musculoskeletal symptoms in patients hospitalized for severe SARS-CoV2 infection during the first two COVID waves in France: a descriptive analysis of the clinical data warehouse of 39 hospitals in France

https://doi.org/10.1016/j.jbspin.2022.105450

Published

6-Aug-22

Study

https://www.sciencedirect.com/science/article/pii/S1297319X22001105

Highlights
Prevalence of musculoskeletal symptoms within 90 days after COVID infection was 8.8%
Patients with musculoskeletal symptoms post-covid infection were older and more comorbid ( obesity, hypertension and diabetes)
Patients with musculoskeletal symptoms post-covid were more likely to receive higher doses of corticosteroids, antivirals and immunosuppressors.
Abstract
Objective: to determine the prevalence of musculoskeletal (MSK) symptoms appearing after a SARS-CoV2 infection.
Methods: this was an observational cohort based on data available at the Assistance Publique-Hôpitaux de Paris (APHP) Clinical Data Warehouse (which includes data of more than 11 million patients treated in the 39 hospitals from AP-HP). The data collected included both ICD-10 codes in discharge summaries, and recurring wording expressions search on medical electronic documents. To be included in the analysis, patients had to have a positive RT-PCR for SARS-CoV2 and be admitted in any department of APHP. Patients with previous history of any MSK condition were excluded. MSK conditions were considered if occurring up to 90 days after the positive RT-PCR. Demographics and disease characteristics including treatment were compared in both groups (MSK yes/no) by T-test or ChiSquare test, accordingly.
Results: 17771 patients had a positive SARS-CoV2 RT-PCR at APHP and were admitted in any department of APHP. Among them, 15601 had no previous history of MSK condition and among them, 1370 (8.8%) presented with MSK symptoms after the viral infection. The most prevalent MSK symptoms were back pain (32.9%), followed by arthralgia (29.9%), radicular pain (20.2%) and arthritis (22.8%). Patients with MSK symptoms (MSK+) were older (67y vs. 64y, p<0.01), more frequently obese (29% vs. 25%, p=0.03), hypertensive (34% vs. 30%, p<0.01) and with diabetes (21% vs. 18%, p<0.01). Treatment for SARS-CoV2 was slightly different in both groups, with higher corticosteroids (40.7% vs. 29.0%, p<0.01), antivirals (21.5% vs. 15.3%, p<0.01) and immunosuppressors (8.5% vs. 4.5%, p<0.01) prescription rates in the MSK+ group. Conclusion: MSK symptoms occurred in almost 9% of patients admitted to the hospital after a SARS-CoV2 infection, particularly in older and more comorbid patients. Further analysis evaluating whether these symptoms remain over time are needed.

Muscles

3311

OO204

D. H. Adeyemi,A. F. Odetayo,M. A. Hamed &R. E. AkhigbeORCID Icon

Impact of COVID 19 on erectile function

https://doi.org/10.1080/13685538.2022.2104833

Published

4-Aug-22

Review

https://www.tandfonline.com/doi/full/10.1080/13685538.2022.2104833

Purpose: COVID-19, a novel infection, presented with several complications, including socioeconomical and reproductive health challenges such as erectile dysfunction (ED). The present review summarizes the available shreds of evidence on the impact of COVID-19 on ED.
Materials and methods: All published peer-reviewed articles from the onset of the COVID-19 outbreak to date, relating to ED, were reviewed.
Results: Available pieces of evidence that ED is a consequence of COVID-19 are convincing. COVID-19 and ED share common risk factors such as disruption of vascular integrity, cardiovascular disease (CVD), cytokine storm, diabetes, obesity, and chronic kidney disease (CKD). COVID-19 also induces impaired pulmonary haemodynamics, increased ang II, testicular damage and low serum testosterone, and reduced arginine-dependent NO bioavailability that promotes reactive oxygen species (ROS) generation and endothelial dysfunction, resulting in ED. In addition, COVID-19 triggers psychological/mental stress and suppresses testosterone-dependent dopamine concentration, which contributes to incident ED.
Conclusions: In conclusion, COVID-19 exerts a detrimental effect on male reproductive function, including erectile function. This involves a cascade of events from multiple pathways. As the pandemic dwindles, identifying the long-term effects of COVID-19-induced ED, and proffering adequate and effective measures in militating against COVID-19-induced ED remains pertinent.

Male reproductive system

3312

OO205

C.V.DegenabM.MikuteitbcJ.NiewolikcT.JoostencD.SchröderdK.VahldiekeU.MückefS.HeinemanndF.MüllerdG.M.N.BehrenscgF.KlawonnehT.LenarzaA.Dopfer-JablonkacgS.Steffensbc

Audiological profile of adult long COVID patients

https://doi.org/10.1016/j.amjoto.2022.103579

Published

5-Aug-22

Study

https://www.sciencedirect.com/science/article/pii/S019607092200206X

Introduction
Hearing loss is one of the self-reported symptoms of Long COVID patients, however data from objective and subjective audiological tests demonstrating diminished hearing in Long COVID patients has not been published.
Materials and methods
Respondents of a large Long COVID online survey were invited to the ENT-department for an otologic exam. The participants were split into three groups based on their history of SARS-CoV-2 infection and persistence of symptoms. Respondents with a history of a SARS-CoV-2 infection were allocated to the Long COVID group, if they reported persistent symptoms and to the Ex COVID group, if they had regained their previous level of health. Participants without a history of SARS-CoV-2 infection made up the No COVID control group. In total, 295 ears were examined with otoscopy, tympanograms, pure tone audiometry and otoacoustic emissions. Ears with known preexisting hearing loss or status post ear surgery, as well as those with abnormal otoscopic findings, non-type A tympanograms or negative Rinne test were excluded.
Results
Compared to the No COVID and Ex COVID groups, we did not find a clinically significant difference in either hearing thresholds or frequency specific TEOAEs. However, at 500 Hz the data from the left ear, but not the right ear showed a significantly better threshold in the Ex COVID group, compared to Long COVID and No COVID groups. Any of the other tested frequencies between 500 Hz and 8 kHz were not significantly different between the different groups. There was a significantly lower frequency-specific signal-to-noise-ratio of the TEOAEs in the Long COVID compared to the No COVID group at 2.8 kHz. At all other frequencies, there were no significant differences between the three groups in the TEOAE signal-to-noise-ratio.
Conclusion
This study detected no evidence of persistent cochlear damage months after SARS-CoV-2 infection in a large cohort of Long COVID patients, as well as those fully recovered.

Ears

3313

OO206

César Fernández-de-las-Peñas 1,2,*ORCID,Ignacio Cancela-Cilleruelo 1,Paloma Moro-López-Menchero 1ORCID,Jorge Rodríguez-Jiménez 1,Víctor Gómez-Mayordomo 3ORCID,Juan Torres-Macho 4,5,Oscar J. Pellicer-Valero 6ORCID,José D. Martín-Guerrero 6ORCID,Valentín Hernández-Barrera 7 andLars Arendt-Nielsen

Prevalence of Musculoskeletal Post-COVID Pain in Hospitalized COVID-19 Survivors Depending on Infection with the Historical, Alpha or Delta SARS-CoV-2 Variant

https://doi.org/10.3390/biomedicines10081951

Published

11-Aug-22

Study

https://www.mdpi.com/2227-9059/10/8/1951/htm

We compared the prevalence of musculoskeletal post-COVID pain between previously hospitalized COVID-19 survivors infected with the historical, Alpha or Delta SARS-CoV-2 variant. Data about musculoskeletal post-COVID pain were systematically collected through a telephone interview involving 201 patients who had survived the historical variant, 211 who had survived the Alpha variant and 202 who had survived the Delta variant six months after hospital discharge. Participants were recruited from non-vaccinated individuals hospitalized due to SARS-CoV-2 infection in one hospital of Madrid (Spain) during three different waves of the pandemic (historical, Alpha or Delta variant). Hospitalization and clinical data were collected from hospital medical records. In addition, anxiety/depressive levels and sleep quality were also assessed. The prevalence of musculoskeletal post-COVID pain was higher (p = 0.003) in patients infected with the historical variant (47.7%) than in those infected with the Alpha (38.3%) or Delta (41%) variants. A significantly (p = 0.002) higher proportion of individuals infected with the historical variant reported generalized pain (20.5%) when compared with those infected with the other variants. The prevalence of new-onset post-COVID musculoskeletal pain reached 80.1%, 75.2% and 79.5% of patients infected with the historical, Alpha or Delta variants, respectively. No specific risk factors for developing post-COVID pain were identified depending on the SARS-CoV-2 variant. In conclusion, this study found that musculoskeletal post-COVID pain is highly prevalent in COVID-19 survivors six months after hospital discharge, with the highest prevalence and most generalized pain symptoms in individuals infected with the historical variant. Approximately 50% developed “de novo” post-COVID musculoskeletal pain symptoms.

Muscles

3314

OO207

Leena Sapra, Chaman Saini, Bhavuk Garg, Ranjan Gupta, Bhupendra Verma, Pradyumna K. Mishra & Rupesh K. Srivastava

Long-term implications of COVID-19 on bone health: pathophysiology and therapeutics

https://doi.org/10.1007/s00011-022-01616-9

Published

28-Jul-22

Study

https://link.springer.com/article/10.1007/s00011-022-01616-9

SARS-CoV-2 is a highly infectious respiratory virus associated with coronavirus disease (COVID-19). Discoveries in the field revealed that inflammatory conditions exert a negative impact on bone metabolism; however, only limited studies reported the consequences of SARS-CoV-2 infection on skeletal homeostasis. Inflammatory immune cells (T helper—Th17 cells and macrophages) and their signature cytokines such as interleukin (IL)-6, IL-17, and tumor necrosis factor-alpha (TNF-α) are the major contributors to the cytokine storm observed in COVID-19 disease. Our group along with others has proven that an enhanced population of both inflammatory innate (Dendritic cells—DCs, macrophages, etc.) and adaptive (Th1, Th17, etc.) immune cells, along with their signature cytokines (IL-17, TNF-α, IFN-γ, IL-6, etc.), are associated with various inflammatory bone loss conditions. Moreover, several pieces of evidence suggest that SARS-CoV-2 infects various organs of the body via angiotensin-converting enzyme 2 (ACE2) receptors including bone cells (osteoblasts—OBs and osteoclasts—OCs). This evidence thus clearly highlights both the direct and indirect impact of SARS-CoV-2 on the physiological bone remodeling process. Moreover, data from the previous SARS-CoV outbreak in 2002–2004 revealed the long-term negative impact (decreased bone mineral density—BMDs) of these infections on bone health.

Bones

3315

OO242

Muhannad A Alnahdi, Maan Alkharashi

Ocular manifestations of COVID-19 in the pediatric age group

https://doi.org/10.1177%2F11206721221116210

Published

27-Jul-22

Review

https://journals.sagepub.com/doi/full/10.1177/11206721221116210

The coronavirus disease 2019 (COVID-19) is now known to be associated with several ocular manifestations. The literature thoroughly discussed those that affect adults, with a lesser focus in the pediatric age group. We aim to outline the various pediatric ocular manifestations described in the literature. The manifestations may be divided into isolated events attributed to COVID-19 or occurring in the new multisystem inflammatory syndrome in children (MIS-C), a novel entity associated by COVID-19 infection. Ocular manifestations have virtually affected all ages. They manifested in neonates, infants, children, and adolescents. Episcleritis, conjunctivitis, optic neuritis, cranial nerve palsies, retinal vein occlusion, retinal vasculitis, retinal changes, orbital myositis, orbital cellulitis were reported in the literature with this emerging viral illness. Conjunctivitis was the most common ocular manifestation in MIS-C in nearly half of the patients. Other ocular manifestations in MIS-C were anterior uveitis, corneal epitheliopathy, optic neuritis, idiopathic intracranial hypertension, and retinitis. The clinical outcome was favorable, and children regain their visual ability with minimal or no deficits in most of the cases. Further follow-up may be warranted to better understand the long-term effects and visual prognosis.

Eyes

3316

OO209

Arup Choudhury, Raseen Tariq, Anuraag Jena, Elissa Kinzelman Vesely, Siddharth Singh, Sahil Khanna, Vishal Sharma

Gastrointestinal manifestations of long COVID: A systematic review and meta-analysis

https://doi.org/10.1177%2F17562848221118403

Published

19-Aug-22

systematic review and meta-analysis

https://journals.sagepub.com/doi/10.1177/17562848221118403

Background:
Prolonged symptoms after COVID-19 are an important concern due to the large numbers affected by the pandemic.
Objectives:
To ascertain the frequency of gastrointestinal (GI) manifestations as part of long GI COVID.
Design:
A systematic review and meta-analysis of studies reporting GI manifestations in long COVID was performed.
Data Sources and Methods:
Electronic databases (Medline, Scopus, Embase, Cochrane Central Register of Controlled Trials, and Web of Science) were searched till 21 December 2021 to identify studies reporting frequency of GI symptoms in long COVID. We included studies reporting overall GI manifestations or individual GI symptoms as part of long COVID. We excluded pediatric studies and those not providing relevant information. We calculated the pooled frequency of various symptoms in all patients with COVID-19 and also in those with long COVID using the inverse variance approach. All analysis was done using R version 4.1.1 using packages ‘meta’ and ‘metafor’.
Results:
A total of 50 studies were included. The frequencies of GI symptoms were 0.12 [95% confidence interval (CI), 0.06–0.22, I2 = 99%] and 0.22 (95% CI, 0.10–0.41, I2 = 97%) in patients with COVID-19 and those with long COVID, respectively. The frequencies of abdominal pain, nausea/vomiting, loss of appetite, and loss of taste were 0.14 (95% CI, 0.04–0.38, I2 = 96%), 0.06 (95% CI, 0.03–0.11, I2 = 98%), 0.20 (95% CI, 0.08–0.43, I2 = 98%), and 0.17 (95% CI, 0.10–0.27, I2 = 95%), respectively, after COVID-19. The frequencies of diarrhea, dyspepsia, and irritable bowel syndrome were 0.10 (95% CI, 0.04–0.23, I2 = 98%), 0.20 (95% CI, 0.06–0.50, I2 = 97%), and 0.17 (95% CI, 0.06–0.37, I2 = 96%), respectively.
Conclusion:
GI symptoms in patients were seen in 12% after COVID-19 and 22% as part of long COVID. Loss of appetite, dyspepsia, irritable bowel syndrome, loss of taste, and abdominal pain were the five most common GI symptoms of long COVID. Significant heterogeneity and small number of studies for some of the analyses are limitations of the systematic review.

Gastro-intestinal

3317

OO210

PoupakFallahiaSilvia MartinaFerraribGiusyEliacSabrina RosariaPaparocArmandoPatriziodEugeniaBalestricValeriaMazzicLauraGragnanieClodoveoFerrifgChiaraBotrinicFrancescaRagusacAlessandroAntonellic

Thyroid autoimmunity and SARS-CoV-2 infection: Report of a large Italian series

https://doi.org/10.1016/j.autrev.2022.103183

Published

23-Aug-22

Survey

https://www.sciencedirect.com/science/article/pii/S1568997222001537

Highlights
•Systemic autoimmune diseases might lend higher risk of SARS-CoV-2 infection.
•Data are discordant about the impact of preexisting thyroid diseases on COVID-19.
•Patients with autoimmune thyroid diseases may be more susceptible to the virus.
Since the beginning of the pandemic, numerous risk factors have been associated with SARS-CoV-2 infection and COVID-19 outcomes, such as older age, male sex, and the presence of comorbidities, such as hypertension, obesity, and diabetes. Preliminary data also suggest epidemiological association between SARS-CoV-2 infection and systemic autoimmune disease. For this reason, we investigated if patients affected by autoimmune thyroid disorders (AITD) are at risk of developing SARS-CoV-2 infection or COVID-19 disease.
From April to September 2020, we have conducted a telephone survey that included 515 consecutive unselected patients with known thyroid disorders, of which 350 were affected by AITD. All 11 definitive diagnosis of COVID-19 (def-sympt-COVID-19) belonged to the AITD group, while the rest 14 cases highly suspected for COVID-19 (suspect-sympt-COVID-19) were equally detected in both group (7 in AITD and 7 in not-AITD). The overall prevalence of symptomatic COVID-19 (def-sympt-COVID-19 + suspect-sympt-COVID-19), recorded in the 350 AITD population was statistically significant higher compared to that reported in the Italian and Tuscan general population at the same time period of the present survey (18/350 = 5.14% vs 516/100000 = 0.51% [p < 0.001; OR = 10.45, 95% CI 6.45–16.92] and vs 394/100000 = 0.39% [p < 0.001; OR = 13.70, 95% CI 8.44–22.25], respectively).
Therefore, our results suggest a higher prevalence of SARS-CoV-2 infection and COVID-19 disease in patients with AITD.

Thyroid gland

3318

OO211

VP

Mohamad Norouzi Masir,Milad Shirvaliloo

Symptomatology and microbiology of the gastrointestinal tract in post-COVID conditions

https://doi.org/10.1002/jgh3.12811

Published

25-Aug-22

Review

https://onlinelibrary.wiley.com/doi/full/10.1002/jgh3.12811

Post-COVID conditions, also known as post-acute sequelae of SARS-CoV-2 (PASC), refer to the persistence of symptoms in COVID-19 long-haulers. Various manifestations of post-COVID conditions are general symptoms and/or manifestations of damage in multiple organs. Besides, SARS-CoV-2 can involve the gastrointestinal tract, resulting in sequelae such as diarrhea, abdominal pain, nausea, anorexia, vomiting, constipation, abdominal distension, acid reflux, and/or gastrointestinal bleeding. Previous investigations point to SARS-CoV-2 entry into enterocytes enhances by the angiotensin-converting enzyme 2 (ACE2) receptors. Interestingly, ACE2 receptors are abundantly expressed in the gut, implying infection with SARS-CoV-2 might occur through this route as well as in the respiratory tract. According to mounting evidence, SARS-CoV-2 RNA has been identified in fecal specimens of patients with COVID-19 during and beyond the acute phase. In addition, studies have shown gut microbiome composition is altered in patients with PASC, hence, another putative mechanism linked to gastrointestinal symptoms is gut dysbiosis. The presence of the gut-lung axis in COVID-19 might have major implications for disease pathogenesis and treatment. This review discussed the prevalence of gastrointestinal symptoms and pathophysiology underlying possible infection of the gut in patients with PASC. Also, SARS-COV-2 induced NLRP3 inflammasome-dependent inflammatory pathways are briefly addressed.

Gastro-intestinal

3319

OO212

Gerardo Cazzato 1,*ORCID,Eliano Cascardi 2,3ORCID,Anna Colagrande 1,Caterina Foti 4,Alessandra Stellacci 5ORCID,Maricla Marrone 5ORCID,Giuseppe Ingravallo 1ORCID,Francesca Arezzo 6,Vera Loizzi 6ORCID,Antonio Giovanni Solimando 7ORCID,Paola Parente 8ORCID,Eugenio Maiorano 1ORCID,Gennaro Cormio 9ORCID,Angelo Vacca 7ORCID andLeonardo Resta

SARS-CoV-2 and Skin: New Insights and Perspectives

https://doi.org/10.3390/biom12091212

Published

31-Aug-22

Review

https://www.mdpi.com/2218-273X/12/9/1212/htm

The SARS-CoV-2 pandemic has disrupted global health systems and brought the entire globe to its knees. Although born as a disease of the respiratory system, COVID-19 can affect different parts of the body, including the skin. Reports of ongoing skin manifestations of COVID-19 have gradually multiplied, pushing researchers to investigate the etiopathogenic mechanisms underlying these phenomena in more depth. In an attempt to investigate the possible association between SARS-CoV-2, ACE2, TMPRSS2 and skin manifestations, we performed immunohistochemical investigations of the ACE2 receptor and TMPRSS2 in nine skin samples from SARS-CoV-2-positive patients compared to a cohort of healthy controls. Furthermore, after consulting public databases regarding ACE2 mRNA expression in various cell populations resident in the skin, we conducted a literature review aimed at outlining the current state of this topic. We did not find statistically different immuno-expression of ACE2 and TMPRSS2 between the group of SARS-CoV-2-positive patients (nine skin biopsies) and the control group. Regarding ACE2, major immunolabeling was present in the epidermal keratinocytes and, rarely, in the fibroblasts and in the adenomeres of the eccrine sweat glands. Regarding the immune expression of TMPRSS2, we found no significant differences between the two groups, with a weak immune staining only in some skin cytotypes. From the review of the literature, we isolated 35 relevant articles according to the inclusion criteria adopted. ACE2 appears to be a target of SARS-CoV-2, although, other receptor molecules may potentially be implicated, such as TMPRSS2. Future studies with large cases and different molecular investigative methods are needed to further elucidate the mechanisms underlying the skin manifestations of SARS-CoV-2.

Skin

3320

OO213

Claudia Leanza,Laura M. Mongioì *ORCID,Rossella CannarellaORCID,Sandro La VigneraORCID,Rosita A. CondorelliORCID andAldo E. CalogeroORCID

The Possible Role of SARS-CoV-2 in Male Fertility: A Narrative Review

https://doi.org/10.3390/endocrines3030046

Published

5-Sep-22

Review

https://www.mdpi.com/2673-396X/3/3/46/htm

The spread of severe acute respiratory syndrome—Coronavirus 2 (SARS-CoV-2) around the world has rapidly sparked the interest of the scientific community to discover its implications in human health. Many studies have suggested that SARS-CoV-2 is directly or indirectly involved in the male reproductive tract impairment. Some evidence supports the possible role of the virus in male infertility. Therefore, this review aims to summarize the relationship between the male urogenital tract, male fertility, and the gonadal hormone profile. The testis is one of the organs with the highest expression of the angiotensin-converting enzyme (ACE) 2-receptor that allows the virus to penetrate human cells. Orchitis is a possible clinical manifestation of COVID-19 and testicular damage has been found on autopsy in the testes of patients who died from the disease. SARS-CoV-2 infection can compromise the blood-testis barrier, favoring testicular damage and the production of anti-sperm autoantibodies. Some studies have detected the presence of SARS-CoV-2 in semen and a high percentage of patients with COVID-19 have altered sperm parameters compared to controls. Finally, lower testosterone levels, higher luteinizing hormone (LH) levels, and decreased follicle-stimulating (FSH)/LH and testosterone/LH ratios suggest primary testicular damage. In conclusion, further studies are needed to evaluate the exact mechanisms by which SARS-CoV-2 affects the male reproductive system and fertility and to evaluate the reversibility of its long-term effects.

Male reproductive system

3321

OO214

Lin, Cheng-Yao MD, MSa,b,c; Su, Shih-Bin MD, PhDd; Chen, Kow-Tong MD, PhDe,f,

An overview of gastrointestinal diseases in patients with COVID-19: A narrative review

https://doi.org/10.1097/MD.0000000000030297

Published

9-Sep-22

Review

https://journals.lww.com/md-journal/Fulltext/2022/09090/An_overview_of_gastrointestinal_diseases_in.96.aspx

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has emerged as a global health concern. This study aimed to review the epidemiology and pathophysiology of COVID-19 and provide evidence for the implementation of control measures.

We utilized several online databases, including MEDLINE (National Library of Medicine, Bethesda, Maryland, USA), PubMed, EMBASE, Web of Science, and Google Scholar, to collect relevant published papers using a combination of the following keywords: “COVID-19,” “SARS-CoV-2,” “novel coronavirus,” “epidemiology,” and “pathophysiology.” The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used in this study.

Globally, approximately 3–46% of patients with SARS-CoV-2 infection experience gastrointestinal symptoms. The clinical spectrum of COVID-19 is wide, ranging from mild to severe, and even fatal. COVID-19 was initially reported as a respiratory tract disease; however, gastrointestinal symptoms have only recently been reported. COVID-19 Patients with gastrointestinal symptoms may have more severe clinical manifestations and poor prognosis.

This study highlights the need to better understand the mechanisms involved in the development of gastrointestinal symptoms in patients with COVID-19 to prevent the further spread of this pathogen.

Gastro-intestinal

3322

OO215

Jason P. Nayar1,2, Aidan J. Heslin2, Damien B. Beck1, Mark R. Wakefield2, Yujiang Fang1,2,*

COVID-19 and Erectile Dysfunction

https://doi.org/10.31083/j.jomh1809190

Published

9-Sep-22

Review

https://www.imrpress.com/journal/JOMH/18/9/10.31083/j.jomh1809190/htm

Background: The SARS-CoV-2 virus displays a strong impact on the respiratory, digestive, and reproductive systems, and has led to questions about long-term effects. Erectile dysfunction is the inability for a male to achieve or sustain an erection during sexual intercourse, and commonly develops in men due to both physiological and psychologic factors. SARS-CoV-2 can affect the vasculature that surrounds endothelial tissue and thus has raised the question of a possible relationship between SARS-CoV-2 infection and erectile dysfunction (ED). Thus far, no studies have established a relationship between COVID-19 and ED. In this review, we analyze current available data and summarize the concepts regarding the current known relationship between COVID-19 and ED. Such a study might be helpful for urologists and andrologists to manage patients with ED and a history off COVID-19 infection. Methods: A systematic review was used to analyze the relationship between COVID-19 and ED. A literature search on three databases, Google Scholar, PubMed, and ResearchGate was conducted. Search terms used were COVID-19, erectile dysfunction, and SARS-CoV-2. All available studies were analyzed up to December 2021. Results: The COVID-19 pandemic led to a significant increase in male reproductive and sexual health diagnoses, including ED, with numbers showing that COVID-19 increases the chance of developing ED nearly sixfold. Physiological issues were also found in the reproductive system of men who had contracted COVID-19. For example, endothelial progenitor cells were much lower in patients positive with COVID-19 even when compared to men with severe ED who had never contracted COVID-19. However, it is still not clear how consistent it is to find SARS-CoV-2 in the reproductive system as one study showed only two out of five testes were positive for SARS-CoV-2 in the reproductive system and another study showed that there were only 3 out of 26 cases in which the SARS-CoV-2 spike existed in the endothelia of the blood-testis barrier, seminiferous tubules, and sperm of the epididymis. Conclusions: Many correlations can be made between COVID-19 and ED. However, future testing and research must be completed to determine a causal relationship between COVID-19 and ED.

Male reproductive system

3323

OO216

Abhinav Grover, MD, MS
Franchesca Choi
Sheng Pei-Wang

33624 Long-term cutaneous manifestations in COVID-19 patients: A systematic review

https://doi.org/10.1016/j.jaad.2022.06.339

Published

1-Sep-22

Systematic review

https://www.jaad.org/article/S0190-9622(22)01387-1/fulltext#relatedArticles

Introduction: Skin lesions have been reported as symptoms in several COVID-19 patients. Moreover, there is evidence describing persistence of pernio, papulosquamous lesions, and livedo reticularis in patients, several weeks after the peak of the disease.
Materials and methods: A primary search for peer-reviewed literature published until May 1st, 2021 was conducted with PubMed and EMBASE. Studies documenting persistent skin lesions in confirmed COVID-19 cases after the initial diagnosis or resolution of symptoms were included. 22 studies (15 case reports, 5 case series, 1 cohort and 1 cross-sectional study) with a total of 236 COVID-19 patients were included.
Results: Cutaneous lesions reported in the 236 long COVID patients (age range = 6-89 years, 164 females, 48 males, 24 no reported gender) were: 196 alopecia, 10 pernio, 4 maculopapular, 2 urticarial, 1 vesicular, 1 purpura, 1 papulosquamous, 1 Kawasaki like, 1 cheilitis, 1 sarcoid granuloma, 1 onychomadesis, and 1 orange nail lesion, while 16 patients did not have a specific lesion reported. The timing of onset of lesions ranged from 7 to 180 days after the initial diagnosis or symptom resolution. The duration of lesions ranged from 6 to 240 days. One patient was hospitalized and one required intubation.
Conclusions: Our description of persistent cutaneous and pathological manifestations may help clinicians understand the spectrum of lesions in long COVID cases and suggests the mechanistic role of persistent inflammation and stress. However, further investigation is needed to determine the full clinical spectrum, mechanism and prognostic significance of such skin lesions.

Skin

3324

OO217

Freedberg, Daniel E.a; Chang, Lin

Gastrointestinal symptoms in COVID-19: the long and the short of it

https://doi.org/10.1097/MOG.0000000000000876

Published

9-Sep-22

Review

https://journals.lww.com/co-gastroenterology/Citation/2022/11000/Gastrointestinal_symptoms_in_COVID_19__the_long.6.aspx

Purpose of review
A large and growing number of patients have persistent gastrointestinal symptoms that they attribute to COVID-19. SARS-CoV-2, the virus that causes COVID-19, replicates within the gut and acute COVID-19 is associated with alteration of the gut microbiome. This article reviews recent observational data related to gastrointestinal symptoms in ‘long COVID’ and discusses pathophysiologic mechanisms that might explain persistent post-COVID gastrointestinal symptoms.

Recent findings
Gastrointestinal symptoms are present in half of the patients with acute COVID-19, persist 6 months after COVID-19 in 10–25% of patients, and are rated as the most bothersome symptom in 11% of all patients. These symptoms include heartburn, constipation, diarrhoea and abdominal pain and decline in prevalence with the passage of time. Long COVID gastrointestinal symptoms are associated with mental health symptoms (anxiety and depression) that predate COVID-19 and also with mental health symptoms that are concurrent, after recovery from COVID-19. The cause of long COVID gastrointestinal symptoms is unknown and hypotheses include the SARS-CoV-2 virus itself, which infects the gastrointestinal tract; COVID-19, which can be accompanied by gut microbiome changes, a profound systemic inflammatory response and critical illness; and/or effects of pandemic stress on gastrointestinal function and symptom perception, which may be unrelated to either SARS-CoV-2 or to COVID-19.

Summary
New, persistent gastrointestinal symptoms are commonly reported after recovery from COVID-19. The pathophysiology of these symptoms is unknown but likely to be multifactorial.

Gastro-intestinal

3325

OO218

HonghaoLaiabManliYangcMingyaoSundBeiPaneQuanWangfJingWanggJinhuiTianehGuowuDingabKehuYangaehXupingSongabLongGeabh

Risk of incident diabetes after COVID-19 infection: A systematic review and meta-analysis

https://doi.org/10.1016/j.metabol.2022.155330

Published

8-Oct-22

Review and Meta Analysis

https://www.sciencedirect.com/science/article/pii/S0026049522002086

Highlights
•Eleven cohorts involving 47.1 million participants were included.
•A 64 % greater risk of diabetes was found in patients with COVID-19.
•A significant association was found for both type 1 diabetes and type 2 diabetes.
•Subgroup analysis and sensitivity analyses proved the robustness.
Abstract
Background
COVID-19 might be a risk factor for various chronic diseases. However, the association between COVID-19 and the risk of incident diabetes remains unclear. We aimed to meta-analyze evidence on the relative risk of incident diabetes in patients with COVID-19.
Methods
In this systematic review and meta-analysis, the Embase, PubMed, CENTRAL, and Web of Science databases were searched from December 2019 to June 8, 2022. We included cohort studies that provided data on the number, proportion, or relative risk of diabetes after confirming the COVID-19 diagnosis. Two reviewers independently screened studies for eligibility, extracted data, and assessed risk of bias. We used a random-effects meta-analysis to pool the relative risk with corresponding 95 % confidence intervals. Prespecified subgroup and meta-regression analyses were conducted to explore the potential influencing factors. We converted the relative risk to the absolute risk difference to present the evidence. This study was registered in advance (PROSPERO CRD42022337841).
Main findings
Ten articles involving 11 retrospective cohorts with a total of 47.1 million participants proved eligible. We found a 64 % greater risk (RR = 1.64, 95%CI: 1.51 to 1.79) of diabetes in patients with COVID-19 compared with non-COVID-19 controls, which could increase the number of diabetes events by 701 (558 more to 865 more) per 10,000 persons. We detected significant subgroup effects for type of diabetes and sex. Type 2 diabetes has a higher relative risk than type 1. Moreover, men may be at a higher risk of overall diabetes than women. Sensitivity analysis confirmed the robustness of the results. No evidence was found for publication bias.
Conclusions
COVID-19 is strongly associated with the risk of incident diabetes, including both type 1 and type 2 diabetes. We should be aware of the risk of developing diabetes after COVID-19 and prepare for the associated health problems, given the large and growing number of people infected with COVID-19. However, the body of evidence still needs to be strengthened.

Pancreas

3326

OO219

Syeda Tayyaba Rehan,Laiba Imran,Hussain Mansoor,Qudsia Sayyeda,Hassan ul Hussain,Mustafa Sajjad Cheema,Muhammad Junaid Tahir,Muhammad Sohaib Asghar,Mohammed Mahmmoud Fadelallah Eljack,Md. Saiful Islam

Effects of SARS-CoV-2 infection and COVID-19 pandemic on menstrual health of women: A systematic review

https://doi.org/10.1002/hsr2.881

Published

8-Oct-22

Systematic Review

https://onlinelibrary.wiley.com/doi/10.1002/hsr2.881

Background
The menstrual cycle in women is the main indicator of their reproductive health which is affected by the ongoing coronavirus disease 2019 (COVID-19) pandemic. This review aims to summarize the effects of the COVID-19 infection and the global pandemic on the menstrual health of women.
Methods
The literature search was conducted in PubMed, Cochrane library, and Google Scholar using keywords “COVID-19,” “Menstrual Cycle,” “Menstrual Cycle Irregularities,” “Amenorrhea,” “Polymenorrhea,” and “Dysmenorrhea.” The articles were selected according to the following inclusion criteria: (i) cross-sectional studies, (ii) cohort studies, (iii) surveys, and (iv) other observational studies observing the effects of SARS-CoV-2 infection or COVID-19 pandemic on menstrual health of women. Exclusion criteria included: case reports, gray literature, and website articles regarding menstrual health.
Results
A total of 30,510 articles were shortlisted after a comprehensive search. Sixteen articles were included out of which 13 studies investigated the effects of the COVID-19 pandemic on the menstrual cycle while 3 evaluated the possible effects of COVID-19 infection on the menstrual health of women. Menstrual disorders or irregularities were a more common finding during the pandemic as compared to before (p = 0.008). Women affected by pandemic-related stress were more prone to changes in the duration of their menses (p = 0.0008), reported heavier bleeding (p = 0.028), and increased incidence of painful periods (p < 0.0001). COVID-19 infected women also reported changes in their menstrual cycle including irregular menstruation, increased symptoms of premenstrual syndrome, and infrequent menstruation.
Conclusions
Women suffering from COVID-19 infection or pandemic-associated stress and anxiety were more likely to experience irregular menstruation, dysmenorrhea, amenorrhea, and other menstrual abnormalities compared to those who were less exposed.

Female reproductive system

3327

OO220

Mohamad Norouzi Masir 1 and Milad Shirvaliloocorresponding author 2

Symptomatology and microbiology of the gastrointestinal tract in post‐COVID conditions

https://doi.org/10.1002%2Fjgh3.12811

Published

25-Aug-22

Review

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9538198/

Post‐COVID conditions, also known as post‐acute sequelae of SARS‐CoV‐2 (PASC), refer to the persistence of symptoms in COVID‐19 long‐haulers. Various manifestations of post‐COVID conditions are general symptoms and/or manifestations of damage in multiple organs. Besides, SARS‐CoV‐2 can involve the gastrointestinal tract, resulting in sequelae such as diarrhea, abdominal pain, nausea, anorexia, vomiting, constipation, abdominal distension, acid reflux, and/or gastrointestinal bleeding. Previous investigations point to SARS‐CoV‐2 entry into enterocytes enhances by the angiotensin‐converting enzyme 2 (ACE2) receptors. Interestingly, ACE2 receptors are abundantly expressed in the gut, implying infection with SARS‐CoV‐2 might occur through this route as well as in the respiratory tract. According to mounting evidence, SARS‐CoV‐2 RNA has been identified in fecal specimens of patients with COVID‐19 during and beyond the acute phase. In addition, studies have shown gut microbiome composition is altered in patients with PASC, hence, another putative mechanism linked to gastrointestinal symptoms is gut dysbiosis. The presence of the gut‐lung axis in COVID‐19 might have major implications for disease pathogenesis and treatment. This review discussed the prevalence of gastrointestinal symptoms and pathophysiology underlying possible infection of the gut in patients with PASC. Also, SARS‐COV‐2 induced NLRP3 inflammasome‐dependent inflammatory pathways are briefly addressed.

Gastro-intestinal

3328

OO221

DrY.CherifDrS.DerbalDrO.HentatiDrD.ChebbiDrN.SreiriDrF.Ben DahmenDrM.Abdallah

Troubles thyroïdiens et pneumopathie Covid-19 : étude monocentrique à propos de 223 cas

https://doi.org/10.1016/j.ando.2022.07.164

Published

24-Sep-22

Study

https://www.sciencedirect.com/science/article/pii/S0003426622002712

Introduction
Les troubles de la fonction thyroïdienne au cours des viroses sont décrits dans la littérature. Le SARS-Cov2 entraîne des manifestations systémiques notamment une atteinte thyroïdienne.
Patients et méthodes
C’est une étude monocentrique type cohorte rétrospective incluant les patients hospitalisés pour une pneumopathie Covid-19 (septembre 2020–février 2022) et ayant une perturbation du bilan thyroïdien. Les patients ayant des antécédents de pathologies thyroïdiennes ont été exclus. Les caractéristiques clinico-biologiques ont été relevées.
Résultats
Durant cette période, 1237 patients ont été hospitalisé pour une pneumopathie Covid-19. Nous avons inclus 256 patients en excluant 33 patients ayant un antécédent de dysthyroïdie. Il s’agissait de 128 (57 %) femmes et 95 (43 %) hommes. L’âge moyen était de 74 ans. Il s’agissait de 191 (85,7 %) cas d’hyperthyroïdie fruste, 24 (10,7 %) cas d’hypothyroïdie fruste et 8 (3,6 %) cas d’hypothyroïdie dont 6 cas de thyroïdite d’Hashimoto avec des anticorps antithyroperoxydases positifs. Il y avait une normalisation du bilan thyroïdien des cas de dysthyroïdie fruste dont le bilan a été contrôlé à distance de l’infection.
Conclusion
L’infection Covid-19, par le billais du stress hypoxique, la sécrétion de glucocorticoïdes et la libération de cytokines pro inflammatoires, peut perturber la fonction thyroïdienne. L’atteinte semble le plus souvent spontanément réversible dans le cas des dysthyroïdies fruste mais l’attention est toujours requise chez les à haut risque de survenu de fibrillation auriculaire. Ceci augmenterait le risque thromboembolique déjà majoré par la COVID-19. D’authentique cas de thyroïdite auto-immunes ont aussi été découvertes. Ceci confirme la relation déjà soulevé entre SARS-cov2 et auto-immunité.

Thyroid gland

3329

OO222

Umberto Tarantino, Virginia V. Visconti https://orcid.org/0000-0002-4543-7770, […], Roberto Bonanni, Andrea Gatti, Martina Marcozzi, Davide Calabrò, and Ida Cariati

Osteosarcopenia and Long-COVID: a dangerous combination

https://doi.org/10.1177/1759720X221130485

Published

26-Oct-22

Review

https://journals.sagepub.com/doi/10.1177/1759720X221130485

SARS-CoV-2 has caused a global pandemic and an unprecedented public health crisis, infecting more than 580 million people worldwide. Moreover, recent evidence has suggested the emergence of a new syndrome known as Long-COVID, a term used to describe a diverse set of physical and mental symptoms that persist after a diagnosed SARS-CoV-2 infection. Epidemiological data have identified myalgias, muscle and joint dysfunction, and bone fragility as common sequelae in patients with moderate and severe forms of this disease. Significant musculoskeletal dysfunction has also been detected in some healed patients, although knowledge about pathophysiological mechanisms of Long-COVID is still rather scarce. In this context, SARS-CoV-2 infection has been suggested to amplify the effects of aging on the musculoskeletal system by aggravating the osteosarcopenic state. Based on this evidence, our review focused on the muscle and bone tissue alterations induced by SARS-CoV-2 infection and Long-COVID, summarizing the current knowledge on the underlying biological mechanisms and highlighting the need for a multidisciplinary approach to predict the musculoskeletal targets and long-term consequences of COVID-19 disease.

Muscles and Bones

3330

OO223

Laure-Alix Clerbaux 1,*ORCID,Sally A. Mayasich 2ORCID,Amalia Muñoz 3,Helena Soares 4ORCID,Mauro Petrillo 5ORCID,Maria Cristina Albertini 6ORCID,Nicolas Lanthier 7ORCID,Lucia Grenga 8ORCID andMaria-Joao Amorim 9,10ORCID

Gut as an Alternative Entry Route for SARS-CoV-2: Current Evidence and Uncertainties of Productive Enteric Infection in COVID-19

https://doi.org/10.3390/jcm11195691

Published

26-Sep-22

Study

https://www.mdpi.com/2077-0383/11/19/5691/htm

The gut has been proposed as a potential alternative entry route for SARS-CoV-2. This was mainly based on the high levels of SARS-CoV-2 receptor expressed in the gastrointestinal (GI) tract, the observations of GI disorders (such as diarrhea) in some COVID-19 patients and the detection of SARS-CoV-2 RNA in feces. However, the underlying mechanisms remain poorly understood. It has been proposed that SARS-CoV-2 can productively infect enterocytes, damaging the intestinal barrier and contributing to inflammatory response, which might lead to GI manifestations, including diarrhea. Here, we report a methodological approach to assess the evidence supporting the sequence of events driving SARS-CoV-2 enteric infection up to gut adverse outcomes. Exploring evidence permits to highlight knowledge gaps and current inconsistencies in the literature and to guide further research. Based on the current insights on SARS-CoV-2 intestinal infection and transmission, we then discuss the potential implication on clinical practice, including on long COVID. A better understanding of the GI implication in COVID-19 is still needed to improve disease management and could help identify innovative therapies or preventive actions targeting the GI tract.

Gastro-intestinal

3331

OO224

RithvikGolla1SudheerVuyyuru1BhaskarKante1PeeyushKumar1David ThomasMathew1GovindMakharia1SaurabhKedia1VineetAhuja1

Long-term gastrointestinal sequelae following COVID-19: A prospective follow-up cohort study

https://doi.org/10.1016/j.cgh.2022.10.015

Published

21-Oct-22

Study

https://www.sciencedirect.com/science/article/pii/S1542356522010047

Background and Aims
COVID-19 is associated with long-term gastrointestinal sequelae; however, prospective longitudinal data are sparse. We prospectively studied the frequency, spectrum and risk factors of post infection functional gastro-intestinal disorders/disorders of gut-brain interaction (PI-FGID/DGBI) following COVID-19.
Methods
320 cases with COVID-19 and two control groups: (Group-A) 320 healthy spouses/family controls and (Group B) 280 healthy COVID serology-negative controls were prospectively followed up at 1,3 and 6 months using validated Rome IV criteria to evaluate the frequency of PI-FGID/DGBI.
Results
Of 320 cases, at 1 month, 36 (11.3%) developed FGID symptoms. Persistent symptoms were noted in 27 (8.4%) at 3 months, and in 21 (6.6%) at 6 months. At 3 months, 8 (2.5%) had irritable bowel syndrome, 7 (2.2%) had functional diarrhea, 6 (1.9%) had functional dyspepsia, 3 (0.9%) had functional constipation, 2 (0.6%) had FD-IBS overlap, and 1 (0.3%) had functional abdominal bloating/distension. Among symptomatic individuals at 3 months, 8 (29.6%) were positive for isolated carbohydrate malabsorption, 1 (3.7%) was positive for post infection malabsorption syndrome (PI-MAS) and 1 (3.7%) was positive for Intestinal methanogen overgrowth (IMO). None of the healthy controls developed FGID up to 6 months of follow up (p<0.01). Predictive factors at 3 and 6 months were severity of infection (p<0.01) and presence of GI symptoms at the time of infection (p<0.01).
Conclusion
COVID-19 led to significantly higher number of new onset PI-FGID/DGBI compared to healthy controls at 3 and 6 months of follow-up. If further investigated some patients can be diagnosed with underlying malabsorption.

Gastro-intestinal

3332

OO225

Raphaela I. Lau, Fen Zhang, Qin Liu, Qi Su, Francis K. L. Chan & Siew C. Ng

Gut microbiota in COVID-19: key microbial changes, potential mechanisms and clinical applications

https://doi.org/10.1038/s41575-022-00698-4

Published

21-Oct-22

Article

https://www.nature.com/articles/s41575-022-00698-4

The gastrointestinal tract is involved in coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The gut microbiota has important roles in viral entry receptor angiotensin-converting enzyme 2 (ACE2) expression, immune homeostasis, and crosstalk between the gut and lungs, the ‘gut–lung axis’. Emerging preclinical and clinical studies indicate that the gut microbiota might contribute to COVID-19 pathogenesis and disease outcomes; SARS-CoV-2 infection was associated with altered intestinal microbiota and correlated with inflammatory and immune responses. Here, we discuss the cutting-edge evidence on the interactions between SARS-CoV-2 infection and the gut microbiota, key microbial changes in relation to COVID-19 severity and host immune dysregulations with the possible underlying mechanisms, and the conceivable consequences of the pandemic on the human microbiome and post-pandemic health. Finally, potential modulatory strategies of the gut microbiota are discussed. These insights could shed light on the development of microbiota-based interventions for COVID-19.

Gastro-intestinal

3333

OO226

Emily M. Cherenack,Ana S. Salazar,Nicholas F. Nogueira,Patricia Raccamarich,Violeta J. Rodriguez,Alejandro M. Mantero,Allison Marsh,Sophia Gerard,Marissa Maddalon,Deborah L. Jones,Nichole R. Klatt,Maria L. Alcaide

Infection with SARS-CoV-2 is associated with menstrual irregularities among women of reproductive age

https://doi.org/10.1371/journal.pone.0276131

Published

26-Oct-22

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0276131

Background
Biological and psychological mechanisms may be responsible for menstrual irregularities occurring among women during the COVID-19 pandemic.
Study design
From January 2019 to September 2021, women (18- to 45-years-old and not using hormonal contraception) were recruited in Miami-Dade County, Florida. Cross-sectional, self-report surveys collected data on menstrual irregularities, COVID-19 vaccination, stress, depression, and loneliness. A EUA approved rapid test assay using whole blood measured SARS-CoV-2 IgG antibodies. Chi-square and Fisher’s exact tests described menstrual irregularities among women recruited before versus after the start of the COVID-19 pandemic and with detectable versus undetectable SARS-CoV-2 IgG antibodies. A logistic regression examined the relationship between the presence of SARS-CoV-2 IgG antibodies and menstrual irregularities controlling for age, stress, depression, and loneliness.
Results
Among 182 women enrolled, 73 were enrolled after pandemic onset, and 36 provided vaccination data. Having detectable SARS-CoV-2 IgG antibodies was associated with a higher percentage of menstrual irregularities among unvaccinated women (0% vs. 39%, p = .026) and among all women regardless of vaccination status (31% vs. 5%; p = .005). Adjusting for age and psychological variables, the odds of menstrual irregularities were 7.03 times (95% CI [1.39, 35.60]; p = .019) higher among women with detectable antibodies compared to women without detectable antibodies. Neither enrollment date, age, nor psychological factors were associated to menstrual irregularities.
Conclusions
Biological mechanisms related to SARS-CoV-2 infection may be responsible for irregular menstruation and should be further examined to mitigate the impact of the COVID-19 pandemic on women’s health.

Female reproductive system

3334

OO227

F Xue, E Duggan, G Jennings, A Monaghan, R Romero-Ortuno

212 FATIGUE EXPERIENCED BY ADULTS WITH LONG-COVID WAS NOT ASSOCIATED WITH AN EMG-DERIVED MUSCLE FATIGUE INDEX

https://doi.org/10.1093/ageing/afac218.183

Published

25-Oct-22

Study

https://academic.oup.com/ageing/article/51/Supplement_3/afac218.183/6770373

Background
One of the most prominent challenges of the COVID-19 pandemic is the emergence of the post-COVID-19 syndrome or ‘long-COVID’ following the acute phase of the viral infection. With a plethora of debilitating symptoms across many physiological systems, the pathophysiology of long-COVID remains elusive and subject of intense research efforts. Adults with long COVID are often affected by prolonged fatigue, which could be linked to neuromuscular function impairment. We hypothesised that there might be a correlation between subjective fatigue and an Electromyograph(EMG)-derived muscle fatigue index in adults with long-COVID.
Methods
As part of a neuro-cardiovascular instability assessment protocol, participants were asked to squeeze the thigh muscles as hard as possible for ten seconds during both supine resting and after active and passive standing (head-up tilt) tests. Surface EMG was used to capture on each leg the physiological activity of the vastus lateralis and rectus femoris during the squeezes, from which the muscle fatigue index was computed based on both the mean and median frequencies of each 10-second maximum prompted muscle contraction. Using two-sided Spearman correlation coefficients, we examined the associations between the muscle fatigue indices and self-reported fatigue measured by the Chalder Fatigue Scale (CFQ).
Results
108 participants were included, 77 female and 31 male, with a mean age of 46 (range 25-78) years, 22% of whom were hospitalised in the acute phase of SARS-CoV-2 infection. Strong intercorrelations were found between the muscle fatigue indices derived from the mean and median frequencies of thigh muscle contractions. However, no significant correlations were detected between the muscle fatigue indices and CFQ scores.
Conclusion
Self-reported fatigue as measured by the CFQ was not associated with an EMG-derived muscle fatigue index in this long-COVID cohort.

Muscles

3335

OO228

J. Zhang, W. Shi, M. Zou, Q. Zeng, Y. Feng, Z. Luo & H. Gan

Prevalence and risk factors of erectile dysfunction in COVID-19 patients: a systematic review and meta-analysis

https://doi.org/10.1007/s40618-022-01945-w

Published

28-Oct-22

Systematic review and meta-analysis

https://link.springer.com/article/10.1007/s40618-022-01945-w

Purpose
Studies have found that erectile dysfunction (ED) may be a short-term or long-term complication in coronavirus disease 2019 (COVID-19) patients, but no relevant studies have completed a pooled analysis of this claim. The purpose of the review was to comprehensively search the relevant literature, summarize the prevalence of ED in COVID-19 patients, assess risk factors for its development, and explore the effect of the COVID-19 infection on erectile function.
Methods
Medline, Embase, and the Cochrane Library was performed from database inception until April 14, 2022. Heterogeneity was analyzed by χ2 tests and I2 was used as a quantitative test of heterogeneity. Subgroup analyses, meta-regression, and sensitivity analyses were used to analyze sources of heterogeneity.
Results
Our review included 8 studies, 4 of which functioned as a control group. There were 250,606 COVID-19 patients (mean age: 31–47.1 years, sample size: 23–246,990). The control group consisted of 10,844,200 individuals (mean age: 32.76–42.4 years, sample size 75–10,836,663). The prevalence of ED was 33% (95% CI 18–47%, I2 = 99.48%) in COVID-19 patients. The prevalence of ED based on the international coding of diseases (ICD-10) was 9% (95% CI 2–19%), which was significantly lower than the prevalence of ED diagnosed based on the International Index of Erectile Function (IIEF-5) (46%, 95% CI 22–71%, I2 = 96.72%). The pooling prevalence of ED was 50% (95% CI 34–67%, I2 = 81.54%) for articles published in 2021, significantly higher than that for articles published in 2022 (17%, 95% CI 7–30%, I2 = 99.55%). The relative risk of developing ED was 2.64 times in COVID-19 patients higher than in non-COVID-19 patients (RR: 2.64, 95% CI 1.01–6.88). The GRADE-pro score showed that the mean incidence of ED events in COVID-19 patients was 1,333/50,606 (2.6%) compared with 52,937/844,200 (0.4%) in controls; the absolute impact of COVID-19 on ED was 656/100,000 (ranging from 4/100,000 to 2352/100,000). Anxiety (OR: 1.13, 95% CI 1.03–1.26, I2 = 0.0%) in COVID-19 patients was a risk factor for ED.
Conclusion
COVID-19 patients have a high risk and prevalence of ED, mainly driven by anxiety. Attention should be paid to patient’s erectile functioning when treating COVID-19.

Male reproductive system

3336

OO229

Francesco Pallotti, Sandro C. Esteves, Fabiana Faja, Alessandra Buonacquisto, Anna Chiara Conflitti, Maria Neve Hirsch, Andrea Lenzi, Donatella Paoli & Francesco Lombardo

COVID-19 and its treatments: lights and shadows on testicular function

https://doi.org/10.1007/s12020-022-03221-6

Published

19-Oct-22

Mini-Review

https://link.springer.com/article/10.1007/s12020-022-03221-6

Purpose
The SARS-CoV-2 pandemic has rapidly spread worldwide and, among the others, the male gender was quickly recognized as an independent risk factor for both the disease and its consequences. Since the possibility of long-term hormonal axis changes and male gamete impairment have been hypothesized but a relatively low levels of evidence has been reached, we focused this narrative mini-review on summarizing key state-of-the-art knowledge on male reproductive effects of COVID-19 as a quick reference for reproductive health specialists.
Methods
A comprehensive Medline/PubMed and Embase search was performed selecting all relevant, peer-reviewed papers in English published from 2020. Other relevant papers were selected from the reference lists.
Results
Available evidence indicates that the likelihood of direct testicular damage from SARS-CoV-2 is somewhat low, but there are many indirect ways (fever, cytokine imbalance, and drugs) through which the pituitary-gonadal axis and spermatogenesis may be disrupted. These alterations are probably transient, but as available evidence is low quality, it cannot be excluded that previous pathologies or comorbidities might modulate the risk of their persistence. On the other hand, available evidence shows high safety regarding andrological health for available vaccines, although studies are mainly focused on mRNA vaccines.
Conclusion
A careful andrological evaluation of men recovering from COVID-19 is highly recommended. Since available evidence is relatively scarce, a careful andrological follow-up and counseling of these patients are mandatory.

Male reproductive system

3337

OO230

Remzi Salar,Güven Erbay,Ahmet Şanlı,Ufuk Yavuz,Emre Kandemir,Harun Turel,Halil FeratÖncel

Effect of COVID-19 infection on the erectile function

https://doi.org/10.1111/andr.13315

Published

17-Oct-22

Study

https://onlinelibrary.wiley.com/doi/abs/10.1111/andr.13315

Objective
It has been understood that COVID-19, which has become a global pandemic in a short time, is a disease affecting multiple organs and systems. Some of the organs and systems affected by the disease also play a role in the pathophysiology of erectile dysfunction (ED), which led us to consider the possible effects of the disease on the erectile function. In this study, we aimed to evaluate changes in the erectile functions of patients with COVID-19 among those that had previously diagnosed with mild and moderate ED in our urology outpatient clinic.
Material and methods
Eighty-one patients aged 18–65 years who were confirmed to have COVID-19 were included in the study. According to disease severity, these patients were divided into two groups as mild (non-hospitalized, n = 60) and moderate (hospitalized but did not require intensive care, n = 21). The patients’ pre- and post-disease scores in the five-item International Index of Erectile Function (IIEF-5) and hormone panel results were compared.
Results
The changes in the IIEF-5 scores of the patients from the pre-disease to the post-disease period were statistically significant for both the mild and moderate groups (p < 0.05). When these changes were compared between the mild and moderate groups, the difference was not statistically significant (p = 0.156). There was also no statistically significant change in the testosterone, follicle-stimulating, luteinizing, and prolactin hormone levels before and after the disease.
Conclusion
In this study, we determined that SARS-CoV-2 infection caused deterioration in existing ED in sexually active male individuals, regardless of the severity of the disease.

Male reproductive system

3338

OO231

Norouzi Masir M1, Shirvaliloo M2

Symptomatology and microbiology of the gastrointestinal tract in post-COVID conditions.

https://doi.org/10.1002/jgh3.12811

Published

25-Aug-22

Review

https://europepmc.org/article/pmc/pmc9538198

Post-COVID conditions, also known as post-acute sequelae of SARS-CoV-2 (PASC), refer to the persistence of symptoms in COVID-19 long-haulers. Various manifestations of post-COVID conditions are general symptoms and/or manifestations of damage in multiple organs. Besides, SARS-CoV-2 can involve the gastrointestinal tract, resulting in sequelae such as diarrhea, abdominal pain, nausea, anorexia, vomiting, constipation, abdominal distension, acid reflux, and/or gastrointestinal bleeding. Previous investigations point to SARS-CoV-2 entry into enterocytes enhances by the angiotensin-converting enzyme 2 (ACE2) receptors. Interestingly, ACE2 receptors are abundantly expressed in the gut, implying infection with SARS-CoV-2 might occur through this route as well as in the respiratory tract. According to mounting evidence, SARS-CoV-2 RNA has been identified in fecal specimens of patients with COVID-19 during and beyond the acute phase. In addition, studies have shown gut microbiome composition is altered in patients with PASC, hence, another putative mechanism linked to gastrointestinal symptoms is gut dysbiosis. The presence of the gut-lung axis in COVID-19 might have major implications for disease pathogenesis and treatment. This review discussed the prevalence of gastrointestinal symptoms and pathophysiology underlying possible infection of the gut in patients with PASC. Also, SARS-COV-2 induced NLRP3 inflammasome-dependent inflammatory pathways are briefly addressed.

Gastro-intestinal

3339

OO232

Monica Bawor 1,Shwetha Sairam 1,Rachel Rozewicz 1,Stuart Viegas 2,Alexander N. Comninos 3,4 andAli Abbara 3,4,*

Rhabdomyolysis after COVID-19 Infection: A Case Report and Review of the Literature

https://doi.org/10.3390/v14102255

Published

14-Oct-22

Case Report and Review

https://www.mdpi.com/1999-4915/14/10/2255/htm

Rhabdomyolysis is a condition in which muscle breaks down potentially leading to renal dysfunction, and often occurs secondary to a precipitating factor. Viral or bacterial infections are common precipitants for initiating rhabdomyolysis. Recently, healthcare systems across the world have been challenged by a pandemic of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causing ‘coronavirus disease 2019’ (COVID-19) disease. SARS-CoV-2 infection is recognized to cause respiratory and cardiovascular compromise, thromboembolic events, and acute kidney injury (AKI); however, it is not known whether it can precipitate rhabdomyolysis, with only a limited number of cases of SARS-CoV-2 infection preceding rhabdomyolysis reported to date. Here, we report the case of a 64-year-old woman who developed rhabdomyolysis shortly after SARS-CoV-2 infection and COVID-19. She initially presented with muscular pain, a creatine kinase level of 119,301 IU/L, and a mild rise in her creatinine level to 92 µmol/L, but successfully recovered with intravenous fluid support. We also review the literature to summarise previously reported cases of rhabdomyolysis precipitated by SARS-CoV-2, highlighting the need to consider this diagnosis in patients presenting with SARS-CoV-2 and myalgia.

Muscles

3340

OO233

BeshoyYanny1MohammedAlkhero2MohammedAlani2DanielStenberg2AryanSaharan3SammySaab1

Post-Covid- 19 Cholangiopathy:A Systematic Review

https://doi.org/10.1016/j.jceh.2022.10.009

Published

30-Oct-22

Review

https://www.sciencedirect.com/science/article/pii/S0973688322005072

Objectives
Post COVID-19 cholangiopathy is a rare but poorly understood and serious complication of COVID-19 infection. We sought to better understand the epidemiology, mechanism of action, histology, imaging findings and outcomes of post-COVID-19 cholangiopathy.
Methods
We searched PubMed, Cochrane Library, Embase, and Web of Science from December 2019 to December 2021. Mesh words used “post-Covid-19 cholangiopathy”, “COVID-19 liver injury”,” Covid-19 and cholangiopathy”, and COVID-19 liver disease”. The data on epidemiology, mechanism of action, histology, imaging findings and outcomes were collected.
Results
Post COVID-19 cholangiopathy was reported in 30 cases during the study period. The mean (standard deviation [SD]) age was 53.7 (5). Men accounted for cases (83.3%). All patients had required intensive level of care and mechanical ventilation. Mean (SD) number of days from COVID infection to severe disease or liver disease was 63.5(38). Peak mean (SD) alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin were 2014 (831.8) U/L, 1555 (2432.8) U/L, 899.72 (1238.6) U/L, and 10.32 (9.32) mg/dl, respectively. Four patients successfully underwent liver transplantation.
Conclusion
Post COVID-19 cholangiopathy is a severe and progressive complication of COVID-19 infection. More research is needed to better understand the pathophysiology and best treatment approach. Clinicians should suspect post COVID-19 cholangiopathy in patients with cholestatic liver injury following COVID-19 infection.

Bile

3341

OO234

Rüdiger Groß & Alexander Kleger

COVID-19 and diabetes — where are we now?

https://doi.org/10.1038/s42255-022-00691-w

Published

11-Nov-22

Comment

https://www.nature.com/articles/s42255-022-00691-w

As emerging clinical analyses suggest an increased risk of new-onset diabetes following COVID-19, a causal link and underlying mechanisms are yet to be established. Persistence of hyperglycaemia after disease regression and the potential infection of non-pancreatic tissue are adding another layer of complexity to the relationship between COVID-19 and diabetes mellitus.

Pancreas

3342

OO235

Baris Ata, Nathalie Vermeulen, Edgar Mocanu, Luca Gianaroli, Kersti Lundin, Satu Rautakallio-Hokkanen, Juha S Tapanainen, Anna Veiga

SARS-CoV-2, fertility and assisted reproduction

https://doi.org/10.1093/humupd/dmac037

Published

14-Nov-22

Review

https://academic.oup.com/humupd/advance-article/doi/10.1093/humupd/dmac037/6827446

BACKGROUND
In 2020, SARS-CoV-2 and the COVID-19 pandemic had a huge impact on the access to and provision of ART treatments. Gradually, knowledge of the virus and its transmission has become available, allowing ART activities to resume. Still, questions on the impact of the virus on human gametes and fertility remain.
OBJECTIVE AND RATIONALE
This article summarizes published data, aiming to clarify the impact of SARS-CoV-2 and the COVID-19 disease on human fertility and assisted reproduction, as well as the impact of vaccination, and from this, provide answers to questions that are relevant for people contemplating pregnancy and for health care professionals.
SEARCH METHODS
PUBMED/MEDLINE and the WHO COVID-19 database were searched from inception to 5 October 2022 with search terms focusing on ‘SARS-CoV-2’ and gametes, embryos, reproductive function, fertility and ART. Non-English studies and papers published prior to 2020 were excluded, as well as reviews and non-peer reviewed publications. Full papers were assessed for relevance and quality, where feasible.
OUTCOMES
From the 148 papers included, the following observations were made. The SARS-CoV-2-binding proteins, angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2), are expressed in the testis, but co-expression remains to be proven. There is some evidence of SARS-CoV-2 RNA in the ejaculate of COVID-19 patients with severe disease, but not in those with mild/moderate disease. SARS-CoV-2 infection can impair spermatogenesis, but this seems to resolve after one spermatogenic cycle. Testosterone levels seem to be lower during and after COVID-19, but long-term data are lacking; disease severity may be associated with testosterone levels. COVID-19 cannot be considered a sexually transmitted disease. There is no co-expression of ACE2 and TMPRSS2 in the myometrium, uterus, ovaries or fallopian tubes. Oocytes seem to have the receptors and protease machinery to be susceptible to SARS-CoV-2 infection; however, viral RNA in oocytes has not been detected so far. Women contemplating pregnancy following COVID-19 may benefit from screening for thyroid dysfunction. There is a possible (transient) impact of COVID-19 on menstrual patterns. Embryos, and particularly late blastocysts, seem to have the machinery to be susceptible to SARS-CoV-2 infection. Most studies have not reported a significant impact of COVID-19 on ovarian reserve, ovarian function or follicular fluid parameters. Previous asymptomatic or mild SARS-CoV-2 infection in females does not seem to negatively affect laboratory and clinical outcomes of ART. There are no data on the minimum required interval, if any, between COVID-19 recovery and ART. There is no evidence of a negative effect of SARS-CoV-2 vaccination on semen parameters or spermatogenesis, ovarian function, ovarian reserve or folliculogenesis. A transient effect on the menstrual cycle has been documented. Despite concerns, cross reactivity between anti-SARS-CoV-2 spike protein antibodies and Syncytin-1, an essential protein in human implantation, is absent. There is no influence of mRNA SARS-CoV-2 vaccine on patients’ performance during their immediate subsequent ART cycle. Pregnancy rates post-vaccination are similar to those in unvaccinated patients.
WIDER IMPLICATIONS
This review highlights existing knowledge on the impact of SARS-CoV-2 infection or COVID-19 on fertility and assisted reproduction, but also identifies gaps and offers suggestions for future research. The knowledge presented should help to provide evidence-based advice for practitioners and couples contemplating pregnancy alike, facilitating informed decision-making in an environment of significant emotional turmoil.

Male reproductive system

3343

OO236

CassandraCalabreseElizabethKirchnerLeonard H.Calabrese

Long COVID and rheumatology: Clinical, diagnostic, and therapeutic implications

https://doi.org/10.1016/j.berh.2022.101794

Published

8-Nov-22

Review

https://www.sciencedirect.com/science/article/pii/S1521694222000535

As of this writing, it is estimated that there have been nearly 600 million cases of coronavirus disease 2019 (COVID-19) around the world with over six million deaths. While shocking, these figures do not fully illustrate the morbidity associated with this disease. It is also estimated that between 10% and 30% of those who survive COVID-19 develop persistent symptoms after the acute infection has passed. These individuals, who most often experienced initial infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) considered mild to moderate in severity, often display a broad array of symptoms. Collectively, this disorder or syndrome is now referred to as Long COVID (among other designations), and it represents a national/international health crisis. The most frequently reported symptoms associated with Long COVID include chronic fatigue with post exertional features, neurocognitive dysfunction, breathlessness, and somatic pain. Long COVID can range in severity from mild to severely debilitating, with resultant loss of quality of life and productivity. For now, there are many unanswered questions surrounding Long COVID: how can it be best defined, what is needed for accurate diagnosis, what is causing it, and how should it be best managed. How rheumatologists will engage in the Long COVID pandemic is another question; at the minimum, we will be called upon to evaluate and manage our own patients with immune-mediated inflammatory diseases who have developed it. This review focuses on addressing the disease essentials, providing both declarative and procedural knowledge to prepare rheumatologists for how to address Long COVID: understanding its origins, its current case definitions, epidemiology, pathobiology and clinical manifestations. Finally, it will provide an outline on how to clinically approach patients with possible Long COVID and initiate treatment and/or guide them on how to best manage it.

Joints

3344

OO237

Sophia Dove
Leryn Turlington
Kate Elmendorf
Kurayi Mahachi
Christine Petersen
David Meyer

Singing Voice Symptomatology Following Presumed SARS-CoV-2 Infection

https://doi.org/10.1016/j.jvoice.2022.11.012

Published

15-Nov-22

Study

https://www.jvoice.org/article/S0892-1997(22)00364-2/fulltext

The impact of continued COVID-19 sequelae on singers’ vocal function has yet to be determined. An online survey of singers who have contracted SARS-CoV-2 infection was designed and administered globally. Participants (n = 1,153) were recruited in Africa, the Americas, Asia, Australia, and Europe. Survey questions included demographics, peri- and post-SARS-CoV-2 infection symptoms, and self-reported sequelae attributed to long-COVID. The survey was made available in English, Portuguese, Spanish, and Traditional and Simplified Mandarin Chinese. Data were statistically analyzed to provide a useful summary of the sample and to evaluate associations between long-COVID and singers’ vocal function. We found that age, gender, and vaccination status were not significantly correlated to a change in singing voice in our sample. However, severity of infection was statistically correlated with a change in singing voice. Of the 34 signs and symptoms presented, lingering cough, shortness of breath, and chronic fatigue were significantly correlated with a change in singing voice. These data and their analyses have added to our understanding of this growing population's unique vocal needs, and may inform strategies for singing voice habilitation in COVID-19 survivors.

Vocal organs

3345

OO238

Kamlesh Khunti, Jonathan Valabhji & Shivani Misra

Diabetes and the COVID-19 pandemic

https://doi.org/10.1007/s00125-022-05833-z

Published

23-Nov-22

Review

https://link.springer.com/article/10.1007/s00125-022-05833-z

Almost immediately after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus emerged, it was evident that people with chronic diseases, including diabetes, were disproportionately affected, with an increased risk of hospitalisation and mortality. Over the ensuing 2 years, the indirect effects of the pandemic on healthcare delivery in the short term have become prominent, along with the lingering effects of the virus in those directly infected. In the wake of the pandemic and without any evidence from high quality studies, a number of national and international consensus recommendations were published, which were subsequently rapidly updated based on observational studies. There have been unprecedented disruptions from both direct and indirect impacts of coronavirus disease-2019 (COVID-19) in people with diabetes. In this review, we summarise the impact of acute COVID-19 in people with diabetes, discuss how the presentation and epidemiology during the pandemic, including presentation of diabetic ketoacidosis and new-onset diabetes, has changed, and we consider the wider impact of the pandemic on patients and healthcare service delivery, including some of the areas of uncertainty. Finally, we make recommendations on prioritising patients as we move into the recovery phase and also how we protect people with diabetes for the future, as COVID-19 is likely to become endemic.

Pancreas

3346

OO239

LornaRenshawabJ MichaelDixonabJuliaAndersoncArran K.Turnbullab

Mondor's disease of the breast: A cutaneous thromboembolic manifestation of Covid-19?

https://doi.org/10.1016/j.breast.2022.11.006

Published

17-Nov-22

Study

https://www.sciencedirect.com/science/article/pii/S0960977622001898

Background
Mondor's disease is a rare disorder characterised by thrombosis of superficial veins within the subcutaneous tissue of the breast and other organs. While factors such as trauma, infection, physical exertion, breast cancer and breast surgery have been implicated, in the majority no cause is identified.
Patients
Twenty patients presented with a clinical diagnosis of Mondor's disease to the Edinburgh Breast Services in 2020. We present the etiopathogenic data as well as clinical and imaging diagnostic findings.
Results
During 2020, the annual incidence of Mondor's disease, in the UK's largest breast unit, increased five-fold compared to data from the previous year. This variation in the frequency of cases corresponded to trends in the frequency of Covid-19 infection during the pandemic. None of the patients had diagnosed COVID and few had any known etiopathogenic causes for their Mondor's.
Conclusion
Several recent studies have provided evidence for links between Covid-19 and thromboembolic events. Isolated reports have proposed a link between Covid-19 and Mondor's disease of the penis. Here we present data on a large series of Mondor's disease of the breast supporting a link between breast Mondor's and Covid-19.

Skin

3347

OO240

SauloGilPhDabGersiel Nascimentode Oliveira JúniorMScaFlavia MoriSartiPhDcWilson JacobFilhoMD, PhDdIgorLongobardiMScaJosé Antonio OrellanaTurriPhDcSamuel KatsuyukiShinjoMD, PhDbEduardoFerriolliMD, PhDeThiago JunqueiraAvelino-SilvaMD, PhDdAlexandre LeopoldBusseMD, PhDdBrunoGualanoPhDabHamiltonRoschelPhDab

Acute Muscle Mass Loss Predicts Long-Term Fatigue, Myalgia, and Health Care Costs in COVID-19 Survivors

https://doi.org/10.1016/j.jamda.2022.11.013

Published

23-Nov-22

Study

https://www.sciencedirect.com/science/article/pii/S152586102200891X

Objective
We examined the impact of loss of skeletal muscle mass in post-acute sequelae of SARS-CoV-2 infection, hospital readmission rate, self-perception of health, and health care costs in a cohort of COVID-19 survivors.
Design
Prospective observational study.
Setting and Participants
Tertiary Clinical Hospital. Eighty COVID-19 survivors age 59 ± 14 years were prospectively assessed.
Methods
Handgrip strength and vastus lateralis muscle cross-sectional area were evaluated at hospital admission, discharge, and 6 months after discharge. Post-acute sequelae of SARS-CoV-2 were evaluated 6 months after discharge (main outcome). Also, health care costs, hospital readmission rate, and self-perception of health were evaluated 2 and 6 months after hospital discharge. To examine whether the magnitude of muscle mass loss impacts the outcomes, we ranked patients according to relative vastus lateralis muscle cross-sectional area reduction during hospital stay into either “high muscle loss” (−18 ± 11%) or “low muscle loss” (−4 ± 2%) group, based on median values.
Results
High muscle loss group showed greater prevalence of fatigue (76% vs 46%, P = .0337) and myalgia (66% vs 36%, P = .0388), and lower muscle mass (−8% vs 3%, P < .0001) than low muscle loss group 6 months after discharge. No between-group difference was observed for hospital readmission and self-perceived health (P > .05). High muscle loss group demonstrated greater total COVID-19-related health care costs 2 ($77,283.87 vs. $3057.14, P = .0223, respectively) and 6 months ($90,001.35 vs $12, 913.27, P = .0210, respectively) after discharge vs low muscle loss group. Muscle mass loss was shown to be a predictor of total COVID-19-related health care costs at 2 (adjusted β = $10, 070.81, P < .0001) and 6 months after discharge (adjusted β = $9885.63, P < .0001).
Conclusions and Implications
COVID-19 survivors experiencing high muscle mass loss during hospital stay fail to fully recover muscle health. In addition, greater muscle loss was associated with a higher frequency of post-acute sequelae of SARS-CoV-2 and greater total COVID-19-related health care costs 2 and 6 months after discharge. Altogether, these data suggest that the loss of muscle mass resulting from COVID-19 hospitalization may incur in an economical burden to health care systems.

Muscles

3348

OO241

Soheila Pourmasumi 1,2,Alireza Nazari 1,3,Zahra Ahmadi 4,Sophia N. Kouni 5,Cesare de Gregorio 6ORCID,Ioanna Koniari 7,Periklis Dousdampanis 8,Virginia Mplani 9,Panagiotis Plotas 10ORCID,Stelios Assimakopoulos 11ORCID,Christos Gogos 12ORCID,Georgios Aidonisdis 13ORCID,Pavlos Roditis 14,Nikos Matsas 15,Dimitrios Velissaris 16,Gianfranco Calogiuri 17,18,Ming-Yow Hung 19,20,21ORCID,Servet Altay 22ORCID andNicholas G. Kounis 23,*ORCID

The Effect of Long COVID-19 Infection and Vaccination on Male Fertility; A Narrative Review

https://doi.org/10.3390/vaccines10121982

Published

22-Nov-22

Review

https://www.mdpi.com/2076-393X/10/12/1982

Earlier research has suggested that the male reproductive system could be particularly vulnerable to SARS-CoV-2 (COVID-19) infection, and infections involving this novel disease not only pose serious health threats but could also cause male infertility. Data from multi-organ research during the recent outbreak indicate that male infertility might not be diagnosed as a possible consequence of COVID-19 infection. Several review papers have summarized the etiology factors on male fertility, but to date no review paper has been published defining the effect of COVID-19 infection on male fertility. Therefore, the aim of this study is to review the published scientific evidence regarding male fertility potential, the risk of infertility during the COVID-19 pandemic, and the impact of COVID-19 vaccination on the male reproductive system. The effects of COVID-19 infection and the subsequent vaccination on seminal fluid, sperm count, sperm motility, sperm morphology, sperm viability, testes and sex hormones are particularly reviewed.

Male reproductive system

3349

OO243

Ramy Emad Nageeb Louz , MSc,Mohamad Amr Salah Eddin , MD,Tamer A. Macky , MD, FRCSEd &Doaa Ahmed Abdelrahman Tolba , MD

Post COVID-19 Retinal Evaluation Using Optical Coherence Tomography Angiography: A Case Control Study

https://doi.org/10.1080/09273948.2022.2141651

Published

22-Nov-22

Case Control Study

https://www.tandfonline.com/doi/abs/10.1080/09273948.2022.2141651

Purpose
To study the effect of coronavirus disease of 2019 (COVID-19) on retinal vasculature by Optical Coherence Tomography Angiography (OCTA).
Methods
Macular OCTA images of patients recovered from COVID-19 infections were studied including foveal avascular zone (FAZ), capillary vascular densities (CVD) of the superficial and deep capillary network (SCP, DCP), and central foveal thickness (CFT).
Results
The FAZ area was significantly larger in post COVID-19 cases compared to the healthy controls (p=0.032). Post COVID-19 cases had significant lower CVDs in perifoveal quadrants of the SCP. They also had lower CVD in the whole area, parafoveal, temporal and inferior perifoveal areas in the DCP. The parafoveal DCP area showed a positive correlation with disease duration (r=0.249, p-value=0.018). The whole SCP was significantly larger in cases with lymphopenia (p-value=0.004).
Conclusion
This study found asymptomatic retinal vascular affection in post COVID-19 eyes showing a relation with disease clinical and laboratory features.

Eyes

3350

OO243

Jessica LHardingabcSofia AOviedoabMohammed KAlideIghoOfotokunfghJennifer CGanderiShivani APateldDianna JMaglianojRachel EPatzerabc

The Bidirectional Association Between Diabetes and Long-COVID-19 – A Systematic Review

https://doi.org/10.1016/j.diabres.2022.110202

Published

7-Dec-22

Review

https://www.sciencedirect.com/science/article/pii/S0168822722010166

Some evidence suggests that diabetes may be a risk factor for the development of post-acute sequelae of COVID-19 (PASC). Recent data also indicate that new-onset diabetes may be a complication of COVID-19. Here, we review the existing evidence.
Following PRISMA guidelines, we conducted a systematic review through August 8, 2022. We included longitudinal studies reporting on the risk of PASC (i.e., sequelae that extend beyond four weeks after initial infection) in people with and without diabetes, and studies reporting on the risk of new-onset diabetes in people with vs. without COVID-19 with a minimum of 4-weeks of follow-up. All studies were published in English.
Among 5,532 studies screened, 39 were included in the final review. Among 25 studies reporting on diabetes and PASC, 44% (n=11) identified diabetes as a significant risk factor for PASC (increased relative risk ranging from 7% to 342%) while 56% (n=14) did not. Among 14 studies reporting on new-onset diabetes, 12 (86%) reported that COVID-19 (vs. no COVID) was significantly associated with new-onset diabetes with increased risks ranging from 11% to 276%.
COVID-19 survivors may be at increased risk for new-onset diabetes, but whether pre-existing diabetes is also a risk factor for PASC remains unclear.

Pancreas

3351

OO244

Jonas J. de Paula, Fabio L. S. Duran, Geraldo Busatto, Debora M. Miranda & Marco A. Romano-Silva

Reply to “Predominance of visuoconstructive impairment after mild COVID-19?” by Díez-Cirarda et al. 2022

https://doi.org/10.1038/s41380-022-01839-6

Published

6-Dec-22

Correspondance

https://www.nature.com/articles/s41380-022-01839-6

In regard to the neuroimaging findings, the choice to inspect the statistical parametric maps with no correction for multiple comparisons was made due to the exploratory nature of the study, and we attempted to minimize false-positive findings by using a relatively strict threshold (p < 0.0005, two-tailed). We agree that it is important to reassess our findings with correction for multiple comparisons, and this is provided in the attached Table (applying family-wise error—FWE methods). The largest cluster of significant negative correlation between white matter volume and neuropsychological test performance retained statistical significance (FWE, cluster level), and so did one of the clusters of negative correlation between glucose metabolism and test performance (located in the right dorsal anterior cingulate cortex) (FWE, voxel-level).
While addressing the comments, we are urged to consider what awaits ahead in terms of recovery and possible interventions. The catching questions are how the virus promotes these changes and why not everyone recovers after a mild acute phase. The pandemic put the spotlight on the neuroinflammation that follows, not only SARS-Cov-2 infection, but also other systemic inflammatory conditions that compromises the whitte matter resulting in cognitive dysfunctions. We hope the comments were satisfactorily answered and make ourselves available for any further discussion about this very important and timely topic.

Eyes

3352

OO245

MinChenabcd1ShihuaLie1ShujunLiuf1YuhangZhanggh1XiuhongCuiaLiminLvfBowenLiuadAihuaZhengghQihuiWangeShuguangDuofFeiGaoabcd

Infection of SARS-CoV-2 causes severe pathological changes in mouse testis

https://doi.org/10.1016/j.jgg.2022.11.011

Published

6-Dec-22

Study

https://www.sciencedirect.com/science/article/pii/S1673852722002557

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected more than 600 million people worldwide. Several organs including lung, intestine, and brain are infected by SARS-CoV-2. It has been reported that SARS-CoV-2 receptor angiotensin-converting enzyme-2 (ACE2) is expressed in human testis. However, whether testis is also affected by SARS-CoV-2 is still unclear. In this study, we generate a human ACE2 (hACE2) transgenic mouse model in which the expression of hACE2 gene is regulated by hACE2 promoter. Sertoli and Leydig cells from hACE2 transgenic mice can be infected by SARS-CoV-2 pseudovirus in vitro, and severe pathological changes are observed after injecting the SARS-CoV-2 pseudovirus into the seminiferous tubules. Further studies reveal that Sertoli and Leydig cells from hACE2 transgenic mice are also infected by authentic SARS-CoV-2 virus in vitro. After testis interstitium injection, authentic SARS-CoV-2 viruses are first disseminated to the interstitial cells, and then detected inside the seminiferous tubules which in turn cause germ cell loss and disruption of seminiferous tubules. Our study demonstrates that testis is most likely a target of SARS-CoV-2 virus. Attention should be paid to the reproductive function in SARS-CoV-2 patients.

Testicles

3353

OO246

Robinson Ramírez-Vélez*, Gaizka Legarra-Gorgoñon, Sergio Oscoz-Ochandorena, Yesenia García-Alonso, Nora García-Alonso, Julio Oteiza, Ander Ernaga Lorea, María Correa-Rodríguez, and Mikel Izquierdo

Reduced Muscle Strength in Patients with Long-COVID-19 Syndrome Is Mediated by Limb Muscle Mass

https://doi.org/10.1152/japplphysiol.00599.2022

Published

30-Nov-22

Study

https://journals.physiology.org/doi/abs/10.1152/japplphysiol.00599.2022

Understanding the impact of COVID-19 on muscle strength may help to elucidate the organ systems that contribute to acute and chronic COVID-19 sequelae. We questioned whether patients with postdischarge symptoms after COVID-19 had compromised muscle strength compared with a control group, and if this potential relationship was mediated by the lower appendicular lean mass index (ALMI). A total of 99 patients with long-COVID-19 and 97 control participants were screened. Maximal grip strength was assessed with a TKK 5101 digital dynamometer, and leg extension 1RM was measured using EGYM Smart Strength machines. Body composition (fat mass percentage, lean mass, visceral fat and appendicular lean mass index) was determined using a whole-body dual-energy X-ray densitometer. Results showed that grip strength and leg extension strength were significantly higher in controls than in COVID-19 survivors (mean [SD], 32.82 [10.01] vs. 26.94 [10.33] kg; difference, 5.87 kg; P < 0.001) and (mean [SD], 93.98 [33.73] vs. 71.59 [33.70] kg; difference, 22.38 kg; P < 0.001), respectively). The relationship between long-COVID syndrome and grip/leg strength levels was partly mediated by ALMI, which explained 52% of the association for grip strength and 39% for leg extension. Our findings provide novel insights into the mechanisms underlying the relationship between long-COVID syndrome and grip/leg strength levels, supporting the negative effects of long-COVID syndrome on muscle function.

Muscles

3354

OO247

Vink, Mark; Grande, Tilman; Kohl, Matthias

Letter to the Editor Regarding Fleischer et al. Neurological Study Does Not Provide Any Evidence that Long COVID is Psychosomatic

https://doi.org/10.1136/gutjnl-2022-328483

Published

Study

https://gut.bmj.com/content/early/2022/12/08/gutjnl-2022-328483

Objectives The long-term consequences of COVID-19 infection on the gastrointestinal tract remain unclear. Here, we aimed to evaluate the prevalence of gastrointestinal symptoms and post-COVID-19 disorders of gut–brain interaction after hospitalisation for SARS-CoV-2 infection.
Design GI-COVID-19 is a prospective, multicentre, controlled study. Patients with and without COVID-19 diagnosis were evaluated on hospital admission and after 1, 6 and 12 months post hospitalisation. Gastrointestinal symptoms, anxiety and depression were assessed using validated questionnaires.
Results The study included 2183 hospitalised patients. The primary analysis included a total of 883 patients (614 patients with COVID-19 and 269 controls) due to the exclusion of patients with pre-existing gastrointestinal symptoms and/or surgery. At enrolment, gastrointestinal symptoms were more frequent among patients with COVID-19 than in the control group (59.3% vs 39.7%, p<0.001). At the 12-month follow-up, constipation and hard stools were significantly more prevalent in controls than in patients with COVID-19 (16% vs 9.6%, p=0.019 and 17.7% vs 10.9%, p=0.011, respectively). Compared with controls, patients with COVID-19 reported higher rates of irritable bowel syndrome (IBS) according to Rome IV criteria: 0.5% versus 3.2%, p=0.045. Factors significantly associated with IBS diagnosis included history of allergies, chronic intake of proton pump inhibitors and presence of dyspnoea. At the 6-month follow-up, the rate of patients with COVID-19 fulfilling the criteria for depression was higher than among controls.
Conclusion Compared with controls, hospitalised patients with COVID-19 had fewer problems of constipation and hard stools at 12 months after acute infection. Patients with COVID-19 had significantly higher rates of IBS than controls.
Trial registration number NCT04691895.

Gastro-intestinal

3355

OO248

Fleischer, Michael; Szepanowski, Fabian; Tovar, Muriel; Herchert, Klaas; Dinse, Hannah; Schweda, Adam; Mausberg, Anne K.; Holle-Lee, Dagny; Köhrmann, Martin; Stögbauer, Julia; Jokisch, Daniel; Jokisch, Martha; Deuschl, Cornelius; Skoda, Eva-Maria; Teufel, Martin; Stettner, Mark; Kleinschnitz, Christoph

Post-COVID-19 Syndrome is Rarely Associated with Damage of the Nervous System: Findings from a Prospective Observational Cohort Study in 171 Patients

https://doi.org/10.1038/s41598-022-25429-2

Published

Study

https://www.nature.com/articles/s41598-022-25429-2

There is conflicting evidence concerning the effect of inflammatory bowel disease (IBD) on COVID-19 incidence and outcome. Hence, we aimed to evaluate the published evidence through a systematic review process and perform a meta-analysis to assess the association between IBD and COVID-19. A compressive literature search was performed in PubMed/Medline, Scopus, Embase, and Cochrane Library from inception to July 2021. A snowball search in Google, Google Scholar, Research Gate, and MedRxiv; and bibliographic research were also performed to identify any other relevant articles. Quantitative observational studies such as cohort, cross-sectional, and case–control studies that assessed the incidence, risk, and outcomes of COVID-19 among the adult IBD patients published in the English language, were considered for this review. The incidence and risk of COVID-19, COVID-19 hospitalization, the severity of COVID-19, and mortality were considered as the outcomes of interest. The Joanna Briggs Institute critical appraisal checklist was used for quality assessment. A subgroup and sensitivity analysis were performed to explore the heterogeneity and robustness of the results, respectively. A total of 86 studies out of 2828 non-duplicate records were considered for this meta-analysis. The studies were single or multicentric internationally from settings such as IBD centres, medical colleges, hospitals, or from the general public. Most of the studies were observed to be of good quality with an acceptable risk of bias. The pooled prevalence of COVID-19, COVID-19 hospitalization, severe COVID-19, and mortality in the IBD population were 6.10%, 10.63%, 40.43%, and 1.94%, respectively. IBD was not significantly (p > 0.05) associated with the risk of COVID-19, COVID-19 hospitalization, severe COVID-19, and mortality. In contrast, ulcerative colitis was significantly associated with a higher risk of COVID-19 (OR 1.37; p = 0.01), COVID-19 hospitalization (OR 1.28; p < 0.00001), and severe COVID-19 (OR 2.45; p < 0.0007). Crohn’s disease was significantly associated with a lesser risk of severe COVID-19 (OR 0.48; p = 0.02). Type of IBD was a potential factor that might have contributed to the higher level of heterogeneity. There was a significant association between ulcerative colitis and increased risk of COVID-19, COVID-19 hospitalization, and severe COVID-19 infection. This association was not observed in patients with Crohns' disease or in those diagnosed non-specifically as IBD.

Gastro-intestinal

3356

OO249

Bessis, D.; Trouillet-Assant, S.; Secco, L. P.; Blatière, V.; Girard, C.; Molinari, N.; Pallure, V.; Peyron, N. Raison; Schwob, E.; Pescarmona, R.; Samaran, Q.; Vincent, T.; Sofonea, M. T.; Belot, A.; Tuaillon, É.

Engelures associées au COVID : plus de lien de causalité avec le virus SARS-CoV-2 et moins d’évidence pour une réponse systémique augmentée de l’interféron de type 1

https://doi.org/10.1016/j.fander.2022.09.165

Published

Journées dermatologiques de Paris, 29 novembre - 3 décembre 2022

https://www.sciencedirect.com/science/article/pii/S2667062322004391

Introduction
Le rôle pathogénique direct du virus SARS-CoV-2 et l’implication d’une surexpression de la voie de l’interféron de type 1 dans la genèse des engelures-COVID restent controversés.
Matériel et méthodes
Étude prospective monocentrique entre avril 2020 et janvier 2022 des enfants et adultes avec engelures-COVID suivis dans les services de dermatologie, Centre de tri COVID, maladies infectieuses, médecine interne et réanimation médicale.
Résultats
Cinquante patients atteints d’engelures-COVID ont été inclus : ratio F/H de 1,5, âge moyen 21 ans, IMC moyen de 19,8. Un phénomène de Raynaud acquis, un syndrome BASCULE et des hémorragies en flammèches sous-unguéales étaient notés, respectivement, dans 18 %, 13 % et 8 % des cas. Après un suivi moyen de 12 mois, la rémission complète, la persistance et la récidive des engelures étaient notées, respectivement, dans 93 %, 7 % et 13 % des cas. Des symptômes extra-cutanés, suggérant une origine infectieuse, étaient rapportés dans 63 % des cas. La PCR nasopharyngée SARS-CoV-2 et la recherche d’anticorps (Ac) anti-SARS-CoV-2 de type IgG et/ou IgM et/ou IgA étaient positives, respectivement, dans 10 % et 23 % des cas. La détection antigénique nucléocapsidique (N) sérique SARS-CoV-2 était positive dans 13 % des cas et la recherche d’Ac neutralisant IgA isolée positive chez 1 patient. Considérant l’ensemble des tests virologiques, une infection SARS-CoV-2 était prouvée dans 22 % des cas, dont 32 % chez l’enfant et 18 % chez l’adulte. Après analyse multivariée, aucune différence significative clinique, histologique ou immunobiologique n’était mise en évidence entre les groupes engelures associées ou non à une infection SARS-CoV-2 prouvée. La mesure sanguine du score de l’IFN (SC-IFN), à partir du début des signes infectieux, était comparée entre le groupe engelures-COVID avec signes infectieux (n=19) et deux groupes COVID sans engelures ayant été hospitalisés en réanimation (n=72) et considérés comme bénins, sans hospitalisation (n=8). À la différence de ces deux derniers groupes, aucun pic significatif de SC-IFN n’était observé dans le groupe engelures-COVID. Dans ce dernier groupe, une augmentation modérée et stable du SC-IFN était notée.
Discussion
Notre étude confirme les principales caractéristiques cliniques précédemment rapportées au cours des engelures-COVID. La forte fréquence du phénomène de Raynaud, du syndrome BASCULE et des hémorragies unguéales pourrait être expliquée par le caractère prospectif de notre étude et l’absence de détails cliniques dans les larges séries. L’utilisation de l’antigénémie sérique N SARS-CoV-2 et la recherche d’anticorps neutralisants augmentent la sensibilité de détection d’une infection virale SARS-CoV-2 associée aux engelures, présente dans près d’un tiers des cas chez l’enfant. Ce dernier résultat est en accord avec la fréquence moyenne de séroconversion observée chez les enfants ayant développé une infection bénigne ou asymptomatique SARS-CoV-2, estimée entre 30 à 37 %. Il conforte le lien de causalité potentiel entre l’infection virale et les engelures-COVID. L’absence d’hypersécrétion systémique d’IFN au cours des engelures-COVID, par comparaison avec les COVID sévères ou bénins sans engelures associées, laisse supposer que le rôle éventuel de l’IFN dans la genèse des engelures serait plus en rapport avec une susceptibilité tissulaire virale qu’à une hypersécrétion systémique d’IFN de type 1.

Skin

3357

OO250

Pesti, Adrián; Danics, Krisztina; Glasz, Tibor; Várkonyi, Tibor; Barbai, Tamás; Reszegi, Andrea; Kovalszky, Ilona; Vályi-Nagy, István; Dobi, Deján; Lotz, Gábor; Schaff, Zsuzsa; Kiss, András

Liver alterations and detection of SARS-CoV-2 RNA and proteins in COVID-19 autopsies

https://doi.org/10.1007/s11357-022-00700-6

Published

Study

https://doi.org/10.1007/s11357-022-00700-6

The most severe alterations in Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) infection are seen in the lung. However, other organs also are affected. Here, we report histopathologic findings in the liver and detection of viral proteins and RNA in COVID-19 autopsies performed at the Semmelweis University (Budapest, Hungary). Between March 2020 through March 2022, 150 autopsies on patients who died of COVID-19 were analyzed. Cause-of-death categories were formed based on the association with SARS-CoV-2 as strong, contributive, or weak. Samples for histopathologic study were obtained from all organs, fixed in formalin, and embedded in paraffin (FFPE). Immunohistochemical study (IHC) to detect SARS-CoV-2 spike protein and nucleocapsid protein (NP), CD31, claudin-5, factor VIII, macrosialin (CD68), and cytokeratin 7, with reverse transcriptase polymerase chain reaction (RT-PCR), and in situ hybridization (ISH, RNAscope®) for SARS-CoV-2 RNA were conducted using FFPE samples of livers taken from 20 autopsies performed ≤ 2 days postmortem. All glass slides were scanned; the digital images were evaluated by semiquantitative scoring and scores were analyzed statistically. Steatosis, single-cell and focal/zonal hepatocyte necrosis, portal fibrosis, and chronic inflammation were found in varying percentages. Sinusoidal ectasia, endothelial cell disruption, and fibrin-filled sinusoids were seen in all cases; these were assessed semiquantitatively for severity (SEF scored). SEF scores did not correlate with cause-of-death categories (p = 0.92) or with severity of lung alterations (p = 0.96). SARS-CoV-2 RNA was detected in 13/20 cases by PCR and in 9/20 by ISH, with IHC demonstration of spike protein in 4/20 cases and NP in 15/20. Viral RNA and proteins were located in endothelial and Kupffer cells, and in portal macrophages, but not in hepatocytes and cholangiocytes. In conclusion, endothelial damage (SEF scores) was the most common alteration in the liver and was a characteristic, but not specific alteration in COVID-19, suggesting an important role in the pathogenesis of COVID-19-associated liver disease. Detection of SARS-CoV-2 RNA and viral proteins in liver non-parenchymal cells suggests that while the most extended primary viral cytotoxic effect occurs in the lung, viral components are present in other organs too, as in the liver. The necrosis/apoptosis and endothelial damage associated with viral infection in COVID-19 suggest that those patients who survive more severe COVID-19 may face prolonged liver repair and accordingly should be followed regularly in the post-COVID period.

Liver

3358

OO251

Er-rachdy, N.; Fliti, A.; Elomari Alaoui, M.; Ismaili, N.; Meziane, M.; Benzekri, L.; Senouci, K.

Nécrolyse épidermique toxique (NET) : manifestation cutanée de COVID-19

https://doi.org/10.1016/j.fander.2022.09.327

Published

Case Report

https://www.sciencedirect.com/science/article/pii/S2667062322006031

Introduction
La nécrolyse épidermique toxique (NET) est classée parmi les toxidermies graves, mais elle peut être également induite par des infections, des tumeurs malignes ou être idiopathique. Nous rapportons un cas d’un syndrome de Lyell induit par l’infection COVID-19.
Observations
Il s’agit d’un patient âgé de 69 ans, sans antécédents pathologiques notable, notamment pas de notion de prise médicamenteuse, qui s’est présenté avec un tableau de fièvre, toux, syndrome pseudo-grippal évoluant depuis 5 jours, associé à une érythrodermie humide avec décollement cutané>30 % et atteinte de la muqueuse génitale. Le patient avait un test COVID-19 positif, avec cultures et sérologies négatives pour toutes les autres infections dépistées. La biopsie a montré un clivage sous-épidermique focale, une nécrose épidermique, une vacuolisation des cellules basales, une dyskératose et un léger infiltrat lymphocytaire périvasculaire superficiel. L’immunofluorescence directe était négative. Le diagnostic de syndrome de Lyell a été retenu avec une bonne évolution sous traitement symptomatique.
Discussion
Bien que le COVID-19 provoque surtout des symptômes respiratoires et des séquelles thromboemboliques, il a également été signalé comme étant associé à des manifestations dermatologiques. De nombreuses manifestations cutanées de COVID-19 ont été rapportées dans la littérature suggérant la possibilité d’une NET induite par l’hydroxychloroquine ou autres médicaments chez des patients atteints du COVID-19, contrairement à notre cas où le syndrome de Lyell était secondaire au COVID-19.

Skin

3359

OO252

Choaib, Ali; Issa, Elio; El Choueiry, Francesca; Eldin, Jade Nasser; Shbaklo, Khodor; Alhajj, Maryline; Sawaya, Ramy Touma; Assi, Ghaith; Nader, Moni; Chatila, Rajaa; Faour, Wissam H.

SARS-CoV-2-mediated liver injury: pathophysiology and mechanisms of disease

https://doi.org/10.1007/s00011-022-01683-y

Published

Review

https://doi.org/10.1007/s00011-022-01683-y

Abstract
Background
SARS-CoV-2-induced severe inflammatory response can be associated with severe medical consequences leading to multi-organ failure, including the liver. The main mechanism behind this assault is the aggressive cytokine storm that induces cytotoxicity in various organs. Of interest, hepatic stellate cells (HSC) respond acutely to liver injury through several molecular mechanisms, hence furthering the perpetuation of the cytokine storm and its resultant tissue damage. In addition, hepatocytes undergo apoptosis or necrosis resulting in the release of pro-inflammatory and pro-fibrogenic mediators that lead to chronic liver inflammation.

Aims
The aim of this review is to summarize available data on SARS-CoV-2-induced liver inflammation in addition to evaluate the potential effect of anti-inflammatory drugs in attenuating SARS-CoV-2-induced liver inflammation.

Methods
Thorough PubMed search was done to gather and summarize published data on SARS-CoV-2-induced liver inflammation. Additionally, various anti-inflammatory potential treatments were also documented.

Results
Published data documented SARS-CoV-2 infection of liver tissues and is prominent in most liver cells. Also, histological analysis showed various features of tissues damage, e.g., hepatocellular necrosis, mitosis, cellular infiltration, and fatty degeneration in addition to microvesicular steatosis and inflammation. Finally, the efficacy of the different drugs used to treat SARS-CoV-2-induced liver injury, in particular the anti-inflammatory remedies, are likely to have some beneficial effect to treat liver injury in COVID-19.

Conclusion
SARS-CoV-2-induced liver inflammation is a serious condition, and drugs with potent anti-inflammatory effect can play a major role in preventing irreversible liver damage in COVID-19.

Liver

3360

OO253

Klepinowski, Tomasz; Klepinowska, Marta; Sagan, Leszek; Syrenicz, Anhelli

Does SARS-CoV-2 Affect Human Semen? A Systematic Review and Meta-Analysis

https://doi.org/10.1007/s10508-022-02520-3

Published

5-Jan-23

Study

https://doi.org/10.1007/s10508-022-02520-3

Contradictory results have been reported regarding effects of the SARS-CoV-2 upon human semen. A timely and up-to-date systematic review with meta-analysis appears necessary. This study aimed to deliver pooled prevalence (PP) of SARS-CoV-2 in semen and pooled semen parameters as compared with the uninfected. The relevant databases were scanned by two authors for observational studies reporting analysis of semen in COVID-19 patients. The SARS-CoV-2-infected were assigned to group A (exposed arm), whereas the uninfected to group B (unexposed arm). Newcastle–Ottawa Scale was used to address the risk of bias. PRISMA guidelines were adopted. In case of homogenous studies, fixed-effects model was followed, whereas for heterogenous studies random-effects model was used. Of 990 studies, 24 were eligible involving 1589 subjects (947 in group A and 642 in group B). The “comparability” domain was biased the most. SARS-CoV-2 RNA was detected in three studies among 8 individuals producing the PP of 1.76% (95% CI 0.72–3.21). Sperm concentration was reduced significantly (WMD = –16.23 [95% CI –25.56 to –6.89], as well as total sperm in ejaculate (WMD = –34.84 [95% CI − 43.51 to –26.17]) and sperm volume (WMD = − 0.48 [95% CI − 0.59 to − 0.36] in group A as compared with controls. There was a non-significant effect upon progressive motility and leukocyte presence in semen. SARS-CoV-2 RNA in semen among the infected individuals is detected infrequently. By this token, sexual transmission through semen is of low probability and little concern for public health. However, significant decrease in sperm volume, sperm concentration, and total sperm in ejaculate has been noted. The current data, though, are limited, and more studies with longer follow-up are needed to evaluate the further impact.

Male reproductive system

3361

OO254

Xu, Evan; Xie, Yan; Al-Aly, Ziyad

Risks and burdens of incident dyslipidaemia in long COVID: a cohort study

https://doi.org/10.1016/S2213-8587(22)00355-2

Published

6-Jan-23

Study

https://www.sciencedirect.com/science/article/pii/S2213858722003552

Background
Non-clinical evidence and a few human studies with short follow-ups suggest increased risk of dyslipidaemia in the post-acute phase of COVID-19 (ie, >30 days after SARS-CoV-2 infection). However, detailed large-scale controlled studies with longer follow-ups and in-depth assessment of the risks and burdens of incident dyslipidaemia in the post-acute phase of COVID-19 are not yet available. We, therefore, aimed to examine the risks and 1-year burdens of incident dyslipidaemia in the post-acute phase of COVID-19 among people who survive the first 30 days of SARS-CoV-2 infection.
Methods
In this cohort study, we used the national health-care databases of the US Department of Veterans Affairs to build a cohort of 51 919 participants who had a positive COVID-19 test and survived the first 30 days of infection between March 1, 2020, and Jan 15, 2021; a non-infected contemporary control group (n=2 647 654) that enrolled patients between March 1, 2020, and Jan 15, 2021; and a historical control group (n=2 539 941) that enrolled patients between March 1, 2018, and Jan 15, 2019. Control groups had no evidence of SARS-CoV-2 infection, and participants in all three cohorts were free of dyslipidaemia before cohort enrolment. We then used inverse probability weighting using predefined and algorithmically-selected high dimensional variables to estimate the risks and 1-year burdens of incident dyslipidaemia, lipid-lowering medications use, and a composite of these outcomes. We reported two measures of risk: hazard ratios (HRs) and burden per 1000 people at 12 months. Additionally, we estimated the risks and burdens of incident dyslipidaemia outcomes in mutually exclusive groups based on the care setting of the acute infection (ie, participants who were non-hospitalised, hospitalised, or admitted to intensive care during the acute phase of SARS-CoV-2 infection).
Findings
In the post-acute phase of the SARS-CoV-2 infection, compared with the non-infected contemporary control group, those in the COVID-19 group had higher risks and burdens of incident dyslipidaemia, including total cholesterol greater than 200 mg/dL (hazard ratio [HR] 1·26, 95% CI 1·22–1·29; burden 22·46, 95% CI 19·14–25·87 per 1000 people at 1 year), triglycerides greater than 150 mg/dL (1·27, 1·23–1·31; 22·03, 18·85–25·30), LDL cholesterol greater than 130 mg/dL (1·24, 1·20–1·29; 18·00, 14·98–21·11), and HDL cholesterol lower than 40 mg/dL (1·20, 1·16–1·25; 15·58, 12·52–18·73). The risk and burden of a composite of these abnormal lipid laboratory outcomes were 1·24 (95% CI 1·21–1·27) and 39·19 (95% CI 34·71–43·73), respectively. There was also increased risk and burden of incident lipid-lowering medications use (HR 1·54, 95% CI 1·48–1·61; burden 25·50, 95% CI 22·61–28·50). A composite of any dyslipidaemia outcome (laboratory abnormality or lipid-lowering medications use) yielded an HR of 1·31 (95% CI 1·28–1·34) and a burden of 54·03 (95% CI 49·21–58·92). The risks and burdens of these post-acute outcomes increased in a graded fashion corresponding to the severity of the acute phase of COVID-19 infection (ie, whether patients were non-hospitalised, hospitalised, or admitted to intensive care). The results were consistent in analyses comparing the COVID-19 group to the non-infected historical control group.
Interpretation
Our findings suggest increased risks and 1-year burdens of incident dyslipidaemia and incident lipid-lowering medications use in the post-acute phase of COVID-19 infection. Post-acute care for those with COVID-19 should involve attention to dyslipidaemia as a potential post-acute sequela of SARS-CoV-2 infection.
Funding
US Department of Veterans Affairs.

Liver

3362

OO255

Aby, Elizabeth S.; Moafa, Ghady; Latt, Nyan; Sultan, Mohammad T.; Cacioppo, Paula A.; Kumar, Sonal; Chung, Raymond T.; Bloom, Patricia P.; Gustafson, Jenna; Daidone, Michael; Reinus, Zoe; Debes, Jose D.; Sandhu, Sunny; Sohal, Aalam; Khalid, Sameeha; Roytman, Marina; Catana, Andreea Maria; Wegermann, Kara; Carr, Rotonya M.; Saiman, Yedidya; Kassab, Ihab; Chen, Vincent L.; Rabiee, Atoosa; Rosenberg, Carly; Nguyen, Veronica; Gainey, Christina; Zhou, Kali; Chavin, Kenneth; Lizaola-Mayo, Blanca C.; Chascsa, David M.; Varelas, Lee; Moghe, Akshata; Dhanasekaran, Renumathy

Long-term clinical outcomes of patients with COVID-19 and chronic liver disease: US multicenter COLD study

https://doi.org/10.1097/01.HC9.0000897224.68874.de

Published

1-Jan-23

Study

https://journals.lww.com/hepcomm/Fulltext/2023/01010/Long_term_clinical_outcomes_of_patients_with.5.aspx

Background:
COVID-19 is associated with higher morbidity and mortality in patients with chronic liver diseases (CLDs). However, our understanding of the long-term outcomes of COVID-19 in patients with CLD is limited.
Methods:
We conducted a multicenter, observational cohort study of adult patients with CLD who were diagnosed with COVID-19 before May 30, 2020, to determine long-term clinical outcomes. We used a control group of patients with CLD confirmed negative for COVID-19.
Results:
We followed 666 patients with CLD (median age 58 years, 52.8% male) for a median of 384 (interquartile range: 31–462) days. The long-term mortality was 8.1%; with 3.6% experiencing delayed COVID-19-related mortality. Compared to a propensity-matched control group of patients with CLD without COVID-19 (n=1332), patients with CLD with COVID-19 had worse long-term survival [p<0.001; hazards ratio (HR): 1.69; 95% CI: 1.19–2.41] and higher rate of hospitalization (p<0.001, HR: 2.00, 1.62–2.48) over a 1-year follow-up period. Overall, 29.9% of patients reported symptoms of long-COVID-19. On multivariable analysis, female sex (p=0.05, HR: 2.45, 1.01–2.11), Hispanic ethnicity (p=0.003, HR: 1.94, 1.26–2.99), and severe COVID-19 requiring mechanical ventilation (p=0.028, HR: 1.74, 1.06–2.86) predicted long-COVID-19. In survivors, liver-related laboratory parameters showed significant improvement after COVID-19 resolution. COVID-19 vaccine status was available for 72% (n=470) of patients with CLD and history of COVID-19, of whom, 70% (n=326) had received the COVID-19 vaccine.
Conclusions:
Our large, longitudinal, multicenter study demonstrates a high burden of long-term mortality and morbidity in patients with CLD and COVID-19. Symptoms consistent with long-COVID-19 were present in 30% of patients with CLD. These results illustrate the prolonged implications of COVID-19 both for recovering patients and for health care systems.

Liver

3363

OO256

Shah, Hemali P.; Bourdillon, Alexandra T.; Panth, Neelima; Ihnat, Jacqueline; Kohli, Nikita

Long-term laryngological sequelae and patient-reported outcomes after COVID-19 infection

https://doi.org/10.1016/j.amjoto.2022.103780

Published

1-Mar-23

Study

https://www.sciencedirect.com/science/article/pii/S0196070922004070

Highlights
•Laryngeal dysfunction can present and persist for months after COVID-19 recovery.
•Sequelae develop in patients who were not intubated or hospitalized for COVID-19.
•Interventions such as voice therapy may improve post-COVID laryngeal sequelae.
•Understanding of such sequelae can inform how clinicians care for these patients.
Abstract
Purpose
We examine prevalence, characteristics, quality of life (QOL) assessments, and long-term effects of interventions for laryngeal dysfunction after recovery from COVID-19 infection.

Materials and methods
653 patients presenting to Yale's COVID clinic from April 2020 to August 2021 were identified retrospectively. Patients with PCR-positive COVID-19 who underwent evaluation by fellowship-trained laryngologists were included. Patient demographics, comorbidities, intubation/tracheostomy, strobolaryngoscopy, voice metrics, and management data were collected. Patient-reported QOL indices were Dyspnea Index (DI), Cough Severity Index (CSI), Voice Handicap Index-10 (VHI-10), Eating Assessment Tool-10 (EAT-10), and Reflux Symptom Index (RSI).

Results
57 patients met inclusion criteria: 37 (64.9 %) were hospitalized for COVID-19 infection and 24 (42.1 %) required intubation. Mean duration between COVID-19 diagnosis and presentation to laryngology was significantly shorter for patients who were intubated compared to non-intubated (175 ± 98 days versus 256 ± 150 days, respectively, p = 0.025). Dysphonia was diagnosed in 40 (70.2 %) patients, dysphagia in 14 (25.0 %) patients, COVID-related laryngeal hypersensitivity in 13 (22.8 %), and laryngotracheal stenosis (LTS) in 10 (17.5 %) patients. Of the 17 patients who underwent voice therapy, 11 (64.7 %) reported improvement in their symptoms and 2 (11.8 %) patients reported resolution. VHI scores decreased for patients who reported symptom improvement. 7 (70 %) patients with LTS required >1 procedural intervention before symptom improvement. Improvement across QOL indices was seen in patients with LTS.

Conclusions
Laryngeal dysfunction commonly presents and is persistent for months after recovery from COVID-19 in non-hospitalized and non-intubated patients. Voice therapy and procedural interventions have the potential to address post-COVID laryngeal dysfunction.

Vocal organs

3364

OO257

Lui, David Tak Wai; Tsoi, Kimberly Hang; Lee, Chi Ho; Cheung, Chloe Yu Yan; Fong, Carol Ho Yi; Lee, Alan Chun Hong; Tam, Anthony Raymond; Pang, Polly; Ho, Tip Yin; Law, Chun Yiu; Lam, Ching Wan; To, Kelvin Kai Wang; Chow, Wing Sun; Woo, Yu Cho; Hung, Ivan Fan Ngai; Tan, Kathryn Choon Beng; Lam, Karen Siu Ling

A prospective follow-up on thyroid function, thyroid autoimmunity and long COVID among 250 COVID-19 survivors

https://doi.org/10.1007/s12020-022-03281-8

Published

3-Jan-23

Study

https://doi.org/10.1007/s12020-022-03281-8

Purpose
We evaluated the evolution of thyroid function and autoimmunity among COVID-19 survivors over 6 months in relation to interferon beta-1b treatment and long COVID.

Methods
We included COVID-19 survivors managed in a major COVID-19 centre between July 2020 and May 2021 who were reassessed three and/or six months after acute COVID-19. Thyroid function tests (TFTs) and anti-thyroid antibody titres were measured at acute COVID-19, 3-month and 6-month.

Results
250 COVID-19 survivors were included (mean age 52.7 years, 50.4% men). Persistent thyroid function abnormalities were more likely in those with abnormal TFTs in acute COVID-19 (P < 0.001). Among 51 patients with abnormal TFTs in acute COVID-19, 82.4% resolved upon follow-up. Of 199 patients with normal TFTs in acute COVID-19, only 4.5% had incident abnormal TFTs, more likely in interferon-treated patients (P = 0.044) and none clinically overt. Among 129 patients with complete 6-month follow-up for anti-thyroid antibody titres, there was no significant change overall, except for modest increase in anti-thyroid antibody titres among the 84 interferon-treated patients (P < 0.05 at both 3 months and 6 months). Long COVID occurred in 19.5% and 10.4% at 3 and 6 months respectively, where TFTs and anti-thyroid antibody titres were not predictive of its occurrence.

Conclusion
Over 6 months, most abnormal TFTs in acute COVID-19 resolved, with no significant incident thyroid dysfunction. SARS-CoV-2 infection did not lead to change in thyroid autoimmunity, while interferon treatment was associated with modest increase in anti-thyroid antibody titres. Thyroid function and anti-thyroid antibodies did not play a significant role in long COVID.

Thyroid gland

3365

OO258

Carneiro, Valdirene Leao; Littlefield, Katherine M.; Watson, Renee; Palmer, Brent E.; Lozupone, Catherine

Inflammation-associated gut microbiome in postacute sequelae of SARS-CoV-2 points towards new therapeutic targets

https://doi.org/10.1136/gutjnl-2022-328757

Published

30-Jan-23

Study

https://gut.bmj.com/content/early/2023/01/29/gutjnl-2022-328757

We read with interest the recent report by Liu et al 1 describing faecal microbiome differences with postacute sequelae of SARS-CoV-2 (PASC), commonly referred to as ‘Long-COVID’. We have previously reported elevated levels of SARS-CoV-2-specific T cells with PASC compared with resolved COVID-19 (RC; no lingering symptoms at the time of sample collection) that correlated with increased levels of the inflammatory marker IL-6, suggesting that elevated inflammation in PASC may be related to immune response to residual virus.2 Although several studies have reported gut microbiome differences during acute COVID-19,3 PASC has received less attention. We, thus, sought to characterise gut microbiome differences in PASC versus RC using faecal samples from our study2 and to relate these differences to inflammation.

The faecal microbiome was evaluated using 16S rRNA gene sequencing. Plasma levels of inflammatory markers IL-6 and C reactive protein (CRP) were measured with ELISA (see online supplemental methods). Cohort information is in table 1. IL-6 and CRP were elevated with PASC (figure 1A). Gut microbiome composition did not significantly differ between the PASC and RC cohorts (PERMANOVA; p=0.087; figure 1B), but did correlate with IL-6 and CRP levels (Adonis; IL-6 p=0.03; CRP p=0.01). IL-6 and CRP also correlated with PC1 from a principal coordinates analysis (figure 1C,D), suggesting a relationship between microbiome composition and inflammation in PASC. Using SELBAL,4 which identifies ratios …

Gastro-intestinal

3366

OO259

Yanachkova, Vesselina; Stankova, Teodora; Staynova, Radiana

Thyroid dysfunction as a long-term post-COVID-19 complication in mild-to-moderate COVID-19

https://doi.org/10.1080/13102818.2023.2170829

Published

2-Feb-23

Study

https://doi.org/10.1080/13102818.2023.2170829

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), may lead to thyroid disorders, including both thyrotoxicosis and suppression of thyroid function. The aim of the present study was to assess the post-COVID-19 effects on thyroid function in patients without history of thyroid disease after complete recovery from mild-to-moderate COVID-19. Thyroid function tests [thyroid-stimulating hormone (TSH), free thyroxine (fT4), antithyroid antibodies] were performed on 113 patients (median age of 43.0 years; 31.0% male) two months after initial SARS-CoV-2 infection. TSH and fT4 were determined again one month later in this observational, prospective study. Thyroid dysfunction was registered in 61.1% of the patients (78.3% subclinical hypothyroidism, 13% subclinical hyperthyroidism and 8.7% overt hypothyroidism) two months after COVID-19. Moderate rather than mild manifestation of COVID-19 was significantly associated with a higher risk of thyroid dysfunction (OR 5.33; 95% CI: 1.70–16.69, p = 0.002), presence of thyroglobulin antibodies and need for levothyroxine therapy. At the follow-up, the subclinical hypothyroidism persisted in 28.3% of the subjects. Moreover, the TSH level was significantly reduced in comparison to the second month after the initial COVID-19 infection in all the patients (p < 0.001), but not in those with subclinical hypothyroidism and without hormone replacement therapy. Our findings indicate that COVID-19 could have long-term, negative effects on thyroid function. Therefore, thyroid function testing should be included in the follow-up algorithm of COVID-19 survivors.

Thyroid gland

3367

OO260

Agergaard, Jane; Yamin Ali Khan, Benjamin; Engell-Sørensen, Thomas; Schiøttz-Christensen, Berit; Østergaard, Lars; Hejbøl, Eva K.; Schrøder, Henrik D.; Andersen, Henning; Blicher, Jakob; Holm Pedersen, Thomas; Harbo, Thomas; Tankisi, Hatice

Myopathy as a cause of Long COVID fatigue: Evidence from quantitative and single fiber EMG and muscle histopathology

https://doi.org/10.1016/j.clinph.2023.01.010

Published

1-Feb-23

Study

https://www.sciencedirect.com/science/article/pii/S1388245723000196

Highlights
•Myopathic changes in qEMG and/or increased jitter in sfEMG were seen in 63% of 84 patients with Long COVID neuromuscular symptoms.
•Low quality of life score correlated with higher mean jitter values in sfEMG but not with qEMG measures.
•Electron microscopy showed damage of terminal nerves and motor endplate.
Abstract
Objective
To describe neurophysiological abnormalities in Long COVID and correlate quantitative electromyography (qEMG) and single fiber EMG (sfEMG) results to clinical scores and histopathology.
Methods
84 patients with non-improving musculoskeletal Long COVID symptoms were examined with qEMG and sfEMG. Muscle biopsies were taken in a subgroup.
Results
Mean motor unit potential (MUP) duration was decreased in ≥1 muscles in 52% of the patients. Mean jitter was increased in 17% of the patients in tibialis anterior and 25% in extensor digitorum communis. Increased jitter was seen with or without myopathic qEMG. Low quality of life score correlated with higher jitter values but not with qEMG measures. In addition to our previously published mitochondrial changes, inflammation, and capillary injury, we show now in muscle biopsies damage of terminal nerves and motor endplate with abundant basal lamina material. At the endplate, axons were present but no vesicle containing terminals. The post-synaptic cleft in areas appeared atrophic with short clefts and coarse crests.
Conclusions
Myopathic changes are common in Long COVID. sfEMG abnormality is less common but may correlate with clinical scores. sfEMG changes may be due to motor endplate pathology.
Significance
These findings may indicate a muscle pathophysiology behind fatigue in Long COVID.

Muscles

3368

OO261

Gorini, Francesca; Vassalle, Cristina

A Literature Review on SARS-CoV-2 and Other Viruses in Thyroid Disorders: Environmental Triggers or No-Guilty Bystanders?

https://doi.org/10.3390/ijerph20032389

Published

1-Jan-23

Review

https://www.mdpi.com/1660-4601/20/3/2389

A growing number of findings indicate a relationship between COVID-19 infection and thyroid dysfunction. This association is also strengthened by knowledge on the potential of viral infections to trigger thyroid disorders, although the exact underlying pathogenetic process remains to be elucidated. This review aimed to describe the available data regarding the possible role of infectious agents, and in particular of SARS-CoV-2, in the development of thyroid disorders, summarizing the proposed mechanisms and levels of evidence (epidemiological, serological or direct presence of the viruses in the thyroid gland) by which the infection could be responsible for thyroid abnormalities/diseases. Novel data on the association and mechanisms involved between SARS-CoV-2 vaccines and thyroid diseases are also discussed. While demonstrating a clear causal link is challenging, numerous clues at molecular and cellular levels and the large amount of epidemiological data suggest the existence of this relationship. Further studies should be taken to further investigate the true nature and strength of this association, to help in planning future preventive and therapeutic strategies for more personal and targeted care with attention to the underlying causes of thyroid dysfunction.

Thyroid gland

3369

OO262

Dellino, Miriam; Vimercati, Antonella; D’Amato, Antonio; Damiani, Gianluca Raffaello; Laganà, Antonio Simone; Cicinelli, Ettore; Pinto, Vincenzo; Malvasi, Antonio; Scacco, Salvatore; Ballini, Andrea; Resta, Leonardo; Ingravallo, Giuseppe; Maiorano, Eugenio; Cazzato, Gerardo; Cascardi, Eliano

“GONE WITH THE WIND”: The Transitory Effects of COVID-19 on the Gynecological System

https://doi.org/10.3390/jpm13020312

Published

1-Feb-23

Review

https://www.mdpi.com/2075-4426/13/2/312

The coronavirus disease no longer seems to represent an insurmountable global problem. This is thanks to the advent of coronavirus vaccines, which have alleviated the most serious symptoms associated with this disease. On the other hand, there are still many extrapulmonary symptoms of COVID-19, and among these also those of a gynecological nature. At the moment, there are several questions in this field, one above all concerns the causal link between COVID-19, vaccines and gynecological alterations. Furthermore, another important aspect is represented by the clinical impact of post-COVID-19 gynecological alterations on the female population which, to date, would seem to be mainly due to their duration, even if the extent of these symptoms is still poorly understood. Furthermore, it is not possible to foresee eventual long-term aggravations, or more serious symptoms caused by other viral variants that may arrive in the future. In this review, we focus on this theme and attempt to reorganize the different pieces of a puzzle which, to date, does not seem to have shown us its complete picture.

Female reproductive system

3370

OO263

Limongelli, Luisa; Favia, Gianfranco; Maiorano, Eugenio; D’Amati, Antonio; Pispero, Alberto; Ingravallo, Giuseppe; Barile, Giuseppe; Tempesta, Angela; Dell’Olio, Fabio; Siciliani, Rosaria Arianna; Capodiferro, Saverio

Oral Lesions with immunohistochemical evidence of Sars-CoV-2 in swab-negative Post-COVID Syndrome

https://doi.org/10.1111/odi.14532

Published

12-Feb-23

Case Report

https://onlinelibrary.wiley.com/doi/abs/10.1111/odi.14532

Objectives Growing evidence exists about Post-COVID condition/syndrome as sequelae of Sars-CoV-2 infection in healed patients, possibly involving the lungs, brain, kidney, cardiovascular and neuromuscular system, as well the persistency of taste disfunction. Such symptoms develop during or after infection and continue for more than 12 weeks with a pathogenesis related to virus persistency but variable by organs or systems. Materials and Methods We recently observed 6 patients recovered from COVID-19 and with negative RT-PCR testing, showing oral mucosa lesions (mainly ulcers) overlapping those occurring in the acute phase, persisting up to 20 days and thus needing a biopsy with histological investigation and spike-protein evaluation by immunohistochemistry. Results We found epithelial ulceration, inflammatory infiltrate, vessels with increased diameter, flattened endothelium but no thrombi formation; also, we found a weak epithelial SARS-CoV-2 positivity limited to the basal/spinosum layers, progressively decreasing towards the periphery, and of the intra-epithelial lymphomonocytes, endothelium and perivascular pericytes too. Conclusions Our findings provide evidence that SARS-CoV-2 can persist, as for other organs/systems, also in the oral epithelium/mucosa after the acute phase and can be responsible for lesions, albeit by a pathogenetic mechanism that should be better defined but certainly referable as the oral mucosa counterpart of post-COVID syndrome.

Mouth

3371

OO264

Brancatella, Alessandro; Viola, Nicola; Satini, Ferruccio; Latrofa, Francesco

COVID-INDUCED THYROID AUTOIMMUNITY

https://doi.org/10.1016/j.beem.2023.101742

Published

5-Feb-23

Review

https://www.sciencedirect.com/science/article/pii/S1521690X23000118

Breakdown of self-tolerance to thyroid antigens (thyroperoxidase, thyroglobulin and the thyrotropin-receptor) is the driver of thyroid autoimmunity. It has been suggested that infectious disease might trigger autoimmune thyroid disease (AITD). Involvement of the thyroid has been reported during severe acute respiratory syndrome virus 2 (SARS-CoV-2) infection, in the form of subacute thyroid in subjects with mild coronavirus disease 19 disease (COVID-19) and of painless, destructive thyroiditis in hospitalized patients with severe infection. In addition, cases of AITD, both Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), have been reported in association with (SARS-CoV-2) infection. In this review, we focus on the relationship between SARS-CoV-2 infection and occurrence of AITD. Nine cases of GD strictly related to SARS-CoV-2 infection and only three cases of HT associated to COVID-19 infection have been reported. No study has demonstrated a role of AITD as a risk factor for a poor prognosis of COVID-19 infection.

Thyroid gland

3372

OO265

Chourasia, Prabal; Goyal, Lokesh; Kansal, Dhruv; Roy, Sasmit; Singh, Rohit; Mahata, Indrajeet; Sheikh, Abu Baker; Shekhar, Rahul

Risk of New-Onset Diabetes Mellitus as a Post-COVID-19 Condition and Possible Mechanisms: A Scoping Review

https://doi.org/10.3390/jcm12031159

Published

1-Jan-23

Review

https://www.mdpi.com/2077-0383/12/3/1159

Long-term effects of COVID-19 are becoming more apparent even as the severity of acute infection is decreasing due to vaccinations and treatment. In this scoping review, we explored the current literature for the relationship between COVID-19 infection and new-onset diabetes mellitus four weeks after acute infection. We systematically searched the peer-reviewed literature published in English between 1 January 2020 and 31 August 2022 to study the risk of new-onset diabetes mellitus post-COVID-19 infection. This scoping review yielded 11 articles based on our inclusion and exclusion criteria. Except for one, all studies suggested an increased risk of new-onset diabetes mellitus 4 weeks after acute infection. This risk appears most in the first six months after the acute COVID-19 infection and seems to increase in a graded fashion based on the severity of the initial COVID-19 infection. Our review suggests a possible association of new-onset diabetes mellitus 4 weeks after acute COVID-19 infection. Since the severity of COVID-19 infection is associated with the development of post-infectious diabetes, vaccination that reduces the severity of acute COVID-19 infection might help to reduce the risk of post-COVID-19 diabetes mellitus. More studies are needed to better understand and quantify the association of post-COVID-19 conditions with diabetes and the role of vaccination in influencing it.

Pancreas

3373

OO266

Faruqi, Jordana; Balasubramanyam, Ashok

COVID-19 and diabetes mellitus: a review of the incidence, pathophysiology and management of diabetes during the pandemic

https://doi.org/10.1080/17446651.2023.2176300

Published

1-Feb-23

Review

https://doi.org/10.1080/17446651.2023.2176300

Introduction The COVID-19 pandemic has changed the landscape of modern medicine on a global scale. An emerging concern is the recognition of a bidirectional relationship between COVID-19 and diabetes. Diabetes is a risk factor for severe COVID-19 illness. Intriguingly, recent epidemiological and in vitro studies suggest that infection with SARS-CoV-2, the causative viral agent of COVID-19, is associated with new-onset diabetes and worsening diabetes control. These factors have affected the management of diabetes.Areas covered This review provides an overview of our current understanding of the incidence and prevalence of diabetes in relation to the COVID-19 pandemic, highlights studies evaluating SARS-CoV-2’s beta cell tropism and its effects on insulin secretion and sensitivity and evaluates the impact of the pandemic on diabetes management and metabolic control.Expert opinion Epidemiological studies have noted an increase in the incidence of new-onset diabetes associated with COVID-19 in patients with phenotypes of type 1 diabetes, type 2 diabetes and Ketosis-Prone Diabetes. Prospective studies are needed to fully elucidate the association between COVID-19 and diabetes and to characterize persons at risk of developing diabetes after SARS-CoV-2 infection, identify those who should be screened for diabetes, and determine the natural histories of different forms of diabetes associated with COVID-19.

Pancreas

3374

OO267

Gök, Alper; Altan, Mehmet; Doğan, Ahmet Emin; Eraslan, Aşır; Uysal, Fahrettin Şamil; Öztürk, Ufuk; Saguner, Ardan Muammer; İmamoğlu, Muhammet Abdurrahim

Does Post-COVID-19 Erectile Dysfunction Improve over Time?

https://doi.org/10.3390/jcm12031241

Published

1-Jan-23

Study

https://www.mdpi.com/2077-0383/12/3/1241

Background: Some studies have shown that there may be an increase in the frequency of erectile dysfunction after COVID-19. However, no long-term study has investigated whether this is permanent or temporary. In this study, we aimed to examine whether there was an increase in the frequency of erectile dysfunction among individuals with a history of COVID-19, and, if there was, whether their condition improved over time. Materials and methods: In this study, a total of 125 healthy male healthcare workers, 95 with and 30 without a history of COVID-19, were evaluated in terms of erectile function. Four study groups were formed. The first three groups consisted of individuals with a history of COVID-19 confirmed by the polymerase chain reaction (PCR) test at different times, who recovered from the disease (time elapsed since COVID-19 positivity: <6 months for Group 1, 6 to 12 months for Group 2, and >12 months for Group 3). The individuals in Group 4 did not have a history of COVID-19 diagnosis. In order to evaluate the erectile function of the participants, they were asked to complete the five-item International Index of Erectile Function questionnaire (IIEF-5). Then, statistical analyses were performed to evaluate whether there was a difference between the groups in terms of the IIEF-5 scores. Results: There was a statistically significant difference between the groups in terms of the IIEF-5 scores (p < 0.001), and this difference was determined to be caused by the significantly higher IIEF-5 scores of Groups 3 and 4 compared to Group 1 (p = 0.004 and p < 0.001, respectively). In addition, the IIEF-5 score of Group 4 was statistically significantly higher than that of Group 2 (p < 0.001). However, the IIEF-5 scores did not statistically significantly differ between Groups 1 and 2, Groups 2 and 3, and Groups 3 and 4 (p > 0.999, p = 0.204, and p = 0.592, respectively). Conclusion: There may be deterioration in erectile function after COVID-19; however, this tends to improve over time, especially from the first year after active infection. Given that vascular, hormonal, and/or psychogenic factors may lead to the development of erectile dysfunction after COVID-19, we consider that in order to easily manage this process, it is important to determine the underlying cause, initiate appropriate treatment, and inform couples that this situation can be temporary.

Male reproductive system

3375

OO268

Boparai, Anoop Kaur; Jain, Ashish; Sehgal, Komal; Alanazi, Sultan; Jameel, Ahmed Saib; Salian, Shrishti; Saluja, Priyanka; Grover, Vishakha

Risk of failure in dental implant osseointegration among people with the post-covid syndrome

https://doi.org/10.47750/pnr.2022.13.S10.094

Published

31-Dec-22

Article

https://www.pnrjournal.com/index.php/home/article/view/8050

Dental implants are a standard of care in contemporary dental practice and are widely employed for the restoration of missing teeth. The long-term utility of an implant is largely dependent on the successful implant osseointegration and maintenance of the same over time. Bone metabolism and inflammatory mechanism are interrelated phenomena and are usually collectively termed osteoimmunology, which may affect the predictability and success of implant osseointegration. Many biochemical mediators of inflammation, especially Interleukin (IL)1, IL-6, and Tumour necrosis factor (TNF)α, have been documented to increase the activity of bone-resorbing cells through the Receptor Activator of Nuclear Factor Kappa-B (RANK) and Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL)systems. Some of the earlier studies with very limited data suggest that SARS-CoV2 infection may also directly affect bone resorption. Thus, it is imperative to understand the pathophysiology of osseointegration in COVID-19 patients, to enhance successful implant osseointegration and prevent peri-implant bone loss in these patients. Here, we present a summary of the connection between inflammatory pathways and bone metabolism on a molecular basis which may assume a significant bearing in situations of exaggerated host immune response as seen in COVID-19 infection.

Bones

3376

OO269

Piekarska, Aleksandra; Góral, Marta; Kozula, Marta; Jawiarczyk-Przybyłowska, Aleksandra; Zawadzka, Katarzyna; Bolanowski, Marek

The Influence of SARS-CoV-2 Infection on the Thyroid Gland

https://doi.org/10.3390/biomedicines11020614

Published

1-Feb-23

Review

https://www.mdpi.com/2227-9059/11/2/614

It is important to acknowledge the impact that COVID-19 has on the thyroid gland and how the thyroid gland status before and during infection affects SARS-CoV-2 severity. To this day those dependencies are not fully understood. It is known that the virus uses angiotensin-converting enzyme-2 as the receptor for cellular entry and it can lead to multiple organ failures due to a cytokine storm. Levels of proinflammatory molecules (such as cytokines and chemokines) which are commonly elevated during infection were significantly higher in observed SARS-CoV-2-positive patients. In terms of hypothyroidism, hyperthyroidism, and autoimmune thyroid diseases, there is no proof that those dysfunctions have a direct impact on the more severe courses of COVID-19. Regarding hyper- and hypothyroidism there was no consequential dependency between the frequency of SARS-CoV-2 infection morbidity and more severe post-infectious complications. When it comes to autoimmune thyroid diseases, more evaluation has to be performed due to the unclear relation with the level of antibodies commonly checked in those illnesses and its binding with the mentioned before virus. Nonetheless, based on analyzed works we found that COVID-19 can trigger the immune system and cause its hyperactivity, sometimes leading to the new onset of autoimmune disorders. We also noticed more acute SARS-CoV-2 courses in patients with mainly reduced free triiodothyronine serum levels, which in the future, might be used as a mortality indicating factor regarding SARS-CoV-2-positive patients. Considering subacute thyroiditis (SAT), no statistically important data proving its direct correlation with COVID-19 infection has been found. Nevertheless, taking into account the fact that SAT is triggered by respiratory tract viral infections, it might be that SARS-CoV-2 can cause it too. There are many heterogenous figures in the symptoms, annual morbidity distribution, and frequency of new cases, so this topic requires further evaluation.

Thyroid gland

3377

OO270

Aschman, Tom; Wyler, Emanuel; Baum, Oliver; Hentschel, Andreas; Legler, Franziska; Preusse, Corinna; Meyer-Arndt, Lil; Büttnerova, Ivana; Förster, Alexandra; Cengiz, Derya; Alves, Luiz Gustavo Teixeira; Schneider, Julia; Kedor, Claudia; Rust, Rebecca; Bellmann-Strobl, Judith; Aminaa, Sanchin; Vajkoczy, Peter; Goebel, Hans-Hilmar; Landthaler, Markus; Corman, Victor; Roos, Andreas; Heppner, Frank L.; Radbruch, Helena; Paul, Friedemann; Scheibenbogen, Carmen; Stenzel, Werner; Dengler, Nora F.

Post-COVID syndrome is associated with capillary alterations, macrophage infiltration and distinct transcriptomic signatures in skeletal muscles

https://doi.org/10.1101/2023.02.15.23285584

Published

16-Feb-23

Study

https://www.medrxiv.org/content/10.1101/2023.02.15.23285584v1

The SARS-CoV-2 pandemic not only resulted in millions of acute infections worldwide, but also caused innumerable cases of post-infectious syndromes, colloquially referred to as “long COVID”. Due to the heterogeneous nature of symptoms and scarcity of available tissue samples, little is known about the underlying mechanisms. We present an in-depth analysis of skeletal muscle biopsies obtained from eleven patients suffering from enduring fatigue and post-exertional malaise after an infection with SARS-CoV-2. Compared to two independent historical control cohorts, patients with post-COVID exertion intolerance had fewer capillaries, thicker capillary basement membranes and increased numbers of CD169+ macrophages. SARS-CoV-2 RNA could not be detected in the muscle tissues, but transcriptomic analysis revealed distinct gene signatures compared to the two control cohorts, indicating immune dysregulations and altered metabolic pathways. We hypothesize that the initial viral infection may have caused immune-mediated structural changes of the microvasculature, potentially explaining the exercise-dependent fatigue and muscle pain.
The SARS-CoV-2 pandemic not only resulted in millions of acute infections worldwide, but also caused innumerable cases of post-infectious syndromes, colloquially referred to as “long COVID”. Due to the heterogeneous nature of symptoms and scarcity of available tissue samples, little is known about the underlying mechanisms. We present an in-depth analysis of skeletal muscle biopsies obtained from eleven patients suffering from enduring fatigue and post-exertional malaise after an infection with SARS-CoV-2. Compared to two independent historical control cohorts, patients with post-COVID exertion intolerance had fewer capillaries, thicker capillary basement membranes and increased numbers of CD169+ macrophages. SARS-CoV-2 RNA could not be detected in the muscle tissues, but transcriptomic analysis revealed distinct gene signatures compared to the two control cohorts, indicating immune dysregulations and altered metabolic pathways. We hypothesize that the initial viral infection may have caused immune-mediated structural changes of the microvasculature, potentially explaining the exercise-dependent fatigue and muscle pain.

Muscles

3378

OO271

Murali, Reshma; Wanjari, Uddesh Ramesh; Mukherjee, Anirban Goutam; Gopalakrishnan, Abilash Valsala; Kannampuzha, Sandra; Namachivayam, Arunraj; Madhyastha, Harishkumar; Renu, Kaviyarasi; Ganesan, Raja

Crosstalk between COVID-19 Infection and Kidney Diseases: A Review on the Metabolomic Approaches

https://doi.org/10.3390/vaccines11020489

Published

1-Feb-23

Review

https://www.mdpi.com/2076-393X/11/2/489

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a respiratory disorder. Various organ injuries have been reported in response to this virus, including kidney injury and, in particular, kidney tubular injury. It has been discovered that infection with the virus does not only cause new kidney disease but also increases treatment difficulty and mortality rates in people with kidney diseases. In individuals hospitalized with COVID-19, urinary metabolites from several metabolic pathways are used to distinguish between patients with acute kidney injury (AKI) and those without. This review summarizes the pathogenesis, pathophysiology, treatment strategies, and role of metabolomics in relation to AKI in COVID-19 patients. Metabolomics is likely to play a greater role in predicting outcomes for patients with kidney disease and COVID-19 with varying levels of severity in the near future as data on metabolic profiles expand rapidly. Here, we also discuss the correlation between COVID-19 and kidney diseases and the available metabolomics approaches.

Metabolic system

3379

OO272

Rago, Vittoria; Perri, Anna

SARS-CoV-2 Infection and the Male Reproductive System: A Brief Review

https://doi.org/10.3390/life13020586

Published

1-Feb-23

Review

https://www.mdpi.com/2075-1729/13/2/586

Many studies have suggested that SARS-CoV-2, directly or indirectly, can affect the male reproductive system, although the underlined mechanisms have not been completely elucidated yet. The purpose of this review is to provide a summary of the current data concerning the impact of SARS-CoV-2 infection on the male urogenital tract, with a particular emphasis on the testes and male fertility. The main data regarding the morphological alterations in the testes emerged from autoptic studies that revealed interstitial congestion, micro thrombosis, reduction of Sertoli, Leydig, and germinal cells, infiltrated immune cells, and atrophic seminiferous tubules consistent with orchitis. Furthermore, men with severe infection exhibit sperm parameter alterations, together with abnormalities of the hypothalamic–pituitary–testis axis, strongly suggesting that SARS-CoV-2 could increase the risk of male infertility. However, despite the inadequate number of longitudinal studies, spermatogenesis and sex hormone imbalance seem to improve after infection resolution. The yet unresolved question is whether the virus acts in a direct or/and indirect manner, as discordant data related to its presence in the testis and semen have been reported. Regardless of the direct effect, it has been postulated that the cytokine storm and the related local and systemic inflammation could strongly contribute to the onset of testis dysfunction, leading to male infertility. Therefore, multicentric and longitudinal studies involving a large number of patients are needed to understand the real impact of SARS-CoV-2 infection on male reproduction.

Male Reproductive System

3380

OO273

Mukherjee, Anirban Goutam; Wanjari, Uddesh Ramesh; Gopalakrishnan, Abilash Valsala; Kannampuzha, Sandra; Murali, Reshma; Namachivayam, Arunraj; Ganesan, Raja; Renu, Kaviyarasi; Dey, Abhijit; Vellingiri, Balachandar; Prabakaran, D. S.

Insights into the Scenario of SARS-CoV-2 Infection in Male Reproductive Toxicity

https://doi.org/10.3390/vaccines11030510

Published

1-Mar-23

Review

https://www.mdpi.com/2076-393X/11/3/510

COVID-19 has become a significant public health concern that has catastrophic consequences for society. Some preliminary evidence suggests that the male reproductive system may be an infection target for SARS-CoV-2. SARS-CoV-2 may be transmitted sexually, according to preliminary research. Testicular cells exhibit a high level of the angiotensin-converting enzyme 2 (ACE2) receptor, which enhances the entry of the SARS-CoV-2 into host cells. Some instances of COVID-19 have been documented to exhibit hypogonadism during the acute stage. Furthermore, systemic inflammatory reactions triggered by SARS-CoV-2 infection may cause oxidative stress (OS), which has been shown to have profoundly deleterious consequences on testicular functioning. This work gives a clear picture of how COVID-19 may affect male reproductive systems and calls attention to the many unanswered questions about the mechanisms by which this virus can be linked to men’s health and fertility.

Male Reproductive System

3381

OO274

Agergaard, J.; Leth, S.; Pedersen, T. H.; Harbo, T.; Blicher, J. U.; Karlsson, P.; Østergaard, L.; Andersen, H.; Tankisi, H.

Myopathic changes in patients with long-term fatigue after COVID-19

https://doi.org/10.1016/j.clinph.2021.04.009

Published

1-Aug-21

Study

https://www.sciencedirect.com/science/article/pii/S1388245721005514

Highlights
•20 patients with persistent neuromuscular symptoms including fatigue, 77–255 (median: 216) days after acute COVID-19 were examined.
•Nerve conduction studies did not show signs of neuropathy but 11 patients (55%) had myopathic changes with quantitative electromyography.
•Myopathy may be an important cause of physical fatigue and myalgia in long-term COVID-19 even in non-hospitalized patients.
Abstract
Objective
To investigate the peripheral nerve and muscle function electrophysiologically in patients with persistent neuromuscular symptoms following Coronavirus disease 2019 (COVID-19).
Methods
Twenty consecutive patients from a Long-term COVID-19 Clinic referred to electrophysiological examination with the suspicion of mono- or polyneuropathy were included. Examinations were performed from 77 to 255 (median: 216) days after acute COVID-19. None of the patients had received treatment at the intensive care unit. Of these, 10 patients were not even hospitalized. Conventional nerve conduction studies (NCS) and quantitative electromyography (qEMG) findings from three muscles were compared with 20 age- and sex-matched healthy controls.
Results
qEMG showed myopathic changes in one or more muscles in 11 patients (55%). Motor unit potential duration was shorter in patients compared to healthy controls in biceps brachii (10.02 ± 0.28 vs 11.75 ± 0.21), vastus medialis (10.86 ± 0.37 vs 12.52 ± 0.19) and anterior tibial (11.76 ± 0.31 vs 13.26 ± 0.21) muscles. All patients with myopathic qEMG reported about physical fatigue and 8 patients about myalgia while 3 patients without myopathic changes complained about physical fatigue.
Conclusions
Long-term COVID-19 does not cause large fibre neuropathy, but myopathic changes are seen.
Significance
Myopathy may be an important cause of physical fatigue in long-term COVID-19 even in non-hospitalized patients.

Muscles

3382

OO275

Dissanayake, Harsha

COVID-19 and metabolic syndrome

https://doi.org/10.1016/j.beem.2023.101753

Published

1-Mar-23

Review

https://www.sciencedirect.com/science/article/pii/S1521690X23000246

Convergence of the two pandemics: metabolic syndrome and COVID-19 over last two years has posed unprecedented challenges to individuals as well as healthcare systems. Epidemiological data suggest a close association between metabolic syndrome and COVID-19 while variety of possible pathogenic connections have been proposed while some have been proven. Despite the evidence of high risk for adverse COVID-19 outcomes in people with metabolic syndrome, little is known about the differences in efficacy and safety among people with metabolic syndrome and without. It is important to recognize that among people with metabolic syndrome This review summarizes the current knowledge and epidemiological evidence on the association between metabolic syndrome and adverse COVID-19 outcomes, pathogenic interrelationships, management considerations for acute COVID-19 and post-COVID sequalae and sustaining care of people living with metabolic syndrome with appraisal of evidence and gaps in knowledge.

Pancreas

3383

OO276

Maher, Michelle; Owens, Lisa

SARS-CoV-2 infection and female reproductive health: a narrative review

https://doi.org/10.1016/j.beem.2023.101760

Published

1-Mar-23

Review

https://www.sciencedirect.com/science/article/pii/S1521690X23000313

The COVID-19 pandemic has had a profound global impact, affecting people’s physical and mental health, and their social and economic circumstances. Mitigation measures have disproportionately affected women. Studies have reported menstrual cycle and psychological disturbance associated with the pandemic. Pregnancy is a risk factor for severe COVID-19 disease. Reports have also demonstrated associations between COVID-19 infection, vaccination and Long COVID syndrome and reproductive health disturbance. However, studies are limited and there may be significant geographical variation. Also there is bias amongst published studies, and menstrual cycle data was not included in COVID-19 and vaccine trials. Longitudinal population based studies are required. In this review we discuss existing data, along with recommendations for further research required in this area. We also discuss a pragmatic approach to women presenting reproductive health disturbance in the era of the pandemic, encompassing a multi-system assessment of psychological, reproductive health and lifestyle.

Female Reproductive System

3384

OO277

Kristina Jevnikar 1,2ORCID,Andrej Meglič 1,Luka Lapajne 1,Mateja Logar 3,4,Nataša Vidovič Valentinčič 1,2,Mojca Globočnik Petrovič 1,2 andPolona Jaki Mekjavić

The Comparison of Retinal Microvascular Findings in Acute COVID-19 and 1-Year after Hospital Discharge Assessed with Multimodal Imaging—A Prospective Longitudinal Cohort Study

https://doi.org/10.3390/ijms24044032

Published

17-Feb-23

Study

https://www.mdpi.com/1422-0067/24/4/4032

This study aimed to quantify possible long-term impairment of the retinal microcirculation and microvasculature by reassessing a cohort of patients with acute COVID-19 without other known comorbidities one year after their discharge from the hospital. Thirty patients in the acute phase of COVID-19 without known systemic comorbidities were enrolled in this prospective longitudinal cohort study. Fundus photography, SS-OCT, and SS-OCTA using swept-source OCT (SS-OCT, Topcon DRI OCT Triton; Topcon Corp., Tokyo, Japan) were performed in the COVID-19 unit and 1-year after hospital discharge. The cohort’s median age was 60 years (range 28–65) and 18 (60%) were male. Mean vein diameter (MVD) significantly decreased over time, from 134.8 μm in the acute phase to 112.4 μm at a 1-year follow-up (p < 0.001). A significantly reduced retinal nerve fiber layer (RNFL) thickness was observed at follow-up in the inferior quadrant of the inner ring (mean diff. 0.80 95% CI 0.01–1.60, p = 0.047) and inferior (mean diff. 1.56 95% CI 0.50–2.61, p < 0.001), nasal (mean diff. 2.21 95% CI 1.16–3.27, p < 0.001), and superior (mean diff. 1.69 95% CI 0.63–2.74, p < 0.001) quadrants of the outer ring. There were no statistically significant differences between the groups regarding vessel density of the superior and deep capillary plexuses. The transient dilatation of the retinal vessels in the acute phase of COVID-19, as well as RNFL thickness changes, could become a biomarker of angiopathy in patients with severe COVID-19.

Eyes

3385

OO278

Migliorini, Filippo; Bell, Andreas; Vaishya, Raju; Eschweiler, Jörg; Hildebrand, Frank; Maffulli, Nicola

Reactive arthritis following COVID-19 current evidence, diagnosis, and management strategies

https://doi.org/10.1186/s13018-023-03651-6

Published

15-Mar-23

Review

https://doi.org/10.1186/s13018-023-03651-6

Background
Immune-mediated conditions associated to Corona Virus Disease-19 (COVID-19) have been reported, including vasculitis, antiphospholipid antibody syndrome, myositis, and lupus. Emerging studies have reported the potential occurrence of reactive arthritis in patients previously infected with COVID-19. This systematic review summarised the current evidence on the occurrence of reactive arthritis in patients previously infected by COVID-19.

Methods
This study was conducted according to the 2020 PRISMA guidelines. All the clinical investigations describing the occurrence of reactive arthritis following COVID-19 were accessed. In September 2022, the following databases were accessed: PubMed, Web of Science, Google Scholar, Embase. The generalities of the study were extracted: author, year and journal of publication, country of the main author, study design, sample size, mean age, number of women, main results of the study. The following data on COVID-19 severity and management were retrieved: type of treatment, hospitalization regimes (inpatient or outpatient), admission to the intensive care unit, need of mechanical ventilation, pharmacological management. The following data on reactive arthritis were collected: time elapsed between COVID-19 infection to the onset of reactive arthritis symptoms (days), pharmacological management, type of arthritis (mono- or bilateral, mono- or polyarticular), extra-articular manifestations, presence of tenosynovitis or enthesitis, synovial examination at microscopic polarised light, imaging (radiography, magnetic resonance, sonography), clinical examination, laboratory findings.

Results
Data from 27 case reports (54 patients) were retrieved, with a mean age of 49.8 ± 14.5 years. 54% (29 of 54 patients) were women. The mean time span between COVID-19 infection and the occurrence of reactive arthritis symptoms was 22.3 ± 10.7 days. Between studies diagnosis and management of reactive arthritis were heterogeneous. Symptoms resolved within few days in all studies considered. At last follow-up, all patients were minimally symptomatic or asymptomatic, and no additional therapy or attentions were required by any patient.

Conclusion
Poor evidence suggests that COVID-19 could target the musculoskeletal system causing reactive arthritis at its post infectious stage. COVID-19 can act as a causative agent or as a trigger for development of reactive arthritis even without presence of antibodies of rheumatological disorders. Treating physicians should have a high index of suspicion while treating post infectious COVID-19 patient with arthralgia.

Level of evidence
Level IV, systematic review.

Joints

3386

OO279

Dai, P.; Qiao, F.; Chen, Y.; Chan, D. Y. L.; Yim, H. C. H.; Fok, K. L.; Chen, H.

SARS-CoV-2 and male infertility: from short- to long-term impacts

https://doi.org/10.1007/s40618-023-02055-x

Published

14-Mar-23

Review

https://doi.org/10.1007/s40618-023-02055-x

Purpose
The coronavirus 2019 (COVID-19) pandemic—caused by a new type of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)—has posed severe impacts on public health worldwide and has resulted in a total of > 6 million deaths. Notably, male patients developed more complications and had mortality rates ~ 77% higher than those of female patients. The extensive expression of the SARS-CoV-2 receptor and related proteins in the male reproductive tract and the association of serum testosterone levels with viral entry and infection have brought attention to COVID-19’s effects on male fertility.

Methods
The peer-reviewed articles and reviews were obtained by searching for the keywords SARS-CoV-2, COVID-19, endocrine, spermatogenesis, epididymis, prostate, and vaccine in the databases of PubMed, Web of Science and Google Scholar from 2020–2022.

Results
This review summarizes the effects of COVID-19 on the male reproductive system and investigates the impact of various types of SARS-CoV-2 vaccines on male reproductive health. We also present the underlying mechanisms by which SARS-CoV-2 affects male reproduction and discuss the potentially harmful effects of asymptomatic infections, as well as the long-term impact of COVID-19 on male reproductive health.

Conclusion
COVID-19 disrupted the HPG axis, which had negative impacts on spermatogenesis and the epididymis, albeit further investigations need to be performed. The development of vaccines against various SARS-CoV-2 variations is important to lower infection rates and long-term COVID risks.

Male Reproductive System

3387

OO280

Wesselingh, Robb; Wesselingh, Steve L

An eye to the future: Acute and long-term neuro-ophthalmological and neurological complications of COVID-19

https://doi.org/10.1111/ceo.14221

Published

1-Mar-23

Review

https://doi.org/10.1111/ceo.14221

COVID-19 has had a significant impact on the global population and has produced compelling evidence of non-pulmonary organ dysfunction, including the nervous system. It is vital that specialists in ophthalmology and neurology are informed of the potential complications of COVID-19 and gain a deeper understanding of how COVID-19 can cause diseases of the nervous system. In this review we detail four possible mechanisms by which COVID-19 infection may result in neurological or neuro-ophthalmological complications: (1) Toxic and metabolic effects of severe pulmonary COVID-19 disease on the neural axis including hypoxia and the systemic hyper-inflammatory state, (2) endothelial dysfunction, (3) dysimmune responses directed again the neuroaxis, and (4) direct neuro-invasion and injury by the virus itself. We explore the pathological evidence for each of these and how they may link to neuro-ophthalmological disorders. Finally, we explore the evidence for long-term neurological and neuro-ophthalmological complications of COVID-19, with a focus on neurodegeneration.

Eyes

3388

OO281

Cornea, Amalia; Lata, Irina; Simu, Mihaela; Rosca, Elena Cecilia

Parsonage-Turner Syndrome Following SARS-CoV-2 Infection: A Systematic Review

https://doi.org/10.3390/biomedicines11030837

Published

1-Mar-23

Review

https://www.mdpi.com/2227-9059/11/3/837

Parsonage-Turner syndrome (PTS) is an inflammatory disorder of the brachial plexus. Hypothesized underlying causes focus on immune-mediated processes, as more than half of patients present some antecedent event or possible predisposing condition, such as infection, vaccination, exercise, or surgery. Recently, PTS was reported following the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We aimed to investigate data on PTS triggered by SARS-CoV-2 infection to provide an extensive perspective on this pathology and to reveal what other, more specific, research questions can be further addressed. In addition, we aimed to highlight research gaps requiring further attention. We systematically reviewed two databases (LitCOVID and the World Health Organization database on COVID-19) to January 2023. We found 26 cases of PTS in patients with previous SARS-CoV-2 infection. The clinical and paraclinical spectrum was heterogeneous, ranging from classical PTS to pure sensory neuropathy, extended neuropathy, spinal accessory nerve involvement, and diaphragmatic palsy. Also, two familial cases were reported. Among them, 93.8% of patients had severe pain, 80.8% were reported to present a motor deficit, and 53.8% of patients presented muscle wasting. Paresthesia was noted in 46.2% of PTS individuals and a sensory loss was reported in 34.6% of patients. The present systematic review highlights the necessity of having a high index of suspicion of PTS in patients with previous SARS-CoV-2 infection, as the clinical manifestations can be variable. Also, there is a need for a standardized approach to investigation and reporting on PTS. Future studies should aim for a comprehensive assessment of patients. Factors including the baseline characteristics of the patients, evolution, and treatments should be consistently assessed across studies. In addition, a thorough differential diagnosis should be employed.

Brachial plexus

3389

OO282

Xu, Evan; Xie, Yan; Al-Aly, Ziyad

Long-term gastrointestinal outcomes of COVID-19

https://doi.org/10.1038/s41467-023-36223-7

Published

7-Mar-23

Study

https://www.nature.com/articles/s41467-023-36223-7

A comprehensive evaluation of the risks and 1-year burdens of gastrointestinal disorders in the post-acute phase of COVID-19 is needed but is not yet available. Here we use the US Department of Veterans Affairs national health care databases to build a cohort of 154,068 people with COVID-19, 5,638,795 contemporary controls, and 5,859,621 historical controls to estimate the risks and 1-year burdens of a set of pre-specified incident gastrointestinal outcomes. We show that beyond the first 30 days of infection, people with COVID-19 exhibited increased risks and 1-year burdens of incident gastrointestinal disorders spanning several disease categories including motility disorders, acid related disorders (dyspepsia, gastroesophageal reflux disease, peptic ulcer disease), functional intestinal disorders, acute pancreatitis, hepatic and biliary disease. The risks were evident in people who were not hospitalized during the acute phase of COVID-19 and increased in a graded fashion across the severity spectrum of the acute phase of COVID-19 (non-hospitalized, hospitalized, and admitted to intensive care). The risks were consistent in comparisons including the COVID-19 vs the contemporary control group and COVID-19 vs the historical control group as the referent category. Altogether, our results show that people with SARS-CoV-2 infection are at increased risk of gastrointestinal disorders in the post-acute phase of COVID-19. Post-covid care should involve attention to gastrointestinal health and disease.

Gastro-intestinal

3390

OO283

Steenblock, Charlotte; Toepfner, Nicole; Beuschlein, Felix; Perakakis, Nikolaos; Mohan Anjana, Ranjit; Mohan, Viswanathan; Mahapatra, Nitish R.; Bornstein, Stefan R.

SARS-CoV-2 infection and its effects on the endocrine system

https://doi.org/10.1016/j.beem.2023.101761

Published

5-Mar-23

Study

https://www.sciencedirect.com/science/article/pii/S1521690X23000325

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing corona virus disease 2019 (COVID-19) can infect multiple tissues, including endocrine organs, such as the pancreas, adrenal, thyroid, and adipose tissue. The main receptor for SARS-CoV-2, ACE2, is ubiquitously expressed in the cells of the endocrine organs and accordingly, the virus has been detected in various amounts in all endocrine tissues in post-mortem samples from COVID-19 patients. The infection with SARS-CoV-2 may directly lead to organ damage or dysfunction, such as hyperglycaemia or in rare cases, new-onset diabetes. Furthermore, an infection with SARS-CoV-2 may have indirect effects affecting the endocrine system. The exact mechanisms are not yet completely understood and have to be further investigated. Conversely, endocrine diseases may affect the severity of COVID-19 and emphasis has to be laid on reducing the prevalence, or enhance the treatment, of these often non-communicable diseases in the future.

Endocrine system

3391

OO284

Muzyka, Iryna; Revenko, Oleh; Kovalchuk, Iryna; Savytska, Maryanna; Bekesevych, Anna; Zayachkivska, Oksana

What is the role of brown adipose tissue in metabolic health: lessons learned and future perspectives in the long COVID?

https://doi.org/10.1007/s10787-023-01195-z

Published

21-Mar-23

Review

https://doi.org/10.1007/s10787-023-01195-z

Metabolic physiology plays a key role in maintaining our health and resilience. Metabolic disorders can lead to serious illnesses, including obesity. The pathogenesis of the new long COVID syndrome in individuals with long-term recovery after SARS-Co-2 infection is still incomplete. Thus there is growing attention in the study of adipose tissue activities, especially brown adipose tissue (BAT) and associated resilience which plays a crucial role in different types of obesity as potential targets for pharmacologic and nutritional interventions in the context of obesity and long COVID. The number of studies examining mechanisms underlying BAT has grown rapidly in the last 10 years despite of role of BAT in individuals with COVID-19 and long COVID is modest. Therefore, this review aims to sum up data examining BAT activities, its resilience in health, obesity, and the possible link to long COVID. The search was conducted on studies published in English mostly between 2004 and 2022 in adult humans and animal models. Database searches were conducted using PubMed, Scopus, and Google Scholar for key terms including adipose tissue, BAT, adipokinins, obesity, VPF/VEGF, and pathogenesis. From the initial search through the database were identified relevant articles that met inclusion and exclusion criteria and our data regarding adipose tissues were presented in this review. It will discuss adiposity tissue activities. Current literature suggests that there are BAT integral effects to whitening and browning fat phenomenons which reflect the homeostatic metabolic adaptive ability for environmental demand or survival/adaptive mechanisms. We also review neural and vascular impacts in BAT that play a role in resilience and obesity. Finally, we discuss the role of BAT in the context of long COVID in basic research and clinical research.

Metabolic system

3392

OO285

Urfalıoğlu, Selma; Akkök, Burcu; Özdemir, Gökhan; Daghan, Betül; Guler, Mete

Évaluation OCTA du flux sanguin oculaire postérieur chez les patients après une infection au COVID-19 sans pneumonie

https://doi.org/10.1016/j.jfo.2023.01.002

Published

24-Mar-23

Study

https://www.sciencedirect.com/science/article/pii/S0181551223001249

Rèsume
Objectif: Nous avions l’intention de montrer le changement des structures du nerf optique et de la rétine microvasculaire avec l’ongiographie par tomographie optique de Koherens chez les patients infectés parla COVID-19. Mèthodes: Ètude Prospective. Le dèbit microvasculaire et les densitès vasculaires de la tête des nerfs optiques, choroıdiens et rètiniens des deux groupes ont été mesurés par OCTA. Résultats: Les mesures OCTA de 122 yeux droits d’un total de 122 patients, 72 patients du groupe COVID-19 et 50 patients du groupe témoin ont été incluses dans l’étude. Zone d’écoulement (FA) des portes profondes en plexus (DCP) ; 1.42±0.23 mm2 dans le groupe témoin dans le cas de la COVID-19, les portes Chorio ètalent en plexus FA, 1.89±0.04 mm2 dans le cas dela COVID-19 1.42±0.23 mm2, 1.5±0.15 mm2 dans le groupe témoin, Choriocapillaire en plexus FA dans le cas de la COVID-19 1.42±0.23 mm2, 1.5±0.15 mm2 dans le groupe témoin, Choriocapillaire en plexus FA dans le cas de la COVID-19, une différence statistiquement significative a du groupe témoin (respectivement p=0.03; p=0.02). Les valeurs de pleksus capillaire profond à toute densité vasculaire (VD) ètaient 58.28±3.88 dans le groupe témoin de 56.76% ±4.16 % dans le cas de la COVID-19; la différence entre les valeurs ètait statistiquement significative entre les deux groupes en termes de zones d’écoulement de la tête du nerf optique et d’autres paramètres examinés dans les quadrants. Conclusions: Les résultats montrent que la microcirculation rétinienne est affectée chez les objets légèrement malades Même si la maladie est bènigne, les patients peuvent devoir être suivis pour les changements rétiniens futurs.
Summary
Introduction: We aimed to demonstrate the changes in optic nerve and retinal microvascular structures with Optical coherence tomography angiography (OCTA) in patients who had COVID-19 infection. Methods: Prospective study. Retina, choroid and optic nerve head microvascular flow and vascular densities of both groups were measured by OCTA. Results: OCTA measurements of 122 right eyes of a total of 122 patients, including 72 patients in the COVID-19 group and 50 patients in the control group, were included in the study. The Deep Capillary Plexus (DCP) Flow Area (FA); in the COVID-19 group was 1.42±0.23 mm2, in the control group was 1.50±0.15 mm2, Choriocapillary Plexus FA was 1.89±0.04 mm2 in the COVID-19 group, was 1.91±0.05 mm2 in the control group, and a statistically significant difference was found between the two groups (respectively; p=0.03; p=0.02). DCP Whole Vascular density (VD) values were 56.76±4.16 % in the COVID-19 group, 58.28±3.88 % in the control group; difference between the values was statistically significant ( p=0.04). There was no statistically significant difference between the two groups in terms of optic nerve head flow areas and other parameters examined according to quadrants. Conclusions: Results shows that the retinal microcirculation in subjects with mild disease is affected. Even if the disease is mild, patients may need to be followed up for retinal changes that may develop in the future.

Eyes

3393

OO286

Wang, Yichen; Guo, Hui; Wang, Gongquan; Zhai, Jiawei; Du, Bing

COVID-19 as a Trigger for type 1 diabetes

https://doi.org/10.1210/clinem/dgad165

Published

23-Mar-23

Article

https://doi.org/10.1210/clinem/dgad165

Type 1 diabetes (T1D) is usually caused by immune-mediated destruction of islet beta-cells, and genetic and environmental factors are thought to trigger autoimmunity. Convincing evidence indicates that viruses are associated with T1D development and progression. During the coronavirus disease 2019(COVID-19) pandemic, cases of hyperglycemia, diabetic ketoacidosis (DKA), and new diabetes increased, suggesting that severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may be a trigger for or unmask T1D. Possible mechanisms of beta-cell damage include virus-triggered cell death, immune-mediated loss of pancreatic beta-cells, and damage to beta-cells due to infection of surrounding cells. This article examines the potential pathways by which SARS-CoV-2 affects islet beta-cells in the above three aspects. Specifically, we emphasize that T1D can be triggered by SARS-CoV-2 through several autoimmune mechanisms, including epitope spread, molecular mimicry and bystander activation. Given that the development of T1D is often a chronic, long-term process, it is difficult to currently draw firm conclusions as to whether SARS-CoV-2 causes T1D. This area needs to be focused on in terms of the long-term outcomes. More in-depth and comprehensive studies with larger cohorts of patients and long-term clinical follow-ups are required.

Pancreas

3394

OO287

Kal, Magdalena; Winiarczyk, Mateusz; Zarębska-Michaluk, Dorota; Odrobina, Dominik; Cieśla, Elżbieta; Płatkowska-Adamska, Bernadetta; Biskup, Michał; Pabjan, Paweł; Głuszek, Stanisław; Mackiewicz, Jerzy

Long-Term Effect of SARS-CoV-2 Infection on the Retinal and Choroidal Microvasculature

https://doi.org/10.3390/jcm12072528

Published

1-Jan-23

Study

https://www.mdpi.com/2077-0383/12/7/2528

The purpose of this study was to evaluate the persistent changes in microvascular parameters based on optical coherence tomography angiography (OCTA) in patients hospitalized due to COVID-19 bilateral pneumonia. The case-control prospective study was carried out among 49 patients with COVID-19 and 45 healthy age- and gender-matched 2 and 8 months after hospital discharge. We found a significantly decreased vessel density (VD) in superficial capillary plexus (SCP) in COVID-19 patients. Significantly decreased vessel density (VD) in the superficial capillary plexus (SCP), the deep capillary plexus (DCP), and choriocapillaris (CC), with significantly increased vessel density observed in the choriocapillaris in the foveal area (FCC). The foveal avascular zone in DCP (FAZd) was significantly increased in the COVID-19 group. We found differences between OCTA parameters according to gender. The foveal VD in SCP and DCP was significantly decreased in women compared to men. The FAZ area in SCP (FAZs) and superior VD in the choriocapillaris (SCC) were significantly increased in women. In conclusion, we noticed persistent changes in the ocular parameters of OCTA in COVID-19 patients. At the second follow-up visit, we observed a widened FAZ zone in SCP and decreased VD in some regions of the retina and choroid.

Eyes

3395

OO288

de Lima, Igor Costa; de Menezes, Daniel Carvalho; Uesugi, Juliana Hiromi Emin; Bichara, Cléa Nazaré Carneiro; da Costa Vasconcelos, Pedro Fernando; Quaresma, Juarez Antônio Simões; Falcão, Luiz Fábio Magno

Liver Function in Patients with Long-Term Coronavirus Disease 2019 of up to 20 Months: A Cross-Sectional Study

https://doi.org/10.3390/ijerph20075281

Published

1-Jan-23

Study

https://www.mdpi.com/1660-4601/20/7/5281

The long-term laboratory aspects of the effects of coronavirus disease 2019 (COVID-19) on liver function are still not well understood. Therefore, this study aimed to evaluate the hepatic clinical laboratory profile of patients with up to 20 months of long-term COVID-19. A total of 243 patients of both sexes aged 18 years or older admitted during the acute phase of COVID-19 were included in this study. Liver function analysis was performed. Changes were identified in the mean levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), gamma-glutamyl transferase (GGT), and ferritin. A ferritin level of >300 U/L was observed in the group that presented more changes in liver function markers (ALT, AST, and GGT). Age ≥ 60 years, male sex, AST level > 25 U/L, and GGT level ≥ 50 or 32 U/L were associated with an ALT level > 29 U/L. A correlation was found between ALT and AST, LDH, GGT, and ferritin. Our findings suggest that ALT and AST levels may be elevated in patients with long-term COVID-19, especially in those hospitalised during the acute phase. In addition, an ALT level > 29 U/L was associated with changes in the levels of other markers of liver injury, such as LDH, GGT, and ferritin.

Liver

3396

OO289

García-Vicente, Patricia; Rodríguez-Valiente, Antonio; Gil, Carmen Górriz; Altemir, Reyes Márquez; Martínez-Pérez, Francisco; López-Pajaro, Luis Fernando; García-Berrocal, Jose Ramón

Chronic cough in post-COVID syndrome: Laryngeal electromyography findings in vagus nerve neuropathy

https://doi.org/10.1371/journal.pone.0283758

Published

30-Mar-23

Study

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0283758

Background Despite being a new entity, there is a large amount of information on the characteristics of SARS-CoV-2 infection and the symptoms of the acute phase; however, there are still many unknowns about the clinical features and pathophysiology of post-COVID syndrome. Refractory chronic cough is one of the most prevalent symptoms and carries both a medical problem and a social stigma. Many recent studies have highlighted the role of SARS-CoV-2 neurotropism, but no studies have demonstrated vagus nerve neuropathy as a cause of persistent chronic cough or other COVID-19 long-term effects. Objective The main objective was to assess the involvement of the vagus nerve neuropathy as a cause of chronic cough and other post-COVID syndrome symptoms. Material and methods This was a single-center observational study with prospective clinical data collected from 38 patients with chronic cough and post-COVID-19 syndrome. Clinical characteristics and laryngeal electromyographic findings were analyzed. Results Clinical data from 38 patients with chronic cough after 12 weeks of the acute phase of COVID-19 infection were analyzed. Of these patients, 81.6% suffered from other post-COVID conditions and, 73.6% reported fluctuating evolution of symptoms. Laryngeal electromyography (LEMG) of the thyroarytenoid (TA) muscles and cricothyroid (CT) muscles was pathological in 76.3% of the patients. Of the patients with abnormal LEMG, chronic denervation was the most frequent finding (82.8%), 10.3% presented acute denervation signs, and 6.9% presented myopathic pattern in LEMG. Conclusions LEMG studies suggest the existence of postviral vagus nerve neuropathy after SARS-CoV-2 infection that could explain chronic cough in post-COVID syndrome.

Vocal organs

3397

OO290

Jie Chee, Ying; Dalan, Rinkoo

Repurposing exercise training and pharmacological therapies to address the post-acute sequelae of COVID-19 (PASC) in diabetes mellitus

https://doi.org/10.1016/j.diabres.2023.110651

Published

1-May-23

Article

https://www.sciencedirect.com/science/article/pii/S0168822723004114

Regarding the role of pharmacological therapies, it is worth considering repurposing antihyperglycaemic medications, such as metformin, SGLT2-inhibitors, and GLP1 receptor agonists, as potential treatment strategies for long COVID. In a recent preprint, metformin has been shown to reduce the risk of long COVID by 63% if started within four days of symptom onset [16]. The postulated benefits of metformin include alleviation of inflammation [17] and inhibition of SARS-CoV-2 viral replication in vitro [18]. The SGLT2 inhibitors potentially target the underlying mechanisms of long COVID, given the anti-inflammatory properties [19]. In addition, SGLT2-inhibition optimizes myocardial substrate utilization, improves cardiac function, promotes skeletal muscle remodelling and exercise capacity in heart failure [19]. Regarding GLP1 receptor agonists, studies have shown benefits in attenuating endothelial dysfunction by reducing the release of adhesion molecules and endothelin I, a potent vasoconstrictor [20]. Despite the above postulated benefits, the role of these medications in treating long COVID is currently uncertain. Further mechanistic studies and clinical trials are required to evaluate the effectiveness of these agents in managing long COVID.

The long COVID syndrome may be a double-edged sword in our efforts to optimize the management of individuals with DM. While nonpharmacological measures such as exercise training may be more challenging, increased public awareness of the long-term sequelae could, in turn, promote the adoption of healthier lifestyle habits. Reappraisal of pharmacological therapies that target the pathophysiology of the long COVID syndrome and assessing their efficacies through rigorous clinical trials will pave the way toward improving outcomes in individuals with DM and long COVID.

Pancreas

3398

OO291

Khan, Saif; Karim, Maryam; Gupta, Vasu; Goel, Heenam; Jain, Rohit

A Comprehensive Review of COVID-19–Associated Endocrine Manifestations

https://doi.org/10.14423/SMJ.0000000000001542

Published

1-Apr-23

Review

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10044587/

Coronavirus disease 2019 (COVID-19) has played a significant part in systematic damage, affecting lives and leading to significant mortality. The endocrine system is one of the systems affected by this pandemic outbreak. The relationship between them has been identified in previous and ongoing research. The mechanism through which severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) can achieve this is similar to that for organs that express angiotensin-converting enzyme 2 receptors, which is the primary binding site of the virus. Endocrine cells widely express angiotensin-converting enzyme 2 receptors and transmembrane serine protease 2, the primary mediators initiating the acute phase of the disease. This review aimed to identify and discuss the endocrine complications of COVID-19. This primary focus is on presenting thyroid disorders or newly diagnosed diabetes mellitus (DM). Thyroid dysfunction with subacute thyroiditis, Graves’ disease, and hypothyroidism caused by primary autoimmune thyroiditis has been reported. Pancreatic damage leads to type 1 DM because of the autoimmune nature of the disease and type 2 DM because of postinflammatory insulin resistance. Because follow-up data on COVID-19 on the endocrine glands are limited, long-term investigations are needed to assess specific effects.
publisher: Wolters Kluwer Health
PMID: 37011583

Endocrine system

3399

OO292

Sandle, Geoffrey I.; Herod, Morgan R.; Fontana, Juan; Lippiat, Jonathan D.; Stockley, Peter G.

Is intestinal transport dysfunctional in COVID-19-related diarrhea?

https://doi.org/10.1152/ajpgi.00021.2023

Published

1-May-23

Article

https://journals.physiology.org/doi/full/10.1152/ajpgi.00021.2023

Diarrhea, often severe, is a recognized and frequently early symptom during acute COVID-19 infection and may persist or develop for the first time in patients with long-COVID, with socioeconomic consequences. Diarrheal mechanisms in these cases are poorly understood. There is evidence for disruption of intestinal epithelial barrier function and also for changes in the gut microbiome, which is critical for gut immunity and metabolism. Whether the SARS-CoV-2 virus has adverse effects on intestinal transport proteins is unclear. However, the ability of the virus to inhibit expression and activity of an aldosterone-regulated epithelial sodium (Na+) channel (ENaC) present in human distal colon, which is responsible for Na+ and water salvage, points to possible disruption of other intestinal transport proteins during COVID-19 infection. In this Perspective, we develop this idea by highlighting possible intestinal transport protein targets for the SARS-CoV-2 virus and discussing how their interactions might be explored in the laboratory.

Intestines

3400

OO293

Zhang, Dongmei; Zhou, Yaya; Ma, Yanling; Chen, Ping; Tang, Jian; Yang, Bohan; Li, Hui; Liang, Mengyuan; Xue, YuE; Liu, Yao; Zhang, Jianchu; Wang, Xiaorong

Gut Microbiota Dysbiosis Correlates With Long COVID-19 at One-Year After Discharge

https://doi.org/10.3346/jkms.2023.38.e120

Published

30-Mar-23

Study

https://doi.org/10.3346/jkms.2023.38.e120

Background
Long coronavirus disease 2019 (COVID-19) in recovered patients (RPs) is gradually recognized by more people. However, how long it will last and the underlining mechanism remains unclear.

Methods
We conducted a prospective follow-up study to evaluate the long-term symptoms and clinical indices of RPs at one-year after discharge from Union Hospital, Wuhan, China between December 2020 to May 2021. We also performed the 16S rRNA sequencing of stool samples from RPs and healthy controls (HCs) and analyzed the correlation between the gut microbiota and long COVID-19.

Results
In total, 187 RPs were enrolled, among them, 84 (44.9%) RPs reported long COVID-19 symptoms at one-year after discharge. The most common long-term symptoms were cardiopulmonary symptoms, including chest tightness after activity (39/187, 20.9%), palpitations on exercise (27/187, 14.4%), sputum (21/187, 11.2%), cough (15/187, 8.0%) and chest pain (13/187, 7.0%), followed by systemic symptoms including fatigue (34/187, 18.2%) and myalgia (20/187, 10.7%), and digestive symptoms including constipation (14/187, 7.5%), anorexia (13/187, 7.0%), and diarrhea (8/187, 4.3%). Sixty-six (35.9%) RPs presented either anxiety or depression (42/187 [22.8%] and 53/187 [28.8%] respectively), and the proportion of anxiety or depression in the long symptomatic group was significantly higher than that in the asymptomatic group (41/187 [50.6%] vs. 25/187 [24.3%]). Compared with the asymptomatic group, scores of all nine 36-Item Short Form General Health Survey domains were lower in the symptomatic group (all P < 0.05). One hundred thirty RPs and 32 HCs (non-severe acute respiratory syndrome coronavirus 2 infected subjects) performed fecal sample sequencing. Compared with HCs, symptomatic RPs had obvious gut microbiota dysbiosis including significantly reduced bacterial diversities and lower relative abundance of short-chain fatty acids (SCFAs)-producing salutary symbionts such as Eubacterium_hallii_group, Subdoligranulum, Ruminococcus, Dorea, Coprococcus, and Eubacterium_ventriosum_group. Meanwhile, the relative abundance of Eubacterium_hallii_group, Subdoligranulum, and Ruminococcus showed decreasing tendencies between HCs, the asymptomatic group, and the symptomatic group.

Conclusion
This study demonstrated the presence of long COVID-19 which correlates with gut microbiota dysbiosis in RPs at one-year after discharge, indicating gut microbiota may play an important role in long COVID-19.

Intestines

3401

OO294

Kemeç, Z.; Akgül, F.

Are Patients with Covid-19 at Risk of Long-Term Chronic Kidney Disease?

https://doi.org/10.4103/njcp.njcp_382_22

Published

1-Mar-23

Study

https://journals.lww.com/njcp/Fulltext/2023/03000/Are_Patients_with_Covid_19_at_Risk_of_Long_Term.15.aspx?context=LatestArticles

Background:
The relationship between Coronavirus Disease 2019 (COVID-19) and acute kidney injury (AKI) is well-established. However, a comprehensive evaluation of kidney outcomes in the long-term course of COVID-19 is not yet been performed. The aim of this study is to investigate whether chronic kidney disease (CKD) develops within six months after hospital discharge in COVID-19 patients who did not have kidney damage at the time of admission to the hospital.
Patients and Methods:
This single-center retrospective study investigated a total of 1008 participants selected from 7500 COVID-19 patients with real-time reverse transcription-polymerase chain reaction (RT-PCR) positivity. All patients had mild/moderate or severe COVID-19. Patients were randomly selected from inpatient and outpatient settings. Critical COVID-19 patients were not included.
Results:
The mean age of the patients was 56.57 ± 16.30 years, and 69.9% of them were male. The comorbidity percentages of the participants were as follows; 19.5% coronary artery disease (CAD), 28.6% diabetes mellitus (DM), 36.2% hypertension (HT), 3.1% cerebrovascular obstruction (CVO), 1.7% malignancy, 2.6% chronic obstructive pulmonary disease (COPD), 9.4% asthma, % 1.7 dementia, 9.9% hyperlipidaemia, and 1.7% hepatitis B virus (HBV). Kidney function tests of these patients at first admission and 6 months later were compared to reveal the relationship between COVID-19 and CKD. Serum glucose, sodium estimated glomerular filtration rate (eGFR), and uric acid levels were found to be high in the post-COVID-19 period (P = 0.001). However, there were a decrease in serum albumin, potassium, alanine aminotransferase (ALT), C-reactive protein (CRP), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and gamma-glutamyl transferase (GGT) levels (P = 0.001). The difference between the first measurement of serum urea and creatinine (Cr) levels and the measurement 6 months later was not statistically significant (P = 0.102 and P = 0.300, respectively).
Conclusions:
Those who survived the mild/moderate and severe clinical manifestations of COVID-19 did not exhibit any risk of kidney outcomes after the acute phase of the disease, suggesting that the kidney can protect itself over a long period of time.

Kidney

3402

OO295

Al-kuraishy, Hayder M.; Al-Gareeb, Ali I.; Alarfaj, Sumaiah J.; Al-Akeel, Rasha Khalifah; Faidah, Hani; El-Bouseary, Maisra M.; Sabatier, Jean-Marc; De Waard, Michel; El-Masry, Thanaa A.; Batiha, Gaber El-Saber

Long COVID and risk of erectile dysfunction in recovered patients from mild to moderate COVID-19

https://doi.org/10.1038/s41598-023-32211-5

Published

12-Apr-23

Study

https://www.nature.com/articles/s41598-023-32211-5

Patients with coronavirus disease 2019 (COVID-19) were shown to have reduced serum testosterone levels compared to healthy individuals. Low testosterone levels are linked with the development of erectile dysfunction (ED). In this case-controlled study, 20 healthy controls and 39 patients with ED 3 months after recovering from mild-to-moderate COVID-19 pneumonia were studied. The patients ranged in age from 31 to 47 years. To identify early and late COVID-19 infections, real-time polymerase-chain reaction (RT-PCR) and COVID-19 antibody testing were done. The levels of luteinizing hormone (LH), follicular stimulating hormone (FSH), total testosterone (TT), free testosterone (FT), free androgenic index (FAI), and sex hormone-binding globulin (SHBG) were measured. The sexual health inventory for patients (SHIM) score was used to measure the erectile function of the patients and controls. When compared to the controls, the TT serum level in long COVID-19 (LC) patients with ED was low (p = 0.01). In contrast to controls, FT and FAI were both lower in LC patients with ED. (p = 0.001). FSH serum levels did not significantly differ (p = 0.07), but in ED patients, LH serum levels were elevated. SHIM scores were associated with low TT (p = 0.30), FT (p = 0.09), and high LH (p = 0.76) in LC patients with ED. Male patients with decreased serum levels of LH and testosterone may have hypothalamic-pituitary–gonadal axis dysfunction, which could lead to the development of LC-induced ED. Therefore, an in-depth research is necessary to confirm the causal link between COVID-19 and ED in LC patients.

Male Reproductive System

3403

OO296

Akbari, Hassan; Taghizadeh-Hesary, Farzad

COVID-19 induced liver injury from a new perspective: Mitochondria

https://doi.org/10.1016/j.mito.2023.04.001

Published

1-May-23

Review

https://www.sciencedirect.com/science/article/pii/S1567724923000338

Highlights
•Patients with COVID-19 are at high risk of liver damage.
•The underlying mechanism is still undefined.
•SARS-CoV-2 can damage mitochondria directly or through systemic inflammation.
•COVID-induced liver injury is more in patients with weaker mitochondria.
•Boosting mitochondria can protect liver from COVID-induced injury.
Abstract
Liver damage is a common sequela of COVID-19 (coronavirus disease 2019), worsening the clinical outcomes. However, the underlying mechanism of COVID-induced liver injury (CiLI) is still not determined. Given the crucial role of mitochondria in hepatocyte metabolism and the emerging evidence denoting SARS-CoV-2 can damage human cell mitochondria, in this mini-review, we hypothesized that CiLI happens following hepatocytes’ mitochondrial dysfunction. To this end, we evaluated the histologic, pathophysiologic, transcriptomic, and clinical features of CiLI from the mitochondria’ eye view. Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), the causative agent of COVID-19, can damage hepatocytes through direct cytopathic effects or indirectly after the profound inflammatory response. Upon entering the hepatocytes, the RNA and RNA transcripts of SARS-CoV-2 engages the mitochondria. This interaction can disrupt the mitochondrial electron transport chain. In other words, SARS-CoV-2 hijacks the hepatocytes’ mitochondria to support its replication. In addition, this process can lead to an improper immune response against SARS-CoV-2. Besides, this review outlines how mitochondrial dysfunction can serve as a prelude to the COVID-associated cytokine storm. Thereafter, we indicate how the nexus between COVID-19 and mitochondria can fill the gap linking CiLI and its risk factors, including old age, male sex, and comorbidities. In conclusion, this concept stresses the importance of mitochondrial metabolism in hepatocyte damage in the context of COVID-19. It notes that boosting mitochondria biogenesis can possibly serve as a prophylactic and therapeutic approach for CiLI. Further studies can reveal this notion.

Liver

3404

OO297

Philips, Cyriac Abby; Madhu, Deepak; Augustine, Philip

Investigating the correlation between COVID-19 and the progression of chronic liver disease

https://doi.org/10.1080/17474124.2023.2206564

Published

22-Apr-23

Review

https://doi.org/10.1080/17474124.2023.2206564

ABSTRACT
Introduction
The novel coronavirus disease 2019 has thrown light on various heterogeneous afflictions of newly emerging viruses on the human body. Early reports demonstrated direct effect of novel coronavirus on the liver, but subsequently, this did not stand up to validation. The SARS-CoV-2 virus affects the liver differentially; in healthy compared to those with preexisting liver disease.

Areas covered
This exhaustive paper reviews the current, literature on mechanisms by which COVID-19 affects the healthy liver and those with preexisting liver disease such as alcohol-related and nonalcoholic fatty liver, autoimmune liver disease, chronic liver disease and cirrhosis, hepatocellular carcinoma, viral hepatitis, and liver transplant recipients, with special mention on drug-and herb-induced liver injury with COVID-19 therapies. Search methodology: the review (Dec. 2022 – Jan. 2023) is based on PubMed (NLM) search using the keyword ‘COVID’ with supplementary searches using ‘fibrosis;’ ‘liver;’ ‘cirrhosis;’ ‘CLD;’ ‘NAFLD;’ ‘NASH;’ ‘hepatocellular carcinoma;’ ‘hepatitis;’ ‘fatty liver;’ ‘alcohol;’ ‘viral;’ ‘transplant;’ and ‘liver failure.’

Expert opinion
Direct liver tropism of SARS-CoV-2 does not cause liver damage. Adverse events following infection depend on the severity of liver disease, the severity of COVID-19, and other risk factors such as metabolic syndrome and older age. Alcohol-related liver disease independently predicts adverse outcomes.

KEYWORDS: Cirrhosisportal hypertensionDILIcoronaviruscovid vaccinehepatocellular carcinomaHBVHCV
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Article highlights
COVID-19 does not directly cause liver injury or liver failure even though it has a high tropism for the hepatobiliary system

Liver test abnormalities are common in severe and critical COVID-19 and are related to gravity of SARS-CoV-2 infection

Alcohol-related liver disease is an independent risk factor for poor clinical outcomes in COVID-19

Non-alcoholic fatty liver disease does not predispose to worse clinical outcomes

Chronic liver disease or cirrhosis does not increase the risk of infection, but once infected, these patients have a poor prognosis depending on the severity of preexisting liver disease and the presence or absence of traditional risk factors for adverse outcomes

In those with preexisting liver disease who survive decompensation or liver failure, no additional negative outcomes in the natural history of the disease were notable
publisher: Taylor & Francis
_eprint: https://doi.org/10.1080/17474124.2023.2206564
PMID: 37086388

Liver

3405

OO298

Sharbatdar, Yasamin; Mousavian, Ronak; Noorbakhsh Varnosfaderani, Seyed Mostafa; Aziziyan, Fatemeh; Liaghat, Mahsa; Baziyar, Payam; Yousefi Rad, Ali; Tavakol, Chanour; Moeini, Amir Mansour; Nabi-Afjadi, Mohsen; Zalpoor, Hamidreza; Kazemi-Lomedasht, Fatemeh

Diabetes as one of the long-term COVID-19 complications: from the potential reason of more diabetic patients’ susceptibility to COVID-19 to the possible caution of future global diabetes tsunami

https://doi.org/10.1007/s10787-023-01215-y

Published

20-Apr-23

Review

https://doi.org/10.1007/s10787-023-01215-y

According to recent researches, people with diabetes mellitus (type 1 and 2) have a higher incidence of coronavirus disease 2019 (COVID-19), which is caused by a SARS-CoV-2 infection. In this regard, COVID-19 may make diabetic patients more sensitive to hyperglycemia by modifying the immunological and inflammatory responses and increasing reactive oxygen species (ROS) predisposing the patients to severe COVID-19 and potentially lethal results. Actually, in addition to COVID-19, diabetic patients have been demonstrated to have abnormally high levels of inflammatory cytokines, increased virus entrance, and decreased immune response. On the other hand, during the severe stage of COVID-19, the SARS-CoV-2-infected patients have lymphopenia and inflammatory cytokine storms that cause damage to several body organs such as β cells of the pancreas which may make them as future diabetic candidates. In this line, the nuclear factor kappa B (NF-κB) pathway, which is activated by a number of mediators, plays a substantial part in cytokine storms through various pathways. In this pathway, some polymorphisms also make the individuals more competent to diabetes via infection with SARS-CoV-2. On the other hand, during hospitalization of SARS-CoV-2-infected patients, the use of some drugs may unintentionally lead to diabetes in the future via increasing inflammation and stress oxidative. Thus, in this review, we will first explain why diabetic patients are more susceptible to COVID-19. Second, we will warn about a future global diabetes tsunami via the SARS-CoV-2 as one of its long-term complications.

Pancreas

3406

OO299

Davis, Pamela B.; Xu, Rong

COVID-19 and Incident Diabetes—Recovery Is Not So Sweet After All

https://doi.org/10.1001/jamanetworkopen.2023.8872

Published

18-Apr-23

Article

https://doi.org/10.1001/jamanetworkopen.2023.8872

Infection with SARS-CoV-2 leads not only to acute disease but also to long-term consequences. Post–COVID-19 condition (colloquially called long COVID) is the most frequent of the postacute sequelae of COVID-19, but SARS-CoV-2 infection can trigger or accelerate other debilitating and costly chronic diseases, including cardiac and neurological disorders. Naveen and colleagues add their Canadian study to the international reports of increased occurrence of diabetes following SARS-CoV-2 infection. A meta-analysis of reports from the US, Norway, the UK, Germany, and multisite consortia found an overall 66% increase in the incidence of new-onset diabetes following SARS-CoV-2 infection. Another review showed that 12 of 14 population-based studies found significantly increased incidence of diabetes following COVID-19, with excess cases ranging from 11% to 276% above control. Where subanalyses were conducted, the rates were usually higher among men than among women, and new diagnoses tended to occur in the first few months following infection and were more likely in patients with more severe COVID-19 infection. Since most studies were conducted in adults, it is likely that most of the new cases are type 2 diabetes, but separation of type 1 diabetes and type 2 diabetes may be difficult in population studies. However, in a US study using electronic health records that was restricted to children with a specified diagnoses of type 1 diabetes, even children younger than 10 years of age had an increased risk of new diagnoses. Naveen and colleagues report a significant, although modest, increase in new diagnosis of diabetes in British Columbia, Canada, among adult men following SARS-CoV-2 infection compared with men who tested negative for SARS-CoV-2 at about the same time. In addition, they provide compelling evidence that the increase in diagnoses of diabetes was associated with severity of COVID-19, with a hazard ratio of 2.42 (95% CI, 1.87-3.15) for persons hospitalized with COVID-19, and a hazard ratio of 3.29 (95% CI, 1.98-5.48) for those who required intensive care. For those with severe COVID-19, the increase in new diagnoses of diabetes was significant for women as well. Results were significant only for non–insulin-dependent diabetes, although this finding may not represent a clean separation into type 2 and type 1 disease. This study represents a population-based investigation that adds to the existing literature suggesting an increased risk for developing diabetes following COVID-19.

Pancreas

3407

OO300

Tkacheva, Olga N.; Klimenko, Natalia S.; Kashtanova, Daria A.; Tyakht, Alexander V.; Maytesyan, Lilit V.; Akopyan, Anna A.; Koshechkin, Stanislav I.; Strazhesko, Irina D.

Gut Microbiome in Post-COVID-19 Patients Is Linked to Immune and Cardiovascular Health Status but Not COVID-19 Severity

https://doi.org/10.3390/microorganisms11041036

Published

1-Apr-23

Study

https://www.mdpi.com/2076-2607/11/4/1036

The composition of the gut microbiome stores the imprints of prior infections and other impacts. COVID-19 can cause changes in inflammatory status that persist for a considerable time after infection ends. As the gut microbiome is closely associated with immunity and inflammation, the infection severity might be linked to its community structure dynamics. Using 16S rRNA sequencing of stool samples, we investigated the microbiome three months after the end of the disease/infection or SARS-CoV-2 contact in 178 post-COVID-19 patients and those who contacted SARS-CoV-2 but were not infected. The cohort included 3 groups: asymptomatic subjects (n = 48), subjects who contacted COVID-19 patients with no further infection (n = 46), and severe patients (n = 86). Using a novel compositional statistical algorithm (nearest balance) and the concept of bacterial co-occurrence clusters (coops), we compared microbiome compositions between the groups as well as with multiple categories of clinical parameters including: immunity, cardiovascular parameters and markers of endothelial dysfunction, and blood metabolites. Although a number of clinical indicators varied drastically across the three groups, no differences in microbiome features were identified between them at this follow-up point. However, there were multiple associations between the microbiome features and clinical data. Among the immunity parameters, the relative lymphocyte number was linked to a balance including 14 genera. Cardiovascular parameters were associated with up to four bacterial cooperatives. Intercellular adhesion molecule 1 was linked to a balance including ten genera and one cooperative. Among the blood biochemistry parameters, calcium was the only parameter associated with the microbiome via a balance of 16 genera. Our results suggest comparable recovery of the gut community structure in the post-COVID-19 period, independently of severity or infection status. The multiple identified associations of clinical analysis data with the microbiome provide hypotheses about the participation of specific taxa in regulating immunity and homeostasis of cardiovascular and other body systems in health, as well as their disruption in SARS-CoV-2 infections and other diseases.

Intestines

3408

OO301

Fernández-de-las-Peñas, César; Torres-Macho, Juan; Guijarro, Carlos; Martín-Guerrero, José D.; Pellicer-Valero, Oscar J.; Plaza-Manzano, Gustavo

Trajectory of Gastrointestinal Symptoms in Previously Hospitalized COVID-19 Survivors: The Long COVID Experience Multicenter Study

https://doi.org/10.3390/v15051134

Published

1-May-23

Study

https://www.mdpi.com/1999-4915/15/5/1134

This multicenter cohort study used Sankey plots and exponential bar plots to visualize the fluctuating evolution and the trajectory of gastrointestinal symptoms in previously hospitalized COVID-19 survivors during the first 18 months after acute SARS-CoV-2 infection. A total of 1266 previously hospitalized COVID-19 survivors were assessed at four points: hospital admission (T0), at 8.4 months (T1), at 13.2 months (T2), and at 18.3 months (T3) after hospitalization. Participants were asked about their overall gastrointestinal symptoms and particularly diarrhea. Clinical and hospitalization data were collected from hospital medical records. The prevalence of overall gastrointestinal post-COVID symptomatology was 6.3% (n = 80) at T1, 3.99% (n = 50) at T2 and 2.39% (n = 32) at T3. The prevalence of diarrhea decreased from 10.69% (n = 135) at hospital admission (T0), to 2.55% (n = 32) at T1, to 1.04% (n = 14) at T2, and to 0.64% (n = 8) at T3. The Sankey plots revealed that just 20 (1.59%) and 4 (0.32%) patients exhibited overall gastrointestinal post-COVID symptoms or diarrhea, respectively, throughout the whole follow-up period. The recovery fitted exponential curves revealed a decreasing prevalence trend, showing that diarrhea and gastrointestinal symptoms recover during the first two or three years after COVID-19 in previously hospitalized COVID-19 survivors. The regression models did not reveal any symptoms to be associated with the presence of gastrointestinal post-COVID symptomatology or post-COVID diarrhea at hospital admission or at T1. The use of Sankey plots revealed the fluctuating evolution of gastrointestinal post-COVID symptoms during the first two years after infection. In addition, exponential bar plots revealed the decreased prevalence of gastrointestinal post-COVID symptomatology during the first three years after infection.

Intestines

3409

OO302

Rosa Santiago, S.m.; Maldonado, V.; Hernandez Moya, K.z.

Secondary Acrocyanosis, the Only Visible Sign Present in a "Long COVID" Patient

Published

1-May-23

Study

https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A5610

Bones

3410

OO303

Pellegrino, Christopher J; Ye, Nancy Y; Chen, Irene K; Abdelsayed, George A

Early and late implications of COVID-19 on male reproductive health: 3 years of data

https://doi.org/10.1093/sxmrev/qead017

Published

2-May-23

Review

https://doi.org/10.1093/sxmrev/qead017

COVID-19 (coronavirus disease 2019), caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), has significantly affected global health. Research has shown that the virus can be found at high concentrations in male gonadal tissue. Yet, the virus’s long-term implications on male reproductive health remains relatively unclear.A comprehensive narrative review of published literature regarding COVID-19’s short- and long-term implications on male reproductive health.A literature search of the PubMed and EMBASE databases was performed for articles ranging from November 2019 to August 2022. Studies that focused on the impact of COVID-19 on male reproductive health were selected for review. Studies were included if they were written in English and reported semen analyses, pathologic gonadal tissue analyses, serum androgen assays, or a combination of these in patients with COVID-19. Moreover, literature was included on COVID-19 vaccinations’ impacts on male reproductive health. Case reports and other narrative reviews were excluded from this review.SARS-CoV-2 has been detected in cadaveric testicular tissue during the initial stages of infection in fatal cases of the disease, demonstrating marked inflammatory changes and decreased spermatogenesis in patients with COVID-19. Several studies have revealed a negative impact on androgens during acute illness and in the ensuing months, but data on the recovery of androgen levels are confounding and limited in scope. COVID-19 does have significant negative impacts on bulk semen parameters, as confirmed in studies comparing pre- and post–COVID-19 semen samples. Vaccination is a valuable tool for protecting patients from the negative impacts of the virus and has been shown to have no negative impact on male reproductive potential.Given the virus’s impacts on testicular tissue, androgens, and spermatogenesis, COVID-19 can negatively affect male reproductive health for an extended period. Therefore, vaccinations should continue to be recommended to all eligible patients.

Male Reproductive System

3411

OO304

Gore, Manal; Pusalkar, Manas; Borkar, Santosh; Yadav, Sunil; Bishnoi, Himanshu

A Prospective Study of the Occurrence of Avascular Necrosis of the Skeletal System in Post Covid 19 Infected Patients with Corticosteroid Use

Published

1-Apr-23

Study

https://www.seronijihou.com/article/a-prospective-study-of-the-occurrence-of-avascular-necrosis-of-the-skeletal-system-in-post-covid-19-infected-patients-with-corticosteroid-use

COVID-19 can have an impact on various biological systems. Avascular necrosis (AVN) as a consequence of "long COVID-19" has not yet been documented in many studies. We predict that the widespread use of life-saving corticosteroids in COVID-19 cases will lead to an increase in AVN cases. We conducted a study documenting the occurrence of AVN in post covid 19 infected patients who had taken corticosteroids during the course of their treatment. The incidence in the current study was 6.5 %. Prednisolone was given to these patients in a mean dose of 760 mg (400-1300 mg) over the course of their treatment, which is less than the mean cumulative dose of around 2000 mg steroid mentioned in the literature for the development of AVN. The average number of days it took for symptoms to appear after the last steroid use was 178 days, or almost six months. According to a literature analysis, developing avascular necrosis on an MRI following steroid treatment in non-covid circumstances takes six to twelve months. The early onset and progression of AVN are accelerated by COVID 19 infection and corticosteroid usage.

Bones

3412

OO305

Kim, Sun H; Arora, Ipsa; Hsia, Daniel S; Knowler, William C; LeBlanc, Erin; Mylonakis, Eleftherios; Pratley, Richard; Pittas, Anastassios G

New-Onset Diabetes After COVID-19

https://doi.org/10.1210/clinem/dgad284

Published

19-May-23

Review

https://doi.org/10.1210/clinem/dgad284

There is evidence suggesting that infection with SARS-CoV-2 can lead to several long-term sequelae including diabetes. This mini-review examines the rapidly evolving and conflicting literature on new-onset diabetes after COVID-19, which we term NODAC. We searched PubMed, MEDLINE, and medRxiv from inception until December 1, 2022, using Medical Subject Headings (MeSH) terms and free text words including “COVID-19,” “SARS-CoV-2,” “diabetes,” “hyperglycemia,” “insulin resistance,” and “pancreatic β-cell.” We also supplemented searches by examining reference lists from retrieved articles. Current evidence suggests that COVID-19 increases the risk of developing diabetes, but the attributable risk is uncertain because of limitations of study designs and the evolving nature of the pandemic, including new variants, widespread population exposure to the virus, diagnostic options for COVID-19, and vaccination status. The etiology of diabetes after COVID-19 is likely multifactorial and includes factors associated with host characteristics (eg, age), social determinants of health (eg, deprivation index), and pandemic-related effects both at the personal (eg, psychosocial stress) and the societal-community level (eg, containment measures). COVID-19 may have direct and indirect effects on pancreatic β-cell function and insulin sensitivity related to the acute infection and its treatment (eg, glucocorticoids); autoimmunity; persistent viral residency in multiple organs including adipose tissue; endothelial dysfunction; and hyperinflammatory state. While our understanding of NODAC continues to evolve, consideration should be given for diabetes to be classified as a post-COVID syndrome, in addition to traditional classifications of diabetes (eg, type 1 or type 2), so that the pathophysiology, natural history, and optimal management can be studied.

Pancreas

3413

OO306

Khan, Benjamin Yamin Ali; Agergaard, Jane; Harbo, Thomas; Schiøttz-Christensen, Berit; Østergaard, Lars; Tankisi, Hatice

N°377 – Are neuromuscular long-term COVID-19 complications chronic? A quantitative and single fiber electromyography follow-up study

https://doi.org/10.1016/j.clinph.2023.03.348

Published

1-Jun-23

Study

https://www.sciencedirect.com/science/article/pii/S1388245723005813

Background Fatigue and myalgia are among the most common long-term COVID-19 (LTC) symptoms. LTC myopathy has been shown on electromyography (EMG) and muscle biopsy. However, the prognosis of having LTC neuromuscular manifestations remains unknown. This study aims at re-assessing the changes in quantitative EMG (qEMG) and single-fiber EMG (sfEMG) in patients with LTC at follow-up. Method Twenty-two LTC patients with myopathic qEMG and/or abnormal sfEMG were re-examined after ∼ 10 months. qEMG of biceps brachii (BB), vastus medialis (VM) and tibialis anterior (TA) and sfEMG of TA were performed. Mean MUP duration, amplitude, percentage of polyphasic potentials, and mean jitter were compared between 1st and 2nd examinations using the Wilcoxon test. Results In BB, MUP duration (median: 9.1 ms (8.8,9.6) vs 9.5 ms (8.8,11.0), p = 0.02) and MUP amplitudes (median: 232 µV (200,274) vs. 258 µV (232,296), p = 0.01) were increased. Polyphasia was unchanged (p = 0.09). In VM, MUP duration was unchanged (p = 0.18), but MUP amplitudes (median:299 µV (246,346) vs 363 µV (290,500), p = 0.003) and polyphasia was increased (median:4.5% (0,10) vs 10% (3.8,20), p = 0.01). In TA, MUP duration was unchanged (p = 0.15), but MUP amplitudes (median:353 µV (296,448) vs 493 µV (437,812), p = 0.0005) and polyphasia (median:23.3% (19,30) vs 30% (25.0,37.5), p = 0.004) was increased. Median jitter in TA did not differ from 1st (median: 35.5 µs (30.1,37.9) to the 2nd (median:36.4 µs (31.1,38.0) (p = 0.67) examinations. Conclusion Patients with Long COVID-19 still have electrophysiological abnormalities after ∼ 10 months. qEMG changes indicate chronicity of myopathic changes and sfEMG values did not show any improvement.

Muscles

3414

OO307

Johansson, Jan; Möller, Marika; Markovic, Gabriela; Borg, Kristian

Vision impairment is common in non-hospitalised patients with post-COVID-19 syndrome

https://doi.org/10.1080/08164622.2023.2213826

Published

18-May-23

Study

https://doi.org/10.1080/08164622.2023.2213826

Clinical relevance Vision-related problems can be part of longstanding sequelae after COVID-19 and hamper the return to work and daily activities. Knowledge about symptoms, visual, and oculomotor dysfunctions is however scarce, particularly for non-hospitalised patients. Clinically applicable tools are needed as support in the assessment and determination of intervention needs.Background The purpose of this study was to evaluate vision-related symptoms, assess visual and oculomotor function, and to test the clinical assessment of saccadic eye movements and sensitivity to visual motion in non-hospitalised post-COVID-19 outpatients. The patients (n = 38) in this observational cohort study were recruited from a post-COVID-19 clinic and had been referred for neurocognitive assessment.Methods Patients who reported vision-related symptoms reading problems and intolerance to movement in the environment were examined. A structured symptom assessment and a comprehensive vision examination were undertaken, and saccadic eye movements and visual motion sensitivity were assessed.Results High symptom scores (26–60%) and prevalence of visual function impairments were observed. An increased symptom score when reading was associated with less efficient saccadic eye movement behaviour (p < 0.001) and binocular dysfunction (p = 0.029). Patients with severe symptoms in visually busy places scored significantly higher on the Visual Motion Sensitivity Clinical Test Protocol (p = 0.029).Conclusion Vision-related symptoms and impairments were prevalent in the study group. The Developmental Eye Movement Test and the Visual Motion Sensitivity Clinical Test Protocol showed promise for clinical assessment of saccadic performance and sensitivity to movement in the environment. Further study will be required to explore the utility of these tools.

Eyes

3415

OO308

Durairajan, Siva Sundara Kumar; Singh, Abhay Kumar; Saravanan, Udhaya Bharathy; Namachivayam, Mayurikaa; Radhakrishnan, Moorthi; Huang, Jian-Dong; Dhodapkar, Rahul; Zhang, Hongjie

Gastrointestinal Manifestations of SARS-CoV-2: Transmission, Pathogenesis, Immunomodulation, Microflora Dysbiosis, and Clinical Implications

https://doi.org/10.3390/v15061231

Published

1-Jun-23

Review

https://www.mdpi.com/1999-4915/15/6/1231

The clinical manifestation of COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in the respiratory system of humans is widely recognized. There is increasing evidence suggesting that SARS-CoV-2 possesses the capability to invade the gastrointestinal (GI) system, leading to the manifestation of symptoms such as vomiting, diarrhea, abdominal pain, and GI lesions. These symptoms subsequently contribute to the development of gastroenteritis and inflammatory bowel disease (IBD). Nevertheless, the pathophysiological mechanisms linking these GI symptoms to SARS-CoV-2 infection remain unelucidated. During infection, SARS-CoV-2 binds to angiotensin-converting enzyme 2 and other host proteases in the GI tract during the infection, possibly causing GI symptoms by damaging the intestinal barrier and stimulating inflammatory factor production, respectively. The symptoms of COVID-19-induced GI infection and IBD include intestinal inflammation, mucosal hyperpermeability, bacterial overgrowth, dysbiosis, and changes in blood and fecal metabolomics. Deciphering the pathogenesis of COVID-19 and understanding its exacerbation may provide insights into disease prognosis and pave the way for the discovery of potential novel targets for disease prevention or treatment. Besides the usual transmission routes, SARS-CoV-2 can also be transmitted via the feces of an infected person. Hence, it is crucial to implement preventive and control measures in order to mitigate the fecal-to-oral transmission of SARS-CoV-2. Within this context, the identification and diagnosis of GI tract symptoms during these infections assume significance as they facilitate early detection of the disease and the development of targeted therapeutics. The present review discusses the receptors, pathogenesis, and transmission of SARS-CoV-2, with a particular focus on the induction of gut immune responses, the influence of gut microbes, and potential therapeutic targets against COVID-19-induced GI infection and IBD.

Intestines

3416

OO309

Gao, Yan; Kok, Wai Ling; Sharma, Vikram; Illsley, Charlotte Sara; Hanks, Sally; Tredwin, Christopher; Hu, Bing

SARS-CoV-2 infection causes periodontal fibrotic pathogenesis through deregulating mitochondrial beta-oxidation

https://doi.org/10.1038/s41420-023-01474-2

Published

26-May-23

Study

https://www.nature.com/articles/s41420-023-01474-2

The global high prevalence of COVID-19 is a major challenge for health professionals and patients. SARS-CoV-2 virus has four structural protein components: the spike protein, envelope protein, membrane protein, and nucleocapsid protein. The SARS-CoV-2 virus mutates predominantly in the spike proteins, whilst the other key viral components usually remain stable. Essentially the pathological functions of the SARS-CoV-2 virus on different cell types are still largely unknown. Previous studies have shown that the human oral cavity can potentially act as reservoir of the SARS-CoV-2 virus. However, the consequence of SARS-CoV-2 viral infection on human oral health has not been systematically examined. COVID-19 can cause severe oral mucosa lesions and is likely to be connected with poor periodontal conditions. Fibroblasts are the major cell type inside periodontal ligament (PDL) and express the SARS-CoV-2 receptor: Angiotensin-converting enzyme 2 (ACE2), whose expression level can increase upon bacterial infection hence potentially provide a direct route of SARS-CoV-2 infection to PDL fibroblasts. In this research, we aimed to study the pathogenicity of SARS-CoV-2 viral components on human fibroblasts. We found that by exposing to SARS-CoV-2, especially to the viral envelope and membrane proteins, the human periodontal fibroblasts could develop fibrotic pathogenic phenotypes, including hyperproliferation that was simultaneously induced with increased apoptosis and senescence. The fibrotic degeneration was mediated by a down-regulation of mitochondrial β-oxidation in the fibroblasts. Fatty acid β-oxidation inhibitor, etomoxir treatment could mirror the same pathological consequence on the cells, similar to SARS-CoV-2 infection. Our results therefore provide novel mechanistic insights into how SARS-CoV-2 infection can affect human periodontal health at the cell and molecular level with potential new therapeutic targets for COVID-19 induced fibrosis.

Mouth

3417

MO01

Andrea Dennis, Malgorzata Wamil, Sandeep Kapur, Johann Alberts, Andrew D. Badley

Multi-organ impairment in low-risk individuals with long COVID

https://doi.org/10.1101/2020.10.14.20212555

pre-print

16-Oct-20

Study

https://www.medrxiv.org/content/10.1101/2020.10.14.20212555v1

A preprint study (not yet peer reviewed) recruiting patients with post-covid symptoms shows 2/3 the presence of deficiencies in at least one organ.
Heart / lungs: 1/3 Pancreas: 1/6
Kidneys / liver: 1/10 Rate: 1/20
In a young, low-risk population with ongoing symptoms, almost 70% of individuals have impairment in one or more organs four months after initial symptoms of SARS-CoV-2 infection
The cohort is 201 patients (70% women), with an average age of 44 years, who were followed for a median of 140 days after the first symptoms. The prevalence of pre-existing morbidity is moderate (obesity: 20%, hypertension: 6%, diabetes: 2%, heart disease: 4%). The most common symptoms are fatigue (98%), muscle pain (88%), shortness of breath (87%), headaches (83%). The impariments concern the heart (32%), the lungs (33%), the kidneys (12%), the liver (10%), the pancreas (17%), the spleen (6%).

Une étude en preprint (non encore relue par les pairs) qui recrutent des patients ayant des symptômes post-covid fait apparaître pour les 2/3 la présence de déficiences sur au moins un organe.
Cœur/poumons : 1/3 Pancréas : 1/6
Reins/foie : 1/10 Rate : 1/20
La cohorte est de 201 patients (70% de femmes), de moyenne d'âge 44 ans, qui ont été suivis sur une médiane de 140 jours après les premiers symptômes.
La prévalence de morbidité préexistante est modérée (obésité : 20%, hypertension : 6%, diabète : 2%, maladie cardiaque : 4%). Les symptômes les + fréquents sont l'état d'épuisement (98%), douleurs musculaires (88%), essoufflement (87%), migraine (83%).
Les déficiences concernent le cœur (32%), les poumons (33%), les reins (12%), le foie (10%), le pancréas (17%), la rate (6%).

3418

MO02

Carole H. Sudre, Benjamin Murray, Thomas Varsavsky, Mark S. Graham, Tim Spector, Claire J. Steves

Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App

https://doi.org/10.1038/s41591-021-01292-y

Published

Article

https://www.nature.com/articles/s41591-021-01292-y
anciennement https://www.medrxiv.org/content/10.1101/2020.10.19.20214494v1

@Timspector's study from @KingsCollegeLon, based on feedback from the COVID Symptom Study app, reports symptoms ≥1 months for 13-14% of participants, ≥3 months for 2.3%, with uncertainties : The study, which is in pre-print (not yet reviewed or published in a journal), qualifies these estimates as conservative, recognizing a series of biases that may under- or overestimate these impacts.
. 558 (13.3%) had symptoms lasting >28 days, 189 (4.5%) for >8 weeks
39 and 95 (2.3%) for >12 weeks. Long-COVID was characterised by symptoms of fatigue,
It is made available under a CC-BY-NC-ND 4.0 International license .(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
medRxiv preprint doi: https://doi.org/10.1101/2020.10.19.20214494; this version posted October 21, 2020. The copyright holder for this preprint
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 40 headache, dyspnoea and anosmia and was more likely with increasing age, BMI and female 41 sex. Experiencing more than five symptoms during the first week of illness was associated 42 with Long-COVID, OR=3.53 [2.76;4.50]

L'étude de @timspector du @KingsCollegeLon, basée sur les retours de l'appli "COVID Symptom Study", rapporte des symptômes ≥1 mois pour 13-14% des participants, ≥3 mois pour 2,3%, avec des incertitudes. L'étude qualifie ces estimations de prudentes, reconnaissant une série de biais pouvant sous- ou sur-estimer ces incidences.

3419

MO03

Gareth Iacobucci

Long covid: Damage to multiple organs presents in young, low risk patients

https://doi.org/10.1136/bmj.m4470

Article publié sur un pre-print

17-Nov-20

News

https://www.bmj.com/content/371/bmj.m4470

Young patients, at low risk, who keep symptoms after an acute phase (only 18% with hospitalization), mainly present deficiencies in one or more organs, according to a study reviewed at the BMJ.

Les patients jeunes, à faible risque, qui gardent des symptômes après une phase aiguë, (seulement 18% avec hospitalisation), présentent majoritairement des déficiences à un ou plusieurs organes, selon une étude en relecture au BMJ. (https://www.medrxiv.org/content/10.1101/2020.10.14.20212555v1)

3420

MO04

Melvin R. Hayden

An Immediate and Long-Term Complication of COVID-19 May Be Type 2 Diabetes Mellitus: The Central Role of β-Cell Dysfunction, Apoptosis and Exploration of Possible Mechanisms

https://doi.org/10.3390/cells9112475

Published

13-Nov-20

Review

https://www.mdpi.com/2073-4409/9/11/2475

A fairly technical study is concerned about the possibility that covid amplifies, or causes, type 2 diabetes in the long term. It describes the processes and phenomena that could come into play.

Une étude assez technique s'inquiète de la possibilité que la covid amplifie, ou provoque, des diabètes de type 2 sur le long terme. Elle décrit les processus et phénomènes qui pourraient entrer en jeu.

3421

MO05

Victoria Higgins,Dorsa Sohaei,Eleftherios P. Diamandis &Ioannis Prassas

COVID-19: from3 an acute to chronic disease? Potential long-term health consequences

https://doi.org/10.1080/10408363.2020.1860895

Published

21-Dec-20

Review

https://www.tandfonline.com/doi/full/10.1080/10408363.2020.1860895

Une revue de la littérature sur les différents aspects d'atteintes aux organes sur le long terme de la covid.
•Pulmonary manifestations
•Cardiovascular "
•Hematologic "
•Renal "
•Central nervous system "
•Post-Intensive care syndrome
•Psychosocial "

N001R

3422

MO06

Satish Kumar Sharma Iqra Rahat

A pathophysiological review on understanding multiorgan effects of COVID-19

Published

1-Dec-20

Review

https://ejmcm.com/article_3640.html

_

3423

MO07

Robert J. Rolfe, Colin M. Smith and Cameron R. Wolfe

The Emerging Chronic Sequelae of COVID-19 and Implications for North Carolina

https://doi.org/10.18043/ncm.82.1.75

Published

1-Jan-21

Research Article

https://www.ncmedicaljournal.com/content/82/1/75.full

Avec l'expérience du SRAS et du MERS, une étude en Caroline du Nord s'intéresse aux séquelles à long terme de la covid, répercutées sur plusieurs organes, et notamment les séquelles neuro-psychiatriques et cérébrovasculaires.

N001R

3424

MO08

KM Capaccione, MD, PhD #
H Yang, MD
E West, MD
E Desperito, MD
C Ruzal-Shapiro, MD
MM Salvatore

Pathophysiology and Imaging Findings of COVID-19 Infection: An Organ-System Based Review

https://doi.org/10.1016/j.acra.2021.01.022

Published

3-Feb-21

REVIEW ARTICLE

https://www.academicradiology.org/article/S1076-6332(21)00031-3/fulltext

Though pulmonary findings are the most prevalent presentation, COVID-19 may have multiple manifestations and recognition of the extrapulmonary manifestations is especially important because of the potential serious and long-term effects of COVID-19 on multiple organ systems.

Les caractéristiques radiologiques en imagerie médicale de la covid sur un ensemble d'organes sont détaillées dans cette revue d'études, pointant des séquelles à long terme de l'infection.

N002

3425

MO09

Mingchao Zhu, Diliang Chen, Ya Zhu, Xusheng Xiong, Yan Ding, Feibo Guo, Mingan Zhu & Junyang Zhou

Long-term sero-positivity for IgG, sequelae of respiratory symptoms, and abundance of malformed sperms in a patient recovered from severe COVID-19

https://doi.org/10.1007/s10096-021-04178-6

Published

8-Feb-21

Brief Report

https://link.springer.com/article/10.1007/s10096-021-04178-6

The patient’s antiviral immunoglobulin G (IgG) continued to be positive for more than 11 months, and his small airway function was abnormal, and he suffered from respiratory problems (cough, chest pain, chest tightness, and shortness of breath), unstructured sleep apnea hypopnea syndrome, and nocturnal sleep hypoxemia. His abnormal sperm rate increased obviously, and sperm activity decreased obviously.

Des altérations des spermatozoïdes dues à la covid sont possibles, comme en témoigne cette étude de cas d'un patient touché par un taux de 96% de déformation des spermatozoïdes et d'une tératospermie.

N003R2

3426

MO10

Sandra Willia b Renata Lüthold b Adam Hunt b Nadescha Viviane Hänggi b Donikë Sejdiu b Camila Scaff b Nicole Bender b1 Kaspar Staub Patricia Schlagenhauf

COVID-19 Sequelae in adults aged less than 50 years: A Systematic Review

https://doi.org/10.1016/j.tmaid.2021.101995

Published

22-Feb-21

Review

https://www.sciencedirect.com/science/article/pii/S1477893921000363

Sequelae persistence since infection spanned 14 days to three months. Sequelae included persistent fatigue (39–73% of assessed persons), breathlessness (39–74%), decrease in quality of life (44–69%), impaired pulmonary function, abnormal CT findings including pulmonary fibrosis (39–83%), evidence of peri-/perimyo-/myocarditis (3–26%), changes in microstructural and functional brain integrity with persistent neurological symptoms (55%), increased incidence of psychiatric diagnoses (5.8% versus 2.5–3.4% in controls), incomplete recovery of olfactory and gustatory dysfunction (33–36% of evaluated persons).

Une revue d'études systématique des différentes séquelles à 3 mois chez les adultes de moins de 50 ans touchés par la covid, qui note l'importance des séquelles pulmonaires, cardiaques et neurologiques.

N003A

3427

MO11

Jia Liu, Yufeng Li, Qian Liu, Qun Yao, Xi Wang, Huanyu Zhang, Rong Chen, Liang Ren, Juan Min, Fei Deng, Bing Yan, Liang Liu, Zhihong Hu, Manli Wang & Yiwu Zhou

SARS-CoV-2 cell tropism and multiorgan infection

https://doi.org/10.1038/s41421-021-00249-2

Published

23-Mar-21

https://www.nature.com/articles/s41421-021-00249-2

In conclusion, our results identified SARS-CoV-2 cell tropism in multiple organs (Fig. 1e), indicating that SARS-CoV-2 infects not only the respiratory system (e.g., lungs and trachea) but also the kidneys, small intestines, pancreas, blood vessels, and other tissues. Recently, we disclosed that SARS-CoV-2 also targeted sweat glands and vascular endothelial cells in the skin15. These findings suggest that direct viral infection could, at least partially, contribute to multiorgan injury. Our results also proved a possible correlation between SARS-CoV-2 organotropism and ACE2 distribution, providing supporting evidence for the multiorgan infection of the virus. While our study was limited by its size, its sheds new light into the mechanism of viral infection/transmission and provides valuable information for COVID-19 control.

Un travail dans Nature relève des preuves indiquant que le système gastro-intestinal pourrait servir de voie de transmission du SARS-CoV-2 et avoir un effet d'amplification. L'étude note les cibles potentielles du virus, outre le système respiratoire : reins, intestin grêle, pancréas, vaisseaux sanguins, ainsi que d'autres organes et tissus évoqués plus récemment, comme les glandes sudoripares et les cellules endothéliales vasculaires de la peau.

N011

3428

MO12

Daniel Ayoubkhani, principal statistician1, Kamlesh Khunti, professor of primary care diabetes and vascular medicine2, Vahé Nafilyan, principal statistician1, Thomas Maddox, statistician1, Ben Humberstone, deputy director of health analysis and life events division1, Ian Diamond, UK national statistician1, Amitava Banerjee

Post-covid syndrome in individuals admitted to hospital with covid-19: retrospective cohort study

https://doi.org/10.1136/bmj.n693

Published

31-Mar-21

https://www.bmj.com/content/372/bmj.n693.full

Over a mean follow-up of 140 days, nearly a third of individuals who were discharged from hospital after acute covid-19 were readmitted (14 060 of 47 780) and more than 1 in 10 (5875) died after discharge, with these events occurring at rates four and eight times greater, respectively, than in the matched control group. Rates of respiratory disease (P<0.001), diabetes (P<0.001), and cardiovascular disease (P<0.001) were also significantly raised in patients with covid-19, with 770 (95% confidence interval 758 to 783), 127 (122 to 132), and 126 (121 to 131) diagnoses per 1000 person years, respectively. Rate ratios were greater for individuals aged less than 70 than for those aged 70 or older, and in ethnic minority groups compared with the white population, with the largest differences seen for respiratory disease (10.5 (95% confidence interval 9.7 to 11.4) for age less than 70 years v 4.6 (4.3 to 4.8) for age ≥70, and 11.4 (9.8 to 13.3) for non-white v 5.2 (5.0 to 5.5) for white individuals).

Conclusions Individuals discharged from hospital after covid-19 had increased rates of multiorgan dysfunction compared with the expected risk in the general population. The increase in risk was not confined to the elderly and was not uniform across ethnicities. The diagnosis, treatment, and prevention of post-covid syndrome requires integrated rather than organ or disease specific approaches, and urgent research is needed to establish the risk factors

_

3429

MO13

Vinod Nikhra

COVID-19 and Long Covid: Organs Damage and Dysfunctions, and Implications for Clinical Course

http://dx.doi.org/10.29328/ebook1005

Published

18-Oct-21

Article

https://www.researchgate.net/publication/355582623_COVID-19_and_Long_Covid_Organs_Damage_and_Dysfunctions_and_Implications_for_Clinical_Course

Like any other infectious disease, the prognosis of COVID-19 is in􀏐luenced by infecting agent, the SARS-CoV-2 virus load and the extent of organs af􀏐liction and damage. COVID-19 having a propensity for multiorgan involvement carries an adverse prognosis during the clinical course as well as later during the post-recovery period persisting as Long Covid. The direct cytopathic effects of SARS-CoV-2 virus and the erratic and hyper-in􀏐lammatory response lead to tissue injury in various organs coupled with physiological dysfunctions and complications. In fact, the multi-system manifestations of COVID-19 are caused by a combination of speci􀏐ic host defence responses with associated in􀏐lammatory activity and vascular involvement with coagulopathy and a distinct propensity to develop thromboembolic complications. Simultaneously, comorbidities such as diabetes, hypertension and cardiovascular diseases in􀏐luence the disease severity and mortality.

3430

MO14

Jude Savarraj, Eun S. Park, Gabriela D. Colpo, Sarah N. Hinds, Diego Morales, Hilda Ahnstedt, Atzhiry S. Paz, Andres Assing, Fudong Liu, Shivanki Juneja, Eunhee Kim, Sung-min Cho, Aaron M. Gusdon, Pramod Dash, Louise D. McCullough & H. Alex Choi

Brain injury, endothelial injury and inflammatory markers are elevated and express sex-specific alterations after COVID-19

https://doi.org/10.1186/s12974-021-02323-8

Published

27-Nov-21

Study

https://link.springer.com/article/10.1186/s12974-021-02323-8

The acute elevation of BIMs, CCs, and EIMs and the robust associations among them at COVID-19 hospitalization are suggestive of brain and endothelial injury. Higher BIM and inflammatory markers in men additionally suggest that men are more susceptible to the risk compared to women.

3431

MO15

VP

Akmaljon Odilov 1,* ,Alexey Volkov 1,2 ,Adhamjon Abdullaev 3 ,Tatiana Gasanova 4 ,Tatiana Lipina 5 andIgor Babichenko 1

COVID-19: Multiorgan Dissemination of SARS-CoV-2 Is Driven by Pulmonary Factors

https://doi.org/10.3390/v14010039

Published

26-Dec-21

Study

https://www.mdpi.com/1999-4915/14/1/39/htm

Multi-organ failure is one of the common causes of fatal outcome in COVID-19 patients. However, the pathogenetic association of the SARS-CoV-2 viral load (VL) level with fatal dysfunctions of the lungs, liver, kidneys, heart, spleen and brain, as well as with the risk of death in COVID-19 patients remains poorly understood. SARS-CoV-2 VL in the lungs, heart, liver, kidneys, brain, spleen and lymph nodes have been measured by RT qPCR using the following formula: NSARS-CoV−2/NABL1 × 100. Dissemination of SARS-CoV-2 in 30.5% of cases was mono-organ, and in 63.9% of cases, it was multi-organ. The average SARS-CoV-2 VL in the exudative phase of diffuse alveolar damage (DAD) was 60 times higher than in the proliferative phase. The SARS-CoV-2 VL in the lungs ranged from 0 to 250,281 copies. The “pulmonary factors” of SARS-CoV-2 multi-organ dissemination are the high level of SARS-CoV-2 VL (≥4909) and the exudative phase of DAD. The frequency of SARS-CoV-2 dissemination to lymph nodes was 86.9%, heart–56.5%, spleen–52.2%, liver–47.8%, kidney–26%, and brain–13%. We found no link between the SARS-CoV-2 VL level in the liver, kidneys, and heart and the serum level of CPK, LDH, ALP, ALT, AST and Cr of COVID-19 patients. Isolated detection of SARS-CoV-2 RNA in the myocardium of COVID-19 patients who died from heart failure is possible. The pathogenesis of COVID-19-associated multi-organ failure requires further research in a larger cohort of patients.

3432

MO16

Jovana Milic, Sara Barbieri, Licia Gozzi, Alberto Brigo, Bianca Beghé, Alessia Verduri, Erica Bacca, Vittorio Iadisernia, Gianluca Cuomo, Giovanni Dolci, Dina Yaacoub, Emanuele Aprile, Michella Belli, Maria Venuta, Marianna Meschiari, Giada Sebastiani, Enrico Clini, Cristina Mussini, Amedeo Lonardo, Giovanni Guaraldi, Paolo Raggi

Metabolic associated fatty liver disease is highly prevalent in the post-acute COVID syndrome

https://doi.org/10.1093/ofid/ofac003

Published

10-Jan-22

Study

https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofac003/6501509

We included 235 patients followed at a single university outpatient clinic. The diagnosis of PACS was based on ≥1 cluster of symptoms: respiratory, neurocognitive, musculoskeletal, psychological, sensory, dermatological. The outcome was prevalence of MAFLD detected by transient elastography during the first post-discharge follow-up outpatient visit. The prevalence of MAFLD at the time of hospital admission was calculated retrospectively using the hepatic steatosis index.
Results
Of 235 patients, 162 (69%) were men (median age 61). The prevalence of MAFLD was 55.3% at follow-up and 37.3% on admission (p<0.001). Insulin resistance (OR=1.5, 95%CI: 1.14-1.96), body mass index (OR=1.14, 95%CI: 1.04-1.24), and the metabolic syndrome (OR=2.54, 95%CI: 1.13-5.68), were independent predictors of MAFLD. The number of PACS clusters was inversely associated with MAFLD (OR=0.86, 95%CI: 0.76-0.97). Thirty-one patients (13.2%) had MAFLD with no other associated PACS clusters. All correlations between MAFLD and other PACS clusters were weak.
Conclusions
MAFLD was highly prevalent after hospital discharge and may represent a specific PACS-cluster phenotype, with potential long-term metabolic and cardiovascular health implications.

3433

MO17

Peter Novak MD, PhD,Shibani S. Mukerji MD, PhD,Haitham S. Alabsi DO,David Systrom MD,Sadie P. Marciano PA-C,Donna Felsenstein MD,William J. Mullally MD,David M. Pilgrim MD

Multisystem Involvement in Post-Acute Sequelae of Coronavirus Disease 19

https://doi.org/10.1002/ana.26286

Published

24-Dec-21

Study

https://onlinelibrary.wiley.com/doi/10.1002/ana.26286

Summary
Post-acute sequelae of coronavirus disease 2019 (COVID-19; PASC) is a complication of COVID-19 disease associated with chronic fatigue, brain fog and orthostatic intolerance. Pathophysiology of PASC is poorly understood.
This study evaluated patients with PASC following mild COVID-19 infection using standardized autonomic assessments, including Valsalva maneuver, deep breathing, sudomotor and tilt tests with cerebral blood flow velocity (CBFv) measurements, and skin biopsies for small fiber neuropathy (SFN).
This study showed that PASC following mild COVID-19 is associated with multisystem involvement, including cerebrovascular and respiratory dysregulation, small fiber neuropathy, and related dysautonomia and chronic inflammation.
Autonomic testing expanded for cerebrovascular measurements and skin biopsies can explain some of the PASC symptoms and could guide treatment.
Objective
The purpose of this study was to describe cerebrovascular, neuropathic, and autonomic features of post-acute sequelae of coronavirus disease 2019 ((COVID-19) PASC).
Methods
This retrospective study evaluated consecutive patients with chronic fatigue, brain fog, and orthostatic intolerance consistent with PASC. Controls included patients with postural tachycardia syndrome (POTS) and healthy participants. Analyzed data included surveys and autonomic (Valsalva maneuver, deep breathing, sudomotor, and tilt tests), cerebrovascular (cerebral blood flow velocity [CBFv] monitoring in middle cerebral artery), respiratory (capnography monitoring), and neuropathic (skin biopsies for assessment of small fiber neuropathy) testing and inflammatory/autoimmune markers.
Results
Nine patients with PASC were evaluated 0.8 ± 0.3 years after a mild COVID-19 infection, and were treated as home observations. Autonomic, pain, brain fog, fatigue, and dyspnea surveys were abnormal in PASC and POTS (n = 10), compared with controls (n = 15). Tilt table test reproduced the majority of PASC symptoms. Orthostatic CBFv declined in PASC (−20.0 ± 13.4%) and POTS (−20.3 ± 15.1%), compared with controls (−3.0 ± 7.5%, p = 0.001) and was independent of end-tidal carbon dioxide in PASC, but caused by hyperventilation in POTS. Reduced orthostatic CBFv in PASC included both subjects without (n = 6) and with (n = 3) orthostatic tachycardia. Dysautonomia was frequent (100% in both PASC and POTS) but was milder in PASC (p = 0.002). PASC and POTS cohorts diverged in frequency of small fiber neuropathy (89% vs 60%) but not in inflammatory markers (67% vs 70%). Supine and orthostatic hypocapnia was observed in PASC.
Interpretation
PASC following mild COVID-19 infection is associated with multisystem involvement including: (1) cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction; (2) small fiber neuropathy and related dysautonomia; (3) respiratory dysregulation; and (4) chronic inflammation. ANN NEUROL 2022

3434

MO18

Shunya Tsuji, Shohei Minami, Rina Hashimoto, Yusuke Konishi, Tatsuya Suzuki, Tamae Kondo, Miwa Sasai, Shiho Torii, Chikako Ono, Shintaro Shichinohe, Shintaro Sato, Masahiro Wakita, Shintaro Okumura, Sosuke Nakano, Tatsuyuki Matsudaira, Tomonori Matsumoto, Shimpei Kawamoto, Masahiro Yamamoto, Tokiko Watanabe, Yoshiharu Matsuura, Kazuo Takayama, Takeshi Kobayashi, Toru Okamoto & Eiji Hara

SARS-CoV-2 infection triggers paracrine senescence and leads to a sustained senescence-associated inflammatory response

https://doi.org/10.1038/s43587-022-00170-7

Published

25-Jan-22

Study

https://www.nature.com/articles/s43587-022-00170-7

Reports of post-acute COVID-19 syndrome, in which the inflammatory response persists even after SARS-CoV-2 has disappeared, are increasing1, but the underlying mechanisms of post-acute COVID-19 syndrome remain unknown. Here, we show that SARS-CoV-2-infected cells trigger senescence-like cell-cycle arrest2,3 in neighboring uninfected cells in a paracrine manner via virus-induced cytokine production. In cultured human cells or bronchial organoids, these SASR-CoV-2 infection-induced senescent cells express high levels of a series of inflammatory factors known as senescence-associated secretory phenotypes (SASPs)4 in a sustained manner, even after SARS-CoV-2 is no longer detectable. We also show that the expression of the senescence marker CDKN2A (refs. 5,6) and various SASP factor4 genes is increased in the pulmonary cells of patients with severe post-acute COVID-19 syndrome. Furthermore, we find that mice exposed to a mouse-adapted strain of SARS-CoV-2 exhibit prolonged signs of cellular senescence and SASP in the lung at 14 days after infection when the virus was undetectable, which could be substantially reduced by the administration of senolytic drugs7. The sustained infection-induced paracrine senescence described here may be involved in the long-term inflammation caused by SARS-CoV-2 infection.

3435

MO19

Maryam Kaviani1†, www.frontiersin.orgSomayeh Keshtkar1,2†, www.frontiersin.orgSaeede Soleimanian1, www.frontiersin.orgFatemeh Sabet Sarvestani1, www.frontiersin.orgNegar Azarpira1* and www.frontiersin.orgSara Pakbaz3

Susceptibility to Metabolic Diseases in COVID-19: To be or Not to be an Issue

https://doi.org/10.3389/fmolb.2022.803314

Published

3-Feb-22

Review

https://www.frontiersin.org/articles/10.3389/fmolb.2022.803314/full

Although COVID-19 primarily affects the lungs, multiple reports exist on the effect of this infection on the kidneys, cardiovascular system, and gastrointestinal tract. Studies have also indicated the increased risk of severe COVID-19 in patients with diabetes. On the other hand, COVID-19 may predispose patients to diabetes, as the most common metabolic disease. Recent studies have shown that Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) binds to Angiotensin-Converting Enzyme 2 (ACE2) receptors, which are expressed in the tissues and organs involved in regulating the metabolic status including pancreas, adipose tissue, gastrointestinal tract, and kidneys. Therefore, SARS-CoV-2 may result in metabolic disturbance. However, there are still many unknowns about SARS-CoV-2, which are required to be explored in basic studies. In this context, special attention to molecular pathways is warranted for understanding the pathogenesis of the disease and achieving therapeutic opportunities. Hence, the present review aims to focus on the molecular mechanisms associated with the susceptibility to metabolic diseases amongst patients recovered from COVID-19.

3436

MO20

Tom Norris
ORCHID logo
; Cameron Razieh; Thomas Yates; Francesco Zaccardi; Clare L. Gillies; Yogini V. Chudasama
ORCHID logo
; Alex Rowlands; Melanie J. Davies; Gerry P. McCann; Amitava Banerjee; Annemarie B. Docherty; Peter J.M. Openshaw; J. Kenneth Baillie; Malcolm G. Semple; Claire A. Lawson; Kamlesh Khunti

Admission Blood Glucose Level and Its Association With Cardiovascular and Renal Complications in Patients Hospitalized With COVID-19

https://doi.org/10.2337/dc21-1709

Published

11-Mar-22

Study

https://diabetesjournals.org/care/article/doi/10.2337/dc21-1709/144732

To investigate the association between admission blood glucose levels and risk of in-hospital cardiovascular and renal complications.
RESEARCH DESIGN AND METHODS
In this multicenter prospective study of 36,269 adults hospitalized with COVID-19 between 6 February 2020 and 16 March 2021 (N = 143,266), logistic regression models were used to explore associations between admission glucose level (mmol/L and mg/dL) and odds of in-hospital complications, including heart failure, arrhythmia, cardiac ischemia, cardiac arrest, coagulation complications, stroke, and renal injury. Nonlinearity was investigated using restricted cubic splines. Interaction models explored whether associations between glucose levels and complications were modified by clinically relevant factors.
RESULTS
Cardiovascular and renal complications occurred in 10,421 (28.7%) patients; median admission glucose level was 6.7 mmol/L (interquartile range 5.8–8.7) (120.6 mg/dL [104.4–156.6]). While accounting for confounders, for all complications except cardiac ischemia and stroke, there was a nonlinear association between glucose and cardiovascular and renal complications. For example, odds of heart failure, arrhythmia, coagulation complications, and renal injury decreased to a nadir at 6.4 mmol/L (115 mg/dL), 4.9 mmol/L (88.2 mg/dL), 4.7 mmol/L (84.6 mg/dL), and 5.8 mmol/L (104.4 mg/dL), respectively, and increased thereafter until 26.0 mmol/L (468 mg/dL), 50.0 mmol/L (900 mg/dL), 8.5 mmol/L (153 mg/dL), and 32.4 mmol/L (583.2 mg/dL). Compared with 5 mmol/L (90 mg/dL), odds ratios at these glucose levels were 1.28 (95% CI 0.96, 1.69) for heart failure, 2.23 (1.03, 4.81) for arrhythmia, 1.59 (1.36, 1.86) for coagulation complications, and 2.42 (2.01, 2.92) for renal injury. For most complications, a modifying effect of age was observed, with higher odds of complications at higher glucose levels for patients age <69 years. Preexisting diabetes status had a similar modifying effect on odds of complications, but evidence was strongest for renal injury, cardiac ischemia, and any cardiovascular/renal complication.
CONCLUSIONS
Increased odds of cardiovascular or renal complications were observed for admission glucose levels indicative of both hypo- and hyperglycemia. Admission glucose could be used as a marker for risk stratification of high-risk patients. Further research should evaluate interventions to optimize admission glucose on improving COVID-19 outcomes.

3437

MO21

Jan K. Hennigs, Tim Oqueka, Lars Harbaum & Hans Klose

Organbezogene Folgeerscheinungen von COVID‑19 bei Erwachsenen
Organ-specific sequelae of COVID-19 in adults

https://doi.org/10.1007/s00103-022-03513-2

Published

16-Mar-22

Review

https://link.springer.com/article/10.1007/s00103-022-03513-2

Organ-specific sequelae after COVID-19 occur frequently and are highly diverse in their features. Sequelae and symptoms persisting for more than four weeks after COVID-19 define the condition “long COVID.”
Organ-specific sequelae of COVID-19 generally occur more often after severe disease. Yet, duration and intensity of organ-specific sequelae are highly variable. While pulmonary sequelae typically persist after more severe acute disease, COVID-19 sequelae may also develop weeks after infection and can affect any organ. The degree of SARS-CoV‑2 specificity of COVID-19 sequelae, however, remains unclear. Thus, diagnosis and treatment of COVID-19 sequelae represent an interdisciplinary challenge. Diagnostic and therapeutic approaches are guided by type, extent, and cause of the specific sequelae as targeted therapy options for long COVID are lacking.
In the present work, we review current knowledge regarding the prevalence/incidence, duration, specificity, type, and extent of organ-specific COVID-19 sequelae and summarize current diagnostic and therapeutic strategies (as of November 2021).

3438

MO22

SavasOzturk1KenanTurgutalp2MustafaArici3NumanGorgulu4Halil ZekiTonbul5NecmiEren6VedatGencer7Mehmet DenizAyli8İremPembegul9Murside EsraDolarslan10ZeynepUral11HulyaColak12Tuba ElifOzler13OzgurCan14Mehmet EminDemir15OrcunAltunoren16BulentHuddam17KursadOnec18…KenanAtes29

The Longitudinal Evolution of Post-COVID-19 Outcomes Among Hemodialysis Patients in Turkey

https://doi.org/10.1016/j.ekir.2022.03.017

Published

25-Mar-22

Study

https://www.sciencedirect.com/science/article/pii/S2468024922012372

Background
Hemodialysis (HD) patients have increased risk for short-term adverse outcomes of COVID-19. However, complications and survival at the post-COVID-19 period have not been published extensively.
Methods
We conducted a national, multicenter observational study that included adult maintenance HD patients recovered from confirmed COVID-19. A control HD group without COVID-19 was selected from patients in the same center. We investigated the characteristics and outcomes in the follow-up of HD patients and compare them with the non-COVID group.
Results
A total of 1223 patients (635 patients in COVID-19 group, 588 patients in non-COVID group) from 47 centers were included in the study. The patients' baseline and HD characteristics were almost similar. 28th day mortality and mortality between 28th day-90th day were higher in the COVID-19 group than non-COVID group [19 (3.0%) patients vs. none (0%); 15 (2.4%) patients vs. 4 (0.7%) patients, respectively]. The presence of respiratory symptoms, rehospitalization, need for home oxygen therapy, lower respiratory tract infection, A-V fistula thrombosis were significantly higher in the COVID-19 group in both the first 28 days and between 28-90 days. In the multivariable analysis, age [Odds ratio (OR) (95% confidence interval[CI]): 1.029(1.004-1.056)], group (COVID-19 group vs. non-COVID group) [OR (95%CI): 7.258(2.538-20.751) and vascular access type (tunneled catheter/AV fistula) [OR(95%CI): 2.512 (1.249-5.051)] were found as independent parameters related to 90-day mortality.
Conclusion
In the post-COVID period, maintenance HD patients who have had COVID-19 have increased rehospitalization, respiratory problems, vascular access problems, and high mortality compared to the non-COVID HD patients.

3439

MO23

Adekunle Sanyaolu, Aleksandra Marinkovic, Stephanie Prakash, Anne Zhao, Vyshnavy Balendra, Nafees Haider, Isha Jain, Teodora Simic & Chuku Okorie

Post-acute Sequelae in COVID-19 Survivors: an Overview

https://doi.org/10.1007/s42399-022-01172-7

Published

6-Apr-22

Review

https://link.springer.com/article/10.1007/s42399-022-01172-7

In the acute phase of SARS-CoV-2 infection, varying degrees of clinical manifestations have been noticed in patients. Some patients who recovered from the infection developed long-term effects which have become of interest to the scientific and medical communities, as it relates to pathogenesis and the multidisciplinary approach to treatment. Long COVID (long-term or long-haul) is the collective term used to define recovered individuals of SARS-CoV-2 infection who have presented with persistent COVID symptoms, as well as the emergence of disorders and complications. Following the review of literature from major scientific databases, this paper investigated long COVID and the resulting post-sequela effects on survivors, regardless of initial disease severity. The clinical manifestations and multisystem complications of the disease specifically, cardiovascular, neurologic and psychologic, hematologic, pulmonary, dermatologic, and other ailments were discussed. Patients with chronic COVID-19 were found to experience heart thrombosis leading to myocardial infarction, inflammation, lung fibrosis, stroke, venous thromboembolism, arterial thromboembolism, “brain fog”, general mood dysfunctions, dermatological issues, and fatigue. As the disease continues to progress and spread, and with the emergence of new variants the management of these persisting symptoms will pose a challenge for healthcare providers and medical systems in the next period of the pandemic. However, more information is needed about long COVID, particularly concerning certain patient populations, variability in follow-up times, the prevalence of comorbidities, and the evolution of the spread of infection. Thus, continued research needs to be conducted concerning the disease pathology to develop preventative measures and management strategies to treat long COVID.

3440

MO24

Andrew J. Morrow, Robert Sykes, Alasdair McIntosh, Anna Kamdar, Catherine Bagot, Hannah K. Bayes, Kevin G. Blyth, Michael Briscoe, Heerajnarain Bulluck, David Carrick, Colin Church, David Corcoran, Iain Findlay, Vivienne B. Gibson, Lynsey Gillespie, Douglas Grieve, Pauline Hall Barrientos, Antonia Ho, Ninian N. Lang, Vera Lennie, David J. Lowe, Peter W. Macfarlane, Patrick B. Mark, Kaitlin J. Mayne, Alex McConnachie, Ross McGeoch, Christopher McGinley, Connor McKee, Sabrina Nordin, Alexander Payne, Alastair J. Rankin, Keith E. Robertson, Giles Roditi, Nicola Ryan, Naveed Sattar, Sarah Allwood-Spiers, David Stobo, Rhian M. Touyz, Gruschen Veldtman, Stuart Watkins, Sarah Weeden, Robin A. Weir, Paul Welsh, Ryan Wereski, CISCO-19 Consortium, Kenneth Mangion & Colin Berry

A multisystem, cardio-renal investigation of post-COVID-19 illness

https://doi.org/10.1038/s41591-022-01837-9

Published

23-May-22

Study

https://www.nature.com/articles/s41591-022-01837-9

The pathophysiology and trajectory of post-Coronavirus Disease 2019 (COVID-19) syndrome is uncertain. To clarify multisystem involvement, we undertook a prospective cohort study including patients who had been hospitalized with COVID-19 (ClinicalTrials.gov ID NCT04403607). Serial blood biomarkers, digital electrocardiography and patient-reported outcome measures were obtained in-hospital and at 28–60 days post-discharge when multisystem imaging using chest computed tomography with pulmonary and coronary angiography and cardio-renal magnetic resonance imaging was also obtained. Longer-term clinical outcomes were assessed using electronic health records. Compared to controls (n = 29), at 28–60 days post-discharge, people with COVID-19 (n = 159; mean age, 55 years; 43% female) had persisting evidence of cardio-renal involvement and hemostasis pathway activation. The adjudicated likelihood of myocarditis was ‘very likely’ in 21 (13%) patients, ‘probable’ in 65 (41%) patients, ‘unlikely’ in 56 (35%) patients and ‘not present’ in 17 (11%) patients. At 28–60 days post-discharge, COVID-19 was associated with worse health-related quality of life (EQ-5D-5L score 0.77 (0.23) versus 0.87 (0.20)), anxiety and depression (PHQ-4 total score 3.59 (3.71) versus 1.28 (2.67)) and aerobic exercise capacity reflected by predicted maximal oxygen utilization (20.0 (7.6) versus 29.5 (8.0) ml/kg/min) (all P < 0.01). During follow-up (mean, 450 days), 24 (15%) patients and two (7%) controls died or were rehospitalized, and 108 (68%) patients and seven (26%) controls received outpatient secondary care (P = 0.017). The illness trajectory of patients after hospitalization with COVID-19 includes persisting multisystem abnormalities and health impairments that could lead to substantial demand on healthcare services in the future.

3441

MO25

Colin Berry 1 and Kenneth Mangion 2

Multisystem involvement is common in post-COVID-19 syndrome

https://doi.org/10.1038/s41591-022-01838-8

Published

23-May-22

Research Briefing

https://www.nature.com/articles/s41591-022-01838-8

A prospective clinical study evaluating patients 28–60 days after hospitalization for COVID-19 reveals increased cardio-renal inflammation, reduced lung function and poorer self-reported clinical outcomes in patients relative to that in control participants.

3442

MO26

NICOLE EICHERT; ALISON TELFORD; ADRIANA ROCA-FERNANDEZ; AZLINDA HAMID; HELENA B. THOMAIDES-BREARS; ANDREA DENNIS; RAJARSHI BANERJEE; SARAH ALI; GAYA THANABALASINGHAM; GRAHAM KEMP; DANIEL CUTHBERTSON; AMITAVA BANERJEE

1166-P: Distinct Phenotypes of Multiorgan Abnormalities in Long COVID and Type 2 Diabetes Identified by Multiparametric Magnetic Resonance Imaging

https://doi.org/10.2337/db22-1166-P

Published

1-Jun-22

Study

https://diabetesjournals.org/diabetes/article/71/Supplement_1/1166-P/146323

Introduction: Both long COVID and Type 2 Diabetes (T2D) are multi-system conditions requiring multi-organ assessment to monitor organ health and detect co-morbidities earlier. Here, we defined multi-organ abnormalities in both patient groups with a rapid, non-contrast MRI scan.
Methods: We recruited 135 long COVID patients (NCT04369807) and 135 T2D patients (NCT04114682) . MRI data were acquired for organ-specific measures of size, fat deposition and fibroinflammation (CoverScan®, Perspectum Ltd.) . Reference values were based on 92 controls and published literature.
Results: There was a high prevalence of organ abnormality in both patient groups (Figure, left) , including increased fat deposition (steatosis) in liver, pancreas, and kidney (Figure, right) . 35% of T2D patients had clustering of abnormalities involving at least 2 organs, compared to 23% in long COVID. Abnormalities affecting the liver and renomegaly were more common in T2D than in long COVID. Considering only obese patients, liver fibroinflammation, hepatomegaly, and renomegaly remained significantly more prevalent in T2D than in long COVID.
Conclusion: Multi-organ MRI assessment can enrich the current blunt assessment of multi-system abnormalities in diverse disease states to inform earlier intervention and treatments.

3443

MO27

Justin J. Frere, Randal A. Serafini, Kerri D. Pryc, Shu Horiuchi, Daisy A. Hoagland, Rasmus Møller, Anne Ruiz, Albana Kodra, Jonathan B. Overdevest, Peter D. Canoll, Alain C. Borczuk, Vasuretha Chandar, Yaron Bram, Robert Schwartz, Stavros Lomvardas, Venetia Zachariou, Benjamin R. tenOever

SARS-CoV-2 infection in hamsters and humans results in lasting and unique systemic perturbations post recovery

https://doi.org/10.1126/scitranslmed.abq3059

Published

7-Jun-22

Study

https://www.science.org/doi/10.1126/scitranslmed.abq3059

The host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in prolonged pathologies collectively referred to as post-acute sequalae of COVID-19 (PASC) or long COVID. To better understand the mechanism underlying long COVID biology, we compared the short- and long-term systemic responses in the golden hamster following either SARS-CoV-2 or influenza A virus (IAV) infection. Results demonstrated that SARS-CoV-2 exceeded IAV in its capacity to cause permanent injury to the lung and kidney and uniquely impacted the olfactory bulb (OB) and epithelium (OE). Despite a lack of detectable infectious virus, the OB and OE demonstrated myeloid and T cell activation, proinflammatory cytokine production, and an interferon response that correlated with behavioral changes extending a month post viral clearance. These sustained transcriptional changes could also be corroborated from tissue isolated from individuals who recovered from COVID-19. These data highlight a molecular mechanism for persistent COVID-19 symptomology and provide a small animal model to explore future therapeutics.

3444

MO28

JihoonShinabShinichiroToyodaaShigekiNishitaniaToshiharuOnoderaaShiroFukudaaShunbunKitaacAtsunoriFukuharaacIichiroShimomuraa

SARS-CoV-2 infection impairs the insulin/IGF signaling pathway in the lung, liver, adipose tissue, and pancreatic cells via IRF1

https://doi.org/10.1016/j.metabol.2022.155236

Published

8-Jun-22

Study

https://www.sciencedirect.com/science/article/pii/S0026049522001147

Highlights
•SARS-CoV-2 infection impairs insulin/IGF signaling pathway genes in the host lung, liver, adipose tissue, and pancreatic cells in part by IRF1 activation.
•IRF1 gene expression is highly relevant to risk factors for severe COVID-19, such as older age, male sex, obesity, and diabetes.
•Critical patients with COVID-19 have higher IRF1 and lower insulin/IGF signaling pathway genes in whole blood.
•Hormonal interventions, such as DHT and DEX, may ameliorate the pathological traits in SARS-CoV-2 infectable cells and tissues.
Background
COVID-19 can cause multiple organ damages as well as metabolic abnormalities such as hyperglycemia, insulin resistance, and new onset of diabetes. The insulin/IGF signaling pathway plays an important role in regulating energy metabolism and cell survival, but little is known about the impact of SARS-CoV-2 infection. The aim of this work was to investigate whether SARS-CoV-2 infection impairs the insulin/IGF signaling pathway in the host cell/tissue, and if so, the potential mechanism and association with COVID-19 pathology.
Methods
To determine the impact of SARS-CoV-2 on insulin/IGF signaling pathway, we utilized transcriptome datasets of SARS-CoV-2 infected cells and tissues from public repositories for a wide range of high-throughput gene expression data: autopsy lungs from COVID-19 patients compared to the control from non-COVID-19 patients; lungs from a human ACE2 transgenic mouse infected with SARS-CoV-2 compared to the control infected with mock; human pluripotent stem cell (hPSC)-derived liver organoids infected with SARS-CoV-2; adipose tissues from a mouse model of COVID-19 overexpressing human ACE2 via adeno-associated virus serotype 9 (AAV9) compared to the control GFP after SARS-CoV-2 infection; iPS-derived human pancreatic cells infected with SARS-CoV-2 compared to the mock control. Gain and loss of IRF1 function models were established in HEK293T and/or Calu3 cells to evaluate the impact on insulin signaling. To understand the mechanistic regulation and relevance with COVID-19 risk factors, such as older age, male sex, obesity, and diabetes, several transcriptomes of human respiratory, metabolic, and endocrine cells and tissue were analyzed. To estimate the association with COVID-19 severity, whole blood transcriptomes of critical patients with COVID-19 compared to those of hospitalized noncritical patients with COVID-19.
Results
We found that SARS-CoV-2 infection impaired insulin/IGF signaling pathway genes, such as IRS, PI3K, AKT, mTOR, and MAPK, in the host lung, adipose tissue, and pancreatic cells. The impairments were attributed to interferon regulatory factor 1 (IRF1), and its gene expression was highly relevant to risk factors for severe COVID-19; increased with aging in the lung, specifically in men; augmented by obese and diabetic conditions in adipose tissue and pancreatic islets. IRF1 activation was significantly associated with the impaired insulin signaling in human cells. IRF1 intron variant rs17622656-A, which previously reported to associated with COVID-19 prevalence, increased the IRF1 gene expression in human tissue and frequently found in American and European population. Critical patients with COVID-19 exhibited higher IRF1 and lower insulin/IGF signaling pathway genes in the whole blood compared to hospitalized noncritical patients. Hormonal interventions, such as dihydrotestosterone and dexamethasone, ameliorated the pathological traits in SARS-CoV-2 infectable cells and tissues.
Conclusions
The present study provides the first scientific evidence that SARS-CoV-2 infection impairs the insulin/IGF signaling pathway in respiratory, metabolic, and endocrine cells and tissues. This feature likely contributes to COVID-19 severity with cell/tissue damage and metabolic abnormalities, which may be exacerbated in older, male, obese, or diabetic patients.

3445

MO29

CPET

Matthew S. Durstenfeld, View ORCID ProfileMichael J. Peluso, Punita Kaveti, Christopher Hill, Danny Li, Erica Sander, Shreya Swaminathan, Victor M. Arechiga, Kaiwen Sun, Yifei Ma, Victor Zepeda, Scott Lu, Sarah A Goldberg, Rebecca Hoh, Ahmed Chenna, Brandon C. Yee, John W. Winslow, View ORCID ProfileChristos J. Petropoulos, Sithu Win, J. Daniel Kelly, David V. Glidden, Timothy J. Henrich, View ORCID ProfileJeffrey N. Martin, Yoo Jin Lee, Mandar A. Aras, Carlin S. Long, Donald J. Grandis, View ORCID ProfileSteven G. Deeks, Priscilla Y. Hsue

Inflammation during early post-acute COVID-19 is associated with reduced exercise capacity and Long COVID symptoms after 1 year

https://doi.org/10.1101/2022.05.17.22275235

pre-print

1-Jun-22

Study

https://www.medrxiv.org/content/10.1101/2022.05.17.22275235v2

BACKGROUND Mechanisms underlying persistent cardiopulmonary symptoms following SARS-CoV-2 infection (post-acute sequelae of COVID-19 “PASC” or “Long COVID”) remain unclear. The purpose of this study was to elucidate the pathophysiology of cardiopulmonary PASC using multimodality cardiovascular imaging including cardiopulmonary exercise testing (CPET), cardiac magnetic resonance imaging (CMR) and ambulatory rhythm monitoring.
METHODS We performed CMR, CPET, and ambulatory rhythm monitoring among adults > 1 year after PCR-confirmed SARS-CoV-2 infection in the UCSF Long-Term Impact of Infection with Novel Coronavirus cohort (LIINC; NCT04362150) and correlated findings with previously measured biomarkers. We used logistic regression to estimate associations with PASC symptoms (dyspnea, chest pain, palpitations, and fatigue) adjusted for confounders and linear regression to estimate differences between those with and without symptoms adjusted for confounders.
RESULTS Out of 120 participants in the cohort, 46 participants (unselected for symptom status) had at least one advanced cardiac test performed at median 17 months following initial SARS-CoV-2 infection. Median age was 52 (IQR 42-61), 18 (39%) were female, and 6 (13%) were hospitalized for severe acute infection. On CMR (n=39), higher extracellular volume was associated with symptoms, but no evidence of late-gadolinium enhancement or differences in T1 or T2 mapping were demonstrated. We did not find arrhythmias on ambulatory monitoring. In contrast, on CPET (n=39), 13/23 (57%) with cardiopulmonary symptoms or fatigue had reduced exercise capacity (peak VO2<85% predicted) compared to 2/16 (13%) without symptoms (p=0.008). The adjusted difference in peak VO2 was 5.9 ml/kg/min lower (−9.6 to −2.3; p=0.002) or −21% predicted (−35 to −7; p=0.006) among those with symptoms. Chronotropic incompetence was the primary abnormality among 9/15 (60%) with reduced peak VO2. Adjusted heart rate reserve <80% was associated with reduced exercise capacity (OR 15.6, 95%CI 1.30-187; p=0.03). Inflammatory markers (hsCRP, IL-6, TNF-α) and SARS-CoV-2 antibody levels measured early in PASC were negatively correlated with peak VO2 more than 1 year later.
CONCLUSIONS Cardiopulmonary symptoms and elevated inflammatory markers present early in PASC are associated with objectively reduced exercise capacity measured on cardiopulmonary exercise testing more than 1 year following COVID-19. Chronotropic incompetence may explain reduced exercise capacity among some individuals with PASC.

3446

MO30

Mahavir Singh, Sathnur Pushpakumar, Nia Bard, Yuting Zheng, Rubens P. Homme, Sri Prakash L. Mokshagundam & Suresh C. Tyagi

Simulation of COVID-19 symptoms in a genetically engineered mouse model: implications for the long haulers

https://doi.org/10.1007/s11010-022-04487-0

Published

22-Jun-22

Study

https://link.springer.com/article/10.1007/s11010-022-04487-0

The ongoing pandemic (also known as coronavirus disease-19; COVID-19) by a constantly emerging viral agent commonly referred as the severe acute respiratory syndrome corona virus 2 or SARS-CoV-2 has revealed unique pathological findings from infected human beings, and the postmortem observations. The list of disease symptoms, and postmortem observations is too long to mention; however, SARS-CoV-2 has brought with it a whole new clinical syndrome in “long haulers” including dyspnea, chest pain, tachycardia, brain fog, exercise intolerance, and extreme fatigue. We opine that further improvement in delivering effective treatment, and preventive strategies would be benefited from validated animal disease models. In this context, we designed a study, and show that a genetically engineered mouse expressing the human angiotensin converting enzyme 2; ACE-2 (the receptor used by SARS-CoV-2 agent to enter host cells) represents an excellent investigative resource in simulating important clinical features of the COVID-19. The ACE-2 mouse model (which is susceptible to SARS-CoV-2) when administered with a recombinant SARS-CoV-2 spike protein (SP) intranasally exhibited a profound cytokine storm capable of altering the physiological parameters including significant changes in cardiac function along with multi-organ damage that was further confirmed via histological findings. More importantly, visceral organs from SP treated mice revealed thrombotic blood clots as seen during postmortem examination. Thus, the ACE-2 engineered mouse appears to be a suitable model for studying intimate viral pathogenesis thus paving the way for identification, and characterization of appropriate prophylactics as well as therapeutics for COVID-19 management.

3447

MO31

Kirsty Minton

Mechanistic insights into Long COVID in hamsters

https://doi.org/10.1038/s41577-022-00757-6

Published

29-Jun-22

Brief Report

https://www.nature.com/articles/s41577-022-00757-6

Using a golden hamster model, Frere et al. compared the short- and long-term responses to SARS-CoV-2 and influenza A virus (IAV) infection to better understand the mechanisms that account for persistent COVID-19 symptoms. At 3 days post infection (3dpi), both viruses induced a robust type I interferon response that cleared acute infection from the respiratory tract. Both viruses also induced an acute inflammatory response in peripheral tissues such as heart, kidney and lung, but by 31dpi (which would be defined as Long COVID in humans), SARS-CoV-2-infected hamsters had greater evidence of peripheral organ damage than IAV-infected hamsters. Furthermore, SARS-CoV-2-infected hamsters uniquely had prolonged inflammation in the olfaction system and various brain regions including striatum and cerebellum. This inflammation was evident in the absence of infectious virus and was associated with behavioural changes.

3448

MO32

Michael J. Paidas, Daniela S. Cosio, Saad Ali, Norma Sue Kenyon & Arumugam R. Jayakumar

Long-Term Sequelae of COVID-19 in Experimental Mice

https://doi.org/10.1007/s12035-022-02932-1

Published

13-Jul-22

Study

https://link.springer.com/article/10.1007/s12035-022-02932-1

We recently reported acute COVID-19 symptoms, clinical status, weight loss, multi-organ pathological changes, and animal death in a murine hepatitis virus-1 (MHV-1) coronavirus mouse model of COVID-19, which were similar to that observed in humans with COVID-19. We further examined long-term (12 months post-infection) sequelae of COVID-19 in these mice. Congested blood vessels, perivascular cavitation, pericellular halos, vacuolation of neuropils, pyknotic nuclei, acute eosinophilic necrosis, necrotic neurons with fragmented nuclei, and vacuolation were observed in the brain cortex 12 months post-MHV-1 infection. These changes were associated with increased reactive astrocytes and microglia, hyperphosphorylated TDP-43 and tau, and a decrease in synaptic protein synaptophysin-1, suggesting the possible long-term impact of SARS-CoV-2 infection on defective neuronal integrity. The lungs showed severe inflammation, bronchiolar airway wall thickening due to fibrotic remodeling, bronchioles with increased numbers of goblet cells in the epithelial lining, and bronchiole walls with increased numbers of inflammatory cells. Hearts showed severe interstitial edema, vascular congestion and dilation, nucleated red blood cells (RBCs), RBCs infiltrating between degenerative myocardial fibers, inflammatory cells and apoptotic bodies and acute myocyte necrosis, hypertrophy, and fibrosis. Long-term changes in the liver and kidney were less severe than those observed in the acute phase. Noteworthy, the treatment of infected mice with a small molecule synthetic peptide which prevents the binding of spike protein to its respective receptors significantly attenuated disease progression, as well as the pathological changes observed post-long-term infection. Collectively, these findings suggest that COVID-19 may result in long-term, irreversible changes predominantly in the brain, lung, and heart.

3449

MO33

Angela R.ShihMDaJosephMisdrajiMDb

COVID-19: Gastrointestinal and Hepatobiliary Manifestations

https://doi.org/10.1016/j.humpath.2022.07.006

Published

16-Jul-22

Review

https://www.sciencedirect.com/science/article/pii/S0046817722001794

SARS-CoV-2 is the viral agent of COVID-19, a pandemic that surfaced in 2019. While predominantly a respiratory ailment, patients with COVID-19 can have gastrointestinal and hepatobiliary manifestations. These manifestations are often mild and transient, but they can be severe and consequential. In the gastrointestinal tract, ischemic enterocolitis is the most common and significant consequence of COVID-19. In the liver, the reported pathologic findings may often be related to consequences of severe systemic viral infection, but reports of hepatitis presumed to be due to SARS-CoV-2 suggest that direct viral infection of the liver may be a rare complication of COVID-19. In both the GI tract and liver, lingering symptoms of GI or hepatic injury after resolution of pulmonary infection may be part of the evolving spectrum of long COVID.

3450

MO34

Luigi di Filippo, Stefano Frara, Mauro Doga & Andrea Giustina

The osteo-metabolic phenotype of COVID-19: an update

https://doi.org/10.1007/s12020-022-03135-3

Published

20-Jul-22

Review

https://link.springer.com/article/10.1007/s12020-022-03135-3

Context
In the multifaceted COVID-19 clinical scenario characterized by a multi-system disorder with negative implications not only on respiratory function but also on cardiac, hematological, neurological and endocrine-metabolic systems, a distinctive osteo-metabolic phenotype with an independent influence on disease severity and recovery of patients affected was early reported.
Aim
To summarize and update the main evidences regarding the distinct components of this phenotype in acute and Long COVID-19, reinforcing its clinical relevance and discussing the main pathophysiological and clinical-therapeutic implications of the most recent reported findings.
Results
This emerging phenotype is characterized by a widespread acute hypocalcemia and hypovitaminosis D with an impaired compensatory parathyroid hormone response, and a high prevalence of skeletal complications such as vertebral fractures. The clinical relevance of this osteo-metabolic phenotype on acute COVID-19 is well characterized, and novel seminal evidences are progressively highlighting its importance also in predicting patient’s long-term outcomes and Long COVID-19 occurrence.
Conclusions
These findings reinforced the central role of a multidisciplinary team, including endocrinologists, in evaluating these patients for a proactive search of each aspect of the osteo-metabolic phenotype components since they may represent suitable therapeutic targets to prevent SARS-CoV-2 infection, poor COVID-19 outcomes, Long COVID-19 occurrence and even possibly better responses to COVID-19 vaccination.

3451

MO35

Francesco Bandera

Return to high-hazard occupations after COVID-19 infection: a cardiopulmonary assessment approach

https://doi.org/10.1093/eurjpc/zwac072

Published

11-Aug-22

Editorial

https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac072/6659216

This editorial refers to ‘Cardiopulmonary assessment prior to returning to high-hazard occupations post symptomatic COVID-19 infection : a position statement of the Aviation and Occupational Cardiology Task Force of the European Association of Preventive Cardiology’ by R. Rienks et al.https://doi.org/doi:10.1093/eurjpc/zwac041.
Since the first outbreak of severe acute respiratory syndrome–related coronavirus 2 in late 2019, and across its progressive spreading to pandemic, medical community has been making constant progresses in prevention, treatment and management of COVID-19 disease. Beyond the efforts to fight the virus spread and to cure the acute infection, the need of bringing back people recovered from COVID-19 to their life has become a priority. Indeed, even if the majority of COVID-19 infections recovers without residual symptoms, a variable percentage of patients experiences the ‘post-COVID-19 syndrome’—a wide spectrum of long-lasting (beyond 12 weeks) clinical manifestations, including cardiopulmonary, renal and neurological problems.1 The prevalence and the severity of post-COVID-19 syndrome are related to the age and the frailty of the subjects, occurring more frequently after severe diseases requiring prolonged hospitalization. Nevertheless, it does not affect only elderly people, being diagnosed in about 40% of subjects between 18 and 49 years.2 Therefore, the need of evaluate active workers before reincorporation, providing a certification or simply reassuring the patient, is a frequent task common to general practitioners and specialists.

3452

MO36

Young Hyun Che1, Yong Jun Kim1,2,3

Understanding the cellular pathogenesis of COVID-19 symptoms using organoid technology

https://doi.org/10.51335/organoid.2022.2.e16

Published

25-Jun-22

Review

https://j-organoid.org/journal/view.php?doi=10.51335/organoid.2022.2.e16

Patients with coronavirus disease 2019 (COVID-19), which has recently caused a pandemic, have reported symptoms of coronavirus infection that are not well understood by the medical community in general. After severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, several symptoms, including acute clinical signs and possible sequelae, manifest in multiple organs. It is necessary to precisely identify the cells susceptible to SARS-CoV-2 infection in order to comprehend the mechanism of symptom occurrence, identify molecular targets for therapeutic development, and prevent current or future threats. Following the use of cell lines, animal models, and stem cell-derived symptom-relevant cells, recent research on the pathophysiology of human diseases has utilized organoid models. This article provides a summary of recent research on the tissue- or organ-specific cellular targets of SARS-CoV-2 aiming to understand the pathophysiology of COVID-19.

3453

MO37

Nicholas L. DePace & Joe Colombo

Long-COVID Syndrome and the Cardiovascular System: A Review of Neurocardiologic Effects on Multiple Systems

https://doi.org/10.1007/s11886-022-01786-2

Published

30-Sep-22

Review

https://link.springer.com/article/10.1007/s11886-022-01786-2

Purpose of Review
Long-COVID syndrome is a multi-organ disorder that persists beyond 12 weeks post-acute SARS-CoV-2 infection (COVID-19). Here, we provide a definition for this syndrome and discuss neuro-cardiology involvement due to the effects of (1) angiotensin-converting enzyme 2 receptors (the entry points for the virus), (2) inflammation, and (3) oxidative stress (the resultant effects of the virus).

Recent Findings
These effects may produce a spectrum of cardio-neuro effects (e.g., myocardial injury, primary arrhythmia, and cardiac symptoms due to autonomic dysfunction) which may affect all systems of the body. We discuss the symptoms and suggest therapies that target the underlying autonomic dysfunction to relieve the symptoms rather than merely treating symptoms. In addition to treating the autonomic dysfunction, the therapy also treats chronic inflammation and oxidative stress. Together with a full noninvasive cardiac workup, a full assessment of the autonomic nervous system, specifying parasympathetic and sympathetic (P&S) activity, both at rest and in response to challenges, is recommended. Cardiac symptoms must be treated directly. Cardiac treatment is often facilitated by treating the P&S dysfunction. Cardiac symptoms of dyspnea, chest pain, and palpitations, for example, need to be assessed objectively to differentiate cardiac from neural (autonomic) etiology.

Summary
Long-term myocardial injury commonly involves P&S dysfunction. P&S assessment usually connects symptoms of Long-COVID to the documented autonomic dysfunction(s).

3454

MO38

Ali A.Rizvia1AmitaKathuriaaWaelAl MahmeedbKhalidAl-RasadicKamilaAl-AlawidMaciejBanachefgYajnavalkaBanerjeehAntonioCerielloiMustafaCesurjFrancescoCosentinokMassimoGalialSu-YenGohmAndrejJaneznSanjayKalraoPeterKemplerpNaderLessanqPauloLotuforNikolaosPapanassRaul D.SantostuAnca P.StoianvPeter P.TothwVijayViswanathanxManfrediRizzoy1

Post-COVID syndrome, inflammation, and diabetes

https://doi.org/10.1016/j.jdiacomp.2022.108336

Published

6-Oct-22

Article

https://www.sciencedirect.com/science/article/pii/S1056872722002483

Highlights
•SARS CoV 2 infection beyond the acute phase may continue to cause symptoms that together form the so-called “Long COVID” or “Post-COVID Syndrome”
•The pathophysiologic mechanisms involve a heightened systemic inflammatory state, cardiometabolic derangements, and glucose intolerance
•Significant hyperglycemia leading to new-onset diabetes or worsening of preexisting disease may occur
•The prediction, course, and management of COVID-related hyperglycemia remain to be fully elucidated
Abstract
The raging COVID-19 pandemic is in its third year of global impact. The SARS CoV 2 virus has a high rate of spread, protean manifestations, and a high morbidity and mortality in individuals with predisposing risk factors. The pathophysiologic mechanisms involve a heightened systemic inflammatory state, cardiometabolic derangements, and varying degrees of glucose intolerance. The latter can be evident as significant hyperglycemia leading to new-onset diabetes or worsening of preexisting disease. Unfortunately, the clinical course beyond the acute phase of the illness may persist in the form of a variety of symptoms that together form the so-called “Long COVID” or “Post-COVID Syndrome”. It is thought that a chronic, low-grade inflammatory and immunologic state persists during this phase, which may last for weeks or months. Although numerous insights have been gained into COVID-related hyperglycemia and diabetes, its prediction, course, and management remain to be fully elucidated.

3455

MO39

Nina L. Stute,Rachel E. Szeghy,Jonathon L. Stickford,Valesha P. Province,Marc A. Augenreich,Stephen M. Ratchford,Abigail S. L. Stickford

Longitudinal observations of sympathetic neural activity and hemodynamics during 6 months recovery from SARS-CoV-2 infection

https://doi.org/10.14814/phy2.15423

Published

23-Sep-22

Study

https://physoc.onlinelibrary.wiley.com/doi/10.14814/phy2.15423

Cross-sectional data indicate that acute SARS-CoV-2 infection increases resting muscle sympathetic nerve activity (MSNA) and alters hemodynamic responses to orthostasis in young adults. However, the longitudinal impact of contracting SARS-CoV-2 on autonomic function remains unclear. The aim of this study was to longitudinally track MSNA, sympathetic transduction to blood pressure (BP), and hemodynamics over 6 months following SARS-CoV-2 infection. Young adults positive with SARS-CoV-2 reported to the laboratory three times over 6 months (V1:41 ± 17, V2:108 ± 21, V3:173 ± 16 days post-infection). MSNA, systolic (SBP) and diastolic (DBP) blood pressure, and heart rate (HR) were measured at rest, during a cold pressor test (CPT), and at 30° head-up tilt (HUT). Basal SBP (p = 0.019) and DBP (p < 0.001) decreased throughout the 6 months, whereas basal MSNA and HR were not different. Basal sympathetic transduction to BP and estimates of baroreflex sensitivity did not change over time. SBP and DBP were lower during CPT (SBP: p = 0.016, DBP: p = 0.007) and HUT at V3 compared with V1 (SBP: p = 0.041, DBP: p = 0.017), with largely no changes in MSNA. There was a trend toward a visit-by-time interaction for burst incidence (p = 0.055) during HUT, wherein at baseline immediately prior to tilting, burst incidence was lower at V3 compared with V1 (p = 0.014), but there were no differences between visits in the 30 HUT position. These results support impairments to cardiovascular health, and potentially autonomic function, which may improve over time. However, the improvements in BP over 6 months recovery from mild SARS-CoV-2 infection are likely not a direct result of changes in sympathetic activity.

3456

MO40

Eulogio Pleguezuelos, Amin Del Carmen, Eva Moreno, Pilar Ortega, Alejandro Robles, Mateo Serra-Prat, Marc Miravitlles, Joan Carles Yebenes & Manuel V. Garnacho-Castaño

Impaired pulmonary and muscle function during moderate exercise in female patients recovered from SARS-CoV-2

https://doi.org/10.1038/s41598-022-24941-9

Published

4-Dec-22

Study

https://www.nature.com/articles/s41598-022-24941-9

This study aimed to assess pulmonary and muscle dysfunction by analyzing the slow component of oxygen uptake (VO2SC), and mechanical and ventilatory efficiency in adult women recovered from the severe acute respiratory syndrome coronavirus type II (SARS-CoV-2) during a constant load test. 32 women (N = 17 patients with SARS-CoV-2; N = 15 control group) performed two cardiopulmonary exercise tests (CPX) on a cycle ergometer. In the first test, the participants performed incremental CPX until extenuation. In the second test the participants performed a 10-min CPX at a constant load intensity (watts) corresponding to the first ventilatory threshold. There was a 48–72 h rest period between the two tests. There was a significant increase in the VO2SC in the patients recovered from SARS-CoV-2 (160.4 ± 60 mL min−1) in comparison with the healthy participants (59.6 ± 65 mL min−1) (P < 0.001). Mechanical efficiency significantly decreased in patients recovered from SARS-CoV-2 compared to the control group (P = 0.04). Ventilatory inefficiency significantly increased in the patients recovered from SARS-CoV-2 compared with the control group (P < 0.001). Adult women recovered from SARS-CoV-2 infection have important pulmonary and muscular dysfunction and fatigue which contributes to increasing the VO2SC and reducing mechanical and ventilatory efficiency during mild-moderate exercise at a constant load.

3457

MO41

Babity, Mate; Zamodics, Mark; Konig, Albert; Kiss, Anna Reka; Horvath, Marton; Gregor, Zsofia; Rakoczi, Reka; Kovacs, Eva; Fabian, Alexandra; Tokodi, Marton; Sydo, Nora; Csulak, Emese; Juhasz, Vencel; Lakatos, Balint Karoly; Vago, Hajnalka; Kovacs, Attila; Merkely, Bela; Kiss, Orsolya

Cardiopulmonary examinations of athletes returning to high-intensity sport activity following SARS-CoV-2 infection

https://doi.org/10.1038/s41598-022-24486-x

Published

Study

https://www.nature.com/articles/s41598-022-24486-x

After SARS-CoV-2 infection, strict recommendations for return-to-sport were published. However, data are insufficient about the long-term effects on athletic performance. After suffering SARS-CoV-2 infection, and returning to maximal-intensity trainings, control examinations were performed with vita-maxima cardiopulmonary exercise testing (CPET). From various sports, 165 asymptomatic elite athletes (male: 122, age: 20y (IQR: 17-24y), training:16 h/w (IQR: 12–20 h/w), follow-up:93.5 days (IQR: 66.8–130.0 days) were examined. During CPET examinations, athletes achieved 94.7 ± 4.3% of maximal heart rate, 50.9 ± 6.0 mL/kg/min maximal oxygen uptake (V̇O2max), and 143.7 ± 30.4L/min maximal ventilation. Exercise induced arrhythmias (n = 7), significant horizontal/descending ST-depression (n = 3), ischemic heart disease (n = 1), hypertension (n = 7), slightly elevated pulmonary pressure (n = 2), and training-related hs-Troponin-T increase (n = 1) were revealed. Self-controlled CPET comparisons were performed in 62 athletes: due to intensive re-building training, exercise time, V̇O2max and ventilation increased compared to pre-COVID-19 results. However, exercise capacity decreased in 6 athletes. Further 18 athletes with ongoing minor long post-COVID symptoms, pathological ECG (ischemic ST-T changes, and arrhythmias) or laboratory findings (hsTroponin-T elevation) were controlled. Previous SARS-CoV-2-related myocarditis (n = 1), ischaemic heart disease (n = 1), anomalous coronary artery origin (n = 1), significant ventricular (n = 2) or atrial (n = 1) arrhythmias were diagnosed. Three months after SARS-CoV-2 infection, most of the athletes had satisfactory fitness levels. Some cases with SARS-CoV-2 related or not related pathologies requiring further examinations, treatment, or follow-up were revealed.

3458

MO42

Khreefa, Zaid; Barbier, Mallory T.; Koksal, Ali Riza; Love, Gordon; Del Valle, Luis

Pathogenesis and Mechanisms of SARS-CoV-2 Infection in the Intestine, Liver, and Pancreas

https://doi.org/10.3390/cells12020262

Published

1-Jan-23

Review

https://www.mdpi.com/2073-4409/12/2/262

The novel coronavirus, SARS-CoV-2, rapidly spread worldwide, causing an ongoing global pandemic. While the respiratory system is the most common site of infection, a significant number of reported cases indicate gastrointestinal (GI) involvement. GI symptoms include anorexia, abdominal pain, nausea, vomiting, and diarrhea. Although the mechanisms of GI pathogenesis are still being examined, viral components isolated from stool samples of infected patients suggest a potential fecal–oral transmission route. In addition, viral RNA has been detected in blood samples of infected patients, making hematologic dissemination of the virus a proposed route for GI involvement. Angiotensin-converting enzyme 2 (ACE2) receptors serve as the cellular entry mechanism for the virus, and these receptors are particularly abundant throughout the GI tract, making the intestine, liver, and pancreas potential extrapulmonary sites for infection and reservoirs sites for developing mutations and new variants that contribute to the uncontrolled spread of the disease and resistance to treatments. This transmission mechanism and the dysregulation of the immune system play a significant role in the profound inflammatory and coagulative cascades that contribute to the increased severity and risk of death in several COVID-19 patients. This article reviews various potential mechanisms of gastrointestinal, liver, and pancreatic injury.

3459

MO43

Balasubramaniam, Arun; Tedbury, Philip R.; Mwangi, Simon M.; Liu, Yunshan; Li, Ge; Merlin, Didier; Gracz, Adam D.; He, Peijian; Sarafianos, Stefan G.; Srinivasan, Shanthi

SARS-CoV-2 Induces Epithelial-Enteric Neuronal Crosstalk Stimulating VIP Release

https://doi.org/10.3390/biom13020207

Published

1-Feb-23

Study

https://www.mdpi.com/2218-273X/13/2/207

Background: Diarrhea is present in up to 30–50% of patients with COVID-19. The mechanism of SARS-CoV-2-induced diarrhea remains unclear. We hypothesized that enterocyte–enteric neuron interactions were important in SARS-CoV-2-induced diarrhea. SARS-CoV-2 induces endoplasmic reticulum (ER) stress in enterocytes causing the release of damage associated molecular patterns (DAMPs). The DAMPs then stimulate the release of enteric neurotransmitters that disrupt gut electrolyte homeostasis. Methods: Primary mouse enteric neurons (EN) were exposed to a conditioned medium from ACE2-expressing Caco-2 colonic epithelial cells infected with SARS-CoV-2 or treated with tunicamycin (ER stress inducer). Vasoactive intestinal peptides (VIP) expression and secretion by EN were assessed by RT-PCR and ELISA, respectively. Membrane expression of NHE3 was determined by surface biotinylation. Results: SARS-CoV-2 infection led to increased expression of BiP/GRP78, a marker and key regulator for ER stress in Caco-2 cells. Infected cells secreted the DAMP protein, heat shock protein 70 (HSP70), into the culture media, as revealed by proteomic and Western analyses. The expression of VIP mRNA in EN was up-regulated after treatment with a conditioned medium of SARS-CoV-2-infected Caco-2 cells. CD91, a receptor for HSP70, is abundantly expressed in the cultured mouse EN. Tunicamycin, an inducer of ER stress, also induced the release of HSP70 and Xbp1s, mimicking SARS-CoV-2 infection. Co-treatment of Caco-2 with tunicamycin (apical) and VIP (basolateral) induced a synergistic decrease in membrane expression of Na+/H+ exchanger (NHE3), an important transporter that mediates intestinal Na+/fluid absorption. Conclusions: Our findings demonstrate that SARS-CoV-2 enterocyte infection leads to ER stress and the release of DAMPs that up-regulates the expression and release of VIP by EN. VIP in turn inhibits fluid absorption through the downregulation of brush-border membrane expression of NHE3 in enterocytes. These data highlight the role of epithelial-enteric neuronal crosstalk in COVID-19-related diarrhea.

3460

MO44

Rizvi, Anam; Ziv, Yonatan; Crawford, James M.; Trindade, Arvind J.

Gastrointestinal and Hepatobiliary Symptoms and Disorders with Long (Chronic) COVID Infection

https://doi.org/10.1016/j.gtc.2022.09.002

Published

1-Mar-23

Review

https://www.gastro.theclinics.com/article/S0889-8553(22)00066-8/fulltext

Long (chronic) COVID syndrome is an evolving multisystem disease occurring 4 to 12 weeks after acute COVID-19 infection.
•Gastrointestinal (GI) and hepatobiliary manifestations of long COVID syndrome are common.
•Abdominal pain, nausea and vomiting, diarrhea, constipation, loss of taste, loss of appetite, weight loss, postinfectious irritable bowel syndrome, dyspepsia, and post-COVID cholangiopathy are GI and hepatobiliary sequelae of long COVID syndrome.
•Vaccination against COVID-19 is currently the best measure to prevent long COVID sequelae.
•Long COVID is likely to pose a significant strain on the health-care system in terms of outpatient care and economic costs in the future.
Background
The COVID-19 pandemic has affected more than 590 million people with about 6 million deaths worldwide to date.1 For many COVID-19 infection has been a transient and acute illness. However, some have experienced a persistence or new development of symptoms not attributable to alternative causes. This has created a new medical disease/syndrome to characterize a postacute COVID-19 syndrome now known as “long COVID,” which is referred to throughout this review (other designations include post–COVID-19 syndrome, post-COVID conditions, postacute COVID-19, or chronic COVID).2 Evidence is accumulating that long COVID is a multiorgan disease, involving the cardiopulmonary, neurologic, gastrointestinal (GI), nephrological, and other systems.3,4 Substantial debate exists regarding the delineation of long COVID syndrome. The National Institute for Health and Care Excellence defines long COVID as sustained symptoms after acute COVID-19, not attributable to alternative diagnoses, including symptomatic COVID-19 from more than 4 to 12 weeks and post–COVID-19 syndrome more than 12 weeks postinfection.5 The US Centers for Disease Control and Prevention (CDC) demarcates long COVID as prolonged sequelae greater than 4 weeks postinfection.6 Due to varying definitions, the prevalence of long COVID syndrome is reported with a wide range from 10% to 87% of patients who were afflicted with COVID-19 infection.3,7,8 If a 10% prevalence is selected more than 50 million patients would be afflicted with long-COVID.9
The associated risk factors and precipitants of long COVID syndrome remain abstruse. Although poor baseline health and severe acute COVID-19 illness have been associated with the development of long COVID,10 puzzlingly it also frequently occurs in patients with mild-to-moderate disease not requiring critical care or respiratory support.11, 12, 13, 14
It is apparent though that long COVID is likely to herald growing challenges to the health-care system.6,15 Long COVID syndrome has extensive economic influence because residual symptoms can cause a loss of quality of life and earnings and an increase in medical spending. The incidence, costs, and impact of long COVID are continually being revised so the impact is difficult to estimate. Recent estimates suggest that long COVID syndrome could cost up to USD 3.7 trillion, with 59% of the total cost secondary to loss of quality of life. For perspective, the economic cost would rival the cost of the Great Recession.16,17 This cost amounts to USD 11,000 per person, or approximately 17% of the pre-COVID US gross domestic product (GDP).16,17 In this case, the increased health-care utilization alone would cost USD 528 billion in total.16,17 Patient’s self-reported experiences agree with these estimates as surveys from the COVID-19 Longhauler Advocacy Project suggest that more than 42% of patients with long COVID have medical bills more than USD 5000 and 51% are able to work fewer hours due to long COVID.18
This article reviews long-COVID syndrome in relation to the GI and hepatobiliary systems.

3461

MO45

Gareau, Mélanie G.; Barrett, Kim E.

Role of the microbiota-gut-brain axis in postacute COVID syndrome

https://doi.org/10.1152/ajpgi.00293.2022

Published

1-Apr-23

Review

https://journals.physiology.org/doi/full/10.1152/ajpgi.00293.2022

The COVID-19 pandemic has resulted in the infection of hundreds of millions of individuals over the past 3 years, coupled with millions of deaths. Along with these more acute impacts of infection, a large subset of patients has developed symptoms that collectively comprise “postacute sequelae of COVID-19” (PASC, also known as long COVID), which can persist for months and maybe even years. In this review, we outline the current knowledge on the role of impaired microbiota-gut-brain (MGB) axis signaling in the development of PASC and the potential mechanisms involved, which may lead to a better understanding of disease progression and treatment options in the future.

3462

MO46

Vaz, Nuno; Franquet, Elisa; Heidari, Pedram; Chow, David Z.; Jacene, Heather A.; Ng, Thomas S. C.

COVID-19: Findings in nuclear medicine from head to toe

https://doi.org/10.1016/j.clinimag.2023.04.003

Published

1-Jul-23

Article

https://www.sciencedirect.com/science/article/pii/S0899707123000797

Highlights
•Clinical and imaging manifestations of COVID-19 may occur outside of the respiratory tract and extend beyond the acute phase.
•Evidence of inflammation involving any organ system should be carefully sought in patients with known or suspected COVID-19.
•The most common nuclear imaging finding of COVID-19 vaccination is hypermetabolic axillary lymphadenopathy.
Abstract
COVID-19 is a multisystemic disease, and hence its potential manifestations on nuclear medicine imaging can extend beyond the lung. Therefore, it is important for the nuclear medicine physician to recognize these manifestations in the clinic. While FDG-PET/CT is not indicated routinely in COVID-19 evaluation, its unique capability to provide a functional and anatomical assessment of the entire body means that it can be a powerful tool to monitor acute, subacute, and long-term effects of COVID-19. Single-photon scintigraphy is routinely used to assess conditions such as pulmonary embolism, cardiac ischemia, and thyroiditis, and COVID-19 may present in these studies. The most common nuclear imaging finding of COVID-19 vaccination to date is hypermetabolic axillary lymphadenopathy. This may pose important diagnostic and management dilemmas in oncologic patients, particularly those with malignancies where the axilla constitutes a lymphatic drainage area. This article aims to summarize the relevant literature published since the beginning of the pandemic on the intersection between COVID-19 and nuclear medicine.

3463

MO47

Joseph, Phillip; Singh, Inderjit; Oliveira, Rudolf; Capone, Christine A.; Mullen, Mary P.; Cook, Dane B.; Stovall, Mary Catherine; Squires, Johanna; Madsen, Kristine; Waxman, Aaron B.; Systrom, David M.

Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-Acute Sequelae of SARS-CoV-2: More in Common Than Not?

https://doi.org/10.1016/j.chest.2023.03.049

Published

11-Apr-23

Review

https://journal.chestnet.org/article/S0012-3692(23)00502-0/abstract

<h2>ABSTRACT</h2><h3>Topic Importance</h3><p>Post-Acute Sequelae of SARS-CoV-2 (PASC) is a long-term consequence of acute infection from coronavirus disease 2019 (COVID-19). Clinical overlap between PASC and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been observed, with shared symptoms including intractable fatigue, postexertional malaise, and orthostatic intolerance. The mechanistic underpinnings of such symptoms are poorly understood.</p><h3>Review Findings</h3><p>Early studies suggest deconditioning as the primary explanation for exertional intolerance in PASC. Cardiopulmonary exercise testing (CPET) reveals perturbations related to systemic blood flow and ventilatory control associated with acute exercise intolerance in PASC, which are not typical of simple detraining. Hemodynamic and gas exchange derangements in PASC have substantial overlap with those observed with ME/CFS, suggestive of shared mechanisms.</p><h3>Summary</h3><p>This review aims to illustrate exercise pathophysiologic commonalities between PASC and ME/CFS that will help guide future diagnostics and treatment.</p>

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Sousa Rêgo, Luma Ornelas; Alves Braga, Lara Landulfo; Vilas-Boas, Gustavo Sampaio; Oliveira Cardoso, Maiana Santos; Duraes, Andre Rodrigues

Cardiovascular and Neurological Complications of COVID-19: A Narrative Review

https://doi.org/10.3390/jcm12082819

Published

1-Jan-23

Review

https://www.mdpi.com/2077-0383/12/8/2819

A novel coronavirus emerged in China in late 2019 as a disease named coronavirus disease 2019. This pathogen was initially identified as causing a respiratory syndrome, but later, it was found that COVID-19 could also affect other body systems, such as the neurological and cardiovascular systems. For didactic purposes, cardiovascular and neurological manifestations of SARS-CoV-2 have been classified in three different groups: acute complications, late complications, and post-vaccine complications. Therefore, the following study has the goal to summarize and disseminate the present knowledge about the cardiovascular and neurological manifestations of COVID-19 based on the latest and most up-to-date data available and, thus, promote more prepared medical care for these conditions as the medical team is updated. Based on what is brought on this revision and its understanding, the medical service becomes more aware of the causal relationship between some conditions and COVID-19 and can better prepare for the most prevalent conditions to associate and, consequently, to treat patients earlier. Therefore, there is a chance of better prognoses in this context and the need to increase the number of studies about complications related to SARS-CoV-2 infection for a better understanding of other associated conditions.

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Gomes-Neto, Mansueto; Conceição, Lino Sérgio Rocha; Gois, Caroline Oliveira; Carvalho, Vitor Oliveira

Comment on: “Low Cardiorespiratory Fitness Post‐COVID‐19: A Narrative Review”

https://doi.org/10.1007/s40279-023-01845-w

Published

24-Apr-23

Letter to editor

https://doi.org/10.1007/s40279-023-01845-w

While Schwendinger et al. [1] provided an excellent narrative review, no meta-analysis was performed. It is important to pool the data to guide researchers and clinicians about the magnitude of V˙
O2peak difference in post-COVID-19 patients in comparison with healthy controls. In this context, using the studies included by Schwendinger et al. [1], we summarize the quantitative data from studies that compared V˙
O2peak between post-COVID-19 patients and healthy controls. When pooling all studies together that compared post-COVID-19 patients with healthy controls, we observed a significantly higher V˙
O2peak in the healthy control group compared with post-COVID-19 patients (mean difference [MD] 6.3 mLO2·kg−1·min−1, 95% confidence interval [CI] 2.8–9.8, I2 = 86%, 9 studies, N = 566, p = 0.0004) (Fig. 1a). In addition, in a subgroup analysis, considering the disease severity (severe vs non-severe post-COVID-19 patients), non-severe post-COVID-19 patients showed higher V˙
O2peak values than severe post-COVID-19 patients (MD 3.7 mLO2·kg−1·min−1, 95% CI 1.9–5.5, I2 = 34%, 5 studies, N = 226, p = 0.000) (Fig. 1b).
Given the results presented by Schwendinger et al. [1] and reinforced by this meta-analysis, the severity of COVID-19 can also be considered a factor associated with impaired cardiorespiratory fitness. Therefore, it is reasonable for health professionals to assess cardiorespiratory fitness in post-COVID-19 patients [3]. Hence, the diagnosis and therapeutic strategies can be adopted, given the association between low cardiorespiratory fitness and lower survival [4]. Thus, it is possible that cardiopulmonary rehabilitation programs, that have exercise as the core component, can contribute to the recovery of these patients and should be part of the care of post-COVID-19 patients.

In conclusion, we congratulate Schwendinger et al. [1] for their work on this important topic. Additionally, the meta-analysis of the included studies showed a difference of 6.3 mL O2·kg−1·min−1 in V˙
O2peak between healthy controls and post-COVID-19 patients. Finally, it is important to reinforce the need for further studies to investigate whether early cardiopulmonary rehabilitation can improve cardiorespiratory fitness more efficiently in these populations.

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MO50

Schwendinger, Fabian; Knaier, Raphael; Radtke, Thomas; Schmidt-Trucksäss, Arno

Response to Comment on: “Low Cardiorespiratory Fitness Post‐COVID‐19: A Narrative Review”

https://doi.org/10.1007/s40279-023-01848-7

Published

24-Apr-23

Letter to editor

https://doi.org/10.1007/s40279-023-01848-7

The analyses by Gomes Neto et al. [1] quantifying the level of CRF of patients post-COVID-19 in relation to healthy counterparts are a valuable addition to the findings of our review, although between-study heterogeneity was large (see test for heterogeneity in Figs. 1 and 2). Among other factors, differences in COVID-19 severity, prevalence and type of persisting symptoms, and follow-up period may contribute to the observed heterogeneity. Moreover, results of our sub-group analysis suggest that acute COVID-19 sequelae and symptoms of post-COVID-19 may indeed be the main driver of low CRF post-COVID-19. The presence of especially asymptomatic comorbidities may contribute only minor to lower CRF compared with healthy controls.

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MO51

Iqbal, Phool; Ata, Fateen; Chaudhry, Hassan; Muthanna, Bassam; Waqas Younas, Hafiz; Munamm, Syed Ata ul; Sharma, Rohit; Fadah, Kahtan; Elazzazy, Shereen; Hamad, Anas; Said Abu Tabar, Osama; Omar, Nabil E.

Post-COVID-19-associated multiorgan complications or “long COVID” with literature review and management strategy discussion: A meta-analysis

https://doi.org/10.1002/hsr2.1211

Published

Systematic review and meta-analysis

https://onlinelibrary.wiley.com/doi/abs/10.1002/hsr2.1211

Objective To investigate the post-COVID-19 long-term complications or long COVID of various organ systems in patients after 3 months of the infection, specifically before the Omicron variant, with comparative literature analysis. Methods A systemic literature search and meta-analysis were conducted using multiple electronic databases (PubMed, Scopus, Cochrane library) with predefined search terms to identify eligible articles. Eligible studies reported long-term complications of COVID-19 infection before the Omicron variant infection. Case reports, case series, observational studies with cross-sectional or prospective research design, case–control studies, and experimental studies that reported post-COVID-19 complications were included. The complications reported after 3 months after the recovery from COVID-19 infection were included in the study. Results The total number of studies available for analysis was 34. The effect size (ES) for neurological complications was 29% with 95% confidence interval (CI): 19%–39%. ES for psychiatric complications was 24% with 95% CI: 7%–41%. ES was 9% for cardiac outcomes, with a 95% CI of 1%–18%. ES was 22%, 95% CI: 5%–39% for the gastrointestinal outcome. ES for musculoskeletal symptoms was 18% with 95% CI: 9%–28%. ES for pulmonary complications was 28% with 95% CI: 18%–37%. ES for dermatological complications was 25%, with a 95% CI of 23%–26%. ES for endocrine outcomes was 8%, with a 95% CI of 8%–9%. ES size for renal outcomes was 3% with a 95% CI of 1%–7%. At the same time, other miscellaneous uncategorized outcomes had ES of 39% with 95% CI of 21%–57%. Apart from analyzing COVID-19 systemic complications outcomes, the ES for hospitalization and intensive care unit admissions were found to be 4%, 95% CI: 0%–7%, and 11% with 95% CI: 8%–14%. Conclusion By acquiring the data and statistically analyzing the post-COVID-19 complications during the prevalence of most virulent strains, this study has generated a different way of understanding COVID-19 and its complications for better community health.

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MO52

Kuznik, B. I.; Shapovalov, K. G.; Chalisova, N. I.

Changes in the State of Vital Systems with Long COVID-19

https://doi.org/10.1134/S2079086423020044

Published

1-Apr-23

Article

https://doi.org/10.1134/S2079086423020044

Long COVID-19 is a chronic disease that continues to be studied. Data on epidemiology and the main symptoms typical for long COVID-19 are presented. Issues related to the pathogenesis of the disease are discussed. At the same time, special attention is paid to the inflammation process (including of the vascular wall endothelium), the state of the immune system (cytokine storm), the hemostasis system (the mechanism for the development of microangiopathy and thrombosis), and oxidative stress. During the analysis, a special place is given to central nervous system disorders (including organic brain damage) and disorders of cognitive functions. In addition, currently known complications from the cardiovascular system and respiratory organs are described. The treatment and rehabilitation of patients with long COVID-19 is not only a medical, but also a significant social problem.

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MO53

Durstenfeld, Matthew S; Peluso, Michael J; Kaveti, Punita; Hill, Christopher; Li, Danny; Sander, Erica; Swaminathan, Shreya; Arechiga, Victor M; Lu, Scott; Goldberg, Sarah A; Hoh, Rebecca; Chenna, Ahmed; Yee, Brandon C; Winslow, John W; Petropoulos, Christos J; Kelly, J Daniel; Glidden, David V; Henrich, Timothy J; Martin, Jeffrey N; Lee, Yoo Jin; Aras, Mandar A; Long, Carlin S; Grandis, Donald J; Deeks, Steven G; Hsue, Priscilla Y

Reduced exercise capacity, chronotropic incompetence, and early systemic inflammation in cardiopulmonary phenotype Long COVID

https://doi.org/10.1093/infdis/jiad131

Published

11-May-23

Study

https://doi.org/10.1093/infdis/jiad131

Mechanisms underlying persistent cardiopulmonary symptoms following SARS-CoV-2 infection (post-acute sequelae of COVID-19 “PASC” or “Long COVID”) remain unclear. This study sought to elucidate mechanisms of cardiopulmonary symptoms and reduced exercise capacity.We conducted cardiopulmonary exercise testing (CPET), cardiac magnetic resonance imaging (CMR) and ambulatory rhythm monitoring among adults > 1 year after confirmed SARS-CoV-2 infection in a post-COVID cohort, compared those with or without symptoms, and correlated findings with previously measured biomarkers.Sixty participants (median age 53, 42% female, 87% non-hospitalized) were studied at median 17.6 months following SARS-CoV-2 infection. On CPET, 18/37 (49%) with symptoms had reduced exercise capacity (<85% predicted) compared to 3/19 (16%) without symptoms (p = 0.02). Adjusted peak VO2 was 5.2 ml/kg/min lower (95%CI 2.1-8.3; p = 0.001) or 16.9% lower percent predicted (95%CI 4.3-29.6; p = 0.02) among those with symptoms. Chronotropic incompetence was common. Inflammatory markers and antibody levels early in PASC were negatively correlated with peak VO2 more than 1 year later. Late-gadolinium enhancement on CMR and arrhythmias were absent.Cardiopulmonary symptoms >1 year following COVID-19 were associated with reduced exercise capacity, which was associated with elevated inflammatory markers early in PASC. Chronotropic incompetence may explain exercise intolerance among some with cardiopulmonary Long COVID.

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MO54

Contreras, Alejandra Meza; Newman, Darrell B.; Cappelloni, Lucio; Niven, Alexander S.; Mueller, Michael R.; Ganesh, Ravindra; Squires, Ray W.; Bonikowske, Amanda R.; Allison, Thomas G.

Cardiopulmonary testing in long COVID-19 versus non–COVID-19 patients with undifferentiated Dyspnea on exertion

https://doi.org/10.1016/j.pcad.2023.05.005

Published

19-May-23

Study

https://www.sciencedirect.com/science/article/pii/S0033062023000531

Background
Dyspnea and fatigue are characteristics of long SARS-CoV-2 (COVID)-19. Cardiopulmonary exercise testing (CPET) can be used to better evaluate such patients.
Research question
How significantly and by what mechanisms is exercise capacity impaired in patients with long COVID who are coming to a specialized clinic for evaluation?
Study design and methods
We performed a cohort study using the Mayo Clinic exercise testing database. Subjects included consecutive long COVID patients without prior history of heart or lung disease sent from the Post-COVID Care Clinic for CPET. They were compared to a historical group of non–COVID patients with undifferentiated dyspnea also without known cardiac or pulmonary disease. Statistical comparisons were performed by t-test or Pearson's chi2 test controlling for age, sex, and beta blocker use where appropriate.
Results
We found 77 patients with long COVID and 766 control patients. Long COVID patients were younger (47 ± 15 vs 50 ± 10 years, P < .01) and more likely female (70% vs 58%, P < .01). The most prominent difference on CPETs was lower percent predicted peak V̇O2 (73 ± 18 vs 85 ± 23%, p < .0001). Autonomic abnormalities (resting tachycardia, CNS changes, low systolic blood pressure) were seen during CPET more commonly in long COVID patients (34 vs 23%, P < .04), while mild pulmonary abnormalities (mild desaturation, limited breathing reserve, elevated V̇E/V̇CO2) during CPET were similar (19% in both groups) with only 1 long COVID patient showing severe impairment.
Interpretation
We identified severe exercise limitation among long COVID patients. Young women may be at higher risk for these complications. Though mild pulmonary and autonomic impairment were common in long COVID patients, marked limitations were uncommon. We hope our observations help to untangle the physiologic abnormalities responsible for the symptomatology of long COVID.

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	A	B	H	J	K	L	M	N	P
1	Scientific publications on long covid / PASC (post-acute sequelae SARS-CoV-2 infection)
2	Si vous appréciez le travail entièrement bénévole qui est fait ici, vous pouvez contribuer au financement de notre association :
3	If you appreciate the entirely voluntary work that is done here, you can contribute to the funding of our association:		Give 5 bucks to	#ApresJ20 - Association Covid Long France				Les éditions chronologiques de la bibliographie :
4		Make a donation (click on "JE FAIS UN DON")	https://www.apresj20.fr/	Number of publications listed			#1	Newsletter Publications scientifiques 2021-02 Février
5				Def LongCovid	486	(Click to go to the	#2	Newsletter Publications scientifiques 2021-03-04 Mars
6	The aim of this bibliography is to present in a neutral* way the essential of the publications			Multi-symptoms	318	sheet)	#3	Newsletter Publications scientifiques 2021-03-16 Mars
7	related to long covid, persistent post-covid symptoms and lasting sequelae of SARS-CoV-2 infections.			Care	375		#4	Newsletter Publications scientifiques 2021-03-25 Mars
8	We are careful not to cherry pick studies.			Immunity/Genetics	384		#5	Newsletter Publications scientifiques 2021-04-15 Avril
9	(*) neutral in the sense of https://en.wikipedia.org/wiki/Wikipedia:Neutral_point_of_view			Cardio-Vascular	348		#6	Newsletter Publications scientifiques 2021-04-27 Avril
10	The selection criteria are:			Respiratory	162		#7	Newsletter Publications scientifiques 2021-05-20 Mai
11	- To appear in the main registries such as Google Scholar		Transversal topics:	Neuro	626		#8	Newsletter Publications scientifiques 2021-05-31 Mai
12	- Not to be published in very confidential journals (or oriented towards therapies considered		Epstein-Barr	Psych	123		#9	Newsletter Publications scientifiques 2021-07 Juillet
13	by scientific consensus as unproven, and not meeting scientific method criteria).		ME/CFS	Renal	32		#10	Newsletter Publications scientifiques 2021-11 Novembre
14			Viral persistence	Children	242
15			PET-SCAN	Other organs	307
16			MRI Xenon	Multi-organ	53
17			Pacing				Zotero link:	https://www.zotero.org/apresj20/library
18			Post-exertional-SE	Total	3456
19							Do you want to provide free access to summaries
20				If you want this bibliography to be improved,			of these studies in your language,
21			Top Publications	feel free to send us your comments and additions!			comments or a translation of the abstract?
22				Contact :	science.apresj20@gmail.com		Go to this document,
23	This document is no longer updated. Find our complete and regularly updated bibliography on: https://www.zotero.org/apresj20/library						where you can share your translations
24							-> Translations
25
26							Other Long Covid bibliographies:
27							https://www.zotero.org/groups/4411227/research_aid_networks_long_covid_library/collections/RE76WMJ4/items/top
28							https://www.ncbi.nlm.nih.gov/research/coronavirus/docsum?filters=e_condition.LongCovid
29							https://www.anrs.fr/fr/ressources/revue-de-litterature-covid-19
30							https://docs.google.com/spreadsheets/d/17sC2yyw6mi1LXZVgAu67XXSzD_b5mLPu/edit?usp=sharing&ouid=117284575146940338416&rtpof=true&sd=true
31
32
33					HOW TO ADD YOURSELF AN ARTICLE OR STUDY?
34					Add here the studies that you found and that are missing from our document:			https://docs.google.com/spreadsheets/d/1BskzHmNYt9P0EyaYUO4bqbaqDuhwpO6Qf64V73FCrCk/edit?usp=sharing
35					I will switch them to the main document
36
37
38					Tips:		Solution		Details
39				#1	Find a selection of articles devoted to long covid in journals with a significant impact factor		Use Google Scholar Alerts		The ones I use (Show up to 20 results): long covid , long term effects covid , covid, PASC, post-covid, intitle:"sars-cov-2"
40				#2	Find the full text of a study		1- Open a browser with an activated VPN, configured outside Europe and America, go to https://sci-hub.se and enter the DOI of the study
41							2- Create an account on the journal's website, this can give access to the full PDF of the study
42							3- Send a polite email to the authors...
43				#3	Create a button for "Altmetric" checks		On a Windows browser, create a bookmark containing the following address:		javascript:((function(){var a;a=function(){var a,b,c,d,e;b=document,e=b.createElement("script"),a=b.body,d=b.location;try{if(!a)throw 0;c="d1bxh8uas1mnw7.cloudfront.net";if(typeof runInject!="function")return e.setAttribute("src",""+d.protocol+"//"+c+"/assets/content.js?cb="+Date.now()),e.setAttribute("type","text/javascript"),e.setAttribute("onload","runInject()"),a.appendChild(e)}catch(f){return console.log(f),alert("Please wait until the page has loaded.")}},a(),void 0})).call(this);
44				#4	Rule out insignificant studies		Rule out case reports, studies with no impact on Altmetric, alternative medicine or not "Evidence based medicine".
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51					Immuno :
52					https://doi.org/10.3389/fmolb.2022.1044964
53					https://doi.org/10.1101/2022.06.21.22276660
54					https://doi.org/10.3389/fimmu.2022.1034159
55					https://doi.org/10.1172/JCI163669
56
57					MultiSymp:
58					https://doi.org/10.1016/j.jval.2022.11.011
59
60					Neuro:
61					https://doi.org/10.1002/hbm.26163
62
63					Respi:
64					https://doi.org/10.1101/2022.11.28.22282811
65
66					Other organs:
67					https://doi.org/10.1016/j.jvoice.2022.11.012
68
69					Care:
70					https://doi.org/10.1101/2022.11.03.22281783
71
72					https://www.nature.com/articles/s41467-022-34616-8
73					https://www.nature.com/articles/s41598-022-24729-x
74					https://www.nature.com/articles/s41591-022-02116-3
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80	Source:	https://www.bloomberg.com/graphics/2020-opinion-covid-long-haulers-chronic-illness/
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